{"paper_id": "77499681", "_pdf_hash": "11f281316fe4638843a83cf559ce4f60aade00f8", "abstract": [{"section": "Abstract", "text": "The purpose of this study is to evaluate the effects of teriparatide administration on fracture healing after intramedullary nailing in atypical femoral fractures. Materials and Methods: We retrospectively reviewed 26 patients (26 cases) with atypical femoral fracture who were treated using intramedullary nailing between January 2009 and December 2013. Teriparatide was not administered to 15 patients (non-injection group) and was administered to 11 patients after surgery (injection group). Clinical results were assessed using the Nakajima score and the visual analogue scale (VAS). Radiographic results were compared for the time of callus formation, callus bridge formation, and bone union between the groups. Results: Time to recover walking ability and to decrease pain in the surgery region (VAS\u22642) were significantly shorter in the injection group than in the non-injection group. The time of callus formation, callus bridge formation, and bone union was significantly shorter in the injection group than in the non-injection group. There were 5 cases of delayed bone union (33.3%) and 1 case of none union (6.7%) in the non-injection group and all cases obtained bone union in injection group. Conclusion: The injection group showed better clinical and radiographic results than the non-injection group after intramedullary nailing in atypical femoral fracture. Therefore, we think that teriparatide administration after intramedullary nailing could be a useful treatment option to promote bone union.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "", "text": "Values are presented as number only or median (range). ", "cite_spans": [], "ref_spans": []}, {"section": "CONFLICTS OF INTEREST", "text": "The authors have nothing to disclose. ", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Bone health and osteoporosis: a report of the surgeon general", "authors": [], "year": 2004, "venue": "", "link": null}, "BIBREF1": {"title": "Medical treatment of atypical femoral fracture", "authors": [{"first": "Y", "middle": ["C"], "last": "Ha", "suffix": ""}, {"first": "Y", "middle": ["K"], "last": "Lee", "suffix": ""}, {"first": "B", "middle": ["W"], "last": "Min", "suffix": ""}], "year": 2013, "venue": "J Korean Orthop Assoc", "link": "71492442"}, "BIBREF2": {"title": "Severely suppressed bone turnover: a potential complication of alendronate therapy", "authors": [{"first": "C", "middle": ["V"], "last": "Odvina", "suffix": ""}, {"first": "J", "middle": ["E"], "last": "Zerwekh", "suffix": ""}, {"first": "D", "middle": ["S"], "last": "Rao", "suffix": ""}, {"first": "N", "middle": [], "last": "Maalouf", "suffix": ""}, {"first": "F", "middle": ["A"], "last": "Gottschalk", "suffix": ""}, {"first": "C", "middle": ["Y"], "last": "Pak", "suffix": ""}], "year": 2005, "venue": "J Clin Endocrinol Metab", "link": "8323353"}, "BIBREF3": {"title": "The incidence of and risk factors for developing atypical femoral fractures in Japan", "authors": [{"first": "Y", "middle": [], "last": "Saita", "suffix": ""}, {"first": "M", "middle": [], "last": "Ishijima", "suffix": ""}, {"first": "A", "middle": [], "last": "Mogami", "suffix": ""}], "year": 2015, "venue": "J Bone Miner Metab", "link": "3224020"}, "BIBREF4": {"title": "Bisphosphonate use and increased incidence of subtrochanteric fracture in South Korea: results from the National Claim Registry", "authors": [{"first": "Y", "middle": ["K"], "last": "Lee", "suffix": ""}, {"first": "Y", "middle": ["C"], "last": "Ha", "suffix": ""}, {"first": "C", "middle": [], "last": "Park", "suffix": ""}, {"first": "J", "middle": ["J"], "last": "Yoo", "suffix": ""}, {"first": "C", "middle": ["S"], "last": "Shin", "suffix": ""}, {"first": "K", "middle": ["H"], "last": "Koo", "suffix": ""}], "year": 2013, "venue": "Osteoporos Int", "link": "10895360"}, "BIBREF5": {"title": "Atypical subtrochanteric and diaphyseal femoral fractures: second report of a task force of the American Society for Bone and Mineral Research", "authors": [{"first": "E", "middle": [], "last": "Shane", "suffix": ""}, {"first": "D", "middle": [], "last": "Burr", "suffix": ""}, {"first": "B", "middle": [], "last": "Abrahamsen", "suffix": ""}], "year": 2014, "venue": "J Bone Miner Res", "link": "42522265"}, "BIBREF6": {"title": "Postoperative outcomes of atypical femoral subtrochanteric fracture in patients on bisphosphonate therapy", "authors": [{"first": "B", "middle": ["J"], "last": "Teo", "suffix": ""}, {"first": "J", "middle": ["S"], "last": "Koh", "suffix": ""}, {"first": "S", "middle": ["K"], "last": "Goh", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Png", "suffix": ""}, {"first": "D", "middle": ["T"], "last": "Chua", "suffix": ""}, {"first": "T", "middle": ["S"], "last": "Howe", "suffix": ""}], "year": 2014, "venue": "Bone Joint J", "link": "8712380"}, "BIBREF7": {"title": "An experimental study about the effects of parathyroid hormone on osteoblasts", "authors": [{"first": "S", "middle": ["W"], "last": "Suh", "suffix": ""}, {"first": "S", "middle": ["H"], "last": "Lee", "suffix": ""}, {"first": "J", "middle": ["S"], "last": "Chang", "suffix": ""}, {"first": "M", "middle": ["K"], "last": "Kim", "suffix": ""}], "year": 1996, "venue": "J Korean Orthop Assoc", "link": "81818630"}, "BIBREF8": {"title": "Increases in callus formation and mechanical strength of healing fractures in old rats treated with parathyroid hormone", "authors": [{"first": "T", "middle": ["T"], "last": "Andreassen", "suffix": ""}, {"first": "C", "middle": [], "last": "Fledelius", "suffix": ""}, {"first": "C", "middle": [], "last": "Ejersted", "suffix": ""}, {"first": "H", "middle": [], "last": "Oxlund", "suffix": ""}], "year": 2001, "venue": "Acta Orthop Scand", "link": "23700352"}, "BIBREF9": {"title": "Chronic response of dogs to parathyroid hormone infusion", "authors": [{"first": "J", "middle": ["A"], "last": "Parsons", "suffix": ""}, {"first": "B", "middle": [], "last": "Reit", "suffix": ""}], "year": 1974, "venue": "Nature", "link": null}, "BIBREF10": {"title": "Preventive effects of conservative treatment with short-term teriparatide on the progression of vertebral body collapse after osteoporotic vertebral compression fracture", "authors": [{"first": "J", "middle": ["H"], "last": "Park", "suffix": ""}, {"first": "K", "middle": ["C"], "last": "Kang", "suffix": ""}, {"first": "D", "middle": ["E"], "last": "Shin", "suffix": ""}, {"first": "Y", "middle": ["G"], "last": "Koh", "suffix": ""}, {"first": "J", "middle": ["S"], "last": "Son", "suffix": ""}, {"first": "B", "middle": ["H"], "last": "Kim", "suffix": ""}], "year": 2014, "venue": "Osteoporos Int", "link": "26069977"}, "BIBREF11": {"title": "Clinical result of surgical treatment for trochanteric fractures in elderly patients", "authors": [{"first": "R", "middle": [], "last": "Nakajima", "suffix": ""}, {"first": "R", "middle": [], "last": "Ito", "suffix": ""}, {"first": "K", "middle": [], "last": "Kawamura", "suffix": ""}], "year": 2008, "venue": "Cent Jap J Orthop Surg Traumatol", "link": null}, "BIBREF13": {"title": "Clamp-assisted reduction of high subtrochanteric fractures of the femur", "authors": [{"first": "G", "middle": ["J"], "last": "", "suffix": ""}], "year": 2009, "venue": "J Bone Joint Surg Am", "link": "683632"}, "BIBREF14": {"title": "Atypical femoral fractures after anti-osteoporotic medication: a Korean multicenter study", "authors": [{"first": "J", "middle": ["S"], "last": "Kang", "suffix": ""}, {"first": "Y", "middle": ["Y"], "last": "Won", "suffix": ""}, {"first": "J", "middle": ["O"], "last": "Kim", "suffix": ""}], "year": 2014, "venue": "Int Orthop", "link": "21162707"}, "BIBREF15": {"title": "Biochemical and molecular mechanisms of action of bisphosphonates", "authors": [{"first": "M", "middle": ["J"], "last": "Rogers", "suffix": ""}, {"first": "J", "middle": ["C"], "last": "Crockett", "suffix": ""}, {"first": "F", "middle": ["P"], "last": "Coxon", "suffix": ""}, {"first": "J", "middle": [], "last": "M\u00f6nkk\u00f6nen", "suffix": ""}], "year": 2011, "venue": "Bone", "link": "2367789"}, "BIBREF16": {"title": "Is surgery necessary for femoral insufficiency fractures after long-term bisphosphonate therapy?", "authors": [{"first": "Y", "middle": ["C"], "last": "Ha", "suffix": ""}, {"first": "M", "middle": ["R"], "last": "Cho", "suffix": ""}, {"first": "K", "middle": ["H"], "last": "Park", "suffix": ""}, {"first": "S", "middle": ["Y"], "last": "Kim", "suffix": ""}, {"first": "K", "middle": ["H"], "last": "Koo", "suffix": ""}], "year": 2010, "venue": "Clin Orthop Relat Res", "link": "35990647"}, "BIBREF17": {"title": "Bisphosphonate-associated femur fractures have high complication rates with operative fixation", "authors": [{"first": "M", "middle": ["L"], "last": "Prasarn", "suffix": ""}, {"first": "J", "middle": [], "last": "Ahn", "suffix": ""}, {"first": "D", "middle": ["L"], "last": "Helfet", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Lane", "suffix": ""}, {"first": "D", "middle": ["G"], "last": "Lorich", "suffix": ""}], "year": 2012, "venue": "Clin Orthop Relat Res", "link": "7087815"}, "BIBREF18": {"title": "Bisphosphonates and nonhealing femoral fractures: analysis of the FDA Adverse Event Reporting System (FAERS) and international safety efforts: a systematic review from the Research on Adverse Drug Events And Reports (RADAR) project", "authors": [{"first": "B", "middle": ["J"], "last": "Edwards", "suffix": ""}, {"first": "A", "middle": ["D"], "last": "Bunta", "suffix": ""}, {"first": "J", "middle": [], "last": "Lane", "suffix": ""}], "year": 2013, "venue": "J Bone Joint Surg Am", "link": null}, "BIBREF19": {"title": "A systematic review on the use of daily subcutaneous administration of teriparatide for treatment of patients with osteoporosis at high risk for fracture in Asia", "authors": [{"first": "J", "middle": ["F"], "last": "Chen", "suffix": ""}, {"first": "K", "middle": ["H"], "last": "Yang", "suffix": ""}, {"first": "Z", "middle": ["L"], "last": "Zhang", "suffix": ""}], "year": 2015, "venue": "Osteoporos Int", "link": "25313158"}, "BIBREF20": {"title": "The US postmarketing surveillance study of adult osteosarcoma and teriparatide: study design and findings from the first 7 years", "authors": [{"first": "E", "middle": ["B"], "last": "Andrews", "suffix": ""}, {"first": "A", "middle": ["W"], "last": "Gilsenan", "suffix": ""}, {"first": "K", "middle": [], "last": "Midkiff", "suffix": ""}], "year": 2012, "venue": "J Bone Miner Res", "link": "15817745"}}, "ref_entries": {"FIGREF0": {"text": "\ube44\uc2a4\ud3ec\uc2a4\ud3ec\ub124\uc774\ud2b8\ub97c \uc7a5\uae30\uac04 \ubcf5\uc6a9\ud55c \uace8\ub2e4\uacf5\uc99d \ud658\uc790\uc5d0\uc11c \uc800 \uc5d0\ub108\uc9c0 \uc190\uc0c1\uc5d0 \uc758\ud574 \ubc1c\uc0dd\ud558\ub294 \ube44\uc815\ud615\uc801 \ub300\ud1f4\uace8 \uace8\uc808 \uc774 \ubcf4\uace0\ub418\uace0 \uc788\ub2e4. 4) \uc774\ub7ec\ud55c \uace8\uc808\uc758 \uc6d0\uc778\uc774 \ube44\uc2a4\ud3ec\uc2a4\ud3ec\ub124\uc774\ud2b8\uc5d0 \uc758\ud55c \uacfc\ub3c4\ud55c \uace8\uad50\uccb4\uc728 \uc5b5\uc81c\ub77c\ub294 \uc8fc\uc7a5\uc774 \uc5ec\ub7ec \uc800\uc790\ub4e4\uc5d0 \uc758\ud574 \uc81c\uae30 \ub418\uace0 \uc788\uc9c0\ub9cc, \ube44\uc815\ud615\uc801 \ub300\ud1f4\uace8 \uace8\uc808\uc758 \uc720\ubcd1\ub960\uc774 \ub192\uc9c0 \uc54a\uc544 \uc544\uc9c1 \uae4c\uc9c0 \uc774\uc5d0 \ub300\ud55c \uba85\ud655\ud55c \uc99d\uac70\ub97c \uc81c\uc2dc\ud55c \uc5f0\uad6c\ub294 \uc5c6\ub2e4. 5) \ub610\ud55c \ube44\uc815\ud615 \uc801 \ub300\ud1f4\uace8 \uace8\uc808\uc5d0 \ub300\ud55c \uba85\ud655\ud55c \uae30\uc900\uc774 \uc5c6\uc5c8\uae30 \ub54c\ubb38\uc5d0 \uae30\uc874\uc758 \ubcf4 \uace0\ub41c \uc5f0\uad6c\uc5d0\uc11c\ub294 \uc800\uc790\ub4e4\ub9c8\ub2e4 \uc11c\ub85c \ub2e4\ub978 \uae30\uc900\uc744 \uc0ac\uc6a9\ud558\uc5ec \uc77c\uad00\uc131 \uc744 \uc5bb\uae30 \uc5b4\ub835\ub2e4\ub294 \ubb38\uc81c\uac00 \uc788\ub2e4. 6) \uadf8\ub9ac\uace0 \ube44\uc815\ud615\uc801 \ub300\ud1f4\uace8 \uace8\uc808\uc5d0 \ub300\ud55c \uc218\uc220\uc801 \uce58\ub8cc \ubc29\ubc95\uc5d0\uc11c \uae08\uc18d\ud310\uacfc \uace8\uc218\uac15 \ub0b4 \uc815\uc744 \ud63c\uc7ac\ud558\uc5ec \uc0ac\uc6a9\ud568\uc73c\ub85c \uc778\ud55c \uce58\ub8cc \uacb0\uacfc\uc5d0 \ubcc0\uc218\uac00 \ubc1c\uc0dd\ud560 \uc704\ud5d8\uc774 \uc788\ub2e4. 7) \ubd80\uac11\uc0c1\uc120\ud638\ub974\ubaac\uc740 \uc2e0\uc7a5\uc5d0\uc11c \uce7c\uc298\uc758 \uc7ac\ud761\uc218\ub97c \ucd09\uc9c4\ud558\uace0 \ubf08\uc5d0 \uce7c \uc298\uc744 \uc800\uc7a5\ud558\uc5ec \uc6b0\ub9ac \ubab8\uc758 \uce7c\uc298 \ud56d\uc0c1\uc131\uc744 \uc720\uc9c0\ud558\ub294 \uc5ed\ud560\uc744 \ud558\ub294 \ud638 \ub974\ubaac\uc774\ub2e4. \uc800\uc6a9\ub7c9\uc744 \uac04\ud5d0\uc801\uc73c\ub85c \ud22c\uc5ec\ud558\ub294 \uacbd\uc6b0 \uace8\uc544\uc138\ud3ec \uc804\uad6c\uccb4 \ub97c \uc790\uadf9\ud558\uace0 \uc138\ud3ec\uc790\uba78\uc0ac\ub97c \uc5b5\uc81c\ud558\uc5ec \uace8\uc544\uc138\ud3ec\uc758 \uc0dd\uc131\uacfc \ubd84\ud654\ub97c \ucd09\uc9c4\ud558\ub294 \ud6a8\uacfc\uac00 \uc788\ub294 \uac83\uc73c\ub85c \uc54c\ub824\uc838 \uc788\ub2e4. 8) \uc5ec\ub7ec \ubd80\uac11\uc0c1\uc120\ud638\ub974\ubaac \uc911 \ud14c\ub9ac\ud30c\ub77c\ud0c0\uc774\ub4dc(teriparatide)\uc758 \uace8\ud615\uc131 \ucd09\uc9c4 \ud6a8\uacfc\ub294 \uc5ec\ub7ec \uc800\uc790 \ub4e4\uc5d0 \uc758\ud574 \ubcf4\uace0\ub41c \ubc14 \uc788\uc73c\uba70, 9,10) \ucd5c\uadfc \uace8\ub2e4\uacf5\uc99d \ubc0f \uace8\ub2e4\uacf5\uc99d\uc131 \uace8 \uc808\uc758 \uce58\ub8cc\uc5d0 \uc0ac\uc6a9\uc774 \uc99d\uac00\ud558\uace0 \uc788\ub2e4. \ud558\uc9c0\ub9cc \uc544\uc9c1\uae4c\uc9c0 \ube44\uc815\ud615\uc801 \ub300 \ud1f4\uace8 \uace8\uc808\uc758 \uce58\ub8cc\uc5d0\uc11c \ubd80\uac11\uc0c1\uc120\ud638\ub974\ubaac\uc758 \ud6a8\uacfc\uc5d0 \ub300\ud574 \uc54c\ub824\uc9c4 \ubc14 \uac00 \ub9ce\uc9c0 \uc54a\ub2e4. 11) \uc800\uc790\ub4e4\uc740 \ube44\uc815\ud615\uc801 \ub300\ud1f4\uace8 \uace8\uc808\ub85c \uc9c4\ub2e8\ub41c \ud658\uc790\uc5d0\uc11c \uc218\uc220 \ud6c4 \ubd80 \uac11\uc0c1\uc120\ud638\ub974\ubaac\uc744 \ud22c\uc5ec\ud55c \uacbd\uc6b0 \uc784\uc0c1\uc801 \ubc0f \ubc29\uc0ac\uc120\uc801 \uacb0\uacfc\uac00 \ub354 \uc88b \uc744 \uac83\uc774\ub77c\ub294 \uac00\uc124\uc744 \uc138\uc6e0\ub2e4. \uadf8\ub9ac\uace0 2013\ub144 \ubbf8\uad6d\uace8\ub300\uc0ac\ud559\ud68c\uc5d0\uc11c \uc81c\uc2dc\ud55c \ube44\uc815\ud615\uc801 \ub300\ud1f4\uace8 \uace8\uc808\uc758 \uae30\uc900\uc744 \ub9cc\uc871\ud558\ub294 \ud658\uc790\ub4e4\uc5d0\uc11c \uace8 \uc218\uac15 \ub0b4 \uc815\uc744 \uc774\uc6a9\ud55c \uc218\uc220 \ud6c4 teriparatide 20 \u03bcg (Forteo \u00ae ; Eli Lilly, Indianapolis, IN, USA)\uc758 \uac04\ud5d0\uc801 \ud22c\uc5ec\uac00 \ubbf8\uce58\ub294 \uc784\uc0c1\uc801 \ubc0f \ubc29\uc0ac\uc120 \uc801 \uc601\ud5a5\uc5d0 \ub300\ud574 \uc54c\uc544\ubcf4\uace0\uc790 \ud558\uc600\ub2e4.\ube44\uc815\ud615\uc801 \ub300\ud1f4\uace8 \uace8\uc808\ub85c \uc218\uc220\uc744 \ubc1b\uc740 30\uba85(32\uc608)\uc744 \ub300\uc0c1\uc73c\ub85c \ud6c4\ud5a5\uc801 \ud658\uc790-\ub300\uc870\uad70 \uc5f0\uad6c\ub97c \uacc4\ud68d\ud558\uc600\ub2e4. \uc774 \uc911 \uae08\uc18d\ud310 \uace0\uc815\uc220\uc744 \ubc1b\uc740 3\uc608\uc640 \uc784\ubc15 \ube44\uc815\ud615\uc801 \ub300\ud1f4\uace8 \uace8\uc808\ub85c \uc218\uc220 \ubc1b\uc740 3 \uc608\ub294 \ubcc0\uc218\ub97c \uc904\uc774\uae30 \uc704\ud574 \uc81c\uc678\ud558\uc600\ub2e4. \ucd5c\uc885\uc801\uc73c\ub85c 26\uba85(26\uc608)\uc744 \ub300\uc0c1\uc73c\ub85c \ud558\uc600\uace0, \uc804\uccb4 \ud658\uc790\ub4e4 \uc911 \uc218\uc220 \ud6c4 teriparatide 20 \u03bcg\uc744 \ud22c \uc5ec\ud558\uc9c0 \uc54a\uc740 15\uc608(\ube44\ud22c\uc5ec\uad70)\uc640 \ud22c\uc5ec\ud55c 11\uc608(\ud22c\uc5ec\uad70)\ub85c \ub098\ub204\uc5b4 \uc5f0 \uad6c\ub97c \uc9c4\ud589\ud558\uc600\ub2e4. \ube44\uc815\ud615\uc801 \ub300\ud1f4\uace8 \uace8\uc808\ub85c \uc9c4\ub2e8\ub41c \ud658\uc790 \uc911 \uace8\ubc00 \ub3c4 \uac80\uc0ac\uc0c1 \uace8\ub2e4\uacf5\uc99d \uc18c\uacac\uc774 \ubcf4\uc774\uace0, \ud608\uc561\uac80\uc0ac(\ud608\uccad \uc624\uc2a4\ud14c\uc624\uce7c\uc2e0 \uacfc \ubd80\uac11\uc0c1\uc120\ud638\ub974\ubaac)\uc640 \uc18c\ubcc0\uac80\uc0ac(\ub370\uc625\uc2dc\ud53c\ub9ac\ub514\ub180\ub9b0)\uc0c1 \uace8\uad50\uccb4\uc728 \uc800\ud558 \uc18c\uacac\uc744 \ubcf4\uc774\uba70, \uc545\uc131 \uace8\uc885\uc591\uc774\ub098 \uace8\uc804\uc774\ub97c \uc9c4\ub2e8\ubc1b\uac70\ub098 \uc2e0 \uc7a5 \uae30\ub2a5\uc5d0 \uc774\uc0c1\uc774 \uc5c6\ub294 \ub300\uc0c1\uc5d0 \ud55c\ud558\uc5ec teriparatide\uc758 \ud22c\uc5ec\ub97c \uad8c\uc720 \ud558\uc600\uace0, \uc774\uc5d0 \ub3d9\uc758\ud558\ub294 \ud658\uc790\uc5d0\uac8c \uc218\uc220 3\uc77c \ud6c4\ubd80\ud130 \ud22c\uc5ec\ud558\uc600\ub2e4. \uac01 \uad70\uc758 demographic data\ub294", "type": "figure"}, "FIGREF1": {"text": "\uc218\uc220 \ud6c4 \uace8\uc808\ubd80\uc758 \uc804\ud6c4\uba74 \ubc0f \uce21\uba74\uc758 \ub2e8\uc21c \ubc29\uc0ac\uc120 \uc0ac\uc9c4\uc744 \ucd2c\uc601\ud558 \uc5ec \ud3c9\uac00\ud558\uc600\ub2e4. \ud658\uc790\uc758 \uae30\ubcf8\uc815\ubcf4 \ubc0f \ubd80\uac11\uc0c1\uc120\ud638\ub974\ubaac\uc758 \ud22c\uc5ec \uc5ec\ubd80 \ub97c \ubaa8\ub974\ub294 \uc815\ud615\uc678\uacfc \uc804\ubb38\uc758 3\uba85\uc774 \ucd5c\ucd08 \uac00\uace8 \ud615\uc131 \uc2dc\uae30, \ucd5c\ucd08 \uac00 \uace8\uad50 \ud615\uc131 \uc2dc\uae30, \uadf8\ub9ac\uace0 \uace8\uc720\ud569 \uc2dc\uae30\ub97c \uacb0\uc815\ud558\uc600\ub2e4. \ubc29\uc0ac\uc120 \uc0ac\uc9c4 \ucd2c\uc601\uc740 \uc218\uc220 \ud6c4 12\uc8fc\uae4c\uc9c0\ub294 2\uc8fc \uac04\uaca9\uc73c\ub85c \uc774\ud6c4\ub294 4\uc8fc \uac04\uaca9\uc73c\ub85c \uc2dc\ud589\ud558\uc600\ub2e4. \uace8\uc720\ud569 \ud310\uc815\uc740 \uc784\uc0c1\uc801\uc73c\ub85c \uace8\uc808\ubd80 \uc555\ud1b5 \ubc0f \uac00\uc131 \uc6b4 \ub3d9\uc774 \uc5c6\uc73c\uba70 \uc644\uc804 \uccb4\uc911 \ubd80\ud558 \uc2dc \ub3d9\ud1b5\uc774 \uc5c6\uace0, \uc804\ud6c4\uba74 \ubc0f \uce21\uba74 \ubc29\uc0ac \uc120 \uc0ac\uc9c4\uc0c1 \uace8\uc808\uc120\uc744 \uc9c0\ub098\ub294 \uac00\uace8\uc758 \ud615\uc131\uc774 \ud53c\uc9c8\uace8 4\uba74 \uc911 3\uba74 \uc774 \uc0c1\uc5d0\uc11c \ubcf4\uc77c \ub54c\ub85c \ud310\uc815\ud558\uc600\ub2e4. 13) \uc9c0\uc5f0\uc720\ud569\uc740 \ucd94\uc2dc \uc8fc\uae30\ub97c \uace0\ub824\ud558 \uc5ec \uc218\uc220 \ud6c4 28\uc8fc(6.5\uac1c\uc6d4)\uc5d0\uc11c 1\ub144 \uc0ac\uc774\uc5d0 \uace8\uc720\ud569\uc744 \uc5bb\uc740 \uacbd\uc6b0\ub85c \uc815\uc758\ud558\uc600\uace0, 1\ub144 \uc774\uc0c1 \uace8\uc720\ud569\uc744 \uc5bb\uc9c0 \ubabb\ud588\uac70\ub098 \uac00\uc131 \uad00\uc808\uc744 \ubcf4\uc774 \ub294 \uacbd\uc6b0 \ubd88\uc720\ud569\uc73c\ub85c \ud310\ub2e8\ud558\uc600\ub2e4. 14) 3. \uc218\uc220 \ubc29\ubc95 \ubc0f \uc7ac\ud65c \uc218\uc220\uc740 \uc804\uc2e0 \ud639\uc740 \ucc99\ucd94 \ub9c8\ucde8\ud558\uc5d0 \ubc29\uc0ac\uc120\uc758 \ud22c\uacfc\uac00 \uac00\ub2a5\ud55c \uace8\uc808 \uc804\uc6a9 \ud14c\uc774\ube14\uc5d0\uc11c \uc559\uc640\uc704\ub85c \uc9c4\ud589\ud558\uc600\ub2e4. \uadfc\uc704 \uace8\uc808\ubd80\uc758 \uc784\uc2dc \uc815\ubcf5 \uc740 \uc131\uacf5\uc801\uc778 \uc218\uc220\uc744 \uc704\ud55c \uac00\uc7a5 \uc911\uc694\ud55c \ub2e8\uacc4\ub85c, \uace8\uacac\uc778\uc744 \ud1b5\ud55c \uac04 \uc811 \uc815\ubcf5\uc220\uc744 \uc8fc\ub85c \uc0ac\uc6a9\ud558\uc600\uc73c\uba70, \ud544\uc694\uc5d0 \ub530\ub77c \uc18c\uc804\uc790 \uc704\uce58\uc758 \ub300 \ud1f4\ubd80 \uc678\uce21\uc5d0 2 cm \uc815\ub3c4\uc758 \uc808\uac1c\ub97c \uc2dc\ud589\ud558\uace0 Hohmann retractor, bone hook, \ud074\ub7a8\ud504 \ub4f1\uc744 \ub300\ud1f4\uace8 \uc804\uba74\uc5d0 \ubd99\uc5ec \uc18c\uc804\uc790\uae4c\uc9c0 \uc804\uc9c4\uc2dc \ud0a8 \ud6c4 \uadfc\uc704 \uace8\ud3b8\uc744 \ub0b4\ud68c\uc804\uc2dc\ud0a4\ub294 \uc9c1\uc811 \uc815\ubcf5\uc220\ub85c \uace8\uc808\ubd80\ub97c \uc815\ubcf5\ud558 \uc600\ub2e4. \ub300\ud1f4\uac04\ubd80 \uace8\uc808\uc740 \ud45c\uc900 \uace8\uc218\uac15 \ub0b4 \uc815\uc744 \uc774\uc6a9\ud558\uc5ec \uace0\uc815\ud558\uc600 \uace0, \uc804\uc790\ud558 \uace8\uc808\uc740 \ub450\ubd80-\uace8\uc218\ud615 \uae08\uc18d\uc815\uc744 \uc774\uc6a9\ud558\uc5ec \uace0\uc815\ud558\uc600\ub2e4. \uc218\uc220 \ud6c4 \ud658\uc790\uac00 \ub3d9\uc758\ud55c \uacbd\uc6b0 teriparatide 20 \u03bcg\uc744 \ud558\ub8e8\uc5d0 1\ubc88 \ud53c\ud558 \ub85c 3\uac1c\uc6d4\uac04 \ud22c\uc5ec\ud558\uc600\ub2e4. \ud658\uc790\ub294 \uc218\uc220 \ud6c4 2\uc77c\ubd80\ud130 \ub300\ud1f4\uadfc \uac15\ud654\ub97c \uc704\ud55c \uadfc\ub825\uc6b4\ub3d9 \ubc0f \uc2ac\uad00 \uc808\uacfc \uace0\uad00\uc808\uc758 \uc9c0\uc18d\uc801 \uc218\ub3d9 \uc6b4\ub3d9\uc744 \uc2dc\uc791\ud558\uc600\ub2e4. \ubcf4\ud589\uae30\ub098 \ubaa9\ubc1c\uc744 \uc774\uc6a9\ud55c \ubd80\ubd84 \uccb4\uc911 \ubd80\ud558\ub294 \uc218\uc220 \ud6c4 2\uc8fc\ubd80\ud130 \ubb34\ub9ac\ud558\uc9c0 \uc54a\ub294 \ubc94\uc704\ub85c \uc2dc\uc791\ud558\uc600\uace0, \ub2e8\uc21c \ubc29\uc0ac\uc120 \uc0ac\uc9c4\uc5d0\uc11c \uac00\uace8 \ubc0f \uac00\uace8\uad50 \ud615\uc131\uc758 \uc9c4\ud589 \uc815\ub3c4\ub97c \uace0\ub824\ud558\uc5ec \uc11c\uc11c\ud788 \uc804\uccb4\uc911 \ubd80\ud558\ub97c \ud5c8\uc6a9\ud558\uc600\ub2e4. 4. \ud1b5\uacc4\ubd84\uc11d \ud1b5\uacc4\uc801 \ubd84\uc11d\uc740 IBM SPSS Statistics ver. 22 \ud504\ub85c\uadf8\ub7a8(IBM Co., Ar- monk, NY, USA)\uc744 \uc0ac\uc6a9\ud558\uc5ec, \ub300\uc0c1\uad70\uc758 \uc815\uaddc\uc131 \ubd84\ud3ec \uc5ec\ubd80\ub97c \uba3c \uc800 \ud655\uc778\ud558\uace0 \uc815\uaddc\uc131\uc744 \ub530\ub974\ub294 \uacbd\uc6b0\uc5d0\ub294 \ubaa8\uc218\uc801 \ubc29\ubc95\uc744, \uc815\uaddc\uc131\uc744 \ub530\ub974\uc9c0 \uc54a\ub294 \uacbd\uc6b0\uc5d0\ub294 \ube44\ubaa8\uc218\uc801 \ubc29\ubc95\uc744 \uc0ac\uc6a9\ud558\uc600\ub2e4. \ub450 \uad70 \uac04\uc758 demographic data\uc640 \uc784\uc0c1\uc801 \uacb0\uacfc \ubc0f \uace8\uc720\ud569 \ub2e8\uacc4\uc5d0 \ub530\ub978 \ubc29\uc0ac\uc120\uc801 \uacb0\uacfc\ub294 Mann-Whitney \uac80\uc815\uc744 \uc774\uc6a9\ud558\uc5ec \ube44\uad50\ud558\uc600\uace0, p-value\uac00 0.05 \uc774\ud558\uc778 \uacbd\uc6b0\ub97c \uc720\uc758\ud55c \uac83\uc73c\ub85c \ud3c9\uac00\ud558\uc600\ub2e4. \uacb0 \uacfc \uc591 \uad70\uc758 \uc218\uc220 \ud6c4 \uc784\uc0c1\uc801 \ubc0f \ubc29\uc0ac\uc120\uc801 \uacb0\uacfc\ub294 Table 2\uc640 \uac19\ub2e4. \uc218\uc220 \uc804 Nakajima \uc810\uc218\ub294 \ube44\ud22c\uc5ec\uad70\uc5d0\uc11c 3\uc810\uc774 11\uc608, 2\uc810\uc774 3\uc608, 1\uc810\uc774 1 \uc608\uc600\uace0, \ud22c\uc5ec\uad70\uc5d0\uc11c 3\uc810\uc774 8\uc608, 2\uc810\uc774 2\uc608, 1\uc810\uc774 1\uc608\uc600\ub2e4. \uc218\uc220 \uc804 \ubd80\ud130 \ubcf4\ud589\uc774 \uc804\ud600 \ubd88\uac00\ub2a5\ud55c \uc0c1\ud0dc\uc600\ub358 \ud658\uc790(2\uc608)\ub97c \uc81c\uc678\ud55c \ubaa8\ub4e0 \ud658 \uc790\ub294 \uc218\uc0c1 \uc804\uc758 \ubcf4\ud589 \uc815\ub3c4\ub85c \ud68c\ubcf5\ud558\uc600\uace0, \ud68c\ubcf5\uc5d0 \uac78\ub9b0 \uae30\uac04\uc740 \ube44 \ud22c\uc5ec\uad70\uc5d0\uc11c \ud3c9\uade0 20.2\uc8fc(12-28\uc8fc), \ud22c\uc5ec\uad70\uc5d0\uc11c \ud3c9\uade0 12.3\uc8fc(10-16 \uc8fc)\uac00 \uac78\ub838\uc73c\uba70, \ud1b5\uacc4\uc801\uc73c\ub85c \uc720\uc758\ud55c \ucc28\uc774\uac00 \uc788\uc5c8\ub2e4(p=0.021). \uc218 \uc220 \ud6c4 \uace8\uc808 \ubd80\uc704\uc758 \ud1b5\uc99d\uc774 VAS 2\uc810 \uc774\ud558\uac00 \ub418\ub294 \ub370 \uac78\ub9b0 \uae30\uac04\uc740 \ube44\ud22c\uc5ec\uad70\uc5d0\uc11c\ub294 \ud3c9\uade0 13.2\uc8fc(10-20\uc8fc), \ud22c\uc5ec\uad70\uc5d0\uc11c\ub294 \ud3c9\uade0 8.9\uc8fc (6-12\uc8fc)\uac00 \uac78\ub838\uc73c\uba70, \ud1b5\uacc4\uc801\uc73c\ub85c \uc720\uc758\ud55c \ucc28\uc774\uac00 \uc788\uc5c8\ub2e4(p=0.001). \uc218\uc220 \ud6c4 \ub450\ud1b5, \uc624\uc2ec, \uc18c\ud654\ubd88\ub7c9 \ubc0f \uac00\ub824\uc6c0\uc744 \ud638\uc18c\ud558\ub294 \ud658\uc790\uac00 \uc788 \uc5c8\uc73c\ub098 \uc218\uc220 \ud6c4 \ud56d\uc0dd\uc81c \ub4f1 \uc5ec\ub7ec \uc57d\uc81c\ub97c \ud568\uaed8 \uc0ac\uc6a9\ud558\uc600\uace0, \ubaa8\ub450 \uc77c \uc8fc\uc77c \uc774\ub0b4\uc5d0 \ud68c\ubcf5\ub418\uc5b4 \uc0c1\uae30 \uc99d\uc0c1\ub4e4\uc774 teriparatide\uc758 \ucd08\uae30 \ud22c\uc5ec\uc5d0 \ub530\ub978 \ubd80\uc791\uc6a9\uc774\ub77c\uace0 \ub2e8\uc815\ud558\uae30 \uc5b4\ub824\uc6e0\ub2e4. \uc774\ud6c4 \uc678\ub798 \ucd94\uc2dc\uc5d0\uc11c\ub3c4 \uc0c1 \uae30 \uc99d\uc0c1\uc744 \ud3ec\ud568\ud55c \uc2e0\uc7a5 \uae30\ub2a5\uc758 \uc774\uc0c1\uc774\ub098 \uc545\uc131 \uace8\uc885\uc591\uc758 \ubc1c\ubcd1\uc740 \uc5c6\uc5c8\ub2e4. \ucd5c\ucd08 \uac00\uace8 \ud615\uc131\uc740 \ube44\ud22c\uc5ec\uad70\uc5d0\uc11c \ud3c9\uade0 7.4\uc8fc(4-12\uc8fc), \ud22c\uc5ec\uad70\uc5d0 \uc11c \ud3c9\uade0 6.7\uc8fc(4-8\uc8fc)\uc5d0 \uad00\ucc30\ub418\uc5c8\uace0(p=0.046), \ucd5c\ucd08 \uac00\uace8\uad50\uc758 \ud615\uc131 \uc740 \ube44\ud22c\uc5ec\uad70\uc5d0\uc11c \ud3c9\uade0 17.0\uc8fc(10-28\uc8fc), \ud22c\uc5ec\uad70\uc5d0\uc11c \ud3c9\uade0 12.4\uc8fc", "type": "figure"}, "FIGREF2": {"text": "Figure 1. A 76-year-old female using bisphosphonate for six years was diagnosed as an atypical femoral fracture (AFF). (A) Anteroposterior radiograph of the left femur shows AFF. (B) Radiographs, obtained immediately operatively, show the fixation using an intramedullary nail. After surgery, the patient started administration of teriparatide 20 \u03bcg a day. (C) Radiographs obtained at 6 weeks after surgey show callus formation at the fracture site. (D) Radiographs obtained at 10 weeks after surgery show callus bridge formation at the fracture site. (E) Radiographs obtained at 24 weeks after surgery show complete bony union at the fracture site.", "type": "figure"}, "FIGREF3": {"text": "\ube44\uc815\ud615\uc801 \ub300\ud1f4\uace8 \uace8\uc808\uc5d0\uc11c \uace8\uc218\uac15 \ub0b4 \uc815\uc744 \uc774\uc6a9\ud55c \ub0b4\uace0\uc815 \ud6c4 \ud14c\ub9ac\ud30c\ub77c\ud0c0\uc774\ub4dc(Teriparatide)\uc758 \ud22c\uc5ec\uac00 \uace8\uc808\uc758 \uce58\ub8cc\uc5d0 \ubbf8\uce58\ub294 \uc601\ud5a5 \ubc15\ucca0\ud604 \u2022 \uc190\uc6b1\uc9c4 \u2022 \ubb38\uc815\uc7ac \u2022 \uc2ec\ubc94\uc9c4 \u2022 \ud5c8\uc7ac\ud76c* \uc601\ub0a8\ub300\ud559\uad50 \uc758\uacfc\ub300\ud559 \uc601\ub0a8\ub300\ud559\uad50\ubcd1\uc6d0 \uc815\ud615\uc678\uacfc\ud559\uad50\uc2e4; *\uac15\ub0a8\ubcd1\uc6d0 \uc815\ud615\uc678\uacfc \ubaa9\uc801: \ube44\uc815\ud615\uc801 \ub300\ud1f4\uace8 \uace8\uc808 \ud658\uc790\uc5d0\uc11c \uace8\uc218\uac15 \ub0b4 \uc815\uc744 \uc774\uc6a9\ud55c \uc218\uc220 \ud6c4 teriparatide\uc758 \ud22c\uc5ec\uac00 \uace8\uc808\uc758 \uce58\uc720\uc5d0 \ubbf8\uce58\ub294 \uc601\ud5a5\uc5d0 \ub300\ud574 \uc54c\uc544 \ubcf4\uace0\uc790 \ud558\uc600\ub2e4. \ub300\uc0c1 \ubc0f \ubc29\ubc95: 2009\ub144 1\uc6d4\ubd80\ud130 2013\ub144 12\uc6d4\uae4c\uc9c0 \ube44\uc815\ud615\uc801 \ub300\ud1f4\uace8 \uace8\uc808\ub85c \uace8\uc218\uac15 \ub0b4 \uc815\uc744 \uc774\uc6a9\ud558\uc5ec \uc218\uc220\uc744 \uc2dc\ud589\ud55c 26\uba85(26\uc608)\uc744 \ub300 \uc0c1\uc73c\ub85c \ud558\uc600\ub2e4. \uc774 \uc911 \uc218\uc220 \ud6c4 teriparatide\ub97c \ud22c\uc5ec\ud558\uc9c0 \uc54a\uc740 15\uc608(\ube44\ud22c\uc5ec\uad70)\uc640 \ud22c\uc5ec\ud55c 11\uc608(\ud22c\uc5ec\uad70)\ub85c \ub098\ub204\uc5b4 \uc784\uc0c1\uc801 \ud3c9\uac00 \ubc0f \ubc29\uc0ac\uc120 \uc801 \ud3c9\uac00\ub97c \uc9c4\ud589\ud558\uc600\ub2e4. \uacb0\uacfc: \uc218\uc0c1 \uc804\uc758 \ubcf4\ud589 \uc815\ub3c4\ub85c \ud68c\ubcf5\ud558\ub294 \ub370 \uac78\ub9b0 \uae30\uac04 \ubc0f \uc218\uc220 \ud6c4 \uace8\uc808 \ubd80\uc704\uc758 \ud1b5\uc99d\uc774 visual analogue scale 2\uc810 \uc774\ud558\uac00 \ub418\ub294 \ub370 \uac78\ub9b0 \uae30\uac04\uc740 \ud22c\uc5ec\uad70\uc5d0\uc11c \ube44\ud22c\uc5ec\uad70\uc5d0 \ube44\ud574 \uc720\uc758\ud558\uac8c \ube68\ub790\ub2e4. \ucd5c\ucd08 \uac00\uace8 \ubc0f \uac00\uace8\uad50 \ud615\uc131 \uc2dc\uae30\uc640 \uace8\uc720\ud569 \uc2dc\uae30\ub294 \ud22c\uc5ec\uad70\uc5d0\uc11c \ube44\ud22c\uc5ec\uad70\uc5d0 \ube44\ud574 \uc720\uc758\ud558\uac8c \ube68\ub790\ub2e4. \uc218\uc220 \ud6c4 \ube44\ud22c\uc5ec\uad70\uc5d0\uc11c\ub294 \uc9c0\uc5f0\uc720\ud569\uc774 5\uc608(33.3%), \ubd88\uc720\ud569\uc774 1\uc608(6.7%) \ubc1c\uc0dd\ud558\uc600\uace0, \ud22c\uc5ec\uad70\uc758 \ubaa8\ub4e0 \ud658\uc790\ub294 \uace8\uc720\ud569\uc744 \uc5bb\uc5c8\ub2e4. \uacb0\ub860: \ube44\uc815\ud615\uc801 \ub300\ud1f4\uace8 \uace8\uc808 \ud658\uc790\uc5d0\uc11c \uace8\uc218\uac15 \ub0b4 \uc815\uc744 \uc774\uc6a9\ud55c \uc218\uc220 \ud6c4 teriparatide\uc758 \ud22c\uc5ec\uac00 \uc784\uc0c1\uc801 \ubc0f \ubc29\uc0ac\uc120\uc801 \uacb0\uacfc\ub97c \ud638\uc804\uc2dc\ucf30\ub2e4. \uadf8\ub7ec\ubbc0\ub85c \ube44\uc815\ud615\uc801 \ub300\ud1f4\uace8 \uace8\uc808 \ud658\uc790\uc5d0\uc11c \uc218\uc220 \ud6c4 teriparatide\uc758 \ud22c\uc5ec\ub294 \uace8\uc808\uc758 \uc720\ud569\uc744 \ucd09\uc9c4\uc2dc\ud0ac \uc218 \uc788\ub294 \uc720\uc6a9\ud55c \ubc29\ubc95\uc774\ub77c\uace0 \uc0dd\uac01\ud55c \ub2e4. \uc0c9\uc778\ub2e8\uc5b4: \ube44\uc815\ud615\uc801 \ub300\ud1f4\uace8 \uace8\uc808, \uace8\uc218\uac15 \ub0b4 \uc815, \ubd80\uac11\uc0c1\uc120\ud638\ub974\ubaac \uc811\uc218\uc77c 2015\ub144 9\uc6d4 1\uc77c \uc218\uc815\uc77c 2015\ub144 10\uc6d4 31\uc77c \uac8c\uc7ac\ud655\uc815\uc77c 2015\ub144 11\uc6d4 23\uc77c \ucc45\uc784\uc800\uc790 \uc190\uc6b1\uc9c4 42415, \ub300\uad6c\uc2dc \ub0a8\uad6c \ud604\ucda9\ub85c 170, \uc601\ub0a8\ub300\ud559\uad50\ubcd1\uc6d0 \uc815\ud615\uc678\uacfc TEL 053-620-3640, FAX 053-628-4020, E-mail ossoj@med.yu.ac.kr *\ubcf8 \ub17c\ubb38\uc758 \uc694\uc9c0\ub294 2015\ub144\ub3c4 \ub300\ud55c\uace8\uc808\ud559\ud68c \ucd98\uacc4\ud559\uc220\ub300\ud68c\uc5d0\uc11c \ubc1c\ud45c\ub418\uc5c8\uc74c.", "type": "figure"}, "TABREF0": {"text": "Table 1\uacfc \uac19\uace0, \ud3c9\uade0 \ucd94\uc2dc \uae30\uac04\ub9cc \ub450 \uad70 \uac04\uc5d0 \uc720\uc758\ud55c \ucc28\uc774\ub97c \ubcf4\uc600\ub2e4. AO \ubd84\ub958\uc0c1 \ub300\ud1f4\uace8\uc758 \uc804\uc790\ud558 \ubc0f \uac04\ubd80", "type": "table"}, "TABREF1": {"text": "Clinical and Radiographic Results between the Non-Injection and Injection Groups", "type": "table"}}}
{"paper_id": "94550656", "_pdf_hash": "42b3e1bd9c4740192f22d8725d470218e86301c8", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Solving ratio-dependent predator-prey system with constant effort harvesting using homotopy perturbation method", "authors": [{"first": "R", "middle": ["G"], "last": "Abdoul", "suffix": ""}, {"first": "A", "middle": [], "last": "Barari", "suffix": ""}, {"first": "D", "middle": ["D"], "last": "Ganji", "suffix": ""}], "year": 2008, "venue": "J. Math. Prob. Eng", "link": "16827035"}, "BIBREF1": {"title": "Numerical analysis of strongly nonlinear oscillation systems using He's max-min method", "authors": [{"first": "H", "middle": [], "last": "Babazadeh", "suffix": ""}, {"first": "G", "middle": [], "last": "Domairry", "suffix": ""}, {"first": "A", "middle": [], "last": "Barari", "suffix": ""}, {"first": "R", "middle": [], "last": "Azami", "suffix": ""}, {"first": "A", "middle": ["G"], "last": "Davodi", "suffix": ""}], "year": 2010, "venue": "Front. Mech. Eng. Chin", "link": "123547559"}, "BIBREF2": {"title": "Application of Homotopy Perturbation Method and Variational Iteration Method to Nonlinear Oscillator Differential Equations", "authors": [{"first": "A", "middle": [], "last": "Barari", "suffix": ""}, {"first": "M", "middle": [], "last": "Omidvar", "suffix": ""}, {"first": "R", "middle": ["G"], "last": "Abdoul", "suffix": ""}, {"first": "D", "middle": ["D"], "last": "Ganji", "suffix": ""}], "year": 2008, "venue": "Acta Appl. Math", "link": "121037939"}, "BIBREF3": {"title": "An approximate solution for boundary value problems in structural engineering and fluid mechanics", "authors": [{"first": "A", "middle": [], "last": "Barari", "suffix": ""}, {"first": "M", "middle": [], "last": "Omidvar", "suffix": ""}, {"first": "D", "middle": ["D"], "last": "Ganji", "suffix": ""}, {"first": "A", "middle": ["P"], "last": "Tahmasebi", "suffix": ""}], "year": 2008, "venue": "J. Math. Problems Eng", "link": "32723622"}, "BIBREF4": {"title": "Variational iteration method and Homotopy-perturbation method for solving different types of wave equations", "authors": [{"first": "A", "middle": [], "last": "Barari", "suffix": ""}, {"first": "R", "middle": ["G"], "last": "Abdoul", "suffix": ""}, {"first": "F", "middle": [], "last": "Farrokhzad", "suffix": ""}, {"first": "D", "middle": ["D"], "last": "Ganji", "suffix": ""}], "year": 2008, "venue": "J. Appl. Sci", "link": "121214298"}, "BIBREF5": {"title": "Application of homotopy perturbation method and variational iteration method to a nonlinear diffusion equation with a reaction term", "authors": [{"first": "A", "middle": [], "last": "Barari", "suffix": ""}, {"first": "A", "middle": [], "last": "Janalizadeh", "suffix": ""}, {"first": "F", "middle": [], "last": "Farrokhzad", "suffix": ""}, {"first": "D", "middle": ["D"], "last": "Ganji", "suffix": ""}], "year": 2009, "venue": "J. Appl. Functional Anal", "link": null}, "BIBREF6": {"title": "Homotopy perturbation method for a conservative x1/3 force nonlinear oscillator", "authors": [{"first": "A", "middle": [], "last": "Bel\u00e9ndez", "suffix": ""}], "year": 2009, "venue": "Comp. Math. Appl", "link": "6411962"}, "BIBREF7": {"title": "Analytical investigation of a fourth order boundary value problem in deformation of beams and plate deflection theory", "authors": [{"first": "A", "middle": ["J"], "last": "Choobbasti", "suffix": ""}, {"first": "A", "middle": [], "last": "Barari", "suffix": ""}, {"first": "F", "middle": [], "last": "Farrokhzad", "suffix": ""}, {"first": "D", "middle": ["D"], "last": "Ganji", "suffix": ""}], "year": 2008, "venue": "J. Appl. Sci", "link": "110888677"}, "BIBREF8": {"title": "Solution of Beam Deformation Equation Using Perturbation and Homotopy-Perturbation Methods", "authors": [{"first": "F", "middle": [], "last": "Farrokhzad", "suffix": ""}, {"first": "A", "middle": ["K"], "last": "Barari", "suffix": ""}, {"first": "A", "middle": [], "last": "Choobasti", "suffix": ""}, {"first": "A", "middle": ["J"], "last": "Ganji", "suffix": ""}, {"first": "D", "middle": ["D"], "last": "", "suffix": ""}], "year": 2009, "venue": "J. Appl. Functional Anal", "link": null}, "BIBREF9": {"title": "Parametric identification of an experimental magneto-elastic oscillator", "authors": [{"first": "B", "middle": ["F"], "last": "Feeny", "suffix": ""}, {"first": "C", "middle": ["M"], "last": "Yuan", "suffix": ""}, {"first": "J", "middle": ["P"], "last": "Cusmano", "suffix": ""}], "year": 2001, "venue": "J. Sound Vib", "link": null}, "BIBREF10": {"title": "Homotopy perturbation method for bifurcation of nonlinear problems", "authors": [{"first": "J", "middle": ["H"], "last": "He", "suffix": ""}], "year": 2005, "venue": "Int. J. Nonlinear. Sci. Numer. Simulat", "link": "122585419"}, "BIBREF11": {"title": "Analysis of Highly Nonlinear Oscillation Systems Using He's Max-Min Method and Comparison with Homotopy Analysis and Energy Balance Methods, Sadhana", "authors": [{"first": "L", "middle": ["B"], "last": "Ibsen", "suffix": ""}, {"first": "A", "middle": [], "last": "Barari", "suffix": ""}, {"first": "A", "middle": [], "last": "Kimiaeifar", "suffix": ""}], "year": 2010, "venue": "", "link": "121280930"}, "BIBREF12": {"title": "Identification of a continuous structure with a geometrical nonlinearity. Part1: conditioned reversed path method", "authors": [{"first": "G", "middle": [], "last": "Kerschen", "suffix": ""}, {"first": "V", "middle": [], "last": "Lenaerts", "suffix": ""}, {"first": "J", "middle": ["C"], "last": "Golinval", "suffix": ""}], "year": 2003, "venue": "J. Sound Vib", "link": null}, "BIBREF13": {"title": "Balancing energy to estimate damping parameters in forced oscillators", "authors": [{"first": "J", "middle": ["W"], "last": "Liang", "suffix": ""}, {"first": "B", "middle": ["F"], "last": "Feeny", "suffix": ""}], "year": 2006, "venue": "J. Sound Vib", "link": "4133243"}, "BIBREF14": {"title": "An Energy-Balance Approach for Oscillator Parameter Identification", "authors": [{"first": "B", "middle": ["P"], "last": "Mann", "suffix": ""}, {"first": "F", "middle": ["A"], "last": "Khasawneh", "suffix": ""}], "year": 2009, "venue": "J. Sound Vib", "link": "122740605"}, "BIBREF15": {"title": "Analysis of Blasius Equation for Flat-Plate Flow with Infinite Boundary Value", "authors": [{"first": "M", "middle": ["O"], "last": "Miansari", "suffix": ""}, {"first": "M", "middle": ["E"], "last": "Miansari", "suffix": ""}, {"first": "A", "middle": [], "last": "Barari", "suffix": ""}, {"first": "G", "middle": [], "last": "Domairry", "suffix": ""}], "year": 2010, "venue": "Intl. J. Comput. Meth. Eng. Sci. Mech", "link": "122863967"}, "BIBREF16": {"title": "Numerical Solution of Boundary Layer Flow and Convection Heat Transfer Over a Flat Plate", "authors": [{"first": "H", "middle": [], "last": "Mirgolbabaei", "suffix": ""}, {"first": "A", "middle": [], "last": "Barari", "suffix": ""}, {"first": "L", "middle": ["B"], "last": "Ibsen", "suffix": ""}, {"first": "M", "middle": ["G"], "last": "Sfahani", "suffix": ""}], "year": 2010, "venue": "Arch. Civil Mech. Eng", "link": null}, "BIBREF17": {"title": "Direct parameter estimation for linear and nonlinear structures", "authors": [{"first": "K", "middle": ["S"], "last": "Mohammad", "suffix": ""}, {"first": "K", "middle": [], "last": "Worden", "suffix": ""}, {"first": "G", "middle": ["R"], "last": "Tomlinson", "suffix": ""}], "year": 1992, "venue": "J. Sound Vib", "link": "119887329"}, "BIBREF18": {"title": "New Class of Solutions for Water Infiltration Problems in Unsaturated Soils, Geomechanics and Geoen-gineering", "authors": [{"first": "M", "middle": [], "last": "Omidvar", "suffix": ""}, {"first": "A", "middle": [], "last": "Barari", "suffix": ""}, {"first": "M", "middle": [], "last": "Momeni", "suffix": ""}, {"first": "D", "middle": ["D"], "last": "Ganji", "suffix": ""}], "year": 2010, "venue": "Int. J", "link": null}, "BIBREF19": {"title": "Mechanical Vibrations", "authors": [{"first": "S", "middle": ["S"], "last": "Rao", "suffix": ""}], "year": 1995, "venue": "", "link": null}, "BIBREF20": {"title": "Textbook of Mechanical Vibrations", "authors": [{"first": "V", "middle": ["D"], "last": "Rao", "suffix": ""}, {"first": "J", "middle": [], "last": "Srinivas", "suffix": ""}], "year": 2004, "venue": "", "link": null}, "BIBREF22": {"title": "Analytical Solutions to Nonlinear Conservative Oscillator with Fifth-Order Non-linearity", "authors": [], "year": "", "venue": "", "link": "123555934"}, "BIBREF23": {"title": "Nonlinear fluctuation, frequency and stability analyses in free vibration of circular sector oscillation systems", "authors": [{"first": "M", "middle": [], "last": "Shaban", "suffix": ""}, {"first": "D", "middle": ["D"], "last": "Ganji", "suffix": ""}, {"first": "M", "middle": ["M"], "last": "Alipour", "suffix": ""}], "year": 2010, "venue": "Curr. Appl. Phys", "link": "93053868"}, "BIBREF24": {"title": "Identification of nonlinear multi-degree-of-freedom systems (presentation of an identification technique)", "authors": [{"first": "K", "middle": [], "last": "Yashuda", "suffix": ""}, {"first": "S", "middle": [], "last": "Kawamura", "suffix": ""}, {"first": "K", "middle": [], "last": "Watanabe", "suffix": ""}], "year": 1988, "venue": "JSME Int. J", "link": null}, "BIBREF25": {"title": "An improvement to homotopy perturbation method for solving system of linear equations", "authors": [{"first": "Yusufo", "middle": [], "last": "Lu", "suffix": ""}, {"first": "E", "middle": [], "last": "", "suffix": ""}], "year": 2009, "venue": "Comp. Math. Appl", "link": "2528406"}}, "ref_entries": {}}
{"paper_id": "94551239", "_pdf_hash": "b355fc0f19e1945bcb585b0f696da8b01aa4578f", "abstract": [], "body_text": [], "bib_entries": {"BIBREF2": {"title": "Optical Near Field Recording-Science and Technology", "authors": [{"first": "J", "middle": [], "last": "Tominaga", "suffix": ""}, {"first": "T", "middle": [], "last": "Nakano", "suffix": ""}], "year": 2005, "venue": "", "link": "108611510"}, "BIBREF3": {"title": "Holographic Data Storage: From Theory to Practical Systems", "authors": [{"first": "M", "middle": [], "last": "Ayers", "suffix": ""}, {"first": "K", "middle": [], "last": "Curtis", "suffix": ""}], "year": 2010, "venue": "", "link": "60055472"}}, "ref_entries": {}}
{"paper_id": "94551546", "_pdf_hash": "9bf1cb19041b8ddfca7aeccc9d2f7689c8aa1c7e", "abstract": [{"section": "Abstract", "text": "Ethanolamine (EA) or ethylenediamine (ED)-functionalized poly(glycidyl methacrylate) (PGMA), namely PGEA or PGED, has recently been used as effective gene carriers because of their low cytotoxicity and high transfection efficiency. In this study, a series of PGMA-based supramolecular polycations (PGED-Gd@PGEAs) with magnetic resonance imaging (MRI) functions were readily constructed by assembling multiple adamantine-headed star PGEA (Ad-PGEA) units with a versatile PGED-CD-Gd backbone, which possessed numerous flanking \u03b2-cyclodextrin species and Gd 3+ ions. The properties of different PGED-Gd@PGEA vectors were systematically characterized, including the plasmid DNA condensation ability, cytotoxicity, gene transfection efficiency, cellular uptake and MRI function. Such supramolecular gene vectors had lower toxicity than 'gold standard' polyethylenimine (PEI, 25 kDa). Furthermore, PGED-Gd@PGEAs exhibited significantly higher transfection efficiencies than PEI or the constituent units (PGED-CD-Gd and Ad-PGEA). The chelation of Gd 3+ ions imparted the PGED-Gd@PGEA vectors with a good MRI ability without obvious adverse effects. The present design of PGMA-based supramolecular polycations with Gd 3+ chelation would provide useful information for the development of low-toxicity and high-efficiency multifunctional gene delivery systems.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "INTRODUCTION", "text": "Gene therapy holds potential for treating many severe diseases, such as cancer and genetic diseases. 1 Successful gene therapy depends on highefficiency gene delivery processes, in which the gene carriers have an essential role. The application of traditional viral vectors has been a challenge because of their toxicity, immunogenicity and low capability for scaling up. 2 There has long been a scientific demand for developing non-viral gene delivery systems that can overcome the drawbacks of viral vectors. 3 Non-viral gene delivery has been advanced by the rapid development of materials science and technology. Numerous novel gene delivery systems have been proposed based on functional cationic polymers, such as polyethylenimine (PEI), [4] [5] [6] [7] [8] [9] poly(2-(dimethylamino) ethyl methacrylate), 4,10 poly(L-lysine), 11 poly(aspartic acid) 12, 13 and polyamidoamine. 14 However, these non-viral gene carriers still have shortcomings, including cytotoxicity, low transfection efficiency and lack of multifunction.", "cite_spans": [{"start": 101, "end": 102, "text": "1", "ref_id": "BIBREF0"}, {"start": 372, "end": 373, "text": "2", "ref_id": "BIBREF1"}, {"start": 511, "end": 512, "text": "3", "ref_id": "BIBREF2"}, {"start": 744, "end": 747, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 748, "end": 751, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 752, "end": 755, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 756, "end": 759, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 760, "end": 763, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 764, "end": 767, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 833, "end": 835, "text": "11", "ref_id": "BIBREF10"}, {"start": 856, "end": 859, "text": "12,", "ref_id": "BIBREF11"}, {"start": 860, "end": 862, "text": "13", "ref_id": "BIBREF12"}, {"start": 883, "end": 885, "text": "14", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "INTRODUCTION", "text": "Recently, we found that ethanolamine (EA) or ethylenediamine (ED)-functionalized poly(glycidyl methacrylate) (PGMA), namely PGEA or PGED, could be used as effective gene carriers. 15, 16 They possess good gene transfection properties. To further improve the performance of PGMA-based gene carriers, several strategies have been applied such as polysaccharide introduction and target molecule binding. 16, 17 Owing to the dynamically unable ability of supramolecular polymers, the application of supramolecular chemistry for gene delivery has been a hot research topic in the biomedical field. 18, 19 The construction of supramolecular polycations via host-guest interaction is a popular strategy for high-efficiency gene delivery systems. 20 In particular, cyclodextrins (CDs) and their derivatives have been widely utilized for constructing supramolecular gene delivery systems, mainly because of their superior biocompatibility. [21] [22] [23] With the host-guest interaction strategy, we successfully prepared one PGEA-based supramolecular delivery system by tying multiple \u03b2-cyclodextrin (\u03b2-CD)cored star PGEA polymers to an adamantine-modified linear PGEA backbone. 24 Such PGEA supramolecules markedly increased transfection efficiencies. Further improvements in functionality and the development of new preparation strategies for PGMA-based supramolecular vectors would benefit the construction of better gene delivery systems.", "cite_spans": [{"start": 180, "end": 183, "text": "15,", "ref_id": "BIBREF14"}, {"start": 184, "end": 186, "text": "16", "ref_id": "BIBREF15"}, {"start": 401, "end": 404, "text": "16,", "ref_id": "BIBREF15"}, {"start": 405, "end": 407, "text": "17", "ref_id": "BIBREF16"}, {"start": 593, "end": 596, "text": "18,", "ref_id": "BIBREF17"}, {"start": 597, "end": 599, "text": "19", "ref_id": "BIBREF18"}, {"start": 739, "end": 741, "text": "20", "ref_id": "BIBREF19"}, {"start": 931, "end": 935, "text": "[21]", "ref_id": "BIBREF20"}, {"start": 936, "end": 940, "text": "[22]", "ref_id": "BIBREF21"}, {"start": 941, "end": 945, "text": "[23]", "ref_id": "BIBREF22"}, {"start": 1171, "end": 1173, "text": "24", "ref_id": "BIBREF23"}], "ref_spans": []}, {"section": "INTRODUCTION", "text": "To construct multifunctional supramolecular vectors, a novel strategy was proposed to flexibly prepare PGMA-based supramolecular delivery systems (PGED-Gd@PGEAs) with magnetic resonance imaging (MRI) functionality, by assembling multiple adamantine-headed star PGEA (Ad-PGEA) units with a versatile PGED-CD-Gd backbone (Scheme 1). This backbone possessed numerous flanking \u03b2-CD species and Gd 3+ ions. MRI technology has received considerable attention because of its high spatial resolution and its applications in areas such as deep tissue imaging. 25, 26 In particular, Gd 3+ ions have been used as contrast agents because of their optimal chemical and magnetic properties. 27, 28 In this work, Gd ions were chelated by diethylenetriaminepentacetate acid (DTPA) immobilized on the PGED backbones to introduce the MRI effect into the resultant PGED-Gd@PGEA supramolecular systems. The physicochemical properties of the PGED-Gd@PGEA assemblies, including plasmid DNA (pDNA) condensation ability, cytotoxicity, gene transfection, cellular uptake and MRI functionality, were examined in detail. The present work provides a new strategy to design multifunctional supramolecular delivery systems.", "cite_spans": [{"start": 551, "end": 554, "text": "25,", "ref_id": "BIBREF24"}, {"start": 555, "end": 557, "text": "26", "ref_id": "BIBREF25"}, {"start": 677, "end": 680, "text": "27,", "ref_id": "BIBREF26"}, {"start": 681, "end": 683, "text": "28", "ref_id": "BIBREF27"}], "ref_spans": []}, {"section": "EXPERIMENTAL PROCEDURE Materials", "text": "Branched PEI (Mw~25 kDa), \u03b2-CD (99%), epichlorohydrin (EP, 99%), 1-adamantanecarboxylic acid chloride (98%), pentaerythritol (98%), 2-bromoisobutyryl bromide (98%), ethyl bromoisobutyrate (99%), glycidyl methacrylate (GMA, 98%), N,N,N\u2032,N\u2033,N\u2033-pentamethyldiethylenetriamine (99%), copper(I) bromide (99%), EA (98%), ED (98%), DTPA (98%), carbodiimide hydrochloride (98%), gadolinium(III) chloride hexahydrate (99%) and 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl tetrazolium bromide were bought from Sigma-Aldrich Chemical Co., St Louis, MO, USA. GMA was used after removal of the inhibitors. The plasmid pRL-CMV, encoding Renilla luciferase, (Promega Co., Cergy Pontoise, France), and the plasmid pEGFP-N1, encoding enhanced green fluorescent protein (EGFP) (BD Biosciences, San ", "cite_spans": [], "ref_spans": []}, {"section": "Ad-Br", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "PGED-CD", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "PGED-CD-Gd", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Ad", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Synthesis of the PGED-CD-Gd backbone", "text": "Linear PGMA was prepared via atom transfer radical polymerization (ATRP). First, 160 \u03bcl of ethyl bromoisobutyrate (1 equiv), 2.1 ml of GMA (60 equiv) and 300 \u03bcl of N,N,N\u2032,N\u2033,N\u2033-pentamethyldiethylenetriamine (2 equiv) were added to a 50 ml flask with 5 ml of dimethyl sulfoxide (DMSO). The reaction system was degassed with argon for 10 min before adding 115 mg of copper(I) bromide (1 equiv). The details of the preparation of PGMA are described in our earlier work. 29 The molar weight of PGMA was 4.6 \u00d7 10 3 g mol \u22121 polydispersity index (PDI) = 1.28. The resultant ED-functionalized PGMA (PGED) was prepared using excess ED, as reported previously. 16 As shown in Scheme 1, before the preparation of CD units containing PGED (PGED-CD), it was necessary to synthesize EP-modified CD (CD-EP), using similar procedures to those reported previously. 30 In brief, 1.5 g of \u03b2-CD was added to a 50 ml round flask with a mixture (v/v, 5/5 ml) of DMSO/i-PrOH. After the \u03b2-CD was thoroughly dissolved, 12.5 ml of 1 M NaOH aqueous solution was then added to the solution, followed by the addition of 2 ml of EP. The reaction proceeded at room temperature in a nitrogen atmosphere for 48 h. The pH of the reaction solution was adjusted to~7.0 with concentrated HCl. Excess acetone was used to precipitate the reaction mixture. The raw CD-EP was dissolved in a small amount of deionized (DI) water and dialyzed against DI water (4 \u00d7 5 l) with a dialysis membrane (MWCO, 1000 Da) at room temperature for 4 h, prior to lyophilization. PGED-CD was prepared subsequently. In a 50 ml flask, PGED (130 mg) and CD-EP (480 mg) were added with 7 ml of water. The molar ratio of the terminal amino groups (of PGED) and CD-EP units was 1.6:1. The reaction was conducted at 80\u00b0C for 48 h. The PGED-CD product was purified by a dialysis method and then lyophilized.", "cite_spans": [{"start": 467, "end": 469, "text": "29", "ref_id": "BIBREF28"}, {"start": 652, "end": 654, "text": "16", "ref_id": "BIBREF15"}, {"start": 849, "end": 851, "text": "30", "ref_id": "BIBREF29"}], "ref_spans": []}, {"section": "Synthesis of the PGED-CD-Gd backbone", "text": "For the preparation of Gd 3+ -chelated PGED-CD (PGED-CD-Gd), the amidation reaction was used to introduce DTPA as the chelating agent of Gd 3+ ions onto PGED-CD according to procedures described previously. 31 In brief, 8 mg of carbodiimide hydrochloride and 40 mg of DTPA were dissolved in 7 ml of water. The molar ratio of carbodiimide hydrochloride and DTPA was kept at 1:5 to avoid cross-linking between the amino groups of PGED-CD and carboxylate groups of DTPA. The solution was stirred for 4 h at room temperature before adding 100 mg of PGED-CD. The molar ratio of the remaining amino groups (of PGED-CD) and DTPA units was 1:1. The reaction proceeded for 48 h to produce PGED-CD-DTPA. The resulting solution was purified by dialyzed with a dialysis membrane (MWCO, 1000 Da) against 0.1 M NaCl for 2 days and then dialyzed against DI water for 1 day. The purified solution of PGED-CD-DTPA was transferred into a flask, and GdCl 3 (GdCl 3 \u20226H 2 O) was added. The molar ratio of DTPA and GdCl 3 (GdCl 3 \u20226H 2 O) was kept at 1:1. The mixing solution was stirred for 24 h at room temperature and then dialyzed against DI water for 24 h. Subsequently, the PGED-CD-Gd product was lyophilized.", "cite_spans": [{"start": 207, "end": 209, "text": "31", "ref_id": "BIBREF30"}], "ref_spans": []}, {"section": "Synthesis of Ad-PGEA", "text": "For the preparation of the Ad-PGEA guest, the adamantine-headed ATRP initiator (Ad-Br) with three initiation sites was first synthesized. Pentaerythritol (1.08 g, 7.94 mmol) was thoroughly dissolved in a 50 ml round flask containing 20 ml of anhydrous N,N-dimethylformamide. Then, 1-adamantanecarboxylic acid chloride (1 g, 5.05 mmol) and K 2 CO 3 (1.33 g, 9.64 mmol) were added. The reaction was conducted at 50\u00b0C for 24 h under magnetic stirring. The final reaction solution was centrifuged, evaporated and distillated under reduced pressure, producing Ad-OH with three hydroxyl groups. The resultant Ad-Br was prepared using the similar procedures described earlier. 29 Next, 447 mg of Ad-OH (1.5 mmol) was added to a 50 ml round flask containing 7 ml of N,Ndimethylformamide. Then, 0.75 ml of 2-bromoisobutyryl bromide (6 mmol) was dropped into the aforementioned solution under an ice bath condition and stirring for 24 h. The reaction mixture was quenched with water and extracted with CH 2 Cl 2 . The organic layer was washed with brine, dried over Na 2 SO 4 and concentrated under reduced pressure. The Ad-Br product was a yellowish syrupy-like liquid.", "cite_spans": [{"start": 670, "end": 672, "text": "29", "ref_id": "BIBREF28"}], "ref_spans": []}, {"section": "Synthesis of Ad-PGEA", "text": "The resultant Ad-PGMA polymers were synthesized under the typical conditions of ATRP. 29 In a 50 ml flask, 120 mg of Ad-Br (1 equiv), 2.3 ml of GMA (100 equiv) and 70 \u03bcl of N,N,N\u2032,N\u2033,N\u2033-pentamethyldiethylenetriamine (2.5 equiv) were added to a 50 ml round flask containing 5 ml of DMSO. The reaction system was degassed by nitrogen for 10 min before adding 22.8 mg copper(I) bromide (1 equiv) under a nitrogen atmosphere. The products with a polymerization time of 20 and 35 min were named Ad-PGMA1 (Mn = 5.5 \u00d7 10 3 g mol \u22121 , PDI = 1.26) and Ad-PGMA2 (Mn = 1.0 \u00d7 10 4 g mol \u22121 , PDI = 1.32), respectively.", "cite_spans": [{"start": 86, "end": 88, "text": "29", "ref_id": "BIBREF28"}], "ref_spans": []}, {"section": "Synthesis of Ad-PGEA", "text": "The resulting EA-functionalized Ad-PGMA (Ad-PGEA) was prepared using excess EA as reported earlier. 15 The crude product was purified using a dialysis membrane (MWCO 3500), followed by lyophilization.", "cite_spans": [{"start": 100, "end": 102, "text": "15", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "Preparation of supramolecular assembly/pDNA complexes", "text": "For the preparation of PGED@PGEA and PGED-Gd@PGEA assemblies, with a 1:1 molar feed ratio of the CD/Ad units, PGED-CD or PGED-CD-Gd was assembled with Ad-PGEA. The concentration of Ad-PGEA was based on the nitrogen concentration of 20 mM. Before use, equal volumes of Ad-PGEA solution and PGED-CD or PGED-CD-Gd solution were mixed, shaken and incubated at ambient temperature for 3 h. The final nitrogen concentration for all polymer solutions was 10 mM in DI water. The polymer to DNA ratio was expressed as the molar ratio of nitrogen (N) in PGMA-based polycations to phosphate (P) in DNA, named as the N/P ratio. The average mass weight per phosphate group of DNA was assumed to be 325. 32 All PGED@PGEA/pDNA and PGED-Gd@PGEA/pDNA polyplexes at different N/P ratios were formed by mixing polymer solution and pDNA solution for 30 min before use.", "cite_spans": [{"start": 690, "end": 692, "text": "32", "ref_id": "BIBREF31"}], "ref_spans": []}, {"section": "Physicochemical characterization", "text": "1 H NMR spectra were measured on a Bruker ARX 400 MHz spectrometer using CDCl 3 (for Ad-Br and Ad-PGMA) and D 2 O (for Ad-PGEA, PGED, CD-EP, PGED-CD, PGED-CD-DTPA) as the solvents with tetramethylsilane (Me 4 Si) as an internal standard. GPC measurements of PGMA and Ad-PGMA were performed on a Waters GPC system, in which DMSO was used as the eluent at a low flow rate of 1.0 ml min \u22121 at 25\u00b0C and monodispersed poly (methyl methacrylate) standards were used to generate the calibration curve. Dynamic light scattering measurements of polyplexes were performed with a Zetasizer Nano ZS (Malvern Instruments, Southborough, MA, USA) equipped with a laser of wavelength 633 nm at a 173\u00b0scattering angle. Atomic force microscopy (AFM) studies were carried out with the Dimension Icon model with a Nanoscope IIIa controller (Bruker, Santa Barbara, CA, USA). The samples were imaged using the ScanAsyst mode. Image analysis was performed using Nanoscope software after removing the background slope after flattening the images. Gel electrophoresis was implemented in a Sub-Cell system (Bio-Rad Laboratories), and then, a UV transilluminator and BioDco-It imaging system (UVP Inc.) was used to record DNA bands.", "cite_spans": [], "ref_spans": []}, {"section": "Cell viability assay", "text": "C6 and Hep G2 cell lines from two common cancers were selected to evaluate the performance of the gene carriers. An 3-(4,5-dimethylthiazol-2yl)-2,5diphenyl tetrazolium bromide assay was used to evaluate the cytotoxicity of polyplexes at a series of N/P ratios in C6 and Hep G2 cells cultured in DMEM (with 10% fetal bovine serum) according to the methods described in our previous studies. 32, 33 In brief, the C6 and Hep G2 cells were cultured in 96-well plates at a density of 2 \u00d7 10 4 cells per well with DMEM (with 10% fetal bovine serum). Then, the culture medium was replaced with 100 \u03bcl of fresh culture medium. The PGEA-based and PEI complexes (6.7 \u03bcl per well containing 0.33 \u03bcg of pDNA) at various N/P ratios were added to the media. Then, the cells were incubated for 4 h, and fresh media were added to the culture for another 20 h. Then, 10 \u03bcl of sterile, filtered 3-(4,5-dimethylthiazol-2yl)-2,5diphenyl tetrazolium bromide solution in phosphate-buffered saline (PBS) (5 mg ml \u22121 ) was added to each well. After 4 h, the unreacted dye was removed, and the produced formazan crystals were dissolved in DMSO (100 \u03bcl per well). The OD values were measured at a wavelength of 570 nm with a Bio-Rad Model 680 Microplate Reader (UK). For each sample, the final absorbance was the average of those measured from six wells in parallel. The cell viability results were expressed as the percentage relative to that of the control.", "cite_spans": [{"start": 390, "end": 393, "text": "32,", "ref_id": "BIBREF31"}, {"start": 394, "end": 396, "text": "33", "ref_id": "BIBREF32"}], "ref_spans": []}, {"section": "In vitro transfection assay", "text": "The plasmid pRL-CMV as the reporter gene was first utilized to estimate the in vitro gene transfection of PGMA-based polycation/pDNA polyplexes in C6 and Hep G2 cell lines. Essentially, the C6 and Hep G2 cells were cultured in 24well plates at a density of 6 \u00d7 10 4 cells per well with DMEM media (with 10% fetal bovine serum). Then, the solutions of polycation/pDNA complexes with different N/P ratios (20 \u03bcl per well with 1.0 \u03bcg of pDNA) were added into the transfection media. The detailed transfection procedures are described in our earlier work. 15, 16, 32, 33 A commercial Promega kit and a luminometer (Berthold Lumat LB 9507, Berthold Technologies GmbH KG, Bad Wildbad, Germany) were used to quantify the luciferase gene expression. Gene expression results were expressed as relative light units per milligram of cell protein lysate (relative light units per mg protein). The plasmid pEGFP-N1 with EGFP gene was also utilized as the reporter gene in C6 and Hep G2 cell lines at the optimal N/P ratio of the polycations to evaluate polymer-mediated gene transfection. The transfected cells were imaged with a Leica DMI3000B fluorescence microscope. The percentage of the EGFP-positive cells was determined by flow cytometry (Beckman Coulter, Brea, CA, USA).", "cite_spans": [{"start": 552, "end": 555, "text": "15,", "ref_id": "BIBREF14"}, {"start": 556, "end": 559, "text": "16,", "ref_id": "BIBREF15"}, {"start": 560, "end": 563, "text": "32,", "ref_id": "BIBREF31"}, {"start": 564, "end": 566, "text": "33", "ref_id": "BIBREF32"}], "ref_spans": []}, {"section": "In vitro cellular uptake", "text": "The in vitro cellular uptake was determined by flow cytometry analysis and imaged using fluorescence microscopy. C6 and Hep G2 cells were seeded into 24-well plates at the density of 8 \u00d7 10 5 cells per well and incubated for 24 h. Then, the cells were incubated with the fresh media containing PGMA-based polycation/pDNA polyplexes for 4 h, where pDNA (pRL-CMV) were labeled with the fluorescent dye YOYO-1. 34 The cells were trypsinized, centrifuged, resuspended in PBS and then analyzed by flow cytometry (BD LSR II, BD, USA). For the fluorescence imaging, after cellular uptake, the cells were washed with PBS five times and stained with 4\u2032,6-diamidino-2-phenylindole for 10 min. The fluorescence images were acquired on a Leica DMI3000B microscope.", "cite_spans": [{"start": 408, "end": 410, "text": "34", "ref_id": "BIBREF33"}], "ref_spans": []}, {"section": "In vitro MRI", "text": "Approximately 5 \u00d7 10 6 C6 or Hep G2 cells were seeded and incubated in cell culture flasks for 24 h. Then, the media were replaced with 5 ml of fresh media containing PGED-CD-Gd or PGED-Gd@PGEA ((Gd) = 0, 5, 10 and 20 \u03bcM, respectively). After incubation at 37\u00b0C for 4 h, the cells were washed with PBS three times and then precipitated by centrifugation. The MRI experiments were performed on a 7.0-T MRI instrument (BioSpec 70/20 USR 7.0 T Bruker) with a wrist receiver coil. The pulse sequence was a T1 map-RATE sequence with the following parameters: TR/TE = 400, 800, 1500, 2500, 4000/7 ms: field of view: 3.5 cm 2 ; matrix: 128 \u00d7 128; number of excitations: 1; slice thickness = 1 mm; slice gap = 0 mm; field of view: 3.5 cm. PGED-Gd@PGEA or detached cells were prepared in PBS at different concentrations in 0.5 ml Eppendorf tubes. The T1 relaxivities were determined via a linear fit of the inverse relaxation time as a function of the Gd 3+ concentration.", "cite_spans": [], "ref_spans": []}, {"section": "Statistical analysis", "text": "All experiments were repeated at least three times. The data are presented as means \u00b1 s.d. Statistical significance (Po0.05) was evaluated by a t-test when two groups of samples were compared, and the statistical significance was set at Po0.05.", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS AND DISCUSSION", "text": "Preparation and characterization of supramolecular polycations with Gd 3+ chelation As shown in Scheme 1, the PGMA-based supramolecular delivery systems (PGED-Gd@PGEAs) with MRI functions were prepared by assembling multiple Ad-PGEA units with a PGED-CD-Gd backbone. The PGED-CD-Gd backbone possessed numerous flanking \u03b2-CD species and Gd 3+ ions. For the preparation of the PGED-CD-Gd backbone, the starting PGMA (Mn = 4.6 \u00d7 10 3 g mol \u22121 , PDI= 1.28) with 32 repeat units was first synthesized via ATRP. Then, PGMA was functionalized with excess ED by ring-opening addition to produce PGED with abundant primary amine groups. Similar to our previous study, 16 it was confirmed that the PGED was successfully prepared from the NMR results ( Supplementary Figure S1(a1) ). To introduce \u03b2-CD units, CD-EP that possessed one epoxy ring (Supplementary Figure S1(a2) ) was immobilized onto PGED via ring-opening Figure S1(a3) ), the molar ratio of \u03b2-CD and ED units was 1:2, indicating that every PGED-CD chain contained 16 \u03b2-CD units. DTPA, the chelating agent of Gd 3+ ions, was subsequently reacted with the remaining primary amine groups of PGED-CD via the amidation reaction, producing PGED-CD-DTPA. Based on the 1 H NMR spectrum of PGED-CD-DTPA ( Supplementary  Figure S1(a4) ), PGED-CD-DTPA contained~12 DPTA units. The resultant PGED-CD-Gd backbone was obtained by the chelation of PGED-CD-DTPA with Gd 3+ ions. According to the thermogravimetric analysis (Supplementary Figure S2) , the PGED-CD-Gd backbone contained~10 Gd 3+ ions, which was fairly consistent with the number of DPTA units.", "cite_spans": [{"start": 659, "end": 661, "text": "16", "ref_id": "BIBREF15"}], "ref_spans": [{"start": 742, "end": 769, "text": "Supplementary Figure S1(a1)", "ref_id": "FIGREF0"}, {"start": 849, "end": 862, "text": "Figure S1(a2)", "ref_id": "FIGREF0"}, {"start": 908, "end": 921, "text": "Figure S1(a3)", "ref_id": "FIGREF0"}, {"start": 1249, "end": 1277, "text": "Supplementary  Figure S1(a4)", "ref_id": "FIGREF0"}, {"start": 1460, "end": 1485, "text": "(Supplementary Figure S2)", "ref_id": "FIGREF2"}]}, {"section": "RESULTS AND DISCUSSION", "text": "The synthesis of the Ad-PGEA guest with three arms was performed in a four-step procedure (Scheme 1). C(CH 2 OH) 4 was compounded with 1-adamantanecarboxylic acid chloride, and the rest of the hydroxyl groups were reacted with 2-bromoisobutyryl bromide to initiate the ATRP process of GMA, followed by ring-opening of epoxy groups of Ad-PGMA with excess EA. Every step of the preparation process of Ad-PGEA was monitored by 1 H NMR (Supplementary Figure S3 ). After the first two steps of the substitution reaction, C-CH 2 -OCO protons and CH 3 -C-Br protons from the newly formed Ad-OH and Ad-Br were observed at~3.89 and 1.95 ppm, respectively. By integrating the corresponding NMR peaks, it was estimated that Ad-Br possessed approximately three initiation sites. The resultant Ad-PGMA1 (Mn = 5.5 \u00d7 10 3 g mol \u22121 , PDI= 1.26) and Ad-PGMA2 (Mn = 1.0 \u00d7 10 4 g mol \u22121 , PDI = 1.32) were prepared by using Ad-Br. The Ad-PGMA species were further functionalized with excess EA to produce the corresponding Ad-PGEA1 and Ad-PGEA2 guests with different molecular weights. Similar to our previous studies, 15, 16 Ad-PGMA and Ad-PGEA were successfully prepared, as shown by the NMR results (Supplementary Figure S3 ). For the preparation of the PGED@PGEA and PGED-Gd@PGEA assemblies, two Ad-PGEA guests were complexed with PGED-CD or PGED-CD-Gd hosts in DI water by the host-guest interaction of Ad and CD species.", "cite_spans": [{"start": 113, "end": 114, "text": "4", "ref_id": "BIBREF3"}, {"start": 1100, "end": 1103, "text": "15,", "ref_id": "BIBREF14"}, {"start": 1104, "end": 1106, "text": "16", "ref_id": "BIBREF15"}], "ref_spans": [{"start": 447, "end": 456, "text": "Figure S3", "ref_id": "FIGREF3"}, {"start": 1198, "end": 1207, "text": "Figure S3", "ref_id": "FIGREF3"}]}, {"section": "RESULTS AND DISCUSSION", "text": "Characterization of polymer/pDNA nanocomplexes For non-viral polycationic gene carriers, the ability to condense pDNA into a nanoparticle is essential because nanocomplexes of carrier and pDNA are more suitable for cellular uptake. In this work, agarose gel electrophoresis, particle size and \u03b6-potential measurements, as well as AFM images, were used to confirm the ability of PGMA-based polycations to condense pDNA. The gel retardation results of polymer/pDNA complexes with increasing N/P ratios are shown in Figure 1 . All PGED@PGEA and PGED-Gd@PGEA could compact pDNA completely within the N/P ratio of 1.5, whereas the PGED-CD-Gd backbone and Ad-PGEA guests only condensed pDNA when N/P ratios reached 2.5. The above results indicated that the pDNAcondensing ability of PGED@PGEA and PGED-Gd@PGEA is better than that of PGED-CD-Gd and Ad-PGEA, which is probably because of the high molecular weight supramolecular structures. 35 The particle size and the \u03b6-potential of polymer/pDNA complexes with increasing N/P ratio are shown in Figure 2 . The particle sizes of all complexes decreased with increasing N/P ratios. At lower N/P ratios, loose aggregates with large size were formed owing to the few positive charges on the polymers. 36 With an increase in the N/P ratios, the diameters of all complexes decreased to 100-150 nm, which enabled the complexes to easily undergo endocytosis. It was also noted that at both low and high N/P ratios, the polycation/pDNA complexes had good stability (Supplementary Figure S4 ). In addition to particle sizes, the \u03b6-potential of polymer/pDNA complexes are another factor that affects cellular uptake. All of the complexes had positive \u03b6-potentials, and the values of the \u03b6-potential slightly increased with the N/P ratios. Owing to the positive charges, polymer/pDNA complexes had a good affinity for the negatively charged cell membrane and were able to facilitate cellular uptake. 37 The \u03b6-potential values of PGED@PGEA and PGED-Gd@PGEA groups were higher than those of the PGED-CD-Gd backbone and Ad-PGEA guests, once again confirming that PGMA-based supramolecular polycations possessed better DNA-compacting ability.", "cite_spans": [{"start": 933, "end": 935, "text": "35", "ref_id": "BIBREF34"}, {"start": 1241, "end": 1243, "text": "36", "ref_id": "BIBREF35"}, {"start": 1932, "end": 1934, "text": "37", "ref_id": "BIBREF36"}], "ref_spans": [{"start": 513, "end": 521, "text": "Figure 1", "ref_id": "FIGREF0"}, {"start": 1039, "end": 1047, "text": "Figure 2", "ref_id": "FIGREF2"}, {"start": 1515, "end": 1524, "text": "Figure S4", "ref_id": "FIGREF4"}]}, {"section": "RESULTS AND DISCUSSION", "text": "The morphology of polymer/pDNA complexes was observed by AFM. Figure 3 shows the representative AFM images of Ad-PGEA1/ pDNA, PGED@PGEA1/pDNA and PGED-Gd@PGEA1/pDNA complexes at the N/P ratio of 15. The AFM images show that the polymers could compact pDNA to form nanoparticles with a diameter of 100 nm, which is consistent with the results of particle size measurement (Figure 2a ).", "cite_spans": [], "ref_spans": [{"start": 62, "end": 70, "text": "Figure 3", "ref_id": "FIGREF3"}, {"start": 371, "end": 381, "text": "(Figure 2a", "ref_id": "FIGREF2"}]}, {"section": "Cell viability assay", "text": "Low cytotoxicity is essential for ideal biomedical materials. To evaluate the cytotoxicity of PGMA-based polycation/pDNA complexes at different N/P ratios, an 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl tetrazolium bromide assay was performed using the C6 and Hep G2 cell lines. The relative cell viabilities of all of the groups in both cell lines decreased with increasing N/P ratios (Figure 4 ). The cytotoxicity of polycations generally increases with their molecular weight. 38 In comparison with the PGED-CD and PGED-CD-Gd backbone, PGED@PGEA and PGED-Gd@PGEA exhibited increased cytotoxicity. However, PGED@PGEA and PGED-Gd@PGEA showed significantly lower cytotoxicity than the gold standard, PEI (25 kDa). For example, at an N/P ratio of 30, for the PGMA-based polycation/pDNA complexes, the relative cell viability values of C6 cells were 450% and those of Hep G2 470%. In our earlier work, 3, 15, 24, 39, 40 it was found that in comparison with PEI, which mainly has secondary amine groups, the nonionic hydrophilic hydroxyl groups of PGEAs can shield the deleterious, excess charges of the cationic complexes, leading to lower cytotoxicity. In addition, no significant differences among the cytotoxicities of Ad-PGEA, PGED@PGEA and PGED-Gd@PGEA were observed. The above results indicated that the supramolecular polymers could achieve a lower cytotoxicity despite their high molecular weights.", "cite_spans": [{"start": 477, "end": 479, "text": "38", "ref_id": "BIBREF37"}, {"start": 897, "end": 899, "text": "3,", "ref_id": "BIBREF2"}, {"start": 900, "end": 903, "text": "15,", "ref_id": "BIBREF14"}, {"start": 904, "end": 907, "text": "24,", "ref_id": "BIBREF23"}, {"start": 908, "end": 911, "text": "39,", "ref_id": "BIBREF38"}, {"start": 912, "end": 914, "text": "40", "ref_id": "BIBREF39"}], "ref_spans": [{"start": 383, "end": 392, "text": "(Figure 4", "ref_id": "FIGREF4"}]}, {"section": "Gene transfection assay", "text": "The gene transfection efficiency of the polycation/pDNA complexes was first analyzed in C6 and Hep G2 cell lines using pRL-CMV as a reporter gene. The C6 and Hep G2 cell lines are documented to be difficult to transfect with synthetic vectors. 41 Figure 5 shows the gene transfection efficiencies mediated by Ad-PGEA, PGED@PGEA and PGED-Gd@PGEA at various N/P ratios in comparison with those mediated by the controls (PEI (25 kDa), PGED-CD and PGED-CD-Gd) at their respective optimal N/P ratios. In general, the transfection efficiency first increases and then decreases slightly with increasing N/P ratio. At lower N/P ratios, cationic polymers cannot efficiently compact DNA, and the resultant loose nanocomplexes cannot easily enter cells. By contrast at higher N/P ratios, the transfection efficiency slightly decreased, probably as a result of the increased toxicity of free cationic polymers. The difference in gene transfection efficiencies at the same N/P ratio was observed between C6 and Hep G2 cells. The transfection efficiencies of gene carriers depend on different cell types because of their different properties. 42 As expected, the transfection efficiencies of PGED@PGEA and PGED-Gd@PGEA were significantly higher than those of Ad-PGEA guests at various N/P ratios because PGED@PGEA and ", "cite_spans": [{"start": 244, "end": 246, "text": "41", "ref_id": "BIBREF40"}, {"start": 1129, "end": 1131, "text": "42", "ref_id": "BIBREF41"}], "ref_spans": []}, {"section": "Figure 5", "text": "In vitro gene transfection efficiencies of the polymer/pDNA complexes at various N/P ratios in (a) C6 and (b) Hep G2 cells in comparison with those mediated by PEI (25 kDa, at its optimal N/P ratio of 10), PGED-CD (at the optimal N/P ratio of 15 for C6 or 25 for G2 cells) and PGED-CD-Gd (at the optimal N/P ratio of 15 for C6 or 25 for Hep G2 cells) (mean \u00b1 s.d., n = 3, *Po0.05).", "cite_spans": [], "ref_spans": []}, {"section": "Figure 5", "text": "PGED-Gd@PGEA might benefit from the better DNA-compacting ability (Figure 1 ) and low toxicities (Figure 4 ) of the supramolecular vectors. Notably, the transfection efficiencies of PGED@PGEA and PGED-Gd@PGEA arising from the same Ad-PGEA guests exhibited no significant difference, indicating that the Gd 3+ ions had no obvious effects on transfection efficiencies. In C6 and Hep G2 cell lines, Ad-PGEA2 exhibited much higher transfection efficiencies than Ad-PGEA1. This indicated that the transfection efficiencies mediated by PGEA-based vectors were dependent on the molecular weight of PGEA. In addition, the transfection efficiencies mediated by PGED@P-GEA and PGED-Gd@PGEA at most N/P ratios were much higher than those mediated by PEI at its optimal ratio of 10.", "cite_spans": [], "ref_spans": [{"start": 66, "end": 75, "text": "(Figure 1", "ref_id": "FIGREF0"}, {"start": 97, "end": 106, "text": "(Figure 4", "ref_id": "FIGREF4"}]}, {"section": "Figure 5", "text": "As shown in Figure 5 , the differences between the transfection efficiencies of Ad-PGEA1 and PGED-Gd@PGEA1 at most N/P ratios are bigger than those of Ad-PGEA2 and PGED-Gd@PGEA2. Thus, PGED-Gd@PGEA1 was selected as the representative supramolecular vector in the following experiments. To visually confirm the gene delivery abilities of PGEA-based vectors, the plasmid pEGFP-N1, Figure 6 Representative images of EGFP expression in (a, a1, a2, a3) C6 and (b, b1, b2, b3) Hep G2 cells transfected with Ad-PGEA1, PGED@PGEA1, PGED-Gd@PGEA1 and PEI at their respective optimal N/P ratios.", "cite_spans": [], "ref_spans": []}, {"section": "Figure 5", "text": "Biomedical applications of polycations Y Zhao et al Figure 7 Fluorescent images and flow cytometry analysis plots of (a) C6 and (b) Hep G2 cells treated with Ad-PGEA1/pDNA, PGED@PGEA1/pDNA and PGED-Gd@PGEA1/pDNA polyplexes for 4 h at the respective optimal N/P ratios. For the fluorescent images, the YOYO-1-labeled pDNA is shown in green, and the 4\u2032,6-diamidino-2-phenylindole -labeled nuclei are shown in blue.", "cite_spans": [], "ref_spans": []}, {"section": "Biomedical applications of polycations", "text": "Y Zhao et al encoding GFP, was used as another reporter gene in C6 and Hep G2 cell lines. Representative images of EGFP gene expression mediated by Ad-PGEA1, PGED@PGEA1 and PGED-Gd@PGEA1 at their respective optimal N/P ratios are shown in Figure 6 . The corresponding merged images are shown in Supplementary Figure S5 . Transfection with PGED@PGEA1 or PGED-Gd@PGEA1 led to more green (EGFPpositive) Hep G2 cells than did Ad-PGEA1 or PEI. The transfection efficiency, as reflected by the percentage of EGFP-positive cells, was quantitatively determined using flow cytometry. The percentages of EGFP-positive cells for Ad-PGEA1, PGED@PGEA1, PGED-Gd@PGEA1 and PEI in C6 (or Hep G2) cells are 13% (or 16%), 43% (or 47%), 41% (or 44%) and 14% (or 23%), respectively, which is fairly consistent with the results for luciferase expression ( Figure 5 ). The above gene transfection assay indicated that the supramolecular structure improved the gene transfection, and Gd 3+ ions had no obvious adverse effects on the transfection process.", "cite_spans": [], "ref_spans": []}, {"section": "Cellular internalization", "text": "To investigate the intracellular fates of the supramolecular vectors, the C6 and Hep G2 cells were treated with the Ad-PGEA1/pDNA, PGED@PGEA1/pDNA and PGED-Gd@PGEA1/pDNA complexes for 4 h at their respective optimal N/P ratios (15 for C6 cells and 25 for Hep G2 cells), whereas the pDNA was labeled by YOYO1, as shown in Figure 7 . YOYO1-labeled pDNA is shown in green. The nuclei stained with 4\u2032,6-diamidino-2-phenylindole are shown in blue. Compared with the cells treated with Ad-PGEA1/pDNA, the cells treated with PGED@PGEA1/pDNA and PGED-Gd@PGEA1/pDNA showed more green aggregations. The corresponding merged images are shown in Supplementary Figure S6 . The cellular uptake of the complexes with YOYO1-labeled pDNA was quantified by flow cytometry. The percentages of YOYO1-positive cells treated with PGED@PGEA1/ pDNA and PGED-Gd@PGEA1/pDNA were almost 90%, much higher than those (65~69%) of the cells treated with Ad-PGEA1/pDNA. This result was consistent with the fluorescent images of cellular uptake, confirming that supramolecular structure enhanced cell uptake, benefiting the resultant gene transfection.", "cite_spans": [], "ref_spans": []}, {"section": "In vitro MRI", "text": "The complexes with gadolinium have been widely used as efficient T1weighted MR contrast agents. 41, 43 PGED-Gd@PGEA was expected to act as an MRI contrast agent (relaxation times were shown in Supplementary Table S1 ). The MRI assay of PGED-Gd@PGEA1 is shown in Figure 8 . A linear curve could be obtained by plotting the inverse T1 as a function of the molar concentration of Gd 3+ ions (Figure 8a, top) . The brightness of the MR images increased with the molar concentration of Gd 3+ ions (Figure 8a, bottom) . Next, the potential to use the PGED-Gd@PGEA1 for MRI of cancer cells was explored. Both C6 and Hep G2 cells were treated for 4 h with PGED-CD-Gd and PGED-Gd@PGEA1 at different Gd 3+ ion concentrations in culture media (0, 5, 10 and 20 \u03bcM,) before imaging with the MR systems. Both the inverse T1 and MR images were presented and collected. The MR images of cancer cells treated with PGED-CD-Gd became slightly brighter with an increasing concentration of Gd 3+ ions (Supplementary Figure S7) . However, the MR images of cancer cells treated with PGED-Gd@PGEA1 evidently became brighter, and the inverse T1 increased with the concentration of Gd 3+ ions (Figure 8b ), likely arising from the higher cellular uptake of PGED-Gd@PGEA1 (Figure 7) . The above results indicated that supramolecular structure could also affect the relaxation time in vitro. PGED-Gd@PGEA could potentially be used as a contrast agent for MR imaging.", "cite_spans": [{"start": 96, "end": 99, "text": "41,", "ref_id": "BIBREF40"}, {"start": 100, "end": 102, "text": "43", "ref_id": "BIBREF42"}], "ref_spans": []}, {"section": "CONCLUSIONS", "text": "A series of PGMA-based supramolecular polycations (PGED-Gd@PGEAs) with MRI functionality were successfully constructed by assembling multiple Ad-PGEA guests with a versatile PGED-CD-Gd host, which possessed numerous flanking Gd 3+ ions. Such PGED-Gd@PGEAs had good DNA condensation abilities and low cell cytotoxicity. Moreover, PGED-Gd@PGEAs exhibited significantly higher transfection efficiencies than PEI (25 kDa) and the constituent units (PGED-CD-Gd and Ad-PGEA). The chelation of Gd 3+ ions imparted PGED-Gd@PGEAs with effective MRI functionality without adverse effects on gene transfection processes. These unique features could allow PGED-Gd@PGEA to become a competitive multifunctional gene delivery system. Figure 8 Linear fitting of the inverse T 1 and the T 1 -weighted MR images of (a) PGED-Gd@PGEA1 solutions and (b) C6 and Hep G2 cells treated with PGED-Gd@PGEA1 at different Gd concentrations.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Cancer statistics", "authors": [{"first": "R", "middle": [], "last": "Siegel", "suffix": ""}, {"first": "D", "middle": [], "last": "Naishadham", "suffix": ""}, {"first": "A", "middle": [], "last": "Jemal", "suffix": ""}], "year": 2012, "venue": "CA Cancer J. Clin", "link": null}, "BIBREF1": {"title": "Enzyme-responsive cell-penetrating peptide conjugated mesoporous silica quantum dot nanocarriers for controlled release of nucleus-targeted drug molecules and real-time intracellular fluorescence imaging of tumor cells", "authors": [{"first": "J", "middle": [], "last": "Li", "suffix": ""}, {"first": "F", "middle": [], "last": "Liu", "suffix": ""}, {"first": "Q", "middle": [], "last": "Shao", "suffix": ""}, {"first": "Y", "middle": [], "last": "Min", "suffix": ""}, {"first": "M", "middle": [], "last": "Costa", "suffix": ""}, {"first": "E", "middle": ["K L"], "last": "Yeow", "suffix": ""}, {"first": "B", "middle": [], "last": "Xing", "suffix": ""}], "year": 2014, "venue": "Adv. Healthc. Mater", "link": "4683185"}, "BIBREF2": {"title": "Nonviral vectors for gene delivery", "authors": [{"first": "M", "middle": ["A"], "last": "Mintzer", "suffix": ""}, {"first": "E", "middle": ["E"], "last": "Simanek", "suffix": ""}], "year": 2008, "venue": "Chem. Rev", "link": "82875295"}, "BIBREF3": {"title": "Polymer vectors via controlled/living radical polymerization for gene delivery", "authors": [{"first": "F", "middle": ["J"], "last": "Xu", "suffix": ""}, {"first": "W", "middle": ["T"], "last": "Yang", "suffix": ""}], "year": 2011, "venue": "Prog. Polym. Sci", "link": "98119828"}, "BIBREF4": {"title": "Gene expression, biodistribution, and pharmacoscintigraphic evaluation of chondroitin sulfate-PEI nano-constructs mediated tumor gene therapy", "authors": [{"first": "A", "middle": [], "last": "Pathak", "suffix": ""}, {"first": "P", "middle": [], "last": "Kumar", "suffix": ""}, {"first": "K", "middle": [], "last": "Chuttani", "suffix": ""}, {"first": "S", "middle": [], "last": "Jain", "suffix": ""}, {"first": "A", "middle": ["K"], "last": "Mishra", "suffix": ""}, {"first": "S", "middle": ["P"], "last": "Vyas", "suffix": ""}, {"first": "K", "middle": ["C"], "last": "Gupta", "suffix": ""}], "year": 2009, "venue": "ACS Nano", "link": "28185772"}, "BIBREF5": {"title": "Controlled Gene delivery by reduced graphene oxide \u2212 polyethylenimine nanocomposite", "authors": [{"first": "H", "middle": [], "last": "Kim", "suffix": ""}, {"first": "W", "middle": ["J"], "last": "Kim", "suffix": ""}], "year": 2014, "venue": "Small", "link": null}, "BIBREF6": {"title": "RGD targeting hyaluronic acid coating system for PEI-PBLG polycation gene carriers", "authors": [{"first": "H", "middle": ["Y"], "last": "Tian", "suffix": ""}, {"first": "L", "middle": [], "last": "Lin", "suffix": ""}, {"first": "J", "middle": [], "last": "Chen", "suffix": ""}, {"first": "X", "middle": ["S"], "last": "Chen", "suffix": ""}, {"first": "T", "middle": ["G"], "last": "Park", "suffix": ""}, {"first": "A", "middle": [], "last": "Maruyama", "suffix": ""}], "year": 2011, "venue": "J. Control. Release", "link": "7171208"}, "BIBREF7": {"title": "Tyroserleutide-based gene vector for suppressing VEGF expression in cancer therapy", "authors": [{"first": "H", "middle": ["Y"], "last": "Wang", "suffix": ""}, {"first": "W", "middle": ["J"], "last": "Yi", "suffix": ""}, {"first": "S", "middle": ["Y"], "last": "Qin", "suffix": ""}, {"first": "C", "middle": [], "last": "Li", "suffix": ""}, {"first": "R", "middle": ["X"], "last": "Zhuo", "suffix": ""}, {"first": "X", "middle": ["Z"], "last": "Zhang", "suffix": ""}], "year": 2012, "venue": "Biomaterials", "link": "5620574"}, "BIBREF8": {"title": "Copolymer of poly(ethylene glycol) and poly(L-lysine) grafting polyethylenimine through a reducible disulfide linkage for siRNA delivery", "authors": [{"first": "J", "middle": ["G"], "last": "Li", "suffix": ""}, {"first": "D", "middle": [], "last": "Cheng", "suffix": ""}, {"first": "T", "middle": ["H"], "last": "Yin", "suffix": ""}, {"first": "W", "middle": ["C"], "last": "Chen", "suffix": ""}, {"first": "Y", "middle": ["J"], "last": "Lin", "suffix": ""}, {"first": "J", "middle": ["F"], "last": "Chen", "suffix": ""}, {"first": "R", "middle": ["T"], "last": "Li", "suffix": ""}, {"first": "X", "middle": ["T"], "last": "Shuai", "suffix": ""}], "year": 2014, "venue": "Nanoscale", "link": "31313658"}, "BIBREF9": {"title": "Redox-cleavable star cationic PDMAEMA by arm-first approach of ATRP as a nonviral vector for gene delivery", "authors": [{"first": "F", "middle": ["Y"], "last": "Dai", "suffix": ""}, {"first": "P", "middle": [], "last": "Sun", "suffix": ""}, {"first": "Y", "middle": ["J"], "last": "Liu", "suffix": ""}, {"first": "W", "middle": ["G"], "last": "Liu", "suffix": ""}], "year": 2010, "venue": "Biomaterials", "link": "5068078"}, "BIBREF10": {"title": "A poly(L-lysine)-based hydrophilic star block copolymer as a protein nano carrier with facile encapsulation and ph-responsive release", "authors": [{"first": "Y", "middle": ["S"], "last": "Yan", "suffix": ""}, {"first": "D", "middle": ["X"], "last": "Wei", "suffix": ""}, {"first": "J", "middle": ["Y"], "last": "Li", "suffix": ""}, {"first": "J", "middle": ["H"], "last": "Zheng", "suffix": ""}, {"first": "G", "middle": ["G"], "last": "Shi", "suffix": ""}, {"first": "W", "middle": ["H"], "last": "Luo", "suffix": ""}, {"first": "Y", "middle": [], "last": "Pan", "suffix": ""}, {"first": "J", "middle": ["Z"], "last": "Wang", "suffix": ""}, {"first": "L", "middle": ["M"], "last": "Zhang", "suffix": ""}, {"first": "X", "middle": ["Y"], "last": "He", "suffix": ""}, {"first": "D", "middle": ["J"], "last": "Liu", "suffix": ""}], "year": 2012, "venue": "Acta. Biomater", "link": "44733737"}, "BIBREF11": {"title": "Odd-even effect of repeating amino-ethylene units in the side chain of N-substituted polyaspartamides on gene transfection profiles", "authors": [{"first": "H", "middle": [], "last": "Uchida", "suffix": ""}, {"first": "K", "middle": [], "last": "Miyata", "suffix": ""}, {"first": "M", "middle": [], "last": "Oba", "suffix": ""}, {"first": "T", "middle": [], "last": "Ishii", "suffix": ""}, {"first": "T", "middle": [], "last": "Suma", "suffix": ""}, {"first": "K", "middle": [], "last": "Itaka", "suffix": ""}, {"first": "N", "middle": [], "last": "Nishiyama", "suffix": ""}, {"first": "K", "middle": [], "last": "Kataoka", "suffix": ""}], "year": 2011, "venue": "J. Am. Chem. Soc", "link": "207069459"}, "BIBREF12": {"title": "Efficient poly(N-3-hydroxypropyl) as partamide-based carriers via ATRP for gene delivery", "authors": [{"first": "Y", "middle": [], "last": "Zhu", "suffix": ""}, {"first": "G", "middle": ["P"], "last": "Tang", "suffix": ""}, {"first": "F", "middle": ["J"], "last": "Xu", "suffix": ""}], "year": 2013, "venue": "ACS Appl. Mater. Interfaces", "link": "22565423"}, "BIBREF13": {"title": "Efficient transfer of genetic material into mammalian cells using starburst polyamidoamine dendrimers", "authors": [{"first": "J", "middle": ["F"], "last": "Kukowska-Latallo", "suffix": ""}, {"first": "A", "middle": ["U"], "last": "Bielinska", "suffix": ""}, {"first": "J", "middle": [], "last": "Johnson", "suffix": ""}, {"first": "R", "middle": [], "last": "Spindler", "suffix": ""}, {"first": "D", "middle": ["A"], "last": "Tomalia", "suffix": ""}, {"first": "J", "middle": ["R"], "last": "Baker", "suffix": ""}], "year": 1996, "venue": "Proc. Natl Acad. Sci. USA", "link": "40686720"}, "BIBREF14": {"title": "Well-defined poly(2-hydroxyl-3-(2-hydroxyethylamino)propyl methacrylate) vectors with low toxicity and high gene transfection efficiency", "authors": [{"first": "F", "middle": ["J"], "last": "Xu", "suffix": ""}, {"first": "M", "middle": ["Y"], "last": "Chai", "suffix": ""}, {"first": "W", "middle": ["B"], "last": "Li", "suffix": ""}, {"first": "Y", "middle": [], "last": "Ping", "suffix": ""}, {"first": "G", "middle": ["P"], "last": "Tang", "suffix": ""}, {"first": "W", "middle": ["T"], "last": "Yang", "suffix": ""}], "year": 2010, "venue": "Biomacromolecules", "link": "21073691"}, "BIBREF15": {"title": "Comparison of ethanolamine/ethylenediamine-functionalized poly(glycidylmethacrylate) for efficient gene delivery", "authors": [{"first": "F", "middle": ["J"], "last": "Xu", "suffix": ""}, {"first": "Y", "middle": [], "last": "Zhu", "suffix": ""}, {"first": "M", "middle": ["Y"], "last": "Chai", "suffix": ""}, {"first": "F", "middle": ["S"], "last": "Liu", "suffix": ""}], "year": 2011, "venue": "Acta Biomater", "link": "20402408"}, "BIBREF16": {"title": "A biocleavable pullulan-based vector via ATRP for liver cell-targeting gene delivery", "authors": [{"first": "X", "middle": ["C"], "last": "Yang", "suffix": ""}, {"first": "N", "middle": ["L"], "last": "Niu", "suffix": ""}, {"first": "N", "middle": ["N"], "last": "Zhao", "suffix": ""}, {"first": "C", "middle": [], "last": "Mao", "suffix": ""}, {"first": "F", "middle": ["J"], "last": "Xu", "suffix": ""}], "year": 2014, "venue": "Biomaterials", "link": "32905809"}, "BIBREF17": {"title": "The role of supramolecular chemistry in responsive vectors for gene delivery", "authors": [{"first": "C", "middle": ["M"], "last": "Lamanna", "suffix": ""}, {"first": "M", "middle": ["W"], "last": "Grinstaff", "suffix": ""}], "year": 2012, "venue": "", "link": "82732655"}, "BIBREF18": {"title": "Rational design of smart supramolecular assemblies for gene delivery, chemical challenges in the creation of artificial viruses", "authors": [{"first": "K", "middle": [], "last": "Miyata", "suffix": ""}, {"first": "N", "middle": [], "last": "Nishiyama", "suffix": ""}, {"first": "K", "middle": [], "last": "Kataoka", "suffix": ""}], "year": 2012, "venue": "Chem. Soc. Rev", "link": "29022577"}, "BIBREF19": {"title": "Cyclodextrin-based host-guest supramolecular nanoparticles for delivery: from design to applications", "authors": [{"first": "Q", "middle": ["D"], "last": "Hu", "suffix": ""}, {"first": "G", "middle": ["P"], "last": "Tang", "suffix": ""}, {"first": "P", "middle": ["K"], "last": "Chu", "suffix": ""}], "year": 2014, "venue": "Acc. Chem. Res", "link": "4805879"}, "BIBREF20": {"title": "Cyclodextrin-based gene delivery systems", "authors": [{"first": "C", "middle": ["O"], "last": "Mellet", "suffix": ""}, {"first": "J", "middle": ["M G"], "last": "Fernandez", "suffix": ""}, {"first": "J", "middle": [], "last": "Benito", "suffix": ""}], "year": 2011, "venue": "Chem. Soc. Rev", "link": "205764556"}, "BIBREF21": {"title": "Cyclodextrin-based supramolecular systems for drug delivery: recent progress and future perspective", "authors": [{"first": "J", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "P", "middle": ["X"], "last": "Ma", "suffix": ""}], "year": 2013, "venue": "Adv. Drug. Deliv. Rev", "link": "25550302"}, "BIBREF22": {"title": "Cyclodextrins in non-viral gene delivery", "authors": [{"first": "W", "middle": ["F"], "last": "Lai", "suffix": ""}], "year": 2014, "venue": "Biomaterials", "link": "12637670"}, "BIBREF23": {"title": "Supramolecular host \u2212 guest pseudo comb conjugates composed of multiple star polycations tied tunably with a linear polycation backbone for gene transfection", "authors": [{"first": "Y", "middle": [], "last": "Hu", "suffix": ""}, {"first": "M", "middle": ["Y"], "last": "Chai", "suffix": ""}, {"first": "W", "middle": ["T"], "last": "Yang", "suffix": ""}, {"first": "F", "middle": ["J"], "last": "Xu", "suffix": ""}], "year": 2013, "venue": "Bioconjug. Chem", "link": "19457945"}, "BIBREF24": {"title": "In vivo visualization of gene expression using magnetic resonance imaging", "authors": [{"first": "A", "middle": ["Y"], "last": "Louie", "suffix": ""}, {"first": "M", "middle": ["M"], "last": "H\u00fcber", "suffix": ""}, {"first": "E", "middle": ["T"], "last": "Ahrens", "suffix": ""}, {"first": "U", "middle": [], "last": "Rothb\u00e4cher", "suffix": ""}, {"first": "R", "middle": [], "last": "Moats", "suffix": ""}, {"first": "R", "middle": ["E"], "last": "Jacobs", "suffix": ""}, {"first": "S", "middle": ["E"], "last": "Fraser", "suffix": ""}, {"first": "T", "middle": ["J"], "last": "Meade", "suffix": ""}], "year": 2000, "venue": "Nat. Biotechnol", "link": "20213897"}, "BIBREF25": {"title": "Europium(III) DOTA-tetraamide complexes as redox-active MRI sensors", "authors": [{"first": "S", "middle": ["J"], "last": "Ratnakar", "suffix": ""}, {"first": "S", "middle": [], "last": "Viswana-Than", "suffix": ""}, {"first": "Z", "middle": [], "last": "Kovacs", "suffix": ""}, {"first": "A", "middle": ["K"], "last": "Jindal", "suffix": ""}, {"first": "K", "middle": ["N"], "last": "Green", "suffix": ""}, {"first": "A", "middle": ["D"], "last": "Sherry", "suffix": ""}], "year": 2012, "venue": "J. Am. Chem. Soc", "link": "207078344"}, "BIBREF26": {"title": "Gadolinium(III) chelates as MRI contrast agents: structure, dynamics, and applications", "authors": [{"first": "P", "middle": [], "last": "Caravan", "suffix": ""}, {"first": "J", "middle": ["J"], "last": "Ellison", "suffix": ""}, {"first": "T", "middle": ["J"], "last": "Mcmurry", "suffix": ""}, {"first": "R", "middle": ["B"], "last": "Lauffer", "suffix": ""}], "year": 1999, "venue": "Chem. Rev", "link": "87756"}, "BIBREF27": {"title": "Gd(III)-based contrast agents for MRI", "authors": [{"first": "S", "middle": [], "last": "Aime", "suffix": ""}, {"first": "M", "middle": [], "last": "Botta", "suffix": ""}, {"first": "E", "middle": [], "last": "Terreno", "suffix": ""}], "year": 2005, "venue": "Adv. Inorg. Chem", "link": "94727149"}, "BIBREF28": {"title": "New low molecular weight polycation-based nanoparticles for effective codelivery of pDNA and drug", "authors": [{"first": "Y", "middle": [], "last": "Zhao", "suffix": ""}, {"first": "B", "middle": [], "last": "Yu", "suffix": ""}, {"first": "H", "middle": [], "last": "Hu", "suffix": ""}, {"first": "Y", "middle": [], "last": "Hu", "suffix": ""}, {"first": "N", "middle": ["N"], "last": "Zhao", "suffix": ""}, {"first": "F", "middle": ["J"], "last": "Xu", "suffix": ""}], "year": 2014, "venue": "ACS Appl. Mater. Interfaces", "link": "206804279"}, "BIBREF29": {"title": "Two roles of guest and crosslinked degree on hydrosoluble \u03b2-cyclodextrin polymer electrorheological fluids", "authors": [{"first": "Z", "middle": [], "last": "Gao", "suffix": ""}, {"first": "X", "middle": [], "last": "Zhao", "suffix": ""}], "year": 2004, "venue": "Polymer", "link": "94293567"}, "BIBREF30": {"title": "A polymeric fastener can easily functionalize liposome surfaceswith gadoliniu m for enhanced magnetic resonance imaging", "authors": [{"first": "C", "middle": ["E"], "last": "Smith", "suffix": ""}, {"first": "A", "middle": [], "last": "Shkumatov", "suffix": ""}, {"first": "S", "middle": ["G"], "last": "Withers", "suffix": ""}, {"first": "B", "middle": [], "last": "Yang", "suffix": ""}, {"first": "J", "middle": ["F"], "last": "Glockner", "suffix": ""}, {"first": "S", "middle": [], "last": "Misra", "suffix": ""}, {"first": "E", "middle": ["J"], "last": "Roy", "suffix": ""}, {"first": "C", "middle": ["H"], "last": "Wong", "suffix": ""}, {"first": "S", "middle": ["C"], "last": "Zimmerman", "suffix": ""}, {"first": "H", "middle": [], "last": "Kong", "suffix": ""}], "year": 2013, "venue": "ACS Nano", "link": null}, "BIBREF31": {"title": "Bioreducible POSS-cored star-shaped polycation for efficient gene delivery", "authors": [{"first": "Y", "middle": ["Y"], "last": "Yang", "suffix": ""}, {"first": "X", "middle": [], "last": "Wang", "suffix": ""}, {"first": "Y", "middle": [], "last": "Hu", "suffix": ""}, {"first": "H", "middle": [], "last": "Hu", "suffix": ""}, {"first": "D", "middle": [], "last": "Wu", "suffix": ""}, {"first": "F", "middle": ["J"], "last": "Xu", "suffix": ""}], "year": 2014, "venue": "ACS Appl. Mater. Interfaces", "link": "39175408"}, "BIBREF32": {"title": "Copolymers of poly(ethylene glycol), poly((2-dimethyl amino)ethyl methacrylate) and poly(2-hydroxyethyl methacrylate) from consecutive atom transfer radical polymerizations for nonviral gene delivery", "authors": [{"first": "F", "middle": ["J"], "last": "Xu", "suffix": ""}, {"first": "H", "middle": ["Z"], "last": "Li", "suffix": ""}, {"first": "J", "middle": [], "last": "Li", "suffix": ""}, {"first": "Z", "middle": ["X"], "last": "Zhang", "suffix": ""}, {"first": "E", "middle": ["T"], "last": "Kang", "suffix": ""}, {"first": "G", "middle": ["N"], "last": "Pentablock", "suffix": ""}], "year": 2008, "venue": "Biomaterials", "link": "9453297"}, "BIBREF33": {"title": "-dimethyl amino)ethyl methacrylate) by combination of ATRP and Click chemistry", "authors": [{"first": "Y", "middle": [], "last": "Zhu", "suffix": ""}, {"first": "X", "middle": [], "last": "Zheng", "suffix": ""}, {"first": "B", "middle": [], "last": "Yu", "suffix": ""}, {"first": "W", "middle": [], "last": "Yang", "suffix": ""}, {"first": "N", "middle": [], "last": "Zhao", "suffix": ""}, {"first": "F", "middle": ["J"], "last": "Xu", "suffix": ""}], "year": 2014, "venue": "ethanolamine-functionalized poly(glycidyl methacrylate), and poly", "link": null}, "BIBREF34": {"title": "Versatile types of polysaccharide-based supramolecular polycation/pDNA nanoplexes for gene delivery", "authors": [{"first": "Y", "middle": [], "last": "Hu", "suffix": ""}, {"first": "N", "middle": [], "last": "Zhao", "suffix": ""}, {"first": "B", "middle": [], "last": "Yu", "suffix": ""}, {"first": "F", "middle": [], "last": "Liu", "suffix": ""}, {"first": "F", "middle": ["J"], "last": "Xu", "suffix": ""}], "year": 2014, "venue": "Nanoscale", "link": "23821256"}, "BIBREF35": {"title": "Cationic micelles self-assembled from cholesterol-conjugated oligopeptides as an efficient gene delivery vector", "authors": [{"first": "X", "middle": ["D"], "last": "Guo", "suffix": ""}, {"first": "F", "middle": [], "last": "Tandiono", "suffix": ""}, {"first": "N", "middle": [], "last": "Wiradharma", "suffix": ""}, {"first": "D", "middle": [], "last": "Khor", "suffix": ""}, {"first": "C", "middle": ["G"], "last": "Tan", "suffix": ""}, {"first": "M", "middle": [], "last": "Khan", "suffix": ""}, {"first": "Y", "middle": [], "last": "Qian", "suffix": ""}, {"first": "Y", "middle": ["Y"], "last": "Yang", "suffix": ""}], "year": 2008, "venue": "Biomaterials", "link": "671947"}, "BIBREF36": {"title": "Enhanced gene transfection efficiency of PDMAEMA by incorporating hydrophobic hyperbranched polymer cores: effect of degree of branching", "authors": [{"first": "S", "middle": [], "last": "Yu", "suffix": ""}, {"first": "J", "middle": [], "last": "Chen", "suffix": ""}, {"first": "R", "middle": [], "last": "Dong", "suffix": ""}, {"first": "Y", "middle": [], "last": "Su", "suffix": ""}, {"first": "B", "middle": [], "last": "Ji", "suffix": ""}, {"first": "Y", "middle": [], "last": "Zhou", "suffix": ""}, {"first": "X", "middle": [], "last": "Zhu", "suffix": ""}, {"first": "D", "middle": [], "last": "Yan", "suffix": ""}], "year": 2012, "venue": "Polym. Chem", "link": "97385612"}, "BIBREF37": {"title": "Cyclodextrin-based supramolecular architectures: Syntheses, structures, and applications for drug and gene delivery", "authors": [{"first": "J", "middle": [], "last": "Li", "suffix": ""}, {"first": "X", "middle": ["J"], "last": "Loh", "suffix": ""}], "year": 2008, "venue": "Adv. Drug. Deliv. Rev", "link": "23285968"}, "BIBREF38": {"title": "A highly fluorescent cationic bifunctional conjugate", "authors": [{"first": "X", "middle": ["C"], "last": "Yang", "suffix": ""}, {"first": "M", "middle": ["Y"], "last": "Chai", "suffix": ""}, {"first": "Y", "middle": [], "last": "Zhu", "suffix": ""}, {"first": "W", "middle": ["T"], "last": "Yang", "suffix": ""}, {"first": "F", "middle": ["J"], "last": "Xu", "suffix": ""}], "year": 2012, "venue": "J. Mater. Chem", "link": "96203707"}, "BIBREF39": {"title": "Series of new \u03b2-cyclodextrin-cored starlike carriers for gene delivery", "authors": [{"first": "R", "middle": ["Q"], "last": "Li", "suffix": ""}, {"first": "Y", "middle": ["L"], "last": "Niu", "suffix": ""}, {"first": "N", "middle": ["N"], "last": "Zhao", "suffix": ""}, {"first": "B", "middle": [], "last": "Yu", "suffix": ""}, {"first": "C", "middle": [], "last": "Mao", "suffix": ""}, {"first": "F", "middle": ["J"], "last": "Xu", "suffix": ""}], "year": 2014, "venue": "ACS Appl. Mater. Interfaces", "link": "19692409"}, "BIBREF40": {"title": "HCV cDNA transfection to HepG2 cells", "authors": [{"first": "N", "middle": [], "last": "Hiramatsu", "suffix": ""}, {"first": "S", "middle": [], "last": "Dash", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Gerber", "suffix": ""}], "year": 1997, "venue": "J. Viral. Hepat", "link": "35367681"}, "BIBREF41": {"title": "Functionalization of chitosan via atom transfer radical polymerization for gene delivery", "authors": [{"first": "Y", "middle": [], "last": "Ping", "suffix": ""}, {"first": "C.-D", "middle": [], "last": "Liu", "suffix": ""}, {"first": "G.-P", "middle": [], "last": "Tang", "suffix": ""}, {"first": "J.-S", "middle": [], "last": "Li", "suffix": ""}, {"first": "J", "middle": [], "last": "Li", "suffix": ""}, {"first": "W.-T", "middle": [], "last": "Yang", "suffix": ""}, {"first": "F.-J", "middle": [], "last": "Xu", "suffix": ""}], "year": 2010, "venue": "Adv. Funct. Mater", "link": "97902332"}, "BIBREF42": {"title": "Multimodal MRI contrast agents", "authors": [{"first": "L", "middle": [], "last": "Frullano", "suffix": ""}, {"first": "T", "middle": [], "last": "Meade", "suffix": ""}], "year": 2007, "venue": "J Biol. Inorg. Chem", "link": "22298268"}}, "ref_entries": {"FIGREF0": {"text": "General procedures for the preparation of different supramolecule-based polyplexes.", "type": "figure"}, "FIGREF1": {"text": "Electrophoretic mobility retardation assay of pDNA in the polyplexes of (a) PGED-CD, (b) PGED-CD-Gd, (c) Ad-PGEA1, (d) Ad-PGEA2, (e) PGED@PGEA1, (f) PGED@PGEA2, (g) PGED-Gd@PGEA1 and (h) PGED-Gd@PGEA2 at various N/P ratios. Biomedical applications of polycations Y Zhao et al reactions between the epoxy group of CD-EP and the amine group of PGED, producing PGED-CD. Based on the 1 H NMR spectrum of PGED-CD (Supplementary", "type": "figure"}, "FIGREF2": {"text": "(a) Particle size and (b) \u03b6-potential of the polymer/pDNA complexes at various N/P ratios.", "type": "figure"}, "FIGREF3": {"text": "AFM images of (a) Ad-PGEA1/pDNA, (b) PGED@PGEA1/pDNA and (c) PGED-Gd@PGEA1/pDNA complexes at the N/P ratio of 15.", "type": "figure"}, "FIGREF4": {"text": "Cytotoxicity of the polymer/pDNA complexes at different N/P ratios in (a) C6 and (b) Hep G2 cells. (mean \u00b1 s.d., n = 6, *Po0.05).", "type": "figure"}, "TABREF0": {"text": "Biomedical applications of polycations Y Zhao et alJose, CA, USA), were amplified in Escherichia coli and purified according to the supplier's protocol (Qiagen GmbH, Hilden, Germany).", "type": "table"}}}
{"paper_id": "94552339", "_pdf_hash": "7dc1bf397fb5aae2fa07e2697ba6f0237a411bb6", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Titanium, its occurrences, chemistry and teohnology", "authors": [{"first": "Jelks", "middle": [], "last": "Baak8dale", "suffix": ""}], "year": 1949, "venue": "", "link": null}, "BIBREF1": {"title": "Applied inorganic analysis", "authors": [{"first": "", "middle": ["L"], "last": "1iii", "suffix": ""}, {"first": "W", "middle": ["P"], "last": "Diwm", "suffix": ""}, {"first": "G", "middle": ["E F"], "last": "Ltnfdell", "suffix": ""}, {"first": "", "middle": [], "last": "1mb", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF2": {"title": "Technical gas analysis", "authors": [{"first": "Gzorge", "middle": [], "last": "Jul'fgz", "suffix": ""}, {"first": "H", "middle": ["R"], "last": "Amsleil", "suffix": ""}], "year": 1934, "venue": "", "link": null}, "BIBREF3": {"title": "Determination of titanium and iron", "authors": [{"first": "B", "middle": ["A"], "last": "8hippy", "suffix": ""}], "year": 1949, "venue": "Anal Chern", "link": "96391263"}}, "ref_entries": {}}
{"paper_id": "94553452", "_pdf_hash": "9e7430a4a367225a96f530e422f0e6f9b540ccea", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "A rate equation for the nocturnal boundary-layer height", "authors": [{"first": "F", "middle": ["T M"], "last": "Nieuwstadt", "suffix": ""}, {"first": "H", "middle": [], "last": "Tennekes", "suffix": ""}], "year": 1981, "venue": "J. Atmos. Sci", "link": "124246661"}, "BIBREF1": {"title": "ECBilt: A dynamic alternative to mixed boundary conditions in ocean models", "authors": [{"first": "J", "middle": ["D R J"], "last": "Opsteegh", "suffix": ""}, {"first": "F", "middle": ["M"], "last": "Haarsma", "suffix": ""}, {"first": "", "middle": [], "last": "Selten", "suffix": ""}], "year": 1998, "venue": "Tellus", "link": "123099232"}, "BIBREF2": {"title": "Representation of the canopy conductance in modelling the surface energy budget for low vegetation", "authors": [{"first": "R", "middle": ["J"], "last": "Ronda", "suffix": ""}, {"first": "H", "middle": ["A R"], "last": "De Bruin", "suffix": ""}, {"first": "A", "middle": ["A M"], "last": "Holtslag", "suffix": ""}], "year": 2001, "venue": "J. Appl. Meteor", "link": "122584099"}, "BIBREF3": {"title": "A model for the dynamics of the inversion above a convective boundary layer", "authors": [{"first": "H", "middle": [], "last": "Tennekes", "suffix": ""}], "year": 1973, "venue": "J. Atmos. Sci", "link": "121611079"}, "BIBREF4": {"title": "On the bulk parameterization of surface fluxes for various conditions and parameter ranges", "authors": [{"first": "B", "middle": ["J J M"], "last": "Van Den Hurk", "suffix": ""}, {"first": "A", "middle": ["A M"], "last": "Holtslag", "suffix": ""}], "year": 1997, "venue": "Boundary-Layer Meteor", "link": "125284463"}, "BIBREF5": {"title": "Evaluation and model impacts of alternative boundary-layer heights formulations", "authors": [{"first": "D", "middle": ["H P"], "last": "Vogelezang", "suffix": ""}, {"first": "A", "middle": ["A M"], "last": "Holtslag", "suffix": ""}], "year": 1996, "venue": "BoundaryLayer Meteor", "link": "121577506"}}, "ref_entries": {}}
{"paper_id": "94555004", "_pdf_hash": "5941fb455884438203153334e4d00032b44b31db", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "94556881", "_pdf_hash": "5c34f301b381e900a80daa7c9baa37dbb00aaa9b", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Review of founding nr.4,1993,s.119-124, (in polish Syntetyczne \u017cu\u017cle pokrywaj\u0105co-rafinuj\u0105ce dla stop\u00f3w miedzi", "authors": [{"first": "C", "middle": [], "last": "Adamski", "suffix": ""}, {"first": "S", "middle": [], "last": "Rzadkosz", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF1": {"title": "The Influence of slag refinement of copper alloys on course of fusion process", "authors": [{"first": "A", "middle": ["W"], "last": "Byda\u0142ek", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF2": {"title": "\u017cu\u017clowej rafinacji stop\u00f3w miedzi na przebieg procesu topienia", "authors": [], "year": 2000, "venue": "", "link": null}, "BIBREF3": {"title": "Assessing the refining abilities of slag by modeling real process of metal melting", "authors": [{"first": "A", "middle": ["W"], "last": "Byda\u0142ek", "suffix": ""}], "year": 2001, "venue": "Journal TAC", "link": null}, "BIBREF4": {"title": "Determination of CO 2 contents in slag and molten salts by B 2 O 3 fusion and KBF 4 fusion methods", "authors": [{"first": "", "middle": [], "last": "Koichorok", "suffix": ""}, {"first": "H", "middle": [], "last": "Yasuhiko", "suffix": ""}], "year": 1988, "venue": "Trans. JIM", "link": "98669634"}, "BIBREF5": {"title": "Dissolved of temperature, alkalinity and stickiness the slagson the alkalic in slag", "authors": [{"first": "J", "middle": [], "last": "Mr\u00f3z", "suffix": ""}, {"first": "R", "middle": [], "last": "Fa\u0142ek", "suffix": ""}, {"first": "M", "middle": [], "last": "Dzienniak", "suffix": ""}], "year": 2002, "venue": "polish Wp\u0142yw temperatury, zasadowo\u015bci i lepko\u015bci zuzla na ilo\u015b\u0107 alkali\u00f3w rozpuszczonych w \u017cu\u017clu, HutnikWiadomo\u015bci Hutnicze", "link": null}, "BIBREF6": {"title": "Organiczieskije ekstragenty dla miedi", "authors": [{"first": "A", "middle": ["W"], "last": "Radusziew", "suffix": ""}, {"first": "A", "middle": ["J"], "last": "Gusiew", "suffix": ""}, {"first": "S", "middle": ["S"], "last": "Nabojczienko", "suffix": ""}], "year": 2002, "venue": "Tja\u017ce\u0142yje Cvet. Mieta\u0142\u0142y", "link": null}, "BIBREF7": {"title": "Superficial phenomena in casting processes\", (in polish \"Zjawiska powierzchniowe w procesach odlewniczych", "authors": [{"first": "M", "middle": [], "last": "Szweycer", "suffix": ""}], "year": 1996, "venue": "", "link": null}, "BIBREF8": {"title": "Thermodynamic studies of liquid C-S-O system", "authors": [{"first": "O", "middle": [], "last": "Toshio", "suffix": ""}, {"first": "T", "middle": [], "last": "Yoichi", "suffix": ""}, {"first": "F", "middle": [], "last": "Yutaka", "suffix": ""}, {"first": "O", "middle": [], "last": "Katsutoshi", "suffix": ""}], "year": 1987, "venue": "Trans. JIM", "link": null}, "BIBREF9": {"title": "The equilibrium partitioning of titanium between Ti 3+ and Ti 4+ valence states in CaO-SiO 2 -TiO slag", "authors": [{"first": "G", "middle": [], "last": "Tranell", "suffix": ""}, {"first": "O", "middle": [], "last": "Ostovski", "suffix": ""}, {"first": "S", "middle": [], "last": "Jahanhahi", "suffix": ""}], "year": 2002, "venue": "Metallurgical and Materials Trans. B", "link": null}, "BIBREF10": {"title": "Physicochemical properties of molten salts, United Stats Steel Corporation", "authors": [{"first": "E", "middle": ["T"], "last": "Turkdogan", "suffix": ""}], "year": 1980, "venue": "", "link": null}, "BIBREF11": {"title": "The influence of Marangoni effect on speed the metallurgical processes", "authors": [{"first": "J", "middle": [], "last": "Wypartowicz", "suffix": ""}, {"first": "K", "middle": [], "last": "Pytel", "suffix": ""}], "year": 2002, "venue": "Hutnik-Wiadomo\u015bci Hutnicze", "link": null}, "BIBREF12": {"title": "The perspective of use of phosphorans slags in founding of copper and her melts", "authors": [{"first": "A", "middle": ["W"], "last": "Byda\u0142ek", "suffix": ""}], "year": 1997, "venue": "Przegl\u0105d Odlewnictwa", "link": null}, "BIBREF13": {"title": "The influence of temperature on propriety the slags in processes of fusion of copper alloys", "authors": [{"first": "A", "middle": ["W"], "last": "Byda\u0142ek", "suffix": ""}], "year": 2003, "venue": "The Archiwum of Technologic of Machines and Automation", "link": null}, "BIBREF14": {"title": "The thermal analysis of the carbides slags solutions", "authors": [{"first": "A", "middle": ["W"], "last": "Byda\u0142ek", "suffix": ""}], "year": 1995, "venue": "Journal of Thermal Analysis", "link": null}, "BIBREF15": {"title": "Assessing the refining abilities of slags by modelling a real process of metal", "authors": [{"first": "A", "middle": ["W"], "last": "Byda\u0142ek", "suffix": ""}], "year": "", "venue": "Journal of Thermal Analysis", "link": "138111016"}}, "ref_entries": {}}
{"paper_id": "94559152", "_pdf_hash": "dd032c803a0a823ac9daf2b812aca7fd1367e427", "abstract": [], "body_text": [{"section": "", "text": "studies to evaluate donor substrates that offer different remediation strategies for DNAPLs as well as studies on toxicity to different steps in the dehalogenation process by PCE and intermediate degradation products (Environ. Sci. Technol., 2002, 36, 3400. We have found that the presence of NAPL and the competition among many different types of bacteria makes it difficult to predict the performance of enhanced dissolution. For example, the transport of compounds may be retarded to different degrees at NAPL zones. The composition of PCE NAPL might be significantly changed due to the partitioning back of dehalogenation products. It is important to gain a general understanding of the behavior of this complex microbial NAPL system using numerical modeling. Progress on this aspect has been accepted for publication recently, and is available on the web (Jour. Contaminant Hydrology, In Press). With a good numerical model, the responses of such a system using different substrate delivery methods can be quickly evaluated; thus, it is possible to optimize the performance of a particular method before conducting actual experiments. One difficulty in modeling the biological reactions under dual transverse mixing is that high reaction rates occur in small regions (<0.2cm); therefore, extremely fine grids are required to correctly model the behaviors of the system. Because our goal is to stimulate a high PCE transformation rate exclusively near DNAPLs, detailed modeling is required to understand the extent of bio-enhanced DNAPL destruction and the dynamics of microbial communities around DNAPLs. A new manuscript directed towards this aspect is underway. One critical limiting factor for enhanced DNAPL dissolution is the toxicity of reaction end products, particularly cDCE. Experimental studies to determine the nature and extent of cDCE toxicity to reductive dehalogenation are also underway.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Research under objective two has focused on the natural enzyme haloalkane dehalogenase A (DhlA), which is capable of hydrolytically dehalogenating short-chain haloalkanes such as 1,2 dichloroethane (1,2 DCA). Directed evolution experiments with DhlA are currently underway with the goal that functional mutants generated will provide a greater understanding of the molecular mechanism of hydrolytic dehalogenation as well as the evolution of environmentally important enzymes. Specifically, isolation of DhlA variants that are capable of dehalogenating structurally similar EPA priority pollutants such as 1,1,1 Trichloroethane (1,1,1 TCA) and 1,1,2 Trichloroethane (1,1,2 TCA) will result in immediate applicability and also guide the future design of synthetic catalysts for dehalogenation. We have successfully established the several DNA shuffling protocols in our laboratory and demonstrated the generating of recombinants from a number of parent dehalogenase genes. In our expression experiments using the generated diversity of dhlA alleles, we noticed that a reduced specific activity towards 1,2 DCA, even with the wild type allele. We examined whether protein folding might be a limiting step in our expression and subsequent screening conditions. Protein misfolding can lead to a high fraction of inactive protein and, thereby, decrease the specific activity of DhlA towards the test substrate. We explored the co-expression of our library in strains with the chaperonins GroEL from E. coli. The groEL genes were carried on a plasmid different from the dhlA containing petBlue-1, induced simultaneously with the dhlA alleles, and screened for activity. We discovered a significant improvement in specific activity in clones co-expressing groEL. In conjunction with our pH indicator-based screen, we can now detect small changes in specific activity in clones from our library. Currently, we are employing this modified experimental system towards detecting small changes in substrate specificity of DhlA. We feel we are making excellent progress towards our goal, and will continue with this approach during the coming year of study.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Research under objective 3 is aimed at determining potential cell components in Pseudomonas stuzeri KC that facilitate the transformation of carbon tetrachloride into carbon dioxide and nonvolatile products, without chloroform formation. This is a unique detoxification reaction mediated by the secreted molecule pyridine-2,6-(bis)thiocarboxylate (PDTC) when it is chelated to copper. Previously we reported on the use of surface enhanced laser desorption ionization time-of-flight mass spectrometry (SELDI-MS) to identify and size cellular components involved in the transformation. We continued those efforts over this past year. Work by Dybas et al. (1995) demonstrated that addition of micromolar levels of ferric iron to an actively transforming culture inhibits CT transformation activity, but the level of iron required to inhibit CT transformation was more than 100-fold higher for washed cells reconstituted with a 10,000-Da supernatant filtrate. Thus, the inhibitory effects of iron are due largely to a supernatant factor or factors with a molecular weight greater than 10,000 Da. We hypothesize that this factor(s) is a protein that binds with ferric iron and possibly to the PDTC-Cu complex. Data from proteinase-treated culture dialysate indicates that this factor consists of one or more proteins. Specific binding assays based on binding interactions of proteins to surfaces containing iron, copper, and nickel were used along with SELDI-MS to identify supernatant proteins that may interact with PDTC-bound metals, and the molecular weights of these proteins were determined. The results indicate that several supernatant proteins bind specifically to surface-bound ferric iron, copper, and nickel. SDS-PAGE gel results showed proteins with sizes that align with those observed in the SELDI-MS spectra. We are currently isolating and sequencing these proteins. Once the sequences are known, we expect to be able to determine the protein functions and to develop an overall model of extracellular processes involved in CT transformation.", "cite_spans": [], "ref_spans": []}, {"section": "Planned Activities", "text": "The numerical model of biologically enhanced DNAPL dissolution is further being developed to better determine the important processes involved, and experimental studies are being conducted to determine the toxicity of cDCE to dehalogenation. We will continue the research to obtain functional mutants that will help better understand hydrolytic dehalogenation. Efforts will continue towards defining the protein(s) that binds to PDTC-Cu.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "SELDI-MS Characterization of Extracellular Proteins Involved in Carbon Tetrachloride Transformation by Pseudomonas stutzeri KC, Abstract", "authors": [{"first": "Q", "middle": ["S"], "last": "Fu", "suffix": ""}, {"first": "S", "middle": ["K"], "last": "Hobbs", "suffix": ""}, {"first": "G", "middle": [], "last": "Shi", "suffix": ""}, {"first": "M", "middle": ["D"], "last": "Bednarski", "suffix": ""}, {"first": "Criddle", "middle": ["C S"], "last": "Washington", "suffix": ""}, {"first": "M", "middle": [], "last": "Chu", "suffix": ""}, {"first": "P", "middle": ["K"], "last": "Kitanidis", "suffix": ""}, {"first": "P", "middle": ["L"], "last": "Mccarty", "suffix": ""}], "year": 2003, "venue": "Press. Corrected Proof now available on the", "link": "83010499"}, "BIBREF1": {"title": "Biologically Enhanced Dissolution of Tetrachloroethene DNAPL", "authors": [{"first": "Y", "middle": [], "last": "Yang", "suffix": ""}, {"first": "P", "middle": ["L"], "last": "Mccarty", "suffix": ""}], "year": 2000, "venue": "Environmental Science & Technology", "link": "93510245"}, "BIBREF2": {"title": "Comparison of Donor Substrates for Biologically Enhanced Tetrachloroethene (PCE) DNAPL Dissolution", "authors": [{"first": "Y", "middle": [], "last": "Yang", "suffix": ""}, {"first": "P", "middle": ["L"], "last": "Mccarty", "suffix": ""}], "year": 2002, "venue": "Environmental Science & Technology", "link": null}}, "ref_entries": {}}
{"paper_id": "159350887", "_pdf_hash": "ecc4270ee451a249dcd41e9f86bb954b79367bf4", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Ministry of External Affairs -Government of India", "authors": [{"first": "A", "middle": [], "last": "Mushtaq", "suffix": ""}, {"first": "", "middle": [], "last": "Kaw", "suffix": ""}], "year": 2017, "venue": "Central Asia in Retrospect and Prospect (Readworthy Publications Pvt Ltd: 2010)", "link": null}, "BIBREF1": {"title": "Ministry of External Affairs -Government of India", "authors": [], "year": 2017, "venue": "", "link": null}, "BIBREF2": {"title": "Central Asia is best place to host centenary of Indian cinema next year", "authors": [{"first": "Sanjay", "middle": [], "last": "Sharmal", "suffix": ""}], "year": 2012, "venue": "", "link": null}, "BIBREF3": {"title": "Bollywood calling: the fall of Uzbekistani cinema", "authors": [{"first": "Maha", "middle": [], "last": "Mussadaq", "suffix": ""}], "year": 2011, "venue": "", "link": null}, "BIBREF4": {"title": "Ministry of External Affairs -Government of India, last modified", "authors": [], "year": 2013, "venue": "", "link": null}, "BIBREF5": {"title": "Historical and cultural links between Kyrgyzstan and India", "authors": [{"first": "U", "middle": [], "last": "Orakbayeva", "suffix": ""}, {"first": "", "middle": [], "last": "Zh", "suffix": ""}, {"first": "", "middle": [], "last": "Medeubayeva", "suffix": ""}], "year": 2016, "venue": "", "link": null}, "BIBREF7": {"title": "Ministry of External Affairs -Government of India", "authors": [], "year": 2016, "venue": "", "link": null}, "BIBREF8": {"title": "India-Kyrgyzstan relations: future prospects and challenges", "authors": [{"first": "", "middle": [], "last": "Subhash Kumar Baitha", "suffix": ""}], "year": 2015, "venue": "International Journal of Applied Social Science", "link": null}, "BIBREF9": {"title": "Ministry of External Affairs -Government of India, last modified", "authors": [], "year": 2016, "venue": "Ministry of Culture -Government of India", "link": null}, "BIBREF10": {"title": "Ministry of External Affairs -Government of India", "authors": [], "year": 2016, "venue": "Ministry of External Affairs -Government of India, last modified 2013", "link": null}, "BIBREF11": {"title": "India-Kyrgyzstan relations: future prospects and challenges", "authors": [{"first": "", "middle": [], "last": "Subhash Kumar Baitha", "suffix": ""}], "year": 2015, "venue": "International Journal of Applied Social Science", "link": null}, "BIBREF12": {"title": "Historical and cultural links between Kyrgyzstan and India", "authors": [{"first": "U", "middle": [], "last": "Orakbayeva", "suffix": ""}, {"first": "", "middle": [], "last": "Zh", "suffix": ""}, {"first": "", "middle": [], "last": "Medeubayeva", "suffix": ""}], "year": 2016, "venue": "", "link": null}, "BIBREF14": {"title": "Joint statement between Turkmenistan and India during the prime minister's visit to Turkmenistan", "authors": [], "year": 2015, "venue": "", "link": null}, "BIBREF15": {"title": "Turkey\u00b4s Relations With Central Asian Republics", "authors": [], "year": 2018, "venue": "", "link": null}, "BIBREF16": {"title": "Iran provides financial and technical assistance to the offices of Iranian Studies, which exist in many Universities of the region. According to the agreement between the Eurasian National University (Kazakhstan) and the Tabatabai University (Iran), the office of Kazakh studies is planned to be opened in the Tabatabai University. 77 Days of culture are held with the screening of Iranian films and 74 \"About us", "authors": [{"first": "", "middle": [], "last": "Ibid", "suffix": ""}], "year": 2018, "venue": "Cultural representation of the Islamic Republic of Iran in", "link": null}, "BIBREF18": {"title": "Cultural and other relation -Mapping Central Asia's relations with other Asian states", "authors": [], "year": "", "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "159352431", "_pdf_hash": "ee8423d68aa15e8fe348ab62a9382e4036c8d7a2", "abstract": [], "body_text": [], "bib_entries": {"BIBREF1": {"title": "Garrow and Fenton's Law of Personal Property in New Zealand (LexisNexis NZ", "authors": [{"first": "Roger", "middle": [], "last": "Fenton", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF2": {"title": "Angelakis Shipping Co SA v Compagnie National Algerienne de Navigation; The Attika Hope", "authors": [{"first": "", "middle": [], "last": "G &amp; N", "suffix": ""}], "year": 1988, "venue": "", "link": null}, "BIBREF6": {"title": "Annangel Glory Compania Naviera SA v M Golodetz Ltd & Ors; The Annangel Glory", "authors": [], "year": 1988, "venue": "", "link": null}, "BIBREF7": {"title": "Lloyd's Rep 45 (QB)", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF14": {"title": "10 years of Personal Property Securities Act in NZ: Lessons and Trends' (Paper presented at Personal Property Security Law Conference", "authors": [{"first": "Michael", "middle": [], "last": "Arthur", "suffix": ""}], "year": 2001, "venue": "", "link": null}, "BIBREF16": {"title": "See Personal Property Securities Act 1999 (NZ) s 23 and Personal Property Securities Act", "authors": [], "year": 2009, "venue": "", "link": null}, "BIBREF17": {"title": "Personal Property Securities Act 1999 (NZ) s 16 ('personal property')", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF20": {"title": "Strategic Finance Limited v Bridgman & Ors (in rec and in liq", "authors": [], "year": 2013, "venue": "", "link": null}, "BIBREF24": {"title": "Ibid s 16 ('security agreement')", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF25": {"title": "Ibid s 16 ('purchase money security interest')", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF26": {"title": "Personal Property Securities Act 1999 (NZ) s 66(a)", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF27": {"title": "Ibid s 66(b)", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF28": {"title": "Ibid s 66(b)", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF29": {"title": "Security over Receivables: an International Handbook", "authors": [{"first": "Mark", "middle": [], "last": "Yarnell", "suffix": ""}, {"first": "Richard", "middle": [], "last": "May", "suffix": ""}], "year": 2008, "venue": "", "link": null}, "BIBREF30": {"title": "In New Zealand preferential claims are set out in the Companies Act 1993 (NZ), schedule 8, clause 1. These claims include liquidator's fee, unpaid PAYE and GST to Inland Revenue, and unpaid wages of employees. These claims have priority over even secured creditors with a security interest in a company's accounts receivable. A secured creditor's", "authors": [], "year": "", "venue": "A shipowner dealing with a charterer in liquidation must be wary of preferential creditor regimes", "link": null}, "BIBREF32": {"title": "Part IV, sections 92 -107 relating to the registration of charges on companies' property has not been brought into effect in accordance with s", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF33": {"title": "United Kingdom Law Commission, Registration of Security Interests: company charges and property other than land", "authors": [], "year": 2002, "venue": "Consultation Paper No", "link": null}}, "ref_entries": {}}
{"paper_id": "159355456", "_pdf_hash": "bd5bc45d33b6d061996fb1562fab2f5eb9be6069", "abstract": [{"section": "Abstract", "text": "The Government of India has presented an expanded support of AYUSH arrangement of medicine and foundation of Indian frameworks of solution strength focuses. Taking this vision forward, the Rashtrapati Bhavan with help of Ministry of AYUSH, Government of India; set up the primary AYUSH Wellness Clinic (AWC) of the nation at President's Estate in July 2015. The AWC has treatment facilities in the surges of Ayurveda, Yoga and Naturopathy, Unani, Siddha and Homeopathy. AWC takes into account the restorative needs of the President, authorities of President's Secretariat and occupants of the President's Estate. This paper exhibits a report on the achievement and the work done at AWC from its origin in July 2015 to January 2018. A sum of 82137 patients was counselled and almost 46443 gotten different treatments endorsed by the doctors amid this day and age. AYUSH mindfulness workshops are being directed for consistently. New activities in the year 2015 incorporate foundation of home grown garden at the AWC premises, assigned touch screen intuitive stand and beginning Skill-improvement and Internship Program for the occupants. New activities in the year 2016 incorporate Village out-achieve program and support in the Festival of Innovation at Rashtrapati Bhavan. As new activity in the year 2017-new therapies were added to the current administrations in Ayurveda wing, Yoga and Naturopathy wing and Unani wing; the therapists and bolster staffs working at AWC were prepared in First-AID and CPR and 22 research papers were distributed in peer evaluated indexed journals.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "OUR MISSION", "text": "Our mission is achieving and maintaining excellence in healthcare services through Indian system of medicine and Homoeopathy. We provide comprehensive healthcare services to our valued beneficiaries in form of consultations and therapy through our Ayurveda, Yoga and Naturopathy, Unani, Siddha & Homeopathy OPDs. Along with consultation, medicine, and therapies; disease prevention and positive health promotion services are also provided at AWC. ", "cite_spans": [], "ref_spans": []}, {"section": "ORGANISATION AND INFRASTRUCTURE/ ADMINISTRATION", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "SERVICE DELIVERY MECHANISM", "text": "Patient data is maintained by the special clinic software designed by National", "cite_spans": [], "ref_spans": []}, {"section": "SERVICE DELIVERY MECHANISM", "text": "Informatics Centre, Ministry of Electronics and IT, Government of India. Automatic OPD cards are generated by entering patient details. The detail of diagnosis and medicine/therapy prescribed is entered into the software by consulting physicians 4 .", "cite_spans": [{"start": 246, "end": 247, "text": "4", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "HUMAN RESOURCE", "text": "The committed human resource working at the clinic includes one male and one female physician in all five wings namely Ayurveda, Yoga and Naturopathy, Unani, Siddha & Homeopathy. Ayurveda, Yoga and Naturopathy, Unani and Siddha wings have one male and one female therapist. Yoga and Naturopathy wing has an additional Yoga therapist.", "cite_spans": [], "ref_spans": []}, {"section": "HUMAN RESOURCE", "text": "Besides this, all wings have one male and one female MTS and all except Yoga and Naturopathy have a pharmacist 4 .", "cite_spans": [{"start": 111, "end": 112, "text": "4", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "OVERVIEW OF PATIENTS RECEIVING SERVICES", "text": "An overwhelming number of patients have benefitted from the healthcare services being provided at AWC. The overview of the beneficiaries from January to December 2017 is given below in Table 1 and Table 2 . ", "cite_spans": [], "ref_spans": [{"start": 185, "end": 204, "text": "Table 1 and Table 2", "ref_id": "TABREF1"}]}, {"section": "INFORMATION, EDUCATION & COMMUNICATION (IEC)", "text": "AWC is promoting Indian system of medicine and Homoeopathy through sustained Safed musli (Chlorophytum borivilianum) and Pomegratnate tree (Punica granatum).", "cite_spans": [], "ref_spans": []}, {"section": "Interactive touch screen Kiosk", "text": "An interactive touch screen kiosk was put in the OPD wing of AWC. This unique kiosk was designated to inform the clinic beneficiaries about the different AYUSH systems, their strength and treatment options available. The subject matter was provided by respectice research councils and the technical support was provided by NIC.", "cite_spans": [], "ref_spans": []}, {"section": "Skill Development and Internship Programme", "text": "Skill ", "cite_spans": [], "ref_spans": []}, {"section": "Festival of Innovation", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "CONCLUSION", "text": "", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Government of India, President's Secretariat. President of India to inaugurate AYUSH wellness clinic at President's Estate", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF1": {"title": "Government of India, President's Secretariat. President of India Inaugurated Ayush Wellness Clinic & a Restored Clock Tower at President's Estate", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF2": {"title": "Model AYUSH Wellness Clinic at President's Estate", "authors": [{"first": "A", "middle": [], "last": "Bakshi", "suffix": ""}, {"first": "T", "middle": [], "last": "Thakur", "suffix": ""}, {"first": "I", "middle": [], "last": "Hasan", "suffix": ""}, {"first": "V", "middle": ["K"], "last": "Shahi", "suffix": ""}], "year": 2017, "venue": "India. Indian Journal of Research", "link": null}, "BIBREF3": {"title": "Annual report 2017-Model AYUSH Wellness Clinic at President's Estate", "authors": [{"first": "A", "middle": [], "last": "Bakshi", "suffix": ""}, {"first": "T", "middle": [], "last": "Thakur", "suffix": ""}, {"first": "I", "middle": [], "last": "Hasan", "suffix": ""}, {"first": "V", "middle": ["K"], "last": "Shahi", "suffix": ""}], "year": 2018, "venue": "India. IAJPS", "link": null}, "BIBREF4": {"title": "NIC special clinic software for AYUSH Wellness Clinic, President's Estate", "authors": [], "year": "", "venue": "", "link": null}}, "ref_entries": {"FIGREF0": {"text": "Minister of India has created AYUSH ministry in November 2014 by elevation of the Department of AYUSH under Ministry of Health and Family Welfare with the vision to encourage the Indian system of medicine and Homeopathy. The Government of India has emphasised increased advocacy of AYUSH system of medicine and establishment of Indian systems of medicine specialty centres.Taking this vision forward, the Rashtrapati Bhavan with help of Ministry of AYUSH built up the principal AYUSH Wellness Clinic (AWC) of the nation with all the five frameworks under one rooftop at President's Estate in July 2015. A feeble working in the President's Estate was revamped and changed over into the AWC. The AWC has treatment offices in the surges of Ayurveda, Yoga and Naturopathy, Unani, Siddha and Homeopathy. The center takes into account the therapeutic needs of the President, authorities of President's Secretariat and inhabitants of the President's Estate 1,2 .", "type": "figure"}, "FIGREF1": {"text": "Figure 1: Department wise new patient cases (July 2015-January 2018)", "type": "figure"}, "FIGREF2": {"text": "Figure 6: Disease wise percentage distribution of patients (July 2015-January 2018)", "type": "figure"}, "FIGREF3": {"text": "efforts at patient communication. At the AWC, IEC material is available at a designated area near the OPD registration counter and respective pharmacies. There is also an interactive touch screen kiosk in the OPD wing. AYUSH awareness workshops are conducted at the AWC premises on yearly basis for the residents of President's Estate. AYUSH awareness workshops conducted in the year 2015: 1. Healthy Kitchen through Ayurveda 2. Naturopathic Diet and Way of Life 3. Simple cure at Home: The Unani way 4. Homeopathy for Child health AYUSH awareness workshops conducted in the year 2016: 1. Ayurveda for Life Style Disorders 2. Use and benefits of Mud Therapy (Naturopathy) Anjali BM Bakshi et al AN UPDATE ON MODEL AYUSH WELLNESS CLINIC AT PRESIDENT'S ESTATE ISSN: 2454-6674 http://internationaljournal.org.in/journal/index.php/ijnms Curry leaves plant (Murraya koenigii), Neem (Azadiracta indica), hldi (Curcuma longa),", "type": "figure"}, "FIGREF4": {"text": "Development and Internship Programme was envisioned as a measure to generate awareness of AYUSH therapies and enhance the talent pool in the streams of Ayurveda, Yoga & Naturopathy, Unani and Siddha systems of medicine. The course curriculum was and developed by physicians working at the AYUSH Wellness Clinic in collaboration with President's Secretariat. Along with different therapies done in the AYUSH system of medicine, the curriculum also included basic training in physiotherapy and First-AID. The course was conducted in the AWC premises by the physicians working at AWC, physiotherapists and First-AID experts from St. John's ambulance. So far 56 students have benefitted from this programme in five batches. NEW INITIATIVES IN 2016 1. Village Outreach Services Village outreach services were started at 5 villages adopted by the Honourable President of India. Village AYUSH centres were developed by President's Secretariat at these five villages namely-Alipur, Rojka Meo, Dhaula, Harchandpur and Tajnagar located in Haryana State and regular village OPD was conducted by the physicians working at the AYUSH wellness Clinic.", "type": "figure"}, "FIGREF5": {"text": "Acrylic material moulds for basti therapy and modified swimming pool goggles for netra tarpan being easy to use, less time and money consuming and can be sterilized for multiple use instead of traditional Urad Dal moulds. NEW INITIATIVES IN 2017 1. New Therapy Additions To cater to the needs of patients visiting AWC, new therapies were added to the existing services in Ayurveda wing, Yoga and Naturopathy wing and Unani wing. The therapies added include-Matravasti, Churna Pinda Sweda (Sarvanga), Churna Pinda Sweda (Ekanga), Udvartan, Lepana (Ekanga) in Ayurveda wing, Hip bath in Yoga & Naturopathy wing and Fire Cupping, Facial Cupping, and Cautery in Unani wing. The removal of warts, moles and external piles through cauterization is simple, painless OPD procedure that does not require anaesthesia or blood loss and is being well appreciated by the patients.", "type": "figure"}, "FIGREF6": {"text": "Staff Training in First Aid and CPR The therapists and support staffs working at AWC were trained in First-AID and CPR during the year 2017. The course was conducted in the AWC premises by First-AID experts from St. John's ambulance. Being a clinic cum therapy centre; this training wasfocus on publication both individually and as a collaborative team effort by the physicians working at AWC 4 .", "type": "figure"}, "TABREF0": {"text": "Manpower including consultants, therapists and MTS staff is being provided by M/O AYUSH, Government of India. The Staff for maintenance, cleanliness and security is being provided by Rashtrapati Bhavan. The infrastructure & equipment is provided by Rashtrapati Bhavan and medicines are provided by M/O AYUSH, Government of India 3 .", "type": "table"}, "TABREF1": {"text": "Overview of Patient Consulted from July 2015-January 2018", "type": "table"}, "TABREF2": {"text": "Disease wise patient distribution (July 2015-January 2018)", "type": "table"}, "TABREF3": {"text": "Estate, held on 12 to19 March, 2016. Innovation at AWC showcased including: \uf0b7 Portable Shirodhara Stands that may be dismantled after use and carried in bag. \uf0b7 Induction plates for heating oil for therapy being affordable, safe and less electricity consuming than hotplates/ heaters.Portable steam generators for steam therapy being affordable, light- weight and less electricity consuming than conventional steam apparatus.", "type": "table"}}}
{"paper_id": "159355939", "_pdf_hash": "e9757e883c52f29e88cce561a07a5d4ba5461459", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "159358374", "_pdf_hash": "1f3828c2607922bc03bc4ff075ffa9ba9d7d9019", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "159359827", "_pdf_hash": "a2916adc84bac7bbb72bbe7b6b8f2741fbe7eb2e", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "18980190", "_pdf_hash": "012f4126d1fa755f25b00ca9a258467c31a07436", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Imaging Spectrometry for Earth Remote Sensing", "authors": [{"first": "J", "middle": ["A H F"], "last": "Goetz", "suffix": ""}, {"first": "G", "middle": [], "last": "Vane", "suffix": ""}, {"first": "J", "middle": ["E"], "last": "Solomon", "suffix": ""}, {"first": "B", "middle": ["N"], "last": "Rock", "suffix": ""}], "year": 1985, "venue": "Science", "link": "20845360"}, "BIBREF1": {"title": "New edge-directed interpolation", "authors": [{"first": "X", "middle": [], "last": "Li", "suffix": ""}, {"first": "M", "middle": [], "last": "Orchard", "suffix": ""}], "year": 2001, "venue": "IEEE Trans. Image Process", "link": "6627072"}, "BIBREF2": {"title": "An edge-guided image interpolation algorithm via directional filtering and data fusion", "authors": [{"first": "L", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "X", "middle": [], "last": "Wu", "suffix": ""}], "year": 2006, "venue": "IEEE Trans. Image Process", "link": "9760560"}, "BIBREF3": {"title": "Regularity-preserving image interpolation", "authors": [{"first": "W", "middle": ["K"], "last": "Carey", "suffix": ""}, {"first": "D", "middle": ["B"], "last": "Chuang", "suffix": ""}, {"first": "S", "middle": ["S"], "last": "Hemami", "suffix": ""}], "year": 1999, "venue": "IEEE Trans. Image Process", "link": "15705701"}, "BIBREF4": {"title": "Image resolution enhancement using inter-sub band correlation in wavelet domain", "authors": [{"first": "Y", "middle": [], "last": "Piao", "suffix": ""}, {"first": "I", "middle": [], "last": "Shin", "suffix": ""}, {"first": "H", "middle": ["W"], "last": "Park", "suffix": ""}], "year": 2007, "venue": "Proc. ICIP", "link": "15330970"}, "BIBREF5": {"title": "A new contrast measure based image enhancement algorithm in the DCT domain", "authors": [{"first": "Q", "middle": [], "last": "Sun", "suffix": ""}, {"first": "J", "middle": [], "last": "Tang", "suffix": ""}], "year": 2003, "venue": "IEEE International Conference Systems, Man and cybernetics", "link": "18456373"}, "BIBREF6": {"title": "Spatially Adaptive Antialiasing for Enhancement of Mobile Imaging System Using Combined Wavelet-Fourier Transform", "authors": [{"first": "Wonseokkang", "middle": [], "last": "Eunjungchae", "suffix": ""}, {"first": "Joonkipaik", "middle": [], "last": "", "suffix": ""}], "year": 2013, "venue": "IEEE transaction on consumer electronics", "link": "3035177"}, "BIBREF7": {"title": "Image Enhancement Using DTCWT Based Cycle Spinning Methodology", "authors": [{"first": "N", "middle": [], "last": "Kundeti", "suffix": ""}, {"first": "H", "middle": ["K"], "last": "Kalluri", "suffix": ""}, {"first": "S", "middle": ["V"], "last": "Krishna", "suffix": ""}], "year": 2013, "venue": "IEEE Conference On Computational Intelligence andComputing Research", "link": "18314517"}, "BIBREF8": {"title": "satellite image resolution enhancement using complex wavelet transform", "authors": [{"first": "H", "middle": [], "last": "Demirel", "suffix": ""}, {"first": "G", "middle": [], "last": "Anbarjafari", "suffix": ""}], "year": 2005, "venue": "IEEE Transactions on Geosciences and Remote Sensing Letters", "link": "5481423"}, "BIBREF9": {"title": "Almost Uniform Distributions for Computer ImageEnhancement", "authors": [{"first": "E", "middle": [], "last": "Hall", "suffix": ""}], "year": 1974, "venue": "Computers, IEEE Transactions", "link": null}, "BIBREF10": {"title": "Interpolative models inrestoration and enhancement of noisy images", "authors": [{"first": "H", "middle": [], "last": "Keshavan", "suffix": ""}, {"first": "M", "middle": [], "last": "Srinath", "suffix": ""}], "year": 1977, "venue": "Acoustics,Speech and Signal Processing", "link": "122822095"}, "BIBREF11": {"title": "Digital Image Enhancement and Noise Filtering byUse of Local Statistics", "authors": [{"first": "J", "middle": [], "last": "Lee", "suffix": ""}], "year": 1980, "venue": "Pattern Analysis and MachineIntelligence", "link": "9060120"}, "BIBREF12": {"title": "FIR Anisotropic filters for image enhancement", "authors": [{"first": "V", "middle": [], "last": "Algazi", "suffix": ""}], "year": 1986, "venue": "Acoustics, Speech, and Signal Processing", "link": "61939206"}, "BIBREF13": {"title": "Image sequenceenhancement using sub-pixel displacements", "authors": [{"first": "D", "middle": [], "last": "Keren", "suffix": ""}, {"first": "S", "middle": [], "last": "Peleg", "suffix": ""}, {"first": "R", "middle": [], "last": "Brada", "suffix": ""}], "year": 1988, "venue": "ComputerVision and Pattern Recognition", "link": null}, "BIBREF14": {"title": "A fast filteringalgorithm for image enhancement", "authors": [{"first": "C", "middle": [], "last": "Hegang", "suffix": ""}, {"first": "L", "middle": [], "last": "Kaufman", "suffix": ""}, {"first": "J", "middle": [], "last": "Hale", "suffix": ""}], "year": 1994, "venue": "Medical Imaging", "link": null}, "BIBREF15": {"title": "Satellite Image ResolutionEnhancement Using Complex Wavelet Transform", "authors": [{"first": "H", "middle": [], "last": "Demirel", "suffix": ""}, {"first": "G", "middle": [], "last": "Anbarjafari", "suffix": ""}], "year": 2010, "venue": "Geoscience and Remote Sensing Letters", "link": "5481423"}, "BIBREF16": {"title": "Discrete Wavelet TransformBasedSatellite Image Resolution Enhancement", "authors": [{"first": "H", "middle": [], "last": "Demirel", "suffix": ""}, {"first": "G", "middle": [], "last": "Anbarjafari", "suffix": ""}], "year": 1997, "venue": "Geoscienceand Remote Sensing", "link": null}}, "ref_entries": {}}
{"paper_id": "18980380", "_pdf_hash": "ffe93b67a395cc51d6dc4c5f438a6bbc08a3f31a", "abstract": [{"section": "Abstract", "text": "This technical note studies Markov decision processes under parameter uncertainty. We adapt the distributionally robust optimization framework, assume that the uncertain parameters are random variables following an unknown distribution, and seek the strategy which maximizes the expected performance under the most adversarial distribution. In particular, we generalize a previous study [1] which concentrates on distribution sets with very special structure to a considerably more generic class of distribution sets, and show that the optimal strategy can be obtained efficiently under mild technical conditions. This significantly extends the applicability of distributionally robust MDPs by incorporating probabilistic information of uncertainty in a more flexible way.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Index Terms-Distributional robustness, Markov decision processes, parameter uncertainty.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "", "text": ". Illustration of the confidence sets.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "optimizing variable and \u03be is the unknown parameter, distributionally robust optimization solves max x\u2208X [inf \u03bc\u2208C E \u03be\u223c\u03bc u(x, \u03be)], where C is an a priori known set of distributions.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "We highlight our contributions by comparing with [1] . In [1] the state-wise ambiguity set is restricted to the following form:C s = {\u03bc s |\u03bc s (O i s ) \u2265 \u03b1 i s \u2200 i = 1, . . . , n s }, where \u03b1 i s \u2264 \u03b1 j s and O i s is a proper set of uncertain parameters with a \"nested-set\" structure, i.e., satisfying O i s \u2286 O j s , for all i < j [see Fig. 1(a) ]. This setup can effectively model distributions with a single mode (such as a Gaussian distribution), but less so when modeling multi-mode distributions such as a mixture Gaussian distribution. Moreover, other probabilistic information such as mean, variance etc. cannot be incorporated. Thus, in this technical note, we extend the distributionally robust MDP approach to handle ambiguity sets with more general structures. In particular, we consider a class of ambiguity sets, first proposed in [18] as a unifying framework for modeling and solving distributionally robust single-stage optimization problems, and embed them into the distributionally robust MDPs setup. These ambiguity sets are considerably more general: they are characterized by a class of O i s which can either be nested or disjoint [as shown in Fig. 1(b) ], and moreover, additional linear constraints are allowed to define the ambiguity set, which can be used to incorporate probabilistic information such as mean, covariance or other variation measures. We show that, under this more general class of ambiguity sets, the resulting distributionally robust MDPs remain tractable under mild technical conditions, and often outperform previous methods thanks to the fact that it can model uncertainty in a more flexible way.", "cite_spans": [{"start": 49, "end": 52, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 58, "end": 61, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 845, "end": 849, "text": "[18]", "ref_id": "BIBREF17"}], "ref_spans": [{"start": 337, "end": 346, "text": "Fig. 1(a)", "ref_id": "FIGREF2"}, {"start": 1166, "end": 1175, "text": "Fig. 1(b)", "ref_id": "FIGREF2"}]}, {"section": "II. PRELIMINARIES", "text": "Throughout the technical note, we use capital letters to denote matrices, and bold face letters to denote column vectors. We use e i (m) to denote the ith elementary vector of length m, and use R n + to denote the nonnegative orthant of R n . If C is the set of joint probability distributions of three random vectors a, b, and c, then (a,b) C denotes the set of marginal distributions of (a, b). We use \u2295 to represent mixture distribution: given two probability distributions F 1 , F 2 and a Bernoulli random variable x which takes value 1 w.p. p, xF 1 \u2295 (1 \u2212 x)F 2 is a random variable such that it follows distribution F 1 w.p. p, and follows F 2 w.p. 1 \u2212 p. We use N (m, \u03c3 2 ) to represent a Gaussian distribution with mean m and variance \u03c3 2 .", "cite_spans": [], "ref_spans": []}, {"section": "II. PRELIMINARIES", "text": "A (finite) Markov Decision Process (MDP) is defined as a 6-tuple T, \u03b3, S, A, p, r . Here, T is the (possibly infinite) decision horizon; 0018-9286 \u00a9 2015 IEEE. Personal use is permitted, but republication/redistribution requires IEEE permission.", "cite_spans": [], "ref_spans": []}, {"section": "II. PRELIMINARIES", "text": "See http://www.ieee.org/publications_standards/publications/rights/index.html for more information.", "cite_spans": [], "ref_spans": []}, {"section": "II. PRELIMINARIES", "text": "\u03b3 \u2208 (0, 1] is the discount factor; S is the state set and A s is the action set of state s \u2208 S, both assumed to be finite. The parameter p and r are the transition probability and the expected reward, respectively. That is, for s \u2208 S and a \u2208 A s , r(s, a) is the expected reward and p(s |s, a) is the probability that the next state is s . Following [2] , we denote the set of all history-dependent randomized strategies by \u03a0 HR . We use subscript s to denote the value associated with the state s: e.g., r s denotes the vector form of the rewards associated with the state s, and \u03c0 s is the (randomized) action chosen at state s for strategy \u03c0.", "cite_spans": [{"start": 350, "end": 353, "text": "[2]", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "II. PRELIMINARIES", "text": "The elements in the vector p s are listed in the following way: the transition probabilities of the same action are arranged in the same block, and inside each block they are listed according to the order of the next state. We use s to denote the (random) state following s, and \u0394(s) to denote the probability simplex on A s . We use to represent Cartesian product, e.g., p = s\u2208S p s . For a given strategy \u03c0 \u2208 \u03a0 HR , we denote the expected (discounted) total-reward under parameters pair (p, r) as u(\u03c0, p, r)", "cite_spans": [], "ref_spans": []}, {"section": "II. PRELIMINARIES", "text": "A Distributionally Ambiguous MDP (DAMDP) is defined as a tuple T, \u03b3, S, A,C S , where the transition probability p and the expected reward r are unknown. Instead, they are assumed to obey a joint distribution \u03bc 0 (also unknown) that belongs to a known ambiguity set", "cite_spans": [], "ref_spans": []}, {"section": "II. PRELIMINARIES", "text": "While the DAMDP framework can be very general, mostC S result in formulations that are computationally intractable (e.g., [1] , [19] ). Hence, we make the following requirement ofC S such that the parameters among different states are independent.", "cite_spans": [{"start": 122, "end": 125, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 128, "end": 132, "text": "[19]", "ref_id": "BIBREF18"}], "ref_spans": []}, {"section": "II. PRELIMINARIES", "text": "Assumption 1: The ambiguity setC S has the following property:", "cite_spans": [], "ref_spans": []}, {"section": "II. PRELIMINARIES", "text": "where \"state-wise ambiguity set\"C s is a set of distributions of parameters of state s. By the definition ofC S , the state-wise property applies to C S as well. This property is the same as the concept of \"s-rectangularity\" in [16] , and is essential for reducing DAMDP to robust MDP in Lemma 1. In addition, [20] showed that the robust MDP with coupled uncertainty sets is computationally challenging, which implies solving DAMDP with nonrectangular ambiguity sets is even harder.", "cite_spans": [{"start": 228, "end": 232, "text": "[16]", "ref_id": "BIBREF15"}, {"start": 310, "end": 314, "text": "[20]", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "II. PRELIMINARIES", "text": "We now discuss the admissible state-wise ambiguity set. Our formulation of the state-wise ambiguity set follows the unifying framework of [18] . In specific, given s \u2208 S, the state-wise ambiguity set is representable with the following standard form:", "cite_spans": [{"start": 138, "end": 142, "text": "[18]", "ref_id": "BIBREF17"}], "ref_spans": []}, {"section": "II. PRELIMINARIES", "text": "are the lower and upper bounds of the probability that parameters belong to a confidence set. Thus, each confidence set O i s provides an estimation of the uncertain parameters pair (p s , r s ,\u0169 s ) subject to a different confidence level. Ambiguity setsC s contain prescribed conic representable confidence sets and mean values residing on an affine manifold, which is rich enough to encompass and extend several ambiguity sets considered in recent literature (e.g., [1] , [19] , [21] ). The set of joint distribution of (p s , r s ) is hence C s \u0394 = (ps ,rs)C s . Notice that a classical technique called \"lifting\" is used here: We introduce an auxiliary random vector\u0169, so that some non-linear relationship can be modeled linearly. For example, a constraint on the variance can be modeled using this standard form (see [22, Example 2] ), which is otherwise impossible without the auxiliary variable. This lifting technique thus allows us to model a rich variety of structural information about the marginal distribution of (p, r) in a unified manner. Note when the ambiguity set only contains the support of random variables, i.e.,", "cite_spans": [{"start": 469, "end": 472, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 475, "end": 479, "text": "[19]", "ref_id": "BIBREF18"}, {"start": 482, "end": 486, "text": "[21]", "ref_id": "BIBREF21"}, {"start": 823, "end": 827, "text": "[22,", "ref_id": "BIBREF22"}], "ref_spans": []}, {"section": "II. PRELIMINARIES", "text": "where the a-priori information of unknown parameters is that they belong to an uncertainty set.", "cite_spans": [], "ref_spans": []}, {"section": "II. PRELIMINARIES", "text": "Assumptions 2 to 4 are standard requirements for the confidence sets, proposed in [18] . The first one asserts the relationship between different confidence sets.", "cite_spans": [{"start": 82, "end": 86, "text": "[18]", "ref_id": "BIBREF17"}], "ref_spans": []}, {"section": "II. PRELIMINARIES", "text": "The nesting condition is illustrated in Fig. 1(b) . Next, for any s \u2208 S we require thatC s satisfies the following regularity condition.", "cite_spans": [], "ref_spans": [{"start": 40, "end": 49, "text": "Fig. 1(b)", "ref_id": "FIGREF2"}]}, {"section": "Assumption 3 (Regularity Conditions forC s ):", "text": "1) The confidence set O ns s is bounded and has probability one, that is, ", "cite_spans": [], "ref_spans": []}, {"section": "Assumption 3 (Regularity Conditions forC s ):", "text": "s are proper cones (i.e., a closed, convex and pointed cone with nonempty interior).", "cite_spans": [], "ref_spans": []}, {"section": "III. FINITE HORIZON DISTRIBUTIONALLY ROBUST MDPS", "text": "This section focuses on DAMDP with a finite number of decision stages. We show that a strategy defined through backward induction, which we call S-robust strategy, is distributionally robust. We further show such a strategy is solvable in polynomial time under mild technical conditions. This generalizes results in [1] to a significantly more general class of ambiguity sets.", "cite_spans": [{"start": 316, "end": 319, "text": "[1]", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "III. FINITE HORIZON DISTRIBUTIONALLY ROBUST MDPS", "text": "Similar to [10] , we assume that when a state is visited multiple times, each time it can take a different parameter realization (nonstationary model). This assumption is justified mainly because the stationary model is generally intractable and a lower-bound of it is given by the non-stationary model. Therefore, multiple visits to a state can be treated as visiting different states. By introducing dummy states as in [1, Assumption 2.2], for finite horizon DAMDP we make the following assumption without loss of generality. This will simplify our exposition.", "cite_spans": [{"start": 11, "end": 15, "text": "[10]", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "III. FINITE HORIZON DISTRIBUTIONALLY ROBUST MDPS", "text": "Assumption 5: 1) Each state belongs to only one stage.", "cite_spans": [], "ref_spans": []}, {"section": "III. FINITE HORIZON DISTRIBUTIONALLY ROBUST MDPS", "text": "2) The terminal reward equals zero.", "cite_spans": [], "ref_spans": []}, {"section": "III. FINITE HORIZON DISTRIBUTIONALLY ROBUST MDPS", "text": "3) The first stage only contains one state s ini .", "cite_spans": [], "ref_spans": []}, {"section": "III. FINITE HORIZON DISTRIBUTIONALLY ROBUST MDPS", "text": "Using the condition 1 of Assumption 5, we partition S according to the stage each state belongs to. That is, we let S t be the set of states belong to tth stage.", "cite_spans": [], "ref_spans": []}, {"section": "III. FINITE HORIZON DISTRIBUTIONALLY ROBUST MDPS", "text": "For \u03c0 \u2208 \u03a0 HR and \u03bc \u2208 C S , we denote the expected performance of a DAMDP as w \u03c0, \u03bc, (s ini ) \u0394 = E (p,r)\u223c\u03bc {u(\u03c0, p, r)} = u(\u03c0, p, r)d\u03bc(p, r).", "cite_spans": [], "ref_spans": []}, {"section": "III. FINITE HORIZON DISTRIBUTIONALLY ROBUST MDPS", "text": "In words, each strategy is evaluated by its expected performance under the (respective) most adversarial distribution of the uncertain parameters, and a distributionally robust strategy is the optimal strategy according to this metric. The main focus of this section is deriving approaches to solve the distributionally robust strategy. To this end, we need the following definition.", "cite_spans": [], "ref_spans": []}, {"section": "III. FINITE HORIZON DISTRIBUTIONALLY ROBUST MDPS", "text": "Definition 2: Given a DAMDP T, \u03b3, S, A,C S , we define the Srobust strategy as follows", "cite_spans": [], "ref_spans": []}, {"section": "III. FINITE HORIZON DISTRIBUTIONALLY ROBUST MDPS", "text": "3) A strategy\u03c0 * is a Srobust strategy if \u2200 s \u2208 S, and every history h that ends at s, we have\u03c0 * s , conditioned on history h, is a S-robust action.", "cite_spans": [], "ref_spans": []}, {"section": "III. FINITE HORIZON DISTRIBUTIONALLY ROBUST MDPS", "text": "The definition requires that the strategy must be robust w.r.t. each sub-problem, and hence the name \"S-robust.\" The following theorem shows any S-robust strategy \u03c0 * is distributionally robust, and is the main result of this technical note.", "cite_spans": [], "ref_spans": []}, {"section": "III. FINITE HORIZON DISTRIBUTIONALLY ROBUST MDPS", "text": "Theorem 1: Let T < \u221e. Under Assumptions 1, 2, 4, and 5, if \u03c0 * is a S-robust strategy, then 1) \u03c0 * is a distributionally robust strategy with respect to C S . 2) There exists \u03bc * \u2208 C s such that (\u03c0 * , \u03bc * ) is a saddle point. That is", "cite_spans": [], "ref_spans": []}, {"section": "III. FINITE HORIZON DISTRIBUTIONALLY ROBUST MDPS", "text": "Proof: We first state a Lemma from [1, Lemma 3.2] without proof.", "cite_spans": [], "ref_spans": []}, {"section": "III. FINITE HORIZON DISTRIBUTIONALLY ROBUST MDPS", "text": "Lemma 1: Under Assumption 1, fix \u03c0 \u2208 \u03a0 HR and \u03bc \u2208 C S , denote p = E \u03bc (p) and r = E \u03bc (r). We have w(\u03c0, \u03bc, (s ini )) = u(\u03c0, p, r).", "cite_spans": [], "ref_spans": []}, {"section": "III. FINITE HORIZON DISTRIBUTIONALLY ROBUST MDPS", "text": "Lemma 1 means for any strategy, the expected performance under an admissible distribution \u03bc only depends on the expected value of parameters under \u03bc. Thus, the distributionally robust MDPs reduce to robust MDPs. Next we characterize the set of expected value of the parameters.", "cite_spans": [], "ref_spans": []}, {"section": "III. FINITE HORIZON DISTRIBUTIONALLY ROBUST MDPS", "text": "Lemma 2: For s \u2208 S and \u03c0 s \u2208 \u0394(s), we define the set Z s = {E \u03bcs (p s , r s )|\u03bc s \u2208 C s }. Then set Z s is convex and compact.", "cite_spans": [], "ref_spans": []}, {"section": "III. FINITE HORIZON DISTRIBUTIONALLY ROBUST MDPS", "text": "Proof: First, we show that, for s \u2208 S and \u03c0 s \u2208 \u0394(s), the set defined asZ s = {E \u03bcs (p s , r s ,\u0169 s )|\u03bc s \u2208C s } is convex and compact. The convexity can be easily shown, which is omitted due to space constraints (see [22] for details). To show the compactness, notice thatC s is weakly closed (i.e., closed w.r.t. to the weak topology) since the feasible set of each of constraint is weakly closed which implies their intersection is also weakly closed. Thus,Z s is closed since it is the image ofC s under expectation (which is a continuous function). This impliesZ s is compact since O ns s is bounded and henceZ s is bounded. Finally, since Z s is the projection onto the first two coordinates of set Z s , its convexity and compactness thus follow.", "cite_spans": [{"start": 218, "end": 222, "text": "[22]", "ref_id": "BIBREF22"}], "ref_spans": []}, {"section": "III. FINITE HORIZON DISTRIBUTIONALLY ROBUST MDPS", "text": "Lemma 2 implies that, for s \u2208 S and \u03c0 s \u2208 \u0394(s), there exists (p * s , r * s ) \u2208 Z s that satisfies inf (ps,rs)\u2208Zs u(\u03c0 s , p s , r s ) = u(\u03c0 s , p * s , r * s ). Since saddle point of the minimax objective exists for robust MDPs (e.g., [10] , [11] ), we can complete the proof of part 2) following a similar procedure as the last portion of proof for [1, Theorem 3.1]. We omit the details due to space constraint (see [22] for details). Part 1) then follows part 2) immediately.", "cite_spans": [{"start": 235, "end": 239, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 242, "end": 246, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 417, "end": 421, "text": "[22]", "ref_id": "BIBREF22"}], "ref_spans": []}, {"section": "III. FINITE HORIZON DISTRIBUTIONALLY ROBUST MDPS", "text": "We now investigate the computational aspect of finding the S-robust action.", "cite_spans": [], "ref_spans": []}, {"section": "III. FINITE HORIZON DISTRIBUTIONALLY ROBUST MDPS", "text": "Theorem 2: Under Assumption 2, 3, 4, and 5, for s \u2208 S t where t < T , the S-robust action is the optimal solution of the following optimization problem (termed Srobust problem hereafter): Proof: The proof essentially follows from [18] and duality of convex optimization [23] , and can be found in the longer version [22] of this technical note.", "cite_spans": [{"start": 230, "end": 234, "text": "[18]", "ref_id": "BIBREF17"}, {"start": 270, "end": 274, "text": "[23]", "ref_id": "BIBREF23"}, {"start": 316, "end": 320, "text": "[22]", "ref_id": "BIBREF22"}], "ref_spans": []}, {"section": "III. FINITE HORIZON DISTRIBUTIONALLY ROBUST MDPS", "text": "Thus, since for s \u2208 S t , \u0394(s) is compact, we can solve the S-robust action in polynomial time if all K i s are \"easy\" cones such as linear, conic quadratic or semidefinite cones. Moreover, using Theorem 1, by backward induction, we can obtain the S-robust strategy efficiently.", "cite_spans": [], "ref_spans": []}, {"section": "III. FINITE HORIZON DISTRIBUTIONALLY ROBUST MDPS", "text": "By virtue of the lifting technique [18, Theorem 5], we show below several widely used ambiguity sets are indeed special cases ofC s defined in (1) . We further derive their corresponding S-robust problems. See [22] for additional examples (variance and expected Huber loss function). ", "cite_spans": [{"start": 143, "end": 146, "text": "(1)", "ref_id": "BIBREF0"}, {"start": 210, "end": 214, "text": "[22]", "ref_id": "BIBREF22"}], "ref_spans": []}, {"section": "III. FINITE HORIZON DISTRIBUTIONALLY ROBUST MDPS", "text": "This example can also be treated via \"classical\" robust optimization by virtue of Lemma 1.", "cite_spans": [], "ref_spans": []}, {"section": "III. FINITE HORIZON DISTRIBUTIONALLY ROBUST MDPS", "text": "The finite horizon DAMDP can be easily extended to discountedreward infinite horizon setup. We can generalize the notion of S-robust strategy, which turns to be distributionally robust in both stationary and non-stationary models. This extension is similar to [1] and can be found in [22] .", "cite_spans": [{"start": 260, "end": 263, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 284, "end": 288, "text": "[22]", "ref_id": "BIBREF22"}], "ref_spans": []}, {"section": "IV. SIMULATION", "text": "In this section, we study two synthetic numerical examples: a machine replacement problem and a path planning problem. In the machine replacement problem, the reward parameters are uncertain; whereas in the path planning problem, the transition probabilities are uncertain. All results were generated on desktop with Intel Core i5-3570 CPU of 3.40 GHz clock speed and 8 GB RAM. The S-robust problems are solved in Matlab using the CVX package [24] .", "cite_spans": [{"start": 443, "end": 447, "text": "[24]", "ref_id": "BIBREF24"}], "ref_spans": []}, {"section": "A. Reward Uncertainty in the Machine Replacement Problem", "text": "We consider a machine replacement problem similar to the one in [12] . Consider the repair cost incurred by a factory that holds a large number of machines, given that each of these machines is modeled with a same underlying MDP for which rewards are subject to uncertainty.", "cite_spans": [{"start": 64, "end": 68, "text": "[12]", "ref_id": "BIBREF11"}], "ref_spans": []}, {"section": "1) Machine Replacement as a MDP With Gaussian Rewards:", "text": "We first consider a machine replacement problem with 50 states, 2 actions (\"repair\" and \"not repair\") for each state, deterministic transitions, a discount factor of 0.8, and uncertain rewards following Gaussian distributions independently [see Fig. 2(a) ]: For the first 48 states, the \"repair\" action has a cost N (130, 1) . The 49th and 50th states of the machine's life are designed to be risky: not repairing at state 50 incurs a highly uncertain cost N (100, 800), while repairing at both states is a more secure but still uncertain option with a cost N (130, 10) . The detailed implementation is as follows: We use the mean value of uncertain rewards to compute the nominal strategy. For both robust and distributionally robust strategy, we construct confidence sets usin\u011d m \u00b1 3\u03c3 for the first 49 states, andm \u00b1 4\u03c3 for state 50 wherem and\u03c3 2 are mean and variance estimated from samples (see [22] for details), as it is more risky and thus hard to estimate. In addition, we construct an extra confidence set (centered at the mean) with 60%-70% confidence level (i.e., \u03b1 1 50 = 0.6, \u03b1 1 50 = 0.7) for distributionally robust strategy. The optimal paths followed by three strategies are shown in Fig. 2(a) .", "cite_spans": [{"start": 899, "end": 903, "text": "[22]", "ref_id": "BIBREF22"}], "ref_spans": [{"start": 245, "end": 254, "text": "Fig. 2(a)", "ref_id": "FIGREF3"}, {"start": 309, "end": 324, "text": "cost N (130, 1)", "ref_id": "FIGREF1"}, {"start": 553, "end": 569, "text": "cost N (130, 10)", "ref_id": "FIGREF1"}, {"start": 1201, "end": 1210, "text": "Fig. 2(a)", "ref_id": "FIGREF3"}]}, {"section": "1) Machine Replacement as a MDP With Gaussian Rewards:", "text": "The performance of the strategies obtained by using the nominal, the robust and the distributionally robust approaches is presented in Fig. 3 . The corresponding average total discounted rewards and computational times are shown in Table I . The nominal strategy results in the highest average total discounted rewards. This is well expected as we are using the exact mean value of the reward as the nominal Fig. 2 . Two instances of a machine replacement problem. Fig. 2(a) shows Gaussian uncertainty in the rewards, while Fig. 2(b) shows mixed Gaussian uncertainty in the rewards. parameter. However, the nominal strategy is highly risky: it cannot prevent bad performance (e.g., \u22120.025) from happening, which is undesirable. While the nominal strategy, blind to any form of risk, finds no advantage in ever repairing, the robust strategy ends up following a highly conservative policy (repairing the machine at state 49 to avoid state 50). In contrast, the distributionally robust optimal strategy makes use of more distributional information and handles the risk efficiently by waiting until state 50 and then repair the machine. Therefore, this strategy beats the nominal and robust strategies in that it strikes a good tradeoff between high mean reward and low variance over 10,000 different trials. These results coincide with what one would typically expect from the three solution concepts. Fig. 4 . Illustration of the confidence sets for two distributionally robust strategies.", "cite_spans": [], "ref_spans": [{"start": 135, "end": 141, "text": "Fig. 3", "ref_id": "FIGREF1"}, {"start": 232, "end": 239, "text": "Table I", "ref_id": "TABREF0"}, {"start": 408, "end": 414, "text": "Fig. 2", "ref_id": "FIGREF3"}, {"start": 465, "end": 474, "text": "Fig. 2(a)", "ref_id": "FIGREF3"}, {"start": 524, "end": 533, "text": "Fig. 2(b)", "ref_id": "FIGREF3"}, {"start": 1400, "end": 1406, "text": "Fig. 4", "ref_id": "FIGREF0"}]}, {"section": "2) Machine Replacement as a MDP With Mixed Gaussian Rewards:", "text": "The second experiment has a similar setup as the previous one, except that not repairing at the 50th state has a reward which follows a mixed Gaussian distribution [see Fig. 2(b) ]. This experiment illustrates the effect of the two different nested-set structures shown in Fig. 1 . In specific, we apply the two different distributionally robust approaches (proposed in [1] and this technical note respectively), and show that our method outperforms. The detailed implementation is as follows: For the robust and two distributionally robust strategies, we construct uncertainty set corresponding to 99% probability support of the rewards for the first 49 states, and 99.9% for the 50th state that is more risky, using estimated mean and variance (see [22] for details). For the first distributionally robust strategy proposed in [1] , we construct two additional nested confidence sets O 1 50 and O 2 50 [see Fig. 4(a) ], which w.p. 40%-50% and 60%-70% respectively the uncertain rewards belong to. In contrast, for the second distributionally robust strategy proposed in this technical note, we construct two disjoint confidence sets O 1 50 and O 2 50 [see Fig. 4 (b)] with 70%-80% and 0%-10% confidence level, respectively. Specifically, we select these two intervals around the peaks of the two Gaussian elements [i.e., N (100, 10) and N (140, 2)] to better model this mixed distribution. The optimal paths followed for the three strategies are shown in Fig. 2(b) .", "cite_spans": [{"start": 370, "end": 373, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 751, "end": 755, "text": "[22]", "ref_id": "BIBREF22"}, {"start": 829, "end": 832, "text": "[1]", "ref_id": "BIBREF0"}], "ref_spans": [{"start": 169, "end": 178, "text": "Fig. 2(b)", "ref_id": "FIGREF3"}, {"start": 273, "end": 279, "text": "Fig. 1", "ref_id": "FIGREF2"}, {"start": 909, "end": 918, "text": "Fig. 4(a)", "ref_id": "FIGREF0"}, {"start": 1158, "end": 1164, "text": "Fig. 4", "ref_id": "FIGREF0"}, {"start": 1457, "end": 1466, "text": "Fig. 2(b)", "ref_id": "FIGREF3"}]}, {"section": "2) Machine Replacement as a MDP With Mixed Gaussian Rewards:", "text": "The performance of the three strategies obtained is presented in Fig. 5 . The corresponding average total discounted rewards and computational times are shown in Table II . As expected, the robust strategy ends up following a highly conservative policy repairing the machine at state 49 to avoid state 50. The first distributionally robust strategy, not modeling the mixture Gaussian distribution well, finds it advantageous to repair at the 50th state. In contrast, capable of capturing the distribution information in a more flexible way, the second distributionally robust strategy better models the uncertainty and finds not repairing the machine at state 50 is optimal. The performance comparison clearly shows the second distributionally robust strategy is more desirable, which highlights the distributionally robust approach with general structure of confidence sets can be beneficial in practice.", "cite_spans": [], "ref_spans": [{"start": 65, "end": 71, "text": "Fig. 5", "ref_id": "FIGREF5"}, {"start": 162, "end": 170, "text": "Table II", "ref_id": "TABREF0"}]}, {"section": "2) Machine Replacement as a MDP With Mixed Gaussian Rewards:", "text": "We remark that, in practice, one can obtain the modality structure of uncertain parameters in a data-driven way by applying clustering algorithms to an initial primitive data set. For example, one may check the histogram of historical observations. If the data concentrates on several distinct and disjoint bins, our multi-model DAMDP approach can be applied. Moreover, we note that networked control systems (NCSs) have recently emerged as a topic of significant interest in the control community. A typical application of NCSs is in modern [25] and [26] proposed a novel two-layer structure to solve the setpoints compensation problem for industrial processes under network-based environment.", "cite_spans": [{"start": 542, "end": 546, "text": "[25]", "ref_id": "BIBREF25"}, {"start": 551, "end": 555, "text": "[26]", "ref_id": "BIBREF26"}], "ref_spans": []}, {"section": "B. Transition Uncertainty in the Path Planning Problem", "text": "We now consider a path planning problem, similar to the one presented in [1] : an agent wants to exit a 4 \u00d7 21 maze [shown in Fig. 6(a) ] using the least possible time. Starting from the upper-left corner, the agent can move up, down, left and right, but can only exit the grid at the lower-right corner. Here, a white box stands for a normal place where the agent needs one time unit to pass through. A shaded box represents a \"shaky\" place: if an agent reaches a \"shaky\" place, then he may risk jumping to the starting point (\"reboot\"). The true transition probability of the jump follows a distribution", "cite_spans": [{"start": 73, "end": 76, "text": "[1]", "ref_id": "BIBREF0"}], "ref_spans": [{"start": 126, "end": 135, "text": "Fig. 6(a)", "ref_id": "FIGREF6"}]}, {"section": "B. Transition Uncertainty in the Path Planning Problem", "text": "The four approaches are implemented as follows: The nominal approach neglects this random jump. The robust approach takes a worst-case analysis, i.e., it assumes that with 30%, the whole probability support of transition, the agent will jump to the spot with the highest costto-go. The first distributionally robust approach takes into account an additional information by using two nested confidence sets: the jump probability parameter belonging to 9%-11% is of a confidence 1 \u2212 \u03bb. The second distributionally robust approach, which is proposed in this technical note, incorporates more information. In specific, we construct an extra confidence interval disjoint with the above 9%-11% interval. It states that the chance of jumping with probability 20% is \u03bb.", "cite_spans": [], "ref_spans": []}, {"section": "B. Transition Uncertainty in the Path Planning Problem", "text": "The performance of strategies of the nominal, the robust and the two distributionally robust approaches is shown in Fig. 6(b) , where the error bars show the standard error of the expected time to exit. The CPU times of computing optimal policies for four strategies are 0.461, 549, 642, and 654 seconds, respectively. The second distributionally robust approach achieves the best performance over virtually the whole spectrum of \u03bb. This is well expected, since additional probabilistic Fig. 6(a) illustrates the maze for the path plawnning problem. Fig. 6(b) shows the performance comparisons between nominal, robust and two distributionally robust strategies over 3,000 runs of the path planning problem.", "cite_spans": [], "ref_spans": [{"start": 116, "end": 125, "text": "Fig. 6(b)", "ref_id": "FIGREF6"}, {"start": 487, "end": 496, "text": "Fig. 6(a)", "ref_id": "FIGREF6"}, {"start": 550, "end": 559, "text": "Fig. 6(b)", "ref_id": "FIGREF6"}]}, {"section": "B. Transition Uncertainty in the Path Planning Problem", "text": "information is available to and incorporated by the second distributionally robust approach which considers ambiguity sets with more general structures.", "cite_spans": [], "ref_spans": []}, {"section": "V. CONCLUSION", "text": "In this technical note, we considered Markov decision problems with uncertainty. Specifically, we generalized the distributionally robust approach proposed in [1] to incorporate more general ambiguity sets proposed in [18] to model a-priori probabilistic information of the uncertain parameters. We proposed a way to compute the distributionally robust strategy through a Bellman type backward induction. We showed that the strategy, which achieves maximum expected utility under the worst admissible distributions of uncertain parameters, can be solved in polynomial time under some mild technical conditions. We believe that many important problems that are usually addressed using standard MDP models could be revisited and better resolved using the proposed models when parameter uncertainty exists, as this formulation naturally enables the decision maker to account for more general parameter uncertainty.", "cite_spans": [{"start": 159, "end": 162, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 218, "end": 222, "text": "[18]", "ref_id": "BIBREF17"}], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Distributionally robust Markov decision processes", "authors": [{"first": "H", "middle": [], "last": "Xu", "suffix": ""}, {"first": "S", "middle": [], "last": "Mannor", "suffix": ""}], "year": 2012, "venue": "Math. Oper. Res", "link": "7229756"}, "BIBREF1": {"title": "Markov Decision Processes: Discrete Stochastic Dynamic Programming", "authors": [{"first": "M", "middle": ["L"], "last": "Puterman", "suffix": ""}], "year": 2014, "venue": "", "link": "57464058"}, "BIBREF2": {"title": "Neuro-dynamic programming (optimization and neural computation series, 3)", "authors": [{"first": "D", "middle": ["P"], "last": "Bertsekas", "suffix": ""}, {"first": "J", "middle": ["N"], "last": "Tsitsiklis", "suffix": ""}], "year": 1996, "venue": "Athena Scientific", "link": null}, "BIBREF3": {"title": "Reinforcement Learning: An Introduction", "authors": [{"first": "A", "middle": ["G"], "last": "Barto", "suffix": ""}], "year": 1998, "venue": "", "link": "9166388"}, "BIBREF4": {"title": "Bias and variance approximation in value function estimates", "authors": [{"first": "S", "middle": [], "last": "Mannor", "suffix": ""}, {"first": "D", "middle": [], "last": "Simester", "suffix": ""}, {"first": "P", "middle": [], "last": "Sun", "suffix": ""}, {"first": "J", "middle": ["N"], "last": "Tsitsiklis", "suffix": ""}], "year": 2007, "venue": "Manag. Sci", "link": "10603007"}, "BIBREF5": {"title": "Convex programming with set-inclusive constraints and applications to inexact linear programming", "authors": [{"first": "A", "middle": ["L"], "last": "Soyster", "suffix": ""}], "year": 1973, "venue": "Oper. Res", "link": null}, "BIBREF6": {"title": "Robust solutions of uncertain linear programs", "authors": [{"first": "A", "middle": [], "last": "Ben-Tal", "suffix": ""}, {"first": "A", "middle": [], "last": "Nemirovski", "suffix": ""}], "year": 1999, "venue": "Oper. Res. Lett", "link": "2474018"}, "BIBREF7": {"title": "The price of robustness", "authors": [{"first": "D", "middle": ["P"], "last": "Bertsimas", "suffix": ""}, {"first": "M", "middle": [], "last": "Sim", "suffix": ""}], "year": 2004, "venue": "Oper. Res", "link": "8946639"}, "BIBREF8": {"title": "Robust Optimization", "authors": [{"first": "A", "middle": [], "last": "Ben-Tal", "suffix": ""}, {"first": "L", "middle": ["El"], "last": "Ghaoui", "suffix": ""}, {"first": "A", "middle": [], "last": "Nemirovski", "suffix": ""}], "year": 2009, "venue": "", "link": null}, "BIBREF9": {"title": "Robust control of Markov decision processes with uncertain transition matrices", "authors": [{"first": "A", "middle": [], "last": "Nilim", "suffix": ""}, {"first": "L", "middle": ["El"], "last": "Ghaoui", "suffix": ""}], "year": 2005, "venue": "Oper. Res", "link": "1537485"}, "BIBREF10": {"title": "Robust dynamic programming", "authors": [{"first": "G", "middle": ["N"], "last": "Iyengar", "suffix": ""}], "year": 2005, "venue": "Math. Oper. Res", "link": "710328"}, "BIBREF11": {"title": "Percentile optimization for Markov decision processes with parameter uncertainty", "authors": [{"first": "E", "middle": [], "last": "Delage", "suffix": ""}, {"first": "S", "middle": [], "last": "Mannor", "suffix": ""}], "year": 2010, "venue": "Oper. Res", "link": "10308849"}, "BIBREF12": {"title": "Markov decision processes with imprecise transition probabilities", "authors": [{"first": "C", "middle": ["C"], "last": "White", "suffix": ""}, {"first": "H", "middle": ["K"], "last": "Eldeib", "suffix": ""}], "year": 1994, "venue": "Oper. Res", "link": "207242061"}, "BIBREF13": {"title": "Solving uncertain Markov decision problems", "authors": [{"first": "A", "middle": [], "last": "Bagnell", "suffix": ""}, {"first": "A", "middle": ["Y"], "last": "Ng", "suffix": ""}, {"first": "J", "middle": [], "last": "Schneider", "suffix": ""}], "year": 2001, "venue": "", "link": "59762877"}, "BIBREF14": {"title": "Learning under ambiguity", "authors": [{"first": "L", "middle": ["G"], "last": "Epstein", "suffix": ""}, {"first": "M", "middle": [], "last": "Schneider", "suffix": ""}], "year": 2007, "venue": "Rev. Econ. Studies", "link": "15546892"}, "BIBREF15": {"title": "Robust Markov decision processes", "authors": [{"first": "W", "middle": [], "last": "Wiesemann", "suffix": ""}, {"first": "D", "middle": [], "last": "Kuhn", "suffix": ""}, {"first": "B", "middle": [], "last": "Rustem", "suffix": ""}], "year": 2013, "venue": "Math. Oper. Res", "link": "6103434"}, "BIBREF16": {"title": "The robustness-performance tradeoff in Markov decision processes", "authors": [{"first": "H", "middle": [], "last": "Xu", "suffix": ""}, {"first": "S", "middle": [], "last": "Mannor", "suffix": ""}, {"first": "B", "middle": [], "last": "Sch\u00f6lkopf", "suffix": ""}, {"first": "J", "middle": [], "last": "Platt", "suffix": ""}, {"first": "T", "middle": [], "last": "Hofmann", "suffix": ""}], "year": 2006, "venue": "Proc. NIPS", "link": "63859912"}, "BIBREF17": {"title": "Distributionally robust convex optimization", "authors": [{"first": "W", "middle": [], "last": "Wiesemann", "suffix": ""}, {"first": "D", "middle": [], "last": "Kuhn", "suffix": ""}, {"first": "M", "middle": [], "last": "Sim", "suffix": ""}], "year": 2014, "venue": "Oper. Res", "link": "16625241"}, "BIBREF18": {"title": "Distributionally robust optimization under moment uncertainty with application to data-driven problems", "authors": [{"first": "E", "middle": [], "last": "Delage", "suffix": ""}, {"first": "Y", "middle": [], "last": "Ye", "suffix": ""}], "year": 2010, "venue": "Oper. Res", "link": null}, "BIBREF19": {"title": "Lightning does not strike twice: Robust MDPs with coupled uncertainty", "authors": [{"first": "S", "middle": [], "last": "Mannor", "suffix": ""}, {"first": "O", "middle": [], "last": "Mebel", "suffix": ""}, {"first": "H", "middle": [], "last": "Xu", "suffix": ""}], "year": 2012, "venue": "Proc. 29th Int. Conf. Machine Learning (ICML'12)", "link": "486400"}, "BIBREF20": {"title": "Available", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF21": {"title": "Distributionally robust joint chance constraints with second-order moment information", "authors": [{"first": "S", "middle": [], "last": "Zymler", "suffix": ""}, {"first": "D", "middle": [], "last": "Kuhn", "suffix": ""}, {"first": "B", "middle": [], "last": "Rustem", "suffix": ""}], "year": 2013, "venue": "Math. Programm", "link": "11547182"}, "BIBREF22": {"title": "Distributionally robust counterpart in Markov decision processes", "authors": [{"first": "P", "middle": [], "last": "Yu", "suffix": ""}, {"first": "H", "middle": [], "last": "Xu", "suffix": ""}], "year": 2015, "venue": "", "link": "18980380"}, "BIBREF23": {"title": "Convex Optimization", "authors": [{"first": "S", "middle": [], "last": "Boyd", "suffix": ""}, {"first": "L", "middle": [], "last": "Vandenberghe", "suffix": ""}], "year": 2004, "venue": "", "link": "37925315"}, "BIBREF24": {"title": "CVX: Matlab Software for Disciplined Convex Programming, Version 2.1", "authors": [{"first": "M", "middle": [], "last": "Grant", "suffix": ""}, {"first": "S", "middle": [], "last": "Boyd", "suffix": ""}], "year": 2014, "venue": "", "link": null}, "BIBREF25": {"title": "A combined adaptive neural network and nonlinear model predictive control for multirate networked industrial process control", "authors": [{"first": "T", "middle": [], "last": "Wang", "suffix": ""}, {"first": "H", "middle": [], "last": "Gao", "suffix": ""}, {"first": "J", "middle": [], "last": "Qiu", "suffix": ""}], "year": 2016, "venue": "IEEE Trans. Neural Netw. Learn. Syst", "link": "18576331"}, "BIBREF26": {"title": "Networked multirate output feedback control for setpoints compensation and its application to rougher flotation process", "authors": [{"first": "F", "middle": [], "last": "Liu", "suffix": ""}, {"first": "H", "middle": [], "last": "Gao", "suffix": ""}, {"first": "J", "middle": [], "last": "Qiu", "suffix": ""}, {"first": "S", "middle": [], "last": "Yin", "suffix": ""}, {"first": "J", "middle": [], "last": "Fan", "suffix": ""}, {"first": "T", "middle": [], "last": "Chai", "suffix": ""}], "year": 2014, "venue": "IEEE Trans. Ind. Electron", "link": "24341930"}}, "ref_entries": {"FIGREF0": {"text": "The condition 1 of Assumption 3 ensures the confidence set with largest index, O ns s , contains the support of the joint unknown parameters pair (p s , r s ,\u0169 s ). The second condition stipulates that there is a probability distribution \u03bc s (p s , r s ,\u0169 s ) \u2208C s that satisfies the probability bounds in (1) as strict inequalities whenever the corresponding probability interval [\u03b1 i s , \u03b1 i s ] is non-degenerate. For each individual O i s , we make the following assumption to ensure tractability.Assumption For s \u2208 S, i \u2208 I s , each nonempty and convex confidence set O i s is defined as", "type": "figure"}, "FIGREF1": {"text": "Here, K i s * represents the cone dual to K i s ; set A(i) \u0394 = {i} \u222a {i \u2208 I s : O i s O i s };\u1e7d t+1 is the vector form of\u1e7d t+1 (s ) for all s \u2208 S t+1 ; and V s \u0394 = [e 1 (|A s |)\u1e7d t+1 , . . . , e |As| (|A s |)\u1e7d t+1 ] .", "type": "figure"}, "FIGREF2": {"text": "Mean Absolute Deviation): Assume that E rs\u223c\u03bcs (rs) [|r s \u2212 m|] \u2264 f for m, f \u2208 R |As| . [18] shows thatC s , which involves the auxiliary random vector\u0169 s \u2208 R |As| , can be expressed asC s = {\u03bc s (r s ,\u0169 s )|E\u0169 s \u223c\u03bcs [\u0169 s ] = f , \u03bc s (\u0169 s \u2265 r s \u2212 m,\u0169 s \u2265 m \u2212 r s ) = 1}. Note that \u03bc s (r s ) \u2208 rsC s . In this case Problem (3) can be rewritten as minimize w,\u03c0s ,\u03ba,\u03bd w subject to \u03ba \u2212 f \u03bd \u2264 w \u03ba + p s\u1e7cs \u03c0 s + m \u03c0 s \u2265 0 \u03c0 s \u2208 \u0394(s), \u03bd \u2265 0.", "type": "figure"}, "FIGREF3": {"text": "Mean): Assume that we only know a noisy empirical estimator of the exact mean of p s . That is, given G \u2208 R M \u00d7(|As|\u00d7|s|) , f \u2208 R M and p s \u223c \u03bc s (p s ), GE ps\u223c\u03bcs(ps) [p s ] K f , where K is a proper cone. [18] shows thatC s , which involves the auxiliary random vector\u0169 s \u2208 R M , can be expressed asC s = {\u03bc s (p s , u s )|E\u0169 s \u223c\u03bcs [\u0169 s ] = f , \u03bc s (Gp s K\u0169s ) = 1}. Note that \u03bc s (p s ) \u2208 psC s . Problem (3) now takes the form minimize w,\u03c0s ,\u03ba,\u03bd", "type": "figure"}, "FIGREF4": {"text": "Performance comparisons between nominal, robust, and distributionally robust strategies on 10,000 runs of the machine replacement problem with Gaussian rewards (The bottom figure focuses on the interval [ \u22120.0045, \u22120.001]).", "type": "figure"}, "FIGREF5": {"text": "Performance comparisons between robust and two distributionally robust strategies on 10,000 runs of the machine replacement problem with mixed Gaussian rewards.", "type": "figure"}, "FIGREF6": {"text": "Fig. 6. Fig. 6(a) illustrates the maze for the path plawnning problem. Fig. 6(b) shows the performance comparisons between nominal, robust and two distributionally robust strategies over 3,000 runs of the path planning problem.", "type": "figure"}, "TABREF0": {"text": "TOTAL DISCOUNTED REWARDS AND COMPUTATIONAL TIMES OF NOMINAL, ROBUST, AND DISTRIBUTIONALLY ROBUST STRATEGIES IN MACHINE REPLACEMENT PROBLEM WITH GAUSSIAN REWARDS", "type": "table"}, "TABREF1": {"text": "TOTAL DISCOUNTED REWARDS AND COMPUTATIONAL TIMES OF ROBUST AND TWO DISTRIBUTIONALLY ROBUST STRATEGIES IN MACHINE REPLACEMENT PROBLEM WITH MIXED GAUSSIAN REWARDS industrial systems, in which the components are often connected over network media. Our multi-model DAMDP approach might be extended for network-based performance tracking control of complex industrial processes, where recent work", "type": "table"}}}
{"paper_id": "18980463", "_pdf_hash": "ac3a8d3545ca7c673ddbfbf2f503e40f6317eb6f", "abstract": [{"section": "Abstract", "text": "Although development of the adult Drosophila compound eye is very well understood, little is known about development of photoreceptors (PRs) in the simple larval eye. We show here that the larval eye is composed of 12 PRs, four of which express blue-sensitive rhodopsin5 (rh5) while the other eight contain green-sensitive rh6. This is similar to the 30:70 ratio of adult blue and green R8 cells. However, the stochastic choice of adult color PRs and the bistable loop of the warts and melted tumor suppressor genes that unambiguously specify rh5 and rh6 in R8 PRs are not involved in specification of larval PRs. Instead, primary PR precursors signal via EGFR to surrounding tissue to develop as secondary precursors, which will become Rh6-expressing PRs. EGFR signaling is required for the survival of the Rh6 subtype. Primary precursors give rise to the Rh5 subtype. Furthermore, the combinatorial action of the transcription factors Spalt, Seven-up, and Orthodenticle specifies the two PR subtypes. Therefore, even though the larval PRs and adult R8 PRs express the same rhodopsins (rh5 and rh6), they use very distinct mechanisms for their specification.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "[Keywords: Drosophila; visual system development; photoreceptor specification; transcription factor interaction; EGFR signaling] Supplemental material is available at http://www.genesdev.org. In spite of the morphological and developmental differences between vertebrate and invertebrate eyes, their basic function to translate light information from the environment to the brain is maintained. In Drosophila, the adult compound eye has been studied in great detail. It consists of \u223c800 individual ommatidia. Each ommatidium contains eight photoreceptor cells (PRs): six outer PRs (R1-R6) and two inner PRs (R7 and R8). Different PRs are sensitive to different wavelengths of light, depending on the rhodopsin gene (rh) they express. Outer PRs are involved in motion detection and contain Rh1, a broad-spectrum photopigment. R7 and R8 each expresses a distinct rh with restricted absorption spectra-rh3, rh4, rh5, and rh6. The type of rh expressed in inner PRs defines two major types of ommatidia: The pale (p) ommatidia have R7 that contain UV-sensitive Rh3 with the corresponding R8 expressing blue Rh5, whereas in yellow (y) ommatidia, R7 expresses UV-sensitive Rh4 and R8 expresses green Rh6.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Recently, substantial progress has been achieved in understanding the molecular basis of how different subtypes of PRs are specified (Wernet and Desplan 2004; Mikeladze-Dvali et al. 2005a ). Initially, R7 and R8 express the transcription factor spalt (sal) that is required to specify them as inner PRs and distinguish them from outer PR identity (Mollereau et al. 2001) . Then, the expression in R7 of the gene prospero (pros), which encodes a homeodomain transcription factor, further distinguishes R7 from R8 by repressing R8 rhs, rh5, and rh6 .", "cite_spans": [{"start": 133, "end": 158, "text": "(Wernet and Desplan 2004;", "ref_id": "BIBREF55"}, {"start": 159, "end": 187, "text": "Mikeladze-Dvali et al. 2005a", "ref_id": "BIBREF32"}, {"start": 347, "end": 370, "text": "(Mollereau et al. 2001)", "ref_id": "BIBREF36"}], "ref_spans": []}, {"section": "Abstract", "text": "The generation of the two types of ommatidia, yellow and pale, includes several steps. First, the stochastic expression of the transcription factor Spineless (Ss) in a subset of R7 cells specifies yellow ommatidia. Ss is required cell autonomously in yR7 for rh4 expression and, further, cell nonautonomously for the underlying R8 cell to acquire y fate and turn on rh6 expression (Wernet et al. 2006) . The coordination between R7 and R8 rhodopsins requires a signal from pR7 that induces the pR8 fate. In sevenless mutants that lack R7, rh5 expression is lost while rh6 is expanded to almost all R8 (Papatsenko et al. 1997; Chou et al. 1999) . The y versus p choice in R8 is then reinforced by a bistable loop of regulation between the tumor suppressor gene warts (wts) and the growth regulator melted (melt) (Mikeladze-Dvali et al. 2005b) : wts is required for rh6 expression, whereas melt is essential for rh5 expression. wts and melt repress each other transcriptionally, thereby ensuring that a robust decision to express either rh5 or rh6 is made. The ho- ", "cite_spans": [{"start": 381, "end": 401, "text": "(Wernet et al. 2006)", "ref_id": "BIBREF56"}, {"start": 601, "end": 625, "text": "(Papatsenko et al. 1997;", "ref_id": "BIBREF42"}, {"start": 626, "end": 643, "text": "Chou et al. 1999)", "ref_id": "BIBREF6"}, {"start": 811, "end": 841, "text": "(Mikeladze-Dvali et al. 2005b)", "ref_id": "BIBREF33"}], "ref_spans": []}], "body_text": [{"section": "", "text": "In spite of the morphological and developmental differences between vertebrate and invertebrate eyes, their basic function to translate light information from the environment to the brain is maintained. In Drosophila, the adult compound eye has been studied in great detail. It consists of \u223c800 individual ommatidia. Each ommatidium contains eight photoreceptor cells (PRs): six outer PRs (R1-R6) and two inner PRs (R7 and R8) . Different PRs are sensitive to different wavelengths of light, depending on the rhodopsin gene (rh) they express. Outer PRs are involved in motion detection and contain Rh1, a broad-spectrum photopigment. R7 and R8 each expresses a distinct rh with restricted absorption spectra-rh3, rh4, rh5, and rh6. The type of rh expressed in inner PRs defines two major types of ommatidia: The pale (p) ommatidia have R7 that contain UV-sensitive Rh3 with the corresponding R8 expressing blue Rh5, whereas in yellow (y) ommatidia, R7 expresses UV-sensitive Rh4 and R8 expresses green Rh6.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Recently, substantial progress has been achieved in understanding the molecular basis of how different subtypes of PRs are specified (Wernet and Desplan 2004; Mikeladze-Dvali et al. 2005a ). Initially, R7 and R8 express the transcription factor spalt (sal) that is required to specify them as inner PRs and distinguish them from outer PR identity (Mollereau et al. 2001) . Then, the expression in R7 of the gene prospero (pros), which encodes a homeodomain transcription factor, further distinguishes R7 from R8 by repressing R8 rhs, rh5, and rh6 .", "cite_spans": [{"start": 133, "end": 158, "text": "(Wernet and Desplan 2004;", "ref_id": "BIBREF55"}, {"start": 159, "end": 187, "text": "Mikeladze-Dvali et al. 2005a", "ref_id": "BIBREF32"}, {"start": 347, "end": 370, "text": "(Mollereau et al. 2001)", "ref_id": "BIBREF36"}], "ref_spans": []}, {"section": "", "text": "The generation of the two types of ommatidia, yellow and pale, includes several steps. First, the stochastic expression of the transcription factor Spineless (Ss) in a subset of R7 cells specifies yellow ommatidia. Ss is required cell autonomously in yR7 for rh4 expression and, further, cell nonautonomously for the underlying R8 cell to acquire y fate and turn on rh6 expression (Wernet et al. 2006) . The coordination between R7 and R8 rhodopsins requires a signal from pR7 that induces the pR8 fate. In sevenless mutants that lack R7, rh5 expression is lost while rh6 is expanded to almost all R8 (Papatsenko et al. 1997; Chou et al. 1999) . The y versus p choice in R8 is then reinforced by a bistable loop of regulation between the tumor suppressor gene warts (wts) and the growth regulator melted (melt) (Mikeladze-Dvali et al. 2005b) : wts is required for rh6 expression, whereas melt is essential for rh5 expression. wts and melt repress each other transcriptionally, thereby ensuring that a robust decision to express either rh5 or rh6 is made. The ho-meoprotein encoded by orthodenticle (otd) is required in both p R7 and R8 to activate rh3 and rh5 through direct binding to their promoter. Otd has only a permissive role: It is expressed in all PRs and its overexpression is not able to induce rh3 or rh5 expression in y ommatidia. Furthermore, the y ommatidial fate does not expand in otd mutants (Tahayato et al. 2003) .", "cite_spans": [{"start": 381, "end": 401, "text": "(Wernet et al. 2006)", "ref_id": "BIBREF56"}, {"start": 601, "end": 625, "text": "(Papatsenko et al. 1997;", "ref_id": "BIBREF42"}, {"start": 626, "end": 643, "text": "Chou et al. 1999)", "ref_id": "BIBREF6"}, {"start": 811, "end": 841, "text": "(Mikeladze-Dvali et al. 2005b)", "ref_id": "BIBREF33"}, {"start": 1410, "end": 1432, "text": "(Tahayato et al. 2003)", "ref_id": "BIBREF51"}], "ref_spans": []}, {"section": "", "text": "Although much is known about the development of the adult visual system, little is known about the development and function of the larval visual system. PRs of the larval eye (Bolwig Organ [BO] ) extend their axonal projections to the larval pacemaker neurons, which control the larval circadian rhythm (Malpel et al. 2002; Hassan et al. 2005; Moncalvo and Campos 2005) . Visual input via the larval eye is crucial for the entrainment of the molecular clock (Malpel et al. 2004; Mazzoni et al. 2005) . Furthermore, both larval PRs and pacemaker neurons control larval photophobic behavior (Mazzoni et al. 2005) . Very simple in structure, the larval eye contains \u223c12-14 PRs (Green et al. 1993) . In contrast to adult ommatidia, BO lacks accessory cells, such as pigment cells or cone cells.", "cite_spans": [{"start": 303, "end": 323, "text": "(Malpel et al. 2002;", "ref_id": "BIBREF29"}, {"start": 324, "end": 343, "text": "Hassan et al. 2005;", "ref_id": "BIBREF18"}, {"start": 344, "end": 369, "text": "Moncalvo and Campos 2005)", "ref_id": "BIBREF37"}, {"start": 458, "end": 478, "text": "(Malpel et al. 2004;", "ref_id": "BIBREF30"}, {"start": 479, "end": 499, "text": "Mazzoni et al. 2005)", "ref_id": "BIBREF31"}, {"start": 589, "end": 610, "text": "(Mazzoni et al. 2005)", "ref_id": "BIBREF31"}, {"start": 674, "end": 693, "text": "(Green et al. 1993)", "ref_id": "BIBREF15"}], "ref_spans": []}, {"section": "", "text": "BO precursor cells develop in the optic placode adjacent to the optic lobe primordium (Green et al. 1993 ). Development of larval PR precursor cells proceeds in a two-step process. First, primary precursors (also called BO founder cells) are specified; they express and require the proneural gene atonal (ato) and the retinal patterning genes sine oculis (so) and eyes absent (eya) as well as hedgehog (hh) signaling (Schmucker et al. 1994; Suzuki and Saigo 2000) . Then, primary precursors signal to the surrounding tissue by expressing the TGF\u2423 homolog spitz (spi), which activates EGF receptor (EGFR) and recruits adjacent cells to develop as secondary precursors (Daniel et al. 1999; Suzuki and Saigo 2000) . tailless (tll), which encodes an orphan nuclear receptor, opposes EGFR signaling in the surrounding optic lobe primordium, preventing adjacent cells from developing as PRs (Daniel et al. 1999) . Subsequently, as immature PRs detach from the optic lobe primordium and start to differentiate, they extend their axons and remain in contact with the optic lobe (Schmucker et al. 1992 (Schmucker et al. , 1997 Dumstrei et al. 2002) . Two distinct PR subtypes can be distinguished in the larval eye: Four PRs contain blue-sensitive Rh5 while eight contain green-sensitive Rh6. This is strongly reminiscent of adult R8 PRs, which express Rh5 in 30% of ommatidia and Rh6 in the remaining 70%. Thus, similar molecular mechanisms could act to specify the two distinct subtypes in larval PRs and in adult R8 cells.", "cite_spans": [{"start": 86, "end": 104, "text": "(Green et al. 1993", "ref_id": "BIBREF15"}, {"start": 417, "end": 440, "text": "(Schmucker et al. 1994;", "ref_id": "BIBREF47"}, {"start": 441, "end": 463, "text": "Suzuki and Saigo 2000)", "ref_id": "BIBREF50"}, {"start": 667, "end": 687, "text": "(Daniel et al. 1999;", "ref_id": "BIBREF9"}, {"start": 688, "end": 710, "text": "Suzuki and Saigo 2000)", "ref_id": "BIBREF50"}, {"start": 885, "end": 905, "text": "(Daniel et al. 1999)", "ref_id": "BIBREF9"}, {"start": 1070, "end": 1092, "text": "(Schmucker et al. 1992", "ref_id": "BIBREF46"}, {"start": 1093, "end": 1117, "text": "(Schmucker et al. , 1997", "ref_id": "BIBREF48"}, {"start": 1118, "end": 1139, "text": "Dumstrei et al. 2002)", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "", "text": "Here we describe the genetic mechanisms underlying the specification of the two larval PR subtypes. We show that primary precursors develop independently of EGFR and give rise to the Rh5 subtype whereas secondary precursors give rise to Rh6-subtype PRs. EGFR signaling is required for the survival of secondary precursors of the Rh6 subtype. The combinatorial action of transcription factors Seven-up (Svp), Sal, and Otd is required to distinguish the two subtypes. The Rh5 subtype requires sal and otd, while the Rh6 subtype requires seven-up (svp). EGFR signaling, otd, svp, and sal are also core components of PR development in the adult retina. However, they play very different roles in the two systems. Thus, even though adult R8 and larval PRs share the same rhodopsin fates, the genetic pathways that control their expression are surprisingly different.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Embryonic development of the larval eye and initiation of rhodopsin expression", "text": "We followed BO PR development from specification of precursors until the end of larval life using anatomical and molecular markers. Larval PRs develop from a group of cells located at the ventral tip of the optic placode, adjacent to the progenitors of the optic lobe primordium (Green et al. 1993) . The earliest precursor cells express the proneural gene ato in a highly dynamic manner during embryonic stages 10-12 ( Fig. 1A ; Daniel et al. 1999; Suzuki and Saigo 2000) (we obtained comparable results using either the ato-Gal4 driver or an anti-Ato antibody; data not shown). Expression of ato in PR precursors decreases during stage 12 until no expression is found after embryonic stage 13. During embryonic stage 12, BO precursors start to express the neuronal marker Elav as well as Kr\u00fcppel (Kr) and Fasciclin II (FasII) (Schmucker et al. 1992; Daniel et al. 1999) , which were used as molecular markers for immature PRs throughout embryogenesis (Figs. 1B, 3A, below). During optic lobe invagination, larval PRs remain connected with the optic lobe primordium by the Bolwig Nerve (BN), which extends while the distance between the PRs and optic lobe primordium gradually increases (Schmucker et al. 1992) . By stage 15, all PRs are largely separated from the optic lobe primordium and BO is positioned at the anterior part of the embryonic head (Fig. 1B) , where it becomes associated with the head skeleton at embryonic stage 17 (Green et al. 1993) .", "cite_spans": [{"start": 279, "end": 298, "text": "(Green et al. 1993)", "ref_id": "BIBREF15"}, {"start": 430, "end": 449, "text": "Daniel et al. 1999;", "ref_id": "BIBREF9"}, {"start": 450, "end": 472, "text": "Suzuki and Saigo 2000)", "ref_id": "BIBREF50"}, {"start": 828, "end": 851, "text": "(Schmucker et al. 1992;", "ref_id": "BIBREF46"}, {"start": 852, "end": 871, "text": "Daniel et al. 1999)", "ref_id": "BIBREF9"}, {"start": 1188, "end": 1211, "text": "(Schmucker et al. 1992)", "ref_id": "BIBREF46"}, {"start": 1437, "end": 1456, "text": "(Green et al. 1993)", "ref_id": "BIBREF15"}], "ref_spans": [{"start": 420, "end": 427, "text": "Fig. 1A", "ref_id": "FIGREF0"}, {"start": 1352, "end": 1361, "text": "(Fig. 1B)", "ref_id": "FIGREF0"}]}, {"section": "Embryonic development of the larval eye and initiation of rhodopsin expression", "text": "Larval PRs, whose number varies from eight to 16, start to express rh5 and rh6 by the end of embryogenesis (stage 16/17) and maintain rh expression throughout larval life (Fig. 1C,D) . Three or four BO PRs express Rh5 and the remaining eight to 10 express Rh6 (Fig. 1C,D) . We verified that rh1, rh3, and rh4, which had been previously reported to be expressed in BO (Pollock and Benzer 1988) were not expressed in the larval eye (data not shown). The PR-specific gene chaoptic (chp) becomes expressed in all larval PRs at about the same developmental stage (Fig. 6D, below) . By the end of embryogenesis, PRs are packed tightly and do not exhibit any obvious signs of further cellular differentiation. However, during early larval life, their morphology changes dramatically; cells become loosely packed and build up arborizationlike protrusions (Fig. 1D, arrow) . While Ato expression quickly disappears, the expression of Chp, Kr, Elav, Rh5, and Rh6 is maintained throughout larval life.", "cite_spans": [{"start": 367, "end": 392, "text": "(Pollock and Benzer 1988)", "ref_id": "BIBREF43"}], "ref_spans": [{"start": 171, "end": 182, "text": "(Fig. 1C,D)", "ref_id": "FIGREF0"}, {"start": 260, "end": 271, "text": "(Fig. 1C,D)", "ref_id": "FIGREF0"}, {"start": 558, "end": 574, "text": "(Fig. 6D, below)", "ref_id": "FIGREF5"}, {"start": 847, "end": 863, "text": "(Fig. 1D, arrow)", "ref_id": "FIGREF0"}]}, {"section": "The Wts/Melt pathway is not involved in the choice of Rh5 versus Rh6", "text": "The expression of Rh5 and Rh6 in larval PRs is strongly reminiscent of the adult R8 PRs. Therefore, we tested whether wts and melt, which form a bistable loop of regulation required for the robust specification of Rh5 or Rh6 fate in adult R8, are also required in larval PRs. However we could not detect expression of wts or melt at any time during embryogenesis, as visualized using wts and melt enhancer trap lines. We also could not detect early maternal expression in embryos (data not shown). To test whether wts and melt are required for the subtype specification in the larval eye, we analyzed Rh5 and Rh6 expression in wts and melt mutant larvae. However, the expression of neither Rh5 nor Rh6 is affected ( Fig. 2A,B) . To manipulate the early phase of PR precursor specification and development, we made use of a sine oculis-Gal4 (so-Gal4), which starts to be expressed in the optic lobe placode at embryonic stage 10 and remains expressed in the optic lobe and all larval PRs throughout embryogenesis and larval life (Supplementary Fig. 1A,C) . Interestingly, the ectopic expression of UAS-wts or UAS-melt under the control of so-Gal4 did also not affect the expression Rh5 and Rh6 (Fig. 2C,D) . Furthermore the total number of larval PRs and the ratio of Rh5 PRs versus Rh6 PRs remain unaltered in both wts and melt gain of function (GOF) as well as in loss of function (LOF) (Fig. 2E) . Thus, in contrast to the adult retina, the specification of the Rh5 and Rh6 subtypes does not depend on wts and melt.", "cite_spans": [], "ref_spans": [{"start": 716, "end": 726, "text": "Fig. 2A,B)", "ref_id": "FIGREF1"}, {"start": 1043, "end": 1053, "text": "Fig. 1A,C)", "ref_id": "FIGREF0"}, {"start": 1193, "end": 1204, "text": "(Fig. 2C,D)", "ref_id": "FIGREF1"}, {"start": 1388, "end": 1397, "text": "(Fig. 2E)", "ref_id": "FIGREF1"}]}, {"section": "The Wts/Melt pathway is not involved in the choice of Rh5 versus Rh6", "text": "Egfr signaling and tll action orchestrate the development of the Rh6 subtype As in the adult eye, recruitment of BO PR precursor cells requires activation of the EGFR pathway. Primary BO precursors produce Spi, which is required in neighboring cells to develop as secondary precursors. In embryos mutant for spi, the immature larval eye only consists of three or four cells (Daniel et al. 1999 ). Therefore, we tested whether EGFR signaling is involved in the specification of larval PR subtypes and whether there is a correlation between primary precursors and rh5-expressing PRs or between secondary and rh6-expressing PRs. Because EGFR signaling has multiple earlier functions in the embryo, we misexpressed a dominant-negative form of EGFR (UAS-EGFR dn ) under the control of so-Gal4 to suppress EGFR activity in BO precursors. This results in the development of only three or four immature PRs as compared with \u223c14 cells in the wild type (Fig. 3A,B) , a phenocopy of the BO in spi mutants (Daniel et al. 1999 ). All of the remaining three or four PRs all express Rh5 (Fig. 3D) as well as the general markers Elav, FasII, Kr, and Chp (Fig. 3B,F) . They also express the Rh5-subtypespecific marker sal (Fig. 3F, see below) , but not the Rh6-subtype-specific marker svp (see below). These results show that EGFR signaling is required for the develop- ment of Rh6 PRs and strongly suggests that primary precursors develop into the Rh5 subtype while secondary precursors give rise to the Rh6 subtype.", "cite_spans": [{"start": 374, "end": 393, "text": "(Daniel et al. 1999", "ref_id": "BIBREF9"}, {"start": 994, "end": 1013, "text": "(Daniel et al. 1999", "ref_id": "BIBREF9"}], "ref_spans": [{"start": 943, "end": 954, "text": "(Fig. 3A,B)", "ref_id": "FIGREF2"}, {"start": 1072, "end": 1081, "text": "(Fig. 3D)", "ref_id": "FIGREF2"}, {"start": 1138, "end": 1149, "text": "(Fig. 3B,F)", "ref_id": "FIGREF2"}, {"start": 1205, "end": 1225, "text": "(Fig. 3F, see below)", "ref_id": "FIGREF2"}]}, {"section": "The Wts/Melt pathway is not involved in the choice of Rh5 versus Rh6", "text": "Activation of the EGFR pathway is relayed to the nucleus through the mitogen-activated protein kinase (MAPK) cascade, which ultimately leads to the phosphorylation of nuclear effectors such as the Ets family transcription factors Pointed (Pnt) and Yan (O'Neill et al. 1994) . Both Yan and Pnt are expressed during stage 10/11 in the developing lobe primordium when larval PRs form; however their expression decreases during embryonic stage 12/13, and no expression can be detected at stage 15 (Supplementary Fig. 2 ; data not shown).", "cite_spans": [{"start": 252, "end": 273, "text": "(O'Neill et al. 1994)", "ref_id": "BIBREF41"}], "ref_spans": [{"start": 508, "end": 514, "text": "Fig. 2", "ref_id": "FIGREF1"}]}, {"section": "The Wts/Melt pathway is not involved in the choice of Rh5 versus Rh6", "text": "The orphan nuclear receptor Tll has an effect opposite to the EGFR signaling in specifying PR precursors versus optic lobe primordium. Tll is expressed in the optic lobe primordium but not in PR precursors. Removing tll function in the embryo leads to supernumerous immature PRs (Daniel et al. 1999) , suggesting that tll acts negatively on the development of secondary precursors. To test which subset is affected, we analyzed Rh5 and Rh6 expression in tll mutants at the end of embryogenesis, before tll mutants die. The number of Rh5 PRs remains largely unchanged. However, the number of Rh6 PRs is dramatically increased to 20-25 instead of the normal eight to 10 (Fig. 4D ). This suggests that tll inhibits adjacent cells from adapting the Rh6 cell fate.", "cite_spans": [{"start": 279, "end": 299, "text": "(Daniel et al. 1999)", "ref_id": "BIBREF9"}], "ref_spans": [{"start": 668, "end": 676, "text": "(Fig. 4D", "ref_id": "FIGREF3"}]}, {"section": "The Wts/Melt pathway is not involved in the choice of Rh5 versus Rh6", "text": "Since the lack of EGFR signaling results in a smaller number of larval PRs due to cell death (Daniel et al. 1999) , the increased Rh6 PRs might result from the survival of adjacent optic lobe primordium cells that failed to die. We therefore expressed the apoptosis inhibitor UAS-p35 in optic lobe primordium under the control of so-Gal4. This leads to a high increase in the number of Rh6 PRs to \u223c20-25, whereas the number of Rh5 PRs remains unchanged, similar to the loss of tll function (Fig. 4F ). This strongly supports the notion that EGFR signaling is required in cells surrounding the primary precursors to prevent their apoptosis induced by tll, and therefore allow their development as Rh6 PRs. In addi- Larval PR-subtype specification tion to its survival function, EGFR signaling might also be required for the acquisition of the Rh6 cell fate. To approach this question, we concomitantly misexpressed UAS-p35 and UAS-EGFR dn under the control of so-Gal4. This leads to a strong increase in the number of Rh6 PRs, to \u223c20-25 without affecting the number of Rh5 PRs (Fig.  4G) , similar to the misexpression of UAS-p35 alone.", "cite_spans": [{"start": 93, "end": 113, "text": "(Daniel et al. 1999)", "ref_id": "BIBREF9"}], "ref_spans": [{"start": 490, "end": 498, "text": "(Fig. 4F", "ref_id": "FIGREF3"}, {"start": 1076, "end": 1086, "text": "(Fig.  4G)", "ref_id": "FIGREF3"}]}, {"section": "The Wts/Melt pathway is not involved in the choice of Rh5 versus Rh6", "text": "Thus EGFR signaling appears to be essential for the survival of the Rh6 subtype. However the immature precursors do not seem to depend on EGFR signaling for adapting the Rh6 cell fate. It is also possible that activity remaining in the EGFR dn context is able to induce the Rh6 fate while higher EGFR activity is required for survival.", "cite_spans": [], "ref_spans": []}, {"section": "Sal and Svp are expressed in distinct PR subtypes", "text": "In order to analyze the development, specification, and differentiation of the two subtypes of larval PRs, we looked for genes expressed in either the Rh5 or the Rh6 subtype. Among the genes required for adult PR development, pros and ss are key players in inner PR specification. However, we could not detect expression of Pros or Ss in developing BO PRs at any point during embryogenesis (data not shown). However, sal and svp are expressed in a subtype-specific fashion in the larval eye. During embryonic development, three or four immature PRs express sal ( Fig. 5A,B ; comparable results were obtained using sal-Gal4 or anti-Salm antibody; data not shown). sal expression starts during stage 13/14 and is maintained throughout embryogenesis and larval life. Its expression coincides precisely with rh5 ( Fig. 5C ) and is excluded from the Rh6 subtype (Fig. 5D) . svp shows the opposite expression pattern: Its expression is initiated during stage 13/14 and is maintained throughout embryogenesis and larval life in the Rh6 subtype, whereas it is excluded from the Rh5 subtype ( Fig. 5E-H anti-Svp antibody; data not shown). Thus sal and svp are expressed in complementary subsets of larval PR subtypes. The expression of both transcription factors precedes rhodopsin expression.", "cite_spans": [], "ref_spans": [{"start": 563, "end": 572, "text": "Fig. 5A,B", "ref_id": "FIGREF4"}, {"start": 810, "end": 817, "text": "Fig. 5C", "ref_id": "FIGREF4"}, {"start": 857, "end": 866, "text": "(Fig. 5D)", "ref_id": "FIGREF4"}, {"start": 1084, "end": 1093, "text": "Fig. 5E-H", "ref_id": "FIGREF4"}]}, {"section": "spalt is required for rh5 expression in larval PRs", "text": "The sal genes encode two zinc finger transcription factors that are specifically expressed in adult inner PRs R7 and R8, where they are required to distinguish them from outer PRs (Mollereau et al. 2001 ). Since sal is exclusively expressed in the Rh5 subtype, prior to rh5 expression, we tested whether it is required for the development of this subtype. We thus analyzed the expression of Rh5 and Rh6 in sal mutants at the end of embryogenesis, when these mutants die. No expression of Rh5 can be detected in sal mutants, even though the correct Cold (Fig. 6C) . However, the general PR markers Elav, FasII, Kr, and Chp remain expressed in all PRs, suggesting that four PRs express neither Rh5 nor Rh6 ( Fig. 6C ; data not shown). Since rh1, rh3, and rh4 expression cannot be detected, these four PRs appear to be \"empty\" and devoid of PR molecules (data not shown). PRs of the larval eye project into the region of the dendritic arborizations of the larval pacemaker neurons. Axon termini of Rh5 and Rh6 PRs are generally directly adjacent to each other (Mazzoni et al. 2005) . In sal mutants, all larval PRs project into the correct target region of the late embryonic brain (Fig. 6G) . We compared the projection termini of empty PRs with those of Rh6 PRs (\"empty\" PR termini are identified by FasII staining and the absence of Rh6 staining). At embryonic stage 17 (just before these mutants die), axonal termini of \"empty\" PRs project correctly to the target region, adjacent to Rh6 termini (Fig.  6H,I ). Therefore sal is essential in the larval eye for the proper differentiation of the Rh5 PRs but not for their early specification or for axonal targeting.", "cite_spans": [{"start": 180, "end": 202, "text": "(Mollereau et al. 2001", "ref_id": "BIBREF36"}, {"start": 1057, "end": 1078, "text": "(Mazzoni et al. 2005)", "ref_id": "BIBREF31"}], "ref_spans": [{"start": 553, "end": 562, "text": "(Fig. 6C)", "ref_id": "FIGREF5"}, {"start": 706, "end": 713, "text": "Fig. 6C", "ref_id": "FIGREF5"}, {"start": 1179, "end": 1188, "text": "(Fig. 6G)", "ref_id": "FIGREF5"}, {"start": 1497, "end": 1508, "text": "(Fig.  6H,I", "ref_id": "FIGREF5"}]}, {"section": "seven-up is required for Rh6-subtype specification and to repress Rh5-subtype fate", "text": "In the adult eye, the orphan nuclear receptor svp is required posterior to the morphogenetic furrow for the specification of the R3/R4 and R1/R6 pairs, but not for their later differentiation (Mlodzik et al. 1990 ). In the larval eye, svp is exclusively expressed in Rh6 PRs prior to rh6 expression, suggesting that it might be involved in the development of this subtype. We analyzed the expression of Rh5 and Rh6 in svp mutant embryos at stage 17 (as for sal, svp mutants die at the end of embryogenesis). While the total number of PRs (as marked by Elav, FasII, Kr, and Chp) remains unchanged (Fig. 6B,E) in svp mutants, all PRs express Rh5 (Fig. 6B ) and no Rh6 expression is detectable. Therefore, Rh6 cells appear to have switched fate toward the Rh5 fate. Consistent with the transformation of PRs into Rh5 subtype, all PRs express sal in svp mutants (Fig. 6E ). This suggests that svp is necessary for the repression of sal in the Rh6 subtype, thus allowing expression of rh6. To test whether svp is sufficient for the Rh6 PR fate, we performed gain-offunction experiments using early (so-Gal4) or later sevenless-Gal4 (sev-Gal4) drivers. The sev-Gal4 driver starts to be expressed in all larval PRs during late embryonic stages 12/13, just after all immature PRs have formed. It remains expressed through larval life ( Supplementary  Fig. 1B,D; data not shown). In larvae that express UASsvp under the control of so-Gal4, no Rh5 expression can be detected, while all BO PRs express rh6 with no change in the overall number of PRs (Fig. 6F) . However, if sal expression is affected, it is not completely abolished, with one to three PRs still weakly expressing Sal (data not shown), arguing that Rh6 is now expressed in the Rh5 subtype. Later expression of UAS-svp under the control of sev-Gal4 does not result in alteration of Rh expression (data not shown). Thus, svp not only acts to repress sal in the Rh6 subtype, but it also acts as an activator of Rh6 expression since Sal and Rh6 can coexist in the same cell. In contrast ectopic expression of UASsalm under the control of so-Gal4 or of sev-Gal4 leads to no change of Rh5 or Rh6 expression. Expression of Svp remains unaffected, with about eight cells still expressing Svp (data not shown). Thus svp is necessary and sufficient to induce the Rh6 fate. In contrast sal is necessary but not sufficient for the Rh5 fate.", "cite_spans": [{"start": 192, "end": 212, "text": "(Mlodzik et al. 1990", "ref_id": "BIBREF34"}], "ref_spans": [{"start": 596, "end": 607, "text": "(Fig. 6B,E)", "ref_id": "FIGREF5"}, {"start": 644, "end": 652, "text": "(Fig. 6B", "ref_id": "FIGREF5"}, {"start": 858, "end": 866, "text": "(Fig. 6E", "ref_id": "FIGREF5"}, {"start": 1328, "end": 1353, "text": "Supplementary  Fig. 1B,D;", "ref_id": "FIGREF0"}, {"start": 1539, "end": 1548, "text": "(Fig. 6F)", "ref_id": "FIGREF5"}]}, {"section": "seven-up is required for Rh6-subtype specification and to repress Rh5-subtype fate", "text": "otd is required in the Rh5 subtype for rh5 expression and rh6 repression The homeodomain protein Otd is required in inner PRs of the adult retina for the activation of rh3 and rh5 in p ommatidia, whereas it is required in outer PRs to repress rh6 (Tahayato et al. 2003 ). In the adult retina, otd is expressed in all PRs. Similarly, otd is expressed in all embryonic immature PRs, and this expression is maintained during larval life. During early development, otd acts as a major component for patterning the anterior region of the embryo (Cohen and Jurgens 1990) . During stages 8/9, otd expression spans the entire cephalic region (Fig. 7A) and becomes subsequently restricted to more anterior regions and regions giving rise to the brain. However otd expression is excluded from large parts of the optic lobe primordium as well as from the region giving rise to larval PRs (Fig. 7B) . Starting at stage 12, however, otd expression is reinitiated in the ventral lateral part of the optic lobe primordium, the region that will give rise to the precursors of larval PRs. otd remains expressed in all PRs throughout embryogenesis and larval life (Fig. 7C-F) . otd is not required for the formation of larval PRs (nor the larval optic lobe primordium): Even though otd-null mutant embryos show severe head involution defects, the normal number of immature PRs is formed (data not shown). To investigate whether otd is involved in larval PR-subtype specification, we analyzed Rh5 and Rh6 expression in viable otd uvi mutants ( Vandendries et al. 1996) . In otd uvi , larval PRs do not express Rh5 while the total number of PRs remains the same (Fig. 7G,H ) and all PRs express Rh6 (Fig. 7G) . About four cells still express sal, but these cells now express Rh6 instead of Rh5 (Fig. 7H) . Interestingly, the number of Svp-expressing cells is not altered, with four Svp-negative PRs expressing Rh6 (data not shown). This indicates that, in the Rh5 subtype, otd acts as an inhibitor of rh6 expression and is required for Rh5 expression. As expression of otd is unaltered in sal mutants (data not shown), otd, like sal, seems to be necessary but not sufficient for Rh5 expression. otd and sal expression does not depend on each other, and since they are both required for Rh5 expression, they appear to act in parallel pathways.", "cite_spans": [{"start": 247, "end": 268, "text": "(Tahayato et al. 2003", "ref_id": "BIBREF51"}, {"start": 540, "end": 564, "text": "(Cohen and Jurgens 1990)", "ref_id": "BIBREF7"}, {"start": 1525, "end": 1549, "text": "Vandendries et al. 1996)", "ref_id": "BIBREF54"}], "ref_spans": [{"start": 634, "end": 643, "text": "(Fig. 7A)", "ref_id": "FIGREF6"}, {"start": 877, "end": 886, "text": "(Fig. 7B)", "ref_id": "FIGREF6"}, {"start": 1146, "end": 1157, "text": "(Fig. 7C-F)", "ref_id": "FIGREF6"}, {"start": 1642, "end": 1652, "text": "(Fig. 7G,H", "ref_id": "FIGREF6"}, {"start": 1679, "end": 1688, "text": "(Fig. 7G)", "ref_id": "FIGREF6"}, {"start": 1774, "end": 1783, "text": "(Fig. 7H)", "ref_id": "FIGREF6"}]}, {"section": "Discussion", "text": "In this study, we describe the genetic mechanisms underlying the specification of BO PR subtypes. The larval eye consists of two distinct PR subtypes, three to four PRs containing blue-sensitive Rh5 and eight to 10 containing green-sensitive Rh6. Primary precursors, which give rise to the Rh5-subtype PRs, signal to the surrounding tissue to develop as secondary precursors, which become the Rh6 subtype. EGFR signaling is required for the survival of these secondary precursors. The combi- natorial action of the three transcription factors Sal, Svp, and Otd then orchestrates the differentiation of the two PR subtypes. Interestingly, even though larval PRs and the adult R8 have the same rhodopsin content, the mechanisms to establish their fates are remarkably different.", "cite_spans": [], "ref_spans": []}, {"section": "Initial specification of PR cell fates", "text": "Specification of adult PRs starts with the proliferation of undifferentiated cells anterior to the morphogenetic furrow and the recruitment of individual PRs into ommatidia posterior to the morphogenetic furrow in a tightly regulated spatiotemporal manner. R8 is first specified by ato and does not depend on EGFR signaling (Jarman et al. 1994; Freeman 1996) . Sequential recruitment of all other PRs (R2/5, R3/4, R1/6, and then R7) is dependent on EGFR signaling (Freeman 1996; Raabe 2000; Nagaraj and Banerjee 2004) . Similarly, in the larval eye, primary precursors express ato and are independent of EGFR signaling while secondary precursors need EGFR signaling for their development. Primary precursors develop into the Rh5 subtype while the Rh6-subtype identity corresponds to secondary precursors.", "cite_spans": [{"start": 324, "end": 344, "text": "(Jarman et al. 1994;", "ref_id": "BIBREF21"}, {"start": 345, "end": 358, "text": "Freeman 1996)", "ref_id": "BIBREF14"}, {"start": 464, "end": 478, "text": "(Freeman 1996;", "ref_id": "BIBREF14"}, {"start": 479, "end": 490, "text": "Raabe 2000;", "ref_id": "BIBREF44"}, {"start": 491, "end": 517, "text": "Nagaraj and Banerjee 2004)", "ref_id": "BIBREF38"}], "ref_spans": []}, {"section": "Promoting and repressing the Rh6 subtype", "text": "During larval PR development, EGFR signaling is required for the Rh6 but not the Rh5 subtype. tll inhibits this process by preventing the adjacent optic lobe primordium from responding to EGFR signaling (Daniel et al. 1999; Dumstrei et al. 2002; Chang et al. 2003a ). However, expression of tll is not negatively regulated by EGFR signaling (Daniel et al. 1999; Dumstrei et al. 2002; Chang et al. 2003a) . Blocking apoptosis or removing tll function both result in supernumerary Rh6 cells, indicating that cells that should have died in response to tll function become Rh6 PRs (Fig. 8A) . Secondary precursors do not appear to require maintenance of EGFR signaling to survive. During later developmental stages, all immature PRs express sevenless, another gene encoding a Receptor Tyrosine Kinase as well as its ligand, Boss (S.G. Specher and C. Desplan, unpubl.), which could act redundantly with EGFR later in development. However, we see no effect of mutating boss or sev, either on larval PR number or on Rh5/Rh6 expression (S.G. Specher and C. Desplan, unpubl.). It could be that late EGFR activity compensates for the loss of Sev activity, comparable with the adult R7 cells, where EGFR is sufficient to replace Sev (Freeman 1996) .", "cite_spans": [{"start": 203, "end": 223, "text": "(Daniel et al. 1999;", "ref_id": "BIBREF9"}, {"start": 224, "end": 245, "text": "Dumstrei et al. 2002;", "ref_id": "BIBREF12"}, {"start": 246, "end": 264, "text": "Chang et al. 2003a", "ref_id": "BIBREF3"}, {"start": 341, "end": 361, "text": "(Daniel et al. 1999;", "ref_id": "BIBREF9"}, {"start": 362, "end": 383, "text": "Dumstrei et al. 2002;", "ref_id": "BIBREF12"}, {"start": 384, "end": 403, "text": "Chang et al. 2003a)", "ref_id": "BIBREF3"}, {"start": 1222, "end": 1236, "text": "(Freeman 1996)", "ref_id": "BIBREF14"}], "ref_spans": [{"start": 577, "end": 586, "text": "(Fig. 8A)", "ref_id": "FIGREF7"}]}, {"section": "Promoting and repressing the Rh6 subtype", "text": "What is the function of the EGFR pathway in antagonizing tll function? The Ets transcription factors yan and pnt are both expressed during the period of secondary precursor specification. In response to EGFR signaling, Yan acts as a repressor and Pnt as an activator. Their tightly controlled activation, cross-regulation, and competition for binding sites are essential for appropriate EGFR signaling. It is difficult, however, to test their function in BO PR formation, as mutants die with strong patterning defects in the embryo. We could test the function of EGFR because we were able to inhibit its function late, specifically in the optic lobe region, by misexpressing a dominant-negative form of EGFR. This likely inhibits but might not completely abolish endogenous EGFR signaling. Thus, even though concomitantly preventing cell death and EGFR signaling restores Rh6 PRs, it is possible that basal levels of EGFR signaling are sufficient for the specification of Rh6 PR specification, but not for survival. The mechanism by which tll affects secondary precursor development remains elusive. tll might prevent cells from developing as secondary precursors, leading them to undergo apoptosis. Only cells that receive enough EGFR signal near primary PR precursors are rescued. Alternatively a second signal could make tll-expressing cells undergo apoptosis. Notch and hedgehog signaling have also been shown to be involved the development of larval PRs and may provide an alternative source for proper subtype specification and tll acts in the surrounding tissue to inhibit secondary precursor development. Primary precursors give rise to the Rh5 PR subtype, whereas secondary precursors give rise to the Rh6 PR subtype. In the Rh5 PR subtype, sal and otd are required for Rh5 expression, and otd further for the repression of Rh6. In the Rh6 subtype, svp is required for Rh6 expression and for the repression of sal expression. (B) The negative feedback loop of wts and melt mediates the decision of R8 to express Rh6 or Rh5. Which way the loop swings depends on an instructive signal of the overlying R7 cell. The presence of gene expression is indicated by black type and its absence is indicated with gray type. Arrows shown in black (for activation) and red (for repression) indicate an active interaction; gray arrows indicate the absence of this interaction.", "cite_spans": [], "ref_spans": []}, {"section": "Promoting and repressing the Rh6 subtype", "text": "Larval PR-subtype specification", "cite_spans": [], "ref_spans": []}, {"section": "GENES & DEVELOPMENT 2191", "text": "Cold Spring Harbor Laboratory Press on November 4, 2016 -Published by genesdev.cshlp.org Downloaded from survival of secondary precursors (Green et al. 1993; Schmucker et al. 1994; Suzuki and Saigo 2000) .", "cite_spans": [{"start": 138, "end": 157, "text": "(Green et al. 1993;", "ref_id": "BIBREF15"}, {"start": 158, "end": 180, "text": "Schmucker et al. 1994;", "ref_id": "BIBREF47"}, {"start": 181, "end": 203, "text": "Suzuki and Saigo 2000)", "ref_id": "BIBREF50"}], "ref_spans": []}, {"section": "Network of transcription factors for PR-subtype specification", "text": "During larval eye development, sal is only required for the expression of Rh5 but not for the specification of Rh5-subtype fate. First, ectopic activation of Sal is not sufficient to induce Rh5 expression. Further, sal is still expressed in cells that have adopted the Rh6 subtype due to ectopic svp expression. In contrast, svp is required and sufficient for the Rh6 subtype where it represses the Rh5-subtype fate. Interestingly, svp is not only required for the repression of sal, but is also necessary for Rh6 expression (Fig. 8A) . In the adult retina, svp is necessary for the specification of the R3/R4 and R1/R6 pairs (Mlodzik et al. 1990; Domingos et al. 2004a,b) where it is also required for the repression of sal: R3/R4 are transformed into R7 cells in svp mutants (Domingos et al. 2004b) . However, the upstream mechanisms by which the expression of sal and svp is controlled in larval PRs remains elusive. There may be an unknown signal from primary precursors that induces secondary precursors by controlling svp expression. This signal is probably not EGFR, since EGFR dn secondary cells that are rescued from death by p35 still express svp.", "cite_spans": [{"start": 626, "end": 647, "text": "(Mlodzik et al. 1990;", "ref_id": "BIBREF34"}, {"start": 777, "end": 800, "text": "(Domingos et al. 2004b)", "ref_id": "BIBREF11"}], "ref_spans": [{"start": 525, "end": 534, "text": "(Fig. 8A)", "ref_id": "FIGREF7"}]}, {"section": "Network of transcription factors for PR-subtype specification", "text": "In the adult retina otd is required for the expression of rh3 and rh5 and for the repression of Rh6 in outer PRs. In the larval eye, is also expressed in all PRs, but it is not required for the formation of larval PRs. During their terminal differentiation, otd is required, only in the Rh5 subtype, for Rh5 expression and Rh6 repression (Fig. 8A) . Since otd only functions in the context of sal expression, it acts as a permissive factor for Rh regulation. It seems likely that otd and sal act in parallel in the Rh5 subtype: Otd expression is not altered in sal mutants and Sal expression is not altered in otd mutants. Further, Otd, which binds directly to the rh3, rh5, and rh6 enhancers in the adult eye, likely acts in a similar fashion in larval PRs (Tahayato et al. 2003) .", "cite_spans": [{"start": 758, "end": 780, "text": "(Tahayato et al. 2003)", "ref_id": "BIBREF51"}], "ref_spans": [{"start": 338, "end": 347, "text": "(Fig. 8A)", "ref_id": "FIGREF7"}]}, {"section": "Specification of PR subtypes: comparison between larval and adult eyes", "text": "There are interesting similarities and differences between PR-subtype specification in the larval and adult eyes. Most strikingly, the two Rhs expressed in the larval eye are R8 Rhs. The type of Rh expressed in R8 is instructed by R7 and maintained by the wts/melt bistable loop (Fig. 8B) . In contrast, in the larva, there are no additional PRs in BO to instruct the Rh5 and Rh6 PR fate and the expression of these genes does not depend on wts and melt. Since misexpression of wts or melt does not affect larval PRs, the downstream effectors of the loop must be absent or not functioning in the larval eye. Rh5 PRs, which are specified first, might be a source of an instructive signal for the Rh6-subtype fate. Alternatively, this signal might arise from non-BO cells. However, we have not yet been able to determine its identity. Finally, larval PRs are not specified or distributed stochastically in BO, as the two groups that express Rhr or Rh6 are physically distinct, presumably explaining why there is not need for the bistable loop of wts and melt. Therefore, even though the Rh fates of larval PRs and adult R8 are identical, they achieve their fates through very distinct mechanisms.", "cite_spans": [], "ref_spans": [{"start": 279, "end": 288, "text": "(Fig. 8B)", "ref_id": "FIGREF7"}]}, {"section": "Larval PR development: similarities to chordotonal organ development", "text": "Primary sensory precursors also induce secondary precursors in the development of the peripheral nervous system, in chordotonal and external sensory organs. After the delamination of chordotonal or sensory organ precursors (SOP), these cells signal to the overlaying ectoderm to induce delamination of secondary precursors (Okabe and Okano 1997; zur Lage and Jarman 1999; zur Lage et al. 2004 ). EGFR signaling is essential for the survival of BO secondary precursors, whereas in SOPs, it induces the delamination of secondary precursors. sal is also required to adopt the proper final cell fate both in larval PR precursors (Rh5 vs. Rh6) and embryonic SOPs (nonneuronal oenocytes vs. sensory neurons) (Elstob et al. 2001 ). However, oenocyte specification completely depends on sal, whereas larval eye primary precursors only require sal for Rh5 expression (Elstob et al. 2001 ). Thus, the two systems use EGFR signaling and Sal differently.", "cite_spans": [{"start": 323, "end": 345, "text": "(Okabe and Okano 1997;", "ref_id": "BIBREF39"}, {"start": 346, "end": 371, "text": "zur Lage and Jarman 1999;", "ref_id": "BIBREF57"}, {"start": 372, "end": 392, "text": "zur Lage et al. 2004", "ref_id": "BIBREF58"}, {"start": 702, "end": 721, "text": "(Elstob et al. 2001", "ref_id": "BIBREF13"}, {"start": 858, "end": 877, "text": "(Elstob et al. 2001", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "Larval PR development: similarities to chordotonal organ development", "text": "Larval PR precursors do not further divide, while SOPs later undergo asymmetric cell division to produce two nonidentical daughter cells. This may be due to the fact that BO only contain two different subtypes, whose identity correlate with primary or secondary precursors. Further, larval PR precursors develop in a group of adjacent cells as part of a placode. Thus, classical SOP specification using Notch signaling and lateral inhibition does not seem to occur to specify PR precursors. It will of great interest to further investigate the similarities and differences in the molecular mechanisms underlying the development of these sensory organs and how they are controlled.", "cite_spans": [], "ref_spans": []}, {"section": "Materials and methods", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Drosophila strains and genetics", "text": "For wild-type comparison we used yw 122 ; yw 122 , sp/CyO, TM2/ TM6b; or heterozygous siblings of mutant alleles. For sal mutant analysis, the sal 16 and a small Deficiency-Df(2L)32FP-5, which removes salm and salr-were used, balanced over CyO, Dfd-YFP; both fly strains gave comparable results (Kuhnlein et al. 1994; Elstob et al. 2001) . For svp mutant analysis, the svp E22 was used, balanced over TM6b, Dfd-YFP (Mlodzik et al. 1990 ). For tll mutant analysis, the tll 1 and tll 149 were used, balanced over TM6b, Dfd-YFP. For sal, tll, and svp, homozygous mutants were identified by the absence of Dfd-YFP (Bloomington Stock Center). We used the viable otd uvi allele (Vandendries et al. 1996) . The following fly strains were used: so-Gal4 (Chang et al. 2003b) , sev-Gal4 (Therrien et al. 1999) , otd-Gal4 (T. Cook, pers. comm.), ato-Gal4 (Hassan et al. 2000) , svp H162 -LacZ (Elstob et al. 2001 (Kuhnlein and Schuh 1996) , UASsvp (Kramer et al. 1995) , UAS-CD8GFP, UAS-p35, UAS-pnt", "cite_spans": [{"start": 295, "end": 317, "text": "(Kuhnlein et al. 1994;", "ref_id": "BIBREF27"}, {"start": 318, "end": 337, "text": "Elstob et al. 2001)", "ref_id": "BIBREF13"}, {"start": 415, "end": 435, "text": "(Mlodzik et al. 1990", "ref_id": "BIBREF34"}, {"start": 672, "end": 697, "text": "(Vandendries et al. 1996)", "ref_id": "BIBREF54"}, {"start": 745, "end": 765, "text": "(Chang et al. 2003b)", "ref_id": "BIBREF4"}, {"start": 777, "end": 799, "text": "(Therrien et al. 1999)", "ref_id": "BIBREF53"}, {"start": 882, "end": 901, "text": "(Elstob et al. 2001", "ref_id": "BIBREF13"}, {"start": 902, "end": 927, "text": "(Kuhnlein and Schuh 1996)", "ref_id": "BIBREF26"}, {"start": 937, "end": 957, "text": "(Kramer et al. 1995)", "ref_id": "BIBREF25"}], "ref_spans": []}, {"section": "P1", "text": ", and UAS-yan (Bloomington). Embryos were staged according to Campos-Ortega and Hartenstein (1997) .", "cite_spans": [{"start": 62, "end": 98, "text": "Campos-Ortega and Hartenstein (1997)", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "Immunohistochemistry and preparation of embryonic and larval specimen", "text": "Embryos were dechorionated, fixed, and immunostained according to previously published protocols (Therianos et al. 1995) . Primary antibodies were rabbit anti-Rh6 1:10,000 (Tahayato et al. 2003) , mouse anti-Rh5 1:20, anti-Rh3 1:20, or anti-Rh4 1:20 (Chou et al. 1996) , mouse anti-Nrt 1:10 (Developmental Studies Hybridoma Bank [DSHB]), mouse anti-Rh1 1:20 (DSHB), mouse anti-FasII 1:10 (Lin and Goodman 1994), rat anti-Elav 1:30 (DSHB), goat anti-Ato 1:1000 (Jarman et al. 1993) , sheep anti-GFP (Biogenesis), rabbit anti-Sal 1:200 (Kuhnlein et al. 1994) , mouse anti-Svp 1:1000 (Kanai et al. 2005) , mouse antiPros 1:50 (DSHB), mouse anti-Chp 1:10 (DSHB), rat anti-Otd 1:200 (Hirth et al. 2003) , rat anti-Kr 1:300 (Kosman et al. 1998) , rab anti-Pnt P1 (Alvarez et al. 2003) , anti-Yan (Rebay and Rubin 1995) , guinea pig anti-Ss 1:500 (Kim et al. 2006) , and mouse anti-\u2424GAL 1:20 (DSHB). Secondary antibodies used for confocal microscopic analysis were Alexa-488, Alexa-555, and Alexa-647 antibodies generated in goat (Molecular probes), all at 1:300-1:500 dilution. Embryos were mounted in Vectashield H-1000 (Vector). For the analysis of the larval BO, the head skeleton was separated from epidermis, imaginal discs, and brain and fixed for 15 min in 4% formaldehyde/PBS. The chitinous head skeleton was then carefully opened on the dorsal and ventral midline using sharpened minutien pins (0.1-mm diameter, Fisher Scientific Tools).", "cite_spans": [{"start": 97, "end": 120, "text": "(Therianos et al. 1995)", "ref_id": "BIBREF52"}, {"start": 172, "end": 194, "text": "(Tahayato et al. 2003)", "ref_id": "BIBREF51"}, {"start": 250, "end": 268, "text": "(Chou et al. 1996)", "ref_id": "BIBREF5"}, {"start": 460, "end": 480, "text": "(Jarman et al. 1993)", "ref_id": "BIBREF20"}, {"start": 534, "end": 556, "text": "(Kuhnlein et al. 1994)", "ref_id": "BIBREF27"}, {"start": 581, "end": 600, "text": "(Kanai et al. 2005)", "ref_id": "BIBREF22"}, {"start": 678, "end": 697, "text": "(Hirth et al. 2003)", "ref_id": "BIBREF19"}, {"start": 718, "end": 738, "text": "(Kosman et al. 1998)", "ref_id": "BIBREF24"}, {"start": 757, "end": 778, "text": "(Alvarez et al. 2003)", "ref_id": "BIBREF0"}, {"start": 790, "end": 812, "text": "(Rebay and Rubin 1995)", "ref_id": "BIBREF45"}, {"start": 840, "end": 857, "text": "(Kim et al. 2006)", "ref_id": "BIBREF23"}], "ref_spans": []}, {"section": "Laser confocal microscopy and image processing", "text": "For laser confocal microscopy, a Leica TCS SP was used. Optical sections ranged from 0.2 to 1.5 \u00b5m, recorded in line average mode with a picture size of 512 \u00d7 512 pixels or 1024 \u00d7 1024 pixels. Captured images from optical sections were arranged and processed using Leica confocal Software (LCS). Complete series of optical sections were imported and processed using ImageJ. Generation of three-dimensional digital models and raw tiff stacks (stacks of optical sections) were done using AMIRA (Mercury Computer Systems) as previously described (Sprecher et al. 2006) .", "cite_spans": [{"start": 543, "end": 565, "text": "(Sprecher et al. 2006)", "ref_id": "BIBREF49"}], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "pannier and pointedP2 act sequentially to regulate Drosophila heart development", "authors": [{"first": "A", "middle": ["D"], "last": "Alvarez", "suffix": ""}, {"first": "W", "middle": ["Y"], "last": "Shi", "suffix": ""}, {"first": "B", "middle": ["A"], "last": "Wilson", "suffix": ""}, {"first": "J", "middle": ["B"], "last": "Skeath", "suffix": ""}], "year": 2003, "venue": "Development", "link": "3239892"}, "BIBREF1": {"title": "Frizzled regulates localization of cellfate determinants and mitotic spindle rotation during asymmetric cell division", "authors": [{"first": "Y", "middle": [], "last": "Bellaiche", "suffix": ""}, {"first": "M", "middle": [], "last": "Gho", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Kaltschmidt", "suffix": ""}, {"first": "A", "middle": ["H"], "last": "Brand", "suffix": ""}, {"first": "F", "middle": [], "last": "Schweisguth", "suffix": ""}], "year": 2001, "venue": "Nat. Cell Biol", "link": "16136920"}, "BIBREF2": {"title": "The embryonic development of Drosophila melanogaster", "authors": [{"first": "J", "middle": ["A"], "last": "Campos-Ortega", "suffix": ""}, {"first": "V", "middle": [], "last": "Hartenstein", "suffix": ""}], "year": 1997, "venue": "", "link": "21926238"}, "BIBREF3": {"title": "Antagonistic relationship between Dpp and EGFR signaling in Drosophila head patterning", "authors": [{"first": "T", "middle": [], "last": "Chang", "suffix": ""}, {"first": "D", "middle": [], "last": "Shy", "suffix": ""}, {"first": "V", "middle": [], "last": "Hartenstein", "suffix": ""}], "year": 2003, "venue": "Dev. Biol", "link": "6776383"}, "BIBREF4": {"title": "Development of neural lineages derived from the sine oculis positive eye field of Drosophila", "authors": [{"first": "T", "middle": [], "last": "Chang", "suffix": ""}, {"first": "A", "middle": [], "last": "Younossi-Hartenstein", "suffix": ""}, {"first": "V", "middle": [], "last": "Hartenstein", "suffix": ""}], "year": 2003, "venue": "Arthropod Struct. Dev", "link": "24243770"}, "BIBREF5": {"title": "Identification of a novel opsin reveals specific patterning of the R7 and R8 photoreceptor cells", "authors": [{"first": "W", "middle": [], "last": "Chou", "suffix": ""}, {"first": "K", "middle": [], "last": "Hall", "suffix": ""}, {"first": "D", "middle": [], "last": "Wilson", "suffix": ""}, {"first": "C", "middle": [], "last": "Wideman", "suffix": ""}, {"first": "S", "middle": [], "last": "Townson", "suffix": ""}, {"first": "L", "middle": [], "last": "Chadwell", "suffix": ""}, {"first": "S", "middle": [], "last": "Britt", "suffix": ""}], "year": 1996, "venue": "Neuron", "link": null}, "BIBREF6": {"title": "Patterning of the R7 and R8 photoreceptor cells of Drosophila: Evidence for induced and default cell-fate specification", "authors": [{"first": "W", "middle": ["H"], "last": "Chou", "suffix": ""}, {"first": "A", "middle": [], "last": "Huber", "suffix": ""}, {"first": "J", "middle": [], "last": "Bentrop", "suffix": ""}, {"first": "S", "middle": [], "last": "Schulz", "suffix": ""}, {"first": "K", "middle": [], "last": "Schwab", "suffix": ""}, {"first": "L", "middle": ["V"], "last": "Chadwell", "suffix": ""}, {"first": "R", "middle": [], "last": "Paulsen", "suffix": ""}, {"first": "S", "middle": ["G"], "last": "Britt", "suffix": ""}], "year": 1999, "venue": "Development", "link": "1653710"}, "BIBREF7": {"title": "Mediation of Drosophila head development by gap-like segmentation genes", "authors": [{"first": "S", "middle": ["M"], "last": "Cohen", "suffix": ""}, {"first": "G", "middle": [], "last": "Jurgens", "suffix": ""}], "year": 1990, "venue": "Nature", "link": null}, "BIBREF8": {"title": "Distinction between color photoreceptor cell fates is controlled by Prospero in Drosophila", "authors": [{"first": "T", "middle": [], "last": "Cook", "suffix": ""}, {"first": "F", "middle": [], "last": "Pichaud", "suffix": ""}, {"first": "R", "middle": [], "last": "Sonneville", "suffix": ""}, {"first": "D", "middle": [], "last": "Papatsenko", "suffix": ""}, {"first": "C", "middle": [], "last": "Desplan", "suffix": ""}], "year": 2003, "venue": "Dev. Cell", "link": "2927625"}, "BIBREF9": {"title": "The control of cell fate in the embryonic visual system by atonal, tailless and EGFR signaling", "authors": [{"first": "A", "middle": [], "last": "Daniel", "suffix": ""}, {"first": "K", "middle": [], "last": "Dumstrei", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Lengyel", "suffix": ""}, {"first": "V", "middle": [], "last": "Hartenstein", "suffix": ""}], "year": 1999, "venue": "Development", "link": "14006830"}, "BIBREF10": {"title": "Regulation of R7 and R8 differentiation by the spalt genes", "authors": [{"first": "P", "middle": ["M"], "last": "Domingos", "suffix": ""}, {"first": "S", "middle": [], "last": "Brown", "suffix": ""}, {"first": "R", "middle": [], "last": "Barrio", "suffix": ""}, {"first": "K", "middle": [], "last": "Ratnakumar", "suffix": ""}, {"first": "B", "middle": ["J"], "last": "Frankfort", "suffix": ""}, {"first": "G", "middle": [], "last": "Mardon", "suffix": ""}, {"first": "H", "middle": [], "last": "Steller", "suffix": ""}, {"first": "B", "middle": [], "last": "Mollereau", "suffix": ""}], "year": 2004, "venue": "Dev. Biol", "link": "2738368"}, "BIBREF11": {"title": "Spalt transcription factors are required for R3/R4 specification and establishment of planar cell polarity in the Drosophila eye", "authors": [{"first": "P", "middle": ["M"], "last": "Domingos", "suffix": ""}, {"first": "M", "middle": [], "last": "Mlodzik", "suffix": ""}, {"first": "C", "middle": ["S"], "last": "Mendes", "suffix": ""}, {"first": "S", "middle": [], "last": "Brown", "suffix": ""}, {"first": "H", "middle": [], "last": "Steller", "suffix": ""}, {"first": "B", "middle": [], "last": "Mollereau", "suffix": ""}], "year": 2004, "venue": "Development", "link": "12389921"}, "BIBREF12": {"title": "Interaction between EGFR signaling and DE-cadherin during nervous system morphogenesis", "authors": [{"first": "K", "middle": [], "last": "Dumstrei", "suffix": ""}, {"first": "F", "middle": [], "last": "Wang", "suffix": ""}, {"first": "D", "middle": [], "last": "Shy", "suffix": ""}, {"first": "U", "middle": [], "last": "Tepass", "suffix": ""}, {"first": "V", "middle": [], "last": "Hartenstein", "suffix": ""}], "year": 2002, "venue": "Development", "link": "7313952"}, "BIBREF13": {"title": "spalt-dependent switching between two cell fates that are induced by the Drosophila EGF receptor", "authors": [{"first": "P", "middle": ["R"], "last": "Elstob", "suffix": ""}, {"first": "V", "middle": [], "last": "Brodu", "suffix": ""}, {"first": "A", "middle": ["P"], "last": "Gould", "suffix": ""}], "year": 2001, "venue": "Development", "link": "26064810"}, "BIBREF14": {"title": "Reiterative use of the EGF receptor triggers differentiation of all cell types in the Drosophila eye", "authors": [{"first": "M", "middle": [], "last": "Freeman", "suffix": ""}], "year": 1996, "venue": "Cell", "link": "13295688"}, "BIBREF15": {"title": "The embryonic development of the Drosophila visual system", "authors": [{"first": "P", "middle": [], "last": "Green", "suffix": ""}, {"first": "A", "middle": ["Y"], "last": "Hartenstein", "suffix": ""}, {"first": "V", "middle": [], "last": "Hartenstein", "suffix": ""}], "year": 1993, "venue": "Cell Tissue Res", "link": "24868933"}, "BIBREF17": {"title": "atonal regulates neurite arborization but does not act as a proneural gene in the Drosophila brain", "authors": [{"first": "H", "middle": ["Y"], "last": "Zoghbi", "suffix": ""}, {"first": "H", "middle": ["J"], "last": "Bellen", "suffix": ""}], "year": 2000, "venue": "Neuron", "link": "4980890"}, "BIBREF18": {"title": "Photic input pathways that mediate the Drosophila larval response to light and circadian rhythmicity are developmentally related but functionally distinct", "authors": [{"first": "J", "middle": [], "last": "Hassan", "suffix": ""}, {"first": "B", "middle": [], "last": "Iyengar", "suffix": ""}, {"first": "N", "middle": [], "last": "Scantlebury", "suffix": ""}, {"first": "V", "middle": ["R"], "last": "Moncalvo", "suffix": ""}, {"first": "R", "middle": [], "last": "Campos", "suffix": ""}], "year": 2005, "venue": "J. Comp. Neurol", "link": "38371869"}, "BIBREF19": {"title": "An urbilaterian origin of the tripartite brain: Developmental genetic insights from Drosophila", "authors": [{"first": "F", "middle": [], "last": "Hirth", "suffix": ""}, {"first": "L", "middle": [], "last": "Kammermeier", "suffix": ""}, {"first": "E", "middle": [], "last": "Frei", "suffix": ""}, {"first": "U", "middle": [], "last": "Walldorf", "suffix": ""}, {"first": "M", "middle": [], "last": "Noll", "suffix": ""}, {"first": "H", "middle": [], "last": "Reichert", "suffix": ""}], "year": 2003, "venue": "Development", "link": "14084538"}, "BIBREF20": {"title": "atonal is a proneural gene that directs chordotonal organ formation in the Drosophila peripheral nervous system", "authors": [{"first": "A", "middle": ["P"], "last": "Jarman", "suffix": ""}, {"first": "Y", "middle": [], "last": "Grau", "suffix": ""}, {"first": "L", "middle": ["Y"], "last": "Jan", "suffix": ""}, {"first": "Jan", "middle": [], "last": "", "suffix": ""}, {"first": "Y", "middle": ["N"], "last": "", "suffix": ""}], "year": 1993, "venue": "Cell", "link": "10169222"}, "BIBREF21": {"title": "Atonal is the proneural gene for Drosophila photoreceptors", "authors": [{"first": "A", "middle": ["P"], "last": "Jarman", "suffix": ""}, {"first": "E", "middle": ["H"], "last": "Grell", "suffix": ""}, {"first": "L", "middle": [], "last": "Ackerman", "suffix": ""}, {"first": "L", "middle": ["Y"], "last": "Jan", "suffix": ""}, {"first": "Jan", "middle": [], "last": "", "suffix": ""}, {"first": "Y", "middle": ["N"], "last": "", "suffix": ""}], "year": 1994, "venue": "Nature", "link": null}, "BIBREF22": {"title": "seven-up Controls switching of transcription factors that specify temporal identities of Drosophila neuroblasts", "authors": [{"first": "M", "middle": ["I"], "last": "Kanai", "suffix": ""}, {"first": "M", "middle": [], "last": "Okabe", "suffix": ""}, {"first": "Y", "middle": [], "last": "Hiromi", "suffix": ""}], "year": 2005, "venue": "Dev. Cell", "link": "22846431"}, "BIBREF23": {"title": "The bHLH-PAS protein Spineless is necessary for the diversification of dendrite morphology of Drosophila dendritic arborization neurons", "authors": [{"first": "M", "middle": ["D"], "last": "Kim", "suffix": ""}, {"first": "L", "middle": ["Y"], "last": "Jan", "suffix": ""}, {"first": "Jan", "middle": [], "last": "", "suffix": ""}, {"first": "Y", "middle": ["N"], "last": "", "suffix": ""}], "year": 2006, "venue": "Genes & Dev", "link": "31640257"}, "BIBREF24": {"title": "Rapid preparation of a panel of polyclonal antibodies to Drosophila segmentation proteins", "authors": [{"first": "D", "middle": [], "last": "Kosman", "suffix": ""}, {"first": "S", "middle": [], "last": "Small", "suffix": ""}, {"first": "J", "middle": [], "last": "Reinitz", "suffix": ""}], "year": 1998, "venue": "Dev. Genes Evol", "link": "12838277"}, "BIBREF25": {"title": "Cell fate control in the Drosophila retina by the orphan receptor seven-up: Its role in the decisions mediated by the ras signaling pathway", "authors": [{"first": "S", "middle": [], "last": "Kramer", "suffix": ""}, {"first": "S", "middle": ["R"], "last": "West", "suffix": ""}, {"first": "Y", "middle": [], "last": "Hiromi", "suffix": ""}], "year": 1995, "venue": "Development", "link": "12962397"}, "BIBREF26": {"title": "Dual function of the regionspecific homeotic gene spalt during Drosophila tracheal system development", "authors": [{"first": "R", "middle": ["P"], "last": "Kuhnlein", "suffix": ""}, {"first": "R", "middle": [], "last": "Schuh", "suffix": ""}], "year": 1996, "venue": "Development", "link": "5808703"}, "BIBREF27": {"title": "spalt encodes an evolutionarily conserved zinc finger protein of novel structure which provides homeotic gene function in the head and tail region of the Drosophila embryo", "authors": [{"first": "R", "middle": ["P"], "last": "Kuhnlein", "suffix": ""}, {"first": "G", "middle": [], "last": "Frommer", "suffix": ""}, {"first": "M", "middle": [], "last": "Friedrich", "suffix": ""}, {"first": "M", "middle": [], "last": "Gonzalez-Gaitan", "suffix": ""}, {"first": "A", "middle": [], "last": "Weber", "suffix": ""}, {"first": "J", "middle": ["F"], "last": "Wagner-Bernholz", "suffix": ""}, {"first": "W", "middle": ["J"], "last": "Gehring", "suffix": ""}, {"first": "H", "middle": [], "last": "Jackle", "suffix": ""}, {"first": "R", "middle": [], "last": "Schuh", "suffix": ""}], "year": 1994, "venue": "EMBO J", "link": "26116881"}, "BIBREF28": {"title": "Ectopic and increased expression of Fasciclin II alters motoneuron growth cone guidance", "authors": [{"first": "D", "middle": ["M"], "last": "Lin", "suffix": ""}, {"first": "C", "middle": ["S"], "last": "Goodman", "suffix": ""}], "year": 1994, "venue": "Neuron", "link": "11045288"}, "BIBREF29": {"title": "Larval optic nerve and adult extra-retinal photoreceptors sequentially associate with clock neurons during Drosophila brain development", "authors": [{"first": "S", "middle": [], "last": "Malpel", "suffix": ""}, {"first": "A", "middle": [], "last": "Klarsfeld", "suffix": ""}, {"first": "F", "middle": [], "last": "Rouyer", "suffix": ""}], "year": 2002, "venue": "Development", "link": "24568065"}, "BIBREF30": {"title": "Circadian synchronization and rhythmicity in larval photoperception-defective mutants of Drosophila", "authors": [{"first": "S", "middle": [], "last": "Malpel", "suffix": ""}, {"first": "A", "middle": [], "last": "Klarsfeld", "suffix": ""}, {"first": "F", "middle": [], "last": "Rouyer", "suffix": ""}], "year": 2004, "venue": "J. Biol. Rhythms", "link": "14067551"}, "BIBREF31": {"title": "Circadian pacemaker neurons transmit and modulate visual information to control a rapid behavioral response", "authors": [{"first": "E", "middle": ["O"], "last": "Mazzoni", "suffix": ""}, {"first": "C", "middle": [], "last": "Desplan", "suffix": ""}, {"first": "J", "middle": [], "last": "Blau", "suffix": ""}], "year": 2005, "venue": "Neuron", "link": "9568853"}, "BIBREF32": {"title": "Flipping coins in the fly retina", "authors": [{"first": "T", "middle": [], "last": "Mikeladze-Dvali", "suffix": ""}, {"first": "C", "middle": [], "last": "Desplan", "suffix": ""}, {"first": "D", "middle": [], "last": "Pistillo", "suffix": ""}], "year": 2005, "venue": "Curr. Top. Dev. Biol", "link": "6921311"}, "BIBREF33": {"title": "The growth regulators warts/lats and melted interact in a bistable loop to specify opposite fates in Drosophila R8 photoreceptors", "authors": [{"first": "T", "middle": [], "last": "Mikeladze-Dvali", "suffix": ""}, {"first": "M", "middle": ["F"], "last": "Wernet", "suffix": ""}, {"first": "D", "middle": [], "last": "Pistillo", "suffix": ""}, {"first": "E", "middle": ["O"], "last": "Mazzoni", "suffix": ""}, {"first": "A", "middle": ["A"], "last": "Teleman", "suffix": ""}, {"first": "Y", "middle": ["W"], "last": "Chen", "suffix": ""}, {"first": "S", "middle": [], "last": "Cohen", "suffix": ""}, {"first": "C", "middle": [], "last": "Desplan", "suffix": ""}], "year": 2005, "venue": "Cell", "link": "6632308"}, "BIBREF34": {"title": "The Drosophila seven-up gene, a member of the steroid receptor gene superfamily, controls photoreceptor cell fates", "authors": [{"first": "M", "middle": [], "last": "Mlodzik", "suffix": ""}, {"first": "Y", "middle": [], "last": "Hiromi", "suffix": ""}, {"first": "U", "middle": [], "last": "Weber", "suffix": ""}, {"first": "C", "middle": ["S"], "last": "Goodman", "suffix": ""}, {"first": "G", "middle": ["M"], "last": "Rubin", "suffix": ""}], "year": 1990, "venue": "Cell", "link": "13427369"}, "BIBREF35": {"title": "A green fluorescent protein enhancer trap screen in Drosophila photoreceptor cells", "authors": [{"first": "B", "middle": [], "last": "Mollereau", "suffix": ""}, {"first": "M", "middle": ["F"], "last": "Wernet", "suffix": ""}, {"first": "P", "middle": [], "last": "Beaufils", "suffix": ""}, {"first": "D", "middle": [], "last": "Killian", "suffix": ""}, {"first": "F", "middle": [], "last": "Pichaud", "suffix": ""}, {"first": "R", "middle": [], "last": "Kuhnlein", "suffix": ""}, {"first": "C", "middle": [], "last": "Desplan", "suffix": ""}], "year": 2000, "venue": "Mech. Dev", "link": "16869461"}, "BIBREF36": {"title": "Two-step process for photoreceptor formation in Drosophila", "authors": [{"first": "B", "middle": [], "last": "Mollereau", "suffix": ""}, {"first": "M", "middle": [], "last": "Dominguez", "suffix": ""}, {"first": "R", "middle": [], "last": "Webel", "suffix": ""}, {"first": "N", "middle": ["J"], "last": "Colley", "suffix": ""}, {"first": "B", "middle": [], "last": "Keung", "suffix": ""}, {"first": "J", "middle": ["F"], "last": "De Celis", "suffix": ""}, {"first": "C", "middle": [], "last": "Desplan", "suffix": ""}], "year": 2001, "venue": "Nature", "link": "4426584"}, "BIBREF37": {"title": "Genetic dissection of trophic interactions in the larval optic neuropil of Drosophila melanogaster", "authors": [{"first": "V", "middle": ["G R"], "last": "Moncalvo", "suffix": ""}, {"first": "A", "middle": ["R"], "last": "Campos", "suffix": ""}], "year": 2005, "venue": "Dev. Biol", "link": null}, "BIBREF38": {"title": "The little R cell that could", "authors": [{"first": "R", "middle": [], "last": "Nagaraj", "suffix": ""}, {"first": "U", "middle": [], "last": "Banerjee", "suffix": ""}], "year": 2004, "venue": "Int. J. Dev. Biol", "link": "38928656"}, "BIBREF39": {"title": "Two-step induction of chordotonal organ precursors in Drosophila embryogenesis", "authors": [{"first": "M", "middle": [], "last": "Okabe", "suffix": ""}, {"first": "H", "middle": [], "last": "Okano", "suffix": ""}], "year": 1997, "venue": "Development", "link": "86925"}, "BIBREF40": {"title": "Spitz and Wingless, emanating from distinct borders, cooperate to establish cell fate across the Engrailed domain in the Drosophila epidermis", "authors": [{"first": "L", "middle": [], "last": "O&apos;keefe", "suffix": ""}, {"first": "S", "middle": ["T"], "last": "Dougan", "suffix": ""}, {"first": "L", "middle": [], "last": "Gabay", "suffix": ""}, {"first": "E", "middle": [], "last": "Raz", "suffix": ""}, {"first": "B", "middle": ["Z"], "last": "Shilo", "suffix": ""}, {"first": "S", "middle": [], "last": "Dinardo", "suffix": ""}], "year": 1997, "venue": "Development", "link": "6535460"}, "BIBREF41": {"title": "The activities of two Ets-related transcription factors required for Drosophila eye development are modulated by the Ras/ MAPK pathway", "authors": [{"first": "E", "middle": ["M"], "last": "O&apos;neill", "suffix": ""}, {"first": "I", "middle": [], "last": "Rebay", "suffix": ""}, {"first": "R", "middle": [], "last": "Tjian", "suffix": ""}, {"first": "G", "middle": ["M"], "last": "Rubin", "suffix": ""}], "year": 1994, "venue": "Cell", "link": null}, "BIBREF42": {"title": "A new rhodopsin in R8 photoreceptors of Drosophila: Evidence for coordinate expression with Rh3 in R7 cells", "authors": [{"first": "D", "middle": [], "last": "Papatsenko", "suffix": ""}, {"first": "G", "middle": [], "last": "Sheng", "suffix": ""}, {"first": "C", "middle": [], "last": "Desplan", "suffix": ""}], "year": 1997, "venue": "Development", "link": "23194626"}, "BIBREF43": {"title": "Transcript localization of four opsin genes in the three visual organs of Drosophila: RH2 is ocellus specific", "authors": [{"first": "J", "middle": [], "last": "Pollock", "suffix": ""}, {"first": "S", "middle": [], "last": "Benzer", "suffix": ""}], "year": 1988, "venue": "Nature", "link": null}, "BIBREF44": {"title": "The sevenless signaling pathway: Variations of a common theme", "authors": [{"first": "T", "middle": [], "last": "Raabe", "suffix": ""}], "year": 2000, "venue": "Biochim. Biophys. Acta", "link": "27219420"}, "BIBREF45": {"title": "Yan functions as a general inhibitor of differentiation and is negatively regulated by activation of the Ras1/MAPK pathway", "authors": [{"first": "I", "middle": [], "last": "Rebay", "suffix": ""}, {"first": "G", "middle": ["M"], "last": "Rubin", "suffix": ""}], "year": 1995, "venue": "Cell", "link": "1888229"}, "BIBREF46": {"title": "Formation of the Drosophila larval photoreceptor organ and its neuronal differentiation require continuous Kruppel gene activity", "authors": [{"first": "D", "middle": [], "last": "Schmucker", "suffix": ""}, {"first": "H", "middle": [], "last": "Taubert", "suffix": ""}, {"first": "Jackle", "middle": [], "last": "", "suffix": ""}, {"first": "H", "middle": [], "last": "", "suffix": ""}], "year": 1992, "venue": "Neuron", "link": null}, "BIBREF47": {"title": "Chromophore-assisted laser inactivation of patched protein switches cell fate in the larval visual system of Drosophila", "authors": [{"first": "D", "middle": [], "last": "Schmucker", "suffix": ""}, {"first": "A", "middle": ["L"], "last": "Su", "suffix": ""}, {"first": "A", "middle": [], "last": "Beermann", "suffix": ""}, {"first": "H", "middle": [], "last": "Jackle", "suffix": ""}, {"first": "Jay", "middle": [], "last": "", "suffix": ""}, {"first": "D", "middle": ["G"], "last": "", "suffix": ""}], "year": 1994, "venue": "Proc. Natl. Acad. Sci", "link": "24976004"}, "BIBREF48": {"title": "Genetic analysis of the larval optic nerve projection in Drosophila", "authors": [{"first": "D", "middle": [], "last": "Schmucker", "suffix": ""}, {"first": "H", "middle": [], "last": "Jackle", "suffix": ""}, {"first": "U", "middle": [], "last": "Gaul", "suffix": ""}], "year": 1997, "venue": "Development", "link": "18791028"}, "BIBREF49": {"title": "The columnar gene vnd is required for tritocerebral neuromere formation during embryonic brain development of Drosophila", "authors": [{"first": "S", "middle": ["G"], "last": "Sprecher", "suffix": ""}, {"first": "R", "middle": [], "last": "Urbach", "suffix": ""}, {"first": "G", "middle": ["M"], "last": "Technau", "suffix": ""}, {"first": "F", "middle": ["M"], "last": "Rijli", "suffix": ""}, {"first": "H", "middle": [], "last": "Reichert", "suffix": ""}, {"first": "F", "middle": [], "last": "Hirth", "suffix": ""}], "year": 2006, "venue": "Development", "link": "11479978"}, "BIBREF50": {"title": "Transcriptional regulation of atonal required for Drosophila larval eye development by concerted action of eyes absent, sine oculis and hedgehog signaling independent of fused kinase and cubitus interruptus", "authors": [{"first": "T", "middle": [], "last": "Suzuki", "suffix": ""}, {"first": "K", "middle": [], "last": "Saigo", "suffix": ""}], "year": 2000, "venue": "Development", "link": "29423415"}, "BIBREF51": {"title": "Otd/ Crx, a dual regulator for the specification of ommatidia subtypes in the Drosophila retina", "authors": [{"first": "A", "middle": [], "last": "Tahayato", "suffix": ""}, {"first": "R", "middle": [], "last": "Sonneville", "suffix": ""}, {"first": "F", "middle": [], "last": "Pichaud", "suffix": ""}, {"first": "M", "middle": ["F"], "last": "Wernet", "suffix": ""}, {"first": "D", "middle": [], "last": "Papatsenko", "suffix": ""}, {"first": "P", "middle": [], "last": "Beaufils", "suffix": ""}, {"first": "T", "middle": [], "last": "Cook", "suffix": ""}, {"first": "C", "middle": [], "last": "Desplan", "suffix": ""}], "year": 2003, "venue": "Dev. Cell", "link": "14985756"}, "BIBREF52": {"title": "Embryonic development of the Drosophila brain: Formation of commissural and descending pathways", "authors": [{"first": "S", "middle": [], "last": "Therianos", "suffix": ""}, {"first": "S", "middle": [], "last": "Leuzinger", "suffix": ""}, {"first": "F", "middle": [], "last": "Hirth", "suffix": ""}, {"first": "C", "middle": ["S"], "last": "Goodman", "suffix": ""}, {"first": "H", "middle": [], "last": "Reichert", "suffix": ""}], "year": 1995, "venue": "Development", "link": "25263392"}, "BIBREF53": {"title": "Functional analysis of CNK in RAS signaling", "authors": [{"first": "M", "middle": [], "last": "Therrien", "suffix": ""}, {"first": "A", "middle": ["M"], "last": "Wong", "suffix": ""}, {"first": "E", "middle": [], "last": "Kwan", "suffix": ""}, {"first": "G", "middle": ["M"], "last": "Rubin", "suffix": ""}], "year": 1999, "venue": "Proc. Natl. Acad. Sci", "link": "22661344"}, "BIBREF54": {"title": "orthodenticle is required for photoreceptor cell development in the Drosophila eye", "authors": [{"first": "E", "middle": ["R"], "last": "Vandendries", "suffix": ""}, {"first": "D", "middle": [], "last": "Johnson", "suffix": ""}, {"first": "R", "middle": [], "last": "Reinke", "suffix": ""}], "year": 1996, "venue": "Dev. Biol", "link": "19604448"}, "BIBREF55": {"title": "Building a retinal mosaic: Cell-fate decision in the fly eye", "authors": [{"first": "M", "middle": ["F"], "last": "Wernet", "suffix": ""}, {"first": "C", "middle": [], "last": "Desplan", "suffix": ""}], "year": 2004, "venue": "Trends Cell Biol", "link": "40199283"}, "BIBREF56": {"title": "Stochastic spineless expression creates the retinal mosaic for colour vision", "authors": [{"first": "M", "middle": ["F"], "last": "Wernet", "suffix": ""}, {"first": "E", "middle": ["O"], "last": "Mazzoni", "suffix": ""}, {"first": "A", "middle": [], "last": "Celik", "suffix": ""}, {"first": "D", "middle": ["M"], "last": "Duncan", "suffix": ""}, {"first": "I", "middle": [], "last": "Duncan", "suffix": ""}, {"first": "C", "middle": [], "last": "Desplan", "suffix": ""}], "year": 2006, "venue": "Nature", "link": "1211520"}, "BIBREF57": {"title": "Antagonism of EGFR and notch signalling in the reiterative recruitment of Drosophila adult chordotonal sense organ precursors", "authors": [{"first": "P", "middle": [], "last": "Zur Lage", "suffix": ""}, {"first": "A", "middle": ["P"], "last": "Jarman", "suffix": ""}], "year": 1999, "venue": "Development", "link": "1057283"}, "BIBREF58": {"title": "EGF receptor signaling triggers recruitment of Drosophila sense organ precursors by stimulating proneural gene autoregulation", "authors": [{"first": "P", "middle": ["I"], "last": "Zur Lage", "suffix": ""}, {"first": "L", "middle": ["M"], "last": "Powell", "suffix": ""}, {"first": "D", "middle": ["R"], "last": "Prentice", "suffix": ""}, {"first": "P", "middle": [], "last": "Mclaughlin", "suffix": ""}, {"first": "A", "middle": ["P"], "last": "Jarman", "suffix": ""}], "year": 2004, "venue": "Dev. Cell", "link": "196706"}, "BIBREF59": {"title": "Access the most recent version at doi", "authors": [], "year": 2007, "venue": "", "link": null}, "BIBREF61": {"title": "This article cites 57 articles, 21 of which can be accessed free at", "authors": [], "year": "", "venue": "", "link": null}}, "ref_entries": {"FIGREF0": {"text": "Figure 1. Development of BO and rhodopsin expression. (A) Lateral view of the head region of an ato-Gal4, UAS-lacZ embryo stained with anti-\u2424-Gal (red) and antiNeurotactin (Nrt) (green). ato-lacZ expression is found in BO precursors (arrow) at late stage 11. (B) Dorsal view of a stage 15 embryonic head: Anti-FasII (green) staining shows the position of BO (arrow). (C) High-magnification image of the BO at late stage 17 immunolabeled with anti-Rh5 (green), anti-Rh6 (red), and anti-Elav (blue). A total of 12 PRs are observed: Eight are stained by anti-Rh6 antibody, and four are stained with anti-Rh5 antibody. (Inset) Three-dimensional reconstruction of the BO PRs. (D) High-magnification image of the BO in third instar larvae immunolabeled with anti-Rh5 (green), anti-Rh6 (red), and anti-Elav (blue). A total of 12 PRs are observed: Eight are stained by anti-Rh6 antibody, and four are stained with anti-Rh5 antibody. PRs build up arborization-like protrusions (arrow).", "type": "figure"}, "FIGREF1": {"text": "Figure 2. wts and melt are not involved in Rh5-and Rh6-subtype specification. High-magnification images of third instar mutant larva BO of melt (A), wts (B), so-Gal4/UAS-melt (C), and so-Gal4/UAS-wts (D) labeled with anti-Rh5 (green, arrow), anti-Rh6 (red), and anti-Elav (blue). (A-D) melt and wts mutants, as well as so-Gal4/UAS-wts and so-Gal4/UAS-melt, display an expression of Rh5 and Rh6 PRs comparable with wild-type larvae. (E) Comparison of the total number of PRs (black bar) and Rh6 (white bar) and Rh5 (red bar) PRs in wild-type (wt), melt LOF, wts LOF, melt GOF, and wats GOF larval eyes (error bars, SD). The number of total PRs and Rh5 and Rh6 PRs in all conditions are comparable with wild type.", "type": "figure"}, "FIGREF2": {"text": "Figure 3. Function of EGFR signaling in Rh6 PR development. (A) High-magnification image of stage 15 wild-type embryonic BO labeled with anti-FasII (green) and antiKr (red). (B) High-magnification image of stage 15 so-Gal4 > UAS-EGFR dn embryonic BO labeled with anti-FasII (green) and antiKr (red). Only three Kr-expressing immature PRs are found (arrows) as compared with 12 in the wild type (shown in A). (C) High-magnification image of third instar larva wild-type BO labeled with anti-Rh5 (green), anti-Rh6 (red), and anti-Elav (blue). A total of 12 PRs are observed: Eight are stained by anti-Rh6 antibody, and four are stained with anti-Rh5 antibody. (D) Highmagnification image of third instar larva so-Gal4 > UAS-EGFR dn BO labeled with anti-Rh5 (green), anti-Rh6 (red), and antiElav (blue). Only three Rh5-expressing cells are found (arrows). (E) High-magnification image of third instar larva wild-type BO labeled with anti-Chp (green, 24B10), anti-Sal (red), and anti-Elav (blue). (F) High-magnification image of third instar larva soGal4,UAS-EGFR dn BO labeled with antiChp (green, 24B10), anti-Sal (red), and antiElav (blue). All four PRs found express Sal.", "type": "figure"}, "FIGREF3": {"text": "Figure 4. Function of EGFR, tll, and apoptosis in Rh6-subtype development. (A) High-magnification image of stage 15 wild-type embryonic BO labeled with anti-FasII (green) and anti-Elav (red). (B) High-magnification image of stage 15 tll mutant embryonic BO labeled with antiFasII (green) and anti-Elav (red). The number of immature PRs is increased to \u223c20-25. (C) High-magnification image of stage 17 wild-type BO labeled with anti-Rh5 (green), anti-Rh6 (red), and anti-Elav (blue). (Inset) Threedimensional reconstruction of the BO PRs. A total of 12 PRs are observed: Eight are stained by anti-Rh6 antibody, and four are stained with anti-Rh5 antibody. (D) Highmagnification image of stage 17 tll mutant BO labeled with anti-Rh5 (green), anti-Rh6 (red), and anti-Elav (blue). (Inset) Three-dimensional reconstruction of the BO PRs. The number of Rh6 PRs is increased to \u223c20-25; the number of Rh5 PRs remains unchanged. (E) Highmagnification image of third instar larva wild-type BO labeled with anti-Rh5 (green), anti-Rh6 (red), and antiElav (blue). (F) High-magnification image of third instar larva so-Gal4,UAS-p35 BO labeled with anti-Rh5 (green), anti-Rh6 (red), and anti-Elav (blue). The number of Rh6 PRs is largely increased to 20-25. (G) High-magnification image of third instar larva so-Gal4,UAS-p35, UAS-EGFR dn BO labeled with anti-Rh5 (green), anti-Rh6 (red), and anti-Elav (blue). The number of Rh6 PRs is largely increased. The number of Rh6 PRs is increased to \u223c20-25; the number of Rh5 PRs remains unchanged.", "type": "figure"}, "FIGREF4": {"text": "Figure 5. Expression of sal and svp in the developing and mature larval PRs. (A) Dorsal view of a sal-Gal4,UAS-H2B-YFP stage 15 embryonic head labeled with anti-GFP (green), anti-FasII (red), and anti-Elav (blue), and GFP expression in BO (arrow). (B) Highmagnification image of the BO in A. Four cells are labeled by anti-GFP staining (arrow). (C) High-magnification image of BO in third instar larva sal-Gal4,UAS-H2B-YFP, labeled with anti-GFP (red), anti-Rh5 (green), and anti-Elav (blue). Anti-GFP labeling coincides with anti-Rh5 staining (arrow). (D) High-magnification image of BO in third instar larva sal-Gal4,UAS-H2B-YFP, labeled with anti-GFP (green), anti-Rh6 (red), and anti-Elav (blue). Anti-GFP labeling is excluded from anti-Rh6 staining (arrows). (E) Dorsal view of a svp-lacZ stage 15 embryonic head labeled with anti-FasII (green) and anti-\u2424Gal (red) expression in BO (arrows). (F,F\u0408) High-magnification image of the BO in E; individual optical sections show four cells are devoid of anti-\u2424Gal staining (arrows). (G) High-magnification image of BO in third instar larva svp-Gal4,UAS-H2B-YFP, labeled with anti-GFP (red), anti-Rh5 (green), and anti-Elav (blue). Anti-GFP labeling is excluded from anti-Rh5 staining (arrows). (H) High-magnification image of BO in third instar larva svp-Gal4,UAS-H2B-YFP, labeled with anti-GFP (green), anti-Rh6 (red), and anti-Elav (blue). Anti-GFP labeling coincides with anti-Rh6 staining, and is excluded for the remaining four PRs (arrows).", "type": "figure"}, "FIGREF5": {"text": "Figure 6. Function of sal and svp in Rh5-and Rh6-subtype specification. (A) Highmagnification image of stage 17 wild-type BO labeled with anti-Rh5 (green), anti-Rh6 (red), and anti-Elav (blue). (Inset) Three-dimensional reconstruction of the BO PRs. (B) High-magnification image of stage 17 svp mutant BO labeled with anti-Rh5 (green), anti-Rh6 (red), and anti-Elav (blue). A total of 12 PRs are found, all expressing Rh5. (Inset) Three-dimensional reconstruction of the BO PRs. (C) High-magnification image of stage 17 sal mutant BO labeled with anti-Rh5 (green), anti-Rh6 (red), and anti-Elav (blue). A total of 12 PRs are detected: Eight express Rh6, whereas four are devoid of anti-Rh5 or anti-Rh6 staining. (D) High-magnification image of stage 17 wildtype BO labeled with anti-Chp (green), anti-Sal (red), and anti-Elav (blue). Four cells express Sal (arrow). (E) High-magnification image of stage 17 svp mutant BO labeled with anti-Chp (green), anti-Sal (red), and anti-Elav (blue). All PRs express Sal (arrow). (F) High-magnification image of third instar larva so-Gal4,UAS-svp BO labeled with anti-Rh5 (green), anti-Rh6 (red), and anti-Elav (blue). All PRs are labeled by anti-Rh6; no anti-Rh5 staining is detected. (G) Axonal projections of larval PRs in sal mutant stage 17 embryos labeled with anti-FasII (green) and anti-Rh6 (red). Axonal terminations are properly formed (arrow). (H,I) High-magnification image of termini of larval PRs in sal mutant labeled with anti-FasII (green) and anti-Rh6 (red). Projections of \"empty\" PRs are devoid of Rh6 expression but labeled with the general marker FasII (cf. arrows in H,I).", "type": "figure"}, "FIGREF6": {"text": "Figure 7. Expression and function of otd in developing and mature larval PRs. (A) Lateral view of a stage 7 embryo (procephalic region) stained with anti-Nrt (green) and anti-Otd (red); the region giving rise to the optic lobe anlage and larval PRs expresses Otd (arrow). (B) Lateral view of a so-Gal4/UAS-H2B-YFP stage 10 embryonic head region stained with anti-GFP (green) and anti-Otd (red); the region giving rise to larval PRS (ventral/lateral tip) is devoid of Otd expression. (C) Dorsal view of a wild-type stage 15 embryonic head labeled with anti-FasII (green), anti-Otd (red), and anti-Otd staining in BO, indicated by arrows. (C\u0408) High-magnification image of C. All immature PRs are labeled by anti-Otd staining. (D) High-magnification image of embryonic stage 15 otd-Gal4/UAS-CD8\u03fbGFP BO labeled with anti-FasII (green) and anti-GFP (red). All immature PRs are labeled by anti-GFP staining. (E) High-magnification image of third instar larva otd-Gal4/UAS-CD8\u03fbGFP BO labeled with anti-GFP (blue) and anti-Rh6 (red). (F) High-magnification image of third instar larva otd-Gal4/UAS-CD8\u03fbGFP BO labeled with anti-GFP (blue) and anti-Rh5 (green). (G) High-magnification image of third instar larva otd vui mutant BO labeled with anti-Rh6 (red) and anti-Elav (blue). All PRs are labeled by anti-Rh6 staining. (H) Highmagnification image of third instar larva otd vui mutant BO labeled with anti-Chp (green), anti-Sal (red), and anti-Elav (blue). Four PRs are labeled by anti-Sal staining.", "type": "figure"}, "FIGREF7": {"text": "Figure 8. Proposed model for development and the specification of rhodopsin fates in the larval eye and comparison with the adult R8. (A) Primary precursors (1\u00b0, blue) express the TGF\u2423 homolog spi, which is required in secondary precursor cells (2\u00b0, green) for their survival. tll acts in the surrounding tissue to inhibit secondary precursor development. Primary precursors give rise to the Rh5 PR subtype, whereas secondary precursors give rise to the Rh6 PR subtype. In the Rh5 PR subtype, sal and otd are required for Rh5 expression, and otd further for the repression of Rh6. In the Rh6 subtype, svp is required for Rh6 expression and for the repression of sal expression. (B) The negative feedback loop of wts and melt mediates the decision of R8 to express Rh6 or Rh5. Which way the loop swings depends on an instructive signal of the overlying R7 cell. The presence of gene expression is indicated by black type and its absence is indicated with gray type. Arrows shown in black (for activation) and red (for repression) indicate an active interaction; gray arrows indicate the absence of this interaction.", "type": "figure"}, "TABREF0": {"text": ") (compa- rable results were obtained using svp-Gal4, svp-LacZ, or", "type": "table"}, "TABREF1": {"text": "), svp 724 -Gal4 (Kyoto Stock Center; kindly provided by J. Urban), sal-Gal4 (Mollereau et al. 2000), UAS-EGFR dn (O'Keefe et al. 1997), wts P1 , melt D1 , melt-LacZ, wts-Gal4, UAS-melt, UAS-lats (Mikeladze-Dvali et al. 2005b), UAS-H2B\u03fbYFP (anti- GFP antibody/Biogenesis recognizes the YFP antigen), r (Bel- laiche et al. 2001), UAS-salm", "type": "table"}}}
{"paper_id": "18980811", "_pdf_hash": "d01a01e0ff9f730517231f9d2aad201e14080795", "abstract": [], "body_text": [], "bib_entries": {"BIBREF1": {"title": "The libsysfs Developers. libsysfs", "authors": [], "year": 2003, "venue": "", "link": null}, "BIBREF2": {"title": "LWN.net. 2.6 driver porting series", "authors": [], "year": 2003, "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "18981111", "_pdf_hash": "f3d9a81079300b70808121b2a16afdc5e08773f0", "abstract": [], "body_text": [{"section": "", "text": "The ability to explore unknown spaces independently, safely and efficiently is a combined product of motor, sensory, and cognitive skills. Normal exercise of this ability directly affects an individual's quality of life. Mental mapping of spaces and of the possible paths for navigating these spaces is essential for the development of efficient orientation and mobility (O&M) skills. Most of the information required for this mental mapping is gathered through the visual channel (Lynch, 1960) . People who are blind lack this information, and in consequence they are required to use compensatory sensorial channels and alternative exploration methods (Jacobson, 1993) . This research is based on the assumption that the supply of appropriate spatial information through compensatory sensorial channels, as an alternative to the (impaired) visual channel, may help to enhance the ability of people who are blind to explore unknown environments (Mioduser, in press) .", "cite_spans": [{"start": 481, "end": 494, "text": "(Lynch, 1960)", "ref_id": "BIBREF13"}, {"start": 653, "end": 669, "text": "(Jacobson, 1993)", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "", "text": "The research on the exploration process of known and unknown spaces by people who are blind refers to the use of both low and high technologies. These technologies serve as alternative sensorial or cognitive channels to the impaired visual channel. There are two types of informationtechnology devices: (a) passive devices -providing the user with information before her/his arrival to the environment (e.g., verbal description, tactile maps and physical models) and (b) dynamic devices -providing the user with information in-situ (e.g., Sonicguide, Kaspa, Talking Signs and Personal Guidance System). Ungar, Blades and Spencer, (1996) report on differences in exploration performance of people who are blind using various technologies (e.g., verbal description, tactile maps and physical models). Warren and Strelow (1985) studied the use of the Sonic-guide device and Easton and Bentzen (1999) focused on the users' ability to navigate using the Kaspa laser-guided device. Additional examples of O&M support under study are the talking signs embedded in the environment (Crandall, Bentzen, Myers, & Mitchell, 1995) , and the global positioning system (GPS), based on satellite communication (Golledge, Klatzky, & Loomis, 1996) .", "cite_spans": [{"start": 603, "end": 636, "text": "Ungar, Blades and Spencer, (1996)", "ref_id": "BIBREF18"}, {"start": 799, "end": 824, "text": "Warren and Strelow (1985)", "ref_id": "BIBREF20"}, {"start": 1073, "end": 1117, "text": "(Crandall, Bentzen, Myers, & Mitchell, 1995)", "ref_id": "BIBREF1"}, {"start": 1194, "end": 1229, "text": "(Golledge, Klatzky, & Loomis, 1996)", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "", "text": "Research on mobility in known and unknown spaces by people who are blind (Golledge, Klatzky, & Loomis, 1996; Ungar, Blades, & Spencer, 1996) , indicates that support for the acquisition of spatial mapping and orientation skills should be supplied at two main levels, perceptual and conceptual. At the perceptual level, hearing, smell, and touch are powerful information suppliers about known as well as unknown spaces. The auditory channel supplies essential information about events, or the presence of other people (or machines or animals) in the environment. In indoor spaces", "cite_spans": [{"start": 73, "end": 108, "text": "(Golledge, Klatzky, & Loomis, 1996;", "ref_id": "BIBREF7"}, {"start": 109, "end": 140, "text": "Ungar, Blades, & Spencer, 1996)", "ref_id": "BIBREF18"}], "ref_spans": []}, {"section": "Exploration of Unknown Spaces by People Who Are Blind Using a Multi-sensory Virtual Environment", "text": "ORLY LAHAV DAVID MIODUSER Tel Aviv University, School of Education Exploration of unknown spaces is essential for the development of efficient orientation and mobility skills. Most of the information required for the exploration is gathered through the visual channel. People who are blind lack this crucial information, facing in consequence difficulties in mapping as well as navigating spaces. This study is based on the assumption that the supply of appropriate spatial information through compensatory sensorial channels may contribute to the spatial performance of people who are blind. The main goals of this study were (a) the development of a haptic virtual environment enabling people who are blind to explore unknown spaces and (b) the study of the exploration process of these spaces by people who are blind. Participants were 31 people who are blind: 21 in the experimental group exploring a new space using a multi-sensory virtual environment, and 10 in the control group directly exploring the real new space. The results of the study showed that the participants in the experimental group mastered the navigation of the unknown virtual space in a short time. Significant differences were found concerning the use of exploration strategies, methods, and processes by participants working with the multi-sensory virtual environment, in comparison with those working in the real space.", "cite_spans": [], "ref_spans": []}, {"section": "Journal of Special Education Technology", "text": "people who are blind can use echo feedback (i.e., by whistling, clapping hands, or talking) to estimate distances (Hill, Rieser, Hill, Hill, Halpin & Halpin, 1993) . The smell channel supplies additional information about particular situations (e.g., perfumery, bookstore, or bakery in a shopping center) or about people. Haptic information appears to be of great potential for supporting appropriate spatial performance. Fritz, Way, and Barner (1996) define haptics as encompassing touch along with kinesthetic information, or a sense of position, motion, or force. For people who are blind, haptic information is commonly supplied by the cane for lowresolution scanning of the immediate surroundings, by palms and fingers for fine recognition of objects form, texture and location, and by the feet regarding surface information.", "cite_spans": [{"start": 114, "end": 163, "text": "(Hill, Rieser, Hill, Hill, Halpin & Halpin, 1993)", "ref_id": "BIBREF8"}, {"start": 422, "end": 451, "text": "Fritz, Way, and Barner (1996)", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "Journal of Special Education Technology", "text": "As for the conceptual level, the focus is on supporting the development of appropriate strategies for the efficient exploration of the space and the generation of efficient navigation paths. For example, Jacobson (1993) , described indoor environment familiarization process by people who are blind as one that starts with the use of a perimeterrecognition-tactic -walking along the room's walls and exploring objects attached to the walls, followed by a gridscanning tactic, aiming to explore the room's interior.", "cite_spans": [{"start": 204, "end": 219, "text": "Jacobson (1993)", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "Journal of Special Education Technology", "text": "Advanced computer technology offers new possibilities for supporting acquisition of orientation and mobility (O&M) skills by people who are blind, and the development of alternative navigation strategies, at both the perceptual and conceptual levels. Current virtual reality (VR) technology facilitates the development of rich virtual models of physical environments and objects to be manipulated, offering people who are blind the possibility to undergo learning or rehabilitation processes without the usual constraints of time, space, and a massive demand of human tutoring (Loomis, Klatzky & Golledge, 2001; Schultheis & Rizzo, 2001; Standen, Brown & Cromby, 2001) . Research on the implementation of haptic technologies within VR spatial simulation environments reports on its potential for supporting rehabilitation training with sighted people (Darken & Banker, 1998; Darken & Peterson, 2002; Waller, Hunt & Knapp, 1998; Witmer, Bailey, Knerr & Parsons 1996) , and perception of virtual textures and objects by people who are blind (Colwell, Petrie, & Kornbrot, 1998; Jansson, Fanger, Konig, & Billberger, 1998; ) .", "cite_spans": [{"start": 577, "end": 611, "text": "(Loomis, Klatzky & Golledge, 2001;", "ref_id": "BIBREF12"}, {"start": 612, "end": 637, "text": "Schultheis & Rizzo, 2001;", "ref_id": "BIBREF15"}, {"start": 638, "end": 668, "text": "Standen, Brown & Cromby, 2001)", "ref_id": "BIBREF17"}, {"start": 851, "end": 874, "text": "(Darken & Banker, 1998;", "ref_id": "BIBREF2"}, {"start": 875, "end": 899, "text": "Darken & Peterson, 2002;", "ref_id": "BIBREF3"}, {"start": 900, "end": 927, "text": "Waller, Hunt & Knapp, 1998;", "ref_id": "BIBREF19"}, {"start": 928, "end": 965, "text": "Witmer, Bailey, Knerr & Parsons 1996)", "ref_id": "BIBREF21"}, {"start": 1039, "end": 1074, "text": "(Colwell, Petrie, & Kornbrot, 1998;", "ref_id": "BIBREF0"}, {"start": 1075, "end": 1118, "text": "Jansson, Fanger, Konig, & Billberger, 1998;", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "Journal of Special Education Technology", "text": "The research reported in this paper follows the assumption that the supply (via technology) of compensatory perceptual and conceptual information may contribute to effective acquaintance with unknown environments by people who are blind. This approach differs from previous research lines and practices in several ways. First, it integrates existing knowledge from different disciplines (namely O&M, learning processes by people who are blind, virtual environments and haptic devices R&D) into a common conceptual framework for the study of O&M skills acquisition using technology. At an additional level it deals with two main drawbacks of technologies currently in use: (a) the need for prerequisite knowledge about the space to be navigated (e.g., the talking signs or GPS systems) and (b) the lack of appropriate resolution of the information supplied about the unknown space (e.g., verbal descriptions or tactile maps). The virtual tool used in this study supplies all required prerequisite knowledge, at a resolution compatible with the features of the simulated environment. To examine the above assumption we developed a multi-sensory virtual environment (MVE) and studied the exploration process of an unknown space by subjects who are blind using the MVE. Their performance was compared to that of a control group of people who are blind who explored the real environment simulated in the MVE. The main research questions of this study were:", "cite_spans": [], "ref_spans": []}, {"section": "Journal of Special Education Technology", "text": "1. What exploration strategies do people who are blind use working with the MVE, in comparison to those used by people whom are blind working directly in the real environment? 2. What characterizes the exploration processes used by people whom are blind working with the MVE, in comparison to the exploration processes used by people whom are blind working in the real environment? 3. What information collection and storage did participants use, in both the experimental and control groups?", "cite_spans": [], "ref_spans": []}, {"section": "THE HAPTIC VIRTUAL ENVIRONMENT", "text": "The MVE prototype developed for this study comprised two modes of operation: (a) developer/teacher mode and (b) learning mode. The core component of the developer/teacher mode was the virtual environment editor, which included three tools: (a) a 3D environment builder, (b) a force-feedback effects editor, and (c) an audio feedback editor (see Figure 1) . By using the 3D-environment editor the developer can define the physical characteristics of the space, e.g., size and shape of the room, or type and size of the objects (i.e., doors, windows and furniture). Using the force feedback effects (FFE) editor the developer was able to attach haptic effects to all objects in the environment. Examples of FFE's were vibrations or attraction/rejection fields surrounding objects. The audio editor allowed the attachment of three kinds of auditory feedback to the objects: (a) labels (e.g., bird chirps) as representative for the windows, (b) explicit names (e.g., first door or second cube), and (c) a guiding agent reporting on features of the objects (e.g., the proximity of corners or required turns). All environments used in this study were composed by the researchers using the system editing tools.", "cite_spans": [], "ref_spans": []}, {"section": "Journal of Special Education Technology", "text": "In the learning mode, the users navigated the environment by means of the force feedback joystick (FFJ). While walking via the FFJ they interacted with the simulated space components (i.e., they perceived the form, dimensions, and relative location of objects; or identified the structural configuration of the room including presence and location of walls, doors, and windows. As part of these interactions the users got haptic feedback through the FFJ along with audio feedback. Figure 2 shows the user-interface screen. The red circles indicate the hot spots that triggered the guiding agent's intervention.", "cite_spans": [], "ref_spans": []}, {"section": "Journal of Special Education Technology", "text": "Several additional features were offered to the teachers during and after the learning session. Monitoring frames, for example, presented updated information on the user's navigation performance (e.g., position or objects already reached). Another feature allowed the recording of the user's navigation path and its replay for analysis and evaluation purposes, as shown in Figure 3 .", "cite_spans": [], "ref_spans": [{"start": 373, "end": 381, "text": "Figure 3", "ref_id": "FIGREF1"}]}, {"section": "METHOD Participants", "text": "The study included 31 participants who were selected on the basis of the following seven criteria: (a) total blindness, (b) minimum of 12 years old, (c) not multi-handicapped, (d) received O&M training, (e) Hebrew speaker, (f) onset of blindness at least two years prior to the experimental period, and (g) comfortable with the use of computers. The participant age range was 12-70 years old. We defined two groups that were similar in gender, age and age of vision loss (i.e., congenitally blind or late blind. The experimental group included 21 participants who explored the unknown space by means of the MVE, and the control group had 10 participants who explored the real unknown space (see Table 1 ).", "cite_spans": [], "ref_spans": [{"start": 695, "end": 702, "text": "Table 1", "ref_id": "TABREF0"}]}, {"section": "METHOD Participants", "text": "To evaluate the participants' initial O&M skills, all completed a questionnaire on O&M issues. The questionnaire results showed no differences in initial ability among both groups' participants.", "cite_spans": [], "ref_spans": []}, {"section": "Variables", "text": "The independent variable in this study was the type of environment (i.e., the multi-sensory virtual environment (MVE) and the real environment.", "cite_spans": [], "ref_spans": []}, {"section": "Variables", "text": "Three groups of dependent variables were defined, concerning (a) exploration strategies, (b) characteristics of the exploration process, and (c) the use of information and storage aids during the exploration.", "cite_spans": [], "ref_spans": []}, {"section": "Variables", "text": "Variables related to the exploration strategies included: 1. Exploration strategies -alternative strategies used by the subjects in their navigation: the \"perimeter\" strategywalking along a room's walls (see Figure 4 , Route 1); the \"grid\" strategy -exploring a room's interior by scanning the room (see Figure 4 , Route 2); the \"object-to-object\" strategywalking from one object to another (see Figure 4 , Route 3); the \"points-of-references\" strategy -walking in the environment and creating landmarks (see Figure 4 , Route 4), or other (new) strategies.", "cite_spans": [], "ref_spans": []}, {"section": "Variables", "text": "2. Frequency -the number of times each strategy was implemented during the exploration.", "cite_spans": [], "ref_spans": []}, {"section": "Variables", "text": "3. Distance traversed -distance traversed using each strategy.", "cite_spans": [], "ref_spans": []}, {"section": "Variables", "text": "Variables related to the characteristics of the exploration process:", "cite_spans": [], "ref_spans": []}, {"section": "Variables", "text": "1. Total duration -the total time spent accomplishing the task.", "cite_spans": [], "ref_spans": []}, {"section": "Variables", "text": "2. Total distance -the total distance traversed. 3. Strategy-switch -the frequency of strategy changes during the exploration task.", "cite_spans": [], "ref_spans": []}, {"section": "Variables", "text": "4. Sequence -the first sequence of two strategies used in the exploration (e.g., pattern strategy first then grid strategy).", "cite_spans": [], "ref_spans": []}, {"section": "Variables", "text": "5. Stops -the number of pauses made during the exploration. Two values were defined: short pauses (4-10 seconds) introduced for technical purposes (e.g., changing the hand that holds the joystick) and long pauses (more then 10 seconds) supposedly used for cognitive processing (e.g., memorization or planning).", "cite_spans": [], "ref_spans": []}, {"section": "Variables", "text": "Variables related to the use of information and storage aids included:", "cite_spans": [], "ref_spans": []}, {"section": "Variables", "text": "1. Aids -use of aids of two types: measurement aids (e.g., counting steps or using echo feedback) and informationretaining-aids (e.g., producing a verbal reconstruction of landmarks or using metaphors).", "cite_spans": [], "ref_spans": []}, {"section": "Research instruments", "text": "The main instruments used in the study were: 1. The unknown space -the space to be explored, both as real physical space and as virtual representation in the MVE (see Figures 5-6 ). The space was a 54 square meters room with three doors, six windows and two columns. There were seven objects in the room, five of them attached to the walls and two placed in the inner space.", "cite_spans": [], "ref_spans": [{"start": 167, "end": 178, "text": "Figures 5-6", "ref_id": "FIGREF3"}]}, {"section": "Research instruments", "text": "2. Exploration task -each participant was asked individually to explore the room, without time limitations. The experimenters informed the participants that they would be asked to describe the room and its components at the end of their exploration.", "cite_spans": [], "ref_spans": []}, {"section": "Research instruments", "text": "In addition a set of three instruments was developed for the collection of quantitative and qualitative data:", "cite_spans": [], "ref_spans": []}, {"section": "Research instruments", "text": "1. Orientation and mobility (O&M) questionnairecomprising 46 questions concerning the participants O&M ability indoors and outdoors, in known and unknown environments. Most of the questions were taken from O&M rehabilitation evaluation instruments (e.g., Dodson-Burk & Hill, 1989; Sonn, Tornquist & Svensson, 1999) . The O&M questionnaire included four parts: (a) 19 descriptive questions (e.g., age; gender; age of vision loss); (b) 8 questions on the subject's O&M ability in known indoor environments (e.g., home; school; work; etc); (c) 12 questions about the subject's O&M ability in known outdoor environments (e.g., street crossing; using public transportation; walking in shopping centers; etc); (d) 7 questions on subject's O&M ability in unknown indoor environments (e.g., what are the O&M devices you use in unknown indoor environments?; next week you are going to move to a new office or classroom. You will be visiting the new place today. What do you need to do to ensure yourself appropriate orientation in the new space next time?). Among the questions 23 O&M-related questions were answered in a four-level ability scale: (i) I cannot do the task, (ii) I need assistance from a sighted person, (iii) I need to use an O&M device, (iv) I can do the task independently.", "cite_spans": [{"start": 255, "end": 280, "text": "Dodson-Burk & Hill, 1989;", "ref_id": "BIBREF4"}, {"start": 281, "end": 314, "text": "Sonn, Tornquist & Svensson, 1999)", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "Research instruments", "text": "2. Observations were video-recorded -the participant's exploration was video-recorded during the task. The information from these recordings was combined with the computer recording.", "cite_spans": [], "ref_spans": []}, {"section": "Research instruments", "text": "3. Computer recording -The computer's recording data enabled the researchers to track the user's exploration in the MVE, in two ways: through a data log and through a film. This enabled the researcher to collect information about users' exploration strategies, distances, total duration, switches of strategies and stops (see Figure 3) .", "cite_spans": [], "ref_spans": [{"start": 326, "end": 335, "text": "Figure 3)", "ref_id": "FIGREF1"}]}, {"section": "Research instruments", "text": "Two data evaluation and coding schemas were developed, one for the participant's O&M skills and the other for his or her acquaintance process with the new space.", "cite_spans": [], "ref_spans": []}, {"section": "Procedure", "text": "All participants worked and were observed individually. The study was carried out in three stages. The first stage focused on the evaluation of the participants' initial O&M skills using the O&M questionnaire. In the second stage the experimental group became acquainted with the virtual environment's components and operation modes. The series of tasks administered at this stage included (a) free navigation, (b) directed navigation, and (c) a task aimed to introduce the auditory feedback. This stage lasted about three hours (two meetings). At the end of it participants learned to work independently with the FFJ, were able to walk directly toward the objects, could say when they bumped into an object or got to one of the room's corners, and could walk around the objects and along the walls by using the FFJ and the audio feedback. The third stage, the main part of the study, focused on participants' exploration of the unknown space. The experimental group explored the space using the virtual environment, while the control group directly explored the real environment. This stage lasted about 1.5 -2.5 hours, the task was video-recorded. For the experimental group the video-recording was combined with computer-recording. The last stage consisted of the processing and analysis of the collected data.", "cite_spans": [], "ref_spans": []}, {"section": "Procedure", "text": "The research results and conclusions are based and represent only the research participants' performance and achievements (n=31). The population target on this research were Israeli people who are blind, selected using the seven criteria above mentioned and that agree to take a part on this study. The actual size of the study's population did not allow a detailed examination of the effect of otherwise relevant variables (e.g., gender or age).", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS", "text": "The results regarding the exploration strategies, methods, and processes manifested by the participants working with the MVE, in comparison with those working in the real space, are presented according to our main research questions.", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS", "text": "Research Question 1: What exploration strategies do people who are blind use working with the MVE, in comparison to those used by people whom are blind working directly in the real environment? The participants in both groups implemented similar exploration strategies, mostly based on the ones they used in their daily navigation in real spaces. Examples of strategies implemented were: (a) perimeter (e.g., walking along the room's walls and exploring objects attached to the walls), (b) grid (e.g., exploring the room's inner-space), (c) object-toobject (e.g., walking from one object to another), and (d) points-of-references (e.g., walking in the environment and creating landmarks). However, an interesting additional finding surfaced in that several participants in the experimental group developed a few new strategies while working within the virtual environment. A constant scanning strategy was identified by which the user collected information about the room's interior while simultaneously ", "cite_spans": [], "ref_spans": []}, {"section": "Journal of Special Education Technology", "text": "collecting perimeter information (e.g., resembling the use of a long cane in real space -as shown in Figure 7 ). Those strategies could be generated only within the MVE, representing an important added value of the work with the computer system.", "cite_spans": [], "ref_spans": []}, {"section": "Journal of Special Education Technology", "text": "As already mentioned, no substantial difference between groups was observed as regards the types of strategies used, but significant difference was found concerning the frequency of use of the strategies, and distance traversed using each strategy. Data in Table 2 indicate that the strategy most frequently used by the experimental group was grid, followed by the perimeter strategy. In contrast, the control group preferred to explore the room's perimeter, and next to use the object-to-object strategy. Examining the distance traversed using each strategy, we found that both groups traversed the longest distance using the perimeter strategy.", "cite_spans": [], "ref_spans": [{"start": 257, "end": 264, "text": "Table 2", "ref_id": "TABREF1"}]}, {"section": "Journal of Special Education Technology", "text": "Research Question 2: What characterizes the exploration processes used by people who are blind working with the MVE, in comparison to the exploration processes used by people whom are blind working in the real environment? Five aspects are of interest as regards to the exploration processes used in the two groups: (a) the duration of the exploration, (b) the distance traversed, (c) the number of switches among strategies, (d) the sequence of main implemented strategies, and (e) the number and kinds of stops made while examining the new space.", "cite_spans": [], "ref_spans": []}, {"section": "Journal of Special Education Technology", "text": "Concerning the duration of the exploration, it should be noted that the participants were not limited in time for accomplishing the task. Participants from the experimental group needed four times more time to explore the new environment (average time of 38 minutes) than the ones from the control group (average time of 10 minutes). This difference was significant (t (28)=7; p=.000). Significant difference was found also for the total length of the exploration path (t (29)=5.44; p=.000). Participants in experimental group traversed an average of three times more distance (M=6.3 m) than the control group subjects (M=1.9 m).", "cite_spans": [], "ref_spans": []}, {"section": "Journal of Special Education Technology", "text": "The experimental group made frequent switches of strategy during their walk in the MVE, in contrast with the control-group performance in the real space. This behavior is reflected in the total and average frequency of use of the various strategies by both groups (see Table 2 ), total frequency of 292 and mean of 14 for the experimental group, and total frequency of 64 and mean of 6.4 for the control group.", "cite_spans": [], "ref_spans": [{"start": 269, "end": 276, "text": "Table 2", "ref_id": "TABREF1"}]}, {"section": "Journal of Special Education Technology", "text": "Significant difference was also found between the groups in the sequence of main strategies implemented (c2(2)=7.55; p<.05). Data in Table 3 indicate that most experimentalgroup participants (62%) used the grid strategy first and then the perimeter strategy. In contrast, most control-group participants (90%) preferred first to explore the room's perimeter and then the objects located in the inner space of the room.", "cite_spans": [], "ref_spans": [{"start": 133, "end": 140, "text": "Table 3", "ref_id": "TABREF2"}]}, {"section": "Journal of Special Education Technology", "text": "Participants from both groups made many pauses during their walk, suggesting that different cognitive operations related to the task in process were activated during these intervals. In terms of duration and function, we defined two types of pauses, short and long. Short pauses (i.e., 4-10 seconds) were used for technical purposes (e.g., changing the hand that holds the force-feedback joystick) or for reflection on a recent action. Long pauses (i.e., more than 10 seconds) were used for memorizing spatial information, reflection on a recently implemented exploration strategy, or planning. As shown in Table 4 , significant difference was found between the groups (t(26)=7.65; p<.001; t(25)=2.56; p<.05 ) for both short and long pauses. The experimental group made about 3 times more short pauses, and 6 times more long pauses.", "cite_spans": [], "ref_spans": [{"start": 607, "end": 614, "text": "Table 4", "ref_id": "TABREF3"}]}, {"section": "Journal of Special Education Technology", "text": "As the results indicate, significant differences were found between the experimental group and the control group concerning the characteristics of the exploration process. These differences were related to four dependent variables: (a) the total duration of the exploration, (b) the total distance traversed, (c) the sequence of main implemented strategies, and (d) the number of pauses made while exploring the unknown space. The experimental group participants, in comparison with the control group, used a more varied range of strategies to explore the room, walked a longer distance to complete the exploration, and made more pauses for technical or reflective purposes.", "cite_spans": [], "ref_spans": []}, {"section": "Journal of Special Education Technology", "text": "Research Question 3: What information collection and storage did participants use, in both the experimental and control groups? The collection and storage of relevant information is inherent to the process of exploring an unknown space. Although only a few participants in this study reported explicitly on the use of tactics and aids for performing these functions, their account on this matter is of interest. Excerpts of these participants' references to the use of such aids follow.", "cite_spans": [], "ref_spans": []}, {"section": "Journal of Special Education Technology", "text": "One important category of information-collection aids was related to measurement to support the estimation of dimensions and distances. One example is the case of T, a 25-year-old, late blind, woman who explored the room using the MVE. After 2 minutes in the system T began to walk and count out aloud steps: \"The blackboard\u2026 ok, the wall, one, two, three, four, five\u2026\".", "cite_spans": [], "ref_spans": []}, {"section": "Journal of Special Education Technology", "text": "The use of echo was another useful measurement aid. For example, the control-group participants used echo for measuring their distance from the wall or from other objects, or the room size. During their exploration those participants spoke, sang or whistled to get echo information.", "cite_spans": [], "ref_spans": []}, {"section": "Journal of Special Education Technology", "text": "The participants in this study used various kinds of information-retaining means. One was verbal reconstruction of landmarks, by which the subject recalled out loud her/his exploration of the space. For example, G, a 25-year-old, late blind man who explored the room by using the MVE, after examining the room's perimeter for 13 minutes said: \"I had door, a prism, a corner, when I walked I had a window at the left side and then I reached the cube, I passed it and in front of it I had a window, column, window, window, column, window\u2026\". A variant of this was to complement the verbal reconstruction with virtual drawing (i.e., accompanying the verbal description with hand movements mimicking the physical presence and distribution of spatial components). For example, G, a 12-year-old, congenitally blind girl working with the MVE, after 22 minutes of exploration discovered the second cube in the room and began to describe out loud: \"second cube, this cube is in the corner of the lower wall, and the wall is here\u2026so the cube is in this corner...of the left wall\u2026[during this verbal reconstruction G moved with her hand on the table indicating where the surveyed objects were located] yes the left wall, yes this wall corner and that wall corner ...there is a cube...\".", "cite_spans": [], "ref_spans": []}, {"section": "Journal of Special Education Technology", "text": "Another interesting aid for the reinforcement of acquired information was the use of metaphors. For example, M, a 39-year-old, congenitally blind woman, after 32 minutes of exploration said: \"\u2026now I am a tourist guide, you are standing in front of the room entrance, now you are going to follow me, we are turning to the left, ok follow me... you have reached the prism, look at the prism, it is a beautiful object. We can not walk to the left, we are stuck in\u2026 we are walking forward\u2026 and we are arriving at the wall\u2026\".", "cite_spans": [], "ref_spans": []}, {"section": "Journal of Special Education Technology", "text": "Only some of the participants explicitly reported on the use of any aid. Table 5 indicates that the participants from the experimental group who reported on the use of aids mentioned mainly retention reinforcement aids (54%). In contrast, half of the control group mentioned such aids (50%), and even more mentioned the use of measuring aids (70%).", "cite_spans": [], "ref_spans": [{"start": 73, "end": 80, "text": "Table 5", "ref_id": "TABREF4"}]}, {"section": "DISCUSSION", "text": "The research reported here is part of an effort aimed to understand if and how, the work with a MVE supports the exploration of unknown environments by people who are blind . Gathering comprehensive information about new spaces is a prerequisite for the construction of effective cognitive maps of these spaces, and for supporting people's ability to navigate them. The results of this study helped uncover several issues concerning the contribution of the MVE to the exploration strategies and learning process of unknown spaces by people who are blind.", "cite_spans": [], "ref_spans": []}, {"section": "Exploration Strategies in the Virtual Environment.", "text": "Walking in the MVE gave participants a comprehensive and thorough acquaintance with the target space. The high degree of compatibility between the components of the virtual system and of the real space on one hand and the exploring methods supported by the MVE on the other, contributed to Journal of Special Education Technology the users' relaxed and safe walking. These features also enabled participants to implement exploration patterns they commonly used in real spaces, but in a qualitatively different manner. The use of real walking strategies in virtual environments was reported in previous studies on spatial performance by sighted participants (Darken & Peterson, 2002; Witmer, Bailey, Knerr & Parsons 1996) . But this study's MVE participants applied the known strategies in novel ways. For example, they preferred to explore the inner part of the room first and only then its boundaries, in contrast with the exploration patterns described by Jacobson, 1993 . Moreover, the MVE participants created new exploration strategies, such as the one simulating walking with a long cane enabling them to walk the perimeter of the room and at the same time to explore its corresponding inner areas -a strategy only possible within the MVE.", "cite_spans": [{"start": 657, "end": 682, "text": "(Darken & Peterson, 2002;", "ref_id": "BIBREF3"}, {"start": 683, "end": 720, "text": "Witmer, Bailey, Knerr & Parsons 1996)", "ref_id": "BIBREF21"}, {"start": 958, "end": 972, "text": "Jacobson, 1993", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "Exploration process in the Virtual Environment.", "text": "Operation features of the MVE (e.g., the game-like physical interface, various types of feedback) contributed to participants' performance with the system while exploring the unknown space. As a result, the exploration process showed interesting qualities concerning spatial, temporal, and thinking-related aspects. Examples of spatial and temporal qualities were the range of scanning strategies implemented, the inclusion of a large number of long and short breaks, or the time spent in examining the space. In addition, the MVE users traveled as much as three times more distance than the control-group participants, allowing them to collect information about the environment at different resolution levels, and to re-evaluate the information already gathered. All these were indications of the richness and comprehensiveness of the exploration process as accomplished by the MVE participants. Although the time measures collected were similar to those reported in Darken and Banker (1998) and Waller et al. (1998) , both studies of sighted participants exploring spaces by means of VEs, it could be expected that exploration time would become shorter as participants got gradually used to working with these systems as tools for learning unknown spaces.", "cite_spans": [{"start": 968, "end": 992, "text": "Darken and Banker (1998)", "ref_id": "BIBREF2"}, {"start": 997, "end": 1017, "text": "Waller et al. (1998)", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "Exploration process in the Virtual Environment.", "text": "Concerning thinking-related aspects of the process, interesting examples were the long breaks made by the participants with the aim to reflect on the exploration steps or to memorize data concerning an explored area, or the use of virtual drawing of spatial features under examination on the table's surface as a reinforcement aid.", "cite_spans": [], "ref_spans": []}, {"section": "Exploration process in the Virtual Environment.", "text": "An important byproduct of the study is related to the definition of specifications and constraints for the appropriate design of haptic virtual learning environments for people who are blind (e.g., force-feedback in high resolution, audio feedback). We expect these virtual environments to become powerful tools for people who are blind in learning processes in which spatial information is crucial, both for understanding new concepts and phenomena, as well as for acting and performing in the real world.", "cite_spans": [], "ref_spans": []}, {"section": "Further Research", "text": "Further studies should examine the participants' construction of spatial cognitive maps of spaces using the MVE and, consequently, their use of these maps for navigating in the real environments. Additional variables to be studied should relate to properties of the environment (e.g., indoor or outdoor spaces, complex public spaces, and irregular surfaces). Finally, a comparison with traditional methods used by people who are blind to learn about unknown environments (e.g., tactile maps, verbal descriptions, human guidance) may serve for comprehensive evaluation of the contribution of the virtual tools to people's spatial performance. Finally, at the implementation level the virtual tool could play a central role in training and rehabilitation processes as well. One possible application is for supporting the acquisition of O&M skills and strategies by persons who are late blind as part of their rehabilitation process. At another level, the development of more comprehensive environmentediting tools for the MVE will support the creation of a variety of models of spaces (e.g., public buildings, shopping areas) enabling pre and post-visit exploration and recall of unknown spaces by people who are blind. These implementations may also serve the research and practitioners community as models for the further development of technology-based tools for supporting learning processes and performance of people with special needs. ", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Haptic virtual reality for blind computer users", "authors": [{"first": "C", "middle": [], "last": "Colwell", "suffix": ""}, {"first": "H", "middle": [], "last": "Petrie", "suffix": ""}, {"first": "D", "middle": [], "last": "Kornbrot", "suffix": ""}], "year": 1998, "venue": "Paper presented at the Assets '98 Conference", "link": "1098608"}, "BIBREF1": {"title": "Transit accessibility improvement through talking signs remote infrared signage, a demonstration and evaluation", "authors": [{"first": "W", "middle": [], "last": "Crandall", "suffix": ""}, {"first": "B", "middle": ["L"], "last": "Bentzen", "suffix": ""}, {"first": "L", "middle": [], "last": "Myers", "suffix": ""}, {"first": "P", "middle": [], "last": "Mitchell", "suffix": ""}], "year": 1995, "venue": "", "link": "106791123"}, "BIBREF2": {"title": "Navigating in natural environments: A virtual environment training transfer study. Paper presented at the IEEE Virtual Reality Annual International Symposium", "authors": [{"first": "R", "middle": ["P"], "last": "Darken", "suffix": ""}, {"first": "W", "middle": ["P"], "last": "Banker", "suffix": ""}], "year": 1998, "venue": "", "link": null}, "BIBREF3": {"title": "Handbook of virtual environments design, implementation, and applications", "authors": [{"first": "R", "middle": ["P"], "last": "Darken", "suffix": ""}, {"first": "B", "middle": [], "last": "Peterson", "suffix": ""}], "year": 2002, "venue": "", "link": "59663322"}, "BIBREF4": {"title": "Preschool orientation and mobility screening. A publication of division IX of the association for education and rehabilitation of the blind and visually impaired", "authors": [{"first": "B", "middle": [], "last": "Dodson-Burk", "suffix": ""}, {"first": "E", "middle": ["W"], "last": "Hill", "suffix": ""}], "year": 1989, "venue": "", "link": null}, "BIBREF5": {"title": "The effect of extended acoustic training on spatial updating in adults who are congenitally blind", "authors": [{"first": "R", "middle": ["D"], "last": "Easton", "suffix": ""}, {"first": "B", "middle": ["L"], "last": "Bgentzen", "suffix": ""}], "year": 1999, "venue": "Journal of Visual Impairment and Blindness", "link": null}, "BIBREF6": {"title": "Haptic representation of scientific data for visually impaired or blind persons", "authors": [{"first": "J", "middle": [], "last": "Fritz", "suffix": ""}, {"first": "T", "middle": [], "last": "Way", "suffix": ""}, {"first": "K", "middle": [], "last": "Barner", "suffix": ""}], "year": 1996, "venue": "Proceedings of the Eleventh Annual Technology and Persons with Disabilities Conference", "link": "1490396"}, "BIBREF7": {"title": "Cognitive mapping and wayfinding by adults without vision", "authors": [{"first": "R", "middle": [], "last": "Golledge", "suffix": ""}, {"first": "R", "middle": [], "last": "Klatzky", "suffix": ""}, {"first": "J", "middle": [], "last": "Loomis", "suffix": ""}], "year": 1996, "venue": "The construction of cognitive maps", "link": "141144493"}, "BIBREF8": {"title": "How persons with visual impairments explore novel spaces: Strategies of good and poor performers", "authors": [{"first": "E", "middle": [], "last": "Hill", "suffix": ""}, {"first": "J", "middle": [], "last": "Rieser", "suffix": ""}, {"first": "M", "middle": [], "last": "Hill", "suffix": ""}, {"first": "M", "middle": [], "last": "Hill", "suffix": ""}, {"first": "J", "middle": [], "last": "Halpin", "suffix": ""}, {"first": "R", "middle": [], "last": "Halpin", "suffix": ""}], "year": 1993, "venue": "Journal of Visual Impairment and Blindness", "link": "149365460"}, "BIBREF9": {"title": "The art and science of teaching orientation and mobility to persons with visual impairments", "authors": [{"first": "W", "middle": ["H"], "last": "Jacobson", "suffix": ""}], "year": 1993, "venue": "", "link": null}, "BIBREF10": {"title": "Visually impaired persons' use of the PHANToM for information about texture and 3D form of virtual objects", "authors": [{"first": "G", "middle": [], "last": "Jansson", "suffix": ""}, {"first": "J", "middle": [], "last": "Fanger", "suffix": ""}, {"first": "H", "middle": [], "last": "Konig", "suffix": ""}, {"first": "K", "middle": [], "last": "Billberger", "suffix": ""}], "year": 1998, "venue": "", "link": "60194517"}, "BIBREF11": {"title": "Proceedings of the Third PHANToM Users Group Workshop", "authors": [{"first": "&amp;", "middle": ["M A"], "last": "Salisbury", "suffix": ""}, {"first": "", "middle": [], "last": "Srinivasan", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF12": {"title": "Navigating without vision: Basic and applied research", "authors": [{"first": "J", "middle": ["M"], "last": "Loomis", "suffix": ""}, {"first": "R", "middle": ["L"], "last": "Klatzky", "suffix": ""}, {"first": "R", "middle": ["G"], "last": "Golledge", "suffix": ""}], "year": 2001, "venue": "Optometry and Vision Science", "link": "8084620"}, "BIBREF13": {"title": "The image of the city", "authors": [{"first": "K", "middle": [], "last": "Lynch", "suffix": ""}], "year": 1960, "venue": "", "link": null}, "BIBREF14": {"title": "From real virtuality in Lascaux to virtual reality today: cognitive processes with cognitive technologies", "authors": [{"first": "D", "middle": [], "last": "Mioduser", "suffix": ""}], "year": "", "venue": "Educational Technology Review", "link": "14071859"}, "BIBREF15": {"title": "The application of virtual reality technology for rehabilitation", "authors": [{"first": "M", "middle": ["T"], "last": "Schultheis", "suffix": ""}, {"first": "A", "middle": ["A"], "last": "Rizzo", "suffix": ""}], "year": 2001, "venue": "Rehabilitation Psychology", "link": null}, "BIBREF16": {"title": "The ADL taxonomy -from individual categorical data to ordinal categorical data", "authors": [{"first": "U", "middle": [], "last": "Sonn", "suffix": ""}, {"first": "K", "middle": [], "last": "Tornquist", "suffix": ""}, {"first": "E", "middle": [], "last": "Svensson", "suffix": ""}], "year": 1999, "venue": "Scandinavian Journal of occupational therapy", "link": "145324498"}, "BIBREF17": {"title": "The effective use of virtual environments in the education and rehabilitation of students with intellectual disabilities", "authors": [{"first": "P", "middle": ["J"], "last": "Standen", "suffix": ""}, {"first": "D", "middle": ["J"], "last": "Brown", "suffix": ""}, {"first": "J", "middle": ["J"], "last": "Cromby", "suffix": ""}], "year": 2001, "venue": "British Journal of Education Technology", "link": "20065511"}, "BIBREF18": {"title": "The construction of cognitive maps by children with visual impairments", "authors": [{"first": "S", "middle": [], "last": "Ungar", "suffix": ""}, {"first": "M", "middle": [], "last": "Blades", "suffix": ""}, {"first": "S", "middle": [], "last": "Spencer", "suffix": ""}], "year": 1996, "venue": "The construction of cognitive maps", "link": null}, "BIBREF19": {"title": "The transfer of spatial knowledge in virtual environment training", "authors": [{"first": "D", "middle": [], "last": "Waller", "suffix": ""}, {"first": "E", "middle": [], "last": "Hunt", "suffix": ""}, {"first": "D", "middle": [], "last": "Knapp", "suffix": ""}], "year": 1998, "venue": "Presence: Teloperators and Virtual Environments", "link": "17900737"}, "BIBREF20": {"title": "Electronic spatial sensing for the blind", "authors": [{"first": "D", "middle": ["H"], "last": "Warren", "suffix": ""}, {"first": "E", "middle": ["R"], "last": "Strelow", "suffix": ""}], "year": 1985, "venue": "", "link": "59976918"}, "BIBREF21": {"title": "Virtual spaces and real world places: Transfer of route knowledge", "authors": [{"first": "B", "middle": ["G"], "last": "Witmer", "suffix": ""}, {"first": "J", "middle": ["H"], "last": "Bailey", "suffix": ""}, {"first": "B", "middle": ["W"], "last": "Knerr", "suffix": ""}, {"first": "K", "middle": ["C"], "last": "Parsons", "suffix": ""}], "year": 1996, "venue": "International Journal of Human-Computer Studies", "link": "42773184"}, "BIBREF22": {"title": "This research was partially supported by grants from the Israeli Ministry of Education, Microsoft Research Ltd., and Israel Foundation Trustees. Send correspondence to Orly Lahav", "authors": [], "year": "", "venue": "", "link": null}}, "ref_entries": {"FIGREF0": {"text": "Figure 1. Multisensory environment editor", "type": "figure"}, "FIGREF1": {"text": "Figure 3. Recorded log and monitoring data", "type": "figure"}, "FIGREF2": {"text": "Figure 4. Exploration strategies", "type": "figure"}, "FIGREF3": {"text": "Figure 6. The Real Environment", "type": "figure"}, "TABREF0": {"text": "The study's participants", "type": "table"}, "TABREF1": {"text": "Exploration strategies, frequency and length", "type": "table"}, "TABREF2": {"text": "Sequence of strategies", "type": "table"}, "TABREF3": {"text": "Short and long breaksp<.05; **p<.001", "type": "table"}, "TABREF4": {"text": "Exploring aids Information-retaining Measurement Group Verbal reconstruction of landmarks Verbal reconstruction with virtual drawing Use of metaphor", "type": "table"}}}
{"paper_id": "18981201", "_pdf_hash": "e99a17163d9cd7b8e55f1687f2608091573c5bae", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "The time course of repetition effects for words and unfamiliar faces", "authors": [{"first": "S", "middle": [], "last": "Bentin", "suffix": ""}, {"first": "M", "middle": [], "last": "Moscovitch", "suffix": ""}], "year": 1988, "venue": "Journal of Experimental Psychology: Genera", "link": "14431648"}, "BIBREF1": {"title": "Recognition-by-components: A theory of human image understanding", "authors": [{"first": "I", "middle": [], "last": "Biederman", "suffix": ""}], "year": 1987, "venue": "Psychological Review", "link": "8054340"}, "BIBREF2": {"title": "Priming contour-deleted images: Evidence for intermediate representations in visual object recognition", "authors": [{"first": "I", "middle": [], "last": "Biederman", "suffix": ""}, {"first": "E", "middle": ["E"], "last": "Cooper", "suffix": ""}], "year": 1989, "venue": "", "link": "5927412"}, "BIBREF3": {"title": "Conditions for the use of verbal associations", "authors": [{"first": "C", "middle": ["N"], "last": "Cofer", "suffix": ""}], "year": 1967, "venue": "Psychological Bulletin", "link": "32556705"}, "BIBREF4": {"title": "Mental representation of three-dimensional objects in visual problem solving and recognition", "authors": [{"first": "L", "middle": ["A"], "last": "Cooper", "suffix": ""}], "year": 1990, "venue": "Journal of Experimental Psychology: Learning. Memory, and Cognition", "link": "210778182"}, "BIBREF5": {"title": "The Penrose triangle and a family of related figures", "authors": [{"first": "S", "middle": ["W"], "last": "Draper", "suffix": ""}], "year": 1978, "venue": "Perception", "link": "7496938"}, "BIBREF6": {"title": "Facilitation in naming and categorizing repeated pictures and words", "authors": [{"first": "F", "middle": ["T"], "last": "Durso", "suffix": ""}, {"first": "M", "middle": ["K"], "last": "Johnson", "suffix": ""}], "year": 1979, "venue": "Journal of Experimental Psychology: Human Learning and Memory", "link": "145564491"}, "BIBREF7": {"title": "Episodic and lexical contributions to the repetition effect in word identification", "authors": [{"first": "T", "middle": [], "last": "Feustel", "suffix": ""}, {"first": "R", "middle": ["M"], "last": "Shiffrin", "suffix": ""}, {"first": "A", "middle": [], "last": "Salasoo", "suffix": ""}], "year": 1983, "venue": "Journal of Experimental Psychology: General", "link": "40608102"}, "BIBREF9": {"title": "Intact priming of patterns despite impaired memory-Neusopsychoiogia", "authors": [{"first": "W", "middle": [], "last": "Milberg", "suffix": ""}, {"first": "M", "middle": ["M"], "last": "Keane", "suffix": ""}, {"first": "S", "middle": [], "last": "Corkin", "suffix": ""}], "year": 1990, "venue": "", "link": null}, "BIBREF10": {"title": "Measures of association for cross classifications", "authors": [{"first": "L", "middle": ["A"], "last": "Goodman", "suffix": ""}, {"first": "W", "middle": ["H"], "last": "Kruskal", "suffix": ""}], "year": 1954, "venue": "Journal of the American Statistical Association", "link": "122008636"}, "BIBREF12": {"title": "Implicit and explicit memory for new associations in normal and amnesic patients", "authors": [{"first": "D", "middle": ["L"], "last": "Schacter", "suffix": ""}], "year": 1985, "venue": "Journal of Experimental Psychology: Learning, Memory, and Cognition", "link": null}, "BIBREF13": {"title": "Contingent dissociation between recognition and fragment completion: The method of triangulation", "authors": [{"first": "C", "middle": ["A G"], "last": "Hayman", "suffix": ""}, {"first": "E", "middle": [], "last": "Tulving", "suffix": ""}], "year": 1989, "venue": "Journal of Experimental Psychology: Learning, Memory, and Cognition", "link": "197667025"}, "BIBREF14": {"title": "Is priming in fragment completion based on a \"traceless\" memory system", "authors": [{"first": "C", "middle": ["A G"], "last": "Hayman", "suffix": ""}, {"first": "E", "middle": [], "last": "Tulving", "suffix": ""}], "year": 1989, "venue": "Journal of Experimental Psychology: Learning, Memory, & Cognition", "link": "14222887"}, "BIBREF15": {"title": "Normal and pathological processes in visual object constancy", "authors": [{"first": "G", "middle": ["W"], "last": "Humphreys", "suffix": ""}, {"first": "P", "middle": ["T"], "last": "Quinlan", "suffix": ""}], "year": 1987, "venue": "Visual object processing: A cognitive neuropsychological approach", "link": "125135848"}, "BIBREF16": {"title": "Perceptual enhancement: Persistent effects of an experience", "authors": [{"first": "L", "middle": ["L"], "last": "Jacoby", "suffix": ""}], "year": 1983, "venue": "Journal of Experimental Psychology: Learning, Memory, and Cognition", "link": "8053429"}, "BIBREF17": {"title": "Episodic effects on picture identification: Implications for theories of concept learning and theories of memory", "authors": [{"first": "L", "middle": ["L"], "last": "Jacoby", "suffix": ""}, {"first": "J", "middle": ["G"], "last": "Baker", "suffix": ""}, {"first": "", "middle": ["L R"], "last": "Brooks", "suffix": ""}], "year": 1989, "venue": "Journal of Experimental Psychology: Learning, Memory, & Cognition", "link": "17568119"}, "BIBREF18": {"title": "A multiple-entry, modular memory system", "authors": [{"first": "M", "middle": ["K"], "last": "Johnson", "suffix": ""}], "year": 1983, "venue": "The psychology of learning and motivation", "link": "142396466"}, "BIBREF19": {"title": "Seeing and imagining in the cerebral hemisphere: A computational approach", "authors": [{"first": "S", "middle": ["M"], "last": "Kosslyn", "suffix": ""}], "year": 1987, "venue": "Psychological Review", "link": "150163234"}, "BIBREF20": {"title": "Recognizing words, pictures, and concepts: A comparison of lexical, object, and reality decisions", "authors": [{"first": "J", "middle": ["F"], "last": "Kroll", "suffix": ""}, {"first": "M", "middle": ["C"], "last": "Potter", "suffix": ""}], "year": 1984, "venue": "Journal of Verbal Learning & Verbal Behavior", "link": "145377299"}, "BIBREF21": {"title": "Vision", "authors": [{"first": "D", "middle": [], "last": "Marr", "suffix": ""}], "year": 1982, "venue": "", "link": null}, "BIBREF22": {"title": "Representation and recognition of the spatial organization of three-dimensional shapes", "authors": [{"first": "D", "middle": [], "last": "Marr", "suffix": ""}, {"first": "H", "middle": ["K"], "last": "Nishihara", "suffix": ""}], "year": 1978, "venue": "Proceedings of the Royal Society", "link": "43759520"}, "BIBREF23": {"title": "Fluent reprocessing as an implicit expression of memory for experience", "authors": [{"first": "M", "middle": ["E J"], "last": "Masson", "suffix": ""}], "year": 1989, "venue": "", "link": "152233198"}, "BIBREF24": {"title": "Implicit memory: Theoretical issues", "authors": [{"first": "", "middle": [], "last": "Kirsner", "suffix": ""}], "year": "", "venue": "", "link": "142953917"}, "BIBREF25": {"title": "Persistent repetition priming in picture naming and its dissociation from recognition memory", "authors": [{"first": "D", "middle": ["B"], "last": "Mitchell", "suffix": ""}, {"first": "A", "middle": ["S"], "last": "Brown", "suffix": ""}], "year": 1988, "venue": "Journal of Experimental Psychology: Learning, Memory, and Cognition", "link": "31748049"}, "BIBREF26": {"title": "Levels of processing versus transfer appropriate processing", "authors": [{"first": "C", "middle": ["D"], "last": "Morris", "suffix": ""}, {"first": "J", "middle": ["D"], "last": "Bransford", "suffix": ""}, {"first": "J", "middle": ["J"], "last": "Franks", "suffix": ""}], "year": 1977, "venue": "Journal of Verbal Learning & Verbal Behavior", "link": "145781904"}, "BIBREF27": {"title": "Implicit and explicit memory for visual patterns", "authors": [{"first": "G", "middle": [], "last": "Musen", "suffix": ""}, {"first": "A", "middle": [], "last": "Treisman", "suffix": ""}], "year": 1990, "venue": "Journal of Experimental Psychology: Learning, Memory, and Cognition", "link": "19835148"}, "BIBREF28": {"title": "A comparison of current measures of the accuracy of feeling-of-kn owing predictions", "authors": [{"first": "T", "middle": ["O"], "last": "Nelson", "suffix": ""}], "year": 1984, "venue": "Psychological Bulletin", "link": null}, "BIBREF29": {"title": "Comparable measurement scales in task-comparison experiments", "authors": [{"first": "T", "middle": ["O"], "last": "Nelson", "suffix": ""}], "year": 1990, "venue": "Journal of Experimental Psychology: General", "link": "32322014"}, "BIBREF30": {"title": "Visual perception and world knowledge: Notes on a model of sensory-cognitive interaction", "authors": [{"first": "S", "middle": ["E"], "last": "Palmer", "suffix": ""}], "year": 1975, "venue": "Explorations in cognition", "link": "140892073"}, "BIBREF32": {"title": "Impossible objects: A special type of visual illusion", "authors": [{"first": "L", "middle": ["S"], "last": "Penrose", "suffix": ""}, {"first": "", "middle": ["R"], "last": "Penrose", "suffix": ""}], "year": 1958, "venue": "British Journal of Psychology", "link": "45243810"}, "BIBREF33": {"title": "Directing spatial attention within an object: Altering the functional equivalence of shape descriptions", "authors": [{"first": "M", "middle": [], "last": "Peterson", "suffix": ""}, {"first": "B", "middle": ["S"], "last": "Gibson", "suffix": ""}], "year": "", "venue": "Journal of Experimental Psychology", "link": "4992237"}, "BIBREF34": {"title": "Visual cognition: An introduction", "authors": [{"first": "S", "middle": [], "last": "Pinker", "suffix": ""}], "year": 1984, "venue": "Cognition", "link": null}, "BIBREF35": {"title": "Structural descriptions and the limitations of visual images", "authors": [{"first": "S", "middle": ["K"], "last": "Reed", "suffix": ""}], "year": 1974, "venue": "Memory and Cognition", "link": "38035220"}, "BIBREF36": {"title": "The analysis of cross-classification", "authors": [{"first": "H", "middle": ["T"], "last": "Reynolds", "suffix": ""}], "year": 1977, "venue": "", "link": null}, "BIBREF37": {"title": "Measures of memory", "authors": [{"first": "A", "middle": [], "last": "Richardson-Kiavehn", "suffix": ""}, {"first": "R", "middle": [], "last": "&amp;bjork", "suffix": ""}], "year": 1988, "venue": "Annual Review of Psychology", "link": null}, "BIBREF38": {"title": "Visual object processing in optic aphasia: A case of semantic access agnosia", "authors": [{"first": "M", "middle": ["J"], "last": "Riddoch", "suffix": ""}, {"first": "G", "middle": ["W"], "last": "Humphreys", "suffix": ""}], "year": 1987, "venue": "Cognitive Neuropsychology", "link": "146152365"}, "BIBREF39": {"title": "Explaining dissociations between implicit and explicit measures of retention: A processing account", "authors": [{"first": "H", "middle": ["L"], "last": "Roediger", "suffix": ""}, {"first": "", "middle": [], "last": "Ill", "suffix": ""}, {"first": "S", "middle": [], "last": "Weldon", "suffix": ""}, {"first": "B", "middle": ["H"], "last": "Challis", "suffix": ""}], "year": 1989, "venue": "Varieties of memory and consciousness: Essays in honor of Endel Tulving", "link": "143081262"}, "BIBREF40": {"title": "Journal of Experimental Psychology: Learning, Memory, and Cognition", "authors": [{"first": "D", "middle": ["L"], "last": "Schacter", "suffix": ""}], "year": 1987, "venue": "", "link": null}, "BIBREF41": {"title": "Perceptual representation systems and implicit memory: Toward a resolution of the multiple memory systems debate", "authors": [{"first": "D", "middle": ["L"], "last": "Schacter", "suffix": ""}], "year": 1990, "venue": "Annals of the New York Academy of Sciences", "link": null}, "BIBREF42": {"title": "Implicit memory for unfamiliar objects depends on access to structural descriptions", "authors": [{"first": "D", "middle": ["L"], "last": "Schacter", "suffix": ""}, {"first": "L", "middle": ["A"], "last": "Cooper", "suffix": ""}, {"first": "S", "middle": ["M"], "last": "Delaney", "suffix": ""}], "year": 1990, "venue": "Journal of Experimental Psychology: General", "link": "3803717"}, "BIBREF43": {"title": "Implicit memory for visual objects and the structural description system", "authors": [{"first": "D", "middle": ["L"], "last": "Schacter", "suffix": ""}, {"first": "L", "middle": ["A"], "last": "Cooper", "suffix": ""}, {"first": "S", "middle": ["M"], "last": "Delaney", "suffix": ""}], "year": 1990, "venue": "Bulletin of the Psychonomic Society", "link": "3819255"}, "BIBREF45": {"title": "Preserved priming of novel objects in patients with memory disorders", "authors": [{"first": "L", "middle": ["A"], "last": "Cooper", "suffix": ""}, {"first": "M", "middle": [], "last": "Tharan", "suffix": ""}, {"first": "A", "middle": ["B"], "last": "Rubens", "suffix": ""}], "year": "", "venue": "Journal of Cognitive Neuwscience", "link": "7262598"}, "BIBREF46": {"title": "Priming of nonverbal information and the nature of implicit memory", "authors": [{"first": "D", "middle": ["L"], "last": "Schacter", "suffix": ""}, {"first": "S", "middle": ["M"], "last": "Delaney", "suffix": ""}, {"first": "E", "middle": ["P"], "last": "Merikle", "suffix": ""}], "year": 1990, "venue": "The psychology of learning and motivation", "link": "141537950"}, "BIBREF48": {"title": "Priming effects in a letter-by-letter reader depend upon access to the word form system", "authors": [{"first": "D", "middle": ["L"], "last": "Schacter", "suffix": ""}, {"first": "S", "middle": [], "last": "Rapcsak", "suffix": ""}, {"first": "A", "middle": ["B"], "last": "Rubens", "suffix": ""}, {"first": "M", "middle": [], "last": "Tharan", "suffix": ""}, {"first": "J", "middle": [], "last": "Laguna", "suffix": ""}], "year": 1990, "venue": "Neuropsychologia", "link": "3784861"}, "BIBREF49": {"title": "The evolution of multiple memory systems", "authors": [{"first": "D", "middle": ["F"], "last": "Sherry", "suffix": ""}, {"first": "D", "middle": ["L"], "last": "Schacter", "suffix": ""}], "year": 1987, "venue": "Psychological Review", "link": "3750846"}, "BIBREF50": {"title": "Problems with the finding of stochastic independence as evidence for the independence of cognitive processes", "authors": [{"first": "A", "middle": ["P"], "last": "Shimamura", "suffix": ""}], "year": 1985, "venue": "Bulletin of the Psychonomic Society", "link": null}, "BIBREF51": {"title": "Priming effects in amnesia: Evidence for a dissociable memory function", "authors": [{"first": "A", "middle": ["P"], "last": "Shimamura", "suffix": ""}], "year": 1986, "venue": "Quarterly Journal of Experimental Psychology", "link": "40204919"}, "BIBREF52": {"title": "Memory and brain", "authors": [{"first": "L", "middle": ["R"], "last": "Squire", "suffix": ""}], "year": 1987, "venue": "", "link": "142531295"}, "BIBREF53": {"title": "Outlines of a theory of pattern recognition in animals and man", "authors": [{"first": "N", "middle": ["S"], "last": "Sutherland", "suffix": ""}], "year": 1968, "venue": "Proceedings of the Royal Society", "link": null}, "BIBREF54": {"title": "Priming and human memory systems", "authors": [{"first": "E", "middle": [], "last": "Tulving", "suffix": ""}, {"first": "D", "middle": ["L"], "last": "Schacler", "suffix": ""}], "year": 1990, "venue": "Science", "link": "40894114"}, "BIBREF55": {"title": "Priming effects in word-fragment completion are independent of recognition memory", "authors": [{"first": "E", "middle": [], "last": "Tulving", "suffix": ""}, {"first": "D", "middle": ["L"], "last": "Schacter", "suffix": ""}, {"first": "H", "middle": ["A"], "last": "Stark", "suffix": ""}], "year": 1982, "venue": "Journal of Experimental Psychology: Learning, Memory, and Cognition", "link": "143013790"}, "BIBREF56": {"title": "Encoding specificity and retrieval processes in episodic memory", "authors": [{"first": "", "middle": ["E"], "last": "Tulving", "suffix": ""}, {"first": "D", "middle": ["M"], "last": "Thomson", "suffix": ""}], "year": 1973, "venue": "Psychological Review", "link": "14879511"}, "BIBREF57": {"title": "The effects of priming on picture recognition", "authors": [{"first": "C", "middle": ["E J"], "last": "Warren", "suffix": ""}, {"first": "J", "middle": [], "last": "Morton", "suffix": ""}], "year": 1982, "venue": "British Journal of Psychology", "link": "8194800"}, "BIBREF58": {"title": "The selective impairment of semantic memory", "authors": [{"first": "E", "middle": ["K"], "last": "Warrington", "suffix": ""}], "year": 1975, "venue": "Quarterly Journal of Experimental Psychology", "link": "145283318"}, "BIBREF59": {"title": "Neuropsychological studies of object recognition", "authors": [{"first": "E", "middle": ["K"], "last": "Warrington", "suffix": ""}], "year": 1982, "venue": "Philosophical Transactions of the Royal Society", "link": "35748345"}, "BIBREF60": {"title": "Two categorical stages of object recognition", "authors": [{"first": "E", "middle": ["K"], "last": "Warrington", "suffix": ""}, {"first": "&amp;", "middle": [], "last": "Taylor", "suffix": ""}, {"first": "A", "middle": ["M"], "last": "", "suffix": ""}], "year": 1978, "venue": "Perception", "link": "27464869"}, "BIBREF61": {"title": "New method of testing long-term retention with special reference to amnesic patients", "authors": [{"first": "E", "middle": ["K"], "last": "Warrington", "suffix": ""}, {"first": "L", "middle": [], "last": "Weiskrantz", "suffix": ""}], "year": 1968, "venue": "Nature", "link": null}, "BIBREF62": {"title": "Altering retrieval demands reverses the picture superiority effect. Memory and Cognition", "authors": [{"first": "M", "middle": ["S"], "last": "Weldon", "suffix": ""}, {"first": "H", "middle": ["L"], "last": "Roediger", "suffix": ""}, {"first": "", "middle": [], "last": "Iii", "suffix": ""}], "year": 1987, "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "18981319", "_pdf_hash": "e585785da4f2e20018126dc1a2a841dd9a1b3c97", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Physics of Intense Charged Particle Beams in High Energy Accelerators", "authors": [{"first": "I", "middle": ["R C"], "last": "Davidson", "suffix": ""}, {"first": "H", "middle": [], "last": "Qin", "suffix": ""}], "year": 2001, "venue": "", "link": "117759753"}, "BIBREF1": {"title": "Physics of Collective Beam Instabilities in High Energy Accelerators", "authors": [{"first": "A", "middle": ["W"], "last": "Chao", "suffix": ""}], "year": 1993, "venue": "", "link": "118093495"}, "BIBREF2": {"title": "Theory and Design of Charged Particle Beams", "authors": [{"first": "M", "middle": [], "last": "Reiser", "suffix": ""}], "year": 1994, "venue": "", "link": "120472763"}, "BIBREF3": {"title": "Proceedings of the 1999 Particle Accelerator Conference (IEEE Catalog Number 99CH36366)", "authors": [{"first": "", "middle": [], "last": "See", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF4": {"title": "Proceedings of the International Heavy Ion Fusion Symposium, Nuclear Instruments and Methods in Physics Research A464", "authors": [{"first": "", "middle": [], "last": "See", "suffix": ""}], "year": "", "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "18981336", "_pdf_hash": "ff543888371d947dc38251850326a56e791a3a01", "abstract": [{"section": "Abstract", "text": "The class of +adequate links contains both alternating and positive links. Generalizing results of Tanaka (for the positive case) and Ng (for the alternating case), we construct fronts of an arbitrary +adequate link A so that the diagram has a ruling, therefore its Thurston-Bennequin number is maximal among Legendrian representatives of A. We derive consequences for the Kauffman polynomial and Khovanov homology of +adequate links.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Maximum Thurston-Bennequin number, denoted by tb, is a knot invariant that has drawn a lot of recent interest. Its definition is possible because Bennequin's inequality, tb \u2264 2g \u2212 1, bounds from above the ThurstonBennequin number of Legendrian representatives 1 of any knot type by (essentially) the genus g of the knot. Either Bennequin's inequality itself or other bounds, for example the so-called Kauffman bound on tb [9], make the extension to links possible.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Recall that the Thurston-Bennequin number is computed from an oriented front diagram by subtracting the number of right cusps from the writhe of the diagram; tb is the maximum of these numbers for all fronts representing a given link type. The Kauffman bound states that tb, and thus tb is strictly 1 To avoid undue repetition and to keep this note short, for the standard definitions of Legendrian knot theory we refer the reader to [2], [5] , or to any number of other publications. Let us only state that we work in R 3 xyz where the contact structure is the kernel of dz \u2212 ydx, so that the front projection is the xz-projection.", "cite_spans": [{"start": 439, "end": 442, "text": "[5]", "ref_id": "BIBREF4"}], "ref_spans": []}], "body_text": [{"section": "", "text": "Maximum Thurston-Bennequin number, denoted by tb, is a knot invariant that has drawn a lot of recent interest. Its definition is possible because Bennequin's inequality, tb \u2264 2g \u2212 1, bounds from above the ThurstonBennequin number of Legendrian representatives 1 of any knot type by (essentially) the genus g of the knot. Either Bennequin's inequality itself or other bounds, for example the so-called Kauffman bound on tb [9] , make the extension to links possible.", "cite_spans": [{"start": 422, "end": 425, "text": "[9]", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "", "text": "Recall that the Thurston-Bennequin number is computed from an oriented front diagram by subtracting the number of right cusps from the writhe of the diagram; tb is the maximum of these numbers for all fronts representing a given link type. The Kauffman bound states that tb, and thus tb is strictly 1 To avoid undue repetition and to keep this note short, for the standard definitions of Legendrian knot theory we refer the reader to [2] , [5] , or to any number of other publications. Let us only state that we work in R 3 xyz where the contact structure is the kernel of dz \u2212 ydx, so that the front projection is the xz-projection.", "cite_spans": [{"start": 434, "end": 437, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 440, "end": 443, "text": "[5]", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "", "text": "less than the minimum v-degree (or \u22121 times the maximum a-degree) of the Kauffman polynomial 2 . The value of tb is known for the following infinite classes of knots and links: positive links [11] (see also [13] ) 2-bridge links [7] and more generally, alternating links [8] , negative torus knots [3] , and Whitehead doubles with sufficiently negative framing [4] .", "cite_spans": [{"start": 192, "end": 196, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 207, "end": 211, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 229, "end": 232, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 271, "end": 274, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 298, "end": 301, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 361, "end": 364, "text": "[4]", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "", "text": "In the positive and alternating cases, the proofs of Tanaka and Ng proceed as follows: For the given knot or link, they construct a certain front diagram. Tanaka uses the Kauffman bound (i.e., establishes that it's sharp for the front) to show that its Thurston-Bennequin number is maximal. Ng uses the so-called Khovanov bound for the same purpose, but it turns out that the Kauffman bound works just as easily in his case as well. (The Kauffman bound is known to be not sharp for many other knots, such as those where the Khovanov bound actually improves it [8] , and also for negative (p, q) torus knots with p > q and q even 3 [4] .) Recently, Rutherford [10] clarified when the Kauffman bound is sharp by verifying the Fuchs conjecture: a necessary and sufficient condition is the existence of a so-called ungraded ruling (a.k.a. decomposition) for at least one Legendrian representative of the link. That representative then has maximum Thurston-Bennequin number.", "cite_spans": [{"start": 560, "end": 563, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 631, "end": 634, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 659, "end": 663, "text": "[10]", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "Definition 1.", "text": "An ungraded ruling is a partial splicing of a front diagram where certain crossings, called switches, are replaced by a pair of arcs as in Figure 1 so that the diagram becomes a (not necessarily disjoint) union of standard unknot diagrams, called eyes. (An eye is a pair of arcs connecting the same two cusps that contain no other cusps and that otherwise do not meet, not even at switches.) We also impose the so-called normality condition: in the vertical (x = const.) slice of the diagram through each switch, the two eyes that meet at the switch follow one of the three configurations in the middle of Figure 1 .", "cite_spans": [], "ref_spans": [{"start": 139, "end": 147, "text": "Figure 1", "ref_id": "FIGREF0"}, {"start": 606, "end": 614, "text": "Figure 1", "ref_id": "FIGREF0"}]}, {"section": "Definition 1.", "text": "The notion of a +adequate link is a common generalization of positive and alternating links 4 , introduced in [6] (see also [12] ). In this paper, we use Rutherford's theorem to unify 5 Tanaka's and Ng's approaches: that is, we 2 It seems to be standard to use either v and z or a = v \u22121 and z as the variables in the Kauffman polynomial; see [1] . The 'Dubrovnik version' has the same degree distribution.", "cite_spans": [{"start": 110, "end": 113, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 124, "end": 128, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 343, "end": 346, "text": "[1]", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "Definition 1.", "text": "3 What Fuchs proves about these is that they do not possess rulings; see below for the significance of this fact in the light of Rutherford's theorem. The same observation also shows that it is not possible to extend the methods of this paper to homogeneous links. 4 Another such generalization, homogeneous links, will be alluded to in Example 7. 5 We could use Proposition 7 of [8] to the same effect. . What is true in the converse direction is that if in a front diagram, the set of all crossings is a ruling (Ng calls these fronts with admissible 0-resolution in [8] ), then that diagram is +adequate. In fact, any +adequate link diagram can be isotoped into a front diagram where the set of all crossings serves as the set of switches in an ungraded ruling. Figure 6 summarizes the procedure; in particular, the eyes in the ruling are exactly the state circles. (To follow the proof below, and in particular the proof of Lemma 5, we suggest to first read pages 1647-1649 of [8] , in particular steps 1, 2, and 3.)", "cite_spans": [{"start": 380, "end": 383, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 568, "end": 571, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 980, "end": 983, "text": "[8]", "ref_id": "BIBREF7"}], "ref_spans": [{"start": 764, "end": 772, "text": "Figure 6", "ref_id": "FIGREF7"}]}, {"section": "Definition 1.", "text": "Proof. We may generalize either Tanaka's or Ng's construction, but the latter seems to be more straightforward. In [8] , it is proved that every alternating link projection can be deformed by a diffeomorphism of the plane into \"Mondrian position\" where the black regions are arbitrarily close to horizontal line segments, and the two arcs in a neighborhood of each crossing are arbitrarily close to vertical line segments connecting the horizontal ones. In such a position, the horizontal line segments are essentially the eyes of an ungraded ruling.", "cite_spans": [{"start": 115, "end": 118, "text": "[8]", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "Definition 1.", "text": "A more precise formulation of Ng's results is the following: A Mondrian diagram is a union of a set of disjoint horizontal line segments and a set of disjoint vertical ones; each of the latter start and end on a horizontal segment, and doesn't intersect other horizontal segments. Contracting a Mondrian diagram means contracting the horizontal segments to points; Ng proves that any 6 planar graph is the contraction of some Mondrian diagram, and then applies this to the graph whose vertices are the black regions of the alternating diagram and whose edges correspond to crossings.", "cite_spans": [], "ref_spans": []}, {"section": "Definition 1.", "text": "In the case of a general +adequate diagram D, state circles are nested, giving rise to a partial ordering among them. An example is shown in Figure  6 . We may first apply Ng's construction to the diagram consisting of those circles that are not contained in others, i.e. ones that are maximal in the partial order (these are 1, 2, 3, and 4 in Figure 6 ). More precisely, define a planar graph whose vertices are the maximal state circles and whose edges correspond to crossings of D connecting two such. Obtain this planar graph as the contraction of a Mondrian diagram. Then, the resulting horizontal line segments (corresponding to the maximal state circles) can be slightly thickened into rectangles to make room for the remaining parts of the diagram, which are arranged again by starting from the outermost state circles. This can be applied successively toward lower and lower levels of the partial order, resulting in an 'iterated Mondrian diagram.' (The upper right subdiagram of Figure 6 is an illustration.) Below, we explain this procedure in greater detail.", "cite_spans": [], "ref_spans": [{"start": 141, "end": 150, "text": "Figure  6", "ref_id": "FIGREF7"}, {"start": 344, "end": 352, "text": "Figure 6", "ref_id": "FIGREF7"}, {"start": 989, "end": 997, "text": "Figure 6", "ref_id": "FIGREF7"}]}, {"section": "Definition 1.", "text": "An important technical difficulty is that the order of outward and inward crossings along any state circle needs to be respected. (See Figure 3 ; note that another distinguishing feature of alternating diagrams is that along their state circles, with the possible exception of a single outermost circle, all crossings are outer.) In our process, we turn each state circle into a narrow horizontal rectangle and we arrange the outward crossings first along the upper and lower sides of the rectangle. Thus, a subdivision of the inward crossings is created into upper and lower ones as well (those inward crossings found at the ends of the rectangle can be arbitrarily assigned to upper or lower).", "cite_spans": [], "ref_spans": [{"start": 135, "end": 143, "text": "Figure 3", "ref_id": "FIGREF3"}]}, {"section": "Definition 1.", "text": "So in order to make the above idea precise, we need a slight strengthening of Proposition 11 of [8] . This is stated as Lemma 5, and is proved after the current proof.", "cite_spans": [{"start": 96, "end": 99, "text": "[8]", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "Definition 1.", "text": "With it, once the first step (Mondrian diagram for the graph of the outermost state circles) is in place, all further steps in our process are carried out as follows. If a horizontal line segment corresponds to a state circle s that contains other state circles, the outermost of which form the graph G, thicken the line segment into a rectangle R. Recall that the crossings of D along s that are inner to s are classified into upper and lower ones. Augment G with the vertices u and l. If the state circle corresponding to the vertex x of G is connected to s through an upper crossing, connect x to u with an edge, and similarly to l if a lower crossing exists between the circle and s. To the resulting planar graph G \u2032 with its two marked vertices, apply the After an isotopy, M can be copied into R so that u \u2032 and v \u2032 (suitably lengthened) are the horizontal sides of R. The inner and outer crossings along s = \u2202R can be properly arranged by the following observation: Let K be one of the half-infinite vertical strips above or below R. Any isotopy of K to itself that fixes \u2202K pointwise and preserves horizontal and vertical lines takes iterated Mondrian diagrams to iterated Mondrian diagrams.", "cite_spans": [], "ref_spans": []}, {"section": "Definition 1.", "text": "The planar diagram that results from the above inductive procedure can easily be turned into a front diagram by applying the operations shown in Figure 4 : any horizontal line segments that weren't thickened into rectangles are now thickened into Legendrian unknot diagrams; rectangles are also isotoped into such; and finally, the vertical segments are changed into crossings.", "cite_spans": [], "ref_spans": [{"start": 145, "end": 153, "text": "Figure 4", "ref_id": "FIGREF2"}]}, {"section": "Definition 1.", "text": "It's very easy to see that the front we constructed has an ungraded ruling: The unknot diagrams we've just constructed (Figure 4 ) from the state circles play the role of eyes and all crossings are switches. The corresponding discs are either disjoint or contained in one another, thus the normality condition is satisfied. Proof. We will take advantage of some of the flexibilities left in Ng's construction. He first builds a 'step-shaped' Mondrian diagram (see Figure 4 of [8] ) for each so-called enhanced cycle C of G. (An enhanced cycle is a subgraph of G obtained as follows: Separate G at its separating crossings. The (outer) boundary cycle of each resulting component, along with any other edges that connect two of its vertices, forms an enhanced cycle.) Instead of steps, we'll construct podium-shaped diagrams, as shown in Figure 5 . The vertices that correspond to top and bottom (base) can be arbitrarily selected. The vertical pieces correspond to the edges of the boundary cycleC of C. We choose the horizontal levels on the two sides so that they are all different. Now all edges in C\\C have an upper and lower horizontal piece to connect. From each upper piece, we drop vertical line segments to the corresponding lower levels, arranged from left to right as suggested by the embedding of C into the plane. Then we extend each left step to the right and each right step to the left to meet all the lower ends designated to it. The planarity of C guarantees that this results in no 'undesignated' intersections between horizontal and vertical segments, hence we get a Mondrian diagram. It is also strong in the sense of [8] , thus step 4 of Ng's construction does not have to be modified at all. Then in step 3, Ng joins these building blocks in a tree-like fashion ( Figure  5 of [8] ), placing the base of each new step/podium onto the extension of the appropriate horizontal line segment. Let us use the enhanced cycle containing l as the root of the tree and, of course, draw its podium-shaped diagram so that its base l \u2032 contracts to l. As they are attached, draw the consecutive podium-shaped diagrams successively smaller so that at least one end of each horizontal piece is visible from above. (For segments that serve as a base at some point, this is achieved by making them stick out slightly from underneath the podium.) When we reach the enhanced cycle containing u in the construction, we select the corresponding horizontal line segment u \u2032 to be uppermost in its podium-shaped diagram. By the above visibility condition, u \u2032 can be arranged to be the uppermost of all horizontal pieces thus far. In order to keep it that way, we need one last modification to Ng's construction: If at a later time, a podium-shaped diagram is to be attached to u \u2032 , we attach it from underneath, i.e. we construct the branch of the tree starting there upside down. Proof. The front we constructed in Theorem 4 has Thurston-Bennequin number as stated, which in turn is maximal and realizes the Kauffman bound by Rutherford's theorem. By the same, the said coefficients of the Kauffman polynomial represent counts of rulings and hence are not negative. The statement on Khovanov homology is a direct consequence of Proposition 8 of [8] .", "cite_spans": [{"start": 476, "end": 479, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 1638, "end": 1641, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 1799, "end": 1802, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 3247, "end": 3250, "text": "[8]", "ref_id": "BIBREF7"}], "ref_spans": [{"start": 119, "end": 128, "text": "(Figure 4", "ref_id": "FIGREF2"}, {"start": 464, "end": 472, "text": "Figure 4", "ref_id": "FIGREF2"}, {"start": 836, "end": 844, "text": "Figure 5", "ref_id": "FIGREF5"}, {"start": 1786, "end": 1795, "text": "Figure  5", "ref_id": "FIGREF5"}]}, {"section": "Definition 1.", "text": "Thistlethwaite [12] observed that up to 11 crossings, every knot or its mirror is +adequate. The invariant tb does distinguish mirrors, but at least for half of the knots up to 11 crosings, Corollary 6 determines tb. Example 7. The Kinoshita-Terasaka knot (11n 42 ) is a so-called adequate knot, i.e. it has a +adequate diagram which remains +adequate after switching all crossings. (Its trivial Alexander polynomial shows that the knot is not homogeneous [1, section 7.6] , in particular it is neither alternating nor positive (or negative).) Thus, we may use our method to construct a maximum tb diagram for both the knot and its mirror, showing that tb(11n 42 ) = \u22127 and tb(11n ", "cite_spans": [{"start": 15, "end": 19, "text": "[12]", "ref_id": "BIBREF11"}], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Knots and Links", "authors": [{"first": "P", "middle": [], "last": "Cromwell", "suffix": ""}], "year": 2004, "venue": "", "link": "117334211"}, "BIBREF1": {"title": "Legendrian and transversal knots, in Handbook of Knot Theory", "authors": [{"first": "J", "middle": [], "last": "Etnyre", "suffix": ""}], "year": 2005, "venue": "", "link": null}, "BIBREF2": {"title": "Knots and contact geometry I: torus knots and the figure eight knot", "authors": [{"first": "J", "middle": [], "last": "Etnyre", "suffix": ""}, {"first": "K", "middle": [], "last": "Honda", "suffix": ""}], "year": 2001, "venue": "J. Symplectic Geom", "link": null}, "BIBREF3": {"title": "Chekanov-Eliashberg invariants of Legendrian knots: existence of augmentations", "authors": [{"first": "D", "middle": [], "last": "Fuchs", "suffix": ""}], "year": 2003, "venue": "J. Geom. Phys", "link": "121562685"}, "BIBREF4": {"title": "Contact homology and one parameter families of Legendrian knots", "authors": [{"first": "T", "middle": [], "last": "K\u00e1lm\u00e1n", "suffix": ""}], "year": 2005, "venue": "Geom. Topol", "link": "8307055"}, "BIBREF5": {"title": "Some links with nontrivial polynomials and their crossing numbers", "authors": [{"first": "W", "middle": ["B R"], "last": "Lickorish", "suffix": ""}, {"first": "M", "middle": ["B"], "last": "Thistlethwaite", "suffix": ""}], "year": 1988, "venue": "Comment. Math. Helv", "link": "122966546"}, "BIBREF6": {"title": "Maximal Thurston-Bennequin number of two-bridge links, Algebr", "authors": [{"first": "L", "middle": [], "last": "Ng", "suffix": ""}], "year": 2001, "venue": "Geom. Topol", "link": null}, "BIBREF7": {"title": "A Legendrian Thurston-Bennequin bound from Khovanov homology", "authors": [{"first": "L", "middle": [], "last": "Ng", "suffix": ""}], "year": 2005, "venue": "Algebr. Geom. Topol", "link": null}, "BIBREF8": {"title": "A congruence between link polynomials", "authors": [{"first": "L", "middle": [], "last": "Rudolph", "suffix": ""}], "year": 1990, "venue": "Math. Proc. Camb. Phil. Soc", "link": "122807457"}, "BIBREF9": {"title": "The Bennequin number, Kauffman polynomial, and ruling invariants of a Legendrian link: the Fuchs conjecture and beyond", "authors": [{"first": "D", "middle": [], "last": "Rutherford", "suffix": ""}], "year": 2006, "venue": "Int. Math. Res. Not", "link": "18340719"}, "BIBREF10": {"title": "Maximal Bennequin numbers and Kauffman polynomials of positive links", "authors": [{"first": "T", "middle": [], "last": "Tanaka", "suffix": ""}], "year": 1999, "venue": "Proc. Amer. Math. Soc", "link": "120818693"}, "BIBREF11": {"title": "On the Kauffman polynomial of an adequate link", "authors": [{"first": "M", "middle": ["B"], "last": "Thistlethwaite", "suffix": ""}], "year": 1988, "venue": "Invent. Math", "link": "119753881"}, "BIBREF12": {"title": "Polynomial invariants of positive links", "authors": [{"first": "Y", "middle": [], "last": "Yokota", "suffix": ""}], "year": 1992, "venue": "Topology", "link": "122445190"}}, "ref_entries": {"FIGREF0": {"text": "Figure 1: Allowed and disallowed configurations for switches of rulings", "type": "figure"}, "FIGREF1": {"text": "Figure 2: Front diagrams for the inadequate knot 11n 95 and its mirror.", "type": "figure"}, "FIGREF2": {"text": "Let A be a +adequate link. Then A possesses a Legendrian representative with an ungraded ruling.", "type": "figure"}, "FIGREF3": {"text": "Figure 3: Outer (o) and inner (i) crossings along a state circle, and a hypothetical classification of the inner ones into three upper ones and one lower.", "type": "figure"}, "FIGREF4": {"text": "Figure 4: Turning an iterated Mondrian diagram into a front diagram", "type": "figure"}, "FIGREF5": {"text": "Let G be a planar graph (possibly with multiple edges but without loop edges) with two marked vertices, u and l, along the unbounded region of the complement of G. Then G is the contraction of a Mondrian diagram so that the horizontal line segment u \u2032 contracting to u is the topmost one and the segment l \u2032 contracting to l is bottommost.", "type": "figure"}, "FIGREF6": {"text": "Figure 5: Podiumshaped Mondrian diagrams for a cycle and for an enhanced cycle.", "type": "figure"}, "FIGREF7": {"text": "In any +adequate diagram D of the knot A, the writhe mi- nus the number of components of s + (D) equals the minimum v-degree of the Kauffman polynomial minus one, which in turn equals tb(A). In the Dubrovnik version of the Kauffman polynomial, all coefficients of maximum a-degree terms are non-negative. Furthermore, these quantities agree with min{ k i\u2212j=k HKh i,j (K) = 0 }, where HKh i,j (K) is the Khovanov ho- mology group in bigrading (i, j).", "type": "figure"}, "FIGREF8": {"text": "Figure 6: Constructing a front diagram of the Kinoshita-Terasaka knot with maximum tb = \u22127.", "type": "figure"}, "FIGREF9": {"text": "Figure 7: Constructing a front diagram of the mirrored Kinoshita-Terasaka knot with maximum tb = \u22124.", "type": "figure"}}}
{"paper_id": "18981358", "_pdf_hash": "95af4fe4e7795a89d3528600e77e1997169109bf", "abstract": [{"section": "Abstract", "text": "Background: Studies in animals and humans indicate that the interruption of body-brain connections following spinal cord injury (SCI) leads to plastic cerebral reorganization.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Objective: To explore whether inducing the Rubber Hand Illusion (RHI) via synchronous multisensory visuo-tactile bodily stimulation may reveal any perceptual correlates of plastic remapping in SCI.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "In 16 paraplegic, 16 tetraplegic and 16 healthy participants we explored whether RHI may be induced by tactile stimuli involving not only the left hand but also the left hemi-face. Touching the participants actual hand or face was either synchronous or asynchronous with tactile stimuli seen on a rubber hand. We assessed two components of the illusion, namely perceived changes in the real hand in space (indexed by proprioceptive drift) and ownership of the rubber hand (indexed by subjective responses to an ad-hoc questionnaire).", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Results: Proprioceptive drift and ownership were found in the healthy group only in the condition where the left real and fake hand were touched simultaneously. In contrast, no drift was found in the SCI patients who, however, showed ownership after both synchronous and asynchronous hand stroking. Importantly, only tetraplegics showed the effect also after synchronous face stroking.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Conclusions: RHI may reveal plastic phenomena in SCI. In hand representation-deprived tetraplegics, stimuli on the face (represented contiguously in the somatic and motor systems), drive the sense of hand ownership. This hand-face remapping phenomenon may be useful for restoring a sense of self in massively deprived individuals.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "INTRODUCTION", "text": "Spinal cord injuries (SCI) cause an irreversible disconnection between the body and the brain. This disconnection implies a deprivation of somatosensory input to and motor output from the brain. The extent of this deprivation depends on the level and completeness of the lesion. While cervical SCI leads to tetraplegia, a clinical condition with impaired sensory-motor functions in both upper and lower limbs, SCI below the seventh cervical spinal cord segment leads to paraplegia, where deficits affect lower but not upper limbs.", "cite_spans": [], "ref_spans": []}, {"section": "INTRODUCTION", "text": "Studies indicate that sensorimotor deprivation in SCI may induce alterations in the bodily-self as indexed by the Rubber Hand Illusion (RHI), where the induction of a visuo-tactile conflict allows rapid changes in body-ownership (Botvinick and Cohen, 1998) . In initial studies of the RHI healthy individuals were asked to look at a rubber hand that was stroked by the examiner, synchronously or asynchronously with their hidden from view real hand. It appeared that only during synchronous stimulation was the rubber hand perceived as part of the participants' own body (index of ownership of an artificial hand) and the position of the real hand was perceived as having shifted toward the rubber hand (\"proprioceptive drift,\" index of illusory perception of body in space) (Botvinick and Cohen, 1998; Ehrsson et al., 2005; Tsakiris and Haggard, 2005; Longo et al., 2008; Mohan et al., 2012; Schaefer et al., 2013) .", "cite_spans": [{"start": 229, "end": 256, "text": "(Botvinick and Cohen, 1998)", "ref_id": "BIBREF11"}, {"start": 775, "end": 802, "text": "(Botvinick and Cohen, 1998;", "ref_id": "BIBREF11"}, {"start": 803, "end": 824, "text": "Ehrsson et al., 2005;", "ref_id": "BIBREF17"}, {"start": 825, "end": 852, "text": "Tsakiris and Haggard, 2005;", "ref_id": "BIBREF60"}, {"start": 853, "end": 872, "text": "Longo et al., 2008;", "ref_id": "BIBREF40"}, {"start": 873, "end": 892, "text": "Mohan et al., 2012;", "ref_id": "BIBREF43"}, {"start": 893, "end": 915, "text": "Schaefer et al., 2013)", "ref_id": "BIBREF57"}], "ref_spans": []}, {"section": "INTRODUCTION", "text": "The first time that the RHI paradigm was applied to SCI participants demonstrated that SCI did not alter subjective indices of the illusory hand ownership (Lenggenhager et al., 2012) . However, proprioceptive drift was found to be deviated only in subjects with defective hand perception, suggesting that plasticity-related cortical changes might influence the dynamics of the bodily-self (Lenggenhager et al., 2012) . The RHI has subsequently been used to induce a restoration of impaired hand somatosensivity in two SCI patients (Lenggenhager et al., 2013) .", "cite_spans": [{"start": 155, "end": 182, "text": "(Lenggenhager et al., 2012)", "ref_id": "BIBREF38"}, {"start": 389, "end": 416, "text": "(Lenggenhager et al., 2012)", "ref_id": "BIBREF38"}, {"start": 531, "end": 558, "text": "(Lenggenhager et al., 2013)", "ref_id": "BIBREF39"}], "ref_spans": []}, {"section": "INTRODUCTION", "text": "In many previous papers the \"proprioceptive drift\" is defined as an objective measure of the RHI. We contend it has to be considered as a subjective response. We suggest that this measure is at least as subjective as the point of subjective equivalence (PSE) (Gescheider, 1997) , i.e., the index widely used in psychophysics research which is computed starting from the participants' answers about the perception or the lack of perception of a stimulus, or the perceived difference between two sensory stimuli. For these reasons in this study we defined, the \"proprioceptive drift\" as a subjective index of perception of the body in space. We propose that psychogalvanic response (Armel and Ramachandran, 2003; Ferri et al., 2013) , the change in temperature (Moseley et al., 2008) , etc. are considered objective indexes in rubber-hand or full-body illusion studies.", "cite_spans": [{"start": 259, "end": 277, "text": "(Gescheider, 1997)", "ref_id": "BIBREF27"}, {"start": 680, "end": 710, "text": "(Armel and Ramachandran, 2003;", "ref_id": "BIBREF6"}, {"start": 711, "end": 730, "text": "Ferri et al., 2013)", "ref_id": "BIBREF19"}, {"start": 759, "end": 781, "text": "(Moseley et al., 2008)", "ref_id": "BIBREF45"}], "ref_spans": []}, {"section": "INTRODUCTION", "text": "Brain reorganization induced by a reduction in somatosensory and motor inputs has been demonstrated in studies on animals and humans (Nahum et al., 2013) . Crucial for the present research, this type of reorganization may follow topographic rules. For example, a single cell recording study on monkeys deprived of somatosensory input due to an extended dorsal rhizotomy, demonstrated that the cortical territories formerly mapping the de-afferented skin regions (e.g., the hand) were driven by inputs coming from brain regions with adjacent, intact representation (e.g., the face) (Pons et al., 1991) . Evidence for the perceptual correlates of this topographic remapping process has been provided by studies on individuals with upper-limb (Ramachandran et al., 1992; Aglioti et al., 1997) , lower-limb (Aglioti et al., 1994a) or breast (Aglioti et al., 1994b) amputation and phantom perception of the lost body part. In particular, tactile stimuli on the face ipsilaterally to hand or finger amputations induced in a considerable number of patients the sensation of being touched not only on the face but also on the phantom hand (Ramachandran et al., 1992) or finger (Aglioti et al., 1997) . Consistent and precise, but topographically disorganized, double sensations were evoked by tactile stimuli applied to the contralesional hypoaesthesic hand in a patient with a selective lesion involving hand representation in the primary somatosensory cortex (Aglioti et al., 1999) .", "cite_spans": [{"start": 133, "end": 153, "text": "(Nahum et al., 2013)", "ref_id": "BIBREF46"}, {"start": 581, "end": 600, "text": "(Pons et al., 1991)", "ref_id": "BIBREF51"}, {"start": 740, "end": 767, "text": "(Ramachandran et al., 1992;", "ref_id": "BIBREF52"}, {"start": 768, "end": 789, "text": "Aglioti et al., 1997)", "ref_id": "BIBREF3"}, {"start": 803, "end": 826, "text": "(Aglioti et al., 1994a)", "ref_id": "BIBREF1"}, {"start": 837, "end": 860, "text": "(Aglioti et al., 1994b)", "ref_id": "BIBREF2"}, {"start": 1131, "end": 1158, "text": "(Ramachandran et al., 1992)", "ref_id": "BIBREF52"}, {"start": 1169, "end": 1191, "text": "(Aglioti et al., 1997)", "ref_id": "BIBREF3"}, {"start": 1453, "end": 1475, "text": "(Aglioti et al., 1999)", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "INTRODUCTION", "text": "Based on the notion that the somatosensory and motor brain representation of the face and the hand are contiguous, double sensations were interpreted as an index of remapping of the face on the de-afferented hand representation. The inherent link between hand and face representations is also supported by studies on healthy subjects in whom complete temporary anaesthesia of the thumb rapidly induced the sensation that the size of the lips increased by up to 50% (Gandevia and Phegan, 1999) . Neurophysiological evidence for face-hand remapping has been provided by an EEG study documenting that tactile stimulation of the hand activates the cortical representation of the face in people who had undergone cosmetic injections of botulinum toxin to treat wrinkles (Haenzi et al., 2014) . As previously mentioned, deprivation related neuroplasticity may also be at play after spinal cord lesions. What remains unknown is whether the perceptual correlates of the plasticity found in SCI follows erratic rules (Moore et al., 2000) or may also occur according to somewhat topographic organization.", "cite_spans": [{"start": 465, "end": 492, "text": "(Gandevia and Phegan, 1999)", "ref_id": "BIBREF25"}, {"start": 765, "end": 786, "text": "(Haenzi et al., 2014)", "ref_id": "BIBREF30"}, {"start": 1008, "end": 1028, "text": "(Moore et al., 2000)", "ref_id": "BIBREF44"}], "ref_spans": []}, {"section": "INTRODUCTION", "text": "We explored this issue by applying a novel version of the classic RHI paradigm to healthy, paraplegic, and tetraplegic people. Based on the study on monkeys with cervical SCI who showed an expansion of the face representation in the primary and non-primary somatosensory cortex toward nearby areas (Tandon et al., 2009) , we hypothesized that tetraplegics, but not paraplegics and healthy people, would experience the RHI after stimulation of their cheek synchronously with rubber hand stimulation. We modified two main aspects of the classic RHI paradigm (Botvinick and Cohen, 1998) . The first concerns the stimulation which was applied not only to the participants real hand but also to their cheek. The second is that rubber hand and real hand were vertically aligned with the former in a higher position with respect to the latter. We measured any possible vertical drift in the perceived position of the participants real hand (Bekrater-Bodmann et al., 2012) . We expected only the tetraplegics to show indices of RHI in the Face-Synchronous condition, due to possible mechanisms of plasticity in the somatosensory networks. Instead, in the paraplegics and healthy individuals, we expected to replicate RHI effects exclusively following Synchronous Hand-stimulation.", "cite_spans": [{"start": 298, "end": 319, "text": "(Tandon et al., 2009)", "ref_id": "BIBREF58"}, {"start": 556, "end": 583, "text": "(Botvinick and Cohen, 1998)", "ref_id": "BIBREF11"}, {"start": 933, "end": 964, "text": "(Bekrater-Bodmann et al., 2012)", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "MATERIALS AND METHODS", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "PARTICIPANTS", "text": "Sixteen tetraplegics, sixteen paraplegics and sixteen neurologically healthy participants participated in the study. All participants were right-handed and had normal or corrected-tonormality vision. The three groups were gender-, age-and education-matched (log-linear analysis on gender data: \u03c7 2 (2) = 2.1646, p = 0.34, One-Way ANOVA on age data: F (2,45) = 0.90, p = 0.41, One-Way ANOVA on education, converted in a numerical value from 1 = junior school to 4 = bachelor degree: F (2,45) = 0.84, p = 0.44).", "cite_spans": [], "ref_spans": []}, {"section": "PARTICIPANTS", "text": "For all SCI participants, the Neurological Level of Injury (NLI) and the American Spinal Injury Association Impairment Scale (AIS, index of completeness of lesion) were collected, according to the International Standards for Neurological Classification of Spinal Cord Injury (Kirshblum et al., 2011) .", "cite_spans": [{"start": 275, "end": 299, "text": "(Kirshblum et al., 2011)", "ref_id": "BIBREF35"}], "ref_spans": []}, {"section": "PARTICIPANTS", "text": "The NLI is defined as the more rostral spinal cord segment where both the sensory and motor functions are spared. This does not exclude the possibility that some motor or sensory functions are spared below this level. This indeed is what may happen in cases of incomplete lesions (Kirshblum et al., 2011) . The AIS gives information about the completeness of lesions. The AIS score (ranging from A to E in a decreasing order of impairment) is calculated on the basis of motor and sensory functions preserved at the level of sacral segments S4-S5 (that are the most caudals) (Kirshblum et al., 2011) . Only SCI participants with scores of \"A\" (absence of sensory and motor functions at S4-S5) or \"B\" (spared sensory but not motor functions at S4-S5) in the AIS were recruited in this study and assigned to the Tetraplegics and Paraplegics groups according to their NLI (upper or lower C7 level, respectively). In the Tetraplegics group, left-hand tactile perception was tested. Taking into consideration both the definitions of NLI and AIS, it is clear that, also even if the NLI is very high and the AIS is \"A,\" there is the possibility of spared sensory sensations in the left hand and, on the other side, that a low NLI and an AIS of \"B\" does not guarantee spared tactile sensations on the left hand. Furthermore, the Spinal Cord Independence Measure-III (SCIM-3) was administered in order to quantify the degree of functional autonomy (Invernizzi et al., 2010) . Demographical and clinical data are reported in Table 1 . The study was approved by the Ethics committee of the Province of Verona (Prot. N. 40378) and was conducted in accordance with the ethical standards of the 1964 Declaration of Helsinki. All participants gave their informed consent. ", "cite_spans": [{"start": 280, "end": 304, "text": "(Kirshblum et al., 2011)", "ref_id": "BIBREF35"}, {"start": 574, "end": 598, "text": "(Kirshblum et al., 2011)", "ref_id": "BIBREF35"}, {"start": 1438, "end": 1463, "text": "(Invernizzi et al., 2010)", "ref_id": "BIBREF34"}], "ref_spans": [{"start": 1514, "end": 1521, "text": "Table 1", "ref_id": "TABREF0"}]}, {"section": "MATERIALS AND PROCEDURE", "text": "As shown in Figure 1A , a wooden box was built to allow the positioning of the left Real Hand and the Rubber Hand, one positioned exactly on top of the other so that they corresponded. The wooden box (H:50 cm, W:30 cm, D:40 cm) was divided into two compartments: the real hand rested upon the dividing plank inside the box, while the rubber hand was positioned on the top of the box (20 cm above the real hand). Both the participants right and left arms were hidden from view by a black cloth. The rubber hand was similar to a normal left hand. A ruler with a sliding indicator was employed so that participants could indicate the perceived position of their real hand during experimental manipulations (see below). The ruler was placed on the left side of the box with the numbers (in mm) covered so that the participants could not see them (range of shifting = 44 cm, 22 cm above and below the real hand).", "cite_spans": [], "ref_spans": [{"start": 12, "end": 21, "text": "Figure 1A", "ref_id": "FIGREF0"}]}, {"section": "Experimental Procedure", "text": "Preparation of the participants: Participants sat in their wheelchair (Tetraplegics and Paraplegics groups) or on a normal chair (Healthy group). The box was placed laterally to the left of each participant. The real hand was placed inside the box in a comfortable position and the rubber hand was placed more or less at the same height as the participants elbow. The participants wore special blinkers to prevent them from seeing the Q-tip approaching their cheek in the Face-conditions. The special blinkers consisted of a simple eyeglass frame with a little (5 \u00d7 4 cm) cloth attached to the left eyeglass temple. Furthermore, the box was covered with a black cloth for the whole duration of the experiment (pauses included), to avoid any additional visuo-spatial information in the experimental conditions (see below). The participants were asked to keep their hands still. Experimental Conditions: The experiment was divided into four conditions ( Figure 1C ) involving a combination of Stimulation Type (Synchronous, Asynchronous) and Body Part Stimulated (Hand, Face). The four conditions were run in separate blocks: (i) Hand-Synchronous; (ii) Hand-Asynchronous; (iii) Face-Synchronous; (iv) Face-Asynchronous. A pause in which participants could move their real hand was allowed after two blocks. The participants left cheek and the index finger of the rubber hand were stimulated by a Q-tip in the Face-conditions and the dorsum of the participants real left index finger and the same location on the rubber hand were stimulated in the Hand-conditions. All conditions were counterbalanced across participants. Each stimulation block consisted of two phases ( Figure 1D ).", "cite_spans": [], "ref_spans": [{"start": 952, "end": 961, "text": "Figure 1C", "ref_id": "FIGREF0"}, {"start": 1668, "end": 1677, "text": "Figure 1D", "ref_id": "FIGREF0"}]}, {"section": "The Observation Phase.", "text": "The participants were asked to observe the rubber hand positioned on the wooden box for 2 min. The rubber hand was then covered and participants had to estimate the vertical position of the real hand (Observation Baseline), using a verbal command to stop the mobile indicator of the ruler (moved by the experimenter) at the perceived position of their hand. When the participants stopped the mobile indicator, the experimenter recorded the position on the ruler (mm). The mobile indicator was then positioned at one of the extremes of its range as the starting position for the subsequent hand position estimation trial. The mobile indicator was thus moved in either top-down or bottom-up alternate directions. This procedure was repeated at intervals of 30 s for a total of 4 measurements (total 90 s.). The direction (top-down or bottom-up) of the first estimate was counterbalanced across participants. 2. The Stimulation Phase.", "cite_spans": [], "ref_spans": []}, {"section": "The Observation Phase.", "text": "While the participants looked at the rubber hand, a stimulation was synchronously or asynchronously administered to both the rubber hand and either the real hand or cheek of the participant. The tactile strokes were manually administered by the experimenter for 2 min by means of Q-tips. In the Hand-conditions, the rubber hand and the real hand were stimulated on dorsum of the index finger, independently of the tactile sensitivity of the real hand. In the Face-conditions, the strokes were administered to the index finger of the rubber hand and along an ideal horizontal line on the participants cheek, starting from the zygomaticus muscle (below the left eye) and moving toward the nose (see Figure 1B) .", "cite_spans": [], "ref_spans": [{"start": 697, "end": 707, "text": "Figure 1B)", "ref_id": "FIGREF0"}]}, {"section": "The Observation Phase.", "text": "While in the Synchronous conditions the two stimulations were administered simultaneously, a temporal discrepancy was introduced in the Asynchronous conditions between the touch to the participants body part and the observed touch on the rubber hand. After stimulation, the rubber hand was covered and the participants were requested to estimate their real hand position (Stim. Estimation, Figure 1D ). Subsequently, the participants answered a 6-item questionnaire ( Table 2 ) derived from one created by Botvinick and Cohen (1998) . They indicated their agreement with each item on a 10-point scale ranging from 0 (\"I totally disagree\") to 10 (\"I totally agree\"). The first three statements were designed to capture the phenomenology of the RHI (Illusion Related Questions, IRQ), whereas the other questions were designed to be Illusion Control Questions (ICQ) (see Table 2 ). The whole experiment lasted about 40 min.", "cite_spans": [{"start": 506, "end": 532, "text": "Botvinick and Cohen (1998)", "ref_id": "BIBREF11"}], "ref_spans": [{"start": 390, "end": 399, "text": "Figure 1D", "ref_id": "FIGREF0"}, {"start": 468, "end": 475, "text": "Table 2", "ref_id": "TABREF1"}, {"start": 868, "end": 875, "text": "Table 2", "ref_id": "TABREF1"}]}, {"section": "Personality and absorption scales", "text": "Studies on healthy individuals suggest that the tendency to experience illusory body phenomena may be related to personality (MacLachlan et al., 2003) . With the aim of exploring possible personality effects on the RHI, all participants were submitted to the Big-Five Inventory (BFI-10, Rammstedt and John, 2007) and the Tellegen Absorption Scale (TAS, Tellegen and Atkinson, 1974) . The BFI-10 is a self-report interview designed to measure five dimensions of personality. The TAS (Tellegen and Atkinson, 1974) assesses the tendency to absorb others experiences, selfaltering experiences and a broader trait of openness to experience.", "cite_spans": [{"start": 125, "end": 150, "text": "(MacLachlan et al., 2003)", "ref_id": "BIBREF41"}, {"start": 287, "end": 312, "text": "Rammstedt and John, 2007)", "ref_id": "BIBREF53"}, {"start": 353, "end": 381, "text": "Tellegen and Atkinson, 1974)", "ref_id": "BIBREF59"}, {"start": 482, "end": 511, "text": "(Tellegen and Atkinson, 1974)", "ref_id": "BIBREF59"}], "ref_spans": []}, {"section": "DATA HANDLING", "text": "All analyses were performed using R (R Development Core Team, 2013), ggplot2 (Wickham, 2009 ) for graphical representations, the package lme4 ver. 1.1-5 for Mixed Linear Effects analyses (Bates et al., 2013) , and \u03b1 was set to 0.05. In multiple testing, significances were adjusted via false-discovery-rate procedure (FDR) (Benjamini and Hochberg, 1995) . For each experimental condition, the drift was computed by subtracting the mean of the estimations in each Observation Baseline from the Stimulation condition. In order to avoid inflation of Type I error, caused by the small sample, we used two alternative approaches that converged on similar results. First of all we dichotomised data and analysed them via log-linear models using as criterion the 95% Confidence-Interval upperbound of all participants (drifts lower than the criterion = 0, otherwise = 1). As post-hoc analyses we used \u03c7 2 tests FDR corrected. Furthermore, a Mixed Linear Effect model was applied to drift data, without any dichotomization. The Mixed Linear Effect Model (for detailed explanations see statistics handbooks like Pinheiro and Bates, 2000; Bates, 2010) , are used in previous studies (e.g., Fugard et al., 2009; Kliegl et al., 2009) . For the overall analysis of the model, parametric bootstrap confidence intervals for the tests (Wald tests) and bootstrapped p-values were computed (see Efron and Tibshirani, 1994) . FDR corrected t-tests were used as post-hoc tests.", "cite_spans": [{"start": 77, "end": 91, "text": "(Wickham, 2009", "ref_id": "BIBREF61"}, {"start": 187, "end": 207, "text": "(Bates et al., 2013)", "ref_id": "BIBREF7"}, {"start": 323, "end": 353, "text": "(Benjamini and Hochberg, 1995)", "ref_id": "BIBREF10"}, {"start": 1103, "end": 1128, "text": "Pinheiro and Bates, 2000;", "ref_id": "BIBREF50"}, {"start": 1129, "end": 1141, "text": "Bates, 2010)", "ref_id": "BIBREF8"}, {"start": 1180, "end": 1200, "text": "Fugard et al., 2009;", "ref_id": "BIBREF24"}, {"start": 1201, "end": 1221, "text": "Kliegl et al., 2009)", "ref_id": "BIBREF36"}, {"start": 1377, "end": 1404, "text": "Efron and Tibshirani, 1994)", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "DATA HANDLING", "text": "Likert scale values in the RHI questionnaire values are organised as ordinal data. Therefore the best suited analyses are the non-parametric ones. The ICQ are questions not related to the illusion, that could be considered as a measure of the participant response bias, namely the tendency of participants to give the answers that they think could be in accord with the experimenter expectancy. This consideration is also supported by the empirical observation that in the majority of RHI experiments, if the illusion is present, the IRQ have higher values while the ICQ have lower values (Botvinick and Cohen, 1998; Aimola Davies et al., 2010; Bekrater-Bodmann et al., 2012) . Therefore, to understand if an illusory effect in a condition was present, testing IRQ vs. ICQ could be an effective test. However, testing IRQ vs. ICQ or Thus, we assessed two dependent variables for each condition, namely: (i) the proprioceptive drift, which is considered to be an index of the perceived position of the limb-in-space and (ii) the subjective report in the questionnaire, considered as an index of ownership of the rubber hand.", "cite_spans": [{"start": 589, "end": 616, "text": "(Botvinick and Cohen, 1998;", "ref_id": "BIBREF11"}, {"start": 617, "end": 644, "text": "Aimola Davies et al., 2010;", "ref_id": "BIBREF5"}, {"start": 645, "end": 675, "text": "Bekrater-Bodmann et al., 2012)", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "DATA HANDLING", "text": "Personality traits (BFI-10), absorption (TAS) and functional independence (SCIM-3) were analysed to test the differences between groups and any effects on drift and IRQ-ICQ.", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "PROPRIOCEPTIVE DRIFT OF THE REAL HAND TOWARD THE RUBBER HAND AS A SUBJECTIVE INDEX OF PERCEPTION OF THE BODY IN SPACE", "text": "A log-linear model was applied to the number of drifts, with Group (Tetraplegics, Paraplegics, Healthy), Stimulation-Type (Synchronous and Asynchronous) and Body-Part (Hand, Face) as factors. The three-way interaction was statistically significant (\u03c7 2 (2) = 7.5073, p = 0.02). Pairwise-\u03c7 2 -tests (FDR corrected) between groups only showed significant differences in the Hand-Synchronous condition, with more drifts in the Healthy group than in the Paraplegics group (drift number: Healthy = 9, Paraplegics = 1; \u03c7 2", "cite_spans": [], "ref_spans": []}, {"section": "PROPRIOCEPTIVE DRIFT OF THE REAL HAND TOWARD THE RUBBER HAND AS A SUBJECTIVE INDEX OF PERCEPTION OF THE BODY IN SPACE", "text": "(1) = 6.879, p = 0.05, \u03c6 = 14.66) and the Tetraplegics group (drift number: Tetraplegics = 0; \u03c7 2 (1) = 9.581, p = 0.02, \u03c6 = 17.30). In the Tetraplegics group, the comparison between subjects with spared hand tactile-sensitivity and subjects with sensory deficits was not significant in any of the conditions (all p-values > 0.56). In Figure 2 a graphical representation.", "cite_spans": [], "ref_spans": [{"start": 335, "end": 343, "text": "Figure 2", "ref_id": "FIGREF1"}]}, {"section": "PROPRIOCEPTIVE DRIFT OF THE REAL HAND TOWARD THE RUBBER HAND AS A SUBJECTIVE INDEX OF PERCEPTION OF THE BODY IN SPACE", "text": "In the Mixed Linear Effect model we used as fixed factors the Stimulation-Type (Synchronous, Asynchronous), the Body Part (Hand, Face) and the Group (Healthy, Paraplegics, Tetraplegics), and Subject as random factor. The three-way interaction turned out to be statistically significant (Wald \u03c7 2 (2) = 9.43, CI = \u22126.39, 20.33, p < 0.01). Post-hoc t-tests FDR corrected were computed, comparing Synchronous vs. Asynchronous stimulation for each Body Part and Group. Only the comparison in the Healthy group in the Hand condition reached the statistical significance (p = 0.0125).", "cite_spans": [], "ref_spans": []}, {"section": "SCORES IN THE QUESTIONNAIRE AS A SUBJECTIVE INDEX OF OWNERSHIP OF A FAKE HAND", "text": "For each group we performed a One-Way Friedman ANOVA on IRQ-ICQ responses, with the Stimulation-Type and Body-Part factors collapsed into a unique 4-level Condition within-subject factor. A significant effect of Condition (Friedman's \u03c7 2 (3) = 77.45, p < 0.0001) was found. The Friedman's tests were still significant after dividing the analysis according to the groups (Healthy group: \u03c7 2 (3) = 28.63, p < 0.0001; Paraplegics group: \u03c7 2 (3) = 39.14, p < 0.0001; Tetraplegics group: \u03c7 2 (3) = 17.46, p < 0.0001). A Kruskal-Wallis test was applied to the IRQ-ICQ scores for the Synchronous condition minus the IRQ-ICQ scores for the Asynchronous condition, with the Group and Body Part factors collapsed in a unique 6-levels factor. The Kruskal-Wallis test showed a statistically significant effect (Kruskal-Wallis \u03c7 2 (5) = 27.2807; p = 0.0001). This result indicates that the three groups have different values in the RHI questionnaire in the different conditions.", "cite_spans": [], "ref_spans": []}, {"section": "SCORES IN THE QUESTIONNAIRE AS A SUBJECTIVE INDEX OF OWNERSHIP OF A FAKE HAND", "text": "In the Tetraplegics group, Wilcoxon tests (FDR corrected) showed significantly greater values in IRQ than ICQ responses in the Hand-Synchronous (W = 550.5, p = 0.0001, r = 0.75), Hand-Asynchronous (W = 292.5, p = 0.026, r = 0.41) and Face-Synchronous conditions (W = 258.5, p = 0.024, r = 0.47). In the Paraplegics group, significant values were found in the Hand-Synchronous (W = 780, p < 0.0001, r = 1.03) and HandAsynchronous conditions (W = 425, p = 0.0002, r = 0.66). Finally, in the Healthy group the only significant effect was in the Hand-Synchronous condition (W = 903, p < 0.0001, r = 1.05).", "cite_spans": [], "ref_spans": []}, {"section": "SCORES IN THE QUESTIONNAIRE AS A SUBJECTIVE INDEX OF OWNERSHIP OF A FAKE HAND", "text": "In the Tetraplegics group, no difference between participants with impaired or spared hand tactile sensitivity was found (all pvalues > 0.24). For a graphical representation, see Figure 3. correlations were found between drifts or questionnaire responses and the TAS, the BFI-10, the SCIM-3 and the NLI.", "cite_spans": [], "ref_spans": [{"start": 179, "end": 188, "text": "Figure 3.", "ref_id": "FIGREF2"}]}, {"section": "PERSONALITY, ABSORPTION AND CLINICAL VARIABLES", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "TAS and BFI-10 values (see", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "This study explored whether RHI (which involves a process of integrating visual and tactile input) may constitute a reliable proxy for exploring and understanding the plasticity of bodily representations in people with SCI who suffer from massive disconnection of the body from the brain. There were three new, potentially important findings. The first is that the level of the lesion seems to influence the probability that the RHI will occur. More specifically, the more massively disconnected Tetraplegics group showed indices of ownership of the fake hand, as inferred from the questionnaire, both in the Hand (Synchronous and Asynchronous) and in the Face-Synchronous conditions. The less massively disconnected Paraplegics group showed subjective indices of RHI only in the two Hand conditions. Finally the Healthy group showed the illusion exclusively in the Hand-Synchronous condition. This picture indicates that the ownership component of RHI is related to different degrees of disconnection-related, topographic plasticity. The second finding is that the index of perception of body in space, as inferred from the drift, was found only in the Healthy group and only in the Hand-Synchronous condition. This suggests that this component of RHI is profoundly altered by somatosensory and motor bodybrain disconnection. Finally, personality traits and the degree of functional autonomy in SCI do not modulate RHI.", "cite_spans": [], "ref_spans": []}, {"section": "PLASTIC INFLUENCES OF SOMATOSENSORY DE-AFFERENTATION/ MOTOR DE-AFFERENTATION ON RHI", "text": "Studies on healthy people demonstrate that if they see a tactile stimulus administered to a fake hand and feel a simultaneous tactile stimulus on their own real hand (hidden from view), an illusion of incorporation of the fake hand is induced and/or the feeling that the felt tactile sensation is projected onto the rubber hand (Pavani et al., 2000; Aimola Davies et al., 2010; Haans et al., 2012) . Moreover, in its canonical description, the manifestation of RHI requires not only synchronicity of stimulation but the rubber hand must also be congruent with the real one in terms of position and identity (Tsakiris and Haggard, 2005; Zopf et al., 2010) . Studies also indicate that the RHI may be stronger in the vertical version (i.e., with the rubber hand positioned above the real hand) as compared to the original horizontal version (BekraterBodmann et al., 2012) . By adopting the vertical version of the RHI paradigm, we confirmed that in healthy subjects the phenomenal component of RHI is triggered by synchronous hand stimulation. Significantly, we demonstrated that for participants with SCI this component of RHI is greater in people with a higher level of the lesion who suffer from more massive deprivation. One likely explanation for these results has to do with evidence of functional and structural reorganization after de-afferentation of regions involved in somatosensory and motor processing (\u00c7ermik et al., 2006; Castro et al., 2007; Wrigley et al., 2009; Aguilar et al., 2010; Freund et al., 2011b; Henderson et al., 2011; Freund et al., 2013; Humanes-Valera et al., 2013; Sabre et al., 2013) . Our result is in keeping with the direct demonstration of possible acrossbody parts remapping in people afflicted by SCI. For example, in tetraplegics who move a body part with intact representation (e.g., the tongue), the focus of neural activity in the primary motor cortex shifts toward the de-afferented upper limb representation with a strong correlation between the degree of SCI and the shift (Mikulis et al., 2002) . In a similar vein, shifts of the cortical sensorimotor representations of intact body parts toward disconnected ones have been reported after SCI (Kokotilo et al., 2009 ). The Face-Hand illusion effect found in tetraplegics (but not in paraplegics and healthy people) may thus be interpreted as a perceptual index of topographical cortical and subcortical remapping (Freund et al., 2013) .This is in keeping with what was reported in an amputee patient who underwent hands transplant, and may be the effect of co-existing hand-face representations (Farn\u00e8 et al., 2002) . The increased sense of ownership of the fake hand as indicated by the questionnaire expands our previous study reporting a comparable effect in SCI and healthy subjects (Lenggenhager et al., 2012) . Moreover, our study contributes to previous studies showing feeling of ownership may occur not only after synchronous stroking but also after asynchronous stroking (Rohde et al., 2011) . Indeed in our study the subjective sense of ownership of the fake hand was induced in SCI groups even in the asynchronous hand stimulation condition. The fact that somatosensory deficits of the hand being stimulated did not correlate with the participants reports in the questionnaire suggests that the integrity of tactuo-proprioceptive information (likely driving bottom-up modulations) does not influence the questionnaire component of the RHI. Thus, we suggest that top-down modulations, exerted as a result of observing the fake hand, mediate the embodiment of the rubber hand and the projection of sensations onto it. This may be in keeping with studies using the mirror box illusion in which amputee patients experience ownership of a rubber hand seen in a mirror in the absence of tactile stimuli on their intact hand (Giummarra et al., 2010) . In a similar vein, studies on brain damaged patients indicate that the mere sight of a rubber hand brings about a sense of incorporation of an alien hand (Fotopoulou et al., 2008; Garbarini et al., 2013) .", "cite_spans": [{"start": 328, "end": 349, "text": "(Pavani et al., 2000;", "ref_id": "BIBREF48"}, {"start": 350, "end": 377, "text": "Aimola Davies et al., 2010;", "ref_id": "BIBREF5"}, {"start": 378, "end": 397, "text": "Haans et al., 2012)", "ref_id": "BIBREF29"}, {"start": 607, "end": 635, "text": "(Tsakiris and Haggard, 2005;", "ref_id": "BIBREF60"}, {"start": 636, "end": 654, "text": "Zopf et al., 2010)", "ref_id": "BIBREF64"}, {"start": 1413, "end": 1434, "text": "(\u00c7ermik et al., 2006;", "ref_id": "BIBREF14"}, {"start": 1435, "end": 1455, "text": "Castro et al., 2007;", "ref_id": "BIBREF13"}, {"start": 1456, "end": 1477, "text": "Wrigley et al., 2009;", "ref_id": "BIBREF63"}, {"start": 1478, "end": 1499, "text": "Aguilar et al., 2010;", "ref_id": "BIBREF4"}, {"start": 1500, "end": 1521, "text": "Freund et al., 2011b;", "ref_id": "BIBREF23"}, {"start": 1522, "end": 1545, "text": "Henderson et al., 2011;", "ref_id": "BIBREF32"}, {"start": 1546, "end": 1566, "text": "Freund et al., 2013;", "ref_id": "BIBREF22"}, {"start": 1567, "end": 1595, "text": "Humanes-Valera et al., 2013;", "ref_id": "BIBREF33"}, {"start": 1596, "end": 1615, "text": "Sabre et al., 2013)", "ref_id": "BIBREF56"}, {"start": 2018, "end": 2040, "text": "(Mikulis et al., 2002)", "ref_id": "BIBREF42"}, {"start": 2189, "end": 2211, "text": "(Kokotilo et al., 2009", "ref_id": "BIBREF37"}, {"start": 2409, "end": 2430, "text": "(Freund et al., 2013)", "ref_id": "BIBREF22"}, {"start": 2591, "end": 2611, "text": "(Farn\u00e8 et al., 2002)", "ref_id": "BIBREF18"}, {"start": 2783, "end": 2810, "text": "(Lenggenhager et al., 2012)", "ref_id": "BIBREF38"}, {"start": 2977, "end": 2997, "text": "(Rohde et al., 2011)", "ref_id": "BIBREF55"}, {"start": 3826, "end": 3850, "text": "(Giummarra et al., 2010)", "ref_id": "BIBREF28"}, {"start": 4007, "end": 4032, "text": "(Fotopoulou et al., 2008;", "ref_id": "BIBREF20"}, {"start": 4033, "end": 4056, "text": "Garbarini et al., 2013)", "ref_id": "BIBREF26"}], "ref_spans": []}, {"section": "SPINAL CORD INJURY ABOLISHES CHANGES IN BODY PERCEPTION IN SPACE INDUCED BY THE RHI", "text": "RHI experiments on healthy subjects typically demonstrate robust proprioceptive drifts that have been considered a strong behavioral proxy to embodiment (Botvinick and Cohen, 1998) . Interestingly however, healthy subjects may not only report the drift when they are asked to judge the position of the finger that has just been stroked, but also report the misallocation of an adjacent finger (Tsakiris and Haggard, 2005) . Thus, although tactile information is very important in terms of inducing the drift, topdown modulations of bodily representations may also influence this component of RHI. In line with this, it has been suggested that the drift occurs only when the observed rubber hand is congruent in terms of posture and identity with the participants unseen hand (Tsakiris and Haggard, 2005) . Measurements of the perceived localization of the participants hand before and after the various different stimulation conditions indicate that, unlike the healthy controls, the SCI subjects did not show any proprioceptive drift. This result is different from what was reported in a previous study where the perceived localization of the body in space, as indicated by the drift, was maximal in SCI patients with defective tactile sensations in the stimulated hand (Lenggenhager et al., 2012) . While no ready explanation for this somewhat paradoxical result is currently available, one may hypothesize that the relative somatosensory impairment of the fingers stimulated in the Lenggenhager et al. (2012) study makes the resulting, noisy stimulation more salient. It is worth noting however, that the two studies cannot be easily compared. There is a clear difference between the two paradigms related to the position of rubber hand relative to real hand which was vertical in the present study, while horizontal in Lenggenhager et al. (2012) . Moreover, the criterion used for detecting drift is here more conservative. Finally, the clinical severity of the Tetraplegics group seems to be greater in the present study. At any rate, a tentative explanation for the absence of drift found in the present study is related to the notion that, under physiological conditions, the stable representation of bodily self is dynamically updated by incoming sensory-motor information (Head and Holmes, 1911) . Thus, we posit that in SCI subjects the interruption of the somatic body-brain connections may induce a bias toward a predominance of the top-down (e.g., mere sight of the rubber hand) over the bottom-up processes (e.g., tactile information from the real hand).", "cite_spans": [{"start": 153, "end": 180, "text": "(Botvinick and Cohen, 1998)", "ref_id": "BIBREF11"}, {"start": 393, "end": 421, "text": "(Tsakiris and Haggard, 2005)", "ref_id": "BIBREF60"}, {"start": 775, "end": 803, "text": "(Tsakiris and Haggard, 2005)", "ref_id": "BIBREF60"}, {"start": 1271, "end": 1298, "text": "(Lenggenhager et al., 2012)", "ref_id": "BIBREF38"}, {"start": 1485, "end": 1511, "text": "Lenggenhager et al. (2012)", "ref_id": "BIBREF38"}, {"start": 1823, "end": 1849, "text": "Lenggenhager et al. (2012)", "ref_id": "BIBREF38"}, {"start": 2281, "end": 2304, "text": "(Head and Holmes, 1911)", "ref_id": "BIBREF31"}], "ref_spans": []}, {"section": "THE QUESTIONNAIRE AND THE DRIFT REVEAL DIFFERENT COMPONENTS OF RHI", "text": "The debate about the processes underlying the RHI is still very vigorous. While the illusion was originally thought to be an effect of the dominant role of vision in intermodal integration (Botvinick and Cohen, 1998) , subsequent studies suggested that it may be induced by other objects than a fake hand and thus stem from a bottom-up Bayesian perceptual learning process rather than from a process of embodiment and change in body self-representation (Armel and Ramachandran, 2003) (but see Tsakiris and Haggard, 2005) . In addition, a recent study demonstrates that the RHI can be induced by the mere observation of an object approaching the rubber hand but without touching it (Ferri et al., 2013) . Studies on healthy subjects suggest that the two RHI components indicating ownership of an artificial hand and the illusory perception of the body in space (hand drift) do not go hand in hand (Rohde et al., 2011) . Our data on SCI subjects provide further evidence of this dissociation between these two components of the RHI. In particular, we posit that the illusory ownership as assessed by the questionnaire may be related to mainly visual, top-down modulation while the proprioceptive drift may be based on bottom-up information processing. Thus, while post-deprivation neural plasticity may amplify illusory ownership in SCI subjects, the lack of afference and bottom-up information may cause lack of drift.", "cite_spans": [{"start": 189, "end": 216, "text": "(Botvinick and Cohen, 1998)", "ref_id": "BIBREF11"}, {"start": 453, "end": 483, "text": "(Armel and Ramachandran, 2003)", "ref_id": "BIBREF6"}, {"start": 493, "end": 520, "text": "Tsakiris and Haggard, 2005)", "ref_id": "BIBREF60"}, {"start": 681, "end": 701, "text": "(Ferri et al., 2013)", "ref_id": "BIBREF19"}, {"start": 896, "end": 916, "text": "(Rohde et al., 2011)", "ref_id": "BIBREF55"}], "ref_spans": []}, {"section": "NO EFFECTS OF PERSONALITY VARIABLES AND FUNCTIONAL AUTONOMY ON THE STRENGTH OF THE RHI", "text": "Although the RHI is largely used as a direct index of bodyownership, studies demonstrate an elevated inter-individual variability in the effect (Haans et al., 2012) as well as a partial independency from bodily awareness (David et al., 2013) . Moreover, the fact that the mere sight of the rubber hand triggers the RHI more than the tactile sensation does (Pavani et al., 2000; Aimola Davies et al., 2010) might suggest that personal variables, such as suggestibility, play a role in the phenomenon beyond neuroplasticity. However, no relationship between the indices of RHI and the results of the personality and susceptibility tests was found in our sample, suggesting that studies with a larger sample are necessary to demonstrate whether the absence of evidence really means that this relationship does not exist. In a previous study on SCI subjects (Pernigo et al., 2012) , we demonstrated that practicing sport was useful in terms of strengthening the visual representation of upper limb body parts and contrasting the effects of somatosensory and motor deprivation. As a result we reasoned that in this study the degree of functional autonomy (which is mainly linked to the extent of the lesion) might influence the effects of the RHI. However, no correlation between these two variables was found. While this negative result may suggest that the visual perception of other people's bodies and RHI are largely independent phenomena, further study on this issue is necessary to explore the link between RHI and somatosensory and motor deprivation. Further insights about face-hand remapping may be revealed by the stroking of different body parts.", "cite_spans": [{"start": 144, "end": 164, "text": "(Haans et al., 2012)", "ref_id": "BIBREF29"}, {"start": 221, "end": 241, "text": "(David et al., 2013)", "ref_id": "BIBREF15"}, {"start": 356, "end": 377, "text": "(Pavani et al., 2000;", "ref_id": "BIBREF48"}, {"start": 378, "end": 405, "text": "Aimola Davies et al., 2010)", "ref_id": "BIBREF5"}, {"start": 854, "end": 876, "text": "(Pernigo et al., 2012)", "ref_id": "BIBREF49"}], "ref_spans": []}, {"section": "QUALITATIVE REPORTS", "text": "At the end of each experiment we asked to the participants if they felt any particular sensation that was not captured by the questionnaires or if they had any additional comments. Normally no sensations and no comments were referred, except in three cases. One tetraplegic participant (T6) reported that in the middle of the Face Synchronous condition he started to feel the touch on the hand that was usually insensible to touch since his spinal cord lesion, 30 years earlier. At the end of the experiment he tried to touch the rubber hand with his own right hand to test whether he could feel the touch again. Unfortunately he couldnt.", "cite_spans": [], "ref_spans": []}, {"section": "QUALITATIVE REPORTS", "text": "Another tetraplegic participant (T5) reported that, starting from the first hand condition, every time we touched the rubber hand with the Q-tip, he felt a light pain sensation at his own hand, that he located at the rubber hand position and not at the real hand position. His real hand was insensible since the traumatic lesion of the spinal cord, 13 years earlier.", "cite_spans": [], "ref_spans": []}, {"section": "QUALITATIVE REPORTS", "text": "A paraplegic participant (P14), reported that, during the Face conditions, the mere vision of the rubber hand was strong enough to feel the embodiment sensation, but the tactile stimulation at the left cheek interrupted this illusion.", "cite_spans": [], "ref_spans": []}, {"section": "QUALITATIVE REPORTS", "text": "The subjective report of T6 seems in line with our result that in Tetraplegics also facial stimulation can evoke ownership illusion, while T5 shows the presence of illusion in both the synchronous and asynchronous Hand conditions. The participant P14, instead, suggests that, in some people, mere vision of the Rubber Hand may cause the illusion, interrupted by the tactile stimulation, similarly to what was observed by Rohde et al. (2011) .", "cite_spans": [{"start": 421, "end": 440, "text": "Rohde et al. (2011)", "ref_id": "BIBREF55"}], "ref_spans": []}, {"section": "LIMITATIONS OF THE CURRENT STUDY", "text": "Some possible limitations of this study deserve discussion. The variety of the NLI levels and in the time interval between the lesion onset and the experimental session in both the Tetraplegics and Paraplegics groups are relevant. These differences imply each individual in the same group does differ in motor, tactile and proprioceptive functions that surely have effects on neuroplastic somatosensory and motor cortical changes. For example, a person affected by paraplegia, with a T1 NLI has dramatically less control of his/her own trunk than people with a L4 lesion. These differences are even more striking in the Tetraplegics group, where a difference among C4, C5, and C6 greatly impact in the possibility of arm movements, from the complete paralysis to the possibility of motion and use of tools. It is also worth noting that more chronic SCI subjects could have learned a higher number functional strategies than a less chronic SCI subject. This should have neuroplastic consequences. Furthermore, even if there are not statistically significant differences between groups, the fact that some Tetraplegics could feel the tactile sensation of the Q-tip in the hand, while other participants could not feel it, probably have some influence on the results of this study. Finally it was not possible to have the MRI scans before and after the SCI thus our suggestions regarding the influence of lesion onset, tactile sensitivity and neuroplastic changes remain speculative.", "cite_spans": [], "ref_spans": []}, {"section": "LIMITATIONS OF THE CURRENT STUDY", "text": "However, finding significant effects in spite of the above reported characteristics of heterogeneity could be an indication of robustness of the effects themselves, thus our results are in keeping with the typical neuroplastic changes following SCI reported in previous literature (Bruehlmeier et al., 1998; Freund et al., 2011a,b) and seem to support the notion that motor and sensory representation of spared body parts shift toward the areas contiguous with de-efferented and de-afferented body parts.", "cite_spans": [{"start": 281, "end": 307, "text": "(Bruehlmeier et al., 1998;", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "CONCLUSION", "text": "This study has demonstrated that indices of ownership of a fake hand can be induced in SCI subjects and that the indication od illusory ownership over the rubber hand is more likely to occur in the presence of upper spinal levels and thus involves greater de-afferentation. In Tetraplegics the phenomenon is also induced by facial stimulation suggesting that deprivation related plasticity may occur according to somatotopic rules. Further studies are needed to understand whether plastic changes following SCI are inherently adaptive or maladaptive (Kokotilo et al., 2009; Nishimura and Isa, 2009 ). The absence of changes in the perceived position of the body in space confirms that these two components of the RHI may be more dissociated in SCI subjects than in healthy individuals (Rohde et al., 2011) .", "cite_spans": [{"start": 550, "end": 573, "text": "(Kokotilo et al., 2009;", "ref_id": "BIBREF37"}, {"start": 574, "end": 597, "text": "Nishimura and Isa, 2009", "ref_id": "BIBREF47"}, {"start": 785, "end": 805, "text": "(Rohde et al., 2011)", "ref_id": "BIBREF55"}], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Anomalous double sensations after damage to the cortical somatosensory representation of the hand in humans", "authors": [{"first": "S", "middle": ["M"], "last": "Aglioti", "suffix": ""}, {"first": "A", "middle": [], "last": "Beltramello", "suffix": ""}, {"first": "A", "middle": [], "last": "Peru", "suffix": ""}, {"first": "N", "middle": [], "last": "Smania", "suffix": ""}, {"first": "M", "middle": [], "last": "Tinazzi", "suffix": ""}], "year": 1999, "venue": "Neurocase", "link": "144150684"}, "BIBREF1": {"title": "Phantom lower limb as a perceptual marker of neural plasticity in the mature human brain", "authors": [{"first": "S", "middle": ["M"], "last": "Aglioti", "suffix": ""}, {"first": "A", "middle": [], "last": "Bonazzi", "suffix": ""}, {"first": "Cortese", "middle": [], "last": "", "suffix": ""}, {"first": "F", "middle": [], "last": "", "suffix": ""}], "year": 1994, "venue": "Proc. R. Soc. B Biol. Sci", "link": "22004065"}, "BIBREF2": {"title": "Rapid sensory remapping in the adult human brain as inferred from phantom breast perception", "authors": [{"first": "S", "middle": ["M"], "last": "Aglioti", "suffix": ""}, {"first": "F", "middle": [], "last": "Cortese", "suffix": ""}, {"first": "M", "middle": [], "last": "Franchini", "suffix": ""}], "year": 1994, "venue": "Neuroreport", "link": "6232588"}, "BIBREF3": {"title": "Spatio-temporal properties of the pattern of evoked phantom sensations in a left index amputee patient", "authors": [{"first": "S", "middle": ["M"], "last": "Aglioti", "suffix": ""}, {"first": "N", "middle": [], "last": "Smania", "suffix": ""}, {"first": "A", "middle": [], "last": "Atzei", "suffix": ""}, {"first": "G", "middle": [], "last": "Berlucchi", "suffix": ""}], "year": 1997, "venue": "Behav. Neurosci", "link": "5751836"}, "BIBREF4": {"title": "Spinal cord injury immediately changes the state of the brain", "authors": [{"first": "J", "middle": [], "last": "Aguilar", "suffix": ""}, {"first": "D", "middle": [], "last": "Humanes-Valera", "suffix": ""}, {"first": "E", "middle": [], "last": "Alonso-Calvi\u00f1o", "suffix": ""}, {"first": "J", "middle": ["G"], "last": "Yague", "suffix": ""}, {"first": "K", "middle": [], "last": "Moxon", "suffix": ""}, {"first": "A", "middle": [], "last": "Oliviero", "suffix": ""}], "year": 2010, "venue": "J. Neurosci", "link": "14433605"}, "BIBREF5": {"title": "Visual capture of action, experience of ownership, and the illusion of self-touch: a new rubber hand paradigm", "authors": [{"first": "Aimola", "middle": [], "last": "Davies", "suffix": ""}, {"first": "A", "middle": ["M"], "last": "White", "suffix": ""}, {"first": "R", "middle": ["C"], "last": "Thew", "suffix": ""}, {"first": "G", "middle": [], "last": "Aimola", "suffix": ""}, {"first": "N", "middle": ["M"], "last": "Davies", "suffix": ""}, {"first": "M", "middle": [], "last": "", "suffix": ""}], "year": 2010, "venue": "Perception", "link": "6242751"}, "BIBREF6": {"title": "Projecting sensations to external objects: evidence from skin conductance response", "authors": [{"first": "K", "middle": ["C"], "last": "Armel", "suffix": ""}, {"first": "V", "middle": ["S"], "last": "Ramachandran", "suffix": ""}], "year": 2003, "venue": "Proc. R. Soc. Lond. B Biol. Sci", "link": "15753211"}, "BIBREF7": {"title": "lme4: Linear Mixed-Effects Models using Eigen and S4", "authors": [{"first": "D", "middle": [], "last": "Bates", "suffix": ""}, {"first": "M", "middle": [], "last": "Maechler", "suffix": ""}, {"first": "B", "middle": [], "last": "Bolker", "suffix": ""}, {"first": "S", "middle": [], "last": "Walker", "suffix": ""}], "year": 2013, "venue": "", "link": null}, "BIBREF8": {"title": "lme4: Mixed-Effects Modeling with R. Available online at", "authors": [{"first": "D", "middle": ["M"], "last": "Bates", "suffix": ""}], "year": 2010, "venue": "", "link": null}, "BIBREF9": {"title": "The perceptual and neuronal stability of the rubber hand illusion across contexts and over time", "authors": [{"first": "R", "middle": [], "last": "Bekrater-Bodmann", "suffix": ""}, {"first": "J", "middle": [], "last": "Foell", "suffix": ""}, {"first": "M", "middle": [], "last": "Diers", "suffix": ""}, {"first": "Flor", "middle": [], "last": "", "suffix": ""}, {"first": "H", "middle": [], "last": "", "suffix": ""}], "year": 2012, "venue": "Brain Res", "link": "24613602"}, "BIBREF10": {"title": "Controlling the false discovery rate: a practical and powerful approach to multiple testing", "authors": [{"first": "Y", "middle": [], "last": "Benjamini", "suffix": ""}, {"first": "Y", "middle": [], "last": "Hochberg", "suffix": ""}], "year": 1995, "venue": "J. R. Stat. Soc. B", "link": "45174121"}, "BIBREF11": {"title": "Rubber hands 'feel' touch that eyes see", "authors": [{"first": "M", "middle": [], "last": "Botvinick", "suffix": ""}, {"first": "J", "middle": [], "last": "Cohen", "suffix": ""}], "year": 1998, "venue": "Nature", "link": null}, "BIBREF12": {"title": "How does the human brain deal with a spinal cord injury?", "authors": [{"first": "M", "middle": [], "last": "Bruehlmeier", "suffix": ""}, {"first": "V", "middle": [], "last": "Dietz", "suffix": ""}, {"first": "K", "middle": ["L"], "last": "Leenders", "suffix": ""}, {"first": "U", "middle": [], "last": "Roelcke", "suffix": ""}, {"first": "J", "middle": [], "last": "Missimer", "suffix": ""}, {"first": "Curt", "middle": [], "last": "", "suffix": ""}, {"first": "A", "middle": [], "last": "", "suffix": ""}], "year": 1998, "venue": "Eur. J. Neurosci", "link": "45099193"}, "BIBREF13": {"title": "How does a short history of spinal cord injury affect movement-related brain potentials?", "authors": [{"first": "A", "middle": [], "last": "Castro", "suffix": ""}, {"first": "F", "middle": [], "last": "D\u00edaz", "suffix": ""}, {"first": "G", "middle": ["J M"], "last": "Van Boxtel", "suffix": ""}], "year": 2007, "venue": "Eur. J. Neurosci", "link": "24603806"}, "BIBREF14": {"title": "Assessment of regional blood flow in cerebral motor and sensory areas in patients with spinal cord injury", "authors": [{"first": "T", "middle": ["F"], "last": "\u00c7ermik", "suffix": ""}, {"first": "H", "middle": [], "last": "Tuna", "suffix": ""}, {"first": "M", "middle": [], "last": "Kaya", "suffix": ""}, {"first": "F", "middle": [], "last": "Tuna", "suffix": ""}, {"first": "A", "middle": [], "last": "G\u00fcltekin", "suffix": ""}, {"first": "O", "middle": ["N"], "last": "Yigitba\u015fi", "suffix": ""}], "year": 2006, "venue": "Brain Res", "link": "9641820"}, "BIBREF15": {"title": "Susceptibility to the rubber hand illusion does not tell the whole body-awareness story", "authors": [{"first": "N", "middle": [], "last": "David", "suffix": ""}, {"first": "F", "middle": [], "last": "Fiori", "suffix": ""}, {"first": "S", "middle": ["M"], "last": "Aglioti", "suffix": ""}], "year": 2013, "venue": "Cogn. Affect. Behav. Neurosci", "link": "8034252"}, "BIBREF16": {"title": "An Introduction to the Bootstrap", "authors": [{"first": "B", "middle": [], "last": "Efron", "suffix": ""}, {"first": "R", "middle": ["J"], "last": "Tibshirani", "suffix": ""}], "year": 1994, "venue": "", "link": "198120286"}, "BIBREF17": {"title": "Touching a rubber hand: feeling of body ownership is associated with activity in multisensory brain areas", "authors": [{"first": "H", "middle": ["H"], "last": "Ehrsson", "suffix": ""}, {"first": "N", "middle": ["P"], "last": "Holmes", "suffix": ""}, {"first": "R", "middle": ["E"], "last": "Passingham", "suffix": ""}], "year": 2005, "venue": "J. Neurosci", "link": "18637842"}, "BIBREF18": {"title": "Face or hand, not both: perceptual correlates of reafferentation in a former amputee", "authors": [{"first": "A", "middle": [], "last": "Farn\u00e8", "suffix": ""}, {"first": "A", "middle": ["C"], "last": "Roy", "suffix": ""}, {"first": "P", "middle": [], "last": "Giraux", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Dubernard", "suffix": ""}, {"first": "A", "middle": [], "last": "Sirigu", "suffix": ""}], "year": 2002, "venue": "Curr. Biol", "link": "15727790"}, "BIBREF19": {"title": "The body beyond the body: expectation of a sensory event is enough to induce ownership over a fake hand", "authors": [{"first": "F", "middle": [], "last": "Ferri", "suffix": ""}, {"first": "A", "middle": ["M"], "last": "Chiarelli", "suffix": ""}, {"first": "A", "middle": [], "last": "Merla", "suffix": ""}, {"first": "V", "middle": [], "last": "Gallese", "suffix": ""}, {"first": "M", "middle": [], "last": "Costantini", "suffix": ""}], "year": 2013, "venue": "Proc. R. Soc. B Biol. Sci", "link": "8643885"}, "BIBREF20": {"title": "The role of motor intention in motor awareness: an experimental study on anosognosia for hemiplegia", "authors": [{"first": "A", "middle": [], "last": "Fotopoulou", "suffix": ""}, {"first": "M", "middle": [], "last": "Tsakiris", "suffix": ""}, {"first": "P", "middle": [], "last": "Haggard", "suffix": ""}, {"first": "A", "middle": [], "last": "Vagopoulou", "suffix": ""}, {"first": "A", "middle": [], "last": "Rudd", "suffix": ""}, {"first": "M", "middle": [], "last": "Kopelman", "suffix": ""}], "year": 2008, "venue": "Brain", "link": "206358981"}, "BIBREF21": {"title": "Corticomotor representation to a human forearm muscle changes following cervical spinal cord injury", "authors": [{"first": "P", "middle": [], "last": "Freund", "suffix": ""}, {"first": "J", "middle": [], "last": "Rothwell", "suffix": ""}, {"first": "M", "middle": [], "last": "Craggs", "suffix": ""}, {"first": "A", "middle": ["J"], "last": "Thompson", "suffix": ""}, {"first": "S", "middle": [], "last": "Bestmann", "suffix": ""}], "year": 2011, "venue": "Eur. J. Neurosci", "link": "26456801"}, "BIBREF22": {"title": "MRI investigation of the sensorimotor cortex and the corticospinal tract after acute spinal cord injury: a prospective longitudinal study", "authors": [{"first": "P", "middle": [], "last": "Freund", "suffix": ""}, {"first": "N", "middle": [], "last": "Weiskopf", "suffix": ""}, {"first": "J", "middle": [], "last": "Ashburner", "suffix": ""}, {"first": "K", "middle": [], "last": "Wolf", "suffix": ""}, {"first": "R", "middle": [], "last": "Sutter", "suffix": ""}, {"first": "D", "middle": ["R"], "last": "Altmann", "suffix": ""}], "year": 2013, "venue": "Lancet Neurol", "link": "13764390"}, "BIBREF23": {"title": "Disability, atrophy and cortical reorganization following spinal cord injury", "authors": [{"first": "P", "middle": [], "last": "Freund", "suffix": ""}, {"first": "N", "middle": [], "last": "Weiskopf", "suffix": ""}, {"first": "N", "middle": ["S"], "last": "Ward", "suffix": ""}, {"first": "C", "middle": [], "last": "Hutton", "suffix": ""}, {"first": "A", "middle": [], "last": "Gall", "suffix": ""}, {"first": "O", "middle": [], "last": "Ciccarelli", "suffix": ""}], "year": 2011, "venue": "Brain", "link": "10446954"}, "BIBREF24": {"title": "How people interpret conditionals: shifts towards the conditional event", "authors": [{"first": "A", "middle": ["J B"], "last": "Fugard", "suffix": ""}, {"first": "N", "middle": [], "last": "Pfeifer", "suffix": ""}, {"first": "B", "middle": [], "last": "Mayerhofer", "suffix": ""}, {"first": "G", "middle": ["D"], "last": "Kleiter", "suffix": ""}], "year": 2009, "venue": "J. Exp. Psychol. Learn. Mem. Cogn", "link": "1789466"}, "BIBREF25": {"title": "Perceptual distortions of the human body image produced by local anaesthesia, pain and cutaneous stimulation", "authors": [{"first": "S", "middle": ["C"], "last": "Gandevia", "suffix": ""}, {"first": "C", "middle": ["M"], "last": "Phegan", "suffix": ""}], "year": 1999, "venue": "J. Physiol", "link": "21813727"}, "BIBREF26": {"title": "Embodiment of an alien hand interferes with intact-hand movements", "authors": [{"first": "F", "middle": [], "last": "Garbarini", "suffix": ""}, {"first": "L", "middle": [], "last": "Pia", "suffix": ""}, {"first": "A", "middle": [], "last": "Piedimonte", "suffix": ""}, {"first": "M", "middle": [], "last": "Rabuffetti", "suffix": ""}, {"first": "P", "middle": [], "last": "Gindri", "suffix": ""}, {"first": "Berti", "middle": [], "last": "", "suffix": ""}, {"first": "A", "middle": [], "last": "", "suffix": ""}], "year": 2013, "venue": "Curr. Biol", "link": "5829997"}, "BIBREF27": {"title": "The classical psychophysical methods", "authors": [{"first": "G", "middle": ["A"], "last": "Gescheider", "suffix": ""}], "year": 1997, "venue": "Psychophysics: The Fundamentals", "link": null}, "BIBREF28": {"title": "The phantom in the mirror: a modified rubberhand illusion in amputees and normals", "authors": [{"first": "M", "middle": ["J"], "last": "Giummarra", "suffix": ""}, {"first": "N", "middle": [], "last": "Georgiou-Karistianis", "suffix": ""}, {"first": "M", "middle": ["E R"], "last": "Nicholls", "suffix": ""}, {"first": "S", "middle": ["J"], "last": "Gibson", "suffix": ""}, {"first": "J", "middle": ["L"], "last": "Bradshaw", "suffix": ""}], "year": 2010, "venue": "Perception", "link": "25577227"}, "BIBREF29": {"title": "Individual differences in the rubber-hand illusion: predicting self-reports of people's personal experiences", "authors": [{"first": "A", "middle": [], "last": "Haans", "suffix": ""}, {"first": "F", "middle": ["G"], "last": "Kaiser", "suffix": ""}, {"first": "D", "middle": ["G"], "last": "Bouwhuis", "suffix": ""}, {"first": "W", "middle": ["A"], "last": "Ijsselsteijn", "suffix": ""}], "year": 2012, "venue": "Acta Psychol", "link": "36855125"}, "BIBREF30": {"title": "Altered cortical activation from the hand after facial botulinum toxin treatment", "authors": [{"first": "S", "middle": [], "last": "Haenzi", "suffix": ""}, {"first": "G", "middle": [], "last": "Stefanics", "suffix": ""}, {"first": "T", "middle": [], "last": "Lanaras", "suffix": ""}, {"first": "M", "middle": [], "last": "Calcagni", "suffix": ""}, {"first": "A", "middle": [], "last": "Ghosh", "suffix": ""}], "year": 2014, "venue": "Ann. Clin. Trans. Neurol", "link": "5609132"}, "BIBREF31": {"title": "Sensory disturbances from cerebral lesions", "authors": [{"first": "H", "middle": [], "last": "Head", "suffix": ""}, {"first": "G", "middle": [], "last": "Holmes", "suffix": ""}], "year": 1911, "venue": "Brain", "link": "58830902"}, "BIBREF32": {"title": "Functional reorganization of the brain in humans following spinal cord injury: evidence for underlying changes in cortical anatomy", "authors": [{"first": "L", "middle": ["A"], "last": "Henderson", "suffix": ""}, {"first": "S", "middle": ["M"], "last": "Gustin", "suffix": ""}, {"first": "P", "middle": ["M"], "last": "Macey", "suffix": ""}, {"first": "P", "middle": ["J"], "last": "Wrigley", "suffix": ""}, {"first": "P", "middle": ["J"], "last": "Siddall", "suffix": ""}], "year": 2011, "venue": "J. Neurosci", "link": "1884287"}, "BIBREF33": {"title": "Reorganization of the intact somatosensory cortex immediately after spinal cord injury", "authors": [{"first": "D", "middle": [], "last": "Humanes-Valera", "suffix": ""}, {"first": "J", "middle": [], "last": "Aguilar", "suffix": ""}, {"first": "G", "middle": [], "last": "Foffani", "suffix": ""}], "year": 2013, "venue": "PLoS ONE", "link": "7568169"}, "BIBREF34": {"title": "Development and validation of the Italian version of the Spinal Cord Independence Measure III", "authors": [{"first": "M", "middle": [], "last": "Invernizzi", "suffix": ""}, {"first": "S", "middle": [], "last": "Carda", "suffix": ""}, {"first": "P", "middle": [], "last": "Milani", "suffix": ""}, {"first": "F", "middle": [], "last": "Mattana", "suffix": ""}, {"first": "D", "middle": [], "last": "Fletzer", "suffix": ""}, {"first": "G", "middle": [], "last": "Iolascon", "suffix": ""}], "year": 2010, "venue": "Disabil. Rehabil", "link": "19680656"}, "BIBREF35": {"title": "International standards for neurological classification of spinal cord injury (Revised", "authors": [{"first": "S", "middle": ["C"], "last": "Kirshblum", "suffix": ""}, {"first": "S", "middle": ["P"], "last": "Burns", "suffix": ""}, {"first": "F", "middle": [], "last": "Biering-Sorensen", "suffix": ""}, {"first": "W", "middle": [], "last": "Donovan", "suffix": ""}, {"first": "D", "middle": ["E"], "last": "Graves", "suffix": ""}, {"first": "A", "middle": [], "last": "Jha", "suffix": ""}], "year": 2011, "venue": "J. Spinal Cord Med", "link": "36808282"}, "BIBREF36": {"title": "Microsaccadic modulation of response times in spatial attention tasks", "authors": [{"first": "R", "middle": [], "last": "Kliegl", "suffix": ""}, {"first": "M", "middle": [], "last": "Rolfs", "suffix": ""}, {"first": "J", "middle": [], "last": "Laubrock", "suffix": ""}, {"first": "R", "middle": [], "last": "Engbert", "suffix": ""}], "year": 2009, "venue": "Psychol. Res", "link": "8782910"}, "BIBREF37": {"title": "Reorganization and preservation of motor control of the brain in spinal cord injury: a systematic review", "authors": [{"first": "K", "middle": ["J"], "last": "Kokotilo", "suffix": ""}, {"first": "J", "middle": ["J"], "last": "Eng", "suffix": ""}, {"first": "Curt", "middle": [], "last": "", "suffix": ""}, {"first": "A", "middle": [], "last": "", "suffix": ""}], "year": 2009, "venue": "J. Neurotr", "link": "21704892"}, "BIBREF38": {"title": "The sense of the body in individuals with spinal cord injury", "authors": [{"first": "B", "middle": [], "last": "Lenggenhager", "suffix": ""}, {"first": "M", "middle": [], "last": "Pazzaglia", "suffix": ""}, {"first": "G", "middle": [], "last": "Scivoletto", "suffix": ""}, {"first": "M", "middle": [], "last": "Molinari", "suffix": ""}, {"first": "S", "middle": ["M"], "last": "Aglioti", "suffix": ""}], "year": 2012, "venue": "PLoS ONE", "link": "18136308"}, "BIBREF39": {"title": "Restoring tactile awareness through the rubber hand illusion in cervical spinal cord injury", "authors": [{"first": "B", "middle": [], "last": "Lenggenhager", "suffix": ""}, {"first": "G", "middle": [], "last": "Scivoletto", "suffix": ""}, {"first": "M", "middle": [], "last": "Molinari", "suffix": ""}, {"first": "M", "middle": [], "last": "Pazzaglia", "suffix": ""}], "year": 2013, "venue": "Neurorehabil. Neural Repair", "link": "206760226"}, "BIBREF40": {"title": "What is embodiment? A psychometric approach", "authors": [{"first": "M", "middle": ["R"], "last": "Longo", "suffix": ""}, {"first": "F", "middle": [], "last": "Sch\u00fc\u00fcr", "suffix": ""}, {"first": "M", "middle": ["P M"], "last": "Kammers", "suffix": ""}, {"first": "M", "middle": [], "last": "Tsakiris", "suffix": ""}, {"first": "P", "middle": [], "last": "Haggard", "suffix": ""}], "year": 2008, "venue": "Cognition", "link": "5689017"}, "BIBREF41": {"title": "Psychological correlates of illusory body experiences", "authors": [{"first": "M", "middle": [], "last": "Maclachlan", "suffix": ""}, {"first": "D", "middle": [], "last": "Desmond", "suffix": ""}, {"first": "O", "middle": [], "last": "Horgan", "suffix": ""}], "year": 2003, "venue": "J. Rehabil. Res. Dev", "link": "7002556"}, "BIBREF42": {"title": "Adaptation in the motor cortex following cervical spinal cord injury", "authors": [{"first": "D", "middle": ["J"], "last": "Mikulis", "suffix": ""}, {"first": "M", "middle": ["T"], "last": "Jurkiewicz", "suffix": ""}, {"first": "W", "middle": ["E"], "last": "Mcilroy", "suffix": ""}, {"first": "W", "middle": ["R"], "last": "Staines", "suffix": ""}, {"first": "L", "middle": [], "last": "Rickards", "suffix": ""}, {"first": "S", "middle": [], "last": "Kalsiryan", "suffix": ""}], "year": 2002, "venue": "Neurology", "link": "2903849"}, "BIBREF43": {"title": "No pain relief with the rubber hand illusion", "authors": [{"first": "R", "middle": [], "last": "Mohan", "suffix": ""}, {"first": "K", "middle": ["B"], "last": "Jensen", "suffix": ""}, {"first": "V", "middle": ["I"], "last": "Petkova", "suffix": ""}, {"first": "A", "middle": [], "last": "Dey", "suffix": ""}, {"first": "N", "middle": [], "last": "Barnsley", "suffix": ""}, {"first": "M", "middle": [], "last": "Ingvar", "suffix": ""}], "year": 2012, "venue": "PLoS ONE", "link": "17168093"}, "BIBREF44": {"title": "Referred phantom sensations and cortical reorganization after spinal cord injury in humans", "authors": [{"first": "C", "middle": ["I"], "last": "Moore", "suffix": ""}, {"first": "C", "middle": ["E"], "last": "Stern", "suffix": ""}, {"first": "C", "middle": [], "last": "Dunbar", "suffix": ""}, {"first": "S", "middle": ["K"], "last": "Kostyk", "suffix": ""}, {"first": "Corkin", "middle": [], "last": "Gehi", "suffix": ""}, {"first": "S", "middle": [], "last": "", "suffix": ""}], "year": 2000, "venue": "Proc. Natl. Acad. Sci. U.S.A", "link": "14938049"}, "BIBREF45": {"title": "Psychologically induced cooling of a specific body part caused by the Frontiers in Human Neuroscience www.frontiersin.org illusory ownership of an artificial counterpart", "authors": [{"first": "G", "middle": ["L"], "last": "Moseley", "suffix": ""}, {"first": "N", "middle": [], "last": "Olthof", "suffix": ""}, {"first": "A", "middle": [], "last": "Venema", "suffix": ""}, {"first": "S", "middle": [], "last": "Don", "suffix": ""}, {"first": "M", "middle": [], "last": "Wijers", "suffix": ""}, {"first": "A", "middle": [], "last": "Gallace", "suffix": ""}], "year": 2008, "venue": "Proc. Natl. Acad. Sci. U.S.A", "link": null}, "BIBREF46": {"title": "Changing Brains Applying Brain Plasticity to Advance and Recover Human Ability", "authors": [{"first": "M", "middle": [], "last": "Nahum", "suffix": ""}, {"first": "H", "middle": [], "last": "Lee", "suffix": ""}, {"first": "M", "middle": ["M"], "last": "Merzenich", "suffix": ""}], "year": 2013, "venue": "Principles of Neuroplasticity-Based Rehabilitation", "link": "141889207"}, "BIBREF47": {"title": "Compensatory changes at the cerebral cortical level after spinal cord injury", "authors": [{"first": "Y", "middle": [], "last": "Nishimura", "suffix": ""}, {"first": "Isa", "middle": [], "last": "", "suffix": ""}, {"first": "T", "middle": [], "last": "", "suffix": ""}], "year": 2009, "venue": "Neuroscientist", "link": "46240131"}, "BIBREF48": {"title": "Visual capture of touch: Outof-the-body experiences with rubber gloves", "authors": [{"first": "F", "middle": [], "last": "Pavani", "suffix": ""}, {"first": "C", "middle": [], "last": "Spence", "suffix": ""}, {"first": "J", "middle": [], "last": "Driver", "suffix": ""}], "year": 2000, "venue": "Psychol. Sci", "link": null}, "BIBREF49": {"title": "Massive somatic deafferentation and motor deefferentation of the lower part of the body impair its visual recognition: a psychophysical study of patients with spinal cord injury", "authors": [{"first": "S", "middle": [], "last": "Pernigo", "suffix": ""}, {"first": "V", "middle": [], "last": "Moro", "suffix": ""}, {"first": "R", "middle": [], "last": "Avesani", "suffix": ""}, {"first": "C", "middle": [], "last": "Miatello", "suffix": ""}, {"first": "C", "middle": [], "last": "Urgesi", "suffix": ""}, {"first": "S", "middle": ["M"], "last": "Aglioti", "suffix": ""}], "year": 2012, "venue": "Eur. J. Neurosci", "link": "30363414"}, "BIBREF50": {"title": "Mixed-Effects Models in S and S-Plus", "authors": [{"first": "J", "middle": ["C"], "last": "Pinheiro", "suffix": ""}, {"first": "D", "middle": ["M"], "last": "Bates", "suffix": ""}], "year": 2000, "venue": "", "link": "117882390"}, "BIBREF51": {"title": "Massive cortical reorganization after sensory deafferentation in adult macaques", "authors": [{"first": "T", "middle": ["P"], "last": "Pons", "suffix": ""}, {"first": "P", "middle": ["E"], "last": "Garraghty", "suffix": ""}, {"first": "A", "middle": ["K"], "last": "Ommaya", "suffix": ""}, {"first": "J", "middle": ["H"], "last": "Kaas", "suffix": ""}, {"first": "E", "middle": [], "last": "Taub", "suffix": ""}, {"first": "M", "middle": [], "last": "Mishkin", "suffix": ""}], "year": 1991, "venue": "Science", "link": "7960162"}, "BIBREF52": {"title": "Perceptual correlates of massive cortical reorganization", "authors": [{"first": "V", "middle": ["S"], "last": "Ramachandran", "suffix": ""}, {"first": "D", "middle": [], "last": "Rogers-Ramachandran", "suffix": ""}, {"first": "M", "middle": [], "last": "Stewart", "suffix": ""}], "year": 1992, "venue": "Science", "link": "37410794"}, "BIBREF53": {"title": "Measuring personality in one minute or less: a 10-item short version of the Big Five Inventory in English and German", "authors": [{"first": "B", "middle": [], "last": "Rammstedt", "suffix": ""}, {"first": "O", "middle": ["P"], "last": "John", "suffix": ""}], "year": 2007, "venue": "J. Res. Personal", "link": "29855114"}, "BIBREF54": {"title": "R: A Language and Environment for Statistical Computing. Vienna: R Foundation for Statistical Computing", "authors": [{"first": "R", "middle": [], "last": "Development Core", "suffix": ""}, {"first": "", "middle": [], "last": "Team", "suffix": ""}], "year": 2013, "venue": "", "link": null}, "BIBREF55": {"title": "The Rubber Hand Illusion: feeling of ownership and proprioceptive drift do not go hand in hand", "authors": [{"first": "M", "middle": [], "last": "Rohde", "suffix": ""}, {"first": "M", "middle": [], "last": "Di Luca", "suffix": ""}, {"first": "M", "middle": ["O"], "last": "Ernst", "suffix": ""}], "year": 2011, "venue": "PLoS ONE", "link": "11263174"}, "BIBREF56": {"title": "Brain activation in the acute phase of traumatic spinal cord injury", "authors": [{"first": "L", "middle": [], "last": "Sabre", "suffix": ""}, {"first": "T", "middle": [], "last": "Tomberg", "suffix": ""}, {"first": "J", "middle": ["K"], "last": "Orv", "suffix": ""}, {"first": "J", "middle": [], "last": "Kepler", "suffix": ""}, {"first": "K", "middle": [], "last": "Kepler", "suffix": ""}, {"first": "U", "middle": [], "last": "Linnam\u00e4gi", "suffix": ""}], "year": 2013, "venue": "Spinal Cord", "link": "24547586"}, "BIBREF57": {"title": "Waking up the alien hand: rubber hand illusion interacts with alien hand syndrome", "authors": [{"first": "M", "middle": [], "last": "Schaefer", "suffix": ""}, {"first": "H.-J", "middle": [], "last": "Heinze", "suffix": ""}, {"first": "I", "middle": [], "last": "Galazky", "suffix": ""}], "year": 2013, "venue": "Neurocase", "link": "5511665"}, "BIBREF58": {"title": "Large-Scale Expansion of the Face Representation in Somatosensory Areas of the Lateral Sulcus after Spinal Cord Injuries in Monkeys", "authors": [{"first": "S", "middle": [], "last": "Tandon", "suffix": ""}, {"first": "N", "middle": [], "last": "Kambi", "suffix": ""}, {"first": "L", "middle": [], "last": "Lazar", "suffix": ""}, {"first": "H", "middle": [], "last": "Mohammed", "suffix": ""}, {"first": "N", "middle": [], "last": "Jain", "suffix": ""}], "year": 2009, "venue": "J. Neurosci", "link": "16632139"}, "BIBREF59": {"title": "Openess to absorbing and self-altering experiences (\"absorption\"), a trait related to hypnotic susceptibility", "authors": [{"first": "A", "middle": [], "last": "Tellegen", "suffix": ""}, {"first": "G", "middle": [], "last": "Atkinson", "suffix": ""}], "year": 1974, "venue": "J. Abnorm. Psychol", "link": "11980747"}, "BIBREF60": {"title": "The rubber hand illusion revisited: visuotactile integration and self-attribution", "authors": [{"first": "M", "middle": [], "last": "Tsakiris", "suffix": ""}, {"first": "P", "middle": [], "last": "Haggard", "suffix": ""}], "year": 2005, "venue": "J. Exp. Psychol. Hum. Percept. Perform", "link": "13955594"}, "BIBREF61": {"title": "ggplot2: elegant graphics for data analysis", "authors": [{"first": "H", "middle": [], "last": "Wickham", "suffix": ""}], "year": 2009, "venue": "", "link": "119972206"}, "BIBREF62": {"title": "Individual comparisons by ranking methods", "authors": [{"first": "F", "middle": [], "last": "Wilcoxon", "suffix": ""}], "year": 1945, "venue": "Biomet. Bull", "link": "53662922"}, "BIBREF63": {"title": "Neuropathic pain and primary somatosensory cortex reorganization following spinal cord injury", "authors": [{"first": "P", "middle": ["J"], "last": "Wrigley", "suffix": ""}, {"first": "S", "middle": ["R"], "last": "Press", "suffix": ""}, {"first": "S", "middle": ["M"], "last": "Gustin", "suffix": ""}, {"first": "V", "middle": ["G"], "last": "Macefield", "suffix": ""}, {"first": "S", "middle": ["C"], "last": "Gandevia", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Cousins", "suffix": ""}], "year": 2009, "venue": "Pain", "link": "7177486"}, "BIBREF64": {"title": "Crossmodal congruency measures of lateral distance effects on the rubber hand illusion", "authors": [{"first": "R", "middle": [], "last": "Zopf", "suffix": ""}, {"first": "G", "middle": [], "last": "Savage", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Williams", "suffix": ""}], "year": 2010, "venue": "Neuropsychologia", "link": "3006496"}, "BIBREF65": {"title": "Conflict of Interest Statement: The authors declare that the research was con", "authors": [], "year": "", "venue": "", "link": null}}, "ref_entries": {"FIGREF0": {"text": "FIGURE 1 | Materials (A) Experimental wooden box (RuH, Rubber Hand; ReH, Real Hand) the mobile indicator was always visible to the participant laterally to the box; (B) Graphical representation of the position and direction of the stimuli in the Synchronous and Asynchronous Face conditions. The dotted lines indicate the ideal line on the left cheek and the RH index finger. Note that in the synchronous conditions, the strokes are administered in a", "type": "figure"}, "FIGREF1": {"text": "FIGURE 2 | Drifts in the position of the participants hand in the various conditions. The mean (SE) number of drifts greater than the 95% CI upper bound for each group is reported. * p < 0.05.", "type": "figure"}, "FIGREF2": {"text": "FIGURE 3 | The illusion according to participants responses to the questionnaire. The differences between responses in IRQ and ICQ (mean values and standard errors) in the three groups are represented for each condition. * p < 0.05; * * * p < 0.001.", "type": "figure"}, "TABREF0": {"text": "Demographic and clinical information relative to the SCI subjects.", "type": "table"}, "TABREF1": {"text": "The Rubber Hand Illusion questionnaire in the version for Face and Hand stimulation.The questions relating to the illusion are indicated by the letters IRQ and the control questions by ICQ.", "type": "table"}, "TABREF2": {"text": "did not differ among groups. SCIM-3 values are reported in Table 1. No statistically significant", "type": "table"}, "TABREF3": {"text": "Psychological and Personality aspects of the groups.", "type": "table"}}}
{"paper_id": "18981625", "_pdf_hash": "fbdb4a4e1f62a31c9ee17c0bab27c429712e795c", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "An algorithm for the traveling salesman problem", "authors": [{"first": "J", "middle": [], "last": "Little", "suffix": ""}, {"first": "K", "middle": [], "last": "Murty", "suffix": ""}, {"first": "D", "middle": [], "last": "Sweeney", "suffix": ""}, {"first": "C", "middle": [], "last": "Karel", "suffix": ""}], "year": 1963, "venue": "Operations Research", "link": "122313212"}, "BIBREF1": {"title": "Genetic algorithms for the traveling salesman problem", "authors": [{"first": "Jean-Yves", "middle": [], "last": "Potvin", "suffix": ""}], "year": 1996, "venue": "Annals of Operations Research", "link": null}, "BIBREF2": {"title": "Identeki Algorithm[Genetic Algorithm", "authors": [{"first": "H", "middle": [], "last": "Kitano", "suffix": ""}], "year": 1993, "venue": "", "link": null}, "BIBREF3": {"title": "A Genetic Algorithm with a Mixed Region Search for the Asymmetric Traveling Salesman Problem", "authors": [{"first": "G", "middle": [], "last": "Fang", "suffix": ""}, {"first": "L", "middle": [], "last": "Hongwei", "suffix": ""}, {"first": "Z", "middle": [], "last": "Qiang", "suffix": ""}, {"first": "C", "middle": [], "last": "Gang", "suffix": ""}], "year": 2003, "venue": "Computers and Operations Research", "link": null}, "BIBREF4": {"title": "An Evolutionary Algorithm Based on the Virus Theory of Evolution", "authors": [{"first": "N", "middle": [], "last": "Naoshi", "suffix": ""}, {"first": "K", "middle": [], "last": "Akinori", "suffix": ""}, {"first": "K", "middle": [], "last": "Kunio", "suffix": ""}], "year": 1999, "venue": "", "link": "92160160"}, "BIBREF5": {"title": "Virus-evolutionary particle swarm optimization algorithm", "authors": [{"first": "F", "middle": [], "last": "Gao", "suffix": ""}, {"first": "H", "middle": [], "last": "Liu", "suffix": ""}, {"first": "Q", "middle": [], "last": "Zhao", "suffix": ""}, {"first": "G", "middle": [], "last": "Cui", "suffix": ""}], "year": 2006, "venue": "", "link": "42481982"}, "BIBREF6": {"title": "Virus theory of evolution", "authors": [{"first": "N", "middle": [], "last": "Hideomi", "suffix": ""}, {"first": "S", "middle": [], "last": "Takashi", "suffix": ""}, {"first": "F", "middle": [], "last": "Takashi", "suffix": ""}], "year": 1986, "venue": "Bulletin of Yamanashi Medical University", "link": null}, "BIBREF7": {"title": "Lateral gene transfer", "authors": [{"first": "O", "middle": [], "last": "Zhaxybayeva", "suffix": ""}, {"first": "W", "middle": [], "last": "Doolittle", "suffix": ""}], "year": 2011, "venue": "Curr. Biol", "link": "14499247"}}, "ref_entries": {}}
{"paper_id": "18982114", "_pdf_hash": "5671677ddee95d06777b3f63d493faaedb204eb2", "abstract": [{"section": "Abstract", "text": "Background. The population in the UK is growing older and the number of elderly patients cared for on intensive care units (ICU) is increasing. This study was designed to identify risk factors for mortality in critically ill patients of .80 yr of age after surgery.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "", "text": "The population in the UK is growing older. In 1951, those aged 85 yr and more constituted only 1.6% of the population, in 2003 this had risen to 5.5%, and by 2031 it is predicted to grow to 7.9%.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "1 This ageing population is consuming increasing amounts of healthcare resources, with the number of elderly patients admitted to intensive care (ICU) growing progressively. 2 In the USA, more than half of all intensive care days are incurred by patients older than 65 yr of age. 3 Recent attempts at healthcare cost containment have fuelled discussions on rationing, using age as a discriminator. 4 Whether or not rationing based on age becomes explicit, age is already having a negative impact on the decision to admit to ICU. 5 -7 Justification for this is based on the physiological decline and the increase in co-morbidities seen with age. The incorrect assumption from these observations is that the chances of survival from a serious illness in the elderly are unlikely: outcome studies examining this suggest that age is not a good predictor of outcome on ICU. 8 -11 In this study, we sought to identify other factors taken from the first 48 h on ICU which would predict length of stay and mortality in the very elderly.", "cite_spans": [{"start": 174, "end": 175, "text": "2", "ref_id": "BIBREF0"}, {"start": 280, "end": 281, "text": "3", "ref_id": "BIBREF1"}, {"start": 398, "end": 399, "text": "4", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "", "text": "UK between April 1, 1998 and March 2003. The Royal United Hospital serves a population of 550 000 people and has an 11-bedded ICU. The ICU admits levels 2 and 3 patients (level 2 patients require close observation or support for a single failing organ system and include those stepping down from level 3; level 3 patients require advanced respiratory support or basic respiratory support plus support for two other organ systems). 12 All patients admitted to the ICU had their variables entered into a clinical database from which data were incorporated into the national case mix programme database coordinated by the Intensive Care National Audit and Research Centre. The target population for this study was patients more than 80 yr of age admitted to the ICU after a surgical procedure. Written consent and formal ethics committee approval were required as suggested by the chair of the committee.", "cite_spans": [{"start": 431, "end": 433, "text": "12", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "", "text": "We identified all patients aged 80 yr or more, who had been admitted to the ICU after a recent surgical procedure. The following data were then recorded for each patient: age, gender, nature of surgical procedure, urgency of surgery, Acute Physiology and Chronic Health Evaluation 2 (APACHE II) score, requirement for ventilation or i.v. vasoactive drugs in the first 24 h, and in the second 24 h on the ICU, survival status at ICU, and hospital discharge. The database was carefully reviewed and, where necessary, supplemental data were extracted from an operating theatre database and patients' paper records. For this study, patients undergoing elective or scheduled operations, as defined by the National Confidential Enquiry into Perioperative Deaths, were categorized as elective and those undergoing urgent or emergency operations were categorized as emergency.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Patients were recorded as 'receiving i.v. vasoactive drugs in their first and second 24 h period' if they received any vasoactive drug [defined as inotropes (e.g. dobutamine) or vasopressors (e.g. noradrenaline)] by infusion at any point during their first or second 24 h, respectively. Patients were recorded as 'receiving ventilation in their first and second 24 h period', if they received any intermittent positive pressure ventilation (including mandatory or assisted modes) via a tracheal tube or trachoestomy at any point during their first or second 24 h, respectively. Patients readmitted to the ICU had only their first admission data used for the APACHE II score and their admissions amalgamated for length of stay and survival. Patients who stayed on the ICU for less than 0.2 days and who did not generate an APACHE II score were not included.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "The primary outcome of the study was hospital mortality; secondary outcomes included ICU mortality and lengths of stay for hospital and ICU. ICU mortality was defined as survival of a patient at ultimate discharge from the ICU and hospital mortality was defined as survival at discharge or transfer from our hospital.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "All data were analysed using Stata Statistical software (version 9.1, # Statacorp). Continuous data were summarized using mean (SD) and medians (IQR). Univariable analysis using logistic regression was used to identify statistically significant prognostic covariates associated with hospital mortality and ICU length of stay (length of stay was divided above and below 3 days and the analysis conducted only on ICU survivors). The crude odds ratios and 95% confidence intervals were adjusted for potential confounding variables: gender, age, and severity of illness (measured using the APACHE II score). A further multivariable model was used to identify independent predictors of hospital mortality. All covariates found to be significant in the univariable analysis were included except APACHE II score. For each subgroup, multivariable analysis was performed twice, for the first 24 h of an admission (i.e. all patients) and secondly for those surviving into the second 24 h of an ICU admission. For length of stay, covariates with an odds ratio ,1 imply a trend towards a stay ,3 days on the ICU. Conversely for hospital mortality, covariates with an odds ratio .1 imply an increased chance of dying. For both univariable and multivariable analysis, differences were considered significant at P,0.05.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "During the study period, 275 patients more than 80 yr of age were identified as being admitted to the ICU after surgery. This represented 8.8% of all admissions during the 5 yr period. Eleven patients were excluded for being on the ICU for less than 0.2 days and did not generate an APACHE II score and nine admissions were recognized as being readmissions. Therefore, 255 patients were submitted for further analysis. The characteristics of the study population are summarized in Table 1 . The median age was 83.0 yr (IQR 81-86), 5.8% were more than 90 yr of age. Sixty per cent of admissions followed an emergency operation. There were 137 (53.7%) laparotomies, 54 (21.2%) For those surviving ICU (n\u00bc203), a univariate analysis was performed against length of stay on ICU, divided into above or below 3 days. Significant predictors of a stay on ICU for more than 3 days (after adjustment for age, sex, and severity of illness) included urgency of surgery (adjOR 0.42; 95% CI, 0.21 -0.83; P\u00bc0.01), use of ventilation on day 1 of an ICU admission (adjOR 0.41; 95% CI, 0.23 -0.83; P\u00bc0.01), use of ventilation on day 2 of an ICU admission (adjOR 0.18; 95% CI, 0.08 -0.41; P,0.001), use of i.v. vasoactive drugs on day 1 of an ICU admission (adjOR) 0.13; 95% CI, 0.06-0.27; P,0.001), use of i.v. vasoactive drugs on day 2 of an ICU admission (adjOR 0.1; 95% CI, 0.04 -0.22; P,0.001).", "cite_spans": [], "ref_spans": [{"start": 481, "end": 488, "text": "Table 1", "ref_id": "TABREF0"}]}, {"section": "Results", "text": "A multivariate analysis using logistic regression was used to evaluate the independent role of each covariate in hospital mortality. Multivariate analysis was conducted on all patients included in the study followed by a further three subgroups: after elective surgery, emergency surgery, and emergency laparotomy. All covariates included in the univariate analysis were submitted to multivariate analysis except APACHE II score because of co-linearity with some of the other covariates. The results of the multivariate analysis are shown in Tables 2 -5 .", "cite_spans": [], "ref_spans": [{"start": 542, "end": 553, "text": "Tables 2 -5", "ref_id": "TABREF2"}]}, {"section": "Results", "text": "For all the patients in the study, those who received i.v. vasoactive drugs within the first 24 h on ICU had a 4.3-fold increased mortality (OR 4.29; 95% CI, 2.35-7.84; P,0.001).", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "Patients who received vasoactive drugs on day 2 had a 3.6-fold increase in mortality (OR 3.63; 95% CI, 1.58-8.37; P,0.01). Patients who received ventilation extending into the second 24 h on ICU had a two-fold increase in mortality (OR 2.1; 95% CI, 0.94-4.7), which was just outside our limit of statistical significance (P\u00bc0.07).", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "After an elective operation, patients who received i.v. vasoactive drugs within the first 24 h on ICU had a 5.8-fold increase rate of death (OR 5.8; 95% CI, 1.86-18.10; P\u00bc0.002); for those who received ventilation on the second day of ICU mortality increased 6.9-fold (OR 6.88; 95% CI, 1.5-45.06; P\u00bc0.04).", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "After an emergency operation, patients who received i.v. vasoactive drugs within the first 24 h on ICU had a four-fold increased mortality rate (OR 4.06; 95% CI, 1.93 -8.53; P,0.001). Those who received vasoactive drugs on the second day of ICU had a four-fold increase in mortality (OR 3.96; 95% CI, 1.53 -10.21; P\u00bc0.004).", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "Finally, after an emergency laparotomy, patients who received i.v. vasoactive drugs within the first 24 h on ICU were 3.9 times more likely to die (OR 3.85; 95% CI, 1.64 -9.02; P\u00bc0.002). No significant prognostic factors were determined by the model on day 2.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "This study has shown a consistent association between the requirement of i.v. vasoactive drugs in the first 48 h and mortality. The use of i.v. vasoactive drugs in the first two 24 h periods after admission was associated with a 3.6 to 5.8-fold increase in the likelihood of dying, depending on the urgency of the surgery. Ventilation extending into the second 24 h was generally associated with an increase in mortality and after elective operations, a 6.9-fold increase in the risk of death. Notably, the use of ventilation in the first 24 h after admission was not associated with increased mortality. Length of stay beyond 3 days was associated with urgency of surgery, use of i.v. vasoactive drugs, and ventilation in the first two 24 h periods.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "Nowhere in these analyses did we find an association between increasing age and mortality. This confirms the previous studies on the critically ill elderly that age per se is not a strong predictor of death on ICU. Over the last decade, there has been increasing numbers of studies focusing on the outcome of the elderly admitted to ICU. Mortality rates have been found to be high. However, many studies have shown that the severity of illness rather than age itself is the strongest predictor of death. Chelluri and colleagues made a comparison between 54 patients aged 75 yr and older and 43 patients aged between 65 and 74 yr admitted to a mixed ICU. Long-term survival was similar between the two age groups but differed significantly between those with low and those with high APACHE II scores. 8 Another similar study by Wu and colleagues compared 130 patients aged 75 yr and older and those aged between 55 and 65 yr, admitted over a 30 month period to a medical ICU. Using logistic regression, the risk of dying was associated with a modified APACHE II score; increased age did not predict mortality. 9 A longitudinal study conducted by Kass and colleagues followed patients over the age of 85 yr admitted to a mixed ICU. In that study, age was not associated with mortality, instead severity of illness determined by the number of organs failing was significantly associated with outcome at: ICU discharge, 30 day post-hospital discharge, and 1 yr. In patients with more than two organ system failure, there was 100% mortality at 1 yr. 10 Severity of illness predicting death more accurately than age applies also to subgroups of patients on ICU. Shabot and colleagues evaluated 1039 trauma patients admitted to a surgical ICU, of which 9.5% were more than 65 yr of age. Age was a poor determinant of survival whereas Injury Severity Score (ISS), Trauma Score (TS), and the Simplified Acute Physiology Score (SAPS) were good determinants of survival.", "cite_spans": [{"start": 800, "end": 801, "text": "8", "ref_id": "BIBREF6"}, {"start": 1109, "end": 1110, "text": "9", "ref_id": "BIBREF7"}, {"start": 1545, "end": 1547, "text": "10", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "11", "text": "Few studies have concentrated specifically on the outcomes after surgery. Stephan and colleagues investigated the outcome of patients on a surgical ICU. They included 106 patients more than the age of 75 and found an ICU mortality of 31.0% and a hospital mortality of 42.4%. 13 Using a multivariate model, hospital mortality was associated with an ICU-acquired nosocomial infection, mechanical ventilation for more than 24 h, modified APACHE II score, duration of preoperative hospitalization, and underlying disease. Similarly, 140 patients more than the age of 90 were studied by Margulies and colleagues. 14 ICU mortality was found to be 4.3% and hospital mortality 17.1%. Udekwas and colleagues evaluated 672 patients aged 70 yr or older admitted to a surgical ICU. The study included 65.5% of elective cases and 50.7% of vascular surgical patients. Hospital mortality was 12.1% and was found to be associated with increasing age, severity of illness, and length of stay. 15 In patients older than 85 yr of age, Yosylius and colleagues found an ICU and hospital mortality of 29% and 45%, respectively. Although this was a mixed ICU population, 73% were admitted after an operation. Independent factors associated with mortality were: impaired level of consciousness, infection on admission, ICU-acquired infection, and severity of illness. 16 The gross variations in survival between the studies are explained by their heterogeneity. The studies differed in age criteria, severity of illness, types of operations, and country of origin.", "cite_spans": [{"start": 275, "end": 277, "text": "13", "ref_id": "BIBREF11"}, {"start": 976, "end": 978, "text": "15", "ref_id": "BIBREF13"}, {"start": 1344, "end": 1346, "text": "16", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "11", "text": "Our study has limitations. First, it is an observational study and therefore there is potential error from unmeasured confounding factors. Secondly, it is assumed in our study that patients who received vasoactive drugs or ventilation 'required it'. As this study is retrospective, the study can have had no influence on decisions to use these interventions and it is likely that the decision to use or not use these interventions is similar in both groups. Thirdly, our subgroup analysis is inevitably of smaller groups and fewer variables appear significantly associated with poorer outcome. Larger studies of these subgroups may be indicated. Lastly, the sickest patients may be subject to a self-fulfilling prophecy in that treatment is withdrawn before the full duration of the disease process. We did not measure the number of patients who had their treatment withdrawn before death. However, our results suggest that increased intervention (rather than withdrawal of such treatment) on days 1 and 2 after admission is associated with increased length of stay and mortality. The strength of the study lies in the external validation. The Royal United Hospital is a large general hospital and performs general surgical, orthopaedic, vascular, urological, and gynaecological operations. Similar cohorts of patients are admitted to many other hospitals across the UK.", "cite_spans": [], "ref_spans": []}, {"section": "11", "text": "In conclusion, this study found that for patients aged 80 and more, admitted to ICU after surgery the strongest association with mortality was the use of i.v. vasoactive drugs during both of their first 2 days on ICU. Length of stay on ICU increased after emergency surgery and in patients who received i.v. vasoactive drugs and ventilation on both the first and second days of admission. After elective operations, ventilation beyond the first 24 h was also a significant predictor of death. ", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Intensive care 1980-1995: change in patient characteristics, nursing workload and outcome", "authors": [{"first": "S", "middle": ["M"], "last": "Jakob", "suffix": ""}, {"first": "H", "middle": ["U"], "last": "Rothen", "suffix": ""}], "year": 1997, "venue": "Intensive Care Med", "link": "24642409"}, "BIBREF1": {"title": "Current and projected workforce requirements for care of the critically ill and patients with pulmonary disease: can we meet the requirements of an aging population", "authors": [{"first": "D", "middle": ["C"], "last": "Angus", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Kelley", "suffix": ""}, {"first": "R", "middle": ["J"], "last": "Schmitz", "suffix": ""}, {"first": "A", "middle": [], "last": "White", "suffix": ""}, {"first": "J", "middle": [], "last": "Popovich", "suffix": ""}], "year": 2000, "venue": "JAMA", "link": "19249133"}, "BIBREF2": {"title": "Age as a criterion for rationing health care", "authors": [{"first": "N", "middle": ["G"], "last": "Levinsky", "suffix": ""}], "year": 1990, "venue": "N Engl J Med", "link": "6571484"}, "BIBREF3": {"title": "Age as a factor in critical care unit admissions", "authors": [{"first": "T", "middle": ["J"], "last": "Nuckton", "suffix": ""}, {"first": "N", "middle": ["D"], "last": "List", "suffix": ""}], "year": 1995, "venue": "Arch Intern Med", "link": "21185397"}, "BIBREF4": {"title": "Triaging patients to the ICU: a pilot study of factors influencing admission decisions and patient outcomes", "authors": [{"first": "M", "middle": [], "last": "Garrouste-Orgeas", "suffix": ""}, {"first": "L", "middle": [], "last": "Montuclard", "suffix": ""}, {"first": "J-F", "middle": [], "last": "Timsit", "suffix": ""}, {"first": "B", "middle": [], "last": "Misset", "suffix": ""}, {"first": "M", "middle": [], "last": "Christias", "suffix": ""}, {"first": "J", "middle": [], "last": "Carlet", "suffix": ""}], "year": 2003, "venue": "Intensive Care Med", "link": "23709312"}, "BIBREF5": {"title": "Patient age and decisions to withhold life sustaining treatments from seriously ill, hospitalized adults", "authors": [{"first": "M", "middle": ["B"], "last": "Hamel", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Teno", "suffix": ""}, {"first": "L", "middle": [], "last": "Goldman", "suffix": ""}], "year": 1999, "venue": "Ann Intern Med", "link": "41240560"}, "BIBREF6": {"title": "Long-term outcome of critically elderly patients requiring intensive care", "authors": [{"first": "L", "middle": [], "last": "Chelluri", "suffix": ""}, {"first": "M", "middle": ["R"], "last": "Pinsky", "suffix": ""}, {"first": "M", "middle": ["P"], "last": "Donahoe", "suffix": ""}, {"first": "A", "middle": [], "last": "Grenvik", "suffix": ""}], "year": 1993, "venue": "JAMA", "link": "24810281"}, "BIBREF7": {"title": "Are elderly people less responsive to intensive care?", "authors": [{"first": "A", "middle": ["W"], "last": "Wu", "suffix": ""}, {"first": "H", "middle": ["R"], "last": "Rubin", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Rosen", "suffix": ""}], "year": 1990, "venue": "JAGS", "link": "25758115"}, "BIBREF8": {"title": "Intensive care unit outcome in the very elderly", "authors": [{"first": "J", "middle": ["E"], "last": "Kass", "suffix": ""}, {"first": "R", "middle": ["J"], "last": "Castriotta", "suffix": ""}, {"first": "F", "middle": [], "last": "Malakoff", "suffix": ""}], "year": 1992, "venue": "Crit Care Med", "link": "72876637"}, "BIBREF9": {"title": "Outcome from critical care in the oldest old trauma patients", "authors": [{"first": "M", "middle": ["M"], "last": "Shabot", "suffix": ""}, {"first": "C", "middle": ["L"], "last": "Johnson", "suffix": ""}], "year": 1995, "venue": "J Trauma", "link": "8898916"}, "BIBREF10": {"title": "Level of care document", "authors": [], "year": 2007, "venue": "", "link": null}, "BIBREF11": {"title": "Nosocomial infections and outcome of critically ill elderly patients after surgery", "authors": [{"first": "F", "middle": [], "last": "Stephan", "suffix": ""}, {"first": "A", "middle": [], "last": "Cheffi", "suffix": ""}, {"first": "F", "middle": [], "last": "Bonnet", "suffix": ""}], "year": 2001, "venue": "Anesthesiology", "link": "23724578"}, "BIBREF12": {"title": "Surgical intensive care in the nonagenarian", "authors": [{"first": "D", "middle": ["R"], "last": "Margulies", "suffix": ""}, {"first": "M", "middle": ["E"], "last": "Lekawa", "suffix": ""}, {"first": "S", "middle": [], "last": "Bjerke", "suffix": ""}, {"first": "J", "middle": ["R"], "last": "Hiatt", "suffix": ""}, {"first": "M", "middle": ["M"], "last": "Shabot", "suffix": ""}], "year": 1993, "venue": "Arch Surg", "link": null}, "BIBREF13": {"title": "Quality of life and functional level in elderly patients surviving surgical intensive care", "authors": [{"first": "P", "middle": [], "last": "Udekwu", "suffix": ""}, {"first": "B", "middle": [], "last": "Gurkin", "suffix": ""}, {"first": "D", "middle": [], "last": "Oller", "suffix": ""}, {"first": "L", "middle": [], "last": "Lapio", "suffix": ""}, {"first": "J", "middle": [], "last": "Bourbina", "suffix": ""}], "year": 2001, "venue": "J Am Coll Surg", "link": "38805115"}, "BIBREF14": {"title": "Determinants of outcome in elderly patients admitted to the intensive care unit", "authors": [{"first": "S", "middle": [], "last": "Yosylius", "suffix": ""}, {"first": "J", "middle": [], "last": "Sipylaite", "suffix": ""}, {"first": "J", "middle": [], "last": "Ivaskevicius", "suffix": ""}], "year": 2005, "venue": "Age Ageing", "link": "1351469"}, "BIBREF15": {"title": "Critically ill octagenarians", "authors": [], "year": "", "venue": "", "link": null}}, "ref_entries": {"TABREF0": {"text": "Baseline characteristics and outcome. LOS, length of stay", "type": "table"}, "TABREF1": {"text": "abdominal aortic aneurysm repairs, 8 (3.2%) other vascular cases, 25 (9.8%) orthopaedic cases, and 31 (12.1%) other cases. As shown in Table 1, the overall ICU and hospital mortality was 20.4% and 33.3%, respectively. For patients who received i.v. vasoactive drugs on day 1 of ICU admis- sion, their ICU mortality was 39.8% and hospital mortality was 54.4%. For patients receiving i.v. vasoactive drugs on day 2 of their ICU admission, their ICU mortality was 44.7% and their hospital mortality was 60.5%. The unadjusted, univariate analysis revealed the follow- ing significant covariates: urgency of surgery, type of operation, APACHE II score, requirement for ventilation on day 1, use of ventilation on day 2 of an ICU admission, and use of vasoactive drugs on days 1 and 2 of an ICU admission. After adjusting for age, sex, and severity of illness the following remained significant: urgency of surgery [adjusted OR (adjOR) 2.79; 95% CI, 1.49 -5.2; P\u00bc0.001], operation type (e.g. AAA, adjOR 0.31; 95% CI, 0.13 -0.70; P\u00bc0.001), use of i.v. vasoactive drugs on day 1 of an ICU admission (adjOR 3.81; 95% CI, 2.11- 6.88; P,0.001), use of i.v. vasoactive drugs on day 2 of an ICU admission (adjOR 5.81; 95% CI, 3.1-10.89; P,0.001), and use of ventilation on day 2 of an ICU admission (adjOR 3.73; 95% CI, 1.95 -7.12; P,0.001).", "type": "table"}, "TABREF2": {"text": "Multivariate analysis of hospital mortality in all patients. Odds ratios (95% CI)", "type": "table"}, "TABREF3": {"text": "Multivariate analysis of hospital mortality in all elective patients.", "type": "table"}, "TABREF4": {"text": "", "type": "table"}, "TABREF5": {"text": "Multivariate analysis of hospital mortality in emergency laparotomy patients. Odds ratio (95% CI)", "type": "table"}}}
{"paper_id": "18982127", "_pdf_hash": "6254cf26f7e2ca76decce8198ed2ee73e5cdf046", "abstract": [{"section": "Abstract", "text": "Abstract. Recently a new graph convexity was introduced, arising from Steiner intervals in graphs that are a natural generalization of geodesic intervals. The Steiner tree of a set W on k vertices in a connected graph G is a tree with the smallest number of edges in G that contains all vertices of W . The Steiner interval I(W ) of W consists of all vertices in G that lie on some Steiner tree with respect to W . Moreover, a set S of vertices in a graph G is k-Steiner convex, denoted g k -convex, if the Steiner interval I(W ) of every set W on k vertices is contained in S. In this paper we consider two types of local convexities. In particular, for every k > 3, we characterize graphs with g k -convex closed neighborhoods around all vertices of the graph. Then we follow with a characterization of graphs with g 4 -convex closed neighborhoods around all g 4 -convex sets of the graph.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "INTRODUCTION", "text": "The study of abstract convexity began in the early fifties and is extensively studied in van de Vel's monograph [14] , where the interval convexity is used for introducing it. The theory of axiomatic convexity is based on just three natural conditions, imposed on a family of subsets of a given set. Definition 1. [14] . A family C of subsets of a set X is called a convexity on X if (C1) the empty set \u2205 and universal set X are in C;", "cite_spans": [{"start": 112, "end": 116, "text": "[14]", "ref_id": "BIBREF18"}, {"start": 314, "end": 318, "text": "[14]", "ref_id": "BIBREF18"}], "ref_spans": []}, {"section": "(C2) C is stable for intersections, that is, if D \u2286 C is non-empty, then D is in C;", "text": "(C3) C is stable for nested unions, that is, if D \u2286 C is non-empty and totally ordered by inclusion, then D is in C.", "cite_spans": [], "ref_spans": []}, {"section": "(C2) C is stable for intersections, that is, if D \u2286 C is non-empty, then D is in C;", "text": "The pair (X, C) is called a convex structure (convexity space) and the members of C are called convex sets.", "cite_spans": [], "ref_spans": []}, {"section": "1", "text": "From axioms (C1) and (C2) it follows that for any subset A of a convex structure X there exists the smallest convex set [A] = {C; A \u2286 C \u2208 C} that contains A and it is called the convex hull of A.", "cite_spans": [], "ref_spans": []}, {"section": "1", "text": "Several natural convexities were studied also in graphs, and problems such as determining the convex hull of points and sets in graphs have been investigated. The most known graph convexities are defined using the intervals of a certain type, such as the geodesic or the monophonic intervals. The corresponding convexities, introduced by Farber and Jamison [8] , are the geodesic and the monophonic convexities, in which the convex sets are defined simply as the sets S in which all intervals (of a certain type) between elements from S lie in S. So a set S of vertices in a graph G is g-convex (m-convex) if it contains the geodesic (monophonic) interval between every pair of vertices in S. For a more extensive study on this topic see [5] .", "cite_spans": [{"start": 357, "end": 360, "text": "[8]", "ref_id": "BIBREF12"}, {"start": 738, "end": 741, "text": "[5]", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "1", "text": "Recently C\u00e1ceres and Oellermann [3] introduced a new convexity in graphs that is defined in terms of Steiner intervals in graphs. Recall that for a connected graph G, the Steiner distance d(S) of a set S with at least two vertices is the size of the smallest connected subgraph of G containing S. Such connected subgraph is a tree and it is called Steiner tree for S. The Steiner interval I(S) of S is the set of all vertices that lie on some Steiner tree for S. Steiner intervals have been studied in several papers, e.g. [1, 10, 13] . Now, a set S of vertices in a graph G is k-Steiner convex [3] , denoted by g k -convex, if the Steiner interval I(R) of every set R on k vertices is contained in S, that is I(R) \u2286 S. Note that a set S is g 2 -convex if and only if it is g-convex, thus the Steiner convexity is a natural generalization of the geodesic convexity.", "cite_spans": [{"start": 32, "end": 35, "text": "[3]", "ref_id": "BIBREF7"}, {"start": 523, "end": 526, "text": "[1,", "ref_id": "BIBREF5"}, {"start": 527, "end": 530, "text": "10,", "ref_id": "BIBREF14"}, {"start": 531, "end": 534, "text": "13]", "ref_id": "BIBREF17"}, {"start": 595, "end": 598, "text": "[3]", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "1", "text": "Several properties of convexities have been investigated. One of them involves extreme points, where a point x of a convex set X is an extreme point of X if X \u2212{x} is convex. The problem in this case is to find characterizations of graphs for which a given convexity presents a convex geometry, i.e., a convexity where each convex set is the convex hull of its extreme points. Such characterizations for the g-and m-convexity are given in [8] , for the g 3 -convexity in [12] and for the m-convexity in [4] .", "cite_spans": [{"start": 439, "end": 442, "text": "[8]", "ref_id": "BIBREF12"}, {"start": 471, "end": 475, "text": "[12]", "ref_id": "BIBREF16"}, {"start": 503, "end": 506, "text": "[4]", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "1", "text": "Farber and Jamison [9] introduced local convexities of graphs and investigated them for geodesic and monophonic convexities. They introduced four types of local convexities, arising from convexities of j-balls of vertices and sets, respectively.", "cite_spans": [{"start": 19, "end": 22, "text": "[9]", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "1", "text": "First some notations. In this paper all graphs will be finite with no loops and multiple edges. Let G = (V, E) be a graph and x, y \u2208 V . We will write x \u223c y if x and y are adjacent in G and x y, otherwise. The distance d G (x, y) between vertices x and y is the length of an x, y-geodesic, i.e., a shortest path between x and y in G. Now we present the above mentioned four local conditions which can be investigated with respect to any convexity associated with the vertex set of a graph G = (V, E).", "cite_spans": [], "ref_spans": []}, {"section": "1", "text": "is convex for every v \u2208 V and every j \u2265 1.", "cite_spans": [], "ref_spans": []}, {"section": "1", "text": "is convex for every convex set S \u2286 V and every j \u2265 1.", "cite_spans": [], "ref_spans": []}, {"section": "1", "text": "It is not hard to see that graphs in which N [S] is convex for every convex set S \u2286 V are exactly the graphs in which N j [S] is convex for every convex set S \u2286 V and every j \u2265 1 in terms of any convexity in graphs, see [6] . Thus it suffices to consider only the first three types of local convexities. Henning, Nielsen and Oellermann recently studied the same local convexities for the g 3 -convexity [7] . They characterized the graphs in which N [v] is g 3 -convex for every vertex v of a graph and the graphs in which N [S] is g 3 -convex for every g 3 -convex set S of a graph. Necessary conditions for the family of g 3 -convex sets to satisfy the local convexity property 2 are given in [7] . It was subsequently shown in [2] that these conditions are also sufficient. A generalization of the m-convexity based on minimal trees between three or more vertices was introduced in [4] and the corresponding local convexity properties have been investigated in [11] . For k > 3, local k-Steiner convexities have not been studied yet, so this problem will be the main topic of this paper.", "cite_spans": [{"start": 220, "end": 223, "text": "[6]", "ref_id": "BIBREF10"}, {"start": 730, "end": 733, "text": "[2]", "ref_id": "BIBREF6"}, {"start": 885, "end": 888, "text": "[4]", "ref_id": "BIBREF8"}, {"start": 964, "end": 968, "text": "[11]", "ref_id": "BIBREF15"}], "ref_spans": []}, {"section": "1", "text": "The paper is organized as follows. In Section 2 we prove several lemmas that are used in the rest of the paper. Then, in Section 3, we characterize graphs in which N [v] is g n -convex for every vertex v of G. We present such characterization for every n > 1. Then we follow with a section in which we characterize graphs with g 4 -convex closed neighborhoods around g 4 -convex sets. Finally we give some open problems about local Steiner convexities.", "cite_spans": [], "ref_spans": []}, {"section": "PRELIMINARY RESULTS", "text": "In this section we present some preliminary observations and prove several lemmas, which will be used during the paper.", "cite_spans": [], "ref_spans": []}, {"section": "PRELIMINARY RESULTS", "text": "A subdivision of a graph G is a graph obtained from G by inserting vertices of degree 2 into the edges of the graph.", "cite_spans": [], "ref_spans": []}, {"section": "PRELIMINARY RESULTS", "text": "Let G be a graph and T an x 1 , x n -path of G. To simplify notation, we denote such path by T [x 1 , x n ]. The notation T [x 1 , x i , x j , x n ] specifies that the path T goes from x 1 to x n and passes through x i and x j , where x i is before x j on this path.", "cite_spans": [], "ref_spans": []}, {"section": "PRELIMINARY RESULTS", "text": "First we describe the structure of any Steiner tree of a set R on four vertices. It is readily seen that a Steiner tree for a set of four vertices is isomorphic to one of the trees described in the following lemma. \u2022 a subdivision of K 1,4 ;", "cite_spans": [], "ref_spans": []}, {"section": "PRELIMINARY RESULTS", "text": "\u2022 a tree with four leaves, two vertices of degree 3 and some vertices (if any) of degree 2;", "cite_spans": [], "ref_spans": []}, {"section": "PRELIMINARY RESULTS", "text": "\u2022 a path.", "cite_spans": [], "ref_spans": []}, {"section": "PRELIMINARY RESULTS", "text": "Let G be a graph, v \u2208 V (G) and let S be an arbitrary g 4 The next two lemmas give some properties of g 4 -convex sets whose closed neighborhoods are not g 4 -convex. Similar results were established for g 3 -convex sets [7] . A graph G that contains no graph F as an induced subgraph is called an F -free graph. Furthermore, if G contains no graph from a family F as induced subgraph, then we say that G is F -free.", "cite_spans": [{"start": 56, "end": 57, "text": "4", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "Lemma 4. Let G be a connected P 5 -free graph which contains a g", "text": "4 -convex set S such that N [S] is not g 4 -convex. Let R = {a, b, c, d} \u2286 N [", "cite_spans": [], "ref_spans": []}, {"section": "S] be a set with the smallest d(R) such that I(R) N [S]. Then for any Steiner tree T of R with", "text": "V (T ) N [S], we have V (T ) \u2229 N [S] = R.", "cite_spans": [], "ref_spans": []}, {"section": "Proof.", "text": "Assume, to the contrary, that there exists ", "cite_spans": [], "ref_spans": []}, {"section": "GRAPHS FOR WHICH CLOSED NEIGHBORHOODS OF VERTICES ARE g n -CONVEX", "text": "In this section we use forbidden induced subgraphs to characterize graph", "cite_spans": [], "ref_spans": []}, {"section": "GRAPHS FOR WHICH CLOSED NEIGHBORHOODS OF VERTICES ARE g n -CONVEX", "text": "Theorem 5. Let G = (V, E) be a graph and n \u2265 2. Then the following assertions are equivalent:", "cite_spans": [], "ref_spans": []}, {"section": "G contains no induced subgraph G , where G is a graph with", "text": "Proof. Assume first that G satisfies Condition 1 of Theorem 5. Suppose that G contains an induced subgraph G described in Condition 2 of Theorem 5 and let", "cite_spans": [], "ref_spans": []}, {"section": "G contains no induced subgraph G , where G is a graph with", "text": "Thus R contains n vertices. From Statements (2c) and (2d) it follows that d(R) = n. Using Statement (2e), we can find a tree T with V (T ) = V (G ) \\ {v 1 }, which is a Steiner tree for R and is not contained in", "cite_spans": [], "ref_spans": []}, {"section": "G contains no induced subgraph G , where G is a graph with", "text": "For the converse suppose that G satisfies Condition 2 of Theorem 5.", "cite_spans": [], "ref_spans": []}, {"section": "G contains no induced subgraph G , where G is a graph with", "text": "Then G satisfies all the statements from Condition 2, which is a contradiction.", "cite_spans": [], "ref_spans": []}, {"section": "G contains no induced subgraph G , where G is a graph with", "text": "The above theorem gives rise to the following problem.", "cite_spans": [], "ref_spans": []}, {"section": "Problem 1.", "text": "Is there a characterization of graphs which satisfies any other type of local n-Steiner convexities, for n > 3?", "cite_spans": [], "ref_spans": []}, {"section": "Problem 1.", "text": "In the following section we restrict ourselves to the case: n = 4.", "cite_spans": [], "ref_spans": []}, {"section": "GRAPHS FOR WHICH CLOSED NEIGHBORHOODS OF g 4 -CONVEX SETS ARE g 4 -CONVEX", "text": "In this section we characterize graphs with g 4 -convex closed neighborhoods around g 4 -convex sets using forbidden induced subgraphs. To prove the main theorem we need the following result.", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 6. Let G be a connected F -free graph which contains a g 4 -convex set", "text": "S such that N [S] is not g 4 -convex. Let R = {a, b, c, d} \u2286 N [S] be a set with the smallest d(R) such that I(R) N [S]. Then R \u2229 S = \u2205.", "cite_spans": [], "ref_spans": []}, {"section": "Proof.", "text": "Let T be a Steiner tree for R with V (T ) Figure (c) ). Thus we may assume that d \u223c c. Again using the fact that G is P 5 -free we get that G contains at least one edge from {ad , bd }. Depending on which of those two edges appear in G, we get one of forbidden induced subgraphs from F (shown in Figure (c) or (e)) or from F \\ F. Therefore we may assume that x a and x \u223c b. Since G is P 5 -free there is at least one edge from {ad , bd }. If a \u223c d , then using the fact that G is P 5 -free, we get that c \u223c d which implies that G contains one of forbidden induced subgraphs from F (shown in Figure (c ", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 7. If a connected graph G = (V, E) is F -free then N [S] is g 4 -convex for every g 4 -convex set S.", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Proof.", "text": "Suppose that G is F -free. Let S \u2286 V be an arbitrary g 4 -convex set in G. , x a is not adjacent to at least one vertex from {b, c, d},  say b. Therefore the vertices a , a, x a , x, b , c either induce a forbidden subgraph from F (shown in Figure (c) ) or they induce a subgraph that contains an induced P 5 , which both leads to a contradiction. Thus d(R) = 4, i.e., all vertices from R are adjacent to x. Since G is F -free not all vertices from R can be adjacent to a . We may assume that b a . Let b be a neighbor of b in S. Since G is P 5 -free there is at least one edge from {a b , ab } in G. First suppose that a \u223c b . Then G contains a forbidden induced subgraph from F (shown in Figure ( Figure (d) ) or from F \\ F. Therefore G contains exactly one edge from {d a, d b} and exactly one edge from {xa, xb} (two edges from either set would give a forbidden subgraph from F \\ F). Since a and b appear symmetrically it is enough to check two cases. In the first case let x and d have the same neighbor from {a, b}, which implies that G contains a forbidden subgraph from F (shown in Figure  ( Figure (c)) , a contradiction. Hence we may assume that d(R) = 4. We distinguish two cases.", "cite_spans": [], "ref_spans": []}, {"section": "Proof.", "text": "Case 1: a z. Since G is P 5 -free, d is adjacent to at least one vertex from {a, b} .  If a \u223c d , then the vertices a, b, z, d, d , c induce in G one of the forbidden subgraphs from F (shown in Figure (a) or (c) Proof. Let G be a connected graph in which N [S] is a g 4 -convex set for every g 4 -convex set S. Let v \u2208 V (G). As S = {v} is g 4 -convex, it follows from Theorem 5 that G is (F \\ F)-free. Suppose now that G contains a graph H from family F as induced subgraph. Let S be the set of vertices in H marked with square in Figure  . Since the set S contains at most three vertices it is a g 4 -convex set and it is easy to check that N [S] is not a g 4 -convex set, a contradiction. Thus G is also an F -free graph.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "A connected graph G is F -free if and only if", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF1": {"title": "It is easy to see that if in a graph G = (V, E), N [S] is g 4 -convex for every g 4 -convex set S, then N j", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF2": {"title": "If G = (V, E) is a connected F -free graph, then N j", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF3": {"title": "Since, for example, P 5 is not F -free, but N j", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF4": {"title": "Is there any characterization of those graphs G, in which, for every j \u2265 1", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF5": {"title": "Narasimha-Shenoi and A. Tepeh Horvat, Steiner intervals, geodesic intervals, and betweenness", "authors": [{"first": "B", "middle": [], "last": "Bre\u0161ar", "suffix": ""}, {"first": "M", "middle": [], "last": "Changat", "suffix": ""}, {"first": "J", "middle": [], "last": "Mathews", "suffix": ""}, {"first": "I", "middle": [], "last": "Peterin", "suffix": ""}, {"first": "P", "middle": ["G"], "last": "", "suffix": ""}], "year": 2009, "venue": "Discrete Math", "link": null}, "BIBREF6": {"title": "On a local 3-Steiner convexity", "authors": [{"first": "B", "middle": [], "last": "Bre\u0161ar", "suffix": ""}, {"first": "T", "middle": [], "last": "Gologranc", "suffix": ""}], "year": 2011, "venue": "European J. Combin", "link": "10095176"}, "BIBREF7": {"title": "On 3-Steiner simplicial orderings", "authors": [{"first": "J", "middle": [], "last": "C\u00e1ceres", "suffix": ""}, {"first": "O", "middle": ["R"], "last": "Oellermann", "suffix": ""}], "year": 2009, "venue": "Discrete Math", "link": "22241926"}, "BIBREF8": {"title": "Minimal trees and monophonic convexity", "authors": [{"first": "J", "middle": [], "last": "C\u00e1ceres", "suffix": ""}, {"first": "O", "middle": ["R"], "last": "Oellermann", "suffix": ""}, {"first": "M", "middle": ["L"], "last": "Puertas", "suffix": ""}], "year": 2012, "venue": "Discuss. Math. Graph Theory", "link": "10259494"}, "BIBREF9": {"title": "Convexities related to path properties on graphs", "authors": [{"first": "M", "middle": [], "last": "Changat", "suffix": ""}, {"first": "H", "middle": ["M"], "last": "Mulder", "suffix": ""}, {"first": "G", "middle": [], "last": "Sierksma", "suffix": ""}], "year": 2005, "venue": "Discrete Math", "link": "6739367"}, "BIBREF10": {"title": "Convexity and HHD-free graphs", "authors": [{"first": "F", "middle": ["F"], "last": "Dragan", "suffix": ""}, {"first": "F", "middle": [], "last": "Nicolai", "suffix": ""}, {"first": "A", "middle": [], "last": "Brandst\u00e4dt", "suffix": ""}], "year": 1999, "venue": "SIAM J. Discrete Math", "link": "12220557"}, "BIBREF12": {"title": "Convexity in graphs and hypergraphs", "authors": [{"first": "M", "middle": [], "last": "Farber", "suffix": ""}, {"first": "R", "middle": ["E"], "last": "Jamison", "suffix": ""}], "year": 1986, "venue": "", "link": "120602845"}, "BIBREF13": {"title": "On local convexity in graphs", "authors": [{"first": "M", "middle": [], "last": "Farber", "suffix": ""}, {"first": "R", "middle": ["E"], "last": "Jamison", "suffix": ""}], "year": 1987, "venue": "Discrete Math", "link": "7887974"}, "BIBREF14": {"title": "Steiner intervals in graphs", "authors": [{"first": "E", "middle": [], "last": "Kubicka", "suffix": ""}, {"first": "G", "middle": [], "last": "Kubicki", "suffix": ""}, {"first": "O", "middle": ["R"], "last": "Oellermann", "suffix": ""}], "year": 1998, "venue": "Discrete Math", "link": "7102051"}, "BIBREF15": {"title": "Local 3-monophonic convexity", "authors": [{"first": "M", "middle": ["H"], "last": "Nielsen", "suffix": ""}, {"first": "O", "middle": ["R"], "last": "Oellermann", "suffix": ""}], "year": 2012, "venue": "J. Combin. Math. and Combin. Comput", "link": null}, "BIBREF16": {"title": "Steiner trees and convex geometries", "authors": [{"first": "M", "middle": ["H"], "last": "Nielsen", "suffix": ""}, {"first": "O", "middle": ["R"], "last": "Oellermann", "suffix": ""}], "year": 2009, "venue": "SIAM J. Discrete Math", "link": "5273153"}, "BIBREF17": {"title": "Steiner intervals and Steiner geodetic numbers in distance-hereditary graphs", "authors": [{"first": "O", "middle": ["R"], "last": "Oellermann", "suffix": ""}, {"first": "M", "middle": ["L"], "last": "Puertas", "suffix": ""}], "year": 2007, "venue": "Discrete Math", "link": "449270"}, "BIBREF18": {"title": "Theory of Convex Structures", "authors": [{"first": "M", "middle": ["J L"], "last": "Van De", "suffix": ""}, {"first": "", "middle": [], "last": "Vel", "suffix": ""}], "year": 1993, "venue": "", "link": "119062322"}}, "ref_entries": {"FIGREF0": {"text": "The set N (v) = {x \u2208 V : x \u223c v} is the open neighborhood and N [v] = N (v) \u222a {v} the closed neighborhood of v. For a set S we define its open neighborhood as N (S) = x\u2208S N (x) and its closed neighborhood as N [S] = N (S) \u222a S. For k \u2265 1, the k-ball N k [v] of v is the set of all vertices at distance at most k from v in G and the k-ball N k [S] of a set S \u2286 V is the set of all vertices at distance at most k from some vertex of S in G. For a set S of vertices of a graph G we denote with G[S] the subgraph of G induced by the vertices of S.", "type": "figure"}, "FIGREF1": {"text": "Let G be a connected graph and R = {a, b, c, d} \u2286 V (G). Then a Steiner tree T of R is one of the following graphs:", "type": "figure"}, "FIGREF2": {"text": "-convex set such that N [S] is not g 4 -convex. From the definition of g 4 -convexity it follows that there exists a set R = {a, b, c, d} of four vertices in N [S] such that I(R) N [S]. Thus I({a, b, c, d}) {a, b, c, d}, which implies that the subgraph of G induced by the vertices of R is not connected, and therefore d(R) \u2265 4.", "type": "figure"}, "FIGREF3": {"text": "Let G be a connected graph that contains a g 4 -convex set S such that N [S] is not g 4 -convex. Let R = {a, b, c, d} \u2286 N [S] be a set with the smallest d(R) such that I(R) N [S]. Then for any Steiner tree T of R with V (T ) N [S] and each y \u2208 R the neighbors of y (if any) in V (T ) \\ R are not in N [S]. Proof. Suppose some vertex in R, say a, has a neighbor a / \u2208 R in T and assume that a \u2208 N [S]. Since V (T ) N [S], G[R] is disconnected and T contains at least one vertex x / \u2208 N [S]. If a is a leaf of T , then T \u2212a is a Steiner tree for {a , b, c, d} \u2286 N [S] of a smaller size than T , containing a vertex not in N [S], contrary to our choice of R. Hence a is not a leaf of T . Therefore, using Lemma 2, T is either a path or a subdivision of K 1,3 with leaves b, c and d. First let T be a path. Without loss of generality let T = T [b, a, c, d]. Note that the neighbors of b and d in T are either from R or V \\ N [S], otherwise we get a contradiction with the choice of R (in the same way as we did in the case where a is a leaf of T , since now b and d are leaves of T ). First suppose that the neighbor of b in T is from V \\ N [S]. Then the b, c-path of T is a Steiner tree for {b, a, a , c} \u2286 N [S] of smaller size than T , containing a vertex not in N [S], contrary to our choice of R. Hence a is the neighbor of b in T . In this case the a, d-path of T is a Steiner tree for {a, a , c, d} \u2286 N [S] with smaller size than T containing a vertex not in N [S], contrary to our choice of R. Finally let T be a subdivision of K 1,3 with leaves b, c and d. Let z be the vertex of degree 3 in T and let x b , x c and x d be the neighbors of b, c and d on T , respectively. Again it is clear that x b , x c , x d are from R or V \\N [S], otherwise we get a contradiction with the choice of R. Furthermore, if one of these three vertices is from R, say x b = a, then the tree obtained from T by deleting b is a Steiner tree for {a, a , c, d} \u2286 N [S] with smaller size than T , containing a vertex not in N [S], which is a contradiction. Hence x b , x c , x d \u2208 V \\ N [S]. Without loss of generality let a lies on the b, c-path of T (if a lies on the b, d-path of T then we change the role of c and d). If a lies on the z, d-path of T then the subtree of T obtained from T by deleting the a , d-path of T except a is a Steiner tree for {a, a , b, c} \u2286 N [S] of a smaller size than T , containing a vertex not in N [S], contrary to our choice of R. Let now a lies on the b, c-path of T . If a or a is the vertex of degree 3 in T then the b, c-path of T is a Steiner tree for {a, a , b, c} \u2286 N [S] of a smaller size than T , containing a vertex not in N [S], contrary to our choice of R. Hence both a and a lie either on the b, z-or on the c, z-path of T . Without loss of generality let a, a lie on the b, z-path of T and without loss of generality let a lies on the b, a -path of T (otherwise we change the role of a and a ). Hence the subtree of T obtained from T by deleting all verteices, except a, on the b, a-path of T is a Steiner tree for {a, a , c, d} \u2286 N [S] of a smaller size than T , containing a vertex not in N [S], which is a final contradiction.", "type": "figure"}, "FIGREF4": {"text": "y is a leaf of T and the neighbor x y of y in T is from R then the tree obtained from T by the removal of y is a Steiner tree for (R \\ {y}) \u222a {a } \u2286 N [S] of a smaller size than T , containing a vertex not in N [S], contrary to our choice of R. Therefore x y \u2208 V \\ N [S] for every leaf y of T . Now we distinguish three cases with respect to Lemma 2. First let T be a path T [a, b, c, d]. Without loss of generality let a lies on the a, c- path of T . Then the a, c-path of T is a Steiner tree for {a, b, c, a } of smaller size than T containing a vertex not in N [S], a contradiction. Now let T be a subdivision of K 1,3 with leaves a, b, c and with z being the vertex of degree 3, or let T be a subdivision of K 1,4 with leaves a, b, c, d and with z being the vertex of degree 4. Without loss of generality let a lies on the a, z-path of T . Then the tree obtained from T by the removal of the a, a -path in T , with the exception of a (or the a, d-path in T with the exception of d if d lies on the a, a -path of T ) is a Steiner tree for {a , b, c, d} \u2286 N [S] of smaller size than T containing a vertex not in N [S], a contradiction. Finally let T be a tree with four leaves, two vertices z 1 , z 2 of degree 3 and maybe some other vertices of degree 2. Furthermore let z 1 lies on the a, z 2 -and b, z 2 -path of T . Since G is P 5 -free and T is a Steiner tree, a cannot lies on the z 1 , z 2 -path of T . Without loss of generality let a lies on the a, z 1 -path of T . Then the tree obtained from T by the removal of a, a -path of T , with the exception of a is a Steiner tree for {a , b, c, d} \u2286 N [S] of smaller size than T containing a vertex not in N [S], a contradiction. Lemma 4 says that if there is a Steiner tree T of a set R \u2286 N [S], with |R| = 4 and if V (T ) N [S] then all vertices of T except those form R are outside N [S]. That is, vertices from R are the only vertices of T that lie in N [S].", "type": "figure"}, "FIGREF5": {"text": "Fig. 1. Family F of forbidden induced subgraphs, where bold edges are optional (in F we have all combinations of graphs with or without such edges).", "type": "figure"}, "FIGREF6": {"text": "with at most three edges and d(R) \u2265 4. Since G is a P 5 -free it follows from Lemma 4 that V (T ) \u2229 N [S] = R. If R is an independent set of vertices in T , then it follows from Lemma 3 that a neighbor of y \u2208 R is from V \\ N [S], and so y belongs to N [S] \\ S. Now we will distinguish three cases with respect to the number of edges in G[R]. First let G[R] contain three edges. Since G[R] is disconnected one vertex from R, say d, is isolated and hence from N [S] \\ S, and the other three vertices from R form a triangle. Let d be a neighbor of d in S. For the purpose of contradiction suppose that at least one vertex from {a, b, c} is from S. Note that a vertex from S can not be adjacent to a vertex from V \\N [S]. Since a, b, c induce a triangle, there exists a Steiner tree T for R which is a path and with V (T ) N [S]. Without loss of generality let T = T [a, b, c, d] which implies that a vertex from S is a or b. We may also assume that a \u2208 S, otherwise we investigate the path T = T [d, c, a, b] instead of T . Since G is P 5 -free we get, using Lemma 4, that d T (c, d) = 2. Let x be the neighbor of d and c on T . Note that since x / \u2208 N [S] and a \u2208 S, a and x are not adjacent. Since G is P 5 -free, G contains at least one edge from {d c, d a} and at least one edge from {bd , bx, cd }. If d c, then G contains a forbidden subgraph from F (shown in Figure (c)). On the other hand, if d \u223c c, then G contains a graph from F (shown in Figure (c), (d) or (e)) or a graph from F \\ F as induced subgraph, depending which of the edges from {ad , bd , xb} appear in G, a contradiction. Now let G[R] contains two edges. We distinguish two possibilities. First let G[R] contain one isolated vertex, say d, and two adjacent edges ab and bc. Since isolated vertices are from N [S] \\ S, there exists a neighbor d of d in S. For the purpose of contradiction suppose that at least one vertex from {a, b, c} is from S. Using Lemma 2, we get that there exists Steiner tree T for R, with V (T ) N [S], which is either a path T = T [a, b, c, d] or a path T = T [c, b, a, d] or a subdivision of K 1,3 with leaves a, c, d in which the vertex of degree 3 is b. Since a and c are symmetrical we can assume without loss of generality that T is either a path T = T [a, b, c, d] or a subdivision of K 1,3 with leaves a, c, d and with b being the vertex of degree 3. First let T = T [a, b, c, d]. Thus c, d / \u2208 S and at least one vertex from {a, b} is from S. In any case we get that d T (c, d) = 2, since G is P 5 -free. Let x / \u2208 N [S] be the neighbor of d and c on T . Since G is P 5 -free and at least one vertex from R is from S, x is adjacent to exactly one vertex from {a, b}. First suppose that x \u223c a and x b. Since G is P 5 -free there is at least one edge from {d b, d c}. If d c, then G contains a forbidden induced subgraph from F (shown in", "type": "figure"}, "FIGREF7": {"text": ")) or from F \\ F depending whether b is adjacent to d or not. Thus we may assume that a d and therefore b \u223c d . In this case G contains a forbidden induced subgraph from F (shown in Figure (d) or (e)) depending whether c is adjacent to d or not, a contradiction. Now let T be a subdivision of K 1,3 with leaves a, c, d where the vertex of degree 3 is b. From Lemma 4 it follows that all vertices of the b, d-path in T are from V (G) \\ N [S]. Thus also b / \u2208 S and hence at least one vertex a or c is from S and without loss of generality let a \u2208 S. Since G is P 5 -free and a \u2208 S, d T (b, d) = 2. Let x / \u2208 N [S] be the neighbor of d and b on T . Again using the fact that G is P 5 -free, it follows that G contains at least one edge from {bd , ad } and at least one edge from {bd , cd , xc}. If x \u223c c, then there exists a Steiner tree T = T [a, b, c, d] on the same vertex set as T , thus we get a contradiction as in the previous case. Hence we may assume that x c. Therefore G contains at least one edge from {bd , cd }. First suppose that b d . Then G contains a forbidden induced subgraph from F (shown in Figure (c)), a contradiction. Thus we may assume that b \u223c d and hence G contains a graph from F (shown in Figure (d)) or from F \\ F as induced subgraph, a contradiction. To conclude the case when G[R] contains two edges, without loss of generality let a \u223c b, c \u223c d. For the purpose of contradiction suppose that at least one vertex from {a, b, c, d} is from S. Using Lemma 2, we get that there exists a Steiner tree T for R, with V (T ) N [S], which is a path and without loss of generality we may assume that T = T [a, b, c, d], where all vertices of b, c-path in T are from V (G) \\ N [S]. Thus a vertex from S is either a or d. Without loss of generality let a \u2208 S. Since G is P 5 -free and a \u2208 S, d T (b, c)=2. Let x / \u2208 N [S] be the neighbor of b and c on T . Since G is P 5 -free d \u223c x and thus d / \u2208 S. Let d \u2208 S be a neighbor of d in S. Since G is P 5 -free, G contains at least one edge from {d b, d a}. If c \u223c d , then G contains one of forbidden induced subgraphs from F (shown in Figure (b) or (c)) or from F \\ F, depending which edges from {bd , ad } appear in G, a contradiction. Hence c d . If just one edge from {d b, d a} appear in G, then G contains one of forbidden induced subgraphs from F (shown in Figure (a) or (c)), a contradiction. Therefore d \u223c b, d \u223c a. Since c \u2208 N (S), there exists a neighbor c of c in S. Now we interchange the roles of c and d from previous case and get a contradiction (the vertices a, b, c, d, x, c induce a forbidden subgraph), unless c is adjacent to both a and b and d c . Now the vertices b, d , a, c , x, c induce a forbidden induced subgraph from F \\ F, a contradiction. Finally let G[R] contain one edge and, without loss of generality, let a and b be adjacent. Thus c and d are isolated and hence from N [S] \\ S. For the purpose of contradiction suppose without loss of generality that a \u2208 S. Since N [S] \u2229 V (T ) = R and a \u2208 S, the only neighbor of a in T is b, which is not a leaf of T and thus it is from N [S] \\ S, because of Lemma 3. Since ab is the only edge in G[R] and G is P 5 -free it follows, from Lemma 4, that T is not a path. Since b is not a leaf of T , T is a subdivision of K 1,3 with leaves a, c, d and let z be the vertex of degree 3 on T . Let d be a neighbor of d in S. Since G is P 5 -free and a \u2208 S, we get that d(R) \u2208 {4, 5} and b is adjacent to z. (Note that it is also possible that b is the vertex of degree 3 on T . But then there exists a Steiner tree T for R with leaves a, c, d and with b being the neighbor of the vertex of degree 3 on T , such that V (T ) = V (T ) N [S]. Thus we can replace T with T .) Without loss of generality let z also be adjacent to c. Hence the distance between z and d is one or two. First suppose that d(R) = 5 and let x d be the neighbor of d on T . Note that G contains at most one edge from {bx d , cx d } since T is a Steiner tree. The fact that G is P 5 -free, implies that G contains at least one edge from {cx d , cd } and at least one edge from {bx d , bd }. In all cases the vertices d , d, x d , z, c, b induce a forbidden subgraph from F (shown in Figure (c)), a contradiction. Hence we may assume that d(R) = 4. Since G is P 5 -free and a \u2208 S, d is adjacent to at least one vertex from {a, b}. If a \u223c d , then the vertices a, b, z, d, d , c induce in G one of forbidden subgraphs from F (shown in Figure (a) or (c)) or from F \\ F, depending on which edges (if any) from {bd , cd } appear in G. It remains to check the case when b \u223c d and a d . If c \u223c d then the vertices a, b, z, d, d , c induce a forbidden subgraph from F (shown in Figure (e)), otherwise there exists a neighbor c of c in S. In this case we get a contradiction in the same way as in previous case (we interchange the roles of c and d), unless c \u223c b, c a, c d. But now the vertices z, c, c , b, a, d induce a forbidden subgraph from F (shown in Figure (d)), a final contradiction.", "type": "figure"}, "FIGREF8": {"text": "For the purpose of contradiction suppose that N [S] is not g 4 -convex. Let R = {a, b, c, d} \u2286 N [S] be a set with the smallest d(R) such that I(R) N [S]. By Lemma 6, R \u2286 N [S]\\S. Let T be a Steiner tree for R containing a vertex in V \\N [S]. From Lemma 4, it follows that V (T ) \u2229 N [S] = R. Since the graphs from F \\ F are forbidden, it follows from Theorem 5 that N [v] is g 4 -convex for every v \u2208 V . Thus R N (v) for every v \u2208 S. Suppose G[R] contains no edges. Since G contains no induced subgraphs from F (shown in Figure (a) and (c)) and every vertex from R has a neighbor in S, there exists a Steiner tree T for R with V (T ) N [S] such that T is subdivision of K 1,4 . Hence the vertices from R are the leaves of T . Let x be the vertex of degree 4 in T and let a be a neighbor of a in S. Since T is a Steiner tree and G is P 5 -free, d(x, y) \u2264 2 for every y \u2208 R. First we prove that d(R) \u2264 5. Suppose that d(R) \u2265 6. Then there exist two vertices from R, say a and b, such that d(a, x) = 2 and d(b, x) = 2. Let x a and x b be the neighbors of a and b on T , respectively. Since G is P 5 -free, x a \u223c x b and thus also a \u223c b. Now the vertices a , a, x a , x b , b, x induce a forbidden subgraph from F (shown in Figure (c)), a contradiction. Hence d(R) \u2208 {4, 5}. First suppose that d(R) = 5 and without loss of generality let d(a, x) = 2 and let x a be the neighbor of a on T . Since T is a Steiner tree", "type": "figure"}, "FIGREF9": {"text": "c)) or from F \\ F. Thus we may assume that a b and hence a \u223c b . Since b is not adjacent to all vertices from R, we may assume that c b . Let c be a neighbour of c that is in S. Now we change the role of a with b and the role of b with c and get b \u223c c , b c (in the same way as we got a \u223c b , a b ). In this case G contains a forbidden induced subgraph from F (shown in Figure (a) or (e)), a contradiction. Let G[R] contains three edges. Since G[R] is disconnected we may assume that d is isolated and a, b, c induce a triangle. Then there exists a Steiner tree T for R with V (T ) N [S] such that T is a path. Without loss of generality let T = T [a, b, c, d]. Let d be a neighbor of d in S. We will first prove that d(R) = 4. Suppose that d(R) > 4 and thus d T (c, d) \u2265 3. Lemma 4 implies, that the inner vertices of the c, d- subpath of T are not adjacent to d . Since G is P 5 -free, d T (c, d) = 3 and c \u223c d . Thus the path a, b, c, d , d is a Steiner tree for R, contrary to the assumption that d(R) > 4. Hence d(R) = 4. Let x be a common neighbor of c and d on T . First suppose that c d . Since G is P 5 -free G contains at least one edge from {xb, d b} and at least one edge from {xa, d a}. If G does not contain both edges xa and xb, then G contains a forbidden subgraph from F (shown in Figure (c)), a contradiction. Hence we may assume that x \u223c a and x \u223c b. If d is adjacent to at least one of a or b then G contains a forbidden subgraph from F \\ F, a contradiction. Let c be a neighbor of c in S. Since G is P 5 -free, G contains at least one edge from {c d , c d}. Depending on which of those two edges appear in G, we get one of forbidden induced subgraphs from F (shown in Figure (c)) or from F \\ F. Thus we may assume that c \u223c d . If there is no edge from {d a, d b} or no edge from {xa, xb} then G contains a forbidden subgraph from F (shown in", "type": "figure"}, "FIGREF10": {"text": "e)), a contradiction. In the second case let x \u223c a, d \u223c b. Then G contains forbidden subgraph from F (shown in Figure (c)), a contradiction. Now let G[R] contain two edges. We distinguish two possibilities. First let G[R] contain one isolated vertex, say d and two adjacent edges ab and bc. Let d be a neighbor of d in S. Using Lemma 2 we get that there exists a Steiner tree T for R, with V (T ) N [S], which is either a path T = T [a, b, c, d] or a path T = T [c, b, a, d] or a subdivision of K 1,3 with leaves a, c, d in which the vertex of degree 3 is b. Since a and c are symmetrical we can assume without loss of generality that T is either a path T = T [a, b, c, d] or a subdivision of K 1,3 with leaves a, c, d and with b being the vertex of degree 3. First let T = T [a, b, c, d]. Since G is P 5 -free and d cannot be adjacent to all vertices of R (otherwise G contains a subgraph of F \\ F), we get that d T (c, d) = 2. Let x / \u2208 N [S] be the neighbor of d and c on T . Since G is P 5 -free G contains at least one edge from {d c, d b, bx} and at least one edge from {ax, bx}. Suppose that x b and thus x \u223c a. If b \u223c d then the vertices a, b, c, x, d, d induce a forbidden subgraph from F (shown in Figure (c)) or from F \\ F, depending on which of the the edges (if any) from {ad , cd } appear in G. Thus we may assume that b d . Since there is at least one edge from {d c, d b, xb}, d must be adjacent to c. Since G is P 5 -free a \u223c d , otherwise the vertices a, b, c, d , d induce a P 5 . But now G contains a forbidden subgraph from F (shown in Figure (e)), a contradiction. Therefore we may assume that b and x are adjacent. Since G is P 5 -free there is at least one edge from {d b, d a, xa}. If d \u223c a then G contains one of forbidden subgraphs from F (shown in Figure (c)) or from F \\ F, a contradiction. Thus we may assume the d a. If d \u223c b, then G contains one of forbidden subgraphs from F (shown in Figure (d) or (e)) or from F \\ F, depending on which of the edges (if any) from {d c, xa} appear in G. Therefore also d and b are not adjacent and thus a \u223c x. If d \u223c c, then G contains a forbidden subgraph from F \\ F, a contradiction. Thus d c and let c be a neighbor of c in S. Since G is P 5 -free there is at least one edge from {d c , c d}. If c \u223c d, then G contains a forbidden subgraph from F \\ F. Therefore we may assume that c d and c \u223c d . But now the vertices c , d , d, x, c, b induce a forbidden subgraph from F shown in Figure (c)), a contradiction. Now let T be a subdivision of K 1,3 with leaves a, c, d where the vertex of degree 3 is b. From Lemma 4 it follows that all vertices of the b, d-path in T are from V (G) \\ N [S]. Let d be a neighbor of d in S. Since G is P 5 -free and d cannot be adjacent to all vertices from R, d T (b, d) = 2. Let x / \u2208 N [S] be the neighbor of d and b on T . Again using the fact that G is P 5 -free, it follows that G contains at least one edge from {bd , ad , xa} and at least one edge from {bd , cd , xc}. If x \u223c a or x \u223c c, then there exists a Steiner tree T which is a path and contains x / \u2208 N [S]. Therefore we get a contradiction as in previous case where T is a path. Thus we may assume that x a, x c. First suppose that b d and hence d \u223c c, d \u223c a. Then G contains a forbidden induced subgraph from F (shown in Figure (c)), a contradiction. Therefore we may assume that b \u223c d . In this case G contains a forbidden subgraph from F (shown in Figure (d)) or from F \\ F, depending on which edges (if any) from {ad , cd } appear in G, a contradiction. To conclude the case when G[R] contains two edges, without loss of generality let a \u223c b, c \u223c d. Using Lemma 2 we get that there exists a Steiner tree T for R, with V (T ) N [S], which is a path and without loss of generality we may assume that T = T [a, b, c, d], where all vertices of the b, c-path in T are from V (G) \\ N [S]. Let d be a neighbor of d in S. Since G contains no graph from F (shown in Figure (a) and (c)), d T (b, c)=2. Let x / \u2208 N [S] be the neighbor of b and c on T . Using the fact that G is P 5 -free we get that G contains at least one edge from {d c, d b, dx} and at least one edge from {ax, dx}. First suppose that d \u223c x. Since G is P 5 -free there is at least one edge from {d b, d a, ax}. Let first a \u223c x. Then a d , b d , otherwise G contains a forbidden subgraph from F \\ F. Let a be a neighbor of a in S. Since G is P 5 -free, there is at least one edge from {d a , a d}. Clearly a d, otherwise G contains a forbidden subgraph from F \\ F. Thus a \u223c d and now the vertices a, a , d , d, x, c induce a forbidden induced subgraph from F (shown in Figure (c)). Therefore we may assume that a x and therefore there is at least one edge from {d b, d a}. If c \u223c d , then G contains one of forbidden subgraphs from F (shown in Figure (b) or (c)) or from F \\ F, depending on which edges from {bd , ad } appear in G, a contradiction. Hence c d . If at most one edge from {d b, d a} appear in G, then G contains one of forbidden subgraph from F (shown in Figure (a) or (c)), a contradiction. Therefore d \u223c b, d \u223c a. Let c be a neighbor of c in S. Now we interchangechange the roles of c and d from previous case and get a contradiction (the vertices a, b, c, d, x, c induce a forbidden subgraph), unless c is adjacent to both a and b and d c . Then the vertices b, d , a, c , x, c induce a forbidden subgraph from F \\ F, a contradiction. Finally let d x which implies that a \u223c x. Let a be a neighbor of a in S (it is also possible that a = d ). Now we distinguish a instead of d and change the roles of a and d from previous case (the case where x is adjacent to d and d is a neighbor of d in S) and gets a contradiction in the same lines. Finally let G[R] contain one edge and without loss of generality let a and b be adjacent. Since G is P 5 -free there exists a Steiner tree T for R that is a subdivision of K 1,3 with leaves a, c, d or b, c, d such that V (T ) N [S]. Without loss of generality we may also assume that the leaves of T are a, c, d, otherwise we change the roles of a and b. Let z be the vertex of degree 3 in T and let d be a neighbor of d in S. Using the fact that the subgraphs from F (shown in Figure (a) and (c)) are forbidden, we get that d(R) \u2208 {4, 5} and we may assume that b is adjacent to z (if b z then there exists a Steiner tree T with V (T ) = V (T ) such that b is adjacent to the vertex of degree 3 on T ). Without loss of generality let z also be adjacent to c. Hence the distance between z and d is 1 or 2. First suppose that d(R) = 5 and let x d be the neighbor of d on T . Note that since T is a Steiner tree, G contains at most one edge from {bx d , cx d }. Using the fact that G is P 5 -free, we get that G contains at least one edge from {cx d , cd } and at least one edge from {bx d , bd }. In all cases the vertices d , d, x d , z, c, b induce a forbidden subgraph from F (shown in", "type": "figure"}, "FIGREF11": {"text": ") or from F \\ F, depending on which edges (if any) from {bd , cd } appear in G. It remains to check the case when b \u223c d and a d . If c \u223c d , then the vertices a, b, z, d, d , c induce a forbidden subgraph from F (shown in Figure (e)), otherwise there exists a neighbor c of c in S. In this case we get a contradiction in the same way as in previous case (we interchange the roles of c and d), unless c \u223c b, c a, c d. But now the vertices z, c, c , b, a, d induce a forbidden subgraph from F (shown in Figure (d)), a contradiction. Case 2: a \u223c z. Case 2.1: a \u223c d . In this case we get forbidden induced subgraph from F (shown in Figure (e)) or from F \\ F depending which edges from {bd , cd } appear in G, unless b \u223c d and c d . Thus let c be a neighbor of c in S. Since G is P 5 -free there is at least one edge from {dc , d c } and at least one edge from {bc , d c }. If d c , then the vertices c, c , d , d, z, b induce a forbidden subgraph from F (shown in Figure (c)). Hence d \u223c c . Similarly we get that b \u223c c . Then the vertices b, c, d, c , d , z induce a forbidden subgraph from F (shown in Figure (e)) or from F \\ F, depending on whether d is adjacent to c or not, a contradiction. Case 2.2: a d . Let a be a neighbor of a in S. If b \u223c d , then the vertices b, a, z, d, d , c induce a forbidden subgraph from F (shown in Figure (d)) or from F \\ F, depending on whether c is adjacent to d or not. Therefore let b d . Since G is P 5 -free G contains at least one edge from {a d , a d}. If there is just one edge from this set then G contains a forbidden subgraph from F (shown in Figure (a), (b) or (c)), depending on which of those two edges appear in G and whether b is adjacent to a or not. Thus we may assume that a \u223c d , a \u223c d. It is also clear that b a , otherwise G contains a forbidden subgraph from F \\ F. Now the vertices a , a, z, d, b, c induce a forbidden subgraph from F (shown in Figure (d)) or from F \\ F, depending on whether c is adjacent to a or not, a final contradiction. Theorem 8. If in a connected graph G, N [S] is g 4 -convex for every g 4 -convex set S, then G is F -free.", "type": "figure"}}}
{"paper_id": "18982341", "_pdf_hash": "19a3dd5862583fea4e7a06a9676bb8a8de85ef8b", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "The organization of economic activity: issues pertinent to the choice of market versus non-market allocation in U.S. Congress, joint economic committee, subcommittee on economy in government, 91st Congress, 1st Session. The analysis and evaluation of public expenditures: the PPB system", "authors": [{"first": "K", "middle": ["J"], "last": "Arrow", "suffix": ""}], "year": 1969, "venue": "", "link": null}, "BIBREF1": {"title": "Coase and Van Zandt on lighthouses", "authors": [{"first": "W", "middle": [], "last": "Barnett", "suffix": ""}, {"first": "W", "middle": [], "last": "Block", "suffix": ""}], "year": 2007, "venue": "Public Finance Review", "link": "153540463"}, "BIBREF2": {"title": "Traditional marginal cost: conceptual problems and some implications", "authors": [{"first": "W", "middle": [], "last": "Barnett", "suffix": ""}, {"first": "M", "middle": ["T"], "last": "Saliba", "suffix": ""}], "year": 2003, "venue": "", "link": null}, "BIBREF3": {"title": "The Coasean analysis of lighthouse financing: myths and realities", "authors": [{"first": "E", "middle": [], "last": "Bertrand", "suffix": ""}], "year": 2006, "venue": "Cambridge Journal of Economics", "link": "154791690"}, "BIBREF4": {"title": "Coase and Demsetz on private property rights", "authors": [{"first": "W", "middle": ["E"], "last": "Block", "suffix": ""}], "year": 1977, "venue": "Journal of Libertarian Studies: An Interdisciplinary Review", "link": "152797572"}, "BIBREF5": {"title": "Ethics, efficiency, Coasean property rights and psychic income: a reply to Demsetz", "authors": [{"first": "W", "middle": ["E"], "last": "Block", "suffix": ""}], "year": 1995, "venue": "Review of Austrian Economics", "link": "203188727"}, "BIBREF6": {"title": "O.J.'s defense: a reductio ad absurdum of the economics of Ronald Coase and Richard Posner", "authors": [{"first": "W", "middle": ["E"], "last": "Block", "suffix": ""}], "year": 1996, "venue": "European Journal of Law and Economics", "link": "146164584"}, "BIBREF7": {"title": "Cost and choice: an inquiry into economic theory", "authors": [{"first": "J", "middle": ["M"], "last": "Buchanan", "suffix": ""}], "year": 1969, "venue": "", "link": null}, "BIBREF9": {"title": "The problem of social cost", "authors": [{"first": "J", "middle": ["M"], "last": "Buchanan", "suffix": ""}, {"first": "G", "middle": [], "last": "Tullock", "suffix": ""}, {"first": "R", "middle": ["H"], "last": "Coase", "suffix": ""}], "year": 1960, "venue": "Journal of Law and Economics", "link": null}, "BIBREF10": {"title": "The lighthouse in economics", "authors": [{"first": "R", "middle": ["H"], "last": "Coase", "suffix": ""}], "year": 1974, "venue": "Journal of Law and Economics", "link": "153715526"}, "BIBREF11": {"title": "The lighthouse in economics", "authors": [{"first": "R", "middle": ["H"], "last": "Coase", "suffix": ""}], "year": 1974, "venue": "The firm, the market, and the law", "link": "153715526"}, "BIBREF12": {"title": "Subjective value, time passage, and the economics of harmful effects", "authors": [{"first": "R", "middle": ["E"], "last": "Cordato", "suffix": ""}], "year": 1989, "venue": "Hamline Law Review", "link": null}, "BIBREF13": {"title": "Knowledge problems and the problem of social cost", "authors": [{"first": "R", "middle": ["E"], "last": "Cordato", "suffix": ""}], "year": 1992, "venue": "Journal of the History of Economic Thought", "link": "154420859"}, "BIBREF14": {"title": "Welfare economics and externalities in an open-ended universe: a modern Austrian perspective", "authors": [{"first": "R", "middle": ["E"], "last": "Cordato", "suffix": ""}], "year": 1992, "venue": "", "link": "154314449"}, "BIBREF15": {"title": "Who's to blame for all the heartache? a response to anti-capitalistic mentalities after Katrina", "authors": [{"first": "D", "middle": ["J"], "last": "D&apos;amico", "suffix": ""}], "year": 2008, "venue": "International Journal of Social Economics", "link": "153644787"}, "BIBREF16": {"title": "The futile fight against (human) nature: a public choice analysis of the US army corps of engineers-special focus on hurricane Katrina", "authors": [{"first": "J", "middle": [], "last": "Dirmeyer", "suffix": ""}], "year": 2008, "venue": "International Journal of Social Economics", "link": "152600856"}, "BIBREF17": {"title": "Dynamics of the mixed economy: toward a theory of interventionism", "authors": [{"first": "S", "middle": [], "last": "Ikeda", "suffix": ""}], "year": 1997, "venue": "", "link": null}, "BIBREF18": {"title": "The general theory of employment, interest, and money", "authors": [{"first": "J", "middle": ["M"], "last": "Keynes", "suffix": ""}], "year": 1936, "venue": "Brace & World", "link": "125626328"}, "BIBREF19": {"title": "Law and the market order: an Austrian critique of the economic analysis of law", "authors": [{"first": "E", "middle": [], "last": "Krecke", "suffix": ""}], "year": 1996, "venue": "Journal des Economistes et des Etudes Humaines", "link": null}, "BIBREF20": {"title": "Method, process and Austrian economics: essays in honor of Ludwig von Mises", "authors": [{"first": "D", "middle": [], "last": "Lavoie", "suffix": ""}], "year": 1982, "venue": "", "link": "155510118"}, "BIBREF21": {"title": "An-arrgh-chy: the law and economics of pirate organization", "authors": [{"first": "P", "middle": ["T"], "last": "Leeson", "suffix": ""}], "year": 2007, "venue": "Journal of Political Economy", "link": "16692227"}, "BIBREF22": {"title": "Commentaries on law & economics", "authors": [{"first": "R", "middle": ["W"], "last": "Mcgee", "suffix": ""}], "year": 1997, "venue": "Yearbook", "link": null}, "BIBREF23": {"title": "Tools of dominion: the case laws of Exodus. Tyler: Institute for Christian Economics", "authors": [{"first": "G", "middle": [], "last": "North", "suffix": ""}], "year": 1990, "venue": "The Coase theorem. Tyler: The Institute for Christian Economics", "link": null}, "BIBREF24": {"title": "Undermining property rights: Coase and Becker", "authors": [{"first": "G", "middle": [], "last": "North", "suffix": ""}], "year": 2002, "venue": "Journal of Libertarian Studies: An Interdisciplinary Review", "link": "155211390"}, "BIBREF25": {"title": "Law, property rights, and air pollution", "authors": [{"first": "M", "middle": ["N"], "last": "Rothbard", "suffix": ""}], "year": 1982, "venue": "Economics and the environment: a reconciliation", "link": "154002114"}, "BIBREF26": {"title": "Interventionism: comment on Lavoie", "authors": [{"first": "M", "middle": ["N"], "last": "Rothbard", "suffix": ""}], "year": 1982, "venue": "Method, process, and Austrian economics", "link": null}, "BIBREF27": {"title": "Kaldor-Hicks efficiency and the problem of central planning", "authors": [{"first": "E", "middle": ["P"], "last": "Stringham", "suffix": ""}], "year": 2001, "venue": "Quarterly Journal of Austrian Economics", "link": null}, "BIBREF28": {"title": "The broken trailer fallacy: seeing the unseen effects of government policies in post-Katrina New Orleans", "authors": [{"first": "E", "middle": ["P"], "last": "Stringham", "suffix": ""}, {"first": "N", "middle": ["A"], "last": "Snow", "suffix": ""}], "year": 2008, "venue": "International Journal of Social Economics", "link": "112186379"}, "BIBREF29": {"title": "Private property, public interest, and the role of the state in nineteenth-century Britain: the case of lighthouses", "authors": [{"first": "J", "middle": [], "last": "Taylor", "suffix": ""}], "year": 2001, "venue": "Historical Journal", "link": "9187790"}, "BIBREF30": {"title": "The lessons of the lighthouse: 'government' or 'private' provision of goods", "authors": [{"first": "D", "middle": ["E"], "last": "Van Zandt", "suffix": ""}], "year": 1993, "venue": "Journal of Legal Studies", "link": "154746784"}, "BIBREF31": {"title": "Omnipotent government", "authors": [{"first": "L", "middle": [], "last": "Von Mises", "suffix": ""}], "year": 1969, "venue": "", "link": null}, "BIBREF32": {"title": "A critique of interventionism", "authors": [{"first": "L", "middle": [], "last": "Von Mises", "suffix": ""}], "year": 1977, "venue": "", "link": null}, "BIBREF33": {"title": "Taking advantage of disaster: misrepresentation of housing shortage for political gain", "authors": [{"first": "V", "middle": [], "last": "Vuk", "suffix": ""}], "year": 2008, "venue": "International Journal of Social Economics", "link": "144888083"}, "BIBREF34": {"title": "The economic institutions of capitalism", "authors": [{"first": "O", "middle": ["E"], "last": "Williamson", "suffix": ""}], "year": 1985, "venue": "", "link": "154506781"}}, "ref_entries": {}}
{"paper_id": "18982460", "_pdf_hash": "0d8e5c189896d5814d870098583766fcca6a41cb", "abstract": [{"section": "Abstract", "text": "Background: Benign prostatic hyperplasia is a common progressive disease in aging men, which leads to a significant impact on daily lives of patients. Continuous bladder irrigation (CBI) is a supplementary option for preventing the adverse events following transurethral resection of the prostate (TURP). Regulation of the flow rate based on the color of drainage bag is significant to prevent the clot formation and retention, which is controlled manually at present. To achieve a better control of flow rate and reduce inappropriate flow rate-related adverse effects, we designed an automatic flow rate controller for CBI applied with wireless sensor and evaluated its clinical efficacy.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Methods: The therapeutic efficacy was evaluated in patients receiving the novel automatic bladder irrigation post-TURP in the experimental group compared with controls receiving traditional bladder irrigation in the control group.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Results: A total of 146 patients were randomly divided into 2 groups-the experimental group (n = 76) and the control group (n = 70). The mean irrigation volume of the experimental group (24.2 \u00b1 3.8 L) was significantly lower than that of the controls (54.6 \u00b1 5.4 L) (P < 0.05). Patients treated with automatic irrigation device had significantly decreased incidence of clot retention (8/76) and cystospasm (12/76) compared to controls (21/70; 39/70, P < 0.05). There was no significant difference between the 2 groups with regard to irrigation time (28.6 \u00b1 2.7 vs 29.5 \u00b1 3.4 hours, P = 0.077).", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "The study suggests that the automatic regulating device applied with wireless sensor for CBI is safe and effective for patients after TURP. However, studies with a large population of patients and a long-term follow-up should be conducted to validate our findings.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Abbreviations: BPH = benign prostatic hyperplasia, CBI = continuous bladder irrigation, TURP = transurethral resection of the prostate.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Benign prostatic hyperplasia (BPH) is a common disease in older men with age of more than 50 years. [1] BPH is characterized by the enlargement of the prostate and clinically associated with lower urinary tract symptoms. Although BPH is not a lifethreatening disease, it has been a health concern and significantly affected the life quality of patients. [2] The current therapies for BPH mainly include transurethral resection of the prostate (TURP) and open prostatectomy. [3] However, the TURP is commonly associated with adverse events in patients following surgery, thus the adjuvant therapy options for preventing the complications are urgently needed.", "cite_spans": [{"start": 100, "end": 103, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 354, "end": 357, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 474, "end": 477, "text": "[3]", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "Introduction", "text": "Continuous bladder irrigation (CBI) is a supplementary approach for BPH management after surgery with a view to preventing clot retention, cystospasm, and hemorrhage postoperatively. [4] Besides, CBI has been proposed to inhibit the hemorrhagic cystitis [5] and increase the survival rate following stem cell transplantation. [6] Although CBI is widely used for preventing the complications following TURP, it is not easy for nurses to take CBI for patients. [7] Nurses are responsible for ensuring a continuous flow of prescribed solution during the whole procedure. Thus, it is imperative to assess the blocked catheter by checking the color of drainage bag and controlling the flow rate. [7] Currently, the flow rate of irrigation fluid is controlled manually by nurse according to the color of drainage fluid. Inappropriate flow rate may result in adverse effects such as clot retention, cystospasm, and hemorrhage. However, research references of the manual to control the flow rate are rare. In order to achieve a better control of flow rate of irrigation fluid and reduce inappropriate flow rate-related adverse effects, we designed the automatic flow rate controller for bladder irrigation applied with wireless sensor and evaluated its clinical efficacy for patients after TURP. We expect that our study would provide therapeutic implication for patients undergoing CBI.", "cite_spans": [{"start": 183, "end": 186, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 254, "end": 257, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 326, "end": 329, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 459, "end": 462, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 691, "end": 694, "text": "[7]", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "Methods", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Patients and groups", "text": "Between July 2013 and July 2014, a total of 146 patients with BPH who were admitted in the urology department of our hospital were included in our study. All the patients underwent TURP and then were subjected to CBI. The age of the included patients ranged from 58 to 80 years, and the prostate volume was less than 80 mL based on transrectal ultrasonography. Patients with coagulation disorders, infectious, cardiovascular, and cerebrovascular diseases were excluded from this study. Magnetic resonance and needle puncture were conducted to exclude patients with prostatic cancer.", "cite_spans": [], "ref_spans": []}, {"section": "Patients and groups", "text": "The included patients were randomly divided into experimental and control groups based on the odevity of admission number. Patients in the control group received conventional bladder irrigation with 0.9% saline solution. Those patients in the experimental group were irrigated with automatic regulating device applied with wireless sensor. All the patients or their parents provided informed consent before the study. Approval was obtained from the ethics committee of the Second Affiliated Hospital of Nantong University.", "cite_spans": [], "ref_spans": []}, {"section": "Conventional bladder irrigation", "text": "The bladder irrigation was performed for patients in the control group at conventional irrigation rate. The irrigation rate was initially managed at 150 dpm within 2 hours postoperatively. At 2 to 8 hours after operation, the elution drop rate was maintained at 120 dpm. The irrigation rate was then adjusted within 30 dpm based on the color of drainage solution. When the flushing fluid was clear or showed reddish color, the bladder irrigation was stopped.", "cite_spans": [], "ref_spans": []}, {"section": "CBI with automatic regulating device", "text": "In the experimental group, the flow rate of bladder irrigation was controlled using the automatic regulating device. The apparatus of automatic bladder irrigation applied with wireless sensor system was composed of 3 modules, including color monitor for drainage solution, flushing fluid rate adjusting controller, and computer microprocessor (Fig. 1) . After TURP, patients were placed in regular hospital beds. The color monitor was mounted on evacuating catheter, and the irrigation adjusting controller was installed in Murphy dropper of flushing line. The light signals for the color change were captured by light/frequency sensor and analyzed by computer microprocessor to automatically adjust irrigation rate (Fig. 1) . The system parameters were set by experts according to the individual patient's condition.", "cite_spans": [], "ref_spans": [{"start": 343, "end": 351, "text": "(Fig. 1)", "ref_id": "FIGREF0"}, {"start": 716, "end": 724, "text": "(Fig. 1)", "ref_id": "FIGREF0"}]}, {"section": "Evaluation", "text": "All the patients were followed up until hospital discharge. During the process of bladder irrigation, the irrigation fluid amount and the time of duration were recorded. Clot retention and cystospasm in patients were observed. Besides, the hospital stays of patients were calculated after leaving hospital.", "cite_spans": [], "ref_spans": []}, {"section": "Statistical analysis", "text": "The statistical analysis was performed by SPSS 16.0 software (SPSS Inc., Chicago, IL). All the data were displayed by mean \u00b1 SD (standard deviation). Measurement data were analyzed by Student t test, and the enumeration data were analyzed by chisquare test. P < 0.05 was considered to be significantly different.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "A total of 146 patients with the mean age of 70.1 years were randomly assigned to experimental (n = 76) and control groups (n = 70). In the control group, there were 68 Han Chinese people and 2 other ethnic people. The patients in the experimental group included 73 Han and 3 other ethnic people. The number of patients with ages ranging from 50 to 70 years was 32 in the control group and 29 in the experimental group. The groups were not significantly different with regard to age, ethnic history, family income, length of illness, BMI, international prostate symptom score, prostate volume, surgery time, and preoperative indwelling catheter (P > 0.05, Table 1 ).", "cite_spans": [], "ref_spans": [{"start": 656, "end": 663, "text": "Table 1", "ref_id": "TABREF0"}]}, {"section": "Results", "text": "As shown in Table 2 , the mean amount of irrigation fluid usage in the experimental group (24.2 \u00b1 3.8 L) was significantly lower than that in the control group (54.6 \u00b1 5.4 L) (P < 0.05). The irrigation duration of patients was not significantly different between the experimental and the control groups (28.6 \u00b1 2.7 hours; 29.5 \u00b1 3.4 hours, P > 0.05). The bladder irrigation with ", "cite_spans": [], "ref_spans": [{"start": 12, "end": 19, "text": "Table 2", "ref_id": "TABREF1"}]}, {"section": "Results", "text": "Medicine automatic regulating device significantly decreased the incidence of clot retention (8/76) and cystospasm (12/76) in patients of the experimental group compared with the controls (21/70; 39/70, P < 0.05). In addition, the patients in the experimental group had significantly shorter hospital stays (5.4 \u00b1 1.2 days) than the controls (5.9 \u00b1 1.9 days) (P < 0.05).", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "Currently, the automatic regulatory device for regulating the irrigation fluid of CBI has been less reported. In this paper, as far as we know, we reported a novel automatic CBI apparatus for the first time and tested its clinical efficacy in patients after TURP. The study found that the novel device was safer and more effective than the traditional irrigation method. The application of this device might improve the clinical outcome of patients and promote the recovery of patients. We anticipate that the application of this device will provide valuable insights into the improvements of outcome in patients after TURP. Our data showed that the incidence rate of clot retention and cystospasm in patients irrigated with automatic regulation device was lower than that in patients with traditional method. It suggests that the automatic regulatory device leads to less-adverse effects and is safer than the traditional method. With regard to the reasons for the difference, in the control group, the flow rate of irrigation fluid is regulated by medical care personnel according to subjective judgment. It is reported that the color recognition for drainage fluid varies for individuals, which leads to incorrect flow rate regulation. [8] Even the color of drainage fluid is observed frequently, the transient changes of color cannot be captured by nurses, which may increase the risk for blood clots formation, cystospasm, and clot retention. In contrast, in the experiment group, the patients were treated with the automatic regulatory device, and the automatic bladder irrigation system was capable to detect the color change timely. In order to realize the quantitative relation between color and flow rate, different stages of color were labeled with flow rate in the computer microprocessor. Therefore, the flow rate was regulated objectively and accurately.", "cite_spans": [{"start": 1239, "end": 1242, "text": "[8]", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "Discussion", "text": "In addition, our results showed that mean irrigation volume in the experimental group (24.2 \u00b1 3.8 L) was significantly lower than that in the control group (54.6 \u00b1 5.4 L) (P < 0.05). This observation might be due to the fact that with the traditional bladder irrigation, the flow rate was regulated at liberty based on subjective experience. Based on the clinical experience, the medical care personnel or patients' family members are inclined to regulate the flow rate faster than theory value, which may increase the irrigation volume. However, fast flow rate cannot prevent the complications of bladder irrigation. The automatic bladder irrigation system was characterized by accurate control, real-time monitor, and automatic adjustment. Therefore, in the experimental group, the flow rate was regulated accurately. Moreover, there were no significant differences with regard to irrigation time and hospital stay between the 2 groups, which suggests that the novel irrigation system does not lengthen the time of irrigation and hospital stays of patients.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "In recent years, although color chart has been designed for controlling the flow rate of bladder irrigation, the flow rate is adjusted manually, [7] which may lead to blood clots formation and retention following irrigation. In this paper, novel automatic regulatory device for CBI based on wireless sensor was designed. The red-green-blue color/frequency sensor module was applied, which consisted of white light source, transparency window, transparency window, and wireless communication part. The output frequency of color/frequency sensor showed linear relation with light intensity. The color data of the drainage solution in the catheter were processed by 32-bit ADuC7026 microprocessor, and the flow regulation was conducted by stepping motor driving by general-purpose input/output. The whole process involved digital data process and digitization, which enhanced the accuracy. Besides, compared with traditional CBI, the color changes of the drainage solution were monitored in the pipe in real time, which also contributed to the accuracy. The study also has some limitations. First, it has a limited sample size. Second, the follow-up is not long enough. A larger number of patients with a longer follow-up are necessary to test the maintenance of clinical efficacy of this automatic bladder irrigation device before its wide application in clinical practice.", "cite_spans": [{"start": 145, "end": 148, "text": "[7]", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "Discussion", "text": "In conclusion, the automatic bladder irrigation device promotes digitization of drainage color and controls the flow rate in a standardized manner. Compared with the traditional bladder irrigation, the novel automatic bladder irrigation decreased the incidence of complications following irrigation.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "The study suggests that it is a safe and effective method for patients after TURP. Our work provides novel insights into flow rate regulation of bladder irrigation.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "The cost of treating the 10 most prevalent diseases in men 50 years of age or older", "authors": [{"first": "T", "middle": ["C"], "last": "Fenter", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Naslund", "suffix": ""}, {"first": "M", "middle": ["B"], "last": "Shah", "suffix": ""}], "year": 2006, "venue": "Am J Managed Care", "link": "34028337"}, "BIBREF1": {"title": "Benign prostatic hyperplasia", "authors": [{"first": "M", "middle": [], "last": "Jonler", "suffix": ""}, {"first": "M", "middle": [], "last": "Riehmann", "suffix": ""}, {"first": "R", "middle": [], "last": "Brinkmann", "suffix": ""}], "year": 2004, "venue": "J R Soc Promot Health", "link": "29522865"}, "BIBREF2": {"title": "Benign prostatic hyperplasia. Practical treatment guidelines", "authors": [{"first": "T", "middle": [], "last": "Tammela", "suffix": ""}], "year": 1997, "venue": "Drugs Aging", "link": null}, "BIBREF3": {"title": "Is continuous bladder irrigation after prostate surgery still needed?", "authors": [{"first": "C", "middle": ["O"], "last": "Okorie", "suffix": ""}], "year": 2015, "venue": "World J Clin Urol", "link": "79775488"}, "BIBREF4": {"title": "Managing hemorrhagic cystitis in BMT patients using continuous bladder irrigation", "authors": [{"first": "J", "middle": ["A"], "last": "Buitrago", "suffix": ""}, {"first": "B", "middle": ["D"], "last": "Cruz", "suffix": ""}, {"first": "R", "middle": [], "last": "Blackburn", "suffix": ""}], "year": 2013, "venue": "Biol Blood Marrow Transplant", "link": "73004806"}, "BIBREF5": {"title": "Hemorrhagic cystitis requiring bladder irrigation is associated with poor mortality in hospitalized stem cell transplant patients", "authors": [{"first": "V", "middle": ["T"], "last": "Raup", "suffix": ""}, {"first": "A", "middle": ["M"], "last": "Potretzke", "suffix": ""}, {"first": "B", "middle": ["J"], "last": "Manley", "suffix": ""}], "year": 2015, "venue": "Int Braz J Urol Off J Braz Soc Urol", "link": "1082420"}, "BIBREF6": {"title": "Assessment and intervention knowledge of nurses in managing catheter patency in continuous bladder irrigation following TURP", "authors": [{"first": "C", "middle": [], "last": "Ng", "suffix": ""}], "year": 2001, "venue": "Urol Nurs", "link": "42712997"}, "BIBREF7": {"title": "Recognition of drainage fluid color of continuous bladder irrigation for doctors and nurses of urological department", "authors": [{"first": "J", "middle": [], "last": "Luo", "suffix": ""}, {"first": "Q", "middle": ["E"], "last": "Zeng", "suffix": ""}, {"first": "J", "middle": [], "last": "Xiao", "suffix": ""}], "year": 2010, "venue": "J Nur (China)", "link": "77149858"}}, "ref_entries": {"FIGREF0": {"text": "Figure 1. The clinical construction of the automatic regulating device for continuous bladder irrigation.", "type": "figure"}, "TABREF0": {"text": "Comparison of basic characteristics of patients between 2 groups.BMI = body mass index, IPSS = international prostate symptom score. * t test. \u2020 Mann-Whitney test. \u2021 chi-square analysis.", "type": "table"}, "TABREF1": {"text": "Clinical results of bladder irrigation in patients of 2 groups.", "type": "table"}}}
{"paper_id": "18982496", "_pdf_hash": "90c21e95578699827c1dc8d85c468cd24e6946e0", "abstract": [{"section": "Abstract", "text": "In this paper I discuss some constraints and implications in accessing fellow academics as research participants, a topic that has rarely been addressed thus far in the literature. I will point out that a lack of cooperation from fellow academics may defeat our research purposes, and will survey some studies involving U.S., European, and Chinese academics as research participants to illustrate education researchers' efforts to work with fellow academics against the odds. By referencing my personal experience of engaging with Chinese academics, I will then discuss the role of personal contacts in research and reflect upon various constraints in accessing fellow academics as research participants. I will suggest that, when we do participate in a fellow researcher's project, the incentive is a desire to support our peers in the spirit of \"academic citizenship.\"", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "", "text": "name and sent by a colleague who has participated in a study of mine before, made me feel that his request was the first I should respond to.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "In an ideal world, we, fellow academics, irrespective of the difference in rank, gender, or seniority, would support each other's research (and hence publications) by responding to requests for helppresumably every response, every bit of contribution to their data would count. (It should be noted that such appeals to fellow academics for help are typically made by academics in education, including language education, where they may have research interests that necessitate the participation of fellow academics across disciplines.) The literature, especially that of health research, has discussed the pros and cons of undertaking qualitative interviews with one's peers in the same profession [1, 2] . However, little reflection is found in the literature on the implications of working with fellow academics who are not necessarily in one's own field of profession or discipline. At the same time, while research methodology books give ample advice on accessing participants beyond academia, little discussion can be found on working with fellow academics as research participants. The present paper will address this gap in the literature. The observations shared here represent personal views, which have not been tested by systematic research. However, a discussion of the phenomenon is worthwhile as accessing target research participants is an important issue for many academics in social sciences.", "cite_spans": [{"start": 698, "end": 701, "text": "[1,", "ref_id": "BIBREF0"}, {"start": 702, "end": 704, "text": "2]", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "", "text": "In the following, I will begin with an example from Braine [3] to illustrate what can result from a lack of cooperation from fellow academics as potential research participants. Then, I will draw examples from the literature to sketch a picture of some studies where researchers in education have tried to involve fellow academics in U.S., European, and Chinese universities, respectively, as their research participants. I will then discuss some related issues by drawing upon my own experiences of working with Chinese academics as my research participants, as a female junior academic based at a university in Hong Kong.", "cite_spans": [{"start": 59, "end": 62, "text": "[3]", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "Lack of Cooperation from Fellow Academics May Defeat Our Research Purpose: An Example", "text": "We normally take precautionary measures against a potentially low response rates. For instance, we may aim to reach an extensive pool of a target population, use a \"snowball strategy\" when selecting participants, or personalize the invitations sent to target participants. When little can be done to change a low level of \"cooperation,\" however, our research purposes can suffer. An example was given by George Braine [3] in an article entitled \"When professors don't cooperate: A critical perspective on EAP research\" (published in the journal of English for Specific Purposes, a flagship journal in a field where cooperation from colleagues across disciplines is often vital). For his doctoral research, conducted at the University of Texas (Austin) in the early 1990s, on undergraduate writing tasks in engineering and natural sciences, Braine received enthusiastic support when requesting written assignment prompts from professors across disciplines at the university; however, when trying to replicate the study at the Chinese University of Hong Kong a few years later (in mid-to late-1990s), as a faculty member in the English Department, he ran into difficulty. With the support of two research assistants, they sent requests to \"223 teachers in the engineering and science faculties who were listed in the timetable as teaching in English or in Cantonese and English, inviting them to participate in the project by sending us their course syllabi and writing assignments\" ( [3] , p. 297):", "cite_spans": [{"start": 418, "end": 421, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 1483, "end": 1486, "text": "[3]", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "Lack of Cooperation from Fellow Academics May Defeat Our Research Purpose: An Example", "text": "\"Within a week, 80 had replied, citing their reasons for being unable to participate: some were too busy, others were not teaching that semester/year, and the rest did not give writing assignments in their courses. In response to follow-up requests, phone calls, and email messages, only five teachers from engineering and four from science agreed to participate in the project. Despite requests through e-mails and telephone calls, 134 teachers did not respond at all.\" (pp. [297] [298] In all, the research team collected 29 assignments from engineering, 22 of which were from two courses, in the form of \"instructions for laboratory experiments\" but were \"too succinct for detailed analysis\"; and none came from science (p. 298). The researchers did, instead, receive a generous donation of student reports, and they ended up trying to \"retrace and reconstruct laboriously, from the students' reports, the teachers' expectations\" (p. 298).", "cite_spans": [], "ref_spans": []}, {"section": "Lack of Cooperation from Fellow Academics May Defeat Our Research Purpose: An Example", "text": "Reflecting on why colleagues in engineering and science faculties were reluctant to share their writing assignments, Braine [3] suggested that \"these teachers may have received little or no instruction in writing during their secondary, undergraduate and graduate studies\" (p. 299); and even having pursued graduate studies in North America usually also means a lack of training in writing for some. Hence, the professors may either take writing assignments from textbooks or give few writing assignments (p. 298 and p. 302). Another reason for the teachers' reluctance to share the materials requested, Braine suggested, might be that they did not want to let an English teacher see their \"poorly written or poorly designed texts\" ([4], p. 33) (cited in [3] , p. 302).", "cite_spans": [{"start": 124, "end": 127, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 755, "end": 758, "text": "[3]", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "Lack of Cooperation from Fellow Academics May Defeat Our Research Purpose: An Example", "text": "Nearly two decades after Braine's effort to reach out to fellow academics at the Chinese University of Hong Kong, there has apparently been heightened awareness for writing across disciplines in Hong Kong universities, and professors across faculties generally seem to possess relatively strong English writing skills, as, after all, a track-record of English publications, coupled with a PhD degree earned at an English-speaking country, has often been an instrumental factor in faculty recruitment. However, there is no guarantee that Braine would have received more positive responses to his request now than over a decade ago.", "cite_spans": [], "ref_spans": []}, {"section": "Academics in Different Parts of the World as Research Participants", "text": "In Braine's [3] study, another factor seems important for the contrast of the responses he received from subject professors at the University of Texas (Austin) and later at the Chinese University of Hong Kong: there was a long-established Writing Across the Curriculum (WAC) program at the former, so that, presumably, the subject professors were accustomed to working with language teachers on a regular basis; while, at the latter university, with the absence of such a program and with a language specialist-subject specialist partnership largely an alien concept at the time of Braine's study, the subject specialists might not feel comfortable moving out of the tradition. However, other than this divergence at the two sites, one may wonder if the difference in responding to the same request might reflect some sort of \"cultural\" difference among the professors on the two sides? Namely, do U.S. academics tend to be more responsive to research-support requests from fellow academics than (Hong Kong) Chinese academics? Such a question will be difficult to answer. However, it may be useful to look into the literature to get a sense of the extent to which academics in different parts of the world are willing to become research participants, by responding to fellow academics' request of completing a questionnaire.", "cite_spans": [{"start": 12, "end": 15, "text": "[3]", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "Academics in Different Parts of the World as Research Participants", "text": "In the following, I will provide an overview of some studies, which were based on data gathered through questionnaires administered to academics across disciplines in U.S., European, and Chinese universities, respectively. I focus on questionnaire-based studies rather than interview-based ones here as the former tend to give clear indications of the response rate (i.e., the percentage of the responding fellow academics in the total target population). Most of the studies examined below were conducted by researchers in language education (which is my own disciplinary area) and a few by researchers in education more generally. The target questionnaire respondents were typically fellow academics across disciplines rather than in the researchers' own discipline (an exception being Min's [5] study, in which the participants were from the researcher's own disciplinary area, i.e., applied linguistics). It should be noted that my selection of the studies is more of a result of my having knowledge of these studies than due to any other reason. For consistency, five studies have been selected from each of the three geographical locations: the U.S., Europe, and several Chinese-speaking regions. The purpose of the overview is to offer a glimpse into some studies that involved academics responding to peers' request for participation in research. There is no intention to pick \"representative\" studies or to make any generalizations based on these studies. Table 1 summarizes five questionnaire-based studies, conducted by language professionals teaching in U.S. universities. These studies, with an aim of informing English for Academic Purposes (EAP) pedagogy, mostly focused on the communication or, especially, the academic writing requirements for students across disciplines. 1518 foreign language (FL) instructors working at the chosen universities, receiving an email containing a secure URL link providing access to an online survey system", "cite_spans": [{"start": 794, "end": 797, "text": "[5]", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "Academics in U.S. Universities as Research Participants", "text": "The extent to which the current university FL instruction is informed by second language writing research 153 (9.92%) FL instructors completed the survey Ferris and Tagg [8] described the response rate they received from fellow academics (at 25.4%, with 234 responses to the 921 delivered surveys) as \"fairly low\" (p. 37). In another study, not included in Table 1 but apparently drawing data from the same questionnaire described in Ferris and Tagg [8] , the same authors [11] focused on listening/speaking tasks for ESL (English as a Second Language) students, and pointed to an (understandable) connection between fellow academics' decision over whether to respond and their perceived relevance of the topic of the study for them: \"As the survey was rather long, it is likely that the respondents were primarily those who had strong interest in or concerns about their ESL students and may thus not be representative of all instructors\" (p. 303).", "cite_spans": [{"start": 170, "end": 173, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 450, "end": 453, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 473, "end": 477, "text": "[11]", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "Academics in U.S. Universities as Research Participants", "text": "While the surveys conducted by Casanave and Hubbard [6] , Jenkins, Jordan, and Weiland [7] , and Ferris and Tagg [8, 11] , in the late 1980s to early 1990s, were paper-based with hard copies of questionnaire mailed to target participants, over time it has increasingly become a norm to conduct surveys using the Internet, by distributing the questionnaire directly via email (as in [9] ) or sending an invitation email containing a URL link to an online survey (as in [10] ). Of the latter, as the researchers Hubert and Bonzo ([10,] p. 521) described: \"The survey was administered using an online instrument to which potential respondents were provided access via a secure URL link. This link was provided to potential respondents via email.\" Table 2 shows five survey-based studies conducted in European universities also by language professionals. In these studies, questionnaires were administered to fellow EAL (English as an Additional Language) academics to find out about their attitudes toward the dominance of English in academia in relation to their first language, perception of difficulties in writing for publication in English, and their related practices in overcoming the potential language barrier. Table 2 . A summary of five surveys conducted by language professionals in European universities.", "cite_spans": [{"start": 52, "end": 55, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 87, "end": 90, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 113, "end": 116, "text": "[8,", "ref_id": "BIBREF7"}, {"start": 117, "end": 120, "text": "11]", "ref_id": "BIBREF10"}, {"start": 382, "end": 385, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 468, "end": 472, "text": "[10]", "ref_id": "BIBREF9"}], "ref_spans": [{"start": 744, "end": 751, "text": "Table 2", "ref_id": "TABREF1"}, {"start": 1217, "end": 1224, "text": "Table 2", "ref_id": "TABREF1"}]}, {"section": "Academics in European Universities as Research Participants", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Authors", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Research site or target respondents' affiliation", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Target respondents and mode of survey Focus of the study Response rate", "text": "Duszak and Lewkowicz [12] A university in Poland", "cite_spans": [{"start": 21, "end": 25, "text": "[12]", "ref_id": "BIBREF11"}], "ref_spans": []}, {"section": "Target respondents and mode of survey Focus of the study Response rate", "text": "The questionnaire was emailed to \"academics in medicine, psychology and language studies\" (p. 111) Polish academics' perception of difficulties in writing for publication in English \"99 completed questionnaires were received\"; response rate is unknown as the population size is not indicated Ferguson, P\u00e9rez-Llantada, and Plo [13] University of Zaragoza, Spain A questionnaire (written in Spanish) was emailed \"through a university server to all 3,000 academic and academic-related staff\" (p. 47)", "cite_spans": [{"start": 326, "end": 330, "text": "[13]", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "Target respondents and mode of survey Focus of the study Response rate", "text": "Scientists' perception of disadvantage in using English in academic/scientific publication \"a modest though not impossibly low response rate of 10 per cent\", with 300 questionnaires returned (p. 47) \"online questionnaires which were posted on the university server during the period April-June 2009\" (p.", "cite_spans": [], "ref_spans": []}, {"section": "Target respondents and mode of survey Focus of the study Response rate", "text": "433)", "cite_spans": [], "ref_spans": []}, {"section": "Target respondents and mode of survey Focus of the study Response rate", "text": "The use of English at undergraduate and postgraduate levels and across disciplines, and the target respondents' attitudes toward the use of English in teaching and research \"highly satisfactory\" response rates: 19% of the target students responded, and 668 (40%) out of 1683 staff responded; excluding administrative personnel and PhD students from the staff category, \"498 teaching and research staff remained\" (p. 433) Table 2 shows that from the researchers' point of view, the response rates ranged from \"disappointingly low\" [15] , \"modest\" [13] , to \"highly satisfactory\" [16] , but, apparently, tipping toward the modest and low side. The top reason for a colleague not to respond, as some suggested, is \"pressures on academics' time\" ( [13] , p. 47). In addition, Duszak and Lewkowicz [12] noted that 62% of their respondents were aged between 22 and 45, which is \"likely to reflect the fact that younger academics are more willing to respond to requests for data of this nature\" (p. 111). This suggestion can be interpreted as implying that younger academics may find the topic of the survey, namely perception of difficulties in writing for publication in English, particularly relevant for them and are therefore more willing to respond. A similar point was made by Ferris and Tagg [8] , as noted earlier.", "cite_spans": [{"start": 530, "end": 534, "text": "[15]", "ref_id": "BIBREF14"}, {"start": 546, "end": 550, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 578, "end": 582, "text": "[16]", "ref_id": "BIBREF15"}, {"start": 744, "end": 748, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 793, "end": 797, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 1293, "end": 1296, "text": "[8]", "ref_id": "BIBREF7"}], "ref_spans": [{"start": 421, "end": 428, "text": "Table 2", "ref_id": "TABREF1"}]}, {"section": "Academics in Chinese Universities as Research Participants", "text": "Finally, Table 3 includes five questionnaire-based studies concerning academics' teaching/research activities, conducted in universities in Mainland China, Hong Kong, and Taiwan, respectively. It can be seen from Table 3 that the studies of Li et al. [17] and Min [5] achieved particularly high response rates: 89.3% (268 responses out of a target of 300) and 76% (38 responses out of 50), respectively. However, this is perhaps not surprising, given that, as indicated in the table, Min [5] identified her target respondents from applied linguists (language educators) she had met at local conferences, so that presumably the researcher and the target respondents were members of a local academic community based on professional relationships. In the case of Li et al.'s [17] study, \"printed surveys were handed out\" (p. 282) to the target respondents, apparently through personal connections and with facilitation of the approval of the study by \"the leaders of the institution\" (p. 279). The potential implication of personal connections (or guanxi) in conducting research in the Chinese context will be re-visited later in the present paper, when I reflect upon my own experience of working with Chinese academics.", "cite_spans": [{"start": 251, "end": 255, "text": "[17]", "ref_id": "BIBREF16"}, {"start": 264, "end": 267, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 488, "end": 491, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 772, "end": 776, "text": "[17]", "ref_id": "BIBREF16"}], "ref_spans": [{"start": 9, "end": 16, "text": "Table 3", "ref_id": "TABREF2"}, {"start": 213, "end": 220, "text": "Table 3", "ref_id": "TABREF2"}]}, {"section": "Academics in Chinese Universities as Research Participants", "text": "Incidentally, questionnaire-based research conducted by language educators with fellow academics across disciplines in mainland Chinese universities is hard to find. This seems to echo the current general lack of exchange and collaboration in EAP instruction between language and subject specialists in the country [21, 22] . In this sense, it can be suggested that access is only likely to occur when there is a desire to access. On the other hand, potential accessibility of subject specialists and language specialists to each other in Chinese universities might, in fact, be a reminder of the existence of opportunities for collaboration between the two parties in EAP teaching and research, with such collaborations having long been advocated in the literature (e.g., [23, 24] ).", "cite_spans": [{"start": 315, "end": 319, "text": "[21,", "ref_id": "BIBREF20"}, {"start": 320, "end": 323, "text": "22]", "ref_id": "BIBREF21"}, {"start": 773, "end": 777, "text": "[23,", "ref_id": "BIBREF22"}, {"start": 778, "end": 781, "text": "24]", "ref_id": "BIBREF23"}], "ref_spans": []}, {"section": "Researchers Conducting Questionnaire-Based Studies with Fellow Academics: Endeavoring to Achieve a Higher Response Rate", "text": "In the above, I summarized a total of 15 questionnaire-based studies conducted by researchers in education, especially language education, among fellow academics mostly working in disciplines other than their own. It can be seen that when questionnaires are distributed within a relatively closely-knit academic community, where the researcher has personal connections, either in the context of one university [16, 17] , or a disciplinary/professional community of which the researcher is a member [5] or to which the researcher has access through a listserv [9] , a high response rate is likely to achieved. We also notice that researchers may express an emotional attitude toward the response rates: while for Ferris and Tagg [8] , a response rate of 25.4% was \"fairly low\" (p. 37), for Ferguson et al. [13] , 10% was \"modest\" (p. 47), and for Olsson and Sheridan [15] , 17.5% was \"disappointingly low\" (p. 39); in addition, a response rate of 40% was \"highly satisfactory\" (p. 433) for Bolton and Kuteeva [16] . Thus, researchers do care about the response rates they receive.", "cite_spans": [{"start": 410, "end": 414, "text": "[16,", "ref_id": "BIBREF15"}, {"start": 415, "end": 418, "text": "17]", "ref_id": "BIBREF16"}, {"start": 498, "end": 501, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 559, "end": 562, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 728, "end": 731, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 805, "end": 809, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 866, "end": 870, "text": "[15]", "ref_id": "BIBREF14"}, {"start": 1008, "end": 1012, "text": "[16]", "ref_id": "BIBREF15"}], "ref_spans": []}, {"section": "Researchers Conducting Questionnaire-Based Studies with Fellow Academics: Endeavoring to Achieve a Higher Response Rate", "text": "Casanave and Hubbard ( [6] , p. 35), Jenkins, Jordan, and Weiland [7] , and Ferris and Tagg ( [11] , p. 303) all admitted that their surveys were long and complex. The trend over the past two decades is probably for questionnaires targeted at academics to become shorter and easier to respond to. Nevertheless, Ferguson et al. [13] suggested that curtailing the number of questions in a questionnaire, including by \"overriding the customary practice of including multiple items focusing on the same target\", \"can sometimes impact on reliability\" (p. 56). Researchers are thus caught in a dilemma: in trying to overcome low response rates, which may threaten the authenticity of the data (e.g., by not being representative of the larger population), they may feel compelled to adopt strategies that can potentially undercut the reliability of the questionnaire. When they do get a low response rate, researchers may have to make a case that the data are trustworthy and usable (presumably justified in doing so). Ferguson et al. [13] , for example, suggested that despite the \"modest\" response rate of 10% that their questionnaire received from their target Spanish academics respondents, the data \"do appear utilizable within the inherent limitations of the methodology\", \"bearing in mind that the sample size is not lower than in many comparable surveys\", plus their survey study was exploratory and would be followed up by interviews with a selection of academics (p. 47).", "cite_spans": [{"start": 23, "end": 26, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 66, "end": 69, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 94, "end": 98, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 327, "end": 331, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 1028, "end": 1032, "text": "[13]", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "My Personal Experience of Working with Chinese Academics as Research Participants", "text": "In the early 2000s, when I first embarked on an academic career, I had ingrained beliefs to dismantle first: having a scholar father specializing in historical Chinese linguistics, I grew up assuming that research should be based on books and study of texts; collecting \"data\" from human beings (including students) for research felt unnatural, and even unethical, to me. However, having decided to study what difficulties Chinese doctoral science students experience in trying to meet the degree conferment requirement of SCI (Science Citation Index) publication (a requirement becoming increasingly popular at Chinese universities at the time), i.e., publishing in (English-medium) international journals included in the SCI, and how they can be supported in the endeavor, I seemed to have little choice but to muster the courage to approach students to collect \"data\" from them. With little training in research methodology at the time, it was curiosity and a desire to learn that sent me onto a track of \"empirical research\"-which was a privileged term in the language education circle in China at the time (and it still is), in reaction to the much-criticized \"impressionistic,\" \"reflective\" tradition in Chinese research [25] . I remember the encouragement I received from an American professor at the time: that my project of working with science students and scientists would be very \"doable,\" as long as I could \"penetrate\" their \"academic tribes\" [26] .", "cite_spans": [{"start": 1227, "end": 1231, "text": "[25]", "ref_id": "BIBREF24"}, {"start": 1457, "end": 1461, "text": "[26]", "ref_id": "BIBREF25"}], "ref_spans": []}, {"section": "My Personal Experience of Working with Chinese Academics as Research Participants", "text": "Over the past decade, in a number of projects on scholarly publication, I have interviewed academics across disciplines in Hong Kong and Mainland China on their attitudes toward and practices in linguistic choice between English and Chinese in research and publication; I have conducted case studies of novice scientists (doctoral science students) in mainland universities writing for publication in English, which included an examination of how supervisors revise papers for novices, and, in particular, how supervisors perceive and tackle the issue of text-based plagiarism in novice texts. Other than working with university-based academics and students, I also accessed the orthopedics department of a Chinese hospital to investigate how medical doctors with doctoral degrees engage in research activities amidst their busy schedules of clinical practice. The challenge of gaining access to, and maintaining, contact with participants in these projects has not been small. On reflection, I would say that, on the whole, opportunities for access have come mostly from personal contacts, while constraints seem to be often related to my geographic location.", "cite_spans": [], "ref_spans": []}, {"section": "Accessing Participants through Personal Contacts", "text": "Personal contacts were formed by my having taught English at a university in a major city in east China, so that I was able to invite my students-doctoral students across disciplines-as my initial participants in my doctoral research project on Chinese novice scientists writing for international publication. The literature is rich with examples of English language professionals working with ESL students to study the latter's academic literacy pratices (e.g., [27, 28] ). In conducting such research, language professionals are able to draw upon their insider knowledge [29] while capitalizing on the advantage of access. As Casanave [30] commented on Spack's [28] three-year study of a Japanese student (named \"Yuko\") at a U.S. university: \"Like many other qualitative studies of writing, this case study used Spack's insider knowledge, contexts, and contacts at her own university to comfortably get access to what she needed from and about Yuko.\"", "cite_spans": [{"start": 463, "end": 467, "text": "[27,", "ref_id": "BIBREF26"}, {"start": 468, "end": 471, "text": "28]", "ref_id": "BIBREF27"}, {"start": 637, "end": 641, "text": "[30]", "ref_id": "BIBREF29"}, {"start": 663, "end": 667, "text": "[28]", "ref_id": "BIBREF27"}], "ref_spans": []}, {"section": "Accessing Participants through Personal Contacts", "text": "During my doctoral years I made painstaking efforts to stay in touch with my participants, so that the number of words I wrote in emails greatly surpassed the total number of words of my doctoral dissertation. In those emails, I played the roles of friend, English teacher, and researcher. I observed the principle of reciprocity [31] , and did what I could for my student participants, above all by editing English papers for them. Over time I got to know some of the students' supervisors, who also participated in my research. Later through the introduction of colleagues and friends, I reached more academics across disciplines, who, regarding me as a previous colleague, kindly accepted my invitation to participate in interviews. Additionally, the relevance of my topic of research, namely the impact of English and English publication requirements, for my target participants may have been a facilitative factor in my access. Examples of such reciprocal relationships between EAP language specialists and EAL academics, or students in disciplinary areas who need to publish in English, can be found in the literature: the former providing instruction, training, or editorial support to the latter, and the latter becoming research participants in interviews, case studies, or questionnaire surveys in return (e.g., [32, 33] ).", "cite_spans": [{"start": 330, "end": 334, "text": "[31]", "ref_id": "BIBREF30"}, {"start": 1327, "end": 1330, "text": "33]", "ref_id": "BIBREF32"}], "ref_spans": []}, {"section": "Accessing Participants through Personal Contacts", "text": "Other personal relations, or family relations to be more specific, have facilitated my access to researchers beyond academia, i.e., doctors and medical students at a Chinese hospital engaging in research for publication (e.g., [34, 35] ). Evidence can be gleaned from the literature to indicate that family relations can sometimes be an important factor in shaping one's research path. For example, we learned that for Dorothy Winsor, an accomplished professional and technical writing researcher, access to engineers through family relations has been critical: \"Winsor realized that with her access to engineers via her husband's profession she was in a position to learn something about engineering writing\" ( [36] , p. 355). Similarly, we learned from Dressen (or \"Dressen-Hammouda\" in her later publications) [37] that her husband was a geologist so that she had opportunities to learn about the discipline \"through osmosis\" (p. 284) and built her research path over time around geology text and geologists' genre mastery.", "cite_spans": [{"start": 227, "end": 231, "text": "[34,", "ref_id": "BIBREF33"}, {"start": 232, "end": 235, "text": "35]", "ref_id": "BIBREF34"}, {"start": 712, "end": 716, "text": "[36]", "ref_id": "BIBREF35"}, {"start": 813, "end": 817, "text": "[37]", "ref_id": "BIBREF36"}], "ref_spans": []}, {"section": "Researching in a Periphery Context as an Academic Based in a Semi-Periphery Region", "text": "To employ notions widely adopted in the literature, in terms of social science power, I am located in a \"semi-periphery\" region, but have conducted research in a \"periphery\" setting, and published in \"center\"/\"semi-periphery\" journals [38, 39] . (\"Semi-peripheral social science power\", according to Alatas ([38] , p. 606), \"may be defined as a social science community that is dependent on ideas originating in the social science centres, but which themselves exert some influence on peripheral social science communities\". From this perspective, Hong Kong may be regarded as a semi-peripheral social science power.) I am aware of the connection between my practice and the scenario described by Canagarajah [40] : that scholars from better-resourced and English-dominant countries/regions utilizing research data in the periphery to develop interpretations, typically through the lens of center-origined theories, and, henceforth, claiming leadership in scholarship by publicizing their work in Englishmedium journals. In contrast to this scenario, had local scholars \"enjoyed similar resources\", they \"would have also possessed the power to orchestrate the whole research enterprise under their own leadership\" and \"present the discovery in a manner favoring their community's interests, knowledge, and values\" ( [40] , p. 5). Canagarajah is sharp in his observation.", "cite_spans": [{"start": 235, "end": 239, "text": "[38,", "ref_id": "BIBREF37"}, {"start": 240, "end": 243, "text": "39]", "ref_id": "BIBREF38"}, {"start": 709, "end": 713, "text": "[40]", "ref_id": "BIBREF39"}, {"start": 1316, "end": 1320, "text": "[40]", "ref_id": "BIBREF39"}], "ref_spans": []}, {"section": "Researching in a Periphery Context as an Academic Based in a Semi-Periphery Region", "text": "As a Hong Kong-based academic conducting research with Chinese mainland fellow academics, I am conscious of the way I might be perceived: unlike some of my target participants, I am not a returnee (having completed graduate studies outside Mainland China and returned to become a mainland-based academic). I suspect that this kind of background gives me both an advantage and disadvantage when I approach my target participants. There may be perceptions that I cannot change; but I do have a clear goal in my research. With the advantage that I may enjoy-e.g., resources and, perhaps, the name of my home institution-my central concern in my work with Chinese academics has been to let the outside world hear their voices. I am indebted to their support of my research; and I decided that the best thing I can do for them in return is to do good research and disseminate my findings so that there will be a more balanced view about Chinese academics on the international stage: that other than corruptive practices that seem to be wide-spread in some quarters of Chinese academia [41, 42] , the general Chinese academics' diligence and studious efforts to achieve success in research and international visibility and impact should also be made known.", "cite_spans": [{"start": 1080, "end": 1084, "text": "[41,", "ref_id": "BIBREF40"}, {"start": 1085, "end": 1088, "text": "42]", "ref_id": "BIBREF41"}], "ref_spans": []}, {"section": "Researching in a Periphery Context as an Academic Based in a Semi-Periphery Region", "text": "I am also aware that I am just one of many education and social science academics in Hong Kong universities who conduct research in Mainland China and publish in English journals (for illustration of this phenomenon, see, for example, [43] ). The steady growth of the number of SSCI (Social Science Citation Index) journal articles co-authored by Chinese and overseas academics [44] seems to indicate a growing interest in exploring Chinese research sites. As the joint publications would indicate, a primary means for academics outside China to access Chinese research sites is to form research partnerships with their Chinese counterparts, with the latter's role possibly ranging from mere data collection to participating in the design of research and writing for publication. Over the years I have not made special efforts to forge research partnerships with mainland Chinese counterparts (of my discipline), partly due to the absence of linguistic or cultural barriers in my doing research in Mainland China-an advantage enjoyed by multilingual researchers, as having been discussed in the literature (e.g., [45] ). Of course, I have often needed the assistance of \"gatekeepers\" [46] in my efforts of access. Yet I have perhaps been viewed as an \"outsider\" sometimes. Outsiders from a reputable university in Hong Kong, a privileged semi-periphery region, are likely to be treated with some politeness; but this does not guarantee their target participants' cooperation. It has been suggested that collecting data in \"emerging societies\" is difficult, \"as there is little tradition of independent enquiry\" and \"asking questions in any form is viewed with suspicion\" ( [47] , p. 164). If this applies to collecting data in Chinese business organizations [47] , this should arguably be less true when working with Chinese academics. However, connections, or what is commonly known as guanxi in the Chinese culture, would still be crucial.", "cite_spans": [{"start": 235, "end": 239, "text": "[43]", "ref_id": "BIBREF42"}, {"start": 378, "end": 382, "text": "[44]", "ref_id": "BIBREF43"}, {"start": 1113, "end": 1117, "text": "[45]", "ref_id": "BIBREF44"}, {"start": 1673, "end": 1677, "text": "[47]", "ref_id": "BIBREF46"}, {"start": 1758, "end": 1762, "text": "[47]", "ref_id": "BIBREF46"}], "ref_spans": []}, {"section": "Accessing Fellow Academics in Hong Kong", "text": "While having mostly worked with mainland Chinese academics, I have also reached out to academics in Hong Kong on two occasions, the first to interview some scholars in humanities and social sciences to find out how they negotiate between local engagement and international participation through publication [43] , and the second in a project on university students writing from sources, with my own university as the research site. In the first study, I approached the target interviewees one-byone by emailing them, and most agreed to be interviewed. In the second study, in an early attempt, I only got three positive responses to my email invitations sent to over three-hundred Turnitin instructors (academic staff who have a Turnitin account) on campus to recruit interview participants in order to explore the issue of plagiarism among students. All these three respondents were expatriates (i.e., English-speaking academics, two from North America and another from the UK). I surmised what has led to the poor response to my request: firstly, an interview is perceived to be more timeconsuming than answering a questionnaire online; secondly, the topic of plagiarism is perhaps not an attractive one for busy colleagues; and thirdly, the fact that three expatriate colleagues responded might indicate that they are probably a little more interested in talking about the issue of plagiarism than the general Cantonese-speaking professors, having come from the Anglo-American academic culture where a concern of the issue has been long institutionalized. As the invitation for voluntary participation did not work, later, with the help of a research assistant, I utilized personal contacts and a snowball sampling approach ( [48] , p. 89) to access target interviewees.", "cite_spans": [{"start": 307, "end": 311, "text": "[43]", "ref_id": "BIBREF42"}, {"start": 1729, "end": 1733, "text": "[48]", "ref_id": "BIBREF47"}], "ref_spans": []}, {"section": "Providing Incentives to Fellow Academics for Them to Become Our Research Participants?", "text": "Reciprocity [31] can be an important principle in our research relationships with fellow academic participants, an obvious example being an English language professional editing English papers for her EAL participants, as mentioned earlier. In this scenario, the two sides are assisting each other in a high-stakes commitment, i.e., research and publication. Nevertheless, such reciprocity, in the form of the researcher giving support to the researched on the latter's work, is not always possible or required. In this situation, I have tried to pay my participants. Some may think paying academics for their participating in research is \"unusual\" (as a reviewer has written in commenting on the budget portion of a research proposal of mine). However, if it is appropriate to compensate research participants, such as by paying patients in health research [49] , it seems reasonable to pay fellow academics a certain token amount to express appreciation of their time and contribution of data, if it is also considered culturally acceptable to do so in a given context. Indeed, the payment can only be a symbolic compensation. An academic's hour spent on being interviewed cannot be measured by a modest honorarium. At the same time, it has to be said that the amount of such a payment is restricted, both by budget and by the consideration that it is important not to give an impression of bribing fellow academics into participation. A question here may be: how much is considered appropriate as a token fee (rather than an act of corruption) in paying a participant academic? It seems that the researcher's judicious judgment, in light of the local culture, will have to be relied upon in the decision. One may also suggest that if it is justifiable to pay a token fee to a fellow academic who participates in an interview, then one who completes a questionnaire should also be paid-yet, the latter is not usually possible, given the typical anonymity of respondents in questionnaire surveys.", "cite_spans": [{"start": 12, "end": 16, "text": "[31]", "ref_id": "BIBREF30"}, {"start": 858, "end": 862, "text": "[49]", "ref_id": "BIBREF48"}], "ref_spans": []}, {"section": "Providing Incentives to Fellow Academics for Them to Become Our Research Participants?", "text": "It should be pointed out that, when participant fellow academics are one's own colleagues at the same university, or have been colleagues with the researcher at one time, payment of token fees may be inappropriate. It is also very likely that, despite not having been a colleague of the researcher, a fellow academic may decline to be paid. In this case, needless to say, the fellow academic's preference should be respected. To be fair, when an academic does become a fellow academic's research participant, and gets paid a token fee, the incentive should not be the honorarium, but rather, a desire to support the fellow academic. This is \"academic citizenship\" [50] at play.", "cite_spans": [{"start": 664, "end": 668, "text": "[50]", "ref_id": "BIBREF49"}], "ref_spans": []}, {"section": "\"Academic Citizenship\" in a Performative Culture", "text": "It seems that nowadays whether we as academics are willing to sacrifice some of our time to help a fellow academic is often hinged on our schedule: the pressure of publication, coupled with the often growing, rather than reducing, load of teaching and administrative duties, means that we have become highly selective in whether or not to respond, not to say that the frequency of such requests that we receive may have led to a sense of fatigue. Of the large number of emails we receive on a daily basis, those addressed to us personally from students, department colleagues, research collaborators, and certain professional colleagues are to be filtered in; while the rest is likely to be filtered out. It does take some conscious collegiality and a desire to support fellow academics for us to respond to a request to fill in an online questionnaire, to participate in an interview, or to share our syllabi or writing assignments (the request made by Braine [3] to fellow academics). It may be fair to suggest that academics nowadays, in general, have become more pragmatic than before: more often than not, we invest time only when something is judged to be \"relevant\" to our personal interest or duty.", "cite_spans": [{"start": 961, "end": 964, "text": "[3]", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "\"Academic Citizenship\" in a Performative Culture", "text": "It might be suggested that if Braine's [3] study were to be conducted today, nearly two decades after it actually took place, he probably would not even get as many as 80 (36% of his total targeted 223) responding and citing reasons for not being able to participate. Olsson and Sheridan ([15] , p. 39), who reported that their survey among Swedish fellow academics got \"a disappointingly low response rate of 17.5%\" with 35 completed questionnaires, noted their questionnaire was partly based on Phillipson and Skutnabb-Kangas's [51] questionnaire, which was administered to Danish scholars two decades earlier and received a nearly 50% response rate with 83 completed questionnaires. Evidence is lacking to claim that the difference in the response rates between the surveys represents any general trend, but we probably have a telling pair of examples here.", "cite_spans": [{"start": 39, "end": 42, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 530, "end": 534, "text": "[51]", "ref_id": "BIBREF50"}], "ref_spans": []}, {"section": "\"Academic Citizenship\" in a Performative Culture", "text": "Macfarlane [50] has insightfully discussed the \"apparent decline of academic citizenship\" (p. 296) and emphasized the essential role of \"service\" to \"the preservation of community life\" (p. 299). \"Service in academic life\", as Macfarlane put it, \"is fundamentally about citizenship inasmuch that it demands participation as a member of a community of scholars rather than simply the individualised (and perhaps, selfish) pursuit of research and teaching interests\" (p. 300). Clearly, supporting fellow academics by playing the role of being their research participants, thus indirectly helping to push forward understanding of educational issues, Macfarlane would agree, is a form of service, just as \"teaching observation, mentoring, reviewing of academic papers and the organisation of conferences\" are (p. 299). However, institutional forces, propelled by a performative culture which emphasizes \"efficiency, effectiveness and profitability\" ( [52] , p. 17), threaten to \"disengage\" [50] academics from their service role. Macfarlane ([50] , p. 309) called for \"more explicit emphasis on the importance of the service role within reward and recognition structures\" to reverse the trend of disengagement. It would be fair to suggest that, even if such structural adjustment cannot occur in the near future, intellectuals can still justifiably resist the trend of disengagement on a personal level, and, henceforth, on a community level.", "cite_spans": [{"start": 11, "end": 15, "text": "[50]", "ref_id": "BIBREF49"}, {"start": 947, "end": 951, "text": "[52]", "ref_id": "BIBREF51"}, {"start": 986, "end": 990, "text": "[50]", "ref_id": "BIBREF49"}], "ref_spans": []}, {"section": "Coda", "text": "Researchers may be taking many issues into consideration in order to maximize the chance of fellow academics' participation: e.g., the mode of surveying (which, nowadays, is typically sending an email invitation, embedded with a link to an online questionnaire, as noted earlier), the design of the questionnaire (user-friendly and focused), the timing of administering the questionnaire, and the mobilization of personal contacts. In addition, researchers make sure the cover letter or invitation is composed professionally, shows their credentials, and connects to the target respondents in a personalized way; they would also aim to clearly state the purpose of the study, what participation in a study involves, what sorts of questions will be asked, etc., all of which are, of course, also required in the application for ethical clearance. On the whole, they may demonstrate an understanding of the pressures in academia, and remarkable resilience and willingness to accommodate the target participants' schedule. An example of a request follows: \"E-mail Request for Participants\" \"I know you are very busy, but I am asking for about half an hour to interview you about intellectual property issues from an administrator's point of view\u2026 \u2026 I am willing to conduct the interview at your convenience during the next two months. \u2026 \u2026 Please reply if you would be willing to help me with this, and I'll try to arrange a time that works for you.\" ( [53] , pp. 154-155)", "cite_spans": [{"start": 1449, "end": 1453, "text": "[53]", "ref_id": "BIBREF52"}], "ref_spans": []}, {"section": "Coda", "text": "After every effort has been made to incentivize fellow academics' participation, how many will give a positive response may be out of a researcher's control.", "cite_spans": [], "ref_spans": []}, {"section": "Coda", "text": "Silverman [54] reminded us that, in qualitative research in particular, we may aim to turn the negative (such as the difficulty in access) into a positive factor. He said: \"Remember that the beauty of qualitative research is that it offers the potential for us to topicalize such difficulties rather than just treat them as methodological constraints. This is an issue of the creative use of troubles.\" (p. 153) Silverman did not illustrate how \"creative use of troubles\" might be achieved. However, it should not be difficult for an experienced researcher to name a couple of examples of how this might be done. Researchers, including those education researchers who need to engage fellow academics as participants, are resilient. Still, lack of cooperation from fellow academics may defeat our research purpose, as suggested earlier in the present paper.", "cite_spans": [{"start": 10, "end": 14, "text": "[54]", "ref_id": "BIBREF54"}], "ref_spans": []}, {"section": "Coda", "text": "By the time I finished writing this paper, I had responded to all three requests from fellow academics, mentioned at the beginning of this paper. I even emailed the requesting colleague in my faculty, after responding to his online questionnaire, that I would be happy to participate in an interview at a later stage if necessary, to elaborate on my responses in the questionnaire. I am glad I have added my two cents in a few fellow academics' research projects.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Interviewing one's peers: Methodological issues in a study of health professionals", "authors": [{"first": "L", "middle": [], "last": "Coar", "suffix": ""}, {"first": "J", "middle": [], "last": "Sim", "suffix": ""}], "year": 2006, "venue": "Scand. J. Prim. Health Care", "link": "7002535"}, "BIBREF1": {"title": "Qualitative research and the problem of judgement: Lessons from interviewing fellow professionals", "authors": [{"first": "C", "middle": ["A"], "last": "Chew-Graham", "suffix": ""}, {"first": "C", "middle": ["R"], "last": "May", "suffix": ""}, {"first": "M", "middle": ["S"], "last": "Perry", "suffix": ""}], "year": 2002, "venue": "Fam. Pract", "link": "12146601"}, "BIBREF2": {"title": "When professors don't cooperate: A critical perspective on", "authors": [{"first": "G", "middle": [], "last": "Braine", "suffix": ""}], "year": 2001, "venue": "EAP. Engl. Specif. Purp", "link": null}, "BIBREF3": {"title": "Initiating ESL students into the academic discourse community: How far should we go? TESOL Q", "authors": [{"first": "R", "middle": [], "last": "Spack", "suffix": ""}], "year": 1988, "venue": "", "link": "143643297"}, "BIBREF4": {"title": "Participating in international academic publishing: A Taiwan perspective. TESOL Q", "authors": [{"first": "H.-T", "middle": [], "last": "Min", "suffix": ""}], "year": 2014, "venue": "", "link": "144648823"}, "BIBREF5": {"title": "The writing assignments and writing problems of doctoral students: Faculty perceptions, pedagogical issues, and needed research", "authors": [{"first": "C", "middle": [], "last": "Casanave", "suffix": ""}, {"first": "P", "middle": [], "last": "Hubbard", "suffix": ""}], "year": 1992, "venue": "Engl. Specif. Purp", "link": "143477878"}, "BIBREF6": {"title": "The role of writing in graduate engineering education: A survey of faculty beliefs and practices", "authors": [{"first": "S", "middle": [], "last": "Jenkins", "suffix": ""}, {"first": "M", "middle": ["K"], "last": "Jordan", "suffix": ""}, {"first": "P", "middle": ["O"], "last": "Weiland", "suffix": ""}], "year": 1993, "venue": "Engl. Specif. Purp", "link": "143588401"}, "BIBREF7": {"title": "Academic oral communication needs of EAP learners: What subject-matter instructors actually require. TESOL Q", "authors": [{"first": "D", "middle": [], "last": "Ferris", "suffix": ""}, {"first": "T", "middle": [], "last": "Tagg", "suffix": ""}], "year": 1996, "venue": "", "link": "145197589"}, "BIBREF8": {"title": "Policies and practices in foreign language writing at the college level: Survey results and implications. Foreign Lang. Ann", "authors": [{"first": "M", "middle": [], "last": "O&apos;donnell", "suffix": ""}], "year": 2007, "venue": "", "link": "145530226"}, "BIBREF9": {"title": "Does second language writing research impact U.S. University foreign language instruction? System", "authors": [{"first": "M", "middle": [], "last": "Hubert", "suffix": ""}, {"first": "J", "middle": [], "last": "Bonzo", "suffix": ""}], "year": 2010, "venue": "", "link": "58239449"}, "BIBREF10": {"title": "Academic listening/speaking tasks for ESL students: Problems, suggestions, and implications. TESOL Q", "authors": [{"first": "D", "middle": [], "last": "Ferris", "suffix": ""}, {"first": "T", "middle": [], "last": "Tagg", "suffix": ""}], "year": 1996, "venue": "", "link": "145762794"}, "BIBREF11": {"title": "Publishing academic texts in english: A Polish perspective", "authors": [{"first": "A", "middle": [], "last": "Duszak", "suffix": ""}, {"first": "J", "middle": [], "last": "Lewkowicz", "suffix": ""}], "year": 2008, "venue": "J. Engl. Acad. Purp", "link": "145375209"}, "BIBREF12": {"title": "English as an international language of scientific publication: A study of attitudes", "authors": [{"first": "G", "middle": [], "last": "Ferguson", "suffix": ""}, {"first": "C", "middle": [], "last": "Perez-Llantada", "suffix": ""}, {"first": "R", "middle": [], "last": "Plo", "suffix": ""}], "year": 2011, "venue": "World Engl", "link": "145349828"}, "BIBREF13": {"title": "Spanish researchers' perceived difficulty writing research articles for English-medium journals: The impact of proficiency in English versus publication experience", "authors": [{"first": "A", "middle": ["I"], "last": "Moreno", "suffix": ""}, {"first": "J", "middle": [], "last": "Rey-Rocha", "suffix": ""}, {"first": "S", "middle": [], "last": "Burgess", "suffix": ""}, {"first": "I", "middle": [], "last": "L\u00f3pez-Navarro", "suffix": ""}, {"first": "I", "middle": [], "last": "Sachdev", "suffix": ""}], "year": 2012, "venue": "", "link": null}, "BIBREF14": {"title": "A case study of Swedish scholars' experiences with and perceptions of the use of English in academic publishing", "authors": [{"first": "A", "middle": [], "last": "Olsson", "suffix": ""}, {"first": "V", "middle": [], "last": "Sheridan", "suffix": ""}], "year": 2012, "venue": "Writ. Commun", "link": "143451417"}, "BIBREF15": {"title": "English as an academic language at a Swedish university: Parallel language use and the 'threat' of English", "authors": [{"first": "K", "middle": [], "last": "Bolton", "suffix": ""}, {"first": "M", "middle": [], "last": "Kuteeva", "suffix": ""}], "year": 2012, "venue": "J. Multiling. Multicult. Dev", "link": "28244693"}, "BIBREF16": {"title": "Young faculty job perceptions in the midst of Chinese higher education reform: The case of Zhejiang University", "authors": [{"first": "Y", "middle": [], "last": "Li", "suffix": ""}, {"first": "J", "middle": [], "last": "Li", "suffix": ""}, {"first": "Y", "middle": [], "last": "Sun", "suffix": ""}], "year": 2013, "venue": "Asia Pac. J. Educ", "link": "144994444"}, "BIBREF17": {"title": "Writing for scholarly publication in English: The case of Hong Kong", "authors": [{"first": "J", "middle": [], "last": "Flowerdew", "suffix": ""}], "year": 1999, "venue": "J. Second Lang. Writ", "link": "62589868"}, "BIBREF18": {"title": "Students' and faculty's perception of academic integrity in Hong Kong. Campus Wide Info. Sys", "authors": [{"first": "T", "middle": [], "last": "Kwong", "suffix": ""}, {"first": "H.-M", "middle": [], "last": "Ng", "suffix": ""}, {"first": "K.-P", "middle": [], "last": "Mark", "suffix": ""}, {"first": "E", "middle": [], "last": "Wong", "suffix": ""}], "year": 2010, "venue": "", "link": null}, "BIBREF19": {"title": "Leading the academy or being led? Hong Kong women academics", "authors": [{"first": "S", "middle": ["J"], "last": "Aiston", "suffix": ""}], "year": 2014, "venue": "High. Educ. Res. Dev", "link": "68869725"}, "BIBREF20": {"title": "Educating Chinese scientists to write for international journals: Addressing the divide between science and technology education and English language teaching", "authors": [{"first": "M", "middle": [], "last": "Cargill", "suffix": ""}, {"first": "P", "middle": [], "last": "O&apos;connor", "suffix": ""}, {"first": "Y", "middle": [], "last": "Li", "suffix": ""}], "year": 2012, "venue": "Engl. Specif. Purp", "link": "143644735"}, "BIBREF21": {"title": "Publish SCI papers or no degree\": Practices of Chinese doctoral supervisors in response to the publication pressure on science students", "authors": [{"first": "Y", "middle": [], "last": "Li", "suffix": ""}], "year": 2015, "venue": "Asia Pac. J. Educ", "link": "145412761"}, "BIBREF22": {"title": "Developing Chinese scientists' skills for publishing in English: Evaluating collaborating-colleague workshops based on genre analysis", "authors": [{"first": "M", "middle": [], "last": "Cargill", "suffix": ""}, {"first": "P", "middle": [], "last": "O&apos;connor", "suffix": ""}], "year": 2006, "venue": "J. Engl. Acad. Purp", "link": "143532027"}, "BIBREF23": {"title": "Developments in English for Specific Purposes", "authors": [{"first": "T", "middle": [], "last": "Dudley-Evans", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "St John", "suffix": ""}], "year": 1998, "venue": "", "link": null}, "BIBREF24": {"title": "Trends in research methods in applied linguistics: China and the West", "authors": [{"first": "Y", "middle": [], "last": "Gao", "suffix": ""}, {"first": "L", "middle": [], "last": "Li", "suffix": ""}, {"first": "J", "middle": [], "last": "L\u00fc", "suffix": ""}], "year": 2001, "venue": "Engl. Specif. Purp", "link": "143966102"}, "BIBREF25": {"title": "Academic Tribes and Territories", "authors": [{"first": "T", "middle": [], "last": "Becher", "suffix": ""}, {"first": "P", "middle": ["R"], "last": "Trowler", "suffix": ""}], "year": 2001, "venue": "", "link": "154037533"}, "BIBREF26": {"title": "Undergraduates in a Second Language: Challenges and Complexities of Academic Literacy Development", "authors": [{"first": "I", "middle": [], "last": "Leki", "suffix": ""}], "year": 2007, "venue": "", "link": "142375679"}, "BIBREF27": {"title": "The acquisition of academic literacy in a second language: A longitudinal case study", "authors": [{"first": "R", "middle": [], "last": "Spack", "suffix": ""}], "year": 1997, "venue": "Writ. Commun", "link": "143989187"}, "BIBREF29": {"title": "Qualitative inquiry in l2 writing", "authors": [{"first": "C", "middle": ["P"], "last": "Casanave", "suffix": ""}], "year": 2015, "venue": "Handbook of Second and Foreign Language Writing", "link": "185297127"}, "BIBREF30": {"title": "Strategies for gaining access to organisations and informants in qualitative studies", "authors": [{"first": "A", "middle": ["K"], "last": "Shenton", "suffix": ""}, {"first": "S", "middle": [], "last": "Hayter", "suffix": ""}], "year": 2004, "venue": "", "link": "18353360"}, "BIBREF32": {"title": "Scientific Writing in a Second Language", "authors": [{"first": "D", "middle": ["I"], "last": "Hanauer", "suffix": ""}, {"first": "K", "middle": [], "last": "Englander", "suffix": ""}], "year": 2013, "venue": "", "link": "144930859"}, "BIBREF33": {"title": "Chinese doctors connecting to the English publishing world: Literature access, editorial services, and training in publication skills", "authors": [{"first": "Y", "middle": [], "last": "Li", "suffix": ""}], "year": 2014, "venue": "Publications", "link": "38250200"}, "BIBREF34": {"title": "Boundary crossing: Chinese orthopedic surgeons as researchers", "authors": [{"first": "Y", "middle": [], "last": "Li", "suffix": ""}], "year": 2014, "venue": "J. Tech. Writ. Commun", "link": "143708528"}, "BIBREF35": {"title": "The mundane, power, and symmetry: A reading of the field with Dorothy Winsor and the tradition of ethnographic research", "authors": [{"first": "S", "middle": [], "last": "Read", "suffix": ""}], "year": 2011, "venue": "Tech. Commun. Q", "link": "144279686"}, "BIBREF36": {"title": "Accounting for Fieldwork in Three Areas of Modern Geology: A Situated Analysis of Textual Silence and Salience", "authors": [{"first": "D", "middle": ["F"], "last": "Dressen", "suffix": ""}], "year": 2002, "venue": "", "link": "134954792"}, "BIBREF37": {"title": "Academic dependency and the global division of labour in the social sciences", "authors": [{"first": "S", "middle": ["F"], "last": "Alatas", "suffix": ""}], "year": 2003, "venue": "Curr. Sociol", "link": "143665363"}, "BIBREF38": {"title": "Alternative Discourses in Asian Social Science: Responses to Eurocentrism", "authors": [{"first": "S", "middle": ["F"], "last": "Alatas", "suffix": ""}], "year": 2006, "venue": "", "link": "142218746"}, "BIBREF39": {"title": "A geopolitics of Academic Writing", "authors": [{"first": "A", "middle": ["S"], "last": "Canagarajah", "suffix": ""}], "year": 2002, "venue": "", "link": "142212388"}, "BIBREF40": {"title": "China's publication bazaar", "authors": [{"first": "M", "middle": [], "last": "Hvistendahl", "suffix": ""}], "year": 2013, "venue": "Science", "link": "32550961"}, "BIBREF41": {"title": "Publish or perish in China", "authors": [{"first": "J", "middle": [], "last": "Qiu", "suffix": ""}], "year": 2010, "venue": "Nature", "link": "205052380"}, "BIBREF42": {"title": "International engagement versus local commitment: Hong Kong academics in the humanities and social sciences writing for publication", "authors": [{"first": "Y", "middle": [], "last": "Li", "suffix": ""}, {"first": "J", "middle": [], "last": "Flowerdew", "suffix": ""}], "year": 2009, "venue": "J. Engl. Acad. Purp", "link": "144458501"}, "BIBREF43": {"title": "Institute of S&T Information of China: Statistical Data of Chinese S&T Papers", "authors": [], "year": 2013, "venue": "", "link": null}, "BIBREF44": {"title": "Two sides of the same coin: Challenges and opportunities for scholars from ESL/EFL backgrounds. In Academic Writing in a Second or Foreign Language: Issues and Challenges Facing ESL/EFL Academic Writers in Higher Education Contexts", "authors": [{"first": "R", "middle": [], "last": "Tang", "suffix": ""}, {"first": "R", "middle": [], "last": "Tang", "suffix": ""}, {"first": "", "middle": [], "last": "Ed", "suffix": ""}], "year": 2012, "venue": "", "link": null}, "BIBREF46": {"title": "Guanxi and professional conduct in China: A management development perspective", "authors": [{"first": "P", "middle": [], "last": "Wright", "suffix": ""}, {"first": "W", "middle": ["F"], "last": "Szeto", "suffix": ""}, {"first": "L", "middle": ["T W"], "last": "Cheng", "suffix": ""}], "year": 2002, "venue": "Int. J. Hum. Resour. Man", "link": "111383643"}, "BIBREF47": {"title": "Qualitative Research from Start to Finish", "authors": [{"first": "R", "middle": ["K"], "last": "Yin", "suffix": ""}], "year": 2011, "venue": "", "link": "60018929"}, "BIBREF48": {"title": "Paying research participants: A study of current practices in Australia", "authors": [{"first": "C", "middle": ["L"], "last": "Fry", "suffix": ""}, {"first": "A", "middle": [], "last": "Ritter", "suffix": ""}, {"first": "S", "middle": [], "last": "Baldwin", "suffix": ""}, {"first": "K", "middle": ["J"], "last": "Bowen", "suffix": ""}, {"first": "P", "middle": [], "last": "Gardiner", "suffix": ""}, {"first": "T", "middle": [], "last": "Holt", "suffix": ""}, {"first": "R", "middle": [], "last": "Jenkinson", "suffix": ""}, {"first": "J", "middle": [], "last": "Johnston", "suffix": ""}], "year": 2005, "venue": "J. Med. Ethics", "link": "1350166"}, "BIBREF49": {"title": "The disengaged academic: The retreat from citizenship", "authors": [{"first": "B", "middle": [], "last": "Macfarlane", "suffix": ""}], "year": 2005, "venue": "", "link": "145256118"}, "BIBREF50": {"title": "Danish scholars and languages of scientific communication", "authors": [{"first": "R", "middle": [], "last": "Phillipson", "suffix": ""}, {"first": "T", "middle": [], "last": "Skutnabb-Kangas", "suffix": ""}], "year": 1996, "venue": "Papers in language policy: Papers from the language policy conference", "link": "210446350"}, "BIBREF51": {"title": "At the critical moment: Conditions and prospects for critical management studies", "authors": [{"first": "V", "middle": [], "last": "Fournier", "suffix": ""}, {"first": "C", "middle": [], "last": "Grey", "suffix": ""}], "year": 2000, "venue": "Hum. Relat", "link": "1828805"}, "BIBREF52": {"title": "Higher education, administration ownership, collaboration, and publication: Connecting or separating the writing of administrators, faculty, and students?", "authors": [{"first": "L", "middle": ["S"], "last": "Bergmann", "suffix": ""}], "year": "", "venue": "Who owns this text?: Plagiarism, Authorship, and Disciplinary Cultures", "link": null}, "BIBREF54": {"title": "Doing Qualitative Research: A Practical Handbook", "authors": [{"first": "D", "middle": [], "last": "Silverman", "suffix": ""}], "year": 2005, "venue": "", "link": "144092634"}, "BIBREF55": {"title": "This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license", "authors": [], "year": "", "venue": "\u00a9 2015 by the author; licensee MDPI", "link": null}}, "ref_entries": {"TABREF0": {"text": "A summary of five surveys conducted by language professionals in U.S. Cont.", "type": "table"}, "TABREF1": {"text": "Cont.", "type": "table"}, "TABREF2": {"text": "A summary of five surveys conducted by language professionals or education researchers in universities in several Chinese-speaking regions.", "type": "table"}, "TABREF3": {"text": "Cont.", "type": "table"}}}
{"paper_id": "18982504", "_pdf_hash": "170db6c7f1e880ef933f219a9ad987320bb4f1ec", "abstract": [{"section": "Abstract", "text": "Abstract-This paper gives a comprehensive study on the modeling and design challenges of Through Silicon Vias (TSVs) in high speed three-dimensional (3D) system integration. To investigate the propagation characteristics incurred by operations within the ultra-broad band frequency range, we propose an equivalent circuit model which accounts for rough sidewall effect and high frequency effect. A closed-form expression for TSV metal oxide semiconductor (MOS) capacitance in both depletion and accumulation regions is proposed. The coupling of TSV arrays and near and far field effect on crosstalk analysis are performed using 3D Electro-Magnetic (EM) field solver. Based on the TSV circuit model, we optimize the TSVs' architecture and manufacturing process parameters and develop effective design guidelines for TSVs, which could be used to resolve the signal integrity issues arising at high frequency data transmission in 3D Integrated Circuits (ICs).", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "INTRODUCTION", "text": "Three-dimensional integrated circuits (3D ICs) have become an inordinately propitious technology. The advantages gained by vertically stacking with multiple dies are: (1) a reduction in form factor, (2) high system speed, (3) high interconnect densities, (4) a decrease in overall wire length, and (5) reduced power consumption [1] [2] [3] . To analyze the electrical performance of 3D ICs, it is crucial to model and design the Through Silicon Vias (TSVs) accurately and efficiently because of their critical roles in the overall communication architecture [4] . TSVs are most commonly fabricated by high aspect ratio deep silicon etchinglined with a dielectric to provide electrical isolation; and super conformed filled with copper. Unlike the conventional interconnects, TSVs are essentially metal insulator semiconductor (MIS) devices [5] wherein the dielectric layer (typically SiO 2 ) is deposited to isolate the conductive metals from the substrate [6] . From the design standpoint, as related to parasitic extraction, TSVs can be incorporated as a separate cell (within conventional design tools) that demands proper analytical modeling and characterization. The ultimate goal is clear and straightforward: low-cost, high-yield process technologies, and successful attainments require concise optimizations of the TSV electrical design process, which demands a comprehensive consideration of complex TSV electrical modeling and analysis [7] .", "cite_spans": [{"start": 167, "end": 170, "text": "(1)", "ref_id": "BIBREF0"}, {"start": 328, "end": 331, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 332, "end": 335, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 336, "end": 339, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 558, "end": 561, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 840, "end": 843, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 957, "end": 960, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 1446, "end": 1449, "text": "[7]", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "INTRODUCTION", "text": "Metal oxide semiconductor (MOS) effect is an important phenomenon in TSV based 3D ICs which could overcome the misestimation that occurs in determining the cylindrical capacitance. When TSVs are operated in the low frequency range, the MOS effect in TSVs can be quite satisfactorily modeled as MOS capacitances [8] ; whereas, when TSVs are operated in the ultra-broad band frequency range, the electrical behavior is considerably altered and deviated into a domain of scarcely imaginable complexity. High speed switching can dynamically bias the TSV-MIS interface and result in regions of electronic accumulation or depletion; the capacitance becomes a nonlinear function of signal bias. In 3D ICs, the MOS capacitance plays a significant role to decrease the total capacitance due to biased substrate and thus it reduces the leakage current into the silicon material [2] .", "cite_spans": [{"start": 311, "end": 314, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 868, "end": 871, "text": "[2]", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "INTRODUCTION", "text": "Most of the TSV modeling approaches focus on the radio frequency (RF) applications with operation frequency of several GHz or even lower, whereas the TSV technology specifically for millimeter wave range (mmW)/THz applications is seldom reported. The mmW communication has emerged as an enabling technology to resolve the spectrum shortage issue due to significant growth of mobile data traffic [9] [10] [11] . There are some outstanding challenges due to electro-magnetic (EM) effects that are associated with the mmW technology such as impedance mismatching, signal reflections, crosstalk, and radiation [12, 13] . It is therefore a prudent consideration to address the critical issues which influence the properties of the TSVs in ultra-high and extremely-high frequency range [7] . These challenges can be addressed by properly modeling and designing the TSVs considering those effects in emerging and attractive 3D integration approach. A cross sectional view of an mmW transceiver module in 3D silicon interposer technology is shown in Figure 1 . One of the most important issues is the sidewall roughness which induces a significant quantity of leakage current within the TSVs [14] . The effect of sidewall roughness must be considered within the mmW frequency range, since the root mean square (rms) height of the sidewall roughness features become comparable to the skin depth. Heretofore, a considerable amount of research work on TSV modeling and analysis have been performed to address the impact of TSVs on high speed signals, to analyze the TSV crosstalk, to study the TSV resistance, as well as to apply the full-chip extraction and optimization [15] [16] [17] [18] [19] [20] [21] [22] . Reasonably comprehensive TSV models have been constructed which characterized resistance, inductance, capacitance, and conductance. These modeling methodologies can be categorized into three discrete classes; depending on the type of electromagnetic technique used: full-wave modeling, quasi-static modeling, and analytical modeling [15] . These three modes correspond to different silicon resistivity levels; (1) a slow wave, low frequency mode, where the electrical field is as if \"screened\" by the silicon substrate, and the magnetic field penetrates somewhat into the substrate; (2) a quasi-transverse electromagnetic mode, wherein both electrical and magnetic fields penetrate deeply into the substrate; and: (3) a very high frequency skin effect mode, where the characteristic dimension of the silicon skin depth is smaller than the TSV spacing.", "cite_spans": [{"start": 395, "end": 398, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 404, "end": 408, "text": "[11]", "ref_id": "BIBREF9"}, {"start": 606, "end": 610, "text": "[12,", "ref_id": "BIBREF10"}, {"start": 611, "end": 614, "text": "13]", "ref_id": "BIBREF11"}, {"start": 780, "end": 783, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 1184, "end": 1188, "text": "[14]", "ref_id": "BIBREF12"}, {"start": 1661, "end": 1665, "text": "[15]", "ref_id": "BIBREF13"}, {"start": 1666, "end": 1670, "text": "[16]", "ref_id": "BIBREF14"}, {"start": 1671, "end": 1675, "text": "[17]", "ref_id": "BIBREF15"}, {"start": 1676, "end": 1680, "text": "[18]", "ref_id": "BIBREF16"}, {"start": 1681, "end": 1685, "text": "[19]", "ref_id": "BIBREF17"}, {"start": 1686, "end": 1690, "text": "[20]", "ref_id": "BIBREF18"}, {"start": 1691, "end": 1695, "text": "[21]", "ref_id": "BIBREF19"}, {"start": 1696, "end": 1700, "text": "[22]", "ref_id": "BIBREF20"}, {"start": 2036, "end": 2040, "text": "[15]", "ref_id": "BIBREF13"}], "ref_spans": [{"start": 1042, "end": 1050, "text": "Figure 1", "ref_id": "FIGREF0"}]}, {"section": "INTRODUCTION", "text": "This paper proposes a closed-form analytic expression for TSV capacitance which accounts for both depletion and accumulation effects. Furthermore, we introduce a rough sidewall TSV model to account for the propagation characteristics within the ultra-broad band frequency range. Our endeavor culminates with an equivalent circuit model that accurately captures all the parasitic elements of various TSVs arrangements. The proposed circuit model accounts for high frequency skin effects, eddy currents in the substrate, MOS effects, and sidewall roughness effects. The model's compactness and compatibility with Simulation Program with Integrated Circuit Emphasis (SPICE) simulators allows Signal TSV Ground TSV Figure 2 . TSV pair with sidewall roughness. Figure 3 . SEM image of TSV with sidewall roughness using Bosch etching [14] .", "cite_spans": [{"start": 828, "end": 832, "text": "[14]", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "INTRODUCTION", "text": "the electrical modeling of various TSVs arrangements without the need for computationally expensive field solvers, which significantly reduces the simulation running time. We also focused on the coupling and cross talk analysis between the TSV interconnections which is critical in signal integrity. Based on the proposed TSV model, we optimize the TSVs' architecture and manufacturing process parameters and develop effective design guidelines for TSVs which could be used to resolve the signal integrity issues arising at high speed data transmission in 3D ICs.", "cite_spans": [], "ref_spans": []}, {"section": "MODELING AND SIMULATION OF TSV IN ULTRA-HIGH FREQUENCY", "text": "Electromagnetic models of differential and complex multi-TSVs are proposed to extract electrical parasitics and obtain analytic equations for lumped model analysis in the frequency domain [16] [17] [18] . Numerical, analytical, and measurement based methods have been extensively applied to extract the TSV parameters and validate EM simulations. High frequency analytical efforts have generated TSV models that include parametric studies of skin and proximity effects towards a comprehension of propagation characteristics [15, 19] . The impacts of differing TSV geometries and structures upon signal integrity can be quantified and the performance of the TSVs can be optimized by using coaxial configuration.", "cite_spans": [{"start": 188, "end": 192, "text": "[16]", "ref_id": "BIBREF14"}, {"start": 193, "end": 197, "text": "[17]", "ref_id": "BIBREF15"}, {"start": 198, "end": 202, "text": "[18]", "ref_id": "BIBREF16"}, {"start": 524, "end": 528, "text": "[15,", "ref_id": "BIBREF13"}, {"start": 529, "end": 532, "text": "19]", "ref_id": "BIBREF17"}], "ref_spans": []}, {"section": "MODELING AND SIMULATION OF TSV IN ULTRA-HIGH FREQUENCY", "text": "To model the TSVs, analytical expressions of RLGC parameters are required; these are obtained from the transmission line theory [23] , and simply extended into the high frequency range [15, 24] . Analytical expressions of frequency dependent RLGC incorporated within the model account for differing geometric parameters, dielectric materials, electromagnetic permeability, and the effects of lossy substrate materials. The skin effect is the critical model factor, because as operating frequency increases, current accumulates at the sidewall. As a consequence, the skin depth decreases; which causes the effective resistance and inductances of TSV to increase by reducing the effective cross-section of the conductor. These frequency dependent additional resistance and inductances are added to the RL parameters of transmission line to get the TSV resistance and inductance. The results of certain previous work [7] relate this skin effect can be modeled as an additional resistance, R 0 (f ) and inductance, L 0 (f ), according to:", "cite_spans": [{"start": 128, "end": 132, "text": "[23]", "ref_id": "BIBREF21"}, {"start": 185, "end": 189, "text": "[15,", "ref_id": "BIBREF13"}, {"start": 190, "end": 193, "text": "24]", "ref_id": "BIBREF22"}, {"start": 914, "end": 917, "text": "[7]", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "MODELING AND SIMULATION OF TSV IN ULTRA-HIGH FREQUENCY", "text": "where h is the height of TSV, r is the radius of TSV, f is the operating frequency in GHz, \u03bc 0 is the permeability of the free space, and \u03c3 Cu is the conductivity of the conductor.", "cite_spans": [], "ref_spans": []}, {"section": "MODELING AND SIMULATION OF TSV IN ULTRA-HIGH FREQUENCY", "text": "The effect of conductor surface roughness is more significant at mmW frequency due to skin effect. In our study, we examined the impact of surface roughness by the creating the TSV structures with and without surface roughness. The TSV surface roughness is illustrated in Figure 2 where a signal TSV is paired with a ground TSV. Also, an experimental study is performed by T. Nakamura et al. [14] to measure the leakage current due to the surface roughness at high frequency. In this experiment, the rough surface TSV shown in Figure 3 is created during a process of \"Bosch etching\".", "cite_spans": [{"start": 392, "end": 396, "text": "[14]", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "MODELING AND SIMULATION OF TSV IN ULTRA-HIGH FREQUENCY", "text": "The roughness of the conductor surface have significant effects on signal integrity and it is important to model the rough surface for proper analysis. The rough surface is characterized by the correlation length l, rms height of roughness \u0394x, and the correlation function. Using the spectral density or the Fourier transformation of the correlation functions, the roughness profile can be generated [25] ;", "cite_spans": [{"start": 400, "end": 404, "text": "[25]", "ref_id": "BIBREF23"}], "ref_spans": []}, {"section": "MODELING AND SIMULATION OF TSV IN ULTRA-HIGH FREQUENCY", "text": "where \u0394x is the height of sidewall roughness and (\u0394x) 2 C(x) the correlation function. Due to the existence of the conductor surface roughness of TSV, an increased resistance is appeared. For the proper modeling of TSV, it has to be taken into account the impact of roughness. A Gaussian distribution function is necessary to approximate the binomial distribution of events;", "cite_spans": [], "ref_spans": []}, {"section": "MODELING AND SIMULATION OF TSV IN ULTRA-HIGH FREQUENCY", "text": "Then applying the continuous Gaussian distribution function and modification of the resistance due to skin effect, the following additional resistance is obtained:", "cite_spans": [], "ref_spans": []}, {"section": "MODELING AND SIMULATION OF TSV IN ULTRA-HIGH FREQUENCY", "text": "where", "cite_spans": [], "ref_spans": []}, {"section": "MODELING AND SIMULATION OF TSV IN ULTRA-HIGH FREQUENCY", "text": "is angular spatial frequency, \u03c3 2 g the variance, and a the mean value of the number of events, and the probability of any integer.", "cite_spans": [], "ref_spans": []}, {"section": "MODELING AND SIMULATION OF TSV IN ULTRA-HIGH FREQUENCY", "text": "The schematic diagram of rough surface TSV is shown in Figure 4 where the geometric parameters are indicated. The complete equivalent circuit model of TSV shown in Figure 5 is obtained by combining all the high frequency RLGC elements that associated with the charge and current density distribution and accounts the sidewall roughness as well.", "cite_spans": [], "ref_spans": [{"start": 55, "end": 63, "text": "Figure 4", "ref_id": "FIGREF1"}, {"start": 164, "end": 172, "text": "Figure 5", "ref_id": "FIGREF2"}]}, {"section": "MODELING AND SIMULATION OF TSV IN ULTRA-HIGH FREQUENCY", "text": "This analytical model includes the parasitic elements that represent the loss, as well as the inductive and capacitive coupling in conductor and insulating sidewall. The accuracy of this analytical model of TSV is verified through the 3D field simulation based model by means of scattering parameters (S-parameters).", "cite_spans": [], "ref_spans": []}, {"section": "MODELING AND SIMULATION OF TSV IN ULTRA-HIGH FREQUENCY", "text": "Simulated results with and without rough sidewall and analytical results with rough sidewall is shown in Table 1 and Table 2 from 10 GHz to 100 GHz. The S-parameters of the TSV pair in 3D ICs studied for this work are calculated with the equivalent circuits illustrated in Figure 5 , and are Table 1 and Table 2 , it has been found that there is a close correlation and good agreement between the values of simulated results and the analytical models. At low frequency as 10 GHz, S parameter value is the same between the rough and smooth sidewall TSV but after that it varies due to the loss mechanism in rough sidewall. As a validation of the proposed model Figure 6 is plotted and it provides the comparison of resistances of TSV pair with and without surface roughness. Figure 7 shows the representation of the measured S 11 parameter.", "cite_spans": [], "ref_spans": [{"start": 105, "end": 124, "text": "Table 1 and Table 2", "ref_id": "TABREF0"}, {"start": 273, "end": 281, "text": "Figure 5", "ref_id": "FIGREF2"}, {"start": 292, "end": 311, "text": "Table 1 and Table 2", "ref_id": "TABREF0"}, {"start": 660, "end": 668, "text": "Figure 6", "ref_id": "FIGREF3"}, {"start": 774, "end": 782, "text": "Figure 7", "ref_id": "FIGREF4"}]}, {"section": "MODELING AND SIMULATION OF TSV IN ULTRA-HIGH FREQUENCY", "text": "Parametric study is being performed and simulation is carried to assess the quantitative influence of physical and geometric parameters of TSV on the impedance and consequently on loss properties. The impact of TSV physical parameters to its electrical response can also be better understood by technology tuning. The insertion and return loss can be set as perform merit matrices to assess the impact of the TSV physical parameters.", "cite_spans": [], "ref_spans": []}, {"section": "MODELING AND SIMULATION OF TSV IN ULTRA-HIGH FREQUENCY", "text": "To optimize the performance and capture the enhancement of the TSV model, the parameters, i.e., thickness of SiO 2 , pitch, and length of the via are investigated independently. The thinnest oxide liner has the highest return loss because a significant amount of reflected wave propagates in Si, which is not an insulator and hence experiences more loss. Whereas, the insertion loss improves for the shorter length of TSV. Therefore, the losses can be minimized by using higher resistivity silicon, thinner oxide line and shorter TSV length.", "cite_spans": [], "ref_spans": []}, {"section": "MODELING OF TSVS WITH VOLTAGE DEPENDENT AND NONLINEAR CAPACITANCE", "text": "New basis functions are introduced to capture the effect of TSV oxide liner that could simulate a large number of TSVs with less computation time [22] . The full wave analysis methods are accurate, but will be computationally intensive due to the large number and multi-scale dimensions (oxide thickness and aspect ratio) of TSVs in the 3D mmW ICs. Another bottleneck of the full wave methods is that it is difficult to be compatible with SPICE simulators. The equivalent circuit methods with lumped Resistance (R), inductance (L), conductance (G), and capacitance (C) elements could be a good alternative and can provide good compatibility with SPICE simulators. Most of the TSV modeling approaches in equivalent methods focus on the RF applications with operation frequency of several GHz or even lower, whereas the TSV technology specifically for mmW/THz applications is seldom reported. The challenges in modeling TSV in 3D mmW integrated circuits comes from the need of accurate broadband model capturing high frequency effect, frequency-dependent losses, coupling, and mismatch.", "cite_spans": [{"start": 146, "end": 150, "text": "[22]", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "MODELING OF TSVS WITH VOLTAGE DEPENDENT AND NONLINEAR CAPACITANCE", "text": "As mentioned in previous sections, TSVs have been mostly modeled assuming that the TSV MIS interface is not biased and the silicon substrate is a lossy, low conductive medium. Ignoring the semiconductor properties of the substrate and the resulting MOS capacitance introduce significant inaccuracies in the TSV modeling. Refs. [27] [28] [29] [30] studied the impact of a bias voltage on TSV characteristics (mostly capacitance) theoretically and experimentally. However, these analyses only consider the static biasing and hence they are only applicable for the small and low-speed signal application. Ref. [31] rigorously modeled the full-wave, both small and large signal wave propagation in a MIS micro strip structure. It requires solving both the full Maxwell equations and Boltzmann transport equation at the same time. Even though the TSVs are small in size and there is no need to consider wave propagation, the Boltzmann equation still needs to be solved simultaneously to consider the carrier accumulation and depletion. Furthermore, it is very difficult to apply the proposed TSV models to the channel simulations. Therefore, we propose a computationally efficient circuit model of the TSVs with the consideration of non-linear and voltage dependent capacitance.", "cite_spans": [{"start": 327, "end": 331, "text": "[27]", "ref_id": "BIBREF24"}, {"start": 337, "end": 341, "text": "[29]", "ref_id": "BIBREF26"}, {"start": 342, "end": 346, "text": "[30]", "ref_id": "BIBREF27"}, {"start": 607, "end": 611, "text": "[31]", "ref_id": "BIBREF28"}], "ref_spans": []}, {"section": "MODELING OF TSVS WITH VOLTAGE DEPENDENT AND NONLINEAR CAPACITANCE", "text": "Since the high speed signals can dynamically bias the TSV MIS interface and drive the TSV MIS into the accumulation or depletion regions, the TSV capacitance is expected to be nonlinear and dependent on the biasing of the TSVs with respect to the substrate. When the TSV MIS is in accumulation region, the electrical field is confined in the SiO 2 liner and the TSV capacitance is equal to the SiO 2 liner capacitance; when TSV MIS is in depletion region, the electrical field can penetrate into the substrate and the TSV capacitance is equal to the SiO 2 liner capacitance in series with the depletion region capacitance. The TSV MIS interface is biased statically. In a p-type substrate, the majority carriers are positively charged holes. A flat band voltage (V F B ) can be defined for MIS interface and it corresponds to the voltage that induces zero net charge in silicon:", "cite_spans": [], "ref_spans": []}, {"section": "MODELING OF TSVS WITH VOLTAGE DEPENDENT AND NONLINEAR CAPACITANCE", "text": "where \u03d5 m and \u03d5 Si are the work functions of TSV metal and silicon; Q S is space charge. C ox is silicon liner capacitance and expressed as, When a voltage V is applied to a TSV, if V < V F B , the positively charged holes in silicon are dragged to Si-SiO 2 interface, and an accumulation layer is formed; if V > V F B , holes are pushed away and a depletion region is formed (as shown in Figure 8 ). V F B depends on material properties as well as fabrication processes (doping, etc.). Note that the similar results could be applied to n-type substrate cases. When the TSV MIS is in accumulation region, the electrical field is confined in the SiO 2 liner and the TSV capacitance is equal to C ox . When TSV MIS is in depletion region, the electrical field can penetrate into the substrate, and the TSV capacitance is equal to C ox in series with C dep . (C ox is the capacitance of the SiO 2 liner, C dep is the capacitance of the depletion region). Accordingly, an analytical formula for depletion capacitance is introduced for the large signal and nonlinear capacitance [18] .", "cite_spans": [{"start": 1074, "end": 1078, "text": "[18]", "ref_id": "BIBREF16"}], "ref_spans": [{"start": 389, "end": 397, "text": "Figure 8", "ref_id": "FIGREF5"}]}, {"section": "MODELING OF TSVS WITH VOLTAGE DEPENDENT AND NONLINEAR CAPACITANCE", "text": "where h is the TSV height, \u03b5 s the dielectric constant of Si, and r ox the radius of a TSV with SiO 2 liner. The depletion width w dep can be calculated by solving the Poisson's equations of scalar potential in the depletion region and a Laplace's equation in the SiO 2 liner. The depletion width w dep is expressed as;", "cite_spans": [], "ref_spans": []}, {"section": "MODELING OF TSVS WITH VOLTAGE DEPENDENT AND NONLINEAR CAPACITANCE", "text": "where t ox is the SiO 2 liner thickness, V F B the flat band voltage, V is supply voltage, \u03b5 ox the dielectric constant of the SiO 2 liner, and N a the silicon doping concentration. We verified the proposed analytical formula by comparing it with the C-V curve obtained from static simulation and measurement with a static bias. The TSV capacitance C TSV (V (t)) is much higher than the capacitance obtained assuming small signal analysis and non-biasing condition [15] .", "cite_spans": [{"start": 465, "end": 469, "text": "[15]", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "MODELING OF TSVS WITH VOLTAGE DEPENDENT AND NONLINEAR CAPACITANCE", "text": "To obtain a faster signal response and lower signal distortion,the TSV process and geometry parameters ought to be tune to achieve minimum TSV capacitance in the desired operating voltage region. Table 3 shows the horizontal eye opening (UI) and vertical eye opening (mv) of the chip level TSV at accumulation region (high Cap.), depletion region (medium Cap.), and deep depletion region (low Cap.). Figure 9 shows the eye diagrams of interposer TSVs without and with optimized depletion capacitance when the signal data rate at 30 Gbps.", "cite_spans": [], "ref_spans": [{"start": 196, "end": 203, "text": "Table 3", "ref_id": "TABREF1"}, {"start": 400, "end": 408, "text": "Figure 9", "ref_id": "FIGREF6"}]}, {"section": "MODELING OF TSVS WITH VOLTAGE DEPENDENT AND NONLINEAR CAPACITANCE", "text": "As shown in the Figure 9 , the eye diagram of interposer TSV is closed when its data rate reaches 30 Gbps. As jitter closes the eye horizontally and noise closes the eye vertically, the sampling area gets squeezed, increasing the chance to sample incorrectly and get bit errors. This could be a very serious performance issue for TSV in silicon interposer, especially for mmW applications. The optimized depletion capacitance is achieved by biasing the TSV into the deep depletion region with low work function metal for p-type Si. Compared with the eye diagram shown in Figure 9 , we find the performance of interposer TSV significantly improved. As shown in both Table 3 and Figure 9 , optimizing the parameters of TSVs architecture and manufacturing process to obtain the minimum depletion capacitance could drastically enhance the TSV electrical performance across wide frequency range. Our study helps in developing design guidelines for TSVs in 3D ICs. ", "cite_spans": [], "ref_spans": [{"start": 16, "end": 24, "text": "Figure 9", "ref_id": "FIGREF6"}, {"start": 571, "end": 579, "text": "Figure 9", "ref_id": "FIGREF6"}, {"start": 665, "end": 672, "text": "Table 3", "ref_id": "TABREF1"}, {"start": 677, "end": 685, "text": "Figure 9", "ref_id": "FIGREF6"}]}, {"section": "COUPLING AND CROSSTALK ANALYSIS OF TSV ARRAYS", "text": "Coupling and cross talk are another important issues in large TSV arrays; such impacts can be analyzed in both time and frequency domain through eye margin analysis [20, 21] , which present the electrical modeling, analysis, and measurement of TSV coupling capacitance without considering the MOS capacitance effect. However, considering the MOS capacitance effect [8, 18] has an influential dominance on determining the TSV mutual capacitance. An important effect which requires special attention is the coupling effect in rough surface TSVs. Consider a numerous amount of closely spaced I/O TSVs co-existing with various mixtures of signal and ground TSVs in high speed circuits and systems [6, 32] ; we simulate the coupling of 4 rough surface TSV pairs arranged in linear configuration with ground and signal TSV in HFSS, as shown in Figure 10 .", "cite_spans": [{"start": 165, "end": 169, "text": "[20,", "ref_id": "BIBREF18"}, {"start": 170, "end": 173, "text": "21]", "ref_id": "BIBREF19"}, {"start": 365, "end": 368, "text": "[8,", "ref_id": "BIBREF7"}, {"start": 369, "end": 372, "text": "18]", "ref_id": "BIBREF16"}, {"start": 693, "end": 696, "text": "[6,", "ref_id": "BIBREF5"}, {"start": 697, "end": 700, "text": "32]", "ref_id": "BIBREF29"}], "ref_spans": [{"start": 838, "end": 847, "text": "Figure 10", "ref_id": "FIGREF0"}]}, {"section": "COUPLING AND CROSSTALK ANALYSIS OF TSV ARRAYS", "text": "The electric and magnetic fields for the TSV arrangement presented in Figure 10 are demonstrated in Figures 11 and 12 . As a MIS structure, the TSV produces electric and magnetic fields induced by current and voltage near the copper conductor which has near field characteristic. Both the electric and magnetic fields are plotted at 100 GHz.", "cite_spans": [], "ref_spans": [{"start": 70, "end": 79, "text": "Figure 10", "ref_id": "FIGREF0"}, {"start": 100, "end": 117, "text": "Figures 11 and 12", "ref_id": "FIGREF0"}]}, {"section": "COUPLING AND CROSSTALK ANALYSIS OF TSV ARRAYS", "text": "The capacitive coupling which is dominated in the TSV structure between the TSVs depend on the permittivity of the oxide, the TSV geometry, the arrangement of surrounding TSVs, and body contacts places. The coupling in the case of nearest adjacent TSVs with respect to the central TSV in a TSV array is higher than the coupling with the TSVs in the diagonal direction. The TSV coupling capacitance and inductance increase as the space between the TSVs decreases. As demonstrated in Figure 13 , S 1 has the strongest coupling to S 2 , compared to couplings to other signal TSVs. The coupling can be reduced by adding the ground TSV and making the TSV pairs fully surrounded by ground vias; following proper design consideration.", "cite_spans": [], "ref_spans": [{"start": 482, "end": 491, "text": "Figure 13", "ref_id": "FIGREF0"}]}, {"section": "COUPLING AND CROSSTALK ANALYSIS OF TSV ARRAYS", "text": "Also the crosstalk between those two adjacent TSVs is obtained. The crosstalk is the outcome (a) (b) of capacitive coupling due to the conductivity of Si substrate and thin SiO 2 that introduces a large capacitance. Both the simulation results, near end crosstalk (NEXT) and the far end crosstalk (FEXT) are shown in Figure 14 . At a frequency beyond 10 GHz, higher NEXT than FEXT is observed. The sharp slope in FEXT at very low frequency is for the slow wave propagation. For the Maxwell-Wagner effect, the velocity of propagation of slow wave mode is much slower and it increases the effective permittivity at lower frequencies. Also, NEXT behaves differently than FEXT at lower frequencies can be explained by the fact of ground planes that provides a shieling effect.", "cite_spans": [], "ref_spans": [{"start": 317, "end": 326, "text": "Figure 14", "ref_id": "FIGREF0"}]}, {"section": "CONCLUSION", "text": "Analytical modeling and 3D electromagnetic field simulation for TSVs have been performed, and the challenges associated with electrical design have been analyzed. A rough sidewall TSV is modeled that captured the impact of conductor sidewall roughness in high speed 3D interconnects. The proposed model is analytically calculated and validated by comparing the S-parameters predicted by both the model and the HFSS simulation up to 100 GHz in both magnitude and phase. From this study, it is found that the effect of TSV sidewall roughness becomes a very important factor when modeling TSVs in the extremely high frequency band. MOS effect and high frequency effect are investigated in mmW/THz frequency range. The impact of the voltage dependent and nonlinear capacitance on the performance of high speed differential signals is analyzed with the data of eye diagram approach. The coupling of TSV arrays under high speed operations using 3D EM field solver is performed and the near and far field effect on crosstalk analysis is observed. Parametric study is performed for the assessment of quantitative influence on loss properties of TSV and the impact of the frequency, pitch, dielectric, and TSV length is observed on the overall performance.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Numerical and experimental study on Cu protrusion of Cu-filled through-silicon vias (TSV)", "authors": [{"first": "F", "middle": ["X"], "last": "Che", "suffix": ""}, {"first": "W", "middle": ["N"], "last": "Putra", "suffix": ""}, {"first": "A", "middle": [], "last": "Heryanto", "suffix": ""}, {"first": "A", "middle": [], "last": "Trigg", "suffix": ""}, {"first": "S", "middle": [], "last": "Gao", "suffix": ""}, {"first": "C", "middle": ["L"], "last": "Gan", "suffix": ""}], "year": 2012, "venue": "Proc. IEEE Int. 3DIC Conf", "link": null}, "BIBREF1": {"title": "Electrical design and modeling challenges for 3D system integration", "authors": [{"first": "M", "middle": [], "last": "Swaminathan", "suffix": ""}], "year": 2012, "venue": "Design Conference", "link": "15309909"}, "BIBREF2": {"title": "3-D ICs: A novel chip design for improving deep-submicrometer interconnect performance and systems-on-chip integration", "authors": [{"first": "K", "middle": [], "last": "Banerjee", "suffix": ""}, {"first": "S", "middle": ["J"], "last": "Souri", "suffix": ""}, {"first": "P", "middle": [], "last": "Kapur", "suffix": ""}, {"first": "K", "middle": ["C"], "last": "Saraswat", "suffix": ""}], "year": 2001, "venue": "Proc. IEEE", "link": "5786126"}, "BIBREF3": {"title": "Future system-onsilicon LSI chips", "authors": [{"first": "M", "middle": [], "last": "Koyanagi", "suffix": ""}, {"first": "H", "middle": [], "last": "Kurino", "suffix": ""}, {"first": "K.-W", "middle": [], "last": "Lee", "suffix": ""}, {"first": "K", "middle": [], "last": "Sakuma", "suffix": ""}, {"first": "N", "middle": [], "last": "Miyakawa", "suffix": ""}, {"first": "H", "middle": [], "last": "Itani", "suffix": ""}], "year": 1998, "venue": "IEEE Micro", "link": null}, "BIBREF4": {"title": "Achieving stable Through-Silicon Via (TSV) capacitance with oxide fixed charge", "authors": [{"first": "L", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "H", "middle": ["Y"], "last": "Li", "suffix": ""}, {"first": "S", "middle": [], "last": "Gao", "suffix": ""}, {"first": "C", "middle": ["S"], "last": "Tan", "suffix": ""}], "year": 2011, "venue": "IEEE Elect. Device Lett", "link": "109382"}, "BIBREF5": {"title": "Equivalent lumped element models for various n-port Through Silicon Vias networks", "authors": [{"first": "K", "middle": [], "last": "Salah", "suffix": ""}, {"first": "H", "middle": [], "last": "Ragai", "suffix": ""}, {"first": "Y", "middle": [], "last": "Ismail", "suffix": ""}, {"first": "A", "middle": ["E"], "last": "Rouby", "suffix": ""}], "year": 2011, "venue": "Proc. 16th ASP-DAC", "link": "3778970"}, "BIBREF6": {"title": "Electrical modeling and analysis of sidewall roughness of Through Silicon Vias in 3D integration", "authors": [{"first": "M", "middle": ["A"], "last": "Ehsan", "suffix": ""}, {"first": "Z", "middle": [], "last": "Zhou", "suffix": ""}, {"first": "Y", "middle": [], "last": "Yi", "suffix": ""}], "year": 2014, "venue": "Proc. IEEE Int. Conf. EMC", "link": "36598960"}, "BIBREF7": {"title": "Electrical modeling of Through Silicon and Package Vias", "authors": [{"first": "T", "middle": [], "last": "Bandyopadhyay", "suffix": ""}, {"first": "R", "middle": [], "last": "Chatterjee", "suffix": ""}, {"first": "D", "middle": [], "last": "Chung", "suffix": ""}, {"first": "M", "middle": [], "last": "Swaminathan", "suffix": ""}, {"first": "R", "middle": [], "last": "Tummala", "suffix": ""}], "year": 2009, "venue": "Proc. IEEE Int. Conf. 3D Syst. Integr", "link": "31116424"}, "BIBREF8": {"title": "Measuring the information society", "authors": [{"first": "", "middle": [], "last": "Itu-D", "suffix": ""}], "year": 2011, "venue": "International Telecommunications Union (ITU), 2011. 10. Federal Communications Commission (FCC)", "link": null}, "BIBREF9": {"title": "An introduction to millimeter-wave mobile broadband systems", "authors": [{"first": "Z", "middle": [], "last": "Pi", "suffix": ""}, {"first": "F", "middle": [], "last": "Khan", "suffix": ""}], "year": 2011, "venue": "IEEE Communications Magazine", "link": null}, "BIBREF10": {"title": "Advanced Millimeter Wave Technologies: Antennas, Packaging, and Circuits", "authors": [{"first": "D", "middle": [], "last": "Liu", "suffix": ""}, {"first": "U", "middle": [], "last": "Pfeiffer", "suffix": ""}, {"first": "J", "middle": [], "last": "Gryzb", "suffix": ""}, {"first": "B", "middle": [], "last": "Gaucher", "suffix": ""}], "year": 2009, "venue": "", "link": "106654924"}, "BIBREF11": {"title": "Building millimeter-wave circuits in silicon", "authors": [{"first": "M", "middle": [], "last": "Oprysko", "suffix": ""}], "year": 2004, "venue": "Proc. IEEE Radio and Wireless Conf. on Adv. in RF and High Speed Syst. Integr", "link": null}, "BIBREF12": {"title": "Comparative study of side-wall roughness effects on leakage currents in through-silicon via interconnects", "authors": [{"first": "T", "middle": [], "last": "Nakamura", "suffix": ""}, {"first": "H", "middle": [], "last": "Kitada", "suffix": ""}, {"first": "Y", "middle": [], "last": "Mizushima", "suffix": ""}, {"first": "N", "middle": [], "last": "Maeda", "suffix": ""}, {"first": "K", "middle": [], "last": "Fujimoto", "suffix": ""}, {"first": "T", "middle": [], "last": "Ohba", "suffix": ""}], "year": 2012, "venue": "Proc. IEEE Int. Conf. 3D Syst. Integr", "link": "17393321"}, "BIBREF13": {"title": "High-frequency modeling of TSVs for 3-D chip integration and silicon interposers considering skin-effect, dielectric quasi-TEM and slow-wave modes", "authors": [{"first": "I", "middle": [], "last": "Ndip", "suffix": ""}, {"first": "B", "middle": [], "last": "Curran", "suffix": ""}, {"first": "K", "middle": [], "last": "Lobbicke", "suffix": ""}, {"first": "S", "middle": [], "last": "Guttowski", "suffix": ""}, {"first": "H", "middle": [], "last": "Reichl", "suffix": ""}, {"first": "K", "middle": [], "last": "Lang", "suffix": ""}, {"first": "H", "middle": [], "last": "Henke", "suffix": ""}], "year": 2011, "venue": "IEEE Trans. Compon. Packag. Manuf. Technol", "link": "45011928"}, "BIBREF14": {"title": "Differential Through-Silicon-Vias modeling and design optimization to benefit 3D IC performance", "authors": [{"first": "Y", "middle": [], "last": "Yi", "suffix": ""}, {"first": "Y", "middle": [], "last": "Zhou", "suffix": ""}], "year": 2013, "venue": "Proc. IEEE 22nd Conf. EPEPS", "link": "40328387"}, "BIBREF15": {"title": "A novel circuit model for multiple Through-Silicon-Vias (TSVs)", "authors": [{"first": "Y", "middle": [], "last": "Yi", "suffix": ""}, {"first": "Y", "middle": [], "last": "Zhou", "suffix": ""}], "year": 2013, "venue": "Proc. IEEE Int. Conf. 3DIC, 1-4", "link": null}, "BIBREF16": {"title": "Modeling differential Through-Silicon-Vias (TSVs) with voltage dependent and nonlinear capacitance", "authors": [{"first": "Y", "middle": [], "last": "Yi", "suffix": ""}, {"first": "Y", "middle": [], "last": "Zhou", "suffix": ""}, {"first": "X", "middle": [], "last": "Fu", "suffix": ""}, {"first": "F", "middle": [], "last": "Shen", "suffix": ""}], "year": 2013, "venue": "J. of Selectd. Area. Microelect", "link": "14713728"}, "BIBREF17": {"title": "Compact AC modeling and performance analysis of Through-Silicon Vias in 3-D ICs", "authors": [{"first": "C", "middle": [], "last": "Xu", "suffix": ""}, {"first": "H", "middle": [], "last": "Li", "suffix": ""}, {"first": "R", "middle": [], "last": "Suaya", "suffix": ""}, {"first": "K", "middle": [], "last": "Banerjee", "suffix": ""}], "year": 2010, "venue": "IEEE Trans. Electron Devices", "link": "18984622"}, "BIBREF18": {"title": "Modeling of crosstalk in Through Silicon Vias", "authors": [{"first": "A", "middle": ["E"], "last": "Engin", "suffix": ""}, {"first": "S", "middle": ["R"], "last": "Narasimhan", "suffix": ""}], "year": 2013, "venue": "IEEE Trans. Electromagn. Compatibil", "link": "2866715"}, "BIBREF19": {"title": "Coupling analysis of Through-Silicon Via (TSV) arrays in silicon interposers for 3D systems", "authors": [{"first": "B", "middle": [], "last": "Xie", "suffix": ""}, {"first": "M", "middle": [], "last": "Swaminathan", "suffix": ""}, {"first": "K", "middle": ["J"], "last": "Han", "suffix": ""}, {"first": "J", "middle": [], "last": "Xie", "suffix": ""}], "year": 2011, "venue": "Proc. IEEE Int. Symp. EMC", "link": "16791793"}, "BIBREF20": {"title": "Electromagnetic modeling of ThroughSilicon Via (TSV) interconnections using cylindrical modal basis functions", "authors": [{"first": "K", "middle": ["J"], "last": "Han", "suffix": ""}, {"first": "M", "middle": [], "last": "Swaminathan", "suffix": ""}, {"first": "T", "middle": [], "last": "Bandyopadhyay", "suffix": ""}], "year": 2010, "venue": "IEEE Trans. Adv. Packag", "link": "24857824"}, "BIBREF21": {"title": "Fields and Waves in Communication Electronics", "authors": [{"first": "S", "middle": [], "last": "Ramo", "suffix": ""}, {"first": "J", "middle": [], "last": "Whinnery", "suffix": ""}, {"first": "T", "middle": [], "last": "Duzer", "suffix": ""}], "year": 1994, "venue": "", "link": "118171150"}, "BIBREF22": {"title": "Analytical, numerical-, and measurement-based methods for extracting the electrical parameters of Through Silicon Vias (TSVs)", "authors": [{"first": "I", "middle": [], "last": "Ndip", "suffix": ""}, {"first": "K", "middle": [], "last": "Zoschke", "suffix": ""}, {"first": "K", "middle": [], "last": "Lobbicke", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Wolf", "suffix": ""}, {"first": "S", "middle": [], "last": "Guttowski", "suffix": ""}, {"first": "H", "middle": [], "last": "Reichl", "suffix": ""}, {"first": "K.-D", "middle": [], "last": "Lang", "suffix": ""}, {"first": "H", "middle": [], "last": "Henke", "suffix": ""}], "year": 2014, "venue": "IEEE Trans. Compon. Packag. Manuf. Technol", "link": "37293519"}, "BIBREF23": {"title": "Random rough surface effects on wave propagation in interconnects", "authors": [{"first": "L", "middle": [], "last": "Tsang", "suffix": ""}, {"first": "H", "middle": [], "last": "Braunisch", "suffix": ""}, {"first": "R", "middle": [], "last": "Ding", "suffix": ""}, {"first": "X", "middle": [], "last": "Gu", "suffix": ""}], "year": 2010, "venue": "IEEE Trans. Adv. Packag", "link": "45589280"}, "BIBREF24": {"title": "Electrical modeling and characterization of through-silicon-via for three dimensional ICs", "authors": [{"first": "G", "middle": [], "last": "Katti", "suffix": ""}, {"first": "M", "middle": [], "last": "Stucchi", "suffix": ""}, {"first": "K", "middle": [], "last": "Meyer", "suffix": ""}, {"first": "W", "middle": [], "last": "Dehaene", "suffix": ""}], "year": 2010, "venue": "IEEE Trans. Electron Devices", "link": "28295279"}, "BIBREF26": {"title": "Device level simulation of wave propagation along metal-insulator-semiconductor interconnects", "authors": [{"first": "G", "middle": [], "last": "Wang", "suffix": ""}, {"first": "R", "middle": ["W"], "last": "Dutton", "suffix": ""}, {"first": "C", "middle": ["S"], "last": "Rafferty", "suffix": ""}], "year": 2002, "venue": "IEEE Trans. Microwave Theory and Tech", "link": "11889887"}, "BIBREF27": {"title": "Rigorous electrical modeling of Through Silicon Vias (TSVs) with MOS capacitance effects", "authors": [{"first": "T", "middle": [], "last": "Bandyopadhyay", "suffix": ""}, {"first": "K", "middle": ["J"], "last": "Han", "suffix": ""}, {"first": "D", "middle": [], "last": "Chung", "suffix": ""}, {"first": "R", "middle": [], "last": "Chatterjee", "suffix": ""}, {"first": "M", "middle": [], "last": "Swaminathan", "suffix": ""}, {"first": "R", "middle": [], "last": "Tummala", "suffix": ""}], "year": 2011, "venue": "IEEE Trans. CPMT", "link": "14796014"}, "BIBREF28": {"title": "Through-Silicon-Via capacitance reduction technique to benefit 3-D IN performance", "authors": [{"first": "G", "middle": [], "last": "Katti", "suffix": ""}, {"first": "M", "middle": [], "last": "Stucchi", "suffix": ""}, {"first": "J", "middle": ["V"], "last": "Olmen", "suffix": ""}, {"first": "K", "middle": [], "last": "Meyer", "suffix": ""}, {"first": "W", "middle": [], "last": "Dehaene", "suffix": ""}], "year": 2001, "venue": "IEEE Electron Dev. Lett", "link": "28539095"}, "BIBREF29": {"title": "Crosstalk modeling and analysis of Through-Silicon-Via connection in 3D integration", "authors": [{"first": "X", "middle": [], "last": "He", "suffix": ""}, {"first": "W", "middle": [], "last": "Wang", "suffix": ""}, {"first": "Q", "middle": [], "last": "Cao", "suffix": ""}], "year": 2013, "venue": "PIERS Proceedings", "link": "114259536"}}, "ref_entries": {"FIGREF0": {"text": "Figure 1. (a) 3D structure of an mmW transceiver module, and (b) cross sectional view of TSV.", "type": "figure"}, "FIGREF1": {"text": "Figure 4. Rough sidewall TSV.", "type": "figure"}, "FIGREF2": {"text": "Figure 5. Equivalent circuit model of TSV.", "type": "figure"}, "FIGREF3": {"text": "Figure 6. Comparison of TSV pair resistances with and without surface roughness.", "type": "figure"}, "FIGREF4": {"text": "Figure 7. HFSS S parameter (S 11 ).", "type": "figure"}, "FIGREF5": {"text": "Figure 8. Accumulation and depletion of TSV MIS.", "type": "figure"}, "FIGREF6": {"text": "Figure 9. (a) Eye diagram of interposer TSV, (b) eye diagram of interposer TSV with optimized depletion capacitance.", "type": "figure"}, "FIGREF7": {"text": "Figure 10. Different TSV configurations for coupling analysis.", "type": "figure"}, "FIGREF8": {"text": "Figure 11. E field distributions of 4 TSV. Figure 12. H field distribution of 4 TSV.", "type": "figure"}, "FIGREF9": {"text": "Figure 11. E field distributions of 4 TSV. Figure 12. H field distribution of 4 TSV.", "type": "figure"}, "FIGREF10": {"text": "Figure 13. Coupling S parameters in different TSV pairs.", "type": "figure"}, "FIGREF11": {"text": "Figure 14. Signal-ground near and far end crosstalk of between two TSV pairs.", "type": "figure"}, "TABREF0": {"text": "Analysis of S parameter (magnitude) with and without rough sidewall in TSV.", "type": "table"}, "TABREF1": {"text": "Horizontal & vertical eye opening.High Cap. Medium Cap. Low Cap. High Cap. Medium Cap. Low Cap.", "type": "table"}}}
{"paper_id": "18982512", "_pdf_hash": "bf1b9d63dec9d08e4de80be6d5a8b6a62023a4da", "abstract": [{"section": "Abstract", "text": "It is shown that the local solution of parabolic equation with nonlocal boundary condition representing entropy can be extended to whole time domain for weights with large L 1 norms. When the weight is identically zero on some part of the boundary, it is shown that the boundary values can decrease even when the other weights are some large.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction.", "text": "This paper is concerned with the investigation of large time behavior of solutions to parabolic initial value problem subject to nonlocal boundary condition which describes the entropy in a quasi-static theory of thermoelasticity, namely, u t (x, t) = \u2206u(x, t) + \u00b5u, (x, t) \u2208 \u2126 \u00d7 (0, T ), u(z, t) = \u2126 f(z, y)u(y, t) dy, z \u2208 \u2202\u2126, 0 < t < T, u(x, 0) = u 0 (x), x \u2208 \u2126, (1.1) where u 0 (x) are assumed to be continuous on \u2126 and \u00b5 is a constant. The function f (z, y) is defined for z \u2208 \u2202\u2126 and y \u2208 \u2126 and continuous functions in y \u2208 \u2126 for each z \u2208 \u2202\u2126. Since for each z \u2208 \u2202\u2126, f (z, y) plays the weight of integration in (1.1), the function f (z, y) is called weights throughout this paper. Denote D T = \u2126 \u00d7 (0, T ) and D T \u222a \u0393 T = \u2126 \u00d7 [0, T ). The variable z stands for a generic point of boundary \u2202\u2126. The large time behavior of the solution u to Problem (1.1) is studied by taking an upper bound for u in Section 2. It is shown that the solution of Problem (1.1) with large weights f (z, \u00b7) for each z \u2208 \u2202\u2126 has an exponential lower bound in Section 3. Moreover, it is shown that the difference between maximum and minimum value on the boundary \u2202\u2126 can decrease if the weights are zero on a nonempty subset of \u2202\u2126 in z and zero on the boundary in y, that is, f (z, y) = 0, z \u2208 \u0393 \u2282 \u2202\u2126 for all y \u2208 \u2126 and f (z, y) = 0, y \u2208 \u2202\u2126.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction.", "text": "A supersolution is defined by reversing inequalities in (1.2). Using the notions of super and subsolution, we state the following: ", "cite_spans": [], "ref_spans": []}, {"section": "Introduction.", "text": "As a corollary, u 0 (x) > 0(< 0) implies u(x, t) > 0(< 0). Moreover, the local existence and uniqueness can be written as:", "cite_spans": [], "ref_spans": []}, {"section": "Introduction.", "text": "For the proofs of the comparison principle and the local existence theorem, see [4] . Here one can see that the results hold without any restriction to constant \u00b5 in the parabolic equation in (1.1). In this paper, we are only interested in the positive solutions of Problem (1.1), and hence we assume that u 0 > 0. Throughout this paper, L 1 and L 2 norm of a function on \u2126 is denoted by \u00b7 1 and \u00b7 2 , respectively.", "cite_spans": [{"start": 80, "end": 83, "text": "[4]", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "Global existence.", "text": "Under the convexity assumption on the domain \u2126 and the following assumptions on the weights;", "cite_spans": [], "ref_spans": []}, {"section": "Global existence.", "text": "it was known ( [3] ) that the maximum modulus max x\u2208\u2126 |v(x, t)| of solution v to the parabolic equation,", "cite_spans": [{"start": 15, "end": 18, "text": "[3]", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "Global existence.", "text": "subject to the nonlocal boundary conditions in (1.1) decreases, moreover, it was shown the exponential decay of the solution; there are some constants c 1 and \u03b3 > 0 such that", "cite_spans": [], "ref_spans": []}, {"section": "Global existence.", "text": "On the other hand, the author of [2] set up an example of one dimensional problem with \u00b5 = 0 and weights that violate (2.1), such that its maximum modulus of solution increases exponentially. In this paper, basic assumption on the weights is that", "cite_spans": [{"start": 33, "end": 36, "text": "[2]", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Global existence.", "text": "for each z \u2208 \u2202\u2126. One of the main concern is to find an upper bound of solutions in (1.2) with nonnegative weights in the integrals of boundary conditions which guarantees the global existence. For Problem (1.1) with arbitrary nonnegative weights, the author could not find other results about global existence. For convenience, let the domain \u2126 = {x = (x 1 , x 2 ) \u2208 R 2 : |x| < 1}. The results derived here can be extended to higher dimension without difficulties.", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 2.1. For the solution u to Problem (1.1) with nonnegative weights f , there is a sufficiently smooth function S(x, t) such that u(x, t) < S(x, t), t > 0. (2.3)", "text": "The choice of the function S(x, t) depends on the weights and sup x\u2208\u2126 u 0 (x).", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 2.1. For the solution u to Problem (1.1) with nonnegative weights f , there is a sufficiently smooth function S(x, t) such that u(x, t) < S(x, t), t > 0. (2.3)", "text": "Proof. Let S = p + q with p and q such that", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 2.1. For the solution u to Problem (1.1) with nonnegative weights f , there is a sufficiently smooth function S(x, t) such that u(x, t) < S(x, t), t > 0. (2.3)", "text": "where r = |x| = x 2 1 + x 2 2 1/2 . The positive constants A, a and \u03ba will be chosen later. Then p and q satisfy", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 2.1. For the solution u to Problem (1.1) with nonnegative weights f , there is a sufficiently smooth function S(x, t) such that u(x, t) < S(x, t), t > 0. (2.3)", "text": "If a satisfies ", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 2.1. For the solution u to Problem (1.1) with nonnegative weights f , there is a sufficiently smooth function S(x, t) such that u(x, t) < S(x, t), t > 0. (2.3)", "text": "Then, by the choice of \u03ba, k and a, we see that S = p + q satisfies", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 2.1. For the solution u to Problem (1.1) with nonnegative weights f , there is a sufficiently smooth function S(x, t) such that u(x, t) < S(x, t), t > 0. (2.3)", "text": "and by the inequality (2.6), we obtain for z \u2208 \u2202\u2126,", "cite_spans": [], "ref_spans": []}, {"section": "S(z, t) = p(z, t) + q(z, t) =", "text": "A e \u03bat + e \u03bat e \u22122a > Ae \u03bat > f (z, \u00b7) 2 ( p(\u00b7, t) 2 + q(\u00b7, t) 2 ) \u2265 \u2126 f(z, y)(p + q) dy = \u2126 f (z, y", "cite_spans": [], "ref_spans": []}, {"section": ")S(y, t) dy, 0 < t < T.", "text": "Note that above inequalities hold for arbitrary positive constant A. After choosing a and \u03ba, let A satisfy 2Ae \u2212a > sup x\u2208\u2126 u 0 (x). Then one has", "cite_spans": [], "ref_spans": []}, {"section": ")S(y, t) dy, 0 < t < T.", "text": "Hence S(x, t) is a supersolution to (1.1), and thus inequality (2.3) holds by Theorem 1.1.", "cite_spans": [], "ref_spans": []}, {"section": ")S(y, t) dy, 0 < t < T.", "text": "By Theorem 2.1, we have a supersolution for any T > 0. Hence the local solution u on D T from Theorem 1.2 is bounded in D T for arbitrary T > 0, and thus u can be extended to the whole time domain.", "cite_spans": [], "ref_spans": []}, {"section": "Decreasing property of boundary values.", "text": "In this section, boundary behavior of the solution to Problem (1.1) is studied. The difference of largest and smallest boundary values grows exponentially (inequality (3.4) ). When the weights are identically zero on some part of boundary, it is shown that the difference can be nonincreasing in Theorem 3.2.", "cite_spans": [], "ref_spans": []}, {"section": "Decreasing property of boundary values.", "text": "From now on, it is assumed that \u00b5 \u2265 0. A lower bound of the solution of Problem (1.1) with weights satisfying for each z \u2208 \u2202\u2126,", "cite_spans": [], "ref_spans": []}, {"section": "Decreasing property of boundary values.", "text": "can be obtained by the following Theorem: ", "cite_spans": [], "ref_spans": []}, {"section": "Decreasing property of boundary values.", "text": "Proof. Let v = u \u22121 , where u is the positive solution to Problem (1.1). By denoting F (z) = f(z, \u00b7) 1 , we see that for arbitrary T > 0,", "cite_spans": [{"start": 101, "end": 102, "text": "1", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "Decreasing property of boundary values.", "text": "Since f (z, \u00b7) 1 /F 2 (z) < 1 for each z \u2208 \u2202\u2126 and \u00b5 \u2265 0, one has v \u2264 c 1 e \u2212\u03b3t for some positive constants c 1 and \u03b3 by (2.2) and Theorem 1.1. Therefore, the solution u to Problem (1.1) satisfies (3.2) with c 2 = c \u22121", "cite_spans": [], "ref_spans": []}, {"section": "Decreasing property of boundary values.", "text": "1 . For weights satisfying (3.1), consider maximum and minimum of boundary values; By the assumption (3.5) and using integration by parts, we see that, for If the nonnegative constant \u00b5 is sufficiently small, then we can set I \u03be (h; y) as nonpositive by taking \u0393 as sufficiently large in the sense of (3.11) while h(z, \u00b7) 1 are large for z \u2208 \u0393 c . This can be done because the eigenvalue \u03bb is fixed negative number and g is a smooth function. Therefore, by the identities (3.6), we get the conclusion.", "cite_spans": [], "ref_spans": []}, {"section": "Decreasing property of boundary values.", "text": "On the other hand, since g(y) is nonnegative for every y \u2208 \u2126, \u2207 n g(\u03c9) in (3.12) is nonpositive. Thus, if \u00b5 > \u2212\u03bb, then I \u03be (h; y) > 0 on arbitrary proper subset \u0393 c of \u2202\u2126. Therefore, u(\u03be, t) is increasing for \u03be \u2208 \u0393 c .", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Extensions of a property of the heat equation to linear thermoelasticity and other theories", "authors": [{"first": "W", "middle": ["A"], "last": "Day", "suffix": ""}], "year": "", "venue": "Quart. Appl. Math", "link": "38221183"}, "BIBREF1": {"title": "A decreasing property of solutions of parabolic equations with applications to thermoelasticity", "authors": [], "year": "", "venue": "Quart. Appl. Math", "link": "40156190"}, "BIBREF2": {"title": "Monotonic decay of solutions of parabolic equations with nonlocal boundary conditions", "authors": [{"first": "A", "middle": [], "last": "Friedman", "suffix": ""}], "year": 1986, "venue": "Quart. Appl. Math", "link": null}, "BIBREF3": {"title": "Comparison principle for some nonlocal problems", "authors": [{"first": "Keng", "middle": [], "last": "Deng", "suffix": ""}], "year": 1992, "venue": "Quart. Appl. Math", "link": "125986059"}, "BIBREF4": {"title": "This work is partially supported by KOSEF", "authors": [], "year": 1998, "venue": "", "link": null}}, "ref_entries": {"FIGREF0": {"text": "Comparison principle: Let f (z, y) be nonnegative and con- tinuous in y on \u2126 for each z \u2208 \u2202\u2126. Let also u and v be subsolution and supersolution of Problem (1.1), respectively, and u", "type": "figure"}, "FIGREF1": {"text": "If \u00b5 \u2265 0 and u is a solution to Problem (1.1) and the weight f satisfies (3.1), then there are positive constants c 2 and \u03b3 such that", "type": "figure"}, "FIGREF2": {"text": "positive constant c by Theorem 3.1. Hence the difference of the boundary values become exponentially large if (3.1) and (3.3) are satisfied. This increasing property fails when some weights are identically zero, that is, for some nonempty set \u0393 \u2282 \u2202\u2126, f (z, \u00b7) \u2261 0 for z \u2208 \u0393. To see this, assume that, for each z \u2208 \u2202\u2126, f (z, y) \u2208 C 2 y (\u2126) and that f (z, y) \u2261 0 for each z \u2208 \u2202\u2126, y \u2208 \u2202\u2126. (3.5)", "type": "figure"}, "FIGREF3": {"text": "if I \u03be (f ; y) \u2265 0 for each y \u2208 \u2126, then the boundary value u(\u03be, t) increases, and if I \u03be (f ; y) \u2264 0, then the boundary value decreases. Since we are interested in the weights for which the value u(\u03be, t) decreases, consider the nonnegative function g on \u2126 such that \u2206g = \u03bbg in \u2126, (3.7) and g = 0 on \u2202\u2126. (3.8) Define the characteristic function on \u2202\u2126 = \u0393 \u222a \u0393 c by \u03c7(z) = 0 for z \u2208 \u0393 1 for z \u2208 \u0393 c ,z, y) = \u03c7(z)g(y). (3.10) Theorem 3.2. If \u0393 is sufficiently large in the sense that \u0393 \u2207 n g(\u03c9) d\u03c9 is sufficiently large, (3.11) then, for sufficiently small \u00b5 \u2265 0, the boundary values of the solution to Problem (1.1) with weights given by (3.10) are nonincreasing. Proof. For \u03be \u2208 \u2202\u2126, I \u03be (h, y) satisfies I \u03be (h; y) = \u03c7(\u03be)\u2206g(y) + \u00b5\u03c7(\u03be)g(y) \u2212 \u2202\u2126 \u03c7(\u03c9)\u03c7(\u03be)g(y)\u2207 n g(\u03c9) d\u03c9 = \u03c7(\u03be)\u2206g(y) + \u00b5\u03c7(\u03be)g(y) \u2212 \u03c7(\u03be) \u0393 c g(y)\u2207 n g(\u03c9) d\u03c9 = \u03c7(\u03be) \u03bb + \u00b5 \u2212 \u0393 c \u2207 n g(\u03c9) d\u03c9 g(y).", "type": "figure"}}}
{"paper_id": "18982781", "_pdf_hash": "bd1a6b12d64d608d8d29ee0e19a792729d17a1ed", "abstract": [{"section": "Abstract", "text": "Abstract Developing methods that result in targeting of therapeutic molecules in gene therapies to target tissues has importance, as targeting can increase efficacy and decrease off target-side-effects. Work from my laboratory previously showed that the extracellular matrix protein Del1 is organized in the extracellular matrix (ECM) via the Del1 deposition domain (DDD). In this work, a fusion protein with DDD was made to assay the ability to immobilize an enzyme without disrupting enzymatic function. A prostatic cancer-derived cell line LNCap that grows in an androgendependent manner was used with 3a-hydroxysteroid dehydrogenase (3 aHD), which catalyzes dihydrotestosterone (DHT). Plasmids encoding a 3aHD:DDD fusion were generated and transfected into cultured cells. The effects of 3aHD immobilized in the ECM by the DDD were evaluated by monitoring growth of LNCap cells and DHT concentrations. It was demonstrated that the DDD could immobilize an enzyme in the ECM without interfering with function.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Mouse Del1 is an ECM protein secreted by embryonic endothelial cells and hypertrophic chondrocytes [1] . Del1 consists of five domains: three epidermal growth factor (EGF) repeat domains (E1, E2, E3) and two Discoidin domains (C1, C2). Work from my laboratory recently showed that the C-termini of the C1 domains are essential for organization of Del1 into the ECM and that both the E3 repeat domain and the N-terminus of the C1 domain play supportive roles in organization into the ECM [2] . We termed this portion of the C1 domain the Del1 deposition domain (DDD). Fusion proteins that include the DDD and an alkaline phosphatase protein as a marker accumulate in the ECM without interfering with enzyme activity of the alkaline phosphatase.", "cite_spans": [{"start": 99, "end": 102, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 487, "end": 490, "text": "[2]", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Introduction", "text": "In some therapeutic treatments, localization of bioactive molecules specifically to the target tissue(s) increases the concentration of bioactive molecules in the target cells. This results in higher efficiency of treatment and because the concentration of the bioactive molecules in non-target tissues is minimized, this can also result in a lower incidence of treatment side effects. The purpose of this study is to ask if addition of DDD to an enzyme can result in localization of that enzyme to the ECM without affecting activity of the enzyme. Because the space between a cell and the ECM is not a simple vacancy, it is important to ask if a fusion protein derived from an enzyme is functional in the microenvironment of the ECM.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "To address this, I designed a cell-based system in which it is possible to readily monitor both an enzyme and the enzymatic products it produces. LNCap cells are prostatic cancer-derived cells that grow in an androgendependent manner and these cells were used as a model target cell in this study [3, 4] . DDD was used to immobilize 3a-hydroxysteroid dehydrogenase (3aHD), which intracellularly catalyzes the conversion of aldehydes and ketones to alcohols, and converts DHT to 5a-androstane-3a-, 17b-diol physiologically [5] . In this study, recombinant 3aHD proteins were secreted extracellularly as a result of addition of a signal sequence at the Nterminus of the recombinant protein (Fig. 1a, b) . The addition of a DDD to the 3aHD protein successfully localized the protein to the ECM. Moreover, the 3aHD in ECM was biochemically active and suppressed growth of LNCap cells.", "cite_spans": [{"start": 297, "end": 300, "text": "[3,", "ref_id": "BIBREF2"}, {"start": 301, "end": 303, "text": "4]", "ref_id": "BIBREF3"}, {"start": 522, "end": 525, "text": "[5]", "ref_id": "BIBREF4"}], "ref_spans": [{"start": 688, "end": 700, "text": "(Fig. 1a, b)", "ref_id": "FIGREF0"}]}, {"section": "Methods", "text": "Cell culture and evaluation of cell growth LNCap (CRL-1740) and Cos-7 (CRL-1651) cells were purchased from ATCC and grown in a-minimum essential medium (Invitrogen, Carlsbad, CA) supplemented with 10% fetal bovine serum (Invitrogen) at 37\u00b0C in an atmosphere containing 5% CO 2 . To evaluate dependency of cell growth on DHT, 50% confluent LNCap cells were prepared in a 24 well plate with 300 ll of a serum free medium, VP-SFM (Invitrogen) and different concentrations of DHT (Wako, Osaka, Japan) were added. After 4 days of culture, 30 ll of WST-1 (Takara, Outs, Japan) were added to the medium, incubated for 1 hour, and the absorbance at 405 nm was measured. The experiment was repeated three times and representative data are shown.", "cite_spans": [], "ref_spans": []}, {"section": "DNA constructs", "text": "First, a synthetic oligonucleotide encoding the signal peptide from Del1 (MKHLVAAWLLVGLSLGVPQFGKGDI) was obtained and cloned into pcDNA3D (Invitrogen) resulting in pcDNA3S. Next, a cDNA fragment encoding the human 3aHD gene (AB178898) was amplified by reverse transcriptase-PCR (RT-PCR) using the forward primer, 5 0 -AAGAATTCATGAACTCCAAATGTCATTG TGTCAT and the reverse primer 5 0 -AAGATATCGT ATTCATCCAAAAATGGCCAATTAG. The amplified fragment was cloned into the 3 0 end of the signal peptide, resulting in p3aHD (Fig. 1a) . Finally, a fragment encoding the DDD (amino acids 122-316 of Del1) was amplified with the forward primer 5 0 -AAGATATCTGTGAAG CTGAGCCTTGCAGAAAT and the reverse primer 5 0 -A ACTCGAGCATGTCCATGTTGAGTGTTCTGAA. This was cloned into the 3 0 end of the 3aHD gene, resulting in the plasmid p3aHD:DDD (Fig. 1a) . The recombinant proteins expressed by these constructs also had a V5 epitope tag at their C terminal ends.", "cite_spans": [], "ref_spans": [{"start": 512, "end": 521, "text": "(Fig. 1a)", "ref_id": "FIGREF0"}, {"start": 817, "end": 826, "text": "(Fig. 1a)", "ref_id": "FIGREF0"}]}, {"section": "Immunoblotting", "text": "ECM samples for immunoblotting analysis were prepared according to Hidai et al. [2] . Briefly, Cos-7 cells in six-well plate were transfected with pcDNA3S, p3aHD or p3aHD:DDD using Lipofectamine 2000 (Invitrogen). After 96 h of culture, conditioned medium was harvested. Then, cells were induced to detach by treatment of EDTA and the remaining ECM was collected with a scraper. The conditioned medium, cells, and ECM were fixed with 10% trichloracetic acid (Wako). The protein samples were separated by SDS-PAGE and transferred to a PVDF membrane (ATTO, Tokyo, Japan). The membrane was incubated with anti-V5 antibody (Invitrogen), followed by incubation with a horseradish peroxidase-conjugated secondary antibody, and immunoreactive proteins were detected using the ECL Advance Western Blotting Detection Kit (Amersham, Piscataway, NJ).", "cite_spans": [{"start": 80, "end": 83, "text": "[2]", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Evaluation of the effects of exogenous 3aHD", "text": "LNCap cells were plated to 50% confluency in a 24-well dish and transfected with 1 lg of pcDNA3S, p3aHD, or p3aHD:DDD using Lipofectamine2000. To test if an excess of p3aHD was introduced, cell growth was monitored after introduction of various amount of p3aHD. To monitor transfection efficiency, 0.1 lg of cDNA for the LacZ gene was co-transfected with each test construct. Expression of LacZ gene was monitored by measuring bgalactosidase enzyme activity using an assay system (Promega, Madison, WI). Cell number was evaluated with WST-1. The values obtained in samples transected with the control plasmid, pcDNA3S, were normalized to 1. The experiment was repeated three times and representative data are shown.", "cite_spans": [], "ref_spans": []}, {"section": "Evaluation of the effects of exogenous 3aHD", "text": "Assays of conditioned ECM ECM conditioned with 3aHD was prepared according to Hidai et al. [2] . Briefly, Cos-7 cells were cultured in a 24-well dish and transfected with 1 lg of pcDNA3S, p3aHD, or p3aHD:DDD using Lipofectamine2000. To standardize transfection efficiency, 0.1 lg of LacZ cDNA were cotransfected. Four days later, the cells were washed with phosphate buffered saline (PBS) and incubated in PBS containing 10 mM EDTA and a protease inhibitor cocktail (PIERCE, Rockford, IL) for 12 h at 48C. Next, cells were harvested by vigorous pipetting, collected by centrifugation, resuspended in 100 ll of tris buffered saline (TBS), and lysed by sonication. b-Galactosidase activity of the cell lysates was then assayed. Next, 1 9 10 4 LNCap cells were plated on the conditioned ECM, cultured for seven days, and evaluated with WST-1. To ask if exogenous DHT could rescue the growth of LNCap cells, various amounts of DHT (Wako) were added to the medium. The values obtained for samples transfected with the control plasmid, pcDNA3S, were normalized to 1. The experiment was repeated three times and representative data are shown.", "cite_spans": [{"start": 91, "end": 94, "text": "[2]", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Evaluation of the effects of exogenous 3aHD", "text": "Measurement of dihydrotestosterone levels ECM conditioned with 3aHD was prepared as described above. Serum obtained from a male volunteer as approved by Nihon University ethics committee was incubated with conditioned ECM in the presence of a protease inhibitor cocktail (PIERCE) for 96 h. The concentration of dihydrotestosterone in the serum was measured using the Dihydrotestosterone ELISA kit (IBL, Hamburg, Germany) according to the manufacture's protocol. The values obtained for samples transfected with the control plasmid, pcDNA3S, were normalized to 1. The experiment was repeated three times and representative data are shown.", "cite_spans": [], "ref_spans": []}, {"section": "Statistical analysis", "text": "Results were expressed as mean \u00b1 SEM. Dunn's tests or a Wilcoxon's test were performed, and statistical significance was set at P \\ 0.01.", "cite_spans": [], "ref_spans": []}, {"section": "Results and discussion", "text": "To confirm characteristics of LNCap cells, the cells were cultured in serum-free medium with various concentrations of DHT. As previously reported [3, 4] , growth of LNCap cells was dose-dependently accelerated by addition of exogenous DHT (Fig. 2a) . Next, the distribution of recombinant proteins in cells, ECM and medium was examined. Cells transfected with the control plasmid pcDNA3S, which encodes only a signal peptide (too small to be detected by SDS-PAGE as shown in Fig. 2b) , were used as a negative control. The expected sizes of the recombinant proteins encoded by p3aHD and p3aHD:DDD were 43 kDa and 65 kDa, respectively (Fig. 2b) . The recombinant protein encoded by p3aHD was not detected in ECM samples but was detected in conditioned medium and in cells. The recombinant protein encoded by p3aHD:DDD was localized to the ECM as expected for a DDD-containing polypeptide. The results also show that the total amount of 3aHD:DDD present in the culture medium was greater than the total amount found in the ECM. However, considering that the volume of medium was much larger than the volume of ECM tested, the concentration of 3aHD:DDD was much higher in ECM than in medium. Thus, it appears that the recombinant protein was concentrated in the ECM by the presence of the DDD.", "cite_spans": [{"start": 147, "end": 150, "text": "[3,", "ref_id": "BIBREF2"}, {"start": 151, "end": 153, "text": "4]", "ref_id": "BIBREF3"}], "ref_spans": [{"start": 240, "end": 249, "text": "(Fig. 2a)", "ref_id": "FIGREF1"}, {"start": 476, "end": 484, "text": "Fig. 2b)", "ref_id": "FIGREF1"}, {"start": 635, "end": 644, "text": "(Fig. 2b)", "ref_id": "FIGREF1"}]}, {"section": "Results and discussion", "text": "To ask if recombinant proteins with 3aHD affect growth of LNCap cells, plasmids encoding various 3aHD-derived constructs were transfected into LNCap cells. Transfection with p3aHD or p3aHD:DDD resulted in reduction of cell growth at day 6 (Fig. 3a) . To check that transfection efficiency did not vary grossly, transfection efficiency was monitored by assaying b-galactosidase activity after cotransfection with a LacZ construct. Transfection of p3aHD:DDD seemed to be more effective than that of p3aHD (Fig. 3a) . In this study, it was unfortunately impossible to standardize protein levels. Strictly speaking, our results cannot address if DDD improves the efficiency or effects of an enzyme by concentrating it in the ECM, as would be relevant to therapeutics [6] . The question may be resolved in an in vivo study, wherein not only the distribution but also the effects and side effects of the recombinant proteins could be evaluated.", "cite_spans": [{"start": 763, "end": 766, "text": "[6]", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Results and discussion", "text": "To determine if there is a dose-dependent relationship between cell growth and the amount of p3aHD DNA transfected into cells, the effect of transfection with different amounts of p3aHD DNA was tested (Fig. 3b) . The effect on cell growth was dependent on the amount of p3aHD added, suggesting that suppression of cell growth was not due to experimental procedures but instead, is the result of 3aHD-specific effects.", "cite_spans": [], "ref_spans": []}, {"section": "Results and discussion", "text": "DHT may be catabolized in cells transfected with the 3aHD construct; thus, I next assayed if a growth suppression effect is induced by ECM conditioned with p3aHD:DDD (Fig. 4a) . To again check that the transfection efficiency did not vary grossly, transfection efficiency was monitored by assaying b-galactosidase activity.", "cite_spans": [], "ref_spans": []}, {"section": "Results and discussion", "text": "Growth of cells on ECM conditioned by cells transfected with p3aHD was not different from growth on control ECM. However, ECM conditioned by cells transfected with p3aHD:DDD significantly suppressed the growth of otherwise untreated LNCap cells.", "cite_spans": [], "ref_spans": []}, {"section": "Results and discussion", "text": "On explanation for the effect observed in this work is that the presence of 3aHD in the ECM decreases the concentration of DHT in serum. To test this, serum was incubated with conditioned ECM and the concentration of DHT was measured in treated and untreated samples (Fig. 4b) . After 96 h, the concentration of DHT in serum incubated with ECM conditioned with p3aHD:DDD had significantly decreased.", "cite_spans": [], "ref_spans": []}, {"section": "Results and discussion", "text": "To confirm that the p3aHD:DDD suppresses the growth of LNCap cells via a decrease of DHT in medium, the ability of exogenously added DHT to reverse the effect was assayed (Fig. 4c) . Administration of exogenous DHT was In a previous study, it was found that alkaline phosphatase protein was efficiently deposited in the ECM in vitro and in vivo [2] . The present study suggests that DDD can fix enzymes in the ECM in a functional state, suggesting some biomedical applications for DDD fusion proteins. In cytotherapy, for example, cells could be preengineered with a cDNA encoding a specific DDD fusion protein. Because DDD has been reported to be effective for targeting to ECMs from various kinds of cells, one can predict that cell choice may be dictated solely according to need and that the ECM conditioned by the cells can then serve as a source of active enzyme.", "cite_spans": [{"start": 345, "end": 348, "text": "[2]", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Results and discussion", "text": "Similarly, a system involving a DDD fusion protein under the control of a tissue-specific promoter could efficiently localize an exogenous protein useful in gene therapy and thus presumably, target the effects of that enzyme to a specific cell type and/or location. This has promise for generating regions of high local concentration while at the same time, resulting in only a low systemic concentration of the therapeutic proteins by virtue of their deposition in ECM. To apply the idea further, one can imagine that chemicals capable of being activated by an enzyme may then by activated in a limited region, such as in a specific target tissue or cell type, via expression of an ECM-anchored version of the activating enzyme.", "cite_spans": [], "ref_spans": []}, {"section": "Results and discussion", "text": "In addition to enzymes, some ligands, such as the FAS ligand, might be used as partners of DDD and the system adapted to other applications [7] . That is, the presence of a cytotoxic ligand may limit the number of cells that can produce the ligand but if that ligand is in the ECM via anchoring by DDD, the ligand may remain active and accessible in the ECM even after death of the cell that initially expressed it. If this type of fusion between DDD and cytotoxic ligands results in a protein that is fixed in the ECM and significantly active, then one can imagine development of additional applications for the system.", "cite_spans": [{"start": 140, "end": 143, "text": "[7]", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "Results and discussion", "text": "Open Access This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited. Fig. 4 The effects of 3aHD localized to ECM by DDD. a The ECM conditioned with p3aHD:DDD suppressed the growth of LNCap cells. LacZ was co-transfected and b-gal activity was assayed as a measure of transfection efficiency. b Concentration of DHT in serum incubated with p3aHD:DDD conditioned ECM as measured by ELISA. c Addition of exogenous DHT restored LNCap cell growth normally suppressed by ECM conditioned with p3aHD:DDD. The results represent mean \u00b1 SEM (n = 6). **P \\ 0.01", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Cloning and characterization of developmental endothelial locus-1: an embryonic endothelial cell protein that binds the avb3 integrin receptor", "authors": [{"first": "C", "middle": [], "last": "Hidai", "suffix": ""}, {"first": "T", "middle": [], "last": "Zupancic", "suffix": ""}, {"first": "K", "middle": [], "last": "Penta", "suffix": ""}], "year": 1998, "venue": "Genes Dev", "link": null}, "BIBREF1": {"title": "Discoidin domain of Del1 protein contributes to its deposition in the extracellular matrix", "authors": [{"first": "C", "middle": [], "last": "Hidai", "suffix": ""}, {"first": "M", "middle": [], "last": "Kawana", "suffix": ""}, {"first": "H", "middle": [], "last": "Kitano", "suffix": ""}], "year": 2007, "venue": "Cell Tissue Res", "link": "22689447"}, "BIBREF2": {"title": "LNCaP model of human prostatic carcinoma", "authors": [{"first": "J", "middle": ["S"], "last": "Horoszewicz", "suffix": ""}, {"first": "S", "middle": ["S"], "last": "Leong", "suffix": ""}, {"first": "E", "middle": [], "last": "Kawinski", "suffix": ""}], "year": 1983, "venue": "Cancer Res", "link": "24904783"}, "BIBREF3": {"title": "Molecular characterization of human prostate carcinoma cell lines", "authors": [{"first": "A", "middle": [], "last": "Van Bokhoven", "suffix": ""}, {"first": "M", "middle": [], "last": "Varella-Garcia", "suffix": ""}, {"first": "C", "middle": [], "last": "Korch", "suffix": ""}], "year": 2003, "venue": "Prostate", "link": "32949167"}, "BIBREF4": {"title": "Human 3a-hydroxysteroid dehydrogenase isoforms (AKR1C1-AKR1C4) of the aldo-keto reductase superfamily: functional plasticity and tissue distribution reveals roles in the inactivation and formation of male and female sex hormones", "authors": [{"first": "T", "middle": ["M"], "last": "Penning", "suffix": ""}, {"first": "M", "middle": ["E"], "last": "Burczynski", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Jez", "suffix": ""}], "year": 2000, "venue": "Biochem J", "link": "7597841"}, "BIBREF5": {"title": "Targeted cancer therapy", "authors": [{"first": "C", "middle": [], "last": "Sawyers", "suffix": ""}], "year": 2004, "venue": "Nature", "link": "8061073"}, "BIBREF6": {"title": "FasL gene therapy: a new therapeutic modality for head and neck cancer", "authors": [{"first": "S", "middle": [], "last": "Elojeimy", "suffix": ""}, {"first": "J", "middle": ["C"], "last": "Mckillop", "suffix": ""}, {"first": "A", "middle": ["M"], "last": "El-Zawahry", "suffix": ""}], "year": 2006, "venue": "Cancer Gene Ther", "link": "25252408"}}, "ref_entries": {"FIGREF0": {"text": "Fig. 1 A schematics for experiments. a DNA constructs generated for transfection experiments. Following CMV promoter sequences (Pcmv), cDNA of signal peptide (SP), cDNA of 3aHD gene (3alphaHD) and cDNA of DDD (DDD) were inserted into pcDNA3D. b A schematic cartoon of transfection experiments. A recombinant protein of 3aHD with DDD is represented by an ellipsoid (3aHD) with a rectangle (DDD). Filled squares and filled triangles indicate DHT and catalyzed DHT, respectively. A zigzag line indicates ECM", "type": "figure"}, "FIGREF1": {"text": "Fig. 2 A cell-based readout of enzymatic activity. a Growth dependence of LNCap cells on DHT. The results represent mean \u00b1 -SEM (n = 6). b Immunoblotting analysis reveals expression of recombinant proteins in cultured medium (Medi), cells, and ECM", "type": "figure"}}}
{"paper_id": "18983082", "_pdf_hash": "9ba4fa0a3a19f222c39301aa98b15be560fc371b", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "High technology of vehicles safety, tum on the epoch of intelligent vehicles", "authors": [], "year": 2007, "venue": "", "link": null}, "BIBREF1": {"title": "Consumer Products", "authors": [], "year": "", "venue": "Mobileye Advance Warning System (AWS)", "link": null}, "BIBREF2": {"title": "The research of vehicle active safety based on machine vision", "authors": [{"first": "Youchun", "middle": [], "last": "Xu", "suffix": ""}], "year": 2003, "venue": "", "link": null}, "BIBREF3": {"title": "Gold: a Parallel Real-Time Stereo Vision System for Generic Obstacle and Lane Detection", "authors": [{"first": "M", "middle": [], "last": "Bertozzi", "suffix": ""}, {"first": "", "middle": ["A"], "last": "Broggi", "suffix": ""}], "year": 1997, "venue": "IEEE Transactions on Image Processing", "link": "18009401"}, "BIBREF4": {"title": "The mixed fuzzy logic control of autonomous wheel robot 'THMR-V", "authors": [{"first": "Bing", "middle": [], "last": "Li", "suffix": ""}], "year": 2003, "venue": "Robot", "link": null}, "BIBREF5": {"title": "Obstacle and lane detection on ARGO. Intelligent Transportation System", "authors": [{"first": "M", "middle": [], "last": "Bertozzi", "suffix": ""}, {"first": "A", "middle": [], "last": "Broggi", "suffix": ""}, {"first": "G", "middle": [], "last": "Conte", "suffix": ""}, {"first": "A", "middle": [], "last": "Fascioli", "suffix": ""}], "year": 1997, "venue": "ITSC 97. IEEE Conference on", "link": null}, "BIBREF6": {"title": "Survey of Intelligent Vehicle Applications Worldwide", "authors": [{"first": "R", "middle": [], "last": "Bishop", "suffix": ""}], "year": 2000, "venue": "Proceedings of the IEEE Intelligent Vehicles Symposium", "link": null}}, "ref_entries": {}}
{"paper_id": "18983391", "_pdf_hash": "9e87b9776d871dcd14c0659b2366bd2211909b3c", "abstract": [{"section": "Abstract", "text": "The conventional approaches to routing ", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Traffic engineering is one of the active research areas in communication networks. The traditional form of routing and resource allocation, as the two major building blocks of traffic engineering cannot address quality of service requirements of flows while optimizing network utilization for complex communication networks. In this paper we consider ant colony algorithms to address this problem. In this approach foraging ants find the shortest path in a synergistic way. While moving back and forth between nest and food, ants mark their paths by secreting pheromone.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "Step-by-step routing decisions are biased based on the local intensity of pheromone field which is the colony's collective and distributed memory. Ants will follow the most dense route in a maximum likelihood way. The actual algorithm implemented in nature by real ants is slow in convergence.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "Our studies show that the ant-based routing models are sensitive to initial parameters settings. Only careful adjustments of these initial parameters results in an acceptable convergence behavior. The robust behavior of the real ant compared to the routing algorithms derived from it justifies the investigation of these algorithms in depth to find the reasons behind their shortcomings. We present results from our study of ant behavior in a quest for a robust algorithm. Most of the ant-based algorithms have been studied with limited sourcedestination traffic. In this work we have extended the algorithm to a more realistic environment in which multiple sourcedestination flows compete for the resources. We study the routing and load balancing behavior that emerges and show how the behavior relates to analytical approaches for optimal minimum delay algorithms by Gallager [3] , Mitra [6] , and others [4] , [5] . We show the results using simulations in OPNET and derive recommendations on the improvement of the ant-like algorithms to achieve load balancing.", "cite_spans": [{"start": 879, "end": 882, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 891, "end": 894, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 908, "end": 911, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 914, "end": 917, "text": "[5]", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "Introduction", "text": "The rest of this paper is organized as follows. In chapter 2 we highlight the problems of traffic engineering. Chapter 3 is dedicated to the ant algorithm to provide the overall view of the ant approach. In chapter 4 we briefly describe the outstanding analytical methods introduced to address the problem of dynamic routing and flow assignment. Our experiments and the results including our view of the ant algorithm is discussed in chapter 5. Finally we conclude the paper in chapter 6.", "cite_spans": [], "ref_spans": []}, {"section": "Traffic Engineering", "text": "Traffic engineering is the process of mapping traffic flows onto the physical topology to meet traffic requirements, to enhance overall network utilization and create a uniform distribution of traffic throughout the network.", "cite_spans": [], "ref_spans": []}, {"section": "Traffic Engineering", "text": "Traffic engineering in the traditional Internet is achieved by manipulating routing metrics, such as monetary cost, hopcount, bandwidth, reliability and delay. Since IGP (Interior Gateway Protocol) route calculation is topology driven and based on a simple additive metric such as the hop-count, it does not consider other important dynamic criteria such as bandwidth availability. As a result, traffic can be unevenly distributed across the network causing inefficient use of resources. Uneven distribution of traffic is complicated since it can be the product of the dynamic routing protocols such as OSPF and IS-IS, that select the shortest paths to forward packets. Hence a solution is required that takes into account more factors than the common path-metrics. While using shortest path conserves network resources, it may cause some other problems, such as congestion on some paths and under utilization of other paths.", "cite_spans": [], "ref_spans": []}, {"section": "Traffic Engineering", "text": "These known problems with routing and the trends in networking and telecommunication provide incentive to look for another approach in routing and flow assignment as two main parts of traffic engineering.", "cite_spans": [], "ref_spans": []}, {"section": "Ant Algorithm", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "History", "text": "Nature has always been an important source of inspiration for academic research. In particular there is much interest in the behavior of ants. Individual ants seem to move at random, do nothing but wander off, and yet groups of ants can accomplish complex tasks. Somehow, a collective intelligence is formed out of many simple elements which is called swarm intelligence. Each agent (ant) processes a very simple algorithm. The collective outcome realizes a much more complex algorithm. The whole system is distributed and adaptive. Ants cannot see or hear. They only sense the environment, and also the food. Ants cannot talk either, they communicate indirectly through the environment. An ant can leave a trial of pheromones which are materials with particular fragrance. Ants can smell and sense the pheromones left by other ants, moreover, ants can detect the density of the pheromones.", "cite_spans": [], "ref_spans": []}, {"section": "Finding the Shortest Path", "text": "Ants find the shortest path to food according to this procedure: two ants start their random walk. They both eventually find the food. The one taking the shorter path finds the food first. Each ant leaves a trail of pheromones behind. Having taken the food the ants follow their pheromone trail towards the nest. The one with the shorter path returns first and arrives back to the nest first. Now a third ant wants to search for food. The ant realizes the trials left behind by its predecessors. Most likely it follows one of the existing trials rather than initiating a new trial and most likely it follows the trial with the higher density of pheromones. This results in even denser pheromone trial on the shorter path and in the long run this results in most ants using the shortest path.", "cite_spans": [], "ref_spans": []}, {"section": "Finding the Shortest Path", "text": "When an ant starts its walk with some small probability it starts a new trial. The first ants may not necessarily have chosen the shortest path but starting new paths helps continue the quest for shorter paths until finding the shortest one and eventually the ants emerge around the shortest path. The pheromones evaporate over time. This is an essential requirement for the dynamism of the algorithm. The algorithm is adaptive because of the evaporation and the fact that ants keep starting new paths with some probability.", "cite_spans": [], "ref_spans": []}, {"section": "Ants in Communications Networks", "text": "Ants in networks are emulated by mobile agents. Mobile agents are carried by packets. Special packets can be used as mobile agents (ants). Pheromones pass the information about the length of the path (time) to other ants. The agents can pass the same information to data packets at the nodes. Ants decide based on the density of the pheromones and some probability values. The probability values can be calculated based on the path information and listed in routing tables in the nodes. Starting with a static routing table for each node, every individual routing table stores the probabilities of using the next hops to reach all possible destinations. The sum of all the probabilities at each row should be equal to one.", "cite_spans": [], "ref_spans": []}, {"section": "Ants in Communications Networks", "text": "Different methods have been used in the literature for implementing and updating the routing tables using the ant approach such as AntNet [1] .", "cite_spans": [{"start": 138, "end": 141, "text": "[1]", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "Analytical Approaches", "text": "In this section we will briefly review existing analytical approaches to addressing the traffic engineering issue. Analytical routing algorithms can be distributed or centralized and also static or dynamic. Static routing algorithms cannot keep themselves up-to-date with the continuing changes in networks. Centralized methods suffer from the lack of scalability and having a single point of failure. Other distributed and dynamic routing and flow assignment algorithms have stability and convergence issues.", "cite_spans": [], "ref_spans": []}, {"section": "Analytical Approaches", "text": "A common characteristic of these methods is their dependence on one or more heuristic parameters that are found based on experiments. In Gallager's algorithm [3] in order to avoid loops the algorithm uses a parameter \u03b7 that should be globally chosen and every router must use it to ensure appropriate behavior but this parameter depends on input traffic pattern. It is impossible to find one working value for all input traffics.", "cite_spans": [{"start": 158, "end": 161, "text": "[3]", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "Analytical Approaches", "text": "In Mitra's approach [6] also a heuristic parameter is used which is critical for the robustness of the algorithm. This factor is called \"bandwidth protection\" R. In [5] again a heuristic is used which is in the form of a function.", "cite_spans": [{"start": 20, "end": 23, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 165, "end": 168, "text": "[5]", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "Our View", "text": "In this section we present our study of the ant colony algorithm based on simulation and discuss the results. We followed [1] for implementing ant colony algorithm, but we also examined modifications to show how the ant approach can be exploited to achieve load balancing.", "cite_spans": [{"start": 122, "end": 125, "text": "[1]", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "Methodology", "text": "Our simulations of the ant algorithm are applied to a fishlike network configuration as illustrated in figure 1 . The network consists of four routers and four hosts at the edges. Ants are generated at routers regularly and addressed to the destination hosts randomly. We use a uniform distribution to assign the destinations to the ants which are called forward ants at this stage.", "cite_spans": [], "ref_spans": []}, {"section": "Figure 1", "text": "The forward ants are routed to output links at each router until they find their way to their assigned destination hosts. A trace of the route traversed by the ant is also stored in the ant. At the host the ants are transformed to backward ants and sent back to the source through the same path that they took to arrive to the destination. At each router across the path the ants will then update the routing table that is used to route data packets. In the original ant colony algorithm the same table is used to route forward ants as well.", "cite_spans": [], "ref_spans": []}, {"section": "Figure 1", "text": "Data packets are generated by the hosts and addressed to certain destination hosts to create data traffic flows. At each router data packets will be routed to output links based on the information listed in the routing table. In an ant colony algorithm the routing table contains a probability number for every destination host though every existing output link. Packets are directed to an output link in proportion to the link probability.", "cite_spans": [], "ref_spans": []}, {"section": "Figure 1", "text": "The forward ants measure the travel time from each interim router to the final destination. The travel time which is a reflection of the route conditions is used to update the probability table when the backward ants come back to the router.", "cite_spans": [], "ref_spans": []}, {"section": "Figure 1", "text": "Except for the routing table, each node also keeps a table with records of the mean and variance of the trip time to every destination (delay). At each node, backward ants update the trip time statistics to the destination in addition to the output link probability. We derived these equations for updating the probabilities [ This equation gives an interim probability value for destination i from this router. In this equation j refers to all output links and k is the link that backward ant came from.", "cite_spans": [], "ref_spans": []}, {"section": "Figure 1", "text": "The probability values are filtered according to the following equation before being set into the routing table. This is to reduce the variations in the table because of temporary increases in the travel times. ", "cite_spans": [], "ref_spans": []}, {"section": "Simulations", "text": "We examined three different approaches. In the first approach we used the original ant colony algorithm. In this approach forward ants are routed at the routers using the probability values in the routing tables similar to data packets.", "cite_spans": [], "ref_spans": []}, {"section": "Simulations", "text": "In the second approach we used round-robin to forward the forward ants to the existing output links. The probability values are used to route only data packets.", "cite_spans": [], "ref_spans": []}, {"section": "Simulations", "text": "In the third approach we modified the probability calculation algorithm while using the same round-robin approach for forward ants.", "cite_spans": [], "ref_spans": []}, {"section": "Analysis and Discussion", "text": "First we consider the results from the first set of experiments based on the first approach. In the majority of scenarios using various settings of the parameters, the ant algorithm reveals a strong tendency towards finding and using a major route to the destination (which is most likely the fastest one). Other routes exist but with much less share of the carried traffic.", "cite_spans": [], "ref_spans": []}, {"section": "Analysis and Discussion", "text": "As shown in figure 2 , even though links 3 and 4 of router 0 are exactly alike, the probability value for link 3 rapidly rises and as a result the traffic from source 1 to destination 2 eventually flows entirely through link 3.", "cite_spans": [], "ref_spans": [{"start": 12, "end": 20, "text": "figure 2", "ref_id": "FIGREF2"}]}, {"section": "Analysis and Discussion", "text": "This result seems to be in agreement with the actual behavior of ants in the real world which is basically directed in finding the best path to the food source while exploring other paths. This behavior leads to finding a robust path to the destination with enough dynamism to adapt to changes and to find new and better paths. multiple routes from source to destination in a balanced way such that overall delay and utilization of the links is optimized over the network. The ant colony implementation of ant behavior does not seem to be the best solution to this situation according to our observations of the results from the first approach.", "cite_spans": [], "ref_spans": []}, {"section": "Analysis and Discussion", "text": "In analytical solutions for the multi-commodity flow assignment problem, information about the links is used at the edge routers in a distributed way to calculate the best distribution of traffic into possible routes to achieve load balancing aimed at reducing delay and increasing link utilization.", "cite_spans": [], "ref_spans": []}, {"section": "Analysis and Discussion", "text": "Using probability tables for forwarding ants in the ant colony algorithm creates a feedback loop in favor of links that have better trip time results. This is the reason behind the convergence behavior of this method.", "cite_spans": [], "ref_spans": []}, {"section": "Figure 3", "text": "In the second approach we eliminate this mechanism and replace it with a round-robin selection of output links for forward ants. As expected the result as shown in figure 3 , shows a better load balancing between existing possible links to the destination represented in the form of closer probability values.", "cite_spans": [], "ref_spans": []}, {"section": "Figure 3", "text": "Inspired by the analytical solutions, in a third approach we used local processing of the link information gathered by the ants to achieve a better load balancing, which also results in a better delay performance and link utilization. Our results, as shown in figure 4 , show that a better and more robust load balancing (closer and more stable probability values) is achieved between link 3 and 4, compared to the previous cases.", "cite_spans": [], "ref_spans": [{"start": 260, "end": 268, "text": "figure 4", "ref_id": "FIGREF4"}]}, {"section": "Figure 3", "text": "Our experiments revealed that somewhere a friendly relationship between analytical and bio-inspired approaches has to be made. We believe the real ant in nature has a robust behavior but this process is slow and also is not necessarily promoting load balancing. While the evaporation property of ant pheromone brings some relevance to the concept of loadsharing, in fact the evaporation in ants is to provide the dynamism necessary for adaptive behavior. In other words ants have completely robust, adaptive and distributed behavior but this behavior is not aimed at load-balancing as an objective.", "cite_spans": [], "ref_spans": []}, {"section": "Figure 3", "text": "On the other hand there are some analytical solutions to balance the load in the whole network and to do resource allocation and resource assignment as a direct result.", "cite_spans": [], "ref_spans": []}, {"section": "Figure 3", "text": "Our findings show that there is opportunity for thinking differently. We can be inspired by the wonders of the nature but we need not imitate them. We are free to modify the bio-inspired approaches (ant in our discussion) to obtain new desired behavior. ", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions and Future Works", "text": "In conclusion, our suggestion regarding the use of ant algorithms is that improved behavior is possible by augmenting it with the analytical computation.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions and Future Works", "text": "Our current work involves applying analytical solutions to ant like algorithms for routing and flow assignment to extract a robust and autonomic routing algorithm capable of tolerating predictable changes in traffic patterns and learn the unpredicted ones. ", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "AntNet: Distributed stigmergetic control of communication networks", "authors": [{"first": "G", "middle": ["D"], "last": "Cario", "suffix": ""}, {"first": "M", "middle": [], "last": "Dorigo", "suffix": ""}], "year": 1998, "venue": "Journal of Artificial Intelligence Research", "link": null}, "BIBREF1": {"title": "A QoS routing algorithm based on ant algorithm", "authors": [{"first": "Z", "middle": [], "last": "Subing", "suffix": ""}, {"first": "L", "middle": [], "last": "Zemin", "suffix": ""}], "year": 2001, "venue": "International Conference on Communications (ICC)", "link": "6944989"}, "BIBREF2": {"title": "A minimum delay routing algorithm using distributed computation", "authors": [{"first": "R", "middle": ["G"], "last": "Gallager", "suffix": ""}], "year": 1977, "venue": "IEEE Trans. On Communications", "link": "15465573"}, "BIBREF3": {"title": "Second derivative algorithm for minimum delay distributed routing in networks", "authors": [{"first": "D", "middle": [], "last": "Bersekas", "suffix": ""}, {"first": "R", "middle": ["G"], "last": "Gallager", "suffix": ""}], "year": 1984, "venue": "IEEE Trans. On Communications", "link": "124909"}, "BIBREF4": {"title": "A practical approach to minimizing delays in internet routing", "authors": [{"first": "J", "middle": ["J"], "last": "Garcia-Luna-Aceves", "suffix": ""}, {"first": "S", "middle": [], "last": "Vutukury", "suffix": ""}, {"first": "W", "middle": ["T"], "last": "Zaumen", "suffix": ""}], "year": 1999, "venue": "International Conference on Communications (ICC)", "link": "5173944"}, "BIBREF5": {"title": "The Structure and Management of SLAs in Networks", "authors": [{"first": "E", "middle": [], "last": "Bouillet", "suffix": ""}, {"first": "D", "middle": [], "last": "Mitra", "suffix": ""}], "year": 1999, "venue": "IEEE JSAC", "link": null}}, "ref_entries": {"FIGREF1": {"text": "instant delay or trip time, mean of delay and standard deviation of the delay.", "type": "figure"}, "FIGREF2": {"text": "Figure 2", "type": "figure"}, "FIGREF3": {"text": "a network of multiple sources and destinations with traffic flows from various sources to various destinations, the desired outcome involves distribution of data traffic across", "type": "figure"}, "FIGREF4": {"text": "Figure 4", "type": "figure"}}}
{"paper_id": "18984129", "_pdf_hash": "92f89edb940f2cf5c12aaa55964f9f6191752002", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "A 110-W AlGaNGaN heterojunction FET on thinned sapphire substrate", "authors": [{"first": "Y", "middle": [], "last": "Ando", "suffix": ""}, {"first": "Y", "middle": [], "last": "Okamoto", "suffix": ""}, {"first": "H", "middle": [], "last": "Miyamoto", "suffix": ""}, {"first": "N", "middle": [], "last": "Hayama", "suffix": ""}, {"first": "T", "middle": [], "last": "Nakayama", "suffix": ""}, {"first": "K", "middle": [], "last": "Kasahara", "suffix": ""}, {"first": "M", "middle": [], "last": "Kuzuhara", "suffix": ""}], "year": 2001, "venue": "IEEE IEDM Tech. Dig", "link": "27646345"}, "BIBREF1": {"title": "10-W/mm AlGaN-GaN HFET with a Field Modulating Plate", "authors": [{"first": "Y", "middle": [], "last": "Ando", "suffix": ""}, {"first": "Y", "middle": [], "last": "Okamoto", "suffix": ""}, {"first": "H", "middle": [], "last": "Miyamoto", "suffix": ""}, {"first": "T", "middle": [], "last": "Nakayama", "suffix": ""}, {"first": "T", "middle": [], "last": "Inoue", "suffix": ""}, {"first": "M", "middle": [], "last": "Kuzuhara", "suffix": ""}], "year": 2003, "venue": "IEEE Electron Device Let.t", "link": "43561203"}, "BIBREF2": {"title": "High-Power Recessed-Gate AlGaN-GaN HFET With a Field-Modulating Plate", "authors": [{"first": "Y", "middle": [], "last": "Okamoto", "suffix": ""}, {"first": "Y", "middle": [], "last": "Ando", "suffix": ""}, {"first": "T", "middle": [], "last": "Nakayama", "suffix": ""}, {"first": "K", "middle": [], "last": "Hataya", "suffix": ""}, {"first": "H", "middle": [], "last": "Miyamoto", "suffix": ""}, {"first": "T", "middle": [], "last": "Inoue", "suffix": ""}, {"first": "M", "middle": [], "last": "Senda", "suffix": ""}, {"first": "K", "middle": [], "last": "Hirata", "suffix": ""}, {"first": "M", "middle": [], "last": "Kosaki", "suffix": ""}, {"first": "N", "middle": [], "last": "Shibata", "suffix": ""}, {"first": "M", "middle": [], "last": "Kuzuhara", "suffix": ""}], "year": 2004, "venue": "IEEE Trans. Electron Device", "link": "30919378"}, "BIBREF3": {"title": "Gate-Recessed AlGaN-GaN HEMTs for High-Performance Millimeter-Wave Applications", "authors": [{"first": "J", "middle": ["S"], "last": "Moon", "suffix": ""}, {"first": "D", "middle": [], "last": "Wu", "suffix": ""}, {"first": "I", "middle": [], "last": "Wong", "suffix": ""}, {"first": "A", "middle": [], "last": "Milosavljevic", "suffix": ""}, {"first": "P", "middle": [], "last": "Conway", "suffix": ""}, {"first": "M", "middle": [], "last": "Hashimoto", "suffix": ""}, {"first": "M", "middle": [], "last": "Hu", "suffix": ""}, {"first": "M", "middle": [], "last": "Antcliffe", "suffix": ""}, {"first": "", "middle": [], "last": "Micovic", "suffix": ""}], "year": 2005, "venue": "IEEE Electron Device Lett", "link": "9413479"}, "BIBREF4": {"title": "8-Watt GaN HEMTs at Millimeter-Wave Frequencies", "authors": [{"first": "Y. -F", "middle": [], "last": "Wu", "suffix": ""}, {"first": "M", "middle": [], "last": "Moor", "suffix": ""}, {"first": "A", "middle": [], "last": "Saxler", "suffix": ""}, {"first": "T", "middle": [], "last": "Wisleder", "suffix": ""}, {"first": "U", "middle": ["K"], "last": "Mishra", "suffix": ""}, {"first": "P", "middle": [], "last": "Parikh", "suffix": ""}], "year": 2005, "venue": "IEEE IEDM Tech. Dig", "link": "33857536"}, "BIBREF5": {"title": "Design of Low-Cost 4W & 6W MMIC High Power Amplifiers for KaBand Modules", "authors": [{"first": "M", "middle": ["R"], "last": "Lyons", "suffix": ""}, {"first": "C", "middle": ["D"], "last": "Grondahl", "suffix": ""}, {"first": "S", "middle": ["M"], "last": "Daoud", "suffix": ""}], "year": 2004, "venue": "IEEE MTT-S Dig", "link": "10108545"}, "BIBREF6": {"title": "AlGaN/GaN Ka-Band 5-W MMIC Amplifier", "authors": [{"first": "A", "middle": ["M"], "last": "Darwish", "suffix": ""}, {"first": "K", "middle": [], "last": "Boutros", "suffix": ""}, {"first": "B", "middle": [], "last": "Luo", "suffix": ""}, {"first": "B", "middle": ["D"], "last": "Huebschman", "suffix": ""}, {"first": "E", "middle": [], "last": "Viveiros", "suffix": ""}, {"first": "H", "middle": ["A"], "last": "Hung", "suffix": ""}], "year": 2006, "venue": "IEEE Trans. Microw. Theory Tech", "link": "17992806"}, "BIBREF7": {"title": "High Power Hybrid and MMIC Amplifiers Using Wide-Bandgap Semiconductor Devices on Semi-insulating SiC Substrates", "authors": [{"first": "S", "middle": ["T"], "last": "Sheppard", "suffix": ""}, {"first": "R", "middle": ["P"], "last": "Smith", "suffix": ""}, {"first": "W", "middle": ["L"], "last": "Pribble", "suffix": ""}, {"first": "Z", "middle": [], "last": "Ring", "suffix": ""}, {"first": "T", "middle": [], "last": "Smith", "suffix": ""}, {"first": "S", "middle": [], "last": "Allen", "suffix": ""}, {"first": "J", "middle": [], "last": "Milligan", "suffix": ""}, {"first": "J", "middle": ["W"], "last": "Palmaour", "suffix": ""}], "year": 2002, "venue": "Device Research Conference", "link": "23224202"}, "BIBREF8": {"title": "100W C-band single-chip GaN FET power amplifier", "authors": [{"first": "Y", "middle": [], "last": "Okamoto", "suffix": ""}, {"first": "A", "middle": [], "last": "Wakejima", "suffix": ""}, {"first": "Y", "middle": [], "last": "Ando", "suffix": ""}, {"first": "T", "middle": [], "last": "Nakayama", "suffix": ""}, {"first": "K", "middle": [], "last": "Matsunaga", "suffix": ""}, {"first": "H", "middle": [], "last": "Miyamoto", "suffix": ""}], "year": "", "venue": "Electron. Lett", "link": null}}, "ref_entries": {}}
{"paper_id": "18984386", "_pdf_hash": "394e657b6c0f2eca0830bba8334b64fad69caeba", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Design Considerations for a New Terminal Area Arrival Scheduler, 10 th AIAA Aviation Technology, Integration and Operations Conference", "authors": [{"first": "J", "middle": [], "last": "Thipphavong", "suffix": ""}, {"first": "D", "middle": [], "last": "Mulfinger", "suffix": ""}], "year": 2010, "venue": "", "link": null}, "BIBREF2": {"title": "Simulation Results for Airborne Precision Spacing along Continuous Descent Arrivals, 8 th AIAA Aviation Technology, Integration and Operations Conference", "authors": [{"first": "", "middle": [], "last": "Baxley", "suffix": ""}], "year": 2008, "venue": "", "link": null}, "BIBREF4": {"title": "Performance of Airborne Precision Spacing Under Realistic Weather Conditions", "authors": [{"first": "", "middle": [], "last": "Houston", "suffix": ""}], "year": 2011, "venue": "", "link": "13027733"}, "BIBREF6": {"title": "Arrival Management with Required Navigation Performance and 3D Paths", "authors": [{"first": "A", "middle": [], "last": "Haraldsdottir", "suffix": ""}, {"first": "J", "middle": [], "last": "Scharl", "suffix": ""}, {"first": "M", "middle": [], "last": "Berge", "suffix": ""}, {"first": "E", "middle": [], "last": "Schoemig", "suffix": ""}, {"first": "M", "middle": [], "last": "Coats", "suffix": ""}], "year": 2007, "venue": "", "link": "208011722"}, "BIBREF8": {"title": "Analysis of Arrival Management Performance with Aircraft Required Time of Arrival Capabilities", "authors": [{"first": "A", "middle": [], "last": "Haraldsdottir", "suffix": ""}, {"first": "J", "middle": [], "last": "Scharl", "suffix": ""}, {"first": "J", "middle": [], "last": "King", "suffix": ""}, {"first": "E", "middle": ["G"], "last": "Schoemig", "suffix": ""}, {"first": "M", "middle": [], "last": "Berge", "suffix": ""}], "year": 2008, "venue": "26th International Congress of the Aeronautical Sciences", "link": "61850599"}, "BIBREF9": {"title": "Arrival Management Architecture and Performance Analysis with Advanced Automation and Avionics Capabilities", "authors": [{"first": "A", "middle": [], "last": "Haraldsdottir", "suffix": ""}, {"first": "J", "middle": [], "last": "Scharl", "suffix": ""}, {"first": "J", "middle": [], "last": "King", "suffix": ""}, {"first": "M", "middle": [], "last": "Berge", "suffix": ""}], "year": 2009, "venue": "9th AIAA Aviation Technology, Integration and Operations Conference", "link": "111730234"}, "BIBREF10": {"title": "Terminal Area Arrival Management Concepts Using Tactical Merge Management Techniques", "authors": [{"first": "A", "middle": [], "last": "Haraldsdottir", "suffix": ""}, {"first": "J", "middle": [], "last": "King", "suffix": ""}, {"first": "J", "middle": [], "last": "Scharl", "suffix": ""}], "year": 2010, "venue": "", "link": "2991053"}, "BIBREF12": {"title": "Design and Evaluation of the Terminal Area Precision Scheduling and Spacing System, 9th USA/Europe Air Traffic Management R&D Seminar", "authors": [{"first": "H", "middle": ["N"], "last": "Swenson", "suffix": ""}, {"first": "J", "middle": [], "last": "Thipphavong", "suffix": ""}, {"first": "A", "middle": [], "last": "Sadovsky", "suffix": ""}, {"first": "L", "middle": [], "last": "Chen", "suffix": ""}, {"first": "C", "middle": [], "last": "Sullivan", "suffix": ""}, {"first": "L", "middle": [], "last": "Martin", "suffix": ""}], "year": 2011, "venue": "", "link": null}, "BIBREF13": {"title": "Evaluation of the Terminal Precision Scheduling and Spacing System for NearTerm NAS Application", "authors": [{"first": "J", "middle": [], "last": "Thipphavong", "suffix": ""}, {"first": "H", "middle": [], "last": "Swenson", "suffix": ""}, {"first": "L", "middle": [], "last": "Martin", "suffix": ""}, {"first": "P", "middle": [], "last": "Lin", "suffix": ""}, {"first": "J", "middle": [], "last": "Nguyen", "suffix": ""}], "year": 2012, "venue": "1st International Conference on Human Factors in Transportation", "link": null}, "BIBREF14": {"title": "Potential Benefits of Terminal Airspace Traffic Automation for Arrivals", "authors": [{"first": "M", "middle": [], "last": "Ballin", "suffix": ""}, {"first": "H", "middle": [], "last": "Erzberger", "suffix": ""}], "year": 1998, "venue": "", "link": "121618885"}, "BIBREF15": {"title": "The Impact of Advanced Technology on Next Generation Air Transportation: A Case Study of Required Navigation Performance (RNP)", "authors": [{"first": "Y", "middle": [], "last": "Yoon", "suffix": ""}, {"first": "M", "middle": [], "last": "Hansen", "suffix": ""}], "year": 2007, "venue": "AIAA Modeling and Simulation Technologies Conference and Exhibit", "link": "112217273"}, "BIBREF16": {"title": "Evaluation of the Potential Environmental Benefits of RNAV/RNP Arrival Procedures, 11th AIAA Aviation Technology, Integration and Operations Conference", "authors": [{"first": "D", "middle": [], "last": "Muller", "suffix": ""}, {"first": "P", "middle": [], "last": "Uday", "suffix": ""}, {"first": "K", "middle": ["B"], "last": "Marais", "suffix": ""}], "year": 2011, "venue": "", "link": null}, "BIBREF17": {"title": "Benefits of Continuous Descent Operations in HighDensity Terminal Airspace Under Scheduling Constraints", "authors": [{"first": "Iii", "middle": [], "last": "Robinson", "suffix": ""}, {"first": "J", "middle": ["E"], "last": "", "suffix": ""}, {"first": "M", "middle": [], "last": "Kamgarpour", "suffix": ""}], "year": 2010, "venue": "10th AIAA Aviation Technology, Integration and Operations Conference", "link": "18672903"}, "BIBREF18": {"title": "Comparison of Trajectory Synthesis Algorithms for Monitoring Final Approach Compression, 11th AIAA Aviation Technology, Integration and Operations Conference", "authors": [{"first": "Iii", "middle": [], "last": "Robinson", "suffix": ""}, {"first": "J", "middle": ["E"], "last": "", "suffix": ""}, {"first": "O", "middle": [], "last": "Diallo", "suffix": ""}, {"first": "R", "middle": ["J"], "last": "Reisman", "suffix": ""}], "year": 2011, "venue": "", "link": null}, "BIBREF19": {"title": "National Plan of Integrated Airport Systems Report", "authors": [], "year": 2010, "venue": "", "link": null}, "BIBREF20": {"title": "Air Traffic Control FAA Order JO 7110.65U Chapter", "authors": [], "year": 2012, "venue": "Federal Aviation Administration", "link": null}, "BIBREF21": {"title": "Air Traffic Control FAA Order JO 7110.567 Interim Procedures for Airbus A388 Flights", "authors": [], "year": 2011, "venue": "", "link": null}, "BIBREF22": {"title": "Aviation System Performance Metrics (ASPM) Airport Efficiency", "authors": [], "year": 2012, "venue": "", "link": null}, "BIBREF23": {"title": "FAA Needs to Implement More Efficient Performance-Based Navigation Procedures and Clarify the Role of the Third Parties", "authors": [{"first": "R", "middle": [], "last": "Koch", "suffix": ""}, {"first": "C", "middle": [], "last": "Treakle", "suffix": ""}, {"first": "R", "middle": [], "last": "Denmark", "suffix": ""}, {"first": "C", "middle": [], "last": "Estada", "suffix": ""}, {"first": "A", "middle": [], "last": "Olsen", "suffix": ""}, {"first": "", "middle": [], "last": "Nossaman", "suffix": ""}], "year": 2010, "venue": "Federal Aviation Administration Report", "link": null}, "BIBREF24": {"title": "A Graph-Based Approach to Defining Nominal Terminal Routing", "authors": [{"first": "S", "middle": [], "last": "Zelinski", "suffix": ""}], "year": 2012, "venue": "31st Digital Avionics System Conference", "link": null}}, "ref_entries": {}}
{"paper_id": "18984455", "_pdf_hash": "48ab931850a1b8e2fefe36938cf51edbfaa077ea", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Design and prototype implementation of sms based home automation system", "authors": [{"first": "H", "middle": [], "last": "Elkamchouchi", "suffix": ""}, {"first": "A", "middle": [], "last": "Eishafee", "suffix": ""}], "year": 2012, "venue": "Electronics Design, Systems and Applications (lCEDSA), 2012 IEEE International Conference on", "link": "15913976"}, "BIBREF2": {"title": "Smart gsmbased home automation system", "authors": [], "year": 2013, "venue": "Systems, Process Control (ICSPC), 2013 IEEE Conference on", "link": null}, "BIBREF3": {"title": "Mobile monitoring system for smart home", "authors": [{"first": "M", "middle": [], "last": "Khandare", "suffix": ""}, {"first": "A", "middle": [], "last": "Mahajan", "suffix": ""}], "year": 2010, "venue": "Emerging Trends in Engineering and Technology (lCETET), 2010 3rd International Conference on", "link": "8964524"}, "BIBREF4": {"title": "Home security system based on picI8f452 microcontroller", "authors": [{"first": "M", "middle": [], "last": "Islam", "suffix": ""}], "year": 2014, "venue": "Electro/Information Technology (EiT)", "link": null}, "BIBREF5": {"title": "Design of intelligent security system based on arm microcontroller", "authors": [{"first": "Z", "middle": [], "last": "Xia", "suffix": ""}, {"first": "L", "middle": [], "last": "Xiaoyan", "suffix": ""}, {"first": "I", "middle": [], "last": "Boxue", "suffix": ""}, {"first": "S", "middle": [], "last": "Jin", "suffix": ""}, {"first": "W", "middle": [], "last": "Yajing", "suffix": ""}], "year": 2010, "venue": "2010 International Conference on", "link": null}, "BIBREF6": {"title": "Sustainable powered microcontroller-based intelligent security system for local and remote area applications", "authors": [{"first": "T", "middle": [], "last": "Ahmed", "suffix": ""}, {"first": "S", "middle": [], "last": "Islam", "suffix": ""}, {"first": "!", "middle": [], "last": "Chowdhury", "suffix": ""}, {"first": "S", "middle": [], "last": "Binzaid", "suffix": ""}], "year": 2012, "venue": "InformatiCS, Electronics Vision (ICIEV), 2012 International Conference on", "link": "27359911"}, "BIBREF7": {"title": "Design and implementation of pyroelectric infrared sensor based security system using microcontroller", "authors": [{"first": "Z", "middle": [], "last": "Chowdhury", "suffix": ""}, {"first": "M", "middle": [], "last": "Imtiaz", "suffix": ""}, {"first": "M", "middle": [], "last": "Azam", "suffix": ""}, {"first": "M", "middle": [], "last": "Sumi", "suffix": ""}, {"first": "N", "middle": [], "last": "Nur", "suffix": ""}], "year": 2011, "venue": "Students' Technology Symposium (TechSym)", "link": "18373647"}, "BIBREF8": {"title": "A multilevel home security system (mhss)", "authors": [{"first": "J.-V", "middle": ["L"], "last": "Jer-Vui Lee", "suffix": ""}, {"first": "Y.-D", "middle": ["C"], "last": "Yea-Dat", "suffix": ""}, {"first": "C.-I", "middle": ["C"], "last": "Chuah", "suffix": ""}, {"first": "", "middle": [], "last": "Chin-Tin", "suffix": ""}, {"first": "", "middle": [], "last": "Chai", "suffix": ""}], "year": 2013, "venue": "International Journal of Smart Home", "link": "110410843"}, "BIBREF9": {"title": "Car black box with speed control in desired areas for collision avoidance", "authors": [{"first": "D", "middle": [], "last": "Pawar", "suffix": ""}, {"first": "P", "middle": [], "last": "Poddar", "suffix": ""}], "year": 2012, "venue": "Technology & Applied Science Research", "link": "109432952"}, "BIBREF10": {"title": "Wireless home and industrial automation security system using gsm", "authors": [{"first": "R", "middle": [], "last": "Anandan", "suffix": ""}], "year": 2013, "venue": "Journal of Global Research in Computer Science", "link": "38940768"}, "BIBREF11": {"title": "Gsm based anti theft security system using at&t command", "authors": [{"first": "V", "middle": ["M"], "last": "Ibrahim", "suffix": ""}, {"first": "A", "middle": ["A"], "last": "Victor", "suffix": ""}, {"first": "S", "middle": [], "last": "Musa", "suffix": ""}], "year": 2012, "venue": "International Journal Of Computational Engineering Research (IJCER)", "link": "9392271"}, "BIBREF12": {"title": "Microcontroller based substation monitoring and control system with gsm modem", "authors": [{"first": "A", "middle": [], "last": "Sachan", "suffix": ""}], "year": 2012, "venue": "IOSR Journal of Electrical and Electronics Engineering", "link": "1289657"}, "BIBREF13": {"title": "Household security system based on ultrasonic sensor technology with sms notification", "authors": [{"first": "B", "middle": ["H"], "last": "Sunil", "suffix": ""}], "year": 2014, "venue": "European Journal of Academic Essays", "link": null}, "BIBREF14": {"title": "Design of wireless home automation and security system using pic microcontroller", "authors": [{"first": "V", "middle": ["S"], "last": "Narayanan", "suffix": ""}, {"first": "S", "middle": [], "last": "Gayathri", "suffix": ""}], "year": "", "venue": "", "link": "8743699"}, "BIBREF15": {"title": "Automobile fuel pump control system using embedded system", "authors": [{"first": "S", "middle": ["K"], "last": "Behera", "suffix": ""}, {"first": "F", "middle": ["A"], "last": "Ali", "suffix": ""}], "year": "", "venue": "", "link": "201861297"}, "BIBREF16": {"title": "Gsm based electrical control system for smart home application", "authors": [{"first": "M", "middle": ["H A"], "last": "Wahab", "suffix": ""}, {"first": "N", "middle": [], "last": "Abdullah", "suffix": ""}, {"first": "A", "middle": [], "last": "Johari", "suffix": ""}, {"first": "H", "middle": ["A"], "last": "Kadir", "suffix": ""}], "year": 2010, "venue": "Journal of Convergence information Technology", "link": "17762663"}}, "ref_entries": {}}
{"paper_id": "18984609", "_pdf_hash": "874ce7e666be840d4a280bb1b0eb082a0e09500f", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Design of Tube-Based Blades and Aluminum-FoilWound Coils for Human Scale Wind Turbines", "authors": [{"first": "Pedro", "middle": [], "last": "Melendez-Vega", "suffix": ""}], "year": 2012, "venue": "", "link": null}, "BIBREF1": {"title": "Modeling of Battery-Charging Turbines", "authors": [{"first": "Justin", "middle": [], "last": "Reed", "suffix": ""}], "year": 2008, "venue": "", "link": null}, "BIBREF2": {"title": "How to build a wind turbine", "authors": [{"first": "H", "middle": [], "last": "Piggott", "suffix": ""}], "year": 2005, "venue": "", "link": null}, "BIBREF3": {"title": "Analysis and Performance of Axial Flux Permanent-Magnet Machine With Air-Cored Nonoverlapping Concentrated Stator Windings", "authors": [{"first": "Maarten", "middle": [], "last": "Kamper", "suffix": ""}, {"first": "Rong-Jie", "middle": [], "last": "Wang", "suffix": ""}, {"first": "Francois", "middle": [], "last": "Rossouw", "suffix": ""}], "year": 2008, "venue": "IEEE Transactions on Industry Applications", "link": "11924898"}, "BIBREF4": {"title": "Modeling of Different Winding Configurations for Fault-Tolerant Permanent Magnet Machines to Restrain Interturn Short-Circuit Current", "authors": [{"first": "P", "middle": [], "last": "Arumugam", "suffix": ""}, {"first": "T", "middle": [], "last": "Hamiti", "suffix": ""}, {"first": "C", "middle": [], "last": "Gerada", "suffix": ""}], "year": 2012, "venue": "IEEE Transactions on Energy Conversion", "link": "27286748"}, "BIBREF5": {"title": "Analysis of Vertical Strip Wound Fault-Tolerant Permanent Magnet Synchronous Machines", "authors": [{"first": "P", "middle": [], "last": "Arumugam", "suffix": ""}, {"first": "T", "middle": [], "last": "Hamiti", "suffix": ""}, {"first": "C", "middle": [], "last": "Brunson", "suffix": ""}, {"first": "C", "middle": [], "last": "Gerada", "suffix": ""}], "year": 2014, "venue": "IEEE Transactions on Industrial Electronics", "link": "24558595"}, "BIBREF6": {"title": "Reduction of Permanent Magnets in Small-Scale Wind Turbines", "authors": [{"first": "Adam", "middle": [], "last": "Shea", "suffix": ""}, {"first": "Dan", "middle": [], "last": "Ludois", "suffix": ""}], "year": "", "venue": "IEEE Energy Conversion Congress and Exposition", "link": "26354618"}, "BIBREF7": {"title": "Foil Field Lundell Alternator with Rotating Power Electronics", "authors": [{"first": "L", "middle": [], "last": "Lorilla", "suffix": ""}], "year": 2006, "venue": "IEEE Power Electronics Specialists Conference", "link": "3189525"}, "BIBREF8": {"title": "Preliminary Study of Using Anodized Aluminum Strip for Electrical Motor Windings", "authors": [{"first": "S", "middle": [], "last": "Babicz", "suffix": ""}, {"first": "S", "middle": ["A"], "last": ".-A. Djennad", "suffix": ""}, {"first": "G", "middle": [], "last": "Velu", "suffix": ""}], "year": 2014, "venue": "2014 IEEE Conference on Electrical Insulation and Dielectric Phenomena (CEIDP)", "link": null}, "BIBREF9": {"title": "Analysis of a Novel Coil Design for Axial Flux Machines", "authors": [{"first": "Sigbjorn", "middle": [], "last": "Lomheim", "suffix": ""}], "year": 2013, "venue": "", "link": null}, "BIBREF10": {"title": "Determination of Critical Parameters in Electrical Machine Thermal Models", "authors": [{"first": "A", "middle": [], "last": "Boglietti", "suffix": ""}, {"first": "A", "middle": [], "last": "Cavagnino", "suffix": ""}, {"first": "D", "middle": [], "last": "Staton", "suffix": ""}], "year": 2008, "venue": "IEEE Transactions on Industry Applications", "link": "14879398"}, "BIBREF12": {"title": "Evolution and Modern Approaches for Thermal Analysis of Electrical Machines", "authors": [{"first": "", "middle": [], "last": "Mejuto", "suffix": ""}], "year": 2009, "venue": "IEEE Transactions on Industrial Electronics", "link": "206698933"}, "BIBREF13": {"title": "Solving the More Difficult Aspects of Electric Motor Thermal Analysis in Small and Medium Size Industrial Induction Motors", "authors": [{"first": "D", "middle": [], "last": "Staton", "suffix": ""}, {"first": "A", "middle": [], "last": "Boglietti", "suffix": ""}, {"first": "A", "middle": [], "last": "Cavagnino", "suffix": ""}], "year": 2005, "venue": "IEEE Transactions on Energy Conversion", "link": "111171955"}, "BIBREF14": {"title": "Investigations of Thermal Modelling of Induction Motors", "authors": [{"first": "Amar", "middle": [], "last": "Bousbaine", "suffix": ""}], "year": 1993, "venue": "", "link": null}, "BIBREF15": {"title": "Steady and Transient States Thermal Analysis of a 7.5-kW Squirrel-Cage Induction Machine at Rated-Load Operation", "authors": [{"first": "O", "middle": [], "last": "Okoro", "suffix": ""}], "year": 2005, "venue": "IEEE Transactions on Energy Conversion", "link": "30670372"}, "BIBREF16": {"title": "Lumped Parameter Thermal Model for Electrical Machines of TEFC Design", "authors": [{"first": "P", "middle": ["H"], "last": "Mellor", "suffix": ""}, {"first": "D", "middle": [], "last": "Roberts", "suffix": ""}, {"first": "D", "middle": ["R"], "last": "Turner", "suffix": ""}], "year": 1991, "venue": "IEE Proceedings", "link": "109835079"}, "BIBREF17": {"title": "Estimation of Equivalent Thermal Parameters of Impregnated Electrical Windings", "authors": [{"first": "N", "middle": [], "last": "Simpson", "suffix": ""}, {"first": "R", "middle": [], "last": "Wrobel", "suffix": ""}, {"first": "P", "middle": ["H"], "last": "Mellor", "suffix": ""}], "year": 2013, "venue": "IEEE Transactions on Industry Applications", "link": "14611484"}, "BIBREF18": {"title": "A General Cuboidal Element for ThreeDimensional Thermal Modelling", "authors": [{"first": "R", "middle": [], "last": "Wrobel", "suffix": ""}, {"first": "P", "middle": ["H"], "last": "Mellor", "suffix": ""}], "year": 2010, "venue": "IEEE Transactions on Magnetics", "link": "35337854"}, "BIBREF19": {"title": "Coaxially Wound Transformers for High Freq High Power", "authors": [{"first": "Mustansir", "middle": [], "last": "Kheraluwala", "suffix": ""}, {"first": "Donald", "middle": [], "last": "Novotny", "suffix": ""}, {"first": "Divan", "middle": [], "last": "Deepakraj", "suffix": ""}], "year": 1992, "venue": "IEEE Transactions on Power Electronics", "link": null}, "BIBREF20": {"title": "Analytical 2-D Slot Model for Predicting AC Losses in Bar-Wound Machine Windings due to Armature Reaction", "authors": [{"first": "Wanjun", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "T", "middle": ["M"], "last": "Jahns", "suffix": ""}], "year": 2014, "venue": "", "link": "31185668"}, "BIBREF21": {"title": "IEEE Transportation Electrification Conference and Expo (ITEC)", "authors": [], "year": 2014, "venue": "", "link": null}, "BIBREF22": {"title": "The Analysis of Stray Losses in Tape Wound Concentrated Windings of the Permanent Magnet Synchronous Motor", "authors": [{"first": "Rafal", "middle": ["M"], "last": "Wojciechowski", "suffix": ""}, {"first": "Cezary", "middle": [], "last": "Jedryczka", "suffix": ""}], "year": 2015, "venue": "COMPEL: The International Journal for Computation and Mathematics in Electrical and Electronic Engineering", "link": "106678542"}, "BIBREF23": {"title": "Eddy Currents. Iliffe Books Ltd", "authors": [{"first": "Jiri", "middle": [], "last": "Lammeraner", "suffix": ""}, {"first": "Milos", "middle": [], "last": "Stafl", "suffix": ""}], "year": 1966, "venue": "", "link": null}, "BIBREF24": {"title": "Sensory Embedded Electronics", "authors": [{"first": "Rtds", "middle": [], "last": "", "suffix": ""}, {"first": "Thermistors", "middle": [], "last": "", "suffix": ""}], "year": 2015, "venue": "Wikipedia, Last modified", "link": null}, "BIBREF25": {"title": "ENSC 388 Lecture Notes", "authors": [{"first": "M", "middle": [], "last": "Bahrami", "suffix": ""}], "year": 2009, "venue": "", "link": null}, "BIBREF27": {"title": "Wikipedia, Last modified", "authors": [{"first": "Prandtl", "middle": [], "last": "Number", "suffix": ""}], "year": 2015, "venue": "", "link": null}, "BIBREF28": {"title": "Wikipedia, Last modified", "authors": [{"first": "Nusselt", "middle": [], "last": "Number", "suffix": ""}], "year": 2015, "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "18984674", "_pdf_hash": "7027e8cd68a07f35fb3a8a1c35b7dbb8e7518a93", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "RTG: A Recursive Realistic Graph Generator Using Random Typing", "authors": [{"first": "L", "middle": [], "last": "Akoglu", "suffix": ""}, {"first": "C", "middle": [], "last": "Faloutsos", "suffix": ""}], "year": 2009, "venue": "DATA MIN KNOWL DISC", "link": "118695096"}, "BIBREF1": {"title": "Friendship and Mobility: User Movement in Location-based Social Networks", "authors": [{"first": "E", "middle": [], "last": "Cho", "suffix": ""}, {"first": "S", "middle": ["A"], "last": "Myers", "suffix": ""}, {"first": "J", "middle": [], "last": "Leskovec", "suffix": ""}], "year": 2011, "venue": "SIGKDD", "link": "1480192"}, "BIBREF2": {"title": "Diffusion wavelets", "authors": [{"first": "R", "middle": ["R"], "last": "Coifman", "suffix": ""}, {"first": "M", "middle": [], "last": "Maggioni", "suffix": ""}], "year": 2006, "venue": "APPL COMPUT HARMON A", "link": "1767868"}, "BIBREF3": {"title": "Gaussian Conditional Random Fields for Aggregation of Operational Aerosol Retrievals", "authors": [{"first": "N", "middle": [], "last": "Djuric", "suffix": ""}, {"first": "V", "middle": [], "last": "Radosavljevic", "suffix": ""}, {"first": "Z", "middle": [], "last": "Obradovic", "suffix": ""}, {"first": "S", "middle": [], "last": "Vucetic", "suffix": ""}], "year": 2015, "venue": "IEEE Geosci. Remote Sens Lett", "link": "13045471"}, "BIBREF4": {"title": "WordNet: an Electronic Lexical Database", "authors": [], "year": 1998, "venue": "", "link": null}, "BIBREF5": {"title": "Extending the Modelling Capacity of Gaussian Conditional Random Fields while Learning Faster", "authors": [{"first": "J", "middle": [], "last": "Glass", "suffix": ""}, {"first": "M", "middle": [], "last": "Ghalwash", "suffix": ""}, {"first": "M", "middle": [], "last": "Vukicevic", "suffix": ""}, {"first": "Z", "middle": [], "last": "Obradovic", "suffix": ""}], "year": 2016, "venue": "AAAI", "link": "10245542"}, "BIBREF6": {"title": "Lifted probabilistic inference", "authors": [{"first": "K", "middle": [], "last": "Kersting", "suffix": ""}], "year": 2012, "venue": "ECAI", "link": "9316760"}, "BIBREF7": {"title": "Conditional Random Fields: Probabilistic Models for Segmenting and Labeling Sequence Data", "authors": [{"first": "J", "middle": [], "last": "Lafferty", "suffix": ""}, {"first": "A", "middle": [], "last": "Mccallum", "suffix": ""}, {"first": "F", "middle": ["C N"], "last": "Pereira", "suffix": ""}], "year": 2001, "venue": "ICML", "link": "277918"}, "BIBREF8": {"title": "Graph Evolution: Densification and Shrinking Diameters", "authors": [{"first": "J", "middle": [], "last": "Leskovec", "suffix": ""}, {"first": "J", "middle": [], "last": "Kleinberg", "suffix": ""}, {"first": "C", "middle": [], "last": "Faloutsos", "suffix": ""}], "year": 2007, "venue": "ACM Trans. Knowledge Discovery from Data", "link": "11761086"}, "BIBREF9": {"title": "Citation Prediction Using Time Series Approach KDD Cup", "authors": [{"first": "J", "middle": ["N"], "last": "Manjunatha", "suffix": ""}, {"first": "K", "middle": ["R"], "last": "Sivaramakrishnan", "suffix": ""}, {"first": "R", "middle": ["K"], "last": "Pandey", "suffix": ""}, {"first": "M", "middle": ["N"], "last": "Murthy", "suffix": ""}], "year": 2003, "venue": "", "link": null}, "BIBREF10": {"title": "Weighted Graph Compression for Parameter-free Clustering With PaCCo", "authors": [{"first": "N", "middle": [], "last": "Mueller", "suffix": ""}, {"first": "K", "middle": [], "last": "Haegler", "suffix": ""}, {"first": "J", "middle": [], "last": "Shao", "suffix": ""}, {"first": "C", "middle": [], "last": "Plant", "suffix": ""}, {"first": "C", "middle": [], "last": "B\u00f6hm", "suffix": ""}], "year": 2011, "venue": "SDM", "link": "12799910"}, "BIBREF11": {"title": "Graph Summarization with Bounded Error", "authors": [{"first": "S", "middle": [], "last": "Navlakha", "suffix": ""}, {"first": "R", "middle": [], "last": "Rastogi", "suffix": ""}, {"first": "N", "middle": [], "last": "Shrivastava", "suffix": ""}], "year": 2008, "venue": "SIGMOD", "link": "9558772"}, "BIBREF12": {"title": "Hospital Pricing Estimation by Gaussian Conditional Random Fields Based Regression on Graphs", "authors": [{"first": "A", "middle": [], "last": "Polychronopoulou", "suffix": ""}, {"first": "Z", "middle": [], "last": "Obradovic", "suffix": ""}], "year": 2014, "venue": "BIBM", "link": "10204594"}, "BIBREF13": {"title": "Global Ranking Using Continuous Conditional Random Fields", "authors": [{"first": "T", "middle": [], "last": "Qin", "suffix": ""}, {"first": "T.-Y", "middle": [], "last": "Liu", "suffix": ""}, {"first": "X.-D", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "D.-S", "middle": [], "last": "Wang", "suffix": ""}, {"first": "H", "middle": [], "last": "Li", "suffix": ""}], "year": 2009, "venue": "NIPS", "link": null}, "BIBREF14": {"title": "Conditional Random Fields for Regression in Remote Sensing", "authors": [{"first": "V", "middle": [], "last": "Radosavljevic", "suffix": ""}, {"first": "S", "middle": [], "last": "Vucetic", "suffix": ""}, {"first": "Z", "middle": [], "last": "Obradovic", "suffix": ""}], "year": 2010, "venue": "ECAI", "link": null}, "BIBREF15": {"title": "Continuous Conditional Random Fields for Efficient Regression in Large Fully Connected Graphs", "authors": [{"first": "K", "middle": [], "last": "Ristovski", "suffix": ""}, {"first": "V", "middle": [], "last": "Radosavljevic", "suffix": ""}, {"first": "S", "middle": [], "last": "Vucetic", "suffix": ""}, {"first": "Z", "middle": [], "last": "Obradovic", "suffix": ""}], "year": 2013, "venue": "AAAI", "link": "8938876"}, "BIBREF16": {"title": "Distributed Gaussian Conditional Random Fields Based Regression for Large Evolving Graphs", "authors": [{"first": "J", "middle": [], "last": "Slivka", "suffix": ""}, {"first": "M", "middle": [], "last": "Nikolic", "suffix": ""}, {"first": "K", "middle": [], "last": "Ristovski", "suffix": ""}, {"first": "V", "middle": [], "last": "Radosavljevic", "suffix": ""}, {"first": "Z", "middle": [], "last": "Obradovic", "suffix": ""}], "year": 2014, "venue": "Proc. 14th SDM Workshop on Mining Networks and Graphs", "link": "7380711"}, "BIBREF17": {"title": "Learning Gaussian Conditional Random Fields for Low-Level Vision", "authors": [{"first": "M", "middle": ["F"], "last": "Tappen", "suffix": ""}, {"first": "C", "middle": [], "last": "Liu", "suffix": ""}, {"first": "E", "middle": ["H"], "last": "Adelson", "suffix": ""}, {"first": "W", "middle": ["T"], "last": "Freeman", "suffix": ""}], "year": 2007, "venue": "CVPR", "link": "1616901"}, "BIBREF18": {"title": "Efficient Aggregation for Graph Summarization", "authors": [{"first": "Y", "middle": [], "last": "Tian", "suffix": ""}, {"first": "R", "middle": ["A"], "last": "Hankins", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Patel", "suffix": ""}], "year": 2008, "venue": "SIGMOD", "link": "15850185"}, "BIBREF19": {"title": "Compression of Weighted Graphs", "authors": [{"first": "H", "middle": [], "last": "Toivonen", "suffix": ""}, {"first": "F", "middle": [], "last": "Zhou", "suffix": ""}, {"first": "A", "middle": [], "last": "Hartikainen", "suffix": ""}, {"first": "A", "middle": [], "last": "Hinkka", "suffix": ""}], "year": 2011, "venue": "SIGKDD", "link": "15257061"}, "BIBREF20": {"title": "Which Links Should I Use? A Variogram-based Selection of Relationship Measures for Prediction of Node Attributes in Temporal Multigraphs", "authors": [{"first": "A", "middle": [], "last": "Uversky", "suffix": ""}, {"first": "D", "middle": [], "last": "Ramljak", "suffix": ""}, {"first": "V", "middle": [], "last": "Radosavljevi\u0107", "suffix": ""}, {"first": "K", "middle": [], "last": "Ristovski", "suffix": ""}, {"first": "Z", "middle": [], "last": "Obradovi\u0107", "suffix": ""}], "year": 2013, "venue": "ASONAM", "link": "3392548"}, "BIBREF21": {"title": "Laplacian solvers and their algorithmic applications", "authors": [{"first": "N", "middle": ["K"], "last": "Vishnoi", "suffix": ""}], "year": 2012, "venue": "THEOR COMPUT SCI", "link": null}, "BIBREF22": {"title": "On the Evolution of User Interaction in Facebook", "authors": [{"first": "B", "middle": [], "last": "Viswanath", "suffix": ""}, {"first": "A", "middle": [], "last": "Mislove", "suffix": ""}, {"first": "M", "middle": [], "last": "Cha", "suffix": ""}, {"first": "K", "middle": ["P"], "last": "Gummadi", "suffix": ""}], "year": 2009, "venue": "Proc. Workshop on Online Social Networks", "link": "2745943"}, "BIBREF23": {"title": "Sparse Gaussian Conditional Random Fields: Algorithms, Theory, and Application to Energy Forecasting. In ICML", "authors": [{"first": "M", "middle": [], "last": "Wytock", "suffix": ""}, {"first": "Z", "middle": [], "last": "Kolter", "suffix": ""}], "year": 2013, "venue": "", "link": null}, "BIBREF24": {"title": "Defining and Evaluating Network Communities Based on Ground-truth", "authors": [{"first": "J", "middle": [], "last": "Yang", "suffix": ""}, {"first": "J", "middle": [], "last": "Leskovec", "suffix": ""}], "year": 2012, "venue": "MDS", "link": "62597678"}, "BIBREF25": {"title": "Discovery-Driven Graph Summarization", "authors": [{"first": "N", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "Y", "middle": [], "last": "Tian", "suffix": ""}, {"first": "J", "middle": [], "last": "Patel", "suffix": ""}], "year": 2010, "venue": "ICDE", "link": "14285133"}, "BIBREF26": {"title": "The Use of Weighted Graphs for Large-Scale Genome Analysis", "authors": [{"first": "F", "middle": [], "last": "Zhou", "suffix": ""}, {"first": "H", "middle": [], "last": "Toivonen", "suffix": ""}, {"first": "R", "middle": ["D"], "last": "King", "suffix": ""}], "year": 2014, "venue": "PLoS ONE", "link": "6729359"}}, "ref_entries": {}}
{"paper_id": "18984807", "_pdf_hash": "0116c69b6575b488035a9472fa392fdb724e1703", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "The reflective practitioner: How professionals think in action", "authors": [{"first": "D", "middle": ["A"], "last": "Schon", "suffix": ""}], "year": 1983, "venue": "", "link": "145408602"}, "BIBREF1": {"title": "Educating the reflective practitioner: Toward a new design for teaching and learning in the professions", "authors": [{"first": "D", "middle": ["A"], "last": "Schon", "suffix": ""}], "year": 1987, "venue": "", "link": "144875090"}, "BIBREF2": {"title": "How Computer Games Help Children Learn", "authors": [{"first": "D", "middle": ["W"], "last": "Shaffer", "suffix": ""}], "year": 2007, "venue": "", "link": "143676819"}, "BIBREF3": {"title": "SodaConstructing knowledge through exploratoids", "authors": [{"first": "G", "middle": [], "last": "Svarovsky", "suffix": ""}, {"first": "D", "middle": ["W"], "last": "Shaffer", "suffix": ""}], "year": 2007, "venue": "Journal of Research in Science Teaching", "link": "145299148"}, "BIBREF4": {"title": "When people get in the way: Promoting civic thinking through epistemic gameplay", "authors": [{"first": "E", "middle": ["A S"], "last": "Bagley", "suffix": ""}, {"first": "D", "middle": ["W"], "last": "Shaffer", "suffix": ""}], "year": 2009, "venue": "International Journal of Gaming and Computer-Mediated Simulations", "link": "39452248"}, "BIBREF5": {"title": "Engineering Design Thinking, Teaching and Learning", "authors": [{"first": "C", "middle": [], "last": "Dym", "suffix": ""}], "year": 2005, "venue": "Journal of Engineering Education", "link": "154340832"}, "BIBREF6": {"title": "Teaching Communication in Capstone Design: The role of the instructor in situated learning", "authors": [{"first": "M", "middle": ["C"], "last": "Paretti", "suffix": ""}], "year": 2008, "venue": "Journal of Engineering Education", "link": "18553168"}, "BIBREF7": {"title": "Unpacking the Digital Zoo: An analysis of the learning process within an engineering epistemic frame. Doctoral Dissertation", "authors": [{"first": "G", "middle": [], "last": "Svarovsky", "suffix": ""}], "year": 2009, "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "18985171", "_pdf_hash": "4fffabbda7ac482adb2b63ebf77419b3619fbeee", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Biometric security technology", "authors": [{"first": "M", "middle": [], "last": "Faundez-Zanuy", "suffix": ""}], "year": 2006, "venue": "IEEE A&E Syst. Mag", "link": "15391381"}, "BIBREF1": {"title": "Fingerprint matching", "authors": [{"first": "A", "middle": ["K"], "last": "Jain", "suffix": ""}, {"first": "J", "middle": [], "last": "Feng", "suffix": ""}, {"first": "K", "middle": [], "last": "Nandakumar", "suffix": ""}], "year": 2010, "venue": "IEEE Computer", "link": "16647761"}, "BIBREF2": {"title": "Method for identifying individuals using lip motion features", "authors": [{"first": "Y", "middle": [], "last": "Shirasawa", "suffix": ""}, {"first": "S", "middle": [], "last": "Miura", "suffix": ""}, {"first": "M", "middle": [], "last": "Nishida", "suffix": ""}, {"first": "Y", "middle": [], "last": "Kageyama", "suffix": ""}, {"first": "S", "middle": [], "last": "Kurisu", "suffix": ""}], "year": 1964, "venue": "ITE Journal", "link": "62711809"}, "BIBREF3": {"title": "A novel face authentication method using trajectory features", "authors": [{"first": "D", "middle": [], "last": "Sasaki", "suffix": ""}, {"first": "Y", "middle": [], "last": "Kajikawa", "suffix": ""}], "year": 2009, "venue": "Proc. of 2009 International Workshop on Smart Info-Media Systems in Asia", "link": null}, "BIBREF4": {"title": "Robust real-time face detection", "authors": [{"first": "P", "middle": [], "last": "Viola", "suffix": ""}, {"first": "M", "middle": [], "last": "Jones", "suffix": ""}], "year": 2004, "venue": "International Journal of Computer Vision", "link": "42281583"}, "BIBREF5": {"title": "Facial feature point extraction method based on combination of shape extraction and pattern matching", "authors": [{"first": "K", "middle": [], "last": "Fukui", "suffix": ""}, {"first": "O", "middle": [], "last": "Yamaguchi", "suffix": ""}], "year": 1998, "venue": "Systems and Computers in Japan", "link": "62666570"}, "BIBREF6": {"title": "Symmetrical invariant LBP texture descriptor and application for image retrieval", "authors": [{"first": "S", "middle": [], "last": "Zhiping", "suffix": ""}, {"first": "Y", "middle": [], "last": "Fei", "suffix": ""}], "year": 2008, "venue": "Proc. of the IEEE International Congress on Image and Signal Processing", "link": "15987184"}, "BIBREF7": {"title": "Finding patterns in time series: A dynamic programming approach", "authors": [{"first": "D", "middle": ["J"], "last": "Berndt", "suffix": ""}, {"first": "J", "middle": [], "last": "Clifford", "suffix": ""}], "year": 1996, "venue": "Advances in Knowledge Discovery and Data Mining", "link": "34673326"}, "BIBREF8": {"title": "Improved boosting algorithms using confidence-rated predictions", "authors": [{"first": "R", "middle": ["E"], "last": "Schapire", "suffix": ""}, {"first": "Y", "middle": [], "last": "Singer", "suffix": ""}], "year": 1999, "venue": "Machine Learning", "link": "2329907"}, "BIBREF9": {"title": "Speaker recognition using kernel mutual subspace method", "authors": [{"first": "M", "middle": [], "last": "Ichino", "suffix": ""}, {"first": "H", "middle": [], "last": "Sakano", "suffix": ""}, {"first": "N", "middle": [], "last": "Komatsu", "suffix": ""}], "year": 2004, "venue": "Proc. of Control, Automation, Robotics and Vision Conference", "link": "13645224"}}, "ref_entries": {}}
{"paper_id": "18985891", "_pdf_hash": "6c882e87881e632aab2241d8e223e0aae826b7b4", "abstract": [{"section": "Abstract", "text": "Background", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Leptospirosis is a zoonotic bacterial disease that occurs in diverse epidemiological settings but imparts its greatest burden on resource-poor populations [1] [2] [3] [4] [5] [6] . The disease has a broad geographical distribution due to the large spectrum of mammalian hosts that harbour and excrete the spirochete agent from their renal tubules [1, 3, 7] . Leptospirosis affects risk groups that are exposed to animal reservoirs or contaminated environments, such as abattoir and sewage workers, military personnel, and individuals partaking in water sports and recreation [8] [9] [10] [11] [12] . However, leptospirosis has a broader health impact as a disease of impoverished subsistence farmers [13] [14] [15] , cash croppers, and pastoralists [16] from tropical regions.", "cite_spans": [{"start": 155, "end": 158, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 159, "end": 162, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 167, "end": 170, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 175, "end": 178, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 347, "end": 350, "text": "[1,", "ref_id": "BIBREF0"}, {"start": 354, "end": 356, "text": "7]", "ref_id": "BIBREF6"}, {"start": 575, "end": 578, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 579, "end": 582, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 583, "end": 587, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 588, "end": 592, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 593, "end": 597, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 700, "end": 704, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 710, "end": 714, "text": "[15]", "ref_id": "BIBREF14"}, {"start": 749, "end": 753, "text": "[16]", "ref_id": "BIBREF15"}], "ref_spans": []}, {"section": "Introduction", "text": "Furthermore, leptospirosis has emerged as a health threat in new settings due the influence of globalization and climate. Disasters and extreme weather events are now recognized to precipitate epidemics [6] . The emergence of leptospirosis in Thailand [17] and Sri Lanka [18] highlight the potential for the disease to rapidly spread and cause large unexplained nationwide outbreaks. Finally, the expansion of urban slums worldwide has created conditions for ratborne transmission [19] [20] [21] [22] [23] [24] . Urban epidemics are reported in cities throughout the developing world [6, 19, 25] and will likely intensify as the world's slum population doubles to two billion by 2030 [26] .", "cite_spans": [{"start": 203, "end": 206, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 252, "end": 256, "text": "[17]", "ref_id": "BIBREF16"}, {"start": 271, "end": 275, "text": "[18]", "ref_id": "BIBREF17"}, {"start": 481, "end": 485, "text": "[19]", "ref_id": "BIBREF18"}, {"start": 486, "end": 490, "text": "[20]", "ref_id": "BIBREF19"}, {"start": 491, "end": 495, "text": "[21]", "ref_id": "BIBREF20"}, {"start": 496, "end": 500, "text": "[22]", "ref_id": "BIBREF21"}, {"start": 501, "end": 505, "text": "[23]", "ref_id": "BIBREF22"}, {"start": 506, "end": 510, "text": "[24]", "ref_id": "BIBREF23"}, {"start": 584, "end": 587, "text": "[6,", "ref_id": "BIBREF5"}, {"start": 588, "end": 591, "text": "19,", "ref_id": "BIBREF18"}, {"start": 592, "end": 595, "text": "25]", "ref_id": "BIBREF24"}, {"start": 684, "end": 688, "text": "[26]", "ref_id": "BIBREF25"}], "ref_spans": []}, {"section": "Introduction", "text": "The major burden attributed to leptospirosis has been its severe life-threatening manifestations. Leptospirosis has emerged as an important cause of pulmonary haemorrhage syndrome [27] [28] [29] [30] and acute kidney injury due to Weil's disease [31] in many regions where transmission is endemic. Case fatality for pulmonary haemorrhage syndrome and Weil's disease is more than 10% and 70% respectively [14] . In addition, leptospirosis is increasingly recognized as an important cause of undifferentiated fever [16, [32] [33] [34] [35] [36] [37] [38] . The majority of leptospirosis patients are not recognized or misdiagnosed as malaria [16] , dengue [39] [40] [41] , and other causes of an acute febrile illness. The lack of an adequate diagnostic test [42, 43] has further contributed to underreporting of cases [44, 45] , as well as deaths [39] . Underestimation of the morbidity and mortality due to leptospirosis is therefore common [44] and has directly contributed to its neglected disease status.", "cite_spans": [{"start": 180, "end": 184, "text": "[27]", "ref_id": "BIBREF26"}, {"start": 185, "end": 189, "text": "[28]", "ref_id": "BIBREF27"}, {"start": 190, "end": 194, "text": "[29]", "ref_id": "BIBREF28"}, {"start": 195, "end": 199, "text": "[30]", "ref_id": "BIBREF29"}, {"start": 246, "end": 250, "text": "[31]", "ref_id": "BIBREF30"}, {"start": 513, "end": 517, "text": "[16,", "ref_id": "BIBREF15"}, {"start": 518, "end": 522, "text": "[32]", "ref_id": "BIBREF31"}, {"start": 523, "end": 527, "text": "[33]", "ref_id": "BIBREF32"}, {"start": 528, "end": 532, "text": "[34]", "ref_id": "BIBREF33"}, {"start": 533, "end": 537, "text": "[35]", "ref_id": "BIBREF34"}, {"start": 538, "end": 542, "text": "[36]", "ref_id": "BIBREF35"}, {"start": 543, "end": 547, "text": "[37]", "ref_id": "BIBREF36"}, {"start": 548, "end": 552, "text": "[38]", "ref_id": "BIBREF37"}, {"start": 640, "end": 644, "text": "[16]", "ref_id": "BIBREF15"}, {"start": 654, "end": 658, "text": "[39]", "ref_id": "BIBREF38"}, {"start": 659, "end": 663, "text": "[40]", "ref_id": "BIBREF39"}, {"start": 664, "end": 668, "text": "[41]", "ref_id": "BIBREF40"}, {"start": 757, "end": 761, "text": "[42,", "ref_id": "BIBREF41"}, {"start": 762, "end": 765, "text": "43]", "ref_id": "BIBREF42"}, {"start": 817, "end": 821, "text": "[44,", "ref_id": "BIBREF43"}, {"start": 822, "end": 825, "text": "45]", "ref_id": "BIBREF44"}, {"start": 846, "end": 850, "text": "[39]", "ref_id": "BIBREF38"}, {"start": 941, "end": 945, "text": "[44]", "ref_id": "BIBREF43"}], "ref_spans": []}, {"section": "Introduction", "text": "The lack of reliable estimates of the leptospirosis burden has hampered efforts to formulate the investment case to address key barriers, such as improved diagnostics, and identify effective prevention and control measures. Leptospirosis is amenable to One Health approaches to intervention [46] , since it is an animal health problem and a cause of economic loss in the same impoverished settings where the human disease burden is high. However, current estimates of cases and deaths rely on national surveillance data compiled from selected countries [47] . Pappas et al performed a review of reports and published literature, which identified regions with high endemicity [7] . Attempts have not been made to systematically estimate the global and regional disease burden, as has been done for other neglected diseases in the Global Burden of Disease (GBD) Study 2010 [48] . The World Health Organization (WHO) convened the Leptospirosis Epidemiology Reference Group (LERG) to guide this task [44] . Herein, we present the findings of a study that aimed to perform a systematic literature review of the data on leptospirosis morbidity and mortality, estimate the annual burden of cases and deaths, and identify GBD and WHO regions with the highest burden to inform local decision making and policy.", "cite_spans": [{"start": 291, "end": 295, "text": "[46]", "ref_id": "BIBREF45"}, {"start": 553, "end": 557, "text": "[47]", "ref_id": "BIBREF46"}, {"start": 675, "end": 678, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 871, "end": 875, "text": "[48]", "ref_id": "BIBREF47"}, {"start": 996, "end": 1000, "text": "[44]", "ref_id": "BIBREF43"}], "ref_spans": []}, {"section": "Methods", "text": "Methods are presented in detail in the accompanying supplementary document (S1 Protocol). The systematic literature review and quality assurance processes were developed during two consultative meetings of the LERG [49, 50] . The findings of the systematic review reported under PRISMA guidelines [51] (S1 Protocol). This independent panel of experts reviewed and provided advice on the methods and interpretation of results for the study.", "cite_spans": [{"start": 215, "end": 219, "text": "[49,", "ref_id": "BIBREF48"}, {"start": 220, "end": 223, "text": "50]", "ref_id": "BIBREF49"}, {"start": 297, "end": 301, "text": "[51]", "ref_id": "BIBREF51"}], "ref_spans": []}, {"section": "Data selection and extraction", "text": "The systematic review covered published reports and grey literature on leptospirosis morbidity and mortality from January 1970 to October 2008. We performed a systematic review of published literature by screening 32 electronic databases (Fig 1) , for search terms (S1 Protocol p.2), without language limitations, according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [51] . We defined all variables for which data were extracted (S2 Protocol). In addition, the LERG requested public health officials and researchers to provide supplementary information from published studies as well as grey literature. Studies that fulfilled the selection criteria (S1 Protocol pp. 3-5) were evaluated for methodology and study design and assigned to four quality assurance categories by two independent raters (S1 Protocol p.5, S1 and S2 Tables). For studies that met the study quality criteria (S3 Table) , we applied LERG-approved definitions (S1 Protocol p. 5) for confirmed leptospirosis cases and deaths and extracted information on crude disease incidence and case fatality ratio. The systematic review also identified case series of leptospirosis patients among the quality assured incidence studies, and extracted information on age and gender-stratified proportions of cases and deaths (S1 Protocol pp. 4-5; S5 Table) . Since standard serologic confirmation of leptospirosis requires evaluation of paired acute and convalescent-phase sera [52] , we reviewed laboratory confirmation procedures and extracted data on proportions of suspected cases that had incomplete diagnostic evaluation (S1 Protocol p. 5) and ratios of clinically-suspected to laboratory-confirmed cases and deaths (S1 Protocol p. 5, S7 Table) . Two published reports (S1 Protocol references [39] , [56] ) were each separated into two studies as they contained separate data from urban and rural populations. c 94 published and 2 grey literature studies.", "cite_spans": [{"start": 414, "end": 418, "text": "[51]", "ref_id": "BIBREF51"}, {"start": 1481, "end": 1485, "text": "[52]", "ref_id": "BIBREF52"}, {"start": 1802, "end": 1806, "text": "[39]", "ref_id": "BIBREF38"}], "ref_spans": [{"start": 238, "end": 245, "text": "(Fig 1)", "ref_id": "FIGREF0"}]}, {"section": "Statistical analysis and reporting", "text": "We evaluated quality-assured studies for sources of heterogeneity due to study design, epidemiological setting, time, and geographic region. When multiple data sources were available for a country, mean estimates of crude country-specific morbidity were calculated, weighted by the size of the study population. Since information on mortality and case fatality was sparse (S4 Table and Fig 2) , we calculated the mean case fatality ratio using all reported data, weighted by study population, and used this estimate together with crude country-specific morbidity to calculate crude country-specific mortality (Fig 3, S10 Table, equation 7 and S1 Protocol p. 6). The majority of studies did not report age and gender-specific incidences. We therefore used the crude country-specific morbidity and mortality estimates, together with data on age and gender-specific risk for disease and death identified from case series reports (S10 Table, Tables, Fig 3 and S1 Protocol p. 5), to obtain estimates for age and gender-specific morbidity and mortality for countries and territories that had quality-assured data (S10 Table, Because data were not available for every sub-region, a multivariable regression model was developed to estimate leptospirosis incidence and mortality for each country and territory. We estimated the age and gender-specific morbidity and mortality and their 95% confidence intervals for each of 222 of the world's countries and territories, (S12 Table) based on a model that was developed with data on age and gender-specific incidences from quality-assured studies (S1 Protocol pp. [6] [7] [8] [9] . After a range of multivariable regression approaches and candidate variables were evaluated to select a country-level prediction model for age and gender-specific morbidity, we used a linear regression model approach to predict the log-transformation of annual morbidity of leptospirosis by country or territory. Annual disease incidence is represented as an exponential colour gradient from white (0-3), yellow (7) (8) (9) (10) , orange (20) (21) (22) (23) (24) (25) to red (over 100), in cases per 100,000 population. Circles and triangles indicate the countries of origin for published and grey literature quality-assured studies, respectively. doi:10.1371/journal.pntd.0003898.g002 leptospirosis morbidity based on country-specific indicator variables (S10 Table, equations 4 and 5, S9 Table and Fig 3) . This model aimed to derive estimates based on the relationship between the mean reported leptospirosis incidence and country-level characteristics such climate, sociodemographic indicators and health indicators. Variables were screened based on plausibility, availability for all countries and territories, and univariable relationship with leptospirosis incidence. The final variables in the prediction model were selected to produce the highest adjusted R 2 in order to yield the smallest prediction error: 1) whether the country is a tropical island, 2) percent urbanization of the population, 3) Distance from the equator in degrees latitude, and 4) the mean years of life expectancy at birth. Since crude mortality was calculated directly from disease incidence estimates, we used the same variables to model age and gender-specific mortality at the country level. We used a Monte Carlo model, which incorporated age and gender-specific incidence estimates and 95% CI for each country and territory as inputs, to obtain country, region, and global estimates and 95% CI of leptospirosis morbidity, mortality, cases and deaths (S10 Table  equation 6 , Fig 3 and S1 Protocol pp. 7-8). These estimates were used to create probability distributions of age and gender-specific incidence and mortality from which random samples were drawn. The ratios of clinically-suspected to laboratory-confirmed cases and deaths and their 95% CI, obtained from case series reports (Fig 3 and S10 Table equation 1) , were used to create normal distributions for the estimated under-reporting ratio for cases and deaths. A random draw from these normal distributions was multiplied by each random sample from estimated incidence and mortality distributions in order to obtain estimates adjusted for incomplete diagnostic testing (S1 Protocol p.7). Population estimates for 2010 were obtained from United Nations Population Division [53] . Morbidity and mortality estimates were calculated for both GBD [48] and WHO [54] geographical regions, described on S1 Protocol p. 2, so that these figures can be compared with information on other neglected diseases. Estimates were rounded to three significant figures, with a precision limit of 100 cases or deaths. Modelling was performed using the R statistical language [55] , and Monte Carlo simulation was performed using the Poptools plug-in for Microsoft Excel 2007 [56] . Maps were created to illustrate estimated morbidity using the rworldmap package for R [57] . Country-specific estimates of leptospirosis mortality and morbidity were shared with each country in compliance with WHO guidelines.", "cite_spans": [{"start": 1602, "end": 1605, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 1606, "end": 1609, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 1610, "end": 1613, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 1614, "end": 1617, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 2032, "end": 2035, "text": "(7)", "ref_id": "BIBREF6"}, {"start": 2036, "end": 2039, "text": "(8)", "ref_id": "BIBREF7"}, {"start": 2040, "end": 2043, "text": "(9)", "ref_id": "BIBREF8"}, {"start": 2044, "end": 2048, "text": "(10)", "ref_id": "BIBREF9"}, {"start": 2058, "end": 2062, "text": "(20)", "ref_id": "BIBREF19"}, {"start": 2063, "end": 2067, "text": "(21)", "ref_id": "BIBREF20"}, {"start": 2068, "end": 2072, "text": "(22)", "ref_id": "BIBREF21"}, {"start": 2073, "end": 2077, "text": "(23)", "ref_id": "BIBREF22"}, {"start": 2078, "end": 2082, "text": "(24)", "ref_id": "BIBREF23"}, {"start": 2083, "end": 2087, "text": "(25)", "ref_id": "BIBREF24"}, {"start": 4344, "end": 4348, "text": "[53]", "ref_id": "BIBREF53"}, {"start": 4414, "end": 4418, "text": "[48]", "ref_id": "BIBREF47"}, {"start": 4427, "end": 4431, "text": "[54]", "ref_id": "BIBREF54"}, {"start": 4726, "end": 4730, "text": "[55]", "ref_id": "BIBREF55"}, {"start": 4919, "end": 4923, "text": "[57]", "ref_id": "BIBREF57"}], "ref_spans": [{"start": 386, "end": 392, "text": "Fig 2)", "ref_id": "FIGREF3"}, {"start": 609, "end": 620, "text": "(Fig 3, S10", "ref_id": "FIGREF0"}, {"start": 938, "end": 951, "text": "Tables, Fig 3", "ref_id": "TABREF2"}, {"start": 2420, "end": 2426, "text": "Fig 3)", "ref_id": "FIGREF2"}, {"start": 3584, "end": 3589, "text": "Fig 3", "ref_id": "FIGREF2"}, {"start": 3895, "end": 3927, "text": "(Fig 3 and S10 Table equation 1)", "ref_id": "TABREF2"}]}, {"section": "Results", "text": "The search strategy and quality assessment and data extraction process yielded eight high-quality and 72 medium-quality studies, including seven grey literature studies (S3 Table and Fig 1) . Inter-evaluator agreement for the quality assessment was high (Kappa 0.93, 95% CI 0.80-1.00). The majority of studies reported data that were published after 1989 (66%) and obtained from five regions, Western Europe (n = 15; 19%), Caribbean (n = 14; 18%), South-East Asia (n = 10; 13%), Tropical Latin America (n = 10; 13%), and Oceania (n = 8; 10%). Among studies, 96% used hospital-based surveillance to identify leptospirosis cases, while 4% performed case ascertainment in community-based outpatient facilities.", "cite_spans": [], "ref_spans": [{"start": 183, "end": 189, "text": "Fig 1)", "ref_id": "FIGREF0"}]}, {"section": "Results", "text": "Reported disease incidence ranged from 0.10 to 975.00 annual cases per 100,000 population (S3 and S8 Tables). We did not identify significant temporal trends in morbidity or mortality (considering 10-year periods), but found differences in reported morbidity and mortality based on study design and population ( Table 1 ). Studies that used active surveillance to identify leptospirosis cases reported significantly higher morbidity than passive surveillance studies (12.09 vs. 2.13 per 100 000 population, p<0.01). Morbidity was also significantly higher in studies of rural populations and tropical regions compared to urban settings.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "Among the 35 studies that reported information on case fatality ratios (S3 Table) ; the mean case fatality ratio was 6.85% (95% CI 5.66-8.03). Ten studies reported age-and gender-stratified data for leptospirosis cases (listed in S5 Table) . Adults and males had a greater risk for leptospirosis than children and females (S6 Table and Fig 4A) , with highest risk (RR, 2.4, 95% CI 0.7-4.1) occurring among adult males with 20-29 years of age. Among three studies with ageand gender-stratified data for deaths from leptospirosis (S5 Table) , the age-specific risk for death was different from that for disease (S6 Table and Fig 4B) , and the highest risk for death occurred in an older age group of males with 50-59 years of age (RR, 3.7, 95% CI 2.6-4.8). Among 10 studies that reported information on the completeness of laboratory confirmation procedures, paired samples were obtained from a mean of 53% of cases (range, 20-88%). A total of 19 and four studies reported data on both clinically-suspected and laboratory-confirmed cases and deaths, respectively, due to leptospirosis (S7 Table) . Among these studies, the mean ratio of clinically-suspected to laboratory-confirmed cases and deaths was 3.1 (95% CI 1.2-5.1) and 2.2 (95% CI, 0.9-3.3), respectively.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "The model selection process screened 147 candidate variables for entry in a multivariable regression model of leptospirosis morbidity (S1 Protocol pp. 6 and 7). Eight variables met statistical, plausibility, and availability screening criteria and were evaluated in multivariable Approach used to estimate global leptospirosis morbidity and mortality. We extracted information on leptospirosis disease incidence, case fatality, age and gender distribution of cases and deaths, and the ratios of clinically suspected to laboratory confirmed cases and deaths from studies that met quality assurance criteria. Data outputs are depicted in open boxes. Processes and analyses are depicted in shaded boxes. Equations are detailed in S10 Table. doi:10.1371/journal.pntd.0003898.g003 Table 1 . Reported leptospirosis morbidity, mortality, and case fatality, according to study characteristic. (Tables 2, S9 and S10, equation 4). This model predicted the natural logarithm of leptospirosis morbidity based on four country-specific variables related to geography and climate (distance from the equator, location on a tropical island), indicators of the population's overall socioeconomic and health status (life expectancy at birth), and urbanization. The adjusted R 2 of the prediction model was 0.600. This model was used to estimate age and gender-specific morbidity and mortality for 222 countries. A Monte Carlo model incorporated age and gender-specific incidence and mortality at the country level to obtain country-specific, regional, and global estimates for incidence and mortality that were adjusted for incomplete diagnostic testing ( (Fig 2 and Table 3 ). Small tropical islands had high estimated incidence of leptospirosis; however, in several cases there was also significant uncertainty associated with those predictions. Morbidity and mortality by WHO sub-region (S11 Table) by country, (S12 Table) and stratified by age and gender (S13 Table) are detailed in the S1 Protocol.", "cite_spans": [], "ref_spans": [{"start": 731, "end": 737, "text": "Table.", "ref_id": "TABREF5"}, {"start": 885, "end": 898, "text": "(Tables 2, S9", "ref_id": "TABREF3"}, {"start": 1637, "end": 1655, "text": "(Fig 2 and Table 3", "ref_id": "FIGREF2"}]}, {"section": "Results", "text": "The model estimated that worldwide there are 1,030,000 cases (95% CI, 434,000-1,750,000) and 58,900 deaths (95% CI, 23,800-95,900) due to leptospirosis annually ( Table 3 ). The majority of leptospirosis cases and deaths occur in tropical regions; 73% of the world's leptospirosis cases and deaths occur in countries situated between the Tropics of Cancer and Capricorn. Highest morbidity occurred among males with 20-29 years of age (35.27 cases per 100,000, 95% CI 13.79-63.89), while highest estimated mortality occurred in older males with 50-59 years of age (2.89 deaths per 100,000, 95% CI 1.22-4.95). A significant proportion of global burden of cases and deaths due to leptospirosis occurred in the demographic group of males with 20-49 years of age (48% [95% CI 40-61%] and 42% [95% CI 34-53%], respectively).", "cite_spans": [], "ref_spans": [{"start": 163, "end": 170, "text": "Table 3", "ref_id": "TABREF2"}]}, {"section": "Discussion", "text": "We estimated that leptospirosis causes 1.03 (95% CI 0.43-1.75) million cases worldwide each year. These estimates place the disease among the leading zoonotic causes of morbidity and mortality. Furthermore, the number of estimated deaths (58,900; 95% CI 23.800-95,900) attributable to leptospirosis approaches or exceeds those for causes of haemorrhagic fever which were investigated in the Global Burden of Disease Study 2010 [48] and other studies [58] . The large majority of the estimated disease burden occurred in tropical regions and the world's poorest countries. The systematic literature review also found that adult males were the principal risk group for leptospirosis. Based on model predictions, morbidity and mortality was estimated to be high in regions, such as South and Southeast Asia, where leptospirosis is an under-recognized public health problem. Our approach had to address key challenges in the estimation of leptospirosis burden. First, the available data was sparsely distributed and not representative of all world regions. We therefore developed a model to estimate morbidity and mortality in regions with limited or no information and identified a final model that captured a significant amount of the variability (R 2 , 0.600) in the data from quality-assured studies. Although 95% confidence intervals for estimates were calculated to account for the variability in our assumptions, we may not have accounted for all potential uncertainties. Leptospirosis is an environmentally-transmitted disease [1] [2] [3] 6] ; disease risk may therefore vary significantly within a region, which in turn would contribute to spatial uncertainty. We applied criteria, accepted by an independent panel of experts (LERG), to select studies that employed appropriate methodologies with respect to case definitions, case ascertainment and case confirmation. Yet regional differences in access to health care facilities and laboratory testing, which are not explained by country-specific indicators of health and socioeconomic wealth, may have contributed to unaccounted variation. The true uncertainty may thus be greater than indicated by the confidence intervals for our estimates. Lastly, because specific countries had atypical characteristics, their model-predicted morbidity and mortality had high uncertainty which resulted in inflated estimates due to exponentiation from the log scale, which incorporates the standard error into the estimate. Estimates are therefore most reliable at the regional and global level, and caution should be taken when interpreting individual country estimates. The second challenge related to incomplete laboratory testing of suspected cases. This is a widespread problem for leptospirosis since case confirmation relies primarily on identifying seroconversion of agglutinating antibodies between acute and convalescent-phase samples [52] . Among studies with information on laboratory confirmation procedures, complete laboratory testing for leptospirosis was not performed in almost 50% of the suspected cases. In order to address this source of under-reporting, we adjusted estimates of morbidity and mortality for the effect of incomplete diagnostic testing. Similar barriers with respect to sparse data and reliance on antiquated serologic tests are shared among many of the neglected diseases [59] , and as with leptospirosis, have directly contributed to their neglected disease status. Although our modelling approach has limitations, it may have a more generalizable application in estimating the disease burden for neglected diseases.", "cite_spans": [{"start": 427, "end": 431, "text": "[48]", "ref_id": "BIBREF47"}, {"start": 450, "end": 454, "text": "[58]", "ref_id": "BIBREF58"}, {"start": 1531, "end": 1534, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 1535, "end": 1538, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 1543, "end": 1545, "text": "6]", "ref_id": "BIBREF5"}, {"start": 2888, "end": 2892, "text": "[52]", "ref_id": "BIBREF52"}, {"start": 3353, "end": 3357, "text": "[59]", "ref_id": "BIBREF59"}], "ref_spans": []}, {"section": "Discussion", "text": "Our estimates likely underestimate the morbidity of leptospirosis, since disease incidence data was obtained from hospital-based surveillance studies (S3 Table) , the majority (65%) of which used passive case ascertainment. Similarly our estimates of mortality represent an underestimation since these were highly sensitive to estimates of morbidity. We obtained information on case fatality ratios from 35 studies, which included 20 (57%) conducted in World Bank upper income countries. The mean case fatality ratio (6.85%) that we used in modelling mortality is likely a significant underestimation of the ratios that occur in resource-poor regions. Worldwide case fatality ratio, based on estimated cases and deaths, was even lower (5.72%) due to the influence of the worldwide age and sex population structure. We opted to use a conservative assumption when faced with uncertainty, rather than attempt to model regional differences in case fatality ratio, or use ad-hoc adjustments. Our estimates of annual leptospirosis cases are higher than the approximately 500,000 cases estimated based on a survey of national surveillance data [47] . The higher estimates obtained from our study are plausible since this survey was conducted among a convenience sample of Ministries of Health.", "cite_spans": [{"start": 1137, "end": 1141, "text": "[47]", "ref_id": "BIBREF46"}], "ref_spans": []}, {"section": "Discussion", "text": "The study's morbidity estimates reflect the incidence of severe leptospirosis, rather than rates for clinical or symptomatic illness, since selected studies used case definitions that relied on detection of severe manifestations [60] . Severe leptospirosis is generally believed to account for a small fraction (5-15%) of all clinical infections [1, 14, 61] . There is a growing recognition that leptospirosis is an important cause of an acute febrile illness: leptospirosis has been shown to be the cause of 5-69% of acute undifferentiated or non-malarial fever cases in different parts of the world [16, 18, [32] [33] [34] [35] [36] [37] [38] 62] . Leptospirosis, as in the case of dengue [58] , may therefore account for a much greater burden than indicated by morbidity estimates of severe disease.", "cite_spans": [{"start": 229, "end": 233, "text": "[60]", "ref_id": "BIBREF60"}, {"start": 346, "end": 349, "text": "[1,", "ref_id": "BIBREF0"}, {"start": 354, "end": 357, "text": "61]", "ref_id": "BIBREF61"}, {"start": 601, "end": 605, "text": "[16,", "ref_id": "BIBREF15"}, {"start": 606, "end": 609, "text": "18,", "ref_id": "BIBREF17"}, {"start": 610, "end": 614, "text": "[32]", "ref_id": "BIBREF31"}, {"start": 615, "end": 619, "text": "[33]", "ref_id": "BIBREF32"}, {"start": 620, "end": 624, "text": "[34]", "ref_id": "BIBREF33"}, {"start": 625, "end": 629, "text": "[35]", "ref_id": "BIBREF34"}, {"start": 630, "end": 634, "text": "[36]", "ref_id": "BIBREF35"}, {"start": 635, "end": 639, "text": "[37]", "ref_id": "BIBREF36"}, {"start": 640, "end": 644, "text": "[38]", "ref_id": "BIBREF37"}, {"start": 645, "end": 648, "text": "62]", "ref_id": "BIBREF62"}, {"start": 691, "end": 695, "text": "[58]", "ref_id": "BIBREF58"}], "ref_spans": []}, {"section": "Discussion", "text": "The study's findings highlight the contribution of geography, climate, and poverty in the worldwide distribution of leptospirosis. Countries situated in the tropics had the highest estimated disease incidence and accounted for 73% of the world's estimated cases. This pattern is attributable to environmental and social conditions which promote the abundance of reservoir animals, survival of the bacterium in soil and surface water, and risk of human exposures with these sources of infection [3, 22, 23] . Tropical climate also favours transmission of leptospirosis, which is often seasonal and increases during periods of heavy rainfall [6, 19] . The disease is well-recognized as a health problem of impoverished rural-subsistence farmers [13, 15] , pastoralists [16, 45, 63] , and urban slum dwellers [19] [20] [21] [22] . We found that life expectancy, which serves in part as a proxy for poverty, was an independent predictor of country-specific disease incidence (Table 2) . Finally, although urban slum environments are an emerging and increasingly important setting for leptospirosis transmission [19] [20] [21] [22] , in our model, country percent urbanization was inversely associated with leptospirosis incidence, reflecting in part the high burden of leptospirosis in rural settings, but also the well-recognized association between lower aggregated country-level percent urbanization and poverty.", "cite_spans": [{"start": 498, "end": 501, "text": "22,", "ref_id": "BIBREF21"}, {"start": 502, "end": 505, "text": "23]", "ref_id": "BIBREF22"}, {"start": 640, "end": 643, "text": "[6,", "ref_id": "BIBREF5"}, {"start": 644, "end": 647, "text": "19]", "ref_id": "BIBREF18"}, {"start": 743, "end": 747, "text": "[13,", "ref_id": "BIBREF12"}, {"start": 748, "end": 751, "text": "15]", "ref_id": "BIBREF14"}, {"start": 767, "end": 771, "text": "[16,", "ref_id": "BIBREF15"}, {"start": 772, "end": 775, "text": "45,", "ref_id": "BIBREF44"}, {"start": 776, "end": 779, "text": "63]", "ref_id": "BIBREF63"}, {"start": 806, "end": 810, "text": "[19]", "ref_id": "BIBREF18"}, {"start": 811, "end": 815, "text": "[20]", "ref_id": "BIBREF19"}, {"start": 816, "end": 820, "text": "[21]", "ref_id": "BIBREF20"}, {"start": 821, "end": 825, "text": "[22]", "ref_id": "BIBREF21"}, {"start": 1107, "end": 1111, "text": "[19]", "ref_id": "BIBREF18"}, {"start": 1112, "end": 1116, "text": "[20]", "ref_id": "BIBREF19"}, {"start": 1117, "end": 1121, "text": "[21]", "ref_id": "BIBREF20"}, {"start": 1122, "end": 1126, "text": "[22]", "ref_id": "BIBREF21"}], "ref_spans": [{"start": 971, "end": 980, "text": "(Table 2)", "ref_id": "TABREF3"}]}, {"section": "Discussion", "text": "The study identified regions within the developing world where the burden of leptospirosis may be significantly under-recognized. The annual morbidity of leptospirosis was estimated to be high in countries of South and Southeast Asia with large populations, such as India (19.7 cases [95% CI 6.8-36.8] per 100,000 population, S12 Table) and Indonesia (39.2 [12.8-78 .0] per 100,000 population, S12 Table) . Although transmission is endemic and large outbreaks have been reported in these countries [15, 62, 64] , surveillance for leptospirosis has not been routinely performed.", "cite_spans": [{"start": 498, "end": 502, "text": "[15,", "ref_id": "BIBREF14"}, {"start": 503, "end": 506, "text": "62,", "ref_id": "BIBREF62"}, {"start": 507, "end": 510, "text": "64]", "ref_id": "BIBREF64"}], "ref_spans": []}, {"section": "Discussion", "text": "An important limitation of the study was the scarce data on disease burden in specific geographical regions. This was particularly evident for regions within Africa, where information on morbidity and mortality rates was available from two studies. Although the burden estimates may not be reliable for this region, there is increasing evidence suggesting their plausibility. A large spectrum of sylvatic and domestic animals are reservoirs for Leptospira in Africa [65, 66] ; leptospirosis is a recognized animal health problem in the region [4] . A recent systematic review found high seroprevalence among human populations in different settings across the continent [4] . Furthermore, surveys of patient populations have found leptospirosis to be a prevalent cause of acute febrile illness [32, 63] . A recent population-based study reported an annual morbidity for leptospirosis of 75-102 cases per 100,000 population in northern Tanzania [45] . Additional locally representative data will be key to validate our estimates for the African continent and other regions with sparse data, though these efforts will require resources and time and may delay decision making with respect to strengthening surveillance and implementing control measures.", "cite_spans": [{"start": 466, "end": 470, "text": "[65,", "ref_id": "BIBREF65"}, {"start": 471, "end": 474, "text": "66]", "ref_id": "BIBREF66"}, {"start": 543, "end": 546, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 669, "end": 672, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 793, "end": 797, "text": "[32,", "ref_id": "BIBREF31"}, {"start": 798, "end": 801, "text": "63]", "ref_id": "BIBREF63"}, {"start": 943, "end": 947, "text": "[45]", "ref_id": "BIBREF44"}], "ref_spans": []}, {"section": "Discussion", "text": "Our study was also limited by the lack of studies that reported age and gender-specific incidence for morbidity and mortality. We extracted data from case series of representative patient populations in order to estimate the age and gender-specific risk for leptospirosis, which in turn was incorporated as an input in our models (S1 Protocol pp. 5-8 and Fig 3) . We found that the risk of acquiring leptospirosis was higher in adults than children and higher in males than females, and highest among adult males with 20 to 29 years of age (S6 Table and Fig 4A) . Male gender preference is a well-recognized phenomenon in leptospirosis and due to the gender-specific occupational and peridomicilary risk activities [22] [23] [24] 67] . The age and genderspecific risk for death had a different pattern: the risk for death increases with increasing age (S6 Table and Fig 4B) , a finding which has been observed in a range of epidemiological settings [14] . Since these estimates were based on small number of case series, additional studies of well-characterized patients from representative sites would therefore improve these estimates. Our systematic review did not include more recent literature from 2008; however there have been few reports on population-based mortality and morbidity rates during this interval. Leptospirosis is caused by a large number of serovar and serogroup agents which vary across regions. We could not evaluate the contribution of such agents on mortality and morbidity estimates, since less than 20% of the studies reported serologic or culture identification of these agents.", "cite_spans": [{"start": 715, "end": 719, "text": "[22]", "ref_id": "BIBREF21"}, {"start": 720, "end": 724, "text": "[23]", "ref_id": "BIBREF22"}, {"start": 725, "end": 729, "text": "[24]", "ref_id": "BIBREF23"}, {"start": 730, "end": 733, "text": "67]", "ref_id": "BIBREF67"}], "ref_spans": [{"start": 355, "end": 361, "text": "Fig 3)", "ref_id": "FIGREF2"}]}, {"section": "Discussion", "text": "Our study provides a baseline estimate to evaluate trends, as processes of climate and land use evolve in the future [6] . By 2037, the majority of the world's population will be inhabitants of urban centres in developing countries. A large proportion of this population will reside in slum settlements, where poor sanitation has created the conditions for annual rainfall-associated epidemics [22, 68] . Extreme weather events and flood-related disasters [6] are predicted to escalate with global climate change [69, 70] . As deforestation and agricultural expansion intensify in tropical regions [71] , rural-based farming populations may be increasingly exposed to leptospirosis. A formal burden of disease calculation will need to be performed to provide estimates based disability-adjusted life years (DALYs). As a caveat, the health outcomes of leptospirosis have been traditionally associated with its acute disease. The disease causes sub-acute and chronic complications, such uveitis [72] , and persistent complaints [73] . However, the frequency and magnitude of long-term sequelae have not been rigorously quantified. Although the disease is life-threatening, the overall DALYs attributable to leptospirosis may be relatively low. Considering the annual number of deaths worldwide, the impact of leptospirosis equals that of canine rabies (59,000 annual deaths) [74] . The burden of leptospirosis, with respect to morbidity, is higher than some other important neglected tropical diseases, including visceral leishmaniasis and severe dengue, and is similar to others, including echinococcosis and cysticercosis [75] .", "cite_spans": [{"start": 117, "end": 120, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 394, "end": 398, "text": "[22,", "ref_id": "BIBREF21"}, {"start": 399, "end": 402, "text": "68]", "ref_id": "BIBREF68"}, {"start": 456, "end": 459, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 513, "end": 517, "text": "[69,", "ref_id": "BIBREF69"}, {"start": 518, "end": 521, "text": "70]", "ref_id": "BIBREF70"}, {"start": 598, "end": 602, "text": "[71]", "ref_id": "BIBREF71"}, {"start": 993, "end": 997, "text": "[72]", "ref_id": "BIBREF72"}, {"start": 1026, "end": 1030, "text": "[73]", "ref_id": "BIBREF73"}, {"start": 1373, "end": 1377, "text": "[74]", "ref_id": "BIBREF74"}, {"start": 1622, "end": 1626, "text": "[75]", "ref_id": "BIBREF75"}], "ref_spans": []}, {"section": "Discussion", "text": "The study provides decision makers with an evidence base to implement effective policy and responses to leptospirosis. As identified in this study and cited in previous reviews [42, 43] the lack of an adequate diagnostic test remains a foremost barrier. The demand for improved diagnostics will be greater than indicated by cases estimated in this study, since these estimates reflect the burden of severe leptospirosis and represent a lower boundary for the actual number. The distribution of the leptospirosis burden (Fig 2) overlaps significantly with that for malaria [48] , dengue [48, 58] , and enteric fever [48] . Misdiagnosis between these diseases is common [16, [39] [40] [41] and in the case of leptospirosis, leads to delayed treatment of severe complications and poor outcomes [40] . Development and roll-out of diagnostic protocols could be leveraged and implemented synergistically that aim to address the multiple causes of acute fever in resource-poor, high-burden regions.", "cite_spans": [{"start": 177, "end": 181, "text": "[42,", "ref_id": "BIBREF41"}, {"start": 182, "end": 185, "text": "43]", "ref_id": "BIBREF42"}, {"start": 572, "end": 576, "text": "[48]", "ref_id": "BIBREF47"}, {"start": 586, "end": 590, "text": "[48,", "ref_id": "BIBREF47"}, {"start": 591, "end": 594, "text": "58]", "ref_id": "BIBREF58"}, {"start": 615, "end": 619, "text": "[48]", "ref_id": "BIBREF47"}, {"start": 668, "end": 672, "text": "[16,", "ref_id": "BIBREF15"}, {"start": 673, "end": 677, "text": "[39]", "ref_id": "BIBREF38"}, {"start": 678, "end": 682, "text": "[40]", "ref_id": "BIBREF39"}, {"start": 683, "end": 687, "text": "[41]", "ref_id": "BIBREF40"}, {"start": 791, "end": 795, "text": "[40]", "ref_id": "BIBREF39"}], "ref_spans": [{"start": 519, "end": 526, "text": "(Fig 2)", "ref_id": "FIGREF3"}]}, {"section": "Discussion", "text": "Finally, the estimation of global burden of leptospirosis now provides the opportunity to evaluate One Health strategies for prevention and control. The lack of recognition of leptospirosis as an important zoonotic disease had previously hampered consideration of such approaches. Our estimates support the assertion that leptospirosis is a leading zoonotic cause of morbidity and mortality in humans. The majority of the estimated morbidity and mortality occurs in regions which have large subsistence farming and pastoral populations and where the disease is a veterinary health problem and cause of lost productivity. Additional work is needed to quantify the economic burden of leptospirosis, which incorporates an assessment of its impact on animal health. Vaccines for leptospirosis are routinely used in livestock and domestic animals, although they do not appear to be transmission-blocking [5] . Investment towards identifying interventions, such as vaccines, may therefore yield synergistic health and societal benefits for poor populations in developing countries. Moreover, more sustainable practices considering ecosystems [76, 77] are needed for disease prevention. Finally, leptospirosis is a social-ecological problem, which often occurs in the context of social inequity. Therefore there is a critical need to evaluate and address the investment case for interventions that target the underlying environmental conditions and infrastructure deficiencies, such as open sewers in urban slum communities [22] [23] [24] , in order to make sustainable progress against this neglected disease. ", "cite_spans": [{"start": 1136, "end": 1140, "text": "[76,", "ref_id": "BIBREF76"}, {"start": 1141, "end": 1144, "text": "77]", "ref_id": "BIBREF77"}, {"start": 1517, "end": 1521, "text": "[22]", "ref_id": "BIBREF21"}, {"start": 1522, "end": 1526, "text": "[23]", "ref_id": "BIBREF22"}, {"start": 1527, "end": 1531, "text": "[24]", "ref_id": "BIBREF23"}], "ref_spans": []}, {"section": "Supporting Information", "text": "", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Leptospira: the dawn of the molecular genetics era for an emerging zoonotic pathogen", "authors": [{"first": "A", "middle": ["I"], "last": "Ko", "suffix": ""}, {"first": "C", "middle": [], "last": "Goarant", "suffix": ""}, {"first": "M", "middle": [], "last": "Picardeau", "suffix": ""}], "year": 2009, "venue": "Nature reviews Microbiology", "link": "7931267"}, "BIBREF1": {"title": "Leptospirosis: a zoonotic disease of global importance", "authors": [{"first": "A", "middle": ["R"], "last": "Bharti", "suffix": ""}, {"first": "J", "middle": ["E"], "last": "Nally", "suffix": ""}, {"first": "J", "middle": ["N"], "last": "Ricaldi", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Matthias", "suffix": ""}, {"first": "M", "middle": ["M"], "last": "Diaz", "suffix": ""}], "year": 2003, "venue": "Lancet Infect Dis", "link": "36947671"}, "BIBREF3": {"title": "Leptospirosis in Sub-Saharan Africa: a systematic review", "authors": [{"first": "S", "middle": ["G"], "last": "De Vries", "suffix": ""}, {"first": "B", "middle": ["J"], "last": "Visser", "suffix": ""}, {"first": "I", "middle": ["M"], "last": "Nagel", "suffix": ""}, {"first": "M", "middle": ["G"], "last": "Goris", "suffix": ""}, {"first": "R", "middle": ["A"], "last": "Hartskeerl", "suffix": ""}], "year": 2014, "venue": "Int J Infect Dis", "link": "22886875"}, "BIBREF5": {"title": "Climate change, flooding, urbanisation and leptospirosis: fuelling the fire?", "authors": [{"first": "C", "middle": ["L"], "last": "Lau", "suffix": ""}, {"first": "L", "middle": ["D"], "last": "Smythe", "suffix": ""}, {"first": "S", "middle": ["B"], "last": "Craig", "suffix": ""}, {"first": "P", "middle": [], "last": "Weinstein", "suffix": ""}], "year": 2010, "venue": "Transactions of the Royal Society of Tropical Medicine and Hygiene", "link": "22675707"}, "BIBREF6": {"title": "The globalization of leptospirosis: worldwide incidence trends", "authors": [{"first": "G", "middle": [], "last": "Pappas", "suffix": ""}, {"first": "P", "middle": [], "last": "Papadimitriou", "suffix": ""}, {"first": "V", "middle": [], "last": "Siozopoulou", "suffix": ""}, {"first": "L", "middle": [], "last": "Christou", "suffix": ""}, {"first": "N", "middle": [], "last": "Akritidis", "suffix": ""}], "year": 2008, "venue": "Int J Infect Dis", "link": "7089742"}, "BIBREF7": {"title": "Leptospirosis in Hawaii, 1974-1998: epidemiologic analysis of 353 laboratory-confirmed cases", "authors": [{"first": "A", "middle": ["R"], "last": "Katz", "suffix": ""}, {"first": "V", "middle": ["E"], "last": "Ansdell", "suffix": ""}, {"first": "P", "middle": ["V"], "last": "Effler", "suffix": ""}, {"first": "C", "middle": ["R"], "last": "Middleton", "suffix": ""}, {"first": "D", "middle": ["M"], "last": "Sasaki", "suffix": ""}], "year": 2002, "venue": "Am J Trop Med Hyg", "link": "8407116"}, "BIBREF8": {"title": "Outbreak of leptospirosis among triathlon participants and community residents in", "authors": [{"first": "J", "middle": [], "last": "Morgan", "suffix": ""}, {"first": "S", "middle": ["L"], "last": "Bornstein", "suffix": ""}, {"first": "A", "middle": ["M"], "last": "Karpati", "suffix": ""}, {"first": "M", "middle": [], "last": "Bruce", "suffix": ""}, {"first": "C", "middle": ["A"], "last": "Bolin", "suffix": ""}], "year": 1998, "venue": "Clin Infect Dis", "link": null}, "BIBREF9": {"title": "Outbreak of leptospirosis after white-water rafting: sign of a shift from rural to recreational leptospirosis in Sri Lanka? Epidemiol Infect", "authors": [{"first": "S", "middle": ["B"], "last": "Agampodi", "suffix": ""}, {"first": "D", "middle": [], "last": "Karunarathna", "suffix": ""}, {"first": "N", "middle": [], "last": "Jayathilala", "suffix": ""}, {"first": "H", "middle": [], "last": "Rathnayaka", "suffix": ""}, {"first": "T", "middle": ["C"], "last": "Agampodi", "suffix": ""}], "year": 2014, "venue": "", "link": null}, "BIBREF10": {"title": "Leptospirosis: an emerging disease in travellers", "authors": [{"first": "C", "middle": [], "last": "Lau", "suffix": ""}, {"first": "L", "middle": [], "last": "Smythe", "suffix": ""}, {"first": "P", "middle": [], "last": "Weinstein", "suffix": ""}], "year": 2010, "venue": "Travel Med Infect Dis", "link": "35011018"}, "BIBREF11": {"title": "Leptospirosis in \"Eco-Challenge\" athletes", "authors": [{"first": "J", "middle": [], "last": "Sejvar", "suffix": ""}, {"first": "Bancroft", "middle": ["E"], "last": "Winthrop", "suffix": ""}, {"first": "K", "middle": [], "last": "Bettinger", "suffix": ""}, {"first": "J", "middle": [], "last": "Bajani", "suffix": ""}, {"first": "M", "middle": [], "last": "", "suffix": ""}], "year": 2000, "venue": "Emerging infectious diseases", "link": null}, "BIBREF12": {"title": "Leptospirosis in a subsistence farming community in Brazil", "authors": [{"first": "H", "middle": ["G"], "last": "Lacerda", "suffix": ""}, {"first": "G", "middle": ["R"], "last": "Monteiro", "suffix": ""}, {"first": "Ccg", "middle": [], "last": "Oliveira", "suffix": ""}, {"first": "F", "middle": ["B"], "last": "Suassuna", "suffix": ""}, {"first": "J", "middle": ["W"], "last": "Queiroz", "suffix": ""}], "year": 2008, "venue": "Transactions of the Royal Society of Tropical Medicine and Hygiene", "link": "9327277"}, "BIBREF14": {"title": "Increasing trends of leptospirosis in northern India: a clinico-epidemiological study", "authors": [{"first": "S", "middle": [], "last": "Sethi", "suffix": ""}, {"first": "N", "middle": [], "last": "Sharma", "suffix": ""}, {"first": "N", "middle": [], "last": "Kakkar", "suffix": ""}, {"first": "J", "middle": [], "last": "Taneja", "suffix": ""}, {"first": "S", "middle": ["S"], "last": "Chatterjee", "suffix": ""}], "year": 2010, "venue": "PLoS Negl Trop Dis", "link": "833551"}, "BIBREF15": {"title": "Etiology of severe nonmalaria febrile illness in Northern Tanzania: a prospective cohort study. PLoS neglected tropical diseases", "authors": [{"first": "J", "middle": ["A"], "last": "Crump", "suffix": ""}, {"first": "A", "middle": ["B"], "last": "Morrissey", "suffix": ""}, {"first": "W", "middle": ["L"], "last": "Nicholson", "suffix": ""}, {"first": "R", "middle": ["F"], "last": "Massung", "suffix": ""}, {"first": "R", "middle": ["A"], "last": "Stoddard", "suffix": ""}], "year": 2013, "venue": "", "link": null}, "BIBREF16": {"title": "Clinical diagnosis and geographic distribution of leptospirosis", "authors": [{"first": "V", "middle": [], "last": "Wuthiekanun", "suffix": ""}, {"first": "N", "middle": [], "last": "Sirisukkarn", "suffix": ""}, {"first": "P", "middle": [], "last": "Daengsupa", "suffix": ""}, {"first": "P", "middle": [], "last": "Sakaraserane", "suffix": ""}, {"first": "A", "middle": [], "last": "Sangkakam", "suffix": ""}], "year": 2007, "venue": "Thailand. Emerg Infect Dis", "link": "15813332"}, "BIBREF17": {"title": "The potential emergence of leptospirosis in Sri Lanka. The Lancet infectious diseases", "authors": [{"first": "S", "middle": [], "last": "Agampodi", "suffix": ""}, {"first": "S", "middle": ["J"], "last": "Peacock", "suffix": ""}, {"first": "V", "middle": [], "last": "Thevanesam", "suffix": ""}], "year": 2009, "venue": "", "link": null}, "BIBREF18": {"title": "Urban epidemic of severe leptospirosis in Brazil. Salvador Leptospirosis Study Group", "authors": [{"first": "A", "middle": ["I"], "last": "Ko", "suffix": ""}, {"first": "Galv\u00e3o", "middle": [], "last": "Reis", "suffix": ""}, {"first": "M", "middle": [], "last": "", "suffix": ""}, {"first": "Ribeiro", "middle": [], "last": "Dourado", "suffix": ""}, {"first": "C", "middle": ["M"], "last": "Johnson", "suffix": ""}, {"first": "W", "middle": ["D"], "last": "Riley", "suffix": ""}, {"first": "L", "middle": ["W"], "last": "", "suffix": ""}], "year": 1999, "venue": "Lancet", "link": "24707880"}, "BIBREF19": {"title": "Household transmission of leptospira infection in urban slum communities", "authors": [{"first": "Eap", "middle": [], "last": "Maciel", "suffix": ""}, {"first": "De", "middle": [], "last": "Carvalho", "suffix": ""}, {"first": "Alf", "middle": [], "last": "Nascimento", "suffix": ""}, {"first": "S", "middle": ["F"], "last": "", "suffix": ""}, {"first": "De", "middle": [], "last": "Matos", "suffix": ""}, {"first": "R", "middle": ["B"], "last": "Gouveia", "suffix": ""}, {"first": "E", "middle": ["L"], "last": "", "suffix": ""}], "year": 2008, "venue": "PLoS Negl Trop Dis", "link": "2842718"}, "BIBREF20": {"title": "Determining risk for severe leptospirosis by molecular analysis of environmental surface waters for pathogenic Leptospira", "authors": [{"first": "C", "middle": ["A"], "last": "Ganoza", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Matthias", "suffix": ""}, {"first": "D", "middle": [], "last": "Collins-Richards", "suffix": ""}, {"first": "K", "middle": ["C"], "last": "Brouwer", "suffix": ""}, {"first": "C", "middle": ["B"], "last": "Cunningham", "suffix": ""}], "year": 2006, "venue": "PLoS Med", "link": "2951766"}, "BIBREF21": {"title": "Impact of environment and social gradient on Leptospira infection in urban slums", "authors": [{"first": "R", "middle": ["B"], "last": "Reis", "suffix": ""}, {"first": "G", "middle": ["S"], "last": "Ribeiro", "suffix": ""}, {"first": "Rdm", "middle": [], "last": "Felzemburgh", "suffix": ""}, {"first": "F", "middle": ["S"], "last": "Santana", "suffix": ""}, {"first": "S", "middle": [], "last": "Mohr", "suffix": ""}], "year": 2008, "venue": "PLoS Negl Trop Dis", "link": "8581650"}, "BIBREF22": {"title": "Prospective study of leptospirosis transmission in an urban slum community: role of poor environment in repeated exposures to the Leptospira agent", "authors": [{"first": "R", "middle": ["D"], "last": "Felzemburgh", "suffix": ""}, {"first": "G", "middle": ["S"], "last": "Ribeiro", "suffix": ""}, {"first": "F", "middle": [], "last": "Costa", "suffix": ""}, {"first": "R", "middle": ["B"], "last": "Reis", "suffix": ""}, {"first": "J", "middle": ["E"], "last": "Hagan", "suffix": ""}], "year": 2014, "venue": "PLoS Negl Trop Dis", "link": "8796045"}, "BIBREF23": {"title": "Influence of Household Rat Infestation on Leptospira Transmission in Urban Slums", "authors": [{"first": "F", "middle": [], "last": "Costa", "suffix": ""}, {"first": "G", "middle": [], "last": "Ribeiro", "suffix": ""}, {"first": "R", "middle": [], "last": "Felzemburgh", "suffix": ""}, {"first": "N", "middle": [], "last": "Santos", "suffix": ""}, {"first": "R", "middle": [], "last": "Reis", "suffix": ""}], "year": 2014, "venue": "PLoS Negl Trop Dis", "link": null}, "BIBREF24": {"title": "Outbreak of Leptospirosis after Flood, the Philippines", "authors": [{"first": "A", "middle": [], "last": "Amilasan", "suffix": ""}, {"first": "M", "middle": [], "last": "Ujiie", "suffix": ""}, {"first": "M", "middle": [], "last": "Suzuki", "suffix": ""}, {"first": "E", "middle": [], "last": "Salva", "suffix": ""}, {"first": "Mcp", "middle": [], "last": "Belo", "suffix": ""}], "year": 2009, "venue": "Emerging Infectious Diseases", "link": "341781"}, "BIBREF25": {"title": "United Nations Human Settlements Programme. The challenge of the slums: Global report on human settlements", "authors": [], "year": 2003, "venue": "", "link": null}, "BIBREF26": {"title": "Leptospirosis associated with outbreak of acute febrile illness and pulmonary haemorrhage", "authors": [{"first": "S", "middle": ["R"], "last": "Zaki", "suffix": ""}, {"first": "W", "middle": ["J"], "last": "Shieh", "suffix": ""}], "year": 1995, "venue": "Lancet", "link": null}, "BIBREF27": {"title": "Clinical spectrum of pulmonary involvement in leptospirosis in a region of endemicity, with quantification of leptospiral burden", "authors": [{"first": "E", "middle": ["R"], "last": "Segura", "suffix": ""}, {"first": "C", "middle": ["A"], "last": "Ganoza", "suffix": ""}, {"first": "K", "middle": ["J"], "last": "Campos", "suffix": ""}, {"first": "J", "middle": ["N"], "last": "Ricaldi", "suffix": ""}, {"first": "S", "middle": [], "last": "Torres", "suffix": ""}], "year": 2005, "venue": "Clinical infectious diseases", "link": "24939300"}, "BIBREF28": {"title": "Leptospirosis-associated severe pulmonary hemorrhagic syndrome", "authors": [{"first": "E", "middle": ["L"], "last": "Gouveia", "suffix": ""}, {"first": "J", "middle": [], "last": "Metcalfe", "suffix": ""}, {"first": "Alf", "middle": [], "last": "De Carvalho", "suffix": ""}, {"first": "Tsf", "middle": [], "last": "Aires", "suffix": ""}, {"first": "J", "middle": ["C"], "last": "Villasboas-Bisneto", "suffix": ""}], "year": 2008, "venue": "Emerg Infect Dis", "link": null}, "BIBREF29": {"title": "Pulmonary involvement and leptospirosis", "authors": [{"first": "A", "middle": [], "last": "Papa", "suffix": ""}, {"first": "D", "middle": [], "last": "Theoharidou", "suffix": ""}, {"first": "A", "middle": [], "last": "Antoniadis", "suffix": ""}], "year": 2009, "venue": "Greece. Emerg Infect Dis", "link": null}, "BIBREF30": {"title": "Acute kidney injury: an increasing global concern", "authors": [{"first": "N", "middle": ["H"], "last": "Lameire", "suffix": ""}, {"first": "A", "middle": [], "last": "Bagga", "suffix": ""}, {"first": "D", "middle": [], "last": "Cruz", "suffix": ""}, {"first": "De", "middle": [], "last": "Maeseneer", "suffix": ""}, {"first": "J", "middle": [], "last": "Endre", "suffix": ""}, {"first": "Z", "middle": [], "last": "", "suffix": ""}], "year": 2013, "venue": "Lancet", "link": "2413518"}, "BIBREF31": {"title": "Retrospective serosurvey of leptospirosis among patients with acute febrile illness and hepatitis in Egypt. The American journal of tropical medicine and hygiene", "authors": [{"first": "T", "middle": ["F"], "last": "Ismail", "suffix": ""}, {"first": "M", "middle": ["O"], "last": "Wasfy", "suffix": ""}, {"first": "B", "middle": [], "last": "Abdul-Rahman", "suffix": ""}, {"first": "C", "middle": ["K"], "last": "Murray", "suffix": ""}, {"first": "D", "middle": ["R"], "last": "Hospenthal", "suffix": ""}], "year": 2006, "venue": "", "link": null}, "BIBREF32": {"title": "Unsuspected leptospirosis is a cause of acute febrile illness in Nicaragua", "authors": [{"first": "M", "middle": ["E"], "last": "Reller", "suffix": ""}, {"first": "E", "middle": ["A"], "last": "Wunder", "suffix": ""}, {"first": "J", "middle": ["J"], "last": "Miles", "suffix": ""}, {"first": "J", "middle": ["E"], "last": "Flom", "suffix": ""}, {"first": "O", "middle": [], "last": "Mayorga", "suffix": ""}], "year": 2014, "venue": "PLoS Negl Trop Dis", "link": "17952687"}, "BIBREF33": {"title": "Causes of nonmalarial fever in Laos: a prospective study", "authors": [{"first": "M", "middle": [], "last": "Mayxay", "suffix": ""}, {"first": "J", "middle": [], "last": "Castonguay-Vanier", "suffix": ""}, {"first": "V", "middle": [], "last": "Chansamouth", "suffix": ""}, {"first": "A", "middle": [], "last": "Dubot-P\u00e9r\u00e8s", "suffix": ""}, {"first": "D", "middle": ["H"], "last": "Paris", "suffix": ""}], "year": 2013, "venue": "Lancet Glob Health", "link": null}, "BIBREF34": {"title": "Acute undifferentiated febrile illness in rural Cambodia: a 3-year prospective observational study", "authors": [{"first": "T", "middle": ["C"], "last": "Mueller", "suffix": ""}, {"first": "S", "middle": [], "last": "Siv", "suffix": ""}, {"first": "N", "middle": [], "last": "Khim", "suffix": ""}, {"first": "S", "middle": [], "last": "Kim", "suffix": ""}, {"first": "E", "middle": [], "last": "Fleischmann", "suffix": ""}], "year": 2014, "venue": "PLoS One", "link": "16882136"}, "BIBREF35": {"title": "Murine typhus and leptospirosis as causes of acute undifferentiated fever, Indonesia. Emerging infectious diseases", "authors": [{"first": "M", "middle": ["H"], "last": "Gasem", "suffix": ""}, {"first": "Jfp", "middle": [], "last": "Wagenaar", "suffix": ""}, {"first": "Mga", "middle": [], "last": "Goris", "suffix": ""}, {"first": "M", "middle": ["S"], "last": "Adi", "suffix": ""}, {"first": "B", "middle": ["B"], "last": "Isbandrio", "suffix": ""}], "year": 2009, "venue": "", "link": null}, "BIBREF36": {"title": "Short report: Leptospirosis as a cause of fever in urban Bangladesh", "authors": [{"first": "E", "middle": ["A"], "last": "Kendall", "suffix": ""}, {"first": "R", "middle": ["C"], "last": "Larocque", "suffix": ""}, {"first": "D", "middle": ["M"], "last": "Bui", "suffix": ""}, {"first": "R", "middle": [], "last": "Galloway", "suffix": ""}, {"first": "M", "middle": ["D"], "last": "Ari", "suffix": ""}], "year": 2010, "venue": "American Journal of Tropical Medicine and Hygiene", "link": null}, "BIBREF37": {"title": "Causes of acute, undifferentiated, febrile illness in rural Thailand: results of a prospective observational study", "authors": [{"first": "C", "middle": [], "last": "Suttinont", "suffix": ""}, {"first": "K", "middle": [], "last": "Losuwanaluk", "suffix": ""}, {"first": "K", "middle": [], "last": "Niwattayakul", "suffix": ""}, {"first": "S", "middle": [], "last": "Hoontrakul", "suffix": ""}, {"first": "W", "middle": [], "last": "Intaranongpai", "suffix": ""}], "year": 2006, "venue": "Ann Trop Med Parasitol", "link": "25778287"}, "BIBREF38": {"title": "Leptospirosis among patients presenting with dengue-like illness in Puerto Rico", "authors": [{"first": "M", "middle": [], "last": "Bruce", "suffix": ""}, {"first": "E", "middle": [], "last": "Sanders", "suffix": ""}, {"first": "J", "middle": [], "last": "Leake", "suffix": ""}, {"first": "O", "middle": [], "last": "Zaidel", "suffix": ""}, {"first": "S", "middle": ["L"], "last": "Bragg", "suffix": ""}], "year": 2005, "venue": "Acta Trop", "link": "10833432"}, "BIBREF39": {"title": "Referral pattern of leptospirosis cases during a large urban epidemic of dengue", "authors": [{"first": "B", "middle": [], "last": "Flannery", "suffix": ""}, {"first": "M", "middle": ["M"], "last": "Pereira", "suffix": ""}, {"first": "F", "middle": [], "last": "Velloso L De", "suffix": ""}, {"first": "C", "middle": [], "last": "Carvalho C De", "suffix": ""}, {"first": "De", "middle": [], "last": "Codes", "suffix": ""}, {"first": "L", "middle": ["G"], "last": "", "suffix": ""}], "year": 2001, "venue": "Am J Trop Med Hyg", "link": "43339792"}, "BIBREF40": {"title": "Leptospirosis during dengue outbreak", "authors": [{"first": "R", "middle": ["C"], "last": "Larocque", "suffix": ""}, {"first": "R", "middle": ["F"], "last": "Breiman", "suffix": ""}, {"first": "M", "middle": ["D"], "last": "Ari", "suffix": ""}, {"first": "R", "middle": ["E"], "last": "Morey", "suffix": ""}, {"first": "F", "middle": ["A"], "last": "Janan", "suffix": ""}], "year": 2005, "venue": "Bangladesh. Emerging infectious diseases", "link": null}, "BIBREF41": {"title": "Rapid tests for diagnosis of leptospirosis: current tools and emerging technologies. Diagnostic microbiology and infectious disease", "authors": [{"first": "M", "middle": [], "last": "Picardeau", "suffix": ""}, {"first": "E", "middle": [], "last": "Bertherat", "suffix": ""}, {"first": "M", "middle": [], "last": "Jancloes", "suffix": ""}, {"first": "A", "middle": ["N"], "last": "Skouloudis", "suffix": ""}, {"first": "K", "middle": [], "last": "Durski", "suffix": ""}], "year": 2014, "venue": "", "link": null}, "BIBREF42": {"title": "Laboratory diagnosis of leptospirosis: A challenge", "authors": [{"first": "D", "middle": [], "last": "Musso", "suffix": ""}, {"first": "La", "middle": [], "last": "Scola", "suffix": ""}, {"first": "B", "middle": [], "last": "", "suffix": ""}], "year": 2013, "venue": "Immunology and Infection", "link": null}, "BIBREF43": {"title": "Estimating the burden of human leptospirosis", "authors": [{"first": "B", "middle": [], "last": "Abela-Ridder", "suffix": ""}, {"first": "R", "middle": [], "last": "Sikkema", "suffix": ""}, {"first": "R", "middle": ["A"], "last": "Hartskeerl", "suffix": ""}], "year": 2010, "venue": "Int J Antimicrob Ag", "link": "205168851"}, "BIBREF44": {"title": "Estimating leptospirosis incidence using hospital-based surveillance and a population-based health care utilization survey in Tanzania", "authors": [{"first": "H", "middle": ["M"], "last": "Biggs", "suffix": ""}, {"first": "J", "middle": ["T"], "last": "Hertz", "suffix": ""}, {"first": "O", "middle": ["M"], "last": "Munishi", "suffix": ""}, {"first": "R", "middle": ["L"], "last": "Galloway", "suffix": ""}, {"first": "F", "middle": [], "last": "Marks", "suffix": ""}], "year": 2013, "venue": "PLoS Neglected Tropical Diseases", "link": "16886609"}, "BIBREF45": {"title": "Towards a conceptual framework to support one-health research for policy on emerging zoonoses. The Lancet infectious diseases", "authors": [{"first": "R", "middle": [], "last": "Coker", "suffix": ""}, {"first": "J", "middle": [], "last": "Rushton", "suffix": ""}, {"first": "S", "middle": [], "last": "Mounier-Jack", "suffix": ""}, {"first": "E", "middle": [], "last": "Karimuribo", "suffix": ""}, {"first": "P", "middle": [], "last": "Lutumba", "suffix": ""}], "year": 2011, "venue": "", "link": null}, "BIBREF46": {"title": "World Health Organization. Leptospirosis worldwide", "authors": [], "year": 1999, "venue": "Weekly Epidemiological Record", "link": null}, "BIBREF47": {"title": "Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study", "authors": [{"first": "R", "middle": [], "last": "Lozano", "suffix": ""}, {"first": "M", "middle": [], "last": "Naghavi", "suffix": ""}, {"first": "K", "middle": [], "last": "Foreman", "suffix": ""}, {"first": "S", "middle": [], "last": "Lim", "suffix": ""}, {"first": "K", "middle": [], "last": "Shibuya", "suffix": ""}], "year": 2010, "venue": "Lancet", "link": "1541253"}, "BIBREF48": {"title": "Report of the first meeting of the leptospirosis burden epidemiology reference group", "authors": [], "year": 2010, "venue": "", "link": null}, "BIBREF49": {"title": "Report of the second meeting of the Leptospirosis Burden Epidemiology Reference Group", "authors": [], "year": 2010, "venue": "", "link": null}, "BIBREF51": {"title": "Preferred reporting items for systematic reviews and metaanalyses: the PRISMA statement", "authors": [{"first": "D", "middle": [], "last": "Moher", "suffix": ""}, {"first": "A", "middle": [], "last": "Liberati", "suffix": ""}, {"first": "J", "middle": [], "last": "Tetzlaff", "suffix": ""}, {"first": "D", "middle": ["G"], "last": "Altman", "suffix": ""}], "year": 2009, "venue": "PLoS Med", "link": "34365192"}, "BIBREF52": {"title": "World Health Organization. International Leptospirosis Society. Human leptospirosis guidelines for Diagnosis, Surveillance, and Control", "authors": [], "year": 2003, "venue": "", "link": null}, "BIBREF53": {"title": "World Urbanization Prospects: The 2009 Revision Population Database", "authors": [{"first": "Unp", "middle": [], "last": "Division", "suffix": ""}], "year": 2010, "venue": "", "link": null}, "BIBREF54": {"title": "World Health Organization. List of Member States by WHO region and mortality stratum", "authors": [], "year": 2003, "venue": "World Health Report", "link": null}, "BIBREF55": {"title": "R: A language and environment for statistical computing", "authors": [{"first": "R", "middle": ["C"], "last": "Team", "suffix": ""}], "year": 2012, "venue": "R Foundation for Statistical Computing", "link": null}, "BIBREF57": {"title": "rworldmap: Mapping global data, vector and raster", "authors": [{"first": "A", "middle": [], "last": "South", "suffix": ""}, {"first": "J", "middle": [], "last": "Scutt-Phillips", "suffix": ""}, {"first": "B", "middle": [], "last": "Rowlingson", "suffix": ""}, {"first": "R", "middle": [], "last": "Bivand", "suffix": ""}, {"first": "P", "middle": [], "last": "Foster", "suffix": ""}], "year": 2012, "venue": "", "link": null}, "BIBREF58": {"title": "The global distribution and burden of dengue", "authors": [{"first": "S", "middle": [], "last": "Bhatt", "suffix": ""}, {"first": "P", "middle": ["W"], "last": "Gething", "suffix": ""}, {"first": "O", "middle": ["J"], "last": "Brady", "suffix": ""}, {"first": "J", "middle": ["P"], "last": "Messina", "suffix": ""}, {"first": "A", "middle": ["W"], "last": "Farlow", "suffix": ""}], "year": 2013, "venue": "Nature", "link": "205233560"}, "BIBREF59": {"title": "Report of the WHO Strategic and Technical Advisory Group for Neglected Tropical Diseases (STAG-NTD): WHO headquarters", "authors": [], "year": 2010, "venue": "", "link": null}, "BIBREF60": {"title": "Leptospirosis outbreak in Sri Lanka in 2008: Lessons for assessing the global burden of disease", "authors": [{"first": "S", "middle": ["B"], "last": "Agampodi", "suffix": ""}, {"first": "S", "middle": ["J"], "last": "Peacock", "suffix": ""}, {"first": "V", "middle": [], "last": "Thevanesam", "suffix": ""}, {"first": "D", "middle": ["B"], "last": "Nugegoda", "suffix": ""}, {"first": "L", "middle": [], "last": "Smythe", "suffix": ""}], "year": 2011, "venue": "Am J Trop Med Hyg", "link": "207524962"}, "BIBREF61": {"title": "Current trends in translational research in leptospirosis", "authors": [{"first": "J", "middle": ["N"], "last": "Ricaldi", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Swancutt", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Matthias", "suffix": ""}], "year": 2013, "venue": "Curr Opin Infect Dis", "link": "2086209"}, "BIBREF62": {"title": "Etiology of acute, non-malaria, febrile illnesses in Jayapura, northeastern Papua, Indonesia. The American journal of tropical medicine and hygiene", "authors": [{"first": "N", "middle": ["H"], "last": "Punjabi", "suffix": ""}, {"first": "Wrj", "middle": [], "last": "Taylor", "suffix": ""}, {"first": "G", "middle": ["S"], "last": "Murphy", "suffix": ""}, {"first": "S", "middle": [], "last": "Purwaningsih", "suffix": ""}, {"first": "H", "middle": [], "last": "Picarima", "suffix": ""}], "year": 2012, "venue": "", "link": null}, "BIBREF63": {"title": "Leptospirosis among Hospitalized Febrile Patients in Northern Tanzania", "authors": [{"first": "H", "middle": ["M"], "last": "Biggs", "suffix": ""}, {"first": "D", "middle": ["M"], "last": "Bui", "suffix": ""}, {"first": "R", "middle": ["L"], "last": "Galloway", "suffix": ""}, {"first": "Stoddard", "middle": [], "last": "Ra", "suffix": ""}, {"first": "S", "middle": ["V"], "last": "Shadomy", "suffix": ""}], "year": 2011, "venue": "Am J Trop Med Hyg", "link": "32819462"}, "BIBREF64": {"title": "Mumbai braces itself for leptospirosis and waterborne infections", "authors": [{"first": "G", "middle": [], "last": "Mudur", "suffix": ""}], "year": 2005, "venue": "BMJ", "link": "28172767"}, "BIBREF65": {"title": "Urban leptospirosis in Africa: a cross-sectional survey of Leptospira infection in rodents in the Kibera urban settlement", "authors": [{"first": "J", "middle": ["E"], "last": "Halliday", "suffix": ""}, {"first": "D", "middle": ["L"], "last": "Knobel", "suffix": ""}, {"first": "K", "middle": ["J"], "last": "Allan", "suffix": ""}, {"first": "Cbbm", "middle": [], "last": "De", "suffix": ""}, {"first": "I", "middle": [], "last": "Handel", "suffix": ""}], "year": 2013, "venue": "Am J Trop Med Hyg", "link": null}, "BIBREF66": {"title": "Leptospirosis in Ethiopia: a serological survey in domestic and wild animals", "authors": [{"first": "R", "middle": ["W"], "last": "Moch", "suffix": ""}, {"first": "E", "middle": ["E"], "last": "Ebner", "suffix": ""}, {"first": "L", "middle": ["S"], "last": "Barsoum", "suffix": ""}, {"first": "B", "middle": ["A"], "last": "Botros", "suffix": ""}], "year": 1975, "venue": "J Trop Med Hyg", "link": "44450604"}, "BIBREF67": {"title": "Factors associated with clinical leptospirosis: a population-based case-control study in the Seychelles (Indian Ocean)", "authors": [{"first": "P", "middle": [], "last": "Bovet", "suffix": ""}, {"first": "C", "middle": [], "last": "Yersin", "suffix": ""}, {"first": "F", "middle": [], "last": "Merien", "suffix": ""}, {"first": "C", "middle": ["E"], "last": "Davis", "suffix": ""}, {"first": "P", "middle": [], "last": "Perolat", "suffix": ""}], "year": 1999, "venue": "International journal of epidemiology", "link": "21250739"}, "BIBREF68": {"title": "Slum health: diseases of neglected populations. BMC international health and human rights", "authors": [{"first": "L", "middle": ["W"], "last": "Riley", "suffix": ""}, {"first": "A", "middle": ["I"], "last": "Ko", "suffix": ""}, {"first": "A", "middle": [], "last": "Unger", "suffix": ""}, {"first": "M", "middle": ["G"], "last": "Reis", "suffix": ""}], "year": 2007, "venue": "", "link": null}, "BIBREF69": {"title": "Climate and health", "authors": [{"first": "P", "middle": ["R"], "last": "Epstein", "suffix": ""}], "year": 1999, "venue": "Science", "link": "56201650"}, "BIBREF70": {"title": "Impact of regional climate change on human health", "authors": [{"first": "J", "middle": ["A"], "last": "Patz", "suffix": ""}, {"first": "D", "middle": [], "last": "Campbell-Lendrum", "suffix": ""}, {"first": "T", "middle": [], "last": "Holloway", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Foley", "suffix": ""}], "year": 2005, "venue": "Nature", "link": "285589"}, "BIBREF71": {"title": "Deforestation driven by urban population growth and agricultural trade in the twenty-first century", "authors": [{"first": "R", "middle": ["S"], "last": "Defries", "suffix": ""}, {"first": "T", "middle": [], "last": "Rudel", "suffix": ""}, {"first": "M", "middle": [], "last": "Uriarte", "suffix": ""}, {"first": "M", "middle": [], "last": "Hansen", "suffix": ""}], "year": 2010, "venue": "Nature Geoscience", "link": "18532582"}, "BIBREF72": {"title": "Ocular leptospirosis. Current opinion in ophthalmology", "authors": [{"first": "S", "middle": ["R"], "last": "Rathinam", "suffix": ""}], "year": 2002, "venue": "", "link": null}, "BIBREF73": {"title": "Towards the burden of human leptospirosis: duration of acute illness and occurrence of post-leptospirosis symptoms of patients in the Netherlands", "authors": [{"first": "Mga", "middle": [], "last": "Goris", "suffix": ""}, {"first": "V", "middle": [], "last": "Kikken", "suffix": ""}, {"first": "M", "middle": [], "last": "Straetemans", "suffix": ""}, {"first": "S", "middle": [], "last": "Alba", "suffix": ""}, {"first": "M", "middle": [], "last": "Goeijenbier", "suffix": ""}], "year": 2013, "venue": "PloS one", "link": "322417"}, "BIBREF74": {"title": "Estimating the global burden of endemic canine rabies", "authors": [{"first": "K", "middle": [], "last": "Hampson", "suffix": ""}, {"first": "L", "middle": [], "last": "Coudeville", "suffix": ""}, {"first": "T", "middle": [], "last": "Lembo", "suffix": ""}, {"first": "M", "middle": [], "last": "Sambo", "suffix": ""}, {"first": "A", "middle": [], "last": "Kieffer", "suffix": ""}], "year": 2015, "venue": "PLoS Negl Trop Dis", "link": "384996"}, "BIBREF75": {"title": "The global burden of disease study 2010: interpretation and implications for the neglected tropical diseases", "authors": [{"first": "P", "middle": ["J"], "last": "Hotez", "suffix": ""}, {"first": "M", "middle": [], "last": "Alvarado", "suffix": ""}, {"first": "M", "middle": ["G"], "last": "Basanez", "suffix": ""}, {"first": "I", "middle": [], "last": "Bolliger", "suffix": ""}, {"first": "R", "middle": [], "last": "Bourne", "suffix": ""}], "year": 2014, "venue": "PLoS Negl Trop Dis", "link": "15759586"}, "BIBREF76": {"title": "Ecosystem approaches to health for a global sustainability agenda", "authors": [{"first": "D", "middle": ["F"], "last": "Charron", "suffix": ""}], "year": 2012, "venue": "Ecohealth", "link": "7962857"}, "BIBREF77": {"title": "Informal consultation on global burden of leptospirosis: methods of assessment", "authors": [{"first": "(", "middle": [], "last": "Lerg) Wholerg", "suffix": ""}], "year": 2009, "venue": "", "link": null}}, "ref_entries": {"FIGREF0": {"text": "Fig 1. Flow diagram for selection of studies. a 65 published and 7 grey literature studies.", "type": "figure"}, "FIGREF2": {"text": "Fig 3 and S1 Protocol pp. 5-6).", "type": "figure"}, "FIGREF3": {"text": "Fig 2. Estimated annual morbidity of leptospirosis by country or territory. Annual disease incidence is represented as an exponential colour gradient from white (0-3), yellow (7-10), orange (20-25) to red (over 100), in cases per 100,000 population. Circles and triangles indicate the countries of origin for published and grey literature quality-assured studies, respectively.", "type": "figure"}, "FIGREF4": {"text": "Fig 2. Estimated annual morbidity of leptospirosis by country or territory. Annual disease incidence is represented as an exponential colour gradient from white (0-3), yellow (7-10), orange (20-25) to red (over 100), in cases per 100,000 population. Circles and triangles indicate the countries of origin for published and grey literature quality-assured studies, respectively.", "type": "figure"}, "FIGREF5": {"text": "Fig 3. Approach used to estimate global leptospirosis morbidity and mortality. We extracted information on leptospirosis disease incidence, case fatality, age and gender distribution of cases and deaths, and the ratios of clinically suspected to laboratory confirmed cases and deaths from studies that met quality assurance criteria. Data outputs are depicted in open boxes. Processes and analyses are depicted in shaded boxes. Equations are detailed in S10 Table.", "type": "figure"}, "FIGREF7": {"text": "Checklist. PRISMA checklist. (DOC) S1 Protocol. Systematic review protocol. (DOCX) S2 Protocol. Manual of definitions. (DOCX) S1", "type": "figure"}, "TABREF1": {"text": "comparing incidence from studies of urban or rural populations). doi:10.1371/journal.pntd.0003898.t001 regression models. A linear regression model yielded the best fit multivariable prediction model", "type": "table"}, "TABREF2": {"text": "S11 and S12 Tables). The annual morbidity and mortality due to leptospirosis worldwide was estimated to be 14.77 cases per 100,000 population (95% CI 4.38-25.03) and 0.84 deaths per 100,000 population (95% CI 0.34-1.37), respectively. Highest disease incidences were estimated in GBD regions of Oceania (150.68 cases per 100,000, 95% CI 40.32-272.29), South-East Asia (55.54, 95% CI 20.", "type": "table"}, "TABREF3": {"text": "Variables incorporated in the final multivariable linear regression prediction model for lepto- spirosis morbidity in 34 countries.", "type": "table"}, "TABREF4": {"text": "Estimated annual leptospirosis morbidity and mortality according to GBD region.", "type": "table"}, "TABREF5": {"text": "Quality assessment criteria. (DOCX) S2 Table. Quality assessment checklist. (DOCX) S3 Table. Characteristics and findings of high and medium quality leptospirosis morbidity (N = 80) and mortality (N = 35) studies, according to GBD region. (DOCX) S4 Table. Geographic distribution of high and medium quality studies, according to GBD region (A) and WHO sub-region (B). (DOCX) S5 Table. Studies that reported information on age and gender proportions of cases and deaths from leptospirosis. (DOCX) S6 Table. Relative risk of leptospirosis cases (N = 10 studies) and deaths (N = 3 studies) according to age and gender group. (DOCX) S7 Table. Studies which reported information on both clinically-suspected and laboratory- confirmed leptospirosis cases and deaths. (DOCX) S8 Table. Reported disease morbidity, mortality, and case fatality, according to GBD region (A) and WHO sub-region (B). (DOCX) S9 Table. Model parameters for leptospirosis morbidity and mortality estimation. (DOCX) S10 Table. Equations. (DOCX) S11 Table. Estimated annual leptospirosis morbidity and mortality by WHO sub-region. (DOCX) S12 Table. Estimated leptospirosis morbidity and mortality by country, grouped according to WHO sub-region. (DOCX) S13 Table. Estimated age group and gender-specific leptospirosis morbidity and mortality, according to WHO sub-region. (DOCX)", "type": "table"}}}
{"paper_id": "18986705", "_pdf_hash": "eedafd43480dbec318dcc8030f329b35884e46eb", "abstract": [{"section": "Abstract", "text": "We describe cloned segments of rDNA that contain short type I insertions of differing lengths. These insertions represent a coterminal subset of sequences from the right hand side of the major 5kb type I insertion. Three of these shorter insertions are flanked on both sides by a short sequence present as a single copy in uninterrupted rDNA units. The duplicated segment is 7, 14 and 15 nucleotides in the different clones. In this respect, the insertions differ from the 5kb type I insertion, where the corresponding sequence is found only at the right hand junction and where at the left hand side there is a deletion of 9 nucleotides of rDNA (Roiha et al. ,1981). One clone is unusual in that it contains two type I insertions, one of which is flanked by a 14 nucleotide repeat. The left hand junction of the second insertion occurs 380 nucleotides downstream in the rDNA unit from the first. It has an identical right hand junction to the other elements and the 380 nucleotide rDNA sequence is repeated on both sides of the insertion. We discuss the variety of sequence rearrangements of the rDNA which flank type I insertions.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "The rDNA of Drosophila melanogaster can contain two types of non-homologous insertion sequences in the 28S gene (1-8). These insertions are unlike intervening sequences found in other genes and appear to have a repressive effect on the transcription of rDNA. It is possible to detect only a few high molecular weight transcripts containing insertion sequences and yet the nucleotide sequence of the region in which rDNA transcription initiates is identical in units containing insertions and those without (9,10).", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "The type I insertions are found in more than 50% of the rDNA units of the X chromosome and not in the rDNA of the Y chromosome (11,12,13). The most common type I insertion is about 5kb long, but in addition shorter insertions have been described which are mainly comprised of 0.5kb and lkb of DNA from the right hand side of the 5kb sequence. Roughly 50% of the type I sequences are found at other chromosomal sites, where they occur predominantly in", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "INTRODUCTION", "text": "The rDNA of Drosophila melanogaster can contain two types of non-homologous insertion sequences in the 28S gene (1-8). These insertions are unlike intervening sequences found in other genes and appear to have a repressive effect on the transcription of rDNA. It is possible to detect only a few high molecular weight transcripts containing insertion sequences and yet the nucleotide sequence of the region in which rDNA transcription initiates is identical in units containing insertions and those without (9,10).", "cite_spans": [], "ref_spans": []}, {"section": "INTRODUCTION", "text": "The type I insertions are found in more than 50% of the rDNA units of the X chromosome and not in the rDNA of the Y chromosome (11,12,13). The most common type I insertion is about 5kb long, but in addition shorter insertions have been described which are mainly comprised of 0.5kb and lkb of DNA from the right hand side of the 5kb sequence. Roughly 50% of the type I sequences are found at other chromosomal sites, where they occur predominantly in tandem arrays (14) . These type I sequences have probably undergone transposition from the nucleolus since the units within the tandem arrays are flanked by very short segments of the 28S gene (15) . Many Dipteran f l i e s have insertion sequences in their rDNA at the same site as D.melanogaster, as determined by low resolution mapping techniques (16) (17) (18) (19) . In the case of D . v i r i l i s the insertions have been shown by sequencing experiments to be at exactly the same site as the type I sequences of D.melanogaster. The D . v i r i l i s insertions, however, are flanked on both sides by a short segment of the gene present only once in uninterrupted units (20) . In our previous sequence analysis of the junctions of several long type I insertions with the D.melanogaster 28S gene, we found only a single copy of this rDNA sequence to the right of the insertion. At the l e f t hand junction nine nucleotides of rDNA are deleted (15) .", "cite_spans": [], "ref_spans": []}, {"section": "INTRODUCTION", "text": "In order to determine whether this was the only arrangement of sequences flanking type I insertions in the genome we decided to sequence the junctions between the short type I insertions and rDNA. In the cloned EcoRI fragments of rDNA which we examine in this paper, the short type I insertions are flanked by a duplicated sequence of 7 to 15 nucleotides with no deletions of flanking rDNA.", "cite_spans": [], "ref_spans": []}, {"section": "MATERIALS AND METHODS", "text": "Construction of Cloned DNAs. Recombinant DNAs were constructed in collaboration with Simon Kidd and Mick Browne. D.melanogaster embryonic DNA was digested to completion with EcoRI and enriched for fragments of 12kb-17kb, either by preparative sucrose gradient sedimentation or preparative electrophoresis on agarose gels (14) . Approximately 0.25ug of gradient purified DNA was ligated to 0.5ug of purified l e f t and right arms of Xgt.xWES (21) at a concentration of about lOOug/ml. The ligated DNA generated 2 x 10 plaque forming units in the in v i t r o packaging reaction (22) .", "cite_spans": [], "ref_spans": []}, {"section": "MATERIALS AND METHODS", "text": "From 2 x 10 plaques which were screened, 77 were selected which hybridised to the lkb BstI fragment and not the 4kb HindiII/BstI fragment of the Dml03 insertion. One of these phages, XMB27, is described in this paper. Approximately lug of the gel purified EcoRI fragments were ligated with 0.5ug of dephosphorylated EcoRI linear molecules of pAT153 (23) . The ligation mix generated 7 x 10 ampicillin resistant transformants of E.coli. Of these, 16 hybridised with the lkb BstI fragment and not with the 2.6kb Smal fragment of Dml03. Two of these recombinants, RI9 and RI10, are described in this paper. DNA Sequencing. All sequencing was performed as described by Maxam and Gilbert (24) . Restriction fragments were labelled by ' f i l l i n g i n ' the cohesive termini using reverse transcriptase (from J . Beard). The Kpnl site was label lee (Amersham).", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "32", "text": "was labelled using terminal transferase mediated addition of P-cordycepin", "cite_spans": [], "ref_spans": []}, {"section": "32", "text": "We have previously examined the nucleotide sequence at the junctions of type I sequences with rDNA in three configurations (15) :", "cite_spans": [], "ref_spans": []}, {"section": "32", "text": "-an rDNA unit containing a 5kb type I insertion (the rDNA segment DmlO3, reference 25); -an rDNA unit containing both a type I insertion and, 51 nucleotides upstream, a type I I insertion (Dm207, references 5 and 8);", "cite_spans": [], "ref_spans": []}, {"section": "32", "text": "-a fragment from the chromocentral heterochromatin consisting of 5 tandemly arranged type I elements, each joined to a 21 segment of rDNA on i t s l e f t and a 13 nucleotide segment on i t s right (Dm219, reference 14) . In each of these cases the junctions are identical. At the l e f t hand side of the type I insertion there is a deletion of nine nucleotides of rDNA. The right hand junction corresponds to the site of the rDNA insertions in D . v i r i l i s .", "cite_spans": [], "ref_spans": []}, {"section": "32", "text": "There are in addition a set of shorter type I insertions which we had not examined in the above experiments. The majority of these are either O.5kb or lkb in length and have sequence homology to the extreme right hand part of the 5kb insertion. We selected clones which would hybridise to sequences from this right hand region but not to sequences from the l e f t hand part of the long type I insertions (see Materials and Methods). We sequenced the entire insertions in three of these clones, RI9, RI10, and MB27, following the strategies shown in figure 1. The 28S rRNA of D.melanogaster consists of four polynucleotide chains (the 2S RNA, 5.8S RNA, 28Sa RNA, and 28Sp RNA) held together by hydrogen bonding. The insertions divide the rDNA coding for 28SB RNA into two regions, 28Sgl and 28Se2, and i t is this region of the 28S gene which is shown by the shaded blocks in figure 1. The top map shows the right hand portion of the 5kb Dml O3 insertion which we have sequenced. This sequence is shown in figure 2 . Each of the shorter insertions is an extremely homologous segment of this sequence, showing only 0.28% to 0.40% sequence divergence (see the legend to Fig.2 ). Each has an identical right hand junction with rDNA to the one found in DmlO3. The positions of the l e f t hand ends of the shorter insertions are indicated by arrows on the Dml O3 with either rDNA or the insertion. The clone MB27 has a lkb insertion flanked by a 7 nucleotide repeat. Again at the l e f t hand junction the contribution of rDNA to the sequence duplication is ambiguous, since the last nucleotide of the repeat is found in the long type I sequence in this position.", "cite_spans": [], "ref_spans": []}, {"section": "32", "text": "The clone RI9 contains a rearranged rDNA segment with two type I insertions 380 nucleotides apart. The shorter of these two insertions is 47 nucleotides long and is flanked on both sides by a 14 nucleotide repeat which appears to be constituted entirely of rDNA sequences (Fig.3) . The larger (747 nucleotide) insertion occurs downstream in the rDNA transcription unit. Its l e f t hand junction is at the unusual site in the 28Sg2 gene indicated by the open arrow above the rDNA sequence in figure 2 . At the right hand junction of this insertion, however, we find the usual sequence junction between type I sequences and the 28Sg gene (Fig.3) . The structure of this rDNA segment could be a result of a large deletion extending from the l e f t of the longer insertion into the previous rDNA unit. Alternatively, a DNA fragment comprised of insertion sequences and adjoining 28Sf}2 sequences could have been inserted into an rDNA unit which already contained an insertion. The effect is a duplication of a 380 nucleotide sequence on both sides of the insertion.", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "Several lines of circumstantial evidence suggest that the type I insertion sequences of D.melanogaster rDNA are specialised transposable elements. In addition to being inserted into a high proportion of the 28S genes of the X chromosome, the sequences are present at other heterochromatic loci and also in a region 102C of the fourth chromosome (13) . Our previous sequencing studies have indicated that the tandemly arranged type I sequences found in the heterochromatic regions outside the nucleolus organiser (14) are flanked by short segments of rDNA (15) . This suggests that the progenitor of these sequences was originally located within the nucleolus organiser and following excision became tandemly amplified either by autonomous replication or by unequal exchange following its insertion at a new chromosomal site. The rDNA segments which flank these type I units are identical to those immediately adjacent to the type I insertions in the cloned EcoRI fragments of rDNA, DmlO3 and Dm207 (15) . The type I insertion in Dml03 is approximately 5kb in length and is representative of about 60% of the rDNA units on the X chromosome. The rDNA segment Dm207 contains both a type I and a type I I insertion. The identity of the sequence junctions in a l l these cases suggests that they represent a principal sequence arrangement in the genome (15) . This is surprising since to the l e f t of the insertion there is a deletion of nine residues of rDNA. Thus i t would seem that an rDNA unit which is incapable of producing functional rRNA has been spread around the genome.", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "In this paper we characterise rDNA units containing type I insertions which d i f f e r from the 5kb insertion in Dml O3 in several respects. These units have shorter insertions which are flanked on both sides by a nucleotide sequence present only once at this site in uninterrupted rDNA units and which do not have deletions in the flanking rDNA sequence. The 5kb and 10kb insertion sequences in the rDNA of D . v i r i l i s occur at this same site and are also flanked by such a duplicated sequence (20) . We have previously referred to this duplicated sequence as the e* segment when making comparisons with D.melanogaster rDNA (15) . I t corresponds to the small segment of rDNA found on the right hand side of the type I elements in Dm219. In this paper we show that the length of the duplicated sequence varies, and so for the purposes of the following discussion we re-define the B* segment as the rDNA sequence which is duplicated. The occurence of insertion elements at identical sites in the rDNA of two Drosophila species could indicate that insertion sequences have been stably maintained at this s i t e , just as the positions of intervening sequences have been conserved in genes which encode polypeptides. However, several pieces of evidence suggest that transpositions of the type I sequences have been ongoing since the divergence of the D.melanogaster and D . v i r i l i s species. The rDNA sequence in this region is strongly conserved throughout eukaryotes. Although the insertions of D . v i r i l i s and D.melanogaster share some homology, thermal denaturation of heteroduplexes formed between the insertions indicates extensive mismatching (16) . In contrast, the chromocentral type I sequences of D.melanogaster show obvious identity with the rDNA insertions. Indeed, the junctions of 21 and 13 nucleotide rDNA segments with chromocentral type I units of Dm219 are identical to the junctions of these sequences in the nucleolar rDNA (15) . This suggests that these insertion sequences together with segments of flanking rDNA have migrated from the nucleolus relatively recently. Furthermore, the shorter type I insertions form a coterminal subset of sequences from the 5kb insertion of DmlO3, suggesting that they have been independently derived from these longer insertion elements.", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "Since the insertions are always found at the same s i t e , i t is l i k e l y that transposition could occur by a process of site specific recombination Whilst this partial homology might favour aberrant excisions at these sites, the \"breakpoint\" has clearly been out of register with the homology. These two insertions are flanked by duplicated sequences which differ in length. This is best explained if there is flexibility of the recombinational exchange within the e* site during the generation of shorter insertions. Once an extrachromosomal element has been generated containing an rDNA segment of a particular length, it could be perpetuated in the genome by homologous recombination into rDNA. Equally any novel rDNA unit generated in such a way could be spread throughout the nucleolus organiser by gene conversion or unequal exchange mechanisms acting on the rDNA units per se.", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "If the rDNA sequence which becomes duplicated is an essential feature of the recognition site, one might expect to find rearrangements on either side of insertions where such a sequence occurs. The deletion of rDNA to the left hand side of the 5kb insertions could be the consequence of an aberrant excision. Similarly one would expect to find evidence of aberrant excisions of sequences extending from a e* element rightwards into the 28Sg2 sequence. The duplication of a much longer part of the 28Sg2 sequence in the clone RI9 could be explained by the re-insertion of such an aberrantly excised element into another rDNA unit containing an insertion. Alternatively, this clone could be the result of a large deletion extending from the left of the 747 nucleotide insertion into the adjoining rDNA unit.", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "There is abundant evidence that many sequence rearrangements have occurred in this region of the 28S gene, and from the present arrangement of sequences we infer that there is a mechanism for site specific recombination at this site. This must, however, remain speculative since direct evidence for ongoing transposition has not yet been presented. Such a mechanism could also allow insertion elements to serve as \"end points\" for the excision of large blocks of rDNA from the tandemly arranged ribosomal genes. The selective advantage of systems that would either allow unequal exchange of blocks of rDNA or extrachromosomal replication of rDNA have been previously extolled as a potential means for correcting deficiencies of rDNA in the phenomenon of rDNA magnification (26, 27) . The sequence analysis that we present in this paper suggests a mechanism whereby the rDNA insertion elements themselves or large blocks of rDNA flanked by insertion elements could participate in such a processs. It will be of interest to examine the involvement of type I sequences in the rDNA magnification process.", "cite_spans": [{"start": 773, "end": 777, "text": "(26,", "ref_id": "BIBREF25"}, {"start": 778, "end": 781, "text": "27)", "ref_id": "BIBREF26"}], "ref_spans": []}], "bib_entries": {"BIBREF25": {"title": "Cold Spring Harbor Symp", "authors": [{"first": "K", "middle": ["D"], "last": "Tartof", "suffix": ""}], "year": 1973, "venue": "Quant. Biol", "link": null}, "BIBREF26": {"title": "Cold Spring Harbor Symp", "authors": [{"first": "F", "middle": [], "last": "Ritossa", "suffix": ""}, {"first": "F", "middle": [], "last": "Scalenghe", "suffix": ""}, {"first": "N", "middle": [], "last": "Di Turi", "suffix": ""}, {"first": "A", "middle": ["M"], "last": "Contini", "suffix": ""}], "year": 1973, "venue": "Quant. Biol", "link": null}}, "ref_entries": {"FIGREF0": {"text": "Figure 1. Sequencing Strategies The physical maps show the regions of the cloned rDNA segments which were sequenced. DmlO3 is the cloned EcoRI fragment described by Glover et al. (25). The selection of the three other cloned EcoRI fragments is described in the Materials and Methods. The arrows show the directions and extent to which sequences were read from the terminally labelled nucleotide. The shaded blocks represent rDNA and the solid lines the insertion sequences. The clone RI9 contains two insertions, which have identical right hand junctions. The dotted lines indicate the displacement of the left hand insertion to bring its right hand junction into alignment with the other cloned segments (Bgl = Bgl11; Bst = BstI; H3 = Haelll; HF = Hinfl; Kpn = Kpnl; Sst = SstI).", "type": "figure"}, "FIGREF1": {"text": "analogous to that utilised by the bacteriophage X genome for integration into and excision from the E.coli chromosome. The duplicated sequence would corrrespond to the duplicated att site sequence found on either side of the bacteriophage genome in lysogens. rDNA insertion sequences flanked by duplicated sequences could be excised by homologous recombination in a \"Campbell-type\" process. This would generate an uninterrupted rDNA unit and an extrachromosomal circle of the insertion sequence, each containing a single copy of the B* element. This extrachromosomal element would then be capable of integration at the same site in other \"empty\" rDNA units. The strong conservation of the sequence arrangement at the right hand junction of the type I insertion in all the clones which we have analysed (see Figs.2 and 3, and reference 15) suggests that this would be the recognition site for the recombinational process. Only one copy of the B* segment at this site may be necessary to promote recombination, since the insertion element in DmlO3 is flanked by a single copy of this sequence and has undergone transposition to alternative chromosomal sites. The 0.5kb element in RI10 could arise by recombination between the sequence TACTA (nucleotides -530 to -526, Fig.2) in a 5kb insertion and its homologue (nucleotides +71 to +75, Fig.2) in rDNA. This would generate an extrachromosomal insertion element with a 15 nucleotide homology to rDNA which could therefore generate a 15 nucleotide duplication upon re- insertion. Homologous pairing need not be an absolute requirement for the generation of new arrangements of insertions. Aberrant excisions of the lambdoid phages can result in a variety of sequence rearrangements about the att site, and similar events could explain the origins of the lkb insertion of MB27 and the 47 nucleotide insertion of RI9. At the position in the DmlO3 sequence corresponding to the left hand \"breakpoint\" necessary to produce these shorter insertions, there is limited homology with the B* sequence (viz. nucleotides -1007 to -1004, TGTC; nucleotides -51 to -49, TGT; Fig.2).", "type": "figure"}}}
{"paper_id": "18986901", "_pdf_hash": "c517d1c69fd9f842c0cff03a6e0d7fd0f7f92665", "abstract": [{"section": "Abstract", "text": "Abstract The formalism of Quantum Mechanics is based by definition on conserving probabilities and thus there is no room for the description of dissipative systems in Quantum Mechanics. The treatment of time-irreversible evolution (the arrow of time) is therefore ruled out by definition in Quantum Mechanics. In Quantum Field Theory it is, however, possible to describe time-irreversible evolution by resorting to the existence of infinitely many unitarily inequivalent representations of the canonical commutation relations (ccr). In this paper I review such a result by discussing the canonical quantization of the damped harmonic oscillator (dho), a prototype of dissipative systems. The irreversibility of time evolution is expressed as tunneling among the unitarily inequivalent representations. Canonical quantization is shown to lead to time dependent SU(1,1) coherent states. The exact action for the dho is derived in the path integral formalism of the quantum Brownian motion developed by Schwinger and by Feynman and Vernon. The doubling of the phase-space degrees of freedom for dissipative systems is related to quantum noise effects. Finally, the r\u00f4le of dissipation in the quantum model of the brain and the occurrence that the cosmological arrow of time, the thermodynamical one and the biological one point into the same direction are shortly mentioned.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "The formalism of Quantum Mechanics (QM) is based on conserving probabilities. In principle, therefore, there is no room for the description of time-irreversible evolution (the arrow of time) in QM. One has to introduce some sort of generalized quantum formalism in order to describe dissipative systems. The developments of the theory of unstable states going beyond the Breit-Wigner treatment and other phenomenological approaches have been frequently reported in the literature. See for example refs. [1] - [5] .", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "Dissipative systems have been analyzed in the path integral formalism by Schwinger [6] and by Feynman and Vernon [7] from the point of view of the quantum theory for Brownian motion and are of course a major topic in non-equilibrium statistical mechanics and non-equilibrium Quantum Field Theory (QFT) at finite temperature [8] - [11] .", "cite_spans": [{"start": 324, "end": 327, "text": "[8]", "ref_id": "BIBREF9"}, {"start": 330, "end": 334, "text": "[11]", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "Introduction", "text": "In this paper I report on the results [12] - [16] on dissipative systems in quantum theory which show that QFT does allow a correct treatment of the arrow of time provided the full set of unitarily inequivalent (ui) representations of the canonical commutation relations (ccr) is used. I show [17] that the proper algebraic structure of QFT is the deformed Hopf algebra [18, 19] and that the doubling of the phase-space degrees of freedom implied by such a structure is related to quantum noise effects in the case of dissipative systems [15] .", "cite_spans": [{"start": 45, "end": 49, "text": "[16]", "ref_id": "BIBREF17"}, {"start": 370, "end": 374, "text": "[18,", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "Introduction", "text": "The microscopic theory for a dissipative system must include the details of the processes responsible for dissipation, including quantum effects. One may start since the beginning with a Hamiltonian that describes the system, the bath and the system-bath interaction. Subsequently, the description of the original dissipative system is recovered by the reduced density matrix obtained by eliminating the bath variables which originate the damping and the fluctuations. The problem with dissipative systems in QM is indeed that ccr are not preserved by time evolution due to damping terms. The r\u00f4le of fluctuating forces is in fact the one of preserving the canonical structure.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "It is known since long time [20] that, at a classical level, the attempt to derive from a variational principle the equations of motion defining the dissipative system requires the introduction of additional complementary equations.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "This latter approach has been pursued since several years also in context of quantum theory. In refs. [21] and [12] - [16] the quantization of the damped harmonic oscillator (dho) has been studied by doubling the phase-space degrees of freedom (see also [22] for the study of unstable particle in QFT). The doubled degrees of freedom play the r\u00f4le of the bath degrees of freedom. Let me observe that the canonical formalism is devised solely for closed systems, therefore in order to produce the canonical quantization of the damped oscillator, it is necessary and sufficient to close the system, namely to \"balance\" the energy flux, the momentum exchange, etc.. For that task, and only for that task, we do not really need to know the details of the environment and not even the details of the system-environment coupling: therefore, for such a limited task, we may \"simulate\" the environment as a collection of oscillators whose k-modes match the k-modes of our damped oscillator. With such a choice the environment, depicted as the system time-reversed double, is treated as the \"effective\" environment. Of course, in those cases in which such a crude simplification is not enough (we might be really interested in the details of the system-environment interface, for example) much more care is needed and the doubling picture is not enough. In Sec. 2 I present the approach based on the system doubling.", "cite_spans": [{"start": 118, "end": 122, "text": "[16]", "ref_id": "BIBREF17"}], "ref_spans": []}, {"section": "Introduction", "text": "I would like to stress that the analysis for dissipative systems and the arrow of time presented in this paper should not be considered to be something just formal. It is a real problem the one of the description of open systems in a mathematically consistent formalism in QFT. QFT is in fact the only available theoretical scheme to describe high energy physics, as well as condensed matter physics, and quantum systems are always open systems interacting with their environment. It is true that in many cases the approximation of treating them as closed systems is very useful and successful for phenomenological computations, nevertheless there are many cases in which dissipative effects and breakdown of time reversal symmetry cannot be neglected. In these latter circumstances we do need a reliable, mathematically consistent QFT formalism.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "The approach here presented has revealed to be useful in several applications of physical interest, ranging from unstable particles [22] , to coherence in quantum Brownian motion [23] , squeezed states in quantum optics [12, 24, 25] , topologically massive theories in the infrared region in 2+1 dimensions [26] , the Chern-Simons-like dynamics of Bloch electrons in solids [26] , and has features also common to two-dimensional gravity models [27] , to the study of quantization arising from the loss of information [28, 29] , to the quantization of matter in curved background [30] . Moreover, it has been applied [31, 32, 33] to the study of the memory capacity problem in the quantum model for the brain [34] .", "cite_spans": [{"start": 625, "end": 628, "text": "33]", "ref_id": "BIBREF42"}], "ref_spans": []}, {"section": "Introduction", "text": "It has been known [21] that in QM time evolution of the dho leads out of the Hilbert space of states; in other words, the QM treatment of dho does not provide a unitary irreducible representation of SU(1,1) [35] . To cure these pathologies one must move to QFT, where infinitely many unitarily inequivalent representations of the ccr are allowed (in the infinite volume or thermodynamic limit). The reason for this is that the set of the states of the damped oscillator splits into ui representations (i.e. into disjoint folia, in the C*-algebra formalism) each one representing the states of the system at time t: the time irreversible evolution is described as tunneling between ui representations. A remarkable feature of this description thus emerges: at microscopic level the irreversibility of time evolution (the arrow of time) is expressed by the non unitary evolution across the ui representations of the ccr.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "I remark that the nature of the ground states of the ui representations is the one of the SU(1,1) generalized coherent states. Furthermore, the squeezed coherent states of light entering quantum optics [36, 24, 25] can be identified [12] , up to elements of the group G of automorphisms of su(1, 1), with the states of the quantum dho.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "It has been also shown [14] that the dho states are time dependent thermal states, as expected due to the statistical nature of dissipation. This is reported in Sec. 3. The formalism for the dho turns out to be similar to the one of real time QFT at finite temperature, also called thermo-field dynamics (TFD) [9, 10, 11] . In refs. [37] and [38] such a connection with TFD has been further analyzed and the master equation has been discussed [37] .", "cite_spans": [{"start": 310, "end": 313, "text": "[9,", "ref_id": "BIBREF10"}, {"start": 318, "end": 321, "text": "11]", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "Introduction", "text": "In ref. [15] the exact action for the dho in the path integral formalism of Schwinger and Feynman and Vernon has been obtained. The initial values of the doubled variables have been related to the probability of quantum fluctuations in the vacuum, a result which is interesting also in the more general case of thermal field theories. I report such results in Sec. 4.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "In Sec. 5 I show that the proper algebraic structure of QFT is the Hopf algebra [24] , which includes the usually considered Weyl-Heisenberg algebra (WH). I then show [17] that dissipative systems are properly described in the frame of the q-deformed Hopf algebra [18, 19, 39] . The q-deformation parameter turns out to be related with time parameter in the case of dho and with temperature in the case of thermal field theory. In both cases, the q-parameter acts as a label for the ui representations. Such a conclusion confirms a general analysis [40] which shows that the Weyl representations in QM and the ui representations in QFT are indeed labeled by the deformation parameter.", "cite_spans": [{"start": 264, "end": 268, "text": "[18,", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "Introduction", "text": "Sec. 6 is devoted to the conclusions. There I mention some recent developments which point to the r\u00f4le of dissipation in the quantization procedure [28, 29] and I also shortly recall the r\u00f4le of dissipation in the quantum model of the brain [31, 34] and on the occurrence that the cosmological arrow of time, the thermodynamical one and the biological one point into the same direction [32, 33] .", "cite_spans": [{"start": 391, "end": 394, "text": "33]", "ref_id": "BIBREF42"}], "ref_spans": []}, {"section": "The damped harmonic oscillator", "text": "In this section I want to perform the canonical quantization of the damped harmonic oscillator with classical equation", "cite_spans": [], "ref_spans": []}, {"section": "The damped harmonic oscillator", "text": "In the following I closely follow the approach of refs. [12] - [14] and [21] . The canonical quantization scheme can only deal with an isolated system. It is then necessary to double the phase-space dimensions [20, 21] in order to close the system (1). The closed system Lagrangian is then written as", "cite_spans": [], "ref_spans": []}, {"section": "The damped harmonic oscillator", "text": "Eq. (1) is obtained by varying eq. (2) with respect to y, whereas variation with respect to x gives m\u00ff \u2212 \u03b3\u1e8f + \u03bay = 0 ,", "cite_spans": [], "ref_spans": []}, {"section": "The damped harmonic oscillator", "text": "which appears to be the time reversed (\u03b3 \u2192 \u2212\u03b3) of eq. (1). y may be thought of as describing an effective degree of freedom for the heat bath to which the system (1) is coupled. The canonical momenta are then given by", "cite_spans": [], "ref_spans": []}, {"section": "The damped harmonic oscillator", "text": "The Hamiltonian is", "cite_spans": [], "ref_spans": []}, {"section": "The damped harmonic oscillator", "text": "For a discussion of Hamiltonian systems of this kind see also [41] . Canonical quantization is performed by introducing the commutators [x,", "cite_spans": [], "ref_spans": []}, {"section": "The damped harmonic oscillator", "text": ", and the corresponding sets of annihilation and creation operators", "cite_spans": [], "ref_spans": []}, {"section": "The damped harmonic oscillator", "text": "I have introduced \u2126 \u2261", "cite_spans": [], "ref_spans": []}, {"section": "The damped harmonic oscillator", "text": ", the common frequency of the two oscillators eq. (1) and eq. (3), assuming \u2126 real, hence \u03ba > \u03b3 2 4m (case of no overdamping). The Feshbach and Tikochinsky [21] quantum Hamiltonian is then obtained as", "cite_spans": [], "ref_spans": []}, {"section": "The damped harmonic oscillator", "text": "In Sec. 4 I show that, at quantum level, the \u03b2 modes allow quantum noise effects arising from the imaginary part of the action [15] . In Sec. 5 the doubling of the degrees of freedom will be shown to be a quite natural operation implied by the physically unavoidable requirement of the additivity of basic observables such as the energy, the angular momentum, etc.. By using the canonical linear transformations A \u2261", "cite_spans": [], "ref_spans": []}, {"section": "The damped harmonic oscillator", "text": "where the decay constant for the classical variable x(t) is denoted by \u0393 \u2261 \u03b3 2m . I observe that the states generated by B \u2020 represent the sink where the energy dissipated by the quantum damped oscillator flows: the B-oscillator represents the reservoir or heat bath coupled to the A-oscillator.", "cite_spans": [], "ref_spans": []}, {"section": "The damped harmonic oscillator", "text": "The dynamical group structure associated with the system of coupled quantum oscillators is that of SU (1, 1). The two mode realization of the algebra su(1, 1) is indeed generated by", "cite_spans": [], "ref_spans": []}, {"section": "The damped harmonic oscillator", "text": "Notice that once one sets the initial condition of positiveness for the eigenvalues of H 0 , such a condition is preserved by the time evolution since H 0 is the Casimir operator (it commutes with H I ). In other words, there is no danger of dealing with energy spectrum unbounded from below. Time evolution for creation and annihilation operators is given by", "cite_spans": [], "ref_spans": []}, {"section": "The damped harmonic oscillator", "text": "and h.c., and the corresponding ones for A(t), B(t) and h.c.. I note that eqs. (14) and (15) are Bogolubov transformations: they are canonical transformations preserving the ccr. Eq. (13) expresses the instability (decay) of the vacuum under the evolution operator exp \u2212it", "cite_spans": [], "ref_spans": []}, {"section": "The damped harmonic oscillator", "text": "h . This means that the QM framework is not suitable for the canonical quantization of the dho. In other words time evolution leads out of the Hilbert space of the states and in ref. [14] it has been shown that the proper way to perform the canonical quantization of the dho is to work in the framework of QFT. In fact for many degrees of freedom the time evolution operator U(t) and the vacuum are formally (at finite volume) given by", "cite_spans": [], "ref_spans": []}, {"section": "The damped harmonic oscillator", "text": "with < 0(t)|0(t) >= 1 , \u2200t . Using the continuous limit relation \u03ba \u2192 V (2\u03c0) 3 d 3 \u03ba, in the infinite-volume limit we have (for d 3 \u03ba \u0393 \u03ba finite and positive)", "cite_spans": [], "ref_spans": []}, {"section": "The damped harmonic oscillator", "text": "and in general, < 0(t)|0(t \u2032 ) >\u2192 0 as V \u2192 \u221e \u2200 t and t \u2032 , t \u2032 = t. At each time t a representation {|0(t) >} of the ccr is defined and turns out to be ui to any other representation {|0(t \u2032 ) > , \u2200t \u2032 = t} in the infinite volume limit. In such a way the quantum dho evolves in time through ui representations of ccr (tunneling). I remark that |0(t) > is a two-mode time dependent generalized coherent state [42, 43] .", "cite_spans": [{"start": 408, "end": 412, "text": "[42,", "ref_id": "BIBREF54"}, {"start": 413, "end": 416, "text": "43]", "ref_id": "BIBREF55"}], "ref_spans": []}, {"section": "The damped harmonic oscillator", "text": "One thus see that the Bogolubov transformations, eqs. (14) and (15) can be implemented for every \u03ba as inner automorphism for the algebra su(1, 1) \u03ba . At each time t we have a copy {A \u03ba (t), A \u2020 \u03ba (t), B \u03ba (t), B \u2020 \u03ba (t) ; |0(t) > | \u2200\u03ba} of the original algebra induced by the time evolution operator which can thus be thought of as a generator of the group of automorphisms of \u03ba su(1, 1) \u03ba parameterized by time t (we have a realization of the operator algebra at each time t, which can be implemented by Gel'fand-Naimark-Segal construction in the C*-algebra formalism [8] ). Notice that the various copies become unitarily inequivalent in the infinite-volume limit, as shown by eqs. (19) : the space of the states splits into ui representations of the ccr each one labeled by time parameter t. As usual, one works at finite volume and only at the end of the computations the limit V \u2192 \u221e is performed.", "cite_spans": [{"start": 568, "end": 571, "text": "[8]", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "Thermal features of quantum dissipation", "text": "In refs. [13] and [14] it has been shown that the representation {|0(t) >} is equivalent to the TFD representation {|0(\u03b2(t) >}, thus recognizing the relation between the dho states and the finite temperature states. In particular, one may introduce the free energy functional for the A-modes", "cite_spans": [{"start": 9, "end": 13, "text": "[13]", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "Thermal features of quantum dissipation", "text": "where H A is the part of H 0 relative to A-modes only, namely H A = \u03bah \u2126 \u03ba A \u2020 \u03ba A \u03ba , and the entropy S A is given by", "cite_spans": [], "ref_spans": []}, {"section": "Thermal features of quantum dissipation", "text": "One then considers the stability condition \u2202F A \u2202\u03d1\u03ba = 0 \u2200\u03ba , \u03d1 \u03ba \u2261 \u0393 \u03ba t to be satisfied in each representation, and using the definition E \u03ba \u2261h\u2126 \u03ba , one finds", "cite_spans": [], "ref_spans": []}, {"section": "Thermal features of quantum dissipation", "text": "namely the Bose distribution for A \u03ba at time t. {|0(t) >} is thus recognized to be a representation of the ccr at finite temperature, equivalent to the TFD representation {|0(\u03b2) >} [9, 10, 11]. I also notice that H 0 and H I in eq. (10) are the free Hamiltonian and the generator of Bogolubov transformations, respectively, also in TFD (provided one sets \u0393t \u2261 \u03b8(\u03b2) and \u2126 is given a proper expression). Use of eq. (21) shows that", "cite_spans": [], "ref_spans": []}, {"section": "Thermal features of quantum dissipation", "text": "One thus see that i 1 2h", "cite_spans": [], "ref_spans": []}, {"section": "\u2202S \u2202t", "text": "is the generator of time translations, namely time evolution is controlled by the entropy variations [22] . It is remarkable that the same dynamical variable S whose expectation value is formally the entropy also controls time evolution: Damping (or, more generally, dissipation) implies indeed the choice of a privileged direction in time evolution (arrow of time) with a consequent breaking of time-reversal invariance. One may also show that dF A = dE A \u2212 define as usual heat as dQ = 1 \u03b2 dS and see that the change in time dN A of particles condensed in the vacuum turns out into heat dissipation dQ.", "cite_spans": [], "ref_spans": []}, {"section": "\u2202S \u2202t", "text": "It is interesting to observe that the thermodynamic arrow of time, whose direction is defined by the increasing entropy direction, points in the same direction of the cosmological arrow of time, namely the inflating time direction for the expanding Universe. This can be shown by considering indeed the quantization of inflationary models [44] (see also [30] ). The concordance between the two arrows of time (also with the psychological arrow of time, cf. Sec. 6) is not at all granted and is a subject of an ongoing debate (see, e.g., [45] ).", "cite_spans": [], "ref_spans": []}, {"section": "Quantum noise and the doubling of the degrees of freedom", "text": "Let me now ask the following question: Does the doubling of the degrees of freedom, namely the introduction of an \"extra coordinate\", make any sense in the context of conventional QM? To answer to such a question I consider the special case of zero mechanical resistance. Let me begins with the Hamiltonian for an isolated particle and the corresponding density matrix equation", "cite_spans": [], "ref_spans": []}, {"section": "Quantum noise and the doubling of the degrees of freedom", "text": "which indeed requires two coordinates (say Q + and Q \u2212 ). In the coordinate representation, we have [15] ih(\u2202/\u2202t) < Q + |\u03c1(t)|Q \u2212 >= (26)", "cite_spans": [], "ref_spans": []}, {"section": "Quantum noise and the doubling of the degrees of freedom", "text": "In terms of the coordinates x and y, it is Q \u00b1 = x \u00b1 (1/2)y, and the density matrix function W (x, y, t) =< x + (1/2)y|\u03c1(t)|x \u2212 (1/2)y >. From eq. (27) the Hamiltonian now reads", "cite_spans": [], "ref_spans": []}, {"section": "Quantum noise and the doubling of the degrees of freedom", "text": ", with p x = \u2212ih(\u2202/\u2202x), p y = \u2212ih(\u2202/\u2202y), which, of course, may be constructed from the \"Lagrangian\"", "cite_spans": [], "ref_spans": []}, {"section": "Quantum noise and the doubling of the degrees of freedom", "text": "One has then the justification for introducing eq. (2) at least for the case \u03b3 = 0. Notice indeed that for V (x \u00b1 (1/2)y) = (1/2)k(x \u00b1 (1/2)y) eq. (28) gives eq. (2) for the case \u03b3 = 0. Next, my task is to explore the manner in which the Lagrangian model for quantum dissipation of refs. [12] - [16] , [21] arises from the formulation of the quantum Brownian motion problem as described by Schwinger [6] and by Feynman and Vernon [7] .", "cite_spans": [{"start": 295, "end": 299, "text": "[16]", "ref_id": "BIBREF17"}], "ref_spans": []}, {"section": "Quantum noise and the doubling of the degrees of freedom", "text": "Let me suppose that the particle interacts with a thermal bath at temperature T . The interaction Hamiltonian between the bath and the particle is taken as H int = \u2212f Q, where Q is the particle coordinate and f is the random force on the particle due to the bath. In the Feynman-Vernon formalism the effective action for the particle has the form", "cite_spans": [], "ref_spans": []}, {"section": "Quantum noise and the doubling of the degrees of freedom", "text": "where L o is defined in eq. (28) and", "cite_spans": [], "ref_spans": []}, {"section": "Quantum noise and the doubling of the degrees of freedom", "text": "In eq. (30) the average is with respect to the thermal bath; \"(.) + \" denotes time ordering and \"(.) \u2212 \" denotes anti-time ordering. If the interaction between the bath and the coordinate Q were turned off, then the operator f of the bath would develop in time according to f (t) = e iH R t/h f e \u2212iH R t/h where H R is the Hamiltonian of the isolated bath (decoupled from the coordinate Q). f (t) is the force operator of the bath to be used in eq. (30) . Assuming that the particle makes contact with the bath at the initial time t i , the reduced density matrix function is at a final time", "cite_spans": [], "ref_spans": []}, {"section": "Quantum noise and the doubling of the degrees of freedom", "text": "The correlation function for the random force on the particle is given by G(t \u2212 s) = (i/h) < f (t)f (s) > . The retarded and advanced Greens functions are defined by", "cite_spans": [], "ref_spans": []}, {"section": "Quantum noise and the doubling of the degrees of freedom", "text": "The mechanical resistance is defined R = lim \u03c9\u21920 ReZ(\u03c9 + i0 + ), with the mechanical impedance Z(\u03b6) (analytic in the upper half complex frequency plane Im \u03b6 > 0) determined by the retarded Greens function \u2212i\u03b6Z(\u03b6) = \u221e 0 dtG ret (t)e i\u03b6t . The time domain quantum noise in the fluctuating random force is", "cite_spans": [], "ref_spans": []}, {"section": "Quantum noise and the doubling of the degrees of freedom", "text": "The time ordered and anti-time ordered Greens functions describe both the retarded and advanced Greens functions as well as the quantum noise,", "cite_spans": [], "ref_spans": []}, {"section": "Quantum noise and the doubling of the degrees of freedom", "text": "The interaction between the bath and the particle is evaluated by following Feynman and Vernon and we find [15] for the real and the imaginary part of the action", "cite_spans": [], "ref_spans": []}, {"section": "Quantum noise and the doubling of the degrees of freedom", "text": "respectively, where the retarded force on y and the advanced force on x are defined as F ret (34) - (36) are rigorously exact for linear passive damping due to the bath when the path integral eq. (32) is employed for the time development of the density matrix.", "cite_spans": [], "ref_spans": []}, {"section": "Quantum noise and the doubling of the degrees of freedom", "text": "I therefore conclude that the lagrangian eq. (2) can be viewed as the approximation to eq. (35) with F ret y = \u03b3\u1e8f and F adv x = \u2212\u03b3\u1e8b. I also observe that at the classical level the \"extra\" coordinate y, is usually constrained to vanish. Note that y(t) = 0 is a true solution to eqs. (3) so that the constraint is not in violation of the equations of motion. From eqs. (34) -(36) one sees that at quantum level nonzero y allows quantum noise effects arising from the imaginary part of the action. On the contrary, in the classical \"h \u2192 0\" limit nonzero y yields an \"unlikely process\" in view of the large imaginary part of the action implicit in eq. (36) . Thus, the meaning of the constraint y = 0 at the classical level is the one of avoiding such \"unlikely process\".", "cite_spans": [], "ref_spans": []}, {"section": "Hopf algebra, q-deformation and quantum dissipation", "text": "Quantum deformations [18, 39] of Lie algebras are well studied mathematical structures and therefore their properties need not to be presented again in this paper. I only recall that they are deformations of the enveloping algebras of Lie algebras and have Hopf algebra structure [19] . In this Section I will show [17] that dissipative systems (as well as the finite temperature non-equilibrium systems) are properly described in the frame of the q-deformed Hopf algebra. Moreover, I will argue that the the proper algebraic structure of QFT is the deformed Hopf algebra. The q-deformation parameter turns out to be related with the time parameter in the case of dho (and with temperature in the case of thermal field theory). In both cases, the q-parameter acts as a label for the ui representations.", "cite_spans": [{"start": 21, "end": 25, "text": "[18,", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "Hopf algebra, q-deformation and quantum dissipation", "text": "I observe that one central ingredient of Hopf algebras is the operator doubling implied by the coalgebra. The coproduct operation is indeed a map \u2206 : A \u2192 A \u2297 A which duplicates the algebra. Lie-Hopf algebras are commonly used in the familiar addition of energy, momentum and angular momentum, e.g., for the \u2032\u2032 addition \u2032\u2032 of the angular momentum J \u03b1 , \u03b1 = 1, 2, 3, of two particles one has: (2). Thus, the physical meaning of the coproduct is that it provides the prescription for operating on two modes.", "cite_spans": [], "ref_spans": []}, {"section": "Hopf algebra, q-deformation and quantum dissipation", "text": "In the following, for simplicity, let me focus on the case of bosons. The conclusions can also be extended to fermions [17] .", "cite_spans": [], "ref_spans": []}, {"section": "Hopf algebra, q-deformation and quantum dissipation", "text": "The bosonic Hopf algebra, also called h (1), is generated by the set of operators {a, a \u2020 , H, N } with commutation relations:", "cite_spans": [], "ref_spans": []}, {"section": "Hopf algebra, q-deformation and quantum dissipation", "text": "Here a and a \u2020 denote generic annihilation and creation operators. For notational simplicity I omit the momentum suffix \u03ba which will be restored later on. Later we will see how the present discussion relates to the dho operators introduced in the previous Sections. H is a central operator, constant in each representation. The Casimir operator is given by C = 2N H \u2212 a \u2020 a. h(1) is equipped with the coproduct operation, defined by", "cite_spans": [], "ref_spans": []}, {"section": "Hopf algebra, q-deformation and quantum dissipation", "text": "I remark that usually one introduces the operator algebra necessary to set up QFT by limiting himself to the introduction of the boson Weyl-Heisenberg (WH) algebra (37) . The assumption of the additivity of some observables such as the energy, the momentum and the angular momentum is so obvious that one does not even bother to spell it out. It is implicitly given as granted. However, if one is asked to express it explicitly and formally, then it becomes natural to introduce the coproduct map, as shown above, and thus to realize that the boson WH algebra (37) is only a part of the full algebraic structure. One needs the Hopf structure. The full algebraic structure which is needed, however, has to take into account one of the very special features of QFT, the one which characterizes it and makes it different from QM, namely the existence of infinitely many representations of the ccr (in QM all the representations of the ccr are unitary equivalent due to the von Neumann theorem). Then one is led to consider the quantum deformation of the Hopf algebra, as it appears from the following.", "cite_spans": [], "ref_spans": []}, {"section": "Hopf algebra, q-deformation and quantum dissipation", "text": "The q-deformation of h (1) is the Hopf algebra h q (1):", "cite_spans": [], "ref_spans": []}, {"section": "Hopf algebra, q-deformation and quantum dissipation", "text": "where N q \u2261 N and H q \u2261 H. The Casimir operator C q is given by", "cite_spans": [], "ref_spans": []}, {"section": "Hopf algebra, q-deformation and quantum dissipation", "text": "whose algebra of course is isomorphic with (40):", "cite_spans": [], "ref_spans": []}, {"section": "Hopf algebra, q-deformation and quantum dissipation", "text": ". Note that h q (1) is a structure different from the commonly considered q-deformation of the harmonic oscillator [39] that does not have a coproduct (and thus cannot allow for the duplication of space).", "cite_spans": [], "ref_spans": []}, {"section": "Hopf algebra, q-deformation and quantum dissipation", "text": "Let me denote by F 1 the single mode Fock space, i.e. the fundamental representation H = 1/2, C = 0. In such a representation h(1) and h q (1) coincide as it happens for su(2) and su q (2) for the spin-1 2 representation. The differences appear in the coproduct and in the higher spin representations.", "cite_spans": [], "ref_spans": []}, {"section": "Hopf algebra, q-deformation and quantum dissipation", "text": "As customary, one requires that a and a \u2020 , and a q and a q \u2020 , are adjoint operators. This implies that q can only be real or of modulus one. In the two mode Fock space F 2 = F 1 \u2297 F 1 , for |q| = 1, the hermitian conjugation of the coproduct must be supplemented by the inversion of the two spaces for consistency with the coproduct isomorphism.", "cite_spans": [], "ref_spans": []}, {"section": "Hopf algebra, q-deformation and quantum dissipation", "text": "Summarizing, on F 2 = F 1 \u2297 F 1 it can be written: ", "cite_spans": [], "ref_spans": []}, {"section": "Hopf algebra, q-deformation and quantum dissipation", "text": "and h.c., with q(\u03b8) \u2261 e 2\u03b8 . A set of commuting operators with canonical commutation relations is given by", "cite_spans": [], "ref_spans": []}, {"section": "Hopf algebra, q-deformation and quantum dissipation", "text": "and h.c. One then introduces", "cite_spans": [], "ref_spans": []}, {"section": "Hopf algebra, q-deformation and quantum dissipation", "text": "All other commutators are equal to zero and A(\u03b8) and B(\u03b8) commute among themselves. Eqs. (50) and (51) are nothing but the Bogolubov transformations for the (A, B) pair, to be compared with the corresponding transformations (14) and (15) in the case of the dho. In other words, eqs. (50), (51) show that the Bogolubov-transformed operators A(\u03b8) and B(\u03b8) are linear combinations of the coproduct operators defined in terms of the deformation parameter q(\u03b8) and of their \u03b8-derivatives.", "cite_spans": [], "ref_spans": []}, {"section": "Hopf algebra, q-deformation and quantum dissipation", "text": "From this point on one can re-obtain the results discussed in the previous Sections for the dho, provided one sets \u03b8 \u2261 \u0393t. Notice that", "cite_spans": [], "ref_spans": []}, {"section": "Hopf algebra, q-deformation and quantum dissipation", "text": "and h.c., where G \u2261 \u2212i(A \u2020 B \u2020 \u2212 AB) denotes the generator of (50) and (51). For a fixed valu\u0113 \u03b8, we have", "cite_spans": [], "ref_spans": []}, {"section": "Hopf algebra, q-deformation and quantum dissipation", "text": "and similar equations for B(\u03b8).", "cite_spans": [], "ref_spans": []}, {"section": "Hopf algebra, q-deformation and quantum dissipation", "text": "In eq.(54) the definition p \u03b8 \u2261 \u2212i \u03b4 \u03b4\u03b8 has been used. It can be regarded as the momentum operator \u2032\u2032 conjugate \u2032\u2032 to the \u2032\u2032 degree of freedom \u2032\u2032 \u03b8, which thus acquires formal definiteness in the sense of the canonical formalism. In the infinite volume limit < 0(\u03b8)|0(\u03b8 \u2032 ) >= 0. In other words, the deformation parameter \u03b8 = 1 2 ln q acts as a label for the inequivalent representations, consistently with the results of Refs. [16, 24] . It is remarkable that the \"conjugate momentum\" p \u03b8 generates transitions among inequivalent (in the infinite volume limit) representations: exp(i\u03b8p \u03b8 ) |0(\u03b8) >= |0(\u03b8 +\u03b8) >.", "cite_spans": [{"start": 428, "end": 432, "text": "[16,", "ref_id": "BIBREF17"}], "ref_spans": []}, {"section": "Hopf algebra, q-deformation and quantum dissipation", "text": "In conclusion, one obtains, by use of the deformed Hopf algebra, the typical structure one deals with in QFT. In this connection, I observe that variation in time of the deformation parameter is related with the so-called heat-term in dissipative systems. In such a case, in fact, the Heisenberg equation for A(t, \u03b8(t)) is", "cite_spans": [], "ref_spans": []}, {"section": "Hopf algebra, q-deformation and quantum dissipation", "text": "where Q \u2261 \u03b4\u03b8 \u03b4t G denotes the heat-term, and H is the Hamiltonian (responsible for the time variation in the explicit time dependence of A(t, \u03b8(t))). H + Q is therefore to be identified with the free energy [14, 22] . In this way the results of Sec. 3 are also recovered. Thus, the conclusion is that variations in time of the deformation parameter actually involve dissipation. When the proper field description is taken into account, A and B carry dependence on the momentum \u03ba and, as customary in QFT, one deals with the algebras \u03ba h \u03ba (1) (cf. Sec. 2).", "cite_spans": [], "ref_spans": []}, {"section": "Concluding remarks", "text": "The dho total Hamiltonian is invariant under the transformations generated by", "cite_spans": [], "ref_spans": []}, {"section": "Concluding remarks", "text": "The vacuum however is not invariant under J 2 (see eq. (19)) in the infinite volume limit. Moreover, at each time t, the representation {|0(t) >} may be characterized by the expectation value in the state |0(t) > of, e.g., J (\u03ba) 3 \u2212 1 2 : thus the total number of particles n A + n B = 2n can be taken as an order parameter. Therefore, at each time t the symmetry under J 2 transformations is spontaneously broken. On the other hand, H I is proportional to J 2 . Thus, in addition to the breakdown of time-reversal (discrete) symmetry, already mentioned in Secion 2, we also have spontaneous breakdown of time translation (continuous) symmetry. In other words, dissipation (i.e. energy non-conservation), has been described as an effect of the breakdown of time translation and time-reversal symmetry. It is an interesting question asking which is the zero-frequency mode, playing the r\u00f4le of the Goldstone mode, related with the breakdown of continuous time translation symmetry: I observe that since n A \u2212 n B is constant in time, the condensation (annihilation and/or creation) of AB-pairs does not contribute to the vacuum energy so that AB-pair may play the r\u00f4le of a zero-frequency mode.", "cite_spans": [], "ref_spans": []}, {"section": "Concluding remarks", "text": "In the discussion presented above a crucial r\u00f4le is played by the existence of infinitely many ui representations of the ccr in QFT. In refs. [24, 40] the q-WH algebra has been discussed in relation with the von Neumann theorem in QM and it has been shown on a general ground that the q-deformation parameter acts as a label for the Weyl systems in QM and for the ui representations in QFT; the mapping between different (i.e. labeled by different values of q) representations (or Weyl systems) being performed by the Bogolubov transformations. Damped harmonic oscillator and finite temperature systems are explicit examples clarifying the physical meaning of such a labeling. Further examples are provided by unstable particles in QFT [22] , by quantization of the matter field in curved space-time [30] , by theories with spontaneous breakdown of symmetry where different values of the order parameter are associated to different ui representations (different phases). In the case of damping, as well as in the case of time-dependent temperature, the system time-evolution is represented as tunneling through ui representations: the non-unitary character of time-evolution (arrow of time) is thus expressed by the non-unitary equivalence of the representations in the infinite volume limit. It is remarkable that at the algebraic level this is made possible through the q-deformation mechanism which organizes the representations in an ordered set by means of the labeling.", "cite_spans": [], "ref_spans": []}, {"section": "Concluding remarks", "text": "In conclusion, from the point of view of boson condensation, time evolution in the presence of damping may be thus thought of as a sort of continuous transition among different phases, each phase corresponding, at time t, to the coherent state representation {|0(t) >}. The damped oscillator thus provides an archetype of system undergoing continuous phase transition.", "cite_spans": [], "ref_spans": []}, {"section": "Concluding remarks", "text": "As already mentioned in the introduction, dissipation in classical deterministic systems (such as the couple of classical oscillators described by eqs. (1) and (3) in Sec. 2) has been shown [29] to lead under suitable conditions to a quantum behavior, as originally proposed by 't Hooft [28] . In particular, dissipation manifests as a geometric Berry-Anandan-like phase [23] and it appears to be responsible for the zero point energy contribution in the oscillator energy spectrum [29] .", "cite_spans": [], "ref_spans": []}, {"section": "Concluding remarks", "text": "The features of the dissipative quantum dynamics discussed in this paper have been also used [31, 32, 33] to implement an infinite memory capacity in the quantum model of brain [34] . The key point is in the fact that dissipative dynamics implies infinitely many degenerate vacua (i.e. the zero eigenvalue eigenstates of H 0 , eqs. (9) and (18)), each of them describing a possible memory state according to the brain model of ref. [34] . Moreover, in view of the thermal character of such vacua illustrated in Sec. 3, the irreversible time evolution of the brain memory states, which is perceived as the arrow of time at a psychological experience level, appears to proceed in the same direction of the thermodynamical and of the cosmological arrow of time mentioned in Sec. 3. It is interesting to note that in a somewhat unexpected way it emerges a possible answer to the questions raised by the ongoing debate [45] on the coincidence (or not) of the directions of the three arrows of times just mentioned. Finally, the dissipative quantum model of brain has revealed to be also interesting in the study of features related with consciousness mechanisms [33] .", "cite_spans": [{"start": 102, "end": 105, "text": "33]", "ref_id": "BIBREF42"}, {"start": 1157, "end": 1161, "text": "[33]", "ref_id": "BIBREF42"}], "ref_spans": []}, {"section": "Concluding remarks", "text": "I ", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF2": {"title": "The Chaotic Universe", "authors": [{"first": "I", "middle": [], "last": "Prigogine", "suffix": ""}], "year": 2000, "venue": "", "link": null}, "BIBREF9": {"title": "Operator Algebras and Quantum Statistical Mechanics", "authors": [{"first": "O", "middle": [], "last": "Bratteli", "suffix": ""}, {"first": "D", "middle": ["W"], "last": "Robinson", "suffix": ""}], "year": 1979, "venue": "", "link": "123560051"}, "BIBREF10": {"title": "Advanced field theory: micro, macro and thermal concepts", "authors": [{"first": "H", "middle": [], "last": "Umezawa", "suffix": ""}], "year": 1993, "venue": "", "link": null}, "BIBREF12": {"title": "Thermo Field Dynamics and Condensed States", "authors": [{"first": "H", "middle": [], "last": "Umezawa", "suffix": ""}, {"first": "H", "middle": [], "last": "Matsumoto", "suffix": ""}, {"first": "M", "middle": [], "last": "Tachiki", "suffix": ""}], "year": 1982, "venue": "", "link": "118117994"}, "BIBREF14": {"title": "Thermal field theories and their applications", "authors": [{"first": "E", "middle": [], "last": "Celeghini", "suffix": ""}, {"first": "M", "middle": [], "last": "Rasetti", "suffix": ""}, {"first": "G", "middle": [], "last": "Vitiello", "suffix": ""}], "year": 1991, "venue": "", "link": "113717426"}, "BIBREF17": {"title": "Proceedings of The Third International Workshop on Thermal Field Theories -Banff/CAP Workshop on Thermal field theory", "authors": [{"first": "A", "middle": [], "last": "Iorio", "suffix": ""}, {"first": "G", "middle": [], "last": "Vitiello", "suffix": ""}, {"first": "; C", "middle": [], "last": "Khanna", "suffix": ""}], "year": 1994, "venue": "", "link": null}, "BIBREF20": {"title": "Proc. ICM", "authors": [{"first": "V", "middle": ["G"], "last": "Drinfeld", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF23": {"title": "Quantum groups and Non-Commutative Geometry, CRM, Montreal", "authors": [{"first": "Yu", "middle": ["I"], "last": "Manin", "suffix": ""}], "year": 1988, "venue": "", "link": null}, "BIBREF36": {"title": "Quantum mechanics and determinism", "authors": [{"first": "G", "middle": [], "last": "Hooft", "suffix": ""}], "year": "", "venue": "", "link": "119524884"}, "BIBREF42": {"title": "My Double unveiled -The dissipative quantum model of brain", "authors": [{"first": "G", "middle": [], "last": "Vitiello", "suffix": ""}], "year": 2001, "venue": "", "link": null}, "BIBREF54": {"title": "Fundamentals of Quantum Optics", "authors": [{"first": "J", "middle": ["R"], "last": "Klauder", "suffix": ""}, {"first": "E", "middle": ["C"], "last": "Sudarshan", "suffix": ""}], "year": 1968, "venue": "", "link": "117928839"}, "BIBREF55": {"title": "Generalized Coherent States and Their Applications", "authors": [{"first": "A", "middle": [], "last": "Perelomov", "suffix": ""}], "year": 1986, "venue": "", "link": "118787587"}}, "ref_entries": {"FIGREF0": {"text": "Note that [a i , a j ] = [a i , a \u2020 j ] = 0, i = j. It is now possible to show that the full set of infinitely many unitarily inequivalent repre- sentations of the ccr in QFT are classified by use of the deformed Hopf algebra. To do that it is sufficient to show that the Bogolubov transformations are directly obtained by use of the deformed copodruct operation. As well known, indeed, the Bogolubov transformations relate different (i.e. unitary inequivalent) representations. I consider therefore the following operators (cf. (41) with H = 1/2):", "type": "figure"}, "FIGREF1": {"text": "am glad to acknowledge the Organizers of the XXIV International Workshop on Fun- damental Problems of High Energy Physics and Field Theory, Protvino, June 2001, and in particular Professor A.A.Logunov and Professor V.A.Petrov for the kind and warm hospitality. I also acknowledge for partial financial support the INFN, INFM, MURST and the ESF Network COSLAB.", "type": "figure"}}}
{"paper_id": "18987532", "_pdf_hash": "ccda15350b648ac9f57dd161a62ff31e71490e0c", "abstract": [{"section": "Abstract", "text": "The activity of recombinant human growth hormone (rhGH) in enhancing CD34 \u0609 cell mobilization elicited by chemotherapy plus recombinant human granulocyte colony-stimulating factor (rhG-CSF) was evaluated in 16 hard-to-mobilize patients, that is, those achieving a peak of circulating CD34 \u0609 cells 10/L or less, or a collection of CD34 \u0609 cells equal to or less than 2 \u060b 10 6 /kg. Patients who had failed a first mobilization attempt with chemotherapy plus rhG-CSF (5 g/kg/d) were remobilized with chemotherapy plus rhG-CSF and rhGH (100 g/kg/d). As compared with rhG-CSF, the combined rhGH/rhG-CSF treatment induced significantly higher (P < .05) median peak values for CD34 \u0609 cells/L (7 versus 29), colonyforming cells (CFCs)/mL (2154 versus 28 510), and long-term culture-initiating cells (LTC-ICs)/mL (25 versus 511). Following rhG-CSF and rhGH/rhG-CSF, the median yields of CD34 \u0609 cells per leukapheresis were 1.1 \u060b 10 6 /kg and 2.3 \u060b 10 6 /kg (P < .008), respectively; the median total collections of CD34 \u0609 cells were 1.1 \u060b 10 6 / kg and 6 \u060b 10 6 /kg (P < ", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Mobilized peripheral blood progenitor cells (PBPCs) have an established role in the management of patients with non-Hodgkin lymphoma (NHL), 1,2 relapsed Hodgkin lymphoma (HL), 3 or multiple myeloma (MM) 4 who are eligible for high-dose sequential chemotherapy and autologous stem cell transplantation (ASCT). Because the number of infused CD34 \u03e9 cells correlates with the rate of hematopoietic reconstitution, the availability of adequate amounts of PBPCs is a prerequisite for the feasibility of high-dose chemotherapy and ASCT. 5 There is a general consensus that patients receiving PBPC autografts containing less than or equal to 2 \u03eb 10 6 CD34 \u03e9 cells/kg are at risk for delayed hematopoietic recovery, increased procedure-related morbidity and mortality, engraftment failure, and myelodysplasia, whereas those receiving 5 \u03eb 10 6 or more CD34 \u03e9 cells/kg experience prompt and durable hematopoietic engraftment. 6 PBPCs are mobilized efficiently by the administration of short courses of recombinant human (rh) granulocyte colony-stimulating factor (G-CSF) alone or during recovery from cytotoxic chemotherapy. [7] [8] [9] Indeed, due to prior chemoradiotherapy, disease stage, or disease-intrinsic factors, a substantial proportion of cancer patients (10%-30%) mobilize suboptimal amounts of CD34 \u03e9 cells (ie, \u0545 2 \u03eb 10 6 CD34 \u03e9 cells/kg). [10] [11] [12] The lack of autologous stem cells raises important issues for the clinical management of patients for whom ASCT has proved to be clinically beneficial.", "cite_spans": [{"start": 176, "end": 177, "text": "3", "ref_id": "BIBREF2"}, {"start": 203, "end": 204, "text": "4", "ref_id": "BIBREF3"}, {"start": 530, "end": 531, "text": "5", "ref_id": "BIBREF4"}, {"start": 915, "end": 916, "text": "6", "ref_id": "BIBREF5"}, {"start": 1114, "end": 1117, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 1118, "end": 1121, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 1122, "end": 1125, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 1343, "end": 1347, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 1348, "end": 1352, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 1353, "end": 1357, "text": "[12]", "ref_id": "BIBREF11"}], "ref_spans": []}, {"section": "Introduction", "text": "PBPC mobilization might be improved by molecules capable of interfering with the mechanisms regulating hematopoietic stem cell trafficking. [13] [14] [15] [16] An increase of CD34 \u03e9 cell mobilization might also be achieved by combinations of cytokines, such as granulocyte-macrophage colony-stimulating factor (rhGM-CSF) plus rhG-CSF, 17 interleukin-3 (rhIL-3) plus rhG-CSF or rhGM-CSF, 18 and PIXY-321. 19 Additionally, PBPC mobilization may be enhanced by incorporating in the standard mobilization regimen early-acting cytokines, such as stem cell factor (rh-SCF) [20] [21] [22] or flt-3 23 ligand. So far, substitutes or adjuncts to rhG-CSF either failed to substantially improve the mobilization of blood progenitors achieved with rhG-CSF alone or resulted in a limited improvement. 24, 25 Growth hormone (GH) is a pleiotropic cytokine targeting a variety of nonhematopoietic and hematopoietic cells by binding to a specific receptor. 26, 27 In vitro, rhGH significantly increases colony formation by human myeloid (granulocyte-macrophage colonyforming unit [CFU-GM]) and erythroid (erythroid burst-forming unit [BFU-E]) progenitors. [28] [29] [30] In vivo, a 7-day course of rhGH induces a significant increase of marrow and spleen CFU-GMs and BFU-Es in both normal and azidothymidine-treated mice. 31 Following syngeneic marrow transplantation, rhGH significantly hastens multilineage hematopoietic recovery in mice. 32 When given for 4 weeks, rhGH restores the age-associated decline of marrow cellularity in rats, 33 as well as the stem cell mobilization capacity in mice. 34 Collectively, these data suggest that bone marrow is an important target for the action of rhGH and allow us to hypothesize that rhGH might enhance rhG-CSF-induced mobilization of CD34 \u03e9 cells by increasing the numbers of marrow stem cells susceptible to be released on a subsequent or concomitant mobilization stimulus.", "cite_spans": [{"start": 140, "end": 144, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 145, "end": 149, "text": "[14]", "ref_id": "BIBREF13"}, {"start": 150, "end": 154, "text": "[15]", "ref_id": "BIBREF14"}, {"start": 155, "end": 159, "text": "[16]", "ref_id": "BIBREF15"}, {"start": 335, "end": 337, "text": "17", "ref_id": "BIBREF16"}, {"start": 387, "end": 389, "text": "18", "ref_id": "BIBREF17"}, {"start": 404, "end": 406, "text": "19", "ref_id": "BIBREF18"}, {"start": 567, "end": 571, "text": "[20]", "ref_id": "BIBREF19"}, {"start": 572, "end": 576, "text": "[21]", "ref_id": "BIBREF20"}, {"start": 577, "end": 581, "text": "[22]", "ref_id": "BIBREF21"}, {"start": 591, "end": 593, "text": "23", "ref_id": "BIBREF22"}, {"start": 788, "end": 791, "text": "24,", "ref_id": "BIBREF23"}, {"start": 792, "end": 794, "text": "25", "ref_id": "BIBREF24"}, {"start": 940, "end": 943, "text": "26,", "ref_id": "BIBREF25"}, {"start": 944, "end": 946, "text": "27", "ref_id": "BIBREF26"}, {"start": 1139, "end": 1143, "text": "[28]", "ref_id": "BIBREF27"}, {"start": 1144, "end": 1148, "text": "[29]", "ref_id": "BIBREF28"}, {"start": 1149, "end": 1153, "text": "[30]", "ref_id": "BIBREF29"}, {"start": 1305, "end": 1307, "text": "31", "ref_id": "BIBREF30"}, {"start": 1424, "end": 1426, "text": "32", "ref_id": "BIBREF31"}, {"start": 1523, "end": 1525, "text": "33", "ref_id": "BIBREF32"}, {"start": 1582, "end": 1584, "text": "34", "ref_id": "BIBREF33"}], "ref_spans": []}, {"section": "Introduction", "text": "Based on these findings, we conducted a pilot study aimed at investigating the feasibility and efficacy of rhGH administration as an adjunct to chemotherapy plus rhG-CSF for enhancing stem cell mobilization. Included in this study were 16 consecutive patients with relapsed or refractory hematologic malignancies who had failed a first mobilization attempt with chemotherapy plus rhG-CSF. Patients were then remobilized with chemotherapy plus rhG-CSF and rhGH. Mobilization failure was defined as a peak value of circulating CD34 \u03e9 cells equal to or less than 10/L, or a collection of CD34 \u03e9 cells equal to or less than 2 \u03eb 10 6 /kg. To eliminate the interpatient variability induced by the considerable heterogeneity in patient characteristics and responses to a given mobilization regimen, we prospectively compared the number of PBPCs mobilized into blood after 2 consecutive cycles of the same chemotherapy regimen administered in the same patient. The objectives of the study were to: (1) assess the activity of rhGH in increasing rhG-CSF-induced mobilization and harvesting of CD34 \u03e9 cells, committed colony-forming cells (CFCs), as well as the more primitive long-term culture-initiating cells (LTCICs), and (2) assess the safety and tolerability of rhGH, given in combination with rhG-CSF. Our data indicate that in the great majority of poor mobilizers addition of rhGH to rhG-CSF allows efficient mobilization and collection of CD34 \u03e9 cells with maintained functional properties.", "cite_spans": [], "ref_spans": []}, {"section": "Patients, materials, and methods", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Patients", "text": "Between September 2000 and December 2002, 16 hard-to-mobilize consecutive patients with relapsed or refractory hematologic malignancies who were eligible for ASCT were enrolled in this study. Demographic and disease characteristics for these patients at the time of study entry are shown in Table 1 . Patients (11 women, 5 men) ranged in age from 19 to 67 years (median, 52 years). Previous chemotherapy was to be completed at least 3 weeks before study entry. Patients were required to have a Karnofsky performance status of 80% or greater, left ventricular ejection fraction more than 50% at rest by echocardiography assessment, and a diffusing capacity of the lung for carbon monoxide (DLCO) more than 50%. Criteria for exclusion were: (1) renal or hepatic insufficiency or severe central nervous system or psychiatric diseases, (2) hepatitis B or C, or HIV tests positive, and (3) pregnancy. The study protocol was approved by Institutional Ethical Committee and written informed consent was obtained from each patient. Patients mobilized with rhGH/rhG-CSF were retrospectively compared with an historical group of hard-to-mobilize patients who were treated at our institution between January 1999 and August 2000, before the present study was conducted. The historical group of hard-to-mobilize patients included 14 transplantation-eligible patients (9 women, 5 men) with a median age of 50 years (range, 28-67 years).", "cite_spans": [], "ref_spans": [{"start": 291, "end": 298, "text": "Table 1", "ref_id": "TABREF0"}]}, {"section": "Study design", "text": "Studied were patients eligible to receive 2 consecutive cycles of the same chemotherapy regimen. An overview of the study is shown in Figure 1 . Following the administration of a first chemotherapy cycle supported by rhG-CSF (5 g/kg/d subcutaneously), patients identified as poor mobilizers (ie, those with a peak value of circulating CD34 \u03e9 cells \u03fd 10/L, or collecting \u0545 2 \u03eb 10 6 CD34 \u03e9 cells/kg) were remobilized with the same chemotherapy regimen supported by rhGH (100 g/kg/d, subcutaneously; maximum daily dose of 6 mg) plus rhG-CSF (5 g/kg/d, subcutaneously). Thus, according to the study design, the kinetics of PBPC mobilization achieved following cycle 1 served as intrapatient control to assess the mobilization achieved following cycle 2. Despite the fact that no prospective control group was envisaged for this pilot study, patients mobilized with rhGH/rhG-CSF were retrospectively compared with an historical group of hard-to-mobilize patients who had failed PBSC mobilization after standard-dose chemotherapy plus rhG-CSF (5 g/kg/d) and were remobilized with the same chemotherapy plus a higher dose of rhG-CSF (15 g/kg/d; Table 6 ). Mobilization treatments were started 48 hours after stopping chemotherapy and administered until the completion of CD34 \u03e9 cell harvest. After each mobilization cycle, absolute numbers of circulating CD34 \u03e9 cells and committed and primitive hematopoietic progenitors were monitored on a daily basis starting when the white blood cell (WBC) counts were 1000/L or higher and until completion of leukapheresis.", "cite_spans": [], "ref_spans": [{"start": 134, "end": 142, "text": "Figure 1", "ref_id": "FIGREF2"}, {"start": 1138, "end": 1145, "text": "Table 6", "ref_id": "TABREF4"}]}, {"section": "Chemotherapy and cytokines", "text": "Standard-dose chemotherapy regimens administered to study patients are listed in Table 2 . rhG-CSF (filgrastim) was from Roche (Milan, Italy) and rhGH (somatropin) was from Serono (Milan, Italy). Both rhG-CSF and rhGH were kept refrigerated at 2 to 8\u00b0C until the time of injection. Lyophilized rhGH was reconstituted with sterile water for injection before subcutaneous administration.", "cite_spans": [], "ref_spans": []}, {"section": "Collection of PBPCs", "text": "PBPC collection was started when equal to or more than 10 CD34 \u03e9 cells/L blood were detected. If the number of circulating CD34 \u03e9 cells remained 10/L or less, leukapheresis procedures were continued daily until the completion of CD34 \u03e9 cell harvest (target cell dose was \u0546 5 \u03eb 10 6 CD34 \u03e9 cells/kg). Each leukapheresis processed approximately 2.5-fold the total blood volume using a Cobe Spectra apparatus (Gambro BCT, Lakewood, CO).", "cite_spans": [], "ref_spans": []}, {"section": "Flow cytometry", "text": "Samples were analyzed for expression of CD34 on a FACScalibur flow cytometry system (Becton Dickinson, San Jose, CA) equipped with a Macintosh PowerMac G4 personal computer (Apple Computer, Cupertino, CA) using Cell Quest (Becton Dickinson) software. Briefly, cells (1 \u03eb 10 6 ) were labeled with either phycoerythrin (PE)-conjugated anti-CD34 (HPCA-2; Becton Dickinson) or with a mouse IgG1-PE antibody (Becton Dickinson) as negative control and analyzed for FL2 and low side scatter. A gate was established from the analysis of forward and light scatter to include all WBCs but to exclude platelets, red blood cells, and debris. CD34 \u03e9 cells were assessed by analysis of a minimum of 50 000 events.", "cite_spans": [], "ref_spans": []}, {"section": "CFU-Mix, BFU-E, CFU-GM assay", "text": "The assay for committed CFCs, including CFU-GMs, BFU-Es, and multilineage progenitors (CFU-Mix), was carried out as previously described. 35 Briefly, 1 to 5 \u03eb 10 4 nucleated cells from mobilized blood or leukapheresis were plated in 35-mm Petri dishes in methylcellulose-based medium (HCC-4100; StemCell Technologies, Vancouver, BC, Canada) supplemented with rhSCF (50 ng/mL; StemCell Technologies), rhIL-3 (10 ng/mL; StemCell Technologies), rhG-CSF (10 ng/mL, StemCell Technologies), rhGM-CSF (10 ng/mL, StemCell Technologies), and erythropoietin (rhEpo, 3 U/mL; R&D Systems, Abingdon, United Kingdom). Progenitor cell growth was evaluated after 14 to 18 days of incubation (37\u00b0C, 5% CO 2 ) in a humidified atmosphere.", "cite_spans": [{"start": 138, "end": 140, "text": "35", "ref_id": "BIBREF34"}], "ref_spans": []}, {"section": "LTC-IC assay", "text": "LTC-ICs were assayed as previously described. 36 Briefly, test cells were resuspended in complete medium consisting of \u2423-medium (Cambrex, Verviers, Belgium) supplemented with fetal bovine serum (12.5%; StemCell Technologies), horse serum (12.5%; StemCell Technologies), Lglutamine (2 mM), 2-mercaptoethanol (10 \u03ea4 M), inositol (0.2 mM), folic acid (20 M), and freshly dissolved hydrocortisone (10 \u03ea6 M). Test cell (5-8 \u03eb 10 6 nucleated cells) suspension was seeded into cultures containing a feeder layer of irradiated (8000 cGy) murine M2-10B4 cells (3 \u03eb 10 4 / cm 2 , kindly provided by Dr C. Eaves, Terry Fox Laboratory, Vancouver, BC, Canada) engineered by retroviral gene transfer to produce human IL-3 and G-CSF. 37 ", "cite_spans": [{"start": 46, "end": 48, "text": "36", "ref_id": "BIBREF35"}, {"start": 719, "end": 721, "text": "37", "ref_id": "BIBREF36"}], "ref_spans": []}, {"section": "Patient evaluation", "text": "Patients with histologic bone marrow involvement at study entry were evaluated by bone marrow biopsies after each mobilization attempt; patients with molecular or cytogenetic markers had their leukapheresis results analyzed using either cytogenetic analysis or polymerase chain reaction (PCR) analysis for immunoglobulin complementarity determining region 3 (CDR3) or Bcl-2 (see \"Consensus IgH and Bcl-2 PCR\"). All lymphoma patients were evaluated using computed tomography (CT) or 67 Ga scanning.", "cite_spans": [], "ref_spans": []}, {"section": "Consensus IgH and Bcl-2 PCR", "text": "PBPC contamination by occult lymphoma cells was studied using CDR3 analysis. Samples of frozen or paraffin-embedded diagnostic lymph node biopsy specimens were obtained at the time of diagnosis. After mobilization treatments, aliquots of harvested PBPCs were saved for PCR analysis and comparison with the above samples. Tumor DNA was amplified using consensus V H .D and J H .D primers (FR1 primers). 39 Amplified DNA was directly Table 2 . Chemotherapy regimens used in the study patients at the first and second mobilization attempts For personal use only. on April 2, 2017. by guest www.bloodjournal.org From sequenced using V H .D and J H .D primers and V H -, D-, J H -regions and N-inserts were identified by sequence comparison. The CDR3 region was identified as the junction of these 3 regions including the N-inserts. The 20mer antisense allele-specific oligonucleotide (ASO) primers were designed from the CDR3 regions including N-insert. DNA from the patient samples was amplified by seminested PCR. The first amplification used the relevant V H .D family and J H .D consensus primers, whereas the second amplification was performed with the same V H .D primer and the designed ASO antisense primer. Amplified DNAs were analyzed by electrophoresis on 1.5% agarose gels containing ethidium bromide and visualized by UV light. Bcl-2/IgH PCR was used if there was no predominant CDR3 clone. For bcl-2/IgH translocation, PCR amplification of major (MBR) and minor (mcr) was performed using oligonucleotide primers originally designed by Gribben et al. 40 ", "cite_spans": [{"start": 402, "end": 404, "text": "39", "ref_id": "BIBREF38"}, {"start": 1560, "end": 1562, "text": "40", "ref_id": "BIBREF39"}], "ref_spans": []}, {"section": "Statistical analysis", "text": "To test the probability of significantly different means or medians at the first and second mobilization attempt, the Student t test for paired data (2-tail) or the Wilcoxon matched pairs test was used, as appropriate. Differences were considered significant if P was less than or equal to .05. Statistical analysis was performed with the statistical package Prism 4.0 (GraphPad Software, San Diego, CA) run on a Macintosh G4 personal computer (Apple Computer).", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Study patients", "text": "Between September 2000 and December 2002, 16 transplantationeligible consecutive patients who failed a first mobilization attempt with chemotherapy plus rhG-CSF were remobilized with the same chemotherapy regimen followed by rhGH/rhG-CSF ( Figure 1 ; Table 2 ). Study patients were defined as poor mobilizers if the peak value of circulating CD34 \u03e9 cells was less than 10/L or the collection was 2 \u03eb 10 6 CD34 \u03e9 cells/kg or less. As shown in Table  1 , the median number of cycles of chemotherapy prior to study entry was 7 (range, 1-25), with 10 of 16 patients (62%) having also received prior radiotherapy. At the time of the study, bone marrow involvement was detected in 4 of 16 patients who showed less than 10% infiltration. The median period from last treatment and inclusion in this study was 4 months (range, 1-36 months). The median interval between the 2 mobilization attempts was 1 month (range, 1-2 months). No chemotherapy or radiotherapy was given during the interval between the 2 mobilization procedures.", "cite_spans": [], "ref_spans": [{"start": 240, "end": 248, "text": "Figure 1", "ref_id": "FIGREF2"}, {"start": 442, "end": 450, "text": "Table  1", "ref_id": "TABREF0"}]}, {"section": "PBPC mobilization", "text": "After both mobilization attempts, WBCs, circulating CD34 \u03e9 cells, CFCs, and LTC-ICs were monitored on a daily basis starting when the recovery WBC count first exceeded 1 \u03eb 10 9 /L (typically on days 10-12). The median duration of cytokine administration was 13 days (range, 9-22 days) and 15 days (range, 10-22 days) after rhG-CSF and rhGH/rhG-CSF, respectively.", "cite_spans": [], "ref_spans": []}, {"section": "PBPC mobilization", "text": "The median peak values of WBC counts were 17.8 \u03eb 10 9 /L (range, 6.6-50 \u03eb 10 9 /L) and 17.5 \u03eb 10 9 /L (range, 8.0-84 \u03eb 10 9 /L; P \u0545 .14) after rhG-CSF and rhGH/rhG-CSF, respectively ( Figure  2A ). The duration of leukocytosis was related to the duration of cytokine administration and no patient experienced any clinical sequelae in association with leukocytosis. Figure 2B shows the peak values of circulating CD34 \u03e9 cells detected in each patient at the first and second mobilization cycle. In all cases, rhGH/rhG-CSF administration resulted in a higher peak of CD34 \u03e9 cells as compared with rhG-CSF administration. Median peak values of CD34 \u03e9 cells/L after rhG-CSF and rhGH/rhG-CSF were 7 (range, 1-20) and 29 (range, 10-130; P \u0545 .0005), respectively, with a median 4-fold increase (range, 2-65; Figure 2C) . By comparing the median days of peak value of CD34 \u03e9 cells at the first and second mobilization attempts (12 versus 13, P \u0546 .05), it is evident that addition of rhGH in the mobilization regimen does not alter the kinetics of rhG-CSF mobilization. Table 3 summarizes the median peak values of circulating CFU-Mix, BFU-Es, and CFU-GMs per milliliter blood. As compared with rhG-CSF administration, the combined rhGH/ rhG-CSF treatment was associated with a median 9-fold (range, 1-828; P \u0545 .0005), 8-fold (range, 2-389; P \u0545 .0005), and 15-fold (range, 1-261; P \u0545 .0005) increase of circulating CFUMix, BFU-Es, and CFU-GMs, respectively (Table 3) . Peak values of total CFCs measured in each patient following rhGH/rhG-CSF were higher than those following rhG-CSF ( Figure 3A) . Median peak values of total CFCs/mL blood after rhG-CSF and rhGH/rhG-CSF were 2154 (range, 76-22 000) and 28 510 (range, 3600-81 600; P \u0545 .0005), respectively, with a median 13-fold increase (range, 2-528; Figure 3B ).", "cite_spans": [], "ref_spans": [{"start": 184, "end": 194, "text": "Figure  2A", "ref_id": "FIGREF3"}, {"start": 365, "end": 374, "text": "Figure 2B", "ref_id": "FIGREF3"}, {"start": 801, "end": 811, "text": "Figure 2C)", "ref_id": "FIGREF3"}, {"start": 1061, "end": 1068, "text": "Table 3", "ref_id": "TABREF1"}, {"start": 1448, "end": 1457, "text": "(Table 3)", "ref_id": "TABREF1"}, {"start": 1577, "end": 1587, "text": "Figure 3A)", "ref_id": "FIGREF4"}, {"start": 1796, "end": 1805, "text": "Figure 3B", "ref_id": "FIGREF4"}]}, {"section": "PBPC mobilization", "text": "The combined rhGH/rhG-CSF administration resulted in significantly higher peaks of circulating LTC-ICs as compared with rhG-CSF administration ( Figure 3C ). Median peak values of LTC-ICs/mL blood after rhG-CSF and rhGH/rhG-CSF were 25 (range, 2-528) and 511 (range, 32-4303; P \u0545 .0005), respectively, with a median 20-fold increase (range, 2-262; Figure 3D ).", "cite_spans": [], "ref_spans": [{"start": 145, "end": 154, "text": "Figure 3C", "ref_id": "FIGREF4"}, {"start": 348, "end": 357, "text": "Figure 3D", "ref_id": "FIGREF4"}]}, {"section": "PBPC harvest", "text": "PBPC harvesting was started when at least 10 CD34 \u03e9 cells/L blood were detected. Such a value of CD34 \u03e9 cells occurred in 8 of 16 patients after rhG-CSF and 16 of 16 patients after rhGH/rhG-CSF. Mobilization with rhG-CSF alone resulted in a short duration of CD34 \u03e9 cell release, which allowed us to perform only one For personal use only. on April 2, 2017. by guest www.bloodjournal.org From leukapheresis in 7 of 8 patients, and 2 leukapheresis procedures in one patient. In striking contrast, after the combined rhGH/rhG-CSF mobilization a sustained CD34 \u03e9 cell release was observed, which allowed us to perform a median of 3 leukapheresis procedures (range, 2-4) in 15 of 16 patients. Patient no. 16 asked to be withdrawn from the study and cell samples were not collected.", "cite_spans": [], "ref_spans": []}, {"section": "PBPC harvest", "text": "Following rhGH/rhG-CSF as compared with rhG-CSF alone, significantly higher median yields per leukapheresis were detected for CD34 \u03e9 cells (2.3 \u03eb 10 6 /kg versus 1.1 \u03eb 10 6 /kg; P \u0545 .008), CFCs (6.3 \u03eb 10 5 /kg versus 3.3 \u03eb 10 5 /kg; P \u0545 .01), and LTC-ICs (1.6 \u03eb 10 4 /kg versus 0.5 \u03eb 10 4 /kg; P \u0545 .01; Table 4 ).", "cite_spans": [], "ref_spans": [{"start": 303, "end": 310, "text": "Table 4", "ref_id": "TABREF2"}]}, {"section": "PBPC harvest", "text": "The median total collection of CD34 \u03e9 cells/kg body weight was 1.1 \u03eb 10 6 (range, 0.8-2 \u03eb 10 6 ) following rhG-CS, and 6 \u03eb 10 6 (range, 2.4-15 \u03eb 10 6 ) following rhGH/rhG-CSF (P \u0545 .008; Figure  4B ). Following rhG-CSF alone, no patient could collect the target cell dose of CD34 \u03e9 cells (ie, \u0546 5 \u03eb 10 6 /kg body weight), whereas following mobilization with rhGH/rhG-CSF 13 of 15 (87%) patients could collect the target cell dose of CD34 \u03e9 cells, with 2 remaining patients collecting 2.4 and 2.5 \u03eb 10 6 CD34 \u03e9 cells/kg, respectively.", "cite_spans": [], "ref_spans": [{"start": 186, "end": 196, "text": "Figure  4B", "ref_id": "FIGREF5"}]}, {"section": "PBPC harvest", "text": "Following rhG-CSF alone and rhGH/rhG-CSF, the median total collections of CFCs/kg were 3.4 \u03eb 10 5 (range, 1.3-6.9 \u03eb 10 5 ) and 19 \u03eb 10 5 (range, 6.3-57 \u03eb 10 5 ; P \u0545 .008), respectively ( Figure  4C) ; the median total collections of LTC-ICs/kg were 0.5 \u03eb 10 4 (range, 0.1-1.6 \u03eb 10 4 ) and 4.1 \u03eb 10 4 (range, 1.6-16 \u03eb 10 4 ; P \u0545 .008), respectively ( Figure 4D ).", "cite_spans": [], "ref_spans": [{"start": 187, "end": 198, "text": "Figure  4C)", "ref_id": "FIGREF5"}, {"start": 350, "end": 359, "text": "Figure 4D", "ref_id": "FIGREF5"}]}, {"section": "Toxicity", "text": "Toxicities occurring during rhGH/rhG-CSF administration were generally consistent with those observed during rhG-CSF administration. During injection of rhGH plus rhG-CSF, 2 of 16 patients experienced a transient hyperglycemia requiring insulin therapy, but not preventing the completion of stem cell mobilization and collection. There were no additional hematologic or extrahematologic toxicities considered possibly, probably, or definitely related to rhGH therapy.", "cite_spans": [], "ref_spans": []}, {"section": "Stimulation of tumor cell growth", "text": "In 4 patients (nos. 3, 6, 9, and 13) with histologic bone marrow involvement, analysis of bone marrow biopsies failed to reveal any evidence of increased tumor cell infiltration following rhGH/rhG-CSF therapy. Five patients with a molecular or cytogenetic marker had their leukapheresis products analyzed to identify contaminating tumor cells. As shown in Table 5 , in no instance could the presence of tumor cells contaminating the leukapheresis products be demonstrated. All patients with nodal masses detectable by CT or 67 Ga scan were evaluated for disease progression after rhGH/rhG-CSF injection, and in no instance could signs of disease progression be detected.", "cite_spans": [], "ref_spans": [{"start": 356, "end": 363, "text": "Table 5", "ref_id": "TABREF3"}]}, {"section": "Engraftment and survival", "text": "Following conditioning with either BEAM (n \u03ed 10; BCNU [bischloroethylnitrosourea], etoposide, ara-C [cytarabine], melphalan) or high-dose melphalan (n \u03ed 1), 11 of 16 patients underwent ASCT with rhGH/rhG-CSF-mobilized stem cells. Of the remaining patients, 3 (nos. 14, 15, and 16) received an allogeneic stem cell transplant from an unrelated marrow donor, whereas 2 (nos. 6 and 12) who had collected less than or equal to 5 \u03eb 10 6 CD34 \u03e9 cells/kg after rhGH/rhG-CSF were reinfused with both rhG-CSF-and rhGH/rhG-CSF-mobilized stem cells and are not considered for engraftment analysis. In patients given autografts with rhGH/rhG-CSF-mobilized PBPCs, the median number of days to achieve absolute neutrophil counts equal to or more than 0.5 \u03eb 10 9 /L and equal to or more than 1 \u03eb 10 9 /L were 9 (range, 8-12) and 10 (range, 9-13), respectively. The median number of days to achieve platelet counts 20 \u03eb 10 9 /L or higher and 50 \u03eb 10 9 /L or higher were 10 (range, 9-16) and 14 (range, 12-18), respectively. After transplantation, all patients required a median of 3 (range, 0-6) platelet transfusions and one (range, 0-6) red blood cell transfusion. No patient experienced early or late graft failure.", "cite_spans": [], "ref_spans": []}, {"section": "Historical controls", "text": "Patients mobilized with rhGH/rhG-CSF were retrospectively compared with an historical control group of poor mobilizers who were treated at our institution between January 1999 and August 2000. This cohort includes 14 transplantation-eligible patients who had failed a first mobilization attempt with standard-dose chemotherapy plus rhG-CSF at 5 g/kg/d and had been remobilized with the same chemotherapy regimen plus a higher dose of rhG-CSF (15 g/kg/d; Table 6 ). The median number of cycles of chemotherapy prior to mobilization was 8 (range, 1-27), with 8 of 14 patients (57%) having also received prior radiotherapy. Bone marrow involvement was detected in 2 of 14 patients who showed less than For personal use only. on April 2, 2017. by guest www.bloodjournal.org From 10% infiltration. The median interval between the 2 mobilization attempts was 1 month (range, 1-2 months). No chemotherapy or radiotherapy was given during the interval between the 2 mobilization procedures.", "cite_spans": [], "ref_spans": [{"start": 454, "end": 461, "text": "Table 6", "ref_id": "TABREF4"}]}, {"section": "Historical controls", "text": "The median duration of cytokine administration was 14 (range, 10-24 days) and 16 days (range, 12-25 days) at the first and the second mobilization attempts, respectively. The median peak values of WBC counts were 26 \u03eb 10 9 /L (range, 12-50 \u03eb 10 9 /L) and 36 \u03eb 10 9 /L (range, 17-65 \u03eb 10 9 /L; P \u0545 .001) after rhG-CSF at 5 and 15 g/kg/d, respectively (Table 6 ). After rhG-CSF at 5 and 15 g/kg/d, the median peak values of CD34 \u03e9 cells/L were 7 (range, 2-25) and 11 (range, 2-33; P \u03ed .30), respectively (Table 6 ). Six (43%) and 9 (64%) patients fulfilled harvesting criteria following rhG-CSF at 5 and 15 g/kg/d, respectively. The first and second mobilization attempts resulted in similar median yields of CD34 \u03e9 cells per leukapheresis (1.4 \u03eb 10 6 /kg, range, 0.3-1.9 \u03eb 10 6 /kg versus 1.5 \u03eb 10 6 /kg; range, 0.5-3 \u03eb 10 6 /kg; P \u03ed .62) and median total CD34 \u03e9 cell collections (1.4 \u03eb 10 6 /kg, range, 0.3-1.9 \u03eb 10 6 / kg versus 2.2 \u03eb 10 6 /kg, range, 0.5-12 \u03eb 10 6 /kg; P \u03ed .31). None of the patients receiving 5 g/kg/d rhG-CSF could collect the target CD34 \u03e9 cell dose, whereas 2 of 14 patients (14%) receiving rhG-CSF at 15 g/kg/d collected the target CD34 \u03e9 cell dose. As compared with historical controls receiving rhG-CSF at 15 g/ kg/d, the combined rhGH/rhG-CSF mobilization was associated with a significantly higher number of patients who could collect the target dose of CD34 \u03e9 cells (P \u0545 .05, by Fisher exact test).", "cite_spans": [], "ref_spans": [{"start": 350, "end": 358, "text": "(Table 6", "ref_id": "TABREF4"}, {"start": 502, "end": 510, "text": "(Table 6", "ref_id": "TABREF4"}]}, {"section": "Discussion", "text": "Data reported in this pilot study clearly demonstrate that the concomitant administration of rhGH and rhG-CSF to poor mobilizers significantly enhances mobilization of CD34 \u03e9 cells, committed (CFU-Mix, BFU-E, CFU-GM) as well as primitive (LTC-IC) progenitors, thus allowing the collection of adequate amounts of functionally competent stem cells. In addition, we show that rhGH given for mobilization purposes at 100 g/kg/d for up to 22 days is well-tolerated and devoid of short-term adverse events.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "Included in this study were patients identified as poor mobilizers following a first mobilization attempt with chemotherapy plus rhG-CSF, that is, those with a peak value of circulating CD34 \u03e9 cells of 10/L or less or a collection of CD34 \u03e9 cells of 2 \u03eb 10 6 /kg or less. These patients were therefore remobilized with the same chemotherapy regimen plus the combined rhGH/rhG-CSF therapy. After mobilization with rhG-CSF alone, only 50% of the patients were eligible for leukapheresis, but in no instance could the target cell dose of 5 \u03eb 10 6 CD34 \u03e9 cells/kg be collected. In striking contrast, the use of rhGH plus rhG-CSF was associated with a For personal use only. on April 2, 2017. by guest www.bloodjournal.org From sustained mobilization of CD34 \u03e9 cells, which allowed 100% of the patients to undergo repeated stem cell collections, and 87% of them to receive the target CD34 \u03e9 cell dose with a median of 3 leukapheresis proceudres. Thus, the combined rhGH/rhG-CSF treatment allows patients to achieve a clinically significant increase of the median collection of CD34 \u03e9 cells (ie, from 1.1 \u03eb 10 6 /kg up to 6 \u03eb 10 6 /kg). CD34 \u03e9 cells mobilized under rhGH/rhG-CSF had a maintained functional activity not only in vitro, but also in vivo, as suggested by the fast hematopoietic engraftment observed in our patients following myeloablative therapy.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "Chemotherapy-induced reduction of massive bone marrow infiltration by tumor cells may result at subsequent mobilization attempts in an improvement of PBPC mobilization. In our series, bone marrow involvement was detected in 4 of 16 patients who showed less than 10% involvement, thus ruling out the possibility that the improved PBPC mobilization achieved under rhGH/rhG-CSF may have resulted from chemotherapy-induced reduction of bone marrow disease.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "The intervals between mobilization and remobilization may affect CD34 \u03e9 cell release. Given the well-known cumulative toxicity of repeated chemotherapy cycles on marrow progenitors, a reduced PBPC mobilization at the second as compared with the first chemotherapy cycle is usually observed when consecutive chemotherapy courses are administered at 4-week intervals. Limited increases in the CD34 \u03e9 cell yield at the second mobilization attempt have been reported in poor mobilizers who had failed the first mobilization attempt. 41 However, in our experience, administration of repeated chemotherapy cycles at 3-to 4-week intervals is associated with a decreased CD34 \u03e9 cell mobilization (data not shown).", "cite_spans": [{"start": 529, "end": 531, "text": "41", "ref_id": "BIBREF40"}], "ref_spans": []}, {"section": "Discussion", "text": "Increasing the dose of rhG-CSF up to 16 g/kg/d at the second mobilization attempt in patients who had failed an initial mobilization has been reported to double the median collection of CD34 \u03e9 cells (ie, from 0.51 \u03eb 10 6 /kg using rhG-CSF at 5 g/kg/d up to 1.1 \u03eb 10 6 /kg using rhG-CSF at 10-16 g/kg/d). 42 A dosedependent mobilization response to rhG-CSF has also been achieved by increasing the dose of rhG-CSF as late as the third week of mobilization (0.07 \u03eb 10 6 /kg using rhG-CSF at 5 g/kg/d versus 2.27 \u03eb 10 6 /kg using rhG-CSF at 10 g/kg/d). 43 In our hard-tomobilize historical controls who had failed an initial mobilization with chemotherapy plus rhG-CSF at 5 g/kg/d, increasing the dose of rhG-CSF up to 15 g/kg/d at the subsequent chemotherapy cycle resulted in a limited increase of the total CD34 \u03e9 cell collection with a modest percentage of patients (14%) being able to collect an optimal target cell dose of CD34 \u03e9 cells.", "cite_spans": [{"start": 304, "end": 306, "text": "42", "ref_id": "BIBREF41"}, {"start": 550, "end": 552, "text": "43", "ref_id": "BIBREF42"}], "ref_spans": []}, {"section": "Discussion", "text": "GH acts on hematopoietic progenitors either directly by binding to specific membrane receptors or indirectly by stimulating the production of insulin-like growth factor I (IGF-I), or interacting with hematopoietic cytokines. 44 The exact mechanism by which rhGH is able to restore the stem cell mobilization capacity in heavily pretreated patients with relapsed or refractory cancers remains a matter of hypothesis. Based on the in vivo capacity of rhGH to expand marrow and spleen hematopoietic progenitors in either normal or hematologically suppressed mice, 31 as well as to reverse age-associated loss of bone marrow progenitor cells in aged rats 33 and mice, 34 it is likely that rhGH-enhanced mobilization is related to the in vivo expansion of primitive or committed marrow stem/progenitor cells that become susceptible to being released on a subsequent or concomitant mobilization stimulus, such as rhG-CSF infusion.", "cite_spans": [{"start": 225, "end": 227, "text": "44", "ref_id": "BIBREF43"}, {"start": 561, "end": 563, "text": "31", "ref_id": "BIBREF30"}, {"start": 651, "end": 653, "text": "33", "ref_id": "BIBREF32"}, {"start": 664, "end": 666, "text": "34", "ref_id": "BIBREF33"}], "ref_spans": []}, {"section": "Discussion", "text": "The stimulation of tumor cells might represent a major concern for the in vivo use of rhGH. 45 Despite the fact that rhGH raises serum levels of IGF-I, which are associated with an increased risk of epithelial cancers, the role of rhGH in carcinogenesis is unclear, 46 and several studies have shown that there is no increase in cancer risk in patients receiving prolonged replacement therapy with rhGH. In a large epidemiologic study, the long-term treatment of GH deficiency has established health benefits without any evidence that rhGH replacement increases cancer risk. 47 Recently, the risk of relapse of acute lymphoblastic leukemia (ALL) and that For personal use only. on April 2, 2017. by guest www.bloodjournal.org From of a second malignancy was compared in long-term survivors (n \u03ed 47) who received rhGH for a median of 4.5 years with those survivors (n \u03ed 860) who had not. 48 By landmark analysis, there was no statistical evidence that rhGH replacement therapy was associated with relapse of ALL or second malignancy. Moreover, no evidence of tumor progression has been reported in patients with AIDS treated with 100 g/kg/d rhGH for 12 weeks. 49 The potential risk of exposing our patients to a short rhGH treatment, which did not imply a chronic stimulation, was adequately outweighed by the clinical benefit deriving from ASCT. In fact, for all patients included in the present study, a high-dose chemotherapy program including autografting of hematopoietic progenitor cells was the only chance of cure, and no better alternative existed. Due to mobilization failure and the lack of autologous stem cells, all these patients should have been excluded from high-dose chemotherapy. Our patients bearing nodal masses were carefully monitored by means of CT or 67 Ga scan, whereas patients with therapy-related acute myelogenous leukemia (t-AML) and NHL were evaluated at the cytogenetic or molecular level. In no instance could radiographic signs as well as cytogenetic or molecular evidence suggesting a tumor growth stimulation be detected. However, a longer observation period and larger patient numbers are required before the concerns of tumor growth stimulation induced by rhGH can be ruled out.", "cite_spans": [{"start": 92, "end": 94, "text": "45", "ref_id": "BIBREF44"}, {"start": 266, "end": 268, "text": "46", "ref_id": "BIBREF45"}, {"start": 575, "end": 577, "text": "47", "ref_id": "BIBREF46"}, {"start": 887, "end": 889, "text": "48", "ref_id": "BIBREF47"}, {"start": 1159, "end": 1161, "text": "49", "ref_id": "BIBREF48"}], "ref_spans": []}, {"section": "Discussion", "text": "The dose of rhGH used in this pilot study (ie, 100 g/kg/d) is the highest dose approved for clinical use and was empirically selected as the dose potentially allowing the highest chance to detect an effect on stem cell mobilization by means of a short treatment. Because our study has provided consistent evidence on the mobilization efficacy of the rhGH/rhG-CSF regimen, a dosefinding study will be required to address the issue of the optimal dose of rhGH to be used for PBPC mobilization.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "According to a recently reported Gruppo Italiano Trapianto Midollo Osseo (GITMO) study, poor mobilizers account for 15% to 20% of chemotherapy-na\u00efve patients and 30% to 40% of patients with relapsed or refractory cancers. 50 No reliable laboratory tests exist for identifying poor mobilizers, and no reliable and effective treatment exists to enhance mobilization in poor mobilizers. Based on our data, the combined rhGH/rhG-CSF therapy represents a very effective and safe strategy that allows efficient mobilizing and collecting of CD34 \u03e9 cells with maintained functional properties in nearly 90% of poor mobilizers. These findings will require confirmation from a larger appropriately controlled study including a more homogeneous cohort of patients.", "cite_spans": [{"start": 222, "end": 224, "text": "50", "ref_id": "BIBREF49"}], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "High-dose chemotherapy and autotransplants: a time for guidelines", "authors": [{"first": "A", "middle": ["M"], "last": "Gianni", "suffix": ""}], "year": 1997, "venue": "Ann Oncol", "link": "45421739"}, "BIBREF1": {"title": "High-dose chemotherapy and autologous bone marrow transplantation compared with MACOP-B in aggressive B-cell lymphoma", "authors": [{"first": "A", "middle": ["M"], "last": "Gianni", "suffix": ""}, {"first": "M", "middle": [], "last": "Bregni", "suffix": ""}, {"first": "S", "middle": [], "last": "Siena", "suffix": ""}], "year": 1997, "venue": "N Engl J Med", "link": "2415184"}, "BIBREF2": {"title": "Intensive salvage therapy with high-dose chemotherapy for patients with advanced Hodgkin's disease in relapse or failure after initial chemotherapy: results of the Groupe d'Etudes des Lymphomes de l'Adulte H89 Trial", "authors": [{"first": "C", "middle": [], "last": "Ferme", "suffix": ""}, {"first": "N", "middle": [], "last": "Mounier", "suffix": ""}, {"first": "M", "middle": [], "last": "Divine", "suffix": ""}], "year": 2002, "venue": "J Clin Oncol", "link": "5702451"}, "BIBREF3": {"title": "High-dose therapy and innovative approaches to treatment of multiple myeloma. Semin Hematol", "authors": [{"first": "B", "middle": [], "last": "Barlogie", "suffix": ""}], "year": 2001, "venue": "", "link": null}, "BIBREF4": {"title": "Therapeutic relevance of CD34 \u03e9 cell dose in blood cell transplantation for cancer therapy", "authors": [{"first": "S", "middle": [], "last": "Siena", "suffix": ""}, {"first": "R", "middle": [], "last": "Schiavo", "suffix": ""}, {"first": "P", "middle": [], "last": "Pedrazzoli", "suffix": ""}, {"first": "Carlo-Stella", "middle": [], "last": "", "suffix": ""}, {"first": "C", "middle": [], "last": "", "suffix": ""}], "year": 2000, "venue": "J Clin Oncol", "link": "42507328"}, "BIBREF5": {"title": "Peripheral blood stem cell mobilization for high-dose chemotherapy", "authors": [{"first": "T", "middle": [], "last": "Demirer", "suffix": ""}, {"first": "W", "middle": ["I"], "last": "Bensinger", "suffix": ""}, {"first": "C", "middle": ["D"], "last": "Buckner", "suffix": ""}], "year": 1999, "venue": "J Hematother", "link": "39334854"}, "BIBREF6": {"title": "Patient characteristics associated with successful mobilizing and autografting of peripheral blood progenitor cells in malignant lymphoma", "authors": [{"first": "R", "middle": [], "last": "Haas", "suffix": ""}, {"first": "R", "middle": [], "last": "Mohle", "suffix": ""}, {"first": "S", "middle": [], "last": "Fruhauf", "suffix": ""}], "year": 1994, "venue": "Blood", "link": "7785081"}, "BIBREF7": {"title": "Peripheral blood stem cells (PBSCs) collected after recombinant granulocyte colony stimulating factor (rhG-CSF): an analysis of factors correlating with the tempo of engraftment after transplantation", "authors": [{"first": "W", "middle": ["I"], "last": "Bensinger", "suffix": ""}, {"first": "K", "middle": [], "last": "Longin", "suffix": ""}, {"first": "F", "middle": [], "last": "Appelbaum", "suffix": ""}], "year": 1994, "venue": "Br J Haematol", "link": "24644569"}, "BIBREF8": {"title": "Progenitor-cell mobilization after low-dose cyclophosphamide and granulocyte colony-stimulating factor: an analysis of progenitor-cell quantity and quality and factors predicting for these parameters in 101 pretreated patients with malignant lymphoma", "authors": [{"first": "M", "middle": ["J"], "last": "Watts", "suffix": ""}, {"first": "A", "middle": ["M"], "last": "Sullivan", "suffix": ""}, {"first": "E", "middle": [], "last": "Jamieson", "suffix": ""}], "year": 1997, "venue": "J Clin Oncol", "link": "20554764"}, "BIBREF9": {"title": "Autologous progenitor cell transplantation: prior exposure to stem cell-toxic drugs determines yield and engraftment of peripheral blood progenitor cell but not of bone marrow grafts", "authors": [{"first": "P", "middle": [], "last": "Dreger", "suffix": ""}, {"first": "M", "middle": [], "last": "Kloss", "suffix": ""}, {"first": "B", "middle": [], "last": "Petersen", "suffix": ""}], "year": 1995, "venue": "Blood", "link": "9740584"}, "BIBREF10": {"title": "An analysis of engraftment kinetics as a function of the CD34 content of peripheral blood progenitor cell collections in 692 patients after the administration of myeloablative chemotherapy", "authors": [{"first": "C", "middle": ["H"], "last": "Weaver", "suffix": ""}, {"first": "B", "middle": [], "last": "Hazelton", "suffix": ""}, {"first": "R", "middle": [], "last": "Birch", "suffix": ""}], "year": 1995, "venue": "Blood", "link": "18319468"}, "BIBREF11": {"title": "High-dose ara-C with autologous peripheral blood progenitor cell support induces a marked progenitor cell mobilization: an indication for patients at risk for low mobilization", "authors": [{"first": "C", "middle": [], "last": "Tarella", "suffix": ""}, {"first": "Di", "middle": [], "last": "Nicola", "suffix": ""}, {"first": "M", "middle": [], "last": "Caracciolo", "suffix": ""}, {"first": "D", "middle": [], "last": "", "suffix": ""}], "year": 2002, "venue": "Bone Marrow Transplant", "link": "2204670"}, "BIBREF12": {"title": "Antibodies to VLA4 integrin mobilize long-term repopulating cells and augment cytokine-induced mobilization in primates and mice", "authors": [{"first": "C", "middle": ["F"], "last": "Craddock", "suffix": ""}, {"first": "B", "middle": [], "last": "Nakamoto", "suffix": ""}, {"first": "R", "middle": ["G"], "last": "Andrews", "suffix": ""}, {"first": "G", "middle": ["V"], "last": "Priestley", "suffix": ""}, {"first": "T", "middle": [], "last": "Papayannopoulou", "suffix": ""}], "year": 1997, "venue": "Blood", "link": "208525133"}, "BIBREF13": {"title": "Rapid mobilization of murine hematopoietic stem cells with enhanced engraftment properties and evaluation of hematopoietic progenitor cell mobilization in rhesus monkeys by a single injection of SB-251353, a specific truncated form of the human CXC chemokine GRO\u2424", "authors": [{"first": "A", "middle": ["G"], "last": "King", "suffix": ""}, {"first": "D", "middle": [], "last": "Horowitz", "suffix": ""}, {"first": "S", "middle": ["B"], "last": "Dillon", "suffix": ""}], "year": 2001, "venue": "Blood", "link": "28929872"}, "BIBREF14": {"title": "Defibrotide in combination with granulocyte colonystimulating factor significantly enhances the mobilization of primitive and committed peripheral blood progenitor cells in mice", "authors": [{"first": "C", "middle": [], "last": "Carlo-Stella", "suffix": ""}, {"first": "Di", "middle": [], "last": "Nicola", "suffix": ""}, {"first": "M", "middle": [], "last": "Magni", "suffix": ""}, {"first": "M", "middle": [], "last": "", "suffix": ""}], "year": 2002, "venue": "Cancer Res", "link": "46160556"}, "BIBREF15": {"title": "Mobilization of hematopoietic progenitor cells in healthy volunteers by AMD3100, a CXCR4 antagonist", "authors": [{"first": "W", "middle": ["C"], "last": "Liles", "suffix": ""}, {"first": "H", "middle": ["E"], "last": "Broxmeyer", "suffix": ""}, {"first": "E", "middle": [], "last": "Rodger", "suffix": ""}], "year": 2003, "venue": "Blood", "link": "21340716"}, "BIBREF16": {"title": "Randomized cross-over trial of progenitor-cell mobilization: high-dose cyclophosphamide plus granulocyte colony-stimulating factor (G-CSF) versus granulocyte-macrophage colony-stimulating factor plus G-CSF", "authors": [{"first": "O", "middle": ["N"], "last": "Koc", "suffix": ""}, {"first": "S", "middle": ["L"], "last": "Gerson", "suffix": ""}, {"first": "B", "middle": ["W"], "last": "Cooper", "suffix": ""}], "year": 2000, "venue": "J Clin Oncol", "link": "13246930"}, "BIBREF17": {"title": "Comparison of four cytokine regimens for mobilization of peripheral blood stem cells: IL-3 alone and combined with GM-CSF or G-CSF", "authors": [{"first": "C", "middle": ["S"], "last": "Rosenfeld", "suffix": ""}, {"first": "B", "middle": [], "last": "Bolwell", "suffix": ""}, {"first": "A", "middle": [], "last": "Lefever", "suffix": ""}], "year": 1996, "venue": "Bone Marrow Transplant", "link": "25356481"}, "BIBREF18": {"title": "Phase I trial of recombinant fusion protein PIXY321 for mobilization of peripheral-blood cells", "authors": [{"first": "M", "middle": ["R"], "last": "Bishop", "suffix": ""}, {"first": "J", "middle": ["D"], "last": "Jackson", "suffix": ""}, {"first": "O&apos;kane-Murphy", "middle": [], "last": "", "suffix": ""}, {"first": "B", "middle": [], "last": "", "suffix": ""}], "year": 1996, "venue": "J Clin Oncol", "link": null}, "BIBREF19": {"title": "A randomized phase 3 study of peripheral blood progenitor cell mobilization with stem cell factor and filgrastim in high-risk breast cancer patients", "authors": [{"first": "E", "middle": ["J"], "last": "Shpall", "suffix": ""}, {"first": "C", "middle": ["A"], "last": "Wheeler", "suffix": ""}, {"first": "S", "middle": ["A"], "last": "Turner", "suffix": ""}], "year": 1999, "venue": "Blood", "link": "6270561"}, "BIBREF20": {"title": "A randomized phase 2 study of PBPC mobilization by stem cell factor and filgrastim in heavily pretreated patients with Hodgkin's disease or non-Hodgkin's lymphoma", "authors": [{"first": "P", "middle": [], "last": "Stiff", "suffix": ""}, {"first": "R", "middle": [], "last": "Gingrich", "suffix": ""}, {"first": "S", "middle": [], "last": "Luger", "suffix": ""}], "year": 2000, "venue": "Bone Marrow Transplant", "link": "28773913"}, "BIBREF21": {"title": "Successful mobilization of peripheral blood stem cells after addition of ancestim (stem cell factor) in patients who had failed a prior mobilization with filgrastim (granulocyte colony-stimulating factor) alone or with chemotherapy plus filgrastim", "authors": [{"first": "L", "middle": ["B"], "last": "To", "suffix": ""}, {"first": "J", "middle": [], "last": "Bashford", "suffix": ""}, {"first": "S", "middle": [], "last": "Durrant", "suffix": ""}], "year": 2003, "venue": "Bone Marrow Transplant", "link": "36360006"}, "BIBREF22": {"title": "Flt3 ligand synergizes with granulocyte-macrophage colony-stimulating factor or granulocyte colony-stimulating factor to mobilize hematopoietic progenitor cells into the peripheral blood of mice", "authors": [{"first": "K", "middle": [], "last": "Brasel", "suffix": ""}, {"first": "H", "middle": ["J"], "last": "Mckenna", "suffix": ""}, {"first": "K", "middle": [], "last": "Charrier", "suffix": ""}, {"first": "P", "middle": ["J"], "last": "Morrissey", "suffix": ""}, {"first": "D", "middle": ["E"], "last": "Williams", "suffix": ""}, {"first": "S", "middle": ["D"], "last": "Lyman", "suffix": ""}], "year": 1997, "venue": "Blood", "link": "10955064"}, "BIBREF23": {"title": "The whys and hows of hematopoietic progenitor and stem cell mobilization", "authors": [{"first": "A", "middle": [], "last": "Kessinger", "suffix": ""}, {"first": "J", "middle": ["G"], "last": "Sharp", "suffix": ""}], "year": 2003, "venue": "Bone Marrow Transplant", "link": "24118928"}, "BIBREF24": {"title": "It's moving day: factors affecting peripheral blood stem mobilization and strategies for improvement", "authors": [{"first": "S", "middle": [], "last": "Fruehauf", "suffix": ""}, {"first": "R", "middle": [], "last": "Seggewiss", "suffix": ""}], "year": 2003, "venue": "Br J Haematol", "link": "71426490"}, "BIBREF25": {"title": "Growth hormone (GH), GH receptor, and signal transduction", "authors": [{"first": "J", "middle": ["J"], "last": "Kopchick", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Andry", "suffix": ""}], "year": 2000, "venue": "Mol Genet Metab", "link": "30796275"}, "BIBREF26": {"title": "Role of neuroendocrine hormones in murine T cell development. Growth hormone exerts thymopoietic effects in vivo", "authors": [{"first": "W", "middle": ["J"], "last": "Murphy", "suffix": ""}, {"first": "S", "middle": ["K"], "last": "Durum", "suffix": ""}, {"first": "D", "middle": ["L"], "last": "Longo", "suffix": ""}], "year": 1992, "venue": "J Immunol", "link": "43461067"}, "BIBREF27": {"title": "Growth hormone: species-specific stimulation of erythropoiesis in vitro", "authors": [{"first": "D", "middle": ["W"], "last": "Golde", "suffix": ""}, {"first": "N", "middle": [], "last": "Bersch", "suffix": ""}, {"first": "C", "middle": ["H"], "last": "Li", "suffix": ""}], "year": 1977, "venue": "Science", "link": "7979960"}, "BIBREF28": {"title": "Enhancement of erythropoiesis in vitro by human growth hormone is mediated by insulin-like growth factor I", "authors": [{"first": "S", "middle": [], "last": "Merchav", "suffix": ""}, {"first": "I", "middle": [], "last": "Tatarsky", "suffix": ""}, {"first": "Z", "middle": [], "last": "Hochberg", "suffix": ""}], "year": 1988, "venue": "Br J Haematol", "link": "6312794"}, "BIBREF29": {"title": "Enhancement of human granulopoiesis in vitro by biosynthetic insulin-like growth factor I/somatomedin C and human growth hormone", "authors": [{"first": "S", "middle": [], "last": "Merchav", "suffix": ""}, {"first": "I", "middle": [], "last": "Tatarsky", "suffix": ""}, {"first": "Z", "middle": [], "last": "Hochberg", "suffix": ""}], "year": 1988, "venue": "J Clin Invest", "link": "19903974"}, "BIBREF30": {"title": "Growth hormone exerts hematopoietic growth-promoting effects in vivo and partially counteracts the myelosuppressive effects of azidothymidine", "authors": [{"first": "W", "middle": ["J"], "last": "Murphy", "suffix": ""}, {"first": "G", "middle": [], "last": "Tsarfaty", "suffix": ""}, {"first": "D", "middle": ["L"], "last": "Longo", "suffix": ""}], "year": 1992, "venue": "Blood", "link": "208198960"}, "BIBREF31": {"title": "Recombinant human growth hormone promotes hematopoietic reconstitution after syngeneic bone marrow transplantation in mice", "authors": [{"first": "Z", "middle": ["G"], "last": "Tian", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Woody", "suffix": ""}, {"first": "R", "middle": [], "last": "Sun", "suffix": ""}], "year": 1998, "venue": "Stem Cells", "link": "12549997"}, "BIBREF32": {"title": "Age-associated loss of bone marrow hematopoietic cells is reversed by GH and accompanies thymic reconstitution", "authors": [{"first": "R", "middle": ["A"], "last": "French", "suffix": ""}, {"first": "S", "middle": ["R"], "last": "Broussard", "suffix": ""}, {"first": "W", "middle": ["A"], "last": "Meier", "suffix": ""}], "year": 2002, "venue": "Endocrinology", "link": "23829118"}, "BIBREF33": {"title": "Ageand irradiation-associated loss of bone marrow hematopoietic function in mice is reversed by recombinant human growth hormone (rhGH)", "authors": [{"first": "C", "middle": [], "last": "Carlo-Stella", "suffix": ""}, {"first": "Di", "middle": [], "last": "Nicola", "suffix": ""}, {"first": "M", "middle": [], "last": "Milani", "suffix": ""}, {"first": "R", "middle": [], "last": "", "suffix": ""}], "year": 2004, "venue": "Exp Hematol", "link": "35804652"}, "BIBREF34": {"title": "Peripheral blood progenitor cell mobilization in healthy donors receiving recombinant human granulocyte colony-stimulating factor", "authors": [{"first": "Carlo-Stella C", "middle": [], "last": "Cesana", "suffix": ""}, {"first": "C", "middle": [], "last": "Regazzi", "suffix": ""}, {"first": "E", "middle": [], "last": "", "suffix": ""}], "year": 2000, "venue": "Exp Hematol", "link": "25613001"}, "BIBREF35": {"title": "Effects of the tyrosine kinase inhibitor AG957 and an anti-Fas receptor antibody on CD34 \u03e9 chronic myelogenous leukemia progenitor cells", "authors": [{"first": "Carlo-Stella C", "middle": [], "last": "Regazzi", "suffix": ""}, {"first": "E", "middle": [], "last": "Sammarelli", "suffix": ""}, {"first": "G", "middle": [], "last": "", "suffix": ""}], "year": 1999, "venue": "Blood", "link": null}, "BIBREF36": {"title": "Differential regulation of primitive human hematopoietic cells in long-term cultures maintained on genetically engineered murine stromal cells", "authors": [{"first": "H", "middle": ["J"], "last": "Sutherland", "suffix": ""}, {"first": "C", "middle": ["J"], "last": "Eaves", "suffix": ""}, {"first": "P", "middle": ["M"], "last": "Lansdorp", "suffix": ""}, {"first": "J", "middle": ["D"], "last": "Tacker", "suffix": ""}, {"first": "D", "middle": ["E"], "last": "Hogge", "suffix": ""}], "year": 1991, "venue": "Blood", "link": "10974955"}, "BIBREF37": {"title": "Characterization and partial purification of human marrow cells capable of initiating long-term hematopoiesis in vitro", "authors": [{"first": "H", "middle": ["J"], "last": "Sutherland", "suffix": ""}, {"first": "C", "middle": ["J"], "last": "Eaves", "suffix": ""}, {"first": "A", "middle": ["C"], "last": "Eaves", "suffix": ""}, {"first": "A", "middle": ["C"], "last": "Dragowska", "suffix": ""}, {"first": "P", "middle": ["M"], "last": "Lansdorp", "suffix": ""}], "year": 1989, "venue": "Blood", "link": "619971"}, "BIBREF38": {"title": "Immunoglobulin gene 'fingerprinting': an approach to analysis of B lymphoid clonality in lymphoproliferative disorders", "authors": [{"first": "M", "middle": [], "last": "Deane", "suffix": ""}, {"first": "J", "middle": ["D"], "last": "Norton", "suffix": ""}], "year": 1991, "venue": "Br J Haematol", "link": "24505589"}, "BIBREF39": {"title": "Immunologic purging of marrow assessed by PCR before autologous bone marrow transplantation for B-cell lymphoma", "authors": [{"first": "J", "middle": ["G"], "last": "Gribben", "suffix": ""}, {"first": "A", "middle": ["S"], "last": "Freedman", "suffix": ""}, {"first": "D", "middle": [], "last": "Neuberg", "suffix": ""}], "year": 1991, "venue": "N Engl J Med", "link": "25438370"}, "BIBREF40": {"title": "Second attempts at mobilization of peripheral blood stem cells in patients with initial low CD34 \u03e9 cell yields", "authors": [{"first": "C", "middle": ["H"], "last": "Weaver", "suffix": ""}, {"first": "K", "middle": [], "last": "Tauer", "suffix": ""}, {"first": "B", "middle": [], "last": "Zhen", "suffix": ""}], "year": 1998, "venue": "J Hematother", "link": "11782332"}, "BIBREF41": {"title": "Remobilization of patients who fail to achieve minimal progenitor thresholds at the first attempt is clinically worthwhile", "authors": [{"first": "M", "middle": ["J"], "last": "Watts", "suffix": ""}, {"first": "S", "middle": ["J"], "last": "Ings", "suffix": ""}, {"first": "M", "middle": [], "last": "Flynn", "suffix": ""}, {"first": "D", "middle": [], "last": "Dodds", "suffix": ""}, {"first": "A", "middle": ["H"], "last": "Goldstone", "suffix": ""}, {"first": "D", "middle": ["C"], "last": "Linch", "suffix": ""}], "year": 2000, "venue": "Br J Haematol", "link": "196387058"}, "BIBREF42": {"title": "Granulocyte colony-stimulating factor (G-CSF) dose-dependent efficacy in peripheral blood stem cell mobilization in patients who had failed initial mobilization with chemotherapy and G-CSF", "authors": [{"first": "A", "middle": ["K"], "last": "Lie", "suffix": ""}, {"first": "C", "middle": ["H"], "last": "Hui", "suffix": ""}, {"first": "T", "middle": [], "last": "Rawling", "suffix": ""}], "year": 1998, "venue": "Bone Marrow Transplant", "link": "33115278"}, "BIBREF43": {"title": "The haematopoietic effects of growth hormone and insulin-like growth factor-I", "authors": [{"first": "S", "middle": [], "last": "Merchav", "suffix": ""}], "year": 1998, "venue": "J Pediatr Endocrinol Metab", "link": "29829392"}, "BIBREF44": {"title": "Risk of cancer after growth-hormone treatment", "authors": [{"first": "E", "middle": [], "last": "Giovannucci", "suffix": ""}, {"first": "M", "middle": [], "last": "Pollak", "suffix": ""}], "year": 2002, "venue": "Lancet", "link": "41192748"}, "BIBREF45": {"title": "Prospective study of colorectal cancer risk in men and plasma levels of insulin-like growth factor (IGF)-I and IGF-binding protein-3", "authors": [{"first": "J", "middle": [], "last": "Ma", "suffix": ""}, {"first": "M", "middle": ["N"], "last": "Pollak", "suffix": ""}, {"first": "E", "middle": [], "last": "Giovannucci", "suffix": ""}], "year": 1999, "venue": "J Natl Cancer Inst", "link": "15983520"}, "BIBREF46": {"title": "Critical evaluation of the safety of recombinant human growth hormone administration: statement", "authors": [], "year": 2001, "venue": "J Clin Endocrinol Metab", "link": null}, "BIBREF47": {"title": "Outcomes of growth hormone replacement therapy in survivors of childhood acute lymphoblastic leukemia", "authors": [{"first": "W", "middle": [], "last": "Leung", "suffix": ""}, {"first": "S", "middle": ["R"], "last": "Rose", "suffix": ""}, {"first": "Y", "middle": [], "last": "Zhou", "suffix": ""}], "year": 2002, "venue": "J Clin Oncol", "link": "25872874"}, "BIBREF48": {"title": "Recombinant human growth hormone in patients with HIV-associated wasting. A randomized, placebo-controlled trial. Serostim Study Group", "authors": [{"first": "M", "middle": [], "last": "Schambelan", "suffix": ""}, {"first": "K", "middle": [], "last": "Mulligan", "suffix": ""}, {"first": "C", "middle": [], "last": "Grunfeld", "suffix": ""}], "year": 1996, "venue": "Ann Intern Med", "link": "41544325"}, "BIBREF49": {"title": "on behalf of GITMO. Treatment modalities and success rate of 1,907 procedures of peripheral blood progenitor cell mobilization: a multicenter study from GITMO (Gruppo Italiano Trapianto Midollo Osseo", "authors": [{"first": "C", "middle": [], "last": "Tarella", "suffix": ""}, {"first": "F", "middle": [], "last": "Pompei", "suffix": ""}, {"first": "L", "middle": [], "last": "Cavazzuti", "suffix": ""}, {"first": "A", "middle": [], "last": "Bacigalupo", "suffix": ""}, {"first": "W", "middle": ["G"], "last": "Arcese", "suffix": ""}], "year": 2002, "venue": "Blood", "link": null}}, "ref_entries": {"FIGREF0": {"text": "After 5 weeks in culture, nonadherent cells and adherent cells harvested by trypsinization were pooled, washed, and assayed together for clonogenic cells in methylcellulose culture. The total number of clonogenic cells (ie, CFU-Mix plus BFU-Es plus CFU-GMs) present in 5-week-old LTCs provides a relative measure of the number of LTC-ICs originally present in the test suspension. Absolute LTC-IC values were calculated by dividing the total number of clonogenic cells by 4, which is the average output of clonogenic cells per LTC-IC. 38", "type": "figure"}, "FIGREF1": {"text": "VNB is ifosfamide (3 g/m 2 , intravenously [IV], days 1-4) and vinorelbine (25 mg/m 2 , IV, days 1 and 5). DHAP is cisplatin (CDDP [cisplatin], 100 mg/m 2 , continuous IV infusion, day 1), cytarabine (ara-C, 2 g/m 2 , IV, every 12 hours, day 2), and dexamethasone (40 mg, IV, day 1-4). DT-PACE is dexamethasone (40 mg, IV, day 1-4), thalidomide (100 mg, by mouth, CDDP (10 mg/m 2 , IV, day 1-4), cyclophosphamide (400 mg/m 2 , IV, day 1-4), doxorubicin (10 mg/m 2 , IV, day 1-4), and etoposide (40 mg/m 2 , IV, day 1-4). FLAG-Ida is fludarabine (30 mg/m 2 , IV, day 1-5), ara-C (2 g/m 2 , IV, day 1-5), rhG-CSF (200 g, subcutaneously, day 0-5), and idarubicin (10 mg/m 2 , IV, day 1-3).", "type": "figure"}, "FIGREF2": {"text": "Figure 1. Study design. Schematic representation of the study. Details on treatment and cytokine dosages are reported in \"Patients, materials, and methods.\"", "type": "figure"}, "FIGREF3": {"text": "Figure 2. WBC counts and circulating CD34 \u0609 cells. Box plots of peripheral WBC counts (A), peak values (B), and box plots (C) of CD34 \u03e9 cells/L blood in poor mobilizers receiving rhG-CSF (n \u03ed 16) or rhGH/rhG-CSF (n \u03ed 16). The peak of CD34 \u03e9 cells was defined as the maximum number of CD34 \u03e9 cells detected in the peripheral blood during mobilization. The boxes extend from the 25th percentile to the 75th percentile, the lines indicate the median values, and the whiskers indicate the range of values. Statistical difference was evaluated using the Wilcoxon matched pairs test (2-tail). Number in panel (A) indicates P value.", "type": "figure"}, "FIGREF4": {"text": "Figure 3. Circulating CFCs and LTC-ICs. Peak values (A,C) and box plots (B,D) of CFCs and LTC-ICs per milliliter of blood in poor mobilizers receiving rhG-CSF (n \u03ed 16) or rhGH/rhG-CSF (n \u03ed 16). CFCs include CFU-GMs, BFU-Es, and CFUMix. Peaks of CFCs and LTC-ICs were defined as the maximum numbers of CFCs or LTC-ICs detected in the peripheral blood during mobilization. The boxes extend from the 25th percentile to the 75th percentile, the lines indicate the median values, and the whiskers indicate the range of values. Statistical difference was evaluated using the Wilcoxon matched pairs test (2-tail). Numbers in the panels (B,D) indicate P values.", "type": "figure"}, "FIGREF5": {"text": "Figure 4. Total yields of TNCs, CD34 \u0609 cells, CFCs, and LTC-ICs. Box plots of total yields of total nucleated cells (TNCs; A), CD34 \u03e9 cells (B), CFCs (C), and LTC-ICs (D) in poor mobilizers receiving rhG-CSF (n \u03ed 8) or rhGH/rhG-CSF (n \u03ed 15). The boxes extend from the 25th percentile to the 75th percentile, the lines indicate the median values, and the whiskers indicate the range of values. Statistical difference was evaluated using the Wilcoxon matched pairs test (2-tail). P values are shown in the panels.", "type": "figure"}, "TABREF0": {"text": "Clinical characteristics of patients at time of studyMOPP, mechlorethamine, vincristine, procarbazine, prednisone; ABVD, adriamycin, bleomycin, vinblastine, dexamethasone; FL, follicular lymphoma; DHAP, cisplatin, cytarabine, dexamethasone; CVP, cyclophosphamide, vincristine, prednisone; 2CdA, cladribine; DLBCL, diffuse large B-cell lymphoma; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; MM, multiple mycloma; PR, partial remission; VAD, vincristine, doxorubicin, dexamethasone; DT-PACE, dexamethasone, thalidomide, cisplatin, cyclophosphamide, doxorubicin, etoposide; t-AML, therapy-related acute myeloid leukemia; CR, complete remission; BEP, bleomycin, etoposide, cisplatin; FLAG-Ida, fludarabine, cytarabine, granulocyte colony-stimulating factor, idarubicin; CBDCA, carboplatin; STNI, subtotal nodal irradiation; and -, patient underwent no previous radiotherapy.", "type": "table"}, "TABREF1": {"text": "Median peak values of circulating CFU-Mix, BFU-Es, and CFU-GMs per milliliter blood at the first and second mobilization cycles", "type": "table"}, "TABREF2": {"text": "Yields of TNCs, CD34 \u0609 cells, CFCs, and LTC-ICs per leukapheresis following chemotherapy plus either rhG-CSF (first cycle) or rhGH/rhG-CSF (second cycle)", "type": "table"}, "TABREF3": {"text": "Cytogenetic and molecular analysis of diagnostic samples and leukapheresis performed after rhGH/rhG-CSF administration", "type": "table"}, "TABREF4": {"text": "CD34 \u0609 cell mobilization and collection in hard-to-mobilize historical controls receiving 2 consecutive cycles of the same chemotherapy regimen plus rhG-CSF at either 5 g/kg/d (first cycle) or 15 g/kg/d (second cycle)IFO-VNB indicates ifosfamide, vinorelbine; MCL, mantle cell lymphoma. Other abbreviations are explained in Tables 1 and 2.", "type": "table"}}}
{"paper_id": "18987535", "_pdf_hash": "4220486498cde8cf64f908fabbbbdce2c7dd05c2", "abstract": [{"section": "Abstract", "text": "Abstract. This study analyzed the spatio-temporal patterns of 4,587 (94% of the total) confirmed dengue cases in Kaohsiung and Fengshan Cities (a two-city area) that occurred in Taiwan from 2001 to 2003. The epidemic had two simultaneous distinct diffusion patterns. One was a contiguous pattern, mostly limited to 1 km from an initial cluster, reflecting that there was a rapid dispersal of infected Aedes aegypti and viremic persons. The second followed a relocation pattern, involving clusters of cases that diffused over 10 weeks starting from the southern and moving to the northern parts of the two-city area. The virus from one clustering site jumped to several distant areas where it rapidly dispersed through a series of human-mosquito transmission cycles to several localities. In both patterns, transmission of disease quickly enlarged the epidemic areas. Future dengue control efforts would benefit from a timely syndromic surveillance system plus extensive public education on how to avoid further transmission.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "INTRODUCTION", "text": "In the last few decades, there have been an increasing number of dengue epidemics in tropical and subtropical countries. 1 The transmission of dengue occurs primarily through infected female mosquitoes, Aedes aegypti or Aedes albopictus, which acquire the virus when taking blood meals from infected humans. 2 Ae. aegypti, which has a multi-meal feeding behavior on several people, is most often found among humans in urban dwellings. 3, 4 Because dengue virus infection can be mildly/atypically symptomatic, even asymptomatic, it is likely that disease can spread silently and can remain in a community without being noticed. 5, 6 As a result, wherever there were clustering dengue cases confirmed for consecutive weeks, there might have been the possibility that infected mosquitoes are present but undetected. 7 Therefore, if the spatial and temporal factors of the clustering of dengue cases were better understood, we could more efficiently prevent and control the transmission of dengue virus.", "cite_spans": [{"start": 121, "end": 122, "text": "1", "ref_id": "BIBREF0"}, {"start": 308, "end": 309, "text": "2", "ref_id": "BIBREF1"}, {"start": 435, "end": 437, "text": "3,", "ref_id": "BIBREF2"}, {"start": 438, "end": 439, "text": "4", "ref_id": "BIBREF3"}, {"start": 627, "end": 629, "text": "5,", "ref_id": "BIBREF4"}, {"start": 630, "end": 631, "text": "6", "ref_id": "BIBREF5"}, {"start": 813, "end": 814, "text": "7", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "INTRODUCTION", "text": "Between 1987 and 2001, there were epidemics of dengue in Taiwan almost every 3-4 years. They started from imported cases, and most of the epidemics were small-scale involving zero or a small number of cases of dengue hemorrhagic fever (DHF). 8 From 2001 to 2003, however, epidemics of dengue/ DHF predominantly caused by dengue virus serotype 2 (DENV-2) occurred in the two-city area of Kaohsiung and Fengshan, where Taiwan experienced its largest and most severe epidemic in 60 years ( Figure 1 ). Previous studies, using geographical point pattern analysis to study outbreaks in other countries, have shown that dengue cases tend to be clustered either within the same household or in nearby neighborhoods. 3, 4, 7, 9 The aim of this study was to characterize in detail the spatio-temporal patterns of the spread of dengue cases in this two-city area during Taiwan's 2001-2003 dengue epidemic. We showed that dengue case clustering occurred in a contiguous pattern at the community level and in a relocated pattern after the virus had rapidly dispersed on large geographical areas.", "cite_spans": [{"start": 242, "end": 243, "text": "8", "ref_id": "BIBREF7"}, {"start": 709, "end": 711, "text": "3,", "ref_id": "BIBREF2"}, {"start": 712, "end": 714, "text": "4,", "ref_id": "BIBREF3"}, {"start": 715, "end": 717, "text": "7,", "ref_id": "BIBREF6"}, {"start": 718, "end": 719, "text": "9", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "MATERIALS AND METHODS", "text": "Study areas, dengue cases, and surveillance of dengue in Taiwan. Kaohsiung City is the second largest metropolitan area in Taiwan. Neighboring Fengshan City, which has become an extension of Kaohsiung City, is located directly to its east ( Figure 1 ). In 2002, the population density of the two-city area was \u223c10,200 people/km 2 . According to the data from the late 1990s, \u223c4.90 million trips were made per day within Kaohsiung City and between the two cities. 10 In addition, there were no obvious differences between the percentage of people living in business districts and residential districts in the two cities. In fact, many people in these two cities may live in one city and work in the other, increasing the frequency of movement of the dengue-infected persons between the two cities during outbreak periods. In addition, there are many night markets, outdoor markets in Fengshan City where susceptible people gather together and transmission of the virus is facilitated. Therefore, this two-city area was the major focus of virus dispersal and the infections there accounted for as much as 78% of all dengue cases occurring during Taiwan's 2001-2003 dengue/DHF epidemic.", "cite_spans": [{"start": 463, "end": 465, "text": "10", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "MATERIALS AND METHODS", "text": "In dengue surveillance, most vector surveillance efforts are implemented more intensively once dengue cases are reported or confirmed in Taiwan. 11 Human surveillance of dengue cases includes passive reporting and semi-active surveillance. Local physicians at all hospitals and clinics in the twocity area are required to report any suspected dengue cases and to collect plasma/serum samples from them for laboratory confirmation during epidemic periods. 12 Another semiactive surveillance system for dengue in Taiwan searching for neglected or hidden dengue cases requires local public health personnel to obtain blood samples of all fever and febrile cases located within a 500-m radius of infected residences, workplaces, and other places with epidemiologically linked to confirmed dengue cases (http://www.cdc.gov.tw). Clinical definition of dengue cases in our study was based on the same definitions of DF and DHF used by the World Health Organization. To further simplify our analysis, only total laboratory confirmed dengue cases were studied. Dengue-positive cases were confirmed by one of the three laboratory methods: molecular diagnosis by reverse transcriptase-polymerase chain reaction (RT-PCR) using dengue virus-specific primers, 2 serologic testing for dengue IgM seropositive but Japanese encephalitis IgM seronegative, 13 or virus isolation in C6/ 36 mosquito cells.", "cite_spans": [{"start": 145, "end": 147, "text": "11", "ref_id": "BIBREF10"}, {"start": 455, "end": 457, "text": "12", "ref_id": "BIBREF11"}, {"start": 1246, "end": 1247, "text": "2", "ref_id": "BIBREF1"}, {"start": 1338, "end": 1340, "text": "13", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "MATERIALS AND METHODS", "text": "14 Because the collection of mosquito density data during that time in Taiwan was not a random sampling, we preferred to use better quality data on dengue cases for further diffusion analysis. If the dengue cases in certain areas persisted for > 2 weeks, it was very likely that infected mosquitoes had not been controlled successfully. Therefore, we analyzed the geographical distribution of 4,869 confirmed dengue cases caused by dengue virus serotype 2 (DENV-2) in the two-city area and summarized the weekly data from the first case (May 5, 2001 ) to the last case (March 7, 2003) for a total of 96 weeks.", "cite_spans": [], "ref_spans": []}, {"section": "MATERIALS AND METHODS", "text": "Spatial and temporal pattern analyses. We mainly focused our analysis of spatio-temporal patterns of transmission on the residences of dengue cases because we assumed that dengue virus was transmitted domestically and peridomestically in those localities where there were many confirmed dengue cases. To do this, we used point pattern analysis, documented in literature, 3, 4 to summarize our weekly data from the first case (May 5, 2001 ) to the last case (March 7, 2003) .", "cite_spans": [{"start": 371, "end": 373, "text": "3,", "ref_id": "BIBREF2"}, {"start": 374, "end": 375, "text": "4", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "MATERIALS AND METHODS", "text": "To identify spatial clusters of dengue cases and to estimate density surfaces of the clusters on the map, we used a two-step method involving K-order nearest neighbor analysis 15, 16 and kernel estimation. 16 K-order nearest neighbor analysis was used to determine the most appropriate bandwidth size, 17 which could reflect the geographic range of infected mosquitoes that might cause dengue cases. A diagram (Figure 2 ) using all Kth nearest neighbor index values was plotted on the y-axis, and the mean distances between each tested case and the K-order nearest neighbor were plotted on the x-axis. The closer the K-order nearest neighbor index was to zero, the more clustering there was in a tested area. Based on a plateau between 450 and 550 m in the K-order nearest neighbor index plot (Figure 2) , we estimated that 500 m (x-axis value before the slope went flat) was the most appropriate bandwidth. To avoid the boundary effect in spatial clustering detection, the circular border correction method in Crimestat II was applied. 15 Next, we used the appropriate bandwidth as the circular searching radius (500 m) to generate spatial surface of dengue risk map from those cases throughout the 96-week FIGURE 1. The two-city area (Kaohsiung City and Fengshan City) located between 22\u00b030\u040830\u0409 to 45\u040830\u0409 N, and 120\u00b014\u040830\u0409 to 23\u040830\u0409 E in southern Taiwan. Names of the districts are labeled. ", "cite_spans": [{"start": 176, "end": 179, "text": "15,", "ref_id": "BIBREF14"}, {"start": 180, "end": 182, "text": "16", "ref_id": "BIBREF15"}, {"start": 206, "end": 208, "text": "16", "ref_id": "BIBREF15"}, {"start": 302, "end": 304, "text": "17", "ref_id": "BIBREF16"}, {"start": 1037, "end": 1039, "text": "15", "ref_id": "BIBREF14"}], "ref_spans": [{"start": 410, "end": 419, "text": "(Figure 2", "ref_id": "FIGREF0"}, {"start": 793, "end": 803, "text": "(Figure 2)", "ref_id": "FIGREF0"}]}, {"section": "RESULTS", "text": "Case georeferencing. The addresses of the 4,869 confirmed dengue cases whose residence information could be found in Taiwan's residence database were converted to geographic coordinates. After excluding those whose addresses we could not find, we were left with 4,587 confirmed dengue cases (94%), which we used to characterize the patterns of disease diffusion.", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS", "text": "The accuracy of geocoding was tested by randomly selecting 454 cases to be compared using a GPS receiver (Garmin, Taiwan), digital aerial photographs (supported by the Aerial Survey Office, Forest Bureau, Council of Agriculture, Taiwan), and the Web GIS household registration database provided by the Kaohsiung Civil Affairs Bureau web site (http:// address.kcg.gov.tw). After eliminating seven outliers (0.2%) resulting from inconsistencies between the GPS receiver and aerial photographs, we found the mean error for 447 residential addresses to be 31.5 m, which was acceptable for data analysis.", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS", "text": "Demographics of the dengue cases. Figure 3C ). Eighty-five percent of the cases in the first wave occurred in a single focal area (Area F), whereas 83% of the cases in the second wave were spread over Areas A-F, a much wider pattern ( Figure 3B and C) . During the first 10 weeks of 2002, dengue cases spread from the south to the north in the A-E epidemic areas ( Figure 3C , arrows). Although 89% of the A-F areas were located in the places where population densities were > 5,000 inhabitants/km 2 ( Figure 3C , the zebra line), not all high population areas in Kaohsiung had a clustering of dengue cases during this epidemic. Only 27% of the areas with > 5,000 inhabitants/km 2 had pockets involving > 12.5 clustering dengue cases/km 2 . As indicated by dashed lines in Figure 4 , the incidence of dengue cases in initial weeks embedded in the E and F epidemic areas overlapped with the most severe regions where the cumulated density of dengue cases during the entire epidemic period was > 125 cases/km 2 , represented by deep gray in Figure 4 . Geographical clustering cases and dynamic dispersion. Although we regarded the 2001-2003 epidemic of dengue/DHF as one epidemic period because only one serotype (serotype 2) and one genotype of dengue virus was isolated from indigenous dengue cases based on high identity of viral sequences, 18 we preformed a detailed analysis of the spatial diffusion patterns of the dengue cases in these two waves. To closely study the spread of the dengue cases in the abovementioned six different clustering areas over time by weekly basis, we designated the week in which the index case oc- Figure 4) , although the index case of these new areas involving dengue cluster cases was identified in Week 24, 2 weeks prior. Apparently, dengue cases at Week 26 involving not only 84% of them originated from previous weeks maintaining the first cluster but also forming the second cluster as peanut-shaped, implying that the newly formed second cluster was relocation diffused from the first cluster. In brief, Area F was found to have concentric circles expanding outward from Week 22 to Week 26 of 2001 with overlapping and expanding boundaries centered on a single epidemic focus, which was initially identified in the 2001. There was an average of 23 new cases/km 2 /wk during this time.", "cite_spans": [{"start": 1342, "end": 1344, "text": "18", "ref_id": "BIBREF17"}], "ref_spans": [{"start": 34, "end": 43, "text": "Figure 3C", "ref_id": "FIGREF1"}, {"start": 235, "end": 251, "text": "Figure 3B and C)", "ref_id": "FIGREF1"}, {"start": 365, "end": 374, "text": "Figure 3C", "ref_id": "FIGREF1"}, {"start": 502, "end": 511, "text": "Figure 3C", "ref_id": "FIGREF1"}, {"start": 773, "end": 781, "text": "Figure 4", "ref_id": "FIGREF3"}, {"start": 1039, "end": 1047, "text": "Figure 4", "ref_id": "FIGREF3"}, {"start": 1631, "end": 1640, "text": "Figure 4)", "ref_id": "FIGREF3"}]}, {"section": "RESULTS", "text": "Wave 2: initiating diffusion of dengue cases in Area E (Weeks 58-62, June-July 2002). In the second wave of the epidemic, the average number of cases in Area E increased dramatically from < 7 (Week 58 in Figure 4 : Area E) to 34 cases/km 2 /wk (Week 61 in Figure 4 : Area E). Between June 10, 2002 and July 12, 2002, the risk area grew outward at an average rate of 19 km 2 /wk ( Figure 4 : Area E). This quickly expanding pattern of dense case distribution made Area E the largest cluster area involving the most cases. In that area, 10 of the 12 cases clustered in the initial week of the second wave (Week 58 of the epidemic period) were located within the 700-m-diameter dashed-line circle. Thirty-one of the 36 new cases that occurred the following week (Week 59) were clustered around the same center as the previous week. The focal area was identical, and the risk area had expanded by 2 km in diameter. This pattern of diffusion in Area E was quite similar to that identified in Area F. By Week 60, relocation diffusion, a phenomena characterized leaving the original area behind to move to new areas, 17 had occurred. Forty-two of the 52 (80.8%) new cases were clustered. In fact, 18 of the 42 cases (42.8%) shared the same addresses or lived in neighboring buildings. They neighbored the cases of Week 58 and also imparted the same living space, which included outdoor day markets, parks, night markets, and areas with high mosquito indices. This made clustering likely to occur. At this time, we found two new clusters located in the northern parts of the two-city metropolitan area, giving the whole risk area a \"Mickey Mouse\" shape (Area E in Figure 4) . In Week 60, sporadic cases located in the southern part of the Mickey Mouse appeared outside of the estimated risk area (e.g., occurring relocation diffusion again). These new areas of sporadic cases were found to be part of even larger cluster areas in the following 2 weeks. In Week 61, new cases increased sharply. Most (106 of 131; 80.9%) were clustered. For Area E, a critical point was reached after Week 60, when the number of cases began increasing sharply.", "cite_spans": [{"start": 1110, "end": 1112, "text": "17", "ref_id": "BIBREF16"}], "ref_spans": [{"start": 204, "end": 212, "text": "Figure 4", "ref_id": "FIGREF3"}, {"start": 256, "end": 264, "text": "Figure 4", "ref_id": "FIGREF3"}, {"start": 380, "end": 388, "text": "Figure 4", "ref_id": "FIGREF3"}, {"start": 1656, "end": 1665, "text": "Figure 4)", "ref_id": "FIGREF3"}]}, {"section": "RESULTS", "text": "Small-scale diffusion in other areas. In contrast, the transmission of dengue in Areas A-D ( Figure 5 ) was quite restricted, staying under 1 km in diameter. Most of the risk areas stayed near the center of the initial outbreak site, showing contiguous diffusion following a concentric circle spreading pattern in Areas A, C, and D but not in Area B ( Figure  5 ). In Area B, where dengue cases spread in a small-scale relocation diffusion pattern, the outbreak started with one initial clustering. That cluster disappeared and reappeared again with a new focus.", "cite_spans": [], "ref_spans": [{"start": 93, "end": 101, "text": "Figure 5", "ref_id": "FIGREF4"}, {"start": 352, "end": 361, "text": "Figure  5", "ref_id": "FIGREF4"}]}, {"section": "DISCUSSION", "text": "A large-scale epidemic of dengue reflects the continuous existence of several series of transmission chains. 1, 19 Spreading can be explained by the movement of either infected mosquitoes or infected people through a neighborhood. [3] [4] [5] [20] [21] [22] [23] [24] [25] In this study, we identified two different spatial diffusion patterns: contiguous diffusion and relocation diffusion. The range of dengue virus distribution began to spread quickly through the two-city area, with relocation diffusion occurring simultaneously with contiguous diffusion. Most importantly, if the number of human-mosquito transmission cycles in a cluster was large enough to successfully create another cluster, a large-scale epidemic could rapidly occur. Hence, relocation diffusion contribute greatly to the increase scale of an epidemic because it facilitates the spread of the virus to different localities (Figure 3) . 26 The change from contiguous diffusion to relocation diffusion in our study could have been because the original contiguous diffusion pattern might have reflected the direction of the outward expanding activity among those infected vectors serving as \"the source of the infection\" for 2-3 weeks. There could have been an increase in herd immunity, limiting the size of the original/earlier epidemic site(s). This could have been followed by the migration of dengue virus infected persons carrying the virus to other areas resulting in \"relocation pattern.\" If this is how the change in diffusion pattern occurred, it would mean that early dengue control would not only limit the size of contiguous diffusion but also minimize the possibility of relocation diffusion and reduce the number of other possible epidemic sites. The two patterns of diffusion occurred in areas with high population densities ( Figure 3C ). Densely populated areas are at increased risk of importing the dengue virus and have enough susceptible people to facilitate contiguous diffusion. Furthermore, dengue virus serotype 2 (DENV-2) has seldom been involved in large epidemics in Kaohsiung before 2001, suggesting that almost none of the population there had built up sufficient herd immunity. This would mean that population density of those susceptible Kaohsiung's residents to DENV-2 would be large in 2002. Together these findings, combined with the fact that the risk ranges in this study were all greater than the mosquito flight range, suggest that the large-scale spread of dengue cases may be more a result of movement of infected people than the movement of the infected mosquitoes. However, the diffusion of dengue was restricted in areas with low population densities, slowing the limited spread of the virus and thus reducing the possibility of large-scope spread there. To reduce the chances of Taiwan becoming a dengue endemic/hyperendemic area, 27 prevention and control of dengue should emphasize more on surveillance of cases with dengue-like illness integrated with mosquito surveillance and source reduction of mosquito breeding sites.", "cite_spans": [{"start": 109, "end": 111, "text": "1,", "ref_id": "BIBREF0"}, {"start": 112, "end": 114, "text": "19", "ref_id": "BIBREF18"}, {"start": 231, "end": 234, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 235, "end": 238, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 239, "end": 242, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 243, "end": 247, "text": "[20]", "ref_id": "BIBREF19"}, {"start": 248, "end": 252, "text": "[21]", "ref_id": "BIBREF20"}, {"start": 253, "end": 257, "text": "[22]", "ref_id": "BIBREF21"}, {"start": 258, "end": 262, "text": "[23]", "ref_id": "BIBREF22"}, {"start": 263, "end": 267, "text": "[24]", "ref_id": "BIBREF23"}, {"start": 268, "end": 272, "text": "[25]", "ref_id": "BIBREF24"}, {"start": 911, "end": 913, "text": "26", "ref_id": "BIBREF25"}, {"start": 2849, "end": 2851, "text": "27", "ref_id": "BIBREF26"}], "ref_spans": [{"start": 898, "end": 908, "text": "(Figure 3)", "ref_id": "FIGREF1"}, {"start": 1815, "end": 1824, "text": "Figure 3C", "ref_id": "FIGREF1"}]}, {"section": "DISCUSSION", "text": "A detailed study of spatial clustering is helpful when attempting to understand the mechanisms underlying the spread of an epidemic. In the contiguous diffusion we observed, the range of risk to dengue illness in the initial 5 weeks was limited geographically to 0.5-2.0 km in diameter, depending on time and place. Therefore, like many other infectious diseases, dengue decreased susceptibility and increased herd immunity, signifying a reduction in transmission and limiting transmission from a particular cluster. The diffusion started from an original focus area and spread outward in each epidemic region, A, D, E, and F (Figures 4 and 5) , indicating that the unidentified or uncontrolled source of infection continued to disseminate the virus in the local community after it was introduced. The contiguous pattern may reflect the active dispersal of infected Ae. aegypti [3] [4] [5] [19] [20] [21] [22] [23] [24] and their multi-meal behavior. 28 However, our case clustering pattern of concentric circles extended beyond the area of individual house, but, like the observations from different countries, we found the dispersal range of mosquitoes to be usually limited to a few hundred meters. 24, 25, [29] [30] [31] According to Gubler and others, 1 dengue cases are presented by a scattering of infected mosquitoes because dengue viruses in the earliest cluster cases are primarily transmitted to mosquitoes and require an extrinsic incubation period (EIP) to be transmitted to the next person.", "cite_spans": [{"start": 878, "end": 881, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 882, "end": 885, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 886, "end": 889, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 890, "end": 894, "text": "[19]", "ref_id": "BIBREF18"}, {"start": 895, "end": 899, "text": "[20]", "ref_id": "BIBREF19"}, {"start": 900, "end": 904, "text": "[21]", "ref_id": "BIBREF20"}, {"start": 905, "end": 909, "text": "[22]", "ref_id": "BIBREF21"}, {"start": 910, "end": 914, "text": "[23]", "ref_id": "BIBREF22"}, {"start": 915, "end": 919, "text": "[24]", "ref_id": "BIBREF23"}, {"start": 951, "end": 953, "text": "28", "ref_id": "BIBREF27"}, {"start": 1202, "end": 1205, "text": "24,", "ref_id": "BIBREF23"}, {"start": 1206, "end": 1209, "text": "25,", "ref_id": "BIBREF24"}, {"start": 1210, "end": 1214, "text": "[29]", "ref_id": "BIBREF28"}, {"start": 1215, "end": 1219, "text": "[30]", "ref_id": "BIBREF29"}, {"start": 1220, "end": 1224, "text": "[31]", "ref_id": "BIBREF30"}], "ref_spans": [{"start": 626, "end": 643, "text": "(Figures 4 and 5)", "ref_id": "FIGREF3"}]}, {"section": "DISCUSSION", "text": "As the clustering of cases continued in our study, a series of human-mosquito transmission cycles occurred in the two-city clustering areas, which might have gone beyond the clustering ranges of Ae. aegypti 22 and dengue cases 3,4 reported previously. In fact, our clustering of dengue cases in the initial 5 weeks after the establishment of the first cluster overlapped with the epidemic foci of Areas A to F, which accounted for 83-85% of cumulative cases. Again, these results re-illustrate the importance of analyzing initial case clusters.", "cite_spans": [{"start": 207, "end": 209, "text": "22", "ref_id": "BIBREF21"}], "ref_spans": []}, {"section": "DISCUSSION", "text": "Human activities, daily movements, and social networks were found to be important in our six epidemic areas when there was relocation diffusion. No or only very few sporadic cases were found in these areas between the previous epidemic wave and newly arising one within 4 km, a distance longer than the flying range of mosquitoes, again suggesting that infected persons might have played a predominant role in speeding up the dispersal of the virus, similar to several literature findings. 24, 25, 29, 30 Interestingly, the accelerated geographic spread of cases in A-F areas occurred just 1 week before the sharp increase in clustering shown in the epidemic curve. The undiagnosed asymptomatic dengue virus infections or unrecognized dengue cases with mild symptoms could also have made possible the silent spread of dengue virus and undetected persistence of transmission in that locality. 5, 7 Therefore, broader surveillance is needed to minimize possible total infection in the communities where dengue viruses are circulating. When doing this, whenever new cases are confirmed or clustering cases are identified in initial weeks of an outbreaks, public health officials must keep in mind that reinforced surveillance is needed to closely watch all possible common exposure sites, particularly common mosquito breeding areas or common areas where humans mingle, including parks, day/night markets, bus stops, school playgrounds, and temples. To do this, geographical information systems (GISs) can be used to locate problems and prevent a possible series of transmissions in a timely manner. This would keep the disease contained within a residence or with the activity area where the index case occurred and prevent it from spreading to surrounding areas. An enlarged cluster diameter (Area E) indicates a failure to control (Figure 4 ). This 2002 epidemic was not contained until the collaboration efforts between local environment protection agency and local department health began working simultaneously door-todoor to reduce mosquito breeding sites in different areas. This only occurred after we used GIS to show government officials that their failure to control this boundary area was a result of two administration units (Kaohsiug City and Fenghsan City) in the junction of the two-city using different control dates. In other words, Kaohiung City's mosquito control campaigns forced those infected mosquitoes to escape and fly toward Fenghsan City (locations of the two cities as shown in the Figure 1) . Their failure to coordinate resulted in the need for much more manpower to do integrated vector control for a larger epidemic.", "cite_spans": [{"start": 490, "end": 493, "text": "24,", "ref_id": "BIBREF23"}, {"start": 494, "end": 497, "text": "25,", "ref_id": "BIBREF24"}, {"start": 498, "end": 501, "text": "29,", "ref_id": "BIBREF28"}, {"start": 502, "end": 504, "text": "30", "ref_id": "BIBREF29"}, {"start": 892, "end": 894, "text": "5,", "ref_id": "BIBREF4"}, {"start": 895, "end": 896, "text": "7", "ref_id": "BIBREF6"}], "ref_spans": [{"start": 1831, "end": 1840, "text": "(Figure 4", "ref_id": "FIGREF3"}]}, {"section": "DISCUSSION", "text": "Besides the contiguous diffusion among epidemic areas of A, D, E, and F, we also observed relocation diffusion at the community level in Areas B (Weeks 66-67), E (Weeks 59-60 and Weeks 60-61), and F (Weeks 25-26). It took \u223c2-4 weeks for the disease to be spread by humans through relocation dispersion to distant areas where new epidemic foci were created. This time interval was close to or slightly longer than the time period needed for one cycle of human-mosquito-human transmission. 29 The dengue viruses spread throughout the two-city metropolitan at a speed of 2.5 km/wk, which was much slower than that reported from Thailand (148 km/mo) 32 and its rapid cross-country dispersion during World War II. 1 Therefore, speed and scale of human transmission is erratic, regardless of whether spread starts from on case or from several sporadic cases imported from different areas.", "cite_spans": [{"start": 488, "end": 490, "text": "29", "ref_id": "BIBREF28"}, {"start": 646, "end": 648, "text": "32", "ref_id": "BIBREF31"}, {"start": 709, "end": 710, "text": "1", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "DISCUSSION", "text": "This study has several limitations. The actual number of dengue cases may have been underestimated. This underestimation might have been because some asymptomatically infected people did not seek medical care or because infected people with mild symptoms/signs were overlooked by unsuspecting physicians. Our follow-up serologic surveillance in Kaohsiung found that the seroprevalence rate of dengue virus infection in schoolchildren was low (C-C King, personal communication), and most dengue cases or dengue virus-infected individuals were adults with lower asymptomatic ratios rather than children with much higher asymptomatic ratios as identified in most Southeast Asian countries. 33 Dengue cases may also have been underreported either because the physician, being less public minded, did not report suspect cases or because patients kept the information secret to avoid authorities from spraying their houses with insecticide and reduce the possibility that neighbors would complain of the smell. Another limitation might be that, in this study, we focused on dengue cases and paid no heed to environmental and climatic factors, which have also be known to contribute to persistent community transmission. Despite these limitations, our main conclusion regarding the two diffusion patterns of dengue cases from this large-scale epidemic shown in this study remain true and relevant. We believe that further research on integrating case findings with environmental conditions and social factors would be very helpful to explain the mechanism underlying the dynamic transmission of the virus between mosquitoes and human activities. Viruses carried from areas of intensive transmission can be readily transmitted to neighboring areas as well as any part of the world. The success of dengue control in many countries can be jeopardized by the reliance on insecticide spray alone, inappropriate use of insecticide, insecticide resistance, 34 a low awareness or lacking of cooperation by local residents regarding the reduction of mosquito breeding sites at the community level, and undetected cases. 11 The method used in this study, which analyzed the number of dengue cases by spatiotemporal clustering, should help in evaluating the effectiveness of control efforts and in locating hidden mosquito breeding sites, 32, 35, 36 particularly during the first 2-3 weeks after a cluster appears. Once dengue cases exceed a certain threshold, large-scale transmission chains in the risk areas will make it more likely for infected humans and mosquitoes in one locality to carry dengue viruses to other localities. As dengue cases are expanding globally and most mosquito control programs are reactive, 11 there is an increasing need to establish a cross-country dengue surveillance network, 37 improve mosquito surveillance, and advise dengue patients to restrict their activities to be better interrupt the transmission chains from human to mosquitoes, minimize the multiple introductions of dengue virus, and improve the health of people wordwide. 1 To prevent and control dengue more effectively in Taiwan and elsewhere, we recommend establishing a surveillance system capable of collecting data on major risk factors before and during an epidemic using GIS to monitor possible spatial trends in the spread of the virus. Such a system can begin to provide rapid and timely feedback so that public health agencies can more efficiently formulate and implement health policies that can respond to an ongoing epidemic.", "cite_spans": [{"start": 687, "end": 689, "text": "33", "ref_id": "BIBREF32"}, {"start": 1943, "end": 1945, "text": "34", "ref_id": "BIBREF33"}, {"start": 2104, "end": 2106, "text": "11", "ref_id": "BIBREF10"}, {"start": 2321, "end": 2324, "text": "32,", "ref_id": "BIBREF31"}, {"start": 2325, "end": 2328, "text": "35,", "ref_id": "BIBREF34"}, {"start": 2329, "end": 2331, "text": "36", "ref_id": "BIBREF35"}, {"start": 2702, "end": 2704, "text": "11", "ref_id": "BIBREF10"}, {"start": 2791, "end": 2793, "text": "37", "ref_id": "BIBREF36"}, {"start": 3050, "end": 3051, "text": "1", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "DISCUSSION", "text": "Received May 27, 2007 . Accepted for publication May 13, 2008. ", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Dengue and Dengue Hemorrhagic Fever", "authors": [{"first": "D", "middle": ["J"], "last": "Gubler", "suffix": ""}, {"first": "S", "middle": ["B"], "last": "Halstead", "suffix": ""}, {"first": "F", "middle": [], "last": "Rodhain", "suffix": ""}, {"first": "L", "middle": [], "last": "Rosen", "suffix": ""}, {"first": "G", "middle": [], "last": "Kuno", "suffix": ""}, {"first": "R", "middle": [], "last": "George", "suffix": ""}, {"first": "Lcs", "middle": [], "last": "Lum", "suffix": ""}, {"first": "N", "middle": [], "last": "Bhamarapravati", "suffix": ""}, {"first": "S", "middle": [], "last": "Nimmannitya", "suffix": ""}, {"first": "E", "middle": ["G"], "last": "Westaway", "suffix": ""}, {"first": "J", "middle": [], "last": "Blok", "suffix": ""}, {"first": "G", "middle": ["J"], "last": "Chang", "suffix": ""}, {"first": "D", "middle": ["J"], "last": "Gubler", "suffix": ""}, {"first": "G", "middle": [], "last": "Kuno", "suffix": ""}], "year": 1997, "venue": "", "link": "90991747"}, "BIBREF1": {"title": "Rapid detection and typing of dengue viruses from clinical samples by using reverse transcriptase-polymerase chain reaction", "authors": [{"first": "R", "middle": ["S"], "last": "Lanciotti", "suffix": ""}, {"first": "C", "middle": ["H"], "last": "Calisher", "suffix": ""}, {"first": "D", "middle": ["J"], "last": "Gubler", "suffix": ""}, {"first": "G", "middle": ["J"], "last": "Chang", "suffix": ""}, {"first": "A", "middle": ["V"], "last": "Vorndam", "suffix": ""}], "year": 1992, "venue": "J Clin Microbiol", "link": "22669060"}, "BIBREF2": {"title": "Dengue spatial and temporal patterns", "authors": [{"first": "A", "middle": [], "last": "Tran", "suffix": ""}, {"first": "X", "middle": [], "last": "Deparis", "suffix": ""}, {"first": "P", "middle": [], "last": "Dussart", "suffix": ""}, {"first": "J", "middle": [], "last": "Morvan", "suffix": ""}, {"first": "P", "middle": [], "last": "Rabarison", "suffix": ""}, {"first": "Remy", "middle": ["F"], "last": "Polidori", "suffix": ""}, {"first": "L", "middle": [], "last": "Gardon", "suffix": ""}, {"first": "J", "middle": [], "last": "", "suffix": ""}], "year": 2001, "venue": "Emerg Infect Dis", "link": null}, "BIBREF3": {"title": "Exploratory space-time analysis of reported dengue cases during an outbreak in Florida", "authors": [{"first": "A", "middle": ["C"], "last": "Morrison", "suffix": ""}, {"first": "A", "middle": [], "last": "Getis", "suffix": ""}, {"first": "M", "middle": [], "last": "Santiago", "suffix": ""}, {"first": "J", "middle": ["G"], "last": "Rigau-Perez", "suffix": ""}, {"first": "P", "middle": [], "last": "Reiter", "suffix": ""}], "year": 1991, "venue": "Am J Trop Med Hyg", "link": null}, "BIBREF4": {"title": "Early detection of dengue infections using cluster sampling around index cases", "authors": [{"first": "C", "middle": ["G"], "last": "Beckett", "suffix": ""}, {"first": "H", "middle": [], "last": "Kosasih", "suffix": ""}, {"first": "I", "middle": [], "last": "Faisal", "suffix": ""}, {"first": "", "middle": [], "last": "Nurhayati", "suffix": ""}, {"first": "R", "middle": [], "last": "Tan", "suffix": ""}, {"first": "S", "middle": [], "last": "Widjaja", "suffix": ""}, {"first": "E", "middle": [], "last": "Listiyaningsih", "suffix": ""}, {"first": "C", "middle": [], "last": "Ma&apos;roef", "suffix": ""}, {"first": "S", "middle": [], "last": "Wuryadi", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Bangs", "suffix": ""}, {"first": "T", "middle": ["K"], "last": "Samsi", "suffix": ""}, {"first": "D", "middle": [], "last": "Yuwono", "suffix": ""}, {"first": "C", "middle": ["G"], "last": "Hayes", "suffix": ""}, {"first": "K", "middle": ["R"], "last": "Porter", "suffix": ""}], "year": 2005, "venue": "Am J Trop Med Hyg", "link": null}, "BIBREF5": {"title": "Silent transmission of the dengue virus in southern Taiwan", "authors": [{"first": "W", "middle": ["J"], "last": "Chen", "suffix": ""}, {"first": "S", "middle": ["L"], "last": "Chen", "suffix": ""}, {"first": "L", "middle": ["J"], "last": "Chien", "suffix": ""}, {"first": "C", "middle": ["C"], "last": "Chen", "suffix": ""}, {"first": "C", "middle": ["C"], "last": "King", "suffix": ""}, {"first": "M", "middle": ["R"], "last": "Harn", "suffix": ""}, {"first": "K", "middle": ["P"], "last": "Hwang", "suffix": ""}, {"first": "J", "middle": ["H"], "last": "Fang", "suffix": ""}], "year": 1996, "venue": "Am J Trop Med Hyg", "link": "25073807"}, "BIBREF6": {"title": "Use of a geographic information system for defining spatial risk for dengue transmission in Bangladesh: role for Aedes albopictus in an urban outbreak", "authors": [{"first": "M", "middle": [], "last": "Ali", "suffix": ""}, {"first": "Y", "middle": [], "last": "Wagatsuma", "suffix": ""}, {"first": "M", "middle": [], "last": "Emch", "suffix": ""}, {"first": "R", "middle": ["F"], "last": "Breiman", "suffix": ""}], "year": 2003, "venue": "Am J Trop Med Hyg", "link": "34883298"}, "BIBREF7": {"title": "Major epidemics of dengue in Taiwan in 1981-2000: related to the intensive virus activities in Asia and public health surveillance", "authors": [{"first": "C", "middle": ["C"], "last": "King", "suffix": ""}, {"first": "Y", "middle": ["C"], "last": "Wu", "suffix": ""}, {"first": "D", "middle": ["Y"], "last": "Chao", "suffix": ""}, {"first": "C", "middle": ["L"], "last": "Kao", "suffix": ""}, {"first": "H", "middle": ["T"], "last": "Wang", "suffix": ""}, {"first": "L", "middle": [], "last": "Chiang", "suffix": ""}, {"first": "C", "middle": ["C"], "last": "Ku", "suffix": ""}, {"first": "H", "middle": ["J"], "last": "Chang", "suffix": ""}, {"first": "L", "middle": [], "last": "Chow", "suffix": ""}, {"first": "T", "middle": ["H"], "last": "Lin", "suffix": ""}, {"first": "L", "middle": ["J"], "last": "Chien", "suffix": ""}, {"first": "J", "middle": ["S"], "last": "Huang", "suffix": ""}, {"first": "K", "middle": ["P"], "last": "Huang", "suffix": ""}, {"first": "M", "middle": ["R"], "last": "Han", "suffix": ""}, {"first": "D", "middle": [], "last": "Gubler", "suffix": ""}], "year": 2000, "venue": "Dengue Bull", "link": null}, "BIBREF8": {"title": "Household survey of dengue infection in central Brazil: spatial point pattern analysis and risk factors assessment", "authors": [{"first": "J", "middle": ["B"], "last": "Siqueira", "suffix": ""}, {"first": "C", "middle": ["M"], "last": "Martelli", "suffix": ""}, {"first": "I", "middle": ["J"], "last": "Maciel", "suffix": ""}, {"first": "R", "middle": ["M"], "last": "Oliveira", "suffix": ""}, {"first": "M", "middle": ["G"], "last": "Ribeiro", "suffix": ""}, {"first": "F", "middle": ["P"], "last": "Amorim", "suffix": ""}, {"first": "B", "middle": ["C"], "last": "Moreira", "suffix": ""}, {"first": "D", "middle": ["D"], "last": "Cardoso", "suffix": ""}, {"first": "W", "middle": ["V"], "last": "Souza", "suffix": ""}, {"first": "A", "middle": ["L"], "last": "Andrade", "suffix": ""}], "year": 2004, "venue": "Am J Trop Med Hyg", "link": "33335382"}, "BIBREF9": {"title": "The Survey of the Household Travel Characteristics in Kaohsiung Metropolitan. Taipei: Institute of Transportation Ministry of Transportation and Communications", "authors": [{"first": "C-H", "middle": [], "last": "Chen", "suffix": ""}, {"first": "L-C", "middle": [], "last": "Lee", "suffix": ""}, {"first": "C-Y", "middle": [], "last": "Chen", "suffix": ""}, {"first": "M-H", "middle": [], "last": "Chunag", "suffix": ""}, {"first": "Y-D", "middle": [], "last": "Lin", "suffix": ""}, {"first": "Y-C", "middle": [], "last": "Tseng", "suffix": ""}, {"first": "T-C", "middle": [], "last": "Ku", "suffix": ""}], "year": 1998, "venue": "", "link": null}, "BIBREF10": {"title": "Integrated control of the dengue vector Aedes aegypti Liu-Chiu Village, Ping-Tung County", "authors": [{"first": "C", "middle": ["H"], "last": "Wang", "suffix": ""}, {"first": "N", "middle": ["T"], "last": "Chang", "suffix": ""}, {"first": "H", "middle": [], "last": "Wu", "suffix": ""}, {"first": "Hm", "middle": [], "last": "Ho", "suffix": ""}, {"first": "C", "middle": ["M"], "last": "", "suffix": ""}], "year": 2000, "venue": "Taiwan. J Am Mosq Control Assoc", "link": null}, "BIBREF11": {"title": "dengue hemorrhagic fever epidemic in Taiwan", "authors": [{"first": "D", "middle": ["Y"], "last": "Chao", "suffix": ""}, {"first": "T", "middle": ["H"], "last": "Lin", "suffix": ""}, {"first": "K", "middle": ["P"], "last": "Hwang", "suffix": ""}, {"first": "J", "middle": ["H"], "last": "Huang", "suffix": ""}, {"first": "C", "middle": ["C"], "last": "Liu", "suffix": ""}, {"first": "C", "middle": ["C"], "last": "King", "suffix": ""}], "year": 1998, "venue": "Emerg Infect Dis", "link": "197858259"}, "BIBREF12": {"title": "Antibody to the nonstructural protein NS1 of Japanese encephalitis virus: potential application of mAb-based indirect ELISA to differentiate infection from vaccination", "authors": [{"first": "P", "middle": ["Y"], "last": "Shu", "suffix": ""}, {"first": "L", "middle": ["K"], "last": "Chen", "suffix": ""}, {"first": "S", "middle": ["F"], "last": "Chang", "suffix": ""}, {"first": "Y", "middle": ["Y"], "last": "Yueh", "suffix": ""}, {"first": "L", "middle": [], "last": "Chow", "suffix": ""}, {"first": "L", "middle": ["J"], "last": "Chien", "suffix": ""}, {"first": "C", "middle": [], "last": "Chin", "suffix": ""}, {"first": "T", "middle": ["H"], "last": "Lin", "suffix": ""}, {"first": "J", "middle": ["H"], "last": "Huang", "suffix": ""}], "year": 2001, "venue": "Vaccine", "link": "1519273"}, "BIBREF13": {"title": "Comparative sensitivity of three mosquito cell lines for isolation of dengue viruses", "authors": [{"first": "G", "middle": [], "last": "Kuno", "suffix": ""}, {"first": "D", "middle": ["J"], "last": "Gubler", "suffix": ""}, {"first": "M", "middle": [], "last": "Velez", "suffix": ""}, {"first": "A", "middle": [], "last": "Oliver", "suffix": ""}], "year": 1985, "venue": "Bull World Health Organ", "link": "36524107"}, "BIBREF14": {"title": "A Spatial Statistics Program for the Analysis of Crime Incident Locations", "authors": [], "year": 2002, "venue": "", "link": null}, "BIBREF15": {"title": "Spatial Point Pattern Analysis and its Application in Geographical Epidemiology", "authors": [{"first": "A", "middle": ["C"], "last": "Gatrell", "suffix": ""}, {"first": "T", "middle": ["C"], "last": "Bailey", "suffix": ""}, {"first": "P", "middle": [], "last": "Diggle", "suffix": ""}, {"first": "B", "middle": ["S"], "last": "Rowlingson", "suffix": ""}], "year": 1996, "venue": "Trans Inst Br Geogr NS", "link": "30441256"}, "BIBREF16": {"title": "Interactive Spatial Data Analysis", "authors": [{"first": "T", "middle": ["C"], "last": "Bailey", "suffix": ""}, {"first": "A", "middle": ["C"], "last": "Gatrell", "suffix": ""}], "year": 1995, "venue": "", "link": "62228752"}, "BIBREF17": {"title": "Epidemiology of dengue fever/dengue hemorrhagic fever in southern Taiwan", "authors": [{"first": "M-H", "middle": [], "last": "Wu", "suffix": ""}], "year": 2001, "venue": "", "link": null}, "BIBREF18": {"title": "The Geographical Structure of Epidemic", "authors": [{"first": "P", "middle": [], "last": "Haggett", "suffix": ""}], "year": 2000, "venue": "", "link": "182827103"}, "BIBREF19": {"title": "Identification of the people from whom engorged Aedes aegypti took blood meals in Florida, Puerto Rico, using polymerase chain reaction-based DNA profiling", "authors": [{"first": "B", "middle": ["J"], "last": "De", "suffix": ""}, {"first": "E", "middle": [], "last": "Chow-Shaffer", "suffix": ""}, {"first": "A", "middle": [], "last": "Costero", "suffix": ""}, {"first": "G", "middle": ["G"], "last": "Clark", "suffix": ""}, {"first": "J", "middle": ["D"], "last": "Edman", "suffix": ""}, {"first": "T", "middle": ["W"], "last": "Scott", "suffix": ""}], "year": 2003, "venue": "Am J Trop Med Hyg", "link": null}, "BIBREF20": {"title": "Possible dengue sequential infection: dengue spread in a neighbourhood during the 1996/97 dengue-2 epidemic in French Polynesia", "authors": [{"first": "X", "middle": [], "last": "Deparis", "suffix": ""}, {"first": "C", "middle": [], "last": "Roche", "suffix": ""}, {"first": "B", "middle": [], "last": "Murgue", "suffix": ""}, {"first": "E", "middle": [], "last": "Chungue", "suffix": ""}], "year": 1998, "venue": "Trop Med Int Health", "link": "19203388"}, "BIBREF21": {"title": "Characteristics of the spatial pattern of the dengue vector, Aedes aegypti", "authors": [{"first": "A", "middle": [], "last": "Getis", "suffix": ""}, {"first": "A", "middle": ["C"], "last": "Morrison", "suffix": ""}, {"first": "K", "middle": [], "last": "Gray", "suffix": ""}, {"first": "T", "middle": ["W"], "last": "Scott", "suffix": ""}], "year": 2003, "venue": "Am J Trop Med Hyg", "link": null}, "BIBREF22": {"title": "Analysis of survival of young and old Aedes aegypti (Diptera: Culicidac) from Puerto Rico and Thailand", "authors": [{"first": "L", "middle": ["C"], "last": "Harrington", "suffix": ""}, {"first": "J", "middle": ["P"], "last": "Buonaccorsi", "suffix": ""}, {"first": "J", "middle": ["D"], "last": "Edman", "suffix": ""}, {"first": "A", "middle": [], "last": "Costero", "suffix": ""}, {"first": "P", "middle": [], "last": "Kittayapong", "suffix": ""}, {"first": "G", "middle": ["G"], "last": "Clark", "suffix": ""}, {"first": "T", "middle": ["W"], "last": "Scott", "suffix": ""}], "year": 2001, "venue": "J Med Entomol", "link": "25869351"}, "BIBREF23": {"title": "Horizontal and vertical dispersal of dengue vector mosquitoes, Aedes aegypti and Aedes albopictus", "authors": [{"first": "C", "middle": [], "last": "Liew", "suffix": ""}, {"first": "C", "middle": ["F"], "last": "Curtis", "suffix": ""}], "year": 2004, "venue": "Med Vet Entomol", "link": null}, "BIBREF24": {"title": "Short report: dispersal of Aedes aegypti in an urban area after blood feeding as demonstrated by rubidium-marked eggs", "authors": [{"first": "P", "middle": [], "last": "Reiter", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Amador", "suffix": ""}, {"first": "R", "middle": ["A"], "last": "Anderson", "suffix": ""}, {"first": "G", "middle": ["G"], "last": "Clark", "suffix": ""}], "year": 1995, "venue": "Am J Trop Med Hyg", "link": "21988077"}, "BIBREF25": {"title": "Epidemiology of measles in Taiwan: dynamics of transmission and timeliness of reporting during an epidemic in 1988-9", "authors": [{"first": "M", "middle": ["S"], "last": "Lee", "suffix": ""}, {"first": "C", "middle": ["C"], "last": "King", "suffix": ""}, {"first": "C", "middle": ["J"], "last": "Chen", "suffix": ""}, {"first": "S", "middle": ["Y"], "last": "Yang", "suffix": ""}, {"first": "M", "middle": ["S"], "last": "Ho", "suffix": ""}], "year": 1995, "venue": "Epidemiol Infect", "link": "45280731"}, "BIBREF26": {"title": "Status of dengue control programme in Taiwan", "authors": [{"first": "H", "middle": ["Y"], "last": "Lei", "suffix": ""}, {"first": "J", "middle": ["H"], "last": "Huang", "suffix": ""}, {"first": "K", "middle": ["J"], "last": "Huang", "suffix": ""}, {"first": "C", "middle": [], "last": "Chang", "suffix": ""}], "year": 2001, "venue": "Dengue Bull", "link": "74099527"}, "BIBREF27": {"title": "Longitudinal studies of Aedes aegypti (Diptera: Culicidae) in Thailand and Puerto Rico: blood feeding frequency", "authors": [{"first": "T", "middle": ["W"], "last": "Scott", "suffix": ""}, {"first": "P", "middle": ["H"], "last": "Amerasinghe", "suffix": ""}, {"first": "A", "middle": ["C"], "last": "Morrison", "suffix": ""}, {"first": "L", "middle": ["H"], "last": "Lorenz", "suffix": ""}, {"first": "G", "middle": ["G"], "last": "Clark", "suffix": ""}, {"first": "D", "middle": [], "last": "Strickman", "suffix": ""}, {"first": "P", "middle": [], "last": "Kittayapong", "suffix": ""}, {"first": "J", "middle": ["D"], "last": "Edman", "suffix": ""}], "year": 2000, "venue": "J Med Entomol", "link": "24657268"}, "BIBREF28": {"title": "Dispersal of the dengue vector Aedes aegypti within and between rural communities", "authors": [{"first": "L", "middle": ["C"], "last": "Harrington", "suffix": ""}, {"first": "T", "middle": ["W"], "last": "Scott", "suffix": ""}, {"first": "K", "middle": [], "last": "Lerdthusnee", "suffix": ""}, {"first": "R", "middle": ["C"], "last": "Coleman", "suffix": ""}, {"first": "A", "middle": [], "last": "Costero", "suffix": ""}, {"first": "G", "middle": ["G"], "last": "Clark", "suffix": ""}, {"first": "J", "middle": ["J"], "last": "Jones", "suffix": ""}, {"first": "S", "middle": [], "last": "Kitthawee", "suffix": ""}, {"first": "P", "middle": [], "last": "Kittayapong", "suffix": ""}, {"first": "R", "middle": [], "last": "Sithiprasasna", "suffix": ""}, {"first": "J", "middle": ["D"], "last": "Edman", "suffix": ""}], "year": 2005, "venue": "Am J Trop Med Hyg", "link": null}, "BIBREF29": {"title": "Dispersal of Aedes aegypti and Aedes albopictus (Diptera: Culicidae) in an urban endemic dengue area in the State of Rio de Janeiro, Brazil", "authors": [{"first": "N", "middle": ["A"], "last": "Honorio", "suffix": ""}, {"first": "W", "middle": ["C"], "last": "Silva", "suffix": ""}, {"first": "P", "middle": ["J"], "last": "Leite", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Goncalves", "suffix": ""}, {"first": "L", "middle": ["P"], "last": "Lounibos", "suffix": ""}, {"first": "R", "middle": [], "last": "Lourenco-De-Oliveira", "suffix": ""}], "year": 2003, "venue": "Mem Inst Oswaldo Cruz", "link": "20611159"}, "BIBREF30": {"title": "The geographic information system as an epidemiological tool in the surveillance of dengue virus-infected Aedes mosquitos", "authors": [{"first": "R", "middle": [], "last": "Sithiprasasna", "suffix": ""}, {"first": "S", "middle": [], "last": "Patpoparn", "suffix": ""}, {"first": "W", "middle": [], "last": "Attatippaholkun", "suffix": ""}, {"first": "S", "middle": [], "last": "Suvannadabba", "suffix": ""}, {"first": "M", "middle": [], "last": "Srisuphanunt", "suffix": ""}], "year": 2004, "venue": "Southeast Asian J Trop Med Public Health", "link": "25199131"}, "BIBREF31": {"title": "Travelling waves in the occurrence of dengue haemorrhagic fever in Thailand", "authors": [{"first": "D", "middle": ["A"], "last": "Cummings", "suffix": ""}, {"first": "R", "middle": ["A"], "last": "Irizarry", "suffix": ""}, {"first": "N", "middle": ["E"], "last": "Huang", "suffix": ""}, {"first": "T", "middle": ["P"], "last": "Endy", "suffix": ""}, {"first": "A", "middle": [], "last": "Nisalak", "suffix": ""}, {"first": "K", "middle": [], "last": "Ungchusak", "suffix": ""}, {"first": "D", "middle": ["S"], "last": "Burke", "suffix": ""}], "year": 2004, "venue": "Nature", "link": "4373726"}, "BIBREF32": {"title": "A prospective study of dengue infections in Bangkok", "authors": [{"first": "D", "middle": ["S"], "last": "Burke", "suffix": ""}, {"first": "A", "middle": [], "last": "Nisalak", "suffix": ""}, {"first": "D", "middle": ["E"], "last": "Johnson", "suffix": ""}, {"first": "R", "middle": ["M"], "last": "Scott", "suffix": ""}], "year": 1988, "venue": "Am J Trop Med Hyg", "link": "22374798"}, "BIBREF33": {"title": "Population dynamics of Aedes aegypti from a dengue hyperendemic urban setting in Colombia", "authors": [{"first": "C", "middle": ["B"], "last": "Ocampo", "suffix": ""}, {"first": "D", "middle": ["M"], "last": "Wesson", "suffix": ""}], "year": 2004, "venue": "Am J Trop Med Hyg", "link": "1160614"}, "BIBREF34": {"title": "Spatial mapping of temporal risk characteristics to improve environmental health risk identification: a case study of a dengue epidemic in Taiwan", "authors": [{"first": "T", "middle": ["H"], "last": "Wen", "suffix": ""}, {"first": "N", "middle": ["H"], "last": "Lin", "suffix": ""}, {"first": "C", "middle": ["H"], "last": "Lin", "suffix": ""}, {"first": "C", "middle": ["C"], "last": "King", "suffix": ""}, {"first": "M", "middle": ["D"], "last": "Su", "suffix": ""}], "year": 2006, "venue": "Sci Total Environ", "link": "33702581"}, "BIBREF35": {"title": "Roof gutters: a key container for Aedes aegypti and Ochlerotatus notoscriptus (Diptera: Culicidae) in Australia", "authors": [{"first": "B", "middle": ["L"], "last": "Montgomery", "suffix": ""}, {"first": "S", "middle": ["A"], "last": "Ritchie", "suffix": ""}], "year": 2002, "venue": "Am J Trop Med Hyg", "link": "43818576"}, "BIBREF36": {"title": "Fever screening at airports and imported dengue", "authors": [{"first": "P", "middle": ["Y"], "last": "Shu", "suffix": ""}, {"first": "L", "middle": ["J"], "last": "Chien", "suffix": ""}, {"first": "S", "middle": ["F"], "last": "Chang", "suffix": ""}, {"first": "C", "middle": ["L"], "last": "Su", "suffix": ""}, {"first": "Y", "middle": ["C"], "last": "Kuo", "suffix": ""}, {"first": "T", "middle": ["L"], "last": "Liao", "suffix": ""}, {"first": "M", "middle": ["S"], "last": "Ho", "suffix": ""}, {"first": "T", "middle": ["H"], "last": "Lin", "suffix": ""}, {"first": "J", "middle": ["H"], "last": "Huang", "suffix": ""}], "year": 2005, "venue": "Emerg Infect Dis", "link": "2437858"}}, "ref_entries": {"FIGREF0": {"text": "FIGURE 2. The K-order nearest neighbor analysis showed the relationship between the nearest neighbor index and observed distance (m) of the Kth nearest neighbor. A 500-m bandwidth was selected from a plateau (450-550 m).", "type": "figure"}, "FIGREF1": {"text": "FIGURE 3. Temporal and spatial distribution of confirmed dengue cases in the two-city area in Taiwan. A, An epidemic curve of weekly confirmed dengue cases between May 5, 2001 (Week 1, first identified case) and March 1, 2003 (Week 96). Arrows indicate the appearance of clustering cases in selected areas. B, Spatio-temporal clusters of dengue cases. Axes x and y are geographical coordinates in Taiwan datum (transverse mercator projection). Onset date of each dengue case is labeled as z-axis. Two-city map projected on x-y plane and grayscale was categorized as four different levels according to the number of dengue case per unit of 0.8 km 2 : (1) < 3 cases (no color), (2) 3-10 cases (light gray color), (3) 11-100 cases (gray color), and (4) \u0546 101 cases (deep gray color). C, Kernel estimated density map of > 10 dengue cases per unit of 0.8 km 2 is shown within the zebra line. Population density was presented as the right top corner (in gray to black colors). Arrows indicate the location of the first clustering cases appearing in each of the selected areas by onset week.", "type": "figure"}, "FIGREF2": {"text": "curred in 2001 as Week 1, the following week as Week 2, and so on until Week 96, when the last dengue case ended in March 2003. Wave 1: initiating diffusion of dengue cases in Area F (Weeks 21-26, October-November 2001). To find out whether there was a consistent dispersal pattern in all six areas (A-F), we generated spatial risk surfaces to study the weekly dy- namic changes of dengue cases during the initial 5 weeks immediately after the first appearance of each cluster in each of the cluster areas (A-F). The first epidemic wave started with the appearance of a single sporadic case (Week 21 of the epidemic) in 2001 before the first clustering in Qianzhen Dis- trict (Figure 4: Area F). One week later, a cluster of 16 den- gue cases was identified in Area F covering a 750-m-diameter area, where the clustering persisted the following week (Week 23). An additional seven cases occurred in the same 750-m area as the previous week. In Weeks 24-25, most den- gue cases (20 of the 22 cases in Week 24 and 14 of the 15 additional cases in Week 25) also occurred in the same areas. By Week 26, we found 25 additional cases and identified other new cluster areas, forming a long axis extending \u223c1.6 km. These changes made the risk area more peanut-shaped. In fact, 21 of these additional 25 cases (84%) in Week 26 indeed occurred within the identified risk areas from previous weeks (areas within the risk areas representing as dashlines in Weeks 22-25 as shown in", "type": "figure"}, "FIGREF3": {"text": "FIGURE 4. Map of spatio-temporal clustering cases in the initial 5 weeks since the first cluster was identified in Areas E and F. Locations of dengue cases were labeled as block dots. Dash-line circled risk area has > 2 cases/0.8 km 2 /wk. Shade area is defined as > 2 cases (light gray), > 10 cases (gray), and > 100 cases (deep gray) in 0.8 km 2 between 2001 and 2003.", "type": "figure"}, "FIGREF4": {"text": "FIGURE 5. Map of spatial-temporal clustering cases in the initial 5 weeks since the first cluster was identified in selected areas. A-D, Locations of dengue cases were label as black dot. A risk area has circled in dash-line as > 2 cases/0.8 km 2 /wk. Shade area is defined as > 2 cases (light gray) and between 11 and 100 cases (gray) in 0.8 km 2 between 2001 and 2003.", "type": "figure"}, "TABREF0": {"text": "TWO CLUSTERING DIFFUSION PATTERNS ON DENGUE IN TAIWAN epidemic by using kernel density estimation on ESRI ArcGIS version 8.3. Weighing for the neighboring dengue cases while scanning all the epidemic areas, we were able to obtain infor- mation on the density of clustering.", "type": "table"}, "TABREF1": {"text": "Based on WHO crite- ria, 4,245 (92.5%) of the 4587 Kaohsiung's confirmed dengue cases were DF cases and 342 were DHF cases. The male-to- female ratio was 0.867 (2,130/2,457). Age was a significant confounder in dengue cases, with most being > 45 years old (2,523 [59.4%] of DF cases, 271 [79.2%] of DHF cases, and 60.9% of total dengue cases; Table 1). Epidemic curve and place. There were two dengue epi- demic waves in the two-city area between 2001 and 2003 (Fig- ure 3A). A small initial wave involving 217 cases (5% of the total cases) occurred between May 2001 and February 2002. A larger-scale epidemic wave involving 4,361 cases followed between May 2002 and February 2003. Viewed from the macro level (A-F) and identified by nearest neighbor analy- sis, we found six statistically significant dengue clustered ar- eas (", "type": "table"}, "TABREF2": {"text": "Distribution of sex and age of the total dengue cases in the epidemic of DF/DHF in Kaohsiung, 2001-2003", "type": "table"}}}
{"paper_id": "18987990", "_pdf_hash": "eb2e6d633e38d8e10e82d1dda1c2661683c01988", "abstract": [{"section": "Abstract", "text": "The \u039b baryons with a single heavy flavor which transfer the quark polarization, have been studied both theoretically and experimentally. The \u039e's with two heavy constituents are well treated in quark-diquark model. In this work we study the production of triply heavy baryons in the perturbative QCD regime and calculate the fragmentation functions for \u2126 ccc and \u2126 bbb in the c and b quark fragmentation, respectively. We then obtain the total fragmentation probability and the average fragmentation parameter for each case.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "The quark model of hadrons has proved to be successful in describing hadrons and their properties. In the heavy quark sector it predicts hadrons having c, b and t quarks as constituents. However, the discovery of the top quark [1] and the determination of its lifetime [2] made it clear that it cannot participate in strong interactions and therefore only the c and b flavors are left to take part in the hadron production interplay.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "Baryon states with heavy flavor fall into three categories. States containing one heavy flavor such as \u039b c and \u039b b are interesting states due to the fact that they carry the original heavy flavor polarization. They are presently being studied experimentally [5] . The second category involves baryons with two heavy flavor like the states \u039e cc , \u039e bb and \u039e bc [6] . They are treated within the approximate quark-diquark model [7] . The model treats the production of the so called diquark perturbatively similar to the states such as B c . Then, it can be proved that the formation of a baryon out of the diquark is almost the same as the fragmentation of an antiquark into a meson. In this way one obtains the fragmentation functions, the total production probabilities and other relevant parameters which specify their properties. In the third category, we have baryons with three heavy constituents. If we follow the scheme used in the case of heavy mesons and assume that their fragmentation functions are calculable in the perturbative regime, then we can calculate Feynman diagrams like the one in figure 1 to obtain the fragmentation functions. There are eight such diagrams in the lowest order contributing triply heavy baryons, i.e. \u2126 ccc , \u2126 ccb , \u2126 cbb and \u2126 bbb production [8] .", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "In this paper our aim is to calculate the fragmentation of the \u2126 ccc and \u2126 bbb baryons in the lowest order perturbative regime and obtain their fragmentation functions in an exact analytical form.", "cite_spans": [], "ref_spans": []}, {"section": "Kinematics", "text": "We consider the fragmentation of a heavy quark Q into a QQQ system with three identical flavor. This procedure is illustrated in Figure 1 . We have used an infinite momentum frame in which all of the particles are moved in the forward direction, i.e. the longitudinal direction along the z axes, where the QQQ moves. We let the original quark keep its transverse momentum. Furthermore, we assume that the two antiquark jets move almost in the same direction. This assumption is justified due to the fact that the very high momentum of the initial heavy quark will predominantly be carried in the forward direction. Due to momentum conservation, the total transverse momentum of the two jets will be identical to the transverse momentum of the initial quark. In this context the four momenta of the particles will assume the following form", "cite_spans": [], "ref_spans": [{"start": 129, "end": 137, "text": "Figure 1", "ref_id": "FIGREF0"}]}, {"section": "Kinematics", "text": "We have used the fragmentation parameter, z, as defined in the literature, i.e.,", "cite_spans": [], "ref_spans": []}, {"section": "Kinematics", "text": "The last step follows form application of the infinite momentum frame.", "cite_spans": [], "ref_spans": []}, {"section": "Kinematics", "text": "Therefore, the final state particle energies are parameterized as follows", "cite_spans": [], "ref_spans": []}, {"section": "Kinematics", "text": "where", "cite_spans": [], "ref_spans": []}, {"section": "Kinematics", "text": "\u2022 is the energy of the baryon. Therefore", "cite_spans": [], "ref_spans": []}, {"section": "Kinematics", "text": "Here the x's are the energy ratios carried by the constituents. Since the constituents are identical and fly together, it is found that x 1 = x 2 = x 3 = 1/3. This is consistent with our argument about the wave function for such states in the next section. We also have assumed that the two anti-quarks which initiate the two jets have equal energies, i.e.", "cite_spans": [], "ref_spans": []}, {"section": "Kinematics", "text": "On the other hand due to our discussion about transverse momentum, we have", "cite_spans": [], "ref_spans": []}, {"section": "Kinematics", "text": "We will discuss this later assumption in the final section.", "cite_spans": [], "ref_spans": []}, {"section": "Calculation of the Fragmentation Functions for \u2126 QQQ", "text": "We are now ready to calculate the diagram shown in figure 1 . The fragmentation of a heavy quark Q into a heavy baryon \u2126 QQQ is obtained by squaring the total amplitude and integrating over final state phase space,", "cite_spans": [], "ref_spans": [{"start": 51, "end": 59, "text": "figure 1", "ref_id": "FIGREF0"}]}, {"section": "Calculation of the Fragmentation Functions for \u2126 QQQ", "text": "where T B is the amplitude of the baryon production which involves the hard scattering amplitude T H and the non-perturbative smearing of the bound state. The average over initial spin states and the sum over final spin states are performed. The heavy hadron production amplitude is composed of a partonic part, which can be calculated using perturbative QCD, and a non-perturbative part, which describes the transition of free quarks into the final state hadron. In the framework of non-relativistic quark model, this non-perturbative part could be accounted for through the wave function which is calculable using potential models. Since at present there is no known information concerning such wave functions, we have assumed a delta function type wave function for them. This assumption guarantees that the constituents will fly parallel and have no transverse momentum with respect to their direction of motion. This is also consistent with our assumptions in section 2. The hard scattering amplitude which is obtained by perturbative calculations of the tree diagram in figure 1 , may be put in the following form [9] ,", "cite_spans": [], "ref_spans": [{"start": 1076, "end": 1084, "text": "figure 1", "ref_id": "FIGREF0"}]}, {"section": "Calculation of the Fragmentation Functions for \u2126 QQQ", "text": "Here \u03b1 s = g 2 /4\u03c0 is the strong interaction coupling constant and \u0393 indicates that part of the amplitude which embeds spinors and gamma matrices. The 1/g's are the propagators of the two gluons and the intermediate fermion respectively.", "cite_spans": [], "ref_spans": []}, {"section": "Calculation of the Fragmentation Functions for \u2126 QQQ", "text": "To absorb the soft behavior of the bound state into hard scattering amplitude we have used the scheme introduced in [7] . The probability amplitude at large momentum transfer factories into a convolution of the hardscattering amplitude T H , and baryon-distribution amplitude \u03c6 M [10] , i.e.,", "cite_spans": [], "ref_spans": []}, {"section": "Calculation of the Fragmentation Functions for \u2126 QQQ", "text": "where T H is given by (8) and \u03c6 B is the probability amplitude to find quarks co-linear up to a scale q \u20322 in the baryonic bound state. In (9), x i 's are the momentum fractions carried by the constituent quarks and", "cite_spans": [], "ref_spans": []}, {"section": "Calculation of the Fragmentation Functions for \u2126 QQQ", "text": ". In view of our early discussion in this section, we propose the following expression for the probability amplitude", "cite_spans": [], "ref_spans": []}, {"section": "Calculation of the Fragmentation Functions for \u2126 QQQ", "text": "where m B is the baryon mass and f B refers to the characteristics of the baryon bound state and is similar to the meson bound state where the decay constant f M is introduced. Putting this expression and (8) in (9) and carrying out the necessary integrations, we find", "cite_spans": [], "ref_spans": []}, {"section": "Calculation of the Fragmentation Functions for \u2126 QQQ", "text": "Now we are able to obtain the fragmentation function in (7) as", "cite_spans": [], "ref_spans": []}, {"section": "Calculation of the Fragmentation Functions for \u2126 QQQ", "text": "Spin sum-average of \u0393\u0393 for Figure 1 is easily calculated using the RE-DUCE. To do the phase space integrations in (12), first we consider the integral,", "cite_spans": [], "ref_spans": [{"start": 27, "end": 35, "text": "Figure 1", "ref_id": "FIGREF0"}]}, {"section": "Calculation of the Fragmentation Functions for \u2126 QQQ", "text": "where", "cite_spans": [], "ref_spans": []}, {"section": "Calculation of the Fragmentation Functions for \u2126 QQQ", "text": "Also we note that", "cite_spans": [], "ref_spans": []}, {"section": "Calculation of the Fragmentation Functions for \u2126 QQQ", "text": "and", "cite_spans": [], "ref_spans": []}, {"section": "Calculation of the Fragmentation Functions for \u2126 QQQ", "text": "Here, instead of performing transverse momentum integrations, for simplicity we have replaced them by their average values. Putting all this back in (12), we obtain the fragmentation function as,", "cite_spans": [], "ref_spans": []}, {"section": "Calculation of the Fragmentation Functions for \u2126 QQQ", "text": "Here we have defined \u03be = p", "cite_spans": [], "ref_spans": []}, {"section": "Calculation of the Fragmentation Functions for \u2126 QQQ", "text": "comes from the propagators and have the following form", "cite_spans": [], "ref_spans": []}, {"section": "Calculation of the Fragmentation Functions for \u2126 QQQ", "text": "and f (z) is due to the energy denominator given by (14). Replacement of f (z) by g(z) which we have done in the original manuscript, changes the fragmentation function only slightly.", "cite_spans": [], "ref_spans": []}, {"section": "Calculation of the Fragmentation Functions for \u2126 QQQ", "text": "The fragmentation function D c\u2192\u2126 ccc (z, \u00b5 \u2022 ) and D b\u2192\u2126 bbb (z, \u00b5 \u2022 ) are easily obtained from the above by letting m = m c , m b and using appropriate f B , \u03b1 s and \u00b5 \u2022 values.", "cite_spans": [], "ref_spans": []}, {"section": "Results and Discussion", "text": "We were able to calculate the process of direct c and b quark fragmentation into \u2126 ccc and \u2126 bbb baryons. In doing so we had to follow certain assumptions. Firstly we have considered only the dominant contributing Feynman diagram in leading order. This assumption reduced the complexity and the length of the calculation and enabled us to obtain analytic forms of the fragmentation functions. Our second assumption concerns kinematics. We believe that the high momentum of the process has to be taken away in the forward direction and let the two antiquarks carry the transverse momentum of the initial heavy quark. Furthermore since they are identical, we have considered equal contribution from them both in magnitude an in direction. Therefore, we have established equations (5) and (6) and used them in our calculation. To see how our later assumption works, we have set the kinematics by allowing k and k \u2032 to share the jet energy-momentum. We have let k = x(1\u2212z)p \u2032 and k \u2032 = (1\u2212x)(1\u2212z)p \u2032 where x is a variable which is between zero and one. We have repeated our calculations and studied the behaviour of \u2126 ccc fragmentation function with the same parameters as before. It is revealed that as x increases, the function grows rapidly and gives the highest peak at x = 1/2. As x increases further, the peak falls rapidly. Since there is not much information about the wave functions of the triply heavy baryons at hand, we have reduced the non-perturbative smearing of the bound state to a delta function times a factor which is much like the meson decay constant. We have denoted this constant by f B and assumed to take 0.25 GeV both for \u2126 ccc and \u2126 bbb baryons.", "cite_spans": [], "ref_spans": []}, {"section": "Results and Discussion", "text": "In obtaining (17) we have not performed the transverse momentum integrations. Instead we have replaced the variables by their average values. However the numerical integration converges well for sufficiently large transverse momentum. Let us now sketch the behaviour of our frag- At leading order in \u03b1 s one has 1 0 P Q\u2192Q (z, \u00b5)dz = 0 [12] , and the evolution equation implies that the fragmentation probability 1 0 D Q\u2192B (z, \u00b5)dz does not evolve with the scale \u00b5. Therefore, the fragmentation probability is a universal characteristic of the production rates. The evolution only moves the z-distribution to small values of z. We have obtained this quantity for \u2126 ccc and \u2126 bbb using our fragmentation functions. The other relevant kinematical parameter is the average fragmentation parameter. Our results for the fragmentation probabilities and z appear in Table 1. It is seen that our analysis give very close z values for \u2126 ccc and \u2126 bbb . The fragmentation probabilities in Table 1 suggest that considerable event rate is expected both at the Tevatron and the LHC .", "cite_spans": [], "ref_spans": [{"start": 978, "end": 985, "text": "Table 1", "ref_id": "TABREF0"}]}], "bib_entries": {"BIBREF14": {"title": "Algebraic Computing with REDUCE", "authors": [{"first": "M", "middle": ["A H"], "last": "", "suffix": ""}, {"first": "Mac", "middle": [], "last": "Collum", "suffix": ""}, {"first": "Fransis", "middle": ["J"], "last": "Wright", "suffix": ""}], "year": 1991, "venue": "", "link": "123228641"}}, "ref_entries": {"FIGREF0": {"text": "Fig. 1. Feynman diagram illustrating the lowest order fragmentation of a heavy quark, Q, into a \u2126 QQQ baryon. The four momenta are labelled.", "type": "figure"}, "FIGREF1": {"text": "Fig. 2. The behavior of \u2126 ccc (solid) and \u2126 bbb (dashed) fragmentation function at the respective fragmentation scale.", "type": "figure"}, "TABREF0": {"text": "Fragmentation probability and z for different states.Frag. Prob. 2.789 \u00d7 10 5 6.459 \u00d7 10 7", "type": "table"}}}
{"paper_id": "18988046", "_pdf_hash": "bb6e50f3698c732c5b8bbaa92585f858f06c3d3e", "abstract": [], "body_text": [{"section": "", "text": "-Reduced EphB4 expression is observed during vein graft adaptation and is associated with increased venous wall thickening. These findings suggest that EphB4 may mediate normal adult venous endothelial cell (EC) function and vein graft adaptation. We therefore tested the functional significance of EphB4 using EC with genetically reduced EphB4 signaling. EC were isolated from EphB4 \u03e9/\u03e9 and EphB4 \u03e9/\u03ea mice. In vitro function was assessed through EC proliferation, migration, nitric oxide (NO) synthesis, and chemokine production. A mouse vein graft model was used to correlate in vitro findings with in vivo vein grafts. Smooth muscle cells (SMC) were subjected to proliferation and migration assays using EphB4 \u03e9/\u03e9 and EphB4 \u03e9/\u03ea EC-conditioned medium. EphB4", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "EC exhibited diminished proliferation (P \u03fd 0.0001, n \u03ed 6), migration (P \u03fd 0.0001, n \u03ed 3), and NO production (P \u03ed 0.0012, n \u03ed 3). EphB4 \u03e9/\u03ea EC had increased VEGF-A mRNA (P \u03ed 0.0006, n \u03ed 6) and protein (P \u03ed 0.0106, n \u03ed 3) as well as increased secretion of VEGF-A (P \u03ed 0.0010, n \u03ed 5), PDGF-BB (P \u03fd 0.0001, n \u03ed 6), and TGF-\u24241 (P \u03fd 0.0001, n \u03ed 6). EphB4 \u03e9/\u03ea -conditioned medium promoted SMC proliferation (P \u03fd 0.0001, n \u03ed 7) and migration (P \u03ed 0.0358, n \u03ed 3). Vein grafts and EphB4 \u03e9/\u03ea EC showed similarity with regard to VEGF-A and eNOS mRNA and protein expression. In conclusion, reduced venous EC EphB4 function is associated with a proangiogenic and mitogenic phenotype. EphB4 \u03e9/\u03ea EC have increased secretion of SMC mitogens and reduced NO production that correlate with the thickened neointima formed during vein graft adaptation. These findings suggest that EphB4 remains active in adult venous EC and that loss of EphB4 plays a role in vein graft adaptation.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "EphB4; venous endothelial cells; vein graft remodeling AUTOGENOUS SAPHENOUS VEIN placed into arterial circulation as a bypass graft remains the gold standard of surgical treatment for critical limb ischemia. Reduced patency is routinely observed with the use of prosthetic graft alternatives, and it is generally believed that this inferior performance occurs secondary to the lack of an intact, functional, antithrombotic endothelium (23) . Following arterialization, human vein grafts initially demonstrate outward remodeling, which in turn is followed by the progressive acquisition of wall stiffness (20) in a process that involves inflammation (21) . Despite adaptive changes, vein graft failure secondary to progressive neointimal hyperplasia remains a major clinical problem. Currently, little is known about the molecular biology of vein graft remodeling especially regarding the balance between necessary adaptation and aberrant venous remodeling that manifests as pathological neointimal hyperplasia and vein graft failure (22) .", "cite_spans": [{"start": 435, "end": 439, "text": "(23)", "ref_id": "BIBREF21"}, {"start": 604, "end": 608, "text": "(20)", "ref_id": "BIBREF18"}, {"start": 649, "end": 653, "text": "(21)", "ref_id": "BIBREF19"}, {"start": 1033, "end": 1037, "text": "(22)", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "", "text": "The molecular distinction between arterial and venous endothelial cells (EC) is determined during embryonic development, and this distinction persists in the adult vasculature (27) . EphB4, a receptor tyrosine kinase, is a marker of adult venous EC, whereas Ephrin-B2, membrane-bound ligand for EphB4, is predominantly expressed by arterial EC (1, 8, 27) . However, it is not currently clear whether EphB4 plays a role in adult EC or whether it is simply a retained embryonic venous cellular identity marker (12) . Analysis of patent human vein grafts has shown that placement of a vein into the arterial circulation results in the loss of EphB4 without an accompanying upregulation of arterial identity markers. This observation suggests that EphB4 may not just be a passive venous identity marker but rather an active mediator in adult EC homeostasis (12) .", "cite_spans": [{"start": 176, "end": 180, "text": "(27)", "ref_id": "BIBREF25"}, {"start": 344, "end": 347, "text": "(1,", "ref_id": "BIBREF0"}, {"start": 348, "end": 350, "text": "8,", "ref_id": "BIBREF7"}, {"start": 351, "end": 354, "text": "27)", "ref_id": "BIBREF25"}, {"start": 508, "end": 512, "text": "(12)", "ref_id": "BIBREF10"}, {"start": 853, "end": 857, "text": "(12)", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "", "text": "Furthermore, Muto et al. (18) have recently shown that EphB4 loss is associated with venous wall thickening and that stimulation of EphB4 signaling during vein graft adaptation facilitates both the preservation of venous identity as well as inhibition of wall thickening. These observations suggest that EphB4 is active in adult veins in vivo and that loss of EphB4 is critical for successful venous adaptation to the arterial environment. To test the functional significance of EphB4 activity in adult cells, we examined the effects of reduced EphB4 signaling on venous EC function in vitro and compared these changes to those that occur during vein graft adaptation in vivo.", "cite_spans": [{"start": 25, "end": 29, "text": "(18)", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "MATERIALS AND METHODS", "text": "Antibodies and reagents. Primary antibodies to the following antigens were obtained as follows: total-Akt, phospho-Akt, total-ERK1/2, phospho-ERK1/2, hsp90, VEGFR2, phosphotyrosine (Cell Signaling Technology, Danvers, MA); eNOS, phospho-eNOS, caveolin-1 (Cav-1; BD Biosciences, San Jose, CA), VEGF-A (Santa Cruz Biotechnology, Santa Cruz, CA), EphB4 (Abcam, Cambridge, MA); PCNA (Sigma-Aldrich, St. Louis, MO); BrdU Cell Proliferation Assay (Cell Signaling Technology); Dip Stain Kit (Volu-Sol, Salt Lake City, UT); and Ephrin-B2/Fc (R&D Systems, Minneapolis, MN).", "cite_spans": [], "ref_spans": []}, {"section": "MATERIALS AND METHODS", "text": "Isolation of mouse lung endothelial cells. All animal procedures were approved by Yale University's Institutional Animal Care and Use Committee and were performed in keeping with the National Institutes of Health ethical guidelines. Primary mouse lung EC were isolated as previously described (18) . Briefly, under sterile conditions, lung tissue was collected from 6-wk-old EphB4 \u03e9/\u03e9 and EphB4 \u03e9/\u03ea mice (8), minced in 0.1% collagenase, and further homogenized by repeated passage through a 14-gauge needle. After 48 h, cells were immortalized by infection with a retrovirus expressing the polyoma middle T antigen. A second sortation was performed using magnetic beads conjugated with anti-mouse CD31; EC were collected using a magnetic sorter, plated, and passaged for experimental use.", "cite_spans": [{"start": 293, "end": 297, "text": "(18)", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "MATERIALS AND METHODS", "text": "Primary vascular smooth muscle cell isolation. Primary mouse vascular smooth muscle cells (SMC) were isolated from the thoracic aortas of C57BL/6 mice using a combined collagenase and elastase digestion method (6) . Isolated cells were then cultured and used for experiment immediately following one passage.", "cite_spans": [{"start": 210, "end": 213, "text": "(6)", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "MATERIALS AND METHODS", "text": "Animal vein graft model. Fifteen-week-old C57BL/6 mice were used to generate in vivo matched vein and vein graft tissue as previously described (18) . In brief, thoracic inferior vena cava (IVC) was harvested from donor mice and transplanted into the infrarenal aorta of recipient mice using reverse interposition grafting. A 10-0 continuous running suture was used to fashion the vein graft anastomosis. All implanted vein grafts were followed by ultrasound to ensure graft patency. Thoracic IVC (vein) and vein graft samples were harvested at 1 wk postoperatively for protein analysis.", "cite_spans": [{"start": 144, "end": 148, "text": "(18)", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "MATERIALS AND METHODS", "text": "Agarose gel electrophoresis of DNA. Total DNA from EphB4", "cite_spans": [], "ref_spans": []}, {"section": "MATERIALS AND METHODS", "text": "and EphB4 \u03e9/\u03ea EC was isolated and amplified using primers as previously published (8) . DNA fragments were then separated out on a 5% agarose gel containing ethidium bromide, and a UV-light box was used for visualization.", "cite_spans": [{"start": 82, "end": 85, "text": "(8)", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "MATERIALS AND METHODS", "text": "ELISA assays. EphB4 \u03e9/\u03e9 and EphB4 \u03e9/\u03ea EC were plated at equal cell densities, and cell-conditioned media were collected following a 24-h period of incubation. Analysis of the conditioned media was then performed using mouse VEGF-A, PDGF-BB, and TGF-\u24241 ELISA assays (R&D Systems). Samples were analyzed in duplicate form, and assays were used as directed by the manufacturer's product protocol.", "cite_spans": [], "ref_spans": []}, {"section": "MATERIALS AND METHODS", "text": "BrdU SMC cell proliferation assay. EphB4 \u03e9/\u03e9 and EphB4 \u03e9/\u03ea EC were plated at equal cell densities, and cell culture supernatants were collected following a 24-h period of incubation. SMC were then seeded at 3 \u03eb 10 4 cells/well in a 96-well plate and incubated with serum-free medium (SFM), 10% fetal bovine serum (FBS), or supernatant from EphB4 \u03e9/\u03e9 and EphB4 \u03e9/\u03ea EC. BrdU solution was prepared according to the manufacturer's protocol and added into cell culture medium. SMC were then incubated for 24 h. BrdU SMC incorporation was assayed according to product protocol, with plate absorbance read at 450 nm.", "cite_spans": [], "ref_spans": []}, {"section": "MATERIALS AND METHODS", "text": "EC proliferating cell nuclear antigen (PCNA) proliferation assay. EphB4 \u03e9/\u03e9 and EphB4 \u03e9/\u03ea EC were seeded at equal cell densities (1 \u03eb 10 4 cells/100 l) and allowed to incubate overnight in FBScontaining culture medium. Following 24 h of incubation, cells were fixed, permeabilized, and incubated with anti-PCNA antibody according to manufacturer's protocol.", "cite_spans": [], "ref_spans": []}, {"section": "SMC migration assay. Prior to beginning SMC migration, EphB4", "text": "\u03e9/\u03e9 and EphB4 \u03e9/\u03ea EC were plated at equal cell densities, and cell culture supernatants were collected following a 24-h period of incubation. SMC were serum starved for 15 h before the migration assay. SMC migration was assessed using 8-m transwell inserts coated with type I collagen (Corning Life Science, Tewksbury, MA); SMC were placed in the transwell upper chambers in equal cell concentrations (1 \u03eb 10 5 cells/100 l). SFM, 10% FBS, and conditioned medium from EphB4 \u03e9/\u03e9 and EphB4 \u03e9/\u03ea EC were used for SMC chemoattraction; chemoattractants were placed in equal volumes into the lower transwell chambers. After 8 h of incubation the cells were fixed and stained. Nonmigratory SMC on the upper side of the insert were scraped off with cotton swabs, and the SMC that migrated onto the lower side of the insert were then counted using light microscopy.", "cite_spans": [], "ref_spans": []}, {"section": "SMC migration assay. Prior to beginning SMC migration, EphB4", "text": "Endothelial cell migration assay. EC migration was assessed in a similar manner. EC were serum starved for 15 h and plated in equal cell concentrations (1.5 \u03eb 10 5 cells/100 l) onto 8-m transwell inserts coated with 0.1% gelatin. SFM, Ephrin-B2/Fc (2 g/ml), and 10% FBS were used for chemoattractants.", "cite_spans": [], "ref_spans": []}, {"section": "SMC migration assay. Prior to beginning SMC migration, EphB4", "text": "Nitric oxide release analysis. Nitric oxide (NO) production by EC was analyzed as previously described (6, 18) . NO production at baseline and poststimulation with VEGF-A (20 ng/ml) was examined in EphB4 \u03e9/\u03e9 and EphB4 \u03e9/\u03ea EC after 24 h of incubation. Collected medium was then processed by a NO-specific chemiluminescence analyzer. Tube formation assay. Matrigel matrix (BD Biosciences, San Jose, CA) was applied to 24-well culture plates and prepared for use. EphB4 \u03e9/\u03e9 and EphB4 \u03e9/\u03ea EC were plated in equal densities (2 \u03eb 10 5 /300 l) with or without VEGF-A (20 ng/ml) and incubated for 18 h at 37\u00b0, 5% CO 2 atmosphere. Tube formation was quantified manually using light microscopy.", "cite_spans": [{"start": 103, "end": 106, "text": "(6,", "ref_id": "BIBREF5"}, {"start": 107, "end": 110, "text": "18)", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "SMC migration assay. Prior to beginning SMC migration, EphB4", "text": "Western blotting. Mouse vein and vein graft tissue were carefully harvested and snap frozen in liquid nitrogen, and protein was extracted using RIPA lysis buffer in combination with manual homogenization. Equal sample amounts of protein were fractionated in a SDS-polyacrylamide gel and then transferred to nitrocellulose. Membranes were then immunoblotted with appropriate primary and secondary antibodies, and membrane signals were detected using enhanced chemiluminescence technique.", "cite_spans": [], "ref_spans": []}, {"section": "SMC migration assay. Prior to beginning SMC migration, EphB4", "text": "Immunoprecipitation. EphB4 \u03e9/\u03e9 and EphB4 \u03e9/\u03ea EC were serum starved for 15 h and then stimulated with 2 g/ml of Ephrin-B2/Fc as previously described (18) . After quantification of individual protein concentrations, sample concentrations were normalized and diluted to 1.5 mg/ml. Samples were incubated overnight at 4\u00b0C with anti-EphB4 antibody and then precipitated with agarose G beads. Samples were subsequently analyzed by Western blot technique. Immunoblotting was performed for phosphotyrosine.", "cite_spans": [{"start": 148, "end": 152, "text": "(18)", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "SMC migration assay. Prior to beginning SMC migration, EphB4", "text": "PCR analysis. Following serum starvation, total RNA was isolated and purified from EphB4 \u03e9/\u03e9 and EphB4 \u03e9/\u03ea EC (RNeasy Mini Kit; Qiagen, Valencia, CA). Total RNA was then reverse transcribed and amplified (SuperScript III First-Strand Synthesis SuperMix; Invitrogen, Grand Island, NY). Primers were used as previously described (18) . Quantitative PCR was performed using duplicates of each sample, and expression values were standardized to control 18S values.", "cite_spans": [{"start": 327, "end": 331, "text": "(18)", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "SMC migration assay. Prior to beginning SMC migration, EphB4", "text": "Statistical analysis. Results are expressed as means \u03ee SE. Comparisons between groups were performed using analysis of variance (ANOVA) or unpaired t-tests as appropriate (Prism 5, GraphPad Software). P values \u05450.05 were considered statistically significant.", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Decreased EphB4 phosphorylation in EphB4", "text": "\u03e9/\u03ea EC. EC were isolated from both wild-type (EphB4 \u03e9/\u03e9 ) and EphB4 \u03e9/\u03ea mice; both EphB4 \u03e9/\u03e9 and EphB4 \u03e9/\u03ea EC expressed EphB4, consistent with a venous phenotype (Fig. 1) . Germline transmission of the original EphB4 locus mutation was confirmed through extraction of total DNA from EphB4 \u03e9/\u03e9 and EphB4 \u03e9/\u03ea EC. Agarose gel electrophoresis demonstrated that EC isolated from EphB4 \u03e9/\u03ea , but not from EphB4 \u03e9/\u03e9 , showed coexpression of EphB4 wild-type (310 base pairs) and EphB4 mutant (420 base pairs) loci (Fig. 1A) , the same germline mutation as previously described (8 (Fig. 2, A and B) . Increased VEGF-A protein expression in EphB4 \u03e9/\u03ea EC was similar to the increased VEGF-A protein expression in mouse vein grafts (Fig. 2C ). There were no differences in VEGFR2 mRNA or protein expression between EphB4 \u03e9/\u03e9 and EphB4 \u03e9/\u03ea EC (Fig. 2, D and E) , although there was diminished VEGFR2 protein expression in vein grafts (Fig. 2F) . Analysis of EC mRNA for VEGF-A autoregulated dual-specificity MAPK phosphatases DUSP1 and DUSP5 showed increased expression levels of both DUSP1 and DUSP5 in EphB4 \u03e9/\u03ea EC (Fig. 2, G and H) . These results are consistent with the finding of increased VEGF-A expression in EphB4 \u03e9/\u03ea EC, e.g., EphB4 is a negative regulator of VEGF-A expression in adult venous EC.", "cite_spans": [{"start": 569, "end": 571, "text": "(8", "ref_id": "BIBREF7"}], "ref_spans": [{"start": 162, "end": 170, "text": "(Fig. 1)", "ref_id": "FIGREF1"}, {"start": 506, "end": 515, "text": "(Fig. 1A)", "ref_id": "FIGREF1"}, {"start": 572, "end": 589, "text": "(Fig. 2, A and B)", "ref_id": "FIGREF2"}, {"start": 720, "end": 728, "text": "(Fig. 2C", "ref_id": "FIGREF2"}, {"start": 830, "end": 847, "text": "(Fig. 2, D and E)", "ref_id": "FIGREF2"}, {"start": 921, "end": 930, "text": "(Fig. 2F)", "ref_id": "FIGREF2"}, {"start": 1104, "end": 1121, "text": "(Fig. 2, G and H)", "ref_id": "FIGREF2"}]}, {"section": "Decreased EphB4 phosphorylation in EphB4", "text": "Reduced proliferation and migration in EphB4 \u03e9/\u03ea EC. Since VEGF-A expression was increased in EphB4 \u03e9/\u03ea EC (Fig. 2) , we examined ERK1/2 activity, a signaling pathway downstream of VEGF and associated with cell proliferation and migration. There were no differences in either phosphor- EC (*P \u03ed 0.0006; n \u03ed 6). B: bar graph of mean densitometry of VEGF-A protein expression levels in EphB4 \u03e9/\u03e9 and EphB4 \u03e9/\u03ea EC (*P \u03ed 0.0106; n \u03ed 3). Representative Western blot is shown below. C: bar graph of mean densitometry of VEGF-A protein expression levels in vein and vein graft (*P \u03ed 0.0002; n \u03ed 3). Representative Western blot is shown below. D: bar graph of mean VEGFR2 mRNA expression levels in EphB4 \u03e9/\u03e9 and EphB4 \u03e9/\u03ea EC (*P \u03ed 0.9697; n \u03ed 6). NS, not significant. E: bar graph of mean densitometry of VEGFR2 protein expression levels in EphB4 \u03e9/\u03e9 and EphB4 \u03e9/\u03ea EC (*P \u03ed 0.9595, n \u03ed 6). Representative Western blot is shown below. F: bar graph of mean densitometry of VEGFR2 protein expression levels in vein and vein graft (*P \u03ed 0.0377, n \u03ed 6). Representative Western blot is shown below. G: bar graph of mean DUSP1 mRNA expression levels in EphB4 \u03e9/\u03e9 and EphB4 \u03e9/\u03ea EC (*P \u03ed 0.0011, n \u03ed 6). H: bar graph of mean DUSP5 mRNA expression levels in EphB4 \u03e9/\u03e9 and EphB4 \u03e9/\u03ea EC (*P \u03ed 0.0008, n \u03ed 6).", "cite_spans": [], "ref_spans": [{"start": 107, "end": 115, "text": "(Fig. 2)", "ref_id": "FIGREF2"}]}, {"section": "ylated or total ERK1/2 protein expression between EphB4", "text": "\u03e9/\u03e9 and EphB4 \u03e9/\u03ea EC (Fig. 3A) . Conversely, consistent with our previous results showing increased ERK1/2 phosphorylation in rabbit vein grafts (29) and proliferation in vein grafts (12, 18) , there was increased phosphorylated ERK1/2 in vein grafts compared with veins (Fig. 3B) . EphB4 \u03e9/\u03ea EC showed a reduced rate of proliferation compared with EphB4 \u03e9/\u03e9 EC, both as assessed with direct cell counts (Fig. 3C ) as well as with assessment of PCNA-positive cells (Fig. 3D) . EphB4 \u03e9/\u03ea EC also showed decreased migration compared with EphB4 \u03e9/\u03e9 cells, both in response to Ephrin-B2/Fc as well as to FBS (Fig. 3E) . These results suggest that the overall increase in ERK1/2 activity in vein grafts (Fig. 3B) is not observed in EphB4 \u03e9/\u03ea EC, which show diminished proliferation and migration, and is consistent with the venous EC monolayer observed during vein graft adaptation (12, 18) .", "cite_spans": [{"start": 145, "end": 149, "text": "(29)", "ref_id": "BIBREF27"}, {"start": 183, "end": 187, "text": "(12,", "ref_id": "BIBREF10"}, {"start": 188, "end": 191, "text": "18)", "ref_id": "BIBREF16"}, {"start": 877, "end": 881, "text": "(12,", "ref_id": "BIBREF10"}, {"start": 882, "end": 885, "text": "18)", "ref_id": "BIBREF16"}], "ref_spans": [{"start": 21, "end": 30, "text": "(Fig. 3A)", "ref_id": "FIGREF3"}, {"start": 271, "end": 280, "text": "(Fig. 3B)", "ref_id": "FIGREF3"}, {"start": 404, "end": 412, "text": "(Fig. 3C", "ref_id": "FIGREF3"}, {"start": 465, "end": 474, "text": "(Fig. 3D)", "ref_id": "FIGREF3"}, {"start": 604, "end": 613, "text": "(Fig. 3E)", "ref_id": "FIGREF3"}, {"start": 698, "end": 707, "text": "(Fig. 3B)", "ref_id": "FIGREF3"}]}, {"section": "Increased angiogenesis and reduced NO production in EphB4", "text": "\u03e9/\u03ea EC. Since VEGF-A expression was increased in EphB4 \u03e9/\u03ea EC ( Fig. 2 ) but ERK1/2 activity was not (Fig. 3 ), we examined whether there was increased activity of the Akt pathway, which is also downstream of VEGF (7). EphB4 \u03e9/\u03ea EC showed increased phosphorylated Akt, without any changes in total Akt expression, compared with EphB4 \u03e9/\u03e9 EC (Fig. 4A) . Vein grafts had increased expression of both phosphorylated and total Akt compared with veins (Fig. 4B) . EphB4 \u03e9/\u03ea EC had decreased NO secretion, both under basal as well as under VEGF-stimulated conditions, compared with EphB4 \u03e9/\u03e9 EC (Fig. 4C) . In contrast, EphB4 \u03e9/\u03ea EC demonstrated increased tube formation with increased branch-point formation, both under basal as well under VEGF-A stimulated conditions, compared with EphB4 \u03e9/\u03e9 EC (Fig. 4D ). Since both VEGF-A expression as well as phosphorylated Akt were increased in EphB4 \u03e9/\u03ea EC, we examined patterns of eNOS expression. EphB4 \u03e9/\u03ea EC had similar amounts of eNOS mRNA transcripts compared with EphB4 \u03e9/\u03e9 EC (Fig. 4E) . However, there was reduced expression of both phosphorylated and total eNOS in EphB4 \u03e9/\u03ea compared with EphB4 \u03e9/\u03e9 EC (Fig. 4F) , similar to the reduced expression of phosphorylated and total eNOS observed in vein grafts (Fig. 4G) .", "cite_spans": [], "ref_spans": [{"start": 64, "end": 70, "text": "Fig. 2", "ref_id": "FIGREF2"}, {"start": 101, "end": 108, "text": "(Fig. 3", "ref_id": "FIGREF3"}, {"start": 341, "end": 350, "text": "(Fig. 4A)", "ref_id": "FIGREF4"}, {"start": 447, "end": 456, "text": "(Fig. 4B)", "ref_id": "FIGREF4"}, {"start": 589, "end": 598, "text": "(Fig. 4C)", "ref_id": "FIGREF4"}, {"start": 792, "end": 800, "text": "(Fig. 4D", "ref_id": "FIGREF4"}, {"start": 1021, "end": 1030, "text": "(Fig. 4E)", "ref_id": "FIGREF4"}, {"start": 1149, "end": 1158, "text": "(Fig. 4F)", "ref_id": "FIGREF4"}, {"start": 1252, "end": 1261, "text": "(Fig. 4G)", "ref_id": "FIGREF4"}]}, {"section": "Increased angiogenesis and reduced NO production in EphB4", "text": "Since eNOS phosphorylation and NO production were both reduced in EphB4 \u03e9/\u03ea EC compared with EphB4 \u03e9/\u03e9 EC (Fig.  4, F and C) , we examined hsp90, a regulatory facilitator of Cav-1 displacement from eNOS. Expression of hsp90 was reduced, and expression of the eNOS inhibitor Cav-1 was elevated in EphB4 \u03e9/\u03ea EC compared with EphB4 \u03e9/\u03e9 EC (Fig.  4, H and J) . These changes in hsp90 and Cav-1 expression were in contrast to vein grafts, in which no changes in hsp90 were observed (Fig. 4I) and Cav-1 protein levels were diminished (Fig. 4K) .", "cite_spans": [], "ref_spans": [{"start": 106, "end": 124, "text": "(Fig.  4, F and C)", "ref_id": "FIGREF4"}, {"start": 336, "end": 354, "text": "(Fig.  4, H and J)", "ref_id": "FIGREF4"}, {"start": 477, "end": 486, "text": "(Fig. 4I)", "ref_id": "FIGREF4"}, {"start": 528, "end": 537, "text": "(Fig. 4K)", "ref_id": "FIGREF4"}]}, {"section": "Increased SMC mitogens and chemoattractants secreted by EphB4", "text": "\u03e9/\u03ea EC. Since EphB4 \u03e9/\u03ea EC have diminished proliferation and migration (Fig. 3) as well as diminished NO secretion and eNOS phosphorylation (Fig. 4) , we hypothesized that EphB4 \u03e9/\u03ea EC may be a functional model of the EC monolayer in vein grafts. Since vein grafts show increased neointimal volume (12, 18) , increased VEGF-A expression (Fig. 2C) , and ERK1/2 phosphorylation (Fig. 3B) , we examined EphB4 \u03e9/\u03ea EC for production of SMC mitogens and chemoattractants that could account for these observations. ELISA of EC-conditioned medium showed increased levels of VEGF-A, PDGF- BB, and TGF-\u24241 proteins secreted by EphB4 \u03e9/\u03ea EC compared with the amounts secreted EphB4 \u03e9/\u03e9 EC (Fig. 5, A-C) . Similarly, mRNA transcript numbers of VEGF-A, PDGF-BB, and TGF-\u24241 were increased in EphB4 \u03e9/\u03ea EC compared with EphB4 \u03e9/\u03e9 EC (Fig. 5, D-F) . SMC showed increased chemotaxis when stimulated with medium conditioned by EphB4 \u03e9/\u03ea EC compared with SFM or medium conditioned by EphB4 \u03e9/\u03e9 EC (Fig. 5G) . Similarly, SMC stimulated with conditioned medium from EphB4 \u03e9/\u03ea EC had increased proliferation compared with SMC stimulated with SFM or conditioned medium from EphB4 \u03e9/\u03e9 EC (Fig. 5H) . These results are consistent with EphB4 \u03e9/\u03ea EC secreting increased levels of SMC chemoattractants and mitogens compared with EphB4 \u03e9/\u03e9 EC.", "cite_spans": [{"start": 298, "end": 302, "text": "(12,", "ref_id": "BIBREF10"}, {"start": 303, "end": 306, "text": "18)", "ref_id": "BIBREF16"}], "ref_spans": [{"start": 71, "end": 79, "text": "(Fig. 3)", "ref_id": "FIGREF3"}, {"start": 140, "end": 148, "text": "(Fig. 4)", "ref_id": "FIGREF4"}, {"start": 337, "end": 346, "text": "(Fig. 2C)", "ref_id": "FIGREF2"}, {"start": 376, "end": 385, "text": "(Fig. 3B)", "ref_id": "FIGREF3"}, {"start": 677, "end": 690, "text": "(Fig. 5, A-C)", "ref_id": "FIGREF5"}, {"start": 817, "end": 830, "text": "(Fig. 5, D-F)", "ref_id": "FIGREF5"}, {"start": 977, "end": 986, "text": "(Fig. 5G)", "ref_id": "FIGREF5"}, {"start": 1163, "end": 1172, "text": "(Fig. 5H)", "ref_id": "FIGREF5"}]}, {"section": "DISCUSSION", "text": "To examine the effects of EphB4 function in venous EC, we compared several functions of EphB4 \u03e9/\u03ea EC to those of EphB4 \u03e9/\u03e9 EC. Our data suggest that EphB4 \u03e9/\u03ea EC have several properties that are consistently different; in particular, EphB4 \u03e9/\u03ea EC have decreased rates of proliferation and migration (Fig. 3) , diminished EphB4 phosphorylation (Fig. 1) , increased VEGF-A synthesis (Fig. 2) and secretion (Fig. 5) , increased DUSP1 and DUSP5 expression (Fig. 2) , decreased eNOS expression and phosphorylation (Fig. 4) as well as decreased hsp90 expression and increased caveolin-1 expression (Fig. 4) . EphB4 \u03e9/\u03ea EC also demonstrate increased secretion of SMC chemoattractants and mitogens compared with EphB4 \u03e9/\u03e9 EC, particularly VEGF-A, PDGF-BB, and TGF-\u24241 (Fig. 5) . These data suggest that EphB4 has numerous effects in adult venous EC and may play an active role in cell physiology, rather than just being a passive marker of venous identity.", "cite_spans": [], "ref_spans": [{"start": 299, "end": 307, "text": "(Fig. 3)", "ref_id": "FIGREF3"}, {"start": 343, "end": 351, "text": "(Fig. 1)", "ref_id": "FIGREF1"}, {"start": 381, "end": 389, "text": "(Fig. 2)", "ref_id": "FIGREF2"}, {"start": 404, "end": 412, "text": "(Fig. 5)", "ref_id": "FIGREF5"}, {"start": 452, "end": 460, "text": "(Fig. 2)", "ref_id": "FIGREF2"}, {"start": 509, "end": 517, "text": "(Fig. 4)", "ref_id": "FIGREF4"}, {"start": 592, "end": 600, "text": "(Fig. 4)", "ref_id": "FIGREF4"}, {"start": 759, "end": 767, "text": "(Fig. 5)", "ref_id": "FIGREF5"}]}, {"section": "DISCUSSION", "text": "There are similarities between the changes in EphB4 \u03e9/\u03ea EC compared with EphB4 \u03e9/\u03e9 EC with those found in vein grafts compared with veins. In particular, both EphB4 \u03e9/\u03ea EC as well as vein grafts show diminished EphB4 function (12, 18; Fig.  1 ). In addition, both EphB4 \u03e9/\u03ea EC as well as vein grafts show increased VEGF-A expression (Fig. 2) , increased Akt phosphorylation (Fig. 4) , and diminished eNOS phosphorylation and expression (Fig. 4) . We believe that these similarities reflect the altered physiological states of both EphB4 \u03e9/\u03ea EC as well as vein grafts and suggest that both loss of EphB4, as well as exposure to the arterial environment in vivo, result in venous EC stress that requires an adaptive response. In particular, diminished NO and increased Akt activation suggest adaptation to stress stimuli (9, 19) , or they may simply reflect diminished eNOS activation with upstream compensation. However, our examination of vein grafts at only a single time point of 1 wk after implantation suggests that additional similarities might be found at other time points. Nevertheless, our finding that reduced levels of EphB4 in EC results in several changes that recapitulate vein graft adaptation suggests that our hypothesis, that EphB4 is active in adult venous EC, is correct.", "cite_spans": [{"start": 819, "end": 822, "text": "(9,", "ref_id": "BIBREF8"}, {"start": 823, "end": 826, "text": "19)", "ref_id": "BIBREF17"}], "ref_spans": [{"start": 235, "end": 242, "text": "Fig.  1", "ref_id": "FIGREF1"}, {"start": 333, "end": 341, "text": "(Fig. 2)", "ref_id": "FIGREF2"}, {"start": 374, "end": 382, "text": "(Fig. 4)", "ref_id": "FIGREF4"}, {"start": 436, "end": 444, "text": "(Fig. 4)", "ref_id": "FIGREF4"}]}, {"section": "DISCUSSION", "text": "On the other hand, there are several differences between EphB4 \u03e9/\u03ea EC and vein grafts, which are summarized in Table 1 . Since vein grafts are composed largely of cells that are not EC, these differences suggest potential functions of vein grafts that are due to the SMC, and other non-EC cell types, rather than the EC monolayer. For example, increase ERK activation in vein grafts (Fig. 3B) suggests that vein graft proliferation is largely due to increases in SMC and other non-EC cell proliferation, consistent with the findings that vein grafts retain a single-cell EC monolayer (2, 12, 18) . Examination of the vein graft at other times beyond 1 wk after implantation might also show additional similarities and differences between EphB4 \u03e9/\u03ea EC and vein grafts; however, early transcriptional changes after implantation, such as for VEGF-A and EphB4, are stable between 1 and 3 wk after implantation (12) .", "cite_spans": [{"start": 584, "end": 587, "text": "(2,", "ref_id": "BIBREF1"}, {"start": 588, "end": 591, "text": "12,", "ref_id": "BIBREF10"}, {"start": 592, "end": 595, "text": "18)", "ref_id": "BIBREF16"}, {"start": 906, "end": 910, "text": "(12)", "ref_id": "BIBREF10"}], "ref_spans": [{"start": 111, "end": 118, "text": "Table 1", "ref_id": "TABREF2"}, {"start": 383, "end": 392, "text": "(Fig. 3B)", "ref_id": "FIGREF3"}]}, {"section": "DISCUSSION", "text": "Diminished EphB4 function appears to result in a cellular phenotype that has some proangiogenic properties, e.g., increased VEGF-A expression, increased tube formation, and increased secretion of SMC mitogens and chemoattractants. In addition, diminished eNOS phosphorylation and NO secretion may also be consistent with this phenotype (3, 11) . It is not clear whether these cellular characteristics are due to differences in activation of pathways downstream from EphB4, whether these pathways require complete suppression for phenotype emergence, or whether other factors are superimposed. The normal histology of veins in EphB4 heterozygous mice (18) suggests that reduced levels of EphB4 activity are sufficient for many of its functions, which is not surprising since complete reduction of EphB4 activity is lethal during embryonic development (27) , providing rationale for redundancy of any putative functions.", "cite_spans": [{"start": 336, "end": 339, "text": "(3,", "ref_id": "BIBREF2"}, {"start": 340, "end": 343, "text": "11)", "ref_id": "BIBREF9"}, {"start": 650, "end": 654, "text": "(18)", "ref_id": "BIBREF16"}, {"start": 850, "end": 854, "text": "(27)", "ref_id": "BIBREF25"}], "ref_spans": []}, {"section": "DISCUSSION", "text": "Increased VEGF-A expression has been previously reported at early times during vein graft adaptation (10, 12, 28) and is consistent with our current findings in both vein grafts as well as EphB4 \u03e9/\u03ea EC (Fig. 2) . The significance of early increases in VEGF-A during vein graft adaptation is not well understood. VEGF-A may play a protective role in preventing intimal hyperplasia (10, 16), but it may also be a mediator of aberrant SMC proliferation and stimulus of intimal hyperplasia (28) . Since VEGF-A stimulates both ERK and Akt activity (13, 14, 17, 24) , our finding of differential effects on ERK (Fig. 3) and Akt (Fig. 4) activation between EphB4 \u03e9/\u03ea EC and vein grafts suggests differential response to VEGF-A in the different cell types of the vein graft and is consistent with SMC having greater proliferation than EC in vein grafts. On the other hand, Akt activation in EC (Fig. 4A) but not in vein grafts (Fig. 4B) suggests the importance of the Akt pathway in EC responses as is observed with shear stress Akt activation in EC and the downstream activation of eNOS and resulting NO production (4, 26) . The paracrine interactions between EC and SMC during vein graft adaptation complicate the interpretation of our vein graft data; however, our findings that EC secrete SMC mitogens and chemoattractants (Fig. 5 ) are consistent with a role for EphB4 in regulating this process. ", "cite_spans": [{"start": 106, "end": 109, "text": "12,", "ref_id": "BIBREF10"}, {"start": 110, "end": 113, "text": "28)", "ref_id": "BIBREF26"}, {"start": 486, "end": 490, "text": "(28)", "ref_id": "BIBREF26"}, {"start": 543, "end": 547, "text": "(13,", "ref_id": "BIBREF11"}, {"start": 548, "end": 551, "text": "14,", "ref_id": "BIBREF12"}, {"start": 552, "end": 555, "text": "17,", "ref_id": "BIBREF15"}, {"start": 556, "end": 559, "text": "24)", "ref_id": "BIBREF22"}, {"start": 1108, "end": 1111, "text": "(4,", "ref_id": "BIBREF3"}, {"start": 1112, "end": 1115, "text": "26)", "ref_id": "BIBREF24"}], "ref_spans": [{"start": 202, "end": 210, "text": "(Fig. 2)", "ref_id": "FIGREF2"}, {"start": 605, "end": 613, "text": "(Fig. 3)", "ref_id": "FIGREF3"}, {"start": 622, "end": 630, "text": "(Fig. 4)", "ref_id": "FIGREF4"}, {"start": 886, "end": 895, "text": "(Fig. 4A)", "ref_id": "FIGREF4"}, {"start": 919, "end": 928, "text": "(Fig. 4B)", "ref_id": "FIGREF4"}, {"start": 1319, "end": 1326, "text": "(Fig. 5", "ref_id": "FIGREF5"}]}], "bib_entries": {"BIBREF0": {"title": "Roles of ephrinB ligands and EphB receptors in cardiovascular development: demarcation of arterial/venous domains, vascular morphogenesis, and sprouting angiogenesis", "authors": [{"first": "R", "middle": ["H"], "last": "Adams", "suffix": ""}, {"first": "G", "middle": ["A"], "last": "Wilkinson", "suffix": ""}, {"first": "C", "middle": [], "last": "Weiss", "suffix": ""}, {"first": "F", "middle": [], "last": "Diella", "suffix": ""}, {"first": "N", "middle": ["W"], "last": "Gale", "suffix": ""}, {"first": "U", "middle": [], "last": "Deutsch", "suffix": ""}, {"first": "W", "middle": [], "last": "Risau", "suffix": ""}, {"first": "R", "middle": [], "last": "Klein", "suffix": ""}], "year": 1999, "venue": "Genes Dev", "link": "25052726"}, "BIBREF1": {"title": "Human venous endothelium can promote intimal hyperplasia in a paracrine manner", "authors": [{"first": "K", "middle": ["E"], "last": "Allen", "suffix": ""}, {"first": "K", "middle": [], "last": "Varty", "suffix": ""}, {"first": "L", "middle": [], "last": "Jones", "suffix": ""}, {"first": "R", "middle": ["D"], "last": "Sayers", "suffix": ""}, {"first": "P", "middle": ["R"], "last": "Bell", "suffix": ""}, {"first": "N", "middle": ["J"], "last": "London", "suffix": ""}], "year": 1994, "venue": "J Vasc Surg", "link": "25933548"}, "BIBREF2": {"title": "Chronic inhibition of nitric oxide production accelerates neointima formation and impairs endothelial function in hypercholesterolemic rabbits", "authors": [{"first": "A", "middle": ["J"], "last": "Cayatte", "suffix": ""}, {"first": "J", "middle": ["J"], "last": "Palacino", "suffix": ""}, {"first": "K", "middle": [], "last": "Horten", "suffix": ""}, {"first": "R", "middle": ["A"], "last": "Cohen", "suffix": ""}], "year": 1994, "venue": "Arterioscler Thromb", "link": "7162885"}, "BIBREF3": {"title": "Activation of nitric oxide synthase in endothelial cells by Aktdependent phosphorylation", "authors": [{"first": "S", "middle": [], "last": "Dimmeler", "suffix": ""}, {"first": "I", "middle": [], "last": "Fleming", "suffix": ""}, {"first": "B", "middle": [], "last": "Fisslthaler", "suffix": ""}, {"first": "C", "middle": [], "last": "Hermann", "suffix": ""}, {"first": "R", "middle": [], "last": "Busse", "suffix": ""}, {"first": "A", "middle": ["M"], "last": "Zeiher", "suffix": ""}], "year": 1999, "venue": "Nature", "link": "4409727"}, "BIBREF4": {"title": "Absence of Akt1 reduces vascular smooth muscle cell migration and survival and induces features of plaque vulnerability and cardiac dysfunction during atherosclerosis", "authors": [{"first": "C", "middle": [], "last": "Fern\u00e1ndez-Hernando", "suffix": ""}, {"first": "L", "middle": [], "last": "J\u00f3zsef", "suffix": ""}, {"first": "D", "middle": [], "last": "Jenkins", "suffix": ""}, {"first": "Di", "middle": [], "last": "Lorenzo", "suffix": ""}, {"first": "A", "middle": [], "last": "Sessa", "suffix": ""}, {"first": "W", "middle": ["C"], "last": "", "suffix": ""}], "year": 2009, "venue": "Arterioscler Thromb Vasc Biol", "link": "8148123"}, "BIBREF5": {"title": "Identification of Golgi-localized acyl transferases that palmitoylate and regulate endothelial nitric oxide synthase", "authors": [{"first": "C", "middle": [], "last": "Fern\u00e1ndez-Hernando", "suffix": ""}, {"first": "M", "middle": [], "last": "Fukata", "suffix": ""}, {"first": "P", "middle": ["N"], "last": "Bernatchez", "suffix": ""}, {"first": "Y", "middle": [], "last": "Fukata", "suffix": ""}, {"first": "M", "middle": ["I"], "last": "Lin", "suffix": ""}, {"first": "D", "middle": ["S"], "last": "Bredt", "suffix": ""}, {"first": "W", "middle": ["C"], "last": "Sessa", "suffix": ""}], "year": 2006, "venue": "J Cell Biol", "link": "15452602"}, "BIBREF6": {"title": "Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3=-kinase/Akt signal transduction pathway. Requirement for Flk-1/KDR activation", "authors": [{"first": "H", "middle": ["P"], "last": "Gerber", "suffix": ""}, {"first": "A", "middle": [], "last": "Mcmurtrey", "suffix": ""}, {"first": "J", "middle": [], "last": "Kowalski", "suffix": ""}, {"first": "M", "middle": [], "last": "Yan", "suffix": ""}, {"first": "B", "middle": ["A"], "last": "Keyt", "suffix": ""}, {"first": "V", "middle": [], "last": "Dixit", "suffix": ""}, {"first": "N", "middle": [], "last": "Ferrara", "suffix": ""}], "year": 1998, "venue": "J Biol Chem", "link": "20438241"}, "BIBREF7": {"title": "Symmetrical mutant phenotypes of the receptor EphB4 and its specific transmembrane ligand ephrin-B2 in cardiovascular development", "authors": [{"first": "S", "middle": ["S"], "last": "Gerety", "suffix": ""}, {"first": "H", "middle": ["U"], "last": "Wang", "suffix": ""}, {"first": "Z", "middle": ["F"], "last": "Chen", "suffix": ""}, {"first": "D", "middle": ["J"], "last": "Anderson", "suffix": ""}], "year": 1999, "venue": "Mol Cell", "link": "45794865"}, "BIBREF8": {"title": "Modulation of phosphatidylinositol 3-kinase signaling reduces intimal hyperplasia in aortocoronary saphenous vein grafts", "authors": [{"first": "J", "middle": ["A"], "last": "Hata", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Petrofski", "suffix": ""}, {"first": "J", "middle": ["N"], "last": "Schroder", "suffix": ""}, {"first": "M", "middle": ["L"], "last": "Williams", "suffix": ""}, {"first": "S", "middle": ["H"], "last": "Timberlake", "suffix": ""}, {"first": "A", "middle": [], "last": "Pippen", "suffix": ""}, {"first": "M", "middle": ["T"], "last": "Corwin", "suffix": ""}, {"first": "A", "middle": ["K"], "last": "Solan", "suffix": ""}, {"first": "A", "middle": [], "last": "Jakoi", "suffix": ""}, {"first": "T", "middle": ["R"], "last": "Gehrig", "suffix": ""}, {"first": "C", "middle": ["D"], "last": "Kontos", "suffix": ""}, {"first": "C", "middle": ["A"], "last": "Milano", "suffix": ""}, {"first": "A", "middle": ["D"], "last": "Hamdan", "suffix": ""}, {"first": "L", "middle": ["P"], "last": "Aiello", "suffix": ""}, {"first": "B", "middle": ["D"], "last": "Misare", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Contreras", "suffix": ""}, {"first": "G", "middle": ["L"], "last": "King", "suffix": ""}, {"first": "F", "middle": ["W"], "last": "Logerfo", "suffix": ""}, {"first": "W", "middle": ["C"], "last": "Quist", "suffix": ""}], "year": 1997, "venue": "J Thorac Cardiovasc Surg", "link": "13480592"}, "BIBREF9": {"title": "Human endothelial nitric oxide synthase gene transfer inhibits vascular smooth muscle cell proliferation and neointima formation after balloon injury in rats", "authors": [{"first": "S", "middle": [], "last": "Janssens", "suffix": ""}, {"first": "D", "middle": [], "last": "Flaherty", "suffix": ""}, {"first": "Z", "middle": [], "last": "Nong", "suffix": ""}, {"first": "O", "middle": [], "last": "Varenne", "suffix": ""}, {"first": "N", "middle": [], "last": "Van Pelt", "suffix": ""}, {"first": "C", "middle": [], "last": "Haustermans", "suffix": ""}, {"first": "P", "middle": [], "last": "Zoldhelyi", "suffix": ""}, {"first": "R", "middle": [], "last": "Gerard", "suffix": ""}, {"first": "Collen", "middle": ["D"], "last": "", "suffix": ""}], "year": 1998, "venue": "Circulation", "link": "25474141"}, "BIBREF10": {"title": "Venous identity is lost but arterial identity is not gained during vein graft adaptation", "authors": [{"first": "F", "middle": ["A"], "last": "Kudo", "suffix": ""}, {"first": "A", "middle": [], "last": "Muto", "suffix": ""}, {"first": "S", "middle": ["P"], "last": "Maloney", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Pimiento", "suffix": ""}, {"first": "S", "middle": [], "last": "Bergaya", "suffix": ""}, {"first": "T", "middle": ["N"], "last": "Fitzgerald", "suffix": ""}, {"first": "T", "middle": ["S"], "last": "Westvik", "suffix": ""}, {"first": "J", "middle": ["C"], "last": "Frattini", "suffix": ""}, {"first": "C", "middle": ["K"], "last": "Breuer", "suffix": ""}, {"first": "C", "middle": ["H"], "last": "Cha", "suffix": ""}, {"first": "T", "middle": [], "last": "Nishibe", "suffix": ""}, {"first": "G", "middle": [], "last": "Tellides", "suffix": ""}, {"first": "W", "middle": ["C"], "last": "Sessa", "suffix": ""}, {"first": "A", "middle": [], "last": "Dardik", "suffix": ""}], "year": 2007, "venue": "Arterioscler Thromb Vasc Biol", "link": "6636486"}, "BIBREF11": {"title": "VEGF increases permeability of the endothelial cell monolayer by activation of PKB/akt, endothelial nitric-oxide synthase, and MAP kinase pathways", "authors": [{"first": "B", "middle": ["K"], "last": "Lal", "suffix": ""}, {"first": "S", "middle": [], "last": "Varma", "suffix": ""}, {"first": "P", "middle": ["J"], "last": "Pappas", "suffix": ""}, {"first": "", "middle": [], "last": "Hobson Rw 2nd", "suffix": ""}, {"first": "W", "middle": ["N"], "last": "Dur\u00e1n", "suffix": ""}], "year": 2001, "venue": "Microvasc Res", "link": "35902587"}, "BIBREF12": {"title": "ERK activation and mitogenesis in human airway smooth muscle cells", "authors": [{"first": "J", "middle": ["H"], "last": "Lee", "suffix": ""}, {"first": "P", "middle": ["R"], "last": "Johnson", "suffix": ""}, {"first": "M", "middle": [], "last": "Roth", "suffix": ""}, {"first": "N", "middle": ["H"], "last": "Hunt", "suffix": ""}, {"first": "J", "middle": ["L"], "last": "Black", "suffix": ""}], "year": 2001, "venue": "Am J Physiol Lung Cell Mol Physiol", "link": "1873833"}, "BIBREF13": {"title": "Molecular basis of the effects of shear stress on vascular endothelial cells", "authors": [{"first": "Y", "middle": ["S"], "last": "Li", "suffix": ""}, {"first": "J", "middle": ["H"], "last": "Haga", "suffix": ""}, {"first": "S", "middle": [], "last": "Chien", "suffix": ""}], "year": 2005, "venue": "J Biomech", "link": "6189400"}, "BIBREF14": {"title": "Reduction of vein graft intimal hyperplasia and preservation of endothelium-dependent relaxation by topical vascular endothelial growth factor", "authors": [{"first": "Z", "middle": [], "last": "Luo", "suffix": ""}, {"first": "T", "middle": [], "last": "Asahara", "suffix": ""}, {"first": "Y", "middle": [], "last": "Tsurumi", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Isner", "suffix": ""}, {"first": "J", "middle": ["F"], "last": "Symes", "suffix": ""}], "year": 1998, "venue": "J Vasc Surg", "link": "29649273"}, "BIBREF15": {"title": "Vascular endothelial growth factor-stimulated actin reorganization and migration of endothelial cells is regulated via the serine/ threonine kinase Akt", "authors": [{"first": "M", "middle": [], "last": "Morales-Ruiz", "suffix": ""}, {"first": "D", "middle": [], "last": "Fulton", "suffix": ""}, {"first": "G", "middle": [], "last": "Sowa", "suffix": ""}, {"first": "L", "middle": ["R"], "last": "Languino", "suffix": ""}, {"first": "Y", "middle": [], "last": "Fujio", "suffix": ""}, {"first": "K", "middle": [], "last": "Walsh", "suffix": ""}, {"first": "W", "middle": ["C"], "last": "Sessa", "suffix": ""}], "year": 2000, "venue": "Circ Res", "link": "23971037"}, "BIBREF16": {"title": "Eph-B4 prevents venous adaptive remodeling in the adult arterial environment", "authors": [{"first": "A", "middle": [], "last": "Muto", "suffix": ""}, {"first": "T", "middle": [], "last": "Yi", "suffix": ""}, {"first": "K", "middle": ["D"], "last": "Harrison", "suffix": ""}, {"first": "A", "middle": [], "last": "D\u00e1valos", "suffix": ""}, {"first": "T", "middle": ["T"], "last": "Fancher", "suffix": ""}, {"first": "K", "middle": ["R"], "last": "Ziegler", "suffix": ""}, {"first": "A", "middle": [], "last": "Feigel", "suffix": ""}, {"first": "Y", "middle": [], "last": "Kondo", "suffix": ""}, {"first": "T", "middle": [], "last": "Nishibe", "suffix": ""}, {"first": "W", "middle": ["C"], "last": "Sessa", "suffix": ""}, {"first": "A", "middle": [], "last": "Dardik", "suffix": ""}], "year": 2011, "venue": "J Exp Med", "link": "5951936"}, "BIBREF17": {"title": "Intracellular oxidative stress induced by nitric oxide synthesis inhibition increases endothelial cell adhesion to neutrophils", "authors": [{"first": "X", "middle": ["F"], "last": "Niu", "suffix": ""}, {"first": "C", "middle": ["W"], "last": "Smith", "suffix": ""}, {"first": "P", "middle": [], "last": "Kubes", "suffix": ""}], "year": 1994, "venue": "Circ Res", "link": "799180"}, "BIBREF18": {"title": "Early biomechanical changes in lower extremity vein grafts-distinct temporal phases of remodeling and wall stiffness", "authors": [{"first": "C", "middle": ["D"], "last": "Owens", "suffix": ""}, {"first": "N", "middle": [], "last": "Wake", "suffix": ""}, {"first": "J", "middle": ["G"], "last": "Jacot", "suffix": ""}, {"first": "M", "middle": [], "last": "Gerhard-Herman", "suffix": ""}, {"first": "P", "middle": [], "last": "Gaccione", "suffix": ""}, {"first": "M", "middle": [], "last": "Belkin", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Creager", "suffix": ""}, {"first": "Conte", "middle": [], "last": "Owens", "suffix": ""}, {"first": "C", "middle": ["D"], "last": "Ms", "suffix": ""}, {"first": "Wake", "middle": ["N"], "last": "Jacot", "suffix": ""}, {"first": "J", "middle": ["G"], "last": "Gerhard-Herman", "suffix": ""}, {"first": "M", "middle": [], "last": "Gaccione", "suffix": ""}, {"first": "P", "middle": [], "last": "Belkin", "suffix": ""}, {"first": "M", "middle": [], "last": "Creager", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Conte", "suffix": ""}, {"first": "M", "middle": ["S"], "last": "", "suffix": ""}], "year": 2006, "venue": "J Vasc Surg", "link": "41759270"}, "BIBREF19": {"title": "Early remodeling of lower extremity vein grafts: inflammation influences biomechanical adaptation", "authors": [{"first": "C", "middle": ["D"], "last": "Owens", "suffix": ""}, {"first": "F", "middle": ["J"], "last": "Rybicki", "suffix": ""}, {"first": "N", "middle": [], "last": "Wake", "suffix": ""}, {"first": "A", "middle": [], "last": "Schanzer", "suffix": ""}, {"first": "D", "middle": [], "last": "Mitsouras", "suffix": ""}, {"first": "M", "middle": ["D"], "last": "Gerhardherman", "suffix": ""}, {"first": "M", "middle": ["S"], "last": "Conte", "suffix": ""}], "year": 2008, "venue": "J Vasc Surg", "link": "7431496"}, "BIBREF20": {"title": "Adaptive changes in autogenous vein grafts for arterial reconstruction: clinical implications", "authors": [{"first": "C", "middle": ["D"], "last": "Owens", "suffix": ""}], "year": 2010, "venue": "J Vasc Surg", "link": "36506770"}, "BIBREF21": {"title": "Long-term results of in situ saphenous vein bypass. Analysis of 2058 cases", "authors": [{"first": "D", "middle": ["M"], "last": "Shah", "suffix": ""}, {"first": "", "middle": [], "last": "Darling", "suffix": ""}, {"first": "B", "middle": ["B"], "last": "Chang", "suffix": ""}, {"first": "K", "middle": ["M"], "last": "Fitzgerald", "suffix": ""}, {"first": "P", "middle": ["S"], "last": "Paty", "suffix": ""}, {"first": "R", "middle": ["P"], "last": "Leather", "suffix": ""}], "year": 1995, "venue": "Ann Surg", "link": "22835974"}, "BIBREF22": {"title": "Erk1 and Erk2 regulate endothelial cell proliferation and migration during mouse embryonic angiogenesis", "authors": [{"first": "R", "middle": [], "last": "Srinivasan", "suffix": ""}, {"first": "T", "middle": [], "last": "Zabuawala", "suffix": ""}, {"first": "H", "middle": [], "last": "Huang", "suffix": ""}, {"first": "J", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "P", "middle": [], "last": "Gulati", "suffix": ""}, {"first": "S", "middle": [], "last": "Fernandez", "suffix": ""}, {"first": "J", "middle": ["C"], "last": "Karlo", "suffix": ""}, {"first": "G", "middle": ["E"], "last": "Landreth", "suffix": ""}, {"first": "G", "middle": [], "last": "Leone", "suffix": ""}, {"first": "M", "middle": ["C"], "last": "Ostrowski", "suffix": ""}], "year": 2009, "venue": "PLos One", "link": "17002124"}, "BIBREF23": {"title": "Eph B4 receptor signaling mediates endothelial cell migration and proliferation via the phosphatidylinositol 3-kinase pathway", "authors": [{"first": "J", "middle": ["J"], "last": "Steinle", "suffix": ""}, {"first": "C", "middle": ["J"], "last": "Meininger", "suffix": ""}, {"first": "R", "middle": [], "last": "Forough", "suffix": ""}, {"first": "G", "middle": [], "last": "Wu", "suffix": ""}, {"first": "M", "middle": ["H"], "last": "Wu", "suffix": ""}, {"first": "H", "middle": ["J"], "last": "Granger", "suffix": ""}], "year": 2002, "venue": "J Biol Chem", "link": "20473151"}, "BIBREF24": {"title": "Vascular endothelial growth factor/vascular permeability actor augments nitric oxide release from quiescent rabbit and human vascular endothelium", "authors": [{"first": "R", "middle": [], "last": "Van Der Zee", "suffix": ""}, {"first": "T", "middle": [], "last": "Murohara", "suffix": ""}, {"first": "Z", "middle": [], "last": "Luo", "suffix": ""}, {"first": "F", "middle": [], "last": "Zollmann", "suffix": ""}, {"first": "J", "middle": [], "last": "Passeri", "suffix": ""}, {"first": "C", "middle": [], "last": "Lekutat", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Isner", "suffix": ""}], "year": 1997, "venue": "Circulation", "link": "34310502"}, "BIBREF25": {"title": "Molecular distinction and angiogenic interaction between embryonic arteries and veins revealed by ephrin-B2 and its receptor Eph-B4", "authors": [{"first": "H", "middle": ["U"], "last": "Wang", "suffix": ""}, {"first": "Z", "middle": ["F"], "last": "Chen", "suffix": ""}, {"first": "D", "middle": ["J"], "last": "Anderson", "suffix": ""}], "year": 1998, "venue": "Cell", "link": "16656630"}, "BIBREF26": {"title": "Intimal growth and neovascularization in human stenotic vein grafts", "authors": [{"first": "A", "middle": [], "last": "Westerband", "suffix": ""}, {"first": "A", "middle": ["T"], "last": "Gentile", "suffix": ""}, {"first": "G", "middle": ["C"], "last": "Hunter", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Gooden", "suffix": ""}, {"first": "M", "middle": ["L"], "last": "Aguirre", "suffix": ""}, {"first": "S", "middle": ["S"], "last": "Berman", "suffix": ""}, {"first": "J", "middle": ["L"], "last": "Mills", "suffix": ""}], "year": 2000, "venue": "J Am Coll Surg", "link": null}, "BIBREF27": {"title": "Antisense basic fibroblast growth factor alters the time course of mitogen-activated protein kinase in arterialized vein graft remodeling", "authors": [{"first": "A", "middle": [], "last": "Yamashita", "suffix": ""}, {"first": "A", "middle": ["K"], "last": "Hanna", "suffix": ""}, {"first": "S", "middle": [], "last": "Hirata", "suffix": ""}, {"first": "A", "middle": [], "last": "Dardik", "suffix": ""}, {"first": "B", "middle": ["E"], "last": "Sumpio", "suffix": ""}], "year": 2003, "venue": "J Vasc Surg", "link": "20129088"}}, "ref_entries": {"FIGREF0": {"text": "Jadlowiec CC, Feigel A, Yang C, Feinstein AJ, Kim ST, Collins MJ, Kondo Y, Muto A, Dardik A. Reduced adult endothelial cell EphB4 function promotes venous remodeling. Am J Physiol Cell Physiol 304: C627-C635, 2013. First published December 26, 2012; doi:10.1152/ajpcell.00333.2012.", "type": "figure"}, "FIGREF1": {"text": "Fig. 1. Decreased EphB4 phosphorylation in EphB4 \u03e9/\u03ea endothelial cells (EC). A: agarose gel electrophoresis of DNA extracted from EphB4 \u03e9/\u03e9 and EphB4 \u03e9/\u03ea EC shows coexpression of EphB4 wild-type (bp 310) and EphB4 mutant (bp 420) loci only in EphB4 \u03e9/\u03ea EC. Representative image from n \u03ed 3 experiments is shown. B: immunoprecipitation (IP) for EphB4 with immunoblotting (IB) performed against phosphotyrosine (p-Tyr) shows diminished EphB4 phosphorylation in EphB4 \u03e9/\u03ea EC (top row); whole cell lysate (WCL) shows equivalent loading (bottom row). Representative image from n \u03ed 3 experiments is shown. C: densitometry analysis of EphB4 IP. AU, arbitrary units; n \u03ed 3. *P \u03ed 0.0105. D: immunofluorescence showing diminished EphB4 phosphorylation (yellow) in EphB4 \u03e9/\u03ea EC following stimulation with Ephrin-B2. Green, Eph-B4; red, phosphotyrosine; yellow, merge; blue, DAPI. Representative image from n \u03ed 3 experiments is shown. Bar, 10 m.", "type": "figure"}, "FIGREF2": {"text": "Fig. 2. Increased VEGF-A expression in both EphB4 \u03e9/\u03ea EC and vein grafts. A: bar graph of mean VEGF-A mRNA expression levels in EphB4 \u03e9/\u03e9 and EphB4 \u03e9/\u03ea", "type": "figure"}, "FIGREF3": {"text": "Fig. 3. Reduced proliferation and migration in EphB4 \u03e9/\u03ea EC. A: bar graph showing the ratio of mean densitometry values of phosphorylated (p) and total (t) ERK1/2 protein expression levels in EphB4 \u03e9/\u03e9 and EphB4 \u03e9/\u03ea EC (*P \u03ed 0.8210; n \u03ed 10). Representative Western blot is shown below. B: bar graph showing the ratio of mean densitometry values of phosphorylated and total ERK1/2 protein expression levels in vein and vein graft (*P \u03ed 0.0358; n \u03ed 3). Representative Western blot is shown below. C: line graph showing mean cell counts in EphB4 \u03e9/\u03e9 () and EphB4 \u03e9/\u03ea (OE) EC over time (day 5: *P \u03fd 0.0001; n \u03ed 7). HPF, high power field. D: bar graph showing mean fraction of PCNA-positive cells in EphB4 \u03e9/\u03e9 and EphB4 \u03e9/\u03ea EC after 5 days in culture (*P \u03fd 0.0001; n \u03ed 6). E: bar graph showing EphB4 \u03e9/\u03e9 and EphB4 \u03e9/\u03ea EC migration in response to serum-free media (SFM), Ephrin-B2/Fc, or fetal bovine serum (FBS). n \u03ed 3. *P \u03fd 0.0001.", "type": "figure"}, "FIGREF4": {"text": "Fig. 4. Increased angiogenesis and reduced NO production in EphB4 \u03e9/\u03ea EC. A: bar graph showing the ratio of mean densitometry values of phosphorylated and total Akt protein expression levels in EphB4 \u03e9/\u03e9 and EphB4 \u03e9/\u03ea EC (*P \u03ed 0.0413; n \u03ed 9). Representative Western blot is shown below. B: bar graph showing the ratio of mean densitometry values of phosphorylated and total Akt protein expression levels in vein and vein graft (n \u03ed 3). Representative Western blot is shown below. C: bar graph showing NO secretion by EphB4 \u03e9/\u03e9 or EphB4 \u03e9/\u03ea EC under basal (*P \u03ed 0.0012; n \u03ed 3) or VEGF-A stimulation (*P \u03ed 0.0023; n \u03ed 3). D: bar graph showing branch-point formation by EphB4 \u03e9/\u03e9 or EphB4 \u03e9/\u03ea EC under basal (*P \u03fd 0.0001; n \u03ed 3) or VEGF-A stimulation (*P \u03fd 0.0001; n \u03ed 3). E: bar graph showing the mean number of eNOS mRNA transcripts (P \u03ed 0.8910; n \u03ed 6). F: bar graph showing the ratio of mean densitometry values of phosphorylated and total eNOS protein expression levels in EphB4 \u03e9/\u03e9 and EphB4 \u03e9/\u03ea EC (*P \u03ed 0.4788; n \u03ed 3). Representative Western blot is shown below. G: bar graph showing the ratio of mean densitometry values of phosphorylated and total eNOS protein expression levels in vein and vein graft (n \u03ed 3). Representative Western blot is shown below. H: bar graph showing the mean densitometry values of hsp90 protein expression levels in EphB4 \u03e9/\u03e9 and EphB4 \u03e9/\u03ea EC (*P \u03ed 0.0003; n \u03ed 6). Representative Western blot is shown below. I: bar graph showing the mean densitometry values of hsp90 expression levels in vein and vein graft (P \u03ed 0.5881; n \u03ed 8). Representative Western blot is shown below. J: bar graph showing the mean densitometry values of caveolin 1 (Cav-1) protein expression levels in EphB4 \u03e9/\u03e9 and EphB4 \u03e9/\u03ea EC (*P \u03ed 0.0030; n \u03ed 6). Representative Western blot is shown below. K: bar graph of mean densitometry of Cav-1 protein expression levels in vein and vein graft (*P \u03ed 0.0106; n \u03ed 8). Representative Western blot is shown below.", "type": "figure"}, "FIGREF5": {"text": "Fig. 5. Increased smooth muscle cell (SMC) mitogens and chemoattractants secreted by EphB4 \u03e9/\u03ea EC. A-C: bar graphs showing amounts of VEGF-A (A), PDGF-BB (B), and TGF-\u24241 (C) protein detected in EphB4 \u03e9/\u03e9 or EphB4 \u03e9/\u03ea EC-conditioned medium. VEGF-A: *P \u03ed 0.0010, n \u03ed 5; PDGF-BB: *P \u03fd 0.0001, n \u03ed 6; TGF-\u24241: *P \u03fd 0.0001, n \u03ed 6. D-F: bar graphs showing amounts of VEGF-A (D), PDGF-BB (E), and TGF-\u24241 (F) mRNA detected in EphB4 \u03e9/\u03e9 or EphB4 \u03e9/\u03ea EC. VEGF-A: *P \u03ed 0.0006, n \u03ed 6; PDGF-BB: *P \u03ed 0.0124, n \u03ed 6; TGF-\u24241: *P \u03ed 0.0001, n \u03ed 6. G: bar graph showing mean number of migrating SMC (number per HPF), stimulated with either SFM, conditioned medium from either EphB4 \u03e9/\u03ea or EphB4 \u03e9/\u03e9 EC, or FBS. *P \u03ed 0.0358; n \u03ed 3. H: bar graph showing mean percentage of proliferating SMC (BrdU incorporation), stimulated with either SFM, conditioned medium from either EphB4 \u03e9/\u03ea or EphB4 \u03e9/\u03e9 EC, or FBS. *P \u03fd 0.0001; n \u03ed 7.", "type": "figure"}, "TABREF0": {"text": "). We have previously shown that EphB4 \u03e9/\u03ea EC have less surface expression of EphB4, as detected with FACS, compared with EphB4 \u03e9/\u03e9 EC (18). Following stimulation with Ephrin-B2/Fc, an activating ligand for EphB4 (18, 25), there was approximately threefold decreased EphB4 phosphorylation in EphB4 \u03e9/\u03ea EC compared with EphB4 \u03e9/\u03e9 EC (Fig. 1, B and C), consistent with reduced EphB4 function in the EphB4 \u03e9/\u03ea EC. These results were confirmed with immunofluorescence staining that showed marked reduction in colocalization of EphB4 and phosphotyrosine in", "type": "table"}, "TABREF1": {"text": "experiments is shown. C: densitometry analysis of EphB4 IP. AU, arbitrary units; n \u03ed 3. *P \u03ed 0.0105. D: immunofluorescence showing diminished EphB4 phosphorylation (yellow) in EphB4 \u03e9/\u03ea EC following stimu- lation with Ephrin-B2. Green, Eph-B4; red, phosphotyrosine; yellow, merge; blue, DAPI. Representative image from n \u03ed 3 experi- ments is shown. Bar, 10 m.", "type": "table"}, "TABREF2": {"text": "Comparison of results in EphB4 \u03e9/\u03ea EC to results in vein graftEC, endothelial cells; Cav-1, caveolin-1.", "type": "table"}}}
{"paper_id": "18988104", "_pdf_hash": "7f0b14ba84d0be551d2818dac236240202cfbda8", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "S, ) is a partially ordered set. By the Hausdorff Maximal Principle, therefore, there exists a nonempty set T \u2286 S such that (T , ) is a linearly ordered set", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF1": {"title": "{U(x): x \u2208 T } has the finite intersection property. (Indeed, if F is any nonempty finite subset of T , then there exists an x * \u2208 F with x * x for all x \u2208 F since is a linear order on F . It thus follows that x * belongs to {U(x): x \u2208 F }, so the latter set is nonempty.) Since S is compact, therefore, we have {U(x): x \u2208 T } = \u2205. Thus there exists an x * \u2208 S with x * \u2208 U(x) for all x \u2208 T . But then x * \u2208 max(S, ), because if y x * for some y \u2208 S, then (T \u222a {y}, ) is continuous regular preference relation on X and define c", "authors": [], "year": "", "venue": "By Lemma", "link": null}, "BIBREF2": {"title": "U(y) := {z \u2208 S: z y}", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF3": {"title": "Moreover, since y / \u2208 max(S, ), there is a z \u2208 U(y) with z y, and it follows that x y, as we sought. It remains to prove that c satisfies the (C)-axiom. We begin with verifying the (C1)-axiom. Take any (x, y) \u2208 I(c), and note that to establish (x, y) \u2208 int(I(c)), it is enough to prove that I(c) contains all but finitely many terms of any sequence that converges to (x, y)", "authors": [], "year": "", "venue": "Notice that if x / \u2208 max(S, ), then x x for some x \u2208 U(y), which is impossible. Thus x \u2208 max(S, )", "link": null}, "BIBREF4": {"title": "Utility theory without the completeness axiom", "authors": [{"first": "R", "middle": [], "last": "Aumann", "suffix": ""}], "year": 1962, "venue": "Econometrica", "link": "153573933"}, "BIBREF5": {"title": "Nash equilibrium in games with incomplete preferences", "authors": [{"first": "S", "middle": [], "last": "Bade", "suffix": ""}], "year": 2005, "venue": "Econ. Theory", "link": "59450432"}, "BIBREF6": {"title": "Characterization of generalized weak orders and revealed preference", "authors": [{"first": "T", "middle": [], "last": "Bandyopadhay", "suffix": ""}, {"first": "K", "middle": [], "last": "Sengupta", "suffix": ""}], "year": 1993, "venue": "Econ. Theory", "link": null}, "BIBREF7": {"title": "Knightian uncertainty theory: Part I. Discussion paper No. 807", "authors": [{"first": "T", "middle": [], "last": "Bewley", "suffix": ""}], "year": 1986, "venue": "", "link": null}, "BIBREF8": {"title": "Rational selection of decision functions", "authors": [{"first": "H", "middle": [], "last": "Chernoff", "suffix": ""}], "year": 1954, "venue": "Econometrica", "link": "156429446"}, "BIBREF9": {"title": "A behavioral model of individual welfare", "authors": [{"first": "E", "middle": [], "last": "Danan", "suffix": ""}], "year": 2003, "venue": "", "link": null}, "BIBREF10": {"title": "Expected utility theory without the completeness axiom", "authors": [{"first": "J", "middle": [], "last": "Dubra", "suffix": ""}, {"first": "F", "middle": [], "last": "Maccheroni", "suffix": ""}, {"first": "E", "middle": ["A"], "last": "Ok", "suffix": ""}], "year": 2004, "venue": "J. Econ. Theory", "link": "1928848"}, "BIBREF11": {"title": "Economic theory of choice and the preference reversal phenomenon", "authors": [{"first": "D", "middle": [], "last": "Grether", "suffix": ""}, {"first": "C", "middle": [], "last": "Plott", "suffix": ""}], "year": 1979, "venue": "Amer. Econ. Rev", "link": "153965105"}, "BIBREF12": {"title": "Choice structures and preference relations", "authors": [{"first": "B", "middle": [], "last": "Hansson", "suffix": ""}], "year": 1968, "venue": "Synthese", "link": "46966243"}, "BIBREF13": {"title": "Preference reversals and the independence axiom", "authors": [{"first": "C", "middle": [], "last": "Holt", "suffix": ""}], "year": 1986, "venue": "Amer. Econ. Rev", "link": "152525523"}, "BIBREF14": {"title": "Adding asymmetrically dominated alternatives: Violations of regularity and the similarity hypothesis", "authors": [{"first": "J", "middle": [], "last": "Huber", "suffix": ""}, {"first": "J", "middle": [], "last": "Payne", "suffix": ""}, {"first": "C", "middle": [], "last": "Puto", "suffix": ""}], "year": 1982, "venue": "J. Cons. Res", "link": "120998684"}, "BIBREF15": {"title": "Rationalizing choice functions by multiple rationales", "authors": [{"first": "G", "middle": [], "last": "Kalai", "suffix": ""}, {"first": "A", "middle": [], "last": "Rubinstein", "suffix": ""}, {"first": "R", "middle": [], "last": "Spiegler", "suffix": ""}], "year": 2002, "venue": "Econometrica", "link": "16798614"}, "BIBREF16": {"title": "Preference reversal' and the observability of preferences by experimental methods", "authors": [{"first": "E", "middle": [], "last": "Karni", "suffix": ""}, {"first": "Z", "middle": [], "last": "Safra", "suffix": ""}], "year": 1987, "venue": "Econometrica", "link": "122059798"}, "BIBREF17": {"title": "Notes on the Theory of Choice", "authors": [{"first": "D", "middle": [], "last": "Kreps", "suffix": ""}], "year": 1988, "venue": "", "link": "152869298"}, "BIBREF18": {"title": "Hard Choices: Decision Making under Unresolved Conflict", "authors": [{"first": "I", "middle": [], "last": "Levi", "suffix": ""}], "year": 1986, "venue": "J. Econ. Theory", "link": "144363176"}, "BIBREF19": {"title": "Observing violations of transitivity by experimental methods", "authors": [{"first": "G", "middle": [], "last": "Loomes", "suffix": ""}, {"first": "C", "middle": [], "last": "Starmer", "suffix": ""}, {"first": "R", "middle": [], "last": "Sugden", "suffix": ""}], "year": 1991, "venue": "Econometrica", "link": "154864907"}, "BIBREF20": {"title": "Incomplete preferences and rational intransitivity of choice", "authors": [{"first": "M", "middle": [], "last": "Mandler", "suffix": ""}], "year": 2005, "venue": "Games Econ. Behav", "link": "16466404"}, "BIBREF21": {"title": "Rational choice with status-quo bias", "authors": [{"first": "Y", "middle": [], "last": "Masatlioglu", "suffix": ""}, {"first": "E", "middle": ["A"], "last": "Ok", "suffix": ""}], "year": 2005, "venue": "J. Econ. Theory", "link": "54652"}, "BIBREF22": {"title": "Choice functions over a finite set: A summary", "authors": [{"first": "H", "middle": [], "last": "Moulin", "suffix": ""}], "year": 1985, "venue": "Soc. Choice Welfare", "link": "120754207"}, "BIBREF23": {"title": "Rational choice and revealed preference without binariness", "authors": [{"first": "K", "middle": [], "last": "Nehring", "suffix": ""}], "year": 1997, "venue": "Soc. Choice Welfare", "link": "56097847"}, "BIBREF24": {"title": "Utility representation of an incomplete preference relation", "authors": [{"first": "E", "middle": ["A"], "last": "Ok", "suffix": ""}], "year": 2002, "venue": "J. Econ. Theory", "link": "18248965"}, "BIBREF25": {"title": "Independence of irrelevant alternatives and rational choice. Mimeo. NYU. Peleg, B., 1970. Utility functions for partially ordered topological spaces", "authors": [{"first": "E", "middle": ["A"], "last": "Ok", "suffix": ""}], "year": 2005, "venue": "Econometrica", "link": null}, "BIBREF26": {"title": "Medical decision making in situations that offer multiple alternatives", "authors": [{"first": "D", "middle": [], "last": "Redelmeier", "suffix": ""}, {"first": "E", "middle": [], "last": "Shafir", "suffix": ""}], "year": 1995, "venue": "J. Amer. Med. Assoc", "link": "23002905"}, "BIBREF27": {"title": "Revealed preference theory", "authors": [{"first": "M", "middle": [], "last": "Richter", "suffix": ""}], "year": 1966, "venue": "Econometrica", "link": "156348375"}, "BIBREF28": {"title": "The democratic political economy of progressive income taxation", "authors": [{"first": "J", "middle": [], "last": "Roemer", "suffix": ""}], "year": 1999, "venue": "Econometrica", "link": "150703369"}, "BIBREF29": {"title": "Preference reversal and nonexpected utility behavior", "authors": [{"first": "Z", "middle": [], "last": "Safra", "suffix": ""}, {"first": "U", "middle": [], "last": "Segal", "suffix": ""}, {"first": "A", "middle": [], "last": "Spivak", "suffix": ""}], "year": 1990, "venue": "Amer. Econ. Rev", "link": "153816098"}, "BIBREF30": {"title": "Anchored preference relations", "authors": [{"first": "J", "middle": [], "last": "Sagi", "suffix": ""}], "year": 2005, "venue": "J. Econ. Theory", "link": "3050113"}, "BIBREF31": {"title": "A note on the pure theory of consumers' behavior", "authors": [{"first": "P", "middle": [], "last": "Samuelson", "suffix": ""}], "year": 1938, "venue": "Economica", "link": null}, "BIBREF32": {"title": "Choice functions, 'rationality' conditions, and variations on the weak axiom of revealed preference", "authors": [{"first": "T", "middle": [], "last": "Schwartz", "suffix": ""}], "year": 1976, "venue": "J. Econ. Theory", "link": "154394056"}, "BIBREF33": {"title": "Does the preference reversal phenomenon necessarily contradict the independence axiom?", "authors": [{"first": "U", "middle": [], "last": "Segal", "suffix": ""}], "year": 1988, "venue": "Amer. Econ. Rev", "link": "154066538"}, "BIBREF34": {"title": "A representation of partially ordered preferences", "authors": [{"first": "T", "middle": [], "last": "Seidenfeld", "suffix": ""}, {"first": "M", "middle": [], "last": "Schervish", "suffix": ""}, {"first": "J", "middle": [], "last": "Kadane", "suffix": ""}], "year": 1995, "venue": "Ann. Statist", "link": "358900"}, "BIBREF35": {"title": "Choice functions and revealed preferences", "authors": [{"first": "A", "middle": [], "last": "Sen", "suffix": ""}], "year": 1971, "venue": "Rev. Econ. Stud", "link": "153687316"}, "BIBREF36": {"title": "Internal consistency of choice", "authors": [{"first": "A", "middle": [], "last": "Sen", "suffix": ""}], "year": 1993, "venue": "Econometrica", "link": null}, "BIBREF37": {"title": "Maximization and the act of choice", "authors": [{"first": "A", "middle": [], "last": "Sen", "suffix": ""}], "year": 1997, "venue": "Econometrica", "link": "14575375"}, "BIBREF38": {"title": "Reason-based choice", "authors": [{"first": "E", "middle": [], "last": "Shafir", "suffix": ""}, {"first": "I", "middle": [], "last": "Simonson", "suffix": ""}, {"first": "A", "middle": [], "last": "Tversky", "suffix": ""}], "year": 1993, "venue": "Cognition", "link": "25323884"}, "BIBREF39": {"title": "Choice based on reasons: The case of attraction and compromise effects", "authors": [{"first": "I", "middle": [], "last": "Simonson", "suffix": ""}], "year": 1989, "venue": "J. Cons. Res", "link": "144558711"}, "BIBREF40": {"title": "The relative importance of probabilities and payoffs in risk-taking", "authors": [{"first": "P", "middle": [], "last": "Slovic", "suffix": ""}, {"first": "S", "middle": [], "last": "Lichtenstein", "suffix": ""}], "year": 1968, "venue": "J. Exper. Psychol", "link": "198882552"}, "BIBREF41": {"title": "Utility representation for partial orders", "authors": [{"first": "D", "middle": [], "last": "Sondermann", "suffix": ""}], "year": 1980, "venue": "J. Econ. Theory", "link": null}, "BIBREF42": {"title": "Choice under conflict: The dynamics of the deferred decision", "authors": [{"first": "K", "middle": [], "last": "Suzumura", "suffix": ""}, {"first": "A", "middle": [], "last": "Tversky", "suffix": ""}, {"first": "E", "middle": [], "last": "Shafir", "suffix": ""}], "year": 1983, "venue": "Psychol. Sci", "link": "2167374"}, "BIBREF43": {"title": "The causes of preference reversal", "authors": [{"first": "A", "middle": [], "last": "Tversky", "suffix": ""}, {"first": "P", "middle": [], "last": "Slovic", "suffix": ""}, {"first": "D", "middle": [], "last": "Kahneman", "suffix": ""}], "year": 1990, "venue": "Amer. Econ. Rev", "link": "153846912"}}, "ref_entries": {}}
{"paper_id": "18988615", "_pdf_hash": "6e45606645d599ed89cc5bdfb373de1ce65d3165", "abstract": [], "body_text": [], "bib_entries": {"BIBREF1": {"title": "Linear Sequential Circuits", "authors": [{"first": "A", "middle": [], "last": "Gill", "suffix": ""}], "year": 1966, "venue": "", "link": "116485667"}, "BIBREF3": {"title": "VeraUgemeinerte Superposition bci bin/itCh Automaten. (To appear in Acta Cybernetica", "authors": [{"first": "M", "middle": ["D"], "last": "G6ssel ~ H", "suffix": ""}, {"first": "", "middle": [], "last": "Modrow", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF4": {"title": "Eine Verallgemeinerung dcr Vertausehbarkeit in der k-wertigen Logik", "authors": [{"first": "W", "middle": [], "last": "Harnau", "suffix": ""}], "year": 1976, "venue": "ElK", "link": null}, "BIBREF5": {"title": "Potsehe Algebren yon Funktionen iiber einer Familie endicher Mengen", "authors": [{"first": "R", "middle": [], "last": "P6scrml", "suffix": ""}], "year": 1973, "venue": "Z. Math. Logik Grundlagen..Math", "link": null}, "BIBREF6": {"title": "Uber die funktionale Vollst~digkeit in den mehrwertigen Logiken", "authors": [{"first": "I", "middle": [], "last": "Rose/Cberg", "suffix": ""}], "year": 1970, "venue": "Rozpravy Ceskoslovenske Akad. Fred Praha", "link": null}, "BIBREF7": {"title": "Functional constructions in k-valued logic", "authors": [{"first": "S", "middle": ["V"], "last": "Y~lonsrdj", "suffix": ""}], "year": 1958, "venue": "Trudy Mat. Inst. Steklov", "link": null}}, "ref_entries": {}}
{"paper_id": "18989067", "_pdf_hash": "a86f763f1e423f378191eaa4aecf3314b43bcb68", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "A survey of free-form object representation and recognition techniques", "authors": [{"first": "R", "middle": ["J"], "last": "Campbell", "suffix": ""}, {"first": "P", "middle": ["J"], "last": "Flynn", "suffix": ""}], "year": 2001, "venue": "computer vision and image understanding", "link": null}, "BIBREF1": {"title": "Intelligent training system integrated in an echocardiography simulator", "authors": [{"first": "M", "middle": [], "last": "Weidenbach", "suffix": ""}, {"first": "S", "middle": [], "last": "Trochim", "suffix": ""}, {"first": "S", "middle": [], "last": "Kreutter", "suffix": ""}, {"first": "C", "middle": [], "last": "Richter", "suffix": ""}, {"first": "T", "middle": [], "last": "Berlage", "suffix": ""}, {"first": "G", "middle": [], "last": "Grunst", "suffix": ""}], "year": 2004, "venue": "Computers In Biology And Medicine", "link": "223394"}, "BIBREF2": {"title": "Introduction to Evolutionary Computing Springer, ISBN", "authors": [{"first": "A", "middle": ["E"], "last": "Eiben", "suffix": ""}, {"first": "J", "middle": ["E"], "last": "Smith", "suffix": ""}], "year": 2003, "venue": "", "link": null}, "BIBREF3": {"title": "Adaptive Meshes and Shells", "authors": [{"first": "M", "middle": [], "last": "Vasilescu", "suffix": ""}, {"first": "D", "middle": [], "last": "Terzopoulos", "suffix": ""}], "year": 1992, "venue": "Proc. IEEE Computer Vision and Pattern Recognition Conf. '92", "link": "59726384"}, "BIBREF4": {"title": "A Finite Element Model for3D Shape Reconstruction and Nonrigid Motion Tracking", "authors": [{"first": "T", "middle": [], "last": "Mcinerney", "suffix": ""}, {"first": "D", "middle": [], "last": "Terzopoulos", "suffix": ""}], "year": 1993, "venue": "Proc. Fourth Int'l Conf. Computer Vision", "link": "11263"}, "BIBREF5": {"title": "Surface Description of Complex Objects from Multiple Range Images", "authors": [{"first": "Y", "middle": [], "last": "Chen", "suffix": ""}, {"first": "G", "middle": [], "last": "Medioni", "suffix": ""}], "year": 1994, "venue": "Proc. IEEE Computer Vision and Pattern Recognition Conf", "link": "31793691"}, "BIBREF6": {"title": "VRML Mall -a 3D gallery", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF7": {"title": "Evolution Strategies: A comprehensive introduction", "authors": [{"first": "H", "middle": ["G"], "last": "Beyer", "suffix": ""}, {"first": "H", "middle": ["P"], "last": "Schwefel", "suffix": ""}], "year": 2002, "venue": "Natural Computing", "link": "271331"}, "BIBREF8": {"title": "Numerishe Optimierung von ComputerModellen mittels der Evolutionstrategie", "authors": [{"first": "H", "middle": ["P"], "last": "Schwefel", "suffix": ""}], "year": 1977, "venue": "", "link": null}, "BIBREF9": {"title": "Measuring error on simplified surfaces", "authors": [{"first": "P", "middle": [], "last": "Cignoni", "suffix": ""}, {"first": "C", "middle": [], "last": "Rocchini", "suffix": ""}, {"first": "R", "middle": [], "last": "Scopigno", "suffix": ""}], "year": 1998, "venue": "Eurographics Association", "link": null}}, "ref_entries": {}}
{"paper_id": "18989187", "_pdf_hash": "931d9cd1657816a0f4409ec96d8882b784035ca5", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Individual differences in reward drive predict neural responses to images of food", "authors": [{"first": "J", "middle": ["D"], "last": "Beaver", "suffix": ""}, {"first": "A", "middle": ["D"], "last": "Lawrence", "suffix": ""}, {"first": "J", "middle": [], "last": "Van Ditzhuijzen", "suffix": ""}, {"first": "M", "middle": ["H"], "last": "Davis", "suffix": ""}, {"first": "A", "middle": [], "last": "Woods", "suffix": ""}, {"first": "A", "middle": ["J"], "last": "Calder", "suffix": ""}], "year": 2006, "venue": "Journal of Neuroscience", "link": null}, "BIBREF1": {"title": "Liking' and 'wanting' food rewards. Brain substrates and roles in eating disorders", "authors": [{"first": "K", "middle": ["C"], "last": "Berridge", "suffix": ""}], "year": 2009, "venue": "Physiology and Behavior", "link": "3139057"}, "BIBREF2": {"title": "Attentional and approach biases for pictorial food cues. Influence of external eating", "authors": [{"first": "C", "middle": [], "last": "Brignell", "suffix": ""}, {"first": "T", "middle": [], "last": "Griffiths", "suffix": ""}, {"first": "B", "middle": ["P"], "last": "Bradley", "suffix": ""}, {"first": "K", "middle": [], "last": "Mogg", "suffix": ""}], "year": 2009, "venue": "Appetite", "link": "38417740"}, "BIBREF3": {"title": "Cognitive biases to healthy and unhealthy food words predict change in BMI", "authors": [{"first": "R", "middle": [], "last": "Calitri", "suffix": ""}, {"first": "E", "middle": ["M"], "last": "Pothos", "suffix": ""}, {"first": "K", "middle": [], "last": "Tapper", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Brunstrom", "suffix": ""}, {"first": "P", "middle": ["J"], "last": "Rogers", "suffix": ""}], "year": 2010, "venue": "", "link": "8260143"}, "BIBREF4": {"title": "Behavioral inhibition, behavioral activation, and affective responses to impending reward and punishment. The BIS/BAS scales", "authors": [{"first": "C", "middle": ["S"], "last": "Carver", "suffix": ""}, {"first": "T", "middle": ["L"], "last": "White", "suffix": ""}], "year": 1994, "venue": "Journal of Personality and Social Psychology", "link": "6452203"}, "BIBREF5": {"title": "Psychobiological traits in the risk profile for overeating and weight gain", "authors": [{"first": "C", "middle": [], "last": "Davis", "suffix": ""}], "year": 2009, "venue": "International Journal of Obesity", "link": "24222962"}, "BIBREF6": {"title": "From motivation to behaviour. A model of reward sensitivity, overeating, and food preferences in the risk profile for obesity", "authors": [{"first": "C", "middle": [], "last": "Davis", "suffix": ""}, {"first": "K", "middle": [], "last": "Patte", "suffix": ""}, {"first": "R", "middle": [], "last": "Levitan", "suffix": ""}, {"first": "C", "middle": [], "last": "Reid", "suffix": ""}, {"first": "S", "middle": [], "last": "Tweed", "suffix": ""}, {"first": "C", "middle": [], "last": "Curtis", "suffix": ""}], "year": 2007, "venue": "Appetite", "link": "2029935"}, "BIBREF7": {"title": "Personality traits and eating behavior in the obese. Poor self-control in emotional and external eating but personality assets in restrained eating", "authors": [{"first": "K", "middle": [], "last": "Elfhag", "suffix": ""}, {"first": "L", "middle": ["C"], "last": "Morey", "suffix": ""}], "year": 2008, "venue": "Eating Behaviors", "link": "22114411"}, "BIBREF8": {"title": "Clarifying the role of impulsivity in bulimia nervosa", "authors": [{"first": "S", "middle": [], "last": "Fischer", "suffix": ""}, {"first": "G", "middle": ["T"], "last": "Smith", "suffix": ""}, {"first": "K", "middle": ["G"], "last": "Anderson", "suffix": ""}], "year": 2003, "venue": "International Journal of Eating Disorders", "link": "12374373"}, "BIBREF9": {"title": "Gray's impulsivity dimension: A distinction between Reward Sensitivity versus Rash Impulsiveness", "authors": [{"first": "I", "middle": ["H A"], "last": "Franken", "suffix": ""}, {"first": "P", "middle": [], "last": "Muris", "suffix": ""}], "year": 2006, "venue": "Personality and Individual Differences", "link": "145713610"}, "BIBREF10": {"title": "Color-word interference. II. An investigation of the role of vocal conflict and hunger in associative priming", "authors": [{"first": "S", "middle": [], "last": "Grand", "suffix": ""}], "year": 1968, "venue": "Journal of Experimental Psychology", "link": "40529938"}, "BIBREF11": {"title": "How impulsiveness and variety influence food intake in a sample of healthy women", "authors": [{"first": "R", "middle": [], "last": "Guerrieri", "suffix": ""}, {"first": "C", "middle": [], "last": "Nederkoorn", "suffix": ""}, {"first": "A", "middle": [], "last": "Jansen", "suffix": ""}], "year": 2007, "venue": "Appetite", "link": "42325049"}, "BIBREF12": {"title": "The influence of trait and induced state impulsivity on food intake in normal-weight healthy women", "authors": [{"first": "R", "middle": [], "last": "Guerrieri", "suffix": ""}, {"first": "C", "middle": [], "last": "Nederkoorn", "suffix": ""}, {"first": "K", "middle": [], "last": "Stankiewicz", "suffix": ""}, {"first": "H", "middle": [], "last": "Alberts", "suffix": ""}, {"first": "N", "middle": [], "last": "Geschwind", "suffix": ""}, {"first": "C", "middle": [], "last": "Martijn", "suffix": ""}], "year": 2007, "venue": "Appetite", "link": "14616231"}, "BIBREF13": {"title": "Negative mood increases selective attention to food cues and subjective appetite", "authors": [{"first": "R", "middle": [], "last": "Hepworth", "suffix": ""}, {"first": "K", "middle": [], "last": "Mogg", "suffix": ""}, {"first": "C", "middle": [], "last": "Brignell", "suffix": ""}, {"first": "B", "middle": ["P"], "last": "Bradley", "suffix": ""}], "year": 2010, "venue": "Appetite", "link": "39459643"}, "BIBREF14": {"title": "Associations among aspects of impulsivity and eating factors in a nonclinical sample", "authors": [{"first": "J", "middle": ["A"], "last": "Lyke", "suffix": ""}, {"first": "M", "middle": [], "last": "Spinella", "suffix": ""}], "year": 2004, "venue": "International Journal of Eating Disorders", "link": "24206169"}, "BIBREF15": {"title": "Psychiatric aspects of impulsivity", "authors": [{"first": "F", "middle": ["G"], "last": "Moeller", "suffix": ""}, {"first": "E", "middle": ["S"], "last": "Barratt", "suffix": ""}, {"first": "D", "middle": ["M"], "last": "Dougherty", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Schmitz", "suffix": ""}, {"first": "A", "middle": ["C"], "last": "Swann", "suffix": ""}], "year": 2001, "venue": "American Journal of Psychiatry", "link": "25393581"}, "BIBREF16": {"title": "A cognitive-motivational analysis of anxiety", "authors": [{"first": "K", "middle": [], "last": "Mogg", "suffix": ""}, {"first": "B", "middle": ["P"], "last": "Bradley", "suffix": ""}], "year": 1998, "venue": "Behaviour Research and Therapy", "link": "26618282"}, "BIBREF17": {"title": "Selective attention to food-related stimuli in hunger. Are attentional biases specific to emotional and psychopathological states, or are they also found in normal drive states?", "authors": [{"first": "K", "middle": [], "last": "Mogg", "suffix": ""}, {"first": "B", "middle": ["P"], "last": "Bradley", "suffix": ""}, {"first": "H", "middle": [], "last": "Hyare", "suffix": ""}, {"first": "S", "middle": [], "last": "Lee", "suffix": ""}], "year": 1998, "venue": "Behaviour Research and Therapy", "link": "41541237"}, "BIBREF18": {"title": "Impulsivity predicts treatment outcome in obese children", "authors": [{"first": "C", "middle": [], "last": "Nederkoorn", "suffix": ""}, {"first": "E", "middle": [], "last": "Jansen", "suffix": ""}, {"first": "S", "middle": [], "last": "Mulkens", "suffix": ""}, {"first": "A", "middle": [], "last": "Jansen", "suffix": ""}], "year": 2007, "venue": "Behaviour Research and Therapy", "link": "18489201"}, "BIBREF19": {"title": "Enhanced processing of food-related pictures in female external eaters", "authors": [{"first": "I", "middle": ["M T"], "last": "Nijs", "suffix": ""}, {"first": "I", "middle": ["H A"], "last": "Franken", "suffix": ""}, {"first": "P", "middle": [], "last": "Muris", "suffix": ""}], "year": 2009, "venue": "Appetite", "link": "39265069"}, "BIBREF20": {"title": "Possible pathways between depression, emotional and external eating. A structural equation model", "authors": [{"first": "M", "middle": ["A"], "last": "Ouwens", "suffix": ""}, {"first": "T", "middle": [], "last": "Van Strien", "suffix": ""}, {"first": "J", "middle": ["F"], "last": "Van Leeuwe", "suffix": ""}], "year": 2009, "venue": "Appetite", "link": "20655522"}, "BIBREF21": {"title": "Factor structure of the Barratt impulsiveness scale", "authors": [{"first": "J", "middle": ["H"], "last": "Patton", "suffix": ""}, {"first": "M", "middle": ["S"], "last": "Stanford", "suffix": ""}, {"first": "E", "middle": ["S"], "last": "Barratt", "suffix": ""}], "year": 1995, "venue": "Journal of Clinical Psychology", "link": "1843498"}, "BIBREF22": {"title": "Cognitive and behavioral correlates of BMI among male and female undergraduate students", "authors": [{"first": "E", "middle": ["M"], "last": "Pothos", "suffix": ""}, {"first": "K", "middle": [], "last": "Tapper", "suffix": ""}, {"first": "R", "middle": [], "last": "Calitri", "suffix": ""}], "year": 2009, "venue": "Appetite", "link": "2205601"}, "BIBREF23": {"title": "Taste, olfactory, and food texture reward processing in the brain and obesity", "authors": [{"first": "E", "middle": ["T"], "last": "Rolls", "suffix": ""}], "year": 2010, "venue": "International Journal of Obesity", "link": "15299519"}, "BIBREF24": {"title": "Normative data and a short form of the Barratt Impulsiveness Scale", "authors": [{"first": "M", "middle": [], "last": "Spinella", "suffix": ""}], "year": 2007, "venue": "The International Journal of Neuroscience", "link": "3165159"}, "BIBREF25": {"title": "Fifty years of the Barratt Impulsiveness Scale. An update and review", "authors": [{"first": "M", "middle": ["S"], "last": "Stanford", "suffix": ""}, {"first": "C", "middle": ["W"], "last": "Mathias", "suffix": ""}, {"first": "D", "middle": ["M"], "last": "Dougherty", "suffix": ""}, {"first": "S", "middle": ["L"], "last": "Lake", "suffix": ""}, {"first": "N", "middle": ["E"], "last": "Anderson", "suffix": ""}, {"first": "J", "middle": ["H"], "last": "Patton", "suffix": ""}], "year": 2009, "venue": "Personality and Individual Differences", "link": "144156880"}, "BIBREF26": {"title": "Relation of obesity to consummatory and anticipatory food reward", "authors": [{"first": "E", "middle": [], "last": "Stice", "suffix": ""}, {"first": "S", "middle": [], "last": "Spoor", "suffix": ""}, {"first": "J", "middle": [], "last": "Ng", "suffix": ""}, {"first": "D", "middle": ["H"], "last": "Zald", "suffix": ""}], "year": 2009, "venue": "Physiology & Behavior", "link": "18508700"}, "BIBREF27": {"title": "Widespread reward-system activation in obese women in response to pictures of high-calorie foods", "authors": [{"first": "L", "middle": ["E"], "last": "Stoeckel", "suffix": ""}, {"first": "R", "middle": ["E"], "last": "Weller", "suffix": ""}, {"first": "E", "middle": ["W"], "last": "Cook", "suffix": ""}, {"first": "", "middle": [], "last": "Iii", "suffix": ""}, {"first": "D", "middle": ["B"], "last": "Twieg", "suffix": ""}, {"first": "R", "middle": ["C"], "last": "Knowlton", "suffix": ""}, {"first": "J", "middle": ["E"], "last": "Cox", "suffix": ""}], "year": 2008, "venue": "Neuroimage", "link": "10246197"}, "BIBREF28": {"title": "Symptoms of attention-deficit/hyperactivity disorder, overeating, and body mass index in men", "authors": [{"first": "R", "middle": [], "last": "Strimas", "suffix": ""}, {"first": "C", "middle": [], "last": "Davis", "suffix": ""}, {"first": "K", "middle": [], "last": "Patte", "suffix": ""}, {"first": "C", "middle": [], "last": "Curtis", "suffix": ""}, {"first": "C", "middle": [], "last": "Reid", "suffix": ""}, {"first": "C", "middle": [], "last": "Mccool", "suffix": ""}], "year": 2008, "venue": "Eating Behaviors", "link": "24318284"}, "BIBREF29": {"title": "The Sensitivity to Punishment and Sensitivity to Reward Questionnaire (SPSRQ) as a measure of Gray's anxiety and impulsivity dimensions", "authors": [{"first": "R", "middle": [], "last": "Torrubia", "suffix": ""}, {"first": "C", "middle": [], "last": "Avila", "suffix": ""}, {"first": "J", "middle": [], "last": "Molto", "suffix": ""}, {"first": "X", "middle": [], "last": "Caseras", "suffix": ""}], "year": 2001, "venue": "Personality and Individual Differences", "link": "143006191"}, "BIBREF30": {"title": "Dutch Eating Behaviour Questionnaire for assessment of restrained, emotional and external eating behaviour", "authors": [{"first": "T", "middle": [], "last": "Van Strien", "suffix": ""}, {"first": "J", "middle": ["E R"], "last": "Fritjers", "suffix": ""}, {"first": "G", "middle": ["P A"], "last": "Bergers", "suffix": ""}, {"first": "P", "middle": ["B"], "last": "Defares", "suffix": ""}], "year": 1986, "venue": "International Journal of Eating Disorders", "link": null}, "BIBREF31": {"title": "Contrasting roles of basolateral amygdala and orbitofrontal cortex in impulsive choice", "authors": [{"first": "C", "middle": ["A"], "last": "Winstanley", "suffix": ""}, {"first": "D", "middle": ["E"], "last": "Theobald", "suffix": ""}, {"first": "R", "middle": ["N"], "last": "Cardinal", "suffix": ""}, {"first": "T", "middle": ["W"], "last": "Robbins", "suffix": ""}], "year": 2004, "venue": "Journal of Neuroscience", "link": null}}, "ref_entries": {}}
{"paper_id": "18989350", "_pdf_hash": "94f7788bdca5cc37af71c694d7b79d73a5413da7", "abstract": [{"section": "Abstract", "text": "Construction of genetic linkage map is essential for genetic and genomic studies. Recent advances in sequencing and genotyping technologies made it possible to generate high-density and high-resolution genetic linkage maps, especially for the organisms lacking extensive genomic resources. In the present work, we constructed a high-density and high-resolution genetic map for channel catfish with three large resource families genotyped using the catfish 250K single-nucleotide polymorphism (SNP) array. A total of 54,342 SNPs were placed on the linkage map, which to our knowledge had the highest marker density among aquaculture species. The estimated genetic size was 3,505.4 cM with a resolution of 0.22 cM for sex-averaged genetic map. The sex-specific linkage maps spanned a total of 4,495.1 cM in females and 2,593.7 cM in males, presenting a ratio of 1.7 : 1 between female and male in recombination fraction. After integration with the previously established physical map, over 87% of physical map contigs were anchored to the linkage groups that covered a physical length of 867 Mb, accounting for \u223c90% of the catfish genome. The integrated map provides a valuable tool for validating and improving the catfish whole-genome assembly and facilitates fine-scale QTL mapping and positional cloning of genes responsible for economically important traits.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Genetic linkage maps are essential for the understanding of genomic levels of organization of inheritance of traits. 1 Construction of highdensity and high-resolution genetic maps is a key step for fine mapping of quantitative trait loci (QTL) and marker-assisted selection. In addition, genetic linkage maps are valuable resources for the generation of chromosome-level assembly of whole-genome sequences and for comparative genome analysis. 2 In most of the recent whole-genome sequencing cases, whole-genome sequences are generated using nextgeneration sequencing (NGS). Short sequence reads are assembled into contigs. Such contigs are generally still relatively short although they vary in sizes from several kilobases to tens of kilobases. Increases in genome sequencing coverage and sequencing libraries can increase the quality of the assembly, allowing the sizes of contigs to be increased. However, NGS methods alone cannot provide the resources to assemble complex genomes at the chromosomal level. Genome sequence assemblies at this level require the assembly of tens of thousands to hundreds of thousands of contigs. Highly segmented genome assemblies prohibit efficient genome analysis. Therefore, various genome resources have been created to reduce the segmentation of the genome assemblies. One of these resources is the large-insert-based physical maps. Historically, several types of large insert libraries have been used. These include yeast artificial chromosomes (YACs), 3 bacterial artificial chromosomes (BACs), 4 and cosmid-based libraries. 5 YACs have the largest capacity for cloning the large inserts, but they are relatively unstable; therefore, their use in genome studies has been limited. Cosmid libraries have the smallest capacity for cloning the large inserts; therefore, their use in large insert libraries has also been limited. BACs are the most popular large insert libraries as they are stable and can hold inserts of up to 200 kb. BAC-based physical maps can organize the entire genome into restriction fingerprint-based contigs. Such contigs are similar to the whole-genome sequencing contigs, but they are constructed using overlapping restriction enzyme fingerprints rather than overlapping sequences themselves for the whole-genome sequence assemblies. By analysis of restriction fingerprints of overlapping genomic clones of BAC inserts, the whole genome can be organized into a limited number of contigs, most often in thousands. For instance, the catfish physical maps had 3,307 contigs and 1,891 contigs. 6, 7 The integrated catfish physical map included over 2,500 contigs (unpublished). Integration of physical maps and whole-genome sequence contigs allows the relationship to be established between the sequence-based contigs and the restriction fingerprint-based contigs, thereby reducing the levels of segmentation of the genome. One of the major applications of genetic linkage map is to integrate physical maps and wholegenome assemblies. Integration of genetic map with physical map is useful for understanding genomes from different dimensions and is essential for comparative genome analysis, 8 fine-scale QTL mapping and positional cloning of genes responsible for performance and production traits. 9, 10 In aquaculture fish species, genetic maps have been constructed in a few species, such as Asian seabass, 11 Atlantic salmon, 12 half-smooth tongue sole, 13 rainbow trout, 14 common carp, 15 and catfish. 2, 9, 16, 17 These maps harbour several hundred to a couple of thousands of markers, with which QTL for agriculturally important performance and production traits can only be mapped in large genomic regions. Integrated maps have been developed in several aquaculture fish species using low-density genetic maps. In Atlantic salmon, in addition to 579 BAC contigs that were integrated into the linkage map using microsatellite markers, identification and mapping of new BAC-anchored single-nucleotide polymorphism (SNP) markers from BAC-end sequences placed 73 additional BAC contigs to Atlantic salmon linkage groups. 18 The second generation of rainbow trout integrated map anchored up to 265 contigs to the genetic map, covering \u223c11% of the genome. 10 In common carp, a total of 463 physical map contigs and 88 single BACs were integrated into the genetic linkage map, which covered 30% of the common carp genome. 15 In catfish, 2,030 BAC-end sequence (BES)-derived microsatellites from 1,481 physical map contigs were used for linkage map construction, which anchored 44.8% of the catfish BAC physical map contigs, covering \u223c52.8% of the genome. 9 Apparently, the level of integration is dependent on the density and resolution of the genetic maps. One objective of this study was to construct a high-density and high-resolution genetic linkage map by using a large number of molecular markers, covering the entire genome and a large resource panel for linkage mapping analysis. In addition to this primary goal, a secondary goal was to increase integration of the linkage and physical maps, using markers derived from BECs for genetic linkage analysis. Our previous genetic linkage analysis used mostly microsatellite markers. In spite of their high polymorphism, and low cost of single marker genotyping, an analysis of tens of thousands of microsatellites with a large number of mapping fish is extremely labourious and costprohibitive. SNPs overcome these difficulties by providing high efficiency and low-cost, large-scale genotyping. SNPs have become markers of choice because of their abundance, even genomic distribution, and easy adaptation to automation. 19 Recent advances in NGS have allowed rapid discovery of genome-wide SNPs in any organism in a cost-effective manner. 20 With the availability of large numbers of SNPs, high-density SNP array platform can be developed for high-throughput and efficient genotyping. Alternatively, an NGS-based genotyping-by-sequencing (GBS) [19] [20] [21] is also highly efficient. SNP arrays and GBS have both been used to genotype large-scale SNPs for genetic mapping and association analyses. 12, [22] [23] [24] [25] [26] [27] [28] Compared with GBS, SNP arrays are more costeffective. In addition, they provide a greater level of genome coverage. For instance, in most cases, the total number of commonly analysed SNPs is limited to several thousands while millions of SNPs can be analysed by using very high-density SNP arrays. In addition, GBS of large resource panels for high-resolution maps is cost-prohibitive. Channel catfish, Ictalurus punctatus, is the primary aquaculture species in the United States. Since the initiation of genome research over two decades ago, several genetic maps have been constructed with different types of molecular markers and various resource families. 2, 9, 16, 17 Up to date, the highest density map was developed to contain 2,030 microsatellites and 100 SNPs. 9 Although this genetic map has been very useful for genetic and genomic analysis, 29, 30 marker density in this map was still fairly low and only facilitated integration to the physical map for \u223c52% of catfish genome. Recently, following efforts to expand catfish genomic resources, we have identified millions of SNPs in channel catfish 31, 32 and developed high-density SNP arrays, 33 which provided the opportunity to develop a high-density and high-resolution SNP-based genetic map. Here we report the construction of genetic linkage map with over 50,000 SNPs in channel catfish, which is, to the best of our knowledge, the highest density genetic map for any aquaculture species. Along with the high density of markers, the utilization of BAC-associated SNPs also allowed significant increase of the integration of the genetic linkage map with the BAC-based physical map in catfish, allowing over 90% of the catfish genome physical map contigs to be mapped to linkage groups. This genetic map should serve as a valuable framework for validating the reference whole-genome sequences, extensive comparative and functional genomic studies, and fine-scale QTL mapping and association studies in catfish.", "cite_spans": [{"start": 117, "end": 118, "text": "1", "ref_id": "BIBREF0"}, {"start": 443, "end": 444, "text": "2", "ref_id": "BIBREF1"}, {"start": 1493, "end": 1494, "text": "3", "ref_id": "BIBREF2"}, {"start": 1536, "end": 1537, "text": "4", "ref_id": "BIBREF3"}, {"start": 1566, "end": 1567, "text": "5", "ref_id": "BIBREF4"}, {"start": 2554, "end": 2556, "text": "6,", "ref_id": "BIBREF6"}, {"start": 2557, "end": 2558, "text": "7", "ref_id": "BIBREF7"}, {"start": 3152, "end": 3153, "text": "8", "ref_id": "BIBREF8"}, {"start": 3260, "end": 3262, "text": "9,", "ref_id": "BIBREF9"}, {"start": 3263, "end": 3265, "text": "10", "ref_id": "BIBREF10"}, {"start": 3371, "end": 3373, "text": "11", "ref_id": "BIBREF11"}, {"start": 3391, "end": 3393, "text": "12", "ref_id": "BIBREF12"}, {"start": 3419, "end": 3421, "text": "13", "ref_id": "BIBREF13"}, {"start": 3437, "end": 3439, "text": "14", "ref_id": "BIBREF14"}, {"start": 3453, "end": 3455, "text": "15", "ref_id": "BIBREF15"}, {"start": 3469, "end": 3471, "text": "2,", "ref_id": "BIBREF1"}, {"start": 3472, "end": 3474, "text": "9,", "ref_id": "BIBREF9"}, {"start": 3475, "end": 3478, "text": "16,", "ref_id": "BIBREF16"}, {"start": 3479, "end": 3481, "text": "17", "ref_id": "BIBREF17"}, {"start": 4087, "end": 4089, "text": "18", "ref_id": "BIBREF18"}, {"start": 4220, "end": 4222, "text": "10", "ref_id": "BIBREF10"}, {"start": 4385, "end": 4387, "text": "15", "ref_id": "BIBREF15"}, {"start": 4618, "end": 4619, "text": "9", "ref_id": "BIBREF9"}, {"start": 5637, "end": 5639, "text": "19", "ref_id": "BIBREF19"}, {"start": 5756, "end": 5758, "text": "20", "ref_id": "BIBREF20"}, {"start": 5961, "end": 5965, "text": "[19]", "ref_id": "BIBREF19"}, {"start": 5966, "end": 5970, "text": "[20]", "ref_id": "BIBREF20"}, {"start": 5971, "end": 5975, "text": "[21]", "ref_id": "BIBREF21"}, {"start": 6116, "end": 6119, "text": "12,", "ref_id": "BIBREF12"}, {"start": 6120, "end": 6124, "text": "[22]", "ref_id": "BIBREF22"}, {"start": 6125, "end": 6129, "text": "[23]", "ref_id": "BIBREF23"}, {"start": 6130, "end": 6134, "text": "[24]", "ref_id": "BIBREF24"}, {"start": 6135, "end": 6139, "text": "[25]", "ref_id": "BIBREF25"}, {"start": 6140, "end": 6144, "text": "[26]", "ref_id": "BIBREF26"}, {"start": 6145, "end": 6149, "text": "[27]", "ref_id": "BIBREF27"}, {"start": 6150, "end": 6154, "text": "[28]", "ref_id": "BIBREF28"}, {"start": 6814, "end": 6816, "text": "2,", "ref_id": "BIBREF1"}, {"start": 6817, "end": 6819, "text": "9,", "ref_id": "BIBREF9"}, {"start": 6820, "end": 6823, "text": "16,", "ref_id": "BIBREF16"}, {"start": 6824, "end": 6826, "text": "17", "ref_id": "BIBREF17"}, {"start": 6924, "end": 6925, "text": "9", "ref_id": "BIBREF9"}, {"start": 7007, "end": 7010, "text": "29,", "ref_id": "BIBREF29"}, {"start": 7011, "end": 7013, "text": "30", "ref_id": "BIBREF30"}, {"start": 7263, "end": 7266, "text": "31,", "ref_id": "BIBREF31"}, {"start": 7267, "end": 7269, "text": "32", "ref_id": "BIBREF32"}, {"start": 7309, "end": 7311, "text": "33", "ref_id": "BIBREF33"}], "ref_spans": []}, {"section": "Materials and methods", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Resource families and DNA preparation", "text": "A total of 576 fish, with 192 full-sibling individuals from each of three full-sibling channel catfish families, were used for linkage mapping. The parent and grandparent samples were also obtained. All DNAs for these samples used in this study were provided by USDA-ARS Warmwater Aquaculture Research Unit, which were prepared following the procedures as previously described.", "cite_spans": [], "ref_spans": []}, {"section": "Resource families and DNA preparation", "text": "Genotyping was conducted by GeneSeek (Lincoln, NE, USA) using the catfish 250K SNP array. 33 Affymetrix CEL files were analysed using Affymetrix Genotyping Console software (version 4.0) for quality control analysis and SNP genotype calling using the Affymetrix AxiomGT1 algorithm. Samples passing the quality control (Dish value > 0.85) and SNP call rates threshold (>95%) were retained for analysis. Following genotyping, an R package, SNPolisher, was used to generate the genotyping outputs. The package produced SNP quality control metrics and divided SNPs into several classes based on the quality of genotype calls. 33 The polymorphic markers with high resolution of cluster separation (high genotyping quality) were remained for further analysis. The CHP files generated from the Affymetrix Genotyping Console were imported into SNP & Variation Suite (SVS version 7, Golden Helix, Inc.) for further filtering to remove SNPs with missing genotypes >10% and minor allele frequency <5%.", "cite_spans": [{"start": 90, "end": 92, "text": "33", "ref_id": "BIBREF33"}, {"start": 622, "end": 624, "text": "33", "ref_id": "BIBREF33"}], "ref_spans": []}, {"section": "Linkage map construction", "text": "Only SNPs that had high quality of genotype calls and were heterozygous in at least one parent were retained for linkage analysis. Based on segregation patterns, SNPs were categorized into three types: 1 : 2 : 1 type (AB \u00d7 AB, segregating in both parents), 1 : 1 type (AB \u00d7 AA or AB \u00d7 BB, segregating only in female), and 1 : 1 type (AA \u00d7 AB or BB \u00d7 AB, segregating only in male). The \u03c7 2 goodness-of-fit tests were performed to examine the segregation distortion. Markers with significant segregation distortion were excluded (P < 0.001). Linkage maps were initially developed independently for the three mapping families. Sex-specific maps were constructed for each parent using 1 : 1 segregation-type markers only (AB \u00d7 AA or AB \u00d7 BB for female map and AA \u00d7 AB or BB \u00d7 AB for male map). The markers of segregation type 1 : 2 : 1 (AB \u00d7 AB) were used to build the sex-averaged map. The LINKMFEX software (version 2.4, http://www.uoguelph.ca/ rdanzman/software.htm) was used to perform linkage analysis for sex-specific markers, and OneMap (R package, version 2.0) was used for linkage analysis of sex-averaged markers. Linkage between markers was examined by estimating logarithm of the odds (LOD) scores for recombination fraction (\u03b8). A LOD threshold of 8.0 was used, and a maximum \u03b8 of 0.35 was set to assign markers into linkage groups.", "cite_spans": [], "ref_spans": []}, {"section": "Linkage map construction", "text": "For markers falling into 'zero recombination clusters', only one marker was picked that had the most informative meiosis as the representative marker of each cluster for linkage map construction to reduce the power required for computation of linkage. Genetic maps were constructed using JoinMap software version 4.0 with the regression mapping algorithm. 34 The Kosambi mapping function was used to convert the recombination frequencies into map distances (centiMorgans). The positions of markers were determined according to the sequential buildup of the map. 35 Briefly, a pair of markers was firstly selected, followed by sequential addition of other markers. The 'ripple' was performed each time after adding one marker. The best fitting position of the added markers was searched based on the goodness-of-fit test for the resulting map. When a marker generated a negative map distance or a large 'jump' value in goodness-of-fit test, the marker was removed, and map calculation was continued to construct a first-round map. Thereafter, the removed markers were added to the first-round map and again subjected to the goodness-of-fit test to generate an optimum order of markers. For the sex-specific markers, the linkage phases were inferred automatically, while for the markers with 1 : 2 : 1 segregation type (AB \u00d7 AB), the linkage phase was deduced based on the genotypes of grandparents to assist the map construction. The consensus maps were then established using the MergeMap 36 by integrating individual maps from three reference families through shared markers. Lastly, the markers falling into 'zero recombination clusters' that were excluded during map construction were anchored to the linkage map, based on the positions of their corresponding representative markers. All genetic linkage maps were drawn using MAP-CHART 2.2. 37 ", "cite_spans": [{"start": 356, "end": 358, "text": "34", "ref_id": "BIBREF34"}, {"start": 562, "end": 564, "text": "35", "ref_id": "BIBREF35"}, {"start": 1489, "end": 1491, "text": "36", "ref_id": "BIBREF36"}, {"start": 1844, "end": 1846, "text": "37", "ref_id": "BIBREF37"}], "ref_spans": []}, {"section": "Differences in recombination rates between families and sexes", "text": "To assess differences in recombination rates among the three resource families, the sex-averaged map was used following the M-test according to Ott's method.", "cite_spans": [], "ref_spans": []}, {"section": "Differences in recombination rates between families and sexes", "text": "where Z i \u00f0\u03b8 i \u00de represents the LOD scores of maximum-likelihood estimation (MLE) for the ith reference family for common marker pairs among the three families. The Z\u00f0\u03b8\u00de represents the total LOD scores of MLE for all three families. The recombination fractions for all mapped locus intervals from each family were obtained from JoinMap.", "cite_spans": [], "ref_spans": []}, {"section": "Differences in recombination rates between families and sexes", "text": "To investigate sex-specific heterogeneity throughout each linkage group, common marker pairs were used to compare the locus intervals across the male-specific map and female-specific map using contingency G-test. 39 ", "cite_spans": [{"start": 213, "end": 215, "text": "39", "ref_id": "BIBREF39"}], "ref_spans": []}, {"section": "Integration of linkage map with physical map", "text": "To integrate previously developed physical map 40 with the highdensity linkage map constructed in the present work, all the mapped SNPs with 70-bp flanking sequences were aligned with BES 8, 40 and BAC-based physical map contig-specific sequences (PMCSS) 41 using", "cite_spans": [{"start": 47, "end": 49, "text": "40", "ref_id": "BIBREF40"}, {"start": 188, "end": 190, "text": "8,", "ref_id": "BIBREF8"}, {"start": 191, "end": 193, "text": "40", "ref_id": "BIBREF40"}, {"start": 255, "end": 257, "text": "41", "ref_id": "BIBREF41"}], "ref_spans": []}, {"section": "Integration of linkage map with physical map", "text": "BLAST with the E-value cut-off 1E\u221210, minimal alignment length of 36, and minimal identity of 95%. The relationship of physical map and genetic map was built up based on the SNP-associated BES and PMCSS. The BAC physical map contigs that harboured BACderived BES and PMCSS were anchored onto the genetic map based on the SNP positions.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Selection of SNP markers", "text": "As summarized in Table 1 , SNP genotypes were obtained from 576 samples of three mapping families (192 samples per family). According to the assessment of genotyping quality and polymorphism in all samples from the three mapping families, genotypes of a total of 121,521 SNPs were used (Table 1 ). Owing to the low genotype calling rate (<95%), nine individuals were excluded for analysis, including one individual from family 1, three individuals from family 2, and five individuals from family 3. After further filtering to remove SNPs with low calling rate (<97%) and non-Mendelian inheritance (P < 0.001), ", "cite_spans": [], "ref_spans": [{"start": 17, "end": 24, "text": "Table 1", "ref_id": "TABREF0"}, {"start": 286, "end": 294, "text": "(Table 1", "ref_id": "TABREF0"}]}, {"section": "Linkage mapping", "text": "Linkage maps were first constructed for each of the three families, separately. For all three mapping families, 29 linkage groups (LGs) were obtained, which was consistent with the number of chromosomes of the catfish haploid genome. The consensus genetic linkage maps were obtained by merging separate maps from three mapping families. A total of 31,387 markers with distinct genetic positions (hereafter referred to as unique markers) were placed on the consensus linkage maps, which included 8,644 SNPs from family 1, 13,477 SNPs from family 2, and 14,343 SNPs from family 3 ( Table 2 ). After anchoring the previously excluded markers that fell into 'zero recombination clusters' based on the genetic positions of representative markers, a total of 54,342 SNP markers were placed onto the current linkage map ( Table 2) . The sex-specific maps were constructed using markers that were heterozygous in only female or male parent. The female genetic map consisted of 18,444 SNPs including 9,746 unique markers, with a total genetic length of 4,495.1 cM (Table 3; Fig. 1 Fig. 2 ). It should be noted that these distances refer to intervals where recombination was detected and of course it should be recognized that in both sexes, the minimum distance observed was 0 cM for completely linked markers. The female-and male-specific maps are illustrated in Figs 1 and 2 , respectively. The detailed map information was provided in Supplementary data S1.", "cite_spans": [], "ref_spans": [{"start": 580, "end": 587, "text": "Table 2", "ref_id": "TABREF1"}, {"start": 815, "end": 823, "text": "Table 2)", "ref_id": "TABREF1"}, {"start": 1055, "end": 1071, "text": "(Table 3; Fig. 1", "ref_id": "FIGREF0"}, {"start": 1072, "end": 1078, "text": "Fig. 2", "ref_id": "FIGREF1"}, {"start": 1355, "end": 1367, "text": "Figs 1 and 2", "ref_id": "FIGREF0"}]}, {"section": "Linkage mapping", "text": "The sex-averaged map was constructed using markers that were heterozygous in both parents. As summarized in Table 4 , a total of 29,081 SNPs were mapped, which consisted of 15,598 unique markers. The sex-averaged map spanned 3,505.4 cM with an average marker interval of 0.22 cM, ranging from 0.17 cM/marker (LG12) to 0.30 cM/marker (LG18). The genetic map is illustrated in Fig. 3 . The detailed map information was provided in Supplementary data S1.", "cite_spans": [], "ref_spans": [{"start": 108, "end": 115, "text": "Table 4", "ref_id": "TABREF3"}, {"start": 375, "end": 381, "text": "Fig. 3", "ref_id": "FIGREF2"}]}, {"section": "Analysis of recombination rates", "text": "Within each linkage group, mild to strong localized specific recombination patterns were observed, whereby recombination rates were usually elevated towards the end and suppressed in the middle of the map (Fig. 4) . Clustered markers that fell into 'zero recombination rate' were observed in every linkage group, especially in positions close to the centromeres in contrast to the telomeres (Supplementary data S1).", "cite_spans": [], "ref_spans": [{"start": 205, "end": 213, "text": "(Fig. 4)", "ref_id": "FIGREF3"}]}, {"section": "Analysis of recombination rates", "text": "There is no significant difference in recombination rate among three mapping families based on the examination with common marker pairs among the three families (see Methods section). In contrast, significant higher recombination rates were observed in a majority of the linkage groups of the female genetic map than that of male genetic map (P < 0.01). Overall, the female genetic map was 1,901.4 cM longer than male genetic map, with an average female-to-male ratio of 1.7 : 1 ( Table 3 ). The ratio varied by linkage groups, ranging from 0.97 : 1 in LG22 to 2.50 : 1 in LG1 (Table 3 ). The largest differences in recombination rate between the female and male maps were observed in LG1, LG5, LG7, LG18, LG27, and LG29. Across all these linkage groups, the female : male recombination ratios exceeded 2.0.", "cite_spans": [], "ref_spans": [{"start": 481, "end": 488, "text": "Table 3", "ref_id": "TABREF2"}, {"start": 577, "end": 585, "text": "(Table 3", "ref_id": "TABREF2"}]}, {"section": "Analysis of recombination rates", "text": "LG22 was unusual in that recombination rates were very similar between the sexes (i.e. 0.97 : 1). Within unique map positions, 504 SNPs were commonly shared between the two sexes, while significantly higher recombination rates were observed in majority of the common locus intervals (P < 0.01) (Fig. 5) .", "cite_spans": [], "ref_spans": []}, {"section": "Integration and validation with physical map", "text": "The integration of the genetic map with the BAC-based physical map anchored 2,728 (83%) of the 3,307 physical map contigs (Table 5) . Together with the 1,481 (44.8%) physical map contigs that were anchored previously, 6 we were able to anchor a total of 2,880 (87.1%) physical map contigs consisting of 28,416 BAC clones (92.9% of total BAC clones). The sizes of anchored physical map contigs varied from 66.0 kb to 2,005.8 kb (Supplementary data S2) , with an average size of 301 kb. Together, a total of 867.4 Mb of the physical map was integrated by genetic linkage map that accounted for \u223c90% of the channel catfish genome (Table 5 ). Detailed information regarding integration of linkage map and physical map is provided in Supplementary data S2.", "cite_spans": [{"start": 218, "end": 219, "text": "6", "ref_id": "BIBREF6"}], "ref_spans": [{"start": 427, "end": 450, "text": "(Supplementary data S2)", "ref_id": "FIGREF1"}]}, {"section": "Integration and validation with physical map", "text": "The integration of linkage map and physical map enabled the cross-validation of the quality of the physical map and the genetic map (Table 6 ). A total of 1,467 physical map contigs containing 2,961 BES-associated SNPs were placed onto linkage maps. With 615 physical map contigs, two or more SNP markers were mapped that allowed the determination of orientation of the physical map contigs along the chromosome. With such contigs, the quality of physical map contigs was assessed based on the mapped markers. An illustration with linkage group 12 is provided in Fig. 6 . The vast majority of physical contigs were validated, but a small fraction of physical map contigs was found incorrectly assembled, or the ordering of the SNP markers onto the map was in error.", "cite_spans": [], "ref_spans": [{"start": 563, "end": 569, "text": "Fig. 6", "ref_id": "FIGREF4"}]}, {"section": "Integration and validation with physical map", "text": "A total of 47 physical map contigs had markers that were mapped in different linkage groups, indicating the potential errors of the physical map assembly or the mapping errors of incorrectly assigned SNPs. These errors could be caused by SNPs falling into duplicated regions of genome. Moreover, of the 2,707 BAC clones with BES-associated SNPs, 238 BAC clones contained at least two BES-associated SNPs. Within this group, 7 BAC clones were mapped onto different LGs, suggesting the misplacement of those SNP markers onto the linkage groups. As an illustration, the integration of sex-averaged linkage map with physical map Contig72 and Contig534 is shown in Fig. 7 , presenting the correct and incorrect physical map assembly, respectively. The manual check of the potential assembly or mapping error warrants the correctness of both physical map and linkage map in the next step.", "cite_spans": [], "ref_spans": []}, {"section": "Integration and validation with physical map", "text": "Physical distances were estimated based on the position of SNP markers within each physical map contig, which allowed for estimation of the ratios of physical distance to genetic distance (Supplementary data S3). On the other hand, recombination frequencies can be calculated for physical map contigs with multiple SNP markers mapped onto the linkage map. With the sex-averaged linkage map, the genetic size of 3,505.4 cM and the physical size of 965,279 kb based on the physical map, we estimated the average genetic size as 3.6 cM per Mb. The ratios observed from the 250 physical map contigs that contained multiple SNPs mapped onto the linkage map ranged from 0 to 2.26 cM per Mb. The markers with higher ratios might indicate the potential loci of recombination hot spots.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "In this work, we constructed a high-density genetic map for channel catfish. This map possesses the highest marker density among all the ", "cite_spans": [], "ref_spans": []}, {"section": "46", "text": "High-density and high-resolution catfish genetic map genetic linkage maps constructed for any aquaculture species. Taking advantage of the catfish 250K SNP array, we were able to efficiently and cost-effectively genotype 250,000 SNPs in the 576 fish from three mapping families (192 fish per family). Such a high-density linkage map should be a valuable resource for analysis and fine-scale QTL mapping in catfish. Although the efficient SNP genotyping technology allowed the construction of high-density linkage map, the high-resolution was yet to be achieved. A large number of markers fell into 'zero recombination clusters' where no recombination events occur during meiosis between the markers among the fish used for mapping analysis. These represent closely arrayed adjacent SNP positions, and their ordering is likely best achieved by assessing their order within the aligned physical map contigs. Conversely, it was also observed that genetic recombination rates could be artificially inflated when genotyping errors occur or when markers with large amounts of missing data are included in the analysis. 42, 43 Similar situations were observed previously in zebrafish during the construction of high-density genetic map. In zebrafish, the genetic sizes of initial map were over 1,000 cM per chromosome. After removal of genotyping errors, the genetic sizes were reduced to around 100 cM. 44 To reduce the effect of clustered markers on the map construction and reduce the computing load, we picked one representative anchor marker that had the most informative meiosis from each of these clusters in the linkage map construction. Afterwards, we rejoined the markers within the 'zero recombination clusters' that were excluded during the initial mapping steps. This procedure relocated the informative markers onto the linkage maps based on the positions of their representative anchor marker. Such clustered markers are still valuable for the chromosome-scale scaffolding.", "cite_spans": [{"start": 1113, "end": 1116, "text": "42,", "ref_id": "BIBREF42"}, {"start": 1117, "end": 1119, "text": "43", "ref_id": "BIBREF43"}, {"start": 1397, "end": 1399, "text": "44", "ref_id": "BIBREF44"}], "ref_spans": []}, {"section": "46", "text": "With the availability of such high-density mapped SNPs, the patterns of marker distribution across chromosomes can be examined. It appears that clustered markers were commonly found in regions around centromeres while less frequently found around the telomeres. This was consistent with observations in various genetic maps previously developed in fish species, such as tilapia, 45 medaka, 46 rainbow trout, 47 Atlantic salmon, 12 and catfish. 9, 16 One potential explanation is that the centromeres contain abundant tandemly repeated, heterochromatic DNA sequences. 48 As shown in Fig. 4 , the distribution of mapped SNP markers across chromosomes in channel catfish is consistent with the observation of telomere and centromere effects, 49 which would result in a higher recombination rate near the telomeres while a lower recombination rate near the centre of the chromosomes. The recombination rates might be positively correlated with GC content, as in human, 50 pig, 51 chicken, 52 rodent, 53 and yeast, 54 or correlated with some other genomic features such as gene density and the presence of genes determining recombination hotspots. The PRDM9 gene was recently found to determine the recombination hotspots in the mammalian genomes. [55] [56] [57] Future investigations on recombination landscape warrant the characterization of genomic features, affecting the meiotic recombination in catfish upon the availability of fully assembled genome sequences. The suppression of recombination in males relative to the females observed in channel catfish (averaged female-to-male ratio is 1.7 : 1) was consistent with our previous observation 2 as well as many other studies. Recombination rates differ between the two sexes in many organisms where recombination occurs more frequently in the homogametic sex than in the heterogametic sex. 50, 58 The similar phenomenon was reported in many other fish species such as Atlantic salmon (1.38 : 1), rainbow trout (1.68 : 1), European sea bass (1.60 : 1), Arctic char (1.69 : 1), and silver carp (1.52 : 1). 12, 14, [58] [59] [60] [61] Striking recombination differences between the sexes were observed in zebrafish (2.74 : 1) 58 and grass carp (2.0 : 1). 62 These observations indicated that even closely related fish species differ in genetic sizes and the extent of sexual dimorphism for recombination fraction, 50 similarly as in mammals. Although the genetic basis for recombination bias between sexes remains unknown, several theories were proposed to explain this observation. One explanation from selection perspective suggests that selection pressure is stronger in male gametes than in Figure 5 . Comparison of the recombination rate between female and male. The inter-marker distances (cM) for all pairs of adjacent markers from both femaleand male-specific maps were used. The diagonal line represents sex-equal recombination rates.", "cite_spans": [{"start": 379, "end": 381, "text": "45", "ref_id": "BIBREF45"}, {"start": 390, "end": 392, "text": "46", "ref_id": "BIBREF46"}, {"start": 408, "end": 410, "text": "47", "ref_id": "BIBREF47"}, {"start": 428, "end": 430, "text": "12", "ref_id": "BIBREF12"}, {"start": 444, "end": 446, "text": "9,", "ref_id": "BIBREF9"}, {"start": 447, "end": 449, "text": "16", "ref_id": "BIBREF16"}, {"start": 567, "end": 569, "text": "48", "ref_id": "BIBREF48"}, {"start": 739, "end": 741, "text": "49", "ref_id": "BIBREF49"}, {"start": 965, "end": 967, "text": "50", "ref_id": "BIBREF50"}, {"start": 973, "end": 975, "text": "51", "ref_id": "BIBREF51"}, {"start": 985, "end": 987, "text": "52", "ref_id": "BIBREF52"}, {"start": 996, "end": 998, "text": "53", "ref_id": "BIBREF53"}, {"start": 1010, "end": 1012, "text": "54", "ref_id": "BIBREF54"}, {"start": 1243, "end": 1247, "text": "[55]", "ref_id": "BIBREF55"}, {"start": 1248, "end": 1252, "text": "[56]", "ref_id": "BIBREF56"}, {"start": 1253, "end": 1257, "text": "[57]", "ref_id": "BIBREF57"}, {"start": 1842, "end": 1845, "text": "50,", "ref_id": "BIBREF50"}, {"start": 1846, "end": 1848, "text": "58", "ref_id": "BIBREF58"}, {"start": 2056, "end": 2059, "text": "12,", "ref_id": "BIBREF12"}, {"start": 2060, "end": 2063, "text": "14,", "ref_id": "BIBREF14"}, {"start": 2064, "end": 2068, "text": "[58]", "ref_id": "BIBREF58"}, {"start": 2069, "end": 2073, "text": "[59]", "ref_id": "BIBREF59"}, {"start": 2074, "end": 2078, "text": "[60]", "ref_id": "BIBREF60"}, {"start": 2079, "end": 2083, "text": "[61]", "ref_id": "BIBREF61"}, {"start": 2175, "end": 2177, "text": "58", "ref_id": "BIBREF58"}, {"start": 2204, "end": 2206, "text": "62", "ref_id": "BIBREF62"}], "ref_spans": [{"start": 582, "end": 588, "text": "Fig. 4", "ref_id": "FIGREF3"}]}, {"section": "46", "text": "female gametes during the haploid life stage. This difference could lead to male-specific selection to maintain beneficial haplotype to decrease the male recombination rate. 58, 63 An alternative explanation is that the female recombination rate is higher to compensate for the apparently less stringent checkpoint for achiasmatic chromosomes compared with males. 50 In human, cytological studies suggested that sex-specific differences in recombination may derive from chromatin differences established prior to the onset of the recombination pathway. 64 The high-density and the relatively high-resolution genetic map provides valuable resource for integrating the physical map and whole-genome assemblies. In this study, we anchored the catfish physical map to genetic linkage map through BES and PMCSS that contain SNP markers. With this linkage map of channel catfish, we were able to anchor 87% of the catfish BAC physical map contigs, covering \u223c92% of the catfish genome. This is a great improvement on map integration compared with our previous efforts that only anchored 44.8% of the catfish BAC physical map contigs accounting for 52.8% of the catfish genome. To our knowledge, this is also the highest percentage of physical maps integration with genetic maps that were obtained in any aquaculture species. The well-integrated map is useful for comprehensive comparative genomic analyses, fine-scale mapping of QTL, and positional cloning for candidate genes. 10 Moreover, the integrated map can be used as an important resource for the validation of the catfish whole-genome assembly.", "cite_spans": [{"start": 174, "end": 177, "text": "58,", "ref_id": "BIBREF58"}, {"start": 178, "end": 180, "text": "63", "ref_id": "BIBREF63"}, {"start": 364, "end": 366, "text": "50", "ref_id": "BIBREF50"}, {"start": 553, "end": 555, "text": "64", "ref_id": "BIBREF64"}, {"start": 1471, "end": 1473, "text": "10", "ref_id": "BIBREF10"}], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "A fine-scale map of recombination rates and hotspots across the human genome", "authors": [{"first": "S", "middle": [], "last": "Myers", "suffix": ""}, {"first": "L", "middle": [], "last": "Bottolo", "suffix": ""}, {"first": "C", "middle": [], "last": "Freeman", "suffix": ""}, {"first": "G", "middle": [], "last": "Mcvean", "suffix": ""}, {"first": "P", "middle": [], "last": "Donnelly", "suffix": ""}], "year": 2005, "venue": "Science", "link": "19058822"}, "BIBREF1": {"title": "Construction of genetic linkage maps and comparative genome analysis of catfish using gene-associated markers", "authors": [{"first": "H", "middle": [], "last": "Kucuktas", "suffix": ""}, {"first": "S", "middle": [], "last": "Wang", "suffix": ""}, {"first": "P", "middle": [], "last": "Li", "suffix": ""}], "year": 2009, "venue": "Genetics", "link": "9511522"}, "BIBREF2": {"title": "Cloning of large segments of exogenous DNA into yeast by means of artificial chromosome vectors", "authors": [{"first": "D", "middle": ["T"], "last": "Burke", "suffix": ""}, {"first": "G", "middle": ["F"], "last": "Carle", "suffix": ""}, {"first": "M", "middle": ["V"], "last": "Olson", "suffix": ""}], "year": 1987, "venue": "Science", "link": "46031127"}, "BIBREF3": {"title": "A physical map of the human genome", "authors": [{"first": "J", "middle": ["D"], "last": "Mcpherson", "suffix": ""}, {"first": "M", "middle": [], "last": "Marra", "suffix": ""}, {"first": "L", "middle": [], "last": "Hillier", "suffix": ""}], "year": 2001, "venue": "Nature", "link": "4422523"}, "BIBREF4": {"title": "Use of an ordered cosmid library to deduce the genomic organization of Mycobacterium leprae", "authors": [{"first": "K", "middle": [], "last": "Eiglmeier", "suffix": ""}, {"first": "N", "middle": [], "last": "Honore", "suffix": ""}, {"first": "S", "middle": [], "last": "Woods", "suffix": ""}, {"first": "B", "middle": [], "last": "Caudron", "suffix": ""}, {"first": "S", "middle": [], "last": "Cole", "suffix": ""}], "year": 1993, "venue": "Mol. Microbiol", "link": "20562618"}, "BIBREF5": {"title": "Example of validation of physical map using the linkage map. (A) shows the correct physical map contig using Contig72 as an example", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF6": {"title": "A BACbased physical map of the channel catfish genome", "authors": [{"first": "P", "middle": [], "last": "Xu", "suffix": ""}, {"first": "S", "middle": [], "last": "Wang", "suffix": ""}, {"first": "L", "middle": [], "last": "Liu", "suffix": ""}, {"first": "J", "middle": [], "last": "Thorsen", "suffix": ""}, {"first": "H", "middle": [], "last": "Kucuktas", "suffix": ""}, {"first": "Z", "middle": [], "last": "Liu", "suffix": ""}], "year": 2007, "venue": "Genomics", "link": "22106663"}, "BIBREF7": {"title": "A first generation BAC-based physical map of the channel catfish genome", "authors": [{"first": "S", "middle": ["M"], "last": "Quiniou", "suffix": ""}, {"first": "G", "middle": ["C"], "last": "Waldbieser", "suffix": ""}, {"first": "M", "middle": ["V"], "last": "Duke", "suffix": ""}], "year": 2007, "venue": "BMC Genomics", "link": "140127722"}, "BIBREF8": {"title": "Comparative analysis of catfish BAC end sequences with the zebrafish genome", "authors": [{"first": "H", "middle": [], "last": "Liu", "suffix": ""}, {"first": "Y", "middle": ["L"], "last": "Jiang", "suffix": ""}, {"first": "S", "middle": ["L"], "last": "Wang", "suffix": ""}], "year": 2009, "venue": "BMC Genomics", "link": "7194808"}, "BIBREF9": {"title": "Second-generation genetic linkage map of catfish and its integration with the BAC-based physical map", "authors": [{"first": "P", "middle": [], "last": "Ninwichian", "suffix": ""}, {"first": "E", "middle": [], "last": "Peatman", "suffix": ""}, {"first": "H", "middle": [], "last": "Liu", "suffix": ""}], "year": 2012, "venue": "G3 (Bethesda)", "link": "8470484"}, "BIBREF10": {"title": "A second generation integrated map of the rainbow trout (Oncorhynchus mykiss) genome: analysis of conserved synteny with model fish genomes", "authors": [{"first": "Y", "middle": [], "last": "Palti", "suffix": ""}, {"first": "C", "middle": [], "last": "Genet", "suffix": ""}, {"first": "G", "middle": [], "last": "Gao", "suffix": ""}], "year": 2012, "venue": "Mar. Biotechnol. (NY)", "link": "2310029"}, "BIBREF11": {"title": "A high-resolution linkage map for comparative genome analysis and QTL fine mapping in Asian seabass", "authors": [{"first": "C", "middle": ["M"], "last": "Wang", "suffix": ""}, {"first": "Z", "middle": ["Y"], "last": "Bai", "suffix": ""}, {"first": "X", "middle": ["P"], "last": "He", "suffix": ""}], "year": 2011, "venue": "Lates calcarifer", "link": null}, "BIBREF12": {"title": "A dense SNP-based linkage map for Atlantic salmon (Salmo salar) reveals extended chromosome homeologies and striking differences in sex-specific recombination patterns", "authors": [{"first": "S", "middle": [], "last": "Lien", "suffix": ""}, {"first": "L", "middle": [], "last": "Gidskehaug", "suffix": ""}, {"first": "T", "middle": [], "last": "Moen", "suffix": ""}], "year": 2011, "venue": "BMC Genomics", "link": "6573013"}, "BIBREF13": {"title": "Construction of a high-density microsatellite genetic linkage map and mapping of sexual and growth-related traits in half-smooth tongue sole (Cynoglossus semilaevis)", "authors": [{"first": "W", "middle": [], "last": "Song", "suffix": ""}, {"first": "Y", "middle": [], "last": "Li", "suffix": ""}, {"first": "Y", "middle": [], "last": "Zhao", "suffix": ""}], "year": 2012, "venue": "PLoS ONE", "link": "18431830"}, "BIBREF14": {"title": "A second generation genetic map for rainbow trout (Oncorhynchus mykiss)", "authors": [{"first": "C", "middle": ["E"], "last": "Rexroad", "suffix": ""}, {"first": "", "middle": [], "last": "Iii", "suffix": ""}, {"first": "Y", "middle": [], "last": "Palti", "suffix": ""}, {"first": "S", "middle": ["A"], "last": "Gahr", "suffix": ""}, {"first": "R", "middle": ["L"], "last": "Vallejo", "suffix": ""}], "year": 2008, "venue": "BMC Genetics", "link": "17313878"}, "BIBREF15": {"title": "A dense genetic linkage map for common carp and its integration with a BAC-based physical map", "authors": [{"first": "L", "middle": [], "last": "Zhao", "suffix": ""}, {"first": "Y", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "P", "middle": [], "last": "Ji", "suffix": ""}], "year": 2013, "venue": "PLoS ONE", "link": "13828658"}, "BIBREF16": {"title": "An AFLP-based genetic linkage map of channel catfish (Ictalurus punctatus) constructed by using an interspecific hybrid resource family", "authors": [{"first": "Z", "middle": [], "last": "Liu", "suffix": ""}, {"first": "A", "middle": [], "last": "Karsi", "suffix": ""}, {"first": "P", "middle": [], "last": "Li", "suffix": ""}, {"first": "D", "middle": [], "last": "Cao", "suffix": ""}, {"first": "R", "middle": [], "last": "Dunham", "suffix": ""}], "year": 2003, "venue": "Genetics", "link": "12188285"}, "BIBREF17": {"title": "A microsatellite-based genetic linkage map for channel catfish, Ictalurus punctatus", "authors": [{"first": "G", "middle": ["C"], "last": "Waldbieser", "suffix": ""}, {"first": "B", "middle": ["G"], "last": "Bosworth", "suffix": ""}, {"first": "D", "middle": ["J"], "last": "Nonneman", "suffix": ""}, {"first": "W", "middle": ["R"], "last": "Wolters", "suffix": ""}], "year": 2001, "venue": "Genetics", "link": "22977982"}, "BIBREF18": {"title": "BAC-based upgrading and physical integration of a genetic SNP map in Atlantic salmon", "authors": [{"first": "S", "middle": [], "last": "Lorenz", "suffix": ""}, {"first": "S", "middle": [], "last": "Brenna-Hansen", "suffix": ""}, {"first": "T", "middle": [], "last": "Moen", "suffix": ""}], "year": 2010, "venue": "Anim. Genet", "link": "24860578"}, "BIBREF19": {"title": "Rapid SNP discovery and genetic mapping using sequenced RAD markers", "authors": [{"first": "N", "middle": ["A"], "last": "Baird", "suffix": ""}, {"first": "P", "middle": ["D"], "last": "Etter", "suffix": ""}, {"first": "T", "middle": ["S"], "last": "Atwood", "suffix": ""}], "year": 2008, "venue": "PLoS ONE", "link": "16258169"}, "BIBREF20": {"title": "Genome-wide genetic marker discovery and genotyping using next-generation sequencing", "authors": [{"first": "J", "middle": ["W"], "last": "Davey", "suffix": ""}, {"first": "P", "middle": ["A"], "last": "Hohenlohe", "suffix": ""}, {"first": "P", "middle": ["D"], "last": "Etter", "suffix": ""}, {"first": "J", "middle": ["Q"], "last": "Boone", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Catchen", "suffix": ""}, {"first": "M", "middle": ["L"], "last": "Blaxter", "suffix": ""}], "year": 2011, "venue": "Nat. Rev. Genet", "link": "15080731"}, "BIBREF21": {"title": "Rapid and cost-effective polymorphism identification and genotyping using restriction site associated DNA (RAD) markers", "authors": [{"first": "M", "middle": ["R"], "last": "Miller", "suffix": ""}, {"first": "J", "middle": ["P"], "last": "Dunham", "suffix": ""}, {"first": "A", "middle": [], "last": "Amores", "suffix": ""}, {"first": "W", "middle": ["A"], "last": "Cresko", "suffix": ""}, {"first": "E", "middle": ["A"], "last": "Johnson", "suffix": ""}], "year": 2007, "venue": "Genome Res", "link": "12934850"}, "BIBREF22": {"title": "Genetic mapping of quantitative trait loci (QTL) for body-weight in Atlantic salmon (Salmo salar) using a 6.5K SNP array", "authors": [{"first": "A", "middle": ["P"], "last": "Gutierrez", "suffix": ""}, {"first": "K", "middle": ["P"], "last": "Lubieniecki", "suffix": ""}, {"first": "E", "middle": ["A"], "last": "Davidson", "suffix": ""}], "year": 2012, "venue": "Aquaculture", "link": "84716335"}, "BIBREF23": {"title": "A high density SNP array for the domestic horse and extant Perissodactyla: utility for association mapping, genetic diversity, and phylogeny studies", "authors": [{"first": "M", "middle": ["E"], "last": "Mccue", "suffix": ""}, {"first": "D", "middle": ["L"], "last": "Bannasch", "suffix": ""}, {"first": "J", "middle": ["L"], "last": "Petersen", "suffix": ""}], "year": 2012, "venue": "PLoS Genet", "link": "2107061"}, "BIBREF24": {"title": "Development and validation of a high density SNP genotyping array for Atlantic salmon (Salmo salar)", "authors": [{"first": "R", "middle": ["D"], "last": "Houston", "suffix": ""}, {"first": "J", "middle": ["B"], "last": "Taggart", "suffix": ""}, {"first": "T", "middle": [], "last": "Cezard", "suffix": ""}], "year": 2014, "venue": "BMC Genomics", "link": "183868"}, "BIBREF25": {"title": "Multiple sex-associated regions and a putative sex chromosome in zebrafish revealed by RAD mapping and population genomics", "authors": [{"first": "J", "middle": ["L"], "last": "Anderson", "suffix": ""}, {"first": "A", "middle": ["R"], "last": "Mari", "suffix": ""}, {"first": "I", "middle": [], "last": "Braasch", "suffix": ""}], "year": 2012, "venue": "PLoS ONE", "link": "3924228"}, "BIBREF26": {"title": "Linkage maps of the Atlantic salmon (Salmo salar) genome derived from RAD sequencing", "authors": [{"first": "S", "middle": [], "last": "Gonen", "suffix": ""}, {"first": "N", "middle": ["R"], "last": "Lowe", "suffix": ""}, {"first": "T", "middle": [], "last": "Cezard", "suffix": ""}, {"first": "K", "middle": [], "last": "Gharbi", "suffix": ""}, {"first": "S", "middle": ["C"], "last": "Bishop", "suffix": ""}, {"first": "R", "middle": ["D"], "last": "Houston", "suffix": ""}], "year": 2014, "venue": "BMC Genomics", "link": "2607866"}, "BIBREF27": {"title": "Meiotic maps of sockeye salmon derived from massively parallel DNA sequencing", "authors": [{"first": "M", "middle": ["V"], "last": "Everett", "suffix": ""}, {"first": "M", "middle": ["R"], "last": "Miller", "suffix": ""}, {"first": "J", "middle": ["E"], "last": "Seeb", "suffix": ""}], "year": 2012, "venue": "BMC Genomics", "link": "6236373"}, "BIBREF28": {"title": "Mapping and validation of the major sex-determining region in Nile Tilapia (Oreochromis niloticus L.) using RAD sequencing", "authors": [{"first": "C", "middle": [], "last": "Palaiokostas", "suffix": ""}, {"first": "M", "middle": [], "last": "Bekaert", "suffix": ""}, {"first": "M", "middle": ["G Q"], "last": "Khan", "suffix": ""}], "year": 2013, "venue": "PLoS ONE", "link": "17385699"}, "BIBREF29": {"title": "Whole genome comparative analysis of channel catfish (Ictalurus punctatus) with four model fish species", "authors": [{"first": "Y", "middle": [], "last": "Jiang", "suffix": ""}, {"first": "X", "middle": [], "last": "Gao", "suffix": ""}, {"first": "S", "middle": [], "last": "Liu", "suffix": ""}], "year": 2013, "venue": "BMC Genomics", "link": "13305232"}, "BIBREF30": {"title": "Comparative genomic analysis of catfish linkage group 8 reveals two homologous chromosomes in zebrafish and other teleosts with extensive inter-chromosomal rearrangements", "authors": [{"first": "Y", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "S", "middle": [], "last": "Liu", "suffix": ""}, {"first": "J", "middle": [], "last": "Lu", "suffix": ""}], "year": 2013, "venue": "BMC Genomics", "link": "18732318"}, "BIBREF31": {"title": "Generation of genome-scale gene-associated SNPs in catfish for the construction of a high-density SNP array", "authors": [{"first": "S", "middle": [], "last": "Liu", "suffix": ""}, {"first": "Z", "middle": [], "last": "Zhou", "suffix": ""}, {"first": "J", "middle": [], "last": "Lu", "suffix": ""}], "year": 2011, "venue": "BMC Genomics", "link": "2791946"}, "BIBREF32": {"title": "Identification and analysis of genomewide SNPs provide insight into signatures of selection and domestication in catfish", "authors": [{"first": "L", "middle": [], "last": "Sun", "suffix": ""}, {"first": "S", "middle": [], "last": "Liu", "suffix": ""}, {"first": "R", "middle": [], "last": "Wang", "suffix": ""}], "year": 2014, "venue": "PLoS ONE", "link": null}, "BIBREF33": {"title": "Development of the catfish 250K SNP array for genome-wide association studies", "authors": [{"first": "S", "middle": [], "last": "Liu", "suffix": ""}, {"first": "L", "middle": [], "last": "Sun", "suffix": ""}, {"first": "Y", "middle": [], "last": "Li", "suffix": ""}], "year": 2014, "venue": "BMC Res. Notes", "link": "5617320"}, "BIBREF34": {"title": "JoinMap 4. Software for the calculation of genetic linkage maps in experimental populations", "authors": [{"first": "J", "middle": [], "last": "Van Ooijen", "suffix": ""}], "year": 2006, "venue": "Kyazma BV", "link": "209562588"}, "BIBREF35": {"title": "Construction of integrated genetic linkage maps by means of a new computer package: Join Map", "authors": [{"first": "P", "middle": [], "last": "Stam", "suffix": ""}], "year": 1993, "venue": "Plant J", "link": "84251807"}, "BIBREF36": {"title": "Accurate construction of consensus genetic maps via integer linear programming", "authors": [{"first": "Y", "middle": [], "last": "Wu", "suffix": ""}, {"first": "T", "middle": ["J"], "last": "Close", "suffix": ""}, {"first": "S", "middle": [], "last": "Lonardi", "suffix": ""}], "year": 2011, "venue": "IEEE/ACM Trans. Comput. Biol. Bioinform", "link": "637341"}, "BIBREF37": {"title": "MapChart: software for the graphical presentation of linkage maps and QTLs", "authors": [{"first": "R", "middle": [], "last": "Voorrips", "suffix": ""}], "year": 2002, "venue": "J. Hered", "link": "27953258"}, "BIBREF38": {"title": "Analysis of human genetic linkage", "authors": [{"first": "J", "middle": [], "last": "Ott", "suffix": ""}], "year": 1999, "venue": "", "link": null}, "BIBREF39": {"title": "On the use of the classical tests for detecting linkage", "authors": [{"first": "A", "middle": [], "last": "Garcia-Dorado", "suffix": ""}, {"first": "A", "middle": [], "last": "Gallego", "suffix": ""}], "year": 1992, "venue": "J. Hered", "link": "20335318"}, "BIBREF40": {"title": "Channel catfish BAC-end sequences for marker development and assessment of syntenic conservation with other fish species", "authors": [{"first": "P", "middle": [], "last": "Xu", "suffix": ""}, {"first": "S", "middle": [], "last": "Wang", "suffix": ""}, {"first": "L", "middle": [], "last": "Liu", "suffix": ""}], "year": 2006, "venue": "Anim. Genet", "link": "19134988"}, "BIBREF41": {"title": "Generation of physical map contig-specific sequences useful for whole genome sequence scaffolding", "authors": [{"first": "Y", "middle": [], "last": "Jiang", "suffix": ""}, {"first": "P", "middle": [], "last": "Ninwichian", "suffix": ""}, {"first": "S", "middle": [], "last": "Liu", "suffix": ""}], "year": 2013, "venue": "PLoS ONE", "link": "2265949"}, "BIBREF42": {"title": "Two-phase analysis in consensus genetic mapping, G3-Genes Genom", "authors": [{"first": "Y", "middle": [], "last": "Ronin", "suffix": ""}, {"first": "D", "middle": [], "last": "Mester", "suffix": ""}, {"first": "D", "middle": [], "last": "Minkov", "suffix": ""}], "year": 2012, "venue": "Genet", "link": null}, "BIBREF43": {"title": "Building reliable genetic maps: different mapping strategies may result in different maps", "authors": [{"first": "Y", "middle": [], "last": "Ronin", "suffix": ""}, {"first": "D", "middle": [], "last": "Mester", "suffix": ""}, {"first": "D", "middle": [], "last": "Minkov", "suffix": ""}, {"first": "A", "middle": [], "last": "Korol", "suffix": ""}], "year": 2010, "venue": "Nat. Sci", "link": "26813831"}, "BIBREF44": {"title": "The zebrafish reference genome sequence and its relationship to the human genome", "authors": [{"first": "K", "middle": [], "last": "Howe", "suffix": ""}, {"first": "M", "middle": ["D"], "last": "Clark", "suffix": ""}, {"first": "C", "middle": ["F"], "last": "Torroja", "suffix": ""}], "year": 2013, "venue": "Nature", "link": "205233806"}, "BIBREF45": {"title": "A genetic linkage map of a cichlid fish, the tilapia", "authors": [{"first": "T", "middle": ["D"], "last": "Kocher", "suffix": ""}, {"first": "W", "middle": ["J"], "last": "Lee", "suffix": ""}, {"first": "H", "middle": [], "last": "Sobolewska", "suffix": ""}, {"first": "D", "middle": [], "last": "Penman", "suffix": ""}, {"first": "B", "middle": [], "last": "Mcandrew", "suffix": ""}], "year": 1998, "venue": "Genetics", "link": null}, "BIBREF46": {"title": "A detailed linkage map of medaka, Oryzias latipes: comparative genomics and genome evolution", "authors": [{"first": "K", "middle": [], "last": "Naruse", "suffix": ""}, {"first": "S", "middle": [], "last": "Fukamachi", "suffix": ""}, {"first": "H", "middle": [], "last": "Mitani", "suffix": ""}], "year": 2000, "venue": "Genetics", "link": "40176368"}, "BIBREF47": {"title": "A microsatellite linkage map of rainbow trout (Oncorhynchus mykiss) characterized by large sex-specific differences in recombination rates", "authors": [{"first": "T", "middle": [], "last": "Sakamoto", "suffix": ""}, {"first": "R", "middle": ["G"], "last": "Danzmann", "suffix": ""}, {"first": "K", "middle": [], "last": "Gharbi", "suffix": ""}], "year": 2000, "venue": "Genetics", "link": "18319553"}, "BIBREF48": {"title": "Why is the centromere so cold?", "authors": [{"first": "K", "middle": ["H A"], "last": "Choo", "suffix": ""}], "year": 1998, "venue": "Genome Res", "link": "30698731"}, "BIBREF49": {"title": "Heterogeneity in rates of recombination across the mouse genome", "authors": [{"first": "M", "middle": ["W"], "last": "Nachman", "suffix": ""}, {"first": "G", "middle": ["A"], "last": "Churchill", "suffix": ""}], "year": 1996, "venue": "Genetics", "link": "28496399"}, "BIBREF50": {"title": "An evolutionary view of human recombination", "authors": [{"first": "G", "middle": [], "last": "Coop", "suffix": ""}, {"first": "M", "middle": [], "last": "Przeworski", "suffix": ""}], "year": 2007, "venue": "Nat. Rev. Genet", "link": "14413278"}, "BIBREF51": {"title": "A high density recombination map of the pig reveals a correlation between sex-specific recombination and GC content", "authors": [{"first": "F", "middle": [], "last": "Tortereau", "suffix": ""}, {"first": "B", "middle": [], "last": "Servin", "suffix": ""}, {"first": "L", "middle": [], "last": "Frantz", "suffix": ""}], "year": 2012, "venue": "BMC Genomics", "link": "15438572"}, "BIBREF52": {"title": "A high-density SNP-based linkage map of the chicken genome reveals sequence features correlated with recombination rate", "authors": [{"first": "M", "middle": ["A"], "last": "Groenen", "suffix": ""}, {"first": "P", "middle": [], "last": "Wahlberg", "suffix": ""}, {"first": "M", "middle": [], "last": "Foglio", "suffix": ""}], "year": 2009, "venue": "Genome Res", "link": "2629501"}, "BIBREF53": {"title": "Comparative recombination rates in the rat, mouse, and human genomes", "authors": [{"first": "M", "middle": ["I"], "last": "Jensen-Seaman", "suffix": ""}, {"first": "T", "middle": ["S"], "last": "Furey", "suffix": ""}, {"first": "B", "middle": ["A"], "last": "Payseur", "suffix": ""}], "year": 2004, "venue": "Genome Res", "link": "1511215"}, "BIBREF54": {"title": "Meiotic recombination hot spots and cold spots", "authors": [{"first": "T", "middle": ["D"], "last": "Petes", "suffix": ""}], "year": 2001, "venue": "Nat. Rev. Genet", "link": "205016033"}, "BIBREF55": {"title": "PRDM9 is a major determinant of meiotic recombination hotspots in humans and mice", "authors": [{"first": "F", "middle": [], "last": "Baudat", "suffix": ""}, {"first": "J", "middle": [], "last": "Buard", "suffix": ""}, {"first": "C", "middle": [], "last": "Grey", "suffix": ""}], "year": 2010, "venue": "Science", "link": "17742322"}, "BIBREF56": {"title": "Drive against hotspot motifs in primates implicates the PRDM9 gene in meiotic recombination", "authors": [{"first": "S", "middle": [], "last": "Myers", "suffix": ""}, {"first": "R", "middle": [], "last": "Bowden", "suffix": ""}, {"first": "A", "middle": [], "last": "Tumian", "suffix": ""}], "year": 2010, "venue": "Science", "link": "12302419"}, "BIBREF57": {"title": "Prdm9 controls activation of mammalian recombination hotspots", "authors": [{"first": "E", "middle": ["D"], "last": "Parvanov", "suffix": ""}, {"first": "P", "middle": ["M"], "last": "Petkov", "suffix": ""}, {"first": "K", "middle": [], "last": "Paigen", "suffix": ""}], "year": 2010, "venue": "", "link": null}, "BIBREF58": {"title": "Sex-specific recombination rates in zebrafish (Danio rerio)", "authors": [{"first": "A", "middle": [], "last": "Singer", "suffix": ""}, {"first": "H", "middle": [], "last": "Perlman", "suffix": ""}, {"first": "Y", "middle": ["L"], "last": "Yan", "suffix": ""}], "year": 2002, "venue": "", "link": "12184216"}, "BIBREF59": {"title": "A microsatellite linkage map of the European sea bass Dicentrarchus labrax L", "authors": [{"first": "D", "middle": ["A"], "last": "Chistiakov", "suffix": ""}, {"first": "B", "middle": [], "last": "Hellemans", "suffix": ""}, {"first": "C", "middle": ["S"], "last": "Haley", "suffix": ""}], "year": 2005, "venue": "Genetics", "link": "16312681"}, "BIBREF60": {"title": "A second generation genetic linkage map for silver carp (Hypophthalmichehys molitrix) using microsatellite markers", "authors": [{"first": "W", "middle": ["J"], "last": "Guo", "suffix": ""}, {"first": "J", "middle": ["G"], "last": "Tong", "suffix": ""}, {"first": "X", "middle": ["M"], "last": "Yu", "suffix": ""}], "year": 2013, "venue": "Aquaculture", "link": "85109077"}, "BIBREF61": {"title": "A genetic linkage map for Arctic char (Salvelinus alpinus): evidence for higher recombination rates and segregation distortion in hybrid versus pure strain mapping parents", "authors": [{"first": "R", "middle": ["A"], "last": "Woram", "suffix": ""}, {"first": "C", "middle": [], "last": "Mcgowan", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Stout", "suffix": ""}], "year": 2004, "venue": "Genome", "link": "7084155"}, "BIBREF62": {"title": "A consensus linkage map of the grass carp (Ctenopharyngodon idella) based on microsatellites and SNPs", "authors": [{"first": "J", "middle": ["H"], "last": "Xia", "suffix": ""}, {"first": "F", "middle": [], "last": "Liu", "suffix": ""}, {"first": "Z", "middle": ["Y"], "last": "Zhu", "suffix": ""}], "year": 2010, "venue": "BMC Genomics", "link": "9437610"}, "BIBREF63": {"title": "Recombination difference between sexes: a role for haploid selection", "authors": [{"first": "T", "middle": [], "last": "Lenormand", "suffix": ""}, {"first": "J", "middle": [], "last": "Dutheil", "suffix": ""}], "year": 2005, "venue": "PLoS Biol", "link": "10535317"}, "BIBREF64": {"title": "Cytological studies of human meiosis: sex-specific differences in recombination originate at, or prior to, establishment of double-strand breaks", "authors": [{"first": "J", "middle": ["R"], "last": "Gruhn", "suffix": ""}, {"first": "C", "middle": [], "last": "Rubio", "suffix": ""}, {"first": "K", "middle": ["W"], "last": "Broman", "suffix": ""}, {"first": "P", "middle": ["A"], "last": "Hunt", "suffix": ""}, {"first": "T", "middle": [], "last": "Hassold", "suffix": ""}], "year": 2013, "venue": "PLoS ONE", "link": "13934638"}}, "ref_entries": {"FIGREF0": {"text": "Figure 1. Illustration of female-specific linkage map.", "type": "figure"}, "FIGREF1": {"text": "Figure 2. Illustration of male-specific linkage map.", "type": "figure"}, "FIGREF2": {"text": "Figure 3. Illustration of sex-averaged linkage map.", "type": "figure"}, "FIGREF3": {"text": "Figure 4. The patterns of localized regional recombination rates along each linkage group.", "type": "figure"}, "FIGREF4": {"text": "Figure 6. Illustration of integration of the linkage map (left) with the physical map (right). The linkage group 12 (LG12) was used for the illustration. Vertical bars represent physical map contigs containing at least two SNPs mapped onto the linkage map, and the dot spots indicate physical map contigs with only one SNP.", "type": "figure"}, "TABREF0": {"text": "SNPs selected for linkage mapping", "type": "table"}, "TABREF1": {"text": "SNPs placed on the linkage maps", "type": "table"}, "TABREF2": {"text": "Summary of the sex-specific linkage maps of channel catfish", "type": "table"}, "TABREF3": {"text": "Summary of the sex-averaged linkage map of channel catfish", "type": "table"}, "TABREF4": {"text": "Integration of channel catfish linkage map with physical mapNumber of physical map contigs anchored to linkage map in this workData obtained from Xu et al.Data obtained from Ninwichian et al.Cross-validation between linkage map and physical map Item Number Number of physical map contigs with BES-associated SNPs 2,790 Number of physical map contigs anchored through BES-associated SNPsNumber of physical map contigs with at least two BES-associated SNPsNumber of physical map contigs mapped onto different LGs 47 Number of BAC clones with BES-associated SNPs 2,707 Number of BAC clones with at least two BES-associated SNPs 238 Number of BAC clones mapped onto different LGs 7", "type": "table"}}}
{"paper_id": "18989559", "_pdf_hash": "b76862d572918546436d7bc825d7bdc709fb1768", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Accessible bibliography on retrial queues, Mathematical and Computer Modeling", "authors": [{"first": "J", "middle": ["R"], "last": "Artalejo", "suffix": ""}], "year": 1999, "venue": "", "link": null}, "BIBREF1": {"title": "A classified bibliography of research on retrial queues: progress in", "authors": [{"first": "J", "middle": ["R"], "last": "Artalejo", "suffix": ""}], "year": 1999, "venue": "", "link": null}, "BIBREF2": {"title": "Steady state analysis of an M/G/1 queue with repeated attempts and two phase service", "authors": [{"first": "J", "middle": ["R"], "last": "Artalejo", "suffix": ""}, {"first": "G", "middle": [], "last": "Choudhury", "suffix": ""}], "year": 2004, "venue": "Quality Technology and Quantitative Management", "link": "15020466"}, "BIBREF3": {"title": "Retrial queueing systems", "authors": [{"first": "J", "middle": ["R"], "last": "Artalejo", "suffix": ""}, {"first": "", "middle": [], "last": "Gomez-Corral", "suffix": ""}], "year": 2008, "venue": "", "link": "123639168"}, "BIBREF4": {"title": "Some aspects of an M/G/1 queueing system with optional second service", "authors": [{"first": "G", "middle": [], "last": "Choudhury", "suffix": ""}], "year": 2003, "venue": "Top", "link": null}, "BIBREF5": {"title": "Templeton Retrial queues", "authors": [{"first": "G", "middle": ["I"], "last": "Falin", "suffix": ""}, {"first": "J", "middle": ["G C"], "last": "", "suffix": ""}], "year": 1997, "venue": "", "link": null}, "BIBREF6": {"title": "An M/G/1 queue with impatient customers,a second optional service and different vacation policies", "authors": [{"first": "Kasturi", "middle": [], "last": "Ramanath", "suffix": ""}, {"first": "K", "middle": [], "last": "Kalidass", "suffix": ""}], "year": 2009, "venue": "", "link": null}, "BIBREF7": {"title": "An M/G/1 queue with second optional service. Queueing systems", "authors": [{"first": "K", "middle": ["C"], "last": "Madan", "suffix": ""}], "year": 2000, "venue": "", "link": null}, "BIBREF8": {"title": "A single server Poisson input queue with a second optional channel. Queueing systems", "authors": [{"first": "J", "middle": [], "last": "Medhi", "suffix": ""}], "year": 2002, "venue": "", "link": null}, "BIBREF9": {"title": "Performance analysis of an M/G/1 retrial queue with non-persistent calls, two phases of heterogeneous service and different vacation policies", "authors": [{"first": "M", "middle": [], "last": "Kumar", "suffix": ""}, {"first": "R", "middle": [], "last": "Arumuganathan", "suffix": ""}], "year": 2009, "venue": "Int. J. of Open Problems in Comp. Sci. and Math", "link": null}}, "ref_entries": {}}
{"paper_id": "18989713", "_pdf_hash": "7fc86f74d8ae6e7e7793d3c7895ad06e27a12074", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "An introduction to chordal graphs and clique trees", "authors": [{"first": "J", "middle": ["R S"], "last": "Blair", "suffix": ""}, {"first": "B", "middle": [], "last": "Peyton", "suffix": ""}], "year": 1993, "venue": "Graph Theory and Sparse Matrix Computations", "link": null}, "BIBREF1": {"title": "Treewidth and pathwidth of permutation graphs", "authors": [{"first": "H", "middle": ["L"], "last": "Bodlaender", "suffix": ""}, {"first": "T", "middle": [], "last": "Kloks", "suffix": ""}, {"first": "D", "middle": [], "last": "Kratsch", "suffix": ""}], "year": 1993, "venue": "Proceedings of the 20th International Colloquium on Automata, Languages and Programming (ICALP'93)", "link": "17720172"}, "BIBREF2": {"title": "Algorithmic Graph Theory and Perfect Graphs", "authors": [{"first": "M", "middle": ["C"], "last": "Golumbic", "suffix": ""}], "year": 1980, "venue": "", "link": "122758481"}, "BIBREF3": {"title": "Weakly triangulated graphs", "authors": [{"first": "R", "middle": [], "last": "Hayward", "suffix": ""}], "year": 1985, "venue": "J. Combin. Theory ser. B", "link": "34139881"}, "BIBREF4": {"title": "Treewidth of circle graphs", "authors": [{"first": "T", "middle": [], "last": "Kloks", "suffix": ""}], "year": 1993, "venue": "Proceedings 4th Annual International Symposium on Algorithms and Computation (ISAAC'93)", "link": "23289552"}, "BIBREF5": {"title": "Computing treewidth and minimum ll-in: All you need are the minimal separators", "authors": [{"first": "T", "middle": [], "last": "Kloks", "suffix": ""}, {"first": "H", "middle": ["L"], "last": "Bodlaender", "suffix": ""}, {"first": "H", "middle": [], "last": "Mller", "suffix": ""}, {"first": "D", "middle": [], "last": "Kratsch", "suffix": ""}], "year": 1993, "venue": "Proceedings First Annual European Symposium on Algorithms (ESA'93)", "link": "38984718"}, "BIBREF6": {"title": "Erratum to the ESA'93 proceedings", "authors": [{"first": "T", "middle": [], "last": "Kloks", "suffix": ""}, {"first": "H", "middle": ["L"], "last": "Bodlaender", "suffix": ""}, {"first": "H", "middle": [], "last": "Mller", "suffix": ""}, {"first": "D", "middle": [], "last": "Kratsch", "suffix": ""}], "year": 1994, "venue": "Proceedings Second Annual European Symposium on Algorithms (ESA'94)", "link": null}, "BIBREF7": {"title": "Finding all minimal separators of a graph", "authors": [{"first": "T", "middle": [], "last": "Kloks", "suffix": ""}, {"first": "D", "middle": [], "last": "Kratsch", "suffix": ""}], "year": 1994, "venue": "Proceedings 11th Annual Symposium on Theoretical Aspects of Computer Science (STACS'94)", "link": "31228789"}, "BIBREF8": {"title": "Treewidth of chordal bipartite graphs", "authors": [{"first": "T", "middle": [], "last": "Kloks", "suffix": ""}, {"first": "D", "middle": [], "last": "Kratsch", "suffix": ""}], "year": 1994, "venue": "Proceedings 11th Annual Symposium on Theoretical Aspects of Computer Science (STACS'94)", "link": "26824546"}, "BIBREF9": {"title": "Structural and Algorithmic Aspects of Chordal Graph Embeddings", "authors": [{"first": "A", "middle": [], "last": "Parra", "suffix": ""}], "year": 1996, "venue": "", "link": "119941785"}, "BIBREF10": {"title": "How to use the minimal separators of a graph for its chordal triangulation", "authors": [{"first": "A", "middle": [], "last": "Parra", "suffix": ""}, {"first": "P", "middle": [], "last": "Sche Er", "suffix": ""}], "year": 1995, "venue": "Proceedings of the 22nd International Colloquium on Automata, Languages and Programming (ICALP'95)", "link": null}, "BIBREF11": {"title": "Graphs minors. II. Algorithmic aspects of tree-width", "authors": [{"first": "N", "middle": [], "last": "Robertson", "suffix": ""}, {"first": "P", "middle": [], "last": "Seymour", "suffix": ""}], "year": 1986, "venue": "J. of Algorithms", "link": null}, "BIBREF12": {"title": "Algorithms for weakly triangulated graphs", "authors": [{"first": "J", "middle": [], "last": "Spinrad", "suffix": ""}, {"first": "R", "middle": [], "last": "Sritharan", "suffix": ""}], "year": 1995, "venue": "Discrete Applied Mathematics", "link": "46398890"}, "BIBREF13": {"title": "Treewidth of circulararc graphs", "authors": [{"first": "R", "middle": [], "last": "Sundaram", "suffix": ""}, {"first": "K", "middle": ["Sher"], "last": "Singh", "suffix": ""}, {"first": "C", "middle": [], "last": "Pandu Rangan", "suffix": ""}], "year": 1994, "venue": "SIAM J. Discrete Math", "link": null}}, "ref_entries": {}}
{"paper_id": "18989842", "_pdf_hash": "f83e896fad495b639a534133770396139ac11ab0", "abstract": [{"section": "Abstract", "text": "Background. Since Aerococcus sanguinicola was designated as a species in 2001, only a few cases of bacteremia have been reported. The aim with this study was to describe the clinical presentation of A sanguinicola bacteremia and to determine the antibiotic susceptibility and the capacity of the bacteria to form biofilm and to induce platelet aggregation.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Methods. Isolates of A sanguinicola from blood cultures were retrospectively identified from 2 clinical microbiology laboratories for 2006 to 2012. Species identity was confirmed through sequencing of the 16S rRNA gene. The medical charts of patients were reviewed. The minimum inhibitory concentration (MIC) for relevant antibiotics was determined. Biofilm formation was measured as the amount of crystal violet absorbed. Platelet aggregation was determined by aggregometry.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Results. Eleven cases of A sanguinicola bacteremia were identified. All patients were male and the median age was 82 years (range 67-93). Nine patients fulfilled criteria for severe sepsis, and 2 patients died at hospital. Two patients were diagnosed with infective endocarditis. Most patients had underlying urinary tract diseases or an indwelling urinary tract catheter. Five patients suffered from dementia. None of the patients was treated with immunosuppressive medications. The MIC values of the isolates were in line with previous reports, with low MICs for penicillin, cefotaxime, and vancomycin. All 11 isolates produced biofilms but not all could induce platelet aggregation.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Conclusions. A sanguinicola can cause severe infections in elderly men with urinary tract abnormalities and the bacteria possess potential virulence mechanisms.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "", "text": "Aerococcus sanguinicola is a cause of urinary tract infections, blood stream infections, and infective endocarditis (IE) [1] [2] [3] . Since it was designated as a species in 2001 [4] , only a few cases of A sanguinicola bacteremia have been reported [4, 5] and only 1 case series, describing 6 patients, addresses the clinical presentation of such infection and has been published [2] . More cases of invasive infections with Aerococcus urinae have been previously described [6, 7] . From urinary samples, A sanguinicola and A urinae are isolated at similar frequencies [1, 2, 8] . Aerococci share features with other Gram-positive bacteria; they appear in clusters or tetrads as staphylococci, but they have similar colony morphology as \u03b1-hemolytic streptococci and are catalase negative. Aerococcal species are not easily distinguishable from each other when using conventional methods based on biochemistry [9] . Importantly, A sanguinicola is consistently being identified as Aerococcus viridans by several commercially available systems such as Vitek 2, API strep, and ID 32 [1, 8] . The misidentification of A sanguinicola in clinical microbiology laboratories has likely led to an underestimation of the incidence and the clinical importance of this species. Matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) has recently been showed to be a fast and reliable method for identification and correct species determination of aerococci including A sanguinicola [8, 10] . Aerococcus sanguinicola is sensitive to most antibiotics likely to be used for empirical treatment of septicaemia such as \u03b2-lactams and vancomycin [5] . However, A sanguinicola has often reduced susceptibility to fluoroquinolones [1, 3, 5] . High-level fluoroquinolone resistance has also been described [11] . Aerococcus urinae has been shown to form biofilm on plastic surfaces in vitro and to activate human platelets [12] . It is not known whether A sanguinicola also possess these potential virulence traits. The aim with this study was to investigate the incidence of A sanguinicola bacteremia in the south of Sweden and to describe the clinical presentation of such infections. Moreover, the antibiotic susceptibility and some virulence properties of the isolates were determined.", "cite_spans": [{"start": 121, "end": 124, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 125, "end": 128, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 129, "end": 132, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 180, "end": 183, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 251, "end": 254, "text": "[4,", "ref_id": "BIBREF3"}, {"start": 255, "end": 257, "text": "5]", "ref_id": "BIBREF4"}, {"start": 382, "end": 385, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 476, "end": 479, "text": "[6,", "ref_id": "BIBREF5"}, {"start": 480, "end": 482, "text": "7]", "ref_id": "BIBREF6"}, {"start": 571, "end": 574, "text": "[1,", "ref_id": "BIBREF0"}, {"start": 575, "end": 577, "text": "2,", "ref_id": "BIBREF1"}, {"start": 578, "end": 580, "text": "8]", "ref_id": "BIBREF7"}, {"start": 911, "end": 914, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 1081, "end": 1084, "text": "[1,", "ref_id": "BIBREF0"}, {"start": 1085, "end": 1087, "text": "8]", "ref_id": "BIBREF7"}, {"start": 1508, "end": 1511, "text": "[8,", "ref_id": "BIBREF7"}, {"start": 1512, "end": 1515, "text": "10]", "ref_id": "BIBREF9"}, {"start": 1665, "end": 1668, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 1748, "end": 1751, "text": "[1,", "ref_id": "BIBREF0"}, {"start": 1752, "end": 1754, "text": "3,", "ref_id": "BIBREF2"}, {"start": 1755, "end": 1757, "text": "5]", "ref_id": "BIBREF4"}, {"start": 1822, "end": 1826, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 1939, "end": 1943, "text": "[12]", "ref_id": "BIBREF11"}], "ref_spans": []}, {"section": "MATERIAL AND METHODS", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Bacterial Isolates", "text": "Isolates were identified by searching the databases of the 2 clinical microbiology laboratories belonging to University and Regional Laboratories of Sk\u00e5ne, Sweden. These laboratories are located in Malm\u00f6 and Lund and serve all hospitals in a region with \u223c1.2 million inhabitants. Searches were performed among all isolates from blood cultures drawn between March 2006 and November 2012. Both laboratories used the BacT/Alert blood culture system (bioM\u00e9rieux, Marcy l'Etoile, France), and Gram stains were used to provide preliminary identification. Growth of catalase-negative bacteria, with colony appearance resembling \u03b1-hemolytic streptococci, in more than 1 bottle resulted routinely in species identification by sequencing of the 16S rRNA gene in Lund (2006 Lund ( -2011 or by Vitek2 (bioM\u00e9r-ieux) in Malm\u00f6 (2006 Malm\u00f6 ( -2011 . Matrix-assisted laser desorption ionization time-of-flight mass spectrometry was introduced in both laboratories in 2011 and was the primary method of species identification during 2011-2012. Bacterial isolates were stored at \u221280 o C. All isolates of A sanguinicola were subjected to sequencing of the 16S rRNA gene [13] to confirm species identity. Reclassification of older isolates from the same time period (2006-2012) was carried out with MALDI-TOF MS, as described in Senneby et al [8] . Reclassification was performed if growth was identified in more than 1 bottle and the isolates had been identified as A viridans by Vitek 2, or isolates that had been identified as \u03b1-hemolytic streptococci or Gram-positive coccus, although preliminary Gram stain had been interpreted as Gram-positive cocci in clusters. The local research ethical committee approved this study (registration number 2010/681).", "cite_spans": [{"start": 1150, "end": 1154, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 1322, "end": 1325, "text": "[8]", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "Patient Information", "text": "The medical chart of each patient was reviewed to extract clinical presentation, underlying conditions, treatment, and outcome. Systemic inflammatory response syndrome (SIRS) was determined as described previously [14] , and organ dysfunction caused by the infection was classified according to the Swedish Society of Infectious Diseases' guidelines as described by Senneby et al [7] .", "cite_spans": [{"start": 214, "end": 218, "text": "[14]", "ref_id": "BIBREF13"}, {"start": 380, "end": 383, "text": "[7]", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "Antimicrobial Testing", "text": "The minimum inhibitory concentration (MIC) for penicillin, cefotaxime, vancomycin, clindamycin, gentamicin, and ciprofloxacin was determined by the use of Etests (bioM\u00e9rieux, Marcy l'Etoile, France) according to the manufacturers' instructions. Muller Hinton agar, supplemented with 5% horse blood, was used and MICs were determined after incubation for 24 hours at 35\u00b0C in 5% CO 2 .", "cite_spans": [], "ref_spans": []}, {"section": "Quantification of Biofilm Formation", "text": "Isolates were cultivated overnight in tryptic soy broth (Difco) with 0.5% glucose at 37\u00b0C with 5% CO 2 , and biofilm was determined using crystal violet as described by Holmberg [15] with modifications as described previously [16] . The experiment was repeated 3 times. Medium alone was used as negative control. The negative control absorbance values were subtracted from the isolates' absorbance values in each experiment. A strain of Enterococcus faecalis, known to be a potent biofilm producer, was used for positive control. Heparinized plasma was obtained by centrifugation of blood from a healthy donor at 1500 g for 10 minutes.", "cite_spans": [{"start": 178, "end": 182, "text": "[15]", "ref_id": "BIBREF14"}, {"start": 226, "end": 230, "text": "[16]", "ref_id": "BIBREF15"}], "ref_spans": []}, {"section": "Platelet Aggregation", "text": "Platelet-rich plasma (PRP) and platelet-poor plasma were prepared from 3 healthy donors as described by Rasmussen et al [17] . Bacterial concentration was set as described [12] , and platelet aggregation was determined by aggregometry as described by Rasmussen et al [17] . Soluble collagen was used as positive control.", "cite_spans": [{"start": 120, "end": 124, "text": "[17]", "ref_id": "BIBREF16"}, {"start": 172, "end": 176, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 267, "end": 271, "text": "[17]", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "RESULTS", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "A sanguinicola Blood Isolates", "text": "From the laboratory in Lund, 7 isolates of A sanguinicola were identified. Three isolates had already been identified through sequencing of the 16S rRNA gene, 2 isolates were originally identified as \u03b1-hemolytic streptococci, and 2 isolates had been identified with MALDI-TOF MS. Four isolates were retrieved in the Malm\u00f6 laboratory. One isolate had been misidentified as A urinae by Vitek2, and 3 isolates were correctly identified by MALDI-TOF MS. Altogether, 11 A sanguinicola isolates were identified and confirmed through sequencing of the 16S rRNA gene. In 10 cases, A sanguinicola was found in more than 1 culture (only 1 blood culture was taken in 1 case). In 5 patients, A sanguinicola was the only organism isolated whereas 6 patients had additional pathogens isolated from their blood ( Table 1) . Abbreviations: Am, amoxicillin; Amp, ampicillin; BC, bladder cancer; BPH, benign prostate hyperplasia; Cf, cefuroxime; Ct, cefotaxime; CHF, congestive heart failure; Ci, ciprofloxacin; Cm, clindamycin; Coa, coagulation dysfunction; Con, confusion; CoNS, coagulase negative staphylococcus; Ct, cefotaxime; CVI, cerebrovascular insult with sequelae; DM2, diabetes mellitus type 2; Fe, fever; Gm, gentamicin; Hep, hepatic dysfunction; HP, hypoperfusion; HT, hypotension; ICU, intensive care unit; IE, infectious endocarditis; IHD, ischaemic heart disease; M, male; Me, meropenem; Met, metronidazole; Ni, nitrofurantoine; PC, prostate cancer; PcG, penicillin G; PcV, penicillin V; Pt, piperacillin-tazobactam; Ren, renal dysfunction; Resp, respiratory dysfunction; Ru, residual urine; UC, urinary catheter; UTI, urinary tract infection; Va, vancomycin.", "cite_spans": [], "ref_spans": [{"start": 798, "end": 806, "text": "Table 1)", "ref_id": "TABREF0"}]}, {"section": "A sanguinicola Blood Isolates", "text": "* The SIRS criteria are expressed as number of criteria met through the total number of criteria given in the medical records. The commas indicate changes of antibiotic treatment, and a plus indicates a combined treatment.", "cite_spans": [], "ref_spans": []}, {"section": "A sanguinicola Blood Isolates", "text": "A sanguinicola Bacteremia and Virulence \u2022 OFID \u2022 3", "cite_spans": [], "ref_spans": []}, {"section": "A sanguinicola in Urinary Cultures", "text": "None of the 11 patients had recorded growth of A sanguinicola in a urinary culture. In 5 patients, no urinary culture was performed and 3 patients had sterile urine. In 2 patients, the urine grew more than 2 species that were not further characterized, and in 1 patient Pseudomonas aeruginosa was identified in the urine culture.", "cite_spans": [], "ref_spans": []}, {"section": "Patient Characteristics", "text": "The clinical presentation is summarized in Table 1 . All patients were male and the median age was 82 years (range, 67-93). Six patients had underlying urinary tract diseases; prostatic malignancy (n = 3), bladder malignancy (n = 1), or benign prostatic hyperplasia (n = 2). Eight of the 11 patients had an indwelling urinary tract catheter. Five patients suffered from Alzheimer's disease or other types of dementia, and another 2 patients had memory impairment. One patient had Trisomy 21. None of the patients was treated with immunosuppressive medications. At presentation in the hospital, 9 patients were febrile. Hematuria was an initial symptom in 5 patients, 1 patient had complains of back pain, and 1 patient had obstruction of his urinary catheter. Ten patients fulfilled the criteria for SIRS and 9 of them had signs of organ dysfunction, most commonly renal failure (n = 8). Thus, 10 patients fulfilled criteria for sepsis and 9 fulfilled criteria for severe sepsis. One patient had septic shock. Nine patients recovered from their infections and 2 patients died at hospital (after 24 h and 15 days of care, respectively). The nonsurvivors were both terminally ill with cancer. The median duration of the hospital stay was 12 days (range, 6-61) for the surviving patients.", "cite_spans": [], "ref_spans": [{"start": 43, "end": 50, "text": "Table 1", "ref_id": "TABREF0"}]}, {"section": "IE With A sanguinicola", "text": "Two of the 11 patients were diagnosed with IE according to Duke's criteria for IE [18] . In 1 case, a 68-year-old man with Trisomy 21 presented with fatigue and fever. The patient had no history of cardiac anomalies. A heart murmur was noted for the first time upon clinical examination, and a transesophageal echocardiography (TEE) visualized a suspected vegetation on the mitral valve. After initial empiric treatment with a broadspectrum cephalosporin, the patient received penicillin for 1 month in combination with gentamicin the first week and recovered without complications. One year later, the patient was treated for suspected recurrent IE due to fever and elevated levels of C-reactive protein. However, in the second episode no bacteria were isolated from the blood. The other case was an 85-year-old man with prostatic cancer, but with no medical history of cardiac disease, who was admitted to the intensive care unit due to fever, respiratory failure, and septic shock. Twice, a TEE was performed without conclusive evidence of IE. However, the aortic valve was too sclerotic to safely disregard the possibility of IE. This patient received penicillin for 1 month in combination with gentamicin the first week and recovered from the infection.", "cite_spans": [{"start": 82, "end": 86, "text": "[18]", "ref_id": "BIBREF17"}], "ref_spans": []}, {"section": "Antibiotic Susceptibility and Antibiotic Treatment", "text": "The MICs for tested antibiotics are presented in Table 2 . The results are in line with previous reports [1, 3, 5] with the bacteria displaying low MICs for penicillin, cefotaxime, and vancomycin. We observed high MICs for ciprofloxacin (range, 4->32 mg/L). The cefotaxime MICs for the isolates from the 2 patients who died at hospital were 0.125 mg/L and 2 mg/L. All 11 patients received empirical treatment with broad-spectrum \u03b2-lactam antibiotic. In 5 cases, this treatment was shifted to intravenous penicillin. Four patients were given gentamycin in combination with penicillin or cefotaxime. As follow-up oral treatment, penicillin or ampicillin were most commonly used, followed by ciprofloxacin. The median treatment length with intravenous antibiotics was 9 days (range, 2-36 days) and the median total treatment length was 14 days (range, 2-36 days).", "cite_spans": [{"start": 105, "end": 108, "text": "[1,", "ref_id": "BIBREF0"}, {"start": 109, "end": 111, "text": "3,", "ref_id": "BIBREF2"}, {"start": 112, "end": 114, "text": "5]", "ref_id": "BIBREF4"}], "ref_spans": [{"start": 49, "end": 56, "text": "Table 2", "ref_id": "TABREF1"}]}, {"section": "Biofilm Formation", "text": "All 11 clinical isolates produced biofilms that were firmly attached to the plastic surface and visible to the eye after 24, 48, and 72 hours. There was a variation in the amount of absorbed crystal violet between the isolates, indicating a difference in the capacity to form biofilm ( Figure 1 ). For 4 isolates, there was a statistically significant increase in the amount of biofilm formed in the presence of plasma compared to the amount of biofilm formed in medium alone (Mann-Whitney U test; P < .05) at 48 hours. At 72 hours, the same comparison resulted in a significant difference for 7 of the 11 isolates (Figure 1 ).", "cite_spans": [], "ref_spans": [{"start": 286, "end": 294, "text": "Figure 1", "ref_id": "FIGREF0"}, {"start": 615, "end": 624, "text": "(Figure 1", "ref_id": "FIGREF0"}]}, {"section": "Platelet Aggregation", "text": "The 11 isolates were tested for their capacity to aggregate human platelets from 3 donors. Three isolates failed to induce platelet aggregation in any donor, 2 isolates induced aggregation of platelets from 1 donor, 5 isolates induced aggregation in 2 donors, and 1 isolate induced aggregation of platelets from all 3 donors. The median time to aggregation for all isolates was 12 minutes (range, 8-24 min). The isolate that induced aggregation from all 3 donors was from one of the patients with IE. The other patients with IE had an isolate that induced aggregation after 8 minutes in 2 donors.", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "Only a few clinical cases of bacteremia with A sanguinicola have been previously presented [2] , and in this study we report an additional 11 cases. The scarcity of reports could be explained by the fact that the bacterium was quite recently designated its own species and that it is easily misidentified as A viridans. Because MALDI-TOF MS is a reliable method of identifying A sanguinicola and A urinae [8, 10] , the introduction of this method in clinical microbiology laboratories will lead to a more accurate identification of aerococcal species and also a better determination of the incidence of these infections. Our study was carried out retrospectively and may have underestimated the actual number of cases with blood stream infections caused by A sanguinicola. Based on our data, the estimated incidence is 1.4 cases per 1 000 000 inhabitants per year. In our material, all patients were elderly men and a majority of them had underlying urological conditions or an indwelling urinary catheter. Neurological disorders were common, 5 patients had some form of dementia, and 1 patient had Trisomy 21. Similar findings were presented by Ibler et al [2] . Four of their 6 patients were of male gender, and all of them had neurological conditions, including 1 patient with Trisomy 21. It is interesting to note that both of the patients with this genetic disorder were diagnosed with IE. Aerococcus urinae, which has been more extensively studied, also infects elderly men with urinary tract abnormalities, but patients with A urinae bacteremia seem to have less neurological disease [7] . Most patients in our study presented fever as a primary symptom of infection, and several had complaints or symptoms from the urinary tract. Aerococcus sanguinicola is most commonly encountered in urinary cultures, and most studies suggest that it has a pathogenic capacity in the urinary tract [1, 3] . Taken together, this result implies that the primary focus of blood stream infections with A sanguinicola is most likely the urinary tract. However, we could not find support for this speculation in our material because no aerococci were isolated from urinary cultures. This result could partly be explained by shortcomings in the clinical management of these patients upon arrival at hospital and possibly also failure to recognize the bacteria in urinary cultures. Ten patients fulfilled the criteria for SIRS and 9 of them had organ dysfunction, which points out the severity of bacteremia with A sanguinicola. Two patients did not survive the hospital stay; however, both of these patients were terminally ill with cancer. In both nonsurvivors, A sanguinicola was isolated in pure cultures from blood. In our hospitals, the fatality of A sanguinicola (2 of 11) is similar to that of A urinae (1 of 16) [7] , although the small number of cases does not permit any definite conclusions. The pathogenic role of A sanguinicola in the 6 patients with polymicrobial bacteremia is less clear, and some of these patients had bacteremia with bacteria of relatively high pathogenic potential such as Escherichia coli and Staphylococcus aureus. Notably, none of the patients with polymicrobial bacteremia succumbed, and consequently the case fatality in bacteremia with A sanguinicola in pure culture was 2 of 5 in this material. Two of the 11 patients were diagnosed with IE, and in an additional 3 patients a TTE was performed, making the possibility of IE in those patients less likely. Thus, in 6 patients, the possibility of IE was not investigated by diagnostic echocardiography and potential IEs could have been missed. Ibler et al [2] reported that 2 of 6 patients had IE, and we have previously reported that 3 of 16 patients with A urinae bacteremia had IE [7] . We find it reasonable to asses all cases of aerococcal bacteremia with diagnostic echocardiography. In our experiment, the 11 clinical isolates of A sanguinicola were all biofilm producers, which probably could facilitate the colonization of indwelling urinary catheters. For most isolates, the biofilm after 72 hours was more pronounced in the presence of human plasma, which indicates that the bacteria could also form biofilm in a situation where plasma exudates due to local inflammation. For S aureus [19, 20] and Propionibacterium acnes [15] , serum or plasma inhibit biofilm formation, but in A urinae, biofilm formation is strongly stimulated by human plasma [12] . The mechanisms behind plasma effects on bacterial biofilm formation remains to be explored, but the fact that aerococci can form biofilm in the presence of plasma supports the possibility that biofilm formation could have a role in IE caused by aerococci. It is interesting to note that the isolates from the 2 patients with IE induced aggregation in PRP from 2 or 3 donors, respectively. These patients had predisposing factors for IE, but it could support the theory that induction of platelet aggregation is to be considered as a virulence property of aerococci [21] . In conclusion, our study shows that A sanguinicola can cause severe infections in elderly men with urinary tract abnormalities and neurological diseases and that the bacterium has virulence mechanisms of potential importance in IE.", "cite_spans": [{"start": 91, "end": 94, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 405, "end": 408, "text": "[8,", "ref_id": "BIBREF7"}, {"start": 409, "end": 412, "text": "10]", "ref_id": "BIBREF9"}, {"start": 1158, "end": 1161, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 1591, "end": 1594, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 1892, "end": 1895, "text": "[1,", "ref_id": "BIBREF0"}, {"start": 1896, "end": 1898, "text": "3]", "ref_id": "BIBREF2"}, {"start": 2807, "end": 2810, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 3633, "end": 3636, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 3761, "end": 3764, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 4273, "end": 4277, "text": "[19,", "ref_id": "BIBREF18"}, {"start": 4278, "end": 4281, "text": "20]", "ref_id": "BIBREF19"}, {"start": 4310, "end": 4314, "text": "[15]", "ref_id": "BIBREF14"}, {"start": 4434, "end": 4438, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 5006, "end": 5010, "text": "[21]", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "Notes", "text": "", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Aerococcus urinae and Aerococcus sanguinicola, two frequently misidentified uropathogens", "authors": [{"first": "V", "middle": [], "last": "Cattoir", "suffix": ""}, {"first": "A", "middle": [], "last": "Kobal", "suffix": ""}, {"first": "P", "middle": [], "last": "Legrand", "suffix": ""}], "year": 2010, "venue": "Scand J Infect Dis", "link": "25258046"}, "BIBREF1": {"title": "Six cases of Aerococcus sanguinicola infection: clinical relevance and bacterial identification", "authors": [{"first": "K", "middle": [], "last": "Ibler", "suffix": ""}, {"first": "Truberg", "middle": [], "last": "Jensen", "suffix": ""}, {"first": "K", "middle": [], "last": "Ostergaard", "suffix": ""}, {"first": "C", "middle": [], "last": "", "suffix": ""}], "year": 2008, "venue": "Scand J Infect Dis", "link": "1560429"}, "BIBREF2": {"title": "Clinical significance and antimicrobial susceptibilities of Aerococcus sanguinicola and Aerococcus urinae", "authors": [{"first": "K", "middle": [], "last": "Shelton-Dodge", "suffix": ""}, {"first": "E", "middle": ["A"], "last": "Vetter", "suffix": ""}, {"first": "P", "middle": ["C"], "last": "Kohner", "suffix": ""}], "year": 2011, "venue": "Diagn Microbiol Infect Dis", "link": "34567746"}, "BIBREF3": {"title": "Aerococcus sanguicola sp. nov., isolated from a human clinical source", "authors": [{"first": "P", "middle": ["A"], "last": "Lawson", "suffix": ""}, {"first": "E", "middle": [], "last": "Falsen", "suffix": ""}, {"first": "K", "middle": [], "last": "Truberg-Jensen", "suffix": ""}], "year": 2001, "venue": "Int J Syst Evol Microbiol", "link": "43403362"}, "BIBREF4": {"title": "Phenotypic description and antimicrobial susceptibilities of Aerococcus sanguinicola isolates from human clinical samples", "authors": [{"first": "R", "middle": [], "last": "Facklam", "suffix": ""}, {"first": "M", "middle": [], "last": "Lovgren", "suffix": ""}, {"first": "P", "middle": ["L"], "last": "Shewmaker", "suffix": ""}], "year": 2003, "venue": "J Clin Microbiol", "link": "20940950"}, "BIBREF5": {"title": "Three cases of serious infection caused by Aerococcus urinae", "authors": [{"first": "P", "middle": ["M"], "last": "Schuur", "suffix": ""}, {"first": "L", "middle": [], "last": "Sabbe", "suffix": ""}, {"first": "A", "middle": ["J"], "last": "Van Der Wouw", "suffix": ""}], "year": 1999, "venue": "Eur J Clin Microbiol Infect Dis", "link": null}, "BIBREF6": {"title": "Clinical and microbiological features of bacteraemia with Aerococcus urinae", "authors": [{"first": "E", "middle": [], "last": "Senneby", "suffix": ""}, {"first": "A", "middle": ["C"], "last": "Petersson", "suffix": ""}, {"first": "M", "middle": [], "last": "Rasmussen", "suffix": ""}], "year": 2012, "venue": "Clin Microbiol Infect", "link": "41032363"}, "BIBREF7": {"title": "Matrix-assisted laser desorption ionization-time of flight mass spectrometry is a sensitive and specific method for identification of aerococci", "authors": [{"first": "E", "middle": [], "last": "Senneby", "suffix": ""}, {"first": "B", "middle": [], "last": "Nilson", "suffix": ""}, {"first": "A", "middle": ["C"], "last": "Petersson", "suffix": ""}], "year": 2013, "venue": "J Clin Microbiol", "link": "7910472"}, "BIBREF8": {"title": "Aerococci and aerococcal infections", "authors": [{"first": "M", "middle": [], "last": "Rasmussen", "suffix": ""}], "year": 2013, "venue": "J Infect", "link": "1087493"}, "BIBREF9": {"title": "Matrix-assisted laser desorption ionization-time of flight mass spectrometry analysis of Gram-positive, catalase-negative cocci not belonging to the Streptococcus or Enterococcus genus and benefits of database extension", "authors": [{"first": "J", "middle": ["J"], "last": "Christensen", "suffix": ""}, {"first": "R", "middle": [], "last": "Dargis", "suffix": ""}, {"first": "M", "middle": [], "last": "Hammer", "suffix": ""}], "year": 2012, "venue": "J Clin Microbiol", "link": "40762370"}, "BIBREF10": {"title": "First molecular characterization of fluoroquinolone resistance in Aerococcus spp", "authors": [{"first": "V", "middle": [], "last": "Cattoir", "suffix": ""}, {"first": "A", "middle": [], "last": "Kobal", "suffix": ""}, {"first": "P", "middle": [], "last": "Legrand", "suffix": ""}], "year": 2011, "venue": "Antimicrob Agents Chemother", "link": "34976753"}, "BIBREF11": {"title": "Platelet activation and biofilm formation by Aerococcus urinae, an endocarditis-causing pathogen", "authors": [{"first": "O", "middle": [], "last": "Shannon", "suffix": ""}, {"first": "M", "middle": [], "last": "M\u00f6rgelin", "suffix": ""}, {"first": "M", "middle": [], "last": "Rasmussen", "suffix": ""}], "year": 2010, "venue": "Infect Immun", "link": "10267635"}, "BIBREF12": {"title": "An immunosuppressed patient with systemic vasculitis suffering from cerebral abscesses due to Nocardia farcinica identified by 16S rRNA gene universal PCR", "authors": [{"first": "A", "middle": [], "last": "Sonesson", "suffix": ""}, {"first": "B", "middle": [], "last": "\u00d6qvist", "suffix": ""}, {"first": "P", "middle": [], "last": "Hagstam", "suffix": ""}], "year": 2004, "venue": "Nephrol Dial Transplant", "link": "16488057"}, "BIBREF13": {"title": "Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis", "authors": [{"first": "R", "middle": ["C"], "last": "Bone", "suffix": ""}, {"first": "R", "middle": ["A"], "last": "Balk", "suffix": ""}, {"first": "F", "middle": ["B"], "last": "Cerra", "suffix": ""}], "year": 1992, "venue": "The ACCP/SCCM Consensus Conference Committee", "link": null}, "BIBREF14": {"title": "Biofilm formation by Propionibacterium acnes is a characteristic of invasive isolates", "authors": [{"first": "A", "middle": [], "last": "Holmberg", "suffix": ""}, {"first": "R", "middle": [], "last": "Lood", "suffix": ""}, {"first": "M", "middle": [], "last": "M\u00f6rgelin", "suffix": ""}], "year": 2009, "venue": "Clin Microbiol Infect", "link": "39206094"}, "BIBREF15": {"title": "Virulence factors in isolates of Enterococcus faecalis from infective endocarditis and from the normal flora", "authors": [{"first": "D", "middle": [], "last": "Johansson", "suffix": ""}, {"first": "M", "middle": [], "last": "Rasmussen", "suffix": ""}], "year": 2013, "venue": "Microb Pathog", "link": "20142184"}, "BIBREF16": {"title": "Clinical isolates of Enterococcus faecalis aggregate human platelets", "authors": [{"first": "M", "middle": [], "last": "Rasmussen", "suffix": ""}, {"first": "D", "middle": [], "last": "Johansson", "suffix": ""}, {"first": "S", "middle": ["K"], "last": "Sobirk", "suffix": ""}], "year": 2010, "venue": "Microbes Infect", "link": "206922486"}, "BIBREF17": {"title": "New criteria for diagnosis of infective endocarditis: utilization of specific echocardiographic findings. Duke Endocarditis Service", "authors": [{"first": "D", "middle": ["T"], "last": "Durack", "suffix": ""}, {"first": "A", "middle": ["S"], "last": "Lukes", "suffix": ""}, {"first": "D", "middle": ["K"], "last": "Bright", "suffix": ""}], "year": 1994, "venue": "Am J Med", "link": "7791907"}, "BIBREF18": {"title": "A low molecular weight component of serum inhibits biofilm formation in Staphylococcus aureus", "authors": [{"first": "N", "middle": ["M"], "last": "Abraham", "suffix": ""}, {"first": "K", "middle": ["K"], "last": "Jefferson", "suffix": ""}], "year": 2010, "venue": "Microb Pathog", "link": "31188202"}, "BIBREF19": {"title": "Staphylococcus aureus extracellular adherence protein contributes to biofilm formation in the presence of serum", "authors": [{"first": "K", "middle": ["M"], "last": "Thompson", "suffix": ""}, {"first": "N", "middle": [], "last": "Abraham", "suffix": ""}, {"first": "K", "middle": ["K"], "last": "Jefferson", "suffix": ""}], "year": 2010, "venue": "FEMS Microbiol Lett", "link": "46729407"}, "BIBREF20": {"title": "The interaction of bacterial pathogens with platelets", "authors": [{"first": "J", "middle": ["R"], "last": "Fitzgerald", "suffix": ""}, {"first": "T", "middle": ["J"], "last": "Foster", "suffix": ""}, {"first": "D", "middle": [], "last": "Cox", "suffix": ""}], "year": 2006, "venue": "Nat Rev Microbiol", "link": null}}, "ref_entries": {"FIGREF0": {"text": "Figure 1. Biofilm formation by Aerococcus sanguinicola after 72 hours of incubation in the presence of medium (gray bars) or medium containing 10% human plasma (black bars). The error bars represent the standard deviation from 3 different experiments. The asterisks indicate a statistically significant increase in the amount of biofilm formed in the presence of plasma compared to the amount of biofilm formed in medium alone. The mean negative control absorbance value was 0.083 (range, 0.055-0.31).", "type": "figure"}, "TABREF0": {"text": "Characteristics of Patients With Aerococcus sanguinicola Bacteremia in Sk\u00e5ne, Sweden From 2006-2012*", "type": "table"}, "TABREF1": {"text": "", "type": "table"}}}
{"paper_id": "199660318", "_pdf_hash": "2b1a4d7451b12f96260adb2adef60ef8ff5c48e9", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "A Taxonomy for learning, teaching, and assessing: A Revision of Bloom's Taxonomy of Educational Objectives", "authors": [{"first": "L", "middle": ["W"], "last": "Anderson", "suffix": ""}, {"first": "P", "middle": ["W"], "last": "Airasian", "suffix": ""}, {"first": "K", "middle": ["A"], "last": "Cruikshank", "suffix": ""}, {"first": "R", "middle": ["E"], "last": "Mayer", "suffix": ""}, {"first": "P", "middle": ["R"], "last": "Pintrich", "suffix": ""}, {"first": "J", "middle": [], "last": "Raths", "suffix": ""}, {"first": "M", "middle": ["C"], "last": "Wittrock", "suffix": ""}], "year": 2001, "venue": "", "link": null}, "BIBREF1": {"title": "Design-based research: Putting a stake in the ground", "authors": [{"first": "S", "middle": [], "last": "Barab", "suffix": ""}, {"first": "K", "middle": [], "last": "Squire", "suffix": ""}], "year": 2004, "venue": "The Journal of the Learning Sciences", "link": "15501905"}, "BIBREF2": {"title": "If design-based research is the answer, what is the question? A Commentary on Collins, Joseph, and Soloway in the JLS special issue on design-based research", "authors": [{"first": "C", "middle": [], "last": "Dede", "suffix": ""}], "year": 2004, "venue": "The Journal of the Learning Sciences", "link": null}, "BIBREF3": {"title": "Innovating the future: From ideas to adoption", "authors": [{"first": "P", "middle": ["J"], "last": "Denning", "suffix": ""}], "year": 2012, "venue": "The Futurist", "link": "60215914"}, "BIBREF4": {"title": "The social life of innovation", "authors": [{"first": "P", "middle": ["J"], "last": "Denning", "suffix": ""}], "year": 2004, "venue": "Communications of the ACM", "link": "16826072"}, "BIBREF5": {"title": "Innovation as language action", "authors": [{"first": "P", "middle": ["J"], "last": "Denning", "suffix": ""}, {"first": "R", "middle": [], "last": "Dunham", "suffix": ""}], "year": 2006, "venue": "Communications of the ACM", "link": "15179720"}, "BIBREF6": {"title": "Design-based research: An Emerging paradigm for educational inquiry", "authors": [], "year": 2003, "venue": "Educa ional Researcher", "link": null}, "BIBREF7": {"title": "Design research: What we learn when we engage in design", "authors": [{"first": "D", "middle": ["C"], "last": "Edelson", "suffix": ""}], "year": 2002, "venue": "The Journal of the Learning Sciences", "link": null}, "BIBREF8": {"title": "Creating a framework for research on systemic technology innovations", "authors": [{"first": "B", "middle": [], "last": "Fishman", "suffix": ""}, {"first": "R", "middle": ["W"], "last": "Marx", "suffix": ""}, {"first": "P", "middle": [], "last": "Blumenfeld", "suffix": ""}, {"first": "J", "middle": [], "last": "Krajcik", "suffix": ""}, {"first": "E", "middle": [], "last": "Soloway", "suffix": ""}], "year": 2004, "venue": "Journal of Research in Science teaching", "link": "15432901"}, "BIBREF11": {"title": "Positioning models in science education and in design and technology education", "authors": [{"first": "J", "middle": ["K"], "last": "Gilbert", "suffix": ""}, {"first": "C", "middle": ["J"], "last": "Boulter", "suffix": ""}, {"first": "R", "middle": [], "last": "Elmer", "suffix": ""}], "year": 2000, "venue": "", "link": "109065840"}, "BIBREF12": {"title": "Change in schools: Facilitating the process", "authors": [{"first": "G", "middle": [], "last": "Hall", "suffix": ""}, {"first": "S", "middle": [], "last": "Hord", "suffix": ""}], "year": 1987, "venue": "", "link": "179155467"}, "BIBREF13": {"title": "Design-based research in science education: One step towards methodology", "authors": [{"first": "K", "middle": [], "last": "Juuti", "suffix": ""}, {"first": "J", "middle": [], "last": "Lavonen", "suffix": ""}], "year": 2006, "venue": "NorDiNa", "link": "141491326"}, "BIBREF14": {"title": "From separation to partnership in science education: Students, laboratories, and the curriculum", "authors": [{"first": "M", "middle": ["C"], "last": "Linn", "suffix": ""}], "year": 1996, "venue": "Microcomputer-based labs: Educa ional research and standards", "link": "150911567"}, "BIBREF15": {"title": "Kehitt\u00e4mistutkimus: Tieto-ja viestint\u00e4tekniikkaa kemian opetukseen. Doctoral dissertation", "authors": [{"first": "J", "middle": [], "last": "Pernaa", "suffix": ""}], "year": 2011, "venue": "", "link": null}, "BIBREF16": {"title": "Chemistry teachers' and students' perceptions of practical work through different ICT learning environments. Problems of Education in the 21 st Century", "authors": [{"first": "J", "middle": [], "last": "Pernaa", "suffix": ""}, {"first": "M", "middle": [], "last": "Aksela", "suffix": ""}], "year": 2009, "venue": "", "link": null}, "BIBREF17": {"title": "Kemian mallit ja visualisointi -kurssin yhteis\u00f6llinen uudistaminen malliteoriaan pohjautuvalla kehitt\u00e4mistutkimuksella", "authors": [{"first": "J", "middle": [], "last": "Pernaa", "suffix": ""}, {"first": "M", "middle": [], "last": "Aksela", "suffix": ""}, {"first": "J", "middle": [], "last": "V\u00e4stinsalo", "suffix": ""}], "year": 2010, "venue": "Tutkiva l\u00e4hestymistapa kemian ope ukseen", "link": null}, "BIBREF18": {"title": "Diffusion of Innovations", "authors": [{"first": "E", "middle": ["M"], "last": "Rogers", "suffix": ""}], "year": 2003, "venue": "", "link": null}, "BIBREF19": {"title": "Design-based research methods for studying learning in context: Introduction", "authors": [{"first": "W", "middle": ["A"], "last": "Sandoval", "suffix": ""}, {"first": "P", "middle": [], "last": "Bell", "suffix": ""}], "year": 2004, "venue": "The Journal of the Learning Sciences", "link": "9235559"}, "BIBREF20": {"title": "Evaluation of a Novel Educational Design Methodology Utilizing Concept Maps", "authors": [{"first": "V", "middle": ["M"], "last": "Vesterinen", "suffix": ""}, {"first": "J", "middle": [], "last": "Pernaa", "suffix": ""}, {"first": "M", "middle": [], "last": "Aksela", "suffix": ""}], "year": 2012, "venue": "E-Proceedings of the ESERA 2011 Conference: Science learning and Citizenship. Lyon France. Electronically retrieved on", "link": null}, "BIBREF21": {"title": "Conditions for classroom technology innovations", "authors": [{"first": "Y", "middle": [], "last": "Zhao", "suffix": ""}, {"first": "K", "middle": [], "last": "Pugh", "suffix": ""}, {"first": "S", "middle": [], "last": "Sheldon", "suffix": ""}, {"first": "J", "middle": [], "last": "Byers", "suffix": ""}], "year": 2002, "venue": "Teachers College Record", "link": "73706352"}}, "ref_entries": {}}
{"paper_id": "199661662", "_pdf_hash": "6f2ef13e434f5e0e283753cfa16c650d7729dd2c", "abstract": [], "body_text": [], "bib_entries": {"BIBREF4": {"title": "Akamai online retail performance report: Milliseconds are critical", "authors": [], "year": 2017, "venue": "", "link": null}, "BIBREF5": {"title": "Flywheel: Google's data compression proxy for the mobile web", "authors": [{"first": "Victor", "middle": [], "last": "Agababov", "suffix": ""}, {"first": "Michael", "middle": [], "last": "Buettner", "suffix": ""}, {"first": "Victor", "middle": [], "last": "Chudnovsky", "suffix": ""}, {"first": "Mark", "middle": [], "last": "Cogan", "suffix": ""}, {"first": "Ben", "middle": [], "last": "Greenstein", "suffix": ""}, {"first": "Shane", "middle": [], "last": "Mcdaniel", "suffix": ""}, {"first": "Michael", "middle": [], "last": "Piatek", "suffix": ""}, {"first": "Colin", "middle": [], "last": "Scott", "suffix": ""}, {"first": "Matt", "middle": [], "last": "Welsh", "suffix": ""}, {"first": "Bolian", "middle": [], "last": "Yin", "suffix": ""}], "year": 2015, "venue": "NSDI", "link": "2360392"}, "BIBREF6": {"title": "Prometheus: Toward quality-of-experience estimation for mobile apps from passive network measurements", "authors": [{"first": "Vaneet", "middle": [], "last": "Aggarwal", "suffix": ""}, {"first": "Emir", "middle": [], "last": "Halepovic", "suffix": ""}, {"first": "Jeffrey", "middle": [], "last": "Pang", "suffix": ""}, {"first": "Shobha", "middle": [], "last": "Venkataraman", "suffix": ""}, {"first": "He", "middle": [], "last": "Yan", "suffix": ""}], "year": 2014, "venue": "Proceedings of the 15th Workshop on Mobile Computing Systems and Applications", "link": "2862419"}, "BIBREF7": {"title": "Modeling web quality-of-experience on cellular networks", "authors": [{"first": "Athula", "middle": [], "last": "Balachandran", "suffix": ""}, {"first": "Vaneet", "middle": [], "last": "Aggarwal", "suffix": ""}, {"first": "Emir", "middle": [], "last": "Halepovic", "suffix": ""}, {"first": "Jeffrey", "middle": [], "last": "Pang", "suffix": ""}, {"first": "Shobha", "middle": [], "last": "Srinivasan Seshan", "suffix": ""}, {"first": "He", "middle": [], "last": "Venkataraman", "suffix": ""}, {"first": "", "middle": [], "last": "Yan", "suffix": ""}], "year": 2014, "venue": "Proceedings of the 20th annual international conference on Mobile computing and networking", "link": "3334152"}, "BIBREF8": {"title": "Developing a predictive model of quality of experience for internet video", "authors": [{"first": "Athula", "middle": [], "last": "Balachandran", "suffix": ""}, {"first": "Vyas", "middle": [], "last": "Sekar", "suffix": ""}, {"first": "Aditya", "middle": [], "last": "Akella", "suffix": ""}, {"first": "Srinivasan", "middle": [], "last": "Seshan", "suffix": ""}, {"first": "Ion", "middle": [], "last": "Stoica", "suffix": ""}, {"first": "Hui", "middle": [], "last": "Zhang", "suffix": ""}], "year": 2013, "venue": "ACM SIGCOMM Computer Communication Review", "link": "8161676"}, "BIBREF9": {"title": "Robinhood: Tail latency aware caching-dynamic reallocation from cacherich to cache-poor", "authors": [{"first": "S", "middle": [], "last": "Daniel", "suffix": ""}, {"first": "Benjamin", "middle": [], "last": "Berger", "suffix": ""}, {"first": "Timothy", "middle": [], "last": "Berg", "suffix": ""}, {"first": "Siddhartha", "middle": [], "last": "Zhu", "suffix": ""}, {"first": "Mor", "middle": [], "last": "Sen", "suffix": ""}, {"first": "", "middle": [], "last": "Harcholbalter", "suffix": ""}], "year": 2018, "venue": "13th {USENIX} Symposium on Operating Systems Design and Implementation ({OSDI} 18)", "link": "52985662"}, "BIBREF10": {"title": "Adaptsize: Orchestrating the hot object memory cache in a content delivery network", "authors": [{"first": "S", "middle": [], "last": "Daniel", "suffix": ""}, {"first": "Ramesh", "middle": ["K"], "last": "Berger", "suffix": ""}, {"first": "Mor", "middle": [], "last": "Sitaraman", "suffix": ""}, {"first": "", "middle": [], "last": "Harchol-Balter", "suffix": ""}], "year": 2017, "venue": "NSDI", "link": "7381414"}, "BIBREF11": {"title": "Measuring the quality of experience of web users", "authors": [{"first": "Enrico", "middle": [], "last": "Bocchi", "suffix": ""}, {"first": "Dario", "middle": [], "last": "Luca De Cicco", "suffix": ""}, {"first": "", "middle": [], "last": "Rossi", "suffix": ""}], "year": 2016, "venue": "ACM SIGCOMM Computer Communication Review", "link": "7328163"}, "BIBREF12": {"title": "The Chubby lock service for loosely-coupled distributed systems", "authors": [{"first": "Mike", "middle": [], "last": "Burrows", "suffix": ""}], "year": 2006, "venue": "OSDI", "link": "1617028"}, "BIBREF13": {"title": "Klotski: Reprioritizing web content to improve user experience on mobile devices", "authors": [{"first": "Michael", "middle": [], "last": "Butkiewicz", "suffix": ""}, {"first": "Daimeng", "middle": [], "last": "Wang", "suffix": ""}, {"first": "Zhe", "middle": [], "last": "Wu", "suffix": ""}, {"first": "V", "middle": [], "last": "Harsha", "suffix": ""}, {"first": "Vyas", "middle": [], "last": "Madhyastha", "suffix": ""}, {"first": "", "middle": [], "last": "Sekar", "suffix": ""}], "year": 2015, "venue": "NSDI", "link": "7121919"}, "BIBREF14": {"title": "Odin: Microsoft's scalable fault-tolerant CDN measurement system", "authors": [{"first": "Matt", "middle": [], "last": "Calder", "suffix": ""}, {"first": "Manuel", "middle": [], "last": "Schr\u00f6der", "suffix": ""}, {"first": "Ryan", "middle": [], "last": "Stewart Ryan", "suffix": ""}, {"first": "Jitendra", "middle": [], "last": "Gao", "suffix": ""}, {"first": "Ratul", "middle": [], "last": "Padhye", "suffix": ""}, {"first": "Ganesh", "middle": [], "last": "Mahajan", "suffix": ""}, {"first": "Ethan", "middle": [], "last": "Ananthanarayanan", "suffix": ""}, {"first": "", "middle": [], "last": "Katz-Bassett", "suffix": ""}], "year": 2018, "venue": "15th USENIX Symposium on Networked Systems Design and Implementation (NSDI 18)", "link": "4842331"}, "BIBREF15": {"title": "End-user mapping: Next generation request routing for content delivery", "authors": [{"first": "Fangfei", "middle": [], "last": "Chen", "suffix": ""}, {"first": "Ramesh", "middle": ["K"], "last": "Sitaraman", "suffix": ""}, {"first": "Marcelo", "middle": [], "last": "Torres", "suffix": ""}], "year": 2015, "venue": "ACM SIGCOMM Computer Communication Review", "link": "2674241"}, "BIBREF16": {"title": "A providerside view of web search response time", "authors": [{"first": "Yingying", "middle": [], "last": "Chen", "suffix": ""}, {"first": "Ratul", "middle": [], "last": "Mahajan", "suffix": ""}, {"first": "Baskar", "middle": [], "last": "Sridharan", "suffix": ""}, {"first": "Zhi-Li", "middle": [], "last": "Zhang", "suffix": ""}], "year": 2013, "venue": "In ACM SIGCOMM Computer Communication Review", "link": null}, "BIBREF17": {"title": "The mystery machine: End-to-end performance analysis of large-scale internet services", "authors": [{"first": "Michael", "middle": [], "last": "Chow", "suffix": ""}, {"first": "David", "middle": [], "last": "Meisner", "suffix": ""}, {"first": "Jason", "middle": [], "last": "Flinn", "suffix": ""}, {"first": "Daniel", "middle": [], "last": "Peek", "suffix": ""}, {"first": "Thomas", "middle": ["F"], "last": "Wenisch", "suffix": ""}], "year": 2014, "venue": "OSDI", "link": "5661499"}, "BIBREF18": {"title": "DQBarge: Improving data-quality tradeoffs in large-scale internet services", "authors": [{"first": "Michael", "middle": [], "last": "Chow", "suffix": ""}, {"first": "Kaushik", "middle": [], "last": "Veeraraghavan", "suffix": ""}, {"first": "J", "middle": [], "last": "Michael", "suffix": ""}, {"first": "Jason", "middle": [], "last": "Cafarella", "suffix": ""}, {"first": "", "middle": [], "last": "Flinn", "suffix": ""}], "year": 2016, "venue": "OSDI", "link": "18126684"}, "BIBREF19": {"title": "Narrowing the gap between QoS metrics and web QoE using above-the-fold metrics", "authors": [{"first": "Diego", "middle": [], "last": "Neves Da Hora", "suffix": ""}, {"first": "Alemnew", "middle": [], "last": "Sheferaw Asrese", "suffix": ""}, {"first": "Vassilis", "middle": [], "last": "Christophides", "suffix": ""}, {"first": "Renata", "middle": [], "last": "Teixeira", "suffix": ""}, {"first": "Dario", "middle": [], "last": "Rossi", "suffix": ""}], "year": 2018, "venue": "International Conference on Passive and Active Network Measurement", "link": "2534011"}, "BIBREF20": {"title": "Understanding the impact of video quality on user engagement", "authors": [{"first": "Florin", "middle": [], "last": "Dobrian", "suffix": ""}, {"first": "Vyas", "middle": [], "last": "Sekar", "suffix": ""}, {"first": "Asad", "middle": [], "last": "Awan", "suffix": ""}, {"first": "Ion", "middle": [], "last": "Stoica", "suffix": ""}, {"first": "Dilip", "middle": [], "last": "Joseph", "suffix": ""}, {"first": "Aditya", "middle": [], "last": "Ganjam", "suffix": ""}, {"first": "Jibin", "middle": [], "last": "Zhan", "suffix": ""}, {"first": "Hui", "middle": [], "last": "Zhang", "suffix": ""}], "year": 2011, "venue": "ACM SIGCOMM Computer Communication Review", "link": "14607360"}, "BIBREF21": {"title": "Fibonacci heaps and their uses in improved network optimization algorithms", "authors": [{"first": "L", "middle": [], "last": "Michael", "suffix": ""}, {"first": "Robert", "middle": ["Endre"], "last": "Fredman", "suffix": ""}, {"first": "", "middle": [], "last": "Tarjan", "suffix": ""}], "year": 1987, "venue": "Journal of the ACM (JACM)", "link": "7904683"}, "BIBREF22": {"title": "Perceived performance of top retail webpages in the wild: Insights from large-scale crowdsourcing of above-the-fold QoE", "authors": [{"first": "Qingzhu", "middle": [], "last": "Gao", "suffix": ""}, {"first": "Prasenjit", "middle": [], "last": "Dey", "suffix": ""}, {"first": "Parvez", "middle": [], "last": "Ahammad", "suffix": ""}], "year": 2017, "venue": "Proceedings of the Workshop on QoE-based Analysis and Management of Data Communication Networks", "link": "9729057"}, "BIBREF23": {"title": "MittOS: Supporting millisecond tail tolerance with fast rejecting SLO-aware OS interface", "authors": [{"first": "Mingzhe", "middle": [], "last": "Hao", "suffix": ""}, {"first": "Huaicheng", "middle": [], "last": "Li", "suffix": ""}, {"first": "Michael", "middle": ["Hao"], "last": "Tong", "suffix": ""}, {"first": "Chrisma", "middle": [], "last": "Pakha", "suffix": ""}, {"first": "O", "middle": [], "last": "Riza", "suffix": ""}, {"first": "Cesar", "middle": ["A"], "last": "Suminto", "suffix": ""}, {"first": "Andrew", "middle": ["A"], "last": "Stuardo", "suffix": ""}, {"first": "", "middle": [], "last": "Chien", "suffix": ""}, {"first": "S", "middle": [], "last": "Haryadi", "suffix": ""}, {"first": "", "middle": [], "last": "Gunawi", "suffix": ""}], "year": 2017, "venue": "Proceedings of the 26th Symposium on Operating Systems Principles", "link": "701296"}, "BIBREF24": {"title": "Zookeeper: Wait-free coordination for internet-scale systems", "authors": [{"first": "Patrick", "middle": [], "last": "Hunt", "suffix": ""}, {"first": "Mahadev", "middle": [], "last": "Konar", "suffix": ""}, {"first": "Benjamin", "middle": [], "last": "Flavio Paiva Junqueira", "suffix": ""}, {"first": "", "middle": [], "last": "Reed", "suffix": ""}], "year": 2010, "venue": "USENIX ATC", "link": "2747585"}, "BIBREF25": {"title": "Speeding up distributed request-response workflows", "authors": [{"first": "Virajith", "middle": [], "last": "Jalaparti", "suffix": ""}, {"first": "Peter", "middle": [], "last": "Bodik", "suffix": ""}, {"first": "Srikanth", "middle": [], "last": "Kandula", "suffix": ""}, {"first": "Ishai", "middle": [], "last": "Menache", "suffix": ""}, {"first": "Mikhail", "middle": [], "last": "Rybalkin", "suffix": ""}, {"first": "Chenyu", "middle": [], "last": "Yan", "suffix": ""}], "year": 2013, "venue": "ACM SIGCOMM Computer Communication Review", "link": "8579892"}, "BIBREF26": {"title": "Eona: Experienceoriented network architecture", "authors": [{"first": "Junchen", "middle": [], "last": "Jiang", "suffix": ""}, {"first": "Xi", "middle": [], "last": "Liu", "suffix": ""}, {"first": "Vyas", "middle": [], "last": "Sekar", "suffix": ""}, {"first": "Ion", "middle": [], "last": "Stoica", "suffix": ""}, {"first": "Hui", "middle": [], "last": "Zhang", "suffix": ""}], "year": 2014, "venue": "Proceedings of the 13th ACM Workshop on Hot Topics in Networks", "link": null}, "BIBREF27": {"title": "A shortest augmenting path algorithm for dense and sparse linear assignment problems", "authors": [{"first": "Roy", "middle": [], "last": "Jonker", "suffix": ""}, {"first": "Anton", "middle": [], "last": "Volgenant", "suffix": ""}], "year": 1987, "venue": "Computing", "link": "7806079"}, "BIBREF28": {"title": "Moving beyond end-to-end path information to optimize CDN performance", "authors": [{"first": "Rupa", "middle": [], "last": "Krishnan", "suffix": ""}, {"first": "V", "middle": [], "last": "Harsha", "suffix": ""}, {"first": "Sridhar", "middle": [], "last": "Madhyastha", "suffix": ""}, {"first": "Sushant", "middle": [], "last": "Srinivasan", "suffix": ""}, {"first": "Arvind", "middle": [], "last": "Jain", "suffix": ""}, {"first": "Thomas", "middle": [], "last": "Krishnamurthy", "suffix": ""}, {"first": "Jie", "middle": [], "last": "Anderson", "suffix": ""}, {"first": "", "middle": [], "last": "Gao", "suffix": ""}], "year": 2009, "venue": "Proceedings of the 9th ACM SIGCOMM conference on Internet measurement", "link": "2401053"}, "BIBREF29": {"title": "Hold'em or fold'em?: Aggregation queries under performance variations", "authors": [{"first": "Gautam", "middle": [], "last": "Kumar", "suffix": ""}, {"first": "Ganesh", "middle": [], "last": "Ananthanarayanan", "suffix": ""}, {"first": "Sylvia", "middle": [], "last": "Ratnasamy", "suffix": ""}, {"first": "Ion", "middle": [], "last": "Stoica", "suffix": ""}], "year": 2016, "venue": "Proceedings of the Eleventh European Conference on Computer Systems", "link": "10750519"}, "BIBREF30": {"title": "Utility accrual resource access protocols with assured timeliness behavior for real-time embedded systems", "authors": [{"first": "Peng", "middle": [], "last": "Li", "suffix": ""}, {"first": "E Douglas", "middle": [], "last": "Binoy Ravindran", "suffix": ""}, {"first": "", "middle": [], "last": "Jensen", "suffix": ""}], "year": 2005, "venue": "ACM SIGPLAN/SIGBED Conference on Languages, Compilers, and Tools for Embedded Systems", "link": "150387498"}, "BIBREF31": {"title": "A utility accrual scheduling algorithm for real-time activities with mutual exclusion resource constraints", "authors": [{"first": "Peng", "middle": [], "last": "Li", "suffix": ""}, {"first": "Haisang", "middle": [], "last": "Wu", "suffix": ""}, {"first": "Binoy", "middle": [], "last": "Ravindran", "suffix": ""}, {"first": "E Douglas", "middle": [], "last": "Jensen", "suffix": ""}], "year": 2006, "venue": "IEEE Transactions on Computers", "link": "6769302"}, "BIBREF32": {"title": "Efficiently delivering online services over integrated infrastructure", "authors": [{"first": "Raajay", "middle": [], "last": "Hongqiang Harry Liu", "suffix": ""}, {"first": "Matt", "middle": [], "last": "Viswanathan", "suffix": ""}, {"first": "Aditya", "middle": [], "last": "Calder", "suffix": ""}, {"first": "Ratul", "middle": [], "last": "Akella", "suffix": ""}, {"first": "Jitendra", "middle": [], "last": "Mahajan", "suffix": ""}, {"first": "Ming", "middle": [], "last": "Padhye", "suffix": ""}, {"first": "", "middle": [], "last": "Zhang", "suffix": ""}], "year": 2016, "venue": "NSDI", "link": "361695"}, "BIBREF33": {"title": "A case for a coordinated internet video control plane", "authors": [{"first": "Xi", "middle": [], "last": "Liu", "suffix": ""}, {"first": "Florin", "middle": [], "last": "Dobrian", "suffix": ""}, {"first": "Henry", "middle": [], "last": "Milner", "suffix": ""}, {"first": "Junchen", "middle": [], "last": "Jiang", "suffix": ""}, {"first": "Vyas", "middle": [], "last": "Sekar", "suffix": ""}, {"first": "Ion", "middle": [], "last": "Stoica", "suffix": ""}, {"first": "Hui", "middle": [], "last": "Zhang", "suffix": ""}], "year": 2012, "venue": "ACM SIGCOMM Computer Communication Review", "link": "10753850"}, "BIBREF34": {"title": "Foundations of statistical natural language processing", "authors": [{"first": "D", "middle": [], "last": "Christopher", "suffix": ""}, {"first": "", "middle": [], "last": "Manning", "suffix": ""}, {"first": "D", "middle": [], "last": "Christopher", "suffix": ""}, {"first": "Hinrich", "middle": [], "last": "Manning", "suffix": ""}, {"first": "", "middle": [], "last": "Sch\u00fctze", "suffix": ""}], "year": 1999, "venue": "", "link": "207927251"}, "BIBREF35": {"title": "Polaris: Faster page loads using fine-grained dependency tracking", "authors": [{"first": "Ravi", "middle": [], "last": "Netravali", "suffix": ""}, {"first": "Ameesh", "middle": [], "last": "Goyal", "suffix": ""}, {"first": "James", "middle": [], "last": "Mickens", "suffix": ""}, {"first": "Hari", "middle": [], "last": "Balakrishnan", "suffix": ""}], "year": 2016, "venue": "NSDI", "link": "15164882"}, "BIBREF36": {"title": "Vesper: Measuring time-to-interactivity for web pages", "authors": [{"first": "Ravi", "middle": [], "last": "Netravali", "suffix": ""}, {"first": "Vikram", "middle": [], "last": "Nathan", "suffix": ""}, {"first": "James", "middle": [], "last": "Mickens", "suffix": ""}, {"first": "Hari", "middle": [], "last": "Balakrishnan", "suffix": ""}], "year": 2018, "venue": "15th USENIX Symposium on Networked Systems Design and Implementation (NSDI)", "link": "3927627"}, "BIBREF37": {"title": "AppInsight: Mobile app performance monitoring in the wild", "authors": [{"first": "Lenin", "middle": [], "last": "Ravindranath", "suffix": ""}, {"first": "Jitendra", "middle": [], "last": "Padhye", "suffix": ""}, {"first": "Sharad", "middle": [], "last": "Agarwal", "suffix": ""}, {"first": "Ratul", "middle": [], "last": "Mahajan", "suffix": ""}, {"first": "Ian", "middle": [], "last": "Obermiller", "suffix": ""}, {"first": "Shahin", "middle": [], "last": "Shayandeh", "suffix": ""}], "year": 2012, "venue": "OSDI", "link": "14292725"}, "BIBREF38": {"title": "Timecard: Controlling user-perceived delays in server-based mobile applications", "authors": [{"first": "Lenin", "middle": [], "last": "Ravindranath", "suffix": ""}, {"first": "Jitendra", "middle": [], "last": "Padhye", "suffix": ""}, {"first": "Ratul", "middle": [], "last": "Mahajan", "suffix": ""}, {"first": "Hari", "middle": [], "last": "Balakrishnan", "suffix": ""}], "year": 2013, "venue": "Proceedings of the Twenty-Fourth ACM Symposium on Operating Systems Principles", "link": "14713407"}, "BIBREF39": {"title": "Push or request: An investigation of HTTP/2 server push for improving mobile performance", "authors": [{"first": "Sanae", "middle": [], "last": "Rosen", "suffix": ""}, {"first": "Bo", "middle": [], "last": "Han", "suffix": ""}, {"first": "Shuai", "middle": [], "last": "Hao", "suffix": ""}, {"first": "Morley", "middle": [], "last": "Mao", "suffix": ""}, {"first": "Feng", "middle": [], "last": "Qian", "suffix": ""}], "year": 2017, "venue": "Proceedings of the 26th International Conference on World Wide Web", "link": "14892955"}, "BIBREF40": {"title": "Accelerating the mobile web with server-aided dependency resolution", "authors": [{"first": "Vaspol", "middle": [], "last": "Ruamviboonsuk", "suffix": ""}, {"first": "Ravi", "middle": [], "last": "Netravali", "suffix": ""}, {"first": "Muhammed", "middle": [], "last": "Uluyol", "suffix": ""}, {"first": "V", "middle": [], "last": "Harsha", "suffix": ""}, {"first": "", "middle": [], "last": "Madhyastha", "suffix": ""}, {"first": "", "middle": [], "last": "Vroom", "suffix": ""}], "year": 2017, "venue": "Proceedings of the Conference of the ACM Special Interest Group on Data Communication", "link": "177776"}, "BIBREF41": {"title": "Engineering egress with edge fabric: Steering oceans of content to the world", "authors": [{"first": "Brandon", "middle": [], "last": "Schlinker", "suffix": ""}, {"first": "Hyojeong", "middle": [], "last": "Kim", "suffix": ""}, {"first": "Timothy", "middle": [], "last": "Cui", "suffix": ""}, {"first": "Ethan", "middle": [], "last": "Katz-Bassett", "suffix": ""}, {"first": "V", "middle": [], "last": "Harsha", "suffix": ""}, {"first": "Italo", "middle": [], "last": "Madhyastha", "suffix": ""}, {"first": "James", "middle": [], "last": "Cunha", "suffix": ""}, {"first": "Saif", "middle": [], "last": "Quinn", "suffix": ""}, {"first": "Petr", "middle": [], "last": "Hasan", "suffix": ""}, {"first": "Hongyi", "middle": [], "last": "Lapukhov", "suffix": ""}, {"first": "", "middle": [], "last": "Zeng", "suffix": ""}], "year": 2017, "venue": "Proceedings of the Conference of the ACM Special Interest Group on Data Communication", "link": "5793954"}, "BIBREF42": {"title": "C3: Cutting tail latency in cloud data stores via adaptive replica selection", "authors": [{"first": "", "middle": [], "last": "P Lalith", "suffix": ""}, {"first": "Marco", "middle": [], "last": "Suresh", "suffix": ""}, {"first": "Stefan", "middle": [], "last": "Canini", "suffix": ""}, {"first": "Anja", "middle": [], "last": "Schmid", "suffix": ""}, {"first": "", "middle": [], "last": "Feldmann", "suffix": ""}], "year": 2015, "venue": "12th USENIX Symposium on Networked Systems Design and Implementation", "link": "17203404"}, "BIBREF43": {"title": "Maximizing a sum of sigmoids. Optimization and Engineering", "authors": [{"first": "Madeleine", "middle": [], "last": "Udell", "suffix": ""}, {"first": "Stephen", "middle": [], "last": "Boyd", "suffix": ""}], "year": 2013, "venue": "", "link": null}, "BIBREF44": {"title": "Deadline-aware datacenter tcp (d2tcp)", "authors": [{"first": "Balajee", "middle": [], "last": "Vamanan", "suffix": ""}, {"first": "Jahangir", "middle": [], "last": "Hasan", "suffix": ""}, {"first": "T", "middle": ["N"], "last": "Vijaykumar", "suffix": ""}], "year": 2012, "venue": "ACM SIGCOMM Computer Communication Review", "link": "14065129"}, "BIBREF45": {"title": "Eyeorg: A platform for crowdsourcing web quality of experience measurements", "authors": [{"first": "Matteo", "middle": [], "last": "Varvello", "suffix": ""}, {"first": "Jeremy", "middle": [], "last": "Blackburn", "suffix": ""}, {"first": "David", "middle": [], "last": "Naylor", "suffix": ""}, {"first": "Konstantina", "middle": [], "last": "Papagiannaki", "suffix": ""}], "year": 2016, "venue": "Proceedings of the 12th International on Conference on emerging Networking EXperiments and Technologies", "link": "16307795"}, "BIBREF46": {"title": "Costlo: Cost-effective redundancy for lower latency variance on cloud storage services", "authors": [{"first": "Zhe", "middle": [], "last": "Wu", "suffix": ""}, {"first": "Curtis", "middle": [], "last": "Yu", "suffix": ""}, {"first": "V", "middle": [], "last": "Harsha", "suffix": ""}, {"first": "", "middle": [], "last": "Madhyastha", "suffix": ""}], "year": 2015, "venue": "NSDI", "link": "7466159"}, "BIBREF47": {"title": "Taking the edge off with Espresso: Scale, reliability and programmability for global internet peering", "authors": [{"first": "Murtaza", "middle": [], "last": "Kok-Kiong Yap", "suffix": ""}, {"first": "Jeremy", "middle": [], "last": "Motiwala", "suffix": ""}, {"first": "Steve", "middle": [], "last": "Rahe", "suffix": ""}, {"first": "Matthew", "middle": [], "last": "Padgett", "suffix": ""}, {"first": "Gary", "middle": [], "last": "Holliman", "suffix": ""}, {"first": "Marcus", "middle": [], "last": "Baldus", "suffix": ""}, {"first": "Taeeun", "middle": [], "last": "Hines", "suffix": ""}, {"first": "Ashok", "middle": [], "last": "Kim", "suffix": ""}, {"first": "Ankur", "middle": [], "last": "Narayanan", "suffix": ""}, {"first": "Victor", "middle": [], "last": "Jain", "suffix": ""}, {"first": "Colin", "middle": [], "last": "Lin", "suffix": ""}, {"first": "Brian", "middle": [], "last": "Rice", "suffix": ""}, {"first": "Arjun", "middle": [], "last": "Rogan", "suffix": ""}, {"first": "Bert", "middle": [], "last": "Singh", "suffix": ""}, {"first": "Manish", "middle": [], "last": "Tanaka", "suffix": ""}, {"first": "Puneet", "middle": [], "last": "Verma", "suffix": ""}, {"first": "Mukarram", "middle": [], "last": "Sood", "suffix": ""}, {"first": "Matt", "middle": [], "last": "Tariq", "suffix": ""}, {"first": "Dzevad", "middle": [], "last": "Tierney", "suffix": ""}, {"first": "Vytautas", "middle": [], "last": "Trumic", "suffix": ""}, {"first": "Calvin", "middle": [], "last": "Valancius", "suffix": ""}, {"first": "Mahesh", "middle": [], "last": "Ying", "suffix": ""}, {"first": "Bikash", "middle": [], "last": "Kallahalla", "suffix": ""}, {"first": "Amin", "middle": [], "last": "Koley", "suffix": ""}, {"first": "", "middle": [], "last": "Vahdat", "suffix": ""}], "year": 2017, "venue": "Proceedings of the Conference of the ACM Special Interest Group on Data Communication", "link": "885151"}, "BIBREF48": {"title": "Tradeoffs in CDN designs for throughput oriented traffic", "authors": [{"first": "Minlan", "middle": [], "last": "Yu", "suffix": ""}, {"first": "Wenjie", "middle": [], "last": "Jiang", "suffix": ""}, {"first": "Haoyuan", "middle": [], "last": "Li", "suffix": ""}, {"first": "Ion", "middle": [], "last": "Stoica", "suffix": ""}], "year": 2012, "venue": "Proceedings of the 8th international conference on Emerging networking experiments and technologies", "link": "1491158"}}, "ref_entries": {}}
{"paper_id": "199661683", "_pdf_hash": "fdf71181a679d1eac6b6969d9d9208c3bdd6e1cb", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Handling sparsity via the horseshoe", "authors": [{"first": "C", "middle": [], "last": "Carvalho", "suffix": ""}, {"first": "N", "middle": [], "last": "Polson", "suffix": ""}, {"first": "J", "middle": [], "last": "Scott", "suffix": ""}], "year": 2009, "venue": "12th International Conference on Artificial Intelligence and Statistics, AISTATS", "link": "1219275"}, "BIBREF1": {"title": "Understanding the complexity of 3G UMTS network performance", "authors": [{"first": "Y", "middle": [], "last": "Chen", "suffix": ""}, {"first": "N", "middle": [], "last": "Duffield", "suffix": ""}, {"first": "P", "middle": [], "last": "Haffner", "suffix": ""}, {"first": "W", "middle": [], "last": "Hsu", "suffix": ""}, {"first": "G", "middle": [], "last": "Jacobson", "suffix": ""}, {"first": "Y", "middle": [], "last": "Jin", "suffix": ""}, {"first": "S", "middle": [], "last": "Sen", "suffix": ""}, {"first": "S", "middle": [], "last": "Venkataraman", "suffix": ""}, {"first": "Z", "middle": [], "last": "Zhang", "suffix": ""}], "year": 2013, "venue": "IFIP Networking Conference", "link": "362005"}, "BIBREF2": {"title": "Adaptive CSI and feedback estimation in LTE and beyond: a Gaussian process regression approach", "authors": [{"first": "A", "middle": [], "last": "Chiumento", "suffix": ""}, {"first": "M", "middle": [], "last": "Bennis", "suffix": ""}, {"first": "C", "middle": [], "last": "Desset", "suffix": ""}, {"first": "L", "middle": ["V"], "last": "Der Perre", "suffix": ""}, {"first": "S", "middle": [], "last": "Pollin", "suffix": ""}], "year": 2015, "venue": "EURASIP Journal on Wireless Communications and Networking", "link": "4656753"}, "BIBREF3": {"title": "A Collaborative Learning Based Approach for Parameter Configuration of Cellular Networks", "authors": [{"first": "G", "middle": [], "last": "Liu", "suffix": ""}, {"first": "X", "middle": [], "last": "Guo", "suffix": ""}, {"first": "X", "middle": [], "last": "Wang", "suffix": ""}, {"first": "X", "middle": [], "last": "Liu", "suffix": ""}, {"first": "C", "middle": [], "last": "Zhu", "suffix": ""}, {"first": "J", "middle": [], "last": "Chuai", "suffix": ""}, {"first": "Z", "middle": [], "last": "Chen", "suffix": ""}, {"first": "F", "middle": [], "last": "Shen", "suffix": ""}], "year": 2019, "venue": "IEEE International Conference on Computer Communications", "link": "86724554"}, "BIBREF4": {"title": "Machine Learning Based Session Drop Prediction in LTE Networks and Its SON Aspects", "authors": [{"first": "B", "middle": [], "last": "Daroczy", "suffix": ""}, {"first": "P", "middle": [], "last": "Vaderna", "suffix": ""}, {"first": "A", "middle": [], "last": "Benczur", "suffix": ""}], "year": 2015, "venue": "2015 IEEE 81st Vehicular Technology Conference", "link": "6331155"}, "BIBREF5": {"title": "Regularized multi-task learning", "authors": [{"first": "T", "middle": [], "last": "Evgeniou", "suffix": ""}, {"first": "M", "middle": [], "last": "Pontil", "suffix": ""}], "year": 2004, "venue": "Proceedings of the tenth ACM SIGKDD International Conference on Knowledge Discovery and Data Mining", "link": "719551"}, "BIBREF6": {"title": "Bayesian Data Analysis", "authors": [{"first": "A", "middle": [], "last": "Gelman", "suffix": ""}, {"first": "J", "middle": ["B"], "last": "Carlin", "suffix": ""}, {"first": "H", "middle": ["S"], "last": "Stern", "suffix": ""}, {"first": "D", "middle": ["B"], "last": "Dunson", "suffix": ""}, {"first": "A", "middle": [], "last": "Vehtari", "suffix": ""}, {"first": "D", "middle": ["B"], "last": "Rubin", "suffix": ""}], "year": 2013, "venue": "", "link": "62610127"}, "BIBREF7": {"title": "Figure 6: Distribution of posteriors at each cell estimated by no pooling method for feature 2", "authors": [{"first": "A", "middle": [], "last": "Gelman", "suffix": ""}, {"first": "J", "middle": [], "last": "Hill", "suffix": ""}], "year": 2006, "venue": "", "link": null}, "BIBREF8": {"title": "Sparse Bayesian multi-task learning", "authors": [{"first": "S", "middle": [], "last": "Guo", "suffix": ""}, {"first": "O", "middle": [], "last": "Zoeter", "suffix": ""}, {"first": "C", "middle": [], "last": "Archambeau", "suffix": ""}], "year": 2011, "venue": "Advances in Neural Information Processing Systems", "link": "11679442"}, "BIBREF9": {"title": "Cellular network configuration via online learning and joint optimization", "authors": [{"first": "X", "middle": [], "last": "Guo", "suffix": ""}, {"first": "G", "middle": [], "last": "Trimponias", "suffix": ""}, {"first": "X", "middle": [], "last": "Wang", "suffix": ""}, {"first": "Z", "middle": [], "last": "Chen", "suffix": ""}, {"first": "Y", "middle": [], "last": "Geng", "suffix": ""}, {"first": "X", "middle": [], "last": "Liu", "suffix": ""}], "year": 2017, "venue": "2017 IEEE International Conference on Big Data (Big Data)", "link": "25116020"}, "BIBREF10": {"title": "The No-U-turn sampler: adaptively setting path lengths in Hamiltonian Monte Carlo", "authors": [{"first": "M", "middle": [], "last": "Hoffman", "suffix": ""}, {"first": "A", "middle": [], "last": "Gelman", "suffix": ""}], "year": 2014, "venue": "Journal of Machine Learning Research", "link": "12948548"}, "BIBREF11": {"title": "Predicting Handoffs in 3G Networks", "authors": [{"first": "U", "middle": [], "last": "Javed", "suffix": ""}, {"first": "D", "middle": [], "last": "Han", "suffix": ""}, {"first": "R", "middle": [], "last": "Caceres", "suffix": ""}, {"first": "J", "middle": [], "last": "Pang", "suffix": ""}, {"first": "S", "middle": [], "last": "Seshan", "suffix": ""}, {"first": "A", "middle": [], "last": "Varshavsky", "suffix": ""}], "year": 2012, "venue": "SIGOPS Oper. Syst. Rev", "link": "53244651"}, "BIBREF12": {"title": "US Presidential Election: What Engaged People on Facebook", "authors": [{"first": "M", "middle": [], "last": "Kharratzadeh", "suffix": ""}, {"first": "D", "middle": [], "last": "\u00dcstebay", "suffix": ""}], "year": 2017, "venue": "International AAAI Conference on Web and Social Media (ICWSM)", "link": "45384754"}, "BIBREF14": {"title": "Using Multilevel Models to Estimate Variation in Foraging Returns", "authors": [{"first": "R", "middle": [], "last": "Mcelreath", "suffix": ""}, {"first": "J", "middle": [], "last": "Koster", "suffix": ""}], "year": 2014, "venue": "Human Nature", "link": null}, "BIBREF15": {"title": "Sparsity information and regularization in the horseshoe and other shrinkage priors", "authors": [{"first": "J", "middle": [], "last": "Piironen", "suffix": ""}, {"first": "A", "middle": [], "last": "Vehtari", "suffix": ""}], "year": 2017, "venue": "Electron. J. Statist", "link": "54584958"}, "BIBREF16": {"title": "Aggregating Distributional Treatment Effects: A Bayesian Hierarchical Analysis of the Microcredit Literature", "authors": [{"first": "R", "middle": [], "last": "Meager", "suffix": ""}], "year": 2018, "venue": "", "link": "52905632"}, "BIBREF17": {"title": "Stan Modeling Language Users Guide and Reference Manual", "authors": [{"first": "Stan", "middle": [], "last": "Development Team", "suffix": ""}], "year": 2018, "venue": "", "link": null}, "BIBREF18": {"title": "Using Big Data for More Dependability: A Cellular Network Tale", "authors": [{"first": "N", "middle": [], "last": "Theera-Ampornpunt", "suffix": ""}, {"first": "S", "middle": [], "last": "Bagchi", "suffix": ""}, {"first": "K", "middle": [], "last": "Joshi", "suffix": ""}, {"first": "R", "middle": [], "last": "Panta", "suffix": ""}], "year": 2013, "venue": "Proceedings of the 9th Workshop on Hot Topics in Dependable Systems (HotDep '13)", "link": "12152749"}, "BIBREF19": {"title": "How Rocky Are They? The Composition Distribution of Kepler's Sub-Neptune Planet Candidates within 0.15 AU", "authors": [{"first": "A", "middle": [], "last": "Wolfgang", "suffix": ""}, {"first": "E", "middle": [], "last": "Lopez", "suffix": ""}], "year": 2015, "venue": "The Astrophysical Journal", "link": "119275094"}}, "ref_entries": {}}
{"paper_id": "199661892", "_pdf_hash": "e44e00fecba758d5ee048aad2d0eebb9ec82be1d", "abstract": [{"section": "Abstract", "text": "Background: Trust is a critical component of competency committees given their high-stakes decisions. Research from outside of medicine on group trust has not focused on trust in group decisions, and \"group trust\" has not been clearly defined. The purpose was twofold: to examine the definition of trust in the context of group decisions and to explore what factors may influence trust from the perspective of those who rely on competency committees through a proposed group trust model. Methods: The authors conducted a literature search of four online databases, seeking articles published on trust in group settings. Reviewers extracted, coded, and analyzed key data including definitions of trust and factors pertaining to group trust. Results: The authors selected 42 articles for full text review. Although reviewers found multiple general definitions of trust, they were unable to find a clear definition of group trust and propose the following: a group-directed willingness to accept vulnerability to actions of the members based on the expectation that members will perform a particular action important to the group, encompassing social exchange, collective perceptions, and interpersonal trust. Additionally, the authors propose a model encompassing individual level factors (trustor and trustee), interpersonal interactions, group level factors (structure and processes), and environmental factors.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Background", "text": "Training competent physicians is, in many ways, a matter of trust. Patients trust providers to competently address their ailments and assist in helping them achieve good health. Accreditation organizations trust that graduate medical education (GME) programs implement policies and procedures to prepare graduates to provide highly competent medical care. GME programs that utilize competency committees trust these groups to make accurate decisions regarding trainee progress. Trust as a core concept is growing in prevalence in the broader education literature and more recently has been discussed in health professions education, but is the nature of trust in each of these contexts the same?", "cite_spans": [], "ref_spans": []}, {"section": "Background", "text": "Health professions education has examined trust in the context of Entrustable Professional Activities (EPAs), which include decisions that supervisors make about the appropriate level of trainee supervision for different clinical responsibilities [1, 2] . While such individual decisions of trust are important, group decisions regarding trainee competence are critical. In some countries, competency committees are an essential part of the postgraduate medical education program. These committees usually consist of training program faculty who collectively determine which trainees are on appropriate paths towards unsupervised clinical practice and which are not. They assess each trainee's progress, and they make recommendations to program directors regarding trainee overall progress, promotion, and remediation [3] [4] [5] . Given the high-stakes decisions shouldered by competency committees, trust is a critical component of these group decisions.", "cite_spans": [{"start": 247, "end": 250, "text": "[1,", "ref_id": "BIBREF0"}, {"start": 251, "end": 253, "text": "2]", "ref_id": "BIBREF2"}, {"start": 818, "end": 821, "text": "[3]", "ref_id": "BIBREF3"}, {"start": 822, "end": 825, "text": "[4]", "ref_id": "BIBREF4"}, {"start": 826, "end": 829, "text": "[5]", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Background", "text": "Although some recent studies describe data sources that competency committees use and how this information may impact their collective decisions [6, 7] , health professions education research has not studied trust within these committees and trust in committee decisions from individuals either within or outside the group. Scholars outside of medicine have explored trust at the individual level and also at the group level (e.g. in work teams) [8] [9] [10] . Even within a group, research suggests that trust occurs at multiple levels encompassing both individual level and group level processes simultaneously [8] . For purposes of this review, we define a group as \"a collection of individuals who have regular contact and frequent interaction, mutual influence, common feeling of camaraderie, and who work together to achieve a common set of goals.\" [11] Research on group trust has focused primarily on trust within a group (e.g. as an aggregate or combination of individual trust) as opposed to trust in group decisions from individuals either within or outside of the group. However, \"group trust\" in any of these contexts has not been clearly defined. Defining trust in group settings is important to informing and potentially improving how competency committees and other groups make collective decisions; proposing a model illustrating various components of group trust may also help such committees implement a more effective and meaningful decision process regarding trainee competence.", "cite_spans": [{"start": 145, "end": 148, "text": "[6,", "ref_id": "BIBREF6"}, {"start": 149, "end": 151, "text": "7]", "ref_id": "BIBREF7"}, {"start": 446, "end": 449, "text": "[8]", "ref_id": "BIBREF8"}, {"start": 450, "end": 453, "text": "[9]", "ref_id": "BIBREF9"}, {"start": 454, "end": 458, "text": "[10]", "ref_id": "BIBREF10"}, {"start": 613, "end": 616, "text": "[8]", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "Background", "text": "The purpose of this scoping review is to examine the definition of trust in the context of group decisions and propose a definition of group trust. Additionally, we examine what factors may influence group trust through a proposed model to illustrate the relationship between individual level and group level trust.", "cite_spans": [], "ref_spans": []}, {"section": "Theoretical framework", "text": "In order for decision-making groups to achieve consensus, communication and interactions between people, objects (i.e. items that help augment human capabilities in a learning or task-oriented setting, such as learning management systems), and the environment are believed to be important. We therefore chose situated cognition as our theoretical framework to support the development of a model and interpretation of the literature, helping to advance our understanding of group processes in the context of competency committees. Situated cognition proposes that thinking and learning are situated (or located) within the larger social and physical context of the environment [12] . This theory suggests that a group setting is highly complex with multiple components (i.e. physical, social, and cultural) and opportunities for interactions between these components. It recognizes the complex relationship between participants, objects (i.e. artifacts) that help to augment individuals' cognitive capabilities, and the environment. Situated cognition emphasizes how these various interactions lead to thinking, learning, and decisions, and the model we propose in this review is built upon all of these interactions.", "cite_spans": [{"start": 676, "end": 680, "text": "[12]", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "Methods", "text": "We chose a scoping review to understand how trust operates in groups making collective decisions and to support the development of a model using situated cognition that can be tested empirically in future studies. This scoping review was conducted based upon the methodology originally outlined by Arksey and O'Malley and expanded upon by Levac et al. [13, 14] We initially reviewed the broad literature on trust at the individual, group, and organizational levels. During this initial review, we identified a multilevel model of trust in work teams from outside of health professions education that we used as a framework to guide our subsequent search and analysis [8] . Recognizing that the medical literature is narrow for this particular subject and the potential benefits of including what is known about trust in group settings from other fields, we chose to expand our search to include other disciplines that involve similar groups (e.g. committees and juries).", "cite_spans": [{"start": 352, "end": 356, "text": "[13,", "ref_id": "BIBREF13"}, {"start": 357, "end": 360, "text": "14]", "ref_id": "BIBREF14"}, {"start": 667, "end": 670, "text": "[8]", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "Methods", "text": "With the assistance of a medical librarian, we conducted a search in MEDLINE, ERIC, PsycINFO, and SCOPUS in April 2018 (our specific search strategy is shown in Supplemental Digital Appendix). We did not limit the publication dates of our searches, but the results were limited to English-language articles.", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "The research team reviewed titles and abstracts using the following initial inclusion criteria: original research or review articles; \"trust\" referenced in the title; and articles that included information about a group, team, committee, or similar collection of individuals. Articles were excluded if they did not meet the inclusion criteria above. We also excluded articles for the following reasons: the word \"trust\" was used in a different context (e.g. trust fund); trust was a narrow focus of the article; no clear link to group processes or dynamics; the link between trust and a group was not clear; the article referenced only virtual groups; and articles from the computer science, information technology, and economics fields. Articles were excluded from these three fields because we felt that the context in which they utilized trust was not applicable to decision-making groups. The research team met regularly and came to complete consensus during this step of the process.", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "A data extraction sheet was modeled after a sensitizing framework in a recently published review of trust in teams outside of medicine and our initial review of the trust literature (See Additional file 1) [8] . We extracted definitions of trust along with factors pertaining to trust at the group level and synthesized this information into our primary outcomes: a definition of group trust, factors that influence group trust, and a proposed model to illustrate the relationship between trust at the individual and group levels. Each article was independently coded by two members of the research team. Discrepancies in coding were resolved in regular in-person research team meetings. Figure 1 outlines the review process.", "cite_spans": [{"start": 206, "end": 209, "text": "[8]", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "Methods", "text": "Consistent with revised scoping review methodology recommendations [14] , we obtained consultation from two independent medical educators outside of our research team who have experience with competency committees. We presented them our preliminary findings, and we incorporated their feedback in our final revision of the results.", "cite_spans": [{"start": 67, "end": 71, "text": "[14]", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "Results", "text": "We identified 406 publications and included 42 articles. The two main reasons for exclusion were that the articles demonstrated no clear link to group dynamics and/or trust was too narrow of a focus (Fig. 1) . A complete list of the 42 included publications is available in Additional file 2. Additionally, a complete list of the excluded publications and the reasons for exclusion are available in Additional files 3, 4, 5, and 6.", "cite_spans": [], "ref_spans": []}, {"section": "Publication characteristics", "text": "Publications were written by 108 unique authors, with 103 (95.4%) contributing once. Twelve countries were represented, and six (14.2%) publications were multi-national collaborations. Five (11.9%) publications involved healthcare work teams. Thirteen (31%) involved undergraduate or graduate students, though none of the included publications focused on health professions education ( Table 1) .", "cite_spans": [], "ref_spans": [{"start": 386, "end": 394, "text": "Table 1)", "ref_id": "TABREF0"}]}, {"section": "Publication types", "text": "Thirty-four (81%) publications were empirical research studies, seven (16.7%) were literature reviews, and one Fig. 1 Flowchart of inclusion/exclusion determinations (2.4%) was a meta-analysis. Of the empirical publications, all were prospective studies; 85.3% used quantitative methods (n = 29: surveys = 27, scenarios = 2), while the remaining utilized qualitative (n = 2) or mixed (n = 3) methods.", "cite_spans": [], "ref_spans": []}, {"section": "Definitions of trust", "text": "The most often cited general definition of trust by articles in this review (n = 28, 66.7%; almost always referring to trust at the individual level) is the \"willingness of a party to be vulnerable to the actions of another party based on the [positive] expectation that the other will perform a particular action important to the trustor, irrespective of the ability to monitor or control that other party.\" [15] Other general definitions of trust cited by articles in this study are provided in Table 2 . Positive expectations are beliefs that the actions of another will be beneficial, favorable, or at least not detrimental [26] . Vulnerability implies that there is something of importance to be lost and involves taking a risk; indeed, risk is also a commonly cited component of trust [17, 18, 21, 22, 24, [27] [28] [29] [30] [31] [32] [33] . Thus, because trust in general can be defined as a willingness to be vulnerable to the actions of another party, trust at any level (e.g. individual or group) can arguably be characterized as a measure of how much risk an individual is willing to incur in relationships.", "cite_spans": [{"start": 409, "end": 413, "text": "[15]", "ref_id": "BIBREF15"}, {"start": 628, "end": 632, "text": "[26]", "ref_id": "BIBREF26"}, {"start": 791, "end": 795, "text": "[17,", "ref_id": "BIBREF17"}, {"start": 796, "end": 799, "text": "18,", "ref_id": "BIBREF18"}, {"start": 800, "end": 803, "text": "21,", "ref_id": "BIBREF21"}, {"start": 804, "end": 807, "text": "22,", "ref_id": "BIBREF22"}, {"start": 808, "end": 811, "text": "24,", "ref_id": "BIBREF24"}, {"start": 812, "end": 816, "text": "[27]", "ref_id": "BIBREF27"}, {"start": 817, "end": 821, "text": "[28]", "ref_id": "BIBREF28"}, {"start": 822, "end": 826, "text": "[29]", "ref_id": "BIBREF29"}, {"start": 827, "end": 831, "text": "[30]", "ref_id": "BIBREF30"}, {"start": 832, "end": 836, "text": "[31]", "ref_id": "BIBREF31"}, {"start": 837, "end": 841, "text": "[32]", "ref_id": "BIBREF32"}, {"start": 842, "end": 846, "text": "[33]", "ref_id": "BIBREF33"}], "ref_spans": [{"start": 497, "end": 504, "text": "Table 2", "ref_id": "TABREF1"}]}, {"section": "Definitions of trust", "text": "Within a group, trust has been proposed by fields outside of medicine (e.g. management, organizational and social psychology, and higher education) to exist at both the individual and group levels of analysis and that conceptualizations of group trust should include individual trust. However, we were unable to find in this review a clear definition of \"group trust.\"", "cite_spans": [], "ref_spans": []}, {"section": "Group trust definition", "text": "We propose the following definition of group trust: \"a group-directed willingness to accept vulnerability to expectation that the other will perform a particular action important to the trustor, irrespective of the ability to monitor or control that other party.\" [15] \"The degree of confidence the members of a team have in the goodwill of its leader, specifically, the extent to which they believe that the leader is honest, sincere, and unbiased in taking their positions into account.\" [16] \"A psychological state that manifests itself in the behaviors towards others, is based on the expectations made upon behaviors of these others, and on the perceived motives and intentions in situations entailing risk for the relationship with those others.\" [17] \"Trust in individuals is an expectation or belief that actions from another party will be motivated by good intentions. Moreover, individuals take a risk in this belief because the other party may not act out of benevolence.\" [18] \"Expectations, assumptions, or beliefs about the likelihood that another's future actions will be beneficial, favorable, or at least not detrimental to one's interests.\" [19] \"A belief (held by an individual or a group) that another individual or group (a) makes good-faith efforts to behave in accordance with any commitments made both explicitly or implicitly, (b) is honest in whatever interactions preceded such commitments, and (c) would not take excessive advantage of another even when the opportunity became available.\" [20] \"The extent to which a person is confident in, and willing to act on the basis of, the words, actions, and decisions of another. Critically, trust requires the presence of uncertainty and risk.\" [21] \"One party's (the trustor) confident expectation that another party (the trustee), on whom the trustor must rely, will help the trustor reach his or her goals in an environment of risk and uncertainty.\" [22] \"The optimistic acceptance of a vulnerable situation in which the truster believes the trustee will care for the truster's interests through the bracketing out of uncertainty. Empirically, we therefore delineate trust in terms of the overlooking of uncertainty and possible negative outcomes based on considerations of the motives and/or competencies of others.\" [23] \"A resolve to bear an experienced risk by confiding in the new and unknown. It goes beyond the blind, unquestioning faith that an infant may have of a parent because there is an acknowledgement of past experience that denotes trust as a risk, especially where there are unknown elements. It is a decision to act in concert with others in anticipation of a return. By placing trust in others, we place ourselves in a position of vulnerability, ceding power. Trust given in the anticipation of reciprocity creates a sense of mutual obligation.\" [24] \"The generalized expectation of predictable and benevolent motives and/or behavior from others.\" [25] actions of the members based on the expectation that members will perform a particular action important to the group, encompassing social exchange, collective perceptions, and interpersonal trust.\" Fig. 2 outlines the relationship between individual trust and various characterizations of group trust in the literature, which include the three broad categories mentioned in our definition: individual (sometimes referred to as interpersonal) trust, social exchange, and collective perceptions. At the individual level, interpersonal trust occurs in dyadic relationships between members in the group, encompassing general features of trust outlined above along with characteristics of both the trustor and the trustee. One important difference between individual and group trust is that instead of existing in dyadic relationships, group trust implies that these components of trust are shared among group members [8] . Scholars note that group trust involves each dyadic relationship within the group along with collective perceptions of trust about the group as a distinct unit [34] . Social exchange, which encompasses individual interactions and interdependent group tasks, is thought to help individuals develop shared perceptions, expectations, and behavioral norms with other group members [35] [36] [37] . Moreover, trust at the group level is also felt to be a matter of shared group membership where individuals may be willing to trust other group members to show that the group is important to them and a meaningful part of their identity [38] .", "cite_spans": [{"start": 264, "end": 268, "text": "[15]", "ref_id": "BIBREF15"}, {"start": 490, "end": 494, "text": "[16]", "ref_id": "BIBREF16"}, {"start": 753, "end": 757, "text": "[17]", "ref_id": "BIBREF17"}, {"start": 984, "end": 988, "text": "[18]", "ref_id": "BIBREF18"}, {"start": 1159, "end": 1163, "text": "[19]", "ref_id": "BIBREF19"}, {"start": 1517, "end": 1521, "text": "[20]", "ref_id": "BIBREF20"}, {"start": 1717, "end": 1721, "text": "[21]", "ref_id": "BIBREF21"}, {"start": 1925, "end": 1929, "text": "[22]", "ref_id": "BIBREF22"}, {"start": 2293, "end": 2297, "text": "[23]", "ref_id": "BIBREF23"}, {"start": 2841, "end": 2845, "text": "[24]", "ref_id": "BIBREF24"}, {"start": 2943, "end": 2947, "text": "[25]", "ref_id": "BIBREF25"}, {"start": 3861, "end": 3864, "text": "[8]", "ref_id": "BIBREF8"}, {"start": 4027, "end": 4031, "text": "[34]", "ref_id": "BIBREF34"}, {"start": 4244, "end": 4248, "text": "[35]", "ref_id": "BIBREF35"}, {"start": 4249, "end": 4253, "text": "[36]", "ref_id": "BIBREF36"}, {"start": 4254, "end": 4258, "text": "[37]", "ref_id": "BIBREF37"}, {"start": 4497, "end": 4501, "text": "[38]", "ref_id": "BIBREF38"}], "ref_spans": []}, {"section": "Proposed model", "text": "The second aim of our study is to explore specific components of groups that may influence how trust can be conceived to work in health professions education group settings, such as competency committees. We propose a preliminary model (Fig. 3) for various elements of trust pertaining to group decisions. Our model includes individual level factors (encompassing both the trustor and the trustee), group level factors (encompassing both group structure and group processes), environmental factors, and importantly interpersonal interactions, which are a key element in situated cognition and have been cited as crucial for competency committees [39] . Below we outline some of the factors in our proposed model (See corresponding Table 3 for a complete description of all the factors, which includes potential implications for competency committees).", "cite_spans": [{"start": 646, "end": 650, "text": "[39]", "ref_id": "BIBREF39"}], "ref_spans": [{"start": 731, "end": 738, "text": "Table 3", "ref_id": "TABREF2"}]}, {"section": "Individual level factors", "text": "Individual trustor factors Trust between two group members requires looking at one individual as the \"trustor\" and the other as the \"trustee,\" noting this relationship can be reciprocal with the roles shifting between members. Trustor factors include vulnerability and an individual's propensity to trust, which is believed to vary with people's different experiences, personality types, and cultures [15] . Showing vulnerability has been shown to be crucial for building trusting group relationships as this demonstrates a Fig. 2 Definition of Group Trust willingness to trust other group members and the group itself [23] .", "cite_spans": [{"start": 401, "end": 405, "text": "[15]", "ref_id": "BIBREF15"}, {"start": 619, "end": 623, "text": "[23]", "ref_id": "BIBREF23"}], "ref_spans": []}, {"section": "Individual level factors", "text": "Individual trustee factors The three trustee characteristics most often cited in the literature are ability (a group of skills and competencies in a specific domain), benevolence (the extent to which a trustee is believed to want to do good to a trustor on the giving end of a trusting relationship), and integrity (the trustor's perception that the trustee adheres to a set of principles that the trustor finds acceptable) [15] . In a collective setting, perceived commitment to the group has also been cited as an important individual trait [41] .", "cite_spans": [{"start": 424, "end": 428, "text": "[15]", "ref_id": "BIBREF15"}, {"start": 543, "end": 547, "text": "[41]", "ref_id": "BIBREF41"}], "ref_spans": []}, {"section": "Interpersonal interactions", "text": "Interpersonal interactions are an important component of situated cognition, and effective interactions can lead to improved social exchange and cohesion, both of which have been shown to enhance the development of interpersonal trust, especially in new product development teams and technology-supported decision-making groups [21, 42] . For decision-making groups and top management teams, a shared mental model is important and may be conceptualized as the shared knowledge and organized understanding of the information and resources used by the group, tasks and problems faced by the group, and individual group members' imported information (the preexisting knowledge, stereotypes, preconceptions, and experiences stored in group members' memories) [40, 43] . The idea of a shared mental model is a critical component of competency committees.", "cite_spans": [{"start": 328, "end": 332, "text": "[21,", "ref_id": "BIBREF21"}, {"start": 333, "end": 336, "text": "42]", "ref_id": "BIBREF42"}, {"start": 755, "end": 759, "text": "[40,", "ref_id": "BIBREF40"}, {"start": 760, "end": 763, "text": "43]", "ref_id": "BIBREF43"}], "ref_spans": []}, {"section": "Interpersonal interactions", "text": "While trust between group members is usually felt to enhance information exchange and establish shared understanding, knowledge brought in by new members may adversely affect group collective beliefs and memory structures, especially in well-established groups [42] . Notably, trust can more easily be violated in relationships of shorter rather than longer duration because parties in newly formed relationships are less likely to have had the opportunity to develop mutual understanding and respect [33] . Additionally, a person's standing in the group, which refers to a person's inclusion or membership status within a group, may influence how more senior or experienced members interact with newer ones [38] .", "cite_spans": [{"start": 261, "end": 265, "text": "[42]", "ref_id": "BIBREF42"}, {"start": 501, "end": 505, "text": "[33]", "ref_id": "BIBREF33"}, {"start": 708, "end": 712, "text": "[38]", "ref_id": "BIBREF38"}], "ref_spans": []}, {"section": "Group level factors", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Group structure", "text": "Regarding a group's composition, diversity amongst members can have multiple influences on trust within the group. Diversity in this context includes both cultural and skill diversity. In undergraduate psychology students, trust was demonstrated to more likely develop in groups when members perceive each other to have similar attitudes, personality, and intellect than in dissimilar groups [22] . Cultural diversity may, in some contexts, negatively impact group performance and communication effectiveness [40] . However, in contrast to cultural diversity, skill diversity has been shown in an applied psychology meta-analysis to positively impact intrateam trust and team performance [34] .", "cite_spans": [{"start": 392, "end": 396, "text": "[22]", "ref_id": "BIBREF22"}, {"start": 509, "end": 513, "text": "[40]", "ref_id": "BIBREF40"}, {"start": 688, "end": 692, "text": "[34]", "ref_id": "BIBREF34"}], "ref_spans": []}, {"section": "Group structure", "text": "Group member stability and group size are also believed to contribute to a group's structure. In general, group Fig. 3 Proposed Group Trust Model. *In certain cases, trust outcomes become inputs into the ongoing system. **Components of a group's climate include a common group identity, group efficacy, psychological safety, psychological collectivism, and psychological ownership. ***Group leadership includes leadership style, characteristics, and behaviors New committee members may be more willing to cooperate with other members given the potential of building stronger future relationships.", "cite_spans": [], "ref_spans": []}, {"section": "Group structure", "text": "Political Skill [44] A social effectiveness construct defined as the ability to effectively understand others at work and to use such knowledge to influence others to act in ways that enhance one's personal and/or organizational objectives A committee member who has particularly strong opinions about a trainee may be more persuasive (and potentially trusted as well) based upon his or her degree of political skill.", "cite_spans": [{"start": 16, "end": 20, "text": "[44]", "ref_id": "BIBREF44"}], "ref_spans": []}, {"section": "Relational Identity Orientation [45]", "text": "One's conception of his/her relatedness to other individuals", "cite_spans": [], "ref_spans": []}, {"section": "Relational Identity Orientation [45]", "text": "Committee members with a high relational identity orientation may take great steps to build relationships within the group and will likely be more trusted as well.", "cite_spans": [], "ref_spans": []}, {"section": "Relational Identity Orientation [45]", "text": "Need for Affiliation [33] An overlapping common factor among group members that motivates them to view each other as trustworthy Procedural Fairness [16, 42, 49, 50] For decision-making groups, this includes consideration of member input and influence over a decision. Fairness of procedures used by a group has been associated with increased levels of trust and commitment to group decisions.", "cite_spans": [{"start": 21, "end": 25, "text": "[33]", "ref_id": "BIBREF33"}, {"start": 149, "end": 153, "text": "[16,", "ref_id": "BIBREF16"}, {"start": 154, "end": 157, "text": "42,", "ref_id": "BIBREF42"}, {"start": 158, "end": 161, "text": "49,", "ref_id": "BIBREF49"}, {"start": 162, "end": 165, "text": "50]", "ref_id": "BIBREF50"}], "ref_spans": []}, {"section": "Relational Identity Orientation [45]", "text": "Committee decisions are likely to be more trustworthy when the group follows procedures that are judged as fair by faculty members and trainees.", "cite_spans": [], "ref_spans": []}, {"section": "Relational Identity Orientation [45]", "text": "Swift Trust [33, 40] Occurs when individuals decide to trust others prior to developing longer term relationships. Swift trust develops as a function of members' own dispositional tendencies, quickly discernable surface-level cues of others, and imported trust-related information.", "cite_spans": [{"start": 12, "end": 16, "text": "[33,", "ref_id": "BIBREF33"}, {"start": 17, "end": 20, "text": "40]", "ref_id": "BIBREF40"}], "ref_spans": []}, {"section": "Relational Identity Orientation [45]", "text": "Initial/swift trust usually occurs in newly formed committees or with new members (especially if they don't work with more established members in other contexts). These individuals will have to decide if they are going to trust other members of the group and the committee itself before developing deeper relationships.", "cite_spans": [], "ref_spans": []}, {"section": "Relational Identity Orientation [45]", "text": "Task Interdependence [8, 34] The degree to which group members rely on one another and interact in order for the group to accomplish its goals, which may have an effect on group trust and trust between group members", "cite_spans": [{"start": 21, "end": 24, "text": "[8,", "ref_id": "BIBREF8"}, {"start": 25, "end": 28, "text": "34]", "ref_id": "BIBREF34"}], "ref_spans": []}, {"section": "Relational Identity Orientation [45]", "text": "Making collective decisions about trainee competence relies on the \"wisdom of the group.\" Each faculty member only has a portion of the data based upon their own experiences. The group must compile performance data and members' experiences to build a collective picture of individual trainee competence.", "cite_spans": [], "ref_spans": []}, {"section": "Relational Identity Orientation [45]", "text": "Climate [36, 41-45, 51, 52] Components include a common group identity, group efficacy, psychological safety, psychological collectivism, and psychological ownership", "cite_spans": [], "ref_spans": []}, {"section": "Relational Identity Orientation [45]", "text": "The internal climate of a committee may be influenced by each of these factors. A common group identity, group efficacy, and psychological safety are probably most important for competency committees.", "cite_spans": [], "ref_spans": []}, {"section": "Relational Identity Orientation [45]", "text": "Leadership [23, 37, 38, 40, 42, 43, 45, 53, 54] Components include leadership style, characteristics, and behaviors", "cite_spans": [{"start": 11, "end": 15, "text": "[23,", "ref_id": "BIBREF23"}, {"start": 16, "end": 19, "text": "37,", "ref_id": "BIBREF37"}, {"start": 20, "end": 23, "text": "38,", "ref_id": "BIBREF38"}, {"start": 24, "end": 27, "text": "40,", "ref_id": "BIBREF40"}, {"start": 28, "end": 31, "text": "42,", "ref_id": "BIBREF42"}, {"start": 32, "end": 35, "text": "43,", "ref_id": "BIBREF43"}, {"start": 36, "end": 39, "text": "45,", "ref_id": "BIBREF45"}, {"start": 40, "end": 43, "text": "53,", "ref_id": "BIBREF53"}, {"start": 44, "end": 47, "text": "54]", "ref_id": "BIBREF54"}], "ref_spans": []}, {"section": "Relational Identity Orientation [45]", "text": "The committee chair is responsible for implementing the training program's policies and procedures related to this committee. Committee chairs may be more effective at building individual and collective trust if they are prototypical of the group, utilize an authentic or transformational leadership style, create a safe atmosphere, manage conflict/discussions, and demonstrate relational behaviors.", "cite_spans": [], "ref_spans": []}, {"section": "Environmental Factors", "text": "Reporting Relationships [54] In settings where groups report to diverse outside entities, these reporting relationships can be associated with role conflict, confusing expectations or role ambiguity, excessive demands, and competing priorities", "cite_spans": [{"start": 24, "end": 28, "text": "[54]", "ref_id": "BIBREF54"}], "ref_spans": []}, {"section": "Environmental Factors", "text": "The committee reports to their respective training program, which in turn reports information about resident performance to various accreditation agencies. If a committee is required to report to another entity outside of this chain, it may decrease trust amongst members of the group, especially member stability tends to positively impact communication patterns, the social interaction of teams, and interpersonal trust [42] . From an external perspective, smaller groups (i.e. less than 10 individuals) have generally been shown to be more trustworthy than larger groups (i.e. 10 or more individuals) in undergraduate psychology students [25] .", "cite_spans": [{"start": 422, "end": 426, "text": "[42]", "ref_id": "BIBREF42"}, {"start": 641, "end": 645, "text": "[25]", "ref_id": "BIBREF25"}], "ref_spans": []}, {"section": "Group processes Group cooperation and monitoring", "text": "Work outside of medicine suggests that cooperation and monitoring behaviors are commonly impacted by the level of trust within a group. Group members who experience high trust tend to cooperate more, share information, accept influences from other members, and feel personally involved with the group. Monitoring behaviors usually occurs at the opposite end of the spectrum when trust between members is low and manifest when members feel a need to be vigilant about the actions and intentions of others. Groups in which members perceive colleagues as trustworthy are likely to demonstrate fewer monitoring behaviors and more cooperative behaviors based upon psychology research on undergraduate students, teams from European social care institutions, and hospital employees [17, 28, 46] .", "cite_spans": [{"start": 775, "end": 779, "text": "[17,", "ref_id": "BIBREF17"}, {"start": 780, "end": 783, "text": "28,", "ref_id": "BIBREF28"}, {"start": 784, "end": 787, "text": "46]", "ref_id": "BIBREF46"}], "ref_spans": []}, {"section": "Group processes Group cooperation and monitoring", "text": "Group conflict Conflict amongst group members appears to have complex associations. Task (cognitive) conflict tends to arise from individual differences in viewpoints, ideas, or opinions when group members participate in a shared undertaking. Conversely, relationship (affective) conflict tends to arise from interpersonal tensions. Scholars argue that these two types of conflict lead to different outcomes and contend that task conflict can be constructive whereas relationship conflict is usually dysfunctional based upon research from strategic decision-making teams, MBA graduate students, and higher education faculty [26, 31, 32] . Higher levels of conflict (especially relationship conflict) in teams are usually associated with lower trust. On the other hand, too much trust within a group may result in almost no conflict whatsoever regardless of type. Thus, the group may lose out on the positive effects of task conflict [47] .", "cite_spans": [{"start": 624, "end": 628, "text": "[26,", "ref_id": "BIBREF26"}, {"start": 629, "end": 632, "text": "31,", "ref_id": "BIBREF31"}, {"start": 633, "end": 636, "text": "32]", "ref_id": "BIBREF32"}, {"start": 933, "end": 937, "text": "[47]", "ref_id": "BIBREF47"}], "ref_spans": []}, {"section": "Group processes Group cooperation and monitoring", "text": "In the management literature, even perceptions of conflict may lead to conflict within a group. How one perceives, defines, and interprets interpersonal discord may be more important than the nature of the conflict itself [33] . When one person distrusts another, that person may interpret ambiguous behaviors as threatening and convey distrust through his or her conduct. The person whose behavior is interpreted as threatening may reciprocate that distrust.", "cite_spans": [{"start": 222, "end": 226, "text": "[33]", "ref_id": "BIBREF33"}], "ref_spans": []}, {"section": "Group processes Group cooperation and monitoring", "text": "Group procedural fairness Two aspects of decision-making procedures have been shown to create perceptions of fairness: consideration of member input and influence over a decision. Consideration of input refers to the extent a group leader listens to and considers group member input during a decision-making Task Complexity and Uncertainty [40, 41] Associated with decreased levels of trust within a group, especially if the group is newly formed For a competency committee, it may be challenging to determine the attainment of various clinical competence domains for all trainees, especially with gaps in evaluation data or for large training programs. Increasing complexity and uncertainty may adversely affect trust by members in the committee's processes and decisions.", "cite_spans": [{"start": 340, "end": 344, "text": "[40,", "ref_id": "BIBREF40"}, {"start": 345, "end": 348, "text": "41]", "ref_id": "BIBREF41"}], "ref_spans": []}, {"section": "Group processes Group cooperation and monitoring", "text": "Outside Group Membership/ Social Ties [41] Group members may be worried that membership in other groups can lead new members to act in ways that harm their own group.", "cite_spans": [{"start": 38, "end": 42, "text": "[41]", "ref_id": "BIBREF41"}], "ref_spans": []}, {"section": "Group processes Group cooperation and monitoring", "text": "Committee members who serve on other hospital committees (e.g. credentials, risk management, etc.) may be perceived as more or less trustworthy from other members. However, this is probably a small contributor to trust within these committees.", "cite_spans": [], "ref_spans": []}, {"section": "Group processes Group cooperation and monitoring", "text": "Threats [41] External dangers or conflict with another group Time pressures and faculty availability (either for individual meetings or to serve longitudinally on the committee) are potential threats to group level trust within a competency committee. However, an understaffed committee may lead to higher trust between group members.", "cite_spans": [{"start": 8, "end": 12, "text": "[41]", "ref_id": "BIBREF41"}], "ref_spans": []}, {"section": "Group processes Group cooperation and monitoring", "text": "Staffing Levels [41] Understaffed groups may develop stronger trust amongst members than larger groups Trust Outcomes Attitudes [22-24, 27, 33, 36, 40 ] May include confidence, resiliency, creativity, group satisfaction and identity, cooperation, and commitment", "cite_spans": [{"start": 16, "end": 20, "text": "[41]", "ref_id": "BIBREF41"}], "ref_spans": []}, {"section": "Group processes Group cooperation and monitoring", "text": "Individual and group level trust within competency committees may lead to greater cooperation, commitment to the group, satisfaction, and confidence in group decisions.", "cite_spans": [], "ref_spans": []}, {"section": "Group processes Group cooperation and monitoring", "text": "Performance [22, 40, 42, 43, 55] May include group performance, group learning, information sharing, and decision quality", "cite_spans": [{"start": 12, "end": 16, "text": "[22,", "ref_id": "BIBREF22"}, {"start": 17, "end": 20, "text": "40,", "ref_id": "BIBREF40"}, {"start": 21, "end": 24, "text": "42,", "ref_id": "BIBREF42"}, {"start": 25, "end": 28, "text": "43,", "ref_id": "BIBREF43"}, {"start": 29, "end": 32, "text": "55]", "ref_id": "BIBREF55"}], "ref_spans": []}, {"section": "Group processes Group cooperation and monitoring", "text": "Individual and group level trust within competency committees may lead to better sharing of information, group learning, and quality of decisions.", "cite_spans": [], "ref_spans": []}, {"section": "Group processes Group cooperation and monitoring", "text": "process. Influence refers to the extent group member input affects or is reflected in the final decision. Fair procedures have been associated with positive attitudes toward the group and leader, resulting in group harmony and trust in the leader. Individual members who perceive fair procedures within the group are believed to be more likely to commit to group decisions based upon research from Fortune 500 management teams and Netherlands undergraduate students [16, 49] .", "cite_spans": [{"start": 466, "end": 470, "text": "[16,", "ref_id": "BIBREF16"}, {"start": 471, "end": 474, "text": "49]", "ref_id": "BIBREF49"}], "ref_spans": []}, {"section": "Group task interdependence", "text": "When task interdependence (the degree to which group members must interact and rely on one another to accomplish goals) is high, trust plays a more influential role because teamwork interactions become critical to achieving group goals [8, 34] .", "cite_spans": [{"start": 236, "end": 239, "text": "[8,", "ref_id": "BIBREF8"}, {"start": 240, "end": 243, "text": "34]", "ref_id": "BIBREF34"}], "ref_spans": []}, {"section": "Group task interdependence", "text": "Group climate A group's climate has multiple components and can be defined as shared perceptions of the kinds of behaviors, practices, and procedures that are supported within a group [56] . Climate may include a group's identity, defined as the degree to which members view the group as \"we\" versus \"I.\" A common group identity may help develop trust, especially in diverse work groups, decrease negative attitudes and increase more positive affective responses toward other group members, and reduce mutual tensions and uncertainty [45] . Related to group identity is group efficacy. Efficacy has been defined in undergraduate Canadian business students at either the individual or group level and refers to an entity's belief in its ability to succeed in specific situations or accomplish a task [44] .", "cite_spans": [{"start": 184, "end": 188, "text": "[56]", "ref_id": "BIBREF56"}, {"start": 534, "end": 538, "text": "[45]", "ref_id": "BIBREF45"}, {"start": 799, "end": 803, "text": "[44]", "ref_id": "BIBREF44"}], "ref_spans": []}, {"section": "Group task interdependence", "text": "Psychological safety, collectivism, and ownership are all distinct and also contribute to a group's climate. In graduate-level business students, psychologically safe group environments encourage authenticity and risk-taking among group members because there is minimal fear of reprisal, punishment, harassment, or ridicule from others [36] . Groups with higher levels of psychological safety tend to have higher levels of trust [41] . Psychological collectivism refers to a person's propensity to favor group affiliation and the collective effort of the group over independent and autonomous effort. Compared with members who have low levels of psychological collectivism, a highly collectivistic individual will likely experience greater satisfaction working in a low-trust group environment, be more willing to work with other members, and more readily identify with that group [36] . Finally, psychological ownership refers to a feeling of possessiveness and attachment to a variety of objects within one's organization. These feelings of ownership lead one to value and take responsibility for those objects. In various industries, individuals who feel ownership may engage in territorial behaviors to communicate and defend their ownership claims, especially in lower trust environments [52] .", "cite_spans": [{"start": 336, "end": 340, "text": "[36]", "ref_id": "BIBREF36"}, {"start": 429, "end": 433, "text": "[41]", "ref_id": "BIBREF41"}, {"start": 881, "end": 885, "text": "[36]", "ref_id": "BIBREF36"}, {"start": 1293, "end": 1297, "text": "[52]", "ref_id": "BIBREF52"}], "ref_spans": []}, {"section": "Group leadership", "text": "Leaders are believed to play a critical role in the development and maintenance of trust within a group. In healthcare and bank employees, authentic and transformational leadership styles have been shown to improve trust amongst members of a group [37, 53] . Legitimacy (e.g. honesty, fairness, respectfulness) of a group leader may also promote a climate of interpersonal trust in groups [42] . Additionally, prototypical leaders, which are leaders who share essential characteristics of their group, may foster employee trust in coworkers [38] .", "cite_spans": [{"start": 248, "end": 252, "text": "[37,", "ref_id": "BIBREF37"}, {"start": 253, "end": 256, "text": "53]", "ref_id": "BIBREF53"}, {"start": 389, "end": 393, "text": "[42]", "ref_id": "BIBREF42"}, {"start": 541, "end": 545, "text": "[38]", "ref_id": "BIBREF38"}], "ref_spans": []}, {"section": "Group leadership", "text": "Leader behaviors may also influence trust. Relational behaviors, those that encourage collaboration and open communication, have been shown to augment trust in top management teams [43] . Other leader behaviors that may foster trust include fairness, particularly for a prototypical group leader [38] , the ability to create a safe atmosphere [23] , establishing behavioral norms and climate of the group [40] , developing unique personal relationships with each group member [45] , managing conflict, and creating a superordinate mission for the group [54] .", "cite_spans": [{"start": 181, "end": 185, "text": "[43]", "ref_id": "BIBREF43"}, {"start": 296, "end": 300, "text": "[38]", "ref_id": "BIBREF38"}, {"start": 343, "end": 347, "text": "[23]", "ref_id": "BIBREF23"}, {"start": 405, "end": 409, "text": "[40]", "ref_id": "BIBREF40"}, {"start": 476, "end": 480, "text": "[45]", "ref_id": "BIBREF45"}, {"start": 553, "end": 557, "text": "[54]", "ref_id": "BIBREF54"}], "ref_spans": []}, {"section": "Environment factors", "text": "Environmental factors also play an important role in situated cognition and may influence trust within a group. External reporting relationships can add complexity to shared tasks. Groups that experience large amounts of pressure and conflict caused by reporting relationships to outside entities may report role conflict, confusing expectations or role ambiguity, and excessive demands resulting in overload and competing priorities [54] . Task complexity and uncertainty can also influence trust amongst a group. The link between task uncertainty and trust has been studied in swift action starting teams, which are highly interdependent teams of skilled individuals in organizations that complete demanding, complex, time-pressured projects and are often formed quickly. High levels of task uncertainty may deplete cognitive resources, so members in these teams may become overly dependent on heuristic-based decisionmaking and rely more heavily on predispositions than would groups in less uncertain situations [40] . Additionally, group members may value predictability within the group, especially with increasingly unpredictable events outside of the group. As a result, established members of a group might be reluctant to trust new members given the uncertainty that they bring to the group [41] . Additional external factors that may impact a group include individuals' memberships in other groups and social ties, threats (e.g. external dangers or conflict with another group), and staffing levels (e.g. if a group is understaffed, trust may develop more strongly than if the group were larger because members are forced to work more closely together) [41] .", "cite_spans": [{"start": 434, "end": 438, "text": "[54]", "ref_id": "BIBREF54"}, {"start": 1015, "end": 1019, "text": "[40]", "ref_id": "BIBREF40"}, {"start": 1300, "end": 1304, "text": "[41]", "ref_id": "BIBREF41"}, {"start": 1663, "end": 1667, "text": "[41]", "ref_id": "BIBREF41"}], "ref_spans": []}, {"section": "Discussion", "text": "Although multiple definitions of general trust exist in the literature and scholars have explored trust within work teams, we were unable to find a clear definition of \"group trust.\" Further, trust in group decisions has not been well studied within or outside of health professions education. We define group trust as a group-directed willingness to accept vulnerability to actions of the members based on the expectation that members will perform a particular action important to the group, encompassing social exchange, collective perceptions, and interpersonal trust (Fig. 2) .", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "In a group, we agree with the literature outside of health professions education that trust occurs at multiple levels encompassing both individual level and group level processes simultaneously. For example, in a competency committee, members must be able to reconcile differences of opinion and work with colleagues on the committee to make decisions that are in the best interests of not only their trainees, but ultimately the patients for whom their trainees provide care. Committee members must also be able to trust one another to pull their own weight on the committee, respect other individuals' opinions, provide constructive input, and make fair judgments.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "Higher levels of interpersonal trust will likely lead to a higher degree of trust at the group level. Higher degrees of trust at both levels have been associated with attitudinal outcomes, such as increased cooperation and satisfaction [22, 33, 40] , and performance outcomes, such as information sharing and quality of group decisions [22, 42, 43, 55] . Additionally, developing a more thorough understanding of trust in the context of competency committees may help these committees implement more meaningful and effective processes to make collective decisions regarding trainee competence.", "cite_spans": [{"start": 236, "end": 240, "text": "[22,", "ref_id": "BIBREF22"}, {"start": 241, "end": 244, "text": "33,", "ref_id": "BIBREF33"}, {"start": 245, "end": 248, "text": "40]", "ref_id": "BIBREF40"}, {"start": 336, "end": 340, "text": "[22,", "ref_id": "BIBREF22"}, {"start": 341, "end": 344, "text": "42,", "ref_id": "BIBREF42"}, {"start": 345, "end": 348, "text": "43,", "ref_id": "BIBREF43"}, {"start": 349, "end": 352, "text": "55]", "ref_id": "BIBREF55"}], "ref_spans": []}, {"section": "Discussion", "text": "Based upon a synthesis of the information uncovered in this scoping review, we propose a model (Fig. 3) to better understand trust at the group level and the various factors that may influence the trust of group decisions. Our model uses situated cognition to incorporate trust at both levels along with other group level factors, environmental factors, and most importantly, the interactions between all of these elements. We also include practical implications for group decision-making, such as competency committees, in Table 3 .", "cite_spans": [], "ref_spans": [{"start": 524, "end": 531, "text": "Table 3", "ref_id": "TABREF2"}]}, {"section": "Discussion", "text": "While this model has been empirically tested in limited settings [57] , future research should further explore our model in group settings to determine the applicability of our proposed definition and factors that we contend influence group trust. We also suggest additional research looking at trust in group decisions from an external stakeholder perspective (e.g. a person who is not a competency committee member) and what, if any differences may exist between this and group trust. For competency committee decisions, this might involve examining how program directors and individual faculty members who are not on a competency committee define trust in this context. Observing additional competency committee meetings with our proposed group trust framework may provide additional insight about how group trust operates in health professions education settings.", "cite_spans": [{"start": 65, "end": 69, "text": "[57]", "ref_id": "BIBREF57"}], "ref_spans": []}, {"section": "Discussion", "text": "Our research is limited by the fact that all of our data came from fields outside of health professions education, and trust in other occupational settings may not be the same as trust in health professions education settings. Similarly, some of the reviewed papers focused on undergraduate and graduate students, and characteristics of these learners may not be the same as trainees in health professions education. However, we attempted to tie together universal characteristics of trust across industries and populations studied to develop a model that may be applicable to health professions education groups and warrants further investigation. Indeed, we also provide specific examples of how the model applies directly to competency committees and the collective decisions they make (Table 3) .", "cite_spans": [], "ref_spans": [{"start": 789, "end": 798, "text": "(Table 3)", "ref_id": "TABREF2"}]}, {"section": "Conclusions", "text": "This scoping review should allow educators and leaders to better appreciate what factors may contribute to trust in group settings (e.g. competency committees). As programs establish and refine policies, procedures, and membership of these committees, our proposed definition and model may help to improve the translation of evaluation data and individual opinions into competency decisions. Educators who understand these factors may also help create a collective environment of trust not only on a competency committee, but potentially within their organization as well. Trainees, patients, and other stakeholders trust competency committees to make carefully weighted decisions, and it is important to determine how these committees can demonstrate that this trust is not misplaced.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Evaluating clinical trainees in the workplace. On supervision, trust and the role of competency committees", "authors": [{"first": "K", "middle": ["E"], "last": "Hauer", "suffix": ""}], "year": "", "venue": "", "link": "58714386"}, "BIBREF2": {"title": "Nuts and bolts of entrustable professional activities", "authors": [{"first": "O", "middle": ["T"], "last": "Cate", "suffix": ""}], "year": 2013, "venue": "J Grad Med Educ", "link": "196370401"}, "BIBREF3": {"title": "Starting a clinical competency committee", "authors": [{"first": "S", "middle": ["B"], "last": "Promes", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Wagner", "suffix": ""}], "year": 2014, "venue": "J Grad Med Educ", "link": "46718331"}, "BIBREF4": {"title": "How do small groups make decisions? A theoretical framework to inform the implementation and study of clinical competency committees", "authors": [{"first": "S", "middle": [], "last": "Chahine", "suffix": ""}, {"first": "S", "middle": [], "last": "Cristancho", "suffix": ""}, {"first": "J", "middle": [], "last": "Padgett", "suffix": ""}, {"first": "L", "middle": [], "last": "Lingard", "suffix": ""}], "year": 2017, "venue": "Perspect Med Educ", "link": "28903367"}, "BIBREF5": {"title": "Ensuring resident competence: a narrative review of the literature on group decision making to inform the work of clinical competency committees", "authors": [{"first": "K", "middle": ["E"], "last": "Hauer", "suffix": ""}, {"first": "O", "middle": ["T"], "last": "Cate", "suffix": ""}, {"first": "C", "middle": ["K"], "last": "Boscardin", "suffix": ""}], "year": 2016, "venue": "J Grad Med Educ", "link": "24115239"}, "BIBREF6": {"title": "Shortening the miles to the milestones: connecting EPA-based evaluations to ACGME milestone reports for internal medicine residency programs", "authors": [{"first": "J", "middle": ["H"], "last": "Choe", "suffix": ""}, {"first": "C", "middle": ["L"], "last": "Knight", "suffix": ""}, {"first": "R", "middle": [], "last": "Stiling", "suffix": ""}, {"first": "K", "middle": [], "last": "Corning", "suffix": ""}, {"first": "K", "middle": [], "last": "Lock", "suffix": ""}, {"first": "K", "middle": ["P"], "last": "Steinberg", "suffix": ""}], "year": 2016, "venue": "Acad Med", "link": "19910103"}, "BIBREF7": {"title": "Use of milestones and development of entrustable professional activities in 2 hematology/oncology training programs", "authors": [{"first": "N", "middle": ["M"], "last": "Shumway", "suffix": ""}, {"first": "J", "middle": ["J"], "last": "Dacus", "suffix": ""}, {"first": "K", "middle": ["I"], "last": "Lathrop", "suffix": ""}, {"first": "E", "middle": ["P"], "last": "Hernandez", "suffix": ""}, {"first": "M", "middle": [], "last": "Miller", "suffix": ""}, {"first": "A", "middle": ["B"], "last": "Karnad", "suffix": ""}], "year": 2015, "venue": "J Grad Med Educ", "link": "25140643"}, "BIBREF8": {"title": "Trust in work teams: an integrative review, multilevel model, and future directions", "authors": [{"first": "A", "middle": [], "last": "Costa", "suffix": ""}, {"first": "C", "middle": ["A"], "last": "Fulmer", "suffix": ""}, {"first": "N", "middle": ["R"], "last": "Anderson", "suffix": ""}], "year": "", "venue": "J Organ Behav", "link": "149273288"}, "BIBREF9": {"title": "At what level (and in whom) we trust: trust across multiple organizational levels", "authors": [{"first": "C", "middle": [], "last": "Fulmer", "suffix": ""}, {"first": "M", "middle": [], "last": "Gelfand", "suffix": ""}], "year": 2012, "venue": "J Manage", "link": "5506486"}, "BIBREF10": {"title": "Measuring trust inside organisations", "authors": [{"first": "G", "middle": [], "last": "Dietz", "suffix": ""}, {"first": "D", "middle": [], "last": "Hartog", "suffix": ""}], "year": 2006, "venue": "Pers Rev", "link": "59142486"}, "BIBREF12": {"title": "Situativity theory: a perspective on how participants and the environment can interact: AMEE guide no. 52", "authors": [{"first": "S", "middle": ["J"], "last": "Durning", "suffix": ""}, {"first": "A", "middle": ["R"], "last": "Artino", "suffix": ""}], "year": 2011, "venue": "Med Teach", "link": "21059159"}, "BIBREF13": {"title": "Scoping studies: towards a methodological framework", "authors": [{"first": "H", "middle": [], "last": "Arksey", "suffix": ""}, {"first": "O", "middle": [], "last": "Malley", "suffix": ""}, {"first": "L", "middle": [], "last": "", "suffix": ""}], "year": 2005, "venue": "Int J Soc Res Method", "link": "12719181"}, "BIBREF14": {"title": "Scoping studies: advancing the methodology", "authors": [{"first": "D", "middle": [], "last": "Levac", "suffix": ""}, {"first": "H", "middle": [], "last": "Colquhoun", "suffix": ""}, {"first": "O", "middle": [], "last": "&apos;brien", "suffix": ""}, {"first": "K", "middle": ["K"], "last": "", "suffix": ""}], "year": 2010, "venue": "Implement Sci", "link": "16489114"}, "BIBREF15": {"title": "An integrative model of organizational trust", "authors": [{"first": "R", "middle": ["C"], "last": "Mayer", "suffix": ""}], "year": 1995, "venue": "Acad Manag Rev", "link": null}, "BIBREF16": {"title": "Building commitment, attachment, and trust in strategic decision-making teams: the role of procedural justice", "authors": [{"first": "M", "middle": [], "last": "Korsgaard", "suffix": ""}, {"first": "D", "middle": [], "last": "Schweiger", "suffix": ""}, {"first": "H", "middle": [], "last": "Sapienza", "suffix": ""}], "year": 1995, "venue": "Acad Manag J", "link": "144268116"}, "BIBREF17": {"title": "Trust within teams: the relation with performance effectiveness", "authors": [{"first": "A", "middle": [], "last": "Costa", "suffix": ""}, {"first": "R", "middle": [], "last": "Roe", "suffix": ""}, {"first": "T", "middle": [], "last": "Taillieu", "suffix": ""}], "year": 2001, "venue": "Eur J Work Organ Psy", "link": "145161392"}, "BIBREF18": {"title": "Trust in the workplace: factors affecting trust formation between team members", "authors": [{"first": "M", "middle": [], "last": "Spector", "suffix": ""}, {"first": "G", "middle": [], "last": "Jones", "suffix": ""}], "year": 2004, "venue": "J Soc Psychol", "link": "22768949"}, "BIBREF19": {"title": "The influence of relationship conflict and trust on the transactive memory: performance relation in top management teams", "authors": [{"first": "D", "middle": [], "last": "Rau", "suffix": ""}], "year": 2005, "venue": "Small Gr Res", "link": "143963918"}, "BIBREF20": {"title": "Team negotiation and perceptions of trustworthiness: the whole versus the sum of the parts", "authors": [{"first": "C", "middle": [], "last": "Naquin", "suffix": ""}, {"first": "T", "middle": [], "last": "Kurtzberg", "suffix": ""}], "year": 2009, "venue": "Group Dyn-Theor Res", "link": "144932846"}, "BIBREF21": {"title": "Effects of culture, social presence, and group composition on trust in technology-supported decision-making groups", "authors": [{"first": "P", "middle": [], "last": "Lowry", "suffix": ""}, {"first": "D", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "L", "middle": [], "last": "Zhou", "suffix": ""}, {"first": "X", "middle": [], "last": "Fu", "suffix": ""}], "year": 2010, "venue": "Inform Syst J", "link": "459838"}, "BIBREF22": {"title": "The importance of trust for satisfaction, motivation, and academic performance in student learning groups", "authors": [{"first": "N", "middle": ["L"], "last": "Ennen", "suffix": ""}, {"first": "E", "middle": [], "last": "Stark", "suffix": ""}, {"first": "A", "middle": [], "last": "Lassiter", "suffix": ""}], "year": 2015, "venue": "Soc Psychol Educ", "link": "141807546"}, "BIBREF23": {"title": "The role of trust in CenteringPregnancy (CP): building interpersonal trust relationships in group-based prenatal Care in the Netherlands", "authors": [{"first": "L", "middle": [], "last": "Kweekel", "suffix": ""}, {"first": "T", "middle": [], "last": "Gerrits", "suffix": ""}, {"first": "M", "middle": [], "last": "Rijnders", "suffix": ""}, {"first": "P", "middle": [], "last": "Brown", "suffix": ""}], "year": 2017, "venue": "Birth", "link": "34639850"}, "BIBREF24": {"title": "Trust: the power that binds in team supervision of doctoral students", "authors": [{"first": "M", "middle": [], "last": "Robertson", "suffix": ""}], "year": 2017, "venue": "High Educ Res Dev", "link": "148624945"}, "BIBREF25": {"title": "In small we trust: lay theories about small and large groups", "authors": [{"first": "S", "middle": ["T"], "last": "Lamacchia", "suffix": ""}, {"first": "W", "middle": ["R"], "last": "Louis", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Hornsey", "suffix": ""}, {"first": "G", "middle": ["J"], "last": "Leonardelli", "suffix": ""}], "year": 2016, "venue": "Personal Soc Psychol Bull", "link": "3451262"}, "BIBREF26": {"title": "Group conflict and faculty engagement: is there a moderating effect of group trust?", "authors": [{"first": "J", "middle": [], "last": "Selmer", "suffix": ""}, {"first": "C", "middle": [], "last": "Jonasson", "suffix": ""}, {"first": "J", "middle": [], "last": "Lauring", "suffix": ""}], "year": 2013, "venue": "J High Educ Pol Manage", "link": "143976745"}, "BIBREF27": {"title": "Work team trust and effectiveness", "authors": [{"first": "A", "middle": [], "last": "Costa", "suffix": ""}], "year": 2003, "venue": "Pers Rev", "link": "144478243"}, "BIBREF28": {"title": "Measuring trust in teams: development and validation of a multifaceted measure of formative and reflective indicators of team trust", "authors": [{"first": "A", "middle": [], "last": "Costa", "suffix": ""}, {"first": "N", "middle": [], "last": "Anderson", "suffix": ""}], "year": 2011, "venue": "Eur J Work Organ Psy", "link": "144502276"}, "BIBREF29": {"title": "Sinking slowly: diversity in propensity to trust predicts downward trust spirals in small groups", "authors": [{"first": "A", "middle": [], "last": "Ferguson", "suffix": ""}, {"first": "R", "middle": [], "last": "Peterson", "suffix": ""}], "year": 2015, "venue": "J Appl Psychol", "link": "32213342"}, "BIBREF30": {"title": "Trust in building highperforming teams -conceptual approach", "authors": [{"first": "M", "middle": [], "last": "Hakanen", "suffix": ""}, {"first": "M", "middle": [], "last": "Hakkinen", "suffix": ""}, {"first": "A", "middle": [], "last": "Soudunsaari", "suffix": ""}], "year": 2015, "venue": "Electron J Bus Ethics Organ Stud", "link": null}, "BIBREF31": {"title": "The downside of self-management: a longitudinal study of the effects of conflict on trust, autonomy, and task interdependence in selfmanaging teams", "authors": [{"first": "C", "middle": [], "last": "Langfred", "suffix": ""}], "year": 2007, "venue": "Acad Manag J", "link": "13895086"}, "BIBREF32": {"title": "The relationship between conflict and decision outcomes: moderating effects of cognitive-and affect-based trust in strategic decision-making teams", "authors": [{"first": "S", "middle": [], "last": "Parayitam", "suffix": ""}, {"first": "R", "middle": [], "last": "Dooley", "suffix": ""}], "year": 2007, "venue": "Int J Confl Manag", "link": null}, "BIBREF33": {"title": "What makes an effective team? The role of trust (dis)confirmation in team development", "authors": [{"first": "I", "middle": [], "last": "Yang", "suffix": ""}], "year": 2014, "venue": "Eur Manage J", "link": "154163526"}, "BIBREF34": {"title": "Trust and team performance: a metaanalysis of main effects, moderators, and covariates", "authors": [{"first": "De", "middle": [], "last": "Jong", "suffix": ""}, {"first": "B", "middle": [], "last": "Dirks", "suffix": ""}, {"first": "K", "middle": [], "last": "Gillespie", "suffix": ""}, {"first": "N", "middle": [], "last": "", "suffix": ""}], "year": 2016, "venue": "J Appl Psychol", "link": "207550427"}, "BIBREF35": {"title": "Cohesion and satisfaction as mediators of the team trust -team effectiveness relationship: an interdependence theory perspective", "authors": [{"first": "P", "middle": [], "last": "Deortentiis", "suffix": ""}, {"first": "J", "middle": [], "last": "Summers", "suffix": ""}, {"first": "A", "middle": [], "last": "Ammeter", "suffix": ""}, {"first": "C", "middle": [], "last": "Douglas", "suffix": ""}, {"first": "G", "middle": [], "last": "Ferris", "suffix": ""}], "year": 2013, "venue": "Career Dev Int", "link": null}, "BIBREF36": {"title": "Psychological collectivism and team effectiveness: moderating effects of trust and psychological safety", "authors": [{"first": "C", "middle": [], "last": "Mayfield", "suffix": ""}, {"first": "J", "middle": [], "last": "Tombaugh", "suffix": ""}, {"first": "M", "middle": [], "last": "Lee", "suffix": ""}], "year": 2016, "venue": "J Organ Cult Comm Confl", "link": "151868227"}, "BIBREF37": {"title": "Transformational leadership and horizontal trust as antecedents of team performance in the healthcare context", "authors": [{"first": "L", "middle": [], "last": "Olvera", "suffix": ""}, {"first": "S", "middle": [], "last": "Llorens", "suffix": ""}, {"first": "H", "middle": [], "last": "Acosta", "suffix": ""}, {"first": "M", "middle": [], "last": "Salanova", "suffix": ""}], "year": 2017, "venue": "Ann Psychol", "link": "151598113"}, "BIBREF38": {"title": "Leader fairness and employees' trust in coworkers: the moderating role of leader group prototypicality", "authors": [{"first": "T", "middle": [], "last": "Seppala", "suffix": ""}, {"first": "J", "middle": [], "last": "Lipponen", "suffix": ""}, {"first": "A", "middle": [], "last": "Pirttila-Backman", "suffix": ""}], "year": 2012, "venue": "Group Dyn-Theor Res", "link": "143844948"}, "BIBREF39": {"title": "We need to talk: clinical competency committees in the key of c(onversation)", "authors": [{"first": "P", "middle": ["A"], "last": "Hemmer", "suffix": ""}, {"first": "W", "middle": ["F"], "last": "Kelly", "suffix": ""}], "year": 2017, "venue": "Perspect Med Educ", "link": "35658984"}, "BIBREF40": {"title": "Trust development in swift starting action teams: a multilevel framework", "authors": [{"first": "J", "middle": [], "last": "Wildman", "suffix": ""}, {"first": "M", "middle": [], "last": "Shuffler", "suffix": ""}, {"first": "E", "middle": [], "last": "Lazzara", "suffix": ""}, {"first": "S", "middle": [], "last": "Fiore", "suffix": ""}, {"first": "C", "middle": [], "last": "Burke", "suffix": ""}, {"first": "E", "middle": [], "last": "Salas", "suffix": ""}, {"first": "S", "middle": [], "last": "Garven", "suffix": ""}], "year": 2012, "venue": "Group Organ Manage", "link": "30784491"}, "BIBREF41": {"title": "Socialization and trust in work groups", "authors": [{"first": "R", "middle": [], "last": "Moreland", "suffix": ""}, {"first": "J", "middle": [], "last": "Levine", "suffix": ""}], "year": 2002, "venue": "Group Process Interg", "link": "144482103"}, "BIBREF42": {"title": "The impact of structural and contextual factors on trust formation in product development teams", "authors": [{"first": "M", "middle": [], "last": "Dayan", "suffix": ""}, {"first": "C", "middle": ["A"], "last": "Benedetto", "suffix": ""}], "year": 2010, "venue": "Ind Market Manag", "link": null}, "BIBREF43": {"title": "CEO relational leadership and strategic decision quality in top management teams: the role of team trust and learning from failure", "authors": [{"first": "A", "middle": [], "last": "Carmeli", "suffix": ""}, {"first": "A", "middle": [], "last": "Tishler", "suffix": ""}, {"first": "A", "middle": [], "last": "Edmondson", "suffix": ""}], "year": 2012, "venue": "Strateg Organ", "link": "155050872"}, "BIBREF44": {"title": "Political skill, trust, and efficacy in teams", "authors": [{"first": "E", "middle": [], "last": "Lvina", "suffix": ""}, {"first": "L", "middle": [], "last": "Maher", "suffix": ""}, {"first": "J", "middle": [], "last": "Harris", "suffix": ""}], "year": 2017, "venue": "J Leadersh Org Stud", "link": "147729033"}, "BIBREF45": {"title": "Social identity patterns and trust in demographically diverse work teams", "authors": [{"first": "K", "middle": [], "last": "Van Der Zee", "suffix": ""}, {"first": "M", "middle": [], "last": "Vos", "suffix": ""}, {"first": "K", "middle": [], "last": "Luijters", "suffix": ""}], "year": 2009, "venue": "Soc Sc Inform", "link": "145774791"}, "BIBREF46": {"title": "The role of group member affect in the relationship between trust and cooperation", "authors": [{"first": "J", "middle": [], "last": "Tanghe", "suffix": ""}, {"first": "B", "middle": [], "last": "Wisse", "suffix": ""}, {"first": "H", "middle": [], "last": "Van Der Flier", "suffix": ""}], "year": 2010, "venue": "Brit J Manage", "link": null}, "BIBREF47": {"title": "Team identification, trust, and conflict: a mediation model", "authors": [{"first": "G", "middle": [], "last": "Han", "suffix": ""}, {"first": "P", "middle": [], "last": "Harms", "suffix": ""}], "year": 2010, "venue": "Int J Confl Manag", "link": "204913405"}, "BIBREF48": {"title": "Task conflict and relationship conflict in top management teams: the pivotal role of intragroup trust", "authors": [{"first": "T", "middle": ["L"], "last": "Simons", "suffix": ""}, {"first": "R", "middle": ["S"], "last": "Peterson", "suffix": ""}], "year": 2000, "venue": "J Appl Psychol", "link": "10732108"}, "BIBREF49": {"title": "Voice in political decisionmaking: the effect of group voice on perceived trustworthiness of decision makers and subsequent acceptance of decisions", "authors": [{"first": "B", "middle": ["W"], "last": "Terwel", "suffix": ""}, {"first": "F", "middle": [], "last": "Harinck", "suffix": ""}, {"first": "N", "middle": [], "last": "Ellemers", "suffix": ""}, {"first": "D", "middle": [], "last": "Daamen", "suffix": ""}], "year": 2010, "venue": "J Exp Psychol Appl", "link": "39808381"}, "BIBREF50": {"title": "Trust in decision-making authorities dictates the form of the interactive relationship between outcome fairness and procedural fairness", "authors": [{"first": "E", "middle": ["C"], "last": "Bianchi", "suffix": ""}, {"first": "J", "middle": [], "last": "Brockner", "suffix": ""}, {"first": "K", "middle": [], "last": "Van Den Bos", "suffix": ""}], "year": 2015, "venue": "Pers Soc Psychol B", "link": "46029836"}, "BIBREF51": {"title": "Beyond shared perceptions of trust and monitoring in teams: implications of asymmetry and dissensus", "authors": [{"first": "De", "middle": [], "last": "Jong", "suffix": ""}, {"first": "B", "middle": [], "last": "Dirks", "suffix": ""}, {"first": "K", "middle": [], "last": "", "suffix": ""}], "year": 2012, "venue": "J Appl Psychol", "link": "11562543"}, "BIBREF52": {"title": "Psychological ownership, territorial behavior, and being perceived as a team contributor: the critical role of trust in the work environment", "authors": [{"first": "G", "middle": [], "last": "Brown", "suffix": ""}, {"first": "C", "middle": [], "last": "Crossley", "suffix": ""}, {"first": "S", "middle": [], "last": "Robinson", "suffix": ""}], "year": 2014, "venue": "Pers Psychol", "link": "144469373"}, "BIBREF53": {"title": "Authentically leading groups: the mediating role of collective psychological capital and trust", "authors": [{"first": "F", "middle": [], "last": "Walumba", "suffix": ""}, {"first": "M", "middle": [], "last": "Shuffler", "suffix": ""}, {"first": "E", "middle": [], "last": "Lazzara", "suffix": ""}], "year": 2011, "venue": "J Organ Behav", "link": null}, "BIBREF54": {"title": "Leadership and trust facilitating cross-functional team success", "authors": [{"first": "S", "middle": [], "last": "Webber", "suffix": ""}], "year": 2002, "venue": "J Manage Dev", "link": "145292765"}, "BIBREF55": {"title": "The connection between trust and knowledge management: what are its implications for team performance", "authors": [{"first": "J", "middle": [], "last": "Poltis", "suffix": ""}], "year": 2003, "venue": "J Knowl Manag", "link": null}, "BIBREF56": {"title": "IT knowledge integration capability and team performance: the role of team climate", "authors": [{"first": "S", "middle": [], "last": "Basaglia", "suffix": ""}, {"first": "L", "middle": [], "last": "Caporarello", "suffix": ""}, {"first": "M", "middle": [], "last": "Magni", "suffix": ""}, {"first": "F", "middle": [], "last": "Pennarola", "suffix": ""}], "year": 2010, "venue": "Int J Inform Manage", "link": "11029011"}, "BIBREF57": {"title": "Group trust in the setting of competency committee decisions: a qualitative observational study", "authors": [{"first": "J", "middle": [], "last": "Sapp", "suffix": ""}, {"first": "K", "middle": [], "last": "Larsen", "suffix": ""}, {"first": "D", "middle": [], "last": "Torre", "suffix": ""}], "year": 2019, "venue": "MedEdPublish", "link": "151269970"}, "BIBREF58": {"title": "Publisher's Note", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF59": {"title": "Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations", "authors": [], "year": "", "venue": "", "link": null}}, "ref_entries": {"TABREF0": {"text": "Demographics Of Manuscripts On Trust And Groups", "type": "table"}, "TABREF1": {"text": "Definitions Of Trust", "type": "table"}, "TABREF2": {"text": "", "type": "table"}, "TABREF4": {"text": "Results (Continued)", "type": "table"}, "TABREF5": {"text": "Results (Continued)", "type": "table"}}}
{"paper_id": "199661969", "_pdf_hash": "e36b9a9cf12f2e3944db735539f22aee003d1048", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "199662147", "_pdf_hash": "c46c12ba836a6ceeb91cd15fd467dc1446777ce9", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "The changing global context of public health", "authors": [{"first": "A", "middle": ["J"], "last": "Mcmichael", "suffix": ""}, {"first": "R", "middle": [], "last": "Beaglehole", "suffix": ""}], "year": 2000, "venue": "Lancet", "link": "20930069"}, "BIBREF1": {"title": "Public health workforce: challenges and policy issues", "authors": [{"first": "R", "middle": [], "last": "Beaglehole", "suffix": ""}, {"first": "Dal", "middle": [], "last": "Poz", "suffix": ""}, {"first": "M", "middle": ["R"], "last": "", "suffix": ""}], "year": 2003, "venue": "Hum Resour Health", "link": "5932633"}, "BIBREF2": {"title": "A strategic approach to public health workforce development and capacity building", "authors": [{"first": "H", "middle": ["D"], "last": "Dean", "suffix": ""}, {"first": "R", "middle": ["L"], "last": "Myles", "suffix": ""}, {"first": "C", "middle": [], "last": "Spears-Jones", "suffix": ""}, {"first": "A", "middle": [], "last": "Bishop-Cline", "suffix": ""}, {"first": "K", "middle": ["A"], "last": "Fenton", "suffix": ""}], "year": 2014, "venue": "Am J Prev Med", "link": "205436888"}, "BIBREF3": {"title": "The public health workforce, 2006: new challenges", "authors": [{"first": "K", "middle": ["M"], "last": "Gebbie", "suffix": ""}, {"first": "B", "middle": ["J"], "last": "Turnock", "suffix": ""}], "year": 2006, "venue": "Health Aff (Millwood)", "link": "46718377"}, "BIBREF4": {"title": "The public health workforce", "authors": [{"first": "K", "middle": [], "last": "Gebbie", "suffix": ""}, {"first": "J", "middle": [], "last": "Merrill", "suffix": ""}, {"first": "H", "middle": ["H"], "last": "Tilson", "suffix": ""}], "year": 2002, "venue": "Health Aff (Millwood)", "link": "39124218"}, "BIBREF5": {"title": "Rebooting our boots on the ground", "authors": [{"first": "E", "middle": ["L"], "last": "Hunter", "suffix": ""}], "year": 2015, "venue": "J Public Health Manag Pract", "link": "205944863"}, "BIBREF6": {"title": "Leadership in public health: new competencies for the future", "authors": [{"first": "N", "middle": [], "last": "Yphantides", "suffix": ""}, {"first": "S", "middle": [], "last": "Escoboza", "suffix": ""}, {"first": "N", "middle": [], "last": "Macchione", "suffix": ""}], "year": 2015, "venue": "Front Public Health", "link": "27116522"}, "BIBREF7": {"title": "Executive leadership at NASA: a behavioral framework", "authors": [{"first": "C", "middle": [], "last": "Williams", "suffix": ""}, {"first": "M", "middle": ["E"], "last": "Derro", "suffix": ""}, {"first": "M", "middle": [], "last": "Jarvis", "suffix": ""}, {"first": "L", "middle": [], "last": "Morris", "suffix": ""}], "year": 2010, "venue": "", "link": null}, "BIBREF8": {"title": "The methods behind PH WINS", "authors": [{"first": "J", "middle": ["P"], "last": "Leider", "suffix": ""}, {"first": "K", "middle": [], "last": "Bharthapudi", "suffix": ""}, {"first": "V", "middle": [], "last": "Pineau", "suffix": ""}, {"first": "L", "middle": [], "last": "Liu", "suffix": ""}, {"first": "E", "middle": [], "last": "Harper", "suffix": ""}], "year": 2015, "venue": "J Public Health Manag Pract", "link": "205944758"}, "BIBREF9": {"title": "The methods of PH WINS 2017: approaches to refreshing nationally representative state-level estimates and creating nationally representative local-level estimates of public health workforce interests and needs", "authors": [{"first": "J", "middle": ["P"], "last": "Leider", "suffix": ""}, {"first": "V", "middle": [], "last": "Pineau", "suffix": ""}, {"first": "K", "middle": [], "last": "Bogaert", "suffix": ""}, {"first": "Q", "middle": [], "last": "Ma", "suffix": ""}, {"first": "K", "middle": [], "last": "Sellers", "suffix": ""}], "year": 2019, "venue": "J Public Health Manag Pract", "link": "73425306"}, "BIBREF10": {"title": "Changes in the state governmental public health workforce: demographics and perceptions", "authors": [{"first": "K", "middle": [], "last": "Bogaert", "suffix": ""}, {"first": "B", "middle": ["C"], "last": "Castrucci", "suffix": ""}, {"first": "E", "middle": [], "last": "Gould", "suffix": ""}, {"first": "K", "middle": [], "last": "Sellers", "suffix": ""}, {"first": "J", "middle": ["P"], "last": "Leider", "suffix": ""}], "year": 2019, "venue": "J Public Health Manag Pract", "link": "73448525"}, "BIBREF11": {"title": "Public Health Workforce Interests and Needs Survey: digital appendix", "authors": [{"first": "", "middle": [], "last": "De Beaumont Foundation", "suffix": ""}], "year": 2019, "venue": "", "link": null}, "BIBREF12": {"title": "Federal workforce: recent trends in federal civilian employment and compensation", "authors": [], "year": 2014, "venue": "US Government Accountability Office", "link": null}, "BIBREF13": {"title": "Federal Employee Viewpoint Survey: government-wide management report", "authors": [], "year": 2018, "venue": "", "link": null}, "BIBREF14": {"title": "Creating the next generation of federal human capital: the 2014 state of human capital management report", "authors": [{"first": "", "middle": [], "last": "Cornerstone", "suffix": ""}], "year": 2017, "venue": "", "link": null}, "BIBREF15": {"title": "Public health's aging workforce", "authors": [{"first": "H", "middle": [], "last": "Heishman", "suffix": ""}], "year": 2007, "venue": "", "link": "166303692"}, "BIBREF16": {"title": "Preparing the people pipeline: a federal succession planning primer", "authors": [{"first": "", "middle": [], "last": "Partnership For Public Service", "suffix": ""}, {"first": "Allen", "middle": [], "last": "Booz", "suffix": ""}, {"first": "", "middle": [], "last": "Hamilton", "suffix": ""}], "year": 2011, "venue": "", "link": null}, "BIBREF17": {"title": "Institute of Medicine, Committee for the Study of the Future of Public Health. The Future of Public Health", "authors": [{"first": "", "middle": [], "last": "Institute Of Medicine", "suffix": ""}], "year": 1988, "venue": "", "link": null}, "BIBREF18": {"title": "The National Public Health Workforce Strategic Roadmap", "authors": [], "year": 2013, "venue": "", "link": null}, "BIBREF19": {"title": "A qualitative analysis to determine the domains and skills necessary to lead in public health", "authors": [{"first": "B", "middle": ["L"], "last": "Grimm", "suffix": ""}, {"first": "S", "middle": [], "last": "Watanabe-Galloway", "suffix": ""}, {"first": "D", "middle": ["H"], "last": "Britigan", "suffix": ""}, {"first": "A", "middle": ["M"], "last": "Schumaker", "suffix": ""}], "year": 2015, "venue": "J Leadersh Studies", "link": "144607692"}, "BIBREF20": {"title": "A call to action: improving first-level supervision of federal employees", "authors": [], "year": 2010, "venue": "?docnumber\u00bc51653 4&version\u00bc517986&application\u00bcACROBAT. Published", "link": null}, "BIBREF21": {"title": "Development coaching: helping scientific and technical professionals make the leap into leadership", "authors": [{"first": "J", "middle": ["L"], "last": "Hurd", "suffix": ""}], "year": 2009, "venue": "Glob Bus Organ Excell", "link": "47047518"}, "BIBREF22": {"title": "Sapienza AM. Managing Scientists: Leadership Strategies in Scientific Research", "authors": [], "year": 2004, "venue": "", "link": null}, "BIBREF23": {"title": "Reshaping the Graduate Education of Scientists and Engineers", "authors": [], "year": 1995, "venue": "", "link": "34658001"}, "BIBREF24": {"title": "Crossing the canyon: from technical expert to first-time leader", "authors": [{"first": "A", "middle": [], "last": "Lang", "suffix": ""}, {"first": "B", "middle": [], "last": "Thomas", "suffix": ""}], "year": 2013, "venue": "", "link": null}, "BIBREF25": {"title": "Transforming scientists into managers", "authors": [{"first": "P", "middle": [], "last": "Brickley", "suffix": ""}], "year": 2001, "venue": "The Scientist", "link": null}, "BIBREF26": {"title": "Appreciative inquiry: a tool for organizational, programmatic, and projectfocused change", "authors": [{"first": "K", "middle": ["L"], "last": "Priest", "suffix": ""}, {"first": "E", "middle": ["K"], "last": "Kaufman", "suffix": ""}, {"first": "K", "middle": [], "last": "Brunton", "suffix": ""}, {"first": "M", "middle": [], "last": "Seibel", "suffix": ""}], "year": 2013, "venue": "J Leadersh Educ", "link": "157010739"}, "BIBREF27": {"title": "The power of learning in action learning: a conceptual analysis of how the five schools of adult learning theories are incorporated within the practice of action learning", "authors": [{"first": "M", "middle": [], "last": "Marquardt", "suffix": ""}, {"first": "D", "middle": [], "last": "Waddill", "suffix": ""}], "year": 2004, "venue": "Actn Learn: Res Pract", "link": "144612023"}, "BIBREF28": {"title": "What makes a leadership development strategy successful?", "authors": [{"first": "Forbes Coaches", "middle": [], "last": "Council", "suffix": ""}], "year": 2016, "venue": "", "link": null}, "BIBREF29": {"title": "Leadership development: learning from best practices", "authors": [{"first": "S", "middle": ["L"], "last": "Leskiw", "suffix": ""}, {"first": "P", "middle": [], "last": "Singh", "suffix": ""}], "year": 2007, "venue": "Leadersh Organ Dev J", "link": "73524884"}}, "ref_entries": {}}
{"paper_id": "199662295", "_pdf_hash": "c237e54ee9c4494494562b8aaca7bb94d10d318a", "abstract": [], "body_text": [{"section": "", "text": "With a series of articles published over the last two years 1-3 E Tahir and colleagues participate in the debate on potential detrimental consequences for cardiac structure and function related to extensive, strenuous exercis. 4, 5 In order to further study the well-described biological significance of elevated cardiac biomarkers seen after extreme endurance competitions they have investigated triathletes by blood sampling and cardiac magnetic imaging before and after competition (mean race time: 3.3 AE 2.7 h). In the current study published in the European Journal of Preventive Cardiology 1 the authors aimed to assess the predictive value of clinical baseline characteristics of their athletes, for example, training history, maximal exercise capacity and exercise blood pressure during ergometry as well as myocardial dimensions and fibrosis assed by cardiac magnetic resonance imaging (CMR) and correlated these to increases of cardiac biomarkers and impairment of myocardial function or structure during the race.", "cite_spans": [{"start": 227, "end": 229, "text": "4,", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "", "text": "The data imply good and bad news for endurance (elite) athletes. First, it was found that despite the fact that serum cardiac biomarkers such as troponin T and N-terminal pro-brain natriuretic peptide (NT-proBNP) significantly increased immediately after the race, maximal exercise strain during a triathlon race does not induce acute overt myocardial inflammation or oedema as assessed by CMR. 1 In a way, these data exonerate such extreme exercise since others had generally observed discrete morphological alterations of the myocardium after endurance competitions, 6, 7 including an increase of physiological strain of the myocardium during volume overload, particularly of the right ventricle. 8, 9 The bad news is that Tahir and colleagues revealed a positive late gadolinium enhancement (LGE) in CMR as a correlate for myocardial fibrosis in a large portion of their athlete male population (33%), a finding more pronounced than in previous investigations. [10] [11] [12] Explanations for the prevalence of myocardial lesions particularly in male athletes are diverse and include genetic predisposition, gender (females are less affected), risk factors for coronary artery disease and coronary ischaemia itself, acute or reactivated myocarditis, pulmonary artery pressure overload and exercise-induced repetitive micro-injury during prolonged exercise stress. 13, 14 However, most importantly the series of data 1,3 adds another potential risk factor to the currently discussed ones, the role of exercise blood pressure on myocardial remodelling and determinant for myocardial injury. The current study has revealed that those athletes with positive LGE had a significantly higher maximal exercise blood pressure (30 mmHg higher compared with LGE negative athletes) at similar maximal exercise capacities between groups. Also, early adaptation typical for arterial hypertension such as left ventricular hypertrophy and left atrial enlargement was observed in the LGE positive group. 1 Furthermore, in LGE positive athletes post-race values demonstrated increased left atrial strain as indicated by a trend towards higher NT-proBNP values. 1 These findings are supported by the research group's previous analysis also investigating triathletes, in which peak exercise systolic blood pressure assessed during ergometry before the race and exercise volume during the race were identified as independent predictors of the presence of LGE. 3 Summing up these data may lead to the hypothesis that a repetitive volume overload of the myocardium induced by repetitive endurance training sessions of several hours per day over many years will have an impact on vascular and myocardial physiological adaptation as well as pathological remodelling, resulting in a consecutive pressure overload with increased blood pressures during exercise ( Figure 1 ). Whether this will eventually lead to increased incidence of atrial fibrillation in athletes exposed to long-term exercise remains to be determined. [15] [16] [17] [18] Among cardiovascular risk factors, arterial hypertension is a key risk factor for coronary artery disease, myocardial dysfunction, left ventricular hypertrophy and remodelling also increasing the risk for clinical events. 19, 20 Even in athletes, hypertension is one of the most common pathologies detected during screening. 21 The role of hypertensive blood pressure values during exercise, however, is uncertain. Epidemiological data assessing exercise blood pressure have demonstrated an increased risk of subsequent development of arterial hypertension as well as cardiovascular events in those with excessive blood pressure values during exercise. [22] [23] [24] [25] [26] [27] Despite this evidence, it has not been included for risk factor assessment in recent European Society of Cardiology (ESC)/European Society of Hypertension arterial hypertension guidelines. 28 Interestingly, elevated blood pressure values during exercise are not uncommon in middle-aged marathon runners 29 and especially high exercise values exceeding the recommended maximal exercise values are seen in 43% of males (>210 mmHg) and 28% in females (>190 mmHg). 30 Moreover, in middleaged competitive athletes of different disciplines a higher prevalence of masked hypertension has been observed. [31] [32] [33] [34] Importantly, very recent data have revealed that higher blood pressure response during exercise was associated with a 3.6-fold increased risk of developing hypertension after 6.5 years of follow-up (26 to 32 years). 35 Therefore, current ESC/European Association of Preventive Cardiology hypertension guidelines of the section of sports cardiology have included the entity in their recommendation. 36, 37 Physiological myocardial adaptation induced by exercise training in athletes is dependent on genetics, family history of hypertension, gender, body composition and exercise volume as well as exercise blood pressure. 30, [38] [39] [40] [41] [42] However, the role of exercise blood pressure on myocardial adaptations has been less appreciated in athletes. 39, 40 According to the currently presented and previously published data 1,3 this will have to be followed more closely and investigated in detail. Even with the current data, though, it is far too early to draw clinical conclusions on treatment of exercise hypertension in athletes. An interesting field of research will have to focus on gender differences between male and female athletes, who have revealed no LGE. 3 Whether this finding will be the key explanation for a lower incidence of sudden cardiac death in female athletes will have to be elucidated. 43 Moreover, the causality of structural adaptations found in athletes and elevated blood pressure during exercise (chicken and egg) as well as the mechanistic underpinnings need to be determined.", "cite_spans": [{"start": 569, "end": 571, "text": "6,", "ref_id": "BIBREF5"}, {"start": 699, "end": 701, "text": "8,", "ref_id": "BIBREF7"}, {"start": 964, "end": 968, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 969, "end": 973, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 974, "end": 978, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 1367, "end": 1370, "text": "13,", "ref_id": "BIBREF12"}, {"start": 2999, "end": 3003, "text": "[15]", "ref_id": "BIBREF14"}, {"start": 3004, "end": 3008, "text": "[16]", "ref_id": "BIBREF15"}, {"start": 3009, "end": 3013, "text": "[17]", "ref_id": "BIBREF16"}, {"start": 3014, "end": 3018, "text": "[18]", "ref_id": "BIBREF17"}, {"start": 3241, "end": 3244, "text": "19,", "ref_id": "BIBREF18"}, {"start": 3672, "end": 3676, "text": "[22]", "ref_id": "BIBREF21"}, {"start": 3677, "end": 3681, "text": "[23]", "ref_id": "BIBREF22"}, {"start": 3682, "end": 3686, "text": "[24]", "ref_id": "BIBREF23"}, {"start": 3687, "end": 3691, "text": "[25]", "ref_id": "BIBREF24"}, {"start": 3692, "end": 3696, "text": "[26]", "ref_id": "BIBREF25"}, {"start": 3697, "end": 3701, "text": "[27]", "ref_id": "BIBREF26"}, {"start": 4298, "end": 4302, "text": "[31]", "ref_id": "BIBREF30"}, {"start": 4303, "end": 4307, "text": "[32]", "ref_id": "BIBREF31"}, {"start": 4308, "end": 4312, "text": "[33]", "ref_id": "BIBREF32"}, {"start": 4313, "end": 4317, "text": "[34]", "ref_id": "BIBREF33"}, {"start": 4716, "end": 4719, "text": "36,", "ref_id": "BIBREF35"}, {"start": 4939, "end": 4942, "text": "30,", "ref_id": "BIBREF29"}, {"start": 4943, "end": 4947, "text": "[38]", "ref_id": "BIBREF37"}, {"start": 4948, "end": 4952, "text": "[39]", "ref_id": "BIBREF38"}, {"start": 4953, "end": 4957, "text": "[40]", "ref_id": "BIBREF39"}, {"start": 4958, "end": 4962, "text": "[41]", "ref_id": "BIBREF40"}, {"start": 4963, "end": 4967, "text": "[42]", "ref_id": "BIBREF41"}, {"start": 5078, "end": 5081, "text": "39,", "ref_id": "BIBREF38"}], "ref_spans": [{"start": 2839, "end": 2847, "text": "Figure 1", "ref_id": "FIGREF1"}]}, {"section": "", "text": "Nonetheless, timely identification of hypertensive athletes is important in the setting of pre-participation cardiovascular screening in order to implement appropriate non-pharmacological as well as pharmacological management and follow-up. 36, 37 Already today, arterial hypertension is the most common cause for exclusion, at least temporarily, from competitive sport participation. 44 Therefore, assessment of blood pressure regulation at rest and during exercise is particularly important across the whole age spectrum, particularly the young and the elderly. Important to note is that children and adolescents have lower blood pressure levels with normal values < 120/80 mmHg in those aged 18 and 19 years and even lower values in adolescents. 45 In elderly master athletes blood pressure regulation independent of pharmacological intervention or after treatment is, however, less clear and should definitely be investigated in upcoming studies. Moreover, the role of supplements, energy drinks, medications (including anti-inflammatory drugs or thyroid hormones for weight reduction), or performance enhancing substances such as erythropoetin and anabolic steroids may be an underestimated cause of secondary hypertension in athletes 46 and should be explored during the evaluation in athletes with recent and unexplained onset of systemic hypertension. 37 If identified, athletes with arterial hypertension should be treated according to the general guidelines for the management of hypertension. 47 Taken together, E Tahir and colleagues have to be congratulated for addressing an underestimated entity for the physiological as well as pathological adaptation of the myocardium during exercise, the role of arterial exercise hypertension, although it remains unclear whether the data of three publications are partly overlapping. [1] [2] [3] Moreover, from a methodological point of view an observational study such as the present one could go further by adding multivariate analyses or, in the case of quantitative data, respectively adjusted regression analyses. Thus, it remains unclear to what extent the conclusions of Tahir et al. are limited by obvious differences in baseline parameters (seven years of age and a body mass index of 1.7 kg/m 2 ) between the subjects with and without CMR evidence of cardiac fibrosis as well as hidden differences, for example, the years in competitive endurance performance, which have not been reported. Thus, it will remain essential to study exercise blood pressure during training and competition as a so far underacknowledged matter in endurance athletes.", "cite_spans": [{"start": 241, "end": 244, "text": "36,", "ref_id": "BIBREF35"}, {"start": 1838, "end": 1841, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 1842, "end": 1845, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 1846, "end": 1849, "text": "[3]", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "Declaration of conflicting interests", "text": "The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Acute impact of an endurance race on cardiac function and biomarkers of myocardial injury in triathletes with and without myocardial fibrosis", "authors": [{"first": "E", "middle": [], "last": "Tahir", "suffix": ""}, {"first": "B", "middle": [], "last": "Scherz", "suffix": ""}, {"first": "J", "middle": [], "last": "Starekova", "suffix": ""}], "year": 2020, "venue": "Eur J Prev Cardiol", "link": "195694949"}, "BIBREF1": {"title": "Impact of myocardial fibrosis on left ventricular function evaluated by feature-tracking myocardial strain cardiac magnetic resonance in competitive male triathletes with normal ejection fraction", "authors": [{"first": "E", "middle": [], "last": "Tahir", "suffix": ""}, {"first": "J", "middle": [], "last": "Starekova", "suffix": ""}, {"first": "K", "middle": [], "last": "Muellerleile", "suffix": ""}], "year": 2019, "venue": "Circulation J", "link": "153301710"}, "BIBREF2": {"title": "Myocardial fibrosis in competitive triathletes detected by contrastenhanced CMR correlates with exercise-induced hypertension and competition history", "authors": [{"first": "E", "middle": [], "last": "Tahir", "suffix": ""}, {"first": "J", "middle": [], "last": "Starekova", "suffix": ""}, {"first": "K", "middle": [], "last": "Muellerleile", "suffix": ""}], "year": 2018, "venue": "JACC Cardiovasc Imaging", "link": "28859866"}, "BIBREF3": {"title": "Focal fibrosis in the endurance athlete's heart: Running scarred or running scared?", "authors": [{"first": "A", "middle": ["L"], "last": "Baggish", "suffix": ""}], "year": 2018, "venue": "JACC Cardiovasc Imaging", "link": null}, "BIBREF4": {"title": "Coronary artery calcification among endurance athletes: ''Hearts of stone", "authors": [{"first": "A", "middle": ["L"], "last": "Baggish", "suffix": ""}, {"first": "B", "middle": ["D"], "last": "Levine", "suffix": ""}], "year": 2017, "venue": "Circulation", "link": "278592"}, "BIBREF5": {"title": "72-h kinetics of highsensitive troponin T and inflammatory markers after marathon", "authors": [{"first": "J", "middle": [], "last": "Scherr", "suffix": ""}, {"first": "S", "middle": [], "last": "Braun", "suffix": ""}, {"first": "T", "middle": [], "last": "Schuster", "suffix": ""}], "year": 2011, "venue": "Med Sci Sports Exerc", "link": "45358982"}, "BIBREF6": {"title": "Troponin and exercise", "authors": [{"first": "T", "middle": [], "last": "Gresslien", "suffix": ""}, {"first": "S", "middle": [], "last": "Agewall", "suffix": ""}], "year": 2016, "venue": "Int J Cardiol", "link": "205232414"}, "BIBREF7": {"title": "Exerciseinduced right ventricular dysfunction and structural remodelling in endurance athletes", "authors": [{"first": "La", "middle": [], "last": "Gerche", "suffix": ""}, {"first": "A", "middle": [], "last": "Burns", "suffix": ""}, {"first": "A", "middle": ["T"], "last": "Mooney", "suffix": ""}, {"first": "D", "middle": ["J"], "last": "", "suffix": ""}], "year": 2012, "venue": "Eur Heart J", "link": null}, "BIBREF8": {"title": "Persistent and reversible cardiac dysfunction among amateur marathon runners", "authors": [{"first": "T", "middle": ["G"], "last": "Neilan", "suffix": ""}, {"first": "D", "middle": ["M"], "last": "Yoerger", "suffix": ""}, {"first": "P", "middle": ["S"], "last": "Douglas", "suffix": ""}], "year": 2006, "venue": "Eur Heart J", "link": "25650653"}, "BIBREF9": {"title": "Myocardial late gadolinium enhancement: Prevalence, pattern, and prognostic relevance in marathon runners", "authors": [{"first": "F", "middle": [], "last": "Breuckmann", "suffix": ""}, {"first": "S", "middle": [], "last": "Mohlenkamp", "suffix": ""}, {"first": "K", "middle": [], "last": "Nassenstein", "suffix": ""}], "year": 2009, "venue": "Radiology", "link": "25838455"}, "BIBREF10": {"title": "Recommendations for participation in competitive and leisure time sport in athletes with cardiomyopathies, myocarditis, and pericarditis: Position statement of the Sport Cardiology Section of the European Association of Preventive Cardiology (EAPC)", "authors": [{"first": "A", "middle": [], "last": "Pelliccia", "suffix": ""}, {"first": "E", "middle": ["E"], "last": "Solberg", "suffix": ""}, {"first": "M", "middle": [], "last": "Papadakis", "suffix": ""}], "year": 2019, "venue": "Eur Heart J", "link": "56178709"}, "BIBREF11": {"title": "Right and left ventricular function and mass in male elite master athletes: A controlled contrast-enhanced cardiovascular magnetic resonance study", "authors": [{"first": "P", "middle": [], "last": "Bohm", "suffix": ""}, {"first": "G", "middle": [], "last": "Schneider", "suffix": ""}, {"first": "L", "middle": [], "last": "Linneweber", "suffix": ""}], "year": 2016, "venue": "Circulation", "link": "20662547"}, "BIBREF12": {"title": "Myocardial fibrosis due to exorbitant exercise or just undetected postinflammatory stages?", "authors": [{"first": "M", "middle": [], "last": "Zdravkovic", "suffix": ""}, {"first": "C", "middle": [], "last": "Tschope", "suffix": ""}, {"first": "B", "middle": [], "last": "Pieske", "suffix": ""}], "year": 2019, "venue": "JACC Cardiovasc Imaging", "link": "73425524"}, "BIBREF13": {"title": "Myocardial fibrosis in athletes", "authors": [{"first": "F", "middle": ["R"], "last": "Van De Schoor", "suffix": ""}, {"first": "V", "middle": ["L"], "last": "Aengevaeren", "suffix": ""}, {"first": "M", "middle": ["T"], "last": "Hopman", "suffix": ""}], "year": 2016, "venue": "Mayo Clin Proc", "link": "35204670"}, "BIBREF14": {"title": "Physical activity volume in relation to risk of atrial fibrillation. A nonlinear meta-regression analysis", "authors": [{"first": "C", "middle": [], "last": "Ricci", "suffix": ""}, {"first": "F", "middle": [], "last": "Gervasi", "suffix": ""}, {"first": "M", "middle": [], "last": "Gaeta", "suffix": ""}], "year": 2018, "venue": "Eur J Prev Cardiol", "link": "4463758"}, "BIBREF15": {"title": "Atrial fibrillation and longterm sports practice: Epidemiology and mechanisms", "authors": [{"first": "S", "middle": [], "last": "Wernhart", "suffix": ""}, {"first": "M", "middle": [], "last": "Halle", "suffix": ""}], "year": 2015, "venue": "Clin Res Cardiol", "link": "21640524"}, "BIBREF16": {"title": "The ambiguity of physical activity, exercise and atrial fibrillation", "authors": [{"first": "B", "middle": [], "last": "Morseth", "suffix": ""}, {"first": "M", "middle": ["L"], "last": "Lochen", "suffix": ""}, {"first": "I", "middle": [], "last": "Ariansen", "suffix": ""}], "year": 2018, "venue": "Eur J Prev Cardiol", "link": "4206164"}, "BIBREF17": {"title": "Atrial fibrillation: A preventable lifestyle disease! Eur", "authors": [{"first": "M", "middle": [], "last": "Halle", "suffix": ""}, {"first": "M", "middle": [], "last": "Haykowsky", "suffix": ""}], "year": 2018, "venue": "J Prev Cardiol", "link": "52158247"}, "BIBREF18": {"title": "Physical activity attenuates the effect of increased left ventricular mass on the risk of ischemic stroke: The Northern Manhattan Stroke Study", "authors": [{"first": "C", "middle": ["J"], "last": "Rodriguez", "suffix": ""}, {"first": "R", "middle": ["L"], "last": "Sacco", "suffix": ""}, {"first": "R", "middle": ["R"], "last": "Sciacca", "suffix": ""}], "year": 2002, "venue": "J Am Coll Cardiol", "link": null}, "BIBREF19": {"title": "Exercise capacity and haemodynamic response among 12,327 individuals with cardio-metabolic risk factors undergoing treadmill exercise", "authors": [{"first": "C", "middle": [], "last": "Chrysohoou", "suffix": ""}, {"first": "J", "middle": [], "last": "Skoumas", "suffix": ""}, {"first": "G", "middle": [], "last": "Georgiopoulos", "suffix": ""}], "year": 2017, "venue": "Eur J Prev Cardiol", "link": "41978262"}, "BIBREF20": {"title": "Global disparities of hypertension prevalence and control: A systematic analysis of population-based studies from 90 countries", "authors": [{"first": "K", "middle": ["T"], "last": "Mills", "suffix": ""}, {"first": "J", "middle": ["D"], "last": "Bundy", "suffix": ""}, {"first": "T", "middle": ["N"], "last": "Kelly", "suffix": ""}], "year": 2016, "venue": "Circulation", "link": "21431752"}, "BIBREF21": {"title": "Exercise blood pressure and future cardiovascular death in asymptomatic individuals", "authors": [{"first": "S", "middle": ["A"], "last": "Weiss", "suffix": ""}, {"first": "R", "middle": ["S"], "last": "Blumenthal", "suffix": ""}, {"first": "A", "middle": ["R"], "last": "Sharrett", "suffix": ""}], "year": 2010, "venue": "Circulation", "link": "1428622"}, "BIBREF22": {"title": "Exercise blood pressure predicts mortality from myocardial infarction", "authors": [{"first": "R", "middle": [], "last": "Mundal", "suffix": ""}, {"first": "S", "middle": ["E"], "last": "Kjeldsen", "suffix": ""}, {"first": "L", "middle": [], "last": "Sandvik", "suffix": ""}], "year": 1996, "venue": "Hypertension", "link": "23717937"}, "BIBREF23": {"title": "Seven-year increase in exercise systolic blood pressure at moderate workload predicts long-term risk of coronary heart disease and mortality in healthy middle-aged men", "authors": [{"first": "P", "middle": ["T"], "last": "Skretteberg", "suffix": ""}, {"first": "I", "middle": [], "last": "Grundvold", "suffix": ""}, {"first": "S", "middle": ["E"], "last": "Kjeldsen", "suffix": ""}], "year": 2013, "venue": "Hypertension", "link": "6154902"}, "BIBREF24": {"title": "Exercise hypertension: An adverse prognosis?", "authors": [{"first": "R", "middle": ["G"], "last": "Smith", "suffix": ""}, {"first": "Rubin", "middle": [], "last": "Sa", "suffix": ""}, {"first": "M", "middle": ["H"], "last": "Ellestad", "suffix": ""}], "year": 2009, "venue": "J Am Soc Hypertens", "link": "13613519"}, "BIBREF25": {"title": "Exercise-induced hypertension, cardiovascular events, and mortality in patients undergoing exercise stress testing: A systematic review and meta-analysis", "authors": [{"first": "M", "middle": ["G"], "last": "Schultz", "suffix": ""}, {"first": "P", "middle": [], "last": "Otahal", "suffix": ""}, {"first": "V", "middle": ["J"], "last": "Cleland", "suffix": ""}], "year": 2013, "venue": "Am J Hypertens", "link": "27601703"}, "BIBREF26": {"title": "Eligibility and disqualification recommendations for competitive athletes with cardiovascular abnormalities: Task Force 6: Hypertension: A scientific statement from the American Heart Association and the American College of Cardiology", "authors": [{"first": "H", "middle": ["R"], "last": "Black", "suffix": ""}, {"first": "D", "middle": [], "last": "Sica", "suffix": ""}, {"first": "K", "middle": [], "last": "Ferdinand", "suffix": ""}], "year": 2015, "venue": "Circulation", "link": null}, "BIBREF27": {"title": "ESC/ESH Guidelines for the management of arterial hypertension", "authors": [{"first": "B", "middle": [], "last": "Williams", "suffix": ""}, {"first": "G", "middle": [], "last": "Mancia", "suffix": ""}, {"first": "W", "middle": [], "last": "Spiering", "suffix": ""}], "year": 2018, "venue": "Eur Heart J", "link": "52138263"}, "BIBREF28": {"title": "Excessive exercise habits of runners as new signs of hypertension and arrhythmia", "authors": [{"first": "Y", "middle": ["J"], "last": "Kim", "suffix": ""}, {"first": "C", "middle": ["H"], "last": "Kim", "suffix": ""}, {"first": "K", "middle": ["M"], "last": "Park", "suffix": ""}], "year": 2016, "venue": "Int J Cardiol", "link": "8253507"}, "BIBREF29": {"title": "Blood pressure response to maximal dynamic exercise testing in an athletic population", "authors": [{"first": "A", "middle": [], "last": "Pressler", "suffix": ""}, {"first": "A", "middle": [], "last": "Jahnig", "suffix": ""}, {"first": "M", "middle": [], "last": "Halle", "suffix": ""}], "year": 2018, "venue": "J Hypertens", "link": "44151572"}, "BIBREF30": {"title": "Masked hypertension and cardiac remodeling in middle-aged endurance athletes", "authors": [{"first": "L", "middle": ["D"], "last": "Trachsel", "suffix": ""}, {"first": "F", "middle": [], "last": "Carlen", "suffix": ""}, {"first": "N", "middle": [], "last": "Brugger", "suffix": ""}], "year": 2015, "venue": "J Hypertens", "link": "205624495"}, "BIBREF31": {"title": "High ambulatory blood pressure in male professional football players", "authors": [{"first": "H", "middle": ["M"], "last": "Berge", "suffix": ""}, {"first": "T", "middle": ["E"], "last": "Andersen", "suffix": ""}, {"first": "E", "middle": ["E"], "last": "Solberg", "suffix": ""}], "year": 2013, "venue": "Br J Sports Med", "link": "19739203"}, "BIBREF32": {"title": "High prevalence of hypertension among collegiate football athletes", "authors": [{"first": "A", "middle": ["R"], "last": "Karpinos", "suffix": ""}, {"first": "C", "middle": ["L"], "last": "Roumie", "suffix": ""}, {"first": "H", "middle": [], "last": "Nian", "suffix": ""}], "year": 2013, "venue": "Circ Cardiovasc Qual Outcomes", "link": "207740916"}, "BIBREF33": {"title": "Prevalence of cardiovascular disease risk factors among National Football League players", "authors": [{"first": "A", "middle": ["M"], "last": "Tucker", "suffix": ""}, {"first": "R", "middle": ["A"], "last": "Vogel", "suffix": ""}, {"first": "A", "middle": ["E"], "last": "Lincoln", "suffix": ""}], "year": 2009, "venue": "JAMA", "link": "15148559"}, "BIBREF34": {"title": "High blood pressure response to exercise predicts future development of hypertension in young athletes", "authors": [{"first": "S", "middle": [], "last": "Caselli", "suffix": ""}, {"first": "A", "middle": [], "last": "Serdoz", "suffix": ""}, {"first": "F", "middle": [], "last": "Mango", "suffix": ""}], "year": 2019, "venue": "Eur Heart J", "link": "58571001"}, "BIBREF35": {"title": "Brief recommendations for participation in competitive sports of athletes with arterial hypertension: Summary of a Position Statement from the Sports Cardiology Section of the European Association of Preventive Cardiology (EAPC)", "authors": [{"first": "J", "middle": [], "last": "Niebauer", "suffix": ""}, {"first": "M", "middle": [], "last": "Borjesson", "suffix": ""}, {"first": "F", "middle": [], "last": "Carre", "suffix": ""}], "year": 2019, "venue": "Eur J Prev Cardiol", "link": "163166758"}, "BIBREF36": {"title": "Recommendations for participation in competitive sports of athletes with arterial hypertension: A position statement from the sports cardiology section of the European Association of Preventive Cardiology (EAPC)", "authors": [{"first": "J", "middle": [], "last": "Niebauer", "suffix": ""}, {"first": "M", "middle": [], "last": "Borjesson", "suffix": ""}, {"first": "F", "middle": [], "last": "Carre", "suffix": ""}], "year": 2018, "venue": "Eur Heart J", "link": "52137604"}, "BIBREF37": {"title": "Effect of sex and sporting discipline on LV adaptation to exercise", "authors": [{"first": "G", "middle": [], "last": "Finocchiaro", "suffix": ""}, {"first": "H", "middle": [], "last": "Dhutia", "suffix": ""}, {"first": "D&apos;", "middle": [], "last": "Silva", "suffix": ""}, {"first": "A", "middle": [], "last": "", "suffix": ""}], "year": 2017, "venue": "JACC Cardiovasc Imaging", "link": null}, "BIBREF38": {"title": "Blood pressure and LV remodeling among American-style football players", "authors": [{"first": "J", "middle": [], "last": "Lin", "suffix": ""}, {"first": "F", "middle": [], "last": "Wang", "suffix": ""}, {"first": "R", "middle": ["B"], "last": "Weiner", "suffix": ""}], "year": 2016, "venue": "JACC Cardiovasc Imaging", "link": "205853590"}, "BIBREF39": {"title": "Impact of family hypertension history on exercise-induced cardiac remodeling", "authors": [{"first": "A", "middle": ["L"], "last": "Baggish", "suffix": ""}, {"first": "R", "middle": ["B"], "last": "Weiner", "suffix": ""}, {"first": "K", "middle": [], "last": "Yared", "suffix": ""}], "year": 2009, "venue": "Am J Cardiol", "link": "5329073"}, "BIBREF40": {"title": "The upper limit of physiologic cardiac hypertrophy in highly trained elite athletes", "authors": [{"first": "A", "middle": [], "last": "Pelliccia", "suffix": ""}, {"first": "B", "middle": ["J"], "last": "Maron", "suffix": ""}, {"first": "A", "middle": [], "last": "Spataro", "suffix": ""}], "year": 1991, "venue": "N Engl J Med", "link": "1924778"}, "BIBREF41": {"title": "Association of body composition and left ventricular dimensions in elite athletes", "authors": [{"first": "A", "middle": [], "last": "Pressler", "suffix": ""}, {"first": "B", "middle": [], "last": "Haller", "suffix": ""}, {"first": "J", "middle": [], "last": "Scherr", "suffix": ""}], "year": 2012, "venue": "Eur J Prev Cardiol", "link": "206775045"}, "BIBREF42": {"title": "Sudden cardiac arrest in sports -need for uniform registration: A position paper from the Sport Cardiology Section of the European Association for Cardiovascular Prevention and Rehabilitation", "authors": [{"first": "E", "middle": ["E"], "last": "Solberg", "suffix": ""}, {"first": "M", "middle": [], "last": "Borjesson", "suffix": ""}, {"first": "S", "middle": [], "last": "Sharma", "suffix": ""}], "year": 2016, "venue": "Eur J Prev Cardiol", "link": "23975615"}, "BIBREF43": {"title": "Athletes with systemic hypertension", "authors": [{"first": "R", "middle": ["H"], "last": "Fagard", "suffix": ""}], "year": 2007, "venue": "Cardiol Clin", "link": "32380943"}, "BIBREF44": {"title": "Home blood pressure normalcy in non-European adolescents", "authors": [{"first": "T", "middle": ["V"], "last": "Jardim", "suffix": ""}, {"first": "C", "middle": [], "last": "De Souza Carneiro", "suffix": ""}, {"first": "P", "middle": [], "last": "Morais", "suffix": ""}], "year": 2018, "venue": "J Hypertens", "link": "22969103"}, "BIBREF45": {"title": "Hypertension in athletes", "authors": [{"first": "J", "middle": ["J"], "last": "Leddy", "suffix": ""}, {"first": "J", "middle": [], "last": "Izzo", "suffix": ""}], "year": 2009, "venue": "J Clin Hypertens (Greenwich)", "link": "41516324"}, "BIBREF46": {"title": "ESH/ ESC guidelines for the management of arterial hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology", "authors": [{"first": "G", "middle": [], "last": "Mancia", "suffix": ""}, {"first": "R", "middle": [], "last": "Fagard", "suffix": ""}, {"first": "K", "middle": [], "last": "Narkiewicz", "suffix": ""}], "year": 2013, "venue": "", "link": null}}, "ref_entries": {"FIGREF1": {"text": "Differences in myocardial adaptation by 'chronic, continuous pressure overload' as in arterial hypertension versus 'transient, repetitive pressure/volume overload' as observed in endurance athletes. It remains unclear whether exercise hypertension over many years of training is the driving risk factor for inducing myocardial injury. LA: left atrium; LV: left ventricle; PV: pulmonary vene.", "type": "figure"}}}
{"paper_id": "199662866", "_pdf_hash": "a65c3a29fdab58724736de117255911a3617a238", "abstract": [{"section": "Abstract", "text": "Abstract: Background and objectives: The Studies have suggested hypercholesterolemia is a risk factor for cerebrovascular disease. However, few of the studies with a small number of patients had tested the effect of hypercholesterolemia on the outcomes and complications among acute ischemic stroke (AIS) patients. We hypothesized that lipid disorders (LDs), though risk factors for AIS, were associated with better outcomes and fewer post-stroke complications. Materials and Method: We performed a retrospective analysis of the Nationwide Inpatient Sample (years 2003-2014) in adult hospitalizations for AIS to determine the outcomes and complications associated with LDs, using ICD-9-CM codes. In 2014, we also aimed to estimate adjusted odds of AIS in patients with LDs compared to patients without LDs. The multivariable survey logistic regression models, weighted to account for sampling strategy, were fitted to evaluate relationship of LDs with AIS among 2014 hospitalizations, and outcomes and complications amongst AIS patients from 2003 -2014 . Results and Conclusions: In 2014, there were 28,212,820 (2.02% AIS and 5.50% LDs) hospitalizations. LDs patients had higher prevalence and odds of having AIS compared with non-LDs. Between 2003-2014, of the total 4,224,924 AIS hospitalizations, 451,645 (10.69%) had LDs. Patients with LDs had lower percentages and odds of mortality, risk of death, major/extreme disability, discharge to nursing facility, and complications including epilepsy, stroke-associated pneumonia, GI-bleeding and hemorrhagic-transformation compared to non-LDs. Although LDs are risk factors for AIS, concurrent LDs in AIS is not only associated with lower mortality and disability but also lower post-stroke complications and higher chance of discharge to home.", "cite_spans": [{"start": 1042, "end": 1046, "text": "2003", "ref_id": "BIBREF18"}, {"start": 1047, "end": 1052, "text": "-2014", "ref_id": "BIBREF33"}], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Hypercholesterolemia is a well-documented risk factor for cardiovascular morbidity and mortality [1] [2] [3] [4] . However, the relationship between ischemic stroke and cholesterol is complex and appears to contain several paradoxes [5] [6] [7] [8] [9] [10] [11] [12] . Many large-scale studies on stroke and cholesterol have not differentiated between ischemic and hemorrhagic stroke, nor among various subtypes of ischemic stroke [6, [8] [9] [10] . It has been demonstrated that cholesterol may increase the risk of only certain types of stroke [13] [14] [15] , and low cholesterol levels predispose to hemorrhagic stroke [10, 16] , thus weakening an association between cholesterol and all stroke. Regardless of increased cardiovascular disease risk with high cholesterol levels and decreased stroke risk with statin use, a higher cholesterol value has been associated with a better stroke outcome in several studies [17] [18] [19] [20] . Further research has shown \"reverse epidemiology\" between cholesterol levels at admission, statin treatment and stroke morbidity. Earlier studies have shown a positive association between elevated admission cholesterol at ischemic stroke onset and improved short-term functional outcome [21] and 10-year survival [22] .", "cite_spans": [{"start": 97, "end": 100, "text": "[1]", "ref_id": "BIBREF6"}, {"start": 101, "end": 104, "text": "[2]", "ref_id": "BIBREF7"}, {"start": 105, "end": 108, "text": "[3]", "ref_id": "BIBREF8"}, {"start": 109, "end": 112, "text": "[4]", "ref_id": "BIBREF9"}, {"start": 233, "end": 236, "text": "[5]", "ref_id": "BIBREF10"}, {"start": 237, "end": 240, "text": "[6]", "ref_id": "BIBREF11"}, {"start": 241, "end": 244, "text": "[7]", "ref_id": "BIBREF12"}, {"start": 245, "end": 248, "text": "[8]", "ref_id": "BIBREF13"}, {"start": 249, "end": 252, "text": "[9]", "ref_id": "BIBREF14"}, {"start": 253, "end": 257, "text": "[10]", "ref_id": "BIBREF15"}, {"start": 258, "end": 262, "text": "[11]", "ref_id": "BIBREF16"}, {"start": 263, "end": 267, "text": "[12]", "ref_id": "BIBREF17"}, {"start": 432, "end": 435, "text": "[6,", "ref_id": "BIBREF11"}, {"start": 436, "end": 439, "text": "[8]", "ref_id": "BIBREF13"}, {"start": 440, "end": 443, "text": "[9]", "ref_id": "BIBREF14"}, {"start": 444, "end": 448, "text": "[10]", "ref_id": "BIBREF15"}, {"start": 547, "end": 551, "text": "[13]", "ref_id": "BIBREF18"}, {"start": 552, "end": 556, "text": "[14]", "ref_id": "BIBREF19"}, {"start": 557, "end": 561, "text": "[15]", "ref_id": "BIBREF20"}, {"start": 624, "end": 628, "text": "[10,", "ref_id": "BIBREF15"}, {"start": 629, "end": 632, "text": "16]", "ref_id": "BIBREF21"}, {"start": 920, "end": 924, "text": "[17]", "ref_id": "BIBREF22"}, {"start": 925, "end": 929, "text": "[18]", "ref_id": "BIBREF23"}, {"start": 930, "end": 934, "text": "[19]", "ref_id": "BIBREF24"}, {"start": 935, "end": 939, "text": "[20]", "ref_id": "BIBREF25"}, {"start": 1229, "end": 1233, "text": "[21]", "ref_id": "BIBREF26"}, {"start": 1255, "end": 1259, "text": "[22]", "ref_id": "BIBREF27"}], "ref_spans": []}, {"section": "Introduction", "text": "These paradoxical observations may be related to differential associations with different stroke subtypes. Several recent studies reported that cholesterol was lowest in cardioembolic strokes [15, 23, 24] . The largest prospective cohort of 4128 adults aged >70 years reported that high or normal/borderline total cholesterol values were associated with good survival compared to low values [25] .", "cite_spans": [{"start": 192, "end": 196, "text": "[15,", "ref_id": "BIBREF20"}, {"start": 197, "end": 200, "text": "23,", "ref_id": "BIBREF28"}, {"start": 201, "end": 204, "text": "24]", "ref_id": "BIBREF29"}, {"start": 391, "end": 395, "text": "[25]", "ref_id": "BIBREF30"}], "ref_spans": []}, {"section": "Introduction", "text": "We aimed to estimate odds of having AIS with LDs, and whether or not LDs in AIS patients were associated with better outcomes.", "cite_spans": [], "ref_spans": []}, {"section": "Materials and Methods", "text": "Data was obtained from the Nationwide Inpatient Sample (NIS) between January 2003 and December 2014. The NIS is the largest publicly available all-payer inpatient care database in the United States and contains discharge-level data provided by states that participate in the HCUP (including a total of 46 in 2011). This administrative dataset contains data on approximately 8 million hospitalizations in 1000 hospitals that were chosen to approximate a 20% stratified sample of all US community hospitals, representing more than 95% of the national population. Criteria used for stratified sampling of hospitals into the NIS include hospital ownership, patient volume, teaching status, urban or rural location, and geographic region. Discharge weights are provided for each patient discharge record, which allow extrapolation to obtain national estimates. Each hospitalization is treated as an individual entry in the database and is coded with one principal diagnosis, up to 24 secondary diagnoses, and 15 procedural diagnoses associated with that stay. Detailed information on NIS is available at http://www.hcup-us.ahrq.gov/db/nation/nis/nisdde.jsp.", "cite_spans": [], "ref_spans": []}, {"section": "Materials and Methods", "text": "The data were taken from the Nationwide Inpatient Sample, which is a deidentified database from \"Health Care Utilization Project (HCUP)\" sponsored by the Agency for Healthcare Research and Quality, USA, thus informed consent or IRB approval was not needed for the study. The relevant ethical oversight and HCUP Data Use Agreement (HCUP-4Q28K90CU) were obtained for the study.", "cite_spans": [], "ref_spans": []}, {"section": "Study Population", "text": "We used the ninth revision of the International Classification of Diseases, clinical modification codes (ICD-9-CM) to identify adult patients admitted with a primary diagnosis of AIS (ICD-9-CM codes 433.01, 433.11, 433.21, 433.31, 433.81, 433.91, 434.01, 434.11, 434.91). These codes have been previously validated and are 35% sensitive, 99% specific, 96% positive predictive value (PPVs), and 79% negative predictive value for the diagnosis of ischemic stroke [26] . Similarly, patients with secondary diagnosis of LDs were identified using ICD-9-CM codes 272.0, 272.1, and 272.2 (sensitivity of 27.0%, specificity of 76.7%, PPV of 71.1%, and NPV of 33.1%) [27] . We used ICD-9-CM codes to identify independent predictors (covariates), including the comorbidities of hypertension, diabetes mellitus, hypercholesterolemia, atrial fibrillation, use of anticoagulant and antiplatelet medications, chronic use of NSAIDs and aspirin, smoking (current/past), use of IV tPA, drug abuse, alcohol dependence, smoking status, mechanical thrombectomy, AV malformation, amyloidosis, atrial fibrillation, nasogastric tube, gastrostomy, endotracheal intubation, non-invasive mechanical ventilation, invasive mechanical ventilation and H. pylori infection. Supplementary Table S1 lists all ICD-9-CM codes that were used for this study.", "cite_spans": [{"start": 461, "end": 465, "text": "[26]", "ref_id": "BIBREF31"}, {"start": 658, "end": 662, "text": "[27]", "ref_id": "BIBREF32"}], "ref_spans": [{"start": 1243, "end": 1265, "text": "Supplementary Table S1", "ref_id": "TABREF0"}]}, {"section": "Study Population", "text": "AIS patients were stratified by LDs status. Age < 18 years and admissions with missing data for age, sex, and race were excluded.", "cite_spans": [], "ref_spans": []}, {"section": "Patient and Hospital Characteristics", "text": "Patient characteristics of interest were sex, age, race, insurance status and concomitant diagnoses as defined above. Race was defined by White (referent), African American, Hispanic, Asian or Pacific Islander, and Native American. Insurance status was defined by Medicare (referent), Medicaid, private insurance, and other/self-pay/no charge. We defined the severity of co-morbid conditions using Deyo's modification of the Charlson co-morbidity index (CCI) (Supplementary Table S2 ). Thirty-one facilities were considered to be teaching hospitals if they have an American Medical Association-approved residency program, are a member of the Council of Teaching Hospitals, or have a full-time equivalent interns and residents to patient's ratio of \u22650. 25 . HCUP NIS contains data on total charges for each hospital in the databases, which represents the amount that hospitals billed for services.", "cite_spans": [{"start": 752, "end": 754, "text": "25", "ref_id": "BIBREF30"}], "ref_spans": [{"start": 474, "end": 482, "text": "Table S2", "ref_id": "TABREF1"}]}, {"section": "Outcomes", "text": "We tested for associations between LDs and AIS amongst the January 2014-December 2014 dataset. We also examined outcomes such as all-cause in hospital mortality, All Patient Refined Diagnosis Related Groups (APR-DRG) risk of death (RoD), APR-DRG loss of function (LoF), discharge disposition (DD) [home vs. transfer to short-term hospital (STH), skilled nursing facility (SNF), intermediate care facility (ICF)], post-stroke complications like epilepsy, stroke-associated pneumonia (SAP), hemorrhagic transformation (HT), upper gastro-intestinal bleeding (UGIB), length of stay (LoS), and cost of hospitalization with LDs amongst AIS hospitalizations (years [2003] [2004] [2005] [2006] [2007] [2008] [2009] [2010] [2011] [2012] [2013] [2014] . The comparison of disability/loss of function was investigated by APR-DRGs severity between patients with LDs and patients without LDs on discharge. Similarly, risk of death was assigned using APR-DRG likelihood of death (risk of death) on discharge. APR-DRGs were assigned using software developed by 3M Health Information Systems, where score 1 indicates minor, 2-moderate, 3-major, 4-extreme loss of function or likelihood of death on discharge.", "cite_spans": [], "ref_spans": []}, {"section": "Statistical Analysis", "text": "All statistical analyses were performed using the weighted survey methods in SAS (version 9.4). Weighted values of patient-level observations were generated to produce a nationally representative estimate of the entire US population of hospitalized patients. Univariate analysis of differences between categorical variables was tested using the chi-square test and analysis of differences between continuous variables (LoS and cost of hospitalization) was tested using Student's t-test. Mixed-effects survey logistic regression models with weighted analysis were used for the categorical dependent variables, including LDs and outcomes of interest, in order to estimate odds ratio (OR) and 95% confidence intervals for the association between AIS and LDs in the 2014 cohort as well as LDs and outcomes amongst AIS hospitalizations during years [2003] [2004] [2005] [2006] [2007] [2008] [2009] [2010] [2011] [2012] [2013] [2014] .", "cite_spans": [], "ref_spans": []}, {"section": "Statistical Analysis", "text": "The hierarchical models (demographics and patient-level factors nested within hospital-level factors) were created as random effects within the model for the outcomes. In the multivariate models, we had included demographics (age, gender, race), patient-level hospitalization variables (admission day, primary payer, admission type, median household income category), hospital-level variables (hospital region, teaching versus nonteaching hospital, hospital bed size), comorbidities/concurrent conditions like hypertension, diabetes mellitus, hypercholesterolemia, atrial fibrillation, obesity, hemorrhagic transformation, smoking status, drug abuse, alcohol abuse, medication use (anticoagulant and antiplatelet medication, chronic use of aspirin), and use of IV tPA during the same hospitalization or in a different institution within the 24 h prior to admission to the facility, mechanical thrombectomy, gastrostomy, nasogastric tube insertion, invasive-noninvasive mechanical ventilation, and CCI. The confounders of the models were tailored according to the need of the individual model.", "cite_spans": [], "ref_spans": []}, {"section": "Statistical Analysis", "text": "We investigated the link between LDs and AIS, LDs and post-AIS outcomes, and LDs and post-AIS complications by creating separate mix effect survey logistic regression models with weights to account for sampling strategy to find out:", "cite_spans": [], "ref_spans": []}, {"section": "Statistical Analysis", "text": "( For each model, C-index was calculated. All statistical tests used were 2-sided, and p < 0.05 was deemed statistically significant.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "LDs and AIS Amongst Year-2014 Hospitalizations", "text": "We identified 28,212,820 total hospitalizations in 2014, ( Figure 1A ) out of which (569,215) 2.02% and (1,550,956) 5.50% patients were hospitalized with primary or secondary diagnosis of AIS and LDs respectively. Out of 569,215 patients with AIS, 50,005 (8.78%) had LDs. Patients with LDs had higher prevalence of having AIS (3.22% vs. 1.95%; p < 0.0001) compared with non-LDs (Table 1) . For each model, C-index was calculated. All statistical tests used were 2-sided, and p < 0.05 was deemed statistically significant.", "cite_spans": [], "ref_spans": [{"start": 59, "end": 68, "text": "Figure 1A", "ref_id": "FIGREF0"}, {"start": 378, "end": 387, "text": "(Table 1)", "ref_id": "TABREF0"}]}, {"section": "Results", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "LDs and AIS Amongst Year-2014 Hospitalizations", "text": "We identified 28,212,820 total hospitalizations in 2014, ( Figure 1A ) out of which (569,215) 2.02% and (1,550,956) 5.50% patients were hospitalized with primary or secondary diagnosis of AIS and LDs respectively. Out of 569,215 patients with AIS, 50,005 (8.78%) had LDs. Patients with LDs had higher prevalence of having AIS (3.22% vs. 1.95%; p < 0.0001) compared with non-LDs ( Table 1 ). Table 2 includes regression models among 2014 hospitalizations with odds of having AIS amongst LDs vs. non-LDs after adjusting for patients' demographics, patients and hospital level characteristics, co-morbidities, and CCI. In multivariate survey logistic regression analysis, LD was associated with higher adjusted odds of having AIS (aOR: 1.18; 95% CI:1.15-1.20; p < 0.0001) compared to non-LDs. The AUC or C statistic of the ROC was used to validate the accuracy of the regressions. The AUC was 0.88, which indicates a precise/good model. ", "cite_spans": [], "ref_spans": [{"start": 59, "end": 68, "text": "Figure 1A", "ref_id": "FIGREF0"}, {"start": 380, "end": 387, "text": "Table 1", "ref_id": "TABREF0"}, {"start": 391, "end": 398, "text": "Table 2", "ref_id": "TABREF1"}]}, {"section": "LDs and Post-AIS Outcomes Amongst AIS Population from Year 2003-2014", "text": "We found a total of 4,224,924 hospitalizations due to AIS from year 2003 to 2014 after excluding patients with age < 18 years and admissions with missing data for age, gender, and race ( Figure 1B) . Out of 4,224,924 AIS hospitalizations, 451,645 (10.69%) had LDs.", "cite_spans": [], "ref_spans": [{"start": 187, "end": 197, "text": "Figure 1B)", "ref_id": "FIGREF0"}]}, {"section": "LDs and Post-AIS Outcomes Amongst AIS Population from Year 2003-2014", "text": "We analyzed prevalence trends of LDs in AIS hospitalizations. As shown in Figure 2 AIS hospitalizations with LDs were more likely to be female (49.35% vs. 46.85%, p < 0.0001). There was no difference in other demographic characteristics like age and race among AIS hospitalizations with and without hyperlipidemia. Co-morbidities such as diabetes (40.02% vs. 33.50%, p < 0.0001), hypertension (86.44% vs. 78.66%, p < 0.0001), and obesity (9.85% vs. 7.63%, p < 0.0001) were higher in patients with LDs than those without LDs. AIS hospitalizations in large, urban (teaching and non-teaching) hospitals and in the Northeast region were more likely to have patients with LDs (Table 3) . AIS hospitalizations with LDs were more likely to be female (49.35% vs. 46.85%, p < 0.0001). There was no difference in other demographic characteristics like age and race among AIS hospitalizations with and without hyperlipidemia. Co-morbidities such as diabetes (40.02% vs. 33.50%, p < 0.0001), hypertension (86.44% vs. 78.66%, p < 0.0001), and obesity (9.85% vs. 7.63%, p < 0.0001) were higher in patients with LDs than those without LDs. AIS hospitalizations in large, urban (teaching and non-teaching) hospitals and in the Northeast region were more likely to have patients with LDs (Table 3) . Table 4 includes outcomes of LDs among AIS hospitalizations. Our outcomes of interest were to identify post-AIS outcomes (in-hospital mortality, discharge, disability, risk of death) and complications (post stroke early epilepsy, stroke associated pneumonia, hemorrhagic transformation and upper gastro-intestinal bleeding) amongst AIS hospitalizations. All cause in-hospital mortality was lower in AIS with LDs (2.93% vs. 5.48%, p < 0.0001) than without LDs. Some 43.14% of patients with LDs had discharged to home compared to 36.81% without LDs (p < 0.0001). Overall, AIS hospitalizations with LDs had a higher prevalence of discharge to home or routine (43.14% vs. 36.81%, p < 0.0001) and a lower prevalence of discharge other than home (56.86% vs. 63.19%, p < 0.0001) compared to patients without LDs. The prevalence of major/severe loss of function was lower (29.92% vs. 37.75%, p < 0.0001) among AIS hospitalizations with LDs than without LDs. The patients with LDs was also associated with lower prevalence major/extreme likelihood of death (15.8% vs. 21.89%, p < 0.0001) in AIS hospitalizations. Prevalence of post stroke early epilepsy (4.68% vs. 6.13%, p < 0.0001), SAP (2.14% vs. 3.70%, p < 0.0001), HT (1.25% vs. 1.71%, p < 0.0001) and UGIB (0.33% vs. 0.45%, p < 0.0001) were lower among AIS hospitalizations with LDs than without LDs. Mean length of stay (4.83 days vs. 5.83 days, p < 0.0001) and total cost of hospitalization were lower amongst patients with LDs ($34,604 vs. 38,547, p < 0.0001) ( Table 4) . Table 5 lists multivariate analysis of outcomes and complications in AIS hospitalizations. LDs were associated with lower adjusted odds of all cause in-hospital mortality (aOR: 0.66, 95% CI: 0.62-0.69, p < 0.0001), discharge disposition (home vs. no-home) (aOR: 0.83, 95% CI: 0.82-0.85, p < 0.0001), APR-DRG loss of function (major/severe vs. minor/moderate) (aOR: 0.80, 95% CI: 0.79-0.82, p < 0.0001), and APR-DRG risk of death (major/severe likelihood vs. minor/moderate likelihood) (aOR: 0.77, 95% CI: 0.75-0.79, p < 0.0001) in comparison to patients without LDs amongst AIS hospitalizations of year 2003-2014 (Models 1-4) . Table 5 . Multivariate logistic regression analysis of outcomes and complications in patients with LDs compared to non-LDs (reference) amongst AIS hospitalizations. All models are adjusted for demographics (age, gender, race), patient-level hospitalization variables (admission day, primary payer, admission type, median household income category), hospital-level variables (hospital region, teaching versus non-teaching hospital, hospital bed-size), comorbidities, concurrent conditions like hypertension, diabetes mellitus, hypercholesterolemia, atrial fibrillation, obesity, amyloidosis, hemorrhagic transformation, smoking status, drug abuse, alcohol abuse, medication use (anticoagulant and antiplatelet medication, platelets inhibitor infusion, chronic use of aspirin), and use of IV tPA during the same hospitalization or in a different institution within the 24 h prior to admission to the facility, mechanical thrombectomy, gastrostomy, nasogastric tube insertion, invasive-noninvasive mechanical ventilation, and Charlson's co-morbidity index (CCI). C statistic was used to validate the accuracy of the regressions. All models have c-index >0.6, which indicates a good model fit (Table 5 ).", "cite_spans": [], "ref_spans": [{"start": 74, "end": 82, "text": "Figure 2", "ref_id": "FIGREF5"}, {"start": 671, "end": 680, "text": "(Table 3)", "ref_id": "TABREF2"}, {"start": 1271, "end": 1280, "text": "(Table 3)", "ref_id": "TABREF2"}, {"start": 1283, "end": 1290, "text": "Table 4", "ref_id": "TABREF5"}, {"start": 2795, "end": 2803, "text": "Table 4)", "ref_id": "TABREF5"}, {"start": 3419, "end": 3431, "text": "(Models 1-4)", "ref_id": "FIGREF0"}]}, {"section": "Odds", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "In this study, we aimed to investigate the link between acute ischemic stroke (AIS) and lipid disorders (LDs), specifically the odds of having AIS with LDs, and whether LDs were associated with better outcomes or less complications in AIS patients as compared to those without LDs. We did this by performing a population-based retrospective cross-sectional analysis of the NIS in adult hospitalizations for AIS.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "Our study found that those with LDs had a higher prevalence of being hospitalized with AIS as compared to those without LDs. Co-morbidities, such as diabetes, hypertension, obesity, and depression were also higher in those with LDs than in those without them. Our findings are similar to a study by Olsen et al. who have reported that patients with hypercholesterolemia are at increased risk of stroke [22] . However, the paradoxical relationship is evident when analyzing for post-AIS outcomes such as in-hospital mortality, discharge status, disability, and risk of death, as well as post-AIS complications such as post-stroke early epilepsy, stroke associated pneumonia, hemorrhagic transformation, and upper GI bleeding.", "cite_spans": [{"start": 402, "end": 406, "text": "[22]", "ref_id": "BIBREF27"}], "ref_spans": []}, {"section": "Discussion", "text": "For AIS patients with lipid disorders, there was reduced in-hospital mortality (aOR: 0.66, p < 0.0001), increased discharge to home (aOR: 0.83, p < 0.0001), decreased major/severe loss of function (aOR: 0.80, p < 0.0001), and decreased major/extreme likelihood of death (aOR: 0.77, p < 0.0001); additionally, there was reduced risk of post stroke epilepsy (aOR:0.89, p < 0.0001), SAP (aOR: 0.75, p < 0.0001), upper GI bleeding (aOR:0.85, p < 0.0001) and hemorrhagic transformation (aOR: 0.82, p < 0.0001) as compared to AIS patients without LDs. There are supporting studies to our paradoxical findings that have reported higher cholesterol levels on admission are associated with better long-term survival or outcomes amongst AIS survivors [22, 28, 29] .", "cite_spans": [{"start": 741, "end": 745, "text": "[22,", "ref_id": "BIBREF27"}, {"start": 746, "end": 749, "text": "28,", "ref_id": "BIBREF33"}, {"start": 750, "end": 753, "text": "29]", "ref_id": "BIBREF34"}], "ref_spans": []}, {"section": "Discussion", "text": "There is thus an incongruity that is seen in AIS patients; on one hand, there is a benefit to reducing cholesterol and LDs in that there is a reduced prevalence of AIS and co-morbidities as compared to those without LDs, as well as for being beneficial for cerebrovascular mortality and morbidity [3, 4] . However, patients with LDs have better post-AIS outcomes and less post-AIS complications.", "cite_spans": [{"start": 297, "end": 300, "text": "[3,", "ref_id": "BIBREF8"}, {"start": 301, "end": 303, "text": "4]", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "Discussion", "text": "This paradox may be explained by the type of stroke that is often seen with those with LDs. Those with LDs may be more predisposed toward small-vessel strokes, and thus will have less severe strokes with better prognoses; as a result, they would have improved post-AIS outcomes and reduced post-AIS complications as compared to those without LDs who may be more prone to the often more severe large brain vessel occlusion. This theory can be supported by our data, as well as that large occlusion of brain vessels as seen in cardio embolic strokes have the lowest total serum cholesterol levels [23, 24] .", "cite_spans": [{"start": 595, "end": 599, "text": "[23,", "ref_id": "BIBREF28"}, {"start": 600, "end": 603, "text": "24]", "ref_id": "BIBREF29"}], "ref_spans": []}, {"section": "Discussion", "text": "Interestingly, the trends of LDs in AIS hospitalizations have decreased from 2003-2014. This may be due to reduced hospitalizations for minor strokes and may support theory that those with LDs are more prone to small-vessel strokes which have better prognoses. Thus, those patients with LDs and minor strokes are often not being hospitalized as much, and if they are, they will show improved post-AIS outcomes and reduced complications as shown in our study. However, in our study AIS was analyzed as a whole, and was not classified into subtypes using TOAST classification. This was one limitation of our study to support the decreasing trends and theory of LDs association with small vessel stroke which have better prognoses.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "This analysis and confirmation of the paradoxical relationship seen between LDs and AIS may have implications for treatment strategies in the future. Statins are certainly beneficial to cardiovascular health, have been proven to have neuroprotective and microvascular benefits in animal stroke models, and may be important in augmenting cerebral repair after ischemic injury [20] . They also have been proven to improve survival for up to a year after stroke.", "cite_spans": [{"start": 375, "end": 379, "text": "[20]", "ref_id": "BIBREF25"}], "ref_spans": []}, {"section": "Discussion", "text": "Further work must be done in order to fully determine why LDs seem to have a beneficial effect on AIS outcomes and complications, and to determine potential treatment strategies. Clinical trials should be run to determine the effects of LDs and statins on AIS, AIS subtypes such as small-vessel disease, and AIS outcomes and complications.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "A major strength of the study was that findings were nationally representative for the USA. NIS data is a large deidentified inpatient database, and our study has good statistical power. The APR-DRG coding systems used in this study to assess the severity of illness and risk of mortality are externally validated. They are very reliable and consistent, and widely used by hospitals, consumers, payers and regulators [30, 31] .", "cite_spans": [{"start": 417, "end": 421, "text": "[30,", "ref_id": "BIBREF35"}, {"start": 422, "end": 425, "text": "31]", "ref_id": "BIBREF36"}], "ref_spans": []}, {"section": "Discussion", "text": "One main limitation to this study mentioned above, AIS was not classified into subtypes using TOAST classification (such as cardio-embolic, small-vessel, or large artery atherothrombotic strokes). Further investigations should classify AIS into these subtypes and determine if there is an association between LDs and these subtypes. This would be able to determine if theory that LDs cause the less severe small-vessel strokes is correct, and thus is the reason why we see better AIS-outcomes and reduced complications with LDs. Another limitation of the study was LDs were identified as a secondary diagnosis (history of LDs or first-time diagnosis) responsible for AIS and we did not have data on statin use prior or during the hospitalization. So neuroprotective role of statin [20] was difficult to differentiate. Other limitations to this study include the fact that we only considered patients who were hospitalized with strokes; between 10%-40% of stroke patients are not admitted to the in-patient hospital [13] . Thus, patients with less severe strokes may not be included in this study. The outcomes evaluated while patients were in hospital and status of patients on discharge, we had not evaluated the long-term outcomes. Additionally, although co-morbidities were accounted for and adjusted for in analysis, other subtler differences between patients such as prior strokes or other unaccounted medications may flaw our design outcomes. Though we had adjusted outcomes model with antiplatelets or anticoagulant use before and during hospitalization, but we had no record on statin use to adjust the models.", "cite_spans": [{"start": 781, "end": 785, "text": "[20]", "ref_id": "BIBREF25"}, {"start": 1015, "end": 1019, "text": "[13]", "ref_id": "BIBREF18"}], "ref_spans": []}, {"section": "Conclusions", "text": "LDs have been shown to have an increased prevalence in patients with AIS hospitalizations as compared to those without LDs. However, we have also confirmed that LDs have paradoxically been shown to improve post-AIS outcomes and reduce post-AIS complications. This complicated relationship between stroke and LDs requires further work and research to determine the reasoning as to the associated benefit between higher lipids and better outcomes, and whether the theory in that LDs have a stronger association in causing small vessel and thus less severe strokes with better prognoses can be confirmed. Clinical trials should be undertaken to further determine the relationship of statin uses and outcomes to refine treatment strategies before and after stroke onset, and further work should be initiated to determine the association between LDs and AIS subtypes such as small-vessel strokes, AIS-subtype outcomes, and AIS-subtype complications.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "Supplementary Materials: The following are available online at http://www.mdpi.com/1010-660X/55/8/475/s1. Table S1 : ICD-9-CM codes used in this analysis, Table S2 ", "cite_spans": [], "ref_spans": [{"start": 106, "end": 114, "text": "Table S1", "ref_id": "TABREF0"}, {"start": 155, "end": 163, "text": "Table S2", "ref_id": "TABREF1"}]}], "bib_entries": {"BIBREF0": {"title": "81) 1,486,581 (37.50) Transfer to Short-term Hospital", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF1": {"title": "Transfer to SNF/ICF/Another Type of Facility", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF3": {"title": "Loss of Function (%)", "authors": [{"first": "Apr-Drg", "middle": [], "last": "Severity", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF4": {"title": "Minor loss of function", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF5": {"title": "Severe loss of function", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF6": {"title": "Heart Disease and Stroke Statistics-2017 Update: A Report From the American Heart Association", "authors": [{"first": "E", "middle": ["J"], "last": "Benjamin", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Blaha", "suffix": ""}, {"first": "S", "middle": ["E"], "last": "Chiuve", "suffix": ""}, {"first": "M", "middle": [], "last": "Cushman", "suffix": ""}, {"first": "S", "middle": ["R"], "last": "Das", "suffix": ""}, {"first": "R", "middle": [], "last": "Deo", "suffix": ""}, {"first": "S", "middle": ["D"], "last": "De Ferranti", "suffix": ""}, {"first": "J", "middle": [], "last": "Floyd", "suffix": ""}, {"first": "M", "middle": [], "last": "Fornage", "suffix": ""}, {"first": "C", "middle": [], "last": "Gillespie", "suffix": ""}], "year": 2017, "venue": "", "link": "207634647"}, "BIBREF7": {"title": "Vital Signs: Recent Trends in Stroke Death Rates-United States", "authors": [{"first": "Q", "middle": [], "last": "Yang", "suffix": ""}, {"first": "X", "middle": [], "last": "Tong", "suffix": ""}, {"first": "L", "middle": [], "last": "Schieb", "suffix": ""}, {"first": "A", "middle": [], "last": "Vaughan", "suffix": ""}, {"first": "C", "middle": [], "last": "Gillespie", "suffix": ""}, {"first": "J", "middle": ["L"], "last": "Wiltz", "suffix": ""}, {"first": "S", "middle": ["C"], "last": "King", "suffix": ""}, {"first": "E", "middle": [], "last": "Odom", "suffix": ""}, {"first": "R", "middle": [], "last": "Merritt", "suffix": ""}, {"first": "Y", "middle": [], "last": "Hong", "suffix": ""}], "year": 2000, "venue": "", "link": null}, "BIBREF8": {"title": "Serum cholesterol in young men and subsequent cardiovascular disease", "authors": [{"first": "M", "middle": ["J"], "last": "Klag", "suffix": ""}, {"first": "D", "middle": ["E"], "last": "Ford", "suffix": ""}, {"first": "L", "middle": ["A"], "last": "Mead", "suffix": ""}, {"first": "J", "middle": [], "last": "He", "suffix": ""}, {"first": "P", "middle": ["K"], "last": "Whelton", "suffix": ""}, {"first": "K", "middle": ["Y"], "last": "Liang", "suffix": ""}, {"first": "D", "middle": ["M"], "last": "Levine", "suffix": ""}], "year": 1993, "venue": "N. Engl. J. Med", "link": "25695328"}, "BIBREF9": {"title": "Lipids and risk of coronary heart disease. The Framingham Study", "authors": [{"first": "W", "middle": ["P"], "last": "Castelli", "suffix": ""}, {"first": "K", "middle": [], "last": "Anderson", "suffix": ""}, {"first": "P", "middle": ["W"], "last": "Wilson", "suffix": ""}, {"first": "D", "middle": [], "last": "Levy", "suffix": ""}], "year": 1992, "venue": "Ann. Epidemiol", "link": "24027525"}, "BIBREF10": {"title": "Treatment and secondary prevention of stroke: Evidence, costs, and effects on individuals and populations", "authors": [{"first": "G", "middle": ["J"], "last": "Hankey", "suffix": ""}, {"first": "C", "middle": ["P"], "last": "Warlow", "suffix": ""}], "year": 1999, "venue": "Lancet", "link": "25241624"}, "BIBREF11": {"title": "Prospective Studies Collaboration. Cholesterol, diastolic blood pressure, and stroke: 13,000 strokes in 450,000 people in 45 prospective cohorts", "authors": [], "year": 1995, "venue": "Lancet", "link": null}, "BIBREF12": {"title": "Is cholesterol a risk factor for stroke?: No", "authors": [{"first": "W", "middle": ["M"], "last": "Landau", "suffix": ""}], "year": 1999, "venue": "Arch. Neurol", "link": "1922762"}, "BIBREF13": {"title": "lipid-lowering agents, and the risk for brain infarction", "authors": [{"first": "P", "middle": [], "last": "Amarenco", "suffix": ""}, {"first": "", "middle": [], "last": "Hypercholesterolemia", "suffix": ""}], "year": 2001, "venue": "Neurology", "link": null}, "BIBREF14": {"title": "Current status of risk factors for stroke", "authors": [{"first": "P", "middle": ["A"], "last": "Wolf", "suffix": ""}, {"first": "W", "middle": ["B"], "last": "Kannel", "suffix": ""}, {"first": "J", "middle": [], "last": "Verter", "suffix": ""}], "year": 1983, "venue": "Neurol. Clin", "link": "44811228"}, "BIBREF15": {"title": "Factors related to stroke incidence in Hawaii Japanese men. The Honolulu Heart Study", "authors": [{"first": "A", "middle": [], "last": "Kagan", "suffix": ""}, {"first": "J", "middle": ["S"], "last": "Popper", "suffix": ""}, {"first": "G", "middle": ["G"], "last": "Rhoads", "suffix": ""}], "year": 1980, "venue": "Stroke", "link": null}, "BIBREF16": {"title": "Serum cholesterol levels and six-year mortality from stroke in 350,977 men screened for the multiple risk factor intervention trial", "authors": [{"first": "H", "middle": [], "last": "Iso", "suffix": ""}, {"first": "D", "middle": ["R"], "last": "Jacobs", "suffix": ""}, {"first": "", "middle": [], "last": "Jr", "suffix": ""}, {"first": "D", "middle": [], "last": "Wentworth", "suffix": ""}, {"first": "J", "middle": ["D"], "last": "Neaton", "suffix": ""}, {"first": "J", "middle": ["D"], "last": "Cohen", "suffix": ""}], "year": 1989, "venue": "N. Engl. J. Med", "link": "25345086"}, "BIBREF17": {"title": "Elevated serum cholesterol is a risk factor for both coronary heart disease and thromboembolic stroke in Hawaiian Japanese men. Implications of shared risk", "authors": [{"first": "R", "middle": [], "last": "Benfante", "suffix": ""}, {"first": "K", "middle": [], "last": "Yano", "suffix": ""}, {"first": "L", "middle": ["J"], "last": "Hwang", "suffix": ""}, {"first": "J", "middle": ["D"], "last": "Curb", "suffix": ""}, {"first": "A", "middle": [], "last": "Kagan", "suffix": ""}, {"first": "W", "middle": [], "last": "Ross", "suffix": ""}], "year": 1994, "venue": "Stroke", "link": "564036"}, "BIBREF18": {"title": "Differences in vascular risk factors between etiological subtypes of ischemic stroke: Importance of population-based studies", "authors": [{"first": "U", "middle": ["G"], "last": "Schulz", "suffix": ""}, {"first": "P", "middle": ["M"], "last": "Rothwell", "suffix": ""}], "year": 2003, "venue": "Stroke", "link": "8537080"}, "BIBREF19": {"title": "Association of cholesterol with stroke risk varies in stroke subtypes and patient subgroups", "authors": [{"first": "D", "middle": ["L"], "last": "Tirschwell", "suffix": ""}, {"first": "N", "middle": ["L"], "last": "Smith", "suffix": ""}, {"first": "S", "middle": ["R"], "last": "Heckbert", "suffix": ""}, {"first": "R", "middle": ["N"], "last": "Lemaitre", "suffix": ""}, {"first": "W", "middle": ["T"], "last": "Longstreth", "suffix": ""}, {"first": "", "middle": [], "last": "Jr", "suffix": ""}, {"first": "B", "middle": ["M"], "last": "Psaty", "suffix": ""}], "year": 2004, "venue": "Neurology", "link": "22582909"}, "BIBREF20": {"title": "Blood lipids in brain infarction subtypes", "authors": [{"first": "P", "middle": [], "last": "Amarenco", "suffix": ""}, {"first": "J", "middle": [], "last": "Labreuche", "suffix": ""}, {"first": "A", "middle": [], "last": "Elbaz", "suffix": ""}, {"first": "P", "middle": ["J"], "last": "Touboul", "suffix": ""}, {"first": "F", "middle": [], "last": "Driss", "suffix": ""}, {"first": "A", "middle": [], "last": "Jaillard", "suffix": ""}, {"first": "E", "middle": [], "last": "Bruckert", "suffix": ""}], "year": 2006, "venue": "Cereb. Dis", "link": "22365838"}, "BIBREF21": {"title": "Eastern Stroke and Coronary Heart Disease Collaborative Research Group. Blood pressure, cholesterol, and stroke in eastern Asia", "authors": [], "year": 1998, "venue": "Lancet", "link": null}, "BIBREF22": {"title": "Influence of cholesterol on survival after stroke: Retrospective study", "authors": [{"first": "A", "middle": ["G"], "last": "Dyker", "suffix": ""}, {"first": "C", "middle": ["J"], "last": "Weir", "suffix": ""}, {"first": "K", "middle": ["R"], "last": "Lees", "suffix": ""}], "year": 1997, "venue": "BMJ", "link": "27632922"}, "BIBREF23": {"title": "Better outcome after stroke with higher serum cholesterol levels", "authors": [{"first": "C", "middle": [], "last": "Vauthey", "suffix": ""}, {"first": "G", "middle": ["R"], "last": "De Freitas", "suffix": ""}, {"first": "G", "middle": [], "last": "Van Melle", "suffix": ""}, {"first": "G", "middle": [], "last": "Devuyst", "suffix": ""}, {"first": "J", "middle": [], "last": "Bogousslavsky", "suffix": ""}], "year": 2000, "venue": "Neurology", "link": "21781069"}, "BIBREF24": {"title": "Low cholesterol levels are associated with short-term mortality in older patients with ischemic stroke", "authors": [{"first": "G", "middle": [], "last": "Zuliani", "suffix": ""}, {"first": "A", "middle": [], "last": "Cherubini", "suffix": ""}, {"first": "A", "middle": ["R"], "last": "Atti", "suffix": ""}, {"first": "A", "middle": [], "last": "Ble", "suffix": ""}, {"first": "C", "middle": [], "last": "Vavalle", "suffix": ""}, {"first": "F", "middle": [], "last": "Di Todaro", "suffix": ""}, {"first": "C", "middle": [], "last": "Benedetti", "suffix": ""}, {"first": "S", "middle": [], "last": "Volpato", "suffix": ""}, {"first": "M", "middle": ["G"], "last": "Marinescu", "suffix": ""}, {"first": "U", "middle": [], "last": "Senin", "suffix": ""}], "year": 2004, "venue": "J. Gerontol. Ser. A Biol. Sci. Med. Sci", "link": "25745711"}, "BIBREF25": {"title": "Association between acute statin therapy, survival, and improved functional outcome after ischemic stroke: The North Dublin Population Stroke Study", "authors": [{"first": "D", "middle": [], "last": "Ni Chroinin", "suffix": ""}, {"first": "E", "middle": ["L"], "last": "Callaly", "suffix": ""}, {"first": "J", "middle": [], "last": "Duggan", "suffix": ""}, {"first": "A", "middle": [], "last": "Merwick", "suffix": ""}, {"first": "N", "middle": [], "last": "Hannon", "suffix": ""}, {"first": "O", "middle": [], "last": "Sheehan", "suffix": ""}, {"first": "M", "middle": [], "last": "Marnane", "suffix": ""}, {"first": "G", "middle": [], "last": "Horgan", "suffix": ""}, {"first": "E", "middle": ["B"], "last": "Williams", "suffix": ""}, {"first": "D", "middle": [], "last": "Harris", "suffix": ""}], "year": 2011, "venue": "Stroke", "link": "5562594"}, "BIBREF26": {"title": "Effects of clinical and laboratory variables at admission and of in-hospital treatment with cardiovascular drugs on short term prognosis of ischemic stroke. The GIFA study", "authors": [{"first": "A", "middle": [], "last": "Tuttolomondo", "suffix": ""}, {"first": "D", "middle": [], "last": "Di Raimondo", "suffix": ""}, {"first": "R", "middle": [], "last": "Di Sciacca", "suffix": ""}, {"first": "C", "middle": [], "last": "Pedone", "suffix": ""}, {"first": "S", "middle": [], "last": "La Placa", "suffix": ""}, {"first": "V", "middle": [], "last": "Arnao", "suffix": ""}, {"first": "A", "middle": [], "last": "Pinto", "suffix": ""}, {"first": "G", "middle": [], "last": "Licata", "suffix": ""}], "year": 2013, "venue": "Nutr. Metab. Cardiovasc. Dis. NMCD", "link": "8537133"}, "BIBREF27": {"title": "Higher total serum cholesterol levels are associated with less severe strokes and lower all-cause mortality: Ten-year follow-up of ischemic strokes in the Copenhagen Stroke Study", "authors": [{"first": "T", "middle": ["S"], "last": "Olsen", "suffix": ""}, {"first": "R", "middle": ["H"], "last": "Christensen", "suffix": ""}, {"first": "L", "middle": ["P"], "last": "Kammersgaard", "suffix": ""}, {"first": "K", "middle": ["K"], "last": "Andersen", "suffix": ""}], "year": 2007, "venue": "Stroke", "link": "2758872"}, "BIBREF28": {"title": "Acute stroke with atrial fibrillation. The Copenhagen Stroke Study", "authors": [{"first": "H", "middle": ["S"], "last": "Jorgensen", "suffix": ""}, {"first": "H", "middle": [], "last": "Nakayama", "suffix": ""}, {"first": "J", "middle": [], "last": "Reith", "suffix": ""}, {"first": "H", "middle": ["O"], "last": "Raaschou", "suffix": ""}, {"first": "T", "middle": ["S"], "last": "Olsen", "suffix": ""}], "year": 1996, "venue": "Stroke", "link": "24217019"}, "BIBREF29": {"title": "Stroke severity in atrial fibrillation. The Framingham Study", "authors": [{"first": "H", "middle": ["J"], "last": "Lin", "suffix": ""}, {"first": "P", "middle": ["A"], "last": "Wolf", "suffix": ""}, {"first": "M", "middle": [], "last": "Kelly-Hayes", "suffix": ""}, {"first": "A", "middle": ["S"], "last": "Beiser", "suffix": ""}, {"first": "C", "middle": ["S"], "last": "Kase", "suffix": ""}, {"first": "E", "middle": ["J"], "last": "Benjamin", "suffix": ""}, {"first": "R", "middle": ["B"], "last": "Agostino", "suffix": ""}], "year": 1996, "venue": "Stroke", "link": "24758427"}, "BIBREF30": {"title": "The value of serum albumin and high-density lipoprotein cholesterol in defining mortality risk in older persons with low serum cholesterol", "authors": [{"first": "S", "middle": [], "last": "Volpato", "suffix": ""}, {"first": "S", "middle": ["G"], "last": "Leveille", "suffix": ""}, {"first": "M", "middle": ["C"], "last": "Corti", "suffix": ""}, {"first": "T", "middle": ["B"], "last": "Harris", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Guralnik", "suffix": ""}], "year": 2001, "venue": "J. Am. Geriatr. Soc", "link": "24238275"}, "BIBREF31": {"title": "Accuracy of ICD-9-CM codes for identifying cardiovascular and stroke risk factors", "authors": [{"first": "E", "middle": [], "last": "Birman-Deych", "suffix": ""}, {"first": "A", "middle": ["D"], "last": "Waterman", "suffix": ""}, {"first": "Y", "middle": [], "last": "Yan", "suffix": ""}, {"first": "D", "middle": ["S"], "last": "Nilasena", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Radford", "suffix": ""}, {"first": "B", "middle": ["F"], "last": "Gage", "suffix": ""}], "year": 2005, "venue": "Med. Care", "link": "23983289"}, "BIBREF32": {"title": "Using Electronic Medical Record to Identify Patients With Dyslipidemia in Primary Care Settings: International Classification of Disease Code Matters From One Region to a National Database", "authors": [{"first": "J", "middle": [], "last": "Oake", "suffix": ""}, {"first": "E", "middle": [], "last": "Aref-Eshghi", "suffix": ""}, {"first": "M", "middle": [], "last": "Godwin", "suffix": ""}, {"first": "K", "middle": [], "last": "Collins", "suffix": ""}, {"first": "K", "middle": [], "last": "Aubrey-Bassler", "suffix": ""}, {"first": "P", "middle": [], "last": "Duke", "suffix": ""}, {"first": "M", "middle": [], "last": "Mahdavian", "suffix": ""}, {"first": "S", "middle": [], "last": "Asghari", "suffix": ""}], "year": 2017, "venue": "Biomed. Inform. Insights", "link": "40086486"}, "BIBREF33": {"title": "High cholesterol levels are associated with improved long-term survival after acute ischemic stroke", "authors": [{"first": "I", "middle": [], "last": "Markaki", "suffix": ""}, {"first": "U", "middle": [], "last": "Nilsson", "suffix": ""}, {"first": "K", "middle": [], "last": "Kostulas", "suffix": ""}, {"first": "C", "middle": [], "last": "Sjostrand", "suffix": ""}], "year": 2014, "venue": "J. Stroke Cerebrovasc. Dis", "link": "22361834"}, "BIBREF34": {"title": "Low cholesterol, statins and outcomes in patients with first-ever acute ischemic stroke", "authors": [{"first": "S", "middle": [], "last": "Koton", "suffix": ""}, {"first": "N", "middle": [], "last": "Molshatzki", "suffix": ""}, {"first": "N", "middle": ["M"], "last": "Bornstein", "suffix": ""}, {"first": "D", "middle": [], "last": "Tanne", "suffix": ""}], "year": 2012, "venue": "Cerebrovasc. Dis", "link": "2892146"}, "BIBREF35": {"title": "Validation of the All Patient Refined Diagnosis Related Group (APR-DRG) Risk of Mortality and Severity of Illness Modifiers as a Measure of Perioperative Risk", "authors": [{"first": "P", "middle": ["J"], "last": "Mccormick", "suffix": ""}, {"first": "H", "middle": ["M"], "last": "Lin", "suffix": ""}, {"first": "S", "middle": ["G"], "last": "Deiner", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Levin", "suffix": ""}], "year": 2018, "venue": "J. Med. Syst", "link": "4441787"}, "BIBREF36": {"title": "Use of the All Patient Refined-Diagnosis Related Group (APR-DRG) Risk of Mortality Score as a Severity Adjustor in the Medical ICU", "authors": [{"first": "D", "middle": [], "last": "Baram", "suffix": ""}, {"first": "F", "middle": [], "last": "Daroowalla", "suffix": ""}, {"first": "R", "middle": [], "last": "Garcia", "suffix": ""}, {"first": "G", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "J", "middle": ["J"], "last": "Chen", "suffix": ""}, {"first": "E", "middle": [], "last": "Healy", "suffix": ""}, {"first": "S", "middle": ["A"], "last": "Riaz", "suffix": ""}, {"first": "P", "middle": [], "last": "Richman", "suffix": ""}], "year": 2008, "venue": "Clin. Med. Circ. Respir. Pul. Med", "link": "6659611"}, "BIBREF37": {"title": "This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license", "authors": [], "year": "", "venue": "\u00a9 2019 by the authors. Licensee MDPI", "link": null}}, "ref_entries": {"FIGREF0": {"text": "Relationship of LDs with AIS amongst year 2014 hospitalizations; (2) Relationship of LDs with post-AIS outcomes and complications amongst AIS hospitalizations from year 2003-2014; Model 1: All cause in hospital mortality; Model 2: Discharge disposition (home vs. non-home); Model 3: APR-DRG loss of function (major/severe vs. minor/moderate); Model 4: APR-DRG risk of death (major/severe likelihood vs. minor/moderate likelihood); Model 5: Post-AIS early epilepsy; Model 6: Stroke Associated Pneumonia (SAP); Model 7: Upper gastro-intestinal bleeding (UGIB); Model 8: Hemorrhagic transformation (HT).", "type": "figure"}, "FIGREF1": {"text": "Discharge disposition (home vs. non-home); Model 3: APR-DRG loss of function (major/severe vs. minor/moderate); Model 4: APR-DRG risk of death (major/severe likelihood vs. minor/moderate likelihood); Model 5: Post-AIS early epilepsy; Model 6: Stroke Associated Pneumonia (SAP); Model 7: Upper gastro-intestinal bleeding (UGIB); Model 8: Hemorrhagic transformation (HT).", "type": "figure"}, "FIGREF2": {"text": "Figure 1. Flowchart detailing cohort selection and analysis modeling.", "type": "figure"}, "FIGREF3": {"text": "Figure 1. Flowchart detailing cohort selection and analysis modeling.", "type": "figure"}, "FIGREF4": {"text": "Figure 2. Prevalence trend of lipid disorders.", "type": "figure"}, "FIGREF5": {"text": "Figure 2. Prevalence trend of lipid disorders.", "type": "figure"}, "FIGREF6": {"text": "APR-DRG loss of function (major/severe vs. minor/moderate)APR-DRG risk of death (major/severe likelihood vs. minor/moderate likelihood)", "type": "figure"}, "FIGREF7": {"text": "LDs were associated with lower adjusted odds of post stroke early epilepsy (aOR:0.89, 95% CI: 0.8-0.86, p < 0.0001), SAP (aOR: 0.75, 95% CI: 0.71-0.80, p < 0.0001), upper GI bleeding (aOR:0.85, 95% CI: 0.73-0.99, p < 0.0001) and hemorrhagic transformation (aOR: 0.82, 95% CI: 0.75-0.89, p < 0.0001) in comparison to patients without LDs (Models 5-8).", "type": "figure"}, "FIGREF8": {"text": ": Deyo's modification of Charlson's co-morbidity index (CCI). Author Contributions: For conceptualization, U.P.; methodology, U.P., M.S.D. (Mandip S. Dhamoon); software, U.P., P.M.; validation, M.D.; formal analysis, U.P.; investigation, U.P., P.M.; resources, M.S.D. (Mandip S. Dhamoon); data curation, U.P., M.D.; writing-original draft preparation, U.P., M.S.D. (Matthew S. DeMasi), M.D.; writing-review and editing, A.L., V.B.J., M.S.D. (Mandip S. Dhamoon); visualization, U.P., P.M.; supervision, A.L., V.B.J.; project administration, P.M.; funding acquisition, none.", "type": "figure"}, "TABREF0": {"text": "Univariate associations of acute ischemic stroke (AIS) with lipid disorders (LDs) in the year 2014.", "type": "table"}, "TABREF1": {"text": "Multivariate logistic regression analysis of predictors of AIS and associations with LDs among year 2014 hospitalizations.", "type": "table"}, "TABREF2": {"text": "Characteristics of patients with lipid disorders (LDs) in AIS population from January 2003- December 2014.", "type": "table"}, "TABREF3": {"text": "Characteristics of patients with lipid disorders (LDs) in AIS population from January 2003- December 2014.", "type": "table"}, "TABREF4": {"text": "Cont.", "type": "table"}, "TABREF5": {"text": "Univariate analysis of outcomes of patients with lipid disorders (LDs) among AIS admissions from January 2003-December 2014.", "type": "table"}}}
{"paper_id": "199664249", "_pdf_hash": "dc3d94db845a48d208f19e502c2cce1f1204e487", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Language and agency. Review of Anthropology 30", "authors": [{"first": "Laura", "middle": ["M"], "last": "Ahearn", "suffix": ""}], "year": 2001, "venue": "", "link": null}, "BIBREF1": {"title": "you HAVE NO IDEA WHAT YOU ARE TALKING ABOUT!\" From e-disagreement to e-impoliteness in two online fora", "authors": [{"first": "Jo &amp; Theodora", "middle": [], "last": "Angouri", "suffix": ""}, {"first": "", "middle": [], "last": "Tseliga", "suffix": ""}], "year": 2010, "venue": "Journal of Politeness Research", "link": "144266359"}, "BIBREF2": {"title": "Who said what: Subject positions, rhetorical strategies and good faith", "authors": [{"first": "Corey &amp; Valeri", "middle": [], "last": "Anton", "suffix": ""}, {"first": "", "middle": [], "last": "Peterson", "suffix": ""}], "year": 2003, "venue": "Communication Studies", "link": "144568684"}, "BIBREF3": {"title": "An alternative model and ideology on communication for an alternative to politeness theory", "authors": [{"first": "Robert", "middle": ["B"], "last": "Arundale", "suffix": ""}], "year": 1999, "venue": "Pragmatics", "link": "73711732"}, "BIBREF4": {"title": "Face as relational and interactional: A communication framework for research on face, facework and politeness", "authors": [{"first": "Robert", "middle": ["B"], "last": "Arundale", "suffix": ""}], "year": 2006, "venue": "Journal of Politeness Research", "link": "143462682"}, "BIBREF5": {"title": "Face as emergent in interpersonal communication: An alternative to Goffman", "authors": [{"first": "Robert", "middle": ["B"], "last": "Arundale", "suffix": ""}], "year": 2009, "venue": "Face, communication and social interaction", "link": "151815449"}, "BIBREF6": {"title": "Constituting face in conversation: Face, facework and interactional achievement", "authors": [{"first": "Robert", "middle": ["B"], "last": "Arundale", "suffix": ""}], "year": 2010, "venue": "Journal of Pragmatics", "link": "144312033"}, "BIBREF7": {"title": "Narrative discourse and identities", "authors": [{"first": "Michael", "middle": [], "last": "Bamberg", "suffix": ""}], "year": 2005, "venue": "Narratology beyond literary criticism", "link": "5627132"}, "BIBREF8": {"title": "Face and politeness: New (insights) for old (concepts)", "authors": [{"first": "Francesca", "middle": [], "last": "Bargiela-Chiappini", "suffix": ""}], "year": 2003, "venue": "Journal of Pragmatics", "link": "92409411"}, "BIBREF9": {"title": "2009. Face, communication and social interaction", "authors": [{"first": "", "middle": [], "last": "Bargliela-Chiappini", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF10": {"title": "Cultural studies and discourse analysis. A dialogue on language and identity", "authors": [{"first": "Chris &amp; Dariusz", "middle": [], "last": "Barker", "suffix": ""}, {"first": "", "middle": [], "last": "Galasinski", "suffix": ""}], "year": 2001, "venue": "", "link": "148718650"}, "BIBREF11": {"title": "Discourse and identity", "authors": [{"first": "Bethan &amp; Elizabeth", "middle": [], "last": "Benwell", "suffix": ""}, {"first": "", "middle": [], "last": "Stokoe", "suffix": ""}], "year": 2006, "venue": "", "link": "142802209"}, "BIBREF12": {"title": "Sociolinguistic scales", "authors": [{"first": "", "middle": [], "last": "Blommaert", "suffix": ""}], "year": 2007, "venue": "Intercultural Pragmatics", "link": "201097173"}, "BIBREF13": {"title": "Grassroots literacy: Writing, identity and voice in central Africa", "authors": [{"first": "", "middle": [], "last": "Blommaert", "suffix": ""}], "year": 2008, "venue": "", "link": "145575214"}, "BIBREF14": {"title": "The sociolinguistics of globalization", "authors": [{"first": "", "middle": [], "last": "Blommaert", "suffix": ""}], "year": 2010, "venue": "", "link": "143640070"}, "BIBREF15": {"title": "The logic of practice", "authors": [{"first": "Pierre", "middle": [], "last": "Bourdieu", "suffix": ""}], "year": 1990, "venue": "", "link": "142794685"}, "BIBREF16": {"title": "Language and symbolic power", "authors": [{"first": "Pierre", "middle": [], "last": "Bourdieu", "suffix": ""}], "year": 1991, "venue": "", "link": "146470222"}, "BIBREF17": {"title": "Impoliteness in interaction", "authors": [{"first": "Derek", "middle": [], "last": "Bousfield", "suffix": ""}], "year": 2008, "venue": "", "link": "61140487"}, "BIBREF18": {"title": "Pragm\u00e1tica sociocultural y componentes de face. Oralia", "authors": [{"first": "Diana", "middle": [], "last": "Bravo", "suffix": ""}], "year": 1999, "venue": "", "link": null}, "BIBREF19": {"title": "Universals in language usage: Politeness phenomena", "authors": [{"first": "Penelope", "middle": ["&amp;"], "last": "Brown", "suffix": ""}, {"first": "C", "middle": [], "last": "Stephen", "suffix": ""}, {"first": "", "middle": [], "last": "Levinson", "suffix": ""}], "year": 1978, "venue": "Questions and politeness. Strategies in social interaction", "link": "153411858"}, "BIBREF20": {"title": "Politeness: Some universals of language usage", "authors": [{"first": "Penelope &amp; Steven", "middle": [], "last": "Brown", "suffix": ""}, {"first": "", "middle": [], "last": "Levinson", "suffix": ""}], "year": 1987, "venue": "", "link": null}, "BIBREF21": {"title": "Identity and interaction: a socio-cultural linguistic approach", "authors": [{"first": "Mary &amp; Kira", "middle": [], "last": "Bucholtz", "suffix": ""}, {"first": "", "middle": [], "last": "Hall", "suffix": ""}], "year": 2005, "venue": "Discourse Studies", "link": "27020925"}, "BIBREF22": {"title": "Finding identity. Theory and data. Multilingua 27", "authors": [{"first": "Mary &amp; Kira", "middle": [], "last": "Bucholtz", "suffix": ""}, {"first": "", "middle": [], "last": "Hall", "suffix": ""}], "year": 2008, "venue": "", "link": null}, "BIBREF23": {"title": "Identity theory", "authors": [{"first": "Peter", "middle": ["J"], "last": "Burke", "suffix": ""}, {"first": "E", "middle": [], "last": "Jan", "suffix": ""}, {"first": "", "middle": [], "last": "Stets", "suffix": ""}], "year": 2009, "venue": "", "link": null}, "BIBREF24": {"title": "Gender Trouble: Feminism and the subversion of identity", "authors": [{"first": "Judith", "middle": [], "last": "Butler", "suffix": ""}], "year": 1990, "venue": "", "link": "147370391"}, "BIBREF25": {"title": "Theoretical continuities in Goffman's work", "authors": [{"first": "Randall", "middle": [], "last": "Collins", "suffix": ""}], "year": 1988, "venue": "", "link": null}, "BIBREF26": {"title": "Reflections on impoliteness, relational work and power", "authors": [{"first": "Jonathan", "middle": [], "last": "Culpeper", "suffix": ""}], "year": 2008, "venue": "Impoliteness and power: Studies on its interplay with power in theory and practice", "link": "59631588"}, "BIBREF27": {"title": "The reluctant self-presentation of Erving Goffman. Times Higher Education Supplement", "authors": [{"first": "Peter", "middle": [], "last": "David", "suffix": ""}], "year": 1980, "venue": "", "link": null}, "BIBREF28": {"title": "2006. Discourse and identity", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF29": {"title": "A critique of politeness theories", "authors": [{"first": "Gino", "middle": [], "last": "Eelen", "suffix": ""}], "year": 1995, "venue": "", "link": "141944506"}, "BIBREF30": {"title": "Analysing discourse: Textual analysis for social research", "authors": [{"first": "Norman", "middle": [], "last": "Fairclough", "suffix": ""}], "year": 2003, "venue": "", "link": "142818871"}, "BIBREF31": {"title": "The Blackwell companion to major social theorists", "authors": [{"first": "Gary", "middle": ["A"], "last": "Fine", "suffix": ""}, {"first": "", "middle": [], "last": "Philip Manning", "suffix": ""}], "year": 1991, "venue": "", "link": "160855460"}, "BIBREF32": {"title": "The archeology of knowledge", "authors": [{"first": "Michel", "middle": [], "last": "Foucault", "suffix": ""}], "year": 1972, "venue": "", "link": null}, "BIBREF33": {"title": "Impoliteness and identity in the American news media: The \"Culture Wars", "authors": [{"first": "Garc\u00e9s-Conejos", "middle": [], "last": "Blitvich", "suffix": ""}, {"first": "Pilar", "middle": [], "last": "", "suffix": ""}], "year": 2009, "venue": "Journal of Politeness Research", "link": "144600638"}, "BIBREF34": {"title": "A genre approach to the study of im-politeness", "authors": [{"first": "Garc\u00e9s-Conejos", "middle": [], "last": "Blitvich", "suffix": ""}, {"first": "Pilar", "middle": [], "last": "", "suffix": ""}], "year": 2010, "venue": "International Review of Pragmatics", "link": "144947731"}, "BIBREF35": {"title": "The status quo and quo-vadis of impoliteness research", "authors": [{"first": "Garc\u00e9s-Conejos", "middle": [], "last": "Blitvich", "suffix": ""}, {"first": "Pilar", "middle": [], "last": "", "suffix": ""}], "year": 2010, "venue": "Intercultural Pragmatics", "link": null}, "BIBREF37": {"title": "El modelo del g\u00e9nero y la des/cortes\u00eda clasificatoria en las evaluaciones de S\u00e1lvame por parte de la audiencia", "authors": [{"first": "Garc\u00e9s-Conejos", "middle": [], "last": "Blitvich", "suffix": ""}, {"first": "Pilar", "middle": [], "last": "", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF38": {"title": "Politics, 'lies' and YouTube: A genre approach to assessments of im/politeness on Obama's 9/9/2009 presidential address", "authors": [{"first": "Garc\u00e9s-Conejos", "middle": [], "last": "Blitvich", "suffix": ""}, {"first": "Pilar", "middle": [], "last": "", "suffix": ""}], "year": "", "venue": "New perspectives on (im)politeness and interpersonal communication", "link": "159000514"}, "BIBREF39": {"title": "A genre approach to impoliteness in a Spanish television talk show: Evidence from corpus-based analysis, questionnaires and focus groups", "authors": [{"first": "Garc\u00e9s-Conejos", "middle": [], "last": "Blitvich", "suffix": ""}, {"first": "Pilar", "middle": [], "last": "", "suffix": ""}, {"first": "Nuria", "middle": [], "last": "Lorenzo-Dus &amp; Patricia Bou-Franch", "suffix": ""}], "year": 2010, "venue": "Intercultural Pragmatics", "link": null}, "BIBREF40": {"title": "An introduction to discourse analysis theory and method. 2 nd edn", "authors": [{"first": "James", "middle": ["P"], "last": "Gee", "suffix": ""}], "year": 2005, "venue": "", "link": null}, "BIBREF41": {"title": "Small stories, interaction and identities", "authors": [{"first": "Alexandra", "middle": [], "last": "Georgakopoulou", "suffix": ""}], "year": 2007, "venue": "", "link": "141889410"}, "BIBREF42": {"title": "The constitution of society", "authors": [{"first": "Anthony", "middle": [], "last": "Giddens", "suffix": ""}], "year": 1984, "venue": "", "link": null}, "BIBREF43": {"title": "The presentation of self in everyday life", "authors": [{"first": "Erving", "middle": [], "last": "Goffman", "suffix": ""}], "year": 1959, "venue": "", "link": "27526144"}, "BIBREF44": {"title": "Stigma. Notes on the management of the spoiled identity", "authors": [{"first": "Erving", "middle": [], "last": "Goffman", "suffix": ""}], "year": 1963, "venue": "", "link": "143845069"}, "BIBREF45": {"title": "Interaction ritual. Essays on face-to-face behaviour", "authors": [{"first": "Erving", "middle": [], "last": "Goffman", "suffix": ""}], "year": 1955, "venue": "", "link": "145051244"}, "BIBREF46": {"title": "Forms of talk. Philadelphia, Penn: University of Pennsylvania Press. Goffman, Erving. 1981b. A reply to Denzin and Keller", "authors": [{"first": "Erving", "middle": [], "last": "Goffman", "suffix": ""}], "year": 1981, "venue": "Contemporary Sociology", "link": null}, "BIBREF47": {"title": "The interaction order", "authors": [{"first": "Erving", "middle": [], "last": "Goffman", "suffix": ""}], "year": 1982, "venue": "American Sociological Review", "link": null}, "BIBREF48": {"title": "Politeness Phenomena in modern Chinese", "authors": [{"first": "Yueguo", "middle": [], "last": "Gu", "suffix": ""}], "year": 1990, "venue": "Journal of Pragmatics", "link": "145205604"}, "BIBREF49": {"title": "Between Michel Foucault and Erving Goffman: Between discourse in the abstract and face-to-face interaction", "authors": [{"first": "Ian", "middle": [], "last": "Hacking", "suffix": ""}], "year": 2004, "venue": "Economy and Society", "link": "145153938"}, "BIBREF50": {"title": "Pierre Bourdieu and the practices of language", "authors": [{"first": "William", "middle": [], "last": "Hanks", "suffix": ""}], "year": 2005, "venue": "Annual Review of Anthropology", "link": "145071619"}, "BIBREF51": {"title": "Anticipated versus inferred politeness", "authors": [{"first": "Michael", "middle": [], "last": "Haugh", "suffix": ""}], "year": 2003, "venue": "Multilingua", "link": "5946658"}, "BIBREF52": {"title": "The discursive challenge to politeness research: An interactional alternative", "authors": [{"first": "Michael", "middle": [], "last": "Haugh", "suffix": ""}], "year": 2007, "venue": "Journal of Politeness Research", "link": "144051780"}, "BIBREF53": {"title": "Face, Communication and Social Interaction. 1-30", "authors": [{"first": "Michael", "middle": [], "last": "Haugh", "suffix": ""}], "year": 2009, "venue": "", "link": "142982274"}, "BIBREF54": {"title": "Jocular mockery, (dis)affiliation and face", "authors": [{"first": "Michael", "middle": [], "last": "Haugh", "suffix": ""}], "year": 2010, "venue": "Journal of Pragmatics", "link": "39543454"}, "BIBREF55": {"title": "When is an email really offensive?: Argumentativity and variability in evaluations of impoliteness", "authors": [{"first": "Michael", "middle": [], "last": "Haugh", "suffix": ""}], "year": 2010, "venue": "Journal of Politeness Research", "link": "144195124"}, "BIBREF56": {"title": "The meta-pragmatics of im/politeness", "authors": [{"first": "Michael", "middle": [], "last": "Haugh", "suffix": ""}], "year": 2010, "venue": "5 th International Symposium on Politeness. Basel", "link": null}, "BIBREF57": {"title": "Editorial. Face in interaction", "authors": [{"first": "Michael &amp; Francesca", "middle": [], "last": "Haugh", "suffix": ""}, {"first": "", "middle": [], "last": "Bargiela-Chiappini", "suffix": ""}], "year": 2010, "venue": "Journal of Pragmatics", "link": null}, "BIBREF58": {"title": "History in person", "authors": [], "year": 2001, "venue": "", "link": null}, "BIBREF59": {"title": "Impoliteness and ethnicity: M\u0101ori and P\u0101keh\u0101 discourses in New Zealand workplaces", "authors": [{"first": "Janet", "middle": [], "last": "Holmes", "suffix": ""}, {"first": "Meredith", "middle": [], "last": "Marra &amp; Stephanie", "suffix": ""}, {"first": "", "middle": [], "last": "Schnurr", "suffix": ""}], "year": 2008, "venue": "Journal of Politeness Research", "link": "144915081"}, "BIBREF60": {"title": "Formal forms and discernment: two neglected aspects of linguistic politeness", "authors": [{"first": "Sachiko", "middle": [], "last": "Ide", "suffix": ""}], "year": 1989, "venue": "Multilingua", "link": null}, "BIBREF61": {"title": "Language and identity: National, Ethnic, Religious", "authors": [{"first": "John", "middle": [], "last": "Joseph", "suffix": ""}], "year": 2004, "venue": "", "link": "152161030"}, "BIBREF62": {"title": "Discursive approaches to politeness", "authors": [{"first": "Daniel", "middle": [], "last": "K\u00e1d\u00e1r", "suffix": ""}], "year": 2011, "venue": "", "link": null}, "BIBREF63": {"title": "Introduction: Politeness research in and across cultures", "authors": [{"first": "Daniel", "middle": [], "last": "K\u00e1d\u00e1r", "suffix": ""}, {"first": "Francesca", "middle": [], "last": "Bargliela-Chiappini", "suffix": ""}], "year": 2011, "venue": "Politeness across cultures", "link": "169783987"}, "BIBREF64": {"title": "Aggression and perceived national face threats in Mainland Chinese and Taiwanese CMC discussion boards", "authors": [], "year": "", "venue": "", "link": "54901047"}, "BIBREF65": {"title": "Understanding professional practice: A synoptic framework", "authors": [{"first": "Stephen", "middle": [], "last": "Kemmis", "suffix": ""}], "year": 2009, "venue": "", "link": "159339283"}, "BIBREF66": {"title": "Disagreeing to agree: Conflict (im)politeness and identity in a computer mediated community", "authors": [{"first": "Sage", "middle": [], "last": "Lambert-Graham", "suffix": ""}], "year": 2007, "venue": "Journal of Pragmatics", "link": "144836610"}, "BIBREF67": {"title": "Handbooks of Applied Linguistics. Issue 2: Interpersonal Communication. 509-540", "authors": [{"first": "Miriam", "middle": [], "last": "Locher", "suffix": ""}], "year": 2008, "venue": "", "link": null}, "BIBREF68": {"title": "Relational work: At the intersection of cognition, interaction and emotion", "authors": [{"first": "Miriam", "middle": ["A"], "last": "Locher", "suffix": ""}, {"first": "Andreas", "middle": [], "last": "Langlotz", "suffix": ""}], "year": 2008, "venue": "Bulletin Suisse de Linguistique Appliqu\u00e9e", "link": null}, "BIBREF69": {"title": "Politeness theory and relational work", "authors": [{"first": "Miriam", "middle": ["A"], "last": "Locher", "suffix": ""}, {"first": "J", "middle": [], "last": "Richard", "suffix": ""}, {"first": "", "middle": [], "last": "Watts", "suffix": ""}], "year": 2005, "venue": "Journal of Politeness Research", "link": "40642079"}, "BIBREF70": {"title": "Relational work and impoliteness: Negotiating norms of linguistic behaviour", "authors": [{"first": "Miriam", "middle": ["A"], "last": "Locher", "suffix": ""}, {"first": "Richard", "middle": [], "last": "Watts", "suffix": ""}], "year": 2008, "venue": "Impoliteness in Language. Studies on its Interplay with Power in Theory and Practice", "link": "147356597"}, "BIBREF71": {"title": "Erving Goffman (1922-1983)", "authors": [{"first": "Philip", "middle": [], "last": "Manning", "suffix": ""}], "year": 2004, "venue": "", "link": null}, "BIBREF72": {"title": "Continuities in Goffman. The interaction order", "authors": [{"first": "Philip", "middle": [], "last": "Manning", "suffix": ""}], "year": 2010, "venue": "The contemporary Goffman", "link": null}, "BIBREF73": {"title": "Beyond politeness theory: \"Face\" revisited and renewed", "authors": [{"first": "Luming", "middle": ["R"], "last": "Mao", "suffix": ""}], "year": 1994, "venue": "Journal of Pragmatics", "link": "144317106"}, "BIBREF74": {"title": "Reexamination of the universality of face", "authors": [{"first": "Yoshiko", "middle": [], "last": "Matusmoto", "suffix": ""}], "year": 1988, "venue": "Journal of Pragmatics", "link": null}, "BIBREF75": {"title": "Gender and politeness", "authors": [{"first": "Sara", "middle": [], "last": "Mills", "suffix": ""}], "year": 2003, "venue": "", "link": "146164843"}, "BIBREF76": {"title": "Discursive approaches to politeness and impoliteness", "authors": [{"first": "Sara", "middle": [], "last": "Mills", "suffix": ""}], "year": 2011, "venue": "", "link": "155503266"}, "BIBREF77": {"title": "Politeness and culture", "authors": [{"first": "Sara &amp; Daniel", "middle": [], "last": "Mills", "suffix": ""}, {"first": "", "middle": [], "last": "K\u00e1d\u00e1r", "suffix": ""}], "year": 2011, "venue": "Politeness in East Asia. 21-43", "link": null}, "BIBREF79": {"title": "Impoliteness and power: Studies on its interplay with power in theory and practice. 231-251. Berlin and New York: Mouton de Gruyter Nwoye, Onuigbo. 1992. Linguistics politeness and socio-cultural variations of the notion of face", "authors": [{"first": "Louise", "middle": [], "last": "Mullany", "suffix": ""}], "year": 2008, "venue": "Journal of Pragmatics", "link": null}, "BIBREF80": {"title": "About face. A defense and elaboration of universal dualism", "authors": [{"first": "Jim", "middle": [], "last": "O&apos;driscoll", "suffix": ""}], "year": 1996, "venue": "Journal of Pragmatics", "link": null}, "BIBREF81": {"title": "Some issues with the concept of face: When, what, how and how much?", "authors": [{"first": "Jim", "middle": [], "last": "O&apos;driscoll", "suffix": ""}], "year": 2011, "venue": "Politeness across cultures", "link": "142652091"}, "BIBREF82": {"title": "Language as local practice", "authors": [{"first": "Alastair", "middle": [], "last": "Pennycook", "suffix": ""}], "year": 2010, "venue": "", "link": null}, "BIBREF83": {"title": "Virtual community and politeness: The use of female markers of identity and solidarity in a transvestites' website", "authors": [{"first": "Gaelle", "middle": [], "last": "Planchenault", "suffix": ""}], "year": 2010, "venue": "Journal of Politeness Research", "link": "143032020"}, "BIBREF84": {"title": "Introduction: Theorizing media and practice", "authors": [{"first": "John", "middle": [], "last": "Postill", "suffix": ""}], "year": 2010, "venue": "", "link": null}, "BIBREF85": {"title": "The interaction order sui generis: Goffman's contribution to social theory", "authors": [{"first": "Anne", "middle": ["W"], "last": "Rawls", "suffix": ""}], "year": 1987, "venue": "Sociological Theory", "link": "147049788"}, "BIBREF86": {"title": "Orders of interaction and intelligibility. Intersections between Goffman and Garfinkel by way of Durkheim", "authors": [{"first": "Anne", "middle": ["W"], "last": "Rawls", "suffix": ""}], "year": 2003, "venue": "Goffman's legacy", "link": null}, "BIBREF87": {"title": "Toward a theory of social practice", "authors": [{"first": "Andreas", "middle": [], "last": "Reckwitz", "suffix": ""}], "year": 2002, "venue": "European Journal of Social Theory", "link": null}, "BIBREF88": {"title": "Social practices. A Wittgensteinian approach to human activity and the social", "authors": [{"first": "Theodore", "middle": [], "last": "Schatzki", "suffix": ""}], "year": 1996, "venue": "", "link": "142963161"}, "BIBREF89": {"title": "The practice turn in contemporary theory", "authors": [{"first": "Theodore", "middle": [], "last": "Schatzki", "suffix": ""}], "year": 2001, "venue": "", "link": null}, "BIBREF90": {"title": "Being (im)polite in New Zealand workplaces: M\u0101ori and P\u0101keh\u0101 leaders", "authors": [{"first": "Stephanie", "middle": [], "last": "Schnurr", "suffix": ""}, {"first": "Meredith", "middle": [], "last": "Marra", "suffix": ""}, {"first": "Janet", "middle": [], "last": "Holmes", "suffix": ""}], "year": 2007, "venue": "Journal of Pragmatics", "link": "143821098"}, "BIBREF91": {"title": "Politeness phenomena and England and Greece: A cross-cultural perspective", "authors": [{"first": "Maria", "middle": [], "last": "Sifianou", "suffix": ""}], "year": 1992, "venue": "", "link": null}, "BIBREF92": {"title": "On the concept of face and politeness", "authors": [{"first": "Maria", "middle": [], "last": "Sifianou", "suffix": ""}], "year": 2011, "venue": "Politeness across cultures", "link": "157036657"}, "BIBREF93": {"title": "Erving Goffman. London: Routledge", "authors": [{"first": "Greg", "middle": [], "last": "Smith", "suffix": ""}], "year": 2006, "venue": "", "link": null}, "BIBREF94": {"title": "Im)Politeness, face and perceptions of rapport: Unpackaging their bases and interrelationships", "authors": [{"first": "Helen", "middle": [], "last": "Spencer-Oatey", "suffix": ""}], "year": 2005, "venue": "Journal of Politeness Research", "link": "144581286"}, "BIBREF95": {"title": "Theories of identity and the analysis of face", "authors": [{"first": "Helen", "middle": [], "last": "Spencer-Oatey", "suffix": ""}], "year": 2007, "venue": "Journal of Pragmatics", "link": "146572055"}, "BIBREF96": {"title": "Cultural variations in the concept of 'face", "authors": [{"first": "Ivo", "middle": [], "last": "Strecker", "suffix": ""}], "year": 1993, "venue": "Multilingua", "link": null}, "BIBREF97": {"title": "An argument for a frame-based approach to politeness: Evidence from the use of the imperative in Cypriot Greek", "authors": [{"first": "Marina", "middle": [], "last": "Terkourafi", "suffix": ""}], "year": 2005, "venue": "", "link": null}, "BIBREF98": {"title": "Beyond the micro-level in politeness research", "authors": [{"first": "Marina", "middle": [], "last": "Terkourafi", "suffix": ""}], "year": 2005, "venue": "Journal of Politeness Research", "link": "17191513"}, "BIBREF99": {"title": "Toward a unified theory of politeness, impoliteness, and rudeness", "authors": [{"first": "Marina", "middle": [], "last": "Terkourafi", "suffix": ""}], "year": 2008, "venue": "Impoliteness in language: Studies on its interplay with power in theory and practice", "link": null}, "BIBREF100": {"title": "Facework competence in intercultural conflict: An updated face-negotiation theory", "authors": [{"first": "Stella &amp; Atsuko", "middle": [], "last": "Ting-Toomey", "suffix": ""}, {"first": "", "middle": [], "last": "Kurogi", "suffix": ""}], "year": 1998, "venue": "International Journal of Intercultural Relations", "link": "144813146"}, "BIBREF101": {"title": "Knowledge as shared procedures", "authors": [{"first": "Stephen", "middle": [], "last": "Toulmin", "suffix": ""}], "year": 1999, "venue": "Perspectives on action theory", "link": "169577285"}, "BIBREF102": {"title": "Identity and impoliteness in computer mediated reader responses", "authors": [{"first": "Shiv", "middle": ["R"], "last": "Upadhyay", "suffix": ""}], "year": 2010, "venue": "Journal of Politeness Research", "link": "143975130"}, "BIBREF103": {"title": "Discourse and practice. New tools for critical discourse analysis", "authors": [{"first": "Theo", "middle": [], "last": "Van Leeuwen", "suffix": ""}], "year": 2008, "venue": "", "link": "61764403"}, "BIBREF104": {"title": "Politeness", "authors": [{"first": "Richard", "middle": ["J"], "last": "Watts", "suffix": ""}], "year": 2003, "venue": "", "link": null}, "BIBREF105": {"title": "Rudeness, conceptual blending theory and relational work", "authors": [{"first": "Richards", "middle": ["J"], "last": "Watts", "suffix": ""}], "year": 2008, "venue": "Journal of Politeness Research", "link": "145155092"}, "BIBREF106": {"title": "A step too far: Discursive psychology, linguistic ethnography and questions of identity", "authors": [{"first": "Margaret", "middle": [], "last": "Wetherell", "suffix": ""}], "year": 2007, "venue": "Journal of Sociolinguistics", "link": "142967587"}, "BIBREF107": {"title": "Different cultures, different languages, different speech acts: Polish vs", "authors": [{"first": "Anna", "middle": [], "last": "Wierzbicka", "suffix": ""}], "year": 1985, "venue": "English. Journal of Pragmatics", "link": "142123775"}, "BIBREF108": {"title": "Towards a deeper understanding of framing, footing and alignment. Teachers College, Columbia University", "authors": [{"first": "Linda", "middle": [], "last": "Wine", "suffix": ""}], "year": 2008, "venue": "Working Papers in TESOL and Applied Linguistics", "link": null}}, "ref_entries": {}}
{"paper_id": "199664457", "_pdf_hash": "a7e9e66061ecbb9f8e502a0c3e422c8cdc9e0131", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Even their nomadic quality mirrors, albeit for distinct reasons, that of the tribes. Cells of the network are akin to, and often called, families. Over time, it became increasingly clear-often from intercepted communications or the accounts of insurgents we had captured-that our enemy was a constellation of fighters organized not by rank but on the basis of relationships and acquaintances, reputation and fame. Who became radicalized in the prisons of Egypt? Who trained together in the pre-9/11 camps in Afghanistan? Who is married to whose sister? Who is making a name for himself", "authors": [{"first": "A", "middle": [], "last": "Stanley", "suffix": ""}], "year": 2009, "venue": "", "link": null}, "BIBREF1": {"title": "The Role of Kinship in Indonesia's Jemaah Islamiya", "authors": [{"first": "See Noor Huda", "middle": [], "last": "Ismail", "suffix": ""}], "year": 2006, "venue": "Terrorism Monitor", "link": null}, "BIBREF2": {"title": "Demystifying Hawala: A Look into its Social Organization and Mechanics", "authors": [{"first": "See", "middle": [], "last": "Gamal Moursi", "suffix": ""}, {"first": "", "middle": [], "last": "Badr", "suffix": ""}], "year": 1978, "venue": "Journal of Scandinavian Studies in Criminology and Crime Prevention", "link": "145753289"}, "BIBREF3": {"title": "It Takes a Network: The New Frontline of Modern Warfare", "authors": [{"first": "A", "middle": [], "last": "Stanley", "suffix": ""}], "year": 2011, "venue": "Foreign Policy", "link": null}, "BIBREF4": {"title": "Fixing Intel: A Blueprint for Making Intelligence Relevant in Afghanistan", "authors": [{"first": "Michael", "middle": ["T"], "last": "See Also", "suffix": ""}, {"first": "Matt", "middle": [], "last": "Flynn", "suffix": ""}, {"first": "Paul", "middle": ["D"], "last": "Pottinger", "suffix": ""}, {"first": "", "middle": [], "last": "Batchelor", "suffix": ""}], "year": 2010, "venue": "", "link": "108197257"}, "BIBREF5": {"title": "Sayyid Qutb, Milestones", "authors": [], "year": 1990, "venue": "", "link": null}, "BIBREF6": {"title": "We are grateful to Didier Chaudet for his observations in this regard, from his research in Afghanistan", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF7": {"title": "Ayman Al Zawahiri, Osama bin Laden's deputy, asked the Yemeni tribes to protect al Qaeda operatives, just as tribes in Pakistan and Afghanistan had done: \"I call on the noble and defiant tribes of the Yemen and tell them: 'Don't be less than your brothers in the defiant Pashtun and Baluch tribes,' \" Mr. Zawahiri said in the recording. Marriages were highlighted", "authors": [{"first": "Charles", "middle": [], "last": "Levinson", "suffix": ""}, {"first": "Margaret", "middle": [], "last": "Coker", "suffix": ""}], "year": 2009, "venue": "Al Qaeda's Deep Tribal Ties Make Yemen a Terror Hub", "link": null}}, "ref_entries": {}}
{"paper_id": "199664595", "_pdf_hash": "261153d45e50844fdd385837ca16a5a1be10fd7d", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "A theoretical foundation for the gravity equation", "authors": [{"first": "J", "middle": [], "last": "Anderson", "suffix": ""}], "year": 1979, "venue": "American Economic Review", "link": "153073248"}, "BIBREF1": {"title": "Intellectual property rights and innovation in developing countries", "authors": [{"first": "Y", "middle": [], "last": "Chen", "suffix": ""}, {"first": "T", "middle": [], "last": "Puttitanun", "suffix": ""}], "year": 2005, "venue": "Journal of Development Economics", "link": "53371260"}, "BIBREF2": {"title": "Do patent rights regimes matter?", "authors": [{"first": "C", "middle": [], "last": "Co", "suffix": ""}], "year": 2004, "venue": "Review of International Economics", "link": "154819725"}, "BIBREF3": {"title": "Technology intensity of U.S. output and trade. Report of the Office of Trade and Investment Analysis", "authors": [{"first": "L", "middle": [], "last": "Davis", "suffix": ""}], "year": 1982, "venue": "", "link": null}, "BIBREF4": {"title": "Determinants of bilateral trade: Does gravity work in a neoclassical world? NBER Working Paper", "authors": [{"first": "A", "middle": [], "last": "Deardorff", "suffix": ""}], "year": 1995, "venue": "", "link": null}, "BIBREF5": {"title": "Patents, appropriate technology, and NorthSouth trade", "authors": [{"first": "I", "middle": [], "last": "Diwan", "suffix": ""}, {"first": "Rodrik", "middle": ["D"], "last": "", "suffix": ""}], "year": 1989, "venue": "", "link": null}, "BIBREF6": {"title": "Will the TRIPS agreement foster appropriate biotechnologies for developing countries", "authors": [{"first": "J", "middle": [], "last": "Gaisford", "suffix": ""}, {"first": "J", "middle": [], "last": "Hobbs", "suffix": ""}, {"first": "W", "middle": [], "last": "Kerr", "suffix": ""}], "year": 2007, "venue": "Journal of Agricultural Economics", "link": "154994111"}, "BIBREF7": {"title": "Do stronger patent rights raise high-tech exports to the developing world", "authors": [{"first": "O", "middle": [], "last": "Ivus", "suffix": ""}], "year": 2010, "venue": "Journal of International Economics", "link": "54958462"}, "BIBREF8": {"title": "Strategic sectors and international competition", "authors": [{"first": "P", "middle": [], "last": "Krugman", "suffix": ""}], "year": 1987, "venue": "", "link": null}, "BIBREF9": {"title": "Trade-related intellectual property rights: Issues and exploratory results", "authors": [{"first": "K", "middle": [], "last": "Maskus", "suffix": ""}, {"first": "Konan", "middle": ["D"], "last": "", "suffix": ""}], "year": 1994, "venue": "", "link": "151253144"}, "BIBREF10": {"title": "How trade related are intellectual property rights", "authors": [{"first": "K", "middle": [], "last": "Maskus", "suffix": ""}, {"first": "M", "middle": [], "last": "Penubarti", "suffix": ""}], "year": 1995, "venue": "Journal of International Economics", "link": "153846267"}, "BIBREF11": {"title": "International patent protection", "authors": [{"first": "W", "middle": ["G"], "last": "Park", "suffix": ""}], "year": 2008, "venue": "Research Policy", "link": null}, "BIBREF12": {"title": "How stronger protection of intellectual property rights affects international trade flows. The World Bank Policy Research Working Paper", "authors": [{"first": "C", "middle": [], "last": "Primo Braga", "suffix": ""}, {"first": "C", "middle": [], "last": "Fink", "suffix": ""}], "year": 1999, "venue": "", "link": null}, "BIBREF13": {"title": "How minilateral trading arrangements may affect the post-Uruguay Round world. The World Bank Policy Research Working Paper", "authors": [{"first": "C", "middle": [], "last": "Primo Braga", "suffix": ""}, {"first": "Yeats", "middle": [], "last": "", "suffix": ""}, {"first": "A", "middle": [], "last": "", "suffix": ""}], "year": 1992, "venue": "", "link": null}, "BIBREF16": {"title": "Are weak patent rights a barrier to", "authors": [{"first": "P", "middle": ["J"], "last": "Smith", "suffix": ""}], "year": 1999, "venue": "Journal of International Economics", "link": null}, "BIBREF17": {"title": "Patent rights and trade: analysis of biological products, medicinals and botanicals, and pharmaceuticals", "authors": [{"first": "P", "middle": ["J"], "last": "Smith", "suffix": ""}], "year": 2002, "venue": "American Journal of Agricultural Economics", "link": "154717580"}, "BIBREF18": {"title": "Intellectual property rights, globalization, and growth", "authors": [{"first": "D", "middle": [], "last": "Stryszowski", "suffix": ""}], "year": 2006, "venue": "Global Economy Journal", "link": "201124196"}, "BIBREF19": {"title": "Do stronger intellectual property rights induce more agricultural trade?: A dynamic panel data model applied to seed trade", "authors": [{"first": "C", "middle": ["H"], "last": "Yang", "suffix": ""}, {"first": "R", "middle": ["J"], "last": "Woo", "suffix": ""}], "year": 2006, "venue": "Agricultural Economics", "link": "154488500"}}, "ref_entries": {}}
{"paper_id": "199664911", "_pdf_hash": "aae87c1bf93dcb2ef5db0fd745609afc8b4f54c2", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Are Depreciations as Contractionary as Devaluations? A Comparison of Selected Emerging and Industrial Economies", "authors": [{"first": "S", "middle": [], "last": "Ahmed", "suffix": ""}, {"first": "C", "middle": ["J"], "last": "Gust", "suffix": ""}, {"first": "S", "middle": ["B"], "last": "Kamin", "suffix": ""}, {"first": "J", "middle": [], "last": "Huntley", "suffix": ""}], "year": 2002, "venue": "International Finance Discussion Papers", "link": null}, "BIBREF1": {"title": "Are Devaluations Contractionary in LDCs?", "authors": [{"first": "M", "middle": [], "last": "Bahmani-Oskooee", "suffix": ""}], "year": 1998, "venue": "Journal of Economic Development", "link": "55252910"}, "BIBREF2": {"title": "Are Devaluations Contractionary in Asia?", "authors": [{"first": "M", "middle": [], "last": "Bahmani-Oskooee", "suffix": ""}, {"first": "S", "middle": [], "last": "Chomsisengphet", "suffix": ""}, {"first": "M", "middle": [], "last": "Kandil", "suffix": ""}], "year": 2002, "venue": "Journal of Post Keynesian Economics", "link": "153016407"}, "BIBREF3": {"title": "Are Devaluations Expansionary or Contractionary: A Survey Article", "authors": [{"first": "M", "middle": [], "last": "Bahmani-Oskooee", "suffix": ""}, {"first": "I", "middle": [], "last": "Miteza", "suffix": ""}], "year": 2003, "venue": "Economic Issues", "link": null}, "BIBREF4": {"title": "Are Devaluations Contractionary? Evidence from Panel Cointegration", "authors": [{"first": "M", "middle": [], "last": "Bahmani-Oskooee", "suffix": ""}, {"first": "I", "middle": [], "last": "Miteza", "suffix": ""}], "year": 2006, "venue": "Economic Issues", "link": "54544168"}, "BIBREF5": {"title": "Are Devaluations Contractionary in Emerging Economies of Eastern Europe", "authors": [{"first": "M", "middle": [], "last": "Bahmani-Oskooee", "suffix": ""}, {"first": "A", "middle": ["M"], "last": "Kutan", "suffix": ""}], "year": 2008, "venue": "Economic Change and Restructuring", "link": "153678592"}, "BIBREF6": {"title": "The Ricardian Approach to Budget Deficits", "authors": [{"first": "R", "middle": ["J"], "last": "Barro", "suffix": ""}], "year": 1989, "venue": "Journal of Economic Perspectives", "link": "67844320"}, "BIBREF7": {"title": "Are Currency Devaluations Effective? A Panel Unit Root Test", "authors": [{"first": "W", "middle": ["L"], "last": "Chou", "suffix": ""}, {"first": "C", "middle": ["C"], "last": "Chao", "suffix": ""}], "year": 2001, "venue": "Economics Letters", "link": "153705122"}, "BIBREF8": {"title": "Currency Devaluation and Output Growth: New Evidence from Panel Data Analysis", "authors": [{"first": "D", "middle": ["K"], "last": "Christopoulos", "suffix": ""}], "year": 2004, "venue": "Applied Economics Letters", "link": "155085411"}, "BIBREF9": {"title": "Are Devaluations Contractionary?", "authors": [{"first": "S", "middle": [], "last": "Edwards", "suffix": ""}], "year": 1986, "venue": "The Review of Economics and Statistics", "link": "154445406"}, "BIBREF10": {"title": "Does Devaluation Improve the Current Account?", "authors": [{"first": "T", "middle": [], "last": "Gylfason", "suffix": ""}, {"first": "O", "middle": [], "last": "Risager", "suffix": ""}], "year": 1984, "venue": "European Economic Review", "link": "155014266"}, "BIBREF11": {"title": "Does Devaluation Cause Stagflation?", "authors": [{"first": "T", "middle": [], "last": "Gylfason", "suffix": ""}, {"first": "M", "middle": [], "last": "Schmid", "suffix": ""}], "year": 1983, "venue": "Canadian Journal of Economics", "link": null}, "BIBREF12": {"title": "A Study of the J-Curve for Seven Selected Latin American Countries", "authors": [{"first": "Y", "middle": [], "last": "Hsing", "suffix": ""}], "year": 2008, "venue": "Global Economy Journal", "link": "201094951"}, "BIBREF13": {"title": "Output and The Real Exchange Rate in Developing Countries: An Application to Mexico", "authors": [{"first": "S", "middle": ["B"], "last": "Kamin", "suffix": ""}, {"first": "J", "middle": ["H"], "last": "Rogers", "suffix": ""}], "year": 2000, "venue": "Journal of Development Economics", "link": "154711170"}, "BIBREF14": {"title": "Output, Inflation and Stabilization in a Small Open Economy: Evidence from Mexico", "authors": [{"first": "J", "middle": ["H"], "last": "Rogers", "suffix": ""}, {"first": "P", "middle": [], "last": "Wang", "suffix": ""}], "year": 1995, "venue": "Journal of Development Economics", "link": "154021401"}, "BIBREF15": {"title": "Contractionary Effects of Devaluation", "authors": [{"first": "P", "middle": [], "last": "Krugman", "suffix": ""}, {"first": "L", "middle": [], "last": "Taylor", "suffix": ""}], "year": 1978, "venue": "Journal of International Economics", "link": "154124565"}, "BIBREF16": {"title": "The Monetary Transmission Mechanism: Some Answers and Further Questions", "authors": [{"first": "K", "middle": ["N"], "last": "Kuttner", "suffix": ""}, {"first": "P", "middle": ["C"], "last": "Mosser", "suffix": ""}], "year": 2002, "venue": "", "link": null}, "BIBREF17": {"title": "Modelling Real Exchange Rate Effects on Output Performance in Latin America", "authors": [{"first": "P", "middle": [], "last": "Mejia-Reyes", "suffix": ""}, {"first": "D", "middle": ["R"], "last": "Osborn", "suffix": ""}, {"first": "M", "middle": [], "last": "Sensier", "suffix": ""}], "year": 2010, "venue": "Applied Economics", "link": "14732413"}, "BIBREF18": {"title": "Depreciation and Recessions in East Asia", "authors": [{"first": "R", "middle": [], "last": "Moreno", "suffix": ""}], "year": 1999, "venue": "Federal Reserve Bank of San Francisco Economic Review", "link": null}, "BIBREF19": {"title": "A Simple, Positive SemiDefinite, Heteroskedasticity and Autocorrelation Consistent Covariance Matrix", "authors": [{"first": "W", "middle": ["K"], "last": "Newey", "suffix": ""}, {"first": "K", "middle": ["D"], "last": "West", "suffix": ""}], "year": 1987, "venue": "Econometrica", "link": null}, "BIBREF20": {"title": "Keynesian Macroeconomics Without the LM Curve", "authors": [{"first": "D", "middle": [], "last": "Romer", "suffix": ""}], "year": 2000, "venue": "Journal of Economic Perspectives", "link": "155485"}, "BIBREF21": {"title": "Advanced Macroeconomics", "authors": [{"first": "D", "middle": [], "last": "Romer", "suffix": ""}], "year": 2006, "venue": "", "link": null}, "BIBREF22": {"title": "Contractionary Effects of Devaluation in Mexico", "authors": [{"first": "W", "middle": ["C"], "last": "Sawyer", "suffix": ""}, {"first": "R", "middle": ["L"], "last": "Sprinkle", "suffix": ""}], "year": 1987, "venue": "Social Science Quarterly", "link": null}, "BIBREF23": {"title": "Open-Economy Inflation Targeting", "authors": [{"first": "L", "middle": ["E O"], "last": "Svensson", "suffix": ""}], "year": 2000, "venue": "Journal of International Economics", "link": "3025718"}, "BIBREF24": {"title": "Discretion versus Policy Rules in Practice", "authors": [{"first": "J", "middle": ["B"], "last": "Taylor", "suffix": ""}], "year": 1993, "venue": "Carnegie-Rochester Conference Series on Public Policy", "link": "53631298"}, "BIBREF25": {"title": "A Historical Analysis of Monetary Policy Rules", "authors": [{"first": "J", "middle": ["B"], "last": "Taylor", "suffix": ""}], "year": 1999, "venue": "NBER Conference Report series", "link": null}, "BIBREF26": {"title": "An Analysis of Devaluations and Output Dynamics in Latin America Using an Estimated DSGE Model", "authors": [{"first": "C", "middle": ["E"], "last": "Tovar", "suffix": ""}], "year": 2006, "venue": "Bank for International Settlements", "link": null}, "BIBREF27": {"title": "Currency Devaluation, Aggregate Output, and the Long Run: An Empirical Study", "authors": [{"first": "K", "middle": ["P"], "last": "Upadhyaya", "suffix": ""}], "year": 1999, "venue": "Economics Letters", "link": "154993856"}, "BIBREF28": {"title": "Exchange Rate Adjustment and Output in Selected Latin American Countries", "authors": [{"first": "K", "middle": ["P"], "last": "Upadhyaya", "suffix": ""}, {"first": "D", "middle": [], "last": "Dhakal", "suffix": ""}, {"first": "F", "middle": ["G"], "last": "Mixon", "suffix": ""}], "year": 2000, "venue": "conomia Internazionale / International Economics", "link": "153388263"}, "BIBREF29": {"title": "Bilateral Trade Balance, Exchange Rates, and Income: Evidence from Malaysia", "authors": [{"first": "M", "middle": ["B"], "last": "Yusoff", "suffix": ""}], "year": 2009, "venue": "Global Economy Journal", "link": "154420519"}}, "ref_entries": {}}
{"paper_id": "199664931", "_pdf_hash": "ae3b824a6fd4517b41e92cf5a39a735fb2ca93ec", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "199665186", "_pdf_hash": "e176a8054b2614cb4217efe01284adf11ca4640c", "abstract": [], "body_text": [{"section": "\"IS SAVING THE WORLD'S POOR PROFITABLY\" GOOD FOR BUSINESS AND GOOD FOR THE WORLD'S POOR?", "text": "\u0160EJLA BABI\u010c people, 1969 -2000 . Source: FAO. WorldHunger Organization 2012 In some districts, half the children born can be expected to die before their fifth birthday. The problem is not that the world cannot produce enough to feed and shelter its people. According to the World Hunger Organization (2011), people in the poor countries consume, on average, 180 kilos of grain a year, while North Americans average around 900 kilos. The difference is caused by the fact that in the rich countries we feed most our grain to animals, converting it into meat, milk, and eggs. Because this is a highly inefficient process, people in rich countries are responsible for the consumption of far more food than those in countries that consume grain and soybeans. A large amount of food would be saved if it could be distributed to those who need it; it would be more than enough to end hunger throughout the world.", "cite_spans": [], "ref_spans": []}, {"section": "\"IS SAVING THE WORLD'S POOR PROFITABLY\" GOOD FOR BUSINESS AND GOOD FOR THE WORLD'S POOR?", "text": "If we explore these facts from the point of view of Virtue Ethics, let us look at the virtue of compassion. Does compassion within us cause any kind of obligation to this situation? What is compassion? Compassion is a form of sympathy; it is sympathy in pain or sadness, in other words, participation in suffering of others. \"Can we really suppose that a fellow-feeling such as that of rejecting with A's pleasure at B's misfortune is morally valuable?\" asks Max Scheler (2008, p.5) . Of course not! But participating in B's is! By adopting a consequentialist approach, we could follow Singer and present an argument which shows clearly an obligation by companies to assist the poor and needy which is motivated by the virtues of compassion. Singer (1993, p.229) proposes that we ought to follow our moral responsibility and carry out the appropriate actions if it is in our power to prevent something very bad from happening, without thereby sacrificing anything of comparable moral significance. We can formulate this argument out more formally from the point of view of the obligations of a corporation towards the needy and poor, it would look like this: Second premise: Absolute poverty is bad.", "cite_spans": [], "ref_spans": []}, {"section": "\"IS SAVING THE WORLD'S POOR PROFITABLY\" GOOD FOR BUSINESS AND GOOD FOR THE WORLD'S POOR?", "text": "Third premise: There is some poverty that a corporation can prevent without sacrificing anything of comparable moral significance.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusion:", "text": "Corporations ought to prevent some absolute poverty (Singer, p.230) .", "cite_spans": [], "ref_spans": []}, {"section": "Conclusion:", "text": "The second premise is grounded on the virtue of compassion. Absolute poverty is bad and any decent human being or corporation cannot tolerate such situations. The motivations behind such corporate actions are based on the virtue of compassion regardless of profitability. It is simply the right thing to do. However, compassion is not generally part of the strategic mission of organisations, profit is. So, we now ask the question, \"how can organisations assist the poor of the world profitably?\" In the next section we will consider some evidence from the work of Prahalad and Hamond (2002) that indicates that corporations can assist the poor of the world profitably.", "cite_spans": [], "ref_spans": []}, {"section": "\"IS SAVING THE WORLD'S POOR PROFITABLY\" GOOD FOR BUSINESS AND THE WORLD'S POOR?", "text": "Corporations can however benefit the poor and the needy of the world and at the same time obtain lucrative gains from people at the bottom of the economic pyramid. Prahalad and Hammond (2002, p.4) suggest that when corporations carry out such action there is a resulting decrease in poverty that produces a range of social benefits, helping to stabilise many developing regions and reduce civil and cross-border conflicts. Prahaland and Hammond also emphasise that reaching that goal does not require companies to create social development initiatives for charitable purposes. Multinationals only need to act in their own self-interest, because there are many business benefits to be gained by entering developing markets.", "cite_spans": [], "ref_spans": []}, {"section": "\"IS SAVING THE WORLD'S POOR PROFITABLY\" GOOD FOR BUSINESS AND THE WORLD'S POOR?", "text": "The world's poor are in no short supply, 65% of the world's population earns less than $200 each per year, and this market is untapped by multinational companies. The reluctance to invest is easy to understand. Companies assume that people with such low incomes have little to spend on goods and services, and what they do spend goes to basic needs like food and shelter. They assume also that various barriers to commerce-corruption, inadequate infrastructure, and currency fluctuations make it impossible to do business profitably in these regions. If we take the assumption that the poor have no money, it sounds obvious on the surface, but it is wrong. While individual incomes may be low, the aggregate buying power of poor communities is actually large. The average per capita income of villagers in rural Bangladesh, for instance, is less than $200 per year, but as a group they are avid consumers of telecommunications services. It is also incorrect to assume that the poor are too concentrated on fulfilling their basic needs to waste money on non-essential goods. In fact, the poor often do buy luxury items. In the Mumbai shantytown of Dharavi, for example, 85% of households own a television set, 75% own a pressure cooker and a mixer. That is because buying a house in Mumbai, for most people at the bottom of the pyramid, is not a realistic option as highlighted by Prahaland and Hammond (2004, p.5 ).", "cite_spans": [], "ref_spans": []}, {"section": "\"IS SAVING THE WORLD'S POOR PROFITABLY\" GOOD FOR BUSINESS AND THE WORLD'S POOR?", "text": "There are several examples that can be presented to show that serving the world's poor is not only good for business, but it also benefits in a sustainable manner the poor and the needy of the world. Prahaland and Hammond (2004, p.7) presents examples such as centres run in Uganda by the Women's Information Resource Electronic Service which provides female entrepreneurs with information on markets and prices, as well as credit and trade support services in local languages. In Bolivia, a start-up has partnered with the Bolivian Association of Ecological Producers Organization to offer business information and communications services to more than 25,000 small producers of eco-agricultural products. Vogel (2005, p.29) presents several examples to show there is an extensive body of academic research that examines the relationship between corporate responsibility and profitability. While many studies report a positive relationship between ethics and profits, some find negative relationships, and still others find the relationships to be either neutral or mixed.", "cite_spans": [], "ref_spans": []}, {"section": "\"IS SAVING THE WORLD'S POOR PROFITABLY\" GOOD FOR BUSINESS AND THE WORLD'S POOR?", "text": "According to Reed (1998, p.47) , research that relates measures of corporate environmental performance to measures of financial performance suffers from several shortcomings. Vogel (2005, p.30 ) also explains that it is difficult to make conclusions about the relationship between CSR and profits as the studies often measure different things. He explains that in the ninety-five studies summarised by Margolis and Walsh, financial performance is measured in seventy different ways and measurements of corporate social performance also vary widely. In ninety-five studies, twenty-seven different data sources were used and not only does the diversity of these measures make drawing conclusions from this literature difficult, but there is also a debate about the validity of some of them.", "cite_spans": [], "ref_spans": []}, {"section": "\"IS SAVING THE WORLD'S POOR PROFITABLY\" GOOD FOR BUSINESS AND THE WORLD'S POOR?", "text": "The most exhausting and widely used measure of CSR is KLD's extensive database of 400, mainly US companies. KLD evaluates five different measures of corporate performance: community relations, diversity, employee relations, natural environment, and product safety and quality. Mahon and Griffen (1997, p.15-31) analysed many literature reviews published between 1979 and 1999 and identified nearly fifty shortcomings of the broader body of research. They agree that the connection between CSR and financial performance has not been established. Therefore, Margolis and Walsh (2001, p.13) summarised both their own analysis on these studies: the clear signal that emerges from thirty years of academic research -indicating that a positive relationship existing between social performance and financial performance -must be treated with caution. Roman, Hayibor and Agle (1999, p.121) conclude that it is difficult to know what to make of the claim that \"those hoping for a positive or neutral impact of social performance on financial performance can feel some satisfaction, because the vast majority of studies lead to poor financial performance.\"", "cite_spans": [], "ref_spans": []}, {"section": "\"IS SAVING THE WORLD'S POOR PROFITABLY\" GOOD FOR BUSINESS AND THE WORLD'S POOR?", "text": "Generally it is seen that CSR activities may not affect short-term earnings, and in the long run more responsible firms will perform better.", "cite_spans": [], "ref_spans": []}, {"section": "\"IS SAVING THE WORLD'S POOR PROFITABLY\" GOOD FOR BUSINESS AND THE WORLD'S POOR?", "text": "If we consider, for example, the US-based firms included in the 1994 bestseller Built to Last on the basis of their having attained extraordinary long-term performance. According to its authors, Collins and Porras (1994, pp.2-3) , these firms are more than successful. They are more than enduring. In most cases, they are the best of the best in their industries, and have been that way for decades. The firms that meet their criteria are American Express, Boeing, Citicorp, Ford, General Electric, Hewlett-Packard, Philip Morris, Sony, Wal-Mart, and Walt Disney. To this list of distinguished financial performers we can add the retailer Mark & Spencer (M&S) which has long enjoyed a reputation as one of Britain's most virtuous companies. It has been a highly benevolent employer, and for many years had a policy of selling only British-made goods. In July 2004, Business in the Community, a prominent British NGO, named M&S Company of the Year for putting responsible business practices at the heart of its strategy and for producing measurable outstanding positive impacts on society. The Dow Jones Sustainability World Index rated M&S the most sustainable retailer in the world. Vogel (2005, p.73) argues that for a subset of firms, CSR does appear to make business sense. These firms fall into two broad categories. The so-called companies with conscience, such as Ben and Jerry's, Seventh Generation, and Patagonia, fall into this category, as do some larger firms, such as Levi Strauss and Starbucks. Their embrace of corporate virtue frequently reflects the values of their owners or major shareholders or the legacies of their founders. A second category of firms for whom CSR makes business sense are those that have been targeted by activists, who are concerned that they could be targeted, largely because of the visibility of their brands. For firms such as Shell, Nike, Home Depot, Dell, and a few others, these firms are highly risk averse, they consider it in their interest to act more responsibly.", "cite_spans": [], "ref_spans": []}, {"section": "\"IS SAVING THE WORLD'S POOR PROFITABLY\" GOOD FOR BUSINESS AND THE WORLD'S POOR?", "text": "Both categories of companies regard their reputations for corporate virtue as important. Accordingly, they have decided that it is in their interest to devote additional resources to improve their social or environmental performance and in many cases to cooperate with NGO and help the needy and poor of the world.", "cite_spans": [], "ref_spans": []}, {"section": "\"IS SAVING THE WORLD'S POOR PROFITABLY\" GOOD FOR BUSINESS AND THE WORLD'S POOR?", "text": "The aim of this discussion has been to argue the case that \"Is saving the world's poor profitably good for business and good for the world's poor?\"", "cite_spans": [], "ref_spans": []}, {"section": "\"IS SAVING THE WORLD'S POOR PROFITABLY\" GOOD FOR BUSINESS AND THE WORLD'S POOR?", "text": "Singer's argument presented in the beginning showed that on the basis of compassion, the right thing to do for any business is to help the poor and needy of the world. However, as can be seen from the mission statements of numerous companies, compassion does not play a role in the strategic plan. Profitability, market share, competitiveness, and marketing to profitable customer groups are the key components that motivate company activities. How can companies therefore assist the poor and needy of the world profitably? The paper then presented several examples from Prahalad and Hammond that demonstrate that companies indeed can be profitable and sustainable business activities can be established. However, Vogel presents several studies that showed there is no direct relationship between CSR activities and profitability. Generally it is seen that CSR activities may not affect short-term earnings; however, in the long run more responsible firms will perform better.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Successful Habits of Visionary Companies", "authors": [{"first": "J", "middle": ["C"], "last": "Collins", "suffix": ""}, {"first": "J", "middle": ["I"], "last": "Porras", "suffix": ""}], "year": 1994, "venue": "", "link": null}, "BIBREF1": {"title": "People and profits. LEA's Organization and Management Series", "authors": [{"first": "J", "middle": ["D"], "last": "Margolis", "suffix": ""}, {"first": "J", "middle": ["P"], "last": "Walsh", "suffix": ""}], "year": 2001, "venue": "", "link": null}, "BIBREF2": {"title": "The Corporate Social Performance and Corporate Financial Performance Debate Twenty-Five Years of Incomparable Research", "authors": [{"first": "J", "middle": [], "last": "Mahon", "suffix": ""}, {"first": "J", "middle": ["J"], "last": "Griffen", "suffix": ""}], "year": 1997, "venue": "Business and Society", "link": "153779779"}, "BIBREF3": {"title": "Serving the World's Poor, Profitably", "authors": [{"first": "C", "middle": ["K"], "last": "Prahalad", "suffix": ""}, {"first": "A", "middle": [], "last": "Hammond", "suffix": ""}], "year": 2002, "venue": "Harvard Business Review", "link": "881964"}, "BIBREF4": {"title": "Green Shareholder Value", "authors": [{"first": "D", "middle": [], "last": "Reed", "suffix": ""}], "year": 1998, "venue": "", "link": null}, "BIBREF5": {"title": "The Relationship between Social and Financial performance", "authors": [{"first": "R", "middle": [], "last": "Roman", "suffix": ""}, {"first": "S", "middle": [], "last": "Hayibor", "suffix": ""}, {"first": "B", "middle": [], "last": "Agle", "suffix": ""}], "year": 1999, "venue": "", "link": "154215121"}, "BIBREF6": {"title": "The Nature of Sympathy", "authors": [{"first": "M", "middle": [], "last": "Scheler", "suffix": ""}], "year": 2008, "venue": "", "link": "143518564"}, "BIBREF7": {"title": "Practical Ethics", "authors": [{"first": "P", "middle": [], "last": "Singer", "suffix": ""}], "year": 1993, "venue": "", "link": null}, "BIBREF8": {"title": "The Market of Virtue: The Potential and Limits of Corporate Social Responsibility", "authors": [{"first": "D", "middle": [], "last": "Vogel", "suffix": ""}], "year": 2005, "venue": "", "link": null}}, "ref_entries": {"FIGREF0": {"text": "Figure 1: Number of hungry people in the world. Source: FAO. World Hunger Organization 2012", "type": "figure"}, "FIGREF1": {"text": "If [a corporation can prevent something bad without sacrificing anything of comparable moral significance] then [the corporation ought to do it].", "type": "figure"}}}
{"paper_id": "199665266", "_pdf_hash": "7f816f011443384504c9709e38123767e60860b7", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "199665542", "_pdf_hash": "13483096b1fc20d9c15bd4a1d8048771eb44d20a", "abstract": [{"section": "Abstract", "text": "Abstract. We prove existence and uniform bounds for critical static Klein-GordonMaxwell-Proca systems in the case of 4-dimensional closed Riemannian manifolds.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Static Klein-Gordon-Maxwell-Proca systems are massive versions of the electrostatic Klein-Gordon-Maxwell systems. The vector field in these systems inherits a mass and is governed by the Proca action which generalizes that of Maxwell. Klein-GordonMaxwell systems are intended to provide a dualistic model for the description of the interaction between a charged relativistic matter scalar field and the electromagnetic field that it generates. The electromagnetic field is both generated by and drives the particle field. In the electrostatic form of the Klein-Gordon-Maxwell systems, looking for standing waves ue iot , the matter field is characterized by the property that u, together with a gauge potential v, solve the electrostatic Klein-Gordon-Maxwell systems (0.3) with m 1 \u00bc 0. In the case of a closed manifold we discuss here the two equations in (0.3) are independent one of another when m 1 \u00bc 0 and the system reduces to the sole Schr\u00f6 dinger equation. The Proca formalism, for m 1 > 0, leads to a deeper phenomenon and is more appropriate to the closed case. The particle in this model interacts via the minimum coupling rule", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "with an external massive vector field \u00f0j; A\u00de which is governed by the Maxwell-Proca Lagrangian. The Proca action is a gauge-fixed version of the Stueckelberg action in the Higgs mechanism (see Goldhaber and Nieto [26], and Ruegg and Ruiz-Altaba [43] ). In the Proca formalism, developped under the influence of de Broglie, the photon inherits a nonzero mass. This issue is of considerable importance and intensively studied in modern physics (see for instance Adelberger, Dvali Gillies and Tu [37] and the references in these papers). When n \u00bc 3, the KGMP equations consist in the nonlinear Klein-Gordon matter equation, the charge continuity equation and the massive modified Maxwell equations in SI units, which are hereafter explicitly written down:", "cite_spans": [{"start": 245, "end": 249, "text": "[43]", "ref_id": "BIBREF42"}], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Static Klein-Gordon-Maxwell-Proca systems are massive versions of the electrostatic Klein-Gordon-Maxwell systems. The vector field in these systems inherits a mass and is governed by the Proca action which generalizes that of Maxwell. Klein-GordonMaxwell systems are intended to provide a dualistic model for the description of the interaction between a charged relativistic matter scalar field and the electromagnetic field that it generates. The electromagnetic field is both generated by and drives the particle field. In the electrostatic form of the Klein-Gordon-Maxwell systems, looking for standing waves ue iot , the matter field is characterized by the property that u, together with a gauge potential v, solve the electrostatic Klein-Gordon-Maxwell systems (0.3) with m 1 \u00bc 0. In the case of a closed manifold we discuss here the two equations in (0.3) are independent one of another when m 1 \u00bc 0 and the system reduces to the sole Schr\u00f6 dinger equation. The Proca formalism, for m 1 > 0, leads to a deeper phenomenon and is more appropriate to the closed case. The particle in this model interacts via the minimum coupling rule q t ! q t \u00fe iqj and ' ! ' \u00c0 iqA \u00f00:1\u00de", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "with an external massive vector field \u00f0j; A\u00de which is governed by the Maxwell-Proca Lagrangian. The Proca action is a gauge-fixed version of the Stueckelberg action in the Higgs mechanism (see Goldhaber and Nieto [26] , and Ruegg and Ruiz-Altaba [43] ). In the Proca formalism, developped under the influence of de Broglie, the photon inherits a nonzero mass. This issue is of considerable importance and intensively studied in modern physics (see for instance Adelberger, Dvali and Gruzinov [1] , Byrne [13] , Goldhaber and Nieto [25] , [26] , Luo and Tu [38] , Luo, Gillies and Tu [37] and the references in these papers). When n \u00bc 3, the KGMP equations consist in the nonlinear Klein-Gordon matter equation, the charge continuity equation and the massive modified Maxwell equations in SI units, which are hereafter explicitly written down:", "cite_spans": [{"start": 213, "end": 217, "text": "[26]", "ref_id": "BIBREF25"}, {"start": 246, "end": 250, "text": "[43]", "ref_id": "BIBREF42"}, {"start": 492, "end": 495, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 504, "end": 508, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 531, "end": 535, "text": "[25]", "ref_id": "BIBREF24"}, {"start": 538, "end": 542, "text": "[26]", "ref_id": "BIBREF25"}, {"start": 556, "end": 560, "text": "[38]", "ref_id": "BIBREF37"}, {"start": 583, "end": 587, "text": "[37]", "ref_id": "BIBREF36"}], "ref_spans": []}, {"section": "Introduction", "text": "' \u00c2 E \u00fe qH qt \u00bc 0 and ':H \u00bc 0:", "cite_spans": [], "ref_spans": []}, {"section": "\u00f00:2\u00de", "text": "These massive Maxwell equations, as modified to Proca form, appear to have been first written in modern format by Schr\u00f6 dinger [46] . The Proca formalism a priori breaks gauge invariance. Gauge invariance can be restaured by the Stueckelberg trick, as pointed out by Pauli [41] , and then by the Higgs mechanism. We refer to Goldhaber and Nieto [26] , Luo, Gillies and Tu [37] , and Ruegg and Ruiz-Altaba [43] for very complete references on the Proca approach.", "cite_spans": [{"start": 127, "end": 131, "text": "[46]", "ref_id": "BIBREF45"}, {"start": 273, "end": 277, "text": "[41]", "ref_id": "BIBREF40"}, {"start": 345, "end": 349, "text": "[26]", "ref_id": "BIBREF25"}, {"start": 372, "end": 376, "text": "[37]", "ref_id": "BIBREF36"}, {"start": 405, "end": 409, "text": "[43]", "ref_id": "BIBREF42"}], "ref_spans": []}, {"section": "\u00f00:2\u00de", "text": "In what follows we let \u00f0M; g\u00de be a smooth compact 3; 4-dimensional Riemannian manifold. We let also 2 ? \u00bc 2n n \u00c0 2 be the critical Sobolev exponent, where n is the dimension of M. Given real numbers q > 0, m 0 ; m 1 > 0, o A \u00f0\u00c0m 0 ; m 0 \u00de, and p A \u00f02; 2 ? , the derivation of the Klein-Gordon-Maxwell-Proca system we investigate in this paper is written as", "cite_spans": [], "ref_spans": []}, {"section": "\u00f00:2\u00de", "text": "where D g \u00bc \u00c0div g ' is the Laplace-Beltrami operator. The system (0.3) corresponds to looking for standing waves ue iot for the full KGMP system in the static case where the massive vector field \u00f0j; A\u00de depends on the sole spatial variable. The system is energy critical when n \u00bc 3 and p \u00bc 6 and when n \u00bc 4 and p \u00bc 4. It is subcritical otherwise, namely when n \u00bc 3 and p A \u00f02; 6\u00de or n \u00bc 4 and p A \u00f02; 4\u00de. In the above model, m 1 is a coupling constant which makes that the two equations in (0.3) are trully coupled (m 1 is the Proca mass in the Maxwell-Proca formalism) while m 0 is the mass of the particle, q is the charge of the particle, u is the amplitude in the writing of the particle, o is its temporal frequency (referred to as the phase in the sequel), and v is the electric potential.", "cite_spans": [], "ref_spans": []}, {"section": "\u00f00:2\u00de", "text": "Let S g stand for the scalar curvature of g, and S p \u00f0o\u00de be the set consisting of the positive smooth solutions U \u00bc \u00f0u; v\u00de of (0.3) with phase o and nonlinear term u p\u00c01 . Namely, Theorem 0.1 (The 3-dimensional case-Druet and Hebey [20] for all x A M. Then (0.3) possesses a smooth positive mountain pass solution. Moreover, for any p A \u00f02; 6\u00de, and any y A \u00f00; 1\u00de, there exists C > 0 such that for any o 0 A K 0 \u00f00\u00de, and any U A S p \u00f0o 0 \u00de, kUk C 2; y e C, where S p \u00f0o 0 \u00de is as in (0.4) and K 0 \u00f00\u00de is as in (0.5). Assuming again (0.6), there also holds that for any y A \u00f00; 1\u00de, kUk C 2; y e C for all U A S 6 \u00f0o 0 \u00de and all o 0 A K 0 \u00f0o\u00de, where C > 0 does not depend on o 0 and U.", "cite_spans": [{"start": 232, "end": 236, "text": "[20]", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "\u00f00:2\u00de", "text": "This result exhibits phase compensation in the 3-dimensional case. We aim in this paper in proving that a similar phenomenon holds true when n \u00bc 4. In this dimension the second equation in (0.3) becomes critical and this leads to serious di\u2030culties. We prove below the existence of smooth positive mountain pass solutions and the existence of uniform bounds for (0.3) in the subcritical cases p A \u00f02; 4\u00de without any conditions, and in the critical case p \u00bc 4 assuming that the mass potential, balanced by the phase, is smaller than the geometric threshold potential of the conformal Laplacian. In doing so we prove that phase compensation still holds true for our systems when n \u00bc 4. Our result, in the subcritical case, is as follows. In the critical case we prove the following result. The geometry of the ambiant inhomogeneous space, through the scalar curvature of g, comes to play a role as in the 3-dimensional case. However, the result now turns out to be local in its existence part. There are two consequences to Theorem 0.3. We list them in points (i)-(ii) below. In point (i) we illustrate the phase compensation e\u00a4ect associated with (0.3). There we always get existence and a priori bounds for all phases o which are close to m 0 . Point (ii) concerns the full range of phases when we assume m 0 is not too large. As an immediate consequence of the C 2; y -bounds in the above results we obtain phase stability for standing waves of the Klein-Gordon-Maxwell-Proca equations in electrostatic form. Standing waves for the Klein-Gordon-Maxwell-Proca equations in electrostatic form are written as S \u00bc ue iot and they are coupled with a gauge potential v, where \u00f0u; v\u00de solves (0.3). Roughly speaking, phase stability means that for any arbitrary sequence of standing waves u a e io a t , with gauge potentials v a , the convergence of the phases o a in R implies the convergence of the amplitudes u a and of the gauge potentials v a in the C 2 -topology. Phase stability prevents the existence of arbitrarily large amplitude standing waves.", "cite_spans": [], "ref_spans": []}, {"section": "\u00f00:2\u00de", "text": "High dimensional KGM systems in Coulomb gauge have been recently investigated by Rodnianski and Tao [42] and with special emphasis in \u00f01 \u00fe 4\u00de-dimensions by Klainerman and Tataru [30] and Selberg [47] . Electrostatic KGM systems in the three dimensional case have been investigated by several authors. Possible references on the physics side are by Benci and Fortunato [5] , [6] , Long [35] , Long and Stuart [36] . Blowing-up solutions to the electrostatic Schr\u00f6 dinger-Maxwell system, a cousin of the electrostaic KGM type systems that we consider here, have been constructed in D'Aprile and Wei [2] , [3] .", "cite_spans": [{"start": 100, "end": 104, "text": "[42]", "ref_id": "BIBREF41"}, {"start": 178, "end": 182, "text": "[30]", "ref_id": "BIBREF29"}, {"start": 195, "end": 199, "text": "[47]", "ref_id": "BIBREF46"}, {"start": 368, "end": 371, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 374, "end": 377, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 385, "end": 389, "text": "[35]", "ref_id": "BIBREF34"}, {"start": 408, "end": 412, "text": "[36]", "ref_id": "BIBREF35"}, {"start": 597, "end": 600, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 603, "end": 606, "text": "[3]", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "\u00f00:2\u00de", "text": "We briefly discuss in Section 1 the physics relevance of (0.3). We prove our theorem in Sections 2 to 4. The existence part in the theorems is proved in Section 2. The C 2; ybound in the subcritical case is established in Section 3. The more delicate C 2; y -bound in the critical case is established in Sections 4. The phase compensation phenomenon in Theorem 0.3 holds true thanks to the 4-dimensional log e\u00a4ect m 2 \u00bc o\u00f0m 2 log m\u00de as m ! 0.", "cite_spans": [], "ref_spans": []}, {"section": "The physics origin of the system", "text": "The Klein-Gordon-Maxwell-Proca system discussed in this work describes an interacting field theory model in theoretical physics. Most electromagnetic phenomena are described by conventional electrodynamics, which is a theory of the coupling of electromagnetic fields to matter fields. Of prime importance for particle physics is fermion electrodynamics in which matter is represented by spinor fields. However one may have also boson electrodynamics in which matter is described by integer spin or bosonic fields. The simplest one is of course the complex scalar field, describing spinless particles having electric charges Gq. It gives rise to scalar electrodynamics, which describes in the nonrelativistic limit the superconductivity of metals at very low temperatures. In the more general context of particle physics, a complex scalar field c may serve to describe scalar mesons in nuclear matter interacting via a massive vector boson field \u00f0j; A\u00de.", "cite_spans": [], "ref_spans": []}, {"section": "The physics origin of the system", "text": "The interaction in this model is described by the minimum substitution rule (0.1) in a nonlinear Klein-Gordon Lagrangian. As for the external massive vector field it is governed by the Maxwell-Proca Lagrangian. More precisely, assuming for short that the manifold is orientable, we define the Lagrangian densities L NKG and L MP of c, j, and A by L NKG \u00f0c; j; A\u00de \u00bc 1 2", "cite_spans": [], "ref_spans": []}, {"section": "The physics origin of the system", "text": "\u00f01:1\u00de", "cite_spans": [], "ref_spans": []}, {"section": "The physics origin of the system", "text": "where '\u00c2 \u00bc ?d, ? is the Hodge dual, c represents the matter complex scalar field, m 0 its mass, q its charge, \u00f0j; A\u00de the electromagnetic vector field, and m 1 its mass. It can be noted that k\u00f0j; A\u00dek", "cite_spans": [], "ref_spans": []}, {"section": "The physics origin of the system", "text": "2 is the square of the Lorentz norm of \u00f0j; A\u00de with respect to the Lorentz metric diag\u00f01; \u00c01; . . . ; \u00c01\u00de. The total action functional for c, f, and A is then given by", "cite_spans": [], "ref_spans": []}, {"section": "The physics origin of the system", "text": "Writing c in polar form as c\u00f0x; t\u00de \u00bc u\u00f0x; t\u00dee iS\u00f0x; t\u00de , taking the variation of S with respect to u, S, j, and A, we get four equations which are written as", "cite_spans": [], "ref_spans": []}, {"section": "The physics origin of the system", "text": "where D g \u00bc \u00c0div g ' is the Laplace-Beltrami operator, D g \u00bc dd is half the Laplacian acting on forms, and d is the codi\u00a4erential. We refer to this system as a nonlinear Klein-GordonMaxwell-Proca system. When n \u00bc 3, D g A \u00bc ' \u00c2 \u00f0' \u00c2 A\u00de and if we let We assume in what follows that u\u00f0x; t\u00de \u00bc u\u00f0x\u00de does not depend on t, S\u00f0x; t\u00de \u00bc ot does not depend on x, and j\u00f0x; t\u00de \u00bc j\u00f0x\u00de, A\u00f0x; t\u00de \u00bc A\u00f0x\u00de do not depend on t. In other words, we look for standing waves solutions of (1.3) and assume that we are in the static case of the system where \u00f0j; A\u00de depends on the sole spatial variable. By the fourth equation in (1.3) we then get that", "cite_spans": [], "ref_spans": []}, {"section": "The physics origin of the system", "text": "This clearly implies that, and is equivalent to, A 1 0 since", "cite_spans": [], "ref_spans": []}, {"section": "The physics origin of the system", "text": "As a remark, assuming that A 1 0, the Lorentz condition for the external Proca field \u00f0j; A\u00de would make j dependent on the sole spatial variables. As for the second equation in (1.3) it reduces to q 2 S qt 2 \u00bc 0. It is automatically satisfied when S\u00f0t\u00de \u00bc ot, and we are thus left with the first and third equations in (1.3). Letting S \u00bc \u00c0ot, and j \u00bc ov, these equations are rewritten as", "cite_spans": [], "ref_spans": []}, {"section": "The physics origin of the system", "text": "In particular, letting j \u00bc ov, in (1.5), we recover our original system (0.3). In other words, our original system (0.3) corresponds to looking for standing waves solutions of the KleinGordon-Maxwell-Proca system (1.3) in static form.", "cite_spans": [], "ref_spans": []}, {"section": "The physics origin of the system", "text": "The functional is well defined since", "cite_spans": [], "ref_spans": []}, {"section": "The physics origin of the system", "text": "H u \u00f0j\u00de:", "cite_spans": [], "ref_spans": []}, {"section": "The physics origin of the system", "text": "By standard minimization arguments there exists j A H 1 \u00f0M\u00de such that \u00d0 M u 2 j dv g \u00bc 1 and", "cite_spans": [], "ref_spans": []}, {"section": "The physics origin of the system", "text": "It is easily seen that F\u00f0u\u00de is unique. By the maximum principle, F\u00f0u\u00de f 0. Noting that", "cite_spans": [], "ref_spans": []}, {"section": "The physics origin of the system", "text": "it also follows from the maximum principle that F\u00f0u\u00de e 1 q . Now we let u; v A H 1 \u00f0M\u00de. We have that", "cite_spans": [], "ref_spans": []}, {"section": "The physics origin of the system", "text": "Multiplying the equation by F\u00f0v\u00de \u00c0 F\u00f0u\u00de, integrating over M, and by the Sobolev embedding theorem, we get that", "cite_spans": [], "ref_spans": []}, {"section": "The physics origin of the system", "text": "In particular, F is locally Lipschitz continuous. We can prove the existence of V u \u00f0j\u00de in (2.5) as when proving the existence of F\u00f0u\u00de. Writing the equation satisfied by F\u00f0u \u00fe j\u00de \u00c0 F\u00f0u\u00de \u00c0 V u \u00f0j\u00de, multiplying the equation by F\u00f0u \u00fe j\u00de \u00c0 F\u00f0u\u00de \u00c0 V u \u00f0j\u00de and integrating over M, we get that", "cite_spans": [], "ref_spans": []}, {"section": "The physics origin of the system", "text": "Then the di\u00a4erentiability of F follows from the continuity of F. In particular, C is di\u00a4er-entiable. By (2.2),", "cite_spans": [], "ref_spans": []}, {"section": "The physics origin of the system", "text": "and we also have that qH qF", "cite_spans": [], "ref_spans": []}, {"section": "The physics origin of the system", "text": "we get that (2.6) holds true. The continuity of DC can be proved directly from (2.6) and the continuity of F. This ends the proof of the lemma. r", "cite_spans": [], "ref_spans": []}, {"section": "The physics origin of the system", "text": "Now we prove the subcritical existence of Theorem 0.2. We proceed by applying the mountain pass lemma to the functional I p in (2.3).", "cite_spans": [], "ref_spans": []}, {"section": "The physics origin of the system", "text": "Proof of existence in Theorem 0.2. By Lemma 2.1,", "cite_spans": [], "ref_spans": []}, {"section": "The physics origin of the system", "text": "There holds I p \u00f00\u00de \u00bc 0 and I p \u00f0tu 0 \u00de ! \u00c0y as t ! \u00fey since p > 2. Since 0 e F\u00f0u\u00de e 1 q for all u, we also have that where P is the class of continuous paths joining 0 to T 0 u 0 . According to the above we can apply the mountain pass lemma and we get the existence of a sequence \u00f0u a \u00de a in H 1 such that I p \u00f0u a \u00de ! c p and DI p \u00f0u a \u00de ! 0 as a ! \u00fey. Writing that I p \u00f0u a \u00de \u00bc c p \u00fe o\u00f01\u00de and that DI p \u00f0u a \u00de:\u00f0u a \u00de \u00bc o\u00f0ku a k H 1 \u00de, we get by Lemma 2.1 that", "cite_spans": [], "ref_spans": []}, {"section": "The physics origin of the system", "text": "By (2.9) we then get that \u00f0u a \u00de a is bounded in H 1 . In particular, there exists u p A H 1 \u00f0M\u00de such that, up to passing to a subsequence,", "cite_spans": [], "ref_spans": []}, {"section": "The physics origin of the system", "text": "and u a ! u p a.e. as a ! \u00fey. Substracting one equation to another in (2.9), letting a ! \u00fey, and since c p 3 0, we get that u p E 0. Writing the equation satisfied by F\u00f0u a \u00de \u00c0 F\u00f0u p \u00de, multiplying the equation by F\u00f0u a \u00de \u00c0 F\u00f0u p \u00de and integrating over M, we get that", "cite_spans": [], "ref_spans": []}, {"section": "The physics origin of the system", "text": "as a ! \u00fey. Now we let j A H 1 . There holds DI p \u00f0u a \u00de:\u00f0j\u00de \u00bc o\u00f01\u00de. Hence, by Lemma 2.1,", "cite_spans": [], "ref_spans": []}, {"section": "The physics origin of the system", "text": "Letting a ! \u00fey in (2.11) we then get by (2.10) that", "cite_spans": [], "ref_spans": []}, {"section": "The physics origin of the system", "text": "Multiplying the equation by u \u00c0 p and integrating over M, it follows that u \u00c0 p 1 0. In particular, u p f 0, u p E 0, and [4] , for any l A R, and C > 0 is independent of a. Also there holds", "cite_spans": [{"start": 122, "end": 125, "text": "[4]", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "The physics origin of the system", "text": "e dv g \u00fe o\u00f01\u00de:", "cite_spans": [], "ref_spans": []}, {"section": "\u00f02:15\u00de", "text": "In what follows we prove the existence part of Theorem 0.3.", "cite_spans": [], "ref_spans": []}, {"section": "\u00f02:15\u00de", "text": "Proof of existence in Theorem 0.3. By standard arguments such as developed in Aubin [4] and Br\u00e9zis and Nirenberg [12] , using parts of what we developed in the preceding proof, we just need to prove that we can choose u 0 A H 1 , u .8). Now we assume that (0.7) holds true for some x A M, in particular for x A M where S g is maximum. We let x 0 A M be such that S g is maximum at x 0 , and \u00f0t e \u00de e be any family of positive real numbers such that the t e 's are bounded. The first estimate we prove is that Proof of the uniform bounds in Theorem 0.2. Let \u00f0o a \u00de a be a sequence in \u00f0\u00c0m 0 ; m 0 \u00de such that o a ! o as a ! \u00fey for some o A \u00bd\u00c0m 0 ; m 0 . Also let p A \u00f02; 4\u00de and \u00f0\u00f0u a ; v a \u00de\u00de a be a sequence of smooth positive solutions of (0.3) with phases o a . Then, ", "cite_spans": [{"start": 84, "end": 87, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 113, "end": 117, "text": "[12]", "ref_id": "BIBREF11"}], "ref_spans": []}, {"section": "\u00f02:15\u00de", "text": "where D is the Euclidean Laplacian. It follows that u is actually smooth and positive, and, since 2 < p < 4, we get a contradiction with the Liouville result of Gidas and Spruck [24] . As a conclusion, (3.2) is not possible and there exists C > 0 such that", "cite_spans": [{"start": 178, "end": 182, "text": "[24]", "ref_id": "BIBREF23"}], "ref_spans": []}, {"section": "\u00f02:15\u00de", "text": "in M for all a. Coming back to (3.1) it follows that the sequences \u00f0u a \u00de a and \u00f0v a \u00de a are actually bounded in H 2; s for all s. Pushing one step further the regularity argument they turn out to be bounded in H 3; s for all s, and by the Sobolev embedding theorem we get that they are also bounded in C 2; y , 0 < y < 1. This ends the proof of the uniform bounds in Theorem 0.2 when p A \u00f02; 4\u00de. r If we assume that o a ! o as a ! \u00fey for some o A \u00f0\u00c0m 0 ; m 0 \u00de, p A \u00f02; 4, and u a ! u and v a ! v in C 2 as a ! \u00fey, then u > 0, v > 0, and u, v are smooth solutions of (0.3). Indeed, given e > 0 su\u2030ciently small, since m", "cite_spans": [], "ref_spans": []}, {"section": "\u00f02:15\u00de", "text": "There holds that 0 e v a e 1 q for all a. In particular, by (3.1) and the Sobolev inequality, for any a g 1 su\u2030ciently large, ", "cite_spans": [], "ref_spans": []}, {"section": "A priori bounds in the critical case", "text": "In what follows we let \u00f0M; g\u00de be a smooth compact 4-dimensional Riemannian manifold, m 0 ; m 1 > 0, and \u00f0o a \u00de a be a sequence in \u00f0\u00c0m 0 ; m 0 \u00de such that o a ! o as a ! \u00fey for some o A \u00bd\u00c0m 0 ; m 0 . Also we let \u00f0\u00f0u a ; v a \u00de\u00de a be a sequence of smooth positive solutions of (0.3) with phases o a and p \u00bc 4. Namely, In what follows we let \u00f0x a \u00de a be a sequence of points in M, and \u00f0r a \u00de a be a sequence of positive real numbers, 0 < r a < i g =7 for all a, where i g is the injectivity radius of \u00f0M; g\u00de. We assume that the x a 's and r a 's satisfy where m a is as in (4.5). The following sharp estimates, see Druet, Hebey and Robert [21] and Druet, Hebey and V\u00e9tois [22] , hold true.", "cite_spans": [{"start": 635, "end": 639, "text": "[21]", "ref_id": "BIBREF20"}, {"start": 668, "end": 672, "text": "[22]", "ref_id": "BIBREF21"}], "ref_spans": []}, {"section": "A priori bounds in the critical case", "text": "Lemma 4.1. Let \u00f0M; g\u00de be a smooth compact Riemannian 4-dimensional manifold, and \u00f0\u00f0u a ; v a \u00de\u00de a be a sequence of smooth positive solutions of (4.1) such that (4.3) holds true.", "cite_spans": [], "ref_spans": []}, {"section": "A priori bounds in the critical case", "text": "Let \u00f0x a \u00de a and \u00f0r a \u00de a be such that (4.4) holds true, and let R f 6 be such that Rr a e 6r a for all a g 1. There exists C > 0 such that, after passing to a subsequence, Lemma 4.1 provides a sharp control on the u a 's, but we need more to conclude. We prove that the following fundamental asymptotic estimate holds true. Lemma 4.2 is the key estimate we need to prove the a priori bounds in the critical case discussed in this section. .5), and H is a harmonic function in B 0 \u00f02\u00de which satisfies that H\u00f00\u00de e 0.", "cite_spans": [], "ref_spans": []}, {"section": "A priori bounds in the critical case", "text": "Proof of Lemma 4.2. Let R f 6 be such that Rr a e 6r a for a g 1. We assume first that r a ! 0 as a ! \u00fey. For x A B 0 \u00f03\u00de we defin\u1ebd", "cite_spans": [], "ref_spans": []}, {"section": "A priori bounds in the critical case", "text": "where h a is as in (4.2). Since r a ! 0 as a ! \u00fey, we have thatg g a ! x in C 2 loc \u00f0R n \u00de as a ! \u00fey, where x is the Euclidean metric. Thanks to Lemma 4.1, j\u0169 u a \u00f0x\u00dej e Cjxj u a dvg g a e C \u00f04:22\u00de and by changing x into m a r a x, we can write that is maximum. Then,", "cite_spans": [], "ref_spans": []}, {"section": "A priori bounds in the critical case", "text": "and it follows from (4.1) that", "cite_spans": [], "ref_spans": []}, {"section": "A priori bounds in the critical case", "text": "Choosing b A \u00f00; 1 such that m", "cite_spans": [], "ref_spans": []}, {"section": "A priori bounds in the critical case", "text": ", we get that u b a \u00f0x a \u00de f Cv a \u00f0x a \u00de for some C > 0 independent of a. This proves (4.25) . In what follows we let X a be the 1-form given by", "cite_spans": [], "ref_spans": []}, {"section": "A priori bounds in the critical case", "text": "where f a \u00f0x\u00de \u00bc 1 2 d g \u00f0x a ; x\u00de 2 , Rc g is the Ricci curvature of g, and K is the musical isomorphism. We apply the Pohozaev identity in Druet-Hebey [19] with the vector field X a to u a in B x a \u00f0r a \u00de. We separate the regular part", "cite_spans": [{"start": 152, "end": 156, "text": "[19]", "ref_id": "BIBREF18"}], "ref_spans": []}, {"section": "A priori bounds in the critical case", "text": "a from the singular part in h a . Then, h a \u00bc A a \u00fe O\u00f0v a \u00de and we get that", "cite_spans": [], "ref_spans": []}, {"section": "A priori bounds in the critical case", "text": "where", "cite_spans": [], "ref_spans": []}, {"section": "A priori bounds in the critical case", "text": "and n is the unit outward normal derivative to B x a \u00f0r a \u00de. We have that", "cite_spans": [], "ref_spans": []}, {"section": "A priori bounds in the critical case", "text": "\u00f04:29\u00de", "cite_spans": [], "ref_spans": []}, {"section": "A priori bounds in the critical case", "text": "and", "cite_spans": [], "ref_spans": []}, {"section": "A priori bounds in the critical case", "text": "Following Druet, Hebey and V\u00e9tois [22] we get from Lemma 4.1, (4.28) and (4.29) that where C > 0 is independent of a since we assumed r a f d 0 > 0. In particular, kv a k L y \u00f0qB a \u00de ! 0 as a ! \u00fey. Then kv v a k L y \u00f0qB\u00de ! 0 as a ! \u00fey, and it follows from the maximum principle and (4.38) that k\u0175 w 1; a k L y \u00f0B\u00de ! 0 as a ! \u00fey. In particular, kw 1; a k L y \u00f0B a \u00de ! 0 as a ! \u00fey. By (4.32) and (4.37) , thanks to what we just obtained about the w 1; a 's, we get that kv a k L y \u00f0B a \u00de ! 0 as a ! \u00fey. Proof of the uniform bounds in Theorem 0.3. Let \u00f0M; g\u00de be a smooth compact Riemannian 4-dimensional manifold and \u00f0\u00f0u a ; v a \u00de\u00de a be a sequence of smooth positive solutions of (4.1) such that (0.7) holds true. By Druet, Hebey and V\u00e9tois [22] there exists C > 0 such that for any a the following holds true: there exist N a A N ? and N a critical points of u a , denoted by \u00f0x 1; a ; x 2; a ; . . . ; x N a ; a \u00de, such that d g \u00f0x i; a ; x j; a \u00deu a \u00f0x i; a \u00de f 1 \u00f04:55\u00de for all i; j A f1; . . . ; N a g, i 3 j, and \u00c0 min Such an N R; a does exist thanks to (4.59). We also have that N R; a f 2 for all R > 1 and that \u00f0N R; a \u00de a is uniformly bounded for all R > 0 thanks to (4.57). In the sequel, we set x x i; a \u00bc d By the above discussion we get that (4.58) holds true. Clearly, this implies that \u00f0N a \u00de a is uniformly bounded. Let \u00f0x a \u00de a be a sequence of maximal points of u a . Thanks to (4.3) and to (4.58), we clearly have that (4.4) holds true for the sequences \u00f0x a \u00de a and r a \u00bc d for some d > 0 fixed. This clearly contradicts Lemma 4.2 and thus concludes the proof of the uniform bounds in Theorem 0.3. r", "cite_spans": [{"start": 34, "end": 38, "text": "[22]", "ref_id": "BIBREF21"}, {"start": 738, "end": 742, "text": "[22]", "ref_id": "BIBREF21"}], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Photon-mass bound destroyed by vortices", "authors": [{"first": "E", "middle": [], "last": "Adelberger", "suffix": ""}, {"first": "G", "middle": [], "last": "Dvali", "suffix": ""}, {"first": "A", "middle": [], "last": "Gruzinov", "suffix": ""}], "year": 2007, "venue": "Phys. Rev. Lett", "link": "31249827"}, "BIBREF1": {"title": "Layered solutions for a semilinear elliptic system in a ball", "authors": [{"first": "T", "middle": [], "last": "D&apos;aprile", "suffix": ""}, {"first": "J", "middle": [], "last": "Wei", "suffix": ""}], "year": 2006, "venue": "J. Di\u00a4. Eq", "link": "120521643"}, "BIBREF2": {"title": "Clustered solutions around harmonic centers to a coupled elliptic system", "authors": [{"first": "T", "middle": [], "last": "D&apos;aprile", "suffix": ""}, {"first": "J", "middle": [], "last": "Wei", "suffix": ""}], "year": 2007, "venue": "Ann. Inst. H. Poincar\u00e9 Anal. Non Lin\u00e9aire", "link": null}, "BIBREF3": {"title": "Equations di\u00a4\u00e9rentielles non lin\u00e9aires et probl\u00e8me de Yamabe concernant la courbure scalaire", "authors": [{"first": "T", "middle": [], "last": "Aubin", "suffix": ""}], "year": 1976, "venue": "J. Math. Pures Appl", "link": null}, "BIBREF4": {"title": "Solitary waves of the nonlinear Klein-Gordon field equation coupled with the Maxwell equations", "authors": [{"first": "V", "middle": [], "last": "Benci", "suffix": ""}, {"first": "D", "middle": [], "last": "Fortunato", "suffix": ""}], "year": 2002, "venue": "Rev. Math. Phys", "link": "120383189"}, "BIBREF5": {"title": "Spinning Q-balls for the Klein-Cordon-Maxwell equations", "authors": [{"first": "V", "middle": [], "last": "Benci", "suffix": ""}, {"first": "D", "middle": [], "last": "Fortunato", "suffix": ""}], "year": "", "venue": "Commun. Math. Phys", "link": null}, "BIBREF6": {"title": "Non-compactness and multiplicity results for the Yamabe problem on S n", "authors": [{"first": "M", "middle": [], "last": "Berti", "suffix": ""}, {"first": "A", "middle": [], "last": "Malchiodi", "suffix": ""}], "year": 2001, "venue": "J. Funct. Anal", "link": "121124572"}, "BIBREF7": {"title": "Blow-up phenomena for the Yamabe equation", "authors": [{"first": "S", "middle": [], "last": "Brendle", "suffix": ""}], "year": 2008, "venue": "J. Amer. Math. Soc", "link": "85507847"}, "BIBREF8": {"title": "On the conformal scalar curvature equation and related problems", "authors": [{"first": "S", "middle": [], "last": "Brendle", "suffix": ""}], "year": 2008, "venue": "Surv. Di\u00a4er. Geom. XII", "link": "17833584"}, "BIBREF9": {"title": "Blow-up phenomena for the Yamabe equation II", "authors": [{"first": "S", "middle": [], "last": "Brendle", "suffix": ""}, {"first": "Marques", "middle": [], "last": "", "suffix": ""}], "year": 2009, "venue": "J. Di\u00a4. Geom", "link": "18797566"}, "BIBREF10": {"title": "Some nonlinear elliptic equations have only constant solutions", "authors": [{"first": "H", "middle": [], "last": "Br\u00e9zis", "suffix": ""}, {"first": "Y", "middle": ["Y"], "last": "Li", "suffix": ""}], "year": 2006, "venue": "J. Part. Di\u00a4. Eq", "link": "16124181"}, "BIBREF11": {"title": "Positive solutions of nonlinear elliptic equations involving critical Sobolev exponents", "authors": [{"first": "H", "middle": [], "last": "Br\u00e9zis", "suffix": ""}, {"first": "L", "middle": [], "last": "Nirenberg", "suffix": ""}], "year": 1983, "venue": "Comm. Pure Appl. Math", "link": "204007073"}, "BIBREF12": {"title": "Cosmic tests of Maxwell's equations, I-A photon rest mass", "authors": [{"first": "J", "middle": ["C"], "last": "Byrne", "suffix": ""}], "year": 1977, "venue": "Astrophys. Space Sci", "link": null}, "BIBREF13": {"title": "Asymptotic symmetry and local behavior of semilinear elliptic equations with critical Sobolev growth", "authors": [{"first": "L", "middle": ["A"], "last": "Ca\u00a4arelli", "suffix": ""}, {"first": "B", "middle": [], "last": "Gidas", "suffix": ""}, {"first": "J", "middle": [], "last": "Spruck", "suffix": ""}], "year": 1989, "venue": "Comm. Pure Appl. Math", "link": "6516067"}, "BIBREF14": {"title": "From one bubble to several bubbles: The low-dimensional case", "authors": [{"first": "O", "middle": [], "last": "Druet", "suffix": ""}], "year": 2003, "venue": "J. Di\u00a4. Geom", "link": "117900405"}, "BIBREF15": {"title": "Compactness for Yamabe metrics in low dimensions", "authors": [{"first": "O", "middle": [], "last": "Druet", "suffix": ""}], "year": 2004, "venue": "Int. Math. Res. Not", "link": "55729610"}, "BIBREF16": {"title": "Elliptic equations of Yamabe type", "authors": [{"first": "O", "middle": [], "last": "Druet", "suffix": ""}, {"first": "E", "middle": [], "last": "Hebey", "suffix": ""}], "year": 2005, "venue": "Int. Math. Res. Surv", "link": "119911705"}, "BIBREF17": {"title": "Stability and instability for Einstein-scalar field Lichnerowicz equations on compact Riemannian manifolds", "authors": [{"first": "O", "middle": [], "last": "Druet", "suffix": ""}, {"first": "E", "middle": [], "last": "Hebey", "suffix": ""}], "year": 2009, "venue": "Math. Z", "link": "121315427"}, "BIBREF18": {"title": "Stability for strongly coupled critical elliptic systems in a fully inhomogeneous medium", "authors": [{"first": "O", "middle": [], "last": "Druet", "suffix": ""}, {"first": "E", "middle": [], "last": "Hebey", "suffix": ""}], "year": 2009, "venue": "Anal. PDEs", "link": "73631566"}, "BIBREF19": {"title": "Existence and a priori bounds for electrostatic Klein-Gordon-Maxwell systems in fully inhomogeneous spaces", "authors": [{"first": "O", "middle": [], "last": "Druet", "suffix": ""}, {"first": "E", "middle": [], "last": "Hebey", "suffix": ""}], "year": "", "venue": "Commun. Contemp. Math", "link": "119623402"}, "BIBREF20": {"title": "Blow-up theory for elliptic PDEs in Riemannian geometry", "authors": [{"first": "O", "middle": [], "last": "Druet", "suffix": ""}, {"first": "E", "middle": [], "last": "Hebey", "suffix": ""}, {"first": "F", "middle": [], "last": "Robert", "suffix": ""}], "year": 2004, "venue": "Math. Notes", "link": "17308412"}, "BIBREF21": {"title": "Bounded stability for strongly coupled critical elliptic systems below the geometric threshold of the conformal Laplacian", "authors": [{"first": "O", "middle": [], "last": "Druet", "suffix": ""}, {"first": "E", "middle": [], "last": "Hebey", "suffix": ""}, {"first": "J", "middle": [], "last": "V\u00e9tois", "suffix": ""}], "year": "", "venue": "J. Funct. Anal", "link": "121420761"}, "BIBREF22": {"title": "Stability of the Pohozaev obstruction in dimension 3", "authors": [{"first": "O", "middle": [], "last": "Druet", "suffix": ""}, {"first": "P", "middle": [], "last": "Laurain", "suffix": ""}], "year": "", "venue": "J. Eur. Math. Soc", "link": null}, "BIBREF23": {"title": "A priori bounds for positive solutions of nonlinear elliptic equations", "authors": [{"first": "B", "middle": [], "last": "Gidas", "suffix": ""}, {"first": "J", "middle": [], "last": "Spruck", "suffix": ""}], "year": 1981, "venue": "Comm. Part. Di\u00a4. Eq", "link": "121294800"}, "BIBREF24": {"title": "Terrestrial and Extraterrestrial limits on the photon mass", "authors": [{"first": "A", "middle": ["S"], "last": "Goldhaber", "suffix": ""}, {"first": "M", "middle": ["M"], "last": "Nieto", "suffix": ""}], "year": 1971, "venue": "Rev. Mod. Phys", "link": "119680346"}, "BIBREF25": {"title": "Photon and Graviton mass limits", "authors": [{"first": "A", "middle": ["S"], "last": "Goldhaber", "suffix": ""}, {"first": "M", "middle": ["M"], "last": "Nieto", "suffix": ""}], "year": 2010, "venue": "Rev. Mod. Phys", "link": "14395472"}, "BIBREF26": {"title": "Critical elliptic systems in potential form", "authors": [{"first": "E", "middle": [], "last": "Hebey", "suffix": ""}], "year": 2006, "venue": "Adv. Di\u00a4. Eq", "link": "117937956"}, "BIBREF27": {"title": "Diagonal compactness for critical elliptic systems in potential form", "authors": [{"first": "E", "middle": [], "last": "Hebey", "suffix": ""}], "year": 2007, "venue": "Comm. P.D.E", "link": "121801527"}, "BIBREF28": {"title": "A compactness theorem for the Yamabe Problem", "authors": [{"first": "M", "middle": [], "last": "Khuri", "suffix": ""}, {"first": "F", "middle": ["C"], "last": "Marques", "suffix": ""}, {"first": "R", "middle": [], "last": "Schoen", "suffix": ""}], "year": "", "venue": "J. Di\u00a4. Geom", "link": "51855503"}, "BIBREF29": {"title": "On the optimal regularity for Yang-Mills equations in R 4\u00fe1", "authors": [{"first": "S", "middle": [], "last": "Klainerman", "suffix": ""}, {"first": "D", "middle": [], "last": "Tataru", "suffix": ""}], "year": 1999, "venue": "Amer. Math. Soc", "link": "39728444"}, "BIBREF30": {"title": "Yamabe type equations on three dimensional Riemannian manifolds", "authors": [{"first": "Y", "middle": ["Y"], "last": "Li", "suffix": ""}, {"first": "L", "middle": [], "last": "Zhang", "suffix": ""}], "year": 1999, "venue": "", "link": "120831561"}, "BIBREF31": {"title": "Liouville-type theorems and Harnack-type inequalities for semilinear elliptic equations", "authors": [{"first": "Y", "middle": ["Y"], "last": "Li", "suffix": ""}, {"first": "L", "middle": [], "last": "Zhang", "suffix": ""}], "year": 2003, "venue": "J. Anal. Math", "link": "9372177"}, "BIBREF32": {"title": "A Harnack type inequality for the Yamabe equations in low dimensions", "authors": [{"first": "Y", "middle": ["Y"], "last": "Li", "suffix": ""}, {"first": "L", "middle": [], "last": "Zhang", "suffix": ""}], "year": 2004, "venue": "Calc. Var. Part. Di\u00a4. Eq", "link": null}, "BIBREF33": {"title": "Compactness of solutions to the Yamabe problem II", "authors": [{"first": "Y", "middle": ["Y"], "last": "Li", "suffix": ""}, {"first": "L", "middle": [], "last": "Zhang", "suffix": ""}], "year": 2005, "venue": "Calc. Var. PDE", "link": "7240184"}, "BIBREF34": {"title": "Existence and stability of solitary waves in non-linear Klein-Gordon-Maxwell equations", "authors": [{"first": "E", "middle": [], "last": "Long", "suffix": ""}], "year": 2006, "venue": "Rev. Math. Phys", "link": "121086751"}, "BIBREF35": {"title": "E\u00a4ective dynamics for solitons in the nonlinear Klein Gordon Maxwell system and the Lorentz force law", "authors": [{"first": "E", "middle": [], "last": "Long", "suffix": ""}, {"first": "D", "middle": [], "last": "Stuart", "suffix": ""}], "year": 2009, "venue": "", "link": "14984086"}, "BIBREF36": {"title": "The mass of the photon", "authors": [{"first": "J", "middle": [], "last": "Luo", "suffix": ""}, {"first": "G", "middle": ["T"], "last": "Gillies", "suffix": ""}, {"first": "L", "middle": ["C"], "last": "Tu", "suffix": ""}], "year": 2005, "venue": "Rep. Prog. Phys", "link": null}, "BIBREF37": {"title": "Experimental tests of Coulomb's Law and the photon rest mass", "authors": [{"first": "J", "middle": [], "last": "Luo", "suffix": ""}, {"first": "L", "middle": ["C"], "last": "Tu", "suffix": ""}], "year": 2004, "venue": "Metrologia", "link": null}, "BIBREF38": {"title": "A priori estimates for the Yamabe problem in the non-locally conformally flat case", "authors": [{"first": "F", "middle": ["C"], "last": "Marques", "suffix": ""}], "year": 2005, "venue": "J. Di\u00a4. Geom", "link": "18169245"}, "BIBREF39": {"title": "Blow-up solutions for asymptotically critical elliptic equations on Riemannian manifolds", "authors": [{"first": "A", "middle": ["M"], "last": "Micheletti", "suffix": ""}, {"first": "A", "middle": [], "last": "Pistoia", "suffix": ""}, {"first": "J", "middle": [], "last": "V\u00e9tois", "suffix": ""}], "year": 2009, "venue": "Indiana Univ. Math. J", "link": "13593501"}, "BIBREF40": {"title": "Relativistic field theories of elementary particles", "authors": [{"first": "W", "middle": [], "last": "Pauli", "suffix": ""}], "year": 1941, "venue": "Rev. Mod. Phys", "link": "120031185"}, "BIBREF41": {"title": "Global regularity for the Maxwell-Klein-Gordon equation with small critical Sobolev norm in high dimensions", "authors": [{"first": "I", "middle": [], "last": "Rodnianski", "suffix": ""}, {"first": "T", "middle": [], "last": "Tao", "suffix": ""}], "year": 2004, "venue": "Comm. Math. Phys", "link": null}, "BIBREF42": {"title": "The Stueckelberg field", "authors": [{"first": "H", "middle": [], "last": "Ruegg", "suffix": ""}, {"first": "M", "middle": [], "last": "Ruiz-Altaba", "suffix": ""}], "year": 2004, "venue": "Int. J. Mod. Phys. A", "link": null}, "BIBREF43": {"title": "Variational theory for the total scalar curvature functional for Riemannian metrics and related topics", "authors": [{"first": "R", "middle": [], "last": "Schoen", "suffix": ""}], "year": 1987, "venue": "Topics in Calculus of Variations", "link": "53535698"}, "BIBREF44": {"title": "On the number of constant scalar curvature metrics in a conformal class, in: Di\u00a4erential Geometry: A Symposium in Honor of Manfredo do Carmo", "authors": [{"first": "R", "middle": [], "last": "Schoen", "suffix": ""}], "year": 1988, "venue": "Proc. Int. Conf. (Rio de", "link": null}, "BIBREF45": {"title": "The Earth's and the Sun's permanent magnetic fields in the unitary field theory", "authors": [{"first": "E", "middle": [], "last": "Schr\u00f6dinger", "suffix": ""}], "year": 1943, "venue": "Proc. Roy. Irish Acad. (A)", "link": null}, "BIBREF46": {"title": "Almost optimal local well-posedness of the Klein-Gordon-Maxwell system in 1 \u00fe 4 dimensions", "authors": [{"first": "S", "middle": [], "last": "Selberg", "suffix": ""}], "year": 2002, "venue": "Comm. Part. Di\u00a4. Eq", "link": null}, "BIBREF47": {"title": "Multiple solutions for nonlinear elliptic equations on compact Riemannian manifolds", "authors": [{"first": "J", "middle": [], "last": "V\u00e9tois", "suffix": ""}], "year": 2007, "venue": "Int. J. Math", "link": "44672076"}}, "ref_entries": {"FIGREF0": {"text": "The subcritical 4-dimensional case). Let \u00f0M; g\u00de be a smooth compact 4-dimensional Riemannian manifold, q > 0, m 0 ; m 1 > 0, o A \u00f0\u00c0m 0 ; m 0 \u00de, and p A \u00f02; 4\u00de. Then (0.3) possesses a smooth positive mountain pass solution. Moreover, for any y A \u00f00; 1\u00de, there exists C > 0 such that for any o 0 A K 0 \u00f00\u00de, and any U A S p \u00f0o 0 \u00de, kUk C 2; y e C, where S p \u00f0o 0 \u00de is as in (0.4) and K 0 \u00f00\u00de is as in (0.5).", "type": "figure"}, "FIGREF1": {"text": "The critical 4-dimensional case). Let \u00f0M; g\u00de be a smooth compact 4-dimensional Riemannian manifold, q > 0, m 0 ; m 1 > 0, o A \u00f0\u00c0m 0 ; m 0 \u00de, and p \u00bc 4.x A M. Then (0.3) possesses a smooth positive mountain pass solution. Assuming that (0.7) holds true for all x A M there also holds that for any y A \u00f00; 1\u00de, kUk C 2; y e C for all U A S 4 \u00f0o 0 \u00de and all o 0 A K 0 \u00f0o\u00de, where C > 0 does not depend on o 0 and U, S 4 \u00f0o 0 \u00de is as in (0.4), and K 0 \u00f0o\u00de is as in (0.5).", "type": "figure"}, "FIGREF2": {"text": "(i) Phase compensation in the critical case. Assume p \u00bc 4 and S g > 0 in M. Then there exists e > 0 such that for any m 0 \u00c0 e < joj < m 0 , (0.3) possesses a smooth positive mountain pass solution. Moreover, for any y A \u00f00; 1\u00de, there exists C > 0 such that kUk C 2; y e C for all U A S 4 \u00f0o\u00de and all m 0 \u00c0 e < joj < m 0 . (iii) Full phase range in the critical case. Assume p \u00bc 4o A \u00f0\u00c0m 0 ; m 0 \u00de, (0.3) possesses a smooth positive mountain pass solution. Moreover, for any y A \u00f00; 1\u00de, there exists C > 0 such that kUk C 2; y e C for all U A S 4 \u00f0o\u00de and all o A \u00f0\u00c0m 0 ; m 0 \u00de.", "type": "figure"}, "FIGREF3": {"text": "the two last equations in (1.3) give rise to the first pair of the Maxwell-Proca equa- tions (0.2) with 0 \u00bc m 0 \u00bc 1 (units are chosen such that c \u00bc 1) and m 2 \u00bc m 2 1 , while the two first equations in (1.4) give rise to the second pair of the equations. The first equation in (1.3) gives rise to the nonlinear Klein-Gordon matter equation. The second", "type": "figure"}, "FIGREF5": {"text": "some d 0 > 0, where c p \u00bc c p \u00f0u 0 \u00de is as in (2", "type": "figure"}, "FIGREF6": {"text": "C 2 > 0 are independent of u, there holds that there exist d 1 ; d 2 > 0 such that d 1 , d 2 are as small as we want, and I 4 \u00f0u\u00de f d 2 for all u such that kuk H 1 \u00bc d 1 . As a conclusion, there exists d 0 > 0 such that (2.16) holds true. This ends the proof of the existence part in Theorem 0.3. r 3. A priori bounds in the subcritical case We prove the uniform bounds in the subcritical case of Theorem 0.2. In what follows p A \u00f02; 4\u00de.", "type": "figure"}, "FIGREF7": {"text": "some C > 0 independent of a. This implies u > 0 and then v > 0. Obviously the posi- tivity of u and v does not hold anymore if we allow o\u00f0e a \u00de a be a sequence of positive real numbers such that e a ! 0 as a ! \u00fey. Let u a \u00bcThen u a ! 0 and v a ! 0 in C 2 as a ! \u00fey, and we do have that \u00f0u a ; v a \u00de solves (a ! \u00fey and the construction provides a counter example to the above statement about the positivity of u and v.", "type": "figure"}, "FIGREF8": {"text": "all a. By the second equation in (4.1), 0 e v a e 1 q for all a. In particular, if we letkh a k L y e C for all a, where C > 0 is independent of a. Assume by contradiction that max M u a ! \u00fey \u00f04:3\u00de as a ! \u00fey.", "type": "figure"}, "FIGREF9": {"text": "Let \u00f0M; g\u00de be a smooth compact Riemannian 4-dimensional manifold and \u00f0\u00f0u a ; v a \u00de\u00de a be a sequence of smooth positive solutions of (4.1) such that (4.3) holds true. Let \u00f0x a \u00de a and \u00f0r a \u00de a be such that (4.4) holds true. Assume (0.7). There holds that r a ! 0 as a ! \u00fey, where r a is as in (4.8). Moreover r a \u00bc O\u00f0r aas a ! \u00fey, where m a is as in (4", "type": "figure"}, "FIGREF10": {"text": "a ! \u00fey, where W satisfies D\u0169 u \u00bc 0 in B 0 R 2 nf0g and D is the Euclidean Laplace-Beltrami operator. Moreover, thanks to (4.16), we know that j\u0169 u\u00f0x\u00dej e CjxjL f 0 and H satisfies DH \u00bc 0 in B 0 R 2 . In order to see that L \u00bc 8, it is su\u2030cient to integrate (4.17) in B 0 \u00f01\u00de to get that \u00c0 \u00d0 qB 0 \u00f01\u00de", "type": "figure"}, "FIGREF12": {"text": "u a dsg g a \u00bc \u00c02o 3 L; \u00f04:24\u00de we get that L \u00bc 8 thanks to (4.22)-(4.24) by passing into the limit in (4.21) as a ! \u00fey. At this point we claim that there exists b A \u00f00; 1 and C > 0 such that", "type": "figure"}, "FIGREF13": {"text": "a ! \u00fey. In order to prove (4.39) we proceed by contradiction and assume that r a f d 0 > 0 for all a g 1. By Lemma 4.1 and (4.25), v a e Cm b a in MnB x a \u00f0r a \u00de; \u00f04:40\u00de", "type": "figure"}, "FIGREF14": {"text": ", for all i. For any R > 0, we also let 1 e N R; a e N a be such that d g \u00f0x 1; a ; x i; a \u00de e Rd a for 1 e i e N R; a ; and d g \u00f0x 1; a ; x i; a \u00de > Rd a for N R; a \u00fe 1 e i e N a :", "type": "figure"}, "FIGREF15": {"text": "1 e i e N a such that d g \u00f0x 1; a ; x i; a \u00de e 1 2 i g . Thanks to (4.56), for any R > 1, there exists C R >u a e C R : \u00f04:61\u00de By the Harnack inequality in Druet, Hebey and V\u00e9tois [22], for any R > 1, there exists D R > 1 such that k'\u00fb u a k L y \u00f0W R; a \u00de e D R su W R; a p\u00fb u a e D 2 R inf W R; a\u00fb u a ; \u00f04:62\u00de where W R; a \u00bc B 0 \u00f0R\u00den S N 2R; a i\u00bc1 Bx x i; a 1 R : wherev v a \u00bc\u00fb u a \u00f00\u00de\u00fb u a . Applying Lemma 4.2 and standard elliptic theory, and thanks to (4.62) and to the above discussion, one easily checks that, after passing to a subsequence, u u a \u00f00\u00de\u00fb u a !\u011c G in C 1 loc \u00f0R n nfx x i g i A I \u00de as a ! \u00fey, where I \u00bc f1; . . .in B 0 \u00f0R\u00de, where 2 e\u00d1 N R e N 2R is such that jx x\u00d1 N R j e R and jx x\u00d1 N R \u00fe1 j > R, where N 2R; a ! N 2R as a ! \u00fey, where l i > 0, and where\u0124 H R is a harmonic function in B 0 \u00f0R\u00de. Since\u011c G f 0, we can write thanks to the maximum principle that, in a neighbourhood of the origin,H\u00f00\u00de f L 2 \u00c0 L 1 R \u00c02 \u00c0 L 2 \u00f0R \u00c0 1\u00de \u00c02 . Choosing R large enough, we can ensure that H H\u00f00\u00de > 0 and this is in contradiction with Lemma 4.2.", "type": "figure"}, "TABREF0": {"text": "). Let \u00f0M; g\u00de be a smooth compact 3-dimensional Riemannian manifold m 0 ; m 1 > 0, o A \u00f0\u00c0m 0 ; m 0 \u00de, and p A \u00f02; 6. When p \u00bc 6 assume", "type": "table"}, "TABREF1": {"text": "and c p \u00bc c p \u00f0u 0 \u00de be given by c p \u00bc inf", "type": "table"}, "TABREF3": {"text": "By (2.15), there exists T 0 g 1 such that I 4 \u00f0T 0 u a \u00de < 0 for all a g 1. There also holds that", "type": "table"}, "TABREF4": {"text": "1\u00deas a ! \u00fey. Let x a A M and m a > 0 be given by u a \u00f0x a \u00de \u00bc max M u a \u00bc mBy (3.2), m a ! 0 as a ! \u00fey. Define\u0169 u a b\u1ef9 u u a \u00f0x\u00de \u00bc mwherev v a is given byv v a \u00f0x\u00de \u00bc v a \u00c0 exp x a \u00f0m a x\u00de \u00c1 . We have\u0169 u a \u00f00\u00de \u00bc 1 and 0 e\u0169 u a e 1. By (3.3) and standard elliptic theory arguments, we can write that, after passing to a subsequence, u u a ! u in C\u00de as a ! \u00fey, where u is such that u\u00f00\u00de \u00bc 1 and 0 e u e 1. Then", "type": "table"}, "TABREF5": {"text": "'u a \u00f0x a \u00de \u00bc 0 for all a; d g \u00f0x a ; x\u00deu a \u00f0x\u00de e C for all x A B x a \u00f07r a \u00de and all a; limWe let m a be given by m a \u00bc u a \u00f0x a \u00dewhere jqB x a \u00f0r\u00dej g is the volume of the sphere of center x a and radius r for the induced metric.as a ! \u00fey, while the definition of r a gives that rj a \u00f0r\u00de is non-increasing in \u00bdLm a ; r a \u00f04:10\u00deLet B a be defined in M by", "type": "table"}, "TABREF6": {"text": "u a \u00f0x\u00de \u00fe d g \u00f0x a ; x\u00dej'u a \u00f0x\u00dej e Cm a d g \u00f0x a ; x\u00dein B x a \u00f02r a \u00denfx a g for all a, where e a ! 0 as a ! \u00fey and S a \u00f0x\u00de \u00bc d g \u00f0x a ; x\u00de \u00c01 for x A Mnfx a g.", "type": "table"}, "TABREF7": {"text": "xa \u00f0r a \u00deAt this point we decompose v a into a quasi-harmonic part with nonzero Dirichlet boundary condition and a quasi-Poisson part with zero Dirichlet boundary condition. More precisely, we write that v a \u00bc w 1; a \u00fe w 2; a \u00f04:32\u00de in B a \u00bc B x a \u00f0r r a \u00de, wherer r a \u00bcLet G a be Green's function of D g \u00fe m 2 1 in B a with zero Dirichlet boundary condition on qB a . By the maximum principle, considering Green's function on a larger ball of radius i g , we obtain by comparison of the two Green functions that there exists C > 0 such that G a \u00f0x; y\u00de e Cd g \u00f0x; y\u00de \u00c02 for all x 3 y in B a . Writing that", "type": "table"}, "TABREF8": {"text": "u a v a jX a \u00f0'u a \u00dej dv g \u00bc o mIn case (i), since v a \u00bc O\u00f01\u00de, we get from Lemma 4.1 and (4.29) that \u00d0 B xa \u00f0r a \u00de v a u 2 a dv g \u00bc O mB xa \u00f0r a \u00de v a u a jX a \u00f0'u a \u00dej dv g \u00bc O mSince there also holds that rH\u00f00\u00de \u00bc 0. Now we assume (ii). From (ii) we get r a f C lnIn particular, kv a k L y \u00f0qB a \u00de ! 0 as a ! \u00fey. Then kv v a k L y \u00f0qB\u00de ! 0 as a ! \u00fey, and it follows from the maximum principle and (4.38) that k\u0175 w 1; a k L y \u00f0B\u00de ! 0 as a ! \u00fey. In particular, kw 1; a k L y \u00f0B a \u00de ! 0 as a ! \u00fey and we get with (4.32), Lemma 4.1, and (4.29), that \u00d0 B xa \u00f0r a \u00deB xa \u00f0r a \u00de v a u a jX a \u00f0'u a \u00dej dv g \u00bc \u00d0 B xa \u00f0r a \u00de w 2; a u a jX a \u00f0'u a \u00dej dv g \u00fe o mLet h : R n ! R be such that h is smooth, 0 e h e 1, h \u00bc 1 in B 0 \u00f01\u00de, and h \u00bc 0 in R n nB 0 \u00f02\u00de. We define h a \u00f0x\u00de \u00bc h d g \u00f0x a ; x\u00de r a \u00f04:46\u00de so that h a \u00bc 1 in B x a \u00f0r a \u00de and h a \u00bc 0 in MnB x a \u00f02r a \u00de. By H\u00f6 lder's inequalities, \u00d0 B xa \u00f0r a \u00de w 2; a uB xa \u00f0r a \u00de u a w 2; a jX a \u00f0'u a \u00dej dv g e \u00d0B xa \u00f0r a \u00de ju a X a \u00f0'u a \u00dej 4=3 dv g \u00bc O\u00f0ma w 2; a , and integrating over M, we get \u00d0\u00f0D g w 2; a \u00fe m 2 1 w 2; a \u00deh 2 a w 2; a dv g e q \u00d0By H\u00f6 lder's and Sobolev inequalities, and by (4.48),a dv g e Cm a kh a w 2; a k H 1 \u00f04:50\u00de and it follows from (4.49) and (4.50) that kh a w 2; a k; a dv g \u00fe Cm a kh a w 2; a k H 1 : \u00f04:51\u00de By (4.37), since j'h a j e CrBy (4.44), (4.47) and (4.48), we then get with (4.52) that \u00d0 B xa \u00f0r a \u00de v a u 2 a dv g \u00bc o mB xa \u00f0r a \u00de u a v a jX a \u00f0'u a \u00dej dv g \u00bc o mBy (4.54) we get that H\u00f00\u00de e 0. At this point it remains to prove that r a \u00bc O\u00f0r a \u00de. We prove that r a \u00bc r a . If it is not the case, then r a < r a and we get with (4.11) thatHence H\u00f00\u00de \u00bc 8 and we get a contradiction with H\u00f00\u00de e 0. In other words, r a \u00bc r a for all a g 1. This ends the proof of the lemma. r Thanks to Lemma 4.2 we can now prove the uniform bounds in Theorem 0.3. This is the subject of what follows.", "type": "table"}, "TABREF9": {"text": "i\u00bc1;...; N a d g \u00f0x i; a ; x\u00de \u00c1 u a \u00f0x\u00de e C \u00f04:56\u00de for all x A M and all a. We define d a \u00bc min 1ei< jeN a d g \u00f0x i; a ; x j; a \u00de: \u00f04:57\u00de If N a \u00bc 1, we set d a \u00bc 1 4 i g , where i g is the injectivity radius of \u00f0M; g\u00de. We claim thatas a ! \u00fey. In order to prove this claim, we proceed by contradiction. Assuming on the contrary that d a ! 0 as a ! \u00fey, we see that N a f 2 for a large, and we can thus assume that the concentration points are ordered in such a way that d a \u00bc d g \u00f0x 1; a ; x 2; a \u00de e d g \u00f0x 1; a ; x 3; a \u00de e \u00c1 \u00c1 \u00c1 e d g \u00f0x 1; a ; x N a ; a \u00de: \u00f04:59\u00de We set, for x A B 0 \u00f0dd \u00c01 a \u00de, 0 < d <u u a \u00f0x\u00de \u00bc d a u a \u00c0 exp x 1; a \u00f0d a x\u00de \u00c1 ; h h a \u00f0x\u00de \u00bc h a \u00c0 exp x 1; a \u00f0d a x\u00de \u00c1 and\u011d g a \u00f0x\u00de \u00bc \u00f0expIt is clear that\u011d g a ! x in Cloc \u00f0R n \u00de as a ! \u00fey since d a ! 0 as a ! \u00fey. Thanks to (4.1) we have D\u011d g a\u00fb u a \u00fe da\u0125 h a\u00fb u a \u00bc\u00fb u", "type": "table"}}}
{"paper_id": "199665735", "_pdf_hash": "cea3329eecd54ef24c394f81aa89c7d50170c5a9", "abstract": [{"section": "Abstract", "text": "Type II arabinogalactan (AG) is a polysaccharide found in Maytenus ilicifolia (Celastraceae), a plant reputed as gastroprotective. Oral and intraperitoneal administration of the AG protected rats from gastric ulcers induced by ethanol. No alteration of mechanisms related to acid gastric secretion and gastrointestinal motility were observed. In vitro, the AG showed a potent scavenging activity against the radical of DPPH (2,2-diphenyl-1-picrylhydrazyl) with an IC 50 value of 9.3 \u00b5M. However, the mechanism of the gastroprotective action remains to be identifi ed.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Maytenus ilicifolia, a plant popularly known in Brazil as \"espinheira santa\", is extensively used to treat stomach disorders (Cruz, 1982; Macaubas et al., 1988) . The gastroprotective properties of various extracts of M. ilicifolia have been shown in experimental ulcer models using rodents (Baggio et al., 2007; Ferreira et al., 2004; Jorge et al., 2004; Souza-Formigoni et al., 1991; Tabach and Oliveira, 2003) . Our laboratory identifi ed inhibition of gastric acid secretion and modulation of nitric oxide in the mechanism of activity of a fl avonoid-rich extract containing galactitol (25%), epicatechin (3.1%), and catechin (2%) as the major components (Baggio et al., 2007) .", "cite_spans": [{"start": 125, "end": 137, "text": "(Cruz, 1982;", "ref_id": "BIBREF5"}, {"start": 138, "end": 160, "text": "Macaubas et al., 1988)", "ref_id": "BIBREF13"}, {"start": 313, "end": 335, "text": "Ferreira et al., 2004;", "ref_id": "BIBREF7"}, {"start": 336, "end": 355, "text": "Jorge et al., 2004;", "ref_id": "BIBREF12"}, {"start": 356, "end": 385, "text": "Souza-Formigoni et al., 1991;", "ref_id": "BIBREF21"}, {"start": 386, "end": 412, "text": "Tabach and Oliveira, 2003)", "ref_id": "BIBREF26"}], "ref_spans": []}, {"section": "Introduction", "text": "The polysaccharide arabinogalactan is found as an essential structural polymer of the cell wall of plants and as a major component of many gums and exudates (Delgobo et al., 1998; Fincher et al., 1983) . Several plants have been reported to contain polysaccharides of this type, and its presence has been correlated with a variety of biological activities such as antiviral, antitumour, immune-stimulating, anti-infl ammatory, anticoagulant, hypoglycemic, and antiulcer (Capek et al., 2003; Nergard et al., 2005; Srivastava and Kulshreshtha, 1989; Yamada, 1994) . Furthermore, our laboratory showed a potent antiulcer activity of this compound in the ethanol-induced gastric injury model (Cipriani et al., 2006) .", "cite_spans": [{"start": 157, "end": 179, "text": "(Delgobo et al., 1998;", "ref_id": "BIBREF6"}, {"start": 180, "end": 201, "text": "Fincher et al., 1983)", "ref_id": "BIBREF8"}, {"start": 470, "end": 490, "text": "(Capek et al., 2003;", "ref_id": "BIBREF3"}, {"start": 491, "end": 512, "text": "Nergard et al., 2005;", "ref_id": "BIBREF14"}, {"start": 513, "end": 547, "text": "Srivastava and Kulshreshtha, 1989;", "ref_id": "BIBREF22"}, {"start": 548, "end": 561, "text": "Yamada, 1994)", "ref_id": "BIBREF27"}, {"start": 688, "end": 711, "text": "(Cipriani et al., 2006)", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "Introduction", "text": "In this study, we screened the effects of the arabinogalactan against the experimental models of gastric hypersecretion, ulcer, and gastrointestinal motility in which Maytenus ilicifolia, from which this compound has been isolated, showed potent gastroprotective activity. Isolation and identifi cation of the AG has been described in detail elsewhere (Cipriani et al., 2006) . The content of this purifi ed AG in M. ilicifolia was 0.38% w/w and its average molar mass (M) was 11400 g/mol.", "cite_spans": [{"start": 352, "end": 375, "text": "(Cipriani et al., 2006)", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "Material and Methods", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Plant material", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Leaves of Maytenus ilicifolia", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Animals", "text": "Female Wistar rats (180 -200 g) and female Swiss mice (25 -30 g) were from UFPR colony and were maintained under standard laboratory conditions [12 h/12 h light/dark cycle, (22 \uf0b1 2) \u00b0C]. Standard pellet food (Nuvital \u00ae ; Quimtia, Curitiba, PR, Brazil) and water were ad libitum. The rats and mice were deprived of food for 16 h and 6 h, respectively, prior to the start of experiments. All experimental protocols using animals were performed according to the \"Principles of Laboratory Animal Care\" (NIH Publication 85 -23, revised 1985) and after approval of the respective protocols by the Committee of Animal Experimentation of Federal University of Paran\u00e1, Curitiba, PR, Brazil (CEUA/BIO-UFPR, protocol 167).", "cite_spans": [], "ref_spans": []}, {"section": "Induction of acute gastric lesions in rats", "text": "The experiment was carried out according to the method described by Robert et al. (1979) . Rats (n = 6) were treated with vehicle [control: water or saline, 0.1 ml/100 g body weight (BW), ", "cite_spans": [{"start": 68, "end": 88, "text": "Robert et al. (1979)", "ref_id": "BIBREF17"}], "ref_spans": []}, {"section": "Induction of hypersecretion by pylorus ligature in rats", "text": "A pylorus ligature according to the method of Shay et al. (1945) was carefully done in fasted female rats (n = 6) under anaesthesia. Either the vehicle [water, 0.1 ml/100 g BW, intraduodenal (i.d.)] or arabinogalactan (AG: 10, 30, and 100 mg/ kg BW, i.d.) was administered immediately after pylorus ligation to the respective groups. Omeprazole (Ome: 40 mg/kg BW, p.o.) was given 1 h before surgery. After 4 h of pylorus ligature, animals were killed, the stomachs were opened, and gastric secretions collected. Volume and total gastric acidity were measured immediately (Baggio et al., 2007) .", "cite_spans": [{"start": 46, "end": 64, "text": "Shay et al. (1945)", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "Determination of gastrointestinal motility", "text": "Fasted female Swiss mice (n = 8) were treated with vehicle (control: water, 0.1 ml/10 g BW, p.o.), arabinogalactan (AG: 10, 30, and 100 mg/kg BW, p.o.) or atropine [A: 3 mg/kg BW, subcutaneous (s.c.)]. After 1 h, animals received 0.5 ml of a semisolid solution of 0.05% phenol red in 1.5% methylcellulose. After 15 min, the animals were killed and the stomach and small intestine quickly removed. Gastric emptying (GE) was measured as the amount of marker that remained in the stomach at the end of the experiment. Each stomach was homogenized with 7 ml distilled water and centrifuged at 1300 x g for 15 min. Equal amounts (1 ml) of supernatant and 0.025 M NaOH were mixed and the absorbance measured using a spectrophotometer at 560 nm. GE (%) was calculated using the equation: %GE = 100 \u2212 (X \u00b7 100/Y), where X is the absorbance of phenol red recovered from the stomach of animals sacrifi ced 15 min after the administration of marker, and Y is the mean (n = 8) absorbance of phenol red recovered from the stomachs of control animals (killed immediately after administration of the marker).", "cite_spans": [], "ref_spans": []}, {"section": "Determination of gastrointestinal motility", "text": "Intestinal transit (IT) was measured as the distance travelled by the marker in the small intestine. Briefl y, the small intestine was dissected from the pylorus to the ileocaecal junction. The total length of the small intestine and the distance travelled by phenol red were then measured. IT was calculated as: %IT = X/Y \u00b7 100, where X is the distance travelled by phenol red, and Y is the total length of the small intestine (Suchitra et al., 2003) .", "cite_spans": [{"start": 428, "end": 451, "text": "(Suchitra et al., 2003)", "ref_id": "BIBREF24"}], "ref_spans": []}, {"section": "DPPH free radical scavenging assay", "text": "The free radical scavenging activity of arabinogalactan using the DPPH (2,2-diphenyl-1-picrylhydrazyl) radical was determined with a slightly modifi ed method described by Blois (1958) . Aliquots of arabinogalactan (0.75 ml, to give fi nal concentrations of 0.3, 3, and 30 \u00b5M) were mixed with 0.25 ml DPPH radical solu-tion in methanol. The decrease in absorbance at 517 nm was measured after 5 min. For all experiments, the vehicle (distilled water) of arabinogalactan was used as negative control; ascorbic acid (300 \u00b5M) was used as a reference control. Experiments were performed in triplicate. Concentrations of DPPH were calculated using an extinction coeffi cient on 0.999 M/cm.", "cite_spans": [{"start": 172, "end": 184, "text": "Blois (1958)", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "Statistical analysis", "text": "Data were expressed as means + standard error of mean (S.E.M.) Statistical signifi cance of the results was determined using one-way analysis of variance (ANOVA) followed by Bonferroni's test. Data were considered different at a significance level of P < 0.05. The inhibitory concentration or dose 50 (IC 50 or ID 50 ) were calculated by fi tting the data to the equation: Vi/Vo = 1/(1 + [I]/ IC 50 ) using the KhaleidaGraph 3.0 for Windows program (Synergy Software, Reading, PA, USA), where Vi is the total activity, Vo is the remaining activity, and [I] is the inhibitor concentration.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Effects on acute gastric lesions", "text": "Oral treatment of animals with the arabinogalactan (10 -100 mg/kg BW) protected the mucosa against gastric lesions induced by ethanol in a dose-related manner. The ID 50 value was 9.3 mg/ kg BW when administered orally (Cipriani et al., 2006) . Intraperitoneal administration of arabinogalactan (10 mg/kg BW) reduced the ethanolinduced gastric lesions by 50% [injured control group value = (47.9 \uf0b1 3.7) mm 2 ] (Fig. 1) . Omeprazole (40 mg/kg BW, p.o.), used as a positive control, reduced the gastric lesions induced by ethanol by 62% (Fig. 1) .", "cite_spans": [{"start": 219, "end": 242, "text": "(Cipriani et al., 2006)", "ref_id": "BIBREF4"}], "ref_spans": [{"start": 410, "end": 418, "text": "(Fig. 1)", "ref_id": "FIGREF1"}, {"start": 535, "end": 543, "text": "(Fig. 1)", "ref_id": "FIGREF1"}]}, {"section": "Effects on gastric acid secretion", "text": "Hypersecretion induced by pylorus ligature for 4 h was not altered by any tested dose of the arabinogalactan up to 100 mg/kg BW (i.d.). Omeprazole, positive control of the test, inhibited the gastric volume and total acidity by 44 and 92%, respectively (Table I) .", "cite_spans": [], "ref_spans": [{"start": 253, "end": 262, "text": "(Table I)", "ref_id": "TABREF1"}]}, {"section": "Effects on gastrointestinal motility", "text": "No alteration on gastric emptying or intestinal transit as measured by the semisolid solution propulsion was observed with doses up to 100 mg/ kg BW (p.o.) arabinogalactan. Atropine, used as positive control, reduced gastric emptying by 47% and the intestinal transit by 70% (Table I) .", "cite_spans": [], "ref_spans": [{"start": 275, "end": 284, "text": "(Table I)", "ref_id": "TABREF1"}]}, {"section": "Effects on DPPH scavenging activity", "text": "Arabinogalactan scavenged DPPH radicals, with an IC 50 value of 9.3 \u00b5M when compared with the control [(0.305 \uf0b1 0.005) M] (Fig. 2) . Ascorbic acid (300 \u00b5M), the reference compound, scavenged DPPH radicals by 68% when tested under the same experimental conditions.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "The results of this study show the potent antiulcer effect of the arabinogalactan isolated from M. ilicifolia against irritant actions of ethanolinduced gastric injury. Ethanol destroys the protective factors of the mucosa, such as mucus barrier (Hirschowitz, 1989) and non-proteic sulfhydryl (NP-SH) groups (Siegmund et al., 2003) . Increase of oxygen-derived free radicals (Pihan et al., 1987) and of vascular permeability (Szabo et al., 1985) as well as apoptosis of gastric cells (Piotrowski et al., 1997) are also known processes involved in ethanol injury. In this study, the effects of the arabinogalactan on the most common pathways of gastroprotection during gastric injury including antioxidant activity, gastric secretion, and motility were determined. The antioxidant potential (DPPH free radical scavenging activity) of the arabinogalactan was moderate. Similar results were pre viously shown for an arabinogalactan isolated from Tinospora cordifolia (Subramanian et al., 2002) .", "cite_spans": [{"start": 246, "end": 265, "text": "(Hirschowitz, 1989)", "ref_id": "BIBREF11"}, {"start": 308, "end": 331, "text": "(Siegmund et al., 2003)", "ref_id": "BIBREF20"}, {"start": 375, "end": 395, "text": "(Pihan et al., 1987)", "ref_id": "BIBREF15"}, {"start": 425, "end": 445, "text": "(Szabo et al., 1985)", "ref_id": "BIBREF25"}, {"start": 484, "end": 509, "text": "(Piotrowski et al., 1997)", "ref_id": "BIBREF16"}, {"start": 964, "end": 990, "text": "(Subramanian et al., 2002)", "ref_id": "BIBREF23"}], "ref_spans": []}, {"section": "Discussion", "text": "Intraduodenal administration of the arabinogalactan in animals with gastric hypersecretion induced by pylorus ligature did not alter the gastric acid secretion of the animals indicating that the histaminergic and muscarinic pathways as well as activity of the gastric ATPase were not involved in the gastroprotection provided by the arabinogalactan. Confi rmatory experiments in vitro using isolated H + ,K + -ATPase showed weak activity (IC 50 = 3.4 mg/ml, data not shown). A topical effect of the compound on the gastric mucosa could explain the gastroprotection against ethanol injury, but since the arabinogalactan maintained its protective activity against ethanol when administered intraperitoneally discards this hypothesis. The effects of the same dose administered either orally or intraperitoneally were comparable (Fig. 1 ). An attempt to explain this observation through pharmacokinetics is diffi cult as no relevant information is currently available. A few pharmacokinetics studies of arabinogalactans showed that the amount of arabinogalactan absorbed following an oral dose remains unclear. Animal studies for larch arabinogalactan using intravenous administration resulted in about 53% of the dose being present in the liver and 30% in the urine 90 min after dosing. Non-absorbed larch arabinogalactan is actively fermented by the intestinal microfl ora and is particularly effective in increasing beneficial anaerobes such as Bifi dobacteria and Lactobacillus (Groman et al., 1994) .", "cite_spans": [{"start": 1478, "end": 1499, "text": "(Groman et al., 1994)", "ref_id": "BIBREF9"}], "ref_spans": [{"start": 825, "end": 832, "text": "(Fig. 1", "ref_id": "FIGREF1"}]}, {"section": "Discussion", "text": "Similarly, no effects were observed in the gastric emptying and intestinal transit models after oral administration of the arabinogalactan. Since the gastric emptying rate is related to a neurohumoral mechanism, which depends on an intact vagal innervation and therefore on the action of several neurotransmitters with acetylcholine as the major regulator (reviewed by Hansen, 2003) , failure of the compound to alter the gastric emptying indicates that cholinergic pathways are not involved in the antiulcer properties of the compound. This result is in agreement with fi ndings in humans where no effect on transit time frequency, Fig. 2 . DPPH scavenging activity of the arabinogalactan from M. ilicifolia. Ascorbic acid (Aa: 300 \u00b5M) was used as a positive control. The results are expressed as mean \uf0b1 S.E.M. All experiments were performed in triplicate. *Statistical comparison was performed using analysis of variance (ANOVA) followed by Bonferroni's test (P < 0.05). fecal weight or pH value and short-chain fatty acids, blood lipids or blood insulin were observed after a three-weeks exposure to arabinogalactan (15 to 30 g) (Robinson et al., 2001) . The results indicate that the arabinogalactan protects the gastric mucosa against irritant agents such as ethanol with a potency that is the highest observed until now for a constituent of M. ilicifolia. Although the mechanism of action of the arabinogalactan in gastric protection is still unknown, we can conclude that these effects do not occur through alterations of the gastrointestinal motility or acid secretion which are the major effects observed with M. ilicifolia. Further studies on the antioxidant capacity need to be performed to determine if this mechanism is the key to the gastroprotective effects of arabinogalactan and hence of M. ilicifolia. ", "cite_spans": [{"start": 369, "end": 382, "text": "Hansen, 2003)", "ref_id": "BIBREF10"}, {"start": 1132, "end": 1155, "text": "(Robinson et al., 2001)", "ref_id": "BIBREF18"}], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "ATPase activity and formation of nitric oxide", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF2": {"title": "Antioxidant determinations by the use of a stable free radical", "authors": [{"first": "M", "middle": ["S"], "last": "Blois", "suffix": ""}], "year": 1958, "venue": "Nature", "link": null}, "BIBREF3": {"title": "Characterization of immunomodulatory polysaccharides from Salvia offi cinalis L", "authors": [{"first": "P", "middle": [], "last": "Capek", "suffix": ""}, {"first": "V", "middle": [], "last": "Hribalova", "suffix": ""}, {"first": "E", "middle": [], "last": "Svandova", "suffix": ""}, {"first": "A", "middle": [], "last": "Ebringerova", "suffix": ""}, {"first": "V", "middle": [], "last": "Sasinkova", "suffix": ""}, {"first": "J", "middle": [], "last": "Masarova", "suffix": ""}], "year": 2003, "venue": "Int. J. Biol. Macromol", "link": "3064769"}, "BIBREF4": {"title": "A polysaccharide from a tea (infusion) of Maytenus ilicifolia leaves with anti-ulcer protective effects", "authors": [{"first": "T", "middle": ["R"], "last": "Cipriani", "suffix": ""}, {"first": "C", "middle": ["G"], "last": "Mellinger", "suffix": ""}, {"first": "L", "middle": ["M"], "last": "De Souza", "suffix": ""}, {"first": "C", "middle": ["H"], "last": "Baggio", "suffix": ""}, {"first": "C", "middle": ["S"], "last": "Freitas", "suffix": ""}, {"first": "M", "middle": ["C A"], "last": "Marques", "suffix": ""}, {"first": "P", "middle": ["A"], "last": "Gorin", "suffix": ""}, {"first": "G", "middle": ["L"], "last": "Sassaki", "suffix": ""}, {"first": "M", "middle": [], "last": "Iacomini", "suffix": ""}], "year": 2006, "venue": "J. Nat. Prod", "link": "35126346"}, "BIBREF5": {"title": "Dicion\u00e1rio das Plantas \u00dateis do Brasil, 2 nd ed. Civiliza\u00e7\u00e3o Brasileira", "authors": [{"first": "G", "middle": ["L"], "last": "Cruz", "suffix": ""}], "year": 1982, "venue": "", "link": null}, "BIBREF6": {"title": "Gum heteropolysaccharide and free reducing mono-and oligosaccharides of Anadenanthera colubrina", "authors": [{"first": "C", "middle": ["L"], "last": "Delgobo", "suffix": ""}, {"first": "P", "middle": ["A"], "last": "Gorin", "suffix": ""}, {"first": "C", "middle": [], "last": "Jones", "suffix": ""}, {"first": "M", "middle": [], "last": "Iacomini", "suffix": ""}], "year": 1998, "venue": "Phytochemistry", "link": "29220932"}, "BIBREF7": {"title": "A lyophilized aqueous extract of Maytenus ilicifolia leaves inhibits histamine-mediated acid secretion in isolated frog gastric mucosa", "authors": [{"first": "P", "middle": ["M"], "last": "Ferreira", "suffix": ""}, {"first": "C", "middle": ["N"], "last": "De Oliveira", "suffix": ""}, {"first": "A", "middle": ["B"], "last": "De Oliveira", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Lopes", "suffix": ""}, {"first": "F", "middle": [], "last": "Alzamora", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Vieira", "suffix": ""}], "year": 2004, "venue": "Planta", "link": "6459932"}, "BIBREF8": {"title": "Arabinogalactan-proteins: structure, biosynthesis, and function", "authors": [{"first": "G", "middle": ["B"], "last": "Fincher", "suffix": ""}, {"first": "B", "middle": ["A"], "last": "Stone", "suffix": ""}, {"first": "Clarke", "middle": ["A E"], "last": "", "suffix": ""}], "year": 1983, "venue": "Annu. Rev. Plant Physiol", "link": "85824060"}, "BIBREF9": {"title": "Arabinogalactan for hepatic drug delivery", "authors": [{"first": "E", "middle": ["V"], "last": "Groman", "suffix": ""}, {"first": "P", "middle": ["M"], "last": "Enriquez", "suffix": ""}, {"first": "C", "middle": [], "last": "Jung", "suffix": ""}, {"first": "Josephson", "middle": ["L"], "last": "", "suffix": ""}], "year": 1994, "venue": "Bioconjug. Chem", "link": "42065172"}, "BIBREF10": {"title": "Neurohumoral control of gastrointestinal motility", "authors": [{"first": "M", "middle": ["B"], "last": "Hansen", "suffix": ""}], "year": 2003, "venue": "Physiol. Res", "link": null}, "BIBREF11": {"title": "Neural and hormonal control of gastric secretion", "authors": [{"first": "B", "middle": ["I"], "last": "Hirschowitz", "suffix": ""}], "year": 1989, "venue": "Handbook of Physiology", "link": "83365497"}, "BIBREF12": {"title": "Evaluation of antinociceptive, anti-infl ammatory and antiulcerogenic activities of Maytenus ilicifolia", "authors": [{"first": "R", "middle": ["M"], "last": "Jorge", "suffix": ""}, {"first": "J", "middle": ["P"], "last": "Leite", "suffix": ""}, {"first": "A", "middle": ["B"], "last": "Oliveira", "suffix": ""}, {"first": "C", "middle": ["A"], "last": "Tagliati", "suffix": ""}], "year": 2004, "venue": "J. Ethnopharmacol", "link": "35471747"}, "BIBREF13": {"title": "Estudo da eventual a\u00e7\u00e3o anti\u00falcera g\u00e1strica do b\u00e1lsamo (Sedum sp.), folha-da-fortuna (Bryophyllum calycinum), couve (Brassica oleraceae) e da espinheira-santa (Maytenus ilicifolia) em ratos", "authors": [{"first": "C", "middle": ["I P"], "last": "Macaubas", "suffix": ""}, {"first": "M", "middle": ["G M"], "last": "Oliveira", "suffix": ""}, {"first": "M", "middle": ["L O"], "last": "Souza-Formigoni", "suffix": ""}, {"first": "N", "middle": ["G"], "last": "Silveira-Filho", "suffix": ""}, {"first": "Carlini", "middle": ["E A B S"], "last": "", "suffix": ""}], "year": 1988, "venue": "Estudo de A\u00e7\u00e3o Anti\u00falcera G\u00e1strica de Plantas Brasileiras (Maytenus ilicifolia -Espinheira Santa e Outras", "link": null}, "BIBREF14": {"title": "Medicinal use of Cochlospermum tinctorium in Mali anti-ulcer-, radical scavenging-and immunomodulating activities of polymers in the aqueous extract of the roots", "authors": [{"first": "C", "middle": ["S"], "last": "Nergard", "suffix": ""}, {"first": "D", "middle": [], "last": "Diallo", "suffix": ""}, {"first": "K", "middle": [], "last": "Inngjerdingen", "suffix": ""}, {"first": "T", "middle": ["E"], "last": "Michaelsen", "suffix": ""}, {"first": "T", "middle": [], "last": "Matsumoto", "suffix": ""}, {"first": "H", "middle": [], "last": "Kiyohara", "suffix": ""}, {"first": "H", "middle": [], "last": "Yamada", "suffix": ""}, {"first": "B", "middle": ["S"], "last": "Paulsen", "suffix": ""}], "year": 2005, "venue": "J. Ethnopharmacol", "link": "338998"}, "BIBREF15": {"title": "Free radicals and lipid peroxidation in ethanol-or aspirin-induced gastric mucosal injury", "authors": [{"first": "G", "middle": [], "last": "Pihan", "suffix": ""}, {"first": "C", "middle": [], "last": "Regillo", "suffix": ""}, {"first": "S", "middle": [], "last": "Szabo", "suffix": ""}], "year": 1987, "venue": "Dig. Dis. Sci", "link": "19237121"}, "BIBREF16": {"title": "Gastric mucosal apoptosis induced by ethanol: effect of antiulcer agents", "authors": [{"first": "J", "middle": [], "last": "Piotrowski", "suffix": ""}, {"first": "E", "middle": [], "last": "Piotrowski", "suffix": ""}, {"first": "D", "middle": [], "last": "Skrodzka", "suffix": ""}, {"first": "A", "middle": [], "last": "Slomiany", "suffix": ""}, {"first": "B", "middle": ["L"], "last": "Slomiany", "suffix": ""}], "year": 1997, "venue": "Biochem. Mol. Biol. Int", "link": "35334944"}, "BIBREF17": {"title": "Cytoprotection by prostaglandins in rats. Prevention of gastric necrosis produced by alcohol, HCl, NaOH, hypertonic NaCl, and thermal injury", "authors": [{"first": "A", "middle": [], "last": "Robert", "suffix": ""}, {"first": "J", "middle": ["E"], "last": "Nezamis", "suffix": ""}, {"first": "C", "middle": [], "last": "Lancaster", "suffix": ""}, {"first": "A", "middle": ["J"], "last": "Hanchar", "suffix": ""}], "year": 1979, "venue": "Gastroenterology", "link": "1421966"}, "BIBREF18": {"title": "Effects of dietary arabinogalactan on gastrointestinal and blood parameters in healthy human subjects", "authors": [{"first": "R", "middle": ["R"], "last": "Robinson", "suffix": ""}, {"first": "J", "middle": [], "last": "Feirtag", "suffix": ""}, {"first": "J", "middle": ["L"], "last": "Slavin", "suffix": ""}], "year": 2001, "venue": "J. Am. Coll. Nutr", "link": "7653616"}, "BIBREF19": {"title": "A simple method for the uniform production of gastric ulceration in the rat", "authors": [{"first": "H", "middle": [], "last": "Shay", "suffix": ""}, {"first": "S", "middle": ["A"], "last": "Komarov", "suffix": ""}, {"first": "S", "middle": ["S"], "last": "Fels", "suffix": ""}, {"first": "D", "middle": [], "last": "Meranze", "suffix": ""}, {"first": "M", "middle": [], "last": "Gruenstein", "suffix": ""}, {"first": "H", "middle": [], "last": "Siplet", "suffix": ""}], "year": 1945, "venue": "Gastroenterology", "link": null}, "BIBREF20": {"title": "Animal models in gastrointestinal alcohol research -a short appraisal of the different models and their results", "authors": [{"first": "S", "middle": [], "last": "Siegmund", "suffix": ""}, {"first": "S", "middle": [], "last": "Haas", "suffix": ""}, {"first": "A", "middle": [], "last": "Schneider", "suffix": ""}, {"first": "M", "middle": ["V"], "last": "Singer", "suffix": ""}], "year": 2003, "venue": "Best Pract. Res. Clin. Gastroenterol", "link": "26885903"}, "BIBREF21": {"title": "Antiulcerogenic effects of two Maytenus species in laboratory animals", "authors": [{"first": "M", "middle": ["L"], "last": "Souza-Formigoni", "suffix": ""}, {"first": "M", "middle": ["G"], "last": "Oliveira", "suffix": ""}, {"first": "M", "middle": ["G"], "last": "Monteiro", "suffix": ""}, {"first": "N", "middle": ["G"], "last": "Da Silveira-Filho", "suffix": ""}, {"first": "S", "middle": [], "last": "Braz", "suffix": ""}, {"first": "Carlini", "middle": ["E A"], "last": "", "suffix": ""}], "year": 1991, "venue": "J. Ethnopharmacol", "link": "38004612"}, "BIBREF22": {"title": "Bio active polysaccharides from plants", "authors": [{"first": "R", "middle": [], "last": "Srivastava", "suffix": ""}, {"first": "D", "middle": ["K"], "last": "Kulshreshtha", "suffix": ""}], "year": 1989, "venue": "Phytochemistry", "link": null}, "BIBREF23": {"title": "Antioxidant properties of a Tinospora cordifolia polysaccharide against iron-mediated lipid damage and gamma-ray induced protein damage", "authors": [{"first": "M", "middle": [], "last": "Subramanian", "suffix": ""}, {"first": "G", "middle": ["J"], "last": "Chintalwar", "suffix": ""}, {"first": "Chattopadhyay", "middle": ["S"], "last": "", "suffix": ""}], "year": 2002, "venue": "Redox Rep", "link": null}, "BIBREF24": {"title": "Relative effi cacy of some prokinetic drugs in morphine-induced gastrointestinal transit delay in mice", "authors": [{"first": "A", "middle": ["D"], "last": "Suchitra", "suffix": ""}, {"first": "S", "middle": ["A"], "last": "Dkhar", "suffix": ""}, {"first": "D", "middle": ["G"], "last": "Shewade", "suffix": ""}, {"first": "C", "middle": ["H"], "last": "Shashindran", "suffix": ""}], "year": 2003, "venue": "World J. Gastroenterol", "link": "28919160"}, "BIBREF25": {"title": "Early vascular injury and increased vascular permeability in gastric mucosal injury caused by ethanol in the rat", "authors": [{"first": "S", "middle": [], "last": "Szabo", "suffix": ""}, {"first": "J", "middle": ["S"], "last": "Trier", "suffix": ""}, {"first": "A", "middle": [], "last": "Brown", "suffix": ""}, {"first": "J", "middle": [], "last": "Schnoor", "suffix": ""}], "year": 1985, "venue": "Gastroenterology", "link": "46335570"}, "BIBREF26": {"title": "Evaluation of the anti-ulcerogenic activity of a dry extract of Maytenus ilicifolia Martius ex. Reiss produced by a jet spouted bed dryer", "authors": [{"first": "R", "middle": [], "last": "Tabach", "suffix": ""}, {"first": "W", "middle": ["P"], "last": "Oliveira", "suffix": ""}], "year": 2003, "venue": "Pharmazie", "link": "40079878"}, "BIBREF27": {"title": "Pectic polysaccharides from Chinese herbs -structure and biological activity", "authors": [{"first": "H", "middle": [], "last": "Yamada", "suffix": ""}], "year": 1994, "venue": "Carbohydr. Polym", "link": "83975900"}}, "ref_entries": {"FIGREF0": {"text": "per os (p.o.) or intraperitoneal (i.p.), respectively], arabinogalactan (AG: 10 mg/kg BW, p.o. or i.p.) or omeprazole (Ome: 40 mg/kg BW, p.o.) 60 min (p.o. treatment) or 30 min (i.p. treatment) be- fore administration of 80% ethanol (0.5 ml/200 g BW, p.o.). Animals were sacrifi ced 1 h later, the stomachs were removed and gastric lesion exten- sion measured as the total injured area (mm 2 ) [= length (mm) \u00b7 width (mm) of injury] (Baggio et al., 2007).", "type": "figure"}, "FIGREF1": {"text": "Fig. 1. Comparison of the gastroprotective effects of the arabinogalactan administered by two routes. Similar gastroprotective potency was observed in the ethanolinduced gastric injury model when the arabinogalactan was administered by oral (p.o.) or intraperitoneal (i.p.) route. The animals received vehicle (C: water or saline, 0.1 ml/100 g BW, p.o. or i.p., respectively), omeprazole (Ome: 40 mg/kg BW, p.o.), and arabinogalactan (AG: 10 mg/kg BW, p.o. or i.p.) 60 min (p.o. treatment) or 30 min (i.p. treatment) before oral administration of 80% ethanol (0.5 ml/200 g BW, p.o.). The results are expressed as mean \uf0b1 S.E.M. (n = 6). *Statistical comparison was performed using analysis of variance (ANO-VA) followed by Bonferroni's test (P < 0.05).", "type": "figure"}, "FIGREF2": {"text": "Baggio C. H., Freitas C. S., Otofuji G. M., Cipriani T. R., Souza L. M., Sassaki G. L., Iacomini M., Marques M. C. A., and Mesia-Vela S. (2007), Flavonoid-rich frac- tion of Maytenus ilicifolia Mart. ex. Reiss protects the gastric mucosa of rodents through inhibition of", "type": "figure"}, "TABREF0": {"text": "Mart. ex Reissek (Celastraceae) were collected in October 2003, at Curitiba (Paran\u00e1, Brazil), and provided by the Central de Produ\u00e7\u00e3o e Comercializa\u00e7\u00e3o de Plantas Medicinais, Arom\u00e1ticas e Condimentares do Paran\u00e1 Ltda, Curitiba, PR, Brazil. A voucher specimen was deposited in the herbarium of the Botany Department of the Federal University of Paran\u00e1, Curitiba, PR, Brazil, under number 30842.vivo/in vitro Studies of the Effects of the Type II Arabinogalactan Isolated from Maytenus ilicifolia Mart. ex Reissek on the Gastrointestinal Tract of Rats", "type": "table"}, "TABREF1": {"text": "Effects of the arabinogalactan (AG) from M. ilicifolia on acid secretion and gastrointestinal motility.NA, not applicable. * Statistical comparison was performed using analysis of variance (ANOVA) followed by Bonferroni's test (P < 0.05).", "type": "table"}}}
{"paper_id": "199665950", "_pdf_hash": "cf2ff07404eb60188ab0c83d8a41e2adca423dbb", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "WTO Dispute Settlement Body, Minutes of Meeting Held on 13-15", "authors": [], "year": 2002, "venue": "", "link": null}, "BIBREF1": {"title": "WTO Dispute Settlement Body, JOB/DS/10", "authors": [], "year": 2012, "venue": "", "link": null}, "BIBREF3": {"title": "Measures to Deal with Members in Category IV of the Administrative Arrangements on Arrears, GATT Docs PC/7, L/7578", "authors": [{"first": "", "middle": [], "last": "Gatt Secretariat", "suffix": ""}], "year": 1994, "venue": "", "link": null}, "BIBREF4": {"title": "Theoi Project (undated), available at", "authors": [{"first": "Argos", "middle": [], "last": "Anon", "suffix": ""}, {"first": "", "middle": [], "last": "Panoptes", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF5": {"title": "As Antigua Considers Cross-Retaliation against US, WIPO Official Creates Stir", "authors": [{"first": "", "middle": [], "last": "Anon", "suffix": ""}], "year": 2008, "venue": "", "link": null}, "BIBREF6": {"title": "Kind Amendment Successfully Cuts Taxpayer-Funded Brazilian Cotton Subsidies", "authors": [{"first": "", "middle": [], "last": "Anon", "suffix": ""}], "year": 2011, "venue": "Press Release", "link": null}, "BIBREF7": {"title": "Pirate Bay and Antigua Explore Launch of Authorized 'Pirate Site", "authors": [{"first": "", "middle": [], "last": "Anon", "suffix": ""}], "year": 2013, "venue": "TorrentFreak", "link": null}, "BIBREF8": {"title": "Finding the Key to the Cotton Issue at the WTO Cannot Wait!", "authors": [{"first": "", "middle": [], "last": "Acp Group", "suffix": ""}], "year": 2011, "venue": "Press Release", "link": null}, "BIBREF9": {"title": "The Case for Tradeable Remedies in the WTO", "authors": [{"first": "Kyle", "middle": [], "last": "Bagwell", "suffix": ""}, {"first": "Petros", "middle": ["C"], "last": "Mavroidis", "suffix": ""}, {"first": "Robert", "middle": ["W"], "last": "Staiger", "suffix": ""}], "year": 2005, "venue": "Economic Development and Multilateral Trade Cooperation", "link": null}, "BIBREF10": {"title": "Auctioning Countermeasures in the WTO", "authors": [{"first": "Kyle", "middle": [], "last": "Bagwell", "suffix": ""}, {"first": "Petros", "middle": ["C"], "last": "Mavroidis", "suffix": ""}, {"first": "Robert", "middle": ["W"], "last": "Staiger", "suffix": ""}], "year": 2007, "venue": "Journal of International Economics", "link": "14701496"}, "BIBREF11": {"title": "Going Beyond Stereotypes: Participation of Developing Countries in WTO Dispute Settlement, 4", "authors": [{"first": "Jan", "middle": [], "last": "Bohanes", "suffix": ""}, {"first": "Fernanda", "middle": [], "last": "Garza", "suffix": ""}], "year": 2012, "venue": "Journal of Trade Law and Development", "link": "154237315"}, "BIBREF12": {"title": "The Law, Economics and Politics of Retaliation in WTO Dispute Settlement", "authors": [], "year": 2010, "venue": "", "link": "150442175"}, "BIBREF13": {"title": "Reconsidering Financial Remedies in WTO Dispute Settlement", "authors": [{"first": "Marco", "middle": [], "last": "Bronckers", "suffix": ""}, {"first": "Freya", "middle": [], "last": "Baetens", "suffix": ""}], "year": 2013, "venue": "Journal of International Law", "link": "154066568"}, "BIBREF14": {"title": "Financial Compensation in the WTO: Improving the Remedies of WTO Dispute Settlement", "authors": [{"first": "Marco", "middle": [], "last": "Bronckers", "suffix": ""}, {"first": "Naboth", "middle": [], "last": "Van Den Broek", "suffix": ""}], "year": 2005, "venue": "Journal of International Economic Law", "link": "39190791"}, "BIBREF15": {"title": "Between Law and Diplomacy: The Social Contexts of Disputing at the World Trade Organization", "authors": [{"first": "Joseph", "middle": [], "last": "Conti", "suffix": ""}], "year": 2011, "venue": "", "link": "153213957"}, "BIBREF16": {"title": "The WTO Dispute Settlement System: The First Ten Years", "authors": [{"first": "Bill", "middle": [], "last": "Davey", "suffix": ""}], "year": 2005, "venue": "Journal of International Economic Law", "link": "155049018"}, "BIBREF17": {"title": "African Cotton Markets at Crossroads: Will the Price Spike Turn into a New Kick-Start?", "authors": [{"first": "Claire", "middle": [], "last": "Delpeuch", "suffix": ""}], "year": 2011, "venue": "World Bank Policy Research Working Paper", "link": "56347057"}, "BIBREF18": {"title": "Multiple Panel Proceedings, Relative \"Equivalence\" and Tradable Retaliation Rights: A \"Travel-Pass\" for Developing Countries in Dispute Settlement? (unpublished, on file with author", "authors": [{"first": "James", "middle": [], "last": "Flett", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF19": {"title": "Faster than Developing Countries? Evaluating the Speed and Momentum of Trade Litigation at the World Trade Organization", "authors": [{"first": "Marc", "middle": [], "last": "Froese", "suffix": ""}], "year": 2011, "venue": "Journal of World Trade", "link": null}, "BIBREF20": {"title": "Making WTO Dispute Settlement Work for African Countries", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF21": {"title": "United States -Anti-Dumping Act of 1916 (Original Complaint by the European Communities) -Recourse to Arbitration by the United States under 22.6 of the DSU, WT/DS136/ARB", "authors": [{"first": "Robert", "middle": [], "last": "Howse", "suffix": ""}, {"first": "Robert", "middle": [], "last": "Staiger", "suffix": ""}], "year": 2004, "venue": "A Legal and Economic Analysis, 4 World Trade Review", "link": null}, "BIBREF23": {"title": "Bridges Weekly 1, 2010. Malacrida, Reto, Towards Sounder and Fairer WTO Retaliation: Suggestions for Possible Additional Procedural Rules Governing Members' Preparation and Adoption of Retaliatory Measures", "authors": [{"first": "&quot;", "middle": [], "last": "Ictsd", "suffix": ""}, {"first": "", "middle": [], "last": "Brazil", "suffix": ""}, {"first": "", "middle": [], "last": "Us Strike", "suffix": ""}], "year": 2008, "venue": "Journal of World Trade", "link": null}, "BIBREF24": {"title": "Developing Country Success in WTO Disputes", "authors": [{"first": "Kristina", "middle": [], "last": "Mitchell", "suffix": ""}], "year": 2013, "venue": "Journal of World Trade", "link": "153652433"}, "BIBREF25": {"title": "Trade and Development", "authors": [{"first": "Hunter", "middle": [], "last": "Nottage", "suffix": ""}], "year": 2009, "venue": "The Oxford Handbook of International Trade Law", "link": "157786408"}, "BIBREF26": {"title": "An Evaluation of the Participation of Commonwealth Small States and Least-Developed Countries in WTO Dispute Settlement and an Analysis of the Constraints They Face (Commonwealth Secretariat Paper", "authors": [{"first": "", "middle": [], "last": "Nottage", "suffix": ""}, {"first": "David", "middle": [], "last": "Hunter", "suffix": ""}, {"first": "", "middle": [], "last": "Versus Goliath", "suffix": ""}], "year": 2012, "venue": "", "link": null}, "BIBREF27": {"title": "Practical Aspects of Monetary Compensation: The US -Copyright Case", "authors": [{"first": "Bernard", "middle": [], "last": "O&apos;connor", "suffix": ""}, {"first": "Margareta", "middle": [], "last": "Djordjevic", "suffix": ""}], "year": 2005, "venue": "Journal of International Economic Law", "link": null}, "BIBREF28": {"title": "Government-Authorized Piracy", "authors": [{"first": "Doug", "middle": [], "last": "Palmer", "suffix": ""}, {"first": "", "middle": [], "last": "Us Warns Antigua", "suffix": ""}, {"first": "", "middle": [], "last": "Against", "suffix": ""}], "year": 2013, "venue": "Reuters", "link": null}, "BIBREF30": {"title": "Developing Country Use of the WTO Dispute Settlement System: Why It Matters, the Barriers Posed", "authors": [{"first": "Gregory", "middle": [], "last": "Shaffer", "suffix": ""}], "year": 2009, "venue": "Trade Disputes and the Dispute Settlement Understanding of the WTO: An Interdisciplinary Assessment", "link": "154705400"}, "BIBREF31": {"title": "The Equivalence Standard under Article 22.4 of the DSU: A \"Tariffic\" Misunderstanding?", "authors": [{"first": "Simon", "middle": [], "last": "Schropp", "suffix": ""}], "year": 2010, "venue": "The Law, Economics and Politics of Retaliation in WTO Dispute Settlement", "link": null}, "BIBREF32": {"title": "Effective Compliance in the DSU: The Mechanics of Monetary Compensation as a Form of Reparation, Trade and Investment Law Clinic Papers, Graduate Institute", "authors": [{"first": "Jordan", "middle": [], "last": "Shepherd", "suffix": ""}], "year": 2012, "venue": "", "link": null}, "BIBREF33": {"title": "Compliance by WTO Members with Adverse WTO Dispute Settlement Rulings: The Record to Date", "authors": [{"first": "Bruce", "middle": [], "last": "Wilson", "suffix": ""}], "year": 2007, "venue": "Journal of International Economic Law", "link": "154363817"}, "BIBREF34": {"title": "Legal Capacity and Developing Country Performance in the Panel Stage of the WTO Dispute Settlement System", "authors": [{"first": "Ka", "middle": [], "last": "Zeng", "suffix": ""}], "year": 2013, "venue": "Journal of World Trade", "link": "152507721"}, "BIBREF35": {"title": "Arbitration, Case Concerning the Air Services Agreement of", "authors": [], "year": 1946, "venue": "XVIII RIAA 417", "link": null}, "BIBREF36": {"title": "Framework Agreement for a Mutually Agreed Solution to the Cotton Dispute in the World Trade Organization (WT/DS267)", "authors": [], "year": 2010, "venue": "", "link": null}, "BIBREF37": {"title": "Measures to Deal with Members in Category IV of the Administrative Arrangements on Arrears, GATT Docs PC/7, L/7578", "authors": [{"first": "", "middle": [], "last": "Gatt Secretariat", "suffix": ""}], "year": 1994, "venue": "", "link": null}, "BIBREF38": {"title": "WTO Arbitrators Decision, EC -Bananas III (Ecuador) (Article 22", "authors": [], "year": 1999, "venue": "WTO Arbitrators Decision, EC -Bananas III (US)", "link": null}, "BIBREF39": {"title": "WTO Arbitrators Decision, Brazil -Aircraft (Article 22.6-Brazil), WT/DS46/ARB, 28", "authors": [], "year": 2000, "venue": "WT/DS136/ARB", "link": null}, "BIBREF40": {"title": "US -Gambling (Article 22.6-US), WT/DS285/ARB, 21", "authors": [], "year": 2007, "venue": "WTO Arbitrators Decision", "link": null}, "BIBREF41": {"title": "WT/ DS267/ARB", "authors": [{"first": "Us -Upland", "middle": [], "last": "Wto Arbitrators Decision", "suffix": ""}, {"first": "", "middle": [], "last": "Cotton", "suffix": ""}], "year": 2009, "venue": "", "link": null}, "BIBREF42": {"title": "WTO Dispute Settlement Body, DSU Negotiations -Special and Differential Treatment for Developing Countries -Proposals on DSU by Cuba", "authors": [], "year": 2002, "venue": "", "link": null}, "BIBREF43": {"title": "WTO Dispute Settlement Body, Minutes of Meeting Held on 13-15", "authors": [], "year": 2002, "venue": "", "link": null}, "BIBREF44": {"title": "WTO Dispute Settlement Body, Notification of a Mutually Satisfactory Temporary Arrangement, WT/DS160/23", "authors": [], "year": 2003, "venue": "", "link": null}, "BIBREF45": {"title": "US -Gambling -Recourse by Antigua and Barbuda to Article 22.2 of the DSU, WT/DS285/22", "authors": [], "year": 2007, "venue": "", "link": null}, "BIBREF46": {"title": "Informal Meeting of the DSB Special Session", "authors": [], "year": 2011, "venue": "", "link": null}, "BIBREF47": {"title": "WTO Dispute Settlement Body, EC and Certain Member States -Large Civil Aircraft", "authors": [], "year": 2011, "venue": "", "link": null}, "BIBREF48": {"title": "Chairman's Remarks: Summary of Recent Work", "authors": [], "year": 2012, "venue": "WTO Dispute Settlement Body, Informal Meeting of the DSB Special Session", "link": null}, "BIBREF49": {"title": "WTO Dispute Settlement Body, US -Gambling (Recourse by Antigua and Barbuda to Article", "authors": [], "year": 2012, "venue": "", "link": null}, "BIBREF50": {"title": "WTO Dispute Settlement Body, Minutes of Meeting on 28", "authors": [], "year": 2013, "venue": "", "link": null}, "BIBREF51": {"title": "Making WTO Dispute Settlement Work for African Countries", "authors": [{"first": "", "middle": [], "last": "Wto General", "suffix": ""}, {"first": "", "middle": [], "last": "Council", "suffix": ""}], "year": 2012, "venue": "Minutes of Meeting on", "link": null}}, "ref_entries": {}}
{"paper_id": "199666740", "_pdf_hash": "48a877d09fe603f469fb746a546e55153bb77eed", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Rating Teams and Analysing Outcomes in One-Day and Test Cricket", "authors": [{"first": "P", "middle": ["E"], "last": "Allsopp", "suffix": ""}, {"first": "S", "middle": ["R"], "last": "Clarke", "suffix": ""}], "year": 2004, "venue": "Journal of the Royal Statistical Society: Series A (Statistics in Society)", "link": "121777522"}, "BIBREF1": {"title": "At First We Thought Batting under Lights was Like Wearing a Blindfold", "authors": [{"first": "I", "middle": [], "last": "Bell", "suffix": ""}], "year": 2007, "venue": "The Guardian", "link": null}, "BIBREF2": {"title": "Rational Adversaries ? Evidence from Randomised Trials in One Day Cricket", "authors": [{"first": "V", "middle": [], "last": "Bhaskar", "suffix": ""}], "year": 2009, "venue": "The Economic Journal", "link": "11764346"}, "BIBREF3": {"title": "Fair Measures of Performance: The World Cup of Cricket", "authors": [{"first": "S", "middle": ["R"], "last": "Clarke", "suffix": ""}, {"first": "P", "middle": [], "last": "Allsopp", "suffix": ""}], "year": 2001, "venue": "The Journal of the Operational Research Society", "link": "62524401"}, "BIBREF4": {"title": "Cricket Must respect the Fan -Dravid", "authors": [], "year": 2011, "venue": "", "link": null}, "BIBREF5": {"title": "To Bat or Not to Bat: An Examination of Match Outcomes in Day-Night Limited Overs Cricket", "authors": [{"first": "P", "middle": [], "last": "Dawson", "suffix": ""}, {"first": "B", "middle": [], "last": "Morley", "suffix": ""}, {"first": "D", "middle": [], "last": "Paton", "suffix": ""}, {"first": "D", "middle": [], "last": "Thomas", "suffix": ""}], "year": 2009, "venue": "Journal of the Operational Research Society", "link": "11406578"}, "BIBREF6": {"title": "Winning the Coin Toss and the Home Team Advantage in One-Day International Cricket Matches", "authors": [{"first": "B", "middle": ["M"], "last": "De Silva", "suffix": ""}, {"first": "T", "middle": ["B"], "last": "Swartz", "suffix": ""}], "year": 1997, "venue": "New Zealand Statistician", "link": "15722919"}, "BIBREF7": {"title": "A Fair Method for Resetting the Target in Interrupted One-Day Cricket Matches", "authors": [{"first": "F", "middle": ["C"], "last": "Duckworth", "suffix": ""}, {"first": "A", "middle": ["J"], "last": "Lewis", "suffix": ""}], "year": 1998, "venue": "Journal of the Operational Research Society", "link": "2421934"}, "BIBREF8": {"title": "Records-One Day Internationals -Match Results", "authors": [{"first": "", "middle": [], "last": "Espn Cricinfo", "suffix": ""}], "year": 2011, "venue": "", "link": null}, "BIBREF9": {"title": "Beausejour Cricket Ground", "authors": [{"first": "", "middle": [], "last": "Espn Cricinfo", "suffix": ""}], "year": 2012, "venue": "", "link": null}, "BIBREF10": {"title": "Effect of Toss and Weather on County Cricket Championship Outcomes", "authors": [{"first": "D", "middle": [], "last": "Forrest", "suffix": ""}, {"first": "R", "middle": [], "last": "Dorsey", "suffix": ""}], "year": 2008, "venue": "Journal of Sports Sciences", "link": "28283415"}, "BIBREF11": {"title": "He Economics and Econometrics of Active Labor Market Programs", "authors": [{"first": "J", "middle": ["J"], "last": "Heckman", "suffix": ""}, {"first": "R", "middle": ["J"], "last": "Lalonde", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Smith", "suffix": ""}], "year": 1999, "venue": "", "link": "153019620"}, "BIBREF12": {"title": "ODI and Test Team Rankings: How they Work and their Suitability for Determining Tournament Qualification", "authors": [{"first": "D", "middle": [], "last": "Kendix", "suffix": ""}], "year": 2011, "venue": "", "link": null}, "BIBREF14": {"title": "Program Evaluation with Non-Experimental Data", "authors": [{"first": "R", "middle": [], "last": "Moffitt", "suffix": ""}], "year": 1991, "venue": "Evaluation Review", "link": null}, "BIBREF15": {"title": "An Investigation of Home Advantage and Other Factors Affecting Outcomes in English One-Day Cricket Matches", "authors": [{"first": "B", "middle": [], "last": "Morley", "suffix": ""}, {"first": "D", "middle": [], "last": "Thomas", "suffix": ""}], "year": 2005, "venue": "Journal of Sports Sciences", "link": "24477771"}, "BIBREF16": {"title": "Identifying the Greatest Team and Captain -A Complex Network Approach to Cricket Matches", "authors": [{"first": "S", "middle": [], "last": "Mukherjee", "suffix": ""}], "year": 2012, "venue": "Physica AStatistical Mechanics and its Applications", "link": "118729564"}, "BIBREF17": {"title": "On the Effect of Home Team Advantage and Winning the Toss in the Outcome of T20 International Cricket Matches", "authors": [{"first": "H", "middle": [], "last": "Saikia", "suffix": ""}, {"first": "D", "middle": [], "last": "Bhattacharjee", "suffix": ""}], "year": 2010, "venue": "Assam University Journal of Science and Technology", "link": "152711604"}, "BIBREF18": {"title": "An Adjusted Duckworth-Lewis Target in Shortened Limited Overs Cricket Matches", "authors": [{"first": "S", "middle": ["E"], "last": "Stern", "suffix": ""}], "year": 2009, "venue": "Journal of the Operational Research Society", "link": "13087693"}, "BIBREF19": {"title": "First Day-Night County Championship Game between Kent and Glamorgan fails to Wow Crowds", "authors": [{"first": "H", "middle": [], "last": "Turbervill", "suffix": ""}], "year": 2011, "venue": "The Telegraph", "link": null}}, "ref_entries": {}}
{"paper_id": "199666746", "_pdf_hash": "487d3988a2507f8d1cfcd9cd6d5c9b908b494d8a", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "199666823", "_pdf_hash": "72ca46fd0de8e5b4b2305358c09bdce304bf52da", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Information Theory and an Extension of the Maximum Likelihood Principle", "authors": [{"first": "H", "middle": [], "last": "Akaike", "suffix": ""}], "year": 1973, "venue": "2nd International Symposium on Information Theory", "link": "64903870"}, "BIBREF1": {"title": "Testing When a Parameter Is on t he Boundary of the Maintained Hypothesis", "authors": [{"first": "D", "middle": ["W K"], "last": "Andrews", "suffix": ""}], "year": 2001, "venue": "Econometrica", "link": "122426005"}, "BIBREF2": {"title": "Optimal Tests When a Nuisance Parameter Is Present Only under the Alternative", "authors": [{"first": "D", "middle": ["W K"], "last": "Andrews", "suffix": ""}, {"first": "W", "middle": [], "last": "Ploberger", "suffix": ""}], "year": 1994, "venue": "Econometrica", "link": "17215343"}, "BIBREF3": {"title": "Are Phillips Curves Useful for Forecasting Inflation", "authors": [{"first": "A", "middle": [], "last": "Atkeson", "suffix": ""}, {"first": "L", "middle": ["E"], "last": "Ohanian", "suffix": ""}], "year": 2001, "venue": "Federal Reserve Bank of Minneapolis Quarterly Review", "link": "210561744"}, "BIBREF4": {"title": "Estimating and Testing Linear Models with Multiple Structural Changes", "authors": [{"first": "J", "middle": [], "last": "Bai", "suffix": ""}, {"first": "P", "middle": [], "last": "Perron", "suffix": ""}], "year": 1998, "venue": "Econometrica", "link": "118328620"}, "BIBREF5": {"title": "Estimation and Comparison of Multiple Change-Point Models", "authors": [{"first": "S", "middle": [], "last": "Chib", "suffix": ""}], "year": 1998, "venue": "Journal of Econometrics", "link": "6137514"}, "BIBREF6": {"title": "Measuring risk aversion from excess returns on a stock index", "authors": [{"first": "R", "middle": [], "last": "Chou", "suffix": ""}, {"first": "R", "middle": ["F"], "last": "Engle", "suffix": ""}, {"first": "A", "middle": [], "last": "Kane", "suffix": ""}], "year": 1992, "venue": "Journal of Econometrics", "link": "153932249"}, "BIBREF7": {"title": "The Power of Tests of Predictive Ability in the Presence of Structural Breaks", "authors": [{"first": "T", "middle": ["E"], "last": "Clark", "suffix": ""}, {"first": "M", "middle": ["W"], "last": "Mccracken", "suffix": ""}], "year": 2005, "venue": "Journal of Econometrics", "link": "120583464"}, "BIBREF8": {"title": "Drifts and Volatilities: Monetary Policies and Outcomes in the", "authors": [{"first": "T", "middle": [], "last": "Cogley", "suffix": ""}, {"first": "T", "middle": ["J"], "last": "Sargent", "suffix": ""}], "year": 2005, "venue": "Review of Economic Dynamics", "link": null}, "BIBREF9": {"title": "Asymptotic Likelihood-Based Prediction Functions", "authors": [{"first": "T", "middle": ["F"], "last": "Cooley", "suffix": ""}, {"first": "W", "middle": ["R"], "last": "Parke", "suffix": ""}], "year": 1990, "venue": "Econometrica", "link": "118257143"}, "BIBREF10": {"title": "An Adaptive Regression Model", "authors": [{"first": "T", "middle": ["F"], "last": "Cooley", "suffix": ""}, {"first": "E", "middle": ["C"], "last": "Prescott", "suffix": ""}], "year": 1973, "venue": "International Economic Review", "link": "153480996"}, "BIBREF11": {"title": "Hypothesis Testing when a N uisance Parameter is Present Only Under the Alternative", "authors": [{"first": "R", "middle": ["B"], "last": "Davies", "suffix": ""}], "year": 1977, "venue": "Biometrika", "link": "209835858"}, "BIBREF12": {"title": "Consistency of the maximum likelihood estimator for general hidden Markov models", "authors": [{"first": "R", "middle": ["E"], "last": "Douc", "suffix": ""}, {"first": "J", "middle": [], "last": "Moulines", "suffix": ""}, {"first": "R", "middle": [], "last": "Olsson", "suffix": ""}, {"first": "", "middle": [], "last": "Van Handel", "suffix": ""}], "year": 2011, "venue": "The Annals of Statistics", "link": "14631345"}, "BIBREF13": {"title": "Asymptotic properties of the maximum likelihood estimator in autoregressive models with Markov regime", "authors": [{"first": "R", "middle": [], "last": "Douc", "suffix": ""}, {"first": "E", "middle": [], "last": "Moulines", "suffix": ""}, {"first": "T", "middle": [], "last": "Ryd\u00e9n", "suffix": ""}], "year": 2004, "venue": "The Annals of Statistics", "link": "8102939"}, "BIBREF14": {"title": "Microarrays, Empirical Bayes and the Two-Groups Model", "authors": [{"first": "B", "middle": [], "last": "Efron", "suffix": ""}], "year": 2008, "venue": "Statistical Science", "link": "8417479"}, "BIBREF15": {"title": "Optimally Testing General Breaking Processes in Linear Time Series Models", "authors": [{"first": "G", "middle": [], "last": "Elliott", "suffix": ""}, {"first": "U", "middle": ["K"], "last": "M\u00fcller", "suffix": ""}], "year": 2006, "venue": "Review of Economic Studies", "link": "55673996"}, "BIBREF16": {"title": "Stochastic Permanent Breaks", "authors": [{"first": "R", "middle": ["F"], "last": "Engle", "suffix": ""}, {"first": "A", "middle": ["D"], "last": "Smith", "suffix": ""}], "year": 1999, "venue": "Review of Economics and Statistics", "link": "140865"}, "BIBREF17": {"title": "How Stable is the Predictive Power of the Yield Curve? Evidence from Germany and the United States", "authors": [{"first": "A", "middle": [], "last": "Estrella", "suffix": ""}, {"first": "A", "middle": ["P"], "last": "Rodrigues", "suffix": ""}, {"first": "S", "middle": [], "last": "Schich", "suffix": ""}], "year": 2003, "venue": "The Review of Economics and Statistics", "link": "153156000"}, "BIBREF18": {"title": "The Hierarchical Hidden Markov Model: Analysis and Applications", "authors": [{"first": "S", "middle": [], "last": "Fine", "suffix": ""}, {"first": "Y", "middle": [], "last": "Singer", "suffix": ""}, {"first": "N", "middle": [], "last": "Tishby", "suffix": ""}], "year": 1998, "venue": "", "link": "3465810"}, "BIBREF19": {"title": "How Stable is the Forecasting Performance of the Yield Curve for Output Growth?", "authors": [{"first": "R", "middle": [], "last": "Giacomini", "suffix": ""}, {"first": "B", "middle": [], "last": "Rossi", "suffix": ""}], "year": 2006, "venue": "Oxford Bulletin of Economics and Statistics", "link": "40592030"}, "BIBREF20": {"title": "Efficient Bayesian Inference for Dynamic Mixture Models", "authors": [{"first": "R", "middle": [], "last": "Gerlach", "suffix": ""}, {"first": "C", "middle": [], "last": "Carter", "suffix": ""}, {"first": "R", "middle": [], "last": "Kohn", "suffix": ""}], "year": 2000, "venue": "Journal of the American Statistical Association", "link": "120532429"}, "BIBREF21": {"title": "Efficient Bayesian Inference for Multiple ChangePoint and Mixture Innovation Models", "authors": [{"first": "P", "middle": [], "last": "Giordani", "suffix": ""}, {"first": "R", "middle": [], "last": "Kohn", "suffix": ""}], "year": 2008, "venue": "Journal of Business and Economic Statistics", "link": null}, "BIBREF22": {"title": "A New Approach to the Economic Analysis of Nonstationary Time Series and the Business Cycle", "authors": [{"first": "J", "middle": ["D"], "last": "Hamilton", "suffix": ""}], "year": 1989, "venue": "Econometrica", "link": null}, "BIBREF24": {"title": "Bayesian Forecasting", "authors": [{"first": "P", "middle": ["J"], "last": "Harrison", "suffix": ""}, {"first": "C", "middle": ["F"], "last": "Stevens", "suffix": ""}], "year": 1976, "venue": "Journal of the Royal Statistical Society, Series B", "link": null}, "BIBREF25": {"title": "Maximum Likelihood Approaches to Variance Component Estimation and to Related Problems", "authors": [{"first": "D", "middle": ["A"], "last": "Harville", "suffix": ""}], "year": 1977, "venue": "Journal of the American Statistical Association", "link": "119989539"}, "BIBREF26": {"title": "Some Estimators for a Linear Model with Random Coefficients", "authors": [{"first": "C", "middle": [], "last": "Hildreth", "suffix": ""}, {"first": "J", "middle": ["P"], "last": "Houck", "suffix": ""}], "year": 1968, "venue": "Journal of the American Statistical Association", "link": "122454523"}, "BIBREF27": {"title": "Predictive Likelihood", "authors": [{"first": "D", "middle": [], "last": "Hinkley", "suffix": ""}], "year": 1979, "venue": "The Annals of Statistics", "link": null}, "BIBREF28": {"title": "Stochastic Volatility: Likelihood Inference and Comparison with ARCH Models", "authors": [{"first": "Kim", "middle": ["S"], "last": "", "suffix": ""}, {"first": "N", "middle": [], "last": "Shephard", "suffix": ""}, {"first": "S", "middle": [], "last": "Chib", "suffix": ""}], "year": 1998, "venue": "Review of Economic Studies", "link": "18381818"}, "BIBREF30": {"title": "Forecasting and Estimating Multiple Change-Point Models", "authors": [{"first": "G", "middle": [], "last": "Koop", "suffix": ""}, {"first": "S", "middle": [], "last": "Potter", "suffix": ""}], "year": 2007, "venue": "Review of Economic Studies", "link": null}, "BIBREF31": {"title": "Sufficiency, Prediction, and Extreme Models", "authors": [{"first": "S", "middle": ["L"], "last": "Lauritzen", "suffix": ""}], "year": 1974, "venue": "Scandinavian Journal of Statistics", "link": "115701585"}, "BIBREF32": {"title": "Maximum-likelihood estimation for hidden Markov models", "authors": [{"first": "B", "middle": ["G"], "last": "Leroux", "suffix": ""}], "year": 1992, "venue": "Stochastic Processes and their Applications", "link": "16066832"}, "BIBREF33": {"title": "Output Fluctuations in the United States: What Has Changed since the 1980s?", "authors": [{"first": "M", "middle": ["M"], "last": "Mcconnell", "suffix": ""}, {"first": "G", "middle": [], "last": "Perez-Quiros", "suffix": ""}], "year": 2000, "venue": "American Economic Review", "link": null}, "BIBREF34": {"title": "Bayesian Inference and Prediction for Mean and Variance Shifts in Autoregressive Time Series", "authors": [{"first": "R", "middle": ["E"], "last": "Mcculloch", "suffix": ""}, {"first": "R", "middle": ["S"], "last": "Tsay", "suffix": ""}], "year": 1993, "venue": "Journal of the American Statistical Association", "link": "119753539"}, "BIBREF35": {"title": "Forecasting Time Series Subject to Multiple Structural Breaks", "authors": [{"first": "M", "middle": ["H"], "last": "Pesaran", "suffix": ""}, {"first": "D", "middle": [], "last": "Pettenuzzo", "suffix": ""}, {"first": "Nd", "middle": ["A"], "last": "Timmermann", "suffix": ""}], "year": 2006, "venue": "Review of Economic Studies", "link": null}, "BIBREF36": {"title": "Forecast Combination Across Estimation Windows", "authors": [{"first": "M", "middle": ["H"], "last": "Pesaran", "suffix": ""}, {"first": "A", "middle": [], "last": "Pick", "suffix": ""}], "year": 2011, "venue": "Journal of Business and Economic Statistics", "link": "16588825"}, "BIBREF37": {"title": "Selection of Estimation Window in the Presence of Breaks", "authors": [{"first": "M", "middle": ["H"], "last": "Pesaran", "suffix": ""}, {"first": "A", "middle": [], "last": "Timmermann", "suffix": ""}], "year": 2007, "venue": "Journal of Econometrics", "link": "15869716"}, "BIBREF38": {"title": "An Empirical Bayes Approach to Statistics", "authors": [{"first": "H", "middle": [], "last": "Robbins", "suffix": ""}], "year": 1955, "venue": "Proceedings of the Third Berkeley Symposium on Mathematics", "link": "26161481"}, "BIBREF39": {"title": "Asymptotic Properties of Maximum Likelihood Estimators and Likelihood Ratio Tests Under non-Standard Conditions", "authors": [{"first": "S", "middle": ["G"], "last": "Self", "suffix": ""}, {"first": "K", "middle": ["Y"], "last": "Liang", "suffix": ""}], "year": 1987, "venue": "Journal of the American Statistical Association", "link": "41600130"}, "BIBREF40": {"title": "Level Shifts and the Illusion of Long Memory in Economic Time Series", "authors": [{"first": "A", "middle": [], "last": "Smith", "suffix": ""}], "year": 2005, "venue": "Journal of Business and Economic Statistics", "link": "13537434"}, "BIBREF41": {"title": "Markov-Switching Model Selection using Kullback-Leibler Divergence", "authors": [{"first": "A", "middle": [], "last": "Smith", "suffix": ""}, {"first": "P", "middle": ["A"], "last": "Naik", "suffix": ""}, {"first": "C", "middle": ["L"], "last": "Tsai", "suffix": ""}], "year": 2006, "venue": "Journal of Econometrics", "link": "125170211"}, "BIBREF42": {"title": "New Indexes of Coincident and Leading Indicators", "authors": [{"first": "J", "middle": ["H"], "last": "Stock", "suffix": ""}, {"first": "M", "middle": ["W"], "last": "Watson", "suffix": ""}], "year": 1989, "venue": "NBER Macroeconomic Annual", "link": null}, "BIBREF43": {"title": "Evidence on S tructural Instability in Macroeconomic Time Series Relations", "authors": [{"first": "J", "middle": ["H"], "last": "Stock", "suffix": ""}, {"first": "M", "middle": ["W"], "last": "Watson", "suffix": ""}], "year": 1996, "venue": "Journal of Business and Economic Statistics", "link": "13936835"}, "BIBREF44": {"title": "Structural Breaks, Incomplete Information, and Stock Prices", "authors": [{"first": "A", "middle": [], "last": "Timmermann", "suffix": ""}], "year": 2001, "venue": "Journal of Business and Economic Statistics", "link": "154164672"}, "BIBREF45": {"title": "Forecast Combinations", "authors": [{"first": "A", "middle": [], "last": "Timmermann", "suffix": ""}], "year": 2006, "venue": "Handbook of Economic Forecasting", "link": null}, "BIBREF46": {"title": "Likelihood Ratio Tests for Model Selection and Non-nested Hypotheses", "authors": [{"first": "Q", "middle": ["H"], "last": "Vuong", "suffix": ""}], "year": 1989, "venue": "Econometrica", "link": "56312024"}, "BIBREF47": {"title": "Asymptotic Inference about Predictive Ability", "authors": [{"first": "K", "middle": ["D"], "last": "West", "suffix": ""}], "year": 1996, "venue": "Econometrica", "link": "117722777"}, "BIBREF48": {"title": "Fixed-Effects and Related Estimators for Correlated RandomCoefficient and Treatment-Effect Panel Data Models", "authors": [{"first": "J", "middle": ["M"], "last": "Wooldridge", "suffix": ""}], "year": 2005, "venue": "Review of Economics and Statistics", "link": "57565555"}}, "ref_entries": {}}
{"paper_id": "199666980", "_pdf_hash": "251e0013f53decf33201f99d6f2f893b2f37e733", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Japanese Religion and Society. Paradigms of Structure and Change", "authors": [{"first": "W", "middle": [], "last": "Davis", "suffix": ""}], "year": 2007, "venue": "", "link": "186681979"}, "BIBREF1": {"title": "fifth impression 1964): The Elementary Forms of Religious Life", "authors": [{"first": "\u00c9", "middle": [], "last": "Durkheim", "suffix": ""}], "year": 1915, "venue": "Shikoku henro no tera, j\u014d ('Shikoku Henro Temples Part A')", "link": null}, "BIBREF2": {"title": "Zenkoku reij\u014d junpai jiten ('Dictionary of pilgrimages in all-Japan')", "authors": [{"first": "D", "middle": [], "last": "Ishihara", "suffix": ""}], "year": 1997, "venue": "", "link": null}, "BIBREF3": {"title": "Shikoku Pilgrimage. A Study of Foreign Pilgrims from a Japanese Point of View. Unpublished Bachelor's thesis", "authors": [{"first": "R", "middle": [], "last": "Kihara", "suffix": ""}], "year": 2009, "venue": "", "link": null}, "BIBREF4": {"title": "Shikoku's Local Authorities and Henro During the Golden Age of the Pilgrimage", "authors": [{"first": "N", "middle": [], "last": "Kouam\u00e9", "suffix": ""}], "year": 1997, "venue": "Japanese Journal of Religious Studies", "link": "163234514"}, "BIBREF5": {"title": "Shikoku Henro. A Study of Japanese and Western Pilgrims on the Shikoku Eighty-Eight Sacred Places Pilgrimage. Unpublished Master's dissertation", "authors": [{"first": "F", "middle": [], "last": "Macgregor", "suffix": ""}], "year": 2002, "venue": "", "link": null}, "BIBREF6": {"title": "The History of Charitable Giving Along the Shikoku Pilgrimage Route. Unpublished Master's dissertation", "authors": [{"first": "D", "middle": [], "last": "Moreton", "suffix": ""}], "year": 2001, "venue": "", "link": null}, "BIBREF7": {"title": "Contemporary Pilgrims' Understanding of the Shikoku Pilgrimage", "authors": [{"first": "R", "middle": [], "last": "Pussel", "suffix": ""}], "year": 2012, "venue": "", "link": null}, "BIBREF8": {"title": "Making Pilgrimages. Meaning and Practice in Shikoku", "authors": [{"first": "I", "middle": [], "last": "Reader", "suffix": ""}], "year": 2005, "venue": "", "link": "29868910"}, "BIBREF9": {"title": "Practically Religious. Worldly Benefits and the Common Religion of Japan", "authors": [{"first": "I", "middle": [], "last": "Reader", "suffix": ""}, {"first": "G", "middle": [], "last": "Tanabe", "suffix": ""}], "year": 1998, "venue": "", "link": "145469173"}, "BIBREF10": {"title": "The Evolution of a Pilgrimage as a Spatial-Symbolic System", "authors": [{"first": "H", "middle": [], "last": "Tanaka", "suffix": ""}], "year": 1981, "venue": "Canadian Geographer XXV", "link": null}, "BIBREF11": {"title": "Religious Experience Reconsidered. A Building-Block Approach to the Study of Religion and Other Special Things", "authors": [{"first": "A", "middle": [], "last": "Taves", "suffix": ""}], "year": 2009, "venue": "", "link": "142254603"}, "BIBREF12": {"title": "Tosashi-shi ('History of Tosa-city')", "authors": [], "year": 1973, "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "199667935", "_pdf_hash": "c5968f6b48d02cd129e91ab1f267c11dd94825f1", "abstract": [], "body_text": [{"section": "", "text": "The development of paediatric critical care registries, a term we take to include national audits and research databases, has been instrumental in helping us understand the state of children's critical care and thereby provide a platform for future improvement. Comprehensive datasets enable monitoring of activity and outcomes for audit, safety and service planning. Registry databases play a crucial role in paediatric critical care research by providing information for observational studies and data to plan multicentre interventional clinical trials. There are a number of examples: the Paediatric Intensive Care Audit Network (PICANet) collects data for every admission to paediatric intensive care units (PICU) in the UK and Ireland, and the Australian and New Zealand Paediatric Intensive Care Registry (ANZPICR) collects data for children admitted to PICUs and adult intensive care units. Virtual Pediatric Systems (VPS) is a large database covering over 135 units and over 1 million cases in the USA, but does not collect data from all national PICUs.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Paediatric intensive care medicine has a number of features, which expose the methodological problems of studies involving either one or few centres. Admission numbers and mortality rates are low (see Table 1 ). Infants and children in PICU present with a heterogeneous range of primary illness and co-morbidities, and the age range is broad-over 40% of admissions are under 1 year of age and a small number (2.4%) over 15 [1] -meaning that the pathophysiology of paediatric critical illness is hugely varied. Aggregation of data in registries helps us to overcome the problem of small numbers and describe patient characteristics, treatments and outcomes.", "cite_spans": [{"start": 423, "end": 426, "text": "[1]", "ref_id": "BIBREF0"}], "ref_spans": [{"start": 201, "end": 208, "text": "Table 1", "ref_id": "TABREF0"}]}, {"section": "", "text": "Use of registry databases to monitor safety and drive quality improvement is well described [2] : this includes transparent reporting of outcomes based on nationally or internationally agreed benchmarks in order to ensure safety and quality. Additionally, registries offer a wellestablished platform for observational studies, leading to a large body of research describing ICU processes, disease states and therapeutic interventions. Linking datasets-for example linking PICU databases to national hospital episodes datasets to provide detailed diagnostic information on children with life-limiting conditions [3] -enhances their explanatory power. Paediatric intensive care databases use mortality prediction models to enable participating units to benchmark their outcomes, and in turn, the data contributed by the participating units are used to construct and update these models in a symbiotic relationship [4] . Although registry studies are observational and hence cannot demonstrate causality, they are integral to the design and conduct of paediatric clinical trials. Databases can be interrogated in the planning stage, to provide epidemiological and outcome data for the diseases or treatments of interest. The data collection infrastructure can then be harnessed to provide high-quality data to the trial. The ChiP trial of tight glycaemic control in critically ill children [5] , the CATCH trial of antibiotic impregnated central venous catheters [6] and the ongoing I-KID trial of infant kidney dialysis and filtration are good examples of this [7] . Recent interest has focussed on registry-based randomised trials [8] which, despite the potential challenges of consent, standardisation and quality of data, may represent a future avenue for high-quality, low-cost clinical trials in PICUs.", "cite_spans": [{"start": 92, "end": 95, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 611, "end": 614, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 912, "end": 915, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 1387, "end": 1390, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 1460, "end": 1463, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 1559, "end": 1562, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 1630, "end": 1633, "text": "[8]", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "", "text": "Moynihan and colleagues [9] have produced an excellent example of the powerful insights offered by a wellestablished and comprehensive paediatric intensive care registry. In this binational 11-year retrospective study of child death in Australia and New Zealand, children admitted to intensive care were identified via ANZPICR. In addition, data from the national census of both countries were used to provide population-based mortality data over the study period. The authors report a decline in both crude and risk-adjusted ICU mortality (0.1% per year) over the 11-year period. 12% of all child deaths in Australia and New Zealand occurred in ICU. Data on mode of death of children in ICU are presented, indicating that half the deaths occurred following withdrawal of life-sustaining therapy, the rate of death despite maximal support was 21% and fell by 0.9% per year, and the rate of diagnosis of brain death rose.", "cite_spans": [{"start": 24, "end": 27, "text": "[9]", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "", "text": "Moynihan and colleagues report longitudinal trends on mode of death from this binational dataset, which is unique in paediatric critical care medicine and comparable in scope to large adult data sets (see Table 1 ). Some encouragement can be found in the decrease in the proportions of deaths taking place despite maximal support; however, questions remain about the role intensive care should play at the end of life for many of these children and their families. Such debates are informed by registrybased research: three decades of data from a single centre in Australia demonstrated that children who would not have been offered intensive care at the beginning of the period are now surviving with moderate or severe disability [10] . A large longitudinal database study from all the PICUs in England showed that 58% of PICU admissions and 73% of PICU deaths were for children with lifelimiting conditions [11] . In addition, children are taking longer to die on the PICU with a pattern of early death due to treatment failure being replaced by death following a prolonged PICU admission [12] . Moynihan and colleagues use their findings to call for an increase in the use of advance planning and palliative care involvement for critically ill children. They are right to do so, and this should form part of a wider discussion [13] about the role that intensive therapies should play in the lives of critically ill children, many of whom are likely to die in childhood.", "cite_spans": [{"start": 732, "end": 736, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 910, "end": 914, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 1092, "end": 1096, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 1331, "end": 1335, "text": "[13]", "ref_id": "BIBREF12"}], "ref_spans": [{"start": 205, "end": 212, "text": "Table 1", "ref_id": "TABREF0"}]}, {"section": "", "text": "To fully understand the impact of critical illness on children and families, there is a need to collect highquality longitudinal data from multiple data sources in a standardised format that will measure the range of outcomes and complexity of processes involved. Understanding the whole patient journey from illness onset to discharge is vital to allow informed, evidence-based planning of paediatric health services. Collecting these additional data will involve the need for funding, technical expertise and governance approvals at a national level. At an international level, harmonising definitions and then using these complex longitudinal data will provide insight into the effects of different organisational social and health structures on the delivery of paediatric critical care. Armed with this information, society can make an informed choice about how, where and what care for critically ill children is delivered in the future. ", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Paediatric Intensive Care Audit Network Annual Report (2018) Universities of Leeds and Leicester", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF1": {"title": "Pediatric intensive care databases for quality improvement", "authors": [{"first": "R", "middle": [], "last": "Wetzel", "suffix": ""}], "year": 2016, "venue": "J Pediatr Intensive Care", "link": "76944401"}, "BIBREF2": {"title": "Children with life-limiting conditions in paediatric intensive care units: a national cohort, data linkage study", "authors": [{"first": "L", "middle": ["K"], "last": "Fraser", "suffix": ""}, {"first": "R", "middle": [], "last": "Parslow", "suffix": ""}], "year": 2018, "venue": "Arch Dis Child", "link": "7162081"}, "BIBREF3": {"title": "Paediatric index of mortality 3", "authors": [{"first": "L", "middle": [], "last": "Straney", "suffix": ""}, {"first": "A", "middle": [], "last": "Clements", "suffix": ""}, {"first": "R", "middle": ["C"], "last": "Parslow", "suffix": ""}], "year": 2013, "venue": "Pediatric Crit Care Med", "link": null}, "BIBREF4": {"title": "A randomized trial of hyperglycemic control in pediatric intensive care", "authors": [{"first": "D", "middle": [], "last": "Macrae", "suffix": ""}, {"first": "R", "middle": [], "last": "Grieve", "suffix": ""}, {"first": "Allen", "middle": ["E"], "last": "", "suffix": ""}], "year": 2014, "venue": "N Engl J Med", "link": null}, "BIBREF5": {"title": "Impregnated central venous catheters for prevention of bloodstream infection in children (the CATCH trial): a randomised controlled trial", "authors": [{"first": "R", "middle": ["E"], "last": "Gilbert", "suffix": ""}, {"first": "Q", "middle": [], "last": "Mok", "suffix": ""}, {"first": "K", "middle": [], "last": "Dwan", "suffix": ""}], "year": 2016, "venue": "Lancet", "link": "26794306"}, "BIBREF6": {"title": "Infant kidney dialysis and filtration: the I-KID study", "authors": [{"first": "J", "middle": [], "last": "Walker", "suffix": ""}], "year": 2017, "venue": "", "link": null}, "BIBREF7": {"title": "The randomized registry trial-the next disruptive technology in clinical research?", "authors": [{"first": "M", "middle": ["S"], "last": "Lauer", "suffix": ""}, {"first": "D", "middle": [], "last": "Agostino", "suffix": ""}, {"first": "R", "middle": ["B"], "last": "", "suffix": ""}], "year": 2013, "venue": "N Engl J Med", "link": "26278676"}, "BIBREF8": {"title": "Epidemiology of childhood death in Australian and New Zealand intensive care units", "authors": [{"first": "K", "middle": ["M"], "last": "Moynihan", "suffix": ""}, {"first": "Pma", "middle": [], "last": "Alexander", "suffix": ""}, {"first": "L", "middle": ["J"], "last": "Schlapbach", "suffix": ""}], "year": 2019, "venue": "Intensive Care Med", "link": "195791209"}, "BIBREF9": {"title": "Three decades of pediatric intensive care: Who was admitted, what happened in intensive care, and what happened afterward", "authors": [{"first": "P", "middle": [], "last": "Namachivayam", "suffix": ""}, {"first": "F", "middle": [], "last": "Shann", "suffix": ""}, {"first": "L", "middle": [], "last": "Shekerdemian", "suffix": ""}], "year": 2010, "venue": "Pediatric Crit Care Med", "link": "1719367"}, "BIBREF10": {"title": "Children with life-limiting conditions in paediatric intensive care units: a national cohort, data linkage study", "authors": [{"first": "L", "middle": ["K"], "last": "Fraser", "suffix": ""}, {"first": "R", "middle": [], "last": "Parslow", "suffix": ""}], "year": 2017, "venue": "Arch Dis Child Archdischild", "link": "7162081"}, "BIBREF11": {"title": "Is it taking longer to die in paediatric intensive care in England and Wales?", "authors": [{"first": "A", "middle": [], "last": "Plunkett", "suffix": ""}, {"first": "R", "middle": ["C"], "last": "Parslow", "suffix": ""}], "year": 2016, "venue": "Arch Dis Child", "link": "21625012"}, "BIBREF12": {"title": "Intensive care: because we can or because we should? Arch Dis Child Archdischild", "authors": [{"first": "G", "middle": ["A"], "last": "Pearson", "suffix": ""}], "year": 2018, "venue": "", "link": null}, "BIBREF13": {"title": "Dilemmas in undertaking research in paediatric intensive care", "authors": [{"first": "H", "middle": ["K"], "last": "Kanthimathinathan", "suffix": ""}, {"first": "B", "middle": ["R"], "last": "Scholefield", "suffix": ""}], "year": 2014, "venue": "Arch Dis Child", "link": "22865730"}, "BIBREF14": {"title": "Epidemiology of death in the PICU at five US teaching hospitals*", "authors": [{"first": "J", "middle": ["P"], "last": "Burns", "suffix": ""}, {"first": "D", "middle": ["E"], "last": "Sellers", "suffix": ""}, {"first": "E", "middle": ["C"], "last": "Meyer", "suffix": ""}], "year": 2014, "venue": "Crit Care Med", "link": "9989618"}, "BIBREF15": {"title": "Characteristics of deaths in paediatric intensive care: a 10-year study", "authors": [{"first": "R", "middle": [], "last": "Sands", "suffix": ""}, {"first": "J", "middle": ["C"], "last": "Manning", "suffix": ""}, {"first": "H", "middle": [], "last": "Vyas", "suffix": ""}, {"first": "A", "middle": [], "last": "Rashid", "suffix": ""}], "year": 2009, "venue": "Nurs Crit Care", "link": "12724432"}, "BIBREF16": {"title": "Key statistics from the Case Mix Programme-adult, general critical care units", "authors": [], "year": 2017, "venue": "ICNARC", "link": null}, "BIBREF17": {"title": "Population estimates for", "authors": [{"first": "England", "middle": [], "last": "Uk", "suffix": ""}, {"first": "Scotland", "middle": [], "last": "Wales", "suffix": ""}, {"first": "Northern", "middle": [], "last": "Ireland", "suffix": ""}], "year": 2018, "venue": "Office for National Statistics", "link": null}}, "ref_entries": {"TABREF0": {"text": "Population differences and differing modes of death in paediatric and adult ICUs. (Adapted and updated from Kanthimathinathan and Scholefield [14]) ICNARC does not systematically report these data. We have assumed that deaths not following withholding/withholding of treatment, or following declaration of brain death, are deaths despite maximal therapy Paediatrics Paediatric Intensive Care Audit Network Annual Report 2018 [1] Adults Key statistics from the Case Mix Programme: 2017-2018, Intensive Care National Audit and Research Centre (ICNARC) [17] Population Office for National Statistics [18] *Children < 16 years **Adults > 16 yearsAuthor details 1 Cardiac Intensive Care Unit, Great Ormond Street Hospital, London WC1N 3JH, UK. 2 School of Medicine, University of Leeds, Leeds LS2 9JT, UK.", "type": "table"}}}
{"paper_id": "199667938", "_pdf_hash": "e6e2427849c7050ede54c5d408d1f730c9317707", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "The role of stereotactic radiosurgery in the management of patients with newly diagnosed brain metastases: a systematic review and evidencebased clinical practice guideline", "authors": [{"first": "M", "middle": ["E"], "last": "Linskey", "suffix": ""}, {"first": "D", "middle": ["W"], "last": "Andrews", "suffix": ""}, {"first": "A", "middle": ["L"], "last": "Asher", "suffix": ""}, {"first": "S", "middle": ["H"], "last": "Burri", "suffix": ""}, {"first": "D", "middle": [], "last": "Kondziolka", "suffix": ""}, {"first": "P", "middle": ["D"], "last": "Robinson", "suffix": ""}, {"first": "M", "middle": [], "last": "Ammirati", "suffix": ""}, {"first": "C", "middle": ["S"], "last": "Cobbs", "suffix": ""}, {"first": "L", "middle": ["E"], "last": "Gaspar", "suffix": ""}, {"first": "J", "middle": ["S"], "last": "Loeffler", "suffix": ""}, {"first": "M", "middle": [], "last": "Mcdermott", "suffix": ""}, {"first": "M", "middle": ["P"], "last": "Mehta", "suffix": ""}, {"first": "T", "middle": [], "last": "Mikkelsen", "suffix": ""}, {"first": "J", "middle": ["J"], "last": "Olson", "suffix": ""}, {"first": "N", "middle": ["A"], "last": "Paleologos", "suffix": ""}, {"first": "R", "middle": ["A"], "last": "Patchell", "suffix": ""}, {"first": "T", "middle": ["C"], "last": "Ryken", "suffix": ""}, {"first": "S", "middle": ["N"], "last": "Kalkanis", "suffix": ""}], "year": 2010, "venue": "J Neurooncol", "link": "215230448"}, "BIBREF1": {"title": "Single dose radiosurgical treatment of recurrent previously irradiated primary brain tumors and brain metastases: final report of RTOG protocol 90-05", "authors": [{"first": "E", "middle": [], "last": "Shaw", "suffix": ""}, {"first": "C", "middle": [], "last": "Scott", "suffix": ""}, {"first": "L", "middle": [], "last": "Souhami", "suffix": ""}, {"first": "R", "middle": [], "last": "Dinapoli", "suffix": ""}, {"first": "R", "middle": [], "last": "Kline", "suffix": ""}, {"first": "J", "middle": [], "last": "Loeffler", "suffix": ""}, {"first": "N", "middle": [], "last": "Farnan", "suffix": ""}], "year": 2000, "venue": "Int J Radiat Oncol Biol Phys", "link": "42137586"}, "BIBREF2": {"title": "Hypofractionated stereotactic radiotherapy in combination with whole brain radiotherapy for brain metastases", "authors": [{"first": "C", "middle": [], "last": "Giubilei", "suffix": ""}, {"first": "G", "middle": [], "last": "Ingrosso", "suffix": ""}, {"first": "D", "middle": [], "last": "&apos;andrea", "suffix": ""}, {"first": "M", "middle": [], "last": "Benassi", "suffix": ""}, {"first": "M", "middle": [], "last": "Santoni", "suffix": ""}, {"first": "R", "middle": [], "last": "", "suffix": ""}], "year": 2009, "venue": "J Neurooncol", "link": "2833963"}, "BIBREF3": {"title": "Irradiated volume as a predictor of brain radionecrosis after linear accelerator stereotactic radiosurgery", "authors": [{"first": "B", "middle": ["J"], "last": "Blonigen", "suffix": ""}, {"first": "R", "middle": ["D"], "last": "Steinmetz", "suffix": ""}, {"first": "L", "middle": [], "last": "Levin", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Lamba", "suffix": ""}, {"first": "R", "middle": ["E"], "last": "Warnick", "suffix": ""}, {"first": "J", "middle": ["C"], "last": "Breneman", "suffix": ""}], "year": 2010, "venue": "Int J Radiat Oncol Biol Phys", "link": "22095619"}, "BIBREF4": {"title": "Single-fraction stereotactic radiosurgery (SRS) alone versus surgical resection and SRS for large brain metastases: a multi-institutional analysis", "authors": [{"first": "R", "middle": ["S"], "last": "Prabhu", "suffix": ""}, {"first": "R", "middle": ["H"], "last": "Press", "suffix": ""}, {"first": "K", "middle": ["R"], "last": "Patel", "suffix": ""}, {"first": "D", "middle": ["M"], "last": "Boselli", "suffix": ""}, {"first": "J", "middle": ["T"], "last": "Symanowski", "suffix": ""}, {"first": "S", "middle": ["P"], "last": "Lankford", "suffix": ""}, {"first": "R", "middle": ["J"], "last": "Mccammon", "suffix": ""}, {"first": "B", "middle": ["J"], "last": "Moeller", "suffix": ""}, {"first": "J", "middle": ["H"], "last": "Heinzerling", "suffix": ""}, {"first": "C", "middle": ["E"], "last": "Fasola", "suffix": ""}, {"first": "A", "middle": ["L"], "last": "Asher", "suffix": ""}, {"first": "A", "middle": ["L"], "last": "Sumrall", "suffix": ""}, {"first": "Z", "middle": ["S"], "last": "Buchwald", "suffix": ""}, {"first": "W", "middle": ["J"], "last": "Curran", "suffix": ""}, {"first": "H", "middle": ["G"], "last": "Shu", "suffix": ""}, {"first": "I", "middle": [], "last": "Crocker", "suffix": ""}, {"first": "S", "middle": ["H"], "last": "Burri", "suffix": ""}], "year": 2017, "venue": "Int J Radiat Oncol Biol Phys", "link": "4507427"}, "BIBREF5": {"title": "Single-fraction versus multifraction (3 \u00d7 9 Gy) stereotactic radiosurgery for large (%3e2 cm) brain metastases: a comparative analysis of local control and risk of radiation-induced brain necrosis", "authors": [{"first": "G", "middle": [], "last": "Minniti", "suffix": ""}, {"first": "C", "middle": [], "last": "Scaringi", "suffix": ""}, {"first": "S", "middle": [], "last": "Paolini", "suffix": ""}, {"first": "G", "middle": [], "last": "Lanzetta", "suffix": ""}, {"first": "A", "middle": [], "last": "Romano", "suffix": ""}, {"first": "F", "middle": [], "last": "Cicone", "suffix": ""}, {"first": "M", "middle": [], "last": "Osti", "suffix": ""}, {"first": "R", "middle": ["M"], "last": "Enrici", "suffix": ""}, {"first": "V", "middle": [], "last": "Esposito", "suffix": ""}], "year": 2016, "venue": "Int J Radiat Oncol Biol Phys", "link": "12931539"}, "BIBREF6": {"title": "Radiosurgery for large brain metastases", "authors": [{"first": "J", "middle": ["H"], "last": "Han", "suffix": ""}, {"first": "D", "middle": ["G"], "last": "Kim", "suffix": ""}, {"first": "H", "middle": ["T"], "last": "Chung", "suffix": ""}, {"first": "S", "middle": ["H"], "last": "Paek", "suffix": ""}, {"first": "C", "middle": ["K"], "last": "Park", "suffix": ""}, {"first": "H", "middle": ["W"], "last": "Jung", "suffix": ""}], "year": 2012, "venue": "Int J Radiat Oncol Biol Phys", "link": "954748"}, "BIBREF7": {"title": "Stereotactic radiotherapy for large solitary brain metastases", "authors": [{"first": "L", "middle": [], "last": "Feuvret", "suffix": ""}, {"first": "S", "middle": [], "last": "Vinchon", "suffix": ""}, {"first": "V", "middle": [], "last": "Martin", "suffix": ""}, {"first": "I", "middle": [], "last": "Lamproglou", "suffix": ""}, {"first": "A", "middle": [], "last": "Halley", "suffix": ""}, {"first": "V", "middle": [], "last": "Calugaru", "suffix": ""}, {"first": "M", "middle": [], "last": "Chea", "suffix": ""}, {"first": "C", "middle": ["A"], "last": "Valery", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Simon", "suffix": ""}, {"first": "J", "middle": ["J"], "last": "Mazeron", "suffix": ""}], "year": 2014, "venue": "Cancer Radiother", "link": "29087555"}, "BIBREF8": {"title": "Treatment of large brain metastases with stereotactic radiosurgery", "authors": [{"first": "A", "middle": ["L"], "last": "Zimmerman", "suffix": ""}, {"first": "E", "middle": ["S"], "last": "Murphy", "suffix": ""}, {"first": "J", "middle": ["H"], "last": "Suh", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Vogelbaum", "suffix": ""}, {"first": "G", "middle": ["H"], "last": "Barnett", "suffix": ""}, {"first": "L", "middle": [], "last": "Angelov", "suffix": ""}, {"first": "M", "middle": [], "last": "Ahluwalia", "suffix": ""}, {"first": "C", "middle": ["A"], "last": "Reddy", "suffix": ""}, {"first": "S", "middle": ["T"], "last": "Chao", "suffix": ""}], "year": 2016, "venue": "Technol Cancer Res Treat", "link": "12025988"}, "BIBREF9": {"title": "Fractionated stereotactic gamma knife radiosurgery for large brain metastases: a retrospective, single center study", "authors": [{"first": "J", "middle": ["W"], "last": "Kim", "suffix": ""}, {"first": "H", "middle": ["R"], "last": "Park", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Lee", "suffix": ""}, {"first": "J", "middle": ["W"], "last": "Kim", "suffix": ""}, {"first": "H", "middle": ["T"], "last": "Chung", "suffix": ""}, {"first": "D", "middle": ["G"], "last": "Kim", "suffix": ""}, {"first": "H", "middle": ["W"], "last": "Jung", "suffix": ""}, {"first": "S", "middle": ["H"], "last": "Paek", "suffix": ""}], "year": 2016, "venue": "PLoS ONE", "link": "2927291"}, "BIBREF10": {"title": "Efficacy and safety of fractionated stereotactic radiosurgery for large brain metastases", "authors": [{"first": "W", "middle": ["J"], "last": "Jeong", "suffix": ""}, {"first": "J", "middle": ["H"], "last": "Park", "suffix": ""}, {"first": "E", "middle": ["J"], "last": "Lee", "suffix": ""}, {"first": "J", "middle": ["H"], "last": "Kim", "suffix": ""}, {"first": "C", "middle": ["J"], "last": "Kim", "suffix": ""}, {"first": "Y", "middle": ["H"], "last": "Cho", "suffix": ""}], "year": 2015, "venue": "J Korean Neurosurg Soc", "link": "6531954"}, "BIBREF12": {"title": "Hypo-fractionated stereotactic radiotherapy alone using volumetric modulated arc therapy for patients with single, large brain metastases unsuitable for surgical resection", "authors": [], "year": "", "venue": "Radiat Oncol", "link": "10489002"}, "BIBREF13": {"title": "Fractionated stereotactic radiosurgery for large brain metastases", "authors": [{"first": "R", "middle": ["E"], "last": "Wegner", "suffix": ""}, {"first": "J", "middle": ["E"], "last": "Leeman", "suffix": ""}, {"first": "P", "middle": [], "last": "Kabolizadeh", "suffix": ""}, {"first": "J", "middle": ["C"], "last": "Rwigema", "suffix": ""}, {"first": "A", "middle": ["H"], "last": "Mintz", "suffix": ""}, {"first": "S", "middle": ["A"], "last": "Burton", "suffix": ""}, {"first": "D", "middle": ["E"], "last": "Heron", "suffix": ""}, {"first": "H", "middle": ["K"], "last": "Inoue", "suffix": ""}, {"first": "H", "middle": [], "last": "Sato", "suffix": ""}, {"first": "K", "middle": [], "last": "Seto", "suffix": ""}, {"first": "K", "middle": [], "last": "Torikai", "suffix": ""}, {"first": "Y", "middle": [], "last": "Suzuki", "suffix": ""}, {"first": "J", "middle": [], "last": "Saitoh", "suffix": ""}, {"first": "S", "middle": ["E"], "last": "Noda", "suffix": ""}, {"first": "T", "middle": [], "last": "Nakano", "suffix": ""}], "year": 2014, "venue": "Five-fraction CyberKnife radiotherapy for large brain metastases in critical areas: impact on the surrounding brain", "link": "31493584"}, "BIBREF14": {"title": "Gy (V14) to avoid radiation necrosis", "authors": [], "year": "", "venue": "J Radiat Res", "link": null}, "BIBREF15": {"title": "Fractionated stereotactic radiotherapy using CyberKnife for the treatment of large brain metastases: a dose escalation study", "authors": [{"first": "T", "middle": [], "last": "Murai", "suffix": ""}, {"first": "H", "middle": [], "last": "Ogino", "suffix": ""}, {"first": "Y", "middle": [], "last": "Manabe", "suffix": ""}, {"first": "M", "middle": [], "last": "Iwabuchi", "suffix": ""}, {"first": "T", "middle": [], "last": "Okumura", "suffix": ""}, {"first": "Y", "middle": [], "last": "Matsushita", "suffix": ""}, {"first": "Y", "middle": [], "last": "Tsuji", "suffix": ""}, {"first": "H", "middle": [], "last": "Suzuki", "suffix": ""}, {"first": "Y", "middle": [], "last": "Shibamoto", "suffix": ""}], "year": 2014, "venue": "Clin Oncol", "link": "25754860"}, "BIBREF16": {"title": "Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group", "authors": [{"first": "P", "middle": ["Y"], "last": "Wen", "suffix": ""}, {"first": "D", "middle": ["R"], "last": "Macdonald", "suffix": ""}, {"first": "D", "middle": ["A"], "last": "Reardon", "suffix": ""}, {"first": "T", "middle": ["F"], "last": "Cloughesy", "suffix": ""}, {"first": "A", "middle": ["G"], "last": "Sorensen", "suffix": ""}, {"first": "E", "middle": [], "last": "Galanis", "suffix": ""}, {"first": "J", "middle": [], "last": "Degroot", "suffix": ""}, {"first": "W", "middle": [], "last": "Wick", "suffix": ""}, {"first": "M", "middle": ["R"], "last": "Gilbert", "suffix": ""}, {"first": "A", "middle": ["B"], "last": "Lassman", "suffix": ""}, {"first": "C", "middle": [], "last": "Tsien", "suffix": ""}, {"first": "T", "middle": [], "last": "Mikkelsen", "suffix": ""}, {"first": "E", "middle": ["T"], "last": "Wong", "suffix": ""}, {"first": "M", "middle": ["C"], "last": "Chamberlain", "suffix": ""}, {"first": "R", "middle": [], "last": "Stupp", "suffix": ""}, {"first": "K", "middle": ["R"], "last": "Lamborn", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Vogelbaum", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Van Den Bent", "suffix": ""}, {"first": "S", "middle": ["M"], "last": "Chang", "suffix": ""}], "year": 2010, "venue": "J Clin Oncol", "link": "25926621"}, "BIBREF17": {"title": "T1/T2 matching to differentiate tumor growth from radiation effects after stereotactic radiosurgery", "authors": [{"first": "H", "middle": [], "last": "Kano", "suffix": ""}, {"first": "D", "middle": [], "last": "Kondziolka", "suffix": ""}, {"first": "J", "middle": [], "last": "Lobato-Polo", "suffix": ""}, {"first": "Zorro", "middle": ["O"], "last": "Flickinger", "suffix": ""}, {"first": "J", "middle": ["C"], "last": "Lunsford", "suffix": ""}, {"first": "L", "middle": ["D"], "last": "", "suffix": ""}], "year": 2010, "venue": "Neurosurgery", "link": "6572704"}, "BIBREF18": {"title": "The diagnosis and treatment of pseudoprogression, radiation necrosis and brain tumor recurrence", "authors": [{"first": "K", "middle": [], "last": "Parvez", "suffix": ""}, {"first": "A", "middle": [], "last": "Parvez", "suffix": ""}, {"first": "G", "middle": [], "last": "Zadeh", "suffix": ""}], "year": 2014, "venue": "Int J Mol Sci", "link": "14890029"}, "BIBREF19": {"title": "Evaluation of dynamic contrast-enhanced T1-weighted perfusion MRI in the differentiation of tumor recurrence from radiation necrosis", "authors": [{"first": "V", "middle": ["A"], "last": "Larsen", "suffix": ""}, {"first": "H", "middle": ["J"], "last": "Simonsen", "suffix": ""}, {"first": "I", "middle": [], "last": "Law", "suffix": ""}, {"first": "H", "middle": ["B"], "last": "Larsson", "suffix": ""}, {"first": "A", "middle": ["E"], "last": "Hansen", "suffix": ""}], "year": 2013, "venue": "Neuroradiology", "link": "38541049"}, "BIBREF20": {"title": "Universal survival curve and single fraction equivalent dose: useful tools in understanding potency of ablative radiotherapy: in regard to Parks", "authors": [{"first": "W", "middle": ["A"], "last": "Tome", "suffix": ""}], "year": 2008, "venue": "Int J Radiat Oncol Biol Phys", "link": null}, "BIBREF21": {"title": "The radiobiology of radiosurgery: rationale for different treatment regimes for AVMs and malignancies", "authors": [{"first": "E", "middle": ["J"], "last": "Hall", "suffix": ""}, {"first": "D", "middle": ["J"], "last": "Brenner", "suffix": ""}], "year": 1993, "venue": "Int J Radiat Oncol Biol Phys", "link": "10005199"}, "BIBREF22": {"title": "Radiobiophysical aspects of stereotaxic radiation treatment of central nervous system diseases", "authors": [{"first": "C", "middle": ["C"], "last": "Ling", "suffix": ""}, {"first": "Y", "middle": ["C"], "last": "Lo", "suffix": ""}, {"first": "D", "middle": ["A"], "last": "Larson", "suffix": ""}], "year": 1995, "venue": "Semin Radiat Oncol", "link": "45918869"}, "BIBREF23": {"title": "Single versus multifraction stereotactic radiosurgery for large brain metastases: an international meta-analysis of 24 trials", "authors": [{"first": "E", "middle": ["J"], "last": "Lehrer", "suffix": ""}, {"first": "J", "middle": ["L"], "last": "Peterson", "suffix": ""}, {"first": "N", "middle": ["G"], "last": "Zaorsky", "suffix": ""}, {"first": "P", "middle": ["D"], "last": "Brown", "suffix": ""}, {"first": "A", "middle": [], "last": "Sahgal", "suffix": ""}, {"first": "V", "middle": ["L"], "last": "Chiang", "suffix": ""}, {"first": "S", "middle": ["T"], "last": "Chao", "suffix": ""}, {"first": "J", "middle": ["P"], "last": "Sheehan", "suffix": ""}, {"first": "D", "middle": ["M"], "last": "Trifiletti", "suffix": ""}], "year": 2019, "venue": "Int J Radiat Oncol Biol Phys", "link": "53244108"}}, "ref_entries": {}}
{"paper_id": "199668067", "_pdf_hash": "0fca265f00be5b69664ae7add2c7746f8821aaa1", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "An update on new antibiotic prophylaxis and treatment for urinary tract infections in children", "authors": [{"first": "J", "middle": ["D"], "last": "Delbet", "suffix": ""}, {"first": "M", "middle": [], "last": "Lorrot", "suffix": ""}, {"first": "T", "middle": [], "last": "Ulinski", "suffix": ""}], "year": 2017, "venue": "Expert Opin Pharmacother", "link": "205819612"}, "BIBREF1": {"title": "Antibiotic resistance patterns of outpatient pediatric urinary tract infections", "authors": [{"first": "R", "middle": ["S"], "last": "Edlin", "suffix": ""}, {"first": "D", "middle": ["J"], "last": "Shapiro", "suffix": ""}, {"first": "A", "middle": ["L"], "last": "Hersh", "suffix": ""}, {"first": "H", "middle": ["L"], "last": "Copp", "suffix": ""}], "year": 2013, "venue": "J Urol", "link": "574252"}, "BIBREF2": {"title": "Drug-resistant gram-negative uropathogens: a review", "authors": [{"first": "S", "middle": [], "last": "Khoshnood", "suffix": ""}, {"first": "M", "middle": [], "last": "Heidary", "suffix": ""}, {"first": "R", "middle": [], "last": "Mirnejad", "suffix": ""}, {"first": "A", "middle": [], "last": "Bahramian", "suffix": ""}, {"first": "M", "middle": [], "last": "Sedighi", "suffix": ""}, {"first": "H", "middle": [], "last": "Mirzaei", "suffix": ""}], "year": 2017, "venue": "Biomed Pharmacother", "link": "33469990"}, "BIBREF3": {"title": "Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance", "authors": [{"first": "A", "middle": ["P"], "last": "Magiorakos", "suffix": ""}, {"first": "A", "middle": [], "last": "Srinivasan", "suffix": ""}, {"first": "R", "middle": ["B"], "last": "Carey", "suffix": ""}, {"first": "Y", "middle": [], "last": "Carmeli", "suffix": ""}, {"first": "M", "middle": ["E"], "last": "Falagas", "suffix": ""}, {"first": "C", "middle": ["G"], "last": "Giske", "suffix": ""}, {"first": "S", "middle": [], "last": "Harbarth", "suffix": ""}, {"first": "J", "middle": ["F"], "last": "Hindler", "suffix": ""}, {"first": "G", "middle": [], "last": "Kahlmeter", "suffix": ""}, {"first": "B", "middle": [], "last": "Olsson-Liljequist", "suffix": ""}, {"first": "D", "middle": ["L"], "last": "Paterson", "suffix": ""}, {"first": "L", "middle": ["B"], "last": "Rice", "suffix": ""}, {"first": "J", "middle": [], "last": "Stelling", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Struelens", "suffix": ""}, {"first": "A", "middle": [], "last": "Vatopoulos", "suffix": ""}, {"first": "J", "middle": ["T"], "last": "Weber", "suffix": ""}, {"first": "D", "middle": ["L"], "last": "Monnet", "suffix": ""}], "year": 2012, "venue": "Clin Microbiol Infect", "link": "25961436"}, "BIBREF4": {"title": "Beta-lactamases in Enterobacteriaceae infections in children", "authors": [{"first": "C", "middle": ["A"], "last": "Moxon", "suffix": ""}, {"first": "S", "middle": [], "last": "Paulus", "suffix": ""}], "year": 2016, "venue": "J Inf Secur", "link": "19049799"}, "BIBREF5": {"title": "Urinary tract infections caused by community-acquired extended-spectrum beta-lactamase-producing and nonproducing bacteria: a comparative study", "authors": [{"first": "N", "middle": [], "last": "Dayan", "suffix": ""}, {"first": "H", "middle": [], "last": "Dabbah", "suffix": ""}, {"first": "I", "middle": [], "last": "Weissman", "suffix": ""}, {"first": "I", "middle": [], "last": "Aga", "suffix": ""}, {"first": "L", "middle": [], "last": "Even", "suffix": ""}, {"first": "D", "middle": [], "last": "Glikman", "suffix": ""}], "year": 2013, "venue": "J Pediatr", "link": "8780127"}, "BIBREF6": {"title": "ESBL-producing Escherichia coli ST131 versus non-ST131: evolution and risk factors of carriage among French children in the community between 2010 and 2015", "authors": [{"first": "A", "middle": [], "last": "Birgy", "suffix": ""}, {"first": "C", "middle": [], "last": "Levy", "suffix": ""}, {"first": "P", "middle": [], "last": "Bidet", "suffix": ""}, {"first": "F", "middle": [], "last": "Thollot", "suffix": ""}, {"first": "V", "middle": [], "last": "Derkx", "suffix": ""}, {"first": "S", "middle": [], "last": "Bechet", "suffix": ""}, {"first": "P", "middle": [], "last": "Marianikurkdjian", "suffix": ""}, {"first": "R", "middle": [], "last": "Cohen", "suffix": ""}, {"first": "S", "middle": [], "last": "Bonacorsi", "suffix": ""}], "year": 2016, "venue": "J Antimicrob Chemother", "link": "205152842"}, "BIBREF7": {"title": "Emergence of extended spectrum-beta-lactamase-producing Escherichia coli O25b-ST131: a major community-acquired uropathogen in infants", "authors": [{"first": "M", "middle": ["F"], "last": "Cheng", "suffix": ""}, {"first": "W", "middle": ["L"], "last": "Chen", "suffix": ""}, {"first": "W", "middle": ["Y"], "last": "Hung", "suffix": ""}, {"first": "I", "middle": ["F"], "last": "Huang", "suffix": ""}, {"first": "Y", "middle": ["H"], "last": "Chiou", "suffix": ""}, {"first": "Y", "middle": ["S"], "last": "Chen", "suffix": ""}, {"first": "S", "middle": ["S"], "last": "Lee", "suffix": ""}, {"first": "C", "middle": ["H"], "last": "Hung", "suffix": ""}, {"first": "J", "middle": ["L"], "last": "Wang", "suffix": ""}], "year": 2015, "venue": "Pediatr Infect Dis J", "link": "33518872"}, "BIBREF8": {"title": "Past and present perspectives on beta-lactamases", "authors": [{"first": "K", "middle": [], "last": "Bush", "suffix": ""}], "year": 2018, "venue": "Antimicrob Agents Chemother", "link": null}, "BIBREF9": {"title": "Treatment of multidrug-resistant Gramnegative infections in children", "authors": [{"first": "A", "middle": ["J"], "last": "Hsu", "suffix": ""}, {"first": "P", "middle": ["D"], "last": "Tamma", "suffix": ""}], "year": 2014, "venue": "Clin Infect Dis", "link": "2400421"}, "BIBREF10": {"title": "Extended-spectrum betalactamase-producing Enterobacteriaceae in children: old foe, emerging threat", "authors": [{"first": "P", "middle": ["J"], "last": "Lukac", "suffix": ""}, {"first": "R", "middle": ["A"], "last": "Bonomo", "suffix": ""}, {"first": "L", "middle": ["K"], "last": "Logan", "suffix": ""}], "year": 2015, "venue": "Clin Infect Dis", "link": "14505750"}, "BIBREF11": {"title": "Extended spectrum beta lactamase (ESBL) producing bacteria urinary tract infections and complex pediatric urology", "authors": [{"first": "R", "middle": [], "last": "Wragg", "suffix": ""}, {"first": "A", "middle": [], "last": "Harris", "suffix": ""}, {"first": "M", "middle": [], "last": "Patel", "suffix": ""}, {"first": "A", "middle": [], "last": "Robb", "suffix": ""}, {"first": "H", "middle": [], "last": "Chandran", "suffix": ""}, {"first": "L", "middle": [], "last": "Mccarthy", "suffix": ""}], "year": 2017, "venue": "J Pediatr Surg", "link": "206427811"}, "BIBREF12": {"title": "Dissemination of extended-spectrum betalactamases and quinolone resistance genes among clinical isolates of uropathogenic Escherichia coli in children", "authors": [{"first": "I", "middle": [], "last": "Sedighi", "suffix": ""}, {"first": "M", "middle": ["R"], "last": "Arabestani", "suffix": ""}, {"first": "A", "middle": [], "last": "Rahimbakhsh", "suffix": ""}, {"first": "Z", "middle": [], "last": "Karimitabar", "suffix": ""}, {"first": "M", "middle": ["Y"], "last": "Alikhani", "suffix": ""}], "year": 2015, "venue": "Jundishapur J Microbiol", "link": "215592968"}, "BIBREF13": {"title": "Extended-spectrum beta-lactamase-producing and third-generation cephalosporin-resistant Enterobacteriaceae in children: trends in the United States", "authors": [{"first": "L", "middle": ["K"], "last": "Logan", "suffix": ""}, {"first": "N", "middle": ["P"], "last": "Braykov", "suffix": ""}, {"first": "R", "middle": ["A"], "last": "Weinstein", "suffix": ""}, {"first": "R", "middle": [], "last": "Laxminarayan", "suffix": ""}], "year": 1999, "venue": "J Pediatric Infect Dis Soc", "link": null}, "BIBREF14": {"title": "Clinical characteristics of Carbapenem-resistant Klebsiella pneumoniae infections in ill and colonized children in Colombia", "authors": [{"first": "A", "middle": [], "last": "Diaz", "suffix": ""}, {"first": "D", "middle": ["C"], "last": "Ortiz", "suffix": ""}, {"first": "M", "middle": [], "last": "Trujillo", "suffix": ""}, {"first": "C", "middle": [], "last": "Garces", "suffix": ""}, {"first": "F", "middle": [], "last": "Jaimes", "suffix": ""}, {"first": "A", "middle": ["V"], "last": "Restrepo", "suffix": ""}], "year": 2016, "venue": "Pediatr Infect Dis J", "link": "205690629"}, "BIBREF15": {"title": "Analysis of beta-lactamase resistance determinants in Enterobacteriaceae from Chicago children: a multicenter survey", "authors": [{"first": "L", "middle": ["K"], "last": "Logan", "suffix": ""}, {"first": "A", "middle": ["M"], "last": "Hujer", "suffix": ""}, {"first": "S", "middle": ["H"], "last": "Marshall", "suffix": ""}, {"first": "T", "middle": ["N"], "last": "Domitrovic", "suffix": ""}, {"first": "S", "middle": ["D"], "last": "Rudin", "suffix": ""}, {"first": "X", "middle": [], "last": "Zheng", "suffix": ""}, {"first": "N", "middle": ["K"], "last": "Qureshi", "suffix": ""}, {"first": "M", "middle": ["K"], "last": "Hayden", "suffix": ""}, {"first": "F", "middle": ["A"], "last": "Scaggs", "suffix": ""}, {"first": "A", "middle": [], "last": "Karadkhele", "suffix": ""}, {"first": "R", "middle": ["A"], "last": "Bonomo", "suffix": ""}], "year": 2016, "venue": "Antimicrob Agents Chemother", "link": "3000"}, "BIBREF16": {"title": "Treatment of infections caused by multidrug-resistant gram-negative bacteria: report of the British Society for Antimicrobial Chemotherapy/Healthcare Infection Society/British Infection Association Joint Working Party", "authors": [{"first": "P", "middle": ["M"], "last": "Hawkey", "suffix": ""}, {"first": "R", "middle": ["E"], "last": "Warren", "suffix": ""}, {"first": "D", "middle": ["M"], "last": "Livermore", "suffix": ""}, {"first": "Cam", "middle": [], "last": "Mcnulty", "suffix": ""}, {"first": "D", "middle": ["A"], "last": "Enoch", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Otter", "suffix": ""}, {"first": "Apr", "middle": [], "last": "Wilson", "suffix": ""}], "year": 2018, "venue": "J Antimicrob Chemother", "link": "3816538"}, "BIBREF17": {"title": "An evaluation of multidrug-resistant Escherichia coli isolates in urinary tract infections from Aguascalientes, Mexico: cross-sectional study", "authors": [{"first": "F", "middle": ["Y"], "last": "Ramirez-Castillo", "suffix": ""}, {"first": "A", "middle": ["C"], "last": "Moreno-Flores", "suffix": ""}, {"first": "F", "middle": ["J"], "last": "Avelar-Gonzalez", "suffix": ""}, {"first": "F", "middle": [], "last": "Marquez-Diaz", "suffix": ""}, {"first": "J", "middle": [], "last": "Harel", "suffix": ""}, {"first": "A", "middle": ["L"], "last": "Guerrero-Barrera", "suffix": ""}], "year": 2018, "venue": "Ann Clin Microbiol Antimicrob", "link": "51717844"}, "BIBREF18": {"title": "Prevalence of multidrug resistant uropathogenic bacteria in pediatric patients of a tertiary care hospital in eastern India", "authors": [{"first": "M", "middle": ["P"], "last": "Mishra", "suffix": ""}, {"first": "R", "middle": [], "last": "Sarangi", "suffix": ""}, {"first": "R", "middle": ["N"], "last": "Padhy", "suffix": ""}], "year": 2016, "venue": "J Infect Public Health", "link": "23220152"}, "BIBREF19": {"title": "International travel is a risk factor for extended-spectrum beta-lactamase-producing Enterobacteriaceae acquisition in children: a case-case-control study in an urban U.S. hospital", "authors": [{"first": "J", "middle": ["P"], "last": "Strysko", "suffix": ""}, {"first": "V", "middle": [], "last": "Mony", "suffix": ""}, {"first": "J", "middle": [], "last": "Cleveland", "suffix": ""}, {"first": "H", "middle": [], "last": "Siddiqui", "suffix": ""}, {"first": "P", "middle": [], "last": "Homel", "suffix": ""}, {"first": "C", "middle": [], "last": "Gagliardo", "suffix": ""}], "year": 2016, "venue": "Travel Med Infect Dis", "link": "19060438"}, "BIBREF20": {"title": "Risk factors for extended-spectrum betalactamase-producing Serratia marcescens and Klebsiella pneumoniae acquisition in a neonatal intensive care unit", "authors": [{"first": "V", "middle": [], "last": "Crivaro", "suffix": ""}, {"first": "M", "middle": [], "last": "Bagattini", "suffix": ""}, {"first": "M", "middle": ["F"], "last": "Salza", "suffix": ""}, {"first": "F", "middle": [], "last": "Raimondi", "suffix": ""}, {"first": "F", "middle": [], "last": "Rossano", "suffix": ""}, {"first": "M", "middle": [], "last": "Triassi", "suffix": ""}, {"first": "R", "middle": [], "last": "Zarrilli", "suffix": ""}], "year": 2007, "venue": "J Hosp Infect", "link": "35694557"}, "BIBREF21": {"title": "The mother as most important risk factor for colonization of very low birth weight (VLBW) infants with extended-spectrum beta-lactamaseproducing Enterobacteriaceae (ESBL-E)", "authors": [{"first": "L", "middle": ["A"], "last": "Denkel", "suffix": ""}, {"first": "F", "middle": [], "last": "Schwab", "suffix": ""}, {"first": "A", "middle": [], "last": "Kola", "suffix": ""}, {"first": "R", "middle": [], "last": "Leistner", "suffix": ""}, {"first": "L", "middle": [], "last": "Garten", "suffix": ""}, {"first": "K", "middle": [], "last": "Von Weizsacker", "suffix": ""}, {"first": "C", "middle": [], "last": "Geffers", "suffix": ""}, {"first": "P", "middle": [], "last": "Gastmeier", "suffix": ""}, {"first": "B", "middle": [], "last": "Piening", "suffix": ""}], "year": 2014, "venue": "J Antimicrob Chemother", "link": "18419641"}, "BIBREF22": {"title": "Extensive household outbreak of urinary tract infection and intestinal colonization due to extendedspectrum beta-lactamase-producing Escherichia coli sequence type 131", "authors": [{"first": "T", "middle": [], "last": "Madigan", "suffix": ""}, {"first": "J", "middle": ["R"], "last": "Johnson", "suffix": ""}, {"first": "C", "middle": [], "last": "Clabots", "suffix": ""}, {"first": "B", "middle": ["D"], "last": "Johnston", "suffix": ""}, {"first": "S", "middle": ["B"], "last": "Porter", "suffix": ""}, {"first": "B", "middle": ["S"], "last": "Slater", "suffix": ""}, {"first": "R", "middle": [], "last": "Banerjee", "suffix": ""}], "year": 2015, "venue": "Clin Infect Dis", "link": "206384301"}, "BIBREF23": {"title": "Rise of community-onset urinary tract infection caused by extended-spectrum beta-lactamase-producing Escherichia coli in children", "authors": [{"first": "N", "middle": ["C"], "last": "Fan", "suffix": ""}, {"first": "H", "middle": ["H"], "last": "Chen", "suffix": ""}, {"first": "C", "middle": ["L"], "last": "Chen", "suffix": ""}, {"first": "L", "middle": ["S"], "last": "Ou", "suffix": ""}, {"first": "T", "middle": ["Y"], "last": "Lin", "suffix": ""}, {"first": "M", "middle": ["H"], "last": "Tsai", "suffix": ""}, {"first": "C", "middle": ["H"], "last": "Chiu", "suffix": ""}], "year": 2014, "venue": "J Microbiol Immunol Infect", "link": "12009572"}, "BIBREF24": {"title": "Risk factors in communityacquired urinary tract infections caused by ESBL-producing bacteria in children", "authors": [{"first": "R", "middle": [], "last": "Topaloglu", "suffix": ""}, {"first": "Er", "middle": ["I"], "last": "Dogan", "suffix": ""}, {"first": "B", "middle": ["G"], "last": "Bilginer", "suffix": ""}, {"first": "Y", "middle": [], "last": "Ozaltin", "suffix": ""}, {"first": "F", "middle": [], "last": "Besbas", "suffix": ""}, {"first": "N", "middle": [], "last": "Ozen", "suffix": ""}, {"first": "S", "middle": [], "last": "Bakkaloglu", "suffix": ""}, {"first": "A", "middle": [], "last": "Gur", "suffix": ""}, {"first": "D", "middle": [], "last": "", "suffix": ""}], "year": 2010, "venue": "Pediatr Nephrol", "link": null}, "BIBREF25": {"title": "Multiresistant E. coli urine infections in children: a case-control study", "authors": [{"first": "G", "middle": [], "last": "Raman", "suffix": ""}, {"first": "B", "middle": [], "last": "Mcmullan", "suffix": ""}, {"first": "P", "middle": [], "last": "Taylor", "suffix": ""}, {"first": "K", "middle": ["A"], "last": "Mallitt", "suffix": ""}, {"first": "S", "middle": ["E"], "last": "Kennedy", "suffix": ""}], "year": 2018, "venue": "Arch Dis Child", "link": "206861016"}, "BIBREF26": {"title": "Urinary tract infection caused by community-acquired extended-spectrum beta-lactamaseproducing bacteria in infants", "authors": [{"first": "Y", "middle": ["H"], "last": "Kim", "suffix": ""}, {"first": "E", "middle": ["M"], "last": "Yang", "suffix": ""}, {"first": "C", "middle": ["J"], "last": "Kim", "suffix": ""}], "year": 2017, "venue": "J Pediatr", "link": null}, "BIBREF27": {"title": "Previous antibiotic exposure increases risk of infection with extended-spectrum-beta-lactamase-and AmpC-producing Escherichia coli and Klebsiella pneumoniae in pediatric patients", "authors": [{"first": "D", "middle": ["M"], "last": "Zerr", "suffix": ""}, {"first": "A", "middle": [], "last": "Miles-Jay", "suffix": ""}, {"first": "M", "middle": ["P"], "last": "Kronman", "suffix": ""}, {"first": "C", "middle": [], "last": "Zhou", "suffix": ""}, {"first": "A", "middle": ["L"], "last": "Adler", "suffix": ""}, {"first": "W", "middle": [], "last": "Haaland", "suffix": ""}, {"first": "S", "middle": ["J"], "last": "Weissman", "suffix": ""}, {"first": "A", "middle": [], "last": "Elward", "suffix": ""}, {"first": "J", "middle": ["G"], "last": "Newland", "suffix": ""}, {"first": "T", "middle": [], "last": "Zaoutis", "suffix": ""}, {"first": "X", "middle": [], "last": "Qin", "suffix": ""}], "year": 2016, "venue": "Antimicrob Agents Chemother", "link": "15612246"}, "BIBREF28": {"title": "Uropathogen resistance and antibiotic prophylaxis: a metaanalysis", "authors": [{"first": "R", "middle": ["E"], "last": "Selekman", "suffix": ""}, {"first": "D", "middle": ["J"], "last": "Shapiro", "suffix": ""}, {"first": "J", "middle": [], "last": "Boscardin", "suffix": ""}, {"first": "G", "middle": [], "last": "Williams", "suffix": ""}, {"first": "J", "middle": ["C"], "last": "Craig", "suffix": ""}, {"first": "P", "middle": [], "last": "Brandstrom", "suffix": ""}, {"first": "M", "middle": [], "last": "Pennesi", "suffix": ""}, {"first": "G", "middle": [], "last": "Roussey-Kesler", "suffix": ""}, {"first": "P", "middle": [], "last": "Hari", "suffix": ""}, {"first": "H", "middle": ["L"], "last": "Copp", "suffix": ""}], "year": 2018, "venue": "Pediatrics", "link": "49607266"}, "BIBREF29": {"title": "Antibiotic resistance patterns of community-acquired urinary tract infections in children with vesicoureteral reflux receiving prophylactic antibiotic therapy", "authors": [{"first": "C", "middle": ["H"], "last": "Cheng", "suffix": ""}, {"first": "M", "middle": ["H"], "last": "Tsai", "suffix": ""}, {"first": "Y", "middle": ["C"], "last": "Huang", "suffix": ""}, {"first": "L", "middle": ["H"], "last": "Su", "suffix": ""}, {"first": "Y", "middle": ["K"], "last": "Tsau", "suffix": ""}, {"first": "C", "middle": ["J"], "last": "Lin", "suffix": ""}, {"first": "C", "middle": ["H"], "last": "Chiu", "suffix": ""}, {"first": "T", "middle": ["Y"], "last": "Lin", "suffix": ""}], "year": 2008, "venue": "Pediatrics", "link": "38529040"}, "BIBREF30": {"title": "Community-acquired urinary tract infection in hospitalized children: etiology and antimicrobial resistance. A comparison between first episode and recurrent infection", "authors": [{"first": "W", "middle": [], "last": "Sakran", "suffix": ""}, {"first": "V", "middle": [], "last": "Smolkin", "suffix": ""}, {"first": "A", "middle": [], "last": "Odetalla", "suffix": ""}, {"first": "R", "middle": [], "last": "Halevy", "suffix": ""}, {"first": "A", "middle": [], "last": "Koren", "suffix": ""}], "year": 2015, "venue": "Clin Pediatr (Phila)", "link": "31205238"}, "BIBREF31": {"title": "Frequency of multidrug-resistant organisms cultured from urine of children undergoing clean intermittent catheterization", "authors": [{"first": "C", "middle": ["S"], "last": "Forster", "suffix": ""}, {"first": "J", "middle": [], "last": "Courter", "suffix": ""}, {"first": "E", "middle": ["C"], "last": "Jackson", "suffix": ""}, {"first": "J", "middle": ["E"], "last": "Mortensen", "suffix": ""}, {"first": "D", "middle": ["B"], "last": "Haslam", "suffix": ""}], "year": 2017, "venue": "J Pediatric Infect Dis Soc", "link": "3776846"}, "BIBREF32": {"title": "Are prophylactic antibiotics necessary with clean intermittent catheterization? A randomized controlled trial", "authors": [{"first": "S", "middle": ["A"], "last": "Clarke", "suffix": ""}, {"first": "M", "middle": [], "last": "Samuel", "suffix": ""}, {"first": "S", "middle": ["A"], "last": "Boddy", "suffix": ""}], "year": 2005, "venue": "J Pediatr Surg", "link": "20623783"}, "BIBREF33": {"title": "The role of bladder function in the pathogenesis and treatment of urinary tract infections in toilet-trained children", "authors": [{"first": "A", "middle": ["J"], "last": "Lorenzo", "suffix": ""}, {"first": "M", "middle": [], "last": "Rickard", "suffix": ""}, {"first": "J", "middle": ["D"], "last": "Santos", "suffix": ""}], "year": 2019, "venue": "Pediatr Nephrol", "link": "58948264"}, "BIBREF34": {"title": "Predictors of antimicrobial resistance among pathogens causing urinary tract infection in children", "authors": [{"first": "N", "middle": [], "last": "Shaikh", "suffix": ""}, {"first": "A", "middle": [], "last": "Hoberman", "suffix": ""}, {"first": "R", "middle": [], "last": "Keren", "suffix": ""}, {"first": "A", "middle": [], "last": "Ivanova", "suffix": ""}, {"first": "N", "middle": [], "last": "Gotman", "suffix": ""}, {"first": "R", "middle": ["W"], "last": "Chesney", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Carpenter", "suffix": ""}, {"first": "M", "middle": [], "last": "Moxey-Mims", "suffix": ""}, {"first": "Wald", "middle": ["Er"], "last": "", "suffix": ""}], "year": 2016, "venue": "J Pediatr", "link": "14290522"}, "BIBREF35": {"title": "Community-onset extendedspectrum beta-lactamase producing Escherichia coli in urinary tract infections in children from 2015 to 2016: prevalence, risk factors, and resistances", "authors": [{"first": "I", "middle": [], "last": "Perez Heras", "suffix": ""}, {"first": "J", "middle": ["C"], "last": "Sanchez-Gomez", "suffix": ""}, {"first": "P", "middle": [], "last": "Beneyto-Martin", "suffix": ""}, {"first": "L", "middle": [], "last": "Ruano-Depablo", "suffix": ""}, {"first": "B", "middle": [], "last": "Losada-Pinedo", "suffix": ""}], "year": 2017, "venue": "Medicine", "link": null}, "BIBREF36": {"title": "Aminoglycosides monotherapy as first-line treatment for febrile urinary tract infection in children", "authors": [{"first": "N", "middle": [], "last": "Poey", "suffix": ""}, {"first": "F", "middle": [], "last": "Madhi", "suffix": ""}, {"first": "S", "middle": [], "last": "Biscardi", "suffix": ""}, {"first": "S", "middle": [], "last": "Bechet", "suffix": ""}, {"first": "R", "middle": [], "last": "Cohen", "suffix": ""}], "year": 2017, "venue": "Pediatr Infect Dis J", "link": "35575535"}, "BIBREF37": {"title": "Systematic review comparing meropenem with imipenem plus cilastatin in the treatment of severe infections", "authors": [{"first": "S", "middle": ["J"], "last": "Edwards", "suffix": ""}, {"first": "C", "middle": ["E"], "last": "Emmas", "suffix": ""}, {"first": "H", "middle": ["E"], "last": "Campbell", "suffix": ""}], "year": 2005, "venue": "Curr Med Res Opin", "link": "7654496"}, "BIBREF38": {"title": "The clinical efficacy and safety of Ertapenem for the treatment of complicated urinary tract infections caused by ESBL-producing bacteria in children", "authors": [{"first": "A", "middle": [], "last": "Karaaslan", "suffix": ""}, {"first": "E", "middle": ["K"], "last": "Kadayifci", "suffix": ""}, {"first": "S", "middle": [], "last": "Atici", "suffix": ""}, {"first": "G", "middle": [], "last": "Akkoc", "suffix": ""}, {"first": "N", "middle": [], "last": "Yakut", "suffix": ""}, {"first": "Ocal", "middle": [], "last": "Demir", "suffix": ""}, {"first": "S", "middle": [], "last": "Soysal", "suffix": ""}, {"first": "A", "middle": [], "last": "Bakir", "suffix": ""}, {"first": "M", "middle": [], "last": "", "suffix": ""}], "year": 2015, "venue": "Int J Nephrol", "link": "215198906"}, "BIBREF39": {"title": "Effect of piperacillin-Tazobactam vs Meropenem on 30-day mortality for patients with E coli or Klebsiella pneumoniae bloodstream infection and ceftriaxone resistance: a randomized clinical trial", "authors": [{"first": "Pna", "middle": [], "last": "Harris", "suffix": ""}, {"first": "P", "middle": ["A"], "last": "Tambyah", "suffix": ""}, {"first": "D", "middle": ["C"], "last": "Lye", "suffix": ""}, {"first": "Y", "middle": [], "last": "Mo", "suffix": ""}, {"first": "T", "middle": ["H"], "last": "Lee", "suffix": ""}, {"first": "M", "middle": [], "last": "Yilmaz", "suffix": ""}, {"first": "T", "middle": ["H"], "last": "Alenazi", "suffix": ""}, {"first": "Y", "middle": [], "last": "Arabi", "suffix": ""}, {"first": "M", "middle": [], "last": "Falcone", "suffix": ""}, {"first": "M", "middle": [], "last": "Bassetti", "suffix": ""}, {"first": "E", "middle": [], "last": "Righi", "suffix": ""}, {"first": "B", "middle": ["A"], "last": "Rogers", "suffix": ""}, {"first": "S", "middle": [], "last": "Kanj", "suffix": ""}, {"first": "H", "middle": [], "last": "Bhally", "suffix": ""}, {"first": "J", "middle": [], "last": "Iredell", "suffix": ""}, {"first": "M", "middle": [], "last": "Mendelson", "suffix": ""}, {"first": "T", "middle": ["H"], "last": "Boyles", "suffix": ""}, {"first": "D", "middle": [], "last": "Looke", "suffix": ""}, {"first": "S", "middle": [], "last": "Miyakis", "suffix": ""}, {"first": "G", "middle": [], "last": "Walls", "suffix": ""}, {"first": "Al", "middle": [], "last": "Khamis", "suffix": ""}, {"first": "M", "middle": [], "last": "Zikri", "suffix": ""}, {"first": "A", "middle": [], "last": "Crowe", "suffix": ""}, {"first": "A", "middle": [], "last": "Ingram", "suffix": ""}, {"first": "P", "middle": [], "last": "Daneman", "suffix": ""}, {"first": "N", "middle": [], "last": "Griffin", "suffix": ""}, {"first": "P", "middle": [], "last": "Athan", "suffix": ""}, {"first": "E", "middle": [], "last": "Lorenc", "suffix": ""}, {"first": "P", "middle": [], "last": "Baker", "suffix": ""}, {"first": "P", "middle": [], "last": "Roberts", "suffix": ""}, {"first": "L", "middle": [], "last": "Beatson", "suffix": ""}, {"first": "S", "middle": ["A"], "last": "Peleg", "suffix": ""}, {"first": "A", "middle": ["Y"], "last": "Harris-Brown", "suffix": ""}, {"first": "T", "middle": [], "last": "Paterson", "suffix": ""}, {"first": "D", "middle": ["L"], "last": "", "suffix": ""}], "year": 2018, "venue": "JAMA", "link": "52193493"}, "BIBREF40": {"title": "Effect of meropenem-vaborbactam vs piperacillin-tazobactam on clinical cure or improvement and microbial eradication in complicated urinary tract infection: the TANGO I randomized clinical trial", "authors": [{"first": "K", "middle": ["S"], "last": "Kaye", "suffix": ""}, {"first": "T", "middle": [], "last": "Bhowmick", "suffix": ""}, {"first": "S", "middle": [], "last": "Metallidis", "suffix": ""}, {"first": "S", "middle": ["C"], "last": "Bleasdale", "suffix": ""}, {"first": "O", "middle": ["S"], "last": "Sagan", "suffix": ""}, {"first": "V", "middle": [], "last": "Stus", "suffix": ""}, {"first": "J", "middle": [], "last": "Vazquez", "suffix": ""}, {"first": "V", "middle": [], "last": "Zaitsev", "suffix": ""}, {"first": "M", "middle": [], "last": "Bidair", "suffix": ""}, {"first": "E", "middle": [], "last": "Chorvat", "suffix": ""}, {"first": "P", "middle": ["O"], "last": "Dragoescu", "suffix": ""}, {"first": "E", "middle": [], "last": "Fedosiuk", "suffix": ""}, {"first": "J", "middle": ["P"], "last": "Horcajada", "suffix": ""}, {"first": "C", "middle": [], "last": "Murta", "suffix": ""}, {"first": "Y", "middle": [], "last": "Sarychev", "suffix": ""}, {"first": "V", "middle": [], "last": "Stoev", "suffix": ""}, {"first": "E", "middle": [], "last": "Morgan", "suffix": ""}, {"first": "K", "middle": [], "last": "Fusaro", "suffix": ""}, {"first": "D", "middle": [], "last": "Griffith", "suffix": ""}, {"first": "O", "middle": [], "last": "Lomovskaya", "suffix": ""}, {"first": "Alexander", "middle": ["El"], "last": "Loutit", "suffix": ""}, {"first": "J", "middle": [], "last": "Dudley", "suffix": ""}, {"first": "M", "middle": ["N"], "last": "Giamarellos-Bourboulis", "suffix": ""}, {"first": "E", "middle": ["J"], "last": "", "suffix": ""}], "year": 2018, "venue": "JAMA", "link": "3651161"}, "BIBREF41": {"title": "New agents for the treatment of infections with gram-negative bacteria: restoring the miracle or false dawn?", "authors": [{"first": "H", "middle": [], "last": "Wright", "suffix": ""}, {"first": "R", "middle": ["A"], "last": "Bonomo", "suffix": ""}, {"first": "D", "middle": ["L"], "last": "Paterson", "suffix": ""}], "year": 2017, "venue": "Clin Microbiol Infect", "link": "4384924"}, "BIBREF42": {"title": "Amikacin monotherapy for treatment of febrile urinary tract infection caused by extended-spectrum betalactamase-producing Escherichia coli in children", "authors": [{"first": "M", "middle": [], "last": "Polat", "suffix": ""}, {"first": "A", "middle": [], "last": "Tapisiz", "suffix": ""}], "year": 2018, "venue": "Pediatr Infect Dis J", "link": "3864952"}, "BIBREF43": {"title": "Fluoroquinolones in children: update of the literature", "authors": [{"first": "C", "middle": [], "last": "Bacci", "suffix": ""}, {"first": "L", "middle": [], "last": "Galli", "suffix": ""}, {"first": "M", "middle": [], "last": "De Martino", "suffix": ""}, {"first": "E", "middle": [], "last": "Chiappini", "suffix": ""}], "year": 2015, "venue": "J Chemother", "link": "5395844"}, "BIBREF44": {"title": "The evaluation of safety and efficacy of colistin use in pediatric intensive care unit: results from two reference hospitals and review of literature", "authors": [{"first": "Sahbudak", "middle": [], "last": "Bal", "suffix": ""}, {"first": "Z", "middle": [], "last": "", "suffix": ""}, {"first": "Kamit", "middle": [], "last": "Can", "suffix": ""}, {"first": "F", "middle": [], "last": "Yazici", "suffix": ""}, {"first": "P", "middle": [], "last": "", "suffix": ""}, {"first": "Berna", "middle": [], "last": "Anil", "suffix": ""}, {"first": "A", "middle": [], "last": "Duyu", "suffix": ""}, {"first": "M", "middle": [], "last": "", "suffix": ""}, {"first": "Yilmaz", "middle": [], "last": "Ciftdogan", "suffix": ""}, {"first": "D", "middle": [], "last": "", "suffix": ""}, {"first": "Nisel", "middle": [], "last": "Yilmaz", "suffix": ""}, {"first": "O", "middle": [], "last": "Cilli", "suffix": ""}, {"first": "F", "middle": [], "last": "Karapinar", "suffix": ""}, {"first": "B", "middle": [], "last": "", "suffix": ""}], "year": 2018, "venue": "J Infect Chemother", "link": null}, "BIBREF45": {"title": "Use of tigecycline in pediatric patients with infections predominantly due to extensively drug-resistant gramnegative bacteria", "authors": [{"first": "E", "middle": [], "last": "Iosifidis", "suffix": ""}, {"first": "A", "middle": [], "last": "Violaki", "suffix": ""}, {"first": "E", "middle": [], "last": "Michalopoulou", "suffix": ""}, {"first": "E", "middle": [], "last": "Volakli", "suffix": ""}, {"first": "E", "middle": [], "last": "Diamanti", "suffix": ""}, {"first": "D", "middle": [], "last": "Koliouskas", "suffix": ""}, {"first": "C", "middle": [], "last": "Antachopoulos", "suffix": ""}, {"first": "V", "middle": [], "last": "Drossou-Agakidou", "suffix": ""}, {"first": "M", "middle": [], "last": "Sdougka", "suffix": ""}, {"first": "E", "middle": [], "last": "Roilides", "suffix": ""}], "year": 2017, "venue": "J Pediatric Infect Dis Soc", "link": "4084158"}, "BIBREF46": {"title": "A pediatric case of New Delhi metallo-beta-lactamase-1-producing Enterobacteriaceae in the United States", "authors": [{"first": "D", "middle": ["A"], "last": "Green", "suffix": ""}, {"first": "N", "middle": [], "last": "Srinivas", "suffix": ""}, {"first": "N", "middle": [], "last": "Watz", "suffix": ""}, {"first": "F", "middle": ["C"], "last": "Tenover", "suffix": ""}, {"first": "M", "middle": [], "last": "Amieva", "suffix": ""}, {"first": "N", "middle": [], "last": "Banaei", "suffix": ""}], "year": 2013, "venue": "Pediatr Infect Dis J", "link": "205697621"}, "BIBREF47": {"title": "Antimicrobial Resistance' of the Paul-EhrlichSociety for Chemotherapy (2014) Occurrence of multidrug resistance to oral antibiotics among Escherichia coli urine isolates from outpatient departments in Germany: extended-spectrum betalactamases and the role of fosfomycin", "authors": [{"first": "M", "middle": [], "last": "Kresken", "suffix": ""}, {"first": "Y", "middle": [], "last": "Pfeifer", "suffix": ""}, {"first": "D", "middle": [], "last": "Hafner", "suffix": ""}, {"first": "R", "middle": [], "last": "Wresch", "suffix": ""}, {"first": "B", "middle": [], "last": "Korber-Irrgang", "suffix": ""}, {"first": "Working", "middle": [], "last": "Party", "suffix": ""}], "year": "", "venue": "Int J Antimicrob Agents", "link": null}, "BIBREF48": {"title": "Fosfomycin for the treatment of multidrug-resistant", "authors": [{"first": "M", "middle": ["E"], "last": "Falagas", "suffix": ""}, {"first": "A", "middle": ["C"], "last": "Kastoris", "suffix": ""}, {"first": "A", "middle": ["M"], "last": "Kapaskelis", "suffix": ""}, {"first": "D", "middle": ["E"], "last": "Karageorgopoulos", "suffix": ""}, {"first": "M", "middle": ["E"], "last": "Falagas", "suffix": ""}, {"first": "E", "middle": ["K"], "last": "Vouloumanou", "suffix": ""}, {"first": "G", "middle": [], "last": "Samonis", "suffix": ""}, {"first": "K", "middle": ["Z"], "last": "Vardakas", "suffix": ""}], "year": 2010, "venue": "Clin Microbiol Rev", "link": null}, "BIBREF49": {"title": "Fosfomycin versus other antibiotics for the treatment of cystitis: a metaanalysis of randomized controlled trials", "authors": [{"first": "M", "middle": ["E"], "last": "Falagas", "suffix": ""}, {"first": "E", "middle": ["K"], "last": "Vouloumanou", "suffix": ""}, {"first": "A", "middle": ["G"], "last": "Togias", "suffix": ""}, {"first": "M", "middle": [], "last": "Karadima", "suffix": ""}, {"first": "A", "middle": ["M"], "last": "Kapaskelis", "suffix": ""}, {"first": "P", "middle": ["I"], "last": "Rafailidis", "suffix": ""}, {"first": "S", "middle": [], "last": "Athanasiou", "suffix": ""}], "year": 2010, "venue": "J Antimicrob Chemother", "link": "14836560"}, "BIBREF50": {"title": "A reappraisal of current dosing strategies for intravenous fosfomycin in children and neonates", "authors": [{"first": "F", "middle": [], "last": "Traunmuller", "suffix": ""}, {"first": "M", "middle": [], "last": "Popovic", "suffix": ""}, {"first": "K", "middle": ["H"], "last": "Konz", "suffix": ""}, {"first": "P", "middle": [], "last": "Vavken", "suffix": ""}, {"first": "A", "middle": [], "last": "Leithner", "suffix": ""}, {"first": "C", "middle": [], "last": "Joukhadar", "suffix": ""}], "year": 2011, "venue": "Clin Pharmacokinet", "link": "45047428"}, "BIBREF51": {"title": "Best oral empirical treatment for pyelonephritis in children: do we need to differentiate between age and gender?", "authors": [{"first": "P", "middle": [], "last": "Salomonsson", "suffix": ""}, {"first": "M", "middle": ["L"], "last": "Von Linstow", "suffix": ""}, {"first": "J", "middle": ["D"], "last": "Knudsen", "suffix": ""}, {"first": "I", "middle": [], "last": "Heiberg", "suffix": ""}, {"first": "G", "middle": [], "last": "Mola", "suffix": ""}, {"first": "T", "middle": ["R"], "last": "Wenger", "suffix": ""}, {"first": "D", "middle": [], "last": "Cortes", "suffix": ""}, {"first": "U", "middle": [], "last": "Nygaard", "suffix": ""}], "year": 2016, "venue": "Infect Dis Ther", "link": "24830950"}, "BIBREF52": {"title": "Activity of mecillinam against ESBL producers in vitro", "authors": [{"first": "K", "middle": [], "last": "Thomas", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Weinbren", "suffix": ""}, {"first": "M", "middle": [], "last": "Warner", "suffix": ""}, {"first": "N", "middle": [], "last": "Woodford", "suffix": ""}, {"first": "D", "middle": [], "last": "Livermore", "suffix": ""}], "year": 2006, "venue": "J Antimicrob Chemother", "link": "12905907"}, "BIBREF53": {"title": "Randomised comparison of ciprofloxacin suspension and pivmecillinam for childhood shigellosis", "authors": [{"first": "M", "middle": ["A"], "last": "Salam", "suffix": ""}, {"first": "U", "middle": [], "last": "Dhar", "suffix": ""}, {"first": "W", "middle": ["A"], "last": "Khan", "suffix": ""}, {"first": "M", "middle": ["L"], "last": "Bennish", "suffix": ""}], "year": 1998, "venue": "Lancet", "link": "21131889"}, "BIBREF54": {"title": "Short-term treatment of acute urinary tract infection in girls. Copenhagen Study Group of Urinary Tract Infections in Children", "authors": [], "year": 1991, "venue": "Scand J Infect Dis", "link": "42392515"}, "BIBREF55": {"title": "Clinical evaluation of guidelines and therapeutic approaches in multi drug-resistant urinary tract infections", "authors": [{"first": "E", "middle": [], "last": "Concia", "suffix": ""}, {"first": "D", "middle": [], "last": "Bragantini", "suffix": ""}, {"first": "F", "middle": [], "last": "Mazzaferri", "suffix": ""}], "year": 2017, "venue": "J Chemother", "link": "33202483"}, "BIBREF56": {"title": "Antibiotics for acute pyelonephritis in children", "authors": [{"first": "Y", "middle": [], "last": "Strohmeier", "suffix": ""}, {"first": "E", "middle": ["M"], "last": "Hodson", "suffix": ""}, {"first": "N", "middle": ["S"], "last": "Willis", "suffix": ""}, {"first": "A", "middle": ["C"], "last": "Webster", "suffix": ""}, {"first": "J", "middle": ["C"], "last": "Craig", "suffix": ""}], "year": 2014, "venue": "Cochrane Database Syst Rev", "link": "25888776"}, "BIBREF57": {"title": "Oral antibiotics for infections due to multidrug-resistant gram-negative organisms", "authors": [{"first": "J", "middle": ["S"], "last": "Glasser", "suffix": ""}, {"first": "A", "middle": ["E"], "last": "Markelz", "suffix": ""}, {"first": "W", "middle": ["C"], "last": "Zera", "suffix": ""}, {"first": "M", "middle": ["L"], "last": "Beckius", "suffix": ""}, {"first": "K", "middle": [], "last": "Mende", "suffix": ""}, {"first": "C", "middle": ["K"], "last": "Murray", "suffix": ""}], "year": 2011, "venue": "Scand J Infect Dis", "link": "22971908"}, "BIBREF59": {"title": "Control of extended-spectrum {beta}-lactamase-producing Klebsiella pneumoniae using a computer-assisted management program to restrict third-generation cephalosporin use", "authors": [{"first": "J", "middle": ["Y"], "last": "Kim", "suffix": ""}, {"first": "J", "middle": ["W"], "last": "Sohn", "suffix": ""}, {"first": "D", "middle": ["W"], "last": "Park", "suffix": ""}, {"first": "Y", "middle": ["K"], "last": "Yoon", "suffix": ""}, {"first": "Y", "middle": ["M"], "last": "Kim", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Kim", "suffix": ""}], "year": 2008, "venue": "J Antimicrob Chemother", "link": "44838033"}, "BIBREF60": {"title": "Antimicrobial prophylaxis for children with vesicoureteral reflux", "authors": [{"first": "A", "middle": [], "last": "Hoberman", "suffix": ""}, {"first": "S", "middle": ["P"], "last": "Greenfield", "suffix": ""}, {"first": "T", "middle": ["K"], "last": "Mattoo", "suffix": ""}, {"first": "R", "middle": [], "last": "Keren", "suffix": ""}, {"first": "R", "middle": [], "last": "Mathews", "suffix": ""}, {"first": "H", "middle": ["G"], "last": "Pohl", "suffix": ""}, {"first": "B", "middle": ["P"], "last": "Kropp", "suffix": ""}, {"first": "S", "middle": ["J"], "last": "Skoog", "suffix": ""}, {"first": "C", "middle": ["P"], "last": "Nelson", "suffix": ""}, {"first": "M", "middle": [], "last": "Moxey-Mims", "suffix": ""}, {"first": "R", "middle": ["W"], "last": "Chesney", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Carpenter", "suffix": ""}], "year": 2014, "venue": "N Engl J Med", "link": "47539442"}, "BIBREF61": {"title": "Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations", "authors": [], "year": "", "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "199668072", "_pdf_hash": "55d73a4ffd868b203b04213ca7b304eb1ee774dd", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "N(CH 2 CH 2 ) 2 CH 2 ))", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF4": {"title": "C(8)); 24.43 (N(CH 2 CH 2 ) 2 CH 2 )", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF5": {"title": "ArCH 2 ); 122.28, 128", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF6": {"title": "C(14)); 151.96 (C(12)). 2-Methyl-4-(morpholinomethyl)-6-(1,7,7-trimethylbicyclo-[2.2.1] hept-exo-2-yl)phenol (6). Beige viscous oil. The yield was 0.59 g (86%)", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF8": {"title": "CH 2 ); 1597 (C=C); 1269, 1192, 1115 (C-O)", "authors": [{"first": "H", "middle": [], "last": "", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF10": {"title": "7 Hz); 3.37, 3.44 (both AB system, 1 H, ArCH 2 , J = 12.7 Hz", "authors": [], "year": "", "venue": "J = 12.7 Hz", "link": null}, "BIBREF11": {"title": "90 (s, 1 \u041d, H(14)); 7.11 (s, 1 \u041d, H(16)). 13 C NMR", "authors": [{"first": "H", "middle": [], "last": "", "suffix": ""}, {"first": "O", "middle": ["H"], "last": "", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF12": {"title": "Molecular sieves 4\u00c5 (1.1 g) and the corresponding amine (0.069 mL, 1.0 mmol) were added to a solution of aldehyde 2 (0.272 g, 1.0 mmol) in MeOH (15 mL). The reaction mixture was refl uxed for 2.5 h (cyclopropylamine), 4 h (n-butylamine), or 24 h (aniline)", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF13": {"title": "After drying, the hydrochloride was suspended in Et 2 O (10 mL), 2 M aqueous NaOH solution (5 mL) was added, the mixture was vigorously stirred until the dissolution of hydrochloride (~30 min), and the aqueous layer was separated. The organic phase containing the free base was washed with 2 M aqueous NaCl solution until pH 7.0, dried over anhydrous K 2 CO 3 , and the solvent was co-evaporated with a small amount of pentane. 4-((Cyclopropylamino)methyl)-2-methyl-6", "authors": [{"first": "M", "middle": [], "last": "Hcl", "suffix": ""}], "year": "", "venue": "mL) was added, the mixture was stirred at room temperature for 1 h, and the white powdery precipitate of hydrochloride was fi ltered off and washed with Et 2 O (5 mL)", "link": null}, "BIBREF15": {"title": "72 (s, 2 H, ArCH 2 )", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF16": {"title": "\uf064: 6.33, 6.45 (NCH-(CH 2 ) 2 ); 12.40 (C(10))", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF17": {"title": "ArCH 2 ); 122.59, 128.64", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF18": {"title": "C(16)); 127.97 (C(14))", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF19": {"title": "7-trimethylbicyclo[2.2.1]hept-exo-2-yl)phenol (8)", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF22": {"title": "NCH 2 CH 2 CH 2 CH 3 , J \uf0bb 7.1 Hz, overlapped with adjacent signals)", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF23": {"title": "C(10)); 13.99 (NCH 2 CH 2 CH 2 CH 3 )", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF24": {"title": "C(12)). 2-Methyl-4-((phenylamino)methyl)-6-(1,7,7-trimethylbicyclo[2.2.1]hept-exo-2-yl)phenol (9). Light yellow viscous oil. The yield was 0", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF26": {"title": "C=C); 1256, 1186 (C-O)", "authors": [], "year": "", "venue": "\uf06e/cm -1 : 3605", "link": null}, "BIBREF27": {"title": "6 Hz); 3.88 (br.s, 1 H, NH)", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF28": {"title": "C(10)); 16.22 (C(17))", "authors": [{"first": "C", "middle": [], "last": "Nmr", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF29": {"title": "C(15)); 125.56 (C(16)); 127.54 (C(14)); 148.35 (C(CH) 2 -(CH) 2 CH); 152.24 (C(12)). Synthesis of N-acetyl derivatives", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF30": {"title": "Triethylamine (0.061 mL, 0.44 mmol) and AcCl (0.031 mL", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF32": {"title": "Khimiopreparaty i Khimioterapiya Grippa [Chemotherapeutic Agents and Chemotherapy of Infl uenza", "authors": [{"first": "O", "middle": ["I"], "last": "Kiselev", "suffix": ""}], "year": 2012, "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "199668440", "_pdf_hash": "8fe3522f9c0683b6a8513c8247f9ed65e85525e4", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "What genomic sequence information has revealed about Vibrio ecology in the ocean-a review", "authors": [{"first": "D", "middle": ["J"], "last": "Grimes", "suffix": ""}, {"first": "C", "middle": ["N"], "last": "Johnson", "suffix": ""}, {"first": "K", "middle": ["S"], "last": "Dillon", "suffix": ""}, {"first": "A", "middle": ["R"], "last": "Flowers", "suffix": ""}, {"first": "Nfn", "middle": [], "last": "Iii", "suffix": ""}, {"first": "T", "middle": [], "last": "Berutti", "suffix": ""}], "year": 2009, "venue": "Microb Ecol", "link": "23046162"}, "BIBREF1": {"title": "An investigation on pathogenic Vibrios distribution in domestic wastewater", "authors": [{"first": "A", "middle": [], "last": "Almasi", "suffix": ""}], "year": 2005, "venue": "Iran J Environ Health Sci Eng", "link": "73644623"}, "BIBREF2": {"title": "Phage therapy and photodynamic therapy: low environmental impact approaches to inactivate microorganisms in fish farming plants", "authors": [{"first": "A", "middle": [], "last": "Almeida", "suffix": ""}, {"first": "A", "middle": [], "last": "Cunha", "suffix": ""}, {"first": "Ncm", "middle": [], "last": "Gomes", "suffix": ""}, {"first": "E", "middle": [], "last": "Alves", "suffix": ""}, {"first": "L", "middle": [], "last": "Costa", "suffix": ""}, {"first": "Maf", "middle": [], "last": "Faustino", "suffix": ""}], "year": 2009, "venue": "Marine Drugs", "link": "2348861"}, "BIBREF3": {"title": "Isolation and identification of Vibrio cholerae and Vibrio parahaemolyticus from prawn (Penaeus monodon) seafood: preservation strategies", "authors": [{"first": "P", "middle": ["R"], "last": "Yaashikaa", "suffix": ""}, {"first": "A", "middle": [], "last": "Saravanan", "suffix": ""}, {"first": "P", "middle": ["S"], "last": "Kumar", "suffix": ""}], "year": 2016, "venue": "Microb Pathog", "link": "11620275"}, "BIBREF4": {"title": "Viruses in marine planktonic systems", "authors": [{"first": "J", "middle": ["A"], "last": "Fuhrman", "suffix": ""}, {"first": "C", "middle": ["A"], "last": "Suttle", "suffix": ""}], "year": 1993, "venue": "Oceanography", "link": "130527937"}, "BIBREF5": {"title": "The significance of viruses to mortality in aquatic microbial communities", "authors": [{"first": "C", "middle": ["A"], "last": "Suttle", "suffix": ""}], "year": 1994, "venue": "Microb Ecol", "link": "42886883"}, "BIBREF6": {"title": "Bacteriophages isolated from Lake Michigan demonstrate broad host-range across several bacterial phyla", "authors": [{"first": "K", "middle": [], "last": "Malki", "suffix": ""}, {"first": "A", "middle": [], "last": "Kula", "suffix": ""}, {"first": "K", "middle": [], "last": "Bruder", "suffix": ""}, {"first": "E", "middle": [], "last": "Sible", "suffix": ""}, {"first": "T", "middle": [], "last": "Hatzopoulos", "suffix": ""}, {"first": "S", "middle": [], "last": "Steidel", "suffix": ""}, {"first": "S", "middle": ["C"], "last": "Watkins", "suffix": ""}, {"first": "C", "middle": [], "last": "Putonti", "suffix": ""}], "year": 2015, "venue": "Virol J", "link": "14490024"}, "BIBREF7": {"title": "Metagenome of the Mediterranean deep chlorophyll maximum studied by direct and fosmid library 454 pyrosequencing", "authors": [{"first": "R", "middle": [], "last": "Ghai", "suffix": ""}, {"first": "A", "middle": ["B"], "last": "Martin-Cuadrado", "suffix": ""}, {"first": "A", "middle": ["G"], "last": "Motto", "suffix": ""}, {"first": "I", "middle": ["G"], "last": "Heredia", "suffix": ""}, {"first": "R", "middle": [], "last": "Cabrera", "suffix": ""}, {"first": "J", "middle": [], "last": "Martin", "suffix": ""}, {"first": "M", "middle": [], "last": "Verd\u00fa", "suffix": ""}, {"first": "P", "middle": [], "last": "Deschamps", "suffix": ""}, {"first": "D", "middle": [], "last": "Moreira", "suffix": ""}, {"first": "P", "middle": [], "last": "L\u00f3pez-Garc\u00eda", "suffix": ""}, {"first": "Mira", "middle": ["A"], "last": "Rodriguez-Valera", "suffix": ""}, {"first": "F", "middle": [], "last": "", "suffix": ""}], "year": 2010, "venue": "ISME J", "link": "6718614"}, "BIBREF8": {"title": "The sorcerer II Global Ocean sampling expedition: northwest Atlantic through eastern tropical Pacific", "authors": [{"first": "D", "middle": ["B"], "last": "Rusch", "suffix": ""}, {"first": "A", "middle": ["L"], "last": "Halpern", "suffix": ""}, {"first": "G", "middle": [], "last": "Sutton", "suffix": ""}, {"first": "K", "middle": ["B"], "last": "Heidelberg", "suffix": ""}, {"first": "S", "middle": [], "last": "Williamson", "suffix": ""}, {"first": "S", "middle": [], "last": "Yooseph", "suffix": ""}, {"first": "D", "middle": [], "last": "Wu", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Eisen", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Hoffman", "suffix": ""}, {"first": "Remington", "middle": ["K"], "last": "Beeson", "suffix": ""}, {"first": "K", "middle": [], "last": "Tran", "suffix": ""}, {"first": "B", "middle": [], "last": "Smith", "suffix": ""}, {"first": "H", "middle": [], "last": "Baden-Tillson", "suffix": ""}, {"first": "H", "middle": [], "last": "Stewart", "suffix": ""}, {"first": "C", "middle": [], "last": "Thorpe", "suffix": ""}, {"first": "J", "middle": [], "last": "Freeman", "suffix": ""}, {"first": "J", "middle": [], "last": "Andrews-Pfannkoch", "suffix": ""}, {"first": "C", "middle": [], "last": "Venter", "suffix": ""}, {"first": "J", "middle": ["E"], "last": "Li", "suffix": ""}, {"first": "K", "middle": [], "last": "Kravitz", "suffix": ""}, {"first": "S", "middle": [], "last": "Heidelberg", "suffix": ""}, {"first": "J", "middle": ["F"], "last": "Utterback", "suffix": ""}, {"first": "T", "middle": [], "last": "Rogers", "suffix": ""}, {"first": "Y", "middle": ["H"], "last": "Falcon", "suffix": ""}, {"first": "L", "middle": ["I"], "last": "Souza", "suffix": ""}, {"first": "V", "middle": [], "last": "Bonilla-Rosso", "suffix": ""}, {"first": "G", "middle": [], "last": "Eguiarte", "suffix": ""}, {"first": "L", "middle": ["E"], "last": "Karl", "suffix": ""}, {"first": "D", "middle": ["M"], "last": "Sathyendranath", "suffix": ""}, {"first": "S", "middle": [], "last": "Platt", "suffix": ""}, {"first": "T", "middle": [], "last": "Bermingham", "suffix": ""}, {"first": "E", "middle": [], "last": "Gallardo", "suffix": ""}, {"first": "V", "middle": [], "last": "Tamayo-Castillo", "suffix": ""}, {"first": "G", "middle": [], "last": "Ferrari", "suffix": ""}, {"first": "M", "middle": ["R"], "last": "Strausberg", "suffix": ""}, {"first": "R", "middle": ["L"], "last": "", "suffix": ""}, {"first": "Nealson", "middle": ["K"], "last": "Friedman", "suffix": ""}, {"first": "R", "middle": [], "last": "Frazier", "suffix": ""}, {"first": "M", "middle": [], "last": "Venter", "suffix": ""}, {"first": "J", "middle": ["C"], "last": "", "suffix": ""}], "year": 2007, "venue": "PLoS Biol", "link": "11883145"}, "BIBREF9": {"title": "Ecogenomics and genome landscapes of marine Pseudoalteromonas phage H105/1", "authors": [{"first": "M", "middle": ["B"], "last": "Duhaime", "suffix": ""}, {"first": "A", "middle": [], "last": "Wichels", "suffix": ""}, {"first": "J", "middle": [], "last": "Waldmann", "suffix": ""}, {"first": "H", "middle": [], "last": "Teeling", "suffix": ""}, {"first": "F", "middle": ["O"], "last": "Gl\u00f6ckner", "suffix": ""}], "year": 2011, "venue": "ISME J Multidiscip J Microb Ecol", "link": "2533010"}, "BIBREF10": {"title": "Complete genomic sequence of bacteriophage H188: a novel Vibrio kanaloae phage isolated from Yellow Sea", "authors": [{"first": "Y", "middle": [], "last": "Li", "suffix": ""}, {"first": "M", "middle": [], "last": "Wang", "suffix": ""}, {"first": "Q", "middle": [], "last": "Liu", "suffix": ""}, {"first": "X", "middle": [], "last": "Song", "suffix": ""}, {"first": "D", "middle": [], "last": "Wang", "suffix": ""}, {"first": "Y", "middle": [], "last": "Ma", "suffix": ""}, {"first": "Y", "middle": [], "last": "Jiang", "suffix": ""}], "year": 2016, "venue": "Curr Microbiol", "link": "16245576"}, "BIBREF11": {"title": "A procedure for the isolation of deoxyribonucleic acid from microorganisms", "authors": [{"first": "J", "middle": [], "last": "Marmur", "suffix": ""}], "year": 1961, "venue": "J Mol Biol", "link": "90153935"}, "BIBREF12": {"title": "Bacteriophage host range and bacterial resistance", "authors": [{"first": "P", "middle": [], "last": "Hyman", "suffix": ""}, {"first": "S", "middle": ["T"], "last": "Abedon", "suffix": ""}], "year": 2010, "venue": "Adv Appl Microbiol", "link": "36309038"}, "BIBREF13": {"title": "Isolation, characterization and genome sequencing of the novel phage SL25 from the Yellow Sea", "authors": [{"first": "Z", "middle": ["Y"], "last": "Liu", "suffix": ""}, {"first": "H", "middle": ["F"], "last": "Li", "suffix": ""}, {"first": "M", "middle": [], "last": "Wang", "suffix": ""}, {"first": "Y", "middle": [], "last": "Jiang", "suffix": ""}, {"first": "Q", "middle": ["W"], "last": "Yang", "suffix": ""}, {"first": "X", "middle": ["H"], "last": "Zhou", "suffix": ""}, {"first": "Z", "middle": [], "last": "Gong", "suffix": ""}, {"first": "Q", "middle": [], "last": "Liu", "suffix": ""}, {"first": "H", "middle": ["B"], "last": "Shao", "suffix": ""}], "year": 2018, "venue": "China. Marine Genom", "link": "90919713"}, "BIBREF14": {"title": "Complete nucleotide sequence analysis of a novel Bacillus subtilis-infecting bacteriophage BSP10 and its effect on poly-gamma-glutamic acid degradation", "authors": [{"first": "K", "middle": [], "last": "Ghosh", "suffix": ""}, {"first": "A", "middle": [], "last": "Senevirathne", "suffix": ""}, {"first": "H", "middle": ["S"], "last": "Kang", "suffix": ""}, {"first": "W", "middle": ["B"], "last": "Hyun", "suffix": ""}, {"first": "J", "middle": ["E"], "last": "Kim", "suffix": ""}, {"first": "K", "middle": ["P"], "last": "Kim", "suffix": ""}], "year": 2018, "venue": "Viruses", "link": "13682379"}, "BIBREF15": {"title": "Bacteriophage \u03c6YeO3-12, Specific for Yersinia enterocolitica Serotype O:3, is related to coliphages T3 and T7", "authors": [{"first": "M", "middle": [], "last": "Pajunen", "suffix": ""}, {"first": "S", "middle": [], "last": "Kiljunen", "suffix": ""}, {"first": "M", "middle": [], "last": "Skurnik", "suffix": ""}], "year": 2000, "venue": "J Bacteriol", "link": "5953411"}, "BIBREF16": {"title": "Isolation and complete genome sequence of a novel Pseudoalteromonas phage PH357 from the Yangtze River estuary", "authors": [{"first": "Z", "middle": [], "last": "Gong", "suffix": ""}, {"first": "M", "middle": [], "last": "Wang", "suffix": ""}, {"first": "Q", "middle": ["W"], "last": "Yang", "suffix": ""}, {"first": "Z", "middle": ["S"], "last": "Li", "suffix": ""}, {"first": "J", "middle": [], "last": "Xia", "suffix": ""}, {"first": "Y", "middle": [], "last": "Gao", "suffix": ""}], "year": 2017, "venue": "Curr Microbiol", "link": "7363822"}, "BIBREF17": {"title": "Thermal and chemical resistance of Lactobacillus casei and Lactobacillus paracasei bacteriophages", "authors": [{"first": "M", "middle": ["L"], "last": "Capra", "suffix": ""}, {"first": "A", "middle": [], "last": "Quiberoni", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Reinheimer", "suffix": ""}], "year": 2004, "venue": "Lett Appl Microbiol", "link": "22502395"}, "BIBREF18": {"title": "Characterization of marine bacteriophages isolated from the Alboran Sea (Western Mediterranean)", "authors": [{"first": "Mdc", "middle": [], "last": "Alonso", "suffix": ""}, {"first": "J", "middle": [], "last": "Rodr\u00edguez", "suffix": ""}, {"first": "J", "middle": ["J"], "last": "Borrego", "suffix": ""}], "year": 2002, "venue": "J Plankton Res", "link": "59354948"}, "BIBREF19": {"title": "Occurrence of Vibrio parahaemolyticus and its specific phages from shrimp ponds in East Coast of India", "authors": [{"first": "K", "middle": ["M"], "last": "Alagappan", "suffix": ""}], "year": 2010, "venue": "Curr Microbiol", "link": "6234391"}, "BIBREF20": {"title": "Isolation and characterisation of KP34-a novel uKMV-like bacteriophage for Klebsiella pneumoniae", "authors": [{"first": "Z", "middle": [], "last": "Druliskawa", "suffix": ""}, {"first": "P", "middle": [], "last": "Mackiewicz", "suffix": ""}, {"first": "A", "middle": [], "last": "Kesikszeloch", "suffix": ""}], "year": 2011, "venue": "Appl Microbiol Biotechnol", "link": null}, "BIBREF21": {"title": "Isolation and characterization of a Siphoviridae phage infecting Bacillus megaterium from a heavily trafficked holy site in Saudi Arabia", "authors": [{"first": "B", "middle": ["A"], "last": "Othman", "suffix": ""}, {"first": "A", "middle": [], "last": "Askora", "suffix": ""}, {"first": "A", "middle": ["S"], "last": "Abo-Senna", "suffix": ""}], "year": 2015, "venue": "Folia Microbiol", "link": "6450833"}, "BIBREF22": {"title": "A novel Roseosiphophage isolated from the oligotrophic South China Sea", "authors": [{"first": "Y", "middle": [], "last": "Yang", "suffix": ""}, {"first": "L", "middle": [], "last": "Cai", "suffix": ""}, {"first": "R", "middle": [], "last": "Ma", "suffix": ""}, {"first": "Y", "middle": [], "last": "Xu", "suffix": ""}, {"first": "Y", "middle": [], "last": "Tong", "suffix": ""}, {"first": "Y", "middle": [], "last": "Huang", "suffix": ""}, {"first": "N", "middle": ["Z"], "last": "Jiao", "suffix": ""}, {"first": "R", "middle": [], "last": "Zhang", "suffix": ""}], "year": 2017, "venue": "Viruses", "link": "20670723"}, "BIBREF23": {"title": "Complete genome sequence of bacteriophage P2559Y, a marine phage that infects Croceibacter atlanticus HTCC2559", "authors": [{"first": "I", "middle": [], "last": "Kang", "suffix": ""}, {"first": "D", "middle": [], "last": "Kang", "suffix": ""}, {"first": "J", "middle": ["C"], "last": "Cho", "suffix": ""}], "year": 2016, "venue": "Marine Genom", "link": "32481275"}, "BIBREF24": {"title": "Isolation and genome sequencing of a novel Pseudoalteromonas phage PH1", "authors": [{"first": "Z", "middle": ["Y"], "last": "Liu", "suffix": ""}, {"first": "M", "middle": [], "last": "Wang", "suffix": ""}, {"first": "X", "middle": [], "last": "Meng", "suffix": ""}, {"first": "Y", "middle": [], "last": "Li", "suffix": ""}, {"first": "D", "middle": ["B"], "last": "Wang", "suffix": ""}, {"first": "Y", "middle": [], "last": "Jiang", "suffix": ""}, {"first": "H", "middle": ["B"], "last": "Shao", "suffix": ""}, {"first": "Y", "middle": ["Y"], "last": "Zhang", "suffix": ""}], "year": 2017, "venue": "Curr Microbiol", "link": "2185806"}, "BIBREF25": {"title": "Characterization, genome sequence, and analysis of Escherichia phage CICC 80001, a bacteriophage infecting an efficient l-aspartic acid producing Escherichia coli", "authors": [{"first": "Y", "middle": ["Q"], "last": "Xu", "suffix": ""}, {"first": "Y", "middle": ["Y"], "last": "Ma", "suffix": ""}, {"first": "S", "middle": [], "last": "Yao", "suffix": ""}, {"first": "Z", "middle": ["Y"], "last": "Jiang", "suffix": ""}, {"first": "J", "middle": ["S"], "last": "Pei", "suffix": ""}, {"first": "C", "middle": [], "last": "Cheng", "suffix": ""}], "year": 2016, "venue": "Food Environ Virol", "link": "18641870"}, "BIBREF26": {"title": "Easyfig: a genome comparison visualizer", "authors": [{"first": "M", "middle": ["J"], "last": "Sullivan", "suffix": ""}, {"first": "N", "middle": ["K"], "last": "Petty", "suffix": ""}, {"first": "S", "middle": ["A"], "last": "Beatson", "suffix": ""}], "year": 2011, "venue": "Bioinformatics", "link": "13063172"}, "BIBREF27": {"title": "Structure of a bifunctional DNA primase-polymerase", "authors": [{"first": "G", "middle": [], "last": "Lipps", "suffix": ""}, {"first": "A", "middle": ["O"], "last": "Weinzierl", "suffix": ""}, {"first": "G", "middle": [], "last": "Von Scheven", "suffix": ""}, {"first": "C", "middle": [], "last": "Buchen", "suffix": ""}, {"first": "P", "middle": [], "last": "Cramer", "suffix": ""}], "year": 2004, "venue": "", "link": null}, "BIBREF29": {"title": "Characterization and genome sequence of marine Alteromonas gracilis phage PB15 isolated from the Yellow Sea, China", "authors": [{"first": "Y", "middle": [], "last": "Gao", "suffix": ""}, {"first": "Q", "middle": [], "last": "Liu", "suffix": ""}, {"first": "M", "middle": [], "last": "Wang", "suffix": ""}, {"first": "G", "middle": ["H"], "last": "Zhao", "suffix": ""}, {"first": "Y", "middle": [], "last": "Jiang", "suffix": ""}, {"first": "G", "middle": [], "last": "Malin", "suffix": ""}, {"first": "Z", "middle": [], "last": "Gong", "suffix": ""}, {"first": "X", "middle": [], "last": "Meng", "suffix": ""}, {"first": "Z", "middle": ["Y"], "last": "Liu", "suffix": ""}, {"first": "T", "middle": ["T"], "last": "Lin", "suffix": ""}, {"first": "Y", "middle": ["T"], "last": "Li", "suffix": ""}, {"first": "H", "middle": ["B"], "last": "Shao", "suffix": ""}], "year": 2017, "venue": "Curr Microbiol", "link": "31670762"}, "BIBREF30": {"title": "Complete genome sequence of virulent bacteriophage SHOU24, which infects foodborne pathogenic Vibrio parahaemolyticus", "authors": [{"first": "L", "middle": [], "last": "Yuan", "suffix": ""}, {"first": "Z", "middle": [], "last": "Cui", "suffix": ""}, {"first": "Y", "middle": [], "last": "Wang", "suffix": ""}, {"first": "X", "middle": [], "last": "Guo", "suffix": ""}, {"first": "Y", "middle": [], "last": "Zhao", "suffix": ""}], "year": 2014, "venue": "Adv Virol", "link": "13319337"}, "BIBREF31": {"title": "Bioinformatic analysis of the Acinetobacter baumannii phage AB1 genome", "authors": [{"first": "P", "middle": [], "last": "Li", "suffix": ""}, {"first": "B", "middle": [], "last": "Chen", "suffix": ""}, {"first": "Z", "middle": [], "last": "Song", "suffix": ""}, {"first": "Y", "middle": [], "last": "Song", "suffix": ""}, {"first": "Y", "middle": [], "last": "Yang", "suffix": ""}, {"first": "P", "middle": [], "last": "Ma", "suffix": ""}, {"first": "H", "middle": [], "last": "Wang", "suffix": ""}, {"first": "J", "middle": [], "last": "Ying", "suffix": ""}, {"first": "P", "middle": [], "last": "Ren", "suffix": ""}, {"first": "L", "middle": [], "last": "Yang", "suffix": ""}, {"first": "G", "middle": [], "last": "Gao", "suffix": ""}, {"first": "Jin", "middle": ["S"], "last": "Bao", "suffix": ""}, {"first": "Q", "middle": [], "last": "Yang", "suffix": ""}, {"first": "H", "middle": [], "last": "", "suffix": ""}], "year": 2012, "venue": "Gene", "link": "205013554"}, "BIBREF32": {"title": "Identification of a bifunctional primase-polymerase domain of corynephage BFK20 replication protein gp43", "authors": [{"first": "N", "middle": [], "last": "Halgasova", "suffix": ""}, {"first": "I", "middle": [], "last": "Mesarosova", "suffix": ""}, {"first": "G", "middle": [], "last": "Bukovska", "suffix": ""}], "year": 2012, "venue": "Virus Res", "link": "205657252"}, "BIBREF33": {"title": "DNA Packaging in dsDNA bacteriophages", "authors": [{"first": "L", "middle": ["W"], "last": "Black", "suffix": ""}], "year": 1989, "venue": "Annu Rev Microbiol", "link": "44917483"}, "BIBREF34": {"title": "Small terminase couples viral DNA binding to genome-packaging atpase activity", "authors": [{"first": "A", "middle": [], "last": "Roy", "suffix": ""}, {"first": "A", "middle": [], "last": "Bhardwaj", "suffix": ""}, {"first": "P", "middle": [], "last": "Datta", "suffix": ""}, {"first": "G", "middle": ["C"], "last": "Lander", "suffix": ""}, {"first": "G", "middle": [], "last": "Cingolani", "suffix": ""}], "year": 2012, "venue": "Structure", "link": "9832558"}, "BIBREF35": {"title": "Isolation and characterization of a bacteriophage phiEap-2 infecting multidrug resistant enterobacter aerogenes", "authors": [{"first": "E", "middle": [], "last": "Li", "suffix": ""}, {"first": "Xiao", "middle": ["W"], "last": "Ma", "suffix": ""}, {"first": "Y", "middle": [], "last": "Zhe", "suffix": ""}, {"first": "Y", "middle": [], "last": "Li", "suffix": ""}, {"first": "H", "middle": [], "last": "Lin", "suffix": ""}, {"first": "W", "middle": [], "last": "Wang", "suffix": ""}, {"first": "X", "middle": [], "last": "Li", "suffix": ""}, {"first": "C", "middle": [], "last": "Shen", "suffix": ""}, {"first": "Z", "middle": [], "last": "Zhao", "suffix": ""}, {"first": "R", "middle": [], "last": "Yang", "suffix": ""}, {"first": "H", "middle": [], "last": "Jiang", "suffix": ""}, {"first": "A", "middle": [], "last": "Yang", "suffix": ""}, {"first": "W", "middle": [], "last": "Yuan", "suffix": ""}, {"first": "J", "middle": [], "last": "Zhao", "suffix": ""}, {"first": "X", "middle": [], "last": "", "suffix": ""}], "year": 2016, "venue": "Sci Rep", "link": null}, "BIBREF36": {"title": "Conserved translational frameshift in dsDNA bacteriophage tail assembly genes", "authors": [{"first": "J", "middle": [], "last": "Xu", "suffix": ""}, {"first": "R", "middle": ["W"], "last": "Hendrix", "suffix": ""}, {"first": "R", "middle": ["L"], "last": "Duda", "suffix": ""}], "year": 2004, "venue": "Mol Cell", "link": "18515736"}, "BIBREF37": {"title": "The host-range, genomics and proteomics of Escherichia coli, O157:H7 bacteriophage rV5", "authors": [{"first": "A", "middle": ["M"], "last": "Kropinski", "suffix": ""}, {"first": "T", "middle": [], "last": "Waddell", "suffix": ""}, {"first": "J", "middle": [], "last": "Meng", "suffix": ""}, {"first": "K", "middle": [], "last": "Franklin", "suffix": ""}, {"first": "H", "middle": ["W"], "last": "Ackermann", "suffix": ""}, {"first": "R", "middle": [], "last": "Ahmed", "suffix": ""}, {"first": "A", "middle": [], "last": "Mazzocco", "suffix": ""}, {"first": "J", "middle": [], "last": "Yates", "suffix": ""}, {"first": "E", "middle": ["J"], "last": "Lingohr", "suffix": ""}, {"first": "R", "middle": ["P"], "last": "Johnson", "suffix": ""}], "year": 2013, "venue": "Virol J", "link": "12427640"}, "BIBREF38": {"title": "Genomic analysis of cold-active Colwelliaphage 9A and psychrophilic phage-host interactions", "authors": [{"first": "J", "middle": ["R"], "last": "Colangelo-Lillis", "suffix": ""}, {"first": "J", "middle": ["W"], "last": "Deming", "suffix": ""}], "year": 2013, "venue": "Extremophiles", "link": "18627554"}, "BIBREF39": {"title": "Unifying classical and molecular taxonomic classification: analysis of the Podoviridae using blastp-based tools", "authors": [{"first": "R", "middle": [], "last": "Lavigne", "suffix": ""}, {"first": "D", "middle": [], "last": "Seto", "suffix": ""}, {"first": "P", "middle": [], "last": "Mahadevan", "suffix": ""}, {"first": "H", "middle": ["W"], "last": "Ackermann", "suffix": ""}, {"first": "A", "middle": ["M"], "last": "Kropinski", "suffix": ""}], "year": 2008, "venue": "Res Microbiol", "link": "28370089"}}, "ref_entries": {}}
{"paper_id": "199668529", "_pdf_hash": "f0513db188a8957448ccbeefdf2aa1e4bb3c14e3", "abstract": [], "body_text": [{"section": "", "text": "Dear readers, It is our pleasure to introduce this special issue of Monatshefte f\u00fcr Chemie-Chemical Monthly, which is a nice selection of papers written by young and beginning analytical chemists. The future and development of each scientific discipline is granted only by young scientists, who bring new ideas, focus on still untouched areas, and continue the work of their predecessors. With generous consent of the Editor-in-Chief of the journal, Prof. Dr. Peter G\u00e4rtner, we present here 19 original papers and four short communications prepared by beginning analytical chemists.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "All the contributions in this volume were written on personal invitation by authors, Ph.D. students of analytical chemistry. The aim has been to support and encourage their creativity and research activities in the field of analytical chemistry, the omnipresent science who determines what and how much creates things around us. The topics of presented contributions cover almost all the aspects of modern analytical chemistry from theoretical problems such as the improvement of calibration methods, through development of new analytical methods and improvement of analytical techniques, to the application of analytical chemistry to solve medicinal, toxicological, environmental, or historical problems. Therefore, this issue represents a unique opportunity to foresee perspectives on future developments of analytical chemistry and enabling to strengthen contacts with young colleagues.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "We hope that you will find all these contributions interesting and you will be assured that a new generation of analytical chemists will protect bright and thrilling future of our science. In that way, analytical chemistry will remain rewarding, exciting, steadily developing science with vivid perspectives and new, unsuspected ways of its innovation and application.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "We take the opportunity to express our deep gratitude to the Editor-in-Chief, Prof. Dr. Peter G\u00e4rtner, and the Managing Editor, Dr. Christian Hametner, for their kind support in the preparation of this issue. We also would thank all referees for constructive comments that improved the quality of the contributions, and to the staff of the Publisher, Springer, Vienna, for all their help to this special issue release.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Enjoy reading this issue, Karel Nesm\u011br\u00e1k and Tom\u00e1\u0161 Navr\u00e1til.", "cite_spans": [], "ref_spans": []}], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "199668547", "_pdf_hash": "eb1561cadd7d4307b7f9a7600520cbd6272062cd", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Effects of environmental change on wildlife health", "authors": [{"first": "K", "middle": [], "last": "Acevedo-Whitehouse", "suffix": ""}, {"first": "Alj", "middle": [], "last": "Duffus", "suffix": ""}], "year": 2009, "venue": "Philos. Trans R Soc Lond B Biol Sci", "link": "10938017"}, "BIBREF1": {"title": "Length-weight relationships and condition factors of six fish species in Atbara River and Khashm el-Girba reservoir", "authors": [{"first": "E", "middle": ["O"], "last": "Ahmed", "suffix": ""}, {"first": "M", "middle": ["E"], "last": "Ali", "suffix": ""}, {"first": "A", "middle": ["A"], "last": "Aziz", "suffix": ""}], "year": 2011, "venue": "Sudan. Int J Agric Sci", "link": "67852204"}, "BIBREF2": {"title": "Length -weight relationship, condition factor and sex-ratio of fish fauna in Badagry Creek", "authors": [{"first": "A", "middle": ["O"], "last": "Akintade", "suffix": ""}, {"first": "C", "middle": ["O"], "last": "Edwin", "suffix": ""}, {"first": "E", "middle": ["A"], "last": "Simon", "suffix": ""}], "year": 2016, "venue": "Int J Mar Sci", "link": null}, "BIBREF3": {"title": "Condition factors of four cichlid species of a man made lake in Imo State, Southeast Nigeria", "authors": [{"first": "A", "middle": [], "last": "Anene", "suffix": ""}], "year": 2005, "venue": "Turkish J Fish Aquatic Sci", "link": null}, "BIBREF4": {"title": "Lengthweight relationship and condition factor of freshwater fish Tilapia mossambica", "authors": [{"first": "J", "middle": [], "last": "Anni", "suffix": ""}, {"first": "M", "middle": ["D"], "last": "Askwith", "suffix": ""}, {"first": "A", "middle": ["P"], "last": "Christina", "suffix": ""}, {"first": "A", "middle": [], "last": "Jeyaseeli", "suffix": ""}], "year": 2016, "venue": "J Biol Innov", "link": null}, "BIBREF5": {"title": "Length weight relationship, condition factor and stomach contents of Hemichromis b i m ac u l a t us", "authors": [{"first": "A", "middle": ["A"], "last": "Ayaode", "suffix": ""}, {"first": "Aoo", "middle": [], "last": "Ikulala", "suffix": ""}], "year": 2007, "venue": "Chromidotilapia guentheri (Perciformes: Cichlidae) in Eleiyele Lake", "link": null}, "BIBREF6": {"title": "Length-weight relationship, condition factor and sex ratio of African mud catfish (Clarias gariepinus) reared in flow-through system tanks", "authors": [{"first": "C", "middle": ["I"], "last": "Ayo-Olalusi", "suffix": ""}], "year": 2014, "venue": "J Fish Aquatic Sci", "link": "87463883"}, "BIBREF7": {"title": "Methods of assessment of fish production in freshwaters", "authors": [{"first": "T", "middle": ["B"], "last": "Bagenal", "suffix": ""}, {"first": "F", "middle": ["W"], "last": "Tesch", "suffix": ""}], "year": 1978, "venue": "", "link": null}, "BIBREF8": {"title": "Geology of the Magadi area", "authors": [], "year": 1958, "venue": "Geol Surv Kenya Rep", "link": null}, "BIBREF9": {"title": "Effects of interspecific interaction-linked habitat factors on moose resource selection and environmental stress", "authors": [{"first": "H", "middle": [], "last": "Bao", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Fryxell", "suffix": ""}, {"first": "H", "middle": [], "last": "Liu", "suffix": ""}, {"first": "H", "middle": [], "last": "Dou", "suffix": ""}, {"first": "Y", "middle": [], "last": "Ma", "suffix": ""}, {"first": "G", "middle": [], "last": "Jiang", "suffix": ""}], "year": 2017, "venue": "Sci Rep", "link": "6850505"}, "BIBREF10": {"title": "Destruction of fisheries in Africa's lakes", "authors": [{"first": "Cdn", "middle": [], "last": "Barel", "suffix": ""}, {"first": "R", "middle": [], "last": "Dorit", "suffix": ""}, {"first": "P", "middle": ["H"], "last": "Greenwood", "suffix": ""}, {"first": "G", "middle": [], "last": "Fryer", "suffix": ""}, {"first": "N", "middle": [], "last": "Hughes", "suffix": ""}, {"first": "Pbn", "middle": [], "last": "Jackson", "suffix": ""}, {"first": "H", "middle": [], "last": "Kawanabe", "suffix": ""}, {"first": "R", "middle": ["L"], "last": "Lowe-Mcconnell", "suffix": ""}, {"first": "M", "middle": [], "last": "Nagoshi", "suffix": ""}, {"first": "A", "middle": ["J"], "last": "Ribbink", "suffix": ""}, {"first": "E", "middle": [], "last": "Trewavas", "suffix": ""}, {"first": "F", "middle": [], "last": "Witte", "suffix": ""}, {"first": "K", "middle": [], "last": "Yamaoka", "suffix": ""}], "year": 1985, "venue": "Nature", "link": null}, "BIBREF11": {"title": "Temperature and sex chromosomes govern sex ratios of the mouth-brooding cichlid fish Oreochromis niloticus", "authors": [{"first": "J", "middle": ["F"], "last": "Baroiller", "suffix": ""}, {"first": "D", "middle": [], "last": "Chourrout", "suffix": ""}, {"first": "A", "middle": [], "last": "Fostier", "suffix": ""}, {"first": "D", "middle": ["B"], "last": "Jalabert", "suffix": ""}], "year": 1995, "venue": "J Exp Zool", "link": "84956462"}, "BIBREF12": {"title": "Alcolapia grahami: IUCN 2011. IUCN Red List of Threatened Species", "authors": [{"first": "J", "middle": [], "last": "Bayona", "suffix": ""}, {"first": "E", "middle": [], "last": "Akinyi", "suffix": ""}], "year": 2006, "venue": "", "link": null}, "BIBREF13": {"title": "Higher rates of sex evolve in spatially heterogenous environments", "authors": [{"first": "L", "middle": [], "last": "Beck", "suffix": ""}, {"first": "A", "middle": ["F"], "last": "Agrawal", "suffix": ""}], "year": 2010, "venue": "Nature", "link": null}, "BIBREF14": {"title": "Sex determination and temperature induced sex differentiation in three natural populations of Nile tilapia (Oreochromis niloticus) adapted to extreme temperature conditions", "authors": [{"first": "E", "middle": [], "last": "Bezault", "suffix": ""}, {"first": "F", "middle": [], "last": "Clota", "suffix": ""}, {"first": "M", "middle": [], "last": "Derivaz", "suffix": ""}, {"first": "B", "middle": [], "last": "Chevassus", "suffix": ""}, {"first": "J", "middle": ["F"], "last": "Baroiller", "suffix": ""}], "year": 2007, "venue": "Aquaculture", "link": "86103020"}, "BIBREF15": {"title": "Metabolism and antioxidant defense in the larval chironomid Tanytarsus minutipalpus: adjustments to diel variations in the extreme conditions of Lake Magadi", "authors": [{"first": "L", "middle": ["F"], "last": "Bianchini", "suffix": ""}, {"first": "C", "middle": ["M"], "last": "Wood", "suffix": ""}, {"first": "H", "middle": ["L"], "last": "Bergman", "suffix": ""}, {"first": "O", "middle": ["E"], "last": "Johannsson", "suffix": ""}, {"first": "P", "middle": [], "last": "Laurent", "suffix": ""}, {"first": "C", "middle": [], "last": "Chevalier", "suffix": ""}, {"first": "M", "middle": ["L"], "last": "Kisipan", "suffix": ""}, {"first": "G", "middle": ["D"], "last": "Kavembe", "suffix": ""}, {"first": "M", "middle": ["B"], "last": "Papah", "suffix": ""}, {"first": "K", "middle": ["V"], "last": "Brix", "suffix": ""}, {"first": "De", "middle": [], "last": "Boeck", "suffix": ""}, {"first": "G", "middle": [], "last": "Maina", "suffix": ""}, {"first": "J", "middle": ["N"], "last": "Ojoo", "suffix": ""}, {"first": "R", "middle": ["O"], "last": "Bianchini", "suffix": ""}, {"first": "A", "middle": [], "last": "", "suffix": ""}], "year": 2017, "venue": "Biol Open", "link": "849046"}, "BIBREF16": {"title": "Sex ratio and body size in Cobitis elongatoides and Sabanejewia balcanica (Cypriniformes, Cobitidae) from a thermal spring", "authors": [{"first": "J", "middle": [], "last": "Bohlen", "suffix": ""}, {"first": "J", "middle": [], "last": "Freyhof", "suffix": ""}, {"first": "A", "middle": [], "last": "Nolte", "suffix": ""}], "year": 2008, "venue": "Folia Zool", "link": "86384739"}, "BIBREF17": {"title": "On a collection of fishes made by Mr. A. Blayney Percival in British East Africa to the East of Lake Baringo", "authors": [{"first": "G", "middle": ["A"], "last": "Boulenger", "suffix": ""}], "year": 1912, "venue": "Proc Zool Soc Lond", "link": null}, "BIBREF18": {"title": "Was the younger Dryas triggered by a flood", "authors": [{"first": "W", "middle": ["S"], "last": "Broecker", "suffix": ""}], "year": 2006, "venue": "Science", "link": null}, "BIBREF19": {"title": "Evolution in constant and fluctuating environments: thermal tolerances of desert pupfish (Cyprinodon)", "authors": [{"first": "J", "middle": [], "last": "Brown", "suffix": ""}, {"first": "C", "middle": [], "last": "Feldmeth", "suffix": ""}], "year": 1971, "venue": "Evolution", "link": "24572977"}, "BIBREF20": {"title": "Radiocarbon dating of East African lake levels", "authors": [{"first": "K", "middle": ["W"], "last": "B\u00fctzer", "suffix": ""}, {"first": "G", "middle": ["L"], "last": "Isacc", "suffix": ""}, {"first": "J", "middle": ["L"], "last": "Richardson", "suffix": ""}, {"first": "C", "middle": [], "last": "Washbourn-Kamau", "suffix": ""}], "year": 1972, "venue": "Science", "link": "38317358"}, "BIBREF21": {"title": "Conservation genetic assessment of the critically endangered Julimes pupfish, Cyprinodon julimes", "authors": [{"first": "E", "middle": ["W"], "last": "Carson", "suffix": ""}, {"first": "M", "middle": [], "last": "De La Maza-Benignos", "suffix": ""}, {"first": "L-Vm", "middle": [], "last": "De Lourdes", "suffix": ""}, {"first": "L", "middle": [], "last": "Velavalladares", "suffix": ""}, {"first": "I", "middle": [], "last": "Banda-Villanueva", "suffix": ""}, {"first": "T", "middle": ["F"], "last": "Turner", "suffix": ""}], "year": 2014, "venue": "Conserv Genet", "link": "15578731"}, "BIBREF22": {"title": "Behaviour responses and ecological consequences", "authors": [{"first": "L", "middle": ["J"], "last": "Chapman", "suffix": ""}, {"first": "D", "middle": ["J"], "last": "Mckenzie", "suffix": ""}], "year": 2009, "venue": "Fish physiology", "link": null}, "BIBREF23": {"title": "Condition factor, K, for salmonid fish. Fisheries Notes", "authors": [{"first": "Psm", "middle": [], "last": "Charles-Barnham", "suffix": ""}, {"first": "A", "middle": [], "last": "Baxter", "suffix": ""}], "year": 1998, "venue": "", "link": null}, "BIBREF24": {"title": "Diel hypoxia in marsh creeks impairs the reproductive capacity of estuarine fish populations", "authors": [{"first": "E", "middle": ["L"], "last": "Charnov", "suffix": ""}, {"first": "C", "middle": ["A"], "last": "Landry", "suffix": ""}, {"first": "S", "middle": ["L"], "last": "Steele", "suffix": ""}, {"first": "S", "middle": [], "last": "Manning", "suffix": ""}], "year": 2004, "venue": "Mar Ecol Prog Ser", "link": "52242394"}, "BIBREF25": {"title": "The last glacial maximum", "authors": [{"first": "P", "middle": ["U"], "last": "Clark", "suffix": ""}, {"first": "A", "middle": ["S"], "last": "Dyke", "suffix": ""}, {"first": "J", "middle": ["D"], "last": "Shakun", "suffix": ""}, {"first": "A", "middle": ["E"], "last": "Carlson", "suffix": ""}, {"first": "J", "middle": [], "last": "Clark", "suffix": ""}, {"first": "B", "middle": [], "last": "Wohlfarth", "suffix": ""}, {"first": "J", "middle": ["X"], "last": "Mitrovica", "suffix": ""}, {"first": "S", "middle": ["W"], "last": "Hostetler", "suffix": ""}, {"first": "A", "middle": ["M"], "last": "Mccabe", "suffix": ""}], "year": 2009, "venue": "Science", "link": "1324559"}, "BIBREF26": {"title": "The biology of Tilapia grahamI (Boulenger) in Lake Magadi", "authors": [{"first": "M", "middle": ["J"], "last": "Coe", "suffix": ""}], "year": 1966, "venue": "Kenya. Acta Trop", "link": null}, "BIBREF27": {"title": "Adaptive significance of temperaturedependent sex determination in a fish", "authors": [{"first": "D", "middle": ["O"], "last": "Conover", "suffix": ""}], "year": 1984, "venue": "Amer Natur", "link": "84536660"}, "BIBREF28": {"title": "Temperaturedependent sex determination in vertebrates", "authors": [{"first": "D", "middle": ["O"], "last": "Conover", "suffix": ""}], "year": 2004, "venue": "Smithsonian Books", "link": null}, "BIBREF29": {"title": "Environmental sex distributioninteraction of temperature and genotype in fish", "authors": [{"first": "D", "middle": ["O"], "last": "Conover", "suffix": ""}, {"first": "B", "middle": ["E"], "last": "Kynard", "suffix": ""}], "year": 1981, "venue": "Science", "link": null}, "BIBREF30": {"title": "Evolution of a balanced sex ratio by frequency-dependent selection in a fish", "authors": [{"first": "D", "middle": ["O"], "last": "Conover", "suffix": ""}, {"first": "D", "middle": ["A"], "last": "Van Voorhees", "suffix": ""}], "year": 1990, "venue": "Science", "link": "31570568"}, "BIBREF31": {"title": "Estrilidad en el pejerry Odontesthes bonariensis en ambientes naturales", "authors": [{"first": "A", "middle": ["M"], "last": "Cornejo", "suffix": ""}], "year": 2003, "venue": "Biologie Aqu\u00e1tica", "link": null}, "BIBREF32": {"title": "Mode and tempo in environmental sex determination in vertebrates", "authors": [{"first": "D", "middle": [], "last": "Crews", "suffix": ""}, {"first": "J", "middle": ["J"], "last": "Bull", "suffix": ""}], "year": 2009, "venue": "Semminars Cell Dev Biol", "link": "27616596"}, "BIBREF33": {"title": "Sedimentology and geochemistry of lacustrine sequences of the upper Pleistocene and Holocene in intertropical area (Lake Magadi and green crater Lake): paleoclimatic implications", "authors": [{"first": "B", "middle": [], "last": "Damnati", "suffix": ""}], "year": 1993, "venue": "J Afric Earth Sci", "link": "129135118"}, "BIBREF34": {"title": "Estimation of length-weight relationship and condition factor of spotted snakehead Channa punctata (Bloch) under different feeding regimes", "authors": [{"first": "S", "middle": ["N"], "last": "Datta", "suffix": ""}, {"first": "V", "middle": ["I"], "last": "Kaur", "suffix": ""}, {"first": "A", "middle": [], "last": "Dhawan", "suffix": ""}, {"first": "G", "middle": [], "last": "Jassal", "suffix": ""}], "year": 2013, "venue": "", "link": "16736799"}, "BIBREF35": {"title": "Seasonal changes in condition factor and weight-length relationships of invasive Carassius gibelio (Bloch, 1782) from Leszczynskie Lakeland. Poland Adv Zool Article No ID 678763", "authors": [{"first": "M", "middle": [], "last": "De Giosa", "suffix": ""}, {"first": "P", "middle": [], "last": "Czerniejewski", "suffix": ""}, {"first": "A", "middle": [], "last": "Rybczyk", "suffix": ""}], "year": 2014, "venue": "", "link": null}, "BIBREF36": {"title": "Sex determination and sex differentiation in fish: an overview of genetic, physiological, and environmental influences", "authors": [{"first": "R", "middle": ["H"], "last": "Devlin", "suffix": ""}, {"first": "Y", "middle": [], "last": "Nagahama", "suffix": ""}], "year": 2002, "venue": "Aquaculture", "link": "84176069"}, "BIBREF37": {"title": "Marine benthic hypoxia: a review of its ecological effects and the behavioural responses on benthic macrofauna", "authors": [{"first": "R", "middle": ["J"], "last": "Diaz", "suffix": ""}, {"first": "R", "middle": [], "last": "Rosenberg", "suffix": ""}], "year": 1995, "venue": "Oceanogr Mar Biol", "link": "87532205"}, "BIBREF38": {"title": "Persistence of an extreme sex-ratio bias in a natural population", "authors": [{"first": "E", "middle": ["A"], "last": "Dyson", "suffix": ""}, {"first": "D", "middle": ["D"], "last": "Hurst", "suffix": ""}], "year": 2004, "venue": "Proc Natl Acad Sci U S A", "link": "30274464"}, "BIBREF39": {"title": "Historical biogeography of the New World pupfish genus Cyprinodon (Teleosti)", "authors": [{"first": "A", "middle": ["A"], "last": "Echelle", "suffix": ""}, {"first": "E", "middle": ["W"], "last": "Carson", "suffix": ""}, {"first": "A", "middle": ["F"], "last": "Echelle", "suffix": ""}, {"first": "R", "middle": ["A"], "last": "Van Den Bussche", "suffix": ""}, {"first": "T", "middle": ["E"], "last": "Dowling", "suffix": ""}, {"first": "A", "middle": [], "last": "Meyer", "suffix": ""}], "year": 1993, "venue": "", "link": null}, "BIBREF40": {"title": "Ecology, sexual selection, and the evolution of mating systems", "authors": [{"first": "S", "middle": ["T"], "last": "Emlen", "suffix": ""}, {"first": "L", "middle": ["W"], "last": "Oring", "suffix": ""}], "year": 1977, "venue": "Science", "link": "16786432"}, "BIBREF41": {"title": "Chemistry and origin of the brines from Lake Magadi", "authors": [{"first": "H", "middle": ["P"], "last": "Eugster", "suffix": ""}], "year": 1970, "venue": "Kenya. Mineral. Soc Amer Special Paper", "link": null}, "BIBREF42": {"title": "Lake Magadi, Kenya, and its Pleistocene precursors. In: Nissenbaum A (ed) Hypersaline brines and evaporitic environments", "authors": [{"first": "H", "middle": ["P"], "last": "Eugster", "suffix": ""}], "year": 1980, "venue": "", "link": null}, "BIBREF43": {"title": "Length-weight relationship and condition factor of four commercial fish species of Oyan Lake, Nigeria. Examines Mar", "authors": [{"first": "O", "middle": [], "last": "Fafioye", "suffix": ""}, {"first": "O", "middle": [], "last": "Ayodele", "suffix": ""}], "year": 2018, "venue": "C Biol Oceanogr", "link": null}, "BIBREF45": {"title": "Scaling of oxygen consumption in Lake Magadi tilapia, Oreochromis alcalicus grahami: a fish living at 37\u00b0C", "authors": [{"first": "C", "middle": ["E"], "last": "Franklin", "suffix": ""}, {"first": "T", "middle": [], "last": "Crockford", "suffix": ""}, {"first": "I", "middle": ["A"], "last": "Johnston", "suffix": ""}, {"first": "C", "middle": [], "last": "Kamunde", "suffix": ""}], "year": 1995, "venue": "J Fish Biol", "link": null}, "BIBREF46": {"title": "Cube law, condition factor and weight-length relationships: history, meta-analysis and recommendations", "authors": [{"first": "R", "middle": [], "last": "Froese", "suffix": ""}], "year": 2006, "venue": "J Appl Ichthyol", "link": "10249165"}, "BIBREF47": {"title": "Rate of growth of seas fishes scientific investigation of fishes Division of Scottish Fisheries", "authors": [{"first": "T", "middle": [], "last": "Fulton", "suffix": ""}], "year": 1902, "venue": "", "link": null}, "BIBREF48": {"title": "U-series disequilibria in early diagenetic minerals from Lake Magadi sediments, Kenya: dating potential", "authors": [{"first": "C", "middle": [], "last": "Goetz", "suffix": ""}, {"first": "C", "middle": [], "last": "Hillaire-Marcel", "suffix": ""}], "year": 1992, "venue": "Geochem. Cosmochim Acta", "link": "140165592"}, "BIBREF49": {"title": "Life history correlates of the evolution of live bearing in fishes", "authors": [{"first": "N", "middle": ["B"], "last": "Goodwin", "suffix": ""}, {"first": "N", "middle": ["K"], "last": "Dukvy", "suffix": ""}, {"first": "J", "middle": ["D"], "last": "Reynolds", "suffix": ""}], "year": 2002, "venue": "Philos. Trans. Roy. Soc., Lond. B", "link": "36926540"}, "BIBREF50": {"title": "Air breathing fishes: evolution, diversity and adaptation", "authors": [{"first": "J", "middle": ["B"], "last": "Graham", "suffix": ""}], "year": 1997, "venue": "", "link": "84450458"}, "BIBREF51": {"title": "Halocene paleoclimates in Africa", "authors": [{"first": "F", "middle": ["A"], "last": "Hassan", "suffix": ""}], "year": 1997, "venue": "Afric. Archeol Rev", "link": null}, "BIBREF52": {"title": "The shallow thermal regime of devils hole, Death Valley National Park", "authors": [{"first": "M", "middle": ["B"], "last": "Hausner", "suffix": ""}, {"first": "K", "middle": ["P"], "last": "Wilson", "suffix": ""}, {"first": "D", "middle": ["B"], "last": "Gaines", "suffix": ""}, {"first": "F", "middle": [], "last": "Su\u00e1rez", "suffix": ""}, {"first": "S", "middle": ["W"], "last": "Tyler", "suffix": ""}], "year": 2013, "venue": "Limnol. Oceanogr: Fluids Enviros", "link": "129102774"}, "BIBREF53": {"title": "Condition factor as an indicator and feeding intensity of Nile Tilapia fingerlings (Oreochromis niloticus) feed on different levels of maltose", "authors": [{"first": "K", "middle": ["A"], "last": "Ighwela", "suffix": ""}, {"first": "A", "middle": ["B"], "last": "Ahmed", "suffix": ""}, {"first": "A", "middle": ["B"], "last": "Abol-Munafi", "suffix": ""}], "year": 2011, "venue": "Amer-Europ J Agric Environ Sci", "link": "54954024"}, "BIBREF54": {"title": "Hypersaline environments: microbiology and biogeochemistry", "authors": [{"first": "B", "middle": [], "last": "Javor", "suffix": ""}], "year": 1989, "venue": "", "link": "83271707"}, "BIBREF55": {"title": "Weight-length relationships and Fulton's condition factors of skipjack tuna (Katsuwonus pelamis) in the western and Central Pacific Ocean", "authors": [{"first": "S", "middle": [], "last": "Jin", "suffix": ""}, {"first": "X", "middle": [], "last": "Yan", "suffix": ""}, {"first": "H", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "W", "middle": [], "last": "Fan", "suffix": ""}], "year": 2015, "venue": "Peer J", "link": "14939417"}, "BIBREF56": {"title": "Air-breathing Magadi tilapia Alcolapia grahami, under normoxic and hyperoxic conditions, and the association with sunlight and reactive oxygen", "authors": [{"first": "O", "middle": ["E"], "last": "Johannsson", "suffix": ""}, {"first": "H", "middle": ["L"], "last": "Bergman", "suffix": ""}, {"first": "C", "middle": ["M"], "last": "Wood", "suffix": ""}, {"first": "P", "middle": [], "last": "Laurent", "suffix": ""}, {"first": "D", "middle": ["G"], "last": "Kavembe", "suffix": ""}, {"first": "A", "middle": [], "last": "Bianchini", "suffix": ""}, {"first": "J", "middle": ["N"], "last": "Maina", "suffix": ""}, {"first": "C", "middle": [], "last": "Chevalier", "suffix": ""}, {"first": "L", "middle": ["F"], "last": "Bianchini", "suffix": ""}, {"first": "M", "middle": ["B"], "last": "Papah", "suffix": ""}, {"first": "R", "middle": ["O"], "last": "Ojoo", "suffix": ""}], "year": 2014, "venue": "J Fish Biol", "link": "9370721"}, "BIBREF57": {"title": "Thermal and developmental ecology of pupfish", "authors": [{"first": "A", "middle": ["C"], "last": "Jones", "suffix": ""}], "year": 2017, "venue": "", "link": null}, "BIBREF58": {"title": "Hydrochemistry of the Lake Magadi Basin", "authors": [{"first": "B", "middle": ["F"], "last": "Jones", "suffix": ""}, {"first": "H", "middle": ["P"], "last": "Eugster", "suffix": ""}, {"first": "S", "middle": ["L"], "last": "Rettig", "suffix": ""}], "year": 1977, "venue": "", "link": null}, "BIBREF59": {"title": "Pronounced genetic differentiation of small, isolated and fragmented tilapia populations inhabiting the Magadi soda Lake in Kenya", "authors": [{"first": "G", "middle": ["D"], "last": "Kavembe", "suffix": ""}, {"first": "G", "middle": [], "last": "Machando-Schiaffino", "suffix": ""}, {"first": "A", "middle": [], "last": "Meyer", "suffix": ""}], "year": 2014, "venue": "Hydrobiologia", "link": "14631698"}, "BIBREF60": {"title": "Genomics of adaptation to multiple concurrent stresses: insights from comparative transcriptomics of a cichlid fish from one of earth's most extreme environments, the hypersaline soda Lake Magadi in Kenya, East Africa", "authors": [{"first": "G", "middle": ["D"], "last": "Kavembe", "suffix": ""}, {"first": "P", "middle": [], "last": "Franchini", "suffix": ""}, {"first": "I", "middle": [], "last": "Irisarri", "suffix": ""}, {"first": "G", "middle": [], "last": "Machado-Schiaffino", "suffix": ""}, {"first": "A", "middle": [], "last": "Meyer", "suffix": ""}], "year": 2015, "venue": "J Mol Evol", "link": "9995178"}, "BIBREF61": {"title": "Fish populations in east African saline lakes", "authors": [{"first": "G", "middle": ["D"], "last": "Kavembe", "suffix": ""}, {"first": "A", "middle": [], "last": "Meyer", "suffix": ""}, {"first": "C", "middle": ["M"], "last": "Wood", "suffix": ""}], "year": 2016, "venue": "", "link": "132904305"}, "BIBREF62": {"title": "Eco-morphological differentiation in Lake Magadi tilapia, an extremophile cichlid fish living in hot, alkaline and hypersaline lakes in East Africa", "authors": [{"first": "G", "middle": ["D"], "last": "Kavembe", "suffix": ""}, {"first": "A", "middle": ["F"], "last": "Kautt", "suffix": ""}, {"first": "G", "middle": [], "last": "Machado-Schiaffino", "suffix": ""}, {"first": "A", "middle": [], "last": "Meyer", "suffix": ""}], "year": 2016, "venue": "Molecular Ecol", "link": "32853899"}, "BIBREF63": {"title": "Effect of broodstock sex ratio on growth and reproductive performance of blue tilapia", "authors": [{"first": "M", "middle": ["M"], "last": "Khalfalla", "suffix": ""}, {"first": "Y", "middle": ["A"], "last": "Hammaouda", "suffix": ""}, {"first": "A", "middle": ["M"], "last": "Tahoun", "suffix": ""}, {"first": "Ham", "middle": [], "last": "Abo-State", "suffix": ""}], "year": 2008, "venue": "Oreochromis aureus (Steindachner) rared in hapas. 8 th international symposium in Tilapia in aquaculture", "link": null}, "BIBREF64": {"title": "Dissolved oxygen and fish behaviour", "authors": [{"first": "D", "middle": ["L"], "last": "Kramer", "suffix": ""}], "year": 1987, "venue": "Environm Biol Fish", "link": null}, "BIBREF65": {"title": "Tiny and tough: Microphytes of east African soda lakes", "authors": [{"first": "L", "middle": [], "last": "Krienitz", "suffix": ""}, {"first": "M", "middle": [], "last": "Schagerl", "suffix": ""}], "year": 2016, "venue": "", "link": "132491625"}, "BIBREF66": {"title": "Lesser flamingo as a central element of the east African avifauna", "authors": [{"first": "L", "middle": [], "last": "Krienitz", "suffix": ""}, {"first": "B", "middle": [], "last": "M\u00e4hnert", "suffix": ""}, {"first": "M", "middle": [], "last": "Schagerl", "suffix": ""}], "year": 2016, "venue": "", "link": "132593405"}, "BIBREF67": {"title": "Length-weight relationships and condition factors of twenty one fish species in Ologe lagoon", "authors": [{"first": "C", "middle": ["A"], "last": "Kumolu-Johnson", "suffix": ""}, {"first": "P", "middle": ["E"], "last": "Ndimele", "suffix": ""}], "year": 2010, "venue": "Asia J Agric Sci", "link": "31753562"}, "BIBREF68": {"title": "The phenotypic plasticity of Death Valley's pupfish", "authors": [{"first": "S", "middle": ["C"], "last": "Lama", "suffix": ""}], "year": 2008, "venue": "Sci Amer", "link": null}, "BIBREF69": {"title": "Long term hypoxia suppresses reproductive capacity in the estuarine fish, Fundulus grandis", "authors": [{"first": "C", "middle": ["A"], "last": "Landry", "suffix": ""}, {"first": "S", "middle": ["L"], "last": "Steele", "suffix": ""}, {"first": "S", "middle": [], "last": "Manning", "suffix": ""}, {"first": "A", "middle": ["O"], "last": "Cheek", "suffix": ""}], "year": 2007, "venue": "Comp Biochem Physiol A", "link": "21567537"}, "BIBREF70": {"title": "The impact of global change on terrestrial vertebrates", "authors": [{"first": "J", "middle": ["D"], "last": "Lebreton", "suffix": ""}], "year": 2011, "venue": "CR Biol", "link": "20414773"}, "BIBREF71": {"title": "A comparative allometric study of the morphometry of the gills of an alkalinity adapted cichilid fish, Oreochromis alcalicus grahami", "authors": [{"first": "J", "middle": ["N"], "last": "Maina", "suffix": ""}, {"first": "S", "middle": ["M"], "last": "Kisia", "suffix": ""}, {"first": "C", "middle": ["M"], "last": "Wood", "suffix": ""}, {"first": "A", "middle": ["B"], "last": "Narahara", "suffix": ""}, {"first": "H", "middle": ["L"], "last": "Bergman", "suffix": ""}, {"first": "P", "middle": [], "last": "Laurent", "suffix": ""}, {"first": "P", "middle": ["J"], "last": "Walsh", "suffix": ""}], "year": 1996, "venue": "Intern J Salt Lake Res", "link": null}, "BIBREF72": {"title": "Guilty as charged: Nile perch was the cause of the haplochromine decline in Lake Victoria", "authors": [{"first": "B", "middle": ["E"], "last": "Marshall", "suffix": ""}], "year": 2018, "venue": "Can J Fish Aquat Sci", "link": "91157820"}, "BIBREF73": {"title": "Diabolical survival in Death Valley: recent pupfish colonization, gene flow and genetic assimilation in the smalles species range on earth", "authors": [{"first": "C", "middle": ["H"], "last": "Martin", "suffix": ""}, {"first": "J", "middle": ["E"], "last": "Crawford", "suffix": ""}, {"first": "B", "middle": ["J"], "last": "Turner", "suffix": ""}, {"first": "L", "middle": ["H"], "last": "Simons", "suffix": ""}], "year": 2016, "venue": "Proc R Soc B", "link": "9913022"}, "BIBREF74": {"title": "Biodiversity is our life", "authors": [{"first": "J", "middle": [], "last": "Marton-Lef\u00e8vre", "suffix": ""}], "year": 2006, "venue": "Science", "link": "7605657"}, "BIBREF75": {"title": "Lake Magadi and the soda lake cycle: a study of the modern sodium carbonates and of Late Pleistocene and Holocene Lacustrine core sediments. Graduate Dissertations and Theses 25", "authors": [{"first": "E", "middle": [], "last": "Mcnulty", "suffix": ""}], "year": 2017, "venue": "?article=1025&context=dissertation_and_theses. Accessed", "link": null}, "BIBREF76": {"title": "Invertebrates of east African Soda Lakes", "authors": [{"first": "S", "middle": [], "last": "Mengistou", "suffix": ""}], "year": 2016, "venue": "", "link": "89084086"}, "BIBREF77": {"title": "Environmental versus genetic sex determination: a possible factor in dinosaur extinction?", "authors": [{"first": "D", "middle": [], "last": "Miller", "suffix": ""}, {"first": "J", "middle": [], "last": "Summers", "suffix": ""}, {"first": "S", "middle": [], "last": "Silber", "suffix": ""}], "year": 2004, "venue": "Fertil Steril", "link": "15035323"}, "BIBREF78": {"title": "Impacts of climate change and environmental factors on reproduction and development in wildlife", "authors": [{"first": "S", "middle": ["R"], "last": "Milligan", "suffix": ""}, {"first": "W", "middle": ["V"], "last": "Holt", "suffix": ""}, {"first": "R", "middle": [], "last": "Lloyd", "suffix": ""}], "year": 2009, "venue": "Philos Trans R Soc Lond Ser B Biol Sci", "link": "10840972"}, "BIBREF79": {"title": "Biological consequences of global change for birds", "authors": [{"first": "A", "middle": ["P"], "last": "M\u00f8ller", "suffix": ""}], "year": 2013, "venue": "Integr Zool", "link": null}, "BIBREF80": {"title": "Respiratory physiology ofthe Lake Magadi tilapia (Oreochromis alcalilcus grahami), a fish adapted to a hot, alkaline, and frequently hypoxic environment", "authors": [{"first": "A", "middle": [], "last": "Narahara", "suffix": ""}, {"first": "H", "middle": ["L"], "last": "Bergman", "suffix": ""}, {"first": "P", "middle": [], "last": "Laurent", "suffix": ""}, {"first": "J", "middle": ["N"], "last": "Maina", "suffix": ""}, {"first": "P", "middle": ["J"], "last": "Walsh", "suffix": ""}, {"first": "C", "middle": ["M"], "last": "Wood", "suffix": ""}], "year": 1996, "venue": "Physiol Biochem Zool", "link": "40223522"}, "BIBREF81": {"title": "The origin of Fulton's condition factor -setting the record straight", "authors": [{"first": "Rdm", "middle": [], "last": "Nash", "suffix": ""}, {"first": "A", "middle": ["H"], "last": "Valencia", "suffix": ""}, {"first": "A", "middle": ["J"], "last": "Geffen", "suffix": ""}], "year": 2006, "venue": "Fisheries", "link": null}, "BIBREF82": {"title": "Soda lakes of the eastern African rift system: the past, the presnt. In: Schagerl M (ed) Soda lakes of East Africa", "authors": [{"first": "S", "middle": ["O"], "last": "Oduor", "suffix": ""}, {"first": "K", "middle": [], "last": "Kotut", "suffix": ""}], "year": 2016, "venue": "", "link": null}, "BIBREF83": {"title": "The decline of the native fishes of lakes Victoria and Kyoga (East Africa) and the impact of introduced species, especially the Nile perch, Lates niloticus and the Nile tilapia", "authors": [{"first": "R", "middle": [], "last": "Ogutu-Ohwayo", "suffix": ""}], "year": 1990, "venue": "Oreochromis niloticus. Environ Biol Fishes", "link": "23435873"}, "BIBREF84": {"title": "On the distribution of fishes of the Kenya's great Rift Valley drainage system", "authors": [{"first": "D", "middle": ["O"], "last": "Okeyo", "suffix": ""}], "year": 2006, "venue": "Discov Innov", "link": "84921189"}, "BIBREF85": {"title": "Fecundity, condition factor, and gonado-somatic index of Hepsetus odoe (African pike) in a tropical reservoir", "authors": [{"first": "J", "middle": ["A"], "last": "Oso", "suffix": ""}, {"first": "E", "middle": ["O"], "last": "Idowu", "suffix": ""}, {"first": "O", "middle": [], "last": "Fagbuaro", "suffix": ""}, {"first": "T", "middle": ["S"], "last": "Olaniran", "suffix": ""}, {"first": "B", "middle": ["E"], "last": "Ayorinde", "suffix": ""}], "year": 2011, "venue": "Southwest Nigeria. World J Fisheries Mar Sci", "link": null}, "BIBREF86": {"title": "Temperature-dependent sex determination in fish revisited: prevalence, a single sex ratio response pattern, and possible effects of climatic change", "authors": [{"first": "N", "middle": [], "last": "Ospina-\u00c1lvarez", "suffix": ""}, {"first": "F", "middle": [], "last": "Piferrer", "suffix": ""}], "year": 2008, "venue": "PLoS One", "link": "17985452"}, "BIBREF87": {"title": "Length-weight relationship, condition factor, length at first maturity and sex ratio of Nile tilapia, Oreochromis niloticus in Lake Naivasha", "authors": [{"first": "O", "middle": ["N"], "last": "Otieno", "suffix": ""}, {"first": "N", "middle": [], "last": "Kitaka", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Njiru", "suffix": ""}], "year": 2014, "venue": "Kenya Intern J Fish Aquatic Studies", "link": "56408990"}, "BIBREF88": {"title": "Morphological evaluation of spermatogenesis in Lake Magadi tilapia (Alcolapia grahami): a fish living on edge", "authors": [{"first": "M", "middle": ["B"], "last": "Papah", "suffix": ""}, {"first": "S", "middle": ["M"], "last": "Kisia", "suffix": ""}, {"first": "R", "middle": ["O"], "last": "Ojoo", "suffix": ""}, {"first": "A", "middle": ["N"], "last": "Makanya", "suffix": ""}, {"first": "C", "middle": ["M"], "last": "Wood", "suffix": ""}, {"first": "G", "middle": ["D"], "last": "Kavembe", "suffix": ""}, {"first": "J", "middle": ["N"], "last": "Maina", "suffix": ""}, {"first": "O", "middle": ["E"], "last": "Johannsson", "suffix": ""}, {"first": "H", "middle": ["L"], "last": "Bergman", "suffix": ""}, {"first": "P", "middle": [], "last": "Laurent", "suffix": ""}, {"first": "C", "middle": [], "last": "Chevalier", "suffix": ""}, {"first": "A", "middle": [], "last": "Bianchini", "suffix": ""}, {"first": "L", "middle": ["F"], "last": "Bianchini", "suffix": ""}, {"first": "D", "middle": ["W"], "last": "Onyango", "suffix": ""}], "year": 2013, "venue": "Tissue Cell", "link": "23434097"}, "BIBREF89": {"title": "The East African trough in the neighbourhood of soda lakes", "authors": [{"first": "J", "middle": [], "last": "Parkinson", "suffix": ""}], "year": 1914, "venue": "Geogr J", "link": "130526068"}, "BIBREF90": {"title": "Climate-driven population divergence in sex-determining systems", "authors": [{"first": "I", "middle": [], "last": "Pen", "suffix": ""}, {"first": "U", "middle": [], "last": "Tobias", "suffix": ""}, {"first": "F", "middle": [], "last": "Barbara", "suffix": ""}, {"first": "A", "middle": [], "last": "Harts", "suffix": ""}, {"first": "G", "middle": ["M"], "last": "While", "suffix": ""}, {"first": "E", "middle": [], "last": "Wapstra", "suffix": ""}], "year": 2010, "venue": "Nature", "link": "4371467"}, "BIBREF91": {"title": "Niche dimensions in fishes: an integrative view", "authors": [{"first": "H", "middle": ["O"], "last": "P\u00f6rtner", "suffix": ""}, {"first": "P", "middle": ["M"], "last": "Schulte", "suffix": ""}, {"first": "C", "middle": ["M"], "last": "Wood", "suffix": ""}, {"first": "F", "middle": [], "last": "Schiemer", "suffix": ""}], "year": 2010, "venue": "Physiol Biochem Zool", "link": "34096160"}, "BIBREF92": {"title": "Length-weight relationships, condition factors and relative weight of five species of Bushehr waters Northern Persian Gulf", "authors": [{"first": "H", "middle": [], "last": "Raeisi", "suffix": ""}, {"first": "M", "middle": [], "last": "Daliri", "suffix": ""}, {"first": "S", "middle": ["Y"], "last": "Paighambari", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Shabani", "suffix": ""}, {"first": "M", "middle": [], "last": "Bibak", "suffix": ""}, {"first": "R", "middle": [], "last": "Davoodi", "suffix": ""}], "year": 2011, "venue": "Afric J Biotech", "link": "86316480"}, "BIBREF93": {"title": "Urea excretion as a strategy for survival in a fish living in a very alkaline environment", "authors": [{"first": "D", "middle": ["J"], "last": "Randall", "suffix": ""}, {"first": "C", "middle": ["M"], "last": "Wood", "suffix": ""}, {"first": "S", "middle": ["F"], "last": "Perry", "suffix": ""}, {"first": "H", "middle": ["L"], "last": "Bergman", "suffix": ""}, {"first": "Gmo", "middle": [], "last": "Maloiy", "suffix": ""}, {"first": "T", "middle": ["P"], "last": "Mommsen", "suffix": ""}, {"first": "P", "middle": ["A"], "last": "Wright", "suffix": ""}], "year": 1989, "venue": "Nature", "link": "4272256"}, "BIBREF94": {"title": "Fish in extreme environments: reproduction and energetics under hypoxia", "authors": [{"first": "E", "middle": ["E"], "last": "Reardon", "suffix": ""}], "year": 2009, "venue": "", "link": null}, "BIBREF95": {"title": "Hypoxia and seasonal temperature: short term effects and long term implications for Acartinatonsa dana", "authors": [{"first": "C", "middle": [], "last": "Richmond", "suffix": ""}, {"first": "N", "middle": ["H"], "last": "Marcus", "suffix": ""}, {"first": "C", "middle": [], "last": "Sedlacek", "suffix": ""}, {"first": "G", "middle": ["A"], "last": "Miller", "suffix": ""}, {"first": "D", "middle": ["C"], "last": "Oppert", "suffix": ""}], "year": 2006, "venue": "J Exp Mar Biol Ecol", "link": "84394087"}, "BIBREF96": {"title": "First observation of fish condition from Sava river in Bosnia and Herzegovina", "authors": [{"first": "S", "middle": [], "last": "Ridanovic", "suffix": ""}, {"first": "Z", "middle": [], "last": "Nedic", "suffix": ""}, {"first": "L", "middle": [], "last": "Ridanovic", "suffix": ""}], "year": 2015, "venue": "J Surv Fisheries Sci", "link": "59430717"}, "BIBREF97": {"title": "Timing of the younger Dryas event in East Africa from lake-level changes", "authors": [{"first": "N", "middle": [], "last": "Roberts", "suffix": ""}, {"first": "M", "middle": [], "last": "Taieb", "suffix": ""}, {"first": "P", "middle": [], "last": "Barker", "suffix": ""}, {"first": "B", "middle": [], "last": "Damnati", "suffix": ""}, {"first": "M", "middle": [], "last": "Icole", "suffix": ""}, {"first": "D", "middle": [], "last": "Williamson", "suffix": ""}], "year": 1993, "venue": "Nature", "link": null}, "BIBREF98": {"title": "Causes and consequences of adult sex ratio imbalance in historical U.S. population", "authors": [{"first": "R", "middle": [], "last": "Schacht", "suffix": ""}, {"first": "K", "middle": ["R"], "last": "Smith", "suffix": ""}], "year": 2017, "venue": "Philos trans R Soc Lond B", "link": "4576058"}, "BIBREF99": {"title": "The ecology of African soda lakes: driven by variable and extreme conditions", "authors": [{"first": "M", "middle": [], "last": "Schagerl", "suffix": ""}, {"first": "A", "middle": [], "last": "Burian", "suffix": ""}], "year": 2016, "venue": "", "link": "131887530"}, "BIBREF100": {"title": "The Oreochromis alcalicus flock (Teleostei: Cichlidae) from Lake Natron and Magadi", "authors": [{"first": "L", "middle": [], "last": "Seegers", "suffix": ""}, {"first": "H", "middle": [], "last": "Tichy", "suffix": ""}], "year": 1999, "venue": "", "link": null}, "BIBREF102": {"title": "with descriptions of two new species", "authors": [{"first": "Kenya", "middle": [], "last": "Tanzania", "suffix": ""}], "year": "", "venue": "Ichthyol Explor Freshwaters", "link": null}, "BIBREF103": {"title": "Aquatic hypoxia is a teratogen and affects fish embryonic development", "authors": [{"first": "Ehh", "middle": [], "last": "Shang", "suffix": ""}, {"first": "S", "middle": ["S"], "last": "Wu", "suffix": ""}], "year": 2004, "venue": "Environm Sci Technol", "link": "24841077"}, "BIBREF104": {"title": "Hypoxia affects sex differentiation and development, leading to a maledominated population in zebrafish (Daniorerio)", "authors": [{"first": "Ehh", "middle": [], "last": "Shang", "suffix": ""}, {"first": "Rmk", "middle": [], "last": "Yu", "suffix": ""}, {"first": "Rss", "middle": [], "last": "Wu", "suffix": ""}], "year": 2006, "venue": "Environm Sci Technol", "link": null}, "BIBREF105": {"title": "Constraint and cost of oxidative stress on reproduction: correlative evidence in laboratory mice and review of the literature", "authors": [{"first": "A", "middle": [], "last": "Stier", "suffix": ""}, {"first": "S", "middle": [], "last": "Reichert", "suffix": ""}, {"first": "S", "middle": [], "last": "Massemin", "suffix": ""}, {"first": "P", "middle": [], "last": "Bize", "suffix": ""}, {"first": "F", "middle": [], "last": "Criscuolo", "suffix": ""}], "year": 2012, "venue": "Front Zool", "link": "11262563"}, "BIBREF106": {"title": "The chemical composition of African lake waters", "authors": [{"first": "J", "middle": ["F"], "last": "Talling", "suffix": ""}, {"first": "I", "middle": ["B"], "last": "Talling", "suffix": ""}], "year": 1965, "venue": "Internat. Revue Geosci Hydrobiol", "link": "128414711"}, "BIBREF107": {"title": "Can environmental or occupational hazards alter sex ratio at birth? A systematic review", "authors": [{"first": "M", "middle": ["L"], "last": "Terrell", "suffix": ""}, {"first": "K", "middle": ["P"], "last": "Hartnett", "suffix": ""}, {"first": "M", "middle": [], "last": "Marcus", "suffix": ""}], "year": 2011, "venue": "Emerging Hlth threats J", "link": "386229"}, "BIBREF108": {"title": "Biomarkers of hypoxia exposure and reproductive function in Atlantic croaker: a review with some preliminary findings from the northern Gulf of Mexico hypoxic zone", "authors": [{"first": "P", "middle": [], "last": "Thomas", "suffix": ""}, {"first": "S", "middle": [], "last": "Rahman", "suffix": ""}], "year": 2009, "venue": "J Explor Mar Biol Ecol", "link": "85021256"}, "BIBREF109": {"title": "Chronic hypoxia impairs gamete maturation in Atlantic croaker induced by progestins through non-genomic mechanisms resulting in reduced reproductive success", "authors": [{"first": "P", "middle": [], "last": "Thomas", "suffix": ""}, {"first": "S", "middle": [], "last": "Rahman", "suffix": ""}], "year": 2009, "venue": "Environm Sci Technol", "link": "30417420"}, "BIBREF110": {"title": "Extensive reproductive disruption, ovarian masculinization and aromatase suppression in Atlantic croaker in the northern Gulf of Mexico hypoxic zone", "authors": [{"first": "P", "middle": [], "last": "Thomas", "suffix": ""}, {"first": "S", "middle": [], "last": "Rahman", "suffix": ""}], "year": 2011, "venue": "Proc R Soc Lond B", "link": "215550455"}, "BIBREF111": {"title": "Reproductive endocrine dysfunction in Atlantic croaker exposed to hypoxia", "authors": [{"first": "P", "middle": [], "last": "Thomas", "suffix": ""}, {"first": "M", "middle": ["S"], "last": "Rahman", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Kummer", "suffix": ""}, {"first": "S", "middle": [], "last": "Lawson", "suffix": ""}], "year": 2006, "venue": "Mar Environm Res", "link": "676855"}, "BIBREF112": {"title": "Widespread endocrine disruption and reproductive impairment in an estuarine fish population exposed to seasonal hypoxia", "authors": [{"first": "P", "middle": [], "last": "Thomas", "suffix": ""}, {"first": "S", "middle": [], "last": "Rahman", "suffix": ""}, {"first": "I", "middle": ["A"], "last": "Khan", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Kummer", "suffix": ""}], "year": 2007, "venue": "Proc R Soc Lond B", "link": "720616"}, "BIBREF113": {"title": "The Oreochromis alcalicus flock (Teleostei: Cichlidae) from lakes Natron and Magadi, Tanzania and Kenya, a model for the evolution of \"new\" species flocks in historical times?", "authors": [{"first": "H", "middle": [], "last": "Tichy", "suffix": ""}, {"first": "L", "middle": [], "last": "Seegers", "suffix": ""}], "year": 1999, "venue": "Ichthyol Explor Freshw", "link": null}, "BIBREF114": {"title": "Temperature-dependent sex determination in vertebrates", "authors": [{"first": "N", "middle": [], "last": "Valenzuela", "suffix": ""}, {"first": "V", "middle": [], "last": "Lance", "suffix": ""}], "year": 2004, "venue": "Smithsonian Books", "link": "83448966"}, "BIBREF115": {"title": "Pattern doesn't equal process: exactly when is sex environmentally determined", "authors": [{"first": "N", "middle": [], "last": "Valenzuela", "suffix": ""}, {"first": "D", "middle": ["C"], "last": "Adams", "suffix": ""}, {"first": "E", "middle": ["J"], "last": "Janzen", "suffix": ""}], "year": 2003, "venue": "", "link": null}, "BIBREF116": {"title": "The ecology of Lake Nakuru (Kenya). II. Biomass and spatial distribution of fish (Tilapia grahami Boulenger; Sarotherodon alcalicum grahami Boulenger)", "authors": [{"first": "E", "middle": [], "last": "Vareschi", "suffix": ""}], "year": 1979, "venue": "Oecologia", "link": "19307203"}, "BIBREF117": {"title": "Some speculations on the sudden occurrence of floods in the history of Lake Magadi", "authors": [{"first": "T", "middle": ["H"], "last": "White", "suffix": ""}], "year": 1953, "venue": "J East Afr Nat Hist", "link": null}, "BIBREF118": {"title": "Genetic structure of Lake Magadi tilapia populations", "authors": [{"first": "P", "middle": ["J"], "last": "Wilson", "suffix": ""}, {"first": "C", "middle": ["M"], "last": "Wood", "suffix": ""}, {"first": "J", "middle": ["N"], "last": "Maina", "suffix": ""}, {"first": "B", "middle": ["N"], "last": "White", "suffix": ""}], "year": 2000, "venue": "J Fish Biol", "link": "85276919"}, "BIBREF119": {"title": "Discordance between genetic structure and morphological, ecological, and physiological adaptation in Lake Magadi tilapia", "authors": [{"first": "P", "middle": ["J"], "last": "Wilson", "suffix": ""}, {"first": "C", "middle": ["M"], "last": "Wood", "suffix": ""}, {"first": "P", "middle": ["J"], "last": "Walsh", "suffix": ""}, {"first": "A", "middle": ["N"], "last": "Bergman", "suffix": ""}, {"first": "H", "middle": ["L"], "last": "Bergman", "suffix": ""}, {"first": "P", "middle": [], "last": "Laurent", "suffix": ""}, {"first": "B", "middle": ["N"], "last": "White", "suffix": ""}], "year": 2004, "venue": "Physiol Biochem Zool", "link": "17137400"}, "BIBREF120": {"title": "Ecological processes and the ecology of stress: the impacts of abiotic environmental factors", "authors": [{"first": "J", "middle": ["C"], "last": "Wingfield", "suffix": ""}], "year": 2013, "venue": "Funct Ecol", "link": "34898407"}, "BIBREF121": {"title": "Urea production, acid-base regulation and their interactions in the Lake Magadi tilapia, a unique teleost adapted to a highly alkaline environment", "authors": [{"first": "C", "middle": ["M"], "last": "Wood", "suffix": ""}, {"first": "H", "middle": ["L"], "last": "Bergman", "suffix": ""}, {"first": "P", "middle": [], "last": "Laurent", "suffix": ""}, {"first": "J", "middle": ["N"], "last": "Maina", "suffix": ""}, {"first": "A", "middle": [], "last": "Narahara", "suffix": ""}, {"first": "P", "middle": [], "last": "Walsh", "suffix": ""}], "year": 1994, "venue": "J Exp Biol", "link": "7587620"}, "BIBREF122": {"title": "Obligatory urea production and the cost of living in the Magadi Tilapia revealed by acclimation to reduced salinity and alkalinity", "authors": [{"first": "C", "middle": ["M"], "last": "Wood", "suffix": ""}, {"first": "P", "middle": [], "last": "Wilson", "suffix": ""}, {"first": "H", "middle": ["L"], "last": "Bergman", "suffix": ""}, {"first": "A", "middle": ["N"], "last": "Bergman", "suffix": ""}, {"first": "P", "middle": [], "last": "Laurent", "suffix": ""}, {"first": "G", "middle": [], "last": "Atiang&apos;a-Owiti", "suffix": ""}, {"first": "P", "middle": ["J"], "last": "Walsh", "suffix": ""}], "year": 2002, "venue": "Physiol Biochem Zool", "link": "26487074"}, "BIBREF123": {"title": "Rh proteins and NH4+-activated Na+-ATPase in the Magadi tilapia (Alcolapia grahami), a 100% ureotelic teleost fish", "authors": [{"first": "C", "middle": ["M"], "last": "Wood", "suffix": ""}, {"first": "C", "middle": ["M"], "last": "Nawata", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Wilson", "suffix": ""}, {"first": "P", "middle": [], "last": "Laurent", "suffix": ""}, {"first": "C", "middle": [], "last": "Chevalier", "suffix": ""}, {"first": "H", "middle": ["L"], "last": "Bergman", "suffix": ""}, {"first": "A", "middle": [], "last": "Bianchini", "suffix": ""}, {"first": "J", "middle": ["N"], "last": "Maina", "suffix": ""}, {"first": "O", "middle": ["E"], "last": "Johannsson", "suffix": ""}, {"first": "L", "middle": ["F"], "last": "Bianchini", "suffix": ""}, {"first": "G", "middle": ["D"], "last": "Kavembe", "suffix": ""}, {"first": "M", "middle": ["B"], "last": "Papah", "suffix": ""}, {"first": "R", "middle": ["O"], "last": "Ojoo", "suffix": ""}], "year": 2013, "venue": "J Exp Biol", "link": "9901443"}, "BIBREF124": {"title": "Mammalian metabolic rates in the hottest fish on earth", "authors": [{"first": "C", "middle": ["M"], "last": "Wood", "suffix": ""}, {"first": "K", "middle": ["V"], "last": "Brix", "suffix": ""}, {"first": "De", "middle": [], "last": "Boeck", "suffix": ""}, {"first": "D", "middle": [], "last": "Bergman", "suffix": ""}, {"first": "H", "middle": ["L"], "last": "Bianchini", "suffix": ""}, {"first": "A", "middle": [], "last": "Bianchini", "suffix": ""}, {"first": "L", "middle": ["F"], "last": "Maina", "suffix": ""}, {"first": "J", "middle": ["N"], "last": "Johannsson", "suffix": ""}, {"first": "O", "middle": ["E"], "last": "Kavembe", "suffix": ""}, {"first": "G", "middle": ["D"], "last": "Papah", "suffix": ""}, {"first": "M", "middle": ["B"], "last": "Kisipan", "suffix": ""}, {"first": "M", "middle": ["L"], "last": "Ojoo", "suffix": ""}, {"first": "R", "middle": ["O"], "last": "", "suffix": ""}], "year": 2016, "venue": "", "link": "619740"}, "BIBREF125": {"title": "Reflections on the evolution of piscine viviparity", "authors": [{"first": "Rj ;", "middle": [], "last": "Wootton", "suffix": ""}, {"first": "", "middle": [], "last": "Chapman", "suffix": ""}, {"first": "London", "middle": [], "last": "Hall", "suffix": ""}, {"first": "J", "middle": ["P"], "last": "Wourms", "suffix": ""}, {"first": "J", "middle": [], "last": "Lombardi", "suffix": ""}], "year": 1992, "venue": "Amer Zool", "link": null}, "BIBREF126": {"title": "Hypoxia: from the molecular responses to ecosystem responses", "authors": [{"first": "Rss", "middle": [], "last": "Wu", "suffix": ""}], "year": 2002, "venue": "Mar Poll Bull", "link": null}, "BIBREF127": {"title": "Effects on fish reproduction and development", "authors": [{"first": "Rss", "middle": [], "last": "Wu", "suffix": ""}], "year": 2009, "venue": "Hypoxia in fishes", "link": null}, "BIBREF128": {"title": "Hypoxia: new insights on an old pressing environmental problem", "authors": [{"first": "Rss", "middle": [], "last": "Wu", "suffix": ""}], "year": 2010, "venue": "", "link": null}, "BIBREF129": {"title": "Aquatic hypoxia is an endocrine disruptor and impairs fish reproduction", "authors": [{"first": "Rss", "middle": [], "last": "Wu", "suffix": ""}, {"first": "B", "middle": ["S"], "last": "Zhou", "suffix": ""}, {"first": "D", "middle": ["J"], "last": "Randall", "suffix": ""}, {"first": "Wys", "middle": [], "last": "Norman", "suffix": ""}, {"first": "Pks", "middle": [], "last": "Lam", "suffix": ""}], "year": 2003, "venue": "Environ Sci Technol", "link": "85138394"}, "BIBREF130": {"title": "The protozoa of soda lakes in East Africa", "authors": [{"first": "A", "middle": ["W"], "last": "Yasindi", "suffix": ""}, {"first": "W", "middle": ["D"], "last": "Taylor", "suffix": ""}], "year": 2016, "venue": "", "link": "88823160"}, "BIBREF131": {"title": "Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations", "authors": [], "year": "", "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "199668877", "_pdf_hash": "0183298ba8922c77a6ae7dcf5e8eed19b0a7b0fc", "abstract": [], "body_text": [{"section": "Introduction", "text": "Open clusters (OCs) are valuable objects for revealing stellar evolution and the structure, chemical and dynamical evolution of the Galactic disk. Be 8 has been studied by Hasegawa et al. (2004) [1] from CCD BVI photometry and by Bukowiecki et al. (2011) [2] from 2MASS JHK s photometry. Be 8 is located close to a portion of the Perseus spiral arm in the second quadrant of the Galaxy (Figure 1 ), according to its equatorial and Galactic coordinates (WEBDA) [3] (rows 1-4 of Table 1 ). The main aim of this paper is to present astrophysical parameters such as reddening, distance and age of Be 8 from four colour indices, (B \u2212 V ) , (V \u2212 I) , (R \u2212 I) and (G BP -G RP ) obtained from deep CCD U BV RI and Gaia photometries. This kind of data is also valuable for classifying early-type stars, Blue Stragglers (BS) and Red Giant/Red Clump (RG/RC) candidates in the colour magnitude diagrams (CMDs), and thus probable candidates are proposed for future spectroscopic observations. We used Gaia DR2 astrometric data (proper motion components and parallaxes) [4, 5] and Gaia DR2 photometry (G -G BP G RP ) for determining the probable members of Be 8. With the Gaia DR2 astrometric data, a membership method was done in the literature [6] [7] [8] . The membership determinations of previous works have been based on the proper motions of Roeser et al. (2010) [9] in combination with the 2MASS JHK s photometry of Skrutskie et al. (2006) [10] . Cantat-Gaudin et al. (2018) [11] state that the proper motion uncertainties of UCAC4 fall in the range of 1-10 mas yr \u22121 [9, 12] . According to Lindegren et al. (2018) [4] and Brown et al.", "cite_spans": [{"start": 172, "end": 194, "text": "Hasegawa et al. (2004)", "ref_id": "BIBREF0"}, {"start": 195, "end": 198, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 230, "end": 254, "text": "Bukowiecki et al. (2011)", "ref_id": "BIBREF1"}, {"start": 255, "end": 258, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 460, "end": 463, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 1056, "end": 1059, "text": "[4,", "ref_id": "BIBREF3"}, {"start": 1060, "end": 1062, "text": "5]", "ref_id": "BIBREF4"}, {"start": 1232, "end": 1235, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 1236, "end": 1239, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 1240, "end": 1243, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 1335, "end": 1355, "text": "Roeser et al. (2010)", "ref_id": "BIBREF8"}, {"start": 1356, "end": 1359, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 1434, "end": 1438, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 1469, "end": 1473, "text": "[11]", "ref_id": "BIBREF11"}, {"start": 1562, "end": 1565, "text": "[9,", "ref_id": "BIBREF8"}, {"start": 1566, "end": 1569, "text": "12]", "ref_id": "BIBREF12"}, {"start": 1585, "end": 1608, "text": "Lindegren et al. (2018)", "ref_id": "BIBREF3"}, {"start": 1609, "end": 1612, "text": "[4]", "ref_id": "BIBREF3"}], "ref_spans": [{"start": 386, "end": 395, "text": "(Figure 1", "ref_id": "FIGREF0"}, {"start": 477, "end": 484, "text": "Table 1", "ref_id": "TABREF0"}]}, {"section": "Introduction", "text": "(2018) [5] , the mean parallax errors of Gaia DR2 catalogue fall in the range 0.02 -0.04 mas for G < 15 and 0.1 The sun is at R = 8.2 \u00b1 0.1 kpc [34] . The image is adapted from the image 1 credit by Robert Hurt, IPAC; Bill Saxton, NRAO/AUI/NSF. This paper is organised as follows: Section 2 describes the observation and reduction techniques. Its dimensions are given in Section 3. Section 4 is devoted for the classification of cluster members. Section 5 describes the derivation of the astrophysical parameters. The classification of BS and RG/RC candidates and its morphological age determination are presented in Section 6. Section 7 focuses into its kinematics and orbital parameters. Discussions and Conclusions are given in Section 8.", "cite_spans": [{"start": 7, "end": 10, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 144, "end": 148, "text": "[34]", "ref_id": "BIBREF34"}], "ref_spans": []}, {"section": "Observations and Reduction techniques", "text": "Observations of Be 8 were carried out, during the photometric night of December 3 2015, with the 0.90m (f/8 Ritchey-Chr\u00e9tien) telescope at Sierra Nevada Observatory (Granada, Spain). A filter wheel with U BV RI filters and a scientific grade Marconi-EEV CCD42-40 were employed. The CCD is a 2048x2048 13.5-\u00b5m square-pixel detector with a nominal gain of 1.35 e \u2212 /ADU and a readout noise of 7.14 e \u2212 at the 2\u00d72 binning employed.", "cite_spans": [], "ref_spans": []}, {"section": "Observations and Reduction techniques", "text": "Along with the optics, it covers a field of view of 13.2 \u00d713.2 arcmin 2 . Apart form Be 8, other open clusters and some Landolt standard fields [13] were observed. Flat fields were also acquired at the beginning of the night and many bias frames were also taken.", "cite_spans": [{"start": 144, "end": 148, "text": "[13]", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "Observations and Reduction techniques", "text": "The data reduction was carried out by R. Michel 2 using the IRAF 3 package and together with some home-made auxiliary Fortran programs and Awk scripts. All the images were bias subtracted and flat-field corrected (CCDRED). Cosmic rays were removed with the L.A. Cosmic 4 script van Dokkum (2001) [14] .", "cite_spans": [{"start": 296, "end": 300, "text": "[14]", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "Observations and Reduction techniques", "text": "The standard magnitudes were taken from the catalogue by Landolt (2009) [13] and supplemented with the secondary photometric standards by Cutri et al. (2013) [15] . As a result, the transformation coefficients were found (FITPARAMS). For magnitude estimation, transformation equations used are", "cite_spans": [{"start": 72, "end": 76, "text": "[13]", "ref_id": "BIBREF13"}, {"start": 138, "end": 157, "text": "Cutri et al. (2013)", "ref_id": "BIBREF15"}, {"start": 158, "end": 162, "text": "[15]", "ref_id": "BIBREF15"}], "ref_spans": []}, {"section": "Observations and Reduction techniques", "text": "where m \u03bb , k 1 , k 2 , C and X are observed instrumental magnitude, primary and secondary extinction coefficients, colour index and air mass, respectively. M \u03bb , \u03b7 \u03bb , \u03b6 \u03bb are standard magnitude, atmospheric extinctioncorrected instrumental magnitude, transformation coefficient and photometric zero point, respectively. The other details of data reduction can be found in the papers of Akkaya et al. (2010) [16] and Akkaya et al. (2015) [17]. Air-mass range and exposure times in each band during the observations are given in rows 5-10 of Table  1 . Figure 2 presents the finding chart Figure 3 . Its mean photometric errors are also listed in Table 2 . Our inspection of Figure  3 and Table 2 ", "cite_spans": [{"start": 409, "end": 413, "text": "[16]", "ref_id": "BIBREF16"}], "ref_spans": [{"start": 542, "end": 550, "text": "Table  1", "ref_id": "TABREF0"}, {"start": 553, "end": 561, "text": "Figure 2", "ref_id": "FIGREF1"}, {"start": 589, "end": 597, "text": "Figure 3", "ref_id": "FIGREF3"}, {"start": 647, "end": 654, "text": "Table 2", "ref_id": "TABREF1"}, {"start": 675, "end": 684, "text": "Figure  3", "ref_id": "FIGREF3"}, {"start": 689, "end": 696, "text": "Table 2", "ref_id": "TABREF1"}]}, {"section": "Dimensions of Be 8", "text": "The stellar radial density profile (RDP) of Be 8 ( Figure 4 ) has been built from Gaia DR2 photometry for the equatorial coordinates (Table 1 ). Its RDP have been constructed by counting stars in concentric rings of increasing width with distance to its centre. We choose \u2206R = 15.0 as the wide external ring of the stellar comparison field. As emphasised by Bonatto and Bica (2007) [18] , the number and width of rings were optimised so that the resulting RDP had adequate spatial resolution with moderate 1 \u03c3 Poisson errors. The solid curve ( Figure 4 ) denotes the fitted King's profile [19] . Here we adopt the two-parameter function, ", "cite_spans": [{"start": 358, "end": 381, "text": "Bonatto and Bica (2007)", "ref_id": "BIBREF18"}, {"start": 382, "end": 386, "text": "[18]", "ref_id": "BIBREF18"}, {"start": 589, "end": 593, "text": "[19]", "ref_id": "BIBREF19"}], "ref_spans": [{"start": 51, "end": 59, "text": "Figure 4", "ref_id": "FIGREF6"}, {"start": 133, "end": 141, "text": "(Table 1", "ref_id": "TABREF0"}, {"start": 544, "end": 552, "text": "Figure 4", "ref_id": "FIGREF6"}]}, {"section": "Classification of cluster members", "text": "For the membership determination of Be 8, our CCD U BV RI photometric data have been matched with Gaia DR2 astrometric (proper motion components and parallaxes) (\u00b5 \u03b1 , \u00b5 \u03b4 and ) and Gaia DR2 photometric data.", "cite_spans": [], "ref_spans": []}, {"section": "Classification of cluster members", "text": "The \u00b5 \u03b1 versus \u00b5 \u03b4 ( mas yr \u22121 ) for all stars of Be 8 (filled dots) is shown in Figure 5 . Grey dots denote the field stars inside R = 15 .0 arcmin centred on Be 8. We have applied Gaussian Mixture method for all stars of Be 8. By applying Gaussian Mixture Model (GMM) [20] to the stars in the cluster region of Be 8, we have determined the membership probability ( P ). The model considers that the distribution of proper motions of the stars in a cluster's region can be represented by two elliptical bivariate Gaussians, by following Wu et al. [8] . P is defined \u03a6 c / \u03a6 . Here \u03a6 = \u03a6 c + \u03a6 f is the total probability distribution. c and f subscripts for cluster and field parameters, respectively. The used parameters for estimation of \u03a6 c and \u03a6 f are \u00b5 \u03b1 , \u00b5 \u03b4 , , \u03c3 \u00b5\u03b1 , \u03c3 \u00b5\u03b4 , \u03c3 . The averages and their uncertainties of proper motion components and parallaxes in the distributions of the cluster and field regions in Figure 5 are listed in Table 3 . Figure 6 (a) shows the membership probability ( P ) histogram, which provides a very clear separation between cluster and field stars. The number of stars with membership probability which is greater than 90 % is 273. These likely members have been considered for deriving astrophysical parameters of Be 8. From the relation of the membership probability (P ) versus G mag ( Figure 6 (b)), high membership probability appears to extend down to G \u223c 21 mag. Table 3 . The medians and their uncertainties of proper motion components ( \u00b5\u03b1 , \u00b5 \u03b4 ) ( mas yr \u22121 ) and parallaxes ( ) (mas) from the distributions of the cluster and field regions on Figure 5 . ", "cite_spans": [{"start": 270, "end": 274, "text": "[20]", "ref_id": "BIBREF20"}, {"start": 548, "end": 551, "text": "[8]", "ref_id": "BIBREF7"}], "ref_spans": [{"start": 81, "end": 89, "text": "Figure 5", "ref_id": "FIGREF7"}, {"start": 925, "end": 933, "text": "Figure 5", "ref_id": "FIGREF7"}, {"start": 958, "end": 966, "text": "Figure 6", "ref_id": "FIGREF9"}, {"start": 1333, "end": 1341, "text": "Figure 6", "ref_id": "FIGREF9"}, {"start": 1599, "end": 1607, "text": "Figure 5", "ref_id": "FIGREF7"}]}, {"section": "Astrophysical parameters of Be 8 open cluster", "text": "The two colour (U \u2212 B) -(B \u2212 V ) (CC) diagram of the 17 probable members for Be 8 is displayed in Figure 7 .", "cite_spans": [], "ref_spans": [{"start": 98, "end": 106, "text": "Figure 7", "ref_id": "FIGREF10"}]}, {"section": "Astrophysical parameters of Be 8 open cluster", "text": "The blue line denotes the reddened main sequence for dwarfs and red giants of Schmidt-Kaler (1982)(SK82) [22] . It appears from Since these issues make it difficult to determine its photometric metal abundance and reddening from CC diagram, we have derived the reddenings, distance moduli and ages of Be 8 from the PARSEC isochrones of Bressan et al. (2012) [24] on the CMDs for four colour indices. The appropriate PARSEC isochrones for different heavy element abundance mass fractions (Z = +0.015, +0.004, +0.008) (left panel of Figure 8 ) and reddenings have been fitted on the CMDs. The 2.8 Gyr PARSEC isochrones for Z = +0.008 abundance gave us a good fit solution on the CMDs: (Figs. 8-9 ). The equation (Figs. 8 -9 ). Table 5 . For five likely members with Gaia DR2 radial velocity data ( V rad ) km s \u22121 ) (Col. 8), Gaia DR2 proper motion components mas yr \u22121 (Cols. 6 -7) and parallaxes (mas) (Col. 9). Their equatorial coordinates (J2000) (Cols. 2 -3) and V and (B \u2212 V ) (Cols. 4 -5) . Probability membership value (last column). ", "cite_spans": [{"start": 105, "end": 109, "text": "[22]", "ref_id": "BIBREF22"}, {"start": 336, "end": 357, "text": "Bressan et al. (2012)", "ref_id": "BIBREF24"}, {"start": 358, "end": 362, "text": "[24]", "ref_id": "BIBREF24"}], "ref_spans": [{"start": 531, "end": 539, "text": "Figure 8", "ref_id": "FIGREF13"}, {"start": 683, "end": 693, "text": "(Figs. 8-9", "ref_id": "FIGREF13"}, {"start": 710, "end": 721, "text": "(Figs. 8 -9", "ref_id": "FIGREF13"}]}, {"section": "Kinematics and Orbital parameters of Be 8", "text": "Five likely members with Gaia DR2 radial velocities (Table 5) Table 6 .", "cite_spans": [], "ref_spans": [{"start": 62, "end": 69, "text": "Table 6", "ref_id": "TABREF6"}]}, {"section": "Kinematics and Orbital parameters of Be 8", "text": "By utilising the \"MWPotential2014\" code in the galpy-code library 1 written by Bovy (2015) [37] , periand apo-galactic distances (R min , R max ) (kpc) and the maximum height distance (z max ) (kpc) have been obtained. The orbital eccentricity (ecc) is estimated via the relation e = (R max \u2212 R min )/(R max + R min ) . Mean orbital radius ( R m ) (kpc) is given as the mean of R min and R max distances. Each member's orbit has been integrated for 2.8 Gyr (Table 4) within the Galactic potential. The galactic potential is a sum of the Galactic components, as given in the paper of Bovy (2015) [37] .", "cite_spans": [{"start": 91, "end": 95, "text": "[37]", "ref_id": "BIBREF37"}, {"start": 595, "end": 599, "text": "[37]", "ref_id": "BIBREF37"}], "ref_spans": [{"start": 457, "end": 466, "text": "(Table 4)", "ref_id": "TABREF4"}]}, {"section": "Kinematics and Orbital parameters of Be 8", "text": "The orbital angular momentum components J x , J y , J z and J \u22a5 (kpc km s \u22121 ) for five members are calculated from the equations of Kepley et al. (2007) [36] . These orbital and angular momentum parameters ( J z , J \u22a5 ) are given in Cols. 6-12 of Table 6 . The total angular momentum J \u22a5 is defined as J \u22a5 = (J to z max = 1.27 kpc . According to Figure 13 of Carney et al. (1996) [38] , thin and thick disk stars have the (Table 4) . A global systematic offset of Gaia DR2 parallaxes is \u2206 = \u22120.029 mas in terms of an inertial reference frame, derived by Lindegren et al. (2018) [4] . Recent values for the zero point shift of parallax have been found as \u2206 = \u22120.045 \u00b1 0.009 mas [39] , \u2206 = \u22120.053 \u00b1 0.003 mas [40] , and \u2206 = \u22120.046 \u00b1 0.013 mas [41] , respectively.A correction of 0.005 mas to the median value of our median parallax gives a closer distance with a difference of 66 pc for Be 8. [42] .", "cite_spans": [{"start": 133, "end": 153, "text": "Kepley et al. (2007)", "ref_id": "BIBREF36"}, {"start": 154, "end": 158, "text": "[36]", "ref_id": "BIBREF36"}, {"start": 360, "end": 380, "text": "Carney et al. (1996)", "ref_id": "BIBREF38"}, {"start": 381, "end": 385, "text": "[38]", "ref_id": "BIBREF38"}, {"start": 555, "end": 578, "text": "Lindegren et al. (2018)", "ref_id": "BIBREF3"}, {"start": 579, "end": 582, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 678, "end": 682, "text": "[39]", "ref_id": "BIBREF39"}, {"start": 708, "end": 712, "text": "[40]", "ref_id": "BIBREF40"}, {"start": 742, "end": 746, "text": "[41]", "ref_id": "BIBREF41"}, {"start": 892, "end": 896, "text": "[42]", "ref_id": "BIBREF42"}], "ref_spans": [{"start": 248, "end": 255, "text": "Table 6", "ref_id": "TABREF6"}, {"start": 347, "end": 356, "text": "Figure 13", "ref_id": "FIGREF0"}, {"start": 423, "end": 432, "text": "(Table 4)", "ref_id": "TABREF4"}]}, {"section": "Discussions and Conclusions", "text": "Two BS candidates reside in core radius of 1.8 of Be 8 ( Figure 10 ). BS stars potentially locate in the inner regions of stellar clusters [43] . According to Ferraro (2016) [44] , their formation ways are explained: mass transfer in binary systems [45] due to the merging of the two stars and stellar collisions [46] .", "cite_spans": [{"start": 139, "end": 143, "text": "[43]", "ref_id": "BIBREF43"}, {"start": 159, "end": 173, "text": "Ferraro (2016)", "ref_id": "BIBREF44"}, {"start": 174, "end": 178, "text": "[44]", "ref_id": "BIBREF44"}, {"start": 249, "end": 253, "text": "[45]", "ref_id": "BIBREF45"}, {"start": 313, "end": 317, "text": "[46]", "ref_id": "BIBREF46"}], "ref_spans": [{"start": 57, "end": 66, "text": "Figure 10", "ref_id": "FIGREF0"}]}, {"section": "Discussions and Conclusions", "text": "It is surprising to find Be 8 with [M/H] = \u22120.27 (close to solar metallicity) at such large galactic radius (R = 10.57 kpc). However, the orbits in Fig.11 (a) and (b) show that the cluster passed a part of its time at galactocentric radius, R = 6 \u2212 7 kpc, and then possibly it was born at that radius, which would explain the metallicity. According to Figure .57 kpc reside in a region of R > 9 kpc (co-rotation gap at 9 kpc). In the sense it may have been originating from different galactic radius or different star formation region [47] .", "cite_spans": [{"start": 535, "end": 539, "text": "[47]", "ref_id": "BIBREF47"}], "ref_spans": [{"start": 148, "end": 154, "text": "Fig.11", "ref_id": "FIGREF0"}]}], "bib_entries": {"BIBREF0": {"title": "New Photometric Data of Old Open Clusters in the Anti-Galactic Center Region", "authors": [{"first": "T", "middle": [], "last": "Hasegawa", "suffix": ""}, {"first": "H", "middle": ["L"], "last": "Malasan", "suffix": ""}, {"first": "K", "middle": ["H"], "last": "Hideyo", "suffix": ""}, {"first": "H", "middle": [], "last": "Obayashi", "suffix": ""}, {"first": "T", "middle": [], "last": "Kurabayashi", "suffix": ""}], "year": 2004, "venue": "Pub. Astron. Soc. Japan", "link": "121285706"}, "BIBREF1": {"title": "Open Clusters in 2MASS Photometry. I. Structural and Basic Astrophysical Parameters", "authors": [{"first": "L", "middle": [], "last": "Bukowiecki", "suffix": ""}, {"first": "G", "middle": [], "last": "Maciejewski", "suffix": ""}, {"first": "P", "middle": [], "last": "Konorski", "suffix": ""}, {"first": "A", "middle": [], "last": "Strobel", "suffix": ""}], "year": 2011, "venue": "Acta Astronomica", "link": null}, "BIBREF2": {"title": "The database for stars in open clusters. II. A progress report on the introduction of new data", "authors": [{"first": "J", "middle": ["C"], "last": "Mermilliod", "suffix": ""}], "year": 1992, "venue": "Bull. Inform. CDS", "link": "59823143"}, "BIBREF3": {"title": "Gaia Data Release 2. The astrometric solution", "authors": [{"first": "L", "middle": [], "last": "Lindegren", "suffix": ""}, {"first": "J", "middle": [], "last": "Hernandez", "suffix": ""}, {"first": "A", "middle": [], "last": "Bombrun", "suffix": ""}, {"first": "S", "middle": [], "last": "Klioner", "suffix": ""}, {"first": "U", "middle": [], "last": "Bastian", "suffix": ""}], "year": 2018, "venue": "Astron. Astrophys", "link": "54497421"}, "BIBREF4": {"title": "Gaia Data Release 2. Summary of the contents and survey properties", "authors": [{"first": "Aga", "middle": [], "last": "Brown", "suffix": ""}, {"first": "A", "middle": [], "last": "Vallenari", "suffix": ""}, {"first": "T", "middle": [], "last": "Prusti", "suffix": ""}, {"first": "Jhj", "middle": [], "last": "De Bruijne", "suffix": ""}, {"first": "C", "middle": [], "last": "Babusiaux", "suffix": ""}], "year": 2018, "venue": "Astron. Astrophys", "link": "49211658"}, "BIBREF5": {"title": "Determination of proper motions and membership of the open clusters NGC 1817 and NGC 1807", "authors": [{"first": "L", "middle": [], "last": "Balaguer-Nunez", "suffix": ""}, {"first": "K", "middle": ["P"], "last": "Tian", "suffix": ""}, {"first": "J", "middle": ["L"], "last": "Zhao", "suffix": ""}], "year": 1998, "venue": "Astron. Astrophys. Suppl", "link": "55410925"}, "BIBREF6": {"title": "Proper motions and membership probabilities of stars in the region of globular cluster NGC 6809", "authors": [{"first": "D", "middle": ["P"], "last": "Sariya", "suffix": ""}, {"first": "Rks", "middle": [], "last": "Yadav", "suffix": ""}, {"first": "A", "middle": [], "last": "Bellini", "suffix": ""}], "year": 2012, "venue": "Astron. Astrophys", "link": "55667793"}, "BIBREF7": {"title": "Astrometric and photometric study of Dias 4, Dias 6, and other five open clusters using ground-based and Gaia DR2 data", "authors": [{"first": "W", "middle": ["S"], "last": "Dias", "suffix": ""}, {"first": "H", "middle": [], "last": "Monteiro", "suffix": ""}, {"first": "Jrd", "middle": [], "last": "Lepine", "suffix": ""}, {"first": "R", "middle": [], "last": "Prates", "suffix": ""}, {"first": "C", "middle": ["D"], "last": "Gneiding", "suffix": ""}], "year": 2018, "venue": "Mon. Not. Roy. Astron. Soc", "link": "119222241"}, "BIBREF8": {"title": "The PPMXL Catalog of Positions and Proper Motions on the ICRS. Combining USNO-B1.0 and the Two Micron All Sky Survey (2MASS)", "authors": [{"first": "S", "middle": [], "last": "Roeser", "suffix": ""}, {"first": "M", "middle": [], "last": "Demleitner", "suffix": ""}, {"first": "E", "middle": [], "last": "Schilbach", "suffix": ""}], "year": 2010, "venue": "Astron. J", "link": null}, "BIBREF9": {"title": "The Two Micron All Sky Survey (2MASS)", "authors": [{"first": "M", "middle": ["F"], "last": "Skrutskie", "suffix": ""}, {"first": "R", "middle": [], "last": "Cutri", "suffix": ""}, {"first": "R", "middle": [], "last": "Stiening", "suffix": ""}, {"first": "M", "middle": ["D"], "last": "Weinberg", "suffix": ""}, {"first": "S", "middle": ["E"], "last": "Schneider", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF11": {"title": "A Gaia DR2 view of the Open Cluster population in the Milky Way", "authors": [{"first": "T", "middle": [], "last": "Cantat-Gaudin", "suffix": ""}, {"first": "C", "middle": [], "last": "Jordi", "suffix": ""}, {"first": "A", "middle": [], "last": "Vallenari", "suffix": ""}, {"first": "A", "middle": [], "last": "Bragaglia", "suffix": ""}, {"first": "L", "middle": [], "last": "Balaguer-Nunez", "suffix": ""}], "year": 2018, "venue": "Astron. Astrophys", "link": "56245426"}, "BIBREF12": {"title": "The Fourth US Naval Observatory CCD Astrograph Catalog (UCAC4)", "authors": [{"first": "N", "middle": [], "last": "Zacharias", "suffix": ""}, {"first": "C", "middle": ["T"], "last": "Finch", "suffix": ""}, {"first": "T", "middle": ["M"], "last": "Girard", "suffix": ""}, {"first": "A", "middle": [], "last": "Henden", "suffix": ""}, {"first": "J", "middle": ["L"], "last": "Bartlett", "suffix": ""}], "year": 2013, "venue": "Astron. J", "link": "119299381"}, "BIBREF13": {"title": "UBVRI Photometric Standard Stars Around the Celestial Equator: Updates and Additions", "authors": [{"first": "A", "middle": ["U"], "last": "Landolt", "suffix": ""}], "year": 2009, "venue": "Astron. J", "link": "118627330"}, "BIBREF14": {"title": "Cosmic-Ray Rejection by Laplacian Edge Detection", "authors": [{"first": "P", "middle": ["G"], "last": "Van Dokkum", "suffix": ""}], "year": 2001, "venue": "Pub. Astron. Soc. Pac", "link": "31868082"}, "BIBREF15": {"title": "VizieR Online Data Catalog: AllWISE Data Release (Cutri+ 2013). VizieR On-line Data Catalog: II/328", "authors": [{"first": "R", "middle": ["M"], "last": "Cutri", "suffix": ""}, {"first": "E", "middle": ["L"], "last": "Wright", "suffix": ""}, {"first": "T", "middle": [], "last": "Conrow", "suffix": ""}, {"first": "J", "middle": ["W"], "last": "Fowler", "suffix": ""}, {"first": "Prm", "middle": [], "last": "Eisenhardt", "suffix": ""}], "year": 2013, "venue": "", "link": null}, "BIBREF16": {"title": "CCD UBVRI Photometry of the Galactic open clusters: Be 89, Ru 135, and Be 10", "authors": [{"first": "", "middle": [], "last": "Akkayai", "suffix": ""}, {"first": "W", "middle": ["J"], "last": "Schuster", "suffix": ""}, {"first": "R", "middle": [], "last": "Michel", "suffix": ""}, {"first": "-K C", "middle": [], "last": "Chavarr\u00eda", "suffix": ""}, {"first": "A", "middle": [], "last": "Moitinho", "suffix": ""}], "year": 2010, "venue": "Rev. Mex. Astron. Astrofis", "link": "118578066"}, "BIBREF17": {"title": "RI)(C) photometry of twenty open clusters", "authors": [{"first": "Akkaya", "middle": [], "last": "Oralhan", "suffix": ""}, {"first": "I", "middle": [], "last": "Karata\u015f", "suffix": ""}, {"first": "Y", "middle": [], "last": "Schuster", "suffix": ""}, {"first": "W", "middle": ["J"], "last": "Michel", "suffix": ""}, {"first": "R", "middle": [], "last": "Chavarr\u00eda", "suffix": ""}, {"first": "-K C. Ccd", "middle": [], "last": "Ubv", "suffix": ""}], "year": 2015, "venue": "New Astronomy", "link": null}, "BIBREF18": {"title": "Old open clusters in the inner Galaxy: FSR1744, FSR89 and FSR31", "authors": [{"first": "C", "middle": ["H"], "last": "Bonatto", "suffix": ""}, {"first": "E", "middle": [], "last": "Bica", "suffix": ""}], "year": 2007, "venue": "Astron. Astrophys", "link": "15532262"}, "BIBREF19": {"title": "The structure of star clusters. III. Some simple dynamical models", "authors": [{"first": "I", "middle": ["R"], "last": "King", "suffix": ""}], "year": 1966, "venue": "Astron. J", "link": null}, "BIBREF20": {"title": "Scikit-learn: Machine Learning in Python", "authors": [{"first": "F", "middle": [], "last": "Pedregosa", "suffix": ""}, {"first": "G", "middle": [], "last": "Varoquaux", "suffix": ""}, {"first": "A", "middle": [], "last": "Gramfort", "suffix": ""}, {"first": "V", "middle": [], "last": "Michel", "suffix": ""}, {"first": "B", "middle": [], "last": "Thirion", "suffix": ""}], "year": 2011, "venue": "The Journal of Machine Learning Research", "link": "10659969"}, "BIBREF21": {"title": "Determination of proper motions and membership of the open star cluster NGC 2548", "authors": [{"first": "Z", "middle": ["Y"], "last": "Wu", "suffix": ""}, {"first": "K", "middle": ["P"], "last": "Tian", "suffix": ""}, {"first": "L", "middle": [], "last": "Balaguer-Nunez", "suffix": ""}, {"first": "C", "middle": [], "last": "Jordi", "suffix": ""}, {"first": "J", "middle": ["L"], "last": "Zhao", "suffix": ""}], "year": 2002, "venue": "Astron. Astrophys", "link": "17818038"}, "BIBREF22": {"title": "Landolt-Bornstein, Numerical Data and Functional Relationships in Science and Technology", "authors": [{"first": "", "middle": [], "last": "Schmidt-Kaler", "suffix": ""}, {"first": "", "middle": [], "last": "Th", "suffix": ""}], "year": 1982, "venue": "", "link": "121183986"}, "BIBREF23": {"title": "Metallicity and absolute magnitude calibrations for UBV photometry", "authors": [{"first": "Y", "middle": [], "last": "Karata\u015f", "suffix": ""}, {"first": "W", "middle": ["J"], "last": "Schuster", "suffix": ""}], "year": 2006, "venue": "Mon. Not. Roy. Astron. Soc", "link": "123405265"}, "BIBREF24": {"title": "PARSEC: stellar tracks and isochrones with the PAdova and TRieste Stellar Evolution Code", "authors": [{"first": "A", "middle": [], "last": "Bressan", "suffix": ""}, {"first": "P", "middle": [], "last": "Marigo", "suffix": ""}, {"first": "L", "middle": [], "last": "Girardi", "suffix": ""}, {"first": "B", "middle": [], "last": "Salasnich", "suffix": ""}, {"first": "Dal", "middle": [], "last": "Cero", "suffix": ""}, {"first": "C", "middle": [], "last": "", "suffix": ""}], "year": 2012, "venue": "Mon. Not. Roy. Astron. Soc", "link": "118303254"}, "BIBREF25": {"title": "A dynamical evolution study of 40 2MASS open clusters", "authors": [{"first": "O", "middle": [], "last": "G\u00fcne\u015f", "suffix": ""}, {"first": "Y", "middle": [], "last": "Karata\u015f", "suffix": ""}, {"first": "C", "middle": [], "last": "Bonatto", "suffix": ""}], "year": 2017, "venue": "Astron. Nachr", "link": "118733100"}, "BIBREF26": {"title": "Reddenings of Cepheids using BVI photometry", "authors": [{"first": "J", "middle": ["F"], "last": "Dean", "suffix": ""}, {"first": "P", "middle": ["R"], "last": "Warren", "suffix": ""}, {"first": "Awj", "middle": [], "last": "Cousins", "suffix": ""}], "year": 1978, "venue": "Mon. Not. Roy. Astron. Soc", "link": "120102257"}, "BIBREF27": {"title": "Interstellar dust and extinction", "authors": [{"first": "J", "middle": [], "last": "Mathis", "suffix": ""}], "year": 1990, "venue": "Annu. Rev. Astron. Astrophys", "link": "121963078"}, "BIBREF29": {"title": "The chemical composition of the oldest nearby open cluster Ruprecht 147", "authors": [{"first": "A", "middle": [], "last": "Bragaglia", "suffix": ""}, {"first": "X", "middle": [], "last": "Fu", "suffix": ""}, {"first": "A", "middle": [], "last": "Mucciarelli", "suffix": ""}, {"first": "G", "middle": [], "last": "Andreuzzi", "suffix": ""}, {"first": "P", "middle": [], "last": "Donati", "suffix": ""}], "year": 2018, "venue": "Astron. Astrophys", "link": "118978490"}, "BIBREF30": {"title": "Development of the Galactic Disk: A Search for the Oldest Open Cluster", "authors": [{"first": "R", "middle": ["L"], "last": "Phelps", "suffix": ""}, {"first": "K", "middle": ["A"], "last": "Janes", "suffix": ""}, {"first": "K", "middle": ["A"], "last": "Montgomery", "suffix": ""}], "year": 1994, "venue": "Astron. J", "link": "121870767"}, "BIBREF31": {"title": "The age of the oldest Open Clusters", "authors": [{"first": "M", "middle": [], "last": "Salaris", "suffix": ""}, {"first": "A", "middle": [], "last": "Weiss", "suffix": ""}, {"first": "S", "middle": ["M"], "last": "Percival", "suffix": ""}], "year": 2004, "venue": "Astron. Astrophys", "link": "12967789"}, "BIBREF32": {"title": "Calculating galactic space velocities and their uncertainties, with an application to the Ursa Major group", "authors": [{"first": "Drh", "middle": [], "last": "Johnson", "suffix": ""}, {"first": "D", "middle": ["R"], "last": "Soderblom", "suffix": ""}], "year": 1987, "venue": "Astron. J", "link": "120758938"}, "BIBREF33": {"title": "Local Kinematics and the Local Standard of Rest", "authors": [{"first": "R", "middle": [], "last": "Sch\u00f6nrich", "suffix": ""}, {"first": "J", "middle": [], "last": "Binney", "suffix": ""}, {"first": "W", "middle": [], "last": "Dehnen", "suffix": ""}], "year": 2010, "venue": "Mon. Not. Roy. Astron. Soc", "link": "118697588"}, "BIBREF34": {"title": "The Galaxy in Context: Structural, Kinematic and Integrated Properties", "authors": [{"first": "J", "middle": [], "last": "Bland-Hawthorn", "suffix": ""}, {"first": "Gerhard", "middle": ["O"], "last": "", "suffix": ""}], "year": 2016, "venue": "Annu. Rev. Astron. Astrophys", "link": "53649594"}, "BIBREF35": {"title": "The Bar and Spiral Structure Legacy (BeSSeL) survey: Mapping the Milky Way with VLBI astrometry", "authors": [{"first": "A", "middle": [], "last": "Brunthaler", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Reid", "suffix": ""}, {"first": "K", "middle": ["M"], "last": "Menten", "suffix": ""}, {"first": "X", "middle": ["W"], "last": "Zheng", "suffix": ""}, {"first": "A", "middle": [], "last": "Bartkiewicz", "suffix": ""}], "year": 2011, "venue": "Astron. Nachr", "link": "118431150"}, "BIBREF36": {"title": "Halo Star Streams in the Solar Neighborhood", "authors": [{"first": "A", "middle": [], "last": "Kepley", "suffix": ""}, {"first": "H", "middle": ["L"], "last": "Morrison", "suffix": ""}, {"first": "A", "middle": [], "last": "Helmi", "suffix": ""}, {"first": "T", "middle": ["D"], "last": "Kinman", "suffix": ""}, {"first": "J", "middle": [], "last": "Van Duyne", "suffix": ""}], "year": 2007, "venue": "Astron. J", "link": "18974102"}, "BIBREF37": {"title": "A python LIBRARY FOR GALACTIC DYNAMICS", "authors": [{"first": "J", "middle": [], "last": "Bovy", "suffix": ""}, {"first": "", "middle": [], "last": "Galpy", "suffix": ""}], "year": 2015, "venue": "Astron. Astrophys. Suppl", "link": null}, "BIBREF38": {"title": "A Survey of Proper Motion Stars. XIII. The Halo Population", "authors": [{"first": "B", "middle": ["W"], "last": "Carney", "suffix": ""}, {"first": "J", "middle": ["B"], "last": "Laird", "suffix": ""}, {"first": "D", "middle": ["W"], "last": "Latham", "suffix": ""}, {"first": "L", "middle": ["A"], "last": "Aguilar", "suffix": ""}], "year": 1996, "venue": "Astron. J", "link": "121668962"}, "BIBREF39": {"title": "A Comprehensive Study of 94 Open Clusters Based on the Data from IPHAS, GAIA DR2, and Other Sky Surveys", "authors": [{"first": "L", "middle": ["N"], "last": "Yalyalieva", "suffix": ""}, {"first": "A", "middle": ["A"], "last": "Chemel", "suffix": ""}, {"first": "E", "middle": ["V"], "last": "Glushkova", "suffix": ""}, {"first": "A", "middle": ["K"], "last": "Dambis", "suffix": ""}, {"first": "A", "middle": ["D"], "last": "Klinichev", "suffix": ""}], "year": 2018, "venue": "Astrophys. Bull", "link": "195096896"}, "BIBREF40": {"title": "Confirmation of the Gaia DR2 parallax zero-point offset using asteroseismology and spectroscopy in the Kepler field", "authors": [{"first": "J", "middle": ["C"], "last": "Zinn", "suffix": ""}, {"first": "M", "middle": ["H"], "last": "Pinsonneault", "suffix": ""}, {"first": "D", "middle": [], "last": "Huber", "suffix": ""}, {"first": "D", "middle": [], "last": "Stello", "suffix": ""}], "year": 2018, "venue": "Astron. J", "link": "150373680"}, "BIBREF41": {"title": "Milky Way Cepheid Standards for Measuring Cosmic Distances and Application to Gaia DR2: Implications for the Hubble Constant", "authors": [{"first": "A", "middle": ["G"], "last": "Riess", "suffix": ""}, {"first": "S", "middle": [], "last": "Casertano", "suffix": ""}, {"first": "W", "middle": [], "last": "Yuan", "suffix": ""}, {"first": "L", "middle": [], "last": "Macri", "suffix": ""}, {"first": "B", "middle": [], "last": "Bucciarelli", "suffix": ""}], "year": 2018, "venue": "Astron. J", "link": "55643027"}, "BIBREF42": {"title": "Star clusters: basic galactic building blocks", "authors": [{"first": "A", "middle": [], "last": "Moitinho", "suffix": ""}, {"first": "", "middle": [], "last": "Lepine", "suffix": ""}], "year": 2010, "venue": "Proceedings IAU Symposium No266", "link": null}, "BIBREF43": {"title": "Star Clusters, Saas-Fee Advanced Course 28", "authors": [{"first": "B", "middle": [], "last": "Carney", "suffix": ""}], "year": 1998, "venue": "Swiss Society for Astrophysics and Astronomy", "link": null}, "BIBREF44": {"title": "IAUS-Star Clusters and Black Holes in Galaxies across Cosmic Time", "authors": [{"first": "F", "middle": ["R"], "last": "Ferraro", "suffix": ""}], "year": 2016, "venue": "Proceedings of the International Astronomical Union, IAU Symposium", "link": null}, "BIBREF45": {"title": "Extended main-sequence of some stellar clusters", "authors": [{"first": "W", "middle": ["H"], "last": "Mccrea", "suffix": ""}], "year": 1964, "venue": "Mon. Not. Roy. Astron. Soc", "link": "123622762"}, "BIBREF46": {"title": "Stellar Collisions in Globular Clusters", "authors": [{"first": "J", "middle": [], "last": "Hills", "suffix": ""}, {"first": "C", "middle": [], "last": "Day", "suffix": ""}], "year": 1976, "venue": "Astrophysical Letters", "link": "118650625"}, "BIBREF47": {"title": "Overlapping abundance gradients and azimuthal gradients related to the spiral structure of the Galaxy", "authors": [{"first": "Jrd", "middle": [], "last": "Lepine", "suffix": ""}, {"first": "Cruz", "middle": ["P"], "last": "Scarano", "suffix": ""}, {"first": "S", "middle": [], "last": "Barros", "suffix": ""}, {"first": "D", "middle": ["A"], "last": "Dias", "suffix": ""}, {"first": "W", "middle": ["S"], "last": "", "suffix": ""}], "year": 2011, "venue": "Mon. Not. Roy. Astron. Soc", "link": "106401067"}}, "ref_entries": {"FIGREF0": {"text": "Figure 1. Spatial distribution (X, Y) (kpc) (filled red circle) of Be 8. See Section 6 for the estimation of (X, Y) values. The sun is at R = 8.2 \u00b1 0.1 kpc [34]. The image is adapted from the image 1 credit by Robert Hurt, IPAC; Bill Saxton, NRAO/AUI/NSF.", "type": "figure"}, "FIGREF1": {"text": "Figure 2. The image of Be 8 for a region of 18.3 x 17.2 (https://www.aavso.org (AAVSO). The red rectangle indicates the field of view of the SNO detector, 13.2 \u00d7 13.2 .", "type": "figure"}, "FIGREF2": {"text": "5 of Be 8 ( 18.3 x 17.2 ). The red rectangle indicates the field of view of the SNO detector, 13.2 \u00d7 13.2 . The photometric errors in V and (R \u2212 I) , (V \u2212 I) , (B \u2212 V ) , (U \u2212 B) of 2 Data may be requested from R. Michel. 3 IRAF is distributed by the National Optical Observatories, operated by the Association of Universities for Research in Astronomy, Inc., under cooperative agreement with the National Science Foundation. 4 http://www.astro.yale.edu/dokkum/lacosmic 5 Obtained from https://www.aavso.org (AAVSO) web page, [accessed 09 June 2019]", "type": "figure"}, "FIGREF3": {"text": "Figure 3. Photometric errors of the V apparent magnitude and four colours against the V magnitude for Be 8.", "type": "figure"}, "FIGREF4": {"text": "indicates that stars brighter than V = 18 have errors smaller than 0.03 in (R \u2212 I) , (V \u2212 I) , (B \u2212 V ) . For V > 20 , the errors in (R \u2212 I) and (V \u2212 I) are larger than 0.03. After V > 18 , the errors in (B \u2212 V ) are up to \u2248 0 m .03 . The errors in (U \u2212 B) are less than 0.01 for V < 14 , whereas for 14 < V \u2264 18 , large errors increase.", "type": "figure"}, "FIGREF5": {"text": "where \u03c3 bg is the residual background density, \u03c3 0 the central density of stars, and R core the core radius. The horizontal red bar shows the stellar background level measured in the comparison field, and the 1\u03c3 profile fit uncertainty is shown by the shaded region. The core and cluster radii from Figure 4 have been determined as R core = 1.8 and R RDP = 15.0 , respectively. These dimensions are quite close to the ones of (R core , R RDP ) = (1.52 , 15.5 ) of Bukowiecki et al. (2011) [2].", "type": "figure"}, "FIGREF6": {"text": "Figure 4. Stellar RDP (filled dots) of Be 8. Solid line shows the best-fit King profile. Horizontal red bar: stellar background level measured in the comparison field. Shaded region: 1\u03c3 King fit uncertainty. The core and cluster radii are obtained as Rcore = 1.8 and RRDP = 15.0 , respectively.", "type": "figure"}, "FIGREF7": {"text": "Figure 5. The \u00b5\u03b1 versus \u00b5 \u03b4 for Be 8 (filled stars). Small grey dots represent the Gaia DR2 astrometric data for a 15 .0 field centred on Be 8.", "type": "figure"}, "FIGREF8": {"text": "[21] which include the proper motion's errors in the frequency function. The expressions used can be found in the papers of Balaquer-Nunez et al. [6], Sariya et al. (2012) [7] and Dias et al. (2018)", "type": "figure"}, "FIGREF9": {"text": "Figure 6. The membership probability histogram P( % ) (left panel) and P( % ) versus G mag (right panel) for all stars of Be 8.", "type": "figure"}, "FIGREF10": {"text": "Figure 7. (U \u2212 B) -(B \u2212 V ) two colour diagram for the 17 likely members (filled dots) of Be 8. The dashed blue line represents the Schmidt-Kaler (SK82) main-sequence. Field stars are shown with small grey dots. Red arrow denotes the reddening.", "type": "figure"}, "FIGREF11": {"text": "Be 8 contains F-type stars which are quite valuable for determining photometric metal abundance, [M/H]. These F type stars with (U \u2212 B) < 0.35 and 0.9 < (B \u2212 V ) < 1.2 have large UV-", "type": "figure"}, "FIGREF12": {"text": "\u03b4(U \u2212 B) = 0.15 \u2212 0.48 . A member star with \u03b4(U \u2212 B) = 0.15 estimates [M/H] = \u22121.0 , which is very poor for Galactic open clusters. The other three members with \u03b4(U \u2212 B) = 0.47 \u2212 0.48 do not allow us determine a reasonable [M/H] value, due to their large UV-excesses which are insensitive to the metal abundance calibration (see the paper of Karata\u015f and Schuster (2006) [23]). Moreover, their photometric errors in (U \u2212 B) are larger at a level of \u03c3 (U \u2212B) = 0.10 \u2212 0.15 .", "type": "figure"}, "FIGREF13": {"text": "Figure 8. For the 268 likely members of Be 8, CMDs of V -(B \u2212 V ) (Left) and V -(V \u2212 I) (Right). Red curves show the PARSEC isochrones interpolated to Z = +0.008 . In Left figure the fitted isochrones Z = +0.015 (blue line) and +0.004 (black line) are also plotted (See Section 5).", "type": "figure"}, "FIGREF14": {"text": "Figure 9. For the 268 likely members of Be 8, CMDs of V -(R \u2212 I) (Left) and G -( GBP \u2212 GRP ) (Right). The meanings of the symbols are the same as Figure 8.", "type": "figure"}, "FIGREF15": {"text": "H] estimates its photometric metal abundance as [M/H] = \u22120.27. Here the solar heavy metal content is adopted as Z = +0.015 . The isochrone is varied until a satisfactory fit to the data has been obtained through the observed main-sequence (MS), turn-off (TO), sub-giant (SG) and Red Giant/Red Clump (RG/RC) sequences on the CMDs, as we followed in the papers of Akkaya et al. (2010) [16], Akkaya et al. (2015) [17] and G\u00fcne\u015f et al. (2012) [25]. Because of the presence of binaries, the PARSEC isochrones have been shifted to the left and below of MS on all CMDs. The vertical shift gives the (true) distance modulus, DM = (V 0 \u2212 M V ) . For its age (A, log(A)), the PARSEC isochrones have been shifted both vertically and horizontally on the CMD's with the expression M V + 3.1E(B \u2212 V ) + DM , for the vertical displacement and C 0 (\u03bb 1 \u2212 \u03bb 2 ) + E(\u03bb 1 \u2212 \u03bb 2 ) , for the horizontal, where \u03bb denotes the wavelengths of BV RI and G, G BP , G RP filters. Here C 0 means de-reddened colour index. The obtained reddenings from four CMDs are E(B \u2212V) = 0.69 \u00b1 0.08, E(V \u2212I) = 0.87 \u00b1 0.10, E(R \u2212I) = 0.44 \u00b1 0.05, E( G BP \u2212 G RP ) = 0.91 \u00b1 0.10, respectively. Its distance moduli (V 0 -M V )/ distances (d (kpc)) and age (Gyr) for four colours are presented in Cols. 2-5 of Table 4. In order to de-redden the distance moduli (Col. 2 of Table 4) for the colour indices (V \u2212 I) , (R \u2212 I) , (G BP \u2212 G RP ), our colour excesses E(V \u2212 I), E(R\u2212I) and E(G BP \u2212 G RP ) have been converted from the relations E(V \u2212 I) = 1.25 E(B \u2212V), E(R \u2212I) = 0.69 E(B \u2212V) [26-28] and E(B\u2212V) = 0.775 E(G BP \u2212 G RP )[29].", "type": "figure"}, "FIGREF16": {"text": "note that six probable Blue Straggler (BS) candidates lie on (B \u2212 V ) < 1.1 , (V \u2212 I) < 1.4 , (R \u2212 I) < 0.7 for V < 17.0 , whereas they occupy the region with G < 16.75 and G BP -G RP < 1.4 . BS candidates blur the main-sequence turn off (TO) to a brighter magnitude. RG/RC candidates populate well the red-giant branch (Figs. 8 -9). These RG/RC stars in old clusters are numerous and luminous as expected. BS (blue plus symbol) and RG/RC (red plus) candidates with P > 90 % have been placed on the nested circles of Figure 10. Two BS candidates reside in core radius of 1.8 of Be 8. Four BS stars occupy the inner regions. 26 RG/RC candidates remain within the cluster radius (R RDP = 15.0 ). Their median Gaia DR2 distances are d = 3953 \u00b1 750 pc ( = 0.253 \u00b1 0.048 mas) (six BS) and d = 4049 \u00b1 610 pc ( = 0.247 \u00b1 0.037 mas) (26 RG/RC), respectively, which are in reasonable agreement with the photometric ones within the uncertainties (Table 4). However, spectroscopic observations of these candidates are needed for their membership confirmation. The CMDs of Be 8 exhibit noticeable TO and RG/RC sequences (Figs. 8 -9). By utilising the definition of the morphological age index (MAI), \u03b41 = (B -V ) T O \u2212(B -V ) RG given by Phelps et al. (1994) [30], we measured V T O = 17.07, (B\u2212V) T O = 1.066 and (B\u2212V) RG = 1.599 on V -(B \u2212 V ) diagram (left panel of Figure 8). These values estimate \u03b41 = 0.533. Here \u03b41 is the difference in the colour indices between the bluest point of TO and the colour at the base of RG branch one magnitude brighter than the TO luminosity. Our \u03b41 value has been transformed into \u03b4V via the equation of \u03b4V = 3.77\u22123.75\u03b41 of Phelps et al. (1994) [30]. Its morphological age has been estimated as log A = 9.45 (A = 2.94 Gyr) from the equation, logA = 0.04\u03b4V 2 +0.34\u03b4V +0.07[F e/H]+8.76 of Salaris et al. (2004) [31], applying its the metal abundance ([M/H] = \u22120.27) and \u03b4V = 1.771. Here we assume [Fe/H] \u2248 [M/H]. Its MAI age (2.94 Gyr) is in good compatible with its isochrone age, 2.80 Gyr.", "type": "figure"}, "FIGREF17": {"text": "Figure 10. The circles have been drawn for the radii of 1.8 and 15.0 arc min on the \u03b12000 versus \u03b42000 of Be 8. Red and blue pluses represent the RG/RC and BS candidates on the CMDs (Figs. 8 -9).", "type": "figure"}, "FIGREF18": {"text": "allow us to calculate heliocentric velocities, ( U , V , W ) from the algorithm of Johnson and Soderblom (1987) [32]. These five members seem to be giant candidates according to their V and (B \u2212 V ) values (left panel of Figure 8). The calculated U , V , W velocities have been transformed to the components U , V , W by correcting for the Solar motion (U, V, W ) = (+11.10, +12.24, +7.25) km s \u22121 with respect to the local standard of rest (LSR) [33]. We adopt R = 8.2\u00b10.1 kpc [34] and V LSR = 239 km s \u22121 [35]. We adopt the right-hand system for the estimations. Their estimated heliocentric cartesian distances (x , y , z ) (kpc) and LRS-velocity components ( U , V , W ) have been transformed to Galactic Rest of Frame (GSR) i.e., ( x , y , z ) (kpc) and (V x , V y , V z ) via the equations given by Kepley et al. (2007) [36]. The Galactocentric velocity component (V \u03a6 ) (km s \u22121 ) (or azimuthal velocity) in a cylindrical frame is estimated via V \u03a6 = xVy\u2212yVx R . V \u03a6 < 0 means prograde. Thus, the obtained kinematic parameters (U, V, W, V \u03a6 ) km s \u22121 are listed in Cols. 2 -5 of", "type": "figure"}, "FIGREF19": {"text": ", the right handed J z value of a star near the Sun is \u22121960 kpc km s \u22121 from the solar values of R and V LSR . The vertical heliocentric velocities of W = [12, 15] km s \u22121 and azimuthal velocities, V \u03a6 = [\u2212183, \u2212197] km s \u22121 of these five likely members indicate that they have typical Galactic disk velocities. They reside in outer Galactic disk, R m > 8.5 kpc with the circular orbits, ecc = [0.23, 0.30]. Their Galactic heights reach", "type": "figure"}, "FIGREF20": {"text": "orbital eccentricities with ecc < [0.25, 0.30] (circular orbits) and 0.30 < ecc < 0.45 (elliptical). In the sense their orbital parameters reflect the properties of the Galactic thin disc. This is also consistent with what is expected of its metal content, [M/H] = -0.27. The Galactic orbits of five probable members of Be 8 are presented in Figure 11(a) and (b). Five likely members with the circular orbits move from \u223c12 kpc to \u223c7 kpc on x -y (kpc) (panel a). On z -R (kpc) (panel b), they reach to z \u223c1.3 kpc for the range of 6 < R < 12 kpc. Here R means the Galactocentric distance. The angular momentums (J \u22a5 , J z ) of these members fall in the range of 220 < J \u22a5 < 262 kpc km s \u22121 for \u22122107 \u2264 J z \u2264 \u22122054 kpc km s \u22121 . Their kinematics, dynamical and angular momentum values imply the indicators of Galactic thin disk population, according to fig. 11 of Kepley et al. (2007) [36].", "type": "figure"}, "FIGREF21": {"text": "Figure 11. The orbits of five probable members of Be 8 on x -y (kpc) (panel a) and z -R (kpc) (panel b). Large circle denotes the position of the Sun, (z , R ) = (0, 8.2 kpc) .", "type": "figure"}, "FIGREF22": {"text": "For the cluster members of Be 8, the reddenings E(B \u2212 V ) = 0.69 \u00b1 0.03 and E( V \u2212 I ) = 0.87 \u00b1 0.10 have been obtained from V -(B \u2212 V ) and V -(V \u2212 I) diagrams (Figure 8). These values are in good concordant with the ones of E(B \u2212 V ) = 0.75 and E(V \u2212 I ) = 0.88, given by Hasegawa et al. (2004) [1]. Our E (B \u2212 V ) value is larger than 0.41 value given by Bukowiecki et al. (2001) [2] for 2MASS JHK s photometry. Our distance modulus and distance from V -(B \u2212V ) are ( V 0 -M V , d(pc)) = (12.66 \u00b1 0.19, 3410 \u00b1 300 pc), which are in good agreement with the value (12.49, 3148 pc) of Hasegawa et al. (2004) [1]. Our value is somewhat smaller than the value (13.34, 3960 pc) of Bukowiecki et al. (2001) [2]. Our distance modulus/distance (pc) and age (Gyr) from G \u2212 (G BP -G RP ) are in quite compatible with the ones of the colour indices, (B \u2212 V ) , (V \u2212 I) and (R \u2212 I) (Table 4). The median Gaia DR2 parallax from 43 likely members ( \u03c3 / < 0.20) gives us = 0.272 \u00b1 0.060 mas which corresponds to d = 3676 \u00b1 810 pc. This distance is in good concordance with the photometric distances (3410-3620 pc) within the uncertainties", "type": "figure"}, "FIGREF23": {"text": "3 -4 ( [M/H] versus R (kpc)) of Lepine et al. (2011) [47], Be 8 with [M/H] = \u22120.27 and R = 10", "type": "figure"}, "TABREF0": {"text": "Rows (1)-(4) mean the central equatorial (J2000) and the Galactic coordinates of WEBDA. Air mass and exposure times (s) of filters are listed in rows 5-10.", "type": "table"}, "TABREF1": {"text": "The mean photometric errors of", "type": "table"}, "TABREF4": {"text": "The derived fundamental astrophysical parameters of Be 8 for four colour indices.", "type": "table"}, "TABREF6": {"text": "Formax , R min , R m , z max (kpc)) and ecc (Cols. 6-10). Their orbital angular momentum values ( Jz and J \u22a5 ) (kpc km s \u22121 ) (Cols. 11 -12).", "type": "table"}, "TABREF7": {"text": "The age of Be 8 is 2.80 \u00b1 0.20 GYr and this is younger than 3.16 GYr of Hasegawa et al. (2004) [1] and Bukowiecki et al. (2001) [2]. Its MAI age (A = 2.94 Gyr) is in concordant with its isochrone age. Discrepancies of the distance moduli, distances and ages as compared to the literature stem from the usage of different heavy element abundances, isochrones, reddenings and photometries such as 2MASS JHK s , as mentioned by Moitinho (2010)", "type": "table"}}}
{"paper_id": "199668887", "_pdf_hash": "aadef1b1e13de9dc836b6b9e9f40b538a40464c4", "abstract": [{"section": "Abstract", "text": "Pervasive computing systems employ distributed and embedded devices in order to raise, communicate, and process data in an anytime-anywhere fashion. Certainly, its most prominent device is the smartphone due to its wide proliferation, growing computation power, and wireless networking capabilities. In this context, we revisit the implementation of digitalized word-of-mouth that suggests exchanging item preferences between smartphones ofine and directly in immediate proximity. Collaboratively and decentrally collecting data in this way has two benefts. First, it allows to attach for instance location-sensitive context information in order to enrich collected item preferences. Second, model building does not require network connectivity. Despite the benefts, the approach naturally raises data privacy and data scarcity issues. In order to address both, we propose Propagate and Filter, a method that translates the traditional approach of fnding similar peers and exchanging item preferences among each other from the feld of decentralized to that of pervasive recommender systems. Additionally, we present preliminary results on a prototype mobile application that implements the proposed device-to-device information exchange. Average ad-hoc connection delays of 25.9 seconds and reliable connection success rates within 6 meters underpin the approach's technical feasibility.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "INTRODUCTION", "text": "Nowadays, the possibility to collect, store, and process very large amounts of data in combination with powerful data transformation and analysis techniques have raised privacy concerns such as when in early 2018, Cambridge Analytica had been granted access to millions of Facebook user profles for political campaigning without users being aware of it. Statutory counter measures to curb data misuse have in particular been undertaken by the European Union in May 2018 by adopting the General Data Protection Regulation (GDPR). The GDPR imposes strict rules on data processing, ownership, information obligation (including raising consent), transparency, and collection of user-related data. Since data protection laws penalize misuse of personal data reactively, they do not actively prohibit misuse on a technical level. In the literature, three major recommender system architectures have been proposed to address privacy issues arising from collecting large authoritative data pools.", "cite_spans": [], "ref_spans": []}, {"section": "INTRODUCTION", "text": "Federated learning produces personalized recommendation models by communicating model building between a central server and mutually disconnected peers holding personal information [10, 22] . Thus, federated learning enacts model building centrally on data that is distributed across personal data owners.", "cite_spans": [{"start": 181, "end": 185, "text": "[10,", "ref_id": "BIBREF11"}, {"start": 186, "end": 189, "text": "22]", "ref_id": "BIBREF24"}], "ref_spans": []}, {"section": "INTRODUCTION", "text": "In contrast, decentralized recommender systems feature direct interactions between distributed peers without a central server. They are commonly built on top of fle-sharing peer-to-peer networks [3, 21, 28, 31] that use gossip mechanisms [19] in order to establish a logic overlay network for fast network search and network resilience in view of peers joining or churning the network. In short, dissimilar peers are dropped from and similar peers are added to views (lists of visible peers in the network) iteratively. In so doing, the network establishes homogenous interest groups, which share recommendations explicitly among each other.", "cite_spans": [{"start": 195, "end": 198, "text": "[3,", "ref_id": "BIBREF2"}, {"start": 199, "end": 202, "text": "21,", "ref_id": "BIBREF23"}, {"start": 203, "end": 206, "text": "28,", "ref_id": "BIBREF30"}, {"start": 207, "end": 210, "text": "31]", "ref_id": "BIBREF33"}, {"start": 238, "end": 242, "text": "[19]", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "INTRODUCTION", "text": "Pervasive (or ubiquitous) recommender systems [23, 27] are systems that often revolve around location-aware recommendations of for instance items in a nearby shop, restaurants, or events in proximity. The location-based approach naturally circumvents transmitting personal data to a central remote authority for recommendation by instead requesting closeby profle as well as context information.", "cite_spans": [{"start": 46, "end": 50, "text": "[23,", "ref_id": "BIBREF25"}, {"start": 51, "end": 54, "text": "27]", "ref_id": "BIBREF29"}], "ref_spans": []}, {"section": "INTRODUCTION", "text": "Pervasive recommender systems are naturally confronted with limited profle data, for usually only a small subpopulation is available in proximity. Fortunately, there are indications that integrating context data into the recommendation process allows to outweigh profle data scarcity [1] .", "cite_spans": [{"start": 284, "end": 287, "text": "[1]", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "INTRODUCTION", "text": "Among these three approaches we believe that pervasive recommender systems yield the highest potential for data privacy for two reasons. First, the availability of context data as well as mobile compute power on smartphones increases rapidly rendering more and more complex recommendation algorithms feasible on smartphones holding personal data. Second, the model building process happens on-device and does not require connectivity to the network. Consequently, peers become invisible in the network when they do not interact with other peers thus adding privacy on the level of model building. In spite of their potential for recommendation, we see two main burdens. First, pervasive recommender systems are susceptible to data privacy issues since the recommendation mechanism usually builds on the exchange of raw profle data with nearby peers. Second, local scarcity of profle data renders item recommendations on location-independent items taxing. We believe that introducing gossip-based mechanisms and data sampling strategies to the feld of pervasive recommender systems can alleviate both issues. We present the following preliminary results:", "cite_spans": [], "ref_spans": []}, {"section": "INTRODUCTION", "text": "\u2022 The design of Propagate and Filter, a gossip-based method that addresses the problem of data privacy and data scarcity in pervasive recommender systems. \u2022 An implementation of the propagation part in the form of an Android mobile application utilizing Google's Nearby Connections API and its evaluation.", "cite_spans": [], "ref_spans": []}, {"section": "RELATED WORK", "text": "In the present work, we propose a method for disseminating recommendations epidemically in combination with an on-device fltering process for which we proposed a mobile software architecture in [5] . The most similar work is that of Barbosa et al. [25] that propose device-to-device raw profle exchanges in an opportunistic networking scenario. Yet, it difers in that they neither address scalability nor privacy issues. Other related work subsumes: Information Dissemination: Technical works on device-to-device information exchange in proximity are key enablers for collaboratively built recommender systems on mobile devices. The Haggle API [24] implements data-centric message forwarding using Bluetooth, Ethernet, and WiFi 1 . In [26] , the authors implement a Bluetooth-based middleware to create opportunistic networks between passing users. On top of such enablers, the authors in [7] leverage real-world social phenomena such as large crowds at sports events for event-based mobile communication.", "cite_spans": [{"start": 194, "end": 197, "text": "[5]", "ref_id": "BIBREF5"}, {"start": 248, "end": 252, "text": "[25]", "ref_id": "BIBREF27"}, {"start": 644, "end": 648, "text": "[24]", "ref_id": "BIBREF26"}, {"start": 735, "end": 739, "text": "[26]", "ref_id": "BIBREF28"}, {"start": 889, "end": 892, "text": "[7]", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "RELATED WORK", "text": "Information Filtering: Many approaches to collaboratively and decentrally build recommender systems on mobile devices in pervasive computing environments disseminate information epidemically and generate recommendations on top of user similarity. User similarities have been found to be reliably estimated by contextual information in the form of proximity at a music festival [11] 1 http://user.it.uu.se/~erikn/papers/haggle-arch.pdf or spatio-temporal information in the tourism domain [16] . Estimating user similarity on rating vectors has been performed on subcommunities [13] or afnity networks [12, 29] .", "cite_spans": [{"start": 377, "end": 381, "text": "[11]", "ref_id": "BIBREF12"}, {"start": 488, "end": 492, "text": "[16]", "ref_id": "BIBREF17"}, {"start": 577, "end": 581, "text": "[13]", "ref_id": "BIBREF14"}, {"start": 601, "end": 605, "text": "[12,", "ref_id": "BIBREF13"}, {"start": 606, "end": 609, "text": "29]", "ref_id": "BIBREF31"}], "ref_spans": []}, {"section": "DESIGN", "text": "At the proposed information dissemination method's core is the social movement of people carrying mobile devices. On top of that core movement, we conceive a background data exchange between devices whenever they are geographically close to each other followed by an on-device customizable fltering process. We call this method Propagate and Filter.", "cite_spans": [], "ref_spans": []}, {"section": "Similarity Data, Peer Preference List, and Neighborhood Preference List", "text": "Each device carries four types of data (see Figure 1 ), where the entire stack of data 2 is used for the derivation of local personalized recommendations.", "cite_spans": [], "ref_spans": [{"start": 44, "end": 52, "text": "Figure 1", "ref_id": "FIGREF0"}]}, {"section": "Similarity Data, Peer Preference List, and Neighborhood Preference List", "text": "\u2022 Peer Preference List: A list of items rated by the peer 3 . It can contain binary or scalar ratings. In our prototype implementation, the peer can rate movies, where each movie is identifed with a unique identifer provided by the publicly available Internet Movie Database 4 (IMDb). Peer preference lists are kept on the device. \u2022 Neighborhood Preference List: Every peer mixes 5 previously collected neighborhood preference lists received from the k most similar peers into a single list of item ratings. It is thus an aggregated preference list of an unknown subset of peers. Neighborhood preference lists get propagated to other peers. Note that every peer controls the amount of his/her own peer preference list that gets propagated to nearby peers. \u2022 Similarity Data: Any kind of data that can be used for peer similarity comparison. Similarity data gets propagated to nearby peers and therefore has to be privacy-preserving. Privacy-preserving similarity comparison can among others be performed on item vectors [4] as well as texting data [15] . \u2022 Context Data: Data that characterizes the encounter such as location, time, weather, or peer activity (running, eating, commuting) that can be sensed (for example via sensors) or retrieved (for example from the web) [6, 30] .", "cite_spans": [{"start": 58, "end": 59, "text": "3", "ref_id": "BIBREF2"}, {"start": 1020, "end": 1023, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 1048, "end": 1052, "text": "[15]", "ref_id": "BIBREF16"}, {"start": 1273, "end": 1276, "text": "[6,", "ref_id": "BIBREF6"}, {"start": 1277, "end": 1280, "text": "30]", "ref_id": "BIBREF32"}], "ref_spans": []}, {"section": "Propagate", "text": "When two or more peers are geographically close to each other, their smartphones establish pairwise fast and secure connections and exchange their neighborhood preference lists and similarity data (propagation). At propagation time the received data is enriched with context data such as time or location characterizing the encounter. ", "cite_spans": [], "ref_spans": []}, {"section": "Filter", "text": "Data collection in the propagation step includes unfltered data from every encounter. It is necessary to flter by similarity in order to arrive at relevant information. Upon receiving data from another peer, the fltering process starts on the device. Three steps happen:", "cite_spans": [], "ref_spans": []}, {"section": "Filter", "text": "(1) Similarity Comparison: Similarity data is used in order to compare peer similarity between sender and receiver. (2) Sample Neighborhood Preference List: If the peer similarity is above the k-th highest, resample the neighborhood preference list on the basis of the peer's preference list and the neighborhood preference lists by the k most similar peers. (3) Update Personal Recommendations: Run a recommendation algorithm 6 on the locally available data (see Figure 1 ) in order to derive new recommendations or update ratings of previously generated recommendations.", "cite_spans": [], "ref_spans": [{"start": 464, "end": 472, "text": "Figure 1", "ref_id": "FIGREF0"}]}, {"section": "Privacy by Disconnection", "text": "Propagate and Filter's propagation step establishes wireless connections between smartphones in proximity in an ad-hoc fashion, exchanges similarity data and neighborhood preference lists, and thereafter terminates the connection. Consequently, the network topology is essentially disconnected and no information on interpeer relationships -such as is the case with Peer-to-Peer network overlays in social networks [20] , recommender systems [3] , or vehicular networks [17] -are exploitable. The entire peers' local databases form a geographically distributed and essentially disconnected database, where every peer holds only a very limited portion of data. Data query and data search are thus not possible at will. Access to other peers' data is limited to the time of contact and amount of data individually made available by nearby peers. 6 Propagate and Filter is independent of any specifc recommendation algorithm. The fltering techniques described in [2] are viable approaches leveraging contextual data.", "cite_spans": [{"start": 415, "end": 419, "text": "[20]", "ref_id": "BIBREF21"}, {"start": 442, "end": 445, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 470, "end": 474, "text": "[17]", "ref_id": "BIBREF18"}, {"start": 844, "end": 845, "text": "6", "ref_id": "BIBREF6"}, {"start": 960, "end": 963, "text": "[2]", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Privacy by Disconnection", "text": "We call this property Privacy by Disconnection. It is Propagate and Filter's contribution to data privacy.", "cite_spans": [], "ref_spans": []}, {"section": "Enhance Locally Available Profle Data", "text": "Gossip protocols require a connected peer-to-peer network in order to converge similar peers toward each other, where network connectivity is retained by peer sampling [18] . In traditional decentralized recommender systems, peer sampling that requires network connectivity is applicable since neither items nor peers are spatial, that is both can be moved in the network at will. In the Propagate and Filter scenario, peers are spatial and cannot be moved in the network at will, though items can. Therefore, Propagate and Filter proposes to converge the recommendation list of latent interest communities in the following way: Peer sampling does not have to be administered by any protocol since it is performed by the global movement of self-organized agents carrying smartphones. Propagate and Filter unfolds its dissemination potential at locations of high degrees of peer mobility such as urban areas [9] . When a peer receives data from a similar peer, he/she resamples his/her neighborhood preference list and else does nothing. As a consequence, Propagate and Filter creates a constant fow of item recommendations that fows between similar peers and dries out between dissimilar peers. This property allows to relay recommendations between peers that have never been geographically close to each other and avoids having to transmit any information on dissimilar peers. In that sense Propagate and Filter addresses the profle data scarcity problem prone to pervasive recommender systems.", "cite_spans": [{"start": 168, "end": 172, "text": "[18]", "ref_id": "BIBREF19"}, {"start": 907, "end": 910, "text": "[9]", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "IMPLEMENTATION", "text": "We present an Android mobile application that implements a prototype of the propagation step described in Section 3.2. We restrict to the transmission of peer preference lists for reasons of simplicity. The application is available in the Google Play Store 7 .", "cite_spans": [], "ref_spans": []}, {"section": "Prepare a Peer Preference List", "text": "The prototype allows to search and rate movies locally which are registered and uniquely identifed in the IMDb. Movie ratings are scalar, ranging from 1 to 5 stars, and stored in the format (userID, movieID, scalarRating). A list of movie ratings implements the peer preference list introduced in Section 3.1. Once ratings have been specifed by the user, he/she can activate sharing.", "cite_spans": [], "ref_spans": []}, {"section": "Propagate via Google Connections API", "text": "The application's active sharing mode applies advertise -the device broadcasts its existence to other devices in proximity -and discover -the device listens on other device's broadcasting. The sharing process is handled by the Google Nearby Connections API 8 and entirely happens in the background. The Google Nearby Connections API connects devices using one of the three wireless technologies Bluetooth, Bluetooth Low Energy (BLE), or WiFi, automatically selecting the most efcient one in each scenario. When two smartphones establish a connection, ratings are exchanged immediately and stored locally. Note that ratings can be exchanged without a connection to the internet as it is commonly d the case in underground trains. As soon as the internet connection is re-established, detailed movie information such as the movie genre, cast or, trailer can be queried via movieIDs.", "cite_spans": [], "ref_spans": []}, {"section": "EVALUATION", "text": "We evaluate the prototype implementation in view of its potential to facilitate the proposed pervasive recommender system sketched in Section 3 in particular in urban areas. We conducted six distinct experiments, where every experiment was conducted with Nexus 5 smartphones that support Bluetooth up to version 4 (including BLE) and Wif direct. We re-ran experiments 10 times by default, unless stated otherwise, with distinct experiment setups in order to have empirical evidence of the results' soundness.", "cite_spans": [], "ref_spans": []}, {"section": "EVALUATION", "text": "(1) Share Large Amounts of Ratings: We share a bulk of 1000 ratings, accounting to roughly 100 kB uncompressed. As soon as the connection is established, all 1000 ratings get transmitted instantly and reliably without any data loss. (2) Share Data Between Multiple Devices: We share ratings between four smartphones simultaneously holding mutually disjoint ratings. Ratings get transmitted correctly and losslessly. (3) Share Data in Public Transportation: We successfully share ratings between three devices in the bus and the underground in the urban city of Berlin being exposed to many WiFi and Bluetooth disturb signals. The loss of internet connectivity does not impair the data transfer. As soon as internet connectivity is re-established, the shared placeholder recommendations get flled with movie metadata fetched from the Open Movie Database 9 (OMDb) API. (4) Efective Transmission Range: Recall that the Nearby Connections API comprises Bluetooth, BLE, and Wif direct under its hood. All three allegedly provide an efective transmission radius of 10 meters for class 2 devices such as smartphones. We tested transmission ranges between 3 and 12 meters, both outdoors and indoors, and with and without obstacles. The results are shown in Table 1 . We conclude that the efective radius of ratings propagation is between 3 and 6 meters. (5) Average Initial Connection Delay: We measure the initial connection delay for two devices, that is the elapsed time before a connection gets established. We place the devices at a distance of 1 meter in order to guarantee connectivity, where the connections were made with distinct app sessions (partner device's id not in cache). The average connection delay (pre-connection) has to be performed continuously, we would like to know whether or not advertising, discovering, and sharing information in the background for extended periods of time is feasible or not. Since we cannot experiment in a real-life scenario with at times no devices to connect to, and then multiple devices to connect to, we only measure the application's pre-connection battery drainage, which therefore presents a lower bound for battery drainage. We use two devices reset to factory settings. We track the battery levels for three distinct scenarios (a) application running in the background with sharing on, (b) with sharing of, and (c) factory settings, where in all three cases the displays were of. The results are shown in Table 2 .", "cite_spans": [], "ref_spans": [{"start": 1249, "end": 1256, "text": "Table 1", "ref_id": "TABREF0"}, {"start": 2456, "end": 2463, "text": "Table 2", "ref_id": "TABREF1"}]}, {"section": "Conclusion", "text": "The experimental fndings indicate that the Propagate and Filter's propagation step works reliably with larger amounts of ratings, in multi-device scenarios, and in areas without internet connectivity such as underground trains. Yet, the implementation has certain limitations. First of all, information can only be disseminated reliably within a radius of 6 meters, which on the one hand strengthens privacy, and on the other limits the number of potential peers to share information with. Furthermore, the average initial connection delay of 25.9 seconds is considerable and does not allow to share information between for instance passing pedestrians, yet includes scenarios such as waiting at the trafc lights, sitting next to each other in a caf\u00e9 or restaurant, or taking public transportation. Last but not least, battery drainage is relatively high at at least 5% per hour, which thus prohibits continuous advertising and discovery. Apart from ever improving transmission standards and hardware, we believe that it is possible to limit activity and inactivity of the sharing process efciently on the logical level leveraging sensor information on smartphones.", "cite_spans": [], "ref_spans": []}, {"section": "FUTURE WORK", "text": "Future work includes the launch of the mobile application for the collection of usage data. Recall that we left the sampling process and the recommendation algorithm as placeholders (see Section 3.3 (2) and (3) respectively). Once usage data is collected it will be possible to test distinct combinations of sampling and recommendation strategies. Furthermore, the evaluation of feedback on the application including the user interface and user experience is due.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Incorporating Contextual Information in Recommender Systems Using a Multidimensional Approach", "authors": [{"first": "Gediminas", "middle": [], "last": "Adomavicius", "suffix": ""}, {"first": "Ramesh", "middle": [], "last": "Sankaranarayanan", "suffix": ""}, {"first": "Shahana", "middle": [], "last": "Sen", "suffix": ""}, {"first": "Alexander", "middle": [], "last": "Tuzhilin", "suffix": ""}], "year": 2005, "venue": "ACM Trans. Inf. Syst", "link": "1914653"}, "BIBREF1": {"title": "Context-Aware Recommender Systems", "authors": [{"first": "Gediminas", "middle": [], "last": "Adomavicius", "suffix": ""}, {"first": "Alexander", "middle": [], "last": "Tuzhilin", "suffix": ""}], "year": 2011, "venue": "", "link": "27707495"}, "BIBREF2": {"title": "A peer-to-peer recommender system for self-emerging user communities based on gossip overlays", "authors": [{"first": "Ranieri", "middle": [], "last": "Baraglia", "suffix": ""}, {"first": "Patrizio", "middle": [], "last": "Dazzi", "suffix": ""}, {"first": "Matteo", "middle": [], "last": "Mordacchini", "suffix": ""}, {"first": "Laura", "middle": [], "last": "Ricci", "suffix": ""}], "year": 2010, "venue": "10th IEEE International Conference on Computer and Information Technology", "link": "15489627"}, "BIBREF3": {"title": "Do You Like What I Like? Similarity Estimation in Proximitybased Mobile Social Networks", "authors": [{"first": "Felix", "middle": [], "last": "Beierle", "suffix": ""}], "year": 2018, "venue": "Proc. 2018 17th IEEE International Conference On Trust, Security And Privacy In Computing And Communications (TrustCom)", "link": "29166981"}, "BIBREF5": {"title": "Collaborating with Users in Proximity for Decentralized Mobile Recommender Systems", "authors": [{"first": "Felix", "middle": [], "last": "Beierle", "suffix": ""}, {"first": "Tobias", "middle": [], "last": "Eichinger", "suffix": ""}], "year": 2019, "venue": "Proceedings of the IEEE 16th International Conference on Ubiquitous Intelligence and Computing (UIC)", "link": "174801060"}, "BIBREF6": {"title": "Context Data Categories and Privacy Model for Mobile Data Collection Apps", "authors": [{"first": "Felix", "middle": [], "last": "Beierle", "suffix": ""}, {"first": "Thuy", "middle": [], "last": "Vinh", "suffix": ""}, {"first": "Mathias", "middle": [], "last": "Tran", "suffix": ""}, {"first": "Patrick", "middle": [], "last": "Allemand", "suffix": ""}, {"first": "Winfried", "middle": [], "last": "Nef", "suffix": ""}, {"first": "Thomas", "middle": [], "last": "Schlee", "suffix": ""}, {"first": "R\u00fcdiger", "middle": [], "last": "Probst", "suffix": ""}, {"first": "Johannes", "middle": [], "last": "Pryss", "suffix": ""}, {"first": "", "middle": [], "last": "Zimmermann", "suffix": ""}], "year": 2018, "venue": "Procedia Computer Science", "link": "49569163"}, "BIBREF7": {"title": "C3PO: A Network and Application Framework for Spontaneous and Ephemeral Social Networks", "authors": [{"first": "Antoine", "middle": [], "last": "Boutet", "suffix": ""}, {"first": "Stephane", "middle": [], "last": "Frenot", "suffix": ""}, {"first": "Frederique", "middle": [], "last": "Laforest", "suffix": ""}, {"first": "Pascale", "middle": [], "last": "Launay", "suffix": ""}, {"first": "Nicolas", "middle": ["Le"], "last": "Sommer", "suffix": ""}, {"first": "Yves", "middle": [], "last": "Maheo", "suffix": ""}, {"first": "Damien", "middle": [], "last": "Reimert", "suffix": ""}], "year": 2015, "venue": "Web Information Systems Engineering -WISE 2015", "link": "2732272"}, "BIBREF9": {"title": "Bagging Predictors", "authors": [{"first": "Leo", "middle": [], "last": "Breiman", "suffix": ""}], "year": 1996, "venue": "Machine Learning", "link": "207738357"}, "BIBREF10": {"title": "Evaluating and Enhancing Information Dissemination in Urban Areas of Interest Using Opportunistic Networks", "authors": [{"first": "L", "middle": [], "last": "Chancay-Garc\u00eda", "suffix": ""}, {"first": "E", "middle": [], "last": "Hern\u00e1ndez-Orallo", "suffix": ""}, {"first": "P", "middle": [], "last": "Manzoni", "suffix": ""}, {"first": "C", "middle": ["T"], "last": "Calafate", "suffix": ""}, {"first": "J", "middle": [], "last": "Cano", "suffix": ""}], "year": 2018, "venue": "IEEE Access", "link": "49558538"}, "BIBREF11": {"title": "Federated Meta-Learning for Recommendation", "authors": [{"first": "Fei", "middle": [], "last": "Chen", "suffix": ""}, {"first": "Zhenhua", "middle": [], "last": "Dong", "suffix": ""}, {"first": "Zhenguo", "middle": [], "last": "Li", "suffix": ""}, {"first": "Xiuqiang", "middle": [], "last": "He", "suffix": ""}], "year": 2018, "venue": "", "link": "3451040"}, "BIBREF12": {"title": "Collaborative fltering based on opportunistic information sharing in mobile ad-hoc networks", "authors": [{"first": "Alexandre", "middle": [], "last": "De Spindler", "suffix": ""}, {"first": "Moira", "middle": ["C"], "last": "Norrie", "suffix": ""}, {"first": "Michael", "middle": [], "last": "Grossniklaus", "suffix": ""}, {"first": ";", "middle": [], "last": "Coopis", "suffix": ""}, {"first": "", "middle": [], "last": "Doa", "suffix": ""}, {"first": "Gada", "middle": [], "last": "Odbase", "suffix": ""}, {"first": "", "middle": [], "last": "Is", "suffix": ""}], "year": 2007, "venue": "On the Move to Meaningful Internet Systems", "link": "8784960"}, "BIBREF13": {"title": "Design of a P2P content recommendation system using afnity networks", "authors": [{"first": "Juan", "middle": [], "last": "Vera Del Campo", "suffix": ""}, {"first": "Josep", "middle": [], "last": "Pegueroles", "suffix": ""}, {"first": "Juan", "middle": [], "last": "Hern\u00e1ndez-Serrano", "suffix": ""}, {"first": "Miguel", "middle": [], "last": "Soriano", "suffix": ""}], "year": 2012, "venue": "Computer Communications", "link": "9353395"}, "BIBREF14": {"title": "difeRS: A Mobile Recommender Service", "authors": [{"first": "L", "middle": [], "last": "Del Prete", "suffix": ""}, {"first": "L", "middle": [], "last": "Capra", "suffix": ""}], "year": 2010, "venue": "2010 Eleventh International Conference on Mobile Data Management. 21-26", "link": "4615414"}, "BIBREF15": {"title": "Bootstrap Methods: Another Look at the Jackknife", "authors": [{"first": "B", "middle": [], "last": "Efron", "suffix": ""}], "year": 1979, "venue": "Ann. Statist", "link": "124426327"}, "BIBREF16": {"title": "Veeraraghavan Sekar, and Sam Tabibzadeh. 2019. afnity: A System for Latent User Similarity Comparison on Texting Data", "authors": [{"first": "Tobias", "middle": [], "last": "Eichinger", "suffix": ""}, {"first": "Felix", "middle": [], "last": "Beierle", "suffix": ""}, {"first": "Robin", "middle": [], "last": "Sumsam Ullah Khan", "suffix": ""}, {"first": "", "middle": [], "last": "Middelanis", "suffix": ""}], "year": 2019, "venue": "", "link": null}, "BIBREF17": {"title": "Mobile Recommender Systems in Tourism", "authors": [{"first": "Damianos", "middle": [], "last": "Gavalas", "suffix": ""}, {"first": "Charalampos", "middle": [], "last": "Konstantopoulos", "suffix": ""}, {"first": "Konstantinos", "middle": [], "last": "Mastakas", "suffix": ""}, {"first": "Grammati", "middle": [], "last": "Pantziou", "suffix": ""}], "year": 2014, "venue": "J. Netw. Comput. Appl", "link": null}, "BIBREF18": {"title": "Overdrive an overlay-based geocast service for smart trafc applications", "authors": [{"first": "B", "middle": [], "last": "Heep", "suffix": ""}, {"first": "M", "middle": [], "last": "Florian", "suffix": ""}, {"first": "J", "middle": [], "last": "Volz", "suffix": ""}, {"first": "I", "middle": [], "last": "Baumgart", "suffix": ""}], "year": 2013, "venue": "2013 10th Annual Conference on Wireless On-demand Network Systems and Services (WONS). 1-8", "link": "9594904"}, "BIBREF19": {"title": "T-Man: Gossip-Based Overlay Topology Management", "authors": [{"first": "M\u00e1rk", "middle": [], "last": "Jelasity", "suffix": ""}, {"first": "Ozalp", "middle": [], "last": "Babaoglu", "suffix": ""}], "year": 2006, "venue": "", "link": "1875854"}, "BIBREF20": {"title": "Gossip-based Peer Sampling", "authors": [{"first": "M\u00e1rk", "middle": [], "last": "Jelasity", "suffix": ""}, {"first": "Spyros", "middle": [], "last": "Voulgaris", "suffix": ""}, {"first": "Rachid", "middle": [], "last": "Guerraoui", "suffix": ""}, {"first": "Anne-Marie", "middle": [], "last": "Kermarrec", "suffix": ""}, {"first": "Maarten", "middle": [], "last": "Van Steen", "suffix": ""}], "year": 2007, "venue": "ACM Trans. Comput. Syst", "link": "6266183"}, "BIBREF21": {"title": "A Peer-to-Peer Social Network Overlay for Efcient Information Retrieval and Difusion", "authors": [{"first": "Salma", "middle": [], "last": "Ktari", "suffix": ""}, {"first": "Artur", "middle": [], "last": "Hecker", "suffix": ""}], "year": 2011, "venue": "Future Information Technology", "link": null}, "BIBREF23": {"title": "Epidemic Trust-Based Recommender Systems", "authors": [{"first": "S", "middle": [], "last": "Magureanu", "suffix": ""}, {"first": "N", "middle": [], "last": "Dokoohaki", "suffix": ""}, {"first": "S", "middle": [], "last": "Mokarizadeh", "suffix": ""}, {"first": "M", "middle": [], "last": "Matskin", "suffix": ""}], "year": 2012, "venue": "2012 International Conference on Privacy, Security, Risk and Trust and 2012 International Confernece on Social Computing", "link": "18551799"}, "BIBREF24": {"title": "Federated Learning of Deep Networks using Model Averaging", "authors": [{"first": "H", "middle": [], "last": "", "suffix": ""}, {"first": "Brendan", "middle": [], "last": "Mcmahan", "suffix": ""}, {"first": "Eider", "middle": [], "last": "Moore", "suffix": ""}, {"first": "Daniel", "middle": [], "last": "Ramage", "suffix": ""}, {"first": "Blaise", "middle": [], "last": "Ag\u00fcera Y Arcas", "suffix": ""}], "year": 2016, "venue": "", "link": "16861557"}, "BIBREF25": {"title": "Ubiquitous recommender systems", "authors": [{"first": "Christos", "middle": [], "last": "Mettouris", "suffix": ""}, {"first": "George", "middle": [], "last": "Papadopoulos", "suffix": ""}], "year": 2014, "venue": "Computing", "link": "11595052"}, "BIBREF26": {"title": "Haggle : A Data-centric Network Architecture for Mobile Devices", "authors": [{"first": "Erik", "middle": [], "last": "Nordstr\u00f6m", "suffix": ""}, {"first": "Per", "middle": [], "last": "Gunningberg", "suffix": ""}, {"first": "Christian", "middle": [], "last": "Rohner", "suffix": ""}], "year": 2009, "venue": "", "link": "15166810"}, "BIBREF27": {"title": "Distributed User-Based Collaborative Filtering on an Opportunistic Network", "authors": [{"first": "L", "middle": ["Nunes"], "last": "Barbosa", "suffix": ""}, {"first": "J", "middle": [], "last": "Gemmell", "suffix": ""}, {"first": "M", "middle": [], "last": "Horvath", "suffix": ""}, {"first": "T", "middle": [], "last": "Heimfarth", "suffix": ""}], "year": 2018, "venue": "2018 IEEE 32nd International Conference on Advanced Information Networking and Applications (AINA)", "link": "52006579"}, "BIBREF28": {"title": "MobiClique: Middleware for Mobile Social Networking", "authors": [{"first": "Anna-Kaisa", "middle": [], "last": "Pietil\u00e4inen", "suffix": ""}, {"first": "Earl", "middle": [], "last": "Oliver", "suffix": ""}, {"first": "Jason", "middle": [], "last": "Lebrun", "suffix": ""}, {"first": "George", "middle": [], "last": "Varghese", "suffix": ""}, {"first": "Christophe", "middle": [], "last": "Diot", "suffix": ""}], "year": 2009, "venue": "Proceedings of the 2Nd ACM Workshop on Online Social Networks (WOSN '09)", "link": "3079350"}, "BIBREF29": {"title": "A Ubiquitous Recommender System Based on Collaborative Filtering and Social Networking Data", "authors": [{"first": "Nikolaos", "middle": [], "last": "Polatidis", "suffix": ""}, {"first": "Christos", "middle": ["K"], "last": "Georgiadis", "suffix": ""}], "year": 2015, "venue": "Int. J. Intell. Eng. Inform", "link": "43583865"}, "BIBREF30": {"title": "A peer-to-peer recommender system based on spontaneous afnities", "authors": [{"first": "Giancarlo", "middle": [], "last": "Rufo", "suffix": ""}, {"first": "Rossano", "middle": [], "last": "Schifanella", "suffix": ""}], "year": 2009, "venue": "ACM Trans. Internet Techn", "link": null}, "BIBREF31": {"title": "MobHinter: Epidemic Collaborative Filtering and Self-organization in Mobile Ad-hoc Networks", "authors": [{"first": "Rossano", "middle": [], "last": "Schifanella", "suffix": ""}, {"first": "Andr\u00e9", "middle": [], "last": "Panisson", "suffix": ""}, {"first": "Cristina", "middle": [], "last": "Gena", "suffix": ""}, {"first": "Giancarlo", "middle": [], "last": "Rufo", "suffix": ""}], "year": 2008, "venue": "Proceedings of the 2008 ACM Conference on Recommender Systems (RecSys '08)", "link": "15005339"}, "BIBREF32": {"title": "Context-Awareness for Mobile Sensing: A Survey and Future Directions", "authors": [{"first": "O", "middle": [], "last": "Yurur", "suffix": ""}, {"first": "C", "middle": [], "last": "Liu", "suffix": ""}, {"first": "Z", "middle": [], "last": "Sheng", "suffix": ""}, {"first": "V", "middle": [], "last": "Leung", "suffix": ""}, {"first": "W", "middle": [], "last": "Moreno", "suffix": ""}, {"first": "K", "middle": [], "last": "Leung", "suffix": ""}], "year": 2014, "venue": "IEEE Communications Surveys Tutorials", "link": "21738890"}, "BIBREF33": {"title": "Towards decentralized recommender systems", "authors": [{"first": "Cai-Nicolas", "middle": [], "last": "Ziegler", "suffix": ""}], "year": 2005, "venue": "Ph.D. Dissertation. Albert-Ludwigs", "link": null}}, "ref_entries": {"FIGREF0": {"text": "Four types of data proposed by Propagate and Filter and their respective use at propagation. Recommendations are calculated on the mobile device upon all four data pools.", "type": "figure"}, "TABREF0": {"text": "Connection success rates subject to transmission range", "type": "table"}, "TABREF1": {"text": "Average battery drain of pre-connection (advertising and discovery) Battery Drainage: Since the advertising and discovery step", "type": "table"}}}
{"paper_id": "199668943", "_pdf_hash": "a3e13aedf6373da60d9529acc000f1f534f86600", "abstract": [{"section": "Abstract", "text": "Estimating 3D human pose from monocular images demands large amounts of 3D pose and in-the-wild 2D pose annotated datasets which are costly and require sophisticated systems to acquire. In this regard, we propose a metric learning based approach to jointly learn a rich embedding and 3D pose regression from the embedding using multi-view synchronised videos of human motions and very limited 3D pose annotations. The inclusion of metric learning to the baseline pose estimation framework improves the performance by 21% when 3D supervision is limited. In addition, we make use of a person-identity based adversarial loss as additional weak supervision to outperform state-of-the-art whilst using a much smaller network. Lastly, but importantly, we demonstrate the advantages of the learned embedding and establish view-invariant pose retrieval benchmarks on two popular, publicly available multi-view human pose datasets, Human 3.6M and MPI-INF-3DHP, to facilitate future research.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Over the years, the performance of monocular 3D Human pose estimation has improved significantly by leveraging complex CNN models. [37, 18, 35] . However, these methods rely heavily on large-scale 3D pose annotated training data, which is difficult and costly to obtain, especially under in-the-wild setting for articulated poses. The two most popular 3D ground-truth annotated datasets, Human3.6M [7] and MPI-INF-3DHP [13] , have 3.6M and 1.3M annotated poses, respectively. Unfortunately, these datasets are biased towards typical indoor setting like uniform background and illumination and lack real-world environment variations [37] . However, it is relatively easier to obtain time-synchronized video streams of human poses from multiple different viewpoints. Therefore, techniques that can employ un-annotated multi-view human-pose data to learn the 3D structure and geometry could prove benefi- * -equal contribution cial for human-pose estimation with small amount of annotated data. To this end, we propose a metric learning based approach to jointly learn a 3D human pose embedding and pose regression using the embedding from synchronized videos of human motion with very limited pose annotations. Our approach doesn't require camera extrinsics or prior background extraction. Therefore, it can be easily extended to train with further un-annotated in-the-wild data. We seek motivation from a recent work in [22] , where image generation in different views via a geometry-aware latent space is used to improve pose-estimation under limited 3D supervision. This method, however, requires camera extrinsics and static background during training, which limits its application to indoor datasets. Our proposed approach is free from these constraints and, therefore, can potentially be used for in-the-wild setting. Moreover, we also show superior performance with faster inference.", "cite_spans": [{"start": 131, "end": 135, "text": "[37,", "ref_id": "BIBREF36"}, {"start": 136, "end": 139, "text": "18,", "ref_id": "BIBREF17"}, {"start": 140, "end": 143, "text": "35]", "ref_id": "BIBREF34"}, {"start": 398, "end": 401, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 419, "end": 423, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 632, "end": 636, "text": "[37]", "ref_id": "BIBREF36"}, {"start": 1419, "end": 1423, "text": "[22]", "ref_id": "BIBREF21"}], "ref_spans": []}, {"section": "Introduction", "text": "We utilize our framework to improve pose estimation accuracy under limited 3D supervision. We show that weak supervision in learning the embedding ensures that our model's performance degrades gracefully when 3D supervision is progressively reduced. Additionally, we eliminate the subject-specific appearance information from our latent embedding with the help of an adversarial mechanism which leads to further improvements and outperforms the current state-of-the-art [22] . Lastly, we use smaller network architecture that affords 3X faster inference time. A simplified overview of our approach and its utilization is shown in Fig. 1 . The formulation of our loss function leads to a view-invariant embedding, and in Sec. 5, we demonstrate the richness of our learned embedding to capture human pose structure invariant to viewpoint by way of carefully designed pose retrieval experiments and establish novel benchmarks on Human3.6M and MPI-INF-3DHP to facilitate future research. A summary of our contributions is,", "cite_spans": [{"start": 470, "end": 474, "text": "[22]", "ref_id": "BIBREF21"}], "ref_spans": []}, {"section": "3D Pose", "text": "Figure 1: A schematic diagram explaining the motivation of our work of learning an pose embedding from multi-view images and utilizing the embedding for 3D pose estimation and view-invariant pose retrieval. The learned embedding space lies on the surface of a multi-dimensional unit hyper sphere. A detailed 2D T-SNE visualization of the embedding space in presented in the supplementary material.", "cite_spans": [], "ref_spans": []}, {"section": "3D Pose", "text": "\u2022 Formulating view-invariant pose retrieval benchmarks based on Human3.6M and MPI-INF-3DHP datasets.", "cite_spans": [], "ref_spans": []}, {"section": "Related Work", "text": "In this section, we first review prior approaches for learning human-pose embedding followed by a discussion of previous weakly supervised methods for monocular 3D human pose estimation to bring out the differences between our approach and the previous art. Later, we discuss the usage of deep metric learning in capturing image similarity.", "cite_spans": [], "ref_spans": []}, {"section": "Human Pose Embedding", "text": "Historically, human-pose embedding have been employed in tracking persons [34, 10] . Estimation of 3D human pose and viewpoint from input silhouettes via learning a low dimension manifold is shown in [4] . Pose regression and retrieval in 2D by learning pose similarity embedding is shown in [9, 16] , but they require 2D annotations. In [27] , the need for 2D annotations is eliminated by using human motion videos and temporal ordering as weak supervision with a metric learning based loss. Unlike the aforementioned approaches, we learn a view-invariant 3D human pose embedding by taking advantage of semantically similar images in synchronized multi-view videos. In [29] a 3D pose embedding learnt using an over-complete autoencoder for better structure preservation, however unlike us they requires require full 3D annotations.", "cite_spans": [{"start": 74, "end": 78, "text": "[34,", "ref_id": "BIBREF33"}, {"start": 79, "end": 82, "text": "10]", "ref_id": "BIBREF9"}, {"start": 200, "end": 203, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 292, "end": 295, "text": "[9,", "ref_id": "BIBREF8"}, {"start": 296, "end": 299, "text": "16]", "ref_id": "BIBREF15"}, {"start": 338, "end": 342, "text": "[27]", "ref_id": "BIBREF26"}, {"start": 670, "end": 674, "text": "[29]", "ref_id": "BIBREF28"}], "ref_spans": []}, {"section": "Weakly Supervised 3D Human Pose Estimation", "text": "Majority of supervised 3D Human Pose Estimation algorithms [14, 12, 31, 21, 17] use 3D pose labels to train a model for regressing 3D joints locations from images or decouple the problem into 2D joint regression followed by 2D-to-3D lifting. In either case, they need large amount of annotated 2D and 3D training data. Another line of work [33, 26] focuses on training for 3D estimation with datasets capturing the scene in multi-view images. In [19] , approximate 3D human joint labels for supervision are generated by triangulating its corresponding 2D annotations from multiple view images. Utilizing multi-view images during training has recently been proposed in [23, 22, 20, 3] . Methods using multi-view images can further be classified into the following categories, strong 2D and limited 3D supervision -Methods mentioned in [23, 20, 3] use full 2D supervision from in-thewild datasets like MPII [1] to either estimate 3D pose from images or perform 2D to 3D pose lifting. In [3] , a latent embedding capturing 3D pose is learned by reconstructing 2D pose from the embedding in a different view. A shallow network requiring much less supervision is subsequently learned to regress 3D pose from the embedding. In [20] , back-projection of predicted 3D pose to its 2D representation and its difference with the input 2D pose is used as a weak supervision in [20] . Additionally, it uses multiple temporally adjacent frames at inference to refine predictions. A network with pre-trained weights for 2D pose estimation is used for 3D estimation in [23] . limited 3D supervision -To alleviate the need for a large amount of 2D annotations, [22] learns an unsupervised embedding and estimates pose from it with limited 3D supervision. Novel view synthesis using synchronized videos from multiple views is used to learn a geometry aware embedding capturing human pose. This method however still requires camera extrinsics and background extraction.", "cite_spans": [{"start": 59, "end": 63, "text": "[14,", "ref_id": "BIBREF13"}, {"start": 64, "end": 67, "text": "12,", "ref_id": "BIBREF11"}, {"start": 68, "end": 71, "text": "31,", "ref_id": "BIBREF30"}, {"start": 72, "end": 75, "text": "21,", "ref_id": "BIBREF20"}, {"start": 76, "end": 79, "text": "17]", "ref_id": "BIBREF16"}, {"start": 340, "end": 344, "text": "[33,", "ref_id": "BIBREF32"}, {"start": 345, "end": 348, "text": "26]", "ref_id": "BIBREF25"}, {"start": 446, "end": 450, "text": "[19]", "ref_id": "BIBREF18"}, {"start": 668, "end": 672, "text": "[23,", "ref_id": "BIBREF22"}, {"start": 673, "end": 676, "text": "22,", "ref_id": "BIBREF21"}, {"start": 677, "end": 680, "text": "20,", "ref_id": "BIBREF19"}, {"start": 681, "end": 683, "text": "3]", "ref_id": "BIBREF2"}, {"start": 834, "end": 838, "text": "[23,", "ref_id": "BIBREF22"}, {"start": 839, "end": 842, "text": "20,", "ref_id": "BIBREF19"}, {"start": 843, "end": 845, "text": "3]", "ref_id": "BIBREF2"}, {"start": 905, "end": 908, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 985, "end": 988, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 1221, "end": 1225, "text": "[20]", "ref_id": "BIBREF19"}, {"start": 1365, "end": 1369, "text": "[20]", "ref_id": "BIBREF19"}, {"start": 1553, "end": 1557, "text": "[23]", "ref_id": "BIBREF22"}, {"start": 1644, "end": 1648, "text": "[22]", "ref_id": "BIBREF21"}], "ref_spans": []}, {"section": "Weakly Supervised 3D Human Pose Estimation", "text": "Our proposed method also utilizes synchronized videos from multiple views to learn a pose embedding but unlike [22] does not require camera extrinsics and background information. Moreover, due to our metric learning based approach, we do not require to perform image-reconstruction that affords smaller networks, Resnet-18 [6] vs. Resnet-50. Subject-specific appearance disentanglement from human pose embedding has been shown in [22] using appearance swap followed by an image reconstruction task. Such swapping mechanism doesn't guarantee removal of appearance from pose embedding as the network has an alternate information pathway through the pose branch. We, on the other hand, adopt the method in [11] using adversarial losses to remove the subject-specific appearance information from our pose embedding.", "cite_spans": [{"start": 111, "end": 115, "text": "[22]", "ref_id": "BIBREF21"}, {"start": 323, "end": 326, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 430, "end": 434, "text": "[22]", "ref_id": "BIBREF21"}, {"start": 703, "end": 707, "text": "[11]", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "Learning Image Similarity", "text": "To learn image similarity, images are mapped to a low dimensional embedding space via a CNN and trained with a contrastive or triplet loss. In contrastive loss [25, 36, 5] , semantically similar image pairs (positive pairs) are mapped close together in the embedding space while those dissimilar content (negative pairs) are mapped far apart. In triplet loss [2, ?] , the hard constraint of contrastive loss is relaxed by ensuring a relative separation between positive and negative image pairs by a pre-determined margin. Hence, the euclidean distance between two images in the embedding space gives the measure of their similarity. For our application a pair of images are semantically same if they represent humans with the same underlying 3D pose.", "cite_spans": [{"start": 160, "end": 164, "text": "[25,", "ref_id": "BIBREF24"}, {"start": 165, "end": 168, "text": "36,", "ref_id": "BIBREF35"}, {"start": 169, "end": 171, "text": "5]", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "Learning Image Similarity", "text": "The performance of models using either of the losses is highly dependant on the quality of dissimilar samples used during training [25, 36] . The current state-of-the-art image descriptor learning framework Hardnet [15] provides a good-trade-off between performance and training time by selecting the hardest negative within a batch. Inspired by its performance and simplicity in training, we adopt the hardnet to learn our pose embedding.", "cite_spans": [{"start": 131, "end": 135, "text": "[25,", "ref_id": "BIBREF24"}, {"start": 136, "end": 139, "text": "36]", "ref_id": "BIBREF35"}, {"start": 215, "end": 219, "text": "[15]", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "Proposed Approach", "text": "Our proposed approach is comprised of two modules i) learning an embedding capturing human pose information from multi-view time synchronised videos using metric learning ii) regressing 3D human pose from the embedding using minimal 3D supervision. We jointly learn the two modules as shown in Fig. 3 . Metric learning provides a weak supervision and reduces the dependency on large 3D annotations in our framework while pose regression guides the framework to learn pose specific features. The following sub-sections explains the two modules,", "cite_spans": [], "ref_spans": [{"start": 294, "end": 300, "text": "Fig. 3", "ref_id": "FIGREF3"}]}, {"section": "Metric Learning", "text": "To learn our pose embedding via metric learning, we utilise Hardnet framework [15] due to its the state-of-the-art performance in image patch matching invariant to camera viewpoints. The datasets used for training have the following generic format. The entire data is divided into images belonging to one of S = {S 1 , S 2 , . . . S n } set of subjects. The set P \u2282 IR 16\u00d73 is the set of all possible poses and each pose is viewed from V = {v 1 , v 2 , . . . v q } set of viewpoints.", "cite_spans": [{"start": 78, "end": 82, "text": "[15]", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "Metric Learning", "text": "In the hardnet training regimen, each batch consists of paired anchor( \u00a7 va p \u2208 X ) and positive( \u00a7 v b p \u2208 X ) images that share same pose p \u2208 P but taken from different viewpoints v a and v b . X \u2282 IR 3\u00d7256\u00d7256 is the set of all images. It is to be noted, since we use time synchronization to choose a pair of anchor and positive, it is implied that they share the same subject. However different anchors within a batch can be from different subjects. We pass both the anchor and positive images through feature extractor (F \u03b8 F : X \u2192 \u03a8; \u03a8 \u2282 IR 512\u00d74\u00d74 ) to generate features {\u03c8", "cite_spans": [], "ref_spans": []}, {"section": "Metric Learning", "text": "The feature extractor network is parameterised by \u03b8 F . The features are then finally passed through an embedding generating network (G \u03b8 G : \u03a8 \u2192 \u03a6; \u03a6 \u2282 IR dim \u03c6 ; where dim \u03c6 is dimension of our embedding). Let's assume we feed anchor and positive images to F in batches of m. Once corresponding features {\u03c6 pi respectively. Mathematically, the sampling is formulated in Eq. 1. Here, \u03b1 denotes the margin.", "cite_spans": [], "ref_spans": []}, {"section": "Metric Learning", "text": "The average triplet loss over the batch is then given by,", "cite_spans": [], "ref_spans": []}, {"section": "Metric Learning", "text": "Similarly, the average contrastive loss is given by,", "cite_spans": [], "ref_spans": []}, {"section": "Metric Learning", "text": "Our anchor and positives examples always share the same subject and it results in unwarranted appearance bias in the embedding. Hence, to improve pose accuracy, it is necessary to disentangle appearance information from our learned embedding. To this end, we introduce an adversarial loss on our ResNet feature extractor F \u03b8 F so as to fool an ap-", "cite_spans": [], "ref_spans": []}, {"section": "Metric Learning", "text": "Our formulation is inspired from [11] where adversarial training is used to disentangle individual identity and other facial information from images of faces. Formally, we define our adversarial formulation with input image x i and subject label y i \u2208 Y and prediction\u0177 i in Eq. 4,", "cite_spans": [{"start": 33, "end": 37, "text": "[11]", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "Metric Learning", "text": "In Eq. 4, L class tries to make the classifier M predict higher probability for the correct target while L adv tries to fool the classifier to predict uniform probability for all subjects by tuning the ResNet feature generator F. At equilibrium, F generates features \u03a8 which are devoid of any subject appearance information. Note that our weak supervision losses namely, L class , L adv , L cnstr / L trip do not require camera extrinsics, background extraction, pose annotations etc. and the only sources of supervision are synchronizing the videos, annotating the subject and pre-trained ImageNet [24] weights.", "cite_spans": [{"start": 599, "end": 603, "text": "[24]", "ref_id": "BIBREF23"}], "ref_spans": []}, {"section": "Pose Regression", "text": "Most 3D human pose estimation approaches focus on regressing pose in the local camera coordinate system. In this representation, frames captured from different camera views but of the same time instant will be associated poses with different 3D co-ordinates values of the body joints. However, the frames are all mapped to the same point in our embedding space irrespective of their viewpoint by our formulation. Hence, regressing pose in this representation from our learned embedding is ambiguous as the relation to be learned by the regressor is one-many. In this regard, one can utilise pose represented in the MoCap system's coordinate system. We term this representation as global pose. In this representation, frames captured from different viewpoints belonging to a particular time instant are associated with one pose. However, frames captured at different time instants can contain poses which are rigid body transforms of one another while having same set of 2D projections. In such cases, regressing pose from our embedding is again learning a one-many relation. In Fig. 2 , an example of such ambiguity is illustrated.", "cite_spans": [], "ref_spans": [{"start": 1078, "end": 1084, "text": "Fig. 2", "ref_id": "FIGREF1"}]}, {"section": "Pose Regression", "text": "To estimate 3D pose from our embedding and bene- fit from the embedding loss, we formulate a corresponding view-invariant pose representation. We term this representation as canonical pose. To ensure consistency among poses captured from different camera views and at different time instants in our canonical pose representation, we ensure that the bone connecting the pelvis to the right hip joint is always parallel to XZ plane. In Human3.6M dataset, the upward direction is +Z axis while XY plane forms the horizontal. So, we rotate the skeleton about the +Z axis until the above mentioned bone is parallel to the XZ axis. This makes the depth aligned along Y axis. We don't require any translation since the joint positions are root relative with pelvis being the root. As an added bonus, unlike pose estimated in camera coordinates, our predicted canonical pose does not change orientation with variations in camera viewpoint. A similar approach to achieve a rotation invariant pose is suggested in [32] . Note that the canonical pose is constructed directly from MoCap system's coordinates and doesn't require camera extrinsics. We learn our canonical pose from the latent embedding \u03a6 space mentioned. To this end, we use a shallow network (H \u03b8 H : \u03a6 \u2192 P), as shown in Fig. 3 . We regress pose using L pose = p \u2212p 1 , with target pose p \u2208 P and predicted posep.", "cite_spans": [{"start": 1004, "end": 1008, "text": "[32]", "ref_id": "BIBREF31"}], "ref_spans": [{"start": 1275, "end": 1281, "text": "Fig. 3", "ref_id": "FIGREF3"}]}, {"section": "Pose Regression", "text": "We train our framework with all the losses simultaneously by default and optimize different network parameters according to Eq. 5. Note that the the gradient from L class does not flow through the network F. We also provide ablation on the different losses to understand their impact on pose estimation accuracy.", "cite_spans": [], "ref_spans": []}, {"section": "Pose Regression", "text": "The metric learning loss used to learn \u03a6 serves as a weak supervision in canonical pose estimation. The L conrst loss ensures latent embeddings \u03c6 ", "cite_spans": [], "ref_spans": []}, {"section": "Implementation and Training Details", "text": "We build our architecture on the ResNet framework and choose the 18 layer version in our implementation. We only use the first 4 residual blocks and initialize them with pretrained ImageNet [24] weights. In addition, we modify the batch-norm layers by turning off the affine parameters as suggested in [15] . When the input image size is 256 \u00d7 256 , the output of the ResNet network is 512 \u00d7 8 \u00d7 8. We down- p are a pair of anchor and positive images taken from different camera views. F is the ResNet based feature extractor. G maps features extracted \u03c8 from F to our embedding \u03c6. The Hard Negative Sampling module performs in-batch hard mining as given in Eq. 1. Network H regresses posep from our embedding \u03c6. Classifier M is used to classify subjects from set S from features \u03c8. L class , L adv and L pose are discussed in Sec. 3.2. Network blocks sharing same colour also share parameters. sample the ResNet output by half using a MaxPooling layer to get \u03a8. The embedding network G maps it to the output embedding of dimension dim \u03c6 , using a Fully-Connected layer and BN layer followed by L2-Normalization as done in [15, 30] . The value of dim \u03c6 is 256 for all our experiments. The classifier network M consists of Conv(512, 256, kernel=1), BN, ReLU, Conv(256, 256, kernel=4), BN, ReLU, FC(256, |S|) with |S| = 5.", "cite_spans": [{"start": 190, "end": 194, "text": "[24]", "ref_id": "BIBREF23"}, {"start": 302, "end": 306, "text": "[15]", "ref_id": "BIBREF14"}, {"start": 1123, "end": 1127, "text": "[15,", "ref_id": "BIBREF14"}, {"start": 1128, "end": 1131, "text": "30]", "ref_id": "BIBREF29"}], "ref_spans": []}, {"section": "Implementation and Training Details", "text": "For regression, similar to [12] , we normalize the dataset for each joint. The pose regression network G consists of fully-connected layer FC(256, 48), with \u03a6 \u2282 IR 256 . We choose the margin \u03b1 for L conrst to be 0.6. Adam [8] with default parameters (\u03b1 = 0.9, \u03b2 = 0.99) is used as the optimizer with initial learning rate 10 \u22123 . The model is trained for 25 epochs with the learning rate dropped by 0.1 after every 15 epochs with a batch size of 128. A schematic diagram of our network architecture is shown in Fig. 3. ", "cite_spans": [{"start": 27, "end": 31, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 222, "end": 225, "text": "[8]", "ref_id": "BIBREF7"}], "ref_spans": [{"start": 511, "end": 518, "text": "Fig. 3.", "ref_id": "FIGREF3"}]}, {"section": "Datasets", "text": "We use the popular Human3.6M [7] and MPI-INF-3DHP [13] datasets.", "cite_spans": [{"start": 29, "end": 32, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 50, "end": 54, "text": "[13]", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "Datasets", "text": "\u2022 Human3.6M -The dataset contains 3.6 million frames captured from an indoor MoCap setting with 4 cameras(V). It comprises of 11 subjects (actors)(S), each performing 16 actions with each action having 2 sub-actions. Following the standard protocol [28] , Protocol 2, we use subjects (S1, S5, S6, S7, S8) for training and (S9, S11) for testing. As used by several other methods, we use images cropped using subject bounding boxes provided with the dataset and temporal sub-sampling to include every 5 th and 64 th frame for training and testing phase, respectively,", "cite_spans": [{"start": 249, "end": 253, "text": "[28]", "ref_id": "BIBREF27"}], "ref_spans": []}, {"section": "Datasets", "text": "\u2022 MPI-INF-3DHP -This dataset is generated from a MoCap system with 12 synchronized cameras in both indoor and outdoor settings. It contains 8 subjects(S) with diverse clothing. We use the 5 chest height cameras(V) for both training and test purposes. Since the test set doesn't contain annotated multi-view data, we use S1-S6 for training and S7-S8 for evaluation.", "cite_spans": [], "ref_spans": []}, {"section": "Evaluation", "text": "We perform the same quantitative experiment as presented in Rhodin et. al [22] to establish the benefits of the learned embedding in pose estimation. We evaluate using two well adopted metrics, MPJPE and Normalized MPJPE (N-MPJPE) (introduced in [23] ) which incorporates a scale normalization to make the evaluation independent of person height as our evaluation metric. We compare our proposed approach and its variants against a baseline which only uses L pose . In addition, we compare our method against the approach proposed by Rhodin et. al [22] and [23] , although it estimates human poses in the camera coordinate system. [22] . Our proposed model outperforms the current state of the art.", "cite_spans": [{"start": 74, "end": 78, "text": "[22]", "ref_id": "BIBREF21"}, {"start": 246, "end": 250, "text": "[23]", "ref_id": "BIBREF22"}, {"start": 548, "end": 552, "text": "[22]", "ref_id": "BIBREF21"}, {"start": 557, "end": 561, "text": "[23]", "ref_id": "BIBREF22"}, {"start": 631, "end": 635, "text": "[22]", "ref_id": "BIBREF21"}], "ref_spans": []}, {"section": "Evaluation", "text": "We also report the performance of Rhodin et. al [22] using ResNet-18 as the feature extractor instead of ResNet-50. It is to be noted [22] uses additional information at training time in form of relative camera rotation and background extraction which requires sophisticated, well calibrated setup. We acknowledge existence of more accurate methods than [22, 23] on Human3.6M when abundant 2D and 3D labels are available. However, like [22] to highlight the point of limited supervision, we omit them in our comparison. We also report performance of [3] which requires limited 3D supervision but uses full 2D supervision from MPII [1] dataset. We did not include the results of [20] as it requires multiple temporally adjacent frames at inference. We report both N-MPJPE values when our model is trained and tested on Human3.6M dataset with progressively less supervision for pose regression in Fig. 4 . The amount of supervision is reduced gradually from full supervision using all 5 subjects, to S1+S6, only S1, 50% S1, 10%S1 and finally 5% S1. Our proposed model clearly outperforms the baseline as 3D supervision is reduced with a gain of 33 mm (21.5%) N-MPJPE when only S1 is used for supervision). The performance of our model shows little degradation even on further reduction in supervision. A variant of our proposed model with appearance not disentangled also beats the baseline convincingly but performs worse compared to when appearance is disentangled. The observation validates the importance of L conrst in providing weak supervision capturing 3D pose and the need to eliminate appearance bias. Qualitative comparison of our method against the baseline is shown in Fig. 4 . In Table. 1, we compare MPJPE and N-MPJPE values of our approach against baseline and [22] . Considering N-MPJPE, our method outperforms [22] by 14 mm when fully supervised on 3D data and by 2 mm when supervision is limited to S1. When MPJPE is considered the difference is 4 mm. Interestingly as mentioned in [22] , the performance of [23] drastically falls when pre-trained weights from strong 2D pose supervision is not used (reported in Table 1 as Rhodin [23] * and Rhodin [23] ). Table 1 : Comparing N-MPJPE and MPJPE values between different approaches on Human 3.6M dataset when supervised on all 5 subjects and on only S1. Note: Pre-trained ImageNet weights are used to initialize the networks by all the methods. Methods or its variants marked with '*' are supervised with large amount of in-the-wild 2D annotations from MPII [1] dataset either during training or by means of a pre-trained 2D pose estimator. All other methods use much weaker supervision by assuming no 2D annotations and ours outperforms the state-of-the-art [22] in such settings.", "cite_spans": [{"start": 48, "end": 52, "text": "[22]", "ref_id": "BIBREF21"}, {"start": 134, "end": 138, "text": "[22]", "ref_id": "BIBREF21"}, {"start": 354, "end": 358, "text": "[22,", "ref_id": "BIBREF21"}, {"start": 359, "end": 362, "text": "23]", "ref_id": "BIBREF22"}, {"start": 436, "end": 440, "text": "[22]", "ref_id": "BIBREF21"}, {"start": 550, "end": 553, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 631, "end": 634, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 678, "end": 682, "text": "[20]", "ref_id": "BIBREF19"}, {"start": 1775, "end": 1779, "text": "[22]", "ref_id": "BIBREF21"}, {"start": 1826, "end": 1830, "text": "[22]", "ref_id": "BIBREF21"}, {"start": 1999, "end": 2003, "text": "[22]", "ref_id": "BIBREF21"}, {"start": 2025, "end": 2029, "text": "[23]", "ref_id": "BIBREF22"}, {"start": 2148, "end": 2152, "text": "[23]", "ref_id": "BIBREF22"}, {"start": 2166, "end": 2170, "text": "[23]", "ref_id": "BIBREF22"}, {"start": 2524, "end": 2527, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 2725, "end": 2729, "text": "[22]", "ref_id": "BIBREF21"}], "ref_spans": [{"start": 895, "end": 901, "text": "Fig. 4", "ref_id": "FIGREF4"}, {"start": 1680, "end": 1686, "text": "Fig. 4", "ref_id": "FIGREF4"}]}, {"section": "Supervision", "text": "Method N-MPJPE MPJPE We additionally compare performance of our learning framework when target pose is represented in MoCap's(global pose) against our canonical representation in Table. 2. The increase in N-MPJPE by 43mm for global pose validates the importance of our canonical representation to the efficacy of our approach.", "cite_spans": [], "ref_spans": []}, {"section": "Supervision", "text": "An additional benefit of our proposed framework is that it uses a much smaller ResNet-18 feature extractor as compared to ResNet-50 used in Rhodin et. al [22] . This enables our model achieve an interference time of 24.8 ms in comparison to 75.3 ms obtained obtained by [22] averaged over batch size of 32 using NVIDIA 1080Ti GPU. Hence, our method performs roughly 3X faster inference while attain- Figure 5 : Qualitative results on canonical pose estimation by our proposed framework (Ours) against our Baseline on Human 3.6M test split (S9, S11). Both the models are trained with supervision from labels of subject S1. Our method produces more accurate estimates for even for challenging poses like 'sitting', 'kneeling', 'bending' ing better accuracy.", "cite_spans": [{"start": 154, "end": 158, "text": "[22]", "ref_id": "BIBREF21"}, {"start": 270, "end": 274, "text": "[22]", "ref_id": "BIBREF21"}], "ref_spans": []}, {"section": "View Invariant Pose Retrieval", "text": "In this section, we demonstrate the quality of our learned embedding through a series of retrieval tasks and provide benchmarks against an oracle on popular human pose datasets. Given a query image of a human from a particular view, our learned embedding ensures that images from all the other views are mapped close to it in the embedding space.", "cite_spans": [], "ref_spans": []}, {"section": "View Invariant Pose Retrieval", "text": "To quantify the view-invariance, we formulate Hit@K which measures the percentage of queries with the exact pose among the top K poses retrieved through the embedding. For example, 85% Hit@5 indicates that out of 100 queries, 85 queries have atleast one of the images with exact pose but from a different viewpoint in the top 5 retrievals. We also define Hit@K All which registers a hit when all of the images with exact pose are present in top K retrievals.", "cite_spans": [], "ref_spans": []}, {"section": "View Invariant Pose Retrieval", "text": "Further, we want to ensure that the images with similar pose should be clustered together in the embedding space. In this regard, we propose Mean PA-MPJPE@K which measures the Procrustes Aligned Mean Per Joint Position Error(PA-MPJPE) of K closest neighbours from other views. The retrieved poses, although similar to the query in terms relative skeleton configuration, can have different orientations. Hence we use PA-MPJPE, which is MPJPE calculated after rigid alignment of retrieved pose with the ground truth of query pose, for a fair evaluation.", "cite_spans": [], "ref_spans": []}, {"section": "Evaluation", "text": "We compare our model against an oracle which uses ground truth 3D annotations. Given a query image, we ensure that the retrieval database contains images taken from viewpoints other than that of the query image. It is done to clearly bring out the view invariance property of the proposed embedding. The aforementioned two performance metrics are used to quantify the pose retrieval performance, namely Mean PA-MPJPE@K and Hit@K. First, we report the Mean PA-MPJPE@K between query pose and its K nearest neighbors in the embedding space. In Fig. 6 , we show comparison of Mean PA-MPJPE@K of retrieved poses when retrieval is done from images with: Case 1: all test subjects including that of query's. Case 2: all test subjects except that of query's, termed as cross. We report our results relative to the oracle. The horizontal plots with low errors suggest that our model picks poses similar to that of oracle irrespective of K. The error is lower for Case 1 than Case 2 due to the presence of images from different viewpoints sharing the exact pose as that of query's.", "cite_spans": [], "ref_spans": []}, {"section": "Evaluation", "text": "Our second metric, similar to [9] , is computing Hit@K which measures the occurrence of a correct pose among top K retrievals using nearest neighbors. A retrieved pose is considered correct if it is exactly same as the query pose but from a different viewpoint. However, unlike [9] , we do not retrieve poses having same viewpoint as that of query. We measure Hit@K under Case 1 settings previously mentioned. Under easy('E') setting, a hit is registered when a retrieved image with the correct pose differs in viewpoint with the query by less than 90", "cite_spans": [{"start": 30, "end": 33, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 278, "end": 281, "text": "[9]", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "Evaluation", "text": "\u2022 . Under hard('H'), the viewpoint difference has to be more than 90", "cite_spans": [], "ref_spans": []}, {"section": "Evaluation", "text": "\u2022 . Unlike, 'E' and 'H', in 'All', a hit is considered when correct poses from every viewpoint other than that of query are present in the top K. The evaluation of this metric on our model is shown in Fig. 7 . We achieve high accuracy rates of more than 85% for easy('E') viewpoint differences on Human3.6M even for low values of K = 2, 5. For hard ('H') viewpoint differences, the performance goes down but still remains above 70%. However, the most impressive performance of our model is shown when retrieving 'All' other views with K = 5. The accuracy is close to 50%. This implies our model retrieves all the 3 corresponding views in the top 5 slots, half of the time. The performance on MPI-INF-3DHP is comparatively lower than Human3.6M, specially on low K values. We attribute this to MPI-INF-3DHP having smaller training data. We have included qualitative results of our retrieval experiments in the supplementary material.", "cite_spans": [], "ref_spans": []}, {"section": "Discussions", "text": "An interesting observation from pose regression results shown in Fig. 4 , is that our proposed model performs worse than the baseline under full 3D supervision. This is also observed in [22] , and one possible explanation is that the additional weak supervision losses lead to a joint optimum which is sub-optimal for pose regression. But in case of reduced 3D supervision, all the losses work in synergy and produce a high improvement over the baseline pose accuracies. To analyse this further, in Table. 3 we show the result of adding progressive pose supervision on Mean PA-MPJPE@5 for cross subject retrieval on Human 3.6M dataset. We observe that even a limited amount of pose supervision (5% S1), reduces Mean PA-MPJPE@K by 13.23mm. We can also see that using only L pose supervision on S1 without other losses, leads to poor retrievals. Here, we note that a single embedding trained with both L pose and L conrst outperforms the respective task specific embeddings, when 3D supervision is limited. ", "cite_spans": [{"start": 186, "end": 190, "text": "[22]", "ref_id": "BIBREF21"}], "ref_spans": [{"start": 65, "end": 71, "text": "Fig. 4", "ref_id": "FIGREF4"}]}, {"section": "Conclusion And Future Work", "text": "In this paper, we demonstrated a metric learning approach to capture 3D human structure and its effectiveness in both pose estimation and pose retrieval tasks. More specifically, the information from our embedding reduces the need for 3D supervision when regressing human pose, enabling our method to outperform contemporary weaklysupervised approaches even while using a smaller network. Further, we provided strong benchmarks for view-invariant pose retrieval on publicly available datasets.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusion And Future Work", "text": "In future, we plan to use multi-view synchronised videos captured in-the-wild and synthetically generated, consisting of images taken from a large no. of viewpoints with diverse appearances, to improve the quality of the embedding and in the wild generalisation. Also, we plan to apply our approach to recognize actions from unseen viewpoints. Figure 8 : Shows top 5 pose retrievals using our embedding on Human3.6M [7] and MPI-INF-3DHP [13] datasets. The top row marked in Red is the query image, the next five rows shows retrieved images taken from different viewpoint having similar poses.", "cite_spans": [{"start": 416, "end": 419, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 437, "end": 441, "text": "[13]", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "Supplementary Material", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Qualitative Pose Retrieval Results", "text": "In Fig. 8 , we provide examples of retrieved poses from viewpoints different to that of the query from the popular Human3.6M [7] and MPI-INF-3DHP [13] datasets.", "cite_spans": [{"start": 125, "end": 128, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 146, "end": 150, "text": "[13]", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "Visualisation of Embedding Space", "text": "In Fig. 9 , a 2D T-SNE visualisation of our leaned pose embedding space is shown. Figure 9 : The top image shows a 2D T-SNE visualisation of our learned embedding space on test split of Human3.6M [7] . In bottom left and right images, zoomed in views of green and red boxes from top are shown respectively. One can observe the clusters of similar poses formed in the zoomed in boxes. Note: The 2D visualization provided is an approximation of the original embedding space which lies on the surface of a multi-dimensional unit hyper-sphere. Hence, there are inconsistency in smoothness in the pose space at some places.", "cite_spans": [{"start": 196, "end": 199, "text": "[7]", "ref_id": "BIBREF6"}], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "2d human pose estimation: New benchmark and state of the art analysis", "authors": [{"first": "M", "middle": [], "last": "Andriluka", "suffix": ""}, {"first": "L", "middle": [], "last": "Pishchulin", "suffix": ""}, {"first": "P", "middle": [], "last": "Gehler", "suffix": ""}, {"first": "B", "middle": [], "last": "Schiele", "suffix": ""}], "year": 2014, "venue": "Proceedings of the IEEE Conference on computer Vision and Pattern Recognition", "link": "206592419"}, "BIBREF1": {"title": "Large scale online learning of image similarity through ranking", "authors": [{"first": "G", "middle": [], "last": "Chechik", "suffix": ""}, {"first": "V", "middle": [], "last": "Sharma", "suffix": ""}, {"first": "U", "middle": [], "last": "Shalit", "suffix": ""}, {"first": "S", "middle": [], "last": "Bengio", "suffix": ""}], "year": 2010, "venue": "Journal of Machine Learning Research", "link": "2087262"}, "BIBREF2": {"title": "Weaklysupervised discovery of geometry-aware representation for 3d human pose estimation", "authors": [{"first": "X", "middle": [], "last": "Chen", "suffix": ""}, {"first": "K.-Y", "middle": [], "last": "Lin", "suffix": ""}, {"first": "W", "middle": [], "last": "Liu", "suffix": ""}, {"first": "C", "middle": [], "last": "Qian", "suffix": ""}, {"first": "L", "middle": [], "last": "Lin", "suffix": ""}], "year": 2019, "venue": "Proceedings of the IEEE Conference on Computer Vision and Pattern Recognition", "link": "84843959"}, "BIBREF3": {"title": "Inferring 3d body pose from silhouettes using activity manifold learning", "authors": [{"first": "A", "middle": [], "last": "Elgammal", "suffix": ""}, {"first": "C.-S", "middle": [], "last": "Lee", "suffix": ""}], "year": 2004, "venue": "Proceedings of the 2004 IEEE Computer Society Conference on Computer Vision and Pattern Recognition", "link": "121923341"}, "BIBREF4": {"title": "Dimensionality reduction by learning an invariant mapping", "authors": [{"first": "R", "middle": [], "last": "Hadsell", "suffix": ""}, {"first": "S", "middle": [], "last": "Chopra", "suffix": ""}, {"first": "Y", "middle": [], "last": "Lecun", "suffix": ""}], "year": 2006, "venue": "IEEE Computer Society Conference on Computer Vision and Pattern Recognition (CVPR'06)", "link": "8281592"}, "BIBREF5": {"title": "Deep residual learning for image recognition", "authors": [{"first": "K", "middle": [], "last": "He", "suffix": ""}, {"first": "X", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "S", "middle": [], "last": "Ren", "suffix": ""}, {"first": "J", "middle": [], "last": "Sun", "suffix": ""}], "year": 2016, "venue": "Proceedings of the IEEE conference on computer vision and pattern recognition", "link": "206594692"}, "BIBREF6": {"title": "Human3. 6m: Large scale datasets and predictive methods for 3d human sensing in natural environments", "authors": [{"first": "C", "middle": [], "last": "Ionescu", "suffix": ""}, {"first": "D", "middle": [], "last": "Papava", "suffix": ""}, {"first": "V", "middle": [], "last": "Olaru", "suffix": ""}, {"first": "C", "middle": [], "last": "Sminchisescu", "suffix": ""}], "year": 2005, "venue": "IEEE transactions on pattern analysis and machine intelligence", "link": "4244548"}, "BIBREF7": {"title": "Adam: A method for stochastic optimization", "authors": [{"first": "D", "middle": ["P"], "last": "Kingma", "suffix": ""}, {"first": "J", "middle": [], "last": "Ba", "suffix": ""}], "year": 2014, "venue": "", "link": "6628106"}, "BIBREF8": {"title": "Thin-slicing for pose: Learning to understand pose without explicit pose estimation", "authors": [{"first": "S", "middle": [], "last": "Kwak", "suffix": ""}, {"first": "M", "middle": [], "last": "Cho", "suffix": ""}, {"first": "I", "middle": [], "last": "Laptev", "suffix": ""}], "year": 2008, "venue": "Proceedings of the IEEE Conference on Computer Vision and Pattern Recognition", "link": "329517"}, "BIBREF9": {"title": "Modeling view and posture manifolds for tracking", "authors": [{"first": "C.-S", "middle": [], "last": "Lee", "suffix": ""}, {"first": "A", "middle": [], "last": "", "suffix": ""}], "year": 2007, "venue": "IEEE 11th International Conference on Computer Vision", "link": "7192536"}, "BIBREF10": {"title": "Exploring disentangled feature representation beyond face identification", "authors": [{"first": "Y", "middle": [], "last": "Liu", "suffix": ""}, {"first": "F", "middle": [], "last": "Wei", "suffix": ""}, {"first": "J", "middle": [], "last": "Shao", "suffix": ""}, {"first": "L", "middle": [], "last": "Sheng", "suffix": ""}, {"first": "J", "middle": [], "last": "Yan", "suffix": ""}, {"first": "X", "middle": [], "last": "Wang", "suffix": ""}], "year": 2018, "venue": "Proceedings of the IEEE Conference on Computer Vision and Pattern Recognition", "link": "4758668"}, "BIBREF11": {"title": "A simple yet effective baseline for 3d human pose estimation", "authors": [{"first": "J", "middle": [], "last": "Martinez", "suffix": ""}, {"first": "R", "middle": [], "last": "Hossain", "suffix": ""}, {"first": "J", "middle": [], "last": "Romero", "suffix": ""}, {"first": "J", "middle": ["J"], "last": "Little", "suffix": ""}], "year": 2017, "venue": "Proceedings of the IEEE International Conference on Computer Vision", "link": "206771080"}, "BIBREF12": {"title": "Monocular 3d human pose estimation in the wild using improved cnn supervision", "authors": [{"first": "D", "middle": [], "last": "Mehta", "suffix": ""}, {"first": "H", "middle": [], "last": "Rhodin", "suffix": ""}, {"first": "D", "middle": [], "last": "Casas", "suffix": ""}, {"first": "P", "middle": [], "last": "Fua", "suffix": ""}, {"first": "O", "middle": [], "last": "Sotnychenko", "suffix": ""}, {"first": "W", "middle": [], "last": "Xu", "suffix": ""}, {"first": "C", "middle": [], "last": "Theobalt", "suffix": ""}], "year": "", "venue": "2017 International Conference on 3D Vision (3DV)", "link": "17012729"}, "BIBREF13": {"title": "Vnect: Real-time 3d human pose estimation with a single rgb camera", "authors": [{"first": "D", "middle": [], "last": "Mehta", "suffix": ""}, {"first": "S", "middle": [], "last": "Sridhar", "suffix": ""}, {"first": "O", "middle": [], "last": "Sotnychenko", "suffix": ""}, {"first": "H", "middle": [], "last": "Rhodin", "suffix": ""}, {"first": "M", "middle": [], "last": "Shafiei", "suffix": ""}, {"first": "H.-P", "middle": [], "last": "Seidel", "suffix": ""}, {"first": "W", "middle": [], "last": "Xu", "suffix": ""}, {"first": "D", "middle": [], "last": "Casas", "suffix": ""}, {"first": "C", "middle": [], "last": "Theobalt", "suffix": ""}], "year": 2017, "venue": "ACM Transactions on Graphics (TOG)", "link": "1640720"}, "BIBREF14": {"title": "Working hard to know your neighbor's margins: Local descriptor learning loss", "authors": [{"first": "A", "middle": [], "last": "Mishchuk", "suffix": ""}, {"first": "D", "middle": [], "last": "Mishkin", "suffix": ""}, {"first": "F", "middle": [], "last": "Radenovic", "suffix": ""}, {"first": "J", "middle": [], "last": "Matas", "suffix": ""}], "year": 2017, "venue": "Advances in Neural Information Processing Systems", "link": "22589592"}, "BIBREF15": {"title": "Pose embeddings: A deep architecture for learning to match human poses", "authors": [{"first": "G", "middle": [], "last": "Mori", "suffix": ""}, {"first": "C", "middle": [], "last": "Pantofaru", "suffix": ""}, {"first": "N", "middle": [], "last": "Kothari", "suffix": ""}, {"first": "T", "middle": [], "last": "Leung", "suffix": ""}, {"first": "G", "middle": [], "last": "Toderici", "suffix": ""}, {"first": "A", "middle": [], "last": "Toshev", "suffix": ""}, {"first": "W", "middle": [], "last": "Yang", "suffix": ""}], "year": 2015, "venue": "", "link": "17267967"}, "BIBREF16": {"title": "Ordinal depth supervision for 3d human pose estimation", "authors": [{"first": "G", "middle": [], "last": "Pavlakos", "suffix": ""}, {"first": "X", "middle": [], "last": "Zhou", "suffix": ""}, {"first": "K", "middle": [], "last": "Daniilidis", "suffix": ""}], "year": 2018, "venue": "Proceedings of the IEEE Conference on Computer Vision and Pattern Recognition", "link": "13679140"}, "BIBREF17": {"title": "Coarse-to-fine volumetric prediction for single-image 3d human pose", "authors": [{"first": "G", "middle": [], "last": "Pavlakos", "suffix": ""}, {"first": "X", "middle": [], "last": "Zhou", "suffix": ""}, {"first": "K", "middle": ["G"], "last": "Derpanis", "suffix": ""}, {"first": "K", "middle": [], "last": "Daniilidis", "suffix": ""}], "year": 2017, "venue": "Proceedings of the IEEE Conference on Computer Vision and Pattern Recognition", "link": "5417293"}, "BIBREF18": {"title": "Harvesting multiple views for marker-less 3d human pose annotations", "authors": [{"first": "G", "middle": [], "last": "Pavlakos", "suffix": ""}, {"first": "X", "middle": [], "last": "Zhou", "suffix": ""}, {"first": "K", "middle": ["G"], "last": "Derpanis", "suffix": ""}, {"first": "K", "middle": [], "last": "Daniilidis", "suffix": ""}], "year": 2017, "venue": "Proceedings of the IEEE conference on computer vision and pattern recognition", "link": "16383951"}, "BIBREF19": {"title": "3d human pose estimation in video with temporal convolutions and semi-supervised training", "authors": [{"first": "D", "middle": [], "last": "Pavllo", "suffix": ""}, {"first": "C", "middle": [], "last": "Feichtenhofer", "suffix": ""}, {"first": "D", "middle": [], "last": "Grangier", "suffix": ""}, {"first": "M", "middle": [], "last": "Auli", "suffix": ""}], "year": 2019, "venue": "Proceedings of the IEEE Conference on Computer Vision and Pattern Recognition", "link": "53806352"}, "BIBREF20": {"title": "Deep multitask architecture for integrated 2d and 3d human sensing", "authors": [{"first": "A.-I", "middle": [], "last": "Popa", "suffix": ""}, {"first": "M", "middle": [], "last": "Zanfir", "suffix": ""}, {"first": "C", "middle": [], "last": "Sminchisescu", "suffix": ""}], "year": 2017, "venue": "Proceedings of the IEEE Conference on Computer Vision and Pattern Recognition", "link": "808308"}, "BIBREF21": {"title": "Unsupervised geometry-aware representation for 3d human pose estimation", "authors": [{"first": "H", "middle": [], "last": "Rhodin", "suffix": ""}, {"first": "M", "middle": [], "last": "Salzmann", "suffix": ""}, {"first": "P", "middle": [], "last": "Fua", "suffix": ""}], "year": 2008, "venue": "Proceedings of the European Conference on Computer Vision (ECCV)", "link": "4607846"}, "BIBREF22": {"title": "Learning monocular 3d human pose estimation from multi-view images", "authors": [{"first": "H", "middle": [], "last": "Rhodin", "suffix": ""}, {"first": "J", "middle": [], "last": "Sp\u00f6rri", "suffix": ""}, {"first": "I", "middle": [], "last": "Katircioglu", "suffix": ""}, {"first": "V", "middle": [], "last": "Constantin", "suffix": ""}, {"first": "F", "middle": [], "last": "Meyer", "suffix": ""}, {"first": "E", "middle": [], "last": "M\u00fcller", "suffix": ""}, {"first": "M", "middle": [], "last": "Salzmann", "suffix": ""}, {"first": "P", "middle": [], "last": "Fua", "suffix": ""}], "year": 2005, "venue": "Proceedings of the IEEE Conference on Computer Vision and Pattern Recognition", "link": "3830407"}, "BIBREF23": {"title": "Imagenet large scale visual recognition challenge", "authors": [{"first": "O", "middle": [], "last": "Russakovsky", "suffix": ""}, {"first": "J", "middle": [], "last": "Deng", "suffix": ""}, {"first": "H", "middle": [], "last": "Su", "suffix": ""}, {"first": "J", "middle": [], "last": "Krause", "suffix": ""}, {"first": "S", "middle": [], "last": "Satheesh", "suffix": ""}, {"first": "S", "middle": [], "last": "Ma", "suffix": ""}, {"first": "Z", "middle": [], "last": "Huang", "suffix": ""}, {"first": "A", "middle": [], "last": "Karpathy", "suffix": ""}, {"first": "A", "middle": [], "last": "Khosla", "suffix": ""}, {"first": "M", "middle": [], "last": "Bernstein", "suffix": ""}], "year": 2015, "venue": "International journal of computer vision", "link": "2930547"}, "BIBREF24": {"title": "Discriminative learning of deep convolutional feature point descriptors", "authors": [{"first": "E", "middle": [], "last": "Simo-Serra", "suffix": ""}, {"first": "E", "middle": [], "last": "Trulls", "suffix": ""}, {"first": "L", "middle": [], "last": "Ferraz", "suffix": ""}, {"first": "I", "middle": [], "last": "Kokkinos", "suffix": ""}, {"first": "P", "middle": [], "last": "Fua", "suffix": ""}, {"first": "F", "middle": [], "last": "Moreno-Noguer", "suffix": ""}], "year": 2015, "venue": "Proceedings of the IEEE International Conference on Computer Vision", "link": "12646079"}, "BIBREF25": {"title": "Hand keypoint detection in single images using multiview bootstrapping", "authors": [{"first": "T", "middle": [], "last": "Simon", "suffix": ""}, {"first": "H", "middle": [], "last": "Joo", "suffix": ""}, {"first": "I", "middle": [], "last": "Matthews", "suffix": ""}, {"first": "Y", "middle": [], "last": "Sheikh", "suffix": ""}], "year": 2017, "venue": "Proceedings of the IEEE conference on Computer Vision and Pattern Recognition", "link": "1263188"}, "BIBREF26": {"title": "Self-supervised learning of pose embeddings from spatiotemporal relations in videos", "authors": [{"first": "O", "middle": [], "last": "Sumer", "suffix": ""}, {"first": "T", "middle": [], "last": "Dencker", "suffix": ""}, {"first": "B", "middle": [], "last": "Ommer", "suffix": ""}], "year": 2017, "venue": "Proceedings of the IEEE International Conference on Computer Vision", "link": "25979715"}, "BIBREF27": {"title": "Integral human pose regression", "authors": [{"first": "X", "middle": [], "last": "Sun", "suffix": ""}, {"first": "B", "middle": [], "last": "Xiao", "suffix": ""}, {"first": "F", "middle": [], "last": "Wei", "suffix": ""}, {"first": "S", "middle": [], "last": "Liang", "suffix": ""}, {"first": "Y", "middle": [], "last": "Wei", "suffix": ""}], "year": 2018, "venue": "Proceedings of the European Conference on Computer Vision (ECCV)", "link": "4055834"}, "BIBREF28": {"title": "Structured prediction of 3d human pose with deep neural networks", "authors": [{"first": "B", "middle": [], "last": "Tekin", "suffix": ""}, {"first": "I", "middle": [], "last": "Katircioglu", "suffix": ""}, {"first": "M", "middle": [], "last": "Salzmann", "suffix": ""}, {"first": "V", "middle": [], "last": "Lepetit", "suffix": ""}, {"first": "P", "middle": [], "last": "Fua", "suffix": ""}], "year": 2016, "venue": "Proceedings of the British Machine Vision Conference 2016", "link": "894265"}, "BIBREF29": {"title": "L2-net: Deep learning of discriminative patch descriptor in euclidean space", "authors": [{"first": "Y", "middle": [], "last": "Tian", "suffix": ""}, {"first": "B", "middle": [], "last": "Fan", "suffix": ""}, {"first": "F", "middle": [], "last": "Wu", "suffix": ""}], "year": 2017, "venue": "Proceedings of the IEEE Conference on Computer Vision and Pattern Recognition", "link": "206596352"}, "BIBREF30": {"title": "Lifting from the deep: Convolutional 3d pose estimation from a single image", "authors": [{"first": "D", "middle": [], "last": "Tome", "suffix": ""}, {"first": "C", "middle": [], "last": "Russell", "suffix": ""}, {"first": "L", "middle": [], "last": "Agapito", "suffix": ""}], "year": 2017, "venue": "Proceedings of the IEEE Conference on Computer Vision and Pattern Recognition", "link": "1867665"}, "BIBREF31": {"title": "Lifting from the deep: Convolutional 3d pose estimation from a single image", "authors": [{"first": "D", "middle": [], "last": "Tome", "suffix": ""}, {"first": "C", "middle": [], "last": "Russell", "suffix": ""}, {"first": "L", "middle": [], "last": "Agapito", "suffix": ""}], "year": 2017, "venue": "Proceedings of the IEEE Conference on Computer Vision and Pattern Recognition", "link": "1867665"}, "BIBREF32": {"title": "Multi-view supervision for single-view reconstruction via differentiable ray consistency", "authors": [{"first": "S", "middle": [], "last": "Tulsiani", "suffix": ""}, {"first": "T", "middle": [], "last": "Zhou", "suffix": ""}, {"first": "A", "middle": ["A"], "last": "Efros", "suffix": ""}, {"first": "J", "middle": [], "last": "Malik", "suffix": ""}], "year": 2017, "venue": "Proceedings of the IEEE conference on computer vision and pattern recognition", "link": "73431591"}, "BIBREF33": {"title": "3d people tracking with gaussian process dynamical models", "authors": [{"first": "R", "middle": [], "last": "Urtasun", "suffix": ""}, {"first": "D", "middle": ["J"], "last": "Fleet", "suffix": ""}, {"first": "P", "middle": [], "last": "Fua", "suffix": ""}], "year": 2006, "venue": "IEEE Computer Society Conference on Computer Vision and Pattern Recognition (CVPR'06)", "link": "518708"}, "BIBREF34": {"title": "Drpose3d: Depth ranking in 3d human pose estimation", "authors": [{"first": "M", "middle": [], "last": "Wang", "suffix": ""}, {"first": "X", "middle": [], "last": "Chen", "suffix": ""}, {"first": "W", "middle": [], "last": "Liu", "suffix": ""}, {"first": "C", "middle": [], "last": "Qian", "suffix": ""}, {"first": "L", "middle": [], "last": "Lin", "suffix": ""}, {"first": "L", "middle": [], "last": "Ma", "suffix": ""}], "year": 2018, "venue": "Proceedings of the Twenty-Seventh International Joint Conference on Artificial Intelligence, IJCAI 2018", "link": "43921689"}, "BIBREF35": {"title": "Lift: Learned invariant feature transform", "authors": [{"first": "K", "middle": ["M"], "last": "Yi", "suffix": ""}, {"first": "E", "middle": [], "last": "Trulls", "suffix": ""}, {"first": "V", "middle": [], "last": "Lepetit", "suffix": ""}, {"first": "P", "middle": [], "last": "Fua", "suffix": ""}], "year": 2016, "venue": "European Conference on Computer Vision", "link": "602850"}, "BIBREF36": {"title": "Weaklysupervised transfer for 3d human pose estimation in the wild", "authors": [{"first": "X", "middle": [], "last": "Zhou", "suffix": ""}, {"first": "Q", "middle": [], "last": "Huang", "suffix": ""}, {"first": "X", "middle": [], "last": "Sun", "suffix": ""}, {"first": "X", "middle": [], "last": "Xue", "suffix": ""}, {"first": "Y", "middle": [], "last": "Wei", "suffix": ""}], "year": 2017, "venue": "IEEE International Conference on Computer Vision, ICCV", "link": "11833172"}}, "ref_entries": {"FIGREF0": {"text": "pm } are computed, we create a distance ma- trix D of size of m \u00d7 m with D(i, j)then sampled from the current batch which lie closest in the embedding space from \u03c6 va i pi and the \u03c6 v b i", "type": "figure"}, "FIGREF1": {"text": "Figure 2: Shows the difference in global and canonical pose representation. The left and middle images shows global poses corresponding to frames captured at two different time instant. The two skeletons have the same relative joint alignments but different orientation w.r.t the MoCap co-ordinate system. The image on the right shows corresponding canonical pose which uniform for both the frames.", "type": "figure"}, "FIGREF2": {"text": "\u03a6) from views v a and v b respectively sharing the same pose p \u2208 P are mapped together in the embedding space. This is consis- tent with canonical pose regression where we estimate the same pose irrespective of viewpoint. The weak supervision as shown later helps in maintaining performance when 3D supervision is reduced.", "type": "figure"}, "FIGREF3": {"text": "Figure 3: Training framework for learning our pose embedding and subsequent canonical pose estimation. x va p and x v b", "type": "figure"}, "FIGREF4": {"text": "Figure 4: N-MPJPE values reported on test split of Human3.6M with progressively less supervision. '*' -Rhodin et.al [22]. Our proposed model outperforms the current state of the art.", "type": "figure"}, "FIGREF5": {"text": "Figure 6: Mean PA-MPJPE for increasing number of retrievals K. Prefix 'Cross-' indicates retrieval done on different subjects from that of query. All values reported are relative to an oracle. Low values indicates our retrieved poses are similar to that of oracle. PAMPJPE is in mm.", "type": "figure"}, "TABREF1": {"text": "Comparing N-MPJPE values when pose estimation is done with global and canonical pose when only subject S1 is used for supervision.", "type": "table"}, "TABREF2": {"text": "Retrieval Mean PA-MPJPE@K upon adding lim- ited pose supervision for K = 5 on Human3.6M dataset Model PA-MPJPE@5 (mm) Only L cnstr , 64.61 L pose on S1 and L cnstr 51.20 L pose on 5%S1 and L cnstr 51.38 L pose on S1 and no L cnstr 70.97", "type": "table"}}}
{"paper_id": "199669259", "_pdf_hash": "754fd022067cd49169700932fee314afd14acecb", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Hyperspectral image classification via weighted joint nearest neighbor and sparse representation", "authors": [{"first": "B", "middle": [], "last": "Tu", "suffix": ""}, {"first": "S", "middle": [], "last": "Huang", "suffix": ""}, {"first": "L", "middle": [], "last": "Fang", "suffix": ""}, {"first": "G", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "J", "middle": [], "last": "Wang", "suffix": ""}, {"first": "B", "middle": [], "last": "Zheng", "suffix": ""}], "year": 2018, "venue": "IEEE J. Sel. Topics Appl. Earth Observ. Remote Sens", "link": "54451996"}, "BIBREF1": {"title": "Nearest neighbor classification of remote sensing images with the maximal margin principle", "authors": [{"first": "E", "middle": [], "last": "Blanzieri", "suffix": ""}, {"first": "F", "middle": [], "last": "Melgani", "suffix": ""}], "year": 2008, "venue": "IEEE Trans. Geosci. Remote Sens", "link": "20512632"}, "BIBREF2": {"title": "GPU parallel implementation of support vector machines for hyperspectral image classification", "authors": [{"first": "K", "middle": [], "last": "Tan", "suffix": ""}, {"first": "J", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "Q", "middle": [], "last": "Du", "suffix": ""}, {"first": "X", "middle": [], "last": "Wang", "suffix": ""}], "year": 2015, "venue": "IEEE J. Sel. Topics Appl. Earth Observ. Remote Sens", "link": "46275095"}, "BIBREF3": {"title": "Subspace-based support vector machines for hyperspectral image classification", "authors": [{"first": "L", "middle": [], "last": "Gao", "suffix": ""}], "year": 2015, "venue": "IEEE Geosci. Remote Sens. Lett", "link": "17894508"}, "BIBREF4": {"title": "Semisupervised hyperspectral image classification via Laplacian least squares support vector machine in sum space and random sampling", "authors": [{"first": "L", "middle": [], "last": "Liu", "suffix": ""}, {"first": "W", "middle": [], "last": "Huang", "suffix": ""}, {"first": "B", "middle": [], "last": "Liu", "suffix": ""}, {"first": "L", "middle": [], "last": "Shen", "suffix": ""}, {"first": "C", "middle": [], "last": "Wang", "suffix": ""}], "year": 2018, "venue": "IEEE J. Sel. Topics Appl. Earth Observ. Remote Sens", "link": "54454192"}, "BIBREF5": {"title": "Investigation of the random forest framework for classification of hyperspectral data", "authors": [{"first": "J", "middle": ["S"], "last": "Ham", "suffix": ""}, {"first": "Y", "middle": [], "last": "Chen", "suffix": ""}, {"first": "M", "middle": ["M"], "last": "Crawford", "suffix": ""}, {"first": "J", "middle": [], "last": "Ghosh", "suffix": ""}], "year": 2005, "venue": "IEEE Trans. Geosci. Remote Sens", "link": null}, "BIBREF6": {"title": "Cascaded random forest for hyperspectral image classification", "authors": [{"first": "Y", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "G", "middle": [], "last": "Cao", "suffix": ""}, {"first": "X", "middle": [], "last": "Li", "suffix": ""}, {"first": "B", "middle": [], "last": "Wang", "suffix": ""}], "year": 2018, "venue": "IEEE J. Sel. Topics Appl. Earth Observ. Remote Sens", "link": "4875462"}, "BIBREF7": {"title": "Random forests unsupervised classification: The detection and mapping of Solanum mauritianum infestations in plantation forestry using hyperspectral data", "authors": [{"first": "K", "middle": ["Y"], "last": "Peerbhay", "suffix": ""}, {"first": "O", "middle": [], "last": "Mutanga", "suffix": ""}, {"first": "R", "middle": [], "last": "Ismail", "suffix": ""}], "year": 2015, "venue": "IEEE J. Sel. Topics Appl. Earth Observ. Remote Sens", "link": "9558600"}, "BIBREF8": {"title": "E 2 LMs: Ensemble extreme learning machines for hyperspectral image classification", "authors": [{"first": "A", "middle": [], "last": "Samat", "suffix": ""}, {"first": "P", "middle": [], "last": "Du", "suffix": ""}, {"first": "S", "middle": [], "last": "Liu", "suffix": ""}, {"first": "J", "middle": [], "last": "Li", "suffix": ""}, {"first": "L", "middle": [], "last": "Cheng", "suffix": ""}], "year": 2014, "venue": "IEEE J. Sel. Topics Appl. Earth Observ. Remote Sens", "link": "37697821"}, "BIBREF9": {"title": "Firefly-algorithm-inspired framework with band selection and extreme learning machine for hyperspectral image classification", "authors": [{"first": "H", "middle": [], "last": "Su", "suffix": ""}, {"first": "Y", "middle": [], "last": "Cai", "suffix": ""}, {"first": "Q", "middle": [], "last": "Du", "suffix": ""}], "year": 2017, "venue": "IEEE J. Sel. Topics Appl. Earth Observ. Remote Sens", "link": "22859637"}, "BIBREF10": {"title": "The effect of unlabeled samples in reducing the small sample size problem and mitigating the Hughes phenomenon", "authors": [{"first": "B", "middle": ["M"], "last": "Shahshahani", "suffix": ""}, {"first": "D", "middle": ["A"], "last": "Landgrebe", "suffix": ""}], "year": 1994, "venue": "IEEE Trans. Geosci. Remote Sens", "link": "11081015"}, "BIBREF11": {"title": "Semi-supervised learning literature survey", "authors": [{"first": "X", "middle": [], "last": "Zhu", "suffix": ""}], "year": 2006, "venue": "Univ. Wisconsin-Madison", "link": null}, "BIBREF12": {"title": "Multiple classifier system for remote sensing image classification: A review", "authors": [{"first": "P", "middle": [], "last": "Du", "suffix": ""}, {"first": "J", "middle": [], "last": "Xia", "suffix": ""}, {"first": "W", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "K", "middle": [], "last": "Tan", "suffix": ""}, {"first": "Y", "middle": [], "last": "Liu", "suffix": ""}, {"first": "S", "middle": [], "last": "Liu", "suffix": ""}], "year": 2012, "venue": "Sensors", "link": "8584223"}, "BIBREF13": {"title": "When semi-supervised learning meets ensemble learning", "authors": [{"first": "Z", "middle": ["H"], "last": "Zhou", "suffix": ""}], "year": 2011, "venue": "Frontiers Electr. Electron. Eng. China", "link": "653872"}, "BIBREF14": {"title": "Semi-supervised graph-based hyperspectral image classification", "authors": [{"first": "G", "middle": [], "last": "Camps-Valls", "suffix": ""}, {"first": "T", "middle": ["V"], "last": "Bandos Marsheva", "suffix": ""}, {"first": "D", "middle": [], "last": "Zhou", "suffix": ""}], "year": 2007, "venue": "IEEE Trans. Geosci. Remote Sens", "link": "15106876"}, "BIBREF15": {"title": "Kernel low-rank and sparse graph for unsupervised and semi-supervised classification of hyperspectral images", "authors": [{"first": "F", "middle": [], "last": "De Morsier", "suffix": ""}, {"first": "M", "middle": [], "last": "Borgeaud", "suffix": ""}, {"first": "V", "middle": [], "last": "Gass", "suffix": ""}, {"first": "J", "middle": ["P"], "last": "Thiran", "suffix": ""}, {"first": "D", "middle": [], "last": "Tuia", "suffix": ""}], "year": 2016, "venue": "IEEE Trans. Geosci. Remote Sens", "link": "206693643"}, "BIBREF16": {"title": "Sparse graph regularization for hyperspectral remote sensing image classification", "authors": [{"first": "Z", "middle": [], "last": "Xue", "suffix": ""}, {"first": "P", "middle": [], "last": "Du", "suffix": ""}, {"first": "J", "middle": [], "last": "Li", "suffix": ""}, {"first": "H", "middle": [], "last": "Su", "suffix": ""}], "year": 2017, "venue": "IEEE Trans. Geosci. Remote Sens", "link": "21403781"}, "BIBREF17": {"title": "Spatial and class structure regularized sparse representation graph for semi-supervised hyperspectral image classification", "authors": [{"first": "Y", "middle": [], "last": "Shao", "suffix": ""}, {"first": "N", "middle": [], "last": "Sang", "suffix": ""}, {"first": "C", "middle": [], "last": "Gao", "suffix": ""}, {"first": "L", "middle": [], "last": "Ma", "suffix": ""}], "year": 2018, "venue": "Pattern Recognit", "link": "49302742"}, "BIBREF18": {"title": "Probabilistic class structure regularized sparse representation graph for semi-supervised hyperspectral image classification", "authors": [{"first": "Y", "middle": [], "last": "Shao", "suffix": ""}, {"first": "N", "middle": [], "last": "Sang", "suffix": ""}, {"first": "C", "middle": [], "last": "Gao", "suffix": ""}, {"first": "L", "middle": [], "last": "Ma", "suffix": ""}], "year": 2017, "venue": "Pattern Recognit", "link": "1226086"}, "BIBREF19": {"title": "Graph-based semi-supervised learning for spectral-spatial hyperspectral image classification", "authors": [{"first": "L", "middle": [], "last": "Ma", "suffix": ""}, {"first": "A", "middle": [], "last": "Ma", "suffix": ""}, {"first": "C", "middle": [], "last": "Ju", "suffix": ""}, {"first": "X", "middle": [], "last": "Li", "suffix": ""}], "year": 2016, "venue": "Pattern Recognit. Lett", "link": "3751005"}, "BIBREF20": {"title": "Semi-supervised classification for hyperspectral imagery based on spatial-spectral label propagation", "authors": [{"first": "L", "middle": [], "last": "Wang", "suffix": ""}, {"first": "S", "middle": [], "last": "Hao", "suffix": ""}, {"first": "Q", "middle": [], "last": "Wang", "suffix": ""}, {"first": "Y", "middle": [], "last": "Wang", "suffix": ""}], "year": 2015, "venue": "ISPRS J. Photogrammetry Remote Sens", "link": "123004626"}, "BIBREF21": {"title": "Spectral-spatial semisupervised hyperspectral classification using adaptive neighborhood", "authors": [{"first": "N", "middle": [], "last": "Jamshidpour", "suffix": ""}, {"first": "A", "middle": [], "last": "Safari", "suffix": ""}, {"first": "S", "middle": [], "last": "Homayouni", "suffix": ""}], "year": 2017, "venue": "IEEE J. Sel. Topics Appl. Earth Observ. Remote Sens", "link": "24504935"}, "BIBREF22": {"title": "A label propagation method using spatial-spectral consistency for hyperspectral image classification", "authors": [{"first": "H", "middle": [], "last": "Li", "suffix": ""}, {"first": "Y", "middle": [], "last": "Wang", "suffix": ""}, {"first": "S", "middle": [], "last": "Xiang", "suffix": ""}, {"first": "J", "middle": [], "last": "Duan", "suffix": ""}, {"first": "F", "middle": [], "last": "Zhu", "suffix": ""}, {"first": "C", "middle": [], "last": "Pan", "suffix": ""}], "year": 2016, "venue": "Int. J. Remote Sens", "link": "56963138"}, "BIBREF23": {"title": "Local-manifold-learningbased graph construction for semisupervised hyperspectral image classification", "authors": [{"first": "L", "middle": [], "last": "Ma", "suffix": ""}, {"first": "M", "middle": ["M"], "last": "Crawford", "suffix": ""}, {"first": "X", "middle": [], "last": "Yang", "suffix": ""}, {"first": "Y", "middle": [], "last": "Guo", "suffix": ""}], "year": 2015, "venue": "IEEE Trans. Geosci. Remote Sens", "link": "19806748"}, "BIBREF24": {"title": "Hyperspectral image classification in the presence of noisy labels", "authors": [{"first": "J", "middle": [], "last": "Jiang", "suffix": ""}, {"first": "J", "middle": [], "last": "Ma", "suffix": ""}, {"first": "Z", "middle": [], "last": "Wang", "suffix": ""}, {"first": "C", "middle": [], "last": "Chen", "suffix": ""}, {"first": "X", "middle": [], "last": "Liu", "suffix": ""}], "year": 2019, "venue": "IEEE Trans. Geosci. Remote Sens", "link": "52197739"}, "BIBREF25": {"title": "Domain adaptation for remote sensing image classification: A low-rank reconstruction and instance weighting label propagation inspired algorithm", "authors": [{"first": "Q", "middle": [], "last": "Shi", "suffix": ""}, {"first": "B", "middle": [], "last": "Du", "suffix": ""}, {"first": "L", "middle": [], "last": "Zhang", "suffix": ""}], "year": 2015, "venue": "IEEE Trans. Geosci. Remote Sens", "link": "11512939"}, "BIBREF26": {"title": "Sparse and low-rank graph for discriminant analysis of hyperspectral imagery", "authors": [{"first": "W", "middle": [], "last": "Li", "suffix": ""}, {"first": "J", "middle": [], "last": "Liu", "suffix": ""}, {"first": "Q", "middle": [], "last": "Du", "suffix": ""}], "year": 2016, "venue": "IEEE Trans. Geosci. Remote Sens", "link": "28230199"}, "BIBREF27": {"title": "Discriminant analysis of hyperspectral imagery using fast kernel sparse and low-rank graph", "authors": [{"first": "L", "middle": [], "last": "Pan", "suffix": ""}, {"first": "H", "middle": ["C"], "last": "Li", "suffix": ""}, {"first": "W", "middle": [], "last": "Li", "suffix": ""}, {"first": "X", "middle": ["D"], "last": "Chen", "suffix": ""}, {"first": "G", "middle": ["N"], "last": "Wu", "suffix": ""}, {"first": "Q", "middle": [], "last": "Du", "suffix": ""}], "year": 2017, "venue": "IEEE Trans. Geosci. Remote Sens", "link": "23396007"}, "BIBREF28": {"title": "Collaborative graph-based discriminant analysis for hyperspectral imagery", "authors": [{"first": "N", "middle": ["H"], "last": "Ly", "suffix": ""}, {"first": "Q", "middle": [], "last": "Du", "suffix": ""}, {"first": "J", "middle": ["E"], "last": "Fowler", "suffix": ""}], "year": 2014, "venue": "IEEE J. Sel. Topics Appl. Earth Observ. Remote Sens", "link": "18023362"}, "BIBREF29": {"title": "Laplacian regularized collaborative graph for discriminant analysis of hyperspectral imagery", "authors": [{"first": "W", "middle": [], "last": "Li", "suffix": ""}, {"first": "Q", "middle": [], "last": "Du", "suffix": ""}], "year": 2016, "venue": "IEEE Trans. Geosci. Remote Sens", "link": "206694463"}, "BIBREF30": {"title": "Spectral-spatial classification for hyperspectral data using rotation forests with local feature extraction and Markov random fields", "authors": [{"first": "J", "middle": [], "last": "Xia", "suffix": ""}, {"first": "J", "middle": [], "last": "Chanussot", "suffix": ""}, {"first": "P", "middle": [], "last": "Du", "suffix": ""}, {"first": "X", "middle": [], "last": "He", "suffix": ""}], "year": 2015, "venue": "IEEE Trans. Geosci. Remote Sens", "link": "1900124"}, "BIBREF31": {"title": "Random forest ensembles and extended multiextinction profiles for hyperspectral image classification", "authors": [{"first": "J", "middle": [], "last": "Xia", "suffix": ""}, {"first": "P", "middle": [], "last": "Ghamisi", "suffix": ""}, {"first": "N", "middle": [], "last": "Yokoya", "suffix": ""}, {"first": "A", "middle": [], "last": "Iwasaki", "suffix": ""}], "year": 2018, "venue": "IEEE Trans. Geosci. Remote Sens", "link": "12977648"}, "BIBREF32": {"title": "Weight-based rotation forest for hyperspectral image classification", "authors": [{"first": "W", "middle": [], "last": "Feng", "suffix": ""}, {"first": "W", "middle": [], "last": "Bao", "suffix": ""}], "year": 2017, "venue": "IEEE Geosci. Remote Sens. Lett", "link": "12123709"}, "BIBREF33": {"title": "Dynamic ensemble selection approach for hyperspectral image classification with joint spectral and spatial information", "authors": [{"first": "B", "middle": ["B"], "last": "Damodaran", "suffix": ""}, {"first": "R", "middle": ["R"], "last": "Nidamanuri", "suffix": ""}, {"first": "Y", "middle": [], "last": "Tarabalka", "suffix": ""}], "year": 2015, "venue": "IEEE J. Sel. Topics Appl. Earth Observ. Remote Sens", "link": "34586567"}, "BIBREF34": {"title": "Matrix-based discriminant subspace ensemble for hyperspectral image spatial-spectral feature fusion", "authors": [{"first": "R", "middle": [], "last": "Hang", "suffix": ""}, {"first": "Q", "middle": [], "last": "Liu", "suffix": ""}, {"first": "H", "middle": [], "last": "Song", "suffix": ""}, {"first": "Y", "middle": [], "last": "Sun", "suffix": ""}], "year": 2016, "venue": "IEEE Trans. Geosci. Remote Sens", "link": "523085"}, "BIBREF35": {"title": "Combining morphological attribute profiles via an ensemble method for hyperspectral image classification", "authors": [{"first": "R", "middle": [], "last": "Bao", "suffix": ""}, {"first": "J", "middle": [], "last": "Xia", "suffix": ""}, {"first": "M", "middle": [], "last": "Mura", "suffix": ""}, {"first": "P", "middle": [], "last": "Du", "suffix": ""}, {"first": "J", "middle": [], "last": "Chanussot", "suffix": ""}, {"first": "J", "middle": [], "last": "Ren", "suffix": ""}], "year": 2016, "venue": "IEEE Geosci. Remote Sens. Lett", "link": "31577186"}, "BIBREF36": {"title": "Hierarchical guidance filtering-based ensemble classification for hyperspectral images", "authors": [{"first": "B", "middle": [], "last": "Pan", "suffix": ""}, {"first": "Z", "middle": [], "last": "Shi", "suffix": ""}, {"first": "X", "middle": [], "last": "Xu", "suffix": ""}], "year": 2017, "venue": "IEEE Trans. Geosci. Remote Sens", "link": "19558484"}, "BIBREF37": {"title": "Dimensionality reduction and classification of hyperspectral images using ensemble discriminative local metric learning", "authors": [{"first": "Y", "middle": [], "last": "Dong", "suffix": ""}, {"first": "B", "middle": [], "last": "Du", "suffix": ""}, {"first": "L", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "L", "middle": [], "last": "Zhang", "suffix": ""}], "year": 2017, "venue": "IEEE Trans. Geosci. Remote Sens", "link": "3754543"}, "BIBREF38": {"title": "Ensemble multiple kernel active learning for classification of multisource remote sensing data", "authors": [{"first": "Y", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "H", "middle": ["L"], "last": "Yang", "suffix": ""}, {"first": "S", "middle": [], "last": "Prasad", "suffix": ""}, {"first": "E", "middle": [], "last": "Pasolli", "suffix": ""}, {"first": "J", "middle": [], "last": "Jung", "suffix": ""}, {"first": "M", "middle": [], "last": "Crawford", "suffix": ""}], "year": 2015, "venue": "IEEE J. Sel. Topics Appl. Earth Observ. Remote Sens", "link": "25680389"}, "BIBREF39": {"title": "Improve computer-aided diagnosis with machine learning techniques using undiagnosed samples", "authors": [{"first": "M", "middle": [], "last": "Li", "suffix": ""}, {"first": "Z", "middle": ["H"], "last": "Zhou", "suffix": ""}], "year": 2007, "venue": "IEEE Trans. Syst. Man, Cybern. Part A, Syst. Humans", "link": "2758814"}, "BIBREF40": {"title": "Semi-supervised random forests", "authors": [{"first": "C", "middle": [], "last": "Leistner", "suffix": ""}, {"first": "A", "middle": [], "last": "Saffari", "suffix": ""}, {"first": "J", "middle": [], "last": "Santner", "suffix": ""}, {"first": "H", "middle": [], "last": "Bischof", "suffix": ""}], "year": 2009, "venue": "Proc. IEEE 12th Int. Conf. Comput. Vision", "link": "1715012"}, "BIBREF41": {"title": "Semi-supervised classification of hyperspectral image using random forest algorithm", "authors": [{"first": "S", "middle": [], "last": "Amini", "suffix": ""}, {"first": "S", "middle": [], "last": "Homayouni", "suffix": ""}, {"first": "A", "middle": [], "last": "Safari", "suffix": ""}], "year": 2014, "venue": "Proc. IEEE Geosci. Remote Send. Symp", "link": "19165248"}, "BIBREF42": {"title": "Label propagation through linear neighborhoods", "authors": [{"first": "F", "middle": [], "last": "Wang", "suffix": ""}, {"first": "C", "middle": [], "last": "Zhang", "suffix": ""}], "year": 2008, "venue": "IEEE Trans. Knowl. Data Eng", "link": "171130"}, "BIBREF43": {"title": "Nearest neighbors in random subspaces", "authors": [{"first": "T", "middle": ["K"], "last": "Ho", "suffix": ""}], "year": 1998, "venue": "Proc. Joint IAPR Int. Workshops Statistical Techn. Pattern Recognit. Structural Syntactic Pattern Recognit", "link": "39796372"}, "BIBREF44": {"title": "Ensembling local learners through multimodal perturbation", "authors": [{"first": "Z", "middle": ["H"], "last": "Zhou", "suffix": ""}, {"first": "Y", "middle": [], "last": "Yu", "suffix": ""}], "year": 2005, "venue": "IEEE Trans. Syst. Man, Cybern. Part B Cybern", "link": null}, "BIBREF45": {"title": "Extreme learning machine: Theory and applications", "authors": [{"first": "G", "middle": ["B"], "last": "Huang", "suffix": ""}, {"first": "Q", "middle": ["Y"], "last": "Zhu", "suffix": ""}, {"first": "C", "middle": ["K"], "last": "Siew", "suffix": ""}], "year": 2006, "venue": "Neurocomputing", "link": "116858"}, "BIBREF46": {"title": "Random subspace ensembles for hyperspectral image classification with extended morphological attribute profiles", "authors": [{"first": "J", "middle": [], "last": "Xia", "suffix": ""}, {"first": "M", "middle": ["D"], "last": "Mura", "suffix": ""}, {"first": "J", "middle": [], "last": "Chanussot", "suffix": ""}, {"first": "P", "middle": [], "last": "Du", "suffix": ""}, {"first": "X", "middle": [], "last": "He", "suffix": ""}], "year": 2015, "venue": "IEEE Trans. Geosci. Remote Sens", "link": "10843390"}, "BIBREF47": {"title": "Ensemble of extreme learning machine for remote sensing image classification", "authors": [{"first": "M", "middle": [], "last": "Han", "suffix": ""}, {"first": "B", "middle": [], "last": "Liu", "suffix": ""}], "year": 2015, "venue": "Neurocomputing", "link": "8005139"}, "BIBREF48": {"title": "Remote sensing image classification based on ensemble extreme learning machine with stacked autoencoder", "authors": [{"first": "F", "middle": [], "last": "Lv", "suffix": ""}, {"first": "M", "middle": [], "last": "Han", "suffix": ""}, {"first": "T", "middle": [], "last": "Qiu", "suffix": ""}], "year": 2017, "venue": "IEEE Access", "link": "28771235"}, "BIBREF49": {"title": "Deep learning-based classification of hyperspectral data", "authors": [{"first": "Y", "middle": [], "last": "Chen", "suffix": ""}, {"first": "Z", "middle": [], "last": "Lin", "suffix": ""}, {"first": "X", "middle": [], "last": "Zhao", "suffix": ""}, {"first": "G", "middle": [], "last": "Wang", "suffix": ""}, {"first": "Y", "middle": [], "last": "Gu", "suffix": ""}], "year": 2014, "venue": "IEEE J. Sel. Topics Appl. Earth Observ. Remote Sens", "link": "44935336"}, "BIBREF50": {"title": "Convolutional neural networks for hyperspectral image classification", "authors": [{"first": "S", "middle": [], "last": "Yu", "suffix": ""}, {"first": "S", "middle": [], "last": "Jia", "suffix": ""}, {"first": "C", "middle": [], "last": "Xu", "suffix": ""}], "year": 2017, "venue": "Neurocomputing", "link": "43828797"}, "BIBREF51": {"title": "Deep feature extraction and classification of hyperspectral images based on convolutional neural networks", "authors": [{"first": "Y", "middle": [], "last": "Chen", "suffix": ""}, {"first": "H", "middle": [], "last": "Jiang", "suffix": ""}, {"first": "C", "middle": [], "last": "Li", "suffix": ""}, {"first": "X", "middle": [], "last": "Jia", "suffix": ""}, {"first": "P", "middle": [], "last": "Ghamisi", "suffix": ""}], "year": 2016, "venue": "IEEE Trans. Geosci. Remote Sens", "link": "2078144"}, "BIBREF52": {"title": "CoinNet: Copy initialization network for multispectral imagery semantic segmentation", "authors": [{"first": "B", "middle": [], "last": "Pan", "suffix": ""}, {"first": "Z", "middle": [], "last": "Shi", "suffix": ""}, {"first": "X", "middle": [], "last": "Xu", "suffix": ""}, {"first": "T", "middle": [], "last": "Shi", "suffix": ""}, {"first": "N", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "X", "middle": [], "last": "Zhu", "suffix": ""}], "year": 2019, "venue": "IEEE Geosci. Remote Sens. Lett", "link": "126089642"}, "BIBREF53": {"title": "Deep recurrent neural networks for hyperspectral image classification", "authors": [{"first": "L", "middle": [], "last": "Mou", "suffix": ""}, {"first": "P", "middle": [], "last": "Ghamisi", "suffix": ""}, {"first": "X", "middle": ["X"], "last": "Zhu", "suffix": ""}], "year": 2017, "venue": "IEEE Trans. Geosci. Remote Sens", "link": "26919601"}, "BIBREF54": {"title": "Learning to diversify deep belief networks for hyperspectral image classification", "authors": [{"first": "P", "middle": [], "last": "Zhong", "suffix": ""}, {"first": "Z", "middle": [], "last": "Gong", "suffix": ""}, {"first": "S", "middle": [], "last": "Li", "suffix": ""}, {"first": "C", "middle": ["B"], "last": "Schonlieb", "suffix": ""}], "year": 2017, "venue": "IEEE Trans. Geosci. Remote Sens", "link": "23217046"}, "BIBREF55": {"title": "Spectral-spatial classification of hyperspectral data based on deep belief network", "authors": [{"first": "Y", "middle": [], "last": "Chen", "suffix": ""}, {"first": "X", "middle": [], "last": "Zhao", "suffix": ""}, {"first": "X", "middle": [], "last": "Jia", "suffix": ""}], "year": 2015, "venue": "IEEE J. Sel. Topics Appl. Earth Observ. Remote Sens", "link": "24309481"}, "BIBREF56": {"title": "Deep fully convolutional network-based spatial distribution prediction for hyperspectral image classification", "authors": [{"first": "L", "middle": [], "last": "Jiao", "suffix": ""}, {"first": "M", "middle": [], "last": "Liang", "suffix": ""}, {"first": "H", "middle": [], "last": "Chen", "suffix": ""}, {"first": "S", "middle": [], "last": "Yang", "suffix": ""}, {"first": "H", "middle": [], "last": "Liu", "suffix": ""}, {"first": "X", "middle": [], "last": "Cao", "suffix": ""}], "year": 2017, "venue": "IEEE Trans. Geosci. Remote Sens", "link": "27377588"}, "BIBREF57": {"title": "Classification of hyperspectral images by Gabor filtering based deep network", "authors": [{"first": "X", "middle": [], "last": "Kang", "suffix": ""}, {"first": "C", "middle": [], "last": "Li", "suffix": ""}, {"first": "S", "middle": [], "last": "Li", "suffix": ""}, {"first": "H", "middle": [], "last": "Lin", "suffix": ""}], "year": 2018, "venue": "IEEE J. Sel. Topics Appl. Earth Observ. Remote Sens", "link": "4880412"}, "BIBREF58": {"title": "Active-learningincorporated deep transfer learning for hyperspectral image classification", "authors": [{"first": "J", "middle": [], "last": "Lin", "suffix": ""}, {"first": "L", "middle": [], "last": "Zhao", "suffix": ""}, {"first": "S", "middle": [], "last": "Li", "suffix": ""}, {"first": "R", "middle": [], "last": "Ward", "suffix": ""}, {"first": "Z", "middle": ["J"], "last": "Wang", "suffix": ""}], "year": 2018, "venue": "IEEE J. Sel. Topics Appl. Earth Observ. Remote Sens", "link": "54450769"}, "BIBREF59": {"title": "Hyperspectral image classification with Markov random fields and a convolutional neural network", "authors": [{"first": "X", "middle": [], "last": "Cao", "suffix": ""}, {"first": "F", "middle": [], "last": "Zhou", "suffix": ""}, {"first": "L", "middle": [], "last": "Xu", "suffix": ""}, {"first": "D", "middle": [], "last": "Meng", "suffix": ""}, {"first": "Z", "middle": [], "last": "Xu", "suffix": ""}, {"first": "J", "middle": [], "last": "Paisley", "suffix": ""}], "year": 2018, "venue": "IEEE Trans. Image Process", "link": null}, "BIBREF60": {"title": "A novel technique for optimal feature selection in attribute profiles based on genetic algorithms", "authors": [{"first": "M", "middle": [], "last": "Pedergnana", "suffix": ""}, {"first": "P", "middle": ["R"], "last": "Marpu", "suffix": ""}, {"first": "M", "middle": ["D"], "last": "Mura", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Benediktsson", "suffix": ""}, {"first": "L", "middle": [], "last": "Bruzzone", "suffix": ""}], "year": 2013, "venue": "IEEE Trans. Geosci. Remote Sens", "link": "27700472"}, "BIBREF61": {"title": "The linear neighborhood propagation method for predicting long non-coding RNA-protein interactions", "authors": [{"first": "W", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "Q", "middle": [], "last": "Qu", "suffix": ""}, {"first": "Y", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "W", "middle": [], "last": "Wang", "suffix": ""}], "year": 2018, "venue": "Neurocomputing", "link": "8633741"}, "BIBREF62": {"title": "The random subspace method for constructing decision forests", "authors": [{"first": "T", "middle": ["K"], "last": "Ho", "suffix": ""}], "year": 1998, "venue": "IEEE Trans. Pattern Anal. Mach. Intell", "link": "206420153"}, "BIBREF63": {"title": "Transductive inference for text classification using support vector machines", "authors": [{"first": "T", "middle": [], "last": "Joachims", "suffix": ""}], "year": 1999, "venue": "Proc. Int. Conf. Mach. Learn", "link": "14591650"}, "BIBREF64": {"title": "Visualizing data using t-SNE", "authors": [{"first": "L", "middle": [], "last": "Van Der Maaten", "suffix": ""}, {"first": "G", "middle": [], "last": "Hinton", "suffix": ""}], "year": 2008, "venue": "J. Mach. Learn. Res", "link": null}, "BIBREF65": {"title": "KNN-based representation of superpixels for hyperspectral image classification", "authors": [{"first": "B", "middle": [], "last": "Tu", "suffix": ""}, {"first": "J", "middle": [], "last": "Wang", "suffix": ""}, {"first": "X", "middle": [], "last": "Kang", "suffix": ""}, {"first": "G", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "X", "middle": [], "last": "Ou", "suffix": ""}, {"first": "L", "middle": [], "last": "Guo", "suffix": ""}], "year": 2018, "venue": "IEEE J. Sel. Topics Appl. Earth Observ. Remote Sens", "link": "54452669"}, "BIBREF66": {"title": "PCA-based edgepreserving features for hyperspectral image classification", "authors": [{"first": "X", "middle": [], "last": "Kang", "suffix": ""}, {"first": "X", "middle": [], "last": "Xiang", "suffix": ""}, {"first": "S", "middle": [], "last": "Li", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Benediktsson", "suffix": ""}], "year": 2017, "venue": "IEEE Trans. Geosci. Remote Sens", "link": "22677105"}, "BIBREF68": {"title": "Classification of hyperspectral images based on multiclass spatial-spectral generative adversarial networks", "authors": [{"first": "J", "middle": [], "last": "Feng", "suffix": ""}, {"first": "H", "middle": [], "last": "Yu", "suffix": ""}, {"first": "L", "middle": [], "last": "Wang", "suffix": ""}, {"first": "X", "middle": [], "last": "Cao", "suffix": ""}, {"first": "X", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "L", "middle": [], "last": "Jiao", "suffix": ""}], "year": "", "venue": "IEEE Trans. Geosci. Remote Sens", "link": "127969304"}, "BIBREF69": {"title": "CNN-based multilayer spatial-spectral feature fusion and sample augmentation with local and nonlocal constraints for hyperspectral image classification", "authors": [{"first": "J", "middle": [], "last": "Feng", "suffix": ""}], "year": 2019, "venue": "IEEE J. Sel. Topics Appl. Earth Observ. Remote Sens", "link": "115199442"}}, "ref_entries": {}}
{"paper_id": "199669503", "_pdf_hash": "6f344efc41bee57db41b17e02bf3f51131b0fbe0", "abstract": [{"section": "Abstract", "text": "It has been shown that the two texture zero neutrino mass matrices in the charged lepton basis predict non-zero 1-3 mixing and are necessarily CP violating with one possible exception in class C for maximal mixing. * dev5703@yahoo.com \u2020", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "", "text": "There is no CP violation in the leptonic sector of the Standard Model (SM) of fundamental particles and interactions. However, in most extensions of SM, there can be several CP phases. In the simplest three generation scenario, there is a Dirac type CP violating phase in the leptonic mixing matrix. However, for Majorana neutrinos, there could be two additional phases (Majorana phases). It is possible to work in a parameterizations in which all the three CP violating phases are situated in the charged current leptonic mixing matrix. Without any loss of generality, one can work in the flavor basis in which the charged lepton mass matrix is diagonal so that the neutrino mass matrix carries all the information about CP violation. In the flavor basis, the mass matrix for Majorana neutrinos contains nine physical parameters including the three mass eigenvalues, three mixing angles and the three CP-violating phases. The two squared-mass differences (\u2206m 2 12 and \u2206m 2 13 ) and the two mixing angles (\u03b8 12 and \u03b8 23 ) have been measured in solar, atmospheric and reactor experiments. The third mixing angle \u03b8 13 and the Dirac-type CP-violating phase \u03b4 are expected to be measured in the forthcoming neutrino oscillation experiments. The possible measurement of the effective Majorana mass in neutrinoless double \u03b2 decay searches will provide an additional constraint on the remaining three neutrino parameters viz. the neutrino mass scale and two Majorana-type CP-violating phases. While the neutrino mass scale will be independently determined by the direct beta decay searches and cosmological observations, the two Majorana phases will not be uniquely determined from the measurement of effective Majorana mass even if the absolute neutrino mass scale is known. Under the circumstances, it is natural to employ other theoretical inputs for the reconstruction of the neutrino mass matrix. The possible forms of these additional theoretical inputs are limited by the existing neutrino data. Several proposals have been made in the literature to restrict the form of the neutrino mass matrix and to reduce the number of free parameters which include presence of texture zeros [1, 2, 3, 4, 5] , requirement of zero determinant [6] , the zero trace condition [7] to name just a few. However, the current neutrino oscillation data are consistent only with a limited number of texture schemes [1, 2, 3, 4, 5] . In particular, the current neutrino oscillation data disallow all neutrino mass matrices with three or more texture zeros in the flavor basis. Out of the fifteen possible neutrino mass matrices with two texture zeros, only seven are compatible with the current neutrino oscillation data. The seven allowed two texture zero mass matrices have been classified into three categories. The two class A matrices of the types A 1 and A 2 give normal hierarchy (NH) of neutrino masses. The class B matrices of types B 1 , B 2 , B 3 and B 4 yield a quasi-degenerate spectrum of neutrino masses. The single class C matrix corresponds to inverted hierarchy (IH) of neutrino masses.", "cite_spans": [{"start": 2184, "end": 2186, "text": "2,", "ref_id": "BIBREF1"}, {"start": 2397, "end": 2399, "text": "2,", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "", "text": "The texture zeros in different positions of the neutrino mass matrix can result from underlying flavor symmetries [8] . They can, also, be realized within the framework of the see-saw mechanism [9] . Such textures can, also, be obtained in the context of GUTs based on SO(10) [10, 11] . Recently, these texture zeros have been derived from a simple flavor group A 4 or its Z 3 subgroup [12] .", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "The existence of two texture zeros implies four real conditions to be satisfied by the neutrino oscillation parameters. It is shown that these four conditions cannot be satisfied if \u03b8 13 = 0. The presence of texture zeros in the neutrino mass matrix, further, demands certain cancellations induced by strong correlations between CP-violating phases. It is shown that neutrino mass matrices with two texture zeros in the charged lepton basis must be necessarily CP-violating with one possible exception in class C for \u03b8 23 = \u03c0 4 and \u03b8 13 = 0 where there will be no Dirac-type CP-violation and we can, only, have Majoranatype CP-violation. This case can become CP conserving for a special choice of m 1 .", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "The neutrino mass matrix, M, can be parameterized in terms of the three neutrino mass eigenvalues (m 1 , m 2 , m 3 ), three neutrino mixing angles (\u03b8 12 , \u03b8 23 , \u03b8 13 ) and one Dirac-type CP violating phase, \u03b4. If neutrinos are Majorana particles, then, there are two additional CP violating phases \u03b1, \u03b2 in the neutrino mixing matrix. The complex symmetric mass matrix M can be diagonalized by a complex unitary matrix V : where s ij = sin \u03b8 ij and c ij = cos \u03b8 ij . The matrix V is called the neutrino mixing matrix or Pontecorvo-Maki-Nakagawa-Sakata matrix. The matrix U is the lepton analogue of the Cabibbo-Kobayashi-Maskawa quark mixing matrix and P contains the two Majorana phases.", "cite_spans": [], "ref_spans": []}, {"section": "Type", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Constraining Equations", "text": "The elements of the neutrino mass matrix can be calculated from Eq. (1). Some of the elements of M, which are equated to zero in the various allowed texture zero schemes, are given by The seven allowed neutrino mass matrices with two texture zeros have been listed in Table 1 .", "cite_spans": [], "ref_spans": [{"start": 268, "end": 275, "text": "Table 1", "ref_id": "TABREF0"}]}, {"section": "Constraining Equations", "text": "For neutrino mass matrices of type A 1 , the conditions m ee = 0 and m \u00b5\u00b5 = 0 imply ", "cite_spans": [], "ref_spans": []}, {"section": "Constraining Equations", "text": "It can be seen from Eqs. (7) and (9) that sin 2\u03b1 must vanish if s 13 is zero. However, the simultaneous solution of Eqs. (6) and (8) under the condition s 13 = 0 implies that m 1 = m 2 = 0 which is inconsistent with solar neutrino data. Therefore, s 13 should be non-zero for neutrino mass matrices of type A 1 [3, 4, 5] which in turn implies a nonvanishing sin 2\u03b1 [Eqs. (7) and (9)]. It can, also, be seen from Eqs. (7) and (9) that sin 2\u03b1 = sin 2\u03b2 = 0 if sin \u03b4 = 0 which is not possible for non-zero s 13 . Similarly, one can show that s 13 and sin \u03b4 are non-zero for neutrino mass matrices of type A 2 . Hence, neutrino mass matrices of class A are necessarily CP-violating [4] .", "cite_spans": [], "ref_spans": []}, {"section": "Constraining Equations", "text": "In category B, for neutrino mass matrices of type B 3 , for example, we have the conditions m e\u00b5 = 0 and m \u00b5\u00b5 = 0 which result in the following four real conditions: ", "cite_spans": [], "ref_spans": []}, {"section": "Constraining Equations", "text": "It can be easily seen from Eqs. (10) and (11) that m 1 = m 2 and sin 2\u03b1 = 0 for \u03b8 13 = 0. Hence, \u03b8 13 and \u03b1 cannot be zero since solar mass squared difference \u2206m 2 12 is non-zero. It follows from Eqs. (11) and (13) ", "cite_spans": [], "ref_spans": []}, {"section": "Constraining Equations", "text": "When, \u03b8 23 is non-maximal, the condition s 13 = 0 gives sin 2\u03b1 = 0 and m 2 m 1 = tan 2 \u03b8 12 < 1 from Eqs. (16) and (17) which contradicts the solar mass hierarchy. It can, also, be shown that the above system of equations cannot simultaneously hold for sin \u03b4 = 0 since Eq. (17) implies that sin 2\u03b1 = 0 under this condition which, again, gives s 13 = 0 which, as discussed above, is inconsistent with the data. Therefore, the neutrino mass matrices of class C are necessarily CP violating for non-maximal 2-3 mixing.", "cite_spans": [], "ref_spans": []}, {"section": "Constraining Equations", "text": "For maximal mixing, \u03b8 23 = \u03c0 4 and the Eqs. (16) and (17) imply that \u03b8 13 = 0. In this case, there will be no Dirac-type CP violation since s 13 = 0 and we are left with the Eqs. ", "cite_spans": [], "ref_spans": []}, {"section": "Constraining Equations", "text": "This solution is valid only for inverted hierarchy with \u2206m 2 13 negative. However, it may be difficult to realize the relationship given in Eq. (23) in a realistic model of lepton masses and mixings. In this special CP-conserving case, the CP parity of \u03bd 2 is odd and that of \u03bd 3 is even. CP is conserved in the region allowed by Eqs. (22) and (23) within the complete parameter space allowed by Eqs. (20) and (21) and in the rest of the allowed parameter space, the neutrino mass matrices of class C with maximal mixing will have CP violation of Majorana type only. This is a consequence of the fact that the third neutrino mass eigenstate \u03bd 3 gets decoupled from the first two mass eigenstates \u03bd 1 and \u03bd 2 for vanishing s 13 and the remaining 2 \u00d7 2 sub-matrix can have only Majorana-type CP violation with a single physical Majorana phase. Hence, the neutrino mass matrices of class C with maximal mixing can be CP conserving only for m 1 given by Eq. (21). For all other values of m 1 , the neutrino mass matrices of class C with maximal mixing will exhibit CP violation with one physical Majorana phase.", "cite_spans": [], "ref_spans": []}, {"section": "Constraining Equations", "text": "It should, also, be noted that the neutrino mass matrices of class C with maximal mixing are \u00b5 \u2212 \u03c4 symmetric since we have M e\u00b5 = \u2212M e\u03c4 and M \u00b5\u00b5 = M \u03c4 \u03c4 = 0 (24) in this special case. However, the neutrino mass matrices of classes A and B can never become \u00b5 \u2212 \u03c4 symmetric which results in a different CP structure of class C as compared to that of classes A and B of neutrino mass matrices.", "cite_spans": [], "ref_spans": []}, {"section": "Constraining Equations", "text": "In conclusion, it has been shown that CP violation is inherent in the two texture zero scheme of Frampton, Glashow and Marfatia [1] and existence of texture zeros in the neutrino mass matrix may provide useful hints for unraveling the dynamics of the CP violation. The existence of the texture zeros in the neutrino mass matrix in the flavor basis could result from a certain flavor symmetry. This, in turn, would require nonzero values of the mixing angle \u03b8 13 and the CP violating phases to ensure the desired cancellations in the specific elements of the neutrino mass matrix.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF1": {"title": "Wanlei Guo and Zhi-zhong Xing", "authors": [{"first": "R", "middle": [], "last": "Bipin", "suffix": ""}, {"first": "D", "middle": ["P"], "last": "Desai", "suffix": ""}, {"first": "Alexander", "middle": ["R"], "last": "Roy", "suffix": ""}, {"first": "Alexander", "middle": [], "last": "Vaucher", "suffix": ""}, {"first": "Werner", "middle": [], "last": "Merle", "suffix": ""}, {"first": "", "middle": [], "last": "Rodejohann", "suffix": ""}], "year": 2002, "venue": "Mod. Phys. Lett A", "link": null}}, "ref_entries": {"FIGREF0": {"text": "The neutrino mixing matrix V can be written as V \u2261 UP = \uf8eb \uf8ec \uf8ed c 12 c 13 s 12 c 13 s 13 e \u2212i\u03b4 \u2212s 12 c 23 \u2212 c 12 s 23 s 13 e i\u03b4 c 12 c 23 \u2212 s 12 s 23 s 13 e i\u03b4 s 23 c 13 s 12 s 23 \u2212 c 12 c 23 s 13 e i\u03b4 \u2212c 12 s 23 \u2212 s 12 c 23 s 13 e i\u03b4 c 23 c 13", "type": "figure"}, "FIGREF1": {"text": "e\u00b5 = c 13 {s 13 s 23 e i\u03b4 (e 2i\u03b2 m 3 \u2212 s 2 12 e 2i\u03b1 m 2 ) \u2212 c 12 c 23 s 12 (m 1 \u2212 e 2i\u03b1 m 2 ) \u2212 c 2 12 s 13 s 23 e i\u03b4 m 1 }, (4) M e\u03c4 = c 13 {s 13 c 23 e i\u03b4 (e 2i\u03b2 m 3 \u2212 s 2 12 e 2i\u03b1 m 2 ) + c 12 s 23 s 12 (m 1 \u2212 e 2i\u03b1 m 2 ) \u2212 c 2 12 s 13 c 23 e i\u03b4 m 1 }, (5) M \u00b5\u00b5 = m 1 (c 23 s 12 + e i\u03b4 c 12 s 13 s 23 ) 2 + e 2i\u03b1 m 2 (c 12 c 23 \u2212 e i\u03b4 s 12 s 13 s 23 ) 2 + e 2i(\u03b2+\u03b4) m 3 c 2 13 s 2 23 (6) and M \u03c4 \u03c4 = m 1 (s 23 s 12 \u2212 e i\u03b4 c 12 s 13 c 23 ) 2 + e 2i\u03b1 m 2 (c 12 s 23 + e i\u03b4 s 12 s 13 c 23 ) 2 + e 2i(\u03b2+\u03b4) m 3 c 2 13 c 2 23 . (7)", "type": "figure"}, "FIGREF2": {"text": "s 13 (m 1 c 2 12 cos \u03b4 + m 2 s 2 12 cos(2\u03b1 + \u03b4) \u2212 m 3 cos(2\u03b2 + \u03b4)) = c 12 c 23 s 12 (m 2 cos 2\u03b1 \u2212 m 1 ) s 23 , (10) s 13 (m 1 c 2 12 sin \u03b4 + m 2 s 2 12 sin(2\u03b1 + \u03b4) \u2212 m 3 sin(2\u03b2 + \u03b4)) = m 2 c 12 c 23 s 12 sin 2\u03b1 s 23 .", "type": "figure"}, "FIGREF3": {"text": "cos \u03b4 + m 2 s 2 12 cos(2\u03b1 + \u03b4) \u2212 m 3 cos(2\u03b2 + \u03b4)) = c 12 c 23 s 12 (m 2 cos 2\u03b1 \u2212 m 1 ) s 23 , (12) s 13 (m 1 c 2 12 sin \u03b4 + m 2 s 2 12 sin(2\u03b1 + \u03b4) \u2212 m 3 sin(2\u03b2 + \u03b4)) = m 2 c 12 c 23 s 12 sin 2\u03b1 s 23 , (13) s 13 (m 2 cos(2\u03b1 + \u03b4) \u2212 m 1 cos \u03b4) = c 2 23 (m 1 s 2 12 + m 2 c 2 12 cos 2\u03b1) + m 3 s 2 23 cos 2(\u03b2 + \u03b4) c 12 c 23 s 12 s 23 (14) and s 13 (m 2 sin(2\u03b1 + \u03b4) \u2212 m 1 sin \u03b4) = m 2 c 2 23 c 2 12 sin 2\u03b1 + m 3 s 2 23 sin 2(\u03b2 + \u03b4) c 12 c 23 s 12 s 23 .", "type": "figure"}, "FIGREF4": {"text": "that sin 2\u03b1 and sin 2\u03b2 are zero if sin \u03b4 = 0 which is not possible since s 13 is non-zero. Therefore, \u03b4 should be non-zero for neutrino mass matrices of type B 3 . Similarly, one can show that \u03b8 13 and \u03b4 are non-zero for other neutrino mass matrices of class B viz. B 1 , B 2 and B 4 . Thus, neutrino mass matrices of class B are, also, necessarily CP violating. The four real conditions to be satisfied by neutrino mass matrices of class C can be written as s 2 13 (m 3 cos 2(\u03b2 + \u03b4) \u2212 m 1 c 2 12 cos 2\u03b4 \u2212 m 2 s 2 12 cos 2(\u03b1 + \u03b4)) = m 1 s 2 12 + m 2 c 2 12 cos 2\u03b1 + m 3 cos 2(\u03b2 + \u03b4), (16) s 2 13 (m 3 sin 2(\u03b2 + \u03b4) \u2212 m 1 c 2 12 sin 2\u03b4 \u2212 m 2 s 2 12 sin 2(\u03b1 + \u03b4)) = m 2 c 2 12 sin 2\u03b1 + m 3 sin 2(\u03b2 + \u03b4), (17) sin 2\u03b8 12 (m 1 cos \u03b4 \u2212 m 2 cos(2\u03b1 + \u03b4))s 13 = \u22122(m 1 s 2 12 + m 2 c 2 12 cos 2\u03b1) cot 2\u03b8 23 (18) and tan \u03b8 12 (m 1 sin \u03b4 \u2212 m 2 sin(2\u03b1 + \u03b4))s 13 = \u2212m 2 sin 2\u03b1 cot 2\u03b8 23 .", "type": "figure"}, "FIGREF5": {"text": "(14) and(15) only which can be written ass 2 12 m 1 + c 2 12 m 2 cos 2\u03b1 = \u2212m 3 cos 2\u03b2, sin 2\u03b1 = \u2212m 3 sin 2\u03b2.(21)From Eqs.(20)and(21), the only possible CP conserving solution for neutrino mass matrices of class C with maximal mixing is given by", "type": "figure"}, "TABREF0": {"text": "Allowed two texture zero mass matrices.", "type": "table"}}}
{"paper_id": "2870029", "_pdf_hash": "85663525ccb996c4ca4680706c283065d9712c13", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Studies of collateral vascular responses", "authors": [{"first": "S", "middle": [], "last": "Bellman", "suffix": ""}, {"first": "H", "middle": ["A"], "last": "Frank", "suffix": ""}, {"first": "P", "middle": ["B"], "last": "Lambert", "suffix": ""}, {"first": "A", "middle": [], "last": "Roy", "suffix": ""}], "year": 1959, "venue": "Angiology", "link": null}, "BIBREF1": {"title": "Experimental microlymphangiography", "authors": [{"first": "S", "middle": [], "last": "Bellman", "suffix": ""}, {"first": "B", "middle": [], "last": "Oden", "suffix": ""}], "year": 1957, "venue": "Acta Radiol", "link": null}, "BIBREF2": {"title": "Observations on the growth of blood vessels as seen in the transparent chamber introduced into the rabbit's ear", "authors": [{"first": "J", "middle": ["C"], "last": "Sandison", "suffix": ""}], "year": 1928, "venue": "Am. J. Anat", "link": "85255693"}, "BIBREF3": {"title": "General observations on the ingrowth of new blood vessels into standardized chambers in the rabbit's ear, and the subsequent changes in the newly grown vessels over a period of months", "authors": [{"first": "E", "middle": ["R"], "last": "Clark", "suffix": ""}, {"first": "W", "middle": ["J"], "last": "Hitschler", "suffix": ""}, {"first": "H", "middle": ["T"], "last": "Kirby-Smith", "suffix": ""}, {"first": "R", "middle": ["O"], "last": "Rex", "suffix": ""}, {"first": "J", "middle": ["H"], "last": "Smith", "suffix": ""}], "year": 1931, "venue": "Anat. Rec", "link": "84942050"}, "BIBREF4": {"title": "The new formation of arterio-venous anastomoses in the rabbit's ear", "authors": [{"first": "E", "middle": ["R"], "last": "Clark", "suffix": ""}, {"first": "E", "middle": ["L"], "last": "Clark", "suffix": ""}], "year": 1934, "venue": "Am. J. Anat", "link": "86213991"}, "BIBREF5": {"title": "Vascular regeneration in experimental wounds and burns", "authors": [{"first": "A", "middle": ["F W"], "last": "Hughes", "suffix": ""}, {"first": "L", "middle": [], "last": "Dann", "suffix": ""}], "year": 1941, "venue": "Brit. J. Exper. Path", "link": "71014378"}, "BIBREF6": {"title": "Vascular transformation in experimental tubed skin pedicles", "authors": [{"first": "E", "middle": [], "last": "Velander", "suffix": ""}, {"first": "S", "middle": [], "last": "Bellman", "suffix": ""}], "year": 1959, "venue": "Brit. J. Plast. Surg", "link": null}, "BIBREF7": {"title": "Revascularization by substitution of a preformed fine vascular plexus for a major blood-vessel", "authors": [{"first": "E", "middle": [], "last": "Friedman", "suffix": ""}, {"first": "P", "middle": ["B"], "last": "Lambert", "suffix": ""}, {"first": "H", "middle": [], "last": "Frank", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF8": {"title": "Regeneration of surgically divided lymph vessels. Acta chir. scandinav", "authors": [{"first": "S", "middle": [], "last": "Bellman", "suffix": ""}, {"first": "B", "middle": [], "last": "Oden", "suffix": ""}], "year": 1959, "venue": "", "link": null}, "BIBREF9": {"title": "Untersuchungen &uuml;ber die Histogenese und Histomechanik des Gef&auml;ss-systems", "authors": [{"first": "R", "middle": [], "last": "Thoma", "suffix": ""}], "year": "", "venue": "Ferdinand Enke", "link": null}, "BIBREF10": {"title": "The stimulus to collateral circulation", "authors": [{"first": "H", "middle": ["T"], "last": "John", "suffix": ""}, {"first": "R", "middle": [], "last": "Warren", "suffix": ""}], "year": 1961, "venue": "Surgery", "link": "37415447"}, "BIBREF11": {"title": "Adaptations of collateral pathways", "authors": [{"first": "P", "middle": ["B"], "last": "Lambert", "suffix": ""}, {"first": "S", "middle": [], "last": "Bellman", "suffix": ""}, {"first": "H", "middle": ["A"], "last": "Frank", "suffix": ""}], "year": 1961, "venue": "Angiology", "link": null}, "BIBREF12": {"title": "Role of blood coagulation and fibrinolysis in the pathogenesis of arteriosclerosis", "authors": [{"first": "T", "middle": [], "last": "Astrup", "suffix": ""}], "year": 1959, "venue": "Connective Tissue, Thrombosis, and Atherosclerosis", "link": "34989347"}, "BIBREF13": {"title": "Fibrinolysis autographs", "authors": [{"first": "A", "middle": ["S"], "last": "Todd", "suffix": ""}], "year": 1958, "venue": "Nature", "link": null}, "BIBREF14": {"title": "The regeneration of the lymphatics", "authors": [{"first": "F", "middle": ["L"], "last": "Reichert", "suffix": ""}], "year": 1926, "venue": "Arch. Surg", "link": "72997439"}}, "ref_entries": {}}
{"paper_id": "2870075", "_pdf_hash": "2b747c668463d72ac8ff4ec4a7a231aa8cf6410d", "abstract": [{"section": "Abstract", "text": "System calibration is fundamental to the overall accuracy of the ultrasonic temperature measurement, and it is basically involved in accurately measuring the path length and the system latency of the ultrasonic system. This paper proposes a method of high accuracy system calibration. By estimating the time delay between the transmitted signal and the received signal at several different temperatures, the calibration equations are constructed, and the calibrated results are determined with the use of the least squares algorithm. The formulas are deduced for calculating the calibration uncertainties, and the possible influential factors are analyzed. The experimental results in distilled water show that the calibrated path length and system latency can achieve uncertainties of 0.058 mm and 0.038 \u03bcs, respectively, and the temperature accuracy is significantly improved by using the calibrated results. The temperature error remains within \u00b10.04\u02daC consistently, and the percentage error is less than 0.15%.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Ultrasonic temperature measurement, as a non-intrusive technique, plays a crucial role in plenty of industrial processes due to its strong environmental adaptability [1, 2] , high reliability [3] , low cost [4] and wide measuring range [5] . The basic principle is that the ultrasound velocity in any medium is generally a function of temperature. In most liquids, the function is linear; in a gaseous environment, the velocity is directly proportional to the square root of the temperature; and in solid mediums, the velocity generally decreases with the increasing of the temperature [6] . Thus, if the ultrasound velocity is measured, the temperature can be determined. In our previous study [7] , we proposed a promising method for highly accurate ultrasonic temperature measurement. Two transducers, mounted face to face, act as the transmitter and the receiver of the ultrasound signals, respectively, and the distance between them is fixed. By estimating the time delay (TD) between the transmitted signal and the received signal, the ultrasound velocity is given, and the temperature can be determined.", "cite_spans": [{"start": 166, "end": 169, "text": "[1,", "ref_id": "BIBREF0"}, {"start": 170, "end": 172, "text": "2]", "ref_id": "BIBREF1"}, {"start": 192, "end": 195, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 207, "end": 210, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 236, "end": 239, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 586, "end": 589, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 695, "end": 698, "text": "[7]", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "Introduction", "text": "However, the estimated TD contains not only the desired time of flight of sound, but also a system latency which includes the time taken by the transmitter to produce the sound, the time taken by the receiver to produce the electrical signal and the time taken by the conditioning circuit [8] . The system latency is an intrinsic hardware constant that need to be estimated in advance. Moreover, the path length of sound is generally not the transducers' geometrical distance, but the travelling sound path length which serves as the acoustic center-to-center distance [5] . The exact path length is not available from direct distance measurement. Therefore, to accurately estimate the path length and the system latency, calibration work of the ultrasonic system should be performed, which is the basis of high accuracy ultrasonic temperature measurement.", "cite_spans": [{"start": 289, "end": 292, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 569, "end": 572, "text": "[5]", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "Introduction", "text": "The calibration methods of path length usually depend on measurement of the acoustic centers of the transducers. Based on the definition that the acoustic center is the position of the point from which the sound pressure varies inversely as distance [9, 10] , most results presented in the literature have been determined from deviations of the amplitude of the sound pressure [11] . Cox attempted to measure the acoustic centers of various transducers using a dismantled lathe bed for positioning the scanning microphone [12] . The comparisons of acoustic centers among several European laboratories were summarized by Rasmussen and Olsen [13] . Juhl [14] measured the acoustic centers by using the boundary value technique and assuming a parabolic movement of the diaphragms. Barrera-Figueroa et al. [15] presented an experimental procedure to determine the position of the acoustic centers of the microphones. Shaw and Hodnett [16] described some typical issues related to calibration and measurement of therapeutic medical ultrasonic equipment. A theoretical model for the transfer characteristics of a hydrophone has been developed, which can help to calculate the system latency [17] . However, the methods mentioned above mainly focused on calibrating the characteristics of the transducers, rather than the ultrasonic system directly. The calibration procedure is very complex, and it is difficult to achieve high calibration performance. This paper proposes a promising calibration method to determine the path length and the system latency of an ultrasonic system for temperature measurement. Calibration equations on the path length and the system latency are presented by estimating the TD between the transmitted signal and received signal at several different temperatures, and the calibrated results are determined simultaneously based on the least squares algorithm. Distilled water is employed as the medium to perform the experiment keeping in a stable temperature environment with an accuracy of 0.01\u00b0C. To achieve highly accurate TD estimation, a continuous wave modulated by maximum length sequence is adopted, and a hybrid method is employed by incorporating both cross-correlation and phase shift. According to the basic calibration principle, the given TD uncertainty and the thermometer uncertainty, the formulas for calculating the path length uncertainty and the system latency uncertainty are presented, and the uncertainty propagation coefficients are also deduced. To validate the effectiveness of the proposed method, the calibrated results are used in ultrasonic temperature measurement, which shows the temperature accuracy is significantly improved.", "cite_spans": [{"start": 250, "end": 253, "text": "[9,", "ref_id": "BIBREF8"}, {"start": 377, "end": 381, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 522, "end": 526, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 640, "end": 644, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 652, "end": 656, "text": "[14]", "ref_id": "BIBREF13"}, {"start": 802, "end": 806, "text": "[15]", "ref_id": "BIBREF14"}, {"start": 930, "end": 934, "text": "[16]", "ref_id": "BIBREF15"}, {"start": 1185, "end": 1189, "text": "[17]", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "Problem formulation", "text": "In Ref. [7] , the authors proposed a promising method for ultrasonic temperature measurement. and the problem of system calibration was also mentioned. In this section, a brief overview is given. The graphic abstract of temperature measurement is shown in Fig 1. If equation C = f(T) represents the inner dependence between the temperature (T) and the ultrasound velocity (C), then T can be determined when C is measured", "cite_spans": [{"start": 8, "end": 11, "text": "[7]", "ref_id": "BIBREF6"}], "ref_spans": [{"start": 256, "end": 262, "text": "Fig 1.", "ref_id": "FIGREF0"}]}, {"section": "Problem formulation", "text": "where f \u22121 () denotes the mapping relationship from the ultrasound velocity to the temperature. Signal source drives the transmitter to produce sound wave, which is captured by the receiver after propagation in the medium. A hybrid technique is adopted to estimate the TD between the transmitted signal and received signal by incorporating both cross-correlation and phase shift. Combining the estimated TD and the calibrated results of the ultrasonic system, the ultrasound velocity of the medium can be expressed as following:", "cite_spans": [], "ref_spans": []}, {"section": "Problem formulation", "text": "where D and \u03c4 sys represent the path length and the system latency, respectively. The temperature to be measured is determined by", "cite_spans": [], "ref_spans": []}, {"section": "Problem formulation", "text": "Accurate temperature is achievable on the basis of estimating TD accurately. And the inaccurate representation of D and \u03c4 sys should be carefully considered. This paper is to calibrate the path length D and the system latency \u03c4 sys exactly.", "cite_spans": [], "ref_spans": []}, {"section": "Calibration of ultrasonic system", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Calibration method", "text": "TD estimation between the transmitted signal and the received signal is performed at M different known temperatures. The calibration equations on D and \u03c4 sys are presented as following:", "cite_spans": [], "ref_spans": []}, {"section": "Calibration method", "text": "where TD m denotes the estimated time delay of the m-th temperature, and e m is the corresponding estimation error. f(T m ) denotes the ultrasound velocity related to the temperature T m , which is measured in advance. By using the least squares which is an optimal algorithm of parameter estimation for linear models [18] , the calibrated path length (D) and system latency ", "cite_spans": [{"start": 318, "end": 322, "text": "[18]", "ref_id": "BIBREF17"}], "ref_spans": []}, {"section": "Calibration method", "text": "To ensure that Eq (5) can be deduced from Eq (4), the matrix A should has a full column rank, which requires f(T) to be a monotone function as T ranges from T 1 to T M . And accurate system calibration is achievable on the basis of estimating time delay and temperature accurately.", "cite_spans": [], "ref_spans": []}, {"section": "Experimental setup", "text": "The experimental setup is shown in Fig 2. It is a typical ultrasonic system for temperature measurement within the dashed box that consists of two transducers, a signal transceiver module and a PC. The transmitter and the receiver both use Vico's WK-21B acoustic piezoelectric transducers, which work at 1 MHz and have an operating temperature within 5\u00b0C * 110\u00b0C. The transducers are fixed on a steel framework face to face. The primary functions of the transceiver module, shown in Fig 2(c) , include signal storage, signal transmission and signal receiving. The FPGA (XILINX XC6SLX45) works as a core function jointed with a 100M-Base PHY (LXT971ALE), an ADC (ADS2806Y), a DAC (DAC2932PFB), dual DDR (MT46V64M8TG) and other external ports. The transmitted signal, generated by the PC, is downloaded through the Ethernet to the DDR. System starts when the PC sends a trigger command. The DAC converts the digital signal from DDR into an analog signal to drive the transmitter. The ADC, with a sampling rate at 10 Msps, works synchronously with the DAC, and the sampled signal is fed back to the DDR and uploaded to the PC for further processing.", "cite_spans": [], "ref_spans": [{"start": 35, "end": 41, "text": "Fig 2.", "ref_id": "FIGREF2"}, {"start": 483, "end": 491, "text": "Fig 2(c)", "ref_id": "FIGREF2"}]}, {"section": "Experimental setup", "text": "Distilled water is selected as the medium to carry out the system calibration from two aspects of concern. First, it is widely accepted that the mapping function between the ultrasound velocity and the temperature in distilled water is sufficiently accurate. Additionally, the temperature of liquid such as distilled water has potential to be accurately measured by a mercuric thermometer, and the changes of temperature can be easily controlled. In 1972, Del Grosso first provided the ultrasound velocity equation of distilled water [19] , and it was approximated by a polynomial [20] :", "cite_spans": [{"start": 534, "end": 538, "text": "[19]", "ref_id": "BIBREF18"}, {"start": 581, "end": 585, "text": "[20]", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "Experimental setup", "text": "where T is the temperature in degrees Celsius, k 0 = 0.140238744 \u00d7 10 . As shown in Fig 3, it is one to one relationship between C and T, which is a basic requirement of our proposed calibration method.", "cite_spans": [], "ref_spans": [{"start": 84, "end": 90, "text": "Fig 3,", "ref_id": "FIGREF3"}]}, {"section": "Experimental setup", "text": "The two transducers are fully immersed into the distilled water, and the temperature is measured using a mercuric thermometer, manufactured by Jing Chuang Instrument (model WNG-01) with a typical accuracy of 0.01\u00b0C. A thermostatic water bath (BILOW-GDW-2011B) is used to monitor and control the temperature of tap water, which exchanges heat with the distilled water. Highly constant and accurate temperature of the distilled water is achievable on the basis of following techniques: (1) The ultrasound wave is not transmitted until the temperature stays at the target point for 10 minutes, which contributes to constructing a stable and uniform temperature environment. (2) By using a transmitted signal that consists of 40 sets of continuous wave, 40 TD estimations are completed in less than a second. In such a short period, the temperature of the distilled water is nearly constant. (3) At the moment of signal transmitting, the thermometer readings are recorded as soon as possible to ensure the accuracy of the temperature. Additionally, air conditioning in the laboratory is also turned on and set at the same temperature to reduce the temperature difference between the air and the distilled water.", "cite_spans": [], "ref_spans": []}, {"section": "Experimental setup", "text": "At each temperature, an ultrasound wave is transmitted by the transmitter, and received by the receiver after propagation in the distilled water. To achieve highly accurate TD estimation, a continuous wave modulated by maximum length sequence is adopted for echo suppression to increase the available length of the received signal, and a hybrid technique incorporating both cross-correlation and phase shift is employed. Cross-correlation initially, based on the transmitted and received signals, produces a rough TD to eliminate the phase ambiguity, and then phase shift refines this rough value to estimate TD with higher accuracy [7] .", "cite_spans": [{"start": 633, "end": 636, "text": "[7]", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "Experimental results and discussion", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Experimental results", "text": "We carried out system calibration at 7 different temperatures (M = 7) ranging from 18\u00b0C to 42\u00b0C, and TD estimation was repeated 40 times at each temperature. The average of estimated TD, summarized in Table 1 , decreases with the increasing of the temperature and has a standard deviation of less than 0.3 ns. Based on Eqs (5) and (6), the path length and the system latency are determined as D = 185.2265 mm and \u03c4 sys = 9.0171 \u03bcs, respectively.", "cite_spans": [], "ref_spans": [{"start": 201, "end": 208, "text": "Table 1", "ref_id": "TABREF1"}]}, {"section": "Uncertainty analysis", "text": "Uncertainty analysis plays a crucial role in evaluation of the calibration performance, and it can help to find out which parameter has the biggest effect and which need only to be roughly given.", "cite_spans": [], "ref_spans": []}, {"section": "Uncertainty analysis", "text": "The calibrated path length and system latency, from Eq (5), can be formally expressed as where f D () and f \u03c4 () represent the functions to determine the path length and the system latency, respectively. Because temperature measurement and TD estimation are independent, both path length uncertainty (u D ) and system latency uncertainty (u \u03c4 ) can be decomposed into two parts:", "cite_spans": [], "ref_spans": []}, {"section": "Uncertainty analysis", "text": "where u D1 and u D2 are the path length uncertainties introduced by temperature measurement and TD estimation, respectively. u \u03c41 and u \u03c42 are the system latency uncertainties introduced by temperature measurement and TD estimation, respectively. Moreover, the inner dependence of uncertainty propagation is strictly proportional, such that", "cite_spans": [], "ref_spans": []}, {"section": "Uncertainty analysis", "text": "where u T denotes the temperature uncertainty, \u03b1 T\u2212D and \u03b1 T\u2212\u03c4 are the propagation coefficients to introduce u T to u D1 and u \u03c41 , respectively. u TD denotes the TD uncertainty, \u03b1 TD\u2212D and \u03b1 TD\u2212\u03c4 are the propagation coefficients to introduce u TD to u D2 and u \u03c42 , respectively. These coefficients are determined by [21] ", "cite_spans": [{"start": 318, "end": 322, "text": "[21]", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "Uncertainty analysis", "text": "The detailed uncertainty of the experiment is shown in Table 2 . The temperature uncertainty (u T ) only depends on the accuracy of the mercuric thermometer. Generally, the temperature error satisfies a uniform distribution within \u00b10.01\u00b0C, so we have u T \u00bc 0:01= ffiffi ffi 3 p % 0:006", "cite_spans": [], "ref_spans": [{"start": 55, "end": 62, "text": "Table 2", "ref_id": "TABREF2"}]}, {"section": "Uncertainty analysis", "text": ". The TD uncertainty (u TD ) is less than 0.3 ns, which depends on the parameters of the received signal, such as the signal-to-noise ratio, the carrier frequency and the signal length [22] . The uncertainties of the calibrated path length and system latency are close to 0.058 mm and 0.038 \u03bcs, respectively. And the temperature measurement has the biggest effect which is approximately 4 times bigger than the effect of TD estimation. To improve the calibration performance, three techniques are useful: (1) using a thermometer with higher accuracy; (2) improving the performance of TD estimation; (3) improving the calibration equations to reduce the uncertainty propagation coefficients.", "cite_spans": [{"start": 185, "end": 189, "text": "[22]", "ref_id": "BIBREF21"}], "ref_spans": []}, {"section": "Temperature measurement using calibrated results", "text": "To further validate the effectiveness of the proposed method, the calibrated results are used in ultrasonic temperature measurement. The experiment was performed at 13 different temperatures ranging from 18\u00b0C to 42\u00b0C, and the temperature, measured by the mercuric thermometer, is regarded as the reference true value. Another experiment was also carried out for comparison, where the system latency remained unchanged (\u03c4 sys = 9.0171 \u03bcs), but the path length was measured by a slide caliper ruler with a typical accuracy of 0.02 mm. The measured path length is D = 184.80 mm. Fig 4 presents the results of measured temperature, where temperature in abscissa represents the reference true value determined by the thermometer. It is shown that the measured temperature, using calibrated results, is highly close to the reference true value. However, system error appears obviously when the path length is measured by a slide caliper ruler. And the system error, shown in Fig 5(a) , increases with the rise of the temperature, which is up to 2.211\u00b0C when the temperature is 41.957\u00b0C. Fig 5(b) shows the temperature error by using the calibrated results, where the temperature accuracy is significantly improved. The temperature error consistently remains within \u00b10.04\u00b0C, and the percentage error is less than 0.15%.", "cite_spans": [], "ref_spans": [{"start": 576, "end": 590, "text": "Fig 4 presents", "ref_id": "FIGREF4"}]}, {"section": "Conclusions", "text": "This paper presents a promising calibration method of an ultrasonic system for temperature measurement. And the following conclusions can be made:", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "\u2022 By estimating TD between the transmitted signal and received signal at several different temperatures, the calibration equations are presented, and the path length and the system latency are determined simultaneously based on the least squares algorithm; \u2022 The formulas for calculating the calibration uncertainties are given, and the uncertainty propagation coefficients are also deduced, which plays a crucial role in finding out which parameter would have the biggest effect and which need only to be roughly considered;", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "\u2022 Both calibration experiment and validation experiment were performed in the distilled water in a stable temperature environment with an accuracy of 0.01\u00b0C;", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "\u2022 The proposed method calibrates the path length and the system latency with uncertainties of 0.058 mm and 0.038 \u03bcs, respectively. With the use of the calibrated results, the performance of temperature measurement is significantly improved. The temperature error consistently remains within \u00b10.04\u00b0C, and the percentage error is less than 0.15%.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "An acoustic pyrometer system for tomographic thermal imaging in power plant boilers", "authors": [{"first": "M", "middle": [], "last": "Bramanti", "suffix": ""}, {"first": "E", "middle": ["A"], "last": "Salerno", "suffix": ""}, {"first": "A", "middle": [], "last": "Tonazzini", "suffix": ""}, {"first": "Pasini", "middle": ["S"], "last": "Gray", "suffix": ""}, {"first": "A", "middle": [], "last": "", "suffix": ""}], "year": 1996, "venue": "IEEE Trans. Instrum. Meas", "link": "110377874"}, "BIBREF1": {"title": "Acoustic pyrometry in flames", "authors": [{"first": "K", "middle": [], "last": "Srinivasan", "suffix": ""}, {"first": "T", "middle": [], "last": "Sundararajan", "suffix": ""}, {"first": "S", "middle": [], "last": "Narayanan", "suffix": ""}, {"first": "Jothi", "middle": [], "last": "Tjs", "suffix": ""}, {"first": "Cslv", "middle": [], "last": "Sarma Rohit", "suffix": ""}], "year": 2013, "venue": "Measurement", "link": "109052758"}, "BIBREF2": {"title": "Acoustic tomographic imaging of temperature and flow fields in air", "authors": [{"first": "A", "middle": [], "last": "Barth M And Raabe", "suffix": ""}], "year": 2011, "venue": "Meas. Sci. Technol", "link": "122313270"}, "BIBREF3": {"title": "A performance analysis of echographic ultrasonic techniques for non-invasive temperature estimation in hyperthermia range using phantoms with scatterers", "authors": [{"first": "I", "middle": [], "last": "Baz\u00e1n", "suffix": ""}, {"first": "M", "middle": [], "last": "Vazquez", "suffix": ""}, {"first": "A", "middle": [], "last": "Ramos", "suffix": ""}, {"first": "Vera", "middle": ["A"], "last": "Leija", "suffix": ""}, {"first": "L", "middle": [], "last": "", "suffix": ""}], "year": 2009, "venue": "Ultrasonics", "link": "32242889"}, "BIBREF4": {"title": "Calibration of an acoustic system for measuring 2-D temperature distribution around hydrothermal vents", "authors": [{"first": "W", "middle": [], "last": "Fan", "suffix": ""}, {"first": "Cta", "middle": [], "last": "Chen", "suffix": ""}, {"first": "Y", "middle": [], "last": "Chen", "suffix": ""}], "year": 2013, "venue": "Ultrasonics", "link": "30603813"}, "BIBREF5": {"title": "Automatic Ultrasonic Thermometry", "authors": [{"first": "X", "middle": ["B"], "last": "Mi", "suffix": ""}, {"first": "S", "middle": ["Y"], "last": "Zhang", "suffix": ""}, {"first": "J", "middle": ["J"], "last": "Zhang", "suffix": ""}, {"first": "Y", "middle": ["T"], "last": "Yang", "suffix": ""}], "year": 2003, "venue": "Journal of Nanjing University", "link": null}, "BIBREF6": {"title": "High-accuracy ultrasonic temperature measurement based on MLS-modulated continuous wave", "authors": [{"first": "C", "middle": [], "last": "Zhou", "suffix": ""}, {"first": "Y", "middle": ["K"], "last": "Wang", "suffix": ""}, {"first": "C", "middle": ["J"], "last": "Qiao", "suffix": ""}, {"first": "S", "middle": [], "last": "Zhao", "suffix": ""}, {"first": "Z", "middle": ["G"], "last": "Huang", "suffix": ""}], "year": 2016, "venue": "Measurement", "link": "112940622"}, "BIBREF7": {"title": "A novel DSSS based ToF measurement method for short baseline and its application in sound velocimeter", "authors": [{"first": "S", "middle": [], "last": "Zhao", "suffix": ""}, {"first": "C", "middle": ["J"], "last": "Qiao", "suffix": ""}, {"first": "C", "middle": [], "last": "Zhou", "suffix": ""}], "year": 2013, "venue": "Sixth International Symposium on Precision Mechanical Measurements", "link": "109402930"}, "BIBREF8": {"title": "International electrotechnical vocabulary", "authors": [], "year": 1994, "venue": "IEC International Standard", "link": null}, "BIBREF10": {"title": "A note on the concept of acoustic center", "authors": [{"first": "F", "middle": [], "last": "Jacobsen", "suffix": ""}, {"first": "S", "middle": ["B"], "last": "Figueroa", "suffix": ""}, {"first": "K", "middle": [], "last": "Rasmussen", "suffix": ""}], "year": 2004, "venue": "J. Acoust. Soc. Am", "link": null}, "BIBREF11": {"title": "Physical limitations on free-field microphone calibration", "authors": [{"first": "J", "middle": ["R"], "last": "Cox", "suffix": ""}], "year": 1954, "venue": "", "link": "110868301"}, "BIBREF12": {"title": "Intercomparison on free-field calibration of microphones", "authors": [{"first": "K", "middle": [], "last": "Rasmussen", "suffix": ""}, {"first": "E", "middle": ["S"], "last": "Olsen", "suffix": ""}], "year": 1993, "venue": "", "link": null}, "BIBREF13": {"title": "A numerical investigation of standard con-denser microphones", "authors": [{"first": "P", "middle": ["M"], "last": "Juhl", "suffix": ""}], "year": 1994, "venue": "J. Sound Vib", "link": "110836413"}, "BIBREF14": {"title": "The acoustic center of laboratory standard microphones", "authors": [{"first": "S", "middle": [], "last": "Barrera-Figueroa", "suffix": ""}, {"first": "K", "middle": [], "last": "Rasmussen", "suffix": ""}, {"first": "F", "middle": [], "last": "Jacobsen", "suffix": ""}], "year": 2006, "venue": "J. Acoust. Soc. Am", "link": "4994215"}, "BIBREF15": {"title": "Calibration and measurement issues for therapeutic ultrasound", "authors": [{"first": "A", "middle": [], "last": "Shaw", "suffix": ""}, {"first": "M", "middle": [], "last": "Hodnett", "suffix": ""}], "year": 2008, "venue": "Ultrasonics", "link": "6093439"}, "BIBREF16": {"title": "A theoretical model describing the transfer characteristics of a membrane hydrophone and validation", "authors": [{"first": "P", "middle": ["N"], "last": "Gelat", "suffix": ""}, {"first": "Preston", "middle": [], "last": "Rc", "suffix": ""}, {"first": "A", "middle": [], "last": "Hurrell", "suffix": ""}], "year": 2005, "venue": "Ultrasonics", "link": null}, "BIBREF17": {"title": "Foundamentals of statistical signal processing volume I: estimation theory", "authors": [{"first": "S", "middle": ["M"], "last": "Kay", "suffix": ""}], "year": 1993, "venue": "", "link": null}, "BIBREF18": {"title": "Speed of sound in pure water", "authors": [{"first": "Del", "middle": [], "last": "Grosso", "suffix": ""}, {"first": "V", "middle": ["A"], "last": "Mader", "suffix": ""}, {"first": "C", "middle": ["W"], "last": "", "suffix": ""}], "year": 1972, "venue": "J. Acoust. Soc. Am", "link": "122025663"}, "BIBREF19": {"title": "Speed of sound in pure water as a function of temperature", "authors": [{"first": "N", "middle": [], "last": "Bilaniuk", "suffix": ""}, {"first": "Gsk", "middle": [], "last": "Wong", "suffix": ""}], "year": 1993, "venue": "J. Acoust. Soc. Am", "link": "121003898"}, "BIBREF20": {"title": "Error theory and data processing", "authors": [{"first": "Y", "middle": ["T"], "last": "Fei", "suffix": ""}], "year": 2010, "venue": "", "link": null}, "BIBREF21": {"title": "Novel method of sound speed measurement based on parameter-estimation of continuous wave", "authors": [{"first": "C", "middle": ["J"], "last": "Qiao", "suffix": ""}, {"first": "W", "middle": ["H"], "last": "Dai", "suffix": ""}, {"first": "C", "middle": [], "last": "Zhou", "suffix": ""}], "year": 2013, "venue": "IEEE 11th International Conference on Electronic Measurement & Instruments", "link": "21231539"}}, "ref_entries": {"FIGREF0": {"text": "Fig 1. Basic principle of ultrasonic temperature measurement.", "type": "figure"}, "FIGREF2": {"text": "Fig 2. The experimental setup. (a) Schematic of the experimental system. (b) Photograph of the actual system. (A) is the trough with distilled water, (B) is one of the transducers, (C) is the mercuric thermometer, (D) is the thermostatic water bath, (E) is the signal transceiver module, (F) is the PC, (G) is the power supply and (H) is the frequency meter. (c) Photograph of the signal transceiver module. (A) is the FPGA, (B) is the DDR memory, (C) is the Ethernet port, (D) are the transmitting channels and (E) are the receiving channels. (d) The Photograph of one of the adopted mercuric thermometers, which ranges from 35\u02daC * 39\u02daC. doi:10.1371/journal.pone.0165335.g002", "type": "figure"}, "FIGREF3": {"text": "Fig 3. The function that ultrasound velocity versus temperature in distilled water. doi:10.1371/journal.pone.0165335.g003", "type": "figure"}, "FIGREF4": {"text": "Fig 4. Results of measured ultrasonic temperature. doi:10.1371/journal.pone.0165335.g004", "type": "figure"}, "TABREF0": {"text": "doi:10.1371/journal.pone.0165335.g001 (t sys ) can be deduced byD", "type": "table"}, "TABREF1": {"text": "The calibrated results.", "type": "table"}, "TABREF2": {"text": "Uncertainty analysis of the calibrated results.\u03b1 T\u2212\u03c4 : 6.477 \u03bcs/\u02daC \u03b1 TD\u2212D : 0.045 mm/ns \u03b1 TD\u2212\u03c4 : 30.080 doi:10.1371/journal.pone.0165335.t002", "type": "table"}}}
{"paper_id": "2870145", "_pdf_hash": "1de5727faa4c6d3ea2d2375781023aaf5701d466", "abstract": [{"section": "Abstract", "text": "Excessive daytime sleepiness (EDS) is a ubiquitous problem that affects public health and safety. A test that can reliably identify individuals that suffer from EDS is needed. In contrast to other methods, salivary biomarkers are an objective, inexpensive, and noninvasive method to identify individuals with inadequate sleep. Although we have previously shown that inflammatory genes are elevated in saliva samples taken from sleep deprived individuals, it is unclear if inflammatory genes will be elevated in clinical populations with EDS. In this study, salivary samples from individuals with sleep apnea were evaluated using the Taqman low density inflammation array. Transcript levels for 3 genes, including prostaglandin-endoperoxide synthase 2 (PTGS2), were elevated in patients with sleep apnea. Interestingly, PTGS2 was also elevated in patients with EDS but who did not have sleep apnea. These data demonstrate the feasibility of using salivary transcript levels to identify individuals that self-report excessive daytime sleepiness.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Inadequate sleep is a pervasive problem in today's society. Insufficient sleep leads to decreased cognitive performance [1] , increased sleepiness [2] [3] [4] , reduced productivity [5] , and increased traffic accidents [6] . Moreover, inadequate sleep increases the susceptibility of individuals to adverse health outcomes, including cardiovascular deficits [7] , increased immune challenges [8, 9] , longer recovery times after injury [10] , increases in sympathetic tone [11, 12] , and reduced lifespan [7] . Given the number and severity of consequences that accompany inadequate sleep, it would be helpful to have a simple and reliable test to identify vulnerable individuals before they experience adverse consequences.", "cite_spans": [{"start": 120, "end": 123, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 147, "end": 150, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 151, "end": 154, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 155, "end": 158, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 182, "end": 185, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 220, "end": 223, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 359, "end": 362, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 393, "end": 396, "text": "[8,", "ref_id": "BIBREF7"}, {"start": 397, "end": 399, "text": "9]", "ref_id": "BIBREF8"}, {"start": 437, "end": 441, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 474, "end": 478, "text": "[11,", "ref_id": "BIBREF10"}, {"start": 479, "end": 482, "text": "12]", "ref_id": "BIBREF11"}, {"start": 506, "end": 509, "text": "[7]", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "Introduction", "text": "One approach to accomplish this objective has been to test candidate biomarkers to determine whether they are consistently altered in subjects with inadequate or insufficient sleep. Biomarkers are objective, often endogenous factors that report changes in body chemistry and correlate with either disease state or the severity of the disease. Several biomarkers, including eyelid closures [13] and balance [14] , as well as biochemical markers from blood [15, 16] , cerebral spinal fluid [17] [18] [19] , and breath analytes [20] have been evaluated as candidate biomarkers of disrupted sleep. Although each of these approaches has had limited success, assessment tools that can be used in real-world settings are not yet widely available. With that in mind, we have hypothesized that saliva, as a rich source of analytes, can be mined to identify biomarkers of sleepiness or inadequate sleep. Saliva is particularly well suited for monitoring sleepiness since it is a readily accessible biological fluid that can be easily collected using noninvasive procedures. Indeed, we have shown that transcripts for -amylase, Filamin-A, maleic enzyme, integrin, M, and integrin, 5, are all elevated in saliva samples following sleep deprivation [21] [22] [23] [24] . Increased levels of salivary -amylase activity have also been shown to correlate with increased sleepiness and decreased cognitive performance in an independent study [25] . However, since endogenous factors are frequently modulated by a variety of physiological conditions (stress, circadian time, etc.), test of sleepiness should be comprised of a panel of independent analytes. Several studies have found that serum markers of inflammation are elevated in populations of individuals with sleep disorders [9] . For example, serum levels of interleukin 6 (IL-6) [26] , interleukin 8 (IL-8) [27, 28] , tumor necrosis factor-(TNF-) [29] , C-reactive protein (CRP) [30] , intracellular adhesion molecule (ICAM) [31] , selectins [32] , and vascular cell adhesion molecule (VCAM) [31] have all been shown to increase in multiple populations of patients with sleep apnea. Therefore, we wanted to determine if levels of salivary inflammation transcripts could be used to identify sleepiness in a clinical population, individuals diagnosed with sleep apnea.", "cite_spans": [{"start": 389, "end": 393, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 406, "end": 410, "text": "[14]", "ref_id": "BIBREF13"}, {"start": 455, "end": 459, "text": "[15,", "ref_id": "BIBREF14"}, {"start": 460, "end": 463, "text": "16]", "ref_id": "BIBREF15"}, {"start": 488, "end": 492, "text": "[17]", "ref_id": "BIBREF16"}, {"start": 493, "end": 497, "text": "[18]", "ref_id": "BIBREF17"}, {"start": 498, "end": 502, "text": "[19]", "ref_id": "BIBREF18"}, {"start": 525, "end": 529, "text": "[20]", "ref_id": "BIBREF19"}, {"start": 1236, "end": 1240, "text": "[21]", "ref_id": "BIBREF20"}, {"start": 1241, "end": 1245, "text": "[22]", "ref_id": "BIBREF21"}, {"start": 1246, "end": 1250, "text": "[23]", "ref_id": "BIBREF22"}, {"start": 1251, "end": 1255, "text": "[24]", "ref_id": "BIBREF23"}, {"start": 1425, "end": 1429, "text": "[25]", "ref_id": "BIBREF24"}, {"start": 1765, "end": 1768, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 1821, "end": 1825, "text": "[26]", "ref_id": "BIBREF25"}, {"start": 1849, "end": 1853, "text": "[27,", "ref_id": "BIBREF26"}, {"start": 1854, "end": 1857, "text": "28]", "ref_id": "BIBREF27"}, {"start": 1889, "end": 1893, "text": "[29]", "ref_id": "BIBREF28"}, {"start": 1921, "end": 1925, "text": "[30]", "ref_id": "BIBREF29"}, {"start": 1967, "end": 1971, "text": "[31]", "ref_id": "BIBREF30"}, {"start": 1984, "end": 1988, "text": "[32]", "ref_id": "BIBREF31"}, {"start": 2034, "end": 2038, "text": "[31]", "ref_id": "BIBREF30"}], "ref_spans": []}, {"section": "Materials and Methods", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "2.", "text": "1. Subjects and Samples. 8 controls, 14 patients confirmed to have sleep apnea, and 18 patients that were suspected to have sleep apnea during their initial screen but did not exhibit sleep apnea during their overnight assessment (sleepy) were evaluated for salivary transcript levels. Both the sleep apnea group and the \"sleepy\" group were referred to the Washington University Sleep Laboratory due to excessive sleepiness. Samples were taken from patients at \u223c9 pm after they had arrived at the sleep lab and prior to beginning polysomnography. The apnea/hypopnea index (AHI) was determined using polysomnography (PSG) as previously described [33] . Subjects were free from psychiatric disorders and prescription medicines [24] . Each subject was administered the Epworth Sleepiness Scale (ESS) and their body mass index (BMI) was calculated. BMI was unavailable for one subject in the \"sleepy\" group. Consent was received from all participants and all protocols were approved by the Washington University School of Medicine Institutional Review Board.", "cite_spans": [{"start": 645, "end": 649, "text": "[33]", "ref_id": "BIBREF32"}, {"start": 725, "end": 729, "text": "[24]", "ref_id": "BIBREF23"}], "ref_spans": []}, {"section": "Low Density Arrays.", "text": "Saliva was taken and cDNA was generated according to the protocol previously described [24] . Briefly, saliva was obtained when subjects chewed on a salivette (Sarstedt, Newton, NC). One mL of RNAlater (Life Technologies, Grand Island, NY) was added to the salivette and immediately frozen on dry ice and stored at \u221280 \u2218 C. At the time of transcript analysis, salivettes were thawed and the saliva-RNAlater extracts were extracted by centrifugation. RNA was purified from cell-free lysates and reversetranscribed using Superscript III (Life Technologies, Grand Island, NY) according to the manufacturer's instructions. Equal amounts of cDNA were loaded into an inflammation Taqman low density array (LDA) (Life Technologies, Grand Island, NY) and Taqman based qPCR was carried out using the 7600 real-time PCR system (Applied Biosystems, Foster City, CA). The LDAs were normalized to 18S RNA. Fold changes were determined using the method described in [34] , known as the comparative C method. Transcript levels for the gene of interest were first normalized within subject to 18S RNA. ", "cite_spans": [{"start": 87, "end": 91, "text": "[24]", "ref_id": "BIBREF23"}, {"start": 952, "end": 956, "text": "[34]", "ref_id": "BIBREF33"}], "ref_spans": []}, {"section": "Statistics.", "text": "All demographic data is presented as average \u00b1 standard deviation. For transcript analysis, if a transcript was not detected in more than 77% of the group, the transcript was deemed undetectable and not analyzed. For all detectable genes, transcript levels for each subject were determined as a fold change from the average levels of the control group. Fold changes were converted to a log 2 scale. From the log data, average and standard error were calculated. Groups of interest were compared to control levels using a two-tailed, unpaired Student's t-test and the significance level was set at 0.05. values were corrected for multiple comparisons using the false discovery method (FDR) with a FDR level of 5% [35] . Transcript levels are presented as a geometric mean and standard error [36] . For ease of presentation, group data, including average, upper, and lower bounds, were then converted back to standard units by raising 2 to the power of the calculated value to obtain fold change values.", "cite_spans": [{"start": 712, "end": 716, "text": "[35]", "ref_id": "BIBREF34"}, {"start": 790, "end": 794, "text": "[36]", "ref_id": "BIBREF35"}], "ref_spans": []}, {"section": "Results", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Demographic Data for Patients with Sleep Apnea.", "text": "We evaluated 14 patients with sleep apnea (11 male and 3 female) and 8 control subjects (5 male and 3 female) for salivary transcriptional changes associated with sleep apnea. Control subjects did not have any prior existing sleep or mental disorders, were not on prescription medications, had not consumed caffeine, and had not eaten 1 hour prior to providing a saliva sample. Subject age was not different between the two groups ( Table 1 ). The subjects with sleep apnea had an average AHI of 48.5 \u00b1 23.6 (mean \u00b1 S.D.). The subjects with sleep apnea had a significantly higher body mass index (BMI) than the controls. Consistent with previous results, subjects with sleep apnea also reported a higher score on the Epworth Sleepiness Scale.", "cite_spans": [], "ref_spans": [{"start": 433, "end": 440, "text": "Table 1", "ref_id": "TABREF0"}]}, {"section": "Evaluation of Salivary Biomarkers Associated with Inflammation in Patients with Sleep Apnea.", "text": "We evaluated salivary transcript levels from subjects with sleep apnea and control subjects using low density arrays. The LDA platform simultaneously evaluates the levels of 96 RNA species. Of the 96 genes tested, 21 transcripts were detected in 11 or more sleep apnea patients. Fold changes from control and value for each gene are presented in Table 2 . The value listed was determined using a two-tailed Student's t-test comparing the controls to sleep apnea for all analyzed genes present in saliva. We performed a correction for multiple comparisons using a FDR set at 5%, which yielded a new value equivalent to = 0.0071 [35] . Compared to controls, 3 transcripts exhibited significant changes in patients with sleep apnea (Table 2) , ANXA1, 2M, and PTGS2 (see Table 2 for abbreviations). These results indicate that several inflammatory transcripts are increased in patients with sleep apnea.", "cite_spans": [{"start": 627, "end": 631, "text": "[35]", "ref_id": "BIBREF34"}], "ref_spans": [{"start": 346, "end": 353, "text": "Table 2", "ref_id": "TABREF1"}, {"start": 729, "end": 738, "text": "(Table 2)", "ref_id": "TABREF1"}, {"start": 767, "end": 774, "text": "Table 2", "ref_id": "TABREF1"}]}, {"section": "Demographic Data for Patients with an Elevated ESS but without Sleep Apnea.", "text": "To assess whether the increased inflammatory markers were due primarily to hypoxia or whether they might be more closely associated with increased sleepiness, we evaluated transcriptional changes in an independent group of people that entered the sleep lab suspected of having sleep apnea due to initial screening but ultimately had a normal AHI as determined by PSG (sleepy). The \"sleepy\" group was composed of 6 males and 12 females. By definition, all individuals in this group had an AHI less than 5. However, all subjects reported ESS scores significantly higher than controls and similar to the subjects with sleep apnea (Tables 1 and 3 ). \"Sleepy\" subjects had a similar age to controls but an increased BMI.", "cite_spans": [], "ref_spans": [{"start": 627, "end": 642, "text": "(Tables 1 and 3", "ref_id": "TABREF0"}]}, {"section": "Salivary Transcript Levels in \"", "text": "Sleepy\" People. Twentyone transcripts were detected in the saliva of 14 or more \"sleepy\" patients. As above, to facilitate comparisons with the apnea patients reported in Table 2, Table 4 includes transcripts for fold changes for each of the 21 transcripts. After and FDR correction for multiple comparisons ( = 0.005), 2 transcripts were significantly changed in the \"sleepy\" population, CASP1 and PTGS2. PTGS2 can be considered an independent replicate of the apnea results and may deserve further consideration. Thus, inflammatory transcripts are elevated under conditions of EDS.", "cite_spans": [], "ref_spans": [{"start": 171, "end": 187, "text": "Table 2, Table 4", "ref_id": "TABREF1"}]}, {"section": "Transcriptional Changes Are Not due to Elevated BMI.", "text": "One possible explanation for elevated inflammatory transcripts is that both the sleep apnea and \"sleepy\" patients have a significantly higher BMI compared to controls. If the observed relationship is due solely to BMI, then patients with high BMI should have increased levels of inflammatory transcripts compared to patients with lower BMI. Similarly, we should detect a significant positive correlation between BMI and the level of salivary transcripts. To test this hypothesis we discretized the data by placing the subjects with a low BMI (\u226430; = 24) into a single group and comparing them to subjects with a high BMI (>38; = 16). As seen in Table 5 , transcripts were not significantly different between subjects in the lower BMI group compared to their counterparts with a higher BMI. In addition, we evaluated the relationship between BMI and transcript levels using a Pearson correlation and found no significant correlations. Examples of transcript expression levels for the genes with the lowest values are plotted in Figure 1 as a function of BMI. These data indicate that, in this dataset, BMI does not account for increases in transcript levels in these patients.", "cite_spans": [], "ref_spans": [{"start": 645, "end": 652, "text": "Table 5", "ref_id": "TABREF4"}, {"start": 1027, "end": 1035, "text": "Figure 1", "ref_id": "FIGREF0"}]}, {"section": "Discussion", "text": "In this paper, we report that salivary transcript levels of inflammatory genes are increased both in patients with sleep apnea and in an independent cohort of patients who self-identified as sleepy and were referred to the sleep lab suspected of having sleep apnea. We have previously used these same human low density arrays as a discovery tool to identify genes that are modified following acute sleep deprivation in healthy adults [24] . In that study, we reported that integrin, M (ITGAM), and annexin A3 (ANXA3) were significantly increased following 24 h and 30 h of waking. Interestingly, neither ITGAM nor ANXA3 were altered in either sleep apnea or \"sleepy\" subjects suggesting that they may be better suited for detecting acute sleep loss than for identifying patients with chronic sleep disruption. In contrast, salivary PTGS2 was significantly increased in both sleep apnea patients and in the \"sleepy\" cohort but was not affected by acute sleep deprivation [24] . Thus, these data support our previous proposal that a panel of biomarkers will be required to accurately identify sleep deprived individuals and further suggest that different sets of biomarkers may be required to distinguish between acute and chronic sleep disruptions.", "cite_spans": [{"start": 434, "end": 438, "text": "[24]", "ref_id": "BIBREF23"}, {"start": 970, "end": 974, "text": "[24]", "ref_id": "BIBREF23"}], "ref_spans": []}, {"section": "Discussion", "text": "Sleep apnea has been particularly difficult to diagnose and treat and the incidence of sleep apnea has been difficult to determine. Estimates of sleep apnea have ranged from as low as 2-4% to as high as 24% of middle aged men [37] , although other studies have estimated the likelihood of sleep apnea to be much higher still [38, 39] . Moreover, it has been suggested that sleep apnea is likely to be substantially underdiagnosed [38, 39] . Indeed, years may transpire between the onset of sleep apnea and the eventual diagnosis [40] . As the population ages and becomes more obese, the prevalence of sleep apnea is expected to increase even further [7, 41, 42] . During these intervening years, the severity and consequences of the sleep apnea may also increase [41, 42] . The associated Mediators of Inflammation 5 consequences of sleep apnea include increased daytime sleepiness [3] and an increased likelihood of automobile accidents [6] . Moreover, sleep apnea has been associated with a host of cardiovascular complications [43, 44] and increased rates of all-cause mortality [7] . Sleep apnea has also been associated with learning impairments [45] . The current gold standard of treatment, continuous positive airway pressure (CPAP), may be able to reverse some of the consequences of sleep apnea, such as sleepiness [2] and restoration of typical sleep stages [2] , and may lower blood pressure [46] but the literature is less conclusive whether cognitive function is improved [4, 47] . Thus, a clinical goal is to have patients begin treatment for sleep apnea as soon as possible. A simple cost-effective biomarker that can be easily used at the point of care may be a useful tool to convince people to go to the sleep lab for a more precise diagnosis and treatment. Since biomarkers are both objective and quantifiable, they are well suited for persuading an individual that they may have an underlying affliction that needs greater attention. In that regard, it is important to note that the well-known relationship between inflammation and sleep deprivation is an advantage since many physicians are likely to be familiar with this relationship and thus more willing to incorporate such a biomarker into their treatment practices. That is, numerous inflammatory markers, including IL-6 [20, 26, 48], IL-8 [27, 28, 48] , TNF- [26] , CRP [49, 50] , monocyte chemoattractant protein-1 (MCP-1) [27] , ICAM [27, 51] , selectins [51] , VCAM [51] , nitric oxide [52] , and isoprostane [20] , are elevated in body fluids of patients with sleep apnea. Moreover, proteomics have identified protein biomarkers in urine [53] . Interestingly, inflammatory markers have also been associated with sleep deprivation in serum [54, 55] and saliva in healthy adults [24] . In this study, transcript levels for PTGS2 were elevated in people with inadequate sleep. Our results parallel findings in mice in which transcript levels for PTGS2 are elevated after acute sleep deprivation [56] . PTGS2, along with PTGS1, is a critical enzyme in prostaglandin synthesis. Prostaglandins initiate a set of molecular cascades that result in an inflammatory response. PTGS2 is induced by several stimuli including proinflammatory signals and converts arachidonic acid to prostaglandin H2 [57] . Thus, PTGS2 plays a role in the inflammatory pathway in addition to being a candidate biomarker for EDS.", "cite_spans": [{"start": 226, "end": 230, "text": "[37]", "ref_id": "BIBREF36"}, {"start": 325, "end": 329, "text": "[38,", "ref_id": "BIBREF37"}, {"start": 330, "end": 333, "text": "39]", "ref_id": "BIBREF38"}, {"start": 430, "end": 434, "text": "[38,", "ref_id": "BIBREF37"}, {"start": 435, "end": 438, "text": "39]", "ref_id": "BIBREF38"}, {"start": 529, "end": 533, "text": "[40]", "ref_id": "BIBREF39"}, {"start": 650, "end": 653, "text": "[7,", "ref_id": "BIBREF6"}, {"start": 654, "end": 657, "text": "41,", "ref_id": "BIBREF40"}, {"start": 658, "end": 661, "text": "42]", "ref_id": "BIBREF41"}, {"start": 763, "end": 767, "text": "[41,", "ref_id": "BIBREF40"}, {"start": 768, "end": 771, "text": "42]", "ref_id": "BIBREF41"}, {"start": 882, "end": 885, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 938, "end": 941, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 1030, "end": 1034, "text": "[43,", "ref_id": "BIBREF42"}, {"start": 1035, "end": 1038, "text": "44]", "ref_id": "BIBREF43"}, {"start": 1082, "end": 1085, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 1151, "end": 1155, "text": "[45]", "ref_id": "BIBREF44"}, {"start": 1325, "end": 1328, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 1369, "end": 1372, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 1404, "end": 1408, "text": "[46]", "ref_id": "BIBREF45"}, {"start": 1486, "end": 1489, "text": "[4,", "ref_id": "BIBREF3"}, {"start": 1490, "end": 1493, "text": "47]", "ref_id": "BIBREF46"}, {"start": 2318, "end": 2322, "text": "[27,", "ref_id": "BIBREF26"}, {"start": 2323, "end": 2326, "text": "28,", "ref_id": "BIBREF27"}, {"start": 2327, "end": 2330, "text": "48]", "ref_id": "BIBREF47"}, {"start": 2338, "end": 2342, "text": "[26]", "ref_id": "BIBREF25"}, {"start": 2349, "end": 2353, "text": "[49,", "ref_id": "BIBREF48"}, {"start": 2354, "end": 2357, "text": "50]", "ref_id": "BIBREF49"}, {"start": 2403, "end": 2407, "text": "[27]", "ref_id": "BIBREF26"}, {"start": 2415, "end": 2419, "text": "[27,", "ref_id": "BIBREF26"}, {"start": 2420, "end": 2423, "text": "51]", "ref_id": "BIBREF50"}, {"start": 2436, "end": 2440, "text": "[51]", "ref_id": "BIBREF50"}, {"start": 2448, "end": 2452, "text": "[51]", "ref_id": "BIBREF50"}, {"start": 2468, "end": 2472, "text": "[52]", "ref_id": "BIBREF51"}, {"start": 2491, "end": 2495, "text": "[20]", "ref_id": "BIBREF19"}, {"start": 2621, "end": 2625, "text": "[53]", "ref_id": "BIBREF52"}, {"start": 2722, "end": 2726, "text": "[54,", "ref_id": "BIBREF53"}, {"start": 2727, "end": 2730, "text": "55]", "ref_id": "BIBREF54"}, {"start": 2760, "end": 2764, "text": "[24]", "ref_id": "BIBREF23"}, {"start": 2975, "end": 2979, "text": "[56]", "ref_id": "BIBREF55"}, {"start": 3269, "end": 3273, "text": "[57]", "ref_id": "BIBREF56"}], "ref_spans": []}, {"section": "Discussion", "text": "It is interesting to note that many studies compare sleep apnea patients to healthy controls. Although this approach has been quite successful, our data suggest that other patients with chronic sleep disruption may also experience some of the same outcomes as patients with sleep apnea. If this turns out to be the case, more generally, assessing chronically sleepy individuals along with patients that have sleep apnea The transcript levels were plotted against the log values of the transcript levels for each of the transcripts that were significant in the sleep apnea or \"sleepy\" groups. In addition the transcripts with the lowest value were plotted to determine if there was a significant correlation with increased weight. For each transcript, there was no significant correlation with increased BMI.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "may facilitate the identification of precise deficits that are due specifically to sleep loss rather than other features of sleep apnea, such as hypoxia [48] . Nonetheless, our results emphasize that PTGS2 cannot distinguish between sleepy patients with and without sleep apnea. While this may seem disappointing, we believe that any diagnosis of a sleep disorder should be made by a qualified sleep physician after fully examining the patient. Indeed, it may not be possible to identify a biomarker that is specific to a single sleep disorder. One example of a promising biomarker is cerebrospinal fluid (CSF) levels of hypocretin-1/orexin (HCRT), which has emerged from research in the narcolepsy field [18, 58] . CSF levels of hypocretin-1/orexin are lower in narcoleptic patients. But for patients without cataplexy, decreased CSF levels of HCRT are not as predictive, even in combination with the genetic marker DBQ. Moreover, decreases in CSF levels of HCRT are also associated now, being associated with other diseases, including dementia with Lewy Body [59] and Alzheimer's disease [60] and Kleine-Levin syndrome [58, 61] . This example illustrates the difficulty of a single biomarker with a given sleep disorder. Nonetheless, a biomarker that can help primary physicians to identify sleepy individuals may be extremely useful for ensuring that they get the appropriate care in a timely manner.", "cite_spans": [{"start": 153, "end": 157, "text": "[48]", "ref_id": "BIBREF47"}, {"start": 705, "end": 709, "text": "[18,", "ref_id": "BIBREF17"}, {"start": 710, "end": 713, "text": "58]", "ref_id": "BIBREF57"}, {"start": 1061, "end": 1065, "text": "[59]", "ref_id": "BIBREF58"}, {"start": 1090, "end": 1094, "text": "[60]", "ref_id": "BIBREF59"}, {"start": 1121, "end": 1125, "text": "[58,", "ref_id": "BIBREF57"}, {"start": 1126, "end": 1129, "text": "61]", "ref_id": "BIBREF60"}], "ref_spans": []}, {"section": "Discussion", "text": "Our protocol has two aspects that may be useful for the real-world application of biomarkers to identify patients with sleep disorders. First, acquiring saliva is a noninvasive procedure and does not, for example, require a private location for sample collection (e.g., urine) or specialized skills to acquire samples (e.g., blood). As a consequence, salivary biomarkers can be readily used both on the roadside and in a doctor's office with equal effectiveness. A second advantage of our protocol is our focus on salivary RNA coupled with the LDA platform for the rapid detection of 96 transcripts simultaneously. LDAs may be an effective way to screen multiple targeted transcripts at once without the burden that NextGen sequencing frequently demands. One advantage of using transcript levels as the biomarker is that nucleotide probes can be generated quickly and are very specific for the target intended as opposed to having to design an antibody against a protein target. Given human variability, the different roles that genes can play throughout the body (pleiotropy), and the likelihood that a given analyte will be induced by a variety of environmental situations, it is likely that no single biomarker will be ideal for reliable diagnosis of sleep apnea. Nonetheless, our data suggest that PTGS2 may be a particularly good candidate for inclusion in a panel of biomarkers.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "There are two potential weaknesses of our study. The first is the sample size of our groups. Low sample sizes may identify significant differences within the subgroup that does not generalize to the rest of the population. In this study, we have tried to balance the difficulty of completing discovery experiments with the expense of a human study. Although our sample size was low for sleep apnea subjects, we were able to confirm the changes in PTGS2 in a separate cohort of \"sleepy\" patients. This confirmation adds to our confidence that PTGS2 is a good candidate for followup studies. A second weakness of this study is that we were not able to control for the levels of BMI between our control subjects and patients with sleep apnea or the \"sleepy\" cohort. To address this issue, we discretized the subjects into groups with low or high BMI. Means testing between the two groups indicated the subjects with low and high BMI were not different from one another. Moreover, Pearson correlation between BMI and transcript levels did not reveal any significant associations. Finally, when examined as a whole, we could find no general trend of inflammatory genes being elevated in subjects with higher BMI. Thus, while BMI is a potential confounder, it did not appear to unduly influence the results of this study.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "Biomarkers have the capacity to serve an important need in maintaining human health. They provide an objective insight into the goings-on of the body. In particular, there is a need to identify individuals with sleep problems that result in EDS. Given the difficulty in identifying individuals, the consequences of sleep apnea and other sleep disorders, and the potential that therapy possesses, objective biomarkers can be a way to convince people to go to the sleep lab for diagnosis. We have demonstrated the feasibility of using saliva to identify changes in inflammatory transcripts that correlate with the presence of EDS. Saliva is an ideal source of biofluid for a potential source of biomarkers. Obtaining saliva is a noninvasive and relatively inexpensive process. Further experiments in larger and independent populations will determine the precision and validity of these biomarkers, but these experiments demonstrate that saliva has the potential to be objective biomarkers to identify subjects with EDS.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "The cumulative cost of additional wakefulness: dose-response effects on neurobehavioral functions and sleep physiology from chronic sleep restriction and total sleep deprivation", "authors": [{"first": "H", "middle": ["P A"], "last": "Van Dongen", "suffix": ""}, {"first": "G", "middle": [], "last": "Maislin", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Mullington", "suffix": ""}, {"first": "D", "middle": ["F"], "last": "Dinges", "suffix": ""}], "year": 2003, "venue": "Sleep", "link": "8030600"}, "BIBREF1": {"title": "Recovery of alertness after CPAP in apnea", "authors": [{"first": "J", "middle": [], "last": "Lamphere", "suffix": ""}, {"first": "T", "middle": [], "last": "Roehrs", "suffix": ""}, {"first": "R", "middle": [], "last": "Wittig", "suffix": ""}, {"first": "F", "middle": [], "last": "Zorick", "suffix": ""}, {"first": "W", "middle": ["A"], "last": "Conway", "suffix": ""}, {"first": "T", "middle": [], "last": "Roth", "suffix": ""}], "year": 1989, "venue": "Chest", "link": "31894497"}, "BIBREF2": {"title": "A new method for measuring daytime sleepiness: the Epworth sleepiness scale", "authors": [{"first": "M", "middle": ["W"], "last": "Johns", "suffix": ""}], "year": 1991, "venue": "Sleep", "link": null}, "BIBREF3": {"title": "Cognitive dysfunction in patients with obstructive sleep apnea (OSA): partial reversibility after continuous positive airway pressure (CPAP)", "authors": [{"first": "L", "middle": [], "last": "Ferini-Strambi", "suffix": ""}, {"first": "C", "middle": [], "last": "Baietto", "suffix": ""}, {"first": "M", "middle": ["R"], "last": "Di Gioia", "suffix": ""}], "year": 2003, "venue": "Brain Research Bulletin", "link": "39480678"}, "BIBREF4": {"title": "Impact of nighttime awakenings on worker productivity and performance", "authors": [{"first": "G", "middle": ["K"], "last": "Zammit", "suffix": ""}, {"first": "V", "middle": ["N"], "last": "Joish", "suffix": ""}, {"first": "M", "middle": ["C"], "last": "Kong", "suffix": ""}, {"first": "R", "middle": [], "last": "Balkrishnan", "suffix": ""}, {"first": "D", "middle": [], "last": "Lerner", "suffix": ""}, {"first": "M", "middle": [], "last": "Rosekind", "suffix": ""}], "year": 2010, "venue": "Journal of Occupational & Environmental Medicine", "link": "24712797"}, "BIBREF5": {"title": "The association between sleep apnea and the risk of traffic accidents", "authors": [{"first": "J", "middle": [], "last": "Teran-Santos", "suffix": ""}, {"first": "A", "middle": [], "last": "Jimenez-Gomez", "suffix": ""}, {"first": "J", "middle": [], "last": "Cordero-Guevara", "suffix": ""}, {"first": "Cooperative Group", "middle": [], "last": "Burgos-Santander", "suffix": ""}], "year": 1999, "venue": "The New England Journal of Medicine", "link": "75728969"}, "BIBREF6": {"title": "Sleep disordered breathing and mortality: eighteen-year follow-up of the Wisconsin sleep cohort", "authors": [{"first": "T", "middle": [], "last": "Young", "suffix": ""}, {"first": "L", "middle": [], "last": "Finn", "suffix": ""}, {"first": "P", "middle": ["E"], "last": "Peppard", "suffix": ""}], "year": 2008, "venue": "Sleep", "link": "21911004"}, "BIBREF7": {"title": "Sleep and immune function: glial contributions and consequences of aging", "authors": [{"first": "A", "middle": ["M"], "last": "Ingiosi", "suffix": ""}, {"first": "M", "middle": ["R"], "last": "Opp", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Krueger", "suffix": ""}], "year": 2013, "venue": "Current Opinion in Neurobiology", "link": "45365138"}, "BIBREF8": {"title": "Serum inflammatory markers in obstructive sleep apnea: a meta-analysis", "authors": [{"first": "R", "middle": [], "last": "Nadeem", "suffix": ""}, {"first": "J", "middle": [], "last": "Molnar", "suffix": ""}, {"first": "E", "middle": ["M"], "last": "Madbouly", "suffix": ""}], "year": 2013, "venue": "Journal of Clinical Sleep Medicine", "link": "45481149"}, "BIBREF9": {"title": "Sleep disruptions mediate the relationship between early postoperative pain and later functioning following total knee replacement surgery", "authors": [{"first": "J", "middle": ["K"], "last": "Cremeans-Smith", "suffix": ""}, {"first": "K", "middle": [], "last": "Millington", "suffix": ""}, {"first": "E", "middle": [], "last": "Sledjeski", "suffix": ""}, {"first": "K", "middle": [], "last": "Greene", "suffix": ""}, {"first": "D", "middle": ["L"], "last": "Delahanty", "suffix": ""}], "year": 2006, "venue": "Journal of Behavioral Medicine", "link": "9051528"}, "BIBREF10": {"title": "Cardiac sympathovagal balance during sleep apnea episodes", "authors": [{"first": "E", "middle": [], "last": "Vanninen", "suffix": ""}, {"first": "A", "middle": [], "last": "Tuunainen", "suffix": ""}, {"first": "M", "middle": [], "last": "Kansanen", "suffix": ""}, {"first": "M", "middle": [], "last": "Uusitupa", "suffix": ""}, {"first": "E", "middle": [], "last": "L\u00e4nsimies", "suffix": ""}], "year": 1996, "venue": "Clinical Physiology", "link": "34594875"}, "BIBREF11": {"title": "Slow-wave sleep and the risk of type 2 diabetes in humans", "authors": [{"first": "E", "middle": [], "last": "Tasali", "suffix": ""}, {"first": "R", "middle": [], "last": "Leproult", "suffix": ""}, {"first": "D", "middle": ["A"], "last": "Ehrmann", "suffix": ""}, {"first": "E", "middle": [], "last": "Van Cauter", "suffix": ""}], "year": 2008, "venue": "Proceedings of the National Academy of Sciences of the United States of America", "link": "26239944"}, "BIBREF12": {"title": "Monitoring eye and eyelid movements by infrared reflectance oculography to measure drowsiness in drivers", "authors": [{"first": "M", "middle": ["W"], "last": "Johns", "suffix": ""}, {"first": "A", "middle": [], "last": "Tucker", "suffix": ""}, {"first": "R", "middle": [], "last": "Chapman", "suffix": ""}, {"first": "K", "middle": [], "last": "Crowley", "suffix": ""}, {"first": "N", "middle": [], "last": "Michael", "suffix": ""}], "year": 2007, "venue": "Somnologie", "link": null}, "BIBREF13": {"title": "Nintendo Wii Fit based sleepiness tester detects impairment of postural steadiness due to 24 h of wakefulness", "authors": [{"first": "A", "middle": [], "last": "Tiet\u00e4v\u00e4inen", "suffix": ""}, {"first": "F", "middle": ["K"], "last": "Gates", "suffix": ""}, {"first": "A", "middle": [], "last": "Meril\u00e4inen", "suffix": ""}, {"first": "J", "middle": ["E"], "last": "Mandel", "suffix": ""}, {"first": "E", "middle": [], "last": "Haeggstr\u00f6m", "suffix": ""}], "year": 2013, "venue": "Medical Engineering and Physics", "link": "35285388"}, "BIBREF14": {"title": "Potential of proteomics as a bioanalytic technique for quantifying sleepiness", "authors": [{"first": "N", "middle": [], "last": "Naidoo", "suffix": ""}], "year": 2011, "venue": "Journal of Clinical Sleep Medicine", "link": "27606429"}, "BIBREF15": {"title": "Plasma levels of neuropeptides and metabolic hormones, and sleepiness 8 Mediators of Inflammation in obstructive sleep apnea", "authors": [{"first": "M", "middle": [], "last": "S\u00e1nchez-De-La-Torre", "suffix": ""}, {"first": "A", "middle": [], "last": "Barcel\u00f3", "suffix": ""}, {"first": "J", "middle": [], "last": "Pi\u00e9rola", "suffix": ""}], "year": 2011, "venue": "Respiratory Medicine", "link": null}, "BIBREF16": {"title": "Hypocretin (orexin) deficiency in human narcolepsy", "authors": [{"first": "S", "middle": [], "last": "Nishino", "suffix": ""}, {"first": "B", "middle": [], "last": "Ripley", "suffix": ""}, {"first": "S", "middle": [], "last": "Overeem", "suffix": ""}, {"first": "G", "middle": ["J"], "last": "Lammers", "suffix": ""}, {"first": "E", "middle": [], "last": "Mignot", "suffix": ""}], "year": 2000, "venue": "The Lancet", "link": "43725707"}, "BIBREF17": {"title": "The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias", "authors": [{"first": "E", "middle": [], "last": "Mignot", "suffix": ""}, {"first": "G", "middle": ["J"], "last": "Lammers", "suffix": ""}, {"first": "B", "middle": [], "last": "Ripley", "suffix": ""}], "year": 2002, "venue": "Archives of Neurology", "link": "1902623"}, "BIBREF18": {"title": "Predictors of hypocretin (orexin) deficiency in narcolepsy without cataplexy", "authors": [{"first": "O", "middle": [], "last": "Andlauer", "suffix": ""}, {"first": "H", "middle": [], "last": "Moore", "suffix": ""}, {"first": "I", "middle": ["V"], "last": "", "suffix": ""}, {"first": "S.-C", "middle": [], "last": "Hong", "suffix": ""}], "year": 2012, "venue": "Sleep", "link": "747239"}, "BIBREF19": {"title": "Increased 8-isoprostane and interleukin-6 in breath condensate of obstructive sleep apnea patients", "authors": [{"first": "G", "middle": ["E"], "last": "Carpagnano", "suffix": ""}, {"first": "S", "middle": ["A"], "last": "Kharitonov", "suffix": ""}, {"first": "O", "middle": [], "last": "Resta", "suffix": ""}, {"first": "M", "middle": ["P"], "last": "Foschinobarbaro", "suffix": ""}, {"first": "E", "middle": [], "last": "Gramiccioni", "suffix": ""}, {"first": "P", "middle": ["J"], "last": "Barnes", "suffix": ""}], "year": 2002, "venue": "Chest", "link": "11882428"}, "BIBREF20": {"title": "Identification of a biomarker for sleep drive in flies and humans", "authors": [{"first": "L", "middle": [], "last": "Seugnet", "suffix": ""}, {"first": "J", "middle": [], "last": "Boero", "suffix": ""}, {"first": "L", "middle": [], "last": "Gottschalk", "suffix": ""}, {"first": "S", "middle": ["P"], "last": "Duntley", "suffix": ""}, {"first": "P", "middle": ["J"], "last": "Shaw", "suffix": ""}], "year": 2006, "venue": "Proceedings of the National Academy of Sciences of the United States of America", "link": "22553651"}, "BIBREF21": {"title": "Identifying sleep regulatory genes using a Drosophila model of insomnia", "authors": [{"first": "L", "middle": [], "last": "Seugnet", "suffix": ""}, {"first": "Y", "middle": [], "last": "Suzuki", "suffix": ""}, {"first": "M", "middle": [], "last": "Thimgan", "suffix": ""}], "year": 2009, "venue": "The Journal of Neuroscience", "link": "17694309"}, "BIBREF22": {"title": "Changes in gene expression with sleep", "authors": [{"first": "M", "middle": ["S"], "last": "Thimgan", "suffix": ""}, {"first": "S", "middle": ["P"], "last": "Duntley", "suffix": ""}, {"first": "P", "middle": ["J"], "last": "Shaw", "suffix": ""}], "year": 2011, "venue": "Journal of Clinical Sleep Medicine", "link": "28953345"}, "BIBREF23": {"title": "Crosstranslational studies in human and Drosophila identify markers of sleep loss", "authors": [{"first": "M", "middle": ["S"], "last": "Thimgan", "suffix": ""}, {"first": "L", "middle": [], "last": "Gottschalk", "suffix": ""}, {"first": "C", "middle": [], "last": "Toedebusch", "suffix": ""}], "year": 2013, "venue": "PLoS ONE", "link": "13666499"}, "BIBREF24": {"title": "Functional ADA polymorphism increases sleep depth and reduces vigilant attention in humans", "authors": [{"first": "V", "middle": [], "last": "Bachmann", "suffix": ""}, {"first": "F", "middle": [], "last": "Klaus", "suffix": ""}, {"first": "S", "middle": [], "last": "Bodenmann", "suffix": ""}], "year": 2012, "venue": "Cerebral Cortex", "link": "25512586"}, "BIBREF25": {"title": "Elevation of plasma cytokines in disorders of excessive daytime sleepiness: role of sleep disturbance and obesity", "authors": [{"first": "A", "middle": ["N"], "last": "Vgontzas", "suffix": ""}, {"first": "D", "middle": ["A"], "last": "Papanicolaou", "suffix": ""}, {"first": "E", "middle": ["O"], "last": "Bixler", "suffix": ""}, {"first": "A", "middle": [], "last": "Kales", "suffix": ""}, {"first": "K", "middle": [], "last": "Tyson", "suffix": ""}, {"first": "G", "middle": ["P"], "last": "Chrousos", "suffix": ""}], "year": 1997, "venue": "The Journal of Clinical Endocrinology and Metabolism", "link": "43871366"}, "BIBREF26": {"title": "Effects of obstructive sleep apnea on circulating ICAM-1, IL-8, and MCP-1", "authors": [{"first": "E", "middle": [], "last": "Ohga", "suffix": ""}, {"first": "T", "middle": [], "last": "Tomita", "suffix": ""}, {"first": "H", "middle": [], "last": "Wada", "suffix": ""}, {"first": "H", "middle": [], "last": "Yamamoto", "suffix": ""}, {"first": "T", "middle": [], "last": "Nagase", "suffix": ""}, {"first": "Y", "middle": [], "last": "Ouchi", "suffix": ""}], "year": 2003, "venue": "Journal of Applied Physiology", "link": "22826904"}, "BIBREF27": {"title": "Lipid peroxides, superoxide dismutase and circulating IL-8 and GCP-2 in patients with severe obstructive sleep apnea: a pilot study", "authors": [{"first": "M", "middle": ["A"], "last": "Alzoghaibi", "suffix": ""}, {"first": "A", "middle": ["S O"], "last": "Bahammam", "suffix": ""}], "year": 2005, "venue": "Sleep and Breathing", "link": "40993319"}, "BIBREF28": {"title": "The relationship between serum cytokine levels with obesity and obstructive sleep apnea syndrome", "authors": [{"first": "T", "middle": ["U"], "last": "Ciftci", "suffix": ""}, {"first": "O", "middle": [], "last": "Kokturk", "suffix": ""}, {"first": "N", "middle": [], "last": "Bukan", "suffix": ""}, {"first": "A", "middle": [], "last": "Bilgihan", "suffix": ""}], "year": 2004, "venue": "Cytokine", "link": "26100718"}, "BIBREF29": {"title": "Sleep pressure correlates of cognitive and behavioral morbidity in snoring children", "authors": [{"first": "L", "middle": ["M"], "last": "O&apos;brien", "suffix": ""}, {"first": "R", "middle": [], "last": "Tauman", "suffix": ""}, {"first": "D", "middle": [], "last": "Gozal", "suffix": ""}], "year": 2004, "venue": "Sleep", "link": "24804855"}, "BIBREF30": {"title": "Circulating ICAM-1 and VCAM-1 levels in patients with obstructive sleep apnea syndrome", "authors": [{"first": "A", "middle": [], "last": "Ursava\u015f", "suffix": ""}, {"first": "M", "middle": [], "last": "Karada\u01e7", "suffix": ""}, {"first": "E", "middle": [], "last": "Rodoplu", "suffix": ""}, {"first": "A", "middle": [], "last": "Yilmaztepe", "suffix": ""}, {"first": "H", "middle": ["B"], "last": "Oral", "suffix": ""}, {"first": "R", "middle": ["O"], "last": "G\u00f6z\u00fc", "suffix": ""}], "year": 2007, "venue": "Respiration", "link": null}, "BIBREF31": {"title": "Effects of nasal continuous positive airway pressure on soluble cell adhesion molecules in patients with obstructive sleep apnea syndrome", "authors": [{"first": "K", "middle": [], "last": "Chin", "suffix": ""}, {"first": "T", "middle": [], "last": "Nakamura", "suffix": ""}, {"first": "K", "middle": [], "last": "Shimizu", "suffix": ""}, {"first": "M", "middle": [], "last": "Mishima", "suffix": ""}, {"first": "M", "middle": [], "last": "Miyasaka", "suffix": ""}, {"first": "M", "middle": [], "last": "Ohi", "suffix": ""}], "year": 2000, "venue": "American Journal of Medicine", "link": "7645035"}, "BIBREF32": {"title": "Characterization of the mu rhythm during rapid eye movement sleep", "authors": [{"first": "S", "middle": ["P"], "last": "Duntley", "suffix": ""}, {"first": "A", "middle": ["H"], "last": "Kim", "suffix": ""}, {"first": "D", "middle": ["L"], "last": "Silbergeld", "suffix": ""}, {"first": "J", "middle": ["W"], "last": "Miller", "suffix": ""}], "year": 2001, "venue": "Clinical Neurophysiology", "link": "9795154"}, "BIBREF33": {"title": "Analysis of relative gene expression data using real-time quantitative PCR and the 2 \u2212 method", "authors": [{"first": "K", "middle": ["J"], "last": "Livak", "suffix": ""}, {"first": "T", "middle": ["D"], "last": "Schmittgen", "suffix": ""}], "year": 2001, "venue": "Methods", "link": null}, "BIBREF34": {"title": "Controlling the false discovery rate: a practical and powerful approach to multiple testing", "authors": [{"first": "Y", "middle": [], "last": "Benjamini", "suffix": ""}, {"first": "Y", "middle": [], "last": "Hochberg", "suffix": ""}], "year": 1995, "venue": "Journal of the Royal Statistical Society Series B: Methodological", "link": "45174121"}, "BIBREF35": {"title": "The geometric mean: confidence limits and significance tests", "authors": [{"first": "E", "middle": ["F"], "last": "Alf", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Grossberg", "suffix": ""}], "year": 1979, "venue": "Perception and Psychophysics", "link": "143866730"}, "BIBREF36": {"title": "The occurrence of sleep-disordered breathing among middleaged adults", "authors": [{"first": "T", "middle": [], "last": "Young", "suffix": ""}, {"first": "M", "middle": [], "last": "Palta", "suffix": ""}, {"first": "J", "middle": [], "last": "Dempsey", "suffix": ""}, {"first": "J", "middle": [], "last": "Skatrud", "suffix": ""}, {"first": "S", "middle": [], "last": "Weber", "suffix": ""}, {"first": "S", "middle": [], "last": "Badr", "suffix": ""}], "year": 1993, "venue": "The New England Journal of Medicine", "link": null}, "BIBREF37": {"title": "Prevalence of symptoms and risk of sleep apnea in the US population: results from the national sleep foundation sleep in America 2005 poll", "authors": [{"first": "D", "middle": ["M"], "last": "Hiestand", "suffix": ""}, {"first": "P", "middle": [], "last": "Britz", "suffix": ""}, {"first": "M", "middle": [], "last": "Goldman", "suffix": ""}, {"first": "B", "middle": [], "last": "Phillips", "suffix": ""}], "year": 2006, "venue": "Chest", "link": null}, "BIBREF38": {"title": "Prevalence of undiagnosed obstructive sleep apnea among adult surgical patients in an academic medical center", "authors": [{"first": "K", "middle": ["J"], "last": "Finkel", "suffix": ""}, {"first": "A", "middle": ["C"], "last": "Searleman", "suffix": ""}, {"first": "H", "middle": [], "last": "Tymkew", "suffix": ""}], "year": 2009, "venue": "Sleep Medicine", "link": "26242593"}, "BIBREF39": {"title": "Delayed diagnosis of obstructive sleep apnea: don't ask, don't tell", "authors": [{"first": "F", "middle": [], "last": "Rahaghi", "suffix": ""}, {"first": "R", "middle": ["C"], "last": "Basner", "suffix": ""}], "year": 1999, "venue": "Sleep and Breathing", "link": "22878742"}, "BIBREF40": {"title": "Longitudinal study of moderate weight change and sleepdisordered breathing", "authors": [{"first": "P", "middle": ["E"], "last": "Peppard", "suffix": ""}, {"first": "T", "middle": [], "last": "Young", "suffix": ""}, {"first": "M", "middle": [], "last": "Palta", "suffix": ""}, {"first": "J", "middle": [], "last": "Dempsey", "suffix": ""}, {"first": "J", "middle": [], "last": "Skatrud", "suffix": ""}], "year": 2000, "venue": "The Journal of the American Medical Association", "link": "14707228"}, "BIBREF41": {"title": "Increased prevalence of sleep-disordered breathing in adults", "authors": [{"first": "P", "middle": ["E"], "last": "Peppard", "suffix": ""}, {"first": "T", "middle": [], "last": "Young", "suffix": ""}, {"first": "J", "middle": ["H"], "last": "Barnet", "suffix": ""}, {"first": "M", "middle": [], "last": "Palta", "suffix": ""}, {"first": "E", "middle": ["W"], "last": "Hagen", "suffix": ""}, {"first": "K", "middle": ["M"], "last": "Hla", "suffix": ""}], "year": 2013, "venue": "The American Journal of Epidemiology", "link": "13694816"}, "BIBREF42": {"title": "Prospective study of the association between sleep-disordered breathing and hypertension", "authors": [{"first": "P", "middle": ["E"], "last": "Peppard", "suffix": ""}, {"first": "T", "middle": [], "last": "Young", "suffix": ""}, {"first": "M", "middle": [], "last": "Palta", "suffix": ""}, {"first": "J", "middle": [], "last": "Skatrud", "suffix": ""}], "year": 2000, "venue": "The New England Journal of Medicine", "link": "29053655"}, "BIBREF43": {"title": "Population-based study of sleep-disordered breathing as a risk factor for hypertension", "authors": [{"first": "T", "middle": [], "last": "Young", "suffix": ""}, {"first": "P", "middle": [], "last": "Peppard", "suffix": ""}, {"first": "M", "middle": [], "last": "Palta", "suffix": ""}], "year": 1997, "venue": "Archives of Internal Medicine", "link": "28864621"}, "BIBREF44": {"title": "Factors impairing daytime performance in patients with sleep apnea/hypopnea syndrome", "authors": [{"first": "K", "middle": [], "last": "Cheshire", "suffix": ""}, {"first": "H", "middle": [], "last": "Engleman", "suffix": ""}, {"first": "I", "middle": [], "last": "Deary", "suffix": ""}, {"first": "C", "middle": [], "last": "Shapiro", "suffix": ""}, {"first": "N", "middle": ["J"], "last": "Douglas", "suffix": ""}], "year": 1992, "venue": "Archives of Internal Medicine", "link": "19158988"}, "BIBREF45": {"title": "Effect of CPAP on blood pressure in patients with obstructive sleep apnea and resistant hypertension: the HIPARCO randomized clinical trial", "authors": [{"first": "M.-\u00c1", "middle": [], "last": "Mart\u00ednez-Garc\u00eda", "suffix": ""}, {"first": "F", "middle": [], "last": "Capote", "suffix": ""}, {"first": "F", "middle": [], "last": "Campos-Rodr\u00edguez", "suffix": ""}], "year": 2013, "venue": "The Journal of the American Medical Association", "link": null}, "BIBREF46": {"title": "Daytime sleepiness, cognitive performance and mood after continuous positive airway pressure for the sleep apnoea/hypopnoea syndrome", "authors": [{"first": "H", "middle": ["M"], "last": "Engleman", "suffix": ""}, {"first": "K", "middle": ["E"], "last": "Cheshire", "suffix": ""}, {"first": "I", "middle": ["J"], "last": "Deary", "suffix": ""}, {"first": "N", "middle": ["J"], "last": "Douglas", "suffix": ""}], "year": 1993, "venue": "Thorax", "link": "23764876"}, "BIBREF47": {"title": "Systemic and airway inflammation in sleep apnea and obesity: the role of ICAM-1 and IL-8", "authors": [{"first": "G", "middle": ["E"], "last": "Carpagnano", "suffix": ""}, {"first": "A", "middle": [], "last": "Spanevello", "suffix": ""}, {"first": "R", "middle": [], "last": "Sabato", "suffix": ""}], "year": 2010, "venue": "Translational Research", "link": "19266398"}, "BIBREF48": {"title": "Elevated C-reactive protein in patients with obstructive sleep apnea", "authors": [{"first": "A", "middle": ["S M"], "last": "Shamsuzzaman", "suffix": ""}, {"first": "M", "middle": [], "last": "Winnicki", "suffix": ""}, {"first": "P", "middle": [], "last": "Lanfranchi", "suffix": ""}], "year": 2002, "venue": "Circulation", "link": "1257609"}, "BIBREF49": {"title": "Elevated levels of Creactive protein and interleukin-6 in patients with obstructive sleep apnea syndrome are decreased by nasal continuous positive airway pressure", "authors": [{"first": "T", "middle": [], "last": "Yokoe", "suffix": ""}, {"first": "K", "middle": [], "last": "Minoguchi", "suffix": ""}, {"first": "H", "middle": [], "last": "Matsuo", "suffix": ""}], "year": 2003, "venue": "Circulation", "link": "2393380"}, "BIBREF50": {"title": "Increased levels of circulating ICAM-1, VCAM-1, and L-selectin in obstructive sleep apnea syndrome", "authors": [{"first": "E", "middle": [], "last": "Ohga", "suffix": ""}, {"first": "T", "middle": [], "last": "Nagase", "suffix": ""}, {"first": "T", "middle": [], "last": "Tomita", "suffix": ""}], "year": 1999, "venue": "Journal of Applied Physiology", "link": "12364450"}, "BIBREF51": {"title": "Exhaled pH, exhaled nitric oxide, and induced sputum cellularity in obese patients with obstructive sleep apnea syndrome", "authors": [{"first": "G", "middle": ["E"], "last": "Carpagnano", "suffix": ""}, {"first": "A", "middle": [], "last": "Spanevello", "suffix": ""}, {"first": "R", "middle": [], "last": "Sabato", "suffix": ""}, {"first": "A", "middle": [], "last": "Depalo", "suffix": ""}, {"first": "V", "middle": [], "last": "Turchiarelli", "suffix": ""}, {"first": "M", "middle": ["P"], "last": "Barbaro", "suffix": ""}], "year": 2008, "venue": "Translational Research", "link": "34139364"}, "BIBREF52": {"title": "Two-dimensional differential in-gel electrophoresis proteomic approaches reveal urine candidate biomarkers in pediatric obstructive sleep apnea", "authors": [{"first": "D", "middle": [], "last": "Gozal", "suffix": ""}, {"first": "S", "middle": [], "last": "Jortani", "suffix": ""}, {"first": "A", "middle": ["B"], "last": "Snow", "suffix": ""}], "year": 2009, "venue": "American Journal of Respiratory and Critical Care Medicine", "link": "23110676"}, "BIBREF53": {"title": "Effects of sleep and sleep deprivation on interleukin-6, growth hormone, cortisol, and melatonin levels in humans", "authors": [{"first": "L", "middle": [], "last": "Redwine", "suffix": ""}, {"first": "R", "middle": ["L"], "last": "Hauger", "suffix": ""}, {"first": "J", "middle": ["C"], "last": "Gillin", "suffix": ""}, {"first": "M", "middle": [], "last": "Irwin", "suffix": ""}], "year": 2000, "venue": "Journal of Clinical Endocrinology and Metabolism", "link": "24471106"}, "BIBREF54": {"title": "The effects of 40 hours of total sleep deprivation on inflammatory markers in healthy young adults", "authors": [{"first": "D", "middle": ["J"], "last": "Frey", "suffix": ""}, {"first": "M", "middle": [], "last": "Fleshner", "suffix": ""}, {"first": "K", "middle": ["P"], "last": "Wright", "suffix": ""}], "year": 2007, "venue": "Brain, Behavior, and Immunity", "link": "15901873"}, "BIBREF55": {"title": "Homer1a is a core brain molecular correlate of sleep loss", "authors": [{"first": "S", "middle": [], "last": "Maret", "suffix": ""}, {"first": "S", "middle": [], "last": "Dorsaz", "suffix": ""}, {"first": "L", "middle": [], "last": "Gurcel", "suffix": ""}], "year": 2007, "venue": "Proceedings of the National Academy of Sciences of the United States of America", "link": "30601698"}, "BIBREF56": {"title": "Prostaglandins and inflammation", "authors": [{"first": "E", "middle": [], "last": "Ricciotti", "suffix": ""}, {"first": "G", "middle": ["A"], "last": "Fitzgerald", "suffix": ""}], "year": 2011, "venue": "Arteriosclerosis, Thrombosis, and Vascular Biology", "link": "2637145"}, "BIBREF57": {"title": "CSF hypocretin-1 levels in narcolepsy, Kleine-Levin syndrome, and other hypersomnias and neurological conditions", "authors": [{"first": "Y", "middle": [], "last": "Dauvilliers", "suffix": ""}, {"first": "C", "middle": ["R"], "last": "Baumann", "suffix": ""}, {"first": "B", "middle": [], "last": "Carlander", "suffix": ""}], "year": 2003, "venue": "Neurosurgery and Psychiatry", "link": "11741953"}, "BIBREF58": {"title": "Altered CSF orexin and alpha-synuclein levels in dementia patients", "authors": [{"first": "M", "middle": [], "last": "Wennstr\u00f6m", "suffix": ""}, {"first": "E", "middle": [], "last": "Londos", "suffix": ""}, {"first": "L", "middle": [], "last": "Minthon", "suffix": ""}, {"first": "H", "middle": ["M"], "last": "Nielsen", "suffix": ""}], "year": 2012, "venue": "Journal of Alzheimer's Disease", "link": null}, "BIBREF59": {"title": "Hypocretin (orexin) loss in Alzheimer's disease", "authors": [{"first": "R", "middle": [], "last": "Fronczek", "suffix": ""}, {"first": "S", "middle": [], "last": "Van Geest", "suffix": ""}, {"first": "M", "middle": [], "last": "Fr\u00f6lich", "suffix": ""}], "year": 2012, "venue": "Neurobiology of Aging", "link": "14599731"}, "BIBREF60": {"title": "Preliminary results on CSF biomarkers for hypothalamic dysfunction in Kleine-Levin syndrome", "authors": [{"first": "R", "middle": [], "last": "Lopez", "suffix": ""}, {"first": "L", "middle": [], "last": "Barateau", "suffix": ""}, {"first": "S", "middle": [], "last": "Chenini", "suffix": ""}, {"first": "Y", "middle": [], "last": "Dauvilliers", "suffix": ""}], "year": 2015, "venue": "Sleep Medicine", "link": "13906702"}}, "ref_entries": {"FIGREF0": {"text": "Figure 1: Correlation of transcript levels with BMI. The transcript levels were plotted against the log values of the transcript levels for each of the transcripts that were significant in the sleep apnea or \"sleepy\" groups. In addition the transcripts with the lowest value were plotted to determine if there was a significant correlation with increased weight. For each transcript, there was no significant correlation with increased BMI.", "type": "figure"}, "TABREF0": {"text": "Demographics for controls and sleep apnea.", "type": "table"}, "TABREF1": {"text": "Salivary transcript levels in patients with sleep apnea compared to controls.", "type": "table"}, "TABREF2": {"text": "Demographics for \"sleepy\" subjects and controls.", "type": "table"}, "TABREF3": {"text": "Salivary transcript levels in \"sleepy\" patients compared to controls.", "type": "table"}, "TABREF4": {"text": "Comparison of transcriptional changes in high and low BMI subjects.", "type": "table"}}}
{"paper_id": "2870252", "_pdf_hash": "85f8592ef627fb02c7ff45b34227c49a1dd10879", "abstract": [{"section": "Abstract", "text": "Background-The signaling cascades responsible for the activation of transcription factors in the hypertrophic growth of cardiac myocytes during hemodynamic overload are largely unknown. Several of the genes upregulated in the hypertrophied heart, including B-type natriuretic peptide (BNP) gene, are controlled by the cardiac-restricted zinc finger transcription factor GATA4. Methods and Results-An in vivo model of intravenous administration of arginine 8 -vasopressin (AVP) for up to 4 hours in conscious normotensive rats was used to study the signaling mechanisms for GATA activation in response to pressure overload. Gel mobility shift assays were used to analyze the trans-acting factors that interact with the GATA motifs of the BNP promoter. AVP-induced increase in mean arterial pressure was followed by a significant increase in the BNP and c-fos mRNA levels in both the endocardial and epicardial layers of the left ventricle, whereas GATA4 and GATA6 mRNA levels remained unchanged. Pressure overload within 15 to 60 minutes produced an increase in left ventricular BNP GATA4 but not GATA5 and GATA6 binding activity, and at 30 minutes a 2.2-fold increase (P\u03fd0.001) in GATA4 binding was noted. The mixed endothelin-1 ET A /ET B receptor antagonist bosentan but not the angiotensin II type 1 receptor antagonist losartan completely inhibited the pressure overload-induced increase in left ventricular BNP GATA4 binding activity. Bosentan alone had no statistically significant effect on GATA4 binding activity of the left ventricle in conscious animals. Conclusions-ET-1 is a signaling molecule that rapidly upregulates GATA4 DNA binding activity in response to pressure overload in vivo. (Circulation. 2001;103:730-735.) ", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "", "text": "T he heart adapts to increased demands for cardiac work by increasing muscle mass through the initiation of a hypertrophic response, which may be a consequence of alterations in specific signaling molecules and their downstream pathways in individual myocytes. Accordingly, identifying the signals that mediate the pathways from biomechanical stress to downstream cellular events is a major area of research interest. [1] [2] [3] Both myocytes and nonmyocytes are direct biomechanical sensors of hemodynamic load. 4, 5 Growth signals are generated by the release of growth factors and cytokines, which lead to a regionally localized response. The factors that have been implicated in this response include peptides that stimulate G protein-coupled receptors, such as endothelin-1 (ET-1) and angiotensin II (Ang II). 2, 3 According to in vitro results, the primary downstream effectors are the mitogen-activated protein kinases (MAPKs), including the extracellular signal-regulated kinases (ERKs), the Jun N-terminal kinases (JNKs), and the p38 MAPKs. 6 At the genetic level, hemodynamic overload is associated with rapid (within 1 hour) and transient upregulation of immediate-early genes that encode transcription factors (cfos, c-jun, and Egr-1). 7 B-type natriuretic peptide (BNP) is also expressed at this early stage. 8, 9 In the medium term (12 to 24 hours), cardiomyocytes activate the fetal gene regulatory program with reexpression of genes for atrial natriuretic peptide (ANP), skeletal muscle \u2423-actin, and \u2424-myosin heavy chain (\u2424-MHC). 2, 7, 10, 11 Several of the genes upregulated during hypertrophy are controlled by the cardiac-restricted zinc finger transcription factor GATA4, [12] [13] [14] and recent work has shown that GATA binding sites appear to be required for activation of \u2424-MHC expression 15 and Ang II type 1a (AT 1A ) receptor expression 16 in response to pressure-overload hypertrophy in rats. Binding on AT 1A receptor and BNP GATA sites in extracts of hypertrophied but not control hearts was also noted, 16 suggesting that GATA binding activity is enhanced in the hypertrophied myocardium. The signaling cascades that affect GATA4 either in vitro or in vivo, however, are not known.", "cite_spans": [{"start": 418, "end": 421, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 422, "end": 425, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 426, "end": 429, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 514, "end": 516, "text": "4,", "ref_id": "BIBREF3"}, {"start": 816, "end": 818, "text": "2,", "ref_id": "BIBREF1"}, {"start": 1323, "end": 1325, "text": "8,", "ref_id": "BIBREF7"}, {"start": 1547, "end": 1549, "text": "2,", "ref_id": "BIBREF1"}, {"start": 1550, "end": 1552, "text": "7,", "ref_id": "BIBREF6"}, {"start": 1553, "end": 1556, "text": "10,", "ref_id": "BIBREF9"}, {"start": 1693, "end": 1697, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 1698, "end": 1702, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 1703, "end": 1707, "text": "[14]", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "", "text": "In the present study, to characterize the time course of induction of cardiac GATA activity, we measured hemody-namics and left ventricular GATA mRNA levels and BNP GATA binding activity at 15 minutes, 30 minutes, 1 hour, 2 hours, and 4 hours after pressure overload produced by intravenous infusion of arginine 8 -vasopressin (AVP) in conscious normotensive rats. We also assessed the effects of the mixed ET A /ET B receptor antagonist bosentan and the AT 1 receptor antagonist losartan on the increase of BNP GATA binding activity to determine whether ET-1 or Ang II plays a causal role in the induction of GATA DNA binding activity by pressure overload in ventricles. Furthermore, the actions of ET-1 and Ang II receptor antagonism on BNP GATA activity under basal conditions (without pressure overload) in conscious rats as well as ET-1 and bosentan effects in myocyte cultures were analyzed.", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Materials", "text": "Bosentan was from F. Hoffmann-La Roche Ltd, Basel, and Actelion Ltd, Allschwil, Switzerland (Dr Martine Clozel) and losartan from DuPont Merck Pharmaceutical Company, Wilmington, Del (Dr Ronald D. Smith).", "cite_spans": [], "ref_spans": []}, {"section": "Experimental Design in Conscious Rats", "text": "The 2-month-old Sprague-Dawley rats were instrumented as previously described. 9 The experiments were started by measurement of mean arterial pressure (MAP) and heart rate in the conscious rats for 30 minutes before baseline hemodynamic measurements were made. Then, AVP (Peninsula Laboratories Europe, 0.05 g \u2150 kg \u03ea1 \u2150 min \u03ea1 IV) or vehicle (0.9% NaCl IV) was infused at 37.5 L/min for 15 minutes, 30 minutes, 1 hour, 2 hours and 4 hours. In a separate series of experiments, bosentan (10 mg/kg), losartan (10 mg/kg), or vehicle (0.9% NaCl) was injected as an intravenous bolus (injection volume 0.1 mL/100 g body wt), followed by 30 minutes of vehicle or AVP infusion. Left ventricles and right atria were prepared for the mRNA determinations and gel mobility shift assays at the end of infusions as previously described. 9 The experimental design was approved by the Animal Use and Care Committee of the University of Oulu.", "cite_spans": [], "ref_spans": []}, {"section": "Cell Culture", "text": "Myocytes were prepared from 1-to 3-day-old neonatal rat hearts as described earlier. 17 After 48 hours of incubation in complete serumfree medium (CSFM), 17 the medium was replaced with CSFM or CSFM supplemented with ET-1 100 nmol/L 18 or bosentan 10 mol/L for 15 minutes, 30 minutes, 1 hour, and 4 hours.", "cite_spans": [], "ref_spans": []}, {"section": "Gel Mobility Shift Assays", "text": "Nuclear extracts were prepared from atrial and ventricular tissue of AVP-or vehicle-infused rats and from neonatal rat myocytes as described previously. 19, 20 Double-stranded synthetic oligonucleotides containing GATA (5\u0408-TGTGTCTGATAAATCAGAGATAAC-CCCACC-3\u0408) or AP-1 (5\u0408-GGAAGTGTTTTTGATGAGTCACC-CCA-3\u0408) motifs of the rat BNP promoter were labeled with [\u2423-32 P]dCTP. Binding reactions contained 30 g of crude nuclear extract or 6 g of nuclear extract from cardiac myocytes and 2 g of poly-(dI-dC) \u2150 (dI-dC) in a buffer containing (in mmol/L) HEPES 10 (pH 7.9), MgCl 2 1, KCl 50, DTT 1, EDTA 0.1, and PMSF 0.25; 10% glycerol; 0.025% NP-40; and 1 mol/L each of aprotinin, leupeptin, and pepstatin; and when appropriate, various molar excesses of unlabeled double-stranded oligonucleotides. Reactions were carried out at room temperature for 20 minutes, and protein-DNA complexes were separated by electrophoresis on 5% polyacrylamide gel in 0.5\u03eb TBE (Tris-borate-EDTA buffer) at 4\u00b0C. Nonlabeled double-stranded oligonucleotides corresponding to GATA or AP-1 binding sites of the BNP promoter and a GATA consensus sequence (Santa Cruz Biotechnology) were used as specific competitor DNAs. Nonspecific competitor DNAs included a double-stranded oligo carrying the mutated binding site for GATA4 (5\u0408-TGTGTCTGGTAAATCAGA GGTAACCCCACC-3\u0408) and Oct-1 as nonrelated DNA. For supershift experiments, 1 g of goat polyclonal GATA4, GATA5, GATA6, c-Fos (4) ", "cite_spans": [{"start": 153, "end": 156, "text": "19,", "ref_id": "BIBREF18"}], "ref_spans": []}, {"section": "Isolation and Analysis of RNA", "text": "RNA was isolated by the guanidine thiocyanate-CsCl method. 9 For the RNA Northern blot analysis, 20-g samples of RNA from the ventricles were separated by electrophoresis and transferred to nylon membranes. A 390-bp fragment of rat BNP cDNA, 21 cDNA probes for rat GATA4 (1417 bp), GATA6 (1175 bp), c-fos (1050 bp), and GAPDH and an oligonucleotide probe complementary to rat 18S ribosomal RNA were labeled, and the membranes were hybridized as described previously. 9", "cite_spans": [], "ref_spans": []}, {"section": "BNP Radioimmunoassay", "text": "The BNP radioimmunoassay was performed as previously described. 9 The sensitivity of the assay was 2 fmol/tube, and 50% displacements of the respective standard curve occurred at 25 fmol/tube. The intra-assay and interassay variations were \u03fd10% and \u03fd15%, respectively. Serial dilutions of the tissue extracts showed parallelism with the standards. Tissue BNP is expressed as a concentration per milligram wet weight.", "cite_spans": [], "ref_spans": []}, {"section": "Statistics", "text": "The results are expressed as mean\u03eeSEM. For the comparison of statistical significance between 2 groups, Student's t test was used. The hemodynamic variables were analyzed with 1-way ANOVA, followed by Student-Newman-Keuls post hoc test. A value of P\u03fd0.05 was considered statistically significant.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Characterization of Pressure-Overload Model", "text": "To study the signaling cascades responsible for the activation of transcription factors during pressure overload, an in vivo model of intravenous administration of AVP for up to 4 hours in conscious normotensive rats was used. 8, 9 MAP rose rapidly and reached maximum value within 15 minutes during AVP infusion, associated with a significant decrease in heart rate ( Figure 1 ). The AVP-induced increase in blood pressure was followed by an increase in the BNP mRNA levels in both the epicardial and endocardial layers of the left ventricle ( Figure  2A) . A 1.7-fold and 3.5-fold increase in left ventricular endocardial BNP mRNA levels was noted after 1 and 4 hours of AVP infusion, respectively ( Figure 2B ). The rapid activation of BNP mRNA gene expression resulted in a significant increase in left ventricular endocardial immunoreactive BNP peptide levels at 2 (from 167\u03ee14 to 260\u03ee12 pmol/g, P\u03fd0.001) and 4 (from 193\u03ee13 to 332\u03ee10 pmol/g, P\u03fd0.001) hours of AVP infusion. Under these experimental conditions, AVP infusion has no effect on right atrial BNP mRNA levels and right atrial pressure, 8 supporting the hypothesis that AVP has no direct effect on cardiac BNP gene expression.", "cite_spans": [{"start": 227, "end": 229, "text": "8,", "ref_id": "BIBREF7"}], "ref_spans": [{"start": 369, "end": 377, "text": "Figure 1", "ref_id": "FIGREF1"}, {"start": 545, "end": 556, "text": "Figure  2A)", "ref_id": "FIGREF2"}, {"start": 702, "end": 711, "text": "Figure 2B", "ref_id": "FIGREF2"}]}, {"section": "Pressure Overload Upregulates Left Ventricular GATA Binding Activity", "text": "Gel mobility shift assays were used to analyze the transacting factors that interact with the GATA or AP-1 motifs of the BNP promoter. AVP infusion for 15 minutes increased DNA binding activity in left ventricular extracts with a 30-bp double-stranded oligonucleotide probe containing the \u03ea90 BNP GATA sites (rBNP-90 GATA probe), and at 30 minutes, a 2.2-fold increase (from 1.96\u03ee0.27 to 4.33\u03ee0.75 arbitrary densitometric units, P\u03fd0.001) was noted ( Figure  3A) . The BNP GATA binding activity also increased in response to 1-hour AVP infusion, whereas at 2 or 4 hours, BNP GATA binding activity remained unchanged. Furthermore, AVP infusion for 15 minutes to 4 hours had no significant effect on DNA binding activity in right atrial nuclear extracts (at 30 minutes: 3.60\u03ee2.51 versus 4.55\u03ee3.03 arbitrary densitometric units, P\u03edNS, n\u03ed6), suggesting that the observed changes in BNP GATA binding activity are related to hemodynamic effects of AVP.", "cite_spans": [], "ref_spans": [{"start": 450, "end": 461, "text": "Figure  3A)", "ref_id": "FIGREF3"}]}, {"section": "Pressure Overload Upregulates Left Ventricular GATA Binding Activity", "text": "To determine the specificity of ventricular GATA binding activity, competition analyses were performed ( Figure 3B ). The formation of complexes with the rBNP-90 GATA probe was effectively inhibited by the unlabeled self ( Figure 3B , lanes 2 to 4) and GATA consensus DNA ( Figure 3B, lane7) , indicating that the DNA-protein complex was the result of a specific interaction. The binding was unaffected by an excess of oligonucleotides corresponding to the nonrelated competitor DNA Oct-1 ( Figure 3B , lane 5) or the mutated BNP GATA site ( Figure 3B, lane 6) . To further confirm that the complex bound to the BNP GATA site contains GATA proteins, supershift assays were carried out using GATA4 ( Figure 3C, lanes 3 and 4) , GATA5 ( Figure 3C , lanes 5 and 6), and GATA6 ( Figure 3C, lanes 7 and 8) antibodies. Experiments using rat ventricular extracts from vehicle-or AVP-infused rats clearly showed antibody-induced supershift of the GATA4 but not GATA5 or GATA6 complexes.", "cite_spans": [], "ref_spans": [{"start": 105, "end": 114, "text": "Figure 3B", "ref_id": "FIGREF3"}, {"start": 223, "end": 232, "text": "Figure 3B", "ref_id": "FIGREF3"}, {"start": 274, "end": 291, "text": "Figure 3B, lane7)", "ref_id": "FIGREF3"}, {"start": 491, "end": 500, "text": "Figure 3B", "ref_id": "FIGREF3"}, {"start": 542, "end": 560, "text": "Figure 3B, lane 6)", "ref_id": "FIGREF3"}, {"start": 699, "end": 724, "text": "Figure 3C, lanes 3 and 4)", "ref_id": "FIGREF3"}, {"start": 735, "end": 744, "text": "Figure 3C", "ref_id": "FIGREF3"}, {"start": 775, "end": 800, "text": "Figure 3C, lanes 7 and 8)", "ref_id": "FIGREF3"}]}, {"section": "Pressure Overload Upregulates Left Ventricular GATA Binding Activity", "text": "Unlike GATA4, the level of BNP AP-1 binding activity was not increased in nuclear extracts from the vehicle-and AVP-infused rat hearts within 15 minutes to 4 hours ( Figure  3A) . Weak supershifts were observed with JunB (N-17) and JunD (329) antibodies, which demonstrate the presence of JunB and JunD in the complex formed between the BNP AP-1 site and proteins in AVP-infused rat heart nuclear extracts (data not shown), as reported previously in extracts from rat hearts 2 days after coarctation. 16", "cite_spans": [], "ref_spans": [{"start": 166, "end": 177, "text": "Figure  3A)", "ref_id": "FIGREF3"}]}, {"section": "GATA4, GATA6, and c-fos mRNA Levels", "text": "We next examined the possibility that the increase in GATA activity could result from an increase in the expression of the GATA4 gene itself or an increase in the stability of the message. Northern blot analysis with both rat GATA4 and GATA6 probes identified a single 3.3-kb and 1.8-kb mRNA species, respectively, in the ventricles of adult rats. Pressure overload had no effect on left ventricular GATA4 or GATA6 mRNA levels during 15-minute to 4-hour AVP infusions (Figure 2A and 2B) . In contrast, expression of c-fos mRNA, which is another early hallmark of the hypertrophic re-sponse, 22 increased markedly in response to pressure overload (Figure 2A ).", "cite_spans": [], "ref_spans": [{"start": 468, "end": 486, "text": "(Figure 2A and 2B)", "ref_id": "FIGREF2"}, {"start": 646, "end": 656, "text": "(Figure 2A", "ref_id": "FIGREF2"}]}, {"section": "Pressure Overload-Induced Upregulation of GATA4 Binding Activity is Inhibited by the ET-1 Receptor Antagonist", "text": "To identify the mechanism by which pressure overload increases GATA4 binding activity, the roles of ET-1 and Ang II were evaluated in a series of experiments in which bosentan and losartan injections were used. When nuclear extracts from bosentan-and bosentan plus AVP-infused rat ventricles were used in gel mobility shift reactions containing the labeled rBNP-90 GATA probe, specific complexes were obtained ( Figure 4A ). The pressure overload-induced increase in GATA binding activity was completely inhibited by the mixed ET A /ET B receptor antagonist bosentan ( Figure 4A and 4B), whereas the AT 1 receptor antagonist losartan had no inhibitory effect on BNP GATA binding activity (data not shown). Bosentan alone had no statistically significant effect on BNP GATA binding activity ( Figure 4A and 4B) . Previously, we showed that in conscious rats, bosentan at a dose of 10 mg/kg IV completely blocked any increase in MAP produced by big ET-1 infusion and losartan at a concentration of 10 mg/kg completely blocked any increase in MAP produced by Ang II infusion. 9 Furthermore, injections of bosentan and losartan did not significantly alter the hemody- namic responses evoked by AVP infusion (data not shown 9 ), thus allowing us to examine the direct action of load versus a requirement for ET-1 and Ang II to mediate pressure overload-induced increase in GATA binding activity.", "cite_spans": [], "ref_spans": [{"start": 412, "end": 421, "text": "Figure 4A", "ref_id": "FIGREF4"}, {"start": 569, "end": 578, "text": "Figure 4A", "ref_id": "FIGREF4"}, {"start": 792, "end": 809, "text": "Figure 4A and 4B)", "ref_id": "FIGREF4"}]}, {"section": "ET-1 Increases GATA Binding Activity in Neonatal Cardiac Myocytes", "text": "The specific complexes were observed in gel mobility shift assays of nuclear extracts prepared from cultured rat neonatal cardiomyocytes. As shown in Figure 4C , ET-1 treatment for 15 to 60 minutes produced an increase in DNA binding activity using rBNP-90 GATA probe. This rapid increase in BNP GATA binding activity in cultured cardiomyocytes was inhibited by the mixed ET A /ET B antagonist bosentan ( Figure  4C, lane 6) . GATA4 mRNA levels remained unchanged in ET-1-treated cultured cardiac myocytes ( Figure 4D ).", "cite_spans": [], "ref_spans": [{"start": 150, "end": 159, "text": "Figure 4C", "ref_id": "FIGREF4"}, {"start": 405, "end": 424, "text": "Figure  4C, lane 6)", "ref_id": "FIGREF4"}, {"start": 508, "end": 517, "text": "Figure 4D", "ref_id": "FIGREF4"}]}, {"section": "Discussion", "text": "Although numerous transcription factors have been implicated in the activation of cardiac genes in response to hypertrophy, 1, 3, 13, 14 how hypertrophic signal transduction pathways are linked to changes in cardiac gene expression is not known. The transcription factors GATA4, -5, and -6 have been shown to activate numerous hypertrophic marker genes 13, 15 containing GATA binding sites required for cardiac-specific expression. It has also been shown that GATA4 DNA binding activity is upregulated in hypertrophied rat hearts 7 days after aortic coarctation. 16 We have previously documented that acute pressure overload produced by AVP infusion is a potent activator of BNP gene expression in the adult rat heart. 9 The present study extends those findings by demonstrating that (1) ventricular BNP GATA4 but not GATA5 and GATA6 binding is activated at a very early stage of pressure overload, well before the development of left ventricular hypertrophy; and (2) the activation of the endothelin signaling pathway plays an important role in mediating pressure overload-dependent GATA4 binding activation.", "cite_spans": [{"start": 124, "end": 126, "text": "1,", "ref_id": "BIBREF0"}, {"start": 127, "end": 129, "text": "3,", "ref_id": "BIBREF2"}, {"start": 130, "end": 133, "text": "13,", "ref_id": "BIBREF12"}, {"start": 353, "end": 356, "text": "13,", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "Discussion", "text": "The mechanisms by which pressure overload is transduced by the cardiac muscle cell and translated into myocyte hypertrophic response remain only partially understood. At the cellular level, hypertrophy is thought to develop in response to a combination of mechanical (hemodynamic load) and neurohumoral stimuli, such as Ang II, ET-1, and adrenergic agents. 4, 5 It has been reported that mechanical stretch is coupled with cellular release of Ang II and ET-1 and that they act as chemical mediators of stretch-induced myocyte hypertrophy in cultured rat cardiomyocytes. 23, 24 The production of ET-1 has also been shown to increase in the hypertrophied rat heart in various models of pressure overload. [25] [26] [27] Thus, endogenous cardiac production of ET-1 may play a functional role in mechanical load-induced cardiac gene expression.", "cite_spans": [{"start": 357, "end": 359, "text": "4,", "ref_id": "BIBREF3"}, {"start": 570, "end": 573, "text": "23,", "ref_id": "BIBREF22"}, {"start": 703, "end": 707, "text": "[25]", "ref_id": "BIBREF24"}, {"start": 708, "end": 712, "text": "[26]", "ref_id": "BIBREF25"}, {"start": 713, "end": 717, "text": "[27]", "ref_id": "BIBREF26"}], "ref_spans": []}, {"section": "Discussion", "text": "A key finding of the present study was that the rapid increase in GATA4 binding activity in cardiac nuclear extracts in response to pressure overload is mediated by ET-1 but not Ang II. The source of ET-1 in the heart may be myocytes or nonmyocytes. It has been shown that endothelial cells to some extent contain stores of ET-1, 28, 29 and when endothelial cells in culture are stretched, ET-1 can be released rapidly. 28 In addition, mRNA levels of ET-1 increase by stretching of cardiac myocytes, 24 ET-1 receptor antagonists decrease hemodynamic load-induced ANP release in vivo, 30 and mechanical strain induces human BNP promoter activity in vitro. 31 Thus, pressure-overload stimulus, by increasing wall stress, appears to release ET-1 from preformed stores, which then participates in the regulation of GATA4 binding activity. In the present study, the increase in GATA4 binding activity was transient, suggesting that cardiac ET-1 stores may be limited. Whether ET-1 is also involved in controlling GATA4 binding activity in chronic pressure overload in vivo remains to be determined.", "cite_spans": [{"start": 330, "end": 333, "text": "28,", "ref_id": "BIBREF27"}], "ref_spans": []}, {"section": "Discussion", "text": "Several signaling pathways, including intracellular calcium, protein kinase C, nonreceptor protein tyrosine kinases, and calcineurin, may be involved in the initiation and maintenance of myocyte hypertrophy. 3, 6, 32 There is also considerable evidence that activation of any of the 3 MAPK cascades can lead to a hypertrophic response in myocytes and that these MAPK subfamilies are activated by ET-1. 18, 33 The activation of ERK, JNK, and p38 MAPK has been demonstrated after the application of mechanical strain in cultured myocytes. 32, 34 -36 Using neonatal rat ventricular myocytes, we found that SB-203580, a potent p38 MAPK inhibitor, inhibited the ET-1-induced increase in BNP GATA4 binding activity (R. Kerkel\u00e4, S. Pikkarainen, N. Hautala, H. Ruskoaho, unpublished observation). This result, together with the observation that the p38 MAPK accounted for 50% of the human BNP promoter strain response in neonatal rat ventricular myocyte cultures, 36 suggests that the p38 MAPK pathway might also mediate the early increase of GATA4 activity in pressure overload in vivo.", "cite_spans": [{"start": 208, "end": 210, "text": "3,", "ref_id": "BIBREF2"}, {"start": 211, "end": 213, "text": "6,", "ref_id": "BIBREF5"}, {"start": 402, "end": 405, "text": "18,", "ref_id": "BIBREF17"}], "ref_spans": []}, {"section": "Discussion", "text": "Previous studies have shown that the activation of rat BNP promoter in cardiac myocytes required GATA binding sites in the promoter. 37 Furthermore, mechanical strain stimulates the activity of a transfected human BNP gene promoter in neonatal rat ventricular myocytes, 38 and this stimulation appears to be derived in part from a direct effect on the cardiac myocyte and in part from an autocrine/paracrine pathway that involves the sequential generation of Ang II and ET-1. 31 However, the inability of the ET-receptor antagonist bosentan to inhibit the early activation of ventricular BNP gene expression in response to pressure overload in vivo 9 suggests that there is a requirement for additional transcription factors that probably act in concert with GATA4 to activate BNP gene expression. In vitro, other transcription factors, such as NF-B 36 and NF-AT, 39 are also important for BNP gene expression, and recent work has suggested that ANP expression may be regulated by cooperative interaction of cis-acting elements with GATA4 and Csx/Nkx2.5. 40 The potential interaction of these transcription factors with GATA4 in promoting the changes in cardiac gene expression during pressure overload represents a logical target for future study.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "In conclusion, this study shows for the first time that ET-1 acts as a mediator of GATA4 binding activity in pressure overload. This may represent a new mechanism for transduction of extrinsic hypertrophic signals to the nucleus in pressure-overload hypertrophy as well as in other pathophys-iological conditions associated with high ET-1 activity, such as heart failure and myocardial ischemia.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Prevention of cardiac hypertrophy by calcineurin inhibition: hope or hype?", "authors": [{"first": "E", "middle": ["N"], "last": "Olson", "suffix": ""}, {"first": "J", "middle": ["D"], "last": "Molkentin", "suffix": ""}], "year": 1999, "venue": "Circ Res", "link": "1231270"}, "BIBREF1": {"title": "Signaling in myocardial hypertrophy: life after calcineurin?", "authors": [{"first": "P", "middle": ["H"], "last": "Sugden", "suffix": ""}], "year": 1999, "venue": "Circ Res", "link": null}, "BIBREF2": {"title": "Signaling pathways for cardiac hypertrophy and failure", "authors": [{"first": "J", "middle": ["J"], "last": "Hunter", "suffix": ""}, {"first": "K", "middle": ["R"], "last": "Chien", "suffix": ""}], "year": 1999, "venue": "N Engl J Med", "link": "43307611"}, "BIBREF3": {"title": "Cardiac hypertrophy: mechanical, neural, and endocrine dependence", "authors": [{"first": "H", "middle": ["E"], "last": "Morgan", "suffix": ""}, {"first": "K", "middle": ["M"], "last": "Baker", "suffix": ""}], "year": 1991, "venue": "Circulation", "link": "45376914"}, "BIBREF4": {"title": "The cellular and molecular response of cardiac myocytes to mechanical stress", "authors": [{"first": "J", "middle": [], "last": "Sadoshima", "suffix": ""}, {"first": "S", "middle": [], "last": "Izumo", "suffix": ""}], "year": 1997, "venue": "Annu Rev Physiol", "link": "1502053"}, "BIBREF5": {"title": "Cellular mechanisms of cardiac hypertrophy", "authors": [{"first": "P", "middle": ["H"], "last": "Sugden", "suffix": ""}, {"first": "A", "middle": [], "last": "Clerk", "suffix": ""}], "year": 1998, "venue": "J Mol Med", "link": "9268035"}, "BIBREF6": {"title": "Transcriptional regulation during cardiac growth and development", "authors": [{"first": "K", "middle": ["R"], "last": "Chien", "suffix": ""}, {"first": "H", "middle": [], "last": "Zhu", "suffix": ""}, {"first": "K", "middle": ["U"], "last": "Knowlton", "suffix": ""}], "year": 1993, "venue": "Annu Rev Physiol", "link": "11673857"}, "BIBREF7": {"title": "Brain natriuretic peptide in plasma, atria, and ventricles of vasopressin-and phenylephrine-infused conscious rats", "authors": [{"first": "J", "middle": [], "last": "Magga", "suffix": ""}, {"first": "M", "middle": [], "last": "Marttila", "suffix": ""}, {"first": "P", "middle": [], "last": "M\u00e4ntymaa", "suffix": ""}], "year": 1994, "venue": "Endocrinology", "link": "24494689"}, "BIBREF8": {"title": "Endothelin-1 is involved in stretch-induced early activation of B-type natriuretic peptide gene expression in atrial but not in ventricular myocytes: acute effects of mixed ET A /ET B and AT 1 receptor antagonists in vivo and in vitro", "authors": [{"first": "J", "middle": [], "last": "Magga", "suffix": ""}, {"first": "O", "middle": [], "last": "Vuolteenaho", "suffix": ""}, {"first": "M", "middle": [], "last": "Marttila", "suffix": ""}], "year": 1997, "venue": "Circulation", "link": "30024147"}, "BIBREF9": {"title": "Atrial natriuretic peptide: synthesis, release, and metabolism", "authors": [{"first": "H", "middle": [], "last": "Ruskoaho", "suffix": ""}], "year": 1992, "venue": "Pharmacol Rev", "link": "9988271"}, "BIBREF10": {"title": "Mechanical and neuroendocrine regulation of the endocrine heart", "authors": [{"first": "A", "middle": ["J"], "last": "De Bold", "suffix": ""}, {"first": "B", "middle": ["G"], "last": "Bruneau", "suffix": ""}, {"first": "Kuroski", "middle": [], "last": "De Bold", "suffix": ""}, {"first": "M", "middle": ["L"], "last": "", "suffix": ""}], "year": 1996, "venue": "Cardiovasc Res", "link": "12541100"}, "BIBREF11": {"title": "Factors involved in cardiogenesis and the regulation of cardiac-specific gene expression", "authors": [{"first": "J", "middle": ["D"], "last": "Mably", "suffix": ""}, {"first": "C", "middle": ["C"], "last": "Liew", "suffix": ""}], "year": 1996, "venue": "Circ Res", "link": "25799754"}, "BIBREF12": {"title": "GATA4: a novel transcriptional regulator of cardiac hypertrophy?", "authors": [{"first": "J", "middle": ["D"], "last": "Molkentin", "suffix": ""}, {"first": "E", "middle": ["N"], "last": "Olson", "suffix": ""}], "year": 1997, "venue": "Circulation", "link": "45258508"}, "BIBREF13": {"title": "Combinatorial interactions regulating cardiac transcription", "authors": [{"first": "D", "middle": [], "last": "Durocher", "suffix": ""}, {"first": "M", "middle": [], "last": "Nemer", "suffix": ""}], "year": 1998, "venue": "Dev Genet", "link": "3177454"}, "BIBREF14": {"title": "cis-Acting sequences that mediate induction of \u2424-myosin heavy chain gene expression during left ventricular hypertrophy due to aortic constriction", "authors": [{"first": "K", "middle": [], "last": "Hasegawa", "suffix": ""}, {"first": "S", "middle": ["J"], "last": "Lee", "suffix": ""}, {"first": "S", "middle": ["M"], "last": "Jobe", "suffix": ""}], "year": 1997, "venue": "Circulation", "link": "31623671"}, "BIBREF15": {"title": "Angiotensin II type 1a receptor gene expression in the heart: AP-1 and GATA-4 participate in the response to pressure overload", "authors": [{"first": "T", "middle": ["C"], "last": "Herzig", "suffix": ""}, {"first": "S", "middle": ["M"], "last": "Jobe", "suffix": ""}, {"first": "H", "middle": [], "last": "Aoki", "suffix": ""}], "year": 1997, "venue": "Proc Natl Acad Sci U S A", "link": "35427122"}, "BIBREF16": {"title": "Basal and acidic fibroblast growth factor-induced atrial natriuretic peptide gene expression and secretion is inhibited by staurosporine", "authors": [{"first": "H", "middle": [], "last": "Tokola", "suffix": ""}, {"first": "K", "middle": [], "last": "Salo", "suffix": ""}, {"first": "O", "middle": [], "last": "Vuolteenaho", "suffix": ""}], "year": 1994, "venue": "Eur J Pharmacol", "link": "6572703"}, "BIBREF17": {"title": "Role of the stress-activated protein kinases in endothelin-induced cardiomyocyte hypertrophy", "authors": [{"first": "G", "middle": [], "last": "Choukroun", "suffix": ""}, {"first": "R", "middle": [], "last": "Hajjar", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Kyriakis", "suffix": ""}], "year": 1998, "venue": "J Clin Invest", "link": "9466489"}, "BIBREF18": {"title": "A one-hour minipreparation technique for extraction of DNA-binding proteins from animal tissues", "authors": [{"first": "F", "middle": [], "last": "Deryckere", "suffix": ""}, {"first": "F", "middle": [], "last": "Gannon", "suffix": ""}], "year": 1994, "venue": "Biotechniques", "link": "34600856"}, "BIBREF19": {"title": "Rapid detection of octamer binding proteins with mini-extracts, prepared from a small number of cells", "authors": [{"first": "E", "middle": [], "last": "Schreiber", "suffix": ""}, {"first": "P", "middle": [], "last": "Matthias", "suffix": ""}, {"first": "M", "middle": [], "last": "Muller", "suffix": ""}], "year": 1989, "venue": "Nucleic Acids Res", "link": "29131482"}, "BIBREF20": {"title": "Natriuretic peptides as cardiac hormones in normotensive and spontaneously hypertensive rats: the ventricle is a major site of synthesis and secretion of brain natriuretic peptide", "authors": [{"first": "Y", "middle": [], "last": "Ogawa", "suffix": ""}, {"first": "K", "middle": [], "last": "Nakao", "suffix": ""}, {"first": "M", "middle": [], "last": "Mukoyama", "suffix": ""}], "year": 1991, "venue": "Circ Res", "link": "6293384"}, "BIBREF21": {"title": "Proto-oncogenes induction and reprogramming of cardiac gene expression produced by pressure overload", "authors": [{"first": "S", "middle": [], "last": "Izumo", "suffix": ""}, {"first": "B", "middle": [], "last": "Nadal-Ginard", "suffix": ""}, {"first": "V", "middle": [], "last": "Mahdavi", "suffix": ""}], "year": 1988, "venue": "Proc Natl Acad Sci U S A", "link": null}, "BIBREF22": {"title": "Autocrine release of angiotensin II mediates stretch-induced hypertrophy of cardiac myocytes in vitro", "authors": [{"first": "J", "middle": [], "last": "Sadoshima", "suffix": ""}, {"first": "Y", "middle": [], "last": "Xu", "suffix": ""}, {"first": "H", "middle": ["S"], "last": "Slayter", "suffix": ""}], "year": 1993, "venue": "Cell", "link": "33375367"}, "BIBREF23": {"title": "Endothelin-1 is involved in mechanical stress-induced cardiomyocyte hypertrophy", "authors": [{"first": "T", "middle": [], "last": "Yamazaki", "suffix": ""}, {"first": "I", "middle": [], "last": "Komuro", "suffix": ""}, {"first": "S", "middle": [], "last": "Kudoh", "suffix": ""}], "year": 1996, "venue": "J Biol Chem", "link": "42123190"}, "BIBREF24": {"title": "Increased production of endothelin-1 in the hypertrophied rat heart due to pressure overload", "authors": [{"first": "R", "middle": [], "last": "Yorikane", "suffix": ""}, {"first": "S", "middle": [], "last": "Sakai", "suffix": ""}, {"first": "T", "middle": [], "last": "Miyauchi", "suffix": ""}], "year": 1993, "venue": "FEBS Lett", "link": "33493373"}, "BIBREF25": {"title": "Contribution of endogenous endothelin-1 to the progression of cardiopulmonary alterations in rats with monocrotaline-induced pulmonary hypertension", "authors": [{"first": "T", "middle": [], "last": "Miyauchi", "suffix": ""}, {"first": "R", "middle": [], "last": "Yorikane", "suffix": ""}, {"first": "S", "middle": [], "last": "Sakai", "suffix": ""}], "year": 1993, "venue": "Circ Res", "link": "16873921"}, "BIBREF26": {"title": "Endothelin-1 is involved in norepinephrine-induced ventricular hypertrophy in vivo: acute effects of bosentan, an orally active, mixed endothelin ET A and ET B receptor antagonist", "authors": [{"first": "S", "middle": [], "last": "Kaddoura", "suffix": ""}, {"first": "J", "middle": ["D"], "last": "Firth", "suffix": ""}, {"first": "K", "middle": ["R"], "last": "Boheler", "suffix": ""}], "year": 1996, "venue": "Circulation", "link": "33922027"}, "BIBREF27": {"title": "Endothelin-1 release from endothelial cells in culture is elevated both acutely and chronically by short periods of mechanical stretch", "authors": [{"first": "H", "middle": [], "last": "Macarthur", "suffix": ""}, {"first": "T", "middle": ["D"], "last": "Warner", "suffix": ""}, {"first": "E", "middle": ["G"], "last": "Wood", "suffix": ""}], "year": 1994, "venue": "Biochem Biophys Res Commun", "link": "29695056"}, "BIBREF28": {"title": "Endothelial cell storage and release of endothelin as a cardioregulatory mechanism", "authors": [{"first": "G", "middle": [], "last": "Mcclellan", "suffix": ""}, {"first": "A", "middle": [], "last": "Weisberg", "suffix": ""}, {"first": "D", "middle": [], "last": "Rose", "suffix": ""}], "year": 1994, "venue": "Circ Res", "link": "38133288"}, "BIBREF29": {"title": "Combined inhibition of endothelin and angiotensin II receptors blocks volume load-induced cardiac hormone release", "authors": [{"first": "H", "middle": [], "last": "Leskinen", "suffix": ""}, {"first": "O", "middle": [], "last": "Vuolteenaho", "suffix": ""}, {"first": "H", "middle": [], "last": "Ruskoaho", "suffix": ""}], "year": 1997, "venue": "Circ Res", "link": "25030956"}, "BIBREF30": {"title": "Autocrine/paracrine determinants of strainactivated brain natriuretic peptide gene expression in cultured cardiac myocytes", "authors": [{"first": "F", "middle": [], "last": "Liang", "suffix": ""}, {"first": "D", "middle": ["G"], "last": "Gardner", "suffix": ""}], "year": 1998, "venue": "J Biol Chem", "link": "20470695"}, "BIBREF31": {"title": "Mechanical stretch rapidly activates multiple signal transduction pathways in cardiac myocytes: potential involvement of an autocrine/paracrine mechanism", "authors": [{"first": "J", "middle": [], "last": "Sadoshima", "suffix": ""}, {"first": "S", "middle": [], "last": "Izumo", "suffix": ""}], "year": 1993, "venue": "EMBO J", "link": "42785117"}, "BIBREF32": {"title": "A role for the p38 mitogenactivated protein kinase pathway in myocardial cell growth, sarcomeric organization, and cardiac-specific gene expression", "authors": [{"first": "D", "middle": [], "last": "Zechner", "suffix": ""}, {"first": "D", "middle": ["J"], "last": "Thuerauf", "suffix": ""}, {"first": "D", "middle": ["S"], "last": "Hanford", "suffix": ""}], "year": 1997, "venue": "J Cell Biol", "link": "15673542"}, "BIBREF33": {"title": "Mechanical stress activates protein kinase cascade of phosphorylation in neonatal rat cardiac myocytes", "authors": [{"first": "T", "middle": [], "last": "Yamazaki", "suffix": ""}, {"first": "I", "middle": [], "last": "Komuro", "suffix": ""}, {"first": "S", "middle": [], "last": "Kudoh", "suffix": ""}], "year": 1995, "venue": "J Clin Invest", "link": "24165889"}, "BIBREF34": {"title": "Mechanical stretch activates the stress-activated protein kinases in cardiac myocytes", "authors": [{"first": "I", "middle": [], "last": "Komuro", "suffix": ""}, {"first": "S", "middle": [], "last": "Kudo", "suffix": ""}, {"first": "T", "middle": [], "last": "Yamazaki", "suffix": ""}], "year": 1996, "venue": "FASEB J", "link": null}, "BIBREF35": {"title": "Mechanical strain activates BNP gene transcription through a p38/NF-kB-dependent mechanism", "authors": [{"first": "F", "middle": [], "last": "Liang", "suffix": ""}, {"first": "D", "middle": ["G"], "last": "Gardner", "suffix": ""}], "year": 1999, "venue": "J Clin Invest", "link": "24104892"}, "BIBREF36": {"title": "A hormone-encoding gene identifies a pathway for cardiac but not skeletal muscle gene transcription", "authors": [{"first": "C", "middle": [], "last": "Grepin", "suffix": ""}, {"first": "L", "middle": ["L"], "last": "Dagnino", "suffix": ""}, {"first": "L", "middle": [], "last": "Robitaille", "suffix": ""}], "year": 1994, "venue": "Mol Cell Biol", "link": "34501229"}, "BIBREF37": {"title": "Mechanical strain increases expression of the brain natriuretic peptide gene in rat cardiac myocytes", "authors": [{"first": "F", "middle": [], "last": "Liang", "suffix": ""}, {"first": "J", "middle": [], "last": "Wu", "suffix": ""}, {"first": "M", "middle": [], "last": "Garami", "suffix": ""}], "year": 1997, "venue": "J Biol Chem", "link": "24241140"}, "BIBREF38": {"title": "A calcineurin-dependent transcriptional pathway for cardiac hypertrophy", "authors": [{"first": "J", "middle": ["D"], "last": "Molkentin", "suffix": ""}, {"first": "J-R", "middle": [], "last": "Lu", "suffix": ""}, {"first": "C", "middle": ["L"], "last": "Antos", "suffix": ""}], "year": 1998, "venue": "Cell", "link": "16574424"}, "BIBREF39": {"title": "The cardiac transcription factors Nkx2-5 and GATA-4 are mutual cofactors", "authors": [{"first": "D", "middle": [], "last": "Durocher", "suffix": ""}, {"first": "F", "middle": [], "last": "Charron", "suffix": ""}, {"first": "R", "middle": [], "last": "Warren", "suffix": ""}], "year": 1997, "venue": "EMBO J", "link": "35165095"}}, "ref_entries": {"FIGREF0": {"text": "-G, c-Fos(K-25)-G, c-Jun/AP-1(N)-G, Jun B(N-17)-G, or Jun D(329)-G affinity-purified IgG (Santa Cruz Biotechnology) were used.", "type": "figure"}, "FIGREF1": {"text": "MAP and heart rate in AVP-infused conscious rats. Vehicle or AVP 0.05 g \u2150 kg \u03ea1 \u2150 min \u03ea1 IV (arrow) was infused for 15 minutes, 30 minutes, 1 hour, 2 hours, and 4 hours. Open square indicates vehicle (n\u03ed9); solid square, AVP (n\u03ed9). Results are expressed as mean\u03eeSEM. *P\u03fd0.001 vs vehicle (1-way ANOVA followed by Student-Newman-Keuls post hoc test).", "type": "figure"}, "FIGREF2": {"text": "A, Northern blot analysis showing effect of AVP on left ventricular BNP mRNA, GATA4 mRNA, GATA6 mRNA, and c-fos mRNA levels in conscious rats. Single 0.9-, 3.3-, 1.8-, and 2.2-kb mRNA species were identified with rat BNP, GATA4, GATA6, and c-fos probes, respectively. Hybridization signal for GAPDH is also shown. Epi indicates epicardium; endo, endocardium. B, Effect of AVP infusion on left ventricular endocardial BNP mRNA, GATA4 mRNA, and GATA6 mRNA levels. mRNA results are expressed as ratio of specific mRNA to GAPDH mRNA as determined by Northern blot analysis. Open bars indicate vehicle; solid bars, AVP. Results are mean\u03eeSEM (n\u03ed6 to 9). *P\u03fd0.05, ***P\u03fd0.001 vs vehicle (Student's t test).", "type": "figure"}, "FIGREF3": {"text": "A, Gel mobility shift assays of nuclear extracts from left ventricles subjected to pressure overload. AVP infusion for 15 minutes (lane 2), 30 minutes (lane 4), and 60 minutes (lane 6) upregulated GATA binding activity but had no effect on AP-1 DNA binding activities. Nuclear extracts were incubated with radiolabeled rBNP-90 GATA or BNP AP-1 oligonucleotide probes. B, Competition gel mobility shift analysis of rat left ventricular nuclear extracts. Binding reaction was incubated with 10-(lane 2), 25-(lane 3), or 50-fold (lane 4) molar excess of unlabeled rBNP-90 GATA DNA, 50-fold molar excess of each nonrelated DNA Oct-1 (lane 5), BNP/mutGATA double-stranded DNA (lane 6), and GATA consensus DNA (lane 7). C, Supershift reactions were performed by incubating binding reactions with 1 g of goat polyclonal GATA4 (lanes 3 and 4), GATA5 (lanes 5 and 6), or GATA6 IgG (lanes 7 and 8).", "type": "figure"}, "FIGREF4": {"text": "A, Effect of bosentan on pressure overload-induced increase in BNP GATA binding activity in conscious rats. Binding reactions were probed with radiolabeled rBNP-90 GATA. Gel mobility shift analysis using nuclear extracts from vehicle-infused hearts is shown in lanes 1 and 3 and from AVP-infused hearts in lanes 2 and 4. B, Effect of bosentan on 30-minute AVP infusion-induced increase in left ventricular BNP GATA binding activity. C indicates vehicle; B, bosentan. Results are mean\u03eeSEM (n\u03ed5). *P\u03fd0.05 vs vehicle (Student's t test). C, Effect of ET-1 on BNP GATA binding activity in cultured neonatal cardiomyocytes. Binding reactions contained nuclear extracts from rat cardiac myocytes stimulated by ET-1 (lanes 2 to 4, 6) or bosentan (lanes 5 and 6). D, Northern blot analysis showing effect of ET-1 on GATA4 mRNA levels in cultured cardiomyocytes. Hybridization signal for 18S is also shown.", "type": "figure"}}}
{"paper_id": "2870542", "_pdf_hash": "e6460eb3cbaa743d130c6c53448dc1fb4126e69a", "abstract": [{"section": "Abstract", "text": ". (2016) Understanding patient safety performance and educational needs using the 'Safety-II' approach for complex systems. Education for Primary Care, 27(6), pp. 443-450. (doi:10.1080Care, 27(6), pp. 443-450. (doi:10. /14739879.2016 This is the author's final accepted version.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "There may be differences between this version and the published version. You are advised to consult the publisher's version if you wish to cite from it.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "http://eprints.gla.ac.uk/131620/ ", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Patient safety education and participation are key components of general practice (GP) specialty training, appraisal and revalidation. Priorities for GP education at all career stages are described in the Royal College of General Practitioners curriculum. Current methods that are taught and employed to improve safety often use a 'find-and-fix' approach to identify 'malfunctioning' components of a system (including humans) and introduce change to improve performance -often by attempting to increase conformity with protocols and guidelines. The complex interactions and inter-dependence between components found in healthcare systems mean that 'cause and effect' are not always linked in a predictable manner, meaning this approach does not always improve performance.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "The Safety-II approach is considered a new way to understand how safety is achieved in complex systems. Understanding and applying this approach may improve quality and safety initiatives and enhance GP and trainee curriculum coverage. Safety-II aims to maximise the number of events with a successful outcome by exploring everyday work.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "ways to achieve success, dependent on work conditions, may be possible. Understanding and managing variability, rather than constraining it, may be a more beneficial approach.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "The application of a Safety-II approach to incident investigation, quality improvement projects, prospective analysis of risk in systems and performance indicators may offer improved insight into system performance leading to more effective change. The way forward may be to combine the Safety-II approach with 'traditional' methods to enhance patient safety training, outcomes and curriculum coverage.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "3", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "As the patient safety agenda has evolved in primary care over the past decade, completion and application of learning on safety and quality methods has become an important component of the general practice (GP) specialty training curriculum and of appraisal and revalidation. [1, 2] The RCGP patient safety curriculum describes the expertise required to practice as a GP in the United Kingdom (UK) and can act as a guide to learning at any career Practice, is now embedded within most GP practices in the UK. [3] [4] [5] Despite this focus on reflecting on care and improving patient safety, firm evidence that patients are now safer is lacking. [6, 7] Berwick's influential report \"A promise to learn -a commitment to act\" stated that, in the vast majority of cases, NHS staff were not to blame for patient safety problems. [8] He emphasised the effect of systems and work conditions on staff performance and that, in certain high profile cases, indicators of impending problems had been ignored. Further, it is argued that a new way of thinking about safety is needed which moves beyond viewing safety through the lens of problems, error and failure. [9] This suggests we should be attempting to understand and teach how safety is achieved in the complex conditions and systems found in healthcare.", "cite_spans": [{"start": 276, "end": 279, "text": "[1,", "ref_id": "BIBREF0"}, {"start": 280, "end": 282, "text": "2]", "ref_id": "BIBREF1"}, {"start": 509, "end": 512, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 513, "end": 516, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 517, "end": 520, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 646, "end": 649, "text": "[6,", "ref_id": "BIBREF5"}, {"start": 650, "end": 652, "text": "7]", "ref_id": "BIBREF6"}, {"start": 825, "end": 828, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 1153, "end": 1156, "text": "[9]", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "Introduction", "text": "In our previous article we described key concepts for those involved in teaching or performing safety and improvement work. [10] In this article we explore some of these concepts in more depth to aid their application and teaching. The field of Resilience Engineering has given rise to a new way of thinking about patient safety now commonly referred to as 'Safety-II'. [11, 12] This approach attempts to explain and potentially resolve some of the intractable problems associated with complex systems such as those found in primary care, which traditional safety management thinking and responses (termed Safety-I) have struggled to adequately understand and improve upon. If successfully conceptualised, taught and implemented, this approach may lead to better reflection by trainees and qualified GPs (and wider primary care teams) on how everyday success is achieved in the challenging working conditions found in general practice thus allowing more effective change to increase the safety of healthcare systems.", "cite_spans": [{"start": 124, "end": 128, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 370, "end": 374, "text": "[11,", "ref_id": "BIBREF10"}, {"start": 375, "end": 378, "text": "12]", "ref_id": "BIBREF11"}], "ref_spans": []}, {"section": "Operational examples of Safety-I", "text": "In primary care, safety and improvement techniques such as Significant Event Analysis (SEA), criterion audit and Plan Do Study Act (PDSA) cycles are employed by practitioners to provide evidence of Quality Improvement (QI) activity for medical appraisal and to satisfy the requirement of workplace based assessment for specialty trainees. [13] All approaches are based on orthodox Safety-I principles, which typically involve an attempt to quantify and analyse incidences of patient harm (or incidents or hazards that have the potential to lead to harm). Incident investigation techniques such as SEA and Root Cause Analysis (RCA) attempt to understand why adverse events occurred by detecting deviations from 'ideal' practice and to design change to prevent recurrence. [14] This is essentially a 'find and fix' mentality where we attempt to isolate specific causal events and rectify such malfunctions so that the accident or incident trajectory that we have identified cannot occur in the future. The logic in this approach allows for unreliable technology and fallible clinical staff to be treated much the same, namely as potentially problematic components that can either function as intended (behave as designed, follow protocols etc.) or not (breakdown, deviate, violate). Errors are thus seen as variability in human performance that should be constrained or eliminated, much like oiling a valve that will not shut and retesting it to check its reliability. The 'fix' for events involving healthcare staff is predominantly a recommended change to protocol or procedure, or the imposition of warnings/reminders or physical barriers aimed at reducing the likelihood of the incident recurring. [15] .", "cite_spans": [{"start": 339, "end": 343, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 1700, "end": 1704, "text": "[15]", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "Operational examples of Safety-I", "text": "This approach is manifest directly in criterion based audit and PDSA cycles, which become synonymous with increasing conformity with evidence-based protocols, often focussing on the behaviour of individuals, in an attempt to reduce the number of unwanted outcomes. It is presumed that if all components of a system, including the humans, function as specified, then nothing will go wrong.", "cite_spans": [], "ref_spans": []}, {"section": "The complexity of healthcare systems", "text": "The RCGP curriculum includes reflecting on the complex interactions found in healthcare systems and how these can affect patient safety. Current QI and incident investigation methods were often developed in industries that are arguably less complex than healthcare.", "cite_spans": [], "ref_spans": []}, {"section": "The complexity of healthcare systems", "text": "They were designed for use in systems (for example, car production lines) where it is often possible to reduce systems to their component parts and understand how each part functions and relates to other parts. In these systems, effect follows cause in a more or less predictable (linear) way. In contrast, everyday primary healthcare systems are complex adaptive systems. Here, effects can be damped or amplified given similar input (non-linear) because of dynamic networks of interacting components. [16] [17] [18] The concept of 'close coupling' means that even small changes in one component can cause a large and unpredictable change in another component. The sociotechnical systems perspective is concerned precisely with the multiple complex interactions and interdependencies between humans (e.g. patients and clinicians and clinicians and colleagues) and technological components (e.g. medical equipment and computerisation) which give rise to expected and unexpected outcomes. [19] Another feature of complexity is that, unlike many mechanical systems (such as car engines or washing machines), healthcare is a relatively 'open' system in that there are many external agents and the boundaries of influence are hard to define. [16] In primary care the functioning of a system may be influenced by regulators, contractual arrangements, secondary care, nursing homes, social work, carers, the media, the time of year and even the weather. In open systems the prompts from wider conditions can change rapidly and in an unpredictable manner. For example, staff may face changes in demand and capacity from new regulation, political change, technological breakthroughs etc.", "cite_spans": [{"start": 502, "end": 506, "text": "[16]", "ref_id": "BIBREF14"}, {"start": 507, "end": 511, "text": "[17]", "ref_id": "BIBREF15"}, {"start": 512, "end": 516, "text": "[18]", "ref_id": "BIBREF16"}, {"start": 987, "end": 991, "text": "[19]", "ref_id": "BIBREF17"}, {"start": 1237, "end": 1241, "text": "[16]", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "The complexity of healthcare systems", "text": "The complexity in healthcare systems continues to increase with, for example, more complex job roles, integration of new technology and an expanding multidisciplinary team.", "cite_spans": [], "ref_spans": []}, {"section": "The complexity of healthcare systems", "text": "An example of system complexity is described in Box 1.", "cite_spans": [], "ref_spans": []}, {"section": "The complexity of healthcare systems", "text": "Resilience Engineering argues that things usually go right because people adjust their performance to the everyday conditions they face. [11] In this way complex systems maintain functioning to allow continued success even when prevailing work conditions mean existing practice/ protocols may be confounded. The presentation of clinical problems is rarely fully specified in available guidelines and protocols. Ways of 'getting things done' form around plans and guides rather than directly through them. People are actually very adept when faced with conditions to which standard ways of working seem misaligned. [20] They anticipate problems and adapt their behaviour by making adjustments to their work in an attempt to continue to achieve success. Performance adjustments are essential for successful functioning in complex systems and differential response should not be automatically seen as unwanted deviations from some idealised norm. Rather, adaptation is often a necessary response to complexity, and in many cases a way to mitigate problems and achieve success.", "cite_spans": [{"start": 137, "end": 141, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 614, "end": 618, "text": "[20]", "ref_id": "BIBREF18"}], "ref_spans": []}, {"section": "The complexity of healthcare systems", "text": "If you take a process such as driving a car as an example, constant adjustment is required to adapt performance to the changing and unexpected conditions (e.g. the actions of others, temporary speed restrictions, traffic lights changing to red, a heavy downpour). Drivers constantly monitor conditions and anticipate and respond to problems to prevent accidents, thereby ensuring safety for themselves and others. They learn from these experiences and so in the future find it easier to monitor, anticipate and adapt. If a standard operating procedure was devised for driving (a seemingly routine task for most people) it would be an enormous challenge to specify all the conditions that could be faced by a driver and a desirable timely response set for each. [21] Primary healthcare guidelines can be helpful but they rarely account for all possible variations of conditions. For example, the management of patients with hypertension varies with their co-morbidities, current medication, their past experience, personal preferences, expectations and perhaps even their personality. It may also vary with the resources available, such as 24 hour or home monitoring systems, equipment and staff to perform an ECG, or current availability of medication. [22] Some of these may be included in guidance but by definition guidance gives a general overview and cannot specific what to do for every intricate case.", "cite_spans": [{"start": 761, "end": 765, "text": "[21]", "ref_id": "BIBREF19"}, {"start": 1253, "end": 1257, "text": "[22]", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "The complexity of healthcare systems", "text": "The incorporation of patient preference is an important part of the RCGP curriculum and is included in many guidelines. The experience and confidence gained in working as a GP often enhances our ability to make decisions tailored in an individual manner for each patient, thus varying how work is completed. The sheer range of conditions we face means each set will often not have been previously considered to allow specific actions to be included in guidelines. Due to this, adjustments made by healthcare workers are approximate.", "cite_spans": [], "ref_spans": []}, {"section": "The complexity of healthcare systems", "text": "Adjustments include workarounds and trade-offs. Workarounds are used when people do not have all the information or equipment that they require; trade-offs are necessary when staff have to cope with competing goals. One well known trade-off is the EfficiencyThoroughness-Trade-Off (ETTO). [23] Examples of ETTOs include signing prescriptions that are not on the patient's normal 'repeat' list without reviewing the patient, or dealing with problems through telephone consultation when it may have been 'best practice' to see and examine the patient. In complex systems, conditions are constantly changing and performance adjustments are constantly required to achieve success. Dealing with this uncertainty is another important area in which trainees need to gain experience. [24] Otherwise, when faced with situations that don't 'fit' the best practice ideal, they will be 'frozen' and unable to act in the best interests of the patient.", "cite_spans": [{"start": 289, "end": 293, "text": "[23]", "ref_id": "BIBREF21"}, {"start": 776, "end": 780, "text": "[24]", "ref_id": "BIBREF22"}], "ref_spans": []}, {"section": "Implication for Safety-I and the potential of Safety-II", "text": "In traditional Safety-I thinking, safety is defined almost completely by the absence of something -the point where as few things as possible go wrong. This is achieved precisely by reduction-examining these 'wrong things' and repairing them. Safety-II aims to increase safety by maximising the number of events with a successful outcome. This means the unit of analysis goes beyond adverse events to studying how things happen under different conditions. This leads to an appreciation of system complexity that may improve incident investigation and quality improvement efforts, and may allow development of more relevant prospective methods to improve safety. Although adverse events are not uncommon (reports suggest one in ten patients admitted to hospital and one to two percent of primary care consultations) it is still true that things usually go right for the vast majority of health care provided. [25, 26] Understanding why they usually go right may allow us to learn more or different things about our systems.", "cite_spans": [{"start": 907, "end": 911, "text": "[25,", "ref_id": "BIBREF23"}, {"start": 912, "end": 915, "text": "26]", "ref_id": "BIBREF24"}], "ref_spans": []}, {"section": "Implications for Incident Investigation", "text": "Current incident investigation techniques (such as SEA and RCA) often work backwards from an event until one or more 'malfunctioning' components are found such as deviations from protocol or a technical problem with equipment. It is often presumed that this 'malfunction' was the 'cause' of the adverse event. 'Human error' is frequently blamed and recommendations often focus on changing individual behaviours. [27] Importantly, performance is often compared to work-as-imagined rather than to work-asdone. Viewing actions objectively as grounded in a dense context is always difficult when something has already gone wrong. Compared with those directly involved in an incident, investigators always have full knowledge of the outcome but analysing events retrospectively can lead to influence from various biases. 'Hindsight' and 'fundamental attribution' biases are two of the most common in these circumstances and can reduce our ability to explore why decisions were made and the multiple interacting contributing factors that often combine unexpectedly to cause adverse events. [28] Some unwanted outcomes investigated through SEA/RCA may indeed be the result of omission or commission errors in following a set of simple tasks or steps [arguably this may be more likely where trainees display knowledge gaps or lack of experience]. But there is evidence that, in complex systems, accidents can and do occur when every component of a system functions perfectly as designed or originally intended, due to the way that goals and context change. [29] Consider this scenario: a patient is discharged from hospital and a blood pressure pill Ramipril is not included on the immediate discharge letter (IDL). As no reason for this is recorded, the GP thought that it had been omitted in error. She kept Ramipril on the repeat medication list and the patient continued to receive it in their blister pack.", "cite_spans": [{"start": 412, "end": 416, "text": "[27]", "ref_id": "BIBREF25"}, {"start": 1084, "end": 1088, "text": "[28]", "ref_id": "BIBREF26"}, {"start": 1549, "end": 1553, "text": "[29]", "ref_id": "BIBREF27"}], "ref_spans": []}, {"section": "Implications for Incident Investigation", "text": "How often do we make similar clinical decisions and how often does this usually 'go right'?", "cite_spans": [], "ref_spans": []}, {"section": "Implications for Incident Investigation", "text": "The GP made a mindful decision to work around the protocol due to previous experience of this type of lack of information from secondary care. Here, efficiency (making the decision to continue the medication) was preferred to the more thorough option (contacting secondary care colleagues to confirm whether it should be stopped). This decision is not best viewed as a 'violation' or 'deviation', but as someone aiming for safe, efficient care based on knowledge, experience and the limited resources (information and time) available to them. Querying every IDL where information is not fully specified (maximum compliance and thoroughness) would simply not be deemed appropriate in this system. When things go well we are often judged (and indeed judge ourselves) on our efficiency; but when they go wrong we are judged on our thoroughness. If the patient develops acute kidney injury and is readmitted, analysis of the event may suggest the GP should have discontinued the medication and clarified the situation with secondary care regardless of the fact that the actions of the GP represented normal, everyday work. Whilst Safety-II is by nature proactive, the implication for retroactive analysis of such events is first to try to understand-\"why does this normally go right\"? This necessitates understanding the variable conditions people are faced with and the workarounds, adaptations, adjustments and tradeoffs that make the system function adequately (work-as-done). This is quite a radical departure from the usual SEA process, which compares what the poor staff have done against protocol, evidence-based guidance, or policy expectations that are based on the ideal or perfect system (work-as-imagined).", "cite_spans": [], "ref_spans": []}, {"section": "Implications for Incident Investigation", "text": "A focus on work-as-done and how to support staff may be useful in the analysis of more emotionally charged events and may help move away from blame/error tendencies which can leave many subtle features unreported or unknown. Some actions that simply cannot be tolerated may of course be identified, but it may become clear that local decisions were valid and that the system is fit-for-purpose. Exploration of how to increase resilience (ways to cope and achieve success given difficult conditions) with trainees and within teams may help in dealing with future pressure and efficiency versus thoroughness decisions.", "cite_spans": [], "ref_spans": []}, {"section": "Implications for Quality Improvement", "text": "QI projects often attempt to standardise work practices and reduce variability of performance through the stressing of protocol adherence and the measurement of compliance. These can act as constraints on alternatives to ensure that work is carried out in a set way. It is hoped that when these tasks are performed reliably that quality and, therefore, safety improves.", "cite_spans": [], "ref_spans": []}, {"section": "Implications for Quality Improvement", "text": "[30] QI can be very successful but in complex systems increasing reliability of components will not necessarily increase safety. . [31, 32] Adherence to one protocol can be a) misaligned with some conditions faced and b) fail to address the many interacting reasons why outcomes may vary. [11] As systems evolve to cope with the work conditions faced, it is unlikely that rules can be produced which cover all eventualities.", "cite_spans": [{"start": 131, "end": 135, "text": "[31,", "ref_id": "BIBREF28"}, {"start": 136, "end": 139, "text": "32]", "ref_id": "BIBREF29"}, {"start": 289, "end": 293, "text": "[11]", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "Implications for Quality Improvement", "text": "Adding a particular set of constraints may not just reduce unwanted variability but may also restrict flexible working and performance adjustments that are essential for successful negotiation in a complex care system.", "cite_spans": [], "ref_spans": []}, {"section": "Implications for Quality Improvement", "text": "In one example known to us, a QI project that included administrative staff contacting patients to discuss changes in medication following hospital discharge initially resulted in several instances of poorer care. Previously, staff had tacit knowledge of which patients were likely to be confused about their medication and would often phone the pharmacy to inform them of changes. The new protocol mandated discussion with patients (and recording that this discussion had taken place). Contacting the pharmacy was consequently downgraded in importance; the time required to contact patients meant that staff felt they did not have time to make another telephone call to the pharmacy. Although the barriers put in place by the new protocol potentially improved care, for some it constrained normal everyday adjustments that were required for success. A Safety-II approach might have involved determining how success was achieved normally (work as done) prior to the implementation of change, focused not just on best practice but on the various adjustments and trade-offs made by healthcare workers to achieve success under the conditions they face, including where resources are limited. The flexibility offered by ad hoc calls to pharmacy (made on case-based judgements driven by experience and local expertise) could then be balanced against the benefits offered by a standard codified procedure which might impact upon the benefits accrued.", "cite_spans": [], "ref_spans": []}, {"section": "Implications for Quality Improvement", "text": "The implication is that protocols should prioritise managing variability rather than simply eliminating it: flexible ways of working that are beneficial can be encouraged (as long as people are mindful of risks and responsibilities) and those that are not can be reduced. This may sound difficult as we are not used to thinking in this manner and it requires that we accept that performance variability is essential and develop ways to monitor and manage it.", "cite_spans": [], "ref_spans": []}, {"section": "Implications for Quality Improvement", "text": "This requires a commitment to understanding work-as-done and the identification of resources and conditions that are essential for successful functioning. Training to consider the best way to achieve success when resources (such as time or equipment) are missing, perhaps through scenario or simulation training, may benefit teams in this regard. For example, staff may be able to act out and discuss together how they would deal with particular scenarios such as a confused patient or a medication change which the GP is not happy to accept.", "cite_spans": [], "ref_spans": []}, {"section": "Implications for Quality Improvement", "text": "As we cannot specify work sufficiently in all parts of our systems it is not possible to develop a checklist or audit criteria that, if consistently implemented, will ensure successful outcomes. Chosen metrics must do more than assess compliance with an evidence based protocol; there may be many paths to success. It may be more valid to consider how people (patients, carers, doctors, administrative staff and pharmacists) co-ordinate and connect to achieve success. Teams may identify metrics that reflect successful work in their local context, thus bringing work-as-done and work-as-imagined closer together. An example may be measuring whether patients were aware of changes to medication regimes and using this measure to learn which approaches work best for different individual patients and/or patient groups.", "cite_spans": [], "ref_spans": []}, {"section": "Prospective Analysis", "text": "The RCGP curriculum suggests that patient safety lessons should be able to be applied ", "cite_spans": [], "ref_spans": []}, {"section": "Implications for Performance indicators", "text": "An extension of prospective system analysis is the development of metrics to monitor performance and allow anticipation of problems, so called 'leading indicators'. [34] Performance indicators are often used in healthcare to measure performance and decide if care is safe or of a high quality. These are usually 'lagging' in that they show us how safe we have been in the past and not how safe we are today. Teams may be able to identify softer 'leading' indicators of where threats may lie and thus be able to plan for such conditions and develop a range of strategies to help maintain successful performance. An example may be that, if a GP has to perform medicines reconciliation for six patients following discharge, mistakes may be more likely. Additionally, if a patient has many medications on their immediate discharge letter, there may be more chance of error. Practices could develop systems to ensure adequate time is available or immediate discharge letters with many medications could be flagged or double checked to ensure safe and effective reconciliation.", "cite_spans": [{"start": 165, "end": 169, "text": "[34]", "ref_id": "BIBREF31"}], "ref_spans": []}, {"section": "The way forward", "text": "Improving safety by reflecting on care and using QI methods, such as SEA, clinical audit, care bundles and PDSA, has been widely encouraged. Safety-II thinking suggests that, for QI approaches to be successful, an understanding of system complexity and a refocus on successful adaptations in context as opposed to simple compliance is required. Safety is an emergent property of a complex system (just like consciousness is an emergent property of the functioning of neurones within our brains). Top down implementation of protocols and guidelines may be problematic unless it considers the local context, maps how work will be done by frontline staff, and identifies the conditions necessary for success. Relationships between individuals, teams and other parts of systems are important, and involving these staff members in the implementation of change is essential. The exact functioning of every part of a system cannot be designed, but ways for staff to co-ordinate and develop safe working practices can be encouraged.", "cite_spans": [], "ref_spans": []}, {"section": "The way forward", "text": "Resilience Engineering does not suggest that we abandon Safety-I methods. Safety-I has brought many improvements and the requirement to learn from failure is based on some sound principles. But perhaps the first step in realising the potential of Safety-II is to adapt our current investigative processes to a) consider also cases of success and b) be ambivalent (at least from the outset) as to whether more standardisation is required as the best way forward.", "cite_spans": [], "ref_spans": []}, {"section": "The way forward", "text": "Methods have been developed to help teams adopt these elements of a systems approach to analysing problems and developing solutions. The prominence of Human promise. [38] For now, perhaps the first step in moving towards Safety-II is to commence investigations of adverse events by involving frontline workers in the analysis of work-asdone as part of everyday clinical work and why things usually go well. Exploring the workarounds and adjustments employed when demand and capacity do not match enables study of the difference between work-as-imagined and work-as-done. The result may be a move from focusing on individual behaviours and compliance/error models to the implementation of changes that acknowledge that a variety of responses may be required dependent on the conditions faced. We need to train new GPs to be able to consider various options; how they should respond in different conditions; to understand when to vary their actions and to consider the positive and negative consequences of such actions. Resilient systems often have several ways to achieve success and so can monitor performance, anticipate problems, respond and learn. Implementation of 'traditional' QI methods that aim to reduce variability could, at times, be counterproductive.", "cite_spans": [{"start": 166, "end": 170, "text": "[38]", "ref_id": "BIBREF36"}], "ref_spans": []}, {"section": "The way forward", "text": "The current culture of performance targets may need to be challenged or adapted. Analysis of past performance is an important part in QI but may not be an indicator of current safety. ", "cite_spans": [], "ref_spans": []}, {"section": "Box 1. Example of system complexity -medicines reconciliation", "text": "When patients are discharged from hospital back to the community, the medication record held by the GP practice needs to be updated to reflect the changes to medication made in hospital and patients need to be aware of these changes. This system involves secondary care doctors and pharmacists completing an immediate discharge letter (IDL) that is then transferred to the practice. It involves administrative staff interacting with technology to process the IDL within the practice, a member of practice staff (often a GP) making the medication changes in the electronic record and a process to communicate these changes to pharmacies and to patients. This system may be influenced by external factors including secondary care wishes (for new medications or tests), hospital bed pressures (that may expedite patient discharge), patient or carer wishes (perhaps to receive medication in a monitored dosage system), requests from pharmacies or nursing homes for medication and requirements of other organisation (perhaps to audit the process). The system is 'open' to these agents and the boundaries are hard to define. Interaction with computer software (email and electronic GP and pharmacy health records) and between people is required -for example the GP may discuss the medication list with secondary care staff, the community pharmacist, the patient or carer and perhaps district nursing staff. This process may involve administrative staff initially contacting the various people and reporting back to the GP.", "cite_spans": [], "ref_spans": []}, {"section": "Box 1. Example of system complexity -medicines reconciliation", "text": "Conditions may change rapidly with clinical requirements, demand (number of IDLs), capacity (number of GPs available to perform medicines reconciliation) or with the systems used to communicate medication changes. If the system changed from the patient handing in a paper copy of the IDL to one where IDLs were emailed from secondary care to the practice, systems within would need to be changed. IDLs may be processed by different administrative staff. IDLs may arrive at a certain time of the day requiring staff to reschedule work and change the systems for completing other tasks. The practice may discover that transferring IDLs electronically works well and may alter other existing systems for handling secondary care communication. But unanticipated problems may arise such as difficulty viewing both the electronic record and electronic IDL simultaneously and slow computer connections to branch surgeries that make the process less efficient. Patients may still be given a paper copy of the IDL on discharge and mistakenly hand this in to GP reception. As IDLs from certain departments in secondary care may still arrive in paper form, the IDL may still be processed and thus double work.", "cite_spans": [], "ref_spans": []}, {"section": "Box 1. Example of system complexity -medicines reconciliation", "text": "Given the same input, outcomes can be amplified, damped or even quite unexpected. For example, an IDL may contain the instruction to take prednisolone 40mg once daily and it may not be clear if the medication is to continue. This could result in the drug being prescribed for one week while clarification is requested from secondary care. After one week, more prednisolone may be requested by the patient. This may be dealt with and given by a locum who might not be fully aware of the systems in the practice. If this continued, health problems due to prolonged high dose prednisolone may result. This outcome could be damped by actions of other components in the system -for example the patient or carer may be aware of the need to reduce and stop the medication or the pharmacist may query the second prescription. The risk could be amplified by absence, due to illness or changing shift pattern, of the secondary care contact. The co-prescription of a non-steroidal anti-inflammatory drug for muscle pain by an out-of-hours doctor who was not aware of the patient's medication may increase the risks of further problems including of gastrointestinal bleeding.", "cite_spans": [], "ref_spans": []}, {"section": "Box 1. Example of system complexity -medicines reconciliation", "text": "Systems in practices often 'evolve'. One member of staff may be responsible for clarifying medication changes with secondary care but may have found that patients will often be aware of instructions and are easier to contact than secondary care staff. This workaround may eventually become known to all staff and become 'normal' practice that seems to be a safe and more efficient way of working but does not follow protocol. ", "cite_spans": [], "ref_spans": []}, {"section": "Box 2 -Application of Safety-II", "text": "", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "The Royal College of General Practitioners", "authors": [], "year": 2015, "venue": "", "link": "79010550"}, "BIBREF1": {"title": "Supporting information for appraisal and revalidation", "authors": [], "year": 2012, "venue": "General Medical Council", "link": null}, "BIBREF2": {"title": "British medical association. 2015/16 General Medical Services (GMS) contract Quality and Outcomes Framework (QOF)", "authors": [{"first": "", "middle": [], "last": "Nhs England", "suffix": ""}], "year": 2015, "venue": "", "link": null}, "BIBREF3": {"title": "The Scottish Patient Safety Programme. Scottish Patient Safety Programme in Primary Care", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF4": {"title": "Productive general practice", "authors": [], "year": "", "venue": "NHS Improving Quality", "link": null}, "BIBREF5": {"title": "Is healthcare getting safer?", "authors": [{"first": "C", "middle": [], "last": "Vincent", "suffix": ""}], "year": 2008, "venue": "BMJ", "link": null}, "BIBREF6": {"title": "Measuring and monitoring safety: a primary care perspective. London: The Health Foundation", "authors": [{"first": "A", "middle": [], "last": "Esmail", "suffix": ""}], "year": 2013, "venue": "", "link": null}, "BIBREF7": {"title": "A promise to learn -a commitment to Act", "authors": [], "year": 2013, "venue": "", "link": null}, "BIBREF8": {"title": "Mobilizing resilience by monitoring the right things for the right people at the right time", "authors": [{"first": "A", "middle": ["J"], "last": "Ross", "suffix": ""}, {"first": "J", "middle": ["E"], "last": "Anderson", "suffix": ""}], "year": 2015, "venue": "", "link": null}, "BIBREF9": {"title": "Understanding and responding when things go wrong: key principles for primary care educators", "authors": [{"first": "D", "middle": [], "last": "Mcnab", "suffix": ""}, {"first": "P", "middle": [], "last": "Bowie", "suffix": ""}, {"first": "A", "middle": [], "last": "Ross", "suffix": ""}, {"first": "J", "middle": [], "last": "Morrison", "suffix": ""}], "year": 2016, "venue": "Education for primary care", "link": "2597801"}, "BIBREF10": {"title": "Resilience Engineering: A New Understanding of Safety", "authors": [{"first": "E", "middle": [], "last": "Hollnagel", "suffix": ""}], "year": 2016, "venue": "J Ergon Soc Korea", "link": "148201090"}, "BIBREF11": {"title": "Safety-I and Safety-II The past and future of safety management", "authors": [{"first": "E", "middle": [], "last": "Hollnagel", "suffix": ""}], "year": 2014, "venue": "Ashgate", "link": "27024622"}, "BIBREF12": {"title": "London 14. National Patient Safety Agency. Seven steps to patient safety: the full reference guide", "authors": [], "year": 2004, "venue": "", "link": null}, "BIBREF13": {"title": "Resilient health care: turning patient safety on its head", "authors": [{"first": "J", "middle": [], "last": "Braithwaite", "suffix": ""}, {"first": "R", "middle": [], "last": "Wears", "suffix": ""}, {"first": "E", "middle": [], "last": "Hollnagel", "suffix": ""}], "year": 2015, "venue": "Int J Qual Health Care", "link": "43390910"}, "BIBREF14": {"title": "The Health Foundation. Evidence Scan: Complex Adaptive Systems", "authors": [], "year": 2010, "venue": "", "link": null}, "BIBREF15": {"title": "Using Complexity Theory to Build Interventions that Improve Health Care Delivery in Primary Care", "authors": [{"first": "D", "middle": [], "last": "Litaker", "suffix": ""}, {"first": "A", "middle": [], "last": "Tomolo", "suffix": ""}, {"first": "V", "middle": [], "last": "Liberatone", "suffix": ""}, {"first": "K", "middle": [], "last": "Stange", "suffix": ""}], "year": 2006, "venue": "J Gen Intern Med", "link": "72710022"}, "BIBREF16": {"title": "Primary Care Practice Development: A Relationship-Centered Approach", "authors": [{"first": "W", "middle": [], "last": "Miller", "suffix": ""}, {"first": "B", "middle": [], "last": "Crabtree", "suffix": ""}, {"first": "P", "middle": [], "last": "Nutting", "suffix": ""}, {"first": "K", "middle": [], "last": "Stange", "suffix": ""}, {"first": "C", "middle": [], "last": "Jaen", "suffix": ""}], "year": 2010, "venue": "Ann Fam Med", "link": "20481250"}, "BIBREF17": {"title": "Socio-Technical Systems Analysis in Health Care: A Research Agenda. IIE transactions on healthcare systems engineering", "authors": [{"first": "P", "middle": [], "last": "Carayon", "suffix": ""}, {"first": "E", "middle": [], "last": "Bass", "suffix": ""}, {"first": "V", "middle": [], "last": "Mollo", "suffix": ""}], "year": 2011, "venue": "", "link": null}, "BIBREF18": {"title": "The resilience of everyday clinical work", "authors": [{"first": "R", "middle": [], "last": "Wears", "suffix": ""}, {"first": "E", "middle": [], "last": "Hollnagel", "suffix": ""}, {"first": "J", "middle": [], "last": "Braithwaite", "suffix": ""}], "year": 2015, "venue": "Resilient Health Care", "link": "141593476"}, "BIBREF19": {"title": "Autonomous vehicles: No drivers required", "authors": [{"first": "M", "middle": [], "last": "Waldrop", "suffix": ""}], "year": "", "venue": "Nature", "link": null}, "BIBREF20": {"title": "National Institute for Health and Care Excellence (NICE) Hypertension in adults: diagnosis and management", "authors": [], "year": 2011, "venue": "", "link": null}, "BIBREF21": {"title": "The ETTO Principle: Efficiency-thoroughness Trade-off: why Things that Go Right Sometimes Go Wrong", "authors": [{"first": "E", "middle": [], "last": "Hollnagel", "suffix": ""}], "year": 2009, "venue": "", "link": null}, "BIBREF22": {"title": "Dealing with uncertainty in general practice: an essential skill for the general practitioner", "authors": [{"first": "M", "middle": [], "last": "O&apos;riordan", "suffix": ""}, {"first": "A", "middle": [], "last": "Dahinden", "suffix": ""}, {"first": "Z", "middle": [], "last": "Aktu", "suffix": ""}], "year": 2011, "venue": "Qual Prim Care", "link": "32020835"}, "BIBREF23": {"title": "The Health Foundation. Evidence scan: levels of harm in primary care", "authors": [], "year": 2011, "venue": "", "link": null}, "BIBREF24": {"title": "Adverse events in British hospitals: Preliminary retrospective record review", "authors": [{"first": "C", "middle": [], "last": "Vincent", "suffix": ""}, {"first": "G", "middle": [], "last": "Neale", "suffix": ""}, {"first": "M", "middle": [], "last": "Woloshynowych", "suffix": ""}], "year": 2001, "venue": "Br Med J", "link": "14848178"}, "BIBREF25": {"title": "A review of significant events analysed in general practice: implications for the quality and safety of patient care", "authors": [{"first": "J", "middle": [], "last": "Mckay", "suffix": ""}, {"first": "N", "middle": [], "last": "Bradley", "suffix": ""}, {"first": "M", "middle": [], "last": "Lough", "suffix": ""}, {"first": "P", "middle": [], "last": "Bowie", "suffix": ""}], "year": 2009, "venue": "BMC Fam Pract", "link": "11795302"}, "BIBREF26": {"title": "The intuitive psychologist and his shortcomings: distortions in the attribution process", "authors": [{"first": "L", "middle": [], "last": "Ross", "suffix": ""}], "year": 1977, "venue": "Advances in experimental social psychology 10", "link": "142829783"}, "BIBREF27": {"title": "New Jersey. 30. The King's Fund. Quality improvement in general practice", "authors": [{"first": "C", "middle": [], "last": "Perrow", "suffix": ""}, {"first": "", "middle": [], "last": "Accidents", "suffix": ""}], "year": 1984, "venue": "", "link": null}, "BIBREF28": {"title": "A systematic narrative review of quality improvement models in health care", "authors": [{"first": "A", "middle": ["E"], "last": "Powell", "suffix": ""}, {"first": "R", "middle": ["K"], "last": "Rushmer", "suffix": ""}, {"first": "Hto", "middle": [], "last": "Davies", "suffix": ""}], "year": 2009, "venue": "Quality Improvement Scotland", "link": "107050553"}, "BIBREF29": {"title": "A New Accident Model for Engineering Safer Systems", "authors": [{"first": "N", "middle": [], "last": "Leveson", "suffix": ""}], "year": 2004, "venue": "Safety Science", "link": "11916845"}, "BIBREF30": {"title": "The problem with incident reporting", "authors": [{"first": "C", "middle": [], "last": "Macrae", "suffix": ""}], "year": 2016, "venue": "BMJ Qual Saf", "link": "19934375"}, "BIBREF31": {"title": "Epilogue -Resilience Engineering Precepts", "authors": [{"first": "E", "middle": [], "last": "Hollnagel", "suffix": ""}, {"first": "D", "middle": ["D"], "last": "Woods", "suffix": ""}], "year": 2006, "venue": "", "link": "106767433"}, "BIBREF32": {"title": "Aldershot: Ashgate p348", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF33": {"title": "Enhancing the effectiveness of significant event analysis: exploring personal impact and applying systems thinking in primary care", "authors": [{"first": "P", "middle": [], "last": "Bowie", "suffix": ""}, {"first": "E", "middle": [], "last": "Mcnaughton", "suffix": ""}, {"first": "D", "middle": [], "last": "Bruce", "suffix": ""}], "year": 2016, "venue": "Journal of Continuing Education in the Health Professions", "link": "3325292"}, "BIBREF34": {"title": "Human factors and ergonomics for primary care, Education for Primary Care", "authors": [{"first": "P", "middle": [], "last": "Bowie", "suffix": ""}, {"first": "S", "middle": [], "last": "Jeffcott", "suffix": ""}], "year": 2016, "venue": "", "link": null}, "BIBREF35": {"title": "Work system design for patient safety: the SEIPS model", "authors": [{"first": "P", "middle": [], "last": "Carayon", "suffix": ""}, {"first": "A", "middle": ["S"], "last": "Hundt", "suffix": ""}, {"first": "B-T", "middle": [], "last": "Karsh", "suffix": ""}], "year": 2006, "venue": "Qual Saf Health Care", "link": "27730582"}, "BIBREF36": {"title": "Where the rubber meets the road: using FRAM to align work-as-imagined with work-as-done when implementing clinical guidelines", "authors": [{"first": "R", "middle": [], "last": "Clay-Williams", "suffix": ""}, {"first": "J", "middle": [], "last": "Hounsgaard", "suffix": ""}, {"first": "E", "middle": [], "last": "Hollnagel", "suffix": ""}], "year": 2015, "venue": "Implementation Science", "link": "16896386"}}, "ref_entries": {"FIGREF0": {"text": "stage. It encourages actions to improve systems through implementation of Human Factors/Ergonomics principles and approaches -for example through understanding of associations between various performance indicators, human error, and variation in clinical practice. Involvement in national safety and quality programmes such as the Quality Outcomes Framework, the Scottish Patient Safety Programme and Productive General", "type": "figure"}, "FIGREF1": {"text": "prospectively. Traditional, reactive methods of investigation of course have a preventive (future) intent. However, many systems become overwhelmed by the number of incidents investigated, resulting in a lack of meaningful feedback leading to learning following an event, and subsequent reduced engagement in incident reporting and analysis. [33] As Safety-II moves from examining what has already gone wrong to examining everyday clinical work it allows prospective analysis of systems (thus eliminating bias introduced by fear of blame) and both prevention of adverse events and facilitation of what is required to ensure successful functioning in differing conditions. Variation may be able to be controlled and managed rather than completely constrained. This position is hard to hold after harm. There is immense pressure to 'change something' because of the a priori knowledge that something has gone wrong. Considering the medicines reconciliation case described above, when developing the protocol with frontline clinical staff, teams could consider how work is actually done, what affects the successful completion of certain tasks and what resources are essential for success? Conditions that could affect performance should be considered: time pressure could result in staff making less safe trade-offs. Unclear, unexpected or contradictory information may affect outcomes, but staff often have ways of working to cope with such (for example contacting patients, carers, secondary care or deciding the medication is not needed). Working through different scenarios to consider the benefits of various actions may not only help trainees and GPs deal with uncertainty but help develop systems that aid safe clinical decision making.", "type": "figure"}, "FIGREF2": {"text": "Ergonomics (HFE) in healthcare has been increasing. A HFE framework has been used in enhanced SEA to help teams gain a deeper understanding of the interacting factors involved in why events occurred and the Systems Engineering Initiative for Patient Safety 2 (SEIPS2) model can be used prospectively to design system changes that take into account the work of frontline individuals and their interactions with other parts of the system. [35, 36, 37] New Safety-II methods may be required and in certain areas the use of the Functional Resonance Analysis Method to aid understanding of complex systems has shown", "type": "figure"}, "FIGREF3": {"text": "is needed into the application of the Safety-II approach in healthcare and the development of new safety 'tools' (or adaptation of existing ones) may be required. This approach may enhance patient safety education and curriculum coverage for trainees but administrative, clinical staff, management and policymakers also require education and evidence of its successful application. [Box 2] Safety-II appears to have potential to broaden our arsenal of QI methods offering the opportunity for the patient safety movement to evolve to be more effective in the complex systems found in healthcare.", "type": "figure"}, "TABREF0": {"text": "QI method How Safety-II can be applied Link to RCGP curriculum Incident investigation Start by understanding and describing current systems. What does work-as-done look like? How does everyday work usually lead to success? When working backwards from an incident consider why decisions were made. Often the same decisions will have been made and a successful outcome achieved. Why did this not happen this time? Were actions consistent with everyday work? Did the person vary their performance in an attempt to achieve success? Have they successfully used this adjustment before? How do others deal with these circumstances? How can we help people consider the outcomes from different choices? Where is variability useful and where should it be reduced? Be able to describe the basic principles of human error Decide the criteria for when the organisation should undertake a root cause analysis or significant event audit Know how organisations and individuals can learn to improve systems by analysing patient safety incidents and near misses Illustrate how changes in behaviour and/or systems can influence patient safety Be able to describe the tools and principles that can be applied in risk management and patient safety issues Describe how the analysis of patient safety incidents can enhance rather than undermine professional integrity and performanceStart by understanding and describing current systems. What does work-as-done look like? How does everyday work usually lead to success? Consider the whole system; are there key Develop and maintain an approach to continuing learning and quality improvement Describe the variation in GP and practice performance and the functions that need to be completed in a certain way? If so this may be an area for checklists or specified criteria. Are there areas where a variety of responses would be beneficial? If so how can staff be helped to make the correct decision? How can variability be managed? Consider the interactions between staff and with technology -can this be simplified or strengthened to improve co-ordinated working? determinants of this Describe the uses and abuses of clinical indicators and metrics such as benchmarking Illustrate how changes in behaviour and/or systems can influenceStart by understanding and describing current systems. What functions are essential for success? Discuss with those who perform the functions, which ones should not vary and for which are there multiple ways to success? Help staff consider what options are available to them, how different actions can have different results and how to select the most appropriate action. How can we ensure that the resources are available when needed to ensure safe functioning? Why does this usually work? Consider the interactions between staff and with technology - can this be simplified or strengthened to improve co-ordinatedDescribe how the lessons of patient safety can be applied prospectively to doctor-patient interactions, especially through the identification and discussion of risk Leading indicators What conditions cause unwanted variation in performance? What can we measure to predict the development of these Describe the uses and abuses of clinical indicators and metrics such as benchmarking conditions? How can this be communicated effectively to staff? Can a range of actions be developed to ensure successful functioning when these conditions are identified? Appraise critically data about practice indicators (e.g. prescribing, referrals, chronic disease management, access and availability)", "type": "table"}}}
{"paper_id": "2870829", "_pdf_hash": "2b90eecce04399cc999ae0f4539481341f0c3633", "abstract": [], "body_text": [], "bib_entries": {"BIBREF2": {"title": "Involvement of singlet oxygen in chloroaluminum phthalocyanine tetrasulfonate-mediated photoenhancement of lipid peroxidation in rat epidermal microsomes", "authors": [{"first": "R", "middle": [], "last": "Agarwal", "suffix": ""}, {"first": "M", "middle": [], "last": "Athar", "suffix": ""}, {"first": "S", "middle": ["A"], "last": "Urban", "suffix": ""}, {"first": "D", "middle": ["R"], "last": "Bickers", "suffix": ""}, {"first": "H", "middle": [], "last": "Mukhtar", "suffix": ""}], "year": 1991, "venue": "Cancer Lett", "link": "22757148"}, "BIBREF3": {"title": "Identification of singlet oxygen as the cytotoxic agent in photoinactivation of a murine tumor", "authors": [{"first": "K", "middle": ["R"], "last": "Weishaupt", "suffix": ""}, {"first": "C", "middle": ["J"], "last": "Gomer", "suffix": ""}, {"first": "T", "middle": ["J"], "last": "Dougherty", "suffix": ""}], "year": 1976, "venue": "Cancer Res", "link": "8748854"}, "BIBREF4": {"title": "Preclinical examination of first and second-generation photosensitizers used in photodynamic therapy", "authors": [{"first": "C", "middle": ["J"], "last": "Gomer", "suffix": ""}], "year": 1991, "venue": "Photochem. Photobiol", "link": "5878322"}, "BIBREF5": {"title": "How does photodynamic therapy work?", "authors": [{"first": "B", "middle": ["W"], "last": "Henderson", "suffix": ""}, {"first": "T", "middle": ["J"], "last": "Dougherty", "suffix": ""}], "year": 1992, "venue": "Photochem. Photobiol", "link": "38884695"}, "BIBREF6": {"title": "Correlation of subcellular and intratumoral photosensitizer localization with ultrastructural features after photodynamic therapy", "authors": [{"first": "Q", "middle": [], "last": "Peng", "suffix": ""}, {"first": "J", "middle": [], "last": "Moan", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Nesland", "suffix": ""}], "year": 1996, "venue": "Ultrastruct. Pathol", "link": "9377116"}, "BIBREF7": {"title": "Apoptosis in response to photodynamic therapy", "authors": [{"first": "N", "middle": ["L"], "last": "Oleinick", "suffix": ""}], "year": 1998, "venue": "Photodynamic News", "link": null}, "BIBREF8": {"title": "The photobiology of photodynamic therapy: cellular targets and mechanisms", "authors": [{"first": "N", "middle": ["L"], "last": "Oleinick", "suffix": ""}, {"first": "H", "middle": ["H"], "last": "Evans", "suffix": ""}], "year": 1998, "venue": "Radiat. Res", "link": "10075120"}, "BIBREF9": {"title": "Photochemotherapy of cancer: experimental research", "authors": [{"first": "J", "middle": [], "last": "Moan", "suffix": ""}, {"first": "K", "middle": [], "last": "Berg", "suffix": ""}], "year": 1992, "venue": "Photochem. Photobiol", "link": "41193040"}, "BIBREF10": {"title": "Protease activation and cleavage of poly(ADP-ribose) polymerase: an integral part of apoptosis in response to photodynamic treatment", "authors": [{"first": "J", "middle": [], "last": "He", "suffix": ""}, {"first": "C", "middle": ["M"], "last": "Whitacre", "suffix": ""}, {"first": "L", "middle": [], "last": "Xue", "suffix": ""}, {"first": "N", "middle": ["A"], "last": "Berger", "suffix": ""}, {"first": "N", "middle": ["L"], "last": "Oleinick", "suffix": ""}], "year": 1998, "venue": "Cancer Res", "link": "17995102"}, "BIBREF11": {"title": "Photodynamic therapy induces rapid cell death by apoptosis in L5178Y mouse lymphoma cells", "authors": [{"first": "M", "middle": ["L"], "last": "Agarwal", "suffix": ""}, {"first": "M", "middle": ["E"], "last": "Clay", "suffix": ""}, {"first": "E", "middle": ["J"], "last": "Harvey", "suffix": ""}, {"first": "H", "middle": ["H"], "last": "Evans", "suffix": ""}, {"first": "A", "middle": ["R"], "last": "Antunez", "suffix": ""}, {"first": "N", "middle": ["L"], "last": "Oleinick", "suffix": ""}], "year": 1991, "venue": "Cancer Res", "link": "32746215"}, "BIBREF12": {"title": "Apoptosis occurs in lymphoma cells but not in hepatoma cells following ionizing radiation and photodynamic therapy", "authors": [{"first": "X", "middle": ["Y"], "last": "He", "suffix": ""}, {"first": "R", "middle": ["A"], "last": "Sikes", "suffix": ""}, {"first": "S", "middle": [], "last": "Thomsen", "suffix": ""}, {"first": "L", "middle": ["W K"], "last": "Chung", "suffix": ""}, {"first": "Jacques", "middle": [], "last": "", "suffix": ""}, {"first": "S", "middle": ["L"], "last": "Laukka", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Wang", "suffix": ""}, {"first": "K", "middle": ["K"], "last": "Bonner", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Luo", "suffix": ""}, {"first": "Y", "middle": [], "last": "Chang", "suffix": ""}, {"first": "C", "middle": ["K"], "last": "Kessel", "suffix": ""}, {"first": "D", "middle": [], "last": "", "suffix": ""}], "year": 1994, "venue": "Photochem. Photobiol", "link": "7377652"}, "BIBREF13": {"title": "Phthalocyanine 4 (Pc 4) photodynamic therapy of human OVCAR-3 tumor xenografts", "authors": [{"first": "V", "middle": ["C"], "last": "Colussi", "suffix": ""}, {"first": "D", "middle": ["K"], "last": "Feyes", "suffix": ""}, {"first": "J", "middle": ["W"], "last": "Mulvihill", "suffix": ""}, {"first": "Y", "middle": ["S"], "last": "Li", "suffix": ""}, {"first": "M", "middle": ["E"], "last": "Kenney", "suffix": ""}, {"first": "C", "middle": ["A"], "last": "Elmets", "suffix": ""}, {"first": "N", "middle": ["L"], "last": "Oleinick", "suffix": ""}, {"first": "H", "middle": [], "last": "Mukhtar", "suffix": ""}], "year": 1999, "venue": "Photochem. Photobiol", "link": "42484100"}, "BIBREF14": {"title": "Specific proteolytic cleavage of poly (ADP-ribose) polymerase: an early marker of chemotherapy-induced apoptosis", "authors": [{"first": "S", "middle": ["H"], "last": "Kaufmann", "suffix": ""}, {"first": "S", "middle": [], "last": "Desnoyers", "suffix": ""}, {"first": "Y", "middle": [], "last": "Ottaviano", "suffix": ""}, {"first": "N", "middle": ["E"], "last": "Davidson", "suffix": ""}, {"first": "G", "middle": ["G"], "last": "Poirier", "suffix": ""}], "year": 1993, "venue": "Cancer Res", "link": "2339073"}, "BIBREF15": {"title": "Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis", "authors": [{"first": "D", "middle": ["W"], "last": "Nicholson", "suffix": ""}, {"first": "A", "middle": [], "last": "Ali", "suffix": ""}, {"first": "N", "middle": ["A"], "last": "Thornberry", "suffix": ""}, {"first": "J", "middle": ["P"], "last": "Vaillancourt", "suffix": ""}, {"first": "C", "middle": ["K"], "last": "Ding", "suffix": ""}, {"first": "M", "middle": [], "last": "Gallant", "suffix": ""}, {"first": "Y", "middle": [], "last": "Gareau", "suffix": ""}, {"first": "P", "middle": ["R"], "last": "Griffin", "suffix": ""}, {"first": "M", "middle": [], "last": "Labelle", "suffix": ""}, {"first": "Y", "middle": ["A"], "last": "Lazebnik", "suffix": ""}, {"first": "N", "middle": ["A"], "last": "Munday", "suffix": ""}, {"first": "S", "middle": ["M"], "last": "Raju", "suffix": ""}, {"first": "M", "middle": ["E"], "last": "Smulson", "suffix": ""}, {"first": "T-T", "middle": [], "last": "Yamin", "suffix": ""}, {"first": "V", "middle": ["L"], "last": "Yu", "suffix": ""}, {"first": "D", "middle": ["K"], "last": "Miller", "suffix": ""}], "year": 1995, "venue": "Nature (Lond.)", "link": "4240789"}, "BIBREF16": {"title": "Factors affecting topotecaninduced programmed cell death: adhesion protects cells from apoptosis and impairs cleavage of poly(ADP-ribose) polymerase", "authors": [{"first": "C", "middle": ["M"], "last": "Whitacre", "suffix": ""}, {"first": "N", "middle": ["A"], "last": "Berger", "suffix": ""}], "year": 1997, "venue": "Cancer Res", "link": "38155457"}, "BIBREF17": {"title": "Different cleavage pattern for poly(ADP-ribose) polymerase during necrosis and apoptosis in HL-60 cells", "authors": [{"first": "G", "middle": ["M"], "last": "Shah", "suffix": ""}, {"first": "R", "middle": ["G"], "last": "Shah", "suffix": ""}, {"first": "G", "middle": ["G"], "last": "Poirier", "suffix": ""}], "year": 1996, "venue": "Biochem. Biophys. Res. Commun", "link": "22561118"}, "BIBREF18": {"title": "Substrate and inhibitor specificity of interleukin-1 beta-converting enzyme and related caspases", "authors": [{"first": "N", "middle": [], "last": "Margolin", "suffix": ""}, {"first": "S", "middle": ["A"], "last": "Raybuck", "suffix": ""}, {"first": "K", "middle": ["P"], "last": "Wilson", "suffix": ""}, {"first": "W", "middle": [], "last": "Chen", "suffix": ""}, {"first": "T", "middle": [], "last": "Fox", "suffix": ""}, {"first": "Y", "middle": [], "last": "Gu", "suffix": ""}, {"first": "D", "middle": ["G"], "last": "Livingston", "suffix": ""}], "year": 1997, "venue": "J. Biol. Chem", "link": "12845050"}, "BIBREF19": {"title": "Characterization of seven murine caspase family members", "authors": [{"first": "M", "middle": [], "last": "Van De Craen", "suffix": ""}, {"first": "P", "middle": [], "last": "Vandenabeele", "suffix": ""}, {"first": "W", "middle": [], "last": "Declercq", "suffix": ""}, {"first": "I", "middle": [], "last": "Van Den Brande", "suffix": ""}, {"first": "G", "middle": [], "last": "Van Loo", "suffix": ""}, {"first": "F", "middle": [], "last": "Molemans", "suffix": ""}, {"first": "P", "middle": [], "last": "Schotte", "suffix": ""}, {"first": "W", "middle": [], "last": "Van Criekinge", "suffix": ""}, {"first": "R", "middle": [], "last": "Beyaert", "suffix": ""}, {"first": "W", "middle": [], "last": "Fiers", "suffix": ""}], "year": 1997, "venue": "FEBS Lett", "link": "21338672"}, "BIBREF20": {"title": "Cleavage of poly (ADP-ribose) polymerase by a proteinase with properties like ICE", "authors": [{"first": "Y", "middle": ["A"], "last": "Lazebnik", "suffix": ""}, {"first": "S", "middle": ["H"], "last": "Kaufmann", "suffix": ""}, {"first": "S", "middle": [], "last": "Desnoyers", "suffix": ""}, {"first": "G", "middle": ["G"], "last": "Poirier", "suffix": ""}, {"first": "W", "middle": ["C"], "last": "Earnshaw", "suffix": ""}], "year": 1994, "venue": "Nature (Lond.)", "link": "4315478"}, "BIBREF21": {"title": "Photodynamic therapy induces caspase-3 activation in HL-60 cells", "authors": [{"first": "D", "middle": ["J"], "last": "Granville", "suffix": ""}, {"first": "J", "middle": ["G"], "last": "Levy", "suffix": ""}, {"first": "D", "middle": ["W"], "last": "Hunt", "suffix": ""}], "year": 1997, "venue": "Cell Death Differ", "link": "8892207"}, "BIBREF22": {"title": "Association of ceramide accumulation with photodynamic treatment-induced cell death", "authors": [{"first": "D", "middle": [], "last": "Kessel", "suffix": ""}, {"first": "Y", "middle": [], "last": "Luo", "suffix": ""}, {"first": "D", "middle": [], "last": "Separovic", "suffix": ""}, {"first": "K", "middle": ["J"], "last": "Mann", "suffix": ""}, {"first": "N", "middle": ["L"], "last": "Oleinick", "suffix": ""}], "year": 1998, "venue": "Photochem. Photobiol", "link": "11689078"}, "BIBREF23": {"title": "Photodynamic therapy results in induction of WAF1/Cip1/P21 leading to cell cycle arrest and apoptosis", "authors": [{"first": "N", "middle": [], "last": "Ahmad", "suffix": ""}, {"first": "D", "middle": ["K"], "last": "Feyes", "suffix": ""}, {"first": "R", "middle": [], "last": "Agarwal", "suffix": ""}, {"first": "H", "middle": [], "last": "Mukhtar", "suffix": ""}], "year": 1998, "venue": "Proc. Natl. Acad. Sci. USA", "link": "32657474"}, "BIBREF24": {"title": "Involvement of nitric oxide during phthalocyanine (Pc 4) photodynamic therapy-mediated apoptosis", "authors": [{"first": "S", "middle": [], "last": "Gupta", "suffix": ""}, {"first": "N", "middle": [], "last": "Ahmad", "suffix": ""}, {"first": "H", "middle": [], "last": "Mukhtar", "suffix": ""}], "year": 1998, "venue": "Cancer Res", "link": "198973219"}, "BIBREF25": {"title": "Stimulation of stress-activated protein kinase and p38 HOG1 kinase in murine keratinocytes following photodynamic therapy with benzoporphyrin derivative", "authors": [{"first": "J", "middle": [], "last": "Tao", "suffix": ""}, {"first": "J", "middle": ["S"], "last": "Sanghera", "suffix": ""}, {"first": "S", "middle": ["L"], "last": "Pelech", "suffix": ""}, {"first": "G", "middle": [], "last": "Wong", "suffix": ""}, {"first": "J", "middle": ["G"], "last": "Levy", "suffix": ""}], "year": 1996, "venue": "J. Biol. Chem", "link": "45160943"}, "BIBREF26": {"title": "Rapid tyrosine phosphorylation of HS1 in the response of mouse lymphoma L5178Y-R cells to photodynamic treatment sensitized by the phthalocyanine Pc 4", "authors": [{"first": "L", "middle": ["Y"], "last": "Xue", "suffix": ""}, {"first": "J", "middle": [], "last": "He", "suffix": ""}, {"first": "N", "middle": ["L"], "last": "Oleinick", "suffix": ""}], "year": 1997, "venue": "Photochem. Photobiol", "link": "39901430"}, "BIBREF27": {"title": "Promotion of photodynamic therapy-induced apoptosis by stress kinases", "authors": [{"first": "L", "middle": ["Y"], "last": "Xue", "suffix": ""}, {"first": "J", "middle": [], "last": "He", "suffix": ""}, {"first": "N", "middle": ["L"], "last": "Oleinick", "suffix": ""}], "year": 1999, "venue": "Cell Death Differ", "link": "44799114"}, "BIBREF28": {"title": "Pyropheophorbide-1 methyl ester-mediated photosensitization activates transcription factor NF-B through the interleukin-1 receptor-dependent signaling pathway", "authors": [{"first": "J.-Y", "middle": [], "last": "Matroule", "suffix": ""}, {"first": "G", "middle": [], "last": "Bonizzi", "suffix": ""}, {"first": "P", "middle": [], "last": "Morliere", "suffix": ""}, {"first": "N", "middle": [], "last": "Paillous", "suffix": ""}, {"first": "R", "middle": [], "last": "Santus", "suffix": ""}, {"first": "V", "middle": [], "last": "Bours", "suffix": ""}, {"first": "J", "middle": [], "last": "Piette", "suffix": ""}], "year": 1999, "venue": "J. Biol. Chem", "link": null}, "BIBREF29": {"title": "Photodynamic therapy mediated induction of early response genes", "authors": [{"first": "M", "middle": ["C"], "last": "Luna", "suffix": ""}, {"first": "S", "middle": [], "last": "Wong", "suffix": ""}, {"first": "Gomer", "middle": [], "last": "", "suffix": ""}, {"first": "C", "middle": ["J"], "last": "", "suffix": ""}], "year": 1994, "venue": "Cancer Res", "link": "12166362"}, "BIBREF30": {"title": "Increased transcription and translation of heme oxygenase in Chinese hamster fibroblasts following photodynamic stress or Photofrin II incubation", "authors": [{"first": "C", "middle": ["J"], "last": "Gomer", "suffix": ""}, {"first": "M", "middle": [], "last": "Luna", "suffix": ""}, {"first": "A", "middle": [], "last": "Ferrario", "suffix": ""}, {"first": "N", "middle": [], "last": "Rucker", "suffix": ""}], "year": 1991, "venue": "Photochem. Photobiol", "link": "11710261"}, "BIBREF31": {"title": "A novel kinase cascade triggered by stress and heat shock that stimulates MAPKAP kinase-2 and phosphorylation of the small heat shock proteins", "authors": [{"first": "J", "middle": [], "last": "Rouse", "suffix": ""}, {"first": "P", "middle": [], "last": "Cohen", "suffix": ""}, {"first": "S", "middle": [], "last": "Trigon", "suffix": ""}, {"first": "M", "middle": [], "last": "Morange", "suffix": ""}, {"first": "A", "middle": [], "last": "Alonso-Llamazares", "suffix": ""}, {"first": "D", "middle": [], "last": "Zamanillo", "suffix": ""}, {"first": "T", "middle": [], "last": "Hunt", "suffix": ""}, {"first": "A", "middle": ["R"], "last": "Nebreda", "suffix": ""}], "year": 1994, "venue": "Cell", "link": "19895515"}, "BIBREF32": {"title": "A protein kinase involved in the regulation of inflammatory cytokine biosynthesis", "authors": [{"first": "J", "middle": ["C"], "last": "Lee", "suffix": ""}, {"first": "J", "middle": ["T"], "last": "Laydon", "suffix": ""}, {"first": "P", "middle": ["C"], "last": "Mcdonnell", "suffix": ""}, {"first": "T", "middle": ["F"], "last": "Gallagher", "suffix": ""}, {"first": "S", "middle": [], "last": "Kumar", "suffix": ""}, {"first": "D", "middle": [], "last": "Green", "suffix": ""}, {"first": "D", "middle": [], "last": "Mcnulty", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Blumenthal", "suffix": ""}, {"first": "J", "middle": ["R"], "last": "Heys", "suffix": ""}, {"first": "S", "middle": ["W"], "last": "Landvatter", "suffix": ""}, {"first": "J", "middle": ["E"], "last": "Strickler", "suffix": ""}, {"first": "M", "middle": ["M"], "last": "Mclaughlin", "suffix": ""}, {"first": "I", "middle": ["R"], "last": "Siemens", "suffix": ""}, {"first": "S", "middle": ["M"], "last": "Fisher", "suffix": ""}, {"first": "G", "middle": ["P"], "last": "Livi", "suffix": ""}, {"first": "J", "middle": ["R"], "last": "White", "suffix": ""}, {"first": "J", "middle": ["L"], "last": "Adams", "suffix": ""}, {"first": "Young", "middle": [], "last": "", "suffix": ""}, {"first": "P", "middle": ["R"], "last": "", "suffix": ""}], "year": 1994, "venue": "Nature (Lond.)", "link": "4306822"}, "BIBREF33": {"title": "A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells", "authors": [{"first": "J", "middle": [], "last": "Han", "suffix": ""}, {"first": "J", "middle": ["D"], "last": "Lee", "suffix": ""}, {"first": "L", "middle": [], "last": "Bibbs", "suffix": ""}, {"first": "R", "middle": ["J"], "last": "Ulevitch", "suffix": ""}], "year": 1994, "venue": "Science", "link": "11712895"}, "BIBREF34": {"title": "Interleukin-1 activates a novel protein kinase cascade that results in the phosphorylation of Hsp27", "authors": [{"first": "N", "middle": ["W"], "last": "Freshney", "suffix": ""}, {"first": "L", "middle": [], "last": "Rawlinson", "suffix": ""}, {"first": "F", "middle": [], "last": "Guesdon", "suffix": ""}, {"first": "E", "middle": [], "last": "Jones", "suffix": ""}, {"first": "S", "middle": [], "last": "Cowley", "suffix": ""}, {"first": "J", "middle": [], "last": "Hsuan", "suffix": ""}, {"first": "J", "middle": [], "last": "Saklatvala", "suffix": ""}], "year": 1994, "venue": "Cell", "link": "37608621"}, "BIBREF35": {"title": "Pro-inflammatory cytokines and environmental stress cause p38 mitogen-activated protein kinase activation by dual phosphorylation on tyrosine and threonine", "authors": [{"first": "J", "middle": [], "last": "Raingeaud", "suffix": ""}, {"first": "S", "middle": [], "last": "Gupta", "suffix": ""}, {"first": "J", "middle": ["S"], "last": "Rogers", "suffix": ""}, {"first": "M", "middle": [], "last": "Dickens", "suffix": ""}, {"first": "J", "middle": [], "last": "Han", "suffix": ""}, {"first": "R", "middle": ["J"], "last": "Ulevitch", "suffix": ""}, {"first": "R", "middle": ["J"], "last": "Davis", "suffix": ""}], "year": 1995, "venue": "J. Biol. Chem", "link": "21563919"}, "BIBREF36": {"title": "Activation of JNK and p38 but not ERK MAP kinases in human skin cells by 5-aminolevulinate-photodynamic therapy", "authors": [{"first": "L", "middle": ["O"], "last": "Klotz", "suffix": ""}, {"first": "C", "middle": [], "last": "Fritsch", "suffix": ""}, {"first": "K", "middle": [], "last": "Briviba", "suffix": ""}, {"first": "N", "middle": [], "last": "Tsacmacidis", "suffix": ""}, {"first": "F", "middle": [], "last": "Schliess", "suffix": ""}, {"first": "H", "middle": [], "last": "Sies", "suffix": ""}], "year": 1998, "venue": "Cancer Res", "link": "14864875"}, "BIBREF37": {"title": "A comparative analysis of silicon phthalocyanine photosensitizers for in vivo photodynamic therapy of RIF-1 tumors in C3H mice", "authors": [{"first": "C", "middle": ["Y"], "last": "Anderson", "suffix": ""}, {"first": "K", "middle": [], "last": "Freye", "suffix": ""}, {"first": "K", "middle": ["A"], "last": "Tubesing", "suffix": ""}, {"first": "Y-S", "middle": [], "last": "Li", "suffix": ""}, {"first": "M", "middle": ["E"], "last": "Kenney", "suffix": ""}, {"first": "H", "middle": [], "last": "Mukhtar", "suffix": ""}, {"first": "C", "middle": ["A"], "last": "Elmets", "suffix": ""}], "year": 1998, "venue": "Photochem. Photobiol", "link": "2321761"}, "BIBREF38": {"title": "Apoptosis during photodynamic therapy-induced ablation of RIF-I tumors", "authors": [{"first": "S", "middle": ["I A"], "last": "Zaidi", "suffix": ""}, {"first": "N", "middle": ["L"], "last": "Oleinick", "suffix": ""}, {"first": "M", "middle": ["T"], "last": "Zaim", "suffix": ""}, {"first": "H", "middle": [], "last": "Mukhtar", "suffix": ""}], "year": 1993, "venue": "Photochem. Photobiol", "link": null}, "BIBREF39": {"title": "Apoptosis is an early event during phthalocyanine photodynamic therapy-induced ablation of chemically induced squamous papillomas in mouse skin", "authors": [{"first": "R", "middle": [], "last": "Agarwal", "suffix": ""}, {"first": "N", "middle": ["J"], "last": "Korman", "suffix": ""}, {"first": "R", "middle": ["R"], "last": "Mohan", "suffix": ""}, {"first": "D", "middle": ["K"], "last": "Feyes", "suffix": ""}, {"first": "S", "middle": [], "last": "Jawed", "suffix": ""}, {"first": "M", "middle": ["T"], "last": "Zaim", "suffix": ""}, {"first": "H", "middle": [], "last": "Mukhtar", "suffix": ""}], "year": 1996, "venue": "Photochem. Photobiol", "link": "6837472"}, "BIBREF40": {"title": "Topotecan increases topoisomerase II\u2423 levels and sensitivity to treatment with etoposide in schedule-dependent process", "authors": [{"first": "C", "middle": ["M"], "last": "Whitacre", "suffix": ""}, {"first": "E", "middle": [], "last": "Zborowska", "suffix": ""}, {"first": "N", "middle": ["H"], "last": "Gordon", "suffix": ""}, {"first": "W", "middle": [], "last": "Mackay", "suffix": ""}, {"first": "N", "middle": ["A"], "last": "Berger", "suffix": ""}], "year": 1997, "venue": "Cancer Res", "link": "39711142"}, "BIBREF41": {"title": "Detection of poly(ADP-ribose) polymerase cleavage in response to treatment with topoisomerase I inhibitors: a potential surrogate end point to assess treatment effectiveness", "authors": [{"first": "C", "middle": ["M"], "last": "Whitacre", "suffix": ""}, {"first": "E", "middle": [], "last": "Zborowska", "suffix": ""}, {"first": "J", "middle": ["K V"], "last": "Willson", "suffix": ""}, {"first": "N", "middle": ["A"], "last": "Berger", "suffix": ""}], "year": 1999, "venue": "Clin. Cancer Res", "link": "6667207"}, "BIBREF42": {"title": "Photodynamic anticancer agent merocyanine 540 inhibits cell growth by apoptosis", "authors": [{"first": "Y", "middle": ["C"], "last": "Chen", "suffix": ""}, {"first": "J", "middle": ["K"], "last": "Lin", "suffix": ""}], "year": 1996, "venue": "Anticancer Res", "link": "12234593"}, "BIBREF43": {"title": "New phthalocyanine photosensitizers for photodynamic therapy", "authors": [{"first": "N", "middle": ["L"], "last": "Oleinick", "suffix": ""}, {"first": "A", "middle": ["R"], "last": "Antunez", "suffix": ""}, {"first": "M", "middle": ["E"], "last": "Clay", "suffix": ""}, {"first": "B", "middle": ["D"], "last": "Rihter", "suffix": ""}, {"first": "M", "middle": ["E"], "last": "Kenney", "suffix": ""}], "year": 1993, "venue": "Photochem. Photobiol", "link": "39527356"}, "BIBREF44": {"title": "ONYX-015, an E1B gene-attenuated adenovirus, causes tumor-specific cytolysis and antitumoral efficacy that can be augmented by standard chemotherapeutic agents", "authors": [{"first": "U", "middle": ["K"], "last": "Laemmli", "suffix": ""}, {"first": "C", "middle": [], "last": "Heise", "suffix": ""}, {"first": "A", "middle": [], "last": "Sampson-Johannes", "suffix": ""}, {"first": "A", "middle": [], "last": "Williams", "suffix": ""}, {"first": "F", "middle": [], "last": "Mccormick", "suffix": ""}, {"first": "D", "middle": ["D"], "last": "Von Hoff", "suffix": ""}, {"first": "D", "middle": ["H"], "last": "Kirn", "suffix": ""}], "year": 1970, "venue": "Nature (Lond.)", "link": null}, "BIBREF45": {"title": "Increased photosensitivity in HL60 cells expressing wild-type p53", "authors": [{"first": "A", "middle": ["M R"], "last": "Fisher", "suffix": ""}, {"first": "K", "middle": [], "last": "Danenberg", "suffix": ""}, {"first": "D", "middle": [], "last": "Banerjee", "suffix": ""}, {"first": "J", "middle": ["R"], "last": "Bertino", "suffix": ""}, {"first": "P", "middle": [], "last": "Danenberg", "suffix": ""}, {"first": "Gomer", "middle": [], "last": "", "suffix": ""}, {"first": "C", "middle": [], "last": "", "suffix": ""}], "year": 1997, "venue": "Photochem. Photobiol", "link": "22081116"}, "BIBREF46": {"title": "Differential photosensitivity in wild-type and mutant p53 human colon carcinioma cell lines", "authors": [{"first": "A", "middle": ["M R"], "last": "Fisher", "suffix": ""}, {"first": "N", "middle": [], "last": "Rucker", "suffix": ""}, {"first": "S", "middle": [], "last": "Wong", "suffix": ""}, {"first": "Gomer", "middle": [], "last": "", "suffix": ""}, {"first": "C", "middle": ["J"], "last": "", "suffix": ""}], "year": 1998, "venue": "J. Photochem. Photobiol", "link": "26453931"}, "BIBREF47": {"title": "Photodynamic therapy sensitivity is not altered in human tumor cells after abrogation of p53 function", "authors": [{"first": "A", "middle": ["M R"], "last": "Fisher", "suffix": ""}, {"first": "A", "middle": [], "last": "Ferrario", "suffix": ""}, {"first": "N", "middle": [], "last": "Rucker", "suffix": ""}, {"first": "S", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "Gomer", "middle": [], "last": "", "suffix": ""}, {"first": "C", "middle": ["J"], "last": "", "suffix": ""}], "year": 1999, "venue": "Cancer Res", "link": null}, "BIBREF48": {"title": "Quantitative analysis of Pc 4 localization in mouse lymphoma (LY-R) cells via double-label confocal fluorescence microscopy", "authors": [{"first": "N", "middle": ["S"], "last": "Trivedi", "suffix": ""}, {"first": "H", "middle": ["W"], "last": "Wang", "suffix": ""}, {"first": "A", "middle": ["L"], "last": "Nieminen", "suffix": ""}, {"first": "N", "middle": ["L"], "last": "Oleinick", "suffix": ""}, {"first": "J", "middle": [], "last": "Izatt", "suffix": ""}], "year": 2000, "venue": "Photochem. Photobiol", "link": "24265451"}, "BIBREF49": {"title": "Photodynamic therapy-induced apoptosis in lymphoma cells: translocation of cytochrome c causes inhibition of respiration as well as caspase activation", "authors": [{"first": "M", "middle": ["E"], "last": "Varnes", "suffix": ""}, {"first": "S", "middle": ["M"], "last": "Chiu", "suffix": ""}, {"first": "L", "middle": ["Y"], "last": "Xue", "suffix": ""}, {"first": "N", "middle": ["L"], "last": "Oleinick", "suffix": ""}, {"first": "S", "middle": [], "last": "Kharbanda", "suffix": ""}, {"first": "S", "middle": [], "last": "Saxena", "suffix": ""}, {"first": "K", "middle": [], "last": "Yoshida", "suffix": ""}, {"first": "P", "middle": [], "last": "Pandey", "suffix": ""}, {"first": "M", "middle": [], "last": "Kaneki", "suffix": ""}, {"first": "Q", "middle": [], "last": "Wang", "suffix": ""}, {"first": "K", "middle": [], "last": "Cheng", "suffix": ""}, {"first": "Y-N", "middle": [], "last": "Chen", "suffix": ""}, {"first": "A", "middle": [], "last": "Campbell", "suffix": ""}, {"first": "T", "middle": [], "last": "Sudha", "suffix": ""}, {"first": "Z-M", "middle": [], "last": "Yuan", "suffix": ""}, {"first": "J", "middle": [], "last": "Narula", "suffix": ""}, {"first": "R", "middle": [], "last": "Weichselbaum", "suffix": ""}, {"first": "C", "middle": [], "last": "Nalin", "suffix": ""}, {"first": "D", "middle": [], "last": "Kufe", "suffix": ""}], "year": 1999, "venue": "Biochem. Biophys. Res. Commun", "link": "25304917"}, "BIBREF50": {"title": "The induction of partial resistance to photodynamic therapy by the protooncogene Bcl-2", "authors": [{"first": "J", "middle": [], "last": "He", "suffix": ""}, {"first": "M", "middle": ["L"], "last": "Agarwal", "suffix": ""}, {"first": "H", "middle": ["E"], "last": "Larkin", "suffix": ""}, {"first": "L", "middle": ["R"], "last": "Friedman", "suffix": ""}, {"first": "L", "middle": ["Y"], "last": "Xue", "suffix": ""}, {"first": "N", "middle": ["L"], "last": "Oleinick", "suffix": ""}], "year": 1996, "venue": "Photochem. Photobiol", "link": "24719023"}, "BIBREF51": {"title": "Overexpression of Bcl-X L prevents caspase-3-mediated activation of DNA fragmentation factor (DFF) produced by treatment with the photochemotherapeutic agent BPD-MA", "authors": [{"first": "D", "middle": ["J"], "last": "Granville", "suffix": ""}, {"first": "H", "middle": [], "last": "Jiang", "suffix": ""}, {"first": "M", "middle": ["T"], "last": "An", "suffix": ""}, {"first": "J", "middle": ["G"], "last": "Levy", "suffix": ""}, {"first": "B", "middle": ["M"], "last": "Mcmanus", "suffix": ""}, {"first": "D", "middle": ["W"], "last": "Hunt", "suffix": ""}], "year": 1998, "venue": "FEBS Lett", "link": "31135111"}, "BIBREF52": {"title": "Bcl-2 overexpression blocks caspase activation and downstream apoptotic events instigated by photodynamic therapy", "authors": [{"first": "D", "middle": ["J"], "last": "Granville", "suffix": ""}, {"first": "H", "middle": [], "last": "Jiang", "suffix": ""}, {"first": "M", "middle": ["T"], "last": "An", "suffix": ""}, {"first": "J", "middle": ["G"], "last": "Levy", "suffix": ""}, {"first": "B", "middle": ["M"], "last": "Mcmanus", "suffix": ""}, {"first": "D", "middle": ["W"], "last": "Hunt", "suffix": ""}], "year": 1999, "venue": "Br. J. Cancer", "link": "1561253"}, "BIBREF53": {"title": "Antisense bcl-2 retrovirus vector increases the sensitivity of a human gastric adenocarcinoma cell line to photodynamic therapy", "authors": [{"first": "W", "middle": ["G"], "last": "Zhang", "suffix": ""}, {"first": "L", "middle": ["P"], "last": "Ma", "suffix": ""}, {"first": "S", "middle": ["W"], "last": "Wang", "suffix": ""}, {"first": "Z", "middle": ["Y"], "last": "Zhang", "suffix": ""}, {"first": "G", "middle": ["D"], "last": "Cao", "suffix": ""}], "year": 1999, "venue": "Photochem. Photobiol", "link": "31207243"}, "BIBREF54": {"title": "Role for Bcl-x L as an inhibitor of cytosolic cytochrome C accumulation in DNA damage-induced apoptosis", "authors": [{"first": "S", "middle": [], "last": "Kharbanda", "suffix": ""}, {"first": "P", "middle": [], "last": "Pandey", "suffix": ""}, {"first": "L", "middle": [], "last": "Schofield", "suffix": ""}, {"first": "S", "middle": [], "last": "Israels", "suffix": ""}, {"first": "R", "middle": [], "last": "Roncinske", "suffix": ""}, {"first": "K", "middle": [], "last": "Yoshida", "suffix": ""}, {"first": "A", "middle": [], "last": "Bharti", "suffix": ""}, {"first": "Z", "middle": ["M"], "last": "Yuan", "suffix": ""}, {"first": "S", "middle": [], "last": "Saxena", "suffix": ""}, {"first": "R", "middle": [], "last": "Weichselbaum", "suffix": ""}, {"first": "C", "middle": [], "last": "Nalin", "suffix": ""}, {"first": "D", "middle": [], "last": "Kufe", "suffix": ""}], "year": 1997, "venue": "Proc. Natl. Acad. Sci. U S A", "link": "187210"}, "BIBREF55": {"title": "Prevention of apoptosis by Bcl-2: release of cytochrome c from mitochondria blocked", "authors": [{"first": "J", "middle": [], "last": "Yang", "suffix": ""}, {"first": "X", "middle": [], "last": "Liu", "suffix": ""}, {"first": "K", "middle": [], "last": "Bhalla", "suffix": ""}, {"first": "C", "middle": ["N"], "last": "Kim", "suffix": ""}, {"first": "A", "middle": ["M"], "last": "Ibrado", "suffix": ""}, {"first": "J", "middle": [], "last": "Cai", "suffix": ""}, {"first": "T", "middle": ["I"], "last": "Peng", "suffix": ""}, {"first": "D", "middle": ["P"], "last": "Jones", "suffix": ""}, {"first": "Wang", "middle": [], "last": "", "suffix": ""}, {"first": "X", "middle": [], "last": "", "suffix": ""}], "year": 1997, "venue": "Science (Washington DC)", "link": "32349676"}, "BIBREF56": {"title": "The release of cytochrome c from mitochondria: a primary site for Bcl-2 regulation of apoptosis", "authors": [{"first": "R", "middle": ["M"], "last": "Kluck", "suffix": ""}, {"first": "E", "middle": [], "last": "Bossy-Wetzel", "suffix": ""}, {"first": "D", "middle": ["R"], "last": "Green", "suffix": ""}, {"first": "D", "middle": ["D"], "last": "Newmeyer", "suffix": ""}], "year": 1997, "venue": "Science", "link": "8025067"}}, "ref_entries": {}}
{"paper_id": "2870859", "_pdf_hash": "66e688a6eaebddedc108dca90640797366447af7", "abstract": [{"section": "Abstract", "text": "Abstract-Bosch has developed and demonstrated a novel direct current (DC) microgrid system that maximizes the efficiency of locally generated photovoltaic energy while offering high reliability, safety, redundancy, and reduced cost compared to equivalent alternating current (AC) systems. Several demonstration projects validating the system feasibility and expected efficiency gains have been completed and additional ones are in progress. This paper gives an overview of the Bosch DC microgrid system and presents key results from a large simulation study done to estimate the energy savings of the Bosch DC microgrid over conventional AC systems. The study examined the system performance in locations across the United States for several commercial building types and operating profiles. It found that the Bosch DC microgrid uses generated PV energy 6%-8% more efficiently than traditional AC systems.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "I. INTRODUCTION", "text": "Zero net energy policy goals for buildings in the United States and across the world imply a high penetration of distributed renewable energy resources and a substantial increase in energy efficiency. According to the National Science and Technology Council, aggressive adoption of energy efficiency technologies will reduce building energy consumption by 60%-70% [1] . The remaining 30%-40% of energy must come from onsite generation to achieve zero net site energy. Distributed renewable energy will be deployed on a large scale only when its assets provide attractive returns to owners and enable utilities and grid operators to safely and reliably mitigate the impact of renewables' intermittency on the electricity distribution infrastructure.", "cite_spans": [{"start": 364, "end": 367, "text": "[1]", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "The direct current (DC) microgrid presented in this paper offers significant energy efficiency, cost, reliability, and safety benefits compared to conventional alternating current (AC) systems. In the Bosch DC microgrid (DCMG) architecture, onsite DC distributed generation such as solar PV is directly connected to energy-efficient DC lighting, DC ventilation, and other DC loads via a 380 V nominal DC bus. A central AC/DC gateway converter provides supplemental grid power whenever local generation cannot fully supply the load. Thus, the DCMG eliminates the use of AC/DC rectifiers at the loads and reduces the need for DC/AC inverters that are currently required to interconnect solar photovoltaics (PV) to the electric utility.", "cite_spans": [], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "The reduction in conversion equipment makes the overall system more efficient and reliable and reduces maintenance costs. The use of a separate DC bus provides a built-in mechanism for operating critical DC loads during grid outages (to the extent that energy is available from local DC generation or storage) without requiring a mechanical transfer switch. From the utility perspective, the DC architecture reduces the size of inverters required to export excess PV energy, thereby mitigating the potential impact of PV variability on the grid. Furthermore, DC-based battery storage can be much more efficiently connected to a DCMG, enabling a more costeffective way to smooth solar power intermittency.", "cite_spans": [], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "By transitioning most of the major hard-wired loads in a building to the DC distribution system, customers can expect up to 30% lower total cost of ownership over the life of the system, higher reliability, and optimized use of renewable generation compared to a conventional AC microgrid. At scale, the capital cost is anticipated at 15%-20% lower than a comparable AC system; the operating costs will also be significantly lower over the 25-year life of the system. The DC system architecture is applicable to a wide variety of commercial buildings, including big-box retail stores, warehouses, distribution centers, and manufacturing facilities.", "cite_spans": [], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "In addition to several systems installed at Bosch facilities, two high-profile DCMG projects are currently underway at external sites. The U.S. Department of Defense has awarded Bosch a demonstration project to be completed in 2015 that involves the retrofit of a building at Fort Bragg in Fayetteville, North Carolina. In addition, the California Energy Commission has awarded Bosch and its partners a demonstration project in southern California that will include 300 kW of installed PV.", "cite_spans": [], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "Section II of this paper provides an overview of the Bosch DCMG system and its components. Sections III and IV summarize the methodology and key results, respectively, for a DCMG simulation study and system energy analysis conducted by the National Renewable Energy Laboratory (NREL). The study estimated the performance of the DCMG for several key metrics, including annual grid energy, system energy efficiency, and PV utilization fraction, for several commercial building types under a variety of operating schedules.", "cite_spans": [], "ref_spans": []}, {"section": "II. SYSTEM OVERVIEW", "text": "Bosch has installed the DCMG at several pilot sites. The purposes of the demonstrations are to validate the expected efficiency gains and to confirm safe and reliable operation of the DCMG. Fig. 1 shows an installation in Charlotte, North Carolina, that has been operating since August 2014. An equivalent AC system was installed next to the DC system for efficiency comparison, and the cumulative data to date show that the DC system uses PV energy about 8% more efficiently than the AC system. This early demonstration is done with DC induction fixtures, whereas current and future installations will have DC LED fixtures. The expected efficiency gain for the DC version of each lighting technology is approximately 4% when compared to equivalent AC technology.", "cite_spans": [], "ref_spans": []}, {"section": "A. Configuration", "text": "The patented system configuration and control enable powering of DC loads (such as lighting and ventilation) directly from PV arrays with only a single conversion stage between the source and load, so that the PV energy is delivered with minimal losses. In contrast, a conventional AC system requires two conversions. Fig. 2 shows the basic DCMG configuration alongside a conventional AC system. In the DC system, only the DC light-emitting diode (LED) driver appears in the PV-to-load path. In the basic configuration, the AC/DC gateway is a rectifier. The PV is sized such that it does not normally exceed the load, so an inverter is not needed.", "cite_spans": [], "ref_spans": []}, {"section": "A. Configuration", "text": "In the Bosch DCMG, maximum power point tracking (MPPT) is performed by the voltage regulation of the AC/DC gateway converter, which is not directly in the PV-to-load path but rather supplies the balance of power required to operate the load. This patented configuration enables higher efficiency and greater reliability than other DC systems which use a dedicated MPPT converter through which all the PV power passes.", "cite_spans": [], "ref_spans": []}, {"section": "A. Configuration", "text": "More advanced configurations include ventilation fans, forklift chargers, flow batteries, ultracapacitors, and bidirectional AC/DC gateways. A bidirectional converter enables the PV system to be sized larger than the load power for more flexibility. Lighting and ventilation are the preferred load types because their profiles are predictable and align well with PV generation profiles.", "cite_spans": [], "ref_spans": []}, {"section": "B. Components 1) AC/DC Gateway:", "text": "In the DC system, the AC/DC gateway replaces a traditional PV inverter. The AC/DC gateway's primary function is to provide power to the load whenever the PV array does not provide sufficient power. The AC/DC gateway is composed of parallel connected rectifiers, inverters, and/or bidirectional AC/DC converters, depending on the size of the PV and loads in a particular installation. Having separate inverter and rectifier stages allows for custom sizing for either direction for highest efficiency and lowest cost. Having multiple parallel stages also increases the redundancy of the system. When drawing energy from the grid or exporting energy to the grid, the efficiency of the DCMG is approximately equal to that of a conventional AC system. For this reason, the systems are sized such that most PV energy is either used immediately or stored on the DC side, without passing through the AC/DC gateway.", "cite_spans": [], "ref_spans": []}, {"section": "B. Components 1) AC/DC Gateway:", "text": "Although the AC/DC gateway provides convenience for operating the DC loads when solar power is not available, it is not necessary for running the DCMG in islanded mode. When a grid outage occurs, the system seamlessly reverts to islanded operation where the light output and fan speed adjust to match available generation and/or energy storage.", "cite_spans": [], "ref_spans": []}, {"section": "2) DC LED Driver:", "text": "In the DCMG, a custom DC-input LED driver replaces the AC-input LED driver. The DC driver does not require a rectifier and is optimized to achieve maximum efficiency within the DC input voltage range. Therefore, the DC LED driver efficiency is approximately 97%-98%, compared to 93%-94% for the highest efficiency 277 V AC drivers.", "cite_spans": [], "ref_spans": []}, {"section": "2) DC LED Driver:", "text": "Compared to an AC driver, the DC LED driver also has a smaller component count and greater reliability because a rectification stage is not present. The expected driver lifetime increases because internal heat generation is significantly reduced and because electrolytic capacitors, which are required for the rectification stage of an AC driver, can be eliminated. Given the extremely long expected lifetime of LEDs, LED drivers are the least reliable component in an LED fixture. Without an electrolytic capacitor, the DC LED driver is potentially much more reliable than an AC one, with early studies indicating that the DC driver electronics will outlast the LEDs themselves in typical building applications.", "cite_spans": [], "ref_spans": []}, {"section": "III. ENERGY ANALYSIS MODEL", "text": "Using best-in-class modeling tools, NREL performed a simulation study to analyze the energy performance of both unidirectional (basic) and bidirectional (advanced) versions of the Bosch DCMG in high bay LED lighting applications for several typical scenarios in various locations throughout the United States. The full study is available in [2] .", "cite_spans": [{"start": 341, "end": 344, "text": "[2]", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "III. ENERGY ANALYSIS MODEL", "text": "In the analysis, NREL assumed a simple lighting system containing only a PV array, an LED load, a DC LED driver, and an AC/DC gateway (Fig. 2) . NREL simulated the performance of this basic system in a variety of scenarios resulting from the combination of: The set of analysis cases (scenarios) examined was not an exhaustive combination of all these categories but rather a selective subset representing likely design cases (see [2] for details). For each case, NREL developed a baseline system model that represents conventional AC technology and an equivalent DCMG system model with identically sized PV generation and lighting load. NREL simulated the AC baseline and DCMG models for each geographic location and compared the systems' performance.", "cite_spans": [{"start": 431, "end": 434, "text": "[2]", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "A. Evaluation Framework", "text": "An unbiased comparison of energy performance between conventional AC technology and an equivalent DCMG system requires that the definitions of energy inputs and outputs are consistent between the two system types. Fig. 3 presents a generic conceptual representation of a building electric power distribution network that contains a PV source, a DC load, and a grid interconnection. This conceptual model is useful for structured comparison of AC and DC distribution systems.", "cite_spans": [], "ref_spans": [{"start": 214, "end": 220, "text": "Fig. 3", "ref_id": "FIGREF1"}]}, {"section": "A. Evaluation Framework", "text": "Three possible converter locations are identified in Fig. 3 : at the PV source, at the load, and at the grid interconnection. The wiring between these converters may be either AC or DC depending on the system configuration. The figure also identifies six power measurement points, -, one on each side of each of the three converters.", "cite_spans": [], "ref_spans": [{"start": 53, "end": 59, "text": "Fig. 3", "ref_id": "FIGREF1"}]}, {"section": "A. Evaluation Framework", "text": "Depending on how converters are selected and configured, the generic network of Fig. 3 may represent either a conventional AC system or the Bosch DCMG. In the AC case, there is no central AC/DC converter and . The PV system uses a conventional PV inverter and the load uses an AC driver. In the DC case, there is instead no converter at the PV source and therefore (except in cases of curtailment; see below). A DC driver matches voltage between the PV source and the lighting load and a central, or gateway, AC/DC converter provides the balance of power. If the available generation exceeds the combined load demand and export capacity of the gateway inverter, then PV curtailment occurs. The model represents the curtailed energy conceptually as a system loss between points and , such that .", "cite_spans": [], "ref_spans": [{"start": 80, "end": 86, "text": "Fig. 3", "ref_id": "FIGREF1"}]}, {"section": "B. Definition of Performance Metrics", "text": "To characterize the performance of the DCMG compared to an AC system, NREL developed seven energy performance metrics. Four metrics-grid energy intensity, energy efficiency, PV utilization fraction, and grid utilization fraction-describe the performance of the high bay lighting electric power distribution system. The remaining three are site metrics that describe the changes in site energy for a building employing a DCMG compared to a building with an AC baseline system. (Source energy and cost metrics were outside the scope of the study, but are recommended for future work.)", "cite_spans": [], "ref_spans": []}, {"section": "B. Definition of Performance Metrics", "text": "To define these annual metrics, let represent an arbitrary time period in a set of time periods that span an entire year, each with duration . Within each time period the system is assumed to operate at steady-state (powers -are constant) such that , , and so forth. The notation indicates an operation that occurs over all time periods in set .", "cite_spans": [], "ref_spans": []}, {"section": "B. Definition of Performance Metrics", "text": "Given these definitions, the grid energy intensity is the annual grid electricity consumption of the high bay lighting system normalized by the floor area ( ).", "cite_spans": [], "ref_spans": []}, {"section": "B. Definition of Performance Metrics", "text": "(1) This metric varies significantly with PV system size and is therefore most useful for comparing analysis scenarios with identically sized PV arrays. Because it measures total energy consumption, this metric provides the fairest point of comparison from a cost perspective.", "cite_spans": [], "ref_spans": []}, {"section": "B. Definition of Performance Metrics", "text": "The system energy efficiency is the ratio of total output (load) energy to total input (source) energy, including energy from both the electric grid and the PV array.", "cite_spans": [], "ref_spans": []}, {"section": "B. Definition of Performance Metrics", "text": "(2) Energy efficiency differs from instantaneous (power) efficiency, which depends on the power flows at a particular instant in time. Energy efficiency is equivalent to weighted average power efficiency with weights proportional to system load at each time step.", "cite_spans": [], "ref_spans": []}, {"section": "B. Definition of Performance Metrics", "text": "The PV utilization fraction is a PV-specific energy efficiency metric defined as the fraction of PV energy that serves a useful purpose; that is, the fraction that is either delivered to the load or exported to the electric grid.", "cite_spans": [], "ref_spans": []}, {"section": "B. Definition of Performance Metrics", "text": "The numerator of (3) sums all useful PV energy: energy delivered to the load ( ) and exported to the grid ( ) whenever PV generation exceeds load, plus the PV array's portion of energy delivered to the load whenever load exceeds PV generation. The denominator sums all PV generation.", "cite_spans": [], "ref_spans": []}, {"section": "B. Definition of Performance Metrics", "text": "The grid utilization fraction is the counterpart to the PV utilization fraction-it provides a measure of the efficiency of grid-to-load energy transfer.", "cite_spans": [], "ref_spans": []}, {"section": "(4)", "text": "The metric applies during grid import operation only; the numerator sums the grid's part of energy delivered to the load whenever load exceeds PV generation.", "cite_spans": [], "ref_spans": []}, {"section": "(4)", "text": "To assess the whole-building (site) impact of the distribution system type, NREL simulated the performance of the entire building using the internal heat gains associated with each system type: the AC baseline and the DCMG (see Section III-C). This process yielded net annual site electricity, natural gas, and total energy consumption for each system type ( , , and , respectively). The three site performance metrics summarize the site impacts normalized by floor area, with the general formula:", "cite_spans": [], "ref_spans": []}, {"section": "(4)", "text": "The site change in electricity intensity includes the change in grid energy intensity of the high bay lighting subsystem rather than being in addition to it. The site change in total energy intensity combines the direct and indirect effects on electricity and gas consumption into a single metric.", "cite_spans": [], "ref_spans": []}, {"section": "C. Modeling Approach", "text": "At present, no single simulation environment is well equipped to model building energy performance and DCMG behavior simultaneously. Therefore, NREL developed a multistep simulation approach that combines three energy modeling tools: EnergyPlus [3] for whole-building energy simulation, System Advisor Model (SAM) [4] for PV array simulation, and tailored MATLAB [5] functions for electric power distribution system efficiency analysis.", "cite_spans": [{"start": 314, "end": 317, "text": "[4]", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "C. Modeling Approach", "text": "Calculating the system power flows requires three inputs:", "cite_spans": [], "ref_spans": []}, {"section": "C. Modeling Approach", "text": "1. High bay lighting load pre-or post-converter ( or ) at each simulation time step 2. PV array power generation pre-or post-converter ( or ) at each simulation time step", "cite_spans": [], "ref_spans": []}, {"section": "C. Modeling Approach", "text": "3. An electric power distribution system model, including converter models for the LED driver, PV inverter, and/or gateway converter, as appropriate.", "cite_spans": [], "ref_spans": []}, {"section": "C. Modeling Approach", "text": "The EnergyPlus models provide the high bay lighting load and the SAM models provide the PV array generation data. The MATLAB functions combine these data and compute the power flows for each distribution system type: AC and DC. To ensure a fair comparison, the building model, DC PV generation, and DC lighting load in each analysis case were identical for the AC baseline and DCMG systems.", "cite_spans": [], "ref_spans": []}, {"section": "C. Modeling Approach", "text": "Simulation and energy analysis proceeded in four steps:", "cite_spans": [], "ref_spans": []}, {"section": "C. Modeling Approach", "text": "1. Developed template models: NREL created building and PV array template models for each combination of building type, operating schedule, and PV array size.", "cite_spans": [], "ref_spans": []}, {"section": "C. Modeling Approach", "text": "2. Simulated the baseline: NREL applied site-specific adjustments and simulated each template model at each of the 554 geographical locations.", "cite_spans": [], "ref_spans": []}, {"section": "Compared the performance of distribution systems:", "text": "NREL used the results from the baseline simulations to develop and simulate site-specific models for both system types for each analysis case.", "cite_spans": [], "ref_spans": []}, {"section": "Evaluated the whole-building impacts:", "text": "NREL used the results of the distribution system energy analysis to evaluate the whole-building energy impacts of the high bay lighting system for both system types.", "cite_spans": [], "ref_spans": []}, {"section": "Evaluated the whole-building impacts:", "text": "NREL then computed each energy performance metric for each analysis case using the simulation results.", "cite_spans": [], "ref_spans": []}, {"section": "Evaluated the whole-building impacts:", "text": "NREL selected a subset of the U.S. Department of Energy Commercial Reference Building Models [6] to provide prototypes for each of the four building types. NREL increased the retail building model size to 98,769 ft\u00b2 to better represent large, or big-box, retail stores; added refrigerated cases to the warehouse model to create a refrigerated warehouse model; modified model schedules to match the five operating schedules used in the analysis; modified the lighting load to represent a typical high bay LED system; and performed various site-specific adjustments (see [2] for details).", "cite_spans": [{"start": 93, "end": 96, "text": "[6]", "ref_id": "BIBREF4"}, {"start": 569, "end": 572, "text": "[2]", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Evaluated the whole-building impacts:", "text": "NREL developed PV array models in SAM for each combination of building type and PV array scaling factor. For each array model, NREL sized the PV array such that the derated array wattage approximately equals the total installed high bay lighting load multiplied by the array scaling factor (see [2] for details). NREL then simulated each PV array model at each of the 554 geographic locations.", "cite_spans": [{"start": 295, "end": 298, "text": "[2]", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Evaluated the whole-building impacts:", "text": "For all analysis cases, the PV array sizes and configurations are identical for the baseline AC and DC systems; the systems differ only in the presence or absence of the PV inverter. Therefore, a single SAM model provides DC production data for both systems. For the baseline system, the SAM model output provides both the DC and AC array power ( and in Fig. 3 ) at each time step. For the DC system, only the DC array power is used as input to the electricity distribution efficiency model. SAM's MPPT algorithm also provides the optimal PV array operating voltage at each time step; this voltage is then assigned to the DC bus in the DCMG system model.", "cite_spans": [], "ref_spans": [{"start": 354, "end": 360, "text": "Fig. 3", "ref_id": "FIGREF1"}]}, {"section": "Evaluated the whole-building impacts:", "text": "Because dedicated tools for the efficiency analysis of mixed AC-DC distribution systems are not readily available, NREL developed tailored models in MATLAB. To model the converters, NREL adapted the Sandia PV inverter model [7] to represent generic power electronics converters. The resulting model has the form: (6) In (6), is the converter input power, is the converter output power, is the converter terminal voltage at the variable voltage terminal, is the nominal voltage at the converter variable voltage terminal, and -are empirically derived converter loss coefficients fit using linear least squares. The distribution system models omit wiring losses, which are generally negligible compared to power electronics conversion losses, such that in all cases .", "cite_spans": [{"start": 224, "end": 227, "text": "[7]", "ref_id": "BIBREF5"}, {"start": 313, "end": 316, "text": "(6)", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "Evaluated the whole-building impacts:", "text": "Given measured performance data and simulation data supplied by Bosch and from public sources, NREL generated best-fit empirical models for each system converter (Table 1 on following page). NREL scaled the converters to correspond to PV generation and connected load for each analysis case (see [2] for details).", "cite_spans": [{"start": 296, "end": 299, "text": "[2]", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Evaluated the whole-building impacts:", "text": "Given the scaled converter models for each analysis case, NREL computed the energy performance for the AC baseline and DCMG system types using the simulation data from the baseline building and PV models as inputs. This procedure yielded powers -for every hour of the year. (Fig. 4) . The DCMG performed well in all climates compared to the AC baseline. The improvement in PV utilization was slightly higher in cloudy climates because the DCMG reduces-or, in the unidirectional case, eliminates-inverter operation at inefficient part-load ratios. The DCMG performed best when the PV array size was well matched to the load. Unidirectional systems in which the PV array was oversized (nominally 125% of the load) had lower PV utilization due to occasional curtailment of surplus PV energy.", "cite_spans": [], "ref_spans": [{"start": 274, "end": 282, "text": "(Fig. 4)", "ref_id": "FIGREF2"}]}, {"section": "Evaluated the whole-building impacts:", "text": "For buildings that operate 5 days/week, however, PV curtailment during low load conditions (weekends) reduced DCMG performance significantly, particularly in sunny climates. For such buildings, the unidirectional DCMG decreases PV energy utilization by up to 20% compared to the AC case (Fig. 4) . The bidirectional DCMG still performs better than the AC baseline because it can export energy; however, the PV energy utilization improvement over baseline is reduced to 2%-5% because gateway inverter losses increase. Thus, without the addition of energy storage, the DCMG is not as well suited to buildings without continuous (7 days/week) operation. (Analysis of the impact of energy storage was outside the scope of the NREL study.)", "cite_spans": [], "ref_spans": [{"start": 287, "end": 295, "text": "(Fig. 4)", "ref_id": "FIGREF2"}]}, {"section": "Evaluated the whole-building impacts:", "text": "Because the lighting load interacts with heating, ventilation, and air-conditioning systems, whole-building energy impacts varied widely by climate zone and building type. For all building types, the DCMG used grid electricity slightly more efficiently than the baseline AC case. As a result, the DCMG reduced internal heat gains to the conditioned space, reducing cooling load (primarily electricity) but increasing heating load (primarily natural gas). In slightly fewer than half the analysis cases, the reduction in cooling energy exceeded the increase in heating energy, resulting in greater site energy savings than achieved by the DCMG alone. Since electricity is typically more expensive than natural gas, the DCMG can save money even in locations where net site energy savings are negligible.", "cite_spans": [], "ref_spans": []}, {"section": "Evaluated the whole-building impacts:", "text": "Site energy reductions were greatest in hot-humid climates (Fig. 5) . The supermarket building type had the greatest site electricity savings because the reduction in internal heat gains significantly reduced refrigeration load in addition to reducing cooling load; the open refrigerated cases in the supermarket model are highly sensitive to changes in space internal gains.", "cite_spans": [], "ref_spans": []}, {"section": "V. CONCLUSION", "text": "Bosch has developed a novel DC microgrid design that connects PV generation to DC loads with a minimal number of energy conversions, significantly increasing energy efficiency compared to a traditional AC system. NREL's simulation study of the DC microgrid concluded that it improves the percentage of PV energy that performs useful work to approximately 97% from a baseline value of 90%, with small variations in response to design parameters, operating conditions, and location.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Federal research and development agenda for net-zero energy, high-performance green buildings", "authors": [], "year": 2008, "venue": "", "link": null}, "BIBREF1": {"title": "Energy savings analysis for a novel DC microgrid platform for high bay lighting systems", "authors": [{"first": "S", "middle": [], "last": "Frank", "suffix": ""}, {"first": "E", "middle": [], "last": "Bonnema", "suffix": ""}, {"first": "J", "middle": [], "last": "Scheib", "suffix": ""}, {"first": "E", "middle": [], "last": "Wilson", "suffix": ""}], "year": 2015, "venue": "", "link": null}, "BIBREF2": {"title": "System Advisor Model Version", "authors": [], "year": 2014, "venue": "", "link": null}, "BIBREF4": {"title": "Department of Energy commercial reference building models of the national building stock", "authors": [{"first": "M", "middle": [], "last": "Deru", "suffix": ""}], "year": 2011, "venue": "", "link": null}, "BIBREF5": {"title": "Performance model for grid-connected photovoltaic inverters", "authors": [{"first": "D", "middle": ["L"], "last": "King", "suffix": ""}, {"first": "S", "middle": [], "last": "Gonzalez", "suffix": ""}, {"first": "G", "middle": ["M"], "last": "Galbraith", "suffix": ""}, {"first": "W", "middle": ["E"], "last": "Boyson", "suffix": ""}], "year": 2007, "venue": "", "link": "110271407"}, "BIBREF6": {"title": "Performance comparison map of site energy intensity (DC microgrid compared to AC baseline): warehouse, 6 a.m.-10 p.m. operation, 7 days/week, unidirectional DC microgrid", "authors": [], "year": "", "venue": "", "link": null}}, "ref_entries": {"FIGREF0": {"text": "Fig. 1. DC microgrid demonstration in Charlotte, North Carolina. Credit: Dusan Brhlik, Bosch", "type": "figure"}, "FIGREF1": {"text": "Fig. 3. Conceptual representation of a building electric power distribution network with local PV generation, DC load, and grid interconnection.", "type": "figure"}, "FIGREF2": {"text": "Fig. 4. Average changes in energy performance metrics: DC microgrid compared to AC baseline. Note differences in scale between buildings with 5 days/week operation and buildings with 7 days/week operation.", "type": "figure"}, "TABREF0": {"text": "building types: retail, supermarket, refrigerated warehouse, and nonrefrigerated warehouse. \uf0b7 Five operating schedules: 6 a.m.-10 p.m. 5 days/week, 6 a.m.-10 p.m. 7 days/week, 8 a.m.-8 p.m. 7 days/ week, 24 hours/day 5 days/week, and 24 hours/day 7 days/week. \uf0b7 Two DCMG types: unidirectional and bidirectional. \uf0b7 Five PV array sizes: 100%, 125%, 150%, 200%, and 250% of installed high bay lighting load capacity. \uf0b7 Five hundred fifty-four geographic locations: 544 in the contiguous United States and 10 in Hawaii.", "type": "table"}, "TABREF1": {"text": "SYSTEM CONVERTER MODELS AND NOMINAL EFFICIENCIESFor buildings that operate 7 days/week, the Bosch unidirectional DCMG improved annual PV energy utilization by approximately 6%-8% and reduced high bay lighting grid electricity consumption by approximately 0.1-0.3 kWh/ft", "type": "table"}}}
{"paper_id": "2871179", "_pdf_hash": "792fe4f2168f7604a5cc4b4eb33b3f6d79b77524", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Fiber Optical Parametric Amplifiers, Oscillators and Related Devices", "authors": [{"first": "M", "middle": [], "last": "Marhic", "suffix": ""}], "year": 2008, "venue": "", "link": "140112336"}, "BIBREF1": {"title": "In vivo three-photon microscopy of subcortical structures within an intact mouse brain", "authors": [{"first": "N", "middle": ["G"], "last": "Horton", "suffix": ""}, {"first": "K", "middle": [], "last": "Wang", "suffix": ""}, {"first": "D", "middle": [], "last": "Kobat", "suffix": ""}, {"first": "C", "middle": ["G"], "last": "Clark", "suffix": ""}, {"first": "F", "middle": ["W"], "last": "Wise", "suffix": ""}, {"first": "C", "middle": ["B"], "last": "Schaffer", "suffix": ""}, {"first": "C", "middle": [], "last": "Xu", "suffix": ""}], "year": 2013, "venue": "Nat. Photonics", "link": "121365416"}, "BIBREF2": {"title": "Near-infrared spectroscopic photoacoustic microscopy using a multi-color fiber laser source", "authors": [{"first": "T", "middle": [], "last": "Buma", "suffix": ""}, {"first": "B", "middle": ["C"], "last": "Wilkinson", "suffix": ""}, {"first": "T", "middle": ["C"], "last": "Sheehan", "suffix": ""}], "year": 2015, "venue": "Opt. Express", "link": "32543825"}, "BIBREF3": {"title": "2 \u00b5m laser sources and their possible applications", "authors": [{"first": "K", "middle": [], "last": "Scholle", "suffix": ""}, {"first": "S", "middle": [], "last": "Lamrini", "suffix": ""}, {"first": "P", "middle": [], "last": "Koopmann", "suffix": ""}, {"first": "P", "middle": [], "last": "Fuhrberg", "suffix": ""}], "year": 2010, "venue": "Frontiers in Guided Wave Optics and Optoelectronics, B. Pal", "link": "34638114"}, "BIBREF4": {"title": "Wide-bandtuning of the gain spectra of one-pump fiber optical parametric amplifiers", "authors": [{"first": "M", "middle": ["E"], "last": "Marhic", "suffix": ""}, {"first": "K", "middle": ["K Y"], "last": "Wong", "suffix": ""}, {"first": "L", "middle": ["G"], "last": "Kazovsky", "suffix": ""}], "year": 2004, "venue": "IEEE J. Sel. Topics Quantum Electron", "link": "20802607"}, "BIBREF5": {"title": "Dispersion-stabilized highly-nonlinear fiber for wideband parametric mixer synthesis", "authors": [{"first": "B", "middle": ["P P"], "last": "Kuo", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Fini", "suffix": ""}, {"first": "L", "middle": ["G"], "last": "Nielsen", "suffix": ""}, {"first": "S", "middle": [], "last": "Radic", "suffix": ""}], "year": 2012, "venue": "Opt. Express", "link": "2209662"}}, "ref_entries": {}}
{"paper_id": "2871295", "_pdf_hash": "07e17f9e9659103d3a7fa8c89948916ede429d43", "abstract": [{"section": "Abstract", "text": "A photosynthetic organism is subjected to photooxidative stress when more light energy is absorbed than is used in photosynthesis. In the light, highly reactive singlet oxygen can be produced via triplet chlorophyll formation in the reaction centre of photosystem II and in the antenna system. In the antenna, triplet chlorophyll is produced directly by excited singlet chlorophyll, while in the reaction centre it is formed via charge recombination of the light-induced charge pair. Changes of the mid-point potential of the primary quinone acceptor in photosystem II modulate the pathway of charge recombination in photosystem II and influence the yield of singlet oxygen production. Singlet oxygen can be quenched by b-carotene, a-tocopherol or can react with the D1 protein of photosystem II as target. If not completely quenched, it can specifically trigger the up-regulation of the expression of genes which are involved in the molecular defence response of plants against photo-oxidative stress.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Singlet oxygen", "text": "Living in an oxygen-rich world carries the potential risk of oxidative stress. Oxygen in the ground state is not directly a problem because it is relatively stable compared with its intermediates (peroxide (H 2 O 2 ), superoxide (O \u00ff 2 ) and hydroxyl radicals (OH )). The relatively stable ground state of oxygen is a triplet state with two unpaired electrons with the same spin quantum number, each located in different antibonding (p*) orbitals. Oxygen can react by oxidizing another molecule, but, despite its high thermodynamic reactivity, its reactions are kinetically slow because of the spin restriction. Electron transfer reactions in the presence of oxygen can give rise to the production of the reactive intermediates, which themselves can produce different kinds of damage in the cell (Halliwell and Gutteridge, 1998) .", "cite_spans": [{"start": 796, "end": 828, "text": "(Halliwell and Gutteridge, 1998)", "ref_id": "BIBREF17"}], "ref_spans": []}, {"section": "Singlet oxygen", "text": "In addition, the very reactive singlet oxygen can be generated by an input of energy. In this state, the spin restriction is removed and therefore the oxidizing ability of the oxygen is greatly increased. Singlet oxygen is produced by light absorption by photosensitizers and, in plants, particularly by the chlorophylls and their precursors. On the one hand chlorophylls are needed for the use of light energy in photosynthesis, on the other hand, the same molecules carry the potential danger of being a singlet oxygen producer (photosensitizer).", "cite_spans": [], "ref_spans": []}, {"section": "Singlet oxygen", "text": "1 O 2 has a short halftime of about 200 ns in cells (Gorman and Rodgers, 1992) , and reacts with target molecules in the immediate neighbourhood. The possible diffusion distance of 1 O 2 has been calculated to be up to 10 nm in a physiologically relevant situation (Sies and Menck, 1992) .", "cite_spans": [{"start": 52, "end": 78, "text": "(Gorman and Rodgers, 1992)", "ref_id": "BIBREF14"}, {"start": 265, "end": 287, "text": "(Sies and Menck, 1992)", "ref_id": "BIBREF62"}], "ref_spans": []}, {"section": "Singlet oxygen", "text": "In the following, the reactions leading to the production of 1 O 2 in the antenna and reaction centres of the photosynthetic apparatus, the potential target molecules and the protection mechanism avoiding 1 O 2 production, are described (Fig. 1 ). In addition, the 'useful' role of 1 O 2 will be discussed, being not only a damaging species but also an element of signal transduction chains leading to the specific expression of stress-related genes.", "cite_spans": [], "ref_spans": []}, {"section": "Special properties of chlorophyll", "text": "Chlorophyll as the main light-absorbing pigment in the lightharvesting complex, the inner antenna, and also in the reaction centres, is very efficient in absorbing light and has the additional advantage that the excited states are long-lived enough (up to a few nanoseconds) to allow the conversion of the excitation energy into an electrochemical potential via charge separation. If the energy is not efficiently used, the spins of the electrons in the excited state can rephase and give rise to a lower energy excited state: the chlorophyll triplet state. The chlorophyll triplet state has an even longer lifetime (a few ls under O 2 -saturated conditions) and can react with 3 O 2 to produce the very reactive 1 O 2 if no efficient quenchers are around. Chl triplet states may be populated in principle either directly by intersystem crossing (changing of the spin) from a singlet excited chlorophyll, or by charge recombination reactions (reversal of the charge separation and electron transfer reactions) in the reaction centres.", "cite_spans": [{"start": 678, "end": 679, "text": "3", "ref_id": "BIBREF26"}], "ref_spans": []}, {"section": "Special properties of chlorophyll", "text": "1 O 2 formation is favoured under certain physiological conditions like exposure to high light intensities or drought, leading to closure of the stomata and low CO 2 concentrations in the chloroplasts. Under such conditions the plastoquinone pool can be in a very reduced state, forward electron transport is very limited, and recombination reactions in PSII can occur. The kinetically limiting step of the photosynthetic electron transport chain is thought to be the quinol oxidation in the Q o site of the cytochrome b 6 f complex.", "cite_spans": [], "ref_spans": []}, {"section": "Special properties of chlorophyll", "text": "Quenching of chl triplet states and photoinhibition of PSII 1 O 2 can react with proteins, pigments, and lipids and is thought to be the most important species responsible for light-induced loss of PSII activity, the degradation of the D1 protein (protein of the reaction centre of PSII) and for pigment bleaching (for reviews on photoinhibition, see Prasil et al., 1992; Aro et al., 1993) .", "cite_spans": [{"start": 351, "end": 371, "text": "Prasil et al., 1992;", "ref_id": "BIBREF50"}, {"start": 372, "end": 389, "text": "Aro et al., 1993)", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "Special properties of chlorophyll", "text": "1 O 2 formation in vivo was measured in the leaves of Arabidopsis thaliana by the use of a fluorescent dye (Hideg et al., 2001; op den Camp et al., 2003) . Trebst and coworkers (Trebst et al., 2002) provided evidence that 1 O 2 is the important damaging species during photoinhibition (i.e. the light-induced loss of PSII activity and of the D1 protein) of Chlamydomonas reinhardtii cells.", "cite_spans": [{"start": 107, "end": 127, "text": "(Hideg et al., 2001;", "ref_id": "BIBREF20"}, {"start": 128, "end": 153, "text": "op den Camp et al., 2003)", "ref_id": "BIBREF47"}, {"start": 177, "end": 198, "text": "(Trebst et al., 2002)", "ref_id": "BIBREF67"}], "ref_spans": []}, {"section": "Special properties of chlorophyll", "text": "The dangerous triplet state of chlorophylls, which is the origin of the observed 1 O 2 , can be quenched directly by carotenoids in close proximity. The edge-to-edge distance between the two molecules must be less than the van der Waals distance (3.6 \u00c5 ), i.e. the electron orbitals must have some overlap. In this spin exchange reaction, the triplet state of the carotenoid is formed which can either dissipate the excess energy directly as heat or by physical quenching via enhanced intersystem crossing with 3 O 2 (Edge and Truscott, 1999) . This possibility is given in the antenna system, but not in the reaction centre, although two b-carotene molecules are present in the PSII reaction centre (Telfer, 2002;  for the location of the carotenes in the reaction centre, see Kamiya and Shen, 2003; Ferreira et al., 2004) . In the reaction centre, the distance between the carotenes and the triplet chlorophyll is too large to allow a direct triplet quenching. The redox potential of the redox couple P 680 /P 680 + is very positive and a too close contact to the carotene would lead to the efficient oxidation of the carotene. Hence the primary function of these b-carotenes is probably the quenching of 1 O 2 produced via the triplet state of P 680 (Telfer, 2002) . The latter was generated by charge recombination in PSII of the primary pair, P 680 Pheo. (Trebst, 2003) . Trebst et al. (2002) showed that inhibition of tocopherol biosynthesis in Chlamydomonas resulted in a stimulation of light-induced loss of PSII activity and D1 protein degradation. This implies that tocopherol comes close to the site of 1 O 2 generation in the reaction centre of PSII. If 1 O 2 produced via chl triplet formation in the reaction centre is not quenched by carotenoids or tocopherol, it is very probable that it reacts with the D1 protein as a target molecule. The rapid turnover of the D1 protein occurs even at low light intensities (Keren et al., 1995) , indicating that there is always some 1 O 2 formation even under low or moderate illumination. Singlet-oxygen-generating chemicals produce the same specific fragments of the D1 protein as are found under the conditions of acceptor side photoinhibition (Okada et al., 1996) . The degradation of the D1 protein may be regarded as a physiological defence system to prevent uncontrolled damage of PSII. The controlled destruction of the D1 protein seems to be an attractive safety valve to detoxify 1 O 2 directly at the place of its generation (Trebst, 2003) . Damaged D1 protein is degraded and PSII is repaired efficiently by the assembly of newly synthesized D1 in the so-called D1 protein damage-repair cycle (for reviews see Prasil et al., 1992; Aro et al., 1993) .", "cite_spans": [{"start": 511, "end": 512, "text": "3", "ref_id": "BIBREF26"}, {"start": 517, "end": 542, "text": "(Edge and Truscott, 1999)", "ref_id": "BIBREF10"}, {"start": 700, "end": 714, "text": "(Telfer, 2002;", "ref_id": "BIBREF66"}, {"start": 778, "end": 800, "text": "Kamiya and Shen, 2003;", "ref_id": "BIBREF24"}, {"start": 801, "end": 823, "text": "Ferreira et al., 2004)", "ref_id": "BIBREF11"}, {"start": 1253, "end": 1267, "text": "(Telfer, 2002)", "ref_id": "BIBREF66"}, {"start": 1360, "end": 1374, "text": "(Trebst, 2003)", "ref_id": "BIBREF68"}, {"start": 1377, "end": 1397, "text": "Trebst et al. (2002)", "ref_id": "BIBREF67"}, {"start": 1927, "end": 1947, "text": "(Keren et al., 1995)", "ref_id": "BIBREF27"}, {"start": 2201, "end": 2221, "text": "(Okada et al., 1996)", "ref_id": "BIBREF48"}, {"start": 2490, "end": 2504, "text": "(Trebst, 2003)", "ref_id": "BIBREF68"}, {"start": 2676, "end": 2696, "text": "Prasil et al., 1992;", "ref_id": "BIBREF50"}, {"start": 2697, "end": 2714, "text": "Aro et al., 1993)", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "Special properties of chlorophyll", "text": "With respect to photoinhibition studies, one has to differentiate between two experimental conditions chosen (Jegersch\u00f6ld et al., 1990; Blubaugh et al., 1991) and is not related to 1 O 2 production .", "cite_spans": [{"start": 109, "end": 135, "text": "(Jegersch\u00f6ld et al., 1990;", "ref_id": "BIBREF22"}, {"start": 136, "end": 158, "text": "Blubaugh et al., 1991)", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "Special properties of chlorophyll", "text": "Triplet chl formation by charge recombination in the reaction centre of PSII In the reaction centre of PSII, the first detectable radical pair formed after excitation by light is P 680 + Pheo \u00ff , with P 680 being the primary electron donor and pheophytin the primary electron acceptor (for a recent review on PSII see Goussias et al., 2002 ; for the X-ray structure of PSII, see Zouni et al., 2001; Kamiya and Shen, 2003; Ferreira et al., 2004) . In isolated PSII reaction centres which lack Q A and a functional donor side, the primary charge pair P 680 + Pheo \u00ff recombines and a high yield of P 680 triplet is formed (Durrant et al., 1990) . In the absence of oxygen, the lifetime of the triplet state is approximately 1 ms and shortens in the presence of O 2 to approximately 30 ls. This effect, and the decrease in the stability of the reaction centre and bleaching of chl, were considered to be indirect evidence for 1 O 2 formation (Durrant et al., 1990) . 1 O 2 formation was detected directly by its luminescence (Macpherson et al., 1993) and by EPR spin trapping (Hideg et al., 1994) .", "cite_spans": [{"start": 318, "end": 339, "text": "Goussias et al., 2002", "ref_id": "BIBREF15"}, {"start": 379, "end": 398, "text": "Zouni et al., 2001;", "ref_id": "BIBREF80"}, {"start": 399, "end": 421, "text": "Kamiya and Shen, 2003;", "ref_id": "BIBREF24"}, {"start": 422, "end": 444, "text": "Ferreira et al., 2004)", "ref_id": "BIBREF11"}, {"start": 619, "end": 641, "text": "(Durrant et al., 1990)", "ref_id": "BIBREF9"}, {"start": 938, "end": 960, "text": "(Durrant et al., 1990)", "ref_id": "BIBREF9"}, {"start": 1021, "end": 1046, "text": "(Macpherson et al., 1993)", "ref_id": "BIBREF40"}, {"start": 1072, "end": 1092, "text": "(Hideg et al., 1994)", "ref_id": "BIBREF18"}], "ref_spans": []}, {"section": "Special properties of chlorophyll", "text": "In isolated functional reaction centres possessing a complete and fuctional donor and acceptor side, the next step of electron transfer after the formation of the primary radical pair (P 680 + Pheo \u00ff ) leads to the reduction of the primary quinone acceptor Q A . Subsequently, P 680 + is reduced by electron donation from the redox active tyrosine Tyr Z , which itself obtains an electron from the water oxidizing complex. Forward electron transfer is much faster than charge recombination reactions. However, charge recombination reactions can occur when the forward electron transport cannot proceed. If the primary quinone acceptor stays reduced because of a block of the forward electron transport (the so-called closed state of the reaction centre), the yield of the primary charge separation is lowered. It has been proposed that the presence of the semiquinone anion Q A \u00ff in closed PSII may raise the energy of the primary pair by an electrostatic interaction so that the driving force of the primary charge separation is decreased compared with open reaction centres (state of the centre with the oxidized quinone, Q A ) (van Gorkom, 1985; Schatz et al., 1988) . In the closed reaction centre, however, if primary charge separation occurs, it is followed by recombination of the charges. Charge recombination in the primary pair will produce either the singlet ground state of P 680 or the triplet state of P 680 . The triplet state in the reaction centre is not localized directly on P 680 , i.e. the chlorophyll thought to bear the positive charge, but delocalized to another monomeric chlorophyll which is tilted by 308 compared with P 680 (van Mieghem et al., 1991; Kamlowski et al., 1996) . In the presence of a large antenna (PSII in vivo), the yield of the primary pair formed in the presence of Q A \u00ff will be low (van Mieghem et al., 1995) .", "cite_spans": [{"start": 1130, "end": 1148, "text": "(van Gorkom, 1985;", "ref_id": "BIBREF69"}, {"start": 1149, "end": 1169, "text": "Schatz et al., 1988)", "ref_id": "BIBREF57"}, {"start": 1652, "end": 1678, "text": "(van Mieghem et al., 1991;", "ref_id": "BIBREF72"}, {"start": 1679, "end": 1702, "text": "Kamlowski et al., 1996)", "ref_id": "BIBREF25"}, {"start": 1830, "end": 1856, "text": "(van Mieghem et al., 1995)", "ref_id": "BIBREF70"}], "ref_spans": []}, {"section": "Special properties of chlorophyll", "text": "Under reducing conditions, i.e. in the presence of dithionite and light (van Mieghem et al., 1989) or anaerobiosis and light (Vass et al., 1992) , Q A becomes doubly reduced, thereby releasing the negative electrostatic effect on the energy of the primary pair, and a high yield of charge separation, recombination, and P 680 triplet formation is observed (van Mieghem et al., 1989) . The double reduction of Q A and the high yield of 3 P 680 formation in such centres have been suggested to have some relevance to photoinhibition (van Mieghem et al., 1989; Vass et al., 1992) . The occurrence of double reduced Q A , however, has never been shown to occur under physiologically relevant conditions.", "cite_spans": [{"start": 72, "end": 98, "text": "(van Mieghem et al., 1989)", "ref_id": "BIBREF71"}, {"start": 125, "end": 144, "text": "(Vass et al., 1992)", "ref_id": "BIBREF73"}, {"start": 356, "end": 382, "text": "(van Mieghem et al., 1989)", "ref_id": "BIBREF71"}, {"start": 531, "end": 557, "text": "(van Mieghem et al., 1989;", "ref_id": "BIBREF71"}, {"start": 558, "end": 576, "text": "Vass et al., 1992)", "ref_id": "BIBREF73"}], "ref_spans": []}, {"section": "Special properties of chlorophyll", "text": "At cryogenic temperatures (around 20 K), different from the situation at ambient temperature, the primary radical pair is formed with a high yield, irrespective of the redox state of Q A and the yield of the triplet state 3 P 680 is high both with Q A \u00ff and Q A H 2 (van Mieghem et al., 1995) . The triplet decay is much faster with Q A \u00ff than with Q A H 2 present. At room temperature, the yield of the primary pair is reduced in the presence of Q A \u00ff , but nevertheless, a significant yield of the primary pair is found in core complexes of Synechococcus (about half of that found in reaction centres with double reduced Q A ) (Schlodder and Brettel, 1988; van Mieghem et al., 1995) . Significant amounts of singlet oxygen are produced in PSII with a large antenna under continuous illumination (Hideg et al., 1994; Fufezan et al., 2002) , and they are most likely linked to chl triplet formation by charge recombination of the primary pair in PSII and not to chl triplet formation in the antenna. The production of singlet oxygen via chl triplet formation by charge recombination reaction is shown by the following experiments: (i) the induction of photoinhibition by repetitive single turnover flashes and (ii) the effect of the mid-point potential of the redox couple Q A /Q A \u00ff on the yield of singlet oxygen production.", "cite_spans": [{"start": 266, "end": 292, "text": "(van Mieghem et al., 1995)", "ref_id": "BIBREF70"}, {"start": 629, "end": 658, "text": "(Schlodder and Brettel, 1988;", "ref_id": "BIBREF58"}, {"start": 659, "end": 684, "text": "van Mieghem et al., 1995)", "ref_id": "BIBREF70"}, {"start": 797, "end": 817, "text": "(Hideg et al., 1994;", "ref_id": "BIBREF18"}, {"start": 818, "end": 839, "text": "Fufezan et al., 2002)", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "Photoinhibition of PSII by repetitive flashes", "text": "If dark-adapted PSII is excited by one single turnover flash (a short saturating flash which leads to one charge separation event in the majority of reaction centres), the state S 2 Q B \u00ff is formed, with S 2 being an oxidation state of the Mn cluster, the water oxidizing complex, and Q B , the secondary quinone acceptor. In the dark, the charges recombine via the formation of the primary radical. As already described above, charge recombination of the primary radical pair leads to the production of the singlet and the triplet state of P 680 . The chl triplet state can react with formation of 1 O 2 which will damage the reaction centre. This flash-induced charge recombination reaction was exploited to investigate the mechanism of photoinhibition under low light in vivo (Keren et al., 1995) and in vitro (Keren et al., 1997) . Keren and coworkers used a series of single turnover flashes, spaced with a dark interval of 32 s, and measured the degree of photoinactivation and loss of the D1 protein. The dark interval is long enough to allow charge recombination between the S 2 or S 3 state and Q B \u00ff to occur (the half-time of S 2 Q B \u00ff recombination is approximately 20 s; Rutherford and Inoue, 1984) . When they used groups of flashes with 0.1 s spacing between the flashes in one group (for example, two flashes with 0.1 s interval and then 32 s dark interval), they observed photoinhibition after an uneven number of flashes per group and no or little photoinhibition after illumination with an even number of flashes per group. An even number of flashes produced the state S 3 Q B H 2 which does not recombine, while after an uneven number of flashes, charge recombination between the S 2 or S 3 state and Q B \u00ff occurs leading to singlet and triplet P 680 . This shows that an overall smaller number of flashes (less light absorption in total) can be more damaging than a greater number of flashes. This study was extended using Ca 2+ -depleted PSII preparations which were not active in water-splitting (Keren et al., 2000) . In Ca 2+ -depleted PSII, the Mn cluster is blocked in the S 3 state (for a review on Ca 2+ -depleted PSII see Debus, 1992) . In the single turnover flash experiments, the loss of PSII activity was measured and compared with active samples. No difference between groups of even and uneven numbers of flashes was seen in Ca 2+ -depleted material. Using an uneven number of flashes, the activity loss was much smaller than in active samples. The yield of primary charge separation was not significantly reduced in Ca 2+ -depleted PSII, even after several single turnover flashes (Keren et al., 2000) , implying that a difference in the charge recombination pathway must be responsible for this phenomenon.", "cite_spans": [{"start": 779, "end": 799, "text": "(Keren et al., 1995)", "ref_id": "BIBREF27"}, {"start": 813, "end": 833, "text": "(Keren et al., 1997)", "ref_id": "BIBREF28"}, {"start": 1184, "end": 1211, "text": "Rutherford and Inoue, 1984)", "ref_id": "BIBREF54"}, {"start": 2019, "end": 2039, "text": "(Keren et al., 2000)", "ref_id": "BIBREF29"}, {"start": 2152, "end": 2164, "text": "Debus, 1992)", "ref_id": "BIBREF7"}, {"start": 2618, "end": 2638, "text": "(Keren et al., 2000)", "ref_id": "BIBREF29"}], "ref_spans": []}, {"section": "Photoinhibition of PSII by repetitive flashes", "text": "Influence of the redox potential of the quinone acceptor on the yield of singlet oxygen formation", "cite_spans": [], "ref_spans": []}, {"section": "Photoinhibition of PSII by repetitive flashes", "text": "In Ca 2+ -and also in Mn-depleted PSII not only the watersplitting activity is inhibited but, in addition, the mid-point potential of the Q A /Q A \u00ff redox couple is up-shifted by about 150 mV. In PSII with an active water-splitting complex, the mid-point potential of the Q A /Q A \u00ff couple was found to be \u00ff80 mV (Krieger and Weis, 1992; Krieger et al., 1995) . In centres with the high potential form of Q A (E m about +65 mV), forward electron flow from Q A to Q B is energetically disfavoured and electron transfer is therefore unlikely to occur (Fig. 2) Krieger et al., 1995; Andr\u00e9asson et al., 1995) . It was proposed that, in such centres, the shift of the mid-point potential of Q A influences the pathway of charge recombination within the reaction centre of PSII. In active PSII, with Q A in its normal, low potential form, charge recombination between the acceptor and the donor side proceeds with a high probability via the formation of the primary pair (P 680 + Pheo \u00ff ), resulting in the formation of singlet and triplet P 680 . In centres with the high potential form of Q A , the formation of the primary pair is not disfavoured (Keren et al., 2000) and charge recombination may occur via an alternative pathway which does not involve the formation of excited chlorophyll species ( Fig. 3 ; see also Johnson et al., 1995; Rutherford and Krieger-Liszkay, 2001 ). As already described above, the loss of PSII activity after excitation by an uneven number of flashes was about 30% less in Ca 2+ -depleted PSII than in active PSII. In addition, no singlet oxygen production could be measured by spin trapping EPR with TEMP under continuous illumination . This shows that the change of the mid-point potential of Q A is an important molecular switch for changing the charge recombination pathway within PSII. By changing the midpoint potential of Q A from low to high potential, the formation of singlet oxygen can be avoided. This regulation mechanism of PSII may be of physiological importance. PSII is assembled without the Mn cluster and with Q A in the high potential form . In the light, during the so-called photoactivation process, the Mn cluster is assembled and the midpoint potential of Q A is switched from high potential to the low potential form, which allows linear electron flow. In the state prior to complete assembly of the functional watersplitting complex, PSII is protected against photodamage induced by 1 O 2 formation. Under high light conditions, the change of the mid-point potential of Q A may also be involved in the pH-dependent control of PSII activity. In addition to the dissipation of excess energy by the formation of zeaxanthin in the antenna (for a review see Demming-Adams, 1990) , the activity of the electron transfer can be altered at the level of the reaction centre of PSII (reaction centre quenching). When, in excess light, the pH in the lumen decreases below a certain threshold value, up to one Ca 2+ per PSII can be released and the mid-point potential of Q A is thereby switched to the high potential form (Krieger and Weis, 1992) . This was demonstrated in thylakoid membranes, in which a proton gradient was maintained by ATP-hydrolysis in the dark, by measuring the chlorophyll fluorescence at the F o -level at different redox potentials as a measure for the reduction state of Q A (Krieger and Weis, 1993) .", "cite_spans": [{"start": 313, "end": 337, "text": "(Krieger and Weis, 1992;", "ref_id": "BIBREF32"}, {"start": 338, "end": 359, "text": "Krieger et al., 1995)", "ref_id": "BIBREF34"}, {"start": 558, "end": 579, "text": "Krieger et al., 1995;", "ref_id": "BIBREF34"}, {"start": 580, "end": 604, "text": "Andr\u00e9asson et al., 1995)", "ref_id": "BIBREF1"}, {"start": 1144, "end": 1164, "text": "(Keren et al., 2000)", "ref_id": "BIBREF29"}, {"start": 1315, "end": 1336, "text": "Johnson et al., 1995;", "ref_id": "BIBREF23"}, {"start": 1337, "end": 1373, "text": "Rutherford and Krieger-Liszkay, 2001", "ref_id": "BIBREF55"}, {"start": 3065, "end": 3089, "text": "(Krieger and Weis, 1992)", "ref_id": "BIBREF32"}, {"start": 3345, "end": 3369, "text": "(Krieger and Weis, 1993)", "ref_id": "BIBREF33"}], "ref_spans": [{"start": 549, "end": 557, "text": "(Fig. 2)", "ref_id": "FIGREF0"}]}, {"section": "Photoinhibition of PSII by repetitive flashes", "text": "It is still unclear how the activity state of the watersplitting complex at the donor side is connected to the midpoint potential of the quinone at the acceptor side of PSII. One possibility is that, upon the release of Ca 2+ , a structural change in a protein subunit of the reaction centre and especially at the Q A binding site occurs, which could be responsible for the observed change in the mid-point potential. It might also be possible that cytochrome b 559 mediates between the donor and acceptor sides. In inactive and non-photoactivated PSII, cytochrome b 559 is in the low potential form and changes upon the assembly of the Mn to the high potential form, characteristic for the active PSII (for review, see Stewart and Brudvig, 1998) . The change of the potential form of cytochrome b 559 was already observed before the process of photoactivation was fully completed (Mizusawa et al., 1997) .", "cite_spans": [{"start": 720, "end": 746, "text": "Stewart and Brudvig, 1998)", "ref_id": "BIBREF63"}, {"start": 881, "end": 904, "text": "(Mizusawa et al., 1997)", "ref_id": "BIBREF43"}], "ref_spans": []}, {"section": "Influence of herbicides on the mid-point potential of Q A and on singlet oxygen production", "text": "The influence of different herbicides on the mid-point potentials of the primary quinone acceptor Q A (KriegerLiszkay and Rutherford, 1998) and single point mutations in D1 (Rappaport et al., 2002) or in D2 (Vavilin and Vermaas, 2000) can be used as a tool to investigate the charge recombination pathways in PSII. Binding of herbicides to the Q B binding site of the D1 protein inhibits linear electron flow and affects the degree of photoinactivation and lightinduced degradation of the D1 protein. In vitro, the urea herbicide DCMU and related herbicides have been reported to retard photodamage (Keren et al., 1995 (Keren et al., , 1997 Kirilovsky et al., 1994) and degradation of the D1 protein (Keren et al., 1995 (Keren et al., , 1997 Nakajima et al., 1996; Jansen et al., 1993; Zer and Ohad, 1995) . By contrast with DCMU, phenolic herbicides, which also bind to the Q B -binding site, have the opposite effect and stimulate the susceptibility of PSII to light (Pallett and Dodge, 1980; Nakajima et al., 1996) and the degradation of D1 (Jansen et al., 1993) . Binding of these herbicides to the Q B binding site influence the mid-point potential of Q A . Phenolic herbicides lower the mid-point potential by approximately 45 mV and DCMU raises it by about 50 mV (Krieger-Liszkay and Rutherford, 1998) . A smaller difference of 60 mV between the redox potential in the presence of bromoxynil and in the presence of DCMU was reported by Roberts et al. (2003) when estimated from the back reaction rate of S 2 Q A \u00ff . The effect of the different types of herbicide on the mid-point potential of Q A was not only observed for the low potential form but also for the high potential form of Q A (Krieger-Liszkay and Rutherford, 1998) . The absolute change in the mid-point potential of Q A by these herbicides was much lower (650 mV) than the shift induced by inactivation of the water-splitting complex (Ca 2+ -or Mn-depletion), but it has, nevertheless, a big effect Fig. 3 . Schematic diagram of the free energy levels of the states involved in recombination of the P + Q A \u00ff radical pair in PSII. The scheme shows the electron transfer reactions after illumination of a dark-adapted PSII. A series of radical pairs is formed, each with a slight loss of energy. The back reactions between these radical pairs require thermal activation and are thus thermodynamically disfavoured. It is assumed that the P 680 + Pheo \u00ff radical pair formed by back reaction from P 680 + Q A \u00ff is at a lower energy level than that formed initially from *P 680 presumably through some kind of relaxation process. When the P 680 + Pheo \u00ff radical is formed by the back reaction from the long-lived P + Q A \u00ff state, there is a high probability for the formation of a triplet state ) and the amount of 1 O 2 produced increases linearly with increasing light intensities. In bacterial reaction centres it has been shown that the free energy gap between the P + Q A \u00ff radical pair and the P + BPheo \u00ff radical pair has a major influence on the back reaction pathway (Gunner et al., 1982; Gopher et al., 1985; Woodbury et al., 1986; Shopes and Wraight, 1987) . When the gap is smaller than 400 meV, the back reaction via the primary pair (P + BPheo \u00ff ) dominates, while under conditions where the gap is greater than this value, a direct recombination pathway dominates (P + Q A \u00ff !PQ A ). This direct recombination pathway involves electron tunnelling reactions. Based on these observations made with the bacterial reaction centre a model was proposed (Fig. 3) showing the influence of the mid-point potential of Q A on the charge recombination pathway within PSII (KriegerLiszkay and Rutherford, 1998; Rutherford and KriegerLiszkay, 2001 ). It seems likely that the modulation of the mid-point potential of Q A by the state of the water-splitting complex and by the herbicides will influence the free energy gap between P 680 + Q A \u00ff and P 680 + Pheo \u00ff . With DCMU it is predicted that the increase in the mid-point potential should increase the free energy gap and thereby diminish the yield of back reaction via the P 680 + Pheo \u00ff radical pair. By analogy to the bacterial reaction centre a direct recombination via P 680 + Q A \u00ff may take place which does not result in the formation of excited singlet or triplet states of P 680 . This model may explain the lower production of 1 O 2 observed in the presence of DCMU in centres with low potential Q A (Fufezan et al., 2002) and the absence of 1 O 2 formation in PSII with high potential Q A .", "cite_spans": [{"start": 173, "end": 197, "text": "(Rappaport et al., 2002)", "ref_id": "BIBREF51"}, {"start": 207, "end": 234, "text": "(Vavilin and Vermaas, 2000)", "ref_id": "BIBREF74"}, {"start": 599, "end": 618, "text": "(Keren et al., 1995", "ref_id": "BIBREF27"}, {"start": 619, "end": 640, "text": "(Keren et al., , 1997", "ref_id": "BIBREF28"}, {"start": 641, "end": 665, "text": "Kirilovsky et al., 1994)", "ref_id": "BIBREF30"}, {"start": 700, "end": 719, "text": "(Keren et al., 1995", "ref_id": "BIBREF27"}, {"start": 720, "end": 741, "text": "(Keren et al., , 1997", "ref_id": "BIBREF28"}, {"start": 742, "end": 764, "text": "Nakajima et al., 1996;", "ref_id": "BIBREF46"}, {"start": 765, "end": 785, "text": "Jansen et al., 1993;", "ref_id": "BIBREF21"}, {"start": 786, "end": 805, "text": "Zer and Ohad, 1995)", "ref_id": "BIBREF78"}, {"start": 995, "end": 1017, "text": "Nakajima et al., 1996)", "ref_id": "BIBREF46"}, {"start": 1044, "end": 1065, "text": "(Jansen et al., 1993)", "ref_id": "BIBREF21"}, {"start": 1270, "end": 1308, "text": "(Krieger-Liszkay and Rutherford, 1998)", "ref_id": "BIBREF36"}, {"start": 1443, "end": 1464, "text": "Roberts et al. (2003)", "ref_id": "BIBREF52"}, {"start": 1697, "end": 1735, "text": "(Krieger-Liszkay and Rutherford, 1998)", "ref_id": "BIBREF36"}, {"start": 3043, "end": 3064, "text": "(Gunner et al., 1982;", "ref_id": "BIBREF16"}, {"start": 3065, "end": 3085, "text": "Gopher et al., 1985;", "ref_id": "BIBREF13"}, {"start": 3086, "end": 3108, "text": "Woodbury et al., 1986;", "ref_id": "BIBREF76"}, {"start": 3109, "end": 3134, "text": "Shopes and Wraight, 1987)", "ref_id": "BIBREF61"}, {"start": 4432, "end": 4454, "text": "(Fufezan et al., 2002)", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "Influence of herbicides on the mid-point potential of Q A and on singlet oxygen production", "text": "On the other hand, the decreased mid-point potential of Q A induced by phenolic herbicides should make the energy gap between P 680 + Q A \u00ff and P 680 + Pheo \u00ff smaller and, therefore, the back reaction via the primary radical pair and the formation of P 680 triplet more likely. Rappaport et al. (2002) investigated the influence of the mid-point potential of the Pheo/Pheo \u00ff redox couple on charge recombination between S 2 Q A \u00ff and showed that the recombination rate is sensitive to the free energy gap between Pheo and Q A . They used mutants of Synechocystis, in which the mid-point potential of Pheo/Pheo \u00ff was shifted by +33 mV or \u00ff74 mV compared with the wild type. The mutant with the potential shift of +33 mV showed an increase in the recombination rate (P 680 + Q A \u00ff ) by a factor of four (measured as the decay of fluorescence after a saturating flash), while lowering of the mid-point potential slowed down the recombination by the same factor. This demonstrates that charge recombination via the formation of the primary radical pair (P 680 + Pheo \u00ff ) is a significant process in PSII reaction centres in which forward electron flow is blocked. In addition they demonstrated that the direct charge recombination pathway which does not involve the repopulation of the primary pair is significant in the mutant with the lowered mid-point potential of Pheo/ Pheo \u00ff . In a different set of experiments, mutations in the CD loop of the D2 protein were made in Synechocystis (Vavilin and Vermaas, 2000) . These mutants show a temperature shift and a decrease in intensity in the thermoluminescence band originating from S 2 Q A \u00ff recombination. This was interpreted as an increase of the proportion of the direct recombination pathway of the P 680 + Q A \u00ff pair which does not lead to the formation of an excited chlorophyll.", "cite_spans": [{"start": 278, "end": 301, "text": "Rappaport et al. (2002)", "ref_id": "BIBREF51"}, {"start": 1484, "end": 1511, "text": "(Vavilin and Vermaas, 2000)", "ref_id": "BIBREF74"}], "ref_spans": []}, {"section": "Influence of herbicides on the mid-point potential of Q A and on singlet oxygen production", "text": "Charge recombination and chl triplet formation in the reaction centre of PSI In PSI, under reducing conditions when the iron sulphur clusters are prereduced or when vitamin K1 is removed from the reaction centre, charge recombination reactions also occur leading to the triplet state of P 700 at room temperature (for a review see Brettel, 1997) . In PSI, the lifetime of the state 3 P 700 is about 6 ls and is not shortened by 3 O 2 , indicating that P 700 is screened from O 2 (S\u00e9tif et al., 1981) . (Suh et al., 2000) . It was shown by Suh et al. (2000) that the Fe-S cluster of the Rieske protein and not the cytochromes are responsible for the 1 O 2 production in the light. The extent to which 1 O 2 generated by the cytochrome b 6 f complex contributes to photoinhibition of PSII is unclear. The cytochrome b 6 f complex contains, in addition to the other cofactors, one chlorophyll with an unknown function. In principle, this chlorophyll could also be involved in 1 O 2 formation acting as a photosensitizer.", "cite_spans": [{"start": 331, "end": 345, "text": "Brettel, 1997)", "ref_id": "BIBREF5"}, {"start": 428, "end": 429, "text": "3", "ref_id": "BIBREF26"}, {"start": 502, "end": 520, "text": "(Suh et al., 2000)", "ref_id": "BIBREF65"}, {"start": 539, "end": 556, "text": "Suh et al. (2000)", "ref_id": "BIBREF65"}], "ref_spans": []}, {"section": "Chlorophyll triplet and singlet oxygen production in the antenna", "text": "Chlorophyll triplet states and consecutive 1 centre, but also by intersystem crossing from a singlet excited chlorophyll in the antenna. In addition, excited states of chlorophyll precursors can lead to the formation of 1 O 2 . In isolated protein/pigment complexes, the rate of intersystem crossing is significant (Kramer and Mathis, 1980) and the formation of triplet chlorophylls in the antenna has been shown in vitro. These states can be distinguished by their spectroscopic characteristics from the triplet chlorophyll in the reaction centre and they do not depend on the redox potential of the medium (Santabarbara et al., 2002) . Two of these triplet states are probably generated in the core complex while the third one may be generated in the light-harvesting complex (Santabarbara et al., 2002) . Formation of 1 O 2 from isolated LHCII has been shown in vitro by spin trapping with TEMP (Rinalducci et al., 2004) . Singlet oxygen may also play a role in the degradation of light-harvesting proteins. The degradation of LHCII is much slower than the degradation of the D1 protein (Lindahl et al., 1995) , but modifications of the protein are already visible after a few hours of low intensity illumination (100 lmol quanta m \u00ff2 s \u00ff1 ) in the isolated complex (Zolla and Rinalducci, 2002) . Degradation of LHCII releases a large number of chl. Light-induced damage might occur from such chl which is energetically uncoupled from the antenna, and will give a high triplet chl and, therefore, possibly high 1 O 2 yield. However, experimental evidence for the production of 1 O 2 by triplet formation in the antenna and their involvement in the light-induced damage in PSII in vivo in mature leaves is still missing. In the antenna 3 chl will be efficiently quenched by nearby carotenoids, so that 3 chl, although formed with a higher probability than by charge recombination in the reaction centre, will rarely be a problem.", "cite_spans": [{"start": 315, "end": 340, "text": "(Kramer and Mathis, 1980)", "ref_id": "BIBREF31"}, {"start": 608, "end": 635, "text": "(Santabarbara et al., 2002)", "ref_id": "BIBREF56"}, {"start": 778, "end": 805, "text": "(Santabarbara et al., 2002)", "ref_id": "BIBREF56"}, {"start": 898, "end": 923, "text": "(Rinalducci et al., 2004)", "ref_id": "BIBREF53"}, {"start": 1090, "end": 1112, "text": "(Lindahl et al., 1995)", "ref_id": "BIBREF38"}, {"start": 1269, "end": 1297, "text": "(Zolla and Rinalducci, 2002)", "ref_id": "BIBREF79"}], "ref_spans": []}, {"section": "Chlorophyll triplet and singlet oxygen production in the antenna", "text": "Production of triplet chlorophyll and 1 O 2 may play a role during the transition from etioplasts to chloroplasts. In greening material, disorganized chlorophyll may act as a photosensitizer (Marder et al., 1998) . Oxygen uptake by thylakoid membranes, isolated from greening material, was measured. Oxygen uptake was significantly quenched by b-carotene and a-tocopherol, indicating that production of singlet oxygen was measured by this method (Caspi et al., 2000) . Protochlorophyllide acts also as photosensitizer, as shown for the Arabidopsis mutant flu (op den Camp et al., 2003) . In this mutant, a protein is inactivated which plays a key role during the negative feedback control of chlorophyll biosynthesis. As a consequence, the mutant accumulates free protochlorophyllide in the dark. In this study, the production of 1 O 2 was shown in leaves by quenching of the fluorescent dye DanePy in vivo after a dark-light transition of the plants op den Camp et al., 2003) . It was also shown previously, by the use of herbicides which block the protoporphyrinogen oxidase, that protoporphyrin IX is a photodynamic pigment which produces high amounts of 1 O 2 in the light (Becerril and Duke, 1989) . 1 O 2 may also be produced by free chlorophyll and chlorophyll degradation products which may be produced during strong photoinhibition. If the light-induced damage exceeds the controlled D1 degradation and repair of PSII, further protein degradation of chl binding subunits may lead to the production of free chls, which are dangerous photosensitizers. These free chls may be bound by ELIP (Early Light Induced Proteins) proteins (Adamska, 1997) or by proteins like WSCP (Water Soluble Chlorophyll Protein) (Schmidt et al., 2003) . The binding of chl to the WSCP reduces the yield of 1 O 2 production by a yet unknown mechanism. This protein is an unusual chl-binding protein in the sense that it does not bind carotenoids, but, nevertheless, efficiently protects bound chl against photodegradation and reduces the yield of O 2 is produced peripherally at the membrane surface and can, therefore, react with compounds of the stroma. Under natural conditions, 1 O 2 will be produced within the reaction centre of PSII and will react with different target molecules than in this mutant. Fischer, however, using inhibitors of the photosynthetic electron transport, studied 1 O 2 formation in PSII and only found a significant up-regulation of the glutathione peroxidase homologous gene from Chlamydomonas (B Fischer, personal communication).", "cite_spans": [{"start": 191, "end": 212, "text": "(Marder et al., 1998)", "ref_id": "BIBREF41"}, {"start": 446, "end": 466, "text": "(Caspi et al., 2000)", "ref_id": "BIBREF6"}, {"start": 567, "end": 585, "text": "Camp et al., 2003)", "ref_id": "BIBREF47"}, {"start": 951, "end": 976, "text": "op den Camp et al., 2003)", "ref_id": "BIBREF47"}, {"start": 1177, "end": 1202, "text": "(Becerril and Duke, 1989)", "ref_id": "BIBREF3"}, {"start": 1636, "end": 1651, "text": "(Adamska, 1997)", "ref_id": "BIBREF0"}, {"start": 1713, "end": 1735, "text": "(Schmidt et al., 2003)", "ref_id": "BIBREF59"}], "ref_spans": []}, {"section": "Chlorophyll triplet and singlet oxygen production in the antenna", "text": "The question arises how an extremely short-lived molecule like 1 O 2 can give rise to a signal that can be transmitted to the nucleus to regulate gene expression. Some other reactive oxygen species like superoxide or peroxide have been shown to act directly as second messengers in the regulation of expression of the oxidative stress response genes such as gutathione peroxidases, glutathione-S-transferases, and ascorbate peroxidase (for reviews see Mullineaux et al., 2000; Vranov\u00e1 et al., 2002) . Because of the short lifetime of it oxidizes a component of a signal transduction chain directly. Instead reaction products originating either from the D1 protein degradation or products of chlorophyll degradation can be envisaged as signal molecules. It has been shown that chlorophyll precursors like Mg-protoporphyrin IX can act as a signalling molecule in a signalling pathway between the chloroplasts and the nucleus (Strand et al., 2003) . By analogy, one can also speculate that a chlorophyll degradation product such as pheophytin, chlorophyllide, or pheophorbide (for chl degradation, see Matile et al., 1999) may act as a signalling molecule. Such a molecule could be transported out of the chloroplast to the cytosol by an ABC protein where it mediates a signal to the nucleus to regulate the expression of genes. It has been shown that a functional ABC protein is required for the transport of protophorhyrin IX (M\u00f8ller et al., 2001) . It was also shown that an ABC transporter in the tonoplast membrane can transport chlorophyll catabolites to the vacuole (Lu et al., 1998) , making it likely that such a transport mechanism is also present in the chloroplast envelope membrane.", "cite_spans": [{"start": 452, "end": 476, "text": "Mullineaux et al., 2000;", "ref_id": "BIBREF45"}, {"start": 477, "end": 498, "text": "Vranov\u00e1 et al., 2002)", "ref_id": "BIBREF75"}, {"start": 923, "end": 944, "text": "(Strand et al., 2003)", "ref_id": "BIBREF64"}, {"start": 1099, "end": 1119, "text": "Matile et al., 1999)", "ref_id": "BIBREF42"}, {"start": 1425, "end": 1446, "text": "(M\u00f8ller et al., 2001)", "ref_id": "BIBREF44"}, {"start": 1570, "end": 1587, "text": "(Lu et al., 1998)", "ref_id": "BIBREF39"}], "ref_spans": []}, {"section": "Chlorophyll triplet and singlet oxygen production in the antenna", "text": "Alternatively, lipid peroxides may function as signalling molecules because unsaturated fatty acids are the preferred targets of 1 O 2 . However, no increase in 1 O 2 -mediated nonenzymatic lipid peroxidation could be found in the flu mutant, which accumulates protochlorophyllide and shows a higher yield of 1 O 2 formation than wild-type plants (Op den Camp et al., 2003) . Linolenic acid was rapidely oxidized upon illumination of the flu mutant, but the oxidation patterns observed were indicative for enzymatic oxidation and not for non-enzymatic oxidation by 1 O 2 . In general, fatty acid-derived signals may be involved in signalling pathways connected with cell death and the expression of stress-related genes (Weber, 2002) .", "cite_spans": [{"start": 347, "end": 373, "text": "(Op den Camp et al., 2003)", "ref_id": "BIBREF47"}, {"start": 720, "end": 733, "text": "(Weber, 2002)", "ref_id": "BIBREF77"}], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "ELIPs-light induced stress proteins", "authors": [{"first": "I", "middle": [], "last": "Adamska", "suffix": ""}], "year": 1997, "venue": "Physiologia Plantarum", "link": "85090630"}, "BIBREF1": {"title": "Ca 2+ -depletion modifies the electron transfer on both donor and acceptor sides in photosystem II from spinach", "authors": [{"first": "L", "middle": ["E"], "last": "Andr\u00e9asson", "suffix": ""}, {"first": "I", "middle": [], "last": "Vass", "suffix": ""}, {"first": "S", "middle": [], "last": "Styring", "suffix": ""}], "year": 1995, "venue": "Biochimica et Biophysica Acta", "link": "84154852"}, "BIBREF2": {"title": "Photoinhibition of photosystem II. inactivation, protein damage and turnover", "authors": [{"first": "E", "middle": ["M"], "last": "Aro", "suffix": ""}, {"first": "I", "middle": [], "last": "Virgin", "suffix": ""}, {"first": "B", "middle": [], "last": "Andersson", "suffix": ""}], "year": 1993, "venue": "Biochimica et Biophysica Acta", "link": "2014803"}, "BIBREF3": {"title": "Protoporphyrin IX content correlates with activity of photobleaching herbicides", "authors": [{"first": "J", "middle": ["M"], "last": "Becerril", "suffix": ""}, {"first": "S", "middle": ["O"], "last": "Duke", "suffix": ""}], "year": 1989, "venue": "Plant Physiology", "link": "132552"}, "BIBREF4": {"title": "Photoinhibition of hydroxylamine-extracted photosystem II membranes: identification of the sites of photodamage", "authors": [{"first": "D", "middle": ["J"], "last": "Blubaugh", "suffix": ""}, {"first": "M", "middle": [], "last": "Atamian", "suffix": ""}, {"first": "G", "middle": ["T"], "last": "Babcock", "suffix": ""}, {"first": "J", "middle": ["H"], "last": "Golbeck", "suffix": ""}, {"first": "G", "middle": ["M"], "last": "Cheniae", "suffix": ""}], "year": 1991, "venue": "Biochemistry", "link": "21773686"}, "BIBREF5": {"title": "Electron transfer and arrangement of the redox factors in photosystem I", "authors": [{"first": "K", "middle": [], "last": "Brettel", "suffix": ""}], "year": 1997, "venue": "Biochimica et Biophysica Acta", "link": "93731271"}, "BIBREF6": {"title": "Oxygen uptake photosensitized by disorganized chlorophyll in model systems and thylakoids of greening barley", "authors": [{"first": "V", "middle": [], "last": "Caspi", "suffix": ""}, {"first": "S", "middle": [], "last": "Malkin", "suffix": ""}, {"first": "J", "middle": ["B"], "last": "Marder", "suffix": ""}], "year": 2000, "venue": "Photochemistry and Photobiology", "link": "9522914"}, "BIBREF7": {"title": "The manganese and calcium ions of photosynthetic oxygen evolution", "authors": [{"first": "R", "middle": ["J"], "last": "Debus", "suffix": ""}], "year": 1992, "venue": "Biochimica et Biophysica Acta", "link": "7976715"}, "BIBREF8": {"title": "Carotenoids and photoprotection in plants: a role for the xanthophyll zeaxanthin", "authors": [{"first": "B", "middle": [], "last": "Demmig-Adams", "suffix": ""}], "year": 1990, "venue": "Biochimica et Biophysica Acta", "link": null}, "BIBREF9": {"title": "Characterization of triplet-states in isolated photosystem II reaction centres-oxygen quenching as a mechanism for photodamage", "authors": [{"first": "J", "middle": ["R"], "last": "Durrant", "suffix": ""}, {"first": "L", "middle": ["B"], "last": "Giorgi", "suffix": ""}, {"first": "J", "middle": [], "last": "Barber", "suffix": ""}, {"first": "D", "middle": ["R"], "last": "Klug", "suffix": ""}, {"first": "G", "middle": [], "last": "Porter", "suffix": ""}], "year": 1990, "venue": "Biochimica et Biophysica Acta", "link": "94923871"}, "BIBREF10": {"title": "Carotenoid radicals and the interaction of carotenoids with active oxygen species", "authors": [{"first": "R", "middle": [], "last": "Edge", "suffix": ""}, {"first": "T", "middle": ["G"], "last": "Truscott", "suffix": ""}], "year": 1999, "venue": "Advances in photosynthesis: the photochemistry of carotenoids", "link": "92347033"}, "BIBREF11": {"title": "Architecture of the photosynthetic oxygen-evolving center", "authors": [{"first": "K", "middle": ["N"], "last": "Ferreira", "suffix": ""}, {"first": "T", "middle": ["M"], "last": "Iverson", "suffix": ""}, {"first": "K", "middle": [], "last": "Maghlaoui", "suffix": ""}, {"first": "J", "middle": [], "last": "Barber", "suffix": ""}, {"first": "S", "middle": [], "last": "Iwata", "suffix": ""}], "year": 2004, "venue": "Science", "link": "31521054"}, "BIBREF12": {"title": "Singlet oxygen production in herbicide-treated photosystem II", "authors": [{"first": "C", "middle": [], "last": "Fufezan", "suffix": ""}, {"first": "A", "middle": ["W"], "last": "Rutherford", "suffix": ""}, {"first": "A", "middle": [], "last": "Krieger-Liszkay", "suffix": ""}], "year": 2002, "venue": "FEBS Letters", "link": "46157018"}, "BIBREF13": {"title": "The effect of an applied electric field on the charge recombination kinetics in reaction centers reconstituted in planar bilayers", "authors": [{"first": "Y", "middle": [], "last": "Gopher", "suffix": ""}, {"first": "A", "middle": [], "last": "Blatt", "suffix": ""}, {"first": "M", "middle": [], "last": "Schonfeld", "suffix": ""}, {"first": "M", "middle": ["Y"], "last": "Okamura", "suffix": ""}, {"first": "G", "middle": [], "last": "Feher", "suffix": ""}, {"first": "M", "middle": [], "last": "Montal", "suffix": ""}], "year": 1985, "venue": "Biophysical Journal", "link": "23650997"}, "BIBREF14": {"title": "Current perspectives of singlet oxygen detection in biological environments", "authors": [{"first": "A", "middle": ["A"], "last": "Gorman", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Rodgers", "suffix": ""}], "year": 1992, "venue": "Journal of Photochemistry and Photobiology", "link": "36433687"}, "BIBREF15": {"title": "Photosystem II and photosynthetic oxidation of water: an overview. Philosophical Transactions of the Royal Society of London B", "authors": [{"first": "C", "middle": [], "last": "Goussias", "suffix": ""}, {"first": "A", "middle": [], "last": "Boussac", "suffix": ""}, {"first": "A", "middle": ["W"], "last": "Rutherford", "suffix": ""}], "year": 2002, "venue": "", "link": null}, "BIBREF16": {"title": "Quinones as prosthetic groups in membrane electron transfer proteins. Systematic replacement of the primary ubiquinone of photochemical reaction centers with other quinones", "authors": [{"first": "M", "middle": ["R"], "last": "Gunner", "suffix": ""}, {"first": "D", "middle": ["M"], "last": "Tiede", "suffix": ""}, {"first": "R", "middle": ["C"], "last": "Prince", "suffix": ""}, {"first": "P", "middle": ["L"], "last": "Dutton", "suffix": ""}], "year": 1982, "venue": "", "link": "99051804"}, "BIBREF17": {"title": "Free radicals in biology and medicine", "authors": [{"first": "B", "middle": [], "last": "Halliwell", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Gutteridge", "suffix": ""}], "year": 1998, "venue": "", "link": "84436692"}, "BIBREF18": {"title": "Singlet oxygen production in thylakoid membranes during photoinhibition as detected by EPR spectroscopy", "authors": [{"first": "E", "middle": [], "last": "Hideg", "suffix": ""}, {"first": "C", "middle": [], "last": "Spetea", "suffix": ""}, {"first": "I", "middle": [], "last": "Vass", "suffix": ""}], "year": 1994, "venue": "Photosynthesis Research", "link": "11942248"}, "BIBREF19": {"title": "Photoinhibition of photosynthesis in vivo results in singlet oxygen production: detection via nitroxide-induced fluorescence quenching in broad bean leaves", "authors": [{"first": "E", "middle": [], "last": "Hideg", "suffix": ""}, {"first": "T", "middle": [], "last": "Kalai", "suffix": ""}, {"first": "K", "middle": [], "last": "Hideg", "suffix": ""}, {"first": "I", "middle": [], "last": "Vass", "suffix": ""}], "year": 1998, "venue": "Biochemistry", "link": "11990886"}, "BIBREF20": {"title": "Singlet oxygen imaging in Arabidopsis thaliana leaves under photoinhibition by excess photosynthetically active radiation", "authors": [{"first": "E", "middle": ["E"], "last": "Hideg", "suffix": ""}, {"first": "K", "middle": [], "last": "Ogawa", "suffix": ""}, {"first": "T", "middle": [], "last": "Kalai", "suffix": ""}, {"first": "K", "middle": [], "last": "Hideg", "suffix": ""}], "year": 2001, "venue": "Physiologia Plantarum", "link": "28273807"}, "BIBREF21": {"title": "Engagement of specific sites in the plastoquinone niche regulates degradation of the D1 protein in photosystem II", "authors": [{"first": "M", "middle": ["A"], "last": "Jansen", "suffix": ""}, {"first": "B", "middle": [], "last": "Depka", "suffix": ""}, {"first": "A", "middle": [], "last": "Trebst", "suffix": ""}, {"first": "M", "middle": [], "last": "Edelman", "suffix": ""}], "year": 1993, "venue": "Journal of Biological Chemistry", "link": "28824413"}, "BIBREF22": {"title": "Light-dependent degradation of the D1 protein in photosystem II is acceleerated after inhibition of the water-splitting reaction", "authors": [{"first": "C", "middle": [], "last": "Jegersch\u00f6ld", "suffix": ""}, {"first": "I", "middle": [], "last": "Virgin", "suffix": ""}, {"first": "S", "middle": [], "last": "Styring", "suffix": ""}], "year": 1990, "venue": "Biochemistry", "link": "19695835"}, "BIBREF23": {"title": "A change in the mid-point potential of the quinone Q A in photosystem II associated with photoactivation of oxygen evolution", "authors": [{"first": "G", "middle": ["N"], "last": "Johnson", "suffix": ""}, {"first": "A", "middle": ["W"], "last": "Rutherford", "suffix": ""}, {"first": "A", "middle": [], "last": "Krieger", "suffix": ""}], "year": 1995, "venue": "Biochimica et Biophysica Acta", "link": "85070818"}, "BIBREF24": {"title": "Crystal structure of oxygen-evolving photosystem II from Thermosynechococcus vulcanus at 3.7 \u00c5 resolution", "authors": [{"first": "N", "middle": [], "last": "Kamiya", "suffix": ""}, {"first": "J", "middle": ["R"], "last": "Shen", "suffix": ""}], "year": 2003, "venue": "Proceedings of the National Academy of Sciences", "link": "21427119"}, "BIBREF25": {"title": "Evidence for the delocalization of the triplet state", "authors": [{"first": "A", "middle": [], "last": "Kamlowski", "suffix": ""}, {"first": "I", "middle": [], "last": "Frankem\u00f6ller", "suffix": ""}, {"first": "A", "middle": [], "last": "Van Der Est", "suffix": ""}, {"first": "D", "middle": [], "last": "Stehlik", "suffix": ""}, {"first": "A", "middle": ["R"], "last": "Holzwarth", "suffix": ""}], "year": 1996, "venue": "", "link": null}, "BIBREF26": {"title": "P 680 in the D 1 D 2 cytb 559 -complex of photosystem II", "authors": [], "year": "", "venue": "Berichte der Bunsen Gesellschaft", "link": null}, "BIBREF27": {"title": "Oscillations of reaction centre II-D1 protein degradation in vivo induced by repetitive flashes", "authors": [{"first": "N", "middle": [], "last": "Keren", "suffix": ""}, {"first": "H", "middle": [], "last": "Gong", "suffix": ""}, {"first": "I", "middle": [], "last": "Ohad", "suffix": ""}], "year": 1995, "venue": "Journal of Biological Chemistry", "link": null}, "BIBREF28": {"title": "Mechanism of photosystem II inactivation and D1 protein degradation at low light intensities: the role of electron back flow", "authors": [{"first": "N", "middle": [], "last": "Keren", "suffix": ""}, {"first": "A", "middle": [], "last": "Berg", "suffix": ""}, {"first": "Pjm", "middle": [], "last": "Van Kan", "suffix": ""}, {"first": "H", "middle": [], "last": "Levanon", "suffix": ""}, {"first": "I", "middle": [], "last": "Ohad", "suffix": ""}], "year": 1997, "venue": "Proceedings of the National Academy of Sciences", "link": null}, "BIBREF29": {"title": "Inhibition of photosystem II activity by saturating single turnover flashes in calcium-depleted and active photosystem II", "authors": [{"first": "N", "middle": [], "last": "Keren", "suffix": ""}, {"first": "I", "middle": [], "last": "Ohad", "suffix": ""}, {"first": "A", "middle": ["W"], "last": "Rutherford", "suffix": ""}, {"first": "F", "middle": [], "last": "Drepper", "suffix": ""}, {"first": "A", "middle": [], "last": "Krieger-Liszkay", "suffix": ""}], "year": 2000, "venue": "Photosynthesis Research", "link": "22967145"}, "BIBREF30": {"title": "Influence of DCMU and ferricyanide on photodamage in photosystem II", "authors": [{"first": "D", "middle": [], "last": "Kirilovsky", "suffix": ""}, {"first": "A", "middle": ["W"], "last": "Rutherford", "suffix": ""}, {"first": "A", "middle": ["L"], "last": "Etienne", "suffix": ""}], "year": 1994, "venue": "Biochemistry", "link": "43739306"}, "BIBREF31": {"title": "Quantum yield and rate of formation of the carotenoid triplet state in photosynthetic structures", "authors": [{"first": "H", "middle": [], "last": "Kramer", "suffix": ""}, {"first": "P", "middle": [], "last": "Mathis", "suffix": ""}], "year": 1980, "venue": "Biochimica et Biophysica Acta", "link": "28839484"}, "BIBREF32": {"title": "Energy-dependent quenching of chlorophyll-a-fluorescence: the involvement of proton-calcium exchange at photosystem 2", "authors": [{"first": "A", "middle": [], "last": "Krieger", "suffix": ""}, {"first": "E", "middle": [], "last": "Weis", "suffix": ""}], "year": 1992, "venue": "Photosynthetica", "link": "89438943"}, "BIBREF33": {"title": "The role of calcium in the pH-dependent control of photosystem II", "authors": [{"first": "A", "middle": [], "last": "Krieger", "suffix": ""}, {"first": "E", "middle": [], "last": "Weis", "suffix": ""}], "year": 1993, "venue": "Photosynthesis Research", "link": "6942238"}, "BIBREF34": {"title": "On the determination of the redox mid-point potential of the primary quinone acceptor, Q A , in photosystem II", "authors": [{"first": "A", "middle": [], "last": "Krieger", "suffix": ""}, {"first": "A", "middle": ["W"], "last": "Rutherford", "suffix": ""}, {"first": "G", "middle": ["N"], "last": "Johnson", "suffix": ""}], "year": 1995, "venue": "Biochimica et Biophysica Acta", "link": null}, "BIBREF35": {"title": "Relationship between activity, D1 loss, and Mn binding in photoinhibition of photosystem II", "authors": [{"first": "A", "middle": [], "last": "Krieger", "suffix": ""}, {"first": "A", "middle": ["W"], "last": "Rutherford", "suffix": ""}, {"first": "I", "middle": [], "last": "Vass", "suffix": ""}, {"first": "E", "middle": [], "last": "Hideg", "suffix": ""}], "year": 1998, "venue": "Biochemistry", "link": "1116041"}, "BIBREF36": {"title": "Influence of herbicide binding on the redox potential of the quinone acceptor in photosystem II: relevance to photodamage and phytotoxicity", "authors": [{"first": "A", "middle": [], "last": "Krieger-Liszkay", "suffix": ""}, {"first": "A", "middle": ["W"], "last": "Rutherford", "suffix": ""}], "year": 1998, "venue": "Biochemistry", "link": "34827314"}, "BIBREF37": {"title": "The glutathione peroxidase homologous gene from Chlamydomonas reinhardtii is transcriptionally up-regulated by singlet oxygen", "authors": [{"first": "U", "middle": [], "last": "Leisinger", "suffix": ""}, {"first": "K", "middle": [], "last": "R\u00fc Fenacht", "suffix": ""}, {"first": "B", "middle": [], "last": "Fischer", "suffix": ""}, {"first": "M", "middle": [], "last": "Pearo", "suffix": ""}, {"first": "A", "middle": [], "last": "Spengler", "suffix": ""}, {"first": "Ajb", "middle": [], "last": "Zehnder", "suffix": ""}, {"first": "Ril", "middle": [], "last": "Eggen", "suffix": ""}], "year": 2001, "venue": "Plant Molecular Biology", "link": "11273514"}, "BIBREF38": {"title": "Regulatory proteolysis of the major light-harvesting chlorophyll a/b protein of photosystem II by light-induced membrane associated enzymic system", "authors": [{"first": "M", "middle": [], "last": "Lindahl", "suffix": ""}, {"first": "D", "middle": ["H"], "last": "Yang", "suffix": ""}, {"first": "B", "middle": [], "last": "Andersson", "suffix": ""}], "year": 1995, "venue": "European Journal of Biochemistry", "link": "25490523"}, "BIBREF39": {"title": "AtMRP2, an Arabidopsis ATP binding cassette transporter able to transport glutathione S-conjugates and chlorophyll catabolites: functional comparisons with Atmrp1", "authors": [{"first": "Y", "middle": ["P"], "last": "Lu", "suffix": ""}, {"first": "Z", "middle": ["S"], "last": "Li", "suffix": ""}, {"first": "Y", "middle": ["M"], "last": "Drozdowicz", "suffix": ""}, {"first": "S", "middle": [], "last": "Hortensteiner", "suffix": ""}, {"first": "E", "middle": [], "last": "Martinoia", "suffix": ""}, {"first": "P", "middle": ["A"], "last": "Rea", "suffix": ""}], "year": 1998, "venue": "The Plant Cell", "link": "37232201"}, "BIBREF40": {"title": "Direct detection of singlet oxygen from isolated photosystem II reaction centres", "authors": [{"first": "A", "middle": ["N"], "last": "Macpherson", "suffix": ""}, {"first": "A", "middle": [], "last": "Telfer", "suffix": ""}, {"first": "T", "middle": ["G"], "last": "Truscott", "suffix": ""}, {"first": "J", "middle": [], "last": "Barber", "suffix": ""}], "year": 1993, "venue": "Biochimica et Biophysica Acta", "link": null}, "BIBREF41": {"title": "Light-dependent thermoluminescence from thylakoids of greening barley leaves: evidence for involvement of oxygen radicals and free chlorophyll", "authors": [{"first": "J", "middle": ["B"], "last": "Marder", "suffix": ""}, {"first": "M", "middle": [], "last": "Droppa", "suffix": ""}, {"first": "V", "middle": [], "last": "Caspi", "suffix": ""}, {"first": "V", "middle": ["I"], "last": "Raskin", "suffix": ""}, {"first": "G", "middle": [], "last": "Horv\u00e1th", "suffix": ""}], "year": 1998, "venue": "Physiologia Plantarum", "link": null}, "BIBREF42": {"title": "Chlorophyll degradation", "authors": [{"first": "P", "middle": [], "last": "Matile", "suffix": ""}, {"first": "S", "middle": [], "last": "Hortensteiner", "suffix": ""}, {"first": "H", "middle": [], "last": "Thomas", "suffix": ""}], "year": 1999, "venue": "Annual Review of Plant Physiology and Plant Molecular Biology", "link": "24621179"}, "BIBREF43": {"title": "Restoration of the high-potential form of cytochrome b 559 of photosystem II occurs via a two-step mechanism under illumination in the presence of manganese ions", "authors": [{"first": "N", "middle": [], "last": "Mizusawa", "suffix": ""}, {"first": "M", "middle": [], "last": "Miyao", "suffix": ""}, {"first": "T", "middle": [], "last": "Yamashita", "suffix": ""}], "year": 1997, "venue": "Biochimica et Biophysica Acta", "link": null}, "BIBREF44": {"title": "A plastidic ABC protein involved in intercompartmental communication of light signaling", "authors": [{"first": "S", "middle": ["G"], "last": "M\u00f8ller", "suffix": ""}, {"first": "T", "middle": [], "last": "Kunkel", "suffix": ""}, {"first": "N", "middle": ["H"], "last": "Chua", "suffix": ""}], "year": 2001, "venue": "Genes and Development", "link": "43150908"}, "BIBREF45": {"title": "Are diverse signalling pathways integrated in the regulation of Arabidopsis antioxidant defense gene expression in response to excess excitation energy? Philosophical Transactions of the", "authors": [{"first": "P", "middle": [], "last": "Mullineaux", "suffix": ""}, {"first": "L", "middle": [], "last": "Ball", "suffix": ""}, {"first": "C", "middle": [], "last": "Escobar", "suffix": ""}, {"first": "B", "middle": [], "last": "Karpinska", "suffix": ""}, {"first": "G", "middle": [], "last": "Creissen", "suffix": ""}, {"first": "S", "middle": [], "last": "Karpinski", "suffix": ""}], "year": 2000, "venue": "Royal Society of London B", "link": null}, "BIBREF46": {"title": "Differential effects of urea/ triazine-type and phenol-type photosystem II inhibitors on inactivation of the electron transport and degradation of the D1 protein during photoinhibition", "authors": [{"first": "Y", "middle": [], "last": "Nakajima", "suffix": ""}, {"first": "S", "middle": [], "last": "Yoshida", "suffix": ""}, {"first": "T", "middle": [], "last": "Ono", "suffix": ""}], "year": 1996, "venue": "Plant Cell Physiology", "link": "84860684"}, "BIBREF47": {"title": "Rapid induction of distinct stress responses after the release of singlet oxygen in Arabidopsis", "authors": [{"first": "Rgl", "middle": [], "last": "Op Den Camp", "suffix": ""}, {"first": "D", "middle": [], "last": "Przybyla", "suffix": ""}, {"first": "C", "middle": [], "last": "Ochsenbein", "suffix": ""}], "year": 2003, "venue": "The Plant Cell", "link": "25290495"}, "BIBREF48": {"title": "Selective and specific cleavage of the D1 and D2 proteins of photosystem II by exposure to singlet oxygen: factors responsible for the susceptibility to cleavage of proteins", "authors": [{"first": "K", "middle": [], "last": "Okada", "suffix": ""}, {"first": "M", "middle": [], "last": "Ikeuchi", "suffix": ""}, {"first": "N", "middle": [], "last": "Yamamoto", "suffix": ""}, {"first": "T", "middle": [], "last": "Ono", "suffix": ""}, {"first": "M", "middle": [], "last": "Miyao", "suffix": ""}], "year": 1996, "venue": "Biochimica et Biophysica Acta", "link": "85966553"}, "BIBREF49": {"title": "Studies into the action of some photosynthetic inhibitor herbicides", "authors": [{"first": "K", "middle": ["E"], "last": "Pallet", "suffix": ""}, {"first": "A", "middle": ["D"], "last": "Dodge", "suffix": ""}], "year": 1980, "venue": "Journal of Experimental Botany", "link": "86157979"}, "BIBREF50": {"title": "Dynamics of photosystem II: mechanism of photoinhibition and recovery process", "authors": [{"first": "O", "middle": [], "last": "Prasil", "suffix": ""}, {"first": "N", "middle": [], "last": "Adir", "suffix": ""}, {"first": "I", "middle": [], "last": "Ohad", "suffix": ""}], "year": 1992, "venue": "Topics in photosynthesis, the photosystems: structure, function and molecular biology", "link": "93173499"}, "BIBREF51": {"title": "Kinetics and pathways of charge recombination in photosystem II", "authors": [{"first": "F", "middle": [], "last": "Rappaport", "suffix": ""}, {"first": "M", "middle": [], "last": "Guergova-Kuras", "suffix": ""}, {"first": "P", "middle": ["J"], "last": "Nixon", "suffix": ""}, {"first": "B", "middle": ["A"], "last": "Diner", "suffix": ""}, {"first": "J", "middle": [], "last": "Lavergne", "suffix": ""}], "year": 2002, "venue": "Biochemistry", "link": "1021720"}, "BIBREF52": {"title": "Acceptor and donor-side interactions of phenolic herbicides in photosystem II", "authors": [{"first": "A", "middle": ["G"], "last": "Roberts", "suffix": ""}, {"first": "W", "middle": [], "last": "Gregor", "suffix": ""}, {"first": "R", "middle": ["D"], "last": "Britt", "suffix": ""}, {"first": "D", "middle": ["M"], "last": "Kramer", "suffix": ""}], "year": 2003, "venue": "Biochimica et Biophysica Acta", "link": null}, "BIBREF53": {"title": "Formation of radicals from singlet oxygen produced during photoinhibition of isolated light-harvesting proteins of photosystem II", "authors": [{"first": "S", "middle": [], "last": "Rinalducci", "suffix": ""}, {"first": "J", "middle": ["Z"], "last": "Pedersen", "suffix": ""}, {"first": "L", "middle": [], "last": "Zolla", "suffix": ""}], "year": 2004, "venue": "Biochimica et Biophysica Acta", "link": "26249113"}, "BIBREF54": {"title": "Oscillation of delayed luminescence from PSII: recombination of S 2 Q B \u00ff and S 3 Q B \u00ff", "authors": [{"first": "A", "middle": ["W"], "last": "Rutherford", "suffix": ""}, {"first": "Y", "middle": [], "last": "Inoue", "suffix": ""}], "year": 1984, "venue": "FEBS Letters", "link": null}, "BIBREF55": {"title": "Herbicide-induced oxidative stress in photosystem II", "authors": [{"first": "A", "middle": ["W"], "last": "Rutherford", "suffix": ""}, {"first": "A", "middle": [], "last": "Krieger-Liszkay", "suffix": ""}], "year": 2001, "venue": "Trends in Biochemical Science", "link": "43175847"}, "BIBREF56": {"title": "Chlorophyll triplet states associated with photosystem II in thylakoids", "authors": [{"first": "S", "middle": [], "last": "Santabarbara", "suffix": ""}, {"first": "E", "middle": [], "last": "Bordignon", "suffix": ""}, {"first": "R", "middle": ["C"], "last": "Jennings", "suffix": ""}, {"first": "D", "middle": [], "last": "Carbonera", "suffix": ""}], "year": 2002, "venue": "Biochemistry", "link": null}, "BIBREF57": {"title": "Kinetic and energetic model for the primary processes in photosystem II", "authors": [{"first": "G", "middle": ["H"], "last": "Schatz", "suffix": ""}, {"first": "H", "middle": [], "last": "Brock", "suffix": ""}, {"first": "A", "middle": ["R"], "last": "Holzwarth", "suffix": ""}], "year": 1988, "venue": "Biophysics Journal", "link": "8789971"}, "BIBREF58": {"title": "Primary charge separation in closed Photosystem II with a lifetime of 11 ns: flash-absorption spectroscopy with O 2 -evolving Photosystem II complexes from Synechococcus", "authors": [{"first": "E", "middle": [], "last": "Schlodder", "suffix": ""}, {"first": "K", "middle": [], "last": "Brettel", "suffix": ""}], "year": 1988, "venue": "Biochimica et Biophysica Acta", "link": "94589903"}, "BIBREF59": {"title": "Recombinant water-soluble chlorophyll protein from Brassica oleracea var. botrys binds various chlorophyll derivatives", "authors": [{"first": "K", "middle": [], "last": "Schmidt", "suffix": ""}, {"first": "C", "middle": [], "last": "Fufezan", "suffix": ""}, {"first": "A", "middle": [], "last": "Krieger-Liszkay", "suffix": ""}, {"first": "H", "middle": [], "last": "Satoh", "suffix": ""}, {"first": "H", "middle": [], "last": "Paulsen", "suffix": ""}], "year": 2003, "venue": "Biochemistry", "link": "20600891"}, "BIBREF60": {"title": "Flash-induced absorption changes in photosystem I, radical pair or triplet state formation?", "authors": [{"first": "P", "middle": [], "last": "S\u00e9tif", "suffix": ""}, {"first": "G", "middle": [], "last": "Hervo", "suffix": ""}, {"first": "P", "middle": [], "last": "Mathis", "suffix": ""}], "year": 1980, "venue": "Biochimica et Biophysica Acta", "link": "95307128"}, "BIBREF61": {"title": "Charge recombination from the P + QA \u00ff state in reaction centres from Rhodopseudomonas viridis", "authors": [{"first": "R", "middle": ["J"], "last": "Shopes", "suffix": ""}, {"first": "C", "middle": ["A"], "last": "Wraight", "suffix": ""}], "year": 1987, "venue": "Biochimica et Biophysica Acta", "link": null}, "BIBREF62": {"title": "Singlet oxygen induced DNA damage", "authors": [{"first": "H", "middle": [], "last": "Sies", "suffix": ""}, {"first": "C", "middle": ["F"], "last": "Menck", "suffix": ""}], "year": 1992, "venue": "Mutation Research", "link": "11035455"}, "BIBREF63": {"title": "Cytochrome b 559 of photosystem II", "authors": [{"first": "D", "middle": ["H"], "last": "Stewart", "suffix": ""}, {"first": "G", "middle": ["W"], "last": "Brudvig", "suffix": ""}], "year": 1998, "venue": "Biochimica et Biophysica Acta", "link": null}, "BIBREF64": {"title": "Chloroplast to nucleus communication triggered by accumulation of Mg-protoporphyrin IX", "authors": [{"first": "A", "middle": [], "last": "Strand", "suffix": ""}, {"first": "T", "middle": [], "last": "Asami", "suffix": ""}, {"first": "J", "middle": [], "last": "Alonso", "suffix": ""}, {"first": "J", "middle": ["R"], "last": "Ecker", "suffix": ""}, {"first": "J", "middle": [], "last": "Chory", "suffix": ""}], "year": 2003, "venue": "Nature", "link": "4430910"}, "BIBREF65": {"title": "Cytochrome b 6 f complex as an indigenous photodynamic generator of singlet oxygen in thylakoid membranes", "authors": [{"first": "H", "middle": ["J"], "last": "Suh", "suffix": ""}, {"first": "C", "middle": ["S"], "last": "Kim", "suffix": ""}, {"first": "Jung", "middle": ["J"], "last": "", "suffix": ""}], "year": 2000, "venue": "Photochemistry and Photobiology", "link": "24399676"}, "BIBREF66": {"title": "What is b-carotene doing in the photosystem II reaction centre?", "authors": [{"first": "A", "middle": [], "last": "Telfer", "suffix": ""}], "year": 2002, "venue": "Philosophical Transactions of the Royal Society of London B", "link": "85599764"}, "BIBREF67": {"title": "A specific role for tocopherol and of chemical singlet oxygen quenchers in the maintenance of photosystem II structure and function in Chlamydomonas reinhardii", "authors": [{"first": "A", "middle": [], "last": "Trebst", "suffix": ""}], "year": 2002, "venue": "FEBS Letters", "link": "40673031"}, "BIBREF68": {"title": "Function of bcarotene and tocopherol in photosystem II", "authors": [{"first": "A", "middle": [], "last": "Trebst", "suffix": ""}, {"first": "B", "middle": [], "last": "Depka", "suffix": ""}, {"first": "H", "middle": [], "last": "Hollander-Czytko", "suffix": ""}], "year": 2003, "venue": "Zeitschrift fu\u00a8r Naturforschung", "link": null}, "BIBREF69": {"title": "Electron transfer in photosystem II", "authors": [{"first": "H", "middle": ["J"], "last": "Van Gorkom", "suffix": ""}], "year": 1985, "venue": "Photosynthesis Research", "link": "195684279"}, "BIBREF70": {"title": "Charge recombination reactions in photosystem II. 1. Yields, recombination pathways, and kinetics of the primary pair", "authors": [{"first": "F", "middle": [], "last": "Van Mieghem", "suffix": ""}, {"first": "K", "middle": [], "last": "Brettel", "suffix": ""}, {"first": "B", "middle": [], "last": "Hillmann", "suffix": ""}, {"first": "A", "middle": [], "last": "Kamlowski", "suffix": ""}, {"first": "A", "middle": ["W"], "last": "Rutherford", "suffix": ""}, {"first": "E", "middle": [], "last": "Schlodder", "suffix": ""}], "year": 1995, "venue": "Biochemistry", "link": "9156533"}, "BIBREF71": {"title": "The influence of the quinone-iron electron acceptor complex on the reaction centre photochemistry of photosystem II", "authors": [{"first": "Fje", "middle": [], "last": "Van Mieghem", "suffix": ""}, {"first": "W", "middle": [], "last": "Nitschke", "suffix": ""}, {"first": "P", "middle": [], "last": "Mathis", "suffix": ""}, {"first": "A", "middle": ["W"], "last": "Rutherford", "suffix": ""}], "year": 1989, "venue": "Biochimica et Biophysica Acta", "link": null}, "BIBREF72": {"title": "A chlorophyll tilted 308 relative to the membrane in the photosystem II reaction center", "authors": [{"first": "Fje", "middle": [], "last": "Van Mieghem", "suffix": ""}, {"first": "K", "middle": [], "last": "Satoh", "suffix": ""}, {"first": "A", "middle": ["W"], "last": "Rutherford", "suffix": ""}], "year": 1991, "venue": "Biochimica et Biophysica Acta", "link": null}, "BIBREF73": {"title": "Reversible and irreversible intermediates during photoinhibition of photosystem II: stable reduced QA species promote chlorophyll triplet formation", "authors": [{"first": "I", "middle": [], "last": "Vass", "suffix": ""}, {"first": "S", "middle": [], "last": "Styring", "suffix": ""}, {"first": "T", "middle": [], "last": "Hundal", "suffix": ""}, {"first": "A", "middle": [], "last": "Koivuniemi", "suffix": ""}, {"first": "E", "middle": ["M"], "last": "Aro", "suffix": ""}, {"first": "B", "middle": [], "last": "Andersson", "suffix": ""}], "year": 1992, "venue": "Proceedings of the National Academy of Sciences", "link": "25889371"}, "BIBREF74": {"title": "Mutations in the CD-loop region of the D2 protein in Synechocystis sp. PCC 6803 modify charge recombination reaction pathways in photosystem II in vivo", "authors": [{"first": "D", "middle": ["V"], "last": "Vavilin", "suffix": ""}, {"first": "Wfj", "middle": [], "last": "Vermaas", "suffix": ""}], "year": 2000, "venue": "Biochemistry", "link": "13301661"}, "BIBREF75": {"title": "Signal transduction during oxidative stress", "authors": [{"first": "E", "middle": [], "last": "Vranov\u00e1", "suffix": ""}, {"first": "D", "middle": [], "last": "Inz\u00e9", "suffix": ""}, {"first": "F", "middle": [], "last": "Van Breusegem", "suffix": ""}], "year": 2002, "venue": "Journal of Experimental Botany", "link": "34138752"}, "BIBREF76": {"title": "Radical pair energetics and decay machanisms in reaction centers containing anthraquinones, naphthoquinones or benzoquinones in place of ubiquinone", "authors": [{"first": "N", "middle": ["W"], "last": "Woodbury", "suffix": ""}, {"first": "W", "middle": ["W"], "last": "Parson", "suffix": ""}, {"first": "M", "middle": ["R"], "last": "Gunner", "suffix": ""}, {"first": "R", "middle": ["C"], "last": "Prince", "suffix": ""}, {"first": "P", "middle": ["L"], "last": "Dutton", "suffix": ""}], "year": 1986, "venue": "Biochimica et Biophysica Acta", "link": "31544381"}, "BIBREF77": {"title": "Fatty acid-derived signals in plants", "authors": [{"first": "H", "middle": [], "last": "Weber", "suffix": ""}], "year": 2002, "venue": "Trends in Plant Sciences", "link": "38244368"}, "BIBREF78": {"title": "Photoinactivation of photosystem II induces changes in the photochemical reaction center II abolishing the regulatory role of the QB site in the D1 protein degradation", "authors": [{"first": "H", "middle": [], "last": "Zer", "suffix": ""}, {"first": "I", "middle": [], "last": "Ohad", "suffix": ""}], "year": 1995, "venue": "European Journal of Biochemistry", "link": "20301759"}, "BIBREF79": {"title": "Involvement of active oxygen species in degradation of light-harvesting proteins under light stresses", "authors": [{"first": "L", "middle": [], "last": "Zolla", "suffix": ""}, {"first": "S", "middle": [], "last": "Rinalducci", "suffix": ""}], "year": 2002, "venue": "Biochemistry", "link": "24350171"}, "BIBREF80": {"title": "Crystal structure of photosystem II from Synechococcus elongatus at 3.8 \u00c5 resolution", "authors": [{"first": "A", "middle": [], "last": "Zouni", "suffix": ""}, {"first": "H", "middle": ["T"], "last": "Witt", "suffix": ""}, {"first": "J", "middle": [], "last": "Kern", "suffix": ""}, {"first": "P", "middle": [], "last": "Fromme", "suffix": ""}, {"first": "N", "middle": [], "last": "Krau\u00df", "suffix": ""}, {"first": "W", "middle": [], "last": "Saenger", "suffix": ""}, {"first": "P", "middle": [], "last": "Orth", "suffix": ""}], "year": 2001, "venue": "Nature", "link": "4344756"}}, "ref_entries": {"FIGREF0": {"text": "Fig. 2. Photosynthetic electron transport. Linear electron flow through PSII (I), cytochrome b 6 f complex, and PSI are shown. If forward electron transport is blocked, charge recombination reactions occur in PSII leading to the formation of triplet chl which reacts with O 2 to 1 O 2 (II). If the water-splitting complex of PSII is inactivated (prior to photoactivation or after Ca 2+ -depletion), the mid-point potential of Q A is shifted and charge recombination reactions are though to occur to the ground state via a safe route (III). Q A 'low potential' is shown as a circle, Q A 'high potential' as a diamond.", "type": "figure"}, "FIGREF1": {"text": "spins had time to randomize. The triplet state of this radical pair can recombine rapidly,The influence of herbicide binding on the mid-point potential of the redox couple Q A /Q A \u00ff is shown (dashed line). When phenolic herbicides are bound, the mid-point potential of Q A /Q A \u00ff is shifted by 50 mV to a more negative value and the back reaction via the P 680 + Pheo \u00ff radical pair is favoured. When DCMU is bound, then the mid-point potential of Q A /Q A \u00ff is shifted by 50 mV to a more positive value and this back reaction is disfavoured and direct recombination to the ground state may occur.the mid-point potential of Q A by binding a herbicide to the Q B binding pocket is not understood. FTIR spectra of Q A obtained in the presence of a phenolic herbicide compared with DCMU indicate that the protein environment of Q A is slightly modified by the phenolic herbicide. The change seen in the spectra is small and approximately in the range of one H-bonding (J Breton and A Krieger-Liszkay, unpublished data). Fufezan et al. (2002) showed that the yield of 1 O 2 production in the presence of a phenolic herbicide in active PSII-enriched membrane fragments (with Q A in the low potential form) is twice as high as in the presence of DCMU. This effect is already seen at relatively low light intensities (400 lmol quanta m \u00ff2 s \u00ff1", "type": "figure"}, "FIGREF2": {"text": "by the cytochrome b 6 f complex Illumination of the isolated cytochrome b 6 f complex results in the formation", "type": "figure"}, "FIGREF3": {"text": ", genes are specifically up-regulated which are involved in the molecular defence response of the plant against photo-oxidative stress (Leisinger et al., 2001; op den Camp et al., 2003; B Fischer, personal communication). Leisinger et al. (2001) showed that, in the presence of photosensitizers like Rose Bengal, a glutathione peroxidase homologous gene from Chlamydomonas is transcriptionally up-regulated by 1 O 2 , while the mRNA level of this gluthathione peroxidase is only weakly ex- pressed by exposure to superoxide or peroxide. Op den Camp et al. (2003) used the flu mutant of Arabidopsis to show that the accumulation of protochlorophyllide and thus the high yield of 1 O 2 formation by transferring these plants from dark to light rapidly activated a number (70) of genes. By contrast, other reactive oxygen species like superoxide did not rapidly up-regulate the expression of these genes. In the flu mutant, 1", "type": "figure"}, "TABREF0": {"text": "can react with carotenoids which act as a catalyst, deactivating 1 O 2 . Another important antioxidant located in the thylakoid membrane is a-tocopherol. Tocopherol is an efficient scavenger, which becomes oxidized when reacting with", "type": "table"}}}
{"paper_id": "2871533", "_pdf_hash": "f225329e6e1a69110c2332fc9928d422aa651ef1", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Intelligent tutoring system with affective learning for mathematics", "authors": [{"first": "R", "middle": ["Z"], "last": "Cabada", "suffix": ""}, {"first": "M", "middle": ["L B"], "last": "Estrada", "suffix": ""}, {"first": "F", "middle": ["G"], "last": "Hern\u00e1ndez", "suffix": ""}, {"first": "R", "middle": ["O"], "last": "Bustillos", "suffix": ""}], "year": 2014, "venue": "Human-Inspired Computing and Its Applications", "link": "28627625"}, "BIBREF1": {"title": "Affect detection: An Interdisciplinary review of models, methods, and their applications", "authors": [{"first": "R", "middle": ["A"], "last": "Calvo", "suffix": ""}, {"first": "S", "middle": [], "last": "Mello", "suffix": ""}], "year": 2010, "venue": "IEEE Transactions on Affective Computing", "link": "753606"}, "BIBREF2": {"title": "Teaching children with attention deficit hyperactivity disorder: instructional strategies and practices", "authors": [{"first": "S", "middle": [], "last": "Jackson", "suffix": ""}], "year": 2004, "venue": "", "link": null}, "BIBREF3": {"title": "Body movements for affective expression: A Survey of automatic recognition and generation", "authors": [{"first": "M", "middle": [], "last": "Karg", "suffix": ""}, {"first": "A", "middle": ["A"], "last": "Samadani", "suffix": ""}, {"first": "R", "middle": [], "last": "Gorbet", "suffix": ""}, {"first": "K", "middle": [], "last": "Kuhnlenz", "suffix": ""}, {"first": "J", "middle": [], "last": "Hoey", "suffix": ""}, {"first": "D", "middle": [], "last": "Kulic", "suffix": ""}], "year": 2013, "venue": "IEEE Transactions on Affective Computing", "link": "8909542"}, "BIBREF4": {"title": "Affective gaming: A Comprehensive survey", "authors": [{"first": "I", "middle": [], "last": "Kotsia", "suffix": ""}, {"first": "S", "middle": [], "last": "Zafeiriou", "suffix": ""}, {"first": "S", "middle": [], "last": "Fotopoulos", "suffix": ""}], "year": 2013, "venue": "Proceedings of the IEEE Conference on Computer Vision and Pattern Recognition Workshops (CVPRW)", "link": "14870991"}, "BIBREF5": {"title": "Real-time EEG-based human emotion recognition and visualization", "authors": [{"first": "Y", "middle": [], "last": "Liu", "suffix": ""}, {"first": "O", "middle": [], "last": "Sourina", "suffix": ""}, {"first": "M", "middle": ["K"], "last": "Nguyen", "suffix": ""}], "year": 2010, "venue": "Proceedings of the IEEE International Conference on Cyberworlds", "link": "16453864"}, "BIBREF6": {"title": "Digital stories targeting social skills for children with disabilities multidimensional learning", "authors": [{"first": "C", "middle": [], "last": "More", "suffix": ""}], "year": 2008, "venue": "Intervention in School and Clinic", "link": "146763190"}, "BIBREF7": {"title": "Automatic analysis of facial expressions", "authors": [{"first": "M", "middle": [], "last": "Pantic", "suffix": ""}], "year": 2014, "venue": "Proceedings of the 2014 ACM/IEEE international conference on Human-robot interaction", "link": "2567620"}, "BIBREF8": {"title": "Adaptive educational games: Providing non-invasive personalized learning experiences", "authors": [{"first": "N", "middle": [], "last": "Peirce", "suffix": ""}, {"first": "O", "middle": [], "last": "Conlan", "suffix": ""}, {"first": "V", "middle": [], "last": "Wade", "suffix": ""}], "year": 2008, "venue": "Second IEEE International Conference on Digital Games and Intelligent Toys Based Education", "link": "15867951"}, "BIBREF9": {"title": "La funci\u00f3n ejecutiva y sus trastornos", "authors": [{"first": "D", "middle": [], "last": "Pineda", "suffix": ""}], "year": 2000, "venue": "", "link": null}, "BIBREF11": {"title": "Editorial: Play and learn: Potentials of game of game-based learning", "authors": [{"first": "M", "middle": [], "last": "Pivec", "suffix": ""}], "year": 2007, "venue": "British Journal of Educational Technology", "link": "205566822"}, "BIBREF12": {"title": "Disfunci\u00f3n ejecutiva en el trastorno por d\u00e9ficit de atenci\u00f3n con hiperactividad en la infancia", "authors": [{"first": "D", "middle": ["M"], "last": "Romero-Ayuso", "suffix": ""}, {"first": "F", "middle": [], "last": "Maest\u00fa", "suffix": ""}, {"first": "J", "middle": [], "last": "Gonz\u00e1lez-Marqu\u00e9s", "suffix": ""}, {"first": "C", "middle": [], "last": "Romo-Barrientos", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Andrade", "suffix": ""}], "year": 2006, "venue": "", "link": null}, "BIBREF14": {"title": "El papel de los padres en el desarrollo y aprendizaje de los ni\u00f1os con trastorno por d\u00e9ficit de atenci\u00f3n con hiperactividad", "authors": [{"first": "B", "middle": [], "last": "Rosell\u00f3", "suffix": ""}, {"first": "R", "middle": [], "last": "Garc\u00eda Castellar", "suffix": ""}, {"first": "R", "middle": [], "last": "T\u00e1rraga M\u00ednguez", "suffix": ""}, {"first": "F", "middle": [], "last": "Mulas", "suffix": ""}], "year": 2003, "venue": "", "link": null}, "BIBREF16": {"title": "Automatic analysis of affective postures and body motion to detect engagement with a game companion", "authors": [{"first": "J", "middle": [], "last": "Sanghvi", "suffix": ""}, {"first": "G", "middle": [], "last": "Castellano", "suffix": ""}, {"first": "I", "middle": [], "last": "Leite", "suffix": ""}, {"first": "A", "middle": [], "last": "Pereira", "suffix": ""}, {"first": "P", "middle": ["W"], "last": "Mcowan", "suffix": ""}, {"first": "A", "middle": [], "last": "Paiva", "suffix": ""}], "year": 2011, "venue": "Proceedings of the 6 th ACM/IEEE International Conference on Human-Robot Interaction (HRI)", "link": "1212510"}, "BIBREF17": {"title": "How does ADHD affect school performance?", "authors": [], "year": 2015, "venue": "", "link": null}, "BIBREF18": {"title": "Technology applications for children with ADHD: Assessing the empirical support. Education and Treatment of Children", "authors": [{"first": "C", "middle": [], "last": "Xu", "suffix": ""}, {"first": "R", "middle": [], "last": "Reid", "suffix": ""}, {"first": "A", "middle": [], "last": "Steckelberg", "suffix": ""}], "year": 2002, "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "2871546", "_pdf_hash": "11dfd12ece9d2494499591475d512e458512624f", "abstract": [], "body_text": [], "bib_entries": {"BIBREF6": {"title": "Clusters and Colloids: From Theory to Application", "authors": [{"first": "J", "middle": ["S"], "last": "Bradley", "suffix": ""}], "year": 1994, "venue": "", "link": "95153241"}, "BIBREF27": {"title": "Adsorption and aggregation of surfactants in solution", "authors": [{"first": "D", "middle": ["W"], "last": "Kim", "suffix": ""}, {"first": "S", "middle": ["I"], "last": "Shin", "suffix": ""}, {"first": "S", "middle": ["G"], "last": "Oh", "suffix": ""}], "year": 2003, "venue": "Surfactant Sciences Series, Marcel Dekker", "link": "92900863"}}, "ref_entries": {}}
{"paper_id": "2871630", "_pdf_hash": "0fcc3c7cfba5e43044a40aa38560e4676733e223", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction", "authors": [{"first": "P", "middle": [], "last": "Chomczynski", "suffix": ""}, {"first": "N", "middle": [], "last": "Sacchi", "suffix": ""}], "year": 1987, "venue": "Analytical Biochemistry", "link": "22369897"}, "BIBREF1": {"title": "Prediction of protein conformation", "authors": [{"first": "P", "middle": ["Y"], "last": "Chou", "suffix": ""}, {"first": "G", "middle": ["D"], "last": "Fasman", "suffix": ""}], "year": 1974, "venue": "Biochemistry", "link": "5133857"}, "BIBREF2": {"title": "Evidence for the direct involvement of the rhinovirus canyon in receptor binding", "authors": [{"first": "R", "middle": ["J"], "last": "Colonno", "suffix": ""}, {"first": "J", "middle": ["H"], "last": "Condra", "suffix": ""}, {"first": "S", "middle": [], "last": "Mizutani", "suffix": ""}, {"first": "P", "middle": ["L"], "last": "Callahan", "suffix": ""}, {"first": "M.-E", "middle": [], "last": "Davies", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Murcko", "suffix": ""}], "year": 1988, "venue": "Proceedings of the National Academy of Sciences, USA", "link": "2665487"}, "BIBREF3": {"title": "PCR Technology : Principles and Applications for DNA Amplification", "authors": [{"first": "H", "middle": ["A"], "last": "Ehrlich", "suffix": ""}], "year": 1989, "venue": "", "link": "84667522"}, "BIBREF4": {"title": "Cell receptors for picornaviruses as determinants of cell tropism and pathogenesis", "authors": [{"first": "D", "middle": ["J"], "last": "Evans", "suffix": ""}, {"first": "F", "middle": ["W"], "last": "Almond", "suffix": ""}], "year": 1998, "venue": "Trends in Microbiology", "link": "34429008"}, "BIBREF5": {"title": "Nucleotide sequence and genome organization of foot-and-mouth disease virus", "authors": [{"first": "S", "middle": [], "last": "Forss", "suffix": ""}, {"first": "K", "middle": [], "last": "Strebel", "suffix": ""}, {"first": "E", "middle": [], "last": "Beck", "suffix": ""}, {"first": "H", "middle": [], "last": "Schaller", "suffix": ""}], "year": 1984, "venue": "Nucleic Acids Research", "link": "18259154"}, "BIBREF6": {"title": "Untersuchungen zur Insertionstoleranz im VP1-Kapsidprotein des Coxsackievirus B3. Dissertation, Ludwig-MaximiliansUniversita$ t Mu$ nchen", "authors": [{"first": "U", "middle": [], "last": "Fortmu$ Ller", "suffix": ""}], "year": 1997, "venue": "", "link": null}, "BIBREF7": {"title": "The cell attachment site on foot-and-mouth disease virus includes the amino acid sequence RGD (arginine-glycine-aspartic acid)", "authors": [{"first": "G", "middle": [], "last": "Fox", "suffix": ""}, {"first": "N", "middle": ["R"], "last": "Parry", "suffix": ""}, {"first": "P", "middle": ["V"], "last": "Barnett", "suffix": ""}, {"first": "B", "middle": [], "last": "Mcginn", "suffix": ""}, {"first": "D", "middle": ["J"], "last": "Rowlands", "suffix": ""}, {"first": "F", "middle": [], "last": "Brown", "suffix": ""}], "year": 1989, "venue": "Journal of General Virology", "link": "1423009"}, "BIBREF8": {"title": "The major human rhinovirus receptor is ICAM-1", "authors": [{"first": "J", "middle": ["M"], "last": "Greve", "suffix": ""}, {"first": "G", "middle": [], "last": "Davis", "suffix": ""}, {"first": "A", "middle": ["M"], "last": "Meyer", "suffix": ""}, {"first": "C", "middle": ["P"], "last": "Forte", "suffix": ""}, {"first": "S", "middle": ["C"], "last": "Yost", "suffix": ""}, {"first": "C", "middle": ["W"], "last": "Marlor", "suffix": ""}, {"first": "M", "middle": ["E"], "last": "Kamarck", "suffix": ""}, {"first": "A", "middle": [], "last": "Mcclelland", "suffix": ""}], "year": 1989, "venue": "Cell", "link": "1294633"}, "BIBREF9": {"title": "Cell staining", "authors": [{"first": "E", "middle": [], "last": "Harlow", "suffix": ""}, {"first": "D", "middle": [], "last": "Lane", "suffix": ""}], "year": 1988, "venue": "Antibodies : A Laboratory Manual", "link": null}, "BIBREF11": {"title": "Members of the low density lipoprotein receptor family mediate cell entry of a minor-group common cold virus", "authors": [{"first": "E", "middle": [], "last": "Kuechler", "suffix": ""}, {"first": "D", "middle": [], "last": "Blass", "suffix": ""}], "year": 1994, "venue": "Proceedings of the National Academy of Sciences, USA 91", "link": null}, "BIBREF12": {"title": "Three-dimensional structure of poliovirus at 2n9 A / resolution", "authors": [{"first": "J", "middle": ["M"], "last": "Hogle", "suffix": ""}, {"first": "M", "middle": [], "last": "Chow", "suffix": ""}, {"first": "D", "middle": ["J"], "last": "Filman", "suffix": ""}], "year": 1985, "venue": "Science", "link": null}, "BIBREF13": {"title": "VCAM-1 is a receptor for encephalomyocarditis virus on murine vascular endothelial cells", "authors": [{"first": "S", "middle": ["A"], "last": "Huber", "suffix": ""}], "year": 1994, "venue": "Journal of Virology", "link": "25376727"}, "BIBREF14": {"title": "Integrins : versatility, modulation, and signaling in cell adhesion", "authors": [{"first": "R", "middle": ["O"], "last": "Hynes", "suffix": ""}], "year": 1992, "venue": "Cell", "link": "32774108"}, "BIBREF15": {"title": "The HeLa cell receptor for enterovirus 70 is decay-accelerating factor (CD55)", "authors": [{"first": "T", "middle": ["M"], "last": "Karnauchow", "suffix": ""}, {"first": "D", "middle": ["L"], "last": "Tolson", "suffix": ""}, {"first": "B", "middle": ["A"], "last": "Harrison", "suffix": ""}, {"first": "E", "middle": [], "last": "Altman", "suffix": ""}, {"first": "D", "middle": ["M"], "last": "Lublin", "suffix": ""}, {"first": "K", "middle": [], "last": "Dimock", "suffix": ""}], "year": 1996, "venue": "Journal of Virology", "link": "28194729"}, "BIBREF16": {"title": "Cleavage of structural proteins during the assembly of the head of bacteriophage T4", "authors": [{"first": "U", "middle": ["K"], "last": "Laemmli", "suffix": ""}], "year": 1970, "venue": "Nature", "link": null}, "BIBREF17": {"title": "Point mutations within the \u03b2G-\u03b2H loop of foot-and-mouth disease virus O \" K affect virus attachment to target cells", "authors": [{"first": "M", "middle": [], "last": "Leippert", "suffix": ""}, {"first": "E", "middle": [], "last": "Beck", "suffix": ""}, {"first": "F", "middle": [], "last": "Weiland", "suffix": ""}, {"first": "E", "middle": [], "last": "Pfaff", "suffix": ""}], "year": 1997, "venue": "Journal of Virology", "link": null}, "BIBREF18": {"title": "Structure of a major immunogenic site on foot-andmouth disease virus", "authors": [{"first": "D", "middle": [], "last": "Logan", "suffix": ""}, {"first": "R", "middle": [], "last": "Abu-Ghazaleh", "suffix": ""}, {"first": "W", "middle": [], "last": "Blakemore", "suffix": ""}, {"first": "S", "middle": [], "last": "Curry", "suffix": ""}, {"first": "T", "middle": [], "last": "Jackson", "suffix": ""}, {"first": "A", "middle": [], "last": "King", "suffix": ""}, {"first": "S", "middle": [], "last": "Lea", "suffix": ""}, {"first": "R", "middle": [], "last": "Lewis", "suffix": ""}, {"first": "J", "middle": [], "last": "Newman", "suffix": ""}, {"first": "N", "middle": [], "last": "Parry", "suffix": ""}, {"first": "D", "middle": [], "last": "Rowlands", "suffix": ""}, {"first": "D", "middle": [], "last": "Stuart", "suffix": ""}, {"first": "E", "middle": [], "last": "Fry", "suffix": ""}], "year": 1993, "venue": "Nature", "link": null}, "BIBREF19": {"title": "The atomic structure of Mengo virus at 3n0 A / resolution", "authors": [{"first": "M", "middle": [], "last": "Luo", "suffix": ""}, {"first": "G", "middle": [], "last": "Vriend", "suffix": ""}, {"first": "G", "middle": [], "last": "Kamer", "suffix": ""}, {"first": "I", "middle": [], "last": "Minor", "suffix": ""}, {"first": "E", "middle": [], "last": "Arnold", "suffix": ""}, {"first": "M.-G", "middle": [], "last": "Rossmann", "suffix": ""}, {"first": "U", "middle": [], "last": "Boege", "suffix": ""}, {"first": "D", "middle": ["G"], "last": "Scraba", "suffix": ""}, {"first": "G", "middle": ["M"], "last": "Duke", "suffix": ""}, {"first": "A", "middle": ["C"], "last": "Palmenberg", "suffix": ""}], "year": 1987, "venue": "Science", "link": null}, "BIBREF20": {"title": "RGD sequence of foot-andmouth disease virus is essential for infecting cells via the natural receptor but can be bypassed by an antibody-dependent enhancement pathway", "authors": [{"first": "P", "middle": ["W"], "last": "Mason", "suffix": ""}, {"first": "E", "middle": [], "last": "Rieder", "suffix": ""}, {"first": "B", "middle": [], "last": "Baxt", "suffix": ""}], "year": 1994, "venue": "Proceedings of the National Academy of Sciences, USA 91", "link": "30185756"}, "BIBREF21": {"title": "Cellular receptor for poliovirus : molecular cloning, nucleotide sequence, and expression of a new member of the immunoglobulin superfamily", "authors": [{"first": "C", "middle": ["L"], "last": "Mendelsohn", "suffix": ""}, {"first": "E", "middle": [], "last": "Wimmer", "suffix": ""}, {"first": "V", "middle": ["R"], "last": "Racaniello", "suffix": ""}], "year": 1989, "venue": "Cell", "link": "44296539"}, "BIBREF22": {"title": "Foot-and-mouth disease virus virulent for cattle utilizes the integrin \u03b1 v \u03b2 $ as its receptor", "authors": [{"first": "S", "middle": [], "last": "Neff", "suffix": ""}, {"first": "D", "middle": [], "last": "Sa! -Carvalho", "suffix": ""}, {"first": "E", "middle": [], "last": "Rieder", "suffix": ""}, {"first": "P", "middle": ["W"], "last": "Mason", "suffix": ""}, {"first": "S", "middle": ["D"], "last": "Blystone", "suffix": ""}, {"first": "E", "middle": ["J"], "last": "Brown", "suffix": ""}, {"first": "B", "middle": [], "last": "Baxt", "suffix": ""}], "year": 1998, "venue": "Journal of Virology", "link": "86775526"}, "BIBREF23": {"title": "High-efficiency utilization of the bovine integrin \u03b1 v \u03b2 $ as a receptor for foot-and-mouth disease virus is dependent on the bovine \u03b2 $ subunit", "authors": [{"first": "S", "middle": [], "last": "Neff", "suffix": ""}, {"first": "P", "middle": ["W"], "last": "Mason", "suffix": ""}, {"first": "B", "middle": [], "last": "Baxt", "suffix": ""}], "year": 2000, "venue": "Journal of Virology", "link": "21103126"}, "BIBREF24": {"title": "Antibodies against a preselected peptide recognize and neutralize foot-and-mouth disease virus", "authors": [{"first": "E", "middle": [], "last": "Pfaff", "suffix": ""}, {"first": "M", "middle": [], "last": "Mussgay", "suffix": ""}, {"first": "H", "middle": ["O"], "last": "Bo$ Hm", "suffix": ""}, {"first": "G", "middle": ["E"], "last": "Schulz", "suffix": ""}, {"first": "H", "middle": [], "last": "Schaller", "suffix": ""}], "year": 1982, "venue": "EMBO Journal", "link": "29424010"}, "BIBREF26": {"title": "Analysis of neutralizing epitopes on foot-and-mouth disease virus", "authors": [], "year": "", "venue": "Journal of Virology", "link": "6740208"}, "BIBREF27": {"title": "Molecular and immunological analysis of foot-and-mouth disease virus mutants. Vaccines (Cold Spring Harbor", "authors": [{"first": "E", "middle": [], "last": "Pfaff", "suffix": ""}, {"first": "H", "middle": [], "last": "Mu$ Ller", "suffix": ""}, {"first": "B", "middle": [], "last": "Haas", "suffix": ""}, {"first": "H.-J", "middle": [], "last": "Thiel", "suffix": ""}], "year": 1989, "venue": "", "link": null}, "BIBREF28": {"title": "Influence of stereochemistry of the sequence Arg-Gly-Asp-Xaa on binding specificity in cell adhesion", "authors": [{"first": "M", "middle": ["D"], "last": "Pierschbacher", "suffix": ""}, {"first": "E", "middle": [], "last": "Ruoslahti", "suffix": ""}], "year": 1987, "venue": "Journal of Biological Chemistry", "link": "6767178"}, "BIBREF30": {"title": "Characterization of echoviruses that bind decay accelerating factor (CD55) : evidence that some haemagglutinating strains use more than one cellular receptor", "authors": [{"first": "J", "middle": ["W"], "last": "Almond", "suffix": ""}], "year": 1998, "venue": "Journal of General Virology", "link": "16746367"}, "BIBREF32": {"title": "RGD-dependent entry of coxsackievirus A9 into host cells and its bypass after cleavage of VP1 protein by intestinal proteases", "authors": [{"first": "T", "middle": [], "last": "Hovi", "suffix": ""}], "year": 1991, "venue": "Journal of Virology", "link": "26891421"}, "BIBREF33": {"title": "Entry of coxsackievirus A9 into host cells : specific interactions with \u03b1 v \u03b2 $ integrin, the vitronectin receptor", "authors": [{"first": "M", "middle": [], "last": "Roivainen", "suffix": ""}, {"first": "L", "middle": [], "last": "Piirainen", "suffix": ""}, {"first": "T", "middle": [], "last": "Hovi", "suffix": ""}, {"first": "I", "middle": [], "last": "Virtanen", "suffix": ""}, {"first": "T", "middle": [], "last": "Riikonen", "suffix": ""}, {"first": "J", "middle": [], "last": "Heino", "suffix": ""}, {"first": "$", "middle": [], "last": "Hyypia", "suffix": ""}, {"first": "T", "middle": [], "last": "", "suffix": ""}], "year": 1994, "venue": "Virology", "link": "85083317"}, "BIBREF34": {"title": "Efficient RGDindependent entry process of coxsackievirus A9", "authors": [{"first": "M", "middle": [], "last": "Roivainen", "suffix": ""}, {"first": "L", "middle": [], "last": "Piirainen", "suffix": ""}, {"first": "T", "middle": [], "last": "Hovi", "suffix": ""}], "year": 1996, "venue": "Archives of Virology", "link": null}, "BIBREF35": {"title": "Structure of a human common cold virus and functional relationship to other picornaviruses", "authors": [{"first": "M", "middle": ["G"], "last": "Rossmann", "suffix": ""}, {"first": "E", "middle": [], "last": "Arnold", "suffix": ""}, {"first": "J", "middle": ["W"], "last": "Erickson", "suffix": ""}, {"first": "E", "middle": ["A"], "last": "Frankenberger", "suffix": ""}, {"first": "J", "middle": ["P"], "last": "Griffith", "suffix": ""}, {"first": "H.-J", "middle": [], "last": "Hecht", "suffix": ""}, {"first": "J", "middle": ["E"], "last": "Johnson", "suffix": ""}, {"first": "G", "middle": [], "last": "Kamer", "suffix": ""}, {"first": "M", "middle": [], "last": "Luo", "suffix": ""}, {"first": "A", "middle": ["G"], "last": "Mosser", "suffix": ""}, {"first": "R", "middle": ["R"], "last": "Rueckert", "suffix": ""}, {"first": "B", "middle": [], "last": "Sherry", "suffix": ""}, {"first": "G", "middle": [], "last": "Vriend", "suffix": ""}], "year": 1985, "venue": "Nature", "link": null}, "BIBREF36": {"title": "Picornaviridae and their replication", "authors": [{"first": "R", "middle": [], "last": "Rueckert", "suffix": ""}, {"first": "E", "middle": [], "last": "Wimmer", "suffix": ""}], "year": 1984, "venue": "Fields and others", "link": null}, "BIBREF37": {"title": "New perspectives in cell adhesion : RGD and integrins", "authors": [{"first": "E", "middle": [], "last": "Ruoslahti", "suffix": ""}, {"first": "M", "middle": ["D"], "last": "Pierschbacher", "suffix": ""}], "year": 1987, "venue": "Science", "link": "27938790"}, "BIBREF38": {"title": "The replication of picornaviruses", "authors": [{"first": "D", "middle": ["V"], "last": "Sangar", "suffix": ""}], "year": 1979, "venue": "Journal of General Virology", "link": "32296427"}, "BIBREF40": {"title": "Coxsackieviruses B1, B3, and B5 use decayaccelerating factor as a receptor for cell attachment", "authors": [{"first": "R", "middle": ["D"], "last": "Barry", "suffix": ""}], "year": 1995, "venue": "Journal of Virology", "link": "18301088"}, "BIBREF42": {"title": "Coxsackievirus A21 binds to decay-accelerating factor but requires intercellular adhesion molecule 1 for cell entry", "authors": [], "year": "", "venue": "Journal of Virology", "link": "26291818"}, "BIBREF44": {"title": "Molecular and biological characteristics of echovirus 22, a representative of a new picornavirus group", "authors": [{"first": "G", "middle": [], "last": "Stanway", "suffix": ""}, {"first": "N", "middle": [], "last": "Kalkkinen", "suffix": ""}, {"first": "M", "middle": [], "last": "Roivainen", "suffix": ""}, {"first": "F", "middle": [], "last": "Ghazi", "suffix": ""}, {"first": "M", "middle": [], "last": "Khan", "suffix": ""}, {"first": "M", "middle": [], "last": "Smyth", "suffix": ""}, {"first": "O", "middle": [], "last": "Meurman", "suffix": ""}, {"first": "$", "middle": [], "last": "Hyypia", "suffix": ""}, {"first": "T", "middle": [], "last": "", "suffix": ""}], "year": 1994, "venue": "Journal of Virology", "link": "19833118"}, "BIBREF46": {"title": "A cell adhesion molecule, ICAM-1, is the major surface receptor for rhinoviruses", "authors": [{"first": "T", "middle": ["A"], "last": "Springer", "suffix": ""}], "year": 1989, "venue": "Cell", "link": "27297558"}, "BIBREF47": {"title": "Structure of integrin, a glycoprotein involved in the transmembrane linkage between fibronectin and actin", "authors": [{"first": "J", "middle": [], "last": "Tamkun", "suffix": ""}, {"first": "D", "middle": ["W"], "last": "Desimone", "suffix": ""}, {"first": "D", "middle": [], "last": "Fonda", "suffix": ""}, {"first": "R", "middle": ["S"], "last": "Patel", "suffix": ""}, {"first": "C", "middle": [], "last": "Buck", "suffix": ""}, {"first": "A", "middle": ["F"], "last": "Horwitz", "suffix": ""}, {"first": "R", "middle": ["O"], "last": "Hynes", "suffix": ""}], "year": 1986, "venue": "Cell", "link": "39198016"}, "BIBREF48": {"title": "HCAR and MCAR : the human and mouse cellular receptors for subgroup C adenoviruses and group B coxsackieviruses", "authors": [{"first": "R", "middle": ["P"], "last": "Tomko", "suffix": ""}, {"first": "R", "middle": [], "last": "Xu", "suffix": ""}, {"first": "L", "middle": [], "last": "Philipson", "suffix": ""}], "year": 1997, "venue": "Proceedings of the National Academy of Sciences", "link": "86296354"}, "BIBREF49": {"title": "Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets : procedure and some applications", "authors": [{"first": "H", "middle": [], "last": "Towbin", "suffix": ""}, {"first": "T", "middle": [], "last": "Staehelin", "suffix": ""}, {"first": "J", "middle": [], "last": "Gordon", "suffix": ""}], "year": 1979, "venue": "Proceedings of the National Academy of Sciences", "link": "33387612"}, "BIBREF50": {"title": "Decay-accelerating factor CD55 is identified as the receptor for echovirus 7 using CELICS, a rapid immuno-focal cloning method", "authors": [{"first": "T", "middle": [], "last": "Ward", "suffix": ""}, {"first": "P", "middle": ["A"], "last": "Pipkin", "suffix": ""}, {"first": "N", "middle": ["A"], "last": "Clarkson", "suffix": ""}, {"first": "D", "middle": ["M"], "last": "Stone", "suffix": ""}, {"first": "P", "middle": ["D"], "last": "Minor", "suffix": ""}, {"first": "J", "middle": ["W"], "last": "Almond", "suffix": ""}], "year": 1994, "venue": "EMBO Journal", "link": "13079462"}, "BIBREF51": {"title": "Fibronectins -adhesive glycoproteins of cell surface and blood", "authors": [{"first": "K", "middle": ["M"], "last": "Yamada", "suffix": ""}, {"first": "K", "middle": [], "last": "Olden", "suffix": ""}], "year": 1978, "venue": "Nature", "link": null}, "BIBREF53": {"title": "Infectious foot-and-mouth disease virus derived from a cloned full-length cDNA", "authors": [], "year": "", "venue": "Journal of Virology", "link": "23508665"}, "BIBREF54": {"title": "Molecular cloning and sequence determination of the complete genome of the virulent echovirus 9 strain Barty", "authors": [{"first": "H", "middle": [], "last": "Zimmermann", "suffix": ""}, {"first": "H", "middle": ["J"], "last": "Eggers", "suffix": ""}, {"first": "B", "middle": [], "last": "Nelsen-Salz", "suffix": ""}], "year": 1996, "venue": "Virus Genes", "link": "30512570"}}, "ref_entries": {}}
{"paper_id": "2871678", "_pdf_hash": "a0b0f5854c65ccd168d96108acb77cf3ffc7a0f4", "abstract": [{"section": "Abstract", "text": "The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is regarded as a potential anticancer agent. However, considerable numbers of cancer cells, especially some highly malignant tumors, are resistant to apoptosis induction by TRAIL, and some cancer cells that were originally sensitive to TRAIL-induced apoptosis can become resistant after repeated exposure (acquired resistance). Understanding the mechanisms underlying such resistance and developing strategies to overcome it are important for the successful use of TRAIL for cancer therapy. Resistance to TRAIL can occur at different points in the signaling pathways of TRAILinduced apoptosis. Dysfunctions of the death receptors DR4 and DR5 due to mutations can lead to resistance. The adaptor protein Fas-associated death domain (FADD) and caspase-8 are essential for assembly of the death-inducing signaling complex, and defects in either of these molecules can lead to TRAIL resistance. Overexpression of cellular FADD-like interleukin-1b-converting enzymeinhibitory protein (cFLIP) correlates with TRAIL resistance in several types of cancer. Overexpression of Bcl-2 or Bcl-X L , loss of Bax or Bak function, high expression of inhibitor of apoptosis proteins, and reduced release of second mitochondria-derived activator of caspases (Smac/Diablo) from the mitochondria to the cytosol have all been reported to result in TRAIL resistance in mitochondriadependent type II cancer cells. Finally, activation of different subunits of mitogen-activated protein kinases or nuclear factor-kappa B can lead to development of either TRAIL resistance or apoptosis in certain types of cancer cells.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "", "text": "T umor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily and has attracted attention not only for its strong antitumor activity in a wide range of cancer cell types but also for its minimal cytotoxity to most normal cells and tissues. 1 Although we and others have demonstrated that introduction of TRAIL to normal human hepatocytes induced massive cell death, 2, 3 we have also demonstrated that the human telomerase reverse transcriptase (hTERT) promoter, the gene that is highly active in more than 85% of human cancers but inactive in most normal cells, can be used to target TRAIL-mediated apoptosis to cancer cells, thus reducing TRAIL's toxicity to normal hepatocytes. 2 In mice, targeted expression of the TRAIL or Bax gene by the hTERT promoter also elicited strong antitumor activity without obvious systemic toxicity, even after systemic administration. 2, 4 Nevertheless, resistance to TRAIL-mediated apoptosis induction in cancer cells remains a challenging issue for the successful application of TRAIL in gene therapy. Although many types of cancers are sensitive to TRAILinduced apoptosis, substantial numbers of cancer cells are resistant to TRAIL, especially some highly malignant tumors such as pancreatic cancer, 5 melanoma, 6 and neuroblastoma. 7 Moreover, we found that repeated application of TRAIL protein or TRAIL-expressing adenovectors to TRAIL-susceptible cancer cells results in selection and expansion of TRAIL-resistant cells, leading to acquired resistance. 8 Thus, characterizing the mechanisms of resistance to TRAIL-mediated apoptosis will not only provide insight regarding transduction of the death signal from membrane to nucleus, but will also be essential for designing strategies to overcome resistance to TRAIL for future clinical applications.", "cite_spans": [{"start": 278, "end": 279, "text": "1", "ref_id": "BIBREF0"}, {"start": 404, "end": 406, "text": "2,", "ref_id": "BIBREF1"}, {"start": 407, "end": 408, "text": "3", "ref_id": "BIBREF2"}, {"start": 719, "end": 720, "text": "2", "ref_id": "BIBREF1"}, {"start": 908, "end": 910, "text": "2,", "ref_id": "BIBREF1"}, {"start": 911, "end": 912, "text": "4", "ref_id": "BIBREF3"}, {"start": 1276, "end": 1277, "text": "5", "ref_id": "BIBREF4"}, {"start": 1288, "end": 1289, "text": "6", "ref_id": "BIBREF5"}, {"start": 1309, "end": 1310, "text": "7", "ref_id": "BIBREF6"}, {"start": 1533, "end": 1534, "text": "8", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "", "text": "Although the detailed mechanisms underlying TRAIL-mediated apoptosis remain to be characterized, some important components and steps in the signaling pathways of this process have been elucidated. A growing body of evidence shows that resistance to TRAIL-mediated apoptosis can occur at different levels in these pathways. Here we summarize some possible mechanisms related to cellular resistance to TRAIL-induced apoptosis.", "cite_spans": [], "ref_spans": []}, {"section": "The signaling pathway of TRAIL-induced apoptosis", "text": "The interaction of TRAIL with its two death receptors DR4 (TRAIL-R1) and DR5 (TRAIL-R2) is the initial step in TRAIL-induced apoptosis. 9, 10 The binding of TRAIL leads to trimerization of the death receptors and activation of receptor-mediated death pathway (Fig 1) . The activated death receptors recruit and activate an adaptor protein called Fas-associated death domain (FADD) through interactions between the death domain (DD) on the death receptors and FADD. The death effector domain (DED) of FADD recruits and activates caspase-8, leading to the formation of the death-inducing signaling complex (DISC). In type I cells, the presence of activated caspase-8, a so-called initiator caspase, is sufficient to induce activation of one or more effector caspases (e.g., caspase-3 or -7), which then act on final death substrates in apoptosis. 7, 11 However, in type II cells, even a small amount of activated caspase-8, although not enough to activate the effector caspases, is sufficient to trigger a mitochondria-dependent apoptotic amplification loop by activating Bid, which induces the accumulation of Bax in mitochondria, the release of cytochrome c from mitochondria, the activation of caspase-9, caspase-3, and caspase-7, and finally, programmed cell death. [11] [12] [13] In addition to inducing apoptosis by caspase-8 recruitment through FADD, TRAIL binding to its receptors also leads to activation of the transcription factor nuclear factor-kappa B (NF-kB) (Fig 1) . TRAIL death receptors, like the TNF receptor 1 (TNFR1), 14 activate NF-kB through the TNFR1-associated death domain protein (TRADD). 15 Activated TRADD recruits the DD-containing protein RIP and TNF receptor-associated factor-2 (TRAF2), leading to activation of the NF-kB pathway; in contrast, dominant-negative TRADD can block the NFkB activation induced by TRAIL receptors. 15 In TNFR1 signaling, TRADD is believed to be upstream of FADD. However, in TRAIL signaling, TRADD may be mediated by FADD, because TRADD recruitment to the DISC is observed only in the presence of FADD. 16 ", "cite_spans": [{"start": 136, "end": 138, "text": "9,", "ref_id": "BIBREF8"}, {"start": 139, "end": 141, "text": "10", "ref_id": "BIBREF9"}, {"start": 845, "end": 847, "text": "7,", "ref_id": "BIBREF6"}, {"start": 848, "end": 850, "text": "11", "ref_id": "BIBREF10"}, {"start": 1268, "end": 1272, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 1273, "end": 1277, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 1278, "end": 1282, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 1537, "end": 1539, "text": "14", "ref_id": "BIBREF13"}, {"start": 1614, "end": 1616, "text": "15", "ref_id": "BIBREF14"}, {"start": 1857, "end": 1859, "text": "15", "ref_id": "BIBREF14"}, {"start": 2062, "end": 2064, "text": "16", "ref_id": "BIBREF15"}], "ref_spans": []}, {"section": "TRAIL death receptors and TRAIL resistance", "text": "So far, five TRAIL receptors have been discovered: the two agonistic receptors DR4 9 and DR5 10 and the three antagonistic decoy receptors DcR1 (TRAIL-R3), 17 DcR2 (TRAIL-R4), 18 and osteoprotegerin. 19 Apart from their extracellular domains, which are capable of binding TRAIL, DR4 and DR5 contain intracellular DD that can trigger the apoptotic signal upon binding TRAIL. 1, 11 On the other hand, DcR1 and DcR2 cannot transmit the apoptotic signal, because they either lack or have a functionally truncated DD. 9, 10, 11, 17, 18 The third decoy receptor, osteoprotegerin, is a secreted TNF receptor family member that can be detected in circulation, suggesting that osteoprotegerin may be a soluble antagonist receptor for TRAIL. 19 More data are needed before the function of osteoprotegerin in the signal pathway of TRAIL-induced apoptosis can be elucidated. Overall, it seems that all of the decoy receptors can inhibit TRAILinduced apoptosis by competing with DR4 or DR5 for TRAIL binding. [17] [18] [19] In humans, the decoy receptors are widely expressed in various tissues. DcR1 mRNA has been detected in peripheral blood leukocytes, ovary, testis, prostate, thymus, spleen, liver, lung, placenta, heart, kidney, and bone marrow, 20, 21 whereas DcR2 mRNA expression has been found in all tissues tested, including peripheral blood leukocytes, ovary, prostate, thymus, spleen, colon, and small intestine. 18 Most of the human tissues tested also expressed the agonistic death receptors DR4 or DR5. 18, 20, 21 As all of the normal tissues that expressed decoy receptors and real death receptors at the same time were resistant to TRAIL-induced apoptosis, and because ectopic expression of DcR1 or DcR2 in some cancer cell lines reduced sensitivity to TRAIL-induced apoptosis, it is reasonable to postulate that DcR1 or DcR2 expression may protect human normal cells and tissues from TRAILinduced apoptosis. 18, 20, 21 However, no correlation has been found between decoy receptor expression and TRAIL resistance in any form of cancer studied thus far. In one study, the TRAIL-resistant melanoma cell line WM3211 expressed mRNA for DR5, but not for DcR1 and DcR2. 22 In contrast, three TRAIL-sensitive melanoma cell lines (WM9, WM793, and WM1205) expressed DcR1, DcR2 or both. 22 In another study, 7 only five of 18 neuroblastoma cell lines tested were sensitive to TRAIL, but all five of those cell lines expressed DcR1, DcR2, or both, at moderate to strong levels. These findings indicate Figure 1 The signaling pathway of TRAIL-induced apoptosis. Death signal from TRAIL receptors may transduce via activated caspase-8 directly by activating effector caspase-3, or indirectly by activating Bid, which in turn translocates into mitochondria and causes cytochrome c and Smac release to cytosol. The released cytochrome c interacts with Apaf-1 and causes caspase-9 activation, which then activates effector caspase-3. The released Smac inhibits IAPs by preventing their binding to capspase-9 and caspase-3. Death receptor apoptosis pathways induced by TRAIL can also activate NF-kB. Different subunit activation of NF-kB determines whether NF-kB favors apoptosis or survival.", "cite_spans": [{"start": 83, "end": 84, "text": "9", "ref_id": "BIBREF8"}, {"start": 176, "end": 178, "text": "18", "ref_id": "BIBREF17"}, {"start": 200, "end": 202, "text": "19", "ref_id": "BIBREF18"}, {"start": 374, "end": 376, "text": "1,", "ref_id": "BIBREF0"}, {"start": 377, "end": 379, "text": "11", "ref_id": "BIBREF10"}, {"start": 513, "end": 515, "text": "9,", "ref_id": "BIBREF8"}, {"start": 516, "end": 519, "text": "10,", "ref_id": "BIBREF9"}, {"start": 520, "end": 523, "text": "11,", "ref_id": "BIBREF10"}, {"start": 524, "end": 527, "text": "17,", "ref_id": "BIBREF16"}, {"start": 528, "end": 530, "text": "18", "ref_id": "BIBREF17"}, {"start": 732, "end": 734, "text": "19", "ref_id": "BIBREF18"}, {"start": 996, "end": 1000, "text": "[17]", "ref_id": "BIBREF16"}, {"start": 1001, "end": 1005, "text": "[18]", "ref_id": "BIBREF17"}, {"start": 1006, "end": 1010, "text": "[19]", "ref_id": "BIBREF18"}, {"start": 1239, "end": 1242, "text": "20,", "ref_id": "BIBREF19"}, {"start": 1243, "end": 1245, "text": "21", "ref_id": "BIBREF20"}, {"start": 1413, "end": 1415, "text": "18", "ref_id": "BIBREF17"}, {"start": 1506, "end": 1509, "text": "18,", "ref_id": "BIBREF17"}, {"start": 1510, "end": 1513, "text": "20,", "ref_id": "BIBREF19"}, {"start": 1514, "end": 1516, "text": "21", "ref_id": "BIBREF20"}, {"start": 1914, "end": 1917, "text": "18,", "ref_id": "BIBREF17"}, {"start": 1918, "end": 1921, "text": "20,", "ref_id": "BIBREF19"}, {"start": 1922, "end": 1924, "text": "21", "ref_id": "BIBREF20"}, {"start": 2170, "end": 2172, "text": "22", "ref_id": "BIBREF21"}, {"start": 2283, "end": 2285, "text": "22", "ref_id": "BIBREF21"}, {"start": 2304, "end": 2305, "text": "7", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "TRAIL death receptors and TRAIL resistance", "text": "indicates activation. B indicates inactivation.", "cite_spans": [], "ref_spans": []}, {"section": "TRAIL death receptors and TRAIL resistance", "text": "TRAIL-induced apoptosis in cancer L Zhang and B Fang that, in cancer, some mechanisms other than protection by decoy receptors exist, which confer resistance to TRAIL.", "cite_spans": [], "ref_spans": []}, {"section": "TRAIL death receptors and TRAIL resistance", "text": "DR4 and DR5, the two agonistic death receptors for TRAIL, are able to transmit apoptotic signals upon TRAIL binding. Theoretically, dysfunctions in either receptor could cause TRAIL resistance. The genes for both DR4 and DR5 have been mapped to chromosome 8p21-22, a segment noted in genome-wide searches to be one of the most common sites of loss of heterozygosity (LOH) in several types of cancers. Thus, it is rational to hypothesize that one or more tumor suppressor genes are located in this region, and to explore the possibility of mutational inactivation of DR4 and DR5 in those forms of cancer. [23] [24] [25] A polymorphism in DR4 has been described in the human ovarian cancer cell line SKOV3 and the human bladder cancer cell line J82. 24 An A-to-G alteration at nucleotide 1322 of DR4 in both cell types results in substitution of an arginine for lysine at codon 441 (K441R) in the DD of DR4. About 20% of normal individuals also had the same base change. 24 Transfection of SW480 colon cancer cells with a vector expressing polymorphic DR4 showed that the polymorphic form was less effective in cell killing than its wild-type counterpart. 24 Another study by the same investigators 23 showed two missense nucleotide substitutions in DR4 in lung cancer, head and neck squamous cell cancer, and gastric adenocarcinoma cells. The first of these substitutions occurred at nucleotide 626 of DR4, where a C-to-G change results in substitution of an arginine for threonine at codon 209 (T209R). The other missense alteration occurred at nucleotide 422 of DR4, where a G-to-A change results in substitution of a histidine for arginine at codon 141 (R141H). Only 13% of a normal control group was homozygous for both the T209R and R141H changes, but 35% of non-small-cell lung cancer specimens, 47% of primary head and neck squamous cell cancer specimens, and 44% of gastric adenocarcinomas specimens were homozygous for both changes. These two amino-acid changes occurred in or near the ligandbinding domain of DR4, suggesting that these changes may cause abnormal death receptor trimerization or TRAIL binding. 23 In another study, 26 mutations in DR4 were identified in three of 34 specimens from breast cancers that had metastasized, but none were found in any of the 23 specimens of breast cancer that had not metastasized. All the three mutations were single-nucleotide substitutions, which resulted in missense mutations within the DD regions of DR4. Breast cancer that had metastasized also showed higher frequency of LOH than breast cancer that had not metastasized, suggesting that DR4 may act like a tumor suppressor gene in some breast cancer and but may lose this function during the progression into metastatic stages. Indeed, expression of mutated DR4 in 293 cells led to the suppression of apoptosis. 26 In one other report, 27 mutation screening in the DD region of DR4 revealed only two missense mutations among 117 samples of human non-Hodgkin's lymphoma (1.7%).", "cite_spans": [{"start": 604, "end": 608, "text": "[23]", "ref_id": "BIBREF22"}, {"start": 609, "end": 613, "text": "[24]", "ref_id": "BIBREF23"}, {"start": 614, "end": 618, "text": "[25]", "ref_id": "BIBREF24"}, {"start": 748, "end": 750, "text": "24", "ref_id": "BIBREF23"}, {"start": 969, "end": 971, "text": "24", "ref_id": "BIBREF23"}, {"start": 1154, "end": 1156, "text": "24", "ref_id": "BIBREF23"}, {"start": 1197, "end": 1199, "text": "23", "ref_id": "BIBREF22"}, {"start": 2119, "end": 2121, "text": "23", "ref_id": "BIBREF22"}, {"start": 2140, "end": 2142, "text": "26", "ref_id": "BIBREF25"}, {"start": 2823, "end": 2825, "text": "26", "ref_id": "BIBREF25"}, {"start": 2847, "end": 2849, "text": "27", "ref_id": "BIBREF26"}], "ref_spans": []}, {"section": "TRAIL death receptors and TRAIL resistance", "text": "Mutations in the DR5 gene have been identified in head and neck cancer, non-small-cell lung cancer, breast cancer, non-Hodgkin's lymphoma, and hepatocellular carcinoma. A screening of 40 primary head and neck cancer specimens for mutations in DR5 revealed two such mutations, one of which was a 2-bp insertion in the DD of DR5 that resulted in a premature stop codon and a truncated DR5. 28 This insertion was also present in the germ line of the affected patient. Transfection of the truncated DR5 mutant into head and neck squamous cell carcinoma and colon and ovarian carcinoma cell lines led to a loss of growth-suppressive function. 28 In another study, 11 of 104 non-small-cell lung cancer specimens (10.6%) were found to have mutations in the DD of DR5, which could not be detected in the corresponding normal tissue samples. Of these 11 samples, seven were hemizygous without LOH. The authors postulated that hemizygously mutated DR5 may bind with other, normal DR5 proteins to form a structurally abnormal DR5 trimer, which could affect binding to adaptor proteins, such as FADD. 29 In the study of DR4 in breast cancer discussed in the previous paragraph, 26 four mutations in DR5 were identified among 34 breast cancer that had metastasized (11.8%), but no mutations in DR5 were found in any of 23 breast cancers that had not metastasized. In contrast to the DR4 mutations in that study, the two DR5 mutations were identified within the DD, and another two mutations were detected in the flanking region of the DD. Still, expression of these mutated DR5 in 293 cells led to suppression of apoptosis. 26 In other studies, one missense mutation was detected in the DD of DR5 among 100 samples of hepatocellular carcinoma (1%), 30 and six point mutations were detected in the coding regions of the DR5 gene among 117 samples of non-Hodgkin's lymphoma (5.1%). 27 ", "cite_spans": [{"start": 388, "end": 390, "text": "28", "ref_id": "BIBREF27"}, {"start": 638, "end": 640, "text": "28", "ref_id": "BIBREF27"}, {"start": 1089, "end": 1091, "text": "29", "ref_id": "BIBREF28"}, {"start": 1166, "end": 1168, "text": "26", "ref_id": "BIBREF25"}, {"start": 1611, "end": 1613, "text": "26", "ref_id": "BIBREF25"}, {"start": 1736, "end": 1738, "text": "30", "ref_id": "BIBREF29"}, {"start": 1867, "end": 1869, "text": "27", "ref_id": "BIBREF26"}], "ref_spans": []}, {"section": "DISC assembly and TRAIL resistance", "text": "Assembly of the DISC is an early molecular event in the signaling pathway of TRAIL-induced apoptosis. Several molecules, including TRAIL, TRAIL death receptors, FADD, caspase-8 or caspase-10, and cFLIP, participate in the formation of the DISC. Most components of the DISC are essential to TRAIL-induced apoptosis, and dysfunction in any of these DISC components can lead to TRAIL resistance. 7, 11 Evidence regarding the roles of FADD, caspase-8, and cFLIP in TRAIL-mediated apoptosis is reviewed below.", "cite_spans": [{"start": 393, "end": 395, "text": "7,", "ref_id": "BIBREF6"}, {"start": 396, "end": 398, "text": "11", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "FADD", "text": "FADD is an adaptor molecule containing both DD and DED. Its essential role in death signal transduction was first identified in FasL-induced apoptosis. Through its interactions with activated Fas at the DD and caspase-8 at the DED, FADD transmits a death signal from Fas to caspase-8. 31 The involvement and importance of FADD in TRAIL signaling are highly controversial. Different 35 In one study using such cells, 36 the overexpression of DR4 by transient transfection into homozygously FADD-deficient (FADD \u00c0/\u00c0 ) mouse embryonic fibroblasts induced apoptosis of those cells. The authors of that study concluded that FADD was not essential, as it was not required for DR4-and possibly DR5-mediated apoptosis. The use of transient transfection for the ectopic expression of death receptors, however, has raised concerns about nonspecific aggregation of the DD in death receptors. 35 In fact, evidence has already shown that overexpression of DR4 or DR5 by transient transfection into TRAIL-sensitive cell lines can lead to apoptosis independent of the TRAIL ligand. 20, 21, 35 However, in stably transfected cells or in physiological situations, expression of these receptors does not lead to cell death, and TRAIL binding to the death receptors is necessary to initiate apoptosis. 35 Specifically, FADD\u00c0/\u00c0 embryonic fibroblasts stably transfected with mouse or human TRAIL death receptors were all resistant to TRAIL-induced cell death, but FADD \u00fe /\u00c0 fibroblasts stably transfected with mouse TRAIL death receptors, and FADD \u00c0/\u00c0 fibroblasts in which FADD had been reconstituted with a retroviral construct, were all sensitive to TRAIL-induced apoptosis. 35 The conclusions from this study, that FADD is essential in TRAIL-induced apoptosis and that dysfunction of FADD can cause TRAIL resistance, are also supported by another study that used Jurkat cells. 37 In that study, FADD-deficient Jurkat cells were resistant to TRAIL even at very high concentrations (1 mg/mL), but wild-type Jurkat cells underwent extensive apoptosis at TRAIL concentrations as low as 10 ng/mL.", "cite_spans": [{"start": 285, "end": 287, "text": "31", "ref_id": "BIBREF30"}, {"start": 382, "end": 384, "text": "35", "ref_id": "BIBREF34"}, {"start": 416, "end": 418, "text": "36", "ref_id": "BIBREF35"}, {"start": 881, "end": 883, "text": "35", "ref_id": "BIBREF34"}, {"start": 1067, "end": 1070, "text": "20,", "ref_id": "BIBREF19"}, {"start": 1071, "end": 1074, "text": "21,", "ref_id": "BIBREF20"}, {"start": 1075, "end": 1077, "text": "35", "ref_id": "BIBREF34"}, {"start": 1283, "end": 1285, "text": "35", "ref_id": "BIBREF34"}, {"start": 1656, "end": 1658, "text": "35", "ref_id": "BIBREF34"}, {"start": 1859, "end": 1861, "text": "37", "ref_id": "BIBREF36"}], "ref_spans": []}, {"section": "Caspase-8", "text": "Convincing evidence is accumulating, which shows caspase-8 to be a key and irreplaceable molecule in TRAIL-induced as well as Fas L-and TNF-a-induced apoptosis. [37] [38] [39] [40] Downregulation or loss of caspase-8 expression can lead to TRAIL resistance. 6, 7 In the first line of evidence, caspase-8-deficient Jurkat cells were shown to be completely resistant to TRAIL, whereas the corresponding wild-type cells remained sensitive to TRAIL. Second, the specific caspase-8 inhibitor Z-IETD-FMK could inhibit TRAIL-induced apoptosis in most TRAIL-sensitive cell lines. 38, 41 However, because Z-IETD-FMK may also inhibit other caspases, especially at high doses, use of a more specific approach such as small inhibitory RNA should be considered to confirm the specificity of caspase-8 inhibition. 42 Third, caspase-10, although structurally similar to caspase-8 and having a DED, is not a functional substitute for caspase-8.", "cite_spans": [{"start": 161, "end": 165, "text": "[37]", "ref_id": "BIBREF36"}, {"start": 166, "end": 170, "text": "[38]", "ref_id": "BIBREF37"}, {"start": 171, "end": 175, "text": "[39]", "ref_id": "BIBREF38"}, {"start": 176, "end": 180, "text": "[40]", "ref_id": "BIBREF39"}, {"start": 258, "end": 260, "text": "6,", "ref_id": "BIBREF5"}, {"start": 261, "end": 262, "text": "7", "ref_id": "BIBREF6"}, {"start": 572, "end": 575, "text": "38,", "ref_id": "BIBREF37"}, {"start": 576, "end": 578, "text": "41", "ref_id": "BIBREF40"}, {"start": 800, "end": 802, "text": "42", "ref_id": "BIBREF41"}], "ref_spans": []}, {"section": "39", "text": "Whether caspase-10 acts as an initiator caspase is controversial. Two groups that used the same mutant caspase-8-deficient Jurkat cells both showed that caspase-10 does act as an initiator caspase in TRAIL deathreceptor signaling and that caspase-10 could replace caspase-8 function in the absence of caspase-8. 43, 44 However, a subsequent study by a third group using the same caspase-8-deficient cell line specifically indicated that caspase-10 does not initiate apoptosis. 39 Although TRAIL could induce cell death in the caspase-8-deficient Jurkat cells, much higher concentrations of TRAIL ligand were needed to achieve the same degree of death induction when compared with caspase-8-expressing wild-type Jurkat cells. 39 Also, the two earlier studies used a transient caspase-10 expression system, which may have led to caspase-10 levels that were too high to be tolerated by the host cells. 43, 44 Moreover, some of the cells in the third study that expressed little or no caspase-10 showed no apparent defects in TRAIL-induced apoptosis. 39 The conclusion from the current data, therefore, is that caspase-8 has one or more unique functions that caspase-10 cannot replace for apoptosis initiation. A fourth line of evidence implicating caspase-8 is the observation that several types of cancer cells, including Ewing's tumor, neuroblastoma, malignant brain tumors, melanoma, and small-cell lung cancer, show resistance to TRAIL-induced apoptosis that correlates with downregulation or absence of caspase-8 expression. Importantly, restoration of caspase-8 expression in these resistant cells rendered them sensitive to TRAIL. 6, 7, [45] [46] [47] In a very few cases, loss of caspase-8 expression resulted from a gene deletion, as demonstrated by Southern blot analysis. In most cases, however, absence of caspase-8 expression resulted from gene silencing by DNA methylation in its promoter region. 6, 7, [45] [46] [47] Treatment of such cells with the demethylation agent 5-aza-2 0 -deoxycytidine reversed the hypermethylation of the caspase-8 promoter, thereby restoring expression of caspase-8 and sensitivity to TRAIL-induced apoptosis.", "cite_spans": [{"start": 312, "end": 315, "text": "43,", "ref_id": "BIBREF42"}, {"start": 316, "end": 318, "text": "44", "ref_id": "BIBREF43"}, {"start": 477, "end": 479, "text": "39", "ref_id": "BIBREF38"}, {"start": 725, "end": 727, "text": "39", "ref_id": "BIBREF38"}, {"start": 899, "end": 902, "text": "43,", "ref_id": "BIBREF42"}, {"start": 903, "end": 905, "text": "44", "ref_id": "BIBREF43"}, {"start": 1047, "end": 1049, "text": "39", "ref_id": "BIBREF38"}, {"start": 1635, "end": 1637, "text": "6,", "ref_id": "BIBREF5"}, {"start": 1638, "end": 1640, "text": "7,", "ref_id": "BIBREF6"}, {"start": 1641, "end": 1645, "text": "[45]", "ref_id": "BIBREF44"}, {"start": 1646, "end": 1650, "text": "[46]", "ref_id": "BIBREF45"}, {"start": 1651, "end": 1655, "text": "[47]", "ref_id": "BIBREF46"}, {"start": 1908, "end": 1910, "text": "6,", "ref_id": "BIBREF5"}, {"start": 1911, "end": 1913, "text": "7,", "ref_id": "BIBREF6"}, {"start": 1914, "end": 1918, "text": "[45]", "ref_id": "BIBREF44"}, {"start": 1919, "end": 1923, "text": "[46]", "ref_id": "BIBREF45"}, {"start": 1924, "end": 1928, "text": "[47]", "ref_id": "BIBREF46"}], "ref_spans": []}, {"section": "6,7 cFLIP", "text": "The apoptosis inhibitor cFLIP is structurally similar to caspase-8. 48 So far, only two forms of cFLIP have been detected, although multiple splicing variants may exist. cFLIP L contains two DEDs and a caspase-like domain, but it cannot activate caspase cascades because that domain lacks a cysteine residue essential for catalytic activity. cFLIP S also contains two DEDs, but it lacks almost the entire caspase-like domain. Both cFLIP L and cFLIP S can be recruited into the DISC, where they bind to either FADD or caspase-8 through DED-DED interactions, resulting in inhibition of caspase-8 activation and inhibition of subsequent apoptosis. 48 Initially, cFLIP was reported to have both proapoptotic [49] [50] [51] [52] and antiapoptotic effects; [53] [54] [55] [56] however, the proapoptotic effect was soon recognized to occur only in transient transfection systems, where excessive cFLIP expression could result in nonspecific cell death. 57 On the other hand, use of stable expression systems and cFLIP-deficient models TRAIL-induced apoptosis in cancer L Zhang and B Fang resulted in only the antiapoptotic effect being observed. 58, 59 Expression of cFLIP was recently reported to correlate strongly with malignant potential in colonic adenocarcinomas, melanoma, and hepatocellular carcinoma. [60] [61] [62] Changes in the cFLIP/caspase-8 ratio have also been reported to correlate with TRAIL resistance in several different tumors, including melanoma, hepatocellular carcinoma, Burkitt's lymphoma, and B-cell chronic lymphocytic leukemia. 62, 63 Downregulation of cFLIP expression by using antisense RNA or siRNA may be a worthwhile strategy to explore for overcoming TRAIL resistance in types of cancer in which cFLIP overexpression is a key determinant of TRAIL resistance.", "cite_spans": [{"start": 68, "end": 70, "text": "48", "ref_id": "BIBREF47"}, {"start": 645, "end": 647, "text": "48", "ref_id": "BIBREF47"}, {"start": 704, "end": 708, "text": "[49]", "ref_id": "BIBREF48"}, {"start": 709, "end": 713, "text": "[50]", "ref_id": "BIBREF49"}, {"start": 714, "end": 718, "text": "[51]", "ref_id": "BIBREF50"}, {"start": 719, "end": 723, "text": "[52]", "ref_id": "BIBREF51"}, {"start": 751, "end": 755, "text": "[53]", "ref_id": "BIBREF52"}, {"start": 756, "end": 760, "text": "[54]", "ref_id": "BIBREF53"}, {"start": 761, "end": 765, "text": "[55]", "ref_id": "BIBREF54"}, {"start": 766, "end": 770, "text": "[56]", "ref_id": "BIBREF55"}, {"start": 946, "end": 948, "text": "57", "ref_id": "BIBREF56"}, {"start": 1139, "end": 1142, "text": "58,", "ref_id": "BIBREF57"}, {"start": 1143, "end": 1145, "text": "59", "ref_id": "BIBREF58"}, {"start": 1303, "end": 1307, "text": "[60]", "ref_id": "BIBREF59"}, {"start": 1308, "end": 1312, "text": "[61]", "ref_id": "BIBREF60"}, {"start": 1313, "end": 1317, "text": "[62]", "ref_id": "BIBREF61"}, {"start": 1550, "end": 1553, "text": "62,", "ref_id": "BIBREF61"}, {"start": 1554, "end": 1556, "text": "63", "ref_id": "BIBREF62"}], "ref_spans": []}, {"section": "6,7 cFLIP", "text": "Despite findings that several types of malignant tumor express high levels of cFLIP and that overexpression of cFLIP can confer resistance to TRAIL and other death ligands, the physiological function of cFLIP remains unclear. However, it was recently postulated that cancer cells may acquire a certain degree of immune privilege by becoming resistant to death ligands such as TRAIL or FasL, and cFLIP may help in this process. 64 One group assessed the effect of cFLIP in tumorigenesis and immune escape by using stable cFLIP transfectants. In that system, inoculation of transfectants expressing little or no cFLIP into immunocompetent mice resulted in rejection of the transfectants in most mice, but inoculation of transfectants with high cFLIP expression into the same types of mice led to tumor development. In contrast, inoculation of either type of transfected cells into nude mice led to the formation of tumors that grew at the same rate regardless of cFLIP expression level. Thus, it seems that tumor cells that express little or no cFLIP can be eliminated to some extent through selective pressure by the immune system, but tumor cells that express high levels of cFLIP can escape immune surveillance. These findings suggest that immune therapy may be another useful approach for cancer therapy. 65 ", "cite_spans": [{"start": 427, "end": 429, "text": "64", "ref_id": "BIBREF63"}, {"start": 1307, "end": 1309, "text": "65", "ref_id": "BIBREF64"}], "ref_spans": []}, {"section": "Bcl-2 family and TRAIL resistance", "text": "During the process of TRAIL-induced apoptosis, activation of the initiator caspase-8 can transmit death signals either through direct activation of the effector caspase-3 or -7, or by means of the proapoptotic Bcl-2 family member Bid, through a mitochondrial pathway. 11 In this mitochondrial death pathway, the ratio of expression of the proapoptotic Bax protein and the antiapoptotic Bcl-2 or Bcl-X L proteins ultimately determines cell death or survival. 12, 13 The importance of the mitochondrial pathway in TRAIL-induced apoptosis depends on the cell type. Evidence implicating Bcl-2, Bcl-X L , Bax, and Bak in the mitochondrial pathway of TRAIL-induced apoptosis is reviewed in the following paragraphs.", "cite_spans": [{"start": 268, "end": 270, "text": "11", "ref_id": "BIBREF10"}, {"start": 458, "end": 461, "text": "12,", "ref_id": "BIBREF11"}, {"start": 462, "end": 464, "text": "13", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "Bcl-2 and Bcl-X L", "text": "Overexpression of Bcl-X L or Bcl-2 can protect some types of cells against TRAIL-mediated apoptosis, suggesting that the mitochondrial pathway predominates in these types of cells. Bcl-X L expression correlated highly with sensitivity to TRAIL-induced apoptosis in three pancreatic adenocarcinoma cell lines. 5 The cell line Colo357, originally sensitive to TRAIL and expressing low levels of Bcl-X L , became resistant to TRAIL after Bcl-X L expression was restored by means of a retrovirus. Interestingly, Bcl-X L -overexpressing Colo357 cells, although resistant to TRAIL, had the same degree of caspase-8 cleavage as did the parental Colo357 cells, suggesting that caspase-8 activation was independent and upstream of the mitochondrial pathway. In another study, 66 overexpression of Bcl-2 conferred protection against TRAIL in neuroblastoma, glioblastoma, and breast cancer cell lines, but reduced TRAIL-induced caspase-8 cleavage, suggesting that caspase-8 was activated both upstream and downstream of the mitochondria in these cells upon treatment with TRAIL. As apoptosis induced by chemotherapy acts mainly through the mitochondrial pathway, 11 downregulation of Bcl-2 or Bcl-X L might restore sensitivity not only to chemotherapy but also to TRAIL in some types of cancer.", "cite_spans": [{"start": 309, "end": 310, "text": "5", "ref_id": "BIBREF4"}, {"start": 767, "end": 769, "text": "66", "ref_id": "BIBREF65"}, {"start": 1152, "end": 1154, "text": "11", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "Bax and Bak", "text": "Mutational inactivation of the proapoptotic genes of Bax or Bak can render cancer cells resistant to apoptosis induced by TRAIL or chemotherapy. The importance of both molecules in apoptosis was demonstrated by the discovery that TRAIL could induce cytochrome c release and apoptosis in wild-type, Bax \u00c0/\u00c0 or Bak \u00c0/\u00c0 mouse embryonic fibroblasts, but not in double-knockout Bax \u00c0/\u00c0 /Bak \u00c0/\u00c0 cells. 67 These findings suggest that, functionally, Bax and Bak can substitute for each other in these cells, because knocking out only one of the two genes was not sufficient to confer resistance to TRAILinduced apoptosis. This does not seem to be the case for other types of cells, however. For example, the human colon cancer cell line HCT116, which expresses Bak, required Bax for TRAIL-induced apoptosis. 68 In that study, TRAIL produced rapid apoptosis in a single-alleleinactivated clone (Bax \u00fe /\u00c0 ) but not in a double-alleleinactivated clone (Bax \u00c0/\u00c0 ). In another study, Bakdeficient Jurkat cells were more resistant than wild-type Jurkat cells to apoptosis induced by UV, staurosporin, VP-16, bleomycin, or cisplatin. Restoring the Bak gene restored cytochrome c release and the sensitivity of the Bak-deficient cells to VP-16. Recombinant Bak could also induce cytochrome c release from mitochondria purified from Bax \u00c0/\u00c0 mice, suggesting that Bak plays an essential role, independent of Bax, in cytochrome c release and overcoming chemoresistance in Jurkat cells. 69 In conclusion, the importance of Bax, Bak or both in TRAIL-or chemotherapy drug-induced apoptosis seems to depend on the cell type.", "cite_spans": [{"start": 397, "end": 399, "text": "67", "ref_id": "BIBREF66"}, {"start": 801, "end": 803, "text": "68", "ref_id": "BIBREF67"}, {"start": 1468, "end": 1470, "text": "69", "ref_id": "BIBREF68"}], "ref_spans": []}, {"section": "Bax and Bak", "text": "Inhibitors of apoptosis (IAP) proteins, Smac/Diablo, and TRAIL resistance IAP proteins can block apoptotic events by inhibiting the catalytic activity of effector caspases (e.g., -3 and -7) or by TRAIL-induced apoptosis in cancer L Zhang and B Fang blocking the activation of the apopsomal caspase-9 by directly interacting with the active sites of these caspases. Each IAP contains one or three tandem repeats of an evolutionarily conserved domain termed baculovirus inhibitory repeat (BIR). Different BIRs are thought to have different preferences for distinct caspases. So far, six mammalian IAPs have been identified: cIAP1, cIAP2, Xlinked inhibitor of apoptosis (XIAP), neuronal apoptosis inhibitory protein (NAIP), survivin, and BIR repeatcontaining ubiquitin-conjugating enzyme (BRUCE). XIAP is the most potent inhibitor of caspase activity. 70, 71 High expression of IAPs in cancer cells can confer resistance to TRAIL-induced apoptosis.", "cite_spans": [{"start": 849, "end": 852, "text": "70,", "ref_id": "BIBREF69"}, {"start": 853, "end": 855, "text": "71", "ref_id": "BIBREF70"}], "ref_spans": []}, {"section": "72,73", "text": "The activity of IAPs can be blocked by Smac/Diablo, a mitochondrial protein that is released into the cytosol at some point during the apoptotic cascade, where it promotes cell death by eliminating IAP inhibition of caspases. 74, 75 Smac/Diablo is thought to interact with the BIR regions on IAPs, thereby releasing the caspases and promoting apoptosis. Blocking the release of Smac/ Diablo from the mitochondria has been associated with resistance to TRAIL in some, but not all, melanoma cell lines. 76 In mitochondria-dependent type II cells, regulation of apoptosis by IAPs and Smac/Diablo is a major determinant of TRAIL sensitivity. TRAIL-resistant cancer cell lines, compared with TRAIL-sensitive cancer cell lines, show a reduced release of Smac/Diablo from the mitochondria to the cytosol. 72, 73, 76 However, overexpression of Smac/Diablo by transfection restored sensitivity to TRAIL in those cells, in addition to downregulating or cleaving XIAP, cIAP1, and cIAP2. 72, 73, 76 The release of Smac/Diablo from mitochondria, like cytochrome c, can be blocked by Bcl-2 overexpression. 76 NF-jB and TRAIL resistance NF-kB is a transcription factor that participates in the control of immune regulation, inflammatory responses, cell growth, and apoptosis. The five component subunits of NF-kB, cRel, cRelA/p65, cRelB, NF-kB1/p50, and NF-kB2/p52 form homodimeric or heterodimeric complexes and control transcription by binding NF-kB consensus sequences in the promoter regions of target genes. 77, 78 The effects of NF-kB on TRAIL signaling are controversial, with some reports showing that NF-kB activation protects cells from TRAIL-induced apoptosis 79, 80 and others showing the opposite effect that NF-kB promotes apoptosis. 81 These discrepancies, however, may reflect differences in the function and relative amounts of the NF-kB subunits. 82 Overexpression of the cRelA subunit, for example, inhibits caspase-8, DR4, and DR5 expression, and enhances IAP1 and IAP2 expression after TRAIL treatment. On the other hand, overexpression of cRel enhances DR4, DR5, and Bcl-X S expression and inhibits cIAP1 and IAP2 expression after TRAIL treatment. The relative amounts of cRel and cRelA in activated NF-kB molecules seem to determine whether the NF-kB favors apoptosis or survival. Thus, regulation of the expression of the different NF-kB subunits may be another new strategy for cancer therapy.", "cite_spans": [{"start": 226, "end": 229, "text": "74,", "ref_id": "BIBREF73"}, {"start": 230, "end": 232, "text": "75", "ref_id": "BIBREF74"}, {"start": 501, "end": 503, "text": "76", "ref_id": "BIBREF75"}, {"start": 798, "end": 801, "text": "72,", "ref_id": "BIBREF71"}, {"start": 802, "end": 805, "text": "73,", "ref_id": "BIBREF72"}, {"start": 806, "end": 808, "text": "76", "ref_id": "BIBREF75"}, {"start": 976, "end": 979, "text": "72,", "ref_id": "BIBREF71"}, {"start": 980, "end": 983, "text": "73,", "ref_id": "BIBREF72"}, {"start": 984, "end": 986, "text": "76", "ref_id": "BIBREF75"}, {"start": 1092, "end": 1094, "text": "76", "ref_id": "BIBREF75"}, {"start": 1498, "end": 1501, "text": "77,", "ref_id": "BIBREF76"}, {"start": 1502, "end": 1504, "text": "78", "ref_id": "BIBREF77"}, {"start": 1656, "end": 1659, "text": "79,", "ref_id": "BIBREF78"}, {"start": 1660, "end": 1662, "text": "80", "ref_id": "BIBREF79"}, {"start": 1733, "end": 1735, "text": "81", "ref_id": "BIBREF80"}, {"start": 1850, "end": 1852, "text": "82", "ref_id": "BIBREF81"}], "ref_spans": []}, {"section": "Mitogen-activated protein (MAP) kinases and TRAIL resistance", "text": "The MAP kinases are a superfamily of proteins that transmit signaling cascades from extracellular stimuli into cells; examples of MAP kinases include extracellular signal-regulated kinases (ERKs), c-jun N-terminal protein kinases (JNKs), and p38 MAP kinases. Like NF-kB, MAP kinases participate in a wide variety of cellular processes, including immunoregulation, inflammation, cell growth, cell differentiation, and cell death. 83 Usually, activation of ERKs in response to death stimuli is believed to have an antiapoptotic effect. In support of this conclusion were findings that TRAIL induced rapid ERK1/2 activation in a group of melanoma cell lines, and the inhibition of that activation sensitized TRAIL-resistant melanoma cells to TRAIL-induced apoptosis, suggesting that ERK1/2 activation can itself protect against TRAIL-induced cell death in these TRAIL-resistant cell lines. 84 However, TRAIL also induced rapid ERK1/2 activation in TRAIL-sensitive melanoma cell lines, indicating that ERK1/2 activation by itself is not sufficient to protect against TRAIL-induced cell death in these TRAIL-sensitive cell lines. We hypothesize here that one or more anti-ERK cofactors exist in the TRAIL-sensitive melanoma cell lines but not in the TRAIL-resistant cell lines. On the other hand, ERK activation has also been reported to have proapoptotic effects. 85 In that study, sensitization of lung cancer cells to TRAIL-induced apoptosis by PG490, a candidate chemotherapeutic agent, seemed to require ERK2 activation in that the sensitization could be blocked by inhibiting ERK2 activation. 85 Studies of p38 MAP kinase and JNK activation in TRAIL-induced apoptosis have also produced inconsistent results. In one such report, 86 use of doxorubicin and cisplatin enhanced the apoptosis-inducing activity of antibodies to TRAIL receptors; this effect was assumed to result from activation of p38 MAP kinase and JNK, as inhibition of these kinases suppressed the apoptotic effect. In another study, 87 inhibition of JNK activation was shown to block apoptosis induced by a combination of the translation inhibitor anisomycin and TRAIL. JNK activation seems to be required for TRAIL-plus-anisomycin-induced apoptosis, but it is not sufficient because activation of JNK by its upstream activator MEKK2 did not sensitize cells to TRAIL-induced apoptosis. Finally, we have noted p38 MAP kinase activation in colon cancer DLD1 cell line upon TRAIL treatment; however, inhibition of that activation was not related to development of TRAIL resistance in that cell line. 88 The functions of MAP kinases in TRAIL-induced apoptosis are further complicated by their involvement in cytokine secretion, particularly TNF-a, IL-1b, and IL-6. 89 ", "cite_spans": [{"start": 429, "end": 431, "text": "83", "ref_id": "BIBREF82"}, {"start": 887, "end": 889, "text": "84", "ref_id": "BIBREF83"}, {"start": 1360, "end": 1362, "text": "85", "ref_id": "BIBREF84"}, {"start": 1594, "end": 1596, "text": "85", "ref_id": "BIBREF84"}, {"start": 1730, "end": 1732, "text": "86", "ref_id": "BIBREF85"}, {"start": 2000, "end": 2002, "text": "87", "ref_id": "BIBREF86"}, {"start": 2564, "end": 2566, "text": "88", "ref_id": "BIBREF87"}, {"start": 2728, "end": 2730, "text": "89", "ref_id": "BIBREF88"}], "ref_spans": []}, {"section": "TRAIL-induced apoptosis in cancer L Zhang and B Fang", "text": "We hypothesize that TRAIL treatment involves different MAP kinases, different cell environments, and different cytokines, all of which interact to tip the balance in favor of cell survival or cell death.", "cite_spans": [], "ref_spans": []}, {"section": "Resistance of normal human cells or tissues to TRAILinduced apoptosis", "text": "Many approaches have been employed to overcome TRAIL resistance in cancer cells, notably by combination therapy of TRAIL with chemotherapy, or radiotherapy. However, a concern has been raised about the toxicity of such combination therapy on normal cells or tissues. 90 It is possible that methods used to sensitize TRAIL-resistant cancer cells can sensitize normal cells as well, leading to side effects. Therefore, elucidating the mechanisms of TRAIL resistance in normal cells or tissues is also an important step in TRAIL cancer therapy.", "cite_spans": [{"start": 267, "end": 269, "text": "90", "ref_id": "BIBREF89"}], "ref_spans": []}, {"section": "Resistance of normal human cells or tissues to TRAILinduced apoptosis", "text": "It is reported that expression of the decoy receptors is attributed to TRAIL resistance in normal human cells. 20, 21 However, accumulative data have already shown that the decoy receptor expression is not the only mechanism of TRAIL resistance of normal cells. For examples, DR5 receptor agonistic antibodies are capable of inducing apoptosis in DR5-expressed cancer cells, but not in normal human fibroblast cells and human hepatocytes. 91 Further studies show that the cancerous tissues express higher levels of DR5 mRNA and protein than do normal cells or tissues. As these DR5 receptor agonistic antibodies have high specificity for binding and activation of DR5 rather than other TRAIL receptors, such as DR4, DcR1, and DcR2, it is obvious that low expression of DR5 contributes to the resistance to the DR5 receptor agonistic antibodies. 91 Furthermore, when DR5 is upregulated by either MYC oncogene or doxorubicin, the normal cells can become sensitive to either the DR5 receptor agonistic antibodies or TRAIL. 24, 92 In most of the normal cells tested, DR4 shows much lower expression than that of DR5, which may also reduce TRAIL sensitivity. 91 In general, current data suggest that, in certain normal cells or tissues, the ratio of expression between real death receptor DR4 and DR5, and decoy receptors DcR1 and DcR2, may determine the TRAIL sensitivity. 20, 21, 24, 91, 92 Liver toxicity is a major concern for application of TRAIL gene therapy to human cancer patients. Although the human liver toxicity could be caused by special TRAIL protein preparation, such as tagged histidine or leucine, 93 the full length of TRAIL protein can readily induce liver toxicity. 2 However, the ratio of expression between death receptors DR4 and DR5, and decoy receptors DcR1 and DcR2, does not correlate with the sensitivity of hepatocytes to TRAIL, 94 suggesting that other molecules in the signaling pathway of TRAILinduced apoptosis may determine the fate of normal cells in response to TRAIL. In fact, in addition to the death receptors, overexpression of cFLIP and IAPs has also been reported to play a major role in protection of certain human normal cells, such as melanocytes and lung and foreskin fibroblasts, from TRAIL-induced apoptosis. 24, 95 However, no cFLIP and IAP expression knockdown experiments are performed in these reports. Therefore, much has to be done before we can completely picture the mechanisms of TRAIL resistance in normal human cells or tissues.", "cite_spans": [{"start": 111, "end": 114, "text": "20,", "ref_id": "BIBREF19"}, {"start": 115, "end": 117, "text": "21", "ref_id": "BIBREF20"}, {"start": 439, "end": 441, "text": "91", "ref_id": "BIBREF90"}, {"start": 845, "end": 847, "text": "91", "ref_id": "BIBREF90"}, {"start": 1020, "end": 1023, "text": "24,", "ref_id": "BIBREF23"}, {"start": 1024, "end": 1026, "text": "92", "ref_id": "BIBREF91"}, {"start": 1154, "end": 1156, "text": "91", "ref_id": "BIBREF90"}, {"start": 1369, "end": 1372, "text": "20,", "ref_id": "BIBREF19"}, {"start": 1373, "end": 1376, "text": "21,", "ref_id": "BIBREF20"}, {"start": 1377, "end": 1380, "text": "24,", "ref_id": "BIBREF23"}, {"start": 1381, "end": 1384, "text": "91,", "ref_id": "BIBREF90"}, {"start": 1385, "end": 1387, "text": "92", "ref_id": "BIBREF91"}, {"start": 1611, "end": 1613, "text": "93", "ref_id": "BIBREF92"}, {"start": 1682, "end": 1683, "text": "2", "ref_id": "BIBREF1"}, {"start": 1854, "end": 1856, "text": "94", "ref_id": "BIBREF93"}, {"start": 2253, "end": 2256, "text": "24,", "ref_id": "BIBREF23"}, {"start": 2257, "end": 2259, "text": "95", "ref_id": "BIBREF94"}], "ref_spans": []}, {"section": "Future prospects", "text": "The concept of using recombinant TRAIL genes and proteins for cancer therapy has attracted much attention in anticancer research. Nevertheless, the potential for hepatotoxicity and the resistance of many tumor cells to TRAIL protein, recombinant or otherwise, has prevented this approach from entering clinical trials. Although TRAIL-mediated systemic toxicity might be prevented by targeted TRAIL gene therapy or other approaches, characterizing the mechanisms of resistance and developing strategies to overcome that resistance are still critical for future successes. Ongoing progress in molecular biology and cancer biology will certainly shed further light on TRAIL-mediated death signal transduction from the membrane to the nucleus, as well as the molecular events that stop this transduction. Although resistance to TRAIL in some cell types remains to be characterized, accumulating evidence suggests that combination therapy with TRAIL protein and chemotherapeutic drugs or radiation may overcome resistance to TRAIL. 96 The synergy can be achieved either through upregulating death receptors DR4 or DR5, caspase-3, caspase-8, or bax, or through downregulating Bcl-X L or cFLIP. This synergy leads to the expectation that the combination of TRAIL with chemotherapy and radiotherapy will play a major role in cancer therapy with TRAIL.", "cite_spans": [{"start": 1027, "end": 1029, "text": "96", "ref_id": "BIBREF95"}], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Induction of apoptosis by Apo-2 ligand, a new member of the tumor necrosis factor cytokine family", "authors": [{"first": "R", "middle": ["M"], "last": "Pitti", "suffix": ""}, {"first": "S", "middle": ["A"], "last": "Marsters", "suffix": ""}, {"first": "S", "middle": [], "last": "Ruppert", "suffix": ""}], "year": 1996, "venue": "J Biol Chem", "link": "23458542"}, "BIBREF1": {"title": "Targeted expression of green fluorescent protein/tumor necrosis factor-related apoptosisinducing ligand fusion protein from human telomerase reverse transcriptase promoter elicits antitumor activity without toxic effects on primary human hepatocytes", "authors": [{"first": "T", "middle": [], "last": "Lin", "suffix": ""}, {"first": "J", "middle": [], "last": "Gu", "suffix": ""}, {"first": "L", "middle": [], "last": "Zhang", "suffix": ""}], "year": 2002, "venue": "Cancer Res", "link": "16037657"}, "BIBREF2": {"title": "Adenoviral gene transfer of tumor necrosis factor-related apoptosis-inducing ligand overcomes an impaired response of hepatoma cells but causes severe apoptosis in primary human hepatocytes", "authors": [{"first": "S", "middle": [], "last": "Armeanu", "suffix": ""}, {"first": "U", "middle": ["M"], "last": "Lauer", "suffix": ""}, {"first": "I", "middle": [], "last": "Smirnow", "suffix": ""}], "year": 2003, "venue": "Cancer Res", "link": "41354376"}, "BIBREF3": {"title": "A novel single tetracyclineregulative adenoviral vector for tumor-specific Bax gene expression and cell killing in vitro and in vivo", "authors": [{"first": "J", "middle": [], "last": "Gu", "suffix": ""}, {"first": "L", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "X", "middle": [], "last": "Huang", "suffix": ""}], "year": 2002, "venue": "Oncogene", "link": "21903938"}, "BIBREF4": {"title": "Bcl-XL protects pancreatic adenocarcinoma cells against CD95-and TRAIL-receptor-mediated apoptosis", "authors": [{"first": "S", "middle": [], "last": "Hinz", "suffix": ""}, {"first": "A", "middle": [], "last": "Trauzold", "suffix": ""}, {"first": "L", "middle": [], "last": "Boenicke", "suffix": ""}], "year": 2000, "venue": "Oncogene", "link": "20564234"}, "BIBREF5": {"title": "Sensitization for death receptor-or drug-induced apoptosis by re-expression of caspase-8 through demethylation or gene transfer. Oncogene", "authors": [{"first": "S", "middle": [], "last": "Fulda", "suffix": ""}, {"first": "M", "middle": ["U"], "last": "Kufer", "suffix": ""}, {"first": "E", "middle": [], "last": "Meyer", "suffix": ""}], "year": 2001, "venue": "", "link": "24679757"}, "BIBREF6": {"title": "Resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in neuroblastoma cells correlates with a loss of caspase-8 expression", "authors": [{"first": "A", "middle": [], "last": "Eggert", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Grotzer", "suffix": ""}, {"first": "T", "middle": ["J"], "last": "Zuzak", "suffix": ""}], "year": 2001, "venue": "Cancer Res", "link": "25949058"}, "BIBREF7": {"title": "Mechanisms involved in development of resistance to adenovirus-mediated proapoptotic gene therapy in DLD1 human colon cancer cell line", "authors": [{"first": "L", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "J", "middle": [], "last": "Gu", "suffix": ""}, {"first": "T", "middle": [], "last": "Lin", "suffix": ""}], "year": 2002, "venue": "Gene Therapy", "link": "27449039"}, "BIBREF8": {"title": "The receptor for the cytotoxic ligand TRAIL", "authors": [{"first": "G", "middle": [], "last": "Pan", "suffix": ""}, {"first": "K", "middle": [], "last": "O&apos;rourke", "suffix": ""}, {"first": "A", "middle": ["M"], "last": "Chinnaiyan", "suffix": ""}], "year": 1997, "venue": "Science", "link": "19984057"}, "BIBREF9": {"title": "TRAIL-R2: a novel apoptosis-mediating receptor for TRAIL", "authors": [{"first": "H", "middle": [], "last": "Walczak", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Degli-Esposti", "suffix": ""}, {"first": "R", "middle": ["S"], "last": "Johnson", "suffix": ""}], "year": 1997, "venue": "EMBO J", "link": "40695710"}, "BIBREF10": {"title": "The kiss of death: promises and failures of death receptors and ligands in cancer therapy", "authors": [{"first": "P", "middle": ["T"], "last": "Daniel", "suffix": ""}, {"first": "T", "middle": [], "last": "Wieder", "suffix": ""}, {"first": "I", "middle": [], "last": "Sturm", "suffix": ""}], "year": 2001, "venue": "Leukemia", "link": "24538645"}, "BIBREF11": {"title": "Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c", "authors": [{"first": "X", "middle": [], "last": "Liu", "suffix": ""}, {"first": "C", "middle": ["N"], "last": "Kim", "suffix": ""}, {"first": "J", "middle": [], "last": "Yang", "suffix": ""}], "year": 1996, "venue": "Cell", "link": "12604356"}, "BIBREF12": {"title": "The release of cytochrome c from mitochondria: a primary site for Bcl-2 regulation of apoptosis", "authors": [{"first": "R", "middle": ["M"], "last": "Kluck", "suffix": ""}, {"first": "E", "middle": [], "last": "Bossy-Wetzel", "suffix": ""}, {"first": "D", "middle": ["R"], "last": "Green", "suffix": ""}], "year": 1997, "venue": "Science", "link": "8025067"}, "BIBREF13": {"title": "Induction of TNF receptor Imediated apoptosis via two sequential signaling complexes", "authors": [{"first": "O", "middle": [], "last": "Micheau", "suffix": ""}, {"first": "J", "middle": [], "last": "Tschopp", "suffix": ""}], "year": 2003, "venue": "Cell", "link": "17145731"}, "BIBREF14": {"title": "Death receptor 5, a new member of the TNFR family, and DR4 induce FADDdependent apoptosis and activate the NF-kappaB pathway", "authors": [{"first": "P", "middle": ["M"], "last": "Chaudhary", "suffix": ""}, {"first": "M", "middle": [], "last": "Eby", "suffix": ""}, {"first": "A", "middle": [], "last": "Jasmin", "suffix": ""}], "year": 1997, "venue": "Immunity", "link": null}, "BIBREF15": {"title": "TRAIL receptors 1 (DR4) and 2 (DR5) signal FADD-dependent apoptosis and activate NF-kappaB", "authors": [{"first": "P", "middle": [], "last": "Schneider", "suffix": ""}, {"first": "M", "middle": [], "last": "Thome", "suffix": ""}, {"first": "K", "middle": [], "last": "Burns", "suffix": ""}], "year": 1997, "venue": "Immunity", "link": "10739543"}, "BIBREF16": {"title": "Cloning and characterization of TRAIL-R3, a novel member of the emerging TRAIL receptor family", "authors": [{"first": "M", "middle": ["A"], "last": "Degli-Esposti", "suffix": ""}, {"first": "P", "middle": ["J"], "last": "Smolak", "suffix": ""}, {"first": "H", "middle": [], "last": "Walczak", "suffix": ""}], "year": 1997, "venue": "J Exp Med", "link": "10947748"}, "BIBREF17": {"title": "The novel receptor TRAIL-R4 induces NF-kappaB and protects against TRAIL-mediated apoptosis, yet retains an incomplete death domain", "authors": [{"first": "M", "middle": ["A"], "last": "Degli-Esposti", "suffix": ""}, {"first": "W", "middle": ["C"], "last": "Dougall", "suffix": ""}, {"first": "P", "middle": ["J"], "last": "Smolak", "suffix": ""}], "year": 1997, "venue": "Immunity", "link": "21589100"}, "BIBREF18": {"title": "Osteoprotegerin is a receptor for the cytotoxic ligand TRAIL", "authors": [{"first": "J", "middle": ["G"], "last": "Emery", "suffix": ""}, {"first": "P", "middle": [], "last": "Mcdonnell", "suffix": ""}, {"first": "M", "middle": ["B"], "last": "Burke", "suffix": ""}], "year": 1998, "venue": "J Biol Chem", "link": "25376129"}, "BIBREF19": {"title": "An antagonist decoy receptor and a death domain-containing receptor for TRAIL", "authors": [{"first": "G", "middle": [], "last": "Pan", "suffix": ""}, {"first": "J", "middle": [], "last": "Ni", "suffix": ""}, {"first": "Y", "middle": ["F"], "last": "Wei", "suffix": ""}], "year": 1997, "venue": "Science", "link": "44751196"}, "BIBREF20": {"title": "Control of TRAIL-induced apoptosis by a family of signaling and decoy receptors", "authors": [{"first": "J", "middle": ["P"], "last": "Sheridan", "suffix": ""}, {"first": "S", "middle": ["A"], "last": "Marsters", "suffix": ""}, {"first": "R", "middle": ["M"], "last": "Pitti", "suffix": ""}], "year": 1997, "venue": "Science", "link": null}, "BIBREF21": {"title": "Intracellular regulation of TRAIL-induced apoptosis in human melanoma cells", "authors": [{"first": "T", "middle": ["S"], "last": "Griffith", "suffix": ""}, {"first": "W", "middle": ["A"], "last": "Chin", "suffix": ""}, {"first": "G", "middle": ["C"], "last": "Jackson", "suffix": ""}], "year": 1998, "venue": "J Immunol", "link": null}, "BIBREF22": {"title": "Nucleotide substitution in the ectodomain of trail receptor DR4 is associated with lung cancer and head and neck cancer", "authors": [{"first": "M", "middle": ["J"], "last": "Fisher", "suffix": ""}, {"first": "A", "middle": ["K"], "last": "Virmani", "suffix": ""}, {"first": "L", "middle": [], "last": "Wu", "suffix": ""}], "year": 2001, "venue": "Clin Cancer Res", "link": "17728940"}, "BIBREF23": {"title": "Molecular determinants of response to TRAIL in killing of normal and cancer cells", "authors": [{"first": "K", "middle": [], "last": "Kim", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Fisher", "suffix": ""}, {"first": "S", "middle": ["Q"], "last": "Xu", "suffix": ""}], "year": 2000, "venue": "Clin Cancer Res", "link": "32572524"}, "BIBREF24": {"title": "Homozygous deletion of the death receptor DR4 gene in a nasopharyngeal cancer cell line is associated with TRAIL resistance", "authors": [{"first": "N", "middle": [], "last": "Ozoren", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Fisher", "suffix": ""}, {"first": "K", "middle": [], "last": "Kim", "suffix": ""}], "year": 2000, "venue": "Int J Oncol", "link": "13159601"}, "BIBREF25": {"title": "Mutations of tumor necrosis factor-related apoptosis-inducing ligand receptor 1 (TRAIL-R1) and receptor 2 (TRAIL-R2) genes in metastatic breast cancers", "authors": [{"first": "M", "middle": ["S"], "last": "Shin", "suffix": ""}, {"first": "H", "middle": ["S"], "last": "Kim", "suffix": ""}, {"first": "S", "middle": ["H"], "last": "Lee", "suffix": ""}], "year": 2001, "venue": "Cancer Res", "link": "40106596"}, "BIBREF26": {"title": "Somatic mutations of TRAIL-receptor 1 and TRAIL-receptor 2 genes in nonHodgkin's lymphoma", "authors": [{"first": "S", "middle": ["H"], "last": "Lee", "suffix": ""}, {"first": "M", "middle": ["S"], "last": "Shin", "suffix": ""}, {"first": "H", "middle": ["S"], "last": "Kim", "suffix": ""}], "year": 2001, "venue": "Oncogene", "link": "23184206"}, "BIBREF27": {"title": "Rare loss-of-function mutation of a death receptor gene in head and neck cancer", "authors": [{"first": "S", "middle": ["I"], "last": "Pai", "suffix": ""}, {"first": "G", "middle": ["S"], "last": "Wu", "suffix": ""}, {"first": "N", "middle": [], "last": "Ozoren", "suffix": ""}], "year": 1998, "venue": "Cancer Res", "link": "23155599"}, "BIBREF28": {"title": "Alterations of the DR5/ TRAIL receptor 2 gene in non-small cell lung cancers", "authors": [{"first": "S", "middle": ["H"], "last": "Lee", "suffix": ""}, {"first": "M", "middle": ["S"], "last": "Shin", "suffix": ""}, {"first": "H", "middle": ["S"], "last": "Kim", "suffix": ""}], "year": 1999, "venue": "Cancer Res", "link": "15639417"}, "BIBREF29": {"title": "Mutation of the DR5/TRAIL receptor 2 gene is infrequent in hepatocellular carcinoma", "authors": [{"first": "Y", "middle": ["M"], "last": "Jeng", "suffix": ""}, {"first": "H", "middle": ["C"], "last": "Hsu", "suffix": ""}], "year": 2002, "venue": "Cancer Lett", "link": "44862631"}, "BIBREF30": {"title": "Cytotoxicitydependent APO-1 (Fas/CD95)-associated proteins form a death-inducing signaling complex (DISC) with the receptor", "authors": [{"first": "F", "middle": ["C"], "last": "Kischkel", "suffix": ""}, {"first": "S", "middle": [], "last": "Hellbardt", "suffix": ""}, {"first": "I", "middle": [], "last": "Behrmann", "suffix": ""}], "year": 1995, "venue": "EMBO J", "link": "34285728"}, "BIBREF31": {"title": "Identification and molecular cloning of two novel receptors for the cytotoxic ligand TRAIL", "authors": [{"first": "M", "middle": [], "last": "Macfarlane", "suffix": ""}, {"first": "M", "middle": [], "last": "Ahmad", "suffix": ""}, {"first": "S", "middle": ["M"], "last": "Srinivasula", "suffix": ""}], "year": 1997, "venue": "J Biol Chem", "link": "41815523"}, "BIBREF32": {"title": "A caspase-8-independent component in TRAIL/Apo-2L-induced cell death in human rhabdomyosarcoma cells", "authors": [{"first": "I", "middle": [], "last": "Petak", "suffix": ""}, {"first": "R", "middle": [], "last": "Vernes", "suffix": ""}, {"first": "K", "middle": ["S"], "last": "Szucs", "suffix": ""}], "year": 2003, "venue": "Cell Death Differ", "link": "37285442"}, "BIBREF33": {"title": "Dominant-negative FADD inhibits TNFR60-, Fas/Apo1-and TRAIL-R/Apo2-mediated cell death but not gene induction", "authors": [{"first": "H", "middle": [], "last": "Wajant", "suffix": ""}, {"first": "F", "middle": ["J"], "last": "Johannes", "suffix": ""}, {"first": "E", "middle": [], "last": "Haas", "suffix": ""}], "year": 1998, "venue": "Curr Biol", "link": "6269984"}, "BIBREF34": {"title": "FADD is required for DR4-and DR5-mediated apoptosis: lack of trail-induced apoptosis in FADD-deficient mouse embryonic fibroblasts", "authors": [{"first": "A", "middle": ["A"], "last": "Kuang", "suffix": ""}, {"first": "G", "middle": ["E"], "last": "Diehl", "suffix": ""}, {"first": "J", "middle": [], "last": "Zhang", "suffix": ""}], "year": 2000, "venue": "J Biol Chem", "link": "25622253"}, "BIBREF35": {"title": "FADD: essential for embryo development and signaling from some, but not all, inducers of apoptosis", "authors": [{"first": "W", "middle": ["C"], "last": "Yeh", "suffix": ""}, {"first": "J", "middle": ["L"], "last": "Pompa", "suffix": ""}, {"first": "M", "middle": ["E"], "last": "Mccurrach", "suffix": ""}], "year": 1998, "venue": "Science", "link": "45417124"}, "BIBREF36": {"title": "TRAIL receptor-2 signals apoptosis through FADD and caspase-8", "authors": [{"first": "J", "middle": ["L"], "last": "Bodmer", "suffix": ""}, {"first": "N", "middle": [], "last": "Holler", "suffix": ""}, {"first": "S", "middle": [], "last": "Reynard", "suffix": ""}], "year": 2000, "venue": "Nat Cell Biol", "link": "13547815"}, "BIBREF37": {"title": "Signaling events triggered by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL): caspase-8 is required for TRAIL-induced apoptosis", "authors": [{"first": "D", "middle": ["W"], "last": "Seol", "suffix": ""}, {"first": "J", "middle": [], "last": "Li", "suffix": ""}, {"first": "M", "middle": ["H"], "last": "Seol", "suffix": ""}], "year": 2001, "venue": "Cancer Res", "link": "17054326"}, "BIBREF38": {"title": "Caspase-10 is recruited to and activated at the native TRAIL and CD95 deathinducing signalling complexes in a FADD-dependent manner but can not functionally substitute caspase-8", "authors": [{"first": "M", "middle": ["R"], "last": "Sprick", "suffix": ""}, {"first": "E", "middle": [], "last": "Rieser", "suffix": ""}, {"first": "H", "middle": [], "last": "Stahl", "suffix": ""}], "year": 2002, "venue": "EMBO J", "link": "12454084"}, "BIBREF39": {"title": "Chemotherapy enhances TNF-related apoptosis-inducing ligand DISC TRAIL-induced apoptosis in cancer L Zhang and B Fang assembly in HT29 human colon cancer cells", "authors": [{"first": "S", "middle": [], "last": "Lacour", "suffix": ""}, {"first": "O", "middle": [], "last": "Micheau", "suffix": ""}, {"first": "A", "middle": [], "last": "Hammann", "suffix": ""}], "year": 2003, "venue": "Oncogene", "link": null}, "BIBREF40": {"title": "Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and TNF-alpha promote the NF-kappaB-dependent maturation of normal and leukemic myeloid cells", "authors": [{"first": "P", "middle": [], "last": "Secchiero", "suffix": ""}, {"first": "D", "middle": [], "last": "Milani", "suffix": ""}, {"first": "A", "middle": [], "last": "Gonelli", "suffix": ""}], "year": 2003, "venue": "J Leukoc Biol", "link": "22710567"}, "BIBREF41": {"title": "Pleiotropic defects in lymphocyte activation caused by caspase-8 mutations lead to human immunodeficiency", "authors": [{"first": "H", "middle": ["J"], "last": "Chun", "suffix": ""}, {"first": "L", "middle": [], "last": "Zheng", "suffix": ""}, {"first": "M", "middle": [], "last": "Ahmad", "suffix": ""}], "year": 2002, "venue": "Nature", "link": "4359174"}, "BIBREF42": {"title": "Caspase-10 is an initiator caspase in death receptor signaling", "authors": [{"first": "J", "middle": [], "last": "Wang", "suffix": ""}, {"first": "H", "middle": ["J"], "last": "Chun", "suffix": ""}, {"first": "W", "middle": [], "last": "Wong", "suffix": ""}], "year": 2001, "venue": "Proc Natl Acad Sci USA", "link": "26651916"}, "BIBREF43": {"title": "Death receptor recruitment of endogenous caspase-10 and apoptosis initiation in the absence of caspase-8", "authors": [{"first": "F", "middle": ["C"], "last": "Kischkel", "suffix": ""}, {"first": "D", "middle": ["A"], "last": "Lawrence", "suffix": ""}, {"first": "A", "middle": [], "last": "Tinel", "suffix": ""}], "year": 2001, "venue": "J Biol Chem", "link": "29074096"}, "BIBREF44": {"title": "Induction of caspase 8 by interferon gamma renders some neuroblastoma (NB) cells sensitive to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) but reveals that a lack of membrane TR1/TR2 also contributes to TRAIL resistance in NB", "authors": [{"first": "X", "middle": [], "last": "Yang", "suffix": ""}, {"first": "M", "middle": ["S"], "last": "Merchant", "suffix": ""}, {"first": "M", "middle": ["E"], "last": "Romero", "suffix": ""}], "year": 2003, "venue": "Cancer Res", "link": "25879634"}, "BIBREF45": {"title": "Caspase 8 is deleted or silenced preferentially in childhood neuroblastomas with amplification of MYCN", "authors": [{"first": "T", "middle": [], "last": "Teitz", "suffix": ""}, {"first": "T", "middle": [], "last": "Wei", "suffix": ""}, {"first": "M", "middle": ["B"], "last": "Valentine", "suffix": ""}], "year": 2000, "venue": "Nat Med", "link": "25747999"}, "BIBREF46": {"title": "Silencing of death receptor and caspase-8 expression in small cell lung carcinoma cell lines and tumors by DNA methylation", "authors": [{"first": "S", "middle": [], "last": "Hopkins-Donaldson", "suffix": ""}, {"first": "A", "middle": [], "last": "Ziegler", "suffix": ""}, {"first": "S", "middle": [], "last": "Kurtz", "suffix": ""}], "year": 2003, "venue": "Cell Death Differ", "link": "19345992"}, "BIBREF47": {"title": "FLICEinhibitory proteins: regulators of death receptor-mediated apoptosis", "authors": [{"first": "A", "middle": [], "last": "Krueger", "suffix": ""}, {"first": "S", "middle": [], "last": "Baumann", "suffix": ""}, {"first": "P", "middle": ["H"], "last": "Krammer", "suffix": ""}], "year": 2001, "venue": "Mol Cell Biol", "link": null}, "BIBREF48": {"title": "CASH, a novel caspase homologue with death effector domains", "authors": [{"first": "Y", "middle": ["V"], "last": "Goltsev", "suffix": ""}, {"first": "A", "middle": ["V"], "last": "Kovalenko", "suffix": ""}, {"first": "E", "middle": [], "last": "Arnold", "suffix": ""}], "year": 1997, "venue": "J Biol Chem", "link": "21556803"}, "BIBREF49": {"title": "MRIT, a novel death-effector domain-containing protein, interacts with caspases and BclXL and initiates cell death", "authors": [{"first": "D", "middle": ["K"], "last": "Han", "suffix": ""}, {"first": "P", "middle": ["M"], "last": "Chaudhary", "suffix": ""}, {"first": "M", "middle": ["E"], "last": "Wright", "suffix": ""}], "year": 1997, "venue": "Proc Natl Acad Sci USA", "link": "11312901"}, "BIBREF50": {"title": "CLARP, a death effector domain-containing protein interacts with caspase-8 and regulates apoptosis", "authors": [{"first": "N", "middle": [], "last": "Inohara", "suffix": ""}, {"first": "T", "middle": [], "last": "Koseki", "suffix": ""}, {"first": "Y", "middle": [], "last": "Hu", "suffix": ""}], "year": 1997, "venue": "Proc Natl Acad Sci USA", "link": "33950166"}, "BIBREF51": {"title": "Casper is a FADD-and caspase-related inducer of apoptosis", "authors": [{"first": "H", "middle": ["B"], "last": "Shu", "suffix": ""}, {"first": "D", "middle": ["R"], "last": "Halpin", "suffix": ""}, {"first": "D", "middle": ["V"], "last": "Goeddel", "suffix": ""}], "year": 1997, "venue": "Immunity", "link": "206121592"}, "BIBREF52": {"title": "I-FLICE, a novel inhibitor of tumor necrosis factor receptor-1-and CD-95-induced apoptosis", "authors": [{"first": "S", "middle": [], "last": "Hu", "suffix": ""}, {"first": "C", "middle": [], "last": "Vincenz", "suffix": ""}, {"first": "J", "middle": [], "last": "Ni", "suffix": ""}], "year": 1997, "venue": "J Biol Chem", "link": "37991856"}, "BIBREF53": {"title": "Inhibition of death receptor signals by cellular FLIP", "authors": [{"first": "M", "middle": [], "last": "Irmler", "suffix": ""}, {"first": "M", "middle": [], "last": "Thome", "suffix": ""}, {"first": "M", "middle": [], "last": "Hahne", "suffix": ""}], "year": 1997, "venue": "Nature", "link": "4341495"}, "BIBREF54": {"title": "Cell death attenuation by 'Usurpin', a mammalian DED-caspase homologue that precludes caspase-8 recruitment and activation by the CD-95 (Fas, APO-1) receptor complex", "authors": [{"first": "D", "middle": ["M"], "last": "Rasper", "suffix": ""}, {"first": "J", "middle": ["P"], "last": "Vaillancourt", "suffix": ""}, {"first": "S", "middle": [], "last": "Hadano", "suffix": ""}], "year": 1998, "venue": "Cell Death Differ", "link": "23395064"}, "BIBREF55": {"title": "FLAME-1, a novel FADD-like anti-apoptotic molecule that regulates Fas/TNFR1-induced apoptosis", "authors": [{"first": "S", "middle": ["M"], "last": "Srinivasula", "suffix": ""}, {"first": "M", "middle": [], "last": "Ahmad", "suffix": ""}, {"first": "S", "middle": [], "last": "Ottilie", "suffix": ""}], "year": 1997, "venue": "J Biol Chem", "link": "1369740"}, "BIBREF56": {"title": "Death-effector filaments: novel cytoplasmic structures that recruit caspases and trigger apoptosis", "authors": [{"first": "R", "middle": ["M"], "last": "Siegel", "suffix": ""}, {"first": "D", "middle": ["A"], "last": "Martin", "suffix": ""}, {"first": "L", "middle": [], "last": "Zheng", "suffix": ""}], "year": 1998, "venue": "J Cell Biol", "link": "8544089"}, "BIBREF57": {"title": "FLIP prevents apoptosis induced by death receptors but not by perforin/ granzyme B, chemotherapeutic drugs, and gamma irradiation", "authors": [{"first": "T", "middle": [], "last": "Kataoka", "suffix": ""}, {"first": "M", "middle": [], "last": "Schroter", "suffix": ""}, {"first": "M", "middle": [], "last": "Hahne", "suffix": ""}], "year": 1998, "venue": "J Immunol", "link": "19971442"}, "BIBREF58": {"title": "Cellular FLICEinhibitory protein splice variants inhibit different steps of caspase-8 activation at the CD95 death-inducing signaling complex", "authors": [{"first": "A", "middle": [], "last": "Krueger", "suffix": ""}, {"first": "I", "middle": [], "last": "Schmitz", "suffix": ""}, {"first": "S", "middle": [], "last": "Baumann", "suffix": ""}], "year": 2001, "venue": "J Biol Chem", "link": "20735019"}, "BIBREF59": {"title": "Increased expression of cFLIP(L) in colonic adenocarcinoma", "authors": [{"first": "B", "middle": ["K"], "last": "Ryu", "suffix": ""}, {"first": "M", "middle": ["G"], "last": "Lee", "suffix": ""}, {"first": "S", "middle": ["G"], "last": "Chi", "suffix": ""}], "year": 2001, "venue": "J Pathol", "link": "21122979"}, "BIBREF60": {"title": "Selective expression of FLIP in malignant melanocytic skin lesions", "authors": [{"first": "R", "middle": ["R"], "last": "Bullani", "suffix": ""}, {"first": "B", "middle": [], "last": "Huard", "suffix": ""}, {"first": "I", "middle": [], "last": "Viard-Leveugle", "suffix": ""}], "year": 2001, "venue": "J Invest Dermatol", "link": "39034908"}, "BIBREF61": {"title": "Cellular FLICE/ caspase-8-inhibitory protein as a principal regulator of cell death and survival in human hepatocellular carcinoma", "authors": [{"first": "H", "middle": [], "last": "Okano", "suffix": ""}, {"first": "K", "middle": [], "last": "Shiraki", "suffix": ""}, {"first": "H", "middle": [], "last": "Inoue", "suffix": ""}], "year": 2003, "venue": "Lab Invest", "link": "19954077"}, "BIBREF62": {"title": "Modulation of caspase-8 and FLICE-inhibitory protein expression as a potential mechanism of Epstein-Barr virus tumorigenesis in Burkitt's lymphoma", "authors": [{"first": "C", "middle": ["G"], "last": "Tepper", "suffix": ""}, {"first": "M", "middle": ["F"], "last": "Seldin", "suffix": ""}], "year": 1999, "venue": "Blood", "link": "22552477"}, "BIBREF63": {"title": "Inhibition of death receptor signaling by FLICE-inhibitory protein as a mechanism for immune escape of tumors", "authors": [{"first": "L", "middle": ["E"], "last": "French", "suffix": ""}, {"first": "J", "middle": [], "last": "Tschopp", "suffix": ""}], "year": 1999, "venue": "J Exp Med", "link": "11739808"}, "BIBREF64": {"title": "Immune escape of tumors in vivo by expression of cellular FLICE-inhibitory protein", "authors": [{"first": "J", "middle": ["P"], "last": "Medema", "suffix": ""}, {"first": "J", "middle": [], "last": "De Jong", "suffix": ""}, {"first": "T", "middle": [], "last": "Van Hall", "suffix": ""}], "year": 1999, "venue": "J Exp Med", "link": "5588285"}, "BIBREF65": {"title": "Inhibition of TRAILinduced apoptosis by Bcl-2 overexpression", "authors": [{"first": "S", "middle": [], "last": "Fulda", "suffix": ""}, {"first": "E", "middle": [], "last": "Meyer", "suffix": ""}, {"first": "K", "middle": ["M"], "last": "Debatin", "suffix": ""}], "year": 2002, "venue": "Oncogene", "link": "25226097"}, "BIBREF66": {"title": "Involvement of proapoptotic molecules Bax and Bak in tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced mitochondrial disruption and apoptosis: differential regulation of cytochrome c and Smac/DIABLO release", "authors": [{"first": "K", "middle": [], "last": "Kandasamy", "suffix": ""}, {"first": "S", "middle": ["M"], "last": "Srinivasula", "suffix": ""}, {"first": "E", "middle": ["S"], "last": "Alnemri", "suffix": ""}], "year": 2003, "venue": "Cancer Res", "link": "29598426"}, "BIBREF67": {"title": "Tumor-cell resistance to death receptor-induced apoptosis through mutational inactivation of the proapoptotic Bcl-2 homolog Bax", "authors": [{"first": "H", "middle": [], "last": "Leblanc", "suffix": ""}, {"first": "D", "middle": [], "last": "Lawrence", "suffix": ""}, {"first": "E", "middle": [], "last": "Varfolomeev", "suffix": ""}], "year": 2002, "venue": "Nat Med", "link": "1366943"}, "BIBREF68": {"title": "A role for mitochondrial Bak in apoptotic response to anticancer drugs", "authors": [{"first": "G", "middle": ["Q"], "last": "Wang", "suffix": ""}, {"first": "B", "middle": ["R"], "last": "Gastman", "suffix": ""}, {"first": "E", "middle": [], "last": "Wieckowski", "suffix": ""}], "year": 2001, "venue": "J Biol Chem", "link": "26113336"}, "BIBREF69": {"title": "A conserved family of cellular genes related to the baculovirus iap gene and encoding apoptosis inhibitors", "authors": [{"first": "C", "middle": ["S"], "last": "Duckett", "suffix": ""}, {"first": "V", "middle": ["E"], "last": "Nava", "suffix": ""}, {"first": "R", "middle": ["W"], "last": "Gedrich", "suffix": ""}], "year": 1996, "venue": "EMBO J", "link": "24069339"}, "BIBREF70": {"title": "Defining a role for the inhibitors of apoptosis proteins in prostate cancer", "authors": [{"first": "K", "middle": ["R"], "last": "Mceleny", "suffix": ""}, {"first": "R", "middle": ["W"], "last": "Watson", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Fitzpatrick", "suffix": ""}], "year": 2001, "venue": "Prostate Cancer Prostatic Dis", "link": "12443173"}, "BIBREF71": {"title": "Synergy is achieved by complementation with Apo2L/TRAIL and actinomycin D in Apo2L/TRAIL-mediated apoptosis of prostate cancer cells: role of XIAP in resistance", "authors": [{"first": "C", "middle": ["P"], "last": "Ng", "suffix": ""}, {"first": "A", "middle": [], "last": "Zisman", "suffix": ""}, {"first": "B", "middle": [], "last": "Bonavida", "suffix": ""}], "year": 2002, "venue": "Prostate", "link": "6189569"}, "BIBREF72": {"title": "X-linked inhibitor of apoptosis (XIAP) blocks Apo2 ligand/tumor necrosis factor-related apoptosisinducing ligand-mediated apoptosis of prostate cancer cells in the presence of mitochondrial activation: sensitization by overexpression of second mitochondria-derived activator of caspase/direct IAP-binding protein with low pl (Smac/ DIABLO)", "authors": [{"first": "C", "middle": ["P"], "last": "Ng", "suffix": ""}, {"first": "B", "middle": [], "last": "Bonavida", "suffix": ""}], "year": 2002, "venue": "Mol Cancer Ther", "link": null}, "BIBREF73": {"title": "Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition", "authors": [{"first": "C", "middle": [], "last": "Du", "suffix": ""}, {"first": "M", "middle": [], "last": "Fang", "suffix": ""}, {"first": "Y", "middle": [], "last": "Li", "suffix": ""}], "year": 2000, "venue": "Cell", "link": "11268259"}, "BIBREF74": {"title": "Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins", "authors": [{"first": "A", "middle": ["M"], "last": "Verhagen", "suffix": ""}, {"first": "P", "middle": ["G"], "last": "Ekert", "suffix": ""}, {"first": "M", "middle": [], "last": "Pakusch", "suffix": ""}], "year": 2000, "venue": "Cell", "link": "3192775"}, "BIBREF75": {"title": "Tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis of human melanoma is regulated by smac/DIABLO release from mitochondria", "authors": [{"first": "X", "middle": ["D"], "last": "Zhang", "suffix": ""}, {"first": "X", "middle": ["Y"], "last": "Zhang", "suffix": ""}, {"first": "C", "middle": ["P"], "last": "Gray", "suffix": ""}], "year": 2001, "venue": "Cancer Res", "link": "10478313"}, "BIBREF76": {"title": "Rel/ NF-kappaB transcription factors protect against tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-induced apoptosis by up-regulating the TRAIL decoy receptor DcR1", "authors": [{"first": "D", "middle": [], "last": "Bernard", "suffix": ""}, {"first": "B", "middle": [], "last": "Quatannens", "suffix": ""}, {"first": "B", "middle": [], "last": "Vandenbunder", "suffix": ""}], "year": 2001, "venue": "J Biol Chem", "link": "26045691"}, "BIBREF77": {"title": "Modulation of tumor necrosis factor apoptosis-inducing ligand-induced NF-kappa B activation by inhibition of apical caspases", "authors": [{"first": "N", "middle": [], "last": "Harper", "suffix": ""}, {"first": "S", "middle": ["N"], "last": "Farrow", "suffix": ""}, {"first": "A", "middle": [], "last": "Kaptein", "suffix": ""}], "year": 2001, "venue": "J Biol Chem", "link": "25204857"}, "BIBREF78": {"title": "TRAIL-mediated apoptosis requires NF-kappaB inhibition and the mitochondrial permeability transition in human hepatoma cells", "authors": [{"first": "Y", "middle": ["S"], "last": "Kim", "suffix": ""}, {"first": "R", "middle": ["F"], "last": "Schwabe", "suffix": ""}, {"first": "T", "middle": [], "last": "Qian", "suffix": ""}], "year": 2002, "venue": "Hepatology", "link": "40991406"}, "BIBREF79": {"title": "TRAIL induced survival and proliferation in cancer cells resistant towards TRAIL-induced apoptosis mediated by NF-kappaB. Oncogene", "authors": [{"first": "H", "middle": [], "last": "Ehrhardt", "suffix": ""}, {"first": "S", "middle": [], "last": "Fulda", "suffix": ""}, {"first": "I", "middle": [], "last": "Schmid", "suffix": ""}], "year": 2003, "venue": "", "link": null}, "BIBREF80": {"title": "Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) upregulates death receptor 5 (DR5) mediated by NFkappaB activation in epithelial derived cell lines", "authors": [{"first": "S", "middle": [], "last": "Shetty", "suffix": ""}, {"first": "J", "middle": ["B"], "last": "Gladden", "suffix": ""}, {"first": "E", "middle": ["S"], "last": "Henson", "suffix": ""}], "year": 2002, "venue": "Apoptosis", "link": "1261353"}, "BIBREF81": {"title": "Differential roles of RelA (p65) and c-Rel subunits of nuclear factor kappa B in tumor necrosis factor-related apoptosis-inducing ligand signaling", "authors": [{"first": "X", "middle": [], "last": "Chen", "suffix": ""}, {"first": "K", "middle": [], "last": "Kandasamy", "suffix": ""}, {"first": "R", "middle": ["K"], "last": "Srivastava", "suffix": ""}], "year": 2003, "venue": "Cancer Res", "link": "24922407"}, "BIBREF82": {"title": "From receptors to stress-activated MAP kinases", "authors": [{"first": "H", "middle": [], "last": "Ichijo", "suffix": ""}], "year": 1999, "venue": "Oncogene", "link": "40760088"}, "BIBREF83": {"title": "Activation of ERK1/2 protects melanoma cells from TRAIL-induced apoptosis by inhibiting Smac/DIABLO release from mitochondria", "authors": [{"first": "X", "middle": ["D"], "last": "Zhang", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Borrow", "suffix": ""}, {"first": "X", "middle": ["Y"], "last": "Zhang", "suffix": ""}], "year": 2003, "venue": "Oncogene", "link": "29186973"}, "BIBREF84": {"title": "PG490-mediated sensitization of lung cancer cells to Apo2L/TRAIL-induced apoptosis requires activation of ERK2", "authors": [{"first": "S", "middle": [], "last": "Frese", "suffix": ""}, {"first": "F", "middle": [], "last": "Pirnia", "suffix": ""}, {"first": "D", "middle": [], "last": "Miescher", "suffix": ""}], "year": 2003, "venue": "Oncogene", "link": "25068159"}, "BIBREF85": {"title": "Synergistic induction of tumor cell apoptosis by death receptor antibody and chemotherapy agent through JNK/p38 and mitochondrial death pathway", "authors": [{"first": "T", "middle": [], "last": "Ohtsuka", "suffix": ""}, {"first": "D", "middle": [], "last": "Buchsbaum", "suffix": ""}, {"first": "P", "middle": [], "last": "Oliver", "suffix": ""}], "year": 2003, "venue": "Oncogene", "link": "7586967"}, "BIBREF86": {"title": "Translation inhibitors sensitize prostate cancer cells to apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) by activating c-Jun N-terminal kinase", "authors": [{"first": "N", "middle": ["K"], "last": "Sah", "suffix": ""}, {"first": "A", "middle": [], "last": "Munshi", "suffix": ""}, {"first": "J", "middle": ["F"], "last": "Kurland", "suffix": ""}], "year": 2003, "venue": "J Biol Chem", "link": "42332676"}, "BIBREF87": {"title": "Lack of p38 MAP kinase activation in TRAIL-resistant cells is not related to the resistance to TRAIL-mediated cell death", "authors": [{"first": "L", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "H", "middle": [], "last": "Zhu", "suffix": ""}, {"first": "J", "middle": ["J"], "last": "Davis", "suffix": ""}], "year": 2004, "venue": "Cancer Biol Ther", "link": "37765613"}, "BIBREF88": {"title": "The p38 signal transduction pathway: activation and function", "authors": [{"first": "K", "middle": [], "last": "Ono", "suffix": ""}, {"first": "J", "middle": [], "last": "Han", "suffix": ""}], "year": 2000, "venue": "Cell Signal", "link": null}, "BIBREF89": {"title": "Enhancement of therapeutic potential of TRAIL by cancer chemotherapy and irradiation: mechanisms and clinical implications", "authors": [{"first": "S", "middle": [], "last": "Shankar", "suffix": ""}, {"first": "R", "middle": ["K"], "last": "Srivastava", "suffix": ""}], "year": 2004, "venue": "Drug Resist Updat", "link": "21338945"}, "BIBREF90": {"title": "Tumoricidal activity of a novel anti-human DR5 monoclonal antibody without hepatocyte cytotoxicity", "authors": [{"first": "K", "middle": [], "last": "Ichikawa", "suffix": ""}, {"first": "W", "middle": [], "last": "Liu", "suffix": ""}, {"first": "L", "middle": [], "last": "Zhao", "suffix": ""}], "year": 2001, "venue": "Nat Med", "link": "39250367"}, "BIBREF91": {"title": "Synthetic lethal targeting of MYC by activation of the DR5 death receptor pathway", "authors": [{"first": "Y", "middle": [], "last": "Wang", "suffix": ""}, {"first": "I", "middle": ["H"], "last": "Engels", "suffix": ""}, {"first": "D", "middle": ["A"], "last": "Knee", "suffix": ""}], "year": 2004, "venue": "Cancer Cell", "link": "22095926"}, "BIBREF92": {"title": "Differential hepatocyte toxicity of recombinant Apo2L/TRAIL versions", "authors": [{"first": "D", "middle": [], "last": "Lawrence", "suffix": ""}, {"first": "Z", "middle": [], "last": "Shahrokh", "suffix": ""}, {"first": "S", "middle": [], "last": "Marsters", "suffix": ""}], "year": 2001, "venue": "Nat Med", "link": "587329"}, "BIBREF93": {"title": "Apoptosis induced in normal human hepatocytes by tumor necrosis factor-related apoptosis-inducing ligand", "authors": [{"first": "M", "middle": [], "last": "Jo", "suffix": ""}, {"first": "T", "middle": ["H"], "last": "Kim", "suffix": ""}, {"first": "D", "middle": ["W"], "last": "Seol", "suffix": ""}], "year": 2000, "venue": "Nat Med", "link": "27334110"}, "BIBREF94": {"title": "Mechanisms of resistance of normal cells to TRAIL induced apoptosis vary between different cell types", "authors": [{"first": "X", "middle": ["D"], "last": "Zhang", "suffix": ""}, {"first": "T", "middle": [], "last": "Nguyen", "suffix": ""}, {"first": "W", "middle": ["D"], "last": "Thomas", "suffix": ""}], "year": 2000, "venue": "FEBS Lett", "link": "12827383"}, "BIBREF95": {"title": "TRAIL and antitumor responses", "authors": [{"first": "M", "middle": ["S"], "last": "Bhojani", "suffix": ""}, {"first": "B", "middle": ["D"], "last": "Rossu", "suffix": ""}, {"first": "A", "middle": [], "last": "Rehemtulla", "suffix": ""}], "year": 2003, "venue": "Cancer Biol Ther", "link": null}}, "ref_entries": {"TABREF0": {"text": "TRAIL-induced apoptosis in cancer L Zhang and B Fang groups have delivered a FADD dominant negative (FADD-DN) construct into TRAIL-sensitive cell lines and obtained conflicting conclusions, with some showing that TRAIL-activated apoptosis depends on FADD and others showing that activation is independent of FADD. 9,16,20,21,32-34 As the use of FADD-DN mutants may inhibit other proteins in addition to FADD, a better model for the study of FADD function is FADD- deficient cell lines.", "type": "table"}}}
{"paper_id": "2871844", "_pdf_hash": "c0ee50a0aaac64381b7140e98b31bb2f1e55a421", "abstract": [{"section": "Abstract", "text": "The association between cardiorespiratory fitness (fitness) and mortality is well described. However, the association between midlife fitness and the development of nonfatal chronic conditions in older age has not been studied.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Conclusions:", "text": "In this cohort of healthy middle-aged adults, fitness was significantly associated with a lower risk of developing chronic disease outcomes during 26 years of follow-up. These findings suggest that higher midlife fitness may be associated with the compression of morbidity in older age.", "cite_spans": [], "ref_spans": []}, {"section": "H EALTHY AGING HAS BEEN", "text": "well studied, with multiple reports [1] [2] [3] [4] [5] [6] [7] describing an association of traditional cardiovascular risk factors, such as smoking and hypertension. Although physical activity (PA) likely represents an important determinant of healthy aging, studies [5] [6] [7] have reported inconsistent results; therefore, the incremental contribution of PA to healthy aging beyond other healthy lifestyle characteristics remains unclear. The inverse association between cardiorespiratory fitness (fitness) and mortality after adjustment for other risk factors is well established. [8] [9] [10] [11] [12] [13] [14] [15] [16] In addition, compared with selfreported measures of PA, fitness levels are more strongly associated with mortality, reflecting, at least in part, the objective nature of their measurement. 15 Therefore, we hypothesized that higher midlife fitness levels would be strongly associated with healthy aging as defined by a low burden of chronic condition (CC) outcomes. To test this hypothesis, we merged individual-level data from the Cooper Center Longitudinal Study (CCLS) with Medicare claims files from the Center for Medicare and Medicaid Services (CMS).", "cite_spans": [{"start": 36, "end": 39, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 40, "end": 43, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 44, "end": 47, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 48, "end": 51, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 52, "end": 55, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 56, "end": 59, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 60, "end": 63, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 269, "end": 272, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 273, "end": 276, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 277, "end": 280, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 587, "end": 590, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 591, "end": 594, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 595, "end": 599, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 600, "end": 604, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 605, "end": 609, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 610, "end": 614, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 615, "end": 619, "text": "[14]", "ref_id": "BIBREF13"}, {"start": 620, "end": 624, "text": "[15]", "ref_id": "BIBREF14"}, {"start": 625, "end": 629, "text": "[16]", "ref_id": "BIBREF15"}, {"start": 819, "end": 821, "text": "15", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "METHODS", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "STUDY SAMPLE", "text": "The study sample was derived from the CCLS, which is a large cohort of individuals who have completed a preventive medicine examination at the Cooper Clinic in Dallas, Texas, from 1970 to 2009. Patients seen at the Cooper Clinic are generally well-educated non-Hispanic whites from middle to upper socioeconomic strata. Patients who are part of the CCLS receive a comprehensive clinical examination that includes selfreported personal and family history, standardized medical examination by a physician, anthropometric measurements, fasting laboratory studies, and a maximal treadmill exercise test. Participants provide written informed consent for inclusion in the research database. The study was reviewed and approved annually by the institutional review board of The Cooper Institute.", "cite_spans": [], "ref_spans": []}, {"section": "STUDY SAMPLE", "text": "Among 73 439 participants in the CCLS who had complete data for analysis, 24 809 became 65 years or older between January 1, 1999, and December 31, 2009, and were eligible to receive Medicare coverage. After excluding 2973 participants (12.0%) lacking traditional Medicare fee-for-service coverage (ie, Medicare Advantage participants lacking claims files), we excluded an additional 2559 participants (10.3%) with a selfreported history of myocardial infarction, stroke, cancer, chronic lung disease, or diabetes mellitus as defined by self-report or fasting blood glucose level of 126 mg/dL or higher (to convert to millimoles per liter, multiply by 0.0555) at study entry. An additional 607 individuals (2.4%) whose CCLS examination occurred after enrollment into a Medicare fee-for-service plan or were receiving early (younger than 65 years) eligibility coverage because of disability or renal dialysis were excluded, leaving a study sample of 18 670 (21.1% women) CCLS participants for the present analysis.", "cite_spans": [], "ref_spans": []}, {"section": "CLINICAL VARIABLES", "text": "Fitness was assessed by maximal effort using the modified Balke protocol, as previously described. 17 The test time using this protocol correlates highly with directly measured maximal oxygen uptake (r=0.92). 18, 19 In accordance with standard approaches to the analysis of fitness data, 8, 9 each participant's treadmill time was classified into age-and sex-specific quintiles of fitness, with low fitness represented as quintile 1. Details of the treadmill times across fitness quintiles are reported by age and sex groups in eTable 1 (http://www.archinternmed.com). Using well-characterized regression equations, treadmill times from the Balke protocol also allow for estimation of fitness level in metabolic equivalents (METs). 18, 20 The measurement of other baseline variables in the CCLS has been well described. 8, 9, 21 Body mass index (calculated as weight in kilograms divided by height in meters squared) was determined using a standard clinical scale and stadiometer. Seated resting blood pressure was obtained with a mercury sphygmomanometer. Venous blood obtained when the participants were fasting was assayed for serum cholesterol and glucose using standardized, automated techniques. Physical activity was measured using the Physical Activity Index, a 5-level PA questionnaire that has been reported 22, 23 (0, no regular PA; 1, some PA other than walking, running, or jogging; 2, walking, jogging, or running \u03fd16 km/wk; 3, walking, jogging, or running 16-32 km/wk; and 4, walking, jogging, or running \u03fe32 km/wk).", "cite_spans": [{"start": 99, "end": 101, "text": "17", "ref_id": "BIBREF16"}, {"start": 209, "end": 212, "text": "18,", "ref_id": "BIBREF17"}, {"start": 213, "end": 215, "text": "19", "ref_id": "BIBREF18"}, {"start": 288, "end": 290, "text": "8,", "ref_id": "BIBREF7"}, {"start": 291, "end": 292, "text": "9", "ref_id": "BIBREF8"}, {"start": 732, "end": 735, "text": "18,", "ref_id": "BIBREF17"}, {"start": 736, "end": 738, "text": "20", "ref_id": "BIBREF19"}, {"start": 820, "end": 822, "text": "8,", "ref_id": "BIBREF7"}, {"start": 823, "end": 825, "text": "9,", "ref_id": "BIBREF8"}, {"start": 826, "end": 828, "text": "21", "ref_id": "BIBREF20"}, {"start": 1318, "end": 1321, "text": "22,", "ref_id": "BIBREF21"}, {"start": 1322, "end": 1324, "text": "23", "ref_id": "BIBREF22"}], "ref_spans": []}, {"section": "OUTCOME MEASURES", "text": "Medicare inpatient claims data were obtained from the CMS for surviving participants who were 65 years or older and were thus eligible for Medicare benefits from 1999 through 2009. The CMS data contain 100% of claims paid by Medicare for covered health care services. Chronic condition diagnoses used in this study were determined from the Chronic Condition Warehouse included in the Beneficiary Annual Summary File. 24 Chronic conditions are defined within the Chronic Condition Warehouse from well-established algorithms for research purposes. [24] [25] [26] A panel of 8 CCs was used for the present analysis: congestive heart failure, ischemic heart disease, stroke, diabetes mellitus, chronic obstructive pulmonary disease, chronic kidney disease, Alzheimer disease, and colon or lung cancer. These conditions were chosen from the Chronic Condition Warehouse in an effort to define a broad panel across multiple organ systems in accordance with definitions of healthy aging as defined by others. 2, 5, 6, 27 Minor conditions (ie, cataracts) and sex-specific outcomes (ie, breast or prostate cancer) were excluded to define a consistent set of conditions between men and women. To create a summary measure of the burden of CCs, the combined number was used as the outcome measure (eg, 0 CCs, 1 CC).", "cite_spans": [{"start": 417, "end": 419, "text": "24", "ref_id": "BIBREF23"}, {"start": 546, "end": 550, "text": "[24]", "ref_id": "BIBREF23"}, {"start": 551, "end": 555, "text": "[25]", "ref_id": "BIBREF24"}, {"start": 556, "end": 560, "text": "[26]", "ref_id": "BIBREF25"}, {"start": 1001, "end": 1003, "text": "2,", "ref_id": "BIBREF1"}, {"start": 1004, "end": 1006, "text": "5,", "ref_id": "BIBREF4"}, {"start": 1007, "end": 1009, "text": "6,", "ref_id": "BIBREF5"}, {"start": 1010, "end": 1012, "text": "27", "ref_id": "BIBREF26"}], "ref_spans": []}, {"section": "STATISTICAL ANALYSIS", "text": "We determined the overall burden of CCs at ages 70, 75, 80, and 85 years by classifying all participants alive at these age thresholds according to the presence or absence of each of the 8 CCs. This required that the earliest indication of the condition occurred before or at the attained age among survivors. We calculated the incidence of CCs by dividing the number of diagnoses by the total observation time. Because patients could develop more than 1 CC during the surveillance period, a modified multivariate failure time model was used. 28, 29 Death during the surveillance period and survival to the end of the surveillance period were considered censoring events. We used attained age as the time scale, relegating all age effects to the baseline hazard characterizing each event stratum. Midlife fitness was entered as a continuous variable (in METs). Men and women were modeled separately. We accommodated possible departures from proportional hazards by testing for and retaining significant covariate by attained age effects. Main effects were estimated at the mean attained age.", "cite_spans": [{"start": 543, "end": 546, "text": "28,", "ref_id": "BIBREF27"}, {"start": 547, "end": 549, "text": "29", "ref_id": "BIBREF28"}], "ref_spans": []}, {"section": "STATISTICAL ANALYSIS", "text": "To assess the association between fitness and (1) the development of a CC or (2) death, we conducted additional analyses among the subset of participants who died during the observation period, using a similar modeling approach. 28, 29 In this model, we treated death as an outcome of interest rather than a censoring event. This model therefore allowed transitions to death as well as to higher CC states. The estimates for the effect of fitness on the transition to (1) an additional CC or (2) death were compared using the Wald 2 statistic. This comparison takes the form of a ratio of relative risks in which each relative risk is for CCs relative to death, and the numerator is evaluated at 1-MET higher fitness than the denominator. We refer to this ratio as the morbidity compression ratio; values significantly less than 1 offer evidence of compression of morbidity. Finally, to compare descriptively the association between fitness and CC burden at the end of life, for each level of fitness we partitioned the remaining years of follow-up according to the time spent at each level of CC burden.", "cite_spans": [{"start": 229, "end": 232, "text": "28,", "ref_id": "BIBREF27"}, {"start": 233, "end": 235, "text": "29", "ref_id": "BIBREF28"}], "ref_spans": []}, {"section": "STATISTICAL ANALYSIS", "text": "P\u03fd.05 (2-sided) was considered statistically significant. All statistical analyses were performed using commercial software (SAS for Windows, release 9.2; SAS Institute, Inc).", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS", "text": "Baseline characteristics for 14 726 men and 3944 women in the study sample are reported in Table 1 , demonstrating low levels of traditional risk factors at study entry. As expected, fitness levels were higher in men compared with women, with higher levels of traditional risk factors in the lower fitness strata. After 120 780 personyears of Medicare follow-up, there was considerable variation in the prevalence of CC burden by attained age and across conditions ( Figure) .", "cite_spans": [], "ref_spans": [{"start": 91, "end": 98, "text": "Table 1", "ref_id": "TABREF1"}]}, {"section": "RESULTS", "text": "The association between midlife fitness and the incidence of CCs is provided in Table 3 ). In men, higher blood pressure, higher total cholesterol, higher body mass index, higher glucose, and smoking prevalence were associated with a higher risk of developing CC outcomes (Table 3) . Overall, a comparable pattern of results was observed for women but with wider CIs.", "cite_spans": [], "ref_spans": [{"start": 80, "end": 87, "text": "Table 3", "ref_id": "TABREF4"}, {"start": 272, "end": 281, "text": "(Table 3)", "ref_id": "TABREF4"}]}, {"section": "RESULTS", "text": "When each of the 8 CCs was removed from the list of CCs in separate sensitivity analyses, the association between lower fitness and the risk of CC outcomes re- Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); BP, blood pressure; CHD, coronary heart disease; IQR, interquartile range; METs, metabolic equivalents; Q, quintile. SI conversion factors: To convert cholesterol to millimoles per liter, multiply by 0.0259; glucose to millimoles per liter, multiply by 0.0555. a Q1 to Q5 represents age-and sex-specific quintiles of fitness based on Balke treadmill times, with Q1 being low fitness. Data are given as mean (SD) unless otherwise indicated.", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS", "text": "b Physical Activity Index is a self-reported scale, for which 0 indicates no regular physical activity; 1, some physical activity other than walking, running, or jogging; 2, walking, jogging, or running less than 16 km/wk; 3, walking, jogging, or running 16 to 32 km/wk; and 4, walking, jogging, or running more than 32 km/wk. c Only 20% of participants reported educational level.", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS", "text": "mained unchanged, suggesting that our findings are insensitive to any particular set of CCs (eTable 2). In an additional sensitivity analysis, when these data were stratified by the median age (49 years) at examination, we observed a similar pattern of results for fitness levels mea- Prevalence of selected chronic conditions in men and women by attained age (N = 18 670). Prevalence of chronic conditions at ages 70, 75, 80, and 85 years was determined by classifying all participants alive at these age thresholds according to the presence or absence of each of the 8 chronic conditions. The presence of a condition required that the earliest indication of the condition occurred before or at the attained age among survivors. Because some participants survived across multiple age thresholds and are represented in more than 1 age category, the numbers listed for the age groups total more than 18 670. ALZ indicates Alzheimer disease; CA, cancer of the colon or lung; CHF, congestive heart failure; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; DM, diabetes mellitus; and IHD, ischemic heart disease. Abbreviations: CC, chronic condition; Q, quintile. a Rates per 100 person-years reported in age-and sex-specific quintiles of fitness based on Balke treadmill times, with Q1 being low fitness and Q5 being high fitness.", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS", "text": "low-up in each fitness group before death. Among decedents with higher levels of midlife fitness, the morbidity compression ratio comparing CC development relative to that of death was significantly lower (0.90 [0.88-0.92] per MET). Thus, higher midlife fitness is associated with the delay in the development of CCs to a greater extent than the extension of the lifespan, suggesting the compression of morbidity nearer the end of life. The association of fitness with the compression of CC burden can also be seen in the proportion of time spent with different numbers of CCs before death. Compared with participants with lower midlife fitness, those with higher midlife fitness appeared to spend a greater proportion of their final 5 years of life with a lower burden of CCs ( Table 4) .", "cite_spans": [], "ref_spans": []}, {"section": "COMMENT", "text": "In the present study, higher fitness measured in midlife was strongly associated with a lower incidence of CCs decades later. Furthermore, higher midlife fitness was more strongly associated with a delay in the onset of CCs than with overall survival, suggesting that higher fitness in midlife is associated with the compression of morbidity in later life.", "cite_spans": [], "ref_spans": []}, {"section": "COMMENT", "text": "We observed clinically significant associations between midlife fitness levels and chronic disease burden in later life. At lower fitness levels, where the association was strongest (Table 2 ), our data suggest that a modest increase in fitness could translate into marked reduction of CCs in older age. For example, a 1-to 2-MET improvement in fitness resulting in promotion from the first to the second fitness quintile at age 50 years was associated with a 20% reduction in the incidence of CCs at ages 65 and older. Previous PA intervention studies [30] [31] [32] have achieved mean fitness gains of this magnitude using a 6-month program of 150 minutes per week of moderate-intensity exercise.", "cite_spans": [{"start": 553, "end": 557, "text": "[30]", "ref_id": "BIBREF29"}, {"start": 558, "end": 562, "text": "[31]", "ref_id": "BIBREF30"}, {"start": 563, "end": 567, "text": "[32]", "ref_id": "BIBREF31"}], "ref_spans": [{"start": 182, "end": 190, "text": "(Table 2", "ref_id": "TABREF0"}]}, {"section": "COMMENT", "text": "Studies have examined the association between risk factors in midlife and healthy aging, 1, 3, 4, 6, 7, 27 demonstrating consistent associations between obesity, smoking, and hypertension and subsequent healthy aging decades later. However, the association between midlife PA patterns and healthy aging has been inconsistent. 1, 4, 6, 7, 15, 27, [33] [34] [35] To our knowledge, the association between midlife fitness and healthy aging has not been reported. In contrast to the more inconsistent associations with PA, we observed that higher midlife fitness was strongly and consistently associated with a lower rate of CC outcomes in later life in men and women. This discordance between PA and fitness is not unexpected given reports 15, 16, 35 demonstrating stronger associations between fitness and mortality compared with PA.", "cite_spans": [{"start": 89, "end": 91, "text": "1,", "ref_id": "BIBREF0"}, {"start": 92, "end": 94, "text": "3,", "ref_id": "BIBREF2"}, {"start": 95, "end": 97, "text": "4,", "ref_id": "BIBREF3"}, {"start": 98, "end": 100, "text": "6,", "ref_id": "BIBREF5"}, {"start": 101, "end": 103, "text": "7,", "ref_id": "BIBREF6"}, {"start": 104, "end": 106, "text": "27", "ref_id": "BIBREF26"}, {"start": 326, "end": 328, "text": "1,", "ref_id": "BIBREF0"}, {"start": 329, "end": 331, "text": "4,", "ref_id": "BIBREF3"}, {"start": 332, "end": 334, "text": "6,", "ref_id": "BIBREF5"}, {"start": 335, "end": 337, "text": "7,", "ref_id": "BIBREF6"}, {"start": 338, "end": 341, "text": "15,", "ref_id": "BIBREF14"}, {"start": 342, "end": 345, "text": "27,", "ref_id": "BIBREF26"}, {"start": 346, "end": 350, "text": "[33]", "ref_id": "BIBREF32"}, {"start": 351, "end": 355, "text": "[34]", "ref_id": "BIBREF33"}, {"start": 356, "end": 360, "text": "[35]", "ref_id": "BIBREF34"}, {"start": 737, "end": 740, "text": "15,", "ref_id": "BIBREF14"}, {"start": 741, "end": 744, "text": "16,", "ref_id": "BIBREF15"}, {"start": 745, "end": 747, "text": "35", "ref_id": "BIBREF34"}], "ref_spans": []}, {"section": "COMMENT", "text": "The inverse association between fitness and mortality has been well studied, [8] [9] [10] [12] [13] [14] 21 but less is known regarding the association between midlife fitness and CCs Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); HR, hazard ratio; MET, metabolic equivalent; SBP, systolic blood pressure.", "cite_spans": [{"start": 77, "end": 80, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 81, "end": 84, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 85, "end": 89, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 90, "end": 94, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 95, "end": 99, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 100, "end": 104, "text": "[14]", "ref_id": "BIBREF13"}, {"start": 105, "end": 107, "text": "21", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "COMMENT", "text": "SI conversion factors: To convert cholesterol to millimoles per liter, multiply by 0.0259; glucose to millimoles per liter, multiply by 0.0555. a All models were adjusted for all covariates listed in the table as well as follow-up entry age, year of examination, and time-dependent interaction terms (see \"Methods\" section for details). ", "cite_spans": [], "ref_spans": []}, {"section": "COMMENT", "text": "In the present study, we combined Medicare administrative claims data with a large cohort of healthy men and women with objectively measured fitness levels, providing an efficient strategy to examine the association between midlife fitness and the development of a diverse set of CCs decades later. Our findings support the hypothesis that fitness in midlife is associated with a lower burden of chronic disease in later life.", "cite_spans": [], "ref_spans": []}, {"section": "COMMENT", "text": "In addition to reducing the burden of CCs, we also observed that higher midlife fitness was associated more strongly with the delay in the onset of CCs than with survival, suggesting that higher midlife fitness may promote the compression of morbidity in later life. [36] [37] [38] [39] Because of the strong correlation between morbidity and mortality, lifestyle patterns that equally delay the onset of both morbidity and mortality could result in more years of life lived with chronic disease. 40 In contrast, lifestyle characteristics that delay the onset of chronic disease to a greater extent than they prolong the lifespan could theoretically compress life-years lived with chronic disease and hence increase the years with improved quality of life and lower health care expenditures. 38, [40] [41] [42] [43] Our findings have important implications for public health and prevention practice by extending our knowledge of the health benefits of exercise in midlife.", "cite_spans": [{"start": 267, "end": 271, "text": "[36]", "ref_id": "BIBREF35"}, {"start": 272, "end": 276, "text": "[37]", "ref_id": "BIBREF36"}, {"start": 277, "end": 281, "text": "[38]", "ref_id": "BIBREF37"}, {"start": 282, "end": 286, "text": "[39]", "ref_id": "BIBREF38"}, {"start": 497, "end": 499, "text": "40", "ref_id": "BIBREF39"}, {"start": 792, "end": 795, "text": "38,", "ref_id": "BIBREF37"}, {"start": 796, "end": 800, "text": "[40]", "ref_id": "BIBREF39"}, {"start": 801, "end": 805, "text": "[41]", "ref_id": "BIBREF40"}, {"start": 806, "end": 810, "text": "[42]", "ref_id": "BIBREF41"}, {"start": 811, "end": 815, "text": "[43]", "ref_id": "BIBREF42"}], "ref_spans": []}, {"section": "COMMENT", "text": "Several studies [37] [38] [39] 44, 45 suggested the importance of physical exercise as a potential source of morbidity compression. However, most were relatively small with few overall deaths, limiting the ability to test for the presence of this phenomenon. In a cohort of middle-aged runners and control individuals monitored for 21 years (N = 961), runners were found to have less disability as assessed by the Health Assessment Questionnaire Disability Index, suggesting that regular physical exercise might delay the onset of disability. 46 However, the authors were not able to assess for the presence or absence of morbidity compression because of the overall small number of deaths in the study sample (n = 225). 46 In the present study, we included 18 670 participants with 2406 deaths, allowing a comparison of the associations between fitness, CCs, and mortality in the final 5 years of life.", "cite_spans": [{"start": 16, "end": 20, "text": "[37]", "ref_id": "BIBREF36"}, {"start": 21, "end": 25, "text": "[38]", "ref_id": "BIBREF37"}, {"start": 26, "end": 30, "text": "[39]", "ref_id": "BIBREF38"}, {"start": 31, "end": 34, "text": "44,", "ref_id": "BIBREF43"}, {"start": 35, "end": 37, "text": "45", "ref_id": "BIBREF44"}, {"start": 543, "end": 545, "text": "46", "ref_id": "BIBREF45"}, {"start": 721, "end": 723, "text": "46", "ref_id": "BIBREF45"}], "ref_spans": []}, {"section": "COMMENT", "text": "Several limitations of this study should be noted. First, outcome data were derived from administrative data from the CMS rather than adjudicated clinical diagnoses. Nevertheless, Medicare data have been shown to be a reliable source of information across multiple clinical outcomes. 25, 26, [47] [48] [49] [50] [51] [52] Furthermore, Medicare data represent a unique and cost-effective resource, providing an opportunity to assess the association between midlife fitness levels and long-term chronic disease outcomes that would be prohibitively expensive, if not impossible, to replicate in a prospective cohort study of comparable size and duration.", "cite_spans": [{"start": 284, "end": 287, "text": "25,", "ref_id": "BIBREF24"}, {"start": 288, "end": 291, "text": "26,", "ref_id": "BIBREF25"}, {"start": 292, "end": 296, "text": "[47]", "ref_id": "BIBREF46"}, {"start": 297, "end": 301, "text": "[48]", "ref_id": "BIBREF47"}, {"start": 302, "end": 306, "text": "[49]", "ref_id": "BIBREF48"}, {"start": 307, "end": 311, "text": "[50]", "ref_id": "BIBREF49"}, {"start": 312, "end": 316, "text": "[51]", "ref_id": "BIBREF50"}, {"start": 317, "end": 321, "text": "[52]", "ref_id": "BIBREF51"}], "ref_spans": []}, {"section": "COMMENT", "text": "Second, we linked individual-level data with Medicare claims files to compare the association between fitness and chronic disease outcomes at age 65 years or older. We were not able to capture outcomes that occurred between study entry and the onset of Medicare eligibility. For example, participants who died before achieving Medicare eligibility were not included in the present analysis. However, merging individual-level data with Medicare claims files has been used by other investigators in a parallel context, providing novel insight into the contribution of traditional risk factors and other Medicare outcomes. 2, [27] [28] [29] We observed a similar pattern of results for fitness levels measured in earlier life (ie, age \u054549 years) as well as in later life (ie, age \u03fe49 years) and closer to Medicare eligibility.", "cite_spans": [{"start": 620, "end": 622, "text": "2,", "ref_id": "BIBREF1"}, {"start": 623, "end": 627, "text": "[27]", "ref_id": "BIBREF26"}, {"start": 628, "end": 632, "text": "[28]", "ref_id": "BIBREF27"}, {"start": 633, "end": 637, "text": "[29]", "ref_id": "BIBREF28"}], "ref_spans": []}, {"section": "COMMENT", "text": "Third, we created an a priori panel of CCs across multiple organ systems and in accordance with definitions of healthy aging defined by others. [4] [5] [6] [7] 27, 53 Although this may have influenced our findings, we observed a similar pattern of results after multiple sensitivity analyses that sequentially excluded one of these CCs (eTable 2). Therefore, we believe that our findings are insensitive to the choice of CC panel and reflect a reasonable estimate of the association between midlife fitness and CC outcomes in older age.", "cite_spans": [{"start": 144, "end": 147, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 148, "end": 151, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 152, "end": 155, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 156, "end": 159, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 160, "end": 163, "text": "27,", "ref_id": "BIBREF26"}, {"start": 164, "end": 166, "text": "53", "ref_id": "BIBREF52"}], "ref_spans": []}, {"section": "COMMENT", "text": "Fourth, the CCLS is a unique cohort with a higher socioeconomic and educational status and a lower prevalence of traditional risk factors when compared with the general population. However, although the level of risk factors is lower than in the general population, prior work suggests that the effects are similar. 54 Finally, additional factors, such as life stress and dietary patterns, were not included in our analyses because these data are limited in the CCLS. Additional covariates could alter the observed associations of CCs and fitness. Follow-up data on fitness and PA are not uniformly available in the CCLS; therefore, we are not able to estimate the effect of changes in fitness with chronic disease burden in older age. However, our primary purpose was to determine the contribution of a single measure of midlife fitness with surrogates for healthy aging decades later. Furthermore, although fitness measures more proximate to the outcome would be of interest, it would also raise concerns regarding the possibility of reverse causation, in which low fitness reflected undiagnosed chronic disease burden. The healthy nature of our cohort and the long duration of follow-up make the presence of undiagnosed CCs at study entry unlikely and further support the hypothesis that greater midlife exercise is associated with a lower burden of chronic disease across the life span.", "cite_spans": [{"start": 316, "end": 318, "text": "54", "ref_id": "BIBREF53"}], "ref_spans": []}, {"section": "COMMENT", "text": "In summary, midlife fitness was associated with a lower risk of common chronic health conditions in men and women older than 65 years enrolled in Medicare. The finding that higher fitness was more strongly associated with CCs than with overall survival suggests that higher midlife fitness may be associated with the compression of morbidity in older age. rity of the data and the accuracy of the data analysis. Dr Berry had final responsibility for the decision to submit for publication. All authors have read and agree to the manuscript as written. (3) nonprofit research institute and provided internal funding for this study. Dr Berry receives funding from the Dedman Family Scholar in Clinical Care endowment at The University of Texas Southwestern Medical Center; grant K23 HL092229 from the National Heart, Lung, and Blood Institute; and grant 10BG1A4280091 from the American Heart Association. Role of the Sponsors: The University of Texas Southwestern Medical Center; the National Heart, Lung, and Blood Institute; and the American Heart Association made no contribution to the design of the study. In addition, the sponsors made no contribution to the collection, management, analysis, or interpretation of the data, or preparation, review, or approval of the manuscript. ", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Successful aging: the contribution of early-life and midlife risk factors", "authors": [{"first": "A", "middle": [], "last": "Britton", "suffix": ""}, {"first": "M", "middle": [], "last": "Shipley", "suffix": ""}, {"first": "A", "middle": [], "last": "Singh-Manoux", "suffix": ""}, {"first": "M", "middle": ["G"], "last": "Marmot", "suffix": ""}], "year": 2008, "venue": "J Am Geriatr Soc", "link": "16934124"}, "BIBREF1": {"title": "Factors associated with healthy aging: the Cardiovascular Health Study", "authors": [{"first": "G", "middle": ["L"], "last": "Burke", "suffix": ""}, {"first": "A", "middle": ["M"], "last": "Arnold", "suffix": ""}, {"first": "D", "middle": ["E"], "last": "Bild", "suffix": ""}], "year": 2001, "venue": "J Am Geriatr Soc", "link": "625172"}, "BIBREF2": {"title": "Favorable cardiovascular risk profile in middle age and health-related quality of life in older age", "authors": [{"first": "M", "middle": ["L"], "last": "Daviglus", "suffix": ""}, {"first": "K", "middle": [], "last": "Liu", "suffix": ""}, {"first": "A", "middle": [], "last": "Pirzada", "suffix": ""}], "year": 2003, "venue": "Arch Intern Med", "link": "2948232"}, "BIBREF3": {"title": "Adiposity and weight change in mid-life in relation to healthy survival after age 70 in women: prospective cohort study", "authors": [{"first": "Q", "middle": [], "last": "Sun", "suffix": ""}, {"first": "M", "middle": ["K"], "last": "Townsend", "suffix": ""}, {"first": "O", "middle": ["I"], "last": "Okereke", "suffix": ""}, {"first": "O", "middle": ["H"], "last": "Franco", "suffix": ""}, {"first": "F", "middle": ["B"], "last": "Hu", "suffix": ""}, {"first": "F", "middle": [], "last": "Grodstein", "suffix": ""}], "year": 2009, "venue": "BMJ", "link": "215220987"}, "BIBREF4": {"title": "Cardiovascular risk factors predictive for survival and morbidity-free survival in the oldest-old Framingham Heart Study participants", "authors": [{"first": "D", "middle": ["F"], "last": "Terry", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Pencina", "suffix": ""}, {"first": "R", "middle": ["S"], "last": "Vasan", "suffix": ""}], "year": 2005, "venue": "J Am Geriatr Soc", "link": "19702474"}, "BIBREF5": {"title": "Midlife risk factors and healthy survival in men", "authors": [{"first": "B", "middle": ["J"], "last": "Willcox", "suffix": ""}, {"first": "Q", "middle": [], "last": "He", "suffix": ""}, {"first": "R", "middle": [], "last": "Chen", "suffix": ""}], "year": 2006, "venue": "JAMA", "link": "10012967"}, "BIBREF6": {"title": "Exceptional longevity in men: modifiable factors associated with survival and function to age 90 years", "authors": [{"first": "L", "middle": ["B"], "last": "Yates", "suffix": ""}, {"first": "L", "middle": [], "last": "Djouss\u00e9", "suffix": ""}, {"first": "T", "middle": [], "last": "Kurth", "suffix": ""}, {"first": "J", "middle": ["E"], "last": "Buring", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Gaziano", "suffix": ""}], "year": 2008, "venue": "Arch Intern Med", "link": "29095523"}, "BIBREF7": {"title": "Physical fitness and all-cause mortality: a prospective study of healthy men and women", "authors": [{"first": "S", "middle": ["N"], "last": "Blair", "suffix": ""}, {"first": "H", "middle": ["W"], "last": "Kohl", "suffix": ""}, {"first": "", "middle": [], "last": "Iii", "suffix": ""}, {"first": "R", "middle": ["S"], "last": "Paffenbarger", "suffix": ""}, {"first": "D", "middle": ["G"], "last": "Clark", "suffix": ""}, {"first": "K", "middle": ["H"], "last": "Cooper", "suffix": ""}, {"first": "L", "middle": ["W"], "last": "Gibbons", "suffix": ""}], "year": 1989, "venue": "JAMA", "link": "5825069"}, "BIBREF8": {"title": "Changes in physical fitness and all-cause mortality: a prospective study of healthy and unhealthy men", "authors": [{"first": "S", "middle": ["N"], "last": "Blair", "suffix": ""}, {"first": "H", "middle": ["W"], "last": "Kohl", "suffix": ""}, {"first": "", "middle": [], "last": "Iii", "suffix": ""}, {"first": "C", "middle": ["E"], "last": "Barlow", "suffix": ""}, {"first": "R", "middle": ["S"], "last": "Paffenbarger", "suffix": ""}, {"first": "L", "middle": ["W"], "last": "Gibbons", "suffix": ""}, {"first": "C", "middle": ["A"], "last": "Macera", "suffix": ""}], "year": 1995, "venue": "JAMA", "link": null}, "BIBREF9": {"title": "Physical fitness as a predictor of cardiovascular mortality in asymptomatic North American men: the Lipid Research Clinics Mortality Follow-up Study", "authors": [{"first": "L", "middle": ["G"], "last": "Ekelund", "suffix": ""}, {"first": "W", "middle": ["L"], "last": "Haskell", "suffix": ""}, {"first": "J", "middle": ["L"], "last": "Johnson", "suffix": ""}, {"first": "F", "middle": ["S"], "last": "Whaley", "suffix": ""}, {"first": "M", "middle": ["H"], "last": "Criqui", "suffix": ""}, {"first": "D", "middle": ["S"], "last": "Sheps", "suffix": ""}], "year": 1988, "venue": "N Engl J Med", "link": null}, "BIBREF10": {"title": "Cardiorespiratory fitness as a quantitative predictor of all-cause mortality and cardiovascular events in healthy men and women: a meta-analysis", "authors": [{"first": "S", "middle": [], "last": "Kodama", "suffix": ""}, {"first": "K", "middle": [], "last": "Saito", "suffix": ""}, {"first": "S", "middle": [], "last": "Tanaka", "suffix": ""}], "year": 2009, "venue": "JAMA", "link": "17881189"}, "BIBREF11": {"title": "Exercise capacity and mortality in black and white men", "authors": [{"first": "P", "middle": [], "last": "Kokkinos", "suffix": ""}, {"first": "J", "middle": [], "last": "Myers", "suffix": ""}, {"first": "J", "middle": ["P"], "last": "Kokkinos", "suffix": ""}], "year": 2008, "venue": "Circulation", "link": "3014979"}, "BIBREF12": {"title": "Enhanced risk assessment in asymptomatic individuals with exercise testing and Framingham risk scores", "authors": [{"first": "S", "middle": [], "last": "Mora", "suffix": ""}, {"first": "R", "middle": ["F"], "last": "Redberg", "suffix": ""}, {"first": "A", "middle": ["R"], "last": "Sharrett", "suffix": ""}, {"first": "R", "middle": ["S"], "last": "Blumenthal", "suffix": ""}], "year": 2005, "venue": "Circulation", "link": "7783072"}, "BIBREF13": {"title": "Exercise capacity and mortality among men referred for exercise testing", "authors": [{"first": "J", "middle": [], "last": "Myers", "suffix": ""}, {"first": "M", "middle": [], "last": "Prakash", "suffix": ""}, {"first": "V", "middle": [], "last": "Froelicher", "suffix": ""}, {"first": "D", "middle": [], "last": "Do", "suffix": ""}, {"first": "S", "middle": [], "last": "Partington", "suffix": ""}, {"first": "J", "middle": ["E"], "last": "Atwood", "suffix": ""}], "year": 2002, "venue": "N Engl J Med", "link": "2991941"}, "BIBREF14": {"title": "Fitness versus physical activity patterns in predicting mortality in men", "authors": [{"first": "J", "middle": [], "last": "Myers", "suffix": ""}, {"first": "A", "middle": [], "last": "Kaykha", "suffix": ""}, {"first": "S", "middle": [], "last": "George", "suffix": ""}], "year": 2004, "venue": "Am J Med", "link": "33570522"}, "BIBREF15": {"title": "Comparison of cardiorespiratory fitness versus leisure time physical activity as predictors of coronary events in men aged \u054565 years and \u03fe65 years", "authors": [{"first": "L", "middle": ["A"], "last": "Talbot", "suffix": ""}, {"first": "C", "middle": ["H"], "last": "Morrell", "suffix": ""}, {"first": "E", "middle": ["J"], "last": "Metter", "suffix": ""}, {"first": "J", "middle": ["L"], "last": "Fleg", "suffix": ""}], "year": 2002, "venue": "Am J Cardiol", "link": "40707553"}, "BIBREF16": {"title": "Secular change in cardiorespiratory fitness of men: Cooper Center Longitudinal Study", "authors": [{"first": "B", "middle": ["L"], "last": "Willis", "suffix": ""}, {"first": "J", "middle": ["R"], "last": "Morrow", "suffix": ""}, {"first": "A", "middle": ["W"], "last": "Jackson", "suffix": ""}, {"first": "L", "middle": ["F"], "last": "Defina", "suffix": ""}, {"first": "K", "middle": ["H"], "last": "Cooper", "suffix": ""}], "year": 2011, "venue": "Med Sci Sports Exerc", "link": "27322981"}, "BIBREF17": {"title": "A comparative analysis of four protocols for maximal treadmill stress testing", "authors": [{"first": "M", "middle": ["L"], "last": "Pollock", "suffix": ""}, {"first": "R", "middle": ["L"], "last": "Bohannon", "suffix": ""}, {"first": "K", "middle": ["H"], "last": "Cooper", "suffix": ""}], "year": 1976, "venue": "Am Heart J", "link": "33729993"}, "BIBREF18": {"title": "Comparative analysis of physiologic responses to three different maximal graded exercise test protocols in healthy women", "authors": [{"first": "M", "middle": ["L"], "last": "Pollock", "suffix": ""}, {"first": "C", "middle": [], "last": "Foster", "suffix": ""}, {"first": "D", "middle": [], "last": "Schmidt", "suffix": ""}, {"first": "C", "middle": [], "last": "Hellman", "suffix": ""}, {"first": "A", "middle": ["C"], "last": "Linnerud", "suffix": ""}, {"first": "A", "middle": [], "last": "Ward", "suffix": ""}], "year": 1982, "venue": "Am Heart J", "link": "20820427"}, "BIBREF19": {"title": "ACSM's Guidelines for Exercise Testing and Prescription", "authors": [{"first": "B", "middle": ["A"], "last": "Franklin", "suffix": ""}, {"first": "M", "middle": ["H"], "last": "Whaley", "suffix": ""}, {"first": "E", "middle": ["T"], "last": "Howley", "suffix": ""}, {"first": "G", "middle": ["J"], "last": "Balady", "suffix": ""}], "year": 2000, "venue": "", "link": "53903849"}, "BIBREF20": {"title": "Influences of cardiorespiratory fitness and other precursors on cardiovascular disease and all-cause mortality in men and women", "authors": [{"first": "S", "middle": ["N"], "last": "Blair", "suffix": ""}, {"first": "J", "middle": ["B"], "last": "Kampert", "suffix": ""}, {"first": "H", "middle": ["W"], "last": "Kohl", "suffix": ""}, {"first": "", "middle": [], "last": "Iii", "suffix": ""}], "year": 1996, "venue": "JAMA", "link": null}, "BIBREF21": {"title": "Surrogate measures of physical activity and physical fitness: evidence for sedentary traits of resting tachycardia, obesity, and low vital capacity", "authors": [{"first": "S", "middle": ["N"], "last": "Blair", "suffix": ""}, {"first": "W", "middle": ["B"], "last": "Kannel", "suffix": ""}, {"first": "H", "middle": ["W"], "last": "Kohl", "suffix": ""}, {"first": "N", "middle": [], "last": "Goodyear", "suffix": ""}, {"first": "P", "middle": ["W"], "last": "Wilson", "suffix": ""}], "year": 1989, "venue": "Am J Epidemiol", "link": "6591031"}, "BIBREF22": {"title": "A mail survey of physical activity habits as related to measured physical fitness", "authors": [{"first": "H", "middle": ["W"], "last": "Kohl", "suffix": ""}, {"first": "S", "middle": ["N"], "last": "Blair", "suffix": ""}, {"first": "R", "middle": ["S"], "last": "Paffenbarger", "suffix": ""}, {"first": "C", "middle": ["A"], "last": "Macera", "suffix": ""}, {"first": "J", "middle": ["J"], "last": "Kronenfeld", "suffix": ""}], "year": 1988, "venue": "Am J Epidemiol", "link": "73044663"}, "BIBREF23": {"title": "Chronic Condition Data Warehouse User Guide. CMS Chronic Condition Warehouse", "authors": [], "year": 2011, "venue": "", "link": null}, "BIBREF24": {"title": "Identifying chronic conditions in Medicare claims data: evaluating the Chronic Condition Data Warehouse algorithm", "authors": [{"first": "Y", "middle": [], "last": "Gorina", "suffix": ""}, {"first": "E", "middle": ["A"], "last": "Kramarow", "suffix": ""}], "year": 2011, "venue": "Health Serv Res", "link": "23483954"}, "BIBREF25": {"title": "Administrative data for public health surveillance and planning", "authors": [{"first": "B", "middle": ["A"], "last": "Virnig", "suffix": ""}, {"first": "M", "middle": [], "last": "Mcbean", "suffix": ""}], "year": 2001, "venue": "Annu Rev Public Health", "link": "38445328"}, "BIBREF26": {"title": "Physical activity at midlife in relation to successful survival in women at age 70 years or older", "authors": [{"first": "Q", "middle": [], "last": "Sun", "suffix": ""}, {"first": "M", "middle": ["K"], "last": "Townsend", "suffix": ""}, {"first": "O", "middle": ["I"], "last": "Okereke", "suffix": ""}, {"first": "O", "middle": ["H"], "last": "Franco", "suffix": ""}, {"first": "F", "middle": ["B"], "last": "Hu", "suffix": ""}, {"first": "F", "middle": [], "last": "Grodstein", "suffix": ""}], "year": 2010, "venue": "Arch Intern Med", "link": "9609370"}, "BIBREF27": {"title": "Regression analysis of multivariate incomplete failure time data by modeling marginal distribution", "authors": [{"first": "L", "middle": ["J"], "last": "Wei", "suffix": ""}, {"first": "D", "middle": ["Y"], "last": "Lin", "suffix": ""}, {"first": "L", "middle": [], "last": "Weissfeld", "suffix": ""}], "year": 1989, "venue": "J Am Stat Assoc", "link": "122386329"}, "BIBREF28": {"title": "The robust inference for the Cox proportional hazards model", "authors": [{"first": "D", "middle": ["Y"], "last": "Lin", "suffix": ""}, {"first": "L", "middle": ["J"], "last": "Wei", "suffix": ""}], "year": 1989, "venue": "J Am Stat Assoc", "link": "121697647"}, "BIBREF29": {"title": "Women walking for health and fitness: how much is enough?", "authors": [{"first": "J", "middle": ["J"], "last": "Duncan", "suffix": ""}, {"first": "N", "middle": ["F"], "last": "Gordon", "suffix": ""}, {"first": "C", "middle": ["B"], "last": "Scott", "suffix": ""}], "year": 1991, "venue": "JAMA", "link": "36472586"}, "BIBREF30": {"title": "Dose response between total volume of physical activity and health and fitness", "authors": [{"first": "P", "middle": [], "last": "Oja", "suffix": ""}], "year": 2001, "venue": "Med Sci Sports Exerc", "link": "7223921"}, "BIBREF31": {"title": "HERITAGE Family Study. Age, sex, race, initial fitness, and response to training: the HERITAGE Family Study", "authors": [{"first": "J", "middle": ["S"], "last": "Skinner", "suffix": ""}, {"first": "A", "middle": [], "last": "Jask\u00f3lski", "suffix": ""}, {"first": "A", "middle": [], "last": "Jask\u00f3lska", "suffix": ""}], "year": 2001, "venue": "J Appl Physiol", "link": "6049767"}, "BIBREF32": {"title": "Predictors of successful aging: a twelve-year study of Manitoba elderly", "authors": [{"first": "N", "middle": ["P"], "last": "Roos", "suffix": ""}, {"first": "B", "middle": [], "last": "Havens", "suffix": ""}], "year": 1991, "venue": "Am J Public Health", "link": "8204339"}, "BIBREF33": {"title": "Predictors of healthy aging: prospective evidence from the Alameda County study", "authors": [{"first": "J", "middle": ["M"], "last": "Guralnik", "suffix": ""}, {"first": "G", "middle": ["A"], "last": "Kaplan", "suffix": ""}], "year": 1989, "venue": "Am J Public Health", "link": "25274671"}, "BIBREF34": {"title": "Comparisons of leisure-time physical activity and cardiorespiratory fitness as predictors of all-cause mortality in men and women", "authors": [{"first": "D", "middle": ["C"], "last": "Lee", "suffix": ""}, {"first": "X", "middle": [], "last": "Sui", "suffix": ""}, {"first": "F", "middle": ["B"], "last": "Ortega", "suffix": ""}], "year": 2011, "venue": "Br J Sports Med", "link": "76096500"}, "BIBREF35": {"title": "Aging, natural death, and the compression of morbidity", "authors": [{"first": "J", "middle": ["F"], "last": "Fries", "suffix": ""}], "year": 1980, "venue": "N Engl J Med", "link": "30140757"}, "BIBREF36": {"title": "Physical activity, the compression of morbidity, and the health of the elderly", "authors": [{"first": "J", "middle": ["F"], "last": "Fries", "suffix": ""}], "year": 1996, "venue": "J R Soc Med", "link": "2976268"}, "BIBREF37": {"title": "Measuring and monitoring success in compressing morbidity", "authors": [{"first": "J", "middle": ["F"], "last": "Fries", "suffix": ""}], "year": 2003, "venue": "Ann Intern Med", "link": "21246039"}, "BIBREF38": {"title": "heart disease, and stroke: the Compression of Morbidity paradigm", "authors": [{"first": "J", "middle": ["F"], "last": "Fries", "suffix": ""}, {"first": "", "middle": [], "last": "Frailty", "suffix": ""}], "year": 2005, "venue": "Am J Prev Med", "link": null}, "BIBREF39": {"title": "The failures of success: 1977", "authors": [{"first": "E", "middle": ["M"], "last": "Gruenberg", "suffix": ""}], "year": 2005, "venue": "Milbank Q", "link": "27595061"}, "BIBREF40": {"title": "Multiple chronic conditions: prevalence, health consequences, and implications for quality, care management, and costs", "authors": [{"first": "C", "middle": [], "last": "Vogeli", "suffix": ""}, {"first": "A", "middle": ["E"], "last": "Shields", "suffix": ""}, {"first": "T", "middle": ["A"], "last": "Lee", "suffix": ""}], "year": 2007, "venue": "J Gen Intern Med", "link": "7374045"}, "BIBREF41": {"title": "Compression, expansion, or dynamic equilibrium? the evolution of health expectancy in New Zealand", "authors": [{"first": "P", "middle": [], "last": "Graham", "suffix": ""}, {"first": "T", "middle": [], "last": "Blakely", "suffix": ""}, {"first": "P", "middle": [], "last": "Davis", "suffix": ""}, {"first": "A", "middle": [], "last": "Sporle", "suffix": ""}, {"first": "N", "middle": [], "last": "Pearce", "suffix": ""}], "year": 2004, "venue": "J Epidemiol Community Health", "link": "9570321"}, "BIBREF42": {"title": "Health Project Consortium. Reducing health care costs by reducing the need and demand for medical services", "authors": [{"first": "J", "middle": ["F"], "last": "Fries", "suffix": ""}, {"first": "C", "middle": ["E"], "last": "Koop", "suffix": ""}, {"first": "C", "middle": ["E"], "last": "Beadle", "suffix": ""}], "year": 1993, "venue": "N Engl J Med", "link": null}, "BIBREF43": {"title": "Risk factors for physical disability in an aging cohort: the NHANES I Epidemiologic Follow-up Study", "authors": [{"first": "H", "middle": ["B"], "last": "Hubert", "suffix": ""}, {"first": "D", "middle": ["A"], "last": "Bloch", "suffix": ""}, {"first": "J", "middle": ["F"], "last": "Fries", "suffix": ""}], "year": 1993, "venue": "J Rheumatol", "link": "23044726"}, "BIBREF44": {"title": "Lifestyle habits and compression of morbidity", "authors": [{"first": "H", "middle": ["B"], "last": "Hubert", "suffix": ""}, {"first": "D", "middle": ["A"], "last": "Bloch", "suffix": ""}, {"first": "J", "middle": ["W"], "last": "Oehlert", "suffix": ""}, {"first": "J", "middle": ["F"], "last": "Fries", "suffix": ""}], "year": 2002, "venue": "J Gerontol A Biol Sci Med Sci", "link": "25121211"}, "BIBREF45": {"title": "Reduced disability and mortality among aging runners: a 21-year longitudinal study", "authors": [{"first": "E", "middle": ["F"], "last": "Chakravarty", "suffix": ""}, {"first": "H", "middle": ["B"], "last": "Hubert", "suffix": ""}, {"first": "V", "middle": ["B"], "last": "Lingala", "suffix": ""}, {"first": "J", "middle": ["F"], "last": "Fries", "suffix": ""}], "year": 2008, "venue": "Arch Intern Med", "link": "76110447"}, "BIBREF46": {"title": "Prevalence, expenditures, and complications of multiple chronic conditions in the elderly", "authors": [{"first": "J", "middle": ["L"], "last": "Wolff", "suffix": ""}, {"first": "B", "middle": [], "last": "Starfield", "suffix": ""}, {"first": "G", "middle": [], "last": "Anderson", "suffix": ""}], "year": 2002, "venue": "Arch Intern Med", "link": "35687078"}, "BIBREF47": {"title": "Linking the Iowa Women's Health Study cohort to Medicare data: linkage results and application to hip fracture", "authors": [{"first": "B", "middle": [], "last": "Virnig", "suffix": ""}, {"first": "S", "middle": ["B"], "last": "Durham", "suffix": ""}, {"first": "A", "middle": ["R"], "last": "Folsom", "suffix": ""}, {"first": "J", "middle": [], "last": "Cerhan", "suffix": ""}], "year": 2010, "venue": "Am J Epidemiol", "link": "14133025"}, "BIBREF48": {"title": "Relation of body mass index in young adulthood and middle age to Medicare expenditures in older age", "authors": [{"first": "M", "middle": ["L"], "last": "Daviglus", "suffix": ""}, {"first": "K", "middle": [], "last": "Liu", "suffix": ""}, {"first": "L", "middle": ["L"], "last": "Yan", "suffix": ""}], "year": 2004, "venue": "JAMA", "link": "26021941"}, "BIBREF49": {"title": "Health care costs in old age are related to overweight and obesity earlier in life. Health Aff (Millwood)", "authors": [{"first": "M", "middle": ["L"], "last": "Daviglus", "suffix": ""}], "year": 2005, "venue": "", "link": null}, "BIBREF50": {"title": "Cardiovascular risk profile earlier in life and Medicare costs in the last year of life", "authors": [{"first": "M", "middle": ["L"], "last": "Daviglus", "suffix": ""}, {"first": "K", "middle": [], "last": "Liu", "suffix": ""}, {"first": "A", "middle": [], "last": "Pirzada", "suffix": ""}], "year": 2005, "venue": "Arch Intern Med", "link": "19604172"}, "BIBREF51": {"title": "Relationship of fruit and vegetable consumption in middle-aged men to Medicare expenditures in older age: the Chicago Western Electric Study", "authors": [{"first": "M", "middle": ["L"], "last": "Daviglus", "suffix": ""}, {"first": "K", "middle": [], "last": "Liu", "suffix": ""}, {"first": "A", "middle": [], "last": "Pirzada", "suffix": ""}], "year": 2005, "venue": "J Am Diet Assoc", "link": "44454692"}, "BIBREF52": {"title": "Successful aging: the contribution of early-life and midlife risk factors", "authors": [{"first": "A", "middle": [], "last": "Britton", "suffix": ""}, {"first": "M", "middle": [], "last": "Shipley", "suffix": ""}, {"first": "A", "middle": [], "last": "Singh-Manoux", "suffix": ""}, {"first": "M", "middle": ["G"], "last": "Marmot", "suffix": ""}], "year": 2008, "venue": "J Am Geriatr Soc", "link": "16934124"}, "BIBREF53": {"title": "Lifetime risks for cardiovascular disease mortality by cardiorespiratory fitness levels measured at ages 45, 55, and 65 years in men: the Cooper Center Longitudinal Study", "authors": [{"first": "J", "middle": ["D"], "last": "Berry", "suffix": ""}, {"first": "B", "middle": [], "last": "Willis", "suffix": ""}, {"first": "S", "middle": [], "last": "Gupta", "suffix": ""}], "year": 2011, "venue": "J Am Coll Cardiol", "link": "205540470"}}, "ref_entries": {"FIGREF0": {"text": "tile of fitness (quintile 5) was associated with a lower in- cidence of chronic conditions compared with the lowest quintile (quintile 1) in men (15.6 [95% CI, 15.0-16.2] vs 28.2 [27.4-29.0] per 100 person-years) and women (11.4 [10.5-12.3] vs 20.1 [18.7 vs 21.6] per 100 person- years). After multivariate adjustment, higher fitness (in METs) was associated with a lower risk of developing chronic conditions in men (hazard ratio, 0.95 [95% CI, 0.94-0.96] per MET) and women (0.94 [0.91-0.96] per MET). Among decedents (2406 [12.9%]), higher fit- ness was associated with lower risk of developing chronic conditions relative to survival (compression hazard ra- tio, 0.90 [95% CI, 0.88-0.92] per MET), suggesting mor- bidity compression.", "type": "figure"}, "FIGREF2": {"text": "Figure. Prevalence of selected chronic conditions in men and women by attained age (N = 18 670). Prevalence of chronic conditions at ages 70, 75, 80, and 85 years was determined by classifying all participants alive at these age thresholds according to the presence or absence of each of the 8 chronic conditions. The presence of a condition required that the earliest indication of the condition occurred before or at the attained age among survivors. Because some participants survived across multiple age thresholds and are represented in more than 1 age category, the numbers listed for the age groups total more than 18 670. ALZ indicates Alzheimer disease; CA, cancer of the colon or lung; CHF, congestive heart failure; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; DM, diabetes mellitus; and IHD, ischemic heart disease.", "type": "figure"}, "FIGREF3": {"text": "Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); HR, hazard ratio; MET, metabolic equivalent; SBP, systolic blood pressure. SI conversion factors: To convert cholesterol to millimoles per liter, multiply by 0.0259; glucose to millimoles per liter, multiply by 0.0555. a All models were adjusted for all covariates listed in the table as well as follow-up entry age, year of examination, and time-dependent interaction terms (see \"Methods\" section for details). b 2 with 1 df. c One MET equals 3.50 mL of oxygen per kilogram per minute. d Status at baseline.", "type": "figure"}, "FIGREF4": {"text": "Abbreviation: Q, quintile. a Data represent the proportion (given as the percentage [95% CI]) of follow-up time based on person-years spent at each level of chronic condition burden according to strata of midlife fitness levels.", "type": "figure"}, "FIGREF5": {"text": "Online-Only Material: The eTables are available at http: //www.archinternmed.com. Additional Contributions: The authors thank Kenneth H. Cooper, MD, MPH, for establishing the Cooper Cen- ter Longitudinal Study in 1970 and the Cooper Clinic phy- sicians and staff for data collection.", "type": "figure"}, "TABREF0": {"text": "demonstrating a higher incidence of CCs across levels of fitness mea- sured in midlife. The highest level of midlife fitness (quin- tile 5) was associated with a lower incidence of CCs com- pared with low midlife fitness (quintile 1) in men (15.6 [95% CI, 15.0-16.2] vs 28.2 [27.4-29.0] per 100 person- years) and women (11.4 [10.5-12.3] vs 20.1 [18.7 vs 21.6] per 100 person-years). After multivariate adjustment, higher fitness was associated with a lower risk of devel- oping CCs (men: hazard ratio [HR], 0.95 [0.94-0.96] per MET; women: HR, 0.94 [0.91-0.96] per MET; P \u03fd .001 for all comparisons) (", "type": "table"}, "TABREF1": {"text": "Baseline Characteristics by Sex and Fitness Quintiles a", "type": "table"}, "TABREF3": {"text": "Rate of CC Burden by Midlife Fitness Measurement in Men and Women a", "type": "table"}, "TABREF4": {"text": "Risk for Developing a Chronic Condition by Fitness and Risk Factor Levels Measured in Midlife a", "type": "table"}, "TABREF5": {"text": "Study concept and design: Willis, DeFina, and Berry. Acquisition of data: Willis. Analysis and interpretation of data: Willis, Gao, Leonard, DeFina, and Berry. Drafting of the manuscript: Willis and Berry. Criti- cal revision of the manuscript for important intellectual con- tent: Willis, Gao, Leonard, DeFina, and Berry. Statistical analysis: Willis, Gao, and Leonard. Obtained funding: Berry. Administrative, technical, and material support: Willis and DeFina. Study supervision: Willis and Berry. Financial Disclosure: Dr Berry has received financial com- pensation from Merck for being a member of its speak- ers' bureau. Funding/Support: The Cooper Institute is a 501(c)", "type": "table"}}}
{"paper_id": "2871896", "_pdf_hash": "06c693bed2a2340aa22fa4f07b1411739f2373ba", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Comparison of bi-stable and delay-based physical unclonable functions from measurements in 65nm bulk CMOS", "authors": [{"first": "M", "middle": [], "last": "Bhargava", "suffix": ""}, {"first": "C", "middle": [], "last": "Cakir", "suffix": ""}, {"first": "K", "middle": [], "last": "Mai", "suffix": ""}], "year": 2012, "venue": "Custom Integrated Circuits Conference (CICC)", "link": "2720192"}, "BIBREF1": {"title": "Differential fault analysis of secret key cryptosystems", "authors": [{"first": "E", "middle": [], "last": "Biham", "suffix": ""}, {"first": "A", "middle": [], "last": "Shamir", "suffix": ""}], "year": 1997, "venue": "Advances in Cryptology (CRYPTO)", "link": "12376527"}, "BIBREF2": {"title": "Efficient helper data key extractor on FPGAs", "authors": [{"first": "C", "middle": [], "last": "B\u00f6sch", "suffix": ""}, {"first": "J", "middle": [], "last": "Guajardo", "suffix": ""}, {"first": "A", "middle": ["R"], "last": "Sadeghi", "suffix": ""}, {"first": "J", "middle": [], "last": "Shokrollahi", "suffix": ""}, {"first": "P", "middle": [], "last": "Tuyls", "suffix": ""}], "year": 2008, "venue": "Cryptographic Hardware and Embedded Systems (CHES)", "link": "12942476"}, "BIBREF3": {"title": "Logically reconfigurable PUFs: Memorybased secure key storage", "authors": [{"first": "I", "middle": [], "last": "Eichhorn", "suffix": ""}, {"first": "P", "middle": [], "last": "Koeberl", "suffix": ""}, {"first": "V", "middle": [], "last": "Van Der Leest", "suffix": ""}], "year": 2011, "venue": "ACM Workshop on Scalable Trusted Computing", "link": "15871394"}, "BIBREF4": {"title": "Towards reliable remote healthcare applications using combined fuzzy extraction", "authors": [{"first": "J", "middle": [], "last": "Guajardo", "suffix": ""}, {"first": "M", "middle": [], "last": "Asim", "suffix": ""}, {"first": "M", "middle": [], "last": "Petkovi\u0107", "suffix": ""}], "year": 2010, "venue": "Towards Hardware-Intrinsic Security", "link": "39814161"}, "BIBREF5": {"title": "Physical unclonable functions and public-key crypto for FPGA IP protection", "authors": [{"first": "J", "middle": [], "last": "Guajardo", "suffix": ""}, {"first": "S", "middle": ["S"], "last": "Kumar", "suffix": ""}, {"first": "G", "middle": ["J"], "last": "Schrijen", "suffix": ""}, {"first": "P", "middle": [], "last": "Tuyls", "suffix": ""}], "year": 2007, "venue": "Field Programmable Logic and Applications (FPL)", "link": "2403412"}, "BIBREF6": {"title": "Brand and IP protection with physical unclonable functions", "authors": [{"first": "J", "middle": [], "last": "Guajardo", "suffix": ""}, {"first": "S", "middle": ["S"], "last": "Kumar", "suffix": ""}, {"first": "G", "middle": ["J"], "last": "Schrijen", "suffix": ""}, {"first": "P", "middle": [], "last": "Tuyls", "suffix": ""}], "year": 2008, "venue": "IEEE International Symposium on Circuits and Systems (ISCAS)", "link": "11237772"}, "BIBREF7": {"title": "Lest we remember: Cold-boot attacks on encryption keys", "authors": [{"first": "J", "middle": ["A"], "last": "Halderman", "suffix": ""}, {"first": "S", "middle": ["D"], "last": "Schoen", "suffix": ""}, {"first": "N", "middle": [], "last": "Heninger", "suffix": ""}, {"first": "W", "middle": [], "last": "Clarkson", "suffix": ""}, {"first": "W", "middle": [], "last": "Paul", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Calandrino", "suffix": ""}, {"first": "A", "middle": ["J"], "last": "Feldman", "suffix": ""}, {"first": "J", "middle": [], "last": "Appelbaum", "suffix": ""}, {"first": "E", "middle": ["W"], "last": "Felten", "suffix": ""}], "year": 2009, "venue": "Communications of the ACM", "link": "7770695"}, "BIBREF8": {"title": "Initial SRAM state as a fingerprint and source of true random numbers for RFID tags", "authors": [{"first": "D", "middle": [], "last": "Holcomb", "suffix": ""}, {"first": "W", "middle": [], "last": "Burleson", "suffix": ""}, {"first": "K", "middle": [], "last": "Fu", "suffix": ""}], "year": 2007, "venue": "Workshop on RFID Security (RFIDSec)", "link": "15225675"}, "BIBREF9": {"title": "Power-Up SRAM state as an identifying fingerprint and source of true random numbers", "authors": [{"first": "D", "middle": [], "last": "Holcomb", "suffix": ""}, {"first": "W", "middle": ["P"], "last": "Burleson", "suffix": ""}, {"first": "K", "middle": [], "last": "Fu", "suffix": ""}], "year": 2009, "venue": "IEEE Transactions on Computers", "link": "60072"}, "BIBREF10": {"title": "DRVfingerprinting: Using data retention voltage of SRAM cells for chip identification", "authors": [{"first": "D", "middle": ["E"], "last": "Holcomb", "suffix": ""}, {"first": "A", "middle": [], "last": "Rahmati", "suffix": ""}, {"first": "M", "middle": [], "last": "Salajegheh", "suffix": ""}, {"first": "W", "middle": ["P"], "last": "Burleson", "suffix": ""}, {"first": "K", "middle": [], "last": "Fu", "suffix": ""}], "year": 2013, "venue": "Radio Frequency Identification. Security and Privacy Issues", "link": "15738008"}, "BIBREF11": {"title": "Differential template attacks on PUF enabled cryptographic devices", "authors": [{"first": "D", "middle": [], "last": "Karakoyunlu", "suffix": ""}, {"first": "B", "middle": [], "last": "Sunar", "suffix": ""}], "year": 2010, "venue": "Workshop on Information Forensics and Security (WIFS)", "link": "16028673"}, "BIBREF12": {"title": "A novel RFID distance bounding protocol based on physically unclonable functions", "authors": [{"first": "S", "middle": [], "last": "Kardas", "suffix": ""}, {"first": "M", "middle": ["S"], "last": "Kiraz", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Bingol", "suffix": ""}, {"first": "H", "middle": [], "last": "Demirci", "suffix": ""}], "year": 2011, "venue": "Radio Frequency Identification: Security and Privacy Issues (RFIDSec)", "link": "5667621"}, "BIBREF13": {"title": "PUFs: Myth, fact or busted? A security evaluation of physically unclonable functions (PUFs) cast in silicon", "authors": [{"first": "S", "middle": [], "last": "Katzenbeisser", "suffix": ""}, {"first": "U", "middle": [], "last": "Kocaba\u015f", "suffix": ""}, {"first": "V", "middle": [], "last": "Ro\u017ei\u0107", "suffix": ""}, {"first": "A", "middle": ["R"], "last": "Sadeghi", "suffix": ""}, {"first": "I", "middle": [], "last": "Verbauwhede", "suffix": ""}, {"first": "C", "middle": [], "last": "Wachsmann", "suffix": ""}], "year": 2012, "venue": "Cryptographic Hardware and Embedded Systems (CHES)", "link": "1938970"}, "BIBREF14": {"title": "Evaluation of a PUF device authentication scheme on a discrete 0.13\u00b5m SRAM", "authors": [{"first": "P", "middle": [], "last": "Koeberl", "suffix": ""}, {"first": "J", "middle": [], "last": "Li", "suffix": ""}, {"first": "R", "middle": [], "last": "Maes", "suffix": ""}, {"first": "A", "middle": [], "last": "Rajan", "suffix": ""}, {"first": "C", "middle": [], "last": "Vishik", "suffix": ""}, {"first": "M", "middle": [], "last": "W\u00f3jcik", "suffix": ""}], "year": 2012, "venue": "International Conference on Trusted Systems (INTRUST)", "link": null}, "BIBREF15": {"title": "A practical device authentication scheme using SRAM PUFs", "authors": [{"first": "P", "middle": [], "last": "Koeberl", "suffix": ""}, {"first": "J", "middle": [], "last": "Li", "suffix": ""}, {"first": "A", "middle": [], "last": "Rajan", "suffix": ""}, {"first": "C", "middle": [], "last": "Vishik", "suffix": ""}, {"first": "W", "middle": [], "last": "Wu", "suffix": ""}], "year": 2011, "venue": "Conference on Trust and Trustworthy Computing (TRUST)", "link": "59741128"}, "BIBREF16": {"title": "Extended abstract: The butterfly PUF protecting IP on every FPGA", "authors": [{"first": "S", "middle": ["S"], "last": "Kumar", "suffix": ""}, {"first": "J", "middle": [], "last": "Guajardo", "suffix": ""}, {"first": "R", "middle": [], "last": "Maes", "suffix": ""}, {"first": "G", "middle": ["J"], "last": "Schrijen", "suffix": ""}, {"first": "P", "middle": [], "last": "Tuyls", "suffix": ""}], "year": 2008, "venue": "Workshop on Hardware-Oriented Security (HOST)", "link": "206713118"}, "BIBREF17": {"title": "Hardware intrinsic security from D flip-flops", "authors": [{"first": "V", "middle": [], "last": "Van Der Leest", "suffix": ""}, {"first": "G", "middle": ["J"], "last": "Schrijen", "suffix": ""}, {"first": "H", "middle": [], "last": "Handschuh", "suffix": ""}, {"first": "P", "middle": [], "last": "Tuyls", "suffix": ""}], "year": 2010, "venue": "ACM Workshop on Scalable Trusted Computing", "link": "9949092"}, "BIBREF18": {"title": "Extracting secret keys from integrated circuits", "authors": [{"first": "D", "middle": [], "last": "Lim", "suffix": ""}, {"first": "J", "middle": ["W"], "last": "Lee", "suffix": ""}, {"first": "B", "middle": [], "last": "Gassend", "suffix": ""}, {"first": "E", "middle": ["G"], "last": "Suh", "suffix": ""}, {"first": "M", "middle": [], "last": "Van Dijk", "suffix": ""}, {"first": "S", "middle": [], "last": "Devadas", "suffix": ""}], "year": 2005, "venue": "IEEE Transactions on Very Large Scale Integration (VLSI) Systems", "link": "11325408"}, "BIBREF19": {"title": "Intrinsic PUFs from flip-flops on reconfigurable devices", "authors": [{"first": "R", "middle": [], "last": "Maes", "suffix": ""}, {"first": "P", "middle": [], "last": "Tuyls", "suffix": ""}, {"first": "I", "middle": [], "last": "Verbauwhede", "suffix": ""}], "year": 2008, "venue": "Benelux Workshop on Information and System Security", "link": "45613285"}, "BIBREF20": {"title": "Side-channel analysis of PUFs and fuzzy extractors", "authors": [{"first": "D", "middle": [], "last": "Merli", "suffix": ""}, {"first": "D", "middle": [], "last": "Schuster", "suffix": ""}, {"first": "F", "middle": [], "last": "Stumpf", "suffix": ""}, {"first": "G", "middle": [], "last": "Sigl", "suffix": ""}], "year": 2011, "venue": "Trust and Trustworthy Computing (TRUST)", "link": "6839885"}, "BIBREF21": {"title": "Algebraic Side-Channel attacks beyond the Hamming weight leakage model", "authors": [{"first": "Y", "middle": [], "last": "Oren", "suffix": ""}, {"first": "M", "middle": [], "last": "Renauld", "suffix": ""}, {"first": "F", "middle": ["X"], "last": "Standaert", "suffix": ""}, {"first": "A", "middle": [], "last": "Wool", "suffix": ""}], "year": 2012, "venue": "Cryptographic Hardware and Embedded Systems (CHES)", "link": "13340461"}, "BIBREF22": {"title": "TARDIS: Time and remanence decay in SRAM to implement secure protocols on embedded devices without clocks", "authors": [{"first": "A", "middle": [], "last": "Rahmati", "suffix": ""}, {"first": "M", "middle": [], "last": "Salajegheh", "suffix": ""}, {"first": "D", "middle": [], "last": "Holcomb", "suffix": ""}, {"first": "J", "middle": [], "last": "Sorber", "suffix": ""}, {"first": "W", "middle": ["P"], "last": "Burleson", "suffix": ""}, {"first": "K", "middle": [], "last": "Fu", "suffix": ""}], "year": 2012, "venue": "USENIX Security Symposium", "link": "2546153"}, "BIBREF23": {"title": "EPIC: ending piracy of integrated circuits", "authors": [{"first": "J", "middle": ["A"], "last": "Roy", "suffix": ""}, {"first": "F", "middle": [], "last": "Koushanfar", "suffix": ""}, {"first": "I", "middle": ["L"], "last": "Markov", "suffix": ""}], "year": 2010, "venue": "Computer", "link": "870812"}, "BIBREF24": {"title": "Enhancing RFID security and privacy by physically unclonable functions", "authors": [{"first": "A", "middle": ["R"], "last": "Sadeghi", "suffix": ""}, {"first": "I", "middle": [], "last": "Visconti", "suffix": ""}, {"first": "C", "middle": [], "last": "Wachsmann", "suffix": ""}], "year": 2010, "venue": "Towards Hardware-Intrinsic Security", "link": "33928714"}, "BIBREF25": {"title": "We can remember it for you wholesale: Implications of data remanence on the use of RAM for true random number generation on RFID tags", "authors": [{"first": "N", "middle": [], "last": "Saxena", "suffix": ""}, {"first": "J", "middle": [], "last": "Voris", "suffix": ""}], "year": 2009, "venue": "", "link": "14417222"}, "BIBREF26": {"title": "Evaluation of 90nm 6T-SRAM as physical unclonable function for secure key generation in wireless sensor nodes", "authors": [{"first": "G", "middle": [], "last": "Selimis", "suffix": ""}, {"first": "M", "middle": [], "last": "Konijnenburg", "suffix": ""}, {"first": "M", "middle": [], "last": "Ashouei", "suffix": ""}, {"first": "J", "middle": [], "last": "Huisken", "suffix": ""}, {"first": "H", "middle": [], "last": "De Groot", "suffix": ""}, {"first": "V", "middle": [], "last": "Van Der Leest", "suffix": ""}, {"first": "G", "middle": ["J"], "last": "Schrijen", "suffix": ""}, {"first": "M", "middle": [], "last": "Van Hulst", "suffix": ""}, {"first": "P", "middle": [], "last": "Tuyls", "suffix": ""}], "year": 2011, "venue": "Circuits and Systems (ISCAS), 2011 IEEE International Symposium on", "link": "1731983"}, "BIBREF27": {"title": "A digital 1.6 pJ/bit chip identification circuit using process variations", "authors": [{"first": "Y", "middle": [], "last": "Su", "suffix": ""}, {"first": "J", "middle": [], "last": "Holleman", "suffix": ""}, {"first": "B", "middle": ["P"], "last": "Otis", "suffix": ""}], "year": 2008, "venue": "IEEE Journal of Solid-State Circuits", "link": "10293466"}, "BIBREF28": {"title": "True random number generator with a metastability-based quality control", "authors": [{"first": "C", "middle": [], "last": "Tokunaga", "suffix": ""}, {"first": "D", "middle": [], "last": "Blaauw", "suffix": ""}, {"first": "T", "middle": [], "last": "Mudge", "suffix": ""}], "year": 2008, "venue": "IEEE Journal of Solid-State Circuits", "link": "62120049"}, "BIBREF29": {"title": "RFID-tags for anti-counterfeiting", "authors": [{"first": "P", "middle": [], "last": "Tuyls", "suffix": ""}, {"first": "L", "middle": [], "last": "Batina", "suffix": ""}], "year": 2006, "venue": "Topics in Cryptology (CT-RSA)", "link": "3781268"}}, "ref_entries": {}}
{"paper_id": "2871940", "_pdf_hash": "fb6b439fdc86d1ea9a0b8cfe44094b5db19344d5", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Defective repair replication of DNA in Xeroderma pigmentosmn", "authors": [{"first": "J", "middle": ["E"], "last": "Cleaver", "suffix": ""}], "year": 1968, "venue": "Nature (Lond.)", "link": null}, "BIBREF1": {"title": "Ebling: Textbook of dermatology II", "authors": [{"first": "H", "middle": ["; D"], "last": "Dorn", "suffix": ""}, {"first": "F", "middle": ["J G"], "last": "Wilkinson", "suffix": ""}], "year": 1969, "venue": "Quoted in A. Rook", "link": null}, "BIBREF2": {"title": "Repair replication in HeLa cells after large doses of Xirradiation", "authors": [{"first": "R", "middle": ["B"], "last": "Painter", "suffix": ""}, {"first": "J", "middle": ["E"], "last": "Cleaver", "suffix": ""}], "year": 1967, "venue": "Nature (Lond.)", "link": "26516168"}, "BIBREF3": {"title": "Normal and abnormal reactions of man to light", "authors": [{"first": "M", "middle": ["A"], "last": "Pathak", "suffix": ""}, {"first": "J", "middle": [], "last": "Epstein", "suffix": ""}, {"first": "", "middle": [], "last": "It", "suffix": ""}], "year": 1971, "venue": "", "link": null}, "BIBREF4": {"title": "Xerodcrma pigmentosum. Clinical and laboratory investigation of its basic defect", "authors": [{"first": "W", "middle": ["B"], "last": "Reed", "suffix": ""}, {"first": "B", "middle": [], "last": "Landig", "suffix": ""}, {"first": "G", "middle": [], "last": "Sugarman", "suffix": ""}, {"first": "J", "middle": ["E"], "last": "Cleaver", "suffix": ""}, {"first": "J", "middle": [], "last": "Melnyk", "suffix": ""}], "year": 1969, "venue": "J. Amcr. reed. Ass", "link": "42495925"}, "BIBREF5": {"title": "of Dermatology Medical Faculty Univ. of Sarajevo Sarajevo Yugoslavia Note Added in Proo", "authors": [{"first": "", "middle": [], "last": "Prof", "suffix": ""}, {"first": "", "middle": ["T"], "last": "Dr", "suffix": ""}, {"first": "", "middle": [], "last": "Dept", "suffix": ""}], "year": "", "venue": "The number of blast cells in the TTL was in both patients significantly decreased", "link": null}}, "ref_entries": {}}
{"paper_id": "2872418", "_pdf_hash": "25f20a4370d456a446e8da4e5634669a666e49bd", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Ordered assembly of nucleoprotein structures at the bacteriophage lambda replication origin during the initiation of DNA replication", "authors": [{"first": "C", "middle": [], "last": "Alfano", "suffix": ""}, {"first": "R", "middle": [], "last": "Mcmacken", "suffix": ""}], "year": 1989, "venue": "J Biol Chem", "link": "42862721"}, "BIBREF1": {"title": "Heat shock protein-mediated disassembly of nucleoprotein structures is required for initiation of bacteriophage DNA replication", "authors": [{"first": "C", "middle": [], "last": "Alfano", "suffix": ""}, {"first": "R", "middle": [], "last": "Mcmacken", "suffix": ""}], "year": 1989, "venue": "J Biol Chem", "link": null}, "BIBREF2": {"title": "Regulation of the switch from early to late bacteriophage DNA replication mode", "authors": [{"first": "S", "middle": [], "last": "Barajska", "suffix": ""}, {"first": "M", "middle": [], "last": "Gabig", "suffix": ""}, {"first": "A", "middle": [], "last": "Wdgrzyn", "suffix": ""}, {"first": "G", "middle": [], "last": "Konopa", "suffix": ""}, {"first": "A", "middle": [], "last": "Herman-Antosiewicz", "suffix": ""}, {"first": "P", "middle": [], "last": "Hernandez", "suffix": ""}, {"first": "J", "middle": ["B"], "last": "Schvartzman", "suffix": ""}, {"first": "D", "middle": ["R"], "last": "Helinski", "suffix": ""}, {"first": "G", "middle": [], "last": "Wdgrzyn", "suffix": ""}], "year": 2001, "venue": "Microbiology", "link": null}, "BIBREF3": {"title": "Directionality of plasmid DNA replication carried out by the heritable replication complex", "authors": [{"first": "S", "middle": [], "last": "Barajska", "suffix": ""}, {"first": "G", "middle": [], "last": "Konopa", "suffix": ""}, {"first": "G", "middle": [], "last": "Wdgrzyn", "suffix": ""}], "year": 2002, "venue": "Nucleic Acids Res", "link": "86557658"}, "BIBREF4": {"title": "Energy-dependent degradation of O protein in Escherichia coli", "authors": [{"first": "I", "middle": [], "last": "Bejarano", "suffix": ""}, {"first": "Y", "middle": [], "last": "Klemes", "suffix": ""}, {"first": "R", "middle": [], "last": "Schoulaker-Schwarz", "suffix": ""}, {"first": "H", "middle": [], "last": "Engelberg-Kulka", "suffix": ""}], "year": 1993, "venue": "J Bacteriol", "link": null}, "BIBREF5": {"title": "Construction and characterization of new cloning vehicles. II. A multipurpose cloning system", "authors": [{"first": "F", "middle": [], "last": "Bolivar", "suffix": ""}, {"first": "R", "middle": ["L"], "last": "Rodriguez", "suffix": ""}, {"first": "P", "middle": ["J"], "last": "Greene", "suffix": ""}, {"first": "M", "middle": ["C"], "last": "Betlach", "suffix": ""}, {"first": "H", "middle": ["L"], "last": "Heyneker", "suffix": ""}, {"first": "H", "middle": ["W"], "last": "Boyer", "suffix": ""}], "year": 1977, "venue": "Gene", "link": "42062280"}, "BIBREF6": {"title": "Bacteriophage lambda replication-coupled processes, genetic elements and regulatory choices", "authors": [{"first": "H", "middle": ["J"], "last": "Bull", "suffix": ""}], "year": 1995, "venue": "", "link": null}, "BIBREF7": {"title": "Electron microscopy", "authors": [{"first": "H", "middle": [], "last": "Burkardt", "suffix": ""}, {"first": "R", "middle": [], "last": "Lurz", "suffix": ""}], "year": 1984, "venue": "Advanced molecular genetics. Srpinger", "link": null}, "BIBREF8": {"title": "Rapid degradation of bacteriophage O protein by ClpP/ClpX protease inXuences the lysis-versus-lysogenization decision of the phage under certain growth conditions of the host cells", "authors": [{"first": "A", "middle": [], "last": "Czyr", "suffix": ""}, {"first": "R", "middle": [], "last": "Zielke", "suffix": ""}, {"first": "G", "middle": [], "last": "Wdgrzyn", "suffix": ""}], "year": 2001, "venue": "Arch Virol", "link": "1100376"}, "BIBREF9": {"title": "The mutation that makes Escherichia coli resistant to P genemediated host lethality is located within DNA initiator gene dnaA of the bacterium", "authors": [{"first": "I", "middle": [], "last": "Datta", "suffix": ""}, {"first": "S", "middle": [], "last": "Banik-Maiti", "suffix": ""}, {"first": "L", "middle": [], "last": "Adhikari", "suffix": ""}, {"first": "S", "middle": [], "last": "Sau", "suffix": ""}, {"first": "N", "middle": [], "last": "Das", "suffix": ""}, {"first": "N", "middle": ["C"], "last": "Mandal", "suffix": ""}], "year": 2005, "venue": "J Biochem Mol Biol", "link": "27393874"}, "BIBREF10": {"title": "The bacteriophage DNA replication protein P inhibits the oriC DNA-and ATP-binding functions of the DNA replication initiator protein DnaA of Escherichia coli", "authors": [{"first": "I", "middle": [], "last": "Datta", "suffix": ""}, {"first": "S", "middle": [], "last": "Sau", "suffix": ""}, {"first": "A", "middle": ["K"], "last": "Sil", "suffix": ""}, {"first": "N", "middle": ["C"], "last": "Mandal", "suffix": ""}], "year": 2005, "venue": "J Biochem Mol Biol", "link": "12194593"}, "BIBREF11": {"title": "Specialized nucleoprotein structures at the origin of replication of bacteriophage : localized unwinding of duplex DNA by a six protein reaction", "authors": [{"first": "M", "middle": [], "last": "Dodson", "suffix": ""}, {"first": "H", "middle": [], "last": "Echols", "suffix": ""}, {"first": "S", "middle": [], "last": "Wickner", "suffix": ""}, {"first": "C", "middle": [], "last": "Alfano", "suffix": ""}, {"first": "K", "middle": [], "last": "Mensa-Wilmot", "suffix": ""}, {"first": "B", "middle": [], "last": "Gomes", "suffix": ""}, {"first": "J", "middle": [], "last": "Lebowitz", "suffix": ""}, {"first": "J", "middle": ["D"], "last": "Roberts", "suffix": ""}, {"first": "R", "middle": [], "last": "Mcmacken", "suffix": ""}], "year": 1986, "venue": "Proc Natl Acad Sci", "link": "25383052"}, "BIBREF12": {"title": "Bacteriophage lambda: alive and well and still doing its thing", "authors": [{"first": "D", "middle": ["I"], "last": "Friedman", "suffix": ""}, {"first": "D", "middle": ["L"], "last": "Court", "suffix": ""}], "year": 2001, "venue": "Curr Opin Microbiol", "link": "45916457"}, "BIBREF13": {"title": "The mechanism of regulation of bacteriophage p R promoter activity by Escherichia coli DnaA protein", "authors": [{"first": "M", "middle": [], "last": "Glinkowska", "suffix": ""}, {"first": "J", "middle": [], "last": "Majka", "suffix": ""}, {"first": "W", "middle": [], "last": "Messer", "suffix": ""}, {"first": "G", "middle": [], "last": "Wdgrzyn", "suffix": ""}], "year": 2003, "venue": "J Biol Chem", "link": null}, "BIBREF14": {"title": "ClpX, an alternative subunit for the ATP-dependent Clp protease of Escherichia coli", "authors": [{"first": "S", "middle": [], "last": "Gottesman", "suffix": ""}, {"first": "W", "middle": ["P"], "last": "Clark", "suffix": ""}, {"first": "V", "middle": [], "last": "De Crecy-Lagard", "suffix": ""}, {"first": "M", "middle": ["R"], "last": "Maurizi", "suffix": ""}], "year": 1993, "venue": "J Biol Chem", "link": null}, "BIBREF15": {"title": "Replication and maintenance of plasmids devoid of the Cro repressor autoregulatory loop in Escherichia coli", "authors": [{"first": "A", "middle": [], "last": "Herman-Antosiewicz", "suffix": ""}, {"first": "S", "middle": [], "last": "Jrutkowska", "suffix": ""}, {"first": "K", "middle": [], "last": "Taylor", "suffix": ""}, {"first": "G", "middle": [], "last": "Wdgrzyn", "suffix": ""}], "year": 1998, "venue": "Plasmid", "link": "84629016"}, "BIBREF16": {"title": "The Escherichia coli \"wild types\" W3110 and MG1655 have an rph frameshift mutation that leads to pyrimidine starvation due to low pyrE expression levels", "authors": [{"first": "K", "middle": ["F"], "last": "Jensen", "suffix": ""}], "year": 1993, "venue": "J Bacteriol", "link": "20572919"}, "BIBREF17": {"title": "DNA of vegetative bacteriophage lambda, VI. Electron microscopic studies of replicating lambda DNA", "authors": [{"first": "J", "middle": ["A"], "last": "Kiger", "suffix": ""}, {"first": "R", "middle": ["L"], "last": "Sinsheimer", "suffix": ""}], "year": 1971, "venue": "Proc Natl Acad Sci", "link": "1908419"}, "BIBREF18": {"title": "Bacteriophage and host mutants causing the rolling-circle DNA replication early after infection", "authors": [{"first": "G", "middle": [], "last": "Konopa", "suffix": ""}, {"first": "S", "middle": [], "last": "Barajska", "suffix": ""}, {"first": "A", "middle": [], "last": "Wdgrzyn", "suffix": ""}, {"first": "G", "middle": [], "last": "Wdgrzyn", "suffix": ""}], "year": 2000, "venue": "FEBS Lett", "link": "85112409"}, "BIBREF19": {"title": "Escherichia coli dnaA initiation function is required for replication of plasmids derived from coliphage lambda", "authors": [{"first": "J", "middle": [], "last": "Kur", "suffix": ""}, {"first": "I", "middle": [], "last": "G\u00f3rska", "suffix": ""}, {"first": "K", "middle": [], "last": "Taylor", "suffix": ""}], "year": 1987, "venue": "J Mol Biol", "link": "43316929"}, "BIBREF20": {"title": "Transcription stimulates the establishment of bidirectional DNA replication in vitro", "authors": [{"first": "B", "middle": [], "last": "Learn", "suffix": ""}, {"first": "A", "middle": ["W"], "last": "Karzai", "suffix": ""}, {"first": "R", "middle": [], "last": "Mcmacken", "suffix": ""}], "year": 1993, "venue": "Cold Spring Harbor Symp Quant Biol", "link": "86024481"}, "BIBREF21": {"title": "Reconstitution of a nine-protein system that initiates bacteriophage DNA replication", "authors": [{"first": "K", "middle": [], "last": "Mensa-Wilmot", "suffix": ""}, {"first": "R", "middle": [], "last": "Seaby", "suffix": ""}, {"first": "C", "middle": [], "last": "Alfano", "suffix": ""}, {"first": "M", "middle": ["S"], "last": "Wold", "suffix": ""}, {"first": "B", "middle": [], "last": "Gomes", "suffix": ""}, {"first": "R", "middle": [], "last": "Mcmacken", "suffix": ""}], "year": 1989, "venue": "J Biol Chem", "link": "11520870"}, "BIBREF22": {"title": "IdentiWcation of the site of interruption in relaxed circles producing during bacteriophage DNA circle replication", "authors": [{"first": "R", "middle": ["C"], "last": "Reuben", "suffix": ""}, {"first": "A", "middle": [], "last": "Skalka", "suffix": ""}], "year": 1977, "venue": "J Virol", "link": null}, "BIBREF23": {"title": "Molecular cloning: a laboratory mannual", "authors": [{"first": "J", "middle": [], "last": "Sambrook", "suffix": ""}, {"first": "E", "middle": ["F"], "last": "Fritsch", "suffix": ""}, {"first": "T", "middle": [], "last": "Maniatis", "suffix": ""}], "year": 1989, "venue": "", "link": "85658872"}, "BIBREF24": {"title": "A method for isolation of plasmid DNA replication intermediates from unsynchronized bacterial cultures for electron microscopy analysis", "authors": [{"first": "S", "middle": [], "last": "Jrutkowska", "suffix": ""}, {"first": "G", "middle": [], "last": "Konopa", "suffix": ""}, {"first": "G", "middle": [], "last": "Wdgrzyn", "suffix": ""}], "year": 1998, "venue": "Acta Biochim Pol", "link": null}, "BIBREF25": {"title": "Detection of DNA replication intermediates after two-dimensional agarose gel electrophoresis using a Xuorescein-labeled probe", "authors": [{"first": "S", "middle": [], "last": "Jrutkowska", "suffix": ""}, {"first": "R", "middle": [], "last": "Caspi", "suffix": ""}, {"first": "M", "middle": [], "last": "Gabig", "suffix": ""}, {"first": "G", "middle": [], "last": "Wdgrzyn", "suffix": ""}], "year": 1999, "venue": "Anal Biochem", "link": "34108824"}, "BIBREF26": {"title": "DnaA-stimulated transcriptional activation of ori : Escherichia coli RNA polymerase subunit as a transcriptional activator contact site", "authors": [{"first": "A", "middle": [], "last": "Szalewska-Paiasz", "suffix": ""}, {"first": "A", "middle": [], "last": "Wdgrzyn", "suffix": ""}, {"first": "A", "middle": [], "last": "Biaszczak", "suffix": ""}, {"first": "K", "middle": [], "last": "Taylor", "suffix": ""}, {"first": "G", "middle": [], "last": "Wdgrzyn", "suffix": ""}], "year": 1998, "venue": "Proc Natl Acad Sci", "link": "924345"}, "BIBREF27": {"title": "Interaction of the Escherichia coli DnaA protein with bacteriophage DNA", "authors": [{"first": "A", "middle": [], "last": "Szalewska-Paiasz", "suffix": ""}, {"first": "C", "middle": [], "last": "Weigel", "suffix": ""}, {"first": "C", "middle": [], "last": "Speck", "suffix": ""}, {"first": "S", "middle": [], "last": "Jrutkowska", "suffix": ""}, {"first": "G", "middle": [], "last": "Konopa", "suffix": ""}, {"first": "R", "middle": [], "last": "Lurz", "suffix": ""}, {"first": "J", "middle": [], "last": "Marszaiek", "suffix": ""}, {"first": "K", "middle": [], "last": "Taylor", "suffix": ""}, {"first": "W", "middle": [], "last": "Messer", "suffix": ""}, {"first": "G", "middle": [], "last": "Wdgrzyn", "suffix": ""}], "year": 1998, "venue": "Mol Gen Genet", "link": null}, "BIBREF28": {"title": "The starting point and direction of rolling-circle replicative intermediates of coliphage DNA", "authors": [{"first": "S", "middle": [], "last": "Takahashi", "suffix": ""}], "year": 1975, "venue": "Mol Gen Genet", "link": "19772607"}, "BIBREF29": {"title": "Rolling circle replicative structure of bacteriophage DNA in a recombination deWcient system", "authors": [{"first": "S", "middle": [], "last": "Takahashi", "suffix": ""}], "year": 1977, "venue": "Mol Gen Genet", "link": "41768577"}, "BIBREF30": {"title": "Replication of coliphage lambda DNA", "authors": [{"first": "K", "middle": [], "last": "Taylor", "suffix": ""}, {"first": "G", "middle": [], "last": "Wdgrzyn", "suffix": ""}], "year": 1995, "venue": "FEMS Microbiol Rev", "link": "43847409"}, "BIBREF31": {"title": "Regulation of bacteriophage replication", "authors": [{"first": "K", "middle": [], "last": "Taylor", "suffix": ""}, {"first": "G", "middle": [], "last": "Wdgrzyn", "suffix": ""}], "year": 1998, "venue": "", "link": "81985220"}, "BIBREF32": {"title": "The ColE1 unidirectional origin acts as a polar replication fork pausing site", "authors": [{"first": "E", "middle": [], "last": "Viguera", "suffix": ""}, {"first": "P", "middle": [], "last": "Hernandez", "suffix": ""}, {"first": "D", "middle": ["B"], "last": "Krimer", "suffix": ""}, {"first": "A", "middle": ["S"], "last": "Boistov", "suffix": ""}, {"first": "R", "middle": [], "last": "Lurz", "suffix": ""}, {"first": "J", "middle": ["C"], "last": "Alonso", "suffix": ""}, {"first": "J", "middle": ["B"], "last": "Schvartzman", "suffix": ""}], "year": 1996, "venue": "J Biol Chem", "link": "40652701"}, "BIBREF33": {"title": "A computer model for the analysis of DNA replication intermediates by two-dimensional (2D) agarose gel electrophoresis", "authors": [{"first": "E", "middle": [], "last": "Viguera", "suffix": ""}, {"first": "A", "middle": [], "last": "Rodr\u00edguez", "suffix": ""}, {"first": "D", "middle": ["B"], "last": "Krimer", "suffix": ""}, {"first": "P", "middle": [], "last": "Hern\u00e1ndez", "suffix": ""}, {"first": "O", "middle": [], "last": "Trelles", "suffix": ""}, {"first": "J", "middle": ["B"], "last": "Schvartzman", "suffix": ""}], "year": 1998, "venue": "Gene", "link": null}, "BIBREF34": {"title": "Phage regulatory circuits and virulence gene expression", "authors": [{"first": "M", "middle": ["K"], "last": "Waldor", "suffix": ""}, {"first": "D", "middle": ["I"], "last": "Friedman", "suffix": ""}], "year": 2005, "venue": "Curr Opin Microbiol", "link": "22463853"}, "BIBREF35": {"title": "Inheritance of the replication complex by one of two daughter copies during plasmid replication in Escherichia coli", "authors": [{"first": "G", "middle": [], "last": "Wdgrzyn", "suffix": ""}, {"first": "K", "middle": [], "last": "Taylor", "suffix": ""}], "year": 1992, "venue": "J Mol Biol", "link": null}, "BIBREF36": {"title": "Inheritance of the replication complex: a unique or common phenomenon in the control of DNA replication?", "authors": [{"first": "A", "middle": [], "last": "Wdgrzyn", "suffix": ""}, {"first": "G", "middle": [], "last": "Wdgrzyn", "suffix": ""}], "year": 2001, "venue": "Arch Microbiol", "link": null}, "BIBREF37": {"title": "Stress responses and replication of plasmids in bacterial cells", "authors": [{"first": "G", "middle": [], "last": "Wdgrzyn", "suffix": ""}, {"first": "A", "middle": [], "last": "Wdgrzyn", "suffix": ""}], "year": 2002, "venue": "Microb Cell Factor", "link": "16097177"}, "BIBREF38": {"title": "Genetic switches during bacteriophage lambda development", "authors": [{"first": "G", "middle": [], "last": "Wdgrzyn", "suffix": ""}, {"first": "A", "middle": [], "last": "Wdgrzyn", "suffix": ""}], "year": 2005, "venue": "Prog Nucleic Acid Res Mol Biol", "link": "37532148"}, "BIBREF39": {"title": "Stability of coliphage DNA replication initiator, the O protein", "authors": [{"first": "G", "middle": [], "last": "Wdgrzyn", "suffix": ""}, {"first": "A", "middle": [], "last": "Pawiowicz", "suffix": ""}, {"first": "K", "middle": [], "last": "Taylor", "suffix": ""}], "year": 1992, "venue": "J Mol Biol", "link": "89487296"}, "BIBREF40": {"title": "Plasmid and host functions required for plasmid replication carried out by the inherited replication complex", "authors": [{"first": "A", "middle": [], "last": "Wdgrzyn", "suffix": ""}, {"first": "G", "middle": [], "last": "Wdgrzyn", "suffix": ""}, {"first": "K", "middle": [], "last": "Taylor", "suffix": ""}], "year": 1995, "venue": "Mol Gen Genet", "link": "38019067"}, "BIBREF41": {"title": "Transcriptional activation of the origin of coliphage DNA replication is regulated by the host DnaA initiator function", "authors": [{"first": "G", "middle": [], "last": "Wdgrzyn", "suffix": ""}, {"first": "A", "middle": [], "last": "Szalewska-Paiasz", "suffix": ""}, {"first": "A", "middle": [], "last": "Wdgrzyn", "suffix": ""}, {"first": "M", "middle": [], "last": "Obuchowski", "suffix": ""}, {"first": "K", "middle": [], "last": "Taylor", "suffix": ""}], "year": 1995, "venue": "Gene", "link": null}, "BIBREF42": {"title": "Involvement of the host initiator function dnaA in the replication of coliphage", "authors": [{"first": "G", "middle": [], "last": "Wdgrzyn", "suffix": ""}, {"first": "A", "middle": [], "last": "Wdgrzyn", "suffix": ""}, {"first": "I", "middle": [], "last": "Konieczny", "suffix": ""}, {"first": "K", "middle": [], "last": "Bielawski", "suffix": ""}, {"first": "G", "middle": [], "last": "Konopa", "suffix": ""}, {"first": "M", "middle": [], "last": "Obuchowski", "suffix": ""}, {"first": "D", "middle": ["R"], "last": "Helinski", "suffix": ""}, {"first": "K", "middle": [], "last": "Taylor", "suffix": ""}], "year": 1995, "venue": "Genetics", "link": null}, "BIBREF43": {"title": "Protein inheritance: plasmid replication perpetuated by the heritable replication complex", "authors": [{"first": "A", "middle": [], "last": "Wdgrzyn", "suffix": ""}, {"first": "G", "middle": [], "last": "Wdgrzyn", "suffix": ""}, {"first": "A", "middle": [], "last": "Herman", "suffix": ""}, {"first": "K", "middle": [], "last": "Taylor", "suffix": ""}], "year": 1996, "venue": "Genes Cells", "link": null}, "BIBREF44": {"title": "ClpP/ClpX-mediated degradation of the bacteriophage O protein and regulation of phage and plasmid replication", "authors": [{"first": "A", "middle": [], "last": "Wdgrzyn", "suffix": ""}, {"first": "A", "middle": [], "last": "Czyr", "suffix": ""}, {"first": "M", "middle": [], "last": "Gabig", "suffix": ""}, {"first": "G", "middle": [], "last": "Wdgrzyn", "suffix": ""}], "year": 2000, "venue": "Arch Microbiol", "link": "35188269"}, "BIBREF45": {"title": "Regulation of bacteriophage lambda development", "authors": [{"first": "G", "middle": [], "last": "Wdgrzyn", "suffix": ""}, {"first": "A", "middle": [], "last": "Wdgrzyn", "suffix": ""}, {"first": "S", "middle": [], "last": "Barajska", "suffix": ""}, {"first": "A", "middle": [], "last": "Czyr", "suffix": ""}], "year": 2001, "venue": "Recent Res Dev Virol", "link": null}, "BIBREF46": {"title": "Bacteriophage replication modules", "authors": [{"first": "C", "middle": [], "last": "Weigel", "suffix": ""}, {"first": "H", "middle": [], "last": "Seitz", "suffix": ""}], "year": 2006, "venue": "FEMS Microbiol Rev", "link": "13212850"}, "BIBREF47": {"title": "Isolation and characterization of ClpX, a new ATP-dependent speciWcity component of the Clp protease of Escherichia coli", "authors": [{"first": "D", "middle": [], "last": "Wojtkowiak", "suffix": ""}, {"first": "C", "middle": [], "last": "Georgopoulos", "suffix": ""}], "year": 1993, "venue": "J Biol Chem", "link": null}, "BIBREF48": {"title": "Initiation of DNA replication with puriWed host-and bacteriophage-encoded proteins: role of the DnaK, DnaJ and GrpE heat shock proteins", "authors": [{"first": "M", "middle": [], "last": "\u00d4ylicz", "suffix": ""}, {"first": "D", "middle": [], "last": "Ang", "suffix": ""}, {"first": "K", "middle": [], "last": "Liberek", "suffix": ""}, {"first": "C", "middle": [], "last": "Georgopoulos", "suffix": ""}], "year": 1989, "venue": "EMBO J", "link": null}, "BIBREF49": {"title": "Formation of the preprimosome protects O from RNA transcriptiondependent proteolysis by ClpP/ClpX", "authors": [{"first": "M", "middle": [], "last": "\u00d4ylicz", "suffix": ""}, {"first": "K", "middle": [], "last": "Liberek", "suffix": ""}, {"first": "A", "middle": [], "last": "Wawrzyn\u00f3w", "suffix": ""}, {"first": "C", "middle": [], "last": "Georgopoulos", "suffix": ""}], "year": 1998, "venue": "Proc Natl Acad Sci", "link": null}}, "ref_entries": {}}
{"paper_id": "2872518", "_pdf_hash": "77aded4248baae284295f9a80b9d8fb0469fc527", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "2872538", "_pdf_hash": "ec3bb4d81aa9be900badbb30e208029c9f473dda", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Empirical analysis for estimating land use transition potential functions -case in the Tokyo metropolitan region", "authors": [{"first": "T", "middle": [], "last": "Arai", "suffix": ""}, {"first": "T", "middle": [], "last": "Akiyama", "suffix": ""}], "year": 2004, "venue": "Computers, Environment and Urban Systems", "link": "35849004"}, "BIBREF1": {"title": "Land-use change in a small catchment of northern Loess Plateau", "authors": [{"first": "L", "middle": [], "last": "Chen", "suffix": ""}, {"first": "J", "middle": [], "last": "Wang", "suffix": ""}, {"first": "B", "middle": [], "last": "Fu", "suffix": ""}, {"first": "Y", "middle": [], "last": "Qiu", "suffix": ""}], "year": 2001, "venue": "Ecosystems & Environment", "link": "84189394"}, "BIBREF2": {"title": "Ordered weighted averaging with fuzzy quantifiers: GIS-based multicriteria evaluation for land-use suitability analysis", "authors": [{"first": "J", "middle": [], "last": "Malczewski", "suffix": ""}], "year": 2006, "venue": "International Journal of Applied Earth Observation and Geoinformation", "link": "42506902"}, "BIBREF3": {"title": "A land-use model based on random utility/rentbidding analysis (RURBAN). Transport Policy, Management and TechnologyTowards", "authors": [{"first": "K", "middle": [], "last": "Miyamoto", "suffix": ""}, {"first": "K", "middle": [], "last": "Kitazume", "suffix": ""}], "year": 1989, "venue": "", "link": null}, "BIBREF4": {"title": "A land use model based on disaggregate behavioural analyses", "authors": [{"first": "K", "middle": [], "last": "Miyamoto", "suffix": ""}, {"first": "H", "middle": [], "last": "Nakamura", "suffix": ""}, {"first": "E", "middle": [], "last": "Shimizu", "suffix": ""}], "year": 1986, "venue": "Proceedings of the Fourth World Conference on Transport Research", "link": null}, "BIBREF5": {"title": "The estimation of the land use change in the Tokyo metropolitan area", "authors": [{"first": "Y", "middle": [], "last": "Murayama", "suffix": ""}], "year": 1993, "venue": "Tsukuba Studies in Human Geography", "link": "135117462"}, "BIBREF6": {"title": "Land-use transportation analysis system for a metropolitan area", "authors": [{"first": "H", "middle": [], "last": "Nakamura", "suffix": ""}, {"first": "Y", "middle": [], "last": "Hayashi", "suffix": ""}, {"first": "K", "middle": [], "last": "Miyamoto", "suffix": ""}], "year": 1983, "venue": "Transportation Research Record", "link": "106718235"}, "BIBREF7": {"title": "Cellular automata and urban simulation: where do we go from here?", "authors": [{"first": "P", "middle": ["M"], "last": "Torrens", "suffix": ""}, {"first": "O", "middle": ["S"], "last": "David", "suffix": ""}], "year": 2001, "venue": "Environment and Planning B", "link": "18575773"}, "BIBREF8": {"title": "The use of constrained cellular automata for highresolution modeling of urban land-use dynamics", "authors": [{"first": "R", "middle": [], "last": "White", "suffix": ""}, {"first": "G", "middle": [], "last": "Engelen", "suffix": ""}, {"first": "I", "middle": [], "last": "Uljee", "suffix": ""}], "year": 1997, "venue": "Environment and Planning B", "link": "60857917"}, "BIBREF9": {"title": "Developing an urban land use simulator for European cities", "authors": [{"first": "R", "middle": [], "last": "White", "suffix": ""}, {"first": "G", "middle": [], "last": "Engelen", "suffix": ""}, {"first": "I", "middle": [], "last": "Uljee", "suffix": ""}, {"first": "C", "middle": [], "last": "Lavalle", "suffix": ""}, {"first": "D", "middle": [], "last": "Erlich", "suffix": ""}], "year": 1999, "venue": "Proceedings of the 5th EC-GIS Workshop", "link": null}}, "ref_entries": {}}
{"paper_id": "2872580", "_pdf_hash": "0b0a0d63e1087f2ff5d97998de0e149c8bb8fa39", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Study the influence of pavetamine on the ion channels (voltage-dependent calcium channel, potassium voltage-gated channel, solute carrier, chloride channel and sodium channel) in the heart", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF1": {"title": "\u2022 Study compounds that can reduce or alleviate the effects of pavetamine in the heart, eg. antioxidants like gallic acid, hesperidin, resveratrol and iron chelators like deferoxamine and 2-pyridylcarboxaldehyde 2-thiophenecarboxyl hydrazone", "authors": [], "year": "", "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "2872613", "_pdf_hash": "0a3617e64dc130abf170b1565b4768d49f521e02", "abstract": [{"section": "Abstract", "text": "Poor balance in older persons contributes to a rise in fall risk and serious injury, yet no consensus has developed on which measures of postural sway can identify those at greatest risk of falling. Postural sway was measured in 161 elderly individuals (81.8y67.4), 24 of which had at least one self-reported fall in the prior six months, and compared to sway measured in 37 young adults (34.9y67.1). Center of pressure (COP) was measured during 4 minutes of quiet stance with eyes opened. In the elderly with fall history, all measures but one were worse than those taken from young adults (e.g., maximal COP velocity was 2.76 greater in fallers than young adults; p,0.05), while three measures of balance were significantly worse in fallers as compared to older persons with no recent fall history (COP Displacement, Short Term Diffusion Coefficient, and Critical Displacement). Variance of elderly subjects' COP measures from the young adult cohort were weighted to establish a balance score (''B-score'') algorithm designed to distinguish subjects with a fall history from those more sure on their feet. Relative to a young adult B-score of zero, elderly ''non-fallers'' had a B-score of 0.334, compared to 0.645 for those with a fall history (p,0.001). A weighted amalgam of postural sway elements may identify individuals at greatest risk of falling, allowing interventions to target those with greatest need of attention.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Incidence of falls escalates with age, events exacerbated by declines in muscle mass, strength, coordination and balance [1, 2] . When considered in concert with age-related decline in bone quality and quantity [3] , this elevated risk of falling portends an increase in the incidence of injury, including fracture [4] . The increase in falls and concomitant injuries not only elevates rates of mortality, it poses significant economic and societal burdens to health care systems worldwide [5] .", "cite_spans": [{"start": 121, "end": 124, "text": "[1,", "ref_id": "BIBREF0"}, {"start": 125, "end": 127, "text": "2]", "ref_id": "BIBREF1"}, {"start": 315, "end": 318, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 490, "end": 493, "text": "[5]", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "Introduction", "text": "Poor postural control is recognized as a major contributor to fall risk, and individuals may rely upon a range of balance strategies to remain upright [6, 7] . Stable posture is maintained by a complex, integrated feedback from the visual, proprioceptive, and vestibular systems, as well as coordinated control by the neuromuscular system [8] [9] [10] . A commonly available -and relatively simplemethod of assessing balance and instability is stabilogram analysis, which entails recording the ground reaction vector, known as center of pressure (COP) [11] [12] [13] . Measures of stabilogram magnitude, peak and average sway velocities, and root-meansquare (RMS) amplitude, are used as predictors of fall-risk [14, 15] , while frequency domain characteristics have been proposed as an alternative way to express the results of COP measures to best capture postural control [16] .", "cite_spans": [{"start": 151, "end": 154, "text": "[6,", "ref_id": "BIBREF5"}, {"start": 155, "end": 157, "text": "7]", "ref_id": "BIBREF6"}, {"start": 339, "end": 342, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 343, "end": 346, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 347, "end": 351, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 552, "end": 556, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 557, "end": 561, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 562, "end": 566, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 711, "end": 715, "text": "[14,", "ref_id": "BIBREF13"}, {"start": 716, "end": 719, "text": "15]", "ref_id": "BIBREF14"}, {"start": 874, "end": 878, "text": "[16]", "ref_id": "BIBREF15"}], "ref_spans": []}, {"section": "Introduction", "text": "With age, diseases such as glaucoma, diabetic neuropathy, and sarcopenia, as well as age-related declines in hearing, diminish the quality of the integrated sensory input systems critical to stability. Inevitably, fall risk is ultimately a complex amalgam of many different system inputs. Nevertheless, regardless of cause, identifying specific components of balance that contribute to elevated risk may help to target interventional strategies or environmental modifications to reduce the occurrence of falls.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "The principal objective of this work was to determine if there were differences in parameters of balance between a young and elderly cohort -both with and without a self-reported history of falls -and use these data to develop an algorithm based on these retrospective data to potentially -and isolate those specific components of the posture measurements which help identify individuals at increased risk of falls. We hypothesized that 'elderly' subjects would be less stable than younger subjects, and that those elderly subjects with a history of falls would have a COP signature distinct from age-matched non-fallers. The comparison of COP measures in elderly fallers vs. non-fallers, and their relationship to the young healthy cohort was then used to iteratively develop a fall predictor algorithm. It is hoped that data such as these may ultimately provide simple, relatively accessible diagnostic infor-W mation from balance to prospectively identify those individuals at greatest risk of falls.", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Study Sample", "text": "Study protocols and participation consents were reviewed and approved by the institutional human subjects review boards (IRBs) at each participating institution, including Hebrew SeniorLife (Harvard Medical School), National Aeronautics and Space Administration, University of Texas Medical Branch at Galveston, and Stony Brook University. After obtaining written informed consent from each volunteer in the trial, participants underwent a screening for eligibility including medical history, medication review, and a dual energy x-ray absorptiometry scan (n.b., signed consent were collected for the ''young'' cohort by University of Texas Medical Branch and National Aeronautics and Space Administration, and for the ''elderly'' volunteers by Hebrew SeniorLife and Harvard Medical School). Those with osteoporosis (T-scores of ,22.5) were excluded from participation.", "cite_spans": [], "ref_spans": []}, {"section": "Study Sample", "text": "Postural control (balance) COP data were collected from 37 healthy young adults (23 males & 14 females), as well as 161 elderly subjects (52 males & 109 females) [17, 18] . The young cohort was recruited from the Houston area (part of a NASAfunded study on chronic bed rest), and the elderly cohort was recruited from the Boston area (part of an NIH-funded study on osteopenia in an aged population). As a principal goal of the NASA study was to determine if chronic bed rest potentiated poor balance, those with a self-reported history of falls were excluded from the study [15] . At baseline evaluation, elderly subjects that had fallen in the prior six-months were identified by questionnaire, in which a fall was defined as an event in which part of the body above the ankle touched the ground, including a fall on the stairs. Each member of the elderly group had to be at least 60 years of age, have a BMI below 30, have no prior history of pharmacologic treatment for osteoporosis, and have a dual-energy x-ray absorptiometry (DXA) based T-score (number of standard deviations above or below the ''young'' normal average) of between 21.0 and 22.5, regardless of fall history [17] . Elderly subjects were healthy, free-living, cognitively intact residents of independent living communities in the Boston area [19] .", "cite_spans": [{"start": 162, "end": 166, "text": "[17,", "ref_id": "BIBREF16"}, {"start": 167, "end": 170, "text": "18]", "ref_id": "BIBREF17"}, {"start": 575, "end": 579, "text": "[15]", "ref_id": "BIBREF14"}, {"start": 1181, "end": 1185, "text": "[17]", "ref_id": "BIBREF16"}, {"start": 1314, "end": 1318, "text": "[19]", "ref_id": "BIBREF18"}], "ref_spans": []}, {"section": "Measurement of Postural Stability", "text": "To assess postural control, each subject was instructed to stand in a relaxed manner on a force plate (Kistler 9286AA, Winterthur, Switzerland), with feet at shoulder width, hands at their sides, and eyes open (closed-eye tests were not permitted by the IRB panels). It was requested of each person to hold this 'relaxed stance' for a period of four minutes. To provide a visual cue during the test, a 2 cm-diameter blue spot was placed on a white wall at eye level, 2 meters from the subject, while other visual interference such as lab equipment was removed from the line of sight to reduce distractions. During data collection a member of the research group stood behind the subject to intervene in case of lost balance or a fall during testing, though no falls occurred during testing. COP measures were recorded by the force plate with an eight-channel amplifier, an analog-digital converter, and Bioware 3.2.6.104 software. Data were oversampled at 1000 Hz, and filtered with a second order Butterworth loss-pass filter at 50 Hz.", "cite_spans": [], "ref_spans": []}, {"section": "Data Analysis", "text": "Data were analyzed using a custom MATLAB program (version 7.0.1, The MathWorks, Natick, Massachusetts) to calculate scalar parameters of COP magnitude and velocity, including maximal COP displacement from the centroid, root mean square (RMS) of COP displacement, maximal COP velocity, and RMS of COP velocity. Power spectral density calculations were performed to the total energy of the signal contained in the 0.2 to 1.0 Hz band which has been associated with the vestibular/somatosensory elements of postural control [20] . Finally, stabilogram diffusion analysis was performed to calculate the Short Term Diffusion Coefficient, a measure of the randomness of sway, the Long Term Scaling Exponent, a measure of the persistence of sway, and the critical displacement, a measure of the average displacement from the stabilogram's centroid which occurs before the postural control system switches from an open loop to a closed loop system [21] .", "cite_spans": [{"start": 520, "end": 524, "text": "[20]", "ref_id": "BIBREF19"}, {"start": 939, "end": 943, "text": "[21]", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "Data Analysis", "text": "To assess fall risk, z-scores for the elderly participants with a history of a fall and for those with no history of falls were calculated. COP measures of sway in the elderly participants were normalized using the equation:", "cite_spans": [], "ref_spans": []}, {"section": "Data Analysis", "text": "n {m s Z n = Normalized Z score for parameter n x n = raw value to be standardized from the elderly group m = mean of the sample (calculated from young normal adults) s = standard deviation of the sample (calculated from young normal adults)", "cite_spans": [], "ref_spans": []}, {"section": "Data Analysis", "text": "To calculate the ''at risk'' threshold value for each COP parameter, the normalized Z-scores of the elderly faller and nonfaller groups were compared using receiver operating characteristic (ROC) analysis. The ROC analysis of the Z-score data to calculate cutoff thresholds ( Fig. 1) , and the value with the strongest specificity and sensitivity was then used as a cutoff, with any value above the threshold being labeled as ''at risk.'' The percentage of parameters tagged as ''at risk'' constituted the ''B-score'' of the subject, which was calculated by the following equations, with the B-score ranging from: 0; representing COP measures defined by the healthy young adult population, to 1; reflecting those at greatest risk of falls:", "cite_spans": [], "ref_spans": [{"start": 276, "end": 283, "text": "Fig. 1)", "ref_id": "FIGREF0"}]}, {"section": "Data Analysis", "text": "T n = Threshold value for parameter n calculated from ROC analysis, and", "cite_spans": [], "ref_spans": []}, {"section": "Data Analysis", "text": "As the postural sway data in this study was non-parametric, the Kruskal-Wallis test was performed to compare multiple groups, and a Mann-Whitney test with post hoc comparisons adjusted for multiple testing using a Bonferroni correction to calculate between-pair significance. Statistical tests were performed using SPSS (version 14.0.0, SPSS Inc, Chicago, IL). As presented, all error bars indicate the standard deviation of the measure. P-values less than 0.05 were considered significant.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "In order to use the information on prior falls in the prediction algorithm, elderly subjects were divided into two groups; those with a record of self-reported recent falls (n = 24; 14.9% of total elderly group) and those who had reported no falls in the prior sixmonth period (n = 137; 85.1% of total elderly group). Of the fallers, 9 were male (37.5%), while 43 of the non-fallers (31.3%) were male, indicating no tendency of males or females in this study sample to have a greater tendency to fall (p.0.05, x 2 = 0.35). However, there was not significant statistical power to determine the impact of gender on study outcomes.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "When the ''fallers'' and ''non-fallers'' in the elderly cohort were considered in concert with the young healthy adults (n = 37), it yielded three groups of subjects for comparative analyses. The young adult group was significantly younger (34.9y67.1) and taller (1.72m60.09) than both elderly fallers (81.8y67.4; 1.64m60.14) and non-fallers (81.9y66.6; 1.62m60.10), with no significant difference in body weight (Table 1) . No significant differences were found between fallers and non-fallers with respect to height, weight, or age. Within each of the groups, neither age, height, weight, nor gender was found to have any association with any specific postural control measure or history of recent falls. Thus, there are no body habitus or gender criteria which appear to predispose any given individual to falls.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "All participants completed the four-minute period of ''quiet stance'' on the force plate with no missing or out-of-range data. Stabilogram analysis revealed that, as compared to the young adults, several stability measures were significantly different in each of the elderly groups (Table 2 ; Fig. 2 ). While there were no significant differences between young and either elderly group in medio-lateral sway parameters, COP measures in the elderly revealed greater instability in multiple antero-posterior measures. For example, in the older group with recent falls, all measures except RMS displacement were significantly worse than in the young adults (e.g., maximal COP velocity was 2.76 greater in fallers than young adults; p,0.05). In comparisons between the two elderly groups, maximal displacement, diffusion coefficient, and scaling exponent were significantly worse in those with a history of fall (e.g., short term diffusion coefficient was 1.6 times greater in elderly fallers than elderly non-fallers).", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "As compared to young, healthy adults, the Z-scores of both elderly fallers and non-fallers were greater in measures of maximal and RMS displacement, maximal and RMS velocity, 0.2 to 1.0 Hz energy, short term diffusion coefficient, long term scaling exponent, and critical displacement (Table 3) . With the exception of the short term diffusion coefficient, elderly with a history of falls had a Z-score approximately twice that of the non-fallers (Fig. 3) . The B-score of elderly participants with a history of recent falls was found to be approximately two times greater than the B-score of elderly non-fallers (p,0.001; Fig. 4 ). ROC analysis of the B-score resulted in an idealized threshold value of 0.385, with a sensitivity of 70.8% and specificity of 73.7%.", "cite_spans": [], "ref_spans": [{"start": 285, "end": 294, "text": "(Table 3)", "ref_id": "TABREF2"}, {"start": 447, "end": 455, "text": "(Fig. 3)", "ref_id": "FIGREF1"}, {"start": 623, "end": 629, "text": "Fig. 4", "ref_id": "FIGREF2"}]}, {"section": "Discussion", "text": "Falls in older persons are a major cause of debilitating injuries, fractures and even death; yet identifying those at greatest risk of falls -allowing a focus on individuals deserving of greatest attention -has proven difficult. The goal of this study was to use simple, readily accessible postural sway characteristics of a young, healthy adult sample with no history of falls to characterize ''idealized'' balance, and then use those parameters to identify similarities and differences of these COP measures to those from two groups of older individuals, those with a history of recent falls and those without. This information was then used to iteratively develop an algorithm, weighted by those parameters within the ''falls'' group that were most different from the young healthy adults, to differentiate those at higher risk of falls.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "Many factors contribute to falls beyond postural sway, and include hazards as diverse as weather (e.g., ice) and obstacles in the home (e.g., rugs, electric cords, pets and stairs). As importantly, many limitations of the protocol must be noted. That the results are based on retrospective analysis of falls, and have not been validated by 'predicting' those that fall, is another limitation that must be emphasized. Extrapolating from 'quiet stance' to the dynamic conditions that are more closely associated with falls is yet another limitation that must be recognized, not fully offset by the goal of collecting 'simple' COP measures from achievable conditions such as standing, rather than more sophisticated challenges such as perturbations of stance, or measures made while walking on a variety of surfaces. But with the robust differences in balance measures identified between the young, the elderly non-fallers, and the elderly fallers, we also believe that an algorithm such as that presented here, from data collected under repeatable conditions, may ultimately help identify those at greatest risk, and thus identify those for whom environmental, physical or pharmacologic interventions might best be targeted.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "Not all measures of balance derived from the COP stabilogram measures were able to distinguish between the young and elderly groups, and thus were not considered critical predictive indices of fall risk and were excluded in the B-score calculation. Additionally, some measures, such as medio-lateral sway magnitude and velocity, which were greater in the elderly group than in the young adult group (p,0.05), showed no difference between the elderly fallers and non-fallers, and were also omitted from the Bscore calculation. Median power (p = 0.86) and the total energy of the COP signal contained in the 0 to 0.2 Hz (p = 0.07) and 1 to 5 Hz bands (p = 0.10), which have been associated with visual and proprioceptive/muscle control respectively [20] , showed no significant difference in fallers and non-fallers, and were also omitted from the algorithm. It is certainly possible that a larger sample size may have revealed a significant difference in mediolateral sway, and thus better justified its contribution to fall risk as identified by previous studies [22] . While power spectral density analysis identified differences between the young healthy adults and the elderly groups (both fallers and non-fallers) in median frequency and when compartmentalized into low, medium and high frequency ranges, the Z-score analysis could identify no differences between older participants with a history of falls and those with no falls, and thus was not included as an essential contributor in the B-score algorithm.", "cite_spans": [{"start": 747, "end": 751, "text": "[20]", "ref_id": "BIBREF19"}, {"start": 1063, "end": 1067, "text": "[22]", "ref_id": "BIBREF21"}], "ref_spans": []}, {"section": "Discussion", "text": "The use of ROC analysis of Z-score measures of sway allows for the prediction of fall risk as based on an iteratively defined threshold, such that subjects with a Z-score for a given parameter over the threshold would be tagged as being at greater risk for falls. However, analysis of the variance of sway parameters indicated Table 1 . Demographic Data of the young adult, elderly without a history of falls, and the elderly population with a self-reported incidence of falls which had occurred in the prior six months. Figure 2 . Stabilogram of a healthy young adult (A) and an elderly subject (B). The trace, collected over the four minute quiet-standing test period, represents movement of the center of pressure, in both the Medial-Lateral direction (side to side), and the Anterior-Posterior direction (front to back). Signs of poorer postural stability are evident in the aged subject, with a larger area of sway, as well as multiple excursions from center. As might be expected, with a longer path-length realized over the four-minute period in the elderly subject, peak sway velocities are also greater. doi:10.1371/journal.pone.0070566.g002", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "that there was significant variation between subjects in terms of which sway parameters were above this threshold; one subject with a fall history may exceed the threshold for maximal displacement and velocity, while another may be over a threshold for RMS displacement, maximal velocity, and/or short term diffusion coefficient. This is most probably a reflection of the diverse range of factors which contribute to age-related declines in balance; an individual suffering from a compromise in vestibular feedback may exhibit different sway characteristics from a person suffering from mild neuropathy, while both may be at high fall risk [23] . Nevertheless, the greater the number of balance measures that were beyond a given threshold for a given parameter, the greater the likelihood that an individual was a member of the ''falls'' group. In fact, fallers exceeded the threshold in 5.17 out of 8 parameters, as compared to only 2.67 parameters in the non-faller group (p,0.001). Considering the range of factors which distinguish 'non-fallers' within the elderly cohort from those with a self-reported history of falls, we worked towards incorporating a multitude of COP parameters into formulating the fall algorithm, rather than relying on any single component, to improve our accuracy in identifying those individuals at greatest risk of falls. Because of the nature of such a metric, it is certainly possible to iteratively change the weighting of any given parameter, or to add additional parameters Table 2 . Postural Stability Measures of the young adult, elderly without a history of falls, and the elderly population with a selfreported incidence of falls which had occurred in the prior six months. ", "cite_spans": [{"start": 640, "end": 644, "text": "[23]", "ref_id": "BIBREF22"}], "ref_spans": []}, {"section": "245.6", "text": "Percent changes relative to the young adult are also given. The majority of postural stability measures significantly deteriorated from young adult to the elderly nonfaller group, and further eroded in the falls group. { p,0.05 from elderly (both groups); * p,0.05 from elderly fallers; # p,0.05 from young adult. doi:10.1371/journal.pone.0070566.t002 to the calculation which were not measured in this study but may be related to fall risk, such as degree of neuropathy (monofilament score), visual acuity, or measures of mobility (sit-to-stand time). It would also be critical to consider parameters such as muscle strength and/or bone quantity and quality, to extend this falls-risk algorithm towards the formulation of a fracture-risk score, and could help account for those with low bone density who avoid fracture by avoiding falls vs. those with high bone density who are prone to fracture because of a tendency to fall.", "cite_spans": [], "ref_spans": []}, {"section": "245.6", "text": "The results of this study build upon the information gathered over the last two decades of fall-risk research. The ability to accurately predict fall risk with high specificity and sensitivity is still an ongoing topic, though the mechanisms of postural control have been well examined. Prospective studies showed a correlation between COP displacement and falls in the elderly, even in subjects without apparent balance issues [24] . And while quiet stance was examined here, it is important to emphasize that the use of perturbations have provided great insight into those at risk of falling, and future prospective trials which incorporate more sophisticated assessment of fall risk are certain to provide critical information on the reactive mechanics of stability and the effects of age-related degradation on individual balance strategies [25, 26] .Another limitation of this study is the dependence of self-reporting of falls, the key parameter used to stratify the elderly groups into those with recent fall history or those with a limited history of falls. Omissions in reporting are inevitable due to lapses of memory, or a given subject's reluctance to admit to a recent fall. Further, no consideration was given for the cause of fall (stumble, collapse, trip, slip, collision, etc.), nor was weighting of records enhanced for those with multiple falls over the six-month period. The elderly participants came from an ongoing trial of volunteers who fulfilled certain pre-specified inclusion and exclusion criteria [17] , and thus may not be readily generalized to other samples of aging populations (e.g., frail elderly, nursing home cohorts, etc.). Further, using a relatively small group as the normal for Z-score analysis (37 young adults with no history of falls) is not necessarily optimal, as a larger group might improve confidence in the calculation of ''idealized'' balance parameters.", "cite_spans": [{"start": 428, "end": 432, "text": "[24]", "ref_id": "BIBREF23"}, {"start": 845, "end": 849, "text": "[25,", "ref_id": "BIBREF24"}, {"start": 850, "end": 853, "text": "26]", "ref_id": "BIBREF25"}, {"start": 1526, "end": 1530, "text": "[17]", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "245.6", "text": "The limitations of focusing on a simple COP measure made from quiet ''static'' stance cannot be overemphasized, particularly considering the numerous other factors beyond control of balance, per se, that contribute to risk of falling, including dynamic parameters of locomotion. Indeed, there is a significant and growing body of work that uses sophisticated measures of gait, dynamic balance and strength, at the very least, as much higherfidelity indices of fall risk [27] [28] [29] . It must be pointed out, however, that this study was designed specifically to approach COP as a relatively accessible and affordable assay and ideally enhance its ability to be used independently -or in conjunction with -more sophisticated measures of fall risk [23] . And certainly, it is entirely possible that those with a history of falls have already ''modified'' their balance control, and thus we are comparing stability measures from those with a ''fear of falling'' to those that have not yet fallen. Finally, it is important to emphasize that this algorithm has been iteratively ''optimized'' as driven by retrospective correlations to fall history, and has not been validated by prospectively predicting falls in the elderly subjects. Ultimately, validation of the B-score fall risk algorithm must be performed in a prospective study that can predict incident falls and can determine the accuracy of the prediction with both short and long-term follow-up [30] . Unfortunately, we are not able to address, here, the fidelity of self-reported falls, the nature of the falls that did occur, the differences that would arise in comparing fallers/non-fallers to more sophisticated measures of stability, or the inherent strategies that a young cohort may use to remain balanced as contrasted with an elderly population. These findings reflect the diagnostic potential of weighting specific components of postural stability to more accurately identify those with a history of falls, and suggest that balance measures from healthy young adults may serve as an idealized ''BScore'' referent to identify those at risk of falling, just as a bone density Z-or T-score may help identify those at greatest risk of fracture due to low quantity [17] . And just as a bone-density score is limited in identifying the source of low bone density (i.e., nutrition, genetics, activity-level, etc.), the B-score presented here is limited in that it does not identify the 'source' of deteriorating stability (i.e., neuromuscular, vestibular, visual, proprioception, etc). Recognizing the many limitations of this study, we do believe that efforts to prospectively validate a B-score based on some balance parameters may help to identify those at greatest risk of falling, and evaluate the efficacy of physical or pharmacologic interventions to directly diminish fall occurrence.", "cite_spans": [{"start": 470, "end": 474, "text": "[27]", "ref_id": "BIBREF26"}, {"start": 475, "end": 479, "text": "[28]", "ref_id": "BIBREF27"}, {"start": 480, "end": 484, "text": "[29]", "ref_id": "BIBREF28"}, {"start": 749, "end": 753, "text": "[23]", "ref_id": "BIBREF22"}, {"start": 1453, "end": 1457, "text": "[30]", "ref_id": "BIBREF29"}, {"start": 2228, "end": 2232, "text": "[17]", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "245.6", "text": "Certainly, postural control as measured during quiet stance must be quantified and combined with other risk factors for falls such as drug side effects, muscle weakness, visual acuity, temporary illness, locomotor instability and environmental factors (e.g., stairs, ice, rugs, pets). Future work could assess differential scaling of sway parameters, co-morbidity, and longitudinal analysis of additional falls, and determine how well fall risk correlates with fractures in the aged. Ultimately, by improving our ability to identify those at highest risk, it will be possible to focus targeted treatments and therapies, as well as prevention strategies and lifestyle modifications to reduce the incidence of injury causing falls.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Bone and fall-related fracture risks in women and men with a recent clinical fracture", "authors": [{"first": "S", "middle": [], "last": "Van Helden", "suffix": ""}, {"first": "A", "middle": ["C"], "last": "Van Geel", "suffix": ""}, {"first": "P", "middle": ["P"], "last": "Geusens", "suffix": ""}, {"first": "A", "middle": [], "last": "Kessels", "suffix": ""}, {"first": "Nieuwenhuijzen", "middle": [], "last": "Kruseman", "suffix": ""}, {"first": "A", "middle": ["C"], "last": "", "suffix": ""}], "year": 2008, "venue": "J Bone Joint Surg Am", "link": "40770385"}, "BIBREF1": {"title": "Hip fractures among the elderly: causes, consequences and control", "authors": [{"first": "R", "middle": [], "last": "Marks", "suffix": ""}, {"first": "J", "middle": ["P"], "last": "Allegrante", "suffix": ""}, {"first": "Ronald", "middle": [], "last": "Mackenzie", "suffix": ""}, {"first": "C", "middle": [], "last": "Lane", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "", "suffix": ""}], "year": 2003, "venue": "Ageing Res Rev", "link": "6544283"}, "BIBREF3": {"title": "Frailty and risk of falls, fracture, and mortality in older women: the study of osteoporotic fractures", "authors": [{"first": "K", "middle": ["E"], "last": "Ensrud", "suffix": ""}, {"first": "S", "middle": ["K"], "last": "Ewing", "suffix": ""}, {"first": "B", "middle": ["C"], "last": "Taylor", "suffix": ""}, {"first": "H", "middle": ["A"], "last": "Fink", "suffix": ""}, {"first": "K", "middle": ["L"], "last": "Stone", "suffix": ""}], "year": 2007, "venue": "JGerontolA BiolSciMedSci", "link": "1651755"}, "BIBREF4": {"title": "Bone Health and Osteoporosis A Report of the Surgeon General", "authors": [{"first": "Services", "middle": [], "last": "Udohah", "suffix": ""}], "year": 2004, "venue": "Office of the Surgeon General", "link": null}, "BIBREF5": {"title": "Immobility in the aged", "authors": [{"first": "P", "middle": [], "last": "Rousseau", "suffix": ""}], "year": 1993, "venue": "Arch Fam Med", "link": "45984956"}, "BIBREF6": {"title": "An update on falls", "authors": [{"first": "B", "middle": ["R"], "last": "Bloem", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Steijns", "suffix": ""}, {"first": "B", "middle": ["C"], "last": "Smits-Engelsman", "suffix": ""}], "year": 2003, "venue": "Curr Opin Neurol", "link": "28349607"}, "BIBREF7": {"title": "Human fiber size and enzymatic properties after 5 and 11 days of spaceflight", "authors": [{"first": "V", "middle": ["R"], "last": "Edgerton", "suffix": ""}, {"first": "M", "middle": ["Y"], "last": "Zhou", "suffix": ""}, {"first": "Y", "middle": [], "last": "Ohira", "suffix": ""}, {"first": "H", "middle": [], "last": "Klitgaard", "suffix": ""}, {"first": "B", "middle": [], "last": "Jiang", "suffix": ""}], "year": 1995, "venue": "J Appl Physiol", "link": "1965029"}, "BIBREF8": {"title": "Triggering of balance corrections and compensatory strategies in a patient with total leg proprioceptive loss", "authors": [{"first": "B", "middle": ["R"], "last": "Bloem", "suffix": ""}, {"first": "J", "middle": ["H"], "last": "Allum", "suffix": ""}, {"first": "M", "middle": ["G"], "last": "Carpenter", "suffix": ""}, {"first": "J", "middle": ["J"], "last": "Verschuuren", "suffix": ""}, {"first": "F", "middle": [], "last": "Honegger", "suffix": ""}], "year": 2002, "venue": "Exp Brain Res", "link": "11936589"}, "BIBREF9": {"title": "The role of plantar cutaneous sensation in unperturbed stance", "authors": [{"first": "P", "middle": ["F"], "last": "Meyer", "suffix": ""}, {"first": "L", "middle": ["I"], "last": "Oddsson", "suffix": ""}, {"first": "De", "middle": [], "last": "Luca", "suffix": ""}, {"first": "C", "middle": ["J"], "last": "", "suffix": ""}], "year": 2004, "venue": "Exp Brain Res", "link": "880041"}, "BIBREF10": {"title": "Respiration effect on standing balance", "authors": [{"first": "B", "middle": ["Y"], "last": "Jeong", "suffix": ""}], "year": 1991, "venue": "Arch Phys Med Rehabil", "link": "46469751"}, "BIBREF11": {"title": "Postural sway biofeedback: its effect on reestablishing stance stability in hemiplegic patients", "authors": [{"first": "A", "middle": [], "last": "Shumway-Cook", "suffix": ""}, {"first": "Anson", "middle": ["D"], "last": "Haller", "suffix": ""}, {"first": "S", "middle": [], "last": "", "suffix": ""}], "year": 1988, "venue": "Arch Phys Med Rehabil", "link": "22164127"}, "BIBREF12": {"title": "Time-frequency analysis of postural sway", "authors": [{"first": "T", "middle": [], "last": "Schumann", "suffix": ""}, {"first": "M", "middle": ["S"], "last": "Redfern", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Furman", "suffix": ""}, {"first": "A", "middle": [], "last": "El-Jaroudi", "suffix": ""}, {"first": "L", "middle": ["F"], "last": "Chaparro", "suffix": ""}], "year": 1995, "venue": "J Biomech", "link": "110140807"}, "BIBREF13": {"title": "The relationship of postural sway in standing to the incidence of falls in geriatric subjects", "authors": [{"first": "G", "middle": ["R"], "last": "Fernie", "suffix": ""}, {"first": "C", "middle": ["I"], "last": "Gryfe", "suffix": ""}, {"first": "P", "middle": ["J"], "last": "Holliday", "suffix": ""}, {"first": "A", "middle": [], "last": "Llewellyn", "suffix": ""}], "year": 1982, "venue": "Age and Ageing", "link": "2131084"}, "BIBREF14": {"title": "Postural instability caused by extended bed rest is alleviated by brief daily exposure to low magnitude mechanical signals", "authors": [{"first": "J", "middle": ["W"], "last": "Muir", "suffix": ""}, {"first": "S", "middle": [], "last": "Judex", "suffix": ""}, {"first": "Y", "middle": ["X"], "last": "Qin", "suffix": ""}, {"first": "C", "middle": [], "last": "Rubin", "suffix": ""}], "year": 2011, "venue": "Gait & Posture", "link": "25005340"}, "BIBREF15": {"title": "Spectral characteristics of postural control in elderly individuals", "authors": [{"first": "H", "middle": ["G"], "last": "Williams", "suffix": ""}, {"first": "B", "middle": ["A"], "last": "Mcclenaghan", "suffix": ""}, {"first": "J", "middle": [], "last": "Dickerson", "suffix": ""}], "year": 1997, "venue": "Arch Phys Med Rehabil", "link": "7582219"}, "BIBREF16": {"title": "Insights from the conduct of a device trial in older persons: low magnitude mechanical stimulation for musculoskeletal health", "authors": [{"first": "D", "middle": ["P"], "last": "Kiel", "suffix": ""}, {"first": "M", "middle": ["T"], "last": "Hannan", "suffix": ""}, {"first": "B", "middle": ["A"], "last": "Barton", "suffix": ""}, {"first": "M", "middle": ["L"], "last": "Bouxsein", "suffix": ""}, {"first": "T", "middle": ["F"], "last": "Lang", "suffix": ""}], "year": 2010, "venue": "ClinTrials", "link": "27639297"}, "BIBREF17": {"title": "Postural instability caused by extended bed rest is alleviated by brief daily exposure to low magnitude mechanical signals", "authors": [{"first": "J", "middle": [], "last": "Muir", "suffix": ""}, {"first": "S", "middle": [], "last": "Judex", "suffix": ""}, {"first": "Y", "middle": ["X"], "last": "Qin", "suffix": ""}, {"first": "C", "middle": [], "last": "Rubin", "suffix": ""}], "year": 2011, "venue": "Gait Posture", "link": "25005340"}, "BIBREF18": {"title": "Insights from the conduct of a device trial in older persons: low magnitude mechanical stimulation for musculoskeletal health", "authors": [{"first": "D", "middle": ["P"], "last": "Kiel", "suffix": ""}, {"first": "M", "middle": ["T"], "last": "Hannan", "suffix": ""}, {"first": "B", "middle": ["A"], "last": "Barton", "suffix": ""}, {"first": "M", "middle": ["L"], "last": "Bouxsein", "suffix": ""}, {"first": "T", "middle": ["F"], "last": "Lang", "suffix": ""}], "year": 2010, "venue": "Clin Trials", "link": "27639297"}, "BIBREF19": {"title": "Visual contribution to self-induced body sway frequencies and visual perception of male professional dancers", "authors": [{"first": "E", "middle": [], "last": "Golomer", "suffix": ""}, {"first": "J", "middle": [], "last": "Cremieux", "suffix": ""}, {"first": "P", "middle": [], "last": "Dupui", "suffix": ""}, {"first": "B", "middle": [], "last": "Isableu", "suffix": ""}, {"first": "T", "middle": [], "last": "Ohlmann", "suffix": ""}], "year": 1999, "venue": "Neurosci Lett", "link": "27176307"}, "BIBREF20": {"title": "Open-loop and closed-loop control of posture: a random-walk analysis of center-of-pressure trajectories", "authors": [{"first": "J", "middle": ["J"], "last": "Collins", "suffix": ""}, {"first": "De", "middle": [], "last": "Luca", "suffix": ""}, {"first": "C", "middle": ["J"], "last": "", "suffix": ""}], "year": 1993, "venue": "Exp Brain Res", "link": "875315"}, "BIBREF21": {"title": "Postural stability in the elderly: a comparison between fallers and non-fallers", "authors": [{"first": "I", "middle": [], "last": "Melzer", "suffix": ""}, {"first": "N", "middle": [], "last": "Benjuya", "suffix": ""}, {"first": "J", "middle": [], "last": "Kaplanski", "suffix": ""}], "year": 2004, "venue": "Age and Ageing", "link": "11674149"}, "BIBREF22": {"title": "The Balance Evaluation Systems Test (BESTest) to differentiate balance deficits", "authors": [{"first": "F", "middle": ["B"], "last": "Horak", "suffix": ""}, {"first": "D", "middle": ["M"], "last": "Wrisley", "suffix": ""}, {"first": "J", "middle": [], "last": "Frank", "suffix": ""}], "year": 2009, "venue": "Phys Ther", "link": null}, "BIBREF23": {"title": "Force platform balance measures as predictors of indoor and outdoor falls in community-dwelling women aged 63-76 years", "authors": [{"first": "S", "middle": [], "last": "Pajala", "suffix": ""}, {"first": "P", "middle": [], "last": "Era", "suffix": ""}, {"first": "M", "middle": [], "last": "Koskenvuo", "suffix": ""}, {"first": "J", "middle": [], "last": "Kaprio", "suffix": ""}, {"first": "T", "middle": [], "last": "Tormakangas", "suffix": ""}], "year": 2008, "venue": "J Gerontol A Biol Sci Med Sci", "link": "12204909"}, "BIBREF24": {"title": "A prospective study of postural balance and risk of falling in an ambulatory and independent elderly population", "authors": [{"first": "B", "middle": ["E"], "last": "Maki", "suffix": ""}, {"first": "P", "middle": ["J"], "last": "Holliday", "suffix": ""}, {"first": "A", "middle": ["K"], "last": "Topper", "suffix": ""}], "year": 1994, "venue": "J Gerontol", "link": "11694774"}, "BIBREF25": {"title": "Reduced plantar sensitivity alters postural responses to lateral perturbations of balance", "authors": [{"first": "P", "middle": ["F"], "last": "Meyer", "suffix": ""}, {"first": "L", "middle": ["I"], "last": "Oddsson", "suffix": ""}, {"first": "De", "middle": [], "last": "Luca", "suffix": ""}, {"first": "C", "middle": ["J"], "last": "", "suffix": ""}], "year": 2004, "venue": "Exp Brain Res", "link": "8197047"}, "BIBREF26": {"title": "The many roles of vision during walking", "authors": [{"first": "D", "middle": [], "last": "Logan", "suffix": ""}, {"first": "T", "middle": [], "last": "Kiemel", "suffix": ""}, {"first": "N", "middle": [], "last": "Dominici", "suffix": ""}, {"first": "G", "middle": [], "last": "Cappellini", "suffix": ""}, {"first": "Y", "middle": [], "last": "Ivanenko", "suffix": ""}], "year": 2010, "venue": "Exp Brain Res", "link": "25995223"}, "BIBREF27": {"title": "The beneficial effects of group-based exercises on fall risk profile and physical activity persist 1 year postintervention in older women with low bone mass: follow-up after withdrawal of exercise", "authors": [{"first": "T", "middle": ["Y"], "last": "Liu-Ambrose", "suffix": ""}, {"first": "K", "middle": ["M"], "last": "Khan", "suffix": ""}, {"first": "J", "middle": ["J"], "last": "Eng", "suffix": ""}, {"first": "G", "middle": ["L"], "last": "Gillies", "suffix": ""}, {"first": "S", "middle": ["R"], "last": "Lord", "suffix": ""}], "year": 2005, "venue": "JAmGeriatrSoc", "link": "34509170"}, "BIBREF28": {"title": "Recovery from forward loss of balance in young and older adults using the stepping strategy", "authors": [{"first": "C", "middle": ["P"], "last": "Carty", "suffix": ""}, {"first": "P", "middle": [], "last": "Mills", "suffix": ""}, {"first": "R", "middle": [], "last": "Barrett", "suffix": ""}], "year": 2011, "venue": "Gait Posture", "link": "26540045"}, "BIBREF29": {"title": "Falls incidence, risk factors, and consequences in Chinese older people: a systematic review", "authors": [{"first": "M", "middle": ["M"], "last": "Kwan", "suffix": ""}, {"first": "J", "middle": ["C"], "last": "Close", "suffix": ""}, {"first": "A", "middle": ["K"], "last": "Wong", "suffix": ""}, {"first": "S", "middle": ["R"], "last": "Lord", "suffix": ""}], "year": 2011, "venue": "J Am Geriatr Soc", "link": "22379116"}}, "ref_entries": {"FIGREF0": {"text": "Figure 1. A: ROC plot of COP displacement variable. Sensitivity and 1-Specificity are plotted as the cutoff value is varied. The ideal location is in the upper left hand quadrant (1,0), where 100% of fallers are detected and 0% of non-fallers are identified (no false positives). The dotted line (line of no-discrimination) represents the location of a value with no predictive value (catches the same percentage of both fallers and non-fallers). B: Plot of chi squared value versus cutoff threshold. Values over 3.84 have a significance of p,0.05, and values over 10.83 have significance of p,0.001. Data from other variables result in similar values. doi:10.1371/journal.pone.0070566.g001", "type": "figure"}, "FIGREF1": {"text": "Figure 3. Box plots of Z-scores for maximal COP displacement (A), RMS of COP displacement (B), Maximal COP Velocity (C), RMS of COP Velocity (D), Median Frequency (E), Short Term Diffusion Coefficient (F), Long Term Scaling Exponent (G), and Critical Displacement (H). All measures but median frequency were significantly greater in fallers than non-fallers. The non-faller group had a number of outliers which were not excluded from data analysis. *p,0.05, **p,0.01. doi:10.1371/journal.pone.0070566.g003", "type": "figure"}, "FIGREF2": {"text": "Figure 4. B-Scores of elderly subjects with and without selfreported falls. The B-score is based on an ''idealized'' postural sway profile, as established by a group of young healthy adults (B-score of zero). Those with at least one self-reported fall in the prior 6 months had a B-score of 0.645, compared to those without falls who had a Bscore of 0.334 (p,0.0001). doi:10.1371/journal.pone.0070566.g004", "type": "figure"}, "TABREF2": {"text": "Z-Scores for Elderly, with and without a recent history of falls.Percent difference between the groups are also given. The majority of the comparisons show significant differences. * p,0.05. doi:10.1371/journal.pone.0070566.t003", "type": "table"}}}
{"paper_id": "2872653", "_pdf_hash": "1d7cceed3dde35f061f99f6dd900f907243fc514", "abstract": [{"section": "Abstract", "text": "Background: The yeast Saccharomyces cerevisiae relies on the high-osmolarity glycerol (HOG) signaling pathway to respond to increases in external osmolarity. The HOG pathway is rapidly activated under conditions of elevated osmolarity and regulates transcriptional and metabolic changes within the cell. Under normal growth conditions, however, a three-component phospho-relay consisting of the histidine kinase Sln1, the transfer protein Ypd1, and the response regulator Ssk1 represses HOG pathway activity by phosphorylation of Ssk1. This inhibition of the HOG pathway is essential for cellular fitness in normal osmolarity. Nevertheless, the extent to and mechanisms by which inhibition is robust to fluctuations in the concentrations of the phospho-relay components has received little attention. Results: We established that the Sln1-Ypd1-Ssk1 phospho-relay is robust-it is able to maintain inhibition of the HOG pathway even after significant changes in the levels of its three components. We then developed a biochemically realistic mathematical model of the phospho-relay, which suggested that robustness is due to buffering by a large excess pool of Ypd1. We confirmed experimentally that depletion of the Ypd1 pool results in inappropriate activation of the HOG pathway. Conclusions: We identified buffering by an intermediate component in excess as a novel mechanism through which a phospho-relay can achieve robustness. This buffering requires multiple components and is therefore unavailable to two-component systems, suggesting one important advantage of multi-component relays.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "The high-osmolarity glycerol (HOG) pathway (Figure 1 ) of the budding yeast Saccharomyces cerevisiae mediates cellular response to increased external osmolarity [1, 2] . A key component of the HOG pathway is a mitogenactivated protein (MAP) kinase cascade. Within the kinase cascade, the MAP3Ks Ssk2 and Ssk22 phosphorylate the MAP2K Pbs2, which in turn phosphorylates the MAP kinase Hog1. Phospho-Hog1 then regulates", "cite_spans": [{"start": 161, "end": 164, "text": "[1,", "ref_id": "BIBREF0"}, {"start": 165, "end": 167, "text": "2]", "ref_id": "BIBREF1"}], "ref_spans": []}], "body_text": [{"section": "", "text": "transcriptional and metabolic changes that increase production and accumulation of the compatible solute glycerol. Mounting a rapid response to increased osmolarity is essential to yeast survival [3, 4] . Accordingly, S. cerevisiae can activate the HOG pathway within one minute of experiencing an osmotic shock [5] . Yeast can also effectively respond to rapid periodic oscillations (with frequencies up to 0.0046 Hz) between low and high external osmolyte concentrations [3] .", "cite_spans": [{"start": 196, "end": 199, "text": "[3,", "ref_id": "BIBREF2"}, {"start": 200, "end": 202, "text": "4]", "ref_id": "BIBREF3"}, {"start": 312, "end": 315, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 473, "end": 476, "text": "[3]", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "", "text": "Despite its importance during periods of increased osmolarity, unintended activation of the HOG pathway during growth in normal osmolarity conditions is severely deleterious [6, 7] . The Sln1-Ypd1-Ssk1 three-component phospho-relay is responsible for maintaining inactivation of the HOG pathway under normal conditions. This three-component phospho-relay is a variant of the twocomponent signaling systems used by many prokaryotes for osmoregulation, chemotaxis, and other key cellular processes. Sln1 is active in vivo as a membrane-bound dimer [6] . Under normal osmolarity conditions, Sln1 autophosphorylates on a histidine residue and then irreversibly transfers the phosphate to an aspartate in its response regulator (RR) domain (Figure 2A ). Aspartatephosphorylated Sln1 binds to the histidine-containing phospho-transfer (HPt) protein Ypd1 and reversibly transfers its phosphate to Ypd1 ( Figure 2B ). Finally, phospho-Ypd1 transfers its phosphate to dimeric Ssk1, preventing it from interacting with Ssk2 (or the functionally redundant Ssk22) and inhibiting HOG pathway activity [5, 8, 9] . The sequence of phosphate transfers in the three-component relay is summarized in Figure 2A . In response to osmotic shock, the phospho-relay is inactivated, and Ssk1 is rapidly dephosphorylated through an as-yet unknown mechanism. Unphosphorylated Ssk1 then activates Ssk2 and Ssk22, leading to induction of the HOG pathway [1, 2] . It is thus the essential controller of HOG pathway activity, and variations in its concentration could compromise fitness.", "cite_spans": [{"start": 174, "end": 177, "text": "[6,", "ref_id": "BIBREF5"}, {"start": 178, "end": 180, "text": "7]", "ref_id": "BIBREF6"}, {"start": 546, "end": 549, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 1088, "end": 1091, "text": "[5,", "ref_id": "BIBREF4"}, {"start": 1092, "end": 1094, "text": "8,", "ref_id": "BIBREF7"}, {"start": 1095, "end": 1097, "text": "9]", "ref_id": "BIBREF8"}, {"start": 1425, "end": 1428, "text": "[1,", "ref_id": "BIBREF0"}, {"start": 1429, "end": 1431, "text": "2]", "ref_id": "BIBREF1"}], "ref_spans": [{"start": 735, "end": 745, "text": "(Figure 2A", "ref_id": "FIGREF1"}, {"start": 897, "end": 906, "text": "Figure 2B", "ref_id": "FIGREF1"}, {"start": 1182, "end": 1191, "text": "Figure 2A", "ref_id": "FIGREF1"}]}, {"section": "", "text": "There is limited existing experimental evidence that the phospho-relay is able to maintain robust phosphorylation of Ssk1 and inactivation of the HOG pathway despite changes in the levels of some pathway components [7, 9, 10] . We undertook a comprehensive characterization of the sensitivity of HOG pathway activation to changes in the expression levels of the phospho-relay proteins Sln1, Ypd1, and Ssk1. We systematically under-and overexpressed the three proteins using the GEV artificial induction system, which allows for rapid and nearly gratuitous induced expression of individual yeast genes [11] . We found that the phospho-relay maintains inactivation of the HOG pathway even after moderate perturbation of Sln1, Ypd1, and Ssk1.", "cite_spans": [{"start": 215, "end": 218, "text": "[7,", "ref_id": "BIBREF6"}, {"start": 219, "end": 221, "text": "9,", "ref_id": "BIBREF8"}, {"start": 222, "end": 225, "text": "10]", "ref_id": "BIBREF9"}, {"start": 601, "end": 605, "text": "[11]", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "", "text": "We developed a detailed, biochemically realistic mathematical model of the HOG pathway three-component phospho-relay to elucidate the mechanism underlying this robustness ( Figure 2C ). Our model incorporates extensive structural and mechanistic information about the phospho-relay and considers nearly all possible interactions between the three relay proteins. We used massaction kinetics and algebraic calculations to characterize the steady-state behavior of the model. Steady-state algebraic models are a useful alternative to existing computational models of the HOG pathway for understanding robust behavior [3, 7, 12] . Unlike numerical simulations [3, 7, 12] , algebraic manipulations can be done without ever assigning specific values to the parameters (i.e., the rate constants in the reaction network), many of which are difficult or impossible to measure experimentally [13] . This advantage enabled us to design and analyze a more biochemically realistic model. A steady-state approximation Phospho-transfer proceeds from Sln1 (after autophosphorylation on H576 and transfer to D1144) to Ypd1 to Ssk1, as indicated by the numbers in circles. B Crystal structure of Ypd1 (green) in complex with the response regulator domain of Sln1 (Sln1-R1, red). Drawn from data presented in [18] . C Reaction network diagram describing our model of the phospho-relay. The network includes nearly all possible interactions between the three proteins subject to the biochemical assumptions outlined in the main text. For clarity, the reaction network is color-coded to indicate the groups of reactions involved in each phosphorylation event. S denotes Sln1, Y denotes Ypd1, and K denotes Ssk1. Phosphorylated residues are denoted by p, unphosphorylated residues by o. D Directed graph describing the subnetwork involving phosphorylation and dephosphorylation of Ssk1. The graph contains four loops that are connected as a branched tree.", "cite_spans": [{"start": 615, "end": 618, "text": "[3,", "ref_id": "BIBREF2"}, {"start": 619, "end": 621, "text": "7,", "ref_id": "BIBREF6"}, {"start": 622, "end": 625, "text": "12]", "ref_id": "BIBREF11"}, {"start": 657, "end": 660, "text": "[3,", "ref_id": "BIBREF2"}, {"start": 661, "end": 663, "text": "7,", "ref_id": "BIBREF6"}, {"start": 664, "end": 667, "text": "12]", "ref_id": "BIBREF11"}, {"start": 883, "end": 887, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 1291, "end": 1295, "text": "[18]", "ref_id": "BIBREF17"}], "ref_spans": [{"start": 173, "end": 182, "text": "Figure 2C", "ref_id": "FIGREF1"}]}, {"section": "", "text": "is appropriate because previous studies have shown that activation of the HOG pathway does not vary under normal growth conditions [3, 4, 12, 14, 15] .", "cite_spans": [{"start": 131, "end": 134, "text": "[3,", "ref_id": "BIBREF2"}, {"start": 135, "end": 137, "text": "4,", "ref_id": "BIBREF3"}, {"start": 138, "end": 141, "text": "12,", "ref_id": "BIBREF11"}, {"start": 142, "end": 145, "text": "14,", "ref_id": "BIBREF13"}, {"start": 146, "end": 149, "text": "15]", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "", "text": "Our steady-state analysis predicted that relative levels of dephosphorylated Ssk1 depend solely on Ypd1 levels and that robustness is achieved by maintaining Ypd1 in large excess. We experimentally tested this prediction by perturbing protein expression levels so as to deplete this buffering pool of Ypd1. All such perturbations compromised the ability of the phospho-relay to inhibit the HOG pathway, leading to hyperactivation in normal osmolarity conditions. The presence of a large buffering pool of an intermediate phospho-relay component is a previously underappreciated mechanism for robustness and suggests a possible advantage of a three-component relay over a two-component system.", "cite_spans": [], "ref_spans": []}, {"section": "Results and discussion", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Inhibition of HOG pathway signaling is robust to moderate overexpression of phospho-relay components", "text": "Inappropriate HOG pathway activation during normal osmolarity growth unnecessarily alters transcription and metabolism [7, 9, 10] . To assess the robustness of HOG pathway inhibition by the three-component phosphorelay, we created strains capable of overexpressing Sln1, Ypd1, and Ssk1 in response to \u03b2-estradiol. For these overexpression experiments, we used diploid strains homozygous for the GEV artificial transcription factor [11] . GEV consists of the Gal4 DNA-binding domain, the estrogen receptor, and the VP16 activation domain. Upon treatment with the hormone \u03b2-estradiol, GEV rapidly translocates to the nucleus, where it activates transcription from promoters containing the Gal4 DNA-binding target sequence. The GEV system enables rapid induction of individual yeast genes with limited off-target effects [11] . To make a given phospho-relay gene GEVinducible, we placed it under the control of the GAL1 promoter (SLN1/P GAL1 -SLN1, YPD1/P GAL1 -YPD1, and SSK1/P GAL1 -SSK1), as described previously [11] .", "cite_spans": [{"start": 119, "end": 122, "text": "[7,", "ref_id": "BIBREF6"}, {"start": 123, "end": 125, "text": "9,", "ref_id": "BIBREF8"}, {"start": 126, "end": 129, "text": "10]", "ref_id": "BIBREF9"}, {"start": 431, "end": 435, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 818, "end": 822, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 1013, "end": 1017, "text": "[11]", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "Inhibition of HOG pathway signaling is robust to moderate overexpression of phospho-relay components", "text": "Inappropriate activation of the HOG pathway is known to cause a growth defect [7, 9, 10] . We therefore measured growth of these GEV strains after induction with \u03b2-estradiol at a range of concentrations to screen for HOG pathway hyperactivity. A strain carrying an inducible allele of Pbs2 (P GAL1 -PBS2/PBS2) was used as a control because Pbs2 overexpression is known to cause severe growth defects from inappropriate activation of the HOG pathway [7] . As shown in Figure 3A , strains overexpressing Pbs2 exhibited a measurable growth defect, while strains overexpressing components of the phospho-relay (Sln1, Ypd1, and Ssk1) showed no significant change.", "cite_spans": [{"start": 78, "end": 81, "text": "[7,", "ref_id": "BIBREF6"}, {"start": 82, "end": 84, "text": "9,", "ref_id": "BIBREF8"}, {"start": 85, "end": 88, "text": "10]", "ref_id": "BIBREF9"}, {"start": 449, "end": 452, "text": "[7]", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "Inhibition of HOG pathway signaling is robust to moderate overexpression of phospho-relay components", "text": "We also assayed for Hog1 phosphorylation following GEV induction of phospho-relay components to obtain direct evidence that moderate overexpression does not cause HOG pathway hyperactivation. We used overexpression of Pbs2 and Ssk2 (also known to cause hyperactivation of the HOG pathway [7] ) as positive controls. After 30 minutes of GEV induction, there was no detectable increase in Hog1 phosphorylation in strains overexpressing phospho-relay components ( Figure 3B ). In contrast, Pbs2 and Ssk2 overexpression caused phosphorylation of Hog1. Interestingly, overexpression of the Ssk2 homolog Ssk22 had the strongest effect on Hog1 phosphorylation.", "cite_spans": [{"start": 288, "end": 291, "text": "[7]", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "Inhibition of HOG pathway signaling is robust to moderate overexpression of phospho-relay components", "text": "We then constructed diploid strains with a single inducible copy of the HOG phospho-relay gene of interest and a single P STL1 -YFP reporter to assay for HOG pathway transcriptional activity in response to overexpression of relay components. Stl1 is a glycerol/H + symporter whose expression is strongly upregulated in response to osmotic shock [16] . We overexpressed all three relay components, Pbs2, and Ssk22. Here we used Ssk22 as a control instead of Ssk2 because it showed a strong effect on Hog1 phosphorylation in the previous experiment. After 120 minutes of induction with 10 \u03bcM \u03b2-estradiol, Ssk22 and Pbs2 overexpression led to HOG-dependent transcription from the STL1 promoter, as indicated by an increase in YFP fluorescence ( Figure 4 ). Over the same period of time, overexpression of the phospho-relay components (Sln1, Ypd1, and Ssk1) caused almost no transcription from the STL1 promoter. After 19 hours, overexpression of Ssk1 and Sln1 did increase expression of YFP from the P STL1 -YFP reporter. These effects on longer time scales may have been due to factors beyond Ssk1 and Sln1 overexpression, however, as there was a population expressing YFP even in the control strain at 19 hours.", "cite_spans": [{"start": 345, "end": 349, "text": "[16]", "ref_id": "BIBREF15"}], "ref_spans": [{"start": 742, "end": 750, "text": "Figure 4", "ref_id": "FIGREF2"}]}, {"section": "Construction of a biochemically realistic model of the HOG pathway phospho-relay", "text": "Growth, phosphorylation, and transcriptional measurements of HOG pathway activity all indicated that HOG pathway activation is robust to fluctuations in the Sln1-Ypd1-Ssk1 phospho-relay components. These results prompted us to investigate the mechanistic basis of this robustness using a biochemical model. The reaction network underlying our model ( Figure 2C ) has 37 nodes and involves 13 species. In this section we discuss the biochemical justification for key assumptions in the model.", "cite_spans": [], "ref_spans": [{"start": 351, "end": 360, "text": "Figure 2C", "ref_id": "FIGREF1"}]}, {"section": "Construction of a biochemically realistic model of the HOG pathway phospho-relay", "text": "There exist high-resolution crystal structures of Ypd1 alone and in complex with the Sln1 receiver domain ( Figure 2B ) [17, 18] . Genetic and biochemical evidence suggest that Sln1 forms an obligate homodimer and that Ypd1 can interact with either half of the dimer [6, 19] , which implies that formation of a Ypd1-Sln1(dimer)-Ypd1 ternary complex is possible. Accordingly, we include Sln1 in the reaction network as a dimer with four relevant phosphorylation sites. The Sln1 dimer is referred to as S H1D1H2D2 , where H1 and D1 denote the phosphorylatable histidine and aspartate residues in one half of the dimer and H2 and D2 denote the corresponding residues in the other half. The dimer is allowed to autophosphorylate on either histidine residue. Phospho-transfer from the histidine to the aspartate in the RR domain is treated as irreversible. A reverse reaction is included with all histidine autophosphorylation steps to account for possible hydrolysis of the phosphate prior to transfer [2, 20] . Each half of the dimer is assumed to be independent from the other. Coincident phosphorylation events (e.g., S OOOO forming S POPO in one step) are therefore considered to be unlikely and are excluded from the model. Following these assumptions, the model includes nine different forms of free Sln1 that are interconverted as shown in the reaction network.", "cite_spans": [{"start": 120, "end": 124, "text": "[17,", "ref_id": "BIBREF16"}, {"start": 125, "end": 128, "text": "18]", "ref_id": "BIBREF17"}, {"start": 267, "end": 270, "text": "[6,", "ref_id": "BIBREF5"}, {"start": 271, "end": 274, "text": "19]", "ref_id": "BIBREF18"}, {"start": 998, "end": 1001, "text": "[2,", "ref_id": "BIBREF1"}, {"start": 1002, "end": 1005, "text": "20]", "ref_id": "BIBREF19"}], "ref_spans": [{"start": 108, "end": 117, "text": "Figure 2B", "ref_id": "FIGREF1"}]}, {"section": "Construction of a biochemically realistic model of the HOG pathway phospho-relay", "text": "In the second leg of the phospho-relay, any Sln1 phospho-form with at least one phosphorylated aspartate is allowed to reversibly associate with unphosphorylated monomeric Ypd1 (Y ) to form a series of binary complexes (YS OOOP , YS OPOO , YS POOP , YS OPPO , and YS OPOP ). Sln1-Ypd1 phospho-transfer has been shown to be reversible [21] . As such, all reactions that produce phospho-Ypd1 (Y P ) are treated as reversible. No", "cite_spans": [{"start": 334, "end": 338, "text": "[21]", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "Figure 3 Moderate overexpression of phospho-relay components does not activate the HOG pathway.", "text": "A Homozygous GEV diploid strains with a single inducible copy of a phospho-relay gene were grown to saturation in different concentrations of \u03b2-estradiol. The optical density (OD 600 ) after 13 hours of growth is plotted. Overexpression of Pbs2 caused a growth defect at higher concentrations of \u03b2-estradiol, while no significant growth defects were observed following overexpression of relay components (beyond the defect in the wild-type due to overexpression of Gal4 target genes) . Each point represents the mean and standard deviation over four replicates. B We assayed for Hog1 phosphorylation using an antibody specific to doubly phosphorylated Hog1 to confirm that moderate overexpression of phospho-relay components does not lead to activation of the HOG pathway. Overexpression of phospho-relay components using a saturating dose (10 \u03bcM) of \u03b2-estradiol did not lead to Hog1 phosphorylation. Overexpression of the positive controls Ssk22, Ssk2, and Pbs2, however, led to clear upregulation of Hog1 phosphorylation after 30 minutes of induction. Total Hog1 is shown as a loading control.", "cite_spans": [], "ref_spans": []}, {"section": "Figure 3 Moderate overexpression of phospho-relay components does not activate the HOG pathway.", "text": "assumption is made about which half Ypd1 binds to in the YS OPOP binary complex because the halves of the Sln1 dimer are considered to be indistinguishable. Accordingly, the YS OPOP complex is allowed to form from either Y P + S OOOP or Y P + S OPOO . Additionally, YS OPOP can bind to a second Y molecule to form a ternary complex (YS OPOP Y ) that produces Y P using either of the Sln1 phospho-aspartate residues.", "cite_spans": [], "ref_spans": []}, {"section": "Figure 3 Moderate overexpression of phospho-relay components does not activate the HOG pathway.", "text": "Phospho-Ypd1 then binds to and phosphorylates Ssk1, which is modeled as a dimer with two phosphorylation sites (K OO ) [9] . The two monophosphorylated forms of Ssk1, which are known to be fully inactive [9] , are assumed to be identical (i.e., K PO = K OP ). Y P can form a complex with K OO , leading to the production of K OP , and in turn Y P can bind to K OP and transfer a phosphate to produce K PP . The network includes one further interaction between Ypd1 and Ssk1 deduced from kinetic data. The half-life of phospho-Ssk1 in vitro has been measured to be dramatically different with and without the presence of Ypd1 (over 40 hours vs. 13 minutes, respectively), suggesting that Ypd1 binds to K OP and K PP to prevent hydrolysis of the phosphate [20, 22] . Accordingly, the reaction network includes the reversible formation of dead-end complexes between Ypd1 and phospho-Ssk1. Finally, unstabilized K PP and K OP are allowed to lose phosphates via spontaneous hydrolysis. Inclusion of these hydrolysis reactions ensures that there is a complete cycle for Ssk1 modification/demodification and that the system can reach a stable steady state. We emphasize, however, that spontaneous hydrolysis of complexed Ssk1 is likely not the mechanism for rapid dephosphorylation of large quantities of Ssk1 in response to osmotic shock. The mechanism for this rapid activation remains unknown but is irrelevant for our model, which is restricted to yeast growing in steady-state normal osmolarity conditions.", "cite_spans": [{"start": 119, "end": 122, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 204, "end": 207, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 754, "end": 758, "text": "[20,", "ref_id": "BIBREF19"}, {"start": 759, "end": 762, "text": "22]", "ref_id": "BIBREF21"}], "ref_spans": []}, {"section": "Derivation of the key invariant", "text": "Robust inactivation of the HOG pathway requires that only a small fraction of total Ssk1 (K T ) be in the active (K OO ) modification form at steady state. The goal of this section is to derive a simple steady-state expression (an invariant) for the ratio of active to total Ssk1. We find an invariant of the form", "cite_spans": [], "ref_spans": []}, {"section": "Derivation of the key invariant", "text": "where the coefficients are combinations of the rate constants. In this section we derive Eq. 1, and in the following section we discuss experimental tests of its predictions. The subnetwork involving Ssk1 contains four loops, which are linked in a branched tree ( Figure 2D ). It is a general feature of such networks that, at steady state, each individual loop is at steady state, irrespective of any other loops in which the components participate [23, 24] .", "cite_spans": [{"start": 450, "end": 454, "text": "[23,", "ref_id": "BIBREF22"}, {"start": 455, "end": 458, "text": "24]", "ref_id": "BIBREF23"}], "ref_spans": [{"start": 264, "end": 273, "text": "Figure 2D", "ref_id": "FIGREF1"}]}, {"section": "Derivation of the key invariant", "text": "If each individual loop is at steady state, then the forward flux through each loop must be balanced by the backward flux, which yields the following four equations:", "cite_spans": [], "ref_spans": []}, {"section": "Derivation of the key invariant", "text": "Because the intermediate complexes Y P K OO and Y P K OP are also at steady state, we can write", "cite_spans": [], "ref_spans": []}, {"section": "Derivation of the key invariant", "text": "from which we deduce that", "cite_spans": [], "ref_spans": []}, {"section": "Derivation of the key invariant", "text": "Substituting Eq. 3 into Eq. 2, we obtain expressions for K OP , K PP , YK OP , and YK PP in terms of K OO , Y , and Y P . From Eq. 3 we already have expressions for Y P K OO and Y P K OP in terms of K OO and Y P . As such, we are able to calculate the total amount of Ssk1 (K T ) in terms of just K OO , Y , and Y P . We have", "cite_spans": [], "ref_spans": []}, {"section": "Derivation of the key invariant", "text": "Substituting for the individual terms, we obtain", "cite_spans": [], "ref_spans": []}, {"section": "Derivation of the key invariant", "text": "The relative concentration of K OO is thus given by the invariant in Eq. 1.", "cite_spans": [], "ref_spans": []}, {"section": "Derivation of the key invariant", "text": "The tree of loops structure of the Ssk1 network has an important consequence. It implies that the steady-state ratio of active to total Ssk1 is independent of the upstream biochemistry (i.e., the mechanistic details of the various Sln1 and Ypd1 reactions) as long as some process exists to generate positive levels of Y and Y P . In that case, the ratio will always be given by Eq. 1, although the numerical value will of course differ depending on steady-state concentrations of Y and Y P . The implications of this result, including its suggestion that robustness in the HOG pathway is independent of putative Sln1 bifunctionality, are considered in the conclusion.", "cite_spans": [], "ref_spans": []}, {"section": "Breakdown of robustness due to depletion of the Ypd1 pool", "text": "The invariant derived from our mathematical model (Eq. 1) suggests that Ypd1 levels are critical to robustness. The denominator of the invariant is quadratic in the concentration of free Y P and linear in the concentration of free Y . Provided that the upstream network favors production of Y P over Y and that there is substantially more Ypd1 than Ssk1, the denominator of Eq. 1 will be large, and the relative concentration of K OO will be maintained at a low level. This situation allows for considerable underor overexpression of pathway components without spurious activation of the HOG pathway, in agreement with our experimental findings.", "cite_spans": [], "ref_spans": []}, {"section": "Breakdown of robustness due to depletion of the Ypd1 pool", "text": "The invariant predicts that massive overexpression of Ypd1 should not cause phosphorylation of Hog1. In fact, additional Ypd1 would drive the [K OO ] K T ratio even closer to zero, lowering the amount of unphophorylated Ssk1 required for HOG pathway activation. In contrast, Ypd1 underexpression should increase the ratio, potentially compromising fitness due to inappropriate activation of the HOG pathway. Similarly, massive overexpression of Ssk1 should deplete free Y and Y P due to increased levels of the four intermediate complexes (Y P K OO , Y P K OP , YK OP , and YK PP ). Under the assumption of tight binding between Ypd1 and Ssk1 in each of these complexes, which is well-supported by existing kinetic data [20, 22] , very little free Ypd1 will be present at steady state if there is much more Ssk1 than Ypd1. As such, Eq. 1 predicts that the ratio will be higher following massive overexpression of Ssk1 than under wild-type conditions.", "cite_spans": [{"start": 720, "end": 724, "text": "[20,", "ref_id": "BIBREF19"}, {"start": 725, "end": 728, "text": "22]", "ref_id": "BIBREF21"}], "ref_spans": []}, {"section": "Breakdown of robustness due to depletion of the Ypd1 pool", "text": "We experimentally validated these three predictions. The GEV system can achieve at most a 10-fold increase in protein expression from a single inducible allele [11] . We created haploid GEV yeast strains carrying high-copy 2\u03bc plasmids with a GEV-inducible allele (P GAL1 -GENE) of a gene of interest, which allowed us to test the model prediction that massive overexpression of Ssk1, but not of Ypd1, should lead to inappropriate HOG pathway activation. These high-copy yeast plasmids are estimated to be present at 15-50 copies per cell [25] [26] [27] [28] .", "cite_spans": [{"start": 160, "end": 164, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 538, "end": 542, "text": "[25]", "ref_id": "BIBREF24"}, {"start": 543, "end": 547, "text": "[26]", "ref_id": "BIBREF25"}, {"start": 548, "end": 552, "text": "[27]", "ref_id": "BIBREF26"}, {"start": 553, "end": 557, "text": "[28]", "ref_id": "BIBREF27"}], "ref_spans": []}, {"section": "Breakdown of robustness due to depletion of the Ypd1 pool", "text": "We measured the growth of these strains in different concentrations of \u03b2-estradiol to assay for growth defects that might be due to HOG pathway hyperactivation. Massive overexpression of both Sln1 and Ssk1 caused a growth defect over a range of \u03b2-estradiol concentrations, but the strain with Ypd1 overexpressed grew as well as a wild-type strain carrying only the empty vector (P GAL1 2\u03bc scURA3) ( Figure 5A ). Examination of growth over a finer range of \u03b2-estradiol concentrations indicated that overexpression of Ssk1 caused a more severe growth defect than overexpression of Sln1 ( Figure 5B ). These defects were also visible on solid media ( Figure 5C ). As such, extreme overexpression of Ssk1 compromises fitness.", "cite_spans": [], "ref_spans": []}, {"section": "Breakdown of robustness due to depletion of the Ypd1 pool", "text": "We again assayed phospho-Hog1 levels to check if overexpression of Sln1 and Ssk1 causes activation of the HOG pathway in normal osmolarity conditions ( Figure 6 ). We measured Hog1 phosphorylation levels after GEVinduction of relay components and of the positive controls Pbs2 and Ssk22 from a multi-copy plasmid. Overexpression of Pbs2, Ssk22, and Ssk1 caused a significant change in Hog1 phosphorylation after 30 minutes ( Figure 6B ). Although some Hog1 phosphorylation was observed after overexpression of Sln1, the increase was insignificant. Interestingly, overexpression of Ypd1 did not cause an increase in the level of phosphorylated Hog1. In fact, levels of Hog1 phosphorylation were reduced in the Ypd1 overexpression strain (p = 0.0246, two-way ANOVA).", "cite_spans": [], "ref_spans": []}, {"section": "Breakdown of robustness due to depletion of the Ypd1 pool", "text": "We could not perform underexpression experiments in a ypd1 background because deletion of Ypd1 is lethal. To underexpress Ypd1, we instead sporulated the diploid strain (P GAL1 -YPD1/YPD1) containing a wild-type copy of YPD1 and a single copy under the control of P GAL1 onto media containing 10 nM \u03b2-estradiol. We reasoned that 10 nM \u03b2-estradiol would give sufficient expression of Ypd1 for cell growth, which was confirmed by observation of four viable spores. We then grew these spores on media containing a range of \u03b2-estradiol concentrations (Figure 7) . Ypd1 underexpression caused a clear growth defect compared to the wild-type control on 0 nM and 5 nM \u03b2-estradiol, indicating that Ypd1 underexpression is toxic. In contrast, underexpression of Sln1 and Ssk1 did not cause a growth defect (Additional file 1: Figure S1 ).", "cite_spans": [], "ref_spans": [{"start": 547, "end": 557, "text": "(Figure 7)", "ref_id": "FIGREF3"}, {"start": 817, "end": 826, "text": "Figure S1", "ref_id": "FIGREF0"}]}, {"section": "The growth defect following Sln1 overexpression is only partially due to HOG pathway activation", "text": "As discussed above, we observed a slight but nonsignificant increase in Hog1 phosphorylation following massive overexpression of Sln1 ( Figure 6 ). We therefore investigated whether the growth defect in response to Sln1 overexpression is only partially due to HOG pathway activation by creating yeast strains null for SSK1. Activation of the HOG cascade through the Sln1 branch requires Ssk1, so in ssk1 strains it is not possible for Sln1 overexpression to activate the HOG pathway.", "cite_spans": [], "ref_spans": []}, {"section": "The growth defect following Sln1 overexpression is only partially due to HOG pathway activation", "text": "Overexpression of Sln1 from a 2\u03bc plasmid using GEV was still detrimental to growth in the ssk1 strain (Figure 8) , indicating that the growth defect due to Sln1 overexpression is only partially due to HOG pathway activation. This result held both for growth in liquid cultures ( Figure 8A ) and on solid media ( Figure 8B ). It is consistent with Sln1 overexpression causing a smaller effect on Hog1 phosphorylation levels ( Figure 6 ).", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "Robustness of the Sln1-Ypd1-Ssk1 phospho-relay is essential to prevent spurious activation of the HOG pathway, which severely compromises yeast fitness. We established that the phospho-relay is robust to perturbations in the concentrations of the three relay components. A theoretical analysis suggested that a large pool of the intermediate component Ypd1 can buffer fluctuations in other pathway components to maintain robustness. This suggestion was consistent with earlier published measurements indicating that Ypd1 is at least 5 times more abundant than Ssk1 at normal expression levels [7, 29] . Although Ypd1 may also bind to the protein Skn7, combined levels of Ssk1 and Skn7 have been measured to be below total Ypd1 levels [29] . Our subsequent experiments confirmed that depletion of this buffering pool of Ypd1 leads to inappropriate activation of the HOG pathway.", "cite_spans": [{"start": 593, "end": 596, "text": "[7,", "ref_id": "BIBREF6"}, {"start": 597, "end": 600, "text": "29]", "ref_id": "BIBREF28"}, {"start": 734, "end": 738, "text": "[29]", "ref_id": "BIBREF28"}], "ref_spans": []}, {"section": "Conclusions", "text": "The differential expression of Ypd1 and Ssk1 enables phosphorylation of excess Ssk1 and stabilization of the new phospho-Ssk1, buffering HOG pathway activation to fluctuations in Ssk1 levels. This novel mechanism of robustness suggests an advantage of a three-component Figure 5 Massive overexpression of phospho-relay components leads to growth defects. A Haploid GEV strains carrying a high-copy plasmid with an inducible HOG pathway gene were grown in different concentrations of \u03b2-estradiol. The OD 600 after 36 hours of growth is plotted as a function of \u03b2-estradiol concentration. Each point represents the mean and standard deviation of four replicates. Overexpression of Sln1 and Ssk1 (but not Ypd1) caused a growth defect. B The same strains were grown over a finer titration of \u03b2-estradiol concentrations. The OD 600 after 36 hours is plotted. At this resolution, it is clear that the growth defect from Ssk1 overexpression is more severe than the growth defect from Sln1 overexpression at low \u03b2-estradiol concentrations. C The same strains were frogged onto plates containing different concentrations of \u03b2-estradiol. Massive overexpression of Sln1 and Ssk1 again caused a growth defect comparable to that from overexpression of Pbs2. In all experiments, the parent strain carrying the empty vector plasmid [2\u03bc P GAL1 scURA3] was used as a negative control.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "architecture over a two-component one. In particular, the implementation of an analogous buffering strategy in a two-component system would be difficult because it would require expressing the sensor histidine kinase at very high levels. This situation might lead to imprecise sensing and various other off-target effects. In contrast, Figure 6 Growth defects following massive overexpression of phospho-relay components are due to activation of the HOG pathway. A We assayed for Hog1 phosphorylation after overexpression of relay components (Sln1, Ypd1, Ssk1) and positive controls (Pbs2, Ssk22). The parental strain carrying the empty plasmid vector was used as a negative control. B We quantified the amount of phosphorylated Hog1 (relative to Hog1) in five biological replicates of this experiment. Error bars represent the standard error. Pbs2, Ssk22, and Ssk1 caused a significant ( * ) change in Hog1 phosphorylation levels after overexpression for 30 minutes (p = 0.0395, 0.0096, and 0.0224, respectively; paired t-test). Hog1 phosphorylation levels were also significantly lower in the Ypd1 overexpression strain (p = 0.0246, two-way ANOVA).", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "the use of an intermediate transfer protein enables robust buffering with both the sensor and response regulator expressed at comparable levels. Our work has thus identified a potential mechanism for circumventing a tradeoff between efficient sensing and robust control. There are other possible advantages for a three-component architecture, including combinatorial control of response regulators by sensor proteins through a common phosphotransfer protein or segregation of sensing and activation functions between the nucleus and cytoplasm. Intriguingly, deletion of YPD1 has recently been shown to cause constitutive activation of the HOG pathway in Candida albicans, suggesting that its buffering capacity might also be important in this organism [30] .", "cite_spans": [{"start": 752, "end": 756, "text": "[30]", "ref_id": "BIBREF29"}], "ref_spans": []}, {"section": "Conclusions", "text": "Robustness in real biological systems is necessarily approximate and apt to be compromised at extreme expression levels of cellular components. In many systems, however, it has proven difficult to characterize where robustness breaks down and to reconcile such results with mathematical models, which often predict exact robustness [31] . Our combined theoretical and experimental results specify a single condition (Ypd1 in large excess) for robust regulation of the HOG pathway.", "cite_spans": [{"start": 332, "end": 336, "text": "[31]", "ref_id": "BIBREF30"}], "ref_spans": []}, {"section": "Conclusions", "text": "The link between bifunctionality and robustness is well-established [31] [32] [33] [34] [35] , and it is known that bifunctionality of EnvZ is essential to robustness in Escherichia coli osmoregulation [36, 37] . As such, it is intriguing that our model suggests that robustness in S. cerevisiae osmoregulation is not dependent on bifunctionality of Sln1. It is important to emphasize, however, that bifunctionality would not compromise robustness. Rather, the model indicates that any upstream process that produces non-zero levels of Y and Y P should enable the same fundamental behavior predicted by Eq. 1. The possibility that Sln1 exhibits phosphatase activity warrants further experimental investigation.", "cite_spans": [{"start": 68, "end": 72, "text": "[31]", "ref_id": "BIBREF30"}, {"start": 78, "end": 82, "text": "[33]", "ref_id": "BIBREF32"}, {"start": 83, "end": 87, "text": "[34]", "ref_id": "BIBREF33"}, {"start": 88, "end": 92, "text": "[35]", "ref_id": "BIBREF34"}, {"start": 202, "end": 206, "text": "[36,", "ref_id": "BIBREF35"}, {"start": 207, "end": 210, "text": "37]", "ref_id": "BIBREF36"}], "ref_spans": []}, {"section": "Methods", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Yeast strains and media", "text": "All yeast strains used in this study are listed in Additional file 2: Table S1 . The homozygous GEV diploid strain, which served as the wild-type background strain for all diploid overexpression experiments, was created by mating haploid GEV strains yMM598 and yMM1101 [11] and picking zygotes to create yMM1104. As described previously [11] , diploid yeast strains capable of overexpressing the desired HOG pathway protein from a single locus (yMM1263, yMM1272, yMM1259) were created by transforming [38] the homozygous GEV diploid strain yMM1104 with the KanMX-P GAL1 cassette amplified from yMM1100 genomic DNA using appropriate oligonucleotide pairs. Transformants were verified by colony PCR and sequencing.", "cite_spans": [{"start": 269, "end": 273, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 337, "end": 341, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 501, "end": 505, "text": "[38]", "ref_id": "BIBREF37"}], "ref_spans": []}, {"section": "Yeast strains and media", "text": "Yeast strains containing 2\u03bc plasmids for massive overexpression of pathway components (yMM1313-yMM1318) were constructed using recombination-mediated plasmid construction [39, 40] to generate the overexpression plasmids pMM330-pMM334 in vivo (as described below). Positive transformants were selected for and maintained on SC-Ura media [38] .", "cite_spans": [{"start": 171, "end": 175, "text": "[39,", "ref_id": "BIBREF38"}, {"start": 176, "end": 179, "text": "40]", "ref_id": "BIBREF39"}, {"start": 336, "end": 340, "text": "[38]", "ref_id": "BIBREF37"}], "ref_spans": []}, {"section": "Yeast strains and media", "text": "Yeast strains containing the P STL1 -YFP reporter of HOG pathway activity and one estradiol-inducible allele of a HOG pathway gene (yMM1296, yMM1298, yMM1300, yMM1301, yMM1304, yMM1305) were constructed by transforming the heterozygous diploid GEV yeast strains (yMM1104, yMM1272, yMM1264, yMM1259 yMM1286, yMM1287) already containing an inducible allele with the product of PCRing yECitrine-HphMX off plasmid pMM280 using appropriate oligonucleotides. The oligonucleotides contained homology such that the STL1 ORF was replaced with the yECitrine-HphMX cassette. Transformants were verified by colony PCR, and expression of YFP in 1M sorbitol was assayed.", "cite_spans": [], "ref_spans": []}, {"section": "Yeast strains and media", "text": "Yeast strains null for the SSK1 gene (ssk1 ) were created by deleting the SSK1 ORF using appropriate oligonucleotide pairs to amplify KanMX from pMM131 and transforming it into yMM630. Transformants were selected for drug resistance and verified by colony PCR and sequencing.", "cite_spans": [], "ref_spans": []}, {"section": "Yeast strains and media", "text": "Standard yeast media was used as noted. Low fluorescence yeast media was prepared as described previously [41] .", "cite_spans": [{"start": 106, "end": 110, "text": "[41]", "ref_id": "BIBREF40"}], "ref_spans": []}, {"section": "Plasmid construction", "text": "All plasmids used in this study are listed in Additional file 3: Table S2 . Plasmid pMM329 (P GAL1 scURA3 2\u03bc) was constructed by PCR of the native GAL1 promoter from genomic DNA prepared from yMM1100 using appropriate primers. This promoter was ligated in pMM12 between the restriction sites KpnI and XhoI (scURA3 2\u03bc) [42] . The resulting plasmid served as a template to create a series of overexpression plasmids with different HOG pathway genes under the control of the GAL1 promoter using yeast recombination-mediated plasmid construction [39, 40] . Appropriate primer pairs were used to amplify Pbs2, Ssk22, Sln1, Ypd1, and Ssk1, respectively, from yMM1100 genomic DNA. These PCR products were then co-transformed with pMM329 linearized Figure 8 Growth defects following Sln1 overexpression are not completely due to HOG pathway activation. A We assayed growth in wild-type and ssk1 strains overexpressing Sln1 in response to \u03b2-estradiol or carrying an empty P GAL1 vector control. Deletion of Ssk1, which prevented HOG pathway activation by Sln1, partially alleviated the growth defect due to Sln1 overexpression. B Growth of cells on plates containing 10 \u03bcM \u03b2-estradiol indicated that ssk1 reduced the toxicity of Sln1 overexpression.", "cite_spans": [{"start": 318, "end": 322, "text": "[42]", "ref_id": "BIBREF41"}, {"start": 542, "end": 546, "text": "[39,", "ref_id": "BIBREF38"}, {"start": 547, "end": 550, "text": "40]", "ref_id": "BIBREF39"}], "ref_spans": []}, {"section": "Plasmid construction", "text": "with XhoI and SalI. The primer pairs used to amplify the HOG pathway genes contained homology with the pMM329 backbone such that the gene of interest was integrated after P GAL1 to create a P GAL1 -HOGGENE plasmid (pMM330-pMM334). Positive transformants in which the plasmid had been repaired were selected for on SC-Ura media. Plasmids were purified from these transformants and verified by sequencing.", "cite_spans": [], "ref_spans": []}, {"section": "Overexpression growth experiments on solid media", "text": "Yeast strains were grown overnight to saturation in appropriate media (YPD or SC-Ura media to maintain plasmids). These saturated cultures were serially diluted in 10-fold increments and frogged onto YPD or SC-URA plates containing 0 nM, 10 nM, 100 nM, 1 \u03bcM, or 10 \u03bcM \u03b2-estradiol (Tocris Biosciences). These plates were incubated at 30\u00b0C for two days before imaging.", "cite_spans": [], "ref_spans": []}, {"section": "Overexpression growth experiments using plate reader", "text": "Yeast strains were grown overnight to saturation in YPD or SC-Ura media. In the morning, each strain was diluted 1:2000 into 200 \u03bcL of the same media containing 0 nM, 100 nM, 1 \u03bcM, or 10 \u03bcM of \u03b2-estradiol in a well of a 96-well flat-bottom plate (Costar). Each strain/estradiol combination was run in four replicates on the same plate. Growth curves were generated using a Synergy H1 microplate reader (BioTek). Cells were grown at 30\u00b0C with continuous, double-orbital (555 cpm) shaking, and OD 600 was measured every 20 minutes. Growth rates were calculated from the growth curves using spline-fits determined with the R package grofit [43] . OD was plotted at the time points indicated in the figure legends.", "cite_spans": [{"start": 637, "end": 641, "text": "[43]", "ref_id": "BIBREF42"}], "ref_spans": []}, {"section": "Underexpression experiments by diploid sporulation", "text": "Diploid GEV strains yMM1104 (control), yMM1259 (SLN1/KanMX-P GAL1 -SLN1), yMM1263 (SSK1/KanMX-P GAL1 -SSK1), yMM1264 (SSK1/KanMX-P GAL1 -SSK1), and yMM1272 (YPD1/KanMXrev-P GAL1 -YPD1) were sporulated in 1% potassium acetate for 3 days and dissected onto YPD plates containing 10 nM \u03b2-estradiol. Two spores from each tetrad contained the wild-type HOG pathway gene (Sln1, Ypd1, or Ssk1), while the other contained the same gene under the control of the GAL1 promoter (KanMX-P GAL1 -SSK1, KanMX-P GAL1 -SLN1, KanMX-P GAL1 -YPD1). After all spores had grown to a sufficient size, they were diluted into YPD and frogged onto YPD plates containing 0 nM, 5 nM, 10 nM, 100 nM, 1 \u03bcM, or 10 \u03bcM \u03b2-estradiol. Spores were allowed to grow at 30\u00b0C for 2 days prior to imaging.", "cite_spans": [], "ref_spans": []}, {"section": "P STL1 -yEVenus induction and flow cytometry", "text": "We created diploid GEV strains that carried both an inducible HOG gene under the control of P GAL1 promoter and a HOG pathway transcriptional reporter (P STL1 -yEVenus) to assay for downstream transcriptional activation in response to overexpression of various HOG pathway proteins. Strains were grown with agitation in low fluorescence media at 30\u00b0C to mid-log (Klett 80), at which point 200 \u03bcl of cell culture was sampled for flow cytometry by adding it to 800 \u03bcl of cold PBS + 0.1% Tween 20 stored at 4\u00b0C. Each culture was induced by adding \u03b2-estradiol to a final concentration of 10 \u03bcM. Cultures were sampled for flow cytometry after induction with \u03b2-estradiol at T = 2 hours and T = 19 hours. Fluorescence was analyzed by flow cytometry on a BD LSRII Multi-Laser Analyzer with HTS (BD Biosciences).", "cite_spans": [], "ref_spans": []}, {"section": "Preparation of protein extracts", "text": "We measured levels of phosphorylated Hog1 following both moderate and massive overexpression of pathway components. For the moderate overexpression experiments, diploid GEV yeast strains yMM1104, yMM1263, yMM1259, yMM1272, and yMM1287, which each contained one estradiol-inducible copy of a HOG pathway gene, were grown to mid-log (Klett 80) in YPD at 30\u00b0C with shaking. To assess the effect of massive overexpression of HOG pathway proteins, yeast strains containing the P GAL1 -HOGGENE scURA3 2\u03bc overexpression plasmids (yMM1313-yMM1318) were grown in SC-Ura media to mid-log (Klett 80) at 30\u00b0C with shaking. For all strains, at T = 0 expression of the gene of interest was induced by addition of 10 \u03bcM \u03b2-estradiol (final concentration). At indicated timepoints, 1.5 ml of culture was sampled.", "cite_spans": [], "ref_spans": []}, {"section": "Preparation of protein extracts", "text": "Protein was prepped from samples immediately after each time point. Each sample was centrifuged (1320 RPM) and the supernatant aspirated. The resulting cell pellet was resuspended in 100 \u03bcl of 1X sample buffer (Invitrogen) with \u03b2-mercaptoethanol (final concentration of 10%), protease inhibitor (Roche), and phosphatase inhibitor (Fisher Scientific). Samples were heated at 95\u00b0C for 5 minutes, vortexed for 2 minutes, and then rapidly frozen in liquid nitrogen and stored at -20\u00b0C.", "cite_spans": [], "ref_spans": []}, {"section": "Western blotting", "text": "Prior to western blotting, samples were thawed and centrifuged at 1320 RPM for 5 minutes. They were run on 4-10% Bis-Tris gels (Invitrogen) and transferred to PVDF membranes (Invitrogen) by electrophoresis at 13 V for 4 hours. Membranes were blocked for 1 hour at room temperature with agitation in 1X TBS, 0.1% Tween-20, and 5% milk. Membranes were then probed with primary antibody overnight at 4\u00b0C.", "cite_spans": [], "ref_spans": []}, {"section": "Western blotting", "text": "The following antibodies were used to detect phosphorylated Hog1, total Hog1, and actin, respectively: antiphospho-p38 MAPK rabbit monoclonal antibodies (Cell Signaling Technology #9215), anti-c-myc goat polyclonal antibodies (Santa Cruz Biotechnology sc-6815), and anti\u03b2-actin antibody (Abcam ab8224). All primary antibodies were diluted 1:1000 in 1X TBS, 0.1% Tween-20, and 5% milk. Following incubation with the primary antibody, membranes were washed (4 \u00d7 5 minutes) with TBST (1X TBS, 1% Tween-20) and then incubated for 1 hour at room temperature with the appropriate secondary antibody conjugated to HRP (anti-rabbit IgG (Cell Signaling #7074, 1:5000 dilution), rabbit anti-goat IgG (Santa Cruz sc-2768, 1:5000 dilution), and anti-mouse IgG (Abcam ab97023, 1:20000 dilution), respectively). All secondary antibodies were diluted in 5% milk, 1X TBS, and 1% Tween-20. After incubation with the secondary antibody, membranes were washed 4 \u00d7 5 minutes with 5% milk, 1X TBS, and 1% Tween-20.", "cite_spans": [], "ref_spans": []}, {"section": "Western blotting", "text": "Western blots were quantified using chemiluminescence. Membranes were developed using the Pierce Supersignal Femto kit following the manufacturer's protocol. Chemiluminescence was quantified using HyBlot CL Autoradiography film. Developed film was scanned on a Epson Perfection 4490 Photo Scanner in transmission mode. Protein levels were quantified by densitometry using the Gel Analysis plug-in in ImageJ [44] .", "cite_spans": [{"start": 407, "end": 411, "text": "[44]", "ref_id": "BIBREF43"}], "ref_spans": []}, {"section": "Western blotting", "text": "Each membrane was probed for phospho-Hog1, betaactin, and total Hog1 (in that order). After the chemiluminescence assay but before re-blocking, the membrane was stripped by washing in stripping buffer (2 \u00d7 10 minutes), phosphate-buffered saline (2 \u00d7 10 minutes) and 1X TBS + 1% Tween-20 (2 \u00d7 5 minutes). Stripping buffer contained 15 g glycine, 1 g SDS, and 10 mL Tween 20 in 1 L ultrapure water, with the pH adjusted to 2.2 using concentrated HCl.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Osmotic stress signaling and osmoadaptation in yeasts", "authors": [{"first": "S", "middle": [], "last": "Hohmann", "suffix": ""}], "year": 2002, "venue": "Microbiol Mol Biol Rev", "link": "14184489"}, "BIBREF1": {"title": "Histidine phosphorylation and two-component signaling in eukaryotic cells", "authors": [{"first": "H", "middle": [], "last": "Saito", "suffix": ""}], "year": 2001, "venue": "Chem Rev", "link": "196683849"}, "BIBREF2": {"title": "Signal processing by the HOG MAP kinase pathway", "authors": [{"first": "P", "middle": [], "last": "Hersen", "suffix": ""}, {"first": "M", "middle": [], "last": "Mcclean", "suffix": ""}, {"first": "L", "middle": [], "last": "Mahadevan", "suffix": ""}, {"first": "S", "middle": [], "last": "Ramanathan", "suffix": ""}], "year": 2008, "venue": "Proc Natl Acad Sci", "link": "14580131"}, "BIBREF3": {"title": "Dynamic signaling in the Hog1 MAPK pathway relies on high basal signal transduction", "authors": [{"first": "J", "middle": [], "last": "Macia", "suffix": ""}, {"first": "S", "middle": [], "last": "Regot", "suffix": ""}, {"first": "T", "middle": [], "last": "Peeters", "suffix": ""}, {"first": "N", "middle": [], "last": "Conde", "suffix": ""}, {"first": "R", "middle": [], "last": "Sole", "suffix": ""}, {"first": "F", "middle": [], "last": "Posas", "suffix": ""}], "year": 2009, "venue": "Sci Signaling", "link": "1829908"}, "BIBREF4": {"title": "Activation of the yeast SSK2 MAP kinase kinase kinase by the SSK1 two-component response regulator", "authors": [{"first": "F", "middle": [], "last": "Posas", "suffix": ""}, {"first": "H", "middle": [], "last": "Saito", "suffix": ""}], "year": 1998, "venue": "EMBO J", "link": null}, "BIBREF5": {"title": "A two-component system that regulates an osmosensing MAP kinase cascade in yeast", "authors": [{"first": "T", "middle": [], "last": "Maeda", "suffix": ""}, {"first": "S", "middle": [], "last": "Wurgler-Murphy", "suffix": ""}, {"first": "H", "middle": [], "last": "Saito", "suffix": ""}], "year": 1994, "venue": "Nature", "link": null}, "BIBREF6": {"title": "Robustness and fragility in the yeast high osmolarity glycerol (HOG) signal-transduction pathway", "authors": [{"first": "M", "middle": [], "last": "Krantz", "suffix": ""}, {"first": "D", "middle": [], "last": "Ahmadpour", "suffix": ""}, {"first": "L-G", "middle": [], "last": "Ottoson", "suffix": ""}, {"first": "J", "middle": [], "last": "Warringer", "suffix": ""}, {"first": "C", "middle": [], "last": "Waltermann", "suffix": ""}, {"first": "B", "middle": [], "last": "Nordlander", "suffix": ""}], "year": 2009, "venue": "Mol Sys Biol", "link": "14778312"}, "BIBREF7": {"title": "Activation of yeast PBS2 MAPKK by MAPKKKs or by binding of an SH3-containing osmosensor", "authors": [{"first": "T", "middle": [], "last": "Maeda", "suffix": ""}, {"first": "M", "middle": [], "last": "Takekawa", "suffix": ""}, {"first": "H", "middle": [], "last": "Saito", "suffix": ""}], "year": 1995, "venue": "Science", "link": "7979573"}, "BIBREF8": {"title": "Phosphorylated Ssk1 prevents unphosphorylated Ssk1 from activating the Ssk2 mitogen-activated protein kinase kinase kinase in the yeast high-osmolarity glycerol osmoregulatory pathway", "authors": [{"first": "T", "middle": [], "last": "Horie", "suffix": ""}, {"first": "K", "middle": [], "last": "Tatebayashi", "suffix": ""}, {"first": "R", "middle": [], "last": "Yamada", "suffix": ""}, {"first": "H", "middle": [], "last": "Saito", "suffix": ""}], "year": 2008, "venue": "Mol Cell Biol", "link": "12596197"}, "BIBREF9": {"title": "Mapping pathways and phenotypes by systematic gene overexpression", "authors": [{"first": "R", "middle": [], "last": "Sopko", "suffix": ""}, {"first": "D", "middle": [], "last": "Huang", "suffix": ""}, {"first": "N", "middle": [], "last": "Preston", "suffix": ""}, {"first": "G", "middle": [], "last": "Chua", "suffix": ""}, {"first": "B", "middle": [], "last": "Papp", "suffix": ""}, {"first": "K", "middle": [], "last": "Kafadar", "suffix": ""}], "year": 2006, "venue": "Mol Cell", "link": "1148836"}, "BIBREF10": {"title": "Fast-acting and nearly gratuitous induction of gene expression and protein depletion in Saccharomyces cerevisiae", "authors": [{"first": "R", "middle": [], "last": "Mcisaac", "suffix": ""}, {"first": "S", "middle": [], "last": "Silverman", "suffix": ""}, {"first": "M", "middle": [], "last": "Mcclean", "suffix": ""}, {"first": "P", "middle": [], "last": "Gibney", "suffix": ""}, {"first": "J", "middle": [], "last": "Macinskas", "suffix": ""}, {"first": "M", "middle": [], "last": "Hickman", "suffix": ""}], "year": 2011, "venue": "Mol Biol Cell", "link": "16748971"}, "BIBREF11": {"title": "Integrative model of the response of yeast to osmotic shock", "authors": [{"first": "E", "middle": [], "last": "Klipp", "suffix": ""}, {"first": "B", "middle": [], "last": "Nordlander", "suffix": ""}, {"first": "R", "middle": [], "last": "Kruger", "suffix": ""}, {"first": "P", "middle": [], "last": "Gennemark", "suffix": ""}, {"first": "S", "middle": [], "last": "Hohmann", "suffix": ""}], "year": 2005, "venue": "Nat Biotechnol", "link": "29487287"}, "BIBREF12": {"title": "Models in systems biology: the parameter problem and the meanings of robustness", "authors": [{"first": "J", "middle": [], "last": "Gunawardena", "suffix": ""}], "year": 2009, "venue": "Elements of Computational Systems Biology", "link": "17906346"}, "BIBREF13": {"title": "Yeast osmoregulation", "authors": [{"first": "S", "middle": [], "last": "Hohmann", "suffix": ""}, {"first": "M", "middle": [], "last": "Krantz", "suffix": ""}, {"first": "B", "middle": [], "last": "Nordlander", "suffix": ""}], "year": 2007, "venue": "Meth Enzymol", "link": "20691740"}, "BIBREF14": {"title": "Control of high osmolarity signalling in the yeast Saccharomyes cerevisaie", "authors": [{"first": "S", "middle": [], "last": "Hohmann", "suffix": ""}], "year": 2009, "venue": "FEBS Lett", "link": null}, "BIBREF15": {"title": "A member of the sugar transporter family, Stl1p is the glycerol/H+ symporter in Saccharomyces cerevisiae", "authors": [{"first": "C", "middle": [], "last": "Ferreira", "suffix": ""}, {"first": "F", "middle": [], "last": "Van Voorst", "suffix": ""}, {"first": "A", "middle": [], "last": "Martins", "suffix": ""}, {"first": "L", "middle": [], "last": "Neves", "suffix": ""}, {"first": "R", "middle": [], "last": "Oliveira", "suffix": ""}, {"first": "M", "middle": [], "last": "Kielland-Brandt", "suffix": ""}], "year": 2005, "venue": "Mol Biol Cell", "link": "6214239"}, "BIBREF16": {"title": "Insights into eukaryotic multistep phosphorelay signal transduction revealed by the crystal structure of Ypd1p from Saccharomyces cerevisiae", "authors": [{"first": "H", "middle": [], "last": "Song", "suffix": ""}, {"first": "J", "middle": [], "last": "Lee", "suffix": ""}, {"first": "M", "middle": [], "last": "Lee", "suffix": ""}, {"first": "J", "middle": [], "last": "Moon", "suffix": ""}, {"first": "Min", "middle": ["K"], "last": "Yang", "suffix": ""}, {"first": "J", "middle": [], "last": "", "suffix": ""}], "year": 1999, "venue": "J Mol Biol", "link": null}, "BIBREF17": {"title": "The yeast YPD1/SLN1 complex: insights into molecular recognition in two-component signaling systems", "authors": [{"first": "Q", "middle": [], "last": "Xu", "suffix": ""}, {"first": "S", "middle": [], "last": "Porter", "suffix": ""}, {"first": "A", "middle": [], "last": "West", "suffix": ""}], "year": 2003, "venue": "Structure", "link": "33532179"}, "BIBREF18": {"title": "A cytoplasmic coiled-coil domain is required for histidine kinase activity of the yeast osmosensor SLN1", "authors": [{"first": "W", "middle": [], "last": "Tao", "suffix": ""}, {"first": "C", "middle": ["L"], "last": "Malone", "suffix": ""}, {"first": "A", "middle": ["D"], "last": "Ault", "suffix": ""}, {"first": "R", "middle": ["J"], "last": "Deschenes", "suffix": ""}, {"first": "J", "middle": ["S"], "last": "Fassler", "suffix": ""}], "year": 2002, "venue": "Mol Microbiol", "link": "39411219"}, "BIBREF19": {"title": "Differential stabilities of phosphorylated response regulator domains reflect functional roles of the yeast osmoregulatory SLN1 and SSK1 proteins", "authors": [{"first": "F", "middle": [], "last": "Janiak-Spens", "suffix": ""}, {"first": "J", "middle": [], "last": "Sparling", "suffix": ""}, {"first": "M", "middle": [], "last": "Gurfinkel", "suffix": ""}, {"first": "A", "middle": [], "last": "West", "suffix": ""}], "year": 1999, "venue": "J Bacteriol", "link": null}, "BIBREF20": {"title": "Kinetic analysis of YPD1-dependent phosphotransfer reactions in the yeast osmoregulatory phosphorelay system", "authors": [{"first": "F", "middle": [], "last": "Janiak-Spens", "suffix": ""}, {"first": "P", "middle": [], "last": "Cook", "suffix": ""}, {"first": "A", "middle": [], "last": "West", "suffix": ""}], "year": 2005, "venue": "Biochemistry", "link": "38758367"}, "BIBREF21": {"title": "Novel role for an HPt domain in stabilizing the phosphorylated state of a response regulator domain", "authors": [{"first": "F", "middle": [], "last": "Janiak-Spens", "suffix": ""}, {"first": "D", "middle": [], "last": "Sparling", "suffix": ""}, {"first": "A", "middle": [], "last": "West", "suffix": ""}], "year": 2000, "venue": "J Bacteriol", "link": "45858722"}, "BIBREF22": {"title": "Multisite protein phosphorylation makes a good threshold but can be a poor switch", "authors": [{"first": "J", "middle": [], "last": "Gunawardena", "suffix": ""}], "year": 2005, "venue": "Proc Natl Acad Sci USA", "link": "29058803"}, "BIBREF23": {"title": "A framework for modeling gene regulation which accommodates non-equilibrium mechanisms", "authors": [{"first": "T", "middle": [], "last": "Ahsendorf", "suffix": ""}, {"first": "F", "middle": [], "last": "Wong", "suffix": ""}, {"first": "R", "middle": [], "last": "Eils", "suffix": ""}, {"first": "J", "middle": [], "last": "Gunawardena", "suffix": ""}], "year": 2014, "venue": "BMC Biol", "link": "8139806"}, "BIBREF24": {"title": "Copy number and partition of the Saccharomyces cerevisiae 2 micron plasmid controlled by transcription regulators", "authors": [{"first": "B", "middle": ["E"], "last": "Veit", "suffix": ""}, {"first": "W", "middle": ["L"], "last": "Fangman", "suffix": ""}], "year": 1988, "venue": "Mol Cell Biol", "link": "36471021"}, "BIBREF25": {"title": "Characterization of plasmid burden and copy number in Saccharomyces cerevisiae for optimization of metabolic engineering applications", "authors": [{"first": "A", "middle": ["S"], "last": "Karim", "suffix": ""}, {"first": "K", "middle": ["A"], "last": "Curran", "suffix": ""}, {"first": "H", "middle": ["S"], "last": "Alper", "suffix": ""}], "year": 2013, "venue": "FEMS Yeast Res", "link": "22276096"}, "BIBREF26": {"title": "Curing of Saccharomyces cerevisiae 2-\u03bcm DNA by transformation", "authors": [{"first": "E", "middle": [], "last": "Erhart", "suffix": ""}, {"first": "C", "middle": ["P"], "last": "Hollenberg", "suffix": ""}], "year": 1981, "venue": "Curr Genet", "link": "6790598"}, "BIBREF27": {"title": "Enhancing the copy number of episomal plasmids in Saccharomyces cerevisiae for improved protein production", "authors": [{"first": "Y", "middle": [], "last": "Chen", "suffix": ""}, {"first": "S", "middle": [], "last": "Partow", "suffix": ""}, {"first": "G", "middle": [], "last": "Scalcinati", "suffix": ""}, {"first": "V", "middle": [], "last": "Siewers", "suffix": ""}, {"first": "J", "middle": [], "last": "Nielsen", "suffix": ""}], "year": 2012, "venue": "FEMS Yeast Res", "link": "25553932"}, "BIBREF28": {"title": "Global analysis of protein expression in yeast", "authors": [{"first": "S", "middle": [], "last": "Ghaemmaghami", "suffix": ""}, {"first": "W", "middle": [], "last": "Huh", "suffix": ""}, {"first": "K", "middle": [], "last": "Bower", "suffix": ""}, {"first": "R", "middle": [], "last": "Howson", "suffix": ""}, {"first": "A", "middle": [], "last": "Belle", "suffix": ""}, {"first": "N", "middle": [], "last": "Dephoure", "suffix": ""}], "year": 2003, "venue": "Nature", "link": "4344864"}, "BIBREF29": {"title": "Two-component histidine phosphotransfer protein Ypd1 is not essential for viability in Candida albicans", "authors": [{"first": "J", "middle": [], "last": "Mavrianos", "suffix": ""}, {"first": "C", "middle": [], "last": "Desai", "suffix": ""}, {"first": "N", "middle": [], "last": "Chauhan", "suffix": ""}], "year": 2014, "venue": "Eukaryot Cell", "link": "206745809"}, "BIBREF30": {"title": "Structural sources of robustness in biochemical reaction networks", "authors": [{"first": "G", "middle": [], "last": "Shinar", "suffix": ""}, {"first": "M", "middle": [], "last": "Feinberg", "suffix": ""}], "year": 2010, "venue": "Science", "link": "22428321"}, "BIBREF32": {"title": "The utility of paradoxical components in biological circuits", "authors": [{"first": "Y", "middle": [], "last": "Hart", "suffix": ""}, {"first": "U", "middle": [], "last": "Alon", "suffix": ""}], "year": 2013, "venue": "Mol Cell", "link": "12350938"}, "BIBREF33": {"title": "Dimerization and bifunctionality confer robustness to the isocitrate dehydrogenase regulatory system in Escherichia coli", "authors": [{"first": "J", "middle": [], "last": "Dexter", "suffix": ""}, {"first": "J", "middle": [], "last": "Gunawardena", "suffix": ""}], "year": 2013, "venue": "J Biol Chem", "link": "27150978"}, "BIBREF34": {"title": "A fundamental trade-off in covalent switching and its circumvention by enzyme bifunctionality in glucose homeostasis", "authors": [{"first": "T", "middle": [], "last": "Dasgupta", "suffix": ""}, {"first": "D", "middle": [], "last": "Croll", "suffix": ""}, {"first": "J", "middle": [], "last": "Owen", "suffix": ""}, {"first": "M", "middle": [], "last": "Vander Heiden", "suffix": ""}, {"first": "J", "middle": [], "last": "Locasale", "suffix": ""}, {"first": "U", "middle": [], "last": "Alon", "suffix": ""}], "year": 2014, "venue": "J Biol Chem", "link": "12600062"}, "BIBREF35": {"title": "Robustness and the cycle of phosphorylation and dephosphorylation in a two-component regulatory system", "authors": [{"first": "E", "middle": [], "last": "Batchelor", "suffix": ""}, {"first": "M", "middle": [], "last": "Goulian", "suffix": ""}], "year": 2003, "venue": "Proc Natl Acad Sci USA", "link": "8208303"}, "BIBREF36": {"title": "Input-output robustness in simple bacterial signaling systems", "authors": [{"first": "G", "middle": [], "last": "Shinar", "suffix": ""}, {"first": "R", "middle": [], "last": "Milo", "suffix": ""}, {"first": "M", "middle": [], "last": "Martinez", "suffix": ""}, {"first": "U", "middle": [], "last": "Alon", "suffix": ""}], "year": 2007, "venue": "Proc Natl Acad Sci USA", "link": "197562"}, "BIBREF37": {"title": "High-efficiency yeast transformation using the LiAc/SS carrier DNA/PEG method", "authors": [{"first": "R", "middle": [], "last": "Gietz", "suffix": ""}, {"first": "R", "middle": [], "last": "Schiestl", "suffix": ""}], "year": 2007, "venue": "Nat Protoc", "link": "39978504"}, "BIBREF38": {"title": "Plasmid construction by homologous recombination in yeast", "authors": [{"first": "H", "middle": [], "last": "Ma", "suffix": ""}, {"first": "S", "middle": [], "last": "Kunes", "suffix": ""}, {"first": "P", "middle": [], "last": "Schatz", "suffix": ""}, {"first": "D", "middle": [], "last": "Botstein", "suffix": ""}], "year": 1987, "venue": "Gene", "link": "32995250"}, "BIBREF39": {"title": "Recombination-mediated PCR-directed plasmid construction in vivo in yeast", "authors": [{"first": "K", "middle": [], "last": "Oldenburg", "suffix": ""}, {"first": "K", "middle": [], "last": "Vo", "suffix": ""}, {"first": "S", "middle": [], "last": "Michaelis", "suffix": ""}, {"first": "C", "middle": [], "last": "Paddon", "suffix": ""}], "year": 1997, "venue": "Nuc Acid Res", "link": "526779"}, "BIBREF40": {"title": "Optimized cassettes for fluorescent protein tagging in Saccharomyces cerevisiae", "authors": [{"first": "M", "middle": [], "last": "Sheff", "suffix": ""}, {"first": "K", "middle": [], "last": "Thorn", "suffix": ""}], "year": 2004, "venue": "Yeast", "link": "14965629"}, "BIBREF41": {"title": "A system of shuttle vectors and yeast host strains designed for efficient manipulation of DNA in Saccharomyces cerevisiae", "authors": [{"first": "R", "middle": [], "last": "Sikorski", "suffix": ""}, {"first": "P", "middle": [], "last": "Hieter", "suffix": ""}], "year": 1989, "venue": "Genetics", "link": "9565525"}, "BIBREF42": {"title": "Grofit: Fitting biological growth curves with R", "authors": [{"first": "M", "middle": [], "last": "Kahn", "suffix": ""}, {"first": "G", "middle": [], "last": "Hasenbrink", "suffix": ""}, {"first": "H", "middle": [], "last": "Lichtenberg-Frate", "suffix": ""}, {"first": "J", "middle": [], "last": "Ludwig", "suffix": ""}, {"first": "M", "middle": [], "last": "Kschischo", "suffix": ""}], "year": 2010, "venue": "J Stat Software", "link": "12256067"}, "BIBREF43": {"title": "NIH Image to ImageJ: 25 years of image analysis", "authors": [{"first": "C", "middle": [], "last": "Schneider", "suffix": ""}, {"first": "W", "middle": [], "last": "Rasband", "suffix": ""}, {"first": "K", "middle": [], "last": "Eliceiri", "suffix": ""}], "year": 2012, "venue": "Nat Methods", "link": "13131970"}}, "ref_entries": {"FIGREF0": {"text": "Structure of the Sln1-Ypd1-Ssk1 relay and the HOG MAPK pathway. Under normal growth conditions, Sln1 activates Ypd1, which in turn inhibits Ssk1. Increased osmolarity inhibits Sln1, resulting in activation of Ssk1 and of the MAP kinase Hog1 through the upstream MAP3Ks Ssk2 and Ssk22 and the MAP2K Pbs2. Activated Hog1 regulates transcriptional and metabolic changes within the cell that increase production and retention of glycerol.", "type": "figure"}, "FIGREF1": {"text": "Biochemically realistic model of the HOG pathway three-component phospho-relay in S. cerevisiae. A Cartoon diagram of the phospho-relay indicating the quaternary structure of each component and the four relevant phosphorylation sites.", "type": "figure"}, "FIGREF2": {"text": "Moderate overexpression of phospho-relay components causes mild activation of HOG pathway transcriptional targets on longtimescales. STL1 is a gene induced in response to active Hog1. We replaced one copy of the STL1 gene with yEVenus in homozygous GEV strains to create a P STL1 -yEVenus transcriptional reporter of HOG pathway activity. We used flow cytometry to analyze yEVenus expression in cells at the start of the experiment and at 2 hours and 19 hours after induction with 10 \u03bcM \u03b2-estradiol. Pbs2 and Ssk22 overexpression caused the strongest activation of the HOG pathway transcriptional reporter. Cell counts are plotted against the natural log of their fluorescence signal [a.u.].", "type": "figure"}, "FIGREF3": {"text": "Underexpression of Ypd1 causes a severe growth defect. A diploid homozygous GEV strain carrying one inducible allele of Ypd1 (YPD1/P GAL1 -YPD1) was sporulated onto 10 nM \u03b2-estradiol, and individual spores were frogged onto plates containing different concentrations of \u03b2-estradiol. At low concentrations of \u03b2-estradiol, spores carrying the inducible allele (P GAL1 -YPD1, row 2 and row 4) exhibited a growth defect due lower levels of Ypd1 and hyperactivation of the HOG pathway. Spores carrying the wild-type allele (row 1 and row 3) showed no growth defect.", "type": "figure"}}}
{"paper_id": "2872803", "_pdf_hash": "cd69ac797692e1bd2cfd93c8434c5051dc3ffae7", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "A model for the prediction of thresholds, loudness, and partial loudness", "authors": [{"first": "B", "middle": ["C J"], "last": "Moore", "suffix": ""}, {"first": "B", "middle": ["R"], "last": "Glasberg", "suffix": ""}, {"first": "T", "middle": [], "last": "Baer", "suffix": ""}], "year": 1997, "venue": "J. Audio Eng. Soc", "link": "109618488"}, "BIBREF1": {"title": "A model of loudness applicable to time-varying sounds", "authors": [{"first": "B", "middle": ["R"], "last": "Glasberg", "suffix": ""}, {"first": "B", "middle": ["C J"], "last": "Moore", "suffix": ""}], "year": 2002, "venue": "J. Audio Eng. Soc", "link": "52265560"}, "BIBREF2": {"title": "The deterioration of hearing with age: Frequency selectivity, the critical ratio, the audiogram, and speech threshold", "authors": [{"first": "R", "middle": ["D"], "last": "Patterson", "suffix": ""}, {"first": "I", "middle": [], "last": "Nimmo-Smith", "suffix": ""}, {"first": "D", "middle": ["L"], "last": "Weber", "suffix": ""}, {"first": "R", "middle": [], "last": "Milroy", "suffix": ""}], "year": 1982, "venue": "J. Acoust. Soc. Am", "link": "21815667"}, "BIBREF3": {"title": "Frequency Analysis and Masking", "authors": [{"first": "B", "middle": ["C J"], "last": "Moore", "suffix": ""}], "year": 1995, "venue": "", "link": null}, "BIBREF4": {"title": "Derivation of auditory filter shapes from notched-noise data", "authors": [{"first": "B", "middle": ["R"], "last": "Glasberg", "suffix": ""}, {"first": "B", "middle": ["C"], "last": "Moore", "suffix": ""}], "year": 1990, "venue": "Hear. Res", "link": "4772612"}, "BIBREF5": {"title": "The growth of auditory sensation", "authors": [{"first": "W", "middle": ["A"], "last": "Munson", "suffix": ""}], "year": 1947, "venue": "J. Acoust. Soc. Am", "link": "119962055"}}, "ref_entries": {}}
{"paper_id": "2872933", "_pdf_hash": "c652b47eed06ee44533eb10672384bc14c6cf5a4", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Diseo de una base de datos speechdat para el idioma gallego", "authors": [{"first": "B", "middle": [], "last": "Gonz\u00e1lez-Rey", "suffix": ""}, {"first": "C", "middle": [], "last": "Garc\u00eda-Mateo", "suffix": ""}], "year": 2000, "venue": "Procesamiento del Lenguaje Natural (SEPLN)", "link": null}, "BIBREF1": {"title": "Flexible speaker adaptation using maximum likelihood linear regression", "authors": [{"first": "C", "middle": ["J"], "last": "Legetter", "suffix": ""}, {"first": "P", "middle": ["C"], "last": "Woodland", "suffix": ""}], "year": 1995, "venue": "Proceedings of the Spoken Language Systems Technology Workshop", "link": "3117210"}, "BIBREF2": {"title": "The demiphone: an efficient contextual subword unit for continuous speech recognition", "authors": [{"first": "J", "middle": ["B"], "last": "Mari\u00f1o", "suffix": ""}, {"first": "A", "middle": [], "last": "Nogueiras", "suffix": ""}, {"first": "P", "middle": [], "last": "Pachs", "suffix": ""}, {"first": "A", "middle": [], "last": "Bonafonte", "suffix": ""}], "year": 2000, "venue": "Speech Communication", "link": "24006875"}, "BIBREF3": {"title": "Spanish fixed network speech corpus", "authors": [{"first": "A", "middle": [], "last": "Moreno", "suffix": ""}, {"first": "R", "middle": [], "last": "Winsky", "suffix": ""}], "year": 1997, "venue": "", "link": null}, "BIBREF4": {"title": "Multilinguality in speech and spoken language", "authors": [{"first": "A", "middle": [], "last": "Waibel", "suffix": ""}, {"first": "P", "middle": [], "last": "Geutner", "suffix": ""}, {"first": "L", "middle": [], "last": "Mayfield Tomokiyo", "suffix": ""}, {"first": "T", "middle": [], "last": "Schultz", "suffix": ""}, {"first": "M", "middle": [], "last": "Woszczyna", "suffix": ""}], "year": 2000, "venue": "Proceedings of the IEEE", "link": null}, "BIBREF5": {"title": "The HTK Book (for HTK Version 2.2)", "authors": [{"first": "S", "middle": [], "last": "Young", "suffix": ""}, {"first": "D", "middle": [], "last": "Kershaw", "suffix": ""}, {"first": "J", "middle": [], "last": "Odell", "suffix": ""}, {"first": "D", "middle": [], "last": "Ollason", "suffix": ""}, {"first": "V", "middle": [], "last": "Valttchev", "suffix": ""}, {"first": "P", "middle": [], "last": "Woodland", "suffix": ""}], "year": 1999, "venue": "", "link": "59809105"}}, "ref_entries": {}}
{"paper_id": "2873021", "_pdf_hash": "4c344f670c93fea02345320be2c91b3e1bafd234", "abstract": [{"section": "Abstract", "text": "With the advances in e-Sciences and the growing complexity of scientific analyses, more and more scientists and researchers are relying on workflow systems for process coordination, derivation automation, provenance tracking, and bookkeeping.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Scientific workflow has become increasingly popular in modern scientific computation as more and more scientists and researchers are relying on workflow systems to conduct their daily science analysis and discovery. With technology advances in both scientific instrumentation and simulation, the amount of scientific datasets is growing exponentially each year, such large data size combined with growing complexity of data analysis procedures and algorithms have rendered traditional manual processing and exploration unfavorable as compared with modern in silico processes automated by scientific workflow systems (SWFS). While the term workflow speaks of different things in different context, we find in general SWFS are engaged and applied to the following aspects of scientific computations: 1) describing complex scientific procedures, 2) automating data derivation processes, 3) high performance computing (HPC) to improve throughput and performance, and 4) provenance management and query.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "Workflows are not a new concept and have been around for decades. There were a number of coordination languages and systems developed in the 80s and 90s [1, 7] , which share many common characteristic with workflow systems (i.e. they describe individual computation components and their ports and channels, and the data and event flow between them). They also coordinate the execution of the components, often on parallel computing resources. Furthermore, business process management systems have been developed and invested in for years; there are many mature commercial products and industry standards such as BPEL [2] . In the scientific community there are also many emerging systems for scientific programming and computation [5, 22] . Before we jump on developing yet another workflow system, a fundamental question to ask is whether we can use existing technologies, or we should invent new languages and systems in order to achieve the four aspects mentioned earlier that are essential to scientific workflow systems. This paper identifies the challenges to workflow development in the context of scientific computation; we present an overview of some of the existing technologies and emerging systems, and discuss opportunities in addressing these challenges.", "cite_spans": [{"start": 153, "end": 156, "text": "[1,", "ref_id": "BIBREF0"}, {"start": 157, "end": 159, "text": "7]", "ref_id": "BIBREF6"}, {"start": 617, "end": 620, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 731, "end": 734, "text": "[5,", "ref_id": "BIBREF4"}, {"start": 735, "end": 738, "text": "22]", "ref_id": "BIBREF21"}], "ref_spans": []}, {"section": "Multi-core processor architectures", "text": "Software development has been on a free ride for performance gain as chipmakers continue to follow Moore's Law in doubling up transistors in minuscule space. Little consideration has been given to code parallelization since it has not been essential for the average computer user until recently, when single CPU core performance growth stagnated and multi-core processors emerged on the market in 2005.", "cite_spans": [], "ref_spans": []}, {"section": "Multi-core processor architectures", "text": "Due to the limitations to effectively increasing processor clock frequency, hardware manufactures started to physically reorganize chips into what we call the multi-core architecture [10] , involving linking several microprocessor cores together on the same semiconductor. Various manufactures from Intel, AMD, IBM, Sun, have released dual-core, quad-core, eight-core, and 64-threaded processors in the past few years [13, 21] . Given that 128-threaded SMP systems are a reality today [21] , it is reasonable to assume that 1024 CPU cores/threads or more per SMP system will be available in the next decade.", "cite_spans": [{"start": 183, "end": 187, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 418, "end": 422, "text": "[13,", "ref_id": "BIBREF12"}, {"start": 423, "end": 426, "text": "21]", "ref_id": "BIBREF20"}, {"start": 485, "end": 489, "text": "[21]", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "Multi-core processor architectures", "text": "The new multi-core architecture will force radical changes in software design and development. We are already seeing significant increase of research interests in concurrency and parallelism, and multi-core software development. The number of multiprocessor research papers has increased sharply since year 2001, surpassing the peak point in all the past years [10] . Concurrency is one of the next big challenges in how we write software simply because our industry has been driven by requirements to write ever larger systems that solve ever more complicated problems and exploit the ever greater computing and storage resources that are available [18] .", "cite_spans": [{"start": 361, "end": 365, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 650, "end": 654, "text": "[18]", "ref_id": "BIBREF17"}], "ref_spans": []}, {"section": "The data deluge challenge in science", "text": "Within the science domain, the data that needs to be processed generally grows faster than computational resources and their speed. The scientific community is facing an imminent flood of data expected from the next generation of experiments, simulations, sensors and satellites. Scientists are now attempting calculations requiring orders of magnitude more computing and communication than was possible only a few years ago. Moreover, in many currently planned and future experiments, they are also planning to generate several orders of magnitude more data than has been collected in the entire human history [9] .", "cite_spans": [{"start": 611, "end": 614, "text": "[9]", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "The data deluge challenge in science", "text": "For instance, in the astronomy domain the Sloan Digital Sky Survey (http://www.sdss.org) has datasets that exceed 10 terabytes in size. They can reach up to 100 terabytes or even petabytes if we consider multiple surveys and the time dimension. In physics, the CMS detector being built to run at CERN's Large Hadron Collider (http://lhc.web.cern.ch/lhc) is expected to generate over a petabyte of data per year. In the bioinformatics domain, the rate of growth of DNA databases such as GenBank (http://www.psc.edu/general/software/packages/genbank/) and EMBL (European Molecular Biology Laboratory, http://www.embl.org) has been following an exponential trend, with a doubling time estimated to be 9-12 months.", "cite_spans": [], "ref_spans": []}, {"section": "The data deluge challenge in science", "text": "To enable the storage and analysis of large quantities of data and to achieve rapid turnaround, data needs to be distributed over thousands to tens of thousands of compute nodes. In such circumstances, data locality is crucial to the successful and efficient use of large scale distributed systems for data-intensive applications [19] . Scientific workflows are generally executed on a shared infrastructure such as TeraGrid (http://www.teragrid.org), Open Science Grid (http://www.opensciencegrid.org), and dedicated clusters, where data movement relies on shared file systems that are known bottlenecks for data intensive operations. If data analysis workloads have locality of reference, then it is feasible to cache and replicate data at each individual compute node, as high initial data movement costs can be offset by many subsequent data operations performed on cached data [15] .", "cite_spans": [{"start": 330, "end": 334, "text": "[19]", "ref_id": "BIBREF18"}, {"start": 882, "end": 886, "text": "[15]", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "The data deluge challenge in science", "text": "Modern scientific workflow systems need to set large scale data management as one of its primary objectives, and to ensure data movement is minimized by intelligent data-aware scheduling both among distributed computing sites (assuming that each site has a local area network shared storage infrastructure), and among compute nodes (assuming that data can be stored on compute nodes' local disk and/or memory).", "cite_spans": [], "ref_spans": []}, {"section": "Supercomputing vs. Grid Computing", "text": "Supercomputers had their golden age back in the 80s when there were virtually no other choices in dealing with compute-intensive tasks. They were applied mostly to scientific modeling and simulation in various disciplines such as high energy physics, earth science, biology, mechanical engineering etc. Some typical applications included weather forecasting, missile trajectory simulation, airplane wind tunnel simulation, genomics etc. However, supercomputers are expensive and scarce resources where only national laboratories, government agencies and some universities have access to them; and the parallel architectures of supercomputers often dictate the use of special programming techniques to exploit their speed, such as special-purposed FORTRAN compilers, PVM, MPI and OpenMP [9] .", "cite_spans": [{"start": 786, "end": 789, "text": "[9]", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "Supercomputing vs. Grid Computing", "text": "Over the last decade, we have observed processor speeds, storage capacity per drive, and network bandwidth increase 100~1000 times. As a consequence, cluster computing and Grid computing environments that leverage the cheaper commodity computing and storage hardware have been actively adopted for scientific computations. Cluster computing usually involves homogeneous machines interconnected by high speed network with locally accessible storage in one administrative domain, where Grid computing focuses on distributed resource sharing and coordination across multiple \"virtual organizations\" that may span many geographically distributed administrative domains. Grids can also be categorized into Computational Grids and Data Grids, where the former mostly tackle computation intensive tasks, and the latter target data-intensive sciences.", "cite_spans": [], "ref_spans": []}, {"section": "Supercomputing vs. Grid Computing", "text": "With the introduction of multi-core architectures, the separation between Grid Computing and Supercomputing is becoming less clear. Many supercomputers are being built on multi-core chips with high speed interconnection. The Cray XT5 system (http://www.cray.com/products/xt5/index.html) uses thousands commodity Quad-Core AMD Opteron\u2122 processors and has a unified Linux environment. The latest IBM BlueGene/P Supercomputer (BG/P, http://www.research.ibm.com/bluegene/) has quad core processors with a total of 160K-cores, and has support for a lightweight Linux kernel on the compute nodes, making it significantly more accessible to new applications [17] . Finally, a smaller system named SiCortex (http://www.sicortex.com/) is also worth mentioning; it boasts 6-core processors for a total of 5832-cores, and runs a standard Linux environment.", "cite_spans": [{"start": 651, "end": 655, "text": "[17]", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "Supercomputing vs. Grid Computing", "text": "Supercomputers (e.g. IBM BlueGene) have traditionally been designed and used for tightly coupled massively parallel applications, typically implemented in MPI. They have not been an ideal preferred platform for executing loosely coupled applications that are typical in many scientific workflows. Grids have seen success in the execution of tightly coupled parallel applications, but they has been the platform of choice for loosely coupled applications mostly due to the flexibility and granularity of the resource management and the execution of single processor jobs with ease. Work is underway within both the Falkon [14] and Condor [20] projects to enable the latest BG/P to efficiently support loosely coupled serial jobs without any modifications to the respective applications, and hence enabling an entirely new class of applications that were never candidates as possible use cases for the BlueGene/P supercomputer.", "cite_spans": [{"start": 621, "end": 625, "text": "[14]", "ref_id": "BIBREF13"}, {"start": 637, "end": 641, "text": "[20]", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "Supercomputing vs. Grid Computing", "text": "Scalability and performance are top priorities for SWFS. To this end, it is necessary to leverage supercomputing resources as well as Grid computing infrastructures for large scale parallel computations.", "cite_spans": [], "ref_spans": []}, {"section": "Existing and emerging workflow technologies", "text": "DAGMan (http://www.cs.wisc.edu/condor/dagman) and Pegasus [6] are two systems that are commonly referred to as workflow systems and have been widely applied in Grid environments. DAGMan provides a workflow engine that manages Condor jobs organized as directed acyclic graphs (DAGs) in which each edge corresponds to an explicit task precedence. Both systems focus on the scheduling and execution of long running jobs.", "cite_spans": [{"start": 58, "end": 61, "text": "[6]", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Existing and emerging workflow technologies", "text": "Taverna [12] is an open source workflow system particularly focused on bioinformatics applications and services, and it is based on the XScufl (XML Simple Conceptual Unified Flow) language. Kepler [11] is a scientific workflow system that builds on the Ptolemy-II system (http://ptolemy.eecs.berkeley.edu/ptolemyII/), which is a visual modeling tool written in Java. Triana [4] is a GUI-based workflow system for coordinating and executing a collection of services. All these systems have some visual interfaces (also referred to as workbenches) that allow the graphical composition of workflows.", "cite_spans": [{"start": 8, "end": 12, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 197, "end": 201, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 374, "end": 377, "text": "[4]", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "Existing and emerging workflow technologies", "text": "While all of the existing SWFS possess great features and address many aspects of workflow specification, execution and management problems, it is unrealistic to expect one system to cover all the bases. The Workflow Bus project [23] instead tries to leverage multiple existing workflow systems to compliment each other in implementing aggregated functions and services.", "cite_spans": [{"start": 229, "end": 233, "text": "[23]", "ref_id": "BIBREF22"}], "ref_spans": []}, {"section": "Existing and emerging workflow technologies", "text": "Finally, the evolutions of workflows themselves (explorations) are vital in scientific analysis. VisTrails [3] captures the notion of an evolving dataflow, and implements a history management mechanism to maintain versions of a dataflow, thus allowing a scientist to return to previous steps, apply a dataflow instance to different input data, explore the parameter space of the dataflow, and (while performing these steps) compare the associated visualization results.", "cite_spans": [{"start": 107, "end": 110, "text": "[3]", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "Existing and emerging workflow technologies", "text": "In response to the pressing demand of scientific applications, and the hunger for computing power, there have been a few emerging languages and systems that try to tackle the problems taking unconventional approaches.", "cite_spans": [], "ref_spans": []}, {"section": "Existing and emerging workflow technologies", "text": "MapReduce [5] is regarded as a power-leveler that solves complicated computation problems using brutalforce computation power. It provides a very simple programming model and powerful runtime system for the processing of large datasets. The programming model is based on just two key functions: \"map\" and \"reduce,\" borrowed from functional languages. The MapReduce runtime system automatically partitions input data and schedules the execution of programs in a large cluster of commodity machines. The system is made fault tolerant by checking worker nodes periodically and reassigning failed jobs to other worker nodes. MapReduce has been mostly applied to document processing problems, such as distributed indexing, sorting, and clustering.", "cite_spans": [{"start": 10, "end": 13, "text": "[5]", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "Existing and emerging workflow technologies", "text": "The Fortress language (http://fortress.sunsource.net) recently released by Sun Microsystems is a new programming language designed for HPC, and aims to improve programmability and productivity in scientific computation. The language has been designed from ground up, supporting mathematical notation (in Unicode) and physical units and dimensions, static type checking of multidimensional arrays and matrices, and rich functionality in libraries. It supports transactions, specification of locality, and implicit parallel computation (e.g. parallel for loops). Although Fortress in a strict sense is not a workflow language, and its adoption remains to be seen, it provides the higher level abstractions and functionalities for building a parallel workflow language.", "cite_spans": [], "ref_spans": []}, {"section": "Existing and emerging workflow technologies", "text": "Microsoft Windows Workflow Foundation (WWF) [16] provides a generic framework for workflow development and execution. It is focused on integrating diverse components within an application, allowing a workflow to be deployed and managed as a native part of the application. The fundamental idea behind WWF is that each activity is modeled as a resumable program statement, and the invocation of an activity is asynchronously organized, thus a program can be compared to a bookmark, which can be frozen in action, serialized into persistent storage, and resumed after arbitrarily long time later. However, WWF is not a full-fledged workflow management system in that it lacks administration, monitoring, retry mechanism, load balancing, etc. for a production environment.", "cite_spans": [{"start": 44, "end": 48, "text": "[16]", "ref_id": "BIBREF15"}], "ref_spans": []}, {"section": "Existing and emerging workflow technologies", "text": "Star-P (http://www.interactivesupercomputing.com) approaches the integration of scientific applications and HPC via language extension -allowing scientists to work in their familiar programming environments such as MATLAB, Python, and R, with some parallel directives. Internally the system can schedule the execution of parallel tasks to a computation cluster preconfigured with scientific calculation libraries. The system has been applied to a wide variety of computation problems, but the performance improvement is mostly intra-application parallelization, instead of inter-component coordination and management.", "cite_spans": [], "ref_spans": []}, {"section": "Existing and emerging workflow technologies", "text": "Swift [22] is an emerging system that bridges scientific workflows with parallel computing. It is a parallel programming tool for rapid and reliable specification, execution, and management of largescale science and engineering workflows. Swift takes a structured approach to workflow specification, scheduling and execution. It consists of a simple scripting language called SwiftScript for concise specifications of complex parallel computations based on dataset typing and iterations, and dynamic dataset mappings for accessing large scale datasets represented in diverse data formats. The runtime system relies on the CoG Karajan workflow engine for efficient scheduling and load balancing, and it integrates the Falkon [14] light-weight task execution service for optimized task throughput and resource efficiency delivered by a streamlined dispatcher, a dynamic resource provisioner, and the data diffusion mechanism to cache datasets in local disk or memory and dispatch tasks according to data locality.", "cite_spans": [{"start": 6, "end": 10, "text": "[22]", "ref_id": "BIBREF21"}, {"start": 724, "end": 728, "text": "[14]", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "Call for scientific workflow systems", "text": "Existing technologies and systems already address many of the fundamental issues in scientific workflow specification and management, and many of them have been successful applied to various scientific applications across multiple science disciplines. However, modern multi-core architectures and parallel and distributed computing technologies, and the exponentially growing scientific data are bound to change the landscape and evolution of scientific workflow systems. As already being manifested by the few emerging systems, the science community is demanding both specialized, domain-specific languages to improve productivity and efficiency in writing concurrent programs and coordination tools, and generic platforms and infrastructures for the execution and management of large scale scientific applications, where scalability and performance are major concerns. High performance computing support has become a indispensable piece of such workflow languages and systems, as there is no other viable way to get around the large storage and computing problems emerging in every discipline of 21 st century e-science, although what may be the best approach to enabling scientists to leverage HPC technologies as transparent and efficient as possible remains unanswered.", "cite_spans": [], "ref_spans": []}, {"section": "Call for scientific workflow systems", "text": "In the science domain, there is an increasing need for programming languages to expose parallelism, whether it's done explicitly or implicitly, to specify the concurrency within a component, or across multiple independent components. There is a need for new parallel or workflow languages that adopt implicit parallelism where data dependencies can be discovered by its compiler, and independent tasks in the orders of hundreds of thousands can be scheduled to run in clustered or Grid environments. Such systems could achieve improvements in both manageability and productivity.", "cite_spans": [], "ref_spans": []}, {"section": "Call for scientific workflow systems", "text": "Scientific workflow systems aim to provide a simple concise notation that allows easy parallelization and supports the composition of large numbers of parallel computations, therefore they may not need all the constructs and features in a full-fledged conventional language, and implicit parallelism is preferred to explicit parallelism specification, as the latter requires expertise and attention to the details of parallel programming, which may be difficult for end users. But in the mean time sometimes scientists do need more control in specifying how to distribute their applications and datasets.", "cite_spans": [], "ref_spans": []}, {"section": "Call for scientific workflow systems", "text": "We are also in need of common generic infrastructures and platforms in the science domain for workflow administration, scheduling, execution, monitoring, provenance tracking etc. While business process management has industry agreed upon standards and steering committees, we don't have these in the science domain, where often time people reinvent the wheel in developing their in-house yet another SWFS, and there is no easy way in integrating various workflow systems and specifications. We also argue that in order to address all the important issues such as scalability, reliability, scheduling and monitoring, data management, collaboration, workflow provenance, and workflow evolution, one system cannot fit all needs. A structured infrastructure that separates the concerns of workflow specification, scheduling, execution etc, yet is organized on top of components that specialize on one or more of the areas would be more appropriate.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Linda and Friends", "authors": [{"first": "S", "middle": [], "last": "Ahuja", "suffix": ""}, {"first": "N", "middle": [], "last": "Carriero", "suffix": ""}, {"first": "D", "middle": [], "last": "Gelernter", "suffix": ""}], "year": 1986, "venue": "IEEE Computer", "link": null}, "BIBREF1": {"title": "Business Process Execution Language for Web Services, Version 1.1. Specification, BEA Systems", "authors": [{"first": "T", "middle": [], "last": "Andrews", "suffix": ""}, {"first": "F", "middle": [], "last": "Curbera", "suffix": ""}, {"first": "H", "middle": [], "last": "Dholakia", "suffix": ""}, {"first": "Y", "middle": [], "last": "Goland", "suffix": ""}, {"first": "J", "middle": [], "last": "Klein", "suffix": ""}, {"first": "F", "middle": [], "last": "Leymann", "suffix": ""}, {"first": "K", "middle": [], "last": "Liu", "suffix": ""}, {"first": "D", "middle": [], "last": "Roller", "suffix": ""}, {"first": "D", "middle": [], "last": "Smith", "suffix": ""}, {"first": "S", "middle": [], "last": "Thatte", "suffix": ""}, {"first": "I", "middle": [], "last": "Trickovic", "suffix": ""}, {"first": "S", "middle": [], "last": "Weerawarana", "suffix": ""}], "year": 2003, "venue": "", "link": null}, "BIBREF2": {"title": "Managing the Evolution of Dataflows with VisTrails", "authors": [{"first": "S", "middle": ["P"], "last": "Callahan", "suffix": ""}, {"first": "J", "middle": [], "last": "Freire", "suffix": ""}, {"first": "E", "middle": [], "last": "Santos", "suffix": ""}, {"first": "C", "middle": ["E"], "last": "Scheidegger", "suffix": ""}, {"first": "C", "middle": ["T"], "last": "Silva", "suffix": ""}, {"first": "H", "middle": ["T"], "last": "Vo", "suffix": ""}], "year": 2006, "venue": "IEEE Workshop on Workflow and Data Flow for Scientific Applications (SciFlow)", "link": "15887619"}, "BIBREF3": {"title": "Programming Scientific and Distributed Workflow with Triana Services", "authors": [{"first": "D", "middle": [], "last": "Churches", "suffix": ""}, {"first": "G", "middle": [], "last": "Gombas", "suffix": ""}, {"first": "A", "middle": [], "last": "Harrison", "suffix": ""}, {"first": "J", "middle": [], "last": "Maassen", "suffix": ""}, {"first": "C", "middle": [], "last": "Robinson", "suffix": ""}, {"first": "M", "middle": [], "last": "Shields", "suffix": ""}, {"first": "I", "middle": [], "last": "Taylor", "suffix": ""}, {"first": "I", "middle": [], "last": "Wang", "suffix": ""}], "year": 2005, "venue": "Concurrency and Computation: Practice and Experience. Special Issue on Scientific Workflows", "link": "18531255"}, "BIBREF4": {"title": "MapReduce: Simplified data processing on large clusters", "authors": [{"first": "J", "middle": [], "last": "Dean", "suffix": ""}, {"first": "S", "middle": [], "last": "Ghemawat", "suffix": ""}], "year": 2004, "venue": "", "link": "207166250"}, "BIBREF5": {"title": "A Framework for Mapping Complex Scientific Workflows onto Distributed Systems. Scientific Programming", "authors": [{"first": "E", "middle": [], "last": "Deelman", "suffix": ""}, {"first": "G", "middle": [], "last": "Singh", "suffix": ""}, {"first": "M.-H", "middle": [], "last": "Su", "suffix": ""}, {"first": "J", "middle": [], "last": "Blythe", "suffix": ""}, {"first": "Y", "middle": [], "last": "Gil", "suffix": ""}, {"first": "C", "middle": [], "last": "Kesselman", "suffix": ""}, {"first": "G", "middle": [], "last": "Mehta", "suffix": ""}, {"first": "K", "middle": [], "last": "Vahi", "suffix": ""}, {"first": "G", "middle": ["B"], "last": "Berriman", "suffix": ""}, {"first": "J", "middle": [], "last": "Good", "suffix": ""}, {"first": "A", "middle": [], "last": "Laity", "suffix": ""}, {"first": "J", "middle": ["C"], "last": "Jacob", "suffix": ""}, {"first": "D", "middle": ["S"], "last": "Katz", "suffix": ""}, {"first": "", "middle": [], "last": "Pegasus", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF6": {"title": "Compositional Parallel Programming Languages", "authors": [{"first": "I", "middle": [], "last": "Foster", "suffix": ""}], "year": 1996, "venue": "ACM Transactions on Programming Languages and Systems", "link": "12973001"}, "BIBREF7": {"title": "Distributed Computing Economics", "authors": [{"first": "J", "middle": [], "last": "Gray", "suffix": ""}], "year": 2003, "venue": "", "link": "3204714"}, "BIBREF8": {"title": "The data deluge: an e-sicence perspective", "authors": [{"first": "T", "middle": [], "last": "Hey", "suffix": ""}, {"first": "A", "middle": [], "last": "Trefethen", "suffix": ""}], "year": 2003, "venue": "Gid Computing: Making the Global Infrastructure a Reality", "link": null}, "BIBREF9": {"title": "Amdahl's Law in the Multicore Era", "authors": [{"first": "M", "middle": [], "last": "Hill", "suffix": ""}, {"first": "Marty", "middle": [], "last": "", "suffix": ""}, {"first": "M", "middle": [], "last": "", "suffix": ""}], "year": 2008, "venue": "The 14th International Symposium on HighPerformance Computer Architecture", "link": "53302661"}, "BIBREF10": {"title": "Scientific Workflow Management and the Kepler System", "authors": [{"first": "B", "middle": [], "last": "Lud\u00e4scher", "suffix": ""}, {"first": "I", "middle": [], "last": "Altintas", "suffix": ""}, {"first": "C", "middle": [], "last": "Berkley", "suffix": ""}, {"first": "D", "middle": [], "last": "Higgins", "suffix": ""}, {"first": "E", "middle": [], "last": "Jaeger-Frank", "suffix": ""}, {"first": "M", "middle": [], "last": "Jones", "suffix": ""}, {"first": "E", "middle": [], "last": "Lee", "suffix": ""}, {"first": "J", "middle": [], "last": "Tao", "suffix": ""}, {"first": "Y", "middle": [], "last": "Zhao", "suffix": ""}], "year": 2005, "venue": "Concurrency and Computation: Practice & Experience", "link": "8207366"}, "BIBREF11": {"title": "Taverna: A tool for the composition and enactment of bioinformatics workflows", "authors": [{"first": "T", "middle": [], "last": "Oinn", "suffix": ""}, {"first": "M", "middle": [], "last": "Addis", "suffix": ""}, {"first": "J", "middle": [], "last": "Ferris", "suffix": ""}, {"first": "D", "middle": [], "last": "Marvin", "suffix": ""}, {"first": "M", "middle": [], "last": "Senger", "suffix": ""}, {"first": "M", "middle": [], "last": "Greenwood", "suffix": ""}, {"first": "T", "middle": [], "last": "Carver", "suffix": ""}, {"first": "K", "middle": [], "last": "Glover", "suffix": ""}, {"first": "M", "middle": ["R"], "last": "Pocock", "suffix": ""}, {"first": "A", "middle": [], "last": "Wipat", "suffix": ""}, {"first": "P", "middle": [], "last": "Li", "suffix": ""}], "year": 2004, "venue": "Bioinformatics Journal", "link": "1375038"}, "BIBREF12": {"title": "The Potential of the Cell Processor for Scientific Computing. Computational Research Division", "authors": [], "year": 2007, "venue": "", "link": null}, "BIBREF13": {"title": "Falkon: a Fast and Lightweight Task Execution Framework", "authors": [{"first": "I", "middle": [], "last": "Raicu", "suffix": ""}, {"first": "Y", "middle": [], "last": "Zhao", "suffix": ""}, {"first": "C", "middle": [], "last": "Dumitrescu", "suffix": ""}, {"first": "I", "middle": [], "last": "Foster", "suffix": ""}, {"first": "M", "middle": [], "last": "Wilde", "suffix": ""}], "year": 2007, "venue": "IEEE/ACM Supercomputing", "link": "6643831"}, "BIBREF14": {"title": "Accelerating Large-scale Data Exploration through Data Diffusion", "authors": [{"first": "I", "middle": [], "last": "Raicu", "suffix": ""}, {"first": "Y", "middle": [], "last": "Zhao", "suffix": ""}, {"first": "I", "middle": [], "last": "Foster", "suffix": ""}, {"first": "A", "middle": [], "last": "Szalay", "suffix": ""}], "year": 2008, "venue": "ACM/IEEE Workshop on Data-Aware Distributed Computing", "link": "17088493"}, "BIBREF15": {"title": "Essential Windows Workflow Foundation (Microsoft .NET Development Series)", "authors": [{"first": "D", "middle": [], "last": "Shukla", "suffix": ""}, {"first": "R", "middle": [], "last": "Schmidt", "suffix": ""}], "year": 2006, "venue": "", "link": null}, "BIBREF16": {"title": "The LLNL/ANL/IBM Collaboration to", "authors": [{"first": "R", "middle": [], "last": "Stevens", "suffix": ""}], "year": 2006, "venue": "", "link": null}, "BIBREF17": {"title": "The Free Lunch Is Over: A Fundamental Turn Toward Concurrency in Software", "authors": [{"first": "H", "middle": [], "last": "Sutter", "suffix": ""}], "year": 2005, "venue": "Dr. Dobb's Journal", "link": "59674034"}, "BIBREF18": {"title": "The Importance of Data Locality in Distributed Computing Applications", "authors": [{"first": "A", "middle": [], "last": "Szalay", "suffix": ""}, {"first": "A", "middle": ["."], "last": "Bunn", "suffix": ""}, {"first": "J", "middle": [], "last": "Gray", "suffix": ""}, {"first": "I", "middle": [], "last": "Foster", "suffix": ""}, {"first": "I", "middle": [], "last": "Raicu", "suffix": ""}], "year": 2006, "venue": "", "link": "59704118"}, "BIBREF19": {"title": "Distributed Computing in Practice: The Condor Experience", "authors": [{"first": "D", "middle": [], "last": "Thain", "suffix": ""}, {"first": "T", "middle": [], "last": "Tannenbaum", "suffix": ""}, {"first": "M", "middle": [], "last": "Livny", "suffix": ""}], "year": 2005, "venue": "Concurrency and Computation: Practice and Experience", "link": "15450656"}, "BIBREF20": {"title": "The world's first true system on a chip", "authors": [{"first": "", "middle": [], "last": "Ultrasparc\u00ae", "suffix": ""}, {"first": "", "middle": [], "last": "Processor", "suffix": ""}], "year": 2008, "venue": "", "link": null}, "BIBREF21": {"title": "Swift: Fast, Reliable, Loosely Coupled Parallel Computation", "authors": [{"first": "Y", "middle": [], "last": "Zhao", "suffix": ""}, {"first": "M", "middle": [], "last": "Hategan", "suffix": ""}, {"first": "B", "middle": [], "last": "Clifford", "suffix": ""}, {"first": "I", "middle": [], "last": "Foster", "suffix": ""}, {"first": "G", "middle": ["V"], "last": "Laszewski", "suffix": ""}, {"first": "I", "middle": [], "last": "Raicu", "suffix": ""}, {"first": "T", "middle": [], "last": "Stef-Praun", "suffix": ""}, {"first": "M", "middle": [], "last": "Wilde", "suffix": ""}], "year": 2007, "venue": "IEEE Workshop on Scientific Workflow", "link": "809177"}, "BIBREF22": {"title": "Distributed execution of aggregated multi domain workflows using an agent framework", "authors": [{"first": "Z", "middle": [], "last": "Zhao", "suffix": ""}, {"first": "A", "middle": [], "last": "Belloum", "suffix": ""}, {"first": "C", "middle": [], "last": "De Laat", "suffix": ""}, {"first": "P", "middle": [], "last": "Adriaans", "suffix": ""}, {"first": "R", "middle": [], "last": "Hertzberger", "suffix": ""}], "year": 2007, "venue": "IEEE Workshop on Scientific Workflow", "link": "14453257"}}, "ref_entries": {}}
{"paper_id": "2873489", "_pdf_hash": "365712d3187e0c669d3dac93a6de213d9366325e", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Identity, Image and Issue Interpretation, Sensemaking During Strategic Change in Academia", "authors": [{"first": "D", "middle": [], "last": "Gioia", "suffix": ""}, {"first": "Thomas", "middle": [], "last": "", "suffix": ""}, {"first": "J", "middle": [], "last": "", "suffix": ""}], "year": 1996, "venue": "Admin. Sci. Quart", "link": "143697560"}, "BIBREF1": {"title": "America's Best Graduate Schools", "authors": [{"first": "R", "middle": [], "last": "Morse", "suffix": ""}, {"first": "S", "middle": [], "last": "Flanigan", "suffix": ""}], "year": 2006, "venue": "U. S. News & World Report online supplement", "link": null}, "BIBREF2": {"title": "Research-Doctorate Programs in the United States: Continuity and Change", "authors": [{"first": "B", "middle": [], "last": "Maher", "suffix": ""}], "year": 1995, "venue": "", "link": "202970458"}, "BIBREF3": {"title": "Our Academic Life: Challenges Facing i-Schools", "authors": [{"first": "H", "middle": [], "last": "Annabi", "suffix": ""}, {"first": "K", "middle": [], "last": "Fisher", "suffix": ""}, {"first": "J.-E", "middle": [], "last": "Mai", "suffix": ""}], "year": 2005, "venue": "", "link": null}, "BIBREF4": {"title": "Split Down the Middle, Fuzzy at the Edges: Defining a Field Epiphenomenally", "authors": [{"first": "G", "middle": [], "last": "Leazer", "suffix": ""}], "year": 2005, "venue": "", "link": null}, "BIBREF5": {"title": "I-Conference Identity and Issues Survey Summary", "authors": [{"first": "M", "middle": [], "last": "Tyworth", "suffix": ""}, {"first": "S", "middle": [], "last": "Sawyer", "suffix": ""}], "year": 2005, "venue": "", "link": null}, "BIBREF6": {"title": "Nothing at the Center? : Academic Legitimacy in the Information Systems Field", "authors": [{"first": "K", "middle": [], "last": "Lyytinen", "suffix": ""}, {"first": "J", "middle": ["L"], "last": "King", "suffix": ""}], "year": 2004, "venue": "J. Assoc. Inform. Syst", "link": null}, "BIBREF7": {"title": "Departmental Conditions and the Emergence of New Disciplines: Two Cases in the Legitimation of African-American Studies", "authors": [{"first": "M", "middle": [], "last": "Small", "suffix": ""}], "year": 1999, "venue": "Theor. Soc", "link": "141375037"}, "BIBREF8": {"title": "Hiring Practices in Finance Education. Linkages Among Top-Ranked Graduate Programs", "authors": [{"first": "J", "middle": [], "last": "Bair", "suffix": ""}], "year": 2003, "venue": "Am. J. Econ. Sociol", "link": "141652985"}, "BIBREF9": {"title": "Prestige Determinants of First Academic Job for New Sociology Ph.D.s 1985-1992", "authors": [{"first": "S", "middle": [], "last": "Baldi", "suffix": ""}], "year": 1995, "venue": "Sociol. Quart", "link": "145308831"}, "BIBREF10": {"title": "The Academic Caste System: Prestige Hierarchies in PhD Exchange Networks", "authors": [{"first": "V", "middle": [], "last": "Burris", "suffix": ""}], "year": 2004, "venue": "Am. Sociol. Rev", "link": "143724478"}, "BIBREF11": {"title": "Entrance into the Academic Career", "authors": [{"first": "J", "middle": [], "last": "Long", "suffix": ""}, {"first": "P", "middle": [], "last": "Allison", "suffix": ""}, {"first": "R", "middle": [], "last": "Mcginnis", "suffix": ""}], "year": 1979, "venue": "Am. Sociol. Rev", "link": "144186325"}, "BIBREF12": {"title": "Academic Stratification in Graduate Management Programs: Departmental Prestige and Faculty Hiring Patterns", "authors": [{"first": "A", "middle": [], "last": "Bedeian", "suffix": ""}, {"first": "H", "middle": [], "last": "Feild", "suffix": ""}], "year": 1980, "venue": "J. Manage", "link": "145727397"}, "BIBREF13": {"title": "Content, Process and the Matthew Effect Among Management Academics", "authors": [{"first": "J", "middle": [], "last": "Hunt", "suffix": ""}, {"first": "J", "middle": [], "last": "Blair", "suffix": ""}], "year": 1987, "venue": "J. Manage", "link": "144715525"}, "BIBREF14": {"title": "Productivity and Academic Position in the Scientific Career", "authors": [{"first": "J", "middle": [], "last": "Long", "suffix": ""}], "year": 1978, "venue": "Am. Sociol. Rev", "link": "143740640"}, "BIBREF15": {"title": "Organizational Context and Scientific Productivity", "authors": [{"first": "J", "middle": [], "last": "Long", "suffix": ""}, {"first": "R", "middle": [], "last": "Mcginnis", "suffix": ""}], "year": 1981, "venue": "Am. Sociol. Rev", "link": "145498927"}, "BIBREF17": {"title": "Ranking the research productivity of library and information science faculty and schools: An evaluation of data sources and research methods", "authors": [{"first": "L", "middle": [], "last": "Meho", "suffix": ""}, {"first": "K", "middle": [], "last": "Spurgin", "suffix": ""}], "year": 2005, "venue": "J. Am. Soc. Inf. Sci. Tec", "link": "15015469"}, "BIBREF18": {"title": "Scaling phenomena in the growth dynamics of scientific output", "authors": [{"first": "K", "middle": [], "last": "Matia", "suffix": ""}], "year": 2005, "venue": "J. Am. Soc. Inf. Sci. Tec", "link": "14892817"}, "BIBREF19": {"title": "Research-Doctorate Programs in the United States: Continuity and Change", "authors": [{"first": "B", "middle": ["A"], "last": "Maher", "suffix": ""}], "year": 1995, "venue": "", "link": "202970458"}, "BIBREF20": {"title": "A Mathematical Theory of Communication", "authors": [{"first": "C", "middle": [], "last": "Shannon", "suffix": ""}], "year": 1948, "venue": "AT&T Tech. J", "link": null}, "BIBREF21": {"title": "Identity and Search in Social Networks", "authors": [{"first": "D", "middle": [], "last": "Watts", "suffix": ""}, {"first": "P", "middle": [], "last": "Dodds", "suffix": ""}, {"first": "M", "middle": [], "last": "Newman", "suffix": ""}], "year": 2002, "venue": "Science", "link": "466762"}}, "ref_entries": {}}
{"paper_id": "2873661", "_pdf_hash": "fc064992a163d395feadd0eb434b98e7a2053697", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Produktionswirtschaft, R. Oldenburg Verlag", "authors": [{"first": "H", "middle": [], "last": "Corsten", "suffix": ""}], "year": 2000, "venue": "", "link": null}, "BIBREF1": {"title": "Federal Statistical Office 2012. Statistisches Jahrbuch. Available at", "authors": [], "year": 2013, "venue": "", "link": null}, "BIBREF2": {"title": "Bev\u00f6lkerung Deutschlands bis 2060", "authors": [], "year": 2009, "venue": "Federal Statistical Office", "link": null}, "BIBREF3": {"title": "Wie die Intelligenz in die Produktion kommt", "authors": [{"first": "J", "middle": [], "last": "Gausemeier", "suffix": ""}, {"first": "", "middle": [], "last": "Bitkom", "suffix": ""}, {"first": "", "middle": [], "last": "Vdma", "suffix": ""}, {"first": "", "middle": [], "last": "Zvei: Zukunftsstrategie", "suffix": ""}], "year": 2013, "venue": "", "link": null}, "BIBREF4": {"title": "Integrierte Forschungsagenda Cyber-Physical Systems, acatech Studie", "authors": [{"first": "E", "middle": [], "last": "Geisberger", "suffix": ""}, {"first": "M", "middle": [], "last": "Broy", "suffix": ""}], "year": 2012, "venue": "", "link": null}, "BIBREF5": {"title": "Was hinter Begriffen wie Industrie 4.0 steckt", "authors": [{"first": "J", "middle": [], "last": "Jasperneite", "suffix": ""}], "year": 2012, "venue": "Computer & Automation. Available at", "link": null}, "BIBREF6": {"title": "Recommendations for implementing the strategic initiative Industrie 4.0 -Final report", "authors": [{"first": "H", "middle": [], "last": "Kagermann", "suffix": ""}, {"first": "W", "middle": [], "last": "Wahlster", "suffix": ""}, {"first": "J", "middle": [], "last": "Helbig", "suffix": ""}], "year": 2013, "venue": "April", "link": null}, "BIBREF7": {"title": "Industrie 4.0: eine Revolution, die nicht aufzuhalten ist", "authors": [{"first": "D", "middle": [], "last": "Kempf", "suffix": ""}], "year": 2013, "venue": "", "link": null}, "BIBREF9": {"title": "Vernetzte Prozesse unterst\u00fctzen den intelligenten Entscheider", "authors": [{"first": "G", "middle": [], "last": "Schuh", "suffix": ""}], "year": 2013, "venue": "ZWF Zeitschrift f\u00fcr wirtschaftlichen Fabrikbetrieb", "link": null}, "BIBREF10": {"title": "Maschinenbau in Zahl und Bild", "authors": [], "year": 2013, "venue": "VDMA 2013", "link": null}, "BIBREF11": {"title": "Industry 4.0 -From Smart Factories to Smart Products", "authors": [{"first": "W", "middle": [], "last": "Wahlster", "suffix": ""}], "year": 2012, "venue": "April", "link": null}, "BIBREF12": {"title": "Die modulare Fabrik -Kundennahe Produktion durch Fertigungsoptimierung", "authors": [{"first": "H", "middle": [], "last": "Wildemann", "suffix": ""}], "year": 1998, "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "2874018", "_pdf_hash": "74394af623a10a905eb2cf99991c9fc25823ea71", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Methods of discovery: Heuristics for the social sciences", "authors": [{"first": "A", "middle": [], "last": "Abbott", "suffix": ""}], "year": 2004, "venue": "", "link": null}, "BIBREF1": {"title": "Making love in the network closet: the benefits and work of family videochat", "authors": [{"first": "M", "middle": ["G"], "last": "Ames", "suffix": ""}, {"first": "J", "middle": [], "last": "Go", "suffix": ""}, {"first": "J", "middle": ["J"], "last": "Kaye", "suffix": ""}, {"first": "M", "middle": [], "last": "Spasojevic", "suffix": ""}], "year": 2010, "venue": "Proceedings of the 2010 ACM conference on Computer supported cooperative work", "link": "37245035"}, "BIBREF2": {"title": "Situated privacies: Do you know where your mother [trucker] is?", "authors": [{"first": "K", "middle": [], "last": "Anderson", "suffix": ""}, {"first": "P", "middle": [], "last": "Dourish", "suffix": ""}], "year": 2005, "venue": "Proceedings of HCI International", "link": null}, "BIBREF3": {"title": "Technology as an occasion for structuring: Evidence from observations of CT Scanners and the social order of radiology departments", "authors": [{"first": "S", "middle": [], "last": "Barley", "suffix": ""}], "year": 1986, "venue": "Administrative Science Quarterly", "link": "15613465"}, "BIBREF4": {"title": "The alignment of technology and structure through roles and ritual", "authors": [{"first": "S", "middle": [], "last": "Barley", "suffix": ""}], "year": 1990, "venue": "Administrative Science Quarterly", "link": null}, "BIBREF5": {"title": "Wireless world: Social and interactional aspects of the mobile age", "authors": [{"first": "B", "middle": [], "last": "Brown", "suffix": ""}, {"first": "N", "middle": [], "last": "Green", "suffix": ""}, {"first": "R", "middle": [], "last": "Harper", "suffix": ""}], "year": 2002, "venue": "", "link": null}, "BIBREF6": {"title": "Information as thing", "authors": [{"first": "M", "middle": ["K"], "last": "Buckland", "suffix": ""}], "year": 1991, "venue": "Journal of the American Society for Information Science", "link": "6020947"}, "BIBREF7": {"title": "Changing patterns or patterns of change: The effects of a change in technology on social network structure and power", "authors": [{"first": "M", "middle": ["E"], "last": "Burkhardt", "suffix": ""}, {"first": "D", "middle": ["J"], "last": "Brass", "suffix": ""}], "year": 1990, "venue": "Administrative Science Quarterly", "link": "53664229"}, "BIBREF8": {"title": "Constructing grounded theory", "authors": [{"first": "K", "middle": [], "last": "Charmaz", "suffix": ""}], "year": 2006, "venue": "", "link": "142264655"}, "BIBREF9": {"title": "Theoretical frameworks for the study of structuring processes in group decision support systems", "authors": [{"first": "N", "middle": ["S"], "last": "Contractor", "suffix": ""}, {"first": "D", "middle": ["R"], "last": "Seibold", "suffix": ""}], "year": 1993, "venue": "Human Communication Research", "link": "2005487"}, "BIBREF10": {"title": "Basics of qualitative research: Techniques and procedures for developing grounded theory", "authors": [{"first": "J", "middle": ["M"], "last": "Corbin", "suffix": ""}, {"first": "A", "middle": ["L"], "last": "Strauss", "suffix": ""}], "year": 2008, "venue": "", "link": "142754635"}, "BIBREF11": {"title": "On the move: Mobility in the modern Western world", "authors": [{"first": "T", "middle": [], "last": "Cresswell", "suffix": ""}], "year": 2006, "venue": "", "link": "141150739"}, "BIBREF12": {"title": "Toward a geography of a world without maps: Lessons from Ptolemy and postal codes", "authors": [{"first": "M", "middle": ["R"], "last": "Curry", "suffix": ""}], "year": 2005, "venue": "Annals of the Association of American Geographers", "link": "42902824"}, "BIBREF13": {"title": "Divining a digital future: Mess and mythology in ubiquitous computing", "authors": [{"first": "P", "middle": [], "last": "Dourish", "suffix": ""}, {"first": "G", "middle": [], "last": "Bell", "suffix": ""}], "year": 2011, "venue": "", "link": "20631727"}, "BIBREF14": {"title": "Media as material: Information representations as material foundations for organizational practice", "authors": [{"first": "P", "middle": [], "last": "Dourish", "suffix": ""}, {"first": "M", "middle": [], "last": "Mazmanian", "suffix": ""}], "year": 2011, "venue": "Third International Symposium on Process Organization Studies", "link": "156884064"}, "BIBREF15": {"title": "Participatory GIS -A people's GIS?", "authors": [{"first": "C", "middle": ["E"], "last": "Dunn", "suffix": ""}], "year": 2007, "venue": "Progress in Human Geography", "link": "15483271"}, "BIBREF16": {"title": "Video conferencing as a technology to support group work: a review of its failures", "authors": [{"first": "C", "middle": [], "last": "Egido", "suffix": ""}], "year": 1988, "venue": "Proceedings of the 1988 ACM Conference on Computer-Supported Cooperative Work", "link": "17504327"}, "BIBREF17": {"title": "Contemporary field research: Perspectives and formulations", "authors": [{"first": "R", "middle": ["M"], "last": "Emerson", "suffix": ""}], "year": 2001, "venue": "", "link": "143206583"}, "BIBREF18": {"title": "Strategies for interpreting qualitative data", "authors": [{"first": "M", "middle": ["S"], "last": "Feldman", "suffix": ""}], "year": 1995, "venue": "", "link": "152377267"}, "BIBREF19": {"title": "Information in organizations as signal and symbol", "authors": [{"first": "M", "middle": ["S"], "last": "Feldman", "suffix": ""}, {"first": "J", "middle": ["G"], "last": "March", "suffix": ""}], "year": 1981, "venue": "Administrative Science Quarterly", "link": "145539616"}, "BIBREF20": {"title": "Our biometric future: Facial recognition technology and the culture of surveillance", "authors": [{"first": "K", "middle": [], "last": "Gates", "suffix": ""}], "year": 2011, "venue": "", "link": "106681214"}, "BIBREF21": {"title": "Examining the computing and centralization debate", "authors": [{"first": "J", "middle": ["F"], "last": "George", "suffix": ""}, {"first": "J", "middle": ["L"], "last": "King", "suffix": ""}], "year": 1991, "venue": "Communications of the ACM", "link": "13847358"}, "BIBREF22": {"title": "Overseers of the poor: Surveillance, resistance, and the limits of privacy", "authors": [{"first": "J", "middle": [], "last": "Gilliom", "suffix": ""}], "year": 2001, "venue": "", "link": "144894562"}, "BIBREF23": {"title": "Software-sorted geographies", "authors": [{"first": "S", "middle": ["D N"], "last": "Graham", "suffix": ""}], "year": 2005, "venue": "Progress in Human Geography", "link": "19119278"}, "BIBREF24": {"title": "The computer game: Detectives, suspects, and technology", "authors": [{"first": "R", "middle": ["R"], "last": "Harper", "suffix": ""}], "year": 1991, "venue": "British Journal of Criminology", "link": null}, "BIBREF25": {"title": "Distributed work", "authors": [{"first": "P", "middle": [], "last": "Hinds", "suffix": ""}, {"first": "S", "middle": [], "last": "Kiesler", "suffix": ""}], "year": 2002, "venue": "", "link": "169968922"}, "BIBREF26": {"title": "Personal, portable, pedestrian: Mobile phones in Japanese life", "authors": [{"first": "M", "middle": [], "last": "Ito", "suffix": ""}, {"first": "D", "middle": [], "last": "Okabe", "suffix": ""}, {"first": "", "middle": [], "last": "Matsuda", "suffix": ""}], "year": 2005, "venue": "", "link": "106623606"}, "BIBREF27": {"title": "Semiotics and the social analysis of material things", "authors": [{"first": "W", "middle": [], "last": "Keane", "suffix": ""}], "year": 2003, "venue": "Language & Communication", "link": "11858855"}, "BIBREF28": {"title": "Information in organizations: Directions for information management", "authors": [{"first": "J", "middle": [], "last": "Kirk", "suffix": ""}], "year": 1999, "venue": "Information Research", "link": null}, "BIBREF29": {"title": "Computerization movements and the mobilization of support for computerization", "authors": [{"first": "R", "middle": [], "last": "Kling", "suffix": ""}, {"first": "S", "middle": [], "last": "Iacono", "suffix": ""}], "year": 1988, "venue": "Ecologies of knowledge", "link": "151194881"}, "BIBREF30": {"title": "Materiality and change: Challenges to building better theory about technology and organizing. Information and Organization", "authors": [{"first": "P", "middle": ["M"], "last": "Leonardi", "suffix": ""}, {"first": "S", "middle": ["R"], "last": "Barley", "suffix": ""}], "year": 2008, "venue": "", "link": null}, "BIBREF31": {"title": "Waste Managers? The New Penology, Crime Fighting, and Parole Agent Identity", "authors": [{"first": "M", "middle": [], "last": "Lynch", "suffix": ""}], "year": 1998, "venue": "Law & Society Review", "link": "144464087"}, "BIBREF32": {"title": "Rehabilitation as Rhetoric The Ideal of Reformation in Contemporary Parole Discourse and Practices", "authors": [{"first": "M", "middle": [], "last": "Lynch", "suffix": ""}], "year": 2000, "venue": "", "link": "146497261"}, "BIBREF33": {"title": "Semiotics and Fieldwork. Thousand Oaks: Sage", "authors": [{"first": "P", "middle": ["K"], "last": "Manning", "suffix": ""}], "year": 1987, "venue": "", "link": null}, "BIBREF34": {"title": "Technological dramas and the police: Statement and counterstatement in organizational analysis", "authors": [{"first": "P", "middle": ["K"], "last": "Manning", "suffix": ""}], "year": 1992, "venue": "Criminology", "link": "143595268"}, "BIBREF36": {"title": "Capital: A critique of political economy", "authors": [{"first": "K", "middle": [], "last": "Marx", "suffix": ""}], "year": 1976, "venue": "", "link": "154932033"}, "BIBREF37": {"title": "Mapping the futures: Local cultures, global change", "authors": [{"first": "D", "middle": [], "last": "Massey", "suffix": ""}], "year": 1993, "venue": "", "link": "145495725"}, "BIBREF38": {"title": "Avoiding the trap of constant connectivity: When congruent frames allow for heterogeneous practices", "authors": [{"first": "M", "middle": [], "last": "Mazmanian", "suffix": ""}], "year": 2013, "venue": "Journal", "link": "145449996"}, "BIBREF39": {"title": "Designing ubiquitous information environments: Sociotechnical issues and challenges (pp. x, 370)", "authors": [{"first": "M", "middle": [], "last": "Mazmanian", "suffix": ""}, {"first": "W", "middle": [], "last": "Orlikowski", "suffix": ""}, {"first": "J", "middle": [], "last": "Yates", "suffix": ""}], "year": 2005, "venue": "", "link": null}, "BIBREF40": {"title": "Ubiquitous email: Individual experiences and organizational consequences of BlackBerry use", "authors": [{"first": "M", "middle": [], "last": "Mazmanian", "suffix": ""}, {"first": "W", "middle": [], "last": "Orlikowski", "suffix": ""}, {"first": "J", "middle": [], "last": "Yates", "suffix": ""}], "year": 2006, "venue": "65th Annual Meeting of the Academy of Management", "link": "168038158"}, "BIBREF41": {"title": "The virtual moment", "authors": [{"first": "D", "middle": [], "last": "Miller", "suffix": ""}], "year": 2003, "venue": "Journal of the Royal Anthropological Institute", "link": null}, "BIBREF42": {"title": "Materiality", "authors": [{"first": "D", "middle": [], "last": "Miller", "suffix": ""}], "year": 2005, "venue": "", "link": null}, "BIBREF43": {"title": "Employee monitoring: privacy in the workplace?", "authors": [{"first": "J", "middle": ["M"], "last": "Mishra", "suffix": ""}, {"first": "S", "middle": ["M"], "last": "Crampton", "suffix": ""}], "year": 1998, "venue": "SAM Advanced Management Journal", "link": "169709280"}, "BIBREF44": {"title": "Watch us wander\": Mobile surveillance and the surveillance of mobility", "authors": [{"first": "J", "middle": ["G"], "last": "Molz", "suffix": ""}], "year": 2006, "venue": "Environment and Planning A", "link": "145772112"}, "BIBREF45": {"title": "Employee Monitoring and Computer Technology: Evaluative Surveilance V. Privacy", "authors": [{"first": "A", "middle": [], "last": "Moore", "suffix": ""}], "year": 2000, "venue": "Business Ethics Quarterly", "link": "144667706"}, "BIBREF46": {"title": "Cold Intimacies\": Community notification, satellite tracking and the ruined privacy of sex offenders", "authors": [{"first": "M", "middle": [], "last": "Nellis", "suffix": ""}], "year": 2012, "venue": "Managing privacy through accountability", "link": "133293356"}, "BIBREF47": {"title": "Community treatment and supervision of sex offenders: How it's done across the country and in California", "authors": [{"first": "M", "middle": [], "last": "Nieto", "suffix": ""}], "year": 2004, "venue": "", "link": null}, "BIBREF48": {"title": "The impact of residency restrictions on sex offenders and correctional management practices: A literature review", "authors": [{"first": "M", "middle": [], "last": "Nieto", "suffix": ""}, {"first": "D", "middle": [], "last": "Jung", "suffix": ""}], "year": 2006, "venue": "", "link": null}, "BIBREF49": {"title": "Privacy in context: Technology, policy, and the integrity of social life", "authors": [{"first": "H", "middle": ["F"], "last": "Nissenbaum", "suffix": ""}], "year": 2010, "venue": "", "link": "167651068"}, "BIBREF50": {"title": "Distance matters. Human-Computer Interaction", "authors": [{"first": "G", "middle": ["M"], "last": "Olson", "suffix": ""}, {"first": "J", "middle": ["S"], "last": "Olson", "suffix": ""}], "year": 2000, "venue": "", "link": null}, "BIBREF51": {"title": "Improvising organizational transformation over time: A situated change perspective", "authors": [{"first": "W", "middle": [], "last": "Orlikowski", "suffix": ""}], "year": 1996, "venue": "Information Systems Research", "link": "9288665"}, "BIBREF52": {"title": "Using technology and constituting structures: A practice lens for studying technology in organizations", "authors": [{"first": "W", "middle": [], "last": "Orlikowski", "suffix": ""}], "year": 2000, "venue": "Organizational Science", "link": "3276924"}, "BIBREF53": {"title": "Sociomaterial practices: Exploring technology at work. Organization Studies", "authors": [{"first": "W", "middle": [], "last": "Orlikowski", "suffix": ""}], "year": 2007, "venue": "", "link": null}, "BIBREF55": {"title": "Can electronic monitoring reduce crime for moderate to high-risk offenders", "authors": [{"first": "M", "middle": [], "last": "Renzema", "suffix": ""}, {"first": "E", "middle": [], "last": "Mayo-Wilson", "suffix": ""}], "year": 2005, "venue": "Journal of Experimental Criminology", "link": "28246856"}, "BIBREF56": {"title": "Beyond the user: Use and non-use in HCI", "authors": [{"first": "C", "middle": [], "last": "Satchell", "suffix": ""}, {"first": "P", "middle": [], "last": "Dourish", "suffix": ""}], "year": 2009, "venue": "Proceedings of the 21st Annual Conference of the Australian Computer-Human Interaction Special Interest Group: Design: Open 24/7", "link": "2194116"}, "BIBREF57": {"title": "Notes on conversational practice: Formulating place", "authors": [{"first": "E", "middle": ["A"], "last": "Schegloff", "suffix": ""}], "year": 1971, "venue": "Studies in social interaction", "link": "150791052"}, "BIBREF58": {"title": "Leakiness and creepiness in app space: User perceptions of privacy and mobile app use", "authors": [{"first": "I", "middle": [], "last": "Shklovski", "suffix": ""}, {"first": "S", "middle": [], "last": "Mainwaring", "suffix": ""}, {"first": "H", "middle": [], "last": "Sk\u00falad\u00f3ttir", "suffix": ""}, {"first": "H", "middle": [], "last": "Borgthorsson", "suffix": ""}], "year": 2014, "venue": "Proceedings of the 2014 ACM International Conference on Human Factors in Computing (CHI", "link": "11716"}, "BIBREF59": {"title": "The commodification of location: Dynamics of power in location-based systems", "authors": [{"first": "I", "middle": [], "last": "Shklovski", "suffix": ""}, {"first": "J", "middle": [], "last": "Vertesi", "suffix": ""}, {"first": "E", "middle": [], "last": "Troshynski", "suffix": ""}, {"first": "P", "middle": [], "last": "Dourish", "suffix": ""}], "year": 2009, "venue": "Proceedings of the 11th International Conference on Ubiquitous Computing", "link": "250802"}, "BIBREF60": {"title": "Poor discipline: Parole and the social control of the underclass", "authors": [{"first": "J", "middle": [], "last": "Simon", "suffix": ""}], "year": 1993, "venue": "", "link": null}, "BIBREF61": {"title": "Managing the monstrous: Sex offenders and the new penology", "authors": [{"first": "J", "middle": [], "last": "Simon", "suffix": ""}], "year": 1998, "venue": "Psychology, Public Policy, and Law", "link": "143099161"}, "BIBREF62": {"title": "Governing through crime: How the war on crime transformed American democracy and created a culture of fear", "authors": [{"first": "J", "middle": [], "last": "Simon", "suffix": ""}], "year": 2007, "venue": "", "link": "153456432"}, "BIBREF63": {"title": "Tales from the police: Rhythms of interaction with mobile technologies. Information and Organization", "authors": [{"first": "C", "middle": [], "last": "Sorensen", "suffix": ""}, {"first": "D", "middle": [], "last": "Pica", "suffix": ""}], "year": 2005, "venue": "", "link": null}, "BIBREF64": {"title": "Normal crimes: Sociological features of the penal code in a public defender office", "authors": [{"first": "D", "middle": [], "last": "Sudnow", "suffix": ""}], "year": 1965, "venue": "Social Problems", "link": "145537475"}, "BIBREF65": {"title": "BYOD: Enabling the chaos", "authors": [{"first": "G", "middle": [], "last": "Thomson", "suffix": ""}], "year": 2012, "venue": "Network Security", "link": "33401723"}, "BIBREF66": {"title": "Information aspects of new organizational designs: Exploring the non-traditional organization", "authors": [{"first": "B", "middle": [], "last": "Travica", "suffix": ""}], "year": 1998, "venue": "Journal of the American Society for Information Science", "link": "149082533"}, "BIBREF67": {"title": "Surveillance technology and the transformation of criminal justice: Monitoring sex offenders with GPS technology", "authors": [{"first": "E", "middle": [], "last": "Troshynski", "suffix": ""}], "year": 2011, "venue": "", "link": null}, "BIBREF68": {"title": "Accountabilities of presence: Reframing location-based systems", "authors": [{"first": "E", "middle": [], "last": "Troshynski", "suffix": ""}, {"first": "C", "middle": [], "last": "Lee", "suffix": ""}, {"first": "P", "middle": [], "last": "Dourish", "suffix": ""}], "year": 2008, "venue": "Proceedings of the Conference on Human Factors in Computing Systems (CHI 2008)", "link": "11811930"}, "BIBREF69": {"title": "Implementation and early outcomes for the San Diego high risk sex offender (HRSO) GPS pilot program report", "authors": [{"first": "S", "middle": [], "last": "Turner", "suffix": ""}, {"first": "J", "middle": [], "last": "Jannetta", "suffix": ""}, {"first": "J", "middle": [], "last": "Hess", "suffix": ""}, {"first": "R", "middle": [], "last": "Myers", "suffix": ""}, {"first": "R", "middle": [], "last": "Shah", "suffix": ""}, {"first": "R", "middle": [], "last": "Werth", "suffix": ""}, {"first": "A", "middle": [], "last": "Whitby", "suffix": ""}], "year": 2007, "venue": "", "link": null}, "BIBREF70": {"title": "I do what I'm told, sort of: Reformed subjects, unruly citizens, and parole", "authors": [{"first": "R", "middle": [], "last": "Werth", "suffix": ""}], "year": 2011, "venue": "Theoretical Criminology", "link": "144550707"}, "BIBREF71": {"title": "The construction and stewardship of responsible yet precarious subjects: Punitive ideology, rehabilitation, and \"tough love\" among parole personnel", "authors": [{"first": "R", "middle": [], "last": "Werth", "suffix": ""}], "year": 2013, "venue": "", "link": "144865410"}, "BIBREF72": {"title": "The power of maps", "authors": [{"first": "D", "middle": [], "last": "Wood", "suffix": ""}], "year": 1992, "venue": "", "link": null}, "BIBREF73": {"title": "In the age of the smart machine: The future of work and power", "authors": [{"first": "S", "middle": [], "last": "Zuboff", "suffix": ""}], "year": 1988, "venue": "", "link": "154805544"}}, "ref_entries": {}}
{"paper_id": "2874048", "_pdf_hash": "debf6cef6396a16a24048351d6eff568222b2edc", "abstract": [{"section": "Abstract", "text": "The study of the spread of influence through a social network has a long history in the social sciences. The first studies focused on the adoption of medical and agricultural innovations, later marketing researchers investigated the \"word-of-mouth\" diffusion process as an important mechanism by which information can reach large populations, possibly influencing public opinion, driving new product market share and brand awareness. Recently, thanks to the success of on-line social networks and microblogging platforms such as Facebook and Twitter, the phenomenon of influence exerted by users of an online social network on other users and in how it propagates in the network, has attracted the interest of computer scientists and IT specialists. One of the key problems in this area is the identification of influential users, by targeting whom certain desirable outcomes can be achieved. Here, targeting could mean giving free (or price discounted) samples of a product and the desired outcome may be to get as many customers to buy the product as possible. In this talk we take a data mining perspective and we discuss what (and how) can be learned from the available traces of past propagations. While doing this we provide a brief survey of some recent progresses in this area, as well as discuss the open problems.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Biography", "text": "Francesco Bonchi is a senior research scientist at Yahoo! Research in Barcelona, Spain, where he is part of the Web Mining Group. His recent research interests include mining query-logs, social networks, and social media, as well as the privacy issues related to mining these kinds of sensible data. In the past he has been interested in data mining query languages, constrained pattern mining, mining spatiotemporal and mobility data, and privacy preserving data mining. He is member of the ECML/PKDD Steering Committee ", "cite_spans": [], "ref_spans": []}], "bib_entries": {}, "ref_entries": {"FIGREF0": {"text": ", Yahoo! Research ambassador for academic relations with Italy, and the organizer of the Yahoo! Research Barcelona Seminars series. He has been program co-chair of the European Conference on Machine Learning and Principles and Practice of Knowledge Discovery in Databases (ECML/PKDD 2010). Dr. Bonchi has also served as program co-chair of the first and second ACM SIGKDD International Workshop on Privacy, Security, and Trust in KDD (PinKDD 2007 and 2008), the 1st IEEE International Workshop on Privacy Aspects of Data Mining (PADM 2006), and the 4th International Workshop on Knowledge Discovery in Inductive Databases (KDID 2005). He is co-editor of the book \"Privacy-Aware Knowledge Discovery: Novel Applications and New Techniques\" published by Chapman & Hall/CRC Press. Francesco Bonchi received the best paper award at WI 2009. He earned his Ph.D. in computer science from the University of Pisa in December 2003.", "type": "figure"}}}
{"paper_id": "2874113", "_pdf_hash": "36a3a3b284049187914e1c5ab6a1da1a071ac0fa", "abstract": [{"section": "Abstract", "text": "Abstract-Orthogonal frequency division multiplexing (OFDM) is a technique that will prevail in the next generation wireless communication. Channel estimation is one of the key challenges in an OFDM system. In this paper, we formulate OFDM channel estimation as a compressive sensing problem, which takes advantage of the sparsity of the channel impulse response and reduces the number of probing measurements, which in turn reduces the ADC speed needed for channel estimation. Specifically, we propose sending out pilots with random phases in order to \"spread out\" the sparse taps in the impulse response over the uniformly downsampled measurements at the low speed receiver ADC, so that the impulse response can still be recovered by sparse optimization. This contribution leads to high resolution channel estimation with low speed ADCs, distinguishing this paper from the existing attempts of OFDM channel estimation. We also propose a novel estimator that performs better than the commonly used 1 minimization. Specifically, it significantly reduces estimation error by combing 1 minimization with iterative support detection and limited-support least-squares. While letting the receiver ADC running at a speed as low as 1/16 of the speed of the transmitter DAC, we simulated various numbers of multipaths and different measurement SNRs. The proposed system has channel estimation resolution as high as the system equipped with the high speed ADCs, and the proposed algorithm provides additional 6 dB gain for signal to noise ratio.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "I. INTRODUCTION", "text": "Orthogonal frequency division multiplexing (OFDM) has been widely applied in wireless communication systems, because it transmits at a high rate, achieves high bandwidth efficiency, and is robust to multipath fading and delay [1] . OFDM applications can be found in digital television and audio broadcasting, wireless networking, and broadband internet access. Current OFDM based WLAN standards (such as IEEE802.11a/g) use variations of QAM schemes for subcarrier modulations which require a coherent detection at the OFDM receiver and consequently requires an accurate (or near accurate) estimation of Channel State Information (CSI). The structure of OFDM signal makes it difficult to balance complexity and performance in channel estimation. The design principles for channel estimators are to reduce the computational complexity and bandwidth overhead while maintaining sufficient estimation accuracy.", "cite_spans": [{"start": 226, "end": 229, "text": "[1]", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "Some channel estimation schemes proposed in literature are based on pilots, which form the reference signal used by both the transmitter and the receiver. This approach has two main challenges: (i) the design of pilots; and (ii) the design of an efficient estimation algorithm (i.e., the estimator).", "cite_spans": [], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "There is a tradeoff between the spectrum efficiency and the channel estimation accuracy. Most of the existing pilotassisted OFDM channel estimation schemes rely on the use of a large number of pilots to increase to estimation accuracy; the spectral efficiency is therefore reduced. For example, there are approaches based on time-multiplexed pilot, frequencymultiplexed pilot, and scattered pilot [2] , all achieving higher estimation accuracy at the price of using more pilots. There have been attempts to reduce the number of pilots, i.e. J. Byun et al. in [3] . The solutions generally require extra \"test signal\" for channel pre-estimation. By sending out \"test signal\", they try to find out how many pilots are needed by firstly inserting a relatively small number of pilots and then, based on the results of the \"test\", the number of pilots are decided. Therefore, there is no guaranteed overall reduction of pilots insertion.", "cite_spans": [{"start": 397, "end": 400, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 559, "end": 562, "text": "[3]", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "As a sensing problem, OFDM channel estimation can benefit from the emerging technique of compressive sensing (CS), which acquires and reconstructs a signal from fewer samples than what is dictated by the Nyquist-Shannon sampling theorem, mainly by utilizing the signal's sparse or compressible property. The field has exploded since the pioneering work by Donoho [4] and Candes, Romberg and Tao [5] . The main idea is to encode a sparse signal by taking its \"incoherent\" linear projections and recover the signal through algorithms such as 1 minimization. To maximize the benefits of CS for OFDM channel estimation, one shall skillfully perform the CS encoding and decoding steps, which are precisely the two focuses of this paper: the designs of pilots and estimator, respectively.", "cite_spans": [{"start": 363, "end": 366, "text": "[4]", "ref_id": "BIBREF4"}, {"start": 395, "end": 398, "text": "[5]", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "Contributions: CS has been applied to channel estimation in [13] [14] [15] [16] , which are reviewed in subsection III-E below. For OFDM channel estimation, there are papers [6] [7] [8] [9] , to which our work differs in various ways as follows. We skillfully design CS encoding and decoding strategies for OFDM channel estimation. Compared to existing work, we are able to obtain channel response in much higher resolutions and from much fewer pilots (thus taking much shorter times). This is achieved by designing pilots with uniform random phases and using a novel estimator. The pilot design preserves the information of high-resolution channel response during aggressive uniform down-sampling, which means that receiver ADC can run at a much lower speed. The estimator is tailored for OFDM channel response; in particular, instead of the generic 1 minimization, iterative support detection (ISD) [17] and limited-support least-squares are adopted in order to take advantage of the characteristics of channel response. The resulting algorithm is very simple and performs better.", "cite_spans": [{"start": 60, "end": 64, "text": "[13]", "ref_id": "BIBREF14"}, {"start": 65, "end": 69, "text": "[14]", "ref_id": "BIBREF15"}, {"start": 70, "end": 74, "text": "[15]", "ref_id": "BIBREF16"}, {"start": 75, "end": 79, "text": "[16]", "ref_id": "BIBREF17"}, {"start": 174, "end": 177, "text": "[6]", "ref_id": "BIBREF6"}, {"start": 178, "end": 181, "text": "[7]", "ref_id": "BIBREF7"}, {"start": 182, "end": 185, "text": "[8]", "ref_id": "BIBREF9"}, {"start": 186, "end": 189, "text": "[9]", "ref_id": "BIBREF10"}, {"start": 901, "end": 905, "text": "[17]", "ref_id": "BIBREF18"}], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "The rest of this paper is organized as follows: Section II reviews the general OFDM system model and sets up the channel estimation formulation. Section III relates channel estimation to CS and present the proposed pilot design. In Section IV, the estimator based on iterative support detection and limited-support least-squares are introduced. Section V give the simulation results. Finally, Section VI concludes this work.", "cite_spans": [], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "II. OFDM SYSTEM MODEL A baseband OFDM system is shown in Figure 1 . In this system, the modulated signal in the frequency domain, represented by X(k), k \u2208 [1, N] , is inserted with pilot signal and guard band, and then an N -point IDFT transforms the signal into the time domain, denoted by x(n), n \u2208 [1, N] , where a cyclic extension of time length T G is added to avoid inter-symbol and inter-subcarrier interferences. The resulting time series data is converted by a digital-to-analog converter (DAC) with a clock speed of 1/T S Hz into an analog signal for transmission. We assume that the channel response comprises P propagation paths, which can be modeled by a time-domain complex-baseband vector with P taps:", "cite_spans": [], "ref_spans": [{"start": 57, "end": 65, "text": "Figure 1", "ref_id": "FIGREF0"}]}, {"section": "I. INTRODUCTION", "text": "where \u03b1 p is a complex multipath component and \u03c4 p is the multipath delay (0 ", "cite_spans": [], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "where \u2297 denotes convolution and \u03be(n), n \u2208 ", "cite_spans": [], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": ", where the guard band and pilot signal will be removed. For pilot assisted OFDM channel estimation, we shall design the pilots X (and thus x) and recover h from the measurements Y (or, equivalently y).", "cite_spans": [], "ref_spans": []}, {"section": "III. COMPRESSIVE SENSING OFDM CHANNEL ESTIMATION", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "A. Motivations", "text": "CS, which will be reviewed in the next subsection, allows sparse signals to be recovered from very few measurements, which translates to slower sampling rates and shorter sensing times. Because the channel impulse response h is very sparse, we are motivated to apply CS to recover h by using a reduced number of pilots so that the estimation becomes much quicker. Furthermore, in sharp contrast to conventional OFDM channel estimation in which ADC and DAC run at the same sampling rate, we can obtain a higher-resolution h by increasing the sampling rate of only the transmitter DAC, or we can reduce the receiver ADC speed which often defines the system cost. In other words, we have N > M. The rest of this section reviews CS and introduces our proposed approach for OFDM channel estimation.", "cite_spans": [], "ref_spans": []}, {"section": "B. CS Background", "text": "CS theories [4] , [10] , [11] state that a S-sparse signal 1 h can be stably recovered from linear measurements y = \u03a6h + \u03be, where \u03a6 is a certain matrix with M rows and N columns, M < N, by minimizing the 1 -norm of h. Classical CS often assumes that \u03a6, after scaling, satisfies the restricted isometry property (RIP)", "cite_spans": [{"start": 12, "end": 15, "text": "[4]", "ref_id": "BIBREF4"}, {"start": 18, "end": 22, "text": "[10]", "ref_id": "BIBREF11"}, {"start": 25, "end": 29, "text": "[11]", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "B. CS Background", "text": "for all S-sparse h, where \u03b4 > 0 is the RIP parameter. The RIP is satisfied with a high probability by a large class of random matrices, e.g., those with entries independently sampled from a subgaussian distribution. By minimizing the 1 -norm, one can stably recover h as long as M \u2265 O(S log N ).", "cite_spans": [], "ref_spans": []}, {"section": "B. CS Background", "text": "The classical random sensing matrices are not admissible in OFDM channel estimation because the channel response h is not directly multiplied by a random matrix; instead, as describe in Section II, h is first convoluted with x, the noise is added, and then the received signal z is uniformly down-sampled to y. Because convolution is a circulant linear operator, we can present this process by y =\u2193 \u03a9 z =\u2193 \u03a9 (Ch + \u03be), where the sensing matrix C is the full circulant (convolution) matrix determined by x, and \u2193 \u03a9 denotes the uniform down sampling at points in", "cite_spans": [], "ref_spans": []}, {"section": "B. CS Background", "text": "As is widely perceived, CS favors fully random matrices, which admit stable recovery from fewest measurements (in terms of order of magnitude), but C is structured and thus much less \"random\". This factor seemingly suggests that C would be not favored by CS. Nevertheless, carefully designed circulant matrices can deliver the same optimal CS performance.", "cite_spans": [], "ref_spans": []}, {"section": "C. Pilot with Random Phases", "text": "To design the sensing matrix C, we propose to generate pilots X in either one of the following two ways: (i) the real and imaginary parts of X(k) are sampled independently from a Gaussian distribution, k = 1, . . . , N; (ii) (same as [15] ) X(k), k = 1, . . . , N, have independent random phases but a uniform amplitude. Note that X(k) of type (i) also have independent random phases. Let F denote the discrete Fourier transform. Following from the convolution theorem", "cite_spans": [{"start": 234, "end": 238, "text": "[15]", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "C. Pilot with Random Phases", "text": "F h, so the measurements y can be written as", "cite_spans": [], "ref_spans": []}, {"section": "C. Pilot with Random Phases", "text": "Let us explain intuitively why (3) is an effective encoding scheme for a sparse vector h. First, it is commonly known that F h is non-sparse and its mass is somewhat evenly spread over all its components. The random phases of X by design are of critical importance. They \"scramble\" F h component wisely and break the delicate relationships among F h's components; as a result, in contrast to the sparse", "cite_spans": [], "ref_spans": []}, {"section": "C. Pilot with Random Phases", "text": "is not sparse at all. Furthermore, X has a random-spreading effect. Due to a phenomenon called concentration of measures [12] , the mass of Ch spreads over its components in a way that, with a high probability, the information of h is preserved by down sampling of a size essentially linear in P -the sparsity of h (whether or not the down-sampling is equally spaced, i.e., uniform). Up to a log factor, the down sampled measurements permit stable 1 recovery. Both types (i) and (ii) of X have similar encoding strength, but X of type (ii) gives an orthogonal C, i.e., C * C = I, so x \u2297 h transforms h into a random orthobasis. Such orthogonality results in multiple benefits such as faster convergence of our recovery algorithm. Due to the page limitation, we omit rigorous mathematical analysis of (3) and its guaranteed recovery.", "cite_spans": [{"start": 121, "end": 125, "text": "[12]", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "C. Pilot with Random Phases", "text": "Note that the proposed sampling \u2193 \u03a9 (F \u22121 diag(X)F ) is very different from partial Fourier sampling \u2193 \u03a9 F . The latter requires a random \u03a9 to avoid the aliasing artifacts in the recovery but the former, with random-phased X, permits both random and uniform \u03a9. Below we numerically demonstrate its encoding efficiency.", "cite_spans": [], "ref_spans": []}, {"section": "D. Numerical Evidence of Effective Random Convolution", "text": "CS performance is measured by the number of measurements required for stable recovery. To compare the proposed sensing schemes with the well-established Gaussian random sensing, we conduct numerical simulations and show its results in Figure 2 . We compare three types of CS encoding matrices: the i.i.d. Gaussian random complex matrix, and the circulant random complex matrices corresponding to X of types (i) and (ii) above, respectively. In addition, 1 minimization is compared to our proposed algorithm CS-OFDM, which is detailed in the next section. The simulations results show that the random convolutions of both types perform as well as the Gaussian random sensing matrix under 1 minimization, and our algorithm CS-OFDM further improves the performance by half of a magnitude.", "cite_spans": [], "ref_spans": []}, {"section": "E. Relationship to Existing Results", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "1) Random Convolution CS:", "text": "Random convolution has been used and proved to be an effective way of taking CS measurements that allow the signal to be recovered using 1 minimization. In [13] , Toeplitz 2 measurement matrices are constructed with i.i.d random row 1 (the same as type (i)) but with only \u00b11 or {\u22121, 0, 1}; their down sampling effectively takes the first M rows; and the number of measurements needed for stable 1 ", "cite_spans": [{"start": 156, "end": 160, "text": "[13]", "ref_id": "BIBREF14"}, {"start": 395, "end": 396, "text": "1", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "recovery is shown as M \u2265 O(S 3 \u00b7 log N/S).", "text": "[14] uses a \"partial\" Toeplits matrix, with i.i.d. Bernoulli or Gaussian row 1, for sparse channel estimation where the down sampling effectively also takes the first M rows. Their scheme requires M \u2265 O(S 2 \u00b7log N ) for stable 1 recovery. In [15] , random convolution of type (ii) above with either random downsampling or random demodulation is proposed and studied. It is shown that the resulting measurement matrix is incoherent with any given sparse basis with a high probability and 1 recovery is stable given M \u2265 O(S \u00b7 log N + log 3 N ). Our proposed type (ii) is motivated by [15] . On the other hand, no existing work proposes uniform down-sampling or shows its recovery guarantees. In addition, most existing analysis is limited to real-valued matrices and signals.", "cite_spans": [{"start": 242, "end": 246, "text": "[15]", "ref_id": "BIBREF16"}, {"start": 582, "end": 586, "text": "[15]", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "2) CS-based Channel Estimation:", "text": "Our work is closely related to [14] and [16] . In [14] , i.i.d. Bernoulli or Gaussian vector is used as training sequence, and downsample is carried out by taking only the first M rows. While channel estimation is obtained as a solution to the Dantzig selector. In [16] , MIMO channels are estimated by activating all sources simultaneously. The receivers measure the cumulative response, which consists of random convolutions between multiple pairs of source signals and channel responses. Their goal is to reduce the channel estimation time. 1 minimization is used to recover channel response.", "cite_spans": [{"start": 31, "end": 35, "text": "[14]", "ref_id": "BIBREF15"}, {"start": 40, "end": 44, "text": "[16]", "ref_id": "BIBREF17"}, {"start": 50, "end": 54, "text": "[14]", "ref_id": "BIBREF15"}, {"start": 265, "end": 269, "text": "[16]", "ref_id": "BIBREF17"}], "ref_spans": []}, {"section": "2) CS-based Channel Estimation:", "text": "Our current work is limited to estimating a signal h-vector. While our work is based on similar random convolution techniques, we have proposed to use a pair of high-speed source and low-speed receiver for the novel goal of high resolution channel estimation. Furthermore, we apply a novel algorithm for the channel response recovery based on iterative support detection and limited-support least-squares, which is described in details in Section IV below.", "cite_spans": [], "ref_spans": []}, {"section": "IV. NUMERICAL ALGORITHM", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "A. Problem Formulation", "text": "As a result of rapid decaying of wireless channels, P -the number of significant multipaths -is small, so the channel response h is a highly sparse signal. Recall that the nonzero components of h only appear in the first\u00d1 components. We shall recover a sparse high-resolution signal h with a constraint from the measurements y at a lower resolution of M . We define operation | \u00b7 | as the amplitude of a complex number, h 0 as the total number of nonzeros of |h| and", "cite_spans": [], "ref_spans": []}, {"section": "A. Problem Formulation", "text": "where \u03c6 denotes \u2193 \u03a9 C in (3), the submatrix of C formed by its rows corresponding to the down-sampling points in \u03a9.", "cite_spans": [], "ref_spans": []}, {"section": "A. Problem Formulation", "text": "Generally speaking, problem (4) is NP-hard and is impossible to solve even for moderate N . A common alternative is its 1 relaxation model with the same constraints.", "cite_spans": [], "ref_spans": []}, {"section": "A. Problem Formulation", "text": "which is convex and has polynomial time algorithms. If y has no noise, both (4) and (5) can recover h exactly given enough measurements, but (5) requires more measurements than (4).", "cite_spans": [], "ref_spans": []}, {"section": "B. Algorithm", "text": "Instead of using a generic algorithm for (5), we design an algorithm to exploit the OFDM system features, including the special structure of h and noisy measurements y. At the same time, we maintain its simplicity to achieve low complexity and match with easy hardware implementation.", "cite_spans": [], "ref_spans": []}, {"section": "B. Algorithm", "text": "First of all, we can simply collaborate two constraints into one by letting the variables beh = [h 1 , h 2 , . . . , h\u00d1 ] and dropping the rest components of h. Let\u03c6 be the matrix formed by first\u00d1 columns of \u03c6. Hence, the only constraints ar\u1ebd \u03c6h = y, which reduces the size of our problem.", "cite_spans": [], "ref_spans": []}, {"section": "B. Algorithm", "text": "We also develop our algorithm CS-OFDM for the purpose of handling noisy measurements. The iterative support detection (ISD) scheme proposed in [17] has a very good performance for solving (5) even with noisy measurements. Our algorithm uses the ISD, as well as a final denoising step. In the main iterative loop, it estimates a support set I from the current reconstruction and reconstructs a new candidate solution by solving the minimization problem min{ i\u2208I c |h i | :\u03c6h = y}, and it iterates these two steps for a small number of iterations. The idea of iteratively updating the index set I helps catch missing spikes and erase fake spikes. This is an 1 -based method but outperforms 1 . Analysis and numerical performance of ISD can be found in [18] . Because the measurements have noise, so reconstruction is never exact. Our algorithm ", "cite_spans": [{"start": 143, "end": 147, "text": "[17]", "ref_id": "BIBREF18"}, {"start": 750, "end": 754, "text": "[18]", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "B. Algorithm", "text": "Returnh uses a final denoising step, which solves least-squares over the final support T , to eliminate tiny spikes likely due to noise. Our pseudocode is listed in Algorithm 1. In Algorithm 1, at each iteration j, (6) solves a weighted 1 problem, and the solution h j is used for support detection to generate a new I j+1 . After the main loop is done, a support T is estimated above a threshold, which is selected based on empirical experiences. If the support detection is executed successfully, T would be the set of all channel multipath delay. Finally,h is constructed by solving a small least-squares problem, andh i , \u2200i \u2208 T fall to zero.", "cite_spans": [], "ref_spans": []}, {"section": "C. Complexity Analysis", "text": "This algorithm is efficient since every step is simple and the total number of iterations needed is small. The subproblem is a standard weighted 1 minimization problem, which can be solved by various 1 solvers. Since \u03c6 is a convolution operator, we choose YALL1 [19] since (i) it allows us to customize the operators involving\u03c6 and its adjoint to take advantages of DFTs, making it easier to implement the algorithm on hardware, (ii) YALL1 is asymptotically geometrically convergent and efficient even when the measurements are noisy. With our customization, all YALL1 operations are either an DFT/IDFT or one dimensional vector operations, so the overall complexity is O (N log N ) . Moreover, for support detection, we run YALL1 with a more forgiving stopping tolerance and always restart it from the last step solution. Furthermore, YALL1 converges faster as the index I j gets closer to the true support. The total number of YALL1 calls is also small since the detect support threshold decays exponentially and bounded below by a positive number. Numerical experience shows that the total number of YALL1 calls never exceeds P . The computational cost of the final least-squares step is negligible because the associated matrix\u03c6 T has its number of columns approximately equal to the number of spikes in h, which is far less than its rows. For example, if the system has P multipaths, the associated matrix for least-squares has size M \u00d7 P . Generally speaking, the complexity for this leastsquares is O(MP + P 3 ). Since P and M are much smaller than N , the complexity of the entire algorithm is dominated by that of YALL1, which O(N log N ).", "cite_spans": [{"start": 262, "end": 266, "text": "[19]", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "V. NUMERICAL SIMULATIONS", "text": "In this section, we perform numerical simulations to illustrate the performance of the proposed CS-OFDM algorithm for high resolution OFDM channel estimation. We focus on the mean square error (MSE) of channel estimation as well as the multipath delay detection when channel profile and signal to noise ratio (SNR) changes.", "cite_spans": [], "ref_spans": []}, {"section": "A. Simulation Settings", "text": "We consider an OFDM system with 1k-point IDFT (N = 1024) at the transmitter and 64-point DFT (M = 64) at the receiver, where we have a compression ratio of 16. The number of silent sub-carrier which acts as guard band is 256 among 1024 sub-carriers. The channel is estimated based on 768 pilot tones with uniformly random phases and a unit amplitude, with the Gaussian noise level ranging from 10 dB to 30 dB. We assume the usage of cyclic prefix and the impulse response of the channel is shorter than cyclic prefix which means there is no inter-symbol interference. For all simulations, we test the total numbers of multipath from 5 to 15. Moreover, we use only one OFDM symbol, i.e. use all non-silent subcarriers only once to carry pilot signals. All reported performances will substantially improve if more pilots are inserted. Figure 3 is a snapshot of one channel estimation simulation. It suggests that the proposed pilot arrangement and CS-OFDM successfully detect an OFDM channel with 7 multipaths when the signal to noise ratio is 30 dB. Our method not only exactly estimates the multipath delays, but also correctly estimates the values of the corresponding multipath components. Figure 4 depicts the MSE performance on OFDM channels with the number of multipaths ranging from 5 to 15 and noise level ranging from 10 dB to 30 dB. When there are only a moderate number of multipaths on the OFDM channel, e.g. 10 multipaths, even when SNR is 20 dB, MSE is as low as \u221217 dB. Figure 5 shows the reconstructed SNR vs. the number of multipaths when the input SNR changes. We can see that CS-OFDM achieves a gain in SNR. For example, when the input SNR is 10 dB, we obtain a reconstructed SNR higher than 20 dB when there are 5 multipaths. As the number of multipaths increases, the SNR gain from the reconstructed signal to the input signal decreases. However, even when the number of multipaths is 10, we still have a 5 dB gain, e.g. reconstructed SNR is 15 dB when the input signal SNR is 10 dB. The similar SNR gain appears for input SNR= 20 dB and SNR= 30 dB cases. From the entire input SNR and the number of multipath range we have tested, there is an average gain of 6 dB from the input SNR to the recovered SNR. Figure 6 and Figure 7 depict the probability of correct detection (POD) of the multipath delay and the false detection rate (FAR) while we change the SNR and the number of multipaths. When the SNR is above 10 dB, simulation shows almost 100% POD when the number of multipaths changing from 5 to 12. When there is a relatively large number of multipaths, e.g. 15, the probability of correct multipath delay detection is higher than 95% as SNR\u2265 10 dB. Even when SNR is low, as long as the number of multipaths does not exceed 10, we still have a POD of greater than 95%. The FAR performance shows the similar results, as the SNR decreases and the number of multipaths increases, performance decreases. But, in a large range, e.g. SNR\u2265 10 dB, the number of multipath\u2264 10, we have almost zero FAR.", "cite_spans": [], "ref_spans": [{"start": 833, "end": 841, "text": "Figure 3", "ref_id": "FIGREF4"}, {"start": 1192, "end": 1200, "text": "Figure 4", "ref_id": "FIGREF5"}, {"start": 1484, "end": 1492, "text": "Figure 5", "ref_id": "FIGREF7"}, {"start": 2226, "end": 2234, "text": "Figure 6", "ref_id": "FIGREF8"}]}, {"section": "B. MSE Performance", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "C. Multipath Delay Detection Performance", "text": "VI. CONCLUSIONS Efficient OFDM channel estimation will drive OFDM to carry the future of wireless networking. A great opportunity for high-efficiency OFDM channel estimation is lent by the sparse nature of channel response. Riding on the recent development of CS, we propose a design of probing pilots with random phases, which preserves the information of channel response during the convolution and down-sampling processes, and a sparse recovery algorithm, which returns the channel response in high SNR. These benefits translate to the high resolution of channel estimation, the lower speed of the receiver ADC, as well as shorter probing times. In this paper, the presentation is limited to an idealized OFDM model, intuitive explanations, and simulated experiments. In the future, we will formalize the work with rigorous theorems and fuse it into more realistic OFDM frameworks. The results presented here hint a high efficiency improvement for OFMD in practice.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "An introduction to orthogonal frequency division multiplexing", "authors": [{"first": "O", "middle": [], "last": "Edfors", "suffix": ""}, {"first": "M", "middle": [], "last": "Sandell", "suffix": ""}, {"first": "J.-J", "middle": [], "last": "Van De Beek", "suffix": ""}, {"first": "D", "middle": [], "last": "Landstr\u00f6m", "suffix": ""}, {"first": "F", "middle": [], "last": "Sj\u00f6berg", "suffix": ""}], "year": 1996, "venue": "", "link": null}, "BIBREF1": {"title": "Pilot-assisted adaptive interpolation channel estimation for OFDM signal reception", "authors": [{"first": "S", "middle": [], "last": "Takaoka", "suffix": ""}, {"first": "F", "middle": [], "last": "Adachi", "suffix": ""}], "year": 2004, "venue": "proceedings of Vehicular Technology Conference", "link": "16736066"}, "BIBREF2": {"title": "False Alarm Rate Vs. No. of Multipath @ Different SNR No. of Multipath", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF3": {"title": "Adaptive pilot utilization for OFDM channel estimation in a time varying channel", "authors": [{"first": "J", "middle": [], "last": "Byun", "suffix": ""}, {"first": "N", "middle": ["P"], "last": "Natarajan", "suffix": ""}], "year": 2009, "venue": "proceedings of Wireless and Microwave Technology Conference", "link": "24056319"}, "BIBREF4": {"title": "Compressed sensing", "authors": [{"first": "D", "middle": [], "last": "Donoho", "suffix": ""}], "year": 2006, "venue": "IEEE Trans. on Information Theory", "link": "206737254"}, "BIBREF5": {"title": "Stable signal recovery from incomplete and inaccurate measurements", "authors": [{"first": "E", "middle": [], "last": "Candes", "suffix": ""}, {"first": "J", "middle": [], "last": "Romberg", "suffix": ""}, {"first": "T", "middle": [], "last": "Tao", "suffix": ""}], "year": "", "venue": "Communications On Pure and Applied Mathematics", "link": "119159284"}, "BIBREF6": {"title": "Compressed sensing for OFDM/MIMO radar", "authors": [{"first": "C", "middle": ["R"], "last": "Berger", "suffix": ""}, {"first": "S", "middle": [], "last": "Zhou", "suffix": ""}, {"first": "P", "middle": [], "last": "Willett", "suffix": ""}, {"first": "B", "middle": [], "last": "Demissie", "suffix": ""}, {"first": "J", "middle": [], "last": "Heckenbach", "suffix": ""}], "year": 2008, "venue": "proceedings of the 42nd Annual Asilomar Conference on Signals, Systems and Computers, CA", "link": "18594323"}, "BIBREF7": {"title": "Signal extraction using compressed sensing for passive radar with OFDM signals", "authors": [{"first": "C", "middle": ["R"], "last": "Berger", "suffix": ""}, {"first": "S", "middle": [], "last": "Zhou", "suffix": ""}, {"first": "P", "middle": [], "last": "Willett", "suffix": ""}], "year": "", "venue": "", "link": "3144079"}, "BIBREF8": {"title": "on Information Fusion", "authors": [{"first": "", "middle": [], "last": "Int", "suffix": ""}, {"first": "", "middle": [], "last": "Conf", "suffix": ""}], "year": 2008, "venue": "", "link": null}, "BIBREF9": {"title": "A compressed sensing technique for OFDM channel estimation in mobile environments: exploiting channel sparsity for reducing pilots", "authors": [{"first": "G", "middle": [], "last": "Taub\u00f6ck", "suffix": ""}, {"first": "F", "middle": [], "last": "Hlawatsch", "suffix": ""}], "year": 2008, "venue": "proceedings of IEEE Int. Conf. on Acoustics, Speech, and Signal Processing (ICASSP)", "link": "8063574"}, "BIBREF10": {"title": "Sparse channel estimation for OFDM: over-complete dictionaries and super-resolution methods", "authors": [{"first": "C", "middle": ["R"], "last": "Berger", "suffix": ""}, {"first": "S", "middle": [], "last": "Zhou", "suffix": ""}, {"first": "W", "middle": [], "last": "Chen", "suffix": ""}, {"first": "Peter", "middle": [], "last": "Willett", "suffix": ""}], "year": 2009, "venue": "proceedings of IEEE Intl. Workshop on Signal Process. Advances in Wireless Comm", "link": "9986467"}, "BIBREF11": {"title": "Robust uncertainty principles: exact signal reconstruction from highly incomplete frequency information", "authors": [{"first": "E", "middle": [], "last": "Candes", "suffix": ""}, {"first": "J", "middle": [], "last": "Romberg", "suffix": ""}, {"first": "T", "middle": [], "last": "Tao", "suffix": ""}], "year": 2006, "venue": "IEEE Trans. on Information Theory", "link": "7033413"}, "BIBREF12": {"title": "Near optimal signal recovery from random projections: universal encoding strategies", "authors": [{"first": "E", "middle": [], "last": "Candes", "suffix": ""}, {"first": "T", "middle": [], "last": "Tao", "suffix": ""}], "year": 2006, "venue": "IEEE Trans. on Information Theory", "link": "1431305"}, "BIBREF13": {"title": "The Concentration of Measure Phenomenon", "authors": [{"first": "Michel", "middle": [], "last": "Ledoux", "suffix": ""}], "year": 2001, "venue": "", "link": "117088211"}, "BIBREF14": {"title": "Toeplitz-structures compressed sensing matrices", "authors": [{"first": "W", "middle": ["U"], "last": "Bajwa", "suffix": ""}, {"first": "J", "middle": ["D"], "last": "Haupt", "suffix": ""}, {"first": "G", "middle": ["M"], "last": "Raz", "suffix": ""}, {"first": "S", "middle": ["J"], "last": "Wright", "suffix": ""}, {"first": "R", "middle": ["D"], "last": "Nowak", "suffix": ""}], "year": 2007, "venue": "proceedings of IEEE/SP 14th Workshop on Statistical Signal Processing", "link": null}, "BIBREF15": {"title": "Toeplitz compressed sensing matrices with applications to sparse channel estimation", "authors": [{"first": "J", "middle": ["D"], "last": "Haupt", "suffix": ""}, {"first": "W", "middle": ["U"], "last": "Bajwa", "suffix": ""}, {"first": "G", "middle": ["M"], "last": "Raz", "suffix": ""}, {"first": "R", "middle": ["D"], "last": "Nowak", "suffix": ""}], "year": 2008, "venue": "", "link": "2811561"}, "BIBREF16": {"title": "Compressive sensing by random convolution", "authors": [{"first": "J", "middle": [], "last": "Romberg", "suffix": ""}], "year": 2009, "venue": "SIAM J. Imaging Sci", "link": "16032731"}, "BIBREF17": {"title": "Sparse channel separation using random probes", "authors": [{"first": "J", "middle": ["K"], "last": "Romberg", "suffix": ""}, {"first": "R", "middle": [], "last": "Neelamani", "suffix": ""}], "year": "", "venue": "", "link": "2077273"}, "BIBREF18": {"title": "Sparse signal reconstruction via iterative support detection", "authors": [{"first": "Y", "middle": [], "last": "Wang", "suffix": ""}, {"first": "W", "middle": [], "last": "Yin", "suffix": ""}], "year": 2009, "venue": "", "link": "2710178"}, "BIBREF19": {"title": "EdgeCS: edge guided compressive sensing reconstruction", "authors": [{"first": "W", "middle": [], "last": "Guo", "suffix": ""}, {"first": "W", "middle": [], "last": "Yin", "suffix": ""}], "year": 2009, "venue": "", "link": "16353389"}, "BIBREF20": {"title": "Alternating direction algorithms for 1 -problems in compressives sensing", "authors": [{"first": "J", "middle": [], "last": "Yang", "suffix": ""}, {"first": "Y", "middle": [], "last": "Zhang", "suffix": ""}], "year": "", "venue": "", "link": "14534974"}}, "ref_entries": {"FIGREF0": {"text": "N] denote the sampled AWGN noise. Passing through the analog-to-digital converter (ADC), z(n), n \u2208 [1, N] is sampled as y(m), m \u2208 [1, M], and the cyclic prefix (CP) is removed. Traditional OFDM channel estimation schemes assume", "type": "figure"}, "FIGREF1": {"text": "Fig. 1. Baseband OFDM System", "type": "figure"}, "FIGREF2": {"text": "Fig. 2. MSE Vs. No. of Multipath for Different Cases (SNR=30dB).", "type": "figure"}, "FIGREF3": {"text": "\u2200i \u2208 {1, 2, . . . ,\u00d1 } while the stopping condition is not met, do Subproblem: h \u2190 arg min i \u2208I j |h i |, s.t.\u03c6h = y. (6) Support detection:I j+1 \u2190 {i : |h j i | \u2265 2 \u2212j hj \u221e }, where hj \u221e = max i {|h j i |}. Weights update: w j+1 i \u2190 0, \u2200i \u2208 I j+1 ; otherwise w j+1 i \u2190 1. j \u2190 j + 1 end while Final least-squares: let T = {i : |h i | > threshold}, then:", "type": "figure"}, "FIGREF4": {"text": "Fig. 3. Multipath Delay Profile.", "type": "figure"}, "FIGREF5": {"text": "Fig. 4. MSE Performance.", "type": "figure"}, "FIGREF7": {"text": "Fig. 5. Reconstructed SNR.", "type": "figure"}, "FIGREF8": {"text": "Fig. 6. Probability of Support Detection.", "type": "figure"}}}
{"paper_id": "2874360", "_pdf_hash": "e7f968042eb41857261100727e45aaa5ad79d1f3", "abstract": [{"section": "Abstract", "text": "Objective. To evaluate the effectiveness of radiation protective curtains in reducing the occupational radiation exposure of medical personnel. Methods. We studied medical staff members who had assisted in 80 consecutive therapeutic endoscopic retrograde cholangiopancreatography (ERCP) procedures. Use of radiation protective curtains mounted to the X-ray tube was determined randomly for each procedure, and radiation doses were measured with electronic pocket dosimeters placed outside the protective apron. Results. When protective curtains were not used, the mean radiation doses to endoscopists, first assistants, second assistants, and nurses were 340.9, 27.5, 45.3, and 33.1 Sv, respectively; doses decreased to 42.6, 4.2, 13.1, and 10.6 Sv, respectively, when protective curtains were used ( < 0.01). When the patient had to be restrained during ERCP ( = 8), the radiation dose to second assistants without protective curtains increased by a factor of 9.95 ( < 0.01) relative to cases in which restraint was not required. Conclusions. During ERCP, not only endoscopists, but also assistants and nurses were exposed to high doses of radiation. Radiation exposure to staff members during ERCP was reduced with the use of protective curtains.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Techniques related to endoscopic retrograde cholangiopancreatography (ERCP) and endoscopic ultrasonography (EUS) are becoming more widely used in the field of gastrointestinal endoscopy [1] . Although such advances have allowed patients to receive minimally invasive treatments, they take longer to perform and, consequently, expose both patients and medical staff members (occupational exposure) to higher doses of radiation. There is no established radiation exposure threshold for patients, because exposure is permitted as long as the benefits of the examination or treatment outweigh the risks of exposure. In contrast, there are strict annual permissible doses for medical personnel, because they receive no benefit from radiation exposure. Reducing the radiation exposure of patients and medical personnel is an important issue [2] [3] [4] [5] [6] .", "cite_spans": [{"start": 186, "end": 189, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 835, "end": 838, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 839, "end": 842, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 843, "end": 846, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 847, "end": 850, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 851, "end": 854, "text": "[6]", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Introduction", "text": "It is already known that scatter radiation with overheadtube fluoroscopic equipment is higher than that with undercouch-tube equipment. Lens injuries induced in nonoptimized interventional radiology laboratories have been reported [7] . However, overhead-tube equipment is still often used in endoscopic procedures. Equipment such as radiation protective clothing and eyewear is used to prevent exposure to scattered radiation from patients, which is the main source of occupational radiation exposure for health care providers. However, these types of protective equipment do not cover some parts of the body, and it is very important to protect the entire body. In an experimental and clinical study, Kurihara et al. found that using a protective lead shield mounted to the X-ray tube was effective in reducing the radiation dose to staff members [8] . However, it is not yet known how effective a protective lead shield would be for protection in clinical practice. In this study, we assessed the level of occupational radiation exposure during ERCP and measured the radiation doses to staff members when a protective lead shield was used and was not used during ERCP to assess the effectiveness of the shield.", "cite_spans": [{"start": 231, "end": 234, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 849, "end": 852, "text": "[8]", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "Materials and Methods", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Subjects.", "text": "The subjects were medical staff members who had assisted in 80 consecutive therapeutic ERCP procedures performed at our hospital between August and October 2012. ERCP-related procedures under this study contained biliary drainage, pancreatic duct drainage, and lithotripsy, but balloon enteroscope-assisted ERCP which should need longer procedure time was excluded. The study design was prospective. Use of a protective lead shield was determined randomly for each ERCP procedure, and doses of scattered radiation to the medical staff members were measured. The randomization was performed using the shield envelope method. Consent regarding the random assignment of protective equipment and measurement of radiation doses was obtained in writing from the medical staff members.", "cite_spans": [], "ref_spans": []}, {"section": "X-Ray Fluoroscopy Generator and Protective Lead Shield.", "text": "The X-ray fluoroscopy generator was a CUREVISTA (Hitachi Medical Corporation, Japan). Examinations were performed at 25 \u00d7 25 cm and 30 pulses/second ( Figure 1 ). The protective lead shield was a Hagoromo X-ray protective curtain (Maeda & Co., Ltd, Tokyo, Japan) that attaches to the X-ray tube, which was modified with the newly developed protect shield created by Itoi and his colleague [9] . The hood of the protective equipment was placed over the X-ray tube and attached to four shielding sheets that hang down to the surface of the operating table. The shielding sheets are made of a lead equivalent that is 0.25 mm thick on the endoscopist's side and 0.125 mm thick on the other three sides. regardless of whether protective curtains were used, a PDM-117 semiconductor-type electronic pocket dosimeter (Hitachi Aloka Medical Co., Ltd., Tokyo, Japan) was affixed to the left anterior chest area of the outside of each staff member's protective lead apron, and radiation doses (in Sv) were measured. Patients were sedated with 0.05-0.23 mg/kg of midazolam during the ERCP procedures. If the patient moved, the medical staff members manually restrained the patient. The cases that the patients were restrained by the medical staff members were made into \"movement (+). \" The patient's skin entrance dose (in mGy), as calculated by the fluoroscopy generator with the numerical dose determination (NDD) method [10] , was used to represent the radiation dose from the X-ray fluoroscopy generator.", "cite_spans": [{"start": 389, "end": 392, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 1412, "end": 1416, "text": "[10]", "ref_id": "BIBREF9"}], "ref_spans": [{"start": 151, "end": 159, "text": "Figure 1", "ref_id": "FIGREF0"}]}, {"section": "Exposure Measurements", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Statistical Analysis.", "text": "Statistical analysis was performed with JMP 9 (SAS Institute, Inc., Cary, NC, USA). Wilcoxon tests or 2 tests were performed, and < 0.05 was considered significant.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Radiation Doses to Patients and Medical Staff Members.", "text": "For the 40 ERCP procedures (27 male patients, 13 female patients) in which protective curtains were not used, the mean procedure time was 26.8 min, and the mean skin entrance dose was 265.4 mGy. For the 40 ERCP procedures (20 male patients, 20 female patients) in which protective curtains were used, the mean procedure time was 28.5 min, and the mean skin entrance dose was 245.1 mGy ( Table 1) .", "cite_spans": [], "ref_spans": [{"start": 387, "end": 395, "text": "Table 1)", "ref_id": "TABREF0"}]}, {"section": "Radiation Doses to Patients and Medical Staff Members.", "text": "The mean radiation doses during ERCP when protective curtains were not used were 340.9, 27.5, 45.3, and 33.1 Sv for endoscopists, first assistants, second assistants, and nurses, respectively (Table 2) .", "cite_spans": [], "ref_spans": [{"start": 192, "end": 201, "text": "(Table 2)", "ref_id": "TABREF1"}]}, {"section": "Radiation Doses to Patients and Medical Staff Members.", "text": "For cases in which the patient's movement had to be restrained during ERCP ( = 8), the mean radiation doses to the medical staff members, in the aforementioned order, were 375.3, 29.0, 161.4, and 63.5 Sv, respectively. For cases in which restraint was not required ( = 32), these mean radiation doses were 332.3, 27.1, 16.2, and 25.5 Sv, respectively. Additionally, for cases in which the patient had to be restrained, the radiation doses to second assistants and nurses when protective curtains were not used increased by factors of 9.95 ( < 0.001) ( Table 3) .", "cite_spans": [], "ref_spans": [{"start": 552, "end": 560, "text": "Table 3)", "ref_id": "TABREF2"}]}, {"section": "Radiation Protective Effects of Protective Curtains.", "text": "When protective curtains were used, the mean radiation doses to medical staff members were 42.6, 4.2, 13.1, and 10.6 Sv for endoscopists, first assistants, second assistants, and nurses, respectively. Use of protective curtains decreased the aforementioned doses by 87.5%, 84.7%, 71.1%, and 68.0% ( < 0.01) ( Table 2 ). The mean radiation doses during the 12 procedures in which protective curtains was used and body movement had to be restrained, in the same order as above, were 78.7, 6.8, 35.7, and 20.8 Sv (Table 4) . Values are presented as mean \u00b1 standard deviation.", "cite_spans": [], "ref_spans": [{"start": 309, "end": 316, "text": "Table 2", "ref_id": "TABREF1"}, {"start": 510, "end": 519, "text": "(Table 4)", "ref_id": "TABREF3"}]}, {"section": "Discussion", "text": "The 1990 Recommendations of the International Commission on Radiological Protection (ICRP) set safety standards for radiation exposure of 500 mSv/year for skin and 150 mSv/year for eyes [11] . Exposure of medical staff members to radiation is a critical problem, but there has been very little discussion about the topic. It is well recognized among diagnostic and interventional radiologists that scatter radiation with overhead-tube fluoroscopic equipment is considerably higher than that with undercouch-tube equipment. Use of overhead-tube equipment is not recommended for interventional procedures that require a long fluoroscopic time [12] . However, overhead-tube equipment is still used frequently in endoscopic procedures. Consequently, the use of effective radiation protectors is important to avoid radiation injuries for medical staff members engaging in ERCP.", "cite_spans": [{"start": 186, "end": 190, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 641, "end": 645, "text": "[12]", "ref_id": "BIBREF11"}], "ref_spans": []}, {"section": "Discussion", "text": "In this study, we assessed the effectiveness of protective curtains in reducing radiation exposure in clinical practice. We measured radiation from the outside of the protective lead apron, because, in a preliminary study, we found that radiation inside the apron was below detectable levels in a small number of cases. Occupational exposure for all medical staff members decreased when a protective curtain was used; the radiation dose to the endoscopist during one ERCP procedure decreased by 87.5%, and the radiation doses to other staff members decreased by 68-85%. Use of protective curtains reduced radiation in the air throughout the entire operating room, which likely contributed to the reduction in the radiation exposure of all medical staff members at the whole-body level. To ensure the safety of medical staff members, it is important to use not only standard protective equipment, such as radiation protective clothing and eyewear, but also protective curtains.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "In this study, we measured radiation doses from each ERCP procedure with high-sensitivity semiconductor-type dosimeters. We found that the radiation dose to endoscopists was approximately ten times greater than that to any other member of the medical staff, which indicates that radiation is a much more substantial issue for endoscopists. Buls et al. and Sulieman et al. similarly found that the radiation dose to endoscopists during ERCP is the highest among all staff members, which is consistent with our results [2, 13] . The endoscopist cannot keep a distance from the patient, and thus multiple levels of protection, consisting of not only protective clothing and eyewear, but also protective curtains, are required to protect the endoscopist from radiation exposure.", "cite_spans": [{"start": 517, "end": 520, "text": "[2,", "ref_id": "BIBREF1"}, {"start": 521, "end": 524, "text": "13]", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "Discussion", "text": "In this study, we measured the radiation doses to staff members during each procedure and found that a patient's movement during the examination greatly influenced these doses. When a patient moved substantially, the radiation dose to second assistants increased by a factor of ten. Substantial patient movement can interfere with the ERCP procedure, and thus a staff member must manually restrain the patient in such cases. This task is typically performed by a second assistant, and it is difficult to keep a distance from the patient when doing so, which is likely why their radiation dose was higher. Although few cases require this kind of restraint, the patient's movement leads to a considerable increase in radiation exposure. Therefore, to reduce exposure, it is important to create an environment in which the staff members are not exposed to scattered radiation, even when close to the patient.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "However, one disadvantage of using protective curtains is that it blocks the surgical team's view of the patient. It is essential to monitor breathing for safety management during ERCP, because patients are sedated, and thus it may be dangerous if the staff cannot visually confirm chest movements. However, it is also possible to monitor breathing with devices such as a pulse oximeter or a capnometer, and we did not experience any issues in this study. In addition, the protective curtains used in this study weighed approximately 8 kg and could potentially damage the fluoroscopy generator if left in place for a long time. Although this study only lasted two months, we have been using the protective curtains continually for approximately a year since the end of the study, and it has not caused any issue with the fluoroscopy generator. In addition, about the patient's exposure, there was no significant difference by the curtain use both in the preliminary phantom experiment and this present study.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "It is essential to ensure the health and safety of medical staff members while providing patients with a higher standard of care. The radiation protective X-ray tube attachment that we tested in this study reduced the radiation dose to all medical staff and should become more widely used in the future.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusion", "text": "Not only endoscopists, but also assistants and nurses are exposed to a high dose of radiation during ERCP, which is why appropriate measures must be taken. Use of protective curtains reduced the radiation dose to all medical staff members by shielding the entire operating room from scattered radiation and thus was very effective in reducing occupational radiation exposure.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Update on advanced endoscopic techniques for the pancreas: endoscopic retrograde cholangiopancreatography, drainage and biopsy, and endoscopic ultrasound", "authors": [{"first": "L", "middle": ["S"], "last": "Lee", "suffix": ""}, {"first": "D", "middle": ["L"], "last": "Conwell", "suffix": ""}], "year": 2012, "venue": "Radiologic Clinics of North America", "link": "5189123"}, "BIBREF1": {"title": "Patient and staff exposure during endoscopic retrograde cholangiopancreatography", "authors": [{"first": "N", "middle": [], "last": "Buls", "suffix": ""}, {"first": "J", "middle": [], "last": "Pages", "suffix": ""}, {"first": "F", "middle": [], "last": "Mana", "suffix": ""}, {"first": "M", "middle": [], "last": "Osteaux", "suffix": ""}], "year": 2002, "venue": "British Journal of Radiology", "link": "22124363"}, "BIBREF2": {"title": "Radiation doses to ERCP patients are significantly lower with experienced endoscopists", "authors": [{"first": "J", "middle": ["E"], "last": "Jorgensen", "suffix": ""}, {"first": "J", "middle": ["H"], "last": "Rubenstein", "suffix": ""}, {"first": "M", "middle": ["M"], "last": "Goodsitt", "suffix": ""}, {"first": "G", "middle": ["H"], "last": "Elta", "suffix": ""}], "year": 2010, "venue": "Gastrointestinal Endoscopy", "link": "28509794"}, "BIBREF3": {"title": "Evaluation of patient doses due to fluoroscopic exposures", "authors": [{"first": "K", "middle": [], "last": "Noto", "suffix": ""}, {"first": "K", "middle": [], "last": "Matsubara", "suffix": ""}, {"first": "K", "middle": [], "last": "Koshida", "suffix": ""}, {"first": "H", "middle": [], "last": "Iida", "suffix": ""}, {"first": "T", "middle": [], "last": "Yamamoto", "suffix": ""}], "year": 2011, "venue": "Radiation Protection Dosimetry", "link": "31472971"}, "BIBREF4": {"title": "Patient and endoscopist radiation doses during ERCP procedures", "authors": [{"first": "V", "middle": [], "last": "Tsapaki", "suffix": ""}, {"first": "K", "middle": ["D"], "last": "Paraskeva", "suffix": ""}, {"first": "N", "middle": [], "last": "Mathou", "suffix": ""}], "year": 2011, "venue": "Radiation Protection Dosimetry", "link": "13143940"}, "BIBREF5": {"title": "Radiation dose to patients during endoscopic retrograde cholangiopancreatography", "authors": [{"first": "J", "middle": [], "last": "Boix", "suffix": ""}, {"first": "V", "middle": [], "last": "Lorenzo-Zuniga", "suffix": ""}], "year": 2011, "venue": "World Journal of Gastrointestinal Endoscopy", "link": "44664252"}, "BIBREF6": {"title": "Lens injuries induced by occupational exposure in non-optimized interventional radiology laboratories", "authors": [{"first": "E", "middle": [], "last": "Va\u00f1\u00f3", "suffix": ""}, {"first": "L", "middle": [], "last": "Gonz\u00e1lez", "suffix": ""}, {"first": "F", "middle": [], "last": "Beneytez", "suffix": ""}, {"first": "F", "middle": [], "last": "Moreno", "suffix": ""}], "year": 1998, "venue": "British Journal of Radiology", "link": "46332285"}, "BIBREF7": {"title": "Novel protective lead shield and pulse fluoroscopy can reduce radiation exposure during the ERCP procedure", "authors": [{"first": "T", "middle": [], "last": "Kurihara", "suffix": ""}, {"first": "T", "middle": [], "last": "Itoi", "suffix": ""}, {"first": "A", "middle": [], "last": "Sofuni", "suffix": ""}], "year": 2012, "venue": "Hepato-Gastroenterology", "link": "20206394"}, "BIBREF8": {"title": "Training for ERCP-related procedures", "authors": [{"first": "T", "middle": [], "last": "Itoi", "suffix": ""}, {"first": "A", "middle": [], "last": "Sofuni", "suffix": ""}, {"first": "F", "middle": [], "last": "Itokawa", "suffix": ""}], "year": 2006, "venue": "Tando", "link": null}, "BIBREF9": {"title": "Medical exposures based on the survey of the X-ray technical conditions and the proposal of guidance level", "authors": [{"first": "T", "middle": [], "last": "Mori", "suffix": ""}, {"first": "H", "middle": [], "last": "Muto", "suffix": ""}, {"first": "H", "middle": [], "last": "Sato", "suffix": ""}, {"first": "M", "middle": [], "last": "Hasegawa", "suffix": ""}], "year": 2000, "venue": "Nippon Igaku Hoshasen Gakkai Zasshi", "link": "34821910"}, "BIBREF10": {"title": "Recommendations of the international commission on radiological protection", "authors": [], "year": 1990, "venue": "Annals of the ICRP", "link": null}, "BIBREF11": {"title": "Avoidance of radiation injuries from medical interventional procedures", "authors": [{"first": "J", "middle": [], "last": "Valentin", "suffix": ""}], "year": 2000, "venue": "Annals of the ICRP", "link": "11562595"}, "BIBREF12": {"title": "Reduction of radiation doses to patients and staff during endoscopic retrograde cholangiopancreatography", "authors": [{"first": "A", "middle": [], "last": "Sulieman", "suffix": ""}, {"first": "G", "middle": [], "last": "Paroutoglou", "suffix": ""}, {"first": "A", "middle": [], "last": "Kapsoritakis", "suffix": ""}], "year": 2011, "venue": "Saudi Journal of Gastroenterology", "link": "207483558"}}, "ref_entries": {"FIGREF0": {"text": "Figure 1: X-ray fluoroscopy generator and protective lead shield. (a) Without protective lead shield. (b) With protective lead shield.", "type": "figure"}, "FIGREF1": {"text": "Figure 2: Positions of staff members relative to the patient and X-ray tube during the ERCP procedure. E: Endoscopist, A: 1st assistant, B: 2nd assistant, N: nurse, and ERCP: endoscopic retrograde cholangiopancreatography.", "type": "figure"}, "TABREF0": {"text": "ERCP conditions.ERCP: endoscopic retrograde cholangiopancreatography. Values are presented as mean \u00b1 standard deviation. * Numerical dose determination.", "type": "table"}, "TABREF1": {"text": "Occupational radiation dose to medical staff members ( Sv).Values are presented as mean \u00b1 standard deviation.", "type": "table"}, "TABREF2": {"text": "Occupational radiation dose to each medical staff member with or without patient movement (without the use of protective curtains) ( Sv).Values are presented as mean \u00b1 standard deviation.", "type": "table"}, "TABREF3": {"text": "Occupational radiation dose to each medical staff member with or without patient movement (with the use of protective cur- tains) ( Sv).", "type": "table"}}}
{"paper_id": "2874456", "_pdf_hash": "3e7788b4d57f05d2dbd8096a9c32d39e85429dac", "abstract": [{"section": "Abstract", "text": "Background: The Personal Responsibility and Work Opportunity Reconciliation Act (PRWORA) of 1996 gave states the option to withdraw Medicaid coverage of nonemergency care from most legal immigrants. Our goal was to assess the effect of PRWORA on hospital uncompensated care in the United States.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Background", "text": "The Personal Responsibility and Work Opportunity Reconciliation Act (PRWORA) of 1996 (US Public Law 104-93) aimed to reduce federal welfare expenditures by changing eligibility criteria for public assistance. An important provision in the legislation determined that legal immigrants entering the United States on or after August 22, 1996 , would no longer be eligible for nonemergency Medicaid services. While PRWORA may have achieved substantial federal welfare savings [1] , there has been little investigation of its financial impact on hospitals that provide nonemergency services to medically uninsured legal immigrants.", "cite_spans": [{"start": 323, "end": 338, "text": "August 22, 1996", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "Background", "text": "A news story in 2000 highlighted instances in which documented and undocumented immigrants without health insurance remained in acute-care facilities after recovery, often resulting in hundreds of thousands of dollars in uncompensated care costs for the hospitals involved [2] . Because uninsured immigrants affected by PRWORA are eligible only for emergency Medicaid, they lack coverage for any form of postdischarge medical care (eg, acute rehabilitation, medical equipment, follow-up outpatient or home health care, and transfer to long-term care facilities or nursing homes) [2] . Since these services often constitute the prevailing standard of care for chronic or disabling conditions, hospitals may incur substantial expenses by keeping Medicaid-ineligible patients in acutecare facilities longer than necessary due to lack of suitable long-term care or rehabilitation options [2] .", "cite_spans": [], "ref_spans": []}, {"section": "Background", "text": "Another news story in 2001 presented cases of legal immigrants who, due to PRWORA, could access funding for nonemergency health care and prescription drugs only through local safety net providers. The quality of these immigrants' health care and the availability of subsidized services varied widely according to the regional distribution of safety net providers and the range of services offered [3] .", "cite_spans": [{"start": 397, "end": 400, "text": "[3]", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Background", "text": "Several studies have investigated the impact of PRWORA on Medicaid and/or welfare participation and patients' access to care [4] [5] [6] [7] [8] , but none have examined the impact of PRWORA on hospitals. A report by the New York Immigration Coalition [9] , as well as discussions by the Greater New York Hospital Association and the media suggest that the PRWORA provisions have had a negative financial impact on hospitals, especially those serving large immigrant populations [2, 11, 12] . In their 2000 case study examining hospitals' ability to meet rising demands for uncompensated care, the authors of the United Hospital Fund report put forward that in New York City, uncompensated care expenses would be expected to increase due to growth in numbers of immigrants ineligible for Medicaid coverage due to welfare reform [10] . Estimating the extent of projected financial loss to hospitals due to this specific policy provision is important to both hospitals and state policymakers as the legislation is renewed and reexamined.", "cite_spans": [{"start": 125, "end": 128, "text": "[4]", "ref_id": "BIBREF2"}, {"start": 133, "end": 136, "text": "[6]", "ref_id": "BIBREF3"}, {"start": 137, "end": 140, "text": "[7]", "ref_id": "BIBREF4"}, {"start": 487, "end": 490, "text": "12]", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Origins of PRWORA", "text": "In the 1990s, Congress moved to reform public spending by reducing the number of beneficiaries on welfare rolls. Reforms focused partly on immigrants, following testimony from the General Accounting Office estimating that slightly more than half of the Supplemental Security Income (SSI) benefits provided to elderly persons were collected by noncitizens in 1995 [13, 14] . In justifying PRWORA [15] , the House Ways and Means Committee stated that it had been a basic tenet of US immigration policy since 1882 that legal immigrants should not be eligible for public benefits. Though Congress did not rescind emergency Medicaid from illegal immigrants, the legislation cited \"a compelling government interest to remove the incentive for illegal immigration provided by the availability of public benefits\" [13] . PRWORA was among several pieces of legislation in the mid-1990s -including California's Proposition 187 in 1994 and the Illegal Immigration Reform and Immigrant Responsibility Act of 1996 [16] -that embodied substantive immigration policy changes, the specific provisions of which have been enforced in varying degrees according to government priorities.", "cite_spans": [{"start": 368, "end": 371, "text": "14]", "ref_id": "BIBREF7"}, {"start": 395, "end": 399, "text": "[15]", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "PRWORA legislation and states' responses", "text": "PRWORA made several key reforms restricting public assistance for qualified immigrants [17] . Prior to the implementation of PRWORA, \"qualified aliens\" were eligible for the same federal means-tested benefits as US citizens. PRWORA makes an important distinction between \"qualified\" and \"non-qualified\" immigrants. The term qualified alien is used synonymously with legal immigrant and designates a noncitizen who falls into one of the following categories: (1) persons lawfully admitted for permanent residence; (2) persons granted asylum; (3) refugees; (4) persons paroled into the United States for at least one year; (5) persons for whom deportation is being withheld; and (6) persons granted conditional entry. The term nonqualified alien includes nonimmigrant visitors and undocumented/illegal immigrants.", "cite_spans": [{"start": 87, "end": 91, "text": "[17]", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "PRWORA legislation and states' responses", "text": "After PRWORA, legal immigrants were declared ineligible for nonemergency Medicaid for their first 5 years in the country, with some exceptions, as described later. The Immigration and Naturalization Service (INS) estimates that there were 10.5 million (\u00b1 350000) legal permanent residents residing in the United States as of April 1996 [18] . To qualify for Medicaid coverage after the ban, noncitizens must not receive public benefits during the 5-year period [15] . Legal immigrants receiving benefits at the time of enactment on August 22, 1996, were denied continuation of those benefits starting January 1, 1997. Benefits both before and after PRWORA for non-qualified aliens remained restricted to emergency Medicaid.", "cite_spans": [{"start": 336, "end": 340, "text": "[18]", "ref_id": "BIBREF11"}, {"start": 461, "end": 465, "text": "[15]", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "PRWORA legislation and states' responses", "text": "Before PRWORA, states did not consider immigration status in granting Medicaid assistance. After PRWORA, however, most legal immigrants arriving after August 1996 were barred from Medicaid and other state-funded assistance, at states' discretion. Exceptions were made for (1) refugees; (2) persons granted asylum and persons whose deportation was being withheld; (3) armed forces personnel or veterans and their dependent family members; and (4) legal permanent residents with 40 qualifying quarters of work [15] .", "cite_spans": [{"start": 508, "end": 512, "text": "[15]", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "PRWORA legislation and states' responses", "text": "Under pressure from the White House and immigrants' advocacy groups, Congress restored some Medicaid benefits to certain legal immigrants as part of the Balanced Budget Act (BBA) of 1997 [19, 20] . Under the BBA, a legal immigrant could qualify for Medicaid (not restricted to emergency Medicaid) through SSI eligibility if he or she was lawfully in the United States and receiving SSI benefits on August 22, 1996 , and subsequently certified under the SSI program as blind or disabled.", "cite_spans": [{"start": 192, "end": 195, "text": "20]", "ref_id": "BIBREF13"}, {"start": 398, "end": 413, "text": "August 22, 1996", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "Immigrant populations and use of health care", "text": "Noncitizens in the United States numbered approximately 17.8 million in 2000, or 6.5 percent of the total population [21] . Previous research has shown noncitizens to be more economically disadvantaged and to possess lower levels of health insurance than naturalized and native citizens. Census data suggest that noncitizens are more likely than citizens to be poor (29% vs 16%), despite the fact that noncitizen families are as likely as citizen families to have at least one full-time worker (82% vs 85%) [22] . In their report on insurance rates for Hispanic immigrants, the Commonwealth Fund Task Force on the Future of Health Insurance found that the longer Hispanic immigrants had been permanent residents of the United States, the more likely they were to be covered by employer-related insurance [23] . Among low-income immigrants in the United States in 1999, 59% were uninsured, compared to 30% of low-income citizens [22] . The Kaiser Commission reports that immigrants may underutilize health care regardless of insurance coverage, out of fear of jeopardizing their citizenship eligibility by incurring costs as public charges [22] .", "cite_spans": [{"start": 507, "end": 511, "text": "[22]", "ref_id": "BIBREF15"}, {"start": 804, "end": 808, "text": "[23]", "ref_id": "BIBREF16"}, {"start": 928, "end": 932, "text": "[22]", "ref_id": "BIBREF15"}, {"start": 1139, "end": 1143, "text": "[22]", "ref_id": "BIBREF15"}], "ref_spans": []}, {"section": "Objective", "text": "Using data from several sources, we present snapshots of information currently available, and consider how the financial impact of PRWORA on hospitals might be estimated. Based on a review of relevant literature, we hypothesized that uncompensated hospital care would be more prevalent in states with lower rates of health insurance coverage, higher percentages of foreign-born residents (used to approximate the population of interest affected by PRWORA), higher rates of poverty, and greater percentages of teaching hospitals [22] [23] [24] [25] [26] . We outline the limitations of available data and discuss what information is needed to accurately estimate the outcome of interest.", "cite_spans": [{"start": 528, "end": 532, "text": "[22]", "ref_id": "BIBREF15"}, {"start": 533, "end": 537, "text": "[23]", "ref_id": "BIBREF16"}, {"start": 538, "end": 542, "text": "[24]", "ref_id": "BIBREF17"}, {"start": 543, "end": 547, "text": "[25]", "ref_id": "BIBREF18"}, {"start": 548, "end": 552, "text": "[26]", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "Methods", "text": "Our goal was to examine the effects of PRWORA on hospital uncompensated care expenditures. The analysis consisted of two parts: a series of \"data snapshots\" to describe relevant information, and a multivariable regression to model drivers of uncompensated care costs. The regression analysis was conducted at the state level because no single source of data includes both patients' immigration status and the amount of uncompensated hospital care provided, thus precluding hospital-or patient-level analyses.", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "We collected the following state-level data for the period from 1994 through 1999: foreign-born, noncitizen population; health uninsurance rates; percentage of teaching hospitals as a proportion of all hospitals reporting data per state; and each state's decision regarding whether to implement the PRWORA Medicaid bar for legal permanent residents or to continue offering nonemergency Medicaid coverage using state-only funds. These factors are thought to influence expenditures per admission for uncompensated hospital care [22] [23] [24] [25] [26] and were examined at the state level for the period from 1994 to 1999 for a total of 300 observations (6 years \u00d7 50 states).", "cite_spans": [{"start": 526, "end": 530, "text": "[22]", "ref_id": "BIBREF15"}, {"start": 531, "end": 535, "text": "[23]", "ref_id": "BIBREF16"}, {"start": 536, "end": 540, "text": "[24]", "ref_id": "BIBREF17"}, {"start": 541, "end": 545, "text": "[25]", "ref_id": "BIBREF18"}, {"start": 546, "end": 550, "text": "[26]", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "Methods", "text": "State-level data on the percentage of the population uninsured and the percentage of the population comprised of foreign-born noncitizens were obtained from the 2000 Current Population Survey, March Supplement, a detailed description of which is available elsewhere [21] . Because the Medicare program covers virtually all Americans aged 65 and older, data on insurance coverage rates among nonelderly populations were used. As the closest available proxy for the percentage of legal immigrants per state, we used the \"foreign born, not a US citizen\" category available in the Public Basic Monthly Survey for 1994 to 2001.", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "State-level poverty data were obtained from the historical poverty tables of the Census Bureau [29] . Poverty thresholds are stable across all regions and are adjusted for inflation every year using the Consumer Price Index for All Urban Consumers (CPI-U).", "cite_spans": [{"start": 95, "end": 99, "text": "[29]", "ref_id": "BIBREF22"}], "ref_spans": []}, {"section": "Methods", "text": "Aggregate data on uncompensated care were obtained from the American Hospital Association's (AHA) nationwide Annual Survey of Hospitals [30] . AHA defines bad debt as the provision for actual or expected uncollectibles resulting from the extension of credit. Charity care services, however, are provided free of charge to individuals who meet certain financial criteria and are never expected to result in cash inflows. Total uncompensated care for hospitals on the state level was estimated as the sum of bad debt and charity care. For each state, we obtained a sample of all hospitals for which both charity care and bad debt data were available yearly from 1994 to 1999. We calculated uncompensated care per hospital admission as a per capita estimate of uncompensated care. These estimates were adjusted to 1999 US dollars using the medical care component of the CPI.", "cite_spans": [{"start": 136, "end": 140, "text": "[30]", "ref_id": "BIBREF23"}], "ref_spans": []}, {"section": "Methods", "text": "Teaching hospital status also was obtained from the AHA Annual Survey of Hospitals. The AHA defines teaching hospitals as those that are members of the Council of Teaching Hospitals of the Association of American Medical Colleges. Teaching hospital percentage refers to the percentage of hospitals classified as teaching hospitals out of the total number of hospitals in a state reporting data to AHA for the years of interest.", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "Although every state, excluding Wyoming and South Dakota, chose to preserve Medicaid coverage for immigrants who were eligible before the enactment of PRWORA (i.e., entering the United States before August 22, 1996) , states' decisions varied on whether to implement the 5-year bar on Medicaid eligibility for qualified immigrants after the enactment of PRWORA. Fourteen states (California, Connecticut, Delaware, Hawaii, Illinois, Maine, Maryland, Massachusetts, Minnesota, Nebraska, Pennsylvania, Rhode Island, Virginia, and Washington) maintained Medicaid eligibility for qualified immigrants entering the United States after August 22, 1996, through state-only funds [31] . We included a dichotomous variable in the model describing each state's implementation decision.", "cite_spans": [{"start": 199, "end": 215, "text": "August 22, 1996)", "ref_id": "BIBREF8"}, {"start": 671, "end": 675, "text": "[31]", "ref_id": "BIBREF24"}], "ref_spans": []}, {"section": "Methods", "text": "A multiple regression analysis was conducted to test the hypothesis that total uncompensated care (the sum of charity care and bad debt) per admission would be affected by a state's percentage of foreign-born residents, poverty rate, uninsurance rate, percentage of hospitals, and the state's implementation decision. Because total uncompensated care was heavily skewed, we used a log-transformed variable as the dependent variable. The resulting log-linear model has the convenient property of measuring the relative change in the dependent variable (uncompensated care) for an absolute change in a given predictor variable, controlling for other predictors in the model. Each year from 1994 through 1999 was entered into the model as a categorical variable, omitting 1994 as the reference year. We used the Huber [32] and White estimator [33, 34] , clustered on states, to obtain robust error estimates that allow for the lack of independence of observations within a given state over time.", "cite_spans": [{"start": 815, "end": 819, "text": "[32]", "ref_id": "BIBREF25"}, {"start": 840, "end": 844, "text": "[33,", "ref_id": "BIBREF26"}, {"start": 845, "end": 848, "text": "34]", "ref_id": "BIBREF27"}], "ref_spans": []}, {"section": "Methods", "text": "Statistical analyses were performed using STATA version 6.0 (Stata Corporation, College Station, Tex) and SPLUS statistical software (Insightful Corporation, Seattle, Wash). This project was approved by the institutional review board of Duke University Medical Center. Figure 1 displays the percentage of immigrants for each state, according to US Census data. States with the highest percentages of foreign-born noncitizens in 1994 were California (18.4%), New York (10.9%), Florida (9.6%), Rhode Island (8.4%), and Nevada (8.4%). The national mean was 3.2 percent (SD, 3.59).", "cite_spans": [], "ref_spans": [{"start": 269, "end": 277, "text": "Figure 1", "ref_id": "FIGREF0"}]}, {"section": "Results", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Data snapshots: state population and hospital characteristics", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Immigrant population", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Health insurance coverage", "text": "The total number of medically uninsured persons living in the United States is estimated to be 42.5 million, or 16% of the population [22] . As shown in Figure 2 , the states with the highest percentages of uninsured residents in 1994 were Texas (24.8%), New Mexico (23.5%), California (21.2%), Arizona (20.5%), and Alabama (19.4%). Texas and California are also among the states with the highest percentage of foreign-born residents, although California did not implement PRWORA's Medicaid eligibility bar.", "cite_spans": [{"start": 134, "end": 138, "text": "[22]", "ref_id": "BIBREF15"}], "ref_spans": []}, {"section": "State implementation decisions", "text": "Of the 6 states with the highest immigrant populations (70% of the total immigrant population of the United States), California and Illinois were the only states that preserved Medicaid coverage for qualified immigrants through state-only funds [22] . Thirty-six states eliminated Medicaid coverage during the 5-year bar [7, 31] Poverty Figure 3 displays the poverty rate for each state, according to US Census data. The national average was 13.1 (SD, 3.93). Three of the 10 states with the highest poverty rates in 1994 were also among the states with the highest percentage of foreign-born residents -Texas (19%), California (18%), and New York (17%). Figure 4 shows the amount of uncompensated care per admission provided by the states with the highest numbers of legal permanent residents (California, Florida, Illinois, New Jersey, New York, and Texas) from 1994 through 1999 and the average uncompensated care cost per year for the three-year periods before and after PRWORA's enactment.", "cite_spans": [{"start": 245, "end": 249, "text": "[22]", "ref_id": "BIBREF15"}, {"start": 321, "end": 324, "text": "[7,", "ref_id": "BIBREF4"}, {"start": 325, "end": 328, "text": "31]", "ref_id": "BIBREF24"}], "ref_spans": [{"start": 654, "end": 662, "text": "Figure 4", "ref_id": "FIGREF3"}]}, {"section": "Uncompensated care", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Regression model", "text": "Exploratory analyses showed that uninsurance was highly correlated with the state's poverty rate (r = 0.70). In addition, percentage foreign-born and percentage teaching hospitals were highly correlated (r = 0.30). To avoid collinearity and create a more robust model, poverty rate was dropped from the final multivariable regression model; percentage of teaching hospitals was dichotomized, assigning a value of 1 to states with 5% or more teaching hospitals. Both the dependent variable -uncompensated care per admission -and percentage foreign-born were used in log form due to nonnormal distributions revealed in exploratory analyses.", "cite_spans": [], "ref_spans": []}, {"section": "Regression model", "text": "Results of the multivariable regression modeling (Table 1) suggest that, controlling for time and a state's foreignborn population, percentage of teaching hospitals, and implementation decision, a 1% increase in a state's uninsured population yields a 4.1% increase in the amount of uncompensated care provided (P < .001). Controlling for all other variables, a 1% increase in the log of a state's foreign-born population yields a 2.2% increase in uncompensated care, though this result was only significant at the .10 level. Percentage of teaching hospitals greater than 5% was found to be a weak predictor of uncompensated care, but was not significant (P = .601). A state's decision to implement PRWORA did not independently predict uncompensated care expenditures in our model. The trend variables corresponding to years were not significant.", "cite_spans": [], "ref_spans": [{"start": 49, "end": 58, "text": "(Table 1)", "ref_id": "TABREF2"}]}, {"section": "Discussion", "text": "PRWORA marked large-scale changes in health, immigration, and welfare policy in the United States. Patients, hos- > 9 percent (3) 7 to 8.9 percent (6) 4 to 6.9 percent (4) 2 to 3.9 percent (12) 0 to 1.9 percent (26) pitals, and state and federal governments have all had a stake in PRWORA's enactment. An accurate monetary estimate of the effects of PRWORA on hospital uncompensated care due to changes in Medicaid coverage would be useful to policymakers as PRWORA periodically comes up for consideration of renewal, and as anecdotal evidence of an adverse financial impact on hospitals continues to mount.", "cite_spans": [{"start": 211, "end": 215, "text": "(26)", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "Discussion", "text": "We hypothesized that hospital uncompensated care expenditures would be greater in states with higher percentages of foreign-born residents, lower rates of insurance coverage, and higher percentages of teaching hospitals.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "Measured at the state level, hospital uncompensated care expenditures were not statistically significantly related to percentage foreign-born, percentage of teaching hospitals, or states' implementation decisions; in our model, higher uninsurance rates emerged as the only significant predictor of uncompensated hospital care expenditures. This finding suggests that efforts to reduce the number of people uninsured or underinsured would reduce hospitals' expenditures on uncompensated care. This implication reinforces claims that high rates of uninsurance in United States have negative effects, but does not directly address our original hypothesis about the immigrant eligibility provisions of PRWORA. As with other studies that have ", "cite_spans": [], "ref_spans": []}, {"section": "16.3", "text": "> 18 percent (6) 16 to 17.9 percent (8) 14 to 15.9 percent (5) 12 to 13.9 percent (13) 0 to 11.9 percent (19) Source: U.S. Census Data.", "cite_spans": [], "ref_spans": []}, {"section": "16.3", "text": "combined disparate data sources to assess the impact of PRWORA on the health or welfare of would-be beneficiaries [4] , data limitations posed a significant challenge to these analyses.", "cite_spans": [{"start": 114, "end": 117, "text": "[4]", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "16.3", "text": "The proxy of percentage foreign-born may not have accurately captured the population of interest -legal immigrants arriving after August 22, 1996 , who were no longer eligible for nonemergency Medicaid coverage. Using the foreign-born category from the Census data relies on the assumption that states with higher foreign-born populations would also have a greater number of legal immigrants whose eligibility for nonemergency Medicaid would be affected by PRWORA. However, the foreignborn noncitizen category used in Census data (defined as any person not born a citizen of the United States and not naturalized) includes categories of persons exempted from PRWORA's Medicaid cuts, such as asylum seekers and refugees. Given that PRWORA requires states that provide health services to report illegal immigrants to authorities, it is unlikely that accurate data on immigration status and date of entry into the United States can be collected in the health care setting. In addition, it is unlikely that any institutional review board would approve the collection of such data in present circumstances.", "cite_spans": [{"start": 130, "end": 145, "text": "August 22, 1996", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "16.3", "text": "Because the main effect of PRWORA was to restrict Medicaid eligibility, thereby increasing demand for uncompensated care, the present analysis focused on state-level parameters linked to demand for medical care. Uncom- pensated care reimbursement pools, common in states with former all-payer rate-setting systems, led to increased uncompensated care expenditures throughout the 1990s. In a deregulated health care system, however, states tended to use these funds to expand Medicaid and/or Medicaid managed care, thus shifting the focus of the pools to reimbursement for charity care only [35] . Because of the nonuniformity of states' approaches to uncompensated care pools, their limited use, and their changing roles over time, we did not include this factor in our final model.", "cite_spans": [{"start": 590, "end": 594, "text": "[35]", "ref_id": "BIBREF28"}], "ref_spans": []}, {"section": "16.3", "text": "A monetary estimate on a national, state, or hospital level of the financial impact of PRWORA remains difficult to ascertain due to data limitations. Ideally, such research would compare the costs before and after 1996 of the nonemergency care that hospitals provided (both as charity care and as bad debt) to the category of immigrants who lost nonemergency Medicaid eligibility due to the implementation of PRWORA. We would expect the extent and implications of this financial impact to vary according to both hospital characteristics and the populations served. Because a patient's immigration status is not recorded concomitantly with hospital resource use in any hospital, state, or federal database, it is not currently possible to isolate charity care and bad debt expenditures on An additional complicating factor is the possibility that, as a result of PRWORA, hospitals may provide and bill for services as emergency services that previously were categorized as nonemergency services in order to secure Medicaid payment. Similarities in income-related eligibility criteria for emergency and nonemergency Medicaid would facilitate reclassification. Further research should examine the extent to which providers reclassify services.", "cite_spans": [], "ref_spans": []}, {"section": "16.3", "text": "Traditionally, safety net hospitals have been supported though public funds, such as disproportionate-share hospital (DSH) payments. The Medicaid DSH payment is based on the assumption that certain hospitals, in addition to providing care to Medicaid enrollees, also serve indigent persons who are ineligible for Medicaid. However, there are some indications that public support mechanisms to hospitals may be in jeopardy [36] . First, DSH payments are large and repeatedly become targets for budget cuts by federal and state governments. As a result of provisions in the BBA, for example, it has been estimated that federal spending on Medicaid DSH will decrease by 11%, or $5.8 billion, during the period from 1998 through 2002. Since more Medicaid beneficiaries are being cared for in private facilities, public safety net hospitals may be affected by both competition for fee-forservice patients and decreases in overall DSH allotments [37] . Finally, safety net hospitals typically use Medicaid revenues to help fund uncompensated care; decreases in Medicaid reimbursements may, therefore, further impede hospitals' ability to provide services to the uninsured [38] .", "cite_spans": [{"start": 422, "end": 426, "text": "[36]", "ref_id": "BIBREF29"}, {"start": 940, "end": 944, "text": "[37]", "ref_id": "BIBREF30"}, {"start": 1166, "end": 1170, "text": "[38]", "ref_id": "BIBREF31"}], "ref_spans": []}, {"section": "16.3", "text": "Existing studies of trends in uncompensated hospital care expenditures have focused primarily on supply-side covariates, such as uncompensated care pools, Medicare and Medicaid DSH payments, and the degree of competition in the local health care marketplace [25, 28, 36, 39, 40] . While a focus on such hospital characteristics has helped to elucidate the factors that affect uncompensated care at the hospital level, the present study sought to examine the impact of the PRWORA legislation by identifying statelevel characteristics affecting total hospital uncompensated care per state from 1994 to 1999. Because data used for the regression model came from multiple sources, comprehensive year-by-year figures from 1994 through 1999 were available for all factors in the model only at the state level. Because PRWORA gave states the option of changing Medicaid coverage, state-level information is useful in understanding how PRWORA was implemented across the United States. However, to better assess the effects of PRWORA on hospitals, detailed hospital-specific information, at least at the level of metropolitan statistical area (MSA), would be needed on the immigration status of populations served. Data limitations currently hamper efforts to obtain a monetary estimate of hospitals' financial losses due specifically to PRWORA. To better quantify the impact of health policy regulations on health care providers, better data sources, particularly at the MSA level, are needed.", "cite_spans": [{"start": 258, "end": 262, "text": "[25,", "ref_id": "BIBREF18"}, {"start": 263, "end": 266, "text": "28,", "ref_id": "BIBREF21"}, {"start": 267, "end": 270, "text": "36,", "ref_id": "BIBREF29"}, {"start": 271, "end": 274, "text": "39,", "ref_id": "BIBREF32"}], "ref_spans": []}, {"section": "Competing interests", "text": "None declared.", "cite_spans": [], "ref_spans": []}, {"section": "Authors' Contributions", "text": "LDC conceived of and designed the study, performed the statistical analysis, interpreted the data, and drafted the manuscript. JWT, VS, and LHC assisted in the statistical analysis, interpretation of data, and drafting of the article. KAF and KAS conceived of and designed the study and obtained funding. All authors read and approved the final manuscript. ", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Congressional Budget Office The Economic and Budget Outlook : An Update", "authors": [{"first": "U", "middle": ["S"], "last": "", "suffix": ""}], "year": 1996, "venue": "Wall Street Journal", "link": null}, "BIBREF1": {"title": "Lost in America: quirk in law creates health-care minefield for legal immigrants", "authors": [{"first": "B", "middle": [], "last": "Newman", "suffix": ""}], "year": 2001, "venue": "Wall Street Journal", "link": null}, "BIBREF2": {"title": "Ellwood MR and Ku L Welfare and immigration reforms: unintended side effects for Medicaid", "authors": [], "year": 1998, "venue": "Borjas GJ Food Insecurity and Public Assistance. Los Angeles", "link": null}, "BIBREF3": {"title": "Welfare Reform and Economic Factors Affected Medicaid Participation: 1984-96", "authors": [{"first": "L", "middle": [], "last": "Ku", "suffix": ""}, {"first": "B", "middle": [], "last": "Garrett", "suffix": ""}, {"first": "", "middle": [], "last": "How", "suffix": ""}], "year": 2000, "venue": "", "link": null}, "BIBREF4": {"title": "The Urban Institute 2000, 8. Zimmermann W and Fix M Declining Immigrant Applications for Medi-Cal and Welfare Benefits in Los Angeles County", "authors": [{"first": "L", "middle": [], "last": "Ku", "suffix": ""}, {"first": "T", "middle": ["S"], "last": "Matani S Immigrants ; Prinz", "suffix": ""}, {"first": "K", "middle": [], "last": "Haslanger", "suffix": ""}, {"first": "D", "middle": [], "last": "Delia", "suffix": ""}, {"first": "S", "middle": [], "last": "Fass", "suffix": ""}, {"first": "S", "middle": [], "last": "Salit", "suffix": ""}, {"first": "Cantor Jc Hospital", "middle": [], "last": "Markets", "suffix": ""}], "year": 1998, "venue": "Access to Health Care and Insurance on the Cusp of Welfare Reform", "link": null}, "BIBREF5": {"title": "Committee on Ways and Means U.S. House of Representatives Summary of Welfare Reforms Made by Public Law", "authors": [], "year": 1996, "venue": "Natl J", "link": null}, "BIBREF6": {"title": "The Personal Responsibility and Work Opportunity Reconciliation Act and Associated Legislation", "authors": [], "year": 1996, "venue": "", "link": null}, "BIBREF7": {"title": "Accounting Office Supplemental Security Income: Noncitizen Caseload Continues to Grow", "authors": [{"first": "U", "middle": ["S"], "last": "", "suffix": ""}], "year": 1996, "venue": "", "link": null}, "BIBREF8": {"title": "Public Law 104-193, Sec. 431, 104th Cong., 2d sess., Personal Responsibility and Work Opportunity Reconciliation Act of", "authors": [{"first": "U", "middle": ["S"], "last": "", "suffix": ""}], "year": 1996, "venue": "", "link": null}, "BIBREF10": {"title": "Department of Health and Human Services Comparison of Prior Law and the Personal Responsibility and Work Opportunity Reconciliation Act of 1996 (P. L. 104-193)", "authors": [], "year": 2001, "venue": "", "link": null}, "BIBREF11": {"title": "Immigration and Naturalization Service Triennial Comprehensive Reports on Immigration", "authors": [{"first": "U", "middle": ["S"], "last": "", "suffix": ""}], "year": 1999, "venue": "", "link": null}, "BIBREF13": {"title": "Advocacy Balanced Budget Act of 1997: Reshaping the Health Safety Net for America's Poor: An Analysis of the Medicaid Provisions", "authors": [], "year": 1997, "venue": "", "link": null}, "BIBREF15": {"title": "Kaiser Commission on Medicaid and the Uninsured Key Facts: Immigrants' Health Care Coverage and Access", "authors": [], "year": 2001, "venue": "", "link": null}, "BIBREF16": {"title": "How Job Characteristics, Immigrant Status, and Family Structure Keep Hispanics Uninsured", "authors": [{"first": "C", "middle": ["L"], "last": "Schur", "suffix": ""}, {"first": "J", "middle": [], "last": "Feldman", "suffix": ""}, {"first": "", "middle": [], "last": "Running In Place", "suffix": ""}], "year": 2001, "venue": "", "link": null}, "BIBREF17": {"title": "A changing picture of uncompensated care", "authors": [{"first": "P", "middle": ["J"], "last": "Cunningham", "suffix": ""}, {"first": "H", "middle": ["T"], "last": "Tu", "suffix": ""}], "year": 1997, "venue": "Health Aff", "link": "36342725"}, "BIBREF18": {"title": "The effect of changing state health policy on hospital uncompensated care", "authors": [{"first": "A", "middle": ["J"], "last": "Davidoff", "suffix": ""}, {"first": "A", "middle": ["T"], "last": "Losasso", "suffix": ""}, {"first": "G", "middle": ["J"], "last": "Bazzoli", "suffix": ""}, {"first": "S", "middle": [], "last": "Zuckerman", "suffix": ""}], "year": 2000, "venue": "Inquiry", "link": "6438902"}, "BIBREF19": {"title": "Managing the safety net: hospital provision of uncompensated care in response to managed care", "authors": [{"first": "J", "middle": [], "last": "Mann", "suffix": ""}, {"first": "G", "middle": [], "last": "Melnick", "suffix": ""}, {"first": "A", "middle": [], "last": "Bamezai", "suffix": ""}, {"first": "J", "middle": [], "last": "Zwanziger", "suffix": ""}], "year": 1995, "venue": "Adv Health Econ Health Serv Res", "link": "22259665"}, "BIBREF20": {"title": "The Commonwealth Fund Task Force on Academic Health Centers A Shared Responsibility: Academic Health Centers and the Provision of Care to the Poor and Uninsured", "authors": [], "year": 2001, "venue": "", "link": null}, "BIBREF21": {"title": "Uncompensated hospital care. Will it be there if we need it?", "authors": [{"first": "J", "middle": [], "last": "Weissman", "suffix": ""}], "year": 1996, "venue": "JAMA", "link": "46350479"}, "BIBREF22": {"title": "United States Bureau of the Census Web site", "authors": [], "year": 2000, "venue": "Dalaker J Poverty in the United States", "link": null}, "BIBREF23": {"title": "American Hospital Association Health Forum LLC (1994-1999) Annual Survey of Hospitals. Chicago, American Hospital Association", "authors": [], "year": 2000, "venue": "", "link": null}, "BIBREF24": {"title": "Snapshots of Public Benefits for Immigrants: A Supplemental Report to \"Patchwork Policies", "authors": [{"first": "K", "middle": ["C"], "last": "Tumlin", "suffix": ""}, {"first": "W", "middle": [], "last": "Zimmermann", "suffix": ""}, {"first": "J", "middle": [], "last": "Ost", "suffix": ""}, {"first": "", "middle": [], "last": "State", "suffix": ""}], "year": 1999, "venue": "", "link": null}, "BIBREF25": {"title": "Huber PJ The behavior of maximum likelihood estimates under non-standard conditions", "authors": [], "year": 1967, "venue": "Proceedings of the Fifth Berkeley Symposium on Mathematical Statistics and Probability", "link": null}, "BIBREF26": {"title": "White H A heteroskedasticity-consistent covariance matrix estimator and a direct test for heteroskedasticity. Econometrica", "authors": [], "year": 1980, "venue": "", "link": null}, "BIBREF27": {"title": "White H Maximum likelihood estimation of misspecified models", "authors": [], "year": 1982, "venue": "Econometrica", "link": null}, "BIBREF28": {"title": "Competition and Uncompensated Care Pools", "authors": [{"first": "R", "middle": ["R"], "last": "Bovbjerg", "suffix": ""}, {"first": "A", "middle": ["E"], "last": "Cuellar", "suffix": ""}, {"first": "J", "middle": [], "last": "Holahan", "suffix": ""}, {"first": "", "middle": [], "last": "Market", "suffix": ""}], "year": 2000, "venue": "", "link": null}, "BIBREF29": {"title": "The evolution of support for safetynet hospitals", "authors": [{"first": "L", "middle": ["E"], "last": "Fishman", "suffix": ""}, {"first": "J", "middle": ["D"], "last": "Bentley", "suffix": ""}], "year": 1997, "venue": "Health Aff", "link": null}, "BIBREF30": {"title": "Medicaid Disproportionate Share Hospital Payment Program: Background and Issues. Washington, DC, The Urban Institute", "authors": [{"first": "T", "middle": ["A"], "last": "Coughlin", "suffix": ""}, {"first": "", "middle": [], "last": "Liska D The", "suffix": ""}], "year": 1997, "venue": "", "link": null}, "BIBREF31": {"title": "Are urban safety-net hospitals losing low-risk Medicaid maternity patients?", "authors": [{"first": "D", "middle": ["J"], "last": "Gaskin", "suffix": ""}, {"first": "Hadley", "middle": ["J"], "last": "", "suffix": ""}, {"first": "Freeman", "middle": [], "last": "Vg", "suffix": ""}], "year": 2001, "venue": "Health Serv Res", "link": "43110273"}, "BIBREF32": {"title": "State trends in hospital uncompensated care", "authors": [{"first": "G", "middle": [], "last": "Atkinson", "suffix": ""}, {"first": "W", "middle": ["D"], "last": "Helms", "suffix": ""}, {"first": "J", "middle": [], "last": "Needleman", "suffix": ""}], "year": 1997, "venue": "Health Aff", "link": "8780295"}}, "ref_entries": {"FIGREF0": {"text": "Figure 1 Percentage of Foreign-Born, Noncitizen Residents by State, 1994", "type": "figure"}, "FIGREF1": {"text": "Figure 2 Percentage of Uninsured Residents by State, 1994", "type": "figure"}, "FIGREF2": {"text": "Figure 3 Poverty Rate by State, 1994", "type": "figure"}, "FIGREF3": {"text": "Figure 4 Uncompensated Care Expenditures Per Admission, 1994-1999. Uncompensated Care Expenditures Per Admission in States With the Most Legal Permanent Residents at the Time of PRWORA Enactment, 1994-1999*", "type": "figure"}, "TABREF1": {"text": "nonreimbursed services for patients whose eligibility for Medicaid has been changed by PRWORA.", "type": "table"}, "TABREF2": {"text": "Predictors of Hospital Charity Care Before and After Enactment of PRWORALogarithm value used in model to handle non-normal distribution \u2020 Significant at \u03b1 < 0.05. \u2021 Variable is dichotomous Note: CI indicates confi- dence interval.", "type": "table"}}}
{"paper_id": "2874531", "_pdf_hash": "57720591390898186fb16c351ae89af9ff0cdc87", "abstract": [{"section": "Abstract", "text": "Die Dokumente auf EconStor d\u00fcrfen zu eigenen wissenschaftlichen Zwecken und zum Privatgebrauch gespeichert und kopiert werden.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Sie d\u00fcrfen die Dokumente nicht f\u00fcr \u00f6ffentliche oder kommerzielle Zwecke vervielf\u00e4ltigen, \u00f6ffentlich ausstellen, \u00f6ffentlich zug\u00e4nglich machen, vertreiben oder anderweitig nutzen.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Sofern die Verfasser die Dokumente unter Open-Content-Lizenzen (insbesondere CC-Lizenzen) zur Verf\u00fcgung gestellt haben sollten, gelten abweichend von diesen Nutzungsbedingungen die in der dort genannten Lizenz gew\u00e4hrten Nutzungsrechte.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "This paper analyzes the impact of shortening the duration of secondary schooling on the accumulation of human capital. In 2003, an educational policy reform was enacted in Saxony-Anhalt, a German state, providing a natural experimental setting. The thirteenth year of schooling was eliminated for those students currently attending the ninth grade. Tenth grade students were unaffected. The academic curriculum remained almost unaltered. Primary data collected from the double cohort of 2007 Abitur graduates reveals significantly negative effects for both genders in mathematics. Only females were negatively effected in English and the results obtained in German literature were statistically insignificant.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "The enactment of educational policies designed to foster scholastic achievement must be a national priority. The schooling opportunities available to the nation's young people are essential ingredients for the cognitive skill formation process. Given today's accelerating technological change, together with an increasingly competitive global economic environment, the importance of cognitive skills has become recognized as essential for increases in individual earnings and aggregate economic outcomes. 1 Previously, public educational policy has been concerned principally with issues relating to the quantity of schooling. The implementation of compulsory education, raising the minimum school drop out age, and lengthening the time allotted for the completion of the necessary university entrance qualifications were enacted to enhance educational outcomes. 2 The opportunity costs associated with these quantity related policies, however, are high. They tend to reduce the time available for graduate studies, for the accumulation of work experience, for the earning of income, and for the starting of a family. Consequently, a superior educational policy should be one whose focus is to promote the quality of the educational experience and not one that simply adds to its quantity. 3 An important question, however, remains unanswered. Is it possible to achieve this goal by increasing the learning intensity ratio, i.e., the ratio of academic curriculum content per unit of instructional time? If the length of time students spend in school is reduced, while at the same time the curriculum content remains the same, is that the optimal way to shorten the duration of schooling without affecting the overall quality of education? Presently, little is known about the relationship between learning intensity, an essential element in the quality of education, and the academic achievement of students, a measure of their human capital accumulation. In this paper, the relationship between increased learning intensity ratios and the student academic achievements that result are investigated.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "International comparisons have shown that Gymnasium (secondary school) graduates in Germany are comparatively older than their counterparts in comparable countries. 4 As a result, almost all of the German states implemented policies designed to reduce the time spent in secondary school by eliminating the thirteenth year. This was done, however, without commensurately reducing the scholastic requirements for graduation. The academic curriculum remained almost unaltered and, therefore, the learning intensity ratio for the twelve-year students was considerably increased. This change was announced in 2003 and was enacted for the first time in 2007 in the state of Saxony-Anhalt. Subsequently, similar changes were implemented in almost all other German states. This educational reform provides a natural experimental setting where comparisons in the scholastic achievement of graduates in this double cohort of students can be compared.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "Using primary data from the Saxony-Anhalt double cohort of 2007 Abitur graduates, yields the following results: The estimated effects of increased learning intensities on the scholastic achievements of students depend on the specific academic subjects considered. In addition, the effects differ by gender. Significantly negative effects were discovered in mathematics for both genders, however, it was much more pronounced for males. Scholastic performance in foreign language was also decreased due to the reform for females, but the effect for males was statistically insignificant. No differences were discovered in German literature.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "There exists only very few published studies where the effects of increased learning intensity are related to scholastic achievements. Pischke (2007) investigated the impact of shortening the instructional time by two short school years 1966-7 in West Germany on grade repetition, secondary schooling opportunities, earnings, and employment. He found no negative effects on earnings and employment but there was an increase in grade repetition and lesser academic track choice. It is, however, the only study considering policy-induced variation in schooling time without a commensurate alteration in the curriculum. As there existed no standardized testing system in Germany at the time, he could not estimate the effect directly on student performance. Consequently, the opportunity for deriving insights concerning the development of human capital is limited for that reason. Furthermore, translating these results into today's world may be difficult, as the composition of the student body has changed substantially. Today there is a trend towards more students seeking diplomas in the highest level of secondary education. Further evidence was provided by Skirbekk (2006) who looked at the effect of variation in the duration of schooling on human capital using test scores from TIMSS for different Swiss cantons. He discovered that differences in the length of the Swiss academic program across regions had no influence on the scholastic achievement in mathematics and aged 19 whereas, e.g., in the Netherlands graduation age is 17-18 years, 18 years in the US, and 17 years in Russia.", "cite_spans": [{"start": 135, "end": 149, "text": "Pischke (2007)", "ref_id": "BIBREF22"}, {"start": 1161, "end": 1176, "text": "Skirbekk (2006)", "ref_id": "BIBREF24"}], "ref_spans": []}, {"section": "Introduction", "text": "science when school specific effects were taken into account. Marcotte (2007) , Lee and Barro (2001), and Woessmann (2003) examined the impact of considarable lower reductions in instructional time on student performance. Using Canadian data, Marcotte (2007) used the variation in school days caused by inclement winter weather to identify the impact of increased learning intensity on test scores. His findings are in line with the results presented herein. Students with less instructional time perform significantly worse than their peers most notably in mathematics. Lee and Barro (2001) investigated the effects of school resources on student performance as measured by internationally comparable test scores across countries. They found significant positive effects of the length of the school term on the mathematics and science scores, but significantly negative effects for reading. Woessmann (2003) discovered significantly positive, albeit relatively small, effects of instruction time on student performance in mathematics and science. This evidence suggests that the effect of increasing learning intensity on the accumulation of knowledge depends on the kind of subject.", "cite_spans": [{"start": 62, "end": 77, "text": "Marcotte (2007)", "ref_id": "BIBREF15"}, {"start": 80, "end": 87, "text": "Lee and", "ref_id": "BIBREF14"}, {"start": 88, "end": 105, "text": "Barro (2001), and", "ref_id": "BIBREF14"}, {"start": 243, "end": 258, "text": "Marcotte (2007)", "ref_id": "BIBREF15"}, {"start": 571, "end": 591, "text": "Lee and Barro (2001)", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "Introduction", "text": "In the Province of Ontario, Canada, an educational reform similar to the German took place.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "In this instance, the length of schooling in high school was reduced by one year. The major difference compared to the German experience, however, consists in a more modified academic curriculum. In Ontario less courses in main subjects like mathematics and the English language were made available for the treatment group and, therefore, the impact of the reform on learning intensity is not determinable. Moreover, the thirteenth year was not a full-fledged academic grade like it was in Germany. Students in Ontario were able to graduate from high school after the twelfth year. Before the educational reform was enacted, students could complete their schooling by utilizing this additional year or not. Morin (2010) estimated the effect of abolishing the thirteenth year on the academic performance of high-ability students in their first year at the university. He found only small effects on student performance. However, Krashinsky (2006) found larger negative impacts on academic performance at the university analyzing the impact of the same educational reform on students with lower high school grade averages. In addition to the differences with respect to learning intensity their analysis varies from the one presented here because we control for more of the student's personal background information. Another advantage of our study is the fact that the measurements of scholastic achievement were made at the completion of schooling. All of the students were required to take the final exams and so there is no potential for a self-selection problem as with Morin (2010) and Krashinsky (2006) who measure the performance later and only for university students.", "cite_spans": [{"start": 707, "end": 719, "text": "Morin (2010)", "ref_id": "BIBREF17"}, {"start": 928, "end": 945, "text": "Krashinsky (2006)", "ref_id": "BIBREF13"}, {"start": 1572, "end": 1584, "text": "Morin (2010)", "ref_id": "BIBREF17"}, {"start": 1589, "end": 1606, "text": "Krashinsky (2006)", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "Introduction", "text": "The present study contributes to the existing literature in several respects. It analyzes a policyinduced large-scale variation in the length of secondary schooling with only minor changes in the academic curriculum, which resulted in a considerably increased level of learning intensity.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "Identical final written exams for both grades allow for the direct assessment of school performance. Primary data was collected from the double cohort of the 2007 graduating class. The estimation model controlled for a number of student performance influencing factors such as family background, student ability, and school fixed effects. Furthermore, a check was made of the reliability of the assumptions inherent in the natural experiment used to identify the educational reform effect.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "The paper is organized into seven sections. Section 2 provides background information regarding the educational reform that took place in Germany. A presentation of the natural experiment and the estimation approach is provided in Section 3. The data set used for the empirical analysis is explained in Section 4 together with some selected sample statistics. The empirical estimates of the educational reform on the scholastic achievement of students are provided in Section 5. Section 6 provides a discussion of the implications from these results. The final section concludes.", "cite_spans": [], "ref_spans": []}, {"section": "Background", "text": "On average, university graduates in Germany are older when they enter the labor market than their counterparts in other comparable countries. This is the result of a longer university curriculum coupled with a prolonged period of secondary schooling (OECD, 2005) . As the result of the Bologna Process, originating with the signing of the Bologna Declaration in 1999, pressure upon Germany to reform its educational system has increased. 5 The responsibility for educational policy, however, including the funding of public schools, is entrusted to the Bundesl\u00e4nder (the German Federal Republic consists of sixteen states).", "cite_spans": [], "ref_spans": []}, {"section": "Schooling in Germany", "text": "The German educational system tends to differ from state to state. In the majority of states, however, students are enrolled in primary school at the age of six and remain there for four years. Upon completion, they are guided, according to their cognitive skills, into three available types of secondary schooling: the basic, the intermediate, and the university preparatory. The", "cite_spans": [], "ref_spans": []}, {"section": "Schooling in Germany", "text": "Hauptschule is the basic secondary school and provides educational instruction through the 5 The Bologna Process is the process of creating a European Higher Education Area (EHEA) by 2010, one that includes the adoption of the academic degrees (Bachelor, Master, and Doctorate) together with the introduction of a credit transfer system that recognizes higher educational course work done at other locations. ninth grade, the minimal required length of schooling. The Realschule provides the intermediate level of instruction through the tenth grade. Afterwards, the graduates from both of these schools usually commence some sort of vocational training in the apprenticeship program. Until recently, all states (with the exception of Saxony and Thuringia) provided thirteen years of university preparatory schooling in their Gymnasium leading to the Abitur (university admittance qualification). In addition to these three types of schools, several states provide an additional type of comprehensive schooling, the Integrierte Gesamtschule (an integrated comprehensive school). In this school, students can graduate after nine, ten, or thirteen years. As such, they are able to obtain the same corresponding academic degrees as offered by the other three types of secondary schooling. The significant difference in this type of schooling is that the students were not guided into a specific academic path before hand.", "cite_spans": [], "ref_spans": []}, {"section": "Schooling in Germany", "text": "As a consequence of the German political reunification, the existing West German schooling system was adopted in the early 1990's by most of the former East German states. Subsequently, a number of additional reforms were implemented as well. Previously, the German Democratic Republic (GDR) had a system of compulsory education, but students were not selected according to scholastic ability before the tenth grade. After the tenth grade only those who demonstrated a high level of cognitive skills in conjunction with an inclination towards the socialist ideological activities promoted by the regime were eligible for admittance into a two-year Gymnasium.", "cite_spans": [], "ref_spans": []}, {"section": "Schooling in Germany", "text": "Subsequently, university entrance qualifications were obtained after the twelfth grade. Two of the East German states, Saxony and Thuringia, introduced a student selection procedure before the tenth grade but retained the twelve-year graduation policy. The scholastic achievement of students in these states has proven to be quite good (PISA-Konsortium Deutschland, 2008) and this has added support to the debate concerning the abolishment of the thirteenth Gymnasium year in most German states.", "cite_spans": [{"start": 353, "end": 371, "text": "Deutschland, 2008)", "ref_id": "BIBREF21"}], "ref_spans": []}, {"section": "The Educational Reform", "text": "Saxony-Anhalt was the first German state to initiate an educational policy reform that shortened the length of secondary schooling by one year. The change was announced in 2003 and was implemented some months later at the beginning of the 2003/2004 academic year. The first students to be effected by this change were at that time in the ninth grade and were the first to receive their Abitur after completing twelve years of schooling. Consequently, in the spring of 2007, Saxony-Anhalt students in the twelfth grade (henceforth referred to as G12) and the thirteenth grade (G13) participated in a joint commencement ceremony. 6 The change was implemented as follows.", "cite_spans": [], "ref_spans": []}, {"section": "The Educational Reform", "text": "For the G12 students, the thirteenth year had been eliminated. The academic requirements for the Abitur, however, remained unaltered. In Germany, only the last two years of secondary schooling are considered when the eligibility for the Abitur is determined. Consequently, the academic curriculum of the twelfth and thirteenth grades now had to be pushed forward. During the transition period, schools had the opportunity to create new classes and/or to teach students from the double cohort jointly. The majority of schools did not establish new classes but provided combined courses for students from both cohorts in some subjects. For the G12 students, the curriculum of the former eleventh grade, called the preliminary grade, was distributed throughout the lower grades. The whole curriculum of instruction was moved forward in German literature as well as in the foreign languages. Only minor reductions were implemented in mathematics and chemistry whereas in some other subjects, (e.g., biology and history) parts of the eleventh grade curriculum were transformed into additional elective courses. The total instructional time for the G12 students had been reduced by one academic year. This loss was eased, however, by the addition of some extra classroom hours. Three instructional hours per week were added in the ninth grade and three in the tenth grade. Individual schools were allowed to decide, however, which subjects would receive these additional instructional hours.", "cite_spans": [], "ref_spans": []}, {"section": "The Educational Reform", "text": "This educational reform, consisting of the loss of a whole instructional year without a compensating reduction in the graduation requirements, must have affected the students involved in a myriad of ways. This research, however, concentrates on the affects of human capital accumulation as measured by the final examination test grades in three different subjects areas: mathematics, German literature, and foreign language (English). Differences might be expected since abolishing one whole year results in less time for instruction and homework, thus increasing the learning intensity. In addition, the time available for extracurricular and leisure activities is also reduced, resulting in the reduced accumulation of some important noncognitive skills. These are capable of improvement at least until the age of twenty (Dahl, 2004) or later (Caspi and Roberts, 1999) and relate to the formation of important human qualities such as self-reliance and discipline.", "cite_spans": [{"start": 823, "end": 835, "text": "(Dahl, 2004)", "ref_id": "BIBREF4"}, {"start": 845, "end": 870, "text": "(Caspi and Roberts, 1999)", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "The Natural Experiment", "text": "The experiences of Saxony-Anhalt in educational policy reform provides a natural experimental setting for the investigation of the effects of shortening the duration of schooling while holding the content of the academic curriculum approximately constant. 7 Standardized written exams were employed and the same academic grading scheme, provided by the state Department of Education, were used to evaluate all of the students involved. The examinations in mathematics and German literature are mandatory. In addition, a foreign language is also required. Students are allowed, however, to make their own selection. The vast majority chooses to take this examination in the English language.", "cite_spans": [], "ref_spans": []}, {"section": "The Natural Experiment", "text": "The assignment of students to the treatment group, G12, and to the control group, G13, can be assumed to be random. This is due to the fact that the public announcement and the policy implementation occurred simultaneously. The impacted students in the treatment group had been enrolled in secondary school for a number of years already and simply received the notification without being required to initiate any actions. If there had been some degree of selection bias between groups this should be observable when comparing the pre-treatment characteristics of the sample. Anticipation of the reform could have created an incentive for parents to move within a very short time span to a different state within Germany. The opportunity cost of such a move, however, would be extraordinarily high. Therefore, this type of anticipation effect is very unlikely. On the other hand, if students attempted to commute to a school in a neighboring state, the closest border is far away (about 50 km) and this option is equally unattractive.", "cite_spans": [], "ref_spans": []}, {"section": "The Natural Experiment", "text": "Assuming that the estimates have internal validity, there still may be concerns with respect to the external validity of the natural experiment, i.e., translating the specific findings from the study into a more general setting (Meyer, 1995) . A serious obstacle could be the existence of a general time trend in the accumulation of human capital. If this were the case, the models presented here would not capture the causal effect of shortening the duration of secondary schooling. Although a time trend in cognitive achievement is perhaps likely in younger children, it is not very likely to be present in the later periods of educational development considered in this study. ", "cite_spans": [{"start": 228, "end": 241, "text": "(Meyer, 1995)", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "The Theoretical Relationship", "text": "Assume that the final examination test grades attained by students are the outcomes of a discrete random variable Y = y, y = {0, 1, 2, ..., 15}, capable of taking only sixteen non-negative integer outcomes. This academic grading scheme consists of ordinal numbers that rank levels of scholastic achievement in increasing order from zero denoting failure to fifteen, the highest level of scholastic excellence. The students receiving these grades are differentiated from one another by numerous personal distinguishing characteristics, originating from a variety of socioeconomic, demographic, and geographic sources. For estimation purposes, these specific characteristics must be observable, measurable, and appropriate for all of the students considered. The columns of the matrix X consist of random variables denoting these characteristics and its rows contain all possible combinations of their outcomes. A joint population probability distribution exists consisting of all the variables heretofore defined. Therefore, the discrete univariate conditional random variables (Y |X), one for each row of the X matrix, have conditional expectations.", "cite_spans": [], "ref_spans": []}, {"section": "The Theoretical Relationship", "text": "Assume that these expectations are linearly related to each other:", "cite_spans": [], "ref_spans": []}, {"section": "The Theoretical Relationship", "text": "(1)", "cite_spans": [], "ref_spans": []}, {"section": "The Theoretical Relationship", "text": "where vector \u03bb determines how the average value of Y changes as elements of X change. In the population the single valued Conditional Expectation Function (CEF) assigns to each possible combination of student characteristics a conditional mean grade.", "cite_spans": [], "ref_spans": []}, {"section": "The Basic Model", "text": "In order to facilitate estimation of the impact of the educational policy reform in question on the observed scholastic achievements attained by the students in the G12 and G13 groups, some additional specification is required. In addition to the pooled data, the grades were also sorted by gender, g = {pooled, female, male}. Green and Oxford (1995) matrix D consists of eleven columns of dummy variables that identify the school in which the grades were earned (there are twelve schools in the sample and school number eleven is taken as the reference), and, finally, the matrix P contains certain relevant personal characteristics describing the students involved.", "cite_spans": [{"start": 327, "end": 350, "text": "Green and Oxford (1995)", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "The Basic Model", "text": "The transpose of the column coefficient vector are: \u03bb s 1g = [\u03b1|\u03b2|\u03b3|\u03b4], where \u03b1 is an intercept term, \u03b2 is the coefficient used to highlight differences in the conditional mean grades attributable to the educational policy change, the coefficients in the vector \u03b3 capture school specific effects, and the coefficients in the vector \u03b4 adjust the conditional mean grades for the personal distinguishing characteristics of students. The estimated Sample Regression Functions are:", "cite_spans": [], "ref_spans": []}, {"section": "The Basic Model", "text": "According to the hereinbefore-stated assumptions, unbiased estimates of the coefficients in the vectors, \u03bb s 1g , are obtained by performing Ordinary Least Squares (OLS) regressions utilizing the observed scholastic grades and the corresponding explanatory variables. Individual regressions were performed as well as gender-pooled regressions. The estimated conditional mean grades obtained, y s g , are minimum Mean Squared Error (MSE) predictions. The estimated coefficients, \u03b2 s g , are of primary interest, however, for they capture the scholastic achievement differences between the students belonging in the treatment group, G12, and those in the control group, G13, due to the policy reform. 9", "cite_spans": [], "ref_spans": []}, {"section": "The Expanded Model", "text": "The expanded version of the model includes additional information concerning the specific school where the members of the G12 and G13 groups earned their grades. The scholastic achievements that were obtained on the centralized exams are likely to be school dependent. Consequently, a twelve-column (one for each school) matrix named D 2 is utilized rather than the dummy vector d. The school-specific columns of the D 2 matrix are dichotomous variables taking one indicating when members of the G12 group earn their grades in particular school and zero for the G13 group. This is surmised to be the case because school-specific factors are deemed to influence the impact of the educational reform. For example, differences can exist in the inherent quality and experience level of the teaching staff, differences in the overall academic climate prevailing that can stimulate students to undertake scholastic achievement, curriculum planning differences leading to the most efficient timing of the instructional periods, differences in the availability of up-to-date academic facilities, or simply differences in the socioeconomic makeup of the student body, to name but a few relevant factors. Therefore, it was deemed necessary to control for these school-specific influences as well. Commensurate with these additional considerations, the Expanded Model is:", "cite_spans": [], "ref_spans": []}, {"section": "The Expanded Model", "text": "The matrix X is now partitioned as: The combined graduating class in 2007 consisted of 1,628 students from the G12 and G13 groups.", "cite_spans": [], "ref_spans": []}, {"section": "The Expanded Model", "text": "Unfortunately, however, only 1,464 questionnaires could be administered because the names and/or addresses of 164 students were unavailable. In the end, 805 responses were returned yielding a response rate of 55%. In order to maintain consistency within the sample, only those students who were continuously enrolled in Germany during their complete schooling were included. Those students who took advantage of an exchange abroad or repeated a grade are excluded from the analysis. 12 This reduced the sample by 81 students, resulting in a final sample size of 724 observations. It should be noted that the numbers of observations in the estimations presented below may differ due to item non-response in some variables. A description of the items collected by the questionnaire is provided in the Appendix.", "cite_spans": [], "ref_spans": []}, {"section": "The Sample", "text": "The proportional distribution of the students in the G12 and G13 groups by gender within the twelve schools is provided in Table 1 . It is noteworthy that the share of male students (37%) is much smaller than that of female students (63%). This finding is not the result of an imbalance in the response rates but it reflects a trend in university preparatory schooling that began in Germany more than a decade ago (destatis, 2009). Moreover, the schools differ significantly in regards to the size of their student body. Geographic location, academic reputation, and/or certain school specific forms of specialization give rise to these differences. Specialized schools usually focus upon the natural sciences, sports, or have a particular religious orientation. The distribution of students between the G12 and G13 groups within specific schools does not differ significantly. Only a slight difference is observed, however, in the male sample for schools number 6. This imbalance within the sample, however, does not affect the estimated effects of the reform because school specific effects are provided for in the model.", "cite_spans": [], "ref_spans": [{"start": 123, "end": 130, "text": "Table 1", "ref_id": "TABREF1"}]}, {"section": "The Sample", "text": "Include Table 1 about here Mean values for a selection of student-specific variables by gender are presented in Table 2 .", "cite_spans": [], "ref_spans": [{"start": 8, "end": 26, "text": "Table 1 about here", "ref_id": "TABREF1"}, {"start": 112, "end": 119, "text": "Table 2", "ref_id": "TABREF2"}]}, {"section": "The Sample", "text": "At the top of this table are the means of the final grades obtained in mathematics, German literature, and English by the students in the G12 and G13 groups. These grades are significantly different for both genders in mathematics. The magnitude of these differences, however, cannot be solely attributed to the reform due to the presence of other relevant factors. Below these values are the analogous grades achieved by these same students in the seventh year of schooling.", "cite_spans": [], "ref_spans": []}, {"section": "The Sample", "text": "These seventh grade achievements display no significant differences for both genders in the three subjects considered. This provides support to the assumption of the natural experiment.", "cite_spans": [], "ref_spans": []}, {"section": "The Sample", "text": "Include Table 2 about here", "cite_spans": [], "ref_spans": [{"start": 8, "end": 15, "text": "Table 2", "ref_id": "TABREF2"}]}, {"section": "The Sample", "text": "The published literature indicates that the degree of intellectual support that the student receives from the family environment is an important ingredient for educational success (Fuchs and Woessmann, 2007, as well as Todd and Wolpin, 2007) . Mean values of certain variables characterizing the family background of the graduates are presented in Table 3 . These variables relating to characteristics of the mothers, the fathers, and other home related items show no great differences between the treatment and control groups of students. Therefore, there is no reason to expect any systematic differences in the outcomes due to the student's home environment. Looking at the items available in the homes of the students shows that on average the households are adequately equipped. There are no significant differences in any of the items between grades.", "cite_spans": [{"start": 180, "end": 190, "text": "(Fuchs and", "ref_id": "BIBREF8"}], "ref_spans": [{"start": 348, "end": 355, "text": "Table 3", "ref_id": "TABREF3"}]}, {"section": "The Sample", "text": "Hence, this further supports a picture of comparability between the treatment group (G12) and the control (G13) group.", "cite_spans": [], "ref_spans": []}, {"section": "Empirical results", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "The Basic Model", "text": "The three academic subject areas considered can be construed as proxies for important intellectual capabilities required by students for further study. Mathematics requires logical thinking and a capacity for abstraction. Literature promotes the linguistic instinct and is useful for developing competence in communication. English demonstrates the ability of German students to acquire foreign language skills. Although one could think of other relevant proficiencies, these three subject areas are considered capable of capturing the main prerequisites for a successful university education. They are, therefore, of vital interest when evaluating the effects caused by a reduction in the length of secondary schooling.", "cite_spans": [], "ref_spans": []}, {"section": "The Basic Model", "text": "The Basic Model was estimated both gender specific and pooled. Furthermore, two versions of the matrix P were considered. An abridged version, hereafter referred to as Basic Model (1), contained only three variables while the matrix utilized in Basic Model (2) contained these plus an additional eleven. These variables relating to specific family background characteristics of the students involved have proven to be relevant in the empirical literature (see, e.g., Fuchs and Woessmann, 2007) .", "cite_spans": [{"start": 467, "end": 493, "text": "Fuchs and Woessmann, 2007)", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "Mathematics", "text": "The estimated coefficients in the pooled sample of approximately \u03b2 M = \u22120.7 reveal the highly significant negative effect of the educational reform in both of the Basic Models (1) and (2), see Table 4 . Consider the average student calculated as the average of the individual means. Basic", "cite_spans": [], "ref_spans": [{"start": 193, "end": 200, "text": "Table 4", "ref_id": "TABREF4"}]}, {"section": "Mathematics", "text": "Model (1), estimated with gender-pooled data, would predict that the conditional mean final grades earned by this student would be reduced by 9.1 percent (7.75 to 7.04) as a result of the educational reform. This is a significant reduction. The reform that was implemented reduced the instructional time but not the content of the curriculum. In the case of mathematics, there seems to exist limitations in the ability of young people to accelerate the accumulation of knowledge. It is reasonable to assume that those students possessing the highest potential to achieve arising from such innate factors as intelligence, self-discipline, scholastic motivation, social background, etc., would fare better than the others. Nevertheless, a reduction in the final grade should be expected.", "cite_spans": [], "ref_spans": []}, {"section": "Mathematics", "text": "Include Table 4 about here When male and female students are considered separately, gender differences become quite apparent. Although students graduating after 12 years experience a decrease in grades in mathematics independently of gender, the negative effect tends to be almost twice as large for males compared to females. Males are on average slightly about 1 point worse off, whereas females are worse off about 0.5 points. Nevertheless, the estimated effects for both genders are significant. For the average male student this translates into a 10.9 percent reduction in his conditional mean final grade (7.79 to 6.94) while the average female student experiences only a 7.9 percent reduction (7.72 to 7.11). These findings clarify the different effects of shortening schooling duration for both genders beyond the gender-specific constant regarded in the pooled estimation. Males and females react differently to the applied changes in learning intensity.", "cite_spans": [], "ref_spans": [{"start": 8, "end": 15, "text": "Table 4", "ref_id": "TABREF4"}]}, {"section": "Mathematics", "text": "Regarding the estimates of the further control variables, the first thing to note is the betweenschool variation in grades. This variation reflects differences in teaching quality, differences in infrastructure, class sizes, and differences in peer groups. As expected, the grades earned by students in their seventh year are highly significant when predicting the final conditional mean grades. The negative sign is due to the inverse relationship that exists between the two grading schemes. 15 The age at initial enrollment has a negative effect on grades, i.e. students that have started schooling at a younger age have a slightly better achievement score in mathematics at graduation. Muehlenweg and Puhani (2009) have shown that this should not be interpreted simply as caused by the age of enrollment, but is more likely to provide a proxy for unobserved ability in the sense that persons with lower unobserved abilities tend to enroll later on average.", "cite_spans": [{"start": 690, "end": 718, "text": "Muehlenweg and Puhani (2009)", "ref_id": "BIBREF18"}], "ref_spans": []}, {"section": "Mathematics", "text": "The presence of a large private book collection at home seems to have a significantly positive influence on the grades of male students, whereas their female counterparts are impacted to a lesser degree. In addition, with regard to the further variables considered to capture details of the background of the student all coefficients show the expected signs.", "cite_spans": [], "ref_spans": []}, {"section": "German Literature", "text": "The estimated coefficients \u03b2 L in the pooled sample (Table 5 ) reveal a non-significant negative effect of about -0.1 in Basic Model (1) and slightly larger in (2). Basic Model (1), estimated with gender-pooled data, would predict that the conditional mean grade earned by the average student calculated as above would almost remain constant (with an increase by 0.4 percent from 8.55 to 8.59 points).", "cite_spans": [], "ref_spans": [{"start": 52, "end": 60, "text": "(Table 5", "ref_id": "TABREF6"}]}, {"section": "German Literature", "text": "Include Table 5 about here 15 From year 2 to 10 students receive grades defined between 1 (excellent) and 6 (failure), the scale after year 10 is defined reversely from 15 (excellent) down to 0 (failure).", "cite_spans": [], "ref_spans": [{"start": 8, "end": 26, "text": "Table 5 about here", "ref_id": "TABREF6"}]}, {"section": "German Literature", "text": "When male and female students are considered separately, once again gender specific differences are apparent. Although females earn on average higher grades, gender specific regressions show that female students would experience no change in their conditional mean final grade (8.82 to 8.83), while the average male student would experience a negligible increase by 1.7 percent (8.08 to 8.22).", "cite_spans": [], "ref_spans": []}, {"section": "German Literature", "text": "In contrast to the effect on the grades in mathematics, there are no significant effects due to shortening the schooling duration on those in German literature. School specific factors remain important with female grades less affected than males. The age of the student at initial enrollment has a non-significant negative impact for the male students. The estimated coefficients for female students are positive but not significant either. The presence of large private book collections at home has a significantly positive influence on the grades of the female students, whereas males are impacted to a lesser degree.", "cite_spans": [], "ref_spans": []}, {"section": "English Language", "text": "Since the English language is not a mandatory subject, there could exist some grade specific self-selection that would affect the outcomes. There are, however, only slight differences in the personal characteristics of the students in the G12 and G13 groups as well as small differences in the grades earned in the seventh grade. Furthermore, the estimated models take this into account and the parameters estimated should be unbiased as a result.", "cite_spans": [], "ref_spans": []}, {"section": "English Language", "text": "Include Table 6 about here The estimated coefficients \u03b2 E in the pooled sample provided in Table 6 reveal a non-significant negative effect of about -0.29 in both Basic Models (1) and (2). Similar to the results for German literature, the parameter estimate of the treatment effect is negative but not statistically significant in the pooled sample. Hence, although students experienced the same amount of education in a different time span this has no effect on the written examinations. Nevertheless, when considering gender differences, heterogeneity in the estimates could be revealed. For females, reducing the schooling duration by one year leads to a significant decrease in achievement scores in English of about 0.6 points. In contrast, males are not affected and the point estimates even show a positive (but insignificant) effect of earlier graduation. Gender specific regressions show that the average female student would experience a significant 4.3 percent reduction in her conditional mean final grade (8.70 to 8.32), while the male counterpart would fare much better with a non-significant 4.7 percent increase (7.56 to 7.91).", "cite_spans": [], "ref_spans": [{"start": 8, "end": 26, "text": "Table 6 about here", "ref_id": "TABREF7"}, {"start": 91, "end": 98, "text": "Table 6", "ref_id": "TABREF7"}]}, {"section": "English Language", "text": "The age of initial enrollment has no significant impact for students. The English language grade earned in the seventh grade is a highly significant variable for both genders. This indicates that some people possess a higher inate ability to learn foreign languages than do others. Having learned the basics early on is an essential ingrediate for a good final grade. The age of students at initial enrollment as well as the existence of private book collections in the home do not exhibit significant effects.", "cite_spans": [], "ref_spans": []}, {"section": "The Expanded Model", "text": "The Expanded Model was estimated to investigate whether there exists a differential effect of the educational reform attributable to specific schools. This type of effect is likely since schools differ not only with respect to the proficiency of their teachers, the existing social interaction within the peer groups, the geographic location, but also due to differences in the administrative implementation of the reform itself. Schools may well have adjusted to the change very differently. The Expanded Model was estimated both gender specific and pooled. Once again, two versions of the matrix P were considered. An abridged version, hereafter referred to as Expanded Model (1), contained only three variables while the matrix utilized in Expanded Model (2) contained these plus an additional eleven.", "cite_spans": [], "ref_spans": []}, {"section": "Mathematics", "text": "Starting with the results for mathematics (Table 7) , the estimates establish some heterogeneity in the effects between schools. Almost all of the point estimates are negative in the pooled sample, however, depending on the model specification only four (Exp. Model (1)) and five (Exp. Model (2)) parameter estimates are significantly different from zero.", "cite_spans": [], "ref_spans": [{"start": 42, "end": 51, "text": "(Table 7)", "ref_id": "TABREF8"}]}, {"section": "Mathematics", "text": "Include Table 7 about here When male and female students are considered separately, gender differences once again become quite apparent. Gender specific regressions show that male students experienced a more pronounced negative effect compared to females and the importance of school specific factors in the prediction of the conditional mean final grades is more important. In some of the schools, students graduating after 12 years obtained even about 3 points lower achievement scores due to the reform.", "cite_spans": [], "ref_spans": [{"start": 8, "end": 15, "text": "Table 7", "ref_id": "TABREF8"}]}, {"section": "German Literature", "text": "No apparent effect of the shortening of secondary schooling on the scholastic achievement scores in German literature was discovered (Table 8 ). There exists no real difference between students graduating in the G12 and G13 groups. Although the results establish some differences in the effects across schools, only a few estimates are clearly significantly different from zero in the pooled and gender-specific samples. Moreover, the signs of the parameter estimates vary across the schools, and in some cases the students graduating in the G12 group were better off compared to those in the G13 group, whereas in others the picture is reversed.", "cite_spans": [], "ref_spans": [{"start": 133, "end": 141, "text": "(Table 8", "ref_id": "TABREF9"}]}, {"section": "German Literature", "text": "Include Table 8 about here", "cite_spans": [], "ref_spans": [{"start": 8, "end": 15, "text": "Table 8", "ref_id": "TABREF9"}]}, {"section": "English Language", "text": "In the gender-pooled as well as in the female only estimation results, graduates in the G12 group are slightly worse off (Table 9 ). This finding, however, is not supported by the results for males.", "cite_spans": [], "ref_spans": [{"start": 121, "end": 129, "text": "(Table 9", "ref_id": "TABREF10"}]}, {"section": "English Language", "text": "Here, despite the differences in the effects significant estimates indicate benefits for males in the G12 group from the educational reform. As only three of the point estimates are statistically significant, this finding is not at all conclusive for the improved human capital achievement.", "cite_spans": [], "ref_spans": []}, {"section": "English Language", "text": "Include Table 9 about here", "cite_spans": [], "ref_spans": [{"start": 8, "end": 15, "text": "Table 9", "ref_id": "TABREF10"}]}, {"section": "The Robustness of the Estimation", "text": "Basic Model (2) was estimated under a variety of data restrictions in order to determine the robustness of the empirical results presented. For the sake of brevity, only those results obtained utilizing gender-pooled data in the subject areas of mathematics (Table 10) and German literature (Table 11 ) are presented.", "cite_spans": [], "ref_spans": [{"start": 258, "end": 268, "text": "(Table 10)", "ref_id": "TABREF1"}, {"start": 291, "end": 300, "text": "(Table 11", "ref_id": "TABREF1"}]}, {"section": "The Robustness of the Estimation", "text": "Include Tables 10 and 11 about here First of all, the data was sorted by city. The model was estimated separately for Magdeburg (MAG) and for Halberstadt (HAL). The estimation results indicate that the effects of the educational reform on the scholastic achievement scores in mathematics differ slightly between regions. The reform, however, made a slightly bigger negative impact in the city of Halberstadt. Despite this small difference, the estimated coefficients are very similar indicating that no strong regional variation is present that is not captured by the school specific effects already accounted for in the model. The results for German literature are quite similar. The estimated coefficient, although insignificant, is a bit lower for the city of Magdeburg.", "cite_spans": [], "ref_spans": [{"start": 8, "end": 35, "text": "Tables 10 and 11 about here", "ref_id": "TABREF1"}]}, {"section": "The Robustness of the Estimation", "text": "Second, the sample was sorted according to the type of school attended. The model was estimated using data only from Gymnasium (GYM) type schools located in the city of Magdeburg (MAG). In this case, the estimated coefficients show a similar effect compared to that when all schools in the city of Magdeburg were considered. This is true for mathematics as well as for German literature, even though the latter effect was insignificant. Finally, the model was estimated using data only from the larger (LAR) schools, i.e., those with more than eighty observations. The estimates demonstrate that the effect on the scholastic achievement grades in mathematics is the smallest yet. This could indicate that the larger schools are more flexible and capable of adjusting to a new situation than are their smaller counterparts. Nevertheless, this result is true only for mathematics. In German literature, the point estimate is positive. It is, however, statistically insignificant.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "Shortening the length of secondary schooling by twelve months without making a commensurate reduction in the academic curriculum affects the behavior of the impacted students in numerous ways. The time available for instructional purposes is reduced in almost all subject areas and only a limited number of additional hours are added in the core subjects. Consequently, the time available for absorbing the relevant material, for accomplishing the necessary homework, for comprehending the essentials, and reiterating the pertinent subject matter declines, while the same academic requirements remain. The learning intensity, the quantity of material to be learned per time period, increases dramatically. This acceleration in the tempo of learning will affect student performance in various ways. Some students may not be able to cope with the increased requirements per year. Therefore, dropout ratios, switching to special schools where graduation is still possible after thirteen years, or repeating grades might become increasingly likely scenarios. Although these behaviors existed before the educational reform was enacted, they may well be reinforced and become increasingly prevalent.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "In order to analyze these reform affects, the number of school dropouts, grade repeaters, and those who changed schools would be required. Unfortunately, access to these numbers is restricted. Therefore, the fraction of students who complete a university qualifying secondary education after the compulsory period of schooling is all that is available. 16 Mandatory schooling in Germany ends after nine years. Thus, students can depart and commence vocational training if they desire. This departure behavior could also be influenced by the educational reform enacted. Therefore, the number of ninth grade students attending the Gymnasium was compared to those who completed the secondary school final examinations in regular time. In the G13 group 78.3 percent of the students graduated. In the G12 group a lower amount, 69.7 percent, was observed. Approximately half of this difference rests on the fact that the rules for spending a year abroad differ in these groups. Students in the G12 group who studied a year abroad had to graduated one year later in 2008 whereas students of the G13 group were allowed to return to their old class. The remaining difference incorporates those students who were not able to cope with the increased learning intensity.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "If especially low ability students disappeared from the G12 group, the average grades of the G12 students would probably be higher than the average grades of the G13 students at the time of final examinations. Estimation of the effects of student performance in the analyzed subjects would have been biased and the results should have been interpreted as the lower bound of the reform effects. However, nothing indicates biased estimators. For the results presented above the difference is relevant if dropout rates are non-random across the grades, since the data used in the empirical analysis comprise retrospective information surveyed from the graduates. As shown above, however, when comparing the pre-reform characteristics of the students, no observable differences with regard to ability or background variables could be established. Therefore, there is no indication that the estimates are biased due to possible self-selection.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "The empirical results suggest substantial differing effects resulting from the shortening of the secondary schooling by one year on human capital accumulation. The impacts are significantly negative on student performance in mathematics for both genders and in foreign language for females only. The effects, however, are insignificant in German literature. One possible explanation for these findings can be the existence of different requirements in higher grades for the subject areas considered here. Whereas, the curriculum in mathematics requires exposure to new fields, e.g., statistics, accompanied by the learning of new methods and the understanding of the underlying concepts. The curriculum in literature and in the foreign languages, however, focuses upon the refinement of familiar concepts and on the application of these concepts. Eren and Henderson (2009) make a similar argument regarding the effects of additional homework on test scores. They find evidence of positive and significant effects of homework on mathematics test scores (see also Aksoy and Link, 2000; Eren and Henderson, 2007) , but little or no impact on test scores in other subjects like literature. There is no educational reform effect discovered in literature. This result does not indicate whether the level of education is satisfying. All in all, however, the marginal contribution of the thirteenth year to native language skills appears to be negligible.", "cite_spans": [{"start": 1062, "end": 1083, "text": "Aksoy and Link, 2000;", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "Discussion", "text": "The marginal contribution to the mathematical skills, however, is highly significant and may have serious consequences on labor demand and supply. To fill the existing shortage of engineers and graduates from the natural sciences, society urgently needs people with excellent mathematical skills. The negative impact of the educational reform indicates that additional responsibility for the preparation of students will be passed on to the universities. Unfortunately, in light of the limitations of instructional time already at the universities, a change in the academic curriculum of the secondary schools will become necessary. The long-term effects of this cannot be evaluated as yet. Due to the fact that graduates from the G12 group perform comparatively worse in mathematics, probably less of them will enroll in engineering or in the natural sciences and the shortages will increase in the future. This will require a change in the allocation of the instructional time across academic subject areas in the schools.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusion", "text": "It is recognized that an adequate amount of instructional time is an essential ingredient in the development of human capital. A sufficient understanding concerning the relationship between these instructional hours and their impact on the human capital enhancement of students, however, is still in its infancy. The gain in human capital that can be attributed to the instructional hours received in schools depends on a diverse set of factors. The innate ability of students to absorb the available knowledge, the amount of effort they expend in this intellectual endeavor, the possibility to interact with stimulating teachers, an amiable social contact with peers, availability of up-to-date academic resources in the school, to name but a few, all play an important role. Presently, there is little evidence concerning the function of the academic curriculum as an important institutional factor in this process of human capital accumulation. The implementation of academic curriculum affects human capital accumulation by its impact on the learning intensity ratio. Consequently, it is useful to study the link between learning intensity and student scholastic achievement. The current lack of evidence in the literature is due to the difficulty in collecting suitable data. This paper attempts to fill this gap and to contribute in this area.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusion", "text": "This study is an econometric examination of a very rare educational policy reform that took place in 2007 in Saxony-Anhalt, Germany. This reform shortened the duration of secondary schooling by one full year while maintaining the academic curriculum requirements for graduation nearly unaltered. This substantially increased the learning intensity ratio experienced by the students involved. The estimated effect of this increased learning intensity on student scholastic achievement depends on the particular subject areas studied and they differ by gender.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusion", "text": "Significantly negative effects on student scholastic performance in mathematics was discovered that was much more severe for males than for their female counterparts. Scholastic achievement in the English language decreased for females, but the effect for males was statistically ", "cite_spans": [], "ref_spans": []}, {"section": "A Appendix", "text": "In order to provide an overview of the available information provided by the survey, the 101 questions can be divided into the following ten categories:", "cite_spans": [], "ref_spans": []}, {"section": "A Appendix", "text": "1. Personal information: The first set of questions cover certain personal characteristics of the student such as date of birth, gender, legal address, place of residence during schooling, number of relocations, nationality, number of close friends, etc.", "cite_spans": [], "ref_spans": []}, {"section": "Family background:", "text": "This category provides details concerning the family of the student, including information about the parents, the siblings, and the household in general. Information about the father and the mother are separate and cover such items as: age, the time of cohabitation with each parent, divorce, deceased, changing partners of the parent, education, occupational degree, unemployment, and personal involvements, e.g., cultural, political, religious, or sport. The family background includes household details including the number of books owned by the parents and other relevant equipment in the household. For these items the use by the student is important, e.g., Internet access, dictionaries, newspapers, reference books, etc. Information about the siblings of the student includes: number, gender, age, education, etc.", "cite_spans": [], "ref_spans": []}, {"section": "Family background:", "text": "3. Schooling, general information: General information includes: the time of pre-school, primary, secondary schooling, changes of residence during that time, grade repetition, etc.", "cite_spans": [], "ref_spans": []}, {"section": "Family background:", "text": "4. Schooling, detailed information: This contains details of the curriculum of the student.", "cite_spans": [], "ref_spans": []}, {"section": "Family background:", "text": "An example are the sequence of enrollment, the grades when courses where started, the duration and the number of foreign languages learned at school. Moreover, information on natural sciences (biology, chemistry, physics) is provided in this category and there are questions covering details of additional in-school education the students attained. Furthermore, a number of questions are devoted to assess the stress and burden of schooling of the students, an assessment of the skills learned at school and the valuation of teaching these skills at school.", "cite_spans": [], "ref_spans": []}, {"section": "Education outside school:", "text": "Classes at school provide a relevant part of individual's education but many students participate in a number of educational activities outside school.", "cite_spans": [], "ref_spans": []}, {"section": "Education outside school:", "text": "These activities comprise, e.g., musical classes, sports, journalistic activities such as student newspapers, political activities, etc. Information on different activities and the number of years of these activities is given by in this category.", "cite_spans": [], "ref_spans": []}, {"section": "6.", "text": "Last year of school and graduation: Questions describing the last year of school and graduation cover the class size, the types of the main courses (basic courses and intensified courses taught with more hours per week), the achievement score in each of these courses, the overall achievement score, activities outside school (working, homework, etc.), the state of health during the last year of school, spending of leisure time and leisure activities (dating friends, reading, chatting, etc.), and consumption of alcoholic beverages and smoking behavior. 7. Support from parents, teachers and other persons: This category comprises the incidence and amount of support with schooling tasks and homework from close relatives, particularly the parents, teachers, and other persons like friends, siblings and peers.", "cite_spans": [], "ref_spans": []}, {"section": "Education after graduation:", "text": "Since students in the survey have graduated in 2007, about 18 months have passed between graduation and the date of interview. The activities that took place during that time are reported in a retrospective monthly calendar covering various states of employment, civil and military service, education, and times spent abroad. In addition, information on the financing of living today, the type of education (apprenticeship, university or university of applied sciences studies), the subject, the aspired degree (e.g., bachelor, master, PhD), and on reasons for the choice of education is provided. 9. Assessment of school: In this category the students were asked to assess the value of schooling for different skills: logical thinking, independence, ability to accept criticism, cooperation in teamwork, practical skills, technical skills, etc. In addition, several items evaluating the relationship between teachers and students were collected.", "cite_spans": [], "ref_spans": []}, {"section": "Education after graduation:", "text": "10. Attitudes and non-cognitive skills: In the final set of questions information concerning various items was collected in order identify certain aspects of the student's personality.", "cite_spans": [], "ref_spans": []}, {"section": "Education after graduation:", "text": "The set of items could be used to derive measures of non-cognitive skill levels. a All standard errors are clustering-robust based on class as the sampling unit. * p < 0.1, * * p < 0.05, * * * p < 0.01 a All standard errors are clustering-robust based on class as the sampling unit. ", "cite_spans": [], "ref_spans": []}, {"section": "Tables", "text": "", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "A Panel Analysis of Student Mathematics Achievement in the US in the 1990s: Does Increasing the Amount of Time in Learning Activities Affect Math Achievement?", "authors": [{"first": "T", "middle": [], "last": "Aksoy", "suffix": ""}, {"first": "C", "middle": ["R"], "last": "Link", "suffix": ""}], "year": 2000, "venue": "Economics of Education Review", "link": "42325967"}, "BIBREF1": {"title": "Personality Continuity and Change across the Life Course", "authors": [{"first": "A", "middle": [], "last": "Caspi", "suffix": ""}, {"first": "B", "middle": ["W"], "last": "Roberts", "suffix": ""}], "year": 1999, "venue": "Handbook of Personality: Theory and Research", "link": "141107272"}, "BIBREF3": {"title": "Critical Analysis of the Current Approaches to Modelling Educational Effectiveness: The Importance of Establishment a Dynamic Model", "authors": [{"first": "B", "middle": [], "last": "Creemers", "suffix": ""}, {"first": "L", "middle": [], "last": "Kyriakides", "suffix": ""}], "year": 2006, "venue": "School Effectiveness and School Improvement", "link": "53633170"}, "BIBREF4": {"title": "Adolescent Brain Development: A Period of Vulnerabilities and Opportunities", "authors": [{"first": "R", "middle": ["E"], "last": "Dahl", "suffix": ""}], "year": 2004, "venue": "Annals of the New York Academy of Sciences", "link": null}, "BIBREF5": {"title": "Sex Differences in Brain Maturation During Childhood and Adolescence", "authors": [{"first": "De", "middle": [], "last": "Bellis", "suffix": ""}, {"first": "M", "middle": ["D"], "last": "", "suffix": ""}, {"first": "M", "middle": ["S"], "last": "Kehavan", "suffix": ""}, {"first": "S", "middle": ["R"], "last": "Beers", "suffix": ""}, {"first": "J", "middle": [], "last": "Hall", "suffix": ""}, {"first": "K", "middle": [], "last": "Frustaci", "suffix": ""}, {"first": "A", "middle": [], "last": "Masalehdan", "suffix": ""}, {"first": "J", "middle": [], "last": "Noll", "suffix": ""}, {"first": "A", "middle": ["M"], "last": "Boring", "suffix": ""}], "year": 2001, "venue": "", "link": null}, "BIBREF6": {"title": "Fachserie 11 Reihe 1-2008/09. Statistisches Bundesamt Deutschland", "authors": [], "year": 2008, "venue": "", "link": null}, "BIBREF7": {"title": "Are we Wasting our Children's Time by Giving them More Homework?", "authors": [{"first": "O", "middle": [], "last": "Eren", "suffix": ""}, {"first": "D", "middle": ["J"], "last": "Henderson", "suffix": ""}], "year": 2008, "venue": "The Econometrics Journal", "link": "33168242"}, "BIBREF8": {"title": "What Accounts for International Differences in Student Performance? A Re-Examination Using PISA Data", "authors": [{"first": "T", "middle": [], "last": "Fuchs", "suffix": ""}, {"first": "L", "middle": [], "last": "Woessmann", "suffix": ""}], "year": 2007, "venue": "Empirical Economics", "link": "4985428"}, "BIBREF9": {"title": "A Closer Look at Learning Strategies, L2 Proficiency, and Gender", "authors": [{"first": "J", "middle": ["M"], "last": "Green", "suffix": ""}, {"first": "R", "middle": [], "last": "Oxford", "suffix": ""}], "year": 1995, "venue": "TESOL Quarterly", "link": "145282793"}, "BIBREF10": {"title": "Is it Enough to Increase Compulsory Education to Raise Earnings? Evidence from French and British Compulsory Schooling Laws", "authors": [{"first": "J", "middle": [], "last": "Grenet", "suffix": ""}], "year": 2009, "venue": "", "link": "198945739"}, "BIBREF11": {"title": "The Economics of School Quality", "authors": [{"first": "E", "middle": ["A"], "last": "Hanushek", "suffix": ""}], "year": 2005, "venue": "", "link": "55370963"}, "BIBREF12": {"title": "The Role of Cognitive Skills in Economic Development", "authors": [{"first": "E", "middle": ["A"], "last": "Hanushek", "suffix": ""}, {"first": "L", "middle": [], "last": "Woessmann", "suffix": ""}], "year": 2008, "venue": "Journal of Economic Literature", "link": "14609452"}, "BIBREF13": {"title": "How Would One Extra Year of High School Affect Academic Performance in University? Evidence from a Unique Policy Change", "authors": [{"first": "H", "middle": [], "last": "Krashinsky", "suffix": ""}], "year": 2006, "venue": "", "link": "43253796"}, "BIBREF14": {"title": "School Quality in a Cross-Section of Countries", "authors": [{"first": "J.-W", "middle": [], "last": "Lee", "suffix": ""}, {"first": "R", "middle": [], "last": "Barro", "suffix": ""}], "year": 2001, "venue": "Economica", "link": null}, "BIBREF15": {"title": "Schooling and Test Scores: A Mother-Natural Experiment", "authors": [{"first": "D", "middle": ["E"], "last": "Marcotte", "suffix": ""}], "year": 2007, "venue": "Economics of Education Review", "link": "154148740"}, "BIBREF16": {"title": "Natural and Quasi-Experiments in Economics", "authors": [{"first": "B", "middle": [], "last": "Meyer", "suffix": ""}], "year": 1995, "venue": "Journal of Business & Economic Statistics", "link": "153877961"}, "BIBREF17": {"title": "Estimating the Benefit of High School for College-Bound Students", "authors": [{"first": "L", "middle": ["P"], "last": "Morin", "suffix": ""}], "year": 2010, "venue": "Canadian Labour Market and Skill Researcher Network", "link": "2885558"}, "BIBREF18": {"title": "The Evolution of the School Entry Age Effect in a School Tracking System", "authors": [{"first": "A", "middle": ["M"], "last": "Muehlenweg", "suffix": ""}, {"first": "P", "middle": ["A"], "last": "Puhani", "suffix": ""}], "year": 2009, "venue": "Journal of Human Resources", "link": null}, "BIBREF19": {"title": "Equally Prepared for Life? How 15-Year-Old Boys and Girls Perform in School", "authors": [], "year": 2002, "venue": "Reading for Change: Perfomance and Engagement Across Countries", "link": null}, "BIBREF20": {"title": "Wage Effects of an Extra Year of Basic Vocational Education", "authors": [{"first": "H", "middle": [], "last": "Oosterbeek", "suffix": ""}, {"first": "H", "middle": ["D"], "last": "Webbink", "suffix": ""}], "year": 2007, "venue": "Economics of Education Review", "link": "54967148"}, "BIBREF21": {"title": "PISA '06: PISA 2006 in Deutschland -Die Kompetenzen der", "authors": [{"first": "Pisa-Konsortium", "middle": [], "last": "Deutschland", "suffix": ""}], "year": 2008, "venue": "Jugendlichen im dritten Laendervergleich. Waxmann", "link": null}, "BIBREF22": {"title": "The Impact of Length of the School Year on Student Performance and Earnings: Evidence From the German Short School Years", "authors": [{"first": "J.-S", "middle": [], "last": "Pischke", "suffix": ""}], "year": 2007, "venue": "The Economic Journal", "link": null}, "BIBREF23": {"title": "Zero Returns to Compulsory Schooling in Germany: Evidence and Interpretation", "authors": [{"first": "J.-S", "middle": [], "last": "Pischke", "suffix": ""}, {"first": "T", "middle": [], "last": "Wachter", "suffix": ""}], "year": 2008, "venue": "The Review of Economics and Statistics", "link": "10284536"}, "BIBREF24": {"title": "Does School Duration Affect Student Performance? Findings from Canton-Based Variation in Swiss Educational Length", "authors": [{"first": "V", "middle": [], "last": "Skirbekk", "suffix": ""}], "year": 2006, "venue": "Swiss Journal of Economics and Statistics", "link": "55218890"}, "BIBREF25": {"title": "Robustness Checks of Estimation: Mathematics a MAG HAL GYM LAR Coeff. Coeff. Coeff. Coeff. \u03b2 M", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF26": {"title": "Robustness Checks of Estimation: German Literature a MAG HAL GYM LAR Coeff", "authors": [], "year": "", "venue": "Table", "link": null}}, "ref_entries": {"FIGREF0": {"text": "Pischke (2007) analyzes the effects of the German short-school years during the 1960's in a similar way.", "type": "figure"}, "FIGREF1": {"text": "confirm that females and males prefer different learning strategies, while De Bellis et al. (2001) included differences in biological and mental development, to conclude that altering the instructional time may lead to differing gender specific results. 8 Subsequently, the sample was also divided into three academic subject areas, s = {M, L, E } , Mathematics (M), German Literature (L), and the English Language(E). The matrix X is partitioned as follows: X 1 = [e|d|D|P]. The column vector e is the all-ones vector, the vector d contains dichotomous elements that equal one corresponding to a grade earned by a student belonging to the G12 group and zero for one in the G13 group, the 8 See also OECD (2009) for a comparison analysis of student performance for boys and girls, fifteen years old.", "type": "figure"}, "FIGREF2": {"text": "column vector e is the all-ones vector, the matrix D 2 consists of twelve columns of dichotomous variables that equal one in the school where a G12 student earned the final grade and zero if that grade was earned by a student in the G13 group, the matrices D and P remain as heretofore defined. Correspondingly, the transpose of the coefficient vector are: \u03bb s 2g = [\u03b1|\u03b2 2 |\u03b3|\u03b4], where the vector \u03b2 2 contains coefficients that provide school specific measurements of the scholastic achievement differences due to the educational reform. The other coefficients remain unaltered. Utilizing this form of the model individual as well as a gender-pooled regression estimates were made. The empirical results are based on primary data obtained from a written questionnaire that was administered to the 2007 Abitur class of twelve secondary schools. Ten of these schools are located in the city of Magdeburg 10 (eight Gymnasium and two Integrierte Gesamtschulen) and two in Halberstadt 11 (Gymnasium). The questionnaire consisted of 101 questions relating to various aspects of the student's personality, social background, and educational experiences. They were distributed in February and March of 2009 with a response deadline stipulated for the end of April.", "type": "figure"}, "FIGREF3": {"text": "insignificant. No differences were discovered on the final grades earned in German literature. These results tend to suggest that linear human capital models where hours of instructional time are positively related to human capital accumulation, represented by test scores, provide an inappropriate explanation of the knowledge gains associated with additional schooling (c.f. Pischke (2007), p. 1240). 17 Some students are not able to cope with the increased learning intensity. Lowering the learning intensity in such demanding subjects as mathematics by additional instructional time at the expense of less intellectually demanding subjects is a reasonable recommendation. Additional research is required to study the role of the duration of schooling upon the skill formation process. The results presented here suggest that the management of the educational process, relating to academic curriculum planning and, as a result, learning intensity ratios, are important. Public educational policy makers should turn their attention from raising the quantity of education to increasing the quality of its delivery. Teddlie, C., and D. Reynolds (2000): The International Handbook of School Effectiveness Research. Falmer Press, London. Todd, P. E., and K. I. Wolpin (2007): \"The Production of Cognitive Achievement in Children: Home, School, and Racial Test Score Gaps,\" Journal of Human Capital, 1, 91-136. White, H. (1980): \"A Heteroskedasticity-Consistent Covariance Matrix Estimator and a Direct Test of Heteroskedasticity,\" Econometrica, 48, 817-838. Woessmann, L. (2003): \"Schooling Resources, Educational Institutions and Student Performance: The International Evidence,\" Oxford Bulletin of Economics and Statistics, 65(2), 117-170.", "type": "figure"}, "FIGREF4": {"text": "435*** -1.217*** -1.545*** -1.294*** -1.269** -0.654 School 5 -1.111** -1.001** -1.514** -1.253** -0259** -1.109** -1.625*** -1.374*** -0.656 -0.690 School 8 -1.128** -1.055** -1.306** -1.119** -0.803 -1.114 School 9 -2.956*** -2.627*** -2.713*** -2.328*** -3.194*** -3.476**Occupational degree of father (reference: apprenticeship or no occupational training) Grad. from Univ./Univ. of Appl.", "type": "figure"}, "FIGREF5": {"text": "560*** -2.478*** -3.047** -3.250** -2.017* -1.947 School 3 -1.755*** -1.378*** -1.634** -1.123 -2.049*** -1Occupational degree of father (reference: apprenticeship or no occupational training) Grad. from Univ./Univ. of Appl.", "type": "figure"}, "FIGREF6": {"text": "* p < 0.1, * * p < 0.05, * * * p < 0.01 Sociodemographic variables Age (enrollment at school) Occupational degree of father (reference: apprenticeship or no occupational training) Grad. from Univ./Univ. of Appl. Sciences 0", "type": "figure"}, "TABREF0": {"text": "With respect to the occupational training, more than half of the parents have finished some form of apprenticeship training. A very small percentage of the parents involved possess no occupational training. Furthermore, the share of university graduates and parents with doctoral degrees are clearly above the societal average. 13 Moreover, the parents are quite active in various areas. Around 70 percent indicated that they are active in community affairs and about half of the parents participate in regular sporting exercise activities. In view of the fact that only those graduates from university preparatory schooling are considered, these findings are not surprising. Political and religious engagement, on the other hand, is reported for a only small fraction of parents.", "type": "table"}, "TABREF1": {"text": "Distribution of Survey Respondents by Schools, Gender and Grades", "type": "table"}, "TABREF2": {"text": "Means of Selected Characteristics by Grade and Gender", "type": "table"}, "TABREF3": {"text": "Means of Selected Background Characteristics by Grade and Gender p-value from t-test on equality of shares.", "type": "table"}, "TABREF4": {"text": "Mathematics (Regression Estimates, Basic Model) a", "type": "table"}, "TABREF5": {"text": "All standard errors are clustering-robust based on class as the sampling unit.", "type": "table"}, "TABREF6": {"text": "German Literature (Regression Estimates, Basic Model) a All standard errors are clustering-robust based on class as the sampling unit.", "type": "table"}, "TABREF7": {"text": "English (Regression Estimates, Basic Model) a All standard errors are clustering-robust based on class as the sampling unit.", "type": "table"}, "TABREF8": {"text": "Mathematics (Regression Estimates, Expanded Model) a", "type": "table"}, "TABREF9": {"text": "German Literature (Regression Estimates, Expanded Model) a", "type": "table"}, "TABREF10": {"text": "English (Regression Estimates, Expanded Model) a", "type": "table"}, "TABREF12": {"text": "All standard errors are clustering-robust based on class as the sampling unit. See text for details. All standard errors are clustering-robust based on class as the sampling unit. See text for details. p < 0.1, * * p < 0.05, * * * p < 0.01", "type": "table"}}}
{"paper_id": "2874570", "_pdf_hash": "c1aac5bee2eb609fbf8562729e138d336d80f9a3", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "2874910", "_pdf_hash": "0654ebec0dfaa607fe44f9fb0693e8ec2e5a37f0", "abstract": [{"section": "Abstract", "text": "-previously to affect LTP induction in an ''inverted U'' doseham. Glucocorticoid receptor activation lowers the threshold for dependent fashion. Very low and high serum CORT titers NMDA-receptor-dependent homosynaptic long-term depression in (as might occur after adrenalectomy and stress, respectively) the hippocampus through activation of voltage-dependent calcium are associated with a suppression of LTP induction, whereas channels. J. Neurophysiol. 78: 1-9, 1997. The effects of the gluco-midrange titers are associated with robust LTP induction corticoid receptor agonist RU-28362 on homosynaptic long-term (Diamond et al. 1992; Kerr et al. 1994;).", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "depression (LTD) were examined in hippocampal slices obtained CORT activates two types of receptors, the mineralocortifrom adrenal-intact adult male rats. Field excitatory postsynaptic coid receptor (type I) and the glucocorticoid receptor (type potentials were evoked by stimulation of the Schaffer collateral/ II). These receptors differ in both their affinity for CORT commissural pathway and recorded in stratum radiatum of area CA1. Low-frequency stimulation (LFS) was delivered at LTD and their cellular effects. Mineralocorticoid receptors have threshold (2 bouts of 600 pulses, 1 Hz, at baseline stimulation a 10-fold higher affinity for CORT than glucocorticoid reintensity). LFS of the Schaffer collaterals did not produce signifi-ceptors (J\u00f6els and de Kloet 1995). At the trough of the cant homosynaptic LTD in control slices. However, identical con-circadian rhythm (i.e., low CORT levels), the mineralocortiditioning in the presence of the glucocorticoid receptor agonist coid receptors are tonically occupied, whereas at the peak RU-28362 (10 mM) produced a robust LTD, which was blocked of the circadian rhythm or under periods of stress, there is ", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "", "text": "tanoic acid (D-AP5) blocked the facilitation. However, the facilita-larization (J\u00f6els and de Kloet 1990), thereby increasing the tion of LTD was not due to a potentiation of the isolated NMDA firing rate of a neuron to a maintained constant stimulus and receptor potential by RU-28362. The facilitation of LTD by thus enhancing neuronal excitability. Conversely, glucocorti-RU-28362 was also blocked by coincubation of the L-type voltage-coid receptor activation enhances the slow afterhyperpolardependent calcium channel (VDCC) antagonist nimodipine. Selec-ization (J\u00f6els and de Kloet 1989; , resulting tive activation of the L-type VDCCs by the agonist Bay K 8644 in neuronal inhibition. The increase in the slow afterhyperpoalso facilitated LTD induction. Both nimodipine and D-AP5 were larization is thought to be mediated by an increase of the effective in blocking the facilitation of LTD by Bay K 8644. These calcium current through voltage-dependent calcium channels results indicate that L-type VDCCs can contribute to NMDA-(VDCCs) (Karst et al. 1994; Kerr et al. 1992 ).", "cite_spans": [{"start": 1041, "end": 1060, "text": "(Karst et al. 1994;", "ref_id": "BIBREF1"}, {"start": 1061, "end": 1077, "text": "Kerr et al. 1992", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "", "text": "receptor-dependent LTD induction.", "cite_spans": [], "ref_spans": []}, {"section": "The opposing actions of the two corticosteroid receptors may account for the inverted U-shaped function relating I N T R O D U C T I O N", "text": "CORT levels and LTP. Thus, under conditions in which mineralocorticoid receptors are selectively activated, CORT Changes in synaptic efficacy have long been hypothesized enhances LTP induction, whereas when glucocorticoid reto be important for memory formation in the CNS (Hebb ceptors are activated, LTP is suppressed (Kerr et al. 1994; 1949) . Two forms of synaptic plasticity are long-term poten- . CORT levels also alter the threshold tiation (LTP) and long-term depression (LTD). Although for LTD induction; either exogenous CORT (Bennett et al. these forms of synaptic plasticity are primarily dependent 1991) or selective activation of the glucocorticoid receptor on glutamatergic transmission for induction, it is apparent (Kerr et al. 1994 ) increases the probability of inducing dethat they are subject to extrinsic modulation by classical pression of the population spike following standard LTP neural transmitters and circulating hormones. induction protocols. This finding was confirmed in the denStressful events release adrenal hormones [e.g., corticotate gyrus . Thus stimuli that are effecsterone (CORT)] that are known to interfere with acquisitive for inducing LTP under low-CORT conditions become tion of certain behavioral learning paradigms (Diamond and effective for inducing LTD when the glucocorticoid receptor Rose 1994; Luine et al. 1994 ) and the induction of LTP (Foy et al. 1987; Shors et al. 1989) . CORT has been shown is activated. More recently, Kim et al. (1996) showed that the duration of the experiment. The slices were exposed to the exposure to an uncontrollable stress in vivo facilitates subsesteroids for a minimum of 2.5 h before LFS. Nimodipine, Bay K quent N-methyl-D-aspartate (NMDA)-receptor-dependent 8644, RU-28362, and RU-38486 were dissolved in 95% ethanol LTD induction in vitro. Thus glucocorticoid activation widand diluted to a final ethanol concentration of \u00f50.1%. CNQX ens the range of stimuli that are effective for LTD induction. was dissolved in 0.1 mM NaOH and diluted to a final NaOH Here we examine in more detail the mechanisms by which concentration of \u00f50.01%. Experiments with nimodipine and Bay stress hormones facilitate LTD induction by using the selec-K 8644 were conducted in a darkened room. tive glucocorticoid receptor agonist RU-28362. Our results Paired and Student's t-tests were performed to assess group indicate that glucocorticoid receptor activation effectively differences between the various treatments. Statistical significance lowers the threshold for LTD induction, and that the en-was determined at a confidence level of P \u00f5 0.05. hancement of LTD is mediated partially by L-type VDCC activity. Aspects of this study have appeared in abstract form R E S U L T S (Coussens et al. 1996; Kerr et al. 1996) .", "cite_spans": [{"start": 1347, "end": 1364, "text": "Luine et al. 1994", "ref_id": "BIBREF6"}, {"start": 1410, "end": 1428, "text": "Shors et al. 1989)", "ref_id": "BIBREF4"}, {"start": 1480, "end": 1497, "text": "Kim et al. (1996)", "ref_id": "BIBREF6"}, {"start": 2774, "end": 2791, "text": "Kerr et al. 1996)", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "The opposing actions of the two corticosteroid receptors may account for the inverted U-shaped function relating I N T R O D U C T I O N", "text": "LFS at 0.5-mV field EPSP strength in normal aCSF resulted in a short-term depression that returned to baseline", "cite_spans": [], "ref_spans": []}, {"section": "The opposing actions of the two corticosteroid receptors may account for the inverted U-shaped function relating I N T R O D U C T I O N", "text": "by 30 min post-LFS (03 { 4%, mean { SE, n \u00c5 6), in Transverse hippocampal slices (400 mm) were prepared from agreement with our previous findings ) adrenal-intact male Sprague-Dawley rats 1995). However, the addition of the glucocorticoid receptor as previously reported (Kerr et al. 1994) . In brief, animals were agonist RU-28362 (10 mM) \u00a22 h before LFS led to the deeply anesthetized with gaseous methoxyfluothane and rapidly induction of a robust LTD (027 { 4%, n \u00c5 9, P \u00f5 0.01, Fig. decapitated. The hippocampus was dissected free in ice-cold me-1A). The facilitatory effect of RU-28362 was not readily dium and area CA3 was removed by a manual knife cut to eliminate possible development of seizurelike activity during stimulation. apparent until after the second bout of LFS. The facilitation Slices were transferred to a submersion chamber and constantly of LTD was not due to a difference in incubation time besuperfused (1-2 ml/min) with an artificial cerebrospinal fluid tween groups, and there was no apparent difference in the (aCSF, saturated with 95% O 2 -5% CO 2 ) consisting of (in mM) stimulation intensity required to evoke the 0.5-mV baseline 124 NaCl, 3.2 KCl, 1.25 NaH 2 PO 4 , 26 NaHCO 3 , 2.5 CaCl 2 , 1.3 test response. The facilitation was dose dependent, because MgCl 2 , and 10 D-glucose. Slices were allowed to equilibrate for 2 conditioning in the presence of 1 mM RU-28362 failed to h before recording while the temperature was slowly raised to the elicit an LTD significantly different from controls (010 { recording temperature of 32.5\u040aC. (1-3 MV) filled with 2 M NaCl was placed in stratum radiatum vented the facilitation of LTD by 10 mM RU-28362 (04 { to record field excitatory postsynaptic potentials (EPSPs). Data 3%, n \u00c5 6, P \u00fa 0.1). Taken together, these data indicate were acquired and stored for off-line analysis with the use of an that the RU-28362 effect is specific to the activation of glu-ASYST-based acquisition software developed in our laboratory. cocorticoid receptors. the NMDA receptor dependence of the RU-28362 effect.", "cite_spans": [], "ref_spans": []}, {"section": "The opposing actions of the two corticosteroid receptors may account for the inverted U-shaped function relating I N T R O D U C T I O N", "text": "Slices exhibiting a maximal field EPSP amplitude \u00f52.0 mV, D-AP5 blocked the facilitation of LTD by RU-28362 signs of hyperexcitability, or unstable baseline potentials (drift of (09 { 3%, n \u00c5 6, not significantly different from untreated responses \u00fa10% over the 20-min baseline recording period) were controls, Fig. 2A ). On washout of the D-AP5, LFS in the discarded from the study. The stimulation intensity was adjusted to produce an 0.5-mV field EPSP amplitude during baseline stimu-presence of RU-28362 induced a significant LTD (023 { lation (0.067 Hz). Conditioning stimulation consisted of two epi-3%, n \u00c5 4, P \u00f5 0.01).", "cite_spans": [], "ref_spans": [{"start": 311, "end": 318, "text": "Fig. 2A", "ref_id": "FIGREF4"}]}, {"section": "The opposing actions of the two corticosteroid receptors may account for the inverted U-shaped function relating I N T R O D U C T I O N", "text": "sodes of low-frequency stimulation (LFS, 1 Hz, 600 pulses at the As noted, one action of glucocorticoid receptor activation baseline stimulation intensity) with 10 min between episodes. This is to increase the calcium current through VDCCs, including ''threshold'' conditioning procedure has been shown to produce the L-type VDCC (Karst et al. 1994; Kerr et al. 1992) . A: 2 episodes of low-frequency stimulation (LFS, 600 pulses, 1 Hz at baseline stimulation strength, denoted by horizontal bars) induced only a short-term depression in control slices (03 { 4%, mean { SE, \u1b7a, n \u00c5 6). In the presence of 10 mM RU-28362, however, LFS induced LTD (027 { 4%, q, n \u00c5 9). Data in this and other figures are mean % change of baseline { SE. Insets: sample traces (average of 5 sweeps) from baseline and 30 min post-LFS. Scale bar is 0.5 mV, 10 ms. B: action of RU-28362 is dose dependent, because 10 mM but not 1 mM (010 { 3, n \u00c5 4) induced a significant LTD. Addition of 30 mM RU-38486 (specific glucocorticoid receptor antagonist) to the superfusate effectively blocked the facilitatory action of the agonist RU-28362 (04 { 3%, n \u00c5 6). Asterisk: significant difference from control group, P \u00f5 0.05).", "cite_spans": [{"start": 330, "end": 349, "text": "(Karst et al. 1994;", "ref_id": "BIBREF1"}, {"start": 350, "end": 367, "text": "Kerr et al. 1992)", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "The opposing actions of the two corticosteroid receptors may account for the inverted U-shaped function relating I N T R O D U C T I O N", "text": "corded for a further 3 h. Instead of an increase in responses, blocked the evoked potential, confirming that the field EPSP was mediated by NMDA receptors (Fig. 3) . RU-28362 administration led to a small decrease in the area under the curve of the NMDA-receptor-mediated potentials To determine whether the facilitation of LTD by RU-28362 can be explained by a direct effect on L-type VDCCs, (09 { 7%, n \u00c5 5), which was not significantly different threshold conditioning stimulation was given in the presence from the small decrease also observed for untreated controls of the selective L-type VDCC agonist Bay K 8644. Bay K (n \u00c5 4, Fig. 3 ). These data clearly indicate that the facilita-8644 (0.5 mM) caused a facilitation of LTD equivalent to tion of LTD by RU-28362 is not due to an upregulation of that produced by RU-28362 (026 { 6%, n \u00c5 5, P \u00f5 0.02, NMDA receptor function. Later in the experiment, 50 mM Fig. 4A ), and this effect was blocked by the coapplication nimodipine was added to the aCSF for the RU-28362-treated of 20 mM nimodipine (06 { 3%, n \u00c5 4, P \u00f5 0.01 vs. Bay slices to see whether L-type VDCCs contribute to the evoked K 8644 alone, Fig. 4A ). Similar to the RU-28362 facilitapotential. Nimodipine application did lead to a further small tion, the LTD induced in the presence of Bay K 8644 was decrease, supporting previous studies (Dingledine 1983; No- still dependent on the activation of NMDA receptors, bewak et al. 1993). However, the control slices, which had cause bath application of 50 mM D-AP5 prevented LTD not received nimodipine, also showed a small response decinduction in the presence of Bay K 8644 (08 { 5%, n \u00c5 rement at the corresponding time in the experiment. Thus it 5, P \u00f5 0.05 vs. Bay K 8644 alone, Fig. 4B ). remains unclear whether VDCCs contribute significantly to the NMDA-receptor-dependent evoked potentials under the The above findings indicate that L-type VDCCs can contribute to the induction of homosynaptic LTD. On the other hand, present conditions. At the end of the experiment, D-AP5 (50 mM) was added to the perfusing medium and completely LTD has typically been reported to be primarily dependent on The present experiments demonstrate that selective activations (Bolshakov and Siegelbaum 1994; Christie et al. 1996;  tion of glucocorticoid receptors facilitates homosynaptic Otani and Connor 1996) . To test whether L-type VDCCs con-LTD induction by threshold conditioning stimulation in a tribute to LTD under stronger stimulation conditions, a more dose-dependent fashion. These results are consistent with robust induction protocol was used whereby stimulation prothe findings of Kim et al. (1996) , who found that behavioral ducing 1-mV responses during LFS was given in the presence stress lowered the threshold for homosynaptic LTD inducof 1 mM PTX, resulting in 020 { 2% LTD (n \u00c5 7). This tion as studied ex vivo. By applying the selective glucocorti-LTD was not blocked by 50 mM nimodipine (017 { 5%, coid receptor agonist RU-23862 directly to the slices, hown \u00c5 6, not significant relative to controls), but was blocked ever, we have been able to exclude other physiological by 50 mM D-AP5 (03 { 4%, n \u00c5 5, P \u00f5 0.05, Fig. 5 ). This responses to stress, such as adrenal medullary hormone resuggests that, under stronger LTD-inducing conditions, L-type lease, as necessary contributors to the LTD facilitation effect. VDCCs become redundant and NMDA receptor activation alone is sufficient to induce LTD.", "cite_spans": [{"start": 2650, "end": 2667, "text": "Kim et al. (1996)", "ref_id": "BIBREF6"}], "ref_spans": [{"start": 913, "end": 920, "text": "Fig. 4A", "ref_id": "FIGREF5"}, {"start": 1159, "end": 1166, "text": "Fig. 4A", "ref_id": "FIGREF5"}, {"start": 1749, "end": 1756, "text": "Fig. 4B", "ref_id": "FIGREF5"}]}, {"section": "The opposing actions of the two corticosteroid receptors may account for the inverted U-shaped function relating I N T R O D U C T I O N", "text": "These data suggest that the LTD facilitation observed by 2/ , 20 mM picrotoxin (PTX)] were maintained for 20 min and then exposed to 10 mM RU-28362 (q). Responses were monitored for an additional 3 h and compared with those from control, untreated slices (\u1b7a), using the area under curve as primary measurement. After 2.5 h, 50 mM nimodipine was added to RU-28362-treated slices (indicated by horizontal bar). After another 30 min (3 h after the start of RU-28362), 50 mM D-AP5 was added to all slices to confirm NMDA receptor dependence of evoked responses. Insets: sample traces (average of 5 sweeps) from baseline (1), 2.5 h after RU-28362 commencement (2), and after D-AP5 application (3). Scale bar: 0.5 mV, 20 ms. Kim et al. (1996) may also have been due primarily to the indicating that activation of L-type VDCCs is critical for this form of LTD. This finding is consistent with the fact activation of glucocorticoid receptors directly in the hippocampus. The possibility that activation of mineralocorticoid that glucocorticoid receptor activation upregulates VDCCs in a protein-synthesis-dependent manner (Kerr et al. 1992) . receptors is necessary, but not sufficient, to observe this effect cannot be ruled out, because in both studies tissue In addition, the similarity between the LTD facilitation by RU-28362 and that promoted by the L-type VDCC agonist was obtained from adrenal-intact animals, which would be expected to exhibit occupation of these high-affinity recep-BAY K 8644 in the present experiments supports the hypothesis that RU-28362 affects LTD through regulation of tors by circulating CORT. Additionally, it may be that dimers of activated mineralocorticoid and glucocorticoid re-VDCCs. The BAY K 8644 experiments also confirm that L-type VDCCs contribute to homosynaptic LTD in adult ceptors, which may increase the functional diversity of corticosteroid action (Trapp and Holsboer 1996; Trapp et al. rats under some circumstances. 1994), mediate the facilitation of LTD.", "cite_spans": [{"start": 719, "end": 736, "text": "Kim et al. (1996)", "ref_id": "BIBREF6"}, {"start": 1114, "end": 1132, "text": "(Kerr et al. 1992)", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "The opposing actions of the two corticosteroid receptors may account for the inverted U-shaped function relating I N T R O D U C T I O N", "text": "Despite the reliance of RU-28362-facilitated LTD on VDCC activation, the LTD also remained NMDA receptor dependent, a finding consistent with the stress-induced faciliFacilitation of homosynaptic LTD and the role of VDCCs tation of LTD observed by Kim et al. (1996) . Thus it appears that L-type VDCCs can work cooperatively with NMDA Although activation of L-type VDCCs has been reported receptors, and that at threshold levels of stimulation, activato facilitate the induction of the heterosynaptic form of LTD tion of neither calcium channel alone is sufficient to generate in the hippocampus (Wickens and Abraham 1991), a block LTD. The fact that at higher strengths of stimulation of VDCCs has not generally affected homosynaptic LTD L-type VDCCs did not contribute to LTD suggests that their (Kerr and Abraham 1995; Mulkey and Malenka 1992) , with contribution at threshold is one of promoting NMDA recepsome exceptions (Bolshakov and Siegelbaum 1994; Christie tor function, although we cannot rule out the possibility et Otani and Conner 1996) . In the present experiments, nimodipine blocked the LTD elicited in RU-28362, that under yet stronger activation conditions, VDCCs may mediate an NMDA-receptor-independent LTD (Otani and channels was greatly reduced by lowering extracellular Mg 2/ , the present experiment does not rule out the possibilConnor 1996). Cooperative interactions could occur through a variety of means. For example, VDCC activation might 1) ity of a contribution by VDCC activation to NMDA receptor channel function by a depolarization mechanism, when promote NMDA receptor activation by elevating membrane depolarization during synaptic activation, 2) add to the tested in normal medium.", "cite_spans": [{"start": 248, "end": 265, "text": "Kim et al. (1996)", "ref_id": "BIBREF6"}, {"start": 798, "end": 821, "text": "(Kerr and Abraham 1995;", "ref_id": "BIBREF2"}, {"start": 822, "end": 846, "text": "Mulkey and Malenka 1992)", "ref_id": "BIBREF7"}, {"start": 1028, "end": 1050, "text": "Otani and Conner 1996)", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "The opposing actions of the two corticosteroid receptors may account for the inverted U-shaped function relating I N T R O D U C T I O N", "text": "A more indirect method for the promotion of LTD by NMDA-receptor-mediated calcium transients occurring during synaptic stimulation, or 3) potentiate NMDA receptor VDCCs is also worth noting. Several labs have reported that activation of NMDA receptors during a period of hyperpolarfunction by activation of calcium-dependent protein kinases or phosphatases that regulate NMDA receptor function. In ization or synaptic inhibition successfully induces homosynaptic LTD (Debanne et al. 1994 ; Stanton and Sejnowski the present experiment we have shown that NMDA receptor function is not upregulated by RU-28362, thus ruling out 1989; Thiels et al. 1994; Xie et al. 1992) . In the present experiments, enhancement of VDCC activity by RU-28362 the latter possibility. This finding is consistent with a previous report showing no change in NMDA receptor binding may promote calcium-dependent slow afterhyperpolarizations, thereby providing the postsynaptic hyperpolarization following stress (Clark and Cotman 1992 (Fig. 6A ). Small increases in activity above resting levels will produce LTD, whereas greater activity will produce LTP. The crossover point between LTD and LTP is termed u M . A similar model has been proposed by Artola and Singer (1993) (ABS rule), who use the term u / in the same way as the BCM model uses u M , but additionally define the threshold for LTD as u 0 . Because the plasticity thresholds are defined in terms of postsynaptic activity (BCM model), reflecting perhaps NMDA receptor activation (Bear et al. 1987) or the level of the postsynaptic calcium transient (ABS rule), then the activity level of a test pathway is only one determinant of which threshold, if either, is crossed. Activity in converging inputs, or modulatory influences by other neurotransmitter systems and circulating hormones, could also have a substantial impact. There is now considerable evidence that binding of corticosteroids to their receptors can influence the direction and degree of synaptic plasticity generated by a particular paradigm. The FIG . 5. L-type VDCC activation is not necessary for LTD under stronger stimulation protocols. In the presence of 1 mM PTX, LFS delivered at 1-mV field excitatory postsynaptic potential (EPSP) strength induced LTD (020 { 2%, n \u00c5 7), which was blocked by 50 mM D-AP5 (03 { 4%, n \u00c5 5). However, coapplication of 50 mM nimodipine had no effect on LTD induction (017 { 5%, n \u00c5 6). Asterisk: significant difference from PTX-only group (P \u00f5 0.05). LTD. Deciding between these possible modes of interaction between VDCCs and NMDA receptors requires further investigation.", "cite_spans": [{"start": 631, "end": 650, "text": "Thiels et al. 1994;", "ref_id": "BIBREF5"}, {"start": 651, "end": 667, "text": "Xie et al. 1992)", "ref_id": "BIBREF7"}], "ref_spans": [{"start": 1009, "end": 1017, "text": "(Fig. 6A", "ref_id": "FIGREF6"}]}, {"section": "The opposing actions of the two corticosteroid receptors may account for the inverted U-shaped function relating I N T R O D U C T I O N", "text": "It is notable that the facilitation of LTD by RU-28362 was not evident until after the second bout of LFS. This pattern also occurs in control slices given conditioning stimulation above threshold for LTD induction (Kerr and Abraham 1995) . It is thus apparent in both instances that although LTD is largely induced by the second bout of LFS, the first bout of LFS ''primes'' the synapses for the subsequent induction of LTD. This priming effect is similar to that previously reported for perforant path-granule cell synapses in vivo (Christie and Abraham 1992). The question is then raised as to whether RU-28362 acts by facilitating priming mechanisms or LTD induction/expression mechanisms. This is a difficult issue to resolve, and is one that also pertains to many other studies of LTD induced by long trains of LFS. For the present purposes, we have ascribed the RU-28362 action to the observable effect, namely, the facilitation of LTD, as is conventional for studies of this kind. However, ing u 0 to the left and u M (u / ) to the right (Fig. 6A) and to make LTP harder to elicit. It should be noted that Induction and reversal of long-term potentiation by low and high-intensity these threshold shifts refer to the level of afferent activity theta pattern stimulation. J. Neurosci. 15: 5402-5410, 1995. that normally is required to induce LTD or LTP, and not BEAR, M. F., COOPER, L. N., AND EBNER, F. F. A physiological basis for a necessarily to subsequent biophysical or biochemical events theory of synaptic modification. Science Wash. DC 237: 42-48, 1987. (e.g., the level of postsynaptic calcium critical for triggering BENNETT The present experiments demonstrate that activation of excitatory amino acid binding. Brain Res. 585: 161-168, 1992. glucocorticoid receptors effectively lowers the threshold for COUSSENS, C., KERR, D. S., AND ABRAHAM, W. C. Facilitation of NMDA receptor-dependent homosynaptic LTD by the type II corticosteroid rehomosynaptic LTD induction in the hippocampus of mature ceptor agonist RU-28362. Soc. Neurosci. Abstr. 22: 1518 rats, a finding in good correspondence with a recent demon-DEBANNE, D., GAHWILER, B. H., AND THOMPSON, S. M. Asynchronous prestration that stress exerts the same effects (Kim et al. 1996) . and postsynaptic activity induces associative long-term depression in area Thus, although homosynaptic LTD is more difficult to in-CA1 of the rat hippocampus in vitro. Proc. Natl. Acad. Sci. USA 91: 1148 -1152 duce in mature rats relative to juveniles (Dudek and Bear Acad. Sci. 746: 411-416, 1994. induction in a novel way, by promoting L-type VDCC acti-DINGLEDINE, R. N-methyl aspartate activates voltage-dependent calcium conductance in rat hippocampal pyramidal cells. J. Physiol. Lond. 343: vation. It is interesting, however, that this LTD nonetheless 385-405, 1983. remains NMDA receptor dependent. These results suggest Acad. Sci. USA 89: 4363-4367, 1992. tions, and therefore contribute to the facilitation of LTD FOY, M. R., STANTON, M. E., LEVINE, S., AND THOMPSON, R. F. Behavioral stress impairs long-term potentiation in rodent hippocampus. Behav. Neuduring stress or aging, which are characterized by an elevaral Biol. 48: 138-149, 1987. tion of circulating CORT (Kim et al. 1996 ", "cite_spans": [{"start": 215, "end": 238, "text": "(Kerr and Abraham 1995)", "ref_id": "BIBREF2"}, {"start": 2239, "end": 2256, "text": "(Kim et al. 1996)", "ref_id": "BIBREF6"}, {"start": 3237, "end": 3253, "text": "(Kim et al. 1996", "ref_id": "BIBREF6"}], "ref_spans": [{"start": 1046, "end": 1055, "text": "(Fig. 6A)", "ref_id": "FIGREF6"}]}], "bib_entries": {"BIBREF0": {"title": "Corticosteroid hormones: endocrine mespotentiation in the dentate gyrus is induced preferentially on the positive sengers in the brain", "authors": [{"first": "M", "middle": [], "last": "J\u00f6 Els", "suffix": ""}, {"first": "E", "middle": ["R"], "last": "De Kloet", "suffix": ""}, {"first": "G", "middle": [], "last": "Nowak", "suffix": ""}, {"first": "I", "middle": ["A"], "last": "Paul", "suffix": ""}, {"first": "P", "middle": [], "last": "Popik", "suffix": ""}, {"first": "A", "middle": [], "last": "Young", "suffix": ""}, {"first": "P", "middle": [";"], "last": "Skolnick", "suffix": ""}, {"first": "M", "middle": [], "last": "J\u00f6 Els", "suffix": ""}, {"first": "E", "middle": ["R"], "last": "De Kloet", "suffix": ""}, {"first": "S", "middle": [], "last": "Otani", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Conner", "suffix": ""}, {"first": "M", "middle": [], "last": "Els", "suffix": ""}, {"first": "E", "middle": ["R"], "last": "De Kloet", "suffix": ""}, {"first": "C", "middle": [], "last": "Pavlides", "suffix": ""}, {"first": "Y", "middle": [], "last": "Greenstein", "suffix": ""}, {"first": "M", "middle": [], "last": "Grudman", "suffix": ""}, {"first": "J", "middle": [], "last": "Winson", "suffix": ""}, {"first": "J", "middle": ["\u00d6"], "last": "Long-Term", "suffix": ""}, {"first": "M", "middle": [], "last": "Els", "suffix": ""}, {"first": "E", "middle": ["R"], "last": "De Kloet", "suffix": ""}], "year": 1988, "venue": "Effects of glucocorticoids and norepinephto induction of long-term depression and long-term potentiation reversal during aging", "link": null}, "BIBREF1": {"title": "Hippodent modulation of calcium currents in rat hippocampal CA1 neurons. campal homosynaptic long-term depression/depotentiation induced by", "authors": [{"first": "H", "middle": [], "last": "Karst", "suffix": ""}, {"first": "W", "middle": ["J"], "last": "Wadman", "suffix": ""}, {"first": "M", "middle": [], "last": "Joels", "suffix": ""}, {"first": "C", "middle": [], "last": "Corticosteroid Receptor-Depen-Pavlides", "suffix": ""}, {"first": "A", "middle": [], "last": "Kimura", "suffix": ""}, {"first": "A", "middle": ["M"], "last": "Magarinos", "suffix": ""}, {"first": "B", "middle": ["S"], "last": "Mcewen", "suffix": ""}], "year": 1994, "venue": "Neuroscience", "link": null}, "BIBREF2": {"title": "Effects of glucocortigovern the induction of homosynaptic long-term depression in the hippocoids on hippocampal long-term potentiation", "authors": [{"first": "D", "middle": ["S"], "last": "Kerr", "suffix": ""}, {"first": "W", "middle": ["C"], "last": "Abraham", "suffix": ""}, {"first": "C", "middle": [], "last": "Pavlides", "suffix": ""}, {"first": "Y", "middle": [], "last": "Watanabe", "suffix": ""}, {"first": "B", "middle": ["S"], "last": "Mcewen", "suffix": ""}], "year": 1993, "venue": "campus. Proc. Natl. Acad. Sci. USA", "link": null}, "BIBREF3": {"title": "NEDELEC, steroid modulation of hippocampal potentials: increased effect with aging", "authors": [{"first": "D", "middle": ["S"], "last": "Kerr", "suffix": ""}, {"first": "L", "middle": ["W"], "last": "Campbell", "suffix": ""}, {"first": "S.-Y", "middle": [], "last": "Hao", "suffix": ""}, {"first": "P", "middle": ["W"], "last": "Landfield", "suffix": ""}, {"first": "D", "middle": [], "last": "Cortico-Philibert", "suffix": ""}, {"first": "G", "middle": [], "last": "Costerousse", "suffix": ""}, {"first": "M", "middle": ["; L"], "last": "Gaillard-Moguilewsky", "suffix": ""}, {"first": "F", "middle": [], "last": "Nique", "suffix": ""}, {"first": "C", "middle": [], "last": "Tournemine", "suffix": ""}, {"first": "G", "middle": [], "last": "Teutsch", "suffix": ""}], "year": 1989, "venue": "Antihor", "link": null}, "BIBREF4": {"title": "versus escapable shock modulates long-term potentiation in the rat hippo", "authors": [{"first": "D", "middle": ["S"], "last": "Kerr", "suffix": ""}, {"first": "L", "middle": ["W"], "last": "Campbell", "suffix": ""}, {"first": "O", "middle": [], "last": "Thibault", "suffix": ""}, {"first": "P", "middle": ["W"], "last": "Landfield", "suffix": ""}, {"first": "T", "middle": ["J"], "last": "Shors", "suffix": ""}, {"first": "T", "middle": ["B"], "last": "Seib", "suffix": ""}, {"first": "S", "middle": [], "last": "Levine", "suffix": ""}, {"first": "R", "middle": ["F"], "last": "Thompson", "suffix": ""}, {"first": "D", "middle": ["S"], "last": "Kerr", "suffix": ""}, {"first": "P", "middle": ["W K"], "last": "Davis", "suffix": ""}, {"first": "W", "middle": ["C"], "last": "Abraham", "suffix": ""}, {"first": "P", "middle": ["K"], "last": "Stanton", "suffix": ""}, {"first": "T", "middle": ["J"], "last": "Sejnowski", "suffix": ""}], "year": 1989, "venue": "Proc. Natl. Acad. Sci", "link": null}, "BIBREF5": {"title": "Excitatory stimulation receptor activation", "authors": [{"first": "Thiels", "middle": [], "last": "Corticosteroid", "suffix": ""}, {"first": "E", "middle": [], "last": "Barrionuevo", "suffix": ""}, {"first": "G", "middle": [], "last": "Berger", "suffix": ""}, {"first": "T", "middle": ["W"], "last": "", "suffix": ""}], "year": 1994, "venue": "Psychobiology", "link": null}, "BIBREF6": {"title": "activity correlated with strong binding to the cytosolic glucocrticoid re-1457-1462, 1994. ceptor followed by an impaired activation", "authors": [{"first": "J", "middle": ["J"], "last": "Kim", "suffix": ""}, {"first": "M", "middle": ["R"], "last": "Foy", "suffix": ""}, {"first": "R", "middle": ["F"], "last": "Thompson", "suffix": ""}, {"first": "T", "middle": [], "last": "Trapp", "suffix": ""}, {"first": "F", "middle": [], "last": "Holsboer", "suffix": ""}, {"first": "V", "middle": [], "last": "Luine", "suffix": ""}, {"first": "M", "middle": [], "last": "Villegas", "suffix": ""}, {"first": "C", "middle": [], "last": "Martinez", "suffix": ""}, {"first": "B", "middle": ["S"], "last": "Mcewen", "suffix": ""}, {"first": "T", "middle": [], "last": "Trapp", "suffix": ""}, {"first": "R", "middle": [], "last": "Rupprecht", "suffix": ""}, {"first": "M", "middle": [], "last": "Castren", "suffix": ""}, {"first": "J", "middle": ["M H M"], "last": "Reul", "suffix": ""}, {"first": "", "middle": [], "last": "Holsboer", "suffix": ""}], "year": 1994, "venue": "Heterodimerization between mineralocorticoid and glucocorticoid re-MOGUILEWSKY, M. AND PHILIBERT, D. RU 38486: potent antiglucocorticoid ceptor: a new principle of glucocorticoid action in the CNS", "link": null}, "BIBREF7": {"title": "homosynaptic long-term depression in area CA1 of the hippocampus", "authors": [{"first": "R", "middle": ["M"], "last": "Mulkey", "suffix": ""}, {"first": "R", "middle": ["C"], "last": "Malenka", "suffix": ""}, {"first": "X", "middle": [], "last": "Xie", "suffix": ""}, {"first": "T", "middle": ["W"], "last": "Berger", "suffix": ""}, {"first": "G", "middle": [], "last": "Barrionuevo", "suffix": ""}, {"first": "C", "middle": ["M"], "last": "Norris", "suffix": ""}, {"first": "D", "middle": ["L"], "last": "Korol", "suffix": ""}, {"first": "T", "middle": [], "last": "Foster", "suffix": ""}], "year": 1991, "venue": "Isolated NMDA receptorNeuron", "link": null}}, "ref_entries": {"FIGREF0": {"text": "by the selective glucocorticoid antagonist RU-38486. The LTD additional binding to the glucocorticoid receptors (de Kloet induced by glucocorticoid receptor activation was dependent on et al. 1987; J\u00f6els and de Kloet 1992). Activation of the N-methyl-D-aspartate (NMDA) receptor activity, because the spe- mineralocorticoid receptor decreases the slow afterhyperpo- cific NMDA receptor antagonist D (0)-2-amino-5-phosphonopen-", "type": "figure"}, "FIGREF1": {"text": "3%, n \u00c5 4, Fig. 1B). Futhermore, coapplication of the spe- A monopolar wire stimulating electrode (25-50 mm diam, stim- cific glucocorticoid receptor antagonist RU-38486 (30 mM) ulation current of 25-70 mA) was placed in the Schaffer collateral/ (Moguilewsky and Philibert 1984; Philibert et al. 1991) pre- commissural pathway in area CA1. A glass recording electrode", "type": "figure"}, "FIGREF2": {"text": "EPSP initial slopes (mV/ms) were measured and expressed as In six slices, the competitive NMDA receptor antagonist percent change from baseline values as previously reported (Kerr D-AP5 (50 mM) was bath applied with the RU-28362 to test and Abraham 1995).", "type": "figure"}, "FIGREF3": {"text": "FIG . 1. Selective activation of glucocorticoid receptors facilitates induction of homosynaptic longterm depression (LTD). A: 2 episodes of low-frequency stimulation (LFS, 600 pulses, 1 Hz at baseline stimulation strength, denoted by horizontal bars) induced only a short-term depression in control slices (03 { 4%, mean { SE, \u1b7a, n \u00c5 6). In the presence of 10 mM RU-28362, however, LFS induced LTD (027 { 4%, q, n \u00c5 9). Data in this and other figures are mean % change of baseline { SE. Insets: sample traces (average of 5 sweeps) from baseline and 30 min post-LFS. Scale bar is 0.5 mV, 10 ms. B: action of RU-28362 is dose dependent, because 10 mM but not 1 mM (010 { 3, n \u00c5 4) induced a significant LTD. Addition of 30 mM RU-38486 (specific glucocorticoid receptor antagonist) to the superfusate effectively blocked the facilitatory action of the agonist RU-28362 (04 { 3%, n \u00c5 6). Asterisk: significant difference from control group, P \u00f5 0.05).", "type": "figure"}, "FIGREF4": {"text": "FIG . 2. Facilitation of LTD by RU-28362 is dependent on N-methyl-D-aspartate (NMDA) receptor and L-type voltagedependent calcium channel (VDCC) activation. A: addition of the NMDA receptor antagonist D (0)-2-amino-5-phosphonopentanoic acid (D-AP5, 50 mM) to the bathing medium markedly reduced induction of LTD in the presence of RU-28362, as measured 30 min post-LFS (09 { 3%, n \u00c5 6). On washout of D-AP5, responses were normalized to 0. LFS in the presence of only RU-28362 induced LTD (023 { 3%, n \u00c5 4). Insets: sample traces (average of 5 sweeps) from baseline (1), 30 min post-LFS (2), after washout of D-AP5 (3), and 30 min post-LFS (4). Scale bar: 0.5 mV, 10 ms. B: the L-type VDCC antagonist nimodipine (50 mM, present throughout experiment) completely blocked RU-28362 facilitation of LTD (07 { 5%, n \u00c5 6). Insets: sample traces (average of 5 sweeps) from baseline and 30 min post-LFS. Scale as in A.", "type": "figure"}, "FIGREF5": {"text": "FIG . 4. Selective upregulation of L-type VDCCs facilitates LTD induction. A: addition of the L-type VDCC agonist Bay K 8644 (0.5 mM) facilitated LTD induction as measured 30 min post-LFS (026 { 6%, q, n \u00c5 5). This effect was blocked by coapplying the L-type VDCC antagonist nimodipine (20 mM, 06 { 3%, \u1b7a, n \u00c5 4). Insets: sample traces (average of 5 sweeps) from baseline and post-LFS. Scale bar: 0.5 mV, 10 ms. B: Bay K 8644-facilitated LTD was still dependent on activation of NMDA receptors, because 50 mM D-AP5 prevented LTD (08 { 5%, n \u00c5 6). Inset: sample traces (average of 5 sweeps) from baseline and post-LFS. Scale bar shown in A.", "type": "figure"}, "FIGREF6": {"text": "FIG . 6. Regulation of plasticity thresholds by glucocorticoid receptor once the mechanisms of LTD priming are better understood, activation. Change in synaptic efficacy is plotted as a function of postsynaptic activity as driven by afferent activity, as described by Bienenstock, it may become necessary to reassess whether stress hor-", "type": "figure"}, "FIGREF7": {"text": ", M. A., DIAMOND, D. M., FLESHNER, M., AND ROSE, G. M. Serum corticosterone level predicts the magnitude of hippocampal primed burst LTD or LTP) that are induced by such activity. potentiation and depression in urethane-anesthetized rats. Psychobiology Although the model in Fig. 6A appears to account reason- 19: 301-307, 1991. ably well for the stress and RU-28362 data, there is at least BIENENSTOCK, E. L., COOPER, L. N., AND MUNRO, P. W. Theory for the one other interpretation. Recent evidence from both the den- development of neuron selectivity: orientation specificity and binocular interaction in visual cortex. J. Neurosci. 2: 32-48, 1982. tate gyrus and area CA1 of the hippocampus suggests that BOLSHAKOV, V. Y. AND SIEGELBAUM, S. A. Postsynaptic induction and pre- if afferent activity is taken to an extreme, then the function synaptic expression of hippocampal long-term depression. Science Wash. curls toward zero again, and less LTP is obtained (Abraham DC 264: 1148-1152, 1994. and Huggett 1997; Barr et al. 1995; Christie et al. 1995). CHRISTIE, B. R. AND ABRAHAM, W. C. Priming of associative long-term With the use of this model, the RU-28362 effects on synaptic depression in the dentate gyrus by u frequency synaptic activity. Neuron 9: 79-84, 1992.", "type": "figure"}, "FIGREF8": {"text": "plasticity might be explained by an overall shift to the left CHRISTIE, B. R., MAGEE, J. C., AND JOHNSTON, D. The role of dendritic of the function (Fig. 6B). Establishing which of these two action potentials and Ca 2/ influx in the induction of homosynaptic long- models is a better representation of the RU-28362 effects term depression in hippocampal CA1 pyramidal neurons. Learn. Memory on plasticity will require a detailed examination across a 3: 160-169, 1996. CHRISTIE, B. R., STELLWAGEN, D., AND ABRAHAM, W. C. Reduction of the wide range of stimulation parameters. threshold for long-term potentiation by prior theta-frequency synaptic activity. Hippocampus 5: 52-59, 1995. Summary and conclusions CLARK, A. S. AND COTMAN, C. W. Adrenal hormone effects on hippocampal", "type": "figure"}, "FIGREF9": {"text": "DE KLOET, E. R., RATKA, A., REUL, J.M.H.M., SUTANTO, W., AND VAN 1992), it is clear that the threshold for this form of LTD EEKELEN, J.A.M. Corticosteroid receptor types in brain: regulation and is dramatically reduced under specific, naturally occurring putative function. Ann. NY Acad. Sci. 512: 351-361, 1987. physiological conditions such as stress or hippocampal theta DIAMOND, D. M., BENNETT, M. C., FLESHNER, M., AND ROSE, G. M. In- rhythm (Huerta and Lisman 1995; Pavlides et al. 1988). verted-U relationship between the level of peripheral corticosterone and the magnitude of hippocampal primed burst potentiation. Hippocampus Thus homosynaptic LTD is readily brought into play at times 2: 421-430, 1992. when memory storage is likely to be of utmost importance. DIAMOND, D. M. AND ROSE, G. M. Stress impairs LTP and hippocampal- Our experiments indicate that RU-23862 facilitates LTD dependent memory. Ann. NY", "type": "figure"}, "FIGREF10": {"text": "DUDEK, S. M. AND BEAR, M. F. Homosynaptic long-term depression in that L-type VDCCs may work synergistically with NMDA area CA1 of hippocampus and effects of N-methyl-D-aspartate receptor receptors to induce LTD under normal physiological condi- blockade. Proc. Natl.", "type": "figure"}, "TABREF3": {"text": "LAMBERT, N. A., HOYT, K., MOORE, S. D., AND WILSON, W. A.", "type": "table"}, "TABREF4": {"text": "; Norris et al. HEBB, D. O. Organization of Behavior. New York: Wiley, 1949. 1996). The contribution by L-type VDCCs to LTD becomes HUERTA, P. T. AND LISMAN, J. E. Bidirectional synaptic plasticity induced redundant, however, under stronger induction conditions that by a single burst during cholinergic theta oscillation in CA1 in vitro. Neuron 15: 1053-1063, 1995. sufficiently activate NMDA receptors.", "type": "table"}}}
{"paper_id": "2875387", "_pdf_hash": "f81e7a94a887b10db9c3e52ec952ba4d95517e70", "abstract": [{"section": "Abstract", "text": "Abstract. This paper describes two ways of improving Burt and Adelson's Laplacian pyramid, a technique developed for image compression. The Laplacian pyramid is a multi-resolution image representation that captures the loss of information occurring through repeated reduction of the spatial resolution. The generation of this data structure involves the use of two complementary functions: EXPAND, which increases the size of an image by a factor of 2, and REDUCE, which performs the reverse operation. The first modification is the adjunction of a pre-filter to the initial EXPAND function in order to guarantee an image extrapolation that is an exact interpolation of the coarser resolution level. The second refinement is a REDUCE operation modified to minimize information loss. The corresponding least squares Laplacian pyramid (LSLP) is generated by adding a post-filter to the initial REDUCE function. These new functions have an efficient implementation using recursive algorithms. Preliminary experiments indicate improved performance: for a Gaussian-like kernel (a = 3), the new EXPAND function exhibits a 2 to 2.5 dB attenuation of the first level of the Laplacian pyramid, while the complete scheme (LSLP) leads to a 4.7 to 8.5 dB improvement in the two images used to test the procedure. For comparable compression ratios, the subjective image quality for the LSLP appears to be significantly better. A theoretical relationship between the present approach and the family of quadrature mirror filter image pyramids is also derived.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Zusammenfassung. Diese Arbeit beschreibt zwei Methoden, die Laplacepyramide yon Burr und Adelson zu verbessern, welche zur Bildkompression dient. Die Laplacepyramide ist eine Bilddarstellung dutch Mehrfachaufl6sung, welche den Informationsverlust erfasst, der durch die wiederholte Reduktion der rS.umlichen Aufl6sung entsteht. Fiir die Erzeugung dieser Datenstruktur werden zwei komplement/ire Funktionen gebraucht : EXPAND, welche das Bild um einen Faktor zwei vergr6s-sert, und REDUCE, welche die inverse Operation durchfiihrt. Die erste Modifikation besteht im Hinzufiigen eines Vorfilters zur EXPAND Funktion, um eine Bildextrapolation zu erreichen, welche eine pr/izise Interpolation des gr6beren Aufl6sungsni-veaus ist~ Die zweite Verbesserung betrifft die REDUCE Funktion, welche modifiziert wird, um einen minimalen Informationsverlust zu erreichen. Die entsprechende Laplacepyramide kleinster Quadrate (LSLP) wird durch Hinzufiigen eines Nachfilters zur REDUCE Funktion erzeugt. Diese zwei neuen Funktionen erlauben eine effiziente Realisierung mithilfe rekursiver Algorithmen. Erste Versuche deuten auf eine deutliche Verbesserung hin: fiir einen Gauss-artigen Kern (a = 3) erreicht die neue EXPAND Funktion eine D/impfung von 2 bis 2.5 dB im ersten Niveau der Laplacepyramide, w/ihrend die vollst/indige Methode (LSLP) eine Verbesserung yon 4.7 bis 8.5 dB fiir zwei Testbilder erreicht. Fiir vergleichbare Bildkompressionsfaktoren ist die subjektive Bildqualit/it von LSLP wesentlich besser. Ferner wird ein theoretischer Zusammenhang zwischen dieser Methode und der Familie Bildpyramiden mit quadratischen Spiegelfiltern hergeleitet.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "R6sum6. Ce papier dbcrit deux faqons d'am61iorer la pyramide Laplacienne de Burt et Adelson, une technique d6veloppee pour la compression d'images. La pyramide Laplacienne est une repr+sentation multi-rbsolution d'image qui code la perte d'information li+e ~i une r6duction r6p6t+e de la r6solution spatiale. La g6n6ration de cette structure s'effectue ~i l'aide de deux opbrations compl6mentaires: EXPAND, qui accro~t la taille de l'image par un facteur deux, et REDUCE qui effectue l'op~ration inverse. La premi6re modification est l'adjonction d'un pr6filtre ~i la fonction EXPAND afin de garantir que l'agrandissement d'une image ~i partir d'une representation plus grossi6re donne lieu ~ une interpolation exacte. La seconde am61ioration est la redefinition de la fonction REDUCE afin de minimiser la perte d'information. Ceci donne lieu/t une repr6sentation pyramidale aux moindres carr6s (LSLP) qui diff6re de la pr6c6dente par la simple adjonction d'un post-filtre. Ces nouvelles fonctions se preterit/t une mise en oeuvre tr6s efficace par filtrage r6cursif. Des experiences pr61iminaires indiquent une am61ioration des performances: pour un noyau quasi-gaussien (a = 3), la nouvelle fonction EXPAND att6nue le premier niveau de la pyramide Elsevier Science Publishers B.V.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "188", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Laplacienne de 2 ',i 2.5 dB, tandis que I'algorithme complet (LSLP) donne lieu ~i une am61ioration de 4.7 ~t 8.5 dB sur les deux images utilis6es afin de tester la proc6dure. Pour des taux de compression comparables, les images cod6es avec LSLP sont de qualit+ subjective sup6rieure. Finalement, un lien th6orique est btabli entre l'approche pr6sente et la famille des repr6sentations pyramidales par filtres mirroirs en quadrature.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Multi-resolution data representations are becoming increasingly popular in image processing applications. Pyramid data structures, in particular, play an important role in coding, and are ideally suited for progressive image transmission [13, 15] . In these data structures, the image is represented hierarchically with each level corresponding to a reduced-resolution approximation. An example of such a coding scheme is the Laplacian pyramid proposed by Burt and Adelson in which the difference between successive levels of a Gaussian pyramid is transmitted [3] . This approach compares favorably with earlier techniques, such as transform or predictive image coding, especially when large compression ratios are desired [7] . Recent developments in pyramid image compression also include subband coding techniques [ 18, 20] , orthogonal pyramid structures [1, 12] and wavelet transforms [9] , which are all based on the concept of quadrature mirror filters (QMF) [4] .", "cite_spans": [{"start": 238, "end": 242, "text": "[13,", "ref_id": "BIBREF12"}, {"start": 243, "end": 246, "text": "15]", "ref_id": "BIBREF14"}, {"start": 560, "end": 563, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 723, "end": 726, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 817, "end": 822, "text": "[ 18,", "ref_id": "BIBREF17"}, {"start": 823, "end": 826, "text": "20]", "ref_id": "BIBREF19"}, {"start": 859, "end": 862, "text": "[1,", "ref_id": "BIBREF0"}, {"start": 863, "end": 866, "text": "12]", "ref_id": "BIBREF11"}, {"start": 890, "end": 893, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 966, "end": 969, "text": "[4]", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "Introduction", "text": "The Laplacian pyramid coding technique described by Burt and Adelson relies on the use of two complementary functions: REDUCE and EXPAND. REDUCE computes a lower resolution level of the Gaussian pyramid by decreasing the resolution by a factor of two. EXPAND performs the reverse operation by mapping the coarser level onto a finer sampling grid. These two functions, as defined initially, were sub-optimal in two respects. First, the basic EXPAND function induces some image blurring, tending to increase the energy of the residual image. Second, the initial REDUCE function fails to minimize the loss of information (in the least squares sense) from one level to the next one. It will be shown here that these limitations can be corrected through the appropriate Signal Processing insertion of additional post-and pre-filtering modules. These operators have an infinite impulse response (IIR) and yet can be implemented very efficiently using simple forward and backward recursions, as discussed in Appendix A.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "The presentation is organized as follows. Following a series of definitions, a brief review of the Laplacian pyramid coding concept is given in Section 2. A modified EXPAND function that guarantees an exact image interpolation is described in Section 3. The least squares Laplacian pyramid is introduced in Section 4 and the corresponding REDUCE function is derived. The performance improvement of this new approach is illustrated both qualitatively and quantitatively with some experimental results in Section 5. Finally, the present approach is reinterpreted in terms of quadrature mirror filters in order to bring out the relationship with recent subband (or wavelet transform) coding techniques.", "cite_spans": [], "ref_spans": []}, {"section": "Burt's Laplacian pyramid", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Notation and operators", "text": "The techniques described in this paper are intended for the processing of digital images. However, to simplify the presentation, we have chosen to concentrate on the pyramidal representation of a one-dimensional signal: {f(k)}k~. All subsequent results carry over directly to higher dimensions if one makes use of separable filtering kernels. In practice, for digital images, this means that a pyramid representation can be obtained from the successive application of one-dimensional operators along the rows and columns.", "cite_spans": [], "ref_spans": []}, {"section": "Notation and operators", "text": "There are two operations that are particularly useful for our purpose: the up-sampling of a signal by an integer multiple m (in particular, m=2), which is defined as (2.6) and the successive coarser resolution levels are constructed iteratively using the REDUCE operator", "cite_spans": [], "ref_spans": []}, {"section": "Notation and operators", "text": "This operation requires some form of lowpass filtering and decimation by a factor of 2. Two examples of pyramid representations are shown in Fig. 1 . Burt and Adelson [3] use a 5-point quasiGaussian pre-filter and their REDUCE function can be described as", "cite_spans": [{"start": 167, "end": 170, "text": "[3]", "ref_id": "BIBREF2"}], "ref_spans": [{"start": 141, "end": 147, "text": "Fig. 1", "ref_id": "FIGREF0"}]}, {"section": "Notation and operators", "text": "We will rely heavily on the z-transform representation of a signal, which, as a reminder, is defined as", "cite_spans": [], "ref_spans": []}, {"section": "Notation and operators", "text": "In particular, Burt's generating kernel [3] is central to the construction of the Gaussian or Laplacian pyramid and is conveniently represented as 8) where the generating kernel w2 is defined by (2.4). The complement of REDUCE is the EXPAND function, which performs a signal extrapolation to a finer resolution level,", "cite_spans": [{"start": 40, "end": 43, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 147, "end": 149, "text": "8)", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "Notation and operators", "text": "This operation involves an up-sampling by a factor of two and some form of interpolation. Burt and Adelson use the following operator [3] :", "cite_spans": [{"start": 134, "end": 137, "text": "[3]", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "Notation and operators", "text": "This operator is symmetric and has a sum equal to two, independent of a. The decimated version of this kernel is 5) and has a sum equal to one.", "cite_spans": [{"start": 113, "end": 115, "text": "5)", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "Notation and operators", "text": "These two procedures are summarized in Figs. 2(a) and 2(b).", "cite_spans": [], "ref_spans": []}, {"section": "The Laplac&n coding concept", "text": "The Laplacian pyramid captures the loss of information resulting from an application of the REDUCE function and is the difference between two successive levels of the Gaussian pyramid:", "cite_spans": [], "ref_spans": []}, {"section": "The Laplac&n coding concept", "text": "(2.11)", "cite_spans": [], "ref_spans": []}, {"section": "Basic REDUCE and EXPAND functions", "text": "The Gaussian pyramid is a multi-resolution representation of a signal. It is characterized by a sequence of signals f0,fl ..... fn, with the number of samples reduced by a factor of two in each of the principal directions from one level to the next. The finer or zero level of the pyramid is given by The key idea in the Laplacian coding scheme is to transmit the sequence of difference images Afl ..... Af, with sample values less extensively correlated than are the initial image pixels. The original image is then recovered by progressively expanding and summing the levels of the Laplacian pyramid, starting at the coarsest level. The main advantage of this approach is that the entropy of GAUSSIAN PYRAMID : the difference images is usually smaller than that of the initial image. Thus, the amount of transmitted information can be reduced by source coding. If one is willing to accept some image degradation, a substantial improvement of performance can be further achieved through quantization. Burt and Adelson have shown that the degradation can be made almost imperceptible through a proper choice of the number of quantization levels. The scheme they propose uses more quantization steps Signal Processing for coarser levels of the pyramid. The sample values at coarser spatial resolutions have to be coded more carefully because their contribution affects a larger number of pixels in the final reconstructed image.", "cite_spans": [], "ref_spans": []}, {"section": "Basic REDUCE and EXPAND functions", "text": "Although this approach achieves excellent image coding performance, we have evidence that it can be further improved. The reason for this is that Burt's construction of the Laplacian pyramid is sub-optimal by several criteria: ", "cite_spans": [], "ref_spans": []}, {"section": "Basic REDUCE and EXPAND functions", "text": "The following sections will show how these criteria can be taken into account.", "cite_spans": [], "ref_spans": []}, {"section": "Basic REDUCE and EXPAND functions", "text": "It is straightforward to verify that (3.2) (3.4) where g is the inverse filter given by", "cite_spans": [], "ref_spans": []}, {"section": "Basic REDUCE and EXPAND functions", "text": "The poles of this filter are -2a+ 4x/~l Zl,2 -(3.6) 1 -2a", "cite_spans": [], "ref_spans": []}, {"section": "The Laplacian pyramid with interpolation", "text": "The major limitation of the method proposed by Burt et al. is that the EXPAND function defined by (2.10) does not produce a valid image interpolation in the sense that the pixel values at the nodes are not preserved when a coarser level is used to approximate the next finer level. In fact,~,~+ l(k) is a smoothed extrapolation off+ 6k) and the energy of the difference signal is therefore unnecessarily large. We have defined a modified EXPAND function that guarantees strict signal interpolation in the sense defined above. This constraint is formally expressed as", "cite_spans": [], "ref_spans": []}, {"section": "The Laplacian pyramid with interpolation", "text": "This condition can be satisfied by applying the previous EXPAND operation to an auxiliary sequence {p,\u00f7t (k) } :", "cite_spans": [], "ref_spans": []}, {"section": "The Laplacian pyramid with interpolation", "text": "l=--o\u00a2 chosen to satisfy the constraint", "cite_spans": [], "ref_spans": []}, {"section": "The Laplacian pyramid with interpolation", "text": "and form a reciprocal pair. For a >~ ~, these poles are real and the system can be decomposed as a cascade or a sum of causal and anti-causal simple exponential filters. For a = I, G(z) = 1 and an exact interpolation can be achieved with no filtering at all. Otherwise, this operator can be implemented recursively with as few as two adds and three multiplies per sample point, as shown in Appendix A (see Table A ). As the signals encountered in practice are of finite extent (e.g. { f(k) Lk = 1 ..... K}), we have chosen to implement both finite and infinite impulse response filters using the following boundary conditions:", "cite_spans": [], "ref_spans": [{"start": 406, "end": 413, "text": "Table A", "ref_id": "TABREF8"}]}, {"section": "The Laplacian pyramid with interpolation", "text": "This type of signal extrapolation using mirror symmetry is commonly used in image processing applications and has the advantage of suppressing border artifacts.", "cite_spans": [], "ref_spans": []}, {"section": "The Laplacian pyramid with interpolation", "text": "Our modified EXPAND operator is represented schematically in Fig. 2 (e) and is described formally", "cite_spans": [], "ref_spans": [{"start": 61, "end": 67, "text": "Fig. 2", "ref_id": "FIGREF1"}]}, {"section": "The Laplacian pyramid with interpolation", "text": "It differs from (2.10) only by the adjunction of a pre-filter (g).", "cite_spans": [], "ref_spans": []}, {"section": "The least squares pyramid", "text": "A further refinement is to choose a compression scheme that minimizes the energy of the Laplacian. For this purpose, it is convenient to use the auxiliary coeff\u00c9cient sequence {pi(k)} defined earlier and to express the Laplacian as", "cite_spans": [], "ref_spans": []}, {"section": "The least squares pyramid", "text": "We now seek the series of coefficients {p~(k)} that minimizes the error criterion,", "cite_spans": [], "ref_spans": []}, {"section": "The least squares pyramid", "text": "As demonstrated in Appendix B, the optimal sequence of coefficients pt(k) satisfies the following equation:", "cite_spans": [], "ref_spans": []}, {"section": "The least squares pyramid", "text": "The solution is determined by first convolvingf_ l with w2, performing a decimation by a factor two, and finally filtering the resulting sequence with the operator h that implements the inverse of [w22]lz:", "cite_spans": [], "ref_spans": []}, {"section": "The least squares pyramid", "text": "By determining [w22]~2(k) explicitly, the corresponding IIR filter is characterized in the z-transform domain,", "cite_spans": [], "ref_spans": []}, {"section": "The least squares pyramid", "text": "The poles of this operator are simple and real for ~< a ~< \u00bd. As shown in Appendix A, h can be implemented recursively with as few as five multiplications and four additions per sample point. The relevant filter parameters for different values of a are given in Table A . By substituting (4.4) in (4.1), we find that the least squares Laplacian is given by", "cite_spans": [], "ref_spans": [{"start": 262, "end": 269, "text": "Table A", "ref_id": "TABREF8"}]}, {"section": "The least squares pyramid", "text": "Similarly, the corresponding REDUCE function is obtained by substitution of (4.4) in (3.3),", "cite_spans": [], "ref_spans": []}, {"section": "The least squares pyramid", "text": "and differs from (2.8) by the inclusion of two additional levels of post-filtering provided by wl and h. By recalling that g, wffk)= ~(k), we note that (4.6) is fully compatible with both (2.11) and the modified EXPAND function defined by (3.8).", "cite_spans": [], "ref_spans": []}, {"section": "The least squares pyramid", "text": "However, a direct evaluation of the least squares Laplacian through (4.6) is preferable for most practical purposes. It is more economical and also reduces the propagation of roundoff errors. These results are summarized in Fig. 2 which provides a block diagram representation of the EXPAND, REDUCE and LAPLACIAN functions and a comparison of the conventional and least squares Laplacian pyramids.", "cite_spans": [], "ref_spans": [{"start": 224, "end": 230, "text": "Fig. 2", "ref_id": "FIGREF1"}]}, {"section": "Results", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Experiments", "text": "The experiments were performed with a =3, unless indicated otherwise. In these comparisons, the three following procedures were considered: (i) the initial Laplacian pyramid (LP) based on (2.8) and (2.10), (ii) the Laplacian pyramid with interpolation (LPI) based on (2.8) and (3.8) , and (iii) the least squares Laplacian pyramid (LSLP) based on (4.6), (4.7) and (3.8).", "cite_spans": [], "ref_spans": []}, {"section": "Experiments", "text": "The Gaussian and least squares pyramidal representations for two test images are shown in Figs. 1 and 3, respectively. In both cases, the sharpness of the least squares pyramid is preserved at all resolution levels, while the corresponding images in the Gaussian pyramid seem increasingly blurred by comparison. The distinction between the two methods is even more striking if one looks at the Laplacian images displayed in Figs. 4 and 5. The same intensity scaling factors were applied to all images to facilitate the comparison. For the initial LP, the amount of information at each level is quite significant and the initial subject is still recognizable. In the case of the LSLP, the energy of the Laplacian is reduced drastically and only very high frequency details are visible in this representation. In a first stage, the performance of the decomposition can be assessed in terms of simple statistics These measures are given in Tables 1 and 2 for test images (a) and (b), respectively. For a = 2, the LPI is superior to the basic LP in all respects (e.g., reduced range, smaller standard deviation and entropy, and better signal approximation). As expected, the LSLP provides an even better signal approximation. In fact, the SNR values obtained for an LSLP extrapolation at a given level i are comparable to those obtained for an LP extrapolation at level i-1 with four times more sample values. The improvement of the LSLP is particularly striking at the finer resolution level at which the residual RMS error is approximately reduced by a factor of 2. Note, however, that this effect is reversed for the coarser levels and that the LSLP has the tendency to pack the energy into the top of the pyramid. In terms of image coding, this means that while fewer bits are required for representing the finer levels of the LSLP, more bits will be necessary for coding the coarser levels, a result consistent with the bit allocation strategy used by Burt and Adelson. For lossless image coding, the number of bits per pixel (bit-rate) necessary to transmit the top of the pyramid up to level i is approximately ", "cite_spans": [], "ref_spans": [{"start": 937, "end": 951, "text": "Tables 1 and 2", "ref_id": "TABREF3"}]}, {"section": "Experiments", "text": "The rate-distortion curves for our test images are given in Fig. 6 . For both images, the LSLP achieves the best performance at all resolution levels. The LP is the worst and the LPI is in between. An aspect that must also be taken into account in this comparison is that the performance of the pyramid decomposition depends on the value of the parameter a. In principle, our modified scheme should result in some improvement for any value of this parameter, although this effect may not always be as dramatic as in the examples discussed above. A case of special interest occurs when a = 0.5 in which case the LP is equivalent to the LPI (i.e. g(k) = identity). The corresponding error statistics for the MRI image are given in Table 3 . The performances of the LPI are slightly superior to those obtained with a = 3. The LSLP performs best but the improvement is not as dramatic as in Table  2 . For comparison, we have also included the results for the LP with a---0.6, the parameter value that resulted in the greatest reduction in entropy and variance in the series of experiments reported by Burt and Adelson [3] . The improvement over 3 the LP with a=~ is substantial, emphasizing the importance of the optimization of this parameter. Despite these excellent results, the optimized LP is still less performant than the LSLP which provides its best results for a = 3.", "cite_spans": [{"start": 1115, "end": 1118, "text": "[3]", "ref_id": "BIBREF2"}], "ref_spans": [{"start": 60, "end": 66, "text": "Fig. 6", "ref_id": "FIGREF3"}, {"start": 729, "end": 736, "text": "Table 3", "ref_id": "TABREF8"}, {"start": 887, "end": 895, "text": "Table  2", "ref_id": "TABREF4"}]}, {"section": "Experiments", "text": "The Laplacian pyramid coding scheme proposed by Burt and Adelson is especially suited for lossy image transmission [3] . The quantization scheme that they propose uses fewer bins for the higher resolution levels of the pyramid, which takes into account the fact that human contrast sensitivity decreases with high spatial frequencies. We have conducted some preliminary experiments to compare the efficiency of the different pyramid representations for this type of image coding. The experimental procedure is similar to the one used in [3] with some minor differences. The important features of the present compression algorithm are as follows:", "cite_spans": [{"start": 115, "end": 118, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 537, "end": 540, "text": "[3]", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "Experiments", "text": "(i) The coding and the decoding are performed in parallel starting at the coarsest level of the pyramid. In the present case, the pyramid has three levels and the coarsest (~) is coded precisely using all eight bits per node (256 gray level values). The corresponding contribution to the total bit-rate is only 8=0.125bits/ pixel. (ii) A Laplacian image is computed from the difference between a particular level of the Gaussian pyramid and the expanded version of the encoded image one level coarser. This technique takes into account quantization errors introduced at coarser resolution levels. (iii) The number of levels for each Laplacian image is fixed and should be determined using psychophysical information. The values of these levels are determined using a discrete form of the Max minimum error quantization algorithm [ 11 ] applied to the histogram of the Table 3 Comparison of performance measures at successive pyramid levels for the 'MRI' image with a=0.5 and a=0. images. The corresponding quantization levels are selected to minimize the approximation error and are not necessarily equidistant as was the case in the approach chosen by Burt and Adelson. In this series of experiments, the Laplacian images 2 and 3 were represented by 5 and 15 levels, respectively. The finest level of the pyramid was either not transmitted at all to achieve bit-rates lower than 1 bit/pixel or represented by 3 levels. (iv) The effective bit-rates are estimated from the entropies of the quantized images using (5.2). These estimates are somewhat optimistic as they ignore the transmission of the code book information. A practical approach to this problem is to summarize this information in terms of the coefficients of a parametric model of the Laplacian histogram (for example, the two parameters a and fl of a generalized exponential model p(Af) = Co e-~lAJ-I/~)~). These parameters can then be used to determine uniquely the optimal quantization levels in the Lloyd Max scheme and their corresponding code words in a variable length Huffman code [6] . Some examples of image coding with bit-rates as low as 0.7 bits/pixel are shown in Fig. 7 . The same number of quantization levels were used in all cases with the exception of Fig. 7(d) . This latter image is an improvement of Fig. 7 (c) obtained by adding a finer level of the LSLP quantized with three levels; it is visually indistinguishable from the original. The image obtained using LP (Fig. 7(a) ) appears to be out of focus and is of lesser quality (both qualitatively and quantitatively) than the results obtained with the LPI and LSLP. The LSLP scheme is clearly superior and appears to preserve most of the image details. The same qualitative behavior has also been observed for different compression ratios and test images. For the test image in Fig. 7 , we have also observed that the quality of the LP reconstruction is noticeably degraded for bit-rates lower than 1.5 bits/pixel, while for the LSLP greater compression ratios still produce acceptable results, as illustrated by Fig. 7(c) . In 197 these preliminary experiments, the performance of LSLP appears to be consistently superior.", "cite_spans": [{"start": 829, "end": 835, "text": "[ 11 ]", "ref_id": "BIBREF10"}, {"start": 2053, "end": 2056, "text": "[6]", "ref_id": "BIBREF5"}], "ref_spans": [{"start": 868, "end": 875, "text": "Table 3", "ref_id": "TABREF8"}, {"start": 2142, "end": 2148, "text": "Fig. 7", "ref_id": "FIGREF4"}, {"start": 2235, "end": 2244, "text": "Fig. 7(d)", "ref_id": "FIGREF4"}, {"start": 2286, "end": 2292, "text": "Fig. 7", "ref_id": "FIGREF4"}, {"start": 2451, "end": 2461, "text": "(Fig. 7(a)", "ref_id": "FIGREF4"}, {"start": 2817, "end": 2823, "text": "Fig. 7", "ref_id": "FIGREF4"}, {"start": 3052, "end": 3061, "text": "Fig. 7(c)", "ref_id": "FIGREF4"}]}, {"section": "Discussion", "text": "Our experimental results show that both the LPI and LSLP should be superior to the standard LP proposed by Burt et al. Two types of improvements have been considered and both seem to be equally 1 helpful, at least for a < ~. The first is the requirement that an image extrapolation be a true interpolation of a lower level approximation. A simple way to enforce this constraint is to add a pre- filter  (g(k) ) to the basic EXPAND operation. The effect of this operator is less significant when a is close to ~, in which case the LP and LPI are essentially equivalent. The second is to minimize the amount of transmitted information. The only adjunction here is a post-filter following the basic REDUCE operation. The LSLP incorporates both of these mechanisms and has surprisingly good compression properties. This approach provides an attractive alternative to the standard LP and should allow greater efficiency in image coding. Since multi-resolution techniques are being used increasingly in image processing, there are many other potential applications including image segmentation [2, 16] , edge detection [10] , feature extraction and a variety of multi-grid algorithms for computer vision [14] .", "cite_spans": [{"start": 1088, "end": 1091, "text": "[2,", "ref_id": "BIBREF1"}, {"start": 1092, "end": 1095, "text": "16]", "ref_id": "BIBREF15"}, {"start": 1113, "end": 1117, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 1198, "end": 1202, "text": "[14]", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "Discussion", "text": "The experimental results presented in Section 5.1 indicate a performance improvement in a lossless progressive data transmission scheme (cf. Fig. 6 ). The reduction of the RMS error also suggests that the LSLP should result in some improvement for lossy image coding as confirmed by our preliminary experiments (cf. Fig. 7 ). These results, however, are still preliminary and require further investigation. For instance, it seems important to determine an optimal bit allocation strategy for a given compression ratio and to compare the coding results for a variety of test images using objective psychovisual criteria. A detailed evaluation of the dependence of the relative performance of the algorithms on the parameter a may also be appropriate. As described in Appendix A, the additional preand post-filters can be implemented very efficiently and the increase in computation is negligible. For instance, the CPU times (standard 16 MHz Apple Macintosh Ilcx) required to compute the first level of the Laplacian of a 256 x 256 image using Burt's LP, the LSI and LSLP are 18 s, 25 s and 27 s, respectively. The complexity of the LSI and LSLP are comparable because the use of the interpolation pre-filter can be avoided in the second scheme (cf. Fig. 2(f) ).", "cite_spans": [], "ref_spans": [{"start": 141, "end": 147, "text": "Fig. 6", "ref_id": "FIGREF3"}, {"start": 316, "end": 322, "text": "Fig. 7", "ref_id": "FIGREF4"}, {"start": 1249, "end": 1258, "text": "Fig. 2(f)", "ref_id": "FIGREF1"}]}, {"section": "Discussion", "text": "The value a--83---0.375 was used for most of our experiments. It is close to the value 0.36 recommended by Burt for the greatest reduction of the side lobes of the transfer function [2] . Note that a =3 corresponds to an implicit choice of a Signal Processing quadratic B-spline interpolator [17] . In terms of performance, this value of a seems to be preferable over others (cf . Tables 2 and 3) , largely because of the smoothness and Gaussian-like shape of the corresponding interpolation kernel, which appears to be most appropriate for a large class of images. The unmodified LP, on the other hand, seems to perform best for a=0.6 [3] . An explanation for this observation is that the corresponding correction filters in our modified scheme have a very fast decay (i.e., g(k)= O(z~ ~1) and h(k)= O(plkl), where Zl = 0.084 and p = 0.074), and can be relatively well approximated by an identity filter. Another value 1 of interest is a = ~. This value leads to a triangular interpolation function and corresponds to image reconstruction by piecewise linear (or bilinear) interpolation. This scheme is equivalent to a firstorder spline interpolation.", "cite_spans": [{"start": 182, "end": 185, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 292, "end": 296, "text": "[17]", "ref_id": "BIBREF16"}, {"start": 636, "end": 639, "text": "[3]", "ref_id": "BIBREF2"}], "ref_spans": [{"start": 379, "end": 396, "text": ". Tables 2 and 3)", "ref_id": "TABREF4"}]}, {"section": "Discussion", "text": "Clearly, the theory presented here is not restricted to the particular form of interpolation function given by (2.4). It is straightforward to adapt these results to any given kernel w(k) ~ W(z). The only constraint is the stability of the approximation and interpolation filters, which, in the general case, are given by", "cite_spans": [], "ref_spans": []}, {"section": "W(z) + W(-z)", "text": "There is another advantage for the use of the least squares pyramid. In a standard complete pyramidal representation the number of nodes is 1 increased by 5 when compared to the initial number of pixels. In the LSLP, the total number I of nodes can be reduced by a (e.g., made equal to the initial number of pixels) because the residual error at each step is orthogonal to the reduced resolution signal approximation. In other words, the LS REDUCE function is a projection operator with the property that", "cite_spans": [], "ref_spans": []}, {"section": "W(z) + W(-z)", "text": "For a bi-dimensional image with M grid points, (5.6) provides us with a set of 1 gM linear constraints. The true number of degrees of freedom of the LS Laplacian is therefore 3M and not M as may be thought initially. In fact, we will show in the last section that the quadrature mirror filter (QMF) concept offers a simple solution for dealing with this redundancy. We will thereby also establish the relationship between the present approach and recent work in orthogonal pyramid structures [1, 12] , wavelet transforms [9] and subband coding techniques [ 18, 20] .", "cite_spans": [{"start": 492, "end": 495, "text": "[1,", "ref_id": "BIBREF0"}, {"start": 496, "end": 499, "text": "12]", "ref_id": "BIBREF11"}, {"start": 521, "end": 524, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 555, "end": 560, "text": "[ 18,", "ref_id": "BIBREF17"}, {"start": 561, "end": 564, "text": "20]", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "Link with QMF pyramids", "text": "Quadrature mirror filters, introduced by Croisier et al. in 1976 [4] , provide an attractive method for splitting a signal into critically sampled filtered components. Such filter banks can be applied iteratively to produce a subband decomposition of the spectrum into octave bandwidth pieces [18] . The two attractive features of this technique are (i) the reversibility of the process (error free reconstruction) and (ii) the fact that the resulting signal decomposition uses no more samples than the initial representation. Recently, several authors have applied this concept to pyramid image compression and have reported substantial improvements in performance [1, 12, 18, 20] . QMF banks also provide an efficient way of computing wavelet transforms, as has been shown recently by Mallat and Daubechies [5, 8, 9] .", "cite_spans": [{"start": 65, "end": 68, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 293, "end": 297, "text": "[18]", "ref_id": "BIBREF17"}, {"start": 666, "end": 669, "text": "[1,", "ref_id": "BIBREF0"}, {"start": 670, "end": 673, "text": "12,", "ref_id": "BIBREF11"}, {"start": 674, "end": 677, "text": "18,", "ref_id": "BIBREF17"}, {"start": 678, "end": 681, "text": "20]", "ref_id": "BIBREF19"}, {"start": 809, "end": 812, "text": "[5,", "ref_id": "BIBREF4"}, {"start": 813, "end": 815, "text": "8,", "ref_id": "BIBREF7"}, {"start": 816, "end": 818, "text": "9]", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "Link with QMF pyramids", "text": "The block diagram of a QMF bank is represented in Fig. 8 . In the basic QMF design [12, 19] , the transfer functions of the filters are chosen such that", "cite_spans": [{"start": 83, "end": 87, "text": "[12,", "ref_id": "BIBREF11"}, {"start": 88, "end": 91, "text": "19]", "ref_id": "BIBREF18"}], "ref_spans": [{"start": 50, "end": 56, "text": "Fig. 8", "ref_id": "FIGREF5"}]}, {"section": "Link with QMF pyramids", "text": "where F(z) is a lowpass filter prototype satisfying the perfect reconstruction property", "cite_spans": [], "ref_spans": []}, {"section": "Link with QMF pyramids", "text": "(5.8)", "cite_spans": [], "ref_spans": []}, {"section": "Link with QMF pyramids", "text": "To establish its relationship to the present approach, we will construct a QMF bank such that its lower branch (lowpass) precisely computes the least squares signal estimates derived in Section 4. We derive this result by manipulating the block diagram in Fig. 9(a) , which performs successively the REDUCE and EXPAND functions described in Sections 3 and 4. The first step is to note that Fig. 9 . QMF interpretation of the least squares approximation procedure: equivalent block diagrams.", "cite_spans": [], "ref_spans": []}, {"section": "Link with QMF pyramids", "text": "the two central filters (W~ (z) and G(z)) cancel each other. Second, the filter H(z) is factored into a product of square-root components ( Fig. 9(b) ). Finally, the filters are moved on each side of the sampling modules by upsampling their impulse response by a factor of two (this is achieved by replacing z by z 2 in their z-transform) ( Fig. 9(c) ).", "cite_spans": [], "ref_spans": []}, {"section": "Link with QMF pyramids", "text": "At the end of this process, we have an equivalent system (i.e., same input and output) for which the pre-filters and post-filters are identical and given by", "cite_spans": [], "ref_spans": []}, {"section": "Link with QMF pyramids", "text": "Using (5.4), it is then easy to verify by substitution that this operator satisfies the perfect reconstruction property (5.8) . Since the final output of the QMF bank is equal to its input, it follows that the corresponding highpass branch precisely codes for the residual signal displayed in the least squares Laplacian pyramid. This approach is easily extended to higher dimensions by iterating the subband decomposition along the rows and columns according to the procedure initially described by Vetterli [ 18] . The main advantage of such a QMF decomposition is that the residual signal is now represented without redundancy (i.e., the sum of the number of lowpass and highpass samples is equal to the initial number of samples).", "cite_spans": [{"start": 509, "end": 514, "text": "[ 18]", "ref_id": "BIBREF17"}], "ref_spans": []}, {"section": "Link with QMF pyramids", "text": "In order to obtain a decomposition closer to our initial design, we choose an alternative, but globally equivalent, factorization with", "cite_spans": [], "ref_spans": []}, {"section": "Link with QMF pyramids", "text": "for which it can be verified that the filters Fo(z) and Go(z) are precisely those required for the REDUCE and EXPAND function described in Sections 3 and 4. The advantage of this latter decomposition is that it can be implemented recursively using the fast algorithms described in Sections 3 and 4 (see Figs. 2(d) and 2(e)) and Appendix A. The highpass components can be evaluated using the same procedure, provided that the FIR smoothing kernel (Wz(z)) (which is used as a pre-and post-filter) is replaced by its modulated and shifted counterparts: z W2(-z) and W2(-z)/z, respectively. We note that this particular choice of filters corresponds to a linear algebraic transform that is non-orthogonal, in contrast to a standard QMF bank as defined by (5.7) (5.8), which can be interpreted as an orthogonal transformation [12] . These results also suggest that a QMF implementation of the present least squares image pyramid could provide a further I improvement by z over the coding procedure used in the experimental part of this paper.", "cite_spans": [{"start": 821, "end": 825, "text": "[12]", "ref_id": "BIBREF11"}], "ref_spans": []}, {"section": "Conclusion", "text": "Two methods for improving the Laplacian pyramid proposed by Burt and Adelson for image coding have been described: (i) The EXPAND function has been redefined to ensure that the expansion of a coarser level onto a finer grid is an exact interpolation. (ii) An improved REDUCE function has been derived in order to minimize the loss of information occurring during resolution conversion.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusion", "text": "It is easy to modify the initial scheme to incorporate these new functions. This is achieved by adding a pre-filter and a post-filter in the expansion and reduction modules, respectively. These filters can be coded very efficiently and the resulting increase of computations is moderate.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusion", "text": "For lossless progressive data transmission, the performance improvement that can be achieved in this way is significant. The least squares scheme performs best according to the quantitative criteria used in this paper. Preliminary results suggest that this approach allows improved image coding according to the lossy scheme developed by Burt and Adelson. The least squares pyramid also stands as an interesting alternative to the widely used Gaussian pyramid and should be useful in a variety of multi-resolution image processing algorithms. It has also been shown that the present approach can be linked to the family of QMF image pyramids (e.g., orthogonal pyramids, wavelet transforms, subband coders). ", "cite_spans": [], "ref_spans": []}, {"section": "Conclusion", "text": "The implementation of these elementary units is based on the decomposition of H(z; z,% into a sum of simple causal and anti-causal first order systems, as given by the right-hand side of (A.3). The corresponding recursive filter equations are also more economical to combine the individual scaling factors in (A.1) and (A.5) or (A.7) into a single multiplication at the end of the process. The relevant filter parameters for implementing some of the operators described in Sections 3 and 4 using this strategy are given in Table A . This approach is also applicable in higher dimensions through the successive use of the same onedimensional filter along the various dimensions of the data. For digital images there is no need for floating point data storage other than the onedimensional array(s) required by the basic onedimensional filtering module.", "cite_spans": [], "ref_spans": [{"start": 523, "end": 530, "text": "Table A", "ref_id": "TABREF8"}]}, {"section": "Conclusion", "text": "We note that the second equation is borrowed from the sum decomposition and is required to initialize the backward recursion correctly.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusion", "text": "All operations in (A.7) (respectively (A.5)) are real, and it is necessary to use one (respectively two) one-dimensional real array(s) for storing the filtered sequences with sufficient precision to avoid a recursive propagation of errors. It is relatively straightforward to write a general subroutine that implements (A. 1) from a succession of simple convolutions of the form (A.5) or (A.7); no additional intermediate storage is necessary for this task. It is", "cite_spans": [], "ref_spans": []}, {"section": "Appendix B. Derivation of the least squares coefficients", "text": "The error criterion (4.2) is decomposed as ", "cite_spans": [], "ref_spans": []}, {"section": "+ ~ pi(k)([w22]+2*pi(k)) -2 y\" p~(k)([w2*f-t]+2(k)).", "text": "(B.1)", "cite_spans": [], "ref_spans": []}, {"section": "+ ~ pi(k)([w22]+2*pi(k)) -2 y\" p~(k)([w2*f-t]+2(k)).", "text": "The partial derivative of (B. 1) with respect to p~(k)", "cite_spans": [], "ref_spans": []}, {"section": "+ ~ pi(k)([w22]+2*pi(k)) -2 y\" p~(k)([w2*f-t]+2(k)).", "text": "is given by The optimal sequence of coefficients is obtained by setting this expression equal to zero, which results in (4.3). Q.E.D.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Orthogonal pyramid transforms for image coding", "authors": [{"first": "E", "middle": ["H"], "last": "Adelson", "suffix": ""}, {"first": "E", "middle": [], "last": "Simoncelli", "suffix": ""}, {"first": "R", "middle": [], "last": "Hingorani", "suffix": ""}], "year": 1987, "venue": "Proc. SPIE Conj. Visual Communication and Image Processing", "link": "7863995"}, "BIBREF1": {"title": "Fast algorithms for estimating local image properties", "authors": [{"first": "P", "middle": ["J"], "last": "Burt", "suffix": ""}], "year": 1983, "venue": "Comput. Graph. Image Process", "link": null}, "BIBREF2": {"title": "The Laplacian pyramid as a compact code", "authors": [{"first": "P", "middle": ["J"], "last": "Burt", "suffix": ""}, {"first": "E", "middle": ["H"], "last": "Adelson", "suffix": ""}], "year": 1983, "venue": "IEEE Trans. Comm", "link": null}, "BIBREF3": {"title": "Perfect channel splitting by use of interpolation, decimation, tree decomposition techniques", "authors": [{"first": "A", "middle": [], "last": "Croisier", "suffix": ""}, {"first": "D", "middle": [], "last": "Esteban", "suffix": ""}, {"first": "C", "middle": [], "last": "Galand", "suffix": ""}], "year": 1976, "venue": "Proc. Internat. Conf. Information Sciences~Systems", "link": null}, "BIBREF4": {"title": "Orthogonal bases of compactly supported wavelets", "authors": [{"first": "I", "middle": [], "last": "Daubechies", "suffix": ""}], "year": 1988, "venue": "Comm. Pure Appl. Math", "link": null}, "BIBREF5": {"title": "Fundamentals of Digital Image Processing", "authors": [{"first": "A", "middle": ["K"], "last": "Jain", "suffix": ""}], "year": 1989, "venue": "", "link": "54119578"}, "BIBREF6": {"title": "Second generation image-coding techniques", "authors": [{"first": "M", "middle": [], "last": "Kunt", "suffix": ""}, {"first": "A", "middle": [], "last": "Ikonomopoulos", "suffix": ""}, {"first": "M", "middle": [], "last": "Kocher", "suffix": ""}], "year": 1985, "venue": "Proc. IEEE", "link": "10177743"}, "BIBREF7": {"title": "Multiresolution approximations and wavelet orthogonal bases of L2(R)", "authors": [{"first": "S", "middle": ["G"], "last": "Mallat", "suffix": ""}], "year": 1989, "venue": "Trans. Amer. Math. Soc", "link": "116098693"}, "BIBREF8": {"title": "A theory ofmultiresolution signal decomposition: The wavelet representation", "authors": [{"first": "S", "middle": ["G"], "last": "Mallat", "suffix": ""}], "year": 1989, "venue": "IEEE Trans. Pattern Anal. Machine lntell", "link": null}, "BIBREF9": {"title": "Theory of edge detection", "authors": [{"first": "D", "middle": [], "last": "Mart", "suffix": ""}, {"first": "E", "middle": [], "last": "Hildreth", "suffix": ""}], "year": 1980, "venue": "Proc. Roy. Soc. London", "link": "2150419"}, "BIBREF10": {"title": "Quantizing for minimum distortion", "authors": [{"first": "J", "middle": [], "last": "Max", "suffix": ""}], "year": 1960, "venue": "IRE Trans. lnJbrm. Theory", "link": "10960406"}, "BIBREF11": {"title": "Non-separable extensions of quadrature mirror filters to multiple dimensions", "authors": [{"first": "E", "middle": ["P"], "last": "Simoncelli", "suffix": ""}, {"first": "E", "middle": ["H"], "last": "Adelson", "suffix": ""}], "year": 1990, "venue": "Proc. IEEE", "link": "14073725"}, "BIBREF12": {"title": "Image transmission with gross information first", "authors": [{"first": "S", "middle": ["L"], "last": "Tanimoto", "suffix": ""}], "year": 1979, "venue": "Comput. Graph. Image Process", "link": "62676622"}, "BIBREF13": {"title": "Multilevel computational processes for visual surface reconstruction", "authors": [{"first": "D", "middle": [], "last": "Terzopoulos", "suffix": ""}], "year": 1983, "venue": "Comput. Vision Graph. Image Process", "link": "630502"}, "BIBREF14": {"title": "Progressive image transmission : a review and comparison of techniques", "authors": [{"first": "K", "middle": ["H"], "last": "Tzou", "suffix": ""}], "year": 1987, "venue": "Optical Engrg", "link": "121586358"}, "BIBREF15": {"title": "Multi-resolution feature extraction and selection for texture segmentation", "authors": [{"first": "M", "middle": [], "last": "Unser", "suffix": ""}, {"first": "M", "middle": [], "last": "Eden", "suffix": ""}], "year": 1989, "venue": "IEEE Trans. Pattern Anal. Mach. lntell", "link": null}, "BIBREF16": {"title": "Fast B-spline transforms for continuous image representation and interpolation", "authors": [{"first": "M", "middle": [], "last": "Unser", "suffix": ""}, {"first": "A", "middle": [], "last": "A|droubi", "suffix": ""}, {"first": "M", "middle": [], "last": "Eden", "suffix": ""}], "year": 1991, "venue": "IEEE Trans. Pattern Anal. Machine lntell", "link": "42151621"}, "BIBREF17": {"title": "Multi-dimensional sub-band coding: some theory and algorithms", "authors": [{"first": "M", "middle": [], "last": "Vetterli", "suffix": ""}], "year": 1984, "venue": "Signal Processing", "link": "120839836"}, "BIBREF18": {"title": "A theory of multirate filter banks", "authors": [{"first": "M", "middle": [], "last": "Vetterli", "suffix": ""}], "year": 1987, "venue": "1EEE Trans. Acoust. Speech Signal Process", "link": "18421232"}, "BIBREF19": {"title": "Sub-band coding of images", "authors": [{"first": "J", "middle": ["W"], "last": "Woods", "suffix": ""}, {"first": "S", "middle": ["D"], "last": "O&apos;neil", "suffix": ""}], "year": 1986, "venue": "IEEE Trans. Acoust. Speech Signal Process", "link": "119958680"}}, "ref_entries": {"FIGREF0": {"text": "Fig. 1. Examples of image pyramids. (0): 208 x 222 'female' image (level 0), (al-a4): levels 1 to 4 of the basic Gaussian pyramid, (bl-b4): levels 1 to 4 of the least squares Gaussian pyramid.", "type": "figure"}, "FIGREF1": {"text": "Fig. 2. Schematic representation of the REDUCE, EXPAND and LAPLACIAN functions for the standard and least squares Gaussian pyramids.", "type": "figure"}, "FIGREF2": {"text": "Fig. 3. Comparison of image pyramids. (0): 238 x 253 'MRI' image (level 0), (al a4): levels 1 to 4 of the basic Gaussian pyramid, (bl-b4) : levels 1 to 4 of the least squares Gaussian pyramid.", "type": "figure"}, "FIGREF3": {"text": "Fig. 6. Rate distortion curves for 'female' and 'MRI' images for the three image pyramids: Gaussian pyramid (GP), Gaussian pyramid with interpolation (GPI) and least squares Gaussian pyramid (LSGP).", "type": "figure"}, "FIGREF4": {"text": "Fig. 7. Comparison of lossy image compression schemes. (a) Laplacian pyramid (LP): B=0.746bits/pixel, SNR=23.02dB; (b) Laplacian pyramid with interpolation (LPI) : B = 0.708 bits/pixel, SNR = 24.51 dB; (c) least squares Laplacian pyramid (LSLP): B = 0.702 bits/pixel, SNR = 27.15 dB; (d) LSLP: B = 1.667 bits/pixel, SNR = 31.90 dB.", "type": "figure"}, "FIGREF5": {"text": "Fig. 8. Block diagram of a quadrature mirror filter bank for signal analysis and synthesis.", "type": "figure"}, "FIGREF6": {"text": "pairs (e.g., if PZN(Zi)=O then P2x(z~-r)=0). These roots, which are assumed to lie outside the unit circle, are denoted by { ( zi , :i' ) l lzil < 1, i: 1 ..... N}. Consequently, H2N(Z ) can be factored as N H,_N(z) =Co [] H(z; z,.),Appendix A. Efficient recursive filter implementation This appendix describes an efficient way to implement the recursive filters required in the generation of a least squares Laplacian pyramid. The transfer functions of these operators are spe- cial cases of a class of IIR symmetrical filters described by the following equation:and {aklk = 0 ..... N-1 } are given con- stant coefficients. Due to the reverse symmetry of its coefficients, the polynomial P2N(Z) of degree 2N is such that z--Np2N(Z)=zNp2N(Z--I). This implies It follows that (A. 1) can be implemented by a cas- cade of simple operators of the form specified by (A.3), each of which has a symmetrical exponential impulse response:", "type": "figure"}, "FIGREF7": {"text": "5) where x(k) and y(k) are the input and output sig- nals, respectively, and where ci = -zi/(1-z 2) is a scaling constant. For boundary conditions speci- fied by (3.7), the recursion is initialized with the Voh 27, No.is such that zl ~'\u00b0p is below some prescribed level of precision. A slightly more economical alter- native is an implementation based on a product decomposition: k=l ..... K, (A.7) k=K-1 ..... 1. y+(k) = x(k) + z,y+(k-1), y(K) = c~(2y+ (K) -x(K) ), y(k) = z~(y(k + 1) -y+(k)),", "type": "figure"}, "FIGREF8": {"text": "-,(k)(w2* [Pilt2(kl).", "type": "figure"}, "FIGREF9": {"text": "(k) = Y4=-~ w2(l)w2(k + l) and mak- ing the appropriate change of variables, this expression is rewritten as e 2= ~ (f_t(k)f +-)t + Z [p,]~2(k)(w22 * [p,]~2(k)) -2 ~ (w2*f i(k))[p~]~2(k). The restriction of the two rightmost terms to the non-zero values of [pi]r2(k) (e.g., a decimation by a factor of 2) yields \u2022 ~= S (f, ,(k)) 2", "type": "figure"}, "TABREF3": {"text": "Comparison of performance measures 3 levels for the 'female' image with a-5 at successive pyramid such as the entropy, the standard deviation or root Pyramid Range RMS Entropy SNR (dB) mean square (RMS) error, and the minimum and level maximum values of the Laplacian images.", "type": "table"}, "TABREF4": {"text": "Comparison of performance measures at successive pyramid levels for the 'MRI' image with a=]", "type": "table"}, "TABREF8": {"text": "Transfer functions and characteristic parameters of interpolation and least squares approximations filters as a function of the parameter a Filter a Transfer function Co Poles: {Izir < l li= 1 ..... N}", "type": "table"}}}
{"paper_id": "2875502", "_pdf_hash": "ea7c08aed26556ea8e3818b090171ea90c5cefa2", "abstract": [], "body_text": [], "bib_entries": {"BIBREF1": {"title": "Managing the Flow of Technology", "authors": [{"first": "T", "middle": ["J"], "last": "Allen", "suffix": ""}], "year": 1977, "venue": "", "link": "155156454"}, "BIBREF2": {"title": "Bridging the boundary: external activity and performance in organizational teams", "authors": [{"first": "D", "middle": ["J"], "last": "Ancona", "suffix": ""}, {"first": "D", "middle": ["F"], "last": "Caldwell", "suffix": ""}], "year": 1992, "venue": "Administrative Science Quarterly", "link": "16900238"}, "BIBREF3": {"title": "Design Rules: The Power of Modularity", "authors": [{"first": "C", "middle": ["Y"], "last": "Baldwin", "suffix": ""}, {"first": "K", "middle": ["B"], "last": "Clark", "suffix": ""}], "year": 2000, "venue": "", "link": "58267404"}, "BIBREF4": {"title": "Models of Core Periphery Structures", "authors": [{"first": "S", "middle": ["P"], "last": "Borgatti", "suffix": ""}, {"first": "M", "middle": ["G"], "last": "Everett", "suffix": ""}], "year": 1999, "venue": "Social Networks", "link": "5227335"}, "BIBREF5": {"title": "Product Development: Past Research, Present Findings, and Future Directions", "authors": [{"first": "S", "middle": ["L"], "last": "Brown", "suffix": ""}, {"first": "K", "middle": ["M"], "last": "Eisenhardt", "suffix": ""}], "year": 1995, "venue": "", "link": "53626962"}, "BIBREF6": {"title": "Structural Holes: The Social Structure of Competition", "authors": [{"first": "R", "middle": ["S"], "last": "Burt", "suffix": ""}], "year": 1992, "venue": "", "link": "155417248"}, "BIBREF7": {"title": "Identification of Coordination Requirements: Implications for Design of Collaboration and Awareness Tools", "authors": [{"first": "M", "middle": [], "last": "Cataldo", "suffix": ""}], "year": 2006, "venue": "Proc. CSCW'06", "link": "15400558"}, "BIBREF8": {"title": "Communication patterns in geographically distributed software development and engineers' contributions to the development effort", "authors": [{"first": "M", "middle": [], "last": "Cataldo", "suffix": ""}, {"first": "J", "middle": ["D"], "last": "Herbsleb", "suffix": ""}], "year": 2008, "venue": "Proc. CHASE'08", "link": "1628991"}, "BIBREF9": {"title": "How do committees invent? Datamation", "authors": [{"first": "M", "middle": ["E"], "last": "Conway", "suffix": ""}], "year": 1968, "venue": "", "link": "108105632"}, "BIBREF10": {"title": "Structural Properties of Work Groups and their Consequences for Performance", "authors": [{"first": "J", "middle": [], "last": "Cummings", "suffix": ""}, {"first": "R", "middle": [], "last": "Cross", "suffix": ""}], "year": 2003, "venue": "Social Networks", "link": "40824708"}, "BIBREF11": {"title": "Human Factors in Software Development", "authors": [{"first": "B", "middle": [], "last": "Curtis", "suffix": ""}], "year": 1981, "venue": "", "link": null}, "BIBREF12": {"title": "A field study of software design process for large systems", "authors": [{"first": "B", "middle": [], "last": "Curtis", "suffix": ""}, {"first": "H", "middle": [], "last": "Kransner", "suffix": ""}, {"first": "N", "middle": [], "last": "Iscoe", "suffix": ""}], "year": 1988, "venue": "Comm. of ACM", "link": null}, "BIBREF13": {"title": "How a Good Software Practice Thwarts Collaboration: The multiple roles of APIs in Software Development", "authors": [{"first": "C", "middle": [], "last": "De Souza", "suffix": ""}], "year": 2004, "venue": "Proc. FSE'04", "link": "12278957"}, "BIBREF14": {"title": "Supporting Collaborative Software Development through Visualization of Socio Technical Dependencies", "authors": [{"first": "C", "middle": [], "last": "De Souza", "suffix": ""}], "year": 2007, "venue": "Proc. GROUP'07", "link": "16470275"}, "BIBREF15": {"title": "A Model-Based Method for Organizing Tasks in Product Development", "authors": [{"first": "S", "middle": ["D"], "last": "Eppinger", "suffix": ""}], "year": 1994, "venue": "", "link": null}, "BIBREF17": {"title": "The Geography of Coordination Dealing with Distance in R&D Work", "authors": [{"first": "R", "middle": ["E"], "last": "Grinter", "suffix": ""}, {"first": "J", "middle": ["D"], "last": "Herbsleb", "suffix": ""}, {"first": "D", "middle": ["E"], "last": "Perry", "suffix": ""}], "year": 1999, "venue": "Proc. GROUP'99", "link": "2320177"}, "BIBREF18": {"title": "Gatekeeper and process promoter: key persons in agile and innovative organizations", "authors": [{"first": "J", "middle": [], "last": "Hauschildt", "suffix": ""}, {"first": "G", "middle": [], "last": "Schewe", "suffix": ""}], "year": 2000, "venue": "International Journal of Agile Management Systems", "link": "110185371"}, "BIBREF19": {"title": "Architectural Innovation: The Reconfiguration of Existing Product Technologies and the Failure of Established Firms", "authors": [{"first": "R", "middle": ["M"], "last": "Henderson", "suffix": ""}, {"first": "K", "middle": ["B"], "last": "Clarck", "suffix": ""}], "year": 1990, "venue": "Administrative Science Quarterly", "link": "6255046"}, "BIBREF20": {"title": "An Empirical Study of Speed and Communication in Globally Distributed Software Development", "authors": [{"first": "J", "middle": ["D"], "last": "Herbsleb", "suffix": ""}, {"first": "A", "middle": [], "last": "Mockus", "suffix": ""}], "year": 2003, "venue": "Trans. on Soft. Eng", "link": "6006584"}, "BIBREF21": {"title": "Structures that Work: Social Structure, Work Structure, and Coordination Ease in Geographically Distributed Teams", "authors": [{"first": "P", "middle": [], "last": "Hinds", "suffix": ""}, {"first": "C", "middle": [], "last": "Mcgrath", "suffix": ""}], "year": 2006, "venue": "Proc. CSCW'06", "link": "9178340"}, "BIBREF22": {"title": "I'd be overwhelmed, but it's just one more thing to do\": availability and interruption in research management", "authors": [{"first": "J", "middle": ["M"], "last": "Hudson", "suffix": ""}], "year": 2002, "venue": "Proc. CHI'02", "link": "2225264"}, "BIBREF23": {"title": "Global Software Development: Managing Virtual Teams and Environments", "authors": [{"first": "D", "middle": ["W"], "last": "Karolak", "suffix": ""}], "year": 1998, "venue": "", "link": "61099238"}, "BIBREF24": {"title": "Managing Software Requirements: A Use Case Approach, 2 nd Edition", "authors": [{"first": "D", "middle": [], "last": "Leffingwell", "suffix": ""}, {"first": "D", "middle": [], "last": "Widrig", "suffix": ""}], "year": 2003, "venue": "", "link": "18445438"}, "BIBREF26": {"title": "An Investigation of Global, Virtual and Collocated New Product Development Teams", "authors": [{"first": "E", "middle": ["F"], "last": "Mcdonough", "suffix": ""}, {"first": "K", "middle": ["B"], "last": "Kahn", "suffix": ""}, {"first": "G", "middle": [], "last": "Barczak", "suffix": ""}], "year": 2001, "venue": "Journal of Prod. Innovation Mgmt", "link": null}, "BIBREF27": {"title": "Predicting risk of software changes", "authors": [{"first": "A", "middle": [], "last": "Mockus", "suffix": ""}, {"first": "D", "middle": ["M"], "last": "Weiss", "suffix": ""}], "year": 2000, "venue": "Bell Labs Tech. Journal", "link": "10267782"}, "BIBREF28": {"title": "Inferring and visualizing social networks on Internet Relay Chat", "authors": [{"first": "P", "middle": [], "last": "Mutton", "suffix": ""}], "year": 2004, "venue": "Proceedings of the Information Visualization Conference (IV '04)", "link": "62216909"}, "BIBREF30": {"title": "On the criteria to be used in decomposing systems into modules", "authors": [{"first": "D", "middle": ["L"], "last": "Parnas", "suffix": ""}], "year": 1972, "venue": "Comm. of ACM", "link": "53856438"}, "BIBREF31": {"title": "Global Software Development Handbook", "authors": [{"first": "R", "middle": [], "last": "Sangwan", "suffix": ""}], "year": 2006, "venue": "", "link": "106685521"}, "BIBREF32": {"title": "The Sciences of the Artificial", "authors": [{"first": "H", "middle": ["A"], "last": "Simon", "suffix": ""}], "year": 1996, "venue": "", "link": null}, "BIBREF33": {"title": "Applied Longitudinal Data Analysis", "authors": [{"first": "J", "middle": ["D"], "last": "Singer", "suffix": ""}, {"first": "J", "middle": ["B"], "last": "Willet", "suffix": ""}], "year": 2003, "venue": "", "link": null}, "BIBREF34": {"title": "The Misalignment of Product Architecture and Organizational Structure in Complex Product Development. Management Science", "authors": [{"first": "M", "middle": ["E"], "last": "Sosa", "suffix": ""}, {"first": "S", "middle": ["D"], "last": "Eppinger", "suffix": ""}, {"first": "C", "middle": ["M"], "last": "Rowles", "suffix": ""}], "year": 2004, "venue": "", "link": null}, "BIBREF35": {"title": "Social networks and the performance of individuals and groups. Academy of Management", "authors": [{"first": "R", "middle": ["T"], "last": "Sparrowe", "suffix": ""}], "year": 2001, "venue": "Journal", "link": null}, "BIBREF36": {"title": "The Structure and Value of Modularity in Software Design", "authors": [{"first": "K", "middle": [], "last": "Sullivan", "suffix": ""}], "year": 2001, "venue": "Proc. FSE'01", "link": null}, "BIBREF37": {"title": "Information Hiding in Product Development: The Design Churn Effect", "authors": [{"first": "A", "middle": [], "last": "Yassine", "suffix": ""}], "year": 2003, "venue": "Research in Engineering Design", "link": "192619791"}}, "ref_entries": {}}
{"paper_id": "2876847", "_pdf_hash": "b0becc892384da2bc9fe0ad15161412016cee34c", "abstract": [{"section": "Abstract", "text": "All humans, animals, and plants are holobionts. Holobionts comprise the host and a myriad of interacting microorganisms-the microbiota. The hologenome encompasses the genome of the host plus the composite of all microbial genomes (the microbiome). In health, there is a fine-tuned and resilient equilibrium within the members of the microbiota and between them and the host. This relative stability is maintained by a high level of microbial diversity, a delicate bio-geographic distribution of microorganisms, and a sophisticated and intricate molecular crosstalk among the multiple components of the holobiont. Pathobionts are temporarily benign microbes with the potential, under modified ecosystem conditions, to become key players in disease. Pathobionts may be endogenous, living for prolonged periods of time inside or on the host, or exogenous, invading the host during opportunistic situations. In both cases, the end result is the transformation of the beneficial microbiome into a health-perturbing pathobiome. We hypothesize that probably all diseases of holobionts, acute or chronic, infectious or non-infectious, and regional or systemic, are characterized by a perturbation of the healthy microbiome into a diseased pathobiome.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Main text", "text": "For more than a century, diseases of humans have been classified in a dichotomous fashion as infectious and non-infectious. In the former group, causality has been framed in the context of Koch's postulates, in most cases linking a single microbe with a single disease. This approach, although incomplete from a patho-physiological point of view, has led to enormous advances in the prevention and treatment of infectious diseases. During the last decade, a huge amount of data has been gathered on the composition of the human microbiota in health and disease. Nowadays, almost no sickness has been overlooked by this trend, and there is expanding information on the complex configuration of the human microbiota in almost every illness. Interestingly, this knowledge includes not only non-infectious chronic diseases such as obesity, diabetes mellitus, inflammatory bowel disease, and many others but also a growing list of infectious diseases that were traditionally ascribed to a single pathogen behaving as a lone warrior against the host. For example, in AIDS, a disease caused by the HIV virus, a perturbed microbiota is found in the vagina of women with a higher predisposition to contract the infection [1] , in the gut of patients already infected with HIV [2] , and also in HIV-negative neonates born to mothers who received successful anti-retroviral therapy [3] . As an additional example, Staphylococcus aureus lives as a dormant pathobiont in the nares of more than a third of healthy individuals. Recent investigations have shown that this bacterium remains confined to the nares due to an intricate interaction with other organisms. For example, the nearby presence of Staphylococcus lugdunensis kills S. aureus through a newly discovered antibiotic termed lugdunin [4] . On the other hand, the adjacent growth of Corynebacterium striatum and S. aureus results in diminished expression of virulence genes of S. aureus but augmented expression of genes involved in non-virulent colonization [5] . Switching roles from defenders to attackers, S. lugdunensis or C. striatum may cause serious infections [6, 7] . S. aureus cohabitating other body sites, for example, the lungs, may increase the virulence of other microbes in the vicinity [8] . Escherichia coli, a major member of the gut microbiota, may cause life-threatening infections. Conversely, probiotic strains of the same bacterium may prevent recurrence of bladder infections in women [9] or the development of rampant cholera infection in experimental settings [10] . Many other microbes, acting as endogenous or exogenous pathobionts, may appear to act as independent aggressors, but their ability to trigger disease is actually orchestrated and regulated by members of the microbiome/microbiota. For example, carriage of the arbovirus is influenced by the microbiota of its mosquito vector [11] and attraction of biting mosquitoes is dependent on the individual's skin microbiota [12] .", "cite_spans": [{"start": 1212, "end": 1215, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 1267, "end": 1270, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 1371, "end": 1374, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 1783, "end": 1786, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 2007, "end": 2010, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 2117, "end": 2120, "text": "[6,", "ref_id": "BIBREF5"}, {"start": 2121, "end": 2123, "text": "7]", "ref_id": "BIBREF6"}, {"start": 2252, "end": 2255, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 2459, "end": 2462, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 2536, "end": 2540, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 2867, "end": 2871, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 2957, "end": 2961, "text": "[12]", "ref_id": "BIBREF11"}], "ref_spans": []}, {"section": "Main text", "text": "We are still in a difficult position to optimally define a \"normal\" or \"healthy\" microbiota. As in ecological niches, there are multiple states of equilibrium corresponding to healthy states. For example, some of the biomarkers for dysbiosis include an increase in beta (between sample) diversity, a decrease in alpha (within sample) diversity, an increase in the abundance of members of Proteobacteria and opportunistic pathobionts, and an increase in inflammatory markers. As summarized in Fig. 1a , these changes happen not only in obese individuals (\"bad\" or \"diseased\" microbiome) but also in women in their third trimester (\"good\" or \"healthy\" microbiome) [13, 14] .", "cite_spans": [{"start": 662, "end": 666, "text": "[13,", "ref_id": "BIBREF12"}, {"start": 667, "end": 670, "text": "14]", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "Main text", "text": "Interestingly, an adverse outcome of influenza and a suboptimal immunogenicity of the flu vaccine are influenced by these conditions, in humans and experimental animals ( Fig. 1) [15] [16] [17] [18] . Similar interactions between pathobionts, the microbiota, and the host are increasingly being described in animals and plants [19] [20] [21] . In sick corals, there is a significant change in the ranking order of viruses that are also present in healthy specimens but with a distinct load for each type of virus [22] . Fig. 1 What is a good microbiome? A typical example of the tripartite interaction between a common virus, the host, and the microbiota. a Some strains of the influenza virus cause more severe disease in obese persons or mice as well as in third-trimester pregnant woman. This occurrence correlates with a disturbed gut microbiota. b In addition, suboptimal responses to the flu vaccine are found in these populations", "cite_spans": [{"start": 179, "end": 183, "text": "[15]", "ref_id": "BIBREF14"}, {"start": 184, "end": 188, "text": "[16]", "ref_id": "BIBREF15"}, {"start": 189, "end": 193, "text": "[17]", "ref_id": "BIBREF16"}, {"start": 194, "end": 198, "text": "[18]", "ref_id": "BIBREF17"}, {"start": 327, "end": 331, "text": "[19]", "ref_id": "BIBREF18"}, {"start": 332, "end": 336, "text": "[20]", "ref_id": "BIBREF19"}, {"start": 337, "end": 341, "text": "[21]", "ref_id": "BIBREF20"}, {"start": 513, "end": 517, "text": "[22]", "ref_id": "BIBREF21"}], "ref_spans": []}, {"section": "Main text", "text": "In light of this paradigm, we suggest that novel ways to establish complex causation, as opposed to associations between a perturbed microbiota and a sick host, should be developed. Under this scheme, elucidation of causality becomes a very difficult task which can be compared metaphorically to untying a Gordian knot. Alternatively, we can apply an ecological approach and recognize that disease affects not the host but the holobiont in all its complexity. When doing research on the microbiota, we are actually dealing with an intricate system composed by microbial individuals interacting in a social fashion. Consequently, when trying to understand holobionts in health and disease, we may apply novel methods developed by social and economic scientists [23] . Relatively simplified biomarkers for selected diseases may be looked for and calculated by complex computational methods based on parameters such as microbial diversity of the microbiota, predominance or absence of specific species of bacteria, levels of defined metabolites, and other.", "cite_spans": [{"start": 760, "end": 764, "text": "[23]", "ref_id": "BIBREF22"}], "ref_spans": []}, {"section": "Main text", "text": "Words have an extraordinary power [24] . Some (like pathogen or pathogenicity) may obscure the right interpretation of biological processes, and other words may facilitate the clarification of complex developments [25] . We claim that the introduction of certain terms to the world of Medicine may greatly improve our understanding of both health and disease. These words include holobionts, pathobionts, and pathobiome (a disturbed or dysbiotic microbiome).", "cite_spans": [{"start": 34, "end": 38, "text": "[24]", "ref_id": "BIBREF23"}, {"start": 214, "end": 218, "text": "[25]", "ref_id": "BIBREF24"}], "ref_spans": []}, {"section": "Main text", "text": "The current classification of diseases into infectious and non-infectious should be revised. While there may be one or more pathobionts playing a central role in the former case, there is a concurrent perturbation of the microbiota which can either precede or follow the introduction of the pathobiont/s into the holobiont system. The diagnosis of classic infectious diseases is performed by well-established methods including microscopic observation of a specific microbe, culture-dependent and culture-independent molecular techniques such as PCR, or the detection of specific antibodies as a result of an active infection. Still, under this approach, important questions remain unanswered. For example, one might ask why certain hosts develop disease, while others remain healthy. In contrast, dysbiotic or perturbed states of the microbiota are not routinely evaluated in clinical practice due to their complexity and the scarcity of simple ways to characterize them. The multiplicity of co-factors and the slow progression of their effects on holobionts complicate the elucidation of the pathogenesis of many metabolic, inflammatory, degenerative, neoplastic, and even psychiatric diseases. The interaction between specific genetic mutations, the microbiota, and environmental factors have been extensively studied in certain diseases such as Crohn's disease, both in humans and animal models [26] . In contrast, the characteristics of the microbiota remain still unexplored in individuals with certain common genetic conditions such as Tay-Sachs, thalassemia, neurofibromatosis, and Jackson-Weiss syndrome. In other examples, such as cystic fibrosis [27] , Huntington disease [28] , severe combined immunodeficiency disorder [29] , and sickle cell disease [30] , a growing body of information is emerging on associated disturbances of the microbiota. The currently consolidating idea that interactive co-evolution of the host with its microbiota is an important driving force for evolution may predict future elucidations in the mechanisms of a holobiont becoming sick [31] . In recent years, the major roles played by environmental factors in the development of these diseases of holobionts have begun to be deciphered. Among others, these factors include overuse of antibiotics-especially at critical periods of life-cesarean sections, avoidance of breast feeding, unhealthy diets, and exposure to toxic substances. The proposed paradigm has the potential to develop novel preventive and therapeutic approaches. We suggest applying a strong ecologic attitude toward the preservation of health in all holobionts on Earth.", "cite_spans": [{"start": 1398, "end": 1402, "text": "[26]", "ref_id": "BIBREF25"}, {"start": 1656, "end": 1660, "text": "[27]", "ref_id": "BIBREF26"}, {"start": 1682, "end": 1686, "text": "[28]", "ref_id": "BIBREF27"}, {"start": 1731, "end": 1735, "text": "[29]", "ref_id": "BIBREF28"}, {"start": 1762, "end": 1766, "text": "[30]", "ref_id": "BIBREF29"}, {"start": 2075, "end": 2079, "text": "[31]", "ref_id": "BIBREF30"}], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Infectious disease. Vaginal microbiome affects HIV risk", "authors": [{"first": "J", "middle": [], "last": "Cohen", "suffix": ""}], "year": 2016, "venue": "Science", "link": "31219252"}, "BIBREF1": {"title": "Inside out: HIV, the gut microbiome, and the mucosal immune system", "authors": [{"first": "J", "middle": [], "last": "Liu", "suffix": ""}, {"first": "B", "middle": [], "last": "Williams", "suffix": ""}, {"first": "D", "middle": [], "last": "Frank", "suffix": ""}, {"first": "S", "middle": ["M"], "last": "Dillon", "suffix": ""}, {"first": "C", "middle": ["C"], "last": "Wilson", "suffix": ""}, {"first": "A", "middle": ["L"], "last": "Landay", "suffix": ""}], "year": 2017, "venue": "J Immunol", "link": "35818971"}, "BIBREF2": {"title": "Maternal HIV infection influences the microbiome of HIV-uninfected infants", "authors": [{"first": "J", "middle": ["M"], "last": "Bender", "suffix": ""}, {"first": "F", "middle": [], "last": "Li", "suffix": ""}, {"first": "S", "middle": [], "last": "Martelly", "suffix": ""}, {"first": "E", "middle": [], "last": "Byrt", "suffix": ""}, {"first": "V", "middle": [], "last": "Rouzier", "suffix": ""}, {"first": "M", "middle": [], "last": "Leo", "suffix": ""}, {"first": "N", "middle": [], "last": "Tobin", "suffix": ""}, {"first": "P", "middle": ["S"], "last": "Pannaraj", "suffix": ""}, {"first": "H", "middle": [], "last": "Adisetiyo", "suffix": ""}, {"first": "A", "middle": [], "last": "Rollie", "suffix": ""}], "year": 2016, "venue": "Sci Transl Med", "link": "22237978"}, "BIBREF3": {"title": "Human commensals producing a novel antibiotic impair pathogen colonization", "authors": [{"first": "A", "middle": [], "last": "Zipperer", "suffix": ""}, {"first": "M", "middle": ["C"], "last": "Konnerth", "suffix": ""}, {"first": "C", "middle": [], "last": "Laux", "suffix": ""}, {"first": "A", "middle": [], "last": "Berscheid", "suffix": ""}, {"first": "D", "middle": [], "last": "Janek", "suffix": ""}, {"first": "C", "middle": [], "last": "Weidenmaier", "suffix": ""}, {"first": "M", "middle": [], "last": "Burian", "suffix": ""}, {"first": "N", "middle": ["A"], "last": "Schilling", "suffix": ""}, {"first": "C", "middle": [], "last": "Slavetinsky", "suffix": ""}, {"first": "M", "middle": [], "last": "Marschal", "suffix": ""}], "year": 2016, "venue": "Nature", "link": "205249755"}, "BIBREF4": {"title": "Staphylococcus aureus shifts toward commensalism in response to Corynebacterium species", "authors": [{"first": "M", "middle": ["M"], "last": "Ramsey", "suffix": ""}, {"first": "M", "middle": ["O"], "last": "Freire", "suffix": ""}, {"first": "R", "middle": ["A"], "last": "Gabrilska", "suffix": ""}, {"first": "K", "middle": ["P"], "last": "Rumbaugh", "suffix": ""}, {"first": "K", "middle": ["P"], "last": "Lemon", "suffix": ""}], "year": 2016, "venue": "Front Microbiol", "link": "14436917"}, "BIBREF5": {"title": "Clinical characteristics and predictive factors for mortality in Coryneform bacteria bloodstream infection in hematological patients", "authors": [{"first": "S", "middle": ["I"], "last": "Kimura", "suffix": ""}, {"first": "A", "middle": [], "last": "Gomyo", "suffix": ""}, {"first": "J", "middle": [], "last": "Hayakawa", "suffix": ""}, {"first": "Y", "middle": [], "last": "Akahoshi", "suffix": ""}, {"first": "N", "middle": [], "last": "Harada", "suffix": ""}, {"first": "T", "middle": [], "last": "Ugai", "suffix": ""}, {"first": "Y", "middle": [], "last": "Komiya", "suffix": ""}, {"first": "K", "middle": [], "last": "Kameda", "suffix": ""}, {"first": "H", "middle": [], "last": "Wada", "suffix": ""}, {"first": "Y", "middle": [], "last": "Ishihara", "suffix": ""}], "year": 2016, "venue": "J Infect Chemother", "link": "7309731"}, "BIBREF6": {"title": "Clinical experience and microbiologic characteristics of invasive Staphylococcus lugdunensis infection in a tertiary center in northern Taiwan", "authors": [{"first": "J", "middle": ["F"], "last": "Lin", "suffix": ""}, {"first": "C", "middle": ["W"], "last": "Cheng", "suffix": ""}, {"first": "A", "middle": ["J"], "last": "Kuo", "suffix": ""}, {"first": "T", "middle": ["P"], "last": "Liu", "suffix": ""}, {"first": "C", "middle": ["C"], "last": "Yang", "suffix": ""}, {"first": "C", "middle": ["T"], "last": "Huang", "suffix": ""}, {"first": "M", "middle": ["H"], "last": "Lee", "suffix": ""}, {"first": "J", "middle": ["J"], "last": "Lu", "suffix": ""}], "year": 2015, "venue": "J Microbiol Immunol Infect", "link": "27382800"}, "BIBREF7": {"title": "Staphylococcus aureus alpha toxin potentiates opportunistic bacterial lung infections", "authors": [{"first": "T", "middle": ["S"], "last": "Cohen", "suffix": ""}, {"first": "J", "middle": ["J"], "last": "Hilliard", "suffix": ""}, {"first": "O", "middle": [], "last": "Jones-Nelson", "suffix": ""}, {"first": "A", "middle": ["E"], "last": "Keller", "suffix": ""}, {"first": "T", "middle": [], "last": "O&apos;day", "suffix": ""}, {"first": "C", "middle": [], "last": "Tkaczyk", "suffix": ""}, {"first": "A", "middle": [], "last": "Digiandomenico", "suffix": ""}, {"first": "M", "middle": [], "last": "Hamilton", "suffix": ""}, {"first": "M", "middle": [], "last": "Pelletier", "suffix": ""}, {"first": "Q", "middle": [], "last": "Wang", "suffix": ""}], "year": 2016, "venue": "Sci Transl Med", "link": "206690245"}, "BIBREF8": {"title": "Deliberate establishment of asymptomatic bacteriuria-a novel strategy to prevent recurrent UTI", "authors": [{"first": "B", "middle": [], "last": "Wullt", "suffix": ""}, {"first": "C", "middle": [], "last": "Svanborg", "suffix": ""}], "year": 2016, "venue": "Pathog", "link": "10560969"}, "BIBREF9": {"title": "Cross feeding of glucose metabolism byproducts of Escherichia coli human gut isolates and probiotic strains affect survival of Vibrio cholerae", "authors": [{"first": "C", "middle": [], "last": "Sengupta", "suffix": ""}, {"first": "M", "middle": [], "last": "Ekka", "suffix": ""}, {"first": "S", "middle": [], "last": "Arora", "suffix": ""}, {"first": "P", "middle": ["D"], "last": "Dhaware", "suffix": ""}, {"first": "R", "middle": [], "last": "Chowdhury", "suffix": ""}, {"first": "S", "middle": [], "last": "Raychaudhuri", "suffix": ""}], "year": 2017, "venue": "Gut Pathog", "link": "215032138"}, "BIBREF10": {"title": "The microbiome modulates arbovirus transmission in mosquitoes", "authors": [{"first": "S", "middle": [], "last": "Hegde", "suffix": ""}, {"first": "J", "middle": ["L"], "last": "Rasgon", "suffix": ""}, {"first": "G", "middle": ["L"], "last": "Hughes", "suffix": ""}], "year": 2015, "venue": "Curr Opin Virol", "link": "36576605"}, "BIBREF11": {"title": "Chemical ecology of interactions between human skin microbiota and mosquitoes", "authors": [{"first": "N", "middle": ["O"], "last": "Verhulst", "suffix": ""}, {"first": "W", "middle": [], "last": "Takken", "suffix": ""}, {"first": "M", "middle": [], "last": "Dicke", "suffix": ""}, {"first": "G", "middle": [], "last": "Schraa", "suffix": ""}, {"first": "R", "middle": ["C"], "last": "Smallegange", "suffix": ""}], "year": 2010, "venue": "FEMS Microbiol Ecol", "link": "25982395"}, "BIBREF12": {"title": "Host remodeling of the gut microbiome and metabolic changes during pregnancy", "authors": [{"first": "O", "middle": [], "last": "Koren", "suffix": ""}, {"first": "J", "middle": ["K"], "last": "Goodrich", "suffix": ""}, {"first": "T", "middle": ["C"], "last": "Cullender", "suffix": ""}, {"first": "A", "middle": [], "last": "Spor", "suffix": ""}, {"first": "K", "middle": [], "last": "Laitinen", "suffix": ""}, {"first": "H", "middle": ["K"], "last": "Backhed", "suffix": ""}, {"first": "A", "middle": [], "last": "Gonzalez", "suffix": ""}, {"first": "J", "middle": ["J"], "last": "Werner", "suffix": ""}, {"first": "L", "middle": ["T"], "last": "Angenent", "suffix": ""}, {"first": "R", "middle": [], "last": "Knight", "suffix": ""}], "year": 2012, "venue": "Cell", "link": "12107857"}, "BIBREF13": {"title": "Gut microbiota from twins discordant for obesity modulate metabolism in mice", "authors": [{"first": "V", "middle": ["K"], "last": "Ridaura", "suffix": ""}, {"first": "J", "middle": ["J"], "last": "Faith", "suffix": ""}, {"first": "F", "middle": ["E"], "last": "Rey", "suffix": ""}, {"first": "J", "middle": [], "last": "Cheng", "suffix": ""}, {"first": "A", "middle": ["E"], "last": "Duncan", "suffix": ""}, {"first": "A", "middle": ["L"], "last": "Kau", "suffix": ""}, {"first": "N", "middle": ["W"], "last": "Griffin", "suffix": ""}, {"first": "V", "middle": [], "last": "Lombard", "suffix": ""}, {"first": "B", "middle": [], "last": "Henrissat", "suffix": ""}, {"first": "J", "middle": ["R"], "last": "Bain", "suffix": ""}], "year": 2013, "venue": "Science", "link": "18889921"}, "BIBREF14": {"title": "Host response: pregnancy impairs flu defences", "authors": [{"first": "E", "middle": [], "last": "Ghedin", "suffix": ""}, {"first": "S", "middle": [], "last": "Schultz-Cherry", "suffix": ""}], "year": 2017, "venue": "Nat Microbiol", "link": "30030451"}, "BIBREF15": {"title": "Diet-induced obesity reduces the production of influenza vaccineinduced antibodies via impaired macrophage function", "authors": [{"first": "W", "middle": ["J"], "last": "Cho", "suffix": ""}, {"first": "D", "middle": ["K"], "last": "Lee", "suffix": ""}, {"first": "S", "middle": ["Y"], "last": "Lee", "suffix": ""}, {"first": "S", "middle": ["H"], "last": "Sohn", "suffix": ""}, {"first": "H", "middle": ["L"], "last": "Park", "suffix": ""}, {"first": "Y", "middle": ["W"], "last": "Park", "suffix": ""}, {"first": "H", "middle": [], "last": "Kim", "suffix": ""}, {"first": "J", "middle": ["H"], "last": "Nam", "suffix": ""}], "year": 2016, "venue": "Acta Virol", "link": "19948882"}, "BIBREF16": {"title": "Obesity-induced chronic inflammation is associated with the reduced efficacy of influenza vaccine", "authors": [{"first": "H", "middle": ["L"], "last": "Park", "suffix": ""}, {"first": "S", "middle": ["H"], "last": "Shim", "suffix": ""}, {"first": "E", "middle": ["Y"], "last": "Lee", "suffix": ""}, {"first": "W", "middle": [], "last": "Cho", "suffix": ""}, {"first": "S", "middle": [], "last": "Park", "suffix": ""}, {"first": "H", "middle": ["J"], "last": "Jeon", "suffix": ""}, {"first": "S", "middle": ["Y"], "last": "Ahn", "suffix": ""}, {"first": "H", "middle": [], "last": "Kim", "suffix": ""}, {"first": "J", "middle": ["H"], "last": "Nam", "suffix": ""}], "year": 2014, "venue": "Hum Vaccin Immunother", "link": "207517296"}, "BIBREF17": {"title": "B cell activity is impaired in human and mouse obesity and is responsive to an essential fatty acid upon murine influenza infection", "authors": [{"first": "R", "middle": [], "last": "Kosaraju", "suffix": ""}, {"first": "W", "middle": [], "last": "Guesdon", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Crouch", "suffix": ""}, {"first": "H", "middle": ["L"], "last": "Teague", "suffix": ""}, {"first": "E", "middle": ["M"], "last": "Sullivan", "suffix": ""}, {"first": "E", "middle": ["A"], "last": "Karlsson", "suffix": ""}, {"first": "S", "middle": [], "last": "Schultz-Cherry", "suffix": ""}, {"first": "K", "middle": [], "last": "Gowdy", "suffix": ""}, {"first": "L", "middle": ["C"], "last": "Bridges", "suffix": ""}, {"first": "L", "middle": ["R"], "last": "Reese", "suffix": ""}], "year": 2017, "venue": "J Immunol", "link": "45751399"}, "BIBREF18": {"title": "Deciphering the pathobiome: intra-and interkingdom interactions involving the pathogen Erysiphe alphitoides", "authors": [{"first": "B", "middle": [], "last": "Jakuschkin", "suffix": ""}, {"first": "V", "middle": [], "last": "Fievet", "suffix": ""}, {"first": "L", "middle": [], "last": "Schwaller", "suffix": ""}, {"first": "T", "middle": [], "last": "Fort", "suffix": ""}, {"first": "C", "middle": [], "last": "Robin", "suffix": ""}, {"first": "C", "middle": [], "last": "Vacher", "suffix": ""}], "year": 2016, "venue": "Microb Ecol", "link": "13523943"}, "BIBREF19": {"title": "The microbiome of animals: implications for conservation biology", "authors": [{"first": "S", "middle": [], "last": "Bahrndorff", "suffix": ""}, {"first": "T", "middle": [], "last": "Alemu", "suffix": ""}, {"first": "T", "middle": [], "last": "Alemneh", "suffix": ""}, {"first": "Lund", "middle": [], "last": "Nielsen", "suffix": ""}, {"first": "J", "middle": [], "last": "", "suffix": ""}], "year": 2016, "venue": "Int J Genomics", "link": "20401353"}, "BIBREF20": {"title": "The role of microorganisms in coral health, disease and evolution", "authors": [{"first": "E", "middle": [], "last": "Rosenberg", "suffix": ""}, {"first": "O", "middle": [], "last": "Koren", "suffix": ""}, {"first": "L", "middle": [], "last": "Reshef", "suffix": ""}, {"first": "R", "middle": [], "last": "Efrony", "suffix": ""}, {"first": "I", "middle": [], "last": "Zilber-Rosenberg", "suffix": ""}], "year": 2007, "venue": "Nat Rev Microbiol", "link": "2967190"}, "BIBREF21": {"title": "Virus-host interactions and their roles in coral reef health and disease", "authors": [{"first": "R", "middle": ["V"], "last": "Thurber", "suffix": ""}, {"first": "J", "middle": ["P"], "last": "Payet", "suffix": ""}, {"first": "A", "middle": ["R"], "last": "Thurber", "suffix": ""}, {"first": "A", "middle": ["M"], "last": "Correa", "suffix": ""}], "year": 2017, "venue": "Nat Rev Microbiol", "link": "7480522"}, "BIBREF22": {"title": "Prediction and explanation in social systems", "authors": [{"first": "J", "middle": ["M"], "last": "Hofman", "suffix": ""}, {"first": "A", "middle": [], "last": "Sharma", "suffix": ""}, {"first": "D", "middle": ["J"], "last": "Watts", "suffix": ""}], "year": 2017, "venue": "Science", "link": "206655390"}, "BIBREF23": {"title": "Antibiotic resistance has a language problem", "authors": [{"first": "M", "middle": [], "last": "Mendelson", "suffix": ""}, {"first": "M", "middle": [], "last": "Balasegaram", "suffix": ""}, {"first": "T", "middle": [], "last": "Jinks", "suffix": ""}, {"first": "C", "middle": [], "last": "Pulcini", "suffix": ""}, {"first": "M", "middle": [], "last": "Sharland", "suffix": ""}], "year": 2017, "venue": "Nature", "link": "4458374"}, "BIBREF24": {"title": "Microbiology: ditch the term pathogen", "authors": [{"first": "A", "middle": [], "last": "Casadevall", "suffix": ""}, {"first": "L", "middle": ["A"], "last": "Pirofski", "suffix": ""}], "year": 2014, "venue": "Nature", "link": "4446326"}, "BIBREF25": {"title": "From sensing to shaping microbiota: insights into the role of NOD2 in intestinal homeostasis and progression of Crohn's disease", "authors": [{"first": "I", "middle": [], "last": "Balasubramanian", "suffix": ""}, {"first": "N", "middle": [], "last": "Gao", "suffix": ""}], "year": 2017, "venue": "Am J Physiol Gastrointest Liver Physiol", "link": "6595129"}, "BIBREF26": {"title": "Lessons from the lower airway microbiome in early CF", "authors": [{"first": "J", "middle": ["E"], "last": "Hoppe", "suffix": ""}, {"first": "E", "middle": ["T"], "last": "Zemanick", "suffix": ""}], "year": 2017, "venue": "Thorax", "link": "3465994"}, "BIBREF27": {"title": "The gut microbiome in human neurological disease: a review", "authors": [{"first": "H", "middle": [], "last": "Tremlett", "suffix": ""}, {"first": "K", "middle": ["C"], "last": "Bauer", "suffix": ""}, {"first": "S", "middle": [], "last": "Appel-Cresswell", "suffix": ""}, {"first": "B", "middle": ["B"], "last": "Finlay", "suffix": ""}, {"first": "E", "middle": [], "last": "Waubant", "suffix": ""}], "year": 2017, "venue": "Ann Neurol", "link": "25394413"}, "BIBREF28": {"title": "Gut microbiome variations during hematopoietic stem cell transplant in severe combined immunodeficiency", "authors": [{"first": "J", "middle": ["P"], "last": "Lane", "suffix": ""}, {"first": "C", "middle": ["J"], "last": "Stewart", "suffix": ""}, {"first": "S", "middle": ["P"], "last": "Cummings", "suffix": ""}, {"first": "A", "middle": ["R"], "last": "Gennery", "suffix": ""}], "year": 2015, "venue": "J Allergy Clin Immunol", "link": "46119395"}, "BIBREF29": {"title": "Neutrophil ageing is regulated by the microbiome", "authors": [{"first": "D", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "G", "middle": [], "last": "Chen", "suffix": ""}, {"first": "D", "middle": [], "last": "Manwani", "suffix": ""}, {"first": "A", "middle": [], "last": "Mortha", "suffix": ""}, {"first": "C", "middle": [], "last": "Xu", "suffix": ""}, {"first": "J", "middle": ["J"], "last": "Faith", "suffix": ""}, {"first": "R", "middle": ["D"], "last": "Burk", "suffix": ""}, {"first": "Y", "middle": [], "last": "Kunisaki", "suffix": ""}, {"first": "J", "middle": ["E"], "last": "Jang", "suffix": ""}, {"first": "C", "middle": [], "last": "Scheiermann", "suffix": ""}], "year": 2015, "venue": "Nature", "link": "4466202"}, "BIBREF30": {"title": "Microbes drive evolution of animals and plants: the hologenome concept", "authors": [{"first": "E", "middle": [], "last": "Rosenberg", "suffix": ""}, {"first": "I", "middle": [], "last": "Zilber-Rosenberg", "suffix": ""}], "year": 2016, "venue": "MBio", "link": "18512626"}}, "ref_entries": {}}
{"paper_id": "2877021", "_pdf_hash": "dd0fffd39258e3d74f325ba9e6b9bd7b457dc441", "abstract": [{"section": "Abstract", "text": "Noise is omnipresent in biomedical systems and signals. Conventional views assume that its presence is detrimental to systems' performance and accuracy. Hence, various analytic approaches and instrumentation have been designed to remove noise. On the contrary, recent contributions have shown that noise can play a beneficial role in biomedical systems. The results of this literature review indicate that noise is an essential part of biomedical systems and often plays a fundamental role in the performance of these systems. Furthermore, in preliminary work, noise has demonstrated therapeutic potential to alleviate the effects of various diseases.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Further research into the role of noise and its applications in medicine is likely to lead to novel approaches to the treatment of diseases and prevention of disability.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Albert Einstein discovered noise accidentally in 1905, when he observed that atoms move according to the Brownian molecular motion [1] . Following his discovery, numerous descriptions of physical and biological systems have made incidental reference to noise, without recognizing its essential contribution. Noise is often regarded as an unwanted component or disturbance to a system, even though it has a tremendous impact on many aspects of science and technology [1] , including medicine and biology. A typical example for such a statement is a field of engineering called signal processing. On one hand, many signal processing algorithms have been designed to remove noise from a system, since greater noise levels are associated with degraded performance of algorithms.", "cite_spans": [{"start": 131, "end": 134, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 466, "end": 469, "text": "[1]", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "Introduction", "text": "On the other hand, noise has been shown to enhance system performance in many areas of signal * Ervin Sejdi\u0107 is with the Department of Electrical and Computer Engineering, Swanson School of Enginering, University of Pittsburgh, Pittsburgh, PA, 15261, USA. E-mail: esejdic@ieee.org. Ervin Sejdi\u0107 is the corresponding author.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "\u2020 Lewis A. Lipsitz is with Harvard Medical School, Beth Israel Deaconess Medical Center and Hebrew Senior Life, processing including stochastic optimization techniques, genetic algorithms, dithering, just to name a few. Similarly, another concept called stochastic resonance (SR), first proposed in 1981 (e.g., [2] , [3] ), describes a positive impact of noise in nonlinear systems. SR refers to the fact that at an optimal level of input noise, signal detection is enhanced [4] , [5] . SR is observed in both man-made and naturally occurring nonlinear systems [6] . For example, paddlefish were shown to use SR to locate and capture prey, implicating this phenomenon in animal behavior [7] . Also, small noisy input can influence the firing patterns of squid axons [8] , enhance breathing stability in pre-term infants [9] , improve postural control in human aging, stroke or peripheral neuropathy [10] , [11] , and stabilize gait in elderly people with recurrent falls [12] .", "cite_spans": [{"start": 311, "end": 314, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 317, "end": 320, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 475, "end": 478, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 481, "end": 484, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 561, "end": 564, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 687, "end": 690, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 766, "end": 769, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 820, "end": 823, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 899, "end": 903, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 906, "end": 910, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 971, "end": 975, "text": "[12]", "ref_id": "BIBREF11"}], "ref_spans": []}, {"section": "Introduction", "text": "The intent of this manuscript is to inform researchers from multiple scientific disciplines that noise (i.e., stochastic processes) is a critical component of many biological and physiological systems that may be exploited in the future to develop interventions for the prevention and treatment of diseases. In other words, this manuscript is a crossover between a review paper and a position paper and as such is meant to initiate further discussions about the role of stochastic processes in modeling of physiological systems.", "cite_spans": [], "ref_spans": []}, {"section": "Search criteria", "text": "To gather previous contributions cited in this manuscript, we utilized PubMed and Google Scholar to find manuscript published in English using a variety of search terms (e.g., \"noise physiology,\" \"noise medicine,\" \"noise brain,\" \"noise aging\"). These search terms yielded thousands of manuscripts and we focused only on representative publications from several fields. Extensive coverage of all topics is beyond the scope of this paper, since excellent extensive reviews of each have been previously published (e.g., [6] , [13] ).", "cite_spans": [{"start": 517, "end": 520, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 523, "end": 527, "text": "[13]", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "Organization of the paper", "text": "The paper is organized as follows: Section 2 introduces various stochastic processes considered in biomedical systems, while also describing the physiological meaning of these processes. Section 3 discusses the important role of noise in fundamental biomedical systems. In Section 4, we discuss several translational applications of noise to treat diseases, while in Section 5, we provide concluding remarks along with an outline of possible future directions.", "cite_spans": [], "ref_spans": []}, {"section": "Organization of the paper", "text": "2 Noise and variability in physiological systems", "cite_spans": [], "ref_spans": []}, {"section": "Description of noise", "text": "By definition, noise is a stochastic process with specific spectral characteristics. While many different stochastic processes exist, we consider here the most common types discussed in the literature.", "cite_spans": [], "ref_spans": []}, {"section": "Description of noise", "text": "White noise is a stochastic process characterized by equal energy over all frequencies. In mathematical terms, its power spectral density is equal to:", "cite_spans": [], "ref_spans": []}, {"section": "Description of noise", "text": "where C w is a constant. The name \"white\" stems from the fact its power spectral density is the same at all frequencies in an analogy to the frequency spectrum of white light. A time-domain realization of the white noise is depicted in Fig. 1 (a), while its power spectral density is depicted in Fig. 1 ", "cite_spans": [], "ref_spans": [{"start": 236, "end": 242, "text": "Fig. 1", "ref_id": "FIGREF0"}, {"start": 296, "end": 302, "text": "Fig. 1", "ref_id": "FIGREF0"}]}, {"section": "(b).", "text": "Pink noise (also called fractal or 1/f noise) is a stochastic process suitable for modeling evolutionary or developmental systems characterized by equal energy per octave as depicted in Fig 1(d) [14]. The power spectral density of pink noise is roughly inversely proportional to frequency [14] :", "cite_spans": [{"start": 289, "end": 293, "text": "[14]", "ref_id": "BIBREF13"}], "ref_spans": [{"start": 186, "end": 194, "text": "Fig 1(d)", "ref_id": "FIGREF0"}]}, {"section": "(b).", "text": "where C f is a constant and 0 < \u03b1 < 2. 1/f noise is a stochastic process between white noise", "cite_spans": [], "ref_spans": []}, {"section": "(b).", "text": "(1/f 0 ) and red (Brownian) noise (1/f 2 ); hence, the name pink noise. Pink or fractal noise is found in numerous biological and physiological processes, including the organization of neural networks, Purkinje fibers in the heart, the vascular tree, bronchial tree, and bone trabeculae, as well as electroencephalographic rhythms, heart rate variability, and respiratory intervals [15] , [16] .The omnipresence of pink noise in many diverse applications has led researchers to speculate that there exists some profound law of nature that applies to all nonequilibrium systems and results in such noise [14] .", "cite_spans": [{"start": 382, "end": 386, "text": "[15]", "ref_id": "BIBREF14"}, {"start": 389, "end": 393, "text": "[16]", "ref_id": "BIBREF15"}, {"start": 603, "end": 607, "text": "[14]", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "(b).", "text": "Because pink or fractal noise arises from the interaction of multiple physiologic or biologic control systems operating over different scales in time or space, it may confer system resiliency, adaptability, and structural integrity. For example, the structural (e.g. bone trabeculae) or functional (e.g., heart rate control) networks that generate such noise retain their integrity or functional ability if individual components are lost or interrupted. This fractal network organization also enables a system to adapt to stress by drawing on specific components and fine tuning its response to overcome a given perturbation [16] . Brownian or red noise is a stochastic process whose power spectral density, as depicted in Fig. 1(f), is defined as:", "cite_spans": [{"start": 625, "end": 629, "text": "[16]", "ref_id": "BIBREF15"}], "ref_spans": []}, {"section": "(b).", "text": "where C b is a constant.Mathematically, the Brownian noise can be defined as the integral of the white noise.", "cite_spans": [], "ref_spans": []}, {"section": "(b).", "text": "There are other types of noise specific to certain applications (e.g., blue noise, diotic noise, and dichotic noise). However, the extensive coverage of these topics is beyond the scope of the current manuscript.", "cite_spans": [], "ref_spans": []}, {"section": "Variability in health and psychosocial functions", "text": "Physiology teaches us that healthy systems are self-regulated to reduce variability and maintain physiologic constancy [17] . However, that is not the case in reality. Small amounts of noise, as depicted in Fig. 2(a) , can have a very beneficial role in physiological systems (e.g., [9] , [10] , [15] , [16] ). Also, the non-linear interactions of multiple regulatory systems and environmental influences operating over different time scales produce highly variable \"noisy\" behaviours in physiological processes that are far from constant [18] . For example, the normal human heartbeat fluctuates in a complex stochastic manner [17] , and can be modeled as a 1/f process (e.g., [19] ).", "cite_spans": [{"start": 283, "end": 286, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 289, "end": 293, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 296, "end": 300, "text": "[15]", "ref_id": "BIBREF14"}, {"start": 303, "end": 307, "text": "[16]", "ref_id": "BIBREF15"}, {"start": 539, "end": 543, "text": "[18]", "ref_id": "BIBREF18"}, {"start": 678, "end": 682, "text": "[19]", "ref_id": "BIBREF19"}], "ref_spans": [{"start": 207, "end": 216, "text": "Fig. 2(a)", "ref_id": "FIGREF1"}]}, {"section": "Variability in health and psychosocial functions", "text": "On the contrary, the stochastic properties of the heartbeat time series degrade in subjects at high risk of sudden death (e.g., congestive heart failure patients) becoming more characteristic of white noise. This situation is depicted in Fig. 2(b) , where a deviation from 1/f noise can result in reduced functional capacity and the onset of disease. Similar counterintuitive results have been obtained in other fields. For example, gene expression can be thought of as a stochastic process [18] , [20] . Stochastic gene variations can have both beneficial and harmful roles. Different patterns of gene expression can influence the stress response, metabolism, development, the cell cycle, circadian rhythms, and aging [18] . Therefore, elucidating the stochastic mechanisms involved in physiologic control systems and complex signaling networks is emerging as a major challenge in the postgenomic era [17] .", "cite_spans": [{"start": 491, "end": 495, "text": "[18]", "ref_id": "BIBREF18"}, {"start": 498, "end": 502, "text": "[20]", "ref_id": "BIBREF20"}, {"start": 719, "end": 723, "text": "[18]", "ref_id": "BIBREF18"}], "ref_spans": [{"start": 238, "end": 247, "text": "Fig. 2(b)", "ref_id": "FIGREF1"}]}, {"section": "The role of noise in fundamental biomedical systems", "text": "A number of studies elucidating the fundamental mechanisms of biological systems suggest that noise is an \"essential ingredient\" in these systems, without which they cannot function. For example, noise plays an important role in molecular transitions or interactions that control cellular behavior (e.g., how cells acquire fate) [21] . Furthermore, several mathematical models used to describe biological processes require a noise term to adequately model the behaviour of these processes.", "cite_spans": [{"start": 329, "end": 333, "text": "[21]", "ref_id": "BIBREF21"}], "ref_spans": []}, {"section": "Cells, genetics/gene networks", "text": "Cellular processes, such as transcription and translation, chromatin remodeling and pathwayspecific regulation, are sources of stochastic events leading to cell-to-cell variability [18] , [22] . In fact, cellular behaviour varies in clonal cell populations despite their development in identical environments [23] .", "cite_spans": [{"start": 181, "end": 185, "text": "[18]", "ref_id": "BIBREF18"}, {"start": 188, "end": 192, "text": "[22]", "ref_id": "BIBREF22"}, {"start": 309, "end": 313, "text": "[23]", "ref_id": "BIBREF23"}], "ref_spans": []}, {"section": "Cells, genetics/gene networks", "text": "Stochastic processes can have a dual role in these systems. One point of view is that the stochasticity obstructs the efficient functioning of cellular processes [24] . The accuracy of cellular processes, such as the circadian oscillator, is limited by noise in gene expression [20] . Noise can interfere with the operation of engineered genetic circuits [25] and cell-to-cell variability can be reduced by engineering a circuit with negative feedback [26] . There is also evidence that aging is associated with increased randomness in gene expression [18] . For example, cell type-specific gene expressions in individual murine cardiac myocytes [27] , murine muscle tissues [28] and C. elegans [29] become increasingly stochastic as the organism ages. While the mechanisms underlying these stochastic phenomena are still unclear, the process of aging may be dependent on the effects of stochastic gene expression [18] . Another interpretation of these observations is that changes in gene expression with aging are associated with a shift from the more adaptive 1/f or fractal-like noise, to more random or white noise-like behavior that cannot adapt to the metabolic demands of the aged cell. This notion will need experimental validation.", "cite_spans": [{"start": 162, "end": 166, "text": "[24]", "ref_id": "BIBREF24"}, {"start": 278, "end": 282, "text": "[20]", "ref_id": "BIBREF20"}, {"start": 355, "end": 359, "text": "[25]", "ref_id": "BIBREF25"}, {"start": 452, "end": 456, "text": "[26]", "ref_id": "BIBREF26"}, {"start": 552, "end": 556, "text": "[18]", "ref_id": "BIBREF18"}, {"start": 646, "end": 650, "text": "[27]", "ref_id": "BIBREF27"}, {"start": 675, "end": 679, "text": "[28]", "ref_id": "BIBREF28"}, {"start": 695, "end": 699, "text": "[29]", "ref_id": "BIBREF29"}, {"start": 914, "end": 918, "text": "[18]", "ref_id": "BIBREF18"}], "ref_spans": []}, {"section": "Cells, genetics/gene networks", "text": "The second point of view is that noise might have beneficial properties [30] . For example, living cells usually acquire their fate deterministically by virtue of their lineage or their proximity to an inductive signal from another cell. However, a cell can choose to differentiate stochastically without apparent regard to environment or history [31] . This random behavior can arise from significant stochastic fluctuations (i.e., noise) in cellular components and biochemical reactions [30] , [32] . Additionally, differences in the micro-environments inhabited by individual cells and preexisting heterogeneity propagated to subsequent cell generations can be sources of such cell-to-cell variations [33] . Cell-to-cell variability is thus a complex function of regulation of gene expression and the regulatory and biochemical networks in which the gene products are embedded [30] .", "cite_spans": [{"start": 72, "end": 76, "text": "[30]", "ref_id": "BIBREF30"}, {"start": 347, "end": 351, "text": "[31]", "ref_id": "BIBREF31"}, {"start": 489, "end": 493, "text": "[30]", "ref_id": "BIBREF30"}, {"start": 496, "end": 500, "text": "[32]", "ref_id": "BIBREF32"}, {"start": 704, "end": 708, "text": "[33]", "ref_id": "BIBREF33"}, {"start": 880, "end": 884, "text": "[30]", "ref_id": "BIBREF30"}], "ref_spans": []}, {"section": "Neural systems", "text": "Neuronal networks are known to have noisy, heterogeneous and compact structures [34] , [35] . There are two points of view regarding the role of noise in these networks. One point of view argues that noise lowers the signal-to-noise ratio causing the performance of these networks to degrade. The second point of view states that noise reduces spike-timing precision and therefore, the information rate is lowered. However, noise can play important and constructive roles for the amplification of information transfer in neuronal networks [36] , [37] .", "cite_spans": [{"start": 80, "end": 84, "text": "[34]", "ref_id": "BIBREF34"}, {"start": 87, "end": 91, "text": "[35]", "ref_id": "BIBREF35"}, {"start": 539, "end": 543, "text": "[36]", "ref_id": "BIBREF36"}, {"start": 546, "end": 550, "text": "[37]", "ref_id": "BIBREF37"}], "ref_spans": []}, {"section": "Neural systems", "text": "Stochastic variations are an essential part of the nervous system [37] , and the effects of these variations in dynamical neurobiological systems have been studied extensively for both single neurons and neural networks. Pioneering works by Derksen and Verveen in 1966 [38] and by Katz and Miledi in 1970 [39] were the first to establish the probabilistic behavior of neurons in the central nervous system [34] . Derksen and Verveen investigated the role of membrane noise in the probabilistic behavior of neurons in the central nervous system [38] , while Katz and Miledi studied signal fluctuations associated with ACh receptor-mediated muscle depolarization [39] . The foundations set by these two groups were later applied to experimental data to gain an insight into the nature of transmembrane-conductance changes and information processing in the brain [34] . Subsequent publications showed that intracellular recordings of cortical neurons consistently display highly complex and irregular activity due to an intense and sustained discharge of presynaptic neurons in the cortical network [36] .", "cite_spans": [{"start": 66, "end": 70, "text": "[37]", "ref_id": "BIBREF37"}, {"start": 269, "end": 273, "text": "[38]", "ref_id": "BIBREF38"}, {"start": 305, "end": 309, "text": "[39]", "ref_id": "BIBREF39"}, {"start": 406, "end": 410, "text": "[34]", "ref_id": "BIBREF34"}, {"start": 544, "end": 548, "text": "[38]", "ref_id": "BIBREF38"}, {"start": 661, "end": 665, "text": "[39]", "ref_id": "BIBREF39"}, {"start": 860, "end": 864, "text": "[34]", "ref_id": "BIBREF34"}, {"start": 1096, "end": 1100, "text": "[36]", "ref_id": "BIBREF36"}], "ref_spans": []}, {"section": "Neural systems", "text": "In addition to synaptic noise, the stochastic activity of ion channels is another significant source of noise in the nervous system. For example, thermal agitation causes voltage-gated ion channels in neuronal membranes to fluctuate randomly between conducting and nonconducting states inducing noisy membrane currents and subthreshold voltage fluctuations [40] , [41] . It is now understood that channel noise affects spike-timing reliability, action potential dynamics, signal detection, the tuning properties of the cell and overall has important effects on neuronal information processing capabilities [36] , [40] , [41] . Lastly, while noise often leads to increased responsiveness in the nervous system, empirical data and neuronal models demonstrate that noise can also subdue or turn off repetitive neuronal activity [8] , [42] .", "cite_spans": [{"start": 357, "end": 361, "text": "[40]", "ref_id": "BIBREF40"}, {"start": 364, "end": 368, "text": "[41]", "ref_id": "BIBREF41"}, {"start": 606, "end": 610, "text": "[36]", "ref_id": "BIBREF36"}, {"start": 613, "end": 617, "text": "[40]", "ref_id": "BIBREF40"}, {"start": 620, "end": 624, "text": "[41]", "ref_id": "BIBREF41"}, {"start": 825, "end": 828, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 831, "end": 835, "text": "[42]", "ref_id": "BIBREF42"}], "ref_spans": []}, {"section": "Brain functions", "text": "Noise generated in the brain may influence brain behavior. Noise is generated in the brain by random spike firing times of neurons [13] . By influencing the variability of the firing of neurons, noise may influence decision-making, memory, and the stability of short-term memory and attention [43] . Furthermore, cognitive operations are also affected by stochasticity in N-methyl-D-aspartate activated receptors, which affect the stability of short-term memory and attention, and in alterations of gamma-amino-butyric acid receptor activated synaptic ion channel conductances which are predicted to influence how likely the system is to jump incorrectly into a pathological state of high activity [13] . Similarly, in motor learning, the brain uses movement errors to adjust planning of future movements. This physiologically plausible strategy is optimally tuned to the properties of motor noise, and likely underlies learning in many motor tasks [44] .", "cite_spans": [{"start": 131, "end": 135, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 293, "end": 297, "text": "[43]", "ref_id": "BIBREF43"}, {"start": 698, "end": 702, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 949, "end": 953, "text": "[44]", "ref_id": "BIBREF44"}], "ref_spans": []}, {"section": "Brain functions", "text": "Overall, noise in the brain promotes decision-making, creativity and the shifting of attention to new tasks [13] . The presence of stochastic brain variations (e.g., due to stochastic variations in spiking of neurons and in synaptic transmissions) is helping investigators and clinicians to understand pathological brain stability states, such as schizophrenia and obsessive-compulsive disorder.", "cite_spans": [{"start": 108, "end": 112, "text": "[13]", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "Brain functions", "text": "One notion is that there is a range of stability states in different individuals. Instability (e.g., due", "cite_spans": [], "ref_spans": []}, {"section": "Brain functions", "text": "to random firing of neurons) contributes to the symptoms of schizophrenia [45] , while too much stability contributes to the symptoms of obsessive-compulsive disorder [45] . Of potentially great importance is that by having a model that is based on the ion channel conductances affected by different neurotransmitters, it is becoming possible to make predictions about what could be favorable combinations of treatments for particular disorders [45] .", "cite_spans": [{"start": 74, "end": 78, "text": "[45]", "ref_id": "BIBREF45"}, {"start": 167, "end": 171, "text": "[45]", "ref_id": "BIBREF45"}, {"start": 445, "end": 449, "text": "[45]", "ref_id": "BIBREF45"}], "ref_spans": []}, {"section": "Human visual and auditory perception", "text": "Noise is omnipresent in sensory systems, ranging from the emission of neurotransmitters from the presynaptic membrane to the behavioral results in visual and auditory experiments (e.g., [6] , [46] , [47] , [48] , [49] , [50] , [51] ). For example, a recent study suggested that the addition of an appropriate amount of external noise can improve the perception of an \"uncertain\" visual signal that is difficult to detect [52] , [53] . Figure 3 depicts how adding an appropriate amount of noise improves image contrast and then degrades as we add too much noise [54] . Noise of a particular magnitude (i.e., the SR effect) also tends to enhance visually evoked responses in electroencephalography (e.g., [55] ) and magnetoencephalography studies (e.g., [56] ). Similarly, in [57] , the authors showed that a certain amount of noise reduced the pedestal effect, i.e., the improved detectability of a grating in the presence of a low-contrast masking grating. Their results supported the idea that a single mechanism underlies the pedestal effect and stochastic resonance in contrast perception [57] . 1/f noise is also effective in driving hallucinatory pattern formation as shown in [58] , where the authors explored the relationship between ordinary stimulus-controlled pattern perception and the autonomous hallucinatory geometrical pattern formation that occurs for unstructured visual stimulation (e.g., empty-field flicker). Similar results were observed in human hearing experiments [4] . ", "cite_spans": [{"start": 186, "end": 189, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 192, "end": 196, "text": "[46]", "ref_id": "BIBREF46"}, {"start": 199, "end": 203, "text": "[47]", "ref_id": "BIBREF47"}, {"start": 206, "end": 210, "text": "[48]", "ref_id": "BIBREF48"}, {"start": 213, "end": 217, "text": "[49]", "ref_id": "BIBREF49"}, {"start": 220, "end": 224, "text": "[50]", "ref_id": "BIBREF50"}, {"start": 227, "end": 231, "text": "[51]", "ref_id": "BIBREF51"}, {"start": 421, "end": 425, "text": "[52]", "ref_id": "BIBREF52"}, {"start": 428, "end": 432, "text": "[53]", "ref_id": "BIBREF53"}, {"start": 561, "end": 565, "text": "[54]", "ref_id": "BIBREF54"}, {"start": 703, "end": 707, "text": "[55]", "ref_id": "BIBREF55"}, {"start": 752, "end": 756, "text": "[56]", "ref_id": "BIBREF56"}, {"start": 774, "end": 778, "text": "[57]", "ref_id": "BIBREF57"}, {"start": 1092, "end": 1096, "text": "[57]", "ref_id": "BIBREF57"}, {"start": 1182, "end": 1186, "text": "[58]", "ref_id": "BIBREF58"}, {"start": 1488, "end": 1491, "text": "[4]", "ref_id": "BIBREF3"}], "ref_spans": [{"start": 435, "end": 443, "text": "Figure 3", "ref_id": "FIGREF2"}]}, {"section": "Models of biological systems that require noise", "text": "Noise is a necessary component even in modeling of certain biomedical systems. In some cases, noise has a specific physiological meaning, while in others, limited knowledge about the systems under investigation yielded creation of a noise category to capture variability observed in experimental data. The next few subsections briefly cover some of the most well-known models requiring a noise term in order to adequately describe a function of a biomedical system. Although there are many more mathematical models that require a noise term in order to accurately model the phenomenon under consideration, it is beyond the scope of this manuscript to review all these different models.", "cite_spans": [], "ref_spans": []}, {"section": "Hodgkin-Huxley model", "text": "The Hodgkin-Huxley model, one of the most important models in biomedicine, describes membrane potential, activation of Na and K currents, and inactivation of Na current [59] . Specifically, the Hodgkin-Huxley model describes the spiking behavior and refractory properties of neurons and serves as a paradigm for spiking neurons based on the nonlinear conductance of ion channels [60] .", "cite_spans": [{"start": 169, "end": 173, "text": "[59]", "ref_id": "BIBREF59"}, {"start": 379, "end": 383, "text": "[60]", "ref_id": "BIBREF60"}], "ref_spans": []}, {"section": "Hodgkin-Huxley model", "text": "The model is given by four nonlinear coupled equations, one for the membrane potential V , and three for gating variables m, n, and h:", "cite_spans": [], "ref_spans": []}, {"section": "Hodgkin-Huxley model", "text": "where m \u221e , h \u221e , n \u221e , \u03c4 m , \u03c4 h , \u03c4 n represent the saturation values and the relaxation times of the gating variables. The membrane potential is driven by three types of currents: ionic current I ion , external stimulus current I ext , and synaptic current I syn . I ion is related to the gating variables of m, n, h and describes the ionic transport through the membrane:", "cite_spans": [], "ref_spans": []}, {"section": "Hodgkin-Huxley model", "text": "where V N a , V K , V l are the corresponding reversal potentials and the constants g N a , g K , and g l are the maximal conductances for ion and leakage channels. I ext is the external stimulus usually serving as a bifurcation parameter of the system. I syn is the sum of the current inputs from all synapses connected to the other neurons and can be modeled as:", "cite_spans": [], "ref_spans": []}, {"section": "Hodgkin-Huxley model", "text": "where \u03be(t) is Gaussian white noise, and \u03c3 and \u03c4 d are the intensity and the correlation time of the synaptic noise, respectively [60] . Fig. 4 examines the effects of varying \u03c3 on the membrane potential, V . As \u03c3 decreases, the potentials become highly regular as depicted in Fig. 4(d) . This shows that without noise in the organism, the human body would be a highly deterministic system, and would not be able to account for any changes in the environment.", "cite_spans": [{"start": 129, "end": 133, "text": "[60]", "ref_id": "BIBREF60"}], "ref_spans": [{"start": 136, "end": 142, "text": "Fig. 4", "ref_id": "FIGREF3"}, {"start": 276, "end": 285, "text": "Fig. 4(d)", "ref_id": "FIGREF3"}]}, {"section": "Hodgkin-Huxley model", "text": "The Hodgkin-Huxley-type models are important not only because their parameters are biophysically meaningful and measurable, but also because they allow us to investigate questions related to synaptic integration, dendritic cable filtering, effects of dendritic morphology, the interplay between ionic currents, and other issues related to single cell dynamics [59] and there are extensions to various other fields such as cardiology (e.g., [61] ) in the literature.", "cite_spans": [{"start": 360, "end": 364, "text": "[59]", "ref_id": "BIBREF59"}, {"start": 440, "end": 444, "text": "[61]", "ref_id": "BIBREF61"}], "ref_spans": []}, {"section": "Fitz Hugh-Nagumo model", "text": "The Fitz Hugh-Nagumo model is a simple but representative example of excitable systems that occur in application ranging from kinetics of chemical reactions and solid-state physics to biomedical processes [62] . Originally it was suggested for the description of nerve pulses [62] , but it found its applications in other fields as well. The equations are:", "cite_spans": [{"start": 205, "end": 209, "text": "[62]", "ref_id": "BIBREF62"}, {"start": 276, "end": 280, "text": "[62]", "ref_id": "BIBREF62"}], "ref_spans": []}, {"section": "Fitz Hugh-Nagumo model", "text": "where \u03b5 << 1 is a small parameter allowing one to separate all fast and slow motions; the parameter \u03b1 governs the character of solutions; and the parameter \u03c3 governs the amplitude of the noisy external force \u03be assumed to be additive white Gaussian noise with zero mean [62] .", "cite_spans": [{"start": 269, "end": 273, "text": "[62]", "ref_id": "BIBREF62"}], "ref_spans": []}, {"section": "Fitz Hugh-Nagumo model", "text": "Similarly as the Hodgkin-Huxley model, the Fitz Hugh-Nagumo model is sensitive to the magnitude of \u03c3 as depicted in Fig. 5 . The presence of noise is necessary in order for the model to accurately represent a biomedical process. ", "cite_spans": [], "ref_spans": [{"start": 116, "end": 122, "text": "Fig. 5", "ref_id": "FIGREF4"}]}, {"section": "Cancer risk modeling", "text": "Cancer is stimulated by successive somatic mutations [63] . Here, we briefly review a stochastic model for the computation of cancer risks based on the hypothesis of two successive mutations [63] .", "cite_spans": [{"start": 53, "end": 57, "text": "[63]", "ref_id": "BIBREF63"}, {"start": 191, "end": 195, "text": "[63]", "ref_id": "BIBREF63"}], "ref_spans": []}, {"section": "Cancer risk modeling", "text": "The model assumes that cells likely to mutate will divide over the lifetime of the tissue. Next, the number of type 1 mutation cells produced over the lifetime of the tissue is distributed according to the Poisson distribution with mean \u00b5. The branching process begins with the appearance of the first type 1 cell. This type 1 cell may die with probability 1 \u2212 p 1 . The second option is that the type 1 cell divides in two type 1 cells with probability p 1 . At each division of a type 1 cell, there is a probability p 2 for each daughter cell to be a type 2 cell. The probability that a branching process started by a single type 1 cell eventually gives birth to at least one type 2 cell may be computed exactly:", "cite_spans": [], "ref_spans": []}, {"section": "Cancer risk modeling", "text": "The number of type 1 branching processes that eventually produce at least one type 2 cell is given by the Poisson distribution with mean \u00b5P b (p 1 , p 2 ). Hence, the probability that cancer will occur in a particular tissue is given by", "cite_spans": [], "ref_spans": []}, {"section": "Cancer risk modeling", "text": "The parameter \u00b5 is crucial in this model as shown in Figure 6 , as its value will dictate the shape of the probability density function of cancer. For small values of \u00b5, the probability of cancer is almost negligible, even when the probability of type 1 cell branching increases past 50%. However, as we increase the mean number of first mutations to \u00b5 = 100, the probability of cancer becomes 100%, as the probability of type 1 cell branching increases past 50%.", "cite_spans": [], "ref_spans": [{"start": 53, "end": 61, "text": "Figure 6", "ref_id": "FIGREF5"}]}, {"section": "Clinical and therapeutic application of noise", "text": "Here, we present several applications of noise to enhance health. Also, we briefly discuss how noise (i.e., stochastic processes) can be used to model the effects of aging or social networks.", "cite_spans": [], "ref_spans": []}, {"section": "Noise-based devices", "text": "Noise-based bioengineering techniques and medical devices can play an important role for treating diseases and enhancing health overall. From a clinical standpoint, noise-based techniques and devices have been used to enhance signal detection in patients with significant sensory deficits, such as older adults [64] , [65] , patients with diabetic neuropathy [66] , patients with stroke [67] , or profoundly deaf people receiving speech cues by direct electrical stimulation of the cochlear nerve [68] . Nose-based devices have been used to increase tactile sensations [69] , [70] to help post-partum women achieve higher pelvic floor muscle activation [71] , or to alleviate postural instability due to ankle sprains [72] , [73] and lower back pain [74] . Noise-based solutions can even be used for the enhancement of brain-to-computer interfaces [75] .", "cite_spans": [{"start": 311, "end": 315, "text": "[64]", "ref_id": "BIBREF64"}, {"start": 359, "end": 363, "text": "[66]", "ref_id": "BIBREF67"}, {"start": 387, "end": 391, "text": "[67]", "ref_id": "BIBREF68"}, {"start": 497, "end": 501, "text": "[68]", "ref_id": "BIBREF69"}, {"start": 569, "end": 573, "text": "[69]", "ref_id": "BIBREF70"}, {"start": 576, "end": 580, "text": "[70]", "ref_id": "BIBREF71"}, {"start": 653, "end": 657, "text": "[71]", "ref_id": "BIBREF72"}, {"start": 718, "end": 722, "text": "[72]", "ref_id": "BIBREF73"}, {"start": 725, "end": 729, "text": "[73]", "ref_id": "BIBREF74"}, {"start": 750, "end": 754, "text": "[74]", "ref_id": "BIBREF75"}, {"start": 848, "end": 852, "text": "[75]", "ref_id": "BIBREF76"}], "ref_spans": []}, {"section": "Noise-based devices", "text": "Noise-based devices, such as randomly vibrating shoe insoles [10] that apply noise during specific activities or throughout the day, may enable people to overcome functional difficulties due to age-related sensory loss [11] , [64] , [76] , [77] , [78] , [79] . Furthermore, noise-based mechanical ventilators can improve gas exchange and could have a significant effect on morbidity by breaking the chain of injury propagation in acute lung injury [80] . These devices could potentially reduce the morbidity associated with various health issues, such as sensory loss and postural instability in elderly and disabled people or to help stroke patients and individuals with muscle and joint injuries in rehabilitation activities [64] . Noise-based techniques could potentially accelerate a patient's rehabilitation. In this regard, the ultimate realization of a noise-based device may be one that provides durable benefit that lasts long after the device is removed [76] .", "cite_spans": [{"start": 61, "end": 65, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 219, "end": 223, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 226, "end": 230, "text": "[64]", "ref_id": "BIBREF64"}, {"start": 233, "end": 237, "text": "[76]", "ref_id": "BIBREF77"}, {"start": 240, "end": 244, "text": "[77]", "ref_id": "BIBREF78"}, {"start": 247, "end": 251, "text": "[78]", "ref_id": "BIBREF79"}, {"start": 254, "end": 258, "text": "[79]", "ref_id": "BIBREF80"}, {"start": 727, "end": 731, "text": "[64]", "ref_id": "BIBREF64"}, {"start": 964, "end": 968, "text": "[76]", "ref_id": "BIBREF77"}], "ref_spans": []}, {"section": "Cognition", "text": "Noise has detrimental effects on cognitive performance due to the competition for attentional resources between the distracting and the target stimuli. This has been observed for a wide variety of tasks and stimuli as well as in different participant populations [81] , [82] . However, recent empirical evidence suggests that noise can also improve central processing and cognitive performance. For example, auditory noise enhanced the speed of arithmetic computations [83] and recall on visual memory tasks [84] . Thus, adding a moderate level of noise to the input of the information processing system can increase its signal-to-noise output. On the other hand, adding too little or too much noise attenuates performance [82] . This is consistent with the phenomenon of SR. Noise exerted a positive effect on cognitive performance for patients with the attention deficit hyperactivity disorder, indicating that these subjects need more noise than controls for optimal cognitive performance [82] . The Moderate Brain Arousal model suggests that noise in the environment introduces internal noise into the neural system through the perceptual system. This noise induces SR in the neurotransmitter systems and makes noise beneficial for cognitive performance [81] . Similarly, a recent experiment showed that background noise had opposing effects on inattentive and attentive children. While it enhanced performance for the former group, background noise deteriorated performance for latter group. Background noise also reduced episodic memory differences between these two groups of school children. This suggests that cognitive performance can be moderated by external background white noise stimulation in a non-clinical group of inattentive participants [82] . However, one should be aware that these stochastic resonance effects were not always present [50] .", "cite_spans": [{"start": 263, "end": 267, "text": "[81]", "ref_id": "BIBREF83"}, {"start": 270, "end": 274, "text": "[82]", "ref_id": "BIBREF84"}, {"start": 469, "end": 473, "text": "[83]", "ref_id": "BIBREF85"}, {"start": 508, "end": 512, "text": "[84]", "ref_id": "BIBREF86"}, {"start": 723, "end": 727, "text": "[82]", "ref_id": "BIBREF84"}, {"start": 992, "end": 996, "text": "[82]", "ref_id": "BIBREF84"}, {"start": 1258, "end": 1262, "text": "[81]", "ref_id": "BIBREF83"}, {"start": 1757, "end": 1761, "text": "[82]", "ref_id": "BIBREF84"}, {"start": 1857, "end": 1861, "text": "[50]", "ref_id": "BIBREF50"}], "ref_spans": []}, {"section": "Aging", "text": "As described above, many healthy physiologic processes exhibit stochastic variations due to multiple regulatory influences operating over different time scales. These influences include biochemical pathways, opening and closing of ion chambers, feed-forward and feed-back loops, temperature fluctuations, circadian rhythms and environmental changes. Together, they produce pink noise in the output signal as is evident in healthy heart rate, blood pressure, respiratory rate, electroencephalographic potentials, or center-of-pressure time series [15] , [16] . These noise signals lose their 1/f characteristics with aging and disease due to the degradation of various control mechanisms and their interactions, becoming more white or Brownian. As a result, the organism loses resiliency or adaptive capacity [15] , [16] .", "cite_spans": [{"start": 546, "end": 550, "text": "[15]", "ref_id": "BIBREF14"}, {"start": 553, "end": 557, "text": "[16]", "ref_id": "BIBREF15"}, {"start": 808, "end": 812, "text": "[15]", "ref_id": "BIBREF14"}, {"start": 815, "end": 819, "text": "[16]", "ref_id": "BIBREF15"}], "ref_spans": []}, {"section": "Aging", "text": "This has been demonstrated in the postural control system by examining the body's centerof-pressure (COP) excursions while standing on a force plate [85] . Under normal circumstances, the COP time series exhibits 1/f behaviour, characteristic of pink noise. However, with the loss of vision, sensation in the feet, or both, there is a progressive loss of complexity and long-range correlations in the data. As a result, the individual has more difficulty adapting to a superimposed cognitive task (e.g., counting backwards while standing) and postural sway increases [85] .", "cite_spans": [{"start": 149, "end": 153, "text": "[85]", "ref_id": "BIBREF87"}, {"start": 567, "end": 571, "text": "[85]", "ref_id": "BIBREF87"}], "ref_spans": []}, {"section": "Aging", "text": "Similarly, anatomic structures lose fractal-like architecture with aging, leading to a loss of functionality. This is evident in degeneration and loss of connectivity of the bone trabecular network leading to osteoporosis and fractures; the breakdown of fractal-like alveoli in the lungs leading to emphysema; and the disruption of the collagen matrix in the dermis leading to skin fragility and hemorrhage. In addition, age-related diseases such as the Alzheimer's (e.g., [86] ) or Parkinson's (e.g., [87] ) diseases affect the stochastic variations of physiological variables. For example, the insole forces during the freezing of gait in patients with the Parkinson's disease have been shown to have stochastic behaviour similar to a Brownian process [87] . Furthermore, Parkinson's patients lose the noisy, fractal-like physiologic tremor of the normal motor control system and develop a highly periodic tremor, which is characteristic of their disease. Fortunately, there is evidence that noise can be restored in at least the postural control system by exploiting the phenomenon of SR. When subsensory vibratory white noise was applied to the soles of the feet in healthy elderly subjects while standing on a force plate, the fractal-like multiscale complexity of COP displacements increased to values similar to those seen in young subjects [65] . This intriguing finding supports the notion that noise is an important component of a healthy, and highly functional, postural control system.", "cite_spans": [{"start": 473, "end": 477, "text": "[86]", "ref_id": "BIBREF88"}, {"start": 502, "end": 506, "text": "[87]", "ref_id": "BIBREF89"}, {"start": 754, "end": 758, "text": "[87]", "ref_id": "BIBREF89"}], "ref_spans": []}, {"section": "Social networks", "text": "Noise has also been shown to play role in the social sciences. For example, the psychic structure long known as the \"self\" is best conceptualized as a dynamical stochastic system [88] . Among the various topics addressed in this field, it has been found that models for opinion formation in a society exhibit a rich variety of nonlinear behavior, such as phase transitions and critical phenomena, stochastic resonance, chaos, and bistability [89] . In fact, the existence of SR in a model of opinion formation yields the appealing implication that there is an optimal noise level for a population to respond to an external \"fashion\" modulation. Lower noise intensities lead to the dominance of the majority's opinion, irrespective of external influences, while sufficiently stronger random fluctuations prevent the formation of a definite collective opinion [90] .", "cite_spans": [{"start": 179, "end": 183, "text": "[88]", "ref_id": "BIBREF90"}, {"start": 442, "end": 446, "text": "[89]", "ref_id": "BIBREF91"}, {"start": 858, "end": 862, "text": "[90]", "ref_id": "BIBREF92"}], "ref_spans": []}, {"section": "Social networks", "text": "Since the recognition of noise at the beginning of the twentieth century, the prevalent view in most fields is that noise degrades system performance and most real-life events do not exhibit noise-like behavior. In this manuscript, we reviewed several biomedical fields where noise plays a constructive role and in some cases is necessary for a biomedical system to function properly. Such a constructive behavior is particularly obvious in systems that depend on the complex interactions of many different components operating on different time scales (i.e., nonlinear systems). Therefore, most of the research efforts have been geared towards:", "cite_spans": [], "ref_spans": []}, {"section": "Social networks", "text": "\u2022 understanding the sources of stochastic fluctuations in biomedical systems and possible advantages and/or adverse consequences of these fluctuations on the systems;", "cite_spans": [], "ref_spans": []}, {"section": "Social networks", "text": "\u2022 understanding why and how these systems have become robust in their noisy environments; and \u2022 how we can use noise to develop treatments and enhance human health.", "cite_spans": [], "ref_spans": []}, {"section": "Social networks", "text": "Further development of noise-based devices or treatments in biomedicine depends on available computational and experimental tools that will answer questions about the the origins of noise in physiological systems and the mechanisms by which noise affects their function. On the computational side, we need to develop more sophisticated algorithms that are capable of simultaneously extracting important stochastic and deterministic variations from the system and handle huge amounts of data. Also, the software applications needed for the understanding of noise in biomedical/physiological systems are almost non-existent. Most computational investigations are carried out using custom-made functions or toolboxes via commercially available packages such as MATLAB (MathWorks, Natick, MA, USA) or SAS (SAS Institute, Cary, NC, USA). On the experimental side, we need to develop experiments and tools that can characterize the noise behavior in systems. The ultimate goal for these advances is to achieve full stochastic resolution over different scales and systems. However, a plan for wide dissemination of data acquired in these experiments should be embedded in these projects to accelerate advances in noise physiology. We anticipate that a limited number of laboratories will have necessary monetary, equipment and staff resources needed to carry some of these sophisticated experiments.", "cite_spans": [], "ref_spans": []}, {"section": "Social networks", "text": "Noise is potentially a very powerful tool in physiology and medicine. We hope this paper will catalyze further research and applications of noise to improve human health and ameliorate diseases.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "The history of noise", "authors": [{"first": "L", "middle": [], "last": "Cohen", "suffix": ""}], "year": 2005, "venue": "IEEE Signal Processing Magazine", "link": null}, "BIBREF1": {"title": "The mechanism of stochastic resonance", "authors": [{"first": "R", "middle": [], "last": "Benzi", "suffix": ""}, {"first": "A", "middle": [], "last": "Sutera", "suffix": ""}, {"first": "A", "middle": [], "last": "Vulpiani", "suffix": ""}], "year": 1981, "venue": "Journal of Physics A: Mathematical and General", "link": "123005407"}, "BIBREF2": {"title": "Stochastic resonance in climatic change", "authors": [{"first": "R", "middle": [], "last": "Benzi", "suffix": ""}, {"first": "G", "middle": [], "last": "Parisi", "suffix": ""}, {"first": "A", "middle": [], "last": "Sutera", "suffix": ""}, {"first": "A", "middle": [], "last": "Vulpiani", "suffix": ""}], "year": 1982, "venue": "Tellus", "link": "208867049"}, "BIBREF3": {"title": "Stochastic resonance in auditory steady-state responses in a magnetoencephalogram", "authors": [{"first": "K", "middle": [], "last": "Tanaka", "suffix": ""}, {"first": "M", "middle": [], "last": "Kawakatsu", "suffix": ""}, {"first": "I", "middle": [], "last": "Nemoto", "suffix": ""}], "year": 2008, "venue": "Clinical Neurophysiology", "link": "12749792"}, "BIBREF4": {"title": "A possible mechanism of stochastic resonance in the light of an extra-classical receptive field model of retinal ganglion cells", "authors": [{"first": "K", "middle": [], "last": "Ghosh", "suffix": ""}, {"first": "S", "middle": [], "last": "Sarkar", "suffix": ""}, {"first": "K", "middle": [], "last": "Bhaumik", "suffix": ""}], "year": 2009, "venue": "Biological Cybernetics", "link": "10514660"}, "BIBREF5": {"title": "Stochastic resonance and sensory information processing: a tutorial and review of application", "authors": [{"first": "F", "middle": [], "last": "Moss", "suffix": ""}, {"first": "L", "middle": ["M"], "last": "Ward", "suffix": ""}, {"first": "W", "middle": ["G"], "last": "Sannita", "suffix": ""}], "year": 2004, "venue": "Clinical Neurophysiology", "link": "4141064"}, "BIBREF6": {"title": "Biophysics: Fishing for function in noise", "authors": [{"first": "J", "middle": ["J"], "last": "Collins", "suffix": ""}], "year": 1999, "venue": "Nature", "link": null}, "BIBREF7": {"title": "Noisy inputs and the induction of on-off switching behavior in a neuronal pacemaker", "authors": [{"first": "D", "middle": [], "last": "Paydarfar", "suffix": ""}, {"first": "D", "middle": ["B"], "last": "Forger", "suffix": ""}, {"first": "J", "middle": ["R"], "last": "Clay", "suffix": ""}], "year": 2006, "venue": "Journal of Neurophysiology", "link": "10035457"}, "BIBREF8": {"title": "Stabilizing immature breathing patterns of preterm infants using stochastic mechanosensory stimulation", "authors": [{"first": "E", "middle": [], "last": "Bloch-Salisbury", "suffix": ""}, {"first": "P", "middle": [], "last": "Indic", "suffix": ""}, {"first": "F", "middle": [], "last": "Bednarek", "suffix": ""}, {"first": "D", "middle": [], "last": "Paydarfar", "suffix": ""}], "year": 2009, "venue": "Journal of Applied Physiology", "link": "5684406"}, "BIBREF9": {"title": "Vibrating insoles and balance control in elderly people", "authors": [{"first": "A", "middle": ["A"], "last": "Priplata", "suffix": ""}, {"first": "J", "middle": ["B"], "last": "Niemi", "suffix": ""}, {"first": "J", "middle": ["D"], "last": "Harry", "suffix": ""}, {"first": "L", "middle": ["A"], "last": "Lipsitz", "suffix": ""}, {"first": "J", "middle": ["J"], "last": "Collins", "suffix": ""}], "year": 2003, "venue": "The Lancet", "link": "33216209"}, "BIBREF10": {"title": "Noise-enhanced balance control in patients with diabetes and patients with stroke", "authors": [{"first": "A", "middle": ["A"], "last": "Priplata", "suffix": ""}, {"first": "B", "middle": ["L"], "last": "Patritti", "suffix": ""}, {"first": "J", "middle": ["B"], "last": "Niemi", "suffix": ""}, {"first": "R", "middle": [], "last": "Hughes", "suffix": ""}, {"first": "D", "middle": ["C"], "last": "Gravelle", "suffix": ""}, {"first": "L", "middle": ["A"], "last": "Lipsitz", "suffix": ""}, {"first": "A", "middle": [], "last": "Veves", "suffix": ""}, {"first": "J", "middle": [], "last": "Stein", "suffix": ""}, {"first": "P", "middle": [], "last": "Bonato", "suffix": ""}, {"first": "J", "middle": ["J"], "last": "Collins", "suffix": ""}], "year": 2006, "venue": "Annals of Neurology", "link": null}, "BIBREF11": {"title": "Subsensory vibrations to the feet reduce gait variability in elderly fallers", "authors": [{"first": "A", "middle": ["M"], "last": "Galica", "suffix": ""}, {"first": "H", "middle": ["G"], "last": "Kang", "suffix": ""}, {"first": "A", "middle": ["A"], "last": "Priplata", "suffix": ""}, {"first": "S", "middle": ["E"], "last": "D&apos;andrea", "suffix": ""}, {"first": "O", "middle": ["V"], "last": "Starobinets", "suffix": ""}, {"first": "F", "middle": ["A"], "last": "Sorond", "suffix": ""}, {"first": "L", "middle": ["A"], "last": "Cupples", "suffix": ""}, {"first": "L", "middle": ["A"], "last": "Lipsitz", "suffix": ""}], "year": 2009, "venue": "Gait and Posture", "link": "24161473"}, "BIBREF12": {"title": "Stochastic dynamics as a principle of brain function", "authors": [{"first": "G", "middle": [], "last": "Deco", "suffix": ""}, {"first": "E", "middle": ["T"], "last": "Rolls", "suffix": ""}, {"first": "R", "middle": [], "last": "Romo", "suffix": ""}], "year": 2009, "venue": "Progress in Neurobiology", "link": "2459234"}, "BIBREF13": {"title": "1/f noise", "authors": [{"first": "M", "middle": ["S"], "last": "Keshner", "suffix": ""}], "year": 1982, "venue": "Proceedings of the IEEE", "link": "921772"}, "BIBREF14": {"title": "Loss of \"complexity\" and aging", "authors": [{"first": "L", "middle": ["A"], "last": "Lipsitz", "suffix": ""}, {"first": "A", "middle": ["L"], "last": "Goldberger", "suffix": ""}], "year": 1992, "venue": "JAMA: The Journal of the American Medical Association", "link": null}, "BIBREF15": {"title": "Dynamics of stability: The physiologic basis of functional health and frailty", "authors": [{"first": "L", "middle": ["A"], "last": "Lipsitz", "suffix": ""}], "year": 2002, "venue": "The Journals of Gerontology Series A: Biological Sciences and Medical Sciences", "link": "20805974"}, "BIBREF17": {"title": "Fractal dynamics in physiology: Alterations with disease and aging", "authors": [{"first": "", "middle": [], "last": "Stanley", "suffix": ""}], "year": 2002, "venue": "Proceedings of the National Academy of Sciences of the United States of America", "link": "17881714"}, "BIBREF18": {"title": "Nature, nurture, or chance: Stochastic gene expression and its consequences", "authors": [{"first": "A", "middle": [], "last": "Raj", "suffix": ""}, {"first": "A", "middle": [], "last": "Van Oudenaarden", "suffix": ""}], "year": 2008, "venue": "Cell", "link": "12804937"}, "BIBREF19": {"title": "Fractal mechanisms and heart rate dynamics: Long-range correlations and their breakdown with disease", "authors": [{"first": "C.-K", "middle": [], "last": "Peng", "suffix": ""}, {"first": "S", "middle": [], "last": "Havlin", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Hausdorff", "suffix": ""}, {"first": "J", "middle": ["E"], "last": "Mietus", "suffix": ""}, {"first": "H", "middle": ["E"], "last": "Stanley", "suffix": ""}, {"first": "A", "middle": ["L"], "last": "Goldberger", "suffix": ""}], "year": 1995, "venue": "Journal of Electrocardiology", "link": "17112910"}, "BIBREF20": {"title": "Noise in gene expression: Origins, consequences, and control", "authors": [{"first": "J", "middle": ["M"], "last": "Raser", "suffix": ""}, {"first": "E", "middle": ["K"], "last": "O&apos;shea", "suffix": ""}], "year": 2005, "venue": "Science", "link": "34044918"}, "BIBREF21": {"title": "Noise in biological circuits", "authors": [{"first": "M", "middle": ["L"], "last": "Simpson", "suffix": ""}, {"first": "C", "middle": ["D"], "last": "Cox", "suffix": ""}, {"first": "M", "middle": ["S"], "last": "Allen", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Mccollum", "suffix": ""}, {"first": "R", "middle": ["D"], "last": "Dar", "suffix": ""}, {"first": "D", "middle": ["K"], "last": "Karig", "suffix": ""}, {"first": "J", "middle": ["F"], "last": "Cooke", "suffix": ""}], "year": 2009, "venue": "Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology", "link": "6770188"}, "BIBREF22": {"title": "Stochastic resonance reveals \"pilot light\" expression in mammalian genes", "authors": [{"first": "A", "middle": [], "last": "Ptitsyn", "suffix": ""}], "year": 2008, "venue": "PLoS ONE", "link": "1280611"}, "BIBREF23": {"title": "Noise in protein expression scales with natural protein abundance", "authors": [{"first": "A", "middle": [], "last": "Bar-Even", "suffix": ""}, {"first": "J", "middle": [], "last": "Paulsson", "suffix": ""}, {"first": "N", "middle": [], "last": "Maheshri", "suffix": ""}, {"first": "M", "middle": [], "last": "Carmi", "suffix": ""}, {"first": "E", "middle": [], "last": "Shea", "suffix": ""}, {"first": "Y", "middle": [], "last": "Pilpel", "suffix": ""}, {"first": "N", "middle": [], "last": "Barkai", "suffix": ""}], "year": 2006, "venue": "Nature Genetics", "link": "9276506"}, "BIBREF24": {"title": "Living with noisy genes: How cells function reliably with inherent variability in gene expression", "authors": [{"first": "N", "middle": [], "last": "Maheshri", "suffix": ""}, {"first": "E", "middle": ["K"], "last": "O&apos;shea", "suffix": ""}], "year": 2007, "venue": "Annual Review of Biophysics and Biomolecular Structure", "link": "14569298"}, "BIBREF25": {"title": "A synthetic oscillatory network of transcriptional regulators", "authors": [{"first": "M", "middle": ["B"], "last": "Elowitz", "suffix": ""}, {"first": "S", "middle": [], "last": "Leibler", "suffix": ""}], "year": 2000, "venue": "Nature", "link": "41632754"}, "BIBREF26": {"title": "Engineering stability in gene networks by autoregulation", "authors": [{"first": "A", "middle": [], "last": "Becskei", "suffix": ""}, {"first": "L", "middle": [], "last": "Serrano", "suffix": ""}], "year": 2000, "venue": "Nature", "link": "4407358"}, "BIBREF27": {"title": "Increased cell-to-cell variation in gene expression in ageing mouse heart", "authors": [{"first": "R", "middle": [], "last": "Bahar", "suffix": ""}, {"first": "C", "middle": ["H"], "last": "Hartmann", "suffix": ""}, {"first": "K", "middle": ["A"], "last": "Rodriguez", "suffix": ""}, {"first": "A", "middle": ["D"], "last": "Denny", "suffix": ""}, {"first": "R", "middle": ["A"], "last": "Busuttil", "suffix": ""}, {"first": "M", "middle": ["E T"], "last": "Dolle", "suffix": ""}, {"first": "R", "middle": ["B"], "last": "Calder", "suffix": ""}, {"first": "G", "middle": ["B"], "last": "Chisholm", "suffix": ""}, {"first": "B", "middle": ["H"], "last": "Pollock", "suffix": ""}, {"first": "C", "middle": ["A"], "last": "Klein", "suffix": ""}, {"first": "J", "middle": [], "last": "Vijg", "suffix": ""}], "year": 2006, "venue": "Nature", "link": "4415893"}, "BIBREF28": {"title": "Transcription occurs in pulses in muscle fibers", "authors": [{"first": "S", "middle": [], "last": "Newlands", "suffix": ""}, {"first": "L", "middle": ["K"], "last": "Levitt", "suffix": ""}, {"first": "C", "middle": ["S"], "last": "Robinson", "suffix": ""}, {"first": "A", "middle": ["B C"], "last": "Karpf", "suffix": ""}, {"first": "V", "middle": ["R"], "last": "Hodgson", "suffix": ""}, {"first": "R", "middle": ["P"], "last": "Wade", "suffix": ""}, {"first": "E", "middle": ["C"], "last": "Hardeman", "suffix": ""}], "year": 1998, "venue": "Genes and Development", "link": "27532735"}, "BIBREF29": {"title": "A stress-sensitive reporter predicts longevity in isogenic populations of caenorhabditis elegans", "authors": [{"first": "S", "middle": ["L"], "last": "Rea", "suffix": ""}, {"first": "D", "middle": [], "last": "Wu", "suffix": ""}, {"first": "J", "middle": ["R"], "last": "Cypser", "suffix": ""}, {"first": "J", "middle": ["W"], "last": "Vaupel", "suffix": ""}, {"first": "T", "middle": ["E"], "last": "Johnson", "suffix": ""}], "year": 2005, "venue": "Nature Genetics", "link": "2442685"}, "BIBREF30": {"title": "Individuality in bacteria", "authors": [{"first": "C", "middle": ["J"], "last": "Davidson", "suffix": ""}, {"first": "M", "middle": ["G"], "last": "Surette", "suffix": ""}], "year": 2008, "venue": "Annual Review of Genetics", "link": "32180166"}, "BIBREF31": {"title": "Stochasticity and cell fate", "authors": [{"first": "R", "middle": [], "last": "Losick", "suffix": ""}, {"first": "C", "middle": [], "last": "Desplan", "suffix": ""}], "year": 2008, "venue": "Science", "link": "10990280"}, "BIBREF32": {"title": "Functional roles for noise in genetic circuits", "authors": [{"first": "A", "middle": [], "last": "Eldar", "suffix": ""}, {"first": "M", "middle": ["B"], "last": "Elowitz", "suffix": ""}], "year": 2010, "venue": "Nature", "link": "12052579"}, "BIBREF33": {"title": "Using movies to analyse gene circuit dynamics in single cells", "authors": [{"first": "J", "middle": ["C W"], "last": "Locke", "suffix": ""}, {"first": "M", "middle": ["B"], "last": "Elowitz", "suffix": ""}], "year": 2009, "venue": "Nature Reviews Microbiology", "link": "346242"}, "BIBREF34": {"title": "Getting the most out of noise in the central nervous system", "authors": [{"first": "S", "middle": ["F"], "last": "Traynelis", "suffix": ""}, {"first": "F", "middle": [], "last": "Jaramillo", "suffix": ""}], "year": 1998, "venue": "Trends in Neurosciences", "link": "11966053"}, "BIBREF35": {"title": "Stochastic cellular automata model of neural networks", "authors": [{"first": "A", "middle": ["V"], "last": "Goltsev", "suffix": ""}, {"first": "F", "middle": ["V"], "last": "De Abreu", "suffix": ""}, {"first": "S", "middle": ["N"], "last": "Dorogovtsev", "suffix": ""}, {"first": "J", "middle": ["F F"], "last": "Mendes", "suffix": ""}], "year": 2010, "venue": "Physical Review E", "link": "6729090"}, "BIBREF36": {"title": "Effects of chemical synapses on the enhancement of signal propagation in coupled neurons near the canard regime", "authors": [{"first": "X", "middle": [], "last": "Li", "suffix": ""}, {"first": "J", "middle": [], "last": "Wang", "suffix": ""}, {"first": "W", "middle": [], "last": "Hu", "suffix": ""}], "year": 2007, "venue": "Physical Review E", "link": "35799434"}, "BIBREF37": {"title": "Random noise paradoxically improves light-intensity encoding in Hermissenda photoreceptor network", "authors": [{"first": "C", "middle": ["R"], "last": "Butson", "suffix": ""}, {"first": "G", "middle": ["A"], "last": "Clark", "suffix": ""}], "year": 2008, "venue": "Journal of Neurophysiology", "link": "10958752"}, "BIBREF38": {"title": "Fluctuations of resting neural membrane potential", "authors": [{"first": "H", "middle": ["E"], "last": "Derksen", "suffix": ""}, {"first": "A", "middle": ["A"], "last": "Verveen", "suffix": ""}], "year": 1966, "venue": "Science", "link": "30453025"}, "BIBREF39": {"title": "Membrane noise produced by acetylcholine", "authors": [{"first": "B", "middle": [], "last": "Katz", "suffix": ""}, {"first": "R", "middle": [], "last": "Miledi", "suffix": ""}], "year": 1970, "venue": "Nature", "link": null}, "BIBREF40": {"title": "Detection of subthreshold pulses in neurons with channel noise", "authors": [{"first": "Y", "middle": [], "last": "Chen", "suffix": ""}, {"first": "L", "middle": [], "last": "Yu", "suffix": ""}, {"first": "S.-M", "middle": [], "last": "Qin", "suffix": ""}], "year": 2008, "venue": "Physical Review E", "link": "17029129"}, "BIBREF41": {"title": "Numerical exploration of the influence of neural noise on the psychometric function at low stimulation intensity levels", "authors": [{"first": "C", "middle": [], "last": "Gmez", "suffix": ""}], "year": 2008, "venue": "Journal of Biosciences", "link": "25137455"}, "BIBREF42": {"title": "Inhibition of rhythmic neural spiking by noise: the occurrence of a minimum in activity with increasing noise", "authors": [{"first": "B", "middle": [], "last": "Gutkin", "suffix": ""}, {"first": "J", "middle": [], "last": "Jost", "suffix": ""}, {"first": "H", "middle": [], "last": "Tuckwell", "suffix": ""}], "year": 2009, "venue": "Naturwissenschaften", "link": "2036735"}, "BIBREF43": {"title": "Decision-making and Weber's law: a neurophysiological model", "authors": [{"first": "G", "middle": [], "last": "Deco", "suffix": ""}, {"first": "E", "middle": ["T"], "last": "Rolls", "suffix": ""}], "year": 2006, "venue": "European Journal of Neuroscience", "link": "15992032"}, "BIBREF44": {"title": "Motor learning is optimally tuned to the properties of motor noise", "authors": [{"first": "R", "middle": ["J"], "last": "Van Beers", "suffix": ""}], "year": 2009, "venue": "Neruon", "link": "195684647"}, "BIBREF45": {"title": "Computational models of schizophrenia and dopamine modulation in the prefrontal cortex", "authors": [{"first": "E", "middle": ["T"], "last": "Rolls", "suffix": ""}, {"first": "M", "middle": [], "last": "Loh", "suffix": ""}, {"first": "G", "middle": [], "last": "Deco", "suffix": ""}, {"first": "G", "middle": [], "last": "Winterer", "suffix": ""}], "year": 2008, "venue": "Nature Reviews Neuroscience", "link": "10538052"}, "BIBREF46": {"title": "Visual perception of stochastic resonance", "authors": [{"first": "E", "middle": [], "last": "Simonotto", "suffix": ""}, {"first": "M", "middle": [], "last": "Riani", "suffix": ""}, {"first": "C", "middle": [], "last": "Seife", "suffix": ""}, {"first": "M", "middle": [], "last": "Roberts", "suffix": ""}, {"first": "J", "middle": [], "last": "Twitty", "suffix": ""}, {"first": "F", "middle": [], "last": "Moss", "suffix": ""}], "year": 1997, "venue": "Physical Review Letters", "link": "18277736"}, "BIBREF47": {"title": "Effect of noise on the contrast detection threshold in visual perception", "authors": [{"first": "H", "middle": [], "last": "Sasaki", "suffix": ""}, {"first": "M", "middle": [], "last": "Todorokihara", "suffix": ""}, {"first": "T", "middle": [], "last": "Ishida", "suffix": ""}, {"first": "J", "middle": [], "last": "Miyachi", "suffix": ""}, {"first": "T", "middle": [], "last": "Kitamura", "suffix": ""}, {"first": "R", "middle": [], "last": "Aoki", "suffix": ""}], "year": 2006, "venue": "Neuroscience Letters", "link": "11971273"}, "BIBREF48": {"title": "Effects of auditory noise on the psychophysical detection of visual signals: Cross-modal stochastic resonance", "authors": [{"first": "E", "middle": [], "last": "Manjarrez", "suffix": ""}, {"first": "I", "middle": [], "last": "Mendez", "suffix": ""}, {"first": "L", "middle": [], "last": "Martinez", "suffix": ""}, {"first": "A", "middle": [], "last": "Flores", "suffix": ""}, {"first": "C", "middle": ["R"], "last": "Mirasso", "suffix": ""}], "year": 2007, "venue": "Neuroscience Letters", "link": "13636078"}, "BIBREF49": {"title": "Human hearing enhanced by noise", "authors": [{"first": "F.-G", "middle": [], "last": "Zeng", "suffix": ""}, {"first": "Q.-J", "middle": [], "last": "Fu", "suffix": ""}, {"first": "R", "middle": [], "last": "Morse", "suffix": ""}], "year": 2000, "venue": "Brain Research", "link": "11934512"}, "BIBREF50": {"title": "Internal noise determines external stochastic resonance in visual perception", "authors": [{"first": "T", "middle": [], "last": "Aihara", "suffix": ""}, {"first": "K", "middle": [], "last": "Kitajo", "suffix": ""}, {"first": "D", "middle": [], "last": "Nozaki", "suffix": ""}, {"first": "Y", "middle": [], "last": "Yamamoto", "suffix": ""}], "year": 2008, "venue": "Vision Research", "link": "15349742"}, "BIBREF51": {"title": "Evidence of stochastic resonance in an auditory discrimination task may reflect response bias", "authors": [{"first": "D", "middle": [], "last": "Shepherd", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Hautus", "suffix": ""}], "year": 1931, "venue": "Attention, Perception, & Psychophysics", "link": "207728403"}, "BIBREF52": {"title": "Suprathreshold stochastic resonance in visual signal detection", "authors": [{"first": "H", "middle": [], "last": "Sasaki", "suffix": ""}, {"first": "S", "middle": [], "last": "Sakane", "suffix": ""}, {"first": "T", "middle": [], "last": "Ishida", "suffix": ""}, {"first": "M", "middle": [], "last": "Todorokihara", "suffix": ""}, {"first": "T", "middle": [], "last": "Kitamura", "suffix": ""}, {"first": "R", "middle": [], "last": "Aoki", "suffix": ""}], "year": 2008, "venue": "Behavioural Brain Research", "link": "44605197"}, "BIBREF53": {"title": "What makes Mona Lisa smile?", "authors": [{"first": "L", "middle": ["L"], "last": "Kontsevich", "suffix": ""}, {"first": "C", "middle": ["W"], "last": "Tyler", "suffix": ""}], "year": 2004, "venue": "Vision Research", "link": "1371454"}, "BIBREF54": {"title": "Adaptive stochastic resonance in noisy neurons based on mutual information", "authors": [{"first": "S", "middle": [], "last": "Mitaim", "suffix": ""}, {"first": "B", "middle": [], "last": "Kosko", "suffix": ""}], "year": 2004, "venue": "IEEE Transactions on Neural Networks", "link": "10438780"}, "BIBREF55": {"title": "Noise-induced entrainment and stochastic resonance in human brain waves", "authors": [{"first": "T", "middle": [], "last": "Mori", "suffix": ""}, {"first": "S", "middle": [], "last": "Kai", "suffix": ""}], "year": 2002, "venue": "Physical Review Letters", "link": "17465587"}, "BIBREF56": {"title": "Temporal encoding in auditory evoked neuromagnetic fields: stochastic resonance", "authors": [{"first": "S", "middle": ["M"], "last": "Stufflebeam", "suffix": ""}, {"first": "D", "middle": [], "last": "Poeppel", "suffix": ""}, {"first": "T", "middle": ["P"], "last": "Roberts", "suffix": ""}], "year": 2008, "venue": "Neuroreport", "link": "16513103"}, "BIBREF57": {"title": "Modelling contrast discrimination data suggest both the pedestal effect and stochastic resonance to be caused by the same mechanism", "authors": [{"first": "R", "middle": ["L T"], "last": "Goris", "suffix": ""}, {"first": "J", "middle": [], "last": "Wagemans", "suffix": ""}, {"first": "F", "middle": ["A"], "last": "Wichmann", "suffix": ""}], "year": 2008, "venue": "Journal of Vision", "link": "8501462"}, "BIBREF58": {"title": "Neural interactions between flicker-induced self-organized visual hallucinations and physical stimuli", "authors": [{"first": "V", "middle": ["A"], "last": "Billock", "suffix": ""}, {"first": "B", "middle": ["H"], "last": "Tsou", "suffix": ""}], "year": 2007, "venue": "Proceedings of the National Academy of Sciences", "link": "19518574"}, "BIBREF59": {"title": "Which model to use for cortical spiking neurons", "authors": [{"first": "E", "middle": ["M"], "last": "Izhikevich", "suffix": ""}], "year": 2004, "venue": "IEEE Transactions on Neural Networks", "link": "7354646"}, "BIBREF60": {"title": "Coherence resonance in a Hodgkin-Huxley neuron", "authors": [{"first": "S.-G", "middle": [], "last": "Lee", "suffix": ""}, {"first": "A", "middle": [], "last": "Neiman", "suffix": ""}, {"first": "S", "middle": [], "last": "Kim", "suffix": ""}], "year": 1998, "venue": "Physical Review E", "link": "120244246"}, "BIBREF61": {"title": "From the Hodgkin-Huxley axon to the virtual heart", "authors": [{"first": "D", "middle": [], "last": "Noble", "suffix": ""}], "year": 2007, "venue": "The Journal of Physiology", "link": null}, "BIBREF62": {"title": "Coherence resonance in a noise-driven excitable system", "authors": [{"first": "A", "middle": ["S"], "last": "Pikovsky", "suffix": ""}, {"first": "J", "middle": [], "last": "Kurths", "suffix": ""}], "year": 1997, "venue": "Physical Review Letters", "link": "933182"}, "BIBREF63": {"title": "A stochastic model for cancer risk", "authors": [{"first": "R", "middle": ["B"], "last": "Schinazi", "suffix": ""}], "year": 2006, "venue": "Genetics", "link": "16258204"}, "BIBREF64": {"title": "Noise-enhanced human balance control", "authors": [{"first": "A", "middle": [], "last": "Priplata", "suffix": ""}, {"first": "J", "middle": [], "last": "Niemi", "suffix": ""}, {"first": "M", "middle": [], "last": "Salen", "suffix": ""}, {"first": "J", "middle": [], "last": "Harry", "suffix": ""}, {"first": "L", "middle": ["A"], "last": "Lipsitz", "suffix": ""}, {"first": "J", "middle": ["J"], "last": "Collins", "suffix": ""}], "year": 2002, "venue": "Physical Review Letters", "link": "6998778"}, "BIBREF66": {"title": "Noise and poise: Enhancement of postural complexity in the elderly with a stochasticresonance-based therapy", "authors": [{"first": "", "middle": [], "last": "Peng", "suffix": ""}], "year": 2007, "venue": "Europhysics Letters", "link": "31847297"}, "BIBREF67": {"title": "Enhancing sensation in diabetic neuropathic foot with mechanical noise", "authors": [{"first": "L", "middle": [], "last": "Khaodhiar", "suffix": ""}, {"first": "J", "middle": ["B"], "last": "Niemi", "suffix": ""}, {"first": "R", "middle": [], "last": "Earnest", "suffix": ""}, {"first": "C", "middle": [], "last": "Lima", "suffix": ""}, {"first": "J", "middle": ["D"], "last": "Harry", "suffix": ""}, {"first": "A", "middle": [], "last": "Veves", "suffix": ""}], "year": 2003, "venue": "Diabetes Care", "link": "9581001"}, "BIBREF68": {"title": "Stochastic resonance stimulation for upper limb rehabilitation poststroke", "authors": [{"first": "J", "middle": [], "last": "Stein", "suffix": ""}, {"first": "R", "middle": [], "last": "Hughes", "suffix": ""}, {"first": "S", "middle": [], "last": "Andrea", "suffix": ""}, {"first": "B", "middle": [], "last": "Therrien", "suffix": ""}, {"first": "J", "middle": [], "last": "Niemi", "suffix": ""}, {"first": "K", "middle": [], "last": "Krebs", "suffix": ""}, {"first": "L", "middle": [], "last": "Langone", "suffix": ""}, {"first": "J", "middle": [], "last": "Harry", "suffix": ""}], "year": 2010, "venue": "American Journal of Physical Medicine and Rehabilitation", "link": "205951314"}, "BIBREF69": {"title": "Enhancement of vowel coding for cochlear implants by addition of noise", "authors": [{"first": "R", "middle": ["P"], "last": "Morse", "suffix": ""}, {"first": "E", "middle": ["F"], "last": "Evans", "suffix": ""}], "year": 1996, "venue": "Nature Medicine", "link": null}, "BIBREF70": {"title": "Noise-enhanced tactile sensation", "authors": [{"first": "J", "middle": ["J"], "last": "Collins", "suffix": ""}, {"first": "T", "middle": ["T"], "last": "Imhoff", "suffix": ""}, {"first": "P", "middle": [], "last": "Grigg", "suffix": ""}], "year": 1996, "venue": "Nature", "link": "3660648"}, "BIBREF71": {"title": "Coincidence-enhanced stochastic resonance: experimental evidence challenges the psychophysical theory behind stochastic resonance", "authors": [{"first": "C", "middle": ["A"], "last": "Perez", "suffix": ""}, {"first": "T", "middle": ["E"], "last": "Cohnb", "suffix": ""}, {"first": "L", "middle": ["E"], "last": "Medina", "suffix": ""}, {"first": "J", "middle": ["R"], "last": "Donoso", "suffix": ""}], "year": 2007, "venue": "Neuroscience Letters", "link": "25301380"}, "BIBREF72": {"title": "Pelvic floor stimulation: What are the good vibrations?", "authors": [{"first": "M", "middle": [], "last": "Lauper", "suffix": ""}, {"first": "A", "middle": [], "last": "Kuhn", "suffix": ""}, {"first": "R", "middle": [], "last": "Gerber", "suffix": ""}, {"first": "H", "middle": [], "last": "Luginbhl", "suffix": ""}, {"first": "L", "middle": [], "last": "Radlinger", "suffix": ""}], "year": 2009, "venue": "Neurourology and Urodynamics", "link": "10951465"}, "BIBREF73": {"title": "Enhanced balance associated with coordination training with stochastic resonance stimulation in subjects with functional ankle instability: an experimental trial", "authors": [{"first": "S", "middle": [], "last": "Ross", "suffix": ""}, {"first": "B", "middle": [], "last": "Arnold", "suffix": ""}, {"first": "J", "middle": ["T"], "last": "Blackburn", "suffix": ""}, {"first": "C", "middle": [], "last": "Brown", "suffix": ""}, {"first": "K", "middle": [], "last": "Guskiewicz", "suffix": ""}], "year": 2007, "venue": "Journal of NeuroEngineering and Rehabilitation", "link": "2460331"}, "BIBREF74": {"title": "Noise-enhanced postural stability in subjects with functional ankle instability", "authors": [{"first": "S", "middle": ["E"], "last": "Ross", "suffix": ""}], "year": 2007, "venue": "British Journal of Sports Medicine", "link": "42214726"}, "BIBREF75": {"title": "The effects of stochastic resonance stimulation on spine proprioception and postural control in chronic low back pain patients", "authors": [{"first": "N", "middle": ["P"], "last": "Reeves", "suffix": ""}, {"first": "J", "middle": [], "last": "Cholewicki", "suffix": ""}, {"first": "A", "middle": ["S"], "last": "Lee", "suffix": ""}, {"first": "L", "middle": ["W"], "last": "Mysliwiec", "suffix": ""}], "year": 2009, "venue": "Spine", "link": "41885368"}, "BIBREF76": {"title": "Applying stochastic resonance to magnify \u00b5 and \u03b2 wave suppression", "authors": [{"first": "C.-C", "middle": ["K"], "last": "Lin", "suffix": ""}, {"first": "M.-S", "middle": [], "last": "Ju", "suffix": ""}, {"first": "C.-W", "middle": [], "last": "Hsu", "suffix": ""}, {"first": "Y.-N", "middle": [], "last": "Sun", "suffix": ""}], "year": 2008, "venue": "Computers in Biology and Medicine", "link": "10381694"}, "BIBREF77": {"title": "Noiseenhanced human sensorimotor function", "authors": [{"first": "J", "middle": ["J"], "last": "Collins", "suffix": ""}, {"first": "A", "middle": ["A"], "last": "Priplata", "suffix": ""}, {"first": "D", "middle": ["C"], "last": "Gravelle", "suffix": ""}, {"first": "J", "middle": [], "last": "Niemi", "suffix": ""}, {"first": "J", "middle": [], "last": "Harry", "suffix": ""}, {"first": "L", "middle": ["A"], "last": "Lipsitz", "suffix": ""}], "year": 2003, "venue": "IEEE Engineering in Medicine and Biology Magazine", "link": null}, "BIBREF78": {"title": "Noise-enhanced balance control in older adults", "authors": [{"first": "D", "middle": ["C"], "last": "Gravelle", "suffix": ""}, {"first": "C", "middle": ["A"], "last": "Laughton", "suffix": ""}, {"first": "N", "middle": ["T"], "last": "Dhruv", "suffix": ""}, {"first": "K", "middle": ["D"], "last": "Katdare", "suffix": ""}, {"first": "J", "middle": ["B"], "last": "Niemi", "suffix": ""}, {"first": "L", "middle": ["A"], "last": "Lipsitz", "suffix": ""}, {"first": "J", "middle": ["J"], "last": "Collins", "suffix": ""}], "year": 2002, "venue": "Neuroreport", "link": null}, "BIBREF79": {"title": "Noiseenhanced vibrotactile sensitivity in older adults, patients with stroke, and patients with diabetic neuropathy", "authors": [{"first": "W", "middle": [], "last": "Liu", "suffix": ""}, {"first": "L", "middle": ["A"], "last": "Lipsitz", "suffix": ""}, {"first": "M", "middle": [], "last": "Montero-Odasso", "suffix": ""}, {"first": "J", "middle": [], "last": "Bean", "suffix": ""}, {"first": "D", "middle": ["C"], "last": "Kerrigan", "suffix": ""}, {"first": "J", "middle": ["J"], "last": "Collins", "suffix": ""}], "year": 2002, "venue": "Archives of Physical Medicine and Rehabilitation", "link": "3133778"}, "BIBREF80": {"title": "Prolonged mechanical noise restores tactile sense in diabetic neuropathic patients", "authors": [{"first": "R", "middle": [], "last": "Cloutier", "suffix": ""}, {"first": "S", "middle": [], "last": "Horr", "suffix": ""}, {"first": "J", "middle": ["B"], "last": "Niemi", "suffix": ""}, {"first": "S", "middle": [], "last": "Andrea", "suffix": ""}, {"first": "C", "middle": [], "last": "Lima", "suffix": ""}, {"first": "J", "middle": ["D"], "last": "Harry", "suffix": ""}, {"first": "A", "middle": [], "last": "Veves", "suffix": ""}], "year": 2009, "venue": "The International Journal of Lower Extremity Wounds", "link": "22881514"}, "BIBREF82": {"title": "Life-support system benefits from noise", "authors": [{"first": "S", "middle": [], "last": "Ingenito", "suffix": ""}, {"first": "H", "middle": ["E"], "last": "Zapperi", "suffix": ""}, {"first": "", "middle": [], "last": "Stanley", "suffix": ""}], "year": 1998, "venue": "Nature", "link": "4416863"}, "BIBREF83": {"title": "Listen to the noise: noise is beneficial for cognitive performance in ADHD", "authors": [{"first": "G", "middle": [], "last": "Soderlund", "suffix": ""}, {"first": "S", "middle": [], "last": "Sikstrom", "suffix": ""}, {"first": "A", "middle": [], "last": "Smart", "suffix": ""}], "year": 2007, "venue": "Journal of Child Psychology and Psychiatry", "link": "23247878"}, "BIBREF84": {"title": "The effects of background white noise on memory performance in inattentive school children", "authors": [{"first": "G", "middle": [], "last": "Soderlund", "suffix": ""}, {"first": "S", "middle": [], "last": "Sikstrom", "suffix": ""}, {"first": "J", "middle": [], "last": "Loftesnes", "suffix": ""}, {"first": "E", "middle": [], "last": "Sonuga-Barke", "suffix": ""}], "year": 2010, "venue": "Behavioral and Brain Functions", "link": "1557672"}, "BIBREF85": {"title": "Stochastic resonance in the speed of memory retrieval", "authors": [{"first": "M", "middle": [], "last": "Usher", "suffix": ""}, {"first": "M", "middle": [], "last": "Feingold", "suffix": ""}], "year": 2000, "venue": "Biological Cybernetics", "link": null}, "BIBREF86": {"title": "Galvanic vestibular stimulation speeds visual memory recall", "authors": [{"first": "D", "middle": [], "last": "Wilkinson", "suffix": ""}, {"first": "S", "middle": [], "last": "Nicholls", "suffix": ""}, {"first": "C", "middle": [], "last": "Pattenden", "suffix": ""}, {"first": "P", "middle": [], "last": "Kilduff", "suffix": ""}, {"first": "W", "middle": [], "last": "Milberg", "suffix": ""}], "year": 2008, "venue": "Experimental Brain Research", "link": "23216075"}, "BIBREF87": {"title": "Physiological complexity and system adaptability: evidence from postural control dynamics of older adults", "authors": [{"first": "B", "middle": [], "last": "Manor", "suffix": ""}, {"first": "M", "middle": ["D"], "last": "Costa", "suffix": ""}, {"first": "K", "middle": [], "last": "Hu", "suffix": ""}, {"first": "E", "middle": [], "last": "Newton", "suffix": ""}, {"first": "O", "middle": [], "last": "Starobinets", "suffix": ""}, {"first": "H", "middle": ["G"], "last": "Kang", "suffix": ""}, {"first": "C", "middle": ["K"], "last": "Peng", "suffix": ""}, {"first": "V", "middle": [], "last": "Novak", "suffix": ""}, {"first": "L", "middle": ["A"], "last": "Lipsitz", "suffix": ""}], "year": 2010, "venue": "Journal of Applied Physiology", "link": "13442452"}, "BIBREF88": {"title": "Fractional gaussian noise, functional MRI and Alzheimer's disease", "authors": [{"first": "V", "middle": [], "last": "Maxim", "suffix": ""}, {"first": "L", "middle": [], "last": "Sendur", "suffix": ""}, {"first": "J", "middle": [], "last": "Fadili", "suffix": ""}, {"first": "J", "middle": [], "last": "Suckling", "suffix": ""}, {"first": "R", "middle": [], "last": "Gould", "suffix": ""}, {"first": "R", "middle": [], "last": "Howard", "suffix": ""}, {"first": "E", "middle": [], "last": "Bullmore", "suffix": ""}], "year": 2005, "venue": "NeuroImage", "link": "25241319"}, "BIBREF89": {"title": "Time series analysis of leg movements during freezing of gait in Parkinson's disease: akinesia, rhyme or reason?", "authors": [{"first": "J", "middle": ["M"], "last": "Hausdorff", "suffix": ""}, {"first": "Y", "middle": [], "last": "Balash", "suffix": ""}, {"first": "N", "middle": [], "last": "Giladi", "suffix": ""}], "year": 2003, "venue": "Physica A: Statistical Mechanics and its Applications", "link": "121701716"}, "BIBREF90": {"title": "The self as a dynamical system", "authors": [{"first": "T", "middle": [], "last": "Marks-Tarlow", "suffix": ""}], "year": 1999, "venue": "Psychology, and Life Sciences", "link": "116976953"}, "BIBREF91": {"title": "Dynamic behavior of a social model for opinion formation", "authors": [{"first": "C", "middle": ["M"], "last": "Bordogna", "suffix": ""}, {"first": "E", "middle": ["V"], "last": "Albano", "suffix": ""}], "year": 2007, "venue": "Physical Review E", "link": "40146690"}, "BIBREF92": {"title": "Stochastic resonance in a model of opinion formation on smallworld networks", "authors": [{"first": "M", "middle": [], "last": "Kuperman", "suffix": ""}, {"first": "D", "middle": [], "last": "Zanette", "suffix": ""}], "year": 2002, "venue": "The European Physical Journal B -Condensed Matter and Complex Systems", "link": "119457944"}}, "ref_entries": {"FIGREF0": {"text": "Figure 1: Examples of various noise processes: (a) white noise; (b) power spectral density of the white noise (grey line denotes the theoretical value, which is a constant for all frequencies); (c) pink noise; (d) power spectral density of the pink noise (the grey line denotes the theoretical value, which is C/f ); (e) Brownian noise; (f) power spectral density of the Brownian noise (the grey line denotes the theoretical value, which is C/f 2 ).", "type": "figure"}, "FIGREF1": {"text": "Figure 2: A dual role of noise in biomedical systems: (a) an optimal noise level can have beneficial effects on signal detection, while any other noise levels will degrade the system performance; (b normative physiological signals can be modeled as 1/f processes, while a change in their stochastic properties to either white (1/f 0 ) or Brownian (1/f 2 ) processes due to aging or diseases is associated with functional loss.", "type": "figure"}, "FIGREF2": {"text": "Figure 3: Nonmonotonic effects of noise on visual perception. Consider the popular \"Lenna\" (Lenna, [image online] Available at: <www.lenna.org> [Accessed 22 March 2012]) image used in the image processing community. We processed the image, I, to obtain I 1 = \u03a6{(I + \u03be) \u2212 T } where \u03a6{i} = 1 for an input pixel value i \u2208 [0, 1] and \u03a6{i} = 0 otherwise; the threshold, T, is 0.12; and \u03be is zero-mean uniform noise with the standard deviation, \u03c3. Please refer to [54] for more information. Image contrast improves as we increase \u03c3, but then decreases past a certain value: (a) \u03c3 = 0; (b) \u03c3 = 0.25; (c) \u03c3 = 0.834; and (d) \u03c3 = 2.2.", "type": "figure"}, "FIGREF3": {"text": "Figure 4: The effect of varying \u03c3 on the membrane potential, V : (a) \u03c3 = 0.2; (b) \u03c3 = 0.1; (c) \u03c3 = 0.05; (d) \u03c3 = 0.", "type": "figure"}, "FIGREF4": {"text": "Figure 5: The effect of varying \u03c3 on the Fitz Hugh-Nagumo model: (a) the variable x for \u03c3 = 0.25; (b) the variable x for \u03c3 = 0; (c) the variable y for \u03c3 = 0.25; (d) the variable y for \u03c3 = 0.", "type": "figure"}, "FIGREF5": {"text": "Figure 6: The effect of varying \u00b5 on the probability of cancer over lifetime: (a) \u00b5 = 0.01 and p 2 = 10 \u22125 ; (b) \u00b5 = 100 and p 2 = 10 \u22125 . Please note that the y-axes are scaled differently (a) and (b).", "type": "figure"}}}
{"paper_id": "2877038", "_pdf_hash": "05f36f20789f8336e6495aaa67d87ed57c3b3566", "abstract": [{"section": "Abstract", "text": "A common pitfall of many proposals on new informationcentric architectures for the Internet is the imbalance of upfront costs and immediate benefits. If properly designed and deployed, information-centric architectures can accommodate the current Internet usage which is at odds with the historical design of the Internet infrastructure. To address this concern, we focus on prospects of incremental adoption of this paradigm by introducing a peer-to-peer based transport protocol for content dissemination named Swift that exhibits properties required in an Information-Centric Network (ICN), yet can be deployed in the existing Internet infrastructure. Our design integrates components while highly prioritizing modularity and sketches a path for piecemeal adoption which we consider a critical enabler of any progress in the field.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "INTRODUCTION", "text": "In this paper, we introduce Swift protocol. Swift was originally designed to be a replacement for the BitTorrent protocol and inherits some of the characteristics that have made BitTorrent successful, but was not intentionally designed according to the principles of information-centric networking (ICN) paradigm. It is, thus, until now a product of (unintentional) evolution towards ICN that we now seek to direct and accelerate, while retaining all the properties that make it work well on top of the existing network.", "cite_spans": [], "ref_spans": []}, {"section": "INTRODUCTION", "text": "We find the ICN concept to be increasingly reflected in both the way Internet is being used and in how Internetbased services are being implemented today. In many cases, we find that the problems we struggle with in the current * Work by Victor Grishchenko was carried out while at the Technical University of Delft incarnation of the Internet are those that ICN design proposals seek to address.", "cite_spans": [], "ref_spans": []}, {"section": "INTRODUCTION", "text": "For example, over 90% of today's Internet bandwidth [4] is effectively devoted to disseminating static multimedia content. In order to do so to an increasingly large and geographically diverse audience, various approaches are used. For example, for web-based content, Content Delivery Networks (CDNs) like Akamai use modified DNS servers that generate responses based on the topological/geographical location of the requester. These \"tricks\" are there to achieve on the current Internet the features that are at the core of ICN.", "cite_spans": [], "ref_spans": []}, {"section": "INTRODUCTION", "text": "During the past years, a chain of new network architectures based on the information-centric paradigm (also content-centric, name-oriented, named-data) have been proposed, including CCN [17] , DONA [20] , NetInf [11] , secure naming by Wong et al [23] , and content-centric router by Arianfar et al [6] to address the limitations of IP, namely the inability to decouple data from storage, inefficient data dissemination, lack of support for middleboxes, ubiquitous availability of data, and security.", "cite_spans": [{"start": 186, "end": 190, "text": "[17]", "ref_id": "BIBREF15"}, {"start": 198, "end": 202, "text": "[20]", "ref_id": "BIBREF18"}, {"start": 212, "end": 216, "text": "[11]", "ref_id": "BIBREF9"}, {"start": 247, "end": 251, "text": "[23]", "ref_id": "BIBREF21"}, {"start": 299, "end": 302, "text": "[6]", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "INTRODUCTION", "text": "The historical conversation-centric end-to-end model, embodied in the TCP/IP stack, is based on message exchange between pairs of peers, typically servers and clients. On the other hand, ICN is a paradigm in which focus shifts away from the mechanics of moving bits between peers (endhosts). Instead, the focus in on the information itself, and the underlying network only a conduit for the information. In a sense, named-data network breaks with the end-to-end abstraction, as there are no ends and the entire network is considered a cloud, which both stores and serves data.", "cite_spans": [], "ref_spans": []}, {"section": "INTRODUCTION", "text": "Similarly, we can see in the evolution of peer-to-peer (P2P) file-sharing technologies how they have adopted ways of managing content that more and more look like ICN. While BitTorrent [10] has always used a SHA-1 hash of the content data to identify that unique content item, it used to be that you also needed a location identifier (the address of the tracker through which the peers hosting the content can be located). However, the current incarnation of BitTorrent instead uses a shared global Distributed Hash Table (DHT) to locate peers using the aforementioned content hash as the key.", "cite_spans": [{"start": 185, "end": 189, "text": "[10]", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "INTRODUCTION", "text": "The historical Usenet discussion system [5] had all the key information-centric features: logical namespace and unique message identifiers, flood message propagation and caching. The git [3] revision control system represents version history of a project as a directed acyclic graph of revisions, where every revision is identified with SHA-1 hash of its contents; repositories push and pull content, thus forming a network of arbitrary topology.", "cite_spans": [{"start": 187, "end": 190, "text": "[3]", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "INTRODUCTION", "text": "This tendency towards information-centricity implies a strong demand for a generic named-data substrate that is not reflected yet in the de jure network architecture. Given this dissonance, some have proposed a networking revolution to dethrone the Internet Protocol (IP) in favor of a cleanslate redesign of the networking infrastructure.", "cite_spans": [], "ref_spans": []}, {"section": "INTRODUCTION", "text": "While intellectually attractive, we do not consider such an approach realistic. Not only because it would require the expensive and disruptive wholesale replacement of the existing infrastructure, but more importantly because such a migration is unlikely to happen before the wholesale conversion of applications to information-centric analogues of the current application ecosystems, and that conversion is unlikely to happen until the required infrastructure is in place.", "cite_spans": [], "ref_spans": []}, {"section": "INTRODUCTION", "text": "Having made this observation, it seems clear that evolution, not revolution, is the best way towards ICN, and by recognizing and helping this along, we can both make ICN happen sooner and ensure that the ICN approach will be one tested in both lab and real-world settings, and hence \"the fittest\".", "cite_spans": [], "ref_spans": []}, {"section": "INTRODUCTION", "text": "We start with the necessary basic properties of any information centric architecture and determine which of them Swift already supports. Further, we determine which information centric primitives Swift does not provide and address them by leveraging existing technologies, such as DHTs to find peers and standard IP to route packets.", "cite_spans": [], "ref_spans": []}, {"section": "INTRODUCTION", "text": "In this paper, we argue that our modular design addresses the gap between Internet usage and the underlying network, without requiring clean-slate redesigning of the architecture. In particular, Swift protocol supports most properties proposed in information-centric architectures like CCN [17] , DONA [20] , and NetInf [11] . First, Swift uses names -flat identifiers -to request content instead of end-point addresses; in addition, it segments named objects in uniquely identified chunks. Second, Swift employs perpacket integrity check, enabling any peer in the network to cache and relay content and verify the integrity of each piece. Third, Swift avoids transmitting additional metadata and is suitable for live/mutable data, by employing Merkle hashes [21] .", "cite_spans": [{"start": 290, "end": 294, "text": "[17]", "ref_id": "BIBREF15"}, {"start": 302, "end": 306, "text": "[20]", "ref_id": "BIBREF18"}, {"start": 320, "end": 324, "text": "[11]", "ref_id": "BIBREF9"}, {"start": 759, "end": 763, "text": "[21]", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "INTRODUCTION", "text": "Moreover, Swift is a receiver-driven chunk-level transport protocol; the receiver may send concurrent requests for chunks to multiple peers in the network in order to enhance its content retrieval rate. To efficiently exploit available bandwidth, Swift employs a delay-based congestion control algorithm named LEDBAT [22] , and to address the issue of middleboxes Swift employs a NAT hole punching mechanism. For peer discovery, Swift can use centralized trackers or DHTs; in Section 7 we explain how Mainline DHT (MDHT) can be used to find peers offering the given data object in sub-second time periods.", "cite_spans": [{"start": 317, "end": 321, "text": "[22]", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "INTRODUCTION", "text": "The paper proceeds as follows. In Section 2 we introduce ICN related work and summarize system description. Section 3 discusses design properties and the resulting separation of transport and internetworking layers. Section 4 describes our variation of the Merkle hashing scheme and its extensions. In Section 5 we introduce a vocabulary of messages that constitutes our protocol. Section 6 describes our UDP-based implementation. Section 7 discusses the implications for peer discovery and packet routing. Section 8 concludes.", "cite_spans": [], "ref_spans": []}, {"section": "BACKGROUND", "text": "Most proposals on ICN architectures -evolutionary and clean-slate designs -aim to define the main building blocks of an information-centric network. In the CCN [17] design, content names have a hierarchical structure and are constructed according to the standard URI form. Content is requested using an interest packet which contains the name of the content. Every content router receiving the interest packet checks if the given packet is in its local cache and thus returns a corresponding data packet along the reverse path, otherwise, it forwards the interest to the correct interface using longest prefix matching. A similar approach for content retrieval is reflected in the PSIRP architecture [2] , albeit it uses flat instead of hierarchical names to address content.", "cite_spans": [{"start": 160, "end": 164, "text": "[17]", "ref_id": "BIBREF15"}], "ref_spans": []}, {"section": "BACKGROUND", "text": "Some recent ICN projects adopt flat, self-certifying, labels to name content. Initially employed in DONA's design [20] , flat names are used by the route-by-name protocol (devised on top of the IP layer) to request content. Similarly, efforts by Dannewitz et al [11] and Wong et al [23] explore secure naming schemes to ensure the data is persistent and not accessed by unauthorized users.", "cite_spans": [{"start": 114, "end": 118, "text": "[20]", "ref_id": "BIBREF18"}, {"start": 262, "end": 266, "text": "[11]", "ref_id": "BIBREF9"}, {"start": 282, "end": 286, "text": "[23]", "ref_id": "BIBREF21"}], "ref_spans": []}, {"section": "BACKGROUND", "text": "Self-certifying (flat) names have been criticized for their lack of scalability (cannot be aggregated), flexibility, and lack of security during the translation of flat names to humanreadable names. However, recent work by Ghodsi et al [13] argues that self-certifying names exhibit better security properties than human-readable names because 1) they can handle better denial-of-service attacks -the network knows the binding between the name and the key thus it can verify that a given object is associated with a given name, and 2) may scale better through explicit aggregation -using concatenations of the form A.B.C, where each letter is a name itself.", "cite_spans": [{"start": 236, "end": 240, "text": "[13]", "ref_id": "BIBREF11"}], "ref_spans": []}, {"section": "BACKGROUND", "text": "Despite differences in the naming scheme, the necessary mainstay of any name-oriented network architecture is to employ either cryptographic hashes or signatures in order to enable indiscriminate caching of data in the network and the possibility of its retrieval from any available peer. In Swift, we employ hashes -Merkle hashes -and argue that they are sufficient to perform any transport function. More specifically, Merkle hash trees [21] allow to identify and verify data, thus enabling any peer in the network to request, relay and store data. Furthermore, our variant of hash trees needs no supplementary transfer metadata, rendering transport into a thinner layer than usual.", "cite_spans": [{"start": 439, "end": 443, "text": "[21]", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "BACKGROUND", "text": "Swift must be implemented by all inter-operating network peers, and its functioning involves cross-layer relaying of the data, known as internetworking (see Figure 1) . Hence, the required functionality needs to be as simple and formalized as possible. It follows naturally that any rich semantic data names or transfer metadata is unnecessary and should therefore not be part of transport.", "cite_spans": [], "ref_spans": [{"start": 157, "end": 166, "text": "Figure 1)", "ref_id": "FIGREF0"}]}, {"section": "BACKGROUND", "text": "We define a natural separation of Swift from the upper naming part which deals with problems inherently semantic and the lower internetworking layer. Leveraging existing deployed routing infrastructure and a simple hash-based naming mechanism, Swift retrieves pieces of content requested by the receiver from peers in the network -functionality that researchers propose to incorporate in any transport protocol for information-centric networks [9, 7] . The naming layer is out of scope, thus we make no specific assumptions.", "cite_spans": [{"start": 444, "end": 447, "text": "[9,", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "DESIGN OVERVIEW", "text": "In our design, content is identified by a single cryptographic hash that is the root hash in a Merkle hash tree, calculated recursively from the content (see details in the Merkle hash extension document [8] ). The ability to verify data against its name allows for storage in the network and retrieval of data from an arbitrary location. Second, as a (packet) network may need to check data integrity piece by piece, possible options boil down to either per-packet signatures, as in CCN, or Merkle hash trees. Differently from signatures, Merkle hash trees provide strict permanent identifiers of static data pieces, so we chose them as the foundation, later extending the approach to dynamic data (see Section 4).", "cite_spans": [{"start": 204, "end": 207, "text": "[8]", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "DESIGN OVERVIEW", "text": "The hashing scheme enables the entire informationcentric stack, illustrated in Figure 1 , in two ways. First, it allows for a perfect application-to-transport handover. Semantically-rich and application-dependent queries are eventually converted into requests to the transport layer for particular data pieces, precisely identified with hashes. Second, hashing enables information-centric internetworking, i.e. identification and relay of data pieces, data verification, and storage in the network.", "cite_spans": [], "ref_spans": [{"start": 79, "end": 87, "text": "Figure 1", "ref_id": "FIGREF0"}]}, {"section": "DESIGN OVERVIEW", "text": "As depicted in Figure 1 , Swift embeds a layer separation scheme very much reminiscent of TCP/IP. Namely, there is a relay internetworking layer that only deals with separate datagrams. On top of it, there is a somewhat more intelligent transport layer that deals with entire data streams, performing verification, caching, and storage.", "cite_spans": [], "ref_spans": [{"start": 15, "end": 23, "text": "Figure 1", "ref_id": "FIGREF0"}]}, {"section": "DESIGN OVERVIEW", "text": "Any peer running Swift may cache content. Technically, there is no difference between a peer and a cache -they run the same protocol; the conceptual difference lies in the intention: a cache \"stores\" content to further disseminate it but is not particularly interested in the given content. The caches may be regular peers or peers put in place by ISPs -who are interested in replicating \"popular\" content within their administrative domains and thus avoid transit traffic and costs to external domains. If operated by ISPs, such caches (interchangeably, peers) may manage the content they offer according to some basic rules, such as LRU or demand.", "cite_spans": [], "ref_spans": []}, {"section": "DESIGN OVERVIEW", "text": "Discovering peers or caches may be done centrally through trackers or ISP-based trackers, or in a decentralized fashion through PEX or DHTs. We explain how discovering new", "cite_spans": [], "ref_spans": []}, {"section": "DESIGN OVERVIEW", "text": "In Swift, data storage and data verification are highly interdependent and important in terms of security. For example, if a caching peer does not verify data integrity, it makes cache poisoning possible. While a final recipient does not accept (drops) incorrect data, an erroneous cache may form a clot in the network, preventing the correct data from passing through. Similarly, data verification requires storage in peers to some degree, as Merkle hash trees need accompanying uncle hash chains to be available in order to verify data pieces.", "cite_spans": [], "ref_spans": []}, {"section": "DESIGN OVERVIEW", "text": "In a sense, hashes replace IP addresses as end-point identifiers. A receiver uses a root hash to \"open\" the connection to the network and retrieve the data. The receiver requests specific pieces of data using a novel method called bin numbers (see details in the RFC document [14] ) which allows the addressing of a binary interval of data using a single integer. This numbering mechanism reduces the amount of state that needs to be stored in each peer and minimizes the space required to denote intervals on the wire. Because the receiver directly addresses the data instead of a single end-point at a particular IP location, it has no control over which peer (replica) will respond; the receiver controls the reception of pieces based on local parameters.", "cite_spans": [{"start": 276, "end": 280, "text": "[14]", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "THE HASHING SCHEME", "text": "We modified Merkle hash trees and focused on smooth operation of both vertical (application to transport) and horizontal (internetworking) handovers to ensure that no peer requires third parties to verify bindings between keys and names (as in CCN [17] ) or to retrieve additional metadata to perform their function. We ensure their operation is as simple and formalized, as possible. In Sec. 4.3, we extend our basic technique to the cases of live data streams and versioned data.", "cite_spans": [{"start": 248, "end": 252, "text": "[17]", "ref_id": "BIBREF15"}], "ref_spans": []}, {"section": "64-bit Merkle Trees", "text": "We developed a variant of the Merkle hash tree scheme [21] to satisfy three key requirements: (a) per-packet data integrity checks, (b) no additional metadata and (c) suitability for live/mutable data. The general concept is to start with the root hash only, then incrementally acquire data and hashes, while verifying every single step.", "cite_spans": [{"start": 54, "end": 58, "text": "[21]", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "64-bit Merkle Trees", "text": "First, content is divided into 1KiB chunks named packets, except for the tail packet, which may have less than 1KiB of data. A cryptographic hash, such as SHA1, is then calculated on every packet. Second, a hash tree is defined over the complete [0, 2 63 ) byte range, which we consider to be a good approximation of infinity in relation to content size. The tree consists of aligned binary intervals called bins, i.e. [i2", "cite_spans": [], "ref_spans": []}, {"section": "64-bit Merkle Trees", "text": "Bins are nested, forming a strict binary tree (see Figure 2) . Each tree contains 2 64 bins of different sizes, including one void and one root bin; the base -the lowest level -of the tree is composed of 2 10 byte long bins. The base of the tree (the leaves) accommodates all the data chunks, starting from the left-most leaf. Normally, the base of the tree is wider than the number of chunks, thus the remaining empty leaves in the tree are assigned hash values of zero. In higher levels of the tree (above base), bins contain hashes which are calculated as a SHA1 hash of a concatenation of two -left and right -child (lower-level) hashes. This hashing process iterates until a hash value for the root bin is calculated, known as the root hash. Figure 2 illustrates an example where the file size is less than 8KiB long. Its [8192, 12288) empty bin has zero hash by definition, as do the rest of empty bins outside the [0, 8192) range. The root hash covers the entire [0, 2 63 ) range; this approach gives us a fixed point of reference when growing the hash tree down from the root.", "cite_spans": [], "ref_spans": [{"start": 51, "end": 60, "text": "Figure 2)", "ref_id": "FIGREF1"}, {"start": 747, "end": 755, "text": "Figure 2", "ref_id": "FIGREF1"}]}, {"section": "Peak Hashes", "text": "The concept of peak hashes enables two cornerstone features: file size proving and unified processing of static data and live streams. In addition, they help avoid the usage of additional transmission metadata. Formally, peak hashes are hashes defined over filled bins, whose parent hashes are defined over incomplete (not filled) bins. A filled bin is a bin which does not extend past the end of the file, or, more precisely, contains no empty packets.", "cite_spans": [], "ref_spans": []}, {"section": "Peak Hashes", "text": "Practically, we use peaks to cover the data range with a logarithmic number of hashes, so each hash is defined over a \"round\" aligned 2 k interval. As an example, suppose a file is l = 7162 bytes long (see Figure 2) . That fits into seven packets ( 7162 1024 < 7), the tail packet being 1018 bytes long. For this particular file we will have three peaks, covering [0, 4096), [4096, 6144) and [6144, 7162) ranges (triangles depicted with double lines). The last range might also be written as [6144, 8192) because we round-up to 1KiB packet size.", "cite_spans": [], "ref_spans": [{"start": 206, "end": 215, "text": "Figure 2)", "ref_id": "FIGREF1"}]}, {"section": "Peak Hashes", "text": "The number of peak hashes can not exceed log 2 l 1024 . Practically, peak hashes provide us with more convenient \"reference roots\", as compared to the root hash which is 53 levels higher than the packets. More importantly, peak hashes allow a sender to quickly prove the file size to a recipient who only knows the root hash; otherwise, file size would have to be supplied as a separate metadata piece and thus separately verified, showing up in the protocol and in the interfaces.", "cite_spans": [], "ref_spans": []}, {"section": "Live Data Streams", "text": "In the case of live data streams, the root hash is undefined or, more precisely, transient, as long as new data keeps coming, filling new packets to the right. Hence a transfer has to be identified with a public key instead of a root hash. Keys are more difficult to deal with than hashes, as they have more degrees of freedom. For example, once a key is compromised, any party may rewrite a pre-existing stream.", "cite_spans": [], "ref_spans": []}, {"section": "Live Data Streams", "text": "Also, while a hash might be derived directly from the data, a signature can only be verified once known.", "cite_spans": [], "ref_spans": []}, {"section": "Live Data Streams", "text": "Because of such issues, we try to minimize key/signature usage by using the same peak hashes scheme as in the case of static data. Indeed, once a peak hash is defined, it never changes. Thus, we only need a logarithmic number of signatures to sign peak hashes. After that, we may deal with the same Merkle hash tree as before.", "cite_spans": [], "ref_spans": []}, {"section": "Live Data Streams", "text": "Signing the peak hashes only requires the sender to issue the newly formed peak hashes with their signatures attached. On the receiver side, the recipient will only have to check the signature of a new peak hash and whether it matches its child hashes. Such a calculation is incremental and local. Otherwise, if the root hash were to be signed instead, this would require constant re-verification of all the encompassing peak hashes.", "cite_spans": [], "ref_spans": []}, {"section": "Live Data Streams", "text": "Until this point, we assumed that the sender emits data in \"round\" 1KiB long packets. What if smaller portions of data need to be committed to the network? We do not equal, but we strongly associate our \"packets\" with linklayer \"frames\". Thus, once data is worth sending, before it fills a packet, then it also needs a hash and a signature.", "cite_spans": [], "ref_spans": []}, {"section": "MESSAGE VOCABULARY", "text": "In this section we describe the set of messages that constitute Swift protocol. In this section, we refer to it as a vocabulary which is instantiated as a transport protocol (as in Figure 1 ). No particular serialization, encapsulation schemes, or message exchange patterns are specified, beyond the very basic requirements.", "cite_spans": [], "ref_spans": [{"start": 181, "end": 189, "text": "Figure 1", "ref_id": "FIGREF0"}]}, {"section": "MESSAGE VOCABULARY", "text": "A DAT A message simply carries pieces of data. A DAT A message must carry a bin of data. Specifically, each DAT A message contains the bin number of the piece and the piece itself. This way, uniform pieces or multiples of pieces can be processed, making it easier to check the data hash tree at once. A HASH message carries the necessary hashes that the receiver needs in order to verify the integrity of a piece. We employ the principle of atomic datagrams, which means that every piece of data must be verified once received and accepted, otherwise dropped. At this point, the sender must make sure the receiver has every hash needed to verify the incoming data immediately. Finally, it is possible to supply the recipient with parts of the hash tree incrementally, to allow for an amortized and local verification of data.", "cite_spans": [], "ref_spans": []}, {"section": "MESSAGE VOCABULARY", "text": "As we allow for the possibility of data retrieval from multiple peers in parallel, the vocabulary employs HIN T and HAV E messages. A HIN T (request) message indicates which pieces of data a receiver wants to retrieve, while a HAV E message conveys what pieces of data a sender has available. On incoming data, a receiver uses ACK messages to acknowledge the received pieces; acknowledgements follow the logic of hash trees, which means that data must be acknowledged in bins as well.", "cite_spans": [], "ref_spans": []}, {"section": "MESSAGE VOCABULARY", "text": "We define channels as a means to identify ongoing transfers, where each transfer is identified by either a hash or a public key. Channel identifiers are conveyed through the datagram headers.", "cite_spans": [], "ref_spans": []}, {"section": "THE UDP IMPLEMENTATION", "text": "As previously stated, Swift [1] protocol is implemented over UDP; the detailed design is described in an IETF draft [14] and an overview is outlined in a technical report [15] . The protocol is a direct implementation of the vocabulary (see Section 5), with some additions and extensions.", "cite_spans": [{"start": 116, "end": 120, "text": "[14]", "ref_id": "BIBREF12"}, {"start": 171, "end": 175, "text": "[15]", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "THE UDP IMPLEMENTATION", "text": "Messages are serialized as fixed-width fields starting with a single-byte message type field, followed by fixed-width payload fields, such as bin numbers, data, hashes and such. Messages are packed into UDP datagrams. Datagram processing is event-driven, fully implementing the atomic datagram concept. This means that every datagram is either immediately committed to storage or immediately dropped; there are no buffer-re-assembly mechanics.", "cite_spans": [], "ref_spans": []}, {"section": "THE UDP IMPLEMENTATION", "text": "The UDP implementation employs LEDBAT [22] congestion control algorithm, which allows streams to run virtually lossless under normal conditions. LEDBAT is a delaybased congestion control algorithm which increases/decreases the congestion window based on the estimated queuing delay. It uses an increased queuing delay as indicator of congestion and thus immediately reacts by backing off (decreasing the rate).", "cite_spans": [{"start": 38, "end": 42, "text": "[22]", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "THE UDP IMPLEMENTATION", "text": "Queuing delay in LEDBAT is known as the one-way delay (label owd in Figure 3 ) and it is calculated as the difference of timestamped packets between the sender and the receiver. The receiver also maintains a minimum over all one-way delays -base delay -which indicates the amount of delay due to queuing. LEDBAT compares this estimated queuing delay against a fixed target delay value (line target in Figure 3) ; the difference determines if the congestion window should be increased or decreased. Figure 3 depicts how LEDBAT predicts congestion and avoids data losses for a given exchange between two peers (the figure only illustrates a preliminary test performed in a controlled environment with several peers spread across continents). In the testing scenario, one peer acts as a content provider -has the whole content -and other peers (requesters) are interested in the given content. The requesters retrieve the pieces, initially from the only content provider, and later on, they continue retrieving pieces from the participating requesters -who already obtained some pieces of the desired content.", "cite_spans": [], "ref_spans": [{"start": 68, "end": 76, "text": "Figure 3", "ref_id": "FIGREF2"}, {"start": 401, "end": 410, "text": "Figure 3)", "ref_id": "FIGREF2"}, {"start": 498, "end": 506, "text": "Figure 3", "ref_id": "FIGREF2"}]}, {"section": "THE UDP IMPLEMENTATION", "text": "Furthermore, Swift implements a unified mechanism of PEX and NAT hole punching functionality [12] . It uses two types of P EX messages -P EX REQ and P EX ADDto retrieve/exchange addresses among the peers, in a gossip fashion. However, P EX messages are transmitted in such a way that they facilitate the communication between peers that are located behind middleboxes: once a peer A introduces peer B to C, it should -within a period of 2 seconds -introduce peer C to B. This mechanism makes Swift agnostic to middleboxes.", "cite_spans": [{"start": 93, "end": 97, "text": "[12]", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "THE UDP IMPLEMENTATION", "text": "To guarantee that a receiver can verify every packet, the sender has to prepend it with the missing hashes. In a network with no data loss, the receiver builds the hash tree incrementally, thus every packet of data needs one hash on average. More precisely, every even packet needs a hash for its sibling, every fourth also needs a hash for its uncle, every eighth also needs a hash for its parent's uncle, and so forth, thus the average is 1. In practice, some packets are lost, so a prudent sender over-provisions hashes to compensate for possible loss. Thus, the actual traffic overhead of hashes is somewhat above the perfect value of 2% (assuming 20 byte hashes for a 1024 byte packet).", "cite_spans": [], "ref_spans": []}, {"section": "THE UDP IMPLEMENTATION", "text": "The protocol needs to keep more state on the transfer progress, as data might arrive out of sequence -mostly because data is delivered from different peers in parallel. The state must also be communicated over the wire, using unreliable datagrams. We adopted a generic compressed-bitmap data structure named binmaps [16] , a hybrid of bitmap and a binary tree, which allows to track data at an arbitrary scale, starting from a single packet. Data is requested and acknowledged in bins; this provides the necessary compression and redundancy as continuous data pieces are acknowledged with a logarithmic number of messages.", "cite_spans": [{"start": 316, "end": 320, "text": "[16]", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "ROUTING AND TRACKING", "text": "In order to retrieve data associated to a root hash, Swift needs to discover peers. This peer discovery process is performed by requesting peers from a tracker.", "cite_spans": [], "ref_spans": []}, {"section": "ROUTING AND TRACKING", "text": "Trackers are used in peer-to-peer systems to keep track of peers sharing a given piece of content. The tracker's interface is simple. Peers can request a list of peers for a given content identifier (a root hash in Swift, an info hash in BitTorrent). Peers also register itself in the tracker to be discovered by others.", "cite_spans": [], "ref_spans": []}, {"section": "ROUTING AND TRACKING", "text": "Swift can use any tracking mechanism regardless of its particular implementation. Tracker mechanisms used in BitTorrent are prime candidates to be used due to their proven merits on large-scale deployments, but other implementations offering equivalent functionality may be used [24] .", "cite_spans": [{"start": 279, "end": 283, "text": "[24]", "ref_id": "BIBREF22"}], "ref_spans": []}, {"section": "ROUTING AND TRACKING", "text": "BitTorrent's trackers can be centralized or DHT-based. In the first case, the URI of the tracker tracking a given piece of content is necessary. The DHT-based option, on the other hand, forms a global tracking system where all content is tracked, thus no tracker URI is needed.", "cite_spans": [], "ref_spans": []}, {"section": "ROUTING AND TRACKING", "text": "We favor the DHT-based tracker mechanism due to the scalability of the DHT and the minimization of metadata for Swift (no tracker URI is needed, just a root hash) to retrieve the data. Scalability is well illustrated by Mainline DHT, the BitTorrent's largest DHT-based tracker on the Internet. Mainline DHT is supported by most of the popular BitTorrent clients, forming a DHT overlay of between 6 and 11 million nodes [19] 1 . It is difficult to estimate how many pieces of content Mainline DHT tracks at a given time, but given the size of the BitTorrent ecosystem, even conservative estimations would yield six-digit numbers.", "cite_spans": [{"start": 419, "end": 423, "text": "[19]", "ref_id": "BIBREF17"}], "ref_spans": []}, {"section": "ROUTING AND TRACKING", "text": "Furthermore, recent measurements [18] have shown that Mainline DHT's response time is consistently low, which makes it suitable for latency-sensitive applications such as on-demand video streaming.", "cite_spans": [{"start": 33, "end": 37, "text": "[18]", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "CONCLUSION", "text": "In this paper, we presented a peer-to-peer based transport protocol for content dissemination named Swift and argued that the protocol exhibits ICN properties that help close the gap between the way Internet applications are used today and the underlying infrastructure supporting such applications. Further, we explored ways Swift may embed additional ICN properties in its behavior by leveraging existing technologies and infrastructure, such as decentralized peer discovery mechanisms and standard IP routing.", "cite_spans": [], "ref_spans": []}, {"section": "ACKNOWLEDGMENTS", "text": "We would like to thank Arno Bakker and Pehr S\u00f6derman for providing us with valuable feedback. The research leading to these results has received funding from the Seventh Framework Programme (FP7/2007-2013) under grant agreement No. 216217 (P2P-Next).", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF2": {"title": "The git source code management system", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF4": {"title": "On content-centric router design and implications", "authors": [{"first": "S", "middle": [], "last": "Arianfar", "suffix": ""}, {"first": "P", "middle": [], "last": "Nikander", "suffix": ""}, {"first": "J", "middle": [], "last": "Ott", "suffix": ""}], "year": "", "venue": "ReARCH'10", "link": "5868862"}, "BIBREF5": {"title": "A Transport Protocol for Content-Centric Networks", "authors": [{"first": "S", "middle": [], "last": "Arianfar", "suffix": ""}, {"first": "J", "middle": [], "last": "Ott", "suffix": ""}, {"first": "L", "middle": [], "last": "Eggert", "suffix": ""}, {"first": "P", "middle": [], "last": "Nikander", "suffix": ""}, {"first": "W", "middle": [], "last": "Wong", "suffix": ""}], "year": "", "venue": "ICNP'10", "link": "15181216"}, "BIBREF6": {"title": "Merkle hash torrent extension", "authors": [{"first": "A", "middle": [], "last": "Bakker", "suffix": ""}], "year": "", "venue": "BEP", "link": null}, "BIBREF7": {"title": "Bandwidth and storage sharing performance in information centric networking", "authors": [{"first": "G", "middle": [], "last": "Carofiglio", "suffix": ""}, {"first": "M", "middle": [], "last": "Gallo", "suffix": ""}, {"first": "L", "middle": [], "last": "Muscariello", "suffix": ""}], "year": "", "venue": "SIGCOMM ICN'11", "link": "8108750"}, "BIBREF8": {"title": "Incentives Build Robustness in BitTorrent", "authors": [{"first": "B", "middle": [], "last": "Cohen", "suffix": ""}], "year": 2003, "venue": "", "link": "108243708"}, "BIBREF9": {"title": "Secure Naming for a Network of Information", "authors": [{"first": "C", "middle": [], "last": "Dannewitz", "suffix": ""}, {"first": "J", "middle": [], "last": "Golic", "suffix": ""}, {"first": "B", "middle": [], "last": "Ohlman", "suffix": ""}, {"first": "B", "middle": [], "last": "Ahlgren", "suffix": ""}], "year": "", "venue": "INFOCOM'10", "link": "9556839"}, "BIBREF10": {"title": "Peer-to-Peer Communication Across Network Address Translators", "authors": [{"first": "B", "middle": [], "last": "Ford", "suffix": ""}, {"first": "P", "middle": [], "last": "Srisuresh", "suffix": ""}, {"first": "D", "middle": [], "last": "Kegel", "suffix": ""}], "year": "", "venue": "", "link": "897"}, "BIBREF11": {"title": "Naming in Content-Oriented Architectures", "authors": [{"first": "A", "middle": [], "last": "Ghodsi", "suffix": ""}, {"first": "T", "middle": [], "last": "Koponen", "suffix": ""}, {"first": "J", "middle": [], "last": "Rajahalme", "suffix": ""}, {"first": "P", "middle": [], "last": "Sarolahti", "suffix": ""}, {"first": "S", "middle": [], "last": "Shenker", "suffix": ""}], "year": "", "venue": "SIGCOMM ICN'11", "link": "13493451"}, "BIBREF12": {"title": "The Generic Multiparty Transport Protocol (swift). draft-grishchenko-ppsp-swift-03", "authors": [{"first": "V", "middle": [], "last": "Grishchenko", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF13": {"title": "On the Design of a Practical Information-Centric Transport", "authors": [{"first": "V", "middle": [], "last": "Grishchenko", "suffix": ""}, {"first": "F", "middle": [], "last": "Osmani", "suffix": ""}, {"first": "R", "middle": [], "last": "Jimenez", "suffix": ""}, {"first": "J", "middle": [], "last": "Pouwelse", "suffix": ""}, {"first": "H", "middle": [], "last": "Sips", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF14": {"title": "Binmaps: hybridizing bitmaps and binary trees", "authors": [{"first": "V", "middle": [], "last": "Grishchenko", "suffix": ""}, {"first": "J", "middle": [], "last": "Pouwelse", "suffix": ""}], "year": "", "venue": "", "link": "14131636"}, "BIBREF15": {"title": "Networking named content", "authors": [{"first": "V", "middle": [], "last": "Jacobson", "suffix": ""}, {"first": "D", "middle": ["K"], "last": "Smetters", "suffix": ""}, {"first": "J", "middle": ["D"], "last": "Thornton", "suffix": ""}, {"first": "M", "middle": ["F"], "last": "Plass", "suffix": ""}, {"first": "N", "middle": ["H"], "last": "Briggs", "suffix": ""}, {"first": "R", "middle": ["L"], "last": "Braynard", "suffix": ""}], "year": "", "venue": "CoNEXT '09", "link": "52895555"}, "BIBREF16": {"title": "Sub-Second Lookups on a Large-Scale Kademlia-Based Overlay", "authors": [{"first": "R", "middle": [], "last": "Jimenez", "suffix": ""}, {"first": "F", "middle": [], "last": "Osmani", "suffix": ""}, {"first": "B", "middle": [], "last": "Knutsson", "suffix": ""}], "year": 2011, "venue": "11th International Conference on Peer-to-Peer Computing", "link": "8585665"}, "BIBREF17": {"title": "BitMON: A Tool for Automated Monitoring of the BitTorrent DHT. In Peer-to-Peer Computing (P2P)", "authors": [{"first": "K", "middle": [], "last": "Junemann", "suffix": ""}, {"first": "P", "middle": [], "last": "Andelfinger", "suffix": ""}, {"first": "J", "middle": [], "last": "Dinger", "suffix": ""}, {"first": "H", "middle": [], "last": "Hartenstein", "suffix": ""}], "year": 2010, "venue": "IEEE Tenth International Conference on", "link": null}, "BIBREF18": {"title": "A data-oriented (and beyond) network architecture", "authors": [{"first": "T", "middle": [], "last": "Koponen", "suffix": ""}, {"first": "M", "middle": [], "last": "Chawla", "suffix": ""}, {"first": "B.-G", "middle": [], "last": "Chun", "suffix": ""}, {"first": "A", "middle": [], "last": "Ermolinskiy", "suffix": ""}, {"first": "K", "middle": ["H"], "last": "Kim", "suffix": ""}, {"first": "S", "middle": [], "last": "Shenker", "suffix": ""}, {"first": "I", "middle": [], "last": "Stoica", "suffix": ""}], "year": "", "venue": "SIGCOMM '07", "link": "6342139"}, "BIBREF19": {"title": "A Digital Signature Based on a Conventional Encryption Function", "authors": [{"first": "R", "middle": ["C"], "last": "Merkle", "suffix": ""}], "year": 1987, "venue": "CRYPTO", "link": "28484604"}, "BIBREF20": {"title": "Low Extra Delay Background Transport (LEDBAT). draft-ietf-ledbat-congestion-04", "authors": [{"first": "S", "middle": [], "last": "Shalunov", "suffix": ""}, {"first": "G", "middle": [], "last": "Hazel", "suffix": ""}, {"first": "J", "middle": [], "last": "Iyengar", "suffix": ""}, {"first": "M", "middle": [], "last": "Kuehlewind", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF21": {"title": "Secure naming in information-centric networks", "authors": [{"first": "W", "middle": [], "last": "Wong", "suffix": ""}, {"first": "P", "middle": [], "last": "Nikander", "suffix": ""}], "year": "", "venue": "ReARCH '10", "link": "12359021"}, "BIBREF22": {"title": "A PPSP Tracker Usage for Reload. draft-xiao-ppsp-reloaddistributed-tracker-03", "authors": [{"first": "L", "middle": [], "last": "Xiao", "suffix": ""}, {"first": "D", "middle": ["A"], "last": "Bryan", "suffix": ""}, {"first": "Y", "middle": [], "last": "Gu", "suffix": ""}, {"first": "X", "middle": [], "last": "Tai", "suffix": ""}], "year": "", "venue": "", "link": null}}, "ref_entries": {"FIGREF0": {"text": "Figure 1: Swift protocol stack: application-dependent queries are translated into requests to the transport layer for particular data -identified with hashes. Transport deals with data streams, their verification and storage.", "type": "figure"}, "FIGREF1": {"text": "Figure 2: Merkle hash tree constructed for a file of size less than 8KiB. Bins for peak hashes are marked with double lines and they cover the ranges [0, 4096), [4096, 6144) and [6144, 7162). Filled bins are marked with solid lines, incomplete bins with dashed lines, and empty bins with dotted lines.", "type": "figure"}, "FIGREF2": {"text": "Figure 3: LEDBAT congestion control adjusts the congestion window cwnd in order to avoid data losses, by comparing estimated queuing delay against a fixed target delay. The figure depicts experimental results when two nodes exchange pieces of content.", "type": "figure"}}}
{"paper_id": "2877272", "_pdf_hash": "9700122b6f343c20d15da1dfb8e591951f241a00", "abstract": [{"section": "Abstract", "text": "Background Arteriovenous malformations (AVMs) of the brain are commonly treated in multimodality fashion, with endovascular embolization followed by surgical extirpation being one of the most effective strategies. Modern endovascular suites enable rotational angiography, also known as cone-beam CT angiography (CBCT-A), using the full capability of modern C-arm digital angiography systems. This imaging modality offers a superior image quality to current options such as digital subtraction angiography, MRI, or CT angiography. Preoperative planning can be greatly aided by the resolution of angioarchitecture seen in CBCT-A images. Furthermore, these images can be used for intraoperative neuronavigation when integrated with widely used frameless stereotactic systems. The utility and outcome of the use of CBCT-A for preoperative planning and intraoperative localization of AVMs was evaluated. Methods A retrospective review was performed of 16 patients in which CBCT-A was performed, including radiological review and all clinical data. Results CBCT-A was successfully employed in all cases including those with (n=9) and without (n=7) rupture. Complete resection confirmed by postoperative angiography was achieved in all cases. Conclusions We present a novel application of CBCT-A in the treatment of AVMs, both for preoperative surgical planning and an intraoperative reference during neuronavigation.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "INTRODUCTION", "text": "Arteriovenous malformations (AVMs) of the brain are commonly treated in multimodality fashion, with endovascular embolization followed by surgical extirpation being one of the most effective strategies. Embolization can reduce blood loss and minimize complications associated with microsurgery for AVMs. Frameless stereotactic image guidance can also be used to make AVM resection safer. Image guidance has become standard in cranial neurosurgery, increasing the accuracy of craniotomy and allowing for smaller scalp incisions and bone flaps. Although image guidance for AVM surgery has been previously described in the literature, the optimal timing and imaging modality have not been established.", "cite_spans": [], "ref_spans": []}, {"section": "INTRODUCTION", "text": "The capabilities of modern angiographic platforms have recently improved substantially. Two-dimensional (2D) digital subtraction angiography (DSA) can now be enhanced by 3D, functional, and axial-anatomic adjunctive technologies. One such technology, rotational angiography, also known as cone-beam CT angiography (CBCT-A), uses the full capability of modern C-arm digital angiography systems available in neuroendovascular suites. An angiographic imaging study immediately prior to surgical resection can provide important information to a cerebrovascular surgeon. In this study we review a series of cases in which CBCT-A was performed preoperatively, either with or without an endovascular intervention, to assist in the image-guided surgical resection of cerebral AVMs. The use of CBCT-A has been tested in laboratory/cadaveric studies by other groups; 1 we report its use in a series of patients at two different institutions.", "cite_spans": [{"start": 857, "end": 858, "text": "1", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "METHODS", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Patient data", "text": "The objective of the study was to retrospectively review demographic, clinical, and imaging data for all patients who underwent surgical treatment of their AVM with the aid of intraoperative image guidance using preoperatively obtained CBCT-A. All such AVM resections done by the senior authors (EAMD, AA) from 2011 to 2014 were retrospectively reviewed. Electronic medical records, including clinic and hospital records, as well as relevant imaging were analyzed.", "cite_spans": [], "ref_spans": []}, {"section": "Cone-beam CT in the neurointerventional suite", "text": "Most neuroendovascular interventions are facilitated by single-plane or biplane C-arm systems. Classically, diagnosis and treatment of vascular anomalies has relied on 2D vascular imaging for visualization. Yet recent advancements have seen a transition from systems employing image-intensifier detectors to flat-panel detectors (FPD). [2] [3] [4] [5] [6] This transition has enabled rapid acquisition of 3D vascular images (3D DSA) as well as CBCT soft tissue imaging, with and without contrast agent present. 2 The acquisition procedure for a C-arm based volumetric scan is as follows: first, images are acquired during a semicircular rotation around the patient, with image acquisition performed at discrete intervals (150-600 images depending on the target). Next, contrast agent is injected and the same acquisition procedure is repeated. The images are processed for detector effects (offset and gain correction) and physical effects (scattered radiation and X-ray beam hardening), and reconstructed using a modification of the filtered back projection (FBP) algorithm. 5 Nonsubtracted images yield CT-like images, while subtraction of the two runs with subsequent reconstruction yields a high-quality representation of the vascular anatomy.", "cite_spans": [{"start": 336, "end": 339, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 340, "end": 343, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 344, "end": 347, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 348, "end": 351, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 352, "end": 355, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 511, "end": 512, "text": "2", "ref_id": "BIBREF1"}, {"start": 1076, "end": 1077, "text": "5", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "Navigation using volumetric data acquired in the interventional suite", "text": "The volumetric data acquired in the interventional suite were exported to the navigation system in the DICOM format using a 512\u00d7512\u00d7396 matrix size and a homogeneous voxel resolution of 0.47 mm. The data were loaded onto the navigation system (StealthStation S7, Medtronic, Minneapolis, Minnesota, USA) using either PACS transfer or manual upload. Additional patient data from preoperatively obtained MRI or CT scanning were imported as well in some cases. The different datasets were registered using rigid registration. Following patient positioning and immobilization using a Mayfield clamp, skin line tracing registration was performed using either DynaCT or Stealth-protocol CT registration models. Approach planning as well as navigation was performed using the datasets from all modalities and the surgeon preference for each modality was noted after the case (figure 1). The minimal voxel resolution yielded by the systems employed (Artis Zee Biplane, Siemens Healthcare, Forchheim, Germany) was 0.46 mm (homogenous voxel side length). Neither navigation nor initial data fusion in the navigation system was impeded.", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Patient clinical demographics", "text": "Our series included 16 patients with AVMs treated at Baylor College of Medicine and Semmes-Murphey Neurologic and Spine Institute (table 1) . Demographics, lesion characteristics, and treatment modalities are similar to modern published series of AVM management. 7 Regardless of whether or not the patients received preoperative endovascular treatment for their AVM, all patients underwent a diagnostic angiogram and DynaCT prior to neurosurgical intervention. This included the nine patients in our cohort who presented with rupture, who also required urgent neurocritical care and intracranial pressure management such as ventriculostomy placement. The embolic agent of choice in most cases was Onyx 18; n-butyl cyanoacrylate (n-BCA) was also used primarily or as an adjunct in some cases (table 1) .", "cite_spans": [{"start": 263, "end": 264, "text": "7", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "Devised workflow", "text": "Patients underwent either staged or immediate preoperative embolization of their lesions. At the end of the final endovascular procedure a CBCT-A was obtained. In non-emergency cases the cerebrovascular surgeon had the opportunity to evaluate and analyze these images in 3D, with custom reconstructions showing lesional angioarchitecture as well as areas of embolization. This is shown in a flowchart (figure 2).", "cite_spans": [], "ref_spans": []}, {"section": "Devised workflow", "text": "CBCT images were noted to have high spatial resolution and homogeneous sub-mm voxel size provided by the FPD-based C-arm system. With the systems used by the authors (Artis Zee Biplane and Artis Zeego, Siemens Medical Solutions), a dedicated scan protocol for neurosurgery yielded three volumes from one dual-spin CBCT acquisition with concurrent contrast agent injection: 3D-DSA, providing a high resolution image of the patient's vasculature, allowing delineation of the nidus and other critical structures for AVM treatment; a CT-like image (DynaCT) displaying the position of injected embolic agent with respect to the patient's anatomy; and a CT angiography (CTA)-like image giving information on the patient's vasculature and the injected embolic agent with respect to the patient's anatomy (DynaCTA) ( figure  3A-C) . In addition, this scan protocol allowed for an accurate representation of the patient's skin line for tracer-based registration on a stereotactic navigation system and focused on including the top of the head and tip of the nose to ease registration (figure 3D).", "cite_spans": [], "ref_spans": [{"start": 809, "end": 822, "text": "figure  3A-C)", "ref_id": "FIGREF1"}]}, {"section": "Devised workflow", "text": "Patients were transferred from the endovascular suite to the operating room and their heads were fixed in a radiolucent Mayfield head-holder. CBCT images were then loaded into the frameless neuronavigation system (Medtronic StealthStation S7). Registration was performed using the 'tracer' method and confirmed with anatomical landmarks. For planning of scalp incision and craniotomy flap, the Medtronic passive planar blunt probe was used. Thereafter, the operating microscope was integrated and used as the navigated instrument. In our series there were two strategies for using the images obtained in the angiography suite; one author used a standard Stealth protocol CT merged with the DynaCTA images (figure 4) while the other author used the DynaCTA images alone. There did not appear to be a difference between these strategies with regard to the quality of images or accuracy of navigation. Most frequently, the CTA-like images in three planes were used for surgical navigation, with the 3D view as an adjunct (figure 4). Indocyanine Green (ICG) video angiograms were used to confirm resection of the AVM prior to closure in most cases, and all cases had postoperative completion angiography to assess for completeness of resection (table 1) . Complete resection was confirmed by postoperative angiography. In two cases abnormal vasculature was identified on postoperative angiography. Perinidal hypervascularity is a common finding and must be distinguished from true AVM nidus both preoperatively and on postoperative angiography. We preoperatively did not intend to resect the areas identified on the postoperative angiograms, and our presumption is that these areas will normalize radiographically over time. No shunting was exhibited on any postoperative angiogram.", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "The modern treatment paradigm for many AVMs now entails a combination of preoperative embolization followed by neurosurgical excision, especially those with Spetzler-Martin grades 3 or B.", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "8 In our series of 16 patients with AVMs treated at two institutions, CBCT-A allowed for safe and accurate surgical extirpation following evaluation and treatment in the angiography suite.", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "AVMs can be assessed preoperatively and intraoperatively with a wide variety of imaging modalities including CT, CTA, AVMs, arteriovenous malformations; n-BCA, n-butyl cyanoacrylate. Figure 2 Workflow to incorporate three-dimensional (3D) angiographic imaging into a navigation system. Following catheter placement, high-quality 3D digital subtraction angiography (DSA) acquisition is performed capturing the head and the nose of the patient. The data acquired yield a soft cone-beam CT (CBCT) with opacified vasculature from fill acquisition, as well as a 3D DSA depicting the angioarchitecture. The data are transferred to the navigation system and vendor-specific image fusion to preoperative data is performed. The CBCT image is selected for skin line registration and navigation is commenced.", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "MRI, and DSA. Each of these modalities has drawbacks, including the time necessary to obtain them. MRI visualization of AVMs often shows a pattern of flow voids 9 and allows assessment of brain parenchyma and proximity to eloquent cortex. MRI yields comparatively little information about angioarchitecture and blood flow, but excels in gyral and sulcal definition and is the best modality for identification of potentially eloquent parenchymal structures. Furthermore, MRI can be timeconsuming and may misrepresent qualities of the nidus, 10 as artifact from dense embolisate such as Onyx or n-BCA can cause significant image degradation. CTA can provide high quality imaging of large vessels, but visualization of small intracranial vasculature and complex pathological anatomy (such as AVMs) remains challenging. This is due to comparably low spatial resolution (\u223c1 mm maximally), differentiation challenges near bony anatomy due to non-subtracted imaging, and the lack of vessel-selective imaging. 11 CTA also suffers from a lack of time resolution, making angiographic evaluation invaluable for a comprehensive understanding of the flow patterns that characterize many of the potential symptoms and complications associated with the natural history and treatment of AVMs.", "cite_spans": [{"start": 161, "end": 162, "text": "9", "ref_id": "BIBREF8"}, {"start": 540, "end": 542, "text": "10", "ref_id": "BIBREF9"}, {"start": 1002, "end": 1004, "text": "11", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "DISCUSSION", "text": "The combination of DSA and CBCT-A, on the other hand, uses the full capability of modern C-arm digital angiography systems. Such imaging provides crucial information on an AVM, its angioarchitecture and relationships to bone and surrounding brain structures, and has distinct advantages over the other imaging modalities. 12 13 Previous authors have described and compared the effectiveness of CBCT-A against DSA in assessing AVM dimension, arterial feeders, venous drainage, nidal density, and shunting; 14 all of this information is further provided in three dimensions instead of two. 15 Furthermore, CBCT-A overcomes the limitations of DSA with use in neuronavigation systems by acquisition of skin line tracings, allowing it to be used as a stand-alone reference image. 1 CBCT-A has also been shown to be useful in the assessment of AVMs following hemorrhage, especially when DSA does not sufficiently show the lesion. 12 Specifically, CBCT-A allows for accurate assessment of the AVM nidus for optimal treatment planning, whether during the preoperative neuroendovascular phase of treatment or during microsurgical intervention. [16] [17] [18] Our use of a low-dose contrast injection while simultaneously repeating the rotational scan allowed subtraction of the radially distributed projection images and subsequent reconstruction of a high-detail volumetric image of the patient's vasculature. This was useful during preoperative planning and intraoperatively. The CTA-like (CBCT-A) images which were reconstructed were loaded into the image guidance system allowed for real-time accounting of the progress of dissection.", "cite_spans": [{"start": 505, "end": 507, "text": "14", "ref_id": "BIBREF13"}, {"start": 588, "end": 590, "text": "15", "ref_id": "BIBREF14"}, {"start": 775, "end": 776, "text": "1", "ref_id": "BIBREF0"}, {"start": 924, "end": 926, "text": "12", "ref_id": "BIBREF11"}, {"start": 1135, "end": 1139, "text": "[16]", "ref_id": "BIBREF15"}, {"start": 1140, "end": 1144, "text": "[17]", "ref_id": "BIBREF16"}, {"start": 1145, "end": 1149, "text": "[18]", "ref_id": "BIBREF17"}], "ref_spans": []}, {"section": "DISCUSSION", "text": "It should be noted that the benefits of CBCT-A do not render traditional DSA obsolete nor supplant it as the gold standard. Instead, CBCT-A functions as an extremely useful adjunct that is most commonly acquired following DSA, offering its own unique strengths. MRI can be (and was) fused with CBCT-A images in our series and provided important contextual brain anatomy, especially for AVMs close to eloquent areas. Hybrid operating rooms have become popular in recent years, allowing both endovascular interventions and traditional neurosurgical procedures to occur without patient transfer, 19 often by the same comprehensive cerebrovascular surgeon. These rooms have the capability of rapid imaging and assessment of the lesion, as well as providing a sterile field for open surgical intervention. In the presented series, CBCT-A and interventions were performed in an endovascular suite separate from the operating room, but our experience with integration of DynaCTA images in neuronavigation suggests that this technology and strategy may be even more seamless in hybrid neurovascular suites. With the benefit of avoiding patient transfer, total operative times can be shortened. Furthermore, intraoperative DynaCTA images could be obtained to allow for updated navigation, to confirm excision, and upon closing to assess for a hematoma. In a hybrid suite, with maintained microsurgical exposure, post-resection confirmation of complete exclusion of the lesion could occur at a far higher resolution than traditional fluoroscopy-based methods. 15 20 The use of this technology and resulting workflow created several evident advantages. Intraoperative differentiation between embolized areas of the AVM and active areas seen via the microscope were confirmed on the DynaCTA navigation. Furthermore, in those cases treated soon after rupture, it enhanced identification of the lesion within the hematoma. Approach to the deep borders of the malformations was greatly aided, minimizing the need for excessive corticectomy. The extent of resection was probably improved with the aid of DynaCTA and could perhaps be further improved with its use in a hybrid neurovascular suite.", "cite_spans": [{"start": 593, "end": 595, "text": "19", "ref_id": "BIBREF18"}], "ref_spans": []}, {"section": "DISCUSSION", "text": "The care of cerebrovascular patients is becoming more integrated in terms of treatment strategies, location of care, and even providers. Potential areas for further development include better integration of the radiographic images and reconstructions with the microscope via more advanced heads-up displays. The enhancement of image quality by a variety of postprocessing techniques has progressed significantly in recent years and should continue. Examples include metallic artifact reduction and region of interest analysis, which can be combined to produce remarkably vivid images despite the presence of dense metal objects. [21] [22] [23] These emerging technologies available with Siemens and other angiography equipment can help visualize AVMs and differentiate residual lesion and embolisate. ", "cite_spans": [{"start": 629, "end": 633, "text": "[21]", "ref_id": "BIBREF20"}, {"start": 634, "end": 638, "text": "[22]", "ref_id": "BIBREF21"}, {"start": 639, "end": 643, "text": "[23]", "ref_id": "BIBREF22"}], "ref_spans": []}, {"section": "Limitations", "text": "There are notable limitations to CBCT-A, but it is not intended to supersede the gold standard, conventional angiography. Other imaging modalities such as MRI provide anatomical context, and are synergistic with CBCT-A through fusion of DICOM images in neuronavigation systems. Most of the AVMs in our series were fed from a single circulation, especially after embolization, and the CBCT-A images were created by injection within a single vessel. Vascular malformations fed by both anterior and posterior circulations, internal and external branches, or bilateral feeding require special consideration. We are currently working with an angiography platform manufacturer on rotational angiography fusion techniques to allow for improved visualization of multiple circulations and radiodense embolic agents using color differentiation. Fusion and post-processing may thus obviate the need for dual catheter injections which increase the risk, complexity, and time of an angiographic procedure.", "cite_spans": [], "ref_spans": []}, {"section": "Limitations", "text": "Nidus that is distal to embolized arteries may be incompletely visualized by CBCT-A following embolization because contrast will not flow into it. MRI is a useful modality for identifying residual nidus in these cases, and was used as an adjunct in most of our cases. Many cases were also imaged intraoperatively with indocyanine videoangiography, which can identify areas of the surgical bed that may deserve closer inspection to rule out the presence of residual nidus. ICG was used in most cases, based on the intraoperative specifics of each surgery. There are welldescribed limitations of ICG videoangiography in AVM surgery, [24] [25] [26] but it can still serve as a useful adjunct-for example, to ensure complete obliteration of feeding to a nidus prior to dividing the main draining vein. One of the most important pitfalls that should be noted, however, is the difficulty in seeing beyond dissected parenchyma to identify residual nidus. Large residuals will illuminate through thin layers of parenchyma but small residuals may very well not be identified. Intraoperative angiography in a proper suite is valuable, a point that should be acknowledged, but is not routinely necessary and carries some risk. Intraoperative DSA, possibly with CBCT-A, in a hybrid operating room may represent the ideal solution in the future.", "cite_spans": [{"start": 631, "end": 635, "text": "[24]", "ref_id": "BIBREF23"}, {"start": 636, "end": 640, "text": "[25]", "ref_id": "BIBREF24"}, {"start": 641, "end": 645, "text": "[26]", "ref_id": "BIBREF25"}], "ref_spans": []}, {"section": "CONCLUSION", "text": "We present a novel application of CBCT-A in the treatment of AVMs, both for preoperative surgical planning and an intraoperative reference during neuronavigation. The additional resolution of AVM angioarchitecture provided by this imaging as well as the efficient workflow inherent in the technology hold promise for further and better integration of the traditional dichotomy ('open' and 'endovascular') in cerebrovascular treatments. Funding This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Frameless neuronavigation based only on 3D digital subtraction angiography using surface-based facial registration", "authors": [{"first": "D", "middle": ["A"], "last": "Stidd", "suffix": ""}, {"first": "J", "middle": [], "last": "Wewel", "suffix": ""}, {"first": "A", "middle": ["J"], "last": "Ghods", "suffix": ""}], "year": 2014, "venue": "J Neurosurg", "link": "46570325"}, "BIBREF1": {"title": "Three-dimensional C-arm cone-beam CT: applications in the interventional suite", "authors": [{"first": "M", "middle": ["J"], "last": "Wallace", "suffix": ""}, {"first": "M", "middle": ["D"], "last": "Kuo", "suffix": ""}, {"first": "C", "middle": [], "last": "Glaiberman", "suffix": ""}], "year": 2008, "venue": "J Vasc Interv Radiol", "link": "33391199"}, "BIBREF2": {"title": "Flat-detector computed tomography (FD-CT)", "authors": [{"first": "W", "middle": ["A"], "last": "Kalender", "suffix": ""}, {"first": "Y", "middle": [], "last": "Kyriakou", "suffix": ""}], "year": 2007, "venue": "Eur Radiol", "link": "23443558"}, "BIBREF3": {"title": "Flat panel detector angiographic CT for stent-assisted coil embolization of broad-based cerebral aneurysms", "authors": [{"first": "G", "middle": [], "last": "Richter", "suffix": ""}, {"first": "T", "middle": [], "last": "Engelhorn", "suffix": ""}, {"first": "T", "middle": [], "last": "Struffert", "suffix": ""}], "year": 2007, "venue": "AJNR Am J Neuroradiol", "link": "14908630"}, "BIBREF4": {"title": "Enhanced 3-D-reconstruction algorithm for C-arm systems suitable for interventional procedures", "authors": [{"first": "K", "middle": [], "last": "Wiesent", "suffix": ""}, {"first": "K", "middle": [], "last": "Barth", "suffix": ""}, {"first": "N", "middle": [], "last": "Navab", "suffix": ""}], "year": 2000, "venue": "IEEE Trans Med Imaging", "link": "15891539"}, "BIBREF5": {"title": "C-arm cone-beam CT: general principles and technical considerations for use in interventional radiology", "authors": [{"first": "R", "middle": ["C"], "last": "Orth", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Wallace", "suffix": ""}, {"first": "M", "middle": ["D"], "last": "Kuo", "suffix": ""}], "year": 2008, "venue": "J Vasc Interv Radiol", "link": "3324612"}, "BIBREF6": {"title": "Comparative effectiveness of treatments for cerebral arteriovenous malformations: trends in nationwide outcomes from", "authors": [{"first": "J", "middle": ["M"], "last": "Davies", "suffix": ""}, {"first": "V", "middle": [], "last": "Yanamadala", "suffix": ""}, {"first": "M", "middle": ["T"], "last": "Lawton", "suffix": ""}], "year": 2000, "venue": "Neurosurg Focus", "link": "2122719"}, "BIBREF7": {"title": "Multimodality management of SpetzlerMartin Grade III arteriovenous malformations", "authors": [{"first": "P", "middle": [], "last": "Pandey", "suffix": ""}, {"first": "M", "middle": ["P"], "last": "Marks", "suffix": ""}, {"first": "C", "middle": ["D"], "last": "Harraher", "suffix": ""}], "year": 2012, "venue": "J Neurosurg", "link": "22567135"}, "BIBREF8": {"title": "Osborn's brain: imaging, pathology, and anatomy. 1st edn", "authors": [{"first": "A", "middle": ["G"], "last": "Osborn", "suffix": ""}], "year": 2013, "venue": "", "link": null}, "BIBREF9": {"title": "Can magnetic resonance imaging alone accurately define the arteriovenous nidus for gamma knife radiosurgery?", "authors": [{"first": "E", "middle": ["J"], "last": "St George", "suffix": ""}, {"first": "P", "middle": [], "last": "Butler", "suffix": ""}, {"first": "P", "middle": ["N"], "last": "Plowman", "suffix": ""}], "year": 2002, "venue": "J Neurosurg", "link": "208198644"}, "BIBREF10": {"title": "CT angiography: current technology and clinical use", "authors": [{"first": "K", "middle": ["K"], "last": "Kumamaru", "suffix": ""}, {"first": "B", "middle": ["E"], "last": "Hoppel", "suffix": ""}, {"first": "R", "middle": ["T"], "last": "Mather", "suffix": ""}], "year": 2010, "venue": "Radiol Clin North Am", "link": "34668603"}, "BIBREF11": {"title": "Benefit of cone-beam computed tomography angiography in acute management of angiographically undetectable ruptured arteriovenous malformations", "authors": [{"first": "J", "middle": ["P"], "last": "Rahal", "suffix": ""}, {"first": "A", "middle": ["M"], "last": "Malek", "suffix": ""}], "year": 2013, "venue": "J Neurosurg", "link": "32951283"}, "BIBREF12": {"title": "Use of Dyna-CT angiography in neuroendovascular decision-making. A case report", "authors": [{"first": "K", "middle": [], "last": "Namba", "suffix": ""}, {"first": "Y", "middle": [], "last": "Niimi", "suffix": ""}, {"first": "J", "middle": ["K"], "last": "Song", "suffix": ""}], "year": 2009, "venue": "Interv Neuroradiol", "link": null}, "BIBREF13": {"title": "Three-dimensional rotational angiography in the assessment of the angioarchitecture of brain arteriovenous malformations", "authors": [{"first": "X", "middle": [], "last": "Combaz", "suffix": ""}, {"first": "O", "middle": [], "last": "Levrier", "suffix": ""}, {"first": "J", "middle": [], "last": "Moritz", "suffix": ""}], "year": 2011, "venue": "J Neuroradiol", "link": "32571161"}, "BIBREF14": {"title": "Intraoperative biplanar rotational angiography during neurovascular surgery. Technical note", "authors": [{"first": "A", "middle": ["R"], "last": "Dehdashti", "suffix": ""}, {"first": "L", "middle": [], "last": "Thines", "suffix": ""}, {"first": "Da", "middle": [], "last": "Costa", "suffix": ""}, {"first": "L", "middle": ["B"], "last": "", "suffix": ""}], "year": 2009, "venue": "J Neurosurg", "link": null}, "BIBREF15": {"title": "Use of CT angiography for anatomic localization of arteriovenous malformation nidal components", "authors": [{"first": "V", "middle": [], "last": "Gupta", "suffix": ""}, {"first": "M", "middle": [], "last": "Chugh", "suffix": ""}, {"first": "B", "middle": ["S"], "last": "Walia", "suffix": ""}], "year": 2008, "venue": "AJNR Am J Neuroradiol", "link": "10093524"}, "BIBREF16": {"title": "Utilization of cone-beam computed tomographic angiography in planning for gamma knife radiosurgery of arteriovenous malformations: a case series and early report", "authors": [{"first": "M", "middle": ["G"], "last": "Safain", "suffix": ""}, {"first": "J", "middle": ["P"], "last": "Rahal", "suffix": ""}, {"first": "A", "middle": [], "last": "Raval", "suffix": ""}], "year": 2014, "venue": "Neurosurgery", "link": null}, "BIBREF17": {"title": "Volumetric analysis of intracranial arteriovenous malformations contoured for CyberKnife radiosurgery with 3-dimensional rotational angiography vs computed tomography/magnetic resonance imaging", "authors": [{"first": "A", "middle": [], "last": "Veeravagu", "suffix": ""}, {"first": "A", "middle": [], "last": "Hansasuta", "suffix": ""}, {"first": "B", "middle": [], "last": "Jiang", "suffix": ""}], "year": 2013, "venue": "Neurosurgery", "link": "11697423"}, "BIBREF18": {"title": "Intraoperative angiography reloaded: a new hybrid operating theater for combined endovascular and surgical treatment of cerebral arteriovenous malformations: a pilot study on 25 patients", "authors": [{"first": "M", "middle": [], "last": "Kotowski", "suffix": ""}, {"first": "A", "middle": [], "last": "Sarrafzadeh", "suffix": ""}, {"first": "B", "middle": [], "last": "Schatlo", "suffix": ""}], "year": 2013, "venue": "Acta Neurochir (Wien)", "link": "19501370"}, "BIBREF19": {"title": "Intraoperative angiography during microsurgical removal of arteriovenous malformations in children", "authors": [{"first": "M", "middle": ["J"], "last": "Ellis", "suffix": ""}, {"first": "A", "middle": ["V"], "last": "Kulkarni", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Drake", "suffix": ""}], "year": 2010, "venue": "J Neurosurg Pediatr", "link": "6161354"}, "BIBREF20": {"title": "Refining a region-of-interest within an available CT image", "authors": [{"first": "E", "middle": [], "last": "Enjilela", "suffix": ""}, {"first": "E", "middle": ["M"], "last": "Hussein", "suffix": ""}], "year": 2013, "venue": "Appl Radiat Isot", "link": "39993048"}, "BIBREF21": {"title": "Separating the wheat from the chaff: completion angiography following complex aneurysm repair using low-dose volume of interest plus metal artifact reduction imaging", "authors": [{"first": "E", "middle": ["A"], "last": "Duckworth", "suffix": ""}, {"first": "D", "middle": [], "last": "Hoit", "suffix": ""}, {"first": "L", "middle": [], "last": "Elijovich", "suffix": ""}], "year": 2014, "venue": "J NeuroIntervent Surg", "link": "75612915"}, "BIBREF22": {"title": "Improving image accuracy of region-of-interest in cone-beam CT using prior image", "authors": [{"first": "J", "middle": [], "last": "Lee", "suffix": ""}, {"first": "J", "middle": ["S"], "last": "Kim", "suffix": ""}, {"first": "S", "middle": [], "last": "Cho", "suffix": ""}], "year": 2014, "venue": "J Appl Clin Med Phys", "link": "4548519"}, "BIBREF23": {"title": "Intra operative indocyanine green video-angiography in cerebrovascular surgery: an overview with review of literature", "authors": [{"first": "S", "middle": [], "last": "Balamurugan", "suffix": ""}, {"first": "A", "middle": [], "last": "Agrawal", "suffix": ""}, {"first": "Y", "middle": [], "last": "Kato", "suffix": ""}], "year": 2011, "venue": "Asian J Neurosurg", "link": "23117825"}, "BIBREF24": {"title": "Evaluation of serial intraoperative surgical microscope-integrated intraoperative near-infrared indocyanine green videoangiography in patients with cerebral arteriovenous malformations", "authors": [{"first": "Y", "middle": [], "last": "Takagi", "suffix": ""}, {"first": "K", "middle": [], "last": "Sawamura", "suffix": ""}, {"first": "N", "middle": [], "last": "Hashimoto", "suffix": ""}], "year": 2012, "venue": "Neurosurgery", "link": "29612041"}, "BIBREF25": {"title": "Uses and limitations of indocyanine green videoangiography for flow analysis in arteriovenous malformation surgery", "authors": [{"first": "Y", "middle": ["P"], "last": "Ng", "suffix": ""}, {"first": "N", "middle": ["K"], "last": "King", "suffix": ""}, {"first": "K", "middle": ["R"], "last": "Wan", "suffix": ""}], "year": 2013, "venue": "J Clin Neurosci", "link": "27698339"}}, "ref_entries": {"FIGREF0": {"text": "Figure 1 (A) StealthStation navigation pane as used in preoperative planning. The views are dynamically customizable and allow for different views to be viewed in different phases of the surgical process. The use of the three-dimensional scalp view allows for incision planning, while the views in (B) are best for craniotomy planning. (B) Intraoperative navigation pane presented to the surgeon. The cross-sectional slice views (left top/ bottom) allow navigation through the complex vasculature with respect to the patient's anatomy and the trajectory views (right top/bottom) allow visualization of the anatomy traversed during dissection.", "type": "figure"}, "FIGREF1": {"text": "Figure 3 Datasets reconstructed from a single cone-beam CT acquisition procedure. (A) Three-dimensional digital subtraction angiography (DSA) of patient's vascular anatomy. The data have been acquired post-embolization of the arteriovenous malformation feeding vessels (the vasculature is displayed in red while the injected agent is displayed in gray). (B) DynaCT after injection of embolic agent. The maximum intensity projection (MIP) display (5.0 mm thickness) allows for delineation of the shape of the injected agent. (C) DynaCTA (CT angiography) after injection of embolic agent. The patient's vasculature with respect to the anatomy is well visualized. (D) Skin line representation of acquired DynaCT required for tracer-based patient registration in navigation system.", "type": "figure"}, "FIGREF2": {"text": "Figure 4 Examples of (A) MRI and (B) DynaCT with three-dimensional reconstruction for intraoperative navigation. Here, orthogonal views are presented (axial, coronal, sagittal), but trajectory views are most useful. Due to various artifacts, MRI has poor resolution of the angioanatomy. Compared with the traditional angiogram, DynaCT offers additional resolution of soft tissue and bony anatomy.", "type": "figure"}, "FIGREF3": {"text": "Study design: AA, EAMD. Data collection, composition of manuscript: VMS, SS. Data review, statistical analysis: VMS. Editing: all authors. Approval of manuscript: all authors. Ethics approval Ethics approval was obtained from the hospital IRB.", "type": "figure"}, "TABREF0": {"text": "", "type": "table"}, "TABREF1": {"text": "-Murphey Neurologic and Spine Institute", "type": "table"}}}
{"paper_id": "2877363", "_pdf_hash": "fdefca5b71eedf9d8580ed3e03a592478b2515d5", "abstract": [{"section": "Abstract", "text": "Linker length and composition were varied in libraries of single-chain Arc repressor, resulting in proteins with effective concentrations ranging over six orders of magnitude (10 M-10 M). Linkers of 11 residues or more were required for biological activity. Equilibrium stability varied substantially with linker length, reaching a maximum for glycine-rich linkers containing 19 residues. The effects of linker length on equilibrium stability arise from significant and sometimes opposing changes in folding and unfolding kinetics. By fixing the linker length at 19 residues and varying the ratio of Ala\u035eGly or Ser\u035eGly in a 16-residue-randomized region, the effects of linker f lexibility were examined. In these libraries, composition rather than sequence appears to determine stability. Maximum stability in the Ala\u035eGly library was observed for a protein containing 11 alanines and five glycines in the randomized region of the linker. In the Ser\u035eGly library, the most stable protein had seven serines and nine glycines in this region. Analysis of folding and unfolding rates suggests that alanine acts largely by accelerating folding, whereas serine acts predominantly to slow unfolding. These results demonstrate an important role for linker design in determining the stability and folding kinetics of single-chain proteins and suggest strategies for optimizing these parameters.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "The construction of single-chain or hybrid proteins is a potentially powerful method for generating proteins with novel functions and improved properties (1-11). A critical element in such efforts is the design of the peptide linkers that serve to connect different protein domains or subunits. Designed linkers are usually glycine-based peptides with lengths calculated to span the minimum distance between the C terminus of one subunit or domain and the N terminus of the next. How important is linker design in determining the properties of single-chain proteins? Alterations in linker regions have been found to affect the stability, oligomeric state, proteolytic resistance, and solubility of single-chain proteins (12-23), but few systematic investigations of these relationships have been reported. Here, we test the effects of linker design on the stability, protein folding kinetics, and biological activity of single-chain Arc repressor. Wild-type Arc is a dimer with identical subunits, and Arc-L1-Arc is a single-chain variant with a 15-residue linker connecting the subunits (see Fig. 1 ). The L1 linker of Arc-L1-Arc holds the subunits at an effective concentration (C eff ) of 3 mM. By varying linker length and composition, we have isolated single-chain variants with effective subunit concentrations ranging from 10 M to 10 M, corresponding to changes in the free energy of unfolding (\u232cG u ) from 3 to 11 kcal\u035emol. These differences in stability arise from changes in the folding and unfolding rates, suggesting that linker design can affect protein stability by altering the free energies of both the native and denatured states.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "", "text": "The construction of single-chain or hybrid proteins is a potentially powerful method for generating proteins with novel functions and improved properties (1) (2) (3) (4) (5) (6) (7) (8) (9) (10) (11) . A critical element in such efforts is the design of the peptide linkers that serve to connect different protein domains or subunits. Designed linkers are usually glycine-based peptides with lengths calculated to span the minimum distance between the C terminus of one subunit or domain and the N terminus of the next. How important is linker design in determining the properties of single-chain proteins? Alterations in linker regions have been found to affect the stability, oligomeric state, proteolytic resistance, and solubility of single-chain proteins (12) (13) (14) (15) (16) (17) (18) (19) (20) (21) (22) (23) , but few systematic investigations of these relationships have been reported. Here, we test the effects of linker design on the stability, protein folding kinetics, and biological activity of single-chain Arc repressor. Wild-type Arc is a dimer with identical subunits, and Arc-L1-Arc is a single-chain variant with a 15-residue linker connecting the subunits (see Fig. 1 ). The L1 linker of Arc-L1-Arc holds the subunits at an effective concentration (C eff ) of 3 mM. By varying linker length and composition, we have isolated single-chain variants with effective subunit concentrations ranging from 10 M to 10 M, corresponding to changes in the free energy of unfolding (\u232cG u ) from 3 to 11 kcal\u035emol. These differences in stability arise from changes in the folding and unfolding rates, suggesting that linker design can affect protein stability by altering the free energies of both the native and denatured states.", "cite_spans": [], "ref_spans": []}, {"section": "MATERIALS AND METHODS", "text": "Cassettes coding for glycine-rich linkers ranging from 3 to 59 residues ( Fig. 3A) were synthesized using an Applied Biosystems 381A DNA synthesizer and were purified as described (9) . A precursor plasmid (pLA3), constructed to facilitate subcloning of linker library cassettes, contains tandem arc genes connected by a GGT ACC GGT adapter, which encodes Gly-Thr-Gly and contains unique KpnI and AgeI restriction sites. Cassette libraries coding for 19-residue linkers with different amounts of Gly or Ala were constructed by synthesizing an oligonucleotide, which formed a hairpin:", "cite_spans": [], "ref_spans": [{"start": 74, "end": 82, "text": "Fig. 3A)", "ref_id": "FIGREF1"}]}, {"section": "MATERIALS AND METHODS", "text": "The underlined sequences are KpnI sites. S represents a mixture of G and C, and thus, the GSA codons encode either glycine (GGA) or alanine (GCA). Three otherwise identical oligonucleotides with different G\u035eC ratios at the randomized positions (1:1; 3:1; 1:3) were synthesized to facilitate identification of a wide range of compositions. A cassette library encoding random combinations of glycine (GGT) and serine (AGT) was constructed in the same manner. Second strand synthesis was carried out using Sequenase v.2.0 (United States Biochemical) for 2 h at 37\u00b0C in Sequenase buffer containing 1 mM dNTPs. Cassettes were digested with KpnI and ligated to the KpnI backbone of pLA3. Following transformation into Escherichia coli strain HB101, colonies were picked randomly and the appropriate region of the single-chain arc gene was sequenced using the dideoxy method. Plasmid DNA encoding in-frame constructs were transformed into E. coli strain UA2F for assays of activity in vivo (24) and into E. coli X90-O cells for protein expression. All single-chain Arc proteins contained a (His) 6 tail to facilitate purification using Ni-nitrilotriacetic acid chromatography. Protein purification, fluorescence and circular dichroism (CD) spectroscopy, analytical ultracentrifugation, and gel mobility-shift assays were performed as described (9, 25) . Protein stability was assayed by urea denaturation by following changes in intrinsic tryptophan fluorescence intensity at 337 nm or CD ellipticity at 234 nm. For these experiments, the protein concentration was 10 M in buffer containing 50 mM Tris\u2150HCl (pH 7.5 at 25\u00b0C), 250 mM KCl, and 0.1 mM EDTA (26) . Values of \u232cG u and m were obtained by fitting denaturation data to a two-state model by nonlinear least squares methods (26 (26) . Stopped-flow kinetic experiments of protein folding and unfolding were monitored by changes in fluorescence at protein concentrations between 1 and 10 M in the buffer used for stability measurements (26) . Unfolding was initiated by urea-jump experiments (mixing ratio 1:10) to yield a final urea concentration of 7 or 9.1 M. Refolding was initiated by mixing protein denatured in 6.0-9.6 M urea with low urea buffer (1:5 ratio) to yield final urea concentrations between 1.0 and 4.5 M. Rate constants were obtained by fitting the kinetic data to single exponentials. In all cases, the residuals of the fits were distributed randomly. For ease of comparison among each library of variants, rates were either measured at a single urea concentration or measured at a series of urea concentrations and extrapolated to this reference concentration by using linear regression of ln(k) vs.", "cite_spans": [{"start": 983, "end": 987, "text": "(24)", "ref_id": "BIBREF24"}], "ref_spans": []}, {"section": "MATERIALS AND METHODS", "text": "[urea] plots (R \u03fe 0.99).", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Variation of Linker Length.", "text": "A library of single-chain arc genes with linkers composed of Gly, Ser, and Thr and lengths varying from 3 to 59 aa was constructed (Fig. 3A) . The fraction of Gly in different linkers ranges from 66 to 80%. The linkers and corresponding proteins are named LLX and Arc-LLX-Arc (Length Library, X \u03ed number of residues), respectively. No intracellular expression of the Arc-LL8-Arc protein was detected. Arc-LL3-Arc expressed to high levels but monomers, dimers, and higher-order oligomers were observed following SDS electrophoresis and Western analysis. This behavior may indicate ''cross-folding'' as has been observed with single-chain antibodies that have very short linkers (27, 28) . The remaining 13 proteins in this library were all expressed at high levels and electrophoresed as monomers. The Arc-LLX-Arc variants were tested for repression of transcription of the P ant promoter in E. coli strain UA2F, using resistance to streptomycin as an assay of biological activity (24) . Arc-LLX-Arc proteins with linkers containing 13 or more residues had wild-type activities. Arc-LL11-Arc was partially active; single-chain molecules with the LL3, LL8, and LL9 linkers were inactive. Modeling studies show that connecting the Arc subunits with linkers shorter than 13 residues would either require the linker to cross the DNA-binding surface of the protein and\u035eor require distortion of the structure.", "cite_spans": [{"start": 980, "end": 984, "text": "(24)", "ref_id": "BIBREF24"}], "ref_spans": [{"start": 131, "end": 140, "text": "(Fig. 3A)", "ref_id": "FIGREF1"}]}, {"section": "Variation of Linker Length.", "text": "Single-chain Arcs with linkers LL9-LL59 were purified for biophysical characterization. All of these single-chain proteins had CD and fluorescence spectra similar to wild-type Arc. Arc-LL11-Arc, Arc-LL19-Arc, and Arc-LL31-Arc were analyzed by analytical ultracentrifugation and found to be monomeric at concentrations between 10 and 100 M (data not shown). Proteins containing the three longest linkers (LL47, LL51, and LL59) tended to precipitate at concentrations \u03fe100 M, possibly because of aggregation caused by cross-folding of the Arc subunits.", "cite_spans": [], "ref_spans": []}, {"section": "Variation of Linker Length.", "text": "The thermodynamic stabilities of Arc-LLX-Arc proteins with linkers from 9 to 57 residues were determined by urea denaturation studies, revealing that the 19-residue linker provides maximal stability. As shown in Fig. 2 for a subset of these proteins, there are large changes in the concentration of urea required for denaturation of proteins with different linker lengths, but the curves are roughly parallel indicating that the denaturant m-values (variation of \u232cG u with urea) are similar. Fig. 3B shows the variations of \u232cG u and C eff with linker length. For linkers from 9 to 19 residues, stability of the single-chain protein increased with length. Arc-L9-Arc was the least stable (\u232cG u \u03f7 3 kcal\u035emol; C eff \u03f7 6 M) and Arc-LL19-Arc was the most stable (\u232cG u \u03ed 8.4 kcal\u035emol; C eff \u03ed 80 mM) of the proteins examined. Increases in linker length past 19 residues resulted in decreasing stability until a plateau was reached at \u03f74.5 kcal\u035emol (C eff \u03f7 150 M) for linkers between 47 and 59 residues.", "cite_spans": [], "ref_spans": [{"start": 492, "end": 499, "text": "Fig. 3B", "ref_id": "FIGREF1"}]}, {"section": "Variation of Linker Length.", "text": "The linker-dependent changes in stability arise from changes in both the folding and unfolding rates, as measured in urea-jump, stopped-flow, kinetic experiments. Fig. 3 C and D show that both the folding and unfolding rate constants vary significantly as the linker length is changed. In 7 M urea, Arc-LL9-Arc unfolds with a rate constant (k u ) of \u03f73,000 s for the Arc-LL13-Arc protein. Decreasing the linker by four residues to a length of nine causes a 30-fold decrease in the folding rate. As the linker length is increased from 13 to 47 residues, the refolding rate also decreases. Over this range, there is a roughly exponential decrease in k f that spans nearly four orders of magnitude. Little change in k f is seen for linkers between 47 and 59 residues. These results show that linker length can have large effects on the free energy difference between the denatured state and the transition state. Moreover, the length optima for equilibrium stability (19 residues), refolding (13 residues), and unfolding (19-59 residues) are different. The 19-residue linker provides the greatest equilibrium stability because it is the best compromise between reasonably fast refolding and slow unfolding.", "cite_spans": [], "ref_spans": [{"start": 163, "end": 169, "text": "Fig. 3", "ref_id": "FIGREF1"}]}, {"section": "Variation of Linker Length.", "text": "Effects of Linker Composition. To asses the effects of varying the number of glycines in the linker, the length of the linker was fixed at 19 residues and 16 internal positions were randomized between Ala and Gly (ALX library) or between Ser and Gly (SLX library) by using the strategy described in Materials and Methods. For these experiments, the libraries were first selected for Arc repressor activity in vivo and then the sequences of individual members were determined. Sixteen proteins comprise the ALX library; the linkers in these proteins contain from 3 to 15 alanines (Fig. 4A) . Ten proteins, with 3-11 serines in the linker region, comprise the SLX library (Fig. 5A) . All of the Arc-ALX-Arc and Arc-SLX-Arc proteins were expressed at high levels, were purified, and had CD and fluorescence spectra similar to wild-type Arc. In the ALX library, variants with eight or more linker alanines showed some tendency to aggregate during purification and handling but were monomeric at concentrations of 1-20 M as judged by analytical ultracentrifugation and the concentration independence of equilibrium stability and refolding rates. All other proteins in the ALX and SLX libraries were highly soluble.", "cite_spans": [], "ref_spans": [{"start": 579, "end": 588, "text": "(Fig. 4A)", "ref_id": "FIGREF2"}]}, {"section": "Variation of Linker Length.", "text": "The number of non-glycine residues in the 19-residue linker has a significant effect on the equilibrium stability of proteins in both the ALX and SLX libraries, as determined by urea denaturation. In the ALX library (Fig. 4 A and B) , Arc-AL11-Arc, which contains 11 alanines and 5 glycines in the randomized portion of the linker, has the maximum stability (\u232cG u \u03f7 11 kcal\u035emol; C eff \u03f7 8 M). Arc-AL3-Arc, with 3 alanines and 13 glycines in the randomized region of the linker, is far less stable (\u232cG u \u03f7 3 kcal\u035emol; C eff \u03f7 10 M), suggesting that too much linker flexibility is detrimental to stability. Fig. 4B shows, however, that stability also decreases when the number of alanines is increased past the optimum value of 11, indicating that linkers that are too inflexible also limit protein stability. The same general trends are observed in the SLX library; proteins with too many or too few glycines are significantly less stable than Arc-SL7-Arc (\u232cG u \u03f7 7 kcal\u035emol; C eff \u03f7 7 mM). There are, however, two significant differences between the ALX and SLX results. Maximum stability occurs for a protein containing eight glycines in the randomized portion of the linker in the SLX library but for a protein containing only five glycines in this region in the ALX library. Moreover, the stabilities of the most stable variants in each library also differ significantly; Arc-AL11-Arc has an effective concentration that is 1,000-fold greater than Arc-SL7-Arc. We interpret these differences as indicating that the identity of the non-glycine residues in the linker is as important as the number of these residues in determining stability. By contrast, the positions of the glycine and non-glycine residues in the randomized portion of the linker seem to be unimportant. Five pairs of variants in the ALX library and three pairs in the SLX library have the same composition but difference sequences. In each of these cases, the stabilities of these variants (indicated by open and closed symbols in Figs. 4B and 5B) were found to be within experimental error.", "cite_spans": [], "ref_spans": [{"start": 216, "end": 232, "text": "(Fig. 4 A and B)", "ref_id": "FIGREF2"}, {"start": 605, "end": 612, "text": "Fig. 4B", "ref_id": "FIGREF2"}, {"start": 2002, "end": 2010, "text": "Figs. 4B", "ref_id": "FIGREF2"}]}, {"section": "Variation of Linker Length.", "text": "Another significant difference between the ALX and SLX libraries is observed in the unfolding kinetics (Figs. 4D and  5D) . In the ALX library, the unfolding rate of different variants only changes by a factor of 20. In the SLX library, the unfolding rates change by \u03fe1,000-fold. In addition, the shapes of these plots are very different. The ALX data is concave upward with minimum occurring for the protein with seven alanines and eight glycines in the randomized portion of the linker. In the SLX library, by contrast, k u decrease exponentially with the number of serines. The rate constants for refolding in the ALX library change by more than five orders of magnitude, reaching a maximum for variants with 11 or 12 alanines in the randomized part of the linker (Fig. 5C ). Because changes in the unfolding rate are small for the ALX proteins, the changes in equilibrium stability arise almost exclusively from changes in the refolding rate. In the SLX library, variants differ over a 300-fold range in refolding rates with a maximum between four and seven serines. Because ", "cite_spans": [], "ref_spans": [{"start": 103, "end": 121, "text": "(Figs. 4D and  5D)", "ref_id": "FIGREF2"}]}, {"section": "5932", "text": "Colloquium Paper: Robinson and Sauer Proc. Natl. Acad. Sci. USA 95 (1998) much larger changes are seen in the unfolding rates, the changes in equilibrium stability for the SLX proteins are dominated by the changes in unfolding kinetics. These results emphasize once again that the chemical identity of the nonglycine residues in the linker can have a profound effect on the biophysical properties of the single-chain proteins.", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "Linker length and composition exert a surprisingly large influence on the stability of single-chain Arc repressor. In the LLX linker length library, the most stable protein has a linker of 19 residues, and adding or deleting a few amino acids decreases stability (Fig. 3B) . These length effects on stability arise from changes in the folding and unfolding rates. In the regime from 59 to 13 residues, shortening the linker accelerates folding. This observation is explained most simply if the denatured subunit domains are constrained to smaller and smaller regions of conformation space by shorter linkers and thus require less random sampling before essential collisions required for folding occur. We note, however, that the length dependence of the stability of single-chain Arc variants in this regime is significantly steeper than for loop-length variants of single-chain Rop (29) and is modeled poorly by simple, random walk, entropic considerations (30) . As the linker length decreases from 13 to 11 to 9 residues, there is a decrease in the folding rate of the corresponding Arc-LLX-Arc protein. At some point, the linkers must become too short to connect the subunits in the native conformation without strain. In fact, in the linker length regime from 19 to 9 residues, the unfolding rates of the corresponding Arc-LLX-Arc proteins increases exponentially as the linkers become shorter, suggesting that shorter tethers in this length range introduce more and more strain into the native structure. Presumably, proteins with the LL17, LL15, and LL13 linkers do not show decreased folding rates because of compensating changes in conformational search efficiency. Glycine is generally used in designed linkers because the absence of a \u2424-carbon permits the polypeptide backbone to access dihedral angles that are energetically forbidden for other amino acids (31) . Thus, a glycine-rich linker will be more flexible than a linker of comparable length composed of non-glycine residues. Our results, however, indicate that too much linker flexibility is detrimental to single-chain protein stability. In the ALX (alanine\u035eglycine) library, maximum stability was observed when the 16-residue-randomized region contained 11 alanines and 5 glycines. In the SLX (serine\u035e glycine) library, the most stable protein had seven serines and nine glycines in the randomized portion of the linker. In both libraries, plots of stability vs, the number of non-glycine residues are relatively regular and proteins with the same linker compositions have comparable stabilities (Figs. 4B and 5B). Both observations suggest that it is the composition rather than the sequence of the linker that is important in determining stability. A single exception to this generalization is provided by Arc-LL19-Arc and Arc-SL3-Arc, which have the same composition but stabilities differing by 3.4 kcal\u035emol. The first three residues of the linker are Gly-Thr-Ser in Arc-SL3-Arc, which has lower stability, and Gly-Gly-Gly in Arc-LL19-Arc, suggesting that the conformational flexibility imparted by glycine may be important at the junction between C terminus of the first subunit and the N terminus of the linker.", "cite_spans": [], "ref_spans": [{"start": 263, "end": 272, "text": "(Fig. 3B)", "ref_id": "FIGREF1"}, {"start": 2568, "end": 2577, "text": "(Figs. 4B", "ref_id": "FIGREF2"}]}, {"section": "DISCUSSION", "text": "In the ALX library, the main effects of alanine composition on stability result from changes in the refolding rate. For example, as the number of alanines in the linker increases from 3 to 11, the folding rates of the corresponding proteins increase by 30,000-fold. Alanine restricts the number of allowed conformations of the linker compared with glycine and, in this length regime, probably accelerates the conformational search that occurs during folding. Increasing the number of alanines to 14 or 15 then reduces the folding rate, probably because these linkers become too inflexible. When serine is substituted for glycine, there are also effects on the refolding rate but with several differences: the optimal number of serines is smaller than the optimal number of alanines (7 Ser vs. 11 Ala), the difference between the fastest and slowest folders are smaller (\u03f72,000-fold for SLX vs, \u03f730,000-fold for ALX), and the maximum folding rates are different (in 2.25 M urea, the fastest ALX protein folds \u03f7250 times faster than the fastest SLX protein). Clearly, alanine and serine affect linker flexibility in rather different ways.", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "Large differences between alanine and serine are also apparent when comparing effects on the unfolding rate. As the number of serines in the linker increases, the unfolding rate continues to decrease over a 5,000-fold range (Fig. 5D) . By contrast, in the alanine library, the minimum unfolding rate is observed for a protein with seven alanines and the total change between the slowest and fastest unfolders is only 15-fold. We presume that the ability of serine to form hydrogen bonds allows formation of new stabilizing interactions in the native state but whether these interactions are within the linker or involve interactions between the linker and the body of the single-chain protein is unknown. Because alanines in the linker primarily affect folding rates whereas serine has the largest effects on unfolding rates, it seems possible that optimizing the composition of Gly, Ser, and Ala in a linker library might produce single-chain molecules with even greater stabilities than those described here. Preliminary studies also suggest that the effects of length and composition may be interdependent. For example, linkers of different lengths may have different optimal compositions.", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "Variations in linker length or composition caused no significant changes in repressor activity in vivo except in proteins with linkers shorter than 11 residues. In gel mobility-shift assays, Arc-LL19-Arc and Arc-LA11-Arc, which have 19-residue linkers, bound operator DNA as strongly as wild-type Arc dimers (data not shown). In earlier work, however, we found that Arc-L1-Arc (which is identical to Arc-LL15-Arc) had a 10-fold enhanced affinity for operator DNA (9, 26) . In single-chain Arc, the linker connects the N-terminal arm of the second subunit to the C terminus of the first subunit; in wild-type Arc, this N-terminal arm is disordered in solution (32) but folds against the operator in the protein-DNA complex (33) . The L1\u035eLL15 linker may increase operator affinity by helping to restrict the conformation of the arm in solution, thereby reducing the entropic penalty for ordering the arm upon DNA binding (9) . By this model, lengthening the linker to 19 residues probably reduces constraints on the arm conformation.", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "In summary, we find that changes in linker length and composition can produce substantial changes in the stability and folding kinetics of single-chain Arc. Poly-glycine linkers maximize the conformational freedom of the polypeptide backbone but do not result in optimal stability. For singlechain or hybrid protein designs that have folding problems, alterations in linker length and\u035eor composition should provide a useful method for increasing stability.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF3": {"title": "Colloquium Paper: Robinson and Sauer Proc. Natl. Acad. Sci. USA 95", "authors": [], "year": 1998, "venue": "", "link": null}, "BIBREF24": {"title": "Proc. Natl. Acad. Sci. USA", "authors": [{"first": "J", "middle": ["U"], "last": "Bowie", "suffix": ""}, {"first": "R", "middle": ["T"], "last": "Sauer", "suffix": ""}], "year": 1989, "venue": "", "link": null}}, "ref_entries": {"FIGREF0": {"text": "FIG. 1. (A) Tandem copies of the arc gene connected by DNA encoding a linker region comprise the gene for single-chain Arc repressor. (B) One model of how a linker might connect the two subunits (colored gray and white) of single-chain Arc. The positions of the N and C termini are indicated. Prepared using MOLSCRIPT (34) and coordinates of wild-type Arc (33).", "type": "figure"}, "FIGREF1": {"text": "FIG. 3. Properties of linker-length variants of single-chain Arc. (A) Linker sequences. (B) Equilibrium stability and effective concentration vary with linker length. Error bars indicate one SD from three independent experiments. (C) Folding rates in 2 M urea. (D) Unfolding rates in 7 M urea. Experimental conditions; protein 1-10 M, 25\u00b0C, 50 mM Tris\u2150HCl (pH 7.5), 250 mM KCl, and 0.1 mM EDTA.", "type": "figure"}, "FIGREF2": {"text": "FIG. 4. Properties of ALX variants with 19-residue linkers and differing in Ala\u035eGly composition numbers of alanines and glycines. (A) Linker sequences. (B) Equilibrium stability and effective concentration vary with number of alanines. For compositional isomers, closed and open symbols represents ''a'' and ''b'' variants, respectively. Error bars indicate one SD from three independent experiments. (C) Folding rates in 4.5 M urea. (D) Unfolding rates in 9.1 M urea. See Fig. 3 for conditions.", "type": "figure"}, "TABREF0": {"text": "). Effective concentrations were calculated by using the equation C eff \u03ed exp[(m 2 \u2022\u232cG 1 \u035em 1 -\u232cG 2 )\u035eRT], where m 1 and \u232cG 1 are values for the single-chain protein, and m 2 and \u232cG 2 are values for wild-type Arc (1.48 kcal\u035emol\u2022M and 10.3 kcal\u035emol, respectively)", "type": "table"}}}
{"paper_id": "2877433", "_pdf_hash": "34fe057e7e0def126293e736bca388410b99a5e3", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Enterprise Architecture Data Team: Construction, collection & curation of NASA's data reference models", "authors": [], "year": 2006, "venue": "NASA", "link": null}, "BIBREF1": {"title": "Semantic web @ NASA", "authors": [{"first": "K", "middle": ["G"], "last": "Clark", "suffix": ""}, {"first": "A", "middle": [], "last": "Schain", "suffix": ""}, {"first": "B", "middle": [], "last": "Parsia", "suffix": ""}], "year": 2006, "venue": "", "link": null}, "BIBREF2": {"title": "eXtensible Access Control Markup Language (XACML) Version 2.0. OASIS Standard", "authors": [{"first": "T", "middle": [], "last": "Moses", "suffix": ""}], "year": 2005, "venue": "", "link": null}, "BIBREF3": {"title": "Analyzing web access control policies", "authors": [{"first": "V", "middle": [], "last": "Kolovski", "suffix": ""}, {"first": "J", "middle": [], "last": "Hendler", "suffix": ""}, {"first": "B", "middle": [], "last": "Parsia", "suffix": ""}], "year": 2007, "venue": "16th International World Wide Web Conference", "link": "8355749"}, "BIBREF4": {"title": "Pellet: A practical OWL-DL reasoner", "authors": [{"first": "E", "middle": [], "last": "Sirin", "suffix": ""}, {"first": "B", "middle": [], "last": "Parsia", "suffix": ""}, {"first": "B", "middle": ["C"], "last": "Grau", "suffix": ""}, {"first": "A", "middle": [], "last": "Kalyanpur", "suffix": ""}, {"first": "Y", "middle": [], "last": "Katz", "suffix": ""}], "year": 2007, "venue": "Journal of Web Semantics", "link": "101226"}, "BIBREF5": {"title": "Core and hierarchical role based access control (RBAC) profile of XACML", "authors": [{"first": "A", "middle": [], "last": "Anderson", "suffix": ""}], "year": 2005, "venue": "", "link": null}, "BIBREF6": {"title": "Shielding the RBAC infrastructures from cyberterrorism", "authors": [{"first": "A", "middle": [], "last": "Belokosztolszki", "suffix": ""}, {"first": "D", "middle": [], "last": "Eyers", "suffix": ""}], "year": 2003, "venue": "Research Directions in Data and Applications Security", "link": null}, "BIBREF7": {"title": "Intrusion detection in RBACadministered databases", "authors": [{"first": "E", "middle": [], "last": "Bertino", "suffix": ""}, {"first": "A", "middle": [], "last": "Kamra", "suffix": ""}, {"first": "E", "middle": [], "last": "Terzi", "suffix": ""}, {"first": "A", "middle": [], "last": "Vakali", "suffix": ""}], "year": 2005, "venue": "ACSAC '05: Proceedings of the 21st Annual Computer Security Applications Conference", "link": null}, "BIBREF8": {"title": "RBAC policy engineering with patterns", "authors": [{"first": "T", "middle": [], "last": "Rochaeli", "suffix": ""}, {"first": "C", "middle": [], "last": "Eckert", "suffix": ""}], "year": 2005, "venue": "Proceedings of the Semantic Web and Policy Workshop", "link": "60035322"}, "BIBREF9": {"title": "Representing web service policies in OWL-DL", "authors": [{"first": "V", "middle": [], "last": "Kolovski", "suffix": ""}, {"first": "B", "middle": [], "last": "Parsia", "suffix": ""}, {"first": "Y", "middle": [], "last": "Katz", "suffix": ""}, {"first": "J", "middle": [], "last": "Hendler", "suffix": ""}], "year": 2005, "venue": "The Semantic Web -ISWC 2005: 4th International Semantic Web Conference", "link": "5556983"}}, "ref_entries": {}}
{"paper_id": "2877504", "_pdf_hash": "5c602cc9c19b39e4e4e6747ade58ad0fd2afe744", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Robust real-time face detection", "authors": [{"first": "P", "middle": [], "last": "Viola", "suffix": ""}, {"first": "M", "middle": [], "last": "Jones", "suffix": ""}], "year": 2004, "venue": "International Journal of Computer Vision", "link": "42281583"}, "BIBREF1": {"title": "Histograms of oriented gradients for human detection", "authors": [{"first": "N", "middle": [], "last": "Dalal", "suffix": ""}, {"first": "B", "middle": [], "last": "Triggs", "suffix": ""}], "year": 2005, "venue": "Proc. CVPR", "link": "206590483"}, "BIBREF2": {"title": "Cascade object detection with deformable part models", "authors": [{"first": "P", "middle": ["F"], "last": "Felzenszwalb", "suffix": ""}, {"first": "R", "middle": ["B"], "last": "Girshick", "suffix": ""}, {"first": "D", "middle": [], "last": "Mcallester", "suffix": ""}], "year": 2010, "venue": "IEEE Computer Society Conference on Computer Vision and Pattern Recognition (CVPR)", "link": "6735187"}, "BIBREF3": {"title": "A network that learns to recognize 3d objects", "authors": [{"first": "T", "middle": [], "last": "Poggio", "suffix": ""}, {"first": "S", "middle": [], "last": "Edelman", "suffix": ""}], "year": 1990, "venue": "Nature", "link": "116970586"}, "BIBREF4": {"title": "3d object modeling and recognition using local affine-invariant image descriptors and multi-view spatial constraints", "authors": [{"first": "F", "middle": [], "last": "Rothganger", "suffix": ""}, {"first": "S", "middle": [], "last": "Lazebnik", "suffix": ""}, {"first": "C", "middle": [], "last": "Schmid", "suffix": ""}, {"first": "J", "middle": [], "last": "Ponce", "suffix": ""}], "year": 2006, "venue": "International Journal of Computer Vision", "link": "1330784"}, "BIBREF5": {"title": "Simultaneous object recognition and segmentation from single or multiple model views", "authors": [{"first": "V", "middle": [], "last": "Ferrari", "suffix": ""}, {"first": "T", "middle": [], "last": "Tuytelaars", "suffix": ""}, {"first": "L", "middle": [], "last": "Van Gool", "suffix": ""}], "year": 2006, "venue": "International Journal of Computer Vision", "link": "5923591"}, "BIBREF6": {"title": "A system for probabilistic joint 3d head tracking and pose estimation in low-resolution, multi-view environments", "authors": [{"first": "M", "middle": [], "last": "Voit", "suffix": ""}, {"first": "R", "middle": [], "last": "Stiefelhagen", "suffix": ""}], "year": 2009, "venue": "", "link": "17009344"}, "BIBREF7": {"title": "Towards multi-view object class detection", "authors": [{"first": "A", "middle": [], "last": "Thomas", "suffix": ""}, {"first": "V", "middle": [], "last": "Ferrari", "suffix": ""}, {"first": "B", "middle": [], "last": "Leibe", "suffix": ""}, {"first": "T", "middle": [], "last": "Tuytelaars", "suffix": ""}, {"first": "B", "middle": [], "last": "Schiele", "suffix": ""}, {"first": "L", "middle": [], "last": "Van Gool", "suffix": ""}], "year": 2006, "venue": "Proceedings IEEE Conference on Computer Vision and Pattern Recognition", "link": "12744328"}, "BIBREF8": {"title": "3d generic object categorization, localization and pose estimation", "authors": [{"first": "S", "middle": [], "last": "Savarese", "suffix": ""}, {"first": "L", "middle": [], "last": "Fei-Fei", "suffix": ""}], "year": 2007, "venue": "IEEE 11th International Conference on", "link": "16934204"}, "BIBREF9": {"title": "Flexible object models for category-level 3d object recognition", "authors": [{"first": "A", "middle": [], "last": "Kushal", "suffix": ""}, {"first": "C", "middle": [], "last": "Schmid", "suffix": ""}, {"first": "J", "middle": [], "last": "Ponce", "suffix": ""}], "year": 2007, "venue": "Proceedings IEEE Conference on Computer Vision and Pattern Recognition", "link": "12425657"}, "BIBREF10": {"title": "Learning a dense multiview representation for detection, viewpoint classification and synthesis of object categories", "authors": [{"first": "H", "middle": [], "last": "Su", "suffix": ""}, {"first": "M", "middle": [], "last": "Sun", "suffix": ""}, {"first": "L", "middle": [], "last": "Fei-Fei", "suffix": ""}, {"first": "S", "middle": [], "last": "Savarese", "suffix": ""}], "year": 2009, "venue": "International Conference on Computer Vision", "link": "7242312"}, "BIBREF11": {"title": "Multiple View Geometry in Computer Vision", "authors": [{"first": "R", "middle": [], "last": "Hartley", "suffix": ""}, {"first": "A", "middle": [], "last": "Zisserman", "suffix": ""}], "year": 2003, "venue": "", "link": "54124999"}, "BIBREF12": {"title": "Beyond bags of features: Spatial pyramid matching for recognizing natural scene categories", "authors": [{"first": "S", "middle": [], "last": "Lazebnik", "suffix": ""}, {"first": "C", "middle": [], "last": "Schmid", "suffix": ""}, {"first": "J", "middle": [], "last": "Ponce", "suffix": ""}], "year": 2006, "venue": "Proc. CVPR", "link": null}, "BIBREF13": {"title": "Image classification using random forests and ferns", "authors": [{"first": "A", "middle": [], "last": "Bosch", "suffix": ""}, {"first": "A", "middle": [], "last": "Zisserman", "suffix": ""}, {"first": "X", "middle": [], "last": "Mu\u00f1oz", "suffix": ""}], "year": 2007, "venue": "IEEE International Conference on Computer Vision (ICCV)", "link": "17584818"}, "BIBREF14": {"title": "Gray scale and rotation invariant texture classification with local binary patterns", "authors": [{"first": "T", "middle": [], "last": "Ojala", "suffix": ""}, {"first": "M", "middle": [], "last": "Pietikainen", "suffix": ""}, {"first": "T", "middle": [], "last": "Maenpaa", "suffix": ""}], "year": 2000, "venue": "Lecture Notes in Computer Science", "link": "16796921"}, "BIBREF15": {"title": "An hog-lbp human detector with partial occlusion handling", "authors": [{"first": "X", "middle": [], "last": "Wang", "suffix": ""}, {"first": "T", "middle": ["X"], "last": "Han", "suffix": ""}, {"first": "S", "middle": [], "last": "Yan", "suffix": ""}], "year": 2009, "venue": "Computer Vision, 2009 IEEE 12th International Conference on", "link": "2475434"}, "BIBREF16": {"title": "Support-vector networks", "authors": [{"first": "C", "middle": [], "last": "Cortes", "suffix": ""}, {"first": "V", "middle": [], "last": "Vapnik", "suffix": ""}], "year": 1995, "venue": "Machine Learning", "link": "52874011"}, "BIBREF17": {"title": "Linear spatial pyramid matching using sparse coding for image classification", "authors": [{"first": "J", "middle": [], "last": "Yang", "suffix": ""}, {"first": "K", "middle": [], "last": "Yu", "suffix": ""}, {"first": "Y", "middle": [], "last": "Gong", "suffix": ""}, {"first": "T", "middle": [], "last": "Huang", "suffix": ""}], "year": 2009, "venue": "Computer Vision and Pattern Recognition", "link": "62091811"}, "BIBREF18": {"title": "Object detection with discriminatively trained part based models", "authors": [{"first": "P", "middle": ["F"], "last": "Felzenszwalb", "suffix": ""}, {"first": "R", "middle": ["B"], "last": "Girshick", "suffix": ""}, {"first": "D", "middle": [], "last": "Mcallester", "suffix": ""}, {"first": "D", "middle": [], "last": "Ramanan", "suffix": ""}], "year": 2009, "venue": "IEEE Transactions on Pattern Analysis and Machine Intelligence", "link": "3198903"}}, "ref_entries": {}}
{"paper_id": "2877521", "_pdf_hash": "d1caf33b27896c6fea52c2a707d3aaf95d8da8e4", "abstract": [{"section": "Abstract", "text": "Regression aims at estimating the conditional mean of output given input. However, regression is not informative enough if the conditional density is multimodal, heteroskedastic, and asymmetric. In such a case, estimating the conditional density itself is preferable, but conditional density estimation (CDE) is challenging in high-dimensional space. A naive approach to coping with high dimensionality is to first perform dimensionality reduction (DR) and then execute CDE. However, a two-step process does not perform well in practice because the error incurred in the first DR step can be magnified in the second CDE step. In this letter, we propose a novel single-shot procedure that performs CDE and DR simultaneously in an integrated way. Our key idea is to formulate DR as the problem of minimizing a squared-loss variant of conditional entropy, and this is solved using CDE. Thus, an additional CDE step is not needed after DR. We demonstrate the usefulness of the proposed method through extensive experiments on various data sets, including humanoid robot transition and computer art.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Analyzing an input-output relationship from samples is one of the central challenges in machine learning. The most common approach is regression, which estimates the conditional mean of output y given input x. However, just analyzing the conditional mean is not informative enough, when the conditional density p(y|x) possesses multimodality, asymmetry, and heteroskedasticity (i.e., input-dependent variance) as a function of output y. In such cases, it would be more appropriate to estimate the conditional density itself (see Figure 2 ). The most naive approach to conditional density estimation (CDE) would be -neighbor kernel density estimation ( -KDE) , which performs standard KDE along y only with nearby samples in the input domain. However, -KDE does not work well in high-dimensional problems because the number of nearby samples is too few. To avoid the small sample problem, KDE may be applied twice to estimate p(x, y) and p(x) separately and the estimated densities may be plugged into the decomposed form p(y|x) = p(x, y)/p(x) to estimate the conditional density. However, taking the ratio of two estimated densities significantly magnifies the estimation error and thus is not reliable. To overcome this problem, an approach to directly estimating the density ratio p(x, y)/p(x) without separate estimation of densities p(x, y) and p(x) has been explored (Sugiyama et al., 2010) . This method, called least-squares CDE (LSCDE), was proved to possess the optimal nonparametric learning rate in the mini-max sense, and its solution can be efficiently and analytically computed. Nevertheless, estimating conditional densities in high-dimensional problems is still challenging.", "cite_spans": [{"start": 1372, "end": 1395, "text": "(Sugiyama et al., 2010)", "ref_id": "BIBREF18"}], "ref_spans": [{"start": 529, "end": 537, "text": "Figure 2", "ref_id": "FIGREF1"}]}, {"section": "Introduction", "text": "A natural idea to cope with the high dimensionality is to perform dimensionality reduction (DR) before CDE. Sufficient DR (Li, 1991; Cook & Ni, 2005 ) is a framework of supervised DR aimed at finding the subspace of input x that contains all information on output y, and a method based on conditional-covariance operators in reproducing kernel Hilbert spaces has been proposed (Fukumizu, Bach, & Jordan, 2009) . Although this method possesses superior theoretical properties, it is not easy to use in practice because no systematic model selection method is available for kernel parameters. To overcome this problem, an alternative sufficient DR method based on squared-loss mutual information (SMI) has been proposed recently (Suzuki & Sugiyama, 2013) . This method involves nonparametric estimation of SMI that is theoretically guaranteed to achieve the optimal estimation rate, and all tuning parameters can be systematically chosen in practice by cross-validation with respect to the SMI approximation error.", "cite_spans": [{"start": 122, "end": 132, "text": "(Li, 1991;", "ref_id": "BIBREF13"}, {"start": 133, "end": 148, "text": "Cook & Ni, 2005", "ref_id": "BIBREF6"}, {"start": 377, "end": 409, "text": "(Fukumizu, Bach, & Jordan, 2009)", "ref_id": "BIBREF9"}, {"start": 727, "end": 752, "text": "(Suzuki & Sugiyama, 2013)", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "Introduction", "text": "Given such state-of-the-art DR methods, performing DR before LSCDE would be a promising approach to improving the accuracy of CDE in highdimensional problems. However, such a two-step approach is not preferable because DR in the first step is performed without regard to CDE in the second step, and thus small errors incurred in the DR step can be significantly magnified in the CDE step.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "In this letter, we propose a single-shot method that integrates DR and CDE. Our key idea is to formulate the sufficient DR problem in terms of the squared-loss conditional entropy (SCE), which includes the conditional density in its definition, and LSCDE is executed when DR is performed. Therefore, when DR is completed, the final conditional density estimator has already been obtained without an additional CDE step (see Figure 1 ). We demonstrate the usefulness of the proposed method, named least-squares conditional entropy (LSCE), through experiments on benchmark data sets, humanoid robot control simulations, and computer art. ", "cite_spans": [], "ref_spans": [{"start": 424, "end": 432, "text": "Figure 1", "ref_id": "FIGREF0"}]}, {"section": "Conditional Density Estimation with Dimensionality Reduction", "text": "In this section, we describe our proposed method for conditional density estimation with dimensionality reduction.", "cite_spans": [], "ref_spans": []}, {"section": "Problem Formulation. Let", "text": "be the input and output domains with dimensionality d x and d y , respectively, and let p(x, y) be a joint probability density on D x \u00d7 D y . Assume that we are given n independent and identically distributed (i.i.d.) training samples from the joint density:", "cite_spans": [], "ref_spans": []}, {"section": "Problem Formulation. Let", "text": "The goal is to estimate the conditional density p(y|x) from the samples. Our implicit assumption is that the input dimensionality d x is large, but its intrinsic dimensionality, denoted by d z , is rather small. More specifically, let W and", "cite_spans": [], "ref_spans": []}, {"section": "Problem Formulation. Let", "text": "is an orthogonal matrix. Then we assume that x can be decomposed into the component z = W x and its perpendicular component z \u22a5 = W \u22a5 x so that y and x are conditionally independent given z: y \u22a5 x|z.", "cite_spans": [], "ref_spans": []}, {"section": "Problem Formulation. Let", "text": "(2.1)", "cite_spans": [], "ref_spans": []}, {"section": "Problem Formulation. Let", "text": "This means that z is the relevant part of x, and the rest z \u22a5 does not contain any information on y. The problem of finding W is called sufficient dimensionality reduction (Li, 1991; Cook & Ni, 2005) .", "cite_spans": [{"start": 172, "end": 182, "text": "(Li, 1991;", "ref_id": "BIBREF13"}, {"start": 183, "end": 199, "text": "Cook & Ni, 2005)", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "Sufficient Dimensionality Reduction with SCE.", "text": "Let us consider a squared-loss variant of conditional entropy, squared-loss CE (SCE):", "cite_spans": [], "ref_spans": []}, {"section": "Sufficient Dimensionality Reduction with SCE.", "text": "By expanding the squared term in equation 2.2, we obtain", "cite_spans": [], "ref_spans": []}, {"section": "Sufficient Dimensionality Reduction with SCE.", "text": "Then we have the following theorem (its proof is given in appendix A), which forms the basis of our proposed method:", "cite_spans": [], "ref_spans": []}, {"section": "Sufficient Dimensionality Reduction with SCE.", "text": "This theorem shows SCE(Y |Z) \u2265 SCE(Y |X ), and the equality holds if and only if", "cite_spans": [], "ref_spans": []}, {"section": "Sufficient Dimensionality Reduction with SCE.", "text": "This is equivalent to the conditional independence, equation 2.1, and therefore sufficient dimensionality reduction can be performed by minimizing SCE(Y |Z) with respect to W :", "cite_spans": [], "ref_spans": []}, {"section": "Sufficient Dimensionality Reduction with SCE.", "text": "(2.5)", "cite_spans": [], "ref_spans": []}, {"section": "Sufficient Dimensionality Reduction with SCE.", "text": "(R) denotes the Grassmann manifold, which is a set of orthogonal matrices without overlaps,", "cite_spans": [], "ref_spans": []}, {"section": "Sufficient Dimensionality Reduction with SCE.", "text": "where I denotes the identity matrix and \u223c represents the equivalence relation: W and W are written as W \u223c W if their rows span the same subspace.", "cite_spans": [], "ref_spans": []}, {"section": "Sufficient Dimensionality Reduction with SCE.", "text": "Since p(y|z) = p(z, y)/p(z), SCE(Y |Z) is equivalent to the negative Pearson divergence (Pearson, 1900) from p(z, y) to p(z), which is a member of the f-divergence class (Ali & Silvey, 1966; Csisz\u00e1r, 1967) with the squaredloss function. Ordinary conditional entropy (CE), defined by", "cite_spans": [{"start": 88, "end": 103, "text": "(Pearson, 1900)", "ref_id": "BIBREF15"}, {"start": 170, "end": 190, "text": "(Ali & Silvey, 1966;", "ref_id": "BIBREF0"}, {"start": 191, "end": 205, "text": "Csisz\u00e1r, 1967)", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "Sufficient Dimensionality Reduction with SCE.", "text": "is the negative Kullback-Leibler divergence (Kullback & Leibler, 1951) from p(z, y) to p(z). Since the Kullback-Leibler divergence is also a member of the f-divergence class (with the log-loss function), CE and SCE have similar properties. Indeed, theorem 1 also holds for ordinary CE. However, the Pearson divergence is shown to be more robust against outliers (Basu, Harris, Hjort, & Jones, 1998; Sugiyama, Suzuki, & Kanamori, 2012) , since the log function, is very sharp near zero, is not included. Furthermore, as we show, SCE can be approximated analytically, and thus its derivative can also be easily computed. This is a critical property for developing a dimensionality-reduction method because we want to minimize SCE with respect to W , where the gradient is highly useful in devising an optimization algorithm. For this reason, we adopt SCE instead of CE below.", "cite_spans": [{"start": 44, "end": 70, "text": "(Kullback & Leibler, 1951)", "ref_id": "BIBREF12"}, {"start": 362, "end": 398, "text": "(Basu, Harris, Hjort, & Jones, 1998;", "ref_id": "BIBREF3"}, {"start": 399, "end": 434, "text": "Sugiyama, Suzuki, & Kanamori, 2012)", "ref_id": "BIBREF17"}], "ref_spans": []}, {"section": "SCE Approximation.", "text": "Since SCE(Y |Z) in equation 2.5 is unknown in practice, we approximate it using samples", "cite_spans": [], "ref_spans": []}, {"section": "SCE Approximation.", "text": "(2.6)", "cite_spans": [], "ref_spans": []}, {"section": "SCE Approximation.", "text": "If we set a = p(y|z), we have", "cite_spans": [], "ref_spans": []}, {"section": "SCE Approximation.", "text": "If we multiply both sides of the above inequality with \u2212p(z) and integrate over z and y, we have", "cite_spans": [], "ref_spans": []}, {"section": "SCE Approximation.", "text": "where minimization with respect to b is now performed as a function of z and y. (For more general discussions on divergence bounding, see Keziou, 2003, and Nguyen, Wainwright, & Jordan, 2010) . Let us consider a linear-in-parameter model for b:", "cite_spans": [{"start": 138, "end": 155, "text": "Keziou, 2003, and", "ref_id": "BIBREF11"}, {"start": 156, "end": 177, "text": "Nguyen, Wainwright, &", "ref_id": "BIBREF14"}, {"start": 178, "end": 191, "text": "Jordan, 2010)", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "SCE Approximation.", "text": "where \u03b1 is a parameter vector and \u03d5(z, y) is a vector of basis functions. If the expectations over densities p(z) and p(z, y) are approximated by sample averages and the 2 -regularizer \u03bb\u03b1 \u03b1/2 (\u03bb \u2265 0) is included, the above minimization problem yields", "cite_spans": [], "ref_spans": []}, {"section": "SCE Approximation.", "text": "The solution \u03b1 is analytically given by", "cite_spans": [], "ref_spans": []}, {"section": "SCE Approximation.", "text": "which yields b(z, y) = \u03b1 \u03d5(z, y). Then, from equation 2.7, we obtain an approximator of SCE(Y |Z) analytically as", "cite_spans": [], "ref_spans": []}, {"section": "SCE Approximation.", "text": "We call this method least-squares conditional entropy (LSCE).", "cite_spans": [], "ref_spans": []}, {"section": "Model Selection by Cross-Validation.", "text": "The SCE approximator depends on the choice of models-i.e., the basis function \u03d5(z, y) and the regularization parameter \u03bb. Such a model can be objectively selected by cross-validation as follows:", "cite_spans": [], "ref_spans": []}, {"section": "Model Selection by Cross-Validation.", "text": "ii. Evaluate the upper bound of SCE obtained by b (M, j) using the hold-out data S j :", "cite_spans": [], "ref_spans": []}, {"section": "Model Selection by Cross-Validation.", "text": "where |S j | denotes the cardinality of S j . b. The average score is computed as", "cite_spans": [], "ref_spans": []}, {"section": "Model Selection by Cross-Validation.", "text": "3. The model that minimizes the average score is chosen:", "cite_spans": [], "ref_spans": []}, {"section": "Model Selection by Cross-Validation.", "text": "4. For the chosen model M, the LSCE solution b is computed from all samples S, and the approximator SCE(Y |Z) is computed.", "cite_spans": [], "ref_spans": []}, {"section": "Model Selection by Cross-Validation.", "text": "In the experiments, we use K = 5.", "cite_spans": [], "ref_spans": []}, {"section": "Dimensionality", "text": "Reduction with SCE. Now we solve the following optimization problem by gradient descent:", "cite_spans": [], "ref_spans": []}, {"section": "Dimensionality", "text": "(2.9)", "cite_spans": [], "ref_spans": []}, {"section": "Dimensionality", "text": "As shown in appendix B, the gradient of SCE(Y |Z = W X ) is given by", "cite_spans": [], "ref_spans": []}, {"section": "Dimensionality", "text": "In the Euclidean space, the above gradient gives the steepest direction. However, on a manifold, the natural gradient (Amari, 1998) gives the steepest direction.", "cite_spans": [{"start": 118, "end": 131, "text": "(Amari, 1998)", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Dimensionality", "text": "The natural gradient \u2207 SCE(W ) at W is the projection of the ordinary", "cite_spans": [], "ref_spans": []}, {"section": "Dimensionality", "text": "is equipped with the canonical metric W , W = 1 2 tr(W W ), the natural gradient is given as follows (Edelman, Arias, & Smith, 1998) :", "cite_spans": [{"start": 101, "end": 132, "text": "(Edelman, Arias, & Smith, 1998)", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "Dimensionality", "text": "Then the geodesic from W to the direction of the natural gradient \u2207 SCE", "cite_spans": [], "ref_spans": []}, {"section": "Dimensionality", "text": "where \"exp\" for a matrix denotes the matrix exponential and O d,d denotes the d \u00d7 d zero matrix. Note that the derivative \u2202 t W t at t = 0 coincides with the natural gradient \u2207 SCE (see Edelman et al., 1998, for details) . Thus, line search along the geodesic in the natural gradient direction is equivalent to finding the minimizer from {W t |t \u2265 0}. Once W is updated, SCE is reestimated with the new W , and gradient descent is performed again. This entire procedure is repeated until W converges. When SCE is reestimated, performing cross-validation in every step is computationally expensive. In our implementation, we perform cross-validation only once every five gradient updates. Furthermore, to find a better local optimal solution, this gradient descent procedure is executed 20 times with randomly chosen initial solutions; the one achieving the smallest value of SCE is chosen.", "cite_spans": [], "ref_spans": []}, {"section": "Conditional Density Estimation with SCE.", "text": "Since the maximum of equation 2.6 is attained at b = a and a = p(y|z) in the current derivation, the optimal b(z, y) is actually the conditional density p(y|z) itself. Therefore, \u03b1 \u03d5(z, y) obtained by LSCE is a conditional density estimator. This implies that the upper-bound minimization procedure described in section 2.3 is equivalent to least-squares conditional density estimation (LSCDE) (Sugiyama et al., 2010) , which minimizes the squared error:", "cite_spans": [{"start": 394, "end": 417, "text": "(Sugiyama et al., 2010)", "ref_id": "BIBREF18"}], "ref_spans": []}, {"section": "Conditional Density Estimation with SCE.", "text": "Then, in the same way as the original LSCDE, we may postprocess the solution \u03b1 to make the conditional density estimator nonnegative and normalized as", "cite_spans": [], "ref_spans": []}, {"section": "Conditional Density Estimation with SCE.", "text": "where \u03b1 l = max \u03b1 l , 0 . Note that even if the solution is postprocessed as equation 2.10, the optimal estimation rate of the LSCDE solution is still maintained (Sugiyama et al., 2010) .", "cite_spans": [{"start": 162, "end": 185, "text": "(Sugiyama et al., 2010)", "ref_id": "BIBREF18"}], "ref_spans": []}, {"section": "Basis Function Design.", "text": "In practice, we use the following gaussian function as the kth basis:", "cite_spans": [], "ref_spans": []}, {"section": "Basis Function Design.", "text": "where (u k , v k ) denotes the kth gaussian center located at (z k , y k ). When the sample size n is too large, we may use only a subset of samples as gaussian centers. \u03c3 denotes the gaussian bandwidth, which is chosen by cross-validation, as explained in section 2.4. We may use different bandwidths for z and y, but this will increase the computation time for model selection. In our implementation, we normalize each element of z and y to have the unit variance in advance and then use the common bandwidth for z and y.", "cite_spans": [], "ref_spans": []}, {"section": "Basis Function Design.", "text": "A notable advantage of using the gaussian function is that the integral over y appeared in\u00af (z) (see equation 2.8) can be computed analytically as", "cite_spans": [], "ref_spans": []}, {"section": "Basis Function Design.", "text": "Similarly, the normalization term in equation 2.10 can also be computed analytically as", "cite_spans": [], "ref_spans": []}, {"section": "Basis Function Design.", "text": "2.8 Discussion. We have proposed minimizing SCE for dimensionality reduction:", "cite_spans": [], "ref_spans": []}, {"section": "Basis Function Design.", "text": "In previous work Suzuki and Sugiyama (2013) , squared-loss mutual information (SMI) was maximized for dimensionality reduction:", "cite_spans": [{"start": 17, "end": 43, "text": "Suzuki and Sugiyama (2013)", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "Basis Function Design.", "text": "This shows that the essential difference is whether p(y) is included in the denominator of the density ratio. Thus, if p(y) is uniform, the proposed dimensionality-reduction method using SCE is reduced to the existing method using SMI. However, if p(y) is not uniform, the density ratio function p(z,y) p(z)p(y) included in SMI may be more fluctuated than p(z,y) p(z) included in SCE. Since a smoother function can be more accurately estimated from a small number of samples in general, the proposed method using SCE is expected to work better than the existing method using SMI. We will experimentally demonstrate this effect in section 3.", "cite_spans": [], "ref_spans": []}, {"section": "Basis Function Design.", "text": "Sufficient dimension reduction based on the conditional density p(y|z) has also been studied in the statistics literature. The density-minimum average variance estimation (dMAVE) method (Xia, 2007) finds a dimensionreduction subspace using local linear regression for the conditional density in a semi-parametric manner. A similar approach has also been taken in the sliced regression for dimension reduction method (Wang & Xia, 2008) , where the cumulative conditional density is used instead of the conditional density. A Bayesian approach to sufficient dimension reduction called the Bayesian dimension reduction (BDR) method (Reich, Bondell, & Li, 2011) has been proposed recently. This method models the conditional density as a gaussian mixture model and obtains a dimension-reduction subspace through sampling from the learned prior distribution of low-dimensional input. These methods have been shown to work well for dimension reduction in real-world data sets, although they are applicable only to univariate output data where d y = 1.", "cite_spans": [{"start": 186, "end": 197, "text": "(Xia, 2007)", "ref_id": "BIBREF22"}, {"start": 416, "end": 434, "text": "(Wang & Xia, 2008)", "ref_id": "BIBREF21"}, {"start": 629, "end": 657, "text": "(Reich, Bondell, & Li, 2011)", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "Basis Function Design.", "text": "In regression, learning with the squared loss is not robust against outliers (Huber, 1981) . However, density estimation (Basu et al., 1998) and density ratio estimation under the Pearson divergence are known to be robust against outliers. Thus, in the same sense, the proposed LSCE estimator would also be robust against outliers. We experimentally investigate the robustness in section 3.", "cite_spans": [{"start": 77, "end": 90, "text": "(Huber, 1981)", "ref_id": "BIBREF10"}, {"start": 121, "end": 140, "text": "(Basu et al., 1998)", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "Experiments", "text": "In this section, we experimentally investigate the practical usefulness of the proposed method. We consider the following dimensionality-reduction schemes:", "cite_spans": [], "ref_spans": []}, {"section": "Experiments", "text": "None: No dimensionality reduction is performed. dMAVE: The density-minimum average variance estimation method where dimension reduction is performed through local linear regression for the conditional density (Xia, 2007) . 1 BDR: The Bayesian dimension-reduction method where the conditional density is modeled by a gaussian mixture model and dimension reduction is performed by sampling from the prior distribution of low-dimensional input (Reich et al., 2011) . 2 LSMI: Dimension reduction is performed by maximizing an SMI approximator called least-squares MI (LSMI) using natural gradients over the Grassmann manifold (Suzuki & Sugiyama, 2013) . LSCE (proposed): Dimension reduction is performed by minimizing the proposed LSCE using natural gradients over the Grassmann manifold. True (reference): The \"true\" subspace is used (only for artificial data).", "cite_spans": [{"start": 209, "end": 220, "text": "(Xia, 2007)", "ref_id": "BIBREF22"}, {"start": 441, "end": 461, "text": "(Reich et al., 2011)", "ref_id": "BIBREF16"}, {"start": 622, "end": 647, "text": "(Suzuki & Sugiyama, 2013)", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "Experiments", "text": "After dimension reduction, we execute the following conditional density estimators:", "cite_spans": [], "ref_spans": []}, {"section": "Experiments", "text": "-KDE: -neighbor kernel density estimation, where is chosen by leastsquares cross-validation. LSCDE: Least-squares conditional density estimation (Sugiyama et al., 2010) .", "cite_spans": [{"start": 145, "end": 168, "text": "(Sugiyama et al., 2010)", "ref_id": "BIBREF18"}], "ref_spans": []}, {"section": "Experiments", "text": "Note that the proposed method, which is the combination of LSCE and LSCDE, does not explicitly require the post-LSCDE step because LSCDE is executed inside LSCE. Since the dMAVE and BDR methods are applicable only to univariate output, they are not included in experiments with multivariate output data.", "cite_spans": [], "ref_spans": []}, {"section": "Experiments", "text": "3.1 Illustration. First, we illustrate the behavior of the plain LSCDE (None/LSCDE) and the proposed method (LSCE/LSCDE). The data sets illustrated in Figure 2 have d x = 5, d y = 1, and d z = 1. The first dimension of input x and output y of the samples is plotted in the graphs, and the other four dimensions of x are just standard normal noise. The results show that the plain LSCDE does not perform well due to the irrelevant noise dimensions of x, while the proposed method gives much better estimates.", "cite_spans": [], "ref_spans": [{"start": 151, "end": 159, "text": "Figure 2", "ref_id": "FIGREF1"}]}, {"section": "Artificial Data Sets.", "text": "Next, we compare the proposed method with the existing dimensionality-reduction methods on conditional density estimation by LSCDE in artificial data sets.", "cite_spans": [], "ref_spans": []}, {"section": "Artificial Data Sets.", "text": "For d x = 5, d y = 1, x \u223c N (x|0, I 5 ), and \u223c N ( |0, 0.25 2 ), where N (\u00b7|\u03bc, ) denotes the normal distribution with mean \u03bc and covariance matrix , we consider the following artificial data sets: a. d z = 2 and y = (x (1) ) 2 + (x (2) ) 2 + . b. d z = 1 and y = x (2) + (x (2) ) 2 + (x (2) ) 3 + . c. d z = 1 and y = (x (1) ) 2 + with 0.85 probability, 2 \u2212 4 with 0.15 probability. The first row of Figure 3 shows the dimensionality-reduction error between true W * and its estimate W for different sample size n, measured by", "cite_spans": [], "ref_spans": [{"start": 400, "end": 408, "text": "Figure 3", "ref_id": "FIGREF2"}]}, {"section": "Artificial Data Sets.", "text": "where \u00b7 Frobenius denotes the Frobenius norm. All methods perform similarly for data set a, and the dMAVE and BDR methods outperform LSCE and LSMI when n = 50. In data set b, LSMI does not work well compared to other methods especially when n \u2265 250. To explain this behavior, we plot the histograms of {y} 400 i=1 in the left column of Figure 4 . They show that the profile of the histogram (a sample approximation of p(y)) in data set b is much sharper than that in data set a. As discussed in section 2.8, the density ratio (y) . For data set c we consider the situation where {y i } n i=1 contain outliers that are not related to x. The data profile of data set c in the right column of Figure 4 illustrates such a situation. The result on data set c shows that the proposed LSCE method is robust against outliers and gives the best subspace estimation accuracy, while the BDR method performs unreliably with large standard errors.", "cite_spans": [], "ref_spans": [{"start": 336, "end": 344, "text": "Figure 4", "ref_id": "FIGREF3"}, {"start": 690, "end": 698, "text": "Figure 4", "ref_id": "FIGREF3"}]}, {"section": "Artificial Data Sets.", "text": "The right column of Figure 3 plots the conditional density estimation error between true p(y|x) and its estimate p(y|x), evaluated by the squared loss:", "cite_spans": [], "ref_spans": [{"start": 20, "end": 28, "text": "Figure 3", "ref_id": "FIGREF2"}]}, {"section": "Artificial Data Sets.", "text": "is a set of test samples that have not been used for training. We set n = 1000. For data sets a and c, all methods with dimension reduction perform equally well, which is much better than no dimension reduction (None/LSCDE) and is comparable to the method with the true subspace (True/LSCDE). For data set b, all methods except LSMI/LSCDE perform well overall and are comparable to the methods with the true subspace.", "cite_spans": [], "ref_spans": []}, {"section": "Benchmark Data Sets.", "text": "Next, we use the UCI benchmark data sets (Bache & Lichman, 2013) . We randomly select n samples from each data set for training, and the rest are used to measure the conditional density estimation error in the test phase. Since the dimensionality of the subspace d z is unknown, we chose it by cross-validation. More specifically, five-fold cross-validation is performed for each combination of the dimensionalityreduction and conditional-density estimation methods to choose subspace dimensionalities d z such that the conditional-density estimation error is minimized. Note that tuning parameters \u03bb and \u03c3 are also chosen based on cross-validation for each method. Since the conditional-density estimation error is equivalent to SCE, choosing the subspace dimensionalities by the conditional-density estimation error in LSCE is equivalent to choosing subspace dimensionalities that give the minimum SCE value.", "cite_spans": [{"start": 41, "end": 64, "text": "(Bache & Lichman, 2013)", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "Benchmark Data Sets.", "text": "The results of univariate output benchmark data sets averaged over 10 runs are summarized in the subspace dimensionalities chosen by cross-validation averaged over 10 runs. It shows that all dimensionality-reduction methods reduce the input dimension significantly, especially for Yacht, Red Wine, and White Wine, where the best method always chooses d z = 1 in all runs.", "cite_spans": [], "ref_spans": []}, {"section": "Benchmark Data Sets.", "text": "The results of multivariate output Stock and Energy benchmark data sets are summarized in Table 3 , showing that the proposed LSCE/LSCDE method also works well for multivariate output data sets and significantly outperforms methods without dimensionality reduction. Table 4 describes the subspace dimensionalities selected by cross-validation, showing that LSMI/LSCDE tends to more aggressively reduce the dimensionality than LSCE/LSCDE.", "cite_spans": [], "ref_spans": [{"start": 90, "end": 97, "text": "Table 3", "ref_id": "TABREF3"}, {"start": 266, "end": 273, "text": "Table 4", "ref_id": "TABREF4"}]}, {"section": "Humanoid Robot.", "text": "We evaluate the performance of the proposed method on humanoid robot transition estimation. We use a simulator of the upper-body part of the humanoid robot CB-i (Cheng et al., 2007;  see Figure 5 ). The robot has nine controllable joints: shoulder pitch, shoulder roll, elbow pitch of the right arm, shoulder pitch, shoulder roll, elbow pitch of the left arm, waist yaw, torso roll, and torso pitch joints.", "cite_spans": [], "ref_spans": []}, {"section": "Humanoid Robot.", "text": "The posture of the robot is described by 18-dimensional real-valued state vector s, which corresponds to the angle and angular velocity of each joint in radians and radians per seconds, respectively. We can control the robot by sending the action command a to the system. The action command a is a nine-dimensional real-valued vector that corresponds to the target angle of each joint. When the robot is at state s and receives action a, the physical control system of the simulator calculates the amount of torque to be applied to each joint. These torques are calculated by the proportional-derivative (PD) controller as", "cite_spans": [], "ref_spans": []}, {"section": "Humanoid Robot.", "text": "where s i ,\u1e61 i , and a i denote the current angle, the current angular velocity, and the received target angle of the ith joint, respectively. K p i and K d i denote the position and velocity gains for the ith joint, respectively. We set K p i = 2000 and K d i = 100 for all joints except K p i = 200 and K d i = 10 for the elbow pitch joints. After the torques are applied to the joints, the physical control system updates the state of the robot to s .", "cite_spans": [], "ref_spans": []}, {"section": "Humanoid Robot.", "text": "In the experiment, we randomly choose the action vector a and simulate a noisy control system by adding a bimodal gaussian noise vector. More specifically, the action a i of the ith joint is first drawn from uniform distribution on [s i \u2212 0.087, s i + 0.087]. The drawn action is then contaminated by gaussian noise with mean 0 and standard deviation 0.034 with probability 0.6 and gaussian noise with mean \u22120.087 and standard deviation 0.034 with probability 0.4. By repeatedly controlling the robot n times, we obtain the transition samples {(s j , a j , s j )} n j=1 . Our goal is to learn the (Sutton & Barto, 1998) . We consider three scenarios: using only two joints (right shoulder pitch and right elbow pitch), only four joints (in addition, right shoulder roll and waist yaw), and all nine joints. Thus, d x = 6 and d y = 4 for the two-joint case, d x = 12 and d y = 8 for the four-joint case, and d x = 27 and d y = 18 for the nine-joint case. We generate 500, 1000, and 1500 transition samples for the two-joint, four-joint, and nine-joint cases. We then randomly choose n = 100, 200, and 500 samples for training, and use the rest for evaluating the test error. The results are summarized also in Table 3 , showing that the proposed method performs well for all three cases. Table 4 describes the Figure 6 : Three actions of the brush, which is modeled as the footprint on a paper canvas. dimensionalities selected by cross-validation, showing that the humanoid robot's transition is highly redundant.", "cite_spans": [{"start": 597, "end": 619, "text": "(Sutton & Barto, 1998)", "ref_id": "BIBREF19"}], "ref_spans": [{"start": 1209, "end": 1216, "text": "Table 3", "ref_id": "TABREF3"}, {"start": 1287, "end": 1294, "text": "Table 4", "ref_id": "TABREF4"}]}, {"section": "Computer Art.", "text": "Finally, we consider the transition estimation problem in sumi-e style brush drawings for nonphotorealistic rendering (Xie, Hachiya, & Sugiyama, 2012) . Our aim is to learn the brush dynamics as state transition probability p(s |s, a) from the real artists' stroke-drawing samples.", "cite_spans": [{"start": 118, "end": 150, "text": "(Xie, Hachiya, & Sugiyama, 2012)", "ref_id": "BIBREF23"}], "ref_spans": []}, {"section": "Computer Art.", "text": "From a video of real brushstrokes, we extract footprints and identify corresponding three-dimensional actions (see Figure 6 ). The state vector consists of six measurements: the angle of the velocity vector and the heading direction of the footprint relative to the medial axis of the drawing shape, the ratio of the offset distance from the center of the footprint to the nearest point on the medial axis over the radius of the footprint, the relative curvatures of the nearest current point and the next point on the medial axis, and the binary signal of the reverse driving or not. Thus, the state transition probability p(s |s, a) has nine-dimensional input and six-dimensional output. We collect 722 transition samples. We randomly choose n = 200, 250, and 300 for training and use the rest for testing.", "cite_spans": [], "ref_spans": []}, {"section": "Computer Art.", "text": "The estimation results are summarized at the bottom of Tables 3 and 4 . These tables show that there exists a low-dimensional sufficient subspace and the proposed method can find it.", "cite_spans": [], "ref_spans": [{"start": 55, "end": 69, "text": "Tables 3 and 4", "ref_id": "TABREF3"}]}, {"section": "Conclusion", "text": "We proposed a new method for conditional-density estimation in highdimension problems. The key idea of the proposed method is to perform sufficient dimensionality reduction by minimizing the square-loss conditional entropy (SCE), which can be estimated by least-squares conditional-density estimation. Thus, dimensionality-reduction and conditional-density estimation are carried out simultaneously in an integrated manner.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusion", "text": "We have shown that SCE and the squared-loss mutual information (SMI) are similar but different in that the output density is included in the denominator of the density ratio in SMI. This means that estimation of SMI is hard when the output density is fluctuated, while the proposed method using SCE does not suffer from this problem. The proposed method is also robust against outliers since minimization of the Pearson divergence automatically weighs down the effects of outlier points. Moreover, the proposed method is applicable to multivariate output data, which is not straightforward to handle in other dimensionality-reduction methods based on conditional probability density. The effectiveness of the proposed method was demonstrated through extensive experiments, including humanoid robot transition and computer art. Using \u2202X \u22121 \u2202 h k \u2202W l,l = \u2212 1 \u03c3 2 n n i=1 \u03d5 k (z i , y i ) ((z (l) i \u2212 u (l) k )(x (l ) i \u2212\u0169 (l ) k )).", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "A general class of coefficients of divergence of one distribution from another", "authors": [{"first": "S", "middle": ["M"], "last": "Ali", "suffix": ""}, {"first": "S", "middle": ["D"], "last": "Silvey", "suffix": ""}], "year": 1966, "venue": "Journal of the Royal Statistical Society, Series B", "link": "117000403"}, "BIBREF1": {"title": "Natural gradient works efficiently in learning", "authors": [{"first": "S", "middle": [], "last": "Amari", "suffix": ""}], "year": 1998, "venue": "Neural Computation", "link": "207585383"}, "BIBREF2": {"title": "UCI machine learning repository", "authors": [{"first": "K", "middle": [], "last": "Bache", "suffix": ""}, {"first": "M", "middle": [], "last": "Lichman", "suffix": ""}], "year": 2013, "venue": "", "link": null}, "BIBREF3": {"title": "Robust and efficient estimation by minimising a density power divergence", "authors": [{"first": "A", "middle": [], "last": "Basu", "suffix": ""}, {"first": "I", "middle": ["R"], "last": "Harris", "suffix": ""}, {"first": "N", "middle": ["L"], "last": "Hjort", "suffix": ""}, {"first": "M", "middle": ["C"], "last": "Jones", "suffix": ""}], "year": 1998, "venue": "Biometrika", "link": "53496021"}, "BIBREF5": {"title": "Cb: A humanoid research platform for exploring neuroscience", "authors": [{"first": "C", "middle": ["J"], "last": "Stephen", "suffix": ""}], "year": 2007, "venue": "Advanced Robotics", "link": "78356"}, "BIBREF6": {"title": "Sufficient dimension reduction via inverse regression", "authors": [{"first": "R", "middle": ["D"], "last": "Cook", "suffix": ""}, {"first": "L", "middle": [], "last": "Ni", "suffix": ""}], "year": 2005, "venue": "Journal of the American Statistical Association", "link": null}, "BIBREF7": {"title": "Information-type measures of difference of probability distributions and indirect observation", "authors": [{"first": "I", "middle": [], "last": "Csisz\u00e1r", "suffix": ""}], "year": 1967, "venue": "Studia Scientiarum Mathematicarum Hungarica", "link": "125038022"}, "BIBREF8": {"title": "The geometry of algorithms with orthogonality constraints", "authors": [{"first": "A", "middle": [], "last": "Edelman", "suffix": ""}, {"first": "T", "middle": ["A"], "last": "Arias", "suffix": ""}, {"first": "S", "middle": ["T"], "last": "Smith", "suffix": ""}], "year": 1998, "venue": "SIAM Journal on Matrix Analysis and Applications", "link": "16632320"}, "BIBREF9": {"title": "Kernel dimension reduction in regression", "authors": [{"first": "K", "middle": [], "last": "Fukumizu", "suffix": ""}, {"first": "F", "middle": ["R"], "last": "Bach", "suffix": ""}, {"first": "M", "middle": ["I"], "last": "Jordan", "suffix": ""}], "year": 2009, "venue": "Annals of Statistics", "link": "7236872"}, "BIBREF10": {"title": "Robust statistics", "authors": [{"first": "P", "middle": ["J"], "last": "Huber", "suffix": ""}], "year": 1981, "venue": "", "link": null}, "BIBREF11": {"title": "Dual representation of \u03c6-divergences and applications", "authors": [{"first": "A", "middle": [], "last": "Keziou", "suffix": ""}], "year": 2003, "venue": "Comptes rendus math\u00e9matique", "link": "121109143"}, "BIBREF12": {"title": "On information and sufficiency", "authors": [{"first": "S", "middle": [], "last": "Kullback", "suffix": ""}, {"first": "R", "middle": ["A"], "last": "Leibler", "suffix": ""}], "year": 1951, "venue": "Annals of Mathematical Statistics", "link": "120349231"}, "BIBREF13": {"title": "Sliced inverse regression for dimension reduction", "authors": [{"first": "K", "middle": [], "last": "Li", "suffix": ""}], "year": 1991, "venue": "Journal of the American Statistical Association", "link": "30158078"}, "BIBREF14": {"title": "Estimating divergence functionals and the likelihood ratio by convex risk minimization", "authors": [{"first": "X", "middle": [], "last": "Nguyen", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Wainwright", "suffix": ""}, {"first": "M", "middle": ["I"], "last": "Jordan", "suffix": ""}], "year": 2010, "venue": "IEEE Transactions on Information Theory", "link": "1292495"}, "BIBREF15": {"title": "On the criterion that a given system of deviations from the probable in the case of a correlated system of variables is such that it can be reasonably supposed to have arisen from random sampling", "authors": [{"first": "K", "middle": [], "last": "Pearson", "suffix": ""}], "year": 1900, "venue": "Philosophical Magazine Series", "link": "123466489"}, "BIBREF16": {"title": "Sufficient dimension reduction via Bayesian mixture modeling", "authors": [{"first": "B", "middle": ["J"], "last": "Reich", "suffix": ""}, {"first": "H", "middle": ["D"], "last": "Bondell", "suffix": ""}, {"first": "L", "middle": [], "last": "Li", "suffix": ""}], "year": 2011, "venue": "Biometrics", "link": "13185935"}, "BIBREF17": {"title": "Density ratio matching under the Bregman divergence: A unified framework of density ratio estimation", "authors": [{"first": "M", "middle": [], "last": "Sugiyama", "suffix": ""}, {"first": "T", "middle": [], "last": "Suzuki", "suffix": ""}, {"first": "T", "middle": [], "last": "Kanamori", "suffix": ""}], "year": 2012, "venue": "Annals of the Institute of Statistical Mathematics", "link": "46615544"}, "BIBREF18": {"title": "Conditional density estimation via least-squares density ratio estimation", "authors": [{"first": "M", "middle": [], "last": "Sugiyama", "suffix": ""}, {"first": "I", "middle": [], "last": "Takeuchi", "suffix": ""}, {"first": "T", "middle": [], "last": "Kanamori", "suffix": ""}, {"first": "T", "middle": [], "last": "Suzuki", "suffix": ""}, {"first": "H", "middle": [], "last": "Hachiya", "suffix": ""}, {"first": "D", "middle": [], "last": "Okanohara", "suffix": ""}], "year": 2010, "venue": "Proceedings of the Thirteenth International Conference on Artificial Intelligence and Statistics (AISTATS2010)", "link": "7813665"}, "BIBREF19": {"title": "Reinforcement learning: An introduction", "authors": [{"first": "R", "middle": ["S"], "last": "Sutton", "suffix": ""}, {"first": "G", "middle": ["A"], "last": "Barto", "suffix": ""}], "year": 1998, "venue": "", "link": "9166388"}, "BIBREF20": {"title": "Sufficient dimension reduction via squared-loss mutual information estimation", "authors": [{"first": "T", "middle": [], "last": "Suzuki", "suffix": ""}, {"first": "M", "middle": [], "last": "Sugiyama", "suffix": ""}], "year": 2013, "venue": "Neural Computation", "link": "17255810"}, "BIBREF21": {"title": "Sliced regression for dimension reduction", "authors": [{"first": "H", "middle": [], "last": "Wang", "suffix": ""}, {"first": "Y", "middle": [], "last": "Xia", "suffix": ""}], "year": 2008, "venue": "Journal of the American Statistical Association", "link": "14159011"}, "BIBREF22": {"title": "A constructive approach to the estimation of dimension reduction directions", "authors": [{"first": "Y", "middle": [], "last": "Xia", "suffix": ""}], "year": 2007, "venue": "Annals of Statistics", "link": null}, "BIBREF23": {"title": "Artist agent: A reinforcement learning approach to automatic stroke generation in oriental ink painting", "authors": [{"first": "N", "middle": [], "last": "Xie", "suffix": ""}, {"first": "H", "middle": [], "last": "Hachiya", "suffix": ""}, {"first": "M", "middle": [], "last": "Sugiyama", "suffix": ""}], "year": 2012, "venue": "Proceedings of 29th International Conference on Machine Learning (ICML2012)", "link": "6424168"}}, "ref_entries": {"FIGREF0": {"text": "Conditional density estimation (CDE) and dimensionality reduction (DR). (a) CDE without DR performs poorly in high-dimensional problems. (b) CDE after DR can magnify the small DR error in the CDE step. (c) CDE with DR (proposed) performs CDE in the DR process in an integrated manner.", "type": "figure"}, "FIGREF1": {"text": "Examples of conditional density estimation by plain LSCDE (None/LSCDE) and the proposed method (LSCE/LSCDE).", "type": "figure"}, "FIGREF2": {"text": "(Left) The mean and standard error of the dimensionality-reduction error over 20 runs. (Right) The mean and standard error of the conditionaldensity estimation error over 20 runs.", "type": "figure"}, "FIGREF3": {"text": "(Left) Example histograms of {y i } 400 i=1 on the artificial data sets. (Right) Example data plot of relevant features of x against y when n = 400 on the artificial data sets. The left distribution in the histogram of data set c is regarded as outliers.", "type": "figure"}, "FIGREF4": {"text": "95(.17) \u22123.03(.14) \u22122.69(.18) \u22122.95(.11) \u22123.13(.13) \u22123.17(.10) \u22122.96(.10) \u22122.95(.12) \u22122.62(.09) \u22122.72(.06) Yacht \u22126.46(.02) \u22126.30(.14) \u22125.63(.26) \u22125.47(.29) \u22126.25(.06) \u22125.97(.12) \u22126.45(.04) \u22126.05(.18) \u22121.72(.04) \u22122.95(.02) Auto MPG \u22121.80(.04) \u22121.75(.05) \u22121.85(.04) \u22121.77(.05) \u22121.98(.04) \u22121.97(.04) \u22121.91(.04) \u22121.84(.05) \u22121.75(.04) \u22121.46(.04) Concrete \u22121.37(.03) \u22121.18(.06) \u22121.30(.03) \u22121.18(.04) \u22121.42(.06) \u22121.15(.05) \u22121.37(.04) \u22121.10(.04) \u22121.11(.02) \u22120.80(.03) Physicochem \u22121.19(.01) \u22120.99(.02) \u22121.20(.01) \u22120.97(.02) \u22121.17(.01) \u22120.93(.02) \u22121.13(.02) \u22120.96(.02) \u22121.19(.01) \u22120.91(.01) Red Wine \u22122.85(.02) \u22121.95(.17) \u22122.82(.03) \u22121.93(.17) \u22122.82(.02) \u22121.93(.20) \u22122.66(.03) \u22122.18(.14) \u22122.03(.02) \u22121.13(.04) White Wine \u22122.31(.01) \u22122.47(.15) \u22122.35(.02) \u22122.60(.12) \u22122.17(.01) \u22122.65(.20) \u22121.97(.02) \u22121.91(.02) \u22122.06(.01) \u22121.89(.01) Forest Fires \u22127.18(.02) \u22126.91(.03) \u22126.93(.04) \u22126.96(.02) \u22127.10(.03) \u22126.93(.04) \u22127.08(.03) \u22126.97(.01) \u22123.40(.07) \u22126.96(.02) Housing \u22121.72(.09) \u22121.58(.08) \u22121.91(.05) \u22121.62(.08) \u22121.76(.11) \u22121.50(.13) \u22121.86(.09) \u22121.74(.03) \u22121.41(.05) \u22121.13(.01) Note: The best methods in terms of the mean error and comparable methods according to the two-sample paired t-test at the significance level 5% are specified in bold.", "type": "figure"}, "FIGREF6": {"text": ")p(y|x)p(x)dxdy,where p(z, z \u22a5 , y) = p(x, y), and dzdz \u22a5 = dx are used. Therefore,SCE(Y |Z) \u2212 SCE(Y|X) y|x) \u2212 p(y|z)) 2 p(x)dxdy.We can also express p(y|x) in terms of p(y|z) asp(y|x) = p(x, \u22a5 |z)p(z)p(y|z)p(z) = p(z, z \u22a5 , y)p(z, y) p(z \u22a5 |z)p(z)p(y|z)p(z) = p(z \u22a5 , y|z)p(z, y) p(z \u22a5 |z)p(y|z)p(z) = p(z \u22a5 , y|z) p(z \u22a5 |z)p(y|z) p(y|z).", "type": "figure"}, "TABREF0": {"text": "Thus, for data set b, the density ratio", "type": "table"}, "TABREF1": {"text": ", showing that LSCDE tends to outperform -KDE and the proposed LSCE/LSCDE method works well overall. Both LSMI/LSCDE and dMAVE/LSCDE methods also perform well in all data sets, while BDR/LSCDE does not work well in the data sets containing outliers such as Red Wine, White Wine, and Forest Fires. Table 2 describes Mean and Standard Error of the Conditional Density Estimation Error over 10 Runs for Univariate Output Data Sets.", "type": "table"}, "TABREF2": {"text": "Mean and Standard Error of the Chosen Subspace Dimensionality over 10 Runs for Univariate Output Data Sets.", "type": "table"}, "TABREF3": {"text": "Mean and Standard Error of the Conditional Density Estimation Error over 10 Runs for Multivariate Output Data Sets.", "type": "table"}, "TABREF4": {"text": "Mean and Standard Error of the Chosen Subspace Dimensionality over 10 Runs for Multivariate Output Data Sets. Simulator of the upper-body part of the humanoid robot CB-i.system dynamic as a state transition probability p(s |s, a) from these samples. Thus, as the conditional density estimation problem, the state-action pair (s , a ) is regarded as input variable x, while the next state s is regarded as output variable y. Such state-transition probabilities are highly useful in model-based reinforcement learning", "type": "table"}}}
{"paper_id": "2878408", "_pdf_hash": "893335125f155c54b4ce9946709ef4796c0170c7", "abstract": [{"section": "Abstract", "text": "Breast cancer is among the most common cancers worldwide. Diabetes is an important chronic health problem associated with insulin resistance, increased insulin level, changes in growth hormones and factors, and activation of mitogen-activating protein kinase (MAPK) pathways, leading to an increased breast cancer risk. \ue062is paper looked at the epidemiologic studies of the association between type 2 diabetes and risk of breast cancer and its effect on overall cancer-speci\ufffdc survival. \ue062e combined evidence overall supported a modest association between type 2 diabetes and the risk of breast cancer, which was found to be more prevalent among postmenopausal women. Effect of oral diabetics and insulin therapy on breast cancer risk was also evaluated. It was found that metformin and thiazolidinones tended to have a protective role. Metformin therapy trials for its use as an adjuvant for breast cancer treatment are still ongoing. Sulfonylurea and insulin therapy were found to be mildly associated with increased overall cancers. No evidence or studies evaluated the association of DPPIV inhibitors and GLP 1 agonists with breast cancer risk because of their recent introduction into the management of diabetes.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Breast cancer is among the most common cancers worldwide and is the second leading cause of cancer death for women in the United States, a\ue09der lung cancer, with an estimated incidence of 226,870 cases and estimated deaths of 39, 510 cases in the year of 2012. \ue062e National Cancer Institute also estimated that 1 in 8 women in the United States has the chance of developing invasive breast cancer throughout her lifetime [1, 2] . Diabetes is also a very common chronic health problem where it is currently estimated that 10% of women in the United States over the age of 20 have type 2 diabetes. Prevalence of diabetes has steadily increased since 1990. \ue062e 2010 CDC study projected that by 2050, as many as one of three US adults could have diabetes if the current trend continues [3, 4] . Association between diabetes and breast cancer has been noted where 16% of older breast cancer patients were found to suffer from diabetes, and this might have important public health implications.", "cite_spans": [{"start": 224, "end": 227, "text": "39,", "ref_id": "BIBREF38"}, {"start": 422, "end": 424, "text": "2]", "ref_id": "BIBREF1"}, {"start": 778, "end": 781, "text": "[3,", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "Pathogenesis", "text": "Different mechanisms contribute to the association between diabetes and breast cancer. Diabetes induces several changes in different hormonal systems including insulin, insulin-like growth factors, estrogen, and other growth factors, all of which may affect the risk for breast cancer development. As shown in Figure 1 , type 2 diabetes mellitus is associated with insulin resistance, in\ufffdammation with increased in\ufffdammatory markers such as Interleukin 6 and increased reactive oxygen species with all of which being related to high insulin level, which in turn activates the insulin receptor, which is a tyrosine kinase receptor, expressed in skeletal muscle, adipose tissue, liver, and other tissues including normal breast tissue. Insulin receptor, once activated, will phosphorylate a number of intracellular proteins, leading to the activation of the extracellular signal-regulated kinase (ERK) cascade, one of the mitogen-activating protein kinase (MAPK) pathways, which increases mitogenesis and breast cancer risk. Insulin also suppresses IGF binding protein-1, thus increasing bioavailable IGF-1. Diabetes is also associated with decreased adiponectin plasma levels, which inhibits the AMP kinase (AMPK) and thus activates the ERK and Akt pathways leading to increased breast cancer risk [5, 6] .", "cite_spans": [{"start": 1296, "end": 1299, "text": "[5,", "ref_id": "BIBREF4"}, {"start": 1300, "end": 1302, "text": "6]", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Association of Diabetes and Incidence of Breast Cancer.", "text": "With regards to the complex association between type 2 diabetes and incidence of breast cancer, several prospective and case-control studies reported increased risk ratios for breast cancer among women with type 2 diabetes [7] [8] [9] [10] [11] [12] [13] [14] . However, other studies found no association [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] . It is important to note that the above studies included small sample size, did not include potential confounders, and were underpowered to look at the real association. One of those studies, however, which was the Iowa Women's Study did adjust for BMI and waist-to-hip ratio and did not reveal an overall association between type 2 diabetes and breast cancer incidence [23] . \ue062e Nurses' Health Study, provided the largest population, had the longest followup that included a total of 116,488 female nurses, whose ages were 30-55 years old and who were free of cancer in 1976, and then followed up through 1996 for the occurrence of type 2 diabetes and through 1998 for the occurrence of incident invasive breast cancer, as veri\ufffded by medical records and pathology reports. Women with type 2 diabetes were found to have a modestly elevated incidence of breast cancer (hazard ratio of ", "cite_spans": [{"start": 223, "end": 226, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 227, "end": 230, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 231, "end": 234, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 235, "end": 239, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 240, "end": 244, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 245, "end": 249, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 250, "end": 254, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 255, "end": 259, "text": "[14]", "ref_id": "BIBREF13"}, {"start": 306, "end": 310, "text": "[15]", "ref_id": "BIBREF14"}, {"start": 311, "end": 315, "text": "[16]", "ref_id": "BIBREF15"}, {"start": 316, "end": 320, "text": "[17]", "ref_id": "BIBREF16"}, {"start": 321, "end": 325, "text": "[18]", "ref_id": "BIBREF17"}, {"start": 326, "end": 330, "text": "[19]", "ref_id": "BIBREF18"}, {"start": 331, "end": 335, "text": "[20]", "ref_id": "BIBREF19"}, {"start": 336, "end": 340, "text": "[21]", "ref_id": "BIBREF20"}, {"start": 341, "end": 345, "text": "[22]", "ref_id": "BIBREF21"}, {"start": 346, "end": 350, "text": "[23]", "ref_id": "BIBREF22"}, {"start": 351, "end": 355, "text": "[24]", "ref_id": "BIBREF23"}, {"start": 356, "end": 360, "text": "[25]", "ref_id": "BIBREF24"}, {"start": 732, "end": 736, "text": "[23]", "ref_id": "BIBREF22"}], "ref_spans": []}, {"section": "Association between Diabetes and Breast Cancer Risk.", "text": "A cohort study within the UK General Practice Research Database found that diabetes was associated with 29% increased breast cancer risk (95% CI: 1.16-1.44), but the association was markedly attenuated when adjusted for age, region, and body mass index (BMI) (HR: 1.12; 95% CI: 0.98-1.29). \ue062is cohort also showed that women with breast cancer who had preexisting diabetes had an overall increased mortality of 49%, (95% CI: 1.17-1.88), as compared to breast cancer without diabetes and this persisted even a\ue09der controlling for age, period, region, BMI, smoking, alcohol, and deprivation [30] . In another study, including 4,390 Asian patients with breast cancer, of which 341 (7.7%) presented with DM, the 5-year breast cancer survival and overall survival was signi\ufffdcantly lower diabetics as compared to nondiabetics (BCS, 85% versus 91%; OS, 79% versus 90%), respectively. \ue062is persisted even a\ue09der adjusting for all clinical variables and comorbidities [31] . In a retrospective study, including breast cancer patients who had undergone mastectomy and completed adjuvant chemotherapy from 1998 to 2010, median disease-free survival was found to be 81 months (95% CI, 61.6-100.4) in nondiabetic patients and 36 months (95% CI, 13.6-58.4) in diabetic patients ( ) [32] . On the other hand, in a retrospective analysis of 265 patients with advanced breast cancer, no difference in overall survival was observed between the diabetic and nondiabetic patients, but this study showed that the overall survival was greater in diabetic patients who had proper metabolic control as compared to those with poor metabolic control [33] . Moreover, in the Fremantle Diabetes Study (FDS), which was a community-based longitudinal observational study of 1426 subjects, 1294 of which had type 2 diabetes, it was found that diabetic men and women had similar risks of prostate and breast cancer like those of controls [34] .", "cite_spans": [{"start": 587, "end": 591, "text": "[30]", "ref_id": "BIBREF29"}, {"start": 954, "end": 958, "text": "[31]", "ref_id": "BIBREF30"}, {"start": 1263, "end": 1267, "text": "[32]", "ref_id": "BIBREF31"}, {"start": 1619, "end": 1623, "text": "[33]", "ref_id": "BIBREF32"}, {"start": 1901, "end": 1905, "text": "[34]", "ref_id": "BIBREF33"}], "ref_spans": []}, {"section": "Association between Diabetes and Breast Cancer Risk.", "text": "A recent meta-analysis showed that the relative risk for breast cancer in women with diabetes was 1.27 (95% con\ufffd-dence interval (CI), 1. [36] .", "cite_spans": [{"start": 137, "end": 141, "text": "[36]", "ref_id": "BIBREF35"}], "ref_spans": []}, {"section": "Association between Diabetes and Breast Cancer Risk.", "text": "In a recent review of the association of diabetes, metabolic syndrome, and breast cancer risk, included were 26 studies, of which 10 were case-control studies, 3 of which directly looked at the association of diabetes and breast cancer [20, 37, 38] , 14 were cohort studies [26, [39] [40] [41] [42] , 5 of which looked at the above association, and 2 were cross-sectional studies [43, 44] . \ue062is paper supported a modest association between type 2 diabetes and the risk of breast cancer, which appears to be more consistent among postmenopausal as compared to premenopausal women. It was proposed in this review that hyperinsulinemic state would suppress SHBG, hence increasing free available estrogen concentrations. In addition, IGF-I stimulates the production of androgens in the ovarian stroma, which displaces estrogens from SHBG. \ue062ey also added that estradiol alters the expression of many components of the IGF-I system; where the ligand-bound estrogen receptor binds to and activates IGF-1R directly and as a result IGF-I signaling enhances estrogen receptor activation leading to the phosphorylation of the estrogen receptor. \ue062is leads to IGF-I and estrogen having a synergistic effects leading to proliferation and increasing breast cancer risk in the presence of the hyperinsulinemic state of type 2 diabetes [45, 46] .", "cite_spans": [{"start": 236, "end": 240, "text": "[20,", "ref_id": "BIBREF19"}, {"start": 241, "end": 244, "text": "37,", "ref_id": "BIBREF36"}, {"start": 245, "end": 248, "text": "38]", "ref_id": "BIBREF37"}, {"start": 274, "end": 278, "text": "[26,", "ref_id": "BIBREF25"}, {"start": 279, "end": 283, "text": "[39]", "ref_id": "BIBREF38"}, {"start": 284, "end": 288, "text": "[40]", "ref_id": "BIBREF39"}, {"start": 289, "end": 293, "text": "[41]", "ref_id": "BIBREF40"}, {"start": 294, "end": 298, "text": "[42]", "ref_id": "BIBREF41"}, {"start": 380, "end": 384, "text": "[43,", "ref_id": "BIBREF42"}, {"start": 385, "end": 388, "text": "44]", "ref_id": "BIBREF43"}, {"start": 1319, "end": 1323, "text": "[45,", "ref_id": "BIBREF44"}, {"start": 1324, "end": 1327, "text": "46]", "ref_id": "BIBREF45"}], "ref_spans": []}, {"section": "Diabetes Medications and Breast Cancer Risk", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Metformin Use and Breast Cancer Risk.", "text": "Several observational studies suggested that metformin use decreases the incidence of several cancers overall [47] [48] [49] [50] . For example, Evans and colleagues [47] reported a decreased risk of breast cancer in diabetics receiving metformin (versus those patients not on metformin), with the protective effect increasing with the increase in metformin exposure. However, \ufffdnd-ings regarding breast cancer and metformin use have been mixed. A recent meta-analysis which included seven independent observational studies supported a protective effect of metformin on breast cancer risk among postmenopausal women with diabetes (OR was 0.83). Stronger associations were noted with longer metformin use [51] . In addition, in the cohort study within the UK General Practice Research Database, it was found that metformin monotherapy had weaker association with breast cancer risk with a hazard ratio of 1.04 (95% CI: 0.79-1.37) as compared to sulfonylurea and insulin where the latter were more associated with breast cancer risk (HR: 1.33; 95% CI: 0.63-2.83) [30] . A case-control study also demonstrated a decreased risk of breast cancer in women who took metformin for several years as compared to short-term users [52] . Moreover, a nested case-control study of the Danish medical registry included 4323 type 2 diabetic perimenopausal or postmenopausal women and showed that those who used metformin for at least 1 year were less likely to be diagnosed with breast cancer as compared to those who did not use metformin. Moreover this association was not altered even a\ue09der adjustment for obesity, diabetes complications, and other predictors of breast cancer [53] .", "cite_spans": [{"start": 110, "end": 114, "text": "[47]", "ref_id": "BIBREF46"}, {"start": 115, "end": 119, "text": "[48]", "ref_id": "BIBREF47"}, {"start": 120, "end": 124, "text": "[49]", "ref_id": "BIBREF48"}, {"start": 125, "end": 129, "text": "[50]", "ref_id": "BIBREF49"}, {"start": 166, "end": 170, "text": "[47]", "ref_id": "BIBREF46"}, {"start": 703, "end": 707, "text": "[51]", "ref_id": "BIBREF50"}, {"start": 1060, "end": 1064, "text": "[30]", "ref_id": "BIBREF29"}, {"start": 1218, "end": 1222, "text": "[52]", "ref_id": "BIBREF51"}, {"start": 1662, "end": 1666, "text": "[53]", "ref_id": "BIBREF52"}], "ref_spans": []}, {"section": "Metformin Use and Breast Cancer Risk.", "text": "As for the proposed protective effect of metformin, it is well known that metformin acts by increasing glucose uptake by skeletal muscle and thus reducing hyperglycemia by improving insulin sensitivity through the stimulation of the adenosine monophosphate-activated protein kinase (AMPK), leading to the suppression of gluconeogenesis, protein, and fatty acid synthesis resulting in partial metabolic normalization of hyperglycemia and insulin resistance [54, 55] . Stimulation of the AMPK inhibits mammalian target of rapamycin (mTOR)/ribosomal S6 kinase pathway. \ue062is would inhibit pathological cell cycle progression, cell growth, and angiogenesis [56, 57] . Moreover stimulation of AMPK by metformin led to decrease cell proliferation in both estrogen receptor alpha (ER alpha) negative and positive human breast cancer cell lines, in addition to the inhibition of aromatase expression in human breast adipose stromal cells [58, 59] . In vitro studies have also shown that metformin use reduces the proliferation of breast cancer cells [60] . \ue062e role of metformin as anti-breast cancer agent has also been attributed to its effect on immune system but this has to be further looked at in more details [61] .", "cite_spans": [{"start": 456, "end": 460, "text": "[54,", "ref_id": "BIBREF53"}, {"start": 461, "end": 464, "text": "55]", "ref_id": "BIBREF54"}, {"start": 651, "end": 655, "text": "[56,", "ref_id": "BIBREF55"}, {"start": 656, "end": 659, "text": "57]", "ref_id": "BIBREF56"}, {"start": 928, "end": 932, "text": "[58,", "ref_id": "BIBREF57"}, {"start": 933, "end": 936, "text": "59]", "ref_id": "BIBREF58"}, {"start": 1040, "end": 1044, "text": "[60]", "ref_id": "BIBREF59"}, {"start": 1205, "end": 1209, "text": "[61]", "ref_id": "BIBREF60"}], "ref_spans": []}, {"section": "Metformin Use and Breast Cancer Risk.", "text": "Recently, an epidemiological study of 2,529 women with breast cancer reported higher pathologic complete response in diabetic patients on neoadjuvant systemic therapy and receiving metformin (pCR 24%) as compared to diabetic patients not receiving metformin (pCR 8%) and nondiabetic patients not receiving metformin (pCR 16%) [62] . However metformin failed to signi\ufffdcantly improve the estimated 3-year relapse-free survival rate in this study. Some prospective clinical trials have been completed in nondiabetic patients who received low doses of metformin (250 mg/day) and showed a reduction in the proliferative activity of colonic epithelium [63] . \ue062is led to ongoing studies involving neoadjuvant metformin treatment of newly diagnosed breast cancer patients, which have also demonstrated that metformin has favorable effects on tumor cell proliferation and apoptosis [64, 65] .", "cite_spans": [{"start": 326, "end": 330, "text": "[62]", "ref_id": "BIBREF61"}, {"start": 646, "end": 650, "text": "[63]", "ref_id": "BIBREF62"}, {"start": 873, "end": 877, "text": "[64,", "ref_id": "BIBREF63"}, {"start": 878, "end": 881, "text": "65]", "ref_id": "BIBREF64"}], "ref_spans": []}, {"section": "Metformin Use and Breast Cancer Risk.", "text": "A currently ongoing phase III trial of metformin versus placebo in early-stage breast cancer, where nondiabetic women or men, younger than age 75 with newly diagnosed early-stage breast cancer, within the previous 12 months, and following their surgery to remove their tumor, will be randomly assigned to take metformin or placebo pills twice a day for 5 years. Participants in the trial may also receive adjuvant hormone and/or radiation therapy, but if chemotherapy (adjuvant or neoadjuvant) was given, it must have been completed prior to joining the study. \ue062is study will mainly monitor to see if metformin would improve disease-free survival, overall survival, and a number of other medical, biological, and quality-of-life endpoints [66] .", "cite_spans": [{"start": 739, "end": 743, "text": "[66]", "ref_id": "BIBREF65"}], "ref_spans": []}, {"section": "Metformin Use and Breast Cancer Risk.", "text": "Other 6 ongoing studies are currently done evaluating the efficacy and safety of treating cancer patients with the metformin. \ue062e European Institute of Oncology in Italy is currently planning a presurgical randomized, double-blind, placebo-controlled phase II trial in which 100 histologically con\ufffdrmed that breast cancer patients not suitable for neoadjuvant therapy will be assigned randomly to either metformin (850 mg twice/daily or placebo until surgery with the aim of evaluating the activity of metformin on Ki67-measured tumor proliferation [67] . Also in Italy, two randomized clinical trial, one of them is the Plotina plan, aim to evaluate the effect of metformin on breast cancer as primary prevention in around 16,000 postmenopausal women, aged 45-74 years, where patients are being randomly assigned to the metformin treatment or placebo, and histologically con\ufffdrmed invasive breast cancer diagnosed a\ue09der recruitment to the trial (date at interview) and before the end of the last follow-up period. \ue062e results of the two trials will clarify the role of metformin as a chemopreventive agent [68] .", "cite_spans": [{"start": 548, "end": 552, "text": "[67]", "ref_id": "BIBREF66"}, {"start": 1103, "end": 1107, "text": "[68]", "ref_id": "BIBREF67"}], "ref_spans": []}, {"section": "Metformin Use and Breast Cancer Risk.", "text": "Another phase II, randomized, open-label, multicentric clinical trial wants to evaluate HER2-related bene\ufffdts of metformin as neoadjuvant chemotherapy with chemotherapy and trastuzumab in women diagnosed with HER2-positive primary breast cancer with the assessment of its effect on a 3-year disease free survival [69] .", "cite_spans": [{"start": 312, "end": 316, "text": "[69]", "ref_id": "BIBREF68"}], "ref_spans": []}, {"section": "\ue0bbiazolinediones and Breast", "text": "Cancer. \ue062ree nested casecontrol studies, included 513 breast cancer patients as compared to 2557 controls, were used to evaluate the risk of breast, colon, and prostate cancers developing in patients exposed to thiazolidinediones (TZDs) as compared with other antidiabetic agents and they showed a neutral effect of TZDs on the likelihood of the development of cancers including colon, prostate, and breast cancers [70] .", "cite_spans": [{"start": 415, "end": 419, "text": "[70]", "ref_id": "BIBREF69"}], "ref_spans": []}, {"section": "\ue0bbiazolinediones and Breast", "text": "\ue062e therapeutic effects of troglitazone, in patients with refractory metastatic breast cancer to at least one chemotherapy regimen (ER negative tumors) or two hormonal regimens (ER positive tumors), were evaluated before it was withdrawn from the market following FDA warnings on hepatic toxicity. No objective responses were observed and it was found to have little apparent clinical value among patients with treatment-refractory metastatic breast cancer [71] . In a study of 1983 consecutive patients with HER2+ breast cancer treated between January 1 1998 and September 30 2010, it was shown that metformin ( , HR = 0.52, 95% CI 0.28-0.97) and thiazolidinediones ( ; HR = 0.41, 95% CI 0.18-0.93) signi\ufffdcantly lengthened survival and decreased breast cancer-speci\ufffdc mortality ( 2 , HR = 0.47, 95% CI 0.24-0.90 and , HR = 0.42, 95% CI 0.18-0.98, resp.) [72] . It was proposed that thiazolenediones has a protective role decreasing breast cancer risk through downregulating Wnt/Catenin Signaling, hence targeting abnormal breast cancer cells directly [73] .", "cite_spans": [{"start": 456, "end": 460, "text": "[71]", "ref_id": "BIBREF70"}, {"start": 854, "end": 858, "text": "[72]", "ref_id": "BIBREF71"}, {"start": 1051, "end": 1055, "text": "[73]", "ref_id": "BIBREF72"}], "ref_spans": []}, {"section": "Sulfonylurea and Breast", "text": "Cancer. In a recent review, it was found that the \ufffdrst and second generation sulfonylureas, but not the third generation glimepiride, and glinides increased the risk of overall cancer, speci\ufffdcally hepatocellular cancer but it was less frequently associated with breast cancer, pancreatic cancer, or bladder cancer. It was also found that this increased but slightly less risk as compared to insulin supported the hypothesis that an increasing insulin level plays an important role in carcinogenesis [74] . No other studies looked at the particular association of sulfonylurea use and breast cancer risk. \ue062eir relatively short-term use clinically does not permit any meaningful data on their malignancy risks. Sitagliptin did show increased pancreatic ductal hyperplasia in a small rodent model study which may predispose to pancreatic cancer risk although one short-term study involving human pancreatic cancer cell lines did not show this [75] [76] [77] . No data is available on the association of DPPIV inhibitors, GLP-1 agonists, and breast cancer risk due to their introduction recently in the diabetes management.", "cite_spans": [{"start": 499, "end": 503, "text": "[74]", "ref_id": "BIBREF73"}, {"start": 940, "end": 944, "text": "[75]", "ref_id": "BIBREF74"}, {"start": 945, "end": 949, "text": "[76]", "ref_id": "BIBREF75"}, {"start": 950, "end": 954, "text": "[77]", "ref_id": "BIBREF76"}], "ref_spans": []}, {"section": "DPPIV Inhibitors and Breast Cancer", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Insulin Treatment and Breast Cancer.", "text": "A recent metaanalysis, including 562,043 participants and 14,085 cases of cancer, was published assessing the risk of cancer during treatment with insulin. It showed that insulin treatment was associated with an increased risk of overall cancer (RR (95% CI) = 1.39 (1.14, 1.70)) especially with pancreatic cancer (RR (95% CI) = 4.78 (3.12, 7.32)) [78] . As for the association of insulin therapy with breast cancer, the UK's General Practice Research Database included a cohort of 15,227 women with type 2 diabetes, treated with insulin glargine (4,579 users) and matched with users of other insulins (10,648 users), and followed up till the \ufffdrst breast cancer diagnosis or until the end of December 2009, of which 246 developed breast cancer during the 8-year followup. It was shown that insulin glargine was not associated with an increased risk of breast cancer during the \ufffdrst 5 years of use. However, longer-term use may increase this risk, particularly in women with the longstanding use of insulin before starting insulin glargine [79] . Signi\ufffdcant association of insulin therapy and breast cancer cases cannot be deduced due to the lack of substantial evidence. In the ORIGIN trial, which was primarily oriented at determining whether the use of insulin glargine, as compared to standard care, in patients with impaired fasting glucose or impaired glucose tolerance, would affect cardiovascular outcome, insulin glargine was not shown to have any signi\ufffdcant increase in cancers (hazard ratio, 1.00; 95% CI, 0.88 to 1.13;", "cite_spans": [{"start": 347, "end": 351, "text": "[78]", "ref_id": "BIBREF77"}, {"start": 1038, "end": 1042, "text": "[79]", "ref_id": "BIBREF78"}], "ref_spans": []}, {"section": "Insulin Treatment and Breast Cancer.", "text": "). It is important to note that this study included 12,537 participants whose mean age was around 65 who had cardiovascular risk factors plus impaired fasting glucose, impaired glucose tolerance, or early diabetes. Insulin glargine was shown to have a neutral effect on cardiovascular outcomes and cancers [80] .", "cite_spans": [{"start": 306, "end": 310, "text": "[80]", "ref_id": "BIBREF79"}], "ref_spans": []}], "bib_entries": {"BIBREF1": {"title": "SEER data submission", "authors": [{"first": "N", "middle": [], "last": "Howlader", "suffix": ""}, {"first": "A", "middle": ["M"], "last": "Noone", "suffix": ""}, {"first": "M", "middle": [], "last": "Krapcho", "suffix": ""}], "year": 1975, "venue": "SEER Cancer Statistics Review", "link": null}, "BIBREF2": {"title": "National diabetes fact sheet: national estimates and general information on diabetes and prediabetes in the United States", "authors": [{"first": "S", "middle": [], "last": "Wild", "suffix": ""}, {"first": "G", "middle": [], "last": "Roglic", "suffix": ""}, {"first": "A", "middle": [], "last": "Green", "suffix": ""}, {"first": "R", "middle": [], "last": "Sicree", "suffix": ""}, {"first": "H", "middle": [], "last": "King", "suffix": ""}, {"first": "Centers", "middle": [], "last": "For", "suffix": ""}, {"first": "Disease", "middle": [], "last": "Control", "suffix": ""}, {"first": "Prevention", "middle": [], "last": "", "suffix": ""}], "year": 2011, "venue": "U.S. Department of Health and Human Services", "link": null}, "BIBREF4": {"title": "Diabetes mellitus and breast cancer", "authors": [{"first": "K", "middle": [], "last": "Masur", "suffix": ""}, {"first": "F", "middle": [], "last": "", "suffix": ""}, {"first": "K", "middle": ["S"], "last": "Znker", "suffix": ""}], "year": 2008, "venue": "Diabetes and Cancer. Epidemiological Evidence and Molecular Links. Front Diabetes", "link": null}, "BIBREF5": {"title": "Insulin resistance and cancer risk: an overview of the pathogenetic mechanisms", "authors": [{"first": "B", "middle": [], "last": "Arcidiacono", "suffix": ""}, {"first": "S", "middle": [], "last": "Iiritano", "suffix": ""}, {"first": "A", "middle": [], "last": "Nocera", "suffix": ""}], "year": 2012, "venue": "Experimental Diabetes Research", "link": "3000481"}, "BIBREF6": {"title": "A prospective study in general practice on breast cancer risk in postmenopausal women", "authors": [{"first": "F", "middle": [], "last": "De Waard", "suffix": ""}, {"first": "E", "middle": ["A"], "last": "Baanders Van Halewijn", "suffix": ""}], "year": 1974, "venue": "International Journal of Cancer", "link": "71196449"}, "BIBREF7": {"title": "Diabetes mellitus and cancer risk: a multisite case-control study", "authors": [{"first": "B", "middle": ["A"], "last": "O&apos;mara", "suffix": ""}, {"first": "T", "middle": [], "last": "Byers", "suffix": ""}, {"first": "E", "middle": [], "last": "Schoenfeld", "suffix": ""}], "year": 1985, "venue": "Journal of Chronic Diseases", "link": null}, "BIBREF8": {"title": "Risk factors in breast carcinoma", "authors": [{"first": "C", "middle": [], "last": "Unger", "suffix": ""}, {"first": "J", "middle": ["C"], "last": "Rageth", "suffix": ""}, {"first": "P", "middle": [], "last": "Wyss", "suffix": ""}, {"first": "M", "middle": [], "last": "Spillmann", "suffix": ""}, {"first": "E", "middle": [], "last": "Hochuli", "suffix": ""}], "year": 1991, "venue": "Schweiz Med Wochenschr", "link": "24202783"}, "BIBREF9": {"title": "Risk of endometrial and breast cancer in patients with diabetes mellitus", "authors": [{"first": "E", "middle": [], "last": "Weiderpass", "suffix": ""}, {"first": "G", "middle": [], "last": "Gridlkey", "suffix": ""}, {"first": "I", "middle": [], "last": "Persson", "suffix": ""}, {"first": "O", "middle": [], "last": "Nyren", "suffix": ""}, {"first": "A", "middle": [], "last": "Ekbom", "suffix": ""}, {"first": "H", "middle": ["O"], "last": "Adami", "suffix": ""}], "year": 1971, "venue": "International Journal of Cancer", "link": "33129938"}, "BIBREF10": {"title": "Cancer among patients with diabetes, obesity and abnormal blood lipids: a population-based register study in Sweden", "authors": [{"first": "B", "middle": [], "last": "Attner", "suffix": ""}, {"first": "M", "middle": [], "last": "Landin-Olsson", "suffix": ""}, {"first": "T", "middle": [], "last": "Lithman", "suffix": ""}, {"first": "D", "middle": [], "last": "Noreen", "suffix": ""}, {"first": "H", "middle": [], "last": "Olsson", "suffix": ""}], "year": 2012, "venue": "Cancer Causes & Control", "link": "14058579"}, "BIBREF11": {"title": "\ue062e in\ufffduence of type 2 diabetes and glucose-lowering therapies on cancer risk in the Taiwanese", "authors": [{"first": "M", "middle": ["C"], "last": "Hsieh", "suffix": ""}, {"first": "T", "middle": ["C"], "last": "Lee", "suffix": ""}, {"first": "S", "middle": ["M"], "last": "Cheng", "suffix": ""}, {"first": "S", "middle": ["T"], "last": "Tu", "suffix": ""}, {"first": "M", "middle": ["H"], "last": "Yen", "suffix": ""}, {"first": "C", "middle": ["H"], "last": "Tseng", "suffix": ""}], "year": 2012, "venue": "Experimental Diabetes Research", "link": "16293912"}, "BIBREF12": {"title": "Breast cancer in the \ue062ai Cohort Study: an exploratory case-control analysis", "authors": [{"first": "S", "middle": [], "last": "Jordan", "suffix": ""}, {"first": "L", "middle": [], "last": "Lim", "suffix": ""}, {"first": "D", "middle": [], "last": "Vilainerun", "suffix": ""}], "year": 2009, "venue": "Breast", "link": "11407831"}, "BIBREF13": {"title": "In\ufffduence of diabetes mellitus type 2 and prolonged estrogen exposure on risk of breast cancer among women in Armenia", "authors": [{"first": "L", "middle": [], "last": "Khachatryan", "suffix": ""}, {"first": "R", "middle": [], "last": "Scharpf", "suffix": ""}, {"first": "S", "middle": [], "last": "Kagan", "suffix": ""}], "year": 2011, "venue": "Healthcare For Women International", "link": "21158347"}, "BIBREF14": {"title": "Prevalence of hypertension and diabetes in breast cancer: a case-control study in 179 patients and age-matched, non-hospitalized controls", "authors": [{"first": "H", "middle": ["O"], "last": "Adami", "suffix": ""}, {"first": "A", "middle": [], "last": "Rimsten", "suffix": ""}], "year": 1978, "venue": "Clinical Oncology", "link": "46617358"}, "BIBREF15": {"title": "Subsequent cancer risk in the incidence cohort of Rochester, Minnesota, residents with diabetes mellitus", "authors": [{"first": "M", "middle": [], "last": "Ragozzino", "suffix": ""}, {"first": "L", "middle": ["J"], "last": "Melton", "suffix": ""}, {"first": "C", "middle": ["P"], "last": "Chu", "suffix": ""}, {"first": "P", "middle": ["J"], "last": "Palumbo", "suffix": ""}], "year": 1982, "venue": "Journal of Chronic Diseases", "link": "27426870"}, "BIBREF16": {"title": "Diabetes and breast cancer risk", "authors": [{"first": "S", "middle": [], "last": "Kopp", "suffix": ""}, {"first": "S", "middle": [], "last": "Tanneberger", "suffix": ""}, {"first": "M", "middle": [], "last": "Mohner", "suffix": ""}, {"first": "R", "middle": [], "last": "Kieser", "suffix": ""}], "year": 1990, "venue": "International Journal of Cancer", "link": "35135591"}, "BIBREF17": {"title": "Breast cancer risk and history of selected medical conditions linked with female hormones", "authors": [{"first": "S", "middle": [], "last": "Franceschi", "suffix": ""}, {"first": "C", "middle": [], "last": "Vecchia", "suffix": ""}, {"first": "E", "middle": [], "last": "Negri", "suffix": ""}, {"first": "F", "middle": [], "last": "Parazzini", "suffix": ""}, {"first": "P", "middle": [], "last": "Boyle", "suffix": ""}], "year": 1990, "venue": "European Journal of Cancer", "link": "45619541"}, "BIBREF18": {"title": "Cancer risk in patients with diabetes mellitus", "authors": [{"first": "H", "middle": ["O"], "last": "Adami", "suffix": ""}, {"first": "J", "middle": [], "last": "Mclaughlin", "suffix": ""}, {"first": "A", "middle": [], "last": "Ekbom", "suffix": ""}], "year": 1991, "venue": "Cancer Causes & Control", "link": "11488895"}, "BIBREF19": {"title": "A case-control study of diabetes mellitus and cancer risk", "authors": [{"first": "C", "middle": ["La"], "last": "Vecchia", "suffix": ""}, {"first": "E", "middle": [], "last": "Negri", "suffix": ""}, {"first": "S", "middle": [], "last": "Franceschi", "suffix": ""}, {"first": "B", "middle": [], "last": "D&apos; Avanzo", "suffix": ""}, {"first": "P", "middle": [], "last": "Boyle", "suffix": ""}], "year": 1994, "venue": "British Journal of Cancer", "link": "5737704"}, "BIBREF20": {"title": "Cancer and diabetes: a follow-up study of two population-based cohorts of diabetic patients", "authors": [{"first": "H", "middle": [], "last": "Hjalgrim", "suffix": ""}, {"first": "M", "middle": [], "last": "Frisch", "suffix": ""}, {"first": "A", "middle": [], "last": "Ekbom", "suffix": ""}, {"first": "K", "middle": ["O"], "last": "Kyvik", "suffix": ""}, {"first": "M", "middle": [], "last": "Melbye", "suffix": ""}, {"first": "A", "middle": [], "last": "Green", "suffix": ""}], "year": 1997, "venue": "Journal of Internal Medicine", "link": "25022583"}, "BIBREF21": {"title": "Breast cancer risk in young women and history of selected medical conditions", "authors": [{"first": "H", "middle": ["A"], "last": "Weiss", "suffix": ""}, {"first": "L", "middle": ["A"], "last": "Brinton", "suffix": ""}, {"first": "N", "middle": ["A"], "last": "Potischman", "suffix": ""}], "year": 1999, "venue": "International Journal of Epidemiology", "link": "34730292"}, "BIBREF22": {"title": "Does body fat distribution promote familial aggregation of adult onset diabetes mellitus and postmenopausal breast cancer", "authors": [{"first": "T", "middle": ["A"], "last": "Sellers", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Spra\ue09ba", "suffix": ""}, {"first": "S", "middle": ["M"], "last": "Gapstur", "suffix": ""}], "year": 1994, "venue": "Epidemiology", "link": "27686538"}, "BIBREF23": {"title": "Diabetes and risk of incident cancer: a large population-based cohort study in Israel", "authors": [{"first": "G", "middle": [], "last": "Chodick", "suffix": ""}, {"first": "A", "middle": ["D"], "last": "Heymann", "suffix": ""}, {"first": "L", "middle": [], "last": "Rosenmann", "suffix": ""}], "year": 2010, "venue": "Cancer Causes & Control", "link": "23762416"}, "BIBREF24": {"title": "Risk of breast cancer a\ue09der onset of type 2 diabetes: evidence of detection bias in postmenopausal women", "authors": [{"first": "S", "middle": ["L"], "last": "Bowker", "suffix": ""}, {"first": "K", "middle": [], "last": "Richardson", "suffix": ""}, {"first": "C", "middle": ["A"], "last": "Marra", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Johnson", "suffix": ""}], "year": 2011, "venue": "Diabetes Care", "link": null}, "BIBREF25": {"title": "Type 2 diabetes and subsequent incidence of breast cancer in the nurses' health study", "authors": [{"first": "K", "middle": ["B"], "last": "Michels", "suffix": ""}, {"first": "C", "middle": ["G"], "last": "Solomon", "suffix": ""}, {"first": "F", "middle": ["B"], "last": "Hu", "suffix": ""}], "year": 2003, "venue": "Diabetes Care", "link": "32534305"}, "BIBREF26": {"title": "Diabetes mellitus and risk of breast cancer: a meta-analysis", "authors": [{"first": "S", "middle": ["C"], "last": "Larsson", "suffix": ""}, {"first": "C", "middle": ["S"], "last": "Mantzoros", "suffix": ""}, {"first": "A", "middle": [], "last": "Wolk", "suffix": ""}], "year": 2007, "venue": "International Journal of Cancer", "link": "20752831"}, "BIBREF27": {"title": "\ue062e association of diabetes with breast cancer incidence and mortality in the Long Island Breast Cancer Study Project", "authors": [{"first": "R", "middle": [], "last": "Cleveland", "suffix": ""}, {"first": "K", "middle": [], "last": "North", "suffix": ""}, {"first": "J", "middle": [], "last": "Stevens", "suffix": ""}, {"first": "S", "middle": [], "last": "Teitelbaum", "suffix": ""}, {"first": "A", "middle": [], "last": "Neugut", "suffix": ""}, {"first": "M", "middle": [], "last": "Gammon", "suffix": ""}], "year": 2012, "venue": "Cancer Causes & Control", "link": "2387144"}, "BIBREF28": {"title": "Diabetes, metformin, and breast cancer in postmenopausal women", "authors": [{"first": "R", "middle": ["T"], "last": "Chlebowski", "suffix": ""}, {"first": "A", "middle": [], "last": "Mctiernan", "suffix": ""}, {"first": "J", "middle": [], "last": "Wactawski-Wende", "suffix": ""}], "year": 2012, "venue": "Journal of Clinical Oncology", "link": "207031377"}, "BIBREF29": {"title": "Associations of type 2 diabetes and diabetes treatment with breast cancer risk and mortality: a populationbased cohort study among British women", "authors": [{"first": "M", "middle": ["T"], "last": "Redaniel", "suffix": ""}, {"first": "M", "middle": [], "last": "Jeffreys", "suffix": ""}, {"first": "M", "middle": ["T"], "last": "May", "suffix": ""}, {"first": "Y", "middle": [], "last": "Ben-Shlomo", "suffix": ""}, {"first": "R", "middle": ["M"], "last": "Martin", "suffix": ""}], "year": 2012, "venue": "Cancer Causes & Control", "link": "17882307"}, "BIBREF30": {"title": "\ue062e impact of diabetes mellitus on prognosis of early breast cancer in Asia", "authors": [{"first": "W", "middle": ["W"], "last": "Chen", "suffix": ""}, {"first": "Y", "middle": ["Y"], "last": "Shao", "suffix": ""}, {"first": "W", "middle": ["Y"], "last": "Shau", "suffix": ""}], "year": 2012, "venue": "Oncologist", "link": "1357398"}, "BIBREF31": {"title": "Type 2 diabetes mellitus and prognosis in early stage breast cancer women", "authors": [{"first": "M", "middle": ["A"], "last": "Kaplan", "suffix": ""}, {"first": "Z", "middle": [], "last": "Pekkolay", "suffix": ""}, {"first": "M", "middle": [], "last": "Kucukoner", "suffix": ""}], "year": 2012, "venue": "Medical Oncology", "link": "26085740"}, "BIBREF32": {"title": "Impact of diabetes and hyperglycemia on survival in advanced breast cancer patients", "authors": [{"first": "C", "middle": [], "last": "Villarreal-Garza", "suffix": ""}, {"first": "R", "middle": [], "last": "Shaw-Dulin", "suffix": ""}, {"first": "F", "middle": [], "last": "Lara-Medina", "suffix": ""}], "year": 2012, "venue": "Experimental Diabetes Research", "link": "6516607"}, "BIBREF33": {"title": "Incidence and predictors of all-cause and site-speci\ufffdc cancer in type 2 diabetes: the Fremantle Diabetes Study", "authors": [{"first": "D", "middle": ["J"], "last": "Magliano", "suffix": ""}, {"first": "W", "middle": ["A"], "last": "Davis", "suffix": ""}, {"first": "J", "middle": ["E"], "last": "Shaw", "suffix": ""}, {"first": "D", "middle": ["G"], "last": "Bruce", "suffix": ""}, {"first": "T", "middle": ["M E"], "last": "Davis", "suffix": ""}], "year": 2012, "venue": "European Journal of Endocrinology", "link": "207126263"}, "BIBREF34": {"title": "Diabetes and breast cancer risk: a meta-analysis", "authors": [{"first": "P", "middle": [], "last": "Boyle", "suffix": ""}, {"first": "M", "middle": [], "last": "Boniol", "suffix": ""}, {"first": "A", "middle": [], "last": "Koechlin", "suffix": ""}], "year": 2012, "venue": "British Journal of Cancer", "link": "5655881"}, "BIBREF35": {"title": "Diabetes, overweight and risk of postmenopausal breast cancer: a case-control study in Uruguay", "authors": [{"first": "A", "middle": ["L"], "last": "Ronco", "suffix": ""}, {"first": "E", "middle": [], "last": "Stefani", "suffix": ""}, {"first": "H", "middle": [], "last": "Deneo-Pellegrini", "suffix": ""}, {"first": "A", "middle": [], "last": "Quarneti", "suffix": ""}], "year": 2012, "venue": "\ue0bbe Asian \ufffdaci\ufffdc Journal of Cancer \ufffdrevention", "link": "10035688"}, "BIBREF36": {"title": "Cancer of the breast, diabetes and pathological glucose tolerance", "authors": [{"first": "B", "middle": ["R"], "last": "Muck", "suffix": ""}, {"first": "S", "middle": [], "last": "Trotnow", "suffix": ""}, {"first": "G", "middle": [], "last": "Hommel", "suffix": ""}], "year": 1975, "venue": "Archiv fur Gynakologie", "link": "24599613"}, "BIBREF37": {"title": "Prevalence of hypertension and diabetes in breast cancer: a case-control study in 179 patients and age-matched, non-hospitalized controls", "authors": [{"first": "H", "middle": ["O"], "last": "Adami", "suffix": ""}, {"first": "A", "middle": [], "last": "Rimsten", "suffix": ""}], "year": 1978, "venue": "Clinical Oncology", "link": "46617358"}, "BIBREF38": {"title": "Risk of endometrial and breast cancer in patients with diabetes mellitus", "authors": [{"first": "E", "middle": [], "last": "Weiderpass", "suffix": ""}, {"first": "G", "middle": [], "last": "Gridley", "suffix": ""}, {"first": "I", "middle": [], "last": "Persson", "suffix": ""}, {"first": "O", "middle": [], "last": "Nyren", "suffix": ""}, {"first": "A", "middle": [], "last": "Ekbom", "suffix": ""}, {"first": "H", "middle": ["O"], "last": "Adami", "suffix": ""}], "year": 1997, "venue": "International Journal of Cancer", "link": "33129938"}, "BIBREF39": {"title": "Serum insulin and glucose levels and breast cancer incidence: the atherosclerosis risk in communities study", "authors": [{"first": "P", "middle": ["J"], "last": "Mink", "suffix": ""}, {"first": "E", "middle": [], "last": "Shahar", "suffix": ""}, {"first": "W", "middle": ["D"], "last": "Rosamond", "suffix": ""}, {"first": "A", "middle": ["J"], "last": "Alberg", "suffix": ""}, {"first": "A", "middle": ["R"], "last": "Folsom", "suffix": ""}], "year": 2002, "venue": "American Journal of Epidemiology", "link": "29857723"}, "BIBREF40": {"title": "Increased prevalence of prior breast cancer in women with newly diagnosed diabetes", "authors": [{"first": "L", "middle": ["L"], "last": "Lipscombe", "suffix": ""}, {"first": "P", "middle": ["J"], "last": "Goodwin", "suffix": ""}, {"first": "B", "middle": [], "last": "Zinman", "suffix": ""}, {"first": "J", "middle": ["R"], "last": "Mclaughlin", "suffix": ""}, {"first": "J", "middle": ["E"], "last": "Hux", "suffix": ""}], "year": 2006, "venue": "Breast Cancer Research and Treatment", "link": "23851376"}, "BIBREF41": {"title": "A prospective study in general practice on breast cancer risk in postmenopausal women", "authors": [{"first": "F", "middle": [], "last": "De Waard", "suffix": ""}, {"first": "E", "middle": ["A"], "last": "Baanders Van Halewijn", "suffix": ""}], "year": 1974, "venue": "International Journal of Cancer", "link": "71196449"}, "BIBREF42": {"title": "Hyperinsulinaemia and increased risk of breast cancer: \ufffdndings from the British women's heart and health study", "authors": [{"first": "D", "middle": ["A"], "last": "Lawlor", "suffix": ""}, {"first": "G", "middle": ["D"], "last": "Smith", "suffix": ""}, {"first": "S", "middle": [], "last": "Ebrahim", "suffix": ""}], "year": 2004, "venue": "Cancer Causes & Control", "link": "12264325"}, "BIBREF43": {"title": "Diabetes mellitus and breast cancer: a retrospective population-based cohort study", "authors": [{"first": "L", "middle": ["L"], "last": "Lipscombe", "suffix": ""}, {"first": "P", "middle": ["J"], "last": "Goodwin", "suffix": ""}, {"first": "B", "middle": [], "last": "Zinman", "suffix": ""}, {"first": "J", "middle": ["R"], "last": "Mclaughlin", "suffix": ""}, {"first": "J", "middle": ["E"], "last": "Hux", "suffix": ""}], "year": 2006, "venue": "Breast Cancer Research and Treatment", "link": "6121999"}, "BIBREF44": {"title": "Modulation of estrogen receptor by insulin and its biologic signi\ufffdcance", "authors": [{"first": "P", "middle": ["K"], "last": "Chaudhuri", "suffix": ""}, {"first": "B", "middle": [], "last": "Chaudhuri", "suffix": ""}, {"first": "N", "middle": [], "last": "Patel", "suffix": ""}], "year": 1986, "venue": "Archives of Surgery", "link": null}, "BIBREF45": {"title": "Breast cancer: biological characteristics in postmenopausal type 2 diabetic women. Identi\ufffdcation of therapeutic targets", "authors": [{"first": "E", "middle": [], "last": "Guastamacchia", "suffix": ""}, {"first": "F", "middle": [], "last": "Resta", "suffix": ""}, {"first": "A", "middle": [], "last": "Mangia", "suffix": ""}], "year": 2003, "venue": "Current Drug Targets. Immune, Endocrine and Metabolic Disorders", "link": "25725774"}, "BIBREF46": {"title": "Metformin and reduced risk of cancer in diabetic patients", "authors": [{"first": "J", "middle": ["M M"], "last": "Evans", "suffix": ""}, {"first": "L", "middle": ["A"], "last": "Donnelly", "suffix": ""}, {"first": "A", "middle": ["M"], "last": "Emslie-Smith", "suffix": ""}, {"first": "D", "middle": ["R"], "last": "Alessi", "suffix": ""}, {"first": "A", "middle": ["D"], "last": "Morris", "suffix": ""}], "year": 2005, "venue": "British Medical Journal", "link": "35920733"}, "BIBREF47": {"title": "Increased cancer-related mortality for patients with type 2 diabetes who use sulfonylureas or insulin", "authors": [{"first": "S", "middle": ["L"], "last": "Bowker", "suffix": ""}, {"first": "S", "middle": ["R"], "last": "Majumdar", "suffix": ""}, {"first": "P", "middle": [], "last": "Veugelers", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Johnson", "suffix": ""}], "year": 2006, "venue": "Diabetes Care", "link": "11008503"}, "BIBREF48": {"title": "Sulphonylureas and cancer: a case-control study", "authors": [{"first": "M", "middle": [], "last": "Monami", "suffix": ""}, {"first": "C", "middle": [], "last": "Lamanna", "suffix": ""}, {"first": "D", "middle": [], "last": "Balzi", "suffix": ""}, {"first": "N", "middle": [], "last": "Marchionni", "suffix": ""}, {"first": "E", "middle": [], "last": "Mannucci", "suffix": ""}], "year": 2009, "venue": "Acta Diabetologica", "link": "20205432"}, "BIBREF49": {"title": "New users of metformin are at low risk of incident cancer: a cohort study among people with type 2 diabetes", "authors": [{"first": "G", "middle": [], "last": "Libby", "suffix": ""}, {"first": "L", "middle": ["A"], "last": "Donnelly", "suffix": ""}, {"first": "P", "middle": ["T"], "last": "Donnan", "suffix": ""}, {"first": "D", "middle": ["R"], "last": "Alessi", "suffix": ""}, {"first": "A", "middle": ["D"], "last": "Morris", "suffix": ""}, {"first": "J", "middle": ["M M"], "last": "Evans", "suffix": ""}], "year": 2009, "venue": "Diabetes Care", "link": null}, "BIBREF50": {"title": "Metformin and breast cancer risk: a metaanalysis and critical literature review", "authors": [{"first": "N", "middle": ["F"], "last": "Col", "suffix": ""}, {"first": "L", "middle": [], "last": "Ochs", "suffix": ""}, {"first": "V", "middle": [], "last": "Springmann", "suffix": ""}, {"first": "A", "middle": ["K"], "last": "Aragaki", "suffix": ""}, {"first": "R", "middle": ["T"], "last": "Chlebowski", "suffix": ""}], "year": 2012, "venue": "Breast Cancer Research and Treatment", "link": "25726804"}, "BIBREF51": {"title": "Long-term metformin use is associated with decreased risk of breast cancer", "authors": [{"first": "M", "middle": [], "last": "Bodmer", "suffix": ""}, {"first": "C", "middle": [], "last": "Meier", "suffix": ""}, {"first": "S", "middle": [], "last": "Kr\u00e4henb\u00fchl", "suffix": ""}, {"first": "S", "middle": ["S"], "last": "Jick", "suffix": ""}, {"first": "C", "middle": ["R"], "last": "Meier", "suffix": ""}], "year": 2010, "venue": "Diabetes Care", "link": "18577247"}, "BIBREF52": {"title": "Metformin and incident breast cancer among diabetic women: a population-based case-control study in Denmark", "authors": [{"first": "J", "middle": ["L F"], "last": "Bosco", "suffix": ""}, {"first": "S", "middle": [], "last": "Antonsen", "suffix": ""}, {"first": "H", "middle": ["T"], "last": "Sorensen", "suffix": ""}, {"first": "L", "middle": [], "last": "Pedersen", "suffix": ""}, {"first": "T", "middle": ["L"], "last": "Lash", "suffix": ""}], "year": 2011, "venue": "Cancer Epidemiology Biomarkers and Prevention", "link": "25582913"}, "BIBREF53": {"title": "AMP-activated protein kinase in metabolic control and insulin signaling", "authors": [{"first": "M", "middle": ["C"], "last": "Towler", "suffix": ""}, {"first": "D", "middle": ["G"], "last": "Hardie", "suffix": ""}], "year": 2007, "venue": "Circulation Research", "link": "12598047"}, "BIBREF54": {"title": "Medicine: the kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin", "authors": [{"first": "R", "middle": ["J"], "last": "Shaw", "suffix": ""}, {"first": "K", "middle": ["A"], "last": "Lamia", "suffix": ""}, {"first": "D", "middle": [], "last": "Vasquez", "suffix": ""}], "year": 2005, "venue": "Science", "link": null}, "BIBREF55": {"title": "Metformin: taking away the candy for cancer?", "authors": [{"first": "M", "middle": [], "last": "Jalving", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Gietema", "suffix": ""}, {"first": "J", "middle": ["D"], "last": "Lefrandt", "suffix": ""}], "year": 2010, "venue": "European Journal of Cancer", "link": "42788419"}, "BIBREF56": {"title": "De\ufffdning the role of mTOR in cancer", "authors": [{"first": "D", "middle": ["A"], "last": "Guertin", "suffix": ""}, {"first": "D", "middle": ["M"], "last": "Sabatini", "suffix": ""}], "year": 2007, "venue": "Cancer Cell", "link": null}, "BIBREF57": {"title": "\ue062erapeutic metformin/AMPK activation promotes the angiogenic phenotype in the ER negative MDA-MB-435 breast cancer model", "authors": [{"first": "K", "middle": ["N"], "last": "Phoenix", "suffix": ""}, {"first": "F", "middle": [], "last": "Vumbaca", "suffix": ""}, {"first": "K", "middle": ["P"], "last": "Claffey", "suffix": ""}], "year": 2009, "venue": "Breast Cancer Research and Treatment", "link": "24710348"}, "BIBREF58": {"title": "Metformin inhibits aromatase expression in human breast adipose stromal cells via stimulation of AMP-activated protein kinase", "authors": [{"first": "K", "middle": ["A"], "last": "Brown", "suffix": ""}, {"first": "N", "middle": ["I"], "last": "Hunger", "suffix": ""}, {"first": "M", "middle": [], "last": "Docanto", "suffix": ""}, {"first": "E", "middle": ["R"], "last": "Simpson", "suffix": ""}], "year": 2010, "venue": "Breast Cancer Research and Treatment", "link": "11717837"}, "BIBREF59": {"title": "Insulin-sensitizing therapy attenuates type 2 diabetes-mediated mammary tumor progression", "authors": [{"first": "Y", "middle": [], "last": "Fierz", "suffix": ""}, {"first": "R", "middle": [], "last": "Novosyadlyy", "suffix": ""}, {"first": "A", "middle": [], "last": "Vijayakumar", "suffix": ""}, {"first": "S", "middle": [], "last": "Yakar", "suffix": ""}, {"first": "D", "middle": [], "last": "Leroith", "suffix": ""}], "year": 2010, "venue": "Diabetes", "link": "14791938"}, "BIBREF60": {"title": "\ue062erapeutic effects of metformin in breast cancer: involvement of the immune system?", "authors": [{"first": "S", "middle": [], "last": "Schott", "suffix": ""}, {"first": "A", "middle": [], "last": "Bierhaus", "suffix": ""}, {"first": "F", "middle": [], "last": "Schuetz", "suffix": ""}], "year": 2011, "venue": "Cancer Immunology, Immunotherapy", "link": "20413057"}, "BIBREF61": {"title": "Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer", "authors": [{"first": "S", "middle": [], "last": "Jiralerspong", "suffix": ""}, {"first": "S", "middle": ["L"], "last": "Palla", "suffix": ""}, {"first": "S", "middle": ["H"], "last": "Giordano", "suffix": ""}], "year": 2009, "venue": "Journal of Clinical Oncology", "link": "24115679"}, "BIBREF62": {"title": "Metformin suppresses colorectal aberrant crypt foci in a short-term clinical trial", "authors": [{"first": "K", "middle": [], "last": "Hosono", "suffix": ""}, {"first": "H", "middle": [], "last": "Endo", "suffix": ""}, {"first": "H", "middle": [], "last": "Takahashi", "suffix": ""}], "year": 2010, "venue": "Cancer Prevention Research", "link": "18800809"}, "BIBREF63": {"title": "Clinical and biologic effects of metformin in early stage breast cancer", "authors": [{"first": "S", "middle": [], "last": "Niraula", "suffix": ""}, {"first": "V", "middle": [], "last": "Stambolic", "suffix": ""}, {"first": "R", "middle": ["J O"], "last": "Dowling", "suffix": ""}], "year": 2010, "venue": "supplement, p. 104s", "link": null}, "BIBREF64": {"title": "Gene signature of metformin actions on primary breast cancer within a window of opportunity randomized clinical trial", "authors": [{"first": "S", "middle": ["M"], "last": "Hadad", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Dewar", "suffix": ""}, {"first": "E", "middle": [], "last": "Elseedawy", "suffix": ""}], "year": "", "venue": "Journal of Clinical Oncology", "link": "76036048"}, "BIBREF65": {"title": "A Phase III Randomized Trial of Metformin vs Placebo in Early Stage Breast Cancer", "authors": [], "year": 2011, "venue": "", "link": null}, "BIBREF66": {"title": "Is it time to test metformin in breast cancer clinical trials", "authors": [{"first": "M", "middle": [], "last": "Cazzaniga", "suffix": ""}, {"first": "B", "middle": [], "last": "Bonanni", "suffix": ""}, {"first": "A", "middle": [], "last": "Guerrieri-Gonzaga", "suffix": ""}, {"first": "A", "middle": [], "last": "Decensi", "suffix": ""}], "year": 2009, "venue": "Cancer Epidemiology Biomarkers and Prevention", "link": "14679671"}, "BIBREF67": {"title": "Metformin, diet and breast cancer: an avenue for chemoprevention", "authors": [{"first": "P", "middle": [], "last": "Muti", "suffix": ""}, {"first": "F", "middle": [], "last": "Berrino", "suffix": ""}, {"first": "V", "middle": [], "last": "Krogh", "suffix": ""}], "year": 2009, "venue": "Cell Cycle", "link": "46272163"}, "BIBREF68": {"title": "Incorporating the antidiabetic drug metformin in HER2-positive breast cancer treated with neo-adjuvant chemotherapy and trastuzumab: an ongoing clinical-translational research experience at the Catalan Institute of Oncology", "authors": [{"first": "B", "middle": [], "last": "Martin-Castillo", "suffix": ""}, {"first": "J", "middle": [], "last": "Dorca", "suffix": ""}, {"first": "A", "middle": [], "last": "Vazquez-Martin", "suffix": ""}], "year": 2010, "venue": "Annals of Oncology", "link": "28125969"}, "BIBREF69": {"title": "Cancer risks in thiazolidinedione users compared to other anti-diabetic agents", "authors": [{"first": "C", "middle": [], "last": "Koro", "suffix": ""}, {"first": "S", "middle": [], "last": "Barrett", "suffix": ""}, {"first": "N", "middle": [], "last": "Qizilbash", "suffix": ""}], "year": 2007, "venue": "Pharmacoepidemiology and Drug Safety", "link": "38586029"}, "BIBREF70": {"title": "Use of the peroxisome proliferator-activated receptor (PPAR) ligand troglitazone as treatment for refractory breast cancer: a phase II study", "authors": [{"first": "H", "middle": ["J"], "last": "Burstein", "suffix": ""}, {"first": "G", "middle": ["D"], "last": "Demetri", "suffix": ""}, {"first": "E", "middle": [], "last": "Mueller", "suffix": ""}, {"first": "P", "middle": [], "last": "Sarraf", "suffix": ""}, {"first": "B", "middle": ["M"], "last": "Spiegelman", "suffix": ""}, {"first": "E", "middle": ["P"], "last": "Winer", "suffix": ""}], "year": 2003, "venue": "Breast Cancer Research and Treatment", "link": "10775375"}, "BIBREF71": {"title": "Metformin and thiazolidinediones are associated with improved breast cancer-speci\ufffdc survival of diabetic women with HER2+ breast cancer", "authors": [{"first": "X", "middle": [], "last": "He", "suffix": ""}, {"first": "F", "middle": ["J"], "last": "Esteva", "suffix": ""}, {"first": "J", "middle": [], "last": "Ensor", "suffix": ""}, {"first": "G", "middle": ["N"], "last": "Hortobagyi", "suffix": ""}, {"first": "M", "middle": ["H"], "last": "Lee", "suffix": ""}, {"first": "S", "middle": ["C"], "last": "Yeung", "suffix": ""}], "year": 2012, "venue": "Annals of Oncology", "link": "28423720"}, "BIBREF72": {"title": "\ue062iazolidinediones downregulate Wnt/ -Catenin signaling via multiple mechanisms in breast cancer cells", "authors": [{"first": "P", "middle": ["S"], "last": "Wang", "suffix": ""}, {"first": "F", "middle": ["S"], "last": "Chou", "suffix": ""}, {"first": "M", "middle": [], "last": "Bloomston", "suffix": ""}], "year": 2009, "venue": "Journal of Surgical Research", "link": "31678252"}, "BIBREF73": {"title": "Oral insulin secretagogues, insulin, and cancer risk in type 2 diabetes mellitus", "authors": [{"first": "C", "middle": ["H"], "last": "Chang", "suffix": ""}, {"first": "J", "middle": ["W"], "last": "Lin", "suffix": ""}, {"first": "L", "middle": ["C"], "last": "Wu", "suffix": ""}, {"first": "M", "middle": ["S"], "last": "Lai", "suffix": ""}, {"first": "L", "middle": ["M"], "last": "Chuang", "suffix": ""}], "year": 2012, "venue": "\ue0bbe Journal of Clinical Endocrinology & Metabolism", "link": "1699329"}, "BIBREF74": {"title": "Progress in the oral treatment of type 2 diabetes: update on DPP-IV inhibitors", "authors": [{"first": "T", "middle": [], "last": "Salvatore", "suffix": ""}, {"first": "O", "middle": [], "last": "Carbonara", "suffix": ""}, {"first": "D", "middle": [], "last": "Cozzolino", "suffix": ""}, {"first": "R", "middle": [], "last": "Torella", "suffix": ""}, {"first": "F", "middle": ["C"], "last": "Sasso", "suffix": ""}], "year": 2009, "venue": "Current Diabetes Reviews", "link": "34447623"}, "BIBREF75": {"title": "Systematic review and meta-analysis of insulin therapy and risk of cancer", "authors": [{"first": "M", "middle": [], "last": "Janghorbani", "suffix": ""}, {"first": "M", "middle": [], "last": "Dehghani", "suffix": ""}, {"first": "M", "middle": [], "last": "Salehi-Marzijarani", "suffix": ""}], "year": 2012, "venue": "Hormones and Cancer", "link": "26023049"}, "BIBREF76": {"title": "Activation of glucagon-like peptide-1 receptor signaling does not modify the growth or apoptosis of human pancreatic cancer cells", "authors": [{"first": "J", "middle": ["A"], "last": "Koehler", "suffix": ""}, {"first": "D", "middle": ["J"], "last": "Drucker", "suffix": ""}], "year": 2006, "venue": "Diabetes", "link": "14305947"}, "BIBREF77": {"title": "Systematic review and meta-analysis of insulin therapy and risk of cancer", "authors": [{"first": "M", "middle": [], "last": "Janghorbani", "suffix": ""}, {"first": "M", "middle": [], "last": "Dehghani", "suffix": ""}, {"first": "M", "middle": [], "last": "Salehi-Marzijarani", "suffix": ""}], "year": 2012, "venue": "Hormones and Cancer", "link": "26023049"}, "BIBREF78": {"title": "Long-term effects of insulin glargine on the risk of breast cancer", "authors": [{"first": "S", "middle": [], "last": "Suissa", "suffix": ""}, {"first": "L", "middle": [], "last": "Azoulay", "suffix": ""}, {"first": "S", "middle": [], "last": "Dell&apos; Aniello", "suffix": ""}, {"first": "M", "middle": [], "last": "Evans", "suffix": ""}, {"first": "J", "middle": [], "last": "Vora", "suffix": ""}, {"first": "M", "middle": [], "last": "Pollak", "suffix": ""}], "year": 2011, "venue": "Diabetologia", "link": "11983577"}, "BIBREF79": {"title": "Basal insulin and cardiovascular and other outcomes in dysglycemia", "authors": [], "year": 2012, "venue": "\ue062e ORIGIN Trial Investigators", "link": null}}, "ref_entries": {"FIGREF0": {"text": "Risk. Dipeptidyl peptidase-IV (DPP-IV) inhibitors, as well as glucagon-like peptide-1 (GLP-1) agonists, are relatively new medications used in the treatment of DM2 where GLP-1 agonists, exe- natide, and liraglutide were \ufffdrst introduced in the USA in 2005 and sitaglipitin, \ufffdrst DPP IV inhibitor introduced in 2006. \ue062ese therapies are effective in preserving -cell mass by improving islet cell function through inhibiting apoptosis.", "type": "figure"}, "TABREF0": {"text": "IgF1: insulin-like-growth-factor-1, IR: Insulin receptor, ERK: extracellular-related-kinase, AMPK: AMP kinase, IL6: Interleukin 6, ROS: Reactive Oxygen Species F\uf769\uf767\uf775\uf772\uf765 1: Link between type 2 diabetes, insulin resistance and increased breast cancer risk of development: pathophysiology. Link of diabetes mellitus type 2 with breast cancer: pathophysiology.", "type": "table"}, "TABREF2": {"text": "16-1.39). Prospective studies showed a lower risk (SRR 1.23 (95% CI, 1.12-1.35)) as compared to retrospective studies (SRR 1.36 (95% CI, 1.13-1.63)). Type 1 diabetes, or diabetes in premenopausal women, was not associated with the risk of breast cancer (SRR 1.00 (95% CI, 0.74-1.35) SRR 0.86 (95% CI, 0.66-1.12), resp.). Studies adjusting for body mass index (BMI) showed lower estimates (SRR 1.16 (95% CI, 1.08-1.24)) as compared with those studies that were not adjusted for BMI (SRR 1.33 (95% CI, 1.18-1.51)). It was concluded that the risk of breast cancer in women with type 2 diabetes is increased by 27%, but decreased to 16% a\ue09der the adjustment for BMI. No increased risk was seen for women at premenopausal ages or with type 1 diabetes [35]. Also, a recent case-control study that evaluated the risk of breast cancer risk in Uruguayan women was carried out between 2004 and 2009, including 912 women of ages between 23 and 69 years (367 new BC cases and 545 nonhospitalized, age-matched controls with a normal mammography). \ue062is study showed that a personal history of diabetes was positively associated to breast cancer risk (OR = 1.64, 95% CI 1.00-2.69), being higher among postmenopausal women (OR = 1.92, 95% CI 1.04-3.52) and even signi\ufffdcantly more increased among postmenopausal women who are overweight and had dislypidemia (OR = 9.33, 95% CI 2.10-41.5) and high fat/muscle ratio (OR = 7.81, 95% CI 2.01-30.3)", "type": "table"}}}
{"paper_id": "2878434", "_pdf_hash": "42d14c80e135fc7350ce82c9125022cb87d96784", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Simulated Annealing: Theory and Applications", "authors": [{"first": "P", "middle": ["V"], "last": "Laarhoven", "suffix": ""}, {"first": "E", "middle": [], "last": "Aarts", "suffix": ""}], "year": 1987, "venue": "", "link": "61815519"}, "BIBREF1": {"title": "Exploiting jamming-caused neighbor changes for jammer localization", "authors": [{"first": "Z", "middle": [], "last": "Liu", "suffix": ""}, {"first": "H", "middle": [], "last": "Liu", "suffix": ""}, {"first": "W", "middle": [], "last": "Xu", "suffix": ""}, {"first": "Y", "middle": [], "last": "Chen", "suffix": ""}], "year": 2012, "venue": "IEEE Transactions on Parallel and Distributed Systems", "link": "1233430"}, "BIBREF2": {"title": "Lightweight jammer localization in wireless networks: System design and implementation", "authors": [{"first": "K", "middle": [], "last": "Pelechrinis", "suffix": ""}, {"first": "I", "middle": [], "last": "Koutsopoulos", "suffix": ""}, {"first": "I", "middle": [], "last": "Broustis", "suffix": ""}, {"first": "S", "middle": ["V"], "last": "Krishnamurthy", "suffix": ""}], "year": 2009, "venue": "Proceedings of the IEEE GLOBECOM", "link": "6402073"}}, "ref_entries": {}}
{"paper_id": "2878772", "_pdf_hash": "c188408411e314d6464721f171fe29e37152c69c", "abstract": [{"section": "Abstract", "text": "This guideline has been discussed by the SOSORT guideline committee prior to the SOSORT consensus meeting in Milan, January 2005 and published in its first version on the SOSORT homepage: http://www.sosort.org/meetings.php. After the meeting it again has been discussed by the members of the SOSORT guideline committee to establish the final 2005 version submitted to Scoliosis, the official Journal of the society, in December 2005.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Scoliosis is defined as a lateral curvature of the spine with torsion of the spine and chest as well as a disturbance of the sagittal profile [2] .", "cite_spans": [{"start": 142, "end": 145, "text": "[2]", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "Abstract", "text": "Idiopathic scoliosis is the most common of all forms of lateral deviation of the spine. By definition, it is a lateral curvature of the spine in an otherwise healthy child, for which a currently recognizable cause has not been found. Less common but better defined etiologies of the disorder include scoliosis of neuromuscular origin, congenital scoliosis, scoliosis in neurofibromatosis, and mesenchymal disorders like Marfan's syndrome [3] .", "cite_spans": [{"start": 438, "end": 441, "text": "[3]", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Abstract", "text": "The prevalence of adolescent idiopathic scoliosis (AIS), when defined as a curvature greater than 10\u00b0 according to Cobb, is 2-3%. The prevalence of curvatures greater than 20\u00b0 is between 0.3 and 0.5%, while curvatures greater than 40\u00b0 Cobb are found in less than 0.1% of the population. All etiologies of scoliosis other than AIS are encountered more rarely [4] .", "cite_spans": [{"start": 358, "end": 361, "text": "[4]", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "Abstract", "text": "The anatomical level of the deformity has received attention from clinicians as a basis for scoliosis classification. The level of the apex vertebra (i.e., thoracic, thoracolumbar, lumbar or double major) forms a simple basis for description. In 1983, King and colleagues [5] classified different curvature patterns by the extent of spinal fusion required; however, recent reports have suggested that", "cite_spans": [{"start": 272, "end": 275, "text": "[5]", "ref_id": "BIBREF3"}], "ref_spans": []}], "body_text": [{"section": "Etiology", "text": "Idiopathic scoliosis is the most common of all forms of lateral deviation of the spine. By definition, it is a lateral curvature of the spine in an otherwise healthy child, for which a currently recognizable cause has not been found. Less common but better defined etiologies of the disorder include scoliosis of neuromuscular origin, congenital scoliosis, scoliosis in neurofibromatosis, and mesenchymal disorders like Marfan's syndrome [3] .", "cite_spans": [{"start": 438, "end": 441, "text": "[3]", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Epidemiology", "text": "The prevalence of adolescent idiopathic scoliosis (AIS), when defined as a curvature greater than 10\u00b0 according to Cobb, is 2-3%. The prevalence of curvatures greater than 20\u00b0 is between 0.3 and 0.5%, while curvatures greater than 40\u00b0 Cobb are found in less than 0.1% of the population. All etiologies of scoliosis other than AIS are encountered more rarely [4] .", "cite_spans": [{"start": 358, "end": 361, "text": "[4]", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "Classifications", "text": "The anatomical level of the deformity has received attention from clinicians as a basis for scoliosis classification. The level of the apex vertebra (i.e., thoracic, thoracolumbar, lumbar or double major) forms a simple basis for description. In 1983, King and colleagues [5] classified different curvature patterns by the extent of spinal fusion required; however, recent reports have suggested that these classifications lack reliability. Recently, a new description has been developed by Lenke and colleagues [6] . This approach calls for clinical assessment of scoliosis and kyphosis with respect to sagittal profile and curvature components. Systems designed for conservative management include the classifications by Lehnert-Schroth [7] (functional three-curve and functional four-curve scoliosis) and by Rigo [8] (brace construction and application).", "cite_spans": [{"start": 272, "end": 275, "text": "[5]", "ref_id": "BIBREF3"}, {"start": 512, "end": 515, "text": "[6]", "ref_id": "BIBREF4"}, {"start": 739, "end": 742, "text": "[7]", "ref_id": "BIBREF5"}, {"start": 816, "end": 819, "text": "[8]", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "Aims of conservative management", "text": "The primary aim of scoliosis management is to stop curvature progression [9] . Improvement of pulmonary function (vital capacity) and treatment of pain are also of major importance. The first of three modes of conservative scoliosis management is based on physical therapy, including M\u00e9thode Lyonaise [10] , Side-Shift [11] , Dobosiewicz [12] , Schroth and others [7] . Although discussed from contrasting viewpoints in the international literature, there is some evidence for the effectiveness of scoliosis treatment by physical therapy alone [13] .", "cite_spans": [{"start": 73, "end": 76, "text": "[9]", "ref_id": "BIBREF7"}, {"start": 301, "end": 305, "text": "[10]", "ref_id": "BIBREF8"}, {"start": 319, "end": 323, "text": "[11]", "ref_id": "BIBREF9"}, {"start": 338, "end": 342, "text": "[12]", "ref_id": "BIBREF10"}, {"start": 364, "end": 367, "text": "[7]", "ref_id": "BIBREF5"}, {"start": 544, "end": 548, "text": "[13]", "ref_id": "BIBREF11"}], "ref_spans": []}, {"section": "Aims of conservative management", "text": "It has to be emphasized that (1) physical therapy for scoliosis is not just general exercises but rather one of the cited methods designed to address the particular nuances of spinal deformity, and (2) application of such methods requires therapists and clinicians specifically trained and certified in those scoliosis specific conservative intervention methods.", "cite_spans": [], "ref_spans": []}, {"section": "Aims of conservative management", "text": "The second mode of conservative management is scoliosis intensive rehabilitation (SIR), which appears to be effective with respect to many signs and symptoms of scoliosis and with respect to impeding curvature progression [14] . The third mode of conservative management is brace treatment, which has been found to be effective in preventing curvature progression and thus in altering the natural history of IS [15, 16] . It appears that brace treatment may reduce the prevalence of surgery [17] , restore the sagittal profile [18] and influence vertebral rotation [19] . There are also indications that the end result of brace treatment can be predicted [20] .", "cite_spans": [{"start": 222, "end": 226, "text": "[14]", "ref_id": "BIBREF12"}, {"start": 411, "end": 415, "text": "[15,", "ref_id": "BIBREF13"}, {"start": 416, "end": 419, "text": "16]", "ref_id": "BIBREF14"}, {"start": 491, "end": 495, "text": "[17]", "ref_id": "BIBREF15"}, {"start": 527, "end": 531, "text": "[18]", "ref_id": "BIBREF16"}, {"start": 565, "end": 569, "text": "[19]", "ref_id": "BIBREF17"}, {"start": 655, "end": 659, "text": "[20]", "ref_id": "BIBREF18"}], "ref_spans": []}, {"section": "Systematic application of the modes of conservative treatment with respect to Cobb angle and maturity", "text": "Guidelines for conservative intervention are based on current information regarding the risk for significant curvature progression in a given period of time. Each case has its own natural history and must be considered on an individual basis, in the context of a thorough clinical evaluation and patient history [21] . Estimation of risk for progression is based on small (n < 1000) epidemiological surveys in which children were diagnosed with scoliosis, and radiographed periodically to quantify changes in curvature magnitude over time . Such surveys support the premise that, among populations of children with a diagnosis of idiopathic scoliosis, risk for progression is highly correlated with potential for growth over the period of observation. In boys, prognosis for progression is more favorable, with relatively fewer individuals having curves that progress to >40 degrees. For SOSORT guidelines, prognostic risk estimation is based on the calculation of Lonstein and Carlson [33] . This calculation is based on curvature progression observed among 727 patients (575 female, 152 male) diagnosed between 1974-1979 in state of Minnesota (United States) school screening programs, and followed until they reached skeletal maturity. (See Figure 1) .", "cite_spans": [{"start": 312, "end": 316, "text": "[21]", "ref_id": "BIBREF19"}, {"start": 986, "end": 990, "text": "[33]", "ref_id": "BIBREF31"}], "ref_spans": []}, {"section": "I. Children (no signs of maturity) [21]", "text": "a. < 15\u00b0 Cobb: Observation (6 -12 month intervals) b. Cobb angle 15-20\u00b0: Outpatient physical therapy with treatment-free intervals (6-12 weeks without physical therapy for those patients at that time have low risk for curve progression). In this context, 'Outpatient physical therapy' is defined here as exercise sessions initiated at the physical therapist's office, plus a home exercise program (two to seven sessions per week according to the physical therapy method being applied). After three months, one exercise session every two weeks may be sufficient. ", "cite_spans": [], "ref_spans": []}, {"section": "V. Adults with Cobb angles > 30\u00b0O", "text": "utpatient physical therapy, scoliosis intensive rehabilitation program (SIR), where available", "cite_spans": [], "ref_spans": []}, {"section": "V. Adults with Cobb angles > 30\u00b0O", "text": "The estimation of the prognostic risk to be used during pubertal growth spurt (modified from Lonstein and Carlson [33] ) Figure 1 The estimation of the prognostic risk to be used during pubertal growth spurt (modified from Lonstein and Carlson [33] ). The numbers in the figure indicate the number of cases that each data point is based on. Note the small number of cases on which the upper margins of the graph are based. Lonstein and Carlson's progression estimation formula is based on curves between 20 and 29 degrees.", "cite_spans": [{"start": 114, "end": 118, "text": "[33]", "ref_id": "BIBREF31"}, {"start": 244, "end": 248, "text": "[33]", "ref_id": "BIBREF31"}], "ref_spans": []}, {"section": "V. Adults with Cobb angles > 30\u00b0O", "text": "VI. Adolescents and adults with scoliosis (of any degree) and chronic pain Outpatient physical therapy, scoliosis intensive rehabilitation program (SIR) where available, with a special pain program (multimodal pain concept/behavioral + physical concept), brace treatment when a positive effect has been proven [45] .", "cite_spans": [{"start": 310, "end": 314, "text": "[45]", "ref_id": "BIBREF43"}], "ref_spans": []}, {"section": "V. Adults with Cobb angles > 30\u00b0O", "text": "The prognostic estimation and corresponding indications for treatment apply to the most prevalent condition, idiopathic scoliosis. In other types of scoliosis a similar procedure can be applied. Exceptions include those cases where the prognosis is clearly worse, for example in neuromuscular scolioses where a wheelchair is necessary (early surgery for maintaining sitting capability may be required). -others to be individually considered [46] ", "cite_spans": [{"start": 441, "end": 445, "text": "[46]", "ref_id": "BIBREF44"}], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Die Biomechanik des Rumpfes. In Wirbels\u00e4ulende-formit\u00e4ten -Konservatives Management Edited by: Weiss HR", "authors": [{"first": "Iaf", "middle": [], "last": "Stokes", "suffix": ""}], "year": 2003, "venue": "", "link": null}, "BIBREF1": {"title": "Classification and Terminology. In Moe's Textbook of Scoliosis and Other Spinal Deformities 2nd edition", "authors": [{"first": "R", "middle": ["B"], "last": "Winter", "suffix": ""}], "year": 1995, "venue": "Philadelphia Saunders", "link": null}, "BIBREF2": {"title": "Natural history. Spine", "authors": [{"first": "S", "middle": ["L"], "last": "Weinstein", "suffix": ""}], "year": 1999, "venue": "", "link": null}, "BIBREF3": {"title": "The selection of fusion levels in thoracic IS", "authors": [{"first": "H", "middle": ["A"], "last": "King", "suffix": ""}, {"first": "Jhy", "middle": [], "last": "Moe", "suffix": ""}, {"first": "D", "middle": ["S"], "last": "Bradford", "suffix": ""}, {"first": "R", "middle": ["B"], "last": "Winter", "suffix": ""}], "year": 1983, "venue": "Journal of Bone and Joint Surgery", "link": null}, "BIBREF4": {"title": "Klassifikation von Wirbels\u00e4ulendeformit\u00e4ten", "authors": [{"first": "P", "middle": ["H"], "last": "Dangerfield", "suffix": ""}], "year": 2003, "venue": "Wirbels\u00e4ulendeformit\u00e4ten -Konservatives Management Edited by: Weiss HR", "link": null}, "BIBREF5": {"title": "Dreidimensionale Skoliosebehandlung 6th edition", "authors": [{"first": "C", "middle": [], "last": "Lehnert-Schroth", "suffix": ""}], "year": 2000, "venue": "", "link": null}, "BIBREF6": {"title": "Intraobserver reliability of a new classification correlating with brace treatment", "authors": [{"first": "M", "middle": [], "last": "Rigo", "suffix": ""}], "year": 2004, "venue": "Pediatric Rehabilitation", "link": null}, "BIBREF7": {"title": "Therapieziel der Korsettbehandlung bei idiopathischer Adoleszentenskoliose. MOT 2003", "authors": [{"first": "F", "middle": [], "last": "Landauer", "suffix": ""}, {"first": "C", "middle": [], "last": "Wimmer", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF8": {"title": "Scolioses structurales mineures and kinesitherapie. Etude statistique comparative des resultats. Kinesitherapie Scientifique", "authors": [{"first": "G", "middle": [], "last": "Mollon", "suffix": ""}, {"first": "J", "middle": ["C"], "last": "Rodot", "suffix": ""}], "year": 1986, "venue": "", "link": null}, "BIBREF9": {"title": "Active auto-correction for early AIS", "authors": [{"first": "M", "middle": ["H"], "last": "Mehta", "suffix": ""}], "year": 1986, "venue": "Journal of Bone and Joint Surgery", "link": null}, "BIBREF10": {"title": "Maruyama and members of the SOSORT: Physical Exercises in the Treatment of Idiopathic Scoliosis at Risk of brace treatment -SOSORT Consensus paper", "authors": [{"first": "H", "middle": ["R"], "last": "Weiss", "suffix": ""}, {"first": "S", "middle": [], "last": "Negrini", "suffix": ""}, {"first": "M", "middle": ["C"], "last": "Hawes", "suffix": ""}, {"first": "M", "middle": [], "last": "Rigo", "suffix": ""}, {"first": "T", "middle": [], "last": "Kotwicki", "suffix": ""}, {"first": "T", "middle": ["B"], "last": "Grivas", "suffix": ""}], "year": 2005, "venue": "", "link": null}, "BIBREF11": {"title": "Physical exercises as a treatment for adolescent idiopathic scoliosis. A systematic review", "authors": [{"first": "S", "middle": [], "last": "Negrini", "suffix": ""}, {"first": "G", "middle": ["I"], "last": "Antoninni", "suffix": ""}, {"first": "R", "middle": [], "last": "Carabalona", "suffix": ""}, {"first": "S", "middle": [], "last": "Minozzi", "suffix": ""}], "year": 2003, "venue": "Pediatric Rehabilitation", "link": "597610"}, "BIBREF12": {"title": "Incidence of curvature progression in idiopathic scoliosis patients treated with scoliosis in-patient rehabilitation (SIR): an age-and sex-matched cotrolled study", "authors": [{"first": "H", "middle": ["R"], "last": "Weiss", "suffix": ""}, {"first": "G", "middle": [], "last": "Weiss", "suffix": ""}, {"first": "F", "middle": [], "last": "Petermann", "suffix": ""}], "year": 2003, "venue": "Pediatric Rehabilitation", "link": "26121210"}, "BIBREF13": {"title": "Members of Brace Study Group of the Scoliosis Research Society: Effectiveness of treatment with a brace in girls who have adolescent idiopathic scoliosis", "authors": [{"first": "A", "middle": ["L"], "last": "Nachemson", "suffix": ""}, {"first": "L", "middle": ["E"], "last": "Peterson", "suffix": ""}], "year": 1995, "venue": "J Bone Joint Surg", "link": null}, "BIBREF14": {"title": "The effect of a modified Boston brace with anti-rotatory blades on the progression of curves in idiopathic scoliosis: aetiologic implications", "authors": [{"first": "T", "middle": ["B"], "last": "Grivas", "suffix": ""}, {"first": "E", "middle": [], "last": "Vasiliadis", "suffix": ""}, {"first": "T", "middle": [], "last": "Chatziargiropoulos", "suffix": ""}, {"first": "V", "middle": ["D"], "last": "Polyzois", "suffix": ""}, {"first": "K", "middle": [], "last": "Gatos", "suffix": ""}], "year": 2003, "venue": "Pediatric Rehabilitation", "link": "23605517"}, "BIBREF15": {"title": "Effect of conservative management on the prevalence of surgery in patients with adolescent idiopathic scoliosis", "authors": [{"first": "M", "middle": [], "last": "Rigo", "suffix": ""}, {"first": "C", "middle": [], "last": "Reiter", "suffix": ""}, {"first": "H", "middle": ["R"], "last": "Weiss", "suffix": ""}], "year": 2003, "venue": "Pediatric Rehabilitation", "link": "22528191"}, "BIBREF16": {"title": "D Correction of Trunk Deformity in Patients with Idiopathic Scoliosis Using Ch\u00eaneau Brace", "authors": [], "year": "", "venue": "Research into Spinal Deformities 2. Studies in Health Technology and Informatics Edited by: Stokes IAF", "link": null}, "BIBREF17": {"title": "Three-dimensional action of Cheneau brace on thoracolumbar scoliosis", "authors": [{"first": "T", "middle": [], "last": "Kotwicki", "suffix": ""}, {"first": "S", "middle": [], "last": "Pietrzak", "suffix": ""}, {"first": "A", "middle": [], "last": "Szulc", "suffix": ""}], "year": 2002, "venue": "Research into Spinal Deformities 3. Studies in Health Technology and Informatics Edited by: Tanguy A", "link": "953702"}, "BIBREF18": {"title": "Estimating the final outcome of brace treatment for idiopathic thoracic scoliosis at 6-month follow-up", "authors": [{"first": "F", "middle": [], "last": "Landauer", "suffix": ""}, {"first": "C", "middle": [], "last": "Wimmer", "suffix": ""}, {"first": "H", "middle": [], "last": "Behensky", "suffix": ""}], "year": 2003, "venue": "Pediatric Rehabilitation", "link": "23615917"}, "BIBREF19": {"title": "Lonstein JE: Patient Evaluation. In Moe's Textbook of Scoliosis and Other Spinal Deformities 2nd edition", "authors": [], "year": 1995, "venue": "", "link": null}, "BIBREF20": {"title": "Natural history of untreated IS after skeletal maturity", "authors": [{"first": "E", "middle": [], "last": "Ascani", "suffix": ""}, {"first": "P", "middle": [], "last": "Bartolozzi", "suffix": ""}, {"first": "C", "middle": ["A"], "last": "Logroscino", "suffix": ""}, {"first": "P", "middle": ["G"], "last": "Marchetti", "suffix": ""}, {"first": "A", "middle": [], "last": "Ponte", "suffix": ""}, {"first": "R", "middle": [], "last": "Savini", "suffix": ""}, {"first": "F", "middle": [], "last": "Travaglini", "suffix": ""}, {"first": "F", "middle": [], "last": "Binazzi", "suffix": ""}, {"first": "Di", "middle": [], "last": "Silvestre", "suffix": ""}, {"first": "M", "middle": [], "last": "", "suffix": ""}], "year": 1986, "venue": "Spine", "link": null}, "BIBREF21": {"title": "Progression in untreated IS after the end of growth", "authors": [{"first": "R", "middle": [], "last": "Bjerkreim", "suffix": ""}, {"first": "I", "middle": [], "last": "Hassan", "suffix": ""}], "year": 1982, "venue": "Acta orthop scand", "link": null}, "BIBREF22": {"title": "Scoliosis: a prospective epidemiological study", "authors": [{"first": "H", "middle": ["L"], "last": "Brooks", "suffix": ""}, {"first": "S", "middle": ["P"], "last": "Azen", "suffix": ""}, {"first": "E", "middle": [], "last": "Gerberg", "suffix": ""}, {"first": "R", "middle": [], "last": "Brooks", "suffix": ""}, {"first": "L", "middle": [], "last": "Chan", "suffix": ""}], "year": 1975, "venue": "Journal of Bone and Joint Surgery", "link": "37597989"}, "BIBREF23": {"title": "The natural history of IS before skeletal maturity", "authors": [{"first": "W", "middle": ["P"], "last": "Bunnell", "suffix": ""}], "year": 1986, "venue": "Spine", "link": null}, "BIBREF24": {"title": "Pronostic evolutif des scolioses idiopathiques mineures de 10-29 degrees, en periode de croissance. In Thesis Lyon France", "authors": [{"first": "P", "middle": [], "last": "Clarisse", "suffix": ""}], "year": 1974, "venue": "", "link": null}, "BIBREF25": {"title": "Long-term followup of patients with idiopathic scoliosis not treated surgically", "authors": [{"first": "D", "middle": ["K"], "last": "Collis", "suffix": ""}, {"first": "I", "middle": ["V"], "last": "Ponseti", "suffix": ""}], "year": 1969, "venue": "Journal of Bone and Joint Surgery", "link": "38065595"}, "BIBREF26": {"title": "Rib hump and supine angle as prognostic factors for mild scoliosis", "authors": [{"first": "G", "middle": [], "last": "Duval-Beaupere", "suffix": ""}], "year": 1992, "venue": "Spine", "link": "45210249"}, "BIBREF27": {"title": "Threshold values for supine and standing Cobb angles and rib hump measurements: prognostic factors for scoliosis", "authors": [{"first": "G", "middle": [], "last": "Duval-Beaupere", "suffix": ""}], "year": 1996, "venue": "European Spine Journal", "link": "11459045"}, "BIBREF28": {"title": "Progression of the curve in boys who have IS", "authors": [{"first": "L", "middle": ["A"], "last": "Karol", "suffix": ""}, {"first": "C", "middle": ["E"], "last": "Johnston", "suffix": ""}, {"first": "R", "middle": ["H"], "last": "Browne", "suffix": ""}, {"first": "M", "middle": [], "last": "Madison", "suffix": ""}], "year": 1993, "venue": "Journal of Bone and Joint Surgery", "link": null}, "BIBREF29": {"title": "Levels of platelet calmodulin for the prediction of progression and severity of AIS", "authors": [{"first": "K", "middle": [], "last": "Kindsfater", "suffix": ""}, {"first": "T", "middle": [], "last": "Lowe", "suffix": ""}, {"first": "D", "middle": [], "last": "Lawellin", "suffix": ""}, {"first": "D", "middle": [], "last": "Weinstein", "suffix": ""}, {"first": "A", "middle": [], "last": "Akmakjian", "suffix": ""}], "year": 1994, "venue": "Journal of Bone and Joint Surgery", "link": null}, "BIBREF30": {"title": "Adult idiopathic lumbar scoliosis: a formula for prediction of progression and review of the literature", "authors": [{"first": "P", "middle": [], "last": "Korovessis", "suffix": ""}, {"first": "G", "middle": [], "last": "Piperos", "suffix": ""}, {"first": "P", "middle": [], "last": "Sidiropoulos", "suffix": ""}, {"first": "A", "middle": [], "last": "Dimas", "suffix": ""}], "year": 1994, "venue": "Spine", "link": "35500456"}, "BIBREF31": {"title": "The prediction of curve progression in untreated idiopathic scoliosis during growth", "authors": [{"first": "J", "middle": ["E"], "last": "Lonstein", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Carlson", "suffix": ""}], "year": 1984, "venue": "Journal of Bone and Joint Surgery", "link": "8691446"}, "BIBREF32": {"title": "Juvenile onset scoliosis followed up to adulthood: orthopedic and functional outcomes", "authors": [{"first": "P", "middle": ["D"], "last": "Masso", "suffix": ""}, {"first": "E", "middle": [], "last": "Meeropol", "suffix": ""}, {"first": "E", "middle": [], "last": "Lennon", "suffix": ""}], "year": 2002, "venue": "Journal of Pediatric Orthopedics", "link": "28201066"}, "BIBREF33": {"title": "Progression of unsupported curves in AIS", "authors": [{"first": "K", "middle": ["P"], "last": "Meade", "suffix": ""}, {"first": "W", "middle": [], "last": "Bunch", "suffix": ""}, {"first": "R", "middle": [], "last": "Vanderby", "suffix": ""}, {"first": "A", "middle": ["G"], "last": "Patwardhan", "suffix": ""}, {"first": "G", "middle": [], "last": "Knight", "suffix": ""}], "year": 1987, "venue": "Spine", "link": null}, "BIBREF34": {"title": "The rib-vertebra angle in the early diagnosis between resolving and progressive infantile scoliosis", "authors": [{"first": "M", "middle": [], "last": "Mehta", "suffix": ""}], "year": 1972, "venue": "", "link": "46133529"}, "BIBREF35": {"title": "A long term followup study of nontreated scoliosis", "authors": [{"first": "A", "middle": [], "last": "Nachemson", "suffix": ""}], "year": 1968, "venue": "Acta Orthop Scand", "link": null}, "BIBREF36": {"title": "Natural history of idiopathic scoliosis in girls and boys", "authors": [{"first": "C", "middle": [], "last": "Picault", "suffix": ""}, {"first": "J", "middle": ["C"], "last": "Mouilleseaux", "suffix": ""}, {"first": "B", "middle": [], "last": "Diana", "suffix": ""}, {"first": "G", "middle": [], "last": "", "suffix": ""}], "year": 1986, "venue": "Spine", "link": null}, "BIBREF37": {"title": "Juvenile IS: Curve patterns and prognosis in 109 patients", "authors": [{"first": "C", "middle": ["M"], "last": "Robinson", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Mcmaster", "suffix": ""}], "year": 1996, "venue": "Journal of Bone and Joint Surgery", "link": null}, "BIBREF38": {"title": "Risk factors for IS: review of a 6-year prospective study", "authors": [{"first": "P", "middle": ["N"], "last": "Soucacas", "suffix": ""}, {"first": "K", "middle": [], "last": "Zacharis", "suffix": ""}, {"first": "K", "middle": [], "last": "Loultanis", "suffix": ""}, {"first": "J", "middle": [], "last": "Gelalis", "suffix": ""}, {"first": "T", "middle": [], "last": "Xenakis", "suffix": ""}, {"first": "A", "middle": ["E"], "last": "Beris", "suffix": ""}], "year": 2000, "venue": "Orthopedics", "link": null}, "BIBREF39": {"title": "Assessment of curve progression in IS", "authors": [{"first": "P", "middle": ["N"], "last": "Soucacos", "suffix": ""}, {"first": "K", "middle": [], "last": "Zacharis", "suffix": ""}, {"first": "K", "middle": [], "last": "Soultanis", "suffix": ""}, {"first": "J", "middle": [], "last": "Gelalis", "suffix": ""}, {"first": "N", "middle": [], "last": "Kalos", "suffix": ""}, {"first": "A", "middle": [], "last": "Beris", "suffix": ""}, {"first": "T", "middle": [], "last": "Xenakis", "suffix": ""}, {"first": "E", "middle": ["O"], "last": "Johnson", "suffix": ""}], "year": 1998, "venue": "European Spine Journal", "link": null}, "BIBREF40": {"title": "Progression of vertebral and spinal 3-D deformities in AIS. A longitudinal study", "authors": [{"first": "I", "middle": [], "last": "Villemure", "suffix": ""}, {"first": "C", "middle": ["E"], "last": "Aubin", "suffix": ""}, {"first": "G", "middle": [], "last": "Grimard", "suffix": ""}, {"first": "J", "middle": [], "last": "Dansereau", "suffix": ""}, {"first": "H", "middle": [], "last": "Labelle", "suffix": ""}], "year": 2001, "venue": "Spine", "link": null}, "BIBREF41": {"title": "Curve progression and spinal growth in brace treated IS", "authors": [{"first": "D", "middle": ["J"], "last": "Wever", "suffix": ""}, {"first": "K", "middle": ["A"], "last": "Tonseth", "suffix": ""}, {"first": "A", "middle": ["G"], "last": "Veldhuizen", "suffix": ""}, {"first": "J", "middle": ["C"], "last": "Cool", "suffix": ""}, {"first": "J", "middle": ["R"], "last": "Vanhorn", "suffix": ""}], "year": 2000, "venue": "Clinical Orthopaedics and Related Research", "link": null}, "BIBREF42": {"title": "Prediction of curve progression in IS based on initial roentgenograms; proposal of an equation", "authors": [{"first": "Y", "middle": [], "last": "Yamauchi", "suffix": ""}, {"first": "T", "middle": [], "last": "Yamaguchi", "suffix": ""}, {"first": "Y", "middle": [], "last": "Asaka", "suffix": ""}], "year": 1988, "venue": "Spine", "link": null}, "BIBREF43": {"title": "Sagittal Realignment Brace\" (physio-logic \u00ae brace) in der Behandlung von erwachsenen Skoliosepatienten mit chronifiziertem R\u00fcckenschmerz -erste vorl\u00e4u-fige Ergebnisse", "authors": [{"first": "Hr:", "middle": [], "last": "Weiss", "suffix": ""}, {"first": "", "middle": [], "last": "Das", "suffix": ""}], "year": 2005, "venue": "Medizinisch Orthop\u00e4dische Technik", "link": null}, "BIBREF44": {"title": "Italian guidelines on rehabilitation treatment of adolescents with scoliosis or other spinal deformities", "authors": [{"first": "S", "middle": [], "last": "Negrini", "suffix": ""}, {"first": "L", "middle": [], "last": "Aulisa", "suffix": ""}, {"first": "C", "middle": [], "last": "Ferraro", "suffix": ""}, {"first": "P", "middle": [], "last": "Fraschini", "suffix": ""}, {"first": "S", "middle": [], "last": "Masiero", "suffix": ""}, {"first": "P", "middle": [], "last": "Simonazzi", "suffix": ""}, {"first": "C", "middle": [], "last": "Tedeschi", "suffix": ""}, {"first": "A", "middle": [], "last": "Venturin", "suffix": ""}], "year": 2005, "venue": "Eura Medicophys", "link": "32839526"}}, "ref_entries": {"FIGREF0": {"text": "c. Cobb angle 20-25\u00b0: Out patient physiotherapy, scolio- sis intensive rehabilitation program (SIR) where availa- ble.). SIR, currently available at clinics in Germany and Spain, includes a 3-to 5-week intensive program (4 -6 hour training sessions per day) for patients with poor prognosis (brace indication, adult with Cobb angle of > 40\u00b0, presence of chronic pain). d. > 25\u00b0 Cobb: Outpatient physical therapy, scoliosis intensive rehabilitation program (SIR) where available and brace wear (part-time, 12-16 hours) II. Children and adolescents, Risser 0-3, first signs of maturation, less than 98% of mature height The following section is based on progression risk rather than on Cobb angle measurement because of the chang- ing risk profiles for deformityas theskeleton matures. For our purposes, progression risk is calculated by the formula shown in figure 1. a. Progression risk less than 40%: Observation (3-month intervals) b. Progression risk 40%: Out patient physiotherapy c. Progression risk 50%: Out patient physiotherapy, scol- iosis intensive rehabilitation program (SIR) where availa- ble d. Progression risk 60%: Out patient physiotherapy, scol- iosis intensive rehabilitation program (SIR) where availa- ble + part-time brace indication (16 -23 hours [low risk]). e. Progression risk 80%: Out patient physiotherapy, scol- iosis intensive rehabilitation program (SIR) where availa- ble + full-time brace indication (23 hours [high risk]) III. Children and adolescents presenting with Risser 4 (more than 98% of mature height) a. < 20\u00b0 according to Cobb: Observation (6 -12 Months intervals) b. 20 -25\u00b0 according to Cobb: Outpatient physical ther- apy c. > 25\u00b0 according to Cobb: Outpatient physical therapy, scoliosis intensive rehabilitation programme (SIR) where available d. > 35\u00b0 according to Cobb: Outpatient physical therapy, scoliosis intensive rehabilitation programme (SIR) where available + brace (part time, about 16 hours are sufficient) e. For brace weaning: Outpatient physical therapy, scolio- sis intensive rehabilitation programme (SIR) where avail- able + brace with reduced wearing time. IV. First presentation with Risser 4-5 (more than 99.5% of mature height before growth is completed) a. > 25\u00b0 Cobb: Outpatient physical therapy b. > 30\u00b0 Cobb: Outpatient physical therapy, scoliosis intensive rehabilitation program (SIR) where available.", "type": "figure"}, "FIGREF1": {"text": "Severe sagittal deviations with structural lumbar kyphosis ('flatback') -Lumbar, thoracolumbar and caudal component of double cur- vatures with a disproportionate rotation compared to the Cobb angle and with high risk for future instability at the caudal junctional zone -Severe contractures and muscles shortening -Reduced mobility of the spine especially in the sagittal plane", "type": "figure"}}}
{"paper_id": "2878780", "_pdf_hash": "43ef2b49e0f775efd32adbdc08abf3a02e544853", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "2878811", "_pdf_hash": "7f8c47533a45e38e2c8ea279b79e6de77657977b", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "2879218", "_pdf_hash": "7ed55cf0ed676f6e86a3e4b3ac1d120da53d5001", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Tracking back references in a write-anywhere file system", "authors": [{"first": "P", "middle": [], "last": "Macko", "suffix": ""}, {"first": "M", "middle": [], "last": "Seltzer", "suffix": ""}, {"first": "K", "middle": [], "last": "Smith", "suffix": ""}], "year": 2010, "venue": "Proceedings of the 8th USENIX conference on File and storage technologies", "link": "7208478"}}, "ref_entries": {}}
{"paper_id": "2879242", "_pdf_hash": "290de70afe43a8b69d2d2c9f8c9e7989314e4d13", "abstract": [], "body_text": [{"section": "Introduction", "text": "The potential role of Human cytomegalovirus (hCM) infection in promoting neoplasia is an active area of scientific research. [1] Although still controversial, there is a growing body of evidence that links hCMV infection to a variety of malignancies, including those of the breast, prostate, colon, lung and brain (gliomas). [2] [3] [4] [5] [6] [7] hCMV induces alterations in regulatory proteins and non-coding RNA that are associated with a malignant phenotype. These changes promote tumour survival by effecting cellular proliferation, invasion, immune evasion, and production of angiogenic factors [8] Constant immune surveillance governs the destruction of the majority of cancer cells and precancerous conditions in the human body. However, the most pathogenic of malignant tumors acquire immune evasion strategies which render them less vulnerable to destruction by immune cells.", "cite_spans": [{"start": 125, "end": 128, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 325, "end": 328, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 329, "end": 332, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 333, "end": 336, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 337, "end": 340, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 341, "end": 344, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 345, "end": 348, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 602, "end": 605, "text": "[8]", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "Introduction", "text": "The characteristic hallmarks of a malignant cell include:", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "1. sustaining proliferative signaling and evading growth suppressors, 2. resisting cell death and enabling replicative immortality, 3. inducing angiogenesis, activating invasion and metastasis. [9] In cancers which are not attributable to infectious agents, chronic inflammation may also play a critical role in the transition from a precancerous condition to invasive malignancy. Inflammation is the seventh hallmark of neoplasia (Table 1) . [10] During chronic inflammation, certain \"promoters,\" such as hepatitis C virus and Epstein-Barr virus (EBV), may facilitate the transformation of a pre-malignant condition to neoplasia. [11, 12] Cancer \"promoters\" are agents that, by themselves, may not have a significant oncogenic impact on normal cells but can drive precancerous cells towards neoplasia. ", "cite_spans": [{"start": 194, "end": 197, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 443, "end": 447, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 631, "end": 635, "text": "[11,", "ref_id": "BIBREF10"}, {"start": 636, "end": 639, "text": "12]", "ref_id": "BIBREF11"}], "ref_spans": [{"start": 431, "end": 440, "text": "(Table 1)", "ref_id": "TABREF0"}]}, {"section": "Chronic inflammation and oncogenesis", "text": "Associations linking chronic infection, chronic inflammation and malignancy have been well chronicled. [13] As many as 25% of all cancers can be traced to chronic infection or other types of chronic inflammation. [14] Infectious agents that cause chronic inflammation promote oncogenesis by complex pathways, and are depicted in Figure 1 . Key mediators of inflammation-induced oncogenesis include generation of mutagenic chemical mediators such as reactive oxygen and nitrogen species, genetic variations in inflammatory cytokines [15] , and creation of a micro-environment with features of chronic inflammation such as nuclear factor kappa B (NF-\u03baB). [16, 17] In such conditions, tumor-associated macrophages (TAMs) play a pivotal role in mediating inflammatory (M1) responses, as well as immunosuppressive and growth (M2) responses. [18] M2-polarized TAMs and the related myeloid-derived suppressor cells are key components of smoldering inflammation that drives neoplastic progression. The M2 responses, while important for wound healing, can promote neoplastic transformation. TAMs respond to cytokines such as Interleukin (IL)-10 and Transforming Growth Factor (TGF)-\u03b2, acquiring M2 properties that promote immune suppression by blocking dendritic cell (DC) maturation and attracting regulatory T-cells (T-regs). [19, 20] T-regs are potent inhibitors of the T-cell antitumor response. [21] Activation of NF-\u03baB pathway mediated by COX-2 and IL-6 via STAT-3 transcriptional activation also promotes malignant transformation. [22] NF-\u03baB is a transcription factor that mediates an inflammatory cascade leading to generation of COX-2, an inducible isoform of nitric oxide synthase (iNOS) and the inflammatory cytokines IL-1\u03b2, IL-6, and Tumor Necrosis Factor (TNF) -\u03b1. These cytokines, in conjunction with nitric oxide produced by TAMs and tumor cells, are present in high concentration in the tumor microenvironment and are important promoters of inflammation-driven oncogenesis and immunosuppression. [23] [24] [25] ", "cite_spans": [{"start": 103, "end": 107, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 213, "end": 217, "text": "[14]", "ref_id": "BIBREF13"}, {"start": 532, "end": 536, "text": "[15]", "ref_id": "BIBREF14"}, {"start": 653, "end": 657, "text": "[16,", "ref_id": "BIBREF15"}, {"start": 658, "end": 661, "text": "17]", "ref_id": "BIBREF16"}, {"start": 836, "end": 840, "text": "[18]", "ref_id": "BIBREF17"}, {"start": 1319, "end": 1323, "text": "[19,", "ref_id": "BIBREF18"}, {"start": 1324, "end": 1327, "text": "20]", "ref_id": "BIBREF19"}, {"start": 1391, "end": 1395, "text": "[21]", "ref_id": "BIBREF20"}, {"start": 1529, "end": 1533, "text": "[22]", "ref_id": "BIBREF21"}, {"start": 2003, "end": 2007, "text": "[23]", "ref_id": "BIBREF22"}, {"start": 2008, "end": 2012, "text": "[24]", "ref_id": "BIBREF23"}, {"start": 2013, "end": 2017, "text": "[25]", "ref_id": "BIBREF24"}], "ref_spans": [{"start": 329, "end": 337, "text": "Figure 1", "ref_id": "FIGREF1"}]}, {"section": "Concept of oncomodulation", "text": "Tumor cells have aberrations in cell cycle signaling, RNA transcription and the production of tumor-suppression proteins. The concept of \"oncomodulation\" suggests that a virus may modulate cellular pathways [26] through changes to viral regulatory proteins and noncoding RNA which eludes to tumor cell properties (cell proliferation, survival, invasion, production of angiogenic factors, and immune evasion). hCMV not only promotes oncogenesis but also contributes to a more malignant tumor cell phenotype ( Figure 2 ). While investigators have long postulated a role for hCMV in human neoplasia, many of the early studies were not reproducible and lacked clear in situ histopathological correlations with the proposed diseases. [27, 28] The concept of \"hit-and-run\" oncogenesis holds that infection with hCMV takes place during an earlier time frame to tumour development. hCMV infection sets into motion processes resulting in malignancy, but the virus is no longer detectable by the time cancer occurs. [29] Several of the more important cellular pathways that could lead to cancer and which are modulated by hCMV are reviewed below.", "cite_spans": [{"start": 207, "end": 211, "text": "[26]", "ref_id": "BIBREF25"}, {"start": 729, "end": 733, "text": "[27,", "ref_id": "BIBREF26"}, {"start": 734, "end": 737, "text": "28]", "ref_id": "BIBREF27"}, {"start": 1006, "end": 1010, "text": "[29]", "ref_id": "BIBREF28"}], "ref_spans": [{"start": 508, "end": 516, "text": "Figure 2", "ref_id": "FIGREF3"}]}, {"section": "Resistance to apoptosis", "text": "Resistance to apoptosis is a common feature of cancer cells. [9, 30, 31] Early research on hCMV infection revealed that hCMV protects the fibroblasts it infects from apoptosis. hCMV immediate early (IE) proteins (e.g., IE2-86 & IE2-72) [32] are able to prevent adenovirus E1A protein-induced apoptosis-by both p53-dependent and independent mechanisms-of hCMV infected fibroblasts. Direct anti-apoptotic activity of hCMV proteins is related to defined transcripts encoded by the hCMV UL36-UL37 genes. [33, 34] The product of the UL36 gene is an inhibitor of caspase activation which binds to the pro-domain of caspase-8 and inhibits Fasmediated apoptosis. [35] Similarly, the UL37 gene product, UL37 exon 1, is a mitochondrial inhibitor of apoptosis and inhibits the recruitment of the pro-apoptotic proteins Bax and Bak to mitochondria, resulting in their functional inactivation. [36] hCMV further protects tumor cells from apoptosis by the induction of cellular proteins, including AKT, Bcl-2, and \u0394Np73\u03b1.", "cite_spans": [{"start": 61, "end": 64, "text": "[9,", "ref_id": "BIBREF8"}, {"start": 69, "end": 72, "text": "31]", "ref_id": "BIBREF29"}, {"start": 236, "end": 240, "text": "[32]", "ref_id": "BIBREF30"}, {"start": 500, "end": 504, "text": "[33,", "ref_id": "BIBREF31"}, {"start": 505, "end": 508, "text": "34]", "ref_id": "BIBREF32"}, {"start": 655, "end": 659, "text": "[35]", "ref_id": "BIBREF33"}, {"start": 881, "end": 885, "text": "[36]", "ref_id": "BIBREF34"}], "ref_spans": []}, {"section": "Resistance to apoptosis", "text": "[37] Induction of the anti-apoptotic protein Bcl-2 by hCMV, results in acquired resistance to cytotoxic drugs such as cisplatin and etoposide. This resistance can be reversed after treatment with the anti-hCMV drug, ganciclovir.", "cite_spans": [], "ref_spans": []}, {"section": "Resistance to apoptosis", "text": "[ 37] Engagement of platelet derived growth factor receptor (PDGFR) \u03b1 or virus co-receptors (including integrins and Toll-like receptor-2) by hCMV glycoproteins can also lead to activation of mitogen-activated protein kinase (MAPK) and/or phosphatidyl-inositol 3-kinase (PI3-K) pathways that can alter apoptotic responses ( Figure 3 ). [38] [39] [40] ", "cite_spans": [{"start": 336, "end": 340, "text": "[38]", "ref_id": "BIBREF36"}, {"start": 341, "end": 345, "text": "[39]", "ref_id": "BIBREF37"}, {"start": 346, "end": 350, "text": "[40]", "ref_id": "BIBREF38"}], "ref_spans": [{"start": 324, "end": 332, "text": "Figure 3", "ref_id": "FIGREF4"}]}, {"section": "Cancer cell adhesion, migration and invasion", "text": "Adhesion of cancer cells to endothelium is critical in promoting metastases. [41] [42] [43] hCMV can facilitate this process by promoting activation of integrins (e.g., \u03b21\u03b15 and B1) on the tumor cell surface, and by increasing adhesion of tumor cells to the neighboring endothelium. Tumor cell adhesion to endothelium is also facilitated by activation of integrin-linked kinases (e.g., phosphorylation of focal adhesion kinase Tyr397). [4,,44 ] Down regulation of adhesion molecule receptors by hCMV (e.g., neural cell adhesion molecule, CD56), causes a focal disruption of endothelial cells facilitating tumor cell transmigration. [1, 45] The net effects of hCMV on adhesion molecules account for decreased binding of cancer cells to each other and Manifestations of Cytomegalovirus Infectionincreased binding to endothelium, which is an important early process in formation of metastasis.", "cite_spans": [{"start": 77, "end": 81, "text": "[41]", "ref_id": "BIBREF39"}, {"start": 82, "end": 86, "text": "[42]", "ref_id": "BIBREF40"}, {"start": 87, "end": 91, "text": "[43]", "ref_id": "BIBREF41"}, {"start": 632, "end": 635, "text": "[1,", "ref_id": "BIBREF0"}, {"start": 636, "end": 639, "text": "45]", "ref_id": "BIBREF43"}], "ref_spans": []}, {"section": "Angiogenesis", "text": "Angiogenesis is the growth of the new blood vessels and is essential for growth of malignant tumors. [9, 46] Through the technique of secretome analysis researchers have shown that proteins secreted from hCMV-infected cells contain increased levels of pro-angiogenic molecules, and increased pro-angiogenic activity in cell-free supernatants. [47] US28 is a hCMV protein seen in high concentrations in the supernatant. This particular protein alters adhesion properties of epithelial cells inducing a pro-angiogenic and transformed phenotype through up-regulation of vascular endothelial growth factor (VEGF). [48] Additional supernatant proteins, including IE1-72 and IE2-86, increase vascular smooth muscle cell migration, proliferation, and expression of PDGF-\u03b2 receptor. Furthermore, IE2-86 promotes endothelial proliferation by binding and inactivating the tumor oncogene p53 in endothelial cells. [49, 50] Expression of IL-8, another well-recognized promoter of tumor angiogenesis, is increased by hCMV via transactivation of IL-8 promoter through the cellular transcription factors NF-\u03baB and AP-1. [51] Binding of hCMV to and signaling through integrin \u03b21, integrin \u03b23, and epidermal growth factor receptor can also promote angiogenesis. [47, 52] ", "cite_spans": [{"start": 101, "end": 104, "text": "[9,", "ref_id": "BIBREF8"}, {"start": 105, "end": 108, "text": "46]", "ref_id": "BIBREF44"}, {"start": 343, "end": 347, "text": "[47]", "ref_id": "BIBREF45"}, {"start": 610, "end": 614, "text": "[48]", "ref_id": "BIBREF46"}, {"start": 903, "end": 907, "text": "[49,", "ref_id": "BIBREF47"}, {"start": 908, "end": 911, "text": "50]", "ref_id": "BIBREF48"}, {"start": 1105, "end": 1109, "text": "[51]", "ref_id": "BIBREF49"}, {"start": 1245, "end": 1249, "text": "[47,", "ref_id": "BIBREF45"}, {"start": 1250, "end": 1253, "text": "52]", "ref_id": "BIBREF50"}], "ref_spans": []}, {"section": "100])", "text": "The Oncogenicity of Human Cytomegalovirus http://dx.doi.org/10.5772/55051", "cite_spans": [], "ref_spans": []}, {"section": "100])", "text": "Expression of thrombospondin (TSP-1), a potent inhibitor of angiogenesis, is suppressed in several hCMV-infected cancer cell lines, suggesting yet another mechanism by which hCMV can promote increased angiogenesis and a more malignant phenotype. [53, 54] hCMVmediated activation of COX-2 may also promote angiogenesis in tumor cells by inducing expression of Fibroblast Growth Factor (FGF), VEGF, PDGF, iNOS, and TGF-\u03b1, and by promoting capillary endothelial cell migration and tube formation (Figure 3 ). [55] ", "cite_spans": [{"start": 246, "end": 250, "text": "[53,", "ref_id": "BIBREF51"}, {"start": 251, "end": 254, "text": "54]", "ref_id": "BIBREF52"}, {"start": 506, "end": 510, "text": "[55]", "ref_id": "BIBREF53"}], "ref_spans": [{"start": 493, "end": 502, "text": "(Figure 3", "ref_id": "FIGREF4"}]}, {"section": "Impact of hCMV on cell cycle", "text": "In hCMV-infected host cells, viral regulatory proteins induce cell cycle arrest and prevent cellular DNA replication, whilst replication of viral DNA remains enabled. [8, 56] While some hCMV regulatory proteins can induce cell cycle arrest, others can promote cell cycle progression. [57, 58] hCMV IE2-86 induces cell cycle arrest by activating ataxia telangiectasia mutated (ATM) gene-dependent phosphorylation of p53, leading to p53-and p21-dependent inhibition of cell cycle progression. [59] In contrast, the hCMV regulatory proteins IE1-72, IE2-86, and the tegument proteins pp71 and UL97 interact with and deactivate proteins of the Rb family, promoting entry into S-phase of the cell cycle. [60] The cell cycle of neoplastic cells is inherently dysfunctional. [9, 31] In precancerous or transformed cells, the function of virus regulatory proteins may depend on the replicative status of the cell. [61, 62] The hCMV protein US28 promotes cell cycle progression and cyclin D1 expression in cells with a neoplastic phenotype; whereas, it induces apoptosis in non-neoplastic cells. [48] Persistent hCMV infection of tumor cells may lead to a selection of virus variants with changes in virus regulatory proteins that have lost their ability to induce cell cycle arrest. [63, 64] ", "cite_spans": [{"start": 167, "end": 170, "text": "[8,", "ref_id": "BIBREF7"}, {"start": 171, "end": 174, "text": "56]", "ref_id": "BIBREF54"}, {"start": 284, "end": 288, "text": "[57,", "ref_id": "BIBREF55"}, {"start": 289, "end": 292, "text": "58]", "ref_id": "BIBREF56"}, {"start": 491, "end": 495, "text": "[59]", "ref_id": "BIBREF57"}, {"start": 698, "end": 702, "text": "[60]", "ref_id": "BIBREF58"}, {"start": 767, "end": 770, "text": "[9,", "ref_id": "BIBREF8"}, {"start": 771, "end": 774, "text": "31]", "ref_id": "BIBREF29"}, {"start": 905, "end": 909, "text": "[61,", "ref_id": "BIBREF59"}, {"start": 910, "end": 913, "text": "62]", "ref_id": "BIBREF60"}, {"start": 1086, "end": 1090, "text": "[48]", "ref_id": "BIBREF46"}, {"start": 1274, "end": 1278, "text": "[63,", "ref_id": "BIBREF61"}, {"start": 1279, "end": 1282, "text": "64]", "ref_id": "BIBREF62"}], "ref_spans": []}, {"section": "Escape of immune surveillance by cancer cells: Role of hCMV", "text": "Immunological tolerance is a process by which the immune system no longer recognizes an aberrant antigen as \"foreign.\" [67] Through \"natural\" or \"self-tolerance\" the body does not mount an immune response to self-antigens. \"Induced tolerance\" to external antigens can be created by manipulating the immune system. Mechanisms of tolerance that exist to prevent autoimmune disease may also preclude the development of an adequate antitumor response. [65] [66] [67] This concept of \"immune tolerance\" may be particularly important in malignancies whose etiology is associated with inflammation. [68] Expression of hCMV proteins by infected tumor cells may induce 'immune tolerance' to tumor cells. Also, several tumor-derived factors contribute to the emergence of complex local and regional immunosuppressive networks, including VEGF, IL-10, TGF-\u03b2, and prostaglandin E-2 (PGE2). [66, 69] hCMV has evolved multiple strategies for immune evasion resulting in persistent viral infection in the host [70] [71] [72] [73] [74] Several hCMV proteins, including those expressed with IE genes, block the host cell MHC class I antigen expression, which is essential for activation of CD8+ T-lymphocyte anti-tumor cytotoxicity. hCMV UL83 protein (pp65) blocks antigen presentation of hCMV epitopes to CD8+ T-cells, and expression of hCMV UL18, a MHC class I homologue, disrupts \"natural killer\" (NK) cell recognition of hCMV-infected cells. [75] Disruption of hCMV antigen presentation by infected cells is mediated by hCMV protein US3, which sequesters MHC class I complexes in the endoplasmic reticulum, and hCMV protein US11 which causes dislocation of the MHC class I heavy chain from the cytoplasm. [76] [77] [78] hCMVencoded IL-10 homologue impairs tumor antigen presentation by inhibiting maturation, normal differentiation and cytokine production of dendritic cells and macrophages.. [79] [80] [81] hCMV induces integrin \u03b1 v \u03b2 6 expression in endothelial cells of blood vessels in different tissues, causing activation of TGF-\u03b21, resulting in interference of host immune responses against tumor cells by blocking the activation of lymphocytes and monocyte derived phagocytes. [82] These direct immune-modulatory effects of hCMV on myeloid cells within the tumor microenvironment, along with expression of immunosuppressive cytokines provide a virtually impassable environment for the host anti-tumor immune system.", "cite_spans": [{"start": 119, "end": 123, "text": "[67]", "ref_id": "BIBREF65"}, {"start": 448, "end": 452, "text": "[65]", "ref_id": "BIBREF63"}, {"start": 453, "end": 457, "text": "[66]", "ref_id": "BIBREF64"}, {"start": 458, "end": 462, "text": "[67]", "ref_id": "BIBREF65"}, {"start": 592, "end": 596, "text": "[68]", "ref_id": "BIBREF66"}, {"start": 877, "end": 881, "text": "[66,", "ref_id": "BIBREF64"}, {"start": 882, "end": 885, "text": "69]", "ref_id": "BIBREF67"}, {"start": 994, "end": 998, "text": "[70]", "ref_id": "BIBREF68"}, {"start": 999, "end": 1003, "text": "[71]", "ref_id": "BIBREF69"}, {"start": 1004, "end": 1008, "text": "[72]", "ref_id": "BIBREF70"}, {"start": 1009, "end": 1013, "text": "[73]", "ref_id": "BIBREF71"}, {"start": 1014, "end": 1018, "text": "[74]", "ref_id": "BIBREF72"}, {"start": 1428, "end": 1432, "text": "[75]", "ref_id": "BIBREF73"}, {"start": 1691, "end": 1695, "text": "[76]", "ref_id": "BIBREF74"}, {"start": 1696, "end": 1700, "text": "[77]", "ref_id": "BIBREF75"}, {"start": 1701, "end": 1705, "text": "[78]", "ref_id": "BIBREF76"}, {"start": 1879, "end": 1883, "text": "[79]", "ref_id": "BIBREF77"}, {"start": 1884, "end": 1888, "text": "[80]", "ref_id": "BIBREF78"}, {"start": 1889, "end": 1893, "text": "[81]", "ref_id": "BIBREF79"}, {"start": 2171, "end": 2175, "text": "[82]", "ref_id": "BIBREF80"}], "ref_spans": []}, {"section": "Influence of CMV on tumor microenvironment", "text": "Persistent hCMV infection of non-neoplastic cells in the tumor microenvironment leads to a paracrine secretion of inflammatory molecules that promote malignancy. [83] The secretome of hCMV-infected fibroblasts contains exceedingly high levels of growth factors, matrix remodeling proteins such as matrix metalloproteinases (MMPs), and angiogenic factors that signal through the TGF-\u03b2 pathway. [47, 84] These paracrine-secreted factors are also able to activate latent growth factors. PDGFs acts as strong mitogens and their overexpression is important in the pathogenesis of multiple malignancies. [85] [86] [87] In addition to growth factors, high levels of many ECM modifiers such as MMPs, tissue inhibitors of metalloproteinases (TIMPs) and urokinase receptor (uPAR) secreted by hCMV infected cells aiding, tumor invasion and metastasis. [84] 6. DNA mutations, impaired DNA repair mechanisms and epigenetic changes by hCMV that leads to genomic instability hCMV infection can drive neoplastic transformation by causing chromosome damage and genetic instability in infected cells, particularly in vulnerable adult stem cells. [88] [89] [90] hCMV in combination with cytotoxic chemotherapy agents synergistically increases genotoxic effects. [91, 92] The virus can induce specific chromosome 1 strand breaks at positions 1q42 and 1q21 in a replication-independent fashion, both of which are associated with DNA repair and replication genes. [89, 93, 94] hCMV IE1-72 and IE2-86 proteins when in conjunction with other viral oncogenic proteins (e.g., adenovirus E1A protein) that disrupt cell cycle can induce oncogenic transformation. [29] hCMV can contribute to genomic instability through a variety of different pathways. In brief, the virus may induce chromosomal aberrations (e.g., production of micronuclei, misaligned chromosomes, chromosomal lagging and bridging) by hCMV UL76 protein. [95, 96] The virus can also disrupt DNA repair pathways, including the activity of ATM and ATM-Rad3 (ATR). [97] More recently, hCMV has been shown to modulate oncogenesis through the telomerase pathway by activating human telomerase reverse transcriptase (hTERT) in fibroblasts and malignant cells. [98] ", "cite_spans": [{"start": 162, "end": 166, "text": "[83]", "ref_id": "BIBREF81"}, {"start": 393, "end": 397, "text": "[47,", "ref_id": "BIBREF45"}, {"start": 398, "end": 401, "text": "84]", "ref_id": "BIBREF82"}, {"start": 598, "end": 602, "text": "[85]", "ref_id": "BIBREF83"}, {"start": 603, "end": 607, "text": "[86]", "ref_id": "BIBREF84"}, {"start": 608, "end": 612, "text": "[87]", "ref_id": "BIBREF85"}, {"start": 841, "end": 845, "text": "[84]", "ref_id": "BIBREF82"}, {"start": 1128, "end": 1132, "text": "[88]", "ref_id": "BIBREF86"}, {"start": 1133, "end": 1137, "text": "[89]", "ref_id": "BIBREF87"}, {"start": 1138, "end": 1142, "text": "[90]", "ref_id": "BIBREF88"}, {"start": 1243, "end": 1247, "text": "[91,", "ref_id": "BIBREF89"}, {"start": 1248, "end": 1251, "text": "92]", "ref_id": "BIBREF90"}, {"start": 1442, "end": 1446, "text": "[89,", "ref_id": "BIBREF87"}, {"start": 1447, "end": 1450, "text": "93,", "ref_id": "BIBREF91"}, {"start": 1451, "end": 1454, "text": "94]", "ref_id": "BIBREF92"}, {"start": 1635, "end": 1639, "text": "[29]", "ref_id": "BIBREF28"}, {"start": 1893, "end": 1897, "text": "[95,", "ref_id": "BIBREF93"}, {"start": 1898, "end": 1901, "text": "96]", "ref_id": "BIBREF94"}, {"start": 2000, "end": 2004, "text": "[97]", "ref_id": "BIBREF95"}, {"start": 2192, "end": 2196, "text": "[98]", "ref_id": "BIBREF96"}], "ref_spans": []}, {"section": "Conclusions", "text": "Significant advances have been made in understanding the roles of chronic inflammation, tumor microenvironment, cancer stem cells, tumor immunology, and infectious agents in the pathobiology of cancer. Several clinical and experimental findings suggest that hCMV may play a role in promoting certain cancers. In cells that are persistently infected with hCMV, the expression of viral proteins may prevent the immune system from identifying or removing these cells, thereby offsetting immune detection of transformed cells. The effects of hCMV in promoting tumor cell immune evasion may prove important in development of cancer immunotherapies, particularly if the hCMV-infected cells are resistant to the action of cytolytic peptides released by activated NK and cytotoxic T-cells. Also, if viral proteins that inhibit apoptosis are expressed by hCMV infected tumour cells, the cancer cells may be less susceptible conventional chemotherapeutic agents. Whether hCMV is ultimately established as an oncogenic virus will require additional research in the areas of virology, epidemiology and molecular oncology, and systematic refinement of the concept of \"oncomodulation.\" Insights into the role of hCMV in oncogenesis may increase understanding of cancer biology and promote development of novel therapeutic strategies. ", "cite_spans": [], "ref_spans": []}, {"section": "Author details", "text": "", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Molecular mechanisms of the modulatory effects of HCMV infection in tumor cell biology. Trends in molecular medicine", "authors": [{"first": "J", "middle": [], "last": "Cinatl", "suffix": ""}, {"first": "M", "middle": [], "last": "Scholz", "suffix": ""}, {"first": "R", "middle": [], "last": "Kotchetkov", "suffix": ""}, {"first": "J", "middle": ["U"], "last": "Vogel", "suffix": ""}, {"first": "H", "middle": ["W"], "last": "Doerr", "suffix": ""}], "year": 2004, "venue": "", "link": null}, "BIBREF1": {"title": "Detection of human cytomegalovirus in normal and neoplastic breast epithelium", "authors": [{"first": "L", "middle": ["E"], "last": "Harkins", "suffix": ""}, {"first": "L", "middle": ["A"], "last": "Matlaf", "suffix": ""}, {"first": "L", "middle": [], "last": "Soroceanu", "suffix": ""}], "year": 2010, "venue": "Herpesviridae", "link": "1213390"}, "BIBREF2": {"title": "Human cytomegalovirus infection and expression in human malignant glioma. Cancer research", "authors": [{"first": "C", "middle": ["S"], "last": "Cobbs", "suffix": ""}, {"first": "L", "middle": [], "last": "Harkins", "suffix": ""}, {"first": "M", "middle": [], "last": "Samanta", "suffix": ""}], "year": 2002, "venue": "", "link": null}, "BIBREF3": {"title": "Human cytomegalovirus induces cellular tyrosine kinase signaling and promotes glioma cell invasiveness", "authors": [{"first": "C", "middle": ["S"], "last": "Cobbs", "suffix": ""}, {"first": "L", "middle": [], "last": "Soroceanu", "suffix": ""}, {"first": "S", "middle": [], "last": "Denham", "suffix": ""}], "year": 2007, "venue": "", "link": "23566659"}, "BIBREF4": {"title": "Detection of oncogenic viruses SV40, BKV, JCV, HCMV, HPV and p53 codon 72 polymorphism in lung carcinoma. Lung Cancer", "authors": [{"first": "L", "middle": [], "last": "Giuliani", "suffix": ""}, {"first": "T", "middle": [], "last": "Jaxmar", "suffix": ""}, {"first": "C", "middle": [], "last": "Casadio", "suffix": ""}], "year": 2007, "venue": "", "link": "21457669"}, "BIBREF5": {"title": "Specific localisation of human cytomegalovirus nucleic acids and proteins in human colorectal cancer", "authors": [{"first": "L", "middle": [], "last": "Harkins", "suffix": ""}, {"first": "A", "middle": ["L"], "last": "Volk", "suffix": ""}, {"first": "M", "middle": [], "last": "Samanta", "suffix": ""}], "year": 2002, "venue": "Lancet", "link": "25966423"}, "BIBREF6": {"title": "Detection of human cytomegalovirus in different histological types of gliomas. Acta neuropathologica", "authors": [{"first": "M", "middle": ["E"], "last": "Scheurer", "suffix": ""}, {"first": "M", "middle": ["L"], "last": "Bondy", "suffix": ""}, {"first": "K", "middle": ["D"], "last": "Aldape", "suffix": ""}, {"first": "T", "middle": [], "last": "Albrecht", "suffix": ""}, {"first": "R", "middle": [], "last": "El-Zein", "suffix": ""}], "year": 2008, "venue": "", "link": null}, "BIBREF7": {"title": "HCMV infection: modulating the cell cycle and cell death. International reviews of immunology", "authors": [{"first": "J", "middle": ["P"], "last": "Castillo", "suffix": ""}, {"first": "T", "middle": ["F"], "last": "Kowalik", "suffix": ""}], "year": 2004, "venue": "", "link": null}, "BIBREF8": {"title": "Hallmarks of cancer: the next generation", "authors": [{"first": "D", "middle": [], "last": "Hanahan", "suffix": ""}, {"first": "R", "middle": ["A"], "last": "Weinberg", "suffix": ""}], "year": 2011, "venue": "Cell", "link": "76502398"}, "BIBREF9": {"title": "Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability. Carcinogenesis", "authors": [{"first": "F", "middle": [], "last": "Colotta", "suffix": ""}, {"first": "P", "middle": [], "last": "Allavena", "suffix": ""}, {"first": "A", "middle": [], "last": "Sica", "suffix": ""}, {"first": "C", "middle": [], "last": "Garlanda", "suffix": ""}, {"first": "A", "middle": [], "last": "Mantovani", "suffix": ""}], "year": 2009, "venue": "", "link": null}, "BIBREF10": {"title": "Inflammation and liver cancer: new molecular links", "authors": [{"first": "C", "middle": [], "last": "Berasain", "suffix": ""}, {"first": "J", "middle": [], "last": "Castillo", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Perugorria", "suffix": ""}, {"first": "M", "middle": ["U"], "last": "Latasa", "suffix": ""}, {"first": "J", "middle": [], "last": "Prieto", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Avila", "suffix": ""}], "year": 2009, "venue": "Annals of the New York Academy of Sciences", "link": null}, "BIBREF11": {"title": "Epstein-Barr virus: 40 years on", "authors": [{"first": "L", "middle": ["S"], "last": "Young", "suffix": ""}, {"first": "A", "middle": ["B"], "last": "Rickinson", "suffix": ""}], "year": 2004, "venue": "Nature reviews. Cancer. Oct", "link": "25803264"}, "BIBREF12": {"title": "Inflammation and cancer: interweaving microRNA, free radical, cytokine and p53 pathways. Carcinogenesis", "authors": [{"first": "A", "middle": ["J"], "last": "Schetter", "suffix": ""}, {"first": "N", "middle": ["H"], "last": "Heegaard", "suffix": ""}, {"first": "C", "middle": ["C"], "last": "Harris", "suffix": ""}], "year": 2010, "venue": "", "link": null}, "BIBREF13": {"title": "Inflammation and cancer: an ancient link with novel potentials", "authors": [{"first": "S", "middle": ["P"], "last": "Hussain", "suffix": ""}, {"first": "C", "middle": ["C"], "last": "Harris", "suffix": ""}], "year": 2007, "venue": "International journal of cancer. Journal international du cancer", "link": "23385068"}, "BIBREF14": {"title": "Paradoxical roles of the immune system during cancer development. Nature reviews. Cancer", "authors": [{"first": "K", "middle": ["E"], "last": "De Visser", "suffix": ""}, {"first": "A", "middle": [], "last": "Eichten", "suffix": ""}, {"first": "L", "middle": ["M"], "last": "Coussens", "suffix": ""}], "year": 2006, "venue": "", "link": null}, "BIBREF15": {"title": "Immunity, inflammation, and cancer. Cell", "authors": [{"first": "S", "middle": ["I"], "last": "Grivennikov", "suffix": ""}, {"first": "F", "middle": ["R"], "last": "Greten", "suffix": ""}, {"first": "M", "middle": [], "last": "Karin", "suffix": ""}], "year": 2010, "venue": "", "link": null}, "BIBREF16": {"title": "Smoldering and polarized inflammation in the initiation and promotion of malignant disease. Cancer cell", "authors": [{"first": "F", "middle": [], "last": "Balkwill", "suffix": ""}, {"first": "K", "middle": ["A"], "last": "Charles", "suffix": ""}, {"first": "A", "middle": [], "last": "Mantovani", "suffix": ""}], "year": 2005, "venue": "", "link": null}, "BIBREF17": {"title": "The Yin-Yang of tumor-associated macrophages in neoplastic progression and immune surveillance. Immunological reviews", "authors": [{"first": "P", "middle": [], "last": "Allavena", "suffix": ""}, {"first": "A", "middle": [], "last": "Sica", "suffix": ""}, {"first": "C", "middle": [], "last": "Garlanda", "suffix": ""}, {"first": "A", "middle": [], "last": "Mantovani", "suffix": ""}], "year": 2008, "venue": "Apr", "link": null}, "BIBREF18": {"title": "Dual roles of immune cells and their factors in cancer development and progression", "authors": [{"first": "B", "middle": ["F"], "last": "Zamarron", "suffix": ""}, {"first": "W", "middle": [], "last": "Chen", "suffix": ""}], "year": 2011, "venue": "International journal of biological sciences", "link": "6516605"}, "BIBREF19": {"title": "Mechanisms of malignant glioma immune resistance and sources of immunosuppression", "authors": [{"first": "G", "middle": ["G"], "last": "Gomez", "suffix": ""}, {"first": "C", "middle": ["A"], "last": "Kruse", "suffix": ""}], "year": 2006, "venue": "Gene therapy & molecular biology", "link": "22138792"}, "BIBREF20": {"title": "Increase of regulatory T cells in the peripheral blood of cancer patients. Clinical cancer research : an official journal of the American Association for Cancer Research", "authors": [{"first": "A", "middle": ["M"], "last": "Wolf", "suffix": ""}, {"first": "D", "middle": [], "last": "Wolf", "suffix": ""}, {"first": "M", "middle": [], "last": "Steurer", "suffix": ""}, {"first": "G", "middle": [], "last": "Gastl", "suffix": ""}, {"first": "E", "middle": [], "last": "Gunsilius", "suffix": ""}, {"first": "B", "middle": [], "last": "Grubeck-Loebenstein", "suffix": ""}], "year": 2003, "venue": "", "link": null}, "BIBREF21": {"title": "IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell", "authors": [{"first": "F", "middle": ["R"], "last": "Greten", "suffix": ""}, {"first": "L", "middle": [], "last": "Eckmann", "suffix": ""}, {"first": "T", "middle": ["F"], "last": "Greten", "suffix": ""}], "year": 2004, "venue": "", "link": null}, "BIBREF22": {"title": "Expression of nitric oxide synthase in human central nervous system tumors. Cancer research", "authors": [{"first": "C", "middle": ["S"], "last": "Cobbs", "suffix": ""}, {"first": "J", "middle": ["E"], "last": "Brenman", "suffix": ""}, {"first": "K", "middle": ["D"], "last": "Aldape", "suffix": ""}, {"first": "D", "middle": ["S"], "last": "Bredt", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Israel", "suffix": ""}], "year": 1995, "venue": "", "link": null}, "BIBREF23": {"title": "Cyclooxygenase-2 and inducible nitric oxide synthase expression in human astrocytic gliomas: correlation with angiogenesis and prognostic significance. Acta neuropathologica", "authors": [{"first": "A", "middle": [], "last": "Hara", "suffix": ""}, {"first": "I", "middle": [], "last": "Okayasu", "suffix": ""}], "year": 2004, "venue": "", "link": null}, "BIBREF24": {"title": "Tumor-infiltrating, myeloid-derived suppressor cells inhibit T cell activity by nitric oxide production in an intracranial rat glioma + vaccination model", "authors": [{"first": "W", "middle": [], "last": "Jia", "suffix": ""}, {"first": "C", "middle": [], "last": "Jackson-Cook", "suffix": ""}, {"first": "M", "middle": ["R"], "last": "Graf", "suffix": ""}], "year": 2010, "venue": "Journal of neuroimmunology", "link": "206274142"}, "BIBREF25": {"title": "Modulatory effects of human cytomegalovirus infection on malignant properties of cancer cells", "authors": [{"first": "J", "middle": [], "last": "Cinatl", "suffix": ""}, {"first": "J", "middle": [], "last": "Cinatl", "suffix": ""}, {"first": "J", "middle": ["U"], "last": "Vogel", "suffix": ""}, {"first": "H", "middle": [], "last": "Rabenau", "suffix": ""}, {"first": "B", "middle": [], "last": "Kornhuber", "suffix": ""}, {"first": "H", "middle": ["W"], "last": "Doerr", "suffix": ""}], "year": 1996, "venue": "Intervirology", "link": "25327331"}, "BIBREF26": {"title": "Cytomegalovirus and cancer of the prostate: in vitro transformation of human cells. Cancer treatment reports", "authors": [{"first": "L", "middle": [], "last": "Geder", "suffix": ""}, {"first": "E", "middle": ["J"], "last": "Sanford", "suffix": ""}, {"first": "T", "middle": ["J"], "last": "Rohner", "suffix": ""}, {"first": "F", "middle": [], "last": "Rapp", "suffix": ""}], "year": 1977, "venue": "", "link": null}, "BIBREF27": {"title": "Evidence for the association of cytomegalovirus with carcinoma of the prostate. The Journal of urology", "authors": [{"first": "E", "middle": ["J"], "last": "Sanford", "suffix": ""}, {"first": "L", "middle": [], "last": "Geder", "suffix": ""}, {"first": "A", "middle": [], "last": "Laychock", "suffix": ""}, {"first": "T", "middle": ["J"], "last": "Rohner", "suffix": ""}, {"first": "Jr", "middle": [], "last": "Rapp", "suffix": ""}, {"first": "F", "middle": [], "last": "", "suffix": ""}], "year": 1977, "venue": "", "link": null}, "BIBREF28": {"title": "Human cytomagalovirus IE1 and IE2 proteins are mutagenic and mediate \"hit-and-run", "authors": [{"first": "Y", "middle": [], "last": "Shen", "suffix": ""}, {"first": "H", "middle": [], "last": "Zhu", "suffix": ""}, {"first": "T", "middle": [], "last": "Shenk", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF29": {"title": "Cell cycle and apoptosis. Neoplasia", "authors": [{"first": "B", "middle": [], "last": "Pucci", "suffix": ""}, {"first": "M", "middle": [], "last": "Kasten", "suffix": ""}, {"first": "A", "middle": [], "last": "Giordano", "suffix": ""}], "year": 2000, "venue": "", "link": null}, "BIBREF30": {"title": "Human cytomegalovirus IE1 and IE2 proteins block apoptosis", "authors": [{"first": "H", "middle": [], "last": "Zhu", "suffix": ""}, {"first": "Y", "middle": [], "last": "Shen", "suffix": ""}, {"first": "T", "middle": [], "last": "Shenk", "suffix": ""}], "year": 1995, "venue": "Journal of virology", "link": null}, "BIBREF31": {"title": "Control of apoptosis by human cytomegalovirus. Current topics in microbiology and immunology", "authors": [{"first": "A", "middle": ["L"], "last": "Mccormick", "suffix": ""}], "year": 2008, "venue": "", "link": null}, "BIBREF32": {"title": "Cytomegalovirus infection blocks apoptosis in cancer cells. Cellular and molecular life sciences : CMLS", "authors": [{"first": "M", "middle": [], "last": "Michaelis", "suffix": ""}, {"first": "R", "middle": [], "last": "Kotchetkov", "suffix": ""}, {"first": "J", "middle": ["U"], "last": "Vogel", "suffix": ""}, {"first": "H", "middle": ["W"], "last": "Doerr", "suffix": ""}, {"first": "J", "middle": [], "last": "Cinatl", "suffix": ""}, {"first": "Jr", "middle": [], "last": "", "suffix": ""}], "year": 2004, "venue": "", "link": null}, "BIBREF33": {"title": "A cytomegalovirus-encoded inhibitor of apoptosis that suppresses caspase-8 activation", "authors": [{"first": "A", "middle": [], "last": "Skaletskaya", "suffix": ""}, {"first": "L", "middle": ["M"], "last": "Bartle", "suffix": ""}, {"first": "T", "middle": [], "last": "Chittenden", "suffix": ""}, {"first": "A", "middle": ["L"], "last": "Mccormick", "suffix": ""}, {"first": "E", "middle": ["S"], "last": "Mocarski", "suffix": ""}, {"first": "V", "middle": ["S"], "last": "Goldmacher", "suffix": ""}], "year": 2001, "venue": "Proceedings of the National Academy of Sciences of the United States of America", "link": "33670469"}, "BIBREF34": {"title": "A cytomegalovirus-encoded mitochondria-localized inhibitor of apoptosis structurally unrelated to Bcl-2", "authors": [{"first": "V", "middle": ["S"], "last": "Goldmacher", "suffix": ""}, {"first": "L", "middle": ["M"], "last": "Bartle", "suffix": ""}, {"first": "A", "middle": [], "last": "Skaletskaya", "suffix": ""}], "year": 1999, "venue": "Proceedings of the National Academy of Sciences of the United States of America", "link": "22388365"}, "BIBREF35": {"title": "Persistent human cytomegalovirus infection induces drug resistance and alteration of programmed cell death in human neuroblastoma cells. Cancer research", "authors": [{"first": "J", "middle": [], "last": "Cinatl", "suffix": ""}, {"first": "J", "middle": [], "last": "Cinatl", "suffix": ""}, {"first": "J", "middle": ["U"], "last": "Vogel", "suffix": ""}], "year": 1998, "venue": "", "link": "18540280"}, "BIBREF36": {"title": "Platelet-derived growth factor-alpha receptor activation is required for human cytomegalovirus infection", "authors": [{"first": "L", "middle": [], "last": "Soroceanu", "suffix": ""}, {"first": "A", "middle": [], "last": "Akhavan", "suffix": ""}, {"first": "C", "middle": ["S"], "last": "Cobbs", "suffix": ""}], "year": 2008, "venue": "Nature", "link": "4312980"}, "BIBREF37": {"title": "Human cytomegalovirus upregulates the phosphatidylinositol 3-kinase (PI3-K) pathway: inhibition of PI3-K activity inhibits viral replication and virus-induced signaling", "authors": [{"first": "R", "middle": ["A"], "last": "Johnson", "suffix": ""}, {"first": "X", "middle": [], "last": "Wang", "suffix": ""}, {"first": "X", "middle": ["L"], "last": "Ma", "suffix": ""}, {"first": "S", "middle": ["M"], "last": "Huong", "suffix": ""}, {"first": "E", "middle": ["S"], "last": "Huang", "suffix": ""}], "year": 2001, "venue": "Journal of virology", "link": "2557141"}, "BIBREF38": {"title": "Activation of the mitogen-activated protein kinase p38 by human cytomegalovirus infection through two distinct pathways: a novel mechanism for activation of p38", "authors": [{"first": "R", "middle": ["A"], "last": "Johnson", "suffix": ""}, {"first": "S", "middle": ["M"], "last": "Huong", "suffix": ""}, {"first": "E", "middle": ["S"], "last": "Huang", "suffix": ""}], "year": 2000, "venue": "Journal of virology", "link": "27289436"}, "BIBREF39": {"title": "Metastasis: cell-autonomous mechanisms versus contributions by the tumor microenvironment. Cellular and molecular life sciences : CMLS", "authors": [{"first": "L", "middle": [], "last": "Kopfstein", "suffix": ""}, {"first": "G", "middle": [], "last": "Christofori", "suffix": ""}], "year": 2006, "venue": "", "link": null}, "BIBREF40": {"title": "Integrin alpha 6 beta 4 promotes migration, invasion through Tiam1 upregulation, and subsequent Rac activation. Neoplasia", "authors": [{"first": "Z", "middle": [], "last": "Cruz-Monserrate", "suffix": ""}, {"first": "O&apos;", "middle": [], "last": "Connor", "suffix": ""}, {"first": "K", "middle": ["L"], "last": "", "suffix": ""}], "year": 2008, "venue": "", "link": "19908832"}, "BIBREF41": {"title": "Type I collagen receptor (alpha2beta1) signaling promotes prostate cancer invasion through RhoC GTPase", "authors": [{"first": "C", "middle": ["L"], "last": "Hall", "suffix": ""}, {"first": "C", "middle": ["W"], "last": "Dubyk", "suffix": ""}, {"first": "T", "middle": ["A"], "last": "Riesenberger", "suffix": ""}, {"first": "D", "middle": [], "last": "Shein", "suffix": ""}, {"first": "E", "middle": ["T"], "last": "Keller", "suffix": ""}, {"first": "K", "middle": ["L"], "last": "Van Golen", "suffix": ""}], "year": 2008, "venue": "Neoplasia. Aug", "link": "29399926"}, "BIBREF42": {"title": "Human cytomegalovirus infection alters PC3 prostate carcinoma cell adhesion to endothelial cells and extracellular matrix. Neoplasia", "authors": [{"first": "R", "middle": ["A"], "last": "Blaheta", "suffix": ""}, {"first": "E", "middle": [], "last": "Weich", "suffix": ""}, {"first": "D", "middle": [], "last": "Marian", "suffix": ""}], "year": 2006, "venue": "", "link": "23416641"}, "BIBREF43": {"title": "Human cytomegalovirus infection of tumor cells downregulates NCAM (CD56): a novel mechanism for virus-induced tumor invasiveness", "authors": [{"first": "R", "middle": ["A"], "last": "Blaheta", "suffix": ""}, {"first": "W", "middle": ["D"], "last": "Beecken", "suffix": ""}, {"first": "T", "middle": [], "last": "Engl", "suffix": ""}], "year": 2004, "venue": "Neoplasia", "link": "7858883"}, "BIBREF44": {"title": "Circulating endothelial cells, endothelial progenitor cells, and endothelial microparticles in cancer", "authors": [{"first": "P", "middle": ["K"], "last": "Goon", "suffix": ""}, {"first": "G", "middle": ["Y"], "last": "Lip", "suffix": ""}, {"first": "C", "middle": ["J"], "last": "Boos", "suffix": ""}, {"first": "P", "middle": ["S"], "last": "Stonelake", "suffix": ""}, {"first": "A", "middle": ["D"], "last": "Blann", "suffix": ""}], "year": 2006, "venue": "Neoplasia. Feb", "link": "39252974"}, "BIBREF45": {"title": "Human cytomegalovirus secretome contains factors that induce angiogenesis and wound healing", "authors": [{"first": "J", "middle": [], "last": "Dumortier", "suffix": ""}, {"first": "D", "middle": ["N"], "last": "Streblow", "suffix": ""}, {"first": "A", "middle": ["V"], "last": "Moses", "suffix": ""}], "year": 2008, "venue": "Journal of virology", "link": "1022045"}, "BIBREF46": {"title": "Human cytomegalovirus-encoded chemokine receptor US28 promotes tumorigenesis", "authors": [{"first": "D", "middle": [], "last": "Maussang", "suffix": ""}, {"first": "D", "middle": [], "last": "Verzijl", "suffix": ""}, {"first": "M", "middle": [], "last": "Van Walsum", "suffix": ""}], "year": 2006, "venue": "Proceedings of the National Academy of Sciences of the United States of America", "link": "39130259"}, "BIBREF47": {"title": "HCMV infection of human vascular smooth muscle cells leads to enhanced expression of functionally intact PDGF betareceptor. Cardiovascular research", "authors": [{"first": "B", "middle": [], "last": "Reinhardt", "suffix": ""}, {"first": "T", "middle": [], "last": "Mertens", "suffix": ""}, {"first": "U", "middle": [], "last": "Mayr-Beyrle", "suffix": ""}], "year": 2005, "venue": "", "link": null}, "BIBREF48": {"title": "Cytoplasmic sequestration of p53 in cytomegalovirus-infected human endothelial cells. The American journal of pathology", "authors": [{"first": "A", "middle": [], "last": "Kovacs", "suffix": ""}, {"first": "M", "middle": ["L"], "last": "Weber", "suffix": ""}, {"first": "L", "middle": ["J"], "last": "Burns", "suffix": ""}, {"first": "H", "middle": ["S"], "last": "Jacob", "suffix": ""}, {"first": "G", "middle": ["M"], "last": "Vercellotti", "suffix": ""}], "year": 1996, "venue": "Nov", "link": null}, "BIBREF49": {"title": "The immediate early gene 1 product of human cytomegalovirus is sufficient for up-regulation of interleukin-8 gene expression. Biochemical and biophysical research communications", "authors": [{"first": "T", "middle": [], "last": "Murayama", "suffix": ""}, {"first": "N", "middle": [], "last": "Mukaida", "suffix": ""}, {"first": "H", "middle": [], "last": "Sadanari", "suffix": ""}], "year": 2000, "venue": "", "link": null}, "BIBREF50": {"title": "Human CMV infection of endothelial cells induces an angiogenic response through viral binding to EGF receptor and beta1 and beta3 integrins", "authors": [{"first": "G", "middle": ["L"], "last": "Bentz", "suffix": ""}, {"first": "A", "middle": ["D"], "last": "Yurochko", "suffix": ""}], "year": 2008, "venue": "Proceedings of the National Academy of Sciences of the United States of America", "link": null}, "BIBREF51": {"title": "Inhibition of angiogenesis in human glioblastomas by chromosome 10 induction of thrombospondin-1. Cancer research", "authors": [{"first": "S", "middle": ["C"], "last": "Hsu", "suffix": ""}, {"first": "O", "middle": ["V"], "last": "Volpert", "suffix": ""}, {"first": "P", "middle": ["A"], "last": "Steck", "suffix": ""}], "year": 1996, "venue": "", "link": null}, "BIBREF52": {"title": "Thrombospondin-1 is downregulated by anoxia and suppresses tumorigenicity of human glioblastoma cells. The Journal of experimental medicine", "authors": [{"first": "M", "middle": [], "last": "Tenan", "suffix": ""}, {"first": "G", "middle": [], "last": "Fulci", "suffix": ""}, {"first": "M", "middle": [], "last": "Albertoni", "suffix": ""}], "year": 2000, "venue": "", "link": null}, "BIBREF53": {"title": "Cyclooxygenase regulates angiogenesis induced by colon cancer cells", "authors": [{"first": "M", "middle": [], "last": "Tsujii", "suffix": ""}, {"first": "S", "middle": [], "last": "Kawano", "suffix": ""}, {"first": "S", "middle": [], "last": "Tsuji", "suffix": ""}, {"first": "H", "middle": [], "last": "Sawaoka", "suffix": ""}, {"first": "M", "middle": [], "last": "Hori", "suffix": ""}, {"first": "R", "middle": ["N"], "last": "Dubois", "suffix": ""}], "year": 1998, "venue": "Cell", "link": "2072460"}, "BIBREF54": {"title": "Subversion of cell cycle regulatory pathways. Current topics in microbiology and immunology", "authors": [{"first": "V", "middle": [], "last": "Sanchez", "suffix": ""}, {"first": "D", "middle": ["H"], "last": "Spector", "suffix": ""}], "year": 2008, "venue": "", "link": null}, "BIBREF55": {"title": "Cytomegalovirus infection induces high levels of cyclins, phosphorylated Rb, and p53, leading to cell cycle arrest", "authors": [{"first": "F", "middle": ["M"], "last": "Jault", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Jault", "suffix": ""}, {"first": "F", "middle": [], "last": "Ruchti", "suffix": ""}], "year": 1995, "venue": "Journal of virology", "link": "2290972"}, "BIBREF56": {"title": "Cell cycle dysregulation by human cytomegalovirus: influence of the cell cycle phase at the time of infection and effects on cyclin transcription", "authors": [{"first": "B", "middle": ["S"], "last": "Salvant", "suffix": ""}, {"first": "E", "middle": ["A"], "last": "Fortunato", "suffix": ""}, {"first": "D", "middle": ["H"], "last": "Spector", "suffix": ""}], "year": 1998, "venue": "Journal of virology", "link": "16020034"}, "BIBREF57": {"title": "Inhibition of cell division by the human cytomegalovirus IE86 protein: role of the p53 pathway or cyclin-dependent kinase 1/cyclin B1", "authors": [{"first": "Y", "middle": ["J"], "last": "Song", "suffix": ""}, {"first": "M", "middle": ["F"], "last": "Stinski", "suffix": ""}], "year": 2005, "venue": "", "link": "18429793"}, "BIBREF58": {"title": "Phosphorylation of retinoblastoma protein by viral protein with cyclin-dependent kinase function. Science", "authors": [{"first": "A", "middle": ["J"], "last": "Hume", "suffix": ""}, {"first": "J", "middle": ["S"], "last": "Finkel", "suffix": ""}, {"first": "J", "middle": ["P"], "last": "Kamil", "suffix": ""}, {"first": "D", "middle": ["M"], "last": "Coen", "suffix": ""}, {"first": "M", "middle": ["R"], "last": "Culbertson", "suffix": ""}, {"first": "R", "middle": ["F"], "last": "Kalejta", "suffix": ""}], "year": 2008, "venue": "", "link": "5870347"}, "BIBREF59": {"title": "Human cytomegalovirus IE1-72 protein interacts with p53 and inhibits p53-dependent transactivation by a mechanism different from that of IE2-86 protein", "authors": [{"first": "E", "middle": ["S"], "last": "Hwang", "suffix": ""}, {"first": "Z", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "H", "middle": [], "last": "Cai", "suffix": ""}], "year": 2009, "venue": "Journal of virology", "link": "37488053"}, "BIBREF60": {"title": "Long-term infection and shedding of human cytomegalovirus in T98G glioblastoma cells", "authors": [{"first": "M", "middle": ["H"], "last": "Luo", "suffix": ""}, {"first": "E", "middle": ["A"], "last": "Fortunato", "suffix": ""}], "year": 2007, "venue": "Journal of virology", "link": "25896480"}, "BIBREF61": {"title": "A variant of human cytomegalovirus derived from a persistently infected culture", "authors": [{"first": "T", "middle": [], "last": "Furukawa", "suffix": ""}], "year": 1984, "venue": "Virology. Aug", "link": "21453470"}, "BIBREF62": {"title": "Human cytomegalovirus persistent infection in a human central nervous system cell line: production of a variant virus with different growth characteristics. The Journal of general virology", "authors": [{"first": "T", "middle": [], "last": "Ogura", "suffix": ""}, {"first": "J", "middle": [], "last": "Tanaka", "suffix": ""}, {"first": "S", "middle": [], "last": "Kamiya", "suffix": ""}, {"first": "H", "middle": [], "last": "Sato", "suffix": ""}, {"first": "H", "middle": [], "last": "Ogura", "suffix": ""}, {"first": "M", "middle": [], "last": "Hatano", "suffix": ""}], "year": 1986, "venue": "", "link": null}, "BIBREF63": {"title": "Cancer immunoediting: from immunosurveillance to tumor escape", "authors": [{"first": "G", "middle": ["P"], "last": "Dunn", "suffix": ""}, {"first": "A", "middle": ["T"], "last": "Bruce", "suffix": ""}, {"first": "H", "middle": [], "last": "Ikeda", "suffix": ""}, {"first": "L", "middle": ["J"], "last": "Old", "suffix": ""}, {"first": "R", "middle": ["D"], "last": "Schreiber", "suffix": ""}], "year": 2002, "venue": "Nature immunology", "link": "3355084"}, "BIBREF64": {"title": "Cancer immunosuppression and autoimmune disease: beyond immunosuppressive networks for tumour immunity", "authors": [{"first": "R", "middle": [], "last": "Kim", "suffix": ""}, {"first": "M", "middle": [], "last": "Emi", "suffix": ""}, {"first": "K", "middle": [], "last": "Tanabe", "suffix": ""}], "year": 2006, "venue": "Immunology. Oct", "link": "30116130"}, "BIBREF65": {"title": "Mechanisms of immune evasion by tumors. Advances in immunology", "authors": [{"first": "C", "middle": ["G"], "last": "Drake", "suffix": ""}, {"first": "E", "middle": [], "last": "Jaffee", "suffix": ""}, {"first": "D", "middle": ["M"], "last": "Pardoll", "suffix": ""}], "year": 2006, "venue": "", "link": null}, "BIBREF66": {"title": "Chronic inflammation and cancer: the role of the mitochondria", "authors": [{"first": "D", "middle": ["W"], "last": "Kamp", "suffix": ""}, {"first": "E", "middle": [], "last": "Shacter", "suffix": ""}, {"first": "S", "middle": ["A"], "last": "Weitzman", "suffix": ""}], "year": 2011, "venue": "Oncology", "link": "4787475"}, "BIBREF67": {"title": "Tumor-driven evolution of immunosuppressive networks during malignant progression. Cancer research", "authors": [{"first": "R", "middle": [], "last": "Kim", "suffix": ""}, {"first": "M", "middle": [], "last": "Emi", "suffix": ""}, {"first": "K", "middle": [], "last": "Tanabe", "suffix": ""}, {"first": "K", "middle": [], "last": "Arihiro", "suffix": ""}], "year": 2006, "venue": "", "link": null}, "BIBREF68": {"title": "Immune evasion by cytomegalovirus--survival strategies of a highly adapted opportunist. Trends in microbiology", "authors": [{"first": "H", "middle": [], "last": "Hengel", "suffix": ""}, {"first": "W", "middle": [], "last": "Brune", "suffix": ""}, {"first": "U", "middle": ["H"], "last": "Koszinowski", "suffix": ""}], "year": 1998, "venue": "", "link": null}, "BIBREF69": {"title": "Immune evasion by human cytomegalovirus: lessons in immunology and cell biology", "authors": [{"first": "W", "middle": ["A"], "last": "Loenen", "suffix": ""}, {"first": "C", "middle": ["A"], "last": "Bruggeman", "suffix": ""}, {"first": "E", "middle": ["J"], "last": "Wiertz", "suffix": ""}], "year": 2001, "venue": "Seminars in immunology", "link": "40898260"}, "BIBREF70": {"title": "Human cytomegalovirus escape from immune detection", "authors": [{"first": "S", "middle": [], "last": "Michelson", "suffix": ""}], "year": 1999, "venue": "Intervirology", "link": "31814102"}, "BIBREF71": {"title": "Human cytomegalovirus retinitis: pathogenicity, immune evasion and persistence. Trends in microbiology", "authors": [{"first": "M", "middle": [], "last": "Scholz", "suffix": ""}, {"first": "H", "middle": ["W"], "last": "Doerr", "suffix": ""}, {"first": "J", "middle": [], "last": "Cinatl", "suffix": ""}], "year": 2003, "venue": "", "link": null}, "BIBREF72": {"title": "Cytomegaloviruses use multiple mechanisms to elude the host immune response. Immunology letters", "authors": [{"first": "E", "middle": [], "last": "Wiertz", "suffix": ""}, {"first": "A", "middle": [], "last": "Hill", "suffix": ""}, {"first": "D", "middle": [], "last": "Tortorella", "suffix": ""}, {"first": "H", "middle": [], "last": "Ploegh", "suffix": ""}], "year": 1997, "venue": "", "link": null}, "BIBREF73": {"title": "Inhibition of natural killer cells by a cytomegalovirus MHC class I homologue in vivo", "authors": [{"first": "H", "middle": ["E"], "last": "Farrell", "suffix": ""}, {"first": "H", "middle": [], "last": "Vally", "suffix": ""}, {"first": "D", "middle": ["M"], "last": "Lynch", "suffix": ""}], "year": 1997, "venue": "Nature", "link": "4367641"}, "BIBREF74": {"title": "Expression dynamics of human cytomegalovirus immune evasion genes US3, US6, and US11 in the blood of lung transplant recipients. The Journal of infectious diseases", "authors": [{"first": "A", "middle": ["E"], "last": "Greijer", "suffix": ""}, {"first": "E", "middle": ["A"], "last": "Verschuuren", "suffix": ""}, {"first": "C", "middle": ["A"], "last": "Dekkers", "suffix": ""}], "year": 2001, "venue": "", "link": null}, "BIBREF75": {"title": "MHC class I-subversive gene functions of cytomegalovirus and their regulation by interferons-an intricate balance", "authors": [{"first": "C", "middle": [], "last": "Benz", "suffix": ""}, {"first": "H", "middle": [], "last": "Hengel", "suffix": ""}], "year": 2000, "venue": "Virus genes", "link": "8930443"}, "BIBREF76": {"title": "Immune evasion proteins gpUS2 and gpUS11 of human cytomegalovirus incompletely protect infected cells from CD8 T cell recognition. Virology", "authors": [{"first": "K", "middle": [], "last": "Besold", "suffix": ""}, {"first": "M", "middle": [], "last": "Wills", "suffix": ""}, {"first": "B", "middle": [], "last": "Plachter", "suffix": ""}], "year": 2009, "venue": "", "link": "205643581"}, "BIBREF77": {"title": "Human cytomegalovirus-encoded interleukin-10 homolog inhibits maturation of dendritic cells and alters their functionality", "authors": [{"first": "W", "middle": ["L"], "last": "Chang", "suffix": ""}, {"first": "N", "middle": [], "last": "Baumgarth", "suffix": ""}, {"first": "D", "middle": [], "last": "Yu", "suffix": ""}, {"first": "P", "middle": ["A"], "last": "Barry", "suffix": ""}], "year": 2004, "venue": "Journal of virology", "link": "15425958"}, "BIBREF78": {"title": "CXCL10 production from cytomegalovirus-stimulated microglia is regulated by both human and viral interleukin-10", "authors": [{"first": "M", "middle": ["C"], "last": "Cheeran", "suffix": ""}, {"first": "S", "middle": [], "last": "Hu", "suffix": ""}, {"first": "W", "middle": ["S"], "last": "Sheng", "suffix": ""}, {"first": "P", "middle": ["K"], "last": "Peterson", "suffix": ""}, {"first": "J", "middle": ["R"], "last": "Lokensgard", "suffix": ""}], "year": 2003, "venue": "Journal of virology", "link": "3174426"}, "BIBREF79": {"title": "HCMV IL-10 suppresses cytokine expression in monocytes through inhibition of nuclear factor-kappaB. Viral immunology", "authors": [{"first": "J", "middle": [], "last": "Nachtwey", "suffix": ""}, {"first": "J", "middle": ["V"], "last": "Spencer", "suffix": ""}], "year": 2008, "venue": "", "link": null}, "BIBREF80": {"title": "Induction of an epithelial integrin alphavbeta6 in human cytomegalovirus-infected endothelial cells leads to activation of transforming growth factor-beta1 and increased collagen production. The American journal of pathology", "authors": [{"first": "T", "middle": [], "last": "Tabata", "suffix": ""}, {"first": "H", "middle": [], "last": "Kawakatsu", "suffix": ""}, {"first": "E", "middle": [], "last": "Maidji", "suffix": ""}], "year": 2008, "venue": "", "link": null}, "BIBREF81": {"title": "Transcriptome analysis reveals human cytomegalovirus reprograms monocyte differentiation toward an M1 macrophage", "authors": [{"first": "G", "middle": [], "last": "Chan", "suffix": ""}, {"first": "E", "middle": ["R"], "last": "Bivins-Smith", "suffix": ""}, {"first": "M", "middle": ["S"], "last": "Smith", "suffix": ""}, {"first": "P", "middle": ["M"], "last": "Smith", "suffix": ""}, {"first": "A", "middle": ["D"], "last": "Yurochko", "suffix": ""}], "year": 2008, "venue": "J Immunol", "link": "34016987"}, "BIBREF82": {"title": "Mechanisms of cytomegalovirus-accelerated vascular disease: induction of paracrine factors that promote angiogenesis and wound healing. Current topics in microbiology and immunology", "authors": [{"first": "D", "middle": ["N"], "last": "Streblow", "suffix": ""}, {"first": "J", "middle": [], "last": "Dumortier", "suffix": ""}, {"first": "A", "middle": ["V"], "last": "Moses", "suffix": ""}, {"first": "S", "middle": ["L"], "last": "Orloff", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Nelson", "suffix": ""}], "year": 2008, "venue": "", "link": null}, "BIBREF83": {"title": "Platelet-derived growth factor-D contributes to aggressiveness of breast cancer cells by up-regulating Notch and NF-kappaB signaling pathways. Breast cancer research and treatment", "authors": [{"first": "A", "middle": [], "last": "Ahmad", "suffix": ""}, {"first": "Z", "middle": [], "last": "Wang", "suffix": ""}, {"first": "D", "middle": [], "last": "Kong", "suffix": ""}], "year": 2011, "venue": "", "link": null}, "BIBREF84": {"title": "Platelet-derived growth factor C induces liver fibrosis, steatosis, and hepatocellular carcinoma", "authors": [{"first": "J", "middle": ["S"], "last": "Campbell", "suffix": ""}, {"first": "S", "middle": ["D"], "last": "Hughes", "suffix": ""}, {"first": "D", "middle": ["G"], "last": "Gilbertson", "suffix": ""}], "year": 2005, "venue": "Proceedings of the National Academy of Sciences of the United States of America", "link": "29055375"}, "BIBREF85": {"title": "Platelet-derived growth factor (PDGF) and glial tumorigenesis. Cancer letters", "authors": [{"first": "A", "middle": ["H"], "last": "Shih", "suffix": ""}, {"first": "E", "middle": ["C"], "last": "Holland", "suffix": ""}], "year": 2006, "venue": "", "link": null}, "BIBREF86": {"title": "Chromosome aberrations in cytomegalovirus-infected human diploid cell culture. Acta virologica", "authors": [{"first": "M", "middle": [], "last": "Hartmann", "suffix": ""}, {"first": "H", "middle": [], "last": "Brunnemann", "suffix": ""}], "year": 1972, "venue": "", "link": null}, "BIBREF87": {"title": "Viral induction of site-specific chromosome damage. Reviews in medical virology", "authors": [{"first": "E", "middle": ["A"], "last": "Fortunato", "suffix": ""}, {"first": "D", "middle": ["H"], "last": "Spector", "suffix": ""}], "year": 2003, "venue": "", "link": null}, "BIBREF88": {"title": "Irminger-Finger I. Mechanisms of chromosome instability in cancers. Critical reviews in oncology/hematology", "authors": [{"first": "C", "middle": ["E"], "last": "Jefford", "suffix": ""}], "year": 2006, "venue": "Jul", "link": null}, "BIBREF89": {"title": "Modulation of the frequency of human cytomegalovirus-induced chromosome aberrations by camptothecin. Virology", "authors": [{"first": "C", "middle": ["Z"], "last": "Deng", "suffix": ""}, {"first": "S", "middle": [], "last": "Abubakar", "suffix": ""}, {"first": "M", "middle": ["P"], "last": "Fons", "suffix": ""}, {"first": "I", "middle": [], "last": "Boldogh", "suffix": ""}, {"first": "T", "middle": [], "last": "Albrecht", "suffix": ""}], "year": 1992, "venue": "", "link": "36614668"}, "BIBREF90": {"title": "Cytomegalovirus-enhanced induction of chromosome aberrations in human peripheral blood lymphocytes treated with potent genotoxic agents. Environmental and molecular mutagenesis", "authors": [{"first": "C", "middle": ["Z"], "last": "Deng", "suffix": ""}, {"first": "S", "middle": [], "last": "Abubakar", "suffix": ""}, {"first": "M", "middle": ["P"], "last": "Fons", "suffix": ""}], "year": 1992, "venue": "", "link": null}, "BIBREF91": {"title": "Specific chromosome 1 breaks induced by human cytomegalovirus", "authors": [{"first": "E", "middle": ["A"], "last": "Fortunato", "suffix": ""}, {"first": "M", "middle": ["L"], "last": "Dell&apos;aquila", "suffix": ""}, {"first": "D", "middle": ["H"], "last": "Spector", "suffix": ""}], "year": 2000, "venue": "Proceedings of the National Academy of Sciences of the United States of America", "link": "32878362"}, "BIBREF92": {"title": "Fluorescence in situ mapping of the human nuclear NAD+ ADP-ribosyltransferase gene (ADPRT) and two secondary sites to human chromosomal bands 1q42, 13q34, and 14q24", "authors": [{"first": "M", "middle": [], "last": "Baumgartner", "suffix": ""}, {"first": "R", "middle": [], "last": "Schneider", "suffix": ""}, {"first": "B", "middle": [], "last": "Auer", "suffix": ""}, {"first": "H", "middle": [], "last": "Herzog", "suffix": ""}, {"first": "M", "middle": [], "last": "Schweiger", "suffix": ""}, {"first": "M", "middle": [], "last": "Hirsch-Kauffmann", "suffix": ""}], "year": 1992, "venue": "Cytogenetics and cell genetics", "link": "46787797"}, "BIBREF93": {"title": "Differential mutagen sensitivity of peripheral blood lymphocytes from smokers and nonsmokers: effect of human cytomegalovirus infection. Environmental and molecular mutagenesis", "authors": [{"first": "T", "middle": [], "last": "Albrecht", "suffix": ""}, {"first": "C", "middle": ["Z"], "last": "Deng", "suffix": ""}, {"first": "S", "middle": ["Z"], "last": "Abdel-Rahman", "suffix": ""}, {"first": "M", "middle": [], "last": "Fons", "suffix": ""}, {"first": "P", "middle": [], "last": "Cinciripini", "suffix": ""}, {"first": "R", "middle": ["A"], "last": "El-Zein", "suffix": ""}], "year": 2004, "venue": "", "link": null}, "BIBREF94": {"title": "Human cytomegalovirus UL76 induces chromosome aberrations", "authors": [{"first": "V", "middle": ["K"], "last": "Siew", "suffix": ""}, {"first": "C", "middle": ["Y"], "last": "Duh", "suffix": ""}, {"first": "S", "middle": ["K"], "last": "Wang", "suffix": ""}], "year": 2009, "venue": "Journal of biomedical science", "link": "1109852"}, "BIBREF95": {"title": "Human cytomegalovirus disrupts both ataxia telangiectasia mutated protein (ATM)-and ATM-Rad3-related kinasemediated DNA damage responses during lytic infection", "authors": [{"first": "M", "middle": ["H"], "last": "Luo", "suffix": ""}, {"first": "K", "middle": [], "last": "Rosenke", "suffix": ""}, {"first": "K", "middle": [], "last": "Czornak", "suffix": ""}, {"first": "E", "middle": ["A"], "last": "Fortunato", "suffix": ""}], "year": 2007, "venue": "Journal of virology", "link": "14485758"}, "BIBREF96": {"title": "Activation of telomerase by human cytomegalovirus", "authors": [{"first": "K", "middle": [], "last": "Straat", "suffix": ""}, {"first": "C", "middle": [], "last": "Liu", "suffix": ""}, {"first": "A", "middle": [], "last": "Rahbar", "suffix": ""}], "year": 2009, "venue": "", "link": "2486093"}, "BIBREF97": {"title": "Oncomodulation by human cytomegalovirus: novel clinical findings open new roads. Medical microbiology and immunology", "authors": [{"first": "M", "middle": [], "last": "Michaelis", "suffix": ""}, {"first": "P", "middle": [], "last": "Baumgarten", "suffix": ""}, {"first": "M", "middle": [], "last": "Mittelbronn", "suffix": ""}, {"first": "P", "middle": ["H"], "last": "Driever", "suffix": ""}, {"first": "H", "middle": ["W"], "last": "Doerr", "suffix": ""}, {"first": "J", "middle": [], "last": "Cinatl", "suffix": ""}, {"first": "Jr", "middle": [], "last": "", "suffix": ""}], "year": 2011, "venue": "", "link": null}, "BIBREF98": {"title": "The story of human cytomegalovirus and cancer: increasing evidence and open questions", "authors": [{"first": "M", "middle": [], "last": "Michaelis", "suffix": ""}, {"first": "H", "middle": ["W"], "last": "Doerr", "suffix": ""}, {"first": "J", "middle": [], "last": "Cinatl", "suffix": ""}], "year": 2009, "venue": "Neoplasia", "link": "42146044"}}, "ref_entries": {"FIGREF1": {"text": "Figure 1. Pathway linking chronic inflammation and oncogenesis. (Adapted from Schetter et. al.", "type": "figure"}, "FIGREF3": {"text": "Figure 2. Concept of Oncomodulation. (Adapted from Michaelis et. al. [99])", "type": "figure"}, "FIGREF4": {"text": "Figure 3. Major signaling pathways activated by hCMV that contribute to oncomodulation by hCMV. (Adapted from from Michaelis et. al . [", "type": "figure"}, "TABREF0": {"text": "The \"seven\" hallmarks of cancer", "type": "table"}, "TABREF1": {"text": "*Address all correspondence to: david.aboulafia@vmmc.org 1 Floyd & Delores Jones Cancer Institute at Virginia Mason Medical Center, Seattle, WA, USA 2 Division of Hematology, University of Washington, Seattle, WA, USA novirus E1A proteins. Proceedings of the National Academy of Sciences of the United States of America. Apr 1 1997;94(7):3341-3345. [30] Plati J, Bucur O, Khosravi-Far R. Dysregulation of apoptotic signaling in cancer: mo- lecular mechanisms and therapeutic opportunities. Journal of cellular biochemistry. Jul 1 2008;104(4):1124-1149.", "type": "table"}}}
{"paper_id": "2879409", "_pdf_hash": "cc0dc5083a89979badf1b11d38262a9b49b2b41a", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Next Generation Web Search: Setting our Sites", "authors": [{"first": "Marti", "middle": [], "last": "Hearst", "suffix": ""}], "year": 2000, "venue": "IEEE Data Engineering Bulletin", "link": "60669262"}, "BIBREF1": {"title": "Web Mining Research: A Survey. SIGKDD Explorations", "authors": [{"first": "Raymond", "middle": [], "last": "Kosala", "suffix": ""}, {"first": "Hendrik", "middle": [], "last": "Blockeel", "suffix": ""}], "year": 2000, "venue": "", "link": null}, "BIBREF2": {"title": "Authoritative Sources in a Hyperlinked Environment", "authors": [{"first": "M", "middle": [], "last": "Kleinberg", "suffix": ""}], "year": 1999, "venue": "Journal of the ACM", "link": "1868144"}, "BIBREF3": {"title": "Finding Related Pages in the World Wide Web", "authors": [{"first": "J", "middle": [], "last": "Dean", "suffix": ""}, {"first": "R", "middle": [], "last": "Henzinger", "suffix": ""}], "year": 1999, "venue": "Computer Networks", "link": "8925072"}, "BIBREF4": {"title": "Hyperlink Analysis for the Web", "authors": [{"first": "R", "middle": [], "last": "Henzinger", "suffix": ""}], "year": 2001, "venue": "IEEE Internet Computing", "link": null}, "BIBREF5": {"title": "Diameter of the World Wide Web", "authors": [{"first": "R", "middle": [], "last": "Albert", "suffix": ""}, {"first": "H", "middle": [], "last": "Jeong", "suffix": ""}, {"first": "A", "middle": [], "last": "Brabasi", "suffix": ""}], "year": 1999, "venue": "Nature", "link": null}, "BIBREF6": {"title": "Graph-Theoretic Web Algorithms: An Overview", "authors": [{"first": "N", "middle": [], "last": "Deo", "suffix": ""}, {"first": "P", "middle": [], "last": "Gupta", "suffix": ""}], "year": 2001, "venue": "Lecture Notes in Computer Science", "link": "5120677"}, "BIBREF7": {"title": "Graph Structure in the Web", "authors": [{"first": "Andrei", "middle": [], "last": "Broder", "suffix": ""}, {"first": "Ravi", "middle": [], "last": "Kumar", "suffix": ""}], "year": 2000, "venue": "Computer Networks", "link": "10094666"}, "BIBREF8": {"title": "The Anatomy of a Large-Scale Hypertextual Web Search Engine. Computer Networks and ISDN Systems", "authors": [{"first": "S", "middle": [], "last": "Brin", "suffix": ""}, {"first": "L", "middle": [], "last": "Page", "suffix": ""}], "year": 1998, "venue": "", "link": null}, "BIBREF9": {"title": "The Structure of Broad Topics on the Web", "authors": [{"first": "S", "middle": [], "last": "Chakrabarti", "suffix": ""}, {"first": "G", "middle": [], "last": "Bhalotia", "suffix": ""}, {"first": "C", "middle": [], "last": "Nakhe", "suffix": ""}], "year": 2002, "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "2879548", "_pdf_hash": "2fb8f5c4a78a746b84848a72efcd90738bc6cad1", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Immunologic basis of antigen-induced airway hyperresponsiveness", "authors": [{"first": "M", "middle": [], "last": "Wills-Karp", "suffix": ""}], "year": 1999, "venue": "Annu. Rev. Immunol", "link": "25969355"}, "BIBREF1": {"title": "Predominant TH2-like bronchoalveolar T-lymphocyte population in atopic asthma", "authors": [{"first": "D", "middle": ["S"], "last": "Robinson", "suffix": ""}, {"first": "Q", "middle": [], "last": "Hamid", "suffix": ""}, {"first": "S", "middle": [], "last": "Ying", "suffix": ""}, {"first": "A", "middle": [], "last": "Tsicopoulos", "suffix": ""}, {"first": "J", "middle": [], "last": "Barkans", "suffix": ""}, {"first": "A", "middle": ["M"], "last": "Bentley", "suffix": ""}, {"first": "C", "middle": [], "last": "Corrigan", "suffix": ""}, {"first": "S", "middle": ["R"], "last": "Durham", "suffix": ""}, {"first": "A", "middle": ["B"], "last": "Kay", "suffix": ""}], "year": 1992, "venue": "N. Engl. J. Med", "link": "32848637"}, "BIBREF2": {"title": "The biology of NKT cells", "authors": [{"first": "A", "middle": [], "last": "Bendelac", "suffix": ""}, {"first": "P", "middle": ["B"], "last": "Savage", "suffix": ""}, {"first": "L", "middle": [], "last": "Teyton", "suffix": ""}], "year": 2007, "venue": "Annu. Rev. Immunol", "link": "37834231"}, "BIBREF3": {"title": "Essential role of NKT cells producing IL-4 and IL-13 in the development of allergeninduced airway hyperreactivity", "authors": [{"first": "O", "middle": [], "last": "Akbari", "suffix": ""}, {"first": "P", "middle": [], "last": "Stock", "suffix": ""}, {"first": "E", "middle": [], "last": "Meyer", "suffix": ""}, {"first": "M", "middle": [], "last": "Kronenberg", "suffix": ""}, {"first": "S", "middle": [], "last": "Sidobre", "suffix": ""}, {"first": "T", "middle": [], "last": "Nakayama", "suffix": ""}, {"first": "M", "middle": [], "last": "Taniguchi", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Grusby", "suffix": ""}, {"first": "R", "middle": ["H"], "last": "Dekruyff", "suffix": ""}, {"first": "D", "middle": ["T"], "last": "Umetsu", "suffix": ""}], "year": 2003, "venue": "Nat. Med", "link": "15154524"}, "BIBREF4": {"title": "Ozone exposure in a mouse model induces airway hyperreactivity that requires the presence of natural killer T cells and IL-17", "authors": [{"first": "M", "middle": [], "last": "Pichavant", "suffix": ""}, {"first": "S", "middle": [], "last": "Goya", "suffix": ""}, {"first": "E", "middle": ["H"], "last": "Meyer", "suffix": ""}, {"first": "R", "middle": ["A"], "last": "Johnston", "suffix": ""}, {"first": "H", "middle": ["Y"], "last": "Kim", "suffix": ""}, {"first": "P", "middle": [], "last": "Matangkasombut", "suffix": ""}, {"first": "M", "middle": [], "last": "Zhu", "suffix": ""}, {"first": "Y", "middle": [], "last": "Iwakura", "suffix": ""}, {"first": "P", "middle": ["B"], "last": "Savage", "suffix": ""}, {"first": "R", "middle": ["H"], "last": "Dekruyff", "suffix": ""}], "year": 2008, "venue": "J. Exp. Med", "link": "45100"}, "BIBREF5": {"title": "Persistent activation of an innate immune response translates respiratory viral infection into chronic lung disease", "authors": [{"first": "E", "middle": ["Y"], "last": "Kim", "suffix": ""}, {"first": "J", "middle": ["T"], "last": "Battaile", "suffix": ""}, {"first": "A", "middle": ["C"], "last": "Patel", "suffix": ""}, {"first": "Y", "middle": [], "last": "You", "suffix": ""}, {"first": "E", "middle": [], "last": "Agapov", "suffix": ""}, {"first": "M", "middle": ["H"], "last": "Grayson", "suffix": ""}, {"first": "L", "middle": ["A"], "last": "Benoit", "suffix": ""}, {"first": "D", "middle": ["E"], "last": "Byers", "suffix": ""}, {"first": "Y", "middle": [], "last": "Alevy", "suffix": ""}, {"first": "J", "middle": [], "last": "Tucker", "suffix": ""}], "year": 2008, "venue": "Nat. Med", "link": "919053"}, "BIBREF6": {"title": "Glycolipid activation of invariant T cell receptor+ NK T cells is sufficient to induce airway hyperreactivity independent of conventional CD4+ T cells", "authors": [{"first": "E", "middle": ["H"], "last": "Meyer", "suffix": ""}, {"first": "S", "middle": [], "last": "Goya", "suffix": ""}, {"first": "O", "middle": [], "last": "Akbari", "suffix": ""}, {"first": "G", "middle": ["J"], "last": "Berry", "suffix": ""}, {"first": "P", "middle": ["B"], "last": "Savage", "suffix": ""}, {"first": "M", "middle": [], "last": "Kronenberg", "suffix": ""}, {"first": "T", "middle": [], "last": "Nakayama", "suffix": ""}, {"first": "R", "middle": ["H"], "last": "Dekruyff", "suffix": ""}, {"first": "D", "middle": ["T"], "last": "Umetsu", "suffix": ""}], "year": 2006, "venue": "Proc. Natl. Acad. Sci. USA", "link": "12557938"}, "BIBREF7": {"title": "Specific high-affinity receptors for 1,25-dihydroxyvitamin D3 in human peripheral blood mononuclear cells: presence in monocytes and induction in T lymphocytes following activation", "authors": [{"first": "A", "middle": ["K"], "last": "Bhalla", "suffix": ""}, {"first": "E", "middle": ["P"], "last": "Amento", "suffix": ""}, {"first": "T", "middle": ["L"], "last": "Clemens", "suffix": ""}, {"first": "M", "middle": ["F"], "last": "Holick", "suffix": ""}, {"first": "S", "middle": ["M"], "last": "Krane", "suffix": ""}], "year": 1983, "venue": "J. Clin. Endocrinol. Metab", "link": "40804928"}, "BIBREF8": {"title": "Manolagas. 1983. 1,25-dihydroxyvitamin D3 receptors in human leukocytes", "authors": [{"first": "D", "middle": ["M"], "last": "Provvedini", "suffix": ""}, {"first": "C", "middle": ["D"], "last": "Tsoukas", "suffix": ""}, {"first": "L", "middle": ["J"], "last": "Deftos", "suffix": ""}, {"first": "S", "middle": ["C"], "last": "", "suffix": ""}], "year": "", "venue": "Science", "link": null}, "BIBREF9": {"title": "1,25-Dihydroxyvitamin D3 reversibly blocks the progression of relapsing encephalomyelitis, a model of multiple sclerosis", "authors": [{"first": "M", "middle": ["T"], "last": "Cantorna", "suffix": ""}, {"first": "C", "middle": ["E"], "last": "Hayes", "suffix": ""}, {"first": "H", "middle": ["F"], "last": "Deluca", "suffix": ""}], "year": 1996, "venue": "Proc. Natl. Acad. Sci. USA", "link": "10156985"}, "BIBREF10": {"title": "1,25-Dihydroxycholecalciferol inhibits the progression of arthritis in murine models of human arthritis", "authors": [{"first": "M", "middle": ["T"], "last": "Cantorna", "suffix": ""}, {"first": "C", "middle": ["E"], "last": "Hayes", "suffix": ""}, {"first": "H", "middle": ["F"], "last": "Deluca", "suffix": ""}], "year": 1998, "venue": "J. Nutr", "link": "4487049"}, "BIBREF11": {"title": "Immunomodulatory role of 1,25-dihydroxyvitamin D3", "authors": [{"first": "J", "middle": ["M"], "last": "Lemire", "suffix": ""}], "year": 1992, "venue": "J. Cell. Biochem", "link": "23001478"}, "BIBREF12": {"title": "The targets of vitamin D depend on the differentiation and activation status of CD4 positive T cells", "authors": [{"first": "B", "middle": ["D"], "last": "Mahon", "suffix": ""}, {"first": "A", "middle": [], "last": "Wittke", "suffix": ""}, {"first": "V", "middle": [], "last": "Weaver", "suffix": ""}, {"first": "M", "middle": ["T"], "last": "Cantorna", "suffix": ""}], "year": 2003, "venue": "J. Cell. Biochem", "link": "426678"}, "BIBREF13": {"title": "A crucial role for the vitamin D receptor in experimental inflammatory bowel diseases", "authors": [{"first": "M", "middle": [], "last": "Froicu", "suffix": ""}, {"first": "V", "middle": [], "last": "Weaver", "suffix": ""}, {"first": "T", "middle": ["A"], "last": "Wynn", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Mcdowell", "suffix": ""}, {"first": "J", "middle": ["E"], "last": "Welsh", "suffix": ""}, {"first": "M", "middle": ["T"], "last": "Cantorna", "suffix": ""}], "year": 2003, "venue": "Mol. Endocrinol", "link": "36490519"}, "BIBREF14": {"title": "Immunoregulation by 1,25-dihydroxyvitamin D3: basic concepts", "authors": [{"first": "E", "middle": [], "last": "Van Etten", "suffix": ""}, {"first": "C", "middle": [], "last": "Mathieu", "suffix": ""}], "year": 2005, "venue": "J. Steroid Biochem. Mol. Biol", "link": "22164952"}, "BIBREF15": {"title": "Failure of T cell homing, reduced CD4/CD8alphaalpha intraepithelial lymphocytes, and inflammation in the gut of vitamin D receptor KO mice", "authors": [{"first": "S", "middle": [], "last": "Yu", "suffix": ""}, {"first": "D", "middle": [], "last": "Bruce", "suffix": ""}, {"first": "M", "middle": [], "last": "Froicu", "suffix": ""}, {"first": "V", "middle": [], "last": "Weaver", "suffix": ""}, {"first": "M", "middle": ["T"], "last": "Cantorna", "suffix": ""}], "year": 2008, "venue": "Proc. Natl. Acad. Sci. USA", "link": "27523510"}, "BIBREF16": {"title": "The vitamin D receptor is required for iNKT cell development", "authors": [{"first": "S", "middle": [], "last": "Yu", "suffix": ""}, {"first": "M", "middle": ["T"], "last": "Cantorna", "suffix": ""}], "year": 2008, "venue": "Proc. Natl. Acad. Sci. USA", "link": "43754909"}, "BIBREF17": {"title": "Vitamin D receptor-deficient mice fail to develop experimental allergic asthma", "authors": [{"first": "A", "middle": [], "last": "Wittke", "suffix": ""}, {"first": "V", "middle": [], "last": "Weaver", "suffix": ""}, {"first": "B", "middle": ["D"], "last": "Mahon", "suffix": ""}, {"first": "A", "middle": [], "last": "August", "suffix": ""}, {"first": "M", "middle": ["T"], "last": "Cantorna", "suffix": ""}], "year": 2004, "venue": "J. Immunol", "link": "25624780"}, "BIBREF18": {"title": "Vitamin D receptor expression by the lung micro-environment is required for maximal induction of lung inflammation", "authors": [{"first": "A", "middle": [], "last": "Wittke", "suffix": ""}, {"first": "A", "middle": [], "last": "Chang", "suffix": ""}, {"first": "M", "middle": [], "last": "Froicu", "suffix": ""}, {"first": "O", "middle": ["F"], "last": "Harandi", "suffix": ""}, {"first": "V", "middle": [], "last": "Weaver", "suffix": ""}, {"first": "A", "middle": [], "last": "August", "suffix": ""}, {"first": "R", "middle": ["F"], "last": "Paulson", "suffix": ""}, {"first": "M", "middle": ["T"], "last": "Cantorna", "suffix": ""}], "year": 2007, "venue": "Arch. Biochem. Biophys", "link": "25556502"}, "BIBREF19": {"title": "25-Dihydroxyvitamin d3 has a direct effect on naive CD4(+) T cells to enhance the development of Th2 cells", "authors": [{"first": "A", "middle": [], "last": "Boonstra", "suffix": ""}, {"first": "F", "middle": ["J"], "last": "Barrat", "suffix": ""}, {"first": "C", "middle": [], "last": "Crain", "suffix": ""}, {"first": "V", "middle": ["L"], "last": "Heath", "suffix": ""}, {"first": "H", "middle": ["F"], "last": "Savelkoul", "suffix": ""}, {"first": "A", "middle": [], "last": "O&apos;garra", "suffix": ""}], "year": 2001, "venue": "J. Immunol", "link": "9510123"}, "BIBREF20": {"title": "1,25-dihydroxyvitamin D3 inhibits IFN-gamma and IL-4 levels during in vitro polarization of primary murine CD4+ T cells", "authors": [{"first": "T", "middle": ["P"], "last": "Staeva-Vieira", "suffix": ""}, {"first": "L", "middle": ["P"], "last": "Freedman", "suffix": ""}], "year": 2002, "venue": "J. Immunol", "link": "19200116"}, "BIBREF21": {"title": "2010. 1,25-dihydroxyvitamin D3 enhances the ability of transferred CD4+ CD25+ cells to modulate T helper type 2-driven asthmatic responses", "authors": [{"first": "S", "middle": [], "last": "Gorman", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Judge", "suffix": ""}, {"first": "J", "middle": ["T"], "last": "Burchell", "suffix": ""}, {"first": "D", "middle": ["J"], "last": "Turner", "suffix": ""}, {"first": "P", "middle": ["H"], "last": "Hart", "suffix": ""}], "year": "", "venue": "Immunology", "link": "25255902"}, "BIBREF22": {"title": "Role of NKT cells in allergic asthma", "authors": [{"first": "C", "middle": [], "last": "Iwamura", "suffix": ""}, {"first": "T", "middle": [], "last": "Nakayama", "suffix": ""}], "year": 2010, "venue": "Curr. Opin. Immunol", "link": "206870116"}, "BIBREF23": {"title": "Functions of T cells in asthma: more than just T(H)2 cells", "authors": [{"first": "C", "middle": ["M"], "last": "Lloyd", "suffix": ""}, {"first": "E", "middle": ["M"], "last": "Hessel", "suffix": ""}], "year": 2010, "venue": "Nat. Rev. Immunol", "link": null}, "BIBREF24": {"title": "Vitamin D deficiency causes deficits in lung function and alters lung structure", "authors": [{"first": "G", "middle": ["R"], "last": "Zosky", "suffix": ""}, {"first": "L", "middle": ["J"], "last": "Berry", "suffix": ""}, {"first": "J", "middle": ["G"], "last": "Elliot", "suffix": ""}, {"first": "A", "middle": ["L"], "last": "James", "suffix": ""}, {"first": "S", "middle": [], "last": "Gorman", "suffix": ""}, {"first": "P", "middle": ["H"], "last": "Hart", "suffix": ""}], "year": 2011, "venue": "Am. J. Respir. Crit. Care Med", "link": "28882501"}, "BIBREF25": {"title": "Vitamin D, the immune system and asthma", "authors": [{"first": "N", "middle": ["E"], "last": "Lange", "suffix": ""}, {"first": "A", "middle": [], "last": "Litonjua", "suffix": ""}, {"first": "C", "middle": ["M"], "last": "Hawrylowicz", "suffix": ""}, {"first": "S", "middle": [], "last": "Weiss", "suffix": ""}], "year": 2009, "venue": "Expert Rev. Clin. Immunol", "link": "36267889"}, "BIBREF26": {"title": "25-dihydroxyvitamin D3 potentiates the beneficial effects of allergen immunotherapy in a mouse model of allergic asthma: role for IL-10 and TGF-beta", "authors": [{"first": "Y", "middle": ["A"], "last": "Taher", "suffix": ""}, {"first": "B", "middle": ["C"], "last": "Van Esch", "suffix": ""}, {"first": "G", "middle": ["A"], "last": "Hofman", "suffix": ""}, {"first": "P", "middle": ["A"], "last": "Henricks", "suffix": ""}, {"first": "A", "middle": ["J"], "last": "Van Oosterhout", "suffix": ""}], "year": 2008, "venue": "J. Immunol", "link": "32155551"}, "BIBREF27": {"title": "Converging pathways lead to overproduction of IL-17 in the absence of vitamin D signaling", "authors": [{"first": "D", "middle": [], "last": "Bruce", "suffix": ""}, {"first": "S", "middle": [], "last": "Yu", "suffix": ""}, {"first": "J", "middle": ["H"], "last": "Ooi", "suffix": ""}, {"first": "M", "middle": ["T"], "last": "Cantorna", "suffix": ""}], "year": 2011, "venue": "Int. Immunol", "link": "205142377"}, "BIBREF28": {"title": "Genes, factor X, and allergens: what causes allergic diseases?", "authors": [{"first": "M", "middle": [], "last": "Wjst", "suffix": ""}, {"first": "S", "middle": [], "last": "Dold", "suffix": ""}], "year": 1999, "venue": "Allergy", "link": "6292636"}, "BIBREF29": {"title": "Invariant natural killer T cells in asthma and chronic obstructive pulmonary disease", "authors": [{"first": "P", "middle": [], "last": "Vijayanand", "suffix": ""}, {"first": "G", "middle": [], "last": "Seumois", "suffix": ""}, {"first": "C", "middle": [], "last": "Pickard", "suffix": ""}, {"first": "R", "middle": ["M"], "last": "Powell", "suffix": ""}, {"first": "G", "middle": [], "last": "Angco", "suffix": ""}, {"first": "D", "middle": [], "last": "Sammut", "suffix": ""}, {"first": "S", "middle": ["D"], "last": "Gadola", "suffix": ""}, {"first": "P", "middle": ["S"], "last": "Friedmann", "suffix": ""}, {"first": "R", "middle": [], "last": "Djukanovic", "suffix": ""}], "year": 2007, "venue": "N. Engl. J. Med", "link": "27042386"}, "BIBREF30": {"title": "CD4+ invariant T-cell-receptor+ natural killer T cells in bronchial asthma", "authors": [{"first": "O", "middle": [], "last": "Akbari", "suffix": ""}, {"first": "J", "middle": ["L"], "last": "Faul", "suffix": ""}, {"first": "E", "middle": ["G"], "last": "Hoyte", "suffix": ""}, {"first": "G", "middle": ["J"], "last": "Berry", "suffix": ""}, {"first": "J", "middle": [], "last": "Wahlstr\u00f6m", "suffix": ""}, {"first": "M", "middle": [], "last": "Kronenberg", "suffix": ""}, {"first": "R", "middle": ["H"], "last": "Dekruyff", "suffix": ""}, {"first": "D", "middle": ["T"], "last": "Umetsu", "suffix": ""}], "year": 2006, "venue": "N. Engl. J. Med", "link": "39257457"}}, "ref_entries": {}}
{"paper_id": "2879621", "_pdf_hash": "a96b169eee7ca51101f77c35157073ccd9d1f5fc", "abstract": [], "body_text": [{"section": "INTRODUCTION", "text": "In a recent paper (Sabelis and Bakker, 1992) we calculated the optimal number of dorsal setae required to minimize somal contact with sticky structures, such as silken threads forming the chaotically structured web spun by two-spotted spider mites. This calculation was based on two vital assumptions: (1) full avoidance of somal contact is achieved when the imaginary central axis is fully covered by the projections of the dorsal setae on this axis; and (2) investment per seta is proportional to setal length to the power 3 (which holds only when the seta is coneshaped and the setal diameter-length ratio is constant). While the first assumption is a gross oversimplification, the second assumption lacks support by hard data. In this paper we will ( 1 ) extend the optimality model to include a more general class of diameter-length relations with respect to dorsal setae, (2) present measurements of diameter-length relations in various genera of the Phytoseiidae and (3) predict the optimal number of setae for comparison with the actual number of dorsal setae. This test of the model will then be used to determine wbether the number of dorsal setae in phytosciid mites can be considered as an adaptation or a phylogenetic constraint.", "cite_spans": [{"start": 18, "end": 44, "text": "(Sabelis and Bakker, 1992)", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "OPTIMAL INVESTMENT IN SETAE", "text": "Suppose that ( I ) the central axis has length L, (2) each seta has !ength l and a hooked shape with e being the length of the part perpendicular to the soma and l -e being the length of the remaining part parallel to the soma, (3) the setae are standing in a longitudinal row, are equal in length and their projections on the central axis (l') do not overlap. Finally, suppose that (4) the per seta investment in terms of resources (r) is proportional to the volume of a cone with length I and diameter d and that (5) because d and l should pass through the origin, the functional relationship is of the form l\" = ~ d, where c~ and a are specific constants for the setae of the mites under study. Based on the last two assumptions total resource investment in setae (R) obeys the following relationship:", "cite_spans": [], "ref_spans": []}, {"section": "OPTIMAL INVESTMENT IN SETAE", "text": "~7\"/\" R = n r = n ~l t', where b = 2a + l and ~ -12\u00b0z 2", "cite_spans": [], "ref_spans": []}, {"section": "OPTIMAL INVESTMENT IN SETAE", "text": "Here, \"7 is a constant of resource-volume proportionality. To obtain 100% protection over the full length of the central axis (L) without overlap of setae the number of setae should be equal to L divided by the projection L L length per seta: n = --or l = e + --. The optimal number of setae is now found (l-e) n by minimizing total resource investment R with respect to L:", "cite_spans": [], "ref_spans": []}, {"section": "R,.#, =min[n~(e+L) t' ]", "text": "The first derivative of R with respect to n yields:", "cite_spans": [], "ref_spans": []}, {"section": "dn=~ e+; -nb e+-~) t~-~]", "text": "Setting the first derivative equal to zero some algebraic manipulation leads to the following unique solution for n:", "cite_spans": [], "ref_spans": []}, {"section": "dn=~ e+; -nb e+-~) t~-~]", "text": "This solution represents the number of setae that minimizes R (the second derivative with respect to n is always positive!). Note that this solution differs by a factor 2 from the one presented in Sabelis and Bakker (1992) ; this was caused by an incorrrect change of sign (n -A in equation 4 of the Appendix should have been n+A).", "cite_spans": [{"start": 197, "end": 222, "text": "Sabelis and Bakker (1992)", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "dn=~ e+; -nb e+-~) t~-~]", "text": "This result shows that optimal investment in setae depends on (1) the difference (= e) between setal length and its projection on the central axis, and on (2) the type of non-linearity (a and thus also b), but not on the details of proportionality (a and thus -also/3) in the functional relationship between setal diameter and length. Hence, it is important to estimate the power for assessment of the type of non-linearity.", "cite_spans": [], "ref_spans": []}, {"section": "DIAMETER-LENGTH RELATIONS IN DORSAL SETAE", "text": "Using a light microscope with an ocular provided with a metric scale (0.25 Ix) the diameter and length of dorsal setae (j l, j3, j4, j5, j6, J2, z2, z4, s4, s6 The exponent a in the expression /\" = a d was estimated by means of linear regression after taking logarithms at both sides and rewriting the expression as:", "cite_spans": [], "ref_spans": []}, {"section": "DIAMETER-LENGTH RELATIONS IN DORSAL SETAE", "text": "From the slope of the regression the exponent a can be calculated, whereas a can be obtained from the constant. The results are presented in Table 1 . Most remarkably, the slopes of three regression lines for Amblyseius, Typhlodromus and a single species in the genus Phytoseiulus are quite similar! This suggests that the structure' of the setae in these three genera have much in common. That the data on Phvtoseius do not conform to this pattern does not come as a surprise as the structure of their dorsal setae is strikingly different; they are very thick and strongly serrated. If we ignore Phytoseius spp., it can be concluded that the most simple and best fitting model to describe the relation between diameter and length for the other three genera is l\"= cr dwith ~ = 5.7 and a = 0.64.", "cite_spans": [], "ref_spans": [{"start": 141, "end": 148, "text": "Table 1", "ref_id": "TABREF1"}]}, {"section": "A FUNCTIONAL VIEW ON HYPOTRICHY IN THE PHYTOSEIIDAE", "text": "Under the assumptions in Sabelis and Bakker (1992) model correction leads to a twofold increase in n*. However, the estimate of a appears to be lower than the value a=l raken in Sabelis and Bakker (1992) and therefore leads to a reduction in n*. Thus, the two modifications have opposite effects on the optimal number of setae and the following formula for n* results:", "cite_spans": [{"start": 25, "end": 50, "text": "Sabelis and Bakker (1992)", "ref_id": "BIBREF2"}, {"start": 178, "end": 203, "text": "Sabelis and Bakker (1992)", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "A FUNCTIONAL VIEW ON HYPOTRICHY IN THE PHYTOSEIIDAE", "text": "This formula is instrumental in inferring whether phytoseiid mites are hypotrichous from a functional point of view. For central axes varying in length (L) from 250 to 350 ~m and for e being maximally I0 ~m, the optimal number of setae for 100% protection of either the margino-dorsal or the mid-dorsal region varies from 32 to 45 (for a definition of the two categories of dorsal setae see Sabelis and Bakker, 1992) . Clearly, Phytoseiidae with maximally I0 margino-dorsal and 12 mid-dorsal setae do not fall within this range. For this number of setae to be optimal the exponent a should be in the range of 0.13 to 0.24, which is definitely much lower and far outside the range of the values estimated from the diameterlength measurements. Note in addition that for Phytoseius with an exponent a larger than 0.64 the difference between predicted n* and the actual number of setae is even more pronounced! From a phylogenetic point of view evolution of idiosomal setation in the Phytoseiidae has proceeded largely through irreversible setal suppression from a holotrichous ancestor (Chant, t993) . Because of this reduced number of setal positions Phytoseiidac are referred to as being hypotrichous. From a functional viewpoint hypotrichy can be expected to evolve when the need for idiosomal protection is small. Foraging on glabrous leaves represents a case where the risk to get stuck is very low and a reduction in the number of setal positions might actually lead to increassed fitness. Hence, if the ancestral phytoseioid mites foraged on glabrous leaves, hypotrichy is likely to have evolved. However, due to the irreversible nature of the setal suppression a reduced number of setal positions may become a constraint when the foraging environment changes such that there is a need for increased protection of the idiosoma; for example, when phytoseioid mites may find profitable prey/food on pubescent leaves or in chaotically structured webs. Thus, the Phytoseiidae may have been trapped in an evolutionary path to hypotrichy and had no option but to lengthen the setae still present.", "cite_spans": [{"start": 391, "end": 416, "text": "Sabelis and Bakker, 1992)", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "A FUNCTIONAL VIEW ON HYPOTRICHY IN THE PHYTOSEIIDAE", "text": "While the optimal allocation model is elegant due to its simplicity, it is not yet clear whether its predictions can stand up to scrutiny. Soil-inhabiting mesostigmatic mites, for example, basically have a larger number of setal positions (e.g. Lasioseius alii Chant has 20 mid-dorsal and 16 margino-dorsal setae; see Lindquist and Evans, 1965) and their soil environment presumably requires full protection, but the larger number of setal positions is still lower than the optimum n*, predicted by our model. Thus, there is much room for a more elaborate model that takes into account that setae have a bended rather than hooked shape, that they are positioned on a hemisphere, not in perfectly straight rows and not equidistantly, that setal structure and protection effect may depend on the type of environment (i.e. the exponent a is not a fixed constraint!) etc'. However, if we succeeded in outlining a quantitative approach to understand evolutionary trends in setal arrangement, we have reached our main goal.", "cite_spans": [{"start": 318, "end": 344, "text": "Lindquist and Evans, 1965)", "ref_id": "BIBREF1"}], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Discontinuous variation in the suppression of idiosomal setae in the family Phytoseiidae (Acari: Gamasina)", "authors": [{"first": "D", "middle": ["A"], "last": "Chant", "suffix": ""}], "year": 1993, "venue": "Exp. Appl. Acarol", "link": "42223285"}, "BIBREF1": {"title": "Taxonomic concepts in the Ascidae, with a modified setal nomenclature for the idiosoma of the Gamasina", "authors": [{"first": "E", "middle": ["E"], "last": "Lindquist", "suffix": ""}, {"first": "G", "middle": ["O"], "last": "Evans", "suffix": ""}], "year": 1965, "venue": "", "link": null}, "BIBREF2": {"title": "How predator) mites cope with the web of their tetranychid prey: a functional view on dorsal chaetotaxy in the Phytoseiidae", "authors": [{"first": "", "middle": ["M W"], "last": "Sabelis", "suffix": ""}, {"first": "F", "middle": ["M"], "last": "Bakker", "suffix": ""}], "year": 1992, "venue": "Exp. Appl. Acarol", "link": "23029133"}}, "ref_entries": {"TABREF0": {"text": ", Z1, Z4, Z5, $2, $4, $5) were measured in slide-mounted specimens of the following species and genera of the Phytoseiidae: 2 Phytoseius spp. (Phytoseius hawaiiensis and macropilis), I1 Amblyseius spp. (Amblyseius andersoni, barkeri, bibens, cucumeris, andersoni deleoni, finlandicus, graminis, idaeus, massei, reductus and teke), 5 Typhlodromus spp. (Typhlodtvmus aberrans, annectens, okanagensis, porresi and pyri), and 6 specimens of Phytoseiulus persimilis.", "type": "table"}, "TABREF1": {"text": "Estimates of the exp~)nent a from linear regression of In (1) on In(d) li.e. the natural logarithms of the length and the basal diameter of dorsal setae). SE = standard error: R 2 = ,',quared correlation coefficient, N = number of data pairs.", "type": "table"}}}
{"paper_id": "2879698", "_pdf_hash": "f618ecbefe7e89b7f90a1473998777747cec3308", "abstract": [{"section": "Abstract", "text": "The demonstrated modified spectrophotometric method makes use of the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical and its specific absorbance properties. The absorbance decreases when the radical is reduced by antioxidants. In contrast to other investigations, the absorbance was measured at a wavelength of 550 nm. This wavelength enabled the measurements of the stable free DPPH radical without interference from microalgal pigments. This approach was applied to methanolic microalgae extracts for two different DPPH concentrations. The changes in absorbance measured vs. the concentration of the methanolic extract resulted in curves with a linear decrease ending in a saturation region. Linear regression analysis of the linear part of DPPH reduction versus extract concentration enabled the determination of the microalgae's methanolic extracts antioxidative potentials which was independent to the employed DPPH concentrations. The resulting slopes showed significant differences (6 -34 \u00b5mol DPPH g -1 extract concentration) between the single different species of microalgae (Anabaena sp., Isochrysis galbana, Phaeodactylum tricornutum, Porphyridium purpureum, Synechocystis sp. PCC6803) in their ability to reduce the DPPH radical. The independency of the signal ", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "In oxygen involving metabolisms like photorespiration and photosynthesis, reactive oxygen species (ROS) are natural byproducts (He and H\u00e4der 2002, Apel and Hirt 2004) in phototrophic microorganisms. Typical ROS are e.g. superoxide, hydroxyl, peroxyl, and alkoxy radicals. Under nonstressed conditions, production and scavenging of ROS in these microorganisms is in equilibrium (Apel and Hirt 2004) .", "cite_spans": [{"start": 127, "end": 134, "text": "(He and", "ref_id": "BIBREF18"}, {"start": 156, "end": 166, "text": "Hirt 2004)", "ref_id": "BIBREF3"}, {"start": 377, "end": 397, "text": "(Apel and Hirt 2004)", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "Introduction", "text": "Different environmental stress factors like pollution, drought, temperature, excessive light intensities, and nutritional limitation are able to increase the production of ROS (Ehling-Schulz and Scherer 1999, Rijstenbil 2002 , Arora et al. 2002 . Oxidative stress is closely associated to these unstable but very reactive radicals (Fang et al. 2002) . Their highly reactive potential is discussed to be responsible for some human diseases e.g. cancer and cardiovascular diseases and is able to cause oxidative damages to proteins, DNA, and lipids (Jacobi and Burri, 1996) in both humans and microorganisms.", "cite_spans": [{"start": 209, "end": 224, "text": "Rijstenbil 2002", "ref_id": "BIBREF38"}, {"start": 225, "end": 244, "text": ", Arora et al. 2002", "ref_id": "BIBREF4"}, {"start": 331, "end": 349, "text": "(Fang et al. 2002)", "ref_id": "BIBREF15"}], "ref_spans": []}, {"section": "Introduction", "text": "Microalgae have to counteract these negative effects by diverse effective enzymatic and nonenzymatic mechanisms (Apel and Hirt, 2004) . Several enzymes like superoxide dismutase, catalase peroxidase are able to scavenge ROS (Blokhina et al. 2003) . Carotenoids and fatty acids are two examples for non-enzymatic classes of substances which are able to protect the organism from oxidative damage (Sies and Stahl, 1995) . Tocopherol, flavonoids, and alkaloids are other examples for substances belonging to this group of non-enzymatic substances.", "cite_spans": [{"start": 112, "end": 133, "text": "(Apel and Hirt, 2004)", "ref_id": "BIBREF3"}, {"start": 395, "end": 417, "text": "(Sies and Stahl, 1995)", "ref_id": "BIBREF40"}], "ref_spans": []}, {"section": "Introduction", "text": "Two major but different mechanisms are known (Prior et al. 2005 ): Both mechanisms lead to a reduction of the radicals but differ in kinetics and propensity for side reactions (Prior et al. 2005 ). For hydrogen atom transfer, the antioxidants quench the free radicals by donating a hydrogen whereas for single electron transfer the antioxidants transfer one electron to the radical.", "cite_spans": [{"start": 45, "end": 63, "text": "(Prior et al. 2005", "ref_id": "BIBREF35"}, {"start": 176, "end": 194, "text": "(Prior et al. 2005", "ref_id": "BIBREF35"}], "ref_spans": []}, {"section": "Introduction", "text": "For estimating the antioxidative potential of chemical components, different experimental approaches were used (Prior et al. 2005 ). Most of them require a spectrophotometric measurement and a certain reaction time in order to obtain reproducible results (Kulisic et al. 2004) .", "cite_spans": [{"start": 111, "end": 129, "text": "(Prior et al. 2005", "ref_id": "BIBREF35"}, {"start": 255, "end": 276, "text": "(Kulisic et al. 2004)", "ref_id": "BIBREF25"}], "ref_spans": []}, {"section": "Introduction", "text": "For example, the \u00df-carotene bleaching test (BCB) is based on the decolorization of \u00df-carotene by its reaction with radicals. This effect is measured at a wavelength of 470 nm after a reaction time of nearly 120 min. Other methods like the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging method or the thiobarbituric acids reactive species (TBARS) assay work similar to the BCB test.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "The TBARS assay uses the production of a pink pigment produced by the reaction of thiobarbituric acid (TBA) with malondialdehyd (MDA) and other secondary lipid peroxidation products (Kulisic et al. 2004) . Absorbance measurements at 532 nm serve as an indicator of the extent of lipid degradation.", "cite_spans": [{"start": 182, "end": 203, "text": "(Kulisic et al. 2004)", "ref_id": "BIBREF25"}], "ref_spans": []}, {"section": "Introduction", "text": "The use of DPPH for a radical scavenging measuring method is described e.g. by Yen and Duh (1994) , Yordanov and Christova (1997), Masuda et al. (1999) , Anderson and Padhye (2004) , and Iwashima et al. (2005) . DPPH is a stable free radical in a methanolic solution. In its oxidized form, the DPPH radical has an absorbance maximum centered at about 520 nm (Molyneux, 2004) . The DPPH method is described as a simple, rapid and convenient method independent of sample polarity for screening of many samples for radical scavenging activity (Koleva et al. 2001 ). These advantages make the DPPH method interesting for testing microalgae as a natural source to scavenge radicals and to find out promising candidates for a commercial sense.", "cite_spans": [{"start": 79, "end": 97, "text": "Yen and Duh (1994)", "ref_id": "BIBREF44"}, {"start": 131, "end": 151, "text": "Masuda et al. (1999)", "ref_id": "BIBREF28"}, {"start": 154, "end": 180, "text": "Anderson and Padhye (2004)", "ref_id": "BIBREF1"}, {"start": 187, "end": 209, "text": "Iwashima et al. (2005)", "ref_id": "BIBREF19"}, {"start": 358, "end": 374, "text": "(Molyneux, 2004)", "ref_id": "BIBREF30"}, {"start": 540, "end": 559, "text": "(Koleva et al. 2001", "ref_id": "BIBREF23"}], "ref_spans": []}, {"section": "Introduction", "text": "Usually, the DPPH absorbance is measured at a wavelength of 515 -520 nm (Bandoniene et al. 2002 , Pavlov et al. 2002 , Gazi et al. 2004 ). But here, demonstrated in Figure 1 , an applied modification of this DPPH-method is described enabling the measurement of the antioxidative potential of the microalgae's specific methanolic extracts. Spolaore et al. 2006 ). The demonstrated modified DPPH-method enables therefore the screening of microalgae as promising candidates in a commercial sense. Furthermore, the modified method can be used, e.g. if the aim of future investigations is the detection of the antioxidative potential of some microalgae influenced by different environmental parameters.", "cite_spans": [{"start": 72, "end": 95, "text": "(Bandoniene et al. 2002", "ref_id": "BIBREF5"}, {"start": 96, "end": 116, "text": ", Pavlov et al. 2002", "ref_id": "BIBREF33"}, {"start": 117, "end": 135, "text": ", Gazi et al. 2004", "ref_id": "BIBREF16"}, {"start": 339, "end": 359, "text": "Spolaore et al. 2006", "ref_id": "BIBREF41"}], "ref_spans": [{"start": 165, "end": 173, "text": "Figure 1", "ref_id": "FIGREF0"}]}, {"section": "Materials and methods", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Microalgae and cultivation conditions", "text": "Two cyanophyceae (Synechocystis sp. PCC6803, Anabaena sp.), one rodophyceae (Porphyridium purpureum) and haptophyceae (Isochrysis galbana) and bacillariophyceae (Phaeodactylum tricornutum) were tested. Isochrysis galbana, Porphyridium purpureum, Phaeodactylum tricornutum were grown in artificial seawater (Tropic Marin, TAGIS, Germany) enriched with F/2 medium nutrients (Guillard and Ryther 1962) at 24 \u00b0C with a constant pH-value of the cultures at 8.3. Anabaena sp. and Synechocystis sp. PCC6803 were grown at 26 \u00b0C in BG-11 medium (Rippka et al. 1979 ) with a constant pH-value of 8.0. Each culture was grown at a constant light regime of 120 \u00b5mol photons m -2 s -1 . The pH-values were kept constant by automatic addition of pure CO 2 . At the end of the cultivation, the cultures were centrifuged, freeze-dried and stored at -20 \u00b0C.", "cite_spans": [{"start": 536, "end": 555, "text": "(Rippka et al. 1979", "ref_id": "BIBREF37"}], "ref_spans": []}, {"section": "Preparation of the methanolic extract", "text": "The protocol of Bandoniene et al. (2002) with minor modifications was used for the preparation of the methanolic extracts. Samples of the freeze-dried microalgae were portioned in aliquots of 0.025 -1 g. Each of these aliquots was homogenized in 5 mL of 100 % methanol (instead of 80 % methanol) for 30 s on ice with an ULTRA-TURRAX T25 (IKA-Labortechnik, Staufen, Germany). Afterwards, the homogenates were injected through 0.2 \u00b5m PTFE-filter (instead of paper filter) into test tubes. The extracts with different biomass concentrations were used for the determination of the antioxidant properties.", "cite_spans": [{"start": 16, "end": 40, "text": "Bandoniene et al. (2002)", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Spectrophotometric measurements", "text": "Wavelength scans from 400 to 750 nm and the decrease in absorbance at 550 nm were measured with a dual-beam UV-VIS spectrophotometer (Uvikon XL, Bio-Tek Instruments, Bad Friedrichshall, Germany). A 550 as used in Equation (1) below was obtained by switching the spectrophotometer modus from a wavelength scan to a fixed wavelength modus.", "cite_spans": [], "ref_spans": []}, {"section": "Spectrophotometric measurements", "text": "DPPH radical. DPPH was obtained from Fluka (Buchs, Switzerland). 2.5 mg DPPH were solved in 5 mL methanol (\u2248 1.27 mmol L -1 ). This stock solution was daily prepared, used for the measurements, and kept in the dark at ambient temperature when not used. Using this stock solution enables the measurement of a calibration curve at 550 nm for calculating the DPPH concentration as follows ", "cite_spans": [], "ref_spans": []}, {"section": "Preparation of reference and measuring cuvette", "text": "2.25 mL methanol, 0.1 mL extract and 0.15 mL DPPH stock solution (resulting in a DPPH concentration of 76 \u00b5mol L -1 ) were mixed in one measuring cuvette. Furthermore, the extracts were measured with a second measuring cuvette containing 2.325 mL methanol, 0.1 mL extract and 0.075 mL DPPH stock solution (resulting in a DPPH concentration of 38 \u00b5mol L -1 ) for verification of the data obtained with the higher DPPH concentration. Additionally a reference cuvette filled with 2.4 mL methanol and 0.1 mL extract was used.", "cite_spans": [], "ref_spans": []}, {"section": "Experimental protocol", "text": "For a proper measurement of the antioxidative potential of the tested microalgae using the DPPH radical, the following procedure was successfully executed. For choosing the suitable wavelength, wavelength scans from 440 to 750 nm were done for both measuring and reference cuvette. The scans were run against pure methanol. Measurements in the measuring cuvette were performed 30 min after addition of DPPH in order to give enough time for the reaction of the cellular antioxidants with DPPH. During this 30 min, reference and measuring cuvette were kept in the dark at ambient temperature. Additionally, the reference cuvette was measured before and after the reaction in the measuring cuvette had taken place for verification that no changes of the absorptive properties of the microalgae extract had occurred in the absence of DPPH.", "cite_spans": [], "ref_spans": []}, {"section": "Experimental protocol", "text": "After wavelength scans were done (3 min) 0.3 mL of the \u03b1-tocopherol solution was added to both measuring and reference cuvette in order to achieve full reduction of the DPPH radicals. Then, the wavelength scans were repeated. This served to select an adequate wavelength which is influenced only by the DPPH radical (here 550 nm).", "cite_spans": [], "ref_spans": []}, {"section": "Experimental protocol", "text": "The absorbance decrease was then measured by using measuring and reference cuvette prepared and treated in the same way described above. But here the absorbance of the measuring cuvette was measured at 550 nm against the reference cuvette for elimination of the absorptive properties of the microalgae extract.", "cite_spans": [], "ref_spans": []}, {"section": "Experimental protocol", "text": "All measurements were performed in triplicate. Here, averages and standard deviations are presented.", "cite_spans": [], "ref_spans": []}, {"section": "Data analysis", "text": "The linear range of the absorbance decrease (see Figure 2 , below) was evaluated by means of a simple linear regression c DPPH = c DPPH , 0 + a 1 c E (2) .", "cite_spans": [{"start": 150, "end": 153, "text": "(2)", "ref_id": "BIBREF1"}], "ref_spans": [{"start": 49, "end": 57, "text": "Figure 2", "ref_id": "FIGREF2"}]}, {"section": "Data analysis", "text": "with c DPPH obtained from Equation (1), c DPPH , 0 is the concentration added to the cuvette, c E the concentration of the microalgae extract. The slope a 1 is determined by linear regression of graphs like those in Figure 2 , below. The slope is used as a parameter for estimating the antioxidative potential of the investigated microalgae. ", "cite_spans": [], "ref_spans": [{"start": 216, "end": 224, "text": "Figure 2", "ref_id": "FIGREF2"}]}, {"section": "Determination of the effective concentration (EC 50 )", "text": "The EC 50 value expresses the amount of microalgae extract necessary to decrease the absorbance of DPPH by 50 % (Antolovich et al. 2002) . The value can be determined graphically by plotting the absorbance against the used extract concentration or calculated by using the slope of the linear regression (Equation (2)).", "cite_spans": [], "ref_spans": [{"start": 112, "end": 136, "text": "(Antolovich et al. 2002)", "ref_id": "FIGREF2"}]}, {"section": "Results and discussion", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Wavelength scans", "text": "Wavelength scans from all extracts were measured. In Figure 1 wavelength scans of reference and measuring cuvette of methanolic extracts of Synechocystis sp. PCC6803 are shown. Whereas the signal from the reference cuvette remained constant in the time between the two measurements at 0 and 30 min (coincident curves in Figure 1 ) the measuring cuvette showed an absorbance decrease below 530 nm after 30 min of DPPH addition. After adding \u03b1-tocopherol to this cuvette, the decrease continued. In contrast to results below 530 nm, the absorbance measured at 550 nm obtained the same value in the measuring cuvette after adding \u03b1-tocopherol (Figure 1) as the absorbance measured in the reference cuvette. Furthermore, the absorbance had a minimum at this wavelength. The absorbance decrease below 530 nm in the measuring cuvette in the presence of \u03b1-tocopherol was not representative for all extracts but showed possible interference of antioxidants and DPPH radical. Nevertheless, for all tested extracts a minimum occurred near 550 nm, and same values were obtained in the measuring and in the reference cuvette at 550 nm after adding \u03b1-tocopherol (data not shown). Therefore, 550 nm was selected as the most adequate wavelength for testing all microalgae extracts. By means of the experiments present in Figure 1 , the most suitable wavelength was determined (here 550 nm). According to the results presented there, absorbance changes at this wavelength reflect the chemical state of the DPPH radicals (oxidized or reduced state). Therefore this wavelength enables a straightforward analysis and interpretation of the measured absorbance decrease.", "cite_spans": [], "ref_spans": [{"start": 53, "end": 61, "text": "Figure 1", "ref_id": "FIGREF0"}, {"start": 320, "end": 328, "text": "Figure 1", "ref_id": "FIGREF0"}, {"start": 640, "end": 650, "text": "(Figure 1)", "ref_id": "FIGREF0"}, {"start": 1306, "end": 1314, "text": "Figure 1", "ref_id": "FIGREF0"}]}, {"section": "Wavelength scans", "text": "For its function as a measure of antioxidant potential, absorbance at the selected wavelength should be mainly influenced by the DPPH radical and not by interference as caused by antioxidants (Bondet et al. 1997 ), e.g. carotenoids and polyunsaturated fatty acids (PUFAs). This problem is illustrated in Figure 1 . Wavelength signals below 530 nm are strongly influenced by carotenoids (Britton 1995 ). This could lead to a misinterpretation of the measured absorbance decrease when a wavelength is chosen which is influenced by both DPPH radical and the absorptive properties of the extract (as by carotenoids).", "cite_spans": [{"start": 192, "end": 211, "text": "(Bondet et al. 1997", "ref_id": "BIBREF9"}, {"start": 386, "end": 399, "text": "(Britton 1995", "ref_id": "BIBREF10"}], "ref_spans": [{"start": 304, "end": 312, "text": "Figure 1", "ref_id": "FIGREF0"}]}, {"section": "Wavelength scans", "text": "A major part of this kind of interference can be eliminated by running the absorbance measurement against a reference cuvette filled with the same extract concentration as in the measuring cuvette.", "cite_spans": [], "ref_spans": []}, {"section": "Absorbance measurements", "text": "The absorbance measurements for all five microalgae were done by the same protocol. Below, in Figures 2 to 5, representative records for two microalgae are shown. The good signal-noise ratio for all measurements enables a straight-forward interpretation of the data.", "cite_spans": [], "ref_spans": []}, {"section": "Absorbance measurements", "text": "Absorbance measurements were done at two concentrations of DPPH. In Figure 2 Adding \u03b1-tocopherol after the DPPH measurements indicate that the remaining DPPH radicals are responsible for the remaining absorbance in Figure 2 . Figure 3 displays the effect of \u03b1-tocopherol on the absorbance measurements at 550 nm for Synechocystis sp. PCC6803. The addition of the vitamin causes a nearly complete decrease of the absorbance to values close to zero. Since this occurs for all extract concentrations it becomes evident that the remaining signal in the absorbance decrease in Figure 2 is due to DPPH radicals not reduced by the extract concentrations of Synechocystis sp. PCC6803. Figure 4 show also a linear, parallel decrease at low extract concentrations. Again, the curves obtained at both DPPH concentrations saturate at higher extract concentrations. However, in contrast to the upper curve in Figure 2 , the upper curve in Figure 4 reaches values near zero. Again, adding \u03b1-tocopherol shows that the remaining absorbance in Figure 4 is due to unreduced DPPH radicals, as it decreases the absorbance to values close to zero ( Figure 5) .", "cite_spans": [], "ref_spans": [{"start": 68, "end": 76, "text": "Figure 2", "ref_id": "FIGREF2"}, {"start": 215, "end": 223, "text": "Figure 2", "ref_id": "FIGREF2"}, {"start": 226, "end": 234, "text": "Figure 3", "ref_id": "FIGREF4"}, {"start": 572, "end": 580, "text": "Figure 2", "ref_id": "FIGREF2"}, {"start": 677, "end": 685, "text": "Figure 4", "ref_id": "FIGREF5"}, {"start": 896, "end": 904, "text": "Figure 2", "ref_id": "FIGREF2"}, {"start": 926, "end": 934, "text": "Figure 4", "ref_id": "FIGREF5"}, {"start": 1027, "end": 1035, "text": "Figure 4", "ref_id": "FIGREF5"}, {"start": 1128, "end": 1137, "text": "Figure 5)", "ref_id": "FIGREF7"}]}, {"section": "Absorbance measurements", "text": "Employing extraction by methanol imposes some caveats with respect to extract concentration and kind of antioxidants. Figures 2 and 4 shows saturation of the absorbance decrease when plotted vs. extract concentration. This saturation can be explained by the limited capacity of methanol to extract the antioxidants from the aliquots of the freeze-dried microalgae. With both DPPH concentrations, the similar amounts of DPPH were oxidised in dependence of biomass concentration. The same decrease in the saturating region indicated that only the amount of antioxidants which were extracted (and not what was in the aliquots) were measured by this procedure. This effect leads to the assumption that the used volume of methanol is not able to extract the complete content of carotenoids and PUFAs from the investigated microalgae samples. This explanation is supported by the effect of \u03b1-tocopherol on the absorbance measurements. Linear regressions calculated according to Equation (2) . Figure 3 and Figure 5 show that the remaining absorbance in Figures 2 and 4 is due to remaining DPPH radicals, because they all can be converted to their reduced form by adding \u03b1-tocopherol. This is indicated by the fact that absorbance at 550 nm reaches values close to zero.", "cite_spans": [{"start": 981, "end": 984, "text": "(2)", "ref_id": "BIBREF1"}], "ref_spans": [{"start": 118, "end": 133, "text": "Figures 2 and 4", "ref_id": "FIGREF2"}, {"start": 987, "end": 995, "text": "Figure 3", "ref_id": "FIGREF4"}, {"start": 1000, "end": 1008, "text": "Figure 5", "ref_id": "FIGREF7"}, {"start": 1047, "end": 1062, "text": "Figures 2 and 4", "ref_id": "FIGREF2"}]}, {"section": "Absorbance measurements", "text": "In the first place, the results of Figures 2 and 4 demonstrate a valuable benefit of the method: The slope in Figures 2 and 4 is a direct measure of the antioxidative potential of the investigated sample of microalgae. Thus, this slope yields a useful tool for the direct comparison of different extracts with respect to their antioxidant potential. The determination of the slope is independent from the selected wavelength. The slope can also be calculated when a different wavelength is employed, which may be more suitable for other microalgae or chemicals. The slope offers the possibility for direct comparison of microalgal antioxidative potential. A further very important result of Figures 2 and 4 is the independence of the slope on DPPH concentration. This provides an important advantage over the interpretation of the antioxidative capacity based on the EC 50 value (Table 1 ). On the other hand, the non-linearity as caused by limited methanol capacity imposes the caveat that the biomass concentration should not be too high, i.e., not exceeding the linear part in Figures 2 and 4 .", "cite_spans": [], "ref_spans": [{"start": 35, "end": 50, "text": "Figures 2 and 4", "ref_id": "FIGREF2"}, {"start": 110, "end": 125, "text": "Figures 2 and 4", "ref_id": "FIGREF2"}, {"start": 691, "end": 706, "text": "Figures 2 and 4", "ref_id": "FIGREF2"}, {"start": 879, "end": 887, "text": "(Table 1", "ref_id": "TABREF1"}, {"start": 1080, "end": 1095, "text": "Figures 2 and 4", "ref_id": "FIGREF2"}]}, {"section": "Absorbance measurements", "text": "In order to make sure that the linear part is not exceeded the experiment should be repeated with different biomass concentrations. Then the linear part can be evaluated by linear regression.", "cite_spans": [], "ref_spans": []}, {"section": "Absorbance measurements", "text": "The other caveat arises from the feature that methanolic extraction excludes the detection of the antioxidative potential of water soluble antioxidative substances, e.g. ascorbat, gluthathion, phycocyanin (Romay et al. 1998 ). Because of the freeze-dried status of the microalgal samples and the use of methanol as extracting agent mainly the carotenoids and fatty acids are the most likely candidates causing the decrease of DPPH absorbance (Figures 2 and 4 , containing the linear regressions by using Equation (2)). Methanolic soluble microalgal compounds like carotenoids and PUFAs as well as some proteins are known to exhibit antioxidative potential (Fang et al. 2002) . Nevertheless, due to the non-specifity of the methanolic extract for one of the two compound classes (carotenoids and PUFAs) it is not possible to find out which substances of each microalgae are responsible for the absorbance decrease of the DPPH solution. This requires further investigations.", "cite_spans": [{"start": 205, "end": 223, "text": "(Romay et al. 1998", "ref_id": "BIBREF39"}, {"start": 656, "end": 674, "text": "(Fang et al. 2002)", "ref_id": "BIBREF15"}], "ref_spans": [{"start": 442, "end": 458, "text": "(Figures 2 and 4", "ref_id": "FIGREF2"}]}, {"section": "Theoretical background", "text": "Describing the reaction of DPPH with the antioxidant as a bimolecular reaction leads to ", "cite_spans": [], "ref_spans": []}, {"section": "Theoretical background", "text": "leads to", "cite_spans": [], "ref_spans": []}, {"section": "Theoretical background", "text": "Transforming Equation (11) Equation (14) still works when A T >> (K \u2022 A SOL ). This result explains the saturation effect of the solvent with increasing A T in Figures 2 and 4 . The dissolved amount of antioxidants is limited by the used amount of the solvent.", "cite_spans": [], "ref_spans": [{"start": 160, "end": 175, "text": "Figures 2 and 4", "ref_id": "FIGREF2"}]}, {"section": "Data analysis of some microalgae", "text": "The analysis of the absorbance measurements at low concentrations of five different microalgae extract's (see Table 1 ) reveals different slopes by using Equation (2) Comparing the data analysed by both DPPH concentrations in Table 1 , it becomes clear that the benefits of the here demonstrated method give better results because the values results from averaged data points compared to EC 50 .", "cite_spans": [], "ref_spans": [{"start": 110, "end": 117, "text": "Table 1", "ref_id": "TABREF1"}, {"start": 226, "end": 233, "text": "Table 1", "ref_id": "TABREF1"}]}, {"section": "Data analysis of some microalgae", "text": "The problem for a proper interpretation of the results is the high variety and a possible influence of the individual composition of carotenoids and fatty acids in each microalgae sample (Wada and Murata 1990 , Yongmanitchai and Ward 1991 , Allakhverdiev et al. 1999 , Kosakowska et al. 2004 ). For a direct comparison of the antioxidative potential of microalgae environmental conditions, e.g. temperature, light intensity, and pH-value must be controlled during the cultivations. This requires a high instrumented photobioreactor system which enables the cultivation of the microalgae under strictly defined conditions (Marxen et al. 2005) and is therefore suitable to investigate the influence of these cultivation parameters on the antioxidative potential of microalgae.", "cite_spans": [{"start": 187, "end": 208, "text": "(Wada and Murata 1990", "ref_id": "BIBREF43"}, {"start": 209, "end": 238, "text": ", Yongmanitchai and Ward 1991", "ref_id": "BIBREF45"}, {"start": 239, "end": 266, "text": ", Allakhverdiev et al. 1999", "ref_id": "BIBREF0"}, {"start": 267, "end": 291, "text": ", Kosakowska et al. 2004", "ref_id": "BIBREF24"}, {"start": 621, "end": 641, "text": "(Marxen et al. 2005)", "ref_id": "BIBREF27"}], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Genetic engineering of the unsaturation of fatty acids in membrane lipids alters the tolerance of Synechocystis to salt stress", "authors": [{"first": "S", "middle": ["I"], "last": "Allakhverdiev", "suffix": ""}, {"first": "Y", "middle": [], "last": "Nishiyama", "suffix": ""}, {"first": "I", "middle": [], "last": "Suzuki", "suffix": ""}, {"first": "Y", "middle": [], "last": "Tasaka", "suffix": ""}, {"first": "N", "middle": [], "last": "Murata", "suffix": ""}], "year": 1999, "venue": "Proc. Natl. Acad. Sci", "link": "37154915"}, "BIBREF1": {"title": "Protein aggregation, radical scavenging capacity, and stability of hydrogen peroxide defense systems in heat-stressed vinca and sweet pea leaves", "authors": [{"first": "J", "middle": ["A"], "last": "Anderson", "suffix": ""}, {"first": "S", "middle": ["R"], "last": "Padhye", "suffix": ""}], "year": 2004, "venue": "J. Am. Soc. Hortic Sci", "link": "38992076"}, "BIBREF2": {"title": "Methods for testing antioxidant activity", "authors": [{"first": "M", "middle": [], "last": "Antolovic", "suffix": ""}, {"first": "P", "middle": ["D"], "last": "Prenzler", "suffix": ""}, {"first": "E", "middle": [], "last": "Patsalides", "suffix": ""}, {"first": "S", "middle": [], "last": "Mcdonald", "suffix": ""}, {"first": "K", "middle": [], "last": "Robards", "suffix": ""}], "year": 2002, "venue": "Analyst", "link": "9804773"}, "BIBREF3": {"title": "Reactive oxygen species: metabolism, oxidative stress and signal transduction", "authors": [{"first": "K", "middle": [], "last": "Apel", "suffix": ""}, {"first": "H", "middle": [], "last": "Hirt", "suffix": ""}], "year": 2004, "venue": "Annu. Rev. Plant Biol", "link": "17229119"}, "BIBREF4": {"title": "Oxidative stress and antioxidative systems in plants", "authors": [{"first": "A", "middle": [], "last": "Arora", "suffix": ""}, {"first": "R", "middle": ["K"], "last": "Sairam", "suffix": ""}, {"first": "G", "middle": ["C"], "last": "Srivastave", "suffix": ""}], "year": 2002, "venue": "Curr. Sci", "link": null}, "BIBREF5": {"title": "Detection and activity evaluation of radical scavenging compounds by using DPPH free radical and online HPLC-DPPH methods", "authors": [{"first": "D", "middle": [], "last": "Bandoniene", "suffix": ""}, {"first": "M", "middle": [], "last": "Murkovic", "suffix": ""}, {"first": "W", "middle": [], "last": "Pfannhauser", "suffix": ""}, {"first": "P", "middle": ["R"], "last": "Venskutonis", "suffix": ""}, {"first": "D", "middle": [], "last": "Gruzdiene", "suffix": ""}], "year": 2002, "venue": "Eur. Food Res. Technol", "link": "84709618"}, "BIBREF6": {"title": "Biological actions of carotenoids", "authors": [{"first": "A", "middle": [], "last": "Bendich", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Olson", "suffix": ""}], "year": 1989, "venue": "FASEB J", "link": "22412394"}, "BIBREF8": {"title": "oxidative damage and oxygen deprivation stress: a review", "authors": [{"first": "", "middle": [], "last": "Antioxidants", "suffix": ""}], "year": 2003, "venue": "Ann. Bot", "link": null}, "BIBREF9": {"title": "Kinetics and mechanisms of antioxidant activity using the DPPH free radical method", "authors": [{"first": "V", "middle": [], "last": "Bondet", "suffix": ""}, {"first": "W", "middle": [], "last": "Brand-Williams", "suffix": ""}, {"first": "C", "middle": [], "last": "Berset", "suffix": ""}], "year": 1997, "venue": "Lebensm. Wiss. Technol", "link": "97125089"}, "BIBREF10": {"title": "Structure and properties of carotenoids in relation of function", "authors": [{"first": "G", "middle": [], "last": "Britton", "suffix": ""}], "year": 1995, "venue": "FASEB J", "link": null}, "BIBREF11": {"title": "Antioxidant defense systems: the role of carotenoids, tocopherols, and thiols", "authors": [{"first": "Di", "middle": [], "last": "Mascio", "suffix": ""}, {"first": "P", "middle": [], "last": "Murphy", "suffix": ""}, {"first": "M", "middle": ["E"], "last": "Sies", "suffix": ""}, {"first": "H", "middle": [], "last": "", "suffix": ""}], "year": 1991, "venue": "Am. J. Clin. Nutr", "link": "25974684"}, "BIBREF12": {"title": "The carotenoids as anti-oxidants -a review", "authors": [{"first": "R", "middle": [], "last": "Edge", "suffix": ""}, {"first": "D", "middle": ["J"], "last": "Mcgarvey", "suffix": ""}, {"first": "T", "middle": ["G"], "last": "Truscott", "suffix": ""}], "year": 1997, "venue": "J. Photoch. Photobio. B", "link": "2260685"}, "BIBREF13": {"title": "UV protection in cyanobacteria", "authors": [{"first": "M", "middle": [], "last": "Ehling-Schulz", "suffix": ""}, {"first": "S", "middle": [], "last": "Scherer", "suffix": ""}], "year": 1999, "venue": "Eur. J. Phycol", "link": "84654177"}, "BIBREF14": {"title": "Xanthophylls in microalgae: From Biosynthesis to biotechnological mass production and application", "authors": [{"first": "J", "middle": [], "last": "Eonseon", "suffix": ""}, {"first": "J", "middle": ["E W"], "last": "Polle", "suffix": ""}, {"first": "H", "middle": ["K"], "last": "Lee", "suffix": ""}, {"first": "S", "middle": ["M"], "last": "Hyun", "suffix": ""}, {"first": "M", "middle": [], "last": "Chang", "suffix": ""}], "year": 2003, "venue": "J. Microbiol. Biotechnol", "link": "83064829"}, "BIBREF15": {"title": "Free radicals, antioxidants, and nutrition", "authors": [{"first": "Y", "middle": ["Z"], "last": "Fang", "suffix": ""}, {"first": "S", "middle": [], "last": "Yang", "suffix": ""}, {"first": "G", "middle": [], "last": "Wu", "suffix": ""}], "year": 2002, "venue": "Nutrition", "link": "31241877"}, "BIBREF16": {"title": "Optimisation of cultural conditions and some properties of radical scavenging substances from sporobolomyces salmonicolor", "authors": [{"first": "M", "middle": ["R"], "last": "Gazi", "suffix": ""}, {"first": "K", "middle": [], "last": "Kanda", "suffix": ""}, {"first": "M", "middle": [], "last": "Yasuda", "suffix": ""}, {"first": "F", "middle": [], "last": "Kato", "suffix": ""}], "year": 2004, "venue": "Pak. J. Biol. Sci", "link": "84925379"}, "BIBREF17": {"title": "Studies of marine planktonic diatoms I. Cyclotella nana Hustedt and Detonula confervacea Cleve", "authors": [{"first": "R", "middle": ["R L"], "last": "Guillard", "suffix": ""}, {"first": "J", "middle": ["H"], "last": "Ryther", "suffix": ""}], "year": 1962, "venue": "Can. J. Microbiol", "link": "1878319"}, "BIBREF18": {"title": "Reactive oxygen species and UV-B: effect on Cyanobacteria", "authors": [{"first": "Y", "middle": ["Y"], "last": "He", "suffix": ""}, {"first": "D", "middle": ["P"], "last": "H\u00e4der", "suffix": ""}], "year": 2002, "venue": "Photochem. Photobiol. Sci", "link": "25417003"}, "BIBREF19": {"title": "Antioxidant and antiviral activities of plastoquinones from the brown alga Sargassum micracanthum, and a new chromene derivative converted from the plastoquinones", "authors": [{"first": "M", "middle": [], "last": "Iwashima", "suffix": ""}, {"first": "J", "middle": [], "last": "Mori", "suffix": ""}, {"first": "X", "middle": [], "last": "Ting", "suffix": ""}, {"first": "T", "middle": [], "last": "Matsunaga", "suffix": ""}, {"first": "K", "middle": [], "last": "Hayashi", "suffix": ""}, {"first": "D", "middle": [], "last": "Shinoda", "suffix": ""}, {"first": "H", "middle": [], "last": "Saito", "suffix": ""}, {"first": "U", "middle": [], "last": "Sankawa", "suffix": ""}, {"first": "T", "middle": [], "last": "Hayashi", "suffix": ""}], "year": 2005, "venue": "Biol. Pharm. Bull", "link": "35974371"}, "BIBREF20": {"title": "Oxidative damage and defense", "authors": [{"first": "R", "middle": ["A"], "last": "Jacob", "suffix": ""}, {"first": "B", "middle": ["J"], "last": "Burri", "suffix": ""}], "year": 1996, "venue": "Am. J. Clin. Nutr", "link": "4457486"}, "BIBREF21": {"title": "The biological properties of carotenoids", "authors": [{"first": "N", "middle": ["I"], "last": "Krinsky", "suffix": ""}], "year": 1994, "venue": "Pure & Appl. Chem", "link": "86260371"}, "BIBREF22": {"title": "Antioxidant role of astaxanthin in the green alga Haematococcus pluvialis", "authors": [{"first": "M", "middle": [], "last": "Kobayashi", "suffix": ""}, {"first": "T", "middle": [], "last": "Kakizono", "suffix": ""}, {"first": "N", "middle": [], "last": "Nishio", "suffix": ""}, {"first": "S", "middle": [], "last": "Nagai", "suffix": ""}, {"first": "Y", "middle": [], "last": "Kurimura", "suffix": ""}, {"first": "Y", "middle": [], "last": "Tsuji", "suffix": ""}], "year": 1997, "venue": "Appl. Microbiol. Biotechnol", "link": "3895246"}, "BIBREF23": {"title": "Screening of plant extracts for antioxidant activity: a comparative study on three testing methods", "authors": [{"first": "I", "middle": ["I"], "last": "Koleva", "suffix": ""}, {"first": "T", "middle": ["A"], "last": "Van Beek", "suffix": ""}, {"first": "J", "middle": ["P H"], "last": "Linssen", "suffix": ""}, {"first": "A", "middle": [], "last": "De Groot", "suffix": ""}, {"first": "L", "middle": ["N"], "last": "Evstatieva", "suffix": ""}], "year": 2001, "venue": "Phytochem. Analysis", "link": "19217081"}, "BIBREF24": {"title": "Qualitative and quantitative composition of Phaedactylum tricornutum (Bacillariophyceae) stressed by iron", "authors": [{"first": "A", "middle": [], "last": "Kosakowska", "suffix": ""}, {"first": "J", "middle": [], "last": "Lewandowska", "suffix": ""}, {"first": "J", "middle": [], "last": "Ston", "suffix": ""}, {"first": "K", "middle": [], "last": "Burkiewicz", "suffix": ""}], "year": 2004, "venue": "J. Biometals", "link": null}, "BIBREF25": {"title": "Use of different methods for testing antioxidative activity of oregano essential oil", "authors": [{"first": "T", "middle": [], "last": "Kulisic", "suffix": ""}, {"first": "A", "middle": [], "last": "Radonic", "suffix": ""}, {"first": "V", "middle": [], "last": "Katalinic", "suffix": ""}, {"first": "M", "middle": [], "last": "Milos", "suffix": ""}], "year": 2004, "venue": "Food Chem", "link": null}, "BIBREF26": {"title": "Production of ketocarotenoids by microalgae", "authors": [{"first": "P", "middle": ["Z"], "last": "Margalith", "suffix": ""}], "year": 1999, "venue": "Appl. Micorbiolol. Biotechnol", "link": "123858"}, "BIBREF27": {"title": "A photobioreactor system for computer controlled cultivation of microalgae", "authors": [{"first": "K", "middle": [], "last": "Marxen", "suffix": ""}, {"first": "K", "middle": ["H"], "last": "Vanselow", "suffix": ""}, {"first": "S", "middle": [], "last": "Lippemeier", "suffix": ""}, {"first": "R", "middle": [], "last": "Hintze", "suffix": ""}, {"first": "A", "middle": [], "last": "Ruser", "suffix": ""}, {"first": "U", "middle": ["P"], "last": "Hansen", "suffix": ""}], "year": 2005, "venue": "J. Appl. Phycol", "link": "8319124"}, "BIBREF28": {"title": "Evaluation of the antioxidant of environmental plants: activity of the leaf extracts from seashore plants", "authors": [{"first": "T", "middle": [], "last": "Masuda", "suffix": ""}, {"first": "S", "middle": [], "last": "Yonemori", "suffix": ""}, {"first": "Y", "middle": [], "last": "Oyama", "suffix": ""}, {"first": "Y", "middle": [], "last": "Takeda", "suffix": ""}, {"first": "T", "middle": [], "last": "Tanaka", "suffix": ""}, {"first": "T", "middle": [], "last": "Andoh", "suffix": ""}, {"first": "A", "middle": [], "last": "Shinohara", "suffix": ""}, {"first": "M", "middle": [], "last": "Nakata", "suffix": ""}], "year": 1999, "venue": "J. Agric. Food Chem", "link": "42288781"}, "BIBREF29": {"title": "Antioxidant activities of carotenes and xanthophylls", "authors": [{"first": "N", "middle": ["J"], "last": "Miller", "suffix": ""}, {"first": "J", "middle": [], "last": "Sampson", "suffix": ""}, {"first": "L", "middle": ["P"], "last": "Candeias", "suffix": ""}, {"first": "P", "middle": ["M"], "last": "Bramley", "suffix": ""}, {"first": "C", "middle": ["A"], "last": "Rice-Evans", "suffix": ""}], "year": 1996, "venue": "FEBS Letters", "link": "40847670"}, "BIBREF30": {"title": "The use of the stable free radical diphenylpicryl-hydrazyl (DPPH) for estimating antioxidant activity", "authors": [{"first": "P", "middle": [], "last": "Molyneux", "suffix": ""}], "year": 2004, "venue": "Songklanakarin J. Sci. Technol", "link": "44225056"}, "BIBREF31": {"title": "Antioxidant activities of astaxanthin and related carotenoids", "authors": [{"first": "Y", "middle": ["M A"], "last": "Naguib", "suffix": ""}], "year": 2000, "venue": "J. Agri. Food Chem", "link": "6005255"}, "BIBREF32": {"title": "\u00df-carotene and other carotenoids as antioxidants", "authors": [{"first": "S", "middle": ["A R"], "last": "Paiva", "suffix": ""}, {"first": "R", "middle": ["M"], "last": "Russell", "suffix": ""}], "year": 1999, "venue": "J. Am. Coll. Nutr", "link": "84590159"}, "BIBREF33": {"title": "Biosynthesis and radical scavenging activity of betalains during the cultivation of red beet (Beta vulgaris) hairy root cultures", "authors": [{"first": "A", "middle": [], "last": "Pavlov", "suffix": ""}, {"first": "P", "middle": [], "last": "Kovatcheva", "suffix": ""}, {"first": "V", "middle": [], "last": "Georgiev", "suffix": ""}, {"first": "I", "middle": [], "last": "Koleva", "suffix": ""}, {"first": "M", "middle": [], "last": "Ilieva", "suffix": ""}], "year": 2002, "venue": "Z. Naturforsch", "link": "27382899"}, "BIBREF34": {"title": "The mechanism of action of antioxidants against lipoprotein peroxidation, evaluation based on kinetic experiments", "authors": [{"first": "I", "middle": [], "last": "Pinchuk", "suffix": ""}, {"first": "D", "middle": [], "last": "Lichtenberg", "suffix": ""}], "year": 2002, "venue": "Prog. Lipid Res", "link": "31358616"}, "BIBREF35": {"title": "Standardized methods for the determination of antioxidant capacity and phenolics in foods and dietary supplements", "authors": [{"first": "R", "middle": ["L"], "last": "Prior", "suffix": ""}, {"first": "X", "middle": [], "last": "Wu", "suffix": ""}, {"first": "K", "middle": [], "last": "Schaich", "suffix": ""}], "year": 2005, "venue": "J. Agric. Food Chem", "link": "19460972"}, "BIBREF36": {"title": "Valuable products from biotechnology of microalgae", "authors": [{"first": "O", "middle": [], "last": "Pulz", "suffix": ""}, {"first": "W", "middle": [], "last": "Gross", "suffix": ""}], "year": 2004, "venue": "Appl. Microbiol. Biotechnol", "link": "42079864"}, "BIBREF37": {"title": "Generic assignments, strain histories and properties of pure cultures of cyanobacteria", "authors": [{"first": "R", "middle": [], "last": "Rippka", "suffix": ""}, {"first": "J", "middle": [], "last": "Deruelles", "suffix": ""}, {"first": "J", "middle": [], "last": "Waterbury", "suffix": ""}, {"first": "M", "middle": [], "last": "Herdman", "suffix": ""}, {"first": "R", "middle": [], "last": "Stanier", "suffix": ""}], "year": 1979, "venue": "J. Gen. Microbiol", "link": "85019329"}, "BIBREF38": {"title": "Assessment of oxidative stress in the planktonic diatom Thalassiosira pseudonana in response to UVA and UVB radiation", "authors": [{"first": "J", "middle": ["W"], "last": "Rijstenbil", "suffix": ""}], "year": 2002, "venue": "J. Plankton Res", "link": "86729477"}, "BIBREF39": {"title": "Antioxidant and antiinflammatory properties of C-phycocyanin from blue-green algae", "authors": [{"first": "C", "middle": [], "last": "Romay", "suffix": ""}, {"first": "J", "middle": [], "last": "Armesto", "suffix": ""}, {"first": "D", "middle": [], "last": "Remirez", "suffix": ""}, {"first": "R", "middle": [], "last": "Gonz\u00e1lez", "suffix": ""}, {"first": "N", "middle": [], "last": "Ledon", "suffix": ""}, {"first": "I", "middle": [], "last": "Garc\u00eda", "suffix": ""}], "year": 1998, "venue": "Inflamm. Res", "link": "672069"}, "BIBREF40": {"title": "Vitamins E and C, \u03b2-carotene, and other carotenoids as antioxidants", "authors": [{"first": "H", "middle": [], "last": "Sies", "suffix": ""}, {"first": "W", "middle": [], "last": "Stahl", "suffix": ""}], "year": 1995, "venue": "Am. J. Clin. Nutr", "link": null}, "BIBREF41": {"title": "Commercial application of microalgae", "authors": [{"first": "P", "middle": [], "last": "Spolaore", "suffix": ""}, {"first": "C", "middle": [], "last": "Joannis-Cassan", "suffix": ""}, {"first": "E", "middle": [], "last": "Duran", "suffix": ""}, {"first": "A", "middle": [], "last": "Isambert", "suffix": ""}], "year": 2006, "venue": "J. Biosci. Bioeng", "link": null}, "BIBREF42": {"title": "Nutritional antioxidants: mechanism of action, analyses of activities and medical applications", "authors": [{"first": "J", "middle": [], "last": "Vaya", "suffix": ""}, {"first": "M", "middle": [], "last": "Aviram", "suffix": ""}], "year": 2001, "venue": "Curr. Med. Chem.-Imm., Endoc. & Metab. Agents", "link": "85353888"}, "BIBREF43": {"title": "Temperature-induced changes in the fatty acid composition of the cyanobacterium, Synechocystis PCC6803", "authors": [{"first": "H", "middle": [], "last": "Wada", "suffix": ""}, {"first": "N", "middle": [], "last": "Murata", "suffix": ""}], "year": 1990, "venue": "Plant Physiol", "link": "35397946"}, "BIBREF44": {"title": "Scavenging effect of methanolic extracts of peanut hulls on free-radical and active-oxygen species", "authors": [{"first": "G", "middle": ["C"], "last": "Yen", "suffix": ""}, {"first": "P", "middle": ["D"], "last": "Duh", "suffix": ""}], "year": 1994, "venue": "J. Agric. Food Chem", "link": "84941355"}, "BIBREF45": {"title": "Growth of and omega-3 fatty acid production by Phaeodactylum tricornutum under different culture conditions", "authors": [{"first": "W", "middle": [], "last": "Yongmanitchai", "suffix": ""}, {"first": "O", "middle": ["P"], "last": "Ward", "suffix": ""}], "year": 1991, "venue": "J. Appl. Environm. Microb", "link": "8503255"}, "BIBREF46": {"title": "Quantitative spectrophotometric and EPR-determination of 1,1-diphenyl-2-picryl-hydrazyl (DPPH). Fresen", "authors": [{"first": "N", "middle": ["D"], "last": "Yordabov", "suffix": ""}, {"first": "A", "middle": ["G"], "last": "Christova", "suffix": ""}], "year": 1997, "venue": "J. Anal. Chem", "link": "95073351"}}, "ref_entries": {"FIGREF0": {"text": "Figure 1. Wavelength scans of Synechocystis sp. PCC6803. Both measuring and reference cuvette are measured against pure methanol. DPPH concentration of the measuring cuvette was 76 \u00b5mol L -1 .", "type": "figure"}, "FIGREF1": {"text": "Tocopherol was obtained from Fluka (Buchs, Switzerland). \u03b1-Tocopherol is an effective antioxidant (Vaya and Aviram 2001). 25 mg \u03b1-tocopherol was solved in 100 mL methanol (\u2248 0.58 mmol L -1 ). The solution was used for a calibration curve of DPPH reduction and as a chemical reference in comparison to the antioxidant capacities of the microalgae extracts.", "type": "figure"}, "FIGREF2": {"text": "Figure 2. Absorbance decrease of the DPPH radical measured at 550 nm for Synechocystis sp. PCC6803. The reference cuvette is filled with the same extract concentration as in the measuring cuvette, but without DPPH radicals. Open circles represent the data for using the low DPPH concentration (38 \u00b5mol L -1 ). Closed circles represent the data for using the high DPPH concentration (76 \u00b5mol L -1 ). The negative algebraic signs represent the reducing of the DPPH radical by the microalgae extract. Linear regressions calculated according to Equation (2).", "type": "figure"}, "FIGREF3": {"text": ", both curves obtained from Synechocystis sp. PCC6803 start with linear, parallel decreases at low extract concentration and end up in horizontal lines. The lower curve approaches values close to zero at approximately 3 g L -1 extract concentration. The upper curve saturates at 20 \u00b5mol L -1 DPPH concentration.", "type": "figure"}, "FIGREF4": {"text": "Figure 3. Absorbance decrease of the DPPH radical measured at 550 nm after adding \u03b1-tocopherol for Synechocystis sp. PCC6803. The reference cuvette is filled with the same extract concentration as in the measuring cuvette. Open circles represent the data obtained from low DPPH concentration (38 \u00b5mol L -1 ). Closed circles represent the data obtained from high DPPH concentration (76 \u00b5mol L -1 ).", "type": "figure"}, "FIGREF5": {"text": "Figure 4 and Figure 5 present results obtained from Isochrysis galbana. Similar to the measurements of Synechocystis sp. PCC 6803, the measurements at low and high DPPH concentrations in Figure 4 show also a linear, parallel decrease at low extract concentrations. Again, the curves obtained at both DPPH concentrations saturate at higher extract concentrations. However, in contrast to the upper curve in Figure 2, the upper curve in Figure 4 reaches values near zero. Again, adding \u03b1-tocopherol shows that the remaining absorbance in Figure 4 is due to unreduced DPPH radicals, as it decreases the absorbance to values close to zero (Figure 5). Employing extraction by methanol imposes some caveats with respect to extract concentration and kind of antioxidants. Figures 2 and 4 shows saturation of the absorbance decrease when plotted vs. extract concentration. This saturation can be explained by the limited capacity of methanol to extract the antioxidants from the aliquots of the freeze-dried microalgae. With both DPPH concentrations, the similar amounts of DPPH were oxidised in dependence of biomass concentration. The same decrease in the saturating region indicated that only the amount of antioxidants which were extracted (and not what was in the aliquots) were measured by this procedure. This effect leads to the assumption that the", "type": "figure"}, "FIGREF6": {"text": "Figure 4. Absorbance decrease of the DPPH radical measured at 550 nm for Isochrysis galbana. The reference cuvette is filled with the same extract concentration as the measuring cuvette. Open circles represent the data for using the low DPPH concentration (38 \u00b5mol L -1 ). Closed circles represent the data for using the high DPPH concentration (76 \u00b5mol L -1 ). The negative algebraic signs represent the reducing of the DPPH radical by the microalgae extract. Linear regressions calculated according to Equation (2).", "type": "figure"}, "FIGREF7": {"text": "Figure 5. Absorbance decrease of the DPPH radical measured at 550 nm after adding \u03b1-tocopherol to extracts of Isochrysis galbana. The reference cuvette is filled with the same extract concentration as in the measuring cuvette. Open circles represent the data for using the low DPPH concentration (38 \u00b5mol L -1 ). Closed circles represent the data for using the high DPPH concentration (76 \u00b5mol L -1 ).", "type": "figure"}, "FIGREF8": {"text": "2, where [DPPH] OX comes close to zero, this can only hold if k 1 /k -1 is very high, i.e., if DPPH reduction is quite irreversible. Under this condition, the maximum decrease in the absorbance signal is independent of the amount of added [DPPH] T . The amount of reduced DPPH radicals is proportional to the amount of oxidized antioxidants. These consequences verify the results ofUS is the amount of undissolved antioxidant [mol], A SOL is the amount of antioxidants initially extracted from the algae [mol], S F is the amount of free solvent [mol], n is the number of mols necessary for binding one mol antioxidants, and k 1 and k 2 are rate constants. As the system is not open, the mass of law conservation holds:T is the total amount of antioxidant [mol] and S T is the total amount of solvent [mol]. Inserting Equation (9) into Equation (", "type": "figure"}, "TABREF0": {"text": "The use of methanol as extract solvent restrict the cellular compounds responsible for scavenge the DPPH radical. Only methanolic soluble substances (like e.g. carotenoids, fatty acids) are involved in this scavenging process. Carotenoids and fatty acids are known to posses antioxidative properties (Di Mascio et al. 1991, Kobayashi et al. 1997, Fang et al. 2002).Margalith 1999, Eonseon et al. 2003, Pulz and Gross 2004,", "type": "table"}, "TABREF1": {"text": "Comparison of the slopes of the absorbance measurements, correlation coefficients and calculated EC 50 values of the different microalgae samples.", "type": "table"}, "TABREF2": {"text": "with [DPPH] OX is the amount of used DPPH radicals still in an oxidized state, A OX is the amount of antioxidants oxidized by DPPH, [A] RED is the remaining amount of reduced antioxidants in the extracts, DPPH RED is the amount of reduced DPPH radicals, and k 1 and k -1 are rate constants. Withwhere A SOL is the amount of antioxidants initially extracted from the algae and DPPH T is the total amount of added DPPH radicals, the following steady state concentrations can be calculated.For [DPPH] T values being high", "type": "table"}, "TABREF3": {"text": "for each extract. The values for both high and low DPPH concentration are presented in Table 1. The highest slope is determined for Anabaena sp. (34.45 \u00b5mol DPPH g -1 extract for a measurement starting with the high DPPH concentration and 31.74 \u00b5mol DPPH g -1 extract for a measurement starting with the low DPPH concentration) followed by Isochrysis galbana (29.51 \u00b5mol DPPH g -1 extract and 28.27 \u00b5mol DPPH g -1 extract). The difference of the slopes between Synechocystis sp. PCC6803 (19.97 \u00b5mol DPPH g -1 extract and 19.24 \u00b5mol DPPH g -1 extract) and Phaeodactylum tricornutum (20.58 \u00b5mol DPPH g -1 extract and 18.71 \u00b5mol DPPH g -1 extract) is low. A minimum slope is obtained from Porphyridium purpureum (7.26 \u00b5mol DPPH g -1 extract and 5.97 \u00b5mol DPPH g -1 extract). The calculated effective concentrations (EC 50 ) obtained from experiments like those in Figures 2 to 4 are shown in Table 1. EC 50 of Anabaena sp. is 1.103 g extract in the absorbance measurement starting with the high DPPH concentration and 0.599 g extract in the measurement starting with the low DPPH concentration. Isochrysis galbana reaches values of 1.288 g extract and 0.672 g extract, respectively. The EC 50 values of Synechocystis sp. PCC6803 (1.902 g extract and 0.988 g extract) and Phaeodactylum tricornutum (1.847 g extract and 1.016 g extract) are in the same range. Porphyridium purpureum (5.234 g extract and 3.182 g extract) reaches the highest EC 50 values.", "type": "table"}}}
{"paper_id": "2879848", "_pdf_hash": "ab92db3f612327cffd219ae8a3010610df38ebef", "abstract": [{"section": "Abstract", "text": "The vestibular system analyses angular and linear accelerations of the head that are important information for perceiving the location of one's own body in space. Vestibular stimulation and in particular galvanic vestibular stimulation (GVS) that allow a systematic modiWcation of vestibular signals has so far mainly been used to investigate vestibular inXuence on sensori-motor integration in eye movements and postural control. Comparatively, only a few behavioural and imaging studies have investigated how cognition of space and body may depend on vestibular processing. This study was designed to diVerentiate the inXuence of left versus right anodal GVS compared to sham stimulation on object-based versus egocentric mental transformations. While GVS was applied, subjects made leftright judgments about pictures of a plant or a human body presented at diVerent orientations in the roll plane. All subjects reported illusory sensations of body self-motion and/ or visual Weld motion during GVS. Response times in the mental transformation task were increased during right but not left anodal GVS for the more diYcult stimuli and the larger angles of rotation. Post-hoc analyses suggested that the interfering eVect of right anodal GVS was only present in subjects who reported having imagined turning themselves to solve the mental transformation task (egocentric transformation) as compared to those subjects having imagined turning the picture in space (object-based mental transformation). We suggest that this eVect relies on shared functional and cortical mechanisms in the posterior parietal cortex associated with both right anodal GVS and mental imagery.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "The vestibular system detects angular and linear accelerations of the head in space. Even though most previous studies on the human vestibular system focus on sensori-motor control of eye movements and posture, various studies in patients and healthy human subjects also suggest an important contribution of the vestibular system to cognitive aspects such as spatial and bodily cognition. Nevertheless, the underlying mechanisms are still largely unknown.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "Clinical evidence suggests that peripheral vestibular loss leads to deWcits in spatial cognition such as spatial navigation, learning or memory abilities Smith et al. 2005) . Thus, patients with unilateral peripheral vestibular loss suVer from deWcits in path integration during active goal-directed locomotion (Glasauer et al. 2002; Peruch et al. 2005 ) and navigation in virtual environments (Peruch et al. 1999 (Peruch et al. , 2005 suggesting that vestibular processing contributes to spatial cognition. Vestibular mechanisms have also been shown to be important for own body processing. For example a functional and anatomical relationship between spatial neglect subsequent to right hemispheric brain damage-leading to deWcits in spatial and bodily processing-and vestibular disturbances has previously been discussed (for an overview see Karnath and Dietrich 2006) . This link is supported by the fact that caloric vestibular stimulation and galvanic vestibular stimulation (GVS) may temporarily decrease symptoms of spatial neglect such as rightwards bias in visuo-spatial tasks (Cappa et al. 1987; Rode et al. 1992; Bottini et al. 2005) as well as symptoms of disturbed bodily awareness (Vallar 1998; Fink et al. 2003) . Vestibular dysfunctions have also been reported in neurological patients with disturbed own body perceptions due to damage in the temporo-parietal cortex (Devinsky et al. 1989; Blanke et al. 2004) . Direct electrical stimulation of this region may also induce out-ofbody experiences (PenWeld and Erickson 1941; Blanke et al. 2002) as well as vestibular illusions (Blanke et al. 2002; Kahane et al. 2003) at similar stimulation sites. Collectively these Wndings suggest an important vestibular contribution to spatial and bodily processing (for review see Lenggenhager et al. 2006; Lopez and Blanke 2007) .", "cite_spans": [{"start": 154, "end": 172, "text": "Smith et al. 2005)", "ref_id": "BIBREF48"}, {"start": 311, "end": 333, "text": "(Glasauer et al. 2002;", "ref_id": "BIBREF16"}, {"start": 334, "end": 352, "text": "Peruch et al. 2005", "ref_id": "BIBREF42"}, {"start": 394, "end": 413, "text": "(Peruch et al. 1999", "ref_id": "BIBREF41"}, {"start": 414, "end": 435, "text": "(Peruch et al. , 2005", "ref_id": "BIBREF42"}, {"start": 1087, "end": 1106, "text": "(Cappa et al. 1987;", "ref_id": "BIBREF8"}, {"start": 1107, "end": 1124, "text": "Rode et al. 1992;", "ref_id": "BIBREF44"}, {"start": 1125, "end": 1145, "text": "Bottini et al. 2005)", "ref_id": "BIBREF5"}, {"start": 1196, "end": 1209, "text": "(Vallar 1998;", "ref_id": "BIBREF50"}, {"start": 1210, "end": 1227, "text": "Fink et al. 2003)", "ref_id": "BIBREF12"}, {"start": 1384, "end": 1406, "text": "(Devinsky et al. 1989;", "ref_id": "BIBREF11"}, {"start": 1407, "end": 1426, "text": "Blanke et al. 2004)", "ref_id": "BIBREF2"}, {"start": 1513, "end": 1540, "text": "(PenWeld and Erickson 1941;", "ref_id": "BIBREF40"}, {"start": 1541, "end": 1560, "text": "Blanke et al. 2002)", "ref_id": "BIBREF4"}, {"start": 1593, "end": 1613, "text": "(Blanke et al. 2002;", "ref_id": "BIBREF4"}, {"start": 1614, "end": 1633, "text": "Kahane et al. 2003)", "ref_id": "BIBREF20"}, {"start": 1785, "end": 1810, "text": "Lenggenhager et al. 2006;", "ref_id": "BIBREF26"}, {"start": 1811, "end": 1833, "text": "Lopez and Blanke 2007)", "ref_id": "BIBREF28"}], "ref_spans": []}, {"section": "Introduction", "text": "Similarly, several studies have reported vestibular contributions to spatial and bodily processing in healthy subjects. Thus, it has been shown that visuo-spatial judgments such as line-bisection, visual vertical judgment and body orientation judgment Mars et al. 2005) , spatial memory (B\u00e4chtold et al. 2001) , and mental transformation (Mast and Meissner 2004; Mast et al. 2006) can be inXuenced by vestibular stimulation. Mast et al. (2006) showed that caloric vestibular stimulation leads to impaired performance in mental transformation tasks, but not in a control task using mental imagery.", "cite_spans": [{"start": 252, "end": 269, "text": "Mars et al. 2005)", "ref_id": "BIBREF32"}, {"start": 287, "end": 309, "text": "(B\u00e4chtold et al. 2001)", "ref_id": "BIBREF0"}, {"start": 338, "end": 362, "text": "(Mast and Meissner 2004;", "ref_id": "BIBREF33"}, {"start": 363, "end": 380, "text": "Mast et al. 2006)", "ref_id": "BIBREF34"}, {"start": 425, "end": 443, "text": "Mast et al. (2006)", "ref_id": "BIBREF34"}], "ref_spans": []}, {"section": "Introduction", "text": "Here we will focus on mental transformation since it is a spatial cognitive ability that may also rely on bodily processing. At least two diVerent kinds of mental transformation have initially been described, object-based mental transformation (Shepard and Metzler 1971) and egocentric mental transformation (Parsons 1987) . Only a few studies have directly investigated the inXuence of vestibular processing on either type of mental transformation (Mast et al. 2006; Mast and Meissner 2004) . Mast and colleagues (2006) showed that performance in mental transformation is generally decreased during caloric vestibular stimulation. More interestingly for the scope of the present study, they showed that in an egocentric mental transformation task performance can be modiWed in a direction-speciWc way by vestibular stimulation during physical body rotations (Mast and Meissner 2004) . In this study, subjects were more accurate when the direction of physical rotation and egocentric mental transformation were congruent, suggesting that egocentric mental transformation shares mechanisms with physical body rotation. Thus, both actual and mental body transformation seem to rely on vestibular cues. This is further corroborated by the Wnding that egocentric mental transformations (imagined sensation of body motion) may induce a direction-speciWc vestibulo-ocular reXex (Rodionov et al. 2004) and that performance in mental transformation of pictures of human bodies and body parts decreases in microgravity (Grabherr et al. 2007 ). Collectively, these data suggest that egocentric mental transformation depends partly on vestibular processing.", "cite_spans": [{"start": 244, "end": 270, "text": "(Shepard and Metzler 1971)", "ref_id": "BIBREF47"}, {"start": 308, "end": 322, "text": "(Parsons 1987)", "ref_id": "BIBREF37"}, {"start": 449, "end": 467, "text": "(Mast et al. 2006;", "ref_id": "BIBREF34"}, {"start": 468, "end": 491, "text": "Mast and Meissner 2004)", "ref_id": "BIBREF33"}, {"start": 859, "end": 883, "text": "(Mast and Meissner 2004)", "ref_id": "BIBREF33"}, {"start": 1372, "end": 1394, "text": "(Rodionov et al. 2004)", "ref_id": "BIBREF45"}, {"start": 1510, "end": 1531, "text": "(Grabherr et al. 2007", "ref_id": "BIBREF17"}], "ref_spans": []}, {"section": "Introduction", "text": "The present study was designed to investigate the eVects of GVS on mental transformations. First, we were interested whether there is an overall decrease in performance in mental transformation tasks during GVS as compared to sham stimulation. Mast et al. (2006) reported impaired performance in a mental transformation task, but not in a non-spatial control task during caloric vestibular stimulation. GVS may interact with mental transformation due to overlapping and interfering neural mechanisms between GVS and mental transformation. The comparison to sham stimulation was chosen to control for attentional eVects due to skin/pain sensation. Second, we also investigated whether the direction of the illusory body motion induced by right and left GVS inXuences diVerently clockwise and counterclockwise mental transformations. Using binaural bipolar GVS it is possible to evoke illusory body motion to the right or the left by reversing electrode polarity (Fitzpatrick and Day 2004) . Therefore, based on the results of Mast and Meissner (2004) , we hypothesized that mental transformation performance might improve when the direction of the illusory body motion and mental transformation are congruent, but deteriorate when incongruent. Third, we investigated whether object-based and egocentric mental transformations are diVerently inXuenced by GVS. Previous literature suggests that subjects tend to use an object-based mental transformation (imagined rotation of the picture in space) when pictures of non-human objects are presented, but use an egocentric perspective-based mental transformation (imagined turning of oneself in space) for pictures of human bodies (Zacks and Tversky 2005) . Based on these results and observations that egocentric perspective-based mental transformation seems to interact with vestibular processing (Rodinov et al. 2004; Mast and Meissner 2004) , we hypothesized that the eVect of GVS would be stronger for pictures representing a human body than a non-human object. Finally, we were interested whether left and right GVS would inXuence mental transformation diVerently. Fink et al. (2003) found diVerent cerebral activation patterns for left versus right GVS. During right anodal stimulation they found bilateral activations in superior temporal, posterior insular and inferior parietal regions as well as right lateral occipito-parietal activations, whereas activations during left anodal GVS were conWned to the right hemisphere only (superior temporal gyrus, posterior insular cortex, anterior inferior parietal cortex). Therefore, based on the above-mentioned assumption of common and interfering neural mechanisms we hypothesised that left and right GVS could diVerently inXuence cortical mental transformation processes.", "cite_spans": [{"start": 244, "end": 262, "text": "Mast et al. (2006)", "ref_id": "BIBREF34"}, {"start": 961, "end": 987, "text": "(Fitzpatrick and Day 2004)", "ref_id": "BIBREF13"}, {"start": 1025, "end": 1049, "text": "Mast and Meissner (2004)", "ref_id": "BIBREF33"}, {"start": 1675, "end": 1699, "text": "(Zacks and Tversky 2005)", "ref_id": "BIBREF56"}, {"start": 1865, "end": 1888, "text": "Mast and Meissner 2004)", "ref_id": "BIBREF33"}, {"start": 2115, "end": 2133, "text": "Fink et al. (2003)", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "Material and methods", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Subjects", "text": "Eleven right-handed (Edinburgh handedness inventory; OldWeld 1971) volunteers (Wve females-six males, 23.3 \u00a7 4 years) without a history of neurological, psychiatric or vestibular disorders (as veriWed by questioning) participated in this study. They all had normal or corrected-tonormal vision. Subjects had no prior experience with galvanic or caloric vestibular stimulation. Informed consent was obtained from all subjects prior to their inclusion in the study. The study protocol was approved by the local ethics research committee at the University of Lausanne and has been performed in accordance with the ethical standards laid down in the Declaration of Helsinki.", "cite_spans": [], "ref_spans": []}, {"section": "Galvanic vestibular stimulation", "text": "Galvanic vestibular stimulation (GVS) was applied using a bipolar, binaural conWguration. A stimulator (Model Grass S48, Astor-Med Inc, West Warwick, RI, USA) was used to deliver a square wave pulse through an isolation unit (Model Grass SIU5) and a constant current stimulus unit (Model Grass CCU1) to the electrodes (diameter, 10 mm; Grass Gold Electrodes). This setting provides a safe and constant current output with the anode on one side and the cathode on the other side (Fig. 1a) . For the GVS, the electrodes were placed on the left and right mastoid processes. We also introduced the principle of sham stimulation, as it is often used in transcranial magnetic stimulation (TMS) studies (George et al. 1996; Pascual-Leone et al. 1996) . The electrodes were placed on the left and right side of the neck \u00bb5 cm below the GVS electrodes. Right GVS refers to right anodal stimulation, and left GVS to left anodal stimulation. Using such a binaural bipolar conWguration, GVS is known to increase the Wring rate in vestibular aVerents on the cathodal side and to decrease the Wring rate on the anodal side (Goldberg et al. 1984) . This change in the Wring rate has been associated with illusory movements of both own body (Mars et al. 2005; Fitzpatrick et al. 2002) and visual Weld (Zink et al. 1998) .", "cite_spans": [{"start": 696, "end": 716, "text": "(George et al. 1996;", "ref_id": "BIBREF15"}, {"start": 717, "end": 743, "text": "Pascual-Leone et al. 1996)", "ref_id": "BIBREF38"}, {"start": 1225, "end": 1243, "text": "(Mars et al. 2005;", "ref_id": "BIBREF32"}, {"start": 1244, "end": 1268, "text": "Fitzpatrick et al. 2002)", "ref_id": "BIBREF14"}, {"start": 1285, "end": 1303, "text": "(Zink et al. 1998)", "ref_id": "BIBREF58"}], "ref_spans": []}, {"section": "Galvanic vestibular stimulation", "text": "The individual threshold for stimulation was determined by progressively increasing the current amplitude (step size of 0.1 mA) separately for right and left GVS as well as for sham stimulations. For GVS, the current amplitude was Wrst progressively increased until the subjects (who were na\u00efve to the eVects of GVS) reported vestibular sensations. Then, accounting for the fact that higher current amplitudes lead to stronger vestibular eVects, the amplitude was further increased to the maximal current amplitude at which skin sensations were still judged as tolerable. The mean current amplitude was 1.0 \u00a7 0.2 mA and did not diVer between right and left GVS. For the sham stimulation no vestibular sensation was elicited and thresholds were Wxed so that subjects reported approximately the same intensity of pain or heat sensation on the skin as during the GVS. The mean current was 0.6 \u00a7 0.2 mA.", "cite_spans": [], "ref_spans": []}, {"section": "Visual stimuli", "text": "All stimuli were presented on a high-resolution computer screen (1,280 \u00a3 1,024 pixels) at 1 m distance from the subject Fig. 1 Stimuli and experimental set-up. a For bipolar, binaural galvanic vestibular or sham stimulation an electrical stimulator was used to deliver a square wave pulse through an isolation unit and a constant current stimulus unit to the two output electrodes. b Object and body stimuli presented during the mental transformation task. c Each trial consisted of a 15 s galvanic stimulation. After an accommodation period of 3 s (with Wxation point), eight pictures of either the plant or the body were shown in a completely darkened and noise-isolated room. The frame of the computer screen was covered in order to narrow the visual Weld to the intended visual scene and to eliminate any horizontal and vertical reference cues.", "cite_spans": [], "ref_spans": []}, {"section": "Visual stimuli", "text": "To measure the subjective visual vertical, a white dotted line (15 cm in length subtending 8.6\u00b0 of the visual Weld) was presented on the screen. The initial position in which the line was shown was either tilted counterclockwise (two trials) or clockwise (two trials) at a randomly chosen angle (in the range of \u00a74\u00b0 with respect to the gravitational vertical).", "cite_spans": [], "ref_spans": []}, {"section": "Visual stimuli", "text": "In the mental transformation task, greyscale pictures of a plant and of a human body (seen from the back) were used (Fig. 1b) . The plant had a big leaf extended to the right or to the left alternatively while the human body showed either an extended left or right arm. Both stimuli subtended 9\u00b0 and 11.3\u00b0 of visual Weld in the horizontal and vertical directions, respectively. Matlab (Mathworks Inc., Natick, MA, USA) with Psychophysics Toolbox v2.54 (Brainard 1997; Pelli 1997 ) was used for stimulus presentation. Stimuli were presented in six diVerent orientations (0\u00b0, 60\u00b0, 120\u00b0, 180\u00b0, 240\u00b0, and 300\u00b0) in the picture plane. We chose transformation in the roll plane because GVS is known to predominantly evoke illusory motion of both body and visual Weld in the roll plane (Fitzpatrick and Day 2004) . Picture rotations of 240\u00b0 and 300\u00b0 correspond to counterclockwise rotations of 120\u00b0 and 60\u00b0, respectively.", "cite_spans": [{"start": 452, "end": 467, "text": "(Brainard 1997;", "ref_id": "BIBREF6"}, {"start": 468, "end": 478, "text": "Pelli 1997", "ref_id": "BIBREF39"}, {"start": 778, "end": 804, "text": "(Fitzpatrick and Day 2004)", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "Experimental procedures", "text": "One experimental session lasted about one hour and consisted of 4 blocks. Each block consisted of a diVerent type of stimulation (GVS with anode left or right; sham stimulation with anode left or right). The sequence of blocks varied randomly across subjects. Within each block the following procedure was used:", "cite_spans": [], "ref_spans": []}, {"section": "Experimental procedures", "text": "First, the subjective visual vertical was measured. The line was presented four times while a rectangular current of 10 s was applied. During these 10 s, subjects were asked to move the line (in 0.2\u00b0-steps) clockwise or counterclockwise by pressing a corresponding right or left keyboard button until they judged the line to be vertically oriented. After the 10 s trial ended, subjects closed their eyes until the start of the next trial to avoid any kind of visual feedback of their previous visual vertical judgment that could have inXuenced the subsequent trial.", "cite_spans": [], "ref_spans": []}, {"section": "Experimental procedures", "text": "Next, we carried out the mental transformation task (six trials with body pictures; six trials with plant pictures). During each trial, GVS was applied for 15 s (during which the visual stimuli were presented) and followed by a 10 s rest period without galvanic stimulation (Fig. 1c) . Each trial contained 8 pictures. The Wrst stimulus was presented after an accommodation phase of 3 s in each trial (see Mars et al. 2005) . Each stimulus was presented for 300 ms and a Wxation point was shown between stimuli (interstimulus interval: 1.5 s). Blocks of body and plant pictures as well as the sequence of pictures within the trial were randomized. In total, this design led to eight stimuli repetitions for each angle of each object per stimulation (total of 96 stimulus presentations per block). Subjects had to indicate with their right hand as fast and as accurately as possible if the right or left hand/leaf was extended. Response time and accuracy were collected with a response box. Two practice sessions were done at the beginning of the experiment to minimize training eVects during the diVerent blocks of the experimental session.", "cite_spans": [{"start": 406, "end": 423, "text": "Mars et al. 2005)", "ref_id": "BIBREF32"}], "ref_spans": []}, {"section": "Questionnaires", "text": "After the experimental sessions, participants Wlled out a questionnaire focused on determining the strategies they used in the mental transformation task (modiWed after Zacks and Tversky 2005) . For body and for plant pictures, subjects were asked whether they had performed an objectbased transformation (I imagined the picture turning), an egocentric transformation (I imagined myself turning), another strategy, or no strategy at all.", "cite_spans": [{"start": 169, "end": 192, "text": "Zacks and Tversky 2005)", "ref_id": "BIBREF56"}], "ref_spans": []}, {"section": "Questionnaires", "text": "Subjects were also given a detailed questionnaire that inquired about the subjective experiences during GVS (modiWed and extended after Stephan et al. 2005; MacDougall et al. 2006 , see electronic supplementary material). This questionnaire included questions about strength, direction and temporal characteristics of the illusory visual Weld and own body movements as well as the aVected body part(s) in the latter. Additionally, we asked subjects about the strength of the experienced side eVects during GVS as previously described in the literature (the questionnaire included a modiWed version of the Simulator Sickness Questionnaire of Lane and Kennedy 1988) . In total, subjects answered 65 questions.", "cite_spans": [{"start": 136, "end": 156, "text": "Stephan et al. 2005;", "ref_id": "BIBREF49"}, {"start": 157, "end": 179, "text": "MacDougall et al. 2006", "ref_id": "BIBREF31"}, {"start": 641, "end": 663, "text": "Lane and Kennedy 1988)", "ref_id": "BIBREF25"}], "ref_spans": []}, {"section": "Data acquisition and processing", "text": "The mean subjective visual vertical (in degrees) was calculated by averaging the four consecutive values for each type of stimulation and each participant.", "cite_spans": [], "ref_spans": []}, {"section": "Data acquisition and processing", "text": "For the mental transformation task, two dependent variables were measured: the error rate and the response time (in ms). Since the mean error rate over all conditions was less than 2.5%, only response times were further analysed. Response times of correct trials were analysed using repeated-measures analyses of variance (ANOVAs) with the variables Type of Stimulation (GVS, sham stimulation), Side of Stimulation (right, left), Object (body, plant), Stimulus Orientation (clockwise, counterclockwise) and Angle of Rotation (0\u00b0, 60\u00b0, 120\u00b0, 180\u00b0) as within-subject factors.", "cite_spans": [], "ref_spans": []}, {"section": "Data acquisition and processing", "text": "Supplementary ANOVAs were performed with the mental transformation Strategy (object-based transformation, egocentric transformation) used by the subjects as a betweensubject factor and the above mentioned within-subject factors. Post-hoc paired t tests were used to further analyse the signiWcant eVects on the ANOVAs. Results were considered statistically signiWcant for P < 0.05.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Subjective experiences during GVS and side eVects", "text": "All subjects reported vestibular eVects during GVS. Most subjects reported a sensation of body tilt in the roll (72%) or yaw (18%) planes, mainly felt for the head. Motion of the visual Weld was experienced either as swaying (36%), translation to a Wxed distance (36%), or rotation to a Wxed angle (55%). With respect to the temporal characteristics of the perceived body motion, subjects reported GVS sensations as continuous (36%), progressive (27%), intermittent (18%), decreasing (18%), or other (55%).", "cite_spans": [], "ref_spans": []}, {"section": "Subjective experiences during GVS and side eVects", "text": "Concerning side eVects of GVS (Table 1) , 91% of the subjects reported mild or moderate sensations of pain on the skin at the site of the anode. Frequent side eVects were general discomfort (55%), mild vertigo (55%), eyestrain (55%), blurred vision (36%), headache (36%), head fullness (36%) and diYculty concentrating (36%).", "cite_spans": [], "ref_spans": [{"start": 30, "end": 39, "text": "(Table 1)", "ref_id": "TABREF0"}]}, {"section": "Subjective visual vertical", "text": "Without stimulation, the subjective visual vertical was judged at 0.4\u00b0 \u00a7 0.9\u00b0. This was systematically changed by right (0.5\u00b0 clockwise) and left GVS (0.4\u00b0 counterclockwise, Fig. 2 ). Repeated-measures ANOVA on the visual vertical deviations showed a main eVect of the Side of Stimulation [F (1,10) = 8.4, P < 0.05] and an interaction eVect of Type of Stimulation \u00a3 Side of Stimulation [F (1,10) = 5.7, P < 0.05] indicating that the diVerent types of stimulation inXuenced the perceived visual vertical diVerently as function of the stimulated side. Detailed analyses showed that right GVS caused a signiWcant tilt of the perceived visual vertical towards the anode (clockwise tilt) compared to the right sham stimulation (t = 3.13, P < 0.05) as well as to the condition without stimulation (t = 3.07, P < 0.05). Finally, right and left sham stimulations did not signiWcantly inXuence the perception of the visual vertical.", "cite_spans": [], "ref_spans": [{"start": 174, "end": 180, "text": "Fig. 2", "ref_id": "FIGREF2"}]}, {"section": "Performances in the mental transformation tasks", "text": "To test our hypotheses we Wrst employed a Wve-way ANOVA with the within-subject factors Type of Stimulation (GVS, sham stimulation), Side of Stimulation (left, right), Object (human, plant), Stimulus Orientation (clockwise, counterclockwise) and Angle of Rotation (60\u00b0, 120\u00b0).", "cite_spans": [], "ref_spans": []}, {"section": "1", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "InXuence of the angle of stimuli rotation", "text": "We found a signiWcant eVect of Angle of rotation [F (1,10) = 83.82, P < 0.001] showing longer response times for 120\u00b0c ompared to 60\u00b0 rotations. No main eVect of Stimulus Orientation was observed suggesting symmetrical response times for clockwise and counterclockwise rotations [F (1,10) = 3.00, P = 0.12]. The main eVect of the Angle of Rotation remained highly signiWcant when all six angles were taken 1 The upright (0\u00b0) and the upside-down conditions (180\u00b0) were not included in this Wrst ANOVA since they cannot be assigned to either a clockwise or counterclockwise Stimulus Orientation and subjects reported having used other strategies than mental rotation for the 180\u00b0angle (see below). into account [F (1,10) = 81.18, P < 0.001] (Fig. 3) . The mental rotation rates were 653\u00b0/s for bodies and 680\u00b0/s for objects which are similar to previously reported rates for mental transformation tasks (Cooper 1975 ).", "cite_spans": [{"start": 901, "end": 913, "text": "(Cooper 1975", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "InXuence of the object presented", "text": "Our data indicate that mental transformation of the plant (mean response time: 553 \u00a7 50 ms) was more diYcult than mental transformation of the body [538 \u00a7 49 ms; F (1,10) = 31.21, P < 0.001]. This is also in agreement with results of our questionnaire, showing that 55% of the subjects considered mental transformation of the plant more diYcult than that of the body while only 18% reported the opposite. Fig. 4b ]. Together, these data suggest that only the right GVS interferes with mental transformation and that this eVect is observed only for the most diYcult object (plant) and angle of rotation (120\u00b0).", "cite_spans": [], "ref_spans": [{"start": 405, "end": 412, "text": "Fig. 4b", "ref_id": "FIGREF1"}]}, {"section": "InXuence of the type and side of stimulation", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "InXuence of the mental transformation strategy", "text": "As vestibular processing has been linked to egocentric-perspective changes and our subjects showed individual diVerences with respect to the strategy that was employed for mental transformation, we also tested whether interference of GVS with mental transformation diVered in subjects employing an egocentric mental transformation than in subjects employing an object-based mental transformation. In the questionnaire on mental transformation strategies 55% of the subjects (n = 6) described that they performed an object-based mental transformation (imagined turning of the image) for pictures of body and plant. The remaining subjects (n = 5) reported an egocentric mental transformation (imagined turning of themselves). All subjects reported having used the same strategy for the pictures of the body and the plant. In addition, 45% of the subjects (n = 5) reported spontaneous use of a diVerent strategy for pictures presented upside-down (180\u00b0) than for the other angles by just mirroring the body/plant in respect to the median vertical axis of the picture and pressing on the left button if the arm/leaf was on the right, and vice-versa. We thus analyzed the performance of both subpopulations of subjects by including Strategy as a between-subject factor in the above-described ANOVAs. For right GVS, we found a signiWcant interaction Strategy \u00a3 Type of stimulation [F (1,9) = 7.10, P < 0.05] for pictures of plant (Fig. 5) , and a trend for pictures of body [F (1,9) = 4.10, P = 0.074]. Post-hoc analyses suggest that the described interfering eVect of right GVS on the mental transformation exists mainly in subjects employing an egocentric mental transformation strategy because only this subpopulation showed a signiWcant diVerence between GVS and sham stimulation (t = 2.9, P < 0.05, compared to t = 0.6, P = 0.55).", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "This study investigated the inXuence of vestibular processing and illusory own body motion on mental transformation. Performance in mental transformation tasks during GVS were compared to performance during sham stimulation (a control condition for attentional inXuence). We tested whether there is an eVect of right versus left GVS on mental transformation, whether a diVerent inXuence of GVS exists for egocentric versus object-based mental transformation, and whether speciWc directional eVects exist when the direction of illusory self-motion and mental transformation are congruent.", "cite_spans": [], "ref_spans": []}, {"section": "General inXuence of galvanic vestibular stimulation versus sham stimulation", "text": "Our data show increased response times for objects presented at larger angles of rotation when applying right anodal GVS. We could not observe the directional eVects of GVS on mental transformation as reported by Mast and Meissner (2004) . This speaks for a more general eVect of GVS on mental transformation due to overlapping and interfering cortical networks. A similar decrease in performance due to vestibular-spatial interaction eVects has been found in other studies that used vestibular stimulation in combination with speciWc cognitive tasks Mars et al. 2005) . Brain imaging studies suggest that areas in the posterior parietal cortex involved in mental transformation (Kosslyn et al. 1998; Zacks et al. 1999) are also activated during GVS-induced illusory body motion (Lobel et al. 1998; Stephan et al. 2005) . Therefore, GVS activation of these areas presumably interferes and impairs mental transformation, corroborating Wndings of Mast et al. (2006) who showed that caloric vestibular stimulation had a disruptive eVect on mental transformation but not on a cognitive control task not involving spatial imagery.", "cite_spans": [{"start": 213, "end": 237, "text": "Mast and Meissner (2004)", "ref_id": "BIBREF33"}, {"start": 551, "end": 568, "text": "Mars et al. 2005)", "ref_id": "BIBREF32"}, {"start": 679, "end": 700, "text": "(Kosslyn et al. 1998;", "ref_id": "BIBREF22"}, {"start": 701, "end": 719, "text": "Zacks et al. 1999)", "ref_id": "BIBREF57"}, {"start": 779, "end": 798, "text": "(Lobel et al. 1998;", "ref_id": "BIBREF27"}, {"start": 799, "end": 819, "text": "Stephan et al. 2005)", "ref_id": "BIBREF49"}, {"start": 945, "end": 963, "text": "Mast et al. (2006)", "ref_id": "BIBREF34"}], "ref_spans": []}, {"section": "InXuence of the mental transformation strategy", "text": "Our data suggest that the disturbing eVects of GVS are only present in subjects who performed egocentric mental transformation and not object-based mental transformation. This suggests that mental transformation simulates the properties of physical egocentric transformation, since real body movements involve vestibular processes whereas physical object transformation does not. The results are in line with previous observations showing that egocentric mental transformation is inXuenced by actual vestibular stimula- Fig. 4 InXuence of the side of stimulation. The histograms show the mean response time in milliseconds ( \u00a7standard error to the mean, vertical bars) for the plant presented at 60\u00b0 and 120\u00b0 (averaged over clockwise and counterclockwise stimuli) during (a) right and (b) left anodal galvanic vestibular stimulation compared to right and left sham stimulation tion during physical body rotations (Mast and Meissner 2004) and that egocentric mental transformation inXuences vestibulo-ocular functions (Rodinov et al. 2004) . DiVering from earlier Wndings (Parsons 1987; Zacks and Tversky 2005) , the strategy our subjects used did not depend on the visually presented stimuli (plant or human body). Our subjects indicated the use of either an object-based mental transformation (55%) or an egocentric perspective-based mental transformation (45%) for both types of pictures. This suggests that mental transformation depends more on idiosyncratic selection of a strategy involving either egocentric or allocentric references, thereby corroborating evidence from studies on spatial navigation (Wraga et al. 2005) and theories of vicarious processing in spatial cognition (Ohlmann and Marendaz 1991) .", "cite_spans": [{"start": 913, "end": 937, "text": "(Mast and Meissner 2004)", "ref_id": "BIBREF33"}, {"start": 1071, "end": 1085, "text": "(Parsons 1987;", "ref_id": "BIBREF37"}, {"start": 1086, "end": 1109, "text": "Zacks and Tversky 2005)", "ref_id": "BIBREF56"}, {"start": 1607, "end": 1626, "text": "(Wraga et al. 2005)", "ref_id": "BIBREF54"}, {"start": 1685, "end": 1712, "text": "(Ohlmann and Marendaz 1991)", "ref_id": "BIBREF35"}], "ref_spans": [{"start": 520, "end": 526, "text": "Fig. 4", "ref_id": "FIGREF1"}]}, {"section": "InXuence of the mental transformation strategy", "text": "What are the anatomical substrates of speciWc interactions between GVS and egocentric mental transformation? Several neuroimaging studies in healthy subjects have shown that cerebral activations associated with egocentric and object-based strategies can be diVerentiated during spatial navigation (Jordan et al. 2002; Hartley et al. 2003) and mental transformation (Zacks and Tversky 2005) . The exact anatomical location of these mental transformation processes is still controversial and seems to depend on additional variables such as sex, handedness, task diYculty and the control task (Kosslyn et al. 1998; Jordan et al. 2002) . Nevertheless, as described in a meta-analysis by Zacks and Michelon (2005) , object-based transformation would rely predominantly on unilateral right fronto-parietal cortex, while egocentric transformation would involve a more bilateral network (temporo-parieto-occipital junction; superior parietal lobule) with either right or left hemispheric predominance (Vallar et al. 1999; Zacks et al. 1999; Creem et al. 2001; Vogeley and Fink 2003; Blanke et al. 2005) . Thus, the more bilateral cortical network activated by right GVS (see below) may interfere more strongly with mental transformation employing egocentric transformation.", "cite_spans": [{"start": 297, "end": 317, "text": "(Jordan et al. 2002;", "ref_id": "BIBREF19"}, {"start": 318, "end": 338, "text": "Hartley et al. 2003)", "ref_id": "BIBREF18"}, {"start": 365, "end": 389, "text": "(Zacks and Tversky 2005)", "ref_id": "BIBREF56"}, {"start": 590, "end": 611, "text": "(Kosslyn et al. 1998;", "ref_id": "BIBREF22"}, {"start": 612, "end": 631, "text": "Jordan et al. 2002)", "ref_id": "BIBREF19"}, {"start": 683, "end": 708, "text": "Zacks and Michelon (2005)", "ref_id": "BIBREF55"}, {"start": 993, "end": 1013, "text": "(Vallar et al. 1999;", "ref_id": "BIBREF51"}, {"start": 1014, "end": 1032, "text": "Zacks et al. 1999;", "ref_id": "BIBREF57"}, {"start": 1033, "end": 1051, "text": "Creem et al. 2001;", "ref_id": "BIBREF10"}, {"start": 1052, "end": 1074, "text": "Vogeley and Fink 2003;", "ref_id": "BIBREF53"}, {"start": 1075, "end": 1094, "text": "Blanke et al. 2005)", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "DiVerences between right and left galvanic vestibular stimulations", "text": "The results of this study indicate that only the right GVS interfered with mental transformation. This Wnding was further conWrmed by the eVects on the subjective visual vertical (only right GVS led to a signiWcant deviation, see below). This selective eVect was not due to diVerent current amplitudes applied during right versus left GVS. We therefore suggest that either a functional asymmetry of the peripheral vestibular apparatus exists or, more likely, a set of common neural mechanisms between right GVS and mental transformation exists that may be responsible for this eVect.", "cite_spans": [], "ref_spans": []}, {"section": "DiVerences between right and left galvanic vestibular stimulations", "text": "Concerning the functional asymmetry of the peripheral vestibular system, several studies have suggested asymmetrical eVects of left and right GVS even on basic parameters such as eye movements and postural control (Quark et al. 1998; Bent et al. 2000) . However, the data on such peripheral asymmetries are contradictory, with some authors reporting a dominance of the left (Lacour et al. 1974) , some the right (Quark et al. 1998) vestibular apparatus, or even a symmetrical sensitivity for both ears (Zink et al. 1998) .", "cite_spans": [{"start": 234, "end": 251, "text": "Bent et al. 2000)", "ref_id": "BIBREF1"}, {"start": 374, "end": 394, "text": "(Lacour et al. 1974)", "ref_id": "BIBREF23"}, {"start": 502, "end": 520, "text": "(Zink et al. 1998)", "ref_id": "BIBREF58"}], "ref_spans": []}, {"section": "DiVerences between right and left galvanic vestibular stimulations", "text": "With respect to the hypothesis of a set of common neural mechanisms between right GVS and mental transformation, our result may be due to more extensive overlap and interference of brain regions activated by right GVS (as opposed to left) with brain regions involved in mental transformation. In an fMRI study, Fink et al. (2003) compared the cortical activation associated with right versus left GVS using a similar stimulation protocol as in the present study. Fig. 5 InXuence of the mental transformation strategy. The histograms show the mean response time in milliseconds ( \u00a7standard error to the mean, vertical bars) for the plant presented at 60\u00b0 and 120\u00b0( averaged over clockwise and counterclockwise stimuli) for subjects using (a) an object-based versus (b) an egocentric mental transformation strategy These authors found that right anodal GVS involved a bilateral hemispheric activation of the superior temporal gyrus, posterior insula, anterior inferior parietal cortex, as well as right lateral occipito-parietal activation, whereas activations during left anodal GVS were conWned to the right hemisphere only (superior temporal gyrus, posterior insula, anterior inferior parietal cortex). As mental transformation has been shown to rely on bilateral parietal and temporooccipital activations (bodies: Zacks et al. 1999; Creem et al. 2001; Blanke et al. 2005 , objects: Kosslyn et al. 1998 Vingerhoets et al. 2001) , we speculate that bilateral activations due to right GVS interfere more strongly with bilateral activations during mental transformation in superior temporal gyrus, posterior insula, and inferior parietal cortex. Interference of right GVS at these sites might thus lead to the observed decrease in task performance.", "cite_spans": [{"start": 311, "end": 329, "text": "Fink et al. (2003)", "ref_id": "BIBREF12"}, {"start": 1316, "end": 1334, "text": "Zacks et al. 1999;", "ref_id": "BIBREF57"}, {"start": 1335, "end": 1353, "text": "Creem et al. 2001;", "ref_id": "BIBREF10"}, {"start": 1354, "end": 1372, "text": "Blanke et al. 2005", "ref_id": "BIBREF3"}, {"start": 1404, "end": 1428, "text": "Vingerhoets et al. 2001)", "ref_id": "BIBREF52"}], "ref_spans": []}, {"section": "DiVerences between right and left galvanic vestibular stimulations", "text": "The diVerential eVects between left and right GVS on mental transformations in the present study were conWrmed by the results of the visual vertical judgments. Only right anodal GVS inXuenced the perception of the vertical signiWcantly, evidenced by a clockwise deviation of the subjective visual vertical. Given that the amplitude of the visual vertical deviation depends on current intensity (Mars et al. 2005) , and that we used small current amplitudes compared to previous studies, our values appear to be consistent with that of previous Wndings (Zink et al. 1998; Mars et al. 2005) . A signiWcantly stronger inXuence of right GVS on the subjective visual vertical has also been reported in patients with right parietal damage (Saj et al. 2006) . Moreover, the brain regions involved in the visual vertical judgment [a bilateral frontoparieto-occipital network including inferior frontal cortex, anterior insula and posterior parietal cortex (Lopez et al. 2005) ] would be more aVected by right than left GVS.", "cite_spans": [{"start": 394, "end": 412, "text": "(Mars et al. 2005)", "ref_id": "BIBREF32"}, {"start": 552, "end": 570, "text": "(Zink et al. 1998;", "ref_id": "BIBREF58"}, {"start": 571, "end": 588, "text": "Mars et al. 2005)", "ref_id": "BIBREF32"}, {"start": 733, "end": 750, "text": "(Saj et al. 2006)", "ref_id": "BIBREF46"}, {"start": 948, "end": 967, "text": "(Lopez et al. 2005)", "ref_id": "BIBREF29"}], "ref_spans": []}, {"section": "Limitations", "text": "While this study revealed disruptive eVects of GVS on mental transformation, the eVects were rather small and speciWc. We believe that this is mainly due to the low intensity and heterogeneous eVects of GVS and/or due to a too low task diYculty (error rate smaller than 2.5%). The large number of stimulus repetitions required the use of a relatively weak mean current of about 1 mA, probably resulting in a reduced strength of overall illusory body motion. The two previous studies that showed vestibular inXuence on mental transformation used actual body rotation (Mast and Meissner 2004) or caloric vestibular stimulation (Mast et al. 2006) , both of which yielded stronger vestibular sensations. Additionally, important inter-individual diVerences in the direction, amplitude and temporal characteristics of the illusory movements due to GVS were reported. MacDougall et al. (2002) suggested that these diVerences result from the unnatural stimulation of all semicircular and otolith organs simultaneously and from individual diVerences in the interpretation of these uncommon vestibular stimuli. The fact that not all subjects reported illusory movement could also account for the lack of direction-speciWc eVects in this study. This is further confounded by the fact that subjects used diVerent mental rotation strategies, and that the direction of the mental transformation diVered across subjects. For example, for a stimulus angle of 60\u00b0 clockwise, subjects using an egocentric strategy would imagine turning their body rightwards while subjects using an object-based transformation would imagine turning the picture leftwards.", "cite_spans": [{"start": 566, "end": 590, "text": "(Mast and Meissner 2004)", "ref_id": "BIBREF33"}, {"start": 625, "end": 643, "text": "(Mast et al. 2006)", "ref_id": "BIBREF34"}, {"start": 861, "end": 885, "text": "MacDougall et al. (2002)", "ref_id": "BIBREF30"}], "ref_spans": []}, {"section": "Conclusion", "text": "Although the interaction between GVS and mental transformation was not as strong as assumed based on previous literature, this study reveals novel results concerning the contribution of the vestibular system to high level spatial and bodily processing. The results suggest that GVS may impair demanding mental transformation tasks. This is mainly true for right GVS and for egocentric mental transformation, suggesting a shared neural processing in the posterior parietal cortex.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusion", "text": "Based on these results several implications for further studies can be derived: Studies on the eVects of GVS and bodily and spatial processing should consider sham stimulation as it is routinely used in transcranial magnetic stimulation studies. Task complexity should generally be high enough in order to observe potential GVS eVects, and these eVects should further be investigated by systematically manipulating task diYculty. Since we found diVerences between left and right GVS, future studies should also investigate GVS over both mastoids separately. Moreover, for mental transformation tasks it would be interesting to assess and manipulate mental transformation strategies, since they seem to rely on diVerent neural processes. Finally, to test our hypothesis of a shared brain mechanism between right GVS and mental transformation it would be important to combine neuroimaging with GVS as done previously to demonstrate this common neural substrate between GVS and line bisection .", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Spatial-and verbal-memory improvement by cold-water caloric stimulation in healthy subjects", "authors": [{"first": "D", "middle": [], "last": "B\u00e4chtold", "suffix": ""}, {"first": "T", "middle": [], "last": "Baumann", "suffix": ""}, {"first": "P", "middle": ["S"], "last": "Sandor", "suffix": ""}, {"first": "M", "middle": [], "last": "Kritos", "suffix": ""}, {"first": "M", "middle": [], "last": "Regard", "suffix": ""}, {"first": "P", "middle": [], "last": "Brugger", "suffix": ""}], "year": 2001, "venue": "Exp Brain Res", "link": "23940976"}, "BIBREF1": {"title": "Magnitude eVects of galvanic vestibular stimulation on the trajectory of human gait", "authors": [{"first": "L", "middle": ["R"], "last": "Bent", "suffix": ""}, {"first": "B", "middle": ["J"], "last": "Mcfadyen", "suffix": ""}, {"first": "V", "middle": ["F"], "last": "Merkley", "suffix": ""}, {"first": "P", "middle": ["M"], "last": "Kennedy", "suffix": ""}, {"first": "J", "middle": ["T"], "last": "Inglis", "suffix": ""}], "year": 2000, "venue": "Neurosci Lett", "link": null}, "BIBREF2": {"title": "Out-of-body experience and autoscopy of neurological origin", "authors": [{"first": "O", "middle": [], "last": "Blanke", "suffix": ""}, {"first": "T", "middle": [], "last": "Landis", "suffix": ""}, {"first": "L", "middle": [], "last": "Spinelli", "suffix": ""}, {"first": "M", "middle": [], "last": "Seeck", "suffix": ""}], "year": 2004, "venue": "Brain", "link": "12047198"}, "BIBREF3": {"title": "Linking out-of-body experience and self processing to mental own-body imagery at the temporoparietal junction", "authors": [{"first": "O", "middle": [], "last": "Blanke", "suffix": ""}, {"first": "C", "middle": [], "last": "Mohr", "suffix": ""}, {"first": "C", "middle": ["M"], "last": "Michel", "suffix": ""}, {"first": "A", "middle": [], "last": "Pascual-Leone", "suffix": ""}, {"first": "P", "middle": [], "last": "Brugger", "suffix": ""}, {"first": "M", "middle": [], "last": "Seeck", "suffix": ""}, {"first": "T", "middle": [], "last": "Landis", "suffix": ""}, {"first": "G", "middle": [], "last": "Thut", "suffix": ""}], "year": 2005, "venue": "J Neurosci", "link": null}, "BIBREF4": {"title": "Stimulating illusory own-body perceptions", "authors": [{"first": "O", "middle": [], "last": "Blanke", "suffix": ""}, {"first": "S", "middle": [], "last": "Ortigue", "suffix": ""}, {"first": "T", "middle": [], "last": "Landis", "suffix": ""}, {"first": "M", "middle": [], "last": "Seeck", "suffix": ""}], "year": 2002, "venue": "Nature", "link": null}, "BIBREF5": {"title": "Left caloric vestibular stimulation ameliorates right hemianesthesia", "authors": [{"first": "G", "middle": [], "last": "Bottini", "suffix": ""}, {"first": "E", "middle": [], "last": "Paulesu", "suffix": ""}, {"first": "M", "middle": [], "last": "Gandola", "suffix": ""}, {"first": "S", "middle": [], "last": "Lovredo", "suffix": ""}, {"first": "P", "middle": [], "last": "Scarpa", "suffix": ""}, {"first": "R", "middle": [], "last": "Sterzi", "suffix": ""}, {"first": "I", "middle": [], "last": "Santilli", "suffix": ""}, {"first": "C", "middle": ["A"], "last": "Defanti", "suffix": ""}, {"first": "G", "middle": [], "last": "Scialfa", "suffix": ""}, {"first": "F", "middle": [], "last": "Fazio", "suffix": ""}, {"first": "G", "middle": [], "last": "Vallar", "suffix": ""}], "year": 2005, "venue": "Neurology", "link": "44694652"}, "BIBREF6": {"title": "The psychophysics toolbox", "authors": [{"first": "D", "middle": ["H"], "last": "Brainard", "suffix": ""}], "year": 1997, "venue": "Spatial Vision", "link": "27687210"}, "BIBREF7": {"title": "Vestibular loss causes hippocampal atrophy and impaired spatial memory in humans", "authors": [{"first": "T", "middle": [], "last": "Brandt", "suffix": ""}, {"first": "F", "middle": [], "last": "Schautzer", "suffix": ""}, {"first": "D", "middle": ["A"], "last": "Hamilton", "suffix": ""}, {"first": "R", "middle": [], "last": "Bruning", "suffix": ""}, {"first": "H", "middle": ["J"], "last": "Markowitsch", "suffix": ""}, {"first": "R", "middle": [], "last": "Kalla", "suffix": ""}, {"first": "C", "middle": [], "last": "Darlington", "suffix": ""}, {"first": "P", "middle": [], "last": "Smith", "suffix": ""}, {"first": "M", "middle": [], "last": "Strupp", "suffix": ""}], "year": 2005, "venue": "Brain", "link": null}, "BIBREF8": {"title": "Remission of hemineglect and anosognosia during vestibular stimulation", "authors": [{"first": "S", "middle": [], "last": "Cappa", "suffix": ""}, {"first": "R", "middle": [], "last": "Sterzi", "suffix": ""}, {"first": "G", "middle": [], "last": "Vallar", "suffix": ""}, {"first": "E", "middle": [], "last": "Bisiach", "suffix": ""}], "year": 1987, "venue": "Neuropsychologia", "link": "17677272"}, "BIBREF9": {"title": "Mental rotation of random two-dimensional shapes", "authors": [{"first": "L", "middle": [], "last": "Cooper", "suffix": ""}], "year": 1975, "venue": "Cogn Psychol", "link": "12557925"}, "BIBREF10": {"title": "An fMRI study of imagined self-rotation", "authors": [{"first": "S", "middle": ["H"], "last": "Creem", "suffix": ""}, {"first": "T", "middle": ["H"], "last": "Downs", "suffix": ""}, {"first": "M", "middle": [], "last": "Wraga", "suffix": ""}, {"first": "G", "middle": ["S"], "last": "Harrington", "suffix": ""}, {"first": "D", "middle": ["R"], "last": "Proytt", "suffix": ""}, {"first": "J", "middle": ["H"], "last": "Downs", "suffix": ""}], "year": 2001, "venue": "Cogn AVect Behav Neurosci", "link": "7975788"}, "BIBREF11": {"title": "Autoscopic phenomena with seizures", "authors": [{"first": "O", "middle": [], "last": "Devinsky", "suffix": ""}, {"first": "E", "middle": [], "last": "Feldmann", "suffix": ""}, {"first": "K", "middle": [], "last": "Burrowes", "suffix": ""}, {"first": "E", "middle": [], "last": "Bromweld", "suffix": ""}], "year": 1989, "venue": "Arch Neurol", "link": "42780537"}, "BIBREF12": {"title": "Performing allocentric visuospatial judgments with induced distortion of the egocentric reference frame: an fMRI study with clinical implications", "authors": [{"first": "G", "middle": ["R"], "last": "Fink", "suffix": ""}, {"first": "J", "middle": ["C"], "last": "Marshall", "suffix": ""}, {"first": "P", "middle": ["H"], "last": "Weiss", "suffix": ""}, {"first": "T", "middle": [], "last": "Stephan", "suffix": ""}, {"first": "C", "middle": [], "last": "Grefkes", "suffix": ""}, {"first": "N", "middle": ["J"], "last": "Shah", "suffix": ""}, {"first": "K", "middle": [], "last": "Zilles", "suffix": ""}, {"first": "M", "middle": [], "last": "Dieterich", "suffix": ""}], "year": 2003, "venue": "Neuroimage", "link": "23603050"}, "BIBREF13": {"title": "Probing the human vestibular system with galvanic stimulation", "authors": [{"first": "R", "middle": ["C"], "last": "Fitzpatrick", "suffix": ""}, {"first": "B", "middle": ["L"], "last": "Day", "suffix": ""}], "year": 2004, "venue": "J Appl Physiol", "link": "8441435"}, "BIBREF14": {"title": "Galvanic vestibular stimulation evokes sensations of body rotation", "authors": [{"first": "R", "middle": ["C"], "last": "Fitzpatrick", "suffix": ""}, {"first": "J", "middle": [], "last": "Marsden", "suffix": ""}, {"first": "S", "middle": ["R"], "last": "Lord", "suffix": ""}, {"first": "B", "middle": ["L"], "last": "Day", "suffix": ""}], "year": 2002, "venue": "Neuroreport", "link": "32077072"}, "BIBREF15": {"title": "Transcranial magnetic stimulation: a neuropsychiatric tool for the 21st century", "authors": [{"first": "M", "middle": ["S"], "last": "George", "suffix": ""}, {"first": "E", "middle": ["M"], "last": "Wassermann", "suffix": ""}, {"first": "R", "middle": ["M"], "last": "Post", "suffix": ""}], "year": 1996, "venue": "J Neuropsychiatry Clin Neurosci", "link": "7959793"}, "BIBREF16": {"title": "DiVerential eVects of labyrinthine dysfunction on distance and direction during blindfolded walking of a triangular path", "authors": [{"first": "S", "middle": [], "last": "Glasauer", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Amorim", "suffix": ""}, {"first": "I", "middle": [], "last": "Viaud-Delmon", "suffix": ""}, {"first": "A", "middle": [], "last": "Berthoz", "suffix": ""}], "year": 2002, "venue": "Exp Brain Res", "link": null}, "BIBREF17": {"title": "Mental transformations of bodies and body-parts in microgravity", "authors": [{"first": "L", "middle": [], "last": "Grabherr", "suffix": ""}, {"first": "S", "middle": [], "last": "Bach", "suffix": ""}, {"first": "K", "middle": [], "last": "Indermaur", "suffix": ""}, {"first": "S", "middle": [], "last": "Metzler", "suffix": ""}, {"first": "F", "middle": [], "last": "Mast", "suffix": ""}], "year": 2007, "venue": "J Vest Res", "link": null}, "BIBREF18": {"title": "The well-worn route and the path less traveled: distinct neural bases of route following and wayWnding in humans", "authors": [{"first": "T", "middle": [], "last": "Hartley", "suffix": ""}, {"first": "E", "middle": ["A"], "last": "Maguire", "suffix": ""}, {"first": "H", "middle": ["J"], "last": "Spiers", "suffix": ""}, {"first": "N", "middle": [], "last": "Burgess", "suffix": ""}], "year": 2003, "venue": "Neuron", "link": "9734714"}, "BIBREF19": {"title": "Women and men exhibit diVerent cortical activation patterns during mental rotation tasks", "authors": [{"first": "K", "middle": [], "last": "Jordan", "suffix": ""}, {"first": "T", "middle": [], "last": "Wustenberg", "suffix": ""}, {"first": "H", "middle": ["J"], "last": "Heinze", "suffix": ""}, {"first": "M", "middle": [], "last": "Peters", "suffix": ""}, {"first": "L", "middle": [], "last": "Jancke", "suffix": ""}], "year": 2002, "venue": "Neuropsychologia", "link": null}, "BIBREF20": {"title": "Reappraisal of the human vestibular cortex by cortical electrical stimulation study", "authors": [{"first": "P", "middle": [], "last": "Kahane", "suffix": ""}, {"first": "D", "middle": [], "last": "Hovmann", "suffix": ""}, {"first": "L", "middle": [], "last": "Minotti", "suffix": ""}, {"first": "A", "middle": [], "last": "Berthoz", "suffix": ""}], "year": 2003, "venue": "Ann Neurol", "link": null}, "BIBREF21": {"title": "Spatial neglect-a vestibular disorder", "authors": [{"first": "H", "middle": ["O"], "last": "Karnath", "suffix": ""}, {"first": "M", "middle": [], "last": "Dieterich", "suffix": ""}], "year": 2006, "venue": "Brain", "link": "17646707"}, "BIBREF22": {"title": "Mental rotation of objects versus hands: neural mechanisms revealed by positron emission tomography", "authors": [{"first": "S", "middle": ["M"], "last": "Kosslyn", "suffix": ""}, {"first": "G", "middle": ["J"], "last": "Digirolamo", "suffix": ""}, {"first": "W", "middle": ["L"], "last": "Thompson", "suffix": ""}, {"first": "N", "middle": ["M"], "last": "Alpert", "suffix": ""}], "year": 1998, "venue": "Psychophysiology", "link": "23825409"}, "BIBREF23": {"title": "Spinal eVects of electric vestibular stimulation in man. Demonstrated evidence of vestibular prevalence and role in motion laterality", "authors": [{"first": "M", "middle": [], "last": "Lacour", "suffix": ""}, {"first": "M", "middle": [], "last": "Bonnet", "suffix": ""}, {"first": "J", "middle": ["P"], "last": "Roll", "suffix": ""}], "year": 1974, "venue": "", "link": "42930572"}, "BIBREF25": {"title": "A new method for quantifying simulator sickness: development and application of the simulator sickness questionnaire (SSQ)", "authors": [{"first": "N", "middle": ["E"], "last": "Lane", "suffix": ""}, {"first": "", "middle": [], "last": "Kennedy", "suffix": ""}, {"first": "", "middle": [], "last": "Rs", "suffix": ""}], "year": 1988, "venue": "", "link": null}, "BIBREF26": {"title": "Functional and neural mechanisms of embodiment: Importance of the vestibular system and the temporal parietal junction", "authors": [{"first": "B", "middle": [], "last": "Lenggenhager", "suffix": ""}, {"first": "S", "middle": [], "last": "Smith", "suffix": ""}, {"first": "O", "middle": [], "last": "Blanke", "suffix": ""}], "year": 2006, "venue": "Rev Neurosci", "link": "8369966"}, "BIBREF27": {"title": "Functional MRI of galvanic vestibular stimulation", "authors": [{"first": "E", "middle": [], "last": "Lobel", "suffix": ""}, {"first": "J", "middle": ["F"], "last": "Kleine", "suffix": ""}, {"first": "D", "middle": ["L"], "last": "Bihan", "suffix": ""}, {"first": "A", "middle": [], "last": "Leroy-Willig", "suffix": ""}, {"first": "A", "middle": [], "last": "Berthoz", "suffix": ""}], "year": 1998, "venue": "J Neurophysiol", "link": "2053973"}, "BIBREF28": {"title": "Neuropsychology and neurophysiology of self-consciousness. Multisensory and vestibular mechanisms", "authors": [{"first": "C", "middle": [], "last": "Lopez", "suffix": ""}, {"first": "O", "middle": [], "last": "Blanke", "suffix": ""}], "year": 2007, "venue": "Hirnforschung und Menschenbild. Beitr\u00e4ge zur interdisziplin\u00e4ren Verst\u00e4ndigung", "link": "201925861"}, "BIBREF29": {"title": "Brain activations during subjective visual vertical judgment: a functional magnetic resonance imaging study", "authors": [{"first": "C", "middle": [], "last": "Lopez", "suffix": ""}, {"first": "M", "middle": [], "last": "Lacour", "suffix": ""}, {"first": "M", "middle": [], "last": "Ballester", "suffix": ""}, {"first": "M", "middle": [], "last": "Dumitrescu", "suffix": ""}, {"first": "Anton J-L", "middle": [], "last": "Nazarian", "suffix": ""}, {"first": "B", "middle": [], "last": "Roth", "suffix": ""}, {"first": "M", "middle": [], "last": "Borel", "suffix": ""}, {"first": "L", "middle": [], "last": "", "suffix": ""}], "year": 2005, "venue": "Gait and Posture", "link": null}, "BIBREF30": {"title": "Between-subject variability and within-subject reliability of the human eye-movement response to bilateral galvanic (DC) vestibular stimulation", "authors": [{"first": "H", "middle": ["G"], "last": "Macdougall", "suffix": ""}, {"first": "A", "middle": ["E"], "last": "Brizuela", "suffix": ""}, {"first": "A", "middle": ["M"], "last": "Burgess", "suffix": ""}, {"first": "I", "middle": ["S"], "last": "Curthoys", "suffix": ""}], "year": 2002, "venue": "Exp Brain Res", "link": "9607853"}, "BIBREF31": {"title": "Modeling postural instability with Galvanic vestibular stimulation", "authors": [{"first": "H", "middle": ["G"], "last": "Macdougall", "suffix": ""}, {"first": "S", "middle": ["T"], "last": "Moore", "suffix": ""}, {"first": "I", "middle": ["S"], "last": "Curthoys", "suffix": ""}, {"first": "F", "middle": ["O"], "last": "Black", "suffix": ""}], "year": 2006, "venue": "Exp Brain Res", "link": "9552152"}, "BIBREF32": {"title": "Dissociation between subjective vertical and subjective body orientation elicited by galvanic vestibular stimulation", "authors": [{"first": "F", "middle": [], "last": "Mars", "suffix": ""}, {"first": "J", "middle": ["L"], "last": "Vercher", "suffix": ""}, {"first": "K", "middle": [], "last": "Popov", "suffix": ""}], "year": 2005, "venue": "Brain Res Bull", "link": "41420424"}, "BIBREF33": {"title": "Mental transformations of perspective during whole-body roll-rotation", "authors": [{"first": "F", "middle": ["W"], "last": "Mast", "suffix": ""}, {"first": "F", "middle": [], "last": "Meissner", "suffix": ""}], "year": 2004, "venue": "J Vestib Res", "link": null}, "BIBREF34": {"title": "Visual mental imagery during caloric vestibular stimulation", "authors": [{"first": "F", "middle": ["W"], "last": "Mast", "suffix": ""}, {"first": "D", "middle": ["M"], "last": "Merfeld", "suffix": ""}, {"first": "S", "middle": ["M"], "last": "Kosslyn", "suffix": ""}], "year": 2006, "venue": "Neuropsychologia", "link": "28657995"}, "BIBREF35": {"title": "Vicarious processes involved in spatial perception. In: Wapner S (ed) Bio-psycho-social factors in cognitive style", "authors": [{"first": "T", "middle": [], "last": "Ohlmann", "suffix": ""}, {"first": "C", "middle": [], "last": "Marendaz", "suffix": ""}], "year": 1991, "venue": "Lawrence Erlbaum", "link": null}, "BIBREF36": {"title": "The assessment and analysis of handedness: the Edinburgh inventory", "authors": [{"first": "R", "middle": ["C"], "last": "Oldweld", "suffix": ""}], "year": 1971, "venue": "Neuropsychologia", "link": "142949831"}, "BIBREF37": {"title": "Imagined spatial transformation of one's body", "authors": [{"first": "L", "middle": ["M"], "last": "Parsons", "suffix": ""}], "year": 1987, "venue": "J Exp Psychol Gen", "link": "16499453"}, "BIBREF38": {"title": "Rapid-rate transcranial magnetic stimulation of left dorsolateral prefrontal cortex in drug-resistant depression", "authors": [{"first": "A", "middle": [], "last": "Pascual-Leone", "suffix": ""}, {"first": "B", "middle": [], "last": "Rubio", "suffix": ""}, {"first": "F", "middle": [], "last": "Pallardo", "suffix": ""}, {"first": "M", "middle": ["D"], "last": "Catala", "suffix": ""}], "year": 1996, "venue": "Lancet", "link": "31457753"}, "BIBREF39": {"title": "The VideoToolbox sotware for visual psychophysics: transforming numbers into movies", "authors": [{"first": "D", "middle": ["G"], "last": "Pelli", "suffix": ""}], "year": 1997, "venue": "Spat Vis", "link": "35717021"}, "BIBREF40": {"title": "Epilepsy and Cerebral Localization", "authors": [{"first": "W", "middle": [], "last": "Penweld", "suffix": ""}, {"first": "T", "middle": [], "last": "Erickson", "suffix": ""}], "year": 1941, "venue": "", "link": "72644813"}, "BIBREF41": {"title": "Spatial performance of unilateral vestibular defective patients in nonvisual versus visual navigation", "authors": [{"first": "P", "middle": [], "last": "Peruch", "suffix": ""}, {"first": "L", "middle": [], "last": "Borel", "suffix": ""}, {"first": "F", "middle": [], "last": "Gaunet", "suffix": ""}, {"first": "G", "middle": [], "last": "Thinus-Blanc", "suffix": ""}, {"first": "J", "middle": [], "last": "Magnan", "suffix": ""}, {"first": "M", "middle": [], "last": "Lacour", "suffix": ""}], "year": 1999, "venue": "J Vestib Res", "link": "22786533"}, "BIBREF42": {"title": "Direction and distance deWcits in path integration after unilateral vestibular loss depend on task complexity", "authors": [{"first": "P", "middle": [], "last": "Peruch", "suffix": ""}, {"first": "L", "middle": [], "last": "Borel", "suffix": ""}, {"first": "J", "middle": [], "last": "Magnan", "suffix": ""}, {"first": "M", "middle": [], "last": "Lacour", "suffix": ""}], "year": 2005, "venue": "Brain Res Cogn Brain Res", "link": "44594265"}, "BIBREF43": {"title": "Low intensity galvanic vestibulo-ocular reXex in normal subjects", "authors": [{"first": "G", "middle": [], "last": "Quarck", "suffix": ""}, {"first": "O", "middle": [], "last": "Etard", "suffix": ""}, {"first": "H", "middle": [], "last": "Normand", "suffix": ""}, {"first": "M", "middle": [], "last": "Pottier", "suffix": ""}, {"first": "Denise", "middle": ["P"], "last": "", "suffix": ""}], "year": 1998, "venue": "Neurophysiol Clin", "link": null}, "BIBREF44": {"title": "Partial remission of hemiplegia and somatoparaphrenia through vestibular stimulation in a case of unilateral neglect", "authors": [{"first": "G", "middle": [], "last": "Rode", "suffix": ""}, {"first": "N", "middle": [], "last": "Charles", "suffix": ""}, {"first": "M", "middle": ["T"], "last": "Perenin", "suffix": ""}, {"first": "A", "middle": [], "last": "Vighetto", "suffix": ""}, {"first": "M", "middle": [], "last": "Trillet", "suffix": ""}, {"first": "G", "middle": [], "last": "Aimard", "suffix": ""}], "year": 1992, "venue": "Cortex", "link": "4479132"}, "BIBREF45": {"title": "Imagination of body rotation can induce eye movements", "authors": [{"first": "V", "middle": [], "last": "Rodionov", "suffix": ""}, {"first": "J", "middle": [], "last": "Zislin", "suffix": ""}, {"first": "J", "middle": [], "last": "Elidan", "suffix": ""}], "year": 2004, "venue": "Acta Otolaryngol", "link": "23213978"}, "BIBREF46": {"title": "Perception of the vertical in patients with right hemispheric lesion: EVect of galvanic vestibular stimulation", "authors": [{"first": "A", "middle": [], "last": "Saj", "suffix": ""}, {"first": "J", "middle": [], "last": "Honore", "suffix": ""}, {"first": "M", "middle": [], "last": "Rousseaux", "suffix": ""}], "year": 2006, "venue": "Neuropsychologia", "link": "29929922"}, "BIBREF47": {"title": "Mental rotation of three-dimensional objects", "authors": [{"first": "R", "middle": ["N"], "last": "Shepard", "suffix": ""}, {"first": "J", "middle": [], "last": "Metzler", "suffix": ""}], "year": 1971, "venue": "Science", "link": "16357397"}, "BIBREF48": {"title": "Does vestibular damage cause cognitive dysfunction in humans?", "authors": [{"first": "P", "middle": ["F"], "last": "Smith", "suffix": ""}, {"first": "Y", "middle": [], "last": "Zheng", "suffix": ""}, {"first": "A", "middle": [], "last": "Horii", "suffix": ""}, {"first": "C", "middle": ["L"], "last": "Darlington", "suffix": ""}], "year": 2005, "venue": "J Vestib Res", "link": "15313209"}, "BIBREF49": {"title": "Functional MRI of galvanic vestibular stimulation with alternating currents at diVerent frequencies", "authors": [{"first": "T", "middle": [], "last": "Stephan", "suffix": ""}, {"first": "A", "middle": [], "last": "Deutschlander", "suffix": ""}, {"first": "A", "middle": [], "last": "Nolte", "suffix": ""}, {"first": "E", "middle": [], "last": "Schneider", "suffix": ""}, {"first": "M", "middle": [], "last": "Wiesmann", "suffix": ""}, {"first": "T", "middle": [], "last": "Brandt", "suffix": ""}, {"first": "M", "middle": [], "last": "Dieterich", "suffix": ""}], "year": 2005, "venue": "Neuroimage", "link": "21768192"}, "BIBREF50": {"title": "Spatial Hemineglect in Human", "authors": [{"first": "G", "middle": [], "last": "Vallar", "suffix": ""}], "year": 1998, "venue": "Trends Cogn Sci", "link": "15366153"}, "BIBREF51": {"title": "A fronto-parietal system for computing the egocentric spatial frame of reference in humans", "authors": [{"first": "G", "middle": [], "last": "Vallar", "suffix": ""}, {"first": "E", "middle": [], "last": "Lobel", "suffix": ""}, {"first": "G", "middle": [], "last": "Galati", "suffix": ""}, {"first": "A", "middle": [], "last": "Berthoz", "suffix": ""}, {"first": "L", "middle": [], "last": "Pizzamiglio", "suffix": ""}, {"first": "Le", "middle": [], "last": "Bihan", "suffix": ""}, {"first": "D", "middle": [], "last": "", "suffix": ""}], "year": 1999, "venue": "Exp Brain Res", "link": "6166886"}, "BIBREF52": {"title": "Regional brain activity during diVerent paradigms of mental rotation in healthy volunteers: a positron emission tomography study", "authors": [{"first": "G", "middle": [], "last": "Vingerhoets", "suffix": ""}, {"first": "P", "middle": [], "last": "Santens", "suffix": ""}, {"first": "K", "middle": [], "last": "Van Laere", "suffix": ""}, {"first": "P", "middle": [], "last": "Lahorte", "suffix": ""}, {"first": "R", "middle": ["A"], "last": "Dierckx", "suffix": ""}, {"first": "De", "middle": [], "last": "Reuck", "suffix": ""}, {"first": "J", "middle": [], "last": "", "suffix": ""}], "year": 2001, "venue": "Neuroimage", "link": "5640672"}, "BIBREF53": {"title": "Neural correlates of the Wrst-person-perspective", "authors": [{"first": "K", "middle": [], "last": "Vogeley", "suffix": ""}, {"first": "G", "middle": ["R"], "last": "Fink", "suffix": ""}], "year": 2003, "venue": "Trends Cogn Sci", "link": null}, "BIBREF54": {"title": "Imagined rotations of self versus objects: an fMRI study", "authors": [{"first": "M", "middle": [], "last": "Wraga", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Shephard", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Church", "suffix": ""}, {"first": "S", "middle": [], "last": "Inati", "suffix": ""}, {"first": "S", "middle": ["M"], "last": "Kosslyn", "suffix": ""}], "year": 2005, "venue": "Neuropsychologia", "link": "1803126"}, "BIBREF55": {"title": "Transformations of visuospatial images", "authors": [{"first": "J", "middle": ["M"], "last": "Zacks", "suffix": ""}, {"first": "P", "middle": [], "last": "Michelon", "suffix": ""}], "year": 2005, "venue": "Behav Cogn Neurosci Rev", "link": "281280"}, "BIBREF56": {"title": "Multiple systems for spatial imagery: transformations of objects and bodies", "authors": [{"first": "J", "middle": ["M"], "last": "Zacks", "suffix": ""}, {"first": "B", "middle": [], "last": "Tversky", "suffix": ""}], "year": 2005, "venue": "Spatial Cognit Comput", "link": null}, "BIBREF57": {"title": "Imagined transformations of bodies: an fMRI investigation", "authors": [{"first": "J", "middle": [], "last": "Zacks", "suffix": ""}, {"first": "B", "middle": [], "last": "Rypma", "suffix": ""}, {"first": "J", "middle": ["D"], "last": "Gabrieli", "suffix": ""}, {"first": "B", "middle": [], "last": "Tversky", "suffix": ""}, {"first": "G", "middle": ["H"], "last": "Glover", "suffix": ""}], "year": 1999, "venue": "Neuropsychologia", "link": "14057658"}, "BIBREF58": {"title": "EVects of galvanic vestibular stimulation on otolithic and semicircular canal eye movements and perceived vertical", "authors": [{"first": "R", "middle": [], "last": "Zink", "suffix": ""}, {"first": "S", "middle": ["F"], "last": "Bucher", "suffix": ""}, {"first": "A", "middle": [], "last": "Weiss", "suffix": ""}, {"first": "T", "middle": [], "last": "Brandt", "suffix": ""}, {"first": "M", "middle": [], "last": "Dieterich", "suffix": ""}], "year": 1998, "venue": "Electroencephalogr Clin Neurophysiol", "link": "42945064"}}, "ref_entries": {"FIGREF1": {"text": "Figure 4 represents the eVects of right and left GVS as compared to sham stimulations on response times in the conditions requiring larger mental transformations. Data show that response times signiWcantly increased only during right GVS and for angles of 120\u00b0. No comparable eVect was found for left GVS or right GVS at 60\u00b0. This was reXected in a signiWcant four-way interaction of Type of stimulation \u00a3 Side of stimulation \u00a3 Object \u00a3 Angle of rotation [F (1,10) = 8.92, P < 0.05]. For the plant, post-hoc tests showed that response times were signiWcantly increased during right GVS (as compared to right sham", "type": "figure"}, "FIGREF2": {"text": "Fig. 2 InXuence of GVS on the subjective visual vertical. Mean subjective visual vertical ( \u00a7standard error to the mean, vertical bars) are shown for each type and side of stimulation. Positive values are corresponding to a counterclockwise deviation (in degree), negative values to a clockwise deviation. * SigniWcant statistical diVerence (P < 0.05) Fig. 3 InXuence of the angle of rotation. The histogram shows the mean response time in milliseconds ( \u00a7standard error to the mean, vertical bars) averaged over body and plant stimuli for each angle of rotation (CW clockwise, CCW counterclockwise). The main eVect of angle revealed a typical mental rotation function", "type": "figure"}, "TABREF0": {"text": "Side eVects of galvanic vestibular stimulation The table shows the side eVects of galvanic stimulation assessed by questionnaire. The values refer to the absolute number of subjects reporting a side eVect", "type": "table"}}}
{"paper_id": "213463721", "_pdf_hash": "bdbdae489522a4c921d651e18917e3caae35b20e", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Webcam child prostitution: An exploration of current and futuristic methods of detection", "authors": [{"first": "K", "middle": ["V"], "last": "A\u00e7ar", "suffix": ""}], "year": 2017, "venue": "International Journal of Cyber Criminology", "link": "54217421"}, "BIBREF1": {"title": "Australian Bureau of Statistics (ABS) 2019. Australian Demographic Statistics", "authors": [], "year": 2019, "venue": "", "link": null}, "BIBREF2": {"title": "Australian Criminal Intelligence Commission", "authors": [], "year": 2019, "venue": "National Police Reference System", "link": null}, "BIBREF3": {"title": "Australian Transaction Reports and Analysis Centre (AUSTRAC) 2019. Combatting the sexual exploitation of children for financial gain: Activity indicators", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF4": {"title": "The characteristics of online sex offenders: A meta-analysis", "authors": [{"first": "K", "middle": ["M"], "last": "Babchishin", "suffix": ""}, {"first": "K &amp;", "middle": [], "last": "Hanson", "suffix": ""}, {"first": "C", "middle": ["A"], "last": "Hermann", "suffix": ""}], "year": 2011, "venue": "Sexual Abuse: a Journal of Research and Treatment", "link": null}, "BIBREF5": {"title": "Internet providers urged to tackle live-streaming of child sex in the Philippines", "authors": [{"first": "E", "middle": [], "last": "Batha", "suffix": ""}], "year": 2016, "venue": "Thomas Reuters Foundation", "link": null}, "BIBREF6": {"title": "What is the profile of child exploitation material offenders? Trends & issues in crime and criminal justice no. 564. Canberra: Australian Institute of Criminology", "authors": [{"first": "R", "middle": [], "last": "Brown", "suffix": ""}, {"first": "S", "middle": [], "last": "Bricknell", "suffix": ""}], "year": 2018, "venue": "", "link": null}, "BIBREF7": {"title": "Westpac's CEO Brian Hartzer resigns over money-laundering scandal. The Guardian, Australia edition", "authors": [{"first": "B", "middle": [], "last": "Butler", "suffix": ""}], "year": 2019, "venue": "", "link": null}, "BIBREF8": {"title": "Convicted child sex offender behind bars again for illicit Skype relationship with Filipino children under the age of 12. Sydney Morning Herald", "authors": [{"first": "", "middle": [], "last": "Cormack L 2019a", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF9": {"title": "Someday I will get found and locked up': Inside the global fight against online child sexual abuse. Sydney Morning Herald", "authors": [{"first": "", "middle": [], "last": "Cormack L 2019b", "suffix": ""}], "year": 2020, "venue": "", "link": null}, "BIBREF10": {"title": "Improving practice in child sexual abuse image investigations through identification of offender characteristics", "authors": [{"first": "N", "middle": [], "last": "Davis", "suffix": ""}, {"first": "C &amp;", "middle": [], "last": "Lennings", "suffix": ""}, {"first": "", "middle": [], "last": "Green", "suffix": ""}], "year": 2018, "venue": "Sexual Abuse in Australia", "link": "148948410"}, "BIBREF11": {"title": "Trends in online child sexual abuse material. Bangkok: ECPAT International ECPAT International", "authors": [{"first": "S", "middle": [], "last": "De Leon", "suffix": ""}], "year": 2013, "venue": "ECPAT International Journal", "link": null}, "BIBREF12": {"title": "Internet organised crime threat assessment 2016. The Hague: Europol Global Alliance against Child Sexual Abuse Online (GACSAO) 2016. 2015 Threat assessment report. Global Alliance against Child Sexual Abuse Online International Justice Mission (IJM) 2019. Cybersex trafficking", "authors": [], "year": 2014, "venue": "European Financial Coalition against Commercial Sexual Exploitation of Children Online (EFC) 2015. Strategic assessment", "link": null}, "BIBREF13": {"title": "Internet Watch Foundation (IWF) 2018. Trends in child sexual exploitation: Examining the distribution of captures of live-streamed child sexual abuse", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF14": {"title": "Webcam child sex abuse", "authors": [{"first": "L", "middle": [], "last": "Masri", "suffix": ""}], "year": 2015, "venue": "CUNY Academic Works", "link": "152211133"}, "BIBREF15": {"title": "Online child exploitation material: Trends and emerging issues: Research report of the Australian National University Cybercrime Observatory with the input of the Office of the Children's eSafety Commissioner. Canberra: Australian National University", "authors": [{"first": "D", "middle": [], "last": "Maxim", "suffix": ""}, {"first": "S", "middle": [], "last": "Orlando", "suffix": ""}, {"first": "K", "middle": [], "last": "Skinner", "suffix": ""}, {"first": "R", "middle": [], "last": "Broadhurst", "suffix": ""}], "year": 2016, "venue": "", "link": "113545080"}, "BIBREF16": {"title": "Webcam child sex tourism: An emerging global issue", "authors": [{"first": "E", "middle": [], "last": "Puffer", "suffix": ""}, {"first": "K", "middle": [], "last": "Mcdonald", "suffix": ""}, {"first": "M &amp;", "middle": [], "last": "Pross", "suffix": ""}, {"first": "D", "middle": [], "last": "Hudson", "suffix": ""}], "year": 2014, "venue": "", "link": "127690748"}, "BIBREF18": {"title": "Child pornography and the internet: Perpetuating a cycle of abuse", "authors": [{"first": "E &amp;", "middle": [], "last": "Quayle", "suffix": ""}, {"first": "M", "middle": [], "last": "Taylor", "suffix": ""}], "year": 2002, "venue": "Deviant Behavior", "link": "5811119"}, "BIBREF19": {"title": "Contact sexual offending by men with online sexual offenses", "authors": [{"first": "M", "middle": ["C"], "last": "Seto", "suffix": ""}, {"first": "K", "middle": ["R"], "last": "Hanson", "suffix": ""}, {"first": "K", "middle": ["M"], "last": "Babchishin", "suffix": ""}], "year": 2011, "venue": "Sexual Abuse: A Journal of Research and Treatment", "link": "206673600"}, "BIBREF20": {"title": "Webcam child sex tourism: Becoming Sweetie: A novel approach to stopping the global rise of webcam child sex tourism. The Hague: Terre des Hommes Virtual Global Taskforce (VGT) 2019. Environmental scan", "authors": [], "year": 2014, "venue": "", "link": null}, "BIBREF21": {"title": "Global threat assessment 2019. London: WeProtect Global Alliance", "authors": [{"first": "", "middle": [], "last": "Weprotect Global Alliance", "suffix": ""}], "year": 2019, "venue": "", "link": null}, "BIBREF22": {"title": "She sat there with an eight-year-old girl on her lap and asked me \"what do you want me to do with her?", "authors": [{"first": "E", "middle": [], "last": "Wight", "suffix": ""}], "year": 2016, "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "213466066", "_pdf_hash": "2f691a8109ca2c14d9542a9277bda802768e717f", "abstract": [{"section": "Abstract", "text": "Improvement in Aerodrome Warning (AW) nowcasts need better prediction for supporting the safety and security of air traffic from extreme weather. AW consists of weather conditions, wind direction and wind speed, and visibility with observing time and validity time of forecast. Weather forecast verification is important for all stakeholders in the airport, so they can prepare and have plans to mitigate undesirable activity disturbance. AW and Automated Weather Observing System (AWOS) data are from Soekarno-Hatta Meteorological Station (07L) and Tanjungpinang Meteorological Station for January to April2019. Statistic test using hits, false alarm, misses, the correct negative is to find the score of POD, Bias, FAR, TS, and HSS which is to measure the magnitude of AW. Overall, AW has good accuracy to predict the extreme weather in the aerodrome.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Aviation meteorology is the most important aspect of supporting the safety and security of air traffic from extreme weather [1] . Weather conditions can cause or contribute to the aviation accidents included wind, visibility or ceiling, high-density altitude, turbulence, carburetor icing, updrafts or downdrafts, precipitation, icing, thunderstorms, wind shear, thermal lift, temperature (T) extremes, and lightning [2] . A weather forecaster is an actor who guarantees the efficiency and effectiveness of airport operational without affected by weather, so they have to observe all the weather parameters such as air temperature, winds, weather condition, and visibility. Furthermore, these parameters are analyzed in an isobar chart, streamline chart, and upper air chart to get an accurate weather forecast.", "cite_spans": [{"start": 124, "end": 127, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 417, "end": 420, "text": "[2]", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Introduction", "text": "Based on Figure 1 , accidents by flight phase as a percentage of all accidents from 1998 to 2017 have dominantly occurred with approach (up to 20%) and landing (up to 50%). Next, it was followed by parking and taxi as a non-fatal hull loss, but it was also essential. Building and cargo in aerodrome may be received damage from the weather such as floods or strong surface winds. To minimize the negative risks, World Meteorological Organization (WMO) has arranged the rules with the use of Aerodrome Warning in Technical Regulations [4] , Volume II, Part I, 7.3. In Indonesia, The Agency for MeteorologyClimatology and Geophysics (BMKG) also compiled the detailed of Aerodrome Warning in PERKA BMKG No. 13 Tahun 2015 [5] . Aerodrome Warning is concise information about meteorological conditions that can affect aircraft and airport service facilities on land such as runway. Aerodrome Warning (AW) consists of weather conditions, wind direction and wind speed, and visibility with observing time and validity time of forecast. Weather conditions as though rainfall, tropical cyclones, thunderstorm, squall, hail, fog, volcanic ash, tsunami, smoke, and toxic chemistry gases should be reported if it occurred or will occur in AW format. Delay avoiding, cargo activities will be fluent and aircraft parking will exists in safety cone and remains sterile if AW is disseminated well [6] .", "cite_spans": [{"start": 718, "end": 721, "text": "[5]", "ref_id": "BIBREF4"}], "ref_spans": [{"start": 9, "end": 17, "text": "Figure 1", "ref_id": "FIGREF0"}]}, {"section": "Introduction", "text": "WIII AD WRNG 02 VALID 170420/170530 HVY TSRA WIND 28015KT MAX 25KT OBSAT 170400 NC= (1)", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "The code form above explains about Aerodrome Warning in Soekarno-Hatta Meteorological Station (WIII) number 2 with time validity on date 17 from 04:20 UTC until 05:30 UTC will occur heavy rain with thunderstorm with the average wind direction is from 280\u2070 (South-West) and wind speed is 15 knot, and maximum wind speed up to 25 knot. The observation of AW was 04:00 UTC on date 17, with no change of phenomena intensity. Improvement in aerodrome warnings nowcasts need better predictions, thus a verification becomes its measurement. Weather forecast verification provides benefits, such as knowing the mistake which causes false prediction [7] . In cases, all stakeholders in the airport can prepare and have plans to mitigate undesirable activity disturbance.", "cite_spans": [{"start": 641, "end": 644, "text": "[7]", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "Introduction", "text": "Aerodrome warning archives from January to April 2019 are needed as the basic materials. A computer, an especially calculator, are used to calculate all formula in statistic verification. Automatic Weather Observation System (AWOS) data from January to April 2019 are collected in one folder including rainfall events, thunderstorm events, the peak of wind speed, and minimum visibility. Aerodrome warning and AWOS data are from Soekarno-Hatta Meteorological Station (07L) and Tanjungpinang Meteorological Station. ", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "Aerodrome warning as a nowcasting forecast and AWOS data as observation references are verified into 5 statistic parameters, such as Probability of Detection (POD), Bias, False Alarm Ratio (FAR), Threat Score (TS), and Heidke Skill Score (HSS). Value of Hits, False Alarms, Misses, and Correct Negatives be required for calculating those 5 parameters. Hits means the prediction and the observation occurred simultaneously, besides Correct Negatives means both of them do not occur. False Alarms shows that the forecast said \"Yes\", but in observation, it does not occur. Misses means that there is no prediction, but there happened extreme weather that passes the threshold.", "cite_spans": [], "ref_spans": []}, {"section": "POD = Hits", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Hits +Misses", "text": "(2)", "cite_spans": [], "ref_spans": []}, {"section": "FAR = False Alarms", "text": "Hits +False Alarms ", "cite_spans": [], "ref_spans": []}, {"section": "TS = Hits", "text": "Hits +False Alarms +Misses (5) Probability events that can be detected by the Probability of detection (POD), is part of the incident what was observed occurred (\"yes\") and predicted. The value between 0 and 1, the best value when POD equals 1. The number of events predicted will occur (\"yes\"), but it does not occur as indicated by False Alarm Ratio (FAR). The value is between 0 and 1which FAR equals 0 is the best value.", "cite_spans": [{"start": 27, "end": 30, "text": "(5)", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "TS = Hits", "text": "Bias is a comparison of the average forecast towards the average observation and shows the frequency of a forecast event compared to observed events. Bias value can show how is the relationship between predictions occurring \"yes\" with \"yes\" observations, can be obtained by equation (1) . The value is between 0 and \u221e, with bias equals 1, is the best value. Threat score (TS) can show a comparison predictions of the occurrence of \"yes\" with observations of events \"yes\", TS values range from 0 and 1, 0 indicates predictions without skill and 1 for the best predictions. HSS = Hits +Correct Negatives \u2212(Expected Correct ) random N \u2212 (Expected Correct ) random", "cite_spans": [{"start": 283, "end": 286, "text": "(1)", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "TS = Hits", "text": "Verification will also be used Hiedke Skill Score (HSS) which can provide relative accuracy of forecasts against the chance of random. The HSS value interval is -\u221e to 1. Value 1 shows the perfect forecasts.", "cite_spans": [], "ref_spans": []}, {"section": "TS = Hits", "text": "Mean Absolute Error (MAE) measures the average magnitude of the errors in a set of forecasts, without considering their direction. It measures accuracy for continuous variables. Expressed in words, the MAE is the average over the verification sample of the absolute values of the differences between forecast and the corresponding observation. MAE is a linear score which means that all the individual differences are weighted equally in the average. Root Mean Squared Error (RMSE) measures the average magnitude of the error. The difference between forecast and corresponding observed values are each squared and then averaged over the sample. Finally, the square root of the average is taken. Since the errors are squared before they are averaged, the RMSE gives a relatively high weight to large errors. This means RMSE is the most useful when large errors are particularly undesirable. MAE and RMSE can be used together to diagnose the variation in the errors in a set of forecasts. RMSE will always be larger or equal to MAE which there isthe difference between them especially for thevariance in the individual errors in the sample. If RMSE is similar to MAE, then all the errors are of the same magnitude. Both the MAE and RMSE can range from 0 to \u221e. They are negatively-oriented scores which are lower values are better.", "cite_spans": [], "ref_spans": []}, {"section": "Results and Discussion a. Tanjungpinang Meteorological Station", "text": "Rainfall variability in the Tanjungpinang was influenced by many factors. Weather patterns in Tanjungpinang were affected by its geographical location which was surrounded by the ocean so that the convection that occurs was more influenced by local factors [8] .", "cite_spans": [{"start": 257, "end": 260, "text": "[8]", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "Results and Discussion a. Tanjungpinang Meteorological Station", "text": "Climatologically, it will go through wet conditions which were the precipitation that occurs quite frequently from November to January and went through dry conditions with little precipitation in February. The Agency for Meteorology Climatology and Geophysics (BMKG) was intensively socialize the making of aerodrome warnings as a basis for early warning for extreme weather events such as heavy rain, low visibility, and strong winds which may occur around the runway or airport. BMKGled Tanjungpinang Meteorological Station to make an aerodrome warning for extreme weather conditions at Raja Haji Fisabilillah International Airport. Precipitation forecasting was one of the difficult parts to predict and was still being studied [9] . It could be done subjectively based on the forecaster point of view and objective by using a statistical or numerical methods. Figure 2 interpreted the aerodrome frequency warning chart produced bythe forecaster of Tanjungpinang Meteorological Station for extreme weather that occurred at the runway of Raja Haji Fisabilillah International Airport. It showed that aerodrome warning issued not routinely given when there was the potential for extreme weatherespecially when rain has occurred, which could affect the safety of airplane operation. Aerodrome warning for January and February was not made by forecasters of Tanjungpinang Meteorological Station during rain event that observed by AWOS or manual observation. Precipitation intensity that occurred in JanuaryandFebruary was mostly in the light intensity where some rainfall events were measured in rain gauge or AWOS as a trace of rain or no measurable accumulation. Rainfall frequency observed by AWOS in March and April also did not record actual rainfall events or measure it as a trace of rain (about 8.33%) a couple of times, but the rainfall ", "cite_spans": [{"start": 731, "end": 734, "text": "[9]", "ref_id": "BIBREF8"}], "ref_spans": [{"start": 864, "end": 872, "text": "Figure 2", "ref_id": "FIGREF2"}]}, {"section": "Monthly Aerodrome Warning and Rainfall Events in AWOS and Observation", "text": "Ad Warning Rainfall in AWOS Rainfall Observation Result AW frequency was smaller compared for January and February(about 53.84%). The frequency of aerodrome warnings in March and April ranged about 41.67% from the occurrence of rain events. It happened because of the rain that occurred is only in light category so the aerodrome warning was not made and disseminated to related parties. Aerodrome warning was verified by using the accuracy of statistical value predictions. The parameter values used to verify aerodrome warning issued by the Tanjungpinang Meteorological Station were presented in Table 3 . Aerodrome warning issued from March to April2019 was verified to find out the accuracy of the actual forecast towards extreme weather events recorded by AWOS. Verification was assessed only when aerodrome warning was issued and extreme weather conditions occurred, especially for the rainfall with light to heavy intensity followed by the potential for strong wind and thunderstorm. As for the dates which became the focus of verification in March 2019 that is 28 and 30 as well as in April 2019 that is on 10, 11, 12, 14, 20, 26, 29, and 30. The results of verification were presented in Table 4 .", "cite_spans": [], "ref_spans": [{"start": 598, "end": 605, "text": "Table 3", "ref_id": "TABREF2"}, {"start": 1197, "end": 1204, "text": "Table 4", "ref_id": "TABREF3"}]}, {"section": "b. Soekarno-Hatta Meteorological Station", "text": "Soekarno-Hatta Meteorological Station has been as a unit that disseminated Aerodrome Warning in Soekarno-Hatta International Airportincluded for 2 runways (07R/25L and 07L/25R) and has added a challenge to cover new runway (06/24). Figure 3 showed that in January and February, there were quite differences counted which recorded in Automatic Weather Observing System (AWOS) and Hellmann rain gauge paper as observation results. It was caused by rainfall pattern that enters to the aerodrome in other points of the runway. ", "cite_spans": [], "ref_spans": [{"start": 232, "end": 240, "text": "Figure 3", "ref_id": "FIGREF4"}]}, {"section": "Monthly Aerodrome Warning and Rainfall Events in AWOS and Observation", "text": "Ad Warning Rainfall in AWOS Rainfall Observation Result AW Furthermore, wind direction and speed was as the main factor of those conditions. 07L point in North runway would be touched if the wind moved from West. Figure 3also interpreted the highest number of aerodrome warning production was in January. Table 5 above indicated that the best score of POD was in Marchand also became the highest Bias value. FAR and TS amount among 4 months were not in big difference and they showed a good prediction. For HSS, it was still around fifty percent that meant the forecast was still in a good based on forecast relative accuracy. However, Soekarno-Hatta Meteorological Station in 4 months above was in critical season that was the rainy season. By analyzing all the values in Table 5 , weather forecasters in Soekarno-Hatta Meteorological Station were capable to provide Aerodrome Warning. ", "cite_spans": [], "ref_spans": [{"start": 213, "end": 225, "text": "Figure 3also", "ref_id": "FIGREF4"}, {"start": 305, "end": 312, "text": "Table 5", "ref_id": "TABREF4"}, {"start": 773, "end": 780, "text": "Table 5", "ref_id": "TABREF4"}]}, {"section": "Misses", "text": "Correct Negative January and February as the peak of the rainy season were needed to minimize False Alarm prediction. Figure 4 illustrated that most of the Hits and Correct Negative were dominating in all data. The bad result of prediction for misses in January was two times higher than February. False Alarm in February was still bigger.To more detail, March exists as the biggest amount of False Alarm ( Figure 5 ). But, Hits number was also in the biggest one. It meant that a weather forecaster wouldbe difficult to predict the time of rainfall occurrence in a transition season. Figure 6showed the number of Aerodrome Warning (AW) issued for wind parameters and visibility. The warning given was in the form of information on increasing wind speed significantly and visibility reduction which could affect aircraft operation. March was a month with the highest number of AW issued for both wind and visibility parameters, while February was a month with the lowest number of AW issued for wind parameters and visibility. Table 6showed the AW verification value issued by comparing AWOS data. Verification for wind and visibility parameters was done by statistical methods, namely MAE and RMSE. Verification was carried out in the AW issued from January to April2019. The verification value would be a good value if MAE and RMSE values were close to zero, so AW was able to Table 6 showed that AW could predict theextreme events specifically wind and visibility parameters. However, AW for wind parameter that issued in February 2019 was not able to predict correctly and showed a large verification value. ", "cite_spans": [], "ref_spans": [{"start": 118, "end": 126, "text": "Figure 4", "ref_id": "FIGREF5"}, {"start": 407, "end": 415, "text": "Figure 5", "ref_id": "FIGREF6"}, {"start": 585, "end": 599, "text": "Figure 6showed", "ref_id": "FIGREF8"}]}], "bib_entries": {"BIBREF0": {"title": "A Review of High Impact Weather for Aviation Meteorology. Pure and Applied Geophysics", "authors": [{"first": "I", "middle": [], "last": "Gultepe", "suffix": ""}, {"first": "R", "middle": [], "last": "Sharman", "suffix": ""}, {"first": "P", "middle": ["D"], "last": "Williams", "suffix": ""}, {"first": "B", "middle": [], "last": "Zhou", "suffix": ""}, {"first": "G", "middle": [], "last": "Ellrod", "suffix": ""}, {"first": "P", "middle": [], "last": "Minnis", "suffix": ""}, {"first": "A", "middle": [], "last": "Neto", "suffix": ""}], "year": 2019, "venue": "", "link": null}, "BIBREF1": {"title": "Review of National Transportation Safety Board (NTSB) weather-related accidents", "authors": [], "year": 2003, "venue": "", "link": null}, "BIBREF2": {"title": "Airbus: A Statistical Analysis of Commercial Aviation Accidents", "authors": [], "year": 1958, "venue": "", "link": null}, "BIBREF4": {"title": "tentang Tata Cara Tetap Pelaksanaan Pembuatan, Penyampaian, Penyebaran, Pembatalan, dan Pengakhiran Wind Shear Warning dan Aerodrome Warning", "authors": [{"first": "", "middle": [], "last": "Bmkg: Perka Bmkg", "suffix": ""}, {"first": "", "middle": [], "last": "No", "suffix": ""}], "year": 2015, "venue": "", "link": null}, "BIBREF6": {"title": "Forecasting in Meteorology", "authors": [{"first": "C", "middle": ["S"], "last": "Ramage", "suffix": ""}], "year": 1993, "venue": "Bull. Amer. Meteor. Soc", "link": "124346885"}, "BIBREF7": {"title": "Simulasi prediksi total hujan bulanan di tanjungpinang (studi kasus tahun 2017). Jurnal Statistika dan Aplikasinya", "authors": [{"first": "D", "middle": ["C"], "last": "Siregar", "suffix": ""}, {"first": "R", "middle": ["A"], "last": "Anugrah", "suffix": ""}, {"first": "", "middle": [], "last": "Tumardi", "suffix": ""}], "year": 2018, "venue": "", "link": null}, "BIBREF8": {"title": "Akurasi prediksi curah hujan harian operasional di jabodetabek: perbandingan dengan model wrf", "authors": [{"first": "I", "middle": [], "last": "Gustari", "suffix": ""}, {"first": "T", "middle": ["W"], "last": "Hadi", "suffix": ""}, {"first": "S", "middle": [], "last": "Hadi", "suffix": ""}, {"first": "F", "middle": [], "last": "Renggono", "suffix": ""}], "year": 2012, "venue": "Jurnal Meteorologi dan Geofisika", "link": null}}, "ref_entries": {"FIGREF0": {"text": "Percentage of all flight phase accidents 1998-2017[3]", "type": "figure"}, "FIGREF2": {"text": "Frequency chart of aerodrome warning toward rain events reported on AWOS or manual observation", "type": "figure"}, "FIGREF4": {"text": "Frequency chart of aerodrome warning toward rain events reported on AWOSor manual", "type": "figure"}, "FIGREF5": {"text": "Distribution of contingency parameters as basic calculation in January (a) and February (b)", "type": "figure"}, "FIGREF6": {"text": "Distribution of contingency parameters as the basic calculation in March (a) and April (b)", "type": "figure"}, "FIGREF8": {"text": "Frequency of AW production on wind and visibility parameters", "type": "figure"}, "FIGREF9": {"text": "The value of MAE and RMSE between wind and visibility By analyzing the contingency table, the verification results showed that Aerodrome Warning in Tanjungpinang Meteorological Station and Soekarno-Hatta Meteorological Station were quite good. The research would be better and more valid by increasing temporal data amounts and inclining weather parameters.", "type": "figure"}, "TABREF0": {"text": "Meteorological stations coordinate", "type": "table"}, "TABREF1": {"text": "Contingency table", "type": "table"}, "TABREF2": {"text": "Contingency table for aerodrome warning verification", "type": "table"}, "TABREF3": {"text": "Contingency table of aerodrome warning verification issued during extreme weather", "type": "table"}, "TABREF4": {"text": "Contingency table of aerodrome warning verification", "type": "table"}}}
{"paper_id": "213467900", "_pdf_hash": "923d864ddd0053520b5bca5e0211d315eeafe7a3", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Photonic crystal devices: some basics and selected topics", "authors": [{"first": "R", "middle": ["M"], "last": "De La Rue", "suffix": ""}, {"first": "C", "middle": [], "last": "Seassal", "suffix": ""}], "year": 2012, "venue": "Laser & Photonics Reviews", "link": "120639405"}, "BIBREF1": {"title": "Direct measurement of directional emission from monolayer ws 2 laser with heterostructure photonic crystal cavities", "authors": [{"first": "X", "middle": [], "last": "Ge", "suffix": ""}, {"first": "M", "middle": [], "last": "Minkov", "suffix": ""}, {"first": "S", "middle": [], "last": "Fan", "suffix": ""}, {"first": "X", "middle": [], "last": "Li", "suffix": ""}, {"first": "W", "middle": [], "last": "Zhou", "suffix": ""}], "year": 2018, "venue": "", "link": "53281846"}, "BIBREF2": {"title": "Electric field effect in atomically thin carbon films", "authors": [{"first": "K", "middle": ["S"], "last": "Novoselov", "suffix": ""}, {"first": "A", "middle": ["K"], "last": "Geim", "suffix": ""}, {"first": "S", "middle": ["V"], "last": "Morozov", "suffix": ""}, {"first": "D", "middle": [], "last": "Jiang", "suffix": ""}, {"first": "Y", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "S", "middle": ["V"], "last": "Dubonos", "suffix": ""}, {"first": "I", "middle": ["V"], "last": "Grigorieva", "suffix": ""}, {"first": "A", "middle": ["A"], "last": "Firsov", "suffix": ""}], "year": 2004, "venue": "science", "link": "5729649"}, "BIBREF3": {"title": "The renaissance of black phosphorus", "authors": [{"first": "X", "middle": [], "last": "Ling", "suffix": ""}, {"first": "H", "middle": [], "last": "Wang", "suffix": ""}, {"first": "S", "middle": [], "last": "Huang", "suffix": ""}, {"first": "F", "middle": [], "last": "Xia", "suffix": ""}, {"first": "M", "middle": ["S"], "last": "Dresselhaus", "suffix": ""}], "year": 2015, "venue": "Proceedings of the National Academy of Sciences", "link": "18773560"}, "BIBREF4": {"title": "Chemical vapor deposition growth and applications of twodimensional materials and their heterostructures", "authors": [{"first": "Z", "middle": [], "last": "Cai", "suffix": ""}, {"first": "B", "middle": [], "last": "Liu", "suffix": ""}, {"first": "X", "middle": [], "last": "Zou", "suffix": ""}, {"first": "H.-M", "middle": [], "last": "Cheng", "suffix": ""}], "year": 2018, "venue": "Chemical reviews", "link": "10841358"}, "BIBREF5": {"title": "Fast and broadband photoresponse of few-layer black phosphorus field-effect transistors", "authors": [{"first": "M", "middle": [], "last": "Buscema", "suffix": ""}, {"first": "D", "middle": ["J"], "last": "Groenendijk", "suffix": ""}, {"first": "S", "middle": ["I"], "last": "Blanter", "suffix": ""}, {"first": "G", "middle": ["A"], "last": "Steele", "suffix": ""}, {"first": "H", "middle": ["S"], "last": "Van Der Zant", "suffix": ""}, {"first": "A", "middle": [], "last": "Castellanos-Gomez", "suffix": ""}], "year": 2014, "venue": "Nano letters", "link": "5261155"}, "BIBREF6": {"title": "Recent advances in synthesis, properties, and applications of phosphorene", "authors": [{"first": "M", "middle": [], "last": "Akhtar", "suffix": ""}, {"first": "G", "middle": [], "last": "Anderson", "suffix": ""}, {"first": "R", "middle": [], "last": "Zhao", "suffix": ""}, {"first": "A", "middle": [], "last": "Alruqi", "suffix": ""}, {"first": "J", "middle": ["E"], "last": "Mroczkowska", "suffix": ""}, {"first": "G", "middle": [], "last": "Sumanasekera", "suffix": ""}, {"first": "J", "middle": ["B"], "last": "Jasinski", "suffix": ""}], "year": 2017, "venue": "npj 2D Materials and Applications", "link": "136365601"}, "BIBREF7": {"title": "Bilayer phosphorene: effect of stacking order on bandgap and its potential applications in thin-film solar cells", "authors": [{"first": "J", "middle": [], "last": "Dai", "suffix": ""}, {"first": "X", "middle": ["C"], "last": "Zeng", "suffix": ""}], "year": 2014, "venue": "The journal of physical chemistry letters", "link": "18465799"}, "BIBREF8": {"title": "Phosphorene: fabrication, properties, and applications", "authors": [{"first": "L", "middle": [], "last": "Kou", "suffix": ""}, {"first": "C", "middle": [], "last": "Chen", "suffix": ""}, {"first": "S", "middle": ["C"], "last": "Smith", "suffix": ""}], "year": 2015, "venue": "The journal of physical chemistry letters", "link": "16184778"}, "BIBREF9": {"title": "Al-doped black phosphorus p-n homojunction diode for high performance photovoltaic", "authors": [{"first": "Y", "middle": [], "last": "Liu", "suffix": ""}, {"first": "Y", "middle": [], "last": "Cai", "suffix": ""}, {"first": "G", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "Y.-W", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "K.-W", "middle": [], "last": "Ang", "suffix": ""}], "year": 2017, "venue": "Advanced Functional Materials", "link": "136115198"}, "BIBREF10": {"title": "Room temperature high-detectivity mid-infrared photodetectors based on black arsenic phosphorus", "authors": [{"first": "M", "middle": [], "last": "Long", "suffix": ""}, {"first": "A", "middle": [], "last": "Gao", "suffix": ""}, {"first": "P", "middle": [], "last": "Wang", "suffix": ""}, {"first": "H", "middle": [], "last": "Xia", "suffix": ""}, {"first": "C", "middle": [], "last": "Ott", "suffix": ""}, {"first": "C", "middle": [], "last": "Pan", "suffix": ""}, {"first": "Y", "middle": [], "last": "Fu", "suffix": ""}, {"first": "E", "middle": [], "last": "Liu", "suffix": ""}, {"first": "X", "middle": [], "last": "Chen", "suffix": ""}, {"first": "W", "middle": [], "last": "Lu", "suffix": ""}], "year": 2017, "venue": "Science advances", "link": "214864547"}, "BIBREF11": {"title": "Mid-wave infrared photoconductors based on black phosphorus-arsenic alloys", "authors": [{"first": "M", "middle": [], "last": "Amani", "suffix": ""}, {"first": "E", "middle": [], "last": "Regan", "suffix": ""}, {"first": "J", "middle": [], "last": "Bullock", "suffix": ""}, {"first": "G", "middle": ["H"], "last": "Ahn", "suffix": ""}, {"first": "A", "middle": [], "last": "Javey", "suffix": ""}], "year": 2017, "venue": "ACS nano", "link": "6730721"}, "BIBREF12": {"title": "Atomically thin noble metal dichalcogenide: a broadband mid-infrared semiconductor", "authors": [{"first": "X", "middle": [], "last": "Yu", "suffix": ""}, {"first": "P", "middle": [], "last": "Yu", "suffix": ""}, {"first": "D", "middle": [], "last": "Wu", "suffix": ""}, {"first": "B", "middle": [], "last": "Singh", "suffix": ""}, {"first": "Q", "middle": [], "last": "Zeng", "suffix": ""}, {"first": "H", "middle": [], "last": "Lin", "suffix": ""}, {"first": "W", "middle": [], "last": "Zhou", "suffix": ""}, {"first": "J", "middle": [], "last": "Lin", "suffix": ""}, {"first": "K", "middle": [], "last": "Suenaga", "suffix": ""}, {"first": "Z", "middle": [], "last": "Liu", "suffix": ""}], "year": 2018, "venue": "Nature communications", "link": "4946771"}, "BIBREF13": {"title": "Near-infrared photodetector based on mos2/black phosphorus heterojunction", "authors": [{"first": "L", "middle": [], "last": "Ye", "suffix": ""}, {"first": "H", "middle": [], "last": "Li", "suffix": ""}, {"first": "Z", "middle": [], "last": "Chen", "suffix": ""}, {"first": "J", "middle": [], "last": "Xu", "suffix": ""}], "year": 2016, "venue": "Acs Photonics", "link": "124011133"}, "BIBREF14": {"title": "Towards low-loss waveguides in soi and ge-on-soi for mid-ir sensing", "authors": [{"first": "U", "middle": [], "last": "Younis", "suffix": ""}, {"first": "X", "middle": [], "last": "Luo", "suffix": ""}, {"first": "B", "middle": [], "last": "Dong", "suffix": ""}, {"first": "L", "middle": [], "last": "Huang", "suffix": ""}, {"first": "S", "middle": ["K"], "last": "Vanga", "suffix": ""}, {"first": "A", "middle": ["E"], "last": "Lim", "suffix": ""}, {"first": ".-J", "middle": [], "last": "Lo", "suffix": ""}, {"first": "P", "middle": ["G"], "last": "", "suffix": ""}, {"first": ".-Q", "middle": [], "last": "Lee", "suffix": ""}, {"first": "C", "middle": [], "last": "Bettiol", "suffix": ""}, {"first": "A", "middle": ["A"], "last": "Ang", "suffix": ""}, {"first": "K.-W", "middle": [], "last": "", "suffix": ""}], "year": 2018, "venue": "Journal of Physics Communications", "link": "53507510"}, "BIBREF15": {"title": "Anomalously enhanced thermal stability of phosphorene via metal adatom doping: An experimental and first-principles study", "authors": [{"first": "X", "middle": [], "last": "Feng", "suffix": ""}, {"first": "V", "middle": ["V"], "last": "Kulish", "suffix": ""}, {"first": "P", "middle": [], "last": "Wu", "suffix": ""}, {"first": "X", "middle": [], "last": "Liu", "suffix": ""}, {"first": "K.-W", "middle": [], "last": "Ang", "suffix": ""}], "year": 2016, "venue": "Nano Research", "link": "137965322"}, "BIBREF16": {"title": "High coupling efficiency surface illuminated 2d metasurface waveguide coupler for mid-ir wavelengths", "authors": [{"first": "A", "middle": [], "last": "Bilal", "suffix": ""}, {"first": "U", "middle": [], "last": "Younis", "suffix": ""}], "year": 2019, "venue": "International Society for Optics and Photonics", "link": "149851540"}, "BIBREF17": {"title": "Phosphorene: an unexplored 2d semiconductor with a high hole mobility", "authors": [{"first": "H", "middle": [], "last": "Liu", "suffix": ""}, {"first": "A", "middle": ["T"], "last": "Neal", "suffix": ""}, {"first": "Z", "middle": [], "last": "Zhu", "suffix": ""}, {"first": "Z", "middle": [], "last": "Luo", "suffix": ""}, {"first": "X", "middle": [], "last": "Xu", "suffix": ""}, {"first": "D", "middle": [], "last": "Tom\u00e1nek", "suffix": ""}, {"first": "Ye", "middle": [], "last": "", "suffix": ""}, {"first": "P", "middle": ["D"], "last": "", "suffix": ""}], "year": 2014, "venue": "ACS nano", "link": "8061668"}, "BIBREF18": {"title": "Quantum espresso: a modular and open-source software project for quantum simulations of materials", "authors": [{"first": "P", "middle": [], "last": "Giannozzi", "suffix": ""}, {"first": "S", "middle": [], "last": "Baroni", "suffix": ""}, {"first": "N", "middle": [], "last": "Bonini", "suffix": ""}, {"first": "M", "middle": [], "last": "Calandra", "suffix": ""}, {"first": "R", "middle": [], "last": "Car", "suffix": ""}, {"first": "C", "middle": [], "last": "Cavazzoni", "suffix": ""}, {"first": "D", "middle": [], "last": "Ceresoli", "suffix": ""}, {"first": "G", "middle": ["L"], "last": "Chiarotti", "suffix": ""}, {"first": "M", "middle": [], "last": "Cococcioni", "suffix": ""}, {"first": "I", "middle": [], "last": "Dabo", "suffix": ""}], "year": 2009, "venue": "Journal of physics: Condensed matter", "link": "5846317"}}, "ref_entries": {}}
{"paper_id": "177045333", "_pdf_hash": "85b5f7a065460b2e746015b1428d07bd4e4661f4", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "213341263", "_pdf_hash": "7e3abc107a57886c715f65959220c6a032a65769", "abstract": [], "body_text": [{"section": "", "text": "22 February 2020 | New Scientist | 5 FOR yet another week, covid-19, the disease caused by the new coronavirus, has remained poised just short of becoming a pandemic. As case counts stabilise in China, and don't take off elsewhere, the big question is: will it happen? \"Every scenario is still on the table,\" said Tedros Ghebreyesus, head of the World Health Organization (WHO), in Geneva, Switzerland, this week.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "To be pandemic, covid-19 has to spread generally in a population outside China, not just in limited clusters triggered by a known case, as has happened so far. \"We are not seeing that,\" Mike Ryan, head of the WHO emergencies programme, said on Monday.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "In China, cases outside Hubei province, whose capital Wuhan is the epidemic epicentre, have stopped rising. Apart from a jump last week as China redefined some 15,000 unconfirmed cases as covid-19, the number of new cases reported daily seems to be falling. \"Hubei peaked around 6 February, and daily case numbers are dropping,\" says David Fisman at the University of Toronto, Canada. He says this is unlikely to be due to cases not being reported, and that the fall was predictable based on trends seen in January.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "On 15 Importantly, this could also mean that the epidemic could sputter out, especially if we can limit super-spreading events. If many places outside Wuhan \"get lucky\" and get few superspreaders, \"this seems the most likely way a pandemic might be averted\", says Marc Lipsitch at Harvard University.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "However, Lipsitch says that seems a lot to hope for, given the number of countries with infections, and the likely number of missed cases. He predicts that covid-19 will go pandemic, infecting between 40 to 70 per cent of people globally.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Lipsitch and Fisman both say that if that is going to happen, unexplained clusters of severe pneumonia in older people outside China will emerge in a few weeks.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "However, Fisman still thinks the threat could fizzle out. Toronto was hit hard by SARS in 2003. \"It felt exactly this hopeless in the middle of it,\" he says. \"This feels like a replay of the same movie.\"", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "The SARS coronavirus moved mainly via super-spreading and the epidemic died out. Whether that is likely to happen this time should become apparent soon. \"The next couple of weeks are going to be like waiting for a bomb to go off,\" says Fisman. \u275a", "cite_spans": [], "ref_spans": []}, {"section": "Coronavirus update", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "10% of cases may be responsible for 80 per cent of transmission", "text": "", "cite_spans": [], "ref_spans": []}], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "213343016", "_pdf_hash": "7bd495af6c1e1474b1ae3f5e0279f0282fe166bd", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Fabrication of two-dimensional photonic crystal patterns on GaN-based light-emitting diodes using thermally curable monomer-based nanoimprint lithography", "authors": [{"first": "Kyeong-Jae", "middle": [], "last": "Byeon", "suffix": ""}], "year": 2007, "venue": "Appl. Phys. Lett", "link": "122882514"}, "BIBREF1": {"title": "III-Nitride LEDs with photonic crystal structures", "authors": [{"first": "J", "middle": ["J"], "last": "Wierer", "suffix": ""}], "year": 2005, "venue": "Proc. of SPIE", "link": "135707268"}, "BIBREF2": {"title": "Elimination of total internal reflection in GaInN light-emitting diodes by graded-refractive-index micropillars", "authors": [{"first": "", "middle": [], "last": "Kim", "suffix": ""}], "year": 2008, "venue": "Appl. Phys. Lett", "link": "119645559"}, "BIBREF3": {"title": "Handbook of Nitride Semiconductors and Devices", "authors": [{"first": "H", "middle": [], "last": "Morko\u00e7", "suffix": ""}], "year": 2008, "venue": "", "link": "55594680"}, "BIBREF4": {"title": "Two-step passivation for enhanced InGaN/GaN light emitting diodes with step graded electron injectors", "authors": [{"first": "V", "middle": [], "last": "Sheremet", "suffix": ""}], "year": 2018, "venue": "Superlattices and Microstructures", "link": "125763466"}, "BIBREF5": {"title": "Distributed contact flip chip InGaN/GaN blue LED; comparison with conventional LEDs", "authors": [{"first": "M", "middle": [], "last": "Gen\u00e7", "suffix": ""}], "year": 2019, "venue": "Superlattices and Microstructures", "link": "128136751"}}, "ref_entries": {}}
{"paper_id": "213344988", "_pdf_hash": "09811a8c859005ac1f8298adf857aa2f2e9ffd03", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Government Policy as a Disincentive to Housing Innovation in Ogun State, Nigeria", "authors": [{"first": "B", "middle": [], "last": "Adedipe", "suffix": ""}, {"first": "Lasisi", "middle": ["A"], "last": "", "suffix": ""}], "year": 2006, "venue": "The Built Environment: Innovation Policy and Sustainable Development", "link": null}, "BIBREF1": {"title": "Nigeria's Housing Policy and Public-Private Partnership (PPP) Strategy\": Reflection in achieving home ownership for low-income group in Abuja-Nigeria. Urban Dynamics and Housing change", "authors": [{"first": "B", "middle": [], "last": "Abdullahi", "suffix": ""}], "year": 2010, "venue": "nd International Housing Research Conference-4 th", "link": null}, "BIBREF2": {"title": "Housing policy Formulation in Developing Countries\": Evidence of programme implementation from Akure", "authors": [{"first": "", "middle": [], "last": "Aribigbola", "suffix": ""}], "year": 2008, "venue": "Journal of Human Ecology", "link": null}, "BIBREF3": {"title": "Affordable and Functional Housing in a developing Economy. A case study of Nigeria", "authors": [{"first": "S", "middle": [], "last": "Daramola", "suffix": ""}], "year": 2006, "venue": "Journal of Land Use and Development Studies", "link": null}, "BIBREF4": {"title": "Australian housing Policy: 50 years of failure. A submission to the Senate Economics Reference Committee", "authors": [{"first": "S", "middle": [], "last": "Eslake", "suffix": ""}], "year": 2013, "venue": "", "link": null}, "BIBREF5": {"title": "Being the text of a paper presented at the conference on sustainable cities, organised by the New Economic Partnership on African Development (NEDAD), held at Transcop Hilton Hotel", "authors": [{"first": "F", "middle": [], "last": "Falade", "suffix": ""}], "year": 2007, "venue": "", "link": null}, "BIBREF6": {"title": "The Concept, Experience and Applicability to Nigeria's Socio-Economic Millieu", "authors": [{"first": "J", "middle": [], "last": "Fasakin", "suffix": ""}], "year": 1998, "venue": "", "link": null}, "BIBREF7": {"title": "Federal Government of Nigeria; National Housing Policy Draft", "authors": [], "year": 2006, "venue": "", "link": null}, "BIBREF8": {"title": "Incremental Construction: A strategy to Facilitate Access to Housing", "authors": [{"first": "", "middle": [], "last": "Greene", "suffix": ""}, {"first": "", "middle": ["E"], "last": "Rojas", "suffix": ""}], "year": 2008, "venue": "Environment and Urbanisation", "link": "59358474"}, "BIBREF9": {"title": "Housing Policy in Nigeria\": An overview", "authors": [{"first": "Ibitoye", "middle": [], "last": "Ibimilua", "suffix": ""}], "year": 2015, "venue": "American International Journal of Contemporary Research", "link": null}, "BIBREF10": {"title": "Government Housing Project and Assessment-The case of government Estate at oregbami Ikpoba Hill and Ogbowo. Dissertation for the award of Bachelor of Science degree in the Department of Geography and Regional Planning", "authors": [{"first": "", "middle": [], "last": "Ikekpeazue", "suffix": ""}], "year": 2004, "venue": "", "link": null}, "BIBREF11": {"title": "Housing Finance in Nigeria: Needed for Re-engineering", "authors": [{"first": "T", "middle": [], "last": "Nubi", "suffix": ""}], "year": 2001, "venue": "Housing Finance International Special Edition Services", "link": null}, "BIBREF12": {"title": "Towards a Sustainable Housing Finance in Nigeria: The Challenges of developing adequate housing stock and road maps\" Housing Finance International Summer", "authors": [{"first": "T", "middle": [], "last": "Nubi", "suffix": ""}], "year": 2010, "venue": "", "link": null}, "BIBREF13": {"title": "Beyond Bricks and Mortar, Inaugural lecture of Professor T.G Nubi", "authors": [{"first": "T", "middle": [], "last": "Nubi", "suffix": ""}], "year": 2012, "venue": "", "link": null}, "BIBREF14": {"title": "Urban Landscape Planning Experience in Nigeria", "authors": [{"first": "A", "middle": [], "last": "Oduwaye", "suffix": ""}], "year": 1998, "venue": "Landscape and Urban Planning", "link": "83566545"}, "BIBREF15": {"title": "Way forward for Housing Supply in developing countries. An oblique view in", "authors": [{"first": "O", "middle": [], "last": "Omange", "suffix": ""}, {"first": "A", "middle": [], "last": "Udegbe", "suffix": ""}], "year": 2000, "venue": "Innovation, Policy and sustainable development in", "link": null}, "BIBREF16": {"title": "Basic Issues in Housing Development", "authors": [{"first": "F", "middle": [], "last": "Omole", "suffix": ""}], "year": 2001, "venue": "", "link": null}, "BIBREF17": {"title": "Partnership between stakeholders in the provision of and access to affordable 5housing in Malaysia", "authors": [{"first": "H", "middle": [], "last": "Ong", "suffix": ""}, {"first": "Lenard", "middle": [], "last": "", "suffix": ""}], "year": 2002, "venue": "", "link": null}, "BIBREF18": {"title": "The state role in popular Housing programmes in Shanghai: from provider to enabler to facilitator forum", "authors": [{"first": "U", "middle": [], "last": "Sengupta", "suffix": ""}, {"first": "S", "middle": [], "last": "Ganesan", "suffix": ""}], "year": 2004, "venue": "", "link": null}, "BIBREF19": {"title": "Housing Finance in Nigeria: Need for Re-Engineering", "authors": [{"first": "A", "middle": [], "last": "Waziri", "suffix": ""}, {"first": "O", "middle": [], "last": "Rookie", "suffix": ""}], "year": 2013, "venue": "Housing Finance International, Special Edition Series", "link": null}}, "ref_entries": {}}
{"paper_id": "147010188", "_pdf_hash": "bce2c273b1297d750b1d6aa6055143bfb031873d", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Tegenstemmen: Een Antwoord op het Neoliberalisme", "authors": [{"first": "J", "middle": [], "last": "Marijnissen", "suffix": ""}], "year": 2010, "venue": "", "link": null}, "BIBREF1": {"title": "We Laten Niemand Los", "authors": [{"first": "Wim", "middle": [], "last": "Kok", "suffix": ""}], "year": 1995, "venue": "", "link": null}, "BIBREF2": {"title": "The March into Socialism", "authors": [{"first": "J", "middle": [], "last": "Schumpeter", "suffix": ""}], "year": 1950, "venue": "American Economic Review", "link": null}, "BIBREF3": {"title": "According to the ruling political fashions of the time, leftist students flirted with Stalinism and Maoism. As a result, they had a wholly different idea of socialism than the generation of Den Uyl. At the same time", "authors": [{"first": "", "middle": [], "last": "Ibid", "suffix": ""}], "year": "", "venue": "the same paragraph, Schumpeter ironically refers to Hayek and the MPS as the sole opposition to these policies", "link": null}, "BIBREF4": {"title": "Both groups held a rigid, old-fashioned view of socialism: one side with the idea of implementing it to further the revolution, the other with the aim of finally getting rid", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF5": {"title": "Relevant is also the reply of Den Uyl to those who criticized the vagueness of The Road to Freedom: 'In his reply, Den Uyl argued that uncertainty is typical for democratic planning. It could always be otherwise, alternatives had to be possible", "authors": [{"first": "De", "middle": [], "last": "Pvda", "suffix": ""}, {"first": "", "middle": [], "last": "Weg", "suffix": ""}, {"first": "", "middle": [], "last": "Vrijheid", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF7": {"title": "We Laten Niemand Los', Den Uyl-lezing", "authors": [{"first": "W", "middle": [], "last": "Kok", "suffix": ""}], "year": 1995, "venue": "", "link": null}, "BIBREF8": {"title": "Its pragmatic ambition to replace the PvdA as the preferred leftist coalition partner for government, and its willingness to implement austerity measures to meet that goal, seem to signal a possible repeat of the PvdA-trajectory. 64 The radical politics of Den Uyl and his pursuit of a left-wing majority have been abandoned for more moderate aims", "authors": [], "year": "", "venue": "that it presents itself as an anti-utopian, realist force", "link": null}, "BIBREF9": {"title": "From sect to mass party", "authors": [{"first": "A", "middle": [], "last": "Jong", "suffix": ""}], "year": 2014, "venue": "Jacobin Magazine", "link": null}}, "ref_entries": {}}
{"paper_id": "147010337", "_pdf_hash": "2155353e862c41740f1002d8f07ade3ab30d74cd", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Revised school chemistry for senior secondary schools", "authors": [{"first": "O", "middle": ["Y"], "last": "Ababio", "suffix": ""}], "year": 2005, "venue": "", "link": null}, "BIBREF1": {"title": "Research and statistics in education and social sciences: Method and application", "authors": [{"first": "E", "middle": ["O"], "last": "Akuezuilo", "suffix": ""}, {"first": "N", "middle": [], "last": "Agu", "suffix": ""}], "year": 2004, "venue": "", "link": null}, "BIBREF2": {"title": "Students view of scientists and the science: Results from the national study", "authors": [{"first": "C", "middle": [], "last": "Barman", "suffix": ""}], "year": 1997, "venue": "Science and children", "link": null}, "BIBREF3": {"title": "Stereotypic image of the scientists: The Draw-a-Scientist-Test", "authors": [{"first": "D", "middle": ["C"], "last": "Chambars", "suffix": ""}], "year": 1983, "venue": "Science Education", "link": null}, "BIBREF4": {"title": "Research methods in education for colleges and universities", "authors": [{"first": "J", "middle": ["F"], "last": "Egbule", "suffix": ""}, {"first": "D", "middle": ["O"], "last": "Okobia", "suffix": ""}], "year": 2001, "venue": "", "link": null}, "BIBREF5": {"title": "Images of scientists: The perceptions of senior school students", "authors": [{"first": "P", "middle": ["C"], "last": "Igbojinwaekwu", "suffix": ""}], "year": 2012, "venue": "The Intuition", "link": null}, "BIBREF6": {"title": "Effectiveness of guided multiple-choice objective questions test on academic achievement in senior school mathematics by school location", "authors": [{"first": "P", "middle": ["C"], "last": "Igbojinwaekwu", "suffix": ""}], "year": 2015, "venue": "Journal of Education and Practice", "link": "142907330"}, "BIBREF7": {"title": "Gender differences in students' experiences , interest and attitudes toward science and scientists", "authors": [{"first": "M", "middle": ["G"], "last": "Jones", "suffix": ""}, {"first": "A", "middle": [], "last": "Howe", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Rua", "suffix": ""}], "year": 2000, "venue": "Science Education", "link": "143478267"}, "BIBREF8": {"title": "Foundations of behavioural research", "authors": [{"first": "F", "middle": ["N"], "last": "Kerlinger", "suffix": ""}], "year": 1979, "venue": "Fundamental of educational research", "link": "167070472"}, "BIBREF9": {"title": "Educational research: Basic issues and methodology", "authors": [{"first": "B", "middle": ["C"], "last": "Nworgu", "suffix": ""}], "year": 1991, "venue": "", "link": null}, "BIBREF10": {"title": "The effects of teaching relevant mathematical topics before and during the teaching of selected topics in chemistry", "authors": [{"first": "F", "middle": ["C"], "last": "Offiah", "suffix": ""}, {"first": "N", "middle": ["N C"], "last": "Samuel", "suffix": ""}], "year": 2008, "venue": "th Annual Conference Proceedings of Science Teachers Association of Nigeria (STAN)", "link": null}, "BIBREF11": {"title": "Bronchure: Guidance for Admissions into Nigeria Universities and other Tertiary Institutions in Nigeria", "authors": [], "year": 2014, "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "147012332", "_pdf_hash": "035d918da1a44ba06c2b177a03cfbf218c3cb5b2", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "147014638", "_pdf_hash": "7db8801d78c65c9648e828b2bb9936c648ca49eb", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "147015306", "_pdf_hash": "ff723fa8122fb381ce2ad2765325dd8788c8c5c8", "abstract": [{"section": "Abstract", "text": "Individuals can simulate and pre-experience the future events. The ability to image the plausible future is termed episodic future thinking. Particularly, it is important for us to construct the detailed scenario about future event. If we couldn't simulate it in detail, we may fail to prepare what is necessary in future or deal with the unexpected event in an appropriate manner. In present study, we investigate how the level of detail specified in episodic future thinking. We supposed two possibilities specifying level of detail in future thinking: one is the retrieval process from past episodic memory and the other is the recombination process of retrieved details into coherent representation. To investigate which process is important for specifying the level of detail, we draw on the association between level of detail and temporal distance. Level of detail of imaged future event was reflected in activation pattern of concept of future temporal distances, and retrieval of detail from episodic memory was reflected in concept of past temporal distance. The results show that details were retrieved from episodic memory when participants construct the detailed image of future events. We suggest that levels of detail in future events are specified in recombination process.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "", "text": "", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Mechanism of specifying level of detail in episodic future thinking ing", "authors": [{"first": "Yuichi", "middle": [], "last": "Ito", "suffix": ""}], "year": "", "venue": "Trends in Cognitive Sciences", "link": "147015306"}, "BIBREF1": {"title": "The association between psychological distance and construal level: evidence from an implicit association test", "authors": [{"first": "Y", "middle": [], "last": "Bar-Anan", "suffix": ""}, {"first": "", "middle": [], "last": "Liberman", "suffix": ""}, {"first": "Y", "middle": [], "last": "Nira &amp; Trope", "suffix": ""}], "year": 2006, "venue": "Journal of Experimental Psychology: General", "link": "12364109"}, "BIBREF2": {"title": "Self-projection and the brain", "authors": [{"first": "R", "middle": [], "last": "Buckner", "suffix": ""}, {"first": "D", "middle": [], "last": "Carroll", "suffix": ""}], "year": 2007, "venue": "Trends in Cognitive Sciences", "link": "12791119"}, "BIBREF3": {"title": "Implementation intentions and facilitation of prospective memory", "authors": [{"first": "A", "middle": ["L"], "last": "Chasteen", "suffix": ""}, {"first": "D", "middle": ["C"], "last": "Park", "suffix": ""}, {"first": "N", "middle": [], "last": "Schwarz", "suffix": ""}], "year": 2001, "venue": "Psychological Science", "link": "13376185"}, "BIBREF4": {"title": "Episodic memories", "authors": [{"first": "M", "middle": ["A"], "last": "Conway", "suffix": ""}], "year": 2009, "venue": "Neuropsychologia", "link": null}, "BIBREF5": {"title": "The construction of autobiographical memories in the self-memory system", "authors": [{"first": "M", "middle": ["A"], "last": "Conway", "suffix": ""}, {"first": "C", "middle": ["W"], "last": "Pleydell\ufffdpearce", "suffix": ""}, {"first": "", "middle": [], "last": "\ufffd2000\ufffd", "suffix": ""}], "year": "", "venue": "Psychological Review", "link": "24238763"}, "BIBREF6": {"title": "Neurophysiological correlates of memory for experienced and imagined events", "authors": [{"first": "M", "middle": ["A"], "last": "Conway", "suffix": ""}, {"first": "C", "middle": ["W"], "last": "Pleydell\ufffdpearce", "suffix": ""}, {"first": "S", "middle": ["E"], "last": "Whitecross", "suffix": ""}, {"first": "H", "middle": [], "last": "Sharpe", "suffix": ""}], "year": 2003, "venue": "Neuropsychologia", "link": "14849182"}, "BIBREF7": {"title": "Tracking the construction of episodic future thoughts", "authors": [{"first": "A", "middle": [], "last": "D&apos;argembeau", "suffix": ""}, {"first": "A", "middle": [], "last": "Mathy", "suffix": ""}], "year": 2011, "venue": "Journal of Experimental Psychology: General", "link": "207725668"}, "BIBREF9": {"title": "Frequency, characteristics and functions of future-oriented thoughts in daily life", "authors": [], "year": "", "venue": "Applied Cognitive Psychology", "link": "143927030"}, "BIBREF10": {"title": "Phenomenal characteristics associated with projecting oneself back into the past and forward into the future: Influence of valence and temporal distance", "authors": [{"first": "A", "middle": [], "last": "D&apos;argembeau", "suffix": ""}, {"first": "M", "middle": [], "last": "Van Der Linden", "suffix": ""}], "year": 2004, "venue": "Consciousness and Cognition", "link": "37248343"}, "BIBREF11": {"title": "Individual differences in the phenomenology of mental time travel: The effect of vivid visual imagery and emotion regulation strategies. Consciousness and Cognition", "authors": [{"first": "D&apos;argembeau &amp;", "middle": [], "last": "Van Der Linden", "suffix": ""}], "year": 2006, "venue": "", "link": null}, "BIBREF12": {"title": "Memory and temporal experience: the effects of episodic memory loss on an amnesic patient's ability to remember the past and imagine the future", "authors": [{"first": "S", "middle": ["B"], "last": "Klein", "suffix": ""}, {"first": "J", "middle": [], "last": "Loftus", "suffix": ""}, {"first": "J", "middle": ["F"], "last": "Kihlstrom", "suffix": ""}], "year": 2002, "venue": "Social Cognition", "link": "19168428"}, "BIBREF13": {"title": "Thinking of the future and past: the roles of the frontal pole and the medial temporal lobes", "authors": [{"first": "J", "middle": [], "last": "Okuda", "suffix": ""}, {"first": "T", "middle": [], "last": "Fujii", "suffix": ""}, {"first": "H", "middle": [], "last": "Ohtake", "suffix": ""}, {"first": "T", "middle": [], "last": "Tsukiura", "suffix": ""}, {"first": "K", "middle": [], "last": "Tanji", "suffix": ""}, {"first": "K", "middle": [], "last": "Suzuki", "suffix": ""}, {"first": "R", "middle": [], "last": "Kawashima", "suffix": ""}, {"first": "H", "middle": [], "last": "Fukuda", "suffix": ""}, {"first": "M", "middle": [], "last": "Itoh", "suffix": ""}, {"first": "A", "middle": [], "last": "Yamadori", "suffix": ""}], "year": 2003, "venue": "NeuroImage", "link": "25549031"}, "BIBREF14": {"title": "The cognitive neuroscience of constructive memory: remembering the past and imagining the future", "authors": [{"first": "D", "middle": ["L"], "last": "Schacter", "suffix": ""}, {"first": "D", "middle": ["R"], "last": "Addis", "suffix": ""}], "year": 2007, "venue": "Philosophical transactions of the Royal Society of London. Series B, Biological Sciences", "link": "45470"}, "BIBREF15": {"title": "On the nature of medial temporal lobe contributions to the constructive simulation of future events", "authors": [{"first": "D", "middle": ["L"], "last": "Schacter", "suffix": ""}, {"first": "D", "middle": ["R"], "last": "Addis", "suffix": ""}], "year": 2009, "venue": "Philosophical transactions of the Royal Society of London. Series B, Biological Sciences", "link": "7281680"}, "BIBREF16": {"title": "Neural substrates of envisioning the future", "authors": [{"first": "K", "middle": ["K"], "last": "Szpunar", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Watson", "suffix": ""}, {"first": "K", "middle": ["B"], "last": "Mcdermott", "suffix": ""}, {"first": "", "middle": [], "last": "\ufffd200\ufffd\ufffd", "suffix": ""}], "year": "", "venue": "Proceedings of the National Academy of Sciences of the United States of America", "link": "15020904"}, "BIBREF17": {"title": "Temporal construal. Psychological Review", "authors": [{"first": "Y", "middle": [], "last": "Trope", "suffix": ""}, {"first": "N", "middle": [], "last": "Liberman", "suffix": ""}], "year": 2003, "venue": "", "link": null}, "BIBREF18": {"title": "Construal-level theory of psychological distance", "authors": [{"first": "Y", "middle": [], "last": "Trope", "suffix": ""}, {"first": "N", "middle": [], "last": "Liberman", "suffix": ""}], "year": 2010, "venue": "Psychological Review", "link": "10044393"}, "BIBREF19": {"title": "Episodic memory: from mind to brain. Annual Review of Psychology", "authors": [{"first": "E", "middle": [], "last": "Tulving", "suffix": ""}], "year": 2002, "venue": "", "link": null}, "BIBREF20": {"title": "When the future becomes the past: Difference in brain activation patterns for episodic memory and episodic future thinking", "authors": [{"first": "J", "middle": [], "last": "Weiler", "suffix": ""}, {"first": "B", "middle": [], "last": "Suchan", "suffix": ""}, {"first": "I", "middle": [], "last": "Daum", "suffix": ""}, {"first": "", "middle": [], "last": "\ufffd2010\ufffd", "suffix": ""}], "year": "", "venue": "Behavioral Brain Research", "link": "20206803"}}, "ref_entries": {"FIGREF0": {"text": "Figure 1: The process of constructing images in episodic future thinking", "type": "figure"}}}
{"paper_id": "147016855", "_pdf_hash": "e9d333b2213e5e57554c64a5ac20ca236d4999a8", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "116981165", "_pdf_hash": "4d1a60ce56c61db2d2a45953febb7b865f3e7d69", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "For a detailed discussion and further references see T. _K. Gaisser and F. Halzen", "authors": [{"first": "I", "middle": [], "last": "", "suffix": ""}], "year": 1985, "venue": "Proceedings of the Aspen Winter Physics Conf_ence", "link": null}, "BIBREF1": {"title": "Multiparticle Dynamics", "authors": [{"first": "F", "middle": [], "last": "Halzen", "suffix": ""}], "year": 1984, "venue": "", "link": null}, "BIBREF2": {"title": "Proceedings of the pp Collider Workshop", "authors": [{"first": "G", "middle": [], "last": "Ciapetti", "suffix": ""}], "year": 1985, "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "116981722", "_pdf_hash": "49550096441d71908980fd4ceef58d0c537931e8", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "116982275", "_pdf_hash": "323a65c05b79c255b8c09f326779a2776024a953", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "116984330", "_pdf_hash": "0a2aa512e99a21c193b32a6e31db93c0f5803cba", "abstract": [], "body_text": [], "bib_entries": {"BIBREF1": {"title": "Significant Visual Properties of Some Fluorescent Pigments", "authors": [{"first": "D", "middle": ["R"], "last": "Hanson", "suffix": ""}, {"first": "A", "middle": ["D"], "last": "Dickson", "suffix": ""}], "year": 1963, "venue": "Highway Research Record", "link": "136552588"}, "BIBREF2": {"title": "Effeet of Sign Position and Brightness on Seeing Simulated Highway Signs", "authors": [{"first": "T", "middle": ["W"], "last": "Forbes", "suffix": ""}], "year": 1967, "venue": "Highway Research Record", "link": null}, "BIBREF3": {"title": "Applied Optics and Optical Engineering", "authors": [{"first": "R", "middle": [], "last": "Kingslake", "suffix": ""}], "year": 1965, "venue": "", "link": "54133830"}, "BIBREF4": {"title": "How We See: A Summary of Basic Principles", "authors": [{"first": "A", "middle": [], "last": "Chapanis", "suffix": ""}], "year": "", "venue": "In Panel on Psychology and Physiology, Committee on Undersea Warfare: A Siirvey Report on Human Factol'S in Undersea Warfare. National Research Council", "link": null}, "BIBREF5": {"title": "Traffic Enginee1\u00b7ing Handbook. Institute of Traffic Engineers", "authors": [{"first": "B", "middle": ["D"], "last": "Greenshields", "suffix": ""}], "year": 1965, "venue": "", "link": null}, "BIBREF6": {"title": "Modern Camouflage", "authors": [{"first": "R", "middle": ["P"], "last": "Breckenridge", "suffix": ""}], "year": 1942, "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "116984815", "_pdf_hash": "a6622764026d388ea0e3d814a0ac199c7650fa6c", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Planar harmonic univalent and related mappings", "authors": [{"first": "O", "middle": ["P"], "last": "Ahuja", "suffix": ""}], "year": 2005, "venue": "J. Inequal. Pure Appl. Math", "link": "15400210"}, "BIBREF1": {"title": "Planar harmonic convolution operators generated by hypergeometric functions", "authors": [{"first": "O", "middle": ["P"], "last": "Ahuja", "suffix": ""}], "year": 2007, "venue": "Integral Transform Spec. Funct", "link": "123233843"}, "BIBREF2": {"title": "Connections between various subclasses of planar harmonic mappings involving hypergeometric functions", "authors": [{"first": "O", "middle": ["P"], "last": "Ahuja", "suffix": ""}], "year": 2008, "venue": "Appl. Math. Comput", "link": "31058385"}, "BIBREF3": {"title": "Noshiro-type harmonic univalent functions", "authors": [{"first": "O", "middle": ["P"], "last": "Ahuja", "suffix": ""}, {"first": "-J", "middle": ["M"], "last": "Jahangiri", "suffix": ""}], "year": 2002, "venue": "Sci. Math. Jpn", "link": null}, "BIBREF4": {"title": "Geometric properties of generalized Bessel functions", "authors": [{"first": "A", "middle": [], "last": "Baricz", "suffix": ""}], "year": 2008, "venue": "Publ. Math. Debrecen", "link": "115799440"}, "BIBREF5": {"title": "Geometric properties of generalized Bessel functions of complex order", "authors": [{"first": "A", "middle": [], "last": "Baricz", "suffix": ""}], "year": 2006, "venue": "Mathematica", "link": null}, "BIBREF6": {"title": "Generalized Bessel functions of the first kind", "authors": [{"first": "A", "middle": [], "last": "Baricz", "suffix": ""}], "year": 2008, "venue": "", "link": "208850571"}, "BIBREF7": {"title": "Generalized Bessel functions of the first kind", "authors": [{"first": "A", "middle": [], "last": "Baricz", "suffix": ""}], "year": 2010, "venue": "Lecture Notes in Math", "link": "117972034"}, "BIBREF8": {"title": "Starlike and prestarlike hypergeometric functions", "authors": [{"first": "B", "middle": ["C B"], "last": "Carleson -D", "suffix": ""}, {"first": "", "middle": [], "last": "Shaffer", "suffix": ""}], "year": 1984, "venue": "SIAM J. Math. Anal", "link": "122352509"}, "BIBREF9": {"title": "Harmonic univalent functions", "authors": [{"first": "J", "middle": [], "last": "Clunie -T Sheil-Small", "suffix": ""}], "year": 1984, "venue": "Ann. Acad. Sci. Fen. Series A.I. Math", "link": "121041434"}, "BIBREF10": {"title": "Harmonic Mappings in the Plane", "authors": [{"first": "P", "middle": [], "last": "Duren", "suffix": ""}], "year": 2004, "venue": "Cambridge Tracts in Mathematics", "link": "3059444"}, "BIBREF11": {"title": "Univalence of Gaussian and confluent hypergeometric functions", "authors": [{"first": "S", "middle": ["T"], "last": "Miller -P", "suffix": ""}, {"first": "", "middle": [], "last": "Mocanu", "suffix": ""}], "year": 1990, "venue": "Proc. Amer. Math. Soc", "link": "123715050"}, "BIBREF12": {"title": "Geometric properties of Generalized Bessel functions", "authors": [{"first": "S", "middle": ["R"], "last": "Mondal", "suffix": ""}, {"first": "-A", "middle": [], "last": "Swaminathan", "suffix": ""}], "year": 2012, "venue": "Bull. Malays. Math. Sci. Soc", "link": "59463106"}, "BIBREF13": {"title": "Univalent and starlike generalized hypergeometric functions", "authors": [{"first": "S", "middle": ["M"], "last": "Owa -H", "suffix": ""}, {"first": "", "middle": [], "last": "Srivastava", "suffix": ""}], "year": 1987, "venue": "Canad. J. Math", "link": "119716731"}, "BIBREF14": {"title": "Starlikeness properties for convolution involving hypergeometric series", "authors": [{"first": "S", "middle": [], "last": "Ponnusamy", "suffix": ""}, {"first": "-F", "middle": [], "last": "R\u00f8nning", "suffix": ""}], "year": 1998, "venue": "Ann. Univ. Mariae Curie-Sklodowska, L. II", "link": null}, "BIBREF15": {"title": "Some connections between various subclasses of planar harmonic mappings involving generalized Bessel functions", "authors": [{"first": "S", "middle": [], "last": "", "suffix": ""}], "year": 2015, "venue": "Afrika Matematika", "link": null}, "BIBREF16": {"title": "Connections between various subclasses of planar harmonic mappings involving generalized Bessel functions", "authors": [{"first": "S", "middle": [], "last": "", "suffix": ""}], "year": 2015, "venue": "Thai J. Math", "link": "116984815"}, "BIBREF17": {"title": "Harmonic starlikeness and convexity of integral operators generated by generalized Bessel functions", "authors": [{"first": "S", "middle": [], "last": "", "suffix": ""}], "year": 2014, "venue": "Acta Math. Vietnam", "link": "122131284"}, "BIBREF18": {"title": "Mapping properties of generalized Bessel functions on some subclasses of univalent functions", "authors": [{"first": "S", "middle": [], "last": "", "suffix": ""}], "year": 2013, "venue": "Analele Universitatii Oradea Fasc. Matematica XX", "link": null}, "BIBREF19": {"title": "Some sufficient condition for generalized Bessel functions associated with conic regions", "authors": [{"first": "S", "middle": [], "last": "Porwal", "suffix": ""}, {"first": "-M", "middle": [], "last": "Ahmad", "suffix": ""}], "year": 2015, "venue": "Vietnam J. Math", "link": "120221565"}, "BIBREF20": {"title": "An application of generalized Bessel functions on certain analytic functions", "authors": [{"first": "S", "middle": ["K"], "last": "Porwal -K", "suffix": ""}, {"first": "", "middle": [], "last": "Dixit", "suffix": ""}], "year": 2013, "venue": "Acta Universitatis Matthiae Belii", "link": null}, "BIBREF21": {"title": "An application of certain convolution operator involving hypergeometric functions", "authors": [{"first": "S", "middle": ["K"], "last": "Porwal -K", "suffix": ""}, {"first": "", "middle": [], "last": "Dixit", "suffix": ""}], "year": 2010, "venue": "J. Raj. Acad. Phy. Sci", "link": null}, "BIBREF22": {"title": "An application of hypergeometric functions on harmonic univalent functions", "authors": [{"first": "S", "middle": ["K"], "last": "Porwal -K", "suffix": ""}, {"first": "", "middle": [], "last": "Dixit", "suffix": ""}], "year": 2010, "venue": "Bull. Math. Anal. Appl", "link": null}, "BIBREF23": {"title": "Goodman-R\u00f8nning-type harmonic univalent functions", "authors": [{"first": "T. Rosy -B", "middle": ["A G"], "last": "Stephen -K", "suffix": ""}, {"first": "", "middle": ["M"], "last": "Subramanian -J", "suffix": ""}, {"first": "", "middle": [], "last": "Jahangiri", "suffix": ""}], "year": 2001, "venue": "Kyungpook Math. J", "link": null}, "BIBREF24": {"title": "On the order of starlikeness of hypergeometric functions", "authors": [{"first": "S", "middle": [], "last": "Ruscheweyh", "suffix": ""}, {"first": "-V", "middle": [], "last": "Singh", "suffix": ""}], "year": 1986, "venue": "J. Math. Anal. Appl", "link": "122988127"}, "BIBREF25": {"title": "Class mappings properties of convolutions involving certain univalent functions associated with hypergeometric functions", "authors": [{"first": "A", "middle": ["K"], "last": "Sharma", "suffix": ""}, {"first": "-S. Porwal -K", "middle": ["K"], "last": "Dixit", "suffix": ""}], "year": 2013, "venue": "Electronic J. Math. Anal. Appl", "link": null}}, "ref_entries": {}}
{"paper_id": "116985999", "_pdf_hash": "77ab2f1019b8c6f0e587ea1762b4329447647958", "abstract": [{"section": "Abstract", "text": "We reanalyzed the data from the Infrared Telescope in Space (IRTS) based on up-to-date observations of zodiacal light, integrated star light and diffuse Galactic light. We confirmed the existence of residual isotropic emission, which is slightly fainter, but at nearly the same level as previously reported. At wavelengths longer than 2 \u00b5m, our result is fairly consistent with recent observations with Japanese infrared astronomy satellite, AKARI. We performed all of our analyses using two different models of zodiacal light (Kelsall and Wright models). In both cases, we detect residual isotropic emission that is significantly brighter than the integrated light of galaxies (though slightly fainter in the case of the Wright model). Thus, we confirm the existence of excess near-infrared emission, independent of the zodiacal light model used. The spectral shape of the excess isotropic emission is similar to that of the recently observed spectrum of excess fluctuations, which suggests the excess brightness and fluctuations may arise from the same source.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Observations of extragalactic background light (EBL) have been obtained over a wide range of wavelengths to examine the energy density of the universe. In particular, near-infrared EBL has been thought to provide important clues for our understanding of the early universe and the evolution of galaxies. Significant near-infrared isotropic emission, that cannot be explained with known foreground emission, was detected with the COsmic Background Explorer (COBE) (Cambr\u00e9sy et al. 2001; Gorjian et al. 2000; Wright and Reese 2000; Levenson et al. 2007 ) and the InfraRed Telescope in Space (IRTS) (Matsumoto et al. (2005) , hereafter referred to as Paper I). Recent AKARI observations (Tsumura et al. 2013d ) also showed a result consistent with COBE and IRTS at wavelengths longer than 2 \u00b5m.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "Due to the recent discovery of large excess fluctuations in the near-infrared sky (Kashlinsky et al. 2005 (Kashlinsky et al. , 2007a Matsumoto et al. 2011; Zemcov et al. 2014) , the excess background emission in the near-infrared has attracted more interest.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "The result of paper I generated broad interest, given that the IRTS detection limit for point sources was much fainter ( \u223c 11 mag) than for COBE, and the low resolution spectroscopy aspect of IRTS was unique. However, as Mattila (2006) pointed out, paper I did not take the contribution of diffuse Galactic light (DGL) into account. Furthermore, uncertainty in the model of zodiacal light (ZL) (Kelsall et al. 1998 ) has been a concern, given that ZL is the dominant foreground emission, and that the spectral shape of the residual isotropic emission is similar to that of ZL (Dwek et al. 2005) .", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "In response to these criticisms, here we have reanalyzed the IRTS data using up-to-date observational results on ZL, integrated star light (ISL), and DGL. Furthermore, we performed the same analysis with a different ZL model (the so-called Wright model, Wright (1998) ), and examined how a different choice of ZL model affects our results.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "In this paper, we briefly present the IRTS observations and the acquisition of raw data in Section 2. In Section 3, we estimate the contribution of foreground emission from ZL, ISL and DGL based on the latest observations. In Section 4, we search for residual isotropic emission using two ZL models based on the correlation of model ZL brightness with the overall sky brightness, after subtracting the ISL and DGL. In section 5, we discuss the astrophysical implications of the detected excess brightness.", "cite_spans": [], "ref_spans": []}, {"section": "IRTS observation", "text": "In this paper, we used the same data set as used in paper I. Here, we give a brief description of the IRTS mission and data acquisition process. Further details of the IRTS mission are described in paper I.", "cite_spans": [], "ref_spans": []}, {"section": "IRTS observation", "text": "IRTS was one of the mission experiments on the small space platform, Space Flyer Unit (SFU), that was launched on March 18, 1995. The orbit was a low-inclination near-earth orbit and IRTS continuously surveyed the sky avoiding the sun and the earth.", "cite_spans": [], "ref_spans": []}, {"section": "IRTS observation", "text": "The IRTS observations lasted for about 30 days, during which 7% of the sky was surveyed (Murakami et al. 1996) .", "cite_spans": [], "ref_spans": []}, {"section": "IRTS observation", "text": "The Near InfraRed Spectrometer (NIRS) was one of the focal plane instruments of IRTS, and was optimized to obtain spectra of the diffuse background (Noda et al. 1994 ).", "cite_spans": [], "ref_spans": []}, {"section": "IRTS observation", "text": "Details of the flight performance of NIRS can be found in Noda et al. (1996) . NIRS covered the wavelength range from 1.4 \u00b5m to 4.0 \u00b5m with a spectral resolution of 0.13 \u00b5m, which provided 24 independent wavelength bands. The beam size was 8 arcmin square and the detection limit for point sources was \u223c11 mag, which is considerably fainter than that of COBE.", "cite_spans": [], "ref_spans": []}, {"section": "IRTS observation", "text": "Data were taken with an integration time of 5 sec, during which no distinguishable stars and no cosmic ray hits were detected in any of the wavelength bands. After subtracting the dark current when the cold shutter was closed, the sky brightness signal was obtained.", "cite_spans": [], "ref_spans": []}, {"section": "IRTS observation", "text": "During each 5 sec exposure, the telescope axis moved about 20 arcmin along a great circle, which resulted in a trapezoidal beam pattern, 8 arcmin \u00d7 20 arcmin.", "cite_spans": [], "ref_spans": []}, {"section": "IRTS observation", "text": "For the analysis of background radiation, the data at high Galactic latitudes (b > 40", "cite_spans": [], "ref_spans": []}, {"section": "IRTS observation", "text": "\u2022 )", "cite_spans": [], "ref_spans": []}, {"section": "IRTS observation", "text": "were considered separately to minimize the foreground contribution from stars and Galactic emission. The highest Galactic latitude was 58", "cite_spans": [], "ref_spans": []}, {"section": "IRTS observation", "text": "\u2022 , while the ecliptic latitude ranged from 12", "cite_spans": [], "ref_spans": []}, {"section": "IRTS observation", "text": "\u2022 to 71", "cite_spans": [], "ref_spans": []}, {"section": "IRTS observation", "text": "\u2022 in the selected region of sky.", "cite_spans": [], "ref_spans": []}, {"section": "IRTS observation", "text": "Finally, complete spectra of the sky were obtained at 1010 fields, which were free from contamination and cosmic rays.", "cite_spans": [], "ref_spans": []}, {"section": "Foreground emission", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Zodiacal light (ZL)", "text": "Zodiacal light (ZL) is emission from within the solar system, which consists of scattered sunlight and thermal emission by interplanetary dust. In paper I, we adopted the model by Kelsall et al. (1998) , which is a physical model constructed by using seasonal variations of ZL observed with the Diffuse InfraRed Background Explorer (DIRBE) on COBE. For the same DIRBE data, Wright (1998) proposed a different physical model based on the so-called \"strong zodi principle\", which assumed no residual emission at 25 \u00b5m toward the ecliptic pole. In this paper, we use both models and examine the resulting difference in EBL. As for the Wright model, we use the model revised by Gorjian et al. (2000) .", "cite_spans": [], "ref_spans": []}, {"section": "Zodiacal light (ZL)", "text": "The model spectrum of ZL for the IRTS bands was obtained for the scattering and thermal emission components separately. For the scattering component, we simply assumed the spectral shape of the sun (ASTM G173-03 Reference System) 1 normalized to the model brightness in the K band. For the thermal component, we extrapolated the model brightness in the M band to the shorter IRTS wavelength bands, assuming a 300K blackbody based on recent AKARI observations (Tsumura et al. 2013b) . We obtained the model spectrum of ZL by summing the scattering and thermal emission components. Compared with the model used in paper I, the ZL component at wavelengths longer than 3 \u00b5m is a bit brighter.", "cite_spans": [], "ref_spans": []}, {"section": "Zodiacal light (ZL)", "text": "We confirm the validity of the assumed ZL spectrum by comparing with observations in Section 4.", "cite_spans": [], "ref_spans": []}, {"section": "Integrated star light (ISL)", "text": "The integrated light from stars fainter than the IRTS magnitude limit (ISL) is a source of foreground emission. The best way to estimate the ISL is to count 2MASS stars in the beam. However, the uncertainty in attitude determination and the irregular beam pattern elongated along the scan path, make this analysis difficult. In paper I, we applied the SKY model (Cohen 1997) , and assumed a simple cosec(b) law to model the ISL in three selected fields. In this paper, we adopt an improved model, the so-called TRILEGAL galaxy model (Girardi et al. 2005) . We calculated the ISL for 12 equally spaced fields along the scan path in the J, H, K, L, and L S bands. We then performed 50 Monte Carlo simulations for each 1 square degree field and assigned the average values to be the typical ISL. However, the uncertainty of the TRILEGAL model is large, so we calibrated the model ISL by comparing with the ISL due to 2MASS stars in the H and K bands. We added a contribution from stars fainter than the 2MASS limiting magnitudes using the TRILEGAL 1 Available in electronic form at http://rredc.nrel.gov/solar/spectra/am1.5/astmg173/astmg173.html model, although this contribution to the ISL was only a few percent. Apart from the model error, we calculated the ISL assuming a limiting magnitude fluctuation of \u00b1 0.5 mag, and added the difference to the errors. This error due to limiting magnitude fluctuations is slightly larger than the error due to the uncertainty in the model ISL. The ISL thus obtained is at a similar level to that of paper I, but based on more reliable brightness and spatial distributions.", "cite_spans": [{"start": 362, "end": 374, "text": "(Cohen 1997)", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "Diffuse Galactic light (DGL)", "text": "In paper I, DGL was not taken into account as a source of foreground emission, as noted by Mattila (2006) . This was because no reliable observation of DGL had been reported at that time, and the contribution of DGL to the overall sky brightness was thought to be small. Using new observations of the near-infrared DGL, we have estimated the foreground contribution of DGL in the IRTS fields and bands. Tsumura et al. (2013c) obtained low resolution spectra of the diffuse sky with AKARI for the wavelength range from 2 \u00b5m to 5 \u00b5m, and detected a clear correlation between the near-infrared sky brightness and far-infrared emission (100 \u00b5m, Schlegel et al. (1998)). The PAH band at 3.3 \u00b5m was clearly detected, however, these observations were limited to the Galactic plane at b < 15", "cite_spans": [], "ref_spans": []}, {"section": "Diffuse Galactic light (DGL)", "text": "\u2022 . Arai et al. (2014) performed a similar correlation analysis with the data of the Low Resolution Spectrometer (LRS) (Tsumura et al. 2013a) , which is one of instruments in the sounding rocket experiment, CIBER (Cosmic Infrared Background ExpeRiment, Zemcov et al. (2013) ). They also detected a clear correlation at high Galactic latitudes, between the near-infrared sky brightness at 1 \u00b5m to 1.5 \u00b5m, and far-infrared emission. We used the far-infrared map compiled by Schlegel et al. (1998) , and retrieved the 100 \u00b5m brightness with a FOV of 12 arcmin diameter for each of the 1010 IRTS fields. Using the ratio of DGL to 100 \u00b5m brightness (Fig.1) , we obtained a DGL estimate for each of the 24 IRTS bands in the 1010 IRTS fields.", "cite_spans": [], "ref_spans": [{"start": 644, "end": 651, "text": "(Fig.1)", "ref_id": "FIGREF0"}]}, {"section": "Residual isotropic emission", "text": "We measured the isotropic emission using the same procedure as in paper I. We first The lower plots in Fig.3 show the residual emission at 1.8 \u00b5m after subtracting all foreground emission components, which shows the residual emission is fairly isotropic.", "cite_spans": [], "ref_spans": []}, {"section": "Residual isotropic emission", "text": "Compared with Paper I (see Fig.9 in paper I), a considerably better isotropy was achieved due to the improved estimation of the foreground emission components. Fig.4 shows the slopes of the linear fit lines for both the Kelsall and Wright models. The spectrum of the ZL can be obtained by multiplying the solar spectrum by these values. In both models, the slopes are a few % larger than 1.0. We assume this represents the deviation of the ZL spectrum from the solar spectrum, which reflects the physical properties of interplanetary dust. It must be noted that there is no clear preference between the two models, since the error levels are roughly the same for the both.", "cite_spans": [], "ref_spans": []}, {"section": "Residual isotropic emission", "text": "As for the error of the ZL model, we adopted the deviation from isotropy. Taking statistical noise into account, we assigned the error of \u00b13% of the ZL brightness at high ecliptic latitudes for all wavelength bands and for both the Kelsall and Wright models. Fig.5 shows the measured residual isotropic emission for both the Kelsall and Wright models, in which two kinds of errors are plotted. Inner and outer error bars indicate random and total errors, respectively. Beyond random error, the systematic error moves the spectrum up and down retaining the spectral shape. Table 1 indicates the numerical values for residual emission and errors for the two models. Compared with the residual emission in paper I based on the Kelsall model, the present result yields \u223c 11 nWm \u22122 sr \u22121 as a lower peak value. A flat spectrum for the three shortest wavelength bands is also a characteristic feature found in this analysis. The Wright model yields \u223c 7 nWm \u22122 sr \u22121 , which is a lower value than that of the Kelsall model, but the spectral shape is very similar in both cases.", "cite_spans": [], "ref_spans": [{"start": 572, "end": 579, "text": "Table 1", "ref_id": "TABREF0"}]}, {"section": "Residual isotropic emission", "text": "The results shown in Fig.5 imply that there exists excess near-infrared EBL independent of the ZL model used.", "cite_spans": [], "ref_spans": []}, {"section": "Residual isotropic emission", "text": "We also performed the same analysis including the thermal part of the DGL. In this case, we estimated the residual emission from the 3.28 \u00b5m PAH feature to be \u223c 20 % (\u223c 2.6 nWm \u22122 sr \u22121 ) lower than that shown in Fig.5 , which results in a sharp absorption feature in the spectrum of residual emission. We also determined the sky brightness at 3.28 \u00b5m after subtracting the ZL component, and found that the ISL shows no correlation with far-infrared sky brightness. These results favor the non-existence of the PAH feature at high Galactic latitude. However, we cannot draw this conclusion, given that the random noise at 3.28 \u00b5m is large. In any case, the contribution of the thermal part of the DGL is nearly negligible and does not cause any significant change in our final result. (Fig.4) . Residual isotropic emission amounts to 1/4 of the ZL, which constitutes a significant signal that cannot be explained with known foreground emission sources. (2010) was adopted. In this analysis, improved consistency was found between IRTS and AKARI data. A blue Rayleigh-Jeans like spectrum of excess emission is clearly seen at wavelengths longer than 1.6 \u00b5m, as noted in Paper I.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "It is believed that fluctuations in the sky background directly provide a characteristic feature of the EBL, given that the fluctuation level of the ZL is so low (Pyo et al. 2012) .", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "Large fluctuations at angles greater than 100 arcsec, that cannot be explained with known foreground sources, have been detected with Spitzer at 3.6 and 4.5 \u00b5m ( ", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF3": {"title": "Diffuse Infrared Radiation and the IRTS eds", "authors": [{"first": "M", "middle": [], "last": "Cohen", "suffix": ""}], "year": 1997, "venue": "ASP Conf. Series", "link": "91810899"}}, "ref_entries": {"FIGREF0": {"text": "Fig.1 shows the correlation between the ISL based on the TRILEGAL model and that based on 2MASS star counts for the 12 selected fields. The left and right panels indicate the results for the H and K bands, respectively. The scatter of the data is mainly caused by fluctuations in the 2MASS star counts, since the ISL from the TRILEGAL model follows a cosec(b) law. Horizontal errors in Fig.1 represent the 1 \u03c3 dispersion of the model ISL as a result of the Monte Carlo simulations. Fig.1 clearly indicates that the ISL due to 2MASS stars is brighter than that of the TRILEGAL model for both the H and K bands. Based on this analysis, we multiplied the ISL from the TRILEGAL model by 1.23 with an 8 % error. The ISL for each of the 24 IRTS bands was estimated by interpolating the model ISL at J, H, K, L, and L S bands assuming a blackbody spectrum with the same limiting magnitude as in paper I. The ISL for 1010 fields observed with IRTS was obtained by interpolation between two neighboring model fields assuming a cosec(b) law.", "type": "figure"}, "FIGREF1": {"text": "Fig.2 shows a summary of their results. The ratios of DGL to far-infrared (100 \u00b5m) emission are shown in units of nWm \u22122 sr \u22121 (DGL) / \u00b5Wm \u22122 sr \u22121 (FIR). Filled and open circles represent the results from CIBER and AKARI, respectively. The CIBER result measures scattered star light by interstellar dust, while the AKARI result traces the thermal emission of fine dust particles transiently heated by a single UV photon. We fitted the scattered light part (shown as a dotted line) with the model ZDA04-BC03 (Brandt and Draine 2012), following the recommendation by Arai et al. (2014). As for the thermal part, it is not clear that the AKARI result can be applied to DGL at high Galactic latitude, since Tsumura et al. (2013c) reported a lower level of thermal DGL than that expected from Fig.2 at higher Galactic latitude. Therefore, we first assumed that no thermal contribution exists in IRTS fields where Galactic latitudes are higher than 40 \u2022 . We discuss the thermal contribution, and particularly the 3.3 \u00b5m PAH feature, again in Section 4. The adopted values for the IRTS bands are shown as open squares in Fig.2, for which an error of \u00b120% was applied.", "type": "figure"}, "FIGREF2": {"text": "subtracted the ISL and DGL from the observed sky brightness and performed a correlation analysis with the model ZL brightness. The upper plots in Fig.3 show the typical correlation diagrams at 1.8 \u00b5m for both the Kelsall model (left panel) and the Wright model (right panel) in which data of 1010 IRTS fields are plotted. For both models, excellent linear correlation was found for all wavelength bands, and the intersection of the linear fit line at x = 0 provides the residual isotropic emission. We regard this residual emission to be the extragalactic background light (EBL).", "type": "figure"}, "FIGREF3": {"text": "Fig.6 shows a breakdown of the emission components whose spectra were obtained as the average brightness at high ecliptic latitude (\u03b2 > 70 \u2022 ) and high Galactic latitude (b > 45 \u2022 ). The spectrum of the ZL indicates the revised spectrum applying the results", "type": "figure"}, "FIGREF4": {"text": "Fig.7 shows a summary of recent EBL observations for which the Kelsall ZL model has been applied. Two typical observations (Cambr\u00e9sy et al. 2001; Levenson et al. 2007) are indicated for the COBE data. The solid line indicates the model for the integrated light of galaxies (ILG) by Totani and Yoshii (2000) which is consistent with deep galaxy counts (Keenan et al. 2010). The near-infrared brightness of this work is a bit lower than that in paper I, but is still consistent with results from COBE and AKARI (Tsumura et al. 2013d). It must be emphasized that observations from three satellites render consistent EBL to within the errors, although beam size and limiting magnitudes are different in each case. In the optical region, two new observations are plotted. First are the results of Matsuoka et al. (2011), who performed a re-analysis of Pioneer 10 and 11 data, where ZL was negligible at near Jupiter orbit. Second are the results of Mattila et al. (2011), who attempted to detect EBL using the shadowing effect of a dark cloud at high Galactic latitude. Both results show low EBL, which is consistent with ILG. However, HST observations by Bernstein (2007) show fairly high EBL, which is at a similar level to the near-infrared EBL.", "type": "figure"}, "FIGREF5": {"text": "Fig.8 shows the excess brightness over the ILG. ILG for each observation was obtained using its own limiting magnitude, where the ILG magnitude relationship by Keenan et al.", "type": "figure"}, "FIGREF6": {"text": "Fig. 1.-The correlation between ISL estimated using the TRILEGAL model and that based on 2MASS star counts. The left and right panels show the cases for the H and K bands, respectively. Straight lines show the best fits for a linear correlation, and dotted lines indicate the adopted \u00b11\u03c3 error.", "type": "figure"}, "FIGREF7": {"text": "Fig. 3.-The upper part of each figure shows the correlation between the sky brightness and model ZL brightness for 1010 IRTS fields after the foreground contributions from ISL and DGL have been subtracted from the observed sky brightness at 1.8 \u00b5m. The left and right panels indicate the using the Kelsall and Wright models, respectively. Solid lines show the best fits for a linear correlation. The lower part in each figure represents the residual emission after subtracting all foreground emission from the observed sky brightness, and the solid black lines show the residual emission obtained by our linear correlation analysis.", "type": "figure"}, "FIGREF8": {"text": "Fig. 6.-A breakdown of the sky brightness at high ecliptic latitude (\u03b2 > 70 \u2022 ). Filled circles, bars, filled squares, open circles, and open diamonds indicate the observed sky brightness, zodiacal light (ZL), residual isotropic emission, integrated star light (ISL) and diffuse Galactic light (DGL), respectively.", "type": "figure"}, "FIGREF9": {"text": "Fig. 7.-Summary of EBL observations. Symbols represent the following data, filled circles: IRTS (this work), open squares: AKARI (Tsumura et al. 2013d), open circles: COBE (Cambr\u00e9sy et al. 2001), filled squares: COBE (Levenson et al. 2007), crosses: HST (Bernstein 2007), filled diamonds: Pioneer 10/11 (Matsuoka et al. 2011), and open diamonds: dark cloud (Mattila et al. 2011). The solid line shows the ILG (Totani and Yoshii 2000).", "type": "figure"}, "TABREF0": {"text": "Surface brightness of the residual isotropic emission and errors in units of", "type": "table"}}}
{"paper_id": "116986096", "_pdf_hash": "20f2601ae92d5821a026aefaa71390a3f74cddc4", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Occluded face recognition based on double layers module sparsity difference", "authors": [{"first": "S", "middle": [], "last": "Zhao", "suffix": ""}, {"first": "Z", "middle": [], "last": "Hu", "suffix": ""}], "year": 2014, "venue": "Advances in Electronics", "link": "59488910"}}, "ref_entries": {}}
{"paper_id": "116987163", "_pdf_hash": "ec4f45d420c4168f3d48194be9a8ecaeecad050b", "abstract": [{"section": "Abstract", "text": "Young massive stars, with their spectacular masers and HII regions, dominate our Galaxy, and are a cornerstone for understanding Galactic structure. I will highlight the role of Parkes in contributing to these studies -past, present and future.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "INTRODUCTION", "text": "On the first day of our symposium. the contributions were entertaining and knowledgable reflections on the early years at Parkes -chiefly recalling an era from which there are few pioneers left with personal experience. Subsequent days focus on active work still continuing at Parkes. I am pleased to be the bridge from the past to the present, especially to the next session of the symposium, dealing with current studies of young massive stars and their masers.", "cite_spans": [], "ref_spans": []}, {"section": "INTRODUCTION", "text": "My main theme will be to show how the Parkes studies of masers and related objects contribute to revolutionizing the picture of our Galaxy, its content and its structure.", "cite_spans": [], "ref_spans": []}, {"section": "GALACTIC STRUCTURE", "text": "2.1. An early view Radio astronomy, with its ability to see through the dusty disc of our Galaxy, gave us the first quantitative realization of the likely extent of the Galactic disc, and hints of its full spiral structure. The history of these discoveries stemming from the earliest HI observations is beautifully summarized by Oort, Kerr & Westerhout (1958) . They present an adventurous first attempt at revealing spiral structure, tempered by an acknowledgment of its very preliminary nature. They also include prescient musings on the likely role of large-scale interstellar magnetic fields influencing the appearance of the spiral arms.", "cite_spans": [], "ref_spans": []}, {"section": "GALACTIC STRUCTURE", "text": "This early picture of spiral structure was largely reinforced by subsequent improved HI observations, and by the newer tool of CO observations, which map the dense molecular clouds that are somewhat more closely related to the expected massive star distribution.", "cite_spans": [], "ref_spans": []}, {"section": "GALACTIC STRUCTURE", "text": "2.2. Tracers of massive stars, the dominant component of spiral structure While the spiral structure of our Galaxy depicted by HI gas was of great interest, the spiral structure seen photographically in nearby galaxies is traced chiefly by a very different population -the hot, young, massive blue stars, and the HII regions that surround them. Optical study of these objects in our Galaxy is impeded by dust and obscuration, so we seek the radio equivalent; the james.caswell@csiro.au HII regions, in particular, are detectable from both their radio continuum emission and their recombination line emission (with the corresponding capability of measuring systemic velocities).", "cite_spans": [], "ref_spans": []}, {"section": "GALACTIC STRUCTURE", "text": "2.3. The value of Parkes for Galactic structure Observations between 1.4 and 10 GHz are excellent for the HII measurements, and thus readily pursued at Parkes. This is complemented by another key attribute of Parkes -its southern hemisphere location (with the Galactic Centre passing nearly overhead) and thus accessing the 70 per cent of Galactic disc that is most important for study of its structure.", "cite_spans": [], "ref_spans": []}, {"section": "GALACTIC STRUCTURE", "text": "The systemic velocity of an HII region, measured from its radio recombination lines, is an excellent first start at determining its distance, able to yield a 'kinematic' distance based on a simple rotation curve for the Galaxy. However, the kinematic distances for Galactic locations nearer the Centre than the sun are generally ambiguous, and the ambiguity needs to be resolved by an alternative means. Fortunately, an enhancement to the Parkes dish, the Parkes interferometer, provided a useful discriminator and was being developed at just the right time.", "cite_spans": [], "ref_spans": []}, {"section": "GALACTIC STRUCTURE", "text": "2.4. The Parkes HI interferometer Yesterday, Ron Ekers described the innovative design of the Parkes interferometer and here I will remind you of its modification and novel use by Radhakrishnan to study the HI spectra towards strong continuum sources (Radhakrishnan et al. 1972a ). The primary purpose was to measure the properties of absorbing HI clouds; but, as a by-product, for sources in the Galactic plane, it could determine kinematic distances of Galactic sources, as amply demonstrated by Radhakrishnan and Miller Goss (Radhakrishnan et al. 1972b ). My first years at Radiophysics overlapped this work, shortly before Rad and Miller both departed from Australia. I was excited at the prospect of getting more distances -a project that would be abandoned if I did not adopt it. I was blessed to inherit a talented team of engineers (John Murray, Dave Cooke and Doug Cole), complemented by astronomy advice and help from Rob Roger, visiting at that time from Penticton (where we had previously worked together), and fresh from planning an HI interferometer there. Upgrades to the Parkes interferometer allowed us to achieve excellent results, leading to a large number of distance determinations for Galactic radio sources, both supernova remants and HII regions (Caswell et al. 1975 ).", "cite_spans": [], "ref_spans": []}, {"section": "NEW SURVEYS OF THE GALACTIC DISC", "text": "Progress in mapping the Galaxy had been good, but needed the impetus of new surveys of Galactic radio objects. We chose to survey the Galactic plane at 5 GHz in another ambitious large project. This was conducted with Raymond Haynes, firstly in the continuum (Haynes, Caswell & Simons 1978) , and then with a recombination line follow-up (Caswell & Haynes 1987 ). This greatly improved our assessment of spiral arms in the southern sky, especially the Carina arm.", "cite_spans": [], "ref_spans": []}, {"section": "NEW SURVEYS OF THE GALACTIC DISC", "text": "3.1. OH and water masers -the early years Until now, I have kept to a chronological order, but that eventually becomes impossible in the real world of overlapping events. It seems appropriate to segue into a quote from Dean Kamen: 'People take the longest possible paths, digress to numerous dead ends, and make all kinds of mistakes. Then historians come along and write summaries of this messy, non-linear process and make it appear like a simple straight line'. More succinct is a related sentiment from Mark Twain: 'In the real world nothing happens at the right place and the right time. It is the job of journalists and historians to correct that'. Hindsight, even if unintentional, modifies the story. But, overall, in my presentation of the subsequent research, I will try to retain the logic and motivation that drove it.", "cite_spans": [], "ref_spans": []}, {"section": "NEW SURVEYS OF THE GALACTIC DISC", "text": "I now backtrack a few years to show where masers fit into the picture. OH maser research in the early 1970s was taking another step forward, with searches for new masers planned. I was fortunate to be able to join Brian Robinson and Miller Goss in these developments.", "cite_spans": [], "ref_spans": []}, {"section": "NEW SURVEYS OF THE GALACTIC DISC", "text": "How many varieties of OH masers? The sample known so far was now growing to the point of recognising different varieties, one of which was a large population associated with massive star formation (Robinson, Caswell & Goss 1974) .", "cite_spans": [], "ref_spans": []}, {"section": "NEW SURVEYS OF THE GALACTIC DISC", "text": "OH masers were certainly fascinating; surely they would also be useful? To answer this question, our intention was to conduct OH survey projects in a prompt and orderly manner but were then interrupted by 'an opportunity that was too good to refuse' -an opportunity to observe water masers in the southern sky.", "cite_spans": [], "ref_spans": []}, {"section": "NEW SURVEYS OF THE GALACTIC DISC", "text": "Ken Johnston from the Naval Research Laboratory had a receiver, we had OH targets, and a first round of improvements to the dish surface at Parkes made it a viable instrument at 22 GHz. The sensitivity was adequate for detecting strong maser emission, and the major challenge was a small beamsize above 20 GHz -a valuable property but with associated problems from pointing errors and uncertainties in our target positions -a hexagonal grid search was needed every time (Johnston et al. 1972) . Calibration was also a challenge. Ken Kellerman reminded us yesterday of early planet observations at Parkes, noting that these were not subsequently continued. In fact, we found Jupiter to be the solution to our calibration problem, since at that epoch it was a southerly object near declination -20 degrees.", "cite_spans": [], "ref_spans": []}, {"section": "NEW SURVEYS OF THE GALACTIC DISC", "text": "For several years we then conducted unbiased surveys for OH masers in the Galactic disc (e.g. , with follow-up of water masers (Batchelor et al. 1980 ). Coincidence of water masers with OH was a matter of dispute -how closely associated were they? Our position accuracy at Parkes was limited to about 10 arcsec, at which level the coincidence seemed good. To understand their relationship we needed more precise positions. Some of our masers were within reach of the VLA, and Rick Forster convinced me that it could provide a partial solution to our problem.", "cite_spans": [], "ref_spans": []}, {"section": "NEW SURVEYS OF THE GALACTIC DISC", "text": "It was an ambitious project for the VLA when it was scheduled in 1983. For a while, Rick and I had the VLA record for data processing requirements: our experiment lasted only a few days, but we had spectral line data at long baselines for nearly 100 sources, and needed high resolution spectral line cubes. The results amply repaid our efforts, and demonstrated the extremely close association for many pairs, plus the excess of water maser sites compared to OH (Forster & Caswell 1989) .", "cite_spans": [], "ref_spans": []}, {"section": "NEW SURVEYS OF THE GALACTIC DISC", "text": "Eventually it was possible to obtain maser positions in the true southern sky, using the Compact Array of the AT. There followed a productive combination of Parkes spectra and Compact Array positions for OH masers, but it was another decade before we could extend the ATCA studies to the 22-GHz water masers.", "cite_spans": [], "ref_spans": []}, {"section": "The methanol 'explosions'", "text": "The discovery of maser emission at 12 GHz was the first of two major impacts by methanol on star formation maser studies. In an abrupt diversion of effort, with an 'off-the-shelf' commercial receiver spedily made suitable for Parkes by Kel Wellington, we were able to use our newly-determined OH maser positions to conduct a search for further examples of the newly discovered 12-GHz methanol transition -with considerable success (Norris et al. 1987) .", "cite_spans": [], "ref_spans": []}, {"section": "The methanol 'explosions'", "text": "Scarcely had we returned to pick up the threads of the OH and water research when the next methanol impact was upon us -the discovery in 1991 (Menten 1991) of methanol maser emission at 6668 MHz -which was found to usually surpass both OH and 12-GHz methanol in intensity. Once again the agility of Parkes, and our receiver group, was demonstrated, as an excellent new receiver was rapidly deployed and enabled us to reveal the full importance of this transition . We finished up with several hundred methanol masers, allowing us to explore the common properties, unusual properties, and even characterise the typical variability, with the first hints of the exciting possibility that some might be periodic variables . Periodicity was eventually confirmed in South Africa several years later (Goedhart et al. 2004 (Goedhart et al. , 2009 . John Whiteoak was a key member of our team and recognised the role that the Compact array could play in methanol studies, despite 6.6 GHz being a frequency outside the nominal ATCA coverage. ATCA accurate positions of the OH and methanol masers then established unequivocally their intimate association (Caswell, Vaile & Forster 1995) , with their common source of excitation provided by a massive embryonic central massive star.", "cite_spans": [], "ref_spans": []}, {"section": "MORE SURVEYS, AND THEIR PURPOSE", "text": "Could those searches for methanol masers be described as a survey? Yesterday, we heard several views on the purposes of surveys, prompted by a presentation from Jasper Wall and Carole Jackson. I have been engaged in rather a lot of surveys, necessitated by exploring the Galaxy. These are some of my reflections:", "cite_spans": [], "ref_spans": []}, {"section": "MORE SURVEYS, AND THEIR PURPOSE", "text": "The purpose obviously depends on previous knowledge, and the space density of the expected population.", "cite_spans": [], "ref_spans": []}, {"section": "MORE SURVEYS, AND THEIR PURPOSE", "text": "If very few objects are known, then the main purpose may be simply to expand the sample.", "cite_spans": [], "ref_spans": []}, {"section": "MORE SURVEYS, AND THEIR PURPOSE", "text": "If the space density is intrinsically low, much of the importance of a uniformly sensitive large survey is to define the regions where there is nothing! In a few cases, e.g. a finite Galactic population, we may discover the whole population! The last point is especially exciting, and seemed applicable to the methanol masers.", "cite_spans": [], "ref_spans": []}, {"section": "The MMB survey", "text": "To fully exploit the value of 6.6-GHz methanol masers, we needed a 'proper' survey that was sensitive, had no bias to pre-selected targets, and covered the quite large area of the whole Galactic disc. We questioned whether to use Parkes (necessarily requiring a multi-beam receiver to map with adequate speed and sensitivity) or the ATCA? We chose the best of both options, with Parkes for the survey proper, and the ATCA as an integral part of the project in providing precise positions to arcsecond accuracy.", "cite_spans": [], "ref_spans": []}, {"section": "The MMB survey", "text": "The Methanol Multibeam (MMB) project proposal to build the receiver was submitted 2001 February, early in the year of the Parkes 40th birthday, with Mal Sinclair as project leader and J. Caswell as project scientist.", "cite_spans": [], "ref_spans": []}, {"section": "The MMB survey", "text": "It was a collaborative venture with Jodrell Bank, with Jim Cohen leading the UK part. Receiver construction was shared between our two institutions and was ready for testing on the Parkes telescope 2006 January. Jim Cohen and I had planned the survey strategy and worked intensively together to get the survey running smoothly and productively immediately after 'first light' on Australia Day of 2006. It was a memorable first year of observations, with Jim Cohen present at all our sessions, and Jim's wife Pat welcomed as an additional enthusiastic team member when needed.", "cite_spans": [], "ref_spans": []}, {"section": "The MMB survey", "text": "Sadly, to our great dismay, Jim died late in 2006, exactly 5 years ago. Over the following few years, we have achieved our goal of completing the survey, and Pat Cohen has been delighted to see these outcomes from the work that consumed so much of Jim's time in the final year of his life; the legacy of the survey is a fitting tribute to his efforts (Green et al. 2009; Caswell et al. 2010) .", "cite_spans": [], "ref_spans": []}, {"section": "The MMB survey", "text": "The outcomes from the survey will be extensive, with many productive follow-ups already completed, and others continuing. There are two areas in particular where the masers have high impact: firstly the far-reaching implications for Galactic structure, where considerable progress has already been made, and which we will return to later; and secondly, the full characterisation of each maser site, by its mass, evolutionary state and environment, and thereby contributing to the ongoing investigation of the poorly understood mechanism of high mass star formation,", "cite_spans": [], "ref_spans": []}, {"section": "EXCITED-STATE OH TRANSITIONS AT PARKES", "text": "Once again we step back, this time to catch up on the OH maser progress. Although OH maser studies of star formation regions mostly focus on the ground-state transitions at 1665 and 1667 MHz, the 6035 and 6030-MHz excited-state transitions have recently been recognised as equally valuable, and sometimes more so. For many years, very few telescopes were equipped with a high performance receiver at this frequency. Then Parkes became one of the first telescopes to acquire this capability -using the 6.6-GHz receiver that had recently been purpose-built for methanol studies. It allowed the discovery of many new 6035-MHz masers accompanying 1665-MHz masers , sparking new interest in the transition. Much rarer is the maser emission from OH in an even more highly excited state, at 13.4 GHz. Again, this is a frequency not commonly covered by high performance receivers on large telescopes. From 1970 until 2002, only one definite maser was known at this transition. Improvements to the Parkes dish surface in 2003 and a receiver of modest performance then provided a combination viable for renewed observational effort, closely following similar renewed efforts at Effelsberg. Parkes was able to detect 8 masers at this transition (Caswell 2004) , most of them new and visible only from the southern hemisphere, and increasing the known number to 11, where the total still remains, pending new Parkes observations,", "cite_spans": [], "ref_spans": []}, {"section": "PARKES AND ITS ROLE IN SPECTROSCOPY WITH THE LBA", "text": "Dave Jauncey and John Reynolds will later describe Australian VLBI more fully, but here I must mention the role of the Australian LBA (Long Baseline Array) in maser studies.", "cite_spans": [], "ref_spans": []}, {"section": "PARKES AND ITS ROLE IN SPECTROSCOPY WITH THE LBA", "text": "The LBA baselines, from just the three ATNF elements (Parkes, the ATCA and Mopra), extend to 300km, very similar to MERLIN in the northern hemisphere, and allow us to do similar work, but in the richer fields of the southern Galaxy.", "cite_spans": [], "ref_spans": []}, {"section": "PARKES AND ITS ROLE IN SPECTROSCOPY WITH THE LBA", "text": "Spectroscopy with the LBA was still in the realm of pioneering work in 1998 when we made our first observations of OH masers at 1665 and 1667 MHz. We were able to observe both transitions with high spectral resolution in a single band covering a large velocity range, and simultaneously observing two polarizations. These capabilities were able to solve earlier problems of precise relative positional registration that had plagued earlier VLBI work. The success of this ambitious project owed much to the ingenuity of John Reynolds who coped with each new problem as it arose. The net result was a series of southern OH maser sites mapped at high resolution, and revealing their magnetic fields from the recognition in the spot distribution of Left and Right hand circular polarization of multiple Zeeman pairs (e.g. Caswell & Reynolds 2001 and subsequent papers) .", "cite_spans": [], "ref_spans": []}, {"section": "PARKES AND ITS ROLE IN SPECTROSCOPY WITH THE LBA", "text": "As remarked earlier, OH maser studies of star formation regions mostly focus on the ground-state transitions at 1665 and 1667 MHz, but the 6035 and 6030-MHz excited-state transitions are even more valuable in clearly displaying the Zeeman pairs from which magnetic fields can be inferred. A high performance 6-GHz receiver at Parkes was the catalyst to extend LBA observations to this transition. In this case, it also allowed precise registration of maser spot distributions at 6035 MHz with those of the weaker 6030-MHz transition, in turn identifying Zeeman pairs and magnetic field distributions (Caswell, Kramer & Reynolds 2011) .", "cite_spans": [], "ref_spans": []}, {"section": "PARKES AND ITS ROLE IN SPECTROSCOPY WITH THE LBA", "text": "The success of the LBA in this OH spectroscopy owes much to the large collecting area and high sensitivity provided by Parkes as a key element.", "cite_spans": [], "ref_spans": []}, {"section": "THE FUTURE -GALACTIC SPIRAL STRUCTURE, VELOCITY FIELD, AND MAGNETIC FIELD", "text": "What does the future look like for Galactic structure, high mass stars and masers?", "cite_spans": [], "ref_spans": []}, {"section": "THE FUTURE -GALACTIC SPIRAL STRUCTURE, VELOCITY FIELD, AND MAGNETIC FIELD", "text": "Preliminary studies of the maser spatial and velocity distribution in the inner Galaxy are already at a stage where they can guide improved Galactic dynamics modelling, since current models are unable to account for the observations (Green et al. 2011 ), but these are only the beginning of a much greater revolution.", "cite_spans": [], "ref_spans": []}, {"section": "THE FUTURE -GALACTIC SPIRAL STRUCTURE, VELOCITY FIELD, AND MAGNETIC FIELD", "text": "A landmark was achieved in 2006, with a demonstration that VLBI had matured to permit accuracies of better than 0.01 mas (Xu et al. 2006) , allowing astrometric parallaxes and precise distance measurements to masers at the Galactic Centre and beyond, extending to the outer edge of the Galaxy (Reid et al. 2009 ). This achievement with the US VLBA at 12 GHz was shortly matched by similar measurements for 22-GHz water masers (which often accompany methanol masers) using the Japanese array VERA (Honma et al. 2007) , and measurements of 6.6-GHz methanol masers using the EVN (Rygl et al. 2010) .", "cite_spans": [], "ref_spans": []}, {"section": "THE FUTURE -GALACTIC SPIRAL STRUCTURE, VELOCITY FIELD, AND MAGNETIC FIELD", "text": "So astrometry of masers can now provide a remarkable opportunity to map our Galaxy in detail, to reveal for the first time its precise geometry and velocity field. These are the parameters that must be replicated by a valid dynamical model of the Galaxy. Southern and northern hemisphere telescopes will be needed to acquire the necessary observations and, in these endeavours, Parkes will be a key high sensitivity element in the southern LBA.", "cite_spans": [], "ref_spans": []}, {"section": "THE FUTURE -GALACTIC SPIRAL STRUCTURE, VELOCITY FIELD, AND MAGNETIC FIELD", "text": "Since OH masers are present at about half of the methanol sites, it will eventually be possible to associate a characteristic magnetic field at each site using Zeeman splitting, and thereby map the magnetic field of the Galaxy, with 'in situ' measurements at each site, rather than the line-of-sight average fields that are commonly obtained by Faraday rotation measurements.", "cite_spans": [], "ref_spans": []}, {"section": "AFTERWORD", "text": "In 1967, the outcomes of a conference held at Charlottesville on the topic 'Interstellar ionised hydrogen', were summarised by Gart Westerhout (Westerhout 1968) . At that time, the recently detected OH masers were the only known species of astrophysical maser. The role of the masers was uncertain. In Gart's words:", "cite_spans": [{"start": 143, "end": 160, "text": "(Westerhout 1968)", "ref_id": "BIBREF28"}], "ref_spans": []}, {"section": "AFTERWORD", "text": "'..how relevant are the OH (maser) observations to astrophysics....? Could it be that the emission is a pointer to regions of incipient star formation? Personally, I would say that the OH (maser) study is an extremely interesting intellectual exercise, which should be vigorously pursued, because such exercises lead almost always to completely new developments, and completely new ideas in both theories and techniques. But I don't think that the OH problem will contribute very much to our further understanding of the interstellar medium at large. ' Has the pursuit of masers over the past 45 years been worthwhile? Perhaps the most emphatic answer is given by the title of a workshop at MPI, Bonn two years ago: 'Masers: the ultimate astrophysical tools' ! I thank the conference organisers for the opportunity of contributing to this meeting, and expressing my gratitude to many close colleagues who have worked with me in the 40 years that I have enjoyed using the Parkes telescope.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF28": {"title": "Interstellar ionized hydrogen, Proceedings of the Symposium on HII regions, held in Charlottesville", "authors": [{"first": "G", "middle": [], "last": "Westerhout", "suffix": ""}], "year": 1967, "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "116988830", "_pdf_hash": "0496b2a341d4c8f01de083a8898c9aa005129eac", "abstract": [{"section": "Abstract", "text": "In this paper, we are concerned with the existence and multiplicity of no-node solutions of the Lazer-McKenna suspension bridge models by using the fixed point theorem in a cone.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "In [1] , the Lazer-McKenna suspension bridge models are proposed as following ", "cite_spans": [{"start": 3, "end": 6, "text": "[1]", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "y y a t y a t z h y z z z a t y a t z h y z y t y t T y t y t T z t z t T z t z t T", "text": "\u03b4 \u03bb \u03b4 \u03bb + + + = \uf8f1 \uf8f4 + + + = \uf8f2 \uf8f4 = + =+ = + =+ \uf8f3 (1) In this paper, by combining the analysis of the sign of Green's functions for the linear damped equation, together with a famous fixed point theorem, we will obtain some existence results for (1) if the nonlinearities satisfy the following semipositone condition (H) The function ( , ) i h y z is bounded below, and maybe change sign, namely, there exists a sufficiently large constant M > 0 such that ( , ) 0.", "cite_spans": [{"start": 48, "end": 51, "text": "(1)", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "y y a t y a t z h y z z z a t y a t z h y z y t y t T y t y t T z t z t T z t z t T", "text": "Such case is called as semipositone problems, see [2] . And one of the common techniques is the Krasnoselskii fixed point theorem on compression and expansion of cones. Lemma 1.1 [3] . Let E be a Banach space\uff0cand K be a cone in E . Assume 1", "cite_spans": [{"start": 50, "end": 53, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 179, "end": 182, "text": "[3]", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "y y a t y a t z h y z z z a t y a t z h y z y t y t T y t y t T z t z t T z t z t T", "text": "be a completely continuous operator such that either (i) 1 2 , ; ,", "cite_spans": [], "ref_spans": []}, {"section": "y y a t y a t z h y z z z a t y a t z h y z y t y t T y t y t T z t z t T z t z t T", "text": "Then, A has a fixed point in", "cite_spans": [], "ref_spans": []}, {"section": "Preliminaries", "text": "If the linear damped equation", "cite_spans": [], "ref_spans": []}, {"section": "Preliminaries", "text": "is nonresonant, namely, its unique T-periodic solution is the trivial one, then as a consequence of Fredholm's alternative in [4] , the nonhomogeneous equation '' ( ) ' ( ) ( ), x h t x a t x e t + + = admits a unique T-periodic solution which can be written as", "cite_spans": [{"start": 126, "end": 129, "text": "[4]", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "T x t G t s e s ds", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "= \u222b", "text": "where G(t; s) is the Green's function of (2) . For convenience,", "cite_spans": [{"start": 41, "end": 44, "text": "(2)", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "= \u222b", "text": "we will assume that the following standing hypothesis is satisfied throughout this paper: ", "cite_spans": [], "ref_spans": []}, {"section": "t a t a t a t M a t M a t", "text": "Also, for r > 0 a positive number, let {( , ) : ( , ) }, ", "cite_spans": [], "ref_spans": []}, {"section": "y y a t y a t z a t a t h y z z z a t y a t z a t a t h y z", "text": "where \u03be is chosen such that ", "cite_spans": [], "ref_spans": []}, {"section": "a t a t h y z a t a t h y z", "text": "\u03be \u03be \u03bb \u03be \u03be \u03be \u03be \u03bb \u03be \u03be+ + \u2212 \u2212 > + + \u2212 \u2212 > \uf025 \uf025 \uf025 \uf025 Let : B K E \u2192 be a map, which defined by 1 2 ( , )( ) ( ( , )( ), ( , )( )) B y z t B y z t B y z t = \uf025 \uf025 \uf025 \uf025 \uf025 \uf025 ,where1 1 12 1 0 2 2 21 2 0 ( , )( ) ( , )[ ( ) ( ) ( ( ), ( ))] , ( , )( ) ( , )[ ( ) ( ) ( ( ), ( ))] , T T", "cite_spans": [], "ref_spans": []}, {"section": "B y z t G t s a s z s F y s z s ds B y z t G t s a s y s F y s z s ds", "text": "= \u2212 + = \u2212 + \u222b \u222b \uf025 \uf025 \uf025 \uf025 \uf025 \uf025 \uf025 \uf025 1 11 12 1 2 21 22 2 ( ( ),( )) ( ) ( ) ( , ), ( ( ), ( )) ( ) ( ) ( , ).", "cite_spans": [], "ref_spans": []}, {"section": "F y s z s a t a t h y z F y s z s a t a t h y z", "text": "\uf025 t is straightforward to verify that the solution of (1) is equivalent to the fixed point Equation ( , )( ) ( ( ), ( )). ", "cite_spans": [], "ref_spans": []}, {"section": "B y z t y t z t", "text": ", we have", "cite_spans": [], "ref_spans": []}, {"section": "B y z t G t s a s z s F y s z s ds", "text": "Then from the above inequalities, it follows that there exists a , we obtain ", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Large-Amplitude Periodic Oscillations in Suspension Bridges: Some New Connections with Nonlinear Analysis", "authors": [{"first": "A", "middle": ["C"], "last": "Lazer", "suffix": ""}, {"first": "P", "middle": ["J"], "last": "Mckenna", "suffix": ""}], "year": 1990, "venue": "Siam Review", "link": "18066117"}, "BIBREF1": {"title": "Periodic Solutions to Non-Autonomous Second-Order Systems", "authors": [{"first": "H", "middle": [], "last": "Wang", "suffix": ""}], "year": 2009, "venue": "Nonlinear Analysis: Theory, Methods & Applications", "link": "28937824"}, "BIBREF2": {"title": "Nonlinear Problems in Abstract Cones", "authors": [{"first": "G", "middle": [], "last": "Dajun", "suffix": ""}, {"first": "V", "middle": [], "last": "Lakshmikantham", "suffix": ""}], "year": 1988, "venue": "", "link": "117750256"}, "BIBREF3": {"title": "Periodic Solutions for Second Order Singular Damped Differential Equations", "authors": [{"first": "J", "middle": [], "last": "Chu", "suffix": ""}, {"first": "N", "middle": [], "last": "Fan", "suffix": ""}, {"first": "P", "middle": ["J"], "last": "Torres", "suffix": ""}], "year": 2012, "venue": "Journal of Mathematical Analysis and Applications", "link": "54776912"}}, "ref_entries": {"FIGREF0": {"text": "If we look for no-node solutions of the form ( , ) ( ) sin( / ),", "type": "figure"}, "FIGREF2": {"text": "Lemma 2.3 [2] Assume that (H), (H1) and (H2) hold. If ,Assume that (H), (H1) and (H2) hold.\u221e = +\u221e , then (1) has two positive periodic solutions for all sufficiently small \u03bb . Proof. (I) On one hand, take R", "type": "figure"}, "FIGREF4": {"text": "Therefore, from Lemma 1.1, it follows that the operator B has at least one fixed point ( , )", "type": "figure"}, "TABREF0": {"text": "are negative T-periodic functions, and satisfy:", "type": "table"}, "TABREF3": {"text": "2", "type": "table"}}}
{"paper_id": "116988896", "_pdf_hash": "21606207e78f9398859e45d058440915f92b9430", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "A. & A., 180, 1. Blades, J. C. 1988, in QSO Absorption Lines: Probing the Universe", "authors": [{"first": "J", "middle": ["A"], "last": "Baldwin", "suffix": ""}, {"first": "M", "middle": ["M"], "last": "Phillips", "suffix": ""}, {"first": "R", "middle": ["F"], "last": "Carswell", "suffix": ""}, {"first": "", "middle": [], "last": "41p", "suffix": ""}, {"first": "J", "middle": [], "last": "Bergeron", "suffix": ""}, {"first": "S", "middle": ["D"], "last": "D&apos;odorico", "suffix": ""}, {"first": "D", "middle": [], "last": "Kunth", "suffix": ""}], "year": 1985, "venue": "", "link": null}, "BIBREF3": {"title": "Physical Processes in the Interstellar Medium", "authors": [{"first": "L", "middle": [], "last": "Spitzer", "suffix": ""}], "year": 1978, "venue": "", "link": "63693396"}}, "ref_entries": {}}
{"paper_id": "116989707", "_pdf_hash": "7b1e2264a94b7f97821e082fcb127210f11c7f39", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "164944031", "_pdf_hash": "5641be1ebbe610becf997e4e33be25ee9e9afeef", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "164945171", "_pdf_hash": "38e4720428c2032418ee57ff514b17626cdca65c", "abstract": [], "body_text": [{"section": "", "text": "for their health benefits. Garlic is known for its ability to modulate the immune system (Venkatesh, 2018) , suppress cancerous cell growth, reduce serum cholesterol levels and reduce the risk of cardiovascular diseases (Madden, Krehbiel, & Clarke, 2017) .", "cite_spans": [{"start": 220, "end": 254, "text": "(Madden, Krehbiel, & Clarke, 2017)", "ref_id": "BIBREF23"}], "ref_spans": []}, {"section": "", "text": "In addition, garlic has immense antibacterial activity (Ain et al., 2017) . S-Allylcysteine (SAC) a bioactive compound produced in large amounts during garlic aging and is responsible for the multiple pharmacological activities of garlic. SAC is formed by the enzymatic hydrolysis of \u03b3-glutamyl-S-allyl cysteine by \u03b3-glutamyl transpeptidase (\u03b3-GTP) (Kodera et al., 2002) .", "cite_spans": [{"start": 55, "end": 73, "text": "(Ain et al., 2017)", "ref_id": "BIBREF1"}, {"start": 349, "end": 370, "text": "(Kodera et al., 2002)", "ref_id": "BIBREF17"}], "ref_spans": []}, {"section": "", "text": "Cirsium setidens Nakai has also been used as a traditional oriental medicine for centuries. It is a perennial herb belonging to the family Compositae and is distributed mainly in the Gangwon Province of Korea . The plant has been used for treating edema, bleeding, and hemoptysis since it contains bioactive compounds such as hispidulin 7-O-neohesperidoside, pectolinarin, luteolin, and apigenin (Thao et al., 2011) . Earlier studies have proven the biological effects of C. setidens Nakai, including antioxidant properties (Lee, Heo, Li, Lee, & Wang, 2008) , hepatoprotective activities (Yoo, Nam, Kim, Choi, & Park, 2008) , and activity against nonalcoholic fatty liver disease (Noh et al., 2013) .", "cite_spans": [{"start": 396, "end": 415, "text": "(Thao et al., 2011)", "ref_id": "BIBREF29"}, {"start": 524, "end": 557, "text": "(Lee, Heo, Li, Lee, & Wang, 2008)", "ref_id": "BIBREF20"}, {"start": 588, "end": 623, "text": "(Yoo, Nam, Kim, Choi, & Park, 2008)", "ref_id": "BIBREF31"}, {"start": 680, "end": 698, "text": "(Noh et al., 2013)", "ref_id": "BIBREF25"}], "ref_spans": []}, {"section": "", "text": "Fermentation of medicinal foods with lactic acid bacteria has been shown to prevent high fat diet-induced hepatic steatosis in mice (Lee, Lee, Yu, Lee, & Cho, 2017) and improve anticancer activities (Kim et al., 2018) . There is, however, limited information on whether a fermented blend of garlic and C. setidens Nakai beverage would result in any health effects. In the quest to prepare a functional beverage from a combination of garlic and C. setidens Nakai, we ascertained the antioxidant-and immune-enhancing abilities of various blends of garlic and C. setidens Nakai to find which blend had the best antioxidant activity, cell proliferation ability, nitric oxide-stimulating activity, and the cytokines the best blend induces.", "cite_spans": [{"start": 132, "end": 164, "text": "(Lee, Lee, Yu, Lee, & Cho, 2017)", "ref_id": "BIBREF18"}, {"start": 199, "end": 217, "text": "(Kim et al., 2018)", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "| MATERIAL S AND ME THODS", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "| Chemicals and reagents", "text": "Trichloroacetic acid (TCA), gallic acid, De Man, Rogosa and Sharpe (MRS) broth, Dulbecco's modified Eagle's medium (DMEM), fetal bovine serum (FBS), and Folin-Ciocalteu's reagent were procured from Sigma-Aldrich, Inc. Dinitrophenyl hydrazine (DNPH) was from ACROS Organics; hydrogen peroxide, methanol, and FeCl 3 were purchased from BDH Chemicals Ltd.; and thiourea, CuSO 4 .5H 2 O, H 2 SO 4 , sodium carbonate, AlCl 3 , potassium acetate, Tris-HCl buffer, FeSO 4 , potassium ferricyanide, and ferric chloride were of analytical grade while the water was glass-distilled.", "cite_spans": [], "ref_spans": []}, {"section": "| Chemicals and reagents", "text": "Lipopolysaccharide (LPS), sodium nitrite (NaNO 2 ), and Griess reagent (0.1% N-(1-naphthyl)ethylenediamine dihydrochloride, 1% sulfanilamide in 5% phosphoric acid) were all prepared in-house from reagents purchased from Sigma-Aldrich Korea. Viscozyme, cellulase, amylase, and protease were supplied by Erom Company Limited.", "cite_spans": [], "ref_spans": []}, {"section": "| Cell culture", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "| Bacteria culture", "text": "Leuconostoc mesenteroides KCTC 13302 was obtained from the Department of Food Science and Biotechnology, Kangwon National University, Chuncheon, Korea, and grown in MRS broth for 36 hr at 37\u00b0C. The culture was centrifuged at 6,000 g for 15 min to obtain the cell pellets and washed twice with double-distilled water. The cells were then diluted with distilled water and stored at 4 degrees until use.", "cite_spans": [], "ref_spans": []}, {"section": "| Animal cell culture", "text": "RAW 264.7 cells (a mouse macrophages cell line) were purchased from the American Type Culture Collection and cultured in DMEM supplemented with FBS (10%), D-glucose (3.5 mg/ml), sodium pyruvate (100 mM), L-glutamine (2 mM), penicillin (100 U/ml), streptomycin (100 \u03bcg/ml), and amphotericin B (250 \u03bcg/ml) at 37\u00b0C and 5% CO 2 .", "cite_spans": [], "ref_spans": []}, {"section": "| Sample preparation", "text": "Garlic (Allium sativum) and C. setidens Nakai were obtained from Erom Company Limited, Korea. Leuconostoc mesenteroides KCTC 13302 was chosen for the fermentation process because it produced the strongest biologically active garlic product in our previous experiments (data not shown).", "cite_spans": [], "ref_spans": []}, {"section": "| Preparation of garlic and Cirsium setidens Nakai", "text": "Garlic was peeled, washed, and dried in a laminar flow hood (Thermo Fisher Scientific) and grounded using a Vitamix 5200 blender (VitaMix Corporation). A portion (100 g) of the ground garlic was weighed with an Ohaus Scout electronic balance (Flinn Scientific) and mixed with 250 ml of distilled water. The mixture was steamed at 100\u00b0C for 1 hr and allowed to cool to 50\u00b0C. Cellulase (0.5 ml) was added amidst stirring for 30 min after which 0.75 ml of protease was added for 1 hr. Amylase (1.25 ml) was then added and heated for 1 hr at 70\u00b0C. The enzymes were then inactivated by increasing the temperature to 90\u00b0C for 30 min, and the mixture was concentrated to obtain 7\u00b0Bx. The sample was concentrated to 17% (v/v). The sample was adjusted to 10\u00b0Bx and freeze-dried.", "cite_spans": [], "ref_spans": []}, {"section": "| Preparation of garlic and Cirsium setidens Nakai", "text": "For C. setidens Nakai preparation, the plant material was extracted with water twice at 90\u00b0C and filtered. The sample was then concentrated to 10\u00b0Bx, freeze-dried, and stored at \u221220\u00b0C until use.", "cite_spans": [], "ref_spans": []}, {"section": "| Preparation of garlic and Cirsium setidens Nakai", "text": "Different proportions of garlic and C. setidens Nakai were mixed in the ratios 90:10, 80:20, 50:50, and 100:0, respectively, and autoclaved.", "cite_spans": [], "ref_spans": []}, {"section": "| Preparation of fermented garlic-Cirsium setidens Nakai blend", "text": "One portion of the different ratios of garlic and C. setidens Nakai ", "cite_spans": [], "ref_spans": []}, {"section": "| Determination of pectolinarin and pectolinarigenin", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Extraction and isolation", "text": "Dried samples (200 g) of C. setidens were extracted with water, filtered, and freeze-dried to obtain 20 g of the dry extract. All the samples (single and blends) were dissolved in methanol and filtered using a 0.45-\u03bcm syringe filter and analyzed using HPLC. A Waters The injection volume was 10 \u03bcL, and flow rate was 1 ml/ min. The UV spectra were recorded at 254 nm for quantification of flavonoids. All injections were performed in triplicate.", "cite_spans": [], "ref_spans": []}, {"section": "Limit of detection (LOD) and limit of quantification (LOQ)", "text": "Validation of the HPLC method for pectolinarin and pectolinarigenin as standard compounds was determined by LOD and LOQ. ", "cite_spans": [], "ref_spans": []}, {"section": "Calibration curves", "text": "Stock solutions (1 mg/ml) of pectolinarin and pectolinarigenin were prepared in MeOH, and the solution content was successively reduced to 10% in order to create different concentrations for calibration curves. The calibration curves for pectolinarin and pectolinarigenin were calculated using peak area (Y), concentration (X, mg/ml), and mean value (n = 3) \u00b1 SD (Table 2) .", "cite_spans": [], "ref_spans": []}, {"section": "| Antioxidant activities", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "| Determination of total phenol content", "text": "The total phenolic content was determined according to the method of Singleton, Orthofer, and Lamuela-Ravent\u00f3s (1999) with slight modifications. Samples of the extracts (200 mg) were dissolved in 1 ml of distilled water and filtered, and 100 \u03bcl was oxidized with 2.5 ml of 10% Folin-Ciocalteu's reagent (v/v) inside a test tube. The samples were then neutralized by adding 2.0 ml of 7.5% sodium carbonate. The reaction mixture was incubated for 40 min at 45\u00b0C, and the absorbance was measured at 765 nm with an Eppendorf Biospectrometer (Eppendorf Biospectrometer\u00ae fluorescence, Eppendorf Korea Ltd.). The total phenolic content of the beverages was subsequently estimated from a standard curve of absorbance of gallic acid and reported as gallic acid equivalent (GAE) ( Table 3) .", "cite_spans": [], "ref_spans": []}, {"section": "Sample number Description", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "S1", "text": "Cirsium setidens Nakai", "cite_spans": [], "ref_spans": []}, {"section": "S1", "text": "TA B L E 1 List of samples and their description", "cite_spans": [], "ref_spans": []}, {"section": "| Total flavonoid content", "text": "The total flavonoid content of the extracts was determined by the aluminum chloride colorimetric method (Chang, Yang, Wen, & Chern, 2002) . In brief, 50 \u03bcl of the samples (1 mg/ml ethanol) was made up to 1 ml with methanol, mixed with 4 ml of distilled water and then 0.3 ml of 5% NaNO 2 solution; 0.3 ml of 10% AlCl 3 solution was added after 5 min of incubation, and the mixture was allowed to stand for 6 min. Then, 2 ml of 1 M NaOH solution was added, and the final volume of the mixture was brought to 10 ml with doubledistilled water. The mixture was allowed to stand for 15 min, and absorbance was measured at 510 nm. The total flavonoid content was estimated from a calibration curve, and the result was expressed as milligram quercetin equivalent (QE) per g dry weight (Table 3) .", "cite_spans": [{"start": 104, "end": 137, "text": "(Chang, Yang, Wen, & Chern, 2002)", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "| Determination of reducing property (FRAP)", "text": "The reducing properties of the extracts were determined by assessing the ability of the extracts to reduce FeCl3 solution as described by Zhao et al. (2008) . An aliquot (2.5 ml) of the aqueous extract was mixed with 2.5 ml 200 mM sodium phosphate buffer (pH 6.6) and 2.5 ml 1% potassium ferricyanide. The mixture was incubated at 50\u00b0C for 20 min, and then, 2.5 ml 10% trichloroacetic acid (v/v) was added. This mixture was centrifuged at 45 g for 10 min, and 5 ml of the supernatant was mixed with an equal volume of water followed by the addition of 1 ml 0.1% ferric chloride (w/v). The absorbance was measured at 593 nm with an Eppendorf Biospectrometer.", "cite_spans": [{"start": 138, "end": 156, "text": "Zhao et al. (2008)", "ref_id": "BIBREF33"}], "ref_spans": []}, {"section": "| Determination of reducing property (FRAP)", "text": "Ascorbic acid was used as a positive control. The ferric reducing antioxidant property was subsequently calculated (Figure 1 ).", "cite_spans": [], "ref_spans": []}, {"section": "| 2,2-diphenyl-1-picrylhydrazyl free radical scavenging ability (DPPH)", "text": "Hydrogen atom or electron-donation ability of the beverage extracts was measured from the bleaching of the purple-colored methanol solution of DPPH. The free radical scavenging abilities of the extracts against DPPH (1,1-diphenyl-2-picrylhydrazyl) free radical were evaluated as already described (Gyamfi, Yonamine, & Aniya, 1999) . FI TRF, USA). The absorbance at 450 nm was subtracted from the absorbance at 690 nm. The ability of the extracts to promote or suppress the growth of the cells was interpreted as their cytotoxicity (Figure 3 ).", "cite_spans": [{"start": 297, "end": 330, "text": "(Gyamfi, Yonamine, & Aniya, 1999)", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "| Nitric oxide stimulation assay", "text": "The ability of the extracts to stimulate NO production in RAW 264.7 cells was performed as previously described (Green et al., 1982) . Briefly, RAW 264.7 cells (99 \u03bcl, plated at 10 6 cells/ml) were treated with extracts (1 \u03bcl). Nitrite was then measured after 24 hr using the Griess reaction. The culture media of the RAW 264.7 cells (80 \u03bcl) were mixed with 80 \u03bcL of Griess reagent, and its absorbance was measured at 550 nm using an Eppendorf Biospectrometer. The nitrite concentrations in the culture media were determined by comparing them with a NaNO 2 standard curve. LPS (1 \u03bcl) was diluted with DMEM, (0.05 \u03bcg/ml) and used as the positive control, and distilled water was the solvent control. Each concentration was assayed three times ( Figure 4a ).", "cite_spans": [{"start": 112, "end": 132, "text": "(Green et al., 1982)", "ref_id": "BIBREF12"}], "ref_spans": [{"start": 744, "end": 753, "text": "Figure 4a", "ref_id": "FIGREF6"}]}, {"section": "| Cytokine measurements in RAW 264.7 cell cultures", "text": "The ability of S6 extract to induce TNF-\u03b1, IL-1\u03b2, and IL-10 production in RAW 264.7 cells cultures was performed as previously described ", "cite_spans": [], "ref_spans": []}, {"section": "| Statistical analysis", "text": "All experiments were carried out in triplicates, and the results were plants have been shown to be directly related to their potential antioxidant capacities in many studies (Demir, Yildiz, Alpaslan, & Hayaloglu, 2014; Zhang et al., 2014) . Garlic is rich in phenolic compounds and SAC which have strong antioxidant properties (Alarc\u00f3n-Flores, Romero-Gonz\u00e1lez, Vidal, & Frenich, 2014) as well as antihypertensive, anti-inflammatory, and anticancer activities (Fratianni et al., 2016) . C. setidens Nakai contains pectolinarin (a glycoside) and pectolinarigenin (an aglycone) which have strong anti-inflammatory properties (Jeong et al., 2013; Lee et al., 2014) .", "cite_spans": [{"start": 174, "end": 218, "text": "(Demir, Yildiz, Alpaslan, & Hayaloglu, 2014;", "ref_id": "BIBREF9"}, {"start": 219, "end": 238, "text": "Zhang et al., 2014)", "ref_id": "BIBREF32"}, {"start": 459, "end": 483, "text": "(Fratianni et al., 2016)", "ref_id": "BIBREF11"}, {"start": 622, "end": 642, "text": "(Jeong et al., 2013;", "ref_id": "BIBREF15"}, {"start": 643, "end": 660, "text": "Lee et al., 2014)", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "| Statistical analysis", "text": "These anti-inflammatory compounds are, however, bound and are not bioavailable as shown in Table 2 . Therefore, fermenting them with L. mesenteroides enabled the release of pectolinarin and pectolinarigenin. This accounts for the high pectolinarin and pectolinarigenin contents in fermented samples relative to the unfermented samples containing C. setidens Nakai. Fermentation of garlic also significantly increased the levels of SAC from 1.8 \u00b1 0.1 mg/g to 4.43 \u00b1 0.67 mg/g (Table 4 ). Furthermore, phenolic and flavonoid compounds generally increased with fermentation (Table 3) . Our results agree with an earlier study in which the phenolic content of fermented okra seeds increased significantly relative to unfermented seeds (Adetuyi & Ibrahim, 2014) . This might be due to the ability of the LAB enzymes to hydrolyze the samples to release bound phenolic and flavonoid compounds during the fermentation process.", "cite_spans": [{"start": 731, "end": 756, "text": "(Adetuyi & Ibrahim, 2014)", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "| Antioxidant activity", "text": "Since phenolic and flavonoid contents of plants have been associated with their antioxidant potencies, the Fe 3+ reducing abilities of the samples were tested (Figure 1 ). The reducing ability of a compound generally depends on the presence of reduc tones which exert the antioxidant activity by breaking the free radical chain via donating a hydrogen atom (Pavithra & Vadivukkarasi, 2015) . Results from this study demonstrated that sample S8 had a higher Fe 3+ to Fe 2+ reducing ability followed by S6, and this could be due to the reductones released during the fermentation process.", "cite_spans": [{"start": 357, "end": 389, "text": "(Pavithra & Vadivukkarasi, 2015)", "ref_id": "BIBREF27"}], "ref_spans": []}, {"section": "| Antioxidant activity", "text": "DPPH, a stable free radical, accepts hydrogen radicals or electrons from donors to become stable diamagnetic molecules. The degree to which a sample decolorizes the dark color of the DPPH radical solution indicates its scavenging potential. In this study, all the extracts scavenged DPPH radicals in a dose-dependent manner (Figure 2 ). Consistent with our observations in the Fe 3+ reducing ability test, sample S8 showed a very high DPPH scavenging activity followed by S6. Since the total polyphenols and flavonoids in the fermented samples increased relative to their unfermented counterparts (Table 3) , the high DPPH radical scavenging activity and reducing ability observed could be attributed to the polyphenols and flavonoids released during the fermentation process.", "cite_spans": [], "ref_spans": []}, {"section": "| Effects of sample extracts on RAW 264.7 cell proliferation", "text": "To test for the potential of the extracts to enhance or suppress cell proliferation, XTT{2,3-bis (2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide innersalt} assay was performed on RAW 264.7 cells (Figure 3) . It was observed that none of the extracts at the concentrations tested suppressed RAW 264.7 cell proliferation.", "cite_spans": [], "ref_spans": []}, {"section": "| Effects of sample extracts on RAW 264.7 cell proliferation", "text": "Generally, all the extracts enhanced cell proliferation in a dose-dependent manner implying that the extracts are nontoxic. The highest cell proliferation was, however, observed after RAW 264.7 cells were treated with 200 \u00b5g/ml of S6 and S8. Treating the cells with 200 \u00b5g/ml of S6 and S8 resulted in no significant differences in cell proliferation (p > 0.05). Lu et al. (Lu et al., 2014) have reported that 50 \u00b5M of pectolinarigenin effectively suppresses the growth of MCF-7 cells (a breast cancer cell line), and our study has shown that the extracts are not toxic to normal cells. This therefore implies that our beverage is safe for consumption and may inhibit tumor growth.", "cite_spans": [{"start": 372, "end": 389, "text": "(Lu et al., 2014)", "ref_id": "BIBREF22"}], "ref_spans": []}, {"section": "| Immunomodulatory activity", "text": "To test the ability of the beverage blends to stimulate the immune system, their ability to induce NO production in RAW 264.7 macrophages was studied as these cells constitute the first line of host defenses against infections (Mehta, Ashkar, & Mossman, 2012) .", "cite_spans": [{"start": 227, "end": 259, "text": "(Mehta, Ashkar, & Mossman, 2012)", "ref_id": "BIBREF24"}], "ref_spans": []}, {"section": "| Immunomodulatory activity", "text": "When NO is generated, it is easily oxidized to nitrite and stored in intracellular and extracellular fluids (Green et al., 1982) . Thus, in experiments, the levels of nitrite (a stable product of NO) are usually measured to reflect the amount of NO (Green et al., 1982) . In macrophages, macrophage-inducible NO synthase is mainly responsible for NO production in response to various stimuli (Tripathi, Tripathi, Kashyap, & Singh, 2007) . NO then acts as an intercellular messenger and is a versatile player in the immune system. In our study, all the concentrations tested induce NO to various extents in a dose-dependent manner (Figure 4a ). S8 and S6 induced similar levels (the highest levels) of NO in the culture supernatant. Even lower concentrations (100 \u03bcg/ml) of S6 and S8 induced NO production and this agrees with an earlier study which reported that 100 \u03bcg/ml of a plant extract strongly induced macNOS mRNA expression (Imanishi et al., 2004) . The ability of the extracts to induce NO secretion by RAW 264.7 cells may reflect the potential to modulate NO-based strategies for pathogen-mediated immune response for treating infections and tumors.", "cite_spans": [{"start": 108, "end": 128, "text": "(Green et al., 1982)", "ref_id": "BIBREF12"}, {"start": 249, "end": 269, "text": "(Green et al., 1982)", "ref_id": "BIBREF12"}, {"start": 392, "end": 436, "text": "(Tripathi, Tripathi, Kashyap, & Singh, 2007)", "ref_id": "BIBREF30"}, {"start": 932, "end": 955, "text": "(Imanishi et al., 2004)", "ref_id": "BIBREF14"}], "ref_spans": [{"start": 630, "end": 640, "text": "(Figure 4a", "ref_id": "FIGREF6"}]}, {"section": "| Immunomodulatory activity", "text": "Due to the high cost of C. setidens Nakai, it was more economical to produce S6 which contained only 20% Cirsium setidens Nakai relative to S8 which contained 50% C. setidens Nakai. Therefore, since they showed comparable effects (cell proliferation ability and NO stimulation), only S6 was selected for further studies. Activated macrophages are known to produce proinflammatory cytokines such as TNF-alpha and IL-1\u03b2 which play critical roles in regulating immune cells. Both cytokines induce fever, inflammation, and apoptosis and inhibit tumorigenesis and viral replication (Arango Duque & Descoteaux, 2014) . For this reason, we measured the levels of TNF-alpha produced after RAW 264.7 cells were treated with S6 ( Figure 4b ). TNF-alpha levels were significantly increased in a dose-dependent manner relative to the control (p < 0.05). However, although IL-1\u03b2 levels increased (relative to the control treatment), they were not significantly different (p > 0.05) when the concentrations of S6 were increased (Figure 4c ).", "cite_spans": [{"start": 577, "end": 610, "text": "(Arango Duque & Descoteaux, 2014)", "ref_id": "BIBREF3"}], "ref_spans": [{"start": 720, "end": 729, "text": "Figure 4b", "ref_id": "FIGREF6"}, {"start": 1014, "end": 1024, "text": "(Figure 4c", "ref_id": "FIGREF6"}]}, {"section": "| Immunomodulatory activity", "text": "Activated macrophages can also produce IL-10 which plays a key role in limiting immune-mediated pathology during many diseases. This anti-inflammatory cytokine ameliorates the excessive production of TNF-\u03b1 which can result in immunopathology during infections (Couper, Blount, & Riley, 2008) . In this study, treatment of ", "cite_spans": [{"start": 260, "end": 291, "text": "(Couper, Blount, & Riley, 2008)", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "CO N FLI C T O F I NTE R E S T", "text": "The authors declare that they have no conflict of interest.", "cite_spans": [], "ref_spans": []}, {"section": "E TH I C A L S TATEM ENT", "text": "The study did not involve any human or animal testing.", "cite_spans": [], "ref_spans": []}, {"section": "O RCI D", "text": "Deog-Hwan Oh https://orcid.org/0000-0002-7472-0436", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Effect of fermentation time on the phenolic, flavonoid and vitamin C contents and antioxidant activities of okra (Abelmoschus esculentus) seeds", "authors": [{"first": "F", "middle": ["O"], "last": "Adetuyi", "suffix": ""}, {"first": "T", "middle": ["A"], "last": "Ibrahim", "suffix": ""}], "year": 2014, "venue": "Nigerian Food Journal", "link": "83450108"}, "BIBREF1": {"title": "Horizontal gene transfer and antibacterial effect of Allium sativum (garlic) on methicillin-resistant Staphylococcus aureus", "authors": [{"first": "N", "middle": ["U"], "last": "Ain", "suffix": ""}, {"first": "S", "middle": [], "last": "Riaz", "suffix": ""}, {"first": "S", "middle": [], "last": "Abrar", "suffix": ""}, {"first": "M", "middle": [], "last": "Ahmad", "suffix": ""}, {"first": "Z", "middle": [], "last": "Khan", "suffix": ""}, {"first": "S", "middle": [], "last": "Hafiz", "suffix": ""}, {"first": "M", "middle": ["H"], "last": "Haider", "suffix": ""}], "year": 2017, "venue": "Annals of Pakistan Institute of Medical Sciences", "link": null}, "BIBREF2": {"title": "Determination of phenolic compounds in artichoke, garlic and spinach by ultra-high-performance liquid chromatography coupled to tandem mass spectrometry", "authors": [{"first": "M", "middle": ["I"], "last": "Alarc\u00f3n-Flores", "suffix": ""}, {"first": "R", "middle": [], "last": "Romero-Gonz\u00e1lez", "suffix": ""}, {"first": "J", "middle": ["L M"], "last": "Vidal", "suffix": ""}, {"first": "A", "middle": ["G"], "last": "Frenich", "suffix": ""}], "year": 2014, "venue": "Food Analytical Methods", "link": "95654747"}, "BIBREF3": {"title": "Macrophage cytokines: Involvement in immunity and infectious diseases", "authors": [{"first": "G", "middle": [], "last": "Arango Duque", "suffix": ""}, {"first": "A", "middle": [], "last": "Descoteaux", "suffix": ""}], "year": 2014, "venue": "Frontiers in Immunology", "link": "6922513"}, "BIBREF4": {"title": "Estimation of total flavonoid content in propolis by two complementary colorimetric methods", "authors": [{"first": "C", "middle": ["C"], "last": "Chang", "suffix": ""}, {"first": "M", "middle": ["H"], "last": "Yang", "suffix": ""}, {"first": "H", "middle": ["M"], "last": "Wen", "suffix": ""}, {"first": "J", "middle": ["C"], "last": "Chern", "suffix": ""}], "year": 2002, "venue": "Journal of Food and Drug Analysis", "link": "20019599"}, "BIBREF5": {"title": "Standardized Cirsium setidens Nakai ethanolic extract suppresses adipogenesis and regulates lipid metabolisms in 3T3-L1 adipocytes and C57BL/6J mice fed high-fat diets", "authors": [{"first": "B", "middle": ["Y"], "last": "Cho", "suffix": ""}, {"first": "M", "middle": ["R"], "last": "Park", "suffix": ""}, {"first": "J", "middle": ["H"], "last": "Lee", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Ra", "suffix": ""}, {"first": "K", "middle": ["C"], "last": "Han", "suffix": ""}, {"first": "I", "middle": ["J"], "last": "Kang", "suffix": ""}, {"first": "O", "middle": ["H"], "last": "Lee", "suffix": ""}], "year": 2017, "venue": "Journal of Medicinal Food", "link": "7263859"}, "BIBREF6": {"title": "IL-10: The master regulator of immunity to infection", "authors": [{"first": "K", "middle": ["N"], "last": "Couper", "suffix": ""}, {"first": "D", "middle": ["G"], "last": "Blount", "suffix": ""}, {"first": "E", "middle": ["M"], "last": "Riley", "suffix": ""}], "year": 2008, "venue": "The Journal of Immunology", "link": "13025984"}, "BIBREF7": {"title": "Levels of inflammatory cytokines from peripheral blood mononuclear cells of children with cow's milk protein allergy. Turkish Archives of Pediatrics/T\u00fcrk Pediatri Ar\u015fivi", "authors": [{"first": "M", "middle": [], "last": "D&apos;apolito", "suffix": ""}, {"first": "A", "middle": [], "last": "Campanozzi", "suffix": ""}, {"first": "I", "middle": [], "last": "Giardino", "suffix": ""}, {"first": "M", "middle": [], "last": "Pettoello-Mantovani", "suffix": ""}], "year": 2017, "venue": "", "link": null}, "BIBREF8": {"title": "Current trends and future perspectives on functional foods and nutraceuticals", "authors": [{"first": "E.-B.-M", "middle": [], "last": "Daliri", "suffix": ""}, {"first": "B", "middle": ["H"], "last": "Lee", "suffix": ""}], "year": 2015, "venue": "Beneficial microorganisms in food and nutraceuticals. Microbiology Monographs", "link": "167357367"}, "BIBREF9": {"title": "Evaluation of volatiles, phenolic compounds and antioxidant activities of rose hip (Rosa L.) fruits in Turkey", "authors": [{"first": "N", "middle": [], "last": "Demir", "suffix": ""}, {"first": "O", "middle": [], "last": "Yildiz", "suffix": ""}, {"first": "M", "middle": [], "last": "Alpaslan", "suffix": ""}, {"first": "A", "middle": ["A"], "last": "Hayaloglu", "suffix": ""}], "year": 2014, "venue": "Science and Technology", "link": "83868156"}, "BIBREF10": {"title": "Functional foods and dietary supplements: Products at the interface between pharma and nutrition", "authors": [{"first": "S", "middle": ["R"], "last": "Eussen", "suffix": ""}, {"first": "H", "middle": [], "last": "Verhagen", "suffix": ""}, {"first": "O", "middle": ["H"], "last": "Klungel", "suffix": ""}, {"first": "J", "middle": [], "last": "Garssen", "suffix": ""}, {"first": "H", "middle": [], "last": "Van Loveren", "suffix": ""}, {"first": "H", "middle": ["J"], "last": "Van Kranen", "suffix": ""}, {"first": "C", "middle": ["J"], "last": "Rompelberg", "suffix": ""}], "year": 2011, "venue": "European Journal of Pharmacology", "link": "22312313"}, "BIBREF11": {"title": "Phenolic constituents, antioxidant, antimicrobial and anti-proliferative activities of different endemic Italian varieties of garlic (Allium sativum L.)", "authors": [{"first": "F", "middle": [], "last": "Fratianni", "suffix": ""}, {"first": "M", "middle": ["N"], "last": "Ombra", "suffix": ""}, {"first": "A", "middle": [], "last": "Cozzolino", "suffix": ""}, {"first": "R", "middle": [], "last": "Riccardi", "suffix": ""}, {"first": "P", "middle": [], "last": "Spigno", "suffix": ""}, {"first": "P", "middle": [], "last": "Tremonte", "suffix": ""}, {"first": "F", "middle": [], "last": "Nazzaro", "suffix": ""}], "year": 2016, "venue": "Journal of Functional Foods", "link": "86333721"}, "BIBREF12": {"title": "Analysis of nitrate, nitrite, and [15N] nitrate in biological fluids", "authors": [{"first": "L", "middle": ["C"], "last": "Green", "suffix": ""}, {"first": "D", "middle": ["A"], "last": "Wagner", "suffix": ""}, {"first": "J", "middle": [], "last": "Glogowski", "suffix": ""}, {"first": "P", "middle": ["L"], "last": "Skipper", "suffix": ""}, {"first": "J", "middle": ["S"], "last": "Wishnok", "suffix": ""}, {"first": "S", "middle": ["R"], "last": "Tannenbaum", "suffix": ""}], "year": 1982, "venue": "Analytical Biochemistry", "link": "29005280"}, "BIBREF13": {"title": "Free-radical scavenging action of medicinal herbs from Ghana: Thonningia sanguinea on experimentally-induced liver injuries", "authors": [{"first": "M", "middle": ["A"], "last": "Gyamfi", "suffix": ""}, {"first": "M", "middle": [], "last": "Yonamine", "suffix": ""}, {"first": "Y", "middle": [], "last": "Aniya", "suffix": ""}], "year": 1999, "venue": "General Pharmacology: The Vascular System", "link": null}, "BIBREF14": {"title": "Inducible activity of ginger rhizome (Zingiber offifinale Rosc.) on the mRNA expression of macrophage-inducible nitric oxide (NO) synthase and NO production in a macrophage cell line, RAW264. 7 cells", "authors": [{"first": "N", "middle": [], "last": "Imanishi", "suffix": ""}, {"first": "N", "middle": [], "last": "Mantani", "suffix": ""}, {"first": "S", "middle": [], "last": "Sakai", "suffix": ""}, {"first": "M", "middle": [], "last": "Sato", "suffix": ""}, {"first": "Y", "middle": [], "last": "Katada", "suffix": ""}, {"first": "K", "middle": [], "last": "Ueda", "suffix": ""}, {"first": "H", "middle": [], "last": "Ochiai", "suffix": ""}], "year": 2004, "venue": "The American Journal of Chinese Medicine", "link": "32364666"}, "BIBREF15": {"title": "Quantification of marker compounds in Cirsium setidens Nakai by HPLC-DAD", "authors": [{"first": "H", "middle": ["C"], "last": "Jeong", "suffix": ""}, {"first": "Y", "middle": ["S"], "last": "Shim", "suffix": ""}, {"first": "Y", "middle": ["K"], "last": "Rhee", "suffix": ""}, {"first": "S", "middle": ["Y"], "last": "Choi", "suffix": ""}, {"first": "H", "middle": ["D"], "last": "Hong", "suffix": ""}, {"first": "J", "middle": [], "last": "Chung", "suffix": ""}, {"first": "C", "middle": ["W"], "last": "Cho", "suffix": ""}], "year": 2013, "venue": "Food Science and Biotechnology", "link": "94700757"}, "BIBREF16": {"title": "The anticancer effects of garlic extracts on bladder cancer compared to cisplatin: A common mechanism of action via centromere protein M", "authors": [{"first": "W", "middle": ["T"], "last": "Kim", "suffix": ""}, {"first": "S.-P", "middle": [], "last": "Seo", "suffix": ""}, {"first": "Y", "middle": ["J"], "last": "Byun", "suffix": ""}, {"first": "H.-W", "middle": [], "last": "Kang", "suffix": ""}, {"first": "Y.-J", "middle": [], "last": "Kim", "suffix": ""}, {"first": "S.-C", "middle": [], "last": "Lee", "suffix": ""}, {"first": "W.-J", "middle": [], "last": "Kim", "suffix": ""}], "year": 2018, "venue": "The American Journal of Chinese Medicine", "link": "4397530"}, "BIBREF17": {"title": "Physical, chemical, and biological properties of S-allylcysteine, an amino acid derived from garlic", "authors": [{"first": "Y", "middle": [], "last": "Kodera", "suffix": ""}, {"first": "A", "middle": [], "last": "Suzuki", "suffix": ""}, {"first": "O", "middle": [], "last": "Imada", "suffix": ""}, {"first": "S", "middle": [], "last": "Kasuga", "suffix": ""}, {"first": "I", "middle": [], "last": "Sumioka", "suffix": ""}, {"first": "A", "middle": [], "last": "Kanezawa", "suffix": ""}, {"first": "K", "middle": [], "last": "Ono", "suffix": ""}], "year": 2002, "venue": "Journal of Agricultural and Food Chemistry", "link": "37553294"}, "BIBREF18": {"title": "Fermentation with Lactobacillus enhances the preventive effect of garlic extract on high fat diet-induced hepatic steatosis in mice", "authors": [{"first": "H", "middle": ["S"], "last": "Lee", "suffix": ""}, {"first": "S", "middle": ["J"], "last": "Lee", "suffix": ""}, {"first": "H", "middle": ["J"], "last": "Yu", "suffix": ""}, {"first": "J", "middle": ["H"], "last": "Lee", "suffix": ""}, {"first": "H", "middle": ["Y"], "last": "Cho", "suffix": ""}], "year": 2017, "venue": "Journal of Functional Foods", "link": "90706260"}, "BIBREF19": {"title": "Nutritional components and physiological activities of Cirsium setidens Nakai", "authors": [{"first": "O", "middle": ["H"], "last": "Lee", "suffix": ""}, {"first": "J", "middle": ["H"], "last": "Kim", "suffix": ""}, {"first": "Y", "middle": ["H"], "last": "Kim", "suffix": ""}, {"first": "Y", "middle": ["J"], "last": "Lee", "suffix": ""}, {"first": "J", "middle": ["S"], "last": "Lee", "suffix": ""}, {"first": "J", "middle": ["H"], "last": "Jo", "suffix": ""}, {"first": "B", "middle": ["Y"], "last": "Lee", "suffix": ""}], "year": 2014, "venue": "Journal of the Korean Society of Food Science and Nutrition", "link": null}, "BIBREF20": {"title": "Antioxidant and hepatoprotective activities of Cirsium setidens Nakai against CCl 4 -induced liver damage", "authors": [{"first": "S", "middle": ["H"], "last": "Lee", "suffix": ""}, {"first": "S", "middle": ["I"], "last": "Heo", "suffix": ""}, {"first": "L", "middle": [], "last": "Li", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Lee", "suffix": ""}, {"first": "M", "middle": ["H"], "last": "Wang", "suffix": ""}], "year": 2008, "venue": "The American Journal of Chinese Medicine", "link": "26554715"}, "BIBREF21": {"title": "Berberine, a natural plant product, activates AMP-activated protein kinase with beneficial metabolic effects in diabetic and insulin-resistant states", "authors": [{"first": "Y", "middle": ["S"], "last": "Lee", "suffix": ""}, {"first": "W", "middle": ["S"], "last": "Kim", "suffix": ""}, {"first": "K", "middle": ["H"], "last": "Kim", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Yoon", "suffix": ""}, {"first": "H", "middle": ["J"], "last": "Cho", "suffix": ""}, {"first": "Y", "middle": [], "last": "Shen", "suffix": ""}, {"first": "J", "middle": ["B"], "last": "Kim", "suffix": ""}], "year": 2006, "venue": "Diabetes", "link": "12514008"}, "BIBREF22": {"title": "Pectolinarigenin-a flavonoid compound from Cirsium japonicum with potential anti-proliferation activity in mcf-7 breast cancer cell", "authors": [{"first": "M", "middle": [], "last": "Lu", "suffix": ""}, {"first": "Q", "middle": [], "last": "Kong", "suffix": ""}, {"first": "X", "middle": [], "last": "Xu", "suffix": ""}, {"first": "H", "middle": [], "last": "Lu", "suffix": ""}, {"first": "Z", "middle": [], "last": "Lu", "suffix": ""}, {"first": "W", "middle": [], "last": "Yu", "suffix": ""}, {"first": "R", "middle": [], "last": "Guo", "suffix": ""}], "year": 2014, "venue": "Tropical Journal of Pharmaceutical Research", "link": "53535583"}, "BIBREF23": {"title": "Garlic-derived compounds increase expression of ABCA1 mRNA in RAW 264.7 murine macrophages", "authors": [{"first": "A", "middle": ["J"], "last": "Madden", "suffix": ""}, {"first": "M", "middle": ["D"], "last": "Krehbiel", "suffix": ""}, {"first": "S", "middle": ["L"], "last": "Clarke", "suffix": ""}], "year": 2017, "venue": "The FASEB Journal", "link": null}, "BIBREF24": {"title": "The nitric oxide pathway provides innate antiviral protection in conjunction with the type I interferon pathway in fibroblasts", "authors": [{"first": "D", "middle": ["R"], "last": "Mehta", "suffix": ""}, {"first": "A", "middle": ["A"], "last": "Ashkar", "suffix": ""}, {"first": "K", "middle": ["L"], "last": "Mossman", "suffix": ""}], "year": 2012, "venue": "PLoS ONE", "link": "8961407"}, "BIBREF25": {"title": "Inhibitory effect of a Cirsium setidens extract on hepatic fat accumulation in mice fed a high-fat diet via the induction of fatty acid \u03b2-oxidation", "authors": [{"first": "H", "middle": [], "last": "Noh", "suffix": ""}, {"first": "H", "middle": [], "last": "Lee", "suffix": ""}, {"first": "E", "middle": [], "last": "Kim", "suffix": ""}, {"first": "L", "middle": [], "last": "Mu", "suffix": ""}, {"first": "Y", "middle": ["K"], "last": "Rhee", "suffix": ""}, {"first": "C", "middle": ["W"], "last": "Cho", "suffix": ""}, {"first": "J", "middle": [], "last": "Chung", "suffix": ""}], "year": 2013, "venue": "Biotechnology, and Biochemistry", "link": null}, "BIBREF26": {"title": "Worldwide consumption of functional foods: A systematic review", "authors": [{"first": "A", "middle": ["E"], "last": "Ozen", "suffix": ""}, {"first": "A", "middle": [], "last": "Pons", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Tur", "suffix": ""}], "year": 2012, "venue": "Nutrition Reviews", "link": "36683377"}, "BIBREF27": {"title": "Evaluation of free radical scavenging activity of various extracts of leaves from Kedrostis foetidissima (Jacq.) Cogn. Food Science and Human Wellness", "authors": [{"first": "K", "middle": [], "last": "Pavithra", "suffix": ""}, {"first": "S", "middle": [], "last": "Vadivukkarasi", "suffix": ""}], "year": 2015, "venue": "", "link": null}, "BIBREF28": {"title": "Analysis of total phenols and other oxidation substrates and antioxidants by means of folin-ciocalteu reagent", "authors": [{"first": "V", "middle": ["L"], "last": "Singleton", "suffix": ""}, {"first": "R", "middle": [], "last": "Orthofer", "suffix": ""}, {"first": "R", "middle": ["M"], "last": "Lamuela-Ravent\u00f3s", "suffix": ""}], "year": 1999, "venue": "Methods in enzymology", "link": "83124453"}, "BIBREF29": {"title": "Simultaneous determination of bioactive flavonoids in some selected Korean thistles by high-performance liquid chromatography", "authors": [{"first": "N", "middle": ["T P"], "last": "Thao", "suffix": ""}, {"first": "T", "middle": ["D"], "last": "Cuong", "suffix": ""}, {"first": "T", "middle": ["M"], "last": "Hung", "suffix": ""}, {"first": "J", "middle": ["H"], "last": "Lee", "suffix": ""}, {"first": "M", "middle": [], "last": "Na", "suffix": ""}, {"first": "J", "middle": ["K"], "last": "Son", "suffix": ""}, {"first": "B", "middle": ["S"], "last": "Min", "suffix": ""}], "year": 2011, "venue": "Archives of Pharmacal Research", "link": "42846686"}, "BIBREF30": {"title": "Immunomodulatory attributes of aged garlic extract and its components", "authors": [{"first": "P", "middle": [], "last": "Tripathi", "suffix": ""}, {"first": "P", "middle": [], "last": "Tripathi", "suffix": ""}, {"first": "L", "middle": [], "last": "Kashyap", "suffix": ""}, {"first": "V", "middle": [], "last": "Singh", "suffix": ""}], "year": 2007, "venue": "FEMS Immunology & Medical Microbiology", "link": "89925411"}, "BIBREF31": {"title": "Pectolinarin and pectolinarigenin of Cirsium setidens prevent the hepatic injury in rats caused by D-galactosamine via an antioxidant mechanism", "authors": [{"first": "Y", "middle": ["M"], "last": "Yoo", "suffix": ""}, {"first": "J", "middle": ["H"], "last": "Nam", "suffix": ""}, {"first": "M", "middle": ["Y"], "last": "Kim", "suffix": ""}, {"first": "J", "middle": [], "last": "Choi", "suffix": ""}, {"first": "H", "middle": ["J"], "last": "Park", "suffix": ""}], "year": 2008, "venue": "Biological and Pharmaceutical Bulletin", "link": "22607818"}, "BIBREF32": {"title": "Phenolic compounds from Origanum vulgare and their antioxidant and antiviral activities", "authors": [{"first": "X", "middle": ["L"], "last": "Zhang", "suffix": ""}, {"first": "Y", "middle": ["S"], "last": "Guo", "suffix": ""}, {"first": "C", "middle": ["H"], "last": "Wang", "suffix": ""}, {"first": "G", "middle": ["Q"], "last": "Li", "suffix": ""}, {"first": "J", "middle": ["J"], "last": "Xu", "suffix": ""}, {"first": "H", "middle": ["Y"], "last": "Chung", "suffix": ""}, {"first": "G", "middle": ["C"], "last": "Wang", "suffix": ""}], "year": 2014, "venue": "Food Chemistry", "link": "25593967"}, "BIBREF33": {"title": "Evaluation of antioxidant activities and total phenolic contents of typical malting barley varieties", "authors": [{"first": "H", "middle": [], "last": "Zhao", "suffix": ""}, {"first": "W", "middle": [], "last": "Fan", "suffix": ""}, {"first": "J", "middle": [], "last": "Dong", "suffix": ""}, {"first": "J", "middle": [], "last": "Lu", "suffix": ""}, {"first": "J", "middle": [], "last": "Chen", "suffix": ""}, {"first": "L", "middle": [], "last": "Shan", "suffix": ""}, {"first": "W", "middle": [], "last": "Kong", "suffix": ""}], "year": 2008, "venue": "Food Chemistry", "link": "84350184"}, "BIBREF34": {"title": "Biological activities of a garlic-Cirsium setidens Nakai blend fermented with Leuconostoc mesenteroides", "authors": [{"first": "Eb-M", "middle": [], "last": "Daliri", "suffix": ""}, {"first": "S-I", "middle": [], "last": "Choi", "suffix": ""}, {"first": "B-Y", "middle": [], "last": "Cho", "suffix": ""}], "year": 2019, "venue": "Food Sci Nutr", "link": "164945171"}}, "ref_entries": {"FIGREF0": {"text": "10, 80:20, 50:50) were inoculated with 0.1% L. mesenteroides KCTC 13302 (v/v) in distilled water. The sample was incubated at 37\u00b0C for 48 hr (Table 1). The sample was then sterilized by heat- ing at 100\u00b0C for 1 hr and concentrated to 30\u00b0Bx. The final pH was between 5.4 and 5.7. All the samples (both fermented and unfer- mented) were freeze-dried and extracted with 99.9% (v/v) ethanol. The extracts were stored at \u221220 degrees till use. 2.6 | Determination of bioactive compounds 2.6.1 | S-allyl cysteine levels by high-performance liquid chromatography (HPLC) The levels of S-allyl-L-cysteine were analyzed by the Korean Food Research Institute (Chonbuk). Briefly, the extracts were filtered through a 0.45-m syringe filter (Merck KGaA) and the filtrate was analyzed using S-allyl-L-cysteine (\u226598%; Sigma-Aldrich) as a stand- ard. A HPLC-UVD system (Shimadzu, Shimadzu Corporation) fixed with a LC-10AD pump, a SPD-10A UV/Vis detector, a CTO-10AC col- umn thermostat, and a manual sample injector was used to analyze S-allyl cysteine content in extracts. The mobile phase consisted of 0.1% H3PO4 solution and acetonitrile (Sigma-Aldrich) with isocratic elution. A flow rate of 0.5 ml/min and injection volume of 10 \u00b5l were applied. The analyte was separated using a LiChroCART\u00ae column (250 \u00d7 4 mm, 5 m, Merck KGaA) at room temperature, and SAC was detected at 210 nm.", "type": "figure"}, "FIGREF1": {"text": "Spherisorb \u00ae INNO column C18 (4.6 \u00d7 250 mm, 5 \u03bcm) was used for analysis of pectolinarin and pectolinarigenin. The mobile phase was dissolved in water (solvent A) and acetonitrile (solvent B). The gradi- ent solvent system was initially composed of solvents A/B (75:25) and then changed to solvents A/B (10:90) for 30 min, solvents A/ B (0:100) for 20 min, and finally to solvents A/B (75:25) for 15 min.", "type": "figure"}, "FIGREF2": {"text": "Method linearity was established by triplicate injections in the range of 0.0001\u22121.0 mg/ml. Five calibration solutions were in- jected in triplicate. Calibration curves were constructed by linear regression of the peak height (Y) of pectolinarin and pectolinar- igenin versus concentration (X) in mg/ml. The relative standard deviation was used as a measure of repeatability. The percent recoveries were evaluated by calculating the ratio of amount detected versus amount added. LOD and LOQ values were de- termined separately at signal-to-noise ratios (S/N) of 3 and 10, respectively.", "type": "figure"}, "FIGREF3": {"text": "The extracts (200 mg) were dissolved in 1 ml of 0.4 mM meth- anolic solution containing DPPH radicals. The mixtures were left in the dark for 30 min, and absorbance was taken at 516 nm with an Eppendorf Biospectrometer. Radical scavenging ability of samples was calculated as the percentage of DPPH free radicals inhibited by samples compared to radical inhibition in the negative control (water). Ascorbic acid (AsA) was used as a positive control. The per- cent DPPH inhibition was calculated from the following equation: where A 0 is the absorbance of the control and A sample is the absorb- ance of the test samples (Figure 2). 2.8 | Immunomodulatory activity 2.8.1 | RAW 264.7 cell proliferation effects of extracts The ability of the extracts to enhance or suppress RAW 264.7 cell proliferation was evaluated by XTT{2,3-bis (2-methoxy-4-nitro-5- sulfophenyl)-2H-tetrazolium-5-carboxanilide innersalt} assay kit (Welgene Inc). RAW 264.7 cells were seeded in 96-well plates at a concentration of 1 \u00d7 10 6 cell in 89% Dulbecco's modified Eagle's medium (DMEM from Thermo Fisher Scientific Solutions LLC) con- taining 10% fetal bovine serum (v/v) and cultured until 100% con- fluence. Each sample was diluted to 50, 100, and 200 \u03bcg/ml. XTT reagent (1 ml) and 20 \u03bcl PMS reagent (N-ethylphenazonium methyl sulfate) were used to prepare a working solution. Equal volumes of the cultured cell supernatant and the working solution (100 \u03bcl) were put into the 96-well plate and were incubated for 4 hr in a CO 2 in- cubator (Thermo Scientific", "type": "figure"}, "FIGREF4": {"text": "by with modifications (D'Apolito, Campanozzi, Giardino, & Pettoello- Mantovani, 2017). Briefly, RAW 264.7 cells (99 \u03bcl, plated at 10 6 cells/ ml) were treated with 50, 100, and 200 \u00b5g/ml of S6 extracts, and the plates were incubated for 5 days at 37 \u00baC. LPS (1 \u03bcL) was diluted with DMEM, (0.05 \u03bcg/ml) and used as the positive control, and dis- tilled water was the solvent control. Each concentration was assayed three times (Figure 4). After incubation, the culture supernatants were harvested, and TNF-\u03b1, IL-10, and IL-1\u03b2 levels were determined F I G U R E 1 Dose-dependent FRAP activity of various extracts. Data show mean + SD (n = 3). Values with different alphabets across a treatment are significantly different (p < 0.05) according to Duncan multiple range test F I G U R E 2 Dose-dependent DPPH radical scavenging activity of various extracts. Data show mean + SD (n = 3). Values with different alphabets across a treatment are significantly different (p < 0.05) according to Duncan multiple range test F I G U R E 3 Effects of beverage blends on RAW 264.7 cell proliferation. RAW 264.7 macrophages were either treated with 50, 100, and 200 \u00b5g/ml of extracts or were given no treatments (control). Results are expressed as means \u00b1 SD of three experiments for separate experiments for each data point. Bars with different alphabets are significantly different (p < 0.05) using commercial enzyme-linked immunosorbent assay kits (R&D Systems, Minneapolis, MN) according to the manufacturer's in- structions. The results are expressed in pg/ml as mean \u00b1 standard deviation.", "type": "figure"}, "FIGREF5": {"text": "expressed as the mean \u00b1 SD. The statistical analysis of data was per- formed using GraphPad Prism 5.0 (2007) statistical software system (GraphPad Software Inc.). p \u2264 0.05 was considered significant ac- cording to Duncan multiple range test. 3 | RE SULTS AND D ISCUSS I ON 3.1 | S-allyl cysteine, pectolinarin, pectolinarigenin, phenolic, and flavonoid contents Phenolic compounds are abundant plant secondary metabolites and are beneficial for human health. The phenolic contents of F I G U R E 4 (a) Nitric oxide (NO) production in supernatants of RAW 264.7 macrophages cell culture after beverage extract treatment. The bars represent means of three independent experiments \u00b1 SD. Bars with the same alphabets are not significantly different (p > 0.05). (b) TNF-\u03b1 production in supernatants of RAW 264.7 macrophages cell culture after S6 extract treatment. The bars represent means of three independent experiments \u00b1 SD. Bars with the same alphabets are not significantly different (p > 0.05). (c) IL-1\u03b2 production in supernatants of RAW 264.7 macrophages cell culture after S6 extract treatment. The bars represent means of three independent experiments \u00b1 S.D. Bars with the same alphabets are not significantly different (p > 0.05). (d) IL-10 production in supernatants of RAW 264.7 macrophages cell culture after S6 extract treatment. The bars represent means of three independent experiments \u00b1 SD. Bars with the same alphabets are not significantly different (p > 0.05)", "type": "figure"}, "FIGREF6": {"text": "Levels of S-allyl cysteine in raw and fermented garlic Sample S-allyl cysteine (mg/g)", "type": "figure"}, "FIGREF7": {"text": "RAW 264.7 cell cultures with S6 extracts induced the production of IL-10 in a dose-dependent manner (Figure 4d). The current study has demonstrated the strong antioxidant- and immune-stimulating abilities of a healthy beverage developed by fermenting a blend of C. Setidens Nakai and garlic. Since the resolution of an infection would require a coordinated response in which initial proinflammatory factors (such as TNF-\u03b1 and IL-1\u03b2) clear the pathogen and (the proinflammatory factors) are subse- quently down-modulated by anti-inflammatory cytokines such as IL-10, consumption of S6 could be a good functional beverage for promoting health. ACK N OWLED G M ENT This research was financially supported by the Ministry of SMEs and Startups (MSS), Korea, under the \"Regional Specialized Industry Development Program (R&D or non-R&D, Grant number R0006438)\" supervised by the Korea Institute for Advancement of Technology (KIAT).", "type": "figure"}, "TABREF0": {"text": "). Absorbance was measured using a mi- croplate reader (Tecan GENios FL Fluorescence Microplate Reader DPPH scavenging effect (%inhibition) = A control \u2212A sample \u2215A control \u00d7 100", "type": "table"}}}
{"paper_id": "164945677", "_pdf_hash": "65aa04c7bb972d885102e8a0f0a76afd02d1fc12", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Photonic Crystal Fibers", "authors": [{"first": "P", "middle": ["J"], "last": "St", "suffix": ""}, {"first": "", "middle": [], "last": "Russell", "suffix": ""}], "year": 2006, "venue": "Journal of Lightwave Technology", "link": "136470113"}, "BIBREF1": {"title": "Laser-cooled atoms inside a hollow core photonic crystal fiber", "authors": [{"first": "M", "middle": [], "last": "Bajcsy", "suffix": ""}, {"first": "S", "middle": [], "last": "Hofferberth", "suffix": ""}, {"first": "T", "middle": [], "last": "Peyronel", "suffix": ""}, {"first": "V", "middle": [], "last": "Balic", "suffix": ""}, {"first": "Q", "middle": [], "last": "Liang", "suffix": ""}, {"first": "A", "middle": ["S"], "last": "Zibrov", "suffix": ""}, {"first": "V", "middle": [], "last": "Vuletic", "suffix": ""}, {"first": "M", "middle": ["D"], "last": "Lukin", "suffix": ""}], "year": 2011, "venue": "Phys. Rev A", "link": "14902646"}, "BIBREF2": {"title": "An atom interferometer inside a hollow-core photonic crystal fiber", "authors": [{"first": "M", "middle": [], "last": "Xin", "suffix": ""}, {"first": "W", "middle": ["S"], "last": "Leong", "suffix": ""}, {"first": "Z", "middle": [], "last": "Chen", "suffix": ""}, {"first": "S.-Y.", "middle": [], "last": "Lan", "suffix": ""}], "year": 2018, "venue": "Science Advances", "link": "13682867"}, "BIBREF3": {"title": "Reduction of Guided Acoustic Wave Brillouin Scattering in Photonic Crystal Fibers", "authors": [{"first": "D", "middle": [], "last": "Elser", "suffix": ""}, {"first": "U", "middle": ["L"], "last": "Andersen", "suffix": ""}, {"first": "A", "middle": [], "last": "Korn", "suffix": ""}, {"first": "O", "middle": [], "last": "Gl\u00f6ckl", "suffix": ""}, {"first": "S", "middle": [], "last": "Lorenz", "suffix": ""}, {"first": "C", "middle": [], "last": "Marquardt", "suffix": ""}, {"first": "G", "middle": [], "last": "Leuchs", "suffix": ""}], "year": 2006, "venue": "Phys. Rev. Lett", "link": "1434423"}, "BIBREF4": {"title": "Forward Brillouin scattering in hollow-core photonic bandgap fibers", "authors": [{"first": "W", "middle": ["H"], "last": "Renninger", "suffix": ""}, {"first": "H", "middle": [], "last": "Shin", "suffix": ""}, {"first": "R", "middle": ["O"], "last": "Behunin", "suffix": ""}, {"first": "P", "middle": [], "last": "Kharel", "suffix": ""}, {"first": "E", "middle": ["A"], "last": "Kittlaus", "suffix": ""}, {"first": "P", "middle": ["T"], "last": "Rakich", "suffix": ""}], "year": 2016, "venue": "New J. Phys", "link": "4572155"}, "BIBREF5": {"title": "Negative Curvature Hollow Core Optical Fiber", "authors": [{"first": "F", "middle": [], "last": "Yu", "suffix": ""}, {"first": "J", "middle": [], "last": "Knight", "suffix": ""}], "year": 2015, "venue": "IEEE J. Sel. Top. Quantum Electron", "link": "43692251"}, "BIBREF6": {"title": "Low loss broadband transmission in hypocycloid-core Kagome hollow-core photonic crystal fiber", "authors": [{"first": "Y", "middle": ["Y"], "last": "Wang", "suffix": ""}, {"first": "N", "middle": ["V"], "last": "Wheeler", "suffix": ""}, {"first": "F", "middle": [], "last": "Couny", "suffix": ""}, {"first": "P", "middle": ["J"], "last": "Roberts", "suffix": ""}, {"first": "F", "middle": [], "last": "Benabid", "suffix": ""}], "year": 2011, "venue": "Opt. Lett", "link": "25101793"}, "BIBREF7": {"title": "Guided-wave Brillouin scattering in air", "authors": [{"first": "W", "middle": ["H"], "last": "Renninger", "suffix": ""}, {"first": "R", "middle": ["O"], "last": "Behunin", "suffix": ""}, {"first": "P", "middle": ["T"], "last": "Rakich", "suffix": ""}], "year": 2016, "venue": "Optica", "link": "119190190"}}, "ref_entries": {}}
{"paper_id": "164948735", "_pdf_hash": "2f02ceebdcd71a6e63b9880bbf2a6c6d30fad497", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "118860172", "_pdf_hash": "780b2b5f1b6b8b73ed3708daa3e29e8f75c9144d", "abstract": [{"section": "Abstract", "text": "We generalize the Rigid-Field Hydrodynamic equations to accommodate arbitrary magnetic field topologies, resulting in a new Arbitrary Rigid-Field Hydrodynamic (ARFHD) formalism. We undertake a critical point calculation of the steady-state ARFHD equations with a CAK-type radiative acceleration and determine the effects of a dipole magnetic field on the usual CAK mass-loss rate and velocity structure. Enforcing the proper optically-thin limit for the radiative line-acceleration is found to decrease both the mass-loss and wind acceleration, while rotation boosts both properties. We define optically-thin-correction and rotation parameters to quantify these effects on the global mass-loss rate and develop scaling laws for the surface massflux as a function of surface colatitude. These scaling laws are found to agree with previous laws derived from magnetohydrodynamic simulations of magnetospheres. The dipole magnetosphere velocity structure is found to differ from a global beta-velocity law, which contradicts a central assumption of the previously-developed XADM model of X-ray emission from magnetospheres.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "INTRODUCTION", "text": "In the last decade, spectropolarimetric surveys of OB stars have revealed that about 5-10% of these massive stars have large-scale, organized magnetic fields (MiMeS: Wade et al. 2014; BOB: Morel et al. 2015) . Such detectable magnetic fields (B 100 G) have a significant effect on the stellar wind, both channelling and trapping plasma within a stellar magnetosphere. This accumulated plasma produces extrastellar emission in optical (e.g. Howarth et al. 2007 , Bohlender & Monin 2011 , Grunhut et al. 2012 and references therein), infrared (Eikenberry et al. 2014) , radio (Linsky et al. 1992; Chandra et al. 2015) , and X-ray (Naz\u00e9 et al. 2014 (Naz\u00e9 et al. , 2015 . Furthermore, this emission exhibits a rotational modulation as the plasma is forced by the magnetic field to co-rotate with the star.", "cite_spans": [{"start": 166, "end": 183, "text": "Wade et al. 2014;", "ref_id": "BIBREF39"}], "ref_spans": []}, {"section": "INTRODUCTION", "text": "Similar advances in magnetosphere theory have also followed, starting with the pioneering magnetohydrodynamics (MHD) simulations of ud-Doula & Owocki (2002) . They developed a \"wind magnetic confinement parameter\" to characterize the interplay between the stellar magnetic field and flow:", "cite_spans": [{"start": 143, "end": 156, "text": "Owocki (2002)", "ref_id": "BIBREF40"}], "ref_spans": []}, {"section": "INTRODUCTION", "text": "email: bard@astro.wisc.edu with\u1e40B=0 and v\u221e,B=0 being the stellar mass-loss rate and terminal velocity if the star had no magnetic field. The confinement parameter \u03b7 * has become the canonical value adopted in scaling relations to explain the size (ud-Doula & Owocki 2002) , the mass-loss (ud-Doula et al. 2008) , the spin-down (ud-Doula et al. 2009 ), and, with the critical rotation fraction \u03c9, the classification (Petit et al. 2013 ) of magnetospheres. However, \u03b7 * itself depends on nonmagnetic values, ignoring any effects of the magnetic field. How does the magnetic field change the mass-loss rate and velocity? Can we use these new values to make a better confinement parameter?", "cite_spans": [{"start": 247, "end": 271, "text": "(ud-Doula & Owocki 2002)", "ref_id": "BIBREF40"}, {"start": 288, "end": 310, "text": "(ud-Doula et al. 2008)", "ref_id": "BIBREF40"}, {"start": 327, "end": 348, "text": "(ud-Doula et al. 2009", "ref_id": "BIBREF40"}], "ref_spans": []}, {"section": "INTRODUCTION", "text": "Traditionally,\u1e40 and v\u221e have been determined by analyzing the equation of motion for a line-driven wind (Castor et al. 1975; hereafter CAK) and solving for the so-called \"critical point\". Over the years, various modifications to the base CAK model (finite-disk effect: Friend & Abbott 1986 , Pauldrach et al. 1986 ; depth-dependent force multiplier parameters: Kudritzki 2002 ) have led to more realistic predictions of the mass-loss and terminal velocities. Other methods have been developed to improve on these estimates, such as a Monte Carlo method (Vink et al. 2000; Noebauer & Sim 2015) and a scattering source function technique (Sundqvist & Owocki 2015) . For now, we use the CAK line-driving force in order to take the first steps towards understanding the effect of a dipole field on a stellar wind.", "cite_spans": [], "ref_spans": []}, {"section": "INTRODUCTION", "text": "In this paper, we present and study the Arbitrary Rigid-Field Hydrodynamics (ARFHD) equations, an extension of Rigid-Field Hydrodynamics (RFHD) (Townsend et al. 2007) to account for non-dipole magnetic geometries (though we will consider only dipolar topologies in this analysis). RFHD was originally developed as an extension of the Rigidly Rotating Magnetosphere (RRM) model (Townsend & Owocki 2005) for centrifugal magnetospheres, whose large magnetic fields make MHD simulations very impractical. In this ansatz, the magnetic fields are assumed to be completely rigid (\u03b7 * \u2192 \u221e), channeling the stellar wind along quasi-onedimensional flux tubes. This allows each field line to be studied and simulated independently from one another, though this does miss important multi-dimensional effects present in the MHD simulations. In essence, the MHD studies approach the subject of massive-star magnetospheres from the regime of low magnetic confinement; ARFHD approaches this subject from the opposite regime of strong magnetic confinement. By blending both studies, we can set limits on the behavior of magnetospheres.", "cite_spans": [], "ref_spans": []}, {"section": "INTRODUCTION", "text": "In Section 2, we present the reformulated ARFHD equations and define all the terms, including external sources of acceleration and cooling. Following this, we develop the critical point equations for an arbitrary magnetic configuration in Section 3 and an algorithm for determing the critical point location in Section 4. Section 5 details the implementation and application of an aligned magnetic dipole radiationdriven wind model which includes the effect of stellar rotation. We present analytic scalings of the surface mass-flux in Section 6 and model results for the critical point location (Section 7), velocity structure (Section 8), and, finally, the global mass-loss rate (Section 9).", "cite_spans": [], "ref_spans": []}, {"section": "ARBITRARY RIGID-FIELD HYDRODYNAMIC EQUATIONS", "text": "Following Townsend et al. (2007) (hereafter T07), we extend the Rigid-Field Hydrodynamics (RFHD) model to incorporate arbitrary magnetic field line configurations, creating an Arbitrary Rigid-Field Hydrodynamics (ARFHD) model. In this section, we recap the key assumptions and equations of RFHD, with additional commentary pertaining to ARFHD when relevant. In the model, the key assumption is that the magnetic field is sufficiently strong to be effectively rigid (corresponding to \u03b7 * \u2192 \u221e). This rigid field is tethered to the star and co-rotates with it. Additionally, since the magnetic Reynolds number in the magnetosphere is so large (\u223c 10 15 ), we assume that the \"frozen flux\" condition of ideal MHD applies. As a result, the stiff magnetic field channels magnetospheric plasma flows along the field lines. These trajectories are pre-determined from the chosen stellar magnetic topology, though the plasma state (density, velocity, temperature, etc.) is determined by the hydrodynamics of the flow along each magnetic field line.", "cite_spans": [], "ref_spans": []}, {"section": "ARBITRARY RIGID-FIELD HYDRODYNAMIC EQUATIONS", "text": "The field lines are approximated as quasi-onedimensional flux tubes, with \"quasi-\" referring to their varying cross-sectional area. Under the requirement that local magnetic flux is conserved (\u2207 \u00b7 B = 0), the cross-sectional areas vary inversely with the local magnetic flux density B \u2261 |B|. Along these tubes, the plasma flow is subject to both internal (pressure gradients) and external (gravity, centrifugal, radiative driving) forces. Interestingly, in the rigidfield approximation, magnetic and Coriolis forces do not directly influence the dynamics of the flow along field lines since they are always directed perpendicular to the instantaneous velocity vector v.", "cite_spans": [], "ref_spans": []}, {"section": "Euler equations", "text": "We can characterize these 1D plasma flows with the conservation form of the quasi-1D Euler equations:", "cite_spans": [], "ref_spans": []}, {"section": "Euler equations", "text": "where the independent variables are t, the time, and s, the arc distance along the field line (relative to an arbitrary zero-point). The dependent variables are density \u03c1, velocity v, pressure P , and total energy per unit mass . The external sources of energy and momentum are the combined gravitocentrifugal acceleration g eff,s (Section 2.5), the radiative driving acceleration g rad,s (Section 2.6), and the volumetric energy loss rate \u039b \u2261 \u039bcc + \u039brc due to both radiative cooling (rc) and inverse Compton scattering (cc) (Section 2.7).", "cite_spans": [], "ref_spans": []}, {"section": "Grid geometry", "text": "The \"arbitrary\" aspect of ARFHD comes from allowing the imposition of any magentic topology, provided that the field lines are physically consistent (i.e. no intersections or discontinuities). This is an improvement over the original RFHD, which allowed only a dipole topology. In the reference Cartesian grid comprising the magnetosphere, we define (0, 0, 0) as the center of the star and the z-axis as the stellar rotation pole. Each field line is a three-dimensional space curve r(s) parameterized by the arc distance s, chosen so that the tangent vector\u015d = dr/ds is everywhere parallel to the local magnetic field vector B. We use the sign of the velocity to indicate the direction of flow; positive (negative) means that the plasma is flowing in the direction of increasing (decreasing) s.", "cite_spans": [], "ref_spans": []}, {"section": "Grid geometry", "text": "The creation of magnetic topologies is outside the scope of this paper, though there has recently been great success in reconstructing magnetic fields of OB stars using surface spectropolarimetry and source-surface reconstruction (Donati et al. 2006; Kochukhov et al. 2011 ).", "cite_spans": [], "ref_spans": []}, {"section": "Equations of state and energy", "text": "In ARFHD, we assume an ideal gas:", "cite_spans": [], "ref_spans": []}, {"section": "Equations of state and energy", "text": "with the Boltzmann constant k b and\u03bc \u2261 \u00b5uatm with uatm the atomic mass unit. The mean molecular weight \u00b5 is determined by an expression appropriate to a fully ionized mixture:", "cite_spans": [], "ref_spans": []}, {"section": "Equations of state and energy", "text": "with XH and Z the usual hydrogen and metal mass fractions. Similarly, for a fully ionized plasma, we define a mean molecular weight per hydrogen atom", "cite_spans": [], "ref_spans": []}, {"section": "Equations of state and energy", "text": "and a mean molecular weight per free electron", "cite_spans": [], "ref_spans": []}, {"section": "Equations of state and energy", "text": "The electron scattering opacity is \u03bae = \u03c3T /\u03bce,", "cite_spans": [], "ref_spans": []}, {"section": "Equations of state and energy", "text": "with \u03c3T the Thomson scattering cross-section. The accompanying equation for the total energy per unit mass is:", "cite_spans": [], "ref_spans": []}, {"section": "Equations of state and energy", "text": "with \u03b3 the usual ratio of specific heats, 5/3 for a monatomic gas.", "cite_spans": [], "ref_spans": []}, {"section": "Stellar surface properties", "text": "Due to rotation, the stellar surface is centrifugally distorted. In the Roche approximation, with the assumptions of a point-like mass distribution and uniform rotation, the surface is an equipotential whose radius R * varies with rotational colatitude \u03b8 as:", "cite_spans": [], "ref_spans": []}, {"section": "Stellar surface properties", "text": "Here, after defining \u2126 as the angular rotation frequency, M * the stellar mass, and Rp the stellar polar radius,", "cite_spans": [], "ref_spans": []}, {"section": "Stellar surface properties", "text": "is the normalized rotation angular frequency, with \u03c9 = 1 corresponding to critical rotation. \u0393 el is the Eddington parameter, defined in the next section.", "cite_spans": [], "ref_spans": []}, {"section": "Gravitocentrifugal acceleration", "text": "The effective gravity, g eff,s , is calculated as the combined gravitocentrifugal acceleration as derived from a scalar effective potential \u03a6 eff and projected along the field line. The effective gravity vector is", "cite_spans": [], "ref_spans": []}, {"section": "Gravitocentrifugal acceleration", "text": "Within the Roche approximation, this effective potential is given by", "cite_spans": [], "ref_spans": []}, {"section": "Gravitocentrifugal acceleration", "text": "where we take into account the effective reduction in gravity due to the outward force from the electron scattering continuum through the Eddington parameter \u0393 el \u2261 \u03baeL * /(4\u03c0cGM * ). In the centrifugal force term,r = |r| with r = [x, y, 0] the vector drawn from the rotation axis to the position at r.", "cite_spans": [], "ref_spans": []}, {"section": "Gravitocentrifugal acceleration", "text": "In order to obtain g eff,s in Equation 2b, we need to translate g eff into an acceleration along the field line:", "cite_spans": [], "ref_spans": []}, {"section": "Gravitocentrifugal acceleration", "text": "with \u03c8 \u2261r \u00b7\u015d and likewise\u03c8 \u2261r \u00b7\u015d. Here,r is the unit radial vector, andr is the unit vector parallel tor. In our rotation analysis (Section 6.3), we do not take into account the effect of rotational gravity darkening on stellar luminosity (Gayley & Owocki 2000) . This will be deferred to future studies.", "cite_spans": [], "ref_spans": []}, {"section": "Radiative driving", "text": "The chief mechanism for wind acceleration is radiation linedriving. To quantify this, we implement the Owocki et al. (1988) version of the usual CAK formalism for line-driven stellar winds. Assuming that the star is a point source of radiation, the acceleration is:", "cite_spans": [], "ref_spans": []}, {"section": "Radiative driving", "text": "whereQ is the dimensionless line strength parameter introduced by Gayley (1995) , \u03b1 is the CAK-power law index, and", "cite_spans": [], "ref_spans": []}, {"section": "Radiative driving", "text": "is the Sobolev optical depth. For \u03b4v, the local velocity gradient, we follow the same procedure as T07 (see their Section 2.5) and assume that the polar velocity derivative vanishes. Thus, we adopt the approximation \u03b4v \u2248 \u2202v/\u2202s.", "cite_spans": [], "ref_spans": []}, {"section": "Radiative driving", "text": "At low \u03c4 sob , Equation 14 correctly reduces to the optically-thin line force. This is an improvement over the previous RFHD implementation, which led to an infinitely large radiative acceleration at zero density (see T07 Equation 25). Finally, we take g rad,s = g rad \u00b7B to get the radiative acceleration along the field line, giving us a final expression:", "cite_spans": [], "ref_spans": []}, {"section": "Radiative driving", "text": "This is a rather simplistic view of line-driven winds, but we emphasize that we are not making any unique insights into the inherent nature of line-driven acceleration. Rather, we are taking the first steps into understanding how a magnetic field affects a line-driven wind. For more detailed massive-star wind models, see e.g. Kudritzki (2002) (modified CAK); M\u00fcller & Vink (2008) (Monte Carlo technique); Sundqvist & Owocki (2015) (scattering).", "cite_spans": [], "ref_spans": []}, {"section": "Cooling", "text": "The volumetric cooling rate \u039b is evaluated as the sum of an inverse Compton cooling term \u039bcc and a radiative cooling term \u039brc. We calculate \u039bcc from the electron pressure nek b T as per Equation 4 of White & Chen (1995) :", "cite_spans": [{"start": 200, "end": 219, "text": "White & Chen (1995)", "ref_id": "BIBREF40"}], "ref_spans": []}, {"section": "Cooling", "text": "with U rad = L * /(4\u03c0r 2 c) the stellar radiation energy density and ne the electron number density. We calculate \u039brc as:", "cite_spans": [], "ref_spans": []}, {"section": "Cooling", "text": "where np is the proton number density. \u039b rad is the optically thin cooling function, typically obtained in tabular form from a plasma emission code (Schure et al. 2009 ), and we define a mass-weighed form \u039bm \u2261 \u039b/\u03bce\u03bcp. Townsend et al. (2007) , with their RFHD approach, simulated colliding wind flows which create reverse shocks that propagate from the apex towards the footprints of each field line. Within each line, these shocks separate a winddriving region from a post-shock cooling region which may also contain a centrifugally-supported disk. The overall field line structure can be considered \"quasi-steady\": the windacceleration and cooling regions each reach a steady state, but the shock location oscillates.", "cite_spans": [], "ref_spans": []}, {"section": "STEADY-STATE WIND ANALYSIS", "text": "In this paper, we analyze only the wind-driving region, which contains the \"critical point\" that sets the steady-state mass-flux and the overall mass-loss rate. This will also allow us to understand how the magnetic field changes the overall velocity structure of the magnetosphere. Before we analyze the ARFHD equations presented above (Section 2.1), we first simplify using several assumptions relevant to the wind-driving region close to the star. We assume the wind is isothermal, and, following Drew (1989) , set the temperature T equal to the stellar effective temperature T eff . Also, we assume that the wind remains optically thick (\u03c4 sob 1) and that it has reached a steady state. In deriving the magnetospheric wind equation of motion, it is convenient to use the primitive variable form of Equation 2a-Equation 2c. Under our stated assumptions, these equations reduce to", "cite_spans": [], "ref_spans": []}, {"section": "STEADY-STATE WIND ANALYSIS", "text": "where \u03bb = \u2202A/\u2202s/A is the areal gradient term and c 2 s = P/\u03c1 = k b T eff /\u03bc is the isothermal sound speed. We can then derive an equation of motion:", "cite_spans": [], "ref_spans": []}, {"section": "STEADY-STATE WIND ANALYSIS", "text": "where we define v \u2261 \u2202v/\u2202s. In the optically thick limit, g rad,s reduces to", "cite_spans": [], "ref_spans": []}, {"section": "STEADY-STATE WIND ANALYSIS", "text": "which is equivalent to Equation 25 of T07. Substituting in the expression (15) for \u03c4 sob , and then eliminating the explicit dependence on density via the continuity equation (19), we obtain after some algebra", "cite_spans": [], "ref_spans": []}, {"section": "STEADY-STATE WIND ANALYSIS", "text": "Here,", "cite_spans": [], "ref_spans": []}, {"section": "STEADY-STATE WIND ANALYSIS", "text": "parameterizes the mass-loss rate, with A * the area of the flux tube at the stellar surface, and\u1e41 * is the mass flux into the tube. Now that we have derived a equation of motion (22) ", "cite_spans": [], "ref_spans": []}, {"section": "STEADY-STATE WIND ANALYSIS", "text": "where u \u2261 v/cs and y \u2261 vv , the equation of motion can be written as", "cite_spans": [], "ref_spans": []}, {"section": "STEADY-STATE WIND ANALYSIS", "text": "Following CAK and Abbott (1980) , we fix the wind critical point by the singularity condition", "cite_spans": [], "ref_spans": []}, {"section": "STEADY-STATE WIND ANALYSIS", "text": "In order that the velocity gradient dv/ds remain bounded at the critical point, it is also necessary that the regularity condition", "cite_spans": [], "ref_spans": []}, {"section": "STEADY-STATE WIND ANALYSIS", "text": "be satisfied at the critical point (this can be derived by taking the total derivative of Equation 27). For a given choice of the parameter \u2206, Equations (27-29) can in principle be solved to find the unknowns (s, y, u) at the critical point (if solutions exist). However, in his analysis of spherical wind outflows, Bjorkman (1995) found that the critical point location was quite sensitive to the surface mass-flux. He concluded that it was much easier to fix the location and then solve for the mass flux. Following his lead, we therefore treat the critical point location scrit as a free parameter, and solve for \u2206, y and s at s = scrit. We defer until later (Section 4) the question of how to choose scrit appropriately.", "cite_spans": [], "ref_spans": []}, {"section": "STEADY-STATE WIND ANALYSIS", "text": "We leave the mathematical derivation of the critical values to Appendix B. In this derivation, we obtain a special function", "cite_spans": [], "ref_spans": []}, {"section": "STEADY-STATE WIND ANALYSIS", "text": "Due to our sign convention (Section 2.2), \u03a6 can be positive or negative, corresponding to a positive/negative \u03c8. This is because plasma accelerating away from the stellar surface flows in the direction of increasing (decreasing) s for positive (negative) \u03c8. Either way, we solve for the critical velocity:", "cite_spans": [], "ref_spans": []}, {"section": "STEADY-STATE WIND ANALYSIS", "text": "with the top (bottom) resulting from the positive (negative) root of Equation 30. Similarly, we obtain the critical y:", "cite_spans": [], "ref_spans": []}, {"section": "STEADY-STATE WIND ANALYSIS", "text": "Remembering that our y = vv , this critical value is nearly identical to CAK Equation 45 in the zero sound-speed limit (\u03a6 \u2192 0), with differences coming from a factor \u03c8 resulting from non-radial paths and from rotational acceleration. Finally, we can solve for our critical eigenvalue and surface mass-flux:", "cite_spans": [], "ref_spans": []}, {"section": "STEADY-STATE WIND ANALYSIS", "text": "A similar procedure for the general critical point values is presented in Appendix C.", "cite_spans": [], "ref_spans": []}, {"section": "STEADY-STATE WIND ANALYSIS", "text": "As noted by Marlborough & Zamir (1984) and Cur\u00e9 & Rial (2004) , this type of analysis implies a range to the allowable critical point position. Here, we require that \u03a6 2 > 0 and \u2206c > 0 at scrit for a trans-critical steady-state wind.", "cite_spans": [], "ref_spans": []}, {"section": "STEADY-STATE WIND ANALYSIS", "text": "Although our ansatz assumes a magnetic star, we can pretend there is no field by defining a radial magnetic topology with a spherically expanding cross-section. This results in \u03c8 = 1 and A * /A = R 2 * /r 2 . In the limit of zero rotation and zero sound speed (\u03a6 \u2192 0), making these subsitutions in Equation 33 yields", "cite_spans": [], "ref_spans": []}, {"section": "STEADY-STATE WIND ANALYSIS", "text": "and a surface mass-flu\u1e8b", "cite_spans": [], "ref_spans": []}, {"section": "STEADY-STATE WIND ANALYSIS", "text": "As defined by Gayley (1995) using hisQ formalism, the CAK mass-loss rate i\u1e61", "cite_spans": [], "ref_spans": []}, {"section": "STEADY-STATE WIND ANALYSIS", "text": "and we see that our derived surface mass-flux is\u1e41 * = MCAK/(4\u03c0R 2 * ). This demonstrates that our general equations correctly reproduce the usual CAK mass-loss rate in the proper limit.", "cite_spans": [], "ref_spans": []}, {"section": "CRITICAL POINT CALCULATION", "text": "The critical point location, scrit, is required to accurately calculate the surface mass-flux, which, through the density, sets the level of radiative driving and emission throughout the magnetosphere. Since scrit is a free parameter in the above critical point calculation, we must provide a boundary condition to obtain scrit and the resulting critical surface mass-flux. This is especially important for calculating a dipole star's mass-loss rate, since the critical mass-flux is sensitive to the critical location (Section 6.1). Following Equation 24 of Bjorkman (1995) , we define the boundary density such that the resultant electron scattering optical depth \u03c4es \u2248 1 at the stellar surface. Thus,", "cite_spans": [], "ref_spans": []}, {"section": "CRITICAL POINT CALCULATION", "text": "where", "cite_spans": [], "ref_spans": []}, {"section": "CRITICAL POINT CALCULATION", "text": "is the pressure scale height, corrected for the electron scattering acceleration. Using the continuity equation and the critical surface mass flux, we can solve for the boundary velocity:", "cite_spans": [], "ref_spans": []}, {"section": "CRITICAL POINT CALCULATION", "text": "where\u1e41 * \u2261 \u03c1 * v * is defined as the surface mass-flux into the field line. Since this introduces a dependence on scrit for both the boundary and critical point velocities, we must use an iterative algorithm to satisfy both conditions simultaneously.", "cite_spans": [], "ref_spans": []}, {"section": "CRITICAL POINT CALCULATION", "text": "The set of equations we use for the integration are the wind equation of motion (Equation 22), the steady-state continuity equation d\u03c1/ds = \u2212\u03c1[\u03bb + (dv/ds)/v], and the isothermal approximation dP/ds = c 2 s d\u03c1/ds. Equation 22 is not easily solved for v , however, since there are multiple roots. There are usually three roots: two positive and one negative. This differs slightly from Kudritzki (2002) , who found two roots; we find an extra one since \u03c4 sob has a dependency on the absolute value of v . Inside of the sonic point, though, there are instead one positive and two negative roots. We always choose a positive root in order to enforce an accelerating outflow. When multiple positive roots exist, we choose the smaller root in the subcritical region and the larger root beyond the critical point (Cassinelli 1979; Abbott 1980) .", "cite_spans": [], "ref_spans": []}, {"section": "CRITICAL POINT CALCULATION", "text": "Our iterative algorithm for calculating scrit is as follows:", "cite_spans": [], "ref_spans": []}, {"section": "CRITICAL POINT CALCULATION", "text": "(i) Choose trial critical point location.", "cite_spans": [], "ref_spans": []}, {"section": "CRITICAL POINT CALCULATION", "text": "(ii) Calculate velocity, mass-flux, density at the critical point.", "cite_spans": [], "ref_spans": []}, {"section": "CRITICAL POINT CALCULATION", "text": "(iii) Integrate to boundary, taking the smallest positive root of the possible velocity derivatives.", "cite_spans": [], "ref_spans": []}, {"section": "CRITICAL POINT CALCULATION", "text": "(iv) If resulting boundary velocity is too high, move scrit out. Else if too low, move scrit in.", "cite_spans": [], "ref_spans": []}, {"section": "CRITICAL POINT CALCULATION", "text": "(v) Repeat from step 2 until correct boundary values are reached.", "cite_spans": [], "ref_spans": []}, {"section": "CRITICAL POINT CALCULATION", "text": "As a check, we calculate the critical radius and massflux for a straight, spherically-diverging flux tube (\u03c8 = 1; A * /A = R 2 * /r 2 ) for the stellar parameters chosen in Bjorkman (1995) ( Table 1) . We calculate rc = scrit = 1.5589R * , which matches well with Bjorkman (1995)'s derived value of 1.5594. The resulting mass-flux,\u1e41 * = 9.2516 \u00d7 10 \u22128 g/cm 2 also fits with his derived surface mass-flux\u1e40 /4\u03c0R 2 p = 9.249 \u00d7 10 \u22128 g/cm 2 .", "cite_spans": [], "ref_spans": [{"start": 191, "end": 199, "text": "Table 1)", "ref_id": "TABREF1"}]}, {"section": "MAGNETIC DIPOLE MODEL", "text": "Now that we have developed our general critical equations, we now derive the critical values for a wind channeled by an magnetic dipole whose pole is aligned with the rotation axis. This field forces the plasma to co-rotate with the star (i.e. a magnetosphere). Instead of assuming a radial outflow, we force the plasma to flow along the magnetic flux tubes. Additionally, we define the combined gravitocentrifugal force in the same manner as the ARFHD formulation (Section 2.5), i.e. with rigid-body rotation. While it is possible to solve the critical point equations with s as the independent variable, it is relatively more convenient here to parameterize the spatial variables with\u03b8, the magnetic colatitude. We do this because although the plasma flows along the magnetic field line, most of our external forces are dependent on r. It is easier to set\u03b8 as the spatial variable rather than have to solve for r in terms of s.", "cite_spans": [], "ref_spans": []}, {"section": "MAGNETIC DIPOLE MODEL", "text": "In an aligned dipole, the magnetic pole is parallel to the rotational pole (the z-axis in our coordinate system; Section 2.2), so we take\u03b8 = \u03b8, where \u03b8 is the rotational colatitude. First, we start with the definition of an aligned dipole field (e.g. T07):", "cite_spans": [], "ref_spans": []}, {"section": "MAGNETIC DIPOLE MODEL", "text": "We note that Rp is the polar radius of the star, not the stellar surface radius R * (Equation 9). From the parametric equation of a dipole field line (e.g. Babel & Montmerle 1997), we have", "cite_spans": [], "ref_spans": []}, {"section": "MAGNETIC DIPOLE MODEL", "text": "where rm \u2261 RpL is the maximum extent of the field line and L is the magnetic shell parameter. Each individual line exists over the range \u03b8m < \u03b8 < \u03c0 \u2212 \u03b8m, with \u03b8m = sin \u22121 R * /(RpL) marking the northern magnetic footprint and \u03c0 \u2212 \u03b8m marking the southern. Each field line can be uniquely identified by L and its magnetic azimuthal coordinate which denotes the half-plane containing that line. For our aligned dipole model, we will place every individual line in the same half-plane and assume azimuthal symmetry. Thus, knowing L or \u03b8m is sufficient for identifying a particular line.", "cite_spans": [], "ref_spans": []}, {"section": "MAGNETIC DIPOLE MODEL", "text": "We can obtain the path length s along the line with", "cite_spans": [], "ref_spans": []}, {"section": "MAGNETIC DIPOLE MODEL", "text": "which, after integrating, yields", "cite_spans": [], "ref_spans": []}, {"section": "MAGNETIC DIPOLE MODEL", "text": "We select our constant of integration to enforce s = 0 where the magnetic field comes out of the stellar surface: the northern footprint (\u03b8 = \u03b8m).", "cite_spans": [], "ref_spans": []}, {"section": "MAGNETIC DIPOLE MODEL", "text": "With these definitions of r and s, we can write all of the spatial variables as functions of \u03b8 (Appendix D). These can be then be used to solve the critical point values derived in Section 3. The general critical point values (Appendix C) can also be parameterized in this manner, using the same spatial variables.", "cite_spans": [], "ref_spans": []}, {"section": "MAGNETIC DIPOLE MODEL", "text": "With our general critical point algorithm established, we now turn our attention to how an aligned dipole magnetic field affects the stellar wind, namely its mass-loss rate and terminal velocity. Additionally, we will study how the stellar rotation rate influences the CAK critial point and resulting wind properties. For this analysis, we generate a grid of 500 dipole field lines with footprints covering the northern hemisphere of the star (0 < \u03b8 < \u03c0/2) in linear space. This is repeated for several critical rotation fractions \u03c9 = [0.0, 0.2, 0.35, 0.5, 0.65, 0.8], giving a total of 3000 dipole lines. Field lines with L > 100Rp are arbitrarily truncated at R = 100Rp; the rest of the lines extend to the magnetic equator. This truncation does not affect the critical value calculations since that only depends on the boundary condition and the field line geometry inside of the critical point. Additionally, as we later show, this trunctation radius is larger than the \"closure radius\" of our model magnetospheres, so our apex velocity calculations will not be affected.", "cite_spans": [], "ref_spans": []}, {"section": "MAGNETIC DIPOLE MODEL", "text": "We calculate the critical point location and resulting surface mass-fluxes using the procedure described in Section 4. After finding the critical values, we integrate from the critical point to the apex of the field line to obtain the apex velocity, vapex. We do this for two different sets of stellar parameters, one representing a centrifugal magnetosphere and one a dynamical magnetosphere (Table 1) . For the centrifugal magnetosphere star, we use parameters from Bjorkman (1995) representing an early-B star similar to the archetype \u03c3 Orionis E.", "cite_spans": [], "ref_spans": [{"start": 393, "end": 402, "text": "(Table 1)", "ref_id": "TABREF1"}]}, {"section": "MAGNETIC DIPOLE MODEL", "text": "For the other star, we follow the MHD simulations of udDoula & Owocki (2002) and choose a \u03b6 Puppis analogue, representing a dynamical magnetosphere: M eff = 25 M , R = 19 R , T eff = 41860 K (such that Lstar = 10 6 L ), \u03b1 = 0.6, Q = 500, and we take solar values for the mass fractions XH and Z. Since the stellar mass above is an effective mass and already takes into account the factor of two reduction below the Newtonian mass due to the electron scattering continuum force, we take M = 50M and \u0393 el = 0.5 in our model.", "cite_spans": [{"start": 63, "end": 76, "text": "Owocki (2002)", "ref_id": "BIBREF40"}], "ref_spans": []}, {"section": "MAGNETIC DIPOLE MODEL", "text": "Since our ansatz assumes an infinite magnetic confinement, the actual magnitude of the dipole field (i.e. B0 in Equation 40a) only matters when estimating which lines are in the closed magnetosphere (Equation 75).", "cite_spans": [], "ref_spans": []}, {"section": "SURFACE MASS FLUX", "text": "6.1 Zero rotation in the optically-thick limit Since magnetic dipole field lines do not come straight out of the stellar surface, the surface mass-flux is tilted relative to a radial mass-flux. Inspired by the MHD simulations presented in ud-Doula & Owocki (2002), Owocki & ud-Doula (2004) (hereafter OD04) used a simple, one-dimensional flow analysis to calculate that the radial mass-flux,\u1e41r, scales a\u1e61", "cite_spans": [], "ref_spans": []}, {"section": "SURFACE MASS FLUX", "text": "where the CAK surface mass-flux is defined a\u1e61", "cite_spans": [], "ref_spans": []}, {"section": "SURFACE MASS FLUX", "text": "and \u00b5B =n \u00b7B withn the unit vector normal to the stellar surface. For a non-rotating star,n =r. One factor of \u00b5B results from the geometric projection of the tilted flow onto the stellar surface normal (\u1e41r = \u00b5B\u1e41 * ). The other factor results from projecting a radial radiative line force along the field line. The tension in the magnetic field line negates any acceleration normal to the line, further lowering the critical mass-flux.", "cite_spans": [], "ref_spans": []}, {"section": "SURFACE MASS FLUX", "text": "We now check this scaling analysis with our dipole model. For simplicity, we note that cs\u03a6/ \u221a 2 \u03b1/(1 \u2212 \u03b1) g eff,s and take", "cite_spans": [], "ref_spans": []}, {"section": "SURFACE MASS FLUX", "text": "From Equation D2 we obtain", "cite_spans": [], "ref_spans": []}, {"section": "SURFACE MASS FLUX", "text": "where \u03b8c is evaluated at the critical radius rc for a given field line and R * is the stellar radius at the footprint colatitude \u03b8m.", "cite_spans": [], "ref_spans": []}, {"section": "SURFACE MASS FLUX", "text": "Combining our eigenvalue relation (Equation 33) with the above equations, we obtain", "cite_spans": [], "ref_spans": []}, {"section": "SURFACE MASS FLUX", "text": "where \u03c8c is evaluated at the critical point. Finally, our surface mass-flux i\u1e61", "cite_spans": [], "ref_spans": []}, {"section": "SURFACE MASS FLUX", "text": "For zero rotation, g eff,s = \u2212(1\u2212\u0393 el )GM * \u03c8/r 2 c and R * = Rp:", "cite_spans": [], "ref_spans": []}, {"section": "SURFACE MASS FLUX", "text": "where we will define\u1e41 dip =\u1e41 dip (rc) as the zero-tilt, zerorotation, optically-thick surface mass-flux for a magnetic dipole:", "cite_spans": [], "ref_spans": []}, {"section": "SURFACE MASS FLUX", "text": "We can thus think of\u1e41 dip as the CAK surface mass-flux corrected for dipole divergence. We can generalize this straight-line base term for any magnetically-induced areal expansion wit\u1e23 when the areal expansion is proportional to r q , q = 3 for a dipole.", "cite_spans": [], "ref_spans": []}, {"section": "SURFACE MASS FLUX", "text": "For our model B star, we calculate\u1e41 dip \u2248 9.53 \u00d7 10 \u22128 g/cm 2 at the pole, with rc = 1.033 Rp. If we keep the \u03a6 term instead of neglecting it (Equation 32), the model calculated mass-flux (\u1e41 \u03b8=0 ) is boosted by about 2%, to\u1e41 \u03b8=0 = 9.709 \u00d7 10 \u22128 g/cm 2 . For our model O star, the polar values are\u1e41 dip \u2248 1.98 \u00d7 10 \u22125 g/cm 2 (with r c,theta=0 \u2248 1.054 Rp) and\u1e41 \u03b8=0 = 2.05 \u00d7 10 \u22125 g/cm 2 , a difference of about 3%. The O-type star has a larger correction than the B-star because of its faster sound speed.", "cite_spans": [], "ref_spans": []}, {"section": "SURFACE MASS FLUX", "text": "We can reproduce Equation 44 with several simplifications, which end up canceling each other out. First, we take rc = r c,\u03b8=0 as constant for every field line (justified in Section 7). Next, we assume that the critical radius is very close to the star (r c,\u03b8=0 \u2212 Rp Rp), which allows us to take \u03b8c \u2248 \u03b8m and \u03c8c \u2248 \u03c8m = \u00b5B. Finally, we correct for neglecting the \u03a6 term by replacing\u1e41 dip with\u1e41 \u03b8=0 to obtain the scaling relation:\u1e41 * \u223c \u00b5B\u1e41 \u03b8=0 .", "cite_spans": [], "ref_spans": []}, {"section": "SURFACE MASS FLUX", "text": "Rather conveniently, it turns out that replacing \u03b8c and \u03c8c with the surface values \u03b8m and \u03c8m produces opposite effects which nearly cancel each other out. Overall, we are able to reproduce OD04's general scaling at zero rotation (Figure 1) , though keeping the exact angular expressions with the constant rc assumption gives an even better fit.", "cite_spans": [], "ref_spans": [{"start": 229, "end": 239, "text": "(Figure 1)", "ref_id": "FIGREF0"}]}, {"section": "Zero rotation in the general case", "text": "In the general line-force critical analysis (Appendix C), an important parameter arises:", "cite_spans": [], "ref_spans": []}, {"section": "Zero rotation in the general case", "text": "Physically, it represents the \"transparency\" of the wind where low \u03c7 means a optically thick wind and high \u03c7 means a optically thin wind. Alternatively, it represents a \"opticallythin correction level\" parameter which characterizes the relative importance of using the general form of g rad,s rather than its optically-thick limit (Equation 23). For opticallythick winds, \u03c4 sob 1 and the line-acceleration reduces to g rad,CAK \u221d \u03c4 \u2212\u03b1 sob . For optically-thin winds, \u03c4 sob \u2192 0 and \u03c7 \u2192 1.", "cite_spans": [], "ref_spans": []}, {"section": "Zero rotation in the general case", "text": "We can repeat the previous section's scaling analysis for a general line force (derivation in Appendix E). With the same approximations as above and zero rotation, we get the scaling\u1e41 * \u2248\u1e41 dip (rc)\u03a30\u03c8c 1 + 3 cos 2 \u03b8m 1 + 3 cos 2 \u03b8c ,", "cite_spans": [], "ref_spans": []}, {"section": "Zero rotation in the general case", "text": "where we have defined an optically-thin-correction (OTC) parameter", "cite_spans": [], "ref_spans": []}, {"section": "Zero rotation in the general case", "text": "with \u03c70 as the value of \u03c7 evaluated at the critical point for zero rotation. Notably, the critical value of \u03c7 is set by the ratio between the non-radiative external forces (gravity, centrifugal, areal gradient) and the optically thin radiative force (c.f. Equation C3 ). With zero rotation, \u03c70", "cite_spans": [], "ref_spans": [{"start": 256, "end": 267, "text": "Equation C3", "ref_id": "FIGREF3"}]}, {"section": "Zero rotation in the general case", "text": "is independent of surface colatitude, which allows us to use a constant \u03a30 across the stellar surface. Essentially, \u03a30 results from the error in assuming an optically-thick wind. In O stars, the increased luminosity drives a much higher surface mass-flux, leading to a more optically-thick wind than in B stars. Thus, \u03c70 is smaller and \u03a30 is closer to unity for more massive stars.", "cite_spans": [], "ref_spans": []}, {"section": "Zero rotation in the general case", "text": "\u03a30 allows us to correct our mass-flux estimates, though the critical radius (and thus the base mass-flux) will be different between the general and optically-thick cases (Section 7). For an optically thick wind, \u03c7 \u2192 0 and \u03a30 \u2192 1, reproducing\u1e41 dip . For an optically thin wind, using l'H\u00f4pital's rule yields", "cite_spans": [], "ref_spans": []}, {"section": "Zero rotation in the general case", "text": "which is expected since the optically-thick line force goes to infinity as the density goes to zero. For our model B star, we calculate \u03a30 \u2248 0.725 and use the polar critical radius r c,\u03b8=0 \u2248 1.0367 to obtai\u1e45 m dip \u2248 9.56 \u00d7 10 \u22128 g/cm 2 . The resulting estimated massflux, \u03a30\u1e41 dip \u2248 6.90 \u00d7 10 \u22128 g/cm 2 compares well with the model-calculated\u1e41 \u03b8=0 \u2248 6.96 \u00d7 10 \u22128 g/cm 2 . Similarly, for the O star, we calculate \u03a30 \u2248 0.974,\u1e41 dip \u2248 1.98 \u00d7 10 \u22125 g/cm 2 (with r c,\u03b8=0 \u2248 1.054 Rp), and \u03a30\u1e41 dip \u2248 1.93 \u00d7 10 \u22125 g/cm 2 . The model polar mass-flux is\u1e41 \u03b8=0 \u2248 2 \u00d7 10 \u22125 g/cm 2 . Simplifying Equation 55 with r c,\u03b8=0 \u2212 Rp Rp, \u03b8c \u2248 \u03b8m, and \u03c8c \u2248 \u03c8m = \u00b5B yields the scalin\u0121", "cite_spans": [], "ref_spans": []}, {"section": "Zero rotation in the general case", "text": "We can correct for approximations made in deriving this equation (Appendix E) by using the model-calculate\u1e0b m gen,\u03b8=0 instead of \u03a30\u1e41 dip : We use\u1e41 gen,\u03b8=0 rather than \u03a30\u1e41 \u03b8=0 because the critical point location is different between the two cases. As in the optically-thick case, our model magnetosphere shows excellent agreement for this OD04-type scaling (Figure 1 ).", "cite_spans": [], "ref_spans": [{"start": 356, "end": 365, "text": "(Figure 1", "ref_id": "FIGREF0"}]}, {"section": "With rotation in the optically-thick limit", "text": "The previous scaling results, however, depend on zero rotation. There are two ways rotation changes the above scaling: \u00b5B and the location of rc (c.f. Section 7). For an oblate star, the surface normal unit vector is:", "cite_spans": [], "ref_spans": []}, {"section": "With rotation in the optically-thick limit", "text": "where R * \u2261 \u2202R * /\u2202\u03b8. Using Equation 40b, the resulting \u00b5B is \u00b5B = 2 cos \u03b8m \u2212 sin \u03b8mR * /R *", "cite_spans": [], "ref_spans": []}, {"section": "With rotation in the optically-thick limit", "text": "where, from taking the derivative of Equation 9,", "cite_spans": [], "ref_spans": []}, {"section": "With rotation in the optically-thick limit", "text": "For a non-rotating star, R * = 0 and \u00b5B is identical to OD04. \u00b5B is affected most at the middle colatitudes, where the stellar surface normal tilts the farthest from the radial direction (Figure 2 ). However, even though \u00b5B gets smaller with increased rotation at the middle colatitudes, the surface mass-flux does not decrease in the same manner. Instead, the rotation of the star boosts the mass-flux above this naive scaling, and, for sufficiently high rotation, actually causes the flux to increase as one moves towards the middle colatitudes. This is chiefly due to the decreased g eff,s as the centrifugal acceleration increases. We can derive a simple scaling for how\u1e41 * depends on rotation, though we will no longer be able to assume a constant rc. We follow the same procedure as in Section 6.1, but this time we keep the rotation. First, we rewrite the effective gravity (Equation 13) using our dipole magnetosphere parameterizations on \u03b8 (Appendix D), specificall\u0233 r = r sin \u03b8 = RpL sin 3 \u03b8 and\u03c8/\u03c8 = 3 sin \u03b8/2:", "cite_spans": [], "ref_spans": [{"start": 187, "end": 196, "text": "(Figure 2", "ref_id": "FIGREF1"}]}, {"section": "With rotation in the optically-thick limit", "text": "where we have defined a rotation effect parameter", "cite_spans": [], "ref_spans": []}, {"section": "With rotation in the optically-thick limit", "text": "where the first line is the general definition and the second is specifically for an aligned dipole. We note that for zero rotation, L = 1/ sin 2 \u03b8m, but the stellar oblateness due to rotation means that this equation no longer applies. Instead, we combine Equation 9 and Equation 41 into", "cite_spans": [], "ref_spans": []}, {"section": "With rotation in the optically-thick limit", "text": "and get an aligned dipole rotation parameter", "cite_spans": [], "ref_spans": []}, {"section": "With rotation in the optically-thick limit", "text": "The above analysis simply multiplies each instance of g eff,s in Equation 49 by a factor \u2135, and yields a mass-flux ", "cite_spans": [], "ref_spans": []}, {"section": "With rotation in the optically-thick limit", "text": "where \u2135c, \u03c8c and \u03b8c are evaluated at the critical point and we take into account stellar oblation due to rotation. Comparing the above approximation against numerical results, we find an error of only \u2248 3.5% (6%) error in the middle colatitudes for a B-type (O-type) star at \u03c9 = 0.8. This increase in error relative to the non-rotating case comes from neglecting \u03a6, which is larger at faster rotation rates. Since the critical radius is no longer constant with colatitude in the rotating cases, we will need to know the critical radius for each magnetic footprint (Section 7) in order to get precise estimates. Interestingly, despite this dependence on rc, we can still take OD04-type approximations to get a reasonable mass-flux estimate for different rotation rates independent of rc! We take \u03c8c(Rp/R * ) 3 \u2248 \u00b5B (\u00b5B given in Equation 61) and \u03b8c \u2248 \u03b8m such that \u2135 is evaluated at the stellar surface:", "cite_spans": [], "ref_spans": []}, {"section": "With rotation in the optically-thick limit", "text": "The resulting scaling relation is the\u1e45 m * \u2248\u1e41 dip (r c,\u03b8=0 )\u00b5B\u2135", "cite_spans": [], "ref_spans": []}, {"section": "With rotation in the optically-thick limit", "text": "As before, we correct for neglecting \u03a6 by using the modelcalculated\u1e41 \u03b8=0 instead of the approximation\u1e41 dip : Figure 3 and Figure 4 show the fortunate agreement of Equation 70 with our model calculations, despite the questionable approximations. Again, we get larger differences between model and scaling for the faster rotation rates. (Table 1) .\u1e41 * is compared to the rotation scaling (dot-dashed line) derived in Equation 74 and \u03a3 0\u1e41CAK , the corrected CAK mass-flux (dashed line).", "cite_spans": [], "ref_spans": [{"start": 109, "end": 117, "text": "Figure 3", "ref_id": "FIGREF3"}, {"start": 122, "end": 130, "text": "Figure 4", "ref_id": "FIGREF5"}, {"start": 335, "end": 344, "text": "(Table 1)", "ref_id": "TABREF1"}]}, {"section": "With rotation in the general case", "text": "Finally, we combine the effects of rotation and the OTC parameter. With a similar derivation as the previous sections, we obtai\u1e45 m * \u2248\u1e41 dip (rc)\u03a3rot Rp R * 3 \u2135 1\u22121/\u03b1 \u03c8c 1 + 3 cos 2 \u03b8m 1 + 3 cos 2 \u03b8c ,", "cite_spans": [], "ref_spans": []}, {"section": "With rotation in the general case", "text": "where, again,\u1e41 dip is the base mass-flux from Equation 51. Unlike before, however, the OTC parameter now has a dependency on rotation:", "cite_spans": [], "ref_spans": []}, {"section": "With rotation in the general case", "text": "At zero rotation, \u2135 = 1 and \u03a3rot reduces to \u03a30. With rotation, \u03c70\u2135 decreases and \u03a3rot moves towards 1. Physically, this occurs because the rotation-boosted mass-flux in the wind further reduces the error from assuming an opticallythick g rad,s . In more massive stars, rotation has less of an effect on the OTC parameter. This is because the error from assuming an optically-thick wind is already small, so increasing the density in the wind does not have a relatively large effect. We can simplify the scaling relation using OD04-type approximations:", "cite_spans": [], "ref_spans": []}, {"section": "With rotation in the general case", "text": "where \u03a3rot,m is calculated at the stellar surface (i.e. Equation 72 with \u2135m instead of \u2135). We correct this for approximations made in Appendix E by using the model-calculate\u1e0b m gen,\u03b8=0 instead of \u03a30\u1e41 dip : the B-and O-type stars. Again, we get larger differences between the model and the scaling relation at faster rotation rates. At \u03c9 = 0.8, we get about a 3% difference for the B star and 4% for the O star.", "cite_spans": [], "ref_spans": []}, {"section": "CRITICAL POINT LOCATIONS", "text": "The critical point location, rc, depends not only on the boundary condition, but also on the inherent properties of the magnetosphere and wind. In CAK theory, this location sets the value of the surface mass-flux, so anything that moves this point influences the amount of material being accelerated off the stellar surface. There has been some discussion in the literature about the physicality of the CAK critical point (e.g. Lamers & Cassinelli 1999; Lucy 2007) and its validity in setting the critical mass-flux. These authors prefer using the sonic point to set the critical mass-flux (e.g. in the models of Vink et al. 2000) . For now, we defer discussion of this issue to future studies.", "cite_spans": [], "ref_spans": []}, {"section": "CRITICAL POINT LOCATIONS", "text": "In the point-star zero sound-speed limit, CAK found that the entire wind is critical; this degeneracy means that the critical radius (rc) is ill-defined for this case. Including the small sound-speed term barely breaks this degeneracy, but the finite-disk correction allows rc to be well-defined by allowing the critical velocity, its derivative, and the massloss rate to vary with radius (Kudritzki et al. 1989; Madura et al. 2007 ). This results in only one radius which satisfies the critical and boundary conditions simultaneously.", "cite_spans": [], "ref_spans": []}, {"section": "CRITICAL POINT LOCATIONS", "text": "Interestingly, dipole divergence also breaks this degeneracy! Although it does not change the critical velocity and its derivative (Equation 46 ), the faster-than-spherical expansion induces a mass-flux dependency on the critical radius (Equation 51). There is then only one radius which allows a self-consistent critical mass-flux. This critical location is close to the star (rc \u2248 1.033Rp for the B-star; \u2248 1.054Rp for the O-star), much like the finite-disk corrected critical radius (\u2248 1.02Rp in Pauldrach et al. (1986) with different stellar properties for their O-star). Next, we study two factors which influence the critical location, the optically-thin correction and stellar rotation. Both these effects work in the same manner, causing the smaller root of Equation 22 and, equivalently, the wind acceleration in the subcritical region to decrease. Even though these factors also lower the critical velocity (Equation 31), they have different effects on rc. The optically-thin wind takes a longer distance to accelerate from the boundary to the critical point, which pushes rc out. However, rotation lowers the critical velocity sufficiently enough that the wind is able to accelerate over a slightly shorter distance, pulling rc in relative to the stellar surface. Stellar oblation, though, will push the critical radius out relative to the center of the star.", "cite_spans": [], "ref_spans": []}, {"section": "CRITICAL POINT LOCATIONS", "text": "Our results for a dipole magnetosphere (Figure 7/Figure 8) show how rc moves out due to rotation and the OTC parameter. We note that the increase in critical radius due to rotation is almost entirely caused by the stellar oblation. In fact, we see that the radial distance of the critical point from the stellar surface is nearly constant with colatitude and rotation. For more massive stars, the error from the optically-thick assumption is reduced (see Section 6.2 for discussion), so there is a smaller difference in rc between the general and optically-thick cases than for later-type stars.", "cite_spans": [], "ref_spans": [{"start": 39, "end": 58, "text": "(Figure 7/Figure 8)", "ref_id": "FIGREF10"}]}, {"section": "CRITICAL POINT LOCATIONS", "text": "Finally, we note that the critical radius does not exist for every field line. In Figure 7 , we see a clear tendency for the footprint colatitude to have a limit. Another interesting aspect is that different rotation rates have different \u03b8m limits, though as we will see, this limit may actually be determined by the field line shell parameter (L). The starting Faster rotation results in a greater L for a given surface colatitude. When we evaluate Lmin corresponding to the maximum \u03b8m for each rotation rate, we get similar values: Lmin \u2248 1.27 \u2212 1.3R * for a B-star, Lmin \u2248 1.32\u22121.33R * for a O-star, with slight differences between the general and optically-thick cases. We stress that these limits are only approximate due to the division of our model stellar surface into 500 discrete magnetic footprints. It is uncertain exactly why this limit, if there is one, exists. For lines close to this limit, there do exist possible critical points, but none satisify the boundary condition. This occurs because the magnetic tension due to line tilt (represented by \u03c8) neuters the wind acceleration so that the flow cannot pass through the critical point for the given boundary condition. For lines much closer to the equator, there are no possible critical points for any boundary condition since \u03a6 2 < 0 (Section 3).", "cite_spans": [], "ref_spans": [{"start": 82, "end": 90, "text": "Figure 7", "ref_id": "FIGREF10"}]}, {"section": "VELOCITY STRUCTURE", "text": "Here, we focus on the wind velocity as it is accelerated along a dipole field line and qualify its behavior.", "cite_spans": [], "ref_spans": []}, {"section": "Is there a beta-velocity law?", "text": "In the CAK zero sound-speed limit, the radial velocity structure is found to be v = v\u221e(1 \u2212 R * /r) \u03b2 , with \u03b2 = 1/2 for this specific case. With the finite-disk correction, the velocity can still be well-represented by this beta-velocity law (Pauldrach et al. 1986 ), which greatly simplifies analytic considerations of the finite-disk correction factor by allowing the factor to be represented as an explicit spatial function (e.g. Madura et al. 2007 ). However, for a magnetosphere, there are two problems with assuming a beta-velocity law: the terminal velocity and the effect of rotation.", "cite_spans": [], "ref_spans": []}, {"section": "Is there a beta-velocity law?", "text": "The faster-than-spherical divergence of the field will lead to higher terminal velocities (Owocki & ud-Doula 2004) than for the spherically-diverging case. With the escape velocity defined as v 2 esc = 2(1 \u2212 \u0393 el )GM * /Rp, we calculate the polar v\u221e \u2248 1.97 vesc (5.9 vesc) for our B-type (O-type) OTC wind. We note that observed terminal velocities of magnetic stars are unlikely to ever reach these limits since the faster-than-spherical divergence of the wind will not continue indefinitely through space. For comparison, the modified CAK terminal velocity for our O-star is 3000 km s \u22121 = 4.23 vesc (ud-Doula et al. 2014); however, this is based on the optically-thick g rad,s which does not properly reduce to the optically-thin limit at low densities. Observations of non-magnetic stars give lower terminal values v\u221e \u2248 1.4vesc for B-stars and v\u221e \u2248 2 \u2212 3 vesc for O-stars (Kudritzki & Puls 2000) .", "cite_spans": [], "ref_spans": []}, {"section": "Is there a beta-velocity law?", "text": "Of course, closed field lines cannot have terminal velocities as they do not extend to infinity. The \"terminal velocities\" we find in this paper for each field line are merely bestfit parameters used to characterize the velocity behavior. To quantify the behavior, we use nonlinear least squares to fit individual beta-velocity laws to the numerically-calculated velocity structure of each line. The velocity structures are calculated from the critical point to the apex, ignoring any possible shocks. Thus, our calculated beta-velocity laws will accurately describe the wind velocity up to the shock, though not past it.", "cite_spans": [], "ref_spans": []}, {"section": "Is there a beta-velocity law?", "text": "We find that that there is no easily-defined global betavelocity law for the magnetosphere. Instead, each line has an independent velocity structure which depends on its own geometry. For a non-rotating magnetic dipole, the best-fit value of both v\u221e and \u03b2 varies throughout the magnetosphere ( Figure 9 ). As one moves toward more polar colatitudes, this best-fit v\u221e approaches the asymptotic limit of the straightline dipole terminal velocity. The magnetic field geometry also affects how quickly the wind accelerates; higher tilt relative to the surface reduces both the \"terminal velocity\" and how long it takes the wind to reach that limit (as represented by a decreasing \u03b2).", "cite_spans": [], "ref_spans": []}, {"section": "Is there a beta-velocity law?", "text": "Interestingly, the best-fit \u03b2 values are quite large for our model O-star (\u03b2 > 2) and not within the usual non-magnetic range 0.7 \u03b2 1 (Kudritzki et al. 1989) . The model B-star shows similar behavior, though the \u03b2 range fits better with non-magnetic values. Both cases imply that the field-line tilt has a large effect on throttling the wind acceleration even as the dipole divergence works to boost it.", "cite_spans": [], "ref_spans": []}, {"section": "Is there a beta-velocity law?", "text": "We note that that finite-disk effect will change these velocity results. Compared to the point-star CAK model, the finite-disk effect leads to a higher terminal velocity because less mass is driven off the star and this lower-density wind sees more of the stellar surface as it accelerates out. However, these modified CAK models use the optically-thick version of g rad,s , which artifically boosts this low-density acceleration and leads to higher terminal velocities. We will implement the finite-disk correction in Paper II and characterize its effect on the velocity structure there.", "cite_spans": [], "ref_spans": []}, {"section": "Is there a beta-velocity law?", "text": "The second issue with a global magnetospheric betavelocity law is the acceleration from rigid-body rotation. Beyond a certain point, centrifugal acceleration will exceed the inward gravitational pull and cause the wind to accelerate; there is no asymptotic limit. This breaks the beta-velocity law assumption and makes it difficult to characterize the velocity structure with a general equation (Figure 10) .", "cite_spans": [], "ref_spans": [{"start": 395, "end": 406, "text": "(Figure 10)", "ref_id": "FIGREF0"}]}, {"section": "Is there a beta-velocity law?", "text": "We note that for the more equatorial lines in our model, the wind did not actually accelerate all the way from the critical point to the line apex. Instead, a kink solution occurs since the equation of motion (Equation 22) stops admitting positive roots for the velocity derivative at some location while still allowing the negative roots (c.f. Cranmer & Owocki 1996; Madura et al. 2007 ). In order to fit a betavelocity law to these lines, we ignored the deceleration after the kink and only fit the portion of the line from the critical point to the deceleration point. This implicity assumes that shocks along each line will prevent the wind from ever reaching a kink, so these fits will represent the behavior of the wind velocity up to the shock.", "cite_spans": [], "ref_spans": []}, {"section": "Closure radius", "text": "There is always a struggle between the wind and the magnetic field within magnetospheres. As quantified by \u03b7 * (Equation 1), the field dominates the wind if its energy is larger than the wind kinetic energy. On the other hand, the wind will escape if its velocity exceeds the local Alfv\u00e9n velocity vA = B/ \u221a 4\u03c0\u03c1. We can thus understand the Alfv\u00e9n radius (RA), the typical length scale of the magnetosphere, as the point where v = vA. Additionally, we can approximate the maximum extent of closed loops in the magnetosphere, the closure radius (Rc), as the L shell for which vapex = vA. This will only be a lower bound in the context of this model (\u03b7 * \u2192 \u221e) since the shocks produced by colliding wind flows will not allow the wind to fully accelerate all the way to the line apex.", "cite_spans": [], "ref_spans": []}, {"section": "Closure radius", "text": "We can compare this to the MHD-derived closure radius scaling (ud-Doula & Owocki 2002) Rc \u2248 R * + 0.7(RA \u2212 R * ),", "cite_spans": [{"start": 62, "end": 86, "text": "(ud-Doula & Owocki 2002)", "ref_id": "BIBREF40"}], "ref_spans": []}, {"section": "Closure radius", "text": "with the dipole Alfv\u00e9n radius given by", "cite_spans": [], "ref_spans": []}, {"section": "Closure radius", "text": "characterizing the maximum radius at which the magnetic field still dominates the wind. For our model stars, we assume the same non-magnetic v\u221e and\u1e40 as the previous subsection. We take the \u03c3 Ori E-like value Beq = 5500 G for our B-star and take Beq = 1857.5 G such that \u03b7 * = 100 for our O-star. This results in Not surprisingly, we obtain larger closure radii than MHD predictions (Table 2 ). This is due to our rigid-field assumption; in reality, the wind will stretch out the polar field lines radially (ud-Doula & Owocki 2002 ) and accelerate more rapidly when \u03c8 moves towards unity. The resulting faster velocities would move Rc towards the MHDapproximated closure radius. This effect is more important for stars with smaller \u03b7 * , since the weaker confinement will allow the wind to have more effect on the magnetic topology. However, we note that the MHD simulations of ud-Doula & Owocki (2002) only considered \u03b7 * 100; our model B star has \u03b7 * \u2248 4\u00d710", "cite_spans": [{"start": 506, "end": 529, "text": "(ud-Doula & Owocki 2002", "ref_id": "BIBREF40"}, {"start": 888, "end": 901, "text": "Owocki (2002)", "ref_id": "BIBREF40"}], "ref_spans": [{"start": 382, "end": 390, "text": "(Table 2", "ref_id": "TABREF4"}]}, {"section": "Closure radius", "text": "5 . Since we are not able to efficiently simulate these B star magnetospheres with MHD codes, it is unclear at the moment how important radial stretching will be for such strong magnetic fields.", "cite_spans": [], "ref_spans": []}, {"section": "Closure radius", "text": "We also see a clear trend of rotation boosting both the apex wind and Alfv\u00e9n velocities. The Alfv\u00e9n velocities increase since, by the conservation of mass, the faster wind velocities result in lower densities. The overall effect is to produce smaller closure radii at faster rotation rates.", "cite_spans": [], "ref_spans": []}, {"section": "GLOBAL MASS LOSS", "text": "Here, we study the effect of the dipole field on the global mass-loss rate for different rotation rates. We can find the global mass-loss rate,\u1e40 global , by integrating the mass-flux Table 3 . Mass-loss rates (in units of 10 \u22129 M / yr) for a B-type star (\u03b7 * = 4.28 \u00d7 10 5 ) as calculated from our model, assuming infinite magnetic confinement where applicable. \"No B\" indicates a CAK-type mass-loss rate calculated from a non-rotating radial flow with spherical divergence. The other mass-loss rates are calculated from a dipole magnetosphere with the given rotation fraction \u03c9. \"OpticallyThick\" indicates the mass-loss calculated from using the optically-thick g rad,s ; the rest use the \"General\" g rad,s . \"True\" is the mass-loss into open field lines (L > Rc), Rc given by the MHD-estimated value (Equation 75). \"Disk\" is the mass-loss into field lines with a centrifugally supported disk (R K < L < Rc). \"Effective\" is the mass-loss which does not fall back to the star; it is the sum of the \"True\" and \"Disk\" mass-loss rates. Numbers in parentheses next to a mass-loss rate represent the ratio of that particular rate to the \"General\" mass-loss at its rotation fraction \u03c9. over the stellar surface:", "cite_spans": [], "ref_spans": []}, {"section": "No", "text": "with \u00b5 * \u2261 cos \u03b8m. Since not every field line has a calculated critical mass-loss rate, we will assume that the various scaling relations for\u1e41 * derived in Section 6 hold for the entire stellar surface. For the non-magnetic case, we take the massflux for a straight line with spherical divergence (\u1e41B=0) and integrate over the stellar surface:", "cite_spans": [], "ref_spans": []}, {"section": "No", "text": "We stress that the mass-loss rate in Equation 77 is not a \"true\" mass-loss rate; the plasma flowing along closed field lines does not easily escape the magnetosphere (ud-Doula et al. 2008; Townsend et al. 2013 ). In our model, our assumption of infinite magnetic confinement means that, technically, none of the stellar wind escapes the magnetic field. Despite this, however,\u1e40 global is still an useful value to calculate, as it will give a better estimate for the wind magnetic confinement parameter (ud-Doula & Owocki 2002) , depending on rotation. The amount of mass that escapes into the interstellar medium depends on the closure radius (Equation 75), which itself depends on the stellar magnetic field strength. Lines with a shell parameter L > Rc are considered \"open\" for the purposes of calculating a \"true\" massloss rate.", "cite_spans": [{"start": 166, "end": 188, "text": "(ud-Doula et al. 2008;", "ref_id": "BIBREF40"}, {"start": 501, "end": 525, "text": "(ud-Doula & Owocki 2002)", "ref_id": "BIBREF40"}], "ref_spans": []}, {"section": "No", "text": "We also calculate a \"disk\" mass-loss rate into a centrifugally-supported disk. Such disks are created because maintaining rigid-body rotation away from the star eventually leads to a balance between the gravitational and centrifugal forces at the Kepler radius (e.g. ud-Doula et al.", "cite_spans": [], "ref_spans": []}, {"section": "2008)", "text": "For lines inside the Kepler radius, the lack of centrifugal support results in a pattern of outflow and infall that leads to a long-term average mass-loss of zero (ud-Doula & Owocki 2002) . However, for lines outside the Kepler radius, the wind never falls back to the star and instead remains in a disk, suspended away from the star. Combining the \"disk\" and \"true\" rates can give us an \"effective\" mass-loss; the star loses mass if it will not return to the surface, either because it settles in a magnetospheric disk or escapes through open field lines.", "cite_spans": [{"start": 163, "end": 187, "text": "(ud-Doula & Owocki 2002)", "ref_id": "BIBREF40"}], "ref_spans": []}, {"section": "2008)", "text": "The results for our model magnetospheres are presented in Table 3 (B-star) and Table 4 (O-star). For zero rotation, the ratio between the general and optically-thick\u1e40 global is well explained by the OTC parameter, \u03a30. For our B-star, we calculate a ratio 7.18 \u00d7 10 \u221210 /1 \u00d7 10 \u22129 \u2248 0.718, which compares well to our approximated \u03a30 \u2248 0.725. For the Ostar, the model\u1e40 global ratio is 3.67 \u00d7 10 \u22126 /3.77 \u00d7 10 \u22126 \u2248 0.973, which fits with our \u03a30\u2248 0.974. Additionally, the ratio between the CAK-type mass-loss rates (\"No B\" in Table 3/Table 4 ) between the general and optically-thick cases can be approximated by \u03a30. The reason why the ratios differ from the actual value of \u03a30 is because rc is different between the general and optically-thick cases, leading to different base mass-fluxes (Equation 51). Nonetheless, multiplying the base mass-loss by the OTC parameter gives an excellent approximation.", "cite_spans": [], "ref_spans": [{"start": 79, "end": 86, "text": "Table 4", "ref_id": "TABREF7"}, {"start": 522, "end": 537, "text": "Table 3/Table 4", "ref_id": "TABREF7"}]}, {"section": "2008)", "text": "The effective mass-loss rates for both our B and O stars imply that most of the plasma falls back to the star at low rotation (about 2/3rds at \u03c9 = 0.2) and nearly none of it falls back at high rotation (1% at \u03c9 = 0.8). This leads to mass-loss of about 20-65% of the non-magnetic, non-rotating CAK value.", "cite_spans": [], "ref_spans": []}, {"section": "2008)", "text": "Since we use Gayley (1995) 'sQ parameterization for the line-acceleration, we must be careful when comparing calculated mass-loss rates with other models which use the more traditional CAK force multipler paradigm (Abbott 1982) . Puls et al. (2000) show that usingQ in g rad,s instead of the CAK k parameter requires an ansatz that does not hold for T * < 35000K. In our model, assuming a wind temperature equal to the stellar effective temperature means that B-star winds will be below this cutoff; the result is an overestimated mass-loss rate (c.f. Table 2 in Puls et al. 2000) by about a factor of 2. Future studies will need to determine the wind temperature to check the validity of the T = T eff assumption.", "cite_spans": [], "ref_spans": [{"start": 552, "end": 559, "text": "Table 2", "ref_id": "TABREF4"}]}, {"section": "2008)", "text": "Further improvements to our global mass-loss rates will require consideration of the finite-disk effect. We will implement this term in Paper II, but for now we can estimate the finite-disk corrected\u1e40 global by dividing our results by two.", "cite_spans": [], "ref_spans": []}, {"section": "2008)", "text": "In this paper, we presented a critical point analysis of the Arbitrary Rigid-Field Hydrodynamic Equations, which represent a CAK-type wind within an arbitrary, infinitely-strong magnetic field. This differs from the usual CAK wind model by including the proper optically-thin maximum line-force, a rigid-body centrifugal acceleration, and a dipole areal divergence. After finding the general critical point values for the mass-flux, velocity and velocity derivative, we confirmed that they reduced to the proper values for a traditional CAK wind, i.e. a non-rotating, non-optically-thin corrected, radial flow with spherical divergence. These benchmarked general critical point equations were then applied to an aligned magnetic dipole field in order to calculate critical point locations and surface mass-fluxes. By integrating from these critical point locations, the velocity structure within the magnetosphere was quantified and studied. Finally, we obtained global mass-loss rates and found that the dipole field effectively reduces the overall mass-loss to 20-65% of the nonmagnetic, non-rotating CAK value.", "cite_spans": [], "ref_spans": []}, {"section": "2008)", "text": "The key results are summarized as follows:", "cite_spans": [], "ref_spans": []}, {"section": "2008)", "text": "(i) We are able to approximately confirm the Owocki & ud-Doula (2004) scaling for the influence of a magnetic dipole on the surface mass-flux,\u1e41r \u2248 \u00b5 2 B\u1e41CAK . While this scaling does not need much improvement, we provide a more accurate scaling equation (Equation 50) and detail which approximations are required to reproduce the OD04 scaling.", "cite_spans": [], "ref_spans": []}, {"section": "2008)", "text": "(ii) The effect of a optically-thin corrected line-force can be encapsulated in a OTC parameter, which we call \u03a30 (Equation 56). Including this does not have much of an effect for O-type stars, since their increased wind density means that there will be less difference in the corrected and uncorrected line-forces. B-type stars, on the other hand, have their surface mass-flux reduced by approximately 25-30% when the optically-thin correction is taken into account.", "cite_spans": [], "ref_spans": []}, {"section": "2008)", "text": "(iii) The effect of rotation can be similarly represented with a rotation-effect parameter, which we call \u2135 (Equation 64a). The amount of rotational boosting of the massflux is found to depend on both the rotational colatitude and the magnetic obliquity angle.", "cite_spans": [], "ref_spans": []}, {"section": "2008)", "text": "(iv) The effects of rotation and the optically-thin correction can not be decoupled, however. We find a different OTC parameter in the case of rotation, \u03a3rot (Equation 72). Rotation is found to reduce the correction by driving a higher surface mass-flux.", "cite_spans": [], "ref_spans": []}, {"section": "2008)", "text": "(v) The velocity structure within a magnetosphere cannot be described by a global beta-velocity law. However, at least for zero rotation, we can well-fit each line with individual beta-velocity laws. The best-fit v\u221e and \u03b2 do vary from line to line, however. With rotation, the beta-velocity law assumption breaks down.", "cite_spans": [], "ref_spans": []}, {"section": "2008)", "text": "(vi) The global mass-loss rate for a optically-thin corrected line-force can be accurately estimated by multiplying the optically-thick mass-loss by the OTC parameter, \u03a3. We find \"effective\" magnetospheric mass-loss rates, in which the plasma does not fall back to the star, to be approximately 20-65% of the non-magnetic, non-rotating CAK mass-loss rate.", "cite_spans": [], "ref_spans": []}, {"section": "2008)", "text": "Overall, we have quantified the effect of a magnetic dipole on a massive star wind with an eye towards better understanding of massive star magnetospheres. Next steps include adding the finite-disk correction parameter and quantifying its effect on the magnetospheric mass-loss and velocity (Paper II). Paper III will add colliding wind shocks and the subsequent \"cooling\" region to each line in order to better quantify the level of X-ray emission coming from each line. This will provide accurate initial conditions for hydrodynamical simulations of centrifugal magnetospheres.", "cite_spans": [], "ref_spans": []}, {"section": "ACKNOWLEDGMENTS", "text": "CB acknowledges support from the NASA GSRP Fellowship (NASA Grant NNX11AK70H). CB and RHDT acknowledge support from NASA ATP Grant NNX12AC72G. The authors thank S. Owocki and J. Cassinelli for helpful discussions and comments. ", "cite_spans": [], "ref_spans": []}, {"section": "ACKNOWLEDGMENTS", "text": "where, as in the optically-thick case, we ignore the Parker term c 2 s \u03bb.", "cite_spans": [], "ref_spans": []}, {"section": "APPENDIX B: CRITICAL VALUES FOR OPTICALLY-THICK WIND", "text": "From the equation of motion (Equation 22), the CAK singularity condition (Equation B2), and the CAK regularity condition (Equation B3), we now solve for the critical values (\u2206c, uc, and yc) as a function of critical point location, scrit. For mathematical simplicity, we will define \u0393 \u2261 (A/A * ) \u03b1 \u03c8/r 2 in the derivation, such that the starting equation of motion is F \u2261 y(1 \u2212 1/u 2 ) \u2212 g eff,s \u2212 \u2206\u0393|y| \u03b1 .", "cite_spans": [], "ref_spans": []}, {"section": "APPENDIX B: CRITICAL VALUES FOR OPTICALLY-THICK WIND", "text": "We continue with evaluating both CAK critical conditions (Equation 28, Equation 29), remembering that g eff,s and \u0393 are wholly functions of s: Starting from the singularity condition, we get", "cite_spans": [], "ref_spans": []}, {"section": "APPENDIX B: CRITICAL VALUES FOR OPTICALLY-THICK WIND", "text": "(1 \u2212 1/u 2 c )yc = \u03b1\u2206c\u0393|yc| \u03b1 .", "cite_spans": [], "ref_spans": []}, {"section": "APPENDIX B: CRITICAL VALUES FOR OPTICALLY-THICK WIND", "text": "Substituting this into Equation 26 yields", "cite_spans": [], "ref_spans": []}, {"section": "APPENDIX B: CRITICAL VALUES FOR OPTICALLY-THICK WIND", "text": "(1 \u2212 \u03b1)\u2206c\u0393|yc| \u03b1 = \u2212g eff,s .", "cite_spans": [], "ref_spans": []}, {"section": "APPENDIX B: CRITICAL VALUES FOR OPTICALLY-THICK WIND", "text": "Combining this and Equation B5 gives us", "cite_spans": [], "ref_spans": []}, {"section": "APPENDIX B: CRITICAL VALUES FOR OPTICALLY-THICK WIND", "text": "From the regularity condition, Equation B3 , we obtain ", "cite_spans": [], "ref_spans": [{"start": 31, "end": 42, "text": "Equation B3", "ref_id": "FIGREF3"}]}, {"section": "APPENDIX B: CRITICAL VALUES FOR OPTICALLY-THICK WIND", "text": "where we define \u03a6 2 \u2261 \u2202g eff,s \u2202s \u2212 g eff,s 1 \u2212 \u03b1 \u03b1\u03bb + 1 \u03c8 \u2202\u03c8 \u2202s \u2212 2\u03c8 r .", "cite_spans": [], "ref_spans": []}, {"section": "APPENDIX B: CRITICAL VALUES FOR OPTICALLY-THICK WIND", "text": "Equation B9 has two possible outcomes: yc/u 2 c = \u00b1cs\u03a6/ \u221a 2. Since u 2 c > 0, the sign of yc determines which solution to choose. For the case of a radiation-driven outflow, the magnetospheric plasma accelerates as it flows away from the stellar surface. However, due to our sign convention (Section 2.2), outflowing plasma can have either a positive or negative velocity. For an increasing arc length away from the stellar surface (\u03c8 > 0), an accelerating outflow has v > 0, dv > 0, and ds > 0, resulting in yc > 0. At the opposite line footprint (\u03c8 < 0), if there is one, an accelerating outflow requires v < 0, dv < 0, and ds < 0, resulting in yc < 0. Thus, we take the positive (negative) root of Equation B9 for positive (negative) \u03c8.", "cite_spans": [], "ref_spans": []}, {"section": "APPENDIX B: CRITICAL VALUES FOR OPTICALLY-THICK WIND", "text": "Next, we solve for the critical velocity using Equation B7 and Equation B9:", "cite_spans": [], "ref_spans": []}, {"section": "APPENDIX B: CRITICAL VALUES FOR OPTICALLY-THICK WIND", "text": "which is Equation 31. Substituting Equation B7 for u 2 c instead allows us to solve for yc:", "cite_spans": [], "ref_spans": []}, {"section": "APPENDIX B: CRITICAL VALUES FOR OPTICALLY-THICK WIND", "text": "Finally, we solve for \u2206c using Equation B6: \u2206c = \u2212 g eff,s (1 \u2212 \u03b1)\u0393| \u00b1 ", "cite_spans": [], "ref_spans": []}, {"section": "APPENDIX B: CRITICAL VALUES FOR OPTICALLY-THICK WIND", "text": "Since the right-hand side of Equation C3 is wholly dependent on scrit, we define", "cite_spans": [], "ref_spans": []}, {"section": "APPENDIX B: CRITICAL VALUES FOR OPTICALLY-THICK WIND", "text": "\u03c4 sob being the Sobolev optical depth. Additionally, we will define the critical value of \u03c7 as \u03c7c = \u03c7c(scrit) \u2261 \u2212g eff,s r 2 /[Q\u0393 el GM * \u03c8].", "cite_spans": [], "ref_spans": []}, {"section": "APPENDIX B: CRITICAL VALUES FOR OPTICALLY-THICK WIND", "text": "We can further simplify this to \u03c7c = \u03c70\u2135c, where", "cite_spans": [], "ref_spans": []}, {"section": "APPENDIX B: CRITICAL VALUES FOR OPTICALLY-THICK WIND", "text": "is the critical \u03c7 value for zero rotation and \u2135c is the rotation effect parameter (Equation 64a) evaluated at the critical point.", "cite_spans": [], "ref_spans": []}, {"section": "APPENDIX B: CRITICAL VALUES FOR OPTICALLY-THICK WIND", "text": "We discuss the physical meaning of \u03c7 as a \"correction level parameter\" in Section 6.2, but we note that \u03c7c is set by the ratio of the non-radiative external forces to the optically thin (\u03c4 sob 1) radiative force. Since \u03c7 can only be between zero and one (since \u03c4 sob > 0), this implies both that, at the critical point, gravity must be stronger than the centrifugal force and the optically thin radiative force must be stronger than the other combined external forces. dipole. In theory, one could write the full critical value equations wholly in terms of \u03b8, but such a representation would be too muddled and provide no benefit. For practical purposes, it is much easier to calculate values along each input magnetic field line and derive the spatial derivatives numerically. The procedure for calculating the dipole critical values for a general line acceleration is identical to above, since the spatial variables are the same.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF23": {"title": "IAU Symposium", "authors": [{"first": "T", "middle": [], "last": "Morel", "suffix": ""}], "year": 2015, "venue": "", "link": null}, "BIBREF39": {"title": "IAU Symposium", "authors": [{"first": "G", "middle": ["A"], "last": "Wade", "suffix": ""}], "year": 2014, "venue": "", "link": null}, "BIBREF40": {"title": "Wolf-Rayet Stars: Binaries", "authors": [{"first": "R", "middle": ["L"], "last": "White", "suffix": ""}, {"first": "W", "middle": [], "last": "Chen", "suffix": ""}, {"first": "A", "middle": [], "last": "Ud-Doula", "suffix": ""}, {"first": "S", "middle": ["P"], "last": "Owocki", "suffix": ""}, {"first": "A", "middle": [], "last": "Ud-Doula", "suffix": ""}, {"first": "S", "middle": ["P"], "last": "Owocki", "suffix": ""}, {"first": "R", "middle": ["H D"], "last": "Townsend", "suffix": ""}, {"first": "A", "middle": [], "last": "Ud-Doula", "suffix": ""}, {"first": "S", "middle": ["P"], "last": "Owocki", "suffix": ""}, {"first": "R", "middle": ["H D"], "last": "Townsend", "suffix": ""}], "year": 1995, "venue": "IAU Symposium", "link": null}}, "ref_entries": {"FIGREF0": {"text": "Figure 1. Surface mass-flux (\u1e41 * ) as a function of line surface colatitude calculated using both the general and optically-thick line-acceleration for a B-type star (Table 1).\u1e41 * is compared to a general scaling \u00b5 B\u1e41\u03b8=0 as derived by OD04 (Equation 44), with a different\u1e41 \u03b8=0 for both cases. We find an excellent agreement between the scaling and model, with similar results for the O-type star not shown.", "type": "figure"}, "FIGREF1": {"text": "Figure 2. Effect of rotation on \u00b5 B , the dot product between the surface normal unit vector and the surface magnetic field unit vector (Equation 61).", "type": "figure"}, "FIGREF3": {"text": "Figure 3. Surface mass-flux (\u1e41 * ; solid line) as a function of line surface colatitude for an optically-thick line force and a B-type star (Table 1).\u1e41 * is compared to the rotation scaling (dot-dashed line) derived in Equation 70 and the CAK mass-flux (Equation 45; dashed line)", "type": "figure"}, "FIGREF5": {"text": "Figure 4. Surface mass-flux (\u1e41 * ; solid line) as a function of line surface colatitude for an optically-thick line force and an O-type star.\u1e41 * is compared to the rotation scaling (dot-dashed line) derived in Equation 70 and the CAK mass-flux (dashed line).", "type": "figure"}, "FIGREF7": {"text": "Figure 5. Surface mass-flux (\u1e41 * ; solid line) as a function of line surface colatitude for a general line force and a B-type star (Table 1).\u1e41 * is compared to the rotation scaling (dot-dashed line) derived in Equation 74 and \u03a3 0\u1e41CAK , the corrected CAK mass-flux (dashed line).", "type": "figure"}, "FIGREF8": {"text": "Figure 5 and Figure 6 show the good agreement of our scaling (Equation 74) with our model calculations for both", "type": "figure"}, "FIGREF9": {"text": "Figure 6. Surface mass-flux (\u1e41 * ; solid line) as a function of line surface colatitude for a general line force and an O-type star. m * is compared to the rotation scaling (dot-dashed line) derived in Equation 74 and \u03a3 0\u1e41CAK , the optically-thin corrected CAK mass-flux (dashed line).", "type": "figure"}, "FIGREF10": {"text": "Figure 7. Critical point location rc in the general (solid) and optically-thick (dot-dashed) cases as a function of critical rotation fraction \u03c9 and dipole line surface colatitude \u03b8m for a B-type star. In general, both rotation and the optically-thin correction move the critical point away from the center of the star, though the rotation effect is caused by the increased stellar radius of an oblate star (Figure 8). Similar results for the O star not shown.", "type": "figure"}, "FIGREF11": {"text": "Figure 8. Critical point location realative to the stellar surface (rc -R * ) in the general (solid) and optically-thick (dot-dashed) cases as a function of critical rotation fraction \u03c9 and dipole line surface colatitude \u03b8m for a B-type star. The optically-thin correction tends to move the critical radius away from the star, but rotation moves the critical radius slightly closer to the star. Similar results for the O star not shown.", "type": "figure"}, "FIGREF12": {"text": "Figure 9. Best-fit velocity-law betas (left) and corresponding terminal velocities (right) for our non-rotating O-star (solid) and B-star (dot-dashed) models. Fit parameters were determined using nonlinear least-squares fitting. The solid black line represents the surface colatitude for L = 100 Rp, our truncation radius; results from more polar colatitudes should be ignored since those model lines were truncated well before reaching an apex.", "type": "figure"}, "FIGREF13": {"text": "Figure 11. Comparison of wind velocity (solid) vs. Alfv\u00e9n velocity (dot-dashed) at apex of each magnetic field line for our optically-thin corrected B-star model. Colored dots indicate approximation of closure colatitude for each rotation rate. The dashed line indicates the non-rotating MHD-predicted closure colatitude. The solid black line represents the surface colatitude for L = 100 Rp, our truncation radius; results from more polar colatitudes should be ignored since those model lines were truncated well before reaching an apex.", "type": "figure"}, "FIGREF14": {"text": "Figure 12. Same as Figure 11, except for our O-star model.", "type": "figure"}, "FIGREF15": {"text": "APPENDIX A: EQUATION OF MOTION IN GENERAL CASE Starting with the general g rad,s (Equation 16), we eliminate the density with the continuity equation (Equation 19):", "type": "figure"}, "FIGREF17": {"text": "eff,s | \u03b1 . (B13) APPENDIX C: CRITICAL VALUES FOR GENERAL CASE As in Appendix B, we will solve for the critical velocity, velocity derivative, and surface mass-flux as a function of the critical point location. First, from the general equation of motion (Equation A2), we make the substitutions y = vv and u = v/cs. Next, for mathematical simplicity,", "type": "figure"}, "TABREF0": {"text": ", we can solve for the values at the critical point. For simplicity, we shall neglect the Parker term c", "type": "table"}, "TABREF1": {"text": "Stellar and wind parameters used throughout this paper to represent a typical magnetic B-type star with a centrifugal magnetosphere and an O-type star with a dynamical magnetosphere. Values are taken from Table 2 in Bjorkman (1995) for the B-star and ud-Doula et al. (2014) for the O-star.", "type": "table"}, "TABREF2": {"text": "Table 1).\u1e41 * is compared to a general scaling \u00b5 B\u1e41\u03b8=0 as derived by OD04 (Equation 44), with a different\u1e41 \u03b8=0 for both cases. We find an excellent agreement between the scaling and model, with similar results for the O-type star not shown.", "type": "table"}, "TABREF4": {"text": "Estimated closure radii (in units Rp) for the model B-star centrifugal magnetosphere and O-star dynamical magne- tosphere at different rotation rates. The MHD scaling estimate (Equation 75) is also included for comparison.", "type": "table"}, "TABREF7": {"text": "Same as Table 3, except for an O-type star with \u03b7 * = 100. All mass-loss rates are given in 10 \u22126 M /yr. Numbers in parentheses next to a mass-loss rate represent the ratio of that particular rate to the \"General\" mass-loss with the same rotation.", "type": "table"}}}
{"paper_id": "118860362", "_pdf_hash": "4e2e842a798f5ab4eff163b67394a8a89002e067", "abstract": [], "body_text": [{"section": "", "text": "physical processes on cosmological scales, have power to reveal detailed properties of the physics responsible for generating the primordial fluctuations. Even qualitative observational features can identify key properties of the fields involved (for example, how many fields and which couplings were most relevant), or alternatively, shed light on the systematic errors in the data. However, because there are so many possibilities from both theory and observation, and because many calculations are very technical involving methods such as higher order perturbation theory, the literature can be daunting.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "In this Special Issue of Advances in Astronomy we have collected articles that summarize the theoretical predictions for departures from Gaussianity or statistical isotropy from a variety of potential sources, together with the observational approaches to test these properties using the CMB or large-scale structure. We hope this collection provides an accessible entry point to these topics as they currently stand, indicating what direction future developments may take and demonstrating why these questions are so compelling. The Special Issue is available at http://www.hindawi.com/journals/aa/2010/si.gsiu.html, and individual articles are also available on the arXiv. ", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "\u2022 Primordial Non-Gaussianity in the Cosmic Microwave Background", "authors": [], "year": "", "venue": "", "link": "118368775"}, "BIBREF1": {"title": "Wandelt \u2022 Primordial Non-Gaussianities from Inflation Models", "authors": [{"first": "P", "middle": ["S"], "last": "Amit", "suffix": ""}, {"first": "", "middle": [], "last": "Yadav", "suffix": ""}, {"first": "D", "middle": [], "last": "Benjamin", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF2": {"title": "\u2022 Non-Gaussianity from Particle Production during Inflation", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF3": {"title": "\u2022 Review of Local Non-Gaussianity from Multifield Inflation", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF4": {"title": "Antonio Riotto \u2022 Second-Order Gauge-Invariant Cosmological Perturbation Theory: Current Status", "authors": [{"first": "Nicola", "middle": [], "last": "Bartolo", "suffix": ""}, {"first": "Sabino", "middle": [], "last": "Matarrese", "suffix": ""}, {"first": ";", "middle": [], "last": "Craig", "suffix": ""}, {"first": "J", "middle": [], "last": "Copi", "suffix": ""}, {"first": "Dragan", "middle": [], "last": "Huterer", "suffix": ""}, {"first": "J", "middle": [], "last": "Dominik", "suffix": ""}, {"first": "Glenn", "middle": ["D"], "last": "Schwarz", "suffix": ""}, {"first": "", "middle": [], "last": "Starkman", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF5": {"title": "\u2022 A comprehensive overview of the Cold Spot", "authors": [], "year": "", "venue": "", "link": "56087498"}}, "ref_entries": {"TABREF0": {"text": "Contents: Invited Reviews \u2022 Non-Gaussianity from Large-Scale Structure Surveys (arXiv:1001.5217) Licia Verde\u2022 Primordial Non-Gaussianity and Bispectrum measurements in the Cosmic Microwave Background and Large-Scale Structure (arXiv:1001.4707) Michele Liguori, Emiliano Sefusatti, James R. Fergusson, E.P.S. Shellard \u2022 Testing Gaussianity, Homogeneity, and Isotropy with the Cosmic Microwave Back- ground (arXiv:1002.3173) L. Raul Abramo, Thiago S. Pereira", "type": "table"}}}
{"paper_id": "118860835", "_pdf_hash": "ef9f7b577c734364f2a73efe51c61014872e400c", "abstract": [{"section": "Abstract", "text": "The equilibrium binding energy is an important factor in the design of materials and devices. However, it presents great computational challenges for materials built up from nanostructures. Here we investigate the binding-energy scaling law from first-principles calculations. We show that the equilibrium binding energy per atom between identical nanostructures can scale up or down with nanostructure size. From the energy scaling law, we predict finite large-size limits of binding energy per atom. We find that there are two competing factors in the determination of the binding energy: Nonadditivities of van der Waals coefficients and center-to-center distance between nanostructures. To uncode the detail, the nonadditivity of the static multipole polarizability is investigated. We find that the higher-order multipole polarizability displays ultra-strong intrinsic nonadditivity, no matter if the dipole polarizability is additive or not.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "I. INTRODUCTION", "text": "There is strong interest in nanomaterials, motivated by the development of nanotechnoloy and by their novel properties arising from quantum confinement. In particular, the discovery of various atomic-level materials has received overwhelming attention for their remarkable properties and wide-ranging applications [1] . A common feature of these materials is the strong adhesive van der Waals (vdW) force due to the instantaneous charge fluctuations. To understand the nature of the vdW force, a variety of experiments ranging from the smallest atomistic to the largest macroscopic scales have been performed recently [2] [3] [4] [5] [6] . However, details of many surprising phenomena due to the vdW interaction have not been well understood at the nanoscale [7] . Here we will ask and answer another such question.", "cite_spans": [{"start": 314, "end": 317, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 618, "end": 621, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 622, "end": 625, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 626, "end": 629, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 630, "end": 633, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 760, "end": 763, "text": "[7]", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "The equilibrium binding energy between identical nanostructures is an important property involving microscopically the short-range contribution arising from the density overlap and the long-range vdW interaction. However, due to the large size of nanostructures, it presents great computational challenges. As such, an energy scaling law showing the variation of equilibrium binding energy per atom with system size is highly desired. We here apply an efficient first-principles method, the vdW-DF-cx [8] density functional, to investigate the energy scaling law, aiming to provide novel insights into nanostructures. Figure 1 shows the energy scaling law for a variety of nanomaterials, while Table II shows the energy scaling law for a variety of nanostructures obtained by fitting to our numerical calculations. We find that the binding-energy scaling law is largely due to the competing size effects of the vdW coefficients and sum of the vdW radii of nanostructures determining the intermolecular distance. Our finding is different from previous works [7, 9, 10] , in which the vdW coefficients and intermolecular distance are treated independently, allowing one to study the dependence of the vdW interaction upon the power of distance.", "cite_spans": [{"start": 501, "end": 504, "text": "[8]", "ref_id": "BIBREF8"}, {"start": 1057, "end": 1060, "text": "[7,", "ref_id": "BIBREF7"}, {"start": 1061, "end": 1063, "text": "9,", "ref_id": "BIBREF9"}, {"start": 1064, "end": 1067, "text": "10]", "ref_id": "BIBREF10"}], "ref_spans": [{"start": 618, "end": 626, "text": "Figure 1", "ref_id": "FIGREF0"}]}, {"section": "II. COMPUTATIONAL METHODS", "text": "The binding energy per atom is defined as E b /N , with N being the total number of C/B/N atoms in a nanostructure. For nanotubes, N is the number of atoms per unit length (in\u00c5). All our calculations of binding energies and distances d cc (center to center) and d ww (wall to wall) were performed with Quantum ESPRESSO [11] , using the vdW-DF-cx [8] nonlocal density functional. We used ultrasoft pesudopotentials with a plane-wave energy cutoff at 680 eV. The binding energy E b is taken as the energy difference between relaxed nanostructures in the conventional unit cell and in the empty space, except for nanowires, in which the distance between two nanowires is fixed at 4.21\u00c5 (the relaxed distance between C-NWs with seven atoms), due to the high instability. For fullerenes, we used 2 \u00d7 2 \u00d7 2 for the k-mesh. For C-PAHs and BN-PAHs, only the \u0393-point is included in the k-mesh, due to the large size of the cell. For nanotubes, we used 6 \u00d7 6 \u00d7 17 to 1 \u00d7 1 \u00d7 17 from (3, 3) to (40, 40) . For nanowires, we used 3 \u00d7 3 \u00d7 2 for all cases.", "cite_spans": [{"start": 319, "end": 323, "text": "[11]", "ref_id": "BIBREF11"}, {"start": 346, "end": 349, "text": "[8]", "ref_id": "BIBREF8"}, {"start": 973, "end": 976, "text": "(3,", "ref_id": "BIBREF2"}, {"start": 977, "end": 979, "text": "3)", "ref_id": "BIBREF2"}, {"start": 983, "end": 987, "text": "(40,", "ref_id": "BIBREF40"}, {"start": 988, "end": 991, "text": "40)", "ref_id": "BIBREF40"}], "ref_spans": []}, {"section": "II. COMPUTATIONAL METHODS", "text": "The nonlocal correlation part of the vdW-DF-cx is the same as in the original Rutgers-Chalmers [12] vdW-DF, which was derived from the fluctuation-dissipation theorem [13] of electron gas for the description of the longrange vdW interaction [14] . The method contains both the leading-order and higher-order contributions, the latter of which are important for solids [15] [16] [17] [18] [19] . Its exchange part is based on a modified semilocal functional, which aims to improve the short-range description.", "cite_spans": [{"start": 95, "end": 99, "text": "[12]", "ref_id": "BIBREF12"}, {"start": 167, "end": 171, "text": "[13]", "ref_id": "BIBREF13"}, {"start": 241, "end": 245, "text": "[14]", "ref_id": "BIBREF14"}, {"start": 368, "end": 372, "text": "[15]", "ref_id": "BIBREF15"}, {"start": 373, "end": 377, "text": "[16]", "ref_id": "BIBREF16"}, {"start": 378, "end": 382, "text": "[17]", "ref_id": "BIBREF17"}, {"start": 383, "end": 387, "text": "[18]", "ref_id": "BIBREF18"}, {"start": 388, "end": 392, "text": "[19]", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "II. COMPUTATIONAL METHODS", "text": "The vdW-DF-cx is a useful first-principles method, as supported by Appendices A and B. The experimental geometries of fullerene solids (Appendix A) and their equilibrium binding energies (Table I and Appendix B) are well reproduced, although C 6 for a fullerene pair is not, as anticipated in Ref. [20] . Like SCAN+rVV10 [21] , and with nearly the same binding energy curve, vdW-DF-cx predicts [22] a chemisorption minimum for graphene on Ni(111) at a distance of 2.1\u00c5 from the top nickel plane, in close agreement with experiment. Some of us have previously argued [14, 21] that a vdW functional can be accurate for equilibrium binding energies, even if it is not for asymptotic interactions.", "cite_spans": [{"start": 298, "end": 302, "text": "[20]", "ref_id": "BIBREF20"}, {"start": 321, "end": 325, "text": "[21]", "ref_id": "BIBREF21"}, {"start": 394, "end": 398, "text": "[22]", "ref_id": "BIBREF22"}, {"start": 566, "end": 570, "text": "[14,", "ref_id": "BIBREF14"}, {"start": 571, "end": 574, "text": "21]", "ref_id": "BIBREF21"}], "ref_spans": [{"start": 187, "end": 195, "text": "(Table I", "ref_id": "TABREF0"}]}, {"section": "II. COMPUTATIONAL METHODS", "text": "To analyse the energy scaling law revealed from our calculation, we have to make use of the efficient yet accurate spherical-shell model within the single-frequency approximation (SFA) [23] [24] [25] to evaluate the vdW coefficients between nanostructures. In the SFA, we assume that (i) only valence electrons in the outermost subshell are polarizable, and (ii) the density is uniform inside the effective radius R l and zero otherwise. Within the SFA, the model dynamic multipole polarizability takes the simple expression", "cite_spans": [{"start": 185, "end": 189, "text": "[23]", "ref_id": "BIBREF23"}, {"start": 190, "end": 194, "text": "[24]", "ref_id": "BIBREF24"}, {"start": 195, "end": 199, "text": "[25]", "ref_id": "BIBREF25"}], "ref_spans": []}, {"section": "II. COMPUTATIONAL METHODS", "text": "where R l is the effective outer radius of the shell,", "cite_spans": [], "ref_spans": []}, {"section": "II. COMPUTATIONAL METHODS", "text": "] describes the coupling of the sphere and cavity plasmon oscillations, and \u03c1 l = (1 \u2212 t l /R l ) 2l+1 describes the shape of the shell, with t l being the shell thickness [24, 26] . \u03c9 l = \u03c9 p l/(2l + 1) is the average sphere plasmon frequency, \u03c9 l = \u03c9 p (l + 1)/(2l + 1) is the cavity plasmon frequency, and \u03c9 p = \u221a 4\u03c0n is the average plasmon frequency of the extended electron gas, withn = N/V l and V l being the l-dependent vdW volume.", "cite_spans": [{"start": 172, "end": 176, "text": "[24,", "ref_id": "BIBREF24"}, {"start": 177, "end": 180, "text": "26]", "ref_id": "BIBREF26"}], "ref_spans": []}, {"section": "II. COMPUTATIONAL METHODS", "text": "Since the geometry effect can be accounted for via \u03b1 l (0), the model is valid for any geometry [23] . For fullerenes,", "cite_spans": [{"start": 96, "end": 100, "text": "[23]", "ref_id": "BIBREF23"}], "ref_spans": []}, {"section": "II. COMPUTATIONAL METHODS", "text": ". For nanotubes, we take a unit length to study. The volume per unit length is given as V l = 2\u03c0R 0 t l , where R 0 is the average radius of a nanotube, which can be accurately calculated from first principles methods [27] [28] [29] [30] [31] , and t l is the effective thickness of the nanotube. For C-NT, we set t l = 3.4 bohr, as adopted for fullerene", "cite_spans": [{"start": 218, "end": 222, "text": "[27]", "ref_id": "BIBREF27"}, {"start": 223, "end": 227, "text": "[28]", "ref_id": "BIBREF28"}, {"start": 228, "end": 232, "text": "[29]", "ref_id": "BIBREF29"}, {"start": 233, "end": 237, "text": "[30]", "ref_id": "BIBREF30"}, {"start": 238, "end": 242, "text": "[31]", "ref_id": "BIBREF31"}], "ref_spans": []}, {"section": "II. COMPUTATIONAL METHODS", "text": ". The volume per unit length is given as V l = 2\u03c0R 0 t l , where R 0 is the average radius of a nanotube, which can be accurately calculated from first principles methods [27] [28] [29] [30] [31] , and t l is the effective thickness of the nanotube. For C-NT, we set t l = 3.4 bohr, as adopted for fullerene molecules [24, 26] , while for BN-NT, we set t l = 2.08 bohr [29] . For PAH and nanowire, we can make a similar analysis by taking carbon or BN atoms as a unit. It has been shown that this model can yield very accurate vdW coefficients [23, 25] .", "cite_spans": [{"start": 171, "end": 175, "text": "[27]", "ref_id": "BIBREF27"}, {"start": 176, "end": 180, "text": "[28]", "ref_id": "BIBREF28"}, {"start": 181, "end": 185, "text": "[29]", "ref_id": "BIBREF29"}, {"start": 186, "end": 190, "text": "[30]", "ref_id": "BIBREF30"}, {"start": 191, "end": 195, "text": "[31]", "ref_id": "BIBREF31"}, {"start": 318, "end": 322, "text": "[24,", "ref_id": "BIBREF24"}, {"start": 323, "end": 326, "text": "26]", "ref_id": "BIBREF26"}, {"start": 369, "end": 373, "text": "[29]", "ref_id": "BIBREF29"}, {"start": 544, "end": 548, "text": "[23,", "ref_id": "BIBREF23"}, {"start": 549, "end": 552, "text": "25]", "ref_id": "BIBREF25"}], "ref_spans": []}, {"section": "III. BINDING-ENERGY SCALING LAW FOR NANOSTRUCTURES", "text": "Ball-to-ball interaction. Fullerene is an important class of nanomaterials with a variety of applications [32] in physics, chemistry, and materials science. The binding energy between fullerene pairs is a typical example of ball-ball interaction [19, 33] . We have calculated the binding energies per atom of fullerene solids with the optimized fcc-type geometries (Appendix A). For C 60 , the experimental value was already extrapolated to 0 K, while for others, the experimental values are available only at high temperature (\u223c 850 K) [34] , due to the strong vdW force. We have estimated the thermal energy correction (\u223c 2 meV/atom) for C 70 solid, for which the heat capacity data are available [34] . For C 76 [35] and C 84 [34] , we take the same thermal correction per atom as for C 70 . From Table I , we observe that the calculated binding energies are generally within the range of thermally corrected experiments, while the intermolecular distance d cc is between the DFT-LSDA [19] (local spin-density approximation) and experimental value [36] (at room temperature). This suggests that the method used in this work is not only reliable for binding energy, but also for the center-to-center distance. See appendix A for further detailed discussion.", "cite_spans": [{"start": 106, "end": 110, "text": "[32]", "ref_id": "BIBREF32"}, {"start": 246, "end": 250, "text": "[19,", "ref_id": "BIBREF19"}, {"start": 251, "end": 254, "text": "33]", "ref_id": "BIBREF33"}, {"start": 537, "end": 541, "text": "[34]", "ref_id": "BIBREF34"}, {"start": 699, "end": 703, "text": "[34]", "ref_id": "BIBREF34"}, {"start": 715, "end": 719, "text": "[35]", "ref_id": "BIBREF35"}, {"start": 729, "end": 733, "text": "[34]", "ref_id": "BIBREF34"}, {"start": 988, "end": 992, "text": "[19]", "ref_id": "BIBREF19"}, {"start": 1051, "end": 1055, "text": "[36]", "ref_id": "BIBREF36"}], "ref_spans": [{"start": 800, "end": 807, "text": "Table I", "ref_id": "TABREF0"}]}, {"section": "III. BINDING-ENERGY SCALING LAW FOR NANOSTRUCTURES", "text": "Figure 1(a) shows that the binding energy of fullerenes per atom decreases slowly (only 3 meV/atom from C 60 to C 84 ) with fullerene size, while Table II shows that the large-size limit of binding energy saturates to a constant 24 meV/atom. From Table I , we can see that the center-to-center distance d cc gradually becomes larger and larger from C 60 to C 84 . With the increase of fullerene size, vdW coefficients per atom pair, in particular the higher-order ones (Table III) , dramatically increase, while the sum of the vdW radii of fullerenes characterized by d cc also increases. These two factors have opposite effects on the energy scaling law, leading to the slow variation of the binding energy with system size. It is interesting to note that the wall-to-wall distance d ww of fullerenes gets slightly shrunk from C 60 to C 84 . This is because the vdW force between fullerenes increases from C 60 to C 84 , pulling two fullerenes slightly closer.", "cite_spans": [], "ref_spans": [{"start": 146, "end": 154, "text": "Table II", "ref_id": "TABREF0"}, {"start": 247, "end": 254, "text": "Table I", "ref_id": "TABREF0"}, {"start": 469, "end": 480, "text": "(Table III)", "ref_id": "TABREF0"}]}, {"section": "III. BINDING-ENERGY SCALING LAW FOR NANOSTRUCTURES", "text": "Plane-to-plane interaction. Polycyclic aromatic hydrocarbons (C-PAHs) are a large class of conjugated \u03c0-electron systems of great importance in many areas such as environmental chemistry, materials science, and astrochemistry [37] . The energy scaling law between C-PAHs reflects the plane-to-plane vdW interaction [38] [39] [40] . Here we focus on the binding energies per atom of C-PAH Table II. dimers with the optimized AA stacking. Crucial to this problem is the fact that the center-to-center distance d cc remains nearly the same for all C-PAH, with a slight decreasing trend similar to d ww for fullerene pairs, as shown in Table I . This is because from benzene to pentacene, the vdW force increases, pulling two planar molecules slightly closer. Since the vdW coefficients per atom rapidly increase with system size [41] , due to the nonadditivity arising from \u03c0-electron delocalization, while their centerto-center distance d cc does not change much, the binding energy between C-PAHs scales up rapidly, as shown in Fig. 1(b) . A similar energy scaling law is also observed for boron-nitride (BN) substitues [42] for the same reason, as shown in Table I and Fig. 1(b) , respectively. From Table II , we see that our energy scaling law predicts the same binding energy 30 meV/atom between two identical long-chain limits of PAH and BN-PAH (AA stacking). Note that this limit is physically different from a bi-layer of infinite two-dimentional sheets.", "cite_spans": [{"start": 226, "end": 230, "text": "[37]", "ref_id": "BIBREF37"}, {"start": 315, "end": 319, "text": "[38]", "ref_id": "BIBREF38"}, {"start": 320, "end": 324, "text": "[39]", "ref_id": "BIBREF39"}, {"start": 325, "end": 329, "text": "[40]", "ref_id": "BIBREF40"}, {"start": 826, "end": 830, "text": "[41]", "ref_id": "BIBREF41"}, {"start": 1119, "end": 1123, "text": "[42]", "ref_id": "BIBREF42"}], "ref_spans": [{"start": 388, "end": 397, "text": "Table II.", "ref_id": "TABREF0"}, {"start": 632, "end": 639, "text": "Table I", "ref_id": "TABREF0"}, {"start": 1027, "end": 1036, "text": "Fig. 1(b)", "ref_id": "FIGREF0"}, {"start": 1157, "end": 1164, "text": "Table I", "ref_id": "TABREF0"}, {"start": 1169, "end": 1178, "text": "Fig. 1(b)", "ref_id": "FIGREF0"}, {"start": 1200, "end": 1208, "text": "Table II", "ref_id": "TABREF0"}]}, {"section": "III. BINDING-ENERGY SCALING LAW FOR NANOSTRUCTURES", "text": "Tube-to-tube interaction. Carbon nanotubes (CNTs) are perhaps one of the most-widely studied nanomaterials, due to their many unusual properties and applications [43] . Study of their energy scaling law is of broad interest. A C-NT has cylindrical symmetry. It is characterized by a pair of integer parameters (n, m), with radius given by ( \u221a 3a/2\u03c0) \u221a n 2 + m 2 + nm, with a being the bond length. When n = m, it takes the armchair structure, while for n = m, it takes the zigzag structure. Their size can be adjusted with n or m. Here we focus on the binding energies per atom of the optimized closepacked solids of infinitely-long armchair C-NTs. /N (in meV/atom) of fullerenes in fcc solids, and of pairs of other identical nanoparticles: C-PAHs and BN-PAHs, C-NTs and BN-NTs, and carbon and BN nanowires with system size, and center-tocenter (dcc) and wall-to-wall (dww) distances (\u00c5). We extrapolated experimental binding energies [34] at 850 K to 0 K for fullerenes, except for C60, which was already extrapolated to 0 K, by estimating the thermal correction per atom from the thermal heat capacity of C70 [34] and then making the same correction per atom from C70 to the experimental values for fullerenes C76 [35] and C84 [34] . Experimental center-to-center distances are from Ref. [36] . All dcc between wires are fixed at 4.21\u00c5. tube size for the AA stacking at the optimized geometry. From Fig. 1 (c), we observe that when the size of C-NT increases from (3, 3) to (40, 40) , the binding energy per atom drops significantly from 44.3 meV/atom to 11.9 meV/atom. Table I shows that the wall-to-wall distance d ww is nearly a constant with tube size, while the center-to-center distance d cc dramatically increases, a situation similar to fullerene. This largely decreases the vdW force, due to the fact that the nonadditivity of vdW coefficients is unable to cancel that of the vdW radii for C-NT pairs, leading to the decreasing trend of the binding energy with tube size. Clearly, this trend has been followed by BN-NTs as shown in Fig. 1 (c) and Table I. However, the binding energy for BN-NTs is slightly smaller than that for C-NTs. A possible explanation is that, because C-NTs and BN-NTs take structures similar to those of their bulks (the BN layered materials), the BN atoms in BN-NTs may not be all on the same surface, as they are for C-NTs. This will increase the band gap (5.5 eV) [44] of BN-NT (a situation similar to h-BN [45] ) and thus decrease the vdW coefficients between BN-NTs, compared to C-NTs, as shown in Table III . The energy scaling law in Table II predicts the binding energies of 12.8 meV for C-NT, and 12.0 meV for BN-NT with AA stacking in the large size limit, which are rather close to 11.5 meV/atom for graphene (quantum Monte Carlo value) [46] and 9.9 meV/atom of h-BN [47] .", "cite_spans": [{"start": 162, "end": 166, "text": "[43]", "ref_id": "BIBREF43"}, {"start": 936, "end": 940, "text": "[34]", "ref_id": "BIBREF34"}, {"start": 1112, "end": 1116, "text": "[34]", "ref_id": "BIBREF34"}, {"start": 1217, "end": 1221, "text": "[35]", "ref_id": "BIBREF35"}, {"start": 1230, "end": 1234, "text": "[34]", "ref_id": "BIBREF34"}, {"start": 1291, "end": 1295, "text": "[36]", "ref_id": "BIBREF36"}, {"start": 1467, "end": 1470, "text": "(3,", "ref_id": "BIBREF2"}, {"start": 1471, "end": 1473, "text": "3)", "ref_id": "BIBREF2"}, {"start": 1477, "end": 1481, "text": "(40,", "ref_id": "BIBREF40"}, {"start": 1482, "end": 1485, "text": "40)", "ref_id": "BIBREF40"}, {"start": 2404, "end": 2408, "text": "[44]", "ref_id": "BIBREF44"}, {"start": 2447, "end": 2451, "text": "[45]", "ref_id": "BIBREF45"}, {"start": 2785, "end": 2789, "text": "[46]", "ref_id": "BIBREF46"}, {"start": 2815, "end": 2819, "text": "[47]", "ref_id": "BIBREF47"}], "ref_spans": [{"start": 1402, "end": 1408, "text": "Fig. 1", "ref_id": "FIGREF0"}, {"start": 1573, "end": 1580, "text": "Table I", "ref_id": "TABREF0"}, {"start": 2044, "end": 2050, "text": "Fig. 1", "ref_id": "FIGREF0"}, {"start": 2540, "end": 2549, "text": "Table III", "ref_id": "TABREF0"}, {"start": 2578, "end": 2586, "text": "Table II", "ref_id": "TABREF0"}]}, {"section": "III. BINDING-ENERGY SCALING LAW FOR NANOSTRUCTURES", "text": "Wire-to-wire interaction. Carbyne is a carbonbased nanowire (C-NW) with an infinite chain of sphybridized carbon atoms, held together by either double or alternating single and triple atomic bonds. It displays unusual properties, such as strong chemical activity and extreme instability in ambient conditions. C-NW and its BN substitute (BN-NW) have attracted great attention recently [7, [48] [49] [50] , due to a variety of remarkable properties. Here we study the variation of binding energy per atom between two AA-stacked finite-length C-NWs with system size. Due to the instability of C-NW, the binding energy is calculated at a fixed distance between two C-NWs, rather than at the relaxed distance (see Computational Methods for detail). As shown by Fig. 1(d) , the binding energy per atom between C-NWs decreases with system size. This is rather similar to those of fullerenes and nanotubes, but with much stronger size-dependence. It is also opposite to the energy scaling law of PAHs. This feature has been inherited by its BN substitute. However, the binding energy between BN-NWs is slightly stronger, due to the additional permanent dipole-dipole interaction between B and N atoms, a similar situation to BN-PAHs. In the large-size limit, the binding energy (16 meV/atom) between C-NWs becomes slightly larger than that (15.2 meV/atom) between BN-NWs, suggesting that crossover arising from the distortion of BN atoms occurs somewhere.", "cite_spans": [{"start": 385, "end": 388, "text": "[7,", "ref_id": "BIBREF7"}, {"start": 389, "end": 393, "text": "[48]", "ref_id": "BIBREF48"}, {"start": 394, "end": 398, "text": "[49]", "ref_id": "BIBREF49"}, {"start": 399, "end": 403, "text": "[50]", "ref_id": "BIBREF50"}], "ref_spans": [{"start": 757, "end": 766, "text": "Fig. 1(d)", "ref_id": "FIGREF0"}]}, {"section": "IV. DISCUSSION", "text": "To understand the energy scaling law of nanostructures, knowledge of the vdW coefficients is essential. Due to the direct relevance of the vdW coefficients to the static multipole polarizability, and in view of the relatively large size of the nanostructures, our starting point is the classical conducting solid or hollow sphere model, which is exact for slowly-varying densities. In this model, the static multipole polarizability satisfies [20] ", "cite_spans": [{"start": 443, "end": 447, "text": "[20]", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "IV. DISCUSSION", "text": "where l is the order of the polarizability, with l = 1 (dipole), 2 (quadrupole), 3 (octupole), etc. (The dipole polarizability of a fullerene can be estimated [26] from", "cite_spans": [{"start": 159, "end": 163, "text": "[26]", "ref_id": "BIBREF26"}], "ref_spans": []}, {"section": "IV. DISCUSSION", "text": ", where R N is the average radius of the nuclear framework of a fullerene, and t is the effective thickness of the shell.) Suppose the sphere contains N i identical atoms with the static multipole polarizability \u03b1 i l (0). Now let the volume of the sphere increase from V i to V f with fixed electron density, so that N i will increase to N f . We seek interpolation relating the multipole polarizabilities at N i and N f , the endpoints of the range over which we know \u03b1 l (0). The dipole polarizability per atom at N i can be written as \u03b1", "cite_spans": [], "ref_spans": []}, {"section": "IV. DISCUSSION", "text": ". If \u03b4 1 = 0, the dipole polarizability is additive. Otherwise, it is nonadditive [51] . Similarly, the higher-order polarizabilities can be written as", "cite_spans": [{"start": 82, "end": 86, "text": "[51]", "ref_id": "BIBREF51"}], "ref_spans": []}, {"section": "IV. DISCUSSION", "text": "where \u03b4 l is a measure of nonadditivity of the multipole polarizability. Substituting Eq. (2) into Eq. (3) and performing some simple algebra, we can express the nonadditivity of the multipole polarizability in terms of that of the dipole polarizability as", "cite_spans": [], "ref_spans": []}, {"section": "IV. DISCUSSION", "text": "The last term of Eq. (4) is the size correction to the nonadditivity of the higher-order multipole polarizability. It vanishes for l = 1 (dipole), and in the classical limit (N f \u2192 \u221e). When the dipole polarizability is additive (i.e., \u03b4 1 = 0), we can still observe the strong nonadditivity of the higher-order multipole polarizability (i.e., \u03b4 l > 0). Therefore, the nonadditivity of the higher-order multipole polarizability is an intrinsic property of a material. For any N i < N < N f , we just replace N f by N in Eq. (4). For the smallest possible data set N i = N f , our formulas would predict \u03b4 l = 0. In other words, the multipole polarizability at a single point N cannot deliver the physical nonadditivity. In order to identify the physical nonadditivity in which the initial value should be taken from an atom [24] , we need the multipole polarizability at N or N f that is reasonably larger than N i . The scaling properties for the static multipole polarizabilities of various nanostructures are given by Table III. [The dipole polarizabilities [52] of nanotubes are taken from Refs. [27] [28] [29] [30] [31] , while the higher-order polarizabilities are estimated from Eq. (2) .] With the scaling properties of the static multipole polarizability, we can study the nonadditivity of the vdW interactions. The vdW coefficients between two identical solid spheres, each having N atoms, take the simple form [24] ", "cite_spans": [{"start": 823, "end": 827, "text": "[24]", "ref_id": "BIBREF24"}, {"start": 1060, "end": 1064, "text": "[52]", "ref_id": "BIBREF52"}, {"start": 1099, "end": 1103, "text": "[27]", "ref_id": "BIBREF27"}, {"start": 1104, "end": 1108, "text": "[28]", "ref_id": "BIBREF28"}, {"start": 1109, "end": 1113, "text": "[29]", "ref_id": "BIBREF29"}, {"start": 1114, "end": 1118, "text": "[30]", "ref_id": "BIBREF30"}, {"start": 1119, "end": 1123, "text": "[31]", "ref_id": "BIBREF31"}, {"start": 1189, "end": 1192, "text": "(2)", "ref_id": "BIBREF1"}, {"start": 1420, "end": 1424, "text": "[24]", "ref_id": "BIBREF24"}], "ref_spans": [{"start": 1020, "end": 1030, "text": "Table III.", "ref_id": "TABREF0"}]}, {"section": "IV. DISCUSSION", "text": "Her\u0113 n is the average valence electron density of the sphere, and h 6 -h 10 are functions ofn determined by the CasimirPolder formula. Our calculation shows thatn is nearly a constant with system size, so that the nonadditivity of vdW coefficients is essentially determined by the nonadditivity of the static multipole polarizability. According to Eqs. (2)- (4), we can express the nonadditivity of the vdW coefficients as", "cite_spans": [], "ref_spans": []}, {"section": "IV. DISCUSSION", "text": "If \u03b4 1 = 0 or the dipole polarizability is additive, so is C 6 . Similarly, we have (4)- (6), we can see that the nonadditivity of the vdW coefficients (2\u03b4 1 for C 6 , \u03b4 1 + \u03b4 2 for C 8 , and \u03b4 1 + \u03b4 3 for C 10 ) largely arises from that of the multipole polarizability. If C 6 is additive, C 8 and C 10 are still nonadditive, because, even if \u03b4 1 = 0, \u03b4 2 and \u03b4 3 are not zero. This finding suggests that the nonadditivity of higher-order vdW coefficients essentially originates from the intrinsic nonadditivity of the multipole polarizability. The scaling properties for the vdW coefficients between nanostructures are also listed in Table III .", "cite_spans": [], "ref_spans": [{"start": 636, "end": 645, "text": "Table III", "ref_id": "TABREF0"}]}, {"section": "IV. DISCUSSION", "text": "With knowledge of the nonadditivity of vdW coefficients, we can now explain the energy scaling law for fullerenes as follows. Let us consider the interaction between two identical classical solid spheres that are close enough [54] . Each sphere has a radius of R = [\u03b1 1 (0)] 1/3 . The vdW coefficients are", "cite_spans": [{"start": 226, "end": 230, "text": "[54]", "ref_id": "BIBREF54"}], "ref_spans": []}, {"section": "IV. DISCUSSION", "text": "This yields", "cite_spans": [], "ref_spans": []}, {"section": "IV. DISCUSSION", "text": "When the spheres are close to each other, all energy terms of the vdW series are independent of R or system size. This nonadditivity cancellation is valid for both solid spheres and hollow spheres with a cavity, because our analysis for solid spheres is also valid for hollow spheres. To demonstrate this cancellation, we have calculated the energy series C 6 /d 6 , C 8 /d 8 and C 10 /d 10 for fullerene solids, with d = d cc given in Table I . Our calculation shows that both the leading-order and higher-order energy terms are nearly size-independent. However, it was found [54] that this series diverges when two identical classical conducting spheres touch, but this spurious divergence can be removed without changing the asymptotic series. Nevertheless, the binding energy per atom ([C 2j /(2R) 2j ]/N ) is decreasing with N , as shown by Fig.  1(a) .", "cite_spans": [{"start": 577, "end": 581, "text": "[54]", "ref_id": "BIBREF54"}], "ref_spans": [{"start": 436, "end": 443, "text": "Table I", "ref_id": "TABREF0"}, {"start": 846, "end": 856, "text": "Fig.  1(a)", "ref_id": "FIGREF0"}]}, {"section": "IV. DISCUSSION", "text": "The physics behind the energy scaling law is now clear. The behavior observed in Fig 1(a)-1(d) is a consequence of a competition between the nonadditivities in the vdW coefficients and in the vdW radii, which are saturated to the bulk values. For ball-ball interactions, there is large cancellation between C 2j and (2R) 2j , leading to a rather slow variation of the binding energy per atom with system size. For plane-plane interactions, the nonadditivity of vdW coefficients is dominant, because the parallel distance d cc is nearly a constant, leading to significant increase in binding energy. For tube-tube interactions, the nonadditivity of vdW coefficients becomes relatively less important due to the much larger size of tubes, compared to that of fullerenes, leading to a faster variation of the binding energy per atom with system size than that between fullerenes. There is a difference between BN atoms in BN-PAH and BN-NT. The reason is that BN atoms of BN-PAH can form \u03c0-electron delocalization, as in C-PAH. However, as in bulk h-BN, BN atoms of BN-NT can not, because both BN-NT and bulk h-BN have large gaps [44, 45] . This difference in bonding explains why the binding energy of BN-PAHs is greater than that of C-PAHs, but the binding energy for BN-NTs is slightly smaller than that for C-NTs. From BN-NW to h-BN bulk material, we can see that the energy gap evolves from a small value (nanowire) to a larger value 5.5 eV (BN-NT), to a even larger value 5.9 ev (h-BN), suggesting the deformation of B atoms from the surface of N atoms and thus a change in energy scaling law from nanowires to nanotubes. Due to the \u03c0-electron delocal-ization, the difference in binding energy scaling between C-PAH and BN-PAH is the same as that between C-NW and BN-NW: BN-based PAHs and BN-based nanowires show faster energy variation with system size than Cbased counterparts. The binding energy per atom of the nanowire dimers may decrease with increasing length due to dilution of the effect of covalent bonding between C atoms at the ends of the dimer.", "cite_spans": [{"start": 1126, "end": 1130, "text": "[44,", "ref_id": "BIBREF44"}, {"start": 1131, "end": 1134, "text": "45]", "ref_id": "BIBREF45"}], "ref_spans": [{"start": 81, "end": 94, "text": "Fig 1(a)-1(d)", "ref_id": "FIGREF0"}]}, {"section": "V. CONCLUSION", "text": "The binding energy determines the stability of nanostructures and is therefore very important in the study of nanostructures. However, it has presented computational challenges. In this work, we have studied the binding energy law of nanostructures based on a first-principles method. We find that there is a binding-energy scaling law between identical nanostructures. From the law, we can predict the binding energy at any structure size. We illustrate this finding with fullerenes, PAHs, nanotubes, and nanowires. Apart from fullerenes, we chose AA stacking in our study. From the energy scaling law, we predict finite large-size limits, which are expected. To understand the energy-scaling law, we have studied the vdW coefficients using the accurate hollow-sphere model within the SFA. We find that the energy scaling law is determined by two competing factors: Nonadditivities of the vdW coefficients and the center-to-center distance. This leads us to conclude that the energy-scaling law in part originates from the nonadditivity of the static multipole polarizability of nanostructures.", "cite_spans": [], "ref_spans": []}, {"section": "VI. ACKNOWLEDGEMENTS", "text": "The authors thank Mark R. ", "cite_spans": [], "ref_spans": []}, {"section": "APPENDICES Appendix A: vdW-DF-cx characterization of Fullerenes", "text": "Here we will show that the vdW-DF-cx functional predicts the geometries of fullerene solids in agreement with what is known experimentally about them. Other evidence for the accuracy of vdW-DF-cx is presented in Appendix B and in Refs. [22, 39, [55] [56] [57] [58] [59] [60] [61] . Figure A1 shows the atom structure of C 60 and the high-symmetry axis (dark gray line) going out of a pair of hexagonal facets; C 60 also has a secondary axis (light gray line) going through a pair of pentagonal facets. The initial coordinates of C 60 , C 70 , C 76 , and C 80 fullerenes are taken from the supplemental material of Ref. [62] . C 60 and C 70 have I h and D 5 symmetry, respectively. Since C 76 , and C 80 have isomers, here we focus on C 76 and C 80 with D 2 symmetry. A1: vdW-DF-cx results for primitive-cell lattice structures when permitting unconstrained unit-cell relaxations. They are all slightly distorted fcc as reflected in the lattice constants (a, b, c) and unit-cell solid angles (\u03b1, \u03b2, \u03b3).", "cite_spans": [{"start": 236, "end": 240, "text": "[22,", "ref_id": "BIBREF22"}, {"start": 241, "end": 244, "text": "39,", "ref_id": "BIBREF39"}, {"start": 250, "end": 254, "text": "[56]", "ref_id": "BIBREF56"}, {"start": 255, "end": 259, "text": "[57]", "ref_id": "BIBREF57"}, {"start": 260, "end": 264, "text": "[58]", "ref_id": "BIBREF58"}, {"start": 265, "end": 269, "text": "[59]", "ref_id": "BIBREF59"}, {"start": 270, "end": 274, "text": "[60]", "ref_id": "BIBREF60"}, {"start": 275, "end": 279, "text": "[61]", "ref_id": "BIBREF61"}, {"start": 619, "end": 623, "text": "[62]", "ref_id": "BIBREF62"}], "ref_spans": [{"start": 282, "end": 291, "text": "Figure A1", "ref_id": "FIGREF0"}]}, {"section": "Molecule", "text": "Lattice system Panel (a) of Fig. A2 shows the primitive (one molecule) and super-cell (four molecules) geometries that we have used to model the fullerene crystals, as illustrated with C 60 . We assume that fullerenes are in crystal structures that are variations of fcc. Cohesive energies are extracted for (super-cell) geometries that have been fully relaxed with the consistent-exchange vdW-DF-cx version, using the BFGS quasi-newton algorithm as available in variable-cell calculations ('vc-relax') with the quantum espresso package. We find no observable deformation of the individual fullerenes in any of the approximateground-state crystals structures that we have studied. Table A1 reports the details of fully unrestrained vdW-DF-cx charactization of the optimal structure of fullerenes, when forced into a primitive cell (panel (a) of Fig. A2 ). Unconstrained relaxation was chosen, because we do not, except for the C 60 crystal, have access to experimental information about alignment of fullerene symmetry axis and of the fullerene crystal. This vdW-DF-cx characterization yielded the following identification of the nature of optimal structures: triclinic (rhombohedral) crystal symmetry for C 60 and C 84 (for C 70 and C 76 ). From these structures, we extracted the vdW-DFcx results for the sublimation energies E b and for the wall-to-wall separations d ww (estimated as the distance to the nearest vertex or bond or facet on one molecule to the corresponding motif on the neighboring molecules). These results have been reported in the main text.", "cite_spans": [], "ref_spans": []}, {"section": "Molecule", "text": "The C 60 crystal motivates further theoretical characterizations because there is experimental data on structure [63] . We note that while our unconstrained relaxation (modeling a primitive cell) predicts a triclinic structure, the actual structure deviation is small (see Table  A1 ). This difference is, in fact, expected. The ground state should have two different alignments of the symmetry axis relative to the crystal directions [63] . In choosing a primitive modeling, we are, on principle grounds, prevented from fully representing the actual C 60 crystal ground state.", "cite_spans": [{"start": 113, "end": 117, "text": "[63]", "ref_id": "BIBREF63"}, {"start": 435, "end": 439, "text": "[63]", "ref_id": "BIBREF63"}], "ref_spans": []}, {"section": "Molecule", "text": "For a deeper discussion, we consider the role of the molecular orientation in the C 60 crystal both in a primitive cell containing one molecule and in an improved modeling relying on 4 molecules per unit cell; the second modeling approach is illustrated in panel (b) of Fig. A2 . The C 60 crystal undergoes a phase transition at 260K. Above that temperature, all molecules can be considered equivalent, having free rotations, in a fcc primitive cell with one C 60 molecule. Below this temperature, however, the C 60 crystal is still fcc, but then in a super-cell configuration of unknown size. There is no free rotation but a forced alignment of the major symmetry axis with the [111] direction of the fcc crystal cell. One can experimentally assign a rotational-angle value, \u03c6, for molecules in the low-temperature systems [63] . However, the alignment must vary over the fcc-type super cell (of unknown size) which has a mixture of alignments: 15 % molecules in a rotational configuration R38 and about 85 % in R98. Figure A3 summarizes the additional structure exploration that we have done to test the ability of vdW-DF-cx to characterize the structural motifs of the C 60 ground state. The figure shows the sublimation-energy variation that results in a single-molecule unit-cell modeling as we vary the alignment of the major symmetry axis with the [111] crystal axis, all in an fcc structure; since the major axis has a three-fold symmetry, it is only necessary to explore constrained relaxations in the range 0 < \u03c6 < 120. Tracking the relaxations in vdW-DF-cx, we thus identify a set of meta-stable configurations, red dots, with specific rotations but with a range of structural symmetries, as further described in Table A2 . This class of metastable fcc structures differs qualitatively from the TABLE A2: Geometries and binding energies of meta-stable C60 crystals as optimized in vdW-DF-cx with constraints. Here, for the single-molecule cell, we force the major C60 symmetry axis to be aligned with the crystal axis and identify meta-stable configurations, denoted Fm3 R\u03c6", "cite_spans": [{"start": 824, "end": 828, "text": "[63]", "ref_id": "BIBREF63"}], "ref_spans": [{"start": 1018, "end": 1027, "text": "Figure A3", "ref_id": "FIGREF4"}]}, {"section": "Molecule", "text": "\u2022 (red dots in Fig. A3 ), with specific rotation \u03c6 values. For the 4-molecule conventionnal unit cell studies, we list all meta-stable configurations that we have found emerging from a fcc starting point while permitting all four rotational angles to differ. The low-energy structure, 'Fm3 R0", "cite_spans": [], "ref_spans": [{"start": 15, "end": 22, "text": "Fig. A3", "ref_id": "FIGREF4"}]}, {"section": "Molecule", "text": "\u2022 ', has the same value for all four angles. The low-energy structure 'Fm3 mix' is short for a four-molecule super cell in rotational configuration R9", "cite_spans": [], "ref_spans": []}, {"section": "Molecule", "text": "\u2022 previously mentioned C 60 triclinic structure, which, instead, has an alignment with the secondary symmetry axis in C 60 . However, as we show later, the energy differences are very small. The dashed line in the left panel of Fig. (A3) represents a guide to the eye among those meta-stable configurations. We assume that a full exploration would stabilize major-axis configurations at more rotational values, when pursued at a super-cell size that reflects the actual ground state. If we furthermore take the dashed line as an approximation for how such additional local minima would be distributed in energies, then we can expect optimal rotational values at around \u03c6 \u2248 40", "cite_spans": [], "ref_spans": [{"start": 228, "end": 237, "text": "Fig. (A3)", "ref_id": "FIGREF4"}]}, {"section": "Molecule", "text": "\u2022 and \u03c6 \u2248 100", "cite_spans": [], "ref_spans": []}, {"section": "Molecule", "text": "\u2022 . It is heartening that these angles coincide with those that emerge as most prevalent in the mixture description obtained in the experimental characterization of C 60 , evident as vertical blue lines in Fig. A3 . Table A2 also reveals that structural optimization in the super cell indicates a very small preference for mixing different molecular rotations. Here again the relaxation is constrained to the experimentally observed major-axis alignment. In a super cell, however, we can allow individual molecules to relax to different orientation values. The structure identified as 'Fm3 mix' is an example of an energetically favorable such meta-stable configuration. Like the actual but unknown ground-state super cell, [63] this structure is characterized by having a mixture of molecular rotations.", "cite_spans": [{"start": 724, "end": 728, "text": "[63]", "ref_id": "BIBREF63"}], "ref_spans": [{"start": 206, "end": 213, "text": "Fig. A3", "ref_id": "FIGREF4"}]}, {"section": "Molecule", "text": "Finally, Table A3 lists the sublimation energies that arises when the [111] crystal axis (red line) is assumed to align with either the major or the secondary symmetry axis for the C 60 crystal. For a single-molecule modeling, and among the cases with major-axis alignment, we find a best case, Fm3 R111", "cite_spans": [], "ref_spans": [{"start": 9, "end": 17, "text": "Table A3", "ref_id": "TABREF9"}]}, {"section": "Molecule", "text": "\u2022 , with a sublimation energy that lies with 0.1 meV/atom of that of the triclinic structure (with the secondary-axis alignment). Also, although the energy differences are still very small, the E b ordering is reversed when instead we consider the best four-molecule super celll case (with correct alignment), denoted 'Fm3 mix'.", "cite_spans": [], "ref_spans": []}, {"section": "Molecule", "text": "Overall, we find that the vdW-DF-cx is able to reflect the known structural motifs of the C 60 crystal (although the C\u221260 ground state is not fully known): (a) preference for a fcc-type super-cell configuration with a mixture of rotational angles, (b) a preference for having predominently a \u03c6 = 100", "cite_spans": [], "ref_spans": []}, {"section": "Molecule", "text": "\u2022 rotational state, and (c) a per-molecule volume value, which for the most-favorable super-cell representation, lies within 2 percent of the experimentally observed value, 692\u00c5", "cite_spans": [], "ref_spans": []}, {"section": "Molecule", "text": "3 . We take this vdW-DF-cx progress as an indication that it can be used to predict the binding structures of the set of investigated nano-structured materials and that it is a good starting point for exploring energy scaling laws.", "cite_spans": [], "ref_spans": []}, {"section": "Appendix B: Asymptotic binding in vdW-DF-cx", "text": "Here we will show that vdW-DF-cx predicts equilibrium binding energies of fullerene solids in agreement with experiment, even though, as anticipated in Ref. [20] it is not accurate for the asymptotic interaction of a fullerene pair.", "cite_spans": [{"start": 157, "end": 161, "text": "[20]", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "Appendix B: Asymptotic binding in vdW-DF-cx", "text": "We have extracted the C 6 values that correspond to an asymptotic vdW-DF-cx description, following prior discussions of the nature of the vdW-DF binding [12, 64] . For the finite fullerene structures, this leads to a determination of the C 6 coefficients using Eq. (5)- (7) of Ref. [33] . The following information is presented to permit a discussion of differences in the asymptotic description from the hollow-shell model [53] . ", "cite_spans": [{"start": 153, "end": 157, "text": "[12,", "ref_id": "BIBREF12"}, {"start": 158, "end": 161, "text": "64]", "ref_id": "BIBREF64"}, {"start": 282, "end": 286, "text": "[33]", "ref_id": "BIBREF33"}, {"start": 424, "end": 428, "text": "[53]", "ref_id": "BIBREF53"}], "ref_spans": []}, {"section": "Symmetry", "text": "Lattice system In the vdW-DF method, we work with a local-field susceptibility \u03b1 and corresponding external-field susceptibility \u03b1 ext = \u03b1/(1 + 4\u03c0\u03b1). This susceptibility (or plasmon propagator) depends on two spatial coordinates but can be represented in a gradient expansion. When investigating the asymptotic interactions, the relevant limit is [12, 64] :", "cite_spans": [{"start": 347, "end": 351, "text": "[12,", "ref_id": "BIBREF12"}, {"start": 352, "end": 355, "text": "64]", "ref_id": "BIBREF64"}], "ref_spans": []}, {"section": "Symmetry", "text": "This susceptibility limit is directly set by the inverse length scale q 0 that enters in the specification of the local plasmon dispersion [12, 14, 64] . We compute this susceptibility limit from the electron-density variation n(r) that we have established in the underlying (full) vdW-DF-cx calculations.", "cite_spans": [{"start": 139, "end": 143, "text": "[12,", "ref_id": "BIBREF12"}, {"start": 144, "end": 147, "text": "14,", "ref_id": "BIBREF14"}, {"start": 148, "end": 151, "text": "64]", "ref_id": "BIBREF64"}], "ref_spans": []}, {"section": "Symmetry", "text": "From the approximation Eq. (B1) we determine, in turn, the asymptotic vdW-DF-cx description of nanostructure interaction from a Casimir-Polder expression of the molecular C 6 coefficients, using a numerical imaginary-frequency integration. The result is a description similar to Eq. (17) of Ref. [12] . We note that this C 6 limit is not an exhaustive representation of the full, regular vdW-DF-cx calculations, for reasons explained in Refs. 12, 14, 33, 64. Table B1 reports our numerical extraction of such vdW-DF-cx based C 6 coefficients for fullerenes with various number of carbon atoms N , here contrasted with TDHF-based values cited in Table 3 of the main text. In general, the nonlocal-correlation part of vdW-DF [12] (same as in vdW-DF-cx) leads to good C 6 values for small-to-medium sized molecules [65] . However, for the hollow fullerenes, the vdW-DF-cx values are about half the size of the results of the shell-model analysis based on TDHF calculations [53] . Also, the vdW-DF-cx results for C 6 /N 2 is nearly independent of N . Thus the vdW-DF-cx descriptions does not reflect the C 6 nonadditivity that is expressed in the TDHF-based C 6 description [53] and hollow-sphere model.", "cite_spans": [{"start": 296, "end": 300, "text": "[12]", "ref_id": "BIBREF12"}, {"start": 723, "end": 727, "text": "[12]", "ref_id": "BIBREF12"}, {"start": 812, "end": 816, "text": "[65]", "ref_id": "BIBREF65"}, {"start": 970, "end": 974, "text": "[53]", "ref_id": "BIBREF53"}, {"start": 1170, "end": 1174, "text": "[53]", "ref_id": "BIBREF53"}], "ref_spans": []}, {"section": "Symmetry", "text": "The vdW-DF-cx functional slightly overestimates the nanostructure binding energies E b , but it is still useful for mapping the energy scaling as it is accurate on structure characterizations (Appendix A and Refs. [8, 39, 56, 59] ), as well as for nanostructure energy differences [8, 22, 57, 59] . Table B1 also reports a comparison of the vdW-DFcx results for fullerene sublimation energies E b and raw experimental observations (no thermal correction); Table  I reports the comparison when the finite-temperature effect is removed from the experimental values.", "cite_spans": [{"start": 214, "end": 217, "text": "[8,", "ref_id": "BIBREF8"}, {"start": 218, "end": 221, "text": "39,", "ref_id": "BIBREF39"}, {"start": 222, "end": 225, "text": "56,", "ref_id": "BIBREF56"}, {"start": 226, "end": 229, "text": "59]", "ref_id": "BIBREF59"}, {"start": 281, "end": 284, "text": "[8,", "ref_id": "BIBREF8"}, {"start": 285, "end": 288, "text": "22,", "ref_id": "BIBREF22"}, {"start": 289, "end": 292, "text": "57,", "ref_id": "BIBREF57"}, {"start": 293, "end": 296, "text": "59]", "ref_id": "BIBREF59"}], "ref_spans": [{"start": 456, "end": 464, "text": "Table  I", "ref_id": "TABREF0"}]}, {"section": "Symmetry", "text": "For the C-PAH dimers in the sandwich or AA configuration, CCSD(T)-based best estimates of the binding energy per atom for benzene, naphthalene, and anthracene [66] [22] . Thus vdW-DF-cx captures the right trends with increasing particle size (being in these cases about 4 meV per carbon atom higher than the best available estimates).", "cite_spans": [{"start": 159, "end": 163, "text": "[66]", "ref_id": "BIBREF66"}, {"start": 164, "end": 168, "text": "[22]", "ref_id": "BIBREF22"}], "ref_spans": []}, {"section": "Symmetry", "text": "Moreover, vdW-DF-cx is accurate in first-principle characterizations of nanostructure-energy differences. It has proven useful for the description of both elastic deformations energies [8, 55, 58, 60] and lattice vibrations [57] [58] [59] [60] . For example, it can accurately reproduce the measurement of all all libration modes in the naphthalene molecular crystal, characterizing the phonon dispersion to within 1 meV (without any experimental input on the molecular-crystal structure) [60] . Some of us have previously (independently) discussed that it is possible for a density functional to fail in the asymptotic description but still be accurate at binding separations [14, 21] . The vdW-DF-cx description of the fullerene crystals gives in example: Appendix A shows that vdW-DF-cx does give an accurate description of structural motifs in fullerene crystals at binding separation even if vdW-DF-cx is not accurate for (and does not give nonadditive) C 6 coefficients, Table B1 . We also note that the vdW-DF-cx is nonadditive in a different sense, namely in its description of the nonlocal correlation interaction at binding separations [67] .", "cite_spans": [{"start": 185, "end": 188, "text": "[8,", "ref_id": "BIBREF8"}, {"start": 193, "end": 196, "text": "58,", "ref_id": "BIBREF58"}, {"start": 197, "end": 200, "text": "60]", "ref_id": "BIBREF60"}, {"start": 224, "end": 228, "text": "[57]", "ref_id": "BIBREF57"}, {"start": 229, "end": 233, "text": "[58]", "ref_id": "BIBREF58"}, {"start": 234, "end": 238, "text": "[59]", "ref_id": "BIBREF59"}, {"start": 239, "end": 243, "text": "[60]", "ref_id": "BIBREF60"}, {"start": 489, "end": 493, "text": "[60]", "ref_id": "BIBREF60"}, {"start": 677, "end": 681, "text": "[14,", "ref_id": "BIBREF14"}, {"start": 682, "end": 685, "text": "21]", "ref_id": "BIBREF21"}, {"start": 1146, "end": 1150, "text": "[67]", "ref_id": "BIBREF67"}], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "A Bridge across Disciplines", "authors": [{"first": "P", "middle": [], "last": "Jena", "suffix": ""}, {"first": "A", "middle": ["W"], "last": "Castleman", "suffix": ""}], "year": 2010, "venue": "", "link": null}, "BIBREF1": {"title": "van der Waals Interactions between Nanotubes and Nanoparticles for Controlled Assembly of Composite Nanostructures", "authors": [{"first": "G", "middle": [], "last": "Rance", "suffix": ""}, {"first": "D", "middle": [], "last": "Marsh", "suffix": ""}, {"first": "S", "middle": [], "last": "Bourne", "suffix": ""}, {"first": "T", "middle": [], "last": "Reade", "suffix": ""}, {"first": "A", "middle": [], "last": "Khlobystov", "suffix": ""}], "year": 2010, "venue": "ACS Nano", "link": "29585496"}, "BIBREF2": {"title": "Macroscale adhesion of gecko setae reflects nanoscale differences in subsurface composition", "authors": [{"first": "P", "middle": [], "last": "Loskill", "suffix": ""}, {"first": "J", "middle": [], "last": "Puthoff", "suffix": ""}, {"first": "M", "middle": [], "last": "Wilkinson", "suffix": ""}, {"first": "K", "middle": [], "last": "Mecke", "suffix": ""}, {"first": "K", "middle": [], "last": "Jacobs", "suffix": ""}, {"first": "K", "middle": [], "last": "Autumn", "suffix": ""}], "year": 2013, "venue": "J. R. Soc. Interface", "link": "11736801"}, "BIBREF3": {"title": "Ultra Long-Range Interactions between Large Area Graphene and Silicon", "authors": [{"first": "S", "middle": ["R"], "last": "Na", "suffix": ""}, {"first": "J", "middle": ["W"], "last": "Suk", "suffix": ""}, {"first": "R", "middle": ["S"], "last": "Ruoff", "suffix": ""}, {"first": "R", "middle": [], "last": "Huang", "suffix": ""}, {"first": "K", "middle": ["M"], "last": "Liechti", "suffix": ""}], "year": 2014, "venue": "ACS Nano", "link": "11669901"}, "BIBREF4": {"title": "van der Waals Screening by Single-Layer Graphene and Molybdenum Disulfide", "authors": [{"first": "S", "middle": [], "last": "Tsoi", "suffix": ""}, {"first": "P", "middle": [], "last": "Dev", "suffix": ""}, {"first": "A", "middle": ["L"], "last": "Friedman", "suffix": ""}, {"first": "R", "middle": [], "last": "Stine", "suffix": ""}, {"first": "J", "middle": ["T"], "last": "Robinson", "suffix": ""}, {"first": "T", "middle": ["L"], "last": "Reinecke", "suffix": ""}, {"first": "P", "middle": ["E"], "last": "Sheehan", "suffix": ""}], "year": 2014, "venue": "ACS Nano", "link": "26019933"}, "BIBREF6": {"title": "Van der Waals interactions and the limits of isolated atom models at interfaces", "authors": [{"first": "", "middle": [], "last": "Meyer", "suffix": ""}], "year": 2016, "venue": "Nat. Commun", "link": "215655917"}, "BIBREF7": {"title": "Wavelike charge density fluctuations and van der Waals interactions at the nanoscale", "authors": [{"first": "A", "middle": [], "last": "Ambrosetti", "suffix": ""}, {"first": "N", "middle": [], "last": "Ferri", "suffix": ""}, {"first": "R", "middle": ["A"], "last": "Distasio", "suffix": ""}, {"first": "A", "middle": [], "last": "Tkatchenko", "suffix": ""}], "year": 2016, "venue": "Science", "link": "10346436"}, "BIBREF8": {"title": "Exchange functional that tests the robustness of the plasmon description of the van der Waals density functional", "authors": [{"first": "K", "middle": [], "last": "Berland", "suffix": ""}, {"first": "P", "middle": [], "last": "Hyldgaard", "suffix": ""}], "year": 2014, "venue": "Phys. Rev. B", "link": "16384643"}, "BIBREF9": {"title": "Cohesive Properties and Asymptotics of the Dispersion Interaction in Graphite by the Random Phase Approximation", "authors": [{"first": "S", "middle": [], "last": "Leb\u00e8gue", "suffix": ""}, {"first": "J", "middle": [], "last": "Harl", "suffix": ""}, {"first": "T", "middle": [], "last": "Gould", "suffix": ""}, {"first": "J", "middle": ["G"], "last": "\u00c1ngya", "suffix": ""}, {"first": "G", "middle": [], "last": "Kresse", "suffix": ""}, {"first": "J", "middle": ["F"], "last": "Dobson", "suffix": ""}], "year": 2010, "venue": "Phys. Rev. Lett", "link": "8742148"}, "BIBREF10": {"title": "Asymptotics of the Dispersion Interaction: Analytic Benchmarks for van der Waals Energy Functionals", "authors": [{"first": "J", "middle": ["F"], "last": "Dobson", "suffix": ""}, {"first": "A", "middle": [], "last": "White", "suffix": ""}, {"first": "A", "middle": [], "last": "Rubio", "suffix": ""}], "year": 2006, "venue": "Phys. Rev. Lett", "link": "31092090"}, "BIBREF11": {"title": "Quantum ESPRESSO: a modular and open-source software project for quantum simulations of materials", "authors": [{"first": "P", "middle": [], "last": "Giannozzi", "suffix": ""}], "year": 2009, "venue": "J. Phys.:Condens.Matter", "link": "5846317"}, "BIBREF12": {"title": "Van der Waals density functional for general geometries", "authors": [{"first": "M", "middle": [], "last": "Dion", "suffix": ""}, {"first": "H", "middle": [], "last": "Rydberg", "suffix": ""}, {"first": "E", "middle": [], "last": "Schr\u00f6der", "suffix": ""}, {"first": "D", "middle": ["C"], "last": "Langreth", "suffix": ""}, {"first": "B", "middle": ["I"], "last": "Lundqvist", "suffix": ""}], "year": 2004, "venue": "Phys. Rev. Lett", "link": "6604518"}, "BIBREF13": {"title": "Accurate density functionals:Approaches using the adiabatic-connection fluctuation-dissipation theorem", "authors": [{"first": "M", "middle": [], "last": "Fuchs", "suffix": ""}, {"first": "X", "middle": [], "last": "Gonze", "suffix": ""}], "year": 2002, "venue": "Phys. Rev. B", "link": "122286696"}, "BIBREF14": {"title": "Interpretation of van der Waals density functionals", "authors": [{"first": "P", "middle": [], "last": "Hyldgaard", "suffix": ""}, {"first": "K", "middle": [], "last": "Berland", "suffix": ""}, {"first": "E", "middle": [], "last": "Schr\u00f6der", "suffix": ""}], "year": 2014, "venue": "Phys. Rev. B", "link": "29097610"}, "BIBREF15": {"title": "A post-Hartree-Fock model of intermolecular interactions: Inclusion of higherorder corrections", "authors": [{"first": "E", "middle": ["R"], "last": "Johnson", "suffix": ""}, {"first": "A", "middle": ["D"], "last": "Becke", "suffix": ""}], "year": 2006, "venue": "J. Chem. Phys", "link": "27950110"}, "BIBREF16": {"title": "A benchmark for non-covalent interactions in solids", "authors": [{"first": "A", "middle": [], "last": "Otero-De-La-Roza", "suffix": ""}, {"first": "E", "middle": ["R"], "last": "Johnson", "suffix": ""}], "year": 2012, "venue": "J. Chem. Phys", "link": "2759753"}, "BIBREF17": {"title": "Dispersion corrected Hartree-Fock and density functional theory for organic structure prediction", "authors": [{"first": "J", "middle": ["G"], "last": "Brandenburg", "suffix": ""}, {"first": "S", "middle": [], "last": "Grimme", "suffix": ""}], "year": 2014, "venue": "Top Curr. Chem", "link": "27211088"}, "BIBREF18": {"title": "Physical adsorption: Theory of van der Waals interactions between particles and clean surfaces", "authors": [{"first": "J", "middle": [], "last": "Tao", "suffix": ""}, {"first": "A", "middle": ["M"], "last": "Rappe", "suffix": ""}], "year": 2014, "venue": "Phys. Rev. Lett", "link": "6224200"}, "BIBREF19": {"title": "Dynamical screening of van der Waals interactions in nanostructured solids: Sublimation of fullerenes", "authors": [{"first": "J", "middle": [], "last": "Tao", "suffix": ""}, {"first": "J", "middle": [], "last": "Yang", "suffix": ""}, {"first": "A", "middle": ["M"], "last": "Rappe", "suffix": ""}], "year": 2015, "venue": "J. Chem. Phys", "link": "708575"}, "BIBREF20": {"title": "Pitarke, van der Waals coefficients for nanostructures: Fullerenes defy conventional wisdom", "authors": [{"first": "A", "middle": [], "last": "Ruzsinszky", "suffix": ""}, {"first": "J", "middle": ["P"], "last": "Perdew", "suffix": ""}, {"first": "J", "middle": [], "last": "Tao", "suffix": ""}, {"first": "G", "middle": ["I"], "last": "Csonka", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "", "suffix": ""}], "year": 2012, "venue": "Phys. Rev. Lett", "link": "21114512"}, "BIBREF21": {"title": "Versatile van der Waals Density Functional Based on a MetaGeneralized Gradient Approximation", "authors": [{"first": "H", "middle": [], "last": "Peng", "suffix": ""}, {"first": "Z.-H", "middle": [], "last": "Yang", "suffix": ""}, {"first": "J", "middle": [], "last": "Sun", "suffix": ""}, {"first": "J", "middle": ["P"], "last": "Perdew", "suffix": ""}], "year": 2016, "venue": "Phys. Rev. X", "link": "37676793"}, "BIBREF22": {"title": "Spin signature of nonlocal correlation bonding in metal-organic frameworks", "authors": [{"first": "T", "middle": [], "last": "Thonhauser", "suffix": ""}, {"first": "S", "middle": [], "last": "Zuluaga", "suffix": ""}, {"first": "C", "middle": ["A"], "last": "Arter", "suffix": ""}, {"first": "K", "middle": [], "last": "Berland", "suffix": ""}, {"first": "E", "middle": [], "last": "Schr\u00f6der", "suffix": ""}, {"first": "P", "middle": [], "last": "Hyldgaard", "suffix": ""}], "year": 2015, "venue": "Phys. Rev. Lett", "link": null}, "BIBREF23": {"title": "Accurate higher-order van der Waals coefficients between molecules from a model dynamic multipole polarizability", "authors": [{"first": "J", "middle": [], "last": "Tao", "suffix": ""}, {"first": "A", "middle": ["M"], "last": "Rappe", "suffix": ""}], "year": 2016, "venue": "J. Chem. Phys. (Communication", "link": null}, "BIBREF24": {"title": "Non-additivity of van der Waals interactions between nanostructures", "authors": [{"first": "J", "middle": [], "last": "Tao", "suffix": ""}, {"first": "J", "middle": ["P"], "last": "Perdew", "suffix": ""}], "year": 2014, "venue": "J. Chem. Phys. (Communication)", "link": null}, "BIBREF25": {"title": "Accurate van der Waals coefficients between fullerenes and fullerenealkali atoms and clusters: Modified single-frequency approximation", "authors": [{"first": "J", "middle": [], "last": "Tao", "suffix": ""}, {"first": "Y", "middle": [], "last": "Mo", "suffix": ""}, {"first": "G", "middle": [], "last": "Tian", "suffix": ""}, {"first": "A", "middle": [], "last": "Ruzsinszky", "suffix": ""}], "year": 2016, "venue": "Phys. Rev. B", "link": "73631939"}, "BIBREF26": {"title": "Quantum Size Effects in the Polarizability of Carbon Fullerenes", "authors": [{"first": "G", "middle": ["K"], "last": "Gueorguiev", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Pacheco", "suffix": ""}, {"first": "D", "middle": [], "last": "Tom\u00e1nek", "suffix": ""}], "year": 2004, "venue": "Phys. Rev. Lett", "link": "15147775"}, "BIBREF27": {"title": "Static Dielectric Properties of Carbon Nanotubes from First Principles", "authors": [{"first": "B", "middle": [], "last": "Kozinsky", "suffix": ""}, {"first": "N", "middle": [], "last": "Marzari", "suffix": ""}], "year": 2006, "venue": "Phys. Rev. Lett", "link": "44468225"}, "BIBREF28": {"title": "Static polarizability of carbon nanotubes: ab initio independent-particle calculations", "authors": [{"first": "G", "middle": ["Y"], "last": "Guo", "suffix": ""}, {"first": "K", "middle": ["C"], "last": "Chu", "suffix": ""}, {"first": "D.-S", "middle": [], "last": "Wang", "suffix": ""}, {"first": "C.-G", "middle": [], "last": "Duan", "suffix": ""}], "year": 2004, "venue": "Comput. Materials Sci", "link": "95322944"}, "BIBREF29": {"title": "Polarizability and hyperpolarizability of BN zigzag nanotubes calculated by the coupled perturbed Kohn-Sham scheme", "authors": [{"first": "M", "middle": [], "last": "Ferrabone", "suffix": ""}, {"first": "B", "middle": [], "last": "Kirtman", "suffix": ""}, {"first": "M", "middle": [], "last": "R\u00e9rat", "suffix": ""}, {"first": "R", "middle": [], "last": "Orlando", "suffix": ""}, {"first": "R", "middle": [], "last": "Dovesi", "suffix": ""}], "year": 2011, "venue": "Phys. Rev. B", "link": null}, "BIBREF30": {"title": "Static dielectric response and Born effective charge of BN nanotubes from ab initio finite electric field calculations", "authors": [{"first": "G", "middle": ["Y"], "last": "Guo", "suffix": ""}, {"first": "S", "middle": [], "last": "Ishibashi", "suffix": ""}, {"first": "T", "middle": [], "last": "Tamura", "suffix": ""}, {"first": "K", "middle": [], "last": "Terakura", "suffix": ""}], "year": 2007, "venue": "Phys. Rev. B", "link": null}, "BIBREF31": {"title": "Static and Optical Transverse and Longitudinal Screened Polarizabilities of Boron Nitride Nanotubes", "authors": [{"first": "L", "middle": [], "last": "Wang", "suffix": ""}, {"first": "J", "middle": [], "last": "Lu", "suffix": ""}, {"first": "L", "middle": [], "last": "Lai", "suffix": ""}, {"first": "W", "middle": [], "last": "Song", "suffix": ""}, {"first": "M", "middle": [], "last": "Ni", "suffix": ""}, {"first": "Z", "middle": [], "last": "Gao", "suffix": ""}, {"first": "W", "middle": ["N"], "last": "Mei", "suffix": ""}], "year": 2007, "venue": "J. Phys. Chem. C", "link": "98000873"}, "BIBREF32": {"title": "Ablative and Flame-Retardant Properties of Fullerenes. Perspectives of Fullerene Nanotechnology", "authors": [{"first": "R", "middle": [], "last": "Loutfy", "suffix": ""}, {"first": "E", "middle": [], "last": "Wexler", "suffix": ""}], "year": 2002, "venue": "Part VII", "link": null}, "BIBREF33": {"title": "Van der Waals density functional calculations of binding in molecular crystals", "authors": [{"first": "K", "middle": [], "last": "Berland", "suffix": ""}, {"first": "\u00d8", "middle": [], "last": "Borck", "suffix": ""}, {"first": "P", "middle": [], "last": "Hyldgaard", "suffix": ""}], "year": 2011, "venue": "Comput. Phys. Commun", "link": "1403269"}, "BIBREF34": {"title": "Sublimation of Higher Fullerenes and Their Interaction with Silicon (100) Surface", "authors": [{"first": "M", "middle": [], "last": "Moalem", "suffix": ""}, {"first": "A", "middle": ["V"], "last": "Balooch", "suffix": ""}, {"first": "R", "middle": ["S"], "last": "Hamza", "suffix": ""}, {"first": "", "middle": [], "last": "Ruoff", "suffix": ""}], "year": 1995, "venue": "J. Phys. Chem", "link": "94474013"}, "BIBREF35": {"title": "Some Thermodynamic Properties of C76 and C84", "authors": [{"first": "B", "middle": [], "last": "Brunetti", "suffix": ""}, {"first": "G", "middle": [], "last": "Gigli", "suffix": ""}, {"first": "E", "middle": [], "last": "Giglio", "suffix": ""}, {"first": "V", "middle": [], "last": "Piacente", "suffix": ""}, {"first": "P", "middle": [], "last": "Scardala", "suffix": ""}], "year": 1997, "venue": "J. Phys. Chem. B", "link": "97826107"}, "BIBREF36": {"title": "Interfullerene Interaction and Properties of Fullerites", "authors": [{"first": "M", "middle": ["N"], "last": "Magomedov", "suffix": ""}], "year": 2005, "venue": "High Temp. (USSR)", "link": "120518947"}, "BIBREF37": {"title": "A Review on Polycyclic Aromatic Hydrocarbon (PAH) Emissions from Energy Generation", "authors": [{"first": "A", "middle": ["M"], "last": "Mastral", "suffix": ""}, {"first": "M", "middle": ["S"], "last": "Call\u00e9n", "suffix": ""}], "year": 2000, "venue": "Environ. Sci. Technol", "link": "13666713"}, "BIBREF38": {"title": "Binding of polycyclic aromatic hydrocarbons and graphene dimers in density functional theory", "authors": [{"first": "S", "middle": ["D"], "last": "Chakarova-K\u00e4ck", "suffix": ""}, {"first": "A", "middle": [], "last": "Vojvodic", "suffix": ""}, {"first": "J", "middle": [], "last": "Kleis", "suffix": ""}, {"first": "P", "middle": [], "last": "Hyldgaard", "suffix": ""}, {"first": "E", "middle": [], "last": "Schr\u00f6der", "suffix": ""}], "year": 2010, "venue": "New J. of Phys", "link": "56472906"}, "BIBREF39": {"title": "Structural and excited-state properties of oligoacene crystals from first principles", "authors": [{"first": "T", "middle": [], "last": "Rangel", "suffix": ""}, {"first": "K", "middle": [], "last": "Berland", "suffix": ""}, {"first": "S", "middle": [], "last": "Sharifzadeh", "suffix": ""}, {"first": "F", "middle": [], "last": "Brownaltvater", "suffix": ""}, {"first": "K", "middle": [], "last": "Lee", "suffix": ""}, {"first": "P", "middle": [], "last": "Hyldgaard", "suffix": ""}, {"first": "L", "middle": [], "last": "Kronik", "suffix": ""}, {"first": "J", "middle": ["B"], "last": "Neaton", "suffix": ""}], "year": 2016, "venue": "Phys. Rev. B", "link": "17250749"}, "BIBREF40": {"title": "Interactions of graphene sheets deduced from properties of polycyclic aromatic hydrocarbons", "authors": [{"first": "R", "middle": [], "last": "Podeszwa", "suffix": ""}], "year": 2010, "venue": "J. Chem. Phys", "link": "23605311"}, "BIBREF41": {"title": "Efficient calculation of van der Waals dispersion coefficients with time-dependent density functional theory in real time: Application to polycyclic aromatic hydrocarbons", "authors": [{"first": "M", "middle": ["A L"], "last": "Marques", "suffix": ""}, {"first": "A", "middle": [], "last": "Castro", "suffix": ""}, {"first": "G", "middle": [], "last": "Malloci", "suffix": ""}, {"first": "G", "middle": [], "last": "Mulas", "suffix": ""}, {"first": "S", "middle": [], "last": "Botti", "suffix": ""}], "year": 2007, "venue": "J. Chem. Phys", "link": "20120112"}, "BIBREF42": {"title": "Synthesis, Properties, and Ceramic Conversion Reactions of Polyborazylene: A High-Yield Polymeric Precursor to Boron Nitride", "authors": [{"first": "P", "middle": ["J"], "last": "Fazen", "suffix": ""}, {"first": "E", "middle": ["E"], "last": "Remsen", "suffix": ""}, {"first": "J", "middle": ["S"], "last": "Beck", "suffix": ""}, {"first": "P", "middle": ["J"], "last": "Carroll", "suffix": ""}, {"first": "A", "middle": ["R"], "last": "Mcghie", "suffix": ""}, {"first": "L", "middle": ["G"], "last": "Sneddon", "suffix": ""}], "year": 1995, "venue": "Chem. Mat", "link": "102054481"}, "BIBREF43": {"title": "Controlled synthesis of singlechirality carbon nanotubes", "authors": [{"first": "J", "middle": ["R"], "last": "Sanchez-Valencia", "suffix": ""}, {"first": "T", "middle": [], "last": "Dienel", "suffix": ""}, {"first": "O", "middle": [], "last": "Gr\u00f6ning", "suffix": ""}, {"first": "I", "middle": [], "last": "Shorubalko", "suffix": ""}, {"first": "A", "middle": [], "last": "Mueller", "suffix": ""}, {"first": "M", "middle": [], "last": "Jansen", "suffix": ""}, {"first": "K", "middle": [], "last": "Amsharov", "suffix": ""}, {"first": "P", "middle": [], "last": "Ruffieux", "suffix": ""}, {"first": "R", "middle": [], "last": "Fasel", "suffix": ""}], "year": 2014, "venue": "Nature", "link": null}, "BIBREF44": {"title": "Stability and Band Gap Constancy of Boron Nitride Nanotubes", "authors": [{"first": "X", "middle": [], "last": "Blase", "suffix": ""}, {"first": "A", "middle": [], "last": "Rubio", "suffix": ""}, {"first": "S", "middle": ["G"], "last": "Louie", "suffix": ""}, {"first": "M", "middle": ["L"], "last": "Cohen", "suffix": ""}], "year": 1994, "venue": "Europhys. Lett", "link": "120010610"}, "BIBREF45": {"title": "Hexagonal boron nitride is an indirect bandgap semiconductor", "authors": [{"first": "G", "middle": [], "last": "Cassabois", "suffix": ""}, {"first": "P", "middle": [], "last": "Valvin", "suffix": ""}, {"first": "B", "middle": [], "last": "Gil", "suffix": ""}], "year": 2016, "venue": "Nat. Photonics", "link": "30762889"}, "BIBREF46": {"title": "Quantum Monte Carlo Calculation of the Binding Energy of Bilayer Graphene", "authors": [{"first": "E", "middle": [], "last": "Mostaani", "suffix": ""}, {"first": "N", "middle": ["D"], "last": "Drummond", "suffix": ""}, {"first": "V", "middle": ["I"], "last": "", "suffix": ""}], "year": 2015, "venue": "Phys. Rev. Lett", "link": "33986700"}, "BIBREF47": {"title": "Stacking in Bulk and Bilayer Hexagonal Boron Nitride", "authors": [{"first": "G", "middle": [], "last": "Constantinescu", "suffix": ""}, {"first": "A", "middle": [], "last": "Kuc", "suffix": ""}, {"first": "T", "middle": [], "last": "Heine", "suffix": ""}], "year": 2013, "venue": "Phys. Rev. Lett", "link": "46463971"}, "BIBREF48": {"title": "Confined linear carbon chains as a route to bulk carbyne", "authors": [{"first": "L", "middle": [], "last": "Shi", "suffix": ""}, {"first": "P", "middle": [], "last": "Rohringer", "suffix": ""}, {"first": "K", "middle": [], "last": "Suenaga", "suffix": ""}, {"first": "Y", "middle": [], "last": "Niimi", "suffix": ""}, {"first": "J", "middle": [], "last": "Kotakoski", "suffix": ""}, {"first": "J", "middle": ["C"], "last": "Meyer", "suffix": ""}, {"first": "H", "middle": [], "last": "Peterlik", "suffix": ""}, {"first": "M", "middle": [], "last": "Wanko", "suffix": ""}, {"first": "S", "middle": [], "last": "Cahangirov", "suffix": ""}, {"first": "A", "middle": [], "last": "Rubio", "suffix": ""}, {"first": "Z", "middle": ["J"], "last": "Lapin", "suffix": ""}, {"first": "L", "middle": [], "last": "Novotny", "suffix": ""}, {"first": "P", "middle": [], "last": "Ayala", "suffix": ""}, {"first": "T", "middle": [], "last": "Pichler", "suffix": ""}], "year": 2016, "venue": "Nat. Materials", "link": "205413206"}, "BIBREF49": {"title": "Yakobson, Carbyne from First Principles: Chain of C Atoms, a Nanorod or a Nanorope", "authors": [{"first": "M", "middle": [], "last": "Liu", "suffix": ""}, {"first": "V", "middle": ["I"], "last": "Artyukhov", "suffix": ""}, {"first": "H", "middle": [], "last": "Lee", "suffix": ""}, {"first": "F", "middle": [], "last": "Xu", "suffix": ""}, {"first": "B", "middle": ["I"], "last": "", "suffix": ""}], "year": 2013, "venue": "ACS Nano", "link": null}, "BIBREF50": {"title": "Experimental Observation of Boron Nitride Chains", "authors": [{"first": "O", "middle": [], "last": "Cretu", "suffix": ""}, {"first": "H.-P", "middle": [], "last": "Komsa", "suffix": ""}, {"first": "O", "middle": [], "last": "Lehtinen", "suffix": ""}, {"first": "G", "middle": [], "last": "Algara-Siller", "suffix": ""}, {"first": "U", "middle": [], "last": "Kaiser", "suffix": ""}, {"first": "K", "middle": [], "last": "Suenaga", "suffix": ""}, {"first": "A", "middle": ["V"], "last": "Krasheninnikov", "suffix": ""}], "year": 2014, "venue": "ACS Nano", "link": "12481144"}, "BIBREF51": {"title": "Accurate and Efficient Method for Many-Body van der Waals Interactions", "authors": [{"first": "A", "middle": [], "last": "Tkatchenko", "suffix": ""}, {"first": "R", "middle": ["A"], "last": "Distasio", "suffix": ""}, {"first": "R", "middle": [], "last": "Car", "suffix": ""}, {"first": "M", "middle": [], "last": "Scheffler", "suffix": ""}], "year": 2012, "venue": "Phys. Rev. Lett", "link": "23507672"}, "BIBREF52": {"title": "Density-functionalbased linear and nonlinear polarizabilities of fullerene and benzene molecules", "authors": [{"first": "A", "middle": ["A"], "last": "Quong", "suffix": ""}, {"first": "M", "middle": ["R"], "last": "Pederson", "suffix": ""}], "year": 1992, "venue": "Phys. Rev. B", "link": "11706442"}, "BIBREF53": {"title": "Non-additivity of polarizabilities and van der Waals C6 coefficients of fullerenes", "authors": [{"first": "J", "middle": [], "last": "Kauczor", "suffix": ""}, {"first": "P", "middle": [], "last": "Norman", "suffix": ""}, {"first": "W", "middle": ["A"], "last": "Saidi", "suffix": ""}], "year": 2013, "venue": "J. Chem. Phys", "link": "27293770"}, "BIBREF54": {"title": "Csonka, van der Waals interaction as a summable asymptotic series", "authors": [{"first": "J", "middle": ["P"], "last": "Perdew", "suffix": ""}, {"first": "A", "middle": [], "last": "Ruzsinszky", "suffix": ""}, {"first": "J", "middle": [], "last": "Sun", "suffix": ""}, {"first": "S", "middle": [], "last": "Glindmeyer", "suffix": ""}, {"first": "G", "middle": ["I"], "last": "", "suffix": ""}], "year": 2012, "venue": "Phys. Rev. A", "link": null}, "BIBREF56": {"title": "Testing several recent van der Waals density functionals for layered structures", "authors": [{"first": "T", "middle": [], "last": "Bj\u00f6rkman", "suffix": ""}], "year": 2014, "venue": "J. Chem. Phys", "link": "9629474"}, "BIBREF57": {"title": "Ab initio phonon dispersion in crystalline naphthalene using van der Waals density functionals", "authors": [{"first": "F", "middle": [], "last": "Brown-Altvater", "suffix": ""}, {"first": "T", "middle": [], "last": "Rangel", "suffix": ""}, {"first": "J", "middle": ["B"], "last": "Neaton", "suffix": ""}], "year": 2016, "venue": "Phys. Rev. B", "link": "124224572"}, "BIBREF58": {"title": "Microscopic origin of thermal conductivity reduction in disordered van der Waals solids", "authors": [{"first": "P", "middle": [], "last": "Erhart", "suffix": ""}, {"first": "P", "middle": [], "last": "Hyldgaard", "suffix": ""}, {"first": "D", "middle": ["O"], "last": "Lindroth", "suffix": ""}], "year": 2015, "venue": "Chem Mater", "link": "94039815"}, "BIBREF59": {"title": "Thermal transport in van der Waals solids from first-principles calculations", "authors": [{"first": "D", "middle": ["O"], "last": "Lindroth", "suffix": ""}, {"first": "P", "middle": [], "last": "Erhart", "suffix": ""}], "year": 2016, "venue": "Phys. Rev. B", "link": null}, "BIBREF60": {"title": "Finitetemperature properties of non-magnetic transition metals: Comparison of the performance of constraint-based semi and nonlocal functionals", "authors": [{"first": "L", "middle": [], "last": "Gharaee", "suffix": ""}, {"first": "P", "middle": [], "last": "Erhart", "suffix": ""}, {"first": "P", "middle": [], "last": "Hyldgaard", "suffix": ""}], "year": 2017, "venue": "Phys. Rev. B", "link": "54212237"}, "BIBREF61": {"title": "Assessment of two hybrid van der Waals density functionals for covalent and noncovalent binding of molecules", "authors": [{"first": "K", "middle": [], "last": "Berland", "suffix": ""}, {"first": "Y", "middle": [], "last": "Jiao", "suffix": ""}, {"first": "J.-H", "middle": [], "last": "Lee", "suffix": ""}, {"first": "T", "middle": [], "last": "Rangel", "suffix": ""}, {"first": "J", "middle": ["B"], "last": "Neaton", "suffix": ""}, {"first": "P", "middle": [], "last": "Hyldgaard", "suffix": ""}], "year": 2017, "venue": "J. Chem. Phys", "link": "41029138"}, "BIBREF62": {"title": "Guide through the nanocarbon jungle", "authors": [{"first": "D", "middle": [], "last": "Tom\u00e1nek", "suffix": ""}], "year": 2014, "venue": "", "link": "108995829"}, "BIBREF63": {"title": "Structural Phase Transitions in the Fullerene C60. EPL", "authors": [{"first": "W", "middle": ["I F"], "last": "David", "suffix": ""}, {"first": "R", "middle": ["M"], "last": "Ibberson", "suffix": ""}, {"first": "T", "middle": ["J S"], "last": "Dennis", "suffix": ""}, {"first": "J", "middle": ["P"], "last": "Hare", "suffix": ""}, {"first": "K", "middle": [], "last": "Prassides", "suffix": ""}], "year": 1992, "venue": "", "link": "123115877"}, "BIBREF64": {"title": "Nature and strength of bonding in a crystal of semiconducting nanotubes: van der Waals density functional calculations and analytical results", "authors": [{"first": "J", "middle": [], "last": "Kleis", "suffix": ""}, {"first": "E", "middle": [], "last": "Schr\u00f6der", "suffix": ""}, {"first": "P", "middle": [], "last": "Hyldgaard", "suffix": ""}], "year": 2008, "venue": "Phys. Rev. B", "link": "1215802"}, "BIBREF65": {"title": "Dispersion interactions from a local polarizability model", "authors": [{"first": "O", "middle": ["A"], "last": "Vydrov", "suffix": ""}, {"first": "T", "middle": [], "last": "Van Voorhis", "suffix": ""}], "year": 2010, "venue": "Phys. Rev. A", "link": "12172225"}, "BIBREF66": {"title": "Pi-pi stacking stacking between polyaromatic hydrocarbon sheets beyond dispersion interactions", "authors": [{"first": "N", "middle": ["J"], "last": "Silva", "suffix": ""}, {"first": "F", "middle": ["B C"], "last": "Machado", "suffix": ""}, {"first": "H", "middle": [], "last": "Lischka", "suffix": ""}, {"first": "A", "middle": ["J A"], "last": "Aquino", "suffix": ""}], "year": 2016, "venue": "Phys. Chem. Chem. Phys", "link": "5569437"}, "BIBREF67": {"title": "Signatures of van der Waals binding: a coupling-constant scaling analysis, submitted to", "authors": [{"first": "Y", "middle": [], "last": "Jiao", "suffix": ""}, {"first": "E", "middle": [], "last": "Schr\u00f6der", "suffix": ""}, {"first": "P", "middle": [], "last": "Hyldgaard", "suffix": ""}], "year": 2017, "venue": "Phys. Rev. B", "link": null}}, "ref_entries": {"FIGREF0": {"text": "FIG. 1: Binding-energy scaling law (in meV/atom) of fullerenes in fcc solids (Panel (a)), and of pairs of other identical nanoparticles: C-PAHs and BN-PAHs in AA stacking dimers (Panel (b)), C-NTs and BN-NTs in AA stacking solids (Panel (c)), as well as carbon nanowires (C-NWs) and boron-nitride substitutes (BN-NWs) in AA stacking dimers (Panel (d)), with system size. N on the vertical axis is the total number of C/B/N atoms in a nanostructure. The dotted curve (yellow for carbon and green for BN) is the analytic modeling from Table II.", "type": "figure"}, "FIGREF1": {"text": "c) shows the variation of binding energy per atom with", "type": "figure"}, "FIGREF2": {"text": "\u03b4 l are given by Eq. (4). (Note that \u03b4 1 + \u03b4 3 = 2\u03b4 2 .) From Eqs.", "type": "figure"}, "FIGREF3": {"text": "FIG. A1: The atomic configuration of C60 as seen perpendicular to (left panel) and along (right panel) the major symmetry axis, shown as a dark gray line in the left panel. The atomic configurations of C70, C76 and C80 fullerenes are shown as inserts in Fig. 1a of the main text. The major symmetry axis of C60 goes through a pair of hexagonal facets and it is experimentally found to be aligned with the [111] direction of the C60 fcc crystal, below 260 K [63]. The C60 molecule also has a secondary symmetry line (lighter gray line in both panels) which goes though a pair of pentagonal facets.", "type": "figure"}, "FIGREF4": {"text": "FIG. A3: Schematic of our test of vdW-DF-cx reliability in describing the internal C60 structural organization. These tests use a one-molecule cell, but track the role of different rotations \u03c6 of the C60 around the major symmetry axis. Panel (a) shows vdW-DF-cx results for the energy variation of such states, denoted R\u03c6; The pair of vertical blue lines identifies the two experimentally observed, optimal rotational states that are both found in the ground state [63]. Panel (b) contrasts the atomic structure having such alignment of the [111] crystal axis with the major (black atoms and bonds) against that of alignment with the minor (gray atoms and bonds) symmetry axis.", "type": "figure"}, "FIGREF5": {"text": "are 13.2, 17.8, and 21.1 meV per carbon atom, versus the vdW-DF-cx values of 17.4, 22.4, and 25.0 meV per carbon atom, respectively. For the corre- sponding benzene, naphthalene, and anthracene molecu-lar crystals, the measured supplimation energies are 22, 41, and 40 meV per carbon atom, versus the vdW-DF- cx values of 25, 46, and 44 meV per carbon atom", "type": "figure"}, "TABREF0": {"text": "Variation of binding energies per atom E b", "type": "table"}, "TABREF2": {"text": "Binding-energy scaling law (", "type": "table"}, "TABREF3": {"text": "for nanos- tructured materials, where the parameters characterized by specific nanostructures are determined by a fit to numerical binding energies in Table I.", "type": "table"}, "TABREF4": {"text": "structures, and the vdW coefficients between identical pairs. N is the number of atoms in a nanostructure. For NTs, it represents the number of atoms per unit length (\u00c5). The static dipole polarizability and C6 for fullerenes are the ab initio values taken from Ref. [53], while the higher-order static polarizabilities and vdW coefficients are calculated in this work. For nanotubes, the static dipole polarizabilities are the ab initio values taken from the literature [27-31], while all others are obtained in this work.", "type": "table"}, "TABREF5": {"text": "Pederson and Roberto Car for valuable comments and suggestions, Jing Yang, Guo- cai Tian, and Haowei Peng for useful discussions and technical help, and Hong Tang for useful comments. YM acknowledges support from the NSF under Grant No. CHE 1640584. JT was supported by the DOE under grant No. de-sc0018194. JT was also supported on Tem- ple start-up from John P. Perdew. YJ and PH acknowl- edge support by the Swedish Research Council (VR) and the Swedish Research Foundation (SSF) under contract SE13-0016. ZY and JPP were supported by the NSF un- der Grant No. DMR-1607868. ZY was also supported by Science Challenge Project No. TZ2016003 (China). JXZ acknowledges the support by the Center for Integrated Nanotechnologies, a DOE BES user facility. Computa- tional support was provided by the HPC at Temple Uni- versity and by the Swedish National Infrastructure for Computing through allocations at HPC2N (Ume\u00e5) and C3SE (Gothenburg).", "type": "table"}, "TABREF6": {"text": "", "type": "table"}, "TABREF9": {"text": "Comparison of geometries and binding energies of C60 crystals in metastable cubic/rhombohedral structures (in which the [111] crystal axis is kept aligned with major symmetry axis) and in alternative triclinic structures (in which [111] is found to be aligned with the secondary C60 symmetry axis). The former is a characteristics of the experimentally observed ground state, while the latter is what emerges in unconstrained relaxations in the one-molecule primitive cell.", "type": "table"}, "TABREF10": {"text": "Rhombohedral 14.07/14.07/14.07 90.4/90.4/90.TABLE B1: Asymptotic van der Waals interaction coefficients C6 and molecular-crystal sublimation (or cohesion) energies E b for fullerenes. The van der Waals interaction coefficients are in atomic units (hartree for energy, bohr for distances) while E b is reported in meV per carbon atom. The vdW-DF-cx results for E b are listed for the primitive (one fullerene per) cell studies (see Appendix A). The experimental results [34, 35] are enthalpies of sublimation without thermal corrections.", "type": "table"}}}
{"paper_id": "118861869", "_pdf_hash": "d344d01aba273593b7730c41ba3b5d193efd5720", "abstract": [{"section": "Abstract", "text": "An eccentric nuclear disk consists of stars moving on apsidally-aligned orbits around a central black hole. The secular gravitational torques that dynamically stabilize these disks can also produce tidal disruption events (TDEs) at very high rates in Newtonian gravity. General relativity, however, is known to quench secular torques via rapid apsidal precession.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Here we show that for a disk to black hole mass ratio of M disk /M \u2022 10 \u22123 , the system is in the full loss cone regime. The magnitude of the torque per orbital period acting on a stellar orbit means that general relativistic precession does not have a major effect on the dynamics. Thus we find that TDE rates from eccentric nuclear disks are not affected by general relativistic precession. Furthermore, we show that orbital elements between successive TDEs from eccentric nuclear disks are correlated, potentially resulting in unique observational signatures.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "INTRODUCTION", "text": "A tidal disruption event (TDE) occurs when a star is violently ripped apart by a black hole's tidal forces (Hills 1975) . When a star is tidally disrupted, roughly half of the stellar debris remains bound to the black hole while the other half of the debris escapes. The gravitationally bound debris forms an accretion disk which feeds the black hole, producing a flare (Rees 1988) . The current detection rate of flares from TDEs is about two per year (van Velzen 2018) and this is expected to increase with new surveys such as the Large Synoptic Survey Telescope (LSST) (van Velzen et al. 2011) .", "cite_spans": [], "ref_spans": []}, {"section": "INTRODUCTION", "text": "TDE flares can provide insight into the mysteries of many areas of astrophysics. They illuminate central black holes in otherwise quiescent galaxies (Maksym et al. 2013; MacLeod et al. 2014) . We can use their observations to test theories of accretion physics and relativistic jets (Zauderer et al. 2011; Bloom et al. 2011; van Velzen et al. 2016; Alexander 2017) . Tidal disruptions of white dwarfs should even produce gravitational waves detectable by the Light Interferometer Space Antenna (LISA) (MacLeod et al. 2014) . Additionally, we can test our understanding of gravitational stellar dynamics near supermassive black holes by comparing theoretical TDE rates with observations. heather.wernke@colorado.edu", "cite_spans": [], "ref_spans": []}, {"section": "Loss cone dynamics", "text": "The rate of TDEs due to stellar two-body relaxation has been studied extensively (Frank & Rees 1976; Lightman & Shapiro 1977; Shapiro & Marchant 1978; Cohn & Kulsrud 1978; Stone & Metzger 2016) . Two-body relaxation is the diffusive process by which stars exchange energy and angular momentum amongst themselves, sometimes scattering a star onto a tidally disrupting orbit. It is faster to reach such an orbit by diffusion in angular momentum than in energy (Frank & Rees 1976) .", "cite_spans": [], "ref_spans": []}, {"section": "Loss cone dynamics", "text": "In order for a star in these systems to get close enough to the supermassive black hole (SMBH) to tidally disrupt, it must enter the loss cone. The loss cone defines the region containing orbits with pericenters inside the tidal disruption radius of the black hole. The tidal disruption radius is:", "cite_spans": [], "ref_spans": []}, {"section": "Loss cone dynamics", "text": "where M \u2022 is the mass of the black hole, M * is the mass of the star, and R * is the radius of the star (Rees 1988) . Orbits within the loss cone have angular momenta less than the angular momentum of an orbit with a pericenter equal to the tidal radius,", "cite_spans": [], "ref_spans": []}, {"section": "Loss cone dynamics", "text": "There are two loss cone regimes, defined by the parameter q,", "cite_spans": [], "ref_spans": []}, {"section": "Loss cone dynamics", "text": "where \u2206J P is the change in angular momentum per orbital period (Lightman & Shapiro 1977) . If q 1, stars take multiple orbital periods to enter the loss cone. This is known as the empty loss cone regime or the diffusion limit because the time for a star to enter the loss cone is greater than the time for the star to be destroyed. If q 1, stars can jump into and out of the loss cone within one orbital period. This is known as the full loss cone regime or the pinhole limit, because the loss cone is continuously populated by stars. The division between the two loss cone regimes for a spherical nuclear star cluster lies close to the radius of influence of the black hole (Lightman & Shapiro 1977) . The TDE rate, in this case, is also dominated by stars coming from this region.", "cite_spans": [], "ref_spans": []}, {"section": "Status of observations of TDEs", "text": "In deriving theoretical TDE rates, we typically assume that stars come from an isotropic, spherical distribution around the black hole and are driven to the black hole through two-body relaxation (Wang & Merritt 2004; Stone & Metzger 2016) . Theoretical TDE rates in these spherical nuclear star clusters have been calculated to be 2.1 \u00d7 10 \u22124 yr \u22121 gal \u22121 (Wang & Merritt 2004) , and more recently 2.9 \u00d7 10 \u22125 yr \u22121 gal \u22121 (Stone & Metzger 2016) . In observations, however, TDEs are preferentially found in post-merger or post-starburst galaxies (K+A/E+A galaxies) at much higher rates. K+A/E+A galaxies are a relatively rare subtype of elliptical galaxy that underwent a major starburst about 1-1.5 Gyr ago (Couch & Sharples 1987; Poggianti 2004) . K+A/E+A galaxies make up 0.2% of the galaxies in the local universe, and yet, the observed TDE rates in these K+A/E+A galaxies are 1 \u2212 3 \u00d7 10 \u22123 yr \u22121 gal \u22121 , which pushes the observed TDE rate of 'normal' galaxies down to 1 \u2212 5 \u00d7 10 \u22126 yr \u22121 gal \u22121 (French et al. 2016 ). There is even (tentative) evidence that the TDE rate could be as high as 10 \u22121 yr \u22121 gal \u22121 in ultra-luminous infrared galaxies (ULIRGs), which are typically in the process of merging (Tadhunter et al. 2017; Dou et al. 2017) . We learn from these observations that merging galaxies and post-merger galaxies tend to have elevated TDE rates.", "cite_spans": [{"start": 733, "end": 748, "text": "Poggianti 2004)", "ref_id": "BIBREF32"}], "ref_spans": []}, {"section": "Status of observations of TDEs", "text": "Several dozen TDE candidates have been identified in the last two decades, from UV/optical to X-ray. TDE candidates are generally identified as flaring events, inconsistent with supernovae, at the centers of galaxies. Candidates are typically excluded if the host galaxy shows signs of AGN activity. There have been a number of alternative ideas to explain these flaring events at galactic centers. Proposed TDE impostors include supernovae in AGN disks and black hole accretion disk instabilities (Saxton et al. 2016) . One distinguishing feature that can be used to discriminate between real TDEs and impostors is the critical black hole mass beyond which a TDE will not be observable, known as the Hills mass (Hills 1975) . The Hills mass results from the fact that the tidal radius and Schwarzschild radius of a black hole scale differently with mass of the black hole. The Schwarzschild radius is given by", "cite_spans": [], "ref_spans": []}, {"section": "Status of observations of TDEs", "text": "where G is the gravitational constant and c is the speed of light. Equating the tidal radius to the Schwarzschild radius yields a Hills mass of \u223c10 8 M for a solar-type star. Above this limit, the star plunges into the black hole without emitting a flare. A rapidly spinning black hole can raise this limit to \u223c10 9 M (Kesden 2012). Recently, van Velzen (2018) presented the black hole mass function of optical/UV-selected TDE candidates and showed a sharp decrease in the number of candidates above M \u2022 = 10 7.5 M . This is consistent with the direct capture of stars when the black hole is above the Hills mass and provides strong evidence that we are seeing TDEs rather than impostors.", "cite_spans": [], "ref_spans": []}, {"section": "Secular dynamics and eccentric nuclear disks", "text": "Two-body relaxation is not the only form of relaxation present in galactic nuclei. Resonant relaxation 1 arises in nearKeplerian potentials (Rauch & Tremaine 1996) . A particle on a near-Keplerian orbit traces out the same path repeatedly. On a timescale less than the precession timescale, the orbits remain \u223cfixed, and exert mutual gravitational torques on each other. Thus, the angular momentum relaxation can be greatly enhanced, while the energy relaxation is unaffected (Rauch & Tremaine 1996) .", "cite_spans": [], "ref_spans": []}, {"section": "Secular dynamics and eccentric nuclear disks", "text": "Resonant relaxation is most effective for stars orbiting close to the central supermassive black hole (in the absence of general relativity). This means that in an isotropic, spherical stellar distribution, where TDEs come most often from near the radius of influence, resonant relaxation will not greatly increase the rate or number of TDEs (Rauch & Ingalls 1998) . Not all galactic nuclei, however, are \u223cspherical like our galactic center. The nucleus of our nearest galactic neighbor, Andromeda (M31), has a very different configuration.", "cite_spans": [], "ref_spans": []}, {"section": "Secular dynamics and eccentric nuclear disks", "text": "The Andromeda Galaxy (M31) has an elongated nucleus that resolves into two distinct brightness peaks. The doublenucleus can be explained by a thick, apsidally-aligned eccentric nuclear disk of Keplerian orbits around a SMBH (Tremaine 1995) . The two brightness peaks correspond to apoapsis and periapsis of the eccentric nuclear disk.", "cite_spans": [], "ref_spans": []}, {"section": "Secular dynamics and eccentric nuclear disks", "text": "While it may seem like the central disk in M31 is an unusual and unlikely arrangement, the fact that we see it in our closest major galaxy suggests that it is a common configuration. In fact, despite observational challenges, Lauer et al. (2005) found that about 20% of nearby, early-type galaxies have features consistent with eccentric nuclear disks seen from different angles on the sky.", "cite_spans": [], "ref_spans": []}, {"section": "TDEs from eccentric nuclear disks", "text": "The stability of eccentric nuclear disks has long been a mystery. One would expect that the apsidal precession of individual orbits would spread out the disk into an axisymmetric structure on a timescale much shorter than the age of the stars. In a recent paper (Madigan et al. 2018) , we proposed that the same secular mechanism that stabilizes eccentric nuclear disks is responsible for producing high rates of TDEs.", "cite_spans": [], "ref_spans": []}, {"section": "TDEs from eccentric nuclear disks", "text": "The forces that cause precession in eccentricity vectors also result in a build-up of gravitational torques between orbits. These torques change the eccentricities of individual orbits as they are perturbed ahead of, or behind, the disk. Differential precession driven by these eccentricity changes holds the disk together. The orbits in an eccentric nuclear disk undergo oscillations in eccentricity. During the high eccentricity phase of an oscillation, a star can be tidally disrupted as it moves through pericenter. The gravitational torques due to secular dynamics are much more efficient at refilling the loss cone than two-body relaxation, which has typically been used to determine TDE rates. We proposed that secular torques in eccentric nuclear disks can produce the observed high rate of TDEs in K+A/E+A galaxies (Madigan et al. 2018) . Hopkins & Quataert (2010a,b) show that eccentric nuclear disks can form via the merging of gas-rich galaxies, meaning that it would be likely to find eccentric nuclear disks in post-merger, K+A/E+A galaxies. TDE rates in eccentric nuclear disks could be as high as \u223c 1 yr \u22121 gal \u22121 at early times in the life of the disk (Madigan et al. 2018) .", "cite_spans": [], "ref_spans": []}, {"section": "TDEs from eccentric nuclear disks", "text": "Several other mechanisms have been theorized to explain the enhanced TDE rates in K+A/E+A galaxies. One of these theories is an enhanced rate due to SMBH binaries after the starburst. Chen et al. (2011) show that the TDE rate should scale weakly with the SMBH mass ratio. This would indicate that TDEs would be seen primarily after minor mergers, which are more common. TDEs are preferentially observed, however, in mergers with a more equal SMBH mass ratio, indicating that the TDE rate is not driven by SMBH binaries (French et al. 2017) . Another theory involves more dense spherical star clusters resulting in enhanced two-body relaxation Stone et al. 2017 ).", "cite_spans": [], "ref_spans": []}, {"section": "This work", "text": "In Madigan et al. (2018) , we evolved eccentric nuclear disks with N-body simulations in Newtonian gravity. Rapid apsidal precession due to general relativity, however, can quench secular dynamical mechanisms; a well-known example of this is the Kozai-Lidov effect (Ford et al. 2000; Blaes et al. 2002; Naoz et al. 2013) . Resonant relaxation in a spherical cluster also gets quenched at low semi-major axes by general relativistic precession as the orbits move too rapidly to allow torques to build up coherently (Rauch & Tremaine 1996; Madigan et al. 2011) .", "cite_spans": [], "ref_spans": []}, {"section": "This work", "text": "Similarly, one might expect general relativistic precession to disrupt the secular torques of the eccentric nuclear disk, greatly decreasing the TDE rate. As eccentricity increases due to secular torques, the general relativistic precession rate also increases (Equation 5). One would therefore expect eccentric orbits to precess ahead of the disk, escaping completely until joining back up on the other side and re-circularizing. In this case, we should see fewer TDEs with general relativity than without it.", "cite_spans": [], "ref_spans": []}, {"section": "This work", "text": "The goal of this work is to explore the effects of general relativity on TDEs occurring in eccentric nuclear disks, and to quantify the distribution of orbital elements of TDEs that originate in eccentric nuclear disks. We do this using N-body simulations with and without general relativity. We present the paper in the following manner: in Section 2 we describe the initial conditions and parameters for our simulations, and compare the number of TDEs that occur with and without general relativity. We track the orbital elements of a single tidally disrupted star in order to show how quickly the orbit is torqued to an extreme eccentricity. In Section 3 we explore the unique orbital elements of tidally disrupted stars from eccentric nuclear disks, including the penetration factor, inclination distribution, and change in eccentricity vector between TDEs. In Section 4 we summarize and discuss our results.", "cite_spans": [], "ref_spans": []}, {"section": "N-BODY SIMULATIONS OF ECCENTRIC NUCLEAR DISKS WITH GENERAL RELATIVISTIC PRECESSION", "text": "We run N-body simulations of eccentric nuclear disks with REBOUND (Rein & Liu 2012) and the IAS15 integrator (Rein & Spiegel 2015) . We implement general relativity as a postNewtonian approximation with REBOUNDX 2 . In this paper, we show results from simulations with the following parameters: N=100 stars 3 , each with an initial eccentricity of 0.8, a range of semi-major axes (a = 1 \u2212 2) with a surface density of \u03a3 \u221d a \u22122 , Rayleigh distributed inclinations with mean 0.1 \u2022 , and a disk mass of 10 \u22122 M \u2022 . We want to qualitatively understand the effects of general relativistic precession rather than obtain an exact number for the TDE rate.", "cite_spans": [], "ref_spans": []}, {"section": "N-BODY SIMULATIONS OF ECCENTRIC NUCLEAR DISKS WITH GENERAL RELATIVISTIC PRECESSION", "text": "In each of these simulations, we examine the effect that general relativity has on the number of tidal disruption events. The orbit-averaged precession rate due to general relativity is given by\u03c9", "cite_spans": [], "ref_spans": []}, {"section": "N-BODY SIMULATIONS OF ECCENTRIC NUCLEAR DISKS WITH GENERAL RELATIVISTIC PRECESSION", "text": "Equation 5 is a first order post-Newtonian approximation in general relativity yielding corrections to Newtonian accelerations of O(v 2 /c 2 ) (Einstein 1916) . We track the general relativistic precession rate in our simulations by calculating the change in the orientation of the eccentricity vector at each time step.", "cite_spans": [], "ref_spans": []}, {"section": "N-BODY SIMULATIONS OF ECCENTRIC NUCLEAR DISKS WITH GENERAL RELATIVISTIC PRECESSION", "text": "A star is considered tidally disrupted if at any point in the simulation its radius \u2264 r t . We treat stars as point masses and do not extract them from our simulation after they are disrupted, but they are counted only once as a TDE.", "cite_spans": [], "ref_spans": []}, {"section": "Effects of General Relativity", "text": "We find that the TDE rate with general relativistic precession is the same as in Newtonian gravity. About 12% of disk stars are tidally disrupted 4 for a 10 6 M black hole during a time of 1000 orbital periods, where each orbital period is roughly 1000 years. We have compiled results from \u223c45 simulations with general relativistic precession and \u223c100 simulations without general relativistic precession. The mean percent and standard deviation of tidally disrupted disk stars is shown in Figure 1 . The number of TDEs is approximately equal for both general relativistic simulations and Newtonian simulations. This means that general relativistic precession does not quench secular torques in eccentric nuclear disks.", "cite_spans": [], "ref_spans": []}, {"section": "Effects of General Relativity", "text": "In order to understand this, we track the orbital elements of a single star (with general relativistic precession) which suffers a tidal disruption event in Figure 2 . We see a star that develops an eccentricity such that its orbital angular momentum is less than the loss cone angular momentum. The star also passes through pericenter while it is at a high eccentricity, meaning that the star is close enough to the black hole to be tidally disrupted. We also see that the star's orbital inclination flips by \u223c180", "cite_spans": [], "ref_spans": [{"start": 157, "end": 165, "text": "Figure 2", "ref_id": "FIGREF0"}]}, {"section": "Effects of General Relativity", "text": "\u2022 as it reaches extreme eccentricity (see discussion in Section 3.2). Panel 4 shows the general relativistic precession rate, which we track by calculating the change of i e in each time step. i e tracks the orientation of the eccentricity vector in the plane of the disk and is given by (Madigan & McCourt 2016) . Here e x and e y are the x and y components of the eccentricity vector. We use i e instead of the argument of periapsis, \u03c9, or the longitude of periapsis, , to avoid effects of changing inclination. As an orbit rolls over its major axis, the eccentricity vector remains close to the x \u2212 y Figure 1 . Mean percent of disk stars tidally disrupted in Newtonian gravity and with general relativistic precession. Here we see that eccentric nuclear disks with Newtonian gravity and with general relativistic precession each have a mean of roughly 12% of disk stars that tidally disrupt. The error bars show the standard deviation. By performing a student's t-test for statistical significance, we find that these are not significantly different.", "cite_spans": [], "ref_spans": []}, {"section": "Effects of General Relativity", "text": "plane, even though the inclination grows. \u03c9 and , however, will change with the flipping inclination. We see that the rate of change of i e is very small until the star reaches pericenter at an extreme eccentricity where there is a large jump due to general relativity. This jump in precession rate is only present for a fraction of an orbital period. The final panel of Figure  2 shows the torque acting on the orbit in units of the circular angular momentum which we explore in the next section.", "cite_spans": [], "ref_spans": [{"start": 371, "end": 380, "text": "Figure  2", "ref_id": "FIGREF0"}]}, {"section": "Magnitude of Torque from Disk", "text": "Here we calculate the magnitude of the torque exerted on a typical orbit by the disk. The orbit is described by its specific angular momentum and energy", "cite_spans": [], "ref_spans": []}, {"section": "Magnitude of Torque from Disk", "text": "For an eccentric orbit, the specific torque is given by \u2022 at the same time it reaches an extreme eccentricity. The fourth panel shows the general relativistic precession rate with the time derivative of the eccentricity vector (i e ) in units of radians per orbital period. The black dashed line shows the analytic general relativistic precession rate (\u03c9 GR ) from Equation 5. General relativistic precession is effective for less than one orbital period, allowing the star to still tidally disrupt. The normalized torque required to produce a TDE is on the order of 10 \u22122 per orbital period. In the last panel, we see that the normalized torque applied to the orbit of the star oscillates around 10 \u22122 per orbital period, ensuring that even with general relativity, the tidal disruption event can occur.", "cite_spans": [], "ref_spans": []}, {"section": "Magnitude of Torque from Disk", "text": "r is the orbital radius and f is the specific gravitational force felt by an orbit due to the rest of the disk. This force is defined by", "cite_spans": [], "ref_spans": []}, {"section": "Magnitude of Torque from Disk", "text": "where M disk is the mass of the eccentric nuclear disk. Approximating r by the semi-major axis a yields a torque", "cite_spans": [], "ref_spans": []}, {"section": "Magnitude of Torque from Disk", "text": "Normalizing the torque by the circular angular momentum", "cite_spans": [], "ref_spans": []}, {"section": "Magnitude of Torque from Disk", "text": "where P = 2\u03c0 a 3 /GM \u2022 is the orbital period. Hence, in our Nbody simulations, in which M disk /M \u2022 = 10 \u22122 , the normalized torque per orbital period should be on the order of 6 \u00d7 10 \u22122 . The final panel in Figure 2 shows that indeed our example star experiences a torque of O(few \u00d7 10 \u22122 ). This magnitude of torque can change an orbit's eccentricity from e \u2248 0.998 to e \u2248 1 within one orbital period. That is, the change in angular momentum required to produce a TDE can occur within one orbital period, suggesting that our system is in the full loss cone regime. By assuming a 10 6 M black hole and a solar-type star, we find from Equation 3, that q \u2248 40 in our simulations, putting the system well within the full loss cone or pinhole regime. This explains why general relativity is ineffective at shutting down the TDE production. In the full loss cone regime, a stellar orbit can be propelled from outside the loss cone to inside in less than an orbital period. General relativistic precession only acts strongly when the star approaches pericenter, at which point it is too late to avoid disruption.", "cite_spans": [], "ref_spans": [{"start": 208, "end": 216, "text": "Figure 2", "ref_id": "FIGREF0"}]}, {"section": "Magnitude of Torque from Disk", "text": "Not all eccentric nuclear disks will be in the full loss cone regime. The transition from full loss cone to empty loss cone occurs when q = 1 such that", "cite_spans": [], "ref_spans": []}, {"section": "Magnitude of Torque from Disk", "text": "For a SMBH of 10 6 M , solar-type stars, and a disk inner edge of a = 0.05 pc, we find that disks with M disk /M \u2022 \u2265 1.5 \u00d7 10 \u22123 are in the full loss cone regime.", "cite_spans": [], "ref_spans": []}, {"section": "UNIQUE ORBITAL ELEMENTS", "text": "Two-body relaxation predicts that the time between individual TDEs (\u223c10 4 years) is much greater than the time it takes for a TDE disk to accrete onto the black hole. If stars come from eccentric nuclear disks however, the typical timescale between individual TDEs can be much shorter (\u223c1-10 yr; Madigan et al. 2018) , and TDE disks could potentially overlap with one another. This could have interesting observational consequences especially if the orbital parameters of TDEs are correlated.", "cite_spans": [], "ref_spans": []}, {"section": "Penetration Factor", "text": "The strength of a tidal disruption may be quantified by the dimensionless penetration factor,", "cite_spans": [], "ref_spans": []}, {"section": "Penetration Factor", "text": "where r t is the tidal radius and r p is the pericenter of the star's orbit (Press & Teukolsky 1977) . In Figure 3 we show the distribution of penetration factors in our simulations. If Figure 3 . The distribution of impact parameters with general relativity. The dashed line shows the critical value of the impact parameter. A star with an impact parameter less than one will be tidally squeezed and stretched (many will even lose mass), but not fully disrupted. A disruption event with an impact parameter greater than 23.5 (corresponding to solar-type stars and a non-spinning 10 6 M black hole) will not be visible to observers because its pericenter is inside the Schwarzschild radius. We see in this figure that our results are consistent with the pinhole regime in which orbits have large steps in angular momentum, allowing stars to jump into the loss cone within an orbital period. The probability distribution function of the impact parameter is well-fit by the curve \u221d \u03b2 \u22122 , as shown by the solid maroon line. The inset shows the same histogram with the curve \u221d \u03b2 \u22122 on a log-log scale.", "cite_spans": [], "ref_spans": []}, {"section": "Penetration Factor", "text": "the penetration factor is greater than or equal to one, the star will be tidally disrupted. If the penetration factor is less than, but close to one, the star may have its outer layers stripped, with a stellar core remaining intact (Ivanov & Novikov 2001; Guillochon & Ramirez-Ruiz 2013; Bogdanovi\u0107 et al. 2014; Mainetti et al. 2017) . If the penetration factor is too large however, the star will fall straight into the black hole without emitting an electromagnetic flare. This occurs when the r p < r s . For a non-spinning, 10 6 M black hole and solar-type stars this occurs at \u03b2 = 23.5.", "cite_spans": [], "ref_spans": []}, {"section": "Penetration Factor", "text": "We see in Figure 3 that the probability distribution function, P \u221d \u03b2 \u22122 , is fully consistent with the full loss cone or pinhole regime (Coughlin et al. 2017) . This is significant because the critical radius (where q = 1) is typically found near the radius of influence of the black hole. We find that eccentric nuclear disks bring the critical radius orders of magnitude within the radius of influence, to a radius smaller than the inner edge of the disk.", "cite_spans": [], "ref_spans": []}, {"section": "Inclination Distribution", "text": "In a spherical, isotropic stellar system dominated by twobody relaxation, there should be no correlation between the orbital angular momentum vectors of consecutive TDEs, and so we would expect to see an isotropic distribution of TDE inclinations. This is quite different in the case that stars are originating in an eccentric nuclear disk.", "cite_spans": [], "ref_spans": []}, {"section": "Inclination Distribution", "text": "We find that whenever a star reaches a high eccentricity in our simulations, it undergoes an inclination flip of 180", "cite_spans": [], "ref_spans": []}, {"section": "Inclination Distribution", "text": "\u2022 . Figure 4 is an example of a double peak in eccentricity corresponding to a double 180", "cite_spans": [], "ref_spans": [{"start": 4, "end": 12, "text": "Figure 4", "ref_id": "FIGREF1"}]}, {"section": "Inclination Distribution", "text": "\u2022 flip in inclination. As the orbit is negatively torqued by the disk to extreme eccentricity (in blue), its angular momentum vector decreases until it passes through zero. At this point, the inclination (in green) flips 180", "cite_spans": [], "ref_spans": []}, {"section": "Inclination Distribution", "text": "\u2022 and the orbit switches from a prograde orientation (with respect to the disk) to a retrograde orientation. The orbit now feels a positive torque causing it to circularize and precess quickly back towards the disk. On the other side of the disk, the angular momentum will again decrease, pass through zero and change direction. The orbit is prograde again after the second flip. These double peaks of inclination were also seen in our Newtonian simulations (Madigan et al. 2018 ). \u2022 to 180", "cite_spans": [], "ref_spans": []}, {"section": "Inclination Distribution", "text": "\u2022 or vice versa, corresponding to the extreme peaks in eccentricity. An orbit with an inclination between 0", "cite_spans": [], "ref_spans": []}, {"section": "Inclination Distribution", "text": "\u2022 and 90", "cite_spans": [], "ref_spans": []}, {"section": "Inclination Distribution", "text": "\u2022 is prograde and an orbit with inclination between 90", "cite_spans": [], "ref_spans": []}, {"section": "Inclination Distribution", "text": "\u2022 and 180", "cite_spans": [], "ref_spans": []}, {"section": "Inclination Distribution", "text": "\u2022 is retrograde.", "cite_spans": [], "ref_spans": []}, {"section": "Inclination Distribution", "text": "As the orbits flip from prograde to retrograde and back, the percentage of stars on retrograde orbits fluctuates throughout a given simulation. Figure 5 is an example of the percentage of retrograde orbits in a disk for a single simulation. Most of these retrograde orbits lie near the inner edge of the disk.", "cite_spans": [], "ref_spans": [{"start": 144, "end": 152, "text": "Figure 5", "ref_id": "FIGREF2"}]}, {"section": "Inclination Distribution", "text": "This may lead to interesting observational signatures in the velocity moments of eccentric nuclear disks. The flipping of orbits in inclination results in an anisotropic distribution of TDE inclinations (see Figure 6 ). Stars prefer- Figure 6 . The distribution of orbital inclinations of disrupted stars with general relativity. The black dashed line shows the isotropic distribution of cosine of inclinations that we would see from a spherical cluster. Stars originating in an eccentric nuclear disk preferentially tidally disrupt at inclinations of 0", "cite_spans": [], "ref_spans": []}, {"section": "Inclination Distribution", "text": "\u2022 and 180", "cite_spans": [], "ref_spans": []}, {"section": "Inclination Distribution", "text": "\u2022 .", "cite_spans": [], "ref_spans": []}, {"section": "Inclination Distribution", "text": "entially tidally disrupt at orbital inclinations of 0 \u2022 and 180", "cite_spans": [], "ref_spans": []}, {"section": "Inclination Distribution", "text": "\u2022 with respect to the disk mid-plane. More disruptions occur at 0", "cite_spans": [], "ref_spans": []}, {"section": "Inclination Distribution", "text": "\u2022 . This is because the stars get the first opportunity to disrupt at an inclination of 0", "cite_spans": [], "ref_spans": []}, {"section": "Inclination Distribution", "text": "\u2022 , while their orbit is ahead of the disk. The probability for a star to disrupt in one orbital period is", "cite_spans": [], "ref_spans": []}, {"section": "Inclination Distribution", "text": "We estimate a \u2248 10 \u22122 r H for the inner edge of the disk, where r H is the radius of influence of the black hole, based on the disks in M31 and the Galactic center (Madigan et al. 2018) .", "cite_spans": [], "ref_spans": []}, {"section": "Inclination Distribution", "text": "We take r H to be 5pc from observations of the Galactic center (Lu et al. 2009 ). We find that P TDE = 0.15. Out of 100 stars vulnerable to disruption, \u223c15 will tidally disrupt at an inclination of 0 \u2022 . 85 stars will then flip inclinations and have a 15% chance (\u223c12-13) of tidally disrupting at an inclination of 180", "cite_spans": [], "ref_spans": []}, {"section": "Inclination Distribution", "text": "\u2022 . Therefore, we find that the number of TDEs at 180", "cite_spans": [], "ref_spans": []}, {"section": "Inclination Distribution", "text": "\u2022 is 85% the number at 0 \u2022 , or in general,", "cite_spans": [], "ref_spans": []}, {"section": "Inclination Distribution", "text": "This explains the height difference that we see in the inclination distribution in Figure 6 . For a spinning Kerr black hole, the tidal and capture cross-sections shift towards negative angular momenta (Beloborodov et al. 1992 ). The asymmetric cross-sections make it easier for stars on retrograde orbits to be captured, meaning that prograde TDEs will be preferentially observed. If the spin angular momentum vector of the black hole is aligned with the orbital angular momentum vector of the disk, then the preference for TDEs from eccentric nuclear disks to have \u223c0", "cite_spans": [], "ref_spans": []}, {"section": "Inclination Distribution", "text": "\u2022 orbital inclination puts them at the perfect orientation to be visibly disrupted by a Kerr black hole.", "cite_spans": [], "ref_spans": []}, {"section": "Eccentricity Vector", "text": "We plot the eccentricity vectors of tidally disrupted stars at the time of TDE in the top panel of Figure 7 . The eccentricity vectors precess together in a prograde direction while remaining in the plane. This means that when a stellar orbit flips in inclination, it flips over its major axis. The bottom panel of Figure 7 shows the angular momentum vectors of the same tidally disrupted stars at the time of TDE. The spread in angular momentum vectors confirms that the orbits roll over their major axes.", "cite_spans": [], "ref_spans": [{"start": 99, "end": 107, "text": "Figure 7", "ref_id": "FIGREF3"}, {"start": 315, "end": 323, "text": "Figure 7", "ref_id": "FIGREF3"}]}, {"section": "Eccentricity Vector", "text": "With TDEs preferentially occurring in the plane with inclinations of 0", "cite_spans": [], "ref_spans": []}, {"section": "Eccentricity Vector", "text": "\u2022 or 180 \u2022 , the debris streams from two sequential TDEs could cross and produce unique observational signatures. Bonnerot & Rossi (2018) derive the conditions necessary for a tidal stream crossing to occur, which depend on disk properties, tidal stream widths, and the time between consecutive TDEs. If the pericenter shift between tidally disrupted stars is positive, the time delay is small, and the inclination offset is less than the width of the tidal streams, crossing of the tidal streams could occur. While our simulations do not allow for the calculation of accurate time delays (due to the low N nature of our simulations) or stream width, we calculate the pericenter shift between two TDEs with an angle, \u2206\u03b8. This \u2206\u03b8 tracks the orientation of the orbit of the first TDE with respect to the orientation of the orbit of the second TDE. We track the orientation of the orbits in our simulation with i e , defined in Equation 6. We, therefore, calculate \u2206\u03b8 between TDEs as", "cite_spans": [], "ref_spans": []}, {"section": "Eccentricity Vector", "text": "We show, in Figure 8 , a distribution of the \u2206\u03b8 between pairs of TDEs in our simulations. We see that about 20% of \u2022 and then precess together in a prograde direction (to the right on our projection plot). The first TDEs begin occurring after about 200 orbital periods, when the disk has precessed to \u223c0", "cite_spans": [], "ref_spans": [{"start": 12, "end": 20, "text": "Figure 8", "ref_id": "FIGREF4"}]}, {"section": "Eccentricity Vector", "text": "\u2022 . When the orbits flip in inclination, they flip over the major axis instead of the latus rectum. The spread in the angular momentum vectors, j, confirms that the orbits roll over their major axes.", "cite_spans": [], "ref_spans": []}, {"section": "Eccentricity Vector", "text": "consecutive TDEs occur with a small (\u2264 20", "cite_spans": [], "ref_spans": []}, {"section": "Eccentricity Vector", "text": "\u2022 ), positive \u2206\u03b8, satisfying one of the conditions for tidal streams crossing. We expect that this condition would be met due to prograde precession of the eccentric nuclear disk.", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "This paper focuses on the dynamics of eccentric nuclear disks with general relativistic precession. In Madigan et al. (2018) , we showed that the same secular mechanism that keeps eccentric nuclear disks stable results in extremely high TDE rates. This work did not include general relativity, however, which is known to quench secular torques via rapid apsidal precession. In this paper, we show that secular gravitational torques push the orbits of stars to extremely high eccentricities within one orbital period (full loss cone regime). This does not allow general relativistic precession enough time to suppress the TDE rate. The geometry of eccentric nuclear disks is key: the torques acting on an orbit from the rest of the disk stars are coherent. Our results point to the following conclusions and implications:", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "1. General relativistic precession does not affect the TDE rate from eccentric nuclear disks as stars at the inner edge of the disk are in the full loss cone regime. TDEs occur in simulations with general relativity as often as they occur in Newtonian simulations.", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "2. TDEs from eccentric nuclear disks do not follow an isotropic distribution of inclinations; they preferentially disrupt at inclinations of 0 \u2022 and 180", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "\u2022 with respect to the mid-plane of the disk. Overlapping TDE disks may have similar (or opposing) angular momenta that can build up (or cancel each other out).", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "3. The probability of disrupting stars on prograde orbits is higher than the probability of disrupting stars on retrograde orbits for a non-spinning, Schwarzschild black hole in an eccentric nuclear disk. Similarly, the number of prograde captured stars (within the Schwarzschild radius so that a flare will not be observed), will also be greater than the number of retrograde captured stars for a non-spinning, Schwarzschild black hole.", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "4. If an eccentric nuclear disk forms during a gas-rich major merger, it is likely that the central gaseous accretion event that produces the disk aligns the disk angular momentum with that of the central SMBH. Spinning, Kerr black holes have asymmetric tidal and capture cross-sections (Beloborodov et al. 1992) . For black holes with mass greater than the Hills mass, the only observable TDEs are those on prograde orbits aligned with the black hole spin. The preference for TDEs from eccentric nuclear disks to have \u223c0", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "\u2022 orbital inclination puts them in the perfect orientation to be observably disrupted by such black holes. There may be evidence of TDEs by extremely massive black holes already. ASSASN-15lh is a TDE candidate found in a galaxy with a central SMBH much more massive than the Schwarzschild Hills mass (\u223c10 8.24 M ) (Leloudas et al. 2016) .", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "5. In steady-state, eccentric nuclear disks have a nonnegligible fraction of retrograde orbiting stars (\u223c10%).", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "Most of these will lie at the inner edge of the disk. This will lead to interesting observational signatures in the velocity moments of eccentric nuclear disks.", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "Finally, we look back to our nearest neighbor, Andromeda (M31). To date, no TDEs have been observed from its center. This may be due to the fact that the eccentric nuclear disk in M31 is very old, on the order of Gyr (Sil'chenko et al. 1998) . Unless continuously replenished, an eccentric nuclear disk loses mass due to stars being destroyed by tidal forces, but it does not lose significant angular momentum. The disk, therefore, becomes less eccentric with time, causing the TDE rate to decrease (Madigan et al. 2018) . At M \u2022 1.4 \u00d7 10 8 M , the mass of the M31 black hole is also greater than the Hills mass (Bender et al. 2005 ). We should not expect to observe TDEs, unless the black hole is spinning.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF32": {"title": "Baryons in Dark Matter Halos", "authors": [{"first": "B", "middle": [], "last": "Poggianti", "suffix": ""}], "year": 2004, "venue": "", "link": null}}, "ref_entries": {"FIGREF0": {"text": "Figure 2. A tidal disruption event (TDE) in an N-body simulation of an eccentric nuclear disk with general relativistic precession. The top panel shows the eccentricity of a star undergoing a tidal disruption event as a function of time in units of orbital periods (P). At the time of tidal disruption, the eccentricity increases from \u223c0.999 to > 0.9999 within one orbital period. The dashed line shows the 1 \u2212 e value such that J = J LC . The second panel shows the orbital radius (in code units) of the same star as a function of time. The star meets the requirement of being at pericenter to be tidally disrupted. The third panel shows that the inclination of this star flips by 180 \u2022 at the same time it reaches an extreme eccentricity. The fourth panel shows the general relativistic precession rate with the time derivative of the eccentricity vector (i e ) in units of radians per orbital period. The black dashed line shows the analytic general relativistic precession rate (\u03c9 GR ) from Equation 5. General relativistic precession is effective for less than one orbital period, allowing the star to still tidally disrupt. The normalized torque required to produce a TDE is on the order of 10 \u22122 per orbital period. In the last panel, we see that the normalized torque applied to the orbit of the star oscillates around 10 \u22122 per orbital period, ensuring that even with general relativity, the tidal disruption event can occur.", "type": "figure"}, "FIGREF1": {"text": "Figure 4. The inclination flip of a star at high eccentricity. The blue line shows the eccentricity of the star, while the green line shows the inclination of the orbit in radians. The inclination flips from 0 \u2022 to 180 \u2022 or vice versa, corresponding to the extreme peaks in eccentricity. An orbit with an inclination between 0 \u2022 and 90 \u2022 is prograde and an orbit with inclination between 90 \u2022 and 180 \u2022 is retrograde.", "type": "figure"}, "FIGREF2": {"text": "Figure 5. The percentage of disk stars on retrograde orbits with time. A typical plot of the changing percentage of retrograde orbits with time for a single simulation. The eccentric nuclear disk simulation begins with all orbits in a prograde orientation. The number of retrograde orbits climbs quickly after about 150 orbital periods to a peak of \u223c20% retrograde and then oscillates around 10% retrograde for the rest of the simulation.", "type": "figure"}, "FIGREF3": {"text": "Figure 7. Aitoff projection of eccentricity and angular momentum vectors of TDEs. Colors indicate the time of TDE in units of orbital periods at the inner edge of the disk. The eccentricity vectors, e, precess together in a prograde direction, staying close to the mid-plane. The orbits start with their eccentricity vectors at about 60 \u2022 and then precess together in a prograde direction (to the right on our projection plot). The first TDEs begin occurring after about 200 orbital periods, when the disk has precessed to \u223c0 \u2022 . When the orbits flip in inclination, they flip over the major axis instead of the latus rectum. The spread in the angular momentum vectors, j, confirms that the orbits roll over their major axes.", "type": "figure"}, "FIGREF4": {"text": "Figure 8. The distribution of \u2206\u03b8 between TDEs. A histogram of \u2206\u03b8 for consecutive TDEs with general relativistic precession. About 20% of the consecutive TDEs occur with a small (\u2264 20 \u2022 ), positive change in i e . This is partially due to the prograde precession of the disk. The clustering of \u2206\u03b8 around 0 and slightly greater than 0 show that the first condition for tidal streams crossing is met for many consecutive TDEs. Prograde precession is in the positive (counter-clockwise) direction.", "type": "figure"}}}
{"paper_id": "118862329", "_pdf_hash": "ce54ecfbb47287c265843efb275b89937b2f60e0", "abstract": [{"section": "Abstract", "text": "We determine the commutation relations satisfied by the quantized electromagnetic field in the presence of macroscopic dielectrics and conductors, with arbitrary dispersive and dissipative properties. We consider in detail the case of two plane-parallel material slabs, separated by an empty gap, and we show that at all points in the empty region between the slabs, including their surfaces, the electromagnetic fields always satisfy free-field canonical equal-time commutation relations. This result is a consequence of general analyticity and fall-off properties at large frequencies satisfied by the reflection coefficients of all real materials. It is also shown that this result does not obtain in the case of conductors, if the latter are modelled as perfect mirrors. In such a case, the free-field form of the commutation relations is recovered only at large distances from the mirrors, in agreement with the findings of previous authors. Failure of perfect-mirror boundary conditions to reproduce the correct form of the commutation relations near the surfaces of the conductors, suggests that caution should be used when these idealized boundary conditions are used in investigations of proximity phenomena originating from the quantized electromagnetic field, like the Casimir effect.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "I. INTRODUCTION", "text": "The interaction of radiation with matter has always been a fascinating subject of investigation, and in fact it is at the roots of quantum mechanics, with Planck's work on black body radiation. Even though, after the development of Quantum Electrodynamics (QED) in the middle years of last century, all fundamental principles involved in this interaction are undoubtedly well understood at the microscopic level, recent experimental advances have prompted much interest in theoretical studies of the quantized electromagnetic (e.m.) field in close proximity to macroscopic bodies. A thorough understanding of this problem is indeed needed for a correct interpretation of numerous important proximity phenomena of e.m. origin, that include cavity QED [1] , the Casimir effect [2] , radiative heat transfer [3] , quantum friction [4] , the Casimir-Polder interaction of Bose-Einstein condensates with a substrate [5] , etc. Apart from the intrinsic interest of these phenomena, it has been shown recently that the quantum fluctuations of the e.m. field surrounding macroscopic bodies, that are at the origin of the Casimir effect, could have exciting application in nanotechnology [6] .", "cite_spans": [{"start": 750, "end": 753, "text": "[1]", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "The common feature of the above e.m. phenomena, is that they all involve several macroscopic bodies and possibly one or more microscopic objects (atoms, ions etc.) placed in a vacuum and separated by distances (typical separations range from a few tens of nanometers * Bimonte@na.infn.it%; to several microns) that, while small from a macroscopic point of view, are still large compared to the interatomic distance in condensed bodies. In such circumstances, the microscopic point of view is not of great help, because the long range character of the e.m. field implies that macroscopically large number of atoms are inevitably involved in the interaction. A much more effective approach would be to describe the influence of the macroscopic bodies on the quantized e.m. field in the vacuum just outside their boundaries, in terms of macroscopic features of the bodies like the electric and/or magnetic permittivities. On physical grounds, one expects that such an approach should be feasible, in certain circumstances at least, because the wavelengths of the e.m. fields participating in these phenomena are expected to be of the order of the bodies separations, and are therefore large on the atomic scale. This being the case, use of macroscopic response functions of the bodies should be legitimate. An inevitable complication that one faces though, when dealing with macroscopic response functions of real bodies, is that they always display dispersion and absorption. As is it well known, the former feature is mathematically reflected in the fact that response functions depend on the frequency \u03c9 (we shall neglect spatial dispersion, and therefore we shall not consider the possible dependence of the response functions on the wave-vector k), while the presence of dissipation entails that the response functions have a non-vanishing imaginary part. The existence of absorption, in particular, greatly complicates explicit quantization of the macroscopic e.m. field. Unfortunately, such a difficulty cannot be disposed of by simply neglecting dissipation, because dispersive, real-valued response functions inevitably violate causality, and must therefore be rejected.", "cite_spans": [], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "Fortunately, though, there exists a way out that avoids the above mentioned difficulties. This is so because a full quantization of the e.m. field is usually not needed, as the quantities of interest are typically statistical averages of quadratic expressions involving the macroscopic e.m. field. For systems that are in thermodynamic equilibrium, such averages can be expressed in terms of (the imaginary part of) suitable macroscopic response functions, as a result of general fluctuation-dissipation theorems derived in the framework of linear-response theory [7] . This general approach was probably pioneered by Rytov [8] in his investigations of e.m. fluctuations in the presence of macroscopic bodies in thermal equilibrium, and it was later used by Lifshitz [9] in his famous theory of dispersion forces between macroscopic condensed bodies. In one form or another, the fluctuation-dissipation theorem is used in all existing approaches to problems involving the quantized e.m. field in the vicinity of or inside macroscopic bodies. In the seventies of last century, Agarwal used it as the basis of a systematic investigation of QED in the presence of dielectrics and conductors [10] . For a review of the most recent work we address the reader to Refs. [11, 12] (see also Refs. therein). It is important to note that this approach is not restricted to systems in global thermodynamic equilibrium, as it is still valid in systems that are only in local thermodynamic equilibrium. This feature permits to include within the scope of the theory other important phenomena, like radiative heat transfer between closely separated bodies (for a recent review see [3] ), and quantum friction [4] . Recently, the theory has also been applied to the investigation of Casimir-Polder [5, 13] and Casimir [14] forces out of thermal equilibrium.", "cite_spans": [{"start": 624, "end": 627, "text": "[8]", "ref_id": "BIBREF15"}], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "In this paper, we reexamine the basic quantum-fieldtheoretical problem of the commutation relations satisfied by the quantized e.m. field in the presence of dielectrics and/or conductors, in the framework of the general macroscopic theory described above. Our interest in this problem arose from a paper by Milonni [15] on the Casimir effect, in which it was found that near a perfectly reflecting slab, the transverse vector potential and the electric field satisfy a set of equal-time canonical commutation relations of a different form form those holding for free fields. This result is quite worrisome, in view of the very fundamental character of commutation relations, because it contradicts one's expectations based on microscopic theory, and therefore it deserves detailed investigation. We remark that unexpected commutation relations between the annihilation and creation operators for the e.m. field inside a cavity were also found more recently in Ref. [16] . A partial resolution of the paradox was offered in Ref. [17] , in which the problem of the e.m. commutation relations was investigated within a simplified form of QED, in one space dimension. By relying on a simple quantum theory of the one-dimensional lossy beam splitter, along the lines of Ref. [18] (see also [19] ), it was shown that the anomalies found in [16] in the commutators of the annihilation and creation operators were associated with a particular choice of the the cavity e.m. modes. The authors of Refs. [17] also showed that the canonical one-dimensional commutation relations involving the vector potential and the electric field do not display any anomalous behavior. No detailed explanation was however provided for the modified form of the equaltime commutators derived in Ref. [15] , apart from the remark that the boundary conditions (b.c.) satisfied by the e.m. field in the case of ideal mirrors are incompatible with the transverse delta function form of the full canonical commutator in three dimensions. These authors further conjecture that standard equal-time commutators would probably be restored after incorporating, in the full three-dimensional setting, the physical requirements of finite reflectivity and absorption losses by the mirrors.", "cite_spans": [], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "Addressing this problem in detail is not only interesting as a matter of principle, but it is also important for a better understanding of the numerous proximity phenomena arising from quantum fluctuations of the e.m. field described earlier. In many theoretical investigations of these phenomena, one deals with conductors that are frequently modelled as ideal mirrors. A famous example of this is provided by original Casimir's derivation [20] of the effect that goes under his name. It is then important to know to what extent conclusions drawn from the ideal-metal model can be trusted. Indeed Casimir physics offers examples where predictions drawn from the idealmetal model are in contradiction with those derived by more realistic modelling of the plates. One such example is still much debated as we write, and it is the problem of determining the influence of temperature on the magnitude of the Casimir force between two metallic plates in vacuum. It turns out the the ideal-metal model predicts a thermal force that, for sufficiently large separations between the plates, attains a magnitude which is twice the one calculated on the basis of realistic dielectric models of a conductor, displaying a finite, though large, dc conductivity (for a review of this puzzle, see for example Ref. [21] and References therein).", "cite_spans": [], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "In order to shed light on this question, in this paper we work out a detailed analysis of the full threedimensional commutators for the e.m. field, in the presence of dielectric and/or conducting walls with arbitrary dispersion and dissipative features. The analysis turns out to be considerably more involved than the simple one-dimensional model studied in [17] . Our main result is that the canonical commutation relations satisfied by free e.m. fields are always valid at all points between two macroscopic dielectric or conducting slabs, including their surfaces, in full agreement with expectations based on the microscopic theory for a system of charged nonrelativistic particles interacting with the e.m. field. This result is consequence of analyticity and fall-off properties at large frequencies of reflection coefficients of all real materials, as it was correctly conjectured in Ref. [17] . We also show that such a result is not recovered, however, in the case of conductors, if they are modelled as perfect mirrors. In this case we find that near the conductors the equal-time commutation relations of the vector potential with the electric field have a different form from the freefield case. Only at points that are sufficiently far from the conductors, the free-fields commutators are recovered. Our results generalize those obtained by Milonni, in the one slab setting, and show that the modified form of the commutation relation entailed by perfect-mirror b.c. are indeed an artifact of these idealized b.c., not shared by real materials.", "cite_spans": [], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "The paper is organized as follows. In Section II we recall the basic commutation relations satisfied, within the microscopic theory, by the e.m. field in vacuum and in the presence of charged particles. In Section III we briefly review some general results of linear response theory, as applied to macroscopic quantum electrodynamics, and derive formulae for the expectation values of the field commutators outside a system of macroscopic bodies, in terms of suitable classical Green's functions. In Section IV we estimate the Green's functions for a system of one or two dielectric and/or conducting slabs in vacuum, and in Sec V we use them to calculate the commutation relations satisfied by the e.m. field outside the slabs. In Sec VI we consider the case of ideal, perfectly reflecting slabs, while Section VII contains our conclusions. Finally, three Appendices close the paper.", "cite_spans": [], "ref_spans": []}, {"section": "II. COMMUTATION RELATIONS FOR E.M. FIELDS: MICROSCOPIC THEORY", "text": "In this Section we briefly recall well known properties of the commutation relations satisfied by e.m. fields, in the framework of a microscopic theory of non-relativistic matter, where ponderable matter is modelled as a collection of non-relativistic charged particles. Here and afterwards, we work in Gaussian e.m. units, and we adopt the Coulomb gauge. As it is well known the Coulomb gauge is very convenient for studying problems where matter is non-relativistic, and high-energy processes are neglected, for it allows a clear separation of electrostatic and magnetic couplings. In this gauge, quantization is straightforward (see for example the book [22] ). We consider first the case of free-fields.", "cite_spans": [{"start": 657, "end": 661, "text": "[22]", "ref_id": "BIBREF30"}], "ref_spans": []}, {"section": "A. Free fields", "text": "In empty space, Maxwell equations imply that the electric field is purely transverse", "cite_spans": [], "ref_spans": []}, {"section": "A. Free fields", "text": "where A \u22a5 is the transverse vector potential:", "cite_spans": [], "ref_spans": []}, {"section": "A. Free fields", "text": "The fields A \u22a5 and E \u22a5 satisfy the following well known equal-time canonical commutation relations: ", "cite_spans": [], "ref_spans": []}, {"section": "A. Free fields", "text": "with k = |k|.", "cite_spans": [], "ref_spans": []}, {"section": "A. Free fields", "text": "B. e.m. fields coupled to charged particles", "cite_spans": [], "ref_spans": []}, {"section": "A. Free fields", "text": "When charged particles are present, the phase space of the total system includes, besides the transverse e.m. fields A \u22a5 and E \u22a5 , the positions x (\u03b1) , the conjugate momenta p (\u03b1) and the spins s (\u03b1) of the particles (labelled by the index \u03b1). They satisfy the standard (equal-time) commutation relations of non-relativistic Quantum Mechanics:", "cite_spans": [], "ref_spans": []}, {"section": "A. Free fields", "text": "[s", "cite_spans": [], "ref_spans": []}, {"section": "A. Free fields", "text": "with all other commutators vanishing. In particular x", "cite_spans": [], "ref_spans": []}, {"section": "A. Free fields", "text": "all commute with the transverse e.m. fields A \u22a5 and E \u22a5 . Finally A \u22a5 and E \u22a5 satisfy the same equal-time commutation relations holding in empty space, Eqs. (3) (4) (5) .", "cite_spans": [], "ref_spans": []}, {"section": "A. Free fields", "text": "When charges are present, the electric field E has also a longitudinal component E :", "cite_spans": [], "ref_spans": []}, {"section": "A. Free fields", "text": "where E \u22a5 is still given by Eq. (1), while E is equal to", "cite_spans": [], "ref_spans": []}, {"section": "A. Free fields", "text": "where U is the scalar potential:", "cite_spans": [], "ref_spans": []}, {"section": "A. Free fields", "text": "with e (\u03b1) the charge of particle \u03b1. The scalar potential has to be regarded as a function of the particles positions, and therefore it is not an independent degree of freedom of the system. Since the particle positions commute among themselves and with the transverse fields, A \u22a5 and E \u22a5 , it follows that", "cite_spans": [], "ref_spans": []}, {"section": "A. Free fields", "text": "The above Equations imply that the equal-time commutation relations Eqs.(3-5) remain valid, irrespective of the number and positions of the charged particles, if we replace everywhere the transverse electric field E \u22a5 j by the total electric field E j :", "cite_spans": [], "ref_spans": []}, {"section": "A. Free fields", "text": "[", "cite_spans": [], "ref_spans": []}, {"section": "A. Free fields", "text": "The obvious conclusion that can be drawn from these elementary remarks is that, within the microscopic theory, the canonical equal-time commutation relations satisfied by the e.m. fields, Eqs. (3) (4) (5) or, alternatively, Eqs. (15) (16) (17) should be valid always, and therefore they should hold, in particular, inside a cavity made of an arbitrary material.", "cite_spans": [], "ref_spans": []}, {"section": "III. COMMUTATION RELATIONS FOR E.M. FIELDS: MACROSCOPIC THEORY", "text": "In this Section, we recall a few basic formulas from linear-response theory and we discuss the type of probes that are needed in order to obtain the commutation relations satisfied by the macroscopic e.m. field in the presence of dielectrics and conductors. For a review of linearresponse theory we address the reader to Refs. [7] .", "cite_spans": [], "ref_spans": []}, {"section": "III. COMMUTATION RELATIONS FOR E.M. FIELDS: MACROSCOPIC THEORY", "text": "In linear-response theory, one considers a quantummechanical system, characterized by a (timeindependent) Hamiltonian H 0 , in a state of thermal equilibrium described by the density matrix \u03c1", "cite_spans": [], "ref_spans": []}, {"section": "III. COMMUTATION RELATIONS FOR E.M. FIELDS: MACROSCOPIC THEORY", "text": "where \u03b2 = 1/(k B T ), with k B Boltzmann constant and T the temperature. The system is then perturbed by an external perturbation of the form:", "cite_spans": [], "ref_spans": []}, {"section": "III. COMMUTATION RELATIONS FOR E.M. FIELDS: MACROSCOPIC THEORY", "text": "where f j (r, t) are the external classical forces, and Q j (r, t) is the dynamical variable of the system conjugate to the force f j (r, t). One may assume, without loss of generality, that the equilibrium values of the quantities Q j (r, t) all vanish: Q j (r, t) = 0. The presence of the external forces causes a deviation \u03b4 Q i (r, t) of the expectation values of Q j (r, t) from their equilibrium values. If the forces f j (r, t) are sufficiently weak, \u03b4 Q i (r, t) can be taken to be linear functionals of the applied forces f j (r, t), and one may write:", "cite_spans": [], "ref_spans": []}, {"section": "III. COMMUTATION RELATIONS FOR E.M. FIELDS: MACROSCOPIC THEORY", "text": "The above Equation assumes that the system was in equilibrium at t = \u2212\u221e, and that it reacts to the external force in a causal way. The quantities \u03c6 ij (r, r \u2032 , t \u2212 t \u2032 ) are called response functions of the system. In principle, they can be measured by applying to the system of interest suitable external classical probes.", "cite_spans": [], "ref_spans": []}, {"section": "III. COMMUTATION RELATIONS FOR E.M. FIELDS: MACROSCOPIC THEORY", "text": "By a straightforward computation in time-dependent perturbation theory one may prove that the response functions \u03c6 ij (r, r \u2032 , t \u2212 t \u2032 ) are related to the equilibrium (i.e. in the absence of the external forces) expectation values of the commutators of the dynamical variables Q i (r, t): (21) where \u03b8(x) is Heaviside step function (\u03b8(x) = 1 for x > 0, \u03b8(x) = 0 for x < 0) and Q i (r, t) is the Heisenberg operator:", "cite_spans": [], "ref_spans": []}, {"section": "III. COMMUTATION RELATIONS FOR E.M. FIELDS: MACROSCOPIC THEORY", "text": "As it is well known, Eq. (21) is the starting point from which several general fluctuation-dissipation theorems can be derived, that allow to express the (symmetrized) correlation functions of the quantities Q i (r, t) in terms of the dissipative component of the response functions \u03c6 ij .", "cite_spans": [], "ref_spans": []}, {"section": "III. COMMUTATION RELATIONS FOR E.M. FIELDS: MACROSCOPIC THEORY", "text": "Since we shall not make use of these theorems in what follows, we shall not present them here, and we address the interested reader to Refs. [7] for details. We wish to exploit Eq. (21) to study the commutation relations satisfied by the macroscopic e.m. field at points placed outside a number of dielectric or conducting bodies. For this purpose, following Agarwal [10] , we take the external probes to be a system of classical electric and magnetic dipoles, with densities P(r, t) and M(r, t) respectively, placed outside the bodies. The external Hamiltonian H ext is then of the form:", "cite_spans": [], "ref_spans": []}, {"section": "III. COMMUTATION RELATIONS FOR E.M. FIELDS: MACROSCOPIC THEORY", "text": "(23) It is convenient for our purposes to have distinct probes for the longitudinal and the transverse components of the e.m. field. This can be achieved by demanding that P (ext) be curl free", "cite_spans": [], "ref_spans": []}, {"section": "III. COMMUTATION RELATIONS FOR E.M. FIELDS: MACROSCOPIC THEORY", "text": "If we now express in Eq. (23) the e.m. field in terms of the scalar and vector potentials:", "cite_spans": [], "ref_spans": []}, {"section": "III. COMMUTATION RELATIONS FOR E.M. FIELDS: MACROSCOPIC THEORY", "text": "after an integration by parts, and exploiting Eq. (24), the external Hamiltonian can be rewritten as:", "cite_spans": [], "ref_spans": []}, {"section": "III. COMMUTATION RELATIONS FOR E.M. FIELDS: MACROSCOPIC THEORY", "text": "where", "cite_spans": [], "ref_spans": []}, {"section": "III. COMMUTATION RELATIONS FOR E.M. FIELDS: MACROSCOPIC THEORY", "text": "is transverse:", "cite_spans": [], "ref_spans": []}, {"section": "III. COMMUTATION RELATIONS FOR E.M. FIELDS: MACROSCOPIC THEORY", "text": "We remark once again that the scalar potential U (r, t), in the external Hamiltonian Eq. (26) does not represent an independent dynamical variable, and it must be regarded as a function of the particle's position, according to Eq. (11) . Therefore, in the absence of matter, no such term is present in the external Hamiltonian, and the scalar potential is zero. The response functions are then computed by solving the classical macroscopic Maxwell Equations with \u03c1 ", "cite_spans": [], "ref_spans": []}, {"section": "III. COMMUTATION RELATIONS FOR E.M. FIELDS: MACROSCOPIC THEORY", "text": "where", "cite_spans": [], "ref_spans": []}, {"section": "III. COMMUTATION RELATIONS FOR E.M. FIELDS: MACROSCOPIC THEORY", "text": "The above equations have to be solved subject to the usual b.c. of macroscopic electrodynamics, namely (i) tangential components of E and H and (ii) normal components of D and B must be continuous across the bodies interfaces, which are assumed to have sharp boundaries. Coherently with the spirit of a macroscopic approach, the dielectrics and the conductors will be described in terms of the appropriate electric and magnetic susceptibilities. We suppose from now on that the bodies are made of nonmagnetic (\u00b5 = 1)), isotropic and spatially non-dispersive materials, characterized by a frequency-dependent electric permittivity \u01eb(r, \u03c9). We also assume that the bodies are homogeneous, in such a way that the permittivity \u01eb(r, \u03c9) is independent of r within the volume occupied by each body, with discontinuities occurring only at the bodies interfaces. By virtue of homogeneity of the bodies, and of linearity of the b.c. at the bodies interface, the field Equations for the scalar potential U (r, t) are completely decoupled from those for the transverse vector potential A(r, t). Therefore, we have two independent sets of Green's functions:", "cite_spans": [], "ref_spans": []}, {"section": "III. COMMUTATION RELATIONS FOR E.M. FIELDS: MACROSCOPIC THEORY", "text": "where G \u22a5 (r, r \u2032 , t \u2212 t \u2032 ) has to be understood as a dyadic Green function.", "cite_spans": [], "ref_spans": []}, {"section": "III. COMMUTATION RELATIONS FOR E.M. FIELDS: MACROSCOPIC THEORY", "text": "From the general result of linear-response theory, Eq. (21), we then obtain the following expressions for the two-times expectation values of the commutators of the e.m. potentials:", "cite_spans": [], "ref_spans": []}, {"section": "III. COMMUTATION RELATIONS FOR E.M. FIELDS: MACROSCOPIC THEORY", "text": "where t > t \u2032 . For our purposes, it is convenient to split the Green's functions, outside the bodies, as sums of an empty-space contribution plus a correction arising from the material bodies:", "cite_spans": [], "ref_spans": []}, {"section": "III. COMMUTATION RELATIONS FOR E.M. FIELDS: MACROSCOPIC THEORY", "text": "and", "cite_spans": [], "ref_spans": []}, {"section": "III. COMMUTATION RELATIONS FOR E.M. FIELDS: MACROSCOPIC THEORY", "text": "\u22a5 denote the Green's functions in free space, while F (mat) and F (mat) \u22a5 describe the effects resulting from the presence of the bodies. Such a splitting presents the advantage that all singularities are included in the free parts G (0) and G", "cite_spans": [], "ref_spans": []}, {"section": "III. COMMUTATION RELATIONS FOR E.M. FIELDS: MACROSCOPIC THEORY", "text": "\u22a5 , while the quantities F (mat) and F (mat) \u22a5 are smooth ordinary functions of r and r \u2032 . The free-field Green's functions have the following well-known expressions:", "cite_spans": [], "ref_spans": []}, {"section": "III. COMMUTATION RELATIONS FOR E.M. FIELDS: MACROSCOPIC THEORY", "text": "and", "cite_spans": [], "ref_spans": []}, {"section": "III. COMMUTATION RELATIONS FOR E.M. FIELDS: MACROSCOPIC THEORY", "text": "(41) The factor \u03b4(t\u2212t \u2032 ) in the expression of G (0) expresses the instantaneous character of the longitudinal electric field in the Coulomb gauge. The expressions for the equaltime commutators of the e.m. fields are easily derived by taking suitable limits of Eqs. (35-37) and of their time derivatives, for t \u2192 t \u2032+ . Upon using Eqs. (38) and (39), and exploiting the following three relations that are obvious consequences of Eq. (1):", "cite_spans": [], "ref_spans": []}, {"section": "III. COMMUTATION RELATIONS FOR E.M. FIELDS: MACROSCOPIC THEORY", "text": "and ", "cite_spans": [], "ref_spans": []}, {"section": "III. COMMUTATION RELATIONS FOR E.M. FIELDS: MACROSCOPIC THEORY", "text": "[A \u22a5i (r, t), E \u22a5j (r \u2032 , t)]", "cite_spans": [], "ref_spans": []}, {"section": "III. COMMUTATION RELATIONS FOR E.M. FIELDS: MACROSCOPIC THEORY", "text": "and", "cite_spans": [], "ref_spans": []}, {"section": "III. COMMUTATION RELATIONS FOR E.M. FIELDS: MACROSCOPIC THEORY", "text": "where we defined", "cite_spans": [], "ref_spans": []}, {"section": "III. COMMUTATION RELATIONS FOR E.M. FIELDS: MACROSCOPIC THEORY", "text": "and are zero. We shall prove below that this indeed the case, as a result of analyticity and fall off properties at large frequencies of the reflection coefficients of all real materials.", "cite_spans": [], "ref_spans": []}, {"section": "III. COMMUTATION RELATIONS FOR E.M. FIELDS: MACROSCOPIC THEORY", "text": "Before we turn to detailed computations, we present below the field Equations satisfied by G and G \u22a5 . They are conveniently expressed in terms of the (one-sided) Fourier transforms of the Green's functions, defined as:", "cite_spans": [], "ref_spans": []}, {"section": "III. COMMUTATION RELATIONS FOR E.M. FIELDS: MACROSCOPIC THEORY", "text": "From Maxwell Equations we then obtain:", "cite_spans": [], "ref_spans": []}, {"section": "III. COMMUTATION RELATIONS FOR E.M. FIELDS: MACROSCOPIC THEORY", "text": "where \u03b4 \u22a5 (r\u2212r \u2032 ) is the transverse delta-function dyad, Eq. (6). These Equations must be solved with the appropriate b.c. at the bodies interfaces, and must be subject to the conditions required for a retarded Green's function [23] . For later use, it is useful to recall the main properties enjoyed by the Green's functions [24] . First of all, they satisfy the following reciprocity relations:", "cite_spans": [{"start": 229, "end": 233, "text": "[23]", "ref_id": "BIBREF31"}], "ref_spans": []}, {"section": "III. COMMUTATION RELATIONS FOR E.M. FIELDS: MACROSCOPIC THEORY", "text": "andG", "cite_spans": [], "ref_spans": []}, {"section": "III. COMMUTATION RELATIONS FOR E.M. FIELDS: MACROSCOPIC THEORY", "text": "that are a consequence of microscopic reversibility. The next set of properties express reality features of the Green' functions, and are a direct consequence of reality of the external sources", "cite_spans": [], "ref_spans": []}, {"section": "III. COMMUTATION RELATIONS FOR E.M. FIELDS: MACROSCOPIC THEORY", "text": "The next set of properties is a consequence of the fact that the permittivity \u01eb(\u03c9) of any causal medium is an analytic function of the frequency w in the upper complex half-plane C + [25] (see also Appendix B)). This implies that the Green's functionsG(r, r \u2032 , \u03c9) andG \u22a5 (r, r \u2032 , \u03c9) are also analytic in C + , as it must be case for a retarded response function. In C + they satisfy the conditionsG", "cite_spans": [{"start": 183, "end": 187, "text": "[25]", "ref_id": "BIBREF33"}], "ref_spans": []}, {"section": "III. COMMUTATION RELATIONS FOR E.M. FIELDS: MACROSCOPIC THEORY", "text": ", that generalize the reality conditions Eq. (61) and Eq. (62), respectively. These more general properties imply that the Green's functions are real along the imaginary frequency axis:", "cite_spans": [], "ref_spans": []}, {"section": "III. COMMUTATION RELATIONS FOR E.M. FIELDS: MACROSCOPIC THEORY", "text": "It is finally useful to write down the inversion formulas expressing the Green's functions, in the time domain, in terms of their Fourier transforms. They are", "cite_spans": [], "ref_spans": []}, {"section": "III. COMMUTATION RELATIONS FOR E.M. FIELDS: MACROSCOPIC THEORY", "text": "where \u0393 is any contour in C + that can be obtained by smoothly deforming the real frequency axis, keeping fixed the end-points at infinity. Analyticity of the Green's functions in C + ensures that the integrals on the r.h.s. are independent of the chosen contour \u0393.", "cite_spans": [], "ref_spans": []}, {"section": "III. COMMUTATION RELATIONS FOR E.M. FIELDS: MACROSCOPIC THEORY", "text": "In the next two sections we shall compute the Green functions at points outside a single dielectric slab, and between two plane parallel slabs.", "cite_spans": [], "ref_spans": []}, {"section": "IV. GREEN'S FUNCTIONS OUTSIDE DIELECTRICS AND CONDUCTORS", "text": "In this Section we evaluate the e.m. Green's functions outside dielectric and/or conducting slabs.", "cite_spans": [], "ref_spans": []}, {"section": "IV. GREEN'S FUNCTIONS OUTSIDE DIELECTRICS AND CONDUCTORS", "text": "In the next two subsections we shall separately consider the cases of one slab in vacuum, and two plane-parallel slabs separated by an empty gap. We choose our cartesian coordinate system such that the z-axis is perpendicular to the slabs. Translational invariance of the system in the (x, y) plane implies that the quantitiesF (mat) and", "cite_spans": [], "ref_spans": []}, {"section": "IV. GREEN'S FUNCTIONS OUTSIDE DIELECTRICS AND CONDUCTORS", "text": "are functions only of z, z \u2032 and (r \u22a5 \u2212 r \u2032 \u22a5 ), where we denote by x \u22a5 the projection of the vector x onto the (x, y) plane. The computation is facilitated if we express", "cite_spans": [], "ref_spans": []}, {"section": "IV. GREEN'S FUNCTIONS OUTSIDE DIELECTRICS AND CONDUCTORS", "text": "\u22a5 in a form that is adapted to the symmetries of our problem. Consider first the free scalar Green's functionG", "cite_spans": [], "ref_spans": []}, {"section": "IV. GREEN'S FUNCTIONS OUTSIDE DIELECTRICS AND CONDUCTORS", "text": "We note thatG (0) is independent of the complex frequency w, as it must be because of the instantaneous character of the longitudinal electric field in the Coulomb gauge. For our purposes, the convenient form ofG (0) is the following well-known Weyl representation:", "cite_spans": [], "ref_spans": []}, {"section": "IV. GREEN'S FUNCTIONS OUTSIDE DIELECTRICS AND CONDUCTORS", "text": "that can be easily obtained by integrating over k 3 the standard plane-wave decomposition ofG (0) . The above expression forG (0) can also be written as", "cite_spans": [], "ref_spans": []}, {"section": "IV. GREEN'S FUNCTIONS OUTSIDE DIELECTRICS AND CONDUCTORS", "text": "where we definek (\u00b1) = k \u22a5 \u00b1ik \u22a5\u1e91 , and the upper (lower) sign is for z \u2265 z \u2032 (z \u2264 z \u2032 ). Consider now the familiar representation ofG", "cite_spans": [], "ref_spans": []}, {"section": "IV. GREEN'S FUNCTIONS OUTSIDE DIELECTRICS AND CONDUCTORS", "text": "\u22a5 :", "cite_spans": [], "ref_spans": []}, {"section": "IV. GREEN'S FUNCTIONS OUTSIDE DIELECTRICS AND CONDUCTORS", "text": "where k 0 = w/c. In Appendix A, we show thatG", "cite_spans": [], "ref_spans": []}, {"section": "IV. GREEN'S FUNCTIONS OUTSIDE DIELECTRICS AND CONDUCTORS", "text": "\u22a5 can be decomposed as the sum of two dyads:", "cite_spans": [], "ref_spans": []}, {"section": "IV. GREEN'S FUNCTIONS OUTSIDE DIELECTRICS AND CONDUCTORS", "text": "Here,\u0168 (0) denotes the tensor of components", "cite_spans": [], "ref_spans": []}, {"section": "IV. GREEN'S FUNCTIONS OUTSIDE DIELECTRICS AND CONDUCTORS", "text": "ij , it can be written as", "cite_spans": [], "ref_spans": []}, {"section": "IV. GREEN'S FUNCTIONS OUTSIDE DIELECTRICS AND CONDUCTORS", "text": "where\u03a8 (0) is the functio\u00f1", "cite_spans": [], "ref_spans": []}, {"section": "IV. GREEN'S FUNCTIONS OUTSIDE DIELECTRICS AND CONDUCTORS", "text": "In both Eqs. (72) and (74) the upper (lower) sign is for z \u2265 z \u2032 (z \u2264 z \u2032 ). It is useful to provide a simple intuitive interpretation for the above Green's functions that will be useful later when we consider the influence of a material slab. Consider first the expression forG (k (\u2212) ). We note that for k 0 > k \u22a5 these modes represent propagating waves, while for k 0 < k \u22a5 they are evanescent waves, that decay exponentially as we move away from z \u2032 . The second contribution toG", "cite_spans": [], "ref_spans": []}, {"section": "IV. GREEN'S FUNCTIONS OUTSIDE DIELECTRICS AND CONDUCTORS", "text": ", can instead be interpreted as representing scalar waves that propagate instantaneously from point r \u2032 in the right (left) direction, with wave-vectork (+) (k (\u2212) ).", "cite_spans": [], "ref_spans": []}, {"section": "IV. GREEN'S FUNCTIONS OUTSIDE DIELECTRICS AND CONDUCTORS", "text": "We are now ready to computeF (bodies) andF (bodies) \u22a5 . We consider first the one-slab case.", "cite_spans": [], "ref_spans": []}, {"section": "A. The case of one slab", "text": "In this Section we compute the Green's functions outside a single dielectric or conducting slab, occupying the half-space z < 0. Following the remarks of the previous Section, outside the slab and on its surface, i.e. for z, z \u2032 \u2265 0 we define:", "cite_spans": [], "ref_spans": []}, {"section": "A. The case of one slab", "text": "and", "cite_spans": [], "ref_spans": []}, {"section": "A. The case of one slab", "text": "Fixing once and for all z \u2032 \u2265 0, we make forF (wall) the following ansatz:", "cite_spans": [], "ref_spans": []}, {"section": "A. The case of one slab", "text": "(77) For z < 0, the complete Green's function is taken to be of the form:", "cite_spans": [], "ref_spans": []}, {"section": "A. The case of one slab", "text": "(78) Both ansatz ensure appropriate fall off for |z| \u2192 \u221e. It is easy to verify that the above ansatz satisfy the b.c. at z = 0, provided that we take:", "cite_spans": [], "ref_spans": []}, {"section": "A. The case of one slab", "text": "andt (w) = 1 \u2212r(w) .", "cite_spans": [], "ref_spans": []}, {"section": "A. The case of one slab", "text": "The chosen forms ofF (wall) , for z > 0, andG (wall) , for z < 0, have a simple physical interpretation, that will be be useful later when we shall consider the more elaborate case of two slabs. In empty space, the source\u03c1(r \u2032 , w) generates \"instantaneous\" scalar waves of (complex) frequency w originating at r \u2032 and propagating in the right direction (i.e. towards larger z) with (complex) wavevectork (+) , and in the left direction with wave-vector k (\u2212) . When a wall is present, the left-moving waves hit the wall and then we have a reflected wave with amplituder(w), and a transmitted wave of amplitudet(w).", "cite_spans": [], "ref_spans": []}, {"section": "A. The case of one slab", "text": "We can now evaluateF", "cite_spans": [], "ref_spans": []}, {"section": "A. The case of one slab", "text": ". In a way analogous to Eq. (71), we decompose it as:", "cite_spans": [], "ref_spans": []}, {"section": "A. The case of one slab", "text": "Inside the slab, for the full Green's function we set instead:", "cite_spans": [], "ref_spans": []}, {"section": "A. The case of one slab", "text": "Linearity of the boundary-value problem permits to determine separately\u0168 (wall) and\u1e7c (wall) . The physical picture of\u0168 (0) as a superposition of TE and TM waves, suggests at once the following ansatz for\u0168 (wall) :", "cite_spans": [], "ref_spans": []}, {"section": "A. The case of one slab", "text": "where r (s) (w, k \u22a5 ) and r (p) (w, k \u22a5 ) are the familiar Fresnel reflections coefficients for TE and TM waves, respectively:", "cite_spans": [], "ref_spans": []}, {"section": "A. The case of one slab", "text": "where q = \u01eb(w)k 2 0 \u2212 k 2 \u22a5 . A somewhat lengthy solution of the boundary-value problem indeed confirms the above intuitive form of\u0168 (wall) ij . Consider now\u1e7c (wall) . Eq. (74) suggests that we set:", "cite_spans": [], "ref_spans": []}, {"section": "A. The case of one slab", "text": "while inside the slab (i.e. for z < 0) we set:", "cite_spans": [], "ref_spans": []}, {"section": "A. The case of one slab", "text": "It can be seen that the appropriate boundary dielectric conditions at z = 0 are satisfied, provided that the functions\u03a8 (0) ,\u03a8 (wall) and\u03a8 (in) fulfill there the following b.c.:", "cite_spans": [], "ref_spans": []}, {"section": "A. The case of one slab", "text": "where a prime denotes a derivative with respect to z. One then finds:", "cite_spans": [], "ref_spans": []}, {"section": "A. The case of one slab", "text": "wherer(\u03c9) is the reflection coefficient in Eq. (79). We note that the expression of\u03a8 (wall) coincides with that of F (wall) . We remark thatF (wall) andF (wall) \u22a5 are analytic functions of the frequency w in the upper complex plane C + , as a result of analyticity in C + of the reflection coefficientsr(w), r (\u03b1) (w) (see Appendix B). Moreover, we note thatF (wall) has no singularities along the real-frequency axis, as it can be easily checked from Eq. (77), if one considers that the reflection coefficientr(w) is finite in C + (see Appendix B). As toF 86)) does not cause any further singularities at w = 0, for it can be verified that these singular terms cancel each other upon taking the sum of\u0168 (wall) ij and\u1e7c (wall) ij , as we now show. Indeed, upon collecting in Eq. (83) and Eq. (86) the terms that are singular at w = 0, we obtain:", "cite_spans": [], "ref_spans": []}, {"section": "A. The case of one slab", "text": "where we made use of the following relations", "cite_spans": [], "ref_spans": []}, {"section": "A. The case of one slab", "text": "to substitute everywhere \u03be (\u00b1) , k (\u00b1) and k z by \u2213ik (\u00b1) , k (\u00b1) and k \u22a5 respectively. Now in Appendix B it is shown that both, for dielectrics and conductors, the difference r (p) \u2212r approaches zero as w 2 :", "cite_spans": [], "ref_spans": []}, {"section": "A. The case of one slab", "text": "Therefore, the ratio (r (p) \u2212r)/w 2 is finite as \u03c9 tends to zero, showing thatF", "cite_spans": [], "ref_spans": []}, {"section": "A. The case of one slab", "text": "is regular at w = 0.", "cite_spans": [], "ref_spans": []}, {"section": "B. The case of two plane-parallel slabs", "text": "In this Section we calculate the Green's functions for the case of a cavity constituted by two non-magnetic homogeneous, isotropic and spatially non-dispersive planeparallel slabs separated by vacuum. We assume that the slabs can be characterized by the respective electric permittivities, \u01eb 1 (w) and \u01eb 2 (w). We choose our cartesian coordinate system in such a way that slab one occupies the region \u2212\u221e < z \u2264 0, while slab two occupies the region d \u2264 z < \u221e, d being the separation between the two slabs. The formulae derived in the preceding Section, for the one slab case, can be easily generalized to the two slabs setting, on the basis of the intuitive physical picture of the free Green's functions as consisting of left and right moving waves originating from r \u2032 . Let us consider first the scalar Green's functionG. Analogously to what we did in the previous Section, inside the cavity (i.e. for 0 \u2264 z, z \u2032 \u2264 d) we set:", "cite_spans": [], "ref_spans": []}, {"section": "B. The case of two plane-parallel slabs", "text": "(96) The expression that one finds forF (cav) is analogous t\u00f5 F (wall) , but of course one must take account now of the possibility of multiple reflections off the two slabs. This is easily done, by inserting for each reflection by slab i the appropriate reflection coefficientsr i (w), that has an expression analogous to Eq. (79) (with \u01eb i (w) in the place of \u01eb(w)). Moreover, a factor e \u22122k \u22a5 d must be included for each round-way trip from one slab to the other and back. One obtains:", "cite_spans": [], "ref_spans": []}, {"section": "B. The case of two plane-parallel slabs", "text": "For the transverse Green's function, we set:", "cite_spans": [], "ref_spans": []}, {"section": "B. The case of two plane-parallel slabs", "text": "withF", "cite_spans": [], "ref_spans": []}, {"section": "B. The case of two plane-parallel slabs", "text": "where the symbols have the obvious meaning, analogously to previous Section. The same arguments that led us to write Eq. (97) now give:", "cite_spans": [], "ref_spans": []}, {"section": "B. The case of two plane-parallel slabs", "text": "where r (\u03b1)", "cite_spans": [], "ref_spans": []}, {"section": "B. The case of two plane-parallel slabs", "text": "i , \u03b1 = s, p are the Fresnel reflection coeffcients of slab i for polarization \u03b1, and", "cite_spans": [], "ref_spans": []}, {"section": "B. The case of two plane-parallel slabs", "text": "we obtain:", "cite_spans": [], "ref_spans": []}, {"section": "B. The case of two plane-parallel slabs", "text": "wher\u1ebd", "cite_spans": [], "ref_spans": []}, {"section": "B. The case of two plane-parallel slabs", "text": "(102) Again we find, as in one slab case, that the expression of\u03a8 (cav) coincides with that ofF (cav) . The same considerations used in the one-slab case can be now repeated forF (cav) andF (cav) \u22a5 to show that both quantities are analytic in C + , and have a finite limit for vanishing w.", "cite_spans": [], "ref_spans": []}, {"section": "V. COMMUTATION RELATIONS FOR THE EM FIELDS INSIDE A CAVITY", "text": "In this Section we compute the quantities A (mat) , A \u22a5ij , respectively. We shall see that they all vanish, as a consequence of the analyticity and fall-off properties at large frequencies of the reflection coefficients of all real materials. As seen in Sec. III, vanishing of these quantities entails that the e.m. field satisfies free-field commutation relations in the empty region between the slabs.", "cite_spans": [], "ref_spans": []}, {"section": "V. COMMUTATION RELATIONS FOR THE EM FIELDS INSIDE A CAVITY", "text": "Consider first the quantity A (cav) (r, r \u2032 ). From its definition Eq. (51) it follows that A (cav) can be expressed in terms ofF (cav) as:", "cite_spans": [], "ref_spans": []}, {"section": "V. COMMUTATION RELATIONS FOR THE EM FIELDS INSIDE A CAVITY", "text": "whereF (cav) is given in Eq. (97). In Appendix B it is shown that the reflection coefficientr(w) of any real material vanishes like w \u22122 for large values of |w| and this implies, as can be seen by inspection of Eq. (97), thatF (cav) approaches zero like w \u22123 . ThereforeF (cav) is absolutely integrable, and then in Eq. (103) we can take the \u03c4 -limit inside the integral. After we do it we obtain:", "cite_spans": [], "ref_spans": []}, {"section": "V. COMMUTATION RELATIONS FOR THE EM FIELDS INSIDE A CAVITY", "text": "The w \u22123 fall-off rate of F (cav) at infinity now permits to close the integration contour in Eq. (104) in the upper complex w-plane C + , and then analyticity ofF (cav) in C + implies at once that the integral is zero. Therefore we conclude", "cite_spans": [], "ref_spans": []}, {"section": "V. COMMUTATION RELATIONS FOR THE EM FIELDS INSIDE A CAVITY", "text": "We turn now to the quantity A (cav) \u22a5ij (r, r \u2032 ). In view of its definition Eq. (52) we have", "cite_spans": [], "ref_spans": []}, {"section": "V. COMMUTATION RELATIONS FOR THE EM FIELDS INSIDE A CAVITY", "text": "and then to prove that it vanishes, we need consider the fall-off properties ofF \u22a5ij . We note first that, because of the k z factors in the exponentials, all terms in the r.h.s. of Eq. (100) decay exponentially fast as w goes to infinity in C + along any direction not parallel to the real axis. Along the real axis, since Fresnel reflection coefficients of all real materials decay like w \u22122 (see Appendix B),\u0168 (cav) \u22a5ij decays at least as fast as w \u22123 (in fact a more careful analysis carried out in Appendix C shows that the rate of decay is actually w \u22124 ). Therefore,F", "cite_spans": [], "ref_spans": []}, {"section": "V. COMMUTATION RELATIONS FOR THE EM FIELDS INSIDE A CAVITY", "text": "(cav) \u22a5ij decays in all directions in C + at least like w \u22123 and then, by following exactly the same reasoning used in the case of A (cav) (r, r \u2032 ) we can prove that", "cite_spans": [], "ref_spans": []}, {"section": "V. COMMUTATION RELATIONS FOR THE EM FIELDS INSIDE A CAVITY", "text": "We remark that the above equation holds also when either r or r \u2032 or both belong to the slabs surfaces. Consider now the quantity B ", "cite_spans": [], "ref_spans": []}, {"section": "V. COMMUTATION RELATIONS FOR THE EM FIELDS INSIDE A CAVITY", "text": "Finally, we consider the quantity C (cav) \u22a5ij (r, r \u2032 ). For this we have", "cite_spans": [], "ref_spans": []}, {"section": "V. COMMUTATION RELATIONS FOR THE EM FIELDS INSIDE A CAVITY", "text": "vanishes requires much more labor, because of the two extra powers of w in the integrand on the r.h.s. of Eq. (110). We relegate the proof in Appendix C, where we show that the decay rate ofF (cav) \u22a5ij is actually w \u22124 , which is sufficiently fast to imply:", "cite_spans": [], "ref_spans": []}, {"section": "V. COMMUTATION RELATIONS FOR THE EM FIELDS INSIDE A CAVITY", "text": "Having proved that the quantities A (cav) , A vanish, we then reach the important conclusion that in the empty space between two dielectric and/or conducting slabs the e.m. fields satisfy free-field equal-time commutation relations, Eq. (12) (13) (14) (15) (16) (17) . This result is consistent with what was expected on the basis of the microscopic theory, for a system of non-relativistic charged particles interacting with the e.m. field, as we have seen in Sec. II. We remark that no singularities are encountered as r and r \u2032 approach the slabs surfaces, and therefore the canonical form of the free-space commutators also holds on the surfaces of the slabs. It is important to realize that these results are intimately tied to analyticity and fall-off properties of the reflection coefficients of real materials.", "cite_spans": [], "ref_spans": []}, {"section": "VI. COMMUTATION RELATIONS OUTSIDE IDEAL CONDUCTORS", "text": "In this Section we investigate the commutation relations satisfied by the e.m. fields outside ideal conductors. Ideal conductors are characterized by the fact that they have constant reflection coefficients. Indeed, by taking the limit \u01eb \u2192 \u221e in Eqs. (79), (84) and (85) is minus one at all frequencies. Obviously, constant reflection coefficients are analytic in C + , and therefore the main difference between ideal conductors and real ones is that the reflection coefficients of the former do not vanish in the limit of large frequencies. We shall see below that this feature entails that the e.m. field outside the conductors, and on their surfaces, fail to satisfy free-field canonical equal-time commutation relations.", "cite_spans": [], "ref_spans": []}, {"section": "VI. COMMUTATION RELATIONS OUTSIDE IDEAL CONDUCTORS", "text": "In order to determine the commutation relations satisfied by the e.m. field we consider again Eqs. (45-50) that remain valid also for ideal conductors. All that we have to do then is to evaluate the quantities on the r.h.s. of these equations, using the values of the reflection coefficients pertaining to ideal conductors. We consider first the simpler case of a single conducting slab.", "cite_spans": [], "ref_spans": []}, {"section": "VI. COMMUTATION RELATIONS OUTSIDE IDEAL CONDUCTORS", "text": "We start by evaluating the quantity F (id wall) , where the superscript (id wall) stands for a slab made of an ideal metal. From Eq. (77) we note that forr(w) = 1,F (id wall) becomes independent of the frequency and, upon taking the inverse time-Fourier transform, one easily finds that F (id wall) is proportional to \u03b4(t \u2212 t \u2032 ). Then F (id wall) is zero for all t > t \u2032 and therefore from Eq. (35) we have", "cite_spans": [], "ref_spans": []}, {"section": "VI. COMMUTATION RELATIONS OUTSIDE IDEAL CONDUCTORS", "text": "Upon taking account also of Eq. (36) we see that outside an ideal conductor, all two-times commutators involving the scalar potential U have vanishing expectation values, and this implies U (r, t) \u2261 0 (ideal conductors).", "cite_spans": [], "ref_spans": []}, {"section": "VI. COMMUTATION RELATIONS OUTSIDE IDEAL CONDUCTORS", "text": "Therefore, outside an ideal conducting slab the longitudinal electric field is zero. We evaluate now the quantity F (id wall) \u22a5ij", "cite_spans": [], "ref_spans": []}, {"section": "VI. COMMUTATION RELATIONS OUTSIDE IDEAL CONDUCTORS", "text": ". Upon using the identity \u2212 e \u22a5i e \u22a5j + \u03be", "cite_spans": [], "ref_spans": []}, {"section": "VI. COMMUTATION RELATIONS OUTSIDE IDEAL CONDUCTORS", "text": "where \u03bb 1 = \u03bb 2 = \u2212\u03bb 3 = 1, one finds that, forr = r (p) = 1 and r (s) = \u22121, Eqs. (81), (83) and (90) lead to:", "cite_spans": [], "ref_spans": []}, {"section": "VI. COMMUTATION RELATIONS OUTSIDE IDEAL CONDUCTORS", "text": "(114) By a similar computation as the one described in Appendix A, it is possible to verify that the r.h.s. of the above equation can also be written in the following form:", "cite_spans": [], "ref_spans": []}, {"section": "VI. COMMUTATION RELATIONS OUTSIDE IDEAL CONDUCTORS", "text": "where 115) is analytic also there), and by noticing that the integrand has poles only at k 0 = \u00b1k. We get:", "cite_spans": [], "ref_spans": []}, {"section": "VI. COMMUTATION RELATIONS OUTSIDE IDEAL CONDUCTORS", "text": "Then, from Eq. (49) we obtain:", "cite_spans": [], "ref_spans": []}, {"section": "VI. COMMUTATION RELATIONS OUTSIDE IDEAL CONDUCTORS", "text": "where we defined", "cite_spans": [], "ref_spans": []}, {"section": "VI. COMMUTATION RELATIONS OUTSIDE IDEAL CONDUCTORS", "text": "We note that \u03b4 (id wall) ij is a smooth function for z + z \u2032 > 0 approaching zero for large z and z \u2032 , but it is singular when both z and z \u2032 belong to the slab surface (i.e. for z = z \u2032 = 0). In particular, for i = j = 1, Eq. (117) gives", "cite_spans": [], "ref_spans": []}, {"section": "VI. COMMUTATION RELATIONS OUTSIDE IDEAL CONDUCTORS", "text": "in agreement with the finding of Ref. [15] . By using Eq. (44), and Eq. (116), it is easy to verify that the canonical commutation relations for the components of the transverse electric field, Eq. (5) remain valid.", "cite_spans": [], "ref_spans": []}, {"section": "VI. COMMUTATION RELATIONS OUTSIDE IDEAL CONDUCTORS", "text": "We turn now to the more elaborate case of two planeparallel ideal slabs. We shall be brief here, the analysis being similar to the one slab case. First we note that, similarly toF (id wall) , also the quantityF (id cav) becomes independent of the frequency when perfectly reflecting slabs are considered, as it is easily seen from Eq. (97). Therefore, F (id cav) is proportional to \u03b4(t \u2212 t \u2032 ), and again we conclude the the scalar potential can be taken to be zero outside the slabs. We consider now the transverse Green's function. A somewhat lengthy, but straightforward computation analogous to the one done for the oneslab case, gives the following expression for the quantity F", "cite_spans": [], "ref_spans": []}, {"section": "VI. COMMUTATION RELATIONS OUTSIDE IDEAL CONDUCTORS", "text": "where", "cite_spans": [], "ref_spans": []}, {"section": "VI. COMMUTATION RELATIONS OUTSIDE IDEAL CONDUCTORS", "text": "By using this Equation, and recalling Eqs. (48) and (50), we easily see that the equal-time commutators for the vector potential on one hand and for the transverse electric field on the other, both vanish inside the cavity and on the slabs surfaces, in agreement with the free-field case, Eq. (3) and Eq. (5). On the other hand, from Eq. (49) we get:", "cite_spans": [], "ref_spans": []}, {"section": "VI. COMMUTATION RELATIONS OUTSIDE IDEAL CONDUCTORS", "text": "where", "cite_spans": [], "ref_spans": []}, {"section": "VI. COMMUTATION RELATIONS OUTSIDE IDEAL CONDUCTORS", "text": "(122) We note that the first and the second terms between the square brackets on the r.h.s. of Eq. (122) represent smooth functions of z and z \u2032 at all points between the slabs, including their surfaces, while the third and fourth terms are singular, respectively, on the surface of slab one (i.e. for z = z \u2032 = 0) and slab two (i.e. for z = z \u2032 = d). Moreover, we observe that in the limit of large separations d, and for fixed z and z \u2032 , the phase factors involving d in the first, second and fourth terms between the square brackets on the r.h.s. of Eq. (122), oscillate more and more rapidly, and so suppress the corresponding terms. In this limit \u03b4 (id cav) ij tends to \u03b4 (id wall) ij , and then Eq. (121) reproduces Eq. (117).", "cite_spans": [], "ref_spans": []}, {"section": "VI. COMMUTATION RELATIONS OUTSIDE IDEAL CONDUCTORS", "text": "From the above analysis, we see that while all other commutators have the free-field form, the presence of the extra terms \u03b4 (id wall) ij and \u03b4 (id cav) ij on the r.h.s. of Eqs. (117) and (121) respectively, implies that perfect-mirror b.c. lead to equal-time commutation relations for the vector potential and the electric field of a different form from the free-field ones, Eq. (4). In the one-slab case, Eqs. (117) and (118) show that the free-field form of the commutators is recovered only when the quantity \u03b4 (id cav) ij can be neglected, and this occurs at points z and z \u2032 that are far from the slab. In the cavity setting, Eqs. (121) and (122) show that free-field commutation relations are recovered only provided that the quantities 2d + z \u2212 z \u2032 , 2d \u2212 z + z \u2032 , z + z \u2032 and 2d \u2212 z \u2212 z \u2032 are simultaneously large. This is only possible for large cavities, and for points z and z \u2032 far form both conductors. This is in contrast with what was found in the previous Section, where we proved that in the case of real materials freefields equal-time canonical commutation relations retain their validity everywhere between the slabs, including on their surfaces.", "cite_spans": [], "ref_spans": []}, {"section": "VII. CONCLUDING REMARKS", "text": "In this paper we have determined the commutation relations satisfied by the quantized e.m. field outside one or two plane-parallel dielectric and/or conducting slabs in vacuum, assuming that the slabs are made of isotropic and homogeneous, spatially non-dispersive materials, with arbitrary frequency-dependent dispersion and absorption. Using a general form of macroscopic quantum electrodynamics, we have found that at all points between the slabs, including on their surfaces, the e.m. field satisfies canonical commutation relations of the same form as in empty space, in full agreement with the microscopic theory. This result is a general consequence of analyticity and fall-off properties at large frequencies satisfied by the reflection coefficients of all real materials.", "cite_spans": [], "ref_spans": []}, {"section": "VII. CONCLUDING REMARKS", "text": "We have also shown that free-field equal-time commutation relations do not obtain outside one or two conducting slabs, if the latter are modelled as perfect mirrors, because of extra terms that appear in the commutator of the vector potential with the electric field. Free-field commutators are only recovered at points that are sufficiently far from the mirror. In the one-slab setting, our findings coincide with those obtained by Milonni [15] in his investigation on the Casimir effect. Since no such deviation from free-field commutators is found in the case of real materials, we draw the conclusion that the modified form of the field commutation relations implied by perfect-mirror b.c. is an artifact of this idealized model, as it was conjectured to be the case in Ref. [17] on the basis of a simplified one-dimensional form of QED. Even if the commutator of the vector potential with the electric field, being a gauge dependent quantity, is not a physically observable quantity, failure of perfect mirror b.c. to reproduce the correct free-field form of the equal-time commutation relations near the surfaces of the conductors, indicates that a certain amount of caution should be used when these idealized b.c. are used in investigations of proximity phenomena originating from the quantized e.m. field in the presence of conductors.", "cite_spans": [], "ref_spans": []}, {"section": "VII. CONCLUDING REMARKS", "text": "Before closing, we would like to comment on possible generalization of the results derived in this paper to other materials, including magnetic materials, and non isotropic or spatially dispersive media. Consideration of isotropic magnetic materials offers no difficulties, because it just requires substituting in our formulae the well-known expression for Fresnel reflection coefficients, for a medium with magnetic permeability \u00b5. On the other hand, it is known today that the general formulae Eq. (35-37) expressing the expectation values of the field commutators in terms of their classical Green's functions, are valid for arbitrary media [27, 28] , and therefore one can use them also in the case of anisotropic and/or spatially dispersive media provided only that one is able to determine the reflection coefficients for a slab made of these materials. Since reflection coefficients of all media are analytic functions of the complex frequency in the upper complex plane, and fall off to zero at large frequencies [26] , it is therefore expected that (free-space) canonical commutation relations remain valid also for these more general materials.", "cite_spans": [{"start": 1022, "end": 1026, "text": "[26]", "ref_id": "BIBREF34"}], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "New Trends in Atomic Physics", "authors": [{"first": "S", "middle": [], "last": "Haroche", "suffix": ""}], "year": 1984, "venue": "", "link": null}, "BIBREF3": {"title": "243 (1993) and references therein", "authors": [{"first": "P", "middle": [], "last": "Meystre", "suffix": ""}], "year": "", "venue": "Phys. Rep", "link": null}, "BIBREF5": {"title": "see also the special issue on Proccedings of the 8th Workshop on Quantum Field Theory under the Influence of External Conditions", "authors": [{"first": "K", "middle": ["A"], "last": "Milton", "suffix": ""}], "year": 2004, "venue": "", "link": null}, "BIBREF14": {"title": "Statistical Mechanics of Equilibrium and Non-Equilibrium Systems", "authors": [{"first": "R", "middle": [], "last": "Kubo", "suffix": ""}], "year": 1965, "venue": "", "link": null}, "BIBREF15": {"title": "Theory of Electrical Fluctuations and Thermal Radiation (Publyshing House, Academy os Sciences", "authors": [{"first": "S", "middle": ["M"], "last": "Rytov", "suffix": ""}], "year": 1953, "venue": "", "link": null}, "BIBREF17": {"title": "Landau and Lifshitz Course of Theoretical Physics: Statistical Physics Part II", "authors": [{"first": "E", "middle": ["M"], "last": "Lifshitz", "suffix": ""}, {"first": "L", "middle": ["P"], "last": "Pitaevskii", "suffix": ""}], "year": 1980, "venue": "", "link": null}, "BIBREF30": {"title": "Photons and Atoms, Introduction to Quantum Electrodynamics", "authors": [{"first": "C", "middle": [], "last": "Cohen-Tannoudji", "suffix": ""}, {"first": "J", "middle": [], "last": "Dupont-Roc", "suffix": ""}, {"first": "G", "middle": [], "last": "Grynberg", "suffix": ""}], "year": 1989, "venue": "", "link": "123590331"}, "BIBREF31": {"title": "Methods of Quantum Fields Theory in Statistical Physics", "authors": [{"first": "A", "middle": ["A"], "last": "Abrikosov", "suffix": ""}, {"first": "L", "middle": ["P"], "last": "Gorkov", "suffix": ""}, {"first": "I", "middle": ["E"], "last": "Dzyaloshinski", "suffix": ""}], "year": 1963, "venue": "", "link": null}, "BIBREF33": {"title": "Landau and Lifshitz Course of Theoretical Physics: Electrodynamics of Continuous Media", "authors": [{"first": "L", "middle": ["D"], "last": "Landau", "suffix": ""}, {"first": "E", "middle": ["M"], "last": "Lifshitz", "suffix": ""}], "year": 1960, "venue": "", "link": null}, "BIBREF34": {"title": "Optical Properties of Solids", "authors": [{"first": "F", "middle": [], "last": "Wooten", "suffix": ""}], "year": 1972, "venue": "", "link": "120739070"}}, "ref_entries": {"FIGREF1": {"text": "Eq. (69): we can interpret is as consisting of a superposition of instantaneous scalar waves originat- ing from point r \u2032 , that propagate to the right (left) with wave-vectork (+) (k (\u2212) ). Consider now our expression forG (0) \u22a5 , Eq.(71). Its first contribution\u0168 (0) , Eq. (72), can be physically interpreted as a superposition of e.m. waves with TE and TM polarization corresponding, re- spectively, to the first and second term between the round brackets in Eq. (72). These waves originate from point r \u2032 and propagate to the right (left) with wave-vector k (+)", "type": "figure"}, "FIGREF2": {"text": "Eq. (83) and Eq. (", "type": "figure"}, "FIGREF3": {"text": "two slab setting consid- ered in the previous Section. The corresponding quanti- ties shall be denoted by A (cav)", "type": "figure"}, "FIGREF4": {"text": "cav) \u22a5ij . According to Eq. (99), it is the sum of two terms:F", "type": "figure"}, "FIGREF5": {"text": "the w \u22123 fall-off rate ofF (cav) \u22a5ij (w), the extra power of w does not spoil convergence of the w-integral on the r.h.s. of Eq. (108), and therefore the same arguments used to prove that A (cav) \u22a5ij is zero can be used to obtain B (cav) \u22a5ij (r, r \u2032 ) = 0 .", "type": "figure"}, "TABREF1": {"text": "from Eqs. (35-37) we obtain:", "type": "table"}, "TABREF4": {"text": "From this expression we see that in the case of an ideal wallFas we found in the case of a slab made of a real material. This fall- off rate is sufficient to prove, by the same steps used in the previous Section, that Eq. (107) remains valid. Therefore we find that also in the case of an ideal slab the equal-time commutators for the vector potential have the canonical form Eq. (3) at all points outside the slab, including its surface. The w \u22122 fall-off rate is not sufficient however to ensure validity of Eq. (109), and we show now that for an ideal conductor Eq. (109) indeed fails to be true. To see this we take the inverse Fourier transform of Eq. (115), as defined in Eq. (66). The frequency integral, for t > t \u2032 can be easily evaluated by closing the contour \u0393 in the lower complex plane (which is possible now because the r.h.s. of Eq. (", "type": "table"}}}
{"paper_id": "118863510", "_pdf_hash": "dca1225cdb32ece467816082f0b9e27026c77473", "abstract": [{"section": "Abstract", "text": "The Barab\u00e1si-Bianconi (BB) fitness model can be solved by a mapping between the original network growth model to an idealized bosonic gas. The well-known transition to Bose-Einstein condensation in the latter then corresponds to the emergence of \"super-hubs\" in the network model. Motivated by the preservation of the scale-free property, thermodynamic stability and self-duality, we generalize the original extensive mapping of the BB fitness model by using the nonextensive Kaniadakis \u03ba-distribution. Through numerical simulation and mean-field calculations we show that deviations from extensivity do not compromise qualitative features of the phase transition. Analysis of the critical temperature yields a monotonically decreasing dependence on the nonextensive parameter \u03ba.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Over the last twenty years, research about complex networks has yielded many insights into a large number of real-world systems in various contexts, with systems as diverse as the World Wide Web, social media, power grids, transportation networks and gene regulation networks being prime examples, cf. [1, 2, 3] for reviews on the field.", "cite_spans": [{"start": 302, "end": 305, "text": "[1,", "ref_id": "BIBREF0"}, {"start": 306, "end": 308, "text": "2,", "ref_id": "BIBREF1"}, {"start": 309, "end": 311, "text": "3]", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "Introduction", "text": "The network paradigm has proven very useful in quantifying the topology of interactions in these systems. In recent years the interest of the scientific community has shifted from analysis of purely static structures towards attempts at gaining insights into dynamically evolving or optimized networks [2] . In many applications statistical physics has provided a powerful toolbox, sometimes discovering surprising parallels between networked systems and other physical systems. One example of such a parallel is the Barab\u00e1si-Bianconi (BB) model [4, 5] , which describes a process of network evolution guided by a combination of preferential attachment and intrinsic fitness properties of nodes [2] .", "cite_spans": [{"start": 302, "end": 305, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 546, "end": 549, "text": "[4,", "ref_id": "BIBREF3"}, {"start": 550, "end": 552, "text": "5]", "ref_id": "BIBREF4"}, {"start": 695, "end": 698, "text": "[2]", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Introduction", "text": "In [5] , a mapping between the growing network and a bosonic gas undergoing a Bose-Einstein condensation was proposed, realized by means of extensive statistical mechanics, and solved via a mean field approach. No interactions between particles or energy level transitions were contemplated. Interesting behaviour is found when introducing a fictitious temperature parameter T regulating the network dynamics. Even for T \u2192 0 the bosonic gas counterpart exhibits a ground state in which only half of the particles reach the minimum energy level, the others being scattered in fixed positions throughout the whole energy spectrum [5, 6] . This anomalous thermodynamic behavior is incompatible with the Boltzmann weight used for the original mapping. In fact, a purely physical perspective would suggest that in equilibrium all the bosons of the Bose-Einstein condensate populate the minimum energy level in the ground state. This anomaly has motivated research into applications of deformed non-Gaussian statistics [7, 8] and it is of interest to generalize the mapping between bosonic gases and growing networks by recurring to a nonextensive deformation of the original equilibrium Boltzmann-Gibbs distribution. Even though Information Theory seems to suggest a link between non-ergodic behavior and nonextensive statistics in nature, the emergence of non-Gaussian statistics for complex systems, as, e.g., growing complex networks, has not yet been fully understood [9] .", "cite_spans": [{"start": 3, "end": 6, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 628, "end": 631, "text": "[5,", "ref_id": "BIBREF4"}, {"start": 632, "end": 634, "text": "6]", "ref_id": "BIBREF5"}, {"start": 1013, "end": 1016, "text": "[7,", "ref_id": "BIBREF6"}, {"start": 1017, "end": 1019, "text": "8]", "ref_id": "BIBREF7"}, {"start": 1467, "end": 1470, "text": "[9]", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "Introduction", "text": "To the best of our knowledge one recent study [10] of the BB model using Tsallis' q-statistics [7] is the only previous investigation of extensions of the BB model to nonextensive statistics. Properties of the q-statistics make it very difficult to find exact results and the insights gained by [10] are limited to numerical simulation. Further, it has been argued [11] that non-extensive statistics should have the following characteristics: (i) preservation of scale-free property, (ii) self-duality, and (iii) thermodynamic stability. Even though the Tsallis q-exponential gives rise to power-laws in many real world modelling applications [7] it does not satisfy self-duality. This gives an added interest to the Kanidakis \u03ba-distribution which meets all three requirements. The \u03ba-deformed statistical mechanics was originally proposed in the context of non-linear kinetics in particle systems and is deeply linked to the structure of special relativity [11] . In the last decade, \u03ba-deformed statistics have been successfully applied to model the distribution of stellar rotational velocities of dwarf stars [12] , cosmic ray fluxes [11] , the formation of Quark-Gluon plasmas [13] , and the income distribution of the USA, UK, Germany and Italy [8] . Moreover, the use of \u03ba-deformed statistics has led to some insight [14] in addressing the inadequacy of the Bose-Einstein distribution in predicting the fluid-superfluid transition temperature in 4 He . The latter gives an additional motivation for our application of \u03ba-deformed statistics to models of network formation.", "cite_spans": [{"start": 46, "end": 50, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 95, "end": 98, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 295, "end": 299, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 365, "end": 369, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 643, "end": 646, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 957, "end": 961, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 1111, "end": 1115, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 1136, "end": 1140, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 1180, "end": 1184, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 1249, "end": 1252, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 1322, "end": 1326, "text": "[14]", "ref_id": "BIBREF13"}, {"start": 1451, "end": 1452, "text": "4", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "Introduction", "text": "In this article we show that the Kaniadakis \u03ba-distribution can be used to generalize the BB bosonic mapping.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "In contrast to previous numerical results based on q-statistics [10] , analytical mean-field results can be retrieved with the \u03ba-deformed distribution. Our findings show that the use of the Kaniadakis \u03ba-distribution does not alter the qualitative presence of condensation. We show both analytically and numerically that the main influence of the nonextensive parameter is a systematic shift of the critical temperature with \u03ba.", "cite_spans": [{"start": 64, "end": 68, "text": "[10]", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "Introduction", "text": "Our paper is organized as follows. In Section I we briefly review some of the properties of the BB fitness model and its original extensive mapping to a Bose-Einstein condensate. In Section II we summarize some basic results of the Kaniadakis \u03ba-distribution and generalize them to the nonextensive mapping. Finally, in Section III numerical results for the critical temperatures for different values of the nonextensive parameter are presented and compared to analytical findings. In the same section, we will also analyze the degree distribution of our generalized model, by using both analytical and numerical methods.", "cite_spans": [], "ref_spans": []}, {"section": "The Barab\u00e1si-Bianconi Fitness Model", "text": "The BB model [5, 4] is a model that describes network evolution as an incremental growth process. At each time step a new node, say j, is added to the growing network and it is assigned a fitness \u03b7 j , i.e. a positive real number randomly drawn from a distribution \u03c1 (\u03b7). Then connections from j to m of the n old nodes are formed one at a time, such that each time old nodes can attract a link from the new node with a probability given by", "cite_spans": [{"start": 13, "end": 16, "text": "[5,", "ref_id": "BIBREF4"}, {"start": 17, "end": 19, "text": "4]", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "The Barab\u00e1si-Bianconi Fitness Model", "text": "which is proportional to both the fitness \u03b7 i and the degree k i of the node. This preferential attachment dynamics consistently reproduces some features present in many real world networks [2, 1] , which exhibit big hubs with different age. The fitness parameter influences the competition for new connections. Without it, as in the \"pure\" preferential attachement model [15] , \"older\" nodes are always on average more connected than younger nodes.", "cite_spans": [{"start": 190, "end": 193, "text": "[2,", "ref_id": "BIBREF1"}, {"start": 194, "end": 196, "text": "1]", "ref_id": "BIBREF0"}, {"start": 372, "end": 376, "text": "[15]", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "The Barab\u00e1si-Bianconi Fitness Model", "text": "Including the fitness aspects, highly connected nodes can be old nodes, but could also be \"young\" nodes with high intrinsic fitness. One of the most interesting features of the Barab\u00e1si-Albert (BA) and BB models is the fact that they both can produce scale-free networks with power-law degree distributions P (k) [5, 4] , namely P (k) \u223c Ax ", "cite_spans": [{"start": 313, "end": 316, "text": "[5,", "ref_id": "BIBREF4"}, {"start": 317, "end": 319, "text": "4]", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "Extensive mapping with a Bose-Einstein system and the Network Condensation", "text": "In [5] , Bianconi realized a mapping between the asymptotic structure of the network and an hypothetical Bose gas by setting \u03b7 i = e \u2212\u03b2 i . In this formulation \u03b2 is the inverse of a fictitious network temperature T and i is the energy level for node i. Every node of the network represents one energy level while every edge between two nodes i and j represents two non-interacting particles, one on level i and the other on level j . It can be shown [5, 4, 6, 16] that preferential attachment driven by the probability \u03a0 undergoes a phase transition at some critical temperature T c , which is formally identical to that of Bose-Einstein condensation. At high temperatures, T > T c , even in the thermodynamic limit the hubs of the network participate in a competition for the \"survival-of-the-fittest\" while at lower temperatures, for T < T c , a unique \"super-hub\" eventually emerges and wins the competition [16] (this represents a \"winner-takes-all \" phenomenon encountered in many real-world applications [2] ). By using the network mapping of edges to a physical system of 2N bosons, it is evident that eventually only half of them can \"reach\" the fundamental energy level of the network, which corresponds to the highest fitness present.", "cite_spans": [{"start": 3, "end": 6, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 450, "end": 453, "text": "[5,", "ref_id": "BIBREF4"}, {"start": 454, "end": 456, "text": "4,", "ref_id": "BIBREF3"}, {"start": 457, "end": 459, "text": "6,", "ref_id": "BIBREF5"}, {"start": 460, "end": 463, "text": "16]", "ref_id": "BIBREF15"}, {"start": 911, "end": 915, "text": "[16]", "ref_id": "BIBREF15"}, {"start": 1010, "end": 1013, "text": "[2]", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Kaniadakis Mapping", "text": "The Kaniadakis \u03ba-distribution [11] , was originally introduced in 2002 and later re-obtained within the framework of a Jaynes Maximum Entropy principle [17] , which starts from a generalized system entropy S \u03ba given by", "cite_spans": [{"start": 30, "end": 34, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 152, "end": 156, "text": "[17]", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "Kaniadakis Mapping", "text": "with p l being the probability of the system being in state l and \u03ba \u2208 (\u22121, 1). It can be shown that the generalized logarithm ln \u03ba (x) is self-scaling and self-dual [17] , as the ordinary logarithm ln (x) of the Boltzmann-Shannon entropy", "cite_spans": [{"start": 165, "end": 169, "text": "[17]", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "Kaniadakis Mapping", "text": "The parameter \u03ba can be seen as a deviation from extensivity, as ln \u03ba (x) recovers the extensive case when \u03ba \u2192 0.", "cite_spans": [], "ref_spans": []}, {"section": "Kaniadakis Mapping", "text": "The inverse of the generalized logarithm is the generalized exponential [11, 17] ,", "cite_spans": [{"start": 72, "end": 76, "text": "[11,", "ref_id": "BIBREF10"}, {"start": 77, "end": 80, "text": "17]", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "Kaniadakis Mapping", "text": "which has power-law tails given by the asymptotics e Mimicking the mapping of the original BA model, we consider the fitness \u03b7 i as", "cite_spans": [], "ref_spans": []}, {"section": "Kaniadakis Mapping", "text": "where the energy level i = \u2212\u03b2 \u22121 ln \u03ba \u03b7 i can be thought of as a transformation of a random variable distributed according to the distribution g ( ), the latter having the physical interpretation of an energy level density. In order for the network to undergo a Bose-Einstein phase transition, it is required that g ( ) \u2192 0 when \u2192 0 [5, 4, 10] .", "cite_spans": [{"start": 333, "end": 336, "text": "[5,", "ref_id": "BIBREF4"}, {"start": 337, "end": 339, "text": "4,", "ref_id": "BIBREF3"}, {"start": 340, "end": 343, "text": "10]", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "Kaniadakis Mapping", "text": "With this generalization, Eq. (1.1) for the degree k i becomes", "cite_spans": [], "ref_spans": []}, {"section": "Kaniadakis Mapping", "text": "where Z \u03ba is our network partition function. We want to look for solutions k i which mimic the analytical form of the solution for the BA model [5] ,", "cite_spans": [{"start": 144, "end": 147, "text": "[5]", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "Kaniadakis Mapping", "text": "where A m depends on the parameter m while f \u03ba = f \u03ba ( i ) is some still unknown dynamic exponent strictly bounded by 0 and 1. This functional form implies that the number of connections of every node increases in time (f \u03ba > 0)", "cite_spans": [], "ref_spans": []}, {"section": "Kaniadakis Mapping", "text": "but not as fast or faster than t itself (f \u03ba < 1). We can solve the above differential equation by applying a mean field approximation, in which we replace the partition sum Z \u03ba by its average Z \u03ba ,", "cite_spans": [], "ref_spans": []}, {"section": "Kaniadakis Mapping", "text": "For this purpose we introduce a chemical potential \u00b5 and a mean fugacity z \u03ba = e \u03b2\u00b5 \u03ba and hence by using the thermodynamical stability of the deformed \u03ba-exponential [17] one obtains:", "cite_spans": [{"start": 165, "end": 169, "text": "[17]", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "Kaniadakis Mapping", "text": "Here \u03b1 = f \u03ba ( )\u22121 < 0 and then t \u03b1 \u2192 0 in the thermodynamic limit. Comparing to the extensive case (obtained when \u03ba \u2192 0), it has to be Z \u03ba \u03ba\u21920 \u2212\u2192 mt/z for big enough networks. As by construction A m is independent of \u03ba we can choose A m = m. Within this approximation Eq. (2.4) has a solution of the same form as given in Eq. (2.5)", "cite_spans": [], "ref_spans": []}, {"section": "Kaniadakis Mapping", "text": "these results recover what is already known in the extensive limit [5] .", "cite_spans": [{"start": 67, "end": 70, "text": "[5]", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "Kaniadakis Mapping", "text": "By the definition of z k and exploiting the self-duality of the \u03ba-exponential [17] , we have that", "cite_spans": [{"start": 78, "end": 82, "text": "[17]", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "Kaniadakis Mapping", "text": "In the integrand of this integral we can recognize the distribution n \u03ba ( ),", "cite_spans": [], "ref_spans": []}, {"section": "Kaniadakis Mapping", "text": "which, in our context, represents a deformed Bose-Einstein distribution, with the very same properties of monotonicity as the original Bose-Einstein distribution n ( ) in the non-extensive case.", "cite_spans": [], "ref_spans": []}, {"section": "Kaniadakis Mapping", "text": "Contrary to the case of the fitness model generalized with the Tsallis entropy [10] , the Bose-Einstein distribution n \u03ba ( ) can be rewritten in a more insightful way by using properties of the \u03ba-deformed exponential [11, 17] . In fact,", "cite_spans": [{"start": 79, "end": 83, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 217, "end": 221, "text": "[11,", "ref_id": "BIBREF10"}, {"start": 222, "end": 225, "text": "17]", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "Kaniadakis Mapping", "text": "by using e ", "cite_spans": [], "ref_spans": []}, {"section": "Kaniadakis Mapping", "text": "This recovers the usual property of exponentials in the extensive limit, i.e. e \u2212\u2192 e x+y . From a physical point of view, it has to be remarked that this \u03ba-deformed sum emerges naturally from the composition law of relativistic momenta in the framework of special relativity [11] . It is straightforward to generalize these formulas to", "cite_spans": [{"start": 275, "end": 279, "text": "[11]", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "Kaniadakis Mapping", "text": "is formally equivalent to a Bose-Einstein-like distribution for a system whose energy levels are distributed according to a certain density g ( ). Here, however, the differences between the single particle energy and the chemical potential of the whole ensemble have to be interpreted in a \u03ba-deformed way.", "cite_spans": [], "ref_spans": []}, {"section": "Kaniadakis Mapping", "text": "Exactly as in the original Bose-Einstein distribution, because of the physical meaning of n \u03ba ( ) as the probability of having a particle with energy between and + d , it has to be", "cite_spans": [], "ref_spans": []}, {"section": "Kaniadakis Mapping", "text": "which, as in the extensive case, implies that \u00b5 \u2264 min = 0 for bosonic systems.", "cite_spans": [], "ref_spans": []}, {"section": "Kaniadakis Mapping", "text": "Similar to the originally proposed model in this generalized BB model a Bose-Einstein phase transition occurs as long as g ( ) \u2192 0 for \u2192 0, i.e. if", "cite_spans": [], "ref_spans": []}, {"section": "Kaniadakis Mapping", "text": "We will present analytical and numerical estimates for the critical temperature in the next section.", "cite_spans": [], "ref_spans": []}, {"section": "Kaniadakis Mapping", "text": "3. Generalized Barab\u00e1si-Bianconi Model: Numerical and Analytical Computations", "cite_spans": [], "ref_spans": []}, {"section": "Critical Temperature and Nonextensivity Parameter", "text": "Following arguments of [5] it can be seen that the Bose-Einstein condensation on the network corresponds to an almost zero value for the chemical potential \u00b5, which can be computed using a preliminary result we obtained while solving Eq. (2.4), i.e.", "cite_spans": [{"start": 23, "end": 26, "text": "[5]", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "Critical Temperature and Nonextensivity Parameter", "text": "where the \u03ba-deformed logarithm was defined as in Eq. (2.1) and where the last approximation was made in order to solve Eq. (2.4). Estimates for the average partition function Z \u03ba over an ensembles of moderately sized networks can be obtained numerically.", "cite_spans": [], "ref_spans": []}, {"section": "Critical Temperature and Nonextensivity Parameter", "text": "We choose a simple distribution for g ( ) which is compatible with the occurrence of condensation and which also allows for easy comparisons with the numerical results of [5, 6] , i.e. we use g ( ) = 2 with corresponding energies", "cite_spans": [{"start": 171, "end": 174, "text": "[5,", "ref_id": "BIBREF4"}, {"start": 175, "end": 177, "text": "6]", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Critical Temperature and Nonextensivity Parameter", "text": ". To obtain the phase diagram |\u00b5| vs T we carried out numerical simulations for varying network size N . As stated in [5] , and confirmed in [10] , for temperatures higher than the critical temperature T By averaging over 800 network realizations we determined a critical temperature T Average fraction of connections for the biggest hub, kmax/mt, inside a generalized BB network of N = {10 3 , 2\u00b710 3 , 5\u00b710 3 , 10 4 } nodes, respectively averaged over {1200, 1200, 600, 150} configurations, all with m = 2 and \u03ba = 0.9. The average fraction of connections kmax/mt does not vanish, in the \"winner-takes-all\" condensate phase, and the system undergoes a gelation phenomenon, in which a large fraction of the nodes inside the network are connected to the same \"gel\" hub [18] . As in the phase diagram, a scaling phenomenon is evident in the condensate phase.", "cite_spans": [{"start": 118, "end": 121, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 141, "end": 145, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 768, "end": 772, "text": "[18]", "ref_id": "BIBREF17"}], "ref_spans": []}, {"section": "Critical Temperature and Nonextensivity Parameter", "text": "The simulation data plotted in Figure 3 .2 show that the phase transition is present in the generalized model, as predicted by our theoretical findings. However it is also evident that the critical temperature of Bose-Einstein condensation depends on the \u03ba parameter. To investigate the dependence of T c on \u03ba we obtained numerical estimates which are shown in Figure 3 .3, suggesting that T c is a monotonically decreasing function of \u03ba.", "cite_spans": [], "ref_spans": []}, {"section": "Critical Temperature and Nonextensivity Parameter", "text": "We next derive an analytical estimate for the dependence of T c on \u03ba. This can be done based on the above mean field arguments, by noting the condition for the phase transition at the critical temperature in the thermodynamical limit T * c\u03ba = 1/\u03b2 c\u03ba , in which \u00b5 has its maximal value, i.e.", "cite_spans": [], "ref_spans": []}, {"section": "Critical Temperature and Nonextensivity Parameter", "text": "where min (t) and max (t) are the minimum and the maximum energy levels (or the maximum and the minimum fitnesses) at time t. Unfortunately, different to the \u03ba = 0 case, the approximation of extending the integral from 0 to infinity is not valid in our case. This is due to the asymptotics of the \u03ba-deformed exponential which vanishes only as e x \u03ba \u223c 2 |\u03bax| 1/|k| and not exponentially when x \u2192 +\u221e.", "cite_spans": [], "ref_spans": []}, {"section": "Critical Temperature and Nonextensivity Parameter", "text": "However, approximating min (t) 0 and max (t) 1 and performing a McLaurin expansion of the integrand function up to the second order leads to:", "cite_spans": [], "ref_spans": []}, {"section": "Critical Temperature and Nonextensivity Parameter", "text": "Notice that this analytical approximation is an underestimation of the lower and upper bounds on the critical temperature in the thermodynamic limit. In particular for \u03ba = 0 our approximation retrieves a rounded upper bound for the critical temperature T * c\u03ba \u2264 0.711, which actually reproduces the first three digits of the approximation for the effective temperature T c 0.711 computed in [6] , by both means of analytic results and numerical experiments. In order to compare our analytical findings with the numerical ones, we have to be aware of the finite size effects ", "cite_spans": [{"start": 391, "end": 394, "text": "[6]", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Critical Temperature and Nonextensivity Parameter", "text": "We notice that the analytical upper bound is in good agreement with numerical simulations for low values of \u03ba. In agreement with the simulations we thus find that the critical temperature for the Bose-Einstein condensation decreases with \u03ba. This is also compatible with a similar result derived in [14] , under slightly less general assumptions on the functional form of the \u03ba-deformed Bose-Einstein distribution.", "cite_spans": [{"start": 298, "end": 302, "text": "[14]", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "Critical Temperature and Nonextensivity Parameter", "text": "All in all, it is interesting to note that the deformations inside the distribution n \u03ba ( ) do not influence the qualitative presence of the condensation, which is ultimately rooted in the properties of the energy density g ( ).", "cite_spans": [], "ref_spans": []}, {"section": "Critical Temperature and Nonextensivity Parameter", "text": "These results suggest that the use of a nonextensive statistics, such as the Kaniadakis one, does not cause any qualitative change of the network dynamics. The main influence of a change from extensive to nonexstensive statistics are quantitative variations in the critical temperature. This observation is in agreement with the results of the numerical experiments reported in [10] for the Tsallis q-distribution. In order to further investigate this claim, we will proceed with the analysis of the degree distributions of our generalized fitness model in the next section.", "cite_spans": [{"start": 378, "end": 382, "text": "[10]", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "Degree Distribution and Nonextensivity Parameter", "text": "In [4] , the authors analyzed the degree distribution P (k) of a fitness model with an exponential fitness distribution \u03c1(\u03b7), obtaining the following estimate", "cite_spans": [{"start": 3, "end": 6, "text": "[4]", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "Degree Distribution and Nonextensivity Parameter", "text": "where F (\u03b7) is the dynamical exponent which determines the growth of node degrees conditional on fitness. Using These substitutions lead to:", "cite_spans": [], "ref_spans": []}, {"section": "Degree Distribution and Nonextensivity Parameter", "text": "Even if the fictitious temperature in \u03b2 only plays the role of a control parameter of the model, it actually has some influence on the degree distribution, entering implicitly in the determination of the scaling exponent via z \u03ba and also via the lower bound of fitness range.", "cite_spans": [], "ref_spans": []}, {"section": "Degree Distribution and Nonextensivity Parameter", "text": "\u03ba , 1] when k > 16 and making use of Jensen's inequality one finds", "cite_spans": [], "ref_spans": []}, {"section": "Degree Distribution and Nonextensivity Parameter", "text": "By using the definition of the \u03ba-deformed logarithm given in Eq. (2.1) one can now compute the expected value of the fitness E[\u03b7] which is a monotonically increasing function of the temperature for every \u03ba \u2208 (0, 1]:", "cite_spans": [], "ref_spans": []}, {"section": "Degree Distribution and Nonextensivity Parameter", "text": "The arguments above motivate our estimate for the degree distribution of a generalized fitness network with a logarithmic distribution of fitnesses over a finite range, in terms of a lower bound given by a power law:", "cite_spans": [], "ref_spans": []}, {"section": "Degree Distribution and Nonextensivity Parameter", "text": "with the exponent \u03b3 \u03ba,T = 1 + (z \u03ba E[\u03b7]) \u22121 implicitly dependent on network temperature and on the nonextensive parameter \u03ba. The fugacity z \u03ba can be determined using Eq. (2.7). In Figure 3 .4 a maximum likelihood fitting procedure [19] reveals scaling exponents for the power-law like parts of the plots statistically compatible with the value \u03b3 0.2,5 = 2.89 \u00b1 0.05 for the ensemble with N = 10 4 and \u03ba = 0.9.", "cite_spans": [{"start": 231, "end": 235, "text": "[19]", "ref_id": "BIBREF18"}], "ref_spans": []}, {"section": "Degree Distribution and Nonextensivity Parameter", "text": "Other scaling exponents for lower values of \u03ba were retrieved, all close to the exponent ( 3) estimated from our analytical upper bound in Eq. (3.7). The maximum-likelihood procedure we used avoids biases generated by adopting a linear binning scheme, which could potentially alter or masque the stretched-exponential region. Our estimate for the scaling parameter is suprisingly close to the one for a growing network with preferential attachment [15, 3] , which is recovered by the generalized model either with the choice \u03c1(\u03b7) = \u03b4(\u03b7 \u2212 \u03b7 0 ) or in the limit T \u2192 +\u221e (in both cases, every node has the same fitness). Furthermore, in the limit T \u2192 \u221e the \u03ba-deformed exponential for the fitnesses recovers the Boltzmann weight, in which case it can be shown analytically that 1/z \u03ba \u2192 1/z \u2192 2 while in the same limit T \u2192 \u221e the average fitness for our model converges to 1, so that the scaling parameter recovers our numerical estimate", "cite_spans": [{"start": 447, "end": 451, "text": "[15,", "ref_id": "BIBREF14"}, {"start": 452, "end": 454, "text": "3]", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "Degree Distribution and Nonextensivity Parameter", "text": "Nonetheless, in [4] , it was shown that the fitness model is not stable under changes of the functional form of the fitness distribution function: The model can give rise to power laws (uniform \u03c1(\u03b7)) or non power-law degree distributions (unbounded exponential distributions \u03c1(\u03b7)).", "cite_spans": [{"start": 16, "end": 19, "text": "[4]", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "Degree Distribution and Nonextensivity Parameter", "text": "In the high temperature region T T theoretical arguments put forward in [6] lead to an estimate of z \u03ba 1 also for the nonextensive case, since e x \u03ba \u223c e x when x 1. Given that the average fitness E(\u03b7) monotonically decreases to 0 when the temperature decreases, then from Eq. (3.7) the scaling exponent \u03b3 \u03ba,T has to increase when T decreases, depending on the nonextensive parameter \u03ba. Nonetheless, as the lower bound in (3.5) is valid only for degrees k > k 0 , only a part of the points on the P (k) plot is shifted and raised from the original behavior, at high degrees, and the result is a stretched exponential, compatible with those shown in 3.4.", "cite_spans": [{"start": 72, "end": 75, "text": "[6]", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Degree Distribution and Nonextensivity Parameter", "text": "Furthermore, as reported in [6] , an accurate theoretical analysis of the network dynamics in the condensate phase for the original BB model g( ) = 2 , \u2208 (0, 1) found evidence for not only one \"gel\" node [18] , (i.e. one unique condensate) but for an infinite hierarchy of condensates, whose degrees grow faster than F (\u03b7) and linearly with time. A similar picture, in which there is not one unique \"winner\", was also presented in [16] .", "cite_spans": [{"start": 28, "end": 31, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 204, "end": 208, "text": "[18]", "ref_id": "BIBREF17"}, {"start": 431, "end": 435, "text": "[16]", "ref_id": "BIBREF15"}], "ref_spans": []}, {"section": "Degree Distribution and Nonextensivity Parameter", "text": "This phenomenon is due to the presence of a crossover timescale \u03c4 (T ) \u223c T \u22122 in the condensate phase. The \"winner-takes-all\" phenomenon occurs only for networks having evolved for times greater than \u03c4 (T ), which diverges at low temperature. For shorter times, a record-driven dynamics [16] is observed instead, with the number D(t) of candidate \"gel\" nodes up to time t growing as D(t) \u223c 2 ln ln t [6] . These super-hubs, which sum up to the condensed fraction 1 \u2212 I \u03b2 , escape our mean-field approach, in which k i has to grow sublinearly in time, according to Eq. (2.5).", "cite_spans": [{"start": 287, "end": 291, "text": "[16]", "ref_id": "BIBREF15"}, {"start": 400, "end": 403, "text": "[6]", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Degree Distribution and Nonextensivity Parameter", "text": "Ultimately, it is those hubs which give rise to the stretched exponential encountered in our numerical experiments in the condensate phase.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "In this paper we have generalized the Barab\u00e1si-Bianconi fitness model by the means of the non-Gaussian Kaniadakis \u03ba-distribution, which was originally proposed in the framework of nonextensive statistical mechanics. Our analytical results show that the resulting generalized fitness model presents a phase transition from a \"fit-get-rich\" phase to a \"gel\" phase, formally equivalent to a Bose-Einstein condensation. Analytical calculations supported by numerical estimates show that the critical temperature T c of the Bose-Einstein condensation on networks decreases when the nonextensive parameter \u03ba is increased from 0 to 1. A numerical analysis of the degree distribution, complemented by an analytically obtained lower bound, reveals the presence of power-law behaviour in the phase of high-temperatures and a linear energy level density for g( ) \u2192 0. In contrast, in the condensate phase stretched exponentials, compatible with the recent finding of a hierarchy of hubs, are retrieved.", "cite_spans": [], "ref_spans": []}, {"section": "Acknowledgements", "text": "MS is personally indebted to Prof. P. Tempesta and Prof. R. A. Leo for the precious insights they provided.", "cite_spans": [], "ref_spans": []}, {"section": "Acknowledgements", "text": "Without the latter, this article would not have been written. MS is also grateful to Cl\u00e9ment Viguier and the whole Complex Systems Simulation DTC at the Institute of Complex Systems Simulation (ICSS), University of Southampton, for their support. MS and MB also acknowledge the use of both MATLAB code written by Aaron Clauset, from [19] , and of the IRIDIS High Performance Computing Facility, and associated support services at the University of Southampton, in the completion of this work.", "cite_spans": [{"start": 333, "end": 337, "text": "[19]", "ref_id": "BIBREF18"}], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "The structure and function of complex networks", "authors": [{"first": "M", "middle": ["E J"], "last": "Newman", "suffix": ""}], "year": 2003, "venue": "SIAM Review", "link": null}, "BIBREF1": {"title": "Scale-Free Networks", "authors": [{"first": "G", "middle": [], "last": "Caldarelli", "suffix": ""}], "year": 2007, "venue": "", "link": "57479176"}, "BIBREF2": {"title": "Statistical mechanics of complex networks", "authors": [{"first": "R", "middle": [], "last": "Albert", "suffix": ""}, {"first": "A.-L", "middle": [], "last": "Barab\u00e1si", "suffix": ""}], "year": 2002, "venue": "Reviews of Modern Physics", "link": "60545"}, "BIBREF3": {"title": "Competition and multiscaling in evolving networks", "authors": [{"first": "G", "middle": [], "last": "Bianconi", "suffix": ""}, {"first": "A.-L", "middle": [], "last": "Barab\u00e1si", "suffix": ""}], "year": 2001, "venue": "Europhysics Letters)", "link": "123032105"}, "BIBREF4": {"title": "Bose-Einstein condensation in complex networks", "authors": [{"first": "G", "middle": [], "last": "Bianconi", "suffix": ""}, {"first": "A", "middle": ["L"], "last": "Barab\u00e1si", "suffix": ""}], "year": 2001, "venue": "Physical Review Letters", "link": "18375451"}, "BIBREF5": {"title": "On leaders and condensates in a growing network", "authors": [{"first": "C", "middle": [], "last": "Godr\u00e9che", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Luck", "suffix": ""}], "year": 2010, "venue": "Journal of Statistical Mechanics: Theory and Experiment", "link": "118363789"}, "BIBREF6": {"title": "Introduction to Nonextensive Statistical Mechanics -Approaching a Complex World", "authors": [{"first": "C", "middle": [], "last": "Tsallis", "suffix": ""}], "year": 2009, "venue": "", "link": "117777721"}, "BIBREF7": {"title": "A new model of income distribution: the k-generalized distribution", "authors": [{"first": "F", "middle": [], "last": "Clementi", "suffix": ""}, {"first": "M", "middle": [], "last": "Gallegati", "suffix": ""}, {"first": "G", "middle": [], "last": "Kaniadakis", "suffix": ""}], "year": 2012, "venue": "Journal of Economics", "link": "155080665"}, "BIBREF8": {"title": "The entropy of non-ergodic complex systems: a derivation from first principles", "authors": [{"first": "S", "middle": [], "last": "Thurner", "suffix": ""}, {"first": "R", "middle": [], "last": "Hanel", "suffix": ""}], "year": 2012, "venue": "International Journal of Modern Physics: Conference Series", "link": "120572462"}, "BIBREF9": {"title": "Tsallis mapping in growing complex networks with fitness", "authors": [{"first": "G", "middle": [], "last": "Su", "suffix": ""}, {"first": "X", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "Y", "middle": [], "last": "Zhang", "suffix": ""}], "year": 2012, "venue": "Communications in Theoretical Physics", "link": "123542317"}, "BIBREF10": {"title": "Statistical mechanics in the context of special relativity", "authors": [{"first": "G", "middle": [], "last": "Kaniadakis", "suffix": ""}], "year": 2002, "venue": "Physical Review E", "link": "45635888"}, "BIBREF11": {"title": "Non-gaussian statistics and stellar rotational velocities of main-sequence field stars", "authors": [{"first": "J", "middle": ["C"], "last": "Carvalho", "suffix": ""}, {"first": "J", "middle": ["D"], "last": "Nascimento", "suffix": ""}, {"first": "R", "middle": [], "last": "Silva", "suffix": ""}, {"first": "J", "middle": ["R D"], "last": "Medeiros", "suffix": ""}], "year": 2009, "venue": "The Astrophysical Journal Letters", "link": "17161421"}, "BIBREF12": {"title": "k-deformed statistics and the formation of a quark-gluon plasma", "authors": [{"first": "A", "middle": ["M"], "last": "Teweldeberhan", "suffix": ""}, {"first": "H", "middle": ["G"], "last": "Miller", "suffix": ""}, {"first": "R", "middle": [], "last": "Tegen", "suffix": ""}], "year": 2003, "venue": "International Journal of Modern Physics E", "link": "118429922"}, "BIBREF13": {"title": "Bose-Einstein condensation in the framework of k-statistics", "authors": [{"first": "A", "middle": [], "last": "Aliano", "suffix": ""}, {"first": "G", "middle": [], "last": "Kaniadakis", "suffix": ""}, {"first": "E", "middle": [], "last": "Miraldi", "suffix": ""}], "year": 2003, "venue": "Physica B: Condensed Matter", "link": null}, "BIBREF14": {"title": "Emergence of scaling in random networks", "authors": [{"first": "A", "middle": ["L"], "last": "Barab\u00e1si", "suffix": ""}, {"first": "R", "middle": [], "last": "Albert", "suffix": ""}], "year": 1999, "venue": "Science", "link": "524106"}, "BIBREF15": {"title": "Dynamics of condensation in growing complex networks", "authors": [{"first": "L", "middle": [], "last": "Ferretti", "suffix": ""}, {"first": "G", "middle": [], "last": "Bianconi", "suffix": ""}], "year": 2008, "venue": "Physical Review E", "link": "28460795"}, "BIBREF16": {"title": "Maximum entropy principle and power-law tailed distributions", "authors": [{"first": "G", "middle": [], "last": "Kaniadakis", "suffix": ""}], "year": 2009, "venue": "The European Physical Journal B", "link": "55421804"}, "BIBREF17": {"title": "Connectivity of growing random networks", "authors": [{"first": "P", "middle": ["L"], "last": "Krapivsky", "suffix": ""}, {"first": "S", "middle": [], "last": "Redner", "suffix": ""}, {"first": "F", "middle": [], "last": "Leyvraz", "suffix": ""}], "year": 2000, "venue": "Physical Review Letters", "link": "16251662"}, "BIBREF18": {"title": "Power-law distributions in empirical data", "authors": [{"first": "A", "middle": [], "last": "Clauset", "suffix": ""}, {"first": "C", "middle": [], "last": "Shalizi", "suffix": ""}, {"first": "M", "middle": [], "last": "Newman", "suffix": ""}], "year": 2009, "venue": "SIAM Review", "link": "9155618"}}, "ref_entries": {"FIGREF0": {"text": "\u2192 +\u221e, with scaling exponents \u03b3 typically between 2 and 3 and compatible with those of many natural and human systems [2, 1].", "type": "figure"}, "FIGREF1": {"text": "for x \u2192 \u00b1\u221e [17]. It has been shown [11] that this \u03ba-deformed exponential is a positive monotonically increasing function which is symmetric with respect to the nonextensive parameter \u03ba", "type": "figure"}, "FIGREF2": {"text": "\u03bax , one can define a \u03ba-deformed sum \u03ba \u2295 [11], such that R,", "type": "figure"}, "FIGREF4": {"text": "Figure 3.1: Phase diagram for different size ensembles of the generalized BB network, with N = {10 3 , 2 \u00b7 10 3 , 5 \u00b7 10 3 , 10 4 } nodes and respectively averaged over {800, 400, 200, 120} different configurations, all with m = 2 and \u03ba = 0.9. The critical temperature T (0.9) c 0.76 is statistically lower than the one reported in the extensive case [5], for \u03ba = 0, Tc 0.8. A scaling phenomenon is evident, following the decrease in temperature.", "type": "figure"}, "FIGREF6": {"text": "Figure 3.2: Average fraction of connections for the biggest hub, kmax/mt, inside a generalized BB network of N = {10 3 , 2\u00b710 3 , 5\u00b710 3 , 10 4 } nodes, respectively averaged over {1200, 1200, 600, 150} configurations, all with m = 2 and \u03ba = 0.9. The average fraction of connections kmax/mt does not vanish, in the \"winner-takes-all\" condensate phase, and the system undergoes a gelation phenomenon, in which a large fraction of the nodes inside the network are connected to the same \"gel\" hub [18]. As in the phase diagram, a scaling phenomenon is evident in the condensate phase.", "type": "figure"}, "FIGREF7": {"text": "Figure 3.3: Main Figure: Critical temperature T \u03ba c vs nonextensive parameter \u03ba (points). The numerical results are based on an ensemble of 800 networks with N = 10 3 nodes. The temperature for \u03ba = 0.9 is (0.732 \u00b1 0.002) and it is statistically compatible with the previous result T (0.9) c = (0.73 \u00b1 0.03) for an ensemble of 90 networks with N = 10000. The upper bound T * c\u03ba + \u2206T is computed numerically (continuous line) and by using our analytical upper bound (dashed line). Inset: Numerically computed T * c\u03ba (dots) vs our analytical upper bound (continuous line). Because of the truncated McLaurin expansion, our approximation underestimates the critical temperature and breaks around \u03ba \u223c 0.5.", "type": "figure"}, "FIGREF8": {"text": "+ \u2206T . Following the results in [6], the finite size correction \u2206T \u03ba c = \u2206T (N, T * c\u03ba ) can be estimated with a first order series expansion from I(\u03b2, \u00b5) at the critical point. One obtains:", "type": "figure"}, "FIGREF9": {"text": "F (\u03b7) is to be identified with f \u03ba ( ) = efitnesses expressed in terms of the energy level distribution g( ).", "type": "figure"}, "FIGREF10": {"text": "Figure 3.4: Complementary cumulative distribution functions P (x \u2265 k) for the degree distribution in a network with N nodes for different values of temperature and nonextensive parameter. Upper Centre:\u03ba = 0.9 and T = 5 for N = 10 3 (crosses), N = 5 \u00b7 10 3 (squares) and N = 10 4 . The dashed straight line is a power law with exponent \u03b3 = 3, for reference. The data shows a power-law like behavior with a cut-off depending on the system finite size. Lower Left: \u03ba = 0.2 and T = 0.5. Lower Right: \u03ba = 0.9 and T = 0.5. The dashed line is the estimate based on a power-law assumption, with scaling exponents respectively \u03b3 0.2,0.5 2.86 and \u03b3 0.9,0.5 2.79. Notice that the first part of the plot is robust to temperature changes, as confirmed by the retrieved scaling exponents. Lowering the temperature stretches the distribution only in the higher degree zone.", "type": "figure"}, "FIGREF11": {"text": ", numerical experiments for the fugacity z \u03ba , performed on an ensenmble of 800 networks with N = 10 3 , suggest that our estimate \u03b3 \u03ba,T is effectively independent of both the temperature and the nonextensive parameter, with \u03b3 \u03ba,T = \u03b3 * 3. This finding agrees with the boundary condition that \u03b3 \u03ba,T \u2192 3 for T \u2192 +\u221e and \u2200\u03ba \u2208 [0, 1] (as stated above, our model degenerates into the Barab\u00e1si-Albert model). Instead, in the low temperature phase T T \u03ba c , any numerical computation of the fugacity z \u03ba suffers from finite size-effects, but", "type": "figure"}}}
{"paper_id": "118863857", "_pdf_hash": "a266ae7d364d9c2e0760cdb2925cd233d906f55e", "abstract": [{"section": "Abstract", "text": "Single-exposure spectra in large spectral surveys are valuable for time domain studies such as stellar variability, but there is no available method to eliminate cosmic rays for single-exposure, multi-fiber spectral images. In this paper, we describe a new method to detect and remove cosmic rays in multi-fiber spectroscopic single exposures. Through the use of two-dimensional profile fitting and a noise model that considers the position-dependent errors, we successfully detect as many as 80% of the cosmic rays and correct the cosmic ray polluted pixels to an average accuracy of 97.8%. Multiple tests and comparisons with both simulated data and real LAMOST data show that the method works properly in detection rate, false detection rate, and validity of cosmic ray correction.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Cosmic rays (CRs, hereafter) are high-energy particles that generate randomly distributed, large signals on charge-coupled devices (CCDs), which could affect the measured fluxes of astronomical objects if not detected or removed properly. Generally, CRs are removed by combining three or more exposures of the same field (Windhorst 1994; Freudling 1995; Fruchter 1997; Gruen 2014; Desai 2016) , as they are unlikely to hit the same pixel in more than one exposure. However, multiple exposures are not always available. Furthermore, there are certain situations in which CR detection in single exposures is desired, such as in time domain studies.", "cite_spans": [{"start": 354, "end": 368, "text": "Fruchter 1997;", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "Introduction", "text": "Various methods have been developed for identifying and replacing CRs in CCD data of single exposures, including median filtering (e.g., Dickinsons IRAF tasks QZAP, XZAP, and XNZAP), applying a threshold on the contrast (e.g., IRAF task COSMIC-RAYS ), trainable classification (Murtagh 1992; Salzberg 1995; Bertin 1996) , convolution with adapted point-spread functions (PSFs; Rhoads 2000) , Laplacian edge detection (van Dokkum 2001) , analysis of the flux histogram (Pych 2004 ) and a fuzzy logic-based method (Shamir 2005) . All of the median filtering or PSF methods remove small CRs from well-sampled data effectively, but problems arise when CRs affect more than half the size of the filter or when the PSF is smaller than the filter (van Dokkum 2001) . All of the methods listed above are designed for photometric data except those of van Dokkum (2001) and Pych (2004) , which work for long-slit spectroscopic data.", "cite_spans": [], "ref_spans": []}, {"section": "Farage (2005) made a comparison between different methods including the IRAF script", "text": "JCRREJ2 of Rhoads (2000) , the IRAF routine L.A.COSMIC of van Dokkum (2001) , the C script of Pych (2004) and the IRAF task XZAP on photometric images. In that paper, Farage concluded that L.A.COSMIC provided the best performance, with a detection efficiency of 86% on the real data sample, whereas other methods could at most detect 78% of the CRs. Increasing object density reduces the efficiency of detection (Farage 2005) , which is unfortunately unavoidable in multi-fiber spectroscopic data where the signals are always dense. Although L.A.COSMIC efficiently detects CRs, it replaces the identified CR candidates with the median value of the surrounding good pixels (van Dokkum 2001) , which is improper when the CR hits are on the ridge or slope of the profile.", "cite_spans": [], "ref_spans": []}, {"section": "Farage (2005) made a comparison between different methods including the IRAF script", "text": "There have been no specific efforts to solve this problem on multi-fiber spectroscopic data, which present distinct challenges compared to photometric data. Multi-fiber images do not have clear isolated point or extended sources as in the photometric data, and the long stripe-like multi-fiber spectra occupy large contiguous regions so that the available area for the local background is much smaller than in the photometric data. Methods with median filtering or interpolation of neighboring pixels are less effective in this case.", "cite_spans": [], "ref_spans": []}, {"section": "Farage (2005) made a comparison between different methods including the IRAF script", "text": "We present an algorithm to detect and replace CRs for Large Sky Area Multi-Object fiber Spectroscopic Telescope (LAMOST) single-exposure images based on a two-dimensional (2D) profile fitting of the spectral aperture. We first pick out CR candidates with Laplacian edge detection and construct a 2D function to fit the image profile in small segments along the spectral trace with these candidates masked out; the final CR list is generated by comparing the fitting residual with a noise model depending on position, and the CR polluted pixels are replaced with the corresponding value of the 2D function. This method is applied to the data processing of LAMOST; in principle, it can also be used for other multi-fiber spectral data after minor modification.", "cite_spans": [], "ref_spans": []}, {"section": "Farage (2005) made a comparison between different methods including the IRAF script", "text": "We describe LAMOST data in \u00a72. The algorithm is explained in \u00a73. In \u00a74, we give some examples and analyze the properties of the algorithm. Finally, in \u00a75 we summarize our work.", "cite_spans": [], "ref_spans": []}, {"section": "LAMOST Data", "text": "LAMOST (Cui 2012 ) is a fiber spectroscopic telescope equipped with 4000 fibers feeding 16 spectrographs. Each spectrograph, holding 250 fibers, is split into blue (37005900\u00c5) and red (57009000\u00c5) arms by a dichroic mirror. Groups of 250 spectra are recorded by two 4k\u00d74k CCDs at the blue and red end, respectively. The typical duration for a single LAMOST exposure ranges from 600 to 1800s, depending on the target brightness and weather conditions. A considerable number of CRs hit the images during the exposure; for example, in a typical 1800s image, the number of pixels polluted by CRs is about 2 \u00d7 10 4 .", "cite_spans": [], "ref_spans": []}, {"section": "LAMOST Data", "text": "The size of a LAMOST image, of which the dispersion direction is along the vertical direction, is 4096\u00d74136 pixels. In the spatial direction, the typical distance between two adjacent fibers is 15\u223c16 pixels. As shown in Figure 1 , the cross section of the fiber profile in the spatial direction could be well described by a S\u00e9rsic function (S\u00e9rsic 1968; Clewley 2002) :", "cite_spans": [{"start": 340, "end": 353, "text": "(S\u00e9rsic 1968;", "ref_id": "BIBREF11"}], "ref_spans": [{"start": 220, "end": 228, "text": "Figure 1", "ref_id": "FIGREF2"}]}, {"section": "LAMOST Data", "text": "where \u03b1, \u03b2, \u03b3, \u03b4 are parameters to be derived. The typical full width at half maximum (FWHM) of the profile is about 7\u223c8 pixels. If d = |x \u2212 \u03b2| is the distance from a given pixel to the fiber profile center in the row (or horizontal/spatial) direction, according to Figure 1 , the flux at d = 8 is less than 0.01% of those at the profile peak. To avoid fiber to fiber cross talk, the magnitude range of objects observed in one LAMOST observation is constrained to be less than 5 magnitudes. In the extreme case, the contribution from the 5 magnitude brighter neighbor to the pixel at d = 8 could be ignored, so the fluxes in the pixels of d \u2264 8 could be considered as the flux from the fiber itself. In 2D data reduction, d = 8 is chosen as the aperture for spectrum extraction. The spectral resolution of LAMOST is about 1800, which corresponds to a FWHM about 5 pixels in the dispersion direction. The PSF changes gradually with position on the CCD chip, but could be considered as constant in a small region (e.g., 20 pixels); we will take advantage of this characteristic to improve the cosmic ray rejection.", "cite_spans": [], "ref_spans": [{"start": 266, "end": 274, "text": "Figure 1", "ref_id": "FIGREF2"}]}, {"section": "Cosmic Ray Detection and Rejection", "text": "CRs are detected and replaced in three steps. First, we use Laplacian edge detection (van Dokkum 2001) to generate a raw CR candidate list. Second, for each fiber, pixels within d = 8 of the fiber trace center are divided into small blocks; each block is then fitted by a 2D profile with those raw CR candidates masked out. The final CR list is determined by comparing the fitting residual with a noise model considering both the intrinsic noise and the uncertainty introduced by profile fitting; the pixels polluted by CRs are replaced by the corresponding fitted value. The details are as follows.", "cite_spans": [], "ref_spans": []}, {"section": "Laplacian edge detection", "text": "Laplacian edge detection has been widely used for highlighting boundaries in processing digital images (e.g., Gonzalez 1992) . van Dokkum (2001) was the first to apply the method to detect CRs in astronomical images. Their publicly available program, L.A.COSMIC, successfully detects CRs in both photometric and long-slit spectroscopic images. We use a similar method to that in Section 3 of van Dokkum (2001) to pick out the raw CR candidates. Since further details can be found in that paper, only basic steps are listed here.", "cite_spans": [{"start": 110, "end": 124, "text": "Gonzalez 1992)", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "Laplacian edge detection", "text": "The original image I with the size of n x \u00d7 n y is subsampled into 2n x \u00d7 2n y :", "cite_spans": [], "ref_spans": []}, {"section": "Laplacian edge detection", "text": "where i = 1, \u00b7 \u00b7 \u00b7 , 2n x and j = 1, \u00b7 \u00b7 \u00b7 , 2n y . The subsampled image is then convolved with a Laplacian kernel:", "cite_spans": [], "ref_spans": []}, {"section": "Laplacian edge detection", "text": "where L is the Laplace operator, * denotes convolution. The Laplace operator L in the above convolution is", "cite_spans": [], "ref_spans": []}, {"section": "Laplacian edge detection", "text": "Since CRs are positive in L, all the negative values are set to zero. L is then resampled to n x \u00d7 n y :", "cite_spans": [], "ref_spans": []}, {"section": "Laplacian edge detection", "text": "where i = 1, \u00b7 \u00b7 \u00b7 , n x and j = 1, \u00b7 \u00b7 \u00b7 , n y .", "cite_spans": [], "ref_spans": []}, {"section": "Laplacian edge detection", "text": "The original image is median filtered with a 5 \u00d7 5 box to construct the noise model", "cite_spans": [], "ref_spans": []}, {"section": "Laplacian edge detection", "text": "where g is the gain in electrons per ADU, I m5 is the image median filtered by a 5\u00d75 box, and \u03c3 rd is the readout noise in electrons. The Laplacian image is then divided by the noise model and the subsampling factor to obtain the deviations from the expected Poisson fluctuations:", "cite_spans": [], "ref_spans": []}, {"section": "Laplacian edge detection", "text": "All structures that are smooth on scales of \u2265 5 pixels are removed by a 5 \u00d7 5 median filter:", "cite_spans": [], "ref_spans": []}, {"section": "Laplacian edge detection", "text": "All pixels that meet S \u2032 > \u03c3 lim are identified as CR candidates, where \u03c3 lim is a given threshold. We adopt \u03c3 lim = 4.5, similar to L.A.COSMIC.", "cite_spans": [], "ref_spans": []}, {"section": "Fiber profile fitting", "text": "Fiber traces are closely aligned on multi-fiber spectral images. In contrast to photometric images, useful signals are quite fully rather than sparsely distributed. As pointed out by Farage Farage (2005) , the increasing object density will certainly reduce the efficiency of the methods designed for photometric data. The ramp on either side of the ridge of the fiber trace is quite steep, so it is hard for the edge detection method to discriminate between real CR hits and good pixels on the ramp, leading to a drop in the detection rate and a rise in the false detection rate. Furthermore, replacing the CR polluted pixels with the median of the surrounding pixels is seemingly unsafe. Along the fiber trace, the shape of the PSF changes slowly. If the PSF is well sampled, then CR discrimination could be improved by its shape difference from the PSF.", "cite_spans": [], "ref_spans": []}, {"section": "Fiber profile fitting", "text": "For an image I of n x \u00d7 n y pixels with n f fibers, the pixels close to the fiber trace center contribute the most to the extracted flux. CRs hitting on these areas will introduce large errors in the final spectra, while those in the trough between fibers have much less impact. Consider a small spectral segment centered on column [c kj ] and row j, where k = 1, \u00b7 \u00b7 \u00b7 , n f , j = 1, \u00b7 \u00b7 \u00b7 , n y and [c kj ] is the trace center of the kth fiber at row j([] denotes the round off of the quotation). Since both the trace center and the shape of the PSF change slowly inside the segment, the shape of the segment could be fitted with a product of two orthogonal vectors:", "cite_spans": [], "ref_spans": []}, {"section": "Fiber profile fitting", "text": "where S(x) is the fiber profile in the spatial direction, P (y) is a polynomical to describe the flux variation in the dispersion direction, and \u03b5 xy is noise. The size of x is the same as the aperture for flux extraction, which is set to d = 8 for LAMOST, as discussed in Section 2. The size of y is chosen to be small enough to keep P (y) smooth but larger than the size of single CR hits, so that P (y) can be fitted with a low-order polynomial and the CR polluted pixels could be better estimated by interpolation. For LAMOST, the segment size is set 17 \u00d7 9, i.e., x = [c kj ] \u2212 8, \u00b7 \u00b7 \u00b7 , [c kj ] + 8 and y = j \u2212 4, \u00b7 \u00b7 \u00b7 , j + 4. We do not try to fit the pixels in the bottom of the valley between fibers, since they contribute little to the final spectrum.", "cite_spans": [], "ref_spans": []}, {"section": "Fiber profile fitting", "text": "The shape of S(x) is determined by the output pupil of the fiber and instrument distortion. Although the typical shape of S(x) could be described by a S\u00e9rsic function (Eq. 1), the actual shape deviates occasionally from the analytic function when the optical distortion is large at the edge of the image or the coupling between the fiber output pupil and the slit is imperfect. Due to the above reason, S(x) is constructed with an empirical profile rather than an analytic function. All the profiles at y = j \u2212 10 \u223c j + 10 are first normalized, center justified in sub-pixel scale and then averaged to derive S(x) with the CR candidates masked out. Fixing the form of S(x), the polynomial coefficients of P (y) are derived by least-square surface fitting to the flux in the segment with the CR candidates masked out. A fitted image F is generated after all segments are handled.", "cite_spans": [], "ref_spans": []}, {"section": "Cosmic ray selection", "text": "A new list of CRs is generated by comparing the noise model with the residual of the image fitting without reference to the old CR list. The noise or uncertainty of our method comes from two parts: one is the intrinsic noise of the input signal, i.e., Poisson noise from the object and the readout noise from the CCD circuit; the other part of the noise comes from the defect of the profile fitting, which is larger when the profile changes more dramatically. Basically, the first part is related to time and the second part is related to position, which could be illustrated as:", "cite_spans": [], "ref_spans": []}, {"section": "Cosmic ray selection", "text": "The first term is sufficient to pick out CRs for most cases when the fit is good, yet it is necessary to add the position-dependent term to avoid false detections in regions where the fit is not perfect. The following steps are implemented to reject the CRs:", "cite_spans": [], "ref_spans": []}, {"section": "Cosmic ray selection", "text": "1. The position dependent terms in 10 are calculated by the average gradients at each pixel. Convolving the fitted image with the following four arrays:", "cite_spans": [], "ref_spans": []}, {"section": "Cosmic ray selection", "text": "a gradient array can be derived as", "cite_spans": [], "ref_spans": []}, {"section": "Cosmic ray selection", "text": "2. Noise models are constructed with and without the second term in Equation 10, respectively,", "cite_spans": [], "ref_spans": []}, {"section": "Cosmic ray selection", "text": "and", "cite_spans": [], "ref_spans": []}, {"section": "Cosmic ray selection", "text": "The noise-weighted differences between the input image I and the fitted image F are defined accordingly:", "cite_spans": [], "ref_spans": []}, {"section": "Cosmic ray selection", "text": "and", "cite_spans": [], "ref_spans": []}, {"section": "Cosmic ray selection", "text": "All pixels with D 1 > 20 or D 2 > 3 are marked as CR candidates in this step. A mask array M is generated with the CR polluted pixels set to 1.", "cite_spans": [], "ref_spans": []}, {"section": "Cosmic ray selection", "text": "3. By setting the previous limits, the number of fake CRs is greatly reduced, but real CRs with a low signal-to-noise ratio (S/N), most of which are indiscernible from noise, are blocked as well. Considering the consecutive pixels occupied by a certain CR hit, the pixels at the edge of the CR hit are more likely to be rejected due to lower signal, though they should have higher probability to be real than the single-pixel event. So a lower limit for those neighbouring pixels will raise the detection rate. To do this, all of the neighboring pixels are first added back to the CR list by convolving the mask array M with", "cite_spans": [], "ref_spans": []}, {"section": "Cosmic ray selection", "text": "for the pixels in the expanded CR list, if the corresponding D 1 > 2 or D 2 > 2, then they will be added to a new mask array M \u2032 .", "cite_spans": [], "ref_spans": []}, {"section": "Cosmic ray selection", "text": "4. Assuming there are sufficient CRs masked out, the residual of the fit (I \u2212 F ) will represent the actual difference between the original CR-free image and the fitted image. The difference can be added back to compensate for imperfect fitting, and a more accurate fit will help to raise the CR detection rate as follows.", "cite_spans": [], "ref_spans": []}, {"section": "Cosmic ray selection", "text": "The difference is derived by median filtering the residual (I \u2212F ) with the CR candidates M \u2032 masked out:", "cite_spans": [], "ref_spans": []}, {"section": "Cosmic ray selection", "text": "where m3 denotes a 3 \u00d7 3 median filter. And the new noise-weighted residual arrays will be", "cite_spans": [], "ref_spans": []}, {"section": "Cosmic ray selection", "text": "and", "cite_spans": [], "ref_spans": []}, {"section": "Cosmic ray selection", "text": "All pixels with D ", "cite_spans": [], "ref_spans": []}, {"section": "Rerun to", "text": "Step 3 and confirm the final CR candidates.", "cite_spans": [], "ref_spans": []}, {"section": "Rerun to", "text": "We do not try to fit the pixels that are either in bad fibers or in the d > 8 gaps between fibers because they contribute little to the final extracted spectra. For those pixels, F is set to 0 and the CR candidates are selected by simply requiring the noise-weighted difference between the original image I and the 5 \u00d7 5 median filtered image I m5 to be larger than 3:", "cite_spans": [], "ref_spans": []}, {"section": "Rerun to", "text": "where N m5 is the same as in Equation 6.", "cite_spans": [], "ref_spans": []}, {"section": "Rerun to", "text": "Combining the above CR candidates, the final CR mask is generated and the value of each CR polluted pixel is replaced by the corresponding value in the fitted image F .", "cite_spans": [], "ref_spans": []}, {"section": "Additional features", "text": "With the profile fitting method, other bad pixels such as the inherent damaged pixels could be replaced with a reasonable value once an initial bad pixel map is known.", "cite_spans": [], "ref_spans": []}, {"section": "Additional features", "text": "On a Dell Precision T5500 (eight 2.0 GHz CPUs), the IDL implementation with one single-threaded processor requires about 20 minutes for an image of 4096\u00d74136 pixels. Most of the time is spent on the 2D profile fitting and the timescales linearly with the number of fibers and image size in the dispersion direction. As the current version of our program is not parallelized, the execution time on the current computer is equivalent to that of a single-core processor and could be greatly reduced after software parallelization.", "cite_spans": [], "ref_spans": []}, {"section": "Examples and Application", "text": "In this section, tests with both simulated data and real data are carried out to illustrate the performance of our method. In these tests, our primary concerns are the following factors: how many pixels of real CRs are detected (efficiency), how many pixels are falsely detected as CRs (false detection rate), and the accuracy of the CR replacement. A better method should have higher efficiency, lower false detection rate, and proper restoration of the pixels polluted by CRs.", "cite_spans": [], "ref_spans": []}, {"section": "Artificial Images", "text": "For multi-fiber spectral observations, to increase the observation efficiency as well as to avoid fiber to fiber cross talk, it is usually a good strategy to divide the targets into different plates according to their brightness so that the S/N of the targets in the same plate are similar in the same exposure time. For plates with bright magnitude, the exposure time is short, so the strength of the sky spectrum is low, but the S/N of the objects is high. On the contrary, the exposure times for the faint plates are long, so the sky spectrum is strong and the object spectrum is weak. Since the efficiency strongly depends on the brightness contrast between the CR and the target, plates with different target brightness are simulated to test our method under different situations.", "cite_spans": [], "ref_spans": []}, {"section": "Artificial Images", "text": "First, we generate a pure CR image of 4136 \u00d7 4096 pixels with 20,000 CR hits (approximately 10 times of those in a 30 minutes exposure LAMOST image). The shape of each CR is set to be an ellipse with the major axis randomly distributed in 1\u223c10 pixels and the minor axis ranges from 1 to 3 pixels, by which almost all kinds of CRs in the real image can be simulated. The direction of the major axis is randomly distributed in 0\u223c 360", "cite_spans": [], "ref_spans": []}, {"section": "Artificial Images", "text": "\u2022 and the intensities are uniformly distributed between 0\u223c20000 ADUs. All CRs with flux less than 5, which is at the readout noise level, are set to 0. In total, 227,451 pixels are polluted by CR hits.", "cite_spans": [], "ref_spans": []}, {"section": "Artificial Images", "text": "Second, to study the methods performance with different target brightness, two CRfree images are generated by combining three consecutive LAMOST exposures of the same targets. The first image (IMG600) is combined from three 600 second exposures in which the spectra are dominated by the strong smooth continuum from the bright objects and the sky emission lines are relatively weak. In the second one (IMG1800), the sky emission lines are more prominent (due to a longer exposure time of 1800 seconds) and the object continuum is relatively weak (due the faint magnitude). The final test images are generated by adding the pure CR image to the CR-free images.", "cite_spans": [], "ref_spans": []}, {"section": "Artificial Images", "text": "Both IMG600 and IMG1800 are tested by our method and the IDL version of L.A.COSMIC, respectively. The results are summarized in Table 1 . For IMG600, the efficiency of our method is 1.9% higher (73.8% versus 71.9%) and the number of false detections is 5820, two orders of magnitude lower than that of L.A.COSMIC. For IMG1800, our efficiency is 4.5higher(80.9% vies 76.4%) and the number of false detections (16,626) is less than half that of L.A.COSMIC(38,912).", "cite_spans": [], "ref_spans": []}, {"section": "Artificial Images", "text": "The efficiency of both methods rises more than 4% from IMG600 to IMG1800. The reason is that the efficiency, for those CRs falling coincidentally into the same pixel with the object spectrum, decreases with the increasing photo noise, while in this case, the CRs are the same in both simulations but the object spectra are much brighter in IMG600 therefore the noise is larger in IMG600 than in IMG1800. Compared with our method, L.A.COSMIC is prone to mistake the wings of the bright profiles as the sharp edges of CRs, especially when the contrast between the background and the profile peak is high, as in IMG600. In IMG1800, as the object brightness decreases, the contrast and thus the number of false detections drops. Our profile fitting method successfully bypasses this sharp edge trap in IMG600, reducing the huge number of fake detections to a reasonable level. As shown in Table 1 , for our method, the number of false detections doubles from IMG600 to IMG1800. There are two reasons for this problem. First, as the SNR of the spectrum becomes lower, more faint pixels are mistaken as CRs (as can be seen from Figure 4) . Second, as the exposure time increases, the intensity of the sky emission lines increases, but the intensity of the underlying object spectra decreases (for the magnitude gets much fainter). In this case, the relative change at some of the exponential wings of the strong sky emission lines becomes too dramatic to have a good polynomial fit; the larger residual induced by the improper fitting leads to an increase of false detections.", "cite_spans": [], "ref_spans": [{"start": 1122, "end": 1131, "text": "Figure 4)", "ref_id": "FIGREF5"}]}, {"section": "Artificial Images", "text": "If we denote the SNR of a CR polluted pixel as", "cite_spans": [], "ref_spans": []}, {"section": "Artificial Images", "text": "where f CR and f clean are the fluxes from the pure CR and the CR-free image, respectively, \u03c3 rd is the readout noise, then Figure 2 shows the detection efficiency against \u03c6. Most of the undetected CRs are those with low \u03c6. The efficiency remains high for \u03c6 > 10 then drop quickly when \u03c6 < 10. The efficiency of our method is higher than that of L.A.COSMIC in all situations except for \u03c6 < 2, where the CRs are too weak to be separated.", "cite_spans": [], "ref_spans": [{"start": 124, "end": 132, "text": "Figure 2", "ref_id": "FIGREF3"}]}, {"section": "Artificial Images", "text": "In Figure 3 , the recovered fluxes of IMG600 are compared to the corresponding fluxes of the CR-free image to see how well our CR replacement works; as shown in the left and the right panel, almost all the replacements properly follow the original fluxes. Also shown in the middle panel is the replacement performance of L.A.COSMIC; most of the replacements are good, but the scatter is larger especially in the high flux region, which is not unexpected, since its replacement method is not specially designed for multi-fiber spectra. The performance of both methods on IMG1800 is similar to IMG600.", "cite_spans": [], "ref_spans": [{"start": 3, "end": 11, "text": "Figure 3", "ref_id": "FIGREF4"}]}, {"section": "Artificial Images", "text": "Since the replacement of the false detections also changes the flux, causing errors in the spectrum, its necessary to test the replacement on those falsely detected CRs. L.A.COSMIC produces too many falsely detected CRs to be comparable with our method in IMG600, so only the results of IMG1800 for both methods are shown in Figure 4 . As shown in the picture, the results of both methods deviate from the true value. Though our method systematically underestimates the flux, most of our replaced fluxes concentrate within 80% of their true value and the true fluxes of most of the pixels are low, so the influence on the extracted spectrum should be small. L.A.COSMIC results show a large variation, with a large number of pixels shifting from the true value to very low fluxes. Some examples are demonstrated in Figure 5 .", "cite_spans": [], "ref_spans": [{"start": 325, "end": 333, "text": "Figure 4", "ref_id": "FIGREF5"}, {"start": 814, "end": 822, "text": "Figure 5", "ref_id": "FIGREF6"}]}, {"section": "Artificial Images", "text": "For spectroscopic data, the extracted spectra are more important than the flux of individual pixels on the 2D image. Figure 6 compares the fluxes of the CR polluted part of the extracted spectra with the CR-free spectra in different situations: from top to bottom, it shows the falsely detected, the properly detected, and the undetected CRs, respectively; in all cases, the average difference between the CR corrected spectra and the original spectra is less than 2.2%, as shown from the distribution in the right column of Figure 6 . Figure  7 shows an extracted spectrum sample; the residual of the CR correction is within a few percent.", "cite_spans": [], "ref_spans": [{"start": 117, "end": 125, "text": "Figure 6", "ref_id": "FIGREF7"}, {"start": 525, "end": 533, "text": "Figure 6", "ref_id": "FIGREF7"}]}, {"section": "Real Data", "text": "We test our algorithm with real data from the LAMOST survey. Figure 8 shows a part of an 1800s LAMOST image (left panel) and its reconstruction by our method (right panel). Visual inspection of our reconstructed image shows that most of the CR hits are properly removed. For a further comparison, the extracted flux of the CR detected pixels vs the flux of the classical multi-exposure-combination method are demonstrated in Figure  9 . The results are comparable to the simulations in Figure 6 , except that the scatter is a bit larger. The reasons for the larger scatter could be the following: first, the simulated image in Figure 6 has a higher SNR than the real data; second, the falsely detected CRs cannot be discriminated from the true CRs in this test, so the scatter should be larger than the true-CR-only situation; and third, the sky flux varies between exposures and the object flux gathered by LAMOST varies with telescope pointing, which make the combined image deviate from individual exposures, leading to a larger scatter.", "cite_spans": [], "ref_spans": [{"start": 61, "end": 69, "text": "Figure 8", "ref_id": "FIGREF8"}, {"start": 425, "end": 434, "text": "Figure  9", "ref_id": "FIGREF9"}, {"start": 486, "end": 494, "text": "Figure 6", "ref_id": "FIGREF7"}, {"start": 627, "end": 635, "text": "Figure 6", "ref_id": "FIGREF7"}]}, {"section": "Conclusion", "text": "We present a method for detecting and removing 2D profile fitting to each segment. A new cosmic ray list is generated by comparing the fitting residual with a noise model depending on both the intrinsic shot noise and the relative position in the profile. We finally produce a more accurate cosmic ray mask table and more reasonable substitution values for CR polluted pixels. The method is tested by both simulations and real data; the results show that our method has a high detection rate, low false detection rate, and proper replacement of the CR polluted pixels.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusion", "text": "Since this method fits the 2D profiles of the fiber spectro-scopic data, which are different from the photometric PSF, it cannot be applied to photometric data. However, it can be used in slit spectroscopic data after minor modifications. The code and samples are available at http://lamostss.bao.ac.cn/~bai/crr. -Performance of our CR correction. F r is the spectral flux extracted at the position of CR influences (any detected or fake or undetected CR within the extraction aperture) from the CR corrected image, and F r is the corresponding flux from the CR-free spectrum. The left column shows the comparison of our result and the clean spectra, with the number density indicated by the grey level. The right column shows the histogram of F r /F c . Rows from top to bottom show the replacement performance of falsely detected, correctly detected and undetected CRs, respectively. The biggest deviation (2.2%) happens in the false detection, since the program tries to replace the falsely detected CRs with lower \"correct\" values. Fig. 7 .-Example of extracted spectra. In the top panel, the dotted line is the spectrum extracted from the image without CR correction, the solid black line is the CR-free spectrum and the solid gray line is our CR corrected result. Spectra have been shifted in the flux direction for clarity. In the middle panel, only the CR-free and the CR corrected spectra are plotted to show more detail. In the bottom panel, the relative difference between the CR-free and the CR corrected spectrum is shown. Figure 6 , the scatter is larger because the uncertainty in the real data is larger than simulations.", "cite_spans": [], "ref_spans": [{"start": 1536, "end": 1544, "text": "Figure 6", "ref_id": "FIGREF7"}]}], "bib_entries": {"BIBREF6": {"title": "Proc. SPIE", "authors": [{"first": "A", "middle": ["S"], "last": "Fruchter", "suffix": ""}, {"first": "R", "middle": ["N"], "last": "Hook", "suffix": ""}], "year": 1997, "venue": "", "link": null}, "BIBREF7": {"title": "Digital Image Processing Gruen", "authors": [{"first": "R", "middle": ["C"], "last": "Gonzalez", "suffix": ""}, {"first": "R", "middle": ["E. ; D"], "last": "Woods", "suffix": ""}, {"first": "S", "middle": [], "last": "Seitz", "suffix": ""}, {"first": "G", "middle": ["M"], "last": "Bernstein", "suffix": ""}], "year": 1992, "venue": "", "link": null}, "BIBREF11": {"title": "Atlas de Galaxias Australes. Observatorio Astronomico, Cordoba Salzberg", "authors": [{"first": "J", "middle": ["L ; S"], "last": "S\u00e9rsic", "suffix": ""}], "year": 1968, "venue": "", "link": null}}, "ref_entries": {"FIGREF0": {"text": "3 or D 1 > 20 or D 2 > 3 are masked as CR candidates in this step.", "type": "figure"}, "FIGREF1": {"text": "Z. Bai acknowledges the support of the National Natural Science Foundation of China (NSFC) (grant no. 11503054). H. Zhang acknowledges the support of NSFC Key Pro- gram (grant no. 11333004) and the National Key Basic Research Program of China (grant 2014CB845700). The Guoshoujing Telescope (the Large Sky Area Multi-Object Fiber Spectro- scopic Telescope, LAMOST) is a National Major Scientific Project built by the Chinese Academy of Sciences. Funding for the project has been provided by the National Devel- opment and Reform Commission. LAMOST is operated and managed by the National Astronomical Observatories, Chinese Academy of Sciences.", "type": "figure"}, "FIGREF2": {"text": "Fig. 1.-Upper panel: the typical shape of a fiber cross section of LAMOST. The black solid line is the data, while the dashed line is the fitted S\u00e9rsic profile. The dot-dashed line shows the center of the profile, and the width between the dotted lines is the FWHM. Lower panel: the residual of the fitting.", "type": "figure"}, "FIGREF3": {"text": "Fig. 2.-Efficiency vs. \u03c6 in different simulations. The upper and lower panels are for IMG600 and IMG1800, respectively. The solid and dashed curves are for the method of this paper and L.A.COSMIC, respectively.", "type": "figure"}, "FIGREF4": {"text": "Fig. 3.-Replacement of good detections on IMG600. In this figure,f r is the corrected flux of the CR polluted pixel, while f c is the flux from the corresponding pixel in the CR-free image. The left and middle panels are the replacements using our method and L.A.COSMIC, respectively; different gray levels represent the relative number density. The right plot shows the histogram of f r /f c in which the black line is our method and the grey line is L.A.COSMIC.", "type": "figure"}, "FIGREF5": {"text": "Fig. 4.-Replacement of the false detections on IMG1800. f r and f c are the same as defined in Figure 3. The left and the middle panels are the replacements of our method and L.A.COSMIC, respectively; number density is indicated by different gray levels. The right plot shows the histogram of f r /f c , in which the black line is our method and the grey line is L.A.COSMIC.", "type": "figure"}, "FIGREF6": {"text": "Fig. 5.-Four examples of CR correction. Rows from top to bottom: the pure CR image, the CR added image, the clean image, the result of our method, and the result of L.A.COSMIC, respectively. Columns a and b show that both methods work well for CRs around low flux fibers. Column c shows that L.A.COSMIC fails to detect a CR hit on the ridge of a fiber trace. Column d shows that L.A.COSMIC mistakes too many good pixels near the edge of the bright fiber trace as CR polluted, which is the biggest problem of L.A.COSMIC.", "type": "figure"}, "FIGREF7": {"text": "Fig. 6.-Performance of our CR correction. F r is the spectral flux extracted at the position of CR influences (any detected or fake or undetected CR within the extraction aperture) from the CR corrected image, and F r is the corresponding flux from the CR-free spectrum. The left column shows the comparison of our result and the clean spectra, with the number density indicated by the grey level. The right column shows the histogram of F r /F c . Rows from top to bottom show the replacement performance of falsely detected, correctly detected and undetected CRs, respectively. The biggest deviation (2.2%) happens in the false detection, since the program tries to replace the falsely detected CRs with lower \"correct\" values.", "type": "figure"}, "FIGREF8": {"text": "Fig. 8.-Left panel is part of a real image from the LAMOST survey, the right panel shows the CR corrected image by our algorithm.", "type": "figure"}, "FIGREF9": {"text": "Fig. 9.-Replacement performance on extracted spectra of real LAMOST data. In the left panel, the horizontal axis represents the spectral flux extracted from the CR corrected image and at the position where there is any detected CR within the extraction aperture(f crr ); the vertical axis is the corresponding flux from the image combined from 3 consecutive exposures (f med ). Right panel: histogram of f crr /f med ; the parameters of the Gaussian fit of the histogram are marked in the panel. Compared with Figure 6, the scatter is larger because the uncertainty in the real data is larger than simulations.", "type": "figure"}}}
{"paper_id": "118864086", "_pdf_hash": "356ab0eeb0fd64ae1beb97f5c72ba506a97beb78", "abstract": [{"section": "Abstract", "text": "Exceptional points are found in the spectrum of a prototypical thermoacoustic system as the parameters of the flame transfer function are varied. At these points, two eigenvalues and the associated eigenfunctions coalesce. The system's sensitivity to changes in the parameters becomes infinite. Two eigenvalue branches collide at the exceptional point as the interaction index is increased. One branch originates from a purely acoustic mode, whereas the other branch originates from an intrinsic thermoacoustic mode. The existence of exceptional points in thermoacoustic systems has implications for physical understanding, computing, modeling and control.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "At exceptional points (EPs), at least two eigenvalues and the associated eigenfunctions coalesce, and the eigenvalue sensitivity with respect to changes in the parameters becomes infinite [1, 2] . Interesting physical phenomena associated with EPs appear across various disciplines from quantum mechanics through optics and acoustics [2, 3, 4] . To the best of the authors' knowledge, the role of exceptional points has not yet been explored in thermoacoustic systems, although points in the parameter space with infinite sensitivity were discussed in a recent review article [5] . In this letter, we show that these points in the thermoacoustic spectrum are exceptional, and that they can be found in a generic thermoacoustic system when two real parameters are varied.", "cite_spans": [{"start": 188, "end": 191, "text": "[1,", "ref_id": "BIBREF0"}, {"start": 192, "end": 194, "text": "2]", "ref_id": "BIBREF1"}, {"start": 334, "end": 337, "text": "[2,", "ref_id": "BIBREF1"}, {"start": 338, "end": 340, "text": "3,", "ref_id": "BIBREF2"}, {"start": 341, "end": 343, "text": "4]", "ref_id": "BIBREF3"}, {"start": 576, "end": 579, "text": "[5]", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "Thermoacoustic instabilities", "text": "Thermoacoustic instabilities are a major challenge for the reliable operation of many technical combustion systems, as reviewed by [5] and references therein. For most practical applications with low-Mach number combustion, thermoacoustic phenomena can be modelled by an inhomogeneous Helmholtz equation, which reads", "cite_spans": [{"start": 131, "end": 134, "text": "[5]", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "Thermoacoustic instabilities", "text": "where \u03c9 is the complex frequency,c is the mean speed of sound, i 2 = \u22121, and \u03b3 is the heat-capacity ratio. p andq are the Fourier-transformed fluctuations 1 of acoustic pressure and heat release rate, respectively. Quantities are non-dimensionalized with a characteristic length, speed of sound, and density. The heat release rate fluctuation is commonly related to a velocity fluctuation at a reference position by a time-delay model [5] , i.e. \u2212i\u03c9(\u03b3 \u2212 1)q = n exp(\u2212i\u03c9\u03c4 ) \u2207p| x ref , where the parameters n and \u03c4 are the interaction index and the time delay, respectively. The thermoacoustic stability problem is generally non-Hermitian because of the flame response term and dissipative boundary conditions. On numerical discretization or travelling-wave decomposition [5] , thermoacoustic stability is governed by a nonlinear eigenvalue problem [6, 7] L(\u03c9; \u03b5)p = 0,", "cite_spans": [{"start": 435, "end": 438, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 771, "end": 774, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 848, "end": 851, "text": "[6,", "ref_id": "BIBREF5"}, {"start": 852, "end": 854, "text": "7]", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "Thermoacoustic instabilities", "text": "where the vector \u03b5 \u2208 R M contains M parameters related to, for example, the mean speed of sound, the geometry, the flame response, and the boundary conditions. L \u2208 C N \u00d7N is an analytic function of \u03b5 and \u03c9 in some subdomain of R M \u00d7 C, where N is the number of degrees of freedom of the discretized equations. For a given \u03b5, the stability of the linear system is characterized by the eigenvalues \u03c9 = \u03c9 r + i\u03c9 i , where \u03c9 r \u2208 R is the angular frequency and \u2212\u03c9 i \u2208 R is the growth rate of the linear oscillation. With this convention, the system is linearly stable if \u03c9 i > 0. The associated thermoacoustic mode shapes are provided by the eigenvectorsp \u2208 C N .", "cite_spans": [], "ref_spans": []}, {"section": "Eigenvalue classification", "text": "Eigenvalues can be classified according to their algebraic and geometric multiplicities, a and g. The algebraic multiplicity is the eigenvalue's multiplicity as a root of the dispersion relation, whereas the geometric multiplicity is the dimension of the associated eigenspace, i.e. the number of linearly independent eigenvectors. An eigenvalue of (2) can be either semi-simple, when a = g; or defective, when a > g. For the special case a = g = 1 an eigenvalue is called simple. Semi-simple eigenvalues with g > 1 and defective eigenvalues are referred to as degenerate eigenvalues. Defective eigenvalues that are branch-point singularities in the parameter space are called exceptional points (EPs). On the one hand, eigenvalues of single-flame longitudinal thermoacoustic systems are typically simple [5, 8] . On the other hand, systems with discrete rotational symmetry, such as annular and can-annular combustors, feature semi-simple degenerate eigenvalues [6, 9] , with fewer simple eigenvalues.", "cite_spans": [{"start": 805, "end": 808, "text": "[5,", "ref_id": "BIBREF4"}, {"start": 809, "end": 811, "text": "8]", "ref_id": "BIBREF7"}, {"start": 963, "end": 966, "text": "[6,", "ref_id": "BIBREF5"}, {"start": 967, "end": 969, "text": "9]", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "Sensitivity at an exceptional point", "text": "Mathematically, in the neighborhood of an EP, the eigenvalue has a perturbation expansion in fractional powers of the parameter (Section II-2.2 in [1] ), also known as Puiseux series. At an EP with a = 2 (hence g = 1), which is assumed in the remainder of this letter, the change of the eigenvalue due to a perturbation to the i-th parameter, \u03b5 i , reads", "cite_spans": [{"start": 147, "end": 150, "text": "[1]", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "Sensitivity at an exceptional point", "text": "where \u03c9 1 is a constant. Thus, the first-order sensitivity \u2202\u03c9/\u2202\u03b5 i | \u03c9EP,\u03b5EP with respect to any parameter,", "cite_spans": [], "ref_spans": []}, {"section": "Sensitivity at an exceptional point", "text": "EP . An equivalent expansion holds for the eigenfunction at the EP.", "cite_spans": [], "ref_spans": []}, {"section": "Calculation of exceptional points in thermoacoustics", "text": "We consider a thermoacoustic system with an n-\u03c4 flame model and calculate EPs as n and \u03c4 are varied. The eigenvalues are the roots of the dispersion relation ", "cite_spans": [], "ref_spans": []}, {"section": "Calculation of exceptional points in thermoacoustics", "text": "] is the characteristic function, which is transcendental and analytic in \u03c9 in some subdomain of the complex plane. For an eigenvalue to have a = 2, (4) must be satisfied with the two following conditions", "cite_spans": [], "ref_spans": []}, {"section": "Calculation of exceptional points in thermoacoustics", "text": "The solution of the two complex-valued equations (4) and (5) is the set of parameters (n EP , \u03c4 EP ) and the defective eigenvalue \u03c9 EP . Equations (4) and (5) would also be satisfied for degenerate semi-simple eigenvalues, such as those found in systems with rotational symmetry. However, in systems without symmetry, which we consider here, degenerate eigenvalues are generically defective [10] . The defective eigenvalue has algebraic multiplicity two, but there is only one associated eigenvectorp EP .", "cite_spans": [{"start": 391, "end": 395, "text": "[10]", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "A prototypical time-delayed thermoacoustic system", "text": "We consider a prototypical thermoacoustic system, which contains the essential physical mechanisms of many thermoacoustic systems [5] . We assume that (i) the frequency of the oscillation is smaller than the cutoff frequency of the duct, i.e. only plane acoustic waves propagate; (ii) the duct has a sound hard end at the upstream boundary (zero acoustic pressure gradient) and an open end at the downstream boundary (acoustic pressure node); (iii) the flame is compact, i.e. it imposes a discontinuity in the mean temperature and acts as a point source for the acoustic field. The flame is located at the non-dimensional location x flm = 0.6; the non-dimensional reference position, at which the acoustic velocity drives the flame, is x ref = 0.5; the ratio of the speeds of sound between the hot and cold side is 2. The reference quantities for non-dimensionalization are the length of the duct and the speed of sound / density of the cold side. The characteristic function for this classical thermoacoustic problem reads Table 1 lists the acoustic mode (n = 0) and the EPs found in the vicinity of it by solving Eqs. (4) and (5). The EPs approach the acoustic eigenvalue as \u03c4 increases, while the magnitude of the associated interaction index n decreases. Section 3 discusses the eigenvalue and eigenvector sensitivity in the vicinity of the EP #1.a. The results for the other EPs in Tab. 1 are qualitatively similar (result not shown).", "cite_spans": [{"start": 130, "end": 133, "text": "[5]", "ref_id": "BIBREF4"}], "ref_spans": [{"start": 1024, "end": 1031, "text": "Table 1", "ref_id": "TABREF0"}]}, {"section": "Exceptional points in the thermoacoustic spectrum", "text": "Because the algebraic multiplicity of the EPs considered here is a = 2, two eigenvalues will be found in the vicinity of the defective eigenvalue as the parameters depart from the exceptional point. In combination with the extreme sensitivity close to the EP, the numerical computation of EPs is therefore challenging for algorithms based on fixed-point iteration, such as those commonly used in thermoacoustic analyses. In the present work, a global contour-integral-based method proposed by Beyn [7] is used. This method provides all the eigenvalues within a given circle in the complex plane, even if they are defective. The integration circle has been centered at the defective eigenvalue #1.a with unit radius. This circle encloses the acoustic eigenvalue \u03c9 ac \u2248 2.2273 + 0i (mode #1). Figure 1 (left panel) shows the eigenvalue trajectories in the vicinity of EP #1.a, which are parametrized by the interaction index n for different levels of \u03c4 . When \u03c4 = \u03c4 EP , while the interaction index n is varied from zero to 3n EP , two eigenvalue trajectories (black lines) approach each other, coalesce at n = n EP and diverge eventually. At the EP, the eigenvalue trajectories cross each other, i.e., they coalesce. This is a manifestation of the branch-point singularity, which implies infinite parameter sensitivity. The acoustic eigenvalue \u03c9 ac is the starting point of the trajectory labeled 'acoustic'. It is neutrally stable because the system without flame is conservative. The trajectory coming from the opposite direction starts far away from the circle with a large positive imaginary part, which, in contrast to the acoustic mode, corresponds to a highly damped mode. As observed in [8] (and references therein), the physical origin of this trajectory is an intrinsic thermoacoustic (ITA) mode, which, for n 1, is highly damped and independent of the geometry. Almost all the trajectories in the vicinity of the EP, thus, originate from either an acoustic mode or an intrinsic mode. The exceptions to this rule are the branches I and II, which are of mixed type, thus, they cannot be unambiguously traced back further than the EP. The investigation of these branches is left for future work. The large parameter sensitivity becomes apparent when considering eigenvalue trajectories that do not pass across the EP. The curvature and spread of these lines show that the parameter sensitivity becomes larger as n and \u03c4 approach the EPs. Figure 1 (right panel) shows the absolute value of the eigenvectors for different points along the exceptional branch (\u03c4 = \u03c4 EP ). Because the exceptional point is a defective eigenvalue, the two mode shapes collapse at n = n EP , i.e. g = 1 (black line). A small perturbation to n significantly changes the mode shape around the EP.", "cite_spans": [{"start": 498, "end": 501, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 1694, "end": 1697, "text": "[8]", "ref_id": "BIBREF7"}], "ref_spans": [{"start": 791, "end": 812, "text": "Figure 1 (left panel)", "ref_id": "FIGREF0"}, {"start": 2445, "end": 2467, "text": "Figure 1 (right panel)", "ref_id": "FIGREF0"}]}, {"section": "Discussion", "text": "Exceptional points in the spectrum of a prototypical thermoacoustic system are found and investigated for the first time, to the best of the authors' knowledge. In contrast to semi-simple degenerate eigenvalues, which are found in the thermoacoustic analysis of annular combustors and have finite sensitivity, EPs do not stem from a geometric symmetry of the system. These points are branch-point singularities in the parameter space. They have fundamental and practical implications for thermoacoustic stability.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "\u2022 Physics: Exceptional points occur when two eigenvalue trajectories with different physical nature collide. One trajectory originates from an acoustic mode, and the other trajectory originates from an intrinsic thermoacoustic mode.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "\u2022 Numerical methods: Iterative methods based on fixed point algorithms, which are commonly used in thermoacoustic stability analysis, do not seem to be robust in the vicinity of exceptional points. A contour-integration-based approach [7] facilitates robust computations of the thermoacoustic spectrum.", "cite_spans": [{"start": 235, "end": 238, "text": "[7]", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "Discussion", "text": "\u2022 Modeling and control: The large sensitivity at an EP may help design new control schemes to mitigate thermoacoustic instabilities with small changes in the design variables. The appropriate expansion at the EP, which can be used to calculate sensitivities to the system's parameters for passive control, is in fractional powers of the parameters. Robust control schemes will be necessary around exceptional points because small uncertainties in the parameters are exceedingly amplified.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "Future research will be aimed at establishing the universality of EPs in thermoacoustic systems, investigate the role of EPs in systems with discrete rotational symmetry, and exploit the properties of EPs, e.g. the large sensitivity to parameters, for control of instabilities.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Perturbation theory for linear operators", "authors": [{"first": "T", "middle": [], "last": "Kato", "suffix": ""}], "year": 1980, "venue": "", "link": "118269102"}, "BIBREF1": {"title": "The physics of exceptional points", "authors": [{"first": "W", "middle": ["D"], "last": "Heiss", "suffix": ""}], "year": 2012, "venue": "Journal of Physics A: Mathematical and Theoretical", "link": "119167805"}, "BIBREF2": {"title": "Emergence, coalescence, and topological properties of multiple exceptional points and their experimental realization", "authors": [{"first": "K", "middle": [], "last": "Ding", "suffix": ""}, {"first": "G", "middle": [], "last": "Ma", "suffix": ""}, {"first": "M", "middle": [], "last": "Xiao", "suffix": ""}, {"first": "Z", "middle": ["Q"], "last": "Zhang", "suffix": ""}, {"first": "C", "middle": ["T"], "last": "Chan", "suffix": ""}], "year": 2016, "venue": "Physical Review X", "link": "73644630"}, "BIBREF3": {"title": "Non-Hermitian acoustic metamaterials: Role of exceptional points in sound absorption", "authors": [{"first": "V", "middle": [], "last": "Achilleos", "suffix": ""}, {"first": "G", "middle": [], "last": "Teocharis", "suffix": ""}, {"first": "O", "middle": [], "last": "Richoux", "suffix": ""}, {"first": "V", "middle": [], "last": "Pagneux", "suffix": ""}], "year": 2017, "venue": "Physical Review B", "link": "119411767"}, "BIBREF4": {"title": "Sensitivity and nonlinearity of thermoacoustic oscillations", "authors": [{"first": "M", "middle": ["P"], "last": "Juniper", "suffix": ""}, {"first": "R", "middle": [], "last": "Sujith", "suffix": ""}], "year": 2018, "venue": "Annual Review of Fluid Mechanics", "link": "125189846"}, "BIBREF5": {"title": "Stability analysis of thermo-acoustic nonlinear eigenproblems in annular combustors. Part I. Sensitivity", "authors": [{"first": "L", "middle": [], "last": "Magri", "suffix": ""}, {"first": "M", "middle": [], "last": "Bauerheim", "suffix": ""}, {"first": "M", "middle": ["P"], "last": "Juniper", "suffix": ""}], "year": 2016, "venue": "Journal of Computational Physics", "link": "36607617"}, "BIBREF6": {"title": "The nonlinear eigenvalue problem", "authors": [{"first": "S", "middle": [], "last": "G\u00fcttel", "suffix": ""}, {"first": "F", "middle": [], "last": "Tisseur", "suffix": ""}], "year": 2017, "venue": "Acta Numerica", "link": "46749298"}, "BIBREF7": {"title": "Thermoacoustic modes of quasi-1D combustors in the region of marginal stability", "authors": [{"first": "C", "middle": ["F"], "last": "Silva", "suffix": ""}, {"first": "K", "middle": ["J"], "last": "Yong", "suffix": ""}, {"first": "L", "middle": [], "last": "Magri", "suffix": ""}], "year": 2018, "venue": "Proceedings of the ASME 2018 Turbomachinery Technical Conference & Exposition", "link": "203057533"}, "BIBREF8": {"title": "Efficient computation of thermoacoustic modes in industrial annular combustion chambers based on Bloch-wave theory", "authors": [{"first": "G", "middle": [], "last": "Mensah", "suffix": ""}, {"first": "G", "middle": [], "last": "Campa", "suffix": ""}, {"first": "J", "middle": [], "last": "Moeck", "suffix": ""}], "year": 2016, "venue": "Journal of Engineering for Gas Turbines and Power", "link": "111401014"}, "BIBREF9": {"title": "Coupling of eigenvalues of complex matrices at diabolic and exceptional points", "authors": [{"first": "A", "middle": ["P"], "last": "Seyranian", "suffix": ""}, {"first": "O", "middle": ["N"], "last": "Kirillov", "suffix": ""}, {"first": "A", "middle": ["A"], "last": "Mailybaev", "suffix": ""}], "year": 2005, "venue": "J. Phys. A: Math. Gen", "link": "14194165"}}, "ref_entries": {"FIGREF0": {"text": "Figure 1: Left: eigenvalue trajectories when n is varied from 0 to 3 times its exceptional value (mode #1.a in Table 1). Blue lines are for \u03c4 < \u03c4 EP while orange lines are for \u03c4 > \u03c4 EP . \u03c4 varies equidistantly between \u03c4 EP \u00b1 0.2 2\u03c0 real(\u03c9 EP ) . The darker the shading, the closer the values are to the exceptional point. The black lines indicate the trajectories for \u03c4 = \u03c4 EP ; their intersection indicates the EP. The colored arrows indicate the direction of increasing n. The thin grey lines highlight solutions for constant n. The markers on the black line depict values of n ranging equidistantly from 0 to 2n EP . Only solutions inside the circle are shown. Right: the eigenvectors corresponding to the markers on the exceptional trajectories. Acoustic branch in green, intrinsic thermoacoustic (ITA) branch in yellow, exceptional branch I in red, exceptional branch II in purple, EP in black.", "type": "figure"}, "TABREF0": {"text": "Acoustic eigenvalue (in grey) and some close-by exceptional points. The parameters n and \u03c4 are given to ten decimal places. With this precision, two eigenvalues are found to be identical up to four decimal places.", "type": "table"}}}
{"paper_id": "118864185", "_pdf_hash": "887aea41b8e661520855039f02f0d9b971343eab", "abstract": [{"section": "Abstract", "text": "I consider whether we can significantly improve the Cardelli et al. (1989) family of extinction laws using new data and techniques. There are six different aspects that need to be treated: The use of monochromatic quantities, the three different wavelength regimes (NIR, optical and UV), the sample, and the photometric calibration. Excluding the behavior in the NIR and UV, I discuss the other four aspects and propose a new family of extinction laws derived from VLT/FLAMES and HST/WFC3 data.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "", "text": "1 The CCM family of extinction laws The Cardelli et al. (1989) or CCM family of extinction laws are the most oft-cited extinction laws in the astronomical literature. Their fame is undoubtedly well deserved since they were the first laws that accurately described the full NIR-optical-UV range with a parameterized form that allowed different tyes of extinction to be considered. Almost a quarter of a century later they are still broadly used in a wide range of applicatons. In this contribution we ask whether the CCM laws are due for an update using new data and techniques.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "The CCM extinction laws are a single-parameter family of functions that extend from x \u2261 1/\u03bb = 0.3 \u00b5m \u22121 (33 333\u00c5) to x = 10 \u00b5m \u22121 (1000\u00c5). The parameter that characterizes the family is R V \u2261 A V /E(B \u2212 V ), which has typical values close to 3 but which in some environments can be slightly lower or significantly higher. The CCM extinction laws are divided into four wavelength ranges, the NIR (x = 0.3-1.1 \u00b5m \u22121 ), the optical (x = 1.1-3.3 \u00b5m \u22121 ), the UV (x = 3.3-8.0 \u00b5m \u22121 ), and the FUV (x = 8.0-10.0 \u00b5m \u22121 ). Each range uses a different functional form but the laws are continuous and differentiable at each boundary. The extinction laws in the NIR and optical were derived from multiband ground-based photometry and in the UV and FUV from IUE spectrophotometry. Three examples of CCM extinction laws are shown in Figs. 1 and 2. . Extinction is normalized to the value at 10 000\u00c5 in each case to emphasize that the extinction laws are the same for longer wavelengths and to better visualize the differences in the optical and NUV ranges. The approximate extent of some filters in three common systems (Johnson-Cousins, Str\u00f6mgren, and WFC3) is shown.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "There are several issues with the CCM laws that need to be discussed in other to study the need for a new family of extinction laws:", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "1. Monochromatic quantities. Using R V as the parameter for the type of extinction is ill defined. R V is a filter-integrated quantity (using Johnson B and V ), not a monochromatic one 1 . That means that unless A(\u03bb) is constant over the extent of the filter (which is never the case), R V is not only a function of the extinction law but also of the input spectral energy distribution and of the amount of extinction. In other words, the same amount and type of dust in front of two stars produces different values of R V and doubling the amount of dust without changing its type also changes R V . For the same reason, using A V or E(B \u2212 V ) to parameterize the amount of extinction is also ill defined. Graphical examples of the problem are shown in Fig. 3 . So what is going on here? Actually, a CCM law with a given R V parameter does not actually produce extinction with A V /(E(B \u2212V ) equal to that value of R V (see Fig. 3 ), an effect that has created confusion in the past. The easiest way to fix it is to select two wavelengths near the center of the B and V filter and substitute the R V (type of extinction) and E(B \u2212V ) (amount of extinction) parameters by monochromatic equivalents. Ma\u00edz Apell\u00e1niz (2004) did this choosing 4405\u00c5 and 5495\u00c5as reference wavelengths for B and V , respectively. Those are also the choices in the current version of CHORIZOS (v 3.2, Ma\u00edz Apell\u00e1niz 2004) and here we follow the same convention. The reason for using those wavelengths to define the equivalents of R V and E(B \u2212 V ), e.g. R 5495 and E(4405 \u2212 5495), is that for hot stars and low extinction [E(4405 \u2212 5495)< 1.0], R V \u2248 R 5495 and E(B \u2212 V ) \u2248 E(4405 \u2212 5495) (Fig. 3) . Therefore, we will use R 5495 as the parameter for both the CCM and new laws.", "cite_spans": [], "ref_spans": [{"start": 753, "end": 759, "text": "Fig. 3", "ref_id": "FIGREF2"}, {"start": 924, "end": 930, "text": "Fig. 3", "ref_id": "FIGREF2"}, {"start": 1664, "end": 1672, "text": "(Fig. 3)", "ref_id": "FIGREF2"}]}, {"section": "", "text": "2. The NIR. In that wavelength range (called simply infrared in the original paper), CCM laws use a power law with a fixed 2 exponent A(\u03bb)/A(10 000\u00c5) = x 1.61 . However, their analysis has been put into question by Nishiyama et al. (2009) and different authors (e.g. Moore et al. 2005; Fitzpatrick & Massa 2009 ) have found that the NIR extinction law changes from one sightline to another, with exponents as low as 1.1 and as high as 2.3. Beyond the K band, the extinction law first flattens and then develops complex structures (Rom\u00e1n-Z\u00fa\u00f1iga et al., 2007; Nishiyama et al., 2009; Gao et al., 2009) .", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "3. The optical range. In order to fit the extinction law there, CCM used a seventhdegree polynomial. That functional form has the advantage of being able to fit the law through their five passbands (U BV RI) but the disadvantage of possibly introducing undesired wiggles in wavelength (Fig. 2) . Such wiggles can be detected when comparing CCM predictions with spectrophotometry or with intermediate-band photometry such as Str\u00f6mgren's. Prior to CCM, Whitford (1958) (see also Ardeberg & Virdefors 1982) had used spectrophotometry to propose a simpler functional form of two straight lines joined near x = 2.25 \u00b5m \u22121 . The point where the two lines are joined is called the \"knee\" and is the most prominent wiggle in the CCM laws in the optical (Fig. 2 , see also Stebbins & Whitford 1943) . CCM were clearly aware of the issue and mentioned that \"The Whitford law may therefore be more accurate for the diffuse ISM near x \u2248 2.25 \u00b5m \u22121 . The virtue of ours, however, is that it joins smoothly onto the UV extinction law from the FM [Fitzpatrick & Massa 1988 ] sample of stars and that it takes into account the differences in the extinction laws of lines of sight with various values of R V \". In other words, they were willing to sacrifice accuracy (in the form of detailed behavior for small wavelength scales) in favor of functionality (in the form of the addition of the R V parameter and the continuity and differentiability for all wavelengths).", "cite_spans": [], "ref_spans": [{"start": 285, "end": 293, "text": "(Fig. 2)", "ref_id": "FIGREF1"}, {"start": 745, "end": 752, "text": "(Fig. 2", "ref_id": "FIGREF1"}]}, {"section": "", "text": "4. The UV and FUV. The emphasis of CCM laid on these wavelength ranges, as appropriate at the end of a decade where IUE revolutionized the study of extinction. Special importance was paid to the ability of a single-parameter family to describe extinction from the IR to UV, as evident in the title of the paper. However, this aspect has been challenged by Fitzpatrick & Massa (2007) , who find that \"With the exception of a few curves with extreme (i.e., large) values of R(V ), the UV and IR portions of Galactic extinction curves are not correlated with each other.\"", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "5. The CCM sample. CCM used a sample of 29 stars, which was a relatively large number for the time. However, more modern extinction studies use hundreds or thousands of stars. Also, their sample had only low or moderate extinction: only three stars have values of (E(B \u2212 V ) greater than 1.0 and even the most reddened (HDE 229 196) of those has an E(B \u2212 V ) of 1.22. Also, the three most reddened stars have a relatively narrow range of R 5495 between 2.6 and 4.2. The solution for high values of R 5495 (> 5.0) depends heavily on a single star, Herschel 36, which has an E(B \u2212 V ) of 0.89 (the other cases with R 5495 > 5.0 have E(B \u2212 V ) < 0.4) and has been recently found to be a multiple system with nearby IR sources (Arias et al., 2006 (Arias et al., , 2010 . Using stars with low extinction to determine an extinction law is quite dangerous since random and systematic (see below) uncertainties can introduce significant errors. One should also take into account that the CCM law has been applied to objects with E(4405 \u2212 5495) significantly larger than 1.0: in those cases one is extrapolating a law beyond the range for which it was derived, thus amplifying any potential errors in the original work. 6. Photometric calibration. The final issue is that of the photometric calibration of the filters used in the NIR and optical ranges. By calibration we mean both the determination of the zero points and the shape of the sensitivity curves. The reader is referred to Ma\u00edz Apell\u00e1niz (2005, 2006, 2007) and references therein for developments in this field after CCM. In particular, it should be noted that old observations in the Johnson U band may be suspect because of the effect of the atmosphere in the sensitivity curve and because the curve straddles the Balmer jump, thus being affected by errors in the spectral type.", "cite_spans": [], "ref_spans": []}, {"section": "The new extinction laws", "text": "Based on the issues discussed in the previous section, we decided to attempt the calculation of a new family of extinction laws. Ideally, to complete such a task one would use high-quality spectrophotometry from the NIR to the UV of a diverse collection of sources in different environments and with different degrees of extinction. Since such dataset is not currently available, we will start by dealing only with some of the issues discussed in the previous section. More specifically, we will ignore extinction in the UV (except for the region closest to the optical) and for the NIR we will simply use the CCM laws. In other words, we will concentrate our efforts in the optical region. Ignoring the UV will not matter to a non-specialist interested only in eliminating the extinction from his/her optical data. Ignoring the NIR may matter if the exponent there is significantly different from the CCM one but only if extinction is very large and even then it may only apply to the total extinction correction, not to e.g. the determination of T eff from the photometry.", "cite_spans": [], "ref_spans": []}, {"section": "The new extinction laws", "text": "To derive the new family of extinction laws we are using two datasets:", "cite_spans": [], "ref_spans": []}, {"section": "The new extinction laws", "text": "\u2022 The VLT/FLAMES Tarantula Survey (Evans et al., 2011) , from which we are using \u223c 200 accurate spectral types of stars (mostly of O type) in 30 Doradus as well as NIR photometry.", "cite_spans": [], "ref_spans": []}, {"section": "The new extinction laws", "text": "\u2022 The WFC3 Early Release Science HST/WFC3 images of the central region of 30 Doradus (De Marchi et al., 2011; Sabbi et al., 2012) , from which photometry in six broadband filters (F336W, F438W, F555W, F814W, F110W, and F160W, which are U BV IJH equivalents) was extracted.", "cite_spans": [], "ref_spans": []}, {"section": "The new extinction laws", "text": "Our analysis is in a quite advanced stage and in the near future we will submit for publication our results. A preliminary view with three examples of the new extinction laws is shown in Figs. 1 and 2 . We have verified that the new laws provide significantly lower residuals when assuming effective temperatures derived from the spectral types and better fits when attempting to derive the effective temperatures from the photometry. We have also applied the new extinction laws to Galactic stars with E(4405 \u2212 5495) between 1.5 and 2.0 and have been able to significantly lower the fits residuals when compared to CCM or to Fitzpatrick (1999) , thus extending the applicability of the new family of optical/NIR extinction laws to the Milky Way 3", "cite_spans": [], "ref_spans": [{"start": 187, "end": 200, "text": "Figs. 1 and 2", "ref_id": "FIGREF0"}]}], "bib_entries": {"BIBREF14": {"title": "The Future of Photometric, Spectrophotometric and Polarimetric Standardization", "authors": [{"first": "J", "middle": [], "last": "Ma\u00edz Apell\u00e1niz", "suffix": ""}], "year": 2007, "venue": "ASP Conf. Series", "link": null}}, "ref_entries": {"FIGREF0": {"text": "Figure 1: CCM and new extinction laws for three values of R 5495 (2.5, 3.2, and 5.0). Extinction is normalized to the value at 10 000\u00c5 in each case to emphasize that the extinction laws are the same for longer wavelengths and to better visualize the differences in the optical and NUV ranges. The approximate extent of some filters in three common systems (Johnson-Cousins, Str\u00f6mgren, and WFC3) is shown.", "type": "figure"}, "FIGREF1": {"text": "Figure 2: As Fig. 1 but with a different normalization to emphasize the differences between extinction laws. In each case we have subtracted a linear fit A(\u03bb)/A(5495\u00c5) = a(R 5495 ) + b(R 5495 )x, with a(R 5495 ) and b(R 5495 ) calculated so that the CCM law for that R 5495 is 0.0 at x = 1.1 and at x = 3.3, the limits for the optical range in CCM.", "type": "figure"}, "FIGREF2": {"text": "Figure 3: R V (left) and E(B \u2212 V ) \u2212 E(4405 \u2212 5495) (right) as a function of E(4405 \u2212 5495) for a CCM extinction law with R 5495 = 3.2 and three main-sequence stars with different T eff . R V \u2248 R 5495 and E(B \u2212 V ) \u2248 E(4405 \u2212 5495) only for hot stars with low extinctions.", "type": "figure"}}}
{"paper_id": "118864492", "_pdf_hash": "f0a4cfa0a6c76dfb25cbbf341f319280c7447347", "abstract": [{"section": "Abstract", "text": "Since the detection of non-thermal radio emission from the bow shock of the massive runaway star BD +43", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "\u2022 3654 simple models have predicted high-energy emission, at X and gamma-rays, from these Galactic sources. Observational searches for this emission so far give no conclusive evidence but a few candidates at gamma rays. In this work we aim at developing a more sophisticated model for the nonthermal emission from massive runaway star bow shocks. The main goal is to establish whether these systems are efficient non-thermal emitters, even if they are not strong enough to be yet detected. For modeling the collision between the stellar wind and the interstellar medium we use 2D hydrodynamic simulations. We then adopt the flow profile of the wind and the ambient medium obtained with the simulation as the plasma state for solving the transport of energetic particles injected in the system, and the non-thermal emission they produce. For this purpose we solve a 3D (2 spatial + energy) advection-diffusion equation in the test-particle approximation. We find that a massive runaway star with a powerful wind converts 0.16-0.4% of the power injected in electrons into non-thermal emission, mostly produced by inverse Compton scattering of dust-emitted photons by relativistic electrons, and secondly by synchrotron radiation. This represents a fraction of \u223c 10 \u22125 \u2212 10 \u22124 of the wind kinetic power. Given the better sensibility of current instruments at radio wavelengths theses systems are more prone to be detected at radio through the synchrotron emission they produce rather than at gamma energies.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "INTRODUCTION", "text": "Runaway massive stars are stars with high spatial velocities (V > 30 km s \u22121 ) that have been expelled from their formation sites (e.g., Hoogerwerf et al. 2000; Tetzlaff et al. 2011) . Massive stars have strong winds that interact with the interstellar medium (ISM) as the stars move supersonicaly through it. In this interaction a bow shock is formed, in some cases detectable in the infrared (IR) (e.g., van Buren & McCray 1988; Kobulnicky et al. 2010) . This last emission is reprocessed stellar light by the dust swept by the bow shock. There are of the order of \u223c 700 stellar bow shocks cataloged so far (Peri et al. 2012 (Peri et al. , 2015 Kobulnicky et al. 2016) .", "cite_spans": [], "ref_spans": []}, {"section": "INTRODUCTION", "text": "The bow shock of the massive runaway star BD +43", "cite_spans": [], "ref_spans": []}, {"section": "INTRODUCTION", "text": "\u2022 3654 was detected at radio wavelengths, and the emission might be synchrotron radiation (Benaglia et al. 2010) . This suggests that a population of high-energy electrons is present in the source, interacting locally with the magnetic field. In the collision between the ISM and the stellar wind a system of two shocks is formed: a forward shock and a reverse shock. This last shock is adiabatic and fast, with velocities of the order of \u223c 10 3 km s \u22121 . Hence it is straight forward to think that this reverse shock might accelerate particles up to highenergies through diffusive shock acceleration (DSA) .", "cite_spans": [], "ref_spans": []}, {"section": "INTRODUCTION", "text": "If the electrons that produce the radio non-thermal emission were accelerated in the reverse shock of BD arXiv:1807.05895v1 [astro-ph.HE] 16 Jul 2018", "cite_spans": [], "ref_spans": []}, {"section": "+43", "text": "\u2022 3654 then they are expected to further interact with the ambient fields: the density and the photons producing high-energy emission via relativistic Bremsstrhalung and inverse Compton (IC) scattering. With this in mind a number of initial models predict non-thermal emission, mainly via IC scattering of IR photons, at X-rays and gamma rays (del Valle & Romero 2012 Pereira et al. 2016 ), see also del Palacio et al. (2018) for a multi-zone model. L\u00f3pez-Santiago et al. (2012) claimed to find the first non-thermal X-ray emission from the bow shock of AE Aurigae, however later it was demonstrated that the emission is not positional coincident with that of AE Aurigae bow shock (Toal\u00e1 et al. 2017) . Nolan et al. (2012) found an unidentified Fermi source locally coincident with the position of the bow shock of the massive star HD 195592, and del Valle et al. (2013) studied the possibility that this gamma emission was being produced in the bow shock. Although theoretically plausible, in the second Fermi catalog this source was reclassified as a pulsar (Abdo et al. 2013) .", "cite_spans": [], "ref_spans": []}, {"section": "+43", "text": "Several searches for high-energy emission from bow shocks of massive runaway stars have followed. At X-rays using both XMM-Newton archived observations (Toal\u00e1 et al. 2017 (Toal\u00e1 et al. , 2016 and dedicated observations (De Becker et al. 2017) , where no non-thermal extended emission was found. De Becker et al. (2017) used the derived upper limits at X-rays and those available at radio wavelength to fit general physical parameters of the sources with a simple model for the non-thermal emission. They found reasonable fit values for 5 out of the 4 targets of the sample. Also, making energetic assumptions for all the bow shocks listed in the E-BOSS catalog, they concluded that a clear identification of non-thermal X-ray emission from massive runaway bow shocks requires one order of magnitude (or higher) sensitivity improvement with respect to present observatories.", "cite_spans": [], "ref_spans": []}, {"section": "+43", "text": "At gamma-ray wavelengths Schulz et al. (2014) searched for emission in Fermi archive data of the 28 bow shocks listed in the E-BOSS catalog (Peri et al. 2012) . From the modeled sources only \u03b6 Oph was detectable, however no emission locally coincident with this source was found in the data; from this it can be concluded that the model predictions were overestimated at least by a factor of \u223c 5. For the rest of the sources upper limits were derived in the energy range from 100 MeV to 300 GeV. A study of the same sources was made by the H.E.S.S. collaboration in the energy range between 0.14 and 18 TeV (H. E. S. S. Collaboration et al. 2017) . No associated emission was found but from the resulting upper limits a constraint on the very high energy emission was obtained: it should be less than 0.1 to 1% of the kinetic wind energy.", "cite_spans": [], "ref_spans": []}, {"section": "+43", "text": "Recently, S\u00e1nchez-Ayaso et al. (2018) presented two runaway stars (Lambda Cephei and LS 2355) whose bow shocks are coincident with two unidentified Fermi gamma-ray sources from the third Fermi 3FGL catalog (Acero et al. 2015) . After cross-correlation between different catalogs at distinct wavelengths, the authors found that these bow shocks are the most peculiar objects in the Fermi position ellipses. Using a simple model for estimating the IC emission they fitted the Fermi data for both sources, obtaining reasonable values for the fitted parameters. This makes these systems promising candidates for gamma-ray bow shocks.", "cite_spans": [], "ref_spans": []}, {"section": "+43", "text": "The growing observational base, the progressive interest of the gamma-ray and X-ray community on searching non-thermal emission from stellar sources, together with the new observational upper limits demand now more accurate models of non-thermal emission from runaway star bow shocks. Here we present such a model, aiming to establish new theoretical predictions on non-thermal emission from these sources and also to establish if these systems can be efficient non-thermal emitters. Detailed theoretical work will help to guide the search of these sources at radio and high energies.", "cite_spans": [], "ref_spans": []}, {"section": "+43", "text": "In this work we implement a hydrodynamic code to simulate the interaction of the wind of high-mass runaway stars with the ambient medium; then we calculate the non-thermal emission associated with this interaction. Assuming that electrons and protons are accelerated via DSA in the reverse shock we solve the transport of particles and their emissions obtaining emission maps and spectral energy distributions (SEDs). Here we do not focus in any particular source, that would be addressed in future works.", "cite_spans": [], "ref_spans": []}, {"section": "+43", "text": "In the next Section we give a general introduction to the model followed by a more detailed description of the hydrodynamics of the wind+ISM interaction and our implementation in Sect. 3. In Sect. 4 we present our model for solving the transport of energetic particles. In Sect. 5 the obtained results are shown and finally in Sect. 6 we present a discussion and give our conclusions in Sect. 7.", "cite_spans": [], "ref_spans": []}, {"section": "INTRODUCTION TO THE MODEL", "text": "As mentioned above, the bow shock of a massive runaway star is formed by the collision of the stellar powerful wind with the incoming ISM, in the star's reference frame. The wind and ISM pressure balance at the contact discontinuity. The characteristic scale of the system is usually taken as the standoff distance R 0 , given by the Figure 1 . Scheme of a runaway massive star bow shock. Five regions can be distinguished: free flowing stellar wind, the shocked wind, hot shocked ISM, cooled ISM, and the ISM itself. Due to thermal conduction two layers of shocked ISM are formed. A hot and low density layer adjacent to the contact discontinuity and an outer one formed of cooled shocked ambient medium (Comeron & Kaper 1998; Meyer et al. 2014 ).", "cite_spans": [], "ref_spans": []}, {"section": "INTRODUCTION TO THE MODEL", "text": "balance of the wind and ambient medium ram pressures:", "cite_spans": [], "ref_spans": []}, {"section": "INTRODUCTION TO THE MODEL", "text": "where\u1e40 w and V w are the wind mass loss rate and velocity, respectively; \u03c1 ISM is the ISM density and v is the star's velocity. In the instantaneous cooling approximation R 0 would directly give the distance from the star to the apsis of the bow shock, however in a real system this distance might vary, due to thermal conduction and cooling, for example (e.g., Raga et al. 1997; Comeron & Kaper 1998; Meyer et al. 2014) .", "cite_spans": [], "ref_spans": []}, {"section": "INTRODUCTION TO THE MODEL", "text": "In the literature a number of works exists on the collision of two fluids and specifically for modeling the bow shocks of massive runaways (e.g. Wilkin 1996; Canto et al. 1996; Raga et al. 1997; Comeron & Kaper 1998; Wilkin 2000; van Marle et al. 2011; Meyer et al. 2014 Meyer et al. , 2016 Meyer et al. , 2017 . A precise description of the phenomenology requires a dynamical treatment implementing numerical simulations. An appropriate treatment of the hydrodynamics of stellar winds should include both optically thin cooling and thermal conduction (e.g., Raga et al. 1997; Comeron & Kaper 1998) .", "cite_spans": [], "ref_spans": []}, {"section": "INTRODUCTION TO THE MODEL", "text": "After the formation of the bow shock the system would reach globally a steady state. A general sketch of a bow shock is shown in Figure 1 . The system is very prone to suffer many instabilities: Rayleigh-Taylor between the dense cooled layer and the hotter less dense one, an instability arising in shocked layers bounded by thermal pressure on one side and ram pressure on the other (e.g., Ryu & Vishniac 1987; Mac Low & Norman 1993; Comeron & Kaper 1998) and Kelvin-Helmholtz due to the velocity shear between the material layers (e.g., Dgani et al. 1996) . A complete analysis of these instabilities is made in Comeron & Kaper (1998) .", "cite_spans": [], "ref_spans": []}, {"section": "INTRODUCTION TO THE MODEL", "text": "In this work we use the PLUTO code (Mignone et al. 2007 ) to solve the 2D hydrodynamic equations following the set-up by Meyer et al. (2014) (see also, Meyer et al. 2016 Meyer et al. , 2017 . At this stage we do not consider the magnetic field in the simulations. As the system reaches a steady state we use that state as a scenario to solve in it the transport of energetic particles, assumed to be accelerated via DSA in the wind shock. We search for the reverse shock position and inject there relativistic electrons and protons; using our own code we solve the diffusion-advection equation for the particles in the 2D domain.", "cite_spans": [], "ref_spans": []}, {"section": "INTRODUCTION TO THE MODEL", "text": "The energetic particles would interact with the magnetic field producing synchrotron emission (only for electrons, proton synchrotron is very inefficient in this case); with the density producing relativistic Bremsstrahlung and p \u2212 p inelastic collisions -for electrons and protons, respectively-; and with the radiation fields: the stellar photon field and the stellar-reprocessed dust emission. Only electrons interact efficiently with the radiation fields, via IC scattering.", "cite_spans": [], "ref_spans": []}, {"section": "INTRODUCTION TO THE MODEL", "text": "Other works that solve the hydrodynamic and magnetohydrodynamic equations together with the transport of high energy particles exist. For example, in de la Cita et al. (2016) they use a similar approach as the one we use, but here we do solve the spatial diffusion of the particles, which is key in the system we are studying. In Pakmor et al. (2016) they solve the hydrodynamics of galactic winds and cosmic-ray diffusion, but they consider this last component as a fluid, without solving the energy dependence of the particles, needed to compute the non-thermal emission; in contrast to this system, the pressure of the energetic particles is negligible in our case. Brose et al. (2016) make a self-consistent treatment of the plasma dynamics, acceleration and transport of cosmic rays in supernova remnants. However their 1D treatment is not appropriate in our problem.", "cite_spans": [], "ref_spans": []}, {"section": "INTRODUCTION TO THE MODEL", "text": "In the following Sections we describe with more detail the hydrodynamic model and the modeling of the transport of relativistic particles.", "cite_spans": [], "ref_spans": []}, {"section": "HYDRODYNAMIC MODELING", "text": "As mentioned previously we use the PLUTO code to solve the 2D hydrodynamic equations following the setup by Meyer et al. (2014) . We consider a 2D cylindrical coordinate system with coordinates (r, z). The system of equations is the following:", "cite_spans": [], "ref_spans": []}, {"section": "HYDRODYNAMIC MODELING", "text": "Here v, \u03c1 and p are the fluid velocity, its density and pressure, respectively; \u03b3 g = 5/3 is the ratio of specific heats for a monoatomic ideal gas, c s is the sound speed, \u03a6 represents the radiative energy gains (heating) and losses (cooling) and F c is the heat flux due to thermal conduction. The total density is \u03c1 = \u00b5nm H with n the total number density and \u00b5 = 0.61, mean molecular weight for a fully ionized medium 1 . The temperature T as a function of density and pressure is given by T = \u00b5 mH kB p \u03c1 , with k B the Boltzmann constant.", "cite_spans": [], "ref_spans": []}, {"section": "HYDRODYNAMIC MODELING", "text": "The radiative term \u03a6 can be written as", "cite_spans": [], "ref_spans": []}, {"section": "HYDRODYNAMIC MODELING", "text": ", where \u0393 \u03b1 represents the heating and \u039b the optically-thin cooling; n H is the hydrogen number density, we consider solar abundances. The cooling term includes the cooling of Hydrogen, Helium and metals (tabulated from Wiersma et al. 2009 ), hydrogen recombination and forbidden lines collisionally exited; the heating term is due to recombination of hydrogen ions. For further details the reader is referred to Meyer et al. (2014) and references therein.", "cite_spans": [], "ref_spans": []}, {"section": "HYDRODYNAMIC MODELING", "text": "The heat flux F c = \u2212\u03ba\u2207T is due to thermal conduction. The classical heat flux given by Spitzer's coefficient in a fully ionized plasma is \u03ba = 5.6 \u00d7 10 \u22127 T 5/2 erg s \u22121 cm \u22121 .", "cite_spans": [], "ref_spans": []}, {"section": "Initial conditions", "text": "We are interested in massive runaway stars with powerful winds, so we consider a typical runaway of mass", "cite_spans": [], "ref_spans": []}, {"section": "Initial conditions", "text": "We use a rectangular box of size [0, 24 pc] \u00d7 [\u221218, 8 pc] and resolution (880 \u00d7 960). Initially the box is filled with ISM of density n ISM = 0.57 and T = 8000 K, and velocity v = \u2212v k . The wind is constantly injected in a region R 2 = r 2 + z 2 < 1 pc centered at the origin. Its density is given by \u03c1 w =\u1e40 w /(4\u03c0v w R 2 ). We use a tracer (passive scalar) to color the wind material. After \u223c 16 t cross , with t cross = R/v , the expanding bubble turns into a steady bow shock (Meyer et al. 2014 ).", "cite_spans": [], "ref_spans": []}, {"section": "Boundary conditions", "text": "In the initial r boundary, because of the symmetry of the problem, we consider axisymmetric boundary conditions. For the end boundary of both r and z we use outflow conditions. Also, we do not allow inflow at the z-lower boundary. In the initial z boundary the condition that fresh ISM enters with v = \u2212v k is imposed.", "cite_spans": [], "ref_spans": []}, {"section": "Boundary conditions", "text": "For solving the dynamic evolution we use a Runge Kutta algorithm of third order, with linear spatial reconstruction. These systems are highly prone to instabilities, hence fluxes are computed using a simple LaxFriedrichs scheme. This also avoids 2D-effects in the symmetry axis. The parabolic term (thermal conduction) is solved using the Super-Time-Stepping scheme implemented in the code.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "In Figure 2 we show the evolution of the density in the simulation domain from t = 0.3 to 1.5 Myr, when the large structure have already reached a steady state. Initially the material expands spherically, the shocked ISM starts to flow surrounding the expanding wind. A thin layer of cooled ISM material starts to form. The structure shows some fingers in the hot-cool shocked ISM interface, possibly due to Rayleigh-Taylor instability. At latter times some instabilities in the windshocked wind interface appear, possibly due to shear (Kelvin-Helmholtz instability), produced by the different velocities of the two layers (see also Fig.3 ). Comparing the bow shock shape from t = 0.9 Myr with that at t = 1.5 Myr we can see that there are few changes in the structure, only in the inner cooling layer due to instabilities; at t = 1.5 Myr the system have already reached a steady state.", "cite_spans": [], "ref_spans": [{"start": 3, "end": 11, "text": "Figure 2", "ref_id": "FIGREF0"}, {"start": 633, "end": 638, "text": "Fig.3", "ref_id": "FIGREF1"}]}, {"section": "Results", "text": "In Figure 3 it is shown (upper plot) a map of the velocity at t = 1.5 Myr. The highest velocities, \u223c 10 3 km s", "cite_spans": [], "ref_spans": [{"start": 3, "end": 11, "text": "Figure 3", "ref_id": "FIGREF1"}]}, {"section": "Results", "text": "correspond to the wind, the shocked ISM flows with velocities of the order of hundreds kilometers-per-second or less. In the bottom plot in the same figure it is shown the temperature map, at the same snapshot. The highest temperature corresponds to the shocked wind, with T \u223c 7 \u00d7 10 7 K. Given the relation T = 2 \u00d7 10 \u22129 V 2 shock K for an adiabatic shock of velocity V shock , this implies a shock velocity V shock \u223c 2 \u00d7 10 3 km s \u22121 \u223c V w . Comparing the cooling time t cool = P (\u03b3g\u22121)\u039b(T )n 2 H with the dynamical time of an specific layer t dyn = \u2206z/v establishes the adiabatic/radiative nature of a shock. For the wind shock T \u223c 7 \u00d7 10 7 K, n \u223c 10 \u223c 10 \u221222 erg cm \u22123 s \u22121 that gives t cool = 2 \u00d7 10 2 Gyr >> t dyn = 0.2 kyr, with \u2206z \u223c 0.1 pc. For the forward shock", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "t cool = 10 kyr, which dominates over the dynamical time that is, for \u2206z = 0.6 pc, t dyn = 0.2 Myr. Hence the shock in the wind is adiabatic, and the shock in the ISM is radiative. Profiles of density and temperature for r = 0, z \u2265 0 are shown in Figure 4 , at t = 1.5 Myr. The density decreases radially as expected from \u03c1 w \u221d R \u22122 , a density jump occurs at z \u223c 2.16 pc that coincides with a jump in the temperature: this is the wind or reverse shock. The contact discontinuity, marked in the figure with a solid vertical line, is located at z \u223c 2.3 pc, a bit further than the position predicted theoretically, i.e. z \u223c R 0 , an effect expected by thermal conduction (e.g., Comeron & Kaper 1998). The density increases slowly after the jump. This increase of mass in the intermediate density layer is caused by thermal conduction (van Buren & McCray 1988) . At z \u223c 4.9 pc another jump in density is encountered, again in company of a jump in temperature, this is the forward shock. The dense layer of the bow shock is in thermal equilibrium with the ISM.", "cite_spans": [], "ref_spans": [{"start": 247, "end": 255, "text": "Figure 4", "ref_id": "FIGREF2"}]}, {"section": "Results", "text": "It is worth mentioning that this profile differs from the more sharply structured typical reverse shock-contact discontinuity-forward shock profile in which the regions of different materials are well delimited. The presence of thermal conduction produces an intermediate density layer. The temperature of the shocked ambient gas is much lower than that of the shocked wind, this causes a flow of energy outwards; in turn a inward flow of matter from the dense layer into the shocked wind region occurs (Comeron & Kaper 1998) . Meyer et al. (2017) demonstrated that the presence of a ISM magnetic field does not change the global shape of the bow shock, but it modifies the thermal conduction and hence the hot bubble size. The magnetohydrodynamic treatment will be addressed in a future work. Analyzing deeply the hydrodynamic of the system is not the goal of this work, many previous works -mentioned in Sect.2-have done this extensively and the readers are referred to them for further inquiries in the subject.", "cite_spans": [], "ref_spans": []}, {"section": "TRANSPORT OF HIGH-ENERGY PARTICLES MODELING", "text": "We solve the transport of electrons and protons in the bow shock of the massive star described in the previous section, using the solution of the HD simulations at t = 1.5 Myr. We use the same cylindrical coordinate system (r, z). The diffusion-advection equation for relativistic protons and electrons that follows N (t, E, r) \u2261 number of particles / unit energy \u00d7 unit volume, is:", "cite_spans": [], "ref_spans": []}, {"section": "TRANSPORT OF HIGH-ENERGY PARTICLES MODELING", "text": "where the first term represents the diffusion in space with diffusion coefficient D(t, E, r), followed by the advection term with v(t, r) the fluid velocity; the third term corresponds to radiative losses where P (t, E, r) is the energy loss rate for a particle with energy E. injected particles / unit energy \u00d7 unit volume \u00d7 unit time.", "cite_spans": [], "ref_spans": []}, {"section": "TRANSPORT OF HIGH-ENERGY PARTICLES MODELING", "text": "We solve Eq. 3 in a 3D grid \u2261 (E, r, z) using our own modular code (see, del Valle et al. 2015 . In what follows we describe each of the terms and the model details.", "cite_spans": [], "ref_spans": []}, {"section": "Injection", "text": "As argued above the particles are thought to be accelerated in the reverse shock. Here we do not simulate directly the acceleration of the relativistic particles, instead we assume that particles are accelerated at a rate t acc = \u03b7r L /c (e.g., Gaisser 1990) . Here r L is the Larmor radius of a particle of energy E, i.e r L = E/e B and B is the magnetic field in the acceleration region. \u03b7 is a phenomenological parameter related to the efficiency of the acceleration process, which can be approximated by \u03b7 \u223c 20/3 (c/V shock ) 2 (Drury 1983) , for a non-relativistic diffusive shock acceleration, in a plane shock in the test particle approximation. We inject continuously a population of relativistic (E > mc 2 ) electrons and protons at the reverse shock position (r rs , z rs ) (see below). This shock is strong everywhere, however the density in the regions of positive z is greater than in the negative region (this is simply because these points are further away from the star) while the wind velocity remains constant. We expect more particles to be injected in the denser regions, hence the injection function scales as \u221d \u03c1(r, z). The particles have a power-law distribution in energy of index \u03b1 = 2, as expected from a DSA mechanism. Then the injection function reads:", "cite_spans": [{"start": 245, "end": 258, "text": "Gaisser 1990)", "ref_id": "BIBREF21"}], "ref_spans": []}, {"section": "Injection", "text": "\u03c1 0 is a reference density value considered at the apsis of the wind shock; Q 0 is a normalization factor which depends on the power available in the system for particle acceleration. The source power for accelerating the particles is the kinetic power of the wind L w = 0.5\u1e40 V 2 w . A fraction \u03be of this kinetic power is transferred to the particles in the acceleration process. Then the power in relativistic particles is L rel = \u03beL w . We use a rather modest value of \u03be = 0.05, for the system considered here L rel \u223c 4.4\u00d710 34 erg s \u22121 . The proton-to-electron flux ratio a, for an acceleration process that leads to a powerlaw in momentum (the same for electrons and protons) is calculated in Pohl (1993) . In the later work the authors assumed that the same number rate of electrons and protons are accelerated from the same initial energy for both species. For a power-law index \u03b1 = 2, a = (m p /m e ) (3\u2212\u03b1)/2 . In the case \u03b1 = 2, a depends very weakly on the particles maximum energies, and is of the order of \u223c 40. Starting from a \u223c 40, the value of a = 100 observed in cosmic rays can be easily explained from propagation effects. In this work we assume a = 40 and in Sect. 6 we discuss the implications of adopting others values for \u03be and a.", "cite_spans": [], "ref_spans": []}, {"section": "Injection", "text": "For obtaining the position (r rs , z rs ) of the reverse shock we search for a jump in the temperature function T (r, z) (shown in the bottom plot of Figure 3 ), in the wind material.", "cite_spans": [], "ref_spans": [{"start": 150, "end": 158, "text": "Figure 3", "ref_id": "FIGREF1"}]}, {"section": "Diffusion", "text": "Stellar winds are very turbulent systems, in particular the system we are studying in which the wind collides with the incoming ISM (see Sect. 3). In such scenario slow particle diffusion is expected, as in the case of the sun where a particle of E \u223c 100 MeV in the solar wind has a mean free path of \u03bb \u223c 1 AU, that gives a diffusion coefficient D \u2248 10 23 erg s \u22121 . We assume the diffusion coefficient to depend only on the particles energy, i.e. D(t, E, r) \u2261 D(E). Close to the shock the diffusion is in the Bohm regime, at certain scale a transition occurs between this slow Bohm diffusion to the fast diffusion estimated in the Galaxy (e.g., Telezhinsky et al. 2012) . The characteristic scale of the system we are studying here, given by Eq. 1, is of the order of parsecs, hence the more convenient assumption of a Galactic-like diffusion coefficient:", "cite_spans": [], "ref_spans": []}, {"section": "Diffusion", "text": "Here D 10 GeV is the value of the diffusion coefficient at E = 10 GeV and \u03b4 is a power-law index varying in the interval 0.3 and 0.6 depending on the power-law spectrum of the turbulence of the magnetic field. Typical values for the Galaxy are D 10 GeV = 10 28 cm 2 s \u22121 and \u03b4 = 0.5 (e.g., Berezinskii et al. 1990 ). As discussed above in this system values much lower than this are expected due to the presence of turbulence.", "cite_spans": [], "ref_spans": []}, {"section": "Diffusion", "text": "In this work we use \u03b4 = 0.5 and two values for D 10 GeV : 10 25 cm 2 s \u22121 for the slow case, and 10 27 cm 2 s \u22121 for a fast diffusion situation. We can estimate a characteristic timescale for diffusion t diff considering the typical spatial scale of the problem R 0 , also this is approximately the minimum distance between the injection position and the bow shock itself (the dense cooled ambient matter),", "cite_spans": [], "ref_spans": []}, {"section": "Diffusion", "text": "Then, t diff \u223c 1.5 and 150 kyr for fast and slow diffusion, respectively (see Figure 7 ).", "cite_spans": [], "ref_spans": [{"start": 78, "end": 86, "text": "Figure 7", "ref_id": "FIGREF5"}]}, {"section": "Advection", "text": "The velocity field responsible for the advection of particles is shown in the upper plot of Figure 3 . As the system is in steady state, v does not depend on time. We can distinguish here between wind advection and ISM advection.", "cite_spans": [], "ref_spans": [{"start": 92, "end": 100, "text": "Figure 3", "ref_id": "FIGREF1"}]}, {"section": "Advection", "text": "We can estimate a characteristic timescale t adv , as done above for the diffusion, for the wind:", "cite_spans": [], "ref_spans": []}, {"section": "Advection", "text": "The velocity is v \u2264 2 \u00d7 10 3 km s \u22121 , then t adv, w \u2265 1 kyr. The vertical advection produced by the ISM is relevant almost everywhere, for v = 40 km s \u22121 , then t adv, ISM \u223c 54 kyr. These time scales are plotted in Figure 7 . It is clear that advection dominates the transport in the case of slow diffusion. A particle injected at z \u223c \u22129 pc would reach the bottom boundary in \u223c 200 kyr. In that time, for the slow regime, a 10 GeV particle would radially diffuse approximately 2.7 pc before it reaches the bottom boundary, and a TeV particle 8.5 pc.", "cite_spans": [], "ref_spans": [{"start": 216, "end": 224, "text": "Figure 7", "ref_id": "FIGREF5"}]}, {"section": "Advection", "text": "Towards the +z direction the situation is more complicated because the advection in the inner regions of the bow shock is not vertical. After being injected the particles are advected in the shocked wind, with v \u223c v w /4.0. The particles reach out a distance \u2248 D/v = 0.08 -0.24 pc for E = 10 GeV -1 TeV, respectively. In the case of fast diffusion these distances are two orders of magnitude higher.", "cite_spans": [], "ref_spans": []}, {"section": "Non-thermal losses", "text": "The third term in Eq. (3) accounts for the relevant non-thermal losses that particles suffer after their injection in the system. For electrons the non-thermal processes considered are: relativistic Bremssthalung, synchrotron, and IC scattering with the stellar and reprocessed stellar photons (dust emission). For protons the only energy losses considered are due to p \u2212 p inelastic collisions. All the target fields: magnetic field, density and radiation fields are inhomogeneous. The density field is directly taken from the simulations, below we describe how we construct the rest of the fields.", "cite_spans": [], "ref_spans": []}, {"section": "Magnetic field", "text": "We reconstruct the magnetic field from the stars's magnetic field B , the ISM magnetic field B ISM and density compression. We assumed no preferred direction for the field, which is assumed to be randomly distributed in all the domain. We consider four regions: the stellar wind region, the shocked wind, the shocked ISM and the ISM itself. For the wind region we use the approach made in Voelk & Forman (1982) , assuming flux conservation they obtained a field which decreases \u221d R \u22121 = \u221a r 2 + z 2 :", "cite_spans": [], "ref_spans": []}, {"section": "Magnetic field", "text": "V rot is the rotational velocity (we use a typical value of 100 km s \u22121 ). In the reverse shock the magnetic field is allowed to compress by a similar factor as the density. Beyond the discontinuity 2 between the wind and ambient material at the coordinates (r dis , z dis ) the magnetic field is assumed to be that of the ISM rescaled with the density field at each point.", "cite_spans": [], "ref_spans": []}, {"section": "Magnetic field", "text": "Hence, B(r, z) reads:", "cite_spans": [], "ref_spans": []}, {"section": "Magnetic field", "text": "Where F 1, 2 = 2(K 2 1, 2 \u2212 1)/3 + 1, with K 1 = \u03c1(r rs , z rs )/\u03c1(r, z), and K 2 = \u03c1(r ISM , z ISM )/\u03c1(r, z). The factors F 1, 2 account for the shock compression effect in the random field; for a strong shock K = 4 and F = \u221a 11. Here we use B \u223c 100 G (Walder et al. 2012 ), however we consider a greater value in Sect. 5. For the ambient medium we use B ISM \u223c 5 \u00b5G. The Figure 5 shows the map of the magnetic field in the computational domain; superimposed in white is plotted the position of the reverse shock: the injection position and in grey the material discontinuity between the shocked wind/ISM.", "cite_spans": [], "ref_spans": [{"start": 372, "end": 380, "text": "Figure 5", "ref_id": "FIGREF3"}]}, {"section": "Target radiation fields", "text": "As stated before the target radiation fields are those from the star and from the bow shock itself. The stellar photon field is assumed to be that of a black body at T eff , decaying as R \u22122 away from the star. For the IC emission calculations we assume the field to be monoenergetic, with E ph = k B T eff .", "cite_spans": [], "ref_spans": []}, {"section": "Target radiation fields", "text": "Computing the radiation field for the reprocessed emission is more complicated because it requires adopt-2 The position of this discontinuity is computed using the tracer values at t = 1.5 Myr. ing a dust model. The emission of the bow shock, mainly at IR, is produced by dust heated by starlight 3 . Here we adopt a thermal approximation for the dust emission, with grains in thermal equilibrium. This treatment is appropriate given that the observed fluxes of the bow shocks are in the mid (MIR) to far IR (FIR).", "cite_spans": [], "ref_spans": []}, {"section": "Target radiation fields", "text": "In order to calculate the equilibrium temperature T gr of the dust grains we equate the absorbed energy with the emitted one. In equilibrium the absorbed energy by the dust should be the same energy it radiates (Lequeux 2005; Draine 2011 ):", "cite_spans": [{"start": 211, "end": 225, "text": "(Lequeux 2005;", "ref_id": "BIBREF25"}, {"start": 226, "end": 237, "text": "Draine 2011", "ref_id": "BIBREF18"}], "ref_spans": []}, {"section": "Target radiation fields", "text": "(10) Here we use a spherical dust grain of radius a. The lefthand-side is the frequency integration of the incident flux from the star, that scales with distance as R \u22122 , multiplied by the absorption efficiency and the grain cross-section. The right-hand-side is the integration over frequency of the surface of the grain times the emitted spectrum. The dust emissivity is a modified black body at T = T gr , this is B \u03bd (T gr ) multiplied by an emissivity function Q em (\u03bd). The emissivity function is a power law in frequency, we use a standard model with Q em \u221d \u03bd 2 . For estimating the temperature above we use the so-called Plank-averaged absorption in the ultraviolet (UV) Q abs and emission efficiencies Q em in the IR (Draine 2011) . In the UV the absorption efficiency can be approximated by unity, this is valid as long as the grain sizes are of the order of the UV photons wavelengths 4 (i.e., 0.01 \u2264 \u03bb \u2264 0.4 \u00b5m). The grain temperature depends on the position, and is given by:", "cite_spans": [{"start": 727, "end": 740, "text": "(Draine 2011)", "ref_id": "BIBREF18"}], "ref_spans": []}, {"section": "Target radiation fields", "text": "We assume no dust in the stellar wind region. Dust grains exhibit a distribution of sizes, believed to be a power law in a. For the sake of simplicity, we consider that all grains have the same radius. The dust temperature is of the order of T gr \u223c 100 K, which is consistent with bow shocks being detected in the IR at \u03bb \u223c 22 \u00b5m (e.g., Peri et al. 2012) , because the maximum of the dust radiation occurs at \u03bb max \u223c 2 \u00d7 10 3 /T gr \u00b5m. The emissivity depends on the amount of dust, i.e. it scales with density, and temperature at each point. The energy loss by IR emission for one dust grain, i.e. the power emitted, is given by: P gr = 4\u03c0 Q em Tgr \u03c3T 4 gr (Draine 2011) . Then for a number of grains per unit volume n gr , the total power per unit volume is P = n gr P gr . For computing n gr we assume a typical gas-todust density ratio of 100 and we estimate the mass of each dust grain as m gr = 4\u03c0a 3 \u03c1 gr , with \u03c1 gr \u223c 2 gr cm \u22123 (Draine & Li 2007) . The resulting expression is (all units are in cgs):", "cite_spans": [{"start": 657, "end": 670, "text": "(Draine 2011)", "ref_id": "BIBREF18"}, {"start": 936, "end": 954, "text": "(Draine & Li 2007)", "ref_id": "BIBREF18"}], "ref_spans": []}, {"section": "Target radiation fields", "text": "(12) Here \u03c7 is a factor such that the luminosity from dust in the region does not exceed the star luminosity, i.e. 4\u03c0\u03c3T 4 R 2 . For obtaining the energy density of the photon field in each point we compute U ph (r, z) = P/(4\u03c0 c d", "cite_spans": [], "ref_spans": []}, {"section": "Target radiation fields", "text": "2 ) dV , with d \u2261 d(x, y, z) the distance of each point to the emitting source and P is given by expression 12. The energy density maps of the target IR photon field is shown in Figure 6 for grain size a \u00b5m = 0.01. Even though P does not depend explicitly on the size of the grain it depends strongly on the dust temperature. In a real source the grains responsible for the IR radiation have a size distribution, however the grain size distribution is a power law with index smaller than \u22123, then it is more probable to encounter smaller dust grains. Note that the grains responsible for the stellar photons absorption 4 This is the case for the relative large dust grains responsible for the IR radiation detected in massive runaway stars bow shocks. can not be smaller than a \u00b5m = 0.01. The IR photon field in the IC calculations is also assumed as monoenergetic, with E ph = k B T gr , where T gr is the mean grain temperature in the computational region.", "cite_spans": [], "ref_spans": [{"start": 178, "end": 186, "text": "Figure 6", "ref_id": "FIGREF4"}]}, {"section": "Maximum particle energies", "text": "The maximum energy that particles achieve in a DSA process depends on many factors. Its estimation is not straight forward given that the mechanism is non-linear. However we can make an order of magnitude estimation by comparing the gain rate per energy with the losses in the acceleration region (only in the case of electrons, in the case of protons their energy losses are not limiting their acceleration) or by the limit imposed by the size of the acceleration region (a constraint valid for both electrons and protons).", "cite_spans": [], "ref_spans": []}, {"section": "Maximum particle energies", "text": "For estimating E max from the losses we equate t acc = min(t synchr (r rs , z rs ); t IC (r rs , z rs )). Given the physical size of the system (see Fig. 2 and Fig. 4 ) the acceleration process then should proceed in a region of size the order of l \u223c 1 pc. Imposing the condition that the precursor size should be smaller than 1 pc and assuming Bohm diffusion for the acceleration, we obtain the maximum energy, i.e. E < 3 e B| shock V shock l/c, we use 10% of this value. Both methods for obtaining the maximum energy are sensitive to the magnetic field and the shock velocity.", "cite_spans": [], "ref_spans": [{"start": 149, "end": 155, "text": "Fig. 2", "ref_id": "FIGREF0"}, {"start": 160, "end": 166, "text": "Fig. 4", "ref_id": "FIGREF2"}]}, {"section": "Maximum particle energies", "text": "For the system analyzed here the size of the acceleration region constrains the maximum energies, giving E max \u223c 1.3 TeV for electrons and protons, with B| shock \u223c 0.7 \u00b5 G. Note that these values are different when other values for the magnetic field are considered (see Sect.5.2).", "cite_spans": [], "ref_spans": []}, {"section": "Time scales", "text": "The time scales discussed so far are plotted in Figure 7 , as a function of the electron energy. The synchrotron losses are shown for two values of the magnetic-field strength, B| shock = 0.7 and B| shock = 7 \u00b5G, with the subindexes 1 and 2, respectively (see Sect. 5.2). This corresponds to two stellar magnetic field values B = 10 2 and 10 3 G. The acceleration time is also plotted for the two B| shock values. The IC losses 5 due to dust photon scattering are plotted for a representative constant value of U of 10 \u221211 erg cm \u22123 (see Fig. 6 ). The time scales for the transport processes are also presented in Figure 7 . For the diffusion we plot the time scale for the two cases studied here: fast and slow. We show the cases of advection produced by the wind and by the ISM. The dashed vertical lines indicate the maximum energy arising from the constraint imposed by the size of the system, for the two values of B| shock considered (see Sect. 4.5) .", "cite_spans": [], "ref_spans": [{"start": 48, "end": 56, "text": "Figure 7", "ref_id": "FIGREF5"}, {"start": 538, "end": 544, "text": "Fig. 6", "ref_id": "FIGREF4"}, {"start": 614, "end": 622, "text": "Figure 7", "ref_id": "FIGREF5"}]}, {"section": "Time scales", "text": "From the Figure we can conclude that transport effects are of great significance and dominate over the losses, at least at the injection position. Fast diffusion dominates the transport for energies greater than 50 GeV. In the case of slow diffusion it dominates the transport over the ISM advection for energies greater than 0.2 TeV and the wind advection for very high energies (i.e. E > 265 TeV).", "cite_spans": [], "ref_spans": []}, {"section": "Calculation details", "text": "Equation (3) is solved using a discrete grid (E, r, z) \u2208 [1 keV, 10 TeV] \u00d7 [0, 24 pc] \u00d7 [\u221212, 10 pc], using the finite-volumes method.", "cite_spans": [], "ref_spans": []}, {"section": "Calculation details", "text": "The energy grid is logarithmically spaced and the spatial grid is uniform. The used grid resolution for (E, r, z) is (L, M, K) = (128, 128, 128), respectively.", "cite_spans": [], "ref_spans": []}, {"section": "Calculation details", "text": "Particles are injected through all the integration time.", "cite_spans": [], "ref_spans": []}, {"section": "Calculation details", "text": "The resulting N (t, E, r, z) for electrons and protons are interpolated into a 3D spatial grid. We calculate the non-thermal radiation produced by the particles as they diffuse through the domain. The integration proceeds until there are no significant changes in the radiation outcome.", "cite_spans": [], "ref_spans": []}, {"section": "Calculation details", "text": "Initially we assume N (0, E, r, z) \u2261 0, i.e. no particles inside the domain. The energy boundary conditions are N (t, E > E max , r, z) = 0 and N (t, E < E min , r, z) = 0This does not influence the system evolution, because the upper limit is above the maximum energy of the in- jected particles, and the advection in the energy space is always directed to smaller energies. The outer boundary condition for r and the inner and outer boundary conditions for z are assumed as outflow; also no inflow is allowed at the inner z boundary. We adopted axial symmetry at the r inner boundary.", "cite_spans": [], "ref_spans": []}, {"section": "Calculation details", "text": "The numerical integration is performed through the operator splitting method. Each time-step integration computes the evolution of the particle density distribution on the grid through four sub-steps: first the losses are integrated, then the spatial advection followed by spatial diffusion and finally the source term is added. The time-steps were chosen in accordance with the CFL stability criterion. Further description of the code is made in del Valle et al. (2015 .", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS", "text": "In the Figure 8 it is shown a map of the distribution of electrons for E = 10 GeV, for different evolution times. The 2D maps are constructed integrating the 3D data along an arbitrary line of sight, chosen here to be on the y-direction. This plot corresponds to the slow diffusion case D 10 GeV = 10 25 cm 2 s \u22121 . The integration time or injection time t inj is taken as 230 kyr. This time is enough for a particle injected at z \u223c -9 pc to cross the bottom boundary. From the maps it can be seen that particles are injected in the reverse shock position, and then advected and diffused in the plane. The maximum number of electrons is always near the injection region and when t = 230 kyr all the domain is reached by particles. Only a few particles, the most energetic ones, reach the wind region, and most of them are advected away by the wind. There are some bright spots in which particles are accumulated, because the velocity is very low in these regions and diffusion is slow (see Fig. 3 ). In the Figure 9 upper plot we show the IC map for E = 10 GeV at the final time t = 230 kyr. The maximum emission occurs in the vicinity of the reverse shock. It becomes stronger in the region above the injection position as the electrons reach by diffusion the regions of highest U ph (see Fig. 6 ), slightly tracing the bow shock structure. This last effect is stronger for the synchrotronemission whose map at E \u2261 1.4 GHz is shown in the bottom plot of Figure 9 . The behavior exhibited by this emission is similar: the maximum here occurs in the shocked wind region and then in the shocked ISM.", "cite_spans": [], "ref_spans": [{"start": 7, "end": 15, "text": "Figure 8", "ref_id": "FIGREF6"}, {"start": 990, "end": 996, "text": "Fig. 3", "ref_id": "FIGREF1"}, {"start": 1007, "end": 1015, "text": "Figure 9", "ref_id": "FIGREF7"}, {"start": 1290, "end": 1296, "text": "Fig. 6", "ref_id": "FIGREF4"}, {"start": 1455, "end": 1463, "text": "Figure 9", "ref_id": "FIGREF7"}]}, {"section": "RESULTS", "text": "The volume integration of the non-thermal luminosity -the SED-for the slow diffusion case is shown in Figure 10 . Only the dominant processes are shown: IC scattering and synchrotron. The luminosity grows with time, as indicated with the black arrow in the plot. However after some time the emission stop growing. This is because a steady state is reached between the injection, advection, losses and diffusion of particles in the domain. This can be appreciated in the pileup of the curves in the SED as time passes. The two IC components, from the star and from the dust emission, can be distinguished in the curves. For illustration we have plotted the contribution from the stellar photons in grey. As can be seen in Fig. 10 this component is rather weak.", "cite_spans": [], "ref_spans": [{"start": 102, "end": 111, "text": "Figure 10", "ref_id": "FIGREF8"}, {"start": 721, "end": 728, "text": "Fig. 10", "ref_id": "FIGREF8"}]}, {"section": "RESULTS", "text": "The emission from interactions with matter (relativistic Bremsstrahlung and p \u2212 p inelastic collisions) is very low when compared with IC, with maximum luminosities \u223c 10 30 erg s \u22121 ; hence the hadronic contribution to the emission is unimportant and the relativistic protons diffuse out of the system almost without energy loss as predicted previously (del Valle et al. 2015) . We are not discussing these emission components any further.", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS", "text": "The spectrum of the resulting SED depends, among other factors, on the shape of the injected particles. A change on the spectral index will alter the photon distribution. In a DSA process at a non-relativistic shock we expect \u03b1 \u223c 2, but the spectral index can deviate from that value (see e.g., Longair 2011). In the case of an injection \u03b1 = 1.8 the emission through all the spectrum diminishes a factor \u223c 2.2 due to a change in the particles normalization (a \u223c 90, see Sect. 4.1). Also, the distribution of radiation in the SED changes and more emission is produced at the highest energies; on the contrary the radiation diminishes at radio and X-rays. At the highest energies the shape of the SED is modified by diffusion, and its shape is influenced by the dependence of the diffusion coefficient with energy.", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS", "text": "The gamma emission coming from z > 0(the apsis of the bowshock) dominates the radiation output. For example, for E = 100 GeV the IC intensity at z = 8 pc is twice that at z = 26 pc , meaning that the radiation density is higher in this region, and the bulk of the emission is coming from here. This is because the IR target radiation field is strong and the injection is higher in this region.", "cite_spans": [], "ref_spans": []}, {"section": "Dependence on diffusion", "text": "We consider slow (D 10 GeV = 10 25 cm 2 s \u22121 ) and fast (D 10 GeV = 10 27 cm 2 s \u22121 ) diffusion to study how these different regimes affect the non-thermal luminosity. In the plots of Figure 11 we show the dominant non-thermal components at t = 23 kyr (up) and at t = 230 kyr (bottom). Initially the differences between the cases are not so important, but in the IC star component, which is stronger in the case of slow diffusion, the particles stay for a longer time in the vicinity of the injection region where the stellar radiation field is stronger. The fast diffusion slightly dominates the synchrotron component for E < 1 eV; this is because the high-energy particles reach regions of stronger magnetic field (see Fig. 5 ). At the final integration time the fast diffusion dominates the SED, except for the IC star component; this is because particles in the slow diffusion are dragged by advection and very few reach the regions of highest magnetic and IR photon field; as discussed in Sect. 4.3, in the slow diffusion case due to advection a typical particle will not reach the denser bow shock.", "cite_spans": [], "ref_spans": [{"start": 184, "end": 193, "text": "Figure 11", "ref_id": "FIGREF9"}, {"start": 721, "end": 727, "text": "Fig. 5", "ref_id": "FIGREF3"}]}, {"section": "Dependence on magnetic field", "text": "Here we assume a greater value for the stellar magnetic field, with B = 1 kG. This might affect the magnetic field in the wind region and it might change the hydrodynamics of the system changing, among other things, the reverse shock position. If the magnetic pressure is of the same order or higher than the wind ram pressure, the pressure balance (see Sect. 2) between the wind and the ISM occurs at greater distances from the star.", "cite_spans": [], "ref_spans": []}, {"section": "Dependence on magnetic field", "text": "The relevance of the effects of the magnetic field on the hydrodynamics can be estimated by comparing the ram pressure \u03c1 w V 2 w with the magnetic pressure of the wind B 2 wind /8\u03c0. The wind ram pressure is given by:", "cite_spans": [], "ref_spans": []}, {"section": "Dependence on magnetic field", "text": "the last factor of Eq.(8) tends to 1 very fast for R > 20 R , then the magnetic pressure is: Then the pressures ratio P r ,w /P B ,w \u223c 7 for this case, and the magnetic field in the wind is not expected to affect dramatically the hydrodynamics, and can be ignored at least at first order.", "cite_spans": [], "ref_spans": []}, {"section": "Dependence on magnetic field", "text": "The magnetic field at the reverse shock B| shock grows by one order of magnitude, hence t acc increases and electrons reach a higher maximum energy in the acceleration process (see Sect. 4). In this case we obtain E e max , E p max \u223c 13.8 TeV.", "cite_spans": [], "ref_spans": []}, {"section": "Dependence on magnetic field", "text": "No great differences in the IC radiation occur, but the ones expected from the change in E e max , that is 10 times higher than in the reference case. The gamma spectrum is shifted towards higher energies, increasing the total Spectral energy distribution, at different integration times, for different diffusion regimes: slow (D10 GeV = 10 25 cm 2 s \u22121 ) and fast (D10 GeV = 10 27 cm 2 s \u22121 ).", "cite_spans": [], "ref_spans": []}, {"section": "Dependence on magnetic field", "text": "emission output (see Sect. 6). Naturally the synchrotron emission is much higher; it dominates the SED in Xrays until E \u223c 6.3 keV; with L syn \u223c 8 \u00d7 10 29 erg s \u22121 at E \u223c 1 keV and L syn \u223c 2 \u00d7 10 27 erg s \u22121 at E \u223c 6.3 keV.", "cite_spans": [], "ref_spans": []}, {"section": "Dependence on the stellar velocity", "text": "The bow shock size and shape of the same type of star changes with v (see e.g., Meyer et al. 2014) . In order to study the impact of this in the non-thermal emission we consider here the same massive star described in Sect. 3, but with a higher velocity: v = 70 km s \u22121 . For this system the global steady state is reached at \u223c 4 Myr. For numerical stability here we use an Harten-Lax-van Leer solver. As can be deduced from the expression of R 0 , see Eq. 1, the whole bow shock structure is smaller.", "cite_spans": [], "ref_spans": []}, {"section": "Dependence on the stellar velocity", "text": "The injection region is closer to the star, hence the magnetic field near the injection region has greater values. The maximum energy particles might achieve is slightly higher than the previous case, with E e max \u223c 2 TeV. We compute the SED for slow diffusion. The synchrotron emission reaches higher energies than in the reference case, as a combination of a greater magnetic field near the injection region and a slightly higher electron maximum energy. Both the synchrotron and IC emission are higher in this case, by a maximum factor of 4 at same energies. This is because the maximum values of the target fields are closer to the injection region, hence particles lose energy more efficiently (see further discussion in Sect. 6).", "cite_spans": [], "ref_spans": []}, {"section": "Synchrotron emission from the tail", "text": "The bow shock tail can extend for several parsecs towards the \u2212z direction. The escaping electrons would produce further synchrotron emission when interacting with the magnetic field of the shocked material in the bow shock tail. In order to evaluate how important is the emission produced further down stream we compute the emission coming from the bottom region, \u221218 < z < \u221217 pc, as an upper limit (further down the number of particles would be more diluted due to diffusion, and the emission per pc would be lower).", "cite_spans": [], "ref_spans": []}, {"section": "Synchrotron emission from the tail", "text": "The luminosity in this bottom region is a fraction 3 \u00d7 10 \u22122 of the total one for both fast and slow diffusion; in particular at 1.4 GHz, the frequency of large-area radio surveys such as FIRST (Becker et al. 1995) and NVSS (Condon et al. 1998 ), the luminosity is some factor of 10 27 erg s \u22121 for the first case, and 10 26 erg s \u22121 for the other. For the fast case this value is of the order of the radio detection limits of 1 \u2212 2.5 mJy that is, for a source located at 1 kpc, 1 \u2212 2.5 \u00d7 10 27 erg s \u22121 . For the case of fast diffusion the synchrotron emission from the tail might be important and detectable for sources at these distances or less; however it would not be higher than the emission coming from the bow shock region. A proper calculation of this contribution is beyond the scopes of this work and would be studied elsewhere.", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "The gamma-ray photons produced in the system can be absorbed by lower energy photons through photonphoton annihilation. The low-energy photon field can be in the source itself or in the propagation path of the gamma ray on its way to the observer. For a Galactic source this last component is negligible, and we focus on photon fields within the bow shock. For the process to occur the energies of the involved photons must fulfil 6 :", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "where E \u03b3 is the energy of the gamma ray and the energy of the target photon. For E \u03b3 = 100 GeV, using \u223c 3/2k B T , T > 40475 K. This means that the stellar photon field can absorb gamma rays above 100 GeV. This is not surprising, a massive star photon field is known to be a significant source of gamma-ray annihilation, for example in a high-mass microquasar (e.g., Romero et al. 2010) or colliding-wind binaries (e.g., Bednarek & Pabich 2011) . The total absorption depends strongly on the geometry and on the relative positions of the gamma ray, the stellar photon field and the observer. However we can make order of magnitude estimates. The optical depth for a gamma ray traversing a Figure 12 . Evolution of the ratio of the total power produced by IC scattering (up) and synchrotron radiation (middle) to the wind's power Lw.The bottom plot shows the evolution of the IC-synchrotron power ratio.", "cite_spans": [], "ref_spans": [{"start": 690, "end": 699, "text": "Figure 12", "ref_id": "FIGREF0"}]}, {"section": "DISCUSSION", "text": "Here n is the number of photons per unit volume, that decreases quadratically with distance. The gamma-gamma cross-section maximum is \u223c \u03c3 T /5, with \u03c3 T the Thomson cross-section, and it occurs close to the threshold energy. We can estimate the maximum d such that \u03c4 \u03b3\u2212\u03b3 1:", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "The last condition gives d 10 \u22124 light-years (\u2261 68 R ). Comparing this distance with the typical scale of the system we get d/R 0 \u223c 10 \u22125 . Even in the least favourable case the region in which the gamma-gamma absorption is important is extremely small compared to the size of the bow shock. Then, given the large extension of the gamma-ray source the absorption produced by the stellar photon field is negligible.", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "The interaction of the stellar wind with the ISM deposits a fraction of the wind power into the ambient medium in different forms of energy. It is interesting to see then how much of the wind's power is converted into non-thermal emission as high-energy emission through IC scattering and low-energy radiation via synchrotron. This fraction as a function of the computational time is presented in Figure 12 (this depends on the assumptions made in L rel , see Sect. 4.1). In this figure it is shown the ratio of the IC emission between 1 keV and E e max (upper plot) to the wind's power \u03c7 IC , for the models we consider in this work; we also show a case without diffusion or advection just for comparison. The most efficient case is that with no transport of particles, with \u03c7 IC \u223c 10 \u22124 (blue line) at the final time, this is expected because particles stay in the box only losing energy by radiative losses. Follows by the case of the star with a higher spatial velocity with a power ratio of 7.4\u00d710", "cite_spans": [], "ref_spans": [{"start": 397, "end": 406, "text": "Figure 12", "ref_id": "FIGREF0"}]}, {"section": "DISCUSSION", "text": "\u22125 (grey line). Next comes the case with B = 1 kG (orange line) with 5.8\u00d710", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "\u22125 , the case of fast diffusion (green line) lies slightly below. Finally the slow diffusion case (red line) that gives \u03c7 IC \u223c 4\u00d710 \u22125 , only 3 times less than the best case. We can see that propagation effects are important. Initially all the cases show differences in \u03c7 IC , but as time evolves all cases reach values \u223c 5\u00d710 \u22125 . In the middle plot of Figure 12 it is shown the ratio of the synchrotron radiation integrated between 10 \u22126 eV and 10 5 eV to the wind's power: \u03c7 S . The most efficient cases do not coincide with those of the IC discussed above. The synchrotron emission is very sensitive to the magnetic field value and in this highly spatially changing environment the propagations effects are really important. This can be noticed when analyzing the case of no diffusion and no advection, the efficiency is the lowest with a ratio to the wind's power of 9\u00d710 \u22126 . Small differences are exhibited at the final times in the case of slow and fast diffusion, with 2\u00d710 \u22125 for the slow and 4\u00d710", "cite_spans": [], "ref_spans": [{"start": 354, "end": 363, "text": "Figure 12", "ref_id": "FIGREF0"}]}, {"section": "DISCUSSION", "text": "\u22125", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "for the fast case: once the particles reach by diffusion the regions of higher magnetic field they radiate more effectively. When the particles are injected in a region where the magnetic field is higher the particles radiate more power, as in the case of a smaller bow shock (grey curve), which \u03c7 S is 2.5\u00d710 \u22125 . The extreme case with a higher stellar magnetic field is very efficient, with \u03c7 S \u223c 10 \u22124 . Again for the final time there are no big differences in the energy injected as synchrotron radiation, that is \u03c7 S \u223c 3\u00d710 \u22125 . From the value of \u03c7 IC we can also estimate what fraction of the injected power is radiated in the IC process: L IC /L rel \u223c \u03c7 IC /\u03be \u223c 8 \u00d7 10 \u22124 \u2212 2 \u00d7 10 \u22123 . For the synchrotron we get a slightly smaller number (see next paragraph). We can see that electron radiation is not efficient and the electrons are transported out of the system by diffusion and advection before they can lose a significant fraction of their power, in accordance with the time-scale estimations presented in Figure 7 .", "cite_spans": [], "ref_spans": [{"start": 1018, "end": 1026, "text": "Figure 7", "ref_id": "FIGREF5"}]}, {"section": "DISCUSSION", "text": "We analyze also the evolution of the power ratio between the two dominant radiation mechanisms. This ratio is shown in the bottom plot of Figure 12 for all the configurations studied here. The synchrotron power only dominates in the case of a higher stellar magnetic field by almost one order of magnitude. In general the ratio between the emitted powers is of order unity, dominated by IC, with the exception of the case with no transport effects. In this case the IC power is one order of magnitude greater than the synchrotron power. Again consistent with the time scales shown in Fig. 7 .", "cite_spans": [], "ref_spans": [{"start": 138, "end": 147, "text": "Figure 12", "ref_id": "FIGREF0"}, {"start": 584, "end": 590, "text": "Fig. 7", "ref_id": "FIGREF5"}]}, {"section": "DISCUSSION", "text": "From the above analysis we can infer very generally the following: ", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "We explicitly show the dependence with the shock efficiency \u03be and proton-to-electron power ratio a.In the case of IC the maximum power is around \u223c 100 GeV with a luminosity of approximately 10% of the above value. These are modest values for a gamma-ray source. For the synchrotron, the maximum luminosity lies around \u223c 1 eV, ignoring the extreme case with B = 1 kG.The value of a changes in two cases. If the injection index changes (this was discussed previously): in the case of a softer index (\u03b1 > 2) a decreases and it increases for harder indexes (\u03b1 < 2). The other case is if the condition for equal injected number rate for both species is relaxed, smaller values can occur if more electrons are injected. The shock efficiency \u03be adopted here is modest, it can be higher, between 10 to 20%, as obtained in numerical simulations (Caprioli & Spitkovsky 2014) or observations of the earth's bow shock (Ellison et al. 1990 Schulz et al. (2014) , although they are for specific sources, for those investigated in De Becker et al. (2017) with distances ranging between 200 and 2000 pc, these upper limits range between 10 33 to 10 35 erg s \u22121 in the 4 energy bands. Not even our most favorable model at gamma rays reach these upper limits; however for the case of a more powerful wind it might reach these levels (see Eq.17). In general, the distances of the bow shocks cataloged in the E-BOSS (Peri et al. 2012 ) also ranged between \u223c 200 and 2000 pc; the theoretical 5\u2212\u03c3 sensitivity of Fermi in the energy range between 1 and 10 GeV is \u223c 10 \u221211 erg s \u22121 cm \u22122 (it can be smaller for sources above the plane). For sources at 200 and 2000 pc the threshold luminosity is \u223c 5 \u00d7 10 31 and 5 \u00d7 10 33 erg s \u22121 , respectively. These values are not unrealistic for our model. However a note of caution is in order: the power in relativistic electrons might be supper estimated, as can be learned from the radio upper limits as discussed below.", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "The 3 \u2212 \u03c3 radio upper limits in the case of the sources from the study of De Becker et al. (2017) are more restrictive than those at gamma rays. These upper limits are obtained from the NRAO VLA Sky Survey (NVSS), a 1.4 GHz (\u223c 5.8 \u00d7 10 \u22126 eV) continuum survey. These values range between 10 27 to 10 28 erg s \u22121 . If these limits are applied to a system like the one we are studying here, then the synchrotron power we obtain with our models is roughly over these limits . This means that in the presence of a relatively high magnetic field the power in electrons assumed here could be overestimated by at least the same factor. If this is the case, then the IC luminosity is lower than the one predicted in our models. Another possibility is that the magnetic field is over estimated.", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "Very low values of the magnetic field are not good either for producing higher values of gamma emission. Particles need magnetic field to be efficiently accelerated in the reverse shock to high energies. A weak magnetic field would not produce electrons energetic enough to produce gamma rays (see Sect. 4.1). An electron to emit synchrotron radiation at a frequency \u03bd needs an energy E = 7.9 (\u03bd/[GHz]) 1/2 (B/[\u00b5G]) \u22121/2 GeV (e.g., Pacholczyk 1970), for \u03bd = 1.4 GHz in the ISM magnetic field E \u223c 4 GeV. Hence a strong radio signal at these fre-quencies does not necessarily imply the presence of relativistic electrons capable of producing gamma radiation at energies higher than 10 GeV. Another possibility that might decrease the synchrotron at 1.4 GHz without assuming a smaller power in relativistic particles is that the injected electrons have a steeper power-law index, i.e. |\u03b1| < 2, as we learn from the previous Section. With a steep injection the emission at long wavelength decreases. A smaller value of |\u03b1| then would give a steeper photon distribution, decreasing the emission in the energy region of interest. However this effect is not expected to produce dramatic changes. It is worth mentioning that given the sensitivity of present observatories the lack of detection does not constitute a strong evidence for a lack of efficient particle acceleration in these sources.", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "The above analysis is made extrapolating the upper limits from a sample of 5 sources to all sources, and this might not be the general case. In particular it does not apply to the case of BD +43", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "\u2022 3654, that was in fact detected at radio. In this system the emission detected at 1.42 and 4.86 GHz is of the order of \u223c 10 30 erg s \u22121 . Such a high luminosity is not even achieved for a higher value of the magnetic field strength (e.g. our B = 1 kG model) .", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "The upper limits at X-rays between 0.3 and 10 keV from previous works are between 10 30 and 10 31 erg s \u22121 ; in the cases studied here, except the case with B = 1 kG, the luminosity between 1 and 10 keV lies below these values. For these cases the analysis made in De Becker et al. (2017) still holds, this is: current detectors are not able to differentiate between the non-thermal emission, if any, and the stellar thermal one. The case of a high stellar magnetic field the emission should be detectable at X-rays with present observatories. A lack of detection might indicate that such a large value for B is not reached in these objects or that the magnetic field in the wind is overestimated.", "cite_spans": [], "ref_spans": []}, {"section": "CONCLUDING REMARKS", "text": "In this work we study a very general case of a massive runaway star bow shock, assuming typical values for describing the system and ordinary assumptions. The strongest assumption that is made in our modeling is the acceleration of electrons through DSA in the wind shock. The only indirect evidence that supports this assumption is the observation of synchrotron emission from the bow shock of BD +43", "cite_spans": [], "ref_spans": []}, {"section": "CONCLUDING REMARKS", "text": "\u2022 3654. This hypothesis will be carefully analyzed in a future work.", "cite_spans": [], "ref_spans": []}, {"section": "CONCLUDING REMARKS", "text": "In what follows we summarize the main conclusions of this study:", "cite_spans": [], "ref_spans": []}, {"section": "CONCLUDING REMARKS", "text": "\u2022 According to our model the non-thermal emission produced in the bow shock of a massive runaway star is mainly made of synchrotron radiation and IC emission at gamma rays, as predicted by previous works.", "cite_spans": [], "ref_spans": []}, {"section": "CONCLUDING REMARKS", "text": "\u2022 In the general case the luminosity predicted here at X-rays lies below the existing X-ray upper limits.", "cite_spans": [], "ref_spans": []}, {"section": "CONCLUDING REMARKS", "text": "In the case of a strong stellar magnetic field the synchrotron radiation is the dominant process at soft X-rays.", "cite_spans": [], "ref_spans": []}, {"section": "CONCLUDING REMARKS", "text": "\u2022 A fraction between 4 \u00d7 10 \u22125 and 10 \u22124 of the wind power is converted into IC radiation; with a maximum around E = 100 GeV.", "cite_spans": [], "ref_spans": []}, {"section": "CONCLUDING REMARKS", "text": "\u2022 A fraction between 9 \u00d7 10 \u22126 and 10 \u22124 of the wind power is converted into synchrotron emission; with a maximum around E = 1 eV.", "cite_spans": [], "ref_spans": []}, {"section": "CONCLUDING REMARKS", "text": "\u2022 Transport effects, advection and diffusion, dominate over radiation losses . Only \u223c 0.16 \u2212 0.4% of the injected power in electrons is radiated, the bulk of the particles leaves the system and radiates elsewhere.", "cite_spans": [], "ref_spans": []}, {"section": "CONCLUDING REMARKS", "text": "\u2022 Synchrotron emission from the bow shock tail, produced by dragged electrons, might be important, especially in the fast diffusion regime.", "cite_spans": [], "ref_spans": []}, {"section": "CONCLUDING REMARKS", "text": "\u2022 The bulk IC radiation is coming from the cup region of the bow shock.", "cite_spans": [], "ref_spans": []}, {"section": "CONCLUDING REMARKS", "text": "\u2022 The hadronic component in the SED is completely negligible; protons diffuse and advect into the ISM almost without loosing energy.", "cite_spans": [], "ref_spans": []}, {"section": "CONCLUDING REMARKS", "text": "\u2022 Given the better sensibility of current instruments at radio wavelengths theses systems are more prone to be detected at radio through the synchrotron emission they produce rather than at gamma energies.", "cite_spans": [], "ref_spans": []}, {"section": "CONCLUDING REMARKS", "text": "\u2022 The lack of detection at radio of specific sources put stringent constraints in the emission expected at gamma rays.", "cite_spans": [], "ref_spans": []}, {"section": "CONCLUDING REMARKS", "text": "M. V. d.V. acknowledges support from the Alexander von Humboldt Foundation. The authors would like to thank Dr. Reinaldo Santos-Lima for fruitful discussions. We also thank the anonymous referee for insightful comments.", "cite_spans": [], "ref_spans": []}, {"section": "CONCLUDING REMARKS", "text": "Software: PLUTO (Mignone et al. 2007) ", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF18": {"title": "Physics of the Interstellar and Intergalactic Medium Draine", "authors": [{"first": "B", "middle": ["T. ; B T"], "last": "Draine", "suffix": ""}, {"first": "A", "middle": [], "last": "Li", "suffix": ""}], "year": 2007, "venue": "", "link": null}, "BIBREF21": {"title": "Cosmic rays and particle physics H", "authors": [{"first": "T", "middle": ["K"], "last": "Gaisser", "suffix": ""}, {"first": "H", "middle": [], "last": "Abdalla", "suffix": ""}], "year": 1990, "venue": "", "link": "118086087"}, "BIBREF25": {"title": "The Interstellar Medium Longair, M. S", "authors": [{"first": "J", "middle": [], "last": "Lequeux", "suffix": ""}, {"first": "J", "middle": [], "last": "Santiago", "suffix": ""}, {"first": "M", "middle": [], "last": "Miceli", "suffix": ""}, {"first": "M", "middle": ["V"], "last": "Del Valle", "suffix": ""}], "year": 2005, "venue": "", "link": null}, "BIBREF33": {"title": "Radio astrophysics. Nonthermal processes in galactic and extragalactic sources", "authors": [{"first": "A", "middle": ["G"], "last": "Pacholczyk", "suffix": ""}], "year": 1970, "venue": "", "link": "121509537"}}, "ref_entries": {"FIGREF0": {"text": "Figure 2. Density maps at different computational times for the interaction of a stellar wind with incoming ISM at a velocity \u2212v . Time evolves from left to right.", "type": "figure"}, "FIGREF1": {"text": "Figure 3. Upper plot: Velocity map at t = 1.5 Myr, the colors indicate the value of the velocity module, \u221a v 2 r + v 2 z , the arrows indicate the direction of the velocity vector v in each point. Bottom plot: Temperature map in the simulation plane, at t = 1.5 Myr.", "type": "figure"}, "FIGREF2": {"text": "Figure 4. Density and temperature profiles for r = 0 as a function of z, the units are cm \u22123 and K, respectively. The reverse shock and forward shock positions are marked with dashed lines.", "type": "figure"}, "FIGREF3": {"text": "Figure 5. Magnetic field map in the computational domain, reconstructed from Eq.(9), BISM and the density map. The white curve shows the position of the wind shock, where the particles are injected into the domain; the grey curve shows the material discontinuity.", "type": "figure"}, "FIGREF4": {"text": "Figure 6. Infrared photon target energy density in the computational domain.", "type": "figure"}, "FIGREF5": {"text": "Figure 7. Time scales involved in the physical processes of the system as a function of the electron energy. The plotted scales are: the synchrotron cooling time for two values of the stellar magnetic field, the cooling time for the IC scattering with dust photons for U = 10 \u221211 erg cm \u22123 , the acceleration time for two values of the stellar magnetic field, the diffusion time for the slow and fast cases, the advection time for the wind and the ISM. The vertical dashed lines show the maximum energies imposed by the system size for two values of the stellar magnetic field. See the text for further details.", "type": "figure"}, "FIGREF6": {"text": "Figure 8. Electron distribution at fixed energy projected along the line of sight for the slow diffusion case; Ee = 10 GeV. Time evolves from left to right.", "type": "figure"}, "FIGREF7": {"text": "Figure 9. Intensity evolution, projected along the line of sight for IC at E = 10 GeV (up) and synchrotron at E \u2261 1.4 GHz (bottom); the figures correspond to t = 230 kyr.", "type": "figure"}, "FIGREF8": {"text": "Figure 10. Spectral energy distribution for different integration times from the bow shock of a massive runaway star. The grey curve illustrates the contribution to the IC of the stellar photons. The black arrow indicates that the radiation grows with time.", "type": "figure"}, "FIGREF9": {"text": "Figure 11. Spectral energy distribution, at different integration times, for different diffusion regimes: slow (D10 GeV = 10 25 cm 2 s \u22121 ) and fast (D10 GeV = 10 27 cm 2 s \u22121 ).", "type": "figure"}, "TABREF0": {"text": "). We can apply Eq.(17) to the case of Lambda Cep associated with a Fermi source (S\u00e1nchez-Ayaso et al. 2018). For\u1e40 \u223c 7 \u00d7 10 \u22126 M yr \u22121 and V w \u223c 2200 km s \u22121 (Mokiem et al. 2007), we get L IC. This result is con- sistent with the gamma source power at 100 GeV of \u223c 10 32 erg s \u22121 . The case of LS 2355 is more complex because the system is interacting with a HII region. According to our model the maximum emission from massive runaway bow shocks is not to occur in the very high energy domain, i.e. > TeV. Our results from Fig- ure 12 are in agreement with H.E.S.S. upper limits, i.e. L IC [0.14\u221218 TeV] < 10 \u22122 L W (H. E. S. S. Collaboration et al. 2017). Concerning the upper limits from Fermi from", "type": "table"}}}
{"paper_id": "118864667", "_pdf_hash": "99c2934d2128c4122e8b9ed9a7bc55ea2177f252", "abstract": [{"section": "Abstract", "text": "We have compiled photometry at 3.4, 4.6, 12 and 22 \u00b5m from the all-sky survey performed by the Wide-field Infrared Survey Explorer (WISE) for all known members of the Taurus complex of dark clouds. Using these data and photometry from the Spitzer Space Telescope, we have identified members with infrared excess emission from circumstellar disks and have estimated the evolutionary stages of the detected disks, which include 31 new full disks and 16 new candidate transitional, evolved, evolved transitional, and debris disks. We have also used the WISE All-Sky Source Catalog to search for new disk-bearing members of Taurus based on their red infrared colors. Through optical and near-infrared spectroscopy, we have confirmed 26 new members with spectral types of M1 -M7. The census of disk-bearing stars in Taurus should now be largely complete for spectral types earlier than \u223cM8 (M 0.03 M ).", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Complete samples of circumstellar disks in star-forming regions and accurate classifications of those disks represent a foundation for studies of star and planet formation. Both the identification of circumstellar disks and their classification are most easily performed using mid-infrared (IR) continuum emission from warm circumstellar dust. Because the atmosphere is bright and strongly absorbing at mid-IR wavelengths, space-based telescopes have provided the most sensitive data of this kind. The all-sky mid-IR images from the Infrared Astronomical Satellite (IRAS; Neugebauer et al. 1984) enabled the first detections of circumstellar disks in star-forming regions. The most thorough census of disks was performed in Taurus because it is nearby (d = 140 pc; Wichmann et al. 1998; Loinard et al. 2005; Torres et al. 2007 Torres et al. , 2009 ) and has a low enough stellar density that its members could be resolved by IRAS (Kenyon & Hartmann 1995) . Subsequent mid-IR telescopes, such as the Infrared Space Observatory (Kessler et al. 1996) and the Spitzer Space Telescope (Werner et al. 2004) , have offered progressively better sensitivity and resolution, enabling detections of disks at fainter levels and in more crowded fields. Due to its modest field of view (5 ), Spitzer primarily observed more compact star-forming regions (Lada et al. 2006; Sicilia-Aguilar et al. 2006; Dahm & Hillenbrand 2007; Hern\u00e1ndez et al. 2007; Luhman et al. 2008; Gutermuth et al. 2009 ), although it was able to map a significant fraction of a few widely distributed populations such as Taurus (Luhman et al. 2010; Rebull et al. 2010 ).", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "The latest mid-IR satellite, the Wide-field Infrared Survey Explorer (WISE; Wright et al. 2010) , has lower spatial resolution than Spitzer but it covered the entire sky. As a result, WISE provides mid-IR photometry for the portions of large star-forming regions and associations that were not imaged by Spitzer. For instance, WISE data have been used to search for new disk-bearing stars in Taurus (Rebull et al. 2011) and to classify disks among the known members of Upper Sco (Luhman & Mamajek 2012) . Because of the importance of Taurus in studies of disks and because proper use of WISE data requires great care, we have performed our own search for new members with disks in Taurus, and have classified all the disks that we have detected around the known members. In this paper we begin by compiling photometry from 3 to 24 \u00b5m from both WISE and Spitzer for all known members of Taurus (Section 2). With these data, we then measure mid-IR excesses (Section 3) and classify the evolutionary stages of the detected disks (Section 4). Finally, we use WISE photometry in conjunction with proper motions, color-magnitude diagrams, and follow up spectroscopy to identify new members of Taurus (Section 5).", "cite_spans": [], "ref_spans": []}, {"section": "Photometric Data", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Known Members of Taurus", "text": "To construct a census of the circumstellar disks in Taurus, we begin by compiling a list of all known members of the region. We adopt the 352 members from Luhman et al. (2010) , four additional stars that have good evidence of membership from previous studies (Section 5.4), 32 members found in a subsequent survey by Luhman (in preparation; 33 if GZ Tau A and B are counted separately), and 25 new members (26 if BS Tau A and B are counted separately) that we have confirmed with spectroscopy (Section 5.3). We also adopt as a member HD 285957, which has a proper motion consistent with that of the Taurus subgroup L1551 (Zacharias et al. 2013; Luhman et al. 2009 ) and exhibits evidence of youth in the form of Li absorption (Wichmann et al. 2000; Sestito et al. 2008) . Known multiple systems are treated as single sources in our census unless they are resolved by either Spitzer or the Two Micron All-Sky Survey (2MASS; Skrutskie et al. 2006) . The resulting catalog contains 414 sources and is presented in Table 1 . The spatial distribution of these members is illustrated in a map of the Taurus dark clouds in Figure 1 .", "cite_spans": [], "ref_spans": [{"start": 1012, "end": 1019, "text": "Table 1", "ref_id": "TABREF5"}, {"start": 1117, "end": 1125, "text": "Figure 1", "ref_id": "FIGREF6"}]}, {"section": "Spitzer Photometry", "text": "We make use of mid-IR photometry for members of Taurus measured with Spitzer's Infrared Array Camera (IRAC; Fazio et al. 2004 ) and the Multiband Imaging Photometer for Spitzer (MIPS; Rieke et al. 2004 ). We consider the four bands of IRAC (3.6, 4.5, 5.8, and 8.0 \u00b5m) and the 24 \u00b5m band of MIPS, which are denoted as Photometry from most Spitzer images for most members of Taurus has been measured by Luhman et al. (2010) (see also Hartmann et al. 2005a; Luhman et al. 2006; Guieu et al. 2007; Rebull et al. 2010) . We have measured photometry of the members that were not considered in Luhman et al. (2010) and all known members appearing in Spitzer images that have become publicly available since that study (Astronomical Observation Requests 26470912, 26471168 26477056, 26475264, 26472704, 26473216, and 23272448) . These data were measured with the methods described by Luhman et al. (2010) and are presented in Tables 2 and 3 . Members identified after Luhman et al. (2010) that were not detected or observed by Spitzer are not included in these tables.", "cite_spans": [], "ref_spans": [{"start": 918, "end": 932, "text": "Tables 2 and 3", "ref_id": "TABREF6"}]}, {"section": "Spitzer Photometry", "text": "In Table 1 , we have constructed a compilation of all Spitzer photometry from Luhman et al. (2010) and Tables 2 and 3 for all known members of Taurus. For members imaged at multiple epochs, we report the mean values weighted by the inverse square of the flux errors. Sources that lack photometry due to saturation, extended emission, or non-detection are indicated. Components of binaries that are resolved by IRAC have separate entries in Table  1 . A few of these pairs are unresolved in the MIPS images. The combined MIPS photometry for these systems is listed under the brighter component. For the 378 members imaged by IRAC, all are detected in at least one band. MIPS observed 331 members and detected 244 of them.", "cite_spans": [], "ref_spans": [{"start": 3, "end": 10, "text": "Table 1", "ref_id": "TABREF5"}, {"start": 103, "end": 117, "text": "Tables 2 and 3", "ref_id": "TABREF6"}, {"start": 440, "end": 448, "text": "Table  1", "ref_id": "TABREF5"}]}, {"section": "WISE Photometry", "text": "In addition to the Spitzer data, we also utilize the more recent mid-IR photometry measured by WISE. The four WISE photometric bands are centered at 3.4, 4.6, 12, and 22 \u00b5m and are denoted as W 1 through W 4 (Wright et al. 2010) . The first three bands have an angular resolution of \u223c6 while W 4 has a resolution of \u223c12 . For unconfused areas near the ecliptic plane, WISE typically achieved a signal-to-noise ratio of 5 at W 1 = 16.8, W 2 = 15.6, W 3 = 11.3, and W 4 = 8.0 (Cutri et al. 2012b ).", "cite_spans": [{"start": 474, "end": 493, "text": "(Cutri et al. 2012b", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "WISE Photometry", "text": "To compile the WISE photometry in Taurus, we began by retrieving all sources from the WISE All-Sky Source Catalog (Cutri et al. 2012a ) within 2 of the known members. We then inspected all images in the four WISE bands for all members that lacked a matching WISE source. We found that IRAS 04166+2706 and IRAS 04368+2557 are dominated by extended emission in W 1 and W 2, which resulted in significant offsets in the coordinates in the WISE catalog from the true positions. HBC 360 and HBC 361 comprise an \u223c8 pair that is only partially resolved by WISE. One source near the midpoint of the pair is present in the All-Sky Catalog but the components have separate sources associated with them in the AllWISE Source Catalog. Although IRAM 04191+1522 does not have a counterpart in the All-Sky Catalog, it is visible in the WISE images and is present in the AllWISE Source Catalog. Therefore, we adopt the data for HBC 360, HBC 361, and IRAM 04191+1522 from the latter. Thirteen companions that were resolved by IRAC and hence have separate entries in our catalog of members were unresolved from their primaries in the WISE images.", "cite_spans": [], "ref_spans": []}, {"section": "WISE Photometry", "text": "We have taken additional steps to verify the reliability of the WISE data in the same manner preformed by Luhman & Mamajek (2012) for Upper Sco. In summary, we omitted measurements of W 2 brighter than a magnitude of 6 because of their large systematic errors (Cutri et al. 2012b) , visually examined all WISE images for false detections, identified sources that may be contaminated by extended emission or the point-spread function (PSF) of another star, and checked for sources whose positions differed significantly among the WISE bands. During the inspection of the images, we noticed that L1521F-IRS was detected in W 3 and W 4 but had a measurement in only W 4 in the All-Sky Catalog. We found W 3 photometry for it in the AllWISE Source Catalog, which we have adopted. For two unresolved multiple systems, HD 28867 A+B+C and XEST 09-042+2MASS J04355949+2238291, the centroid of the WISE source shifts with wavelength, leading us to ascribe different bands to different components of the systems. In total, we report WISE photometry in at least one WISE band for 401 of the entries in Table 1 .", "cite_spans": [{"start": 260, "end": 280, "text": "(Cutri et al. 2012b)", "ref_id": "BIBREF9"}], "ref_spans": [{"start": 1091, "end": 1098, "text": "Table 1", "ref_id": "TABREF5"}]}, {"section": "Measurement of Infrared Excess Emission", "text": "Circumstellar disks emit radiation predominately at IR and millimeter wavelengths. Beyond \u223c5 \u00b5m, this radiation surpasses photospheric emission in brightness and can be used to detect the presence of a disk. Following a similar procedure to Luhman & Mamajek (2012) , we identify and measure excess emission of Taurus members using colors produced by the Spitzer and WISE data relative to the K band (2.2 \u00b5m). In this analysis, we use the average Spitzer measurements in Table 1 . For most members, we adopt K s photometry from the 2MASS Point Source Catalog. We use the K magnitudes for HV Tau C, IRAS 04111+2800G, and DG Tau B from Terada et al. (2007) , the United Kingdom Infrared Telescope Infrared Deep Sky Survey (UKIDSS; Lawrence et al. 2007) , and the 2MASS Extended Source Catalog, respectively. We exclude the 2MASS K s magnitudes for the binary system J1-4872 A and B because of their large uncertainties (see Luhman et al. 2010) . IRAS 04368+2557, IRAM 04191+1522, L1521F-IRS, IRAS 04166+2706, and SST Tau 041831.2+28161 are known protostars (Furlan et al. 2008; Furlan et al. 2011) and are too heavily obscured for K measurements. We also exclude any WISE or Spitzer data with errors \u22650.25 mag from our analysis. As in Luhman & Mamajek (2012) We have corrected the Spitzer and WISE colors for extinction prior to measuring excess emission. To do this, we used extinction estimates at J from a variety of sources, as indicated in Table 1 . These extinctions are the same as those adopted by Furlan et al. (2011) for the stars appearing in that study. The values of A J were converted to color excesses with the two reddening curves for high (A K > 1) and low (A K \u2264 1) extinction from McClure (2009). We did not attempt to deredden the colors for the 47 sources that lack extinction estimates, such as protostars and edge-on disks (see Furlan et al. 2011 ).", "cite_spans": [], "ref_spans": [{"start": 470, "end": 477, "text": "Table 1", "ref_id": "TABREF5"}, {"start": 1442, "end": 1449, "text": "Table 1", "ref_id": "TABREF5"}]}, {"section": "Measurement of Infrared Excess Emission", "text": "Since photospheric colors vary with spectral type, we plot the dereddened colors versus spectral type in Figure 2 . Stars without extinction estimates are plotted at their observed colors. For each color, the stellar photospheres form a narrow, blue sequence while stars with disks have a broad distribution of redder colors. The color thresholds used for identifying excesses are shown in Figure 2 . In the remainder of this section, we discuss the measurements of excess emission in each of the six Spitzer and WISE bands that we have considered. The bands exhibiting excess emission relative to K are indicated in Table 1 for each member of Taurus. We also analyzed the excesses of members that lack K photometry. J1-4872 A and B show no excess at longer wavelengths when compared to [3.6] . Since the remaining sources without K are protostellar, we mark each of their detected bands as having an excess. To identify the stars that exhibit significant excesses, we have selected a boundary that follows the sequences of stellar photospheres in the diagrams for K s \u2212 [4.5] and K s \u2212 W 2 versus spectral type in Figure 2 . The boundary is defined by the lines connecting the points (B0, 0.19), (K2, 0.26), (M2, 0.34), (M8.5, 0.74), and (L0, 1.6). The boundary is uncertain later than M8.5 because there are few members in this regime and the colors increase rapidly at these latest spectral types. At L0, the boundary is placed just above the colors of 2MASS J04373705+2331080 since it lacks an excess at longer wavelengths (Luhman et al. 2010) . Since the average offset between [4.5] and W 2 is only \u223c1% (Cutri et al. 2012b ), we use the same boundary for both colors. We also examined the objects in Figure 2 that lack spectral types. All of these sources exhibit large excesses if we adopt the spectral types that are consistent with their photometry.", "cite_spans": [{"start": 1609, "end": 1628, "text": "(Cutri et al. 2012b", "ref_id": "BIBREF9"}], "ref_spans": [{"start": 105, "end": 113, "text": "Figure 2", "ref_id": "FIGREF7"}, {"start": 390, "end": 398, "text": "Figure 2", "ref_id": "FIGREF7"}, {"start": 617, "end": 624, "text": "Table 1", "ref_id": "TABREF5"}, {"start": 1115, "end": 1123, "text": "Figure 2", "ref_id": "FIGREF7"}, {"start": 1706, "end": 1714, "text": "Figure 2", "ref_id": "FIGREF7"}]}, {"section": "Measurement of Infrared Excess Emission", "text": "We checked for discrepancies between excesses in [4.5] Figure 2 . We define our threshold for excess by connecting the points (B0, 0.19), (K2, 0.32), (M0, 0.45), (M8.5, 1.01), and (L0, 2.2). As done in the previous section, we use 2MASS J04215450+2652315 to guide the L0 boundary. All objects that have excesses at [8.0] also exhibit excess emission at longer wavelengths when such data are available. One star, V410 X-ray 7, has no excess at W 2 or [4.5], a slight excess at [8.0] and is unresolved from a nearby bright star at [24] . We tentatively conclude that V410 X-ray 7 has excess emission at [8.0] . The remaining stars without photometry at longer wavelengths have fairly large excesses at [", "cite_spans": [], "ref_spans": [{"start": 55, "end": 63, "text": "Figure 2", "ref_id": "FIGREF7"}]}, {"section": "Excess in W 3", "text": "There are 358 members of Taurus with detections in W 3 after excluding sources with errors \u22650.25. Members without photometry were either unresolved from a nearby star or not detected. Our boundary for excess is defined by the points at (B0, 0.18), (G8, 0.33), and (M9, 1.52). As done in previous bands, we checked whether sources with W 3 excesses have excesses at longer wavelengths. 2MASS J04215851+1520145 has a small excess in W 3, was not detected in W 4, and was not imaged by MIPS. The detection limit in W 4 does not place a useful constraint on the presence of excess emission. All other W 3 excesses are large or are supported by detections of excess in W 4 or [24] .", "cite_spans": [], "ref_spans": []}, {"section": "Excess in [24] and W 4", "text": "We discuss the analysis of [24] and W 4 together because they have similar effective wavelengths (23.7 and 22 \u00b5m). As done with W 3, we only analyzed measurements with errors less than 0.25, corresponding to 242 and 244 sources with [24] and W 4, respectively. Among the 66 sources with data in W 4 but not [24], 45 were not imaged by MIPS, 20 were saturated in MIPS, and one (MHO 2) was unresolved from a saturated source. MIPS provided data for 64 members that were not detected reliably at W 4 (\u03c3 W4 \u2265 0.25 or not detected). Data in at least one of these two bands is available for 308 members of Taurus.", "cite_spans": [], "ref_spans": []}, {"section": "Excess in [24] and W 4", "text": "Because advanced stages of disk evolution (e.g., debris disks; see Section 4) can have arbitrarily small excesses at 24 \u00b5m and no excesses at shorter wavelengths, we have selected a boundary that attempts to identify the smallest excesses that appear to be significant. This boundary is defined as (B0, 0.11), (K6, 0.56), and (M9, 1.38). Since the sequence of diskless members is not well-populated in W 4, we adopt this boundary for W 4 as well.", "cite_spans": [], "ref_spans": []}, {"section": "Excess in [24] and W 4", "text": "We find that 256 members exhibit excess emission at W 4 or [24] . Thirteen of these stars lack excess at shorter wavelengths, consisting of 10 stars for which [24] excesses have been noted previously (Furlan et al. 2011; Luhman et al. 2010 , references therein) and new detections of excesses in W 4 or [24] for 2MASS J04400174+2556292, 2MASS J04414565+2301580, and 2MASS J04242321+2650084. The latter excesses were not identified in previous studies because we have adopted a lower boundary for [24] excess, the star was not imaged by MIPS, and the object was recently added to the membership list, respectively.", "cite_spans": [], "ref_spans": []}, {"section": "Excess in [24] and W 4", "text": "Among the 106 objects without reliable photometry in either W 4 or [24] , 86 lack excess emission at shorter wavelengths. Seven of the 86 stars have early spectral types, and hence are bright, but they lack good limits on W 4 or [24] because they are unresolved from other stars, dominated by extended emission, or were not imaged by the more sensitive MIPS. For the 79 remaining stars, which have late types, the limits on [24] and W 4 do not place useful constraints on the presence of excess emission.", "cite_spans": [], "ref_spans": []}, {"section": "Excess in [24] and W 4", "text": "Although we did not analyze any bands at wavelengths longer than [24]/W 4, we were able to perform two tests of our identifications of excesses. First, we compared the results between W 4 and [24]. Although we identified HD 286178 as a candidate member because of its W 4 excess (see Section 5.4), it does not show an excess at [24] . HD 28929 also shows excess at W 4 and not at [24] . Because the MIPS photometry is more accurate, we list these two stars as not having an excess in either band. For all other stars with data at both [24] and W 4, the detections of excesses agree between the two bands. As a second test of the excesses, for the 13 stars with excess emission at [24]/W 4 and not at shorter wavelengths, we examined available 70 \u00b5m photometry from the Photodetector Array Camera and Spectrometer (PACS; Poglitsch et al. 2010 ) on the Herschel Space Observatory (Pilbratt et al. 2010) . Because the PACS images are not sensitive enough to detect the stellar photospheres of these stars, any detections indicate the presence of excess emission at 70 \u00b5m. V819 Tau, JH 56, FW Tau, RXJ 0432.8+1735, 2MASS J04403979+2519061, XEST 17-036, and 2MASS J04414565+2301580 are detected by PACS, while LkCa 19, V410 X-ray 3, 2MASS J04400174+2556292, and 2MASS J04242321+2650084 were imaged by PACS but were not detected (Howard et al. 2013 ). The two remaining stars, LkHa 332/G2 A+B and XEST 08-003, have not been imaged by Herschel. Because they are only slightly above our W 4/[24] thresholds and were not detected or imaged by Herschel, we report only tentative detections of excesses for XEST 08-003, V410 X-ray 3, LkHa 332/G2 A+B, and 2MASS J04400174+2556292.", "cite_spans": [], "ref_spans": []}, {"section": "Classification of Disks", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Terminology", "text": "A variety of names, definitions, and classification schemes have been proposed for the evolutionary stages of circumstellar disks. We adopt the disk classes from Espaillat et al. (2012) , which are defined as follows: full disks are optically thick at IR wavelengths and lack significant clearing of primordial dust and gas; pre-transitional and transitional disks have large inner gaps or holes in their dust distributions, respectively; evolved disks are becoming optically thin but have not experienced significant clearing; evolved transitional disks are optically thin and have large holes; debris disks are composed of dust generated by collisions of planetesimals. Using the classification scheme described in Luhman & Mamajek (2012) and the Spitzer and WISE photometry that we have complied, we have estimated the disk classes for Taurus members that exhibit IR excess emission (Section 3) based on their IR colors, as described in this section.", "cite_spans": [], "ref_spans": []}, {"section": "Disk Classes in Taurus", "text": "We estimated the evolutionary stages of disks using extinction-corrected color excesses relative to photospheric colors (e.g., E(K s \u2212[24])). The excess in a given band was computed as the difference between the observed color and the average color for young stellar photospheres at the spectral type in question. For the Spitzer bands, we adopted the photospheric colors from Luhman et al. (2010) Luhman & Mamajek (2012) , they have been adjusted slightly to produce nearly the same classifications in Taurus as those from Luhman et al. (2010) . Because of their similar mid-IR spectral energy distributions (Carpenter et al. 2009 ), debris disks and evolved transitional disks require measurements of gas content to be distinguished from each other. Although GM Aur is slightly above the boundary for full disks in the middle panel of Figure 3 , we mark it as transitional since it has been widely treated as such. Meanwhile, UX Tau A is classified as a primordial disk because it is above the boundary in K s \u2212 [8.0], but it does have a relatively low value of K s \u2212 W 3, which reflects the fact that it is a pre-transitional disk (Furlan et al. 2006) . Although previously classified as full by Luhman et al. (2010) , 2MASS J04214631+2659296 is most likely a transitional disk that is becoming optically thin because of its unusual spectral shape (Furlan et al. 2011 ) and faint [24]/W 4 photometry, which places it below the boundary for full disks in the second panel of Figure 3 and above in the third panel. Our disk classifications are listed in Table 1 . Known or suspected protostars (class 0 or I) are also indicated (Furlan et al. 2008; Furlan et al. 2011) . The 414 entries in Table 1 contain 239 full disks, 10 transitional disks, 13 evolved disks, 13 evolved transitional/debris disks, and one disk that is either evolved or transitional. The remaining 138 members lack excess emission. For members known prior to this study, our classifications agree with those given in Luhman et al. (2010) and Furlan et al. (2011) Luhman et al. (2010) suggested a full disk. We now classify it as an evolved disk after including the WISE bands. 2MASS J04284263+2714039 is classified as an evolved disk in this study but not by Luhman et al. (2010) because we have used extinction-corrected colors rather than observed colors. In addi-tion, the new members that we have added to our census of Taurus (see Section 2.1) contain seven evolved disks (V1195 Tau, 2MASS J04380191+2519266, 2MASS J04374333+3056563, 2MASS J04215851+1520145, 2MASS J04284199+1533535, 2MASS J05073903+2311068, and 2MASS J05122759+2253492), three transitional disks (2MASS J04355760+2253574, 2MASS J04343128+1722201, and 2MASS J05080709+2427123), one evolved transitional/debris disk (2MASS J04242321+2650084), and 31 full disks.", "cite_spans": [], "ref_spans": [{"start": 837, "end": 845, "text": "Figure 3", "ref_id": "FIGREF8"}, {"start": 1477, "end": 1485, "text": "Figure 3", "ref_id": "FIGREF8"}, {"start": 1555, "end": 1562, "text": "Table 1", "ref_id": "TABREF5"}, {"start": 1691, "end": 1698, "text": "Table 1", "ref_id": "TABREF5"}]}, {"section": "Identification of New Members of Taurus", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Candidate Members from WISE", "text": "In addition to identifying and classifying the disks of known members of Taurus, we have searched for new members that have disks via their red WISE colors. We began by retrieving from the WISE All-Sky Source Catalog all objects between 4 h 00 m -5 h 10 m in right ascension and 15", "cite_spans": [], "ref_spans": []}, {"section": "Candidate Members from WISE", "text": "\u2022 -31", "cite_spans": [], "ref_spans": []}, {"section": "Candidate Members from WISE", "text": "\u2022 in declination (J2000), which encompasses all known dark clouds and young stars in Taurus (see Figure 1) . In our analysis, we considered only data with errors less than 0.1 mag. We excluded sources that are spurious detections of diffraction spikes in W 1 or W 2, as indicated by the parameter \"cc flag\" in the WISE catalog. Known members of Taurus were also removed from the list. These criteria resulted in a list of \u223c1.4 million sources.", "cite_spans": [], "ref_spans": [{"start": 97, "end": 106, "text": "Figure 1)", "ref_id": "FIGREF6"}]}, {"section": "Candidate Members from WISE", "text": "We searched the catalog from WISE for objects with colors similar to those of known disk-bearing members of Taurus. To demonstrate how this was done, we show in Figure 4 color-color and color-magnitude diagrams constructed from the WISE bands for the known members of Taurus and for the other WISE sources in our survey field. To minimize contamination by non-members, we selected boundaries that cover the smallest range of colors while also encompassing most of the known disks. The only disk-bearing member not enclosed within these boundaries, IRAS 04302+2247, has unusual colors because it is seen in scattered light (Furlan et al. 2008) . We also defined boundaries that enclose most of the members that lack excesses and have photospheric colors. The definitions of these boundaries are provided in Table 4 . Using these boundaries, we identified as candidate disk-bearing members of Taurus the WISE sources that satisfy all of the following: 1) W 1 \u2264 14, 2) excess in at least one diagram, 3) excesses in all available bands long ward of some wavelength, and 4) in the excess or photosphere regions in all diagrams (i.e., not in the lower right or upper left in either color-color diagram). In addition, we rejected sources with non-detections or large errors (\u03c3 > 0.1 mag) in both W 3 and W 4 where the limits of the respective colors exclude the presence of excess emission. These criteria produced 1062 candidates, which are split among Tables 5, 6 , and 7, as described in the following sections.", "cite_spans": [], "ref_spans": [{"start": 161, "end": 169, "text": "Figure 4", "ref_id": "FIGREF9"}]}, {"section": "Additional Membership Constraints", "text": "Given that Taurus contains \u223c250 known members with disks, it is likely that most of the 1062 candidates from WISE are not members. To further refine this sample of candidates, we have employed visual inspection of available images, optical/IR color-magnitude diagrams, IRAC photometry, and proper motions.", "cite_spans": [], "ref_spans": []}, {"section": "Additional Membership Constraints", "text": "We visually inspected the images of each candidate from DSS, the Sloan Digital Sky Survey (SDSS, York et al. 2000) , 2MASS, and WISE. Objects were rejected if 1) reliable detections were not present in the WISE bands that exhibited excess emission, 2) the WISE source was contaminated by emission from a nearby object, 3) the centroid shifted among the WISE bands, indicating that the WISE source was a blend of multiple objects, or 4) the candidate was resolved as a galaxy in any of the surveys. This inspection eliminated 454 sources. We also rejected 39 other candidates that have been previously classified as galaxies, planetary nebulae, asymptotic giant branch stars, cataclysmic variables, or other nonmembers according to the SIMBAD database. The candidates WISE J043809.73+254731.5, J041810.61+284447.3 and J041556.86+290750.9 are non-members based on unpublished spectra from a separate survey (K. Luhman, in preparation).", "cite_spans": [], "ref_spans": []}, {"section": "Additional Membership Constraints", "text": "In Figure 5 , we show color-magnitude diagrams constructed from 2MASS, WISE, and USNO-B1.0 (B R I; Monet et al. 2003) for the known Taurus members and the 1062 WISE candidates. For objects with USNO data at two epochs, we adopted the more recent measurements. As done in the previous section, we have selected boundaries in these diagrams that encompass most of the known members, which are defined in Table 8 . The few members that are below these boundaries are known or suspected to be seen in scattered light (e.g., edge-on disks), resulting in their underluminous positions. For candidates detected by 2MASS with K s > 7.5, we rejected sources that are below or to the left of the boundaries in any of the three 2MASS/USNO diagrams. For candidates that were not detected by 2MASS, we applied the criteria from the WISE/USNO diagrams instead (W 1 > 7). In total, we reject 631 and 96 sources with the 2MASS/USNO and WISE/USNO criteria, respectively. Some of our WISE candidates were identified based only on red W 1 \u2212 W 2 colors, and lacked detections in W 3 or W 4 that could confirm the presence of excess emission. These objects were also found to follow the spatial distribution of the Taurus dark clouds. Since a large area in Taurus We can use proper motions to further constrain the membership of the WISE candidates. Using proper motions from UCAC4 (Zacharias et al. 2013) , we reject WISE candidates that differ by more than 2 \u03c3 from all of the average motions of the Taurus groups (Luhman et al. 2009 ). For candidates rejected by UCAC4 proper motions but not the other criteria described above and for candidates without UCAC4 data, we examined the proper motions from other catalogs (Monet et al. 2003; R\u00f6ser et al. (2008) ; Roeser et al. 2010; Zacharias et al. 2010 ). Three of these stars, 2MASS J04124068+2438157, 2MASS J05080709+2427123, and 2MASS J05073903+2311068, have proper motions from those catalogs that support membership, while 2MASS J04322815+2711228 is rejected. In addition, we examined images from DSS and 2MASS for the 1062 candidates to check for visually discernible motions, which would be significantly larger than that of Taurus ( 100 mas/yr). We have rejected 161 WISE candidates through these proper motion criteria.", "cite_spans": [], "ref_spans": [{"start": 3, "end": 11, "text": "Figure 5", "ref_id": "FIGREF10"}]}, {"section": "Additional Membership Constraints", "text": "The criteria described above rejected 976 of the 1062 WISE candidates as likely nonmembers. These objects and the criteria that they failed to satisfy are listed in Table 5 . Although 2MASS J04051434+2008214 (HD 284154) passed all criteria, it is rejected as a Taurus member because it and a common proper motion companion ([WKS96] 4) are both fainter than expected for members of Taurus with their spectral types.", "cite_spans": [], "ref_spans": []}, {"section": "Spectroscopy of Candidate Members", "text": "We obtained optical and near-IR spectra of 10 and 41 WISE candidates, respectively. We also performed IR spectroscopy on candidate companions to BS Tau and 2MASS J04485789+2913548 that were noticed in their acquisition images. Because we began spectroscopy of candidates before applying all of the membership constraints from the previous section, seven of the targets have positions in the USNO/2MASS/WISE color-magnitude diagrams that are indicative of non-members. They consist of six galaxies and a young star (2MASS J04591661+2840468). The optical observations were performed with the Marcario LowResolution Spectrograph (LRS) on the Hobby-Eberly Telescope (HET) on the nights of 2012 December 5, 8, and 9. The instrument was operated with the G3 grism and the 2 slit, which provided a wavelength coverage of 6200-9100\u00c5 and a resolution of R = 1100. The near-IR spectra were collected with SpeX at the NASA Infrared Telescope Facility (IRTF) on the nights of 2012 December 28, 2013 January 1 and 3, and 2013 August 26. The SpeX data were collected in the prism mode with a 0. 8 slit, providing a wavelength coverage of 0.8-2.5 \u00b5m and a resolution of R = 100 for all targets except 2MASS J04221376+1525298, which was observed with the SXD mode (R = 800). The data were reduced with the Spextool package (Cushing et al. 2004 ) and corrected for telluric absorption (Vacca et al. 2003) . The optical and near-IR spectra of the stars that we classify as new members are presented in Figures 6 and 7 , respectively.", "cite_spans": [], "ref_spans": [{"start": 1484, "end": 1499, "text": "Figures 6 and 7", "ref_id": "FIGREF11"}]}, {"section": "Spectroscopy of Candidate Members", "text": "For our spectroscopic sample, we distinguished young stars from field dwarfs by gravitysensitive features (K I, Na I, H 2 O) and the strength of H\u03b1 emission. Galaxies were identified by their redshifted emission lines. We measured spectral types and extinctions for the young objects by comparing strengths of the VO, TiO and H 2 O absorption bands to those of previously known members of Taurus and average spectra of standard dwarfs and giants classified at optical wavelengths (Luhman 1999) . Our resulting classifications are presented in Table 6 . We classify 24 candidates and the companions to BS Tau and 2MASS J04485789+2913548 as young stars, and hence likely members of Taurus. The remaining 27 sources that we classify as non-members are included in the full list of rejected candidates in Table 5 . A few of the new members have some previous evidence of youth (e.g., BS Tau) but have lacked spectral classifications. The spatial distribution of these new members is shown in Figure  1 . The 34 remaining viable candidates that have not been observed with spectroscopy are presented in Table 7 .", "cite_spans": [], "ref_spans": [{"start": 988, "end": 997, "text": "Figure  1", "ref_id": "FIGREF6"}]}, {"section": "Spectroscopy of Candidate Members", "text": "We have additional comments on the classifications of some of the objects in our spectroscopic sample. BS Tau is a 1.3 binary with spectral types M2.5 and M5.5. The primary appears to be the source of the WISE excess based on a comparison of astrometry in 2MASS and WISE and its strong H\u03b1 emission, which is a signature of accretion. 2MASS J04332789+1758436, 2MASS J04485789+2913548, and Haro 6-39 are very red and show H emission lines. They are not fit well by any standards and probably have both blue and red excesses. 2MASS J04591661+2840468 may be seen in scattered light since it is very faint for its color (e.g., edge-on disk). Our near-IR spectrum of 2MASS J04221376+1525298 is indicative of a early F star with a reddening that corresponds to A V \u223c 4 and significant K-band continuum veiling. The latter combined with the WISE excess emission suggest that it has a disk, and hence is a young star. However, it is fainter than expected for an F-type member of Taurus, indicating that it is seen in scattered light or is a background young star. We classify it as the latter for the purposes of this study. We note that this star also shows strong absorption in He I at 1.083 \u00b5m (W \u03bb \u223c 5\u00c5), which is unusual for an F star and may be due to a wind (Edwards et al. 2003) . Among the seven M dwarfs that we classify as non-members, five have only marginal excesses in a single band and thus probably do not have real excesses. The remaining two M dwarfs, 2MASS J04152336+3006258 and 2MASS J04503102+1514127, seem to have significant excesses and are much fainter than typical members at their spectral types. Since these two stars do not show any evidence of being edge-on disks, they are probably field M dwarfs that have debris disks or that are unresolved from background red galaxies.", "cite_spans": [], "ref_spans": []}, {"section": "Other New Members", "text": "While searching for new disk-bearing members based on red WISE colors, we found that four excess candidates already had sufficient evidence of membership from previous work for inclusion in our initial sample of members (Section 2.1). These stars consist of V1195 Tau, HD 31305, RXJ 0432.7+1809, and HD 286178. V1195 Tau is a 1 binary (K\u00f6hler & Leinert 1998 ) that is somewhat isolated from known members. Its proper motion (R\u00f6ser et al. 2008 ) and radial velocity (Wichmann et al. 2000) are consistent with membership (Luhman et al. 2009 ). Since Wichmann et al. (2000) did not detect Li, V1195 Tau has generally been considered a background star. However, it was detected by Mart\u00edn & Magazz\u00fa (1999) and Nguyen et al. (2012) . HD 31305 is close to known members, is an X-ray source (Wichmann et al. 1996) , and has a proper motion (Zacharias et al. 2013 ) that agrees with the closest subgroup (Luhman et al. 2009 ). Its photometry is consistent with a A0 zero age main sequence (ZAMS) star at the distance of Taurus, which makes it the second most massive/hottest star in that group behind AB Aur. We estimate that its position on the Hertzsprung-Russell (H-R) diagram (log(T ef f ) 3.96, log(L/L ) 1.32) is consistent with being somewhat older (5-10 Myr) than AB Aur (1.5 Myr; Palla & Stahler 2002) , but similar in age to MWC 480 (7.4 Myr; Manoj et al. 2006) . Cody et al. (2013) and Mooley et al. (2013) 1 identified HD 31305 as a probable member of Taurus based on variability and proper motion, respectively. RXJ 0432.7+1809 and HD 286178 were classified by Wichmann et al. (1996) as young stars because of their X-ray emission and Li absorption. In addition, Sestito et al. (2008) confirmed the Li detection for HD 286178. The proper motions of these stars are consistent with membership in Taurus (R\u00f6ser et al. 2008; Zacharias et al. 2013) . We identified HD 286178 as a candidate because the criteria in Figure 3 suggested it had an excess at W 4. However, the more detailed analysis that we applied to the known members indicates that it probably does not have an excess.", "cite_spans": [], "ref_spans": [{"start": 1914, "end": 1922, "text": "Figure 3", "ref_id": "FIGREF8"}]}, {"section": "Comparison to Rebull et al. 2011", "text": "We compare the results of our survey for new disk-bearing members of Taurus with the WISE-based search performed by Rebull et al. (2011) . That study recovered 18 can-didate members originally found by Rebull et al. (2010) and identified 94 additional candidates. Among those 112 candidates, 39 are rejected through the criteria in Section 5.2, 12 are beyond the limit of our survey (W 1 > 14), 23 do not satisfy our criteria for excess emission, 26 are outside our search area, one is the member V1195 Tau (see Section 5.4), and 11 are included in our spectroscopic sample. In this last group, one is rejected (2MASS J04221376+1525298) and ten are confirmed as members by our spectra. Meanwhile, four of our new members are among the stars rejected by Rebull et al. (2011) , which are 2MASS J04343128+1722201, 2MASS J04485789+2913548, 2MASS J04591661+2840468, and 2MASS J05080709+2427123. They also described HD 31305 as a likely field star, which we classify as a member (Section 5.4). Twenty-five of our candidates in Table 7 were examined by Rebull et al. (2011) , who classified them as likely galaxies based on their spectral energy distributions. The remaining 9 candidates were not considered in Rebull et al. (2011) . They also did not evaluate eight of our spectroscopically confirmed members. Finally, the list of known members from Rebull et al. (2011) includes two stars, St H\u03b1 34 and IRAS 04262+2735, that we have omitted as non-members (Hartmann et al. 2005b; Luhman et al. 2009) 2 .", "cite_spans": [], "ref_spans": []}, {"section": "Completeness of Census of Members with Disks", "text": "We now evaluate the completeness of the current census of Taurus for disk-bearing members. The WISE catalog is \u223c 95% complete at W 1 = 16.9 and W 2 = 15.5 for uncrowded areas with the depth of coverage found in Taurus (Cutri et al. 2012b) . Meanwhile, our criteria in Table 4 encompass nearly all known members of Taurus with mid-IR excesses. Therefore, our sample of candidates for new disks in Taurus should have a high level of completeness down to our adopted limit of W 1 = 14. The magnitudes of the 34 candidates with uncertain membership status are indicated in Figure 4 . There are no candidates with W 1 < 13, indicating that the census of known Taurus members with IR excess should be largely complete in this magnitude range, with the exception of objects that are unresolved from brighter stars. Among the 26 known members of Taurus from M7 to M8, the faintest W 1 measurement is 13.05. Thus, our census of disk-bearing members should be complete to \u223cM8. The completeness is lower at fainter levels, but most of these candidates are probably galaxies based on their very red colors (Rebull et al. 2011) , although a few may be protostars.", "cite_spans": [{"start": 218, "end": 238, "text": "(Cutri et al. 2012b)", "ref_id": "BIBREF9"}], "ref_spans": [{"start": 569, "end": 577, "text": "Figure 4", "ref_id": "FIGREF9"}]}, {"section": "Conclusions", "text": "We have performed a survey of circumstellar disks in the Taurus star-forming region using WISE. Our results are summarized as follows:", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "1. We have examined all images from the cryogenic phase of WISE for all known members of Taurus to check for false detections, blends with nearby objects, and extended emission. We have presented the resulting catalog of vetted photometry in the WISE bands at 3.4, 4.6, 12, and 22 \u00b5m (W 1-W 4). All resolved, unblended members are detected by WISE in at least one band.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "2. By using colors constructed from K s and six Spitzer and WISE bands, we have identified Taurus members showing excess emission from circumstellar disks and have estimated the evolutionary stages of the detected disks, consisting of full, transitional, evolved, evolved transitional, and debris disks. Our classifications are generally consistent with those found by Luhman et al. (2010) and Furlan et al. (2011) . We have found 31 new full disks and 16 new candidate disks in the more advanced evolutionary stages.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "3. Using photometry from WISE, Spitzer, 2MASS, and USNO, proper motions from UCAC4 and other catalogs, and our optical and near-IR spectroscopy, we have found 26 new members of Taurus with spectral types of M1 -M7. The census of disk-bearing stars in Taurus should now be largely complete for W 1 < 13 ( M8; M 0.03 M ).", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "T.E. and K.L. were supported by grant NNX12AI58G from the NASA Astrophysics Data Analysis Program. E.E.M. acknowledges support from NSF grants AST-1008908 and AST-1313029. This publication makes use of data products from the Wide-field Infrared Survey Explorer, which is a joint project of the University of California, Los Angeles, and the Jet Propulsion Laboratory/California Institute of Technology, and NEOWISE, which is a project of the Jet Propulsion Laboratory/California Institute of Technology. WISE and NEOWISE are funded by the National Aeronautics and Space Administration (NASA). The Spitzer Space Telescope and the IPAC Infrared Science Archive (IRSA) are operated by JPL and Caltech under contract with NASA. 2MASS is a joint project of the University of Massachusetts and the Infrared Processing and Analysis Center (IPAC) at Caltech, funded by NASA and the NSF. The IRTF is operated by the University of Hawaii under cooperative agreement NNX-08AE38A with NASA. The HET is a joint project of the University of Texas at Austin, the Pennsylvania State University, Stanford University, LudwigMaximillians-Universit\u00e4t M\u00fcnchen, and Georg-August-Universit\u00e4t G\u00f6ttingen and is named in honor of its principal benefactors, William P. Hobby and Robert E. Eberly. The Marcario Low-Resolution Spectrograph at HET is named for Mike Marcario of High Lonesome Optics, who fabricated several optics for the instrument but died before its completion; it is a joint project of the HET partnership and the Instituto de Astronom\u00eda de la Universidad Nacional Aut\u00f3noma de M\u00e9xico. The Digitized Sky Survey was produced at the Space Telescope Science Institute under U.S. Government grant NAG W-2166. The images of these surveys are based on photographic data obtained using the Oschin Schmidt Telescope on Palomar Mountain and the UK Schmidt Telescope. The plates were processed into the present compressed digital form with the permission of these institutions. The Center for Exoplanets and Habitable Worlds is supported by the Pennsylvania State University, the Eberly College of Science, and the Pennsylvania Space Grant Consortium.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "A. Comments on B/A stars from Mooley et. al (2013) From among the five new proposed B/A-type Taurus candidates from Mooley et al. (2013) , we retain only HD 31305 as a probable Taurus member (see 5.4) and reject the other four stars (HD 28929, \u03c4 Tau, 72 Tau, and HD 26212) . Below, we describe our reasoning for excluding the latter stars from our membership sample.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "HD 28929 is a B8V star (Kenyon et al. 1994 ) with a common proper motion companion, HD 28929B (2MASS J04343987+2857347, UCAC4 595-013167, TYC 1841-1391-1). The BVJHK s photometry for HD 28929B is similar to that of a F6V star (Ofek 2008) , and so if it has the same reddening as HD 28929A (E(B-V) 0.05), then it is likely a mid-F star. If the revised Hipparcos parallax for HD 28929A ( = 6.72 \u00b1 0.34 mas) is adopted, then the companion has M V 4.2, which is more consistent with a main sequence star rather than a pre-main sequence star. Zorec & Royer (2012) estimates an isochronal age of HD 28929 of \u223c600 Myr. Using the estimated H-R diagram position for HD 28929 A of T ef f = 12850 K and log(L/L ) 2.30, we estimate an age of \u223c120 Myr using the Bertelli et al. (2009) evolutionary tracks. Although the tangential motion of HD 28929 differs from that of the nearest Taurus subgroups at a level of only \u223c2-3 km/s, and it appears to be co-distant with Taurus, the HD 28929 system is isolated and has no other known Taurus members within a degree. Based on all of these considerations, and the lack of indicators of extreme youth for either component, we conclude that the HD 28929 system is likely to be a \u223c120 Myr-old interloper.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "\u03c4 Tau (HD 29763) is a B3V triple system (Lesh 1968) . We disagree with the assessment of Mooley et al. (2013) that the star appears to be a kinematic match to the Tau V subgroup, which is in its vicinity. Combining the systemic velocity from Petrie & Ebbighausen (1961) (12.3 km/s) with the revised Hipparcos astrometry, we estimate its space motion to be (U, V, W) -10, -8, -12 km/s, which is not near that of the Taurus subgroups (see Table 8 of Luhman et al. 2009 ). The star's tangential motion differs by \u223c4-6 km/s from the mean motion of the nearest Tau subgroups (IV and V), with its proper motion in right ascension going the wrong direction, and the systemic radial velocity differs by \u223c4 km/s from that of Taurus. \u03c4 Tau A is not near the ZAMS (log(T ef f ) 4.20 \u00b1 0.01 dex, log(L/L bol ) 2.9 \u00b1 0.1 dex); indeed, we estimate an isochronal age of \u223c60 Myr using the Bertelli et al. (2009) tracks. \u03c4 Tau B is a A1V star (Tolbert 1964) , for which we estimate M V 1.6. As a \u223c2.1 M main sequence star, it would take a star of \u03c4 Tau B's mass \u223c8 Myr to contract to reach the main sequence, which sets a strong lower limit on the age of the \u03c4 Tau system, and rules out the possibility that \u03c4 Tau A might be in the pre-main sequence phase. We conclude that the \u03c4 Tau system is a \u223c60 Myr-old interloper.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "72 Tau (HD 28149) is a B7V star (Lesh 1968 ) near the Tau V subgroup. Its tangential motion differs by \u223c6 km/s from that of the Tau V group (Luhman et al. 2009 ). The radial velocity for 72 Tau (7.3 \u00b1 2.6 km/s) is significantly different from that of Tau V (15.7 km/s). Its space velocity (U, V, W = -5.9, -5.3, -7.4 km/s; Anderson & Francis 2012) differs from that of the Tau V subgroup by 11 km/s (Luhman et al. 2009 ). Zorec & Royer (2012) estimates an isochronal age of 179 \u00b1 87 Myr, although our estimated H-R diagram position for 72 Tau (log(T ef f ) 4.16, log(L/L ) 2.32) places the star closer to the ZAMS (<15 Myr?). Despite its youth, we find that 72 Tau is a poor kinematic match for Taurus membership, and consider it an interloper. HD 26212 is a A5V star (Grenier et al. 1999; Mooley et al. 2013) at a distance of 100 \u00b1 7 pc (van Leeuwen 2007), placing it >5\u03c3 closer than the mean distance to Taurus (140 pc). HD 26212 is not in the vicinity of any of the Taurus subgroups (>2 deg from Tau VIII), and its velocity (U, V, W = -18, -5, -12 km/s; Anderson & Francis 2012) is not a good match to the Taurus subgroups (Luhman et al. 2009 ). We estimate that the star is lightly reddened (E(B-V) = 0.04 \u00b1 0.02) with an H-R diagram position of log(T ef f ) = 3.907 \u00b1 0.007 dex, log(L/L ) = 1.01 \u00b1 0.07 dex. Comparing this position to pre-main-sequence isochrones and members of Upper Sco in Figure 14 of Pecaut et al. (2012) , it appears that HD 26212 is a ZAMS star and is below the Upper Sco (\u223c11 Myr) A-star sequence. Hence, it is almost certainly >10 Myr, and not a pre-main-sequence star. Given the discordance of its position, distance, velocity, and age compared to Taurus, and lack of secondary youth indicators (e.g., IR excess), we consider HD 26212 an interloper. Note. -Entries of \"\u00b7 \u00b7 \u00b7\" and \"out\" indicate measurements that are absent because of non-detection and a position outside the field of view of the camera, respectively. Note. - Table 5 is available in a machine-readable format, a portion is shown here for guidance regarding its form and content.", "cite_spans": [], "ref_spans": [{"start": 1397, "end": 1406, "text": "Figure 14", "ref_id": "FIGREF6"}]}, {"section": "Conclusions", "text": "a Coordinate-based identifications from the WISE All-Sky Source Catalog.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "b Coordinate-based identifications from the 2MASS Point Source Catalog when available.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "c Probable non-members based on: false = spurious WISE detection in all bands or bands that seem to show excesses; mismatch = different sources dominate in W 1/W 2 and W 3/W 4; galaxy = resolved galaxy; extended = extended in 2MASS, DSS or SDSS images, indicating that it may be a galaxy; blend = unreliable photometry because of blending with other sources.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "d Probably non-members based on the listed spectroscopic classification Table 6 . IR Excess Sources Observed with Spectroscopy Table 7 . IR Excess Sources with Undetermined Membership in Taurus \u00b5m from Spitzer are shown when available. Otherwise, measurements at similar wavelengths from WISE are used (W 2 and W 4). We have indicated known protostars (class I and 0, triangles), candidate transitional disks (crosses), candidate evolved disks (stars), and candidate debris disks or evolved transitional disks (circles). The reddest protostars are beyond the limits of these diagrams. In the middle and lower diagrams, we have marked the lower boundaries that we have adopted for full disks (dotted lines). . We have defined regions that separately encompass most of the members with and without excesses from disks (solid lines). Middle: Among WISE sources that are not known Taurus members (points), we have identified those that have colors indicative of disks based on the boundaries defined on the left (red points). Right: Some of the IR excess sources from the middle diagrams are probable non-members (Table 5) .", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "We show the positions of the remaining candidates that have been confirmed as members through spectroscopy (Table 6 , points) and that have undetermined membership status (Table 7 , circles). Most of the latter are probably galaxies based on their faint magnitudes and very red colors. The spectra have been corrected for extinction, which is quantified in parentheses by the magnitude difference of the reddening between 0.6 and 0.9 \u00b5m (E(0.6-0.9)). The spectra have a resolution of 7\u00c5 and are normalized at 7500\u00c5. Fig. 7 .-Near-IR spectra of new members of Taurus. The spectra with measured spectral types have been corrected for extinction. These data have a resolution of R = 100 and are normalized at 1.68 \u00b5m.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF9": {"title": "Explanatory Supplement to the WISE All-Sky Data Release Products", "authors": [{"first": "R", "middle": ["M"], "last": "Cutri", "suffix": ""}, {"first": "E", "middle": ["L"], "last": "Wright", "suffix": ""}, {"first": "T", "middle": [], "last": "Conrow", "suffix": ""}], "year": 2012, "venue": "", "link": null}}, "ref_entries": {"FIGREF0": {"text": "], respectively. IRAC produced images with a field of view of 5. 2 \u00d7 5. 2 and FWHM of 1. 6 \u2212 1. 9 for [3.6] to [8.0]. MIPS had a field of view of 5. 4 \u00d7 5. 4 and a FWHM of 5. 9 for [24].", "type": "figure"}, "FIGREF1": {"text": ". The K s \u2212 W 2 and K s \u2212 W 4 colors were approximated by the similar K s \u2212 [4.5] and K s \u2212 [24] colors, respectively. We determined the photospheric colors for K s \u2212 W 3 by a fit to the observed diskless sequence in Figure 2. The resulting excesses of Taurus members are plotted in Figure 3. Because of their similar wavelengths, data from [4.5]/W 2 and [24]/W 4 are presented together. When both Spitzer and WISE data are available in those bands, we plot the former. IRAS 04016+2610, Haro 6-5B, GV Tau A+B, and CoKu Tau/1 have large excesses in all bands and are too red to appear within the selected boundaries of Figure 3. Following the procedure of Luhman & Mamajek (2012), we classify the disks using the K s \u2212 [8.0], K s \u2212 W 3, and K s \u2212 [24]/W 4 colors. In Figure 3, we show the boundaries between full disks and other sources, which are defined by the lines connecting the points (E(K s \u2212 [24]/W 4), E(K s \u2212 [8.0])) = (2.75, 1.25), (3.36, 0.90), and (5.5, 0.90) in the middle panel and (", "type": "figure"}, "FIGREF2": {"text": "We also classified the disks for members that lacked W 3, [8.0], and/or [24]/W 4 but had excesses. Disks without [24]/W 4 data were classified as full if the excesses at [8.0] or W 3 were sufficiently high to exclude other disks types. If the excesses at [8.0] and W 3 were both too small for full disks, the disks were classified as evolved if the upper limits on [24]/W 4 excluded transitional disks and were marked as evolved or transitional if the [24]/W 4 limits did not provide useful constraints. Objects with [4.5]/W 2 excesses but no data at longer wavelengths were classified as full. Finally, all members that lack spectral classifications or K-band photometry (mostly protostars) have large enough excesses to indicate the presence of full disks.", "type": "figure"}, "FIGREF3": {"text": "was imaged by IRAC, we can use the available [5.8] and [8.0] data as an independent verification of excess at [4.5]/W 2 for this subset of candidates. The boundary [5.8] \u2212 [8.0] > 0.4 divides known members with and without excess at [4.5]/W 2. Using photometry from all IRAC images of Taurus (Luhman et al. 2006; Luhman et al. 2010), we have rejected 69 WISE candidates that lack W 3 and W 4 detections and that have [5.8] \u2212 [8.0] < 0.4. Given that these candidates are projected against the dark clouds in Taurus, they are probably background stars that are red in W 1 \u2212 W 2 because of extinction. This source of contamination should be largely eliminated from our candidate list since IRAC imaged most of the Taurus dark clouds.", "type": "figure"}, "FIGREF4": {"text": "J \u2212 H and J \u2212 K= derived from these 2MASS colors assuming pho- tospheric near-infrared colors; CTTS = derived from J \u2212 H and H \u2212 K colors assuming intrinsic CTTS colors from Meyer et al. (1997); opt. spec. = derived from an optical spectrum; SpeX = derived from SpeX spectrum; (1) = Bricen\u00f1o et al. (1998); (2) = Luhman (2000); (3) = Strom & Strom (1994); (4) = Beck (2007); (5) = White & Ghez (2001); (6) = DeWarf et al. (2003); (7) = Calvet et al. (2004).", "type": "figure"}, "FIGREF6": {"text": "Fig. 1.-Spatial distribution of previously known members of the Taurus star-forming region (circles) and new members from this work (crosses). The dark clouds in Taurus are displayed with a map of extinction (gray scale; Dobashi et al. 2005).", "type": "figure"}, "FIGREF7": {"text": "Fig. 2.-Extinction-corrected IR colors versus spectral type for members of Taurus from Spitzer (left) and WISE (right). The solid lines are used to identify the presence of excess emission from circumstellar disks. We have indicated known protostars (class I and 0, triangles), candidate transitional disks (crosses), candidate evolved disks (stars), and candidate debris disks or evolved transitional disks (circles).", "type": "figure"}, "FIGREF8": {"text": "Fig. 3.-Extinction-corrected IR color excesses for members of Taurus. Data at 4.5 and 24 \u00b5m from Spitzer are shown when available. Otherwise, measurements at similar wavelengths from WISE are used (W 2 and W 4). We have indicated known protostars (class I and 0, triangles), candidate transitional disks (crosses), candidate evolved disks (stars), and candidate debris disks or evolved transitional disks (circles). The reddest protostars are beyond the limits of these diagrams. In the middle and lower diagrams, we have marked the lower boundaries that we have adopted for full disks (dotted lines).", "type": "figure"}, "FIGREF9": {"text": "Fig. 4.-Left: WISE color-magnitude and color-color diagrams for known members of Taurus (same labels as Figs. 2-3). We have defined regions that separately encompass most of the members with and without excesses from disks (solid lines). Middle: Among WISE sources that are not known Taurus members (points), we have identified those that have colors indicative of disks based on the boundaries defined on the left (red points). Right: Some of the IR excess sources from the middle diagrams are probable non-members (Table 5). We show the positions of the remaining candidates that have been confirmed as members through spectroscopy (Table 6, points) and that have undetermined membership status (Table 7, circles). Most of the latter are probably galaxies based on their faint magnitudes and very red colors.", "type": "figure"}, "FIGREF10": {"text": "Fig. 5.-Color-magnitude diagrams for known members of Taurus and other WISE sources with IR excesses that are indicative of young stars (Figure 4). These diagrams are based on data from WISE (W 1), 2MASS (K s ), and USNO-B1.0 (BRI). The lines indicate the lower boundaries of the population of known members.", "type": "figure"}, "FIGREF11": {"text": "Fig. 6.-Optical spectra of new members of Taurus. The spectra have been corrected for extinction, which is quantified in parentheses by the magnitude difference of the reddening between 0.6 and 0.9 \u00b5m (E(0.6-0.9)). The spectra have a resolution of 7\u00c5 and are normalized at 7500\u00c5.", "type": "figure"}, "TABREF0": {"text": ", we examine [4.5], [8.0], [24], W 2, W 3, and W 4 for excess emission.", "type": "table"}, "TABREF1": {"text": "or not imaged by IRAC. Members without W 2 are too bright for good photometry, dominated by extended emission, or blended with another object. All of the stars imaged by IRAC without [4.5] also lack W 2 photometry, while 44 of the stars without W 2 are mea- sured in [4.5]. The 39 stars that were not observed by IRAC in [4.5] were detected by WISE, although two of them, MWC 480 and HD 29763, are too bright for good photometry in this band. Consequently, 404 and 322 members have data in at least one or both of these two bands, respectively.", "type": "table"}, "TABREF2": {"text": "and W 2 and data at other bands. 2MASS J04215450+2652315 and V410 Tau have a small excess in W 2 and W 2/[4.5], re- spectively. However, both stars have colors consistent with stellar photospheres at longer wavelengths. GM Aur shows excess in [4.5] and other bands but is slightly below our bound- ary in W 2. We indicate the presence of excess in W 2 for this star in Table 1. For all other sources with excesses in [4.5] and W 2, excess emission is also detected at longer wavelengths.Photometry at [8.0] has been measured for 369 members of Taurus. Stars that lack [8.0] were either saturated or not observed by IRAC. Since excess emission from disks increases at longer wavelength, the gap between the diskless and disk-bearing members is larger for K s \u2212 [8.0] than it was for K s \u2212 [4.5] and K s \u2212 W 2, as shown in", "type": "table"}, "TABREF3": {"text": "72, 2.02) and (3.55, 1.25) in the lower panel. We classify disks above one or both boundaries as full. For bluer sources, we apply the following criteria: transitional disks have E(K s \u2212 [24]/W 4) > 3.55; evolved disks have E(K s \u2212 [24]/W 4) < 3.55, E(K s \u2212 [8.0]) > 0.3, and E(K s \u2212 W 3) > 0.5; and debris disks and evolved transitional disks have E(K s \u2212 [24]/W 4) < 3.55, E(K s \u2212 [8.0]) < 0.3, and E(K s \u2212 W 3) < 0.5. While these boundaries reproduce the results in", "type": "table"}, "TABREF4": {"text": "ex- cept for the following: 2MASS J04400174+2556292, 2MASS J04414565+2301580, 2MASS J04214631+2659296, 2MASS J04390163+2336029, and 2MASS J04284263+2714039. The first three have been discussed earlier in this study. 2MASS J04390163+2336029 lacks [4.5] and [8.0], and the data in [5.8] and [24] considered by", "type": "table"}, "TABREF5": {"text": "Spitzer and WISE Data for Members of TaurusNote. -The table is available in a machine-readable format.Source names for HBC 360, HBC 361, and IRAM 04191+1522 are from the ALLWISE Source Catalog.", "type": "table"}, "TABREF6": {"text": "New IRAC Photometry for Members of Taurus", "type": "table"}, "TABREF7": {"text": "Continued51\u00b10.02 6.38\u00b10.02 6.10\u00b10.03 5.18\u00b10.03 2004 Feb 14 out 6.44\u00b10.02 out 5.21\u00b10.03 2008 Nov 1 J04571766+1525094 HD 286178 7.69\u00b10.02 7.73\u00b10.02 7.65\u00b10.03 7.66\u00b10.03 2004 Sep 7", "type": "table"}, "TABREF8": {"text": "New MIPS 24 \u00b5m Photometry for Members of Taurus Table 5. IR Excess Sources that are Probable Non-members", "type": "table"}}}
{"paper_id": "118866026", "_pdf_hash": "21b81cfc740a0b44f335008a91bc0aaa3fa99276", "abstract": [{"section": "Abstract", "text": "Abstract: The semi-constrained NMSSM (scNMSSM) extends the MSSM by a singlet field, and requires unification of the soft SUSY breaking terms in the squark and slepton sectors, while it allows that in the Higgs sector to be different. We try to interpret the muon g-2 in the scNMSSM, under the constraints of 125 GeV Higgs data, B physics, searches for low and high mass resonances, searches for SUSY particles at the LHC, dark matter relic density by WMAP/Planck, and direct searches for dark matter by LUX, XENON1T, and PandaX-II. We find that under the above constraints, the scNMSSM can still (i) satisfy muon g-2 at 1\u03c3 level, with a light muon sneutrino and light chargino; (ii) predict a highly-singlet-dominated 95 GeV Higgs, with a diphoton rate as hinted at by CMS data, because of a light higgsino-like chargino and moderate \u03bb; (iii) get low fine tuning from the GUT scale with small \u00b5 eff , M0, M 1/2 , andA0, with a lighter stop mass which can be as low as about 500 GeV, which can be further checked in future studies with search results from the 13 TeV LHC; (iv) have the lightest neutralino be singlino-dominated or higgsino-dominated, while the bino and wino are heavier because of high gluino bounds at the LHC and universal gaugino conditions at the GUT scale; (v) satisfy all the above constraints, although it is not easy for the lightest neutralino, as the only dark matter candidate, to get enough relic density. Several ways to increase relic density are discussed.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "In July 2012, the Higgs boson was discovered at the LHC [1, 2] , and searching for physics beyond the Standard Model (SM) has now become the main objective in high energy physics. Supersymmetry (SUSY) is one of the most popular theories for new physics. As the simplest SUSY model, the minimal supergravity model (mSUGRA) has attracted a lot of attention from both theorists and experimentalists. However, it cannot predict a 125 GeV SM-like Higgs when considering all the constraints, including muon g-2 at 2\u03c3 level, and dark matter [3, 4] . When we give up uniform parameters at the grand unification (GUT) scale, the MSSM can satisfy all the constraints well, but there is a problem with fine-tuning [4] .", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "After the Higgs boson was discovered, it became necessary to ask whether there is a second Higgs-like particle. Searches at LEP, the Tevatron, and the LHC have excluded a lighter SM-like Higgs, while a lighter second Higgs with rates lower than the SM-like one could still be possible. Recently, the CMS collaboration presented their searches for low-mass new resonances decaying to two photons. For both the 8 TeV and 13 TeV dataset, a small excess around 95 GeV was hinted at, with approximately 2.8\u03c3 local (1.3\u03c3 global) significance for a hypothetical mass of 95.3 GeV in combined analysis [5] . This result has been interpreted or discussed in several papers [6] . The MSSM cannot predict such a lighter second Higgs together with a 125 GeV SM-like Higgs under other constraints like the muon g-2 and dark matter [4] .", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "The next-to-minimal supersymmetric Standard Model (NMSSM) has more freedom to predict a SMlike 125 GeV Higgs, under all the constraints and with low fine-tuning [4] . At the same time, it can also predict a lighter second Higgs with rates lower than the SM-like one [7, 8] . Since simple models are usually more favoured, the fully constrained NMSSM (cNMSSM) [9] [10] [11] and the semi-constrained NMSSM (scNMSSM) are also being studied [12, 13] . For the full cNMSSM, with all soft SUSY breaking terms unified at the GUT scale, including M Hu = M H d = M S = M 0 , there should be only four continuous parameters, the same as mSUGRA. While in many studies of the cNMSSM [9] [10] [11] , there is an additional parameter \u03bb, for a singlet scalar M S does not in fact need to be unified. Such an issue was also pointed out in Ref. [14] . In the 5-parameter and 4-parameter cNMSSM, the SM-like Higgs cannot get to 125 GeV under all the constraints including muon g-2 [9, 11] . The scNMSSM is also called the non-universal Higgs mass (NUHM) version of the NMSSM, for it allows the soft SUSY breaking terms in the Higgs sector to be different. In Ref. [9] , the parameter \u03bb is always less than 0.1, so the results in Higgs sector may not be much different from the NUHM version of MSSM, e.g., the 125 GeV SM-like Higgs is always the lightest Higgs. In Refs. [12, 13] , the muon g-2 constraint is set aside. In this paper, we consider all the constraints, including muon g-2, and also require a lighter Higgs with rates constrained by LEP, Tevatron, and LHC searches. For the dark matter relic density, we only apply the upper bound [8] , considering that there may be other sources of dark matter [15] . We focus on the muon g-2, its relation to model parameters, SUSY particle masses, and other constraints like the dark matter relic density. This paper is organized as follows. First, we briefly introduce the NMSSM and scNMSSM in Section 2. In Section 3, we discuss the constraints on the model, present our numerical results and have some discussion. Finally, we draw our conclusions in Section 4.", "cite_spans": [], "ref_spans": []}, {"section": "The NMSSM and scNMSSM", "text": "In the NMSSM, the Higgs sector consists of two complex doublet superfields\u0124 u and\u0124 d , and one complex singlet superfield\u015c. Then the superpotential of the NMSSM with Z 3 symmetry is given by [16] ", "cite_spans": [], "ref_spans": []}, {"section": "The NMSSM and scNMSSM", "text": "where W F is the superpotential of the MSSM without the \u00b5-term, which is the Yukawa couplings of\u0124 u and\u0124 d to the quark and lepton superfields [17] . At electroweak symmetry breaking, the Higgs fields\u0124 u ,\u0124 d and\u015c get their vacuum expectation values (VEVs) v u , v d and v s respectively, with tan\u03b2 \u2261 v u /v d . Then their scalar component fields can be written as", "cite_spans": [], "ref_spans": []}, {"section": "The NMSSM and scNMSSM", "text": "where H + i , \u03c6 i and \u03d5 i (i = u,d) represent the charged, neutral CP-even and neutral CP-odd component fields respectively. So the first term in W NMSSM generates an effective \u00b5-term, \u00b5 eff =\u03bbv s .", "cite_spans": [], "ref_spans": []}, {"section": "The NMSSM and scNMSSM", "text": "With the superpotential, we can get the so-called 'Fterm' of the Lagrangian [16] ,", "cite_spans": [], "ref_spans": []}, {"section": "The NMSSM and scNMSSM", "text": "where 12 =\u2212 21 =1 and 11 = 22 =0. With this rotation,", "cite_spans": [], "ref_spans": []}, {"section": "The NMSSM and scNMSSM", "text": "where G + and G 0 are Goldstone bosons eaten by W + and Z respectively, and", "cite_spans": [], "ref_spans": []}, {"section": "The NMSSM and scNMSSM", "text": "GeV is the VEV of the Higgs field in the SM. Thus the field H 2 is the SM Higgs field.", "cite_spans": [], "ref_spans": []}, {"section": "The NMSSM and scNMSSM", "text": "In the CP-conserving NMSSM, the field S 1 , S 2 and S 3 mix to form the three physical CP-even Higgs bosons h i (i = 1,2,3), and the fields P 1 and P 2 mix to form the two physical CP-odd Higgs bosons a i (i=1,2).", "cite_spans": [], "ref_spans": []}, {"section": "The NMSSM and scNMSSM", "text": "In the basis {S 1 ,S 2 ,S 3 }, the elements of the corresponding mass matrix are given by [18] :", "cite_spans": [], "ref_spans": []}, {"section": "The NMSSM and scNMSSM", "text": "where M A is the mass scale of the doublet field H 1 , and it is given by", "cite_spans": [], "ref_spans": []}, {"section": "The NMSSM and scNMSSM", "text": "The mass matrix in Eq.(12) can be diagonalized by an orthogonal matrix [S ij ] . We can get the mass eigenstates of CP-even states h i as", "cite_spans": [], "ref_spans": []}, {"section": "The NMSSM and scNMSSM", "text": "where S ij are the coefficients of S j in the mass eigenstate ", "cite_spans": [], "ref_spans": []}, {"section": "The NMSSM and scNMSSM", "text": "We assume that the lightest neutralino is the lightest SUSY particle (LSP) and makes up dark matter.", "cite_spans": [], "ref_spans": []}, {"section": "The NMSSM and scNMSSM", "text": "In the basis {B,W 0 ,H u ,H d ,S }, the tree-level neutralino mass matrix takes the form [16, 19] ", "cite_spans": [], "ref_spans": []}, {"section": "The NMSSM and scNMSSM", "text": "Chargino sector: The charged higgsinosH", "cite_spans": [], "ref_spans": []}, {"section": "The NMSSM and scNMSSM", "text": "(with mass scale around \u00b5 eff ) and the charged gauginoW \u00b1 (with mass scale M 2 ) can also mix respectively, forming two couples of physical charginos \u03c7", "cite_spans": [], "ref_spans": []}, {"section": "The NMSSM and scNMSSM", "text": "Gluino sector: As a gauge boson, each gluon also has a same-color superpartner, which is also sorted into gauginos, and whose mass is close to its soft mass M 3 .", "cite_spans": [], "ref_spans": []}, {"section": "The NMSSM and scNMSSM", "text": "Squark and slepton sector: Each quark or charged lepton has two chiral-eigenstate superpartners f L andf R , which mix to form two mass-eigenstate superpartners. The mass difference between the two mass eigenstates is proportional to the corresponding trilinear couplings A f . Since the Yukawa couplings of the first two generations of fermions are very weak, the two superpartners of each fermion can be seen as mass-degenerate. In the NMSSM, with only the left-hand state, each neutrino has only one superpartner, whose mass is equal or close to its soft mass ml.", "cite_spans": [], "ref_spans": []}, {"section": "The NMSSM and scNMSSM", "text": "scNMSSM:", "cite_spans": [], "ref_spans": []}, {"section": "The NMSSM and scNMSSM", "text": "In the fully constrained NMSSM (cNMSSM), like the fully constrained MSSM (cMSSM/mSUGRA), the soft SUSY breaking terms in the Higgs sector are assumed to be unified with those of the squark and slepton sectors at the GUT scale. However, in the semi-constrained NMSSM (scNMSSM), we allow the soft SUSY breaking terms in the Higgs sector to be different. So, in the scNMSSM at the GUT scale, the universal parameters are [12, 13] :", "cite_spans": [], "ref_spans": []}, {"section": "The NMSSM and scNMSSM", "text": "The Higgs soft masses", "cite_spans": [], "ref_spans": []}, {"section": "The NMSSM and scNMSSM", "text": "and M", "cite_spans": [], "ref_spans": []}, {"section": "2", "text": "S are allowed to be different from M 2 0 , and the trilinear couplings A \u03bb , A \u03ba can be different from A 0 . Since we have three minimisation equations for the VEVs [20] , the three Higgs soft masses can be determined with other parameters. Hence, in the scNMSSM we choose the complete parameter sector as:", "cite_spans": [], "ref_spans": []}, {"section": "2", "text": "Parameters running in scNMSSM: Parameters at the GUT scale should run via renormalization group equations (RGEs) to SUSY-breaking scale M SUSY . The GUT scale is usually about 10", "cite_spans": [], "ref_spans": []}, {"section": "2", "text": "16 GeV, and M SUSY is usually chosen to be at 10 3 GeV scale. Then, the approximate running of some parameters can be written as [21, 22] :", "cite_spans": [], "ref_spans": []}, {"section": "2", "text": "3 Numerical results and discussion", "cite_spans": [], "ref_spans": []}, {"section": "2", "text": "In this work, we use the program NMSPEC MCMC [10] in NMSSMTools 5.2.0 [21] to scan the parameter space of the scNMSSM by considering various experimental constraints. We chose the parameter space to scan as follows: 0.3<\u03bb<0.7, 0<\u03ba<0.7, 1<tan\u03b2 <30,", "cite_spans": [], "ref_spans": []}, {"section": "2", "text": "where we have the following considerations in our choice of parameter space: 1) Small \u00b5 eff and M 0 , to get large muon g-2 and also low fine tuning.", "cite_spans": [], "ref_spans": []}, {"section": "2", "text": "2) Large \u03bb (>0.3) to make our results much different from those of the MSSM in Higgs physics, since there is only one term different in the superpotential between NMSSM and MSSM: \u03bb\u015c\u0124 u\u0124d in Eq. (1), for the doubletsinglet mixing.", "cite_spans": [], "ref_spans": []}, {"section": "2", "text": "3) Smaller tan\u03b2 (< 30) than in MSSM, as in the NMSSM scenario of h 2 as the 125 GeV SM-like Higgs.", "cite_spans": [], "ref_spans": []}, {"section": "2", "text": "In this scenario, we should have |M 23 | |M 33 | < M 22 in the Higgs mass matrix Eq. (12), thus", "cite_spans": [], "ref_spans": []}, {"section": "2", "text": "A \u03bb at the SUSY breaking scale should not be too large, since we have another term of doublet-singlet mixing \u03bbA \u03bb SH u .H d in the soft breaking terms in Eq. (6).", "cite_spans": [], "ref_spans": []}, {"section": "2", "text": "In the scan, we required the surviving samples to satisfy the following constraints:", "cite_spans": [], "ref_spans": []}, {"section": "2", "text": "1) Theoretical constraints of vacuum stability, and no Landau pole in running \u03bb, \u03ba, and Yukawa couplings below M GUT [10, 21] .", "cite_spans": [], "ref_spans": []}, {"section": "2", "text": "2) The second light scalar CP-even Higgs, h 2 , as the SM-like Higgs boson with mass around 125 GeV (e.g., 123 < m h 2 < 127 GeV), with its production rates fitting LHC data globally. For the global fit we used a method like that in our former works [7, 23] , with the Higgs data updated with Fig. 3 from Ref. [24] and the left part of Fig. 5 from Ref. [25] . There are 20 experimental data sets in total, so we require \u03c7 2 \u2264 31.4, which means each surviving sample fits 20 experimental data sets at 95% confidence level.", "cite_spans": [{"start": 310, "end": 314, "text": "[24]", "ref_id": "BIBREF58"}], "ref_spans": [{"start": 293, "end": 299, "text": "Fig. 3", "ref_id": "FIGREF6"}]}, {"section": "2", "text": "3) Constraints of searches for low mass and high mass resonances at LEP, Tevatron, and LHC. These constrain the production rates of light and heavy Higgs. We implemented these constraints by the package HiggsBounds-5.1.1beta [26] . We also required the mass of the light Higgs to be 65\u223c122 GeV, since we checked that below 65 GeV its diphoton rate is always very small because of the strong constraints at LEP. Also, when the light Higgs is lighter than 62 GeV, exotic decays of the 125 GeV Higgs will be generated, which we have discussed in detail in our former paper [7] . 4) Constraints of searches for squarks of the first two generations and gluinos at Run I of the LHC 1) . We follow the result in Ref. [13] :", "cite_spans": [], "ref_spans": []}, {"section": "2", "text": "We use the constraints of mass bounds of chargino and 1) For the stop mass, we checked that our result satisfies the simulation result of mt 1 500 GeV in Ref. [27] . For 13 TeV search results at the LHC, all these bounds may be a little higher, but we checked that with stricter constraints, e.g., mq 1,2 >1200 GeV, mg >1800 GeV, and mt 1 >600 GeV, our results, such as muon g-2, do not change much. We will check the exact bounds of these sparticle masses in this model in our future work by doing detailed simulations.", "cite_spans": [], "ref_spans": []}, {"section": "2", "text": "sleptons from LEP. We also checked our surviving samples with SModelS-v1. . (23) 6) Constraints from dark matter relic density from WMAP/Planck [38, 39] , the spin-independent (SI) results of direct searches for dark matter at LUX 2017 [40] , PandaX-II 2017 [41] , and XENON1T 2018 [42] , and the spin-dependent (SD) results of direct searches for dark matter by PICO, LUX, and PandaX-II in 2016 [43] . We require the lightest neutralino \u03c7 0 1 to be the dark matter candidate. For the relic density, we only apply the upper bound, e.g., 0 \u2126 0.131, considering that there may be other sources of dark matter [8, 21] .", "cite_spans": [], "ref_spans": []}, {"section": "2", "text": "7) The constraint of the muon anomalous magnetic moment (muon g-2) at 2\u03c3 level including the theoretical error. For the experimental data and SM calculation without boson contributions, we use [44, 45] :", "cite_spans": [], "ref_spans": []}, {"section": "2", "text": "We calculate the SUSY contribution \u03b4a \u00b5 including SMlike bosons, and require it to satisfy \u03b4a \u00b5 at 2\u03c3 level. We also include our error in the SUSY \u03b4a \u00b5 calculation, which is about 1.5\u00d710 \u221210 . 8) The theoretical constraint of low fine tuning from the GUT scale, which is defined by [46] :", "cite_spans": [], "ref_spans": []}, {"section": "2", "text": "where each p GUT i denotes a parameter at the GUT scale:", "cite_spans": [], "ref_spans": []}, {"section": "2", "text": "where g = g 2 1 +g 2 2 /2, y t is the Yukawa coupling of the top quark, and M GUT is the GUT scale. We require F T <1000 for each surviving sample.", "cite_spans": [], "ref_spans": []}, {"section": "2", "text": "We take a modified multi-path Markov Chain Monte Carlo (MCMC) scan in parameter space, where we do not use likelihood functions. Instead we require each good point to satisfy all our experimental constraints at 2\u03c3 level, or below the upper limits of 95% (for the DM direct detection, it is 90% following data released by the collaborations). Each time we get a good point surviving all our constraints, we save the point, and search for the next good point around the former one. Since we use a Gaussian random number and set a not-small standard step, the later good point can be much different from the former one, which ensures we get as much as possible of the surviving parameter space available. In total, we get nearly 10 6 surviving samples. As some samples may be very similar to each other, we remove most repetitive samples by calculating the distance between them. First, we normalize all samples by using min-max normalization (MMN), which is just a linear transformation of the original data. We normalize each sample to 9 dimensions, as there are 9 free parameters x i in the scanx", "cite_spans": [], "ref_spans": []}, {"section": "2", "text": "After this linear transformation, all of these 9 new parametersx i will fall in [0,1]. Then we calculate the Euclidean distance between all these surviving samples. If the distance between two points is too small, we just select one of them randomly. For each panel in the following figures, to make them look good and be of small size, we take a MMN similarly but in 3 dimensions, which are the horizontal, vertical and color-indicated quantities.", "cite_spans": [], "ref_spans": []}, {"section": "2", "text": "In Fig. 1 , we project the surviving samples on the \u03bb\u2212tan\u03b2, A 0 \u2212M 1/2 and A 0 \u2212M 0 planes. We show fine tuning from the GUT scale (left and middle panels) and the lighter stop mass mt 1 (right panel) by different colors. We can see from the left and middle panels that fine tuning F T can be as low as around 150 at most. In the left panel, we can also see that low-fine-tuning samples are mostly located in the tan\u03b2 15, or 15 tan\u03b2 25 but \u03bb 0.4 regions. This is because, according to the minimisation equation of v u [46] ,", "cite_spans": [], "ref_spans": [{"start": 3, "end": 9, "text": "Fig. 1", "ref_id": "FIGREF1"}]}, {"section": "2", "text": "where", "cite_spans": [], "ref_spans": []}, {"section": "2", "text": "is a function of \u03bb, tan\u03b2, etc. We checked that for most of the surviving samples, the largest fine tuning comes from parameter M Hu , and that of the rest comes from parameter \u03bb. According to RGE running, |M 2 Hu | is related to M 0 , M 1/2 , andA 0 , thus we can see from the middle panel that samples with small M 1/2 and A 0 usually 2) This includes many constraints on stopt 1 [30] [31] [32] [33] , chargino \u03c7 \u00b1 1 and neutralino \u03c7 0 2 [34, 35] . We checked that it cannot give the surviving samples further strong constraints, because for the surviving samples: \u03c7 have low fine tuning. From the middle and right panels, we can see that these surviving regions are not symmetric around A 0 = 0, where negative A 0 is more favored. This is because at SUSY-breaking scale we have M ", "cite_spans": [], "ref_spans": []}, {"section": "2", "text": "according to the RGEs. We have M 1/2 700 GeV, mainly because we require mg 1400 GeV, while at SUSYbreaking scale M 3 \u2248 2.4M 1/2 . Later we can see from Fig. 4 that M 1/2 has upper bounds of about 1500 GeV mainly because of the constraint of muon g-2. Finally, in the right panel, we can see the mass of the stop can be as low as about 500 GeV. We will continue studying these light-stop cases in our future work, by doing detailed simulations based on the search results at the 13 TeV LHC.", "cite_spans": [], "ref_spans": [{"start": 152, "end": 158, "text": "Fig. 4", "ref_id": "FIGREF7"}]}, {"section": "2", "text": "In Fig. 2 , we project the surviving samples on the \u03bb versus \u03ba (left), and R(pp\u2192h 1 \u2192\u03b3\u03b3) versus m h 1 (middle and right) planes respectively. We show the singlet component in h 1 (left and middle panels) and the reduced squared coupling |C h 1 \u03b3\u03b3 /SM | 2 (right panel) by different colors. We can see from the left and middle panels that most of the samples have |S 13 | 2 approaching 1, which means they are highly singlet-dominated. The singlet component in h 1 is 0.5 at least, since h 2 is the SM-like Higgs. It can be sorted into two regions in the \u03bb\u2212\u03ba plane: ", "cite_spans": [], "ref_spans": [{"start": 3, "end": 9, "text": "Fig. 2", "ref_id": "FIGREF5"}]}, {"section": "2", "text": "The samples of |S 13 | 2 0.9 are mainly in the latter region, because in the former region, with small \u03ba/\u03bb we will have |M . This is because for the former samples, we have light higgsino-like chargino (see Fig. 4 ) and moderate \u03bb, thus large h 1 \u03b3\u03b3 loop-reduced coupling and large h 1 \u2192 \u03b3\u03b3 branching ratio. For the latter samples, the h 1 reduced coupling to \u03b3\u03b3 can be smaller than to other SM particles like bb, thus the h 1 \u2192\u03b3\u03b3 branching ratio cannot be large. We checked that the reduced h 1 \u03b3\u03b3 coupling can be two times that of the doublet component in h 1 (1\u2212|S 13 | 2 ) for the former, while it can only be about 0.5 for the latter. According to the latest result of the search for low-mass resonances by CMS, the suspected resonance is at around 95 GeV, with a diphoton rate of about 0.5\u00b10. 2 [5] . We can see that we have some samples providing such a signal. In Table 1 , we provide the detailed information of four such samples for further study. The search results for lowmass resonances by ATLAS at Run I of the LHC [47] are also shown on the middle and right panels. We can see that the upper limit from ATLAS is higher than that from CMS, and further results from ATLAS are needed to cross check the suspected excess.", "cite_spans": [], "ref_spans": [{"start": 207, "end": 213, "text": "Fig. 4", "ref_id": "FIGREF7"}]}, {"section": "2", "text": "In Fig. 3 we show the properties of dark matter in the scNMSSM. In this work, we require the lightest neutralino \u03c7 Table 1 . Four representative samples predicting the diphoton rate hinted at by CMS data, where R h 1 \u2192\u03b3\u03b3 is the same as R(gg\u2192h1 \u2192\u03b3\u03b3) elsewhere in this paper. a ratio of \u2126/\u2126 0 , with the right relic density \u2126 0 h 2 =0.1187 [38, 39] . Hence we adjust the SI scattering cross section of each sample by tuning the corresponding ratio \u2126/\u2126 0 . Since the results of searches for gluinos at the LHC require M 3 mg 1400 GeV, and the universal gaugino mass at GUT scale requires", "cite_spans": [], "ref_spans": [{"start": 3, "end": 9, "text": "Fig. 3", "ref_id": "FIGREF6"}]}, {"section": "2", "text": "while \u00b5 eff <200 GeV and \u03bav S =\u00b5 eff \u00b7\u03ba/\u03bb, according to the tree-level neutralino mass matrix Eq. (16), we can infer that the main components of \u03c7 ", "cite_spans": [], "ref_spans": []}, {"section": "2", "text": "We can categorize the surviving samples into three classes, which can be called the h/Z funnel, focus point, and A 1 funnel scenarios respectively, as in Ref. [48] . 1) From the middle and right panels of Fig. 3 , we can see that in the h/Z funnel scenario, its mass m \u03c7 0 1 m h 2 /2, and its relic density is only about 1/10 of the WMAP data at most. For some samples the SI scattering cross section before adjustment with \u2126/\u2126 0 are above the exclusion limit by XENON1T 2018, LUX 2017, and PandaX-II 2017. Combining with the left panel, we can see that, in the h/Z funnel scenario, the larger \u03bb the smaller its relic density. This is because a pair of singlet-dominated \u03c7 2) In the focus point scenario, when m \u03c7 0 1 is slightly larger than m W , the main annihilation mechanism is \u03c7 . The relic density cannot be even larger, because it is very hard for a higgsino-like \u03c7 0 1 to unlimitedly approximate to m W , and also the results for SI scattering cross section in 2018 give even stronger constraints on this scenario.", "cite_spans": [], "ref_spans": [{"start": 205, "end": 211, "text": "Fig. 3", "ref_id": "FIGREF6"}]}, {"section": "2", "text": "3) For the other samples, including both singletdominated and higgsino-dominated \u03c7 0 1 cases, the main annihilation mechanism is the A 1 funnel, where the light CP-odd scalar A 1 is usually singlet-dominated ( 90%), but has a \u03d5 d composition of several percent. Thus there can be a large A 1 \u03c7 0 1 \u03c7 0 1 coupling for large \u03bb or \u03ba, and a considerable A 1 bb coupling for the \u03d5 d composition and large tan\u03b2. In this scenario, a pair of \u03c7 0 1 mainly annihilates through A 1 , and bb and \u03c4 + \u03c4 \u2212 are produced. We also consider the spin-dependent (SD) results of direct detection for dark matter [43] . However, we checked that the current upper exclusion limits of SD results are much higher than the SI ones, and they impose no further constraints on our surviving samples. So in this work, we do not discuss the SD results further.", "cite_spans": [], "ref_spans": []}, {"section": "2", "text": "From the left panel of Fig. 4 , we can interpret muon g-2 (\u03b4a \u00b5 ) at 1\u03c3 level, and the main contribution comes from the loop of chargino \u03c7 Fig. 4 we can see that the chargino loop can contribute much because both the chargino \u03c7 0 1 and muon sneutrino\u03bd \u00b5 can be very light. The lighter they are, the larger muon g-2 is. From the right panel, the sneutrino mass is mainly determined by M 0 and M 1/2 . In fact, the relation is roughly", "cite_spans": [], "ref_spans": [{"start": 23, "end": 29, "text": "Fig. 4", "ref_id": "FIGREF7"}, {"start": 139, "end": 145, "text": "Fig. 4", "ref_id": "FIGREF7"}]}, {"section": "2", "text": "we can infer and have checked that, with higher gluino mass mg \u22482 TeV, the sneutrino mass can still be low as about 400 GeV, and thus muon g-2 can still satisfy the data at 1\u03c3 level.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "In this work, we have checked the status of the scN-MSSM under current constraints, such as 125 GeV Higgs data, searches for low and high mass resonances, searches for SUSY particles at the LHC, B physics, muon g-2, dark matter relic density by WMAP/Planck, and direct searches for dark matter by LUX 2017, PandaX-II 2017, and XENON1T 2018. First, we scanned the parameter space of the scNMSSM in 9 dimensions with the MCMC method. For each valid sample, we calculated its various physical quantities and required them to satisfy corresponding constraints. For the surviving samples, we analyzed fine tuning from the GUT scale, SUSY particle masses, the light scalar and its diphoton signal, dark matter relic density and direct detection, muon g-2, and their favoured parameter space. Finally, we come to the following conclusions regarding the scNMSSM: 1) For low fine tuning samples, small \u00b5 eff , M 0 , M 1/2 , A 0 , are more favored, and the lighter stop mass can be as low as about 500 GeV, which can be further checked in future works with search results at the 13 TeV LHC.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "2) For light higgsino-like charginos and moderate \u03bb, the highly-singlet-dominated light scalar can have a considerable diphoton rate, satisfying the latest results of the search for low-mass resonances by CMS.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "3) For high gluino bounds at the LHC and the condition of universal gauginos at the GUT scale, the lightest neutralino can only be singlino-dominated or higgsino- 4) For light muon sneutrino and light higgsino-like charginos, we can get large muon g-2, while the contribution of neutralinos cannot be large because bino-like and wino-like neutralinos are heavy.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "5) The model can satisfy all the above constraints, although it is not easy for the lightest neutralino, as the only dark matter candidate, to get enough relic density.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "Considering the disadvantage of the scNMSSM, one can try three main kinds of ways to raise the relic density: 1) Considering other source of relic density, e.g., the effects of modifications of the expansion rate and of the entropy content in the early universe.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "2) Changing the LSP to another sparticle, such as bino-like neutralinos in the non-universal gaugino cases, or sneutrinos in the right-handed neutrinos extended case.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "3) Reducing \u03bb and \u03ba in the h/Z funnel scenario, although this way may lose a light Higgs.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF39": {"title": "AIP Conf. Proc", "authors": [{"first": "U", "middle": [], "last": "Ellwanger", "suffix": ""}], "year": 2009, "venue": "", "link": null}, "BIBREF58": {"title": "The ATLAS collaboration", "authors": [], "year": "", "venue": "", "link": null}}, "ref_entries": {"FIGREF0": {"text": "decay to \u03c7 0 1 and a pair of quarks, each channel with about 10-20 percent; most charginos and neutralinos are lighter thant 1 . Thust 1 can have many decay channels, where even the dominant channel, e.g.,t 1 \u2192b\u03c7 + 1 , cannot be over half.", "type": "figure"}, "FIGREF1": {"text": "Fig. 1. (color online) Surviving samples in the tan\u03b2 versus \u03bb (left), M 1/2 versus A0 (middle), and M0 versus A0 (right) planes. Colors in the left and middle panels indicate fine tuning from GUT scale, while colors in the right panel indicate the mass of the lighter stopt1.", "type": "figure"}, "FIGREF3": {"text": "\u03bb 1.5\u03ba region,where h 1 are highly\u2212singlet\u2212dominated (|S 13 |", "type": "figure"}, "FIGREF4": {"text": ", which will result in very little mixing be- tween singlet and SM-like doublet, thus very little singlet component in h 2 and very little doublet component in h 1 . From the middle panel, we find that doublet-singlet mixing can only be considerable (|S 13 | 2 0.9) when m h 1 90 GeV. Combining the middle and right panels we can also see that some highly-singlet-dominated h 1 samples (|S 13 | 2 0.8) can provide a considerable dipho- ton rate R(pp\u2192h 1 \u2192\u03b3\u03b3), while the rates are not so large for smaller-|S 13 | 2 samples (0.5 |S 13 | 2 0.8)", "type": "figure"}, "FIGREF5": {"text": "Fig. 2. (color online) Surviving samples in the \u03ba versus \u03bb (left), and diphoton production rate of the lightest Higgs h1 versus its mass m h 1 (middle and right) planes. In the middle and right panels, the black dotted and dashed line indicates the observed exclusion limits (95% CL) from ATLAS [47] and CMS [5] on R(pp\u2192h1 \u2192\u03b3\u03b3) respectively. Colors in the left and middle panels indicate the singlet component in h1, while colors in the right panel indicate the squared effective coupling of h1 with two photons, reduced by its corresponding SM value, i.e. |C h 1 \u03b3\u03b3 /SM | 2 .", "type": "figure"}, "FIGREF6": {"text": "Fig. 3. Surviving samples in the \u03ba versus \u03bb (left), dark matter relic density \u2126h 2 versus the lightest neutralino (LSP) mass m \u03c7 0 1 (middle), and spin-independent dark matter and nucleon scattering cross section (\u03c3SI\u00d7\u2126/\u21260) versus LSP mass m \u03c7 0 1 (right) planes. In the middle and right panels, the black dotted, dot-dashed, and dashed lines indicate the observed exclusion limits (90% CL) on \u03c3SI\u00d7\u2126/\u21260 released by LUX 2017, PandaX-II 2017 and XENON1T 2018, respectively. Colors in the left and middle panels indicate the singlino component in \u03c7 0 1 , while colors in the right panel indicate the ratio of LSP relic density in the observed value (\u2126/\u21260), where \u21260h 2 =0.1187 [38, 39].", "type": "figure"}, "FIGREF7": {"text": "Fig. 4. (color online) Surviving samples in the neutralino-smuon contribution \u03b4n versus chargino-sneutrino contribution \u03b4c to muon g-2 (left), light chargino mass m \u03c7 \u00b1 1 versus muon sneutrino mass m\u03bd \u00b5 (middle), and m\u03bd \u00b5 versus parameter M0 (right) planes. Colors in the left and middle panels indicate muon g-2 (\u03b4a\u00b5), while colors in the right panel indicate parameter M 1/2 .", "type": "figure"}, "FIGREF8": {"text": "can only be the singlino and higgsino. From the left panel of Fig.3, we can see clearly that when \u03bb 1.5\u03ba: |N 15 |", "type": "figure"}, "FIGREF10": {"text": "\u2212 though the t or u channel chargino, or s channel Z or scalars. A peak of relic density ap- pears around m \u03c7 0 1 \u2248 m W in the middle panel of Fig. 3, because the relic density is inversely proportional", "type": "figure"}, "FIGREF11": {"text": "smuon\u03bc i cannot contribute as much as in the MSSM, because \u03c7 0 1 is singlino-dominated or higgsino-dominated, neither of which has a strong enough coupling with the muon and its partner. From the middle panel of", "type": "figure"}, "FIGREF12": {"text": ", and annihilation scenarios are mainly h/Z funnel and focus point respectively. The results for SI scattering cross section in 2017/2018 give strong constraints, especially for the focus point scenario.", "type": "figure"}, "TABREF0": {"text": "and we assume that m h 1 <m h 2 <m h 3 . In this work, we regard h 2 as the 125 GeV SM-like Higgs boson, thus |S 23 |", "type": "table"}, "TABREF1": {"text": "1.1 [28] (including database v1.", "type": "table"}, "TABREF3": {"text": "since |S 22 | |S 23 | |S 21 |, |N 15 | |N 13,14 | |N 11,12 |, and \u03bb>\u03ba. Besides, the SI scattering of \u03c7 0 1 with SM particles is also mainly mediated by the SM-like h 2 . Thus, we can infer that, with smaller \u03bb, the relic density of \u03c7 0 1 can be larger, and the SI scattering cross section can be smaller. Of course, to have \u03c7 0 1 singlino-dominated, we also need even smaller \u03ba.", "type": "table"}}}
{"paper_id": "118867819", "_pdf_hash": "364485865df4db344edfcf728e1d5dae8b54c869", "abstract": [], "body_text": [], "bib_entries": {"BIBREF1": {"title": "Introduction to Modern Cryptography", "authors": [{"first": "J", "middle": ["L"], "last": "Katz", "suffix": ""}, {"first": "Y", "middle": [], "last": "", "suffix": ""}], "year": 2007, "venue": "", "link": null}, "BIBREF2": {"title": "New directions in cryptography", "authors": [{"first": "W", "middle": ["H"], "last": "Diffie", "suffix": ""}, {"first": "M", "middle": [], "last": "", "suffix": ""}], "year": 1976, "venue": "IEEE Transactions on Information Theory", "link": null}, "BIBREF4": {"title": "The EPR paradox, Bell's inequality, and the question of locality", "authors": [{"first": "G", "middle": ["D"], "last": "Blaylock", "suffix": ""}], "year": 2010, "venue": "American Journal of PHysics", "link": "118520639"}, "BIBREF5": {"title": "Public-key cryptography standards (PKCS)# 1: RSA cryptography specifications version 2.1", "authors": [{"first": "J", "middle": ["A K"], "last": "Jonsson", "suffix": ""}, {"first": "Burt", "middle": [], "last": "", "suffix": ""}], "year": 2003, "venue": "", "link": "30953293"}, "BIBREF6": {"title": "Authentication and Authenticated Key Exchanges", "authors": [{"first": "W", "middle": ["V O"], "last": "Diffie", "suffix": ""}, {"first": "Paul", "middle": ["C"], "last": "Wiener", "suffix": ""}, {"first": "Michael", "middle": ["J"], "last": "", "suffix": ""}], "year": 1992, "venue": "Designs, Codes and Cryptography", "link": "7356608"}, "BIBREF7": {"title": "Provably secure password-authenticated key exchange using DiffieHellman", "authors": [{"first": "V", "middle": ["A M"], "last": "Boyko", "suffix": ""}, {"first": "Philip", "middle": [], "last": "Patel", "suffix": ""}, {"first": "Sarvar", "middle": [], "last": "", "suffix": ""}], "year": 2000, "venue": "", "link": "14890191"}, "BIBREF9": {"title": "Diffie-Hellman key agreement method", "authors": [{"first": "E", "middle": [], "last": "Rescorla", "suffix": ""}], "year": 1999, "venue": "", "link": "40014368"}, "BIBREF10": {"title": "Diffie-Hellman Key Exchange -A Non-Mathematician's Explanation", "authors": [{"first": "K", "middle": [], "last": "Palmgren", "suffix": ""}], "year": 2006, "venue": "ISSA J", "link": null}, "BIBREF11": {"title": "Protecting data for the long term with forward secrecy", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF12": {"title": "Forward-secure-survey An overview", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF14": {"title": "Can quantum-mechanical description of physical reality be considered complete?", "authors": [{"first": "B", "middle": ["P A"], "last": "Einstein", "suffix": ""}, {"first": "N", "middle": [], "last": "Rosen", "suffix": ""}], "year": 1935, "venue": "Phys. Rev", "link": "124342155"}, "BIBREF15": {"title": "Nonlocality for two particles without inequalities for almost all entangled states", "authors": [{"first": "B", "middle": ["L"], "last": "Hardy", "suffix": ""}], "year": 1993, "venue": "Phys. Rev. Lett", "link": "11839894"}, "BIBREF16": {"title": "On the Einstein-Poldolsky-Rosen paradox", "authors": [{"first": "J", "middle": ["C"], "last": "Bell", "suffix": ""}], "year": 1964, "venue": "Physics", "link": null}}, "ref_entries": {}}
{"paper_id": "118869358", "_pdf_hash": "b8c8cdc26f8ebfa3e7751f67559d71331bd36a66", "abstract": [{"section": "Abstract", "text": "We investigate the approximate quantum state sharing protocol based on random unitary channels, which is secure against any exterior or interior attackers in principle. Although the protocol leaks small information for a security parameter \u03b5, the scheme still preserves its information-theoretic secrecy, and reduces some pre-shared classical secret keys for a private quantum channel between a sender and two receivers. The approximate private quantum channels constructed via random unitary channels play a crucial role in the proposed quantum state sharing protocol.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "I. INTRODUCTION", "text": "Quantum physics allows us a perfect randomness, so most of all quantum information-theoretic primitives try to offer an unconditional security under the randomness. For examples, quantum key distribution protocols such as BB84 [1] and B92 [2] highly depend on a random measurements for given classified non-orthogonal quantum states.", "cite_spans": [{"start": 227, "end": 230, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 239, "end": 242, "text": "[2]", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "Instead of the random measurement on non-orthogonal states, we can consider a direct randomization of quantum states through a quantum channel. This randomizing procedures are efficiently accomplished via the private quantum channels (PQC) or quantum one-time pads [3] . In the paper we are interest to some schemes for approximate encryptions (no perfect) and we make an attempt to reducing some classical communication resources. We would like to call the randomizing procedures or maps as random unitary channels (RUC) in terms of quantum channels. There are several methods for the approximate randomizing quantum states, for examples, [4, 5, 8] : We here adapt the procedure of Hayden et al. [4] .", "cite_spans": [{"start": 265, "end": 268, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 640, "end": 643, "text": "[4,", "ref_id": "BIBREF3"}, {"start": 644, "end": 646, "text": "5,", "ref_id": "BIBREF4"}, {"start": 647, "end": 649, "text": "8]", "ref_id": "BIBREF7"}, {"start": 697, "end": 700, "text": "[4]", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "Many applications of RUC in quantum protocols (See e.g., [4, 6, 7] .) are started from the approximate version of PQC. Here we will propose new approximate quantum state sharing (AQSS) scheme, which uses two approximate PQCs (APQC) and reduces the classical pre-shared secrets about one-half as compared with a perfect protocol. Actually our protocol could be including the (well-known) quantum secret sharing protocols [9, 10] , because a quantum state itself is able to operate special quantum tasks, though those are impossible in the classical power. Imagine that if there is a quantum computer only activated under a bipartite quantum state (or quantum key), then our AQSS protocol will give a efficient and secure solution for the quantum key. These approximate quantum state sharing protocols may offer us more opportunities as compared with the quantum secret sharing.", "cite_spans": [{"start": 57, "end": 60, "text": "[4,", "ref_id": "BIBREF3"}, {"start": 61, "end": 63, "text": "6,", "ref_id": "BIBREF5"}, {"start": 64, "end": 66, "text": "7]", "ref_id": "BIBREF6"}, {"start": 420, "end": 423, "text": "[9,", "ref_id": "BIBREF8"}, {"start": 424, "end": 427, "text": "10]", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "Let's take account of the pre-shared secrets for the approximate quantum state sharing protocols under RUC-based PQC roughly. Assume that a sender Charlie prepares a quantum state \u03d5 AB (two-qudit) and transmits the state through two independent RUCs, then two distant agents Alice and Bob will receive some output state of including high entropy. For the state \u03d5 AB the perfect randomization protocol will require exactly the amount of 4 log d-unitary matrices (Pauli matrices). On the other hand, the construction of Hayden et al. [4] for our AQSS scheme implies that only 2 log d + o(log d)-unitaries sufficient. In other words, the perfect quantum state sharing protocol needs to 2l bits of pre-shared secret information, while the AQSS protocol demands about l bits of information. Note that the works in [5, 8] will give a similar result for l bits bound.", "cite_spans": [{"start": 532, "end": 535, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 809, "end": 812, "text": "[5,", "ref_id": "BIBREF4"}, {"start": 813, "end": 815, "text": "8]", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "We will prove the information-theoretic security of the AQSS scheme in two kinds of eavesdropping: an interior and exterior attackers. The proof of having higher entropy condition for the exterior attacks is not easy fact, so we split the input state \u03d5 AB to separable and entangled cases. As a result, the von Neumann entropy in both cases can be chosen sufficiently larger, and a leakage information will be arbitrarily small. Finally the authors show that our bipartite AQSS scheme naturally can be generalized to an one-sender and multiparty-receivers schemes.", "cite_spans": [], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "In section II we introduce the definition of random unitary channels, and briefly mention about special property known as the destruction of quantum states on a product random unitary channel. We present our AQSS protocol based on two approximate PQCs in section III, and investigate the security of AQSS of considering two attacks: an exterior and interior strategies. we finally conclude our results in section IV. ", "cite_spans": [], "ref_spans": []}, {"section": "II. SOME PROPERTIES OF RANDOM UNITARY CHANNELS", "text": "Now let us define the random unitary channel, and then construct an approximate private quantum channels. For all density matrices \u03d5 \u2208 B(C d ), a completely positive trace-preserving map N :", "cite_spans": [], "ref_spans": []}, {"section": "II. SOME PROPERTIES OF RANDOM UNITARY CHANNELS", "text": "where the trace norm is defined by", "cite_spans": [], "ref_spans": []}, {"section": "II. SOME PROPERTIES OF RANDOM UNITARY CHANNELS", "text": "This definition directly induces the notion of random unitary channels. That is, for every \u03d5, a quantum channel N :", "cite_spans": [], "ref_spans": []}, {"section": "II. SOME PROPERTIES OF RANDOM UNITARY CHANNELS", "text": "is \u03b5-randomizing, where the unitary operators U i \u2208 U(d), and the probability p i 's are all positives with i p i = 1.", "cite_spans": [], "ref_spans": []}, {"section": "II. SOME PROPERTIES OF RANDOM UNITARY CHANNELS", "text": "(The notation B(C d ) denotes the set of bounded linear operators from C d to itself and", "cite_spans": [], "ref_spans": []}, {"section": "II. SOME PROPERTIES OF RANDOM UNITARY CHANNELS", "text": "Note that the parameter n is the number of Kraus operation elements for RUC, so it corresponds to the dimension of arbitrary environment.", "cite_spans": [], "ref_spans": []}, {"section": "II. SOME PROPERTIES OF RANDOM UNITARY CHANNELS", "text": "For the approximate constructions of RUC, it was known that for all \u03b5 > 0 there exist random unitary channels in sufficiently larger dimension d, such that n can be taken to be O(d log d/\u03b5 2 ) in [4] and O(d/\u03b5 2 ) in [12] where U i 's are chosen randomly according to the Haar measure. We here fix the number n of having exactly n = 150d \u03b5 2 , the Theorem 1 in [12] .", "cite_spans": [{"start": 196, "end": 199, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 217, "end": 221, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 361, "end": 365, "text": "[12]", "ref_id": "BIBREF11"}], "ref_spans": []}, {"section": "II. SOME PROPERTIES OF RANDOM UNITARY CHANNELS", "text": "As mentioned in the Introduction, most intuitive application of the random unitary channel is the approximate private quantum channel [4] , which is a modification of the perfect private quantum channel [3] via RUC. The RUCbased APQC is the main tool of constructing the proposed AQSS protocol.", "cite_spans": [{"start": 134, "end": 137, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 203, "end": 206, "text": "[3]", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "II. SOME PROPERTIES OF RANDOM UNITARY CHANNELS", "text": "The security of PQC is preserved by the argument of the accessible information in which the leakage information is less than \u03b5. Although small information is leaked to exterior attackers, Bob's decoding state is almost equal to Alice's original state \u03d5. The FIG. 1 describes the total procedure of APQC.", "cite_spans": [], "ref_spans": [{"start": 254, "end": 264, "text": "The FIG. 1", "ref_id": "FIGREF0"}]}, {"section": "II. SOME PROPERTIES OF RANDOM UNITARY CHANNELS", "text": "In the next section we use two one-way independent PQCs between a sender Charlie and a receiver Alice, and the sender Charlie and another receiver Bob. Let's define two RUCs, from the definition of (Eq. (2)), such that", "cite_spans": [], "ref_spans": []}, {"section": "II. SOME PROPERTIES OF RANDOM UNITARY CHANNELS", "text": "where we fix the probability as an equally weighted probabilities p i = 1 nA and p j = 1 nB for all i, j, and assume that the number of n A is equal to n B , i.e., n A = n B = 150d/\u03b5 2 . For an approximate state sharing of any bipartite quantum state, above two channels play an important role in the approximate quantum state sharing scheme. ", "cite_spans": [], "ref_spans": []}, {"section": "II. SOME PROPERTIES OF RANDOM UNITARY CHANNELS", "text": "where a security parameter \u03b5 be a positive less than 1. The relation above asserts that all encoding states are information-theoretically secure. Unfortunately, for any entangled states proving the bound is not a simple task. Note that the argument for the (efficient) randomization is related to a destruction of correlations in quantum states [4, 11] . The following section gives the AQSS protocol and the security of the protocol. The last of the section, we briefly describe a multiparty AQSS scheme.", "cite_spans": [{"start": 345, "end": 348, "text": "[4,", "ref_id": "BIBREF3"}, {"start": 349, "end": 352, "text": "11]", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "III. APPROXIMATE QUANTUM STATE SHARING PROTOCOL", "text": "Let us assume that Charlie-Alice and Charlie-Bob have independent two APQCs, and Charlie wants to sharing a bipartite quantum state \u03d5 AB securely between Alice and Bob.", "cite_spans": [], "ref_spans": []}, {"section": "III. APPROXIMATE QUANTUM STATE SHARING PROTOCOL", "text": "The protocol for a bipartite quantum state sharing is simple ( See FIG. 2 ):", "cite_spans": [], "ref_spans": [{"start": 63, "end": 73, "text": "See FIG. 2", "ref_id": "FIGREF1"}]}, {"section": "III. APPROXIMATE QUANTUM STATE SHARING PROTOCOL", "text": "(i) The sender Charlie selects a quantum state \u03d5 AB and transmits the state through the channel N A \u2297 N B to the receivers Alice and Bob.", "cite_spans": [], "ref_spans": []}, {"section": "III. APPROXIMATE QUANTUM STATE SHARING PROTOCOL", "text": "(ii) Distant two parties Alice and Bob just hold the state N A \u2297 N B (\u03d5 AB ) they received.", "cite_spans": [], "ref_spans": []}, {"section": "III. APPROXIMATE QUANTUM STATE SHARING PROTOCOL", "text": "(iii) When Alice and Bob want to reveal the original state \u03d5 AB , they must cooperate in a single location. They perform the inverse unitary operations under the locally shared keys.", "cite_spans": [], "ref_spans": []}, {"section": "III. APPROXIMATE QUANTUM STATE SHARING PROTOCOL", "text": "The security of the AQSS protocol is divided two cases of an exterior and interior attacks. Actually the security is based on information-theoretic assumption, which means that the intercepted states must have the higher von Neumann entropy. Thus any attackers cannot obtain sufficient information for the original states.", "cite_spans": [], "ref_spans": []}, {"section": "III. APPROXIMATE QUANTUM STATE SHARING PROTOCOL", "text": "First, let us consider an attack accomplished by an exterior Eve. Assume that Eve intercepts the state N A \u2297 N B (\u03d5 AB ). We here claim that", "cite_spans": [], "ref_spans": []}, {"section": "III. APPROXIMATE QUANTUM STATE SHARING PROTOCOL", "text": "as d goes to infinity. We don't know the accurate description for the state N A \u2297 N B (\u03d5 AB ) for all inputs, so we will divide the state \u03d5 AB into the separable and entangled one and investigate the behavior each other. If product state is given, it is possible to infer the inequality Eq. (4) easily. By using the triangle inequality with respect to the trace norm for the two RUCs, if", "cite_spans": [], "ref_spans": []}, {"section": "III. APPROXIMATE QUANTUM STATE SHARING PROTOCOL", "text": ", a separable state is given, then", "cite_spans": [], "ref_spans": []}, {"section": "III. APPROXIMATE QUANTUM STATE SHARING PROTOCOL", "text": "where the inequalities Eq. (6) and Eq. (7) come from the norm convexity and the triangle inequality, respectively [4] . Thus any separable inputs for the product channel are very close to the maximally mixed state", "cite_spans": [{"start": 114, "end": 117, "text": "[4]", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "III. APPROXIMATE QUANTUM STATE SHARING PROTOCOL", "text": "For the separable input cases, there is another bound that depends on the dimension parameter d and n: We can prove that the expectation value for the difference between the channel output and the maximally mixed state (with respect to the trace norm) is very close, that is,", "cite_spans": [], "ref_spans": []}, {"section": "III. APPROXIMATE QUANTUM STATE SHARING PROTOCOL", "text": "where E {Ui,j } denotes the total expectation value of", "cite_spans": [], "ref_spans": []}, {"section": "III. APPROXIMATE QUANTUM STATE SHARING PROTOCOL", "text": "and {U j } nB j=1 for the independent RUCs N A and N B , respectively. The Appendix in this paper states that the inequality Eq. (8) is non-trivial and obtained precisely by exploiting the relation between the trace norm and the Hilbert-Schmidt norm. As mentioned above, let's take", "cite_spans": [], "ref_spans": []}, {"section": "III. APPROXIMATE QUANTUM STATE SHARING PROTOCOL", "text": "This implies that Eve's attack is impossible in principle. What can we do for an entangled input state? Though a direct proof could be impossible, there is an evidence for the statement, the Eq. (5). The Theorem III.3 in [4] states that, for a positive operator-valued measure (POVM) {L i } which is implemented using local operation and classical communication (LOCC), i p i \u2212 q i 1 \u2264 \u03b5, where Bob cannot obtain any information for \u03d5 A without Charlie-Alice's key information. Symmetrically Alice's attack is useless. In other words, the Charlie's aim of sharing a quantum state \u03d5 AB between Alice and Bob will be securely accomplished.", "cite_spans": [{"start": 221, "end": 224, "text": "[4]", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "III. APPROXIMATE QUANTUM STATE SHARING PROTOCOL", "text": "At least above-mentioned two attacks (exterior and interior eavesdropping) cannot break the security of the proposed AQSS protocol. so the cooperation between Alice and Bob always restores the original state approximately.", "cite_spans": [], "ref_spans": []}, {"section": "III. APPROXIMATE QUANTUM STATE SHARING PROTOCOL", "text": "In the proposed scenarios, the perfect protocol for quantum state sharing requires exactly d 4 unitary operators, while our protocol only needs to total 22500d 2 /\u03b5 4 unitaries for sufficiently larger d. This fact directly means that some pre-shared key bits are reduced by factor 2, since the AQSS is needed 2 log d \u2212 4 log \u03b5 + O(1) secret bits, but the perfect QSS is required 4 log d bits. For any state \u03d5 AB \u2208 B(C d 2 ), and for any channel N AB (for an \u03b5 > 0 is arbitrary), let's consider a relation like that", "cite_spans": [], "ref_spans": []}, {"section": "III. APPROXIMATE QUANTUM STATE SHARING PROTOCOL", "text": "Then, it is sufficient to construct the perfect QSS (\u03b5 = 0) with d 4 Pauli operators for the channel N AB in the sense of PQC [4, 8] . In the case of our approximate QSS, the product channel of two RUCs (N AB = N A \u2297 N B ) just consume of half secret bits, so we say that it is efficient in weak sense (though small information is always leaking).", "cite_spans": [{"start": 126, "end": 129, "text": "[4,", "ref_id": "BIBREF3"}, {"start": 130, "end": 132, "text": "8]", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "III. APPROXIMATE QUANTUM STATE SHARING PROTOCOL", "text": "Without loss of generality, a direct extension of the bipartite quantum state sharing protocol (Eq. (8)) gives the security of a multiparty approximate quantum state sharing (MAQSS). Assume that a sender Charlie (C) prepares an m-qudit \u03d5 A1A2\u00b7\u00b7\u00b7Am . If they initially have shared PQCs between C-A 1 , C-A 2 and so on, then, for any \u03b5 > 0,", "cite_spans": [], "ref_spans": []}, {"section": "III. APPROXIMATE QUANTUM STATE SHARING PROTOCOL", "text": "The above Eq. (12) implies that any exterior attacks will be failed. Furthermore all interior attacks (including group conspiracy) will be frustrated to obtain the whole state without others secrets, it has similar reason to the two receivers protocol. Let's look at the cost of secret bits for the MAQSS scheme. Roughly speaking, the perfect scheme requires 2m log d secret bits, but MAQSS only m log d + o(log d)-bits sufficient.", "cite_spans": [{"start": 14, "end": 18, "text": "(12)", "ref_id": "BIBREF11"}], "ref_spans": []}, {"section": "IV. CONCLUSIONS", "text": "We studied that the approximate quantum state sharing schemes are efficient from the classical information cost of view and those are robust to the two kinds of attacks. The proposed AQSS protocol basically depends on an approximate private quantum channel, which is constructed via two independent random unitary channels. Although the protocol leaks small information corresponding to the security parameter \u03b5, the scheme preserves its informationtheoretic security, and so the AQSS and MAQSS schemes can be interpreted as some high-efficiency state sharing protocols for any bipartite and multipartite quantum states.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Quantum cryptography: Public-key distribution and coin tossing", "authors": [{"first": "C", "middle": ["H"], "last": "Bennett", "suffix": ""}, {"first": "G", "middle": [], "last": "Brassard", "suffix": ""}], "year": 1984, "venue": "Proceedings of IEEE International Conference on Computers, Systems and Signal Processing", "link": "27022972"}, "BIBREF1": {"title": "Quantum cryptography using any two nonorthogonal states", "authors": [{"first": "C", "middle": ["H"], "last": "Bennett", "suffix": ""}], "year": 1992, "venue": "Phys. Rev. Lett", "link": "19708593"}, "BIBREF2": {"title": "Private quantum channels", "authors": [{"first": "A", "middle": [], "last": "Ambainis", "suffix": ""}, {"first": "M", "middle": [], "last": "Mosca", "suffix": ""}, {"first": "A", "middle": [], "last": "Tapp", "suffix": ""}, {"first": "R", "middle": [], "last": "De Wolf", "suffix": ""}], "year": 2000, "venue": "IEEE Symposium on Foundations of Computer Sciences (FOCS)", "link": "3204092"}, "BIBREF3": {"title": "Randomizing quantum states: Constructions and applications", "authors": [{"first": "P", "middle": [], "last": "Hayden", "suffix": ""}, {"first": "D", "middle": [], "last": "Leung", "suffix": ""}, {"first": "P", "middle": ["W"], "last": "Shor", "suffix": ""}, {"first": "A", "middle": [], "last": "Winter", "suffix": ""}], "year": 2004, "venue": "Commun. Math. Phys", "link": "10430173"}, "BIBREF4": {"title": "Small Pseudo-Random Families of Matrices: Derandomizing Approximate Quantum Encryption", "authors": [{"first": "A", "middle": [], "last": "Ambainis", "suffix": ""}, {"first": "A", "middle": [], "last": "Smith", "suffix": ""}], "year": 2004, "venue": "Proceedings of RANDOM", "link": "308430"}, "BIBREF5": {"title": "Superdense coding of quantum states", "authors": [{"first": "A", "middle": [], "last": "Harrow", "suffix": ""}, {"first": "P", "middle": [], "last": "Hayden", "suffix": ""}, {"first": "D", "middle": [], "last": "Leung", "suffix": ""}], "year": 2004, "venue": "Phys. Rev. Lett", "link": "14184339"}, "BIBREF6": {"title": "Remote preparation of quantum states", "authors": [{"first": "C", "middle": ["H"], "last": "Bennett", "suffix": ""}, {"first": "P", "middle": [], "last": "Hayden", "suffix": ""}, {"first": "D", "middle": [], "last": "Leung", "suffix": ""}, {"first": "P", "middle": ["W"], "last": "Shor", "suffix": ""}, {"first": "A", "middle": [], "last": "Winter", "suffix": ""}], "year": 2005, "venue": "IEEE Trans. Inf. Theory", "link": "8726928"}, "BIBREF7": {"title": "Approximate Randomization of Quantum States With Fewer Bits of Key", "authors": [{"first": "P", "middle": ["A"], "last": "Dickinson", "suffix": ""}, {"first": "A", "middle": [], "last": "Nayak", "suffix": ""}], "year": 2006, "venue": "AIP Conference Proceedings", "link": "15741056"}, "BIBREF8": {"title": "Quantum secret sharing", "authors": [{"first": "M", "middle": [], "last": "Hillery", "suffix": ""}, {"first": "V", "middle": [], "last": "Bu\u017eek", "suffix": ""}, {"first": "A", "middle": [], "last": "Berthiaume", "suffix": ""}], "year": 1999, "venue": "Phys. Rev. A", "link": "55165469"}, "BIBREF9": {"title": "Quantum entanglement for secret sharing and secret splitting", "authors": [{"first": "A", "middle": [], "last": "Karlsson", "suffix": ""}, {"first": "M", "middle": [], "last": "Koashi", "suffix": ""}, {"first": "N", "middle": [], "last": "Imoto", "suffix": ""}], "year": 1999, "venue": "Phys. Rev. A", "link": "120589665"}, "BIBREF10": {"title": "Quantum, clasical, and total amount of correlations in a quantum state", "authors": [{"first": "B", "middle": [], "last": "Groisman", "suffix": ""}, {"first": "S", "middle": [], "last": "Popescu", "suffix": ""}, {"first": "A", "middle": [], "last": "Winter", "suffix": ""}], "year": 2005, "venue": "Phys. Rev. A", "link": null}, "BIBREF11": {"title": "On Almost Randomizing Channels with a Short Kraus Decomposition", "authors": [{"first": "G", "middle": [], "last": "Aubrun", "suffix": ""}], "year": 2009, "venue": "Commun. Math. Phys", "link": null}}, "ref_entries": {"FIGREF0": {"text": "FIG. 1: Approximate private quantum channel: Alice applies some Ui's and Bob decodes N (\u03d5) with i of having pre-shared log n bits classical information.", "type": "figure"}, "FIGREF1": {"text": "FIG. 2: Approximate QSS: If Charlie-Alice and Charlie-Bob have shared two independent PQCs each other, then the product channel NA \u2297 NB preserves the security with high probability for any attacks. The arrow denotes that Alice must go to Bob's location to obtain the state.", "type": "figure"}, "FIGREF2": {"text": "For given two RUCs N A and N B , and for all input \u03d5 AB , we must bound the trace norm for the difference between an output state of the product channel N A \u2297 N B and maximally mixed \u00bd/d 2 , such that", "type": "figure"}, "FIGREF3": {"text": "They pointed out that the unitary operations of the amount corresponding to the quantum mutual information I[A : B] = S[\u03d5 A ] + S[\u03d5 B ] \u2212 S[\u03d5 AB ] efficiently destroy the total correlation of any quantum states [11], where S[\u033a] = \u2212tr\u033a log \u033a the von Neumann entropy. For the maximally entangled state \u03d5 AB = 1 d i,j |ii jj| AB , I[A : B] = 2 log d, which might be related to the Eq. (5).", "type": "figure"}, "FIGREF4": {"text": ") with a maximally entangled state s.t. \u03d5 AB = 1 d d i,j |ii jj| AB and \u03d5 B = tr A \u03d5 AB . Natural extension is possible as adding the channel N B : Define p i = tr(L i (N A \u2297 N B )(\u03d5 AB )) and q i = tr(L i ( \u00bdAB d 2 )), then also i p i \u2212 q i 1 \u2264 \u03b5. Therefore, we can conclude the state N A \u2297 N B (\u03d5 AB ) is close to \u00bd d 2 under the LOCC-implemented POVM. In this reason any input state \u03d5 AB through the product channel N A \u2297 N B have high entropy for d \u226b 1. Second, we must consider a situation when Alice or Bob is malicious. Assume that Bob intercepts the Alice's state N A (\u03d5 A ), Bob's decoded state looks like (N A \u2297 N * B )(N A \u2297 N B )(\u03d5 AB ) = (N A \u2297 \u00bd B )(\u03d5 AB ), (10) where * denotes the inverse operation for Bob's RUC N B , but S[N A (\u03d5 A )] has still high entropy values. The intercepted state tr B (N A \u2297 \u00bd B )(\u03d5 AB ) is still almost maximally mixed state by the definition of the RUC N A (\u03d5 A ). As a result,", "type": "figure"}}}
{"paper_id": "84882469", "_pdf_hash": "a42d8a8e9bdd18934214464dac763e30b4c06597", "abstract": [{"section": "Abstract", "text": "In this research, three different hormones and five different hormone dosages were applied on cuttings were taken from Anatolian sage plants (Salvia fruticosa Mill.) before flowering period. NAA, IBA (0, 60, 120, 180, 240 ppm) and IAA hormones (0, 100, 200, 300, 400 ppm) were prepared by dissolving in distilled water. Stem cuttings were kept in hormone solution for 24 hours and they were planted in perlit medium under greenhouse conditions. After a month, the number of rooted stem cutting, the number of root per stem cuttings, root length and root weight were determined on stem cuttings. Rooting was observed in all of the cuttings for both samples to which hormone was applied and to which hormone was not applied. According to the result of the variance analysis, the effects of the hormones and hormone doses on the examined characters were found significant as statistically. According to the results obtained, IAA application increased root number considerably. While high hormone dose applications caused the notable increase in root weight and root number in all of three hormones, low hormone applications did not affect root length.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Anatolia is the main centre of Salvia species in Asia, and its 89 species, half of which are endemic, were determined in Anatolia's natural vegetation. Salvia fruticosa Mill., being one of the commercial species with its essential oil that is over %1, spreads in Mediterranean mainly in Turkey and Greece [1] - [4] .", "cite_spans": [{"start": 305, "end": 308, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 311, "end": 314, "text": "[4]", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "Introduction", "text": "In Turkey, the leaves of Anatolian sage (Salvia fruticosa Mill.) are used instead of medical sage (Salvia officinals L.). Its leaves resemble medical sage's leaves in terms of chemical structure and treatment effects. Its essential oil has gastric, gastral, diuretic and saccharic effects. Externally, it can be used as wound healer and antiseptic [5] and [6] . In addition to these features, it is informed that it is among the plants of sage having the best antioxidant activity [7] . Along with internal consumption, sage (Salvia fruticosa Mill.) is gathered from natural vegetation from the west of Turkey and is exported being dry [8] . Related to the increasing export, efforts for the plant's production have increased in recent years.", "cite_spans": [{"start": 348, "end": 351, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 356, "end": 359, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 481, "end": 484, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 636, "end": 639, "text": "[8]", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "Introduction", "text": "Sage production can be made by the separation of secondary stems growing from seed, cutting and roots. Being an effective method in producing many plants, vegetative production with cuttings is seen as an attractive method for plant production industry [9] . Cuttings to which hormone is applied generally root much more rapidly than those to which hormones is not applied and construct a stronger root system, thus moulding in the lower parts of cuttings diminishes with accelerating of rooting. In their study they conducted with different species of Lamiaceae family, [10] detected the highest root height and root number values in Salvia fruticosa species in 3000 ppm IBA application for a period of 5 minutes.", "cite_spans": [{"start": 253, "end": 256, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 571, "end": 575, "text": "[10]", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "Introduction", "text": "In this study, it was aimed at determining the effects of different hormones and hormone doses in S. fruticosa cuttings upon the growth of seedling root.", "cite_spans": [], "ref_spans": []}, {"section": "Material and Method", "text": "In the research, Anatolian sage (S. fruticosa Mill.) grown in the previous years in the experiment fields of Nam\u0131k Kemal University Agricultural Faculty Field Crops was used as material. In the premergence phase, for three different hormones and five different doses, totally 1875 cuttings including 125 cuttings peculiar to each dose were obtained by observing the plant growth. Cuttings were obtained in the form of 3-5 internodes in 12-15 cm length in the morning hours. In the doses in which NAA and IBA are 1. 0 , 2. 60, 3. 120, 4. 180, 5. 240 ppm, whereas IAA is 1. 0, 2. 100, 3. 200, 4. 300, 5. 400 ppm, they were prepared in pure water by dissolving in the laboratory. The obtained cuttings were planted in the greenhouse after being waited in the hormone solutions for 24 hours. The experiment was organised according to split parcels experimental design. In the greenhouses, pearlite was used as rooting environment. By unravelling cuttings after 30 days, number of rooted cutting, root number per cutting, root length and their weight were determined. In the assessment of the collected data, JMP statistical programme was used.", "cite_spans": [], "ref_spans": []}, {"section": "Results and Discussion", "text": "In the study where NAA, IAA and IBA hormones and these hormones' five different levels were applied, at the level of 0.01 in terms of root weight and root number, hormone doses, hormone x hormone interactions, at the level of 0.01 among the hormones and hormone x hormone interactions in terms of root length and at the level of 0.05 among the hormone doses, significant differences were determined.", "cite_spans": [], "ref_spans": []}, {"section": "Root Weight", "text": "The effects of NAA, IAA and IBA hormones and these hormones' five different doses on Anatolia sage's root weight are given in Fig. 1 and Table 1 . while hormone x hormone doses interactions are given in Table 2 . The highest root weight values were obtained from NAA and IAA hormones, and the root weight of cuttings which NAA and IAA were applied to was notable high than those to which IBA was applied. While root weight in cuttings in which hormone was not applied was 1.824 g, significant increases in root weight were seen with hormone applications. While root weight in the lowest hormone application was 1.822 g, this value was 3.051 in the highest hormone application. While the highest root weight was obtained from the highest hormone level, significant differences between cuttings to which hormone was applied and the low dose applications. When the effects of hormone x hormone doses interactions on root weight was examined, it was seen that the highest root weight value was obtained from 240 ppm dose of NAA applcation, which was followed by 300, 400 and 200 ppm doses of IAA. The lowest root weights were obtained from those whcih hormone was not applied to and the low dose applications of IBA and IAA.", "cite_spans": [], "ref_spans": [{"start": 137, "end": 144, "text": "Table 1", "ref_id": "TABREF0"}, {"start": 203, "end": 210, "text": "Table 2", "ref_id": "TABREF1"}]}, {"section": "Root Number", "text": "The effects of three different hormones and these hormones' five different doses on the root number of sage cuttings are given Fig. 2 and Table 2 . Hormone applications and root numbers changed between 44.000-70.750, and considerable root numbers were obtaibed from IAA applications and NAA and IBA applications. Between NAA and IBA applications, no difference was seen in terms of the quality examined. With the increase of hormone doses, significant increases were seen in root numbers. While the highest root number values (77.397) were obtained from the highest hormone dose application, the lowest root numbers were obtained from cuttings to which hormone was not applied and to which the lowest hormone dose was applied (28.000 and 32.3889). As can be seen from Table 2 , the highest root numbers were obtained from 300, 400 and 200 ppm doses of IAA application, and this is followed by 240 ppm dose application of IAA and IBA. ", "cite_spans": [], "ref_spans": [{"start": 127, "end": 133, "text": "Fig. 2", "ref_id": "FIGREF0"}, {"start": 138, "end": 145, "text": "Table 2", "ref_id": "TABREF1"}, {"start": 768, "end": 775, "text": "Table 2", "ref_id": "TABREF1"}]}, {"section": "Root Length", "text": "The effects of different hormones and hormone doses on root length are given in Fig. 3 . and while hormone x hormone interactions are given in Table 4 . The longest root was obtained from NAA and IAA applications while the lowest root values were obtained from IBA application. Root lengths changed between 10.487-11.416 cm according to the applied hormone doses, and the highest hormone values were obtained from the highest hormone doses. As can be seen from Table 4 , values concerning root length changed between 9.610-12.428. The longest roots were obtained from 60 ppm dose of IAA while the shortest roots were obtained from 200 ppm of IAA. With the dose increase in IBA, it was seen that root lengths increased.", "cite_spans": [], "ref_spans": [{"start": 80, "end": 86, "text": "Fig. 3", "ref_id": "FIGREF1"}, {"start": 143, "end": 150, "text": "Table 4", "ref_id": "TABREF3"}, {"start": 461, "end": 468, "text": "Table 4", "ref_id": "TABREF3"}]}, {"section": "Root Length", "text": "While in hormone x hormone interaction, 11.125 cm root length was measured in the plants to which IAA hormone was not applied, root length in low hormone values diminished, and 240 ppm application gave the same results with those not applied. In NAA application, increases occurred in 60, 120 and 240 ppm applications. In IBA application, especially in 300 and 400 ppm application, notable increases in root length was supplied. The study of [11] , [12] and [10] has similarities with our results. According to the results obtained, IAA application increased root number considerably. While high hormone dose applications caused the notable increase in root weight and root number in all of three hormones, low hormone applications did not affect root length.", "cite_spans": [{"start": 442, "end": 446, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 449, "end": 453, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 458, "end": 462, "text": "[10]", "ref_id": "BIBREF9"}], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "T\u0131bbi Bitkiler II (U\u00e7ucu Ya\u011f Bitkileri). Ege \u00dcni. Ziraat Fak. Yay\u0131n No:481. Sf", "authors": [{"first": "", "middle": [], "last": "Ceylan", "suffix": ""}], "year": 1996, "venue": "", "link": null}, "BIBREF1": {"title": "Bat\u0131 Anadolu Floras\u0131nda Yeti\u015fen Anadolu Ada\u00e7ay\u0131( Salvia fruticosa Mill )'nda uygun Tiplerin Seleksiyonu \u00dczerinde Ara\u015ft\u0131rma", "authors": [{"first": "E", "middle": [], "last": "Bayram", "suffix": ""}], "year": 2001, "venue": "Turk J. of Agr. and For", "link": null}, "BIBREF2": {"title": "Aromatic biodiversity among the flowering plant taxa of Turkey", "authors": [{"first": "K", "middle": ["H C"], "last": "Ba\u015fer", "suffix": ""}], "year": 2002, "venue": "Appl. Chem", "link": "97714012"}, "BIBREF3": {"title": "Sustainable use of medicinal and aromatic plants and employment of women in its production", "authors": [{"first": "G", "middle": [], "last": "\u00d6zdemir", "suffix": ""}, {"first": "C", "middle": [], "last": "Sa\u011flam", "suffix": ""}], "year": 2009, "venue": "", "link": null}, "BIBREF4": {"title": "T\u00fcrkiye'de Bitkiler \u0130le Tedavi Ge\u00e7mi\u015fte ve Bug\u00fcn", "authors": [{"first": "T", "middle": [], "last": "Baytop", "suffix": ""}], "year": 1999, "venue": "", "link": null}, "BIBREF5": {"title": "The range of medicinal herbs and spices. Handbook of herbs and spices", "authors": [{"first": "Tsc2006", "middle": [], "last": "Li", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF6": {"title": "Antioxidant and Free Radical Scavenging Activities of Eight Salvia Species", "authors": [{"first": "B", "middle": [], "last": "Bozan", "suffix": ""}, {"first": "N", "middle": [], "last": "\u00d6zt\u00fcrk", "suffix": ""}, {"first": "M", "middle": [], "last": "Ko\u015far", "suffix": ""}, {"first": "Z", "middle": [], "last": "Tunal\u0131er", "suffix": ""}, {"first": "C", "middle": ["H K"], "last": "Ba\u015fer", "suffix": ""}], "year": 2002, "venue": "Chemistry of Natural Compounds", "link": "40506974"}, "BIBREF7": {"title": "Production of Salvia oil in Mediterranean countries", "authors": [{"first": "K", "middle": ["H C"], "last": "Ba\u015fer", "suffix": ""}], "year": 2000, "venue": "Med. and Arom. Plants-Ind. Prof. Sage, the genus Salvia. Edited by Spiridon E. Kintzios", "link": null}, "BIBREF8": {"title": "Adventitious Rooting: Examining the Role of Auxin in an Easy and a Difficult-to-root Plant", "authors": [{"first": "Y", "middle": ["Y"], "last": "Ford", "suffix": ""}, {"first": "E", "middle": ["C"], "last": "Bonham", "suffix": ""}, {"first": "Cameron", "middle": [], "last": "Blake", "suffix": ""}, {"first": "H", "middle": ["L"], "last": "", "suffix": ""}], "year": 2001, "venue": "Plant Growth Regulator", "link": "10504443"}, "BIBREF9": {"title": "Root\u0131ng performance of some aromatical plants from lamiaceae The Labiatae: Advances in Production, Biotechnology and Utilization 22-25", "authors": [{"first": "S", "middle": [], "last": "Tu\u011frulay", "suffix": ""}, {"first": "E", "middle": [], "last": "U\u00e7ar", "suffix": ""}, {"first": ";", "middle": ["K"], "last": "Turgut", "suffix": ""}], "year": 2006, "venue": "", "link": null}, "BIBREF10": {"title": "Ada\u00e7ay\u0131 (Salvia officinalis L.)' \u0131nda tohum tutma oran\u0131 ve \u00e7elik alma zaman\u0131 ile \u0130ndol Butirik Asidin (IBA) g\u00f6vde \u00e7eliklerinin k\u00f6klenmesine etkileri \u00fczerinde ara\u015ft\u0131rmalar. TUB\u0130TAK Tr", "authors": [{"first": "N", "middle": [], "last": "Arslan", "suffix": ""}, {"first": "B", "middle": [], "last": "G\u00fcrb\u00fcz", "suffix": ""}, {"first": "G", "middle": [], "last": "Y\u0131lmaz", "suffix": ""}], "year": 1995, "venue": "J. of Agriculture and Forestry", "link": null}, "BIBREF11": {"title": "Propagation of some native grown medicinal plants by stem cuttings Journal of herbs, spices & medicinal plants", "authors": [{"first": "F", "middle": [], "last": "Ayano\u011flu", "suffix": ""}, {"first": "A", "middle": [], "last": "Mert", "suffix": ""}, {"first": "C", "middle": [], "last": "Erdo\u011fan", "suffix": ""}, {"first": "A", "middle": [], "last": "Kaya", "suffix": ""}], "year": 2002, "venue": "", "link": null}}, "ref_entries": {"FIGREF0": {"text": "Fig. 2. Root numbers average changes in different hormones and in hormone doses", "type": "figure"}, "FIGREF1": {"text": "Fig. 3. Average changes in root length in different hormone and hormone doses", "type": "figure"}, "TABREF0": {"text": "Average Results Concerning Root Weight and Root Number and Significance GroupsFig. 1. Root weight average values in different hormone and hormone doses", "type": "table"}, "TABREF1": {"text": "Hormone x hormone doses interaction concerning root weight and root number and significance groups", "type": "table"}, "TABREF2": {"text": "Average values concerning root length and significance groups", "type": "table"}, "TABREF3": {"text": "Hormone x hormone interaction concerning root length and significance level", "type": "table"}}}
{"paper_id": "84883393", "_pdf_hash": "294a52aa426b4e0ef5dbc8b1b64d7e2deaa739b3", "abstract": [], "body_text": [{"section": "Introduction", "text": "The results of an investigation of the stratigraphy and diatom sequence in the Windermere deposits have already been published (Pennington 1943) . The present paper deals with the results of pollen analysis of selected profiles on a transect across the lake, and with the macroscopic plant remains found in the deposits, especially those of late-glacial age. Evidence obtained from these latter investigations has made it possible to date the lake deposits with more accuracy than formerly, and by the light it throws on the late-glacial and post-glacial vegetational sequence in the Windermere basin has made it possible to fit this region into the general picture of the Quaternary history of the British Isles. Further examination of the late-glacial plant-bearing layer described in the previous paper has confirmed the view that it represents a late-glacial climatic amelioration followed by a colder period and then by the final retreat of the ice. A similar layer has been recognized right across Ireland, and its discovery in England was expected. It seems possible that it may be correlated with a similar succession in Denmark and other parts of north-west Europe, and afford a means whereby the British succession could be linked with the Continental succession and De Geer's geochronology; the evidence in favour of such a correlation is put forward in the course of this paper.", "cite_spans": [{"start": 127, "end": 144, "text": "(Pennington 1943)", "ref_id": "BIBREF52"}], "ref_spans": []}, {"section": "M ethod", "text": "The principles of the pollen-analysis method have been described by Godwin (1934) . They apply to subaqueous in the same way as to terrestrial deposits. Samples of the Windermere deposits were obtained by the Jenkin core-sampler, which has already been described (Jenkin, Mortimer & Pennington 1941 ).", "cite_spans": [{"start": 68, "end": 81, "text": "Godwin (1934)", "ref_id": "BIBREF21"}, {"start": 263, "end": 298, "text": "(Jenkin, Mortimer & Pennington 1941", "ref_id": "BIBREF33"}], "ref_spans": []}, {"section": "M ethod", "text": "It will be apparent that some of the indicator species-Fagus, Carpinus-present in the deposits of southern England are absent in Windermere. This makes it difficult to compare the later stages in the two localities, but the earlier post-glacial stages correspond closely, and the Windermere profile carries back the story into the late-glacial period, the deposits of which have not yet been described from southern England, though they have been recognized, e.g. in Cornwall (Godwin 1940 \u00a3) .", "cite_spans": [], "ref_spans": []}, {"section": "M ethod", "text": "It seems unlikely that it will ever be possible to obtain any direct archaeological correlation with the Windermere deposits, but the site is in some ways unique in its association of organic deposits with laminated clays which have every appearance of being true waterlain varves, and hence offer a possibility of applying a geochronological time-scale.", "cite_spans": [], "ref_spans": []}, {"section": "Preparation", "text": "(1) Organic muds While still wet, the muds readily went into suspension in water, though prolonged stirring was necessary with the clays. Plant remains were extracted by sieving this suspension through a fine sieve (0T6 mm. mesh). In nearly all deposits from deep water the plant remains were in a very finely divided state, but this treatment collected all fragments of recognizable size.", "cite_spans": [], "ref_spans": []}, {"section": "Preparation", "text": "For pollen counts, either fresh wet mud or the sieved suspension after centrifuging was treated by a modification of Erdtman's technique, involving oxidation by sodium chlorate followed by hydrolysis with hot acid. After washing, the samples from marginal sites were then mixed with hot safranin-glycerine jelly and stirred; four comparable slides were then made from this suspension. Samples from deep water were, after acid hydrolysis and washing, boiled from 2 to 3 min. in concentrated hydrofluoric acid to remove silica and silic ate sth ey were then washed first in 7 % hydrochloric acid and then in water, and mounted as described. This removal of silica and silicates was necessary in all samples from deep water, in order to obtain a sufficient concentration of pollen for counting. Even so, in some of these samples it was not possible to count more than 100 grains of tree pollen. In most samples, 150 grains of tree pollen were counted.", "cite_spans": [], "ref_spans": []}, {"section": "Preparation", "text": "The results of the pollen counts are expressed as percentages of total tree pollen, Corylus and Salix not being included in the tree pollen. Non-tree pollens, including Corylus and Salix, are expressed as percentages of the total tree pollen.", "cite_spans": [], "ref_spans": []}, {"section": "Preparation", "text": "(2) The laminated clays", "cite_spans": [], "ref_spans": []}, {"section": "Preparation", "text": "In any attem pt to measure or count the varves, the most satisfactory treatment of the laminated clays was found to be to allow the core to dry completely, when a plane surface could be prepared by scraping the clay with a razor. The difference in texture between the summer and winter layers could then be shown up more clearly by treating the core with a mixture of oil and xylol (or petrol) in approximately equal proportions, a method for which I am indebted to Professor T. M. Harris. It was inevitable that cracks and breaks should appear in the core during the drying process; these interfered with the measurement and counting of the varves, and were especially troublesome in the lower part of the laminated clay, where the texture differences were more marked. It seems possible that some technique of impregnation may be found to prevent the cracking on drying. Glycerine, recommended by De Geer, was not satisfactory, since it produced a crumbly texture and made it impossible to prepare the plane surface necessary for microscopic examination. Melted paraffin wax, used by Carruthers (1939) would not penetrate until the clay had dried out sufficiently to initiate cracks; but impregnation with paraffin wax did serve to harden the specimens and render them more portable.", "cite_spans": [{"start": 1086, "end": 1103, "text": "Carruthers (1939)", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "Local influences", "text": "In peat deposits formed subaerially, the pollen content may include a component derived from the vegetation which grew on the actual surface of the peat. Godwin (1940 points out that this local component may materially influence the pollen diagrams from Fenland. The Windermere deposits, on the other hand, must have received all their pollen from the surrounding land, since there is no evidence whatever to suggest that the lake level has at any time since the formation of the lake been lower than it is to-day. The changing composition of the pollen content of the lake deposits can therefore be expected to reflect the forest history of the surrounding land, undisturbed by purely local influences.", "cite_spans": [], "ref_spans": []}, {"section": "Local influences", "text": "There is, however, at some horizons, a marked difference between the pollen spectra of similar age from deep-and shallow-water profiles respectively, suggesting that the marginal pollen rain may be different in composition from that reaching the middle of the lake. Other possible causes of this difference, which related chiefly to the proportions of Pirns to deciduous pollens, are discussed later.", "cite_spans": [], "ref_spans": []}, {"section": "W IN IFRED PENNINGTON ON THE", "text": "Though the accumulation oflake deposits is not subject to direct climatic effects such as the possible erosion of peat deposits during a dry period, the pollen diagrams show that the rate of accumulation of deposit must have varied considerably both in different parts of the lake at the same time, and at different times in the same part of the lake. Mitchell (1940) found similar variations demonstrated by the deposits of an old lake basin in Eire. These variations in deposition rate in lakes in glaciated areas must presumably be due to indirect climatic effects; partly to the decrease in readily transported debris as the post-glacial climatic amelioration led to stabilization of the land surface by a plant cover, and partly to the effects of erosion and deposition by wind-produced currents in the water. The effect of these variations is to complicate the interpretation of the pollen diagrams and make it necessary to consider profiles from many parts of the lake before drawing any conclusions about either the relative length of the successive phases of forest history and the climatic periods which they indicate, or the relation of the stratigraphy of the deposits to the time-scale provided by forest history.", "cite_spans": [{"start": 352, "end": 367, "text": "Mitchell (1940)", "ref_id": "BIBREF43"}], "ref_spans": []}, {"section": "W IN IFRED PENNINGTON ON THE", "text": "Derived pollen from the boulder clay has been shown to be present in lacustrine clay beds in Denmark (Iversen 1936) , but in view of the fact that no more than an occasional grain of pollen has been found in the Windermere lower laminated clay, which presumably contains redeposited boulder clay, it is probable that there is very little derived pollen in the succeeding deposits.", "cite_spans": [{"start": 101, "end": 115, "text": "(Iversen 1936)", "ref_id": "BIBREF32"}], "ref_spans": []}, {"section": "W IN IFRED PENNINGTON ON THE", "text": "General stratigraphy (notes additional to 1943 paper) ( ", "cite_spans": [], "ref_spans": []}, {"section": "1) Laminated clays", "text": "The appearance of the laminated clays forming the lower part of the deposits suggests strongly that the laminations represent varves, or annual laminations formed by the seasonal deposition from glacial drainage into standing water. They could therefore be compared with the Swedish varved clays, deposited by the Scandinavian ice-sheet in a fresh-water portion of the Baltic, which form the basis of De Geer's geochronology (De Geer 1908 et seq.) . In his later work (De Geer 1921 , 1927 , 1929 and 1930 De Geer claimed to have extended the varve correlations not only throughout Sweden but both transAtlantically and trans-equatorially. Time and further work will show whether these 'teleconnexions' will stand critical examination, but the correlations and consequent time-scale for Sweden are now generally accepted, and it would appear possible that the correlation might be extended into the British Isles.", "cite_spans": [{"start": 468, "end": 481, "text": "(De Geer 1921", "ref_id": "BIBREF9"}, {"start": 482, "end": 488, "text": ", 1927", "ref_id": "BIBREF42"}, {"start": 489, "end": 495, "text": ", 1929", "ref_id": "BIBREF34"}, {"start": 496, "end": 504, "text": "and 1930", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "1) Laminated clays", "text": "Certainly the laminations in the Windermere clays conform closely to De Geer's description of the essential characteristics of a varve (see figure 15 <2, plate 2). Each layer of coarse, more or less sandy material (the deposit of the spring-summer melt), passes gradually upwards into the fine layer of often greasy clay (the finest fraction of the sediment which settled slowly out of suspension, almost certainly under ice, during the winter). The fine layer is then succeeded abruptly by the coarse layer of the following spring melt. Each varve, or annual deposit, therefore consists of the layer which lies between two of these abrupt boundaries, and the thickness of the varve is fairly easy to determine, though the boundary between the coarse and fine deposits of a single year is often indeterminate. This interpretation of the alternations in texture in the clays is borne out by the observations of Kindle (1930) on sedimentation in a glacial lake-Lake Cavell in the Canadian Rockies, which receives a stream from a glacier ending J mile above the lake. Difficulties may arise in the measurement of varves owing to the presence of deceptive bands resembling the winter layers. Such layers, which De Geer calls digraphs and tri graphs, can often be distinguished by the absence of the typical sharp winter-spring junction, but in varves as narrow as those of Windermere this may be difficult to see. These very narrow varves, here averaging about 1 mm., are what De Geer (1940) 'microdistal' varves, which he supposes to have been deposited, in Sweden, at a great distance from the ice border. This would explain the narrowness of the Windermere varves, since all the samples obtained are from positions a mile or more below the delta of the main inflow, and Kindle showed that the greater part of the suspended sediment from the inflow of Lake Cavell was deposited in the delta region. In Sweden, sections have been found showing the transition from wide varves, measured in centimetres, upwards to such microdistal varves, as the ice border retreated north and hence farther and farther from the section. The Windermere varved clay shows a similar upward passage from the lowest varves, immediately overlying a stony clay equivalent to the boulder clay, and averaging 0-5 to 1*0 cm. in width, upwards to the topmost varves which may be only 0-2 mm. in width. This upward decrease in width of the Windermere varves may well correspond to shrinkage in the size of the glacier supplying the sediment and hence to a decrease in volume of sediment supplied.", "cite_spans": [{"start": 1473, "end": 1487, "text": "De Geer (1940)", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "1) Laminated clays", "text": "Laminated clays have, of course, been found in other parts of northern England (Trotter & Hollingworth 1932) and in Scotland (De Geer 1935) in terrestrial positions. Carruthers (1939) suggests that some at least of the terrestrial laminated clays of north-east England and the Eden valley may be explained as 'the banded dirts of the englacial detritus released by the rising bottom m elt', rather than as representing periods of ice recession and deposition in standing water. The Windermere laminated clays, however, strongly resemble the true water-lain microdistal varves described by De Geer, and bear no resemblance to any of the laminated clays described or figured by Carruthers. Faults occur occasionally in the Windermere clays, as in the Swedish varves (De Geer 1940) , but never the gross contortions and overfolds shown by some of Carruthers's specimens which he interprets as Alpine structures imposed when the 'banded dirts' were frozen muds. The graded bedding which De Geer describes as typical of varved clays was also recog nized in the discussion following Carruthers's paper (1939) as characteristic of waterlain laminated clays, and is shown by all the laminated clays in Windermere.", "cite_spans": [{"start": 79, "end": 89, "text": "(Trotter &", "ref_id": "BIBREF56"}, {"start": 90, "end": 112, "text": "Hollingworth 1932) and", "ref_id": "BIBREF56"}, {"start": 166, "end": 183, "text": "Carruthers (1939)", "ref_id": "BIBREF3"}, {"start": 764, "end": 778, "text": "(De Geer 1940)", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "1) Laminated clays", "text": "The general bedding of the Windermere varves is strikingly regular and horizontal, apart from microscopic irregularities in the winter-spring contact planes which give the varves a wavy outline under the microscope (figure 15 plate 2). In places where the lake floor shelves steeply (figure 2, position 4), the laminations often slope at a considerable angle, but the regular bedding is not disturbed by this. Undisturbed varved clays extend into very shallow water-i.e. to within a few yards of the edge of the lake in sheltered positions in the bays; this suggests that the lake level may have been higher when the varves were deposited, since very slight shore erosion would prevent the deposition of such fine material.", "cite_spans": [], "ref_spans": []}, {"section": "1) Laminated clays", "text": "In deep water, i.e. within the 35 m. contour, the laminated clays often show marked sloping of the bedding planes, probably formed as the clay deposits filled up hollows in the original lake floor. In some positions, the very marked differences between the laminated clays in core samples taken within a few feet of each other (i.e. without moving the pontoon's anchors) suggest that deposition of the varves in deep water was by no means uniform, and that by some means marked discontinuities arose. In shallow water on both sides of the lake, however, the varve series appears very uniform in all sections taken, and conspicuous varves can be correlated easily with the naked eye.", "cite_spans": [], "ref_spans": []}, {"section": "1) Laminated clays", "text": "Measurement of the varves. Hitherto, only preliminary attempts to measure the varves have been made, and there are still considerable difficulties to be overcome, owing partly to the difficulty of distinguishing digraphs and trigraphs in such very narrow varves, and partly to the wavy outlines of the boundaries which make it difficult to measure the width of metres water surface each varve with accuracy. The narrowness of the varves makes it necessary to use a microscope with a graduated mechanical stage. Though in shallow water the widest and most conspicuous varves can be recognized with ease and correlated from one core to another, some difficulty has been experienced with the intervening narrow varves, and the relation of the varve series in shallow water to that in the deep central region has not yet been worked out. Before any attem pt at correlation with the Swedish diagrams is made, it will be necessary to work out many diagrams from different cores so that a representative series for the lake as a whole, exclusive of local variations, is obtained (De Geer 1940) . It is hoped that this may form the next stage in investigation of the Windermere deposits. Only when the improved model of the core-sampler can be made will it be possible to obtain the full sequence of the laminated clays in deep water, since the length of core obtainable at present (6-5 m.) penetrates only the topmost part of the clay in deep water, where the maximum thickness of deposit is found (figure 2).", "cite_spans": [{"start": 1072, "end": 1086, "text": "(De Geer 1940)", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "1) Laminated clays", "text": "(2) Detritus silt layer within the laminated clay", "cite_spans": [], "ref_spans": []}, {"section": "1) Laminated clays", "text": "In shallow water, the lower laminated clay consists of relatively wide varves at the base; these pass upwards into narrow varves which may be only 0-2 mm. thick. These narrow, microdistal varves grade upwards into a deposit of unlaminated pinkish grey clay, which in turn passes gradually into a layer of grey detritus silt. This reaches its maximum thickness of about 50 cm. in water of 3 to 10 m. depth, and becomes thinner as the water depth increases, until it disappears at about the 25 m. contour. Within this contour, the layer of grey detritus silt is not represented, but at the same horizon in the laminated clay there may occur either a very narrow layer of unlaminated clay or an interruption in the regular sequence of varves. The grey detritus silt is everywhere capped by a layer of grey clay 2 to 5 cm. thick, which may contain plant remains. This grey clay grades upwards, within the next 1 to 2 cm. thickness, into the upper laminated clay, which consists through out of very narrow microdistal varves.", "cite_spans": [], "ref_spans": []}, {"section": "1) Laminated clays", "text": "The clays consist mainly of very minute particles, which remain suspended almost indefinitely in water, plus' a varying proportion of fine gravel particles, 0-5 mm. or more in diameter. In the grey layer of detritus silt the mineral particles are mainly of the fine sand or silt grade-i.e. coarser than the clays, with fine gravel particles in addition. The detailed stratigraphy of the grey layer varies from place to place (figure 11), and it may contain layers which are almost entirely clay.", "cite_spans": [], "ref_spans": []}, {"section": "1) Laminated clays", "text": "The detritus consists almost entirely of plant remains in a more or less finely divided state; these occur mainly towards the top of this layer and are sometimes found in bands of almost pure plant detritus.", "cite_spans": [], "ref_spans": []}, {"section": "1) Laminated clays", "text": "This layer of grey detritus silt, which apparently represents a temporary change of climate and deposition, has been found, in the water depths stated above, on both sides of the lake in the latitude of Low Wray Bay, and all along the western shore from the mouth of Blelham Beck to High Wray Bay. It therefore seems fair to conclude that it is widely developed in the North Basin in shallow water. From purely stratigraphical evidence it could be supposed that this layer was formed during a warm period in which glacial drainage was no longer entering the lake, and that this warm period was followed by a return of a colder climate which again produced glaciers in the upper valleys, the drainage from which led to the deposition of the upper laminated clay. It will be shown later that the pollen and plant remains found within the layer of detritus silt confirm this hypothesis, and support the correlation with the Allerod deposits of north-west Europe which was tentatively put forward in a former paper (Pennington 1943) .", "cite_spans": [{"start": 1011, "end": 1028, "text": "(Pennington 1943)", "ref_id": "BIBREF52"}], "ref_spans": []}, {"section": "Zoning of pollen diagrams (1) Marginal profiles (a) Late-glacial", "text": "The period generally recognized as the late-glacial corresponds (Godwin 1940a ) with that of the upper and lower Dryas clays separated by the cold temperate Allerod deposits described by continental workers (e.g. Jessen 1935; Gross 1937; Nilsson 1935; and Schutrum pf 1936) ; these three layers form Zones I to III in the zonation scheme adopted by Jessen for Denmark (Jessen 1935) and Ireland (Jessen & Farrington 1938) . Godwin (1940 suggests that if and when corresponding late-glacial deposits are found in this country, a similar zonation should be adopted.", "cite_spans": [{"start": 64, "end": 77, "text": "(Godwin 1940a", "ref_id": "BIBREF22"}, {"start": 213, "end": 225, "text": "Jessen 1935;", "ref_id": "BIBREF35"}, {"start": 226, "end": 237, "text": "Gross 1937;", "ref_id": "BIBREF25"}, {"start": 238, "end": 251, "text": "Nilsson 1935;", "ref_id": "BIBREF47"}, {"start": 368, "end": 381, "text": "(Jessen 1935)", "ref_id": "BIBREF35"}, {"start": 394, "end": 420, "text": "(Jessen & Farrington 1938)", "ref_id": "BIBREF37"}], "ref_spans": []}, {"section": "Zoning of pollen diagrams (1) Marginal profiles (a) Late-glacial", "text": "The stratigraphy of the Windermere deposits suggested what has since been borne out by the pollen diagrams-i.e. that here the lower laminated clay, grey detritus silt and upper laminated clay probably represent respectively Zones I, II and III, which in Denmark are represented by the lower Dryas clay, the Allerod deposits and the upper Dryas clay. This succession of deposits indicates that in both localities the climatic succession was: first, a cold period (shown by the Arctic Dryas flora of the lower Dryas clay in Denmark and by the evidence for glacial drainage shown by the lower laminated clay in Windermere) followed by a cold temperate period, that is, a climatic amelioration (shown by the plant species identified from the Allerod deposits and from the grey detritus silt layer in Windermere) followed by a return of cold conditions (producing the upper Dryas clay in Denmark and the upper laminated clay in Windermere). Jessen & Farrington (1938) tentatively correlate with the succession in Denmark that which occurs in several filled-up lake basins in Ireland, where the cold periods of Zones I and III are represented by clays or solifluction earths, Arctic plants having been recovered from the upper (Zone III), while between them is a lake mud containing remains of temperate plants. Since in all three countries the second cold period is followed by post-glacial deposits, this cold period may be interpreted as corresponding to the last major halt, or possibly slight advance, of the retreating ice-sheet. The question of how far this last cold period may be regarded as contemporaneous in the three countries will be discussed later.", "cite_spans": [{"start": 936, "end": 962, "text": "Jessen & Farrington (1938)", "ref_id": "BIBREF37"}], "ref_spans": []}, {"section": "Zoning of pollen diagrams (1) Marginal profiles (a) Late-glacial", "text": "Zone I -lower laminated clay. Pollen is here practically absent, which agrees with what Jessen & Farrington found in this zone in the Irish profiles from Ballybetagh and Ralaghan, and Mitchell (1940) in the lacustrine deposits at Dunshaughlin, Co. Meath. (Mitchell found that in the blue-grey sandy clay which represents this zone at Dunshaughlin, the only vegetation remains were a few moss stems. Similar moss stems occur in the Windermere deposits in the silty clay forming the transition from this zone to the next.)", "cite_spans": [{"start": 184, "end": 199, "text": "Mitchell (1940)", "ref_id": "BIBREF43"}], "ref_spans": []}, {"section": "Zoning of pollen diagrams (1) Marginal profiles (a) Late-glacial", "text": "Zone II-grey detritus silt. The lowest deposit which contains any appreciable quantity of pollen is the silty clay forming the transition from Zone I to Zone II. Here the non-tree pollen, mainly grass, is high relative to the tree pollen, and Salix pollen is relatively abundant; the tree pollen is practically entirely Betula, with a very little Pirns. As the more or less clayey transitional deposits pass upwards into detritus silt, the ratio of both non-tree pollen and of Salix pollen to tree pollen falls sharply, indicating replacement of open vegetation by Betula woodlands as the climate became warmer. Towards the top of the detritus silt the relative amounts of grass and of Salix to tree pollen again rise, presumably corresponding with the fall in temperature at the end of the warm period. The resultant concave shape of the curves for non-tree pollen ( ), grass and Salix pollen (figures 3, 4 and 10) is characteristic of all pollen diagrams from the Allerod deposits (Jessen 1939; Nilsson 1935; Gross 1937) . Pollen of Myriophyllum alterniflorum occurs as scattered grains throughout this layer, though never in any great quantity.", "cite_spans": [{"start": 997, "end": 1010, "text": "Nilsson 1935;", "ref_id": "BIBREF47"}, {"start": 1011, "end": 1022, "text": "Gross 1937)", "ref_id": "BIBREF25"}], "ref_spans": []}, {"section": "Zoning of pollen diagrams (1) Marginal profiles (a) Late-glacial", "text": "Zone III-upper laminated clay. Pollen is very sparse in this deposit, and not even by boiling twice in hydrofluoric acid was it possible to obtain a sufficient concentration to yield counts which are statistically significant. This again agrees with conditions in the Irish profiles. The transition between Zones II and III is marked by a sharp rise in Pirns pollen, and Pirns also forms a high percentage of the tree pollen at the end of this zonei.e. the III to IV transition (figures 3 and 4). The evidence available for the laminated clay suggests that what little tree pollen is present is mainly throughout; this may indicate that in the absence of local pollen, Pirns transported from a distance was more important than in the preceding and following periods, when local pollen was abundant. The apparent absence of local pollen during this period strengthens the hypothesis that it was one of intense cold with only sparse vegetation.", "cite_spans": [], "ref_spans": []}, {"section": "(b) Post-glacial", "text": "The top of the laminated clay is taken as marking the end of any intense glacial activity in the Lake District, and the succeeding deposits are therefore classed as post-glacial. In the marginal profiles these deposits consist of brown detritus mud (gyttja) which in places (mainly in sheltered positions where the water is 2 to 5 m. deep) contains a very high proportion of plant fragments so that the deposit resembles a fine peat. The deposit in deeper water or more exposed positions contains a much higher proportion of mineral material, fewer plant remains, and much less pollen. A layer of whitish clay containing abundant diatom skeletons but very little carbonaceous material occurs in a definite relation to the mouth of each small inflow stream, in the bays where sampling has taken place.", "cite_spans": [], "ref_spans": []}, {"section": "(b) Post-glacial", "text": "The zonation scheme adopted by Godwin for East Anglia (1940 and the rest of England and Wales (1940^, 1945) , does not correspond with Jessen's zonation of Danish (1935) and Irish (1938) diagrams, but it is hoped that with further publication a common scheme will be evolved. It is proposed, at present, therefore, as far as possible, to apply to the Windermere deposits the zonation system originally worked out by Godwin (1940 for the East Anglian fenland, and then applied by him to the profiles from other parts of England and Wales (1940 b ) .In the later post-glacial zones this system cannot be applied very closely to the Windermere diagrams, and it may be that these will show more affinity with Jessen's Irish diagrams than with those from the east and south of England.", "cite_spans": [], "ref_spans": []}, {"section": "(b) Post-glacial", "text": "Zone IV -Betula-Pinus zone. This zone is conspicuous in the marginal profiles, where about 30 cm. of deposit fall within it (figures 3, 4 and 10). Pirns shows a sharp fall from the high percentage present at the III to IV transition, presumably as with increasing warmth the production of local tree pollen, mainly B e t u l a, diminished the transported from a distance (cf. Jessen, as quoted by Mitchell, 1940) . Betula is by far the most important tree in this zone, providing about 90% of the total tree pollen. Corylus and Quercus are present, sometimes discontinuously, in very small quantities; the other warmth-loving trees are absent. The end of the zone is marked, as in East Anglia (Godwin 1940 a) , by a sharp fall in the non-tree/tree pollen ratio, suggesting that with increasing temperature the forest cover was becoming denser. There is a conspicuous Salix maximum in this zone in the Windermere deposits, which agrees with Jessen's Irish diagrams from Ballybetagh and Ralaghan, but differs from profiles from Shropshire (Hardy 1939) and East Anglia (Godwin 1940#) , where the Salix maximum does not occur until Zone V.", "cite_spans": [{"start": 397, "end": 412, "text": "Mitchell, 1940)", "ref_id": "BIBREF43"}, {"start": 1037, "end": 1049, "text": "(Hardy 1939)", "ref_id": "BIBREF27"}], "ref_spans": []}, {"section": "(b) Post-glacial", "text": "Zone V-Pinus zone. This zone is not so well marked as in East Anglia (Godwin 1940 a) , but in each profile from shallow water there is a maximum of Pirns with a corresponding decrease in B e t u l a, about 50 cm. above the top of the laminated clay, at the beginning of the sharp rise in Corylus (figures 3 and 4). Above this horizon, however, Betula again becomes more abundant than Pirns, so that the graphs for these two trees are not strictly comparable in the diagrams from Windermere and from the east of England respectively, but this persistence of Betula as the dominant tree throughout Zone V and the earlier part of Zone VI is characteristic of most profiles from the west of England and Wales (Godwin 1940 b, figures 5, 6) . Quercus is present in small amounts, Aims and Ulmus either absent or very scanty, and Tilia completely absent. Salix decreases in this zone until it is practically absent. Corylus begins to expand very rapidly, as in most British profiles, and reaches the very high values characteristic of northern and western sites.", "cite_spans": [], "ref_spans": []}, {"section": "(b) Post-glacial", "text": "Zone V I --Pinus-Corylus zone. In the early part of this zone, Betula is still the dominant tree, and the Corylus curve shows a single very pronounced maximum which may reach 8 0 % of the total tree pollen. Ulmus and Quercus appear to have spread very little, corresponding with other northern sites, but one profile (figure 10) shows a small maximum of Ulmus. Tilia is absent, Aims and Salix practically so. This early part corresponds to the subzone distinguished by Godwin as V ia.", "cite_spans": [], "ref_spans": []}, {"section": "(b) Post-glacial", "text": "In other parts of England, the second subzone, VI is distinguished by an increase in Quercus, but this is not apparent in Windermere, where this subzone is obscure. Throughout the latter two-thirds of Zone VI, Betula and Corylus decrease steadily. In the latter part of this zone, Pinus shows a second maximum as in some other British sites; this is rapidly followed by a very sudden expansion of Quercus and particularly Aims, with a corresponding abrupt decrease in Betula and Pinus. This rapid advance of Quercus and Aims falls into what is distinguished as subzone VI in the rest of England and Wales. In Windermere, round the margin of the lake, it corresponds exactly with a stratigraphic change from brown gyttja to a whitish clay. The secondary expansion of Pinus at the beginning of VI c is in many parts of western Europe correlated with a dry period giving a growth of Pinus on the dry bog surfaces; in Windermere this maximum may indicate growth of Pinus on drying bog surfaces in the drainage basin. The very sudden expansion of Aims, replacing Pinus, almost certainly indicates increasing wetness (the Boreal-Atlantic contact), and the stratigraphic change to what is apparently an alluvial clay deposited off each stream mouth is additional evidence for increased wetness of climate. The clay is rich in lake diatoms, and so is obviously waterlain.", "cite_spans": [], "ref_spans": []}, {"section": "(b) Post-glacial", "text": "Zone VII-alder-mixed oak forest zone. The subsequent phases in the forest history of the Windermere region are not well represented in the marginal profiles, since the three cores examined all show truncation of the upper deposits to a greater or lesser extent (possible", "cite_spans": [], "ref_spans": []}, {"section": "19-2", "text": "reasons for this truncation will be discussed later). The longest marginal profile (figure 4) shows that above the V Ic/V H boundary, Aim continues 60 % of the total tree pollen are reached, Quercus meanwhile falling off. Tilia appears and expands early in Zone V II in this profile (contrast diagrams from the south and east where Tilia appears earlier, i.e. in V I ); U l m u sr emains fairly constant at 10 to 15% of Pinus at the extreme top of this profile agrees with what is found in the most recent deposits in deep water, and in this marginal site it probably indicates discontinuity in deposition during the phases after the early part of Zone V II.", "cite_spans": [], "ref_spans": []}, {"section": "19-2", "text": "(2) Profiles from the middle of the lake (i a) Late-glacial In most of the cores obtained from deep water the late-glacial deposits are entirely inorganic, consisting of laminated clays with sometimes thin layers of sand or unlaminated clay. The grey detritus silt of shallow water which, it has been suggested, represents Zone II, or the Allerod layer, is not found within the 15 m. contour, but in some places in deeper water there is, at what is apparently a similar horizon, in the laminated clay, a narrow band of grey silty clay or an interruption in the regular bedding of the varves. This presumably indicates an interruption in the deposition of the varves at the time when the detritus silt was forming in shallow water, i.e. Zone II, followed by the regularly bedded varves of Zone III.", "cite_spans": [], "ref_spans": []}, {"section": "19-2", "text": "Zone IV -Betula-Pinus zone. The most striking feature of the pollen diagrams from deep water as compared with those from shallow water is the immense preponderance of Pinus in the early post-glacial zones in deep water. In the middle of the lake, the Betula phase of Zone IV is either absent (figure 8) or represented only by a small maximum of Betula in the 10 to 15 cm. of deposit immediately above the top of the laminated clay (figure 9).", "cite_spans": [], "ref_spans": []}, {"section": "19-2", "text": "Zone V-Pinus zone. The phase of tremendous dominance of Pinus extends from the top of this narrow Zone IV (or, where this is absent, from the top of the laminated clay) to the horizon about 1 m. above this, where Pinus is replaced by the rapidly expanding , i.e. Zone VI c .Within this metre of deposit, tree pollen other than Pinus is exceedingly sparse, and the only means of determining the boundaries of Zones V/VI is provided by the curve for Corylus. If Corylus is expressed as percentage of the total tree pollen, its curve has no definite form, but if the amount of Corylus is expressed as a percentage of the tree pollen excluding P i n u s , a very sharply defined peak corresponding to that shown by Corylu in marginal profiles is obtained. This peak, the sharp rise of which determines the boundary between Zones V and V ia occurs about 25 cm. above the top of the laminated clay. Zones IV and V are therefore represented by a much greater thickness of deposit in shallow water than in the middle of the lake.", "cite_spans": [], "ref_spans": []}, {"section": "19-2", "text": "Zone VI-Pinus-Corylus zone. The complete dominance of Pinus over all the other trees is maintained, with Corylus (expressed as percentage of tree pollen minus Pinus) falling steadily from its single maximum, until the horizon is reached at which Pinus falls off very abruptly and is replaced by the broad-leaved trees (VI , Quercus and Ulmus all expand simultaneously, and Betula also shows a percentage increase, but this is almost certainly not an absolute increase, but only relative, due to the decrease in Pinus. This sudden expansion of the broad-leaved trees corresponds, just as it does in shallow water, with a distinct stratigraphical horizon-here the topmost of the narrow clay bands. The implications of this will be discussed after the series showing the transition from marginal to central profiles has been considered.", "cite_spans": [], "ref_spans": []}, {"section": "19-2", "text": "Zone VII-Alder-mixed oak forest zone. The early part of this zone resembles the same horizon in the marginal profiles, with 7 Ilia coming in just above the Instead of the truncation which is present in all marginal profiles, however, 3 to 4 m. of brown gyttja are present above the V Ir/V II transition in deep-water profiles, and no consistent change in the proportions of the tree pollens takes place until the topmost 50 cm. of deposit are reached. Pirns falls off very rapidly just above the VI r/V II transition, and practically disappears for several metres of deposit. There is no trace of any increase in Betula, and this, combined with the complete absence of Fagus and Carpinus, makes it impossible to apply any further the zonation worked out for East Anglia and the rest of England and Wales. Possibly the Windermere diagrams may have more affinities with Jessen's hitherto unpublished profiles from Eire.", "cite_spans": [], "ref_spans": []}, {"section": "19-2", "text": "P irns, after its virtual disappearance some 2 m. below the mud surface, reappears at about 50 cm. below the mud surface and increases rapidly, until in the surface deposits it may reach 50 % of the total tree pollen. This suggests that the native P. sylvestris may have died out at some point in Zone V II, and that the reappearance of Pirns pollen in the most recent deposits may be due to planting.", "cite_spans": [], "ref_spans": []}, {"section": "19-2", "text": "The curve for grass pollen shows a steady rise from shortly after the beginning of Zone V II onwards, but the rise is greatly accelerated some 50 cm. below the point where Pirns reappears (figures 8, 9). The implications of this will be considered later.", "cite_spans": [], "ref_spans": []}, {"section": "19-2", "text": "(3)", "cite_spans": [], "ref_spans": []}, {"section": "Series of pollen diagrams along a transverse section of the North Basin of the lake", "text": "The eight cores on which pollen analyzes have been made form approximately a transverse section across the North Basin. A more detailed individual consideration of these cores will trace the transition from the marginal to the central stratigraphical and pollen sequence.", "cite_spans": [], "ref_spans": []}, {"section": "Series of pollen diagrams along a transverse section of the North Basin of the lake", "text": "(a) Cores 1 and 2, marginal, figures 3 and 4. These are from water of 3 and 3-5 m. depth respectively. Core 1 represents conditions off the stony shore in the middle of the curve of Low Wray Bay, and core 2 is from a position 150 yards to the north of this, in a sheltered site off the mouth of a small inflow stream near the northern horn of the bay (figure 1). The late-glacial zones correspond almost exactly in these two cores; the post-glacial sequence is more complete in the second. Though the two cores are not on the same transect across the lake, they illustrate two types of marginal sequence which may occur in closely adjacent positions.", "cite_spans": [], "ref_spans": []}, {"section": "Series of pollen diagrams along a transverse section of the North Basin of the lake", "text": "Zones I, II and III are represented by the stratigraphical succession described in the preceding section as typical of the late-glacial deposits in the lake. Zone II, the detritus silt, is thicker (61 cm. as against 54 cm.) and contains more organic remains in core 1, from nearer the shore, probably due to the drift of sediment controlled by the water currents prevailing at the time. The pollen curves for the late-glacial correspond exactly in the two diagrams (figures 3 and 4), with Betula making up more than 90% of the pollen in the detritus silt, Pirns occasional, and Quercus appearing at the top. The curves for and grass pollen have the concave shape characteristic of deposits of the Allerod oscillation. The upper laminated clay (Zone III) corresponds exactly in these two cores, there being about six conspicuous grey varves which can be readily correlated with the naked eye. Zone IV is also closely similar in the two cores. Stratigraphically it is a clay-gyttja in which the clay content decreases rapidly on passing upwards from the top of the upper laminated clay. The point at which this pinkish clay-gyttja passes upwards into brown detritus gyttja is indeterminate, but corresponds approximately with what appears to be the IV/V transition, i.e. the point where a maximum of Pinus begins to develop and about the point where the falling grass crosses the rising Corylus curve. Zone IV therefore almost corresponds with this clay-gyttja in these two cores, the latter being about 25 cm. thick and Zone IV 25 to 35 cm., according to where the boundary is fixed. Zones V and VI a are again exactly similar in the two cores, with Betula recovering its dominance after the small Pirns maximum of Zone V, and Corylus rising ex to very high values. The deposit is a brown detritus gyttja containing very abundant plant remains in a finely divided state. So abundant are these vegetable fragments that the gyttja has an appearance approaching that of a very fine peat.", "cite_spans": [], "ref_spans": []}, {"section": "Series of pollen diagrams along a transverse section of the North Basin of the lake", "text": "The topmost deposits of core 1 (apart from possibly 1 or 2 cm. of unconsolidated surface ooze which tends to wash out of the sampler) belong to Zone VI a-i.e. are of Boreal age. This truncation of the profile suggests that the deposits continued to accumulate until the surface was built up into the zone of wave erosion, after which no further deposition was possible. The present depth of water at this site at mean lake level is 3 m.", "cite_spans": [], "ref_spans": []}, {"section": "Series of pollen diagrams along a transverse section of the North Basin of the lake", "text": "The post-glacial deposits of core 2 (water depth 3-5 m.) extend for a further 2-5 m. above the horizon at which core 1 is truncated; presumably this represents deposition in a hollow in the late-glacial lake floor. Zone V I shows the features described in the preceding section, and covers a total thickness of about 2 m. The marked stratigraphical change from gyttja to whitish clay which accompanies the rapid expansion of and (less strikingly) Quercus, in VI c ,has already received comment. Along the western shores of the North Basin this clay is thickest off the mouths of small inflow streams (core 2 being from such a position), from which it thins out both laterally and towards the middle of the lake, but further analysis will be necessary in order to determine its depth-time relationships at the margin of each deposit. In Zone V II Pinus falls off rapidly to very low values, and Tilia shows an expansion (characteristic of early Zone V II in all the Windermere diagrams) followed by a rapid falling off. Alnus maintains its predominance until the topmost 10 cm. is reached; here Pinus shows a rapid expansion corresponding with the stratigraphical change from the topmost part of the clay, here brown and indurated, to soft black, more or less uncon solidated gyttja. Comparison with the profiles from the middle of the lake suggests that the black gyttja containing Pinus is recent, so it appears that this core was truncated about 90 cm. above the base of ZoneV I I ; thePm&y-containing gyttja maybe unconsolidated deposit still undergoing wave erosion, or it may be that changes in the prevailing wind and hence in currents have made accumulation possible again in this position after a discontinuity. ", "cite_spans": [], "ref_spans": []}, {"section": "(b)", "text": "Core 3, in 10 m. of water, and in addition the basal part of core 3 from 7-6 m. of water was analyzed. In these cores the upper and lower laminated clays resemble the corresponding deposits in the marginal profiles, but the intervening detritus silt is much thinner there than in cores 1 and 2, and is very different in character. Whereas in those cores Zone II is a detritus silt which in places becomes almost pure plant detritus, in cores 3 and 3 a the corresponding deposit contains much less organic matter, practically no plant remains, and very little pollen, and it is practically a pure silt with a little clay admixture.", "cite_spans": [], "ref_spans": []}, {"section": "(b)", "text": "So sparse is the pollen in this silt that it was not possible to construct any pollen cufves for the late-glacial in these cores. The few counts available show that is more abundant than Betula in the silt layer. From its position between the upper and lower laminated clays this layer must be correlated with Zone II in the marginal profiles, and there Betula is dominant throughout this zone. The relative increase in on passing into deeper water may be due to the same causes as the corresponding phenomenon in the post-glacial deposit, which is discussed at the end of this section.", "cite_spans": [], "ref_spans": []}, {"section": "(b)", "text": "In these two cores, Zones IV, V and VI are very narrow compared with the marginal sites (figures 5 and 6), and it is difficult to define their boundaries accurately. After an initial phase of high Pirns at the transition from the upper laminated clay to the post-glacial deposits, there is in both cores a narrow layer where Betula is present in appreciable quantity, this Betula phase being better developed in 3 (7-6 m.) than in 3 (10 m.). , however, remains the dominant species throughout these early zones in both cores. In 3 a,Corylus shows a well-marked single maximum with its peak (Zone V ia) just above the Betula maximum, and the Corylus curve retains this form when Corylus is expressed as percentage of total tree pollen minus Pinus. In core 3, Corylus shows no maximum when plotted as percentage of total tree pollen, but if plotted as percentage of total tree pollen minus P i n u s, a conspicuous maximum appears at a corresponding horizon to that in core 3a, i.e. just above the Betula maximum. In both cores the Corylus maximum (Zone V ia) is followed almost immediately by the very rapid expansion of Alnus and Quercus with corresponding decrease in P i n u s, characteristic of Zone VI and the subsequent form the pollen curves is similar to that already described for Zone V II. At 1 m. below the mud surface, Tilia and Ulmus practically disappear-this may represent Zone V II and correspond with the similar disappearance of these two species at the top of the diatomaceous white clay in core 2. The deposits of cores 3 and 3 are stratigraphically uniform (brown gyttja) from Zone VI cu ntil the 20 cm. of surface ooze is reac shows the marked increase which has already been mentioned as occurring in the recent deposits.", "cite_spans": [], "ref_spans": []}, {"section": "(b)", "text": "These two cores therefore show two striking differences from the marginal cores. First, there is the compression of Zones IV, V and VI into about 25 cm. of deposit as compared with 250 cm. in core 2, and the fact that all three pollen zones are here included in the stratigraphical zone of clay-gyttja, whereas in cores 1 and 2 Zone IV covered the entire thickness of this deposit. Secondly, there is the overwhelming dominance of Pirns in these early zones, contrasted with the same zones in the marginal profiles, where Pirns occurs in roughly the same (or somewhat smaller) proportions to the other trees as at corresponding levels in pollen diagrams from the rest of England (Godwin 1940 \u00a3) . In immediately post glacial times, therefore, deposition must have been much more rapid at the margins (3 m.) than in water 7 to 10 m. deep, and the deposit in the more central position was claygyttja throughout the period until the Boreal-Atlantic transition, whereas at the margin this facies developed only in Zone IV, being followed by detritus gyttja in Zones V and VI.", "cite_spans": [], "ref_spans": []}, {"section": "(b)", "text": "(c) Core 4, from 27 m. of water. The present floor of the lake slopes steeply at this point (figure 2), and the junction between the top of the laminated clay and the post-glacial gyttja shows that the late-glacial lake floor also sloped steeply. It was immediately evident from the stratigraphy of this core that a discontinuity was present at the top of the laminated clay, which was overlain by brown detritus gyttja without any trace of the transitional claygyttja present in both deeper and shallower water. The whole of the laminated clay in this core resembles the lower laminated clay rather than the upper, because the laminations are all relatively wide. The total thickness of the detritus gyttja (brown mud) is here much less than in cores from either deeper or shallower water. All these factors agree in suggesting that a strong unconformity is present, and pollen analysis confirmed this (figure 7). The relatively wide laminations of the clay place it in Zone I, which means that the whole of Zones II and III are missing. The base of the gyttja (brown mud), i.e. at the contact of this deposit with the laminated clay, has a pollen spectrum characteristic of Zone V II, with Aims reaching nearly 4 0 %, high , Tilia present, and Betula and Pirns present in only small quantities. The pollen curves above this point take the form characteristic of Zone V II in Windermere, and there is the usual increase in Pinus corresponding with the development of the surface ooze. It is obvious that in this core there are missing not only Zones II and III, but also IV, V, VI and the early part of V II (before the appearance of Tilia). Clearly either the conditions during the period of formation of Zones Il/V IIa were such that no deposition took place, or else violent erosion removed these deposits before the deposition of the existing gyttja-i.e. approxi mately Zone V II c.The former explanation seems more probable, since it is easier imagine climatic plus topographical conditions which would produce an off-shore current preventing deposition, than to suggest any possible cause of sufficiently powerful erosion in this depth of water.", "cite_spans": [], "ref_spans": []}, {"section": "(d)", "text": "Cores 6, in 46 m. of water, and 7, in 65 m. of water. Both these cores are from the middle of the lake, and their position on the profile of this transect is shown in figure Core 7 is from the deepest central part of the lake, i.e. about 600 yards to the south of the line of the transect. The two cores correspond almost exactly with each other, except that in core 7 each post-glacial zone and stratigraphical horizon is expanded as compared with core 6, the total thickness of deposit above the laminated clay being 5*3 m. in core 7 compared with 4*2 m. in core 6. The pollen diagrams from these cores have already been described. Zones IV, V and VI are difficult to distinguish, since the enormous preponderance of Pirns pollen (average 9 0 %) masks the other changes. Pollen other than Pirns is very sparse. The very high peak of the Corylus maximum which appears when Corylus is plotted as percentage of the tree pollen minus", "cite_spans": [], "ref_spans": []}, {"section": "(d)", "text": "Pinus fixes the horizon of Zone V ia, but otherwise no boundaries can be assigned to these first three post-glacial zones. The thickness of deposit included in these zones is 50 cm. in core 6 and 140 cm. in core 7, and in each core this corresponds exactly with the stratigraphical zone of clay-gyttja, or zone of narrow clay bands (the latter referring to the narrow bands of pink unlaminated clay which are present in the claygyttja in deep water (Pennington 1943) ). In each core, the topmost of these narrow clay bands corresponds exactly with the rapid expansion of the broad-leaved trees (particularly Alnus) with corresponding decrease in P i n u s, i.e. the Zone V Ir/V II boundar curves for Zone V II have already been described, as also has the increase in Pinus corresponding with the surface ooze.", "cite_spans": [{"start": 449, "end": 466, "text": "(Pennington 1943)", "ref_id": "BIBREF52"}], "ref_spans": []}, {"section": "(d)", "text": "(e) Core 8, marginal, from 4*8 m. on the eastern side of the lake. This core corresponds almost exactly with the marginal cores from the western shore, being intermediate between cores 1 and 2 in most respects. The late glacial zones and Zone IV correspond exactly in all three cores; core 8 is truncated very early in Zone V II, and the thickness of deposit in Zones IV to VI is rather less than in core 2 (figure 10). (4) Conclusions drawn from zonation of pollen diagrams The width of the zones in shallow water and deep water respectively shows that in lateglacial and early post-glacial times, organic deposits accumulated much more rapidly at the margins than in deep water, where deposition was very slow. Deposition at the margins apparently ceased when the mud surface came within about 3 m. of the water surface. The shore-line of Low Wray Bay on the position of the transect is stony and the site of core 1 (3 m. water depth) was the shallowest place where the bottom was consistently soft. It is known from recent sedimentation experiments (Pennington, in preparation) that turbulence in the lake water may pick up sediment which has already been deposited on the bottom, even in water depths considerably greater than 3 m. These results of observations in Low Wray Bay suggest that where the shore-line is stony to a depth of about 3 m., no further accumulation of sediment is taking place, and therefore in such a position under present circumstances-the lake floor will never rise above the water-line; therefore there is no hydrosere (Tutin 1941) . Mitchell (1940) found that in the old lake basin at Dunshaughlin, Co. Meath, the early post-glacial zones were very narrow in the central part of the basin-i.e. that here also deposition was rapid at the margins compared with the centre in the early post-glacial stages. At Dunshaughlin, however, the marginal accumulation continued until the deposits were built up above water-level, and in time the shallow basin was almost completely filled by this process combined with more rapid accumulation qf detritus mud in the centre during and after Zone V II (Jessen's zonation-'the first period in which Aims reaches a dominant position'). Comparing figure 2 b with Mitchell's figure 7, it will be seen that appreciable deposition in the central part of Windermere began at about the same period but was much more rapid, presumably because of the much greater volume of sediment entering the lake. The differences can all be related to the great contrast in size and shape between the two basins, the late-glacial floor of Windermere forming a basin, reaching a maximum depth of c. 70 m., and with an area whereas at Dunshaughlin the late-glacial basin was only about 6 m. deep and 1 mile long by | mile wide. This means that wave action would be very much restricted in the Dunshaughlin basin compared with Windermere, so that the marginal deposits accumu lated continuously until they reached water-level, when peat formation began. These two lake basins are an interesting example of the contrast in the method of filling up of a small shallow and a large deep lake respectively. Considering the pollen zonation in relation to the stratigraphy, while the late-glacial Zones I, II and III correspond exactly with stratigraphical horizons, the early post-glacial zones present a more complex picture. In both marginal and central positions, the earliest post-glacial deposit is a transitional clay-gyttja, thicker in the centre than at the margins and containing a characteristic diatom flora (Pennington 1943) . It was formerly assumed that this clay-gyttja (or 'zone of narrow clay bands' in deep water) was contemporaneous in deep and in shallow water, but the results of pollen analysis show that this is not so. In the marginal sites, the clay-gyttja corresponds approximately with Zone IV, but in deep water the zone of narrow clay bands includes Zones IV, V and VI, so that only the basal part, at most that below the lowest clay band, is contemporaneous with the shallowwater clay-gyttja. The upper part of the zone of narrow clay bands in deep water is there fore contemporaneous with 'brown m ud' (detritus gyttja) in shallow water. In the intermediate water depths where the lake floor shelves steeply, pollen analysis has confirmed the results ofstratigraphical observation-i.e. that there is a strong unconformity (figure", "cite_spans": [{"start": 1550, "end": 1562, "text": "(Tutin 1941)", "ref_id": "BIBREF57"}, {"start": 1565, "end": 1580, "text": "Mitchell (1940)", "ref_id": "BIBREF43"}, {"start": 3556, "end": 3573, "text": "(Pennington 1943)", "ref_id": "BIBREF52"}], "ref_spans": []}, {"section": "(d)", "text": "The distribution of Pirns pollen shows two striking features. Its frequency is high at t beginning and end of Zone III, and possibly also in the main part of Zone III. Jessen (1929) suggests that this apparent importance of Pinus in cold periods may be due to the undue prominence of pollen transported from a distance when local pollen is sparse. Groschopf (1936) quotes evidence (Knoll 1932 ) that long-distance transport of Pinus does not occur to any great extent, but believes that differential settling of pollen may occur in lake deposits (Ernst 1934 ) where a marked dominance of Pinus may occur.", "cite_spans": [{"start": 168, "end": 181, "text": "Jessen (1929)", "ref_id": "BIBREF34"}, {"start": 348, "end": 364, "text": "Groschopf (1936)", "ref_id": "BIBREF24"}, {"start": 381, "end": 392, "text": "(Knoll 1932", "ref_id": "BIBREF40"}, {"start": 546, "end": 557, "text": "(Ernst 1934", "ref_id": "BIBREF17"}], "ref_spans": []}, {"section": "(d)", "text": "This last is interesting in view of the second striking feature in the distribution of Pinus pollen in Windermere, which is its extremely high frequency in the middle of the lake in Zones IV, V and VI, while at the margins the frequency of in these zones is much lower. A similar example of difference in composition of the pollen spectrum of marginal and central deposits is recorded by H arri (1940) from a Swiss 'moss' which was originally a moraine-dammed lake; here Fagus is better represented in the centre and Abies at the margins. Such a difference may be explained either by a difference between the local (marginal) pollen rain and the general (regional) pollen rain which reaches the middle of the lake, or by differential settling or preservation of the pollen of various species in deep and in shallow water.", "cite_spans": [], "ref_spans": []}, {"section": "(d)", "text": "In Windermere there is no positive evidence that Pinus was so overwhelmingly dominant in the regional pollen rain as it is in the deposits from the centre of the lake. In the nearest terrestrial profiles analyzed (e.g. Hardy 1939 ) Pinus is present in Zones IV, V and VI in proportions approximately similar to those found at the same horizons in the marginal deposits of Windermere-i.e. there is much less Pinus pollen in these terrestrial deposits than in the central deposits of Windermere. Moreover, the Boreal hazel maximum, which is a feature recognized throughout north-west Europe to the west of Ireland, becomes apparent in the central deposits of Windermere only when Corylus is plotted as a percentage of tree pollen minus Pinus. This suggests that the spectrum of the marginal deposits gives the truest picture of the amount of Pinus in the drainage basin as a whole, and that Pinus is strongly over-represented in the centre.", "cite_spans": [{"start": 219, "end": 229, "text": "Hardy 1939", "ref_id": "BIBREF27"}], "ref_spans": []}, {"section": "(d)", "text": "No quantitative estimates have been made of the absolute frequency of and the deciduous pollens, but it is obvious that the marginal deposits are much richer in pollen than are those in the centre. Pollen of the deciduous trees is very sparse throughout the central deposits; the relative abundance of pollen in the lower central deposits is due entirely to the great quantities of Pinus pollen present. It therefore appears little pollen except that of Pinus becomes incorporated in the central deposits, so that whenever Pinus is present in the vegetation it becomes over-represented in these central deposits.", "cite_spans": [], "ref_spans": []}, {"section": "(d)", "text": "Further experimental work would probably help to elucidate the reasons for this. A pollen count from the surface mud in the centre of the lake gave a spectrum containing 5 0 % P i n u s; this appears to be an over-estimate of its proportion in the surrounding vege tation, but it is not possible to say this with certainty until we know more of the relative amounts of pollen produced by different trees. The sources of the pollen which becomes incorporated in the central deposits could be investigated by examining the content of (1) the inflow water, and (2) the pollen rain reaching the water surface in the middle of the lake; this would show whether Pinus is already over-represented in this. If not, it is probable that differential settling or differential preservation favours the accumulation of Pinus rather than the deciduous pollens.", "cite_spans": [], "ref_spans": []}, {"section": "(d)", "text": "The change from the marginal type of deposit to the central in which , if occurring, is over-represented, occurs in 4 to 10 m. of water in Low Wray Bay, and coincides with a stratigraphical change from very organic brown mud (gyttja) containing abundant plant detritus, to the much less organic brown mud characteristic of the centre of the lake. The absolute pollen frequency is high in the marginal gyttja and low in deposits from water of more than 8 m. deep. It seems likely that this depth of water indicates the position, on this transect, of the boundary between the deposits of predominantly littoral origin and those originating from material carried in by the inflow.", "cite_spans": [], "ref_spans": []}, {"section": "(d)", "text": "The curve for grass pollen expressed as percentage of the total tree pollen shows the characteristic concave shape in Zones I, II and III, indicating that woodland had more or less replaced open grassland at the height of the climatic amelioration in Zone II. Grass pollen is again abundant at the opening of Zone IV, and falls rapidly throughout this zone with the advance of the forest cover. In Zone VI the relative amount of grass pollen slowly begins to rise, and this rise is greatly accelerated in the topmost 1 to 1*5 m. of deposit (figures 7, 8 and 9) . This rise may indicate forest clearance (cf. Iversen 1941) while this topmost 1 to 1-5 m. was accumulating; if so, forest clearance in the district probably began 2000 to 2500 years ago. For a discussion of this point see Pearsall & Pennington (1947) .", "cite_spans": [{"start": 785, "end": 813, "text": "Pearsall & Pennington (1947)", "ref_id": "BIBREF51"}], "ref_spans": []}, {"section": "Macroscopic plant remains (1) From late-glacial detritus silt", "text": "All the late-glacial plant remains which have been recovered came from this detritus silt layer; no plant remains have been found in either the upper or the lower laminated clay in any part of the lake. The detritus silt contains plant remains only in the marginal cores-i.e. those from very shallow water. The plants listed here were all found in cores 1, 2 and 8 already described, or in cores from equally shallow water in the bays in the western shore between High Wray Bay and the mouth of Blelham Beck. In water deeper than 5 m. the deposits of this layer are mainly inorganic with very little plant detritus.", "cite_spans": [], "ref_spans": []}, {"section": "Macroscopic plant remains (1) From late-glacial detritus silt", "text": "The lowest and, therefore, presumably the oldest organic remains found in the lake were almost leafless moss stems, apparently much eroded, present in the greyish pink clay forming the transitional deposit between the lower laminated clay (Zone I) and the detritus silt (Zone II). Mitchell (1940) found similar moss stems occurring as the oldest ", "cite_spans": [{"start": 281, "end": 296, "text": "Mitchell (1940)", "ref_id": "BIBREF43"}], "ref_spans": []}, {"section": "21", "text": "organic remains in a former lake basin in Ireland, at the base of Zone II. There seems no possibility of identifying the moss stems from Windermere unless specimens in a better state of preservation are found, but it was apparently a long-stemmed, probably creeping type. The grey-pink clay passes upwards into a transitional clay-silt, containing stems and leaves of mosses belonging to the genera Hypnum and , and leaves identified as those of Poly trichum alpinum. One fragment of a larger leaf (figure 12) resembles Salix phylicifolia, which Jessen & Farrington (1938) record from what they regard as Zone II at Ballybetagh, near Dublin, and Hartz & Milthers (1901) from Zone I at Allerod; in all instances the fossil leaf is distinguished from S. repens by its flat margin, the margin of the leaf of S. repens being recurved. The Windermere specimen is, however, too fragmentary to be identified other than tentatively. (The present distribution of S. phylicifolia in northern Britain is along streams on limestone above the 600 ft. contour (Pearsall in litt.) .) In this transitional clay-silt the pollen diagrams show that the ratio of non-tree pollen (mainly grass) to tree pollen was high; in conjunction with the above plant list this may be regarded as indicating that the vegetation was open and included at least some species having a northern distribution at the present day.", "cite_spans": [{"start": 546, "end": 572, "text": "Jessen & Farrington (1938)", "ref_id": "BIBREF37"}], "ref_spans": []}, {"section": "21", "text": "The transitional clay-silt passes upwards into the main detritus silt, which is in parts very rich in plant remains. This corresponds to the horizon where Betula pollen is very strongly dominant-i.e. Zone II, and probably represents a period when birch woodland was the prevailing vegetation, since the ratio n .t.p ./t.p . is low. Catkin scales and fruits of Betula corresponding to those of B. pubescens Ehrh. em. Koch (Lindman 1926) occur throughout this middle part of Zone II, and are commonest about two-thirds of the way up (table 1); this appears to have been the height of the birchwood phase. No remains of B. nana were found in any layer in Windermere. The pollen grains of Betula from the lateglacial layers were all measured, but the size-frequency graphs gave no consistent indication of a bi-modal curve, such as would have been expected had the smaller grains of B. nana been present (Godwin 1934) . Moss stems and leaves, some in a fairly good state of preser vation, are common, including Barbula cf.", "cite_spans": [{"start": 421, "end": 435, "text": "(Lindman 1926)", "ref_id": "BIBREF41"}, {"start": 900, "end": 913, "text": "(Godwin 1934)", "ref_id": "BIBREF21"}], "ref_spans": []}, {"section": "21", "text": "r u b e, Rhacomitrium cf. fasci spp., Hypnum spp., etc. Other terrestrial plants identified from this phase of Zone II are Rubus saxatilis (seed), Viola palustris (seed), Thalictrum minus (fruit), Menyanthes trifoliata (seed), Andromeda polifolia (leaf fragments) and Populus tremula (catkin scale) (figures 13 and 14). Fruits and perianth segments of a Rumex were common in the upper part of this horizon; the perianth segments (see figure 12) were fairly large, cordate at the base, without tubercles, and with undulated margins to the epidermal cells, and the nut was 3 to 3'5 mm. long. This suggests that the species was R. but does not exclude R. arifolius (recorded by G. C. Druce three times from the Scottish mountains), or R. thyrsijlorus (a Scandinavian species). Jessen (1938) , recording R. Acetosa from the lake mud which he regards as the equivalent of the Allerod layer at Ballybetagh, near Dublin, comments that 'it goes far up over the forest limit in Scandinavia'. It is possible that the occurrence of R. Acetosa in considerable quantity in the deposit above the maximum Betula development indicates the beginning of cooler conditions with consequent decrease in tree growth, but since it is such a common plant in the district to-day this is by no means conclusive.", "cite_spans": [{"start": 774, "end": 787, "text": "Jessen (1938)", "ref_id": "BIBREF36"}], "ref_spans": [{"start": 434, "end": 444, "text": "figure 12)", "ref_id": "FIGREF1"}]}, {"section": "21", "text": "Unidentified fragments of the leaves of broad-leaved plants, twigs and bark are very common in this main part of the detritus silt. Many of the larger leaf fragments are almost certainly those of a large-leaved B e t u l a, but are too small to be identified with c The most abundant of all the plant remains in this layer are the leaf segments of Myriophyllum, which in places occur as an almost pure deposit (figure 15 plate 2). Like most of the organic remains they appear to have suffered considerable erosion; it is therefore impossible to determine their original length, and hence not possible to refer them to a species with any certainty. The segments are more slender than seems usual in M. and on the whole they are wider than the long segments of the aquatic form of M. verticillatum, so it is reasonable to suggest that they are most likely to be M. alterniflorum. This would agree with the fact that the only Myriophyllum pollen found in this layer is that of 21-2 ", "cite_spans": [], "ref_spans": []}, {"section": "M .", "text": "alternijiorum , but is, of course, in no sense proved by this. Whatever the species it seems certain that a luxuriant littoral growth of Myriophyllum was a feature of the lake vegetation during this period. In all the cores examined the detritus silt is overlain by 2 to 5 cm. of grey clay containing plant remains which forms the topmost deposit of Zone II. Plant remains, like the pollen, are sparser in this clay than in the detritus silt, but the leaves of Polytrichum alpinum are common, and the fruit and perianth segments of Oxyria digyna were found at the base of this clay in one core (figure 12). Fruits of Car ex and Scirpus spp. are also common. Oxyria digyna is recorded by Jessen (1938) from Zone III at Ballybetagh; its present distribution is markedly Arctic-Alpine. Its appearance here at the top of Zone II, accompanied by Polytrichum a l p i n u m , a mountain and moorland species, together with the fact that here the n .t.p ./t.p . ratio again becomes high, suggests that this 2 to 5 cm. of grey clay was deposited under conditions colder than the preceding, when the climate was again becoming severe. The grey clay is everywhere overlain by horizontally bedded laminated clay (Zone III), showing that there were again glaciers in the drainage basin.", "cite_spans": [{"start": 687, "end": 700, "text": "Jessen (1938)", "ref_id": "BIBREF36"}], "ref_spans": []}, {"section": "M .", "text": "Correlation of this late-glacial detritus silt with the Altered layer of north-western Europe which has been recognized in Ireland. All the evidence from Windermere, from stratigraphy, pollen analysis and macroscopic plant remains, supports the view that this detritus silt represents a temporary period of relative warmth during the retreat of the ice-sheet. T hat this period was not of interglacial magnitude is shown by the relative narrowness of its deposits (maximum 50 cm.) and by the fact that it is overlain only by a comparatively thin deposit of laminated (and therefore presumably waterlain) clay. This shows that there was no readvance of ice over the site after the temperate period, but presumably only a downward movement of valley glaciers from the central mountains towards the lake. This is in contrast with the interglacial deposits of the neighbouring coastal plain (Kendall 1881; Eastwood, Dixon, Hollingworth & Smith 1931) where peat beds containing the remains of temperate plants are sometimes several feet thick and are overlain by boulder clay, presumably deposited in situ. It would appear probable that the layer of detritus silt in Windermere was produced as the result of a temporary fluctuation during the final retreat of the icei.e. subsequently to the formation of the upper layer of boulder clay on the coast.", "cite_spans": [{"start": 887, "end": 901, "text": "(Kendall 1881;", "ref_id": "BIBREF39"}, {"start": 902, "end": 945, "text": "Eastwood, Dixon, Hollingworth & Smith 1931)", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "M .", "text": "The deposits of a similar climatic fluctuation, involving a temporary warmer period, have been described by many continental workers, and correlated with Jessen's zonation in Denmark, where the deposits of Zone II (the temperate or cool-temperate period) are known as the Allerod layer, from the locality where they were first described (Hartz & Milthers 1901) . Deposits referable to the 'Allerod period', i.e. Jessen's Zone II, have been discovered in west Norway (Nordmann 1912; Faegri 1936) , south Sweden (Nilsson 1935) , north Germany, east Prussia and the Baltic States (Gross 1937 (Gross ,1938 , as well as in Denmark. Mention has already been made of the late-glacial lake mud found in Ireland which has been tentatively correlated by Jessen with the Danish Allerod (Jessen & Farrington 1938; Mitchell 1940) . These deposits all agree in possessing certain characters which are also possessed by the Windermere deposits described in this paper as Zone II. Typically the temperate or cool-temperate ' Allerod layer ' consists of a fresh-water deposit resting on the clay of Zone I, which is either boulder clay, or clay containing Arctic plants, or laminated clay resting on glacial sands or boulder clay, as in Windermere. The overlying deposit of Zone III is not a boulder clay deposited in , but usually a clay which may contain Arctic plants, or else, as in Ireland, an unsorted mineral deposit apparently originating by solifluction. In each locality the deposit of Zone III is the uppermost (and hence the latest) deposit showing any trace of Arctic influence, and each of the above authors places the late-glacial/post-glacial boundary at the upper limit of Zone III. This agrees completely with the succession in Windermere.", "cite_spans": [{"start": 466, "end": 481, "text": "(Nordmann 1912;", "ref_id": "BIBREF48"}, {"start": 482, "end": 494, "text": "Faegri 1936)", "ref_id": "BIBREF18"}, {"start": 510, "end": 524, "text": "(Nilsson 1935)", "ref_id": "BIBREF47"}, {"start": 577, "end": 588, "text": "(Gross 1937", "ref_id": "BIBREF25"}, {"start": 589, "end": 601, "text": "(Gross ,1938", "ref_id": "BIBREF26"}, {"start": 775, "end": 801, "text": "(Jessen & Farrington 1938;", "ref_id": "BIBREF37"}, {"start": 802, "end": 816, "text": "Mitchell 1940)", "ref_id": "BIBREF43"}], "ref_spans": []}, {"section": "M .", "text": "The plants identified, either by pollen or macroscopic plant remains, show that the vegetation of the Windermere region at this period had many features in common with that of the continental localities described by the above authors. At the height of the climatic amelioration, the prevailing vegetation was woodland, predominantly the large Betula species (i.e. other than B. nana), with some Pirns and Populus tremula (Jessen 1939; Gross 1937) . If plants have been identified from the underlying and oveflying deposits (usually clays) some Arctic-Alpine species are usually included (Jessen 1935, etc.; Hartz & Milthers 1901) ; in Denmark Zones I and III are known as the lower and upper Dry as clays, and D. octopetala commonly occurs at these horizons in other localities. No trace of this species has been found in Windermere, but three species, Polytrichum alpinum, Oxyria digyna and Salix p h y l i c i f o l i a , having a northern distribution have been found at the base and top of Zone II. Myriophyllum a l t e r n i f l o r u m , common in Zone II in Windermere, is a species characteristic of late-glacial and pre-Boreal deposits (Nilsson 1935; Erdtm an 1943; Von Post 1935) . The flora of the Allerod layer, cool-temperate at the height of the period, contrasts with that of interglacial deposits in Denmark, in which remains of a warmthloving flora, mixed oak forest with T ilia,A cer campestre and Carpinus , in the summers in this interglacial period were warmer than at the present day (Jessen & Milthers 1928 ).", "cite_spans": [{"start": 435, "end": 446, "text": "Gross 1937)", "ref_id": "BIBREF25"}, {"start": 1145, "end": 1159, "text": "(Nilsson 1935;", "ref_id": "BIBREF47"}, {"start": 1506, "end": 1529, "text": "(Jessen & Milthers 1928", "ref_id": "BIBREF38"}], "ref_spans": []}, {"section": "(2) From post-glacial deposits", "text": "Most of the plant remains in the deep-water deposits are too finely divided to be identified, though an exception occurs in the layers of what is apparently flood debris which occur in positions off the mouths of larger inflow streams (Pennington 1943) .", "cite_spans": [{"start": 235, "end": 252, "text": "(Pennington 1943)", "ref_id": "BIBREF52"}], "ref_spans": []}, {"section": "(2) From post-glacial deposits", "text": "In very shallow water, where the post-glacial deposits above the basal clay-gyttja consist of very organic gyttja with large quantities of visible plant remains (see previous section), the leaf segments of M y r i o p h y l l u m, probably a l, are abunda but not in later deposits. Fragments of leaves, twigs and bark, and pieces of wood up to 1 cm. cube, occur occasionally in these deposits. The wood is much decayed, and it has not yet been possible to identify it by microscopic examination.", "cite_spans": [], "ref_spans": []}, {"section": "General discussion", "text": "(1) Dating the deposits; possible correlations [a) Late-glacial. Evidence has been given in the preceding section for correlating the late-glacial sequence in Windermere with that found in Ireland and north-west Europe. If this evidence is accepted, it establishes that, both in north-west England and Ireland on the one side and north-west Europe on the other, there occurred a temporary warmer period with temperate or cold-temperate birchwoods, during the last stages of retreat of the Quaternary ice-sheets. The cold period following this warmer period represented the last appreciable advance or halt of the Quaternary ice, and the deposits of this cold period contain the last records of Arctic-Alpine plants in lowland districts. The deposits of the temporary warm period, the Allerod, have been recognized all round the southern edge of the Scandinavian ice-sheet, from western Norway to western Russia (see previous section). In Ireland the deposits so far described indicate that a similar climatic oscillation occurred during the final retreat of valley glaciers from the mountains of Wicklow and north-west Ireland (Jessen & Farrington 1938; Mitchell 1940) .", "cite_spans": [{"start": 1127, "end": 1153, "text": "(Jessen & Farrington 1938;", "ref_id": "BIBREF37"}, {"start": 1154, "end": 1168, "text": "Mitchell 1940)", "ref_id": "BIBREF43"}], "ref_spans": []}, {"section": "General discussion", "text": "In all these localities the sequence of deposits shows that the last cold period was followed by the gradually improving climate of the post-glacial period, the climatic sequence being that described by Blytt & Sernander-i.e. a gradual increase in average temperature through the dry pre-Boreal and Boreal periods, followed by the wet warm Atlantic period in which occurred the so-called climatic optimum, followed by decreasing temperature. Forest development as shown by pollen analysis followed a parallel course through open birchwood, birch-pine, pine forests, and then the incoming of mixed oak forest with alder at the opening of the Atlantic period. This parallel development of climate and vegetation strongly suggests that the last cold period on the margins of the north-west European centres of glaciation was roughly contemporaneous in all these localities (Zeuner 1946) , since to suppose otherwise would be to assume that the succeeding phases of forest development were not contemporaneous, and if this were so it is difficult to understand why they followed such a parallel course in localities from western Ireland and Norway to western Russia.", "cite_spans": [{"start": 870, "end": 883, "text": "(Zeuner 1946)", "ref_id": "BIBREF60"}], "ref_spans": []}, {"section": "General discussion", "text": "If it is found possible to correlate the series of varves in Windermere with the Swedish series, this should give valuable evidence of this question of contemporaneity of the Allerod layer in the different localities, though the interpretation of the varves which occur in Zone I (i.e. below the lake mud) at Allerod itself appears still to be controversial (De Geer 1916; Nordmann 1922; Milthers 1927) . The time-scale based on the Swedish varves, developed by De Geer (1908 et seq., 1940 appears to be the most promising source of a late-glacial chronology on which direct time correlations could be based. The difficulties incurred in measurement of the Windermere varves have been discussed, but it is probable that improvements in technique may enable these difficulties to be overcome.", "cite_spans": [{"start": 373, "end": 387, "text": "Nordmann 1922;", "ref_id": "BIBREF49"}, {"start": 388, "end": 402, "text": "Milthers 1927)", "ref_id": "BIBREF42"}, {"start": 462, "end": 475, "text": "De Geer (1908", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "General discussion", "text": "Meanwhile the Windermere varves have provided one positive piece of evidence in favour of direct correlation with the continental succession. It is now generally considered by continental workers (Gross 1937; Gams 1938) , in spite of the earlier controversies, that the cold period which followed the Allerod oscillation was that during which the Fennoscandian moraines were formed-i.e. the last major halt of the retreating Scandinavian ice-sheet. De Geer (1910 \u00a3) pointed out that this period when the ice border was stationary at the Fennoscandian moraines was the last period when an Arctic marine fauna flourished in the Baltic. Also (1908) he showed, from varve counts on a transect at right angles to the general trend of these moraines, that the ice border remained stationary for between 100 and 200 years, and then retreated only very slowly during the next 300 years-i.e. that the cold period lasted 400 to 500 years. A count of the annual laminations in the upper laminated clay of Windermere (i.e. the cold period following the deposition of the detritus silt which is correlated with the Allerod layer) gave 377 as the total, and if the grey claysilt layer containing Oxyria digyna at the base of the laminated clay is included, 400 to 500 years would be a reasonable estimate for this period. (It should, however, be noted that this figure of 377 annual laminations could be altered very considerably if composite varves (cf. De Geer's digraphs and trigraphs) were regarded as several distinct narrow varves, and that until direct comparison has been made with De Geer's Swedish material the counting method must be regarded as somewhat subjective.) In addition, De Geer's estimate of the length of this period differs from that of Sauramo (1939) , who estimated the period of formation of the Salpausselkas, in Finland, as c. 700 years.", "cite_spans": [{"start": 196, "end": 208, "text": "(Gross 1937;", "ref_id": "BIBREF25"}, {"start": 209, "end": 219, "text": "Gams 1938)", "ref_id": "BIBREF20"}, {"start": 449, "end": 465, "text": "De Geer (1910 \u00a3)", "ref_id": "BIBREF7"}, {"start": 1747, "end": 1761, "text": "Sauramo (1939)", "ref_id": "BIBREF54"}], "ref_spans": []}, {"section": "General discussion", "text": "There does, however, appear to be sufficient evidence available on which to build a tentative correlation of these English late-glacial deposits with those of Ireland and the Continent. Assuming that the deposits of Zone II (the Allerod layer) are contemporaneous in Windermere and Ireland, the upper laminated clay of Windermere (Zone III) would be contemporaneous with the valley glaciation of the Wicklow mountains (Jessen & Farrington j 938) which took place while the solifluction layer of Zone III was forming at Ballybetagh. According to Charlesworth (1939) and Farrington (1945) this Wicklow valley glaciation ( = the Athdown mountain glaciation) probably belongs to the cold period of the Antrim coast readvance which followed that during which the readvance of Scottish ice on to the coast of Cumberland occurred (Charlesworth 1939) . This period of the Scottish (Solway) readvance would therefore be that during which Zone I or the lower laminated clay was formed in Windermere, and the latter is therefore dated as contemporaneous with the Upper (Red) Boulder Clay of the Cumberland coast, which is considered to be the deposit of this readvance of the Scottish ice (Eastwood 1931; Trotter & Hollingworth 1932 ). This agrees with the conclusion of these latter workers that during this period any advance of the glaciers in the centre of the Lake District was confined to the upper ends of the valleys and that there was no outward movement of the Lake District ice beyond the boundary of the mountain group (Hollingworth 1931) . T hat is, it seems probable that the drainage from these glaciers was producing laminated clays in Windermere but that the ice front did not reach the lake. On the other hand, there is no evidence of a break between the lower laminated clay and the underlying stony clay, so it is conceivable that this latter may represent the deposits of the valley glaciers at the height of the period of the Scottish readvance, followed by laminated clays as the retreat at the end of the period began; but it seems more likely that the basal stony clay is the deposit of the ice of the preceding period -i.e. the main glaciation of the north-west (Eastwood 1931 )-which presumably deposited the morainic dam at the foot of the lake. The laminated clay of Zone III on this correlation would represent a cold period later than that of the Scottish readvance, with valley glaciers in the Lake District corresponding to the valley glaciation of the Wicklow mountains and possibly to the valley glaciation of the Scottish Highlands (Movius 1942 ), but possibly not (Farrington 1945) . Table 1 shows these tentative correlations with what are regarded as the corresponding deposits on the Continent, if it is accepted that Zone II in Windermere corresponds to the Allerod amelioration of Jessen and the other continental workers quoted. It should be noted that the correlation of Zone III in Windermere (upper laminated clay) with both Zone I II in Ireland (the Athdown mountain glaciation) and the formation of the Fennoscandian (Ra) moraines, is confirmed by Farrington's suggested correlation of these two latter periods (Farrington 1945) . In the opinion of most Quaternary geologists there is as yet insufficient evidence for any correlation between the glacial periods of the British Isles and those of Europe, so the only correlations suggested are those for which evidence has been brought forward, and no attempt has been made to suggest any correlation with the Alpine glacial periods, though from those suggested by Gams (1938) and others (Movius 1942; Zeuner 1945 ) the most likely correlation seems to be to regard Zone I, which in Britain is probably equivalent to the Solway Scottish readvance, as equivalent in Europe to the Buhl Stadium or Wiirm III in the Alps. This agrees with the suggestion of Trotter & Hollingworth (1932) , and fits in with what Boswell (1936) and Bisat (1940) regard as the most likely correlation, if it is assumed that the Solway Scottish readvance belonged to the next cold period following the advance of the ice to the York moraines and deposition of the Hunstanton boulder-clay, which they regard as being most probably equivalent to Wiirm II. De Geer (1925 et seq.) considers that 8300 to 7874 b.c. is the probable extent of the cold period during which the ice border was more or less stationary in the region of the Fennoscandian moraines, and that the Allerod layer was probably formed at some time between 10,000 and 8300 b.c. (see also Movius 1942) . The relation of these dates to the time-scale already suggested for the Windermere deposits (Pennington 1943) , based on sedimentation rates, will be discussed in the following section.", "cite_spans": [{"start": 545, "end": 564, "text": "Charlesworth (1939)", "ref_id": "BIBREF4"}, {"start": 569, "end": 586, "text": "Farrington (1945)", "ref_id": "BIBREF19"}, {"start": 823, "end": 842, "text": "(Charlesworth 1939)", "ref_id": "BIBREF4"}, {"start": 1178, "end": 1193, "text": "(Eastwood 1931;", "ref_id": "BIBREF16"}, {"start": 1194, "end": 1221, "text": "Trotter & Hollingworth 1932", "ref_id": "BIBREF56"}, {"start": 1520, "end": 1539, "text": "(Hollingworth 1931)", "ref_id": "BIBREF31"}, {"start": 2177, "end": 2191, "text": "(Eastwood 1931", "ref_id": "BIBREF16"}, {"start": 2557, "end": 2569, "text": "(Movius 1942", "ref_id": "BIBREF46"}, {"start": 2590, "end": 2607, "text": "(Farrington 1945)", "ref_id": "BIBREF19"}, {"start": 3148, "end": 3165, "text": "(Farrington 1945)", "ref_id": "BIBREF19"}, {"start": 3551, "end": 3562, "text": "Gams (1938)", "ref_id": "BIBREF20"}, {"start": 3574, "end": 3587, "text": "(Movius 1942;", "ref_id": "BIBREF46"}, {"start": 3588, "end": 3599, "text": "Zeuner 1945", "ref_id": "BIBREF59"}, {"start": 3839, "end": 3868, "text": "Trotter & Hollingworth (1932)", "ref_id": "BIBREF56"}, {"start": 3893, "end": 3907, "text": "Boswell (1936)", "ref_id": "BIBREF1"}, {"start": 4513, "end": 4525, "text": "Movius 1942)", "ref_id": "BIBREF46"}, {"start": 4620, "end": 4637, "text": "(Pennington 1943)", "ref_id": "BIBREF52"}], "ref_spans": []}, {"section": "General discussion", "text": "( b) Post-glacial. If it is correct to correlate Zone III, the upper laminated clay, with the period of formation of the Fennoscandian moraines, the date of the top of the laminated clay in Windermere is about 7874 b.c. according to De Geer's time-scale. He considers that the post-glacial period began in Sweden with the bipartition of the retreating ice at Ragunda, 1074 years later, i.e. 6800 b .c. Swedish workers (Nilsson 1935) consider that in south Sweden, this was the approximate date of the transition from the period of the hazel maximum to the incoming of the mixed oak forest, and that the peak of the hazel maximum occurred between 7500 and 6800 b .c. Nilsson gives 6200 b.c. as the possible date of the Boreal-Atlantic transition, i.e. the boundary between Zones VI and V II in Godwin's scheme. In the Windermere deposits, this horizon is marked by the very sudden expansion to dominance of Aims, and on the time-scale published for the Windermere deposits (Pennington 1943 ) falls between 6000 and 6300 b .c.", "cite_spans": [{"start": 418, "end": 432, "text": "(Nilsson 1935)", "ref_id": "BIBREF47"}, {"start": 972, "end": 988, "text": "(Pennington 1943", "ref_id": "BIBREF52"}], "ref_spans": []}, {"section": "General discussion", "text": "This time-scale for the Windermere deposits was based on the present rate of sedi mentation of mineral matter, knowledge of the water content (i.e. the packing factor) at successive levels in the deposits, and the assumption that the rate of sedimentation of mineral m atter has been approximately constant since the immediately post-glacial stages, but was rapid at the close of the late-glacial period (Pennington 1943) . On this time-scale the date of the top of the laminated clay is about 8560 b .c. compared with 7874 b .c. on De Geer's geochronology. Since the estimate of the present sedimentation rate is probably an under-estimate rather than an over-estimate, and the estimated rate for the late-glacial/ post-glacial transition is somewhat arbitrary, it is not surprising that the above calculation rather over-estimated the length of the period. The Allerod oscillation probably occurred at some time between 10,000 and 8300 b.c. (De Geer etc., see Movius 1942) , and since the laminated clay of Zone I below the Allerod layer is the oldest waterlain deposit, the esti mate of about 12,000 years as the age of the lake (Pennington 1943 ) agrees reasonably well with this. This fairly good agreement between the two time-scales suggests that the assumptions about sedimentation made in the previous paper are reasonably true, in so far as they apply to deep water.", "cite_spans": [{"start": 404, "end": 421, "text": "(Pennington 1943)", "ref_id": "BIBREF52"}, {"start": 1132, "end": 1148, "text": "(Pennington 1943", "ref_id": "BIBREF52"}], "ref_spans": []}, {"section": "General discussion", "text": "(2) Results of pollen analysis in relation to previous work on the deposits (a) Diatom zonation. When the zonation based on pollen analysis is compared with the diatom zonation already published (Pennington 1943) , some discrepancies are apparent, but a consideration of the conditions of formation of the deposits suggests an explanation of this.", "cite_spans": [{"start": 195, "end": 212, "text": "(Pennington 1943)", "ref_id": "BIBREF52"}], "ref_spans": []}, {"section": "General discussion", "text": "In the late-glacial period, zonation based either on pollen analysis or on the diatom flora corresponds with the sharp stratigraphical boundaries between the lower laminated clay, the detritus silt ('grey layer') and the upper laminated clay. The laminated clays contain few or no organic remains; thus all the available evidence suggests that these, i.e. Zones I and III, represent periods when there was practically no organic production in the lake or vegetation round its shores. The diatom flora of Zone II contains some planktonic species, but the bulk of the diatom population consists of heavy bottom dwelling littoral species, and no diatoms are found at this horizon in deep water. This agrees with the type of diatom population which other workers (Brander 1935 ) have found to be characteristic of cold or cold-temperate periods such as the immediately post-glacial phase in the Baltic region.", "cite_spans": [{"start": 759, "end": 772, "text": "(Brander 1935", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "General discussion", "text": "A similar diatom population is found in the immediately post-glacial deposits of Windermere, and here the apparent discrepancy between the diatom and pollen zonation arises. The predominantly bottom-dwelling diatom flora, here characterized by arenaria var. hungarica is confined to the clay-gyttja (Zone IV) in shallow water, but appa rently persists throughout the zone of narrow clay bands in deep water. These two deposits were therefore regarded as belonging to the same time-zone, but pollen analysis has shown that the zone of narrow clay bands in deep water includes Zones IV, V and VI, so that only the basal part of this deposit (i.e. that below the lowest clay band) can be equated with the clay gyttja in shallow water. A quantitative survey of the diatom population in deep water, in the deposits between the lowest and the topmost clay band (Pennington 1943, figure 9) shows that the large, mainly bottom-dwelling species, reach their maximum numbers in association with each narrow clay band, i.e. just above or below each band of pure clay. The deposits intervening between the clay bands are, in appearance and organic content, very similar to those of the overlying brown mud (gyttja). It is therefore suggested that the large bottom-dwelling diatoms are here mainly secondarily depositedi.e. that the great floods or breachings of glacial dams in the upper valleys, which produced the clay bands, also carried down these large diatoms from the earlier deposits of smaller, possibly now drained, glacial lakes in the upper valleys of the main inflows.", "cite_spans": [], "ref_spans": []}, {"section": "General discussion", "text": "Above the upper limit of the bottom-dwelling diatom flora characterized by Melosira arenaria var. hungarica, the diatom flora is very uniform, and no further zones could be distinguished until the Asterionella ooze was reached. Pollen analysis has provided a method by which certain horizons in the upper gyttja deposits can now be recognized.", "cite_spans": [], "ref_spans": []}, {"section": "General discussion", "text": "(b) Stratigraphicalresults. T h e contribution o f pollen analysis to the elucidation o f the late-glacial stratigraphy has been to confirm the view th a t the period o f in terru p tio n in the regular varve deposition w hich in shallow w ater led to the form ation o f detritus silt was in fact a tem porarily w arm er clim atic period. Since the lam inated clays contain practically no pollen or organic rem ains, any possible explanation of the m arked irregu larities sometimes found in the deep-w ater lam inated clays m ust aw ait fu rth er geological investigation, notably of the varve sequences. These irregularities m ay be due to channels in the late-glacial deposits, grounding of icebergs, the presence of persistent blocks o f dead ice, or to slum ping of the deposited clays sim ilar to th a t described in Palaeozoic subm arine clays (H eim , 1908) .", "cite_spans": [], "ref_spans": []}, {"section": "General discussion", "text": "The evidence of pollen zonation shows that the immediately post-glacial deposits of Zone IV were, like the late-glacial Zone II, deposited much more rapidly at the margins than in the middle of the lake, where Zone II is not represented by any deposit and Zone IV is very narrow. The material forming these two zones was therefore presumably derived from littoral erosion, and possibly, during the colder parts of the periods, from solifluction. In Zones V and VI, on the transect investigated, the deposits at the margins are consider ably thicker than those in the centre, but the difference between marginal and central thickness is less than in the earlier zones. The truncation of the marginal profiles 3 to 4 m. below the water surface suggests that however much material is available, no further accumulation takes place on a stony shore such as Low Wray Bay once this water depth is reached. The material forming the deep-water deposits is probably derived chiefly from the main inflow and organic production within the lake; this would at least partially explain the relatively slow accumulation in Zone IV, 10 to 15 cm. in about 400 yearsfirst because it would be expected that at this early stage in the lake's post-glacial history the bulk of the sediment entering the lake by the inflow would be coarse and hence rapidly deposited in the delta region (Pearsall 1921 etc.; Kindle 1930) , and secondly because both the low temperature and the low concentration of nutrient salts would restrict organic production in the lake (Pearsall 1921, etc.) . If the above time estimate is correct, the average annual increment in Zone IV is seen to be about 0-2 to 0-3 mm., and the water content of this deposit is about 5 0 %, while at present in this position the annual increment is about 2'5 mm. with a water content of 9 3 % ; the ratio of sedimentation rates of solid m atter in the immediately post-glacial period to that at present is therefore about 1:10 in annual thickness, and 5 :7 in volume of solid m atter deposited. The corresponding ratio for the amount of carbon deposited per annum is 1 : 7. This means that the sediment accumulating in the middle of the lake each year in immediately post-glacial times was of about five-sevenths the volume of solid m atter and about one-seventh the volume of organic m atter of the sediment accumulating at present. The previous assumption (Pennington 1943 ) that sedimentation of mineral m atter was relatively rapid in this immediately post-glacial period is therefore proved to be wrong when applied to the middle of the lake; only at the margins and probably in the delta region is it true.", "cite_spans": [{"start": 2396, "end": 2412, "text": "(Pennington 1943", "ref_id": "BIBREF52"}], "ref_spans": []}, {"section": "General discussion", "text": "The work described in this paper has been made possible by grants from the Royal Society and the Freshwater Biological Association. I am greatly indebted to Dr H. Godwin, F.R.S., for his continued and stimulating interest in the work.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "1939 (1940) Older and newer drift in East Yorkshire", "authors": [{"first": "W", "middle": ["S"], "last": "Bisat", "suffix": ""}], "year": "", "venue": "Proc. Yorks. Geol. Soc", "link": null}, "BIBREF1": {"title": "Problems of the borderland of archaeology and geology in Britain", "authors": [{"first": "P", "middle": ["G H"], "last": "Boswell", "suffix": ""}], "year": 1936, "venue": "Proc. Prehist. Soc. E. Angl. p", "link": null}, "BIBREF2": {"title": "Balen-See-Studien des Geologischen Instituts der Stockholms Hogskola. 2. Die baltische Diatomeen-Succession des", "authors": [{"first": "G", "middle": [], "last": "Brander", "suffix": ""}], "year": 1935, "venue": "B&len-Bechens. Geol. Foren. Stockh. Fork", "link": null}, "BIBREF3": {"title": "On northern glacial drifts: some peculiarities and their significance", "authors": [{"first": "R", "middle": ["G"], "last": "Carruthers", "suffix": ""}], "year": 1939, "venue": "Quart. J. Geol. Soc. Lond", "link": "129028898"}, "BIBREF4": {"title": "Some observations on the glaciation of north-east Ireland", "authors": [{"first": "J", "middle": ["K"], "last": "Charlesworth", "suffix": ""}], "year": 1939, "venue": "Proc. Roy. Irish Acad. B, 45", "link": null}, "BIBREF5": {"title": "On Late Quaternary time and climate", "authors": [{"first": "De", "middle": [], "last": "Geer", "suffix": ""}, {"first": "G", "middle": [], "last": "", "suffix": ""}], "year": 1908, "venue": "Geol. Foren. Stockh", "link": "140165255"}, "BIBREF6": {"title": "1910 a Dal's Ed. Some stationary ice-borders of the last glaciation", "authors": [{"first": "De", "middle": [], "last": "Geer", "suffix": ""}, {"first": "G", "middle": [], "last": "", "suffix": ""}], "year": "", "venue": "Int. Geol. Cong. Stockholm , Excursions", "link": null}, "BIBREF7": {"title": "De Geer, G. 1912 A geochronology of the last 12,000 years", "authors": [{"first": "De", "middle": [], "last": "Geer", "suffix": ""}, {"first": "G", "middle": [], "last": "", "suffix": ""}], "year": "", "venue": "Geol. Foren. Stockh. Forh", "link": null}, "BIBREF9": {"title": "Correlation of late glacial clay varves in north America with the Swedish time-scale", "authors": [{"first": "De", "middle": [], "last": "Geer", "suffix": ""}, {"first": "G", "middle": [], "last": "", "suffix": ""}], "year": 1921, "venue": "Geol. Foren. Stockh. Forh", "link": "129008247"}, "BIBREF10": {"title": "Forhistoriska tidsbestamningar och kulturutvecklingen. Ymer, 1925. De Geer, G. 1927 Late glacial varves in Argentina", "authors": [{"first": "De", "middle": [], "last": "Geer", "suffix": ""}, {"first": "G", "middle": [], "last": "", "suffix": ""}], "year": 1925, "venue": "Geogr. Ann", "link": null}, "BIBREF11": {"title": "Gotiglacial clay varves in southern Chile", "authors": [{"first": "De", "middle": [], "last": "Geer", "suffix": ""}, {"first": "G", "middle": [], "last": "", "suffix": ""}], "year": 1929, "venue": "Geogr. Ann", "link": "134888505"}, "BIBREF12": {"title": "The finiglacial subepoch in Sweden, Finland and the New World, Data 15", "authors": [{"first": "De", "middle": [], "last": "Geer", "suffix": ""}, {"first": "G", "middle": [], "last": "", "suffix": ""}], "year": 1930, "venue": "Geogr. Ann", "link": null}, "BIBREF13": {"title": "Dating of the Ice Age in Scotland", "authors": [{"first": "De", "middle": [], "last": "Geer", "suffix": ""}, {"first": "G", "middle": [], "last": "", "suffix": ""}], "year": 1935, "venue": "Trans. Geol. Soc. Glasg", "link": "128837021"}, "BIBREF14": {"title": "Geochronologica Suecica; Principles", "authors": [{"first": "De", "middle": [], "last": "Geer", "suffix": ""}, {"first": "G", "middle": [], "last": "", "suffix": ""}], "year": 1940, "venue": "", "link": null}, "BIBREF15": {"title": "An Introduction to Pollen Analysis", "authors": [{"first": "G", "middle": [], "last": "Erdtman", "suffix": ""}], "year": 1943, "venue": "", "link": "86902201"}, "BIBREF16": {"title": "The geology of the Whitehaven and Workington District", "authors": [{"first": "T", "middle": [], "last": "Eastwood", "suffix": ""}, {"first": "E", "middle": ["E L"], "last": "Dixon", "suffix": ""}, {"first": "S", "middle": ["E"], "last": "Hollingworth", "suffix": ""}, {"first": "B", "middle": [], "last": "Smith", "suffix": ""}], "year": 1931, "venue": "Mem. Geol. Surv. U.K", "link": null}, "BIBREF17": {"title": "Zur Geschichte der Moore, Marschen und Walder Nordwestdeutschlands. Untersuchungen in Nordfriesland", "authors": [{"first": "O", "middle": [], "last": "Ernst", "suffix": ""}], "year": 1934, "venue": "Schr. naturw. Ver. Schl.-Holst", "link": null}, "BIBREF18": {"title": "Quatargeologische Untersuchungen im westlichen Norwegen. I. fiber zwei praboreale Klimaschwankungen im siidwestlichsten Teil", "authors": [{"first": "K", "middle": [], "last": "Faegri", "suffix": ""}], "year": 1935, "venue": "Bergens Mus. Aarb", "link": null}, "BIBREF19": {"title": "The level of the ocean in glacial and late-glacial times", "authors": [{"first": "A", "middle": [], "last": "Farrington", "suffix": ""}], "year": 1945, "venue": "Proc. Roy. Irish Acad. B", "link": null}, "BIBREF20": {"title": "Die bisherigen Ergebnisse der Mikrostratigraphie fur die Gliederung der letzen Eiszeit und des Jung palaolithikums in Mittel-und Nordeuropa", "authors": [{"first": "H", "middle": [], "last": "Gams", "suffix": ""}], "year": 1938, "venue": "", "link": null}, "BIBREF21": {"title": "Pollen analysis. An outline of the problems and potentialities of the method. Part I. Technique and Interpretation. Part II. General applications of pollen analysis", "authors": [{"first": "H", "middle": [], "last": "Godwin", "suffix": ""}], "year": 1934, "venue": "New Phytol", "link": null}, "BIBREF22": {"title": "Studies of the post-glacial history of British vegetation. III. Fenland pollen diagrams. IV. Post-glacial changes of relative land-and sea-level in the English Fenland", "authors": [{"first": "H", "middle": [], "last": "Godwin", "suffix": ""}], "year": 1940, "venue": "Phil. Trans. B", "link": "86706713"}, "BIBREF23": {"title": "Coastal peat-beds of the North Sea region, as indices of land-and sea-level changes", "authors": [{"first": "H", "middle": [], "last": "Godwin", "suffix": ""}], "year": 1945, "venue": "New Phytol", "link": "84782406"}, "BIBREF24": {"title": "Die postglaziale Entwicklung des Grossen Ploner Sees in Ostholstein auf Grund pollenanalytischer Sedimentuntersuchungen", "authors": [{"first": "Paul", "middle": [], "last": "Groschopf", "suffix": ""}], "year": 1936, "venue": "Arch. Hydrobiol", "link": null}, "BIBREF25": {"title": "Nachweis der Allerodschwankung in slid und ostbaltischen", "authors": [{"first": "H", "middle": [], "last": "Gross", "suffix": ""}], "year": 1937, "venue": "Gebiet. Beih. bot. Zbl", "link": null}, "BIBREF26": {"title": "Auf den altesten Spuren des Menschen in Altpreussen", "authors": [{"first": "H", "middle": [], "last": "Gross", "suffix": ""}], "year": 1938, "venue": "", "link": null}, "BIBREF27": {"title": "Studies of the post-glacial history of British vegetation. V. The Shropshire and Flint Maelor Mosses", "authors": [{"first": "E", "middle": ["M"], "last": "Hardy", "suffix": ""}], "year": 1939, "venue": "New Phytol", "link": null}, "BIBREF28": {"title": "Stratigraphie und Waldgeschichte des Wauwilermooses. Veroff. Geobot. Inst. Riibel, 17. Hartz, N. 1912 Allerod-Muld: Allerod-Gytjens Landfacies. Medd. dansk geol. Foren. 4", "authors": [{"first": "H", "middle": [], "last": "Harri", "suffix": ""}], "year": 1940, "venue": "", "link": null}, "BIBREF30": {"title": "Ueber rezente und fossile subaquatische Rutschungen und deren lithologische Bedeutung", "authors": [{"first": "A", "middle": [], "last": "Heim", "suffix": ""}], "year": 1908, "venue": "Neues Jahrb. Min", "link": null}, "BIBREF31": {"title": "The glaciation of western Edenside and adjoining areas and the drumlins of Edenside and the Solway basin", "authors": [{"first": "S", "middle": ["E"], "last": "Hollingworth", "suffix": ""}], "year": 1931, "venue": "Quart. J. Geol. Soc", "link": "129548683"}, "BIBREF32": {"title": "Sekundares Pollen als Fehlerguelle. Eine Korrektionsmethode zur Pollenanalyse minerogener Sedimente", "authors": [{"first": "J", "middle": [], "last": "Iversen", "suffix": ""}], "year": 1936, "venue": "", "link": null}, "BIBREF33": {"title": "The study of lake deposits", "authors": [{"first": "J", "middle": [], "last": "Iversen", "suffix": ""}, {"first": "B", "middle": ["M"], "last": "Jenkin", "suffix": ""}, {"first": "C", "middle": ["H"], "last": "Mortimer", "suffix": ""}, {"first": "W", "middle": [], "last": "Pennington", "suffix": ""}], "year": 1941, "venue": "Landnam i Danmarks Stenalder. Danm. geol. Unders", "link": null}, "BIBREF34": {"title": "Senkvartaere Studier fra Mors. Danm. geol. Unders. 4, 2", "authors": [{"first": "K", "middle": [], "last": "Jessen", "suffix": ""}], "year": 1929, "venue": "", "link": null}, "BIBREF35": {"title": "Archaeological dating in the history of north Jutland's vegetation", "authors": [{"first": "K", "middle": [], "last": "Jessen", "suffix": ""}], "year": 1935, "venue": "Acta Archaeol", "link": null}, "BIBREF36": {"title": "Some west Baltic pollen diagrams. Quatar, 1. Jessen, K. 1939 Naturforholdene og Mennesket i Danm", "authors": [{"first": "K", "middle": [], "last": "Jessen", "suffix": ""}], "year": 1938, "venue": "", "link": null}, "BIBREF37": {"title": "The bogs of Ballybetagh near Dublin, with remarks on lateglacial conditions in Ireland", "authors": [{"first": "K", "middle": [], "last": "Jessen", "suffix": ""}, {"first": "A", "middle": [], "last": "Farrington", "suffix": ""}], "year": 1938, "venue": "Proc. Roy. Irish Acad. B", "link": null}, "BIBREF38": {"title": "Interglacial fresh-water deposits in Jutland and north-west Germany", "authors": [{"first": "K", "middle": [], "last": "Jessen", "suffix": ""}, {"first": "V", "middle": [], "last": "Milthers", "suffix": ""}], "year": 1928, "venue": "Danm. geol. Unders", "link": null}, "BIBREF39": {"title": "Interglacial deposits of west Cumberland and north Lancashire", "authors": [{"first": "J", "middle": ["D"], "last": "Kendall", "suffix": ""}], "year": "", "venue": "Quart. Geol. Soc", "link": "129437670"}, "BIBREF40": {"title": "Dber die Fernverbreitung des Blutenstaubs durch den Wind", "authors": [{"first": "F", "middle": [], "last": "Knoll", "suffix": ""}], "year": 1932, "venue": "Forsch. Fortschr. dtsch. Wiss", "link": null}, "BIBREF41": {"title": "Svensk Fanerogamflora", "authors": [{"first": "C", "middle": ["A M"], "last": "Lindman", "suffix": ""}], "year": 1926, "venue": "", "link": null}, "BIBREF42": {"title": "On the so-called Gothi-glacial limit in Denmark", "authors": [{"first": "V", "middle": [], "last": "Milthers", "suffix": ""}], "year": 1927, "venue": "Geogr. Ann", "link": null}, "BIBREF43": {"title": "Studies in Irish Quaternary deposits; some lacustrine deposits near Dunshaughlin", "authors": [{"first": "G", "middle": ["F"], "last": "Mitchell", "suffix": ""}], "year": 1940, "venue": "Co. Meath. Proc. Roy. Irish Acad. B", "link": null}, "BIBREF44": {"title": "Studies in Irish Quaternary deposits. 2. Some lacustrine deposits near Ratoath", "authors": [{"first": "G", "middle": ["F"], "last": "Mitchell", "suffix": ""}], "year": 1941, "venue": "Co. Meath. Proc. Roy. Irish Acad. B", "link": null}, "BIBREF45": {"title": "A composite pollen diagram from Co. Meath, Ireland. New Phytol. 41, 257. Mitchell, G. F. 1942 \u00a3 A late-glacial flora in Co", "authors": [{"first": "G", "middle": ["F"], "last": "Mitchell", "suffix": ""}], "year": 1942, "venue": "", "link": null}, "BIBREF46": {"title": "The Chronology of the Irish Stone Age", "authors": [{"first": "Hallam", "middle": ["L"], "last": "Movius", "suffix": ""}], "year": 1942, "venue": "", "link": null}, "BIBREF47": {"title": "Die pollenanalytische Zonengliederung der spat-und post-glazialen Bildungen Schonens", "authors": [{"first": "Tage", "middle": [], "last": "Nilsson", "suffix": ""}], "year": 1935, "venue": "Geol. Foren. Stockh. Fork", "link": null}, "BIBREF48": {"title": "Allerod Oscillationem og Kristianiafjordens senglaciale Dannelser. Medd. dansk geol", "authors": [{"first": "V", "middle": [], "last": "Nordmann", "suffix": ""}], "year": 1912, "venue": "", "link": null}, "BIBREF49": {"title": "Nye Iagttagelser over den glaciale, isdaemmede So ved Stenstrup paa Fyn", "authors": [{"first": "V", "middle": [], "last": "Nordmann", "suffix": ""}], "year": 1922, "venue": "Medd. dansk geol. Foren", "link": null}, "BIBREF50": {"title": "The development of vegetation in the English Lakes, considered in relation to the general evolution of glacial lakes and rock basins", "authors": [{"first": "W", "middle": ["H"], "last": "Pearsall", "suffix": ""}], "year": 1921, "venue": "Proc. Roy. Soc. B", "link": "129052263"}, "BIBREF51": {"title": "Ecological history of the English Lake District", "authors": [{"first": "W", "middle": ["H"], "last": "Pearsall", "suffix": ""}, {"first": "W", "middle": [], "last": "Pennington", "suffix": ""}], "year": 1947, "venue": "J. Ecology", "link": "87956506"}, "BIBREF52": {"title": "Lake sediments; the bottom deposits of the North Basin of Windermere with special reference to the diatom succession", "authors": [{"first": "W", "middle": [], "last": "Pennington", "suffix": ""}], "year": 1943, "venue": "New Phytol", "link": "84472134"}, "BIBREF53": {"title": "Das altsteinzeitliche Rentier]dgerlager Meiendorf. (With pollen analyses, etc", "authors": [{"first": "A", "middle": [], "last": "Rust", "suffix": ""}], "year": 1937, "venue": "", "link": null}, "BIBREF54": {"title": "The mode of land upheaval in Fennoscandia during Late-Quaternary time", "authors": [{"first": "M", "middle": [], "last": "Sauramo", "suffix": ""}], "year": 1939, "venue": "C.R. Soc. geol. Fin", "link": null}, "BIBREF56": {"title": "The glacial sequence in the north of England", "authors": [{"first": "F", "middle": ["M"], "last": "Trotter", "suffix": ""}, {"first": "S", "middle": ["E"], "last": "Hollingworth", "suffix": ""}], "year": 1932, "venue": "Geol. Mag", "link": "131100625"}, "BIBREF57": {"title": "Von Post, L. 1935 Balen-See-Studien des Geologischen Instituts der Stockholms Hogskola. 3. Myriophyllum alterniflorum DC. in den Balen-See-Ablagerungen", "authors": [{"first": "T", "middle": ["G"], "last": "Tutin", "suffix": ""}], "year": 1941, "venue": "Geol. Foren. Stockh. Forh", "link": null}, "BIBREF58": {"title": "The Quaternary Ice Age", "authors": [{"first": "W", "middle": ["B"], "last": "Wright", "suffix": ""}], "year": 1937, "venue": "", "link": "128412709"}, "BIBREF59": {"title": "The Pleistocene Period", "authors": [{"first": "F", "middle": ["E"], "last": "Zeuner", "suffix": ""}], "year": 1945, "venue": "", "link": "149931314"}, "BIBREF60": {"title": "Dating the Past", "authors": [{"first": "F", "middle": ["E"], "last": "Zeuner", "suffix": ""}], "year": 1946, "venue": "London. PRINTED IN GREAT BRITAIN FOR THE ROYAL SOCIETY AT THE UNIVERSITY PRESS", "link": "38419796"}}, "ref_entries": {"FIGREF0": {"text": "Results of pollen analysis in relation (b) Post-glacial 146 to previous work on the deposits: 171 (2) Profiles from the middle of the lake: 148 (a) Diatom zonation 171 (a) Late-glacial 148 (. b) Stratigraphical results 172 (. b) Post-glacial 148", "type": "figure"}, "FIGREF1": {"text": "Figure 1. Map of the North Basin of Windermere showing approximate positions of cores analyzed and the line of section shown in figure 2.", "type": "figure"}, "FIGREF2": {"text": "Figure 2. ( a) Diagrammatic section, east to west, across the North Basin of Windermere, showing stratigraphy of deposits. (For more detailed map and section, see Pennington 1943.) ( ) Diagrammatic east to west section showing stratigraphy with pollen zonation superimposed. (Continuous lines represent boundaries between zones; broken line represents approximate boundary between Zones V and VI; stratigraphy indicated by shading.)", "type": "figure"}, "FIGREF3": {"text": "V ol. 233. B. 19", "type": "figure"}, "FIGREF4": {"text": "Figure 3. Pollen diagram from core 1, in 3 m. of water in Low Wray Bay (littoral).", "type": "figure"}, "FIGREF5": {"text": "Figure 4. Pollen diagram from core 2, in 3-5 m. of water in Low Wray Bay, 150 yards north of core 1. (Gores 1 and 2 are separated by a jutting promontory of rock.)", "type": "figure"}, "FIGREF6": {"text": "Figure 5. Pollen diagram from core 3 a, in 7-6 m. of water in Low Wray Bay. Dotted li shows Corylus expressed as percentage of tree pollen minus Pirns.", "type": "figure"}, "FIGREF7": {"text": "Figure 6. Pollen diagram from core 3, in 10 m. o f water in Low W ray Bay.", "type": "figure"}, "FIGREF9": {"text": "Figure 7. Pollen diagram from core 4, in 27 m. of water outside Low Wray Bay.", "type": "figure"}, "FIGREF10": {"text": "Figure 8. Pollen diagram from core 6, in 46 m. of water outside Low Wray Bay. Dotted line shows Corylus expressed as percentage of tree pollen minus Pinus.", "type": "figure"}, "FIGREF11": {"text": "Figure 9. Pollen diagram from core 7, in 65 m. of water. Dotted line shows Corylus expressed as percentage of tree pollen minus Pinus.", "type": "figure"}, "FIGREF12": {"text": "Figure 10. Pollen diagram from core 8, in 4-8 m. of water off Ecclerigg House.", "type": "figure"}, "FIGREF13": {"text": "Figure 11. Stratigraphy of detritus silt layer (Zone II) in several cores, showing position of plant remains identified. Localities: LWB = Low Wray Bay; HWB = High Wray Bay; ERB = Ecclerigg.", "type": "figure"}, "FIGREF14": {"text": "Figure 12. Plant remains from the detritus silt layer (Zone II) in shallow water. (I) Leaf fragment tentatively identified as Salix phylicifolia, from base of detritus silt. (II) (a) Perianth segment of Rumex, probably R. acetosa; (b) Epidermal cells of (IIa), showing sinuose margins. (I ll) Oxyria digyna, fragments of perianth.", "type": "figure"}, "FIGREF15": {"text": "Figure 13. Plant remains from detritus silt layer (Zone II) in shallow water. (I) Leaf of Polytrichum alpinum, showing characteristic cells at apex of lamellae. (II) Tracheids, probably Pinus. (I ll) Catkin scales, ( a) Populus tremula; (b) Betula pubescens. (IV) Fruits of Betula pubescens. (V) Leaf fragments of Andromeda polifolia. (VI) Fruit of Thalictrum minus. (VII) Seed of Rubus saxatilis.", "type": "figure"}, "FIGREF16": {"text": "Figure 14. Distribution of the plant remains in the detritus silt in core 1.", "type": "figure"}, "TABREF1": {"text": "V o l . 233. B. 22 T able 1. T able of tentative correlations; time-scale based on data from D e Geer and T age N ilsson; for later work of Liden and Sauramo on varve datings SEE ZEUNER (1946).10,000 b .c.", "type": "table"}}}
{"paper_id": "84886121", "_pdf_hash": "85a16bc33f6489dd458ced63a8c213882621e1c6", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Wang prepared WS-30-R24. We thank R. O'Keefe", "authors": [{"first": "Y.-Z", "middle": [], "last": "", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF1": {"title": "Projects 40920124002 and 41372016 were supported by the National Natural Science Foundation of China. Project 123102 was supported by State Key Laboratory of Palaeobiology and Stratigraphy (Nanjing Institute of Geology and Palaeontology", "authors": [{"first": "", "middle": [], "last": "Fraser", "suffix": ""}], "year": "", "venue": "Chinese Academy of Sciences)", "link": null}, "BIBREF2": {"title": "1889. Palaeohatteria Credner, and the Proganosauria", "authors": [{"first": "G", "middle": [], "last": "Baur", "suffix": ""}], "year": "", "venue": "American Journal of Science", "link": "131417503"}, "BIBREF3": {"title": "Fist complete pistosauroid from the Triassic of China", "authors": [{"first": "Y.-N", "middle": [], "last": "Cheng", "suffix": ""}, {"first": "T", "middle": [], "last": "Sato", "suffix": ""}, {"first": "X.-C", "middle": [], "last": "Wu", "suffix": ""}, {"first": "C", "middle": [], "last": "Li", "suffix": ""}], "year": 2006, "venue": "Journal of Vertebrate Paleontology", "link": "198127851"}, "BIBREF4": {"title": "A new eosauropterygian (Diapsida, Sauropterygia) from the Triassic of China", "authors": [{"first": "Y.-N", "middle": [], "last": "Cheng", "suffix": ""}, {"first": "X.-C", "middle": [], "last": "Wu", "suffix": ""}, {"first": "T", "middle": [], "last": "Sato", "suffix": ""}, {"first": "H.-Y.", "middle": [], "last": "Shan", "suffix": ""}], "year": 2012, "venue": "Journal of Vertebrate Paleontology", "link": "85253142"}, "BIBREF5": {"title": "Progress of the research on the marine reptile faunas in Guizhou, China", "authors": [{"first": "J.-L", "middle": [], "last": "Li", "suffix": ""}, {"first": "F", "middle": [], "last": "Jin", "suffix": ""}], "year": 2003, "venue": "Progress in Natural Science", "link": null}, "BIBREF6": {"title": "A new nothosaur from Middle Triassic of Guizhou", "authors": [{"first": "J.-L", "middle": [], "last": "Li", "suffix": ""}, {"first": "O", "middle": [], "last": "Rieppel", "suffix": ""}], "year": 2004, "venue": "China. Vertebrate PalAsiatica", "link": null}, "BIBREF7": {"title": "A new species of Lariosaurus (Sauropterygia: Nothosauridae) from Triassic of Guizhou", "authors": [{"first": "J.-L", "middle": [], "last": "Li", "suffix": ""}, {"first": "J", "middle": [], "last": "Liu", "suffix": ""}, {"first": "O", "middle": [], "last": "Rieppel", "suffix": ""}], "year": 2002, "venue": "", "link": null}, "BIBREF8": {"title": "A new species of Macrocnemus (Reptilia: Protorosauria) from the Middle Triassic of southwestern China and its palaeogeographical implication", "authors": [{"first": "C", "middle": [], "last": "Li", "suffix": ""}, {"first": "L.-J", "middle": [], "last": "Zhao", "suffix": ""}, {"first": "L.-T", "middle": [], "last": "Wang", "suffix": ""}], "year": 2007, "venue": "Science in China Series D: Earth Sciences", "link": "195308225"}, "BIBREF9": {"title": "Vorl\u00e4ufige Nachricht\u00fcber einige neue Reptilien im Muschelkalke von Baiern. Neues Jahrbuch f\u00fcr Miniralogie, Geognosie", "authors": [{"first": "G", "middle": [], "last": "M\u00fcnster", "suffix": ""}], "year": 1934, "venue": "Geologie und Petrefaktenkunde", "link": null}, "BIBREF10": {"title": "1860. Palaeontology; or, a Systematic Summary of Extinct Animals and Their Geologic Remains", "authors": [{"first": "R", "middle": [], "last": "Owen", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF11": {"title": "The status of the sauropterygian reptile Nothosaurus juvenilis from the Middle Triassic of Germany", "authors": [{"first": "O", "middle": [], "last": "Rieppel", "suffix": ""}], "year": 1994, "venue": "Palaeontology", "link": "135025683"}, "BIBREF12": {"title": "The status of the sauropterygian reptile genera Ceresiosaurus, Lariosaurus, and Silvestrosaurus from the Middle Triassic of Europe", "authors": [{"first": "O", "middle": [], "last": "Rieppel", "suffix": ""}], "year": 1998, "venue": "Fieldiana: Geology", "link": null}, "BIBREF13": {"title": "Sauropterygia I: Placodontia, Pachypleurosauria, Nothosauroidea", "authors": [{"first": "O", "middle": [], "last": "Rieppel", "suffix": ""}], "year": 2000, "venue": "", "link": null}, "BIBREF14": {"title": "A new species of Nothosaurus (Reptilia: Sauropterygia) from the Upper Muschelkalk (Lower Ladinian) of southwestern Germany", "authors": [{"first": "O", "middle": [], "last": "Rieppel", "suffix": ""}], "year": 2001, "venue": "Palaeontographica, Abteilung A", "link": null}, "BIBREF15": {"title": "Lariosaurus xingyiensis (Reptilia: Sauropterygia) from the Triassic of China", "authors": [{"first": "O", "middle": [], "last": "Rieppel", "suffix": ""}, {"first": "J.-L", "middle": [], "last": "Li", "suffix": ""}, {"first": "J", "middle": [], "last": "Liu", "suffix": ""}], "year": 2003, "venue": "Canadian Journal of Earth Sciences", "link": "140172324"}, "BIBREF16": {"title": "A new species of the thalattosaur genus Anshunsaurus (Reptilia: Thalattosauria) from the Middle Triassic of Guizhou Province, Southwestern China", "authors": [{"first": "O", "middle": [], "last": "Rieppel", "suffix": ""}, {"first": "J", "middle": [], "last": "Liu", "suffix": ""}, {"first": "C", "middle": [], "last": "Li", "suffix": ""}], "year": 2006, "venue": "Vertebrata PalAsiatica", "link": null}, "BIBREF17": {"title": "Journal of Vertebrate Paleontology", "authors": [{"first": "O", "middle": [], "last": "Rieppel", "suffix": ""}, {"first": "D.-Y", "middle": [], "last": "Jiang", "suffix": ""}, {"first": "N", "middle": ["C"], "last": "Fraser", "suffix": ""}, {"first": "W.-C", "middle": [], "last": "Hao", "suffix": ""}, {"first": "R", "middle": [], "last": "Motani", "suffix": ""}, {"first": "Y.-L", "middle": [], "last": "Sun", "suffix": ""}, {"first": "Z.-Y.", "middle": [], "last": "Sun", "suffix": ""}], "year": 2008, "venue": "Tanystropheus cf. T. Longobardicus from the early Late Triassic of Guizhou Province, Southwestern China", "link": null}, "BIBREF18": {"title": "On Neusticosaurus pusillus (Fraas), an amphibious reptile having affinities with terrestrial Nothosauria and with marine Plesiosauria", "authors": [{"first": "H", "middle": ["G"], "last": "Seeley", "suffix": ""}], "year": "", "venue": "Quarterly Journal of the Geological Society of London", "link": "129470178"}, "BIBREF19": {"title": "On the new Pachypleurosauroidea from Kweichow, southwest China", "authors": [{"first": "C.-C", "middle": [], "last": "Young", "suffix": ""}], "year": 1958, "venue": "Vertebrata PalAsiatica", "link": null}, "BIBREF20": {"title": "The most complete pistosauroid skeleton from the Triassic of Yunnan", "authors": [{"first": "L.-J", "middle": [], "last": "Zhao", "suffix": ""}, {"first": "T", "middle": [], "last": "Sato", "suffix": ""}, {"first": "C", "middle": [], "last": "Li", "suffix": ""}], "year": 2008, "venue": "China. Acta Geologica Sinica", "link": "129593187"}, "BIBREF21": {"title": "Review and prospect of the Triassic marine reptiles in China", "authors": [{"first": "L.-J", "middle": [], "last": "Zhao", "suffix": ""}, {"first": "L.-T", "middle": [], "last": "Wang", "suffix": ""}, {"first": "C", "middle": [], "last": "Li", "suffix": ""}], "year": 2008, "venue": "Acta Palaeontologica Sinica", "link": null}}, "ref_entries": {}}
{"paper_id": "84887049", "_pdf_hash": "8115f5f3d67a975674c1e9597623bcfdb9ddc244", "abstract": [{"section": "Abstract", "text": "Th is paper provides an overview of the life and scientifi c work of Dr. Christo Deltshev, the doyen of Bulgarian araneology. It also analyses his more important research contributions and provides a list of his scientifi c publications and the species he described.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Biography, Christo Deltshev, spiders, bibliography, Bulgaria It is both diffi cult and easy to write about the doyen of Bulgarian araneology Christo Deltshev. It is diffi cult because his work, although in one area -the study of spiders, is rather varied. And yet it is easy because we, the authors of this biography, know our colleague and friend Christo Deltshev and his development as a zoologist very well. We have witnessed how before our very eyes the enthusiastic lover of spiders, caves and mountains gradually turned into an erudite araneologist enjoying the respect of his colleagues from many countries. Th e seventieth anniversary of Christo Deltshev is reason enough to look back on his achievements in science and life and outline his", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "", "text": "position in the international arachnological community and among Bulgarian zoologists. Th is we did during the celebration of his anniversary at the National Museum of Natural History.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Christo Deltshev was born on January 22, 1939 in Sofi a. More than two thirds of the seventy years, which have passed since then, he devoted to the study of spiders, fi rst as a speleologist and then as a professional scientist with the Institute of Zoology. His father Deltcho Deltshev was from Komotini (now in northern Greece) and his mother Victoria Gospodinova was from Sofi a. Even as a pupil Christo (or Itso as most of his friends and colleagues call him) showed great interest in nature, and in the parks of Sofi a and Vitosha Mountain he collected diff erent insects and spiders, which then he brought home in shoe boxes to look after them. At school his interest in animals grew stronger and he became the head of the biology group. Th e anti-communist inclinations of his father had a negative aff ect on the way Christo's life would turn out. At the time of fi erce repressions by the Communist party the son of the former convict was subject to great pressure. Despite his wish, he was not allowed to study at the university and after he served in the army from 1957 to 1959 he was forced to start as a common worker.", "cite_spans": [{"start": 37, "end": 40, "text": "22,", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "", "text": "Luckily, at that particular time the law was changed and after successfully passing the exams in 1960, Christo Deltshev was accepted as a student at the University of Sofi a. It was then that he met a group of ardent speleologists -Petar Tranteev, Vassil Gu\u00e9orgiev, Petar Beron, Vladimir Beshkov, Tanyu Michev, Stoitze Andreev and Alexi Popov -and with them he started exploring the caves of Bulgaria and their fauna. Th is helped him make an important decision -to devote his scientifi c interests to spiders. Almost fi fty years have passed since then and Christo Deltshev is still collecting, observing, describing and studying spiders with the same vigour and passion.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "He received his fi rst instructions on the organization and conduct of scientifi c research and an acquaintance with diff erent methods from Dr. Ivan Buresch, member of the Bulgarian Academy of Sciences and founder of contemporary zoology and biospeleology in Bulgaria. He acquainted him with the work of Associate Professor Dr. Pencho Drensky, and gave Christo reprints of the publications by this eminent Bulgarian arachnologist and part of his bibliography fi les on spiders. Years later, as a sign of respect to his mentor Deltshev (1975 [12] 1 ) named a newly discovered cave spider Troglohyphantes bureschianus. At the same time, at the beginning of 1962, he got to know Pencho Drensky himself, who gave him his fi rst lessons in araneology. Unfortunately, due to the death of P. Drensky just a few months later, Christo lost the opportunity to share with him his ideas on spider studies and hear his advice.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Christo Deltshev received his degree from the Invertebrate Zoology Department of the St. Kliment Ohridsky University of Sofi a in 1965 with a thesis entitled \"Th e spiders (Araneae) of Vitosha Mountain\". Th at same year he was appointed as a biologist at the Institute of Zoology with the Bulgarian Academy of Sciences (then 1 Th e number in the square brackets after each citation designates the serial number from the List of Christo Deltshev's publications at the end of the paper.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Institute of Zoology and Museum), where he still works to this day. From 1972 to 1985 he was an Assistant Professor. His PhD thesis, which he defended in 1977, was entitled \"Faunistic, taxonomic, ecological and zoogeographical investigations on the cave spiders of Bulgaria (Araneae)\". Since 1985 he has been an Associate Professor. Th e director of the Institute of Zoology appreciated his organizational and management skills and in 1995 Christo Deltshev was elected head of the Department of Taxonomy, Faunistics and Zoogeography. He has occupied this position ever since. Two years later he was appointed Secretary of the Scientifi c Council of Zoology and Ecology with the High Attestation Commission. As an administrator he is still involved with the organization and procedures for thesis defense by zoologists and ecologists in Bulgaria. His work for the Council puts him in touch with many young people who share with him their passion for zoology. With his typical responsiveness and friendliness he was able to help many of them on diff erent occasions; indeed it is hard to fi nd anyone among the Bulgarian zoological community who doesn't know Christo Deltshev.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "His valuable scientifi c results derive from his qualities and perseverance as a fi eld researcher. He has been connected with nature his whole life and is well acquainted with the Bulgarian mountains. We, the authors of this biography, had to overcome together with him storms, fog and hail and we know that his desire for explorations of caves and mountains is inextinguishable. In sunny and in stormy weather he never loses his good spirits.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Th e head of the Institute of Zoology, Professor Alexander Valkanov, took Christo, just after he started work, to his summer expeditions to explore the high-mountain lakes of Rila and Pirin. During one of these expeditions to the Seven Rila Lakes, together with German hydrobiologists, one evening at the camp fi re he found out that Christo was a fi re-dancer. Fire-dancing is an ancient folk custom from Strandzha Mountain in south-east Bulgaria during which the dancers -in a trance-like state -dance bare-foot over live coals. To the professor's question \"Will you do it?\" Christo took off his shoes, set the glowing embers ready, went around them and then several times walked over the still glowing coal. \"I have lived to see this miracle as well!\", Professor Valkanov exclaimed, and was amazed to see there were no burn marks on Christo's feet. Christo's participation in Professor Valkanov's expeditions stirred his interest in the fauna of the high-mountain spiders of Bulgaria.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "In the beginning of his scientifi c career he established cooperation with arachnologists from other countries (Carl Friedrich Roewer and Hermann Wiehle from Germany, Pierre Bonnet and Louis Fage from France, Josef Kratochvil and Franti\u0161ek Miller from the former Czechoslovakia, Herbert Levi from the USA). In 1972 he described his fi rst spider Protoleptoneta bulgarica, which turned out to be both a new genus and species. To make sure he was not mistaken he sought the opinion of Paolo Marcello Brignolli and Franti\u0161ek Miller, who were at the time among the best taxonomists of this group in Europe. Years later, already an established spider expert himself, Dr. Deltshev advised young zoologists during their fi rst steps in araneology and confi rmed the new species they had discovered.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Christo's love for caves started during his university years. Th e fi rst cave he visited was Kolkina Dupka at the village of Zimevitsa in the Stara Planina Mountain. When entering this precipice cave in 1960, he had to clamber over the corpses of several dead pigs. Th e more experienced cavers who were leading him saw that he did not shrink at the unpleasant sight and realized the boy would turn out to be a true speleologist. And so he did. His infatuation with caves did not diminish with time, even after an incident of almost tragic proportions took place. In August 1964, when he was climbing down the Bankovitsa abyss at Karlukovo village near Lukovit, several of the rungs of the self-made rope ladder broke and Christo fell 12 metres. His hip was broken in fi ve pieces and he had to spend four months in cast, with recovery taking another four months. From then on, throughout his life the injury tormented him whenever the weather got worse or when he strained himself, but it did not stop Christo from continuing his researches in high mountains and caves or from enjoying nature as a tourist with his family and friends.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Th us it was no wonder that it was in a cave that Christo held his wedding. It happened in 1968 in Temnata Dupka Cave in Iskar Gorge near Lakatnik. Christo had already graduated and started working as a researcher and thought it was time to start a family. And so Elena entered his life and she would become the pillar and support of his further progress. Th ey had three children, one after another, which was a rare case for a family of intellectuals in Bulgaria during the second half of the 20th century.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "So far Dr. Deltshev has visited and studied the fauna of several hundred caves in Bulgaria. He discovered some of them and for many he was among their fi rst explorers. He participated in the organization of many international, national and club caving expeditions. As well as Bulgaria, Christo also took part in international caving expeditions in Slovenia (1963), the Caucasus (1967), Austria (1968) and the Moravian karst in the Czech Republic (1980). His achievements in speleology were largely due to the infl uence which the inspirer of the speleological movement in Bulgaria, Petar Tranteev, had on him. Christo proposed to him his idea to make ascenders, which were produced by Vesselin Gyaurov, and Christo tested them himself. His speleological organizational work concerns the Bulgarian Federation of Speleology -of w hich he was the vice-chairman from 1968 until 1993 -as well as the Academic Students' Speleological Club of which he was the chairman in the period 1978-1996. Since 1972 Christo Deltshev has taught a speleology course in the National Sports Academy and is the author of a textbook on speleology.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Christo is a friendly guy. He likes to entertain his colleagues and friends with stories of his expeditions and interesting things he had witnessed. For many years he used to dress like Santa Claus and give away presents to cavers in some mountain hut, and now he is doing this for the children and grandchildren of his colleagues.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "In his more than 40 years of scientifi c research the araneological contributions of Christo Deltshev have been many in number. Th e main areas of his work and publications are taxonomy, faunistics, zoogeography and ecology of spiders in Bulgaria and the other Balkan countries. He has described as new the genera Protoleptoneta and Cryphoecina, as well as 34 species and 2 subspecies of spiders from 8 families. Th e largest number of taxa described by him belongs to the families Linyphiidae (17 species and 2 subspecies), Agelenidae (6 species), Leptonetidae (1 genus and 3 species) and Amaurobiidae (3 species). If we look at the genera, the largest number of newly described taxa belong to Centromerus (4 species and 1 subspecies), Malthonica (4 species), Lepthyphantes and Eurocoelotes (3 species each). Christo is a skilled illustrator and this gift largely helps his taxonomic work. Th e scale of his contributions can be judged also by the fact that all but one of the 38 taxa have been described by him alone. And the quality of his contribution can be estimated by the validity of all the described taxa; again with only one exception (Lepthyphantes gueorguievi has been synonymized). Th e newly described taxa all come from the Balkan Peninsula: Bulgaria (1 genus, 24 species and 2 subspecies), Greece (7 species), Serbia (2 species), Montenegro (1 genus and 1 species). Almost an equal number of the new taxa have been found in caves (16 species) and in mountains (17 species and subspecies), and another 3 species along the coast and in the lowlands. His permanent interest in taxonomy is evident from the even distribution of newly described taxa throughout time: 1970s (12 taxa), 1980s (10 taxa), 1990s (9 taxa) and the fi rst decade of the 21st century (9 species).", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Christo Deltshev has conducted some other taxonomic modifi cations such as the establishment of 25 new synonyms and designation of lectotypes of 7 species. He revised the genus Tenuiphantes, the European species of Bolyphantes, the species of Centromerus in the caves of the Balkan Peninsula, and the genera Erigone, Tegenaria, Coelotes and Zodarion in Bulgaria. He also critically revised the spider species of the Balkan Peninsula described by Dr. P. Drensky (Deltshev 2003 [111] ). Considerable too are his faunistic contributions to the distribution of spiders across the Balkan countries. Due to his research over many years the number of known species in Bulgaria increased by 237, in Serbia -by 73, in Macedonia (FYROM) -by 22 and in Greece by 11. He also discovered two families (one still unpublished) new for the fauna of Bulgaria. Another aspect of his contribution is the complex research and analysis of the araneofauna from the diff erent regions of Bulgaria. An excellent fi eld researcher, he conducted and published his studies on the spiders of the mountains Central Stara Planina, Rila, Pirin, the Eastern Rhodopes, Lyulin, Vitosha and Sashtinska Sredna Gora; of plain areas in Bulgaria such as the Black Sea Coast and Ludogorie; of some small but zoogeographically interesting territories such as Srebarna Lake, Shabla-Ezerets wetland, the Sofi a Region, Zemen and Kresna gorges and Sandanski-Petrich Kettle.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Th e climax of Christo Deltshev's work on the study of spiders in the northern part of the Balkan Peninsula are the critical checklist of Bulgarian spiders (Deltshev and Blagoev 2001 [104] ) and the monograph \"Th e Spiders of Serbia\" (Deltshev et al. 2003 [113] ). Th e checklist contains 910 species according to data based on 173 publications. It has been updated with an online list (Blagoev et al. 2002 [107] ) containing up-to-date current information on 1007 species in 41 families based on the review of 226 items of literature. Th e monograph constitutes a critical catalogue of 618 species of 36 families based on all the literature fi ndings and new data from intensive faunistic research in Serbia. Th e localities of each species are plotted on a UTM map.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Zoogeography has always interested Christo Deltshev and because of this almost all of his taxonomic works are accompanied by a zoogeographic analysis. In his analysis of spiders of the Balkan Peninsula (Deltshev 1999 [87] ) he concentrated on 1409 species from 47 families and selected the regions with the highest species diversity. In this research he established that 26.9 % of spiders (379 species) are endemic for the region and proved the important role of the Balkan Peninsula as a speciation center in Europe. Similar zoogeographic analyses have been published on the spiders of Bulgaria as well (Deltshev 2005 [124] ), on endemic spiders of Bulgaria (Deltshev 1996 [67] ) and the Balkan Peninsula (Deltshev 2000 [94] ), and on troglobitic spiders of the Balkan Peninsula (Deltshev 1978 [20] , 2008 [132] ).", "cite_spans": [{"start": 807, "end": 812, "text": "[132]", "ref_id": "BIBREF122"}], "ref_spans": []}, {"section": "", "text": "Some ecological problems also received Christo Deltshev's attention. He studied the population structure of spiders inhabiting cave entrances (Deltshev 1973 [7] ) and researched the impact of pasture management on the number and biomass of spiders (Deltshev and Kajak 1974 [11] ). He is interested in the factors which determine the assemblage structure of spiders (Popov et al. 2000 [102] ). In the sphere of applied zoology he compared the biodiversity of spiders in genetically modifi ed and conventional potato fi elds (Kalushkov et al. 2008 [134] ).", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "In the last 15 years Dr. Deltshev has carried out intensive studies on the issues regarding the protection of invertebrates in Bulgaria. He is one of the leading experts in drafting the National Strategy for Biodiversity Conservation of Invertebrates (Deltshev et al. 1998 [82] ) and identifi ed the conservation signifi cance of spiders in the main protected territories in Bulgaria: the three national parks and some of the nature parks.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Th e overall number of publications by Dr. Deltshev as of June 2009 (including that in press) is 140. It includes the monograph \"Spiders of Serbia\" (Deltshev et al. 2003 [113] ), a textbook on speleology and caving (Deltshev 1979 [23] ) and books of popular science \"Th e descendants of Arachna\" (Deltshev 1988 [47] ) and \"Biodiversity of Pirin National Park\" (Popov et al. 2005 [122] ). Several practical faunistic methods have been introduced into Bulgaria by Christo Deltshev. He introduced UTM mapping (Lehrer and Deltshev 1978 [21] ), which is actively used even now by Bulgarian zoologists. Together with colleagues he proposed methods of collecting, managing and recording faunistic information (Deltshev et al. 1998 [86] ), which are also widely used, particularly in studies of biodiversity protection.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Th ere are not so many Bulgarian zoologists who, like Dr. Deltshev, have established their own school of followers. A group has emerged which jointly continues the study of spiders in Bulgaria. He has been the advisor of 4 PhD and 8 graduate students. Two of his PhD students have successfully defended their theses on araneological topics and are currently research associates with the Institute of Zoology in Sofi a and the Biodiversity Institute of Ontario in Guelph, Canada. Christo is also an advisor to young zoologists from other Balkan countries. One of the aspects of Christo Deltshev's international activities is his participation in the major arachnological and related associations. He became a member of the International Society of Arachnology (ISA), now seated in Berlin, almost from its beginnings 45 years ago, and he is currently the regional representative for Bulgaria for this most prestigious organization of arachnologists. Christo is also a member of the European Society of Arachnology (ESA), seated in Nancy (France), where he is now a member of the society's Council. In the European Invertebrate Survey (EIS), registered in the Netherlands, he is a member of the organization's Committee and he is also member of Arachnologische Gesellschaft (AraGes) seated in Bayreuth (Germany).", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "His Arachnologists and biospeleologists from diff erent countries have described species which they named after Christo Deltshev in acknowledgement of his work. Altogether, one genus and 13 species bear Christo's name. Nine of the species are spiders, there is one harvestman, one millipede and 2 beetles.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Th e celebration of Christo Deltshev's anniversary at the National Museum of Natural History took place in the hall with a temporary exhibition called Spider Museum -an appropriate backdrop for the evaluation of his work. Th e results of his work reveal Dr. Deltshev to be an excellent araneologist, acknowledged as one of the most promi- nent European spider taxonomists. It is thanks to him that the Institute of Zoology possesses a perfectly arranged collection of spiders and database on their distribution across the Balkan countries.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "In the year of Christo Deltshev's anniversary we wish him further success as a researcher, administrator and mentor to young researchers. New spider species are yet to be discovered and described by Christo, and more territories on the Balkan Peninsula await his study. ", "cite_spans": [], "ref_spans": []}, {"section": "List of genera and species named in honour of Christo Deltshev", "text": "", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "A new Protoleptoneta from Bulgarian caves", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}], "year": 1977, "venue": "", "link": null}, "BIBREF2": {"title": "Genus Nesticus (Nesticidae, Araneae) from Bulgarian caves", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}], "year": 1977, "venue": "Proccedings of the 6th Interna tional Congress of Speleology", "link": null}, "BIBREF3": {"title": "Th e tenuis group of Lepthyphantes Menge (Araneae, Linyphiidae)", "authors": [{"first": "P", "middle": [], "last": "Van Helsdingen", "suffix": ""}, {"first": "K", "middle": [], "last": "Th Aler", "suffix": ""}, {"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}], "year": 1977, "venue": "Tijdschrift voor Entomologie", "link": null}, "BIBREF4": {"title": "A new Histopona (Araneae, Agelenidae) from Bulgarian caves", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}], "year": 1978, "venue": "Acta zoologica bulgarica", "link": null}, "BIBREF5": {"title": "Th e origin, formation and zoogeography of troglobitic spiders of the Balkan Peninsula", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}], "year": 1978, "venue": "Symposia of the Zoological Society of London", "link": null}, "BIBREF6": {"title": "Modern methods for biogeographical mapping of Bulgaria", "authors": [{"first": "A", "middle": [], "last": "Lehrer", "suffix": ""}, {"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}], "year": 1978, "venue": "Acta zoologica bulgarica", "link": null}, "BIBREF7": {"title": "A contribution to the study of cave spiders (Araneae) in Greece. Four new species (Araneae, Nesticidae, Linyphiidae) from the islands of Crete and Th era", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}], "year": 1979, "venue": "Acta zoologica bulgarica", "link": null}, "BIBREF9": {"title": "A review of the biospeleological researches in Bulgaria and their future problems", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}, {"first": "V", "middle": [], "last": "Gu\u00e9orguiev", "suffix": ""}], "year": 1979, "venue": "Proceedings of the IIIrd National Conference of Speleology, Sofi a", "link": null}, "BIBREF10": {"title": "On the high altitude spiders (Araneae) in Bulgaria", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}], "year": 1980, "venue": "Proceedings of the 8th International Congress of Arachnology", "link": null}, "BIBREF11": {"title": "Spiders (Araneae) from the high altitude belt of the Vitosha Mountain", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}], "year": 1980, "venue": "Acta zoologica bulgarica", "link": null}, "BIBREF12": {"title": "A contribution to the taxonomical study of pallidus group of genus Lepthyphantes Menge (Araneae, Linyphiidae) in Bulgaria", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}], "year": 1980, "venue": "Acta zoologica bulgarica", "link": null}, "BIBREF13": {"title": "Rare and threatened Arachnida species (Arachnida, Solifugae, Araneae) in south-west Bulgaria. Regional Symposium under Project 8-MAB, Conservation of Natural Areas and of the Genetic Material they contain", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}], "year": 1980, "venue": "", "link": null}, "BIBREF14": {"title": "New data on the distribution of cave spiders (Araneae) in Bulgaria", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}], "year": 1982, "venue": "Acta zoologica bulgarica", "link": null}, "BIBREF16": {"title": "Slunchev bryag", "authors": [], "year": 1982, "venue": "", "link": null}, "BIBREF17": {"title": "Zoogeographical review of Bulgarian cave spiders (Araneae)", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}], "year": 1983, "venue": "Proceedings of the European Regional Conference on Speleology, Sofi a-Bulgaria", "link": null}, "BIBREF18": {"title": "A contribution to the taxonomical study of sylvaticus group of genus Centromerus F. Dahl (Araneae, Linyphiidae) in Bulgaria", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}], "year": 1983, "venue": "Acta zoologica bulgarica", "link": null}, "BIBREF19": {"title": "Notes on spiders of the genus Erigone Audouin (Araneae, Erigonidae) in Bulgaria", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}], "year": 1983, "venue": "Acta zoologica bulgarica", "link": "88983898"}, "BIBREF20": {"title": "A contribution to the taxonomical and faunistic study of genus Lepthyphantes Menge (Araneae, Linyphiidae) from Pirin Mountain", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}], "year": 1983, "venue": "Acta zoologica bulgarica", "link": null}, "BIBREF21": {"title": "Proceedings of the IVth National Conference of Speleology", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}], "year": 1983, "venue": "", "link": null}, "BIBREF22": {"title": "A new Diplocephalus species from the Bulgarian mountains (Arachnida", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}], "year": 1984, "venue": "Araneae, Erigonidae). Reichenbachia", "link": null}, "BIBREF23": {"title": "Proceedings of the IVth National Conference of Zoology", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}], "year": 1984, "venue": "", "link": null}, "BIBREF24": {"title": "A review of the high altitude spider fauna (Araneae) of Southwestern Bulgaria", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}], "year": 1984, "venue": "Proceedings of the IVth National Conference of Zoology", "link": null}, "BIBREF25": {"title": "New data concerning cave spiders (Araneae) in Greece with description of a new Leptonetela (Araneae, Leptonetidae)", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}], "year": 1985, "venue": "Acta zoologica bulgarica", "link": "89462330"}, "BIBREF26": {"title": "A contribution to the study of the family Erigonidae (Araneae) from Pirin Mountain, Bulgaria, with a description of a new species (Metopobactrus orbelicus sp. n.)", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}], "year": 1985, "venue": "Bulletin of the British arachnological Society", "link": null}, "BIBREF29": {"title": "A critical review of genus Zodarion Walckenaer (Araneae, Zodariidae) in Bulgaria", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}], "year": 1987, "venue": "Acta zoologica bulgarica", "link": null}, "BIBREF30": {"title": "A review of spiders (Araneae) in caves in Bulgaria", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}], "year": 1987, "venue": "", "link": null}, "BIBREF31": {"title": "A critical review of genus Araeoncus Simon in Bulgaria, with description of a new species (Araeoncus clivifrons sp. n.) (Arachnida, Araneae, Erigonidae)", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}], "year": 1987, "venue": "Reichenbachia", "link": null}, "BIBREF32": {"title": "Review of the species from the family Lycosidae (Araneae) from Pirin Mountain", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}, {"first": "H", "middle": [], "last": "Deltshev", "suffix": ""}], "year": 1988, "venue": "Fauna of southwestern Bulgaria, Sofi a", "link": null}, "BIBREF33": {"title": "A contribution to the study of genus Lepthyphantes Menge (Araneae, Linyphiidae) from the Pirin Mountain with a description of a new species (Lepthyphantes rectilamellus sp. n.)", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}, {"first": "H", "middle": [], "last": "Deltshev", "suffix": ""}], "year": 1988, "venue": "Acta zoologica bulgarica", "link": null}, "BIBREF36": {"title": "Th e genus Fageiella Kratochvil and the genus Antrohyphantes Dumitresco (Araneae, Linyphiidae, Lepthyphanteae) in the caves of Balkan peninsula", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}], "year": 1988, "venue": "", "link": null}, "BIBREF37": {"title": "Biotopical distribution of wolf-spiders (Araneae, Lycosidae) in the Zemen Gorge", "authors": [{"first": "G", "middle": [], "last": "Blagoev", "suffix": ""}, {"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}], "year": 1989, "venue": "Southwestern Bulgaria. Ecologia (Sofi a)", "link": null}, "BIBREF38": {"title": "A critical review of genus Coelotes Blackwall in Bulgaria with description of a new species (Coelotes drenskii sp. n.) (Araneae, Agelenidae)", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}], "year": 1990, "venue": "Acta zoologica bulgarica", "link": "82723630"}, "BIBREF39": {"title": "Th e high-altitude spiders (Araneae) in the Pirin Mountains", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}], "year": 1990, "venue": "Acta Zoologica Fennica", "link": null}, "BIBREF40": {"title": "Conservation problems of the Bulgarian cave fauna", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}], "year": 1990, "venue": "Proceedings of the 10th International Congress of Speleology", "link": null}, "BIBREF41": {"title": "A contribution to the study of spiders (Araneae: Dysderidae, Salticidae, Agelenidae) in Greece, with a description of a new species (Malthonica spinipalpis Deltshev, sp. n. Agelenidae)", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}, {"first": "I", "middle": [], "last": "Paraschi", "suffix": ""}], "year": 1990, "venue": "Biologia Gallo-Hellenica", "link": "91449446"}, "BIBREF42": {"title": "A critical review of family Th eridiidae (Araneae) in Bulgaria", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}], "year": 1992, "venue": "Acta zoologica bulgarica", "link": null}, "BIBREF43": {"title": "Drepanotylus pirinicus n. sp. from Pirin Mountain (Bulgaria), with comparative remarks on the other species of the genus", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}], "year": 1992, "venue": "", "link": null}, "BIBREF45": {"title": "A faunistic and zoogeographic analysis of spiders (Araneae) in Zemen gorge (Southwestern Bulgaria)", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}, {"first": "G", "middle": [], "last": "Blagoev", "suffix": ""}], "year": 1992, "venue": "Acta zoologica bulgarica", "link": "88832912"}, "BIBREF46": {"title": "Th e genus Tegenaria Latreille in Bulgaria: A critical review with description of two sibling species (Arach nida, Araneae: Agelenidae)", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}], "year": 1993, "venue": "Vereins in Innsbruck", "link": null}, "BIBREF47": {"title": "memoriam: P. Drensky (bibliography)", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}], "year": 1993, "venue": "", "link": null}, "BIBREF49": {"title": "Biotopical distribution and seasonal activity of model species of the family Gnaphosidae (Araneae) in Zemen gorge", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}, {"first": "G", "middle": [], "last": "Blagoev", "suffix": ""}], "year": 1994, "venue": "SW Bulgaria). Arachnologische Mitteilungen", "link": "129962466"}, "BIBREF51": {"title": "Vikariante Verbreitung im Artenkomplex von Lepthyphantes annulatus in Europa und ihre Deutung (Araneae, Linyphiidae)", "authors": [{"first": "K", "middle": [], "last": "Th Aler", "suffix": ""}, {"first": "P", "middle": [], "last": "Van Helsdingen", "suffix": ""}, {"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}], "year": 1994, "venue": "Zoologischer Anzeiger", "link": null}, "BIBREF52": {"title": "A review of family Agelenidae (Araneae) in Bulgaria. Taxonomic, faunistic and zoogeographical analysis", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}], "year": 1995, "venue": "European Journal of Entomology", "link": "83423981"}, "BIBREF53": {"title": "Spiders (Araneae) from the high altitude zone of Rila Mountain (Bulgaria)", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}], "year": 1995, "venue": "Berichte des naturwissenschaftlich-medizinischen Vereins in Innsbruck", "link": null}, "BIBREF54": {"title": "A critical review of family Lycosidae (Araneae) in Bulgaria", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}, {"first": "G", "middle": [], "last": "Blagoev", "suffix": ""}], "year": 1995, "venue": "Revue Arachnologique", "link": "132561224"}, "BIBREF55": {"title": "Fauna of the Pirin and Slavianka Mountains", "authors": [{"first": "D", "middle": [], "last": "Nankinov", "suffix": ""}, {"first": "V", "middle": [], "last": "Beshkov", "suffix": ""}, {"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}, {"first": "P", "middle": [], "last": "Kalushkov", "suffix": ""}], "year": 1995, "venue": "In: Zagorchev I (Ed.) Pirin: Geological guidebook, Sofi a", "link": null}, "BIBREF56": {"title": "Th e origin, formation and zoogeography of endemic spiders of Bulgaria (Araneae)", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}], "year": 1996, "venue": "", "link": null}, "BIBREF57": {"title": "Further report on cavedwelling spiders (Araneae, Arachnida) from Serbia", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}, {"first": "B", "middle": [], "last": "\u0106ur\u010di\u0107", "suffix": ""}, {"first": "R", "middle": [], "last": "Dimitrijevi\u0107", "suffix": ""}, {"first": "S", "middle": [], "last": "Makarov", "suffix": ""}, {"first": "L", "middle": [], "last": "Lu\u010di\u0107", "suffix": ""}], "year": 1996, "venue": "Archives of Biological Sciences", "link": null}, "BIBREF58": {"title": "A new Coelotes (C. brevispinus sp. n.) from Bulgarian mountains (Araneae, Agelenidae)", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}, {"first": "D", "middle": [], "last": "Dimitrov", "suffix": ""}], "year": 1996, "venue": "Revue Arachnologique", "link": null}, "BIBREF59": {"title": "Cryphoecina deelemanae gen. n., sp. n., a remarkable spider from the mountains of Montenegro (Yugoslavia) (Arachnida, Araneae, Hahniidae)", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}], "year": 1997, "venue": "Revue suisse de Zoologie", "link": "88540669"}, "BIBREF60": {"title": "A new species of Cybaeidae: Cybaeus balkanus spec. nov. from the mountains of Balkan peninsula (Arachnida: Araneae)", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}], "year": 1997, "venue": "Reichenbachia", "link": null}, "BIBREF61": {"title": "Spiders (Araneae) from the coastal habitats of Shabla-Ezerets Lake", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}], "year": 1997, "venue": "Acta zoologica bulgarica", "link": null}, "BIBREF62": {"title": "50 years Institute of Zoology at the Bulgarian Academy of Sciences", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}], "year": 1997, "venue": "", "link": null}, "BIBREF63": {"title": "Conservation priorities of arachnids (non Acari) in Bulgaria. Proceedings of the 10th International Colloquium of the European Invertebrate Survey, Saarbr\u00fccken", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}], "year": 1995, "venue": "", "link": null}, "BIBREF64": {"title": "Th e spiders of Pirin Mountain (Bulgaria). Taxonomic, faunistic and zoogeographical analysis (Araneae)", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}, {"first": "G", "middle": [], "last": "Blagoev", "suffix": ""}], "year": 1997, "venue": "", "link": null}, "BIBREF65": {"title": "Contribution to the knowledge of the group europaeus of Centromerus Dahl (Linyphiidae, Araneae) in the Balkan Peninsula", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}, {"first": "B", "middle": [], "last": "\u0106ur\u010di\u0107", "suffix": ""}], "year": 1997, "venue": "Revue suisse de Zoologie", "link": null}, "BIBREF66": {"title": "Additional report on cave-dwelling spiders (Araneae, Arachnida) from Serbia", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}, {"first": "B", "middle": [], "last": "\u0106ur\u010di\u0107", "suffix": ""}, {"first": "R", "middle": [], "last": "Dimitrijevi\u0107", "suffix": ""}, {"first": "S", "middle": [], "last": "Makarov", "suffix": ""}, {"first": "L", "middle": [], "last": "Lu\u010di\u0107", "suffix": ""}, {"first": "V", "middle": [], "last": "Tomi\u0107", "suffix": ""}], "year": 1997, "venue": "Archives of Biological Sciences", "link": null}, "BIBREF69": {"title": "Economic signifi cance and problems of fauna protection", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}, {"first": "M", "middle": [], "last": "Karapetkova", "suffix": ""}, {"first": "V", "middle": [], "last": "Popov", "suffix": ""}, {"first": "D", "middle": [], "last": "Nankinov", "suffix": ""}], "year": 1997, "venue": "", "link": null}, "BIBREF70": {"title": "Spiders from the high altitude zone of Central Stara Planina Mountain (Bulgaria) (Araneae, Arachnida)", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}], "year": 1998, "venue": "Vereins in Innsbruck", "link": null}, "BIBREF71": {"title": "Bulgaria's biological diversity. Conservation status and needs assessment", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}, {"first": "S", "middle": [], "last": "Andreev", "suffix": ""}, {"first": "G", "middle": [], "last": "Blagoev", "suffix": ""}, {"first": "V", "middle": [], "last": "Golemansky", "suffix": ""}, {"first": "G", "middle": [], "last": "Milojkova", "suffix": ""}, {"first": "V", "middle": [], "last": "Peneva", "suffix": ""}, {"first": "D", "middle": [], "last": "Dobrev", "suffix": ""}, {"first": "M", "middle": [], "last": "Todorov", "suffix": ""}, {"first": "Z", "middle": [], "last": "Hubenov", "suffix": ""}], "year": 1998, "venue": "Washington", "link": null}, "BIBREF72": {"title": "Biodiversity of the Srebarna Biosphere Reserve. Checklist and bibliography, Context & Pensoft, Sofi a", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}, {"first": "G", "middle": [], "last": "Blagoev", "suffix": ""}], "year": 1998, "venue": "", "link": null}, "BIBREF73": {"title": "Conser vation priorities on biodiversity of invertebrates (non-Insecta) in Bulgarian mountains", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}, {"first": "G", "middle": [], "last": "Blagoev", "suffix": ""}, {"first": "Z", "middle": [], "last": "Hubenov", "suffix": ""}], "year": 1998, "venue": "Ambio", "link": "88748196"}, "BIBREF74": {"title": "On cave and litter-dwelling spiders (Araneae) from East Serbia", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}, {"first": "B", "middle": [], "last": "\u0106ur\u010di\u0107", "suffix": ""}, {"first": "R", "middle": [], "last": "Dimitrijevi\u0107", "suffix": ""}, {"first": "S", "middle": [], "last": "Makarov", "suffix": ""}, {"first": "L", "middle": [], "last": "Lu\u010di\u0107", "suffix": ""}, {"first": "V", "middle": [], "last": "Tomi\u0107", "suffix": ""}], "year": 1998, "venue": "Yugoslavia. Archives of Biological Sciences", "link": null}, "BIBREF75": {"title": "Modern methods of collecting, managing and keeping faunistic data", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}, {"first": "Z", "middle": [], "last": "Hubenov", "suffix": ""}, {"first": "G", "middle": [], "last": "Blagoev", "suffix": ""}, {"first": "D", "middle": [], "last": "Dobrev", "suffix": ""}], "year": 1998, "venue": "Historia naturalis bulgarica", "link": null}, "BIBREF76": {"title": "A faunistic and zoogeographical review of the spiders (Araneae) of the Balkan Peninsula", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}], "year": 1999, "venue": "Journal of Arachnology", "link": "131940298"}, "BIBREF77": {"title": "On some cave-dwelling spiders (Araneae, Arachnida) from Serbia", "authors": [{"first": "B", "middle": [], "last": "\u0106ur\u010di\u0107", "suffix": ""}, {"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}, {"first": "R", "middle": [], "last": "Dimitrijevi\u0107", "suffix": ""}, {"first": "O", "middle": [], "last": "Karamata", "suffix": ""}, {"first": "V", "middle": [], "last": "Tomi\u0107", "suffix": ""}, {"first": "S", "middle": [], "last": "\u0106ur\u010di\u0107", "suffix": ""}, {"first": "N", "middle": [], "last": "\u0106ur\u010di\u0107", "suffix": ""}], "year": 1999, "venue": "Archives of Biological Sciences", "link": null}, "BIBREF78": {"title": "First report on some leaf litter spiders (Araneae, Arachnida) from Serbia", "authors": [{"first": "B", "middle": [], "last": "\u0106ur\u010di\u0107", "suffix": ""}, {"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}, {"first": "S", "middle": [], "last": "Makarov", "suffix": ""}, {"first": "O", "middle": [], "last": "Karamata", "suffix": ""}, {"first": "V", "middle": [], "last": "Tomi\u0107", "suffix": ""}], "year": 1999, "venue": "Archives of Biological Sciences", "link": null}, "BIBREF79": {"title": "On some leaflitter spiders (Araneae, Arachnida) from West Serbia", "authors": [{"first": "B", "middle": [], "last": "\u0106ur\u010di\u0107", "suffix": ""}, {"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}, {"first": "S", "middle": [], "last": "Makarov", "suffix": ""}, {"first": "V", "middle": [], "last": "Tomi\u0107", "suffix": ""}, {"first": "S", "middle": [], "last": "\u0106ur\u010di\u0107", "suffix": ""}, {"first": "N", "middle": [], "last": "\u0106ur\u010di\u0107", "suffix": ""}], "year": 1999, "venue": "Archives of Biological Sciences", "link": null}, "BIBREF80": {"title": "Faunistic diversity of invertebrates (non Insecta) in Rila National Park", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}, {"first": "P", "middle": [], "last": "Beron", "suffix": ""}, {"first": "G", "middle": [], "last": "Blagoev", "suffix": ""}, {"first": "V", "middle": [], "last": "Golemansky", "suffix": ""}, {"first": "V", "middle": [], "last": "Najdenov", "suffix": ""}, {"first": "V", "middle": [], "last": "Peneva", "suffix": ""}, {"first": "P", "middle": [], "last": "Stoev", "suffix": ""}, {"first": "M", "middle": [], "last": "Todorov", "suffix": ""}, {"first": "Z", "middle": [], "last": "Hubenov", "suffix": ""}], "year": 1999, "venue": "", "link": null}, "BIBREF81": {"title": "Faunistic diversity of invertebrates (non Insecta) in Central Balkan National Park", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}, {"first": "P", "middle": [], "last": "Beron", "suffix": ""}, {"first": "G", "middle": [], "last": "Blagoev", "suffix": ""}, {"first": "V", "middle": [], "last": "Golemansky", "suffix": ""}, {"first": "V", "middle": [], "last": "Peneva", "suffix": ""}, {"first": "P", "middle": [], "last": "Stoev", "suffix": ""}, {"first": "M", "middle": [], "last": "Todorov", "suffix": ""}, {"first": "Z", "middle": [], "last": "Hubenov", "suffix": ""}], "year": 1999, "venue": "", "link": null}, "BIBREF82": {"title": "Conservation problems of the faunistic diversity of invertebrates in Vitosha Nature Park", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}, {"first": "A", "middle": [], "last": "Popov", "suffix": ""}, {"first": "Z", "middle": [], "last": "Hubenov", "suffix": ""}, {"first": "M", "middle": [], "last": "Todorov", "suffix": ""}], "year": 1999, "venue": "Litera, Sofi a", "link": null}, "BIBREF83": {"title": "Th e endemic spiders (Araneae) of the Balkan peninsula", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}], "year": 2000, "venue": "Ekol\u00f3gia (Bratislava)", "link": "4672354"}, "BIBREF84": {"title": "On some leaf-litter spiders (Araneae, Arachnida) from West Serbia, Yugoslavia. Part II", "authors": [{"first": "B", "middle": [], "last": "\u0106ur\u010di\u0107", "suffix": ""}, {"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}, {"first": "V", "middle": [], "last": "Tomi\u0107", "suffix": ""}], "year": 2000, "venue": "Archives of Biological Sciences", "link": null}, "BIBREF85": {"title": "A contribution to the study of some spiders (Araneae) in Macedonia", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}, {"first": "G", "middle": [], "last": "Blagoev", "suffix": ""}, {"first": "E", "middle": [], "last": "Stojkoska", "suffix": ""}], "year": 2000, "venue": "Archives of Biological Sciences", "link": null}, "BIBREF86": {"title": "On some soil and cave spiders (Araneae, Arachnida) from Serbia", "authors": [{"first": "B", "middle": [], "last": "\u0106ur\u010di\u0107", "suffix": ""}, {"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}, {"first": "G", "middle": [], "last": "Blagoev", "suffix": ""}, {"first": "S", "middle": [], "last": "\u0106ur\u010di\u0107", "suffix": ""}, {"first": "V", "middle": [], "last": "Tomi\u0107", "suffix": ""}, {"first": "S", "middle": [], "last": "Makarov", "suffix": ""}], "year": 2000, "venue": "Archives of Biological Sciences", "link": null}, "BIBREF87": {"title": "Faunistic diversity of invertebrates (non Insecta) in Central Balkan National Park", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}, {"first": "P", "middle": [], "last": "Beron", "suffix": ""}, {"first": "G", "middle": [], "last": "Blagoev", "suffix": ""}, {"first": "V", "middle": [], "last": "Golemansky", "suffix": ""}, {"first": "V", "middle": [], "last": "Peneva", "suffix": ""}, {"first": "P", "middle": [], "last": "Stoev", "suffix": ""}, {"first": "M", "middle": [], "last": "Todorov", "suffix": ""}, {"first": "Z", "middle": [], "last": "Hubenov", "suffix": ""}], "year": 2000, "venue": "Biological Diversity of the Central", "link": null}, "BIBREF88": {"title": "Faunistic diversity of invertebrates (non Insecta) of the Rila National Park", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}, {"first": "P", "middle": [], "last": "Beron", "suffix": ""}, {"first": "G", "middle": [], "last": "Blagoev", "suffix": ""}, {"first": "V", "middle": [], "last": "Golemansky", "suffix": ""}, {"first": "V", "middle": [], "last": "Najdenov", "suffix": ""}, {"first": "V", "middle": [], "last": "Peneva", "suffix": ""}, {"first": "P", "middle": [], "last": "Stoev", "suffix": ""}, {"first": "M", "middle": [], "last": "Todorov", "suffix": ""}, {"first": "Z", "middle": [], "last": "Hubenov", "suffix": ""}], "year": 2000, "venue": "Biological Diversity of the Rila National Park. Pensoft, Sofi a", "link": null}, "BIBREF89": {"title": "High mountain treeless zone of the Central Balkan national Park. Biological diversity and problems of its conservation", "authors": [{"first": "A", "middle": [], "last": "Popov", "suffix": ""}, {"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}, {"first": "Z", "middle": [], "last": "Hubenov", "suffix": ""}, {"first": "V", "middle": [], "last": "Beschovski", "suffix": ""}, {"first": "D", "middle": [], "last": "Dobrev", "suffix": ""}, {"first": "B", "middle": [], "last": "Gu\u00e9orguiev", "suffix": ""}], "year": 2000, "venue": "BSBCP, Sofi a", "link": "134863005"}, "BIBREF90": {"title": "High mountain treeless zone of the Central Balkan National Park. Biological diversity and problems of its conservation", "authors": [{"first": "A", "middle": [], "last": "Popov", "suffix": ""}, {"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}, {"first": "Z", "middle": [], "last": "Hubenov", "suffix": ""}, {"first": "V", "middle": [], "last": "Beschovski", "suffix": ""}, {"first": "D", "middle": [], "last": "Dobrev", "suffix": ""}, {"first": "B", "middle": [], "last": "Gu\u00e9orguiev", "suffix": ""}], "year": 2000, "venue": "BSBCP", "link": "134863005"}, "BIBREF91": {"title": "Epigeobiont animal assemblages from two landscapes of the Bulgarian Black Sea Coast: Relationship to habitat type, assemblage structure and biodiversity II. Spiders (Araneae)", "authors": [{"first": "V", "middle": [], "last": "Popov", "suffix": ""}, {"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}, {"first": "G", "middle": [], "last": "Blagoev", "suffix": ""}, {"first": "I", "middle": [], "last": "Krusteva", "suffix": ""}, {"first": "D", "middle": [], "last": "Deltshev", "suffix": ""}], "year": 2000, "venue": "Acta zoologica bulgarica", "link": "82026995"}, "BIBREF92": {"title": "Spiders (Araneae) in Kresna Gorge", "authors": [{"first": "G", "middle": [], "last": "Blagoev", "suffix": ""}, {"first": "S", "middle": [], "last": "Lazarov", "suffix": ""}, {"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}], "year": 2001, "venue": "", "link": null}, "BIBREF93": {"title": "A critical check list of Bulgarian spiders (Araneae)", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}, {"first": "G", "middle": [], "last": "Blagoev", "suffix": ""}], "year": 2001, "venue": "British arachnological Society", "link": null}, "BIBREF94": {"title": "Th e spiders (Araneae) of Sashtinska Sredna Gora Mountain (Bulgaria). Faunistic and Zoogeographical analysis", "authors": [{"first": "S", "middle": [], "last": "Lazarov", "suffix": ""}, {"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}, {"first": "G", "middle": [], "last": "Blagoev", "suffix": ""}], "year": 2001, "venue": "Acta zoologica bulgarica", "link": null}, "BIBREF95": {"title": "Th e European species of Bolyphantes with an attempt of a phylogenetic analysis (Araneae, Linyphiidae)", "authors": [{"first": "P", "middle": [], "last": "Van Helsdingen", "suffix": ""}, {"first": "K", "middle": [], "last": "Th Aler", "suffix": ""}, {"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}], "year": 2001, "venue": "Memorie della Societ\u00e0 Entomologica Italiana", "link": null}, "BIBREF96": {"title": "Th e spiders (Araneae) of Bulgaria. Institute of Zoology", "authors": [{"first": "G", "middle": [], "last": "Blagoev", "suffix": ""}, {"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}, {"first": "S", "middle": [], "last": "Lazarov", "suffix": ""}], "year": 2002, "venue": "Bulgarian Academy of Sciences", "link": null}, "BIBREF97": {"title": "A contribution to the study of the genus Centromerus Dahl (Araneae: Linyphiidae) in caves of the Balkan Peninsula", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}, {"first": "B", "middle": [], "last": "\u0106ur\u010di\u0107", "suffix": ""}], "year": 2002, "venue": "Revue suisse de Zoologie", "link": null}, "BIBREF98": {"title": "Th e underground faunistic diversity of Bulgaria", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}, {"first": "I", "middle": [], "last": "Pandoursky", "suffix": ""}], "year": 2002, "venue": "Journal of the Bulgarian Academy of Sciences", "link": null}, "BIBREF99": {"title": "Diversity and conservation signifi canse of arachnids (Arachnida: Araneae) in Rila Monastery Nature Park", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}], "year": 2003, "venue": "", "link": null}, "BIBREF100": {"title": "A critical review of the spider species (Araneae) described by P. Drensky in the period 1915-1942 from the Balkans", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}], "year": 2003, "venue": "Berichte des naturwissenschaftlich-medizinischen Vereins in Innsbruck", "link": "81340185"}, "BIBREF101": {"title": "On the diversity of some spiders (Aranea: Arachnida) from Serbia", "authors": [{"first": "B", "middle": [], "last": "\u0106ur\u010di\u0107", "suffix": ""}, {"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}, {"first": "G", "middle": [], "last": "Blagoev", "suffix": ""}, {"first": "S", "middle": [], "last": "\u0106ur\u010di\u0107", "suffix": ""}, {"first": "V", "middle": [], "last": "Tomi\u0107", "suffix": ""}], "year": 2003, "venue": "Archives of Biological Sciences", "link": "84416084"}, "BIBREF102": {"title": "Th e spiders of Serbia", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}, {"first": "B", "middle": [], "last": "\u0106ur\u010di\u0107", "suffix": ""}, {"first": "G", "middle": [], "last": "Blagoev", "suffix": ""}], "year": 2003, "venue": "Committee for Karst and Speleology -Serbian Academy of Sciences and Arts", "link": null}, "BIBREF104": {"title": "A contribution to the study of spiders (Araneae) from the caves of Bulgaria", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}, {"first": "S", "middle": [], "last": "Lazarov", "suffix": ""}, {"first": "B", "middle": [], "last": "Petrov", "suffix": ""}], "year": 2003, "venue": "Acta zoologica bulgarica", "link": "89310409"}, "BIBREF105": {"title": "Spiders (Araneae) from Sandanski-Petrich Valley (SW Bulgaria). Mitteilungen aus dem Museum f\u00fcr Naturkunde in Berlin", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}], "year": 2004, "venue": "Zoologische Reihe", "link": null}, "BIBREF106": {"title": "A zoogeographical review of the spiders of the Balkan Peninsula (Araneae)", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}], "year": 2004, "venue": "Balkan Biodiversity. Pattern and Process in the European hotspot", "link": null}, "BIBREF107": {"title": "A review of the family Linyphiidae (Araneae) in Bulgaria, faunistic and zoogeographical analyses", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}], "year": 2003, "venue": "Arthropoda Selecta, Special Issue", "link": null}, "BIBREF108": {"title": "Ecology of the City of Sofi a. Species and communities in an urban environment", "authors": [{"first": "A", "middle": [], "last": "Antov", "suffix": ""}, {"first": "S", "middle": [], "last": "Lazarov", "suffix": ""}, {"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}, {"first": "G", "middle": [], "last": "Blagoev", "suffix": ""}], "year": 2004, "venue": "", "link": null}, "BIBREF109": {"title": "On some leaf-litter and cave-dwelling spiders (Aranea: Arachnida) from the Republic of Macedonia", "authors": [{"first": "B", "middle": [], "last": "\u0106ur\u010di\u0107", "suffix": ""}, {"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}, {"first": "G", "middle": [], "last": "Blagoev", "suffix": ""}, {"first": "V", "middle": [], "last": "Tomi\u0107", "suffix": ""}, {"first": "S", "middle": [], "last": "\u0106ur\u010di\u0107", "suffix": ""}, {"first": "S", "middle": [], "last": "Makarov", "suffix": ""}, {"first": "B", "middle": [], "last": "Miti\u0107", "suffix": ""}, {"first": "E", "middle": [], "last": "Stojkoska", "suffix": ""}, {"first": "S", "middle": [], "last": "Stankovi\u0107", "suffix": ""}], "year": 2004, "venue": "Archives of Biological Sciences", "link": "84704012"}, "BIBREF110": {"title": "On the diversity of some soil and cave spiders (Aranea: Arachnida) from Serbia", "authors": [{"first": "B", "middle": [], "last": "\u0106ur\u010di\u0107", "suffix": ""}, {"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}, {"first": "G", "middle": [], "last": "Blagoev", "suffix": ""}, {"first": "V", "middle": [], "last": "Tomi\u0107", "suffix": ""}, {"first": "S", "middle": [], "last": "\u0106ur\u010di\u0107", "suffix": ""}, {"first": "B", "middle": [], "last": "Miti\u0107", "suffix": ""}, {"first": "L", "middle": [], "last": "Djorovi\u0107", "suffix": ""}, {"first": "N", "middle": [], "last": "Victoria", "suffix": ""}], "year": 2004, "venue": "Archives of Biological Sciences", "link": null}, "BIBREF111": {"title": "Spiders (Araneae) from the Eastern Rhodopes (Bulgaria and Greece)", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}, {"first": "S", "middle": [], "last": "Lazarov", "suffix": ""}, {"first": "G", "middle": [], "last": "Blagoev", "suffix": ""}], "year": 2004, "venue": "Biodiversity of Bulgaria. 2. Biodiversity of Eastern Rhodopes (Bulgaria and Greece). Pensoft & National Museum of Natural History, Sofi a", "link": "202713967"}, "BIBREF113": {"title": "A new Hypomma species from Stara Planina Mountains", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}], "year": 2005, "venue": "Revue suisse de Zoologie", "link": null}, "BIBREF114": {"title": "Fauna and zoogeography of spiders (Araneae) of Bulgaria", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}], "year": 2005, "venue": "Journal of Arachnology", "link": null}, "BIBREF115": {"title": "Faunistic diversity of Class Arachnida (non Acari) in Bulgaria -present state, importance and perspectives", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}, {"first": "B", "middle": [], "last": "Petrov", "suffix": ""}, {"first": "P", "middle": [], "last": "Mitov", "suffix": ""}], "year": 2005, "venue": "", "link": null}, "BIBREF116": {"title": "Zelotes balcanicus sp. n., a new and widespread species from the Balkan Peninsula (Araneae, Gnaphosidae). A new Zelotes species", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}, {"first": "R", "middle": [], "last": "Bosmans", "suffix": ""}, {"first": "W", "middle": [], "last": "De Spiegelaere", "suffix": ""}, {"first": "L", "middle": [], "last": "Provoost", "suffix": ""}], "year": 2006, "venue": "Revue suisse de Zoologie", "link": null}, "BIBREF117": {"title": "Fauna and zoogeography of spiders of the family Linyphiidae (Araneae) in Bulgaria", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}], "year": 2007, "venue": "Biogeography and Ecology of Bulgaria. Monographiae Biologicae Series", "link": "80908918"}, "BIBREF118": {"title": "Biodiversity of spiders: on some taxa new to Serbia and to science", "authors": [{"first": "B", "middle": [], "last": "\u0106ur\u010di\u0107", "suffix": ""}, {"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}, {"first": "V", "middle": [], "last": "Tomi\u0107", "suffix": ""}, {"first": "S", "middle": [], "last": "\u0106ur\u010di\u0107", "suffix": ""}], "year": 2007, "venue": "Archives of Biological Sciences", "link": "83849046"}, "BIBREF119": {"title": "A contribution to the study of spiders (Ara neae) from the caves of the Republic of Macedonia", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}, {"first": "S", "middle": [], "last": "Lazarov", "suffix": ""}, {"first": "E", "middle": [], "last": "Stojkoska", "suffix": ""}], "year": 2007, "venue": "Acta zoologica bulgarica", "link": "89162913"}, "BIBREF120": {"title": "First record of Nephila pilipes (Fabricius, 1793) from Nepal (Araneae: Nephilidae)", "authors": [{"first": "D", "middle": [], "last": "Bechev", "suffix": ""}, {"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}], "year": 2008, "venue": "Bugs \"R\" All", "link": null}, "BIBREF121": {"title": "Two new spider species, Malthonica bozhkovi sp. nov. and Tegenaria paragamiani sp. nov. from Rhodopy Mountains (Bulgaria and Greece) (Araneae: Agelenidae)", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}], "year": 2008, "venue": "Zootaxa", "link": "87918183"}, "BIBREF122": {"title": "Faunistic diversity and zoogeography of cave-dwelling spiders on the Balkan Peninsula", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}], "year": 2008, "venue": "Advances in Arachnology and Developmental Biology. Papers dedicated to Prof. Dr. Bo\u017eidar \u0106ur\u010di\u0107. Institute of Zoology", "link": null}, "BIBREF123": {"title": "Th e spiders (Araneae) in the caves of the Western Rhodope Mountains (Bulgaria)", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}, {"first": "B", "middle": [], "last": "Petrov", "suffix": ""}], "year": 2008, "venue": "Acta zoologica bulgarica", "link": "86033883"}, "BIBREF124": {"title": "Biodiversity of epigeic spiders in genetically modifi ed (Bt) and conventional (non-Bt) potato fi elds in Bulgaria", "authors": [{"first": "P", "middle": [], "last": "Kalushkov", "suffix": ""}, {"first": "G", "middle": [], "last": "Blagoev", "suffix": ""}, {"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}], "year": 2008, "venue": "Acta zoologica bulgarica", "link": "88817366"}, "BIBREF125": {"title": "New data for Harpactea sanctaeinsulae Brignoli, 1978 and description of the unknown female (Araneae, Dysderidae)", "authors": [{"first": "S", "middle": [], "last": "Lazarov", "suffix": ""}, {"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}], "year": 2008, "venue": "Turkish Journal of Arachnology", "link": null}, "BIBREF126": {"title": "Spiders (Araneae) from Lyulin Mountain (West Bulgaria)", "authors": [{"first": "M", "middle": [], "last": "Naumova", "suffix": ""}, {"first": "G", "middle": [], "last": "Blagoev", "suffix": ""}, {"first": "S", "middle": [], "last": "Lazarov", "suffix": ""}, {"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}], "year": 2008, "venue": "Acta zoologica bulgarica", "link": null}, "BIBREF127": {"title": "Spiders from the Skopje Region. A faunistic and zoogeographical analysis", "authors": [{"first": "D", "middle": [], "last": "Stefanovska", "suffix": ""}, {"first": "M", "middle": [], "last": "Naumova", "suffix": ""}, {"first": "D", "middle": [], "last": "Prelik", "suffix": ""}, {"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}, {"first": "S", "middle": [], "last": "Lazarov", "suffix": ""}], "year": 2008, "venue": "Historia naturalis bulgarica", "link": "81867549"}, "BIBREF128": {"title": "Preliminary investigation of the diel activity of myriapods (Diplopoda, Chilopoda) and spiders (Araneae) in anthropogenic and rural habitats in the town of Shumen and Shumensko Plateau (NE Bulgaria)", "authors": [{"first": "D", "middle": [], "last": "Bachvarova", "suffix": ""}, {"first": "P", "middle": [], "last": "Stoev", "suffix": ""}, {"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}], "year": 2007, "venue": "Special issues of the Macedonian Ecological Society", "link": null}, "BIBREF129": {"title": "Eurocoelotes xinpingwangi sp n., a new spider species from the Rila Mountains, SW Bulgaria (Araneae, Amaurobiidae)", "authors": [{"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}], "year": 2009, "venue": "Zoosystematics and Evolution", "link": "84164227"}, "BIBREF130": {"title": "Pardosa roscai (Roewer, 1951) a spider new to fauna of Turkey (Araneae: Lycosidae)", "authors": [{"first": "A", "middle": [], "last": "Bayram", "suffix": ""}, {"first": "L", "middle": [], "last": "Efi L", "suffix": ""}, {"first": "C", "middle": [], "last": "Deltshev", "suffix": ""}], "year": "", "venue": "Turkish Journal of Zoology", "link": "83043583"}, "BIBREF131": {"title": "Coleoptera) -Bulgaria, now junior synonym of D. (Paraduvalius) zivkovi (Knirsch, 1925) Prodicus delcevi Strasser, 1973 (Diplopoda) -Bulgaria, now Anamastigona delcevi Amilenus deltshevi Dunlop & Mitov, 2009 (Opiliones) -Germany, Palaeogene, Oligocene: Chattian Coelotes deltshevi Dimitrov, 1996 (Araneae) -Bulgaria, now Eurocoelotes deltshevi Ectatosticta deltshevi Platnick & J\u00e4ger, 2009 (Araneae) -China Halodromus deltshevi Muster, 2009 (Araneae) -Yemen Harpactea deltshevi Dimitrov & Lazarov, 1999 (Araneae) -Bulgaria Lepthyphantes christodeltshev Helsdingen, 2009 (Araneae) -Greece Microbianor deltshevi Logunov, 2009 (Araneae) -Madagascar Protoleptoneta deltshevi Brignoli, 1979 (Araneae) -Turkey, now Leptonetela deltshevi Saraina deltshevi Azarkina", "authors": [], "year": 1965, "venue": "Genus Deltshevia Marusik & Fet, 2009 (Araneae) Genotype: Deltshevia danovi Marusik & Fet, 2009 -Turkmenistan Species Agrilus (Duttus) delchevi Curletti & Sakalian, 2009 (Coleoptera) -Kenya Duvalius (Paraduvalius) zivkovi deltshevi Gu\u00e9orguiev", "link": null}}, "ref_entries": {"FIGREF0": {"text": "Figure 1. Christo Deltshev in the Elata Cave near the village of Zimevitsa, Bulgaria, in 1961 (photo Petko Nedkov).", "type": "figure"}, "FIGREF1": {"text": "Figure 2. Christo and Elena's wedding in the Temnata Dupka Cave, with the offi cial announcement hung on the Lakatnik rock s close to the cave's entrance, November, 1968 (photo Konstantin Spassov).", "type": "figure"}, "FIGREF2": {"text": "Figure 3. Christo with his wife Elena, his daughter Victoria and sons Delyan and Ivan in front of the Svirchovitsa Cave near the village of Karlukovo, Bulgaria, in 1983 (photo Christo Deltshev).", "type": "figure"}, "FIGREF3": {"text": "Figure 4. Christo collecting spiders in the Vorontsovskaya Cave, Abkhazia, in July, 1967 (photo Stoitze Andreev).", "type": "figure"}, "FIGREF4": {"text": "Figure 5. Christo, Peter van Helsdingen and Konrad Th aler in Szombathely, Hungary, July, 2002 (photo Stoyan Lazarov).", "type": "figure"}, "FIGREF5": {"text": "Figure 6. Christo and his students Stoyan Lazarov and Gergin Blagoev, April, 2002 (photo Boris Andreev).", "type": "figure"}, "FIGREF6": {"text": "Figure 7. Christo Deltshev at his fi rst International Arachnological Congress in Brno, Czechoslovakia, August, 1971 (congress photo).", "type": "figure"}, "FIGREF7": {"text": "international debut came at the 5th International Congress of Arachnology in Brno in 1971. Since then he participated in 23 international congresses, conferences and symposia; at eleven of which he was an invited speaker. Most of them were arach- nological, such as eight international congresses of arachnology between 1971 (Brno) and 2004 (Gent), six European colloquia of arachnology between 1988 (Berlin) and 2008 (Bern). Other congresses were devoted to speleology (Olomouc, 1973; Budapest, 1989), invertebrate studies (Saarbr\u00fccken, 1995), mountain ecosystems (Abisco, 1997) and biodiversity of the Balkan fauna (Ohrid, 1998; Koper, 2001). Christo Deltshev's organizational skills were fully employed during the prepara- tions for the 22nd European Colloquium of Arachnology, held in Blagoevgrad in Au- gust 2005. A total of 115 participants from 27 countries came to Bulgaria. Th e results of the symposium were published in a special issue of Acta zoologica bulgarica (Del- tshev C, Stoev P (Eds) 2006. European Arachnology 2005. Proceedings of the 22nd European Colloquium of Arachnology, Blagoevgrad 2005. Acta zoologica bulgarica, Suppl. 1, 343 pp.). Th e participants brought home unforgettable memories of the collo quium, as well as the joys of the Melnik earth pyramids, and the Rhozhen and Rila monasteries, which they visited during a post-colloquium excursion. Not only his Bulgarian and foreign colleagues pay respect to Christo Deltshev. Dif- ferent Bulgarian state and scientifi c institutions have presented him with awards. For his contribution to speleology Dr. Deltshev was awarded an Aleko medal (1972) and a medal for Special Merits (1984). He also received insignia of honour from the State Agency for Youth and Sports, the Bulgarian Tourist Union, the Bulgarian Federation of Speleology, the National Museum of Natural History, and the Institute of Zoology.", "type": "figure"}, "FIGREF8": {"text": "Figure 8. Christo at the 22nd European Colloquium of Arachnology, Blagoevgrad, showing the fi rst prize for best presentation given by young scientist (photo Dmitri Logunov).", "type": "figure"}, "FIGREF9": {"text": "Figure 9. Christo Deltshev on a collecting trip to Samothraki Island, Greece, May, 2008 (photo Lyubomir Alexiev).", "type": "figure"}, "FIGREF10": {"text": "H] (1971) Neue Daten \u00fcber die Verbreitung der Gattung Meta (Ara- neae, Araneidae) in bulgarischen H\u00f6hlen. Bulletin de l`Institute de zoologie et mus\u00e9e (Sofi a) 32: 89-92. [in Bulgarian, with German and Russian summaries] 3. Deltshev C (1972) A review of spiders (Araneae) from Bulgarian caves. In: Folk C (Ed.) Proceedings of the 5th International Congress of Arachnology, Brno, 99-104. 4. Deltshev C [Delshev C] (1972) A contribution to the study of spiders (Araneae) from the caves in Bulgaria. Bulletin de l`Institute de zoologie et mus\u00e9e (Sofi a) 34: 171-175. [in Bulgarian, with English and Russian summaries] 5. Deltshev C [Deltchev C] (1972) A contribution to the study of spiders (Araneae) from the caves in Bulgaria. II. Genus Lepthyphantes in Bulgarian caves. Bulletin de l`Institute de zoologie et mus\u00e9e (Sofi a) 36: 137-147. 6. Deltshev C (1972) A new genus of Bulgarian cave spiders (Protoleptoneta bulgarica, n. g., n. sp., Leptonetidae). International Journal of Speleology 4: 275-283. 7. Deltshev C (1973) A contribution to the study (Araneae) of spiders from the caves of Bulgaria. III. Ecological notes on spiders (Araneae) from the entrance parts of the caves. Bulletin de l`Institute de zoologie et mus\u00e9e (Sofi a) 38: 39-47. [in Bulgarian, with English and Russian summaries] 8. Deltshev C (1973) A new Troglohyphantes from Bulgarian caves (Araneae, Linyphiidae). International Journal of Speleology 5: 103-109. 9. Deltshev C (1973) Redescription of Centromerus bulgarianus (Drensky, 1931) and Cen- tromerus lakatnikensis (Drensky, 1931) (Araneae, Linyphiidae). International Journal of Speleology 5: 117-126. 10. Deltshev C (1974) A new Centromerus from Bulgarian caves (Araneae, Linyphiidae). International Journal of Speleology 6: 81-86. 11. Deltshev C [Delchev K], Kajak A (1974) Analysis of a sheep pasture ecosystem in the Pi- eniny Mountains (the Carpathians). XVI. Eff ect of pasture management on the number and biomass of spiders (Araneae) in two climatic regions (the Pieniny and the Sredna Gora Mountains). Ekologia polska 22(3/4): 693-710. 12. Deltshev C (1975) A new species (Troglohyphantes bureschianus n. sp., Araneae, Linyphi- idae) from Bulgarian caves. Acta zoologica bulgarica 3: 99-104. 13. Deltshev C (1975) Th e genus Lepthyphantes in Bulgarian caves. Proceedings of the 6th International Arachnological Congrees, Amsterdam, 210-213. 14. Deltshev C [Deltshev H] (1977) Spiders (Araneae) along the Bulgarian Black Sea coast.", "type": "figure"}, "TABREF0": {"text": "Type locality: Bulgaria: Rila Mts., Granchar Cottage, 2200 m. Current status: Th e species is now assigned to genus Malthonica (see Guseinov et al.Tegenaria paragamiani Deltshev, 2008 Zootaxa 1872: 40. Type locality: Greece: East Rhodope Mts., Maronia Cave, village of Maronia, 250 m. AMAUROBIIDAE Coelotes brevispinus Deltshev & Dimitrov, 1996 Revue Arachnologique 11 (7): 77. Type locality: Bulgaria: Slavyanka Mts., Hambar Dere, 1500 m. Current status: Th e species is now assigned to genus Eurocoelotes (cf. Wang 2002 Bulle- tin of the American Museum of Natural History 269, p. 76).drenskii Deltshev, 1990 Acta zoologica bulgarica 40: 30. Type locality: Bulgaria: Stara Planina Mts., Drenovska peshtera Cave, Kotel Town. Current status: Th e species is now assigned to genus Eurocoelotes (cf. Wang 2002 Bulle- tin of the American Museum of Natural History 269, p. 76).xinpingwangi Deltshev, 2009 Zoosystematics and Evolution 85 (2): 293. Type locality: Bulgaria: Rila Mts., Rila Monastery, Kirilova Polyana, 1460 m. CYBAEIDAE Cybaeus balkanus Deltshev, 1997 Reichenbachia 32 (1): 1. Type locality: Bulgaria: Sredna Gora Mts. GNAPHOSIDAE Zelotes balcanicus Deltshev, 2006 in: Deltshev, Bosmans, de Spigelaere, Provoost, Re- vue suisse de Zoologie 113(4): 711. Type locality: Bulgaria: Shabla Town, dunes. HAHNIDAE Cryphoecina Deltshev, 1997 Revue suisse de Zoologie 104 (3): 485. Typus generis: Cryphoecina deelemanae Deltshev, 1997 Cryphoecina deelemanae Deltshev, 1997 Revue suisse de Zoologie 104 (3): 487. Type locality: Montenegro: Petrovac-Virpazar, Petrovacka Gora, oak woodland, 600 m. LEPTONETIDAE Leptonetela andreevi Deltshev, 1985 Acta zoologica bulgarica 7: 41. Type locality: Greece: Paros Island: Kalabaki Cave, village of Drios. Protoleptoneta Deltshev, 1972 International Journal of Speleology 4: 275. Typus generis: Protoleptoneta bulgarica Deltshev, 1972 Protoleptoneta beroni Deltshev, 1977 Acta zoologica bulgarica 7: 3. Type locality: Bulgaria: Belimelska Cave, village of Belimel, Montana Distr. Protoleptoneta bulgarica Deltshev, 1972 International Journal of Speleology 4: 276. Type locality: Bulgaria: Bezimenna 22 Cave, village of Karlukovo, Lovech Distr. LINYPHIIDAE Araeoncus clivifrons Deltshev, 1987 Reichenbachia 25 (19): 97. Type locality: Bulgaria: Pirin Mts., Tevno Ezero, 2500 m. Centromerus acutidentatus Deltshev, 2002 in: Deltshev and \u0106ur\u010di\u0107, Revue suisse de Zoologie 109 (1): 171. Type locality: Serbia: entrance of Monastery Cave I, village of Sela\u010dka near Minicevo. Centromerus milleri Deltshev, 1974 International Journal of Speleology 6: 81. Type locality: Bulgaria: East Rhodope Mts, Karangil Cave near Kardzhali Town. Centromerus serbicus Deltshev, 2002 in: Deltshev and \u0106ur\u010di\u0107, Revue suisse de Zoologie 109 (1): 168. Type locality: Serbia: Zlotska Pe\u0107ina (Lazareva Pe\u0107ina) Cave, village of Zlot near Bor. Centromerus sylvaticus paucidentatus Deltshev, 1983 Acta zoologica bulgarica 21: 54. Type locality: Bulgaria: Pirin Mts., Prevala Lake, 2300 m. Centromerus valkanovi Deltshev, 1983 Acta zoologica bulgarica 21: 53. Type locality: Bulgaria: Varna, Asparuhovo, forest.altimontanus Deltshev, 1984 Reichenbachia 22 (11): 91. Type locality: Bulgaria: Pirin Mts., Vihren Peak, 2914 m.pirinicus Deltshev, 1992 Berichte des naturwissenschaftlich-medizini- schen Vereins in Innsbruck 79: 173. Type locality: Bulgaria: Pirin Mts., Vihren Peak, 2550 m.longipalpis pirini Deltshev, 1983 Acta zoologica bulgarica 22: 72. Type locality: Bulgaria: Pirin Mts., Tevno Ezero. Hypomma aemonicum Deltshev, 2005 Revue suisse de Zoologie 112 (1): 115. Type locality: Bulgaria: Stara Planina Mts., Vezhen Peak, 2170 m. Lepthyphantes beroni Deltshev, 1979 Acta zoologica bulgarica 13: 61. Type locality: Greece: Th era Island: Zoodochus Cave, village of Kamari. Lepthyphantes beshkovi Deltshev, 1979 Acta zoologica bulgarica 13: 57. Type locality: Greece: Crete: Tzani Cave, village of Omalos.brignolianus Deltshev, 1979 Acta zoologica bulgarica 13: 54. Type localities of syntypes: Greece: Crete: Tzani Cave, village of Omalos; Dikteon Antron Cave, village of Psychro; Trapezas Cave, village of Cermadion; Arkandas Cave, village of Catholiko.rectilamellus Deltshev, 1988 Acta zoologica bulgarica 36: 53. Type locality: Bulgaria: Pirin Mts., Tiyatsite, 2200 m. Current status: Th e species is now assigned to genus Mansuphantes. Lepthyphantes lithoclasicolus Deltshev, 1983 Acta zoologica bulgarica 23: 25. Type locality: Bulgaria: Pirin Mts., Vihren Peak. Current status: Th e species is now assigned to genus Mughiphantes (recte: M. lithoclasicola). Lepthyphantes gueorguievi Deltshev, 1980 Acta zoologica bulgarica 16: 48. Type locality: Bulgaria: Dupcheto Cave near Velingrad Town. Current status: junior synonym of Palliduphantes spelaeorum (Kulczy\u0144ski, 1914), see Deeleman-Reinhold 1985, M\u00e9moires de Biosp\u00e9ologie 12: 39.orbelicus Deltshev, 1985 Bulletin of the British arachnological Society 6: 363. Type locality: Bulgaria: Pirin Mts., Vihren Peak, 2914 m.bureschianus Deltshev, 1975 Acta zoologica bulgarica 3: 99. Type locality: Bulgaria: Western Rhodopes Mts.: Zmeini Borun Cave, village of Mos- tovo, Plovdiv Distr.drenskii Deltshev, 1973 International Journal of Speleology 5: 103. Type locality: Bulgaria: Suhata Peshtera Cave, Velingrad Town. NESTICIDAE Nesticus beroni Deltshev, 1973 Proceedings of the 6th International Congress of Spe- leology, Olomouc 5: 75. Type locality: Bulgaria: Western Rhodope Mts., Dupkata Cave, village of Mostovo, Plovdiv Distr. Nesticus beshkovi Deltshev, 1979 Acta zoologica bulgarica 13: 53. Type locality: Greece: Crete: Trapezas Cave, village of Cermadion.", "type": "table"}}}
{"paper_id": "84887251", "_pdf_hash": "2da0b0a2b351a3709683d98643984e4675376a0f", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Coral-bacterial communities before and after a coral mass spawning event on Ningaloo Reef", "authors": [{"first": "J", "middle": [], "last": "Ceh", "suffix": ""}, {"first": "J", "middle": ["B"], "last": "Raina", "suffix": ""}, {"first": "R", "middle": ["M"], "last": "Soo", "suffix": ""}, {"first": "M", "middle": [], "last": "Van Keulen", "suffix": ""}, {"first": "D", "middle": ["G"], "last": "Bourne", "suffix": ""}], "year": 2012, "venue": "PLOS ONE", "link": "3536711"}, "BIBREF1": {"title": "The dynamic of microbial partnerships in the coral Isopora palifera", "authors": [{"first": "C", "middle": ["P"], "last": "Chen", "suffix": ""}, {"first": "C", "middle": ["H"], "last": "Teseng", "suffix": ""}, {"first": "C", "middle": ["A"], "last": "Chen", "suffix": ""}, {"first": "S", "middle": ["L"], "last": "Tang", "suffix": ""}], "year": 2011, "venue": "ISME J", "link": null}, "BIBREF2": {"title": "The analysis of oral microbial communities of wild-type and toll-like receptor 2-deficient mice using a 454 GS FLX Titanium pyrosequencer", "authors": [{"first": "J", "middle": [], "last": "Chun", "suffix": ""}, {"first": "K", "middle": ["Y"], "last": "Kim", "suffix": ""}, {"first": "", "middle": [], "last": "Leejh", "suffix": ""}, {"first": "Y", "middle": [], "last": "Choi", "suffix": ""}], "year": 2010, "venue": "BMC Microbiol", "link": null}, "BIBREF3": {"title": "Marine viruses and global climate change", "authors": [{"first": "R", "middle": [], "last": "Danovaro", "suffix": ""}, {"first": "C", "middle": [], "last": "Corinaldesi", "suffix": ""}, {"first": "A", "middle": [], "last": "Dellanno", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Fuhrman", "suffix": ""}, {"first": "J", "middle": ["J"], "last": "Middelburg", "suffix": ""}, {"first": "R", "middle": ["T"], "last": "Noble", "suffix": ""}, {"first": "C", "middle": ["A"], "last": "Suttle", "suffix": ""}], "year": 2011, "venue": "FEMS", "link": "14930914"}, "BIBREF4": {"title": "Seasonal abundance of total and pathogenic Vibrio parahaemolyticus bacteria in Alabama oysters", "authors": [{"first": "A", "middle": [], "last": "Depaola", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Nordstrom", "suffix": ""}, {"first": "J", "middle": [], "last": "Bowers", "suffix": ""}, {"first": "J", "middle": ["G"], "last": "Wells", "suffix": ""}, {"first": "D", "middle": ["W"], "last": "Cook", "suffix": ""}], "year": 2003, "venue": "Appl Environ Microbiol", "link": null}, "BIBREF5": {"title": "Characterization of bacteria in ballast water unsing MALDI-TOF mass sepctrometry", "authors": [{"first": "K", "middle": [], "last": "Emani", "suffix": ""}, {"first": "V", "middle": [], "last": "Askari", "suffix": ""}, {"first": "M", "middle": [], "last": "Ullrich", "suffix": ""}, {"first": "K", "middle": [], "last": "Mohinudeen", "suffix": ""}, {"first": "A", "middle": ["C"], "last": "Anill", "suffix": ""}, {"first": "L", "middle": [], "last": "Khandeparker", "suffix": ""}, {"first": "J", "middle": ["G"], "last": "Burgess", "suffix": ""}, {"first": "E", "middle": [], "last": "Mesbahi", "suffix": ""}], "year": 2012, "venue": "PLOS ONE", "link": null}, "BIBREF6": {"title": "A latitudinal diversity gradient in planktonic marine bacteria", "authors": [{"first": "J", "middle": ["A"], "last": "Fuhrman", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Steele", "suffix": ""}, {"first": "I", "middle": [], "last": "Hewson", "suffix": ""}, {"first": "M", "middle": ["S"], "last": "Schwalbach", "suffix": ""}, {"first": "M", "middle": ["V"], "last": "Brown", "suffix": ""}, {"first": "J", "middle": ["L"], "last": "Green", "suffix": ""}, {"first": "J", "middle": ["H"], "last": "Brown", "suffix": ""}], "year": 2008, "venue": "PNAS", "link": "7596459"}, "BIBREF7": {"title": "Pronounced summer to winter differences and higher wintertime richness in coastal antarctic marine bacterioplankton", "authors": [{"first": "J", "middle": ["F"], "last": "Ghiglione", "suffix": ""}, {"first": "A", "middle": ["E"], "last": "Murray", "suffix": ""}], "year": 2012, "venue": "Environ Microbiol", "link": "205527458"}, "BIBREF8": {"title": "Defining seasonal marine microbial community dynamics", "authors": [{"first": "J", "middle": ["A"], "last": "Gilbert", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Steele", "suffix": ""}, {"first": "J", "middle": ["G"], "last": "Caporaso", "suffix": ""}, {"first": "L", "middle": [], "last": "Steinbruck", "suffix": ""}, {"first": "J", "middle": [], "last": "Reeder", "suffix": ""}, {"first": "B", "middle": [], "last": "Temperton", "suffix": ""}, {"first": "S", "middle": [], "last": "Huse", "suffix": ""}, {"first": "A", "middle": ["C"], "last": "Mchardy", "suffix": ""}, {"first": "R", "middle": [], "last": "Knight", "suffix": ""}, {"first": "I", "middle": [], "last": "Joint", "suffix": ""}, {"first": "P", "middle": [], "last": "Somerfield", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Fuhrman", "suffix": ""}, {"first": "D", "middle": [], "last": "Field", "suffix": ""}], "year": 2012, "venue": "ISME J", "link": "1860573"}, "BIBREF9": {"title": "Seasonality in ocean microbial communities", "authors": [{"first": "S", "middle": ["J"], "last": "Giovannoni", "suffix": ""}, {"first": "K", "middle": ["L"], "last": "Vergin", "suffix": ""}], "year": 2012, "venue": "Science", "link": "42747185"}, "BIBREF10": {"title": "Fast UniFrac: facilitating high-throughput phylogenetic analyses of microbial communities including analysis of pyrosequencing and PhyloChip data", "authors": [{"first": "M", "middle": [], "last": "Hamady", "suffix": ""}, {"first": "C", "middle": [], "last": "Lozupone", "suffix": ""}, {"first": "R", "middle": [], "last": "Knight", "suffix": ""}], "year": 2010, "venue": "ISME J", "link": "2937344"}, "BIBREF11": {"title": "A global map of human impact on marine ecosystems", "authors": [{"first": "B", "middle": ["S"], "last": "Halpern", "suffix": ""}, {"first": "S", "middle": [], "last": "Walbridge", "suffix": ""}, {"first": "K", "middle": ["A"], "last": "Selkoe", "suffix": ""}, {"first": "C", "middle": ["V"], "last": "Kappel", "suffix": ""}, {"first": "F", "middle": [], "last": "Micheli", "suffix": ""}, {"first": "D", "middle": [], "last": "&apos;agarosa", "suffix": ""}, {"first": "C", "middle": [], "last": "Bruno", "suffix": ""}, {"first": "J", "middle": ["F"], "last": "Casey", "suffix": ""}, {"first": "K", "middle": ["S"], "last": "Ebert", "suffix": ""}, {"first": "C", "middle": [], "last": "Fox", "suffix": ""}, {"first": "H", "middle": ["E"], "last": "Fujita", "suffix": ""}, {"first": "R", "middle": [], "last": "Heinemann", "suffix": ""}, {"first": "D", "middle": [], "last": "Lenihan", "suffix": ""}, {"first": "H", "middle": ["S"], "last": "Madin", "suffix": ""}, {"first": "E", "middle": ["M"], "last": "Perry", "suffix": ""}, {"first": "M", "middle": ["T"], "last": "Seliq", "suffix": ""}, {"first": "E", "middle": ["R"], "last": "Spalding", "suffix": ""}, {"first": "M", "middle": [], "last": "Steneck", "suffix": ""}, {"first": "R", "middle": [], "last": "Watson", "suffix": ""}, {"first": "R", "middle": [], "last": "", "suffix": ""}], "year": 2008, "venue": "Science", "link": "26206024"}, "BIBREF12": {"title": "The impacts of climate change in coastal marine systems", "authors": [{"first": "C", "middle": ["D"], "last": "Harley", "suffix": ""}, {"first": "R", "middle": [], "last": "Hughes", "suffix": ""}, {"first": "K", "middle": ["M"], "last": "Hultgren", "suffix": ""}, {"first": "B", "middle": ["G"], "last": "Miner", "suffix": ""}, {"first": "C", "middle": ["J"], "last": "Sorte", "suffix": ""}, {"first": "C", "middle": ["S"], "last": "Thomber", "suffix": ""}, {"first": "L", "middle": ["F"], "last": "Rodriquez", "suffix": ""}, {"first": "L", "middle": [], "last": "Tomanek", "suffix": ""}, {"first": "S", "middle": ["L"], "last": "Williams", "suffix": ""}], "year": 2006, "venue": "Ecol Lett", "link": null}, "BIBREF13": {"title": "Emerging marine diseases-climate links and anthropogenic factors", "authors": [{"first": "C", "middle": ["D"], "last": "Harvell", "suffix": ""}, {"first": "K", "middle": [], "last": "Kim", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Burkholder", "suffix": ""}, {"first": "R", "middle": ["R"], "last": "Colwell", "suffix": ""}, {"first": "P", "middle": ["R"], "last": "Epstein", "suffix": ""}, {"first": "D", "middle": ["J"], "last": "Grimes", "suffix": ""}, {"first": "E", "middle": ["E"], "last": "Hofmann", "suffix": ""}, {"first": "E", "middle": ["K"], "last": "Lipp", "suffix": ""}, {"first": "A", "middle": ["D"], "last": "Osterhaus", "suffix": ""}, {"first": "R", "middle": ["M"], "last": "Overstreet", "suffix": ""}, {"first": "J", "middle": ["W"], "last": "Porter", "suffix": ""}, {"first": "G", "middle": ["W"], "last": "Smith", "suffix": ""}, {"first": "G", "middle": ["R"], "last": "Vasta", "suffix": ""}], "year": 1999, "venue": "Science", "link": "29182486"}, "BIBREF14": {"title": "Bellerophon: A program to detect chimeric sequences in multiple sequence aligmemts", "authors": [{"first": "T", "middle": [], "last": "Huber", "suffix": ""}, {"first": "G", "middle": [], "last": "Fraulkner", "suffix": ""}, {"first": "P", "middle": [], "last": "Hugenholtz", "suffix": ""}], "year": 2004, "venue": "Bioinformatics", "link": null}, "BIBREF15": {"title": "Effect of genetically modified Poplars on soil microbial communities during the phytoremediation of waste mine tailings", "authors": [{"first": "M", "middle": [], "last": "Hur", "suffix": ""}, {"first": "Y", "middle": [], "last": "Kim", "suffix": ""}, {"first": "H", "middle": ["R"], "last": "Song", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Kim", "suffix": ""}, {"first": "Y", "middle": ["I"], "last": "Choi", "suffix": ""}, {"first": "H", "middle": [], "last": "Yi", "suffix": ""}], "year": 2011, "venue": "Appl Environ Microbiol", "link": "6221408"}, "BIBREF16": {"title": "Relationships between environmental factors and pathogenic vibrios in the Northern Gulf of Mexico", "authors": [{"first": "C", "middle": ["N"], "last": "Johnson", "suffix": ""}, {"first": "A", "middle": ["R"], "last": "Flowers", "suffix": ""}, {"first": "Iii", "middle": [], "last": "Noriea", "suffix": ""}, {"first": "", "middle": [], "last": "Nf", "suffix": ""}, {"first": "A", "middle": ["M"], "last": "Zimmerman", "suffix": ""}, {"first": "J", "middle": ["C"], "last": "Bowers", "suffix": ""}, {"first": "A", "middle": [], "last": "Depaola", "suffix": ""}, {"first": "D", "middle": ["J"], "last": "Grimes", "suffix": ""}], "year": 2010, "venue": "Appl Environ Microbiol", "link": "37164170"}, "BIBREF17": {"title": "Ecology of Vibrio parahaemolyticus in Chesapeake Bay", "authors": [{"first": "T", "middle": [], "last": "Kaneko", "suffix": ""}, {"first": "R", "middle": ["R"], "last": "Colwell", "suffix": ""}], "year": 1973, "venue": "J Bacteriol", "link": "22735110"}, "BIBREF18": {"title": "Impact of enrofloxacin on the human intestinal microbiota revealed by comparative molecular analysis", "authors": [{"first": "B", "middle": ["S"], "last": "Kim", "suffix": ""}, {"first": "J", "middle": ["N"], "last": "Kim", "suffix": ""}, {"first": "S", "middle": ["H"], "last": "Yoon", "suffix": ""}, {"first": "J", "middle": [], "last": "Chun", "suffix": ""}, {"first": "C", "middle": ["E"], "last": "Cerniglia", "suffix": ""}], "year": 2012, "venue": "Anaerobe", "link": "32198764"}, "BIBREF19": {"title": "Introducing Eztaxoneaz prokaryotic 16S rRNA gene sequence database with phylotypes that represent uncultured species", "authors": [{"first": "O", "middle": ["S"], "last": "Kim", "suffix": ""}, {"first": "Y", "middle": ["J"], "last": "Cho", "suffix": ""}, {"first": "K", "middle": [], "last": "Lee", "suffix": ""}, {"first": "S", "middle": ["H"], "last": "Yoon", "suffix": ""}, {"first": "M", "middle": [], "last": "Kim", "suffix": ""}, {"first": "H", "middle": [], "last": "Na", "suffix": ""}, {"first": "S", "middle": ["C"], "last": "Park", "suffix": ""}, {"first": "Y", "middle": ["S"], "last": "Jeon", "suffix": ""}, {"first": "J", "middle": ["H"], "last": "Lee", "suffix": ""}, {"first": "H", "middle": [], "last": "Yi", "suffix": ""}, {"first": "S", "middle": [], "last": "Won", "suffix": ""}, {"first": "J", "middle": [], "last": "Chun", "suffix": ""}], "year": 2012, "venue": "Int J Sys Evol Microbiol", "link": null}, "BIBREF20": {"title": "Global marine bacterial diversity peaks at high latitudes in winter", "authors": [{"first": "J", "middle": [], "last": "Ladau", "suffix": ""}, {"first": "T", "middle": ["J"], "last": "Sharpton", "suffix": ""}, {"first": "M", "middle": ["M"], "last": "Finucane", "suffix": ""}, {"first": "G", "middle": [], "last": "Jospin", "suffix": ""}, {"first": "S", "middle": ["W"], "last": "Kembel", "suffix": ""}, {"first": "J", "middle": [], "last": "O&apos;dwyer", "suffix": ""}, {"first": "A", "middle": ["F"], "last": "Koeppel", "suffix": ""}, {"first": "J", "middle": ["L"], "last": "Green", "suffix": ""}, {"first": "K", "middle": ["S"], "last": "Pollard", "suffix": ""}], "year": 2013, "venue": "ISME J", "link": "16821351"}, "BIBREF21": {"title": "Spatial and species variations in bacterial communities associated with corals from the Red Sea as revealed by pyrosequencing", "authors": [{"first": "O", "middle": ["O"], "last": "Lee", "suffix": ""}, {"first": "J", "middle": [], "last": "Yang", "suffix": ""}, {"first": "S", "middle": [], "last": "Bougouffa", "suffix": ""}, {"first": "Y", "middle": [], "last": "Wang", "suffix": ""}, {"first": "Z", "middle": [], "last": "Batang", "suffix": ""}, {"first": "R", "middle": [], "last": "Tian", "suffix": ""}, {"first": "A", "middle": [], "last": "Alsuwailem", "suffix": ""}, {"first": "P", "middle": ["Y"], "last": "Qian", "suffix": ""}], "year": 2012, "venue": "Appl Environ Microbiol", "link": "36585001"}, "BIBREF22": {"title": "Highly heterogeneous bacterial communities associated with the South China reef corals Portes lutea, Galaxea fascicularis and Acropora millepora", "authors": [{"first": "J", "middle": [], "last": "Li", "suffix": ""}, {"first": "Q", "middle": [], "last": "Chen", "suffix": ""}, {"first": "S", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "H", "middle": [], "last": "Huang", "suffix": ""}, {"first": "J", "middle": [], "last": "Yang", "suffix": ""}, {"first": "X", "middle": ["P"], "last": "Tian", "suffix": ""}, {"first": "L", "middle": ["J"], "last": "Long", "suffix": ""}], "year": 2013, "venue": "PLOS ONE", "link": "14405872"}, "BIBREF23": {"title": "Characterization of geographically distinct bacterial communities associated with the coral mucus from Acropora spp", "authors": [{"first": "B", "middle": [], "last": "Mckew", "suffix": ""}, {"first": "A", "middle": ["J"], "last": "Dumbrell", "suffix": ""}, {"first": "S", "middle": ["D"], "last": "Daud", "suffix": ""}, {"first": "L", "middle": [], "last": "Hepburn", "suffix": ""}, {"first": "E", "middle": [], "last": "Thorpe", "suffix": ""}, {"first": "L", "middle": [], "last": "Mogensen", "suffix": ""}, {"first": "C", "middle": [], "last": "Whitby", "suffix": ""}], "year": 2012, "venue": "Appl Environ Microbiol", "link": null}, "BIBREF24": {"title": "Bacterial associates of two Caribbean coral species reveal speciesspecific distribution and geographic variability", "authors": [{"first": "K", "middle": ["M"], "last": "Morrow", "suffix": ""}, {"first": "A", "middle": ["G"], "last": "Moss", "suffix": ""}, {"first": "N", "middle": ["F"], "last": "Chadwick", "suffix": ""}, {"first": "M", "middle": ["F"], "last": "Liles", "suffix": ""}], "year": 2012, "venue": "Appl Environ Microbiol", "link": "23522347"}, "BIBREF25": {"title": "Influence of water temperature and salinity on Vibrio vulnificus in Northern Gulf and Atlantic Coast oysters (Crassostrea virginica)", "authors": [{"first": "M", "middle": ["L"], "last": "Motes", "suffix": ""}, {"first": "D", "middle": ["W"], "last": "Depaola", "suffix": ""}, {"first": "J", "middle": ["E"], "last": "Cook", "suffix": ""}, {"first": "J", "middle": ["E"], "last": "Veazey", "suffix": ""}, {"first": "W", "middle": ["E"], "last": "Hunsucker", "suffix": ""}, {"first": "R", "middle": ["J"], "last": "Garthright", "suffix": ""}, {"first": "R", "middle": ["J"], "last": "Blodgett", "suffix": ""}, {"first": "S", "middle": ["J"], "last": "Chirtel", "suffix": ""}], "year": 1998, "venue": "Appl Environ Microbiol", "link": "30797269"}, "BIBREF26": {"title": "Global patterns of diversity and community structure in marine bacterioplankton", "authors": [{"first": "T", "middle": [], "last": "Pommier", "suffix": ""}, {"first": "B", "middle": [], "last": "Canback", "suffix": ""}, {"first": "L", "middle": [], "last": "Riemann", "suffix": ""}, {"first": "K", "middle": ["H"], "last": "Bostrom", "suffix": ""}, {"first": "K", "middle": [], "last": "Simu", "suffix": ""}, {"first": "P", "middle": [], "last": "Lundberg", "suffix": ""}, {"first": "A", "middle": [], "last": "Tunlid", "suffix": ""}, {"first": "A", "middle": [], "last": "Haqstrom", "suffix": ""}], "year": 2007, "venue": "Mol Ecol", "link": "23240613"}, "BIBREF27": {"title": "Marine bacteria exhibit a bipolar distribution", "authors": [{"first": "W", "middle": ["J"], "last": "Sul", "suffix": ""}, {"first": "T", "middle": ["A"], "last": "Oliver", "suffix": ""}, {"first": "H", "middle": ["W"], "last": "Ducklow", "suffix": ""}, {"first": "L", "middle": ["A"], "last": "Amaral-Zettler", "suffix": ""}, {"first": "M", "middle": ["L"], "last": "Sogin", "suffix": ""}], "year": 2013, "venue": "PNAS", "link": "13582957"}, "BIBREF28": {"title": "Threatened corals provide underexplored microbial habitats", "authors": [{"first": "S", "middle": [], "last": "Sunagawa", "suffix": ""}, {"first": "C", "middle": ["M"], "last": "Woodley", "suffix": ""}, {"first": "M", "middle": [], "last": "Median", "suffix": ""}], "year": 2010, "venue": "PLOS ONE", "link": "3765110"}}, "ref_entries": {}}
{"paper_id": "84889665", "_pdf_hash": "884510751c647de93797dbc45fe96df089308734", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "A fi eld study of the life history of an endemic Hawaiian succineid land snail", "authors": [{"first": "F", "middle": ["C"], "last": "Baker", "suffix": ""}, {"first": "S", "middle": ["G"], "last": "Brown", "suffix": ""}, {"first": "B", "middle": ["K"], "last": "Spain", "suffix": ""}, {"first": "K", "middle": [], "last": "Crowell", "suffix": ""}], "year": 1939, "venue": "Fieldbook of Illinois Land Snails. Illinois Natural History Survey", "link": null}, "BIBREF1": {"title": "A fi eld study of the life history of the endemic Hawaiian snail Succinea newcombinana", "authors": [{"first": "S", "middle": ["G"], "last": "Brown", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Spain", "suffix": ""}, {"first": "M", "middle": [], "last": "Arizumi", "suffix": ""}], "year": 2006, "venue": "Malacologia", "link": null}, "BIBREF2": {"title": "A literature database on the mating behavior of stylommatophoran land snails and slugs", "authors": [{"first": "A", "middle": [], "last": "Davison", "suffix": ""}, {"first": "P", "middle": [], "last": "Mordan", "suffix": ""}], "year": 2007, "venue": "American Malacological Bulletin", "link": "84302839"}, "BIBREF3": {"title": "Variations in the anatomy of the succineid gastropod, Oxyloma retusa", "authors": [{"first": "D", "middle": ["S"], "last": "Franzen", "suffix": ""}], "year": 1963, "venue": "The Nautilus", "link": null}, "BIBREF4": {"title": "Annotated checklist of the land snails of Maryland and the District of Columbia", "authors": [{"first": "F", "middle": ["W"], "last": "Grimm", "suffix": ""}], "year": 1971, "venue": "Sterkiana", "link": null}, "BIBREF5": {"title": "Life history strategies", "authors": [{"first": "J", "middle": [], "last": "Heller", "suffix": ""}], "year": 2001, "venue": "The Biology of Terrestrial Molluscs", "link": "70520758"}, "BIBREF6": {"title": "Zur Kenntnis der mitteleurop\u00e4ischen Bernsteinschnecken (Succineidae). I", "authors": [{"first": "U", "middle": [], "last": "Hecker", "suffix": ""}], "year": 1965, "venue": "Archiv f\u00fcr Molluskenkunde", "link": null}, "BIBREF7": {"title": "The distributions of the native land mollusks of the eastern United States", "authors": [{"first": "L", "middle": [], "last": "Hubricht", "suffix": ""}], "year": 1985, "venue": "Fieldiana", "link": null}, "BIBREF8": {"title": "Some observations on biology of reproduction of Succinea Draparnaud (Gastropoda, Pulmonata)", "authors": [{"first": "M", "middle": [], "last": "Jackiewicz", "suffix": ""}], "year": 1980, "venue": "Annales Zoologici", "link": "86233984"}, "BIBREF9": {"title": "Mate choice in the hermaphroditic land snail Succinea putris (Stylommatophora: Succineidae)", "authors": [{"first": "K", "middle": [], "last": "Jordaens", "suffix": ""}, {"first": "J", "middle": [], "last": "Pinceel", "suffix": ""}, {"first": "T", "middle": [], "last": "Backeljau", "suffix": ""}], "year": 2005, "venue": "Animal Behaviour", "link": "53158367"}, "BIBREF10": {"title": "Distribution, dispersion, and behavioral ecology of the land snail Oxyloma retusa (Succineidae)", "authors": [{"first": "M", "middle": ["J"], "last": "Lannoo", "suffix": ""}, {"first": "R", "middle": ["V"], "last": "Bovbjerg", "suffix": ""}], "year": 1985, "venue": "Proceedings of Iowa Academy of Science", "link": "42128794"}, "BIBREF11": {"title": "The family Succineidae (Gastropoda: Pulmonata) in Kansas. The University of Kansas Science Bulletin", "authors": [{"first": "C", "middle": ["D"], "last": "Miles", "suffix": ""}], "year": 1958, "venue": "", "link": null}, "BIBREF12": {"title": "Gastropods", "authors": [{"first": "R", "middle": ["C"], "last": "Moore", "suffix": ""}], "year": 1952, "venue": "Invertebrate Fossils", "link": null}, "BIBREF13": {"title": "Natural diet of Oxyloma retusa (Pulmonata: Succineidae)", "authors": [{"first": "A", "middle": [], "last": "\u00d6rstan", "suffix": ""}], "year": 2006, "venue": "", "link": null}, "BIBREF14": {"title": "The Academy of Natural Sciences of Philadelphia", "authors": [{"first": "H", "middle": [], "last": "Pilsbry", "suffix": ""}], "year": 1948, "venue": "", "link": "133761248"}, "BIBREF15": {"title": "Growth and reproduction in Hawaiian succineid land snails", "authors": [{"first": "R", "middle": ["J"], "last": "Rundell", "suffix": ""}, {"first": "R", "middle": ["H"], "last": "Cowie", "suffix": ""}], "year": 2003, "venue": "Journal of Molluscan Studies", "link": "86290504"}, "BIBREF16": {"title": "Feeding behavior of three species of succineid snails", "authors": [{"first": "A", "middle": ["L"], "last": "Shrader", "suffix": ""}], "year": 1972, "venue": "Malacological Review", "link": null}, "BIBREF17": {"title": "The habitats of Iowa succineas", "authors": [{"first": "B", "middle": [], "last": "Shimek", "suffix": ""}], "year": 1935, "venue": "The Nautilus", "link": null}, "BIBREF18": {"title": "Contrasting objectives in environmental mediation, reconnaissance biology, and endangered species protection -a case study in the Kanab ambersnail, Oxyloma haydeni kanabensis Pilsbry", "authors": [{"first": "E", "middle": ["E"], "last": "Spamer", "suffix": ""}, {"first": "A", "middle": ["E"], "last": "Bogan", "suffix": ""}], "year": 1948, "venue": "Gastropoda: Stylommatophora: Succineidae)", "link": null}, "BIBREF19": {"title": "Quantitative study of a snail population", "authors": [{"first": "E", "middle": ["J"], "last": "Strandine", "suffix": ""}], "year": 1941, "venue": "Ecology", "link": "89772135"}, "BIBREF20": {"title": "Life cycle and fi eld abundance of the snail Succinea costaricana (Stylommatophora: Succineidae), a tropical agricultural pest", "authors": [{"first": "C", "middle": ["M"], "last": "Villalobos", "suffix": ""}, {"first": "J", "middle": [], "last": "Monge-N\u00e1jera", "suffix": ""}, {"first": "Z", "middle": [], "last": "Barrientos", "suffix": ""}, {"first": "J", "middle": [], "last": "Franco", "suffix": ""}], "year": 1995, "venue": "Revista de Biologia Tropical", "link": "82852497"}, "BIBREF21": {"title": "Yearly body size distribution in the terrestrial snail Succinea costaricana (Stylommatophora: Succineidae)", "authors": [{"first": "C", "middle": ["M"], "last": "Villalobos", "suffix": ""}, {"first": "J", "middle": [], "last": "Monge-N\u00e1jera", "suffix": ""}], "year": 2004, "venue": "Brenesia", "link": null}, "BIBREF22": {"title": "On the sexology of Catinella (Mediappendix) avara (Say) or C. (M.) vermeta (Say)", "authors": [{"first": "G", "middle": ["R"], "last": "Webb", "suffix": ""}], "year": 1977, "venue": "Gastropodia", "link": null}, "BIBREF23": {"title": "Some sexologic observations on Oxyloma retusa (Lea)", "authors": [{"first": "G", "middle": ["R"], "last": "Webb", "suffix": ""}], "year": 1977, "venue": "Gastropodia", "link": null}, "BIBREF24": {"title": "Notes on the succineid land snails of New Mexico", "authors": [{"first": "S", "middle": [], "last": "Wu", "suffix": ""}], "year": 1993, "venue": "Malacological Review", "link": null}}, "ref_entries": {}}
{"paper_id": "123621459", "_pdf_hash": "b6f0593c6ef8cad148c4d3e34882182b0f353717", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "A Mathematical Theory", "authors": [{"first": "C", "middle": ["E"], "last": "References &quot;shannon", "suffix": ""}], "year": "", "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "123621513", "_pdf_hash": "a42494e6eea74d6fc554e0cc264f009b49d65730", "abstract": [{"section": "Abstract", "text": "Nor mally, cyl in der pres sure was used as a cri te rion of com bus tion oc cur rence, while in some con di tions, it may be un re li able when iden ti fy ing lean mix ture combus tion. This is par tic u larly im", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Nowdays, de mands for emis sion re duc tion of the ve hi cle be came very ur gent which lead to stricter emis sion reg u la tion. The cold start emis sion at -7 \u00b0C en vi ron men tal tem per a ture was re quired in the Eu rope and the USA emis sion reg u la tion [1] . The re search shows that 50%~80% HC and CO emis sions was pro duced dur ing the cold start [2, 3] . Since the 1990s, many re searches about HC emis sions dur ing the cold start were car ried out of China. Re cently, the sim i lar re search was car ried on in China. Pro fes sor Huang [4, 5] etc. stud ied the HC emissions and their in flu enc ing fac tors dur ing cold start. Yong [3, 6] etc., com bined with study of the light off char ac ter is tic of the three-way-cat a lytic con verter, stud ied the emis sions and af fect ing fac tors dur ing cold start and warm-up.", "cite_spans": [{"start": 262, "end": 265, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 359, "end": 362, "text": "[2,", "ref_id": "BIBREF1"}, {"start": 363, "end": 365, "text": "3]", "ref_id": "BIBREF2"}, {"start": 552, "end": 555, "text": "[4,", "ref_id": "BIBREF3"}, {"start": 556, "end": 558, "text": "5]", "ref_id": "BIBREF4"}, {"start": 649, "end": 652, "text": "[3,", "ref_id": "BIBREF2"}, {"start": 653, "end": 655, "text": "6]", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Abstract", "text": "Those stud ies show that the ex cess air co ef fi cient was the key pa ram e ter for the first fir ing cy cle (FFC) dur ing cold start. The mix ture con cen tra tion be ing too rich or too lean will increase the HC emis sions of the FFC dur ing cold start sharply. There fore, the main ob ject was to op ti mize the ex cess air co ef fi cient in the FFC dur ing cold start. HC emis sions were one of the judg ments for the op ti mum mix ture con cen tra tion. While, study of HC emis sions were not ", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "In tro duc tion", "text": "Nowdays, de mands for emis sion re duc tion of the ve hi cle be came very ur gent which lead to stricter emis sion reg u la tion. The cold start emis sion at -7 \u00b0C en vi ron men tal tem per a ture was re quired in the Eu rope and the USA emis sion reg u la tion [1] . The re search shows that 50%~80% HC and CO emis sions was pro duced dur ing the cold start [2, 3] . Since the 1990s, many re searches about HC emis sions dur ing the cold start were car ried out of China. Re cently, the sim i lar re search was car ried on in China. Pro fes sor Huang [4, 5] etc. stud ied the HC emissions and their in flu enc ing fac tors dur ing cold start. Yong [3, 6] etc., com bined with study of the light off char ac ter is tic of the three-way-cat a lytic con verter, stud ied the emis sions and af fect ing fac tors dur ing cold start and warm-up.", "cite_spans": [{"start": 262, "end": 265, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 359, "end": 362, "text": "[2,", "ref_id": "BIBREF1"}, {"start": 363, "end": 365, "text": "3]", "ref_id": "BIBREF2"}, {"start": 552, "end": 555, "text": "[4,", "ref_id": "BIBREF3"}, {"start": 556, "end": 558, "text": "5]", "ref_id": "BIBREF4"}, {"start": 649, "end": 652, "text": "[3,", "ref_id": "BIBREF2"}, {"start": 653, "end": 655, "text": "6]", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "In tro duc tion", "text": "Those stud ies show that the ex cess air co ef fi cient was the key pa ram e ter for the first fir ing cy cle (FFC) dur ing cold start. The mix ture con cen tra tion be ing too rich or too lean will increase the HC emis sions of the FFC dur ing cold start sharply. There fore, the main ob ject was to op ti mize the ex cess air co ef fi cient in the FFC dur ing cold start. HC emis sions were one of the judg ments for the op ti mum mix ture con cen tra tion. While, study of HC emis sions were not enough to mon i tor for ma tion of the mix ture, com bus tion in the cyl in der and the cre ation of emis sion in de tails on spark ig ni tion (SI) en gine. The real time NO emis sions can judge whether the com bus tion in cyl in der hap pened or not be cause NO emis sions come out with com bus tion and in creas ing with the com bus tion tem per a ture. There fore, the real time NO emis sions were an other judg ment for the op ti mi za tion of the ex cess air co ef fi cient ex cept for cyl in der pres sure and HC. The study about the real time NO emis sions started firstly by Peckham [7, 8] . He studied the real time NO emis sions emit ted from the cyl in der and ex haust valve on SI en gine equipped with the real time NO de tec tion. Hands [9] stud ied the real time NO, CO, and HC emis sions dur ing the first 505 sec onds of the FTP75 on four cyl in ders SI en gine. So far, no pa per were puplished about the real time NO emis sions dur ing cold start.", "cite_spans": [{"start": 1090, "end": 1093, "text": "[7,", "ref_id": "BIBREF6"}, {"start": 1094, "end": 1096, "text": "8]", "ref_id": "BIBREF7"}, {"start": 1250, "end": 1253, "text": "[9]", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "Equipments and test meth ods", "text": "The study was done in a four-stroke air-cooled port fu eled in jec tion SI sin gle cyl in der en gine fu eled with LPG (en gine pa ram e ters are shown in tab. 1). A sin gle in jec tor was equipped on the in take port. The LPG was in jected at gas phase on 0.14 MPa con stant pres sure. The ro ta tion en coder of CHA-1 and Kistler6125b cyl in der pres sure (con nected with WDF-3 charge am pli fier) was equipped on the en gine. The mea sure ment res o lu tion of cyl in der pres sure was 1 \u00b0CA. The test was done at the con di tion of 20 \u00b0C am bi ent tem per a ture, stan dard at mo sphere and 12 V bat tery volt age. The real time anal y sis and mea sure instru ment -CombustionfNOx400 was used to test the NO emis sions of the FFC dur ing cold start. Com pared with the tra di tional elec tronic chem is try meth ods, the re sponse time of NO was short ened ap par ently by CombustionfNOx400. The re sponse time for real time NO was about 4 ms. The po sition of NO probe was near the ex haust valve ( fig. 1 ). The NO emis sions sig nal, crankshaft ro ta tion an gle sig nal (CHA-1), cylinder pres sure (Kistler6125b), and en gine running pa ram e ter (the wa ter and cyl in der temper a ture, throt tle open postion) were measured by the real time data ac qui si tion sys tem.", "cite_spans": [], "ref_spans": []}, {"section": "Equipments and test meth ods", "text": "The re search was car ried out based on the cy cle by cy cle anal y sis of the first fir ing cy cle dur ing the cold start. The pis ton of the sin gle cyl in der en gine usu ally stops be fore the com pres sion top dead cen ter (TDC). At that time, the in take valve closed, the fuel in jec tion at that time will en ter the cyl in der in the next cy cle. There fore the first fir ing cy cle in the ory was the next cy cle of the first in jec tion hap pened with crank ing, i. e. the sec ond cy cle dur ing cold start. It was named as in ject ing then fir ing. In the first crank ing cy cle, fuel quan tity of in jec tion and the ig ni tion ad vance an gle was con trolled by soft ware. The real time data of en gine pa ram e ters were mea sured by the high speed data acqui si tion sys tem. The LPG in jec tor was pro duced by KEIHIN. The re la tion ship be tween in jection pulse width and the ex cess air co ef fi cient was shown in fig. 2 .", "cite_spans": [], "ref_spans": []}, {"section": "Test re sults and anal y sis", "text": "The judg ment of the fir ing dur ing the cold start", "cite_spans": [], "ref_spans": []}, {"section": "Test re sults and anal y sis", "text": "Fig ure 3 shows the en gine char ac ter is tic using 2.2 ms in jec tion pulse width dur ing cold start. From fig. 2 , the ex cess air co ef fi cient corre spond ing to that in jec tion pulse width was a lit tle big ger, which means the mix ture con centra tion was very lean. Al though each cy cle had one time fuel in jec tion, the mix ture con cen tration was not in creased im me di ately. The engine did not fire un til the 5 th cy cle when cranking. The cyl in der pres sure and si mul ta neous crank shaft speed af ter com bus tion in creased ob vi ously com pared to the other cy cle. The real time NO in creased to more than 1200 ppm, the peak value of cyl in der pres sure was 4 MPa, and speed was nearly 1600 rpm. Be cause of the leaner mix ture, the fol low ing cy cle mis fired which can be judged by the cyl in der pres sure, speed, and NO emis sions.", "cite_spans": [], "ref_spans": []}, {"section": "Test re sults and anal y sis", "text": "The fuel in jec tion can be set on the de fined cy cle by en gine con trol unit. As shown in fig. 4 , the fuel was in jected only in the 5 th and 6 th cycle dur ing the cold start; the other cy cle was crank ing cy cle with starter mo tor with out fuel in jec tion. Be cause the fuel was in jected into the in let air port be fore the com pres sion TDC, the mix ture can not en ter into cyl in der im me di ately but in the fol low ing cy cle. There fore, the en gine fired in the 6 th and 17 th cy cle af ter the in jec tion in the 5 th and the 16 th cy cle . Fig ure 4 shows the real time NO emis sion, the cyl in der pres sure, and the speed in creased rap idly in the cer tain cy cle. The two dif fer ent fir ing cy cles had al most 2.5 MPa peak value of cyl in der pres sure, and en gine speed is greater than 1500 rpm. For two fir ing cy cles, the real time NO emis sions in creased from 0 to 1500 ppm rap idly. Since no fuel in jec tion in the fol low ing cy cle, the speed and cyl in der pres sure in the cy cle next to the two fir ing cy cles drop quickly, and the real time NO emis sions de creased grad u ally. It was seen that the re sid ual NO in the cyl in der dropped step by step, fi nally be came zero. ", "cite_spans": [], "ref_spans": []}, {"section": "The judg ment of mis fir ing cy cle dur ing cold start", "text": "Fig ure 5 shows that the en gine speed, cyl inder pres sure, and the real time NO emis sions change with the con stant in jec tion pulse width. That con stant pulse width is shorter than nor mal which means the mix ture fuel is lean. It shows that the first two drag ging cy cle fail to fire. It can be seen from lower cyl in der pres sure and cranking speed. Be cause no com bus tion, the NO emis sions did not in crease. Al though there was no com bus tion in the first two cy cles, the fuel mix ture con cen tra tion be came higher be cause of the re sid ual fuel. It led to the fir ing in the third cy cle. The cor re spond ing peak value of cyl in der pres sure in creased to 3 MPa, the speed in creased to 1500 rpm and NO changed greatly to 1000 ppm. The 4 th cy cle mis fired be cause of the lean mix ture again. The NO emis sion dropped quickly, the cyl in der pres sure and speed de creased as well. The 1 st fir ing cy cle in creased the cylin der tem per a ture, made the com bus tion con di tion better. There fore, the en gine fired suc cessfully af ter the 5 th cy cle. From fig. 5 , the NO emis sion in the 5 th cy cle in creased sharply. Compared with the 5 th cy cle, the NO emis sions de creased ob vi ously in the 6 th cy cle. It shows that the NO emis sion de creased when en gine runs smoothly in idle. At that time, en gine did not need too much fuel to sus tain the com bus tion and com bus tion tem per a ture de creased. Whether the combus tion is suc cess ful or not can be judged clearly based on the real time NO emis sions ( fig. 5 ).", "cite_spans": [], "ref_spans": []}, {"section": "The judg ment of mis fir ing cy cle dur ing cold start", "text": "Fig ure 6 shows the same curve as fig. 5 . But the in jec tion pulse width in creased 100 ms compared with fig. 5 . The en gine suc ceed to fire in the 2 nd cy cle, the peak value of cyl in der pres sure ex ceeded the 2 MPa, the speed in creased to 1400 rpm, the real time NO emis sion in creased greatly from 0 to 1200 ppm. Due to the lean mix ture, the 3 rd and 4 th cy cle mis fired af ter the 2 nd cy cle. The NO emis sions de creased grad u ally. The 5 th cy cle had a vi o lent fir ing. In that cy cle, the peak value of cyl in der pres sure in creased to 4.5 MPa rapidly, the NO emis sions in creased greatly to 2200 ppm, the speed in creased to 1500 rpm. The 6 th cy cle be longed to the sta ble com bus tion cy cle. The cyl in der pres sure de creased a lit tle com pared with the for mer cy cle. The NO emis sions had a small peak value be fore the open ing of the ex haust valve. But the lean mix ture made the un stable com bus tion and mis fir ing in the 7 th cy cle.", "cite_spans": [], "ref_spans": []}, {"section": "The char ac ter is tics of the real time NO emis sions dur ing cold start", "text": "The main quan tity of the real time NO emis sions came out in the 1 st sev eral cy cles during cold start. The NO emis sions de creased grad u ally in the fol low ing cy cle. Be cause of the worse com bus tion con di tion dur ing cold start, the richer mix ture con cen tra tion was used for the 1 st sev eral cy cles to make sure of the suc cess ful com bus tion. At that time, the cyl in der pres sure and com bus tion tem per a ture in creased sharply which lead to greats of NO emis sions. When engine run smoothly in idle, the en gine need less com bus tion heat to sus tain as the 1 st sev eral cycles of cold start. The com bus tion heat and NO emis sions de creased grad u ally . Fig ure 7 shows that the in stan ta neous crank shaft ro ta tion speed, cyl in der pres sure, and the NO emis sions when the ex cess air co ef fi cient was 0.78 in the 1 st cy cle (us ing the same in jec tion pulse width and ig nition ad vance an gle in the fol low ing cy cle). As shown in fig ure, with the suc cess ful fir ing in the 1 st cy cle, the en gine speed in creased to 1500 rpm rap idly and was sta ble around the idle speed in the fol low ing cy cle. The cyl in der pres sure in creased to 4.4 MPa with the success ful fir ing and de creased grad u ally in the fol low ing sta ble com bus tion. When the exhaust valve open in the 1 st cy cle, the real time NO emis sions in creased rap idly to 2200 ppm. It shows that the com bus tion tem per a ture in the cyl in der in creased greatly which lead to a lot of NO emis sions. Fol low ing the suc cess ful cold start, the cylin der pres sure and en gine speed come to stable, the NO emis sions de creased. Be cause of the fast chang ing of the ex cess air co ef fi cient and higher tem per a ture in cyl in der in the 1 st several cy cles, the NO emis sions in creased rap idly. That phe nom e non was very sim i lar to ac cel er ation pro cess. The rule can be found to op ti mize the com bus tion and re duce the real time NO emis sions.", "cite_spans": [], "ref_spans": []}, {"section": "The char ac ter is tics of the real time NO emis sions dur ing cold start", "text": "Fig ure 8 shows the real time NO emis sions vs. the ig ni tion ad vance an gle at the 1 st cycle. The ex cess air co ef fi cient was 0.78 at the 1 st cy cle. The ig ni tion ad vance an gle was 20 \u00b0CA bTDC, 15 \u00b0CA bTDC, and 10 \u00b0CA bTDC at the 1 st cy cle. The fol low ing cy cle had same ig ni tion ad vance an gle and fuel in jec tion quan tity. Only the real time NO emis sions were shown in fig. 8 , not in clud ing the cyl in der pres sure and en gine speed curve cor re spond ing to those three ig ni tion ad vance an gle. The en gine had suc cess fully sta ble idle af ter cold start ( fig. 8 sim i lar to fig.7 ). The NO emis sions mainly came out from the early pe riod of cold start ( fig. 8) . The NO emis sions de creased grad u ally with the stable idle speed. Af ter ex haust valve open at the first cy cle, the real time NO emis sions in creased greatly in all three ig ni tion advance an gles. The 20 \u00b0CA bTDC had the high est peak value of NO emis sions (2500 ppm). NO emis sions at 15 \u00b0CA bTDC and 10 \u00b0CA bTDC are 2200 ppm and 2000 ppm, re spec tively. With the same fuel in jec tion at the 1 st cy cle, the NO emis sions in creased with ad vanc ing of the ig ni tion ad vance angle. The NO emis sions in the fol low ing cy - cles de creased grad u ally and were al most same be cause of the same ig ni tion ad vance an gle and fuel in jec tion quan tity.", "cite_spans": [], "ref_spans": []}, {"section": "Con clu sions", "text": "Because the NO emissions coming out together with combustion, the real time NO emissions can be used as the criterion for the firing cycle during cold start. This test proved that the real time NO emissions can be used as the criterion for misfiring cycle during cold start because of no combustion in the misfiring cycle. Because the worse combustion condition, a richer mixture was used in the 1 st several cycles to make sure the successful cold start. The real time NO emissions were mainly produced in the first several cycles during cold start, decreased gradually in the following cycles when engine speed came to stable. When the mixture concentration keeps constant during cold start, the real time NO emissions increased with the advancing of the ignition advance angle.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Cold-Start Hy dro car bon Emis sions in Port-In jected Gas o line En gines, Prog ress in En ergy and Com bus tion Sci ence", "authors": [{"first": "N", "middle": ["A"], "last": "Henein", "suffix": ""}, {"first": "M", "middle": ["K"], "last": "Tagomori", "suffix": ""}], "year": 1999, "venue": "", "link": null}, "BIBREF1": {"title": "The Cold Start Re search Based on the Con trol la ble Fir ing Cy cle in an EFI Gas o line En gine, The Au to mo bile En gi neer ing", "authors": [{"first": "L", "middle": [], "last": "Li", "suffix": ""}], "year": 2004, "venue": "", "link": null}, "BIBREF2": {"title": "Anal y sis of Com bus tion Be hav ior dur ing Cold-Start and Warm-up Pro cess of SI Engine, SAE pa per", "authors": [{"first": "Y", "middle": [], "last": "Cheng", "suffix": ""}], "year": 2001, "venue": "", "link": null}, "BIBREF3": {"title": "The Study of the Un burned HC Pro cess dur ing Cold Start and Idle in a SI En gine", "authors": [{"first": "Z", "middle": [], "last": "Huang", "suffix": ""}], "year": 1997, "venue": "Combus tion Sci ence and Tech nol ogy", "link": null}, "BIBREF4": {"title": "The Ef fects of the Ox y gen Fuel on Un burned HC dur ing Cold Start and Idle in a SI Engine", "authors": [{"first": "Z", "middle": [], "last": "Huang", "suffix": ""}], "year": 1998, "venue": "Small In ter nal Com bus tion En gine", "link": null}, "BIBREF5": {"title": "The Study of Re duc tion of HC Emis sions Dur ing Cold Start and Warm-up in Gas o line En gine", "authors": [{"first": "Y", "middle": [], "last": "Cheng", "suffix": ""}], "year": 2002, "venue": "ter nal Com bus tion En gine Trans ac tion", "link": null}, "BIBREF6": {"title": "Si mul ta neous Fast Re sponse NO and HC Mea sure ments from a Spark Ig nition En gine", "authors": [{"first": "M", "middle": ["S"], "last": "Peckham", "suffix": ""}, {"first": "N", "middle": [], "last": "Collings", "suffix": ""}], "year": 1997, "venue": "", "link": null}, "BIBREF7": {"title": "Real Time In-Cyl in der and Ex haust NO Mea sure ments in a Produc tion SI En gine", "authors": [{"first": "M", "middle": ["S"], "last": "Peckaham", "suffix": ""}, {"first": "T", "middle": [], "last": "Hands", "suffix": ""}, {"first": "J", "middle": [], "last": "Burell", "suffix": ""}], "year": 1998, "venue": "", "link": null}, "BIBREF8": {"title": "Tran sient SI En gine Emis sions Mea sure ments on the FTP75 Drive Cy cle with a Fast Re sponse CO In stru ment", "authors": [{"first": "T", "middle": [], "last": "Hands", "suffix": ""}, {"first": "M", "middle": [], "last": "Peckham", "suffix": ""}, {"first": "B", "middle": [], "last": "Camp Bell", "suffix": ""}], "year": "", "venue": "", "link": null}}, "ref_entries": {"FIGREF0": {"text": "Figure 1. The location of the sample head", "type": "figure"}, "FIGREF1": {"text": "Figure 3. Cold start characteristic of continuous lean fuel injected", "type": "figure"}, "FIGREF2": {"text": "Figure 5. Characteristics of NO emissions for the misfiring cycle during cold start", "type": "figure"}, "FIGREF3": {"text": "Figure 7. Transient characteristics during cold start", "type": "figure"}}}
{"paper_id": "123621809", "_pdf_hash": "be029ed4e16f9eaa16abda8a4135b1fc2552ebb5", "abstract": [], "body_text": [], "bib_entries": {"BIBREF1": {"title": "Smart Antennas: Adaptive Arrays, Algorithms & Wireless Position Location", "authors": [{"first": "T", "middle": [], "last": "Rappaport", "suffix": ""}], "year": 1998, "venue": "", "link": "109029054"}, "BIBREF2": {"title": "Smart Antennas for Wireless Communications: IS-95 and Third Generation CDMA Applications", "authors": [{"first": "J", "middle": [], "last": "Liberti", "suffix": ""}, {"first": "T", "middle": [], "last": "Rappaport", "suffix": ""}], "year": 1999, "venue": "", "link": "106838247"}, "BIBREF3": {"title": "Capacity Improvement with Base-Station Antenna Arrays in Cellular CDMA", "authors": [{"first": "A", "middle": [], "last": "Naguib", "suffix": ""}, {"first": "A", "middle": [], "last": "Paularj", "suffix": ""}, {"first": "T", "middle": [], "last": "Kailath", "suffix": ""}], "year": 1994, "venue": "IEEE Transactions on Vehicular Technology", "link": "62736176"}, "BIBREF4": {"title": "Combination of an Adaptive Antenna Array and a Canceller of Interferences for Direct-Sequence Spread Spectrum Multiple-Access System", "authors": [{"first": "R", "middle": [], "last": "Kohno", "suffix": ""}, {"first": "H", "middle": [], "last": "Imai", "suffix": ""}, {"first": "S", "middle": [], "last": "Pasupathy", "suffix": ""}], "year": 1990, "venue": "IEEE journal on Selected Areas in Communications", "link": null}, "BIBREF5": {"title": "Evaluation of Beamforming Algorithm Effectiveness for the Smart Wireless LAN System", "authors": [{"first": "G", "middle": [], "last": "Okamoto", "suffix": ""}, {"first": "S.-S", "middle": [], "last": "Jeng", "suffix": ""}, {"first": "S", "middle": [], "last": "Tseng", "suffix": ""}, {"first": "G", "middle": [], "last": "Xu", "suffix": ""}], "year": 1998, "venue": "Proc. IEEE VTC'98", "link": "61325467"}, "BIBREF6": {"title": "Implementation of Smart Antennas for Wireless LAN Systems", "authors": [{"first": "G", "middle": [], "last": "Okamoto", "suffix": ""}, {"first": "Chapter", "middle": [], "last": "On", "suffix": ""}], "year": 2004, "venue": "", "link": "59894502"}, "BIBREF7": {"title": "Applications of Antenna Arrays to Mobile Communications, Part I: Performance Improvement, Feasibility, and System Considerations", "authors": [{"first": "L", "middle": ["C"], "last": "Godara", "suffix": ""}], "year": 1997, "venue": "Proceedings of the IEEE", "link": "16756279"}, "BIBREF8": {"title": "Applications of Antenna Arrays to Mobile Communications, Part II: Beam-Forming and Directionof-Arrival Considerations", "authors": [{"first": "L", "middle": ["C"], "last": "Godara", "suffix": ""}], "year": 1997, "venue": "Proceedings of the IEEE", "link": "28573669"}, "BIBREF9": {"title": "Jammer Nulling via Low Complexity Blind Beamforming Algorithm", "authors": [{"first": "G", "middle": [], "last": "Okamoto", "suffix": ""}], "year": 2007, "venue": "Proc. IEEE Antennas and Propagation Society Conference", "link": "44194466"}, "BIBREF10": {"title": "Software Improves Connections to Robots", "authors": [{"first": "G", "middle": [], "last": "Jean", "suffix": ""}], "year": 2009, "venue": "", "link": null}, "BIBREF11": {"title": "Ultra Low Complexity Adaptive Beamforming via Non-Eigen Decomposition", "authors": [{"first": "C.-W", "middle": [], "last": "Chen", "suffix": ""}, {"first": "G", "middle": [], "last": "Okamoto", "suffix": ""}], "year": 2004, "venue": "Proc. IEEE Vehicular Technology Conference", "link": "22545853"}, "BIBREF12": {"title": "Minimal Complexity Blind Interference Mitigation via Non-Eigen Decomposition Beamforming", "authors": [{"first": "G", "middle": [], "last": "Okamoto", "suffix": ""}, {"first": "C.-W", "middle": [], "last": "Chen", "suffix": ""}], "year": 2008, "venue": "Proc. IEEE Military Communications Conference", "link": "24487409"}, "BIBREF13": {"title": "Tracking and Interference Suppression Performance for the Minimal Computational Complexity Non-Eigen Decomposition Beamformer", "authors": [{"first": "G", "middle": [], "last": "Okamoto", "suffix": ""}, {"first": "C.-W", "middle": [], "last": "Chen", "suffix": ""}], "year": 2010, "venue": "Proc. SPIE Defense, Security, and Sensing Conference", "link": "121738317"}, "BIBREF14": {"title": "Design, Control and Applications of Real-World Multirobot Systems", "authors": [{"first": "", "middle": [], "last": "Kitts", "suffix": ""}, {"first": "M", "middle": [], "last": "Egerstedt", "suffix": ""}], "year": 2008, "venue": "IEEE Robotics and Automation Magazine", "link": null}, "BIBREF15": {"title": "Cluster Space Specification and Control of Mobile Multi-Robot Systems", "authors": [{"first": "C", "middle": [], "last": "Kitts", "suffix": ""}, {"first": "I", "middle": [], "last": "Mas", "suffix": ""}], "year": 2009, "venue": "IEEE/ASME Transactions on Mechatronics", "link": "36460764"}, "BIBREF16": {"title": "The Design, Simulation and Implementation of Multi-Robot Collaborative Control from the Cluster Perspective", "authors": [{"first": "R", "middle": [], "last": "Ishizu", "suffix": ""}], "year": 2005, "venue": "C. Kitts, Adv", "link": null}, "BIBREF17": {"title": "Design and Implementation of a Cluster Space Trajectory Controller for Multiple Holonomic Robots", "authors": [{"first": "P", "middle": [], "last": "Connolley", "suffix": ""}], "year": 2006, "venue": "C. Kitts, Adv", "link": null}, "BIBREF18": {"title": "Automated Cluster Space Trajectory Control of Two Non-Holonomic Robots", "authors": [{"first": "T", "middle": [], "last": "To", "suffix": ""}], "year": 2006, "venue": "C. Kitts, Adv", "link": null}, "BIBREF19": {"title": "Design and Implementation of a Cluster Space Human Interface Controller, including Applications to Multi-Robot Piloting and Multi-Robot Object Manipulation", "authors": [{"first": "M", "middle": [], "last": "Kalkbrenner", "suffix": ""}], "year": 2006, "venue": "C. Kitts, Adv", "link": null}, "BIBREF20": {"title": "Cluster Space Piloting of a Nonholonomic Multi-Robot System", "authors": [{"first": "B", "middle": [], "last": "Tully", "suffix": ""}], "year": 2006, "venue": "C. Kitts, Adv", "link": null}, "BIBREF21": {"title": "Model-Based Cluster-Space Control of Multiple Robot Systems", "authors": [{"first": "R", "middle": [], "last": "Lee", "suffix": ""}], "year": 2007, "venue": "C. Kitts, Adv", "link": null}, "BIBREF22": {"title": "Cluster Space Collision Avoidance for Mobile Two-Robot Systems", "authors": [{"first": "C", "middle": [], "last": "Kitts", "suffix": ""}, {"first": "K", "middle": [], "last": "Stanhouse", "suffix": ""}, {"first": "P", "middle": [], "last": "Chindaphorn", "suffix": ""}], "year": 2009, "venue": "Proc. IEEE/RSJ International Conference on Intelligent Robots and Systems", "link": "2800937"}, "BIBREF23": {"title": "Cluster Space Obstacle Avoidance for Two Non-Holonomic Robots", "authors": [{"first": "P", "middle": [], "last": "Chindaphorn", "suffix": ""}], "year": 2006, "venue": "C. Kitts, Adv", "link": null}, "BIBREF24": {"title": "Cluster Space Obstacle Avoidance for Mobile Multi-Robot Systems", "authors": [{"first": "K", "middle": [], "last": "Stanhouse", "suffix": ""}], "year": 2006, "venue": "C. Kitts, Adv", "link": null}, "BIBREF25": {"title": "Cluster space specification and control of a 3-robot mobile system", "authors": [{"first": "I", "middle": [], "last": "Mas", "suffix": ""}, {"first": "O", "middle": [], "last": "Petrovic", "suffix": ""}, {"first": "C", "middle": [], "last": "Kitts", "suffix": ""}], "year": 2008, "venue": "Proc. IEEE International Conference on Robotics and Automation", "link": "1414290"}, "BIBREF26": {"title": "Error Characterization in the Vicinity of Singularities in Multi-Robot Cluster Space Control", "authors": [{"first": "I", "middle": [], "last": "Mas", "suffix": ""}, {"first": "J", "middle": [], "last": "Acain", "suffix": ""}, {"first": "O", "middle": [], "last": "Petrovic", "suffix": ""}, {"first": "C", "middle": [], "last": "Kitts", "suffix": ""}], "year": 2009, "venue": "Proc. IEEE International Conference on Robotics and Biomimetics", "link": "15054794"}, "BIBREF27": {"title": "Design and Implementation of Four Robot Cluster Space Control", "authors": [{"first": "E", "middle": [], "last": "Girod", "suffix": ""}], "year": 2008, "venue": "C. Kitts, Adv", "link": null}, "BIBREF28": {"title": "Cluster Space Control of Autonomous Surface Vessels", "authors": [{"first": "P", "middle": [], "last": "Mahacek", "suffix": ""}, {"first": "I", "middle": [], "last": "Mas", "suffix": ""}, {"first": "O", "middle": [], "last": "Petrovic", "suffix": ""}, {"first": "J", "middle": [], "last": "Acain", "suffix": ""}, {"first": "C", "middle": [], "last": "Kitts", "suffix": ""}], "year": 2009, "venue": "Marine Technology Society Journal", "link": "109943414"}, "BIBREF29": {"title": "Entrapment/Escorting and Patrolling Missions in Multi-Robot Cluster Space Control", "authors": [{"first": "I", "middle": [], "last": "Mas", "suffix": ""}, {"first": "S", "middle": [], "last": "Li", "suffix": ""}, {"first": "J", "middle": [], "last": "Acain", "suffix": ""}, {"first": "C", "middle": [], "last": "Kitts", "suffix": ""}], "year": 2009, "venue": "Proc. IEEE/RSJ International Conference on Intelligent Robots and Systems", "link": "3082005"}}, "ref_entries": {}}
{"paper_id": "123624411", "_pdf_hash": "abf6155312bd8ab8751a98e5f8ff5e1a90c56c31", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "A Unification Algorithm for Typed \u03bb-Calculus", "authors": [{"first": "G", "middle": ["P"], "last": "Huet", "suffix": ""}], "year": 1975, "venue": "Theoretical Computer Science", "link": "12226962"}}, "ref_entries": {}}
{"paper_id": "123624889", "_pdf_hash": "783f2a7c312fb742b1c78623f1f7e2aa10a717df", "abstract": [], "body_text": [], "bib_entries": {"BIBREF14": {"title": "Computational Electrodynamics: The Finite-Difference Time-Domain Method", "authors": [{"first": "A", "middle": [], "last": "Taflove", "suffix": ""}, {"first": "S", "middle": ["C"], "last": "Hagness", "suffix": ""}], "year": 2000, "venue": "", "link": "56592124"}, "BIBREF18": {"title": "Field and Wave Electromagnetics", "authors": [{"first": "D", "middle": ["K"], "last": "Cheng", "suffix": ""}], "year": 1983, "venue": "", "link": "118456994"}, "BIBREF19": {"title": "Semiconductor Physics", "authors": [{"first": "E", "middle": [], "last": "Liu", "suffix": ""}, {"first": "B", "middle": [], "last": "Zhu", "suffix": ""}, {"first": "J", "middle": [], "last": "Luo", "suffix": ""}], "year": 1994, "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "123625503", "_pdf_hash": "d0b77ef879fd54944e9fca0bee8acb9aa93d5980", "abstract": [], "body_text": [], "bib_entries": {"BIBREF1": {"title": "A hemispherical electronic eye camera based on compressible silicon optoelectronics", "authors": [{"first": "J", "middle": ["B"], "last": "Yu", "suffix": ""}, {"first": "J", "middle": [], "last": "Geddes", "suffix": ""}, {"first": "S", "middle": [], "last": "Xiao", "suffix": ""}, {"first": "Y", "middle": [], "last": "Wang", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Huang", "suffix": ""}, {"first": "", "middle": [], "last": "Rogers", "suffix": ""}], "year": "", "venue": "Nature \u0351London\u0352 \u0351unpublished\u0352", "link": "4408472"}, "BIBREF11": {"title": "Whitesides", "authors": [{"first": "N", "middle": [], "last": "Bowden", "suffix": ""}, {"first": "S", "middle": [], "last": "Brittain", "suffix": ""}, {"first": "A", "middle": ["G"], "last": "Evans", "suffix": ""}, {"first": "J", "middle": ["W"], "last": "Hutchinson", "suffix": ""}, {"first": "G", "middle": [], "last": "", "suffix": ""}], "year": "", "venue": "Nature \u0351London\u0352", "link": null}, "BIBREF22": {"title": "FIG. 2. \u0351Color online\u0352 The amplitude A vs the applied strain a for a 0.3 m thick Au film \u0351E f = 78 GPa, f = 0.42\u0352 on a wavy PDMS substrate \u0351E S = 2 MPa, S = 0.48\u0352 with the wavelength =49 m and several", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF23": {"title": "The ratio of applied strain to the maximum film strain, a / max , vs the ratio of initial amplitude to wavelength, A 0 / , obtained by the analytical solution for A 0 / h = 10", "authors": [], "year": "", "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "123625563", "_pdf_hash": "f7150c50c024431803c97aee3bd30657e935b834", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "123626979", "_pdf_hash": "e13cc892a5794226730de88c595504f78ffad0d9", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "123629093", "_pdf_hash": "8dd0dcc8daca042dfb1fb82fcc42b4249fc73fe6", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Three-Dimensional Television, Video, and Display Technologies", "authors": [], "year": 2002, "venue": "", "link": "60328157"}, "BIBREF1": {"title": "Three dimensional imaging and display using computational holographic imaging", "authors": [{"first": "Y", "middle": [], "last": "Frauel", "suffix": ""}, {"first": "T", "middle": [], "last": "Naughton", "suffix": ""}, {"first": "O", "middle": [], "last": "Matoba", "suffix": ""}, {"first": "E", "middle": [], "last": "Tahajuerce", "suffix": ""}, {"first": "B", "middle": [], "last": "Javidi", "suffix": ""}], "year": 2006, "venue": "Proc. of IEEE 94", "link": null}, "BIBREF2": {"title": "Selected Papers on 3D Displays", "authors": [{"first": "S", "middle": [], "last": "Benton", "suffix": ""}], "year": 2001, "venue": "", "link": null}, "BIBREF3": {"title": "La photographie int\u00e9grale", "authors": [{"first": "G", "middle": [], "last": "Lippmann", "suffix": ""}], "year": 1908, "venue": "Compte-Rendus", "link": null}, "BIBREF4": {"title": "Analysis of resolution limitation of integral photography", "authors": [{"first": "H", "middle": [], "last": "Hoshino", "suffix": ""}, {"first": "F", "middle": [], "last": "Okano", "suffix": ""}, {"first": "H", "middle": [], "last": "Isono", "suffix": ""}, {"first": "I", "middle": [], "last": "Yuyama", "suffix": ""}], "year": 1998, "venue": "J. Opt. Soc. Am. A", "link": "119527542"}, "BIBREF5": {"title": "Three-dimensional image sensing, visualization, and processing using integral imaging", "authors": [{"first": "A", "middle": [], "last": "Stern", "suffix": ""}, {"first": "B", "middle": [], "last": "Javidi", "suffix": ""}], "year": 2006, "venue": "Proc. IEEE 94", "link": "8431492"}, "BIBREF7": {"title": "Improved resolution 3-D object sensing and recognition using time multiplexed computational integral imaging", "authors": [{"first": "S", "middle": [], "last": "Kishk", "suffix": ""}, {"first": "B", "middle": [], "last": "Javidi", "suffix": ""}], "year": 2003, "venue": "Opt. Exp", "link": "27472923"}, "BIBREF8": {"title": "Improved viewing resolution of three-dimensional integral imaging by use of nonstationary micro-optics", "authors": [{"first": "J.-S", "middle": [], "last": "Jang", "suffix": ""}, {"first": "B", "middle": [], "last": "Javidi", "suffix": ""}], "year": 2002, "venue": "Opt. Lett", "link": "33930705"}, "BIBREF9": {"title": "Three dimensional imaging with randomly distributed sensors", "authors": [{"first": "M", "middle": [], "last": "Daneshpanah", "suffix": ""}, {"first": "B", "middle": [], "last": "Javidi", "suffix": ""}, {"first": "E", "middle": ["A"], "last": "Watson", "suffix": ""}], "year": 2008, "venue": "Opt. Express", "link": "9544933"}, "BIBREF10": {"title": "Profilometry and optical slicing by passive three-dimensional imaging", "authors": [{"first": "M", "middle": [], "last": "Daneshpanah", "suffix": ""}, {"first": "B", "middle": [], "last": "Javidi", "suffix": ""}], "year": 2009, "venue": "Opt. Lett", "link": "36790393"}, "BIBREF11": {"title": "Light fields and computational imaging", "authors": [{"first": "M", "middle": [], "last": "Levoy", "suffix": ""}], "year": 2006, "venue": "IEEE Computer Magazine", "link": "206447782"}, "BIBREF12": {"title": "Progress in 3-D Multiperspective Display by Integral Imaging", "authors": [{"first": "R", "middle": [], "last": "Martinez-Cuenca", "suffix": ""}, {"first": "G", "middle": [], "last": "Saavedra", "suffix": ""}, {"first": "M", "middle": [], "last": "Martinez-Corral", "suffix": ""}, {"first": "B", "middle": [], "last": "Javidi", "suffix": ""}], "year": 2009, "venue": "Proceedings of the IEEE", "link": null}, "BIBREF13": {"title": "Recent processing in three-dimensional information processing based on integral imaging", "authors": [{"first": "J", "middle": [], "last": "Park", "suffix": ""}, {"first": "K", "middle": [], "last": "Hong", "suffix": ""}, {"first": "B", "middle": [], "last": "Lee", "suffix": ""}], "year": 2009, "venue": "Appl.Opt", "link": "24425232"}, "BIBREF14": {"title": "Three-dimensional recognition of photon starved events using computational integral imaging and statistical sampling", "authors": [{"first": "I", "middle": [], "last": "Moon", "suffix": ""}, {"first": "B", "middle": [], "last": "Javidi", "suffix": ""}], "year": 2009, "venue": "Opt. Lett", "link": "45262132"}, "BIBREF15": {"title": "Three dimensional imaging and recognition using truncated photon counting model and parametric maximum likelihood estimator", "authors": [{"first": "I", "middle": [], "last": "Moon", "suffix": ""}, {"first": "B", "middle": [], "last": "Javidi", "suffix": ""}], "year": 2009, "venue": "Opt. Exp", "link": "8800264"}, "BIBREF16": {"title": "Three-dimensional speckle-noise reduction by using coherent integral imaging", "authors": [{"first": "I", "middle": [], "last": "Moon", "suffix": ""}, {"first": "B", "middle": [], "last": "Javidi", "suffix": ""}], "year": 2009, "venue": "Opt. Lett", "link": "46508562"}, "BIBREF17": {"title": "Digital Image Processing Using MATLAB", "authors": [{"first": "R", "middle": [], "last": "Gonzalez", "suffix": ""}, {"first": "R", "middle": [], "last": "Woods", "suffix": ""}, {"first": "S", "middle": [], "last": "Eddins", "suffix": ""}], "year": 2003, "venue": "", "link": "44708800"}, "BIBREF18": {"title": "Probability and Statistical Inference", "authors": [{"first": "N", "middle": [], "last": "Mukhopadhyay", "suffix": ""}], "year": 2000, "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "123629972", "_pdf_hash": "063bc4333636843854d1f617eb1c56bc1308ca04", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Refractive indices of orthorhombic KNbO3. I . Dispersion and temperature dependence", "authors": [{"first": "B", "middle": [], "last": "Zysset", "suffix": ""}, {"first": "I", "middle": [], "last": "Biaggio", "suffix": ""}, {"first": "P", "middle": [], "last": "Gunter", "suffix": ""}], "year": 1992, "venue": "J. Opt. Soc. Am. B", "link": "119796913"}, "BIBREF1": {"title": "Refractive indices of orthorhombic KNbO. II .Phasematching configurations for nonlinear-optical interactions", "authors": [{"first": "I", "middle": [], "last": "Biaggio", "suffix": ""}, {"first": "P", "middle": [], "last": "Kerkoc", "suffix": ""}, {"first": "L. -S", "middle": [], "last": "Wu", "suffix": ""}, {"first": "P", "middle": [], "last": "Gunter", "suffix": ""}, {"first": "B", "middle": [], "last": "Zysset", "suffix": ""}], "year": 1992, "venue": "J. Opt. Soc. Am. B", "link": "123034584"}, "BIBREF2": {"title": "A temperature-dependent dispersion equation for KNbO3", "authors": [{"first": "D", "middle": ["H"], "last": "Jundt", "suffix": ""}, {"first": "P", "middle": [], "last": "Gunter", "suffix": ""}, {"first": "B", "middle": [], "last": "Zysset", "suffix": ""}], "year": 1993, "venue": "Nonlinear Opt", "link": null}, "BIBREF3": {"title": "Dispersion of therrno-optic coefficients in a potassium niobate nonlinear crystal", "authors": [{"first": "G", "middle": [], "last": "Ghosh", "suffix": ""}], "year": 1994, "venue": "Appi .Phys .Lett", "link": null}, "BIBREF5": {"title": "Type-II phase-matched KNbO3 optical parametric oscillator", "authors": [{"first": "W", "middle": ["R"], "last": "Bosenherg", "suffix": ""}, {"first": "R", "middle": ["H"], "last": "Jarman", "suffix": ""}], "year": 1993, "venue": "Opt. Lett", "link": "46531839"}, "BIBREF6": {"title": "Single-mode BBO/KNB optical parametric oscillator amplifier system", "authors": [{"first": "A", "middle": [], "last": "Fix", "suffix": ""}, {"first": "R", "middle": [], "last": "Urschel", "suffix": ""}, {"first": "G", "middle": [], "last": "Goeritz", "suffix": ""}, {"first": "A", "middle": [], "last": "Borsutzky", "suffix": ""}, {"first": "R", "middle": [], "last": "Wallenstein", "suffix": ""}], "year": 1994, "venue": "Conference on Lasers and Electro-Optics", "link": null}, "BIBREF7": {"title": "High-repetition-rate femtosecond optical parametric oscillator based on KNbO3", "authors": [{"first": "D", "middle": ["E"], "last": "Spence", "suffix": ""}, {"first": "S", "middle": [], "last": "Wielandy", "suffix": ""}, {"first": "C", "middle": ["L C"], "last": "Tang", "suffix": ""}, {"first": "P", "middle": [], "last": "Bosshard", "suffix": ""}, {"first": "", "middle": [], "last": "Gunter", "suffix": ""}], "year": 1995, "venue": "Opt. Lett", "link": "42818240"}, "BIBREF8": {"title": "Mid-infrared femtosecond optical parametric amplification in potassium niobate", "authors": [{"first": "V", "middle": [], "last": "Petrov", "suffix": ""}, {"first": "F", "middle": [], "last": "Noack", "suffix": ""}], "year": 1996, "venue": "Opt. Lett", "link": "35350327"}, "BIBREF9": {"title": "Broadly tunable KNbO3 OPOs pumped by Ti:sapphire lasers", "authors": [{"first": "P", "middle": [], "last": "Rambaldi", "suffix": ""}, {"first": "M", "middle": [], "last": "Douard", "suffix": ""}, {"first": "B", "middle": [], "last": "Vezin", "suffix": ""}, {"first": "J", "middle": ["P"], "last": "Wolf", "suffix": ""}, {"first": "D", "middle": [], "last": "Rytz", "suffix": ""}], "year": 1997, "venue": "Opt.Commun", "link": "135777387"}, "BIBREF10": {"title": "Nonlinear optical properties of KNbO3 single crystals in the orthorhombic phase", "authors": [{"first": "Y", "middle": [], "last": "Uematsu", "suffix": ""}], "year": 1974, "venue": "Jpn. J. AppI. Phys", "link": "122230546"}, "BIBREF11": {"title": "Diode laser pumped blue-light source at 473nm using intracavity frequency doubling of a 946nm Nd:YAG laser", "authors": [{"first": "W", "middle": ["P"], "last": "Risk", "suffix": ""}, {"first": "R", "middle": [], "last": "Pon", "suffix": ""}, {"first": "W", "middle": [], "last": "Lenth", "suffix": ""}], "year": 1989, "venue": "AppI. Phys. Lett", "link": null}, "BIBREF12": {"title": "Second-harmonic generation with Gai-xAlxAs lasers and KNbO3 crystals", "authors": [{"first": "P", "middle": [], "last": "Gunter", "suffix": ""}, {"first": "P", "middle": ["M"], "last": "Asbeck", "suffix": ""}, {"first": "S", "middle": ["K"], "last": "Kurtz", "suffix": ""}], "year": 1979, "venue": "Appl. Phys. Lett", "link": null}, "BIBREF13": {"title": "High-efficiency second-harmonic generation at 4250-4680 A in KNbO3", "authors": [{"first": "K", "middle": [], "last": "Kato", "suffix": ""}], "year": 1979, "venue": "IEEE J. Quantum Electron. QE-1S", "link": null}, "BIBREF14": {"title": "Near-infrared noncritically phase-matched second-harmonic generation in KNbO3", "authors": [{"first": "P", "middle": [], "last": "Gunter", "suffix": ""}], "year": 1979, "venue": "AppI. Phys. Lett", "link": "123017980"}, "BIBREF15": {"title": "High efficiency second-harmonic generation in KNbO3 crystals", "authors": [{"first": "J. -C", "middle": [], "last": "Baumert", "suffix": ""}, {"first": "P", "middle": [], "last": "Gunter", "suffix": ""}, {"first": "H", "middle": [], "last": "Melchior", "suffix": ""}], "year": 1983, "venue": "Opt .Commun", "link": "122082450"}, "BIBREF16": {"title": "Efficient blue emission from an intracavity-doubled 946-nm Nd:YAG laser", "authors": [{"first": "G", "middle": ["J"], "last": "Dixon", "suffix": ""}, {"first": "Z", "middle": ["M"], "last": "Zhang", "suffix": ""}, {"first": "R", "middle": ["F S"], "last": "Chang", "suffix": ""}, {"first": "N", "middle": [], "last": "Djeu", "suffix": ""}], "year": 1988, "venue": "Opt. Left", "link": "40155451"}, "BIBREF17": {"title": "Generation of 41mW of blue radiation by frequency doubling of a GaA1AS diode laser", "authors": [{"first": "W", "middle": ["J"], "last": "Kozlovsky", "suffix": ""}, {"first": "W", "middle": [], "last": "Lenth", "suffix": ""}, {"first": "E", "middle": ["F"], "last": "Latta", "suffix": ""}, {"first": "A", "middle": [], "last": "Moser", "suffix": ""}, {"first": "G", "middle": ["L"], "last": "Bona", "suffix": ""}], "year": 1990, "venue": "Appl. Phys. Lett", "link": null}, "BIBREF18": {"title": "High-efficiency intracavity frequency doubling of Ti:Al203 lasers with KNbO3 crystals", "authors": [{"first": "L. -S", "middle": [], "last": "Wu", "suffix": ""}, {"first": "H", "middle": [], "last": "Looser", "suffix": ""}, {"first": "P", "middle": [], "last": "Gunter", "suffix": ""}], "year": 1990, "venue": "AppI. Phys. Lett", "link": null}, "BIBREF19": {"title": "Blue light generation by frequency doubling of AIGaAs broad area amplifier emission", "authors": [{"first": "L", "middle": [], "last": "Goldberg", "suffix": ""}, {"first": "L", "middle": [], "last": "Busse", "suffix": ""}, {"first": "D", "middle": [], "last": "Mehuys", "suffix": ""}], "year": 1992, "venue": "Appl. Phys. Lett", "link": "119443279"}, "BIBREF20": {"title": "Potassium niobate optical parametric oscillator pumped by the secomd harmonic of a garnet laser", "authors": [{"first": "V", "middle": ["A"], "last": "", "suffix": ""}, {"first": "V", "middle": ["1"], "last": "Pryalkin", "suffix": ""}, {"first": "I", "middle": [], "last": "Kholodnykh", "suffix": ""}], "year": 1981, "venue": "Soy. J. Quantum Electron", "link": "123322399"}, "BIBREF21": {"title": "Nonlinear optical effects in KNbO3 crystals at AlxGai-As, dye, ruby, and Nd:YAG laser wavelengths", "authors": [{"first": "J. -C", "middle": [], "last": "Baumert", "suffix": ""}, {"first": "J", "middle": [], "last": "Hoffnagle", "suffix": ""}, {"first": "P", "middle": [], "last": "Gunter", "suffix": ""}], "year": 1984, "venue": "1984 European Conference on Optics, Optical Systems, and Applications", "link": null}, "BIBREF22": {"title": "Second-harmonic generation and degradation in critical phase-matched KNbO3 with diode pumped Q-switched Nd:YLF laser", "authors": [{"first": "W", "middle": [], "last": "Seelert", "suffix": ""}, {"first": "P", "middle": [], "last": "Kortz", "suffix": ""}, {"first": "D", "middle": [], "last": "Rytz", "suffix": ""}, {"first": "B", "middle": [], "last": "Zysset", "suffix": ""}, {"first": "D", "middle": [], "last": "Ellegehausen", "suffix": ""}, {"first": "G", "middle": [], "last": "Mizell", "suffix": ""}], "year": 1992, "venue": "Opt. Left", "link": null}, "BIBREF23": {"title": "High-efficiency high-power parametric oscillation in KNbO3", "authors": [{"first": "K", "middle": [], "last": "Kato", "suffix": ""}], "year": 1982, "venue": "IEEE J. Quantum Electron. QE", "link": null}}, "ref_entries": {}}
{"paper_id": "138410295", "_pdf_hash": "d41fc8107401cc19d723c8109736fe64b8d19ce0", "abstract": [{"section": "Abstract", "text": "Photon upconversion is used to facilitate the production of a solar fuel. This is done by collocating a triplet-triplet annihilation upconversion system in a microfluidic device with a molecular solar thermal energy storage system. Incoherent truncated white light is used to drive the reaction and the green part of the spectrum is upconverted to blue light, which in turn is absorbed by the solar fuel.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "", "text": "The inability to absorb sub-bandgap photons and energy relaxation to the bandgap level when absorbing high energy photons are unavoidable defects in solar energy conversion systems. The Shockley and Queisser limit sets a solar power conversion efficiency limitation on all single bandgap silicon photovoltaic devices.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "1 Similar limits also exist for organic photovoltaic devices as well as for molecular solar thermal systems.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "2,3 A generic approach to circumvent the Shockley and Queisser limit is photon upconversion. 4, 5 By transforming two low energy photons into one high energy photon, the solar spectrum is modi\ue103ed towards increased intensity in the high energy end of the spectrum. This modi\ue103cation is particularly relevant for energy technologies where high photon energy quanta are needed to drive energy conversion processes, such as photoinduced water splitting, 6 high bandgap solar cells and photoinduced chemical transformations such as molecular solar thermal systems (MOST). 7, 8 Photon upconversion has been around for some time, e.g. second harmonic generation, but it requires very intense coherent irradiation sources like pulsed lasers to give satisfactory quantum efficiencies. 9 However, by combining \ue104uorophores capable of performing triplet-triplet annihilation (TTA) with a triplet sensitizer, photon upconversion at relatively low photon densities has been achieved in solution, on nanoparticle surfaces, and in polymer and micellar matrices. [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] It should be noted that TTA photon upconversion as opposed to second harmonic generation does not require a coherent light source. Two recent publications have elegantly demonstrated the enhancement of solar energy production by TTA photon upconversion. 23, 24 Laser powered TTA photon upconversion was used to facilitate WO 3 catalyzed water splitting as well as for enhancing the efficiency of a hydrogenated amorphous silicon solar cell. This was carried out by co-locating a freeze-pumped cuvette containing the TTA photon upconversion material with the respective photo-reaction. Here, for the \ue103rst time, we demonstrate TTA photon upconversion facilitated production of a solar fuel using non-coherent truncated white light. This is achieved by using a micro\ue104uidic device having a large illuminated area (approximately 400 mm 2 ), and the ability of the TTA photon upconversion material to facilitate solar fuel production is demonstrated over several hours. A molecular solar thermal energy storage system was used as the solar fuel. This kind of molecular system stores the solar energy in chemical bonds and has been proposed as a solution to the intermittency issues with solar energy harvesting. 25 The molecular solar thermal system used in this study is a fulvalene diruthenium (FvRu 2 ) derivative (Fig. 1) .", "cite_spans": [], "ref_spans": [{"start": 2421, "end": 2429, "text": "(Fig. 1)", "ref_id": "FIGREF3"}]}, {"section": "", "text": "7 Upon exposure to light, it isomerizes to a high energy photoisomer, capable of long time energy storage and on-demand energy delivery. 26, 27 The lowest lying absorption band of FvRu 2 is centered close to 400 nm and tails into the visible region of the solar spectrum, whereas the high energy photoisomer does not absorb in the visible wavelength range at all, securing selective excitation of the low energy isomer. We will show that the absorption of the solar fuel is effectively extended into the 500-550 nm wavelength region by employing TTA photon upconversion.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "The upconversion system used consists of palladium(II)-octaethylporphyrin (PdOEP), which absorbs in the 500-550 nm region and 9,10-diphenylanthracene (DPA) which has a \ue104uo-rescence spectrum that spectrally matches the absorption spectrum of the solar fuel ( Fig. 1 ). This is a well-studied TTA photon upconversion system that has an external quantum upconversion efficiency exceeding 1% and it works as follows: [28] [29] [30] a\ue09der photoexcitation of the porphyrin, it quickly relaxes to the lowest lying triplet state with high quantum efficiency. ", "cite_spans": [], "ref_spans": [{"start": 258, "end": 264, "text": "Fig. 1", "ref_id": "FIGREF3"}]}, {"section": "", "text": "While in the triplet state, the porphyrin collides with and transfers its triplet energy to the anthracene. ", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Two anthracenes both in their triplet state then, upon collision, undergo triplet-triplet annihilation, in which one relaxes to the ground state and the other gains energy to an excited singlet state, capable of emitting one high energy photon.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "There is a possible shortcut to this high energy \ue104uorescence through back sensitization of the PdOEP singlet excited state. 31 Two mechanisms might be operative: non-radiative energy transfer (FRET) and radiative (trivial) energy transfer. The former is close to negligible at the PdOEP concentration used in this experiment (0.9 mM, see ESI \u2020) and the latter is minimized through the use of very short optical path lengths. Nevertheless, as can be seen in Fig. 1 the DPA \ue104uorescence spectrum is slightly distorted in the blue edge where it overlaps with the red edge of the porphyrin Soret band. This reabsorption of the upconverted light does not severely hamper the function of the device and has therefore not been considered quantitatively in the analysis.", "cite_spans": [], "ref_spans": [{"start": 457, "end": 463, "text": "Fig. 1", "ref_id": "FIGREF3"}]}, {"section": "", "text": "In order to use the upconverted photons from the PdOEP-DPA system to facilitate the energy conversion of the solar fuel a micro\ue104uidic device was constructed. The device functions as a \ue104ow reactor for continuous harvesting of solar energy, and is made up of two identical custom made micro\ue104uidic fused silica chips (Litcon). The chips contain a 60 mm deep and 3.5 mm wide winding channel, forming a total irradiated area of 400 mm 2 and an internal volume of 25 ml. The two glass chips are placed on top of each other with the solar fuel being pumped through the top one and the TTA photon upconversion \ue104uid \ue104owing through the lower chip (Fig. 2) . A syringe pump was used to control the \ue104ow speed of the solar fuel (dissolved in toluene-d 8 ), whereas the TTA photon upconversion system dissolved in toluene was, a\ue09der careful deaeration by Argon, \ue104owed through the chip by the aid of Journal of Materials Chemistry A Communication gravity. To ensure that Argon bubbling creates a sufficiently deaerated environment for the upconversion process to occur, a control experiment in a spectro\ue104uorometer was performed. A\ue09der Argon bubbling the upconversion \ue104uid was transferred by a similar tubing system to that used in the device to a cuvette, and the upconversion quantum yield was determined to be 0.5%, which is in good agreement with the reported value of 1%. 28 At moderate light intensities the upconversion quantum yield is dependent on both light intensity and concentration, meaning that the quantum yield will not be exactly the same in the device as in this control experiment. However, the control experiment shows that the deareating and transferring methods used are sufficiently sophisticated to allow the upconversion process to occur.", "cite_spans": [], "ref_spans": [{"start": 637, "end": 645, "text": "(Fig. 2)", "ref_id": "FIGREF4"}]}, {"section": "", "text": "In the experimental device setup, a 150 W metal-halide lamp was used to deliver white light having a color temperature of 4200 K (Osram Powerstar HQI-R). The irradiated device was immersed in a water bath (30 C) to keep it at a constant temperature throughout the course of the experiment. A\ue09der reaching the device, the light from the lamp \ue103rst passed through a glass \ue103lter (cut-on wavelength \u00bc 495 nm; Newport) which removed most of the high energy photons capable of direct excitation of the solar fuel. The truncated light then passed through the chip containing the solar fuel to reach the chip containing the TTA upconversion material, there being absorbed, upconverted, and reemitted to enhance the solar fuel production. In Fig. 3 the photochemical conversion of the low energy FvRu 2 isomer to the high energy photoisomer as a function of residence time in the \ue104ow reactor, in the presence and absence of TTA photon upconversion, is shown. At the very low conversions observed in this experiment the extent of reaction varies close to linearly with the residence time. The enhancement of the solar fuel production by the TTA upconversion system is 130%. This enhancement is due to the light in the 500-550 nm wavelength range, not being absorbed by the solar fuel but instead by PdOEP, upconverted and reemitted in the 400-500 nm wavelength range, which is the light that the solar fuel is capable of absorbing. In the \ue104ow reactor FvRu 2 is dissolved in toluene-d 8 , and the photochemical conversion is monitored by NMR without further sample preparation from the \ue104uid exiting the \ue104ow reactor. This requires an accumulated volume of 0.5 ml. Thus, each data point in Fig. 3 , showing the photochemical conversion as a function of residence time in the \ue104ow reactor, is the average result of 20 reactor volumes (which equals to 1.4-6.1 h depending on the \ue104ow speed). The data points are taken in random order and no fouling of the channels could be observed by the naked eye a\ue09der the complete dataset was acquired, showing, at least on a lab scale, the high stability of the system. A closer examination of Fig. 3 reveals that the data points having a longer residence time are slightly biased to lower photochemical conversion than those having a shorter residence time. This is true both in the presence and absence of TTA photon upconversion, indicating that this phenomenon is not related to the upconversion as such but rather to the stability of the photoisomer. The photoisomer is sensitive to molecular oxygen, and the longer residence time requires a longer storage time from photoconversion to analysis, during which some oxygen might have reacted with the photoproduct. From an application point of view this tendency of degradation by molecular oxygen should not be a major problem since this kind of solar fuel is intended to work in a closed cycle with no oxygen contact.", "cite_spans": [], "ref_spans": [{"start": 731, "end": 737, "text": "Fig. 3", "ref_id": "FIGREF6"}, {"start": 1675, "end": 1681, "text": "Fig. 3", "ref_id": "FIGREF6"}, {"start": 2113, "end": 2119, "text": "Fig. 3", "ref_id": "FIGREF6"}]}, {"section": "Conclusions", "text": "In summary, we have shown for the \ue103rst time that non-coherent light can be used to drive a TTA photon upconversion process which in turn is used to facilitate a solar energy harvesting reaction. This has been achieved by locating upconversion materials and a molecular solar thermal system on top of each other in a micro\ue104uidic device, working as a \ue104ow reactor, having an irradiated surface area of 400 mm 2 . The setup is stable in the sense that the solar fuel production scales with the residence time of the reactor, and that no fouling in the micro\ue104uidic channels, even a\ue09der 50 h of run time, could be observed. When considering practical applications, one limiting factor in the used FvRu 2 system is the quantum yield of photochemical conversion of 0.2% in toluene. For efficient and practical applications, new MOST systems with near unity quantum yield are preferred.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "3 We believe that employing TTA photon upconversion will become a general, straightforward and economically feasible method to supersede the Shockley and Queisser limit of solar light harvesting devices in the course of time. In this regard, the development of more efficient TTA-UC systems operating under natural solar irradiation conditions is highly desirable. ", "cite_spans": [], "ref_spans": []}, {"section": "Notes and references", "text": "", "cite_spans": [], "ref_spans": []}], "bib_entries": {}, "ref_entries": {"FIGREF0": {"text": "Chalmers University of Technology/Department of Chemical and Biological Engineering/Applied Chemistry, 41296 G\u00f6teborg, Sweden. E-mail: kasper. moth-poulsen@chalmers.se b Chalmers University of Technology/Department of Chemical and Biological Engineering/Physical Chemistry, 41296 G\u00f6teborg, Sweden \u2020 Electronic supplementary information (ESI) available: Experimental section, additional \ue103gures (negative of the photolithographic mask, experiment setup, and NMR spectra), and discussion on possible reabsorption of upconverted photons. See DOI: 10.1039/c3ta12002c Cite this: J. Mater. Chem. A, 2013, 1, 8521", "type": "figure"}, "FIGREF3": {"text": "Fig. 1 (a) The fulvalene diruthenium derivative (green/black; R \u00bc 1,1-dimethyltridecyl) used as a recyclable solar fuel and the TTA photon upconversion system based on the sensitizer PdOEP (red) and emitter DPA (blue). (b) Normalized absorption spectra of FvRu 2 (green/black) and PdOEP (red), fluorescence spectrum of DPA in the presence of PdOEP (blue), and transmission spectrum of the glass filter (grey).", "type": "figure"}, "FIGREF4": {"text": "Fig. 2 A schematic picture of the microfluidic flow reactor. The white light traverses a glass filter (cut-on wavelength \u00bc 495 nm) to reach the microfluidic glass chips. The first chip contains the solar fuel and in the second one the TTA photon upconversion fluid resides.", "type": "figure"}, "FIGREF5": {"text": "1 W. Shockley and H. J. Queisser, J. Appl. Phys., 1961, 32, 510- 519. 2 M. J. Y. Tayebjee, L. C. Hirst, N. J. Ekins-Daukes and T. W. Schmidt, J. Appl. Phys., 2010, 108, 124506-124512. 3 K. B\u00f6rjesson, A. Lennartson and K. Moth-Poulsen, ACS Sustainable Chem. Eng., 2013, 1, 585-590.", "type": "figure"}, "FIGREF6": {"text": "Fig. 3 Conversion efficiency (%) of photoisomerized FvRu 2 , in the presence (blue squares) and absence (red circles) of TTA photon upconversion, as a function of residence time in the microfluidic flow reactor.", "type": "figure"}}}
{"paper_id": "138410358", "_pdf_hash": "ab4ee7a6f10d387cf11cfe5529ccc2c4d503e019", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "An advanced high strength graphitized steel for machining and cold forging uses", "authors": [{"first": "T", "middle": [], "last": "Iwamoto", "suffix": ""}, {"first": "T", "middle": [], "last": "Hoshino", "suffix": ""}, {"first": "K", "middle": [], "last": "Amano", "suffix": ""}, {"first": "Y", "middle": [], "last": "Nakano", "suffix": ""}], "year": 1996, "venue": "2nd Internat. Symp. on Microalloyed Bar & Forging Steel", "link": null}, "BIBREF1": {"title": "On the mechanism of graphitization of high-carbon steel", "authors": [{"first": "N", "middle": [], "last": "Yamanaka", "suffix": ""}, {"first": "K", "middle": [], "last": "Kusaka", "suffix": ""}], "year": 1962, "venue": "Tetsu-to-Hagan\u00e9", "link": "138796119"}, "BIBREF2": {"title": "Graphite nucleation on boron nitride in 0.53%C Steel. Tetsuto-Hagan\u00e9", "authors": [{"first": "T", "middle": [], "last": "Iwamoto", "suffix": ""}, {"first": "H", "middle": [], "last": "Ota", "suffix": ""}, {"first": "T", "middle": [], "last": "Hoshino", "suffix": ""}, {"first": "K", "middle": [], "last": "Amano", "suffix": ""}, {"first": "J", "middle": [], "last": "Shimomura", "suffix": ""}], "year": 1998, "venue": "", "link": null}, "BIBREF3": {"title": "Effects of boron and nitrogen on graphitization and hardenability in 0.53%C steel", "authors": [{"first": "T", "middle": [], "last": "Iwamoto", "suffix": ""}, {"first": "T", "middle": [], "last": "Hoshino", "suffix": ""}, {"first": "A", "middle": [], "last": "Matsuzaki", "suffix": ""}, {"first": "K", "middle": [], "last": "Amano", "suffix": ""}], "year": 2002, "venue": "ISIJ Int", "link": "137167061"}, "BIBREF4": {"title": "96th and 97th Nishiyama Memorial Seminar", "authors": [{"first": "T", "middle": [], "last": "Ohno", "suffix": ""}], "year": 1984, "venue": "", "link": null}, "BIBREF5": {"title": "Free cutting steel containing BN inclusions without lead addition", "authors": [{"first": "T", "middle": [], "last": "Murakami", "suffix": ""}, {"first": "T", "middle": [], "last": "Shiraga", "suffix": ""}], "year": 2002, "venue": "", "link": null}, "BIBREF6": {"title": "Correlation of machinability with inclusion characterisitics in resulphurized Bessemer steels", "authors": [{"first": "L", "middle": ["H"], "last": "Van Vlack", "suffix": ""}], "year": 1953, "venue": "Trans. ASM", "link": null}, "BIBREF7": {"title": "Morphology control of MnS in steel during solidifi cation", "authors": [{"first": "K", "middle": [], "last": "Oikawa", "suffix": ""}, {"first": "H", "middle": [], "last": "Ohtani", "suffix": ""}, {"first": "K", "middle": [], "last": "Ishida", "suffix": ""}, {"first": "T", "middle": [], "last": "Nishizawa", "suffix": ""}], "year": 1994, "venue": "Tetsu-to-Hagan\u00e9", "link": null}, "BIBREF8": {"title": "Thermodynamic database for Fe-S base multi-component alloy", "authors": [{"first": "K", "middle": [], "last": "Oikawa", "suffix": ""}, {"first": "H", "middle": [], "last": "Mitsui", "suffix": ""}, {"first": "K", "middle": [], "last": "Ishida", "suffix": ""}], "year": 2003, "venue": "CAMP-ISIJ", "link": null}, "BIBREF9": {"title": "Materials control through bar and wire rod rolling", "authors": [{"first": "T", "middle": [], "last": "Shiraga", "suffix": ""}], "year": 1999, "venue": "CAMP-ISIJ", "link": null}}, "ref_entries": {}}
{"paper_id": "138411647", "_pdf_hash": "dab686d098d9668e8da995549e2f6b2dda79097c", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "138411734", "_pdf_hash": "00e896a6ca7ec7b423b448d49335444100e320e2", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Micromechanical Interpretation of Fracture Toughness of Particulate-Filled Thermoplastics", "authors": [{"first": "J", "middle": [], "last": "Bohse", "suffix": ""}, {"first": "S", "middle": [], "last": "Grellmann", "suffix": ""}, {"first": "S", "middle": [], "last": "Seidler", "suffix": ""}], "year": 1991, "venue": "J. Mat. Sci", "link": "189836130"}, "BIBREF1": {"title": "Toughening of Polypropylene with Calcium Carbonate Particles", "authors": [{"first": "W", "middle": ["C J"], "last": "Zuiderduin", "suffix": ""}, {"first": "C", "middle": [], "last": "Westzaan", "suffix": ""}, {"first": "H", "middle": [], "last": "Huetink", "suffix": ""}, {"first": "R", "middle": ["J"], "last": "Gaymans", "suffix": ""}], "year": 2001, "venue": "SPE ANTEC", "link": "135912381"}, "BIBREF2": {"title": "Novel Mechanisms of Toughening Semi-Crystalline Polymers", "authors": [{"first": "A", "middle": ["S"], "last": "Argon", "suffix": ""}, {"first": "Z", "middle": [], "last": "Bartczak", "suffix": ""}, {"first": "R", "middle": ["E"], "last": "Cohen", "suffix": ""}, {"first": "O", "middle": ["K"], "last": "Muratoglu", "suffix": ""}], "year": 2000, "venue": "Toughening of Plastics: Testing Methods and Advances in Modeling and Experiments", "link": "138232069"}, "BIBREF3": {"title": "Toughness mechanism in semi-crystalline polymer blends: II. High-density polyethylene toughened with calcium carbonate filler particles", "authors": [{"first": "Z", "middle": [], "last": "Bartczak", "suffix": ""}, {"first": "A", "middle": ["S"], "last": "Argon", "suffix": ""}, {"first": "R", "middle": ["E"], "last": "Cohen", "suffix": ""}, {"first": "M", "middle": [], "last": "Weinberg", "suffix": ""}], "year": 1999, "venue": "Polymer", "link": "135894357"}, "BIBREF4": {"title": "The morphology and orientation of polyethylene in films of sub-micron thickness crystallized in contact with calcite and rubber substrates", "authors": [{"first": "Z", "middle": [], "last": "Bartczak", "suffix": ""}, {"first": "A", "middle": ["S"], "last": "Argon", "suffix": ""}, {"first": "R", "middle": ["E"], "last": "Cohen", "suffix": ""}, {"first": "T", "middle": [], "last": "Kowalewski", "suffix": ""}], "year": 1999, "venue": "Polymer", "link": "136030237"}, "BIBREF5": {"title": "Polyethylene toughened by rigid inorganic particles", "authors": [{"first": "Q", "middle": [], "last": "Fu", "suffix": ""}, {"first": "G", "middle": [], "last": "Wang", "suffix": ""}], "year": 1992, "venue": "Polym. Eng. Sci", "link": "135711452"}, "BIBREF7": {"title": "Effect of morphology on brittleductile transition of HDPE/CaCO 3 blends", "authors": [{"first": "Q", "middle": [], "last": "Fu", "suffix": ""}, {"first": "G", "middle": [], "last": "Wang", "suffix": ""}], "year": 1985, "venue": "J. Appl. Polym. Sci", "link": null}, "BIBREF8": {"title": "Polyethylene toughened by CaCO 3 particles-percolation model of brittle -ductile transition in HDPE/CaCO 3 blends", "authors": [{"first": "Q", "middle": [], "last": "Fu", "suffix": ""}, {"first": "G", "middle": [], "last": "Wang", "suffix": ""}], "year": 1993, "venue": "Polym. Int", "link": "136868542"}, "BIBREF10": {"title": "Rigid Particle Toughening of Aliphatic Polyketone Polymer", "authors": [{"first": "W", "middle": ["C J"], "last": "Zuiderduin", "suffix": ""}, {"first": "C", "middle": [], "last": "Westzaan", "suffix": ""}, {"first": "H", "middle": [], "last": "Huetink", "suffix": ""}, {"first": "R", "middle": ["J"], "last": "Gaymans", "suffix": ""}], "year": 2001, "venue": "SPE ANTEC", "link": "136665851"}, "BIBREF11": {"title": "The Performance of Ultrafine Talc in Rigid PVC", "authors": [{"first": "H", "middle": ["E"], "last": "Wiebking", "suffix": ""}], "year": 1996, "venue": "Journal of Vinyl & Additive Technology", "link": "137585593"}, "BIBREF12": {"title": "Plastic Performance: Benefits of PCC as a PVC Additive", "authors": [{"first": "D", "middle": ["W"], "last": "Cornwell", "suffix": ""}], "year": 2001, "venue": "Industrial Minerals", "link": null}}, "ref_entries": {}}
{"paper_id": "138411863", "_pdf_hash": "795703e5de302f61c99bc587ca7c20be80420030", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "138414337", "_pdf_hash": "b53b66370e877dd29e3b767b569e527919d54d86", "abstract": [], "body_text": [{"section": "UNDER PAINT FILM USING EXPOSURE SAMPLE", "text": "Tomohiro TANAKA and Tetsutaro KAWAKAMI ", "cite_spans": [], "ref_spans": []}], "bib_entries": {}, "ref_entries": {"TABREF0": {"text": "Key Words: Paint film, Degradation, Exposure sample, Nondestructive evaluation method , Coating thin plate", "type": "table"}}}
{"paper_id": "138415670", "_pdf_hash": "76160decf42cedfe89891df90c372c77cdfa4ddb", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Effect of rubber composition on foaming and properties of EVA/NR/PP thermoplastic vulcanisates (TPVs)", "authors": [{"first": "N", "middle": [], "last": "Lopattananon", "suffix": ""}, {"first": "N", "middle": [], "last": "Wangpradit", "suffix": ""}, {"first": "C", "middle": [], "last": "Nakason", "suffix": ""}, {"first": "A", "middle": [], "last": "Kaesaman", "suffix": ""}], "year": 2014, "venue": "J. Rubber Res", "link": "150376537"}, "BIBREF1": {"title": "Physical properties of ethylene vinyl acetate copolymer (EVA)/natural rubber (NR) blend based foam", "authors": [{"first": "M", "middle": ["S"], "last": "Kim", "suffix": ""}, {"first": "C", "middle": ["C"], "last": "Park", "suffix": ""}, {"first": "S", "middle": ["R"], "last": "Chowdhury", "suffix": ""}, {"first": "G", "middle": ["H"], "last": "Kim", "suffix": ""}], "year": 2004, "venue": "J. Appl. Polym. Sci", "link": "135780991"}, "BIBREF2": {"title": "Effect of compatibilizer and silane coupling agent on physical properties of ethylene vinyl acetate copolymer/ethylene-1-butene copolymer/clay nanocomposite foams", "authors": [{"first": "D", "middle": ["W"], "last": "Kim", "suffix": ""}, {"first": "K", "middle": ["W"], "last": "Park", "suffix": ""}, {"first": "S", "middle": ["R"], "last": "Chowdhury", "suffix": ""}, {"first": "G", "middle": ["H"], "last": "Kim", "suffix": ""}], "year": 2006, "venue": "J. Appl. Polym. Sci", "link": "137362982"}, "BIBREF3": {"title": "Effect of clay dispersion on the cell structure of LDPE/clay nanocomposite foams", "authors": [{"first": "S", "middle": ["M"], "last": "Seraji", "suffix": ""}, {"first": "M", "middle": ["K"], "last": "Razavi Aghjeh", "suffix": ""}, {"first": "M", "middle": [], "last": "Davari", "suffix": ""}, {"first": "M", "middle": [], "last": "Hosseini", "suffix": ""}, {"first": "S", "middle": ["H"], "last": "Khelgati", "suffix": ""}], "year": 2011, "venue": "Polym. Compos", "link": "135792379"}, "BIBREF4": {"title": "Effect of dispersion state of organoclay on cellular foam structure and mechanical properties of ethylene vinyl acetate copolymer/ethylene-1-butene copolymer/organoclay nanocomposite foams", "authors": [{"first": "K", "middle": ["W"], "last": "Park", "suffix": ""}, {"first": "S", "middle": ["R"], "last": "Chowdhury", "suffix": ""}, {"first": "C", "middle": ["C"], "last": "Park", "suffix": ""}, {"first": "G", "middle": ["H"], "last": "Kim", "suffix": ""}], "year": 2007, "venue": "J. Appl. Polym. Sci", "link": null}, "BIBREF5": {"title": "The role of nanofillers on (Natural Rubber)/(Ethylene VinylAcetate)/clay nanocomposite in blending and foaming", "authors": [{"first": "N", "middle": [], "last": "Lopattananon", "suffix": ""}, {"first": "J", "middle": [], "last": "Julyanon", "suffix": ""}, {"first": "A", "middle": [], "last": "Masa", "suffix": ""}, {"first": "A", "middle": [], "last": "Kaesaman", "suffix": ""}, {"first": "C", "middle": [], "last": "Thongpin", "suffix": ""}, {"first": "T", "middle": [], "last": "Sakai", "suffix": ""}], "year": 2014, "venue": "J. Vinyl Addit. Technol. DOI", "link": "135969952"}, "BIBREF6": {"title": "A process for making microcellular thermoplastic parts", "authors": [{"first": "V", "middle": [], "last": "Kumar", "suffix": ""}, {"first": "N", "middle": ["P"], "last": "Suh", "suffix": ""}], "year": 1990, "venue": "Polym. Eng. Sci", "link": "137214197"}}, "ref_entries": {}}
{"paper_id": "138417760", "_pdf_hash": "4b8bf929dd9163aa63502efaedbe37212a161b72", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Influence de la torsi&oacute;n sur la longueur d'un fil&eacute;s, L'Industrie Textile", "authors": [{"first": "M", "middle": ["C"], "last": "Besset", "suffix": ""}], "year": 1948, "venue": "", "link": null}, "BIBREF1": {"title": "Consideraciones analiticas sobre la torsi&oacute;n y consecuencias inmediatas que se observan, Ingenieria Textil", "authors": [{"first": "T", "middle": ["E"], "last": "L&amp;oacute;Pez-Amo", "suffix": ""}, {"first": "", "middle": [], "last": "Federico", "suffix": ""}], "year": 1945, "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "138418300", "_pdf_hash": "13b50aafa31cf86e791a3b1980e6f49bd6a44592", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "138418447", "_pdf_hash": "9fa556c9588dd2a386a227e0b48d53b9a23c3374", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Investigations of Physical and Rheological Properties of Aged Rubberised Bitumen", "authors": [{"first": "Asim", "middle": [], "last": "Ali", "suffix": ""}, {"first": "", "middle": [], "last": "Hassan", "suffix": ""}, {"first": "", "middle": [], "last": "Mashaan", "suffix": ""}, {"first": "S", "middle": [], "last": "Nuha", "suffix": ""}, {"first": "Mohamed", "middle": [], "last": "Karim", "suffix": ""}, {"first": "", "middle": [], "last": "Rehan", "suffix": ""}], "year": 2013, "venue": "Advances in Materials Science and Engineering", "link": "53401233"}, "BIBREF1": {"title": "Improving Asphalt Resistance to Aging by Using Waste Tyre Rubber", "authors": [{"first": "Asim", "middle": [], "last": "Ali", "suffix": ""}, {"first": "S", "middle": [], "last": "Hassan", "suffix": ""}, {"first": "", "middle": [], "last": "Mashaan", "suffix": ""}, {"first": "", "middle": [], "last": "Nuha", "suffix": ""}, {"first": "Mohamed", "middle": [], "last": "Karim", "suffix": ""}, {"first": "", "middle": [], "last": "Rehan", "suffix": ""}], "year": 2012, "venue": "International Conference on Innovation and Technology for Sustainable Built Environment", "link": null}, "BIBREF2": {"title": "The Asphalt Paving Industry-A Global Perspective", "authors": [], "year": 2011, "venue": "", "link": null}, "BIBREF3": {"title": "Validation of a Particle Sze determination Method for Nano-particles by Dynamic Lazer Light Scattering", "authors": [{"first": "J", "middle": [], "last": "Brunotte", "suffix": ""}, {"first": "M", "middle": [], "last": "Darter", "suffix": ""}, {"first": "J", "middle": [], "last": "Vaughn", "suffix": ""}, {"first": "V", "middle": [], "last": "Kulkarni", "suffix": ""}], "year": 2010, "venue": "", "link": null}, "BIBREF4": {"title": "Performance and Durability of Bituminous Materials", "authors": [{"first": "J", "middle": ["G"], "last": "Cabrera", "suffix": ""}, {"first": "J", "middle": ["R"], "last": "Dixon", "suffix": ""}], "year": 1996, "venue": "", "link": "139828772"}, "BIBREF5": {"title": "Principles of Transportation Engineering", "authors": [{"first": "Partha", "middle": [], "last": "Chakroborty", "suffix": ""}, {"first": "Animesh", "middle": [], "last": "Das", "suffix": ""}], "year": 2005, "venue": "", "link": null}, "BIBREF6": {"title": "Characterization of Activated Carbon of Coconut Shell, Rice Husk and Karanja Oil Cake. (Bachelor of Technology", "authors": [{"first": "Smrutirekha", "middle": [], "last": "Das", "suffix": ""}], "year": 2014, "venue": "", "link": null}, "BIBREF7": {"title": "Construction Material: Their nature and Behaviour", "authors": [{"first": "Peter", "middle": [], "last": "Domone", "suffix": ""}, {"first": "John", "middle": [], "last": "Illston", "suffix": ""}], "year": 2010, "venue": "", "link": null}, "BIBREF8": {"title": "Dynamic Light Scattering Common Term defined", "authors": [], "year": 2011, "venue": "", "link": null}, "BIBREF10": {"title": "Softening Point and Penetration Index of Bitumen from parts of Southwestern Nigeria", "authors": [], "year": "", "venue": "NAFTA", "link": "107399911"}, "BIBREF11": {"title": "Engen penetration Grade Bitumens", "authors": [{"first": "", "middle": [], "last": "Engen", "suffix": ""}], "year": 2009, "venue": "", "link": null}, "BIBREF12": {"title": "Aging Properties and Mechanism og the Modified Asphalt by Packig Waste Polyethylene and Waste Rubber Powder", "authors": [{"first": "Changqing", "middle": [], "last": "Fanga", "suffix": ""}, {"first": "", "middle": [], "last": "Wua", "suffix": ""}, {"first": "", "middle": [], "last": "Caixia", "suffix": ""}, {"first": "", "middle": [], "last": "Yua", "suffix": ""}, {"first": "", "middle": [], "last": "Truien", "suffix": ""}, {"first": "", "middle": [], "last": "Zhangb", "suffix": ""}, {"first": "", "middle": [], "last": "Zengping", "suffix": ""}, {"first": "Min", "middle": [], "last": "Zhanga", "suffix": ""}, {"first": "", "middle": [], "last": "Zhoua", "suffix": ""}, {"first": "", "middle": [], "last": "Shisheng", "suffix": ""}], "year": 2013, "venue": "Polymer Advance Technologies", "link": null}, "BIBREF13": {"title": "The Canadian Encyclopedia", "authors": [{"first": "G", "middle": ["R"], "last": "Gray", "suffix": ""}, {"first": "R", "middle": [], "last": "Luhning", "suffix": ""}], "year": 2013, "venue": "", "link": null}, "BIBREF14": {"title": "Asphalt in Road Construction", "authors": [{"first": "Robert", "middle": ["N"], "last": "Hunter", "suffix": ""}], "year": 2000, "venue": "", "link": null}, "BIBREF15": {"title": "Viscosity Grading. Retrieved", "authors": [{"first": "Pavement", "middle": [], "last": "Interactive", "suffix": ""}], "year": 2007, "venue": "", "link": null}, "BIBREF16": {"title": "Determining the Rheological Properties of Neat and Rubber Modified Soft Bitumen", "authors": [{"first": "Andreas", "middle": [], "last": "Kjosavik", "suffix": ""}, {"first": "", "middle": [], "last": "Meling", "suffix": ""}], "year": 2013, "venue": "", "link": "135813721"}, "BIBREF17": {"title": "A Study on the Performance of Crumb Rubber Modified Bitumen by Varying the Sizes of Crumb Rubber", "authors": [{"first": "Nabin", "middle": [], "last": "Magar", "suffix": ""}, {"first": "", "middle": [], "last": "Rana", "suffix": ""}], "year": 2014, "venue": "International Journal of Engineering Trends and Technology (IJETT)", "link": null}, "BIBREF18": {"title": "Properties of rubberised bitumen binder and its effect on the bituminous mix", "authors": [{"first": "A", "middle": [], "last": "Mahrez", "suffix": ""}], "year": 1999, "venue": "", "link": null}, "BIBREF19": {"title": "Effect of crumb rubber concentration on the physical and rheological properties of rubberised bitumen binders", "authors": [{"first": "Nuha", "middle": ["S"], "last": "Mashaan", "suffix": ""}, {"first": "", "middle": [], "last": "Ali", "suffix": ""}, {"first": "H", "middle": [], "last": "Asim", "suffix": ""}, {"first": "Mohamed", "middle": [], "last": "Karim", "suffix": ""}, {"first": "", "middle": [], "last": "Rehan", "suffix": ""}, {"first": "", "middle": [], "last": "Abdelaziz", "suffix": ""}, {"first": "", "middle": [], "last": "Mahrez", "suffix": ""}], "year": 2011, "venue": "International Journal of the Physical Sciences", "link": "11686219"}, "BIBREF21": {"title": "Polymer Modified Bitumen: Properties and Characterisation", "authors": [{"first": "Tony", "middle": [], "last": "Mcnally", "suffix": ""}], "year": 2011, "venue": "", "link": "135617981"}, "BIBREF22": {"title": "Highway Engineering: desktop publisher", "authors": [{"first": "", "middle": [], "last": "Mohd Rosli Hainin", "suffix": ""}, {"first": "Che", "middle": [], "last": "Ismail", "suffix": ""}, {"first": "", "middle": [], "last": "Ros", "suffix": ""}, {"first": "", "middle": [], "last": "Yaacob", "suffix": ""}, {"first": "", "middle": [], "last": "Haryati", "suffix": ""}], "year": 2014, "venue": "", "link": null}, "BIBREF23": {"title": "Evaluation of Palm Oil Fuel Ash as Mineral Filler in Hot Mix Asphalt. (BEng (Hons) in Civil Engineering)", "authors": [{"first": "Juzer", "middle": [], "last": "Moosajee", "suffix": ""}, {"first": "", "middle": [], "last": "Naushad", "suffix": ""}], "year": 2011, "venue": "", "link": null}, "BIBREF24": {"title": "Experimental Study on Partial Replacement of Cement with Coconut Shell Ash in Concrete", "authors": [{"first": "Vignesh", "middle": [], "last": "Nagarajan", "suffix": ""}, {"first": "", "middle": [], "last": "Kumar", "suffix": ""}, {"first": "S", "middle": [], "last": "Devi", "suffix": ""}, {"first": "", "middle": [], "last": "Aruna", "suffix": ""}, {"first": "S", "middle": ["P"], "last": "Manohari", "suffix": ""}, {"first": "M", "middle": [], "last": "Santha", "suffix": ""}, {"first": "", "middle": [], "last": "Maria", "suffix": ""}], "year": 2014, "venue": "International Journal of Science and Research (IJSR)", "link": null}, "BIBREF25": {"title": "Preparation and Characterization of Activated Carbon Made From Palm-Kernel Shell, Coconut Shell, Groundnut Shell and Obeche Wood (Investigation of Apparent Density, Total Ash Content, Moisture Content, Particle Size Distribution Parameters", "authors": [{"first": "D", "middle": ["N"], "last": "Olowoyo", "suffix": ""}, {"first": "E", "middle": ["E"], "last": "Orere", "suffix": ""}], "year": 2012, "venue": "International Journal of Research in Chemistry and Environment", "link": null}, "BIBREF26": {"title": "The Shell Bitumen Handbook", "authors": [{"first": "John", "middle": [], "last": "Read", "suffix": ""}, {"first": "David", "middle": [], "last": "Whiteoak", "suffix": ""}], "year": 2003, "venue": "", "link": "137630183"}, "BIBREF27": {"title": "Experimental Analysis of the Use of Coconut Shell as Coarse Aggregate", "authors": [{"first": "B", "middle": [], "last": "Reddy", "suffix": ""}, {"first": "", "middle": [], "last": "Damodhara", "suffix": ""}, {"first": "S", "middle": [], "last": "Jyothy", "suffix": ""}, {"first": "", "middle": [], "last": "Aruna", "suffix": ""}, {"first": "", "middle": [], "last": "Shaik", "suffix": ""}, {"first": "", "middle": [], "last": "Fawaz", "suffix": ""}], "year": 2014, "venue": "IOSR Journal of Mechanical and Civil Engineering (IOSR-JMCE)", "link": null}, "BIBREF28": {"title": "Effect of Rubber Waste on Hot Mix Asphalt Properties", "authors": [{"first": "Nurfazilah", "middle": [], "last": "Salleh", "suffix": ""}, {"first": "", "middle": [], "last": "Mat", "suffix": ""}], "year": 2010, "venue": "", "link": null}, "BIBREF29": {"title": "Effect of Elastomeric Base Waste on Hot Mix Asphalt", "authors": [{"first": "Chua", "middle": [], "last": "Szu", "suffix": ""}, {"first": "", "middle": [], "last": "Sy", "suffix": ""}], "year": 2008, "venue": "", "link": null}, "BIBREF30": {"title": "Construction Cost of Highways in Malaysia", "authors": [{"first": "Transport", "middle": [], "last": "Malaysia", "suffix": ""}], "year": 2014, "venue": "", "link": null}, "BIBREF31": {"title": "Chemistry for Engineers", "authors": [{"first": "Teh", "middle": [], "last": "Yen", "suffix": ""}, {"first": "", "middle": [], "last": "Fu", "suffix": ""}], "year": 2008, "venue": "", "link": "92900844"}, "BIBREF32": {"title": "Asphaltenes and Asphalts", "authors": [{"first": "Teh", "middle": [], "last": "Yen", "suffix": ""}, {"first": "", "middle": [], "last": "Fu", "suffix": ""}, {"first": "G", "middle": ["V"], "last": "Chilingarian", "suffix": ""}], "year": 2000, "venue": "", "link": "92882641"}, "BIBREF33": {"title": "Polymer modification of bitumen: Advances and challenges", "authors": [{"first": "Jiqing", "middle": [], "last": "Zhu", "suffix": ""}, {"first": "", "middle": [], "last": "Birgisson", "suffix": ""}, {"first": "", "middle": [], "last": "Bj\u00f6rn", "suffix": ""}, {"first": "Niki", "middle": [], "last": "Kringos", "suffix": ""}], "year": 2014, "venue": "European Polymer Journal", "link": "53545463"}}, "ref_entries": {}}
{"paper_id": "138418611", "_pdf_hash": "940a70432e731154ae78b941e9c0800381fdba58", "abstract": [{"section": "Abstract", "text": "This investigation has been carried out to study on preparation, thermal conductivity and dielectric strength of Ag-WO 3 hybrid nanofluid while the base fluid was transformer oil. The reasons of selecting silver and WO 3 as nanoparticles have been completely discussed. Applied nanofluids have been prepared by a one-step method known as Electrical Explosion of Wire (E.E.W). Measuring zeta potential of utilized hybrid nanofluids in three different weight fractions of 1%, 2% and 4% has been experimentally carried out. Thermal conductivity of applied nanofluids in temperature range of 40-100\u00b0C has been measured by a KD2 pro thermal properties analyzer. The results showed that thermal conductivity of applied hybrid nanofluids increased by 41% in higher weight fraction and 100\u00b0C. Finally, it has been observed that electrical conductivity of hybrid nanofluids decreased to 35 kV in 4% wt. \u00d3 2016 Faculty of Engineering, Alexandria University. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Suspending nano sized particles to conventional base fluids such as water, ethylene glycol and oil which is known as nanofluid, has been studied over to the two past decades. Since the inventing nanofluid by Choi [1] in Argonne National Laboratory (ANL) and its development by the other pioneers [2] [3] [4] [5] [6] , so many studies have been carried out to evaluate the thermo-physical properties and thermal characteristics of arious nanofluids. For example, Syam Sundar et al. [7] studied the mixture of ethylene glycol and water based Al 2 O 3 and CuO nanofluids. They reported that, the thermal conductivity of Al 2 O 3 and CuO nanofluids increased by rising the working temperature and nanoparticle concentration. They also reported that CuO nanoparticles have a better performance in enhancing thermal conductivity rather than Al 2 O 3 in the same volume fraction and temperature. Aberoumand et al. [8] studied Ag/oil nanofluids experimentally. They observed enhancements up to 35% for thermal conductivity. They also released the results of their experiments on viscosity and reported that increasing in the nanoparticles concentration can enhance the viscosity of nanofluid. Fakoor Pakdaman et al. [9] carried out an experimental work on thermo-physical characteristics of MWCNT based heat transfer oil nanofluids in weight fractions of 0.1%, 0.2% and 0.4% and they reported that the higher enhancement of thermal conductivity is 15% at 70\u00b0C. The maximum viscosity enhancement of their utilized nanofluids has been reported to be around 27%.", "cite_spans": [{"start": 213, "end": 216, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 296, "end": 299, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 300, "end": 303, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 304, "end": 307, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 308, "end": 311, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 312, "end": 315, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 481, "end": 484, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 907, "end": 910, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 1208, "end": 1211, "text": "[9]", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "Introduction", "text": "Besides, studying on heat transfer characteristics of nanofluids has been attracting the researchers of this field. The nanofluid capability of enhancing the convective heat transfer coefficient and Nusselt number has made the nanofluids as an interesting and potential fluid to work on. Some of the published papers have been reviewed here:", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "Abbasian et al. [10] conducted an experiment on Ag/ oil nanofluid. They applied their nanofluid in an annular tube with a constant heat flux condition of 204 W to study the performance of the nanofluid in convective heat transfer improvement. The impact of Ag/oil nanofluid on the forced and free convective heat transfer in curved tubes is investigated in [11] . They reported an average of enhancement in the convective heat transfer coefficient and Nusselt number in the condition of mixed convection heat transfer. In addition, Cu/ oil nanofluid has been studied in annular tubes in order to study the forced convective heat transfer in a constant thermal flux rate boundary condition by Jafarimoghaddam et al. [12] . Based on their study, Cu/ oil nanofluid does not have a substantial advantage than Ag/ oil nanofluid in convective heat transfer and even the Nusselt number.", "cite_spans": [{"start": 16, "end": 20, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 357, "end": 361, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 715, "end": 719, "text": "[12]", "ref_id": "BIBREF11"}], "ref_spans": []}, {"section": "Introduction", "text": "In the very recent decade, researchers have been attracted to the hybrid nanofluids because of the impact of each material type of nanoparticles on the thermal properties of nanofluids individually. H. Hemmat Esfe et al. [13] studied rheological properties of Ag-MgO water hybrid nanofluids to achieve a better thermal conductivity, chemical stability and physical strength than individual nanofluids. They also proposed two correlations to predict thermal conductivity and viscosity of their applied nanofluids. Esfe et al. [14] reported the results of their investigation on thermal conductivity of Cu/TiO 2 -water/EG hybrid nanofluids and a model that has been generated from neural network. They reported an enhancement of about 40% in thermal conductivity of their hybrid nanofluid in the higher weight fraction.Botha et al. [15] studied physicochemical properties of Ag-Silica/ transformer oil nanofluids. An enhancement in thermal conductivity of 15% was observed in their study when 0.60 wt.% silver was supported on 0.07 wt.% silica. They also reported that the viscosity of hybrid nanofluid was lower than individual nanofluids. Afrand [16] carried out an experiment study on the thermal conductivity of MgO-MWCNT hybrid nanofluid based Ethylene Glycol and reported a maximum enhancement of 21.3%. Afrand et al. [17] [18] [19] [20] [21] [22] [23] recently published several empirical studies on the properties of hybrid nanofluids. They almost released their results with an enhancement in thermo-physical properties of their utilized nanofluids.", "cite_spans": [{"start": 221, "end": 225, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 525, "end": 529, "text": "[14]", "ref_id": "BIBREF13"}, {"start": 830, "end": 834, "text": "[15]", "ref_id": "BIBREF14"}, {"start": 1146, "end": 1150, "text": "[16]", "ref_id": "BIBREF15"}, {"start": 1322, "end": 1326, "text": "[17]", "ref_id": "BIBREF16"}, {"start": 1327, "end": 1331, "text": "[18]", "ref_id": "BIBREF17"}, {"start": 1332, "end": 1336, "text": "[19]", "ref_id": "BIBREF18"}, {"start": 1337, "end": 1341, "text": "[20]", "ref_id": "BIBREF19"}, {"start": 1342, "end": 1346, "text": "[21]", "ref_id": "BIBREF20"}, {"start": 1347, "end": 1351, "text": "[22]", "ref_id": "BIBREF21"}, {"start": 1352, "end": 1356, "text": "[23]", "ref_id": "BIBREF22"}], "ref_spans": []}, {"section": "Introduction", "text": "The main aims of this study were to measure thermal conductivity and dielectric strength of WO 3 -Ag/transformer oil hybrid nanofluids. In synthesis of the applied hybrid nanofluids, Electrical Explosion of Wire (E.E.W) as a novel one-step method has been implemented and the stability of hybrid nanofluids was measured due to measuring zeta potential. E.E.W has been used for preparing Ag/ oil and Cu/ Ethylene Glycol by Aberoumand et al. [8] , Jafarimoghaddam et al. [24] and Abbasian Arani et al. [10] as a potential one-step method for preparing nanofluids. Transformer oil because of its high applications in industries which need high heat transfer rate, and the lack of investigation of it in the literature, was used as base fluid of this study. WO 3 , because of its capacity in dielectric strength and silver, due to the high capability in thermal conductivity have been selected to be suspended in the base fluid.", "cite_spans": [{"start": 440, "end": 443, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 469, "end": 473, "text": "[24]", "ref_id": "BIBREF23"}, {"start": 500, "end": 504, "text": "[10]", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "Nanofluid preparation", "text": "For preparing utilized hybrid nanofluid, first of all, WO 3 nanoparticles with purity of 99.9% and maximum particle diameter of 60 nm were bought from PNF nano technology Co. These nanoparticles were dispersed in transformer oil via a novel one-step method known as Electrical Explosion of Wire (E.E.W) which has been described in detail below. Then, produced WO 3 /transformer oil nanofluid was used as the base fluid for suspending Ag nanoparticles with E.E.W again, to produce Ag-WO 3 / -transformer oil hybrid nanofluids.", "cite_spans": [], "ref_spans": []}, {"section": "W method", "text": "The Electrical Explosion Wire (E.E.W) that has been known as a one-step method was applied to prepare utilized nanofluids. As a simple explanation on the method, considering Fig. 1 , the nanofluid will be produced via an explosion in container of base fluid and thin metal wire. High current and electric voltage are the main operators of the explosion. The operating device is known as PNC1K which is shown in Fig. 1 . In fact, nanoparticles and nanofluid production are made simultaneously in the PNC1K [25] [26] [27] . The main operating conditions and input and output characteristics are summarized in Table 1 .", "cite_spans": [{"start": 505, "end": 509, "text": "[25]", "ref_id": "BIBREF24"}, {"start": 510, "end": 514, "text": "[26]", "ref_id": "BIBREF25"}, {"start": 515, "end": 519, "text": "[27]", "ref_id": "BIBREF26"}], "ref_spans": [{"start": 174, "end": 180, "text": "Fig. 1", "ref_id": "FIGREF0"}, {"start": 411, "end": 417, "text": "Fig. 1", "ref_id": "FIGREF0"}, {"start": 607, "end": 614, "text": "Table 1", "ref_id": "TABREF0"}]}, {"section": "W method", "text": "One of the best advantages of EEW is its capability of producing nanoparticle and of course nanofluid from any material that can make a thin wire from it.", "cite_spans": [], "ref_spans": []}, {"section": "Stability", "text": "Zeta potential measurement as one of the ways of evaluating the stability of nanofluids has been applied in this work. Assessing the stability by the zeta potential index is related to the electrostatic repulsion forces between the nanoparticles. When the repulsion is high, it can be concluded that the collisions between nanoparticles will be low. So, the nanofluid can be classified as a stable one. Nanofluid with a measured zeta potential greater than 30 mV is generally known as stable type [28, 29] . Moreover, zeta potential lower than 20 mV indicates the poor stability of nanofluids [30] . Zeta potential of utilized nanofluids in three weight concentrations of 1%, 2% and 4% at two different temperatures of 313 K and 373 K was measured by a Zetasizer Nano ZS made by Malvern, Britain. The results show a very good stability for all of the test samples and Fig. 2 indicates the excellent stability of applied hybrid nanofluids.", "cite_spans": [{"start": 497, "end": 501, "text": "[28,", "ref_id": "BIBREF27"}, {"start": 502, "end": 505, "text": "29]", "ref_id": "BIBREF28"}, {"start": 593, "end": 597, "text": "[30]", "ref_id": "BIBREF29"}], "ref_spans": [{"start": 868, "end": 874, "text": "Fig. 2", "ref_id": "FIGREF1"}]}, {"section": "Thermal conductivity measurement", "text": "A KD2 Pro made by Decagon Devices Inc. with the maximum deviation of 5.0% was utilized to measure thermal conductivity of applied hybrid nanofluids. Thermal conductivity in the range of 0.02-2.00 with the accuracy of AE0:001 could be measured by this device. Fig. 3 shows the used KD2 Pro in this experimental work. As it can be seen from Fig. 3 , there is a probe with inside sensors to measure thermal conductivity and the working temperature. It is noted that KD2 can measure the thermal conductivity of oil based nanofluids accurately up to around 110\u00b0C, while this temperature is 70 for water based nanofluids. This is because of the low thermal diffusivity of oil. Oils can hold thermal much longer than water and it can help us to measure the thermal conductivity of oil based nanofluids at 100\u00b0C much accurate than water based nanofluids. The measurements were done four times for each temperature and weight fraction for more reliability, and the averages are presented in Fig. 4 . As observed from Fig. 4 , the increasing trend of thermal conductivity of the nanofluids is because of the increasing in bulk temperature which affects the growing of Brownian motion of nanoparticles. On the other hand, as it can be seen, temperature rising does not affect the thermal conductivity of pure transformer oil increasingly. In addition, the certificate of quality assurance of the used KD2 Pro in this study is shown in Fig. 5 for further considerations of the readers. Predicting thermal conductivity of nanofluids depends on several parameters which are mainly nanoparticle concentration, bulk temperature of nanofluids and type of nanoparticles. These parameters affect Brownian movement of nanoparticles and thermal conductivity is affected by that. Due to the fact that Brownian movement is so difficult to be measured accurately, a reliable way to derive a general correlation for thermal conductivity is based on the published experimental results till now. A reliable correlation that is based on experimental results of any type of oil based nanofluids, has published recently in [8] and is introduced as Eq. (1) . Although this equation does not include the published results of hybrid oil based nanofluids, the predicted values are considerable. k nf \u00f0T; u; k np \u00de \u00bc \u00f03:9 \u00c2 10 \u00c05 T \u00c0 0:0305\u00deu 2 \u00fe \u00f00:086 \u00c0 1:6 \u00c2 10 \u00c04 T\u00de \u00c2 u \u00fe 3:1 \u00c2 10 \u00c04 T \u00fe 0:129 \u00c0 5:77 \u00c2 10 \u00c06 k np \u00c0 40 \u00c2 10 \u00c04 \u00f01\u00de On the other hand, T is the bulk nanofluid temperature in Celsius degrees and u is the volume fraction which ranged from 0% to 2%. Moreover, k np is referred to as the thermal conductivity of the nanoparticle material. Fig. 6 indicates a comparison between measured results of thermal conductivity ratio of applied hybrid nanofluids and predicted values by Eq. (1).", "cite_spans": [{"start": 2093, "end": 2096, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 2122, "end": 2125, "text": "(1)", "ref_id": "BIBREF0"}], "ref_spans": [{"start": 259, "end": 265, "text": "Fig. 3", "ref_id": "FIGREF2"}, {"start": 339, "end": 345, "text": "Fig. 3", "ref_id": "FIGREF2"}, {"start": 982, "end": 988, "text": "Fig. 4", "ref_id": "FIGREF4"}, {"start": 1008, "end": 1014, "text": "Fig. 4", "ref_id": "FIGREF4"}, {"start": 1424, "end": 1430, "text": "Fig. 5", "ref_id": "FIGREF3"}]}, {"section": "Dielectric strength", "text": "The dielectric strength of transformer oil based nanofluids should be studied because of the fact that transformer oil is designed to be an electrical insulator in transformer devices work under high electrical fields. Transformer oils will be failed, if the dielectric strength of oil is not able to prevent reaching the maximum electric field strength.", "cite_spans": [], "ref_spans": []}, {"section": "Dielectric strength", "text": "So, having a high dielectric strength is a main factor of good quality transformer oil. The dielectric strength of the transformer oil-based nanofluids containing WO 3 and Ag, was investigated. The results are mentioned in Table 2 .", "cite_spans": [], "ref_spans": [{"start": 223, "end": 230, "text": "Table 2", "ref_id": "TABREF1"}]}, {"section": "Dielectric strength", "text": "As it can be seen in Table 2 , due to introducing WO 3 to the oil known as low electrical conductivity, the dielectric strength is reduced a little in comparison with the pure transformer oil. Another reason for this reduction is the electrical conductivity of silver nanoparticles. But, due to our first demand that was observing an enhancement in thermal conductivity, silver as a conductive metal cannot be ignored.", "cite_spans": [], "ref_spans": [{"start": 21, "end": 28, "text": "Table 2", "ref_id": "TABREF1"}]}, {"section": "Conclusion", "text": "Tungsten (III) oxide (WO3)-Silver/Transformer Oil Hybrid Nanofluid in three weight fractions of 1%, 2% and 4% has been prepared via Electrical Explosion of Wire and its stability was evaluated by measuring zeta potential. In addition, thermal conductivity of hybrid nanofluids has been experimentally studied. An enhancement of 41% was observed in 4% wt and the thermal conductivity increased in an increasing way in contrast to pure transformer oil which behaves in a decreasing way. Finally, dielectric strength of hybrid nanofluids has been measured and in comparison with pure oil, a reduction has been observed which was probably due to the electrical conductivity of silver nanoparticles, because, WO 3 nanoparticles have a low electrical conductivity in all known nanoparticles till now. Figure 6 Thermal conductivity ratio of utilized nanofluids (measured and predicted by Eq. (1)). ", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Enhancing thermal conductivity of fluids with nanoparticles", "authors": [{"first": "S", "middle": ["U S"], "last": "Choi", "suffix": ""}], "year": 1995, "venue": "ASME FED", "link": "210524644"}, "BIBREF1": {"title": "Enhanced thermal conductivity through the development of nanofluids", "authors": [{"first": "J", "middle": ["A"], "last": "Eastman", "suffix": ""}, {"first": "S", "middle": ["U S"], "last": "Choi", "suffix": ""}, {"first": "S", "middle": [], "last": "Li", "suffix": ""}, {"first": "L", "middle": ["J"], "last": "Thompson", "suffix": ""}, {"first": "S", "middle": [], "last": "Lee", "suffix": ""}], "year": 1997, "venue": "Nanophase and Nanocomposite Materials II", "link": "97906609"}, "BIBREF2": {"title": "Thermal conductivity of nanoparticle-fluid mixture", "authors": [{"first": "X", "middle": [], "last": "Wang", "suffix": ""}, {"first": "X", "middle": [], "last": "Xu", "suffix": ""}, {"first": "S", "middle": ["U S"], "last": "Choi", "suffix": ""}], "year": 1999, "venue": "J. Thermophys. Heat Transf", "link": "15704046"}, "BIBREF3": {"title": "Measuring thermal conductivity of fluids containing oxide nanoparticles", "authors": [{"first": "S", "middle": [], "last": "Lee", "suffix": ""}, {"first": "S", "middle": ["U S"], "last": "Choi", "suffix": ""}, {"first": "S", "middle": [], "last": "Li", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Eastman", "suffix": ""}], "year": 1999, "venue": "ASME J. Heat Transf", "link": "96153752"}, "BIBREF4": {"title": "Heat transfer enhancement of nanofluids", "authors": [{"first": "Y", "middle": [], "last": "Xuan", "suffix": ""}, {"first": "Q", "middle": [], "last": "Li", "suffix": ""}], "year": 2000, "venue": "Int. J. Heat Fluid Flow", "link": "119796620"}, "BIBREF5": {"title": "Thermal conductivity and viscosity of Al2O3 nanofluid based on car engine coolant", "authors": [{"first": "M", "middle": [], "last": "Kole", "suffix": ""}, {"first": "T", "middle": ["K"], "last": "Dey", "suffix": ""}], "year": 2010, "venue": "J. Phys. D Appl. Phys", "link": "93401576"}, "BIBREF6": {"title": "Experimental thermal conductivity of ethylene glycol and water mixture based low volume concentration of Al2O3 and CuO nanofluids", "authors": [{"first": "L", "middle": [], "last": "Sundar", "suffix": ""}, {"first": "Md", "middle": ["Hashim"], "last": "Farooky", "suffix": ""}, {"first": "S", "middle": [], "last": "Sarada", "suffix": ""}, {"first": "M", "middle": ["K"], "last": "Singh", "suffix": ""}], "year": 2013, "venue": "Int. Commun. Heat Mass Transf", "link": "119825478"}, "BIBREF7": {"title": "Experimental study on the rheological behavior of silver-heat transfer oil nanofluid and suggesting two empirical based correlations for thermal conductivity and viscosity of oil based nanofluids", "authors": [{"first": "Sadegh", "middle": [], "last": "Aberoumand", "suffix": ""}, {"first": "Amin", "middle": [], "last": "Jafarimoghaddam", "suffix": ""}, {"first": "Mojtaba", "middle": [], "last": "Moravej", "suffix": ""}, {"first": "Hossein", "middle": [], "last": "Aberoumand", "suffix": ""}, {"first": "Kourosh", "middle": [], "last": "Javaherdeh", "suffix": ""}], "year": 2016, "venue": "Appl. Therm. Eng", "link": "112217896"}, "BIBREF8": {"title": "An experimental investigation on thermo-physical properties and overall performance of MWCNT/heat transfer oil nanofluid flow inside vertical helically coiled tubes", "authors": [{"first": "M", "middle": [], "last": "Fakoor Pakdaman", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Akhavan-Behabadi", "suffix": ""}, {"first": "P", "middle": [], "last": "Razi", "suffix": ""}], "year": 2012, "venue": "Exp. Therm. Fluid Sci", "link": null}, "BIBREF9": {"title": "An empirical investigation on thermal characteristics and pressure drop of Ag-oil nanofluid in concentric annular tube", "authors": [{"first": "A", "middle": ["A"], "last": "Arani", "suffix": ""}, {"first": "H", "middle": [], "last": "Aberoumand", "suffix": ""}, {"first": "S", "middle": [], "last": "Aberoumand", "suffix": ""}, {"first": "A", "middle": [], "last": "Moghaddam", "suffix": ""}, {"first": "M", "middle": [], "last": "Dastanian", "suffix": ""}], "year": 2015, "venue": "Heat Mass Transf", "link": "123855608"}, "BIBREF10": {"title": "Mixed convection heat transfer of nanofluids inside curved tubes: an experimental study", "authors": [{"first": "", "middle": [], "last": "Sadegh", "suffix": ""}, {"first": "", "middle": [], "last": "Aberoumand", "suffix": ""}, {"first": "", "middle": [], "last": "Amin", "suffix": ""}, {"first": "", "middle": [], "last": "Jafarimoghaddam", "suffix": ""}], "year": 2016, "venue": "Appl. Therm. Eng", "link": "113657716"}, "BIBREF11": {"title": "Experimental study on Cu/oil nanofluids through concentric annular tube: a correlation", "authors": [{"first": "A", "middle": [], "last": "Jafarimoghaddam", "suffix": ""}, {"first": "S", "middle": [], "last": "Aberoumand", "suffix": ""}, {"first": "H", "middle": [], "last": "Aberoumand", "suffix": ""}, {"first": "K", "middle": [], "last": "Javaherdeh", "suffix": ""}], "year": 2016, "venue": "Heat Trans. Asian Res", "link": "125754027"}, "BIBREF12": {"title": "Experimental determination of thermal conductivity and dynamic viscosity of Ag-MgO/water hybrid nanofluid", "authors": [{"first": "Mohammad", "middle": [], "last": "Hemmat Esfe", "suffix": ""}, {"first": "Ali", "middle": [], "last": "Akbar Abbasian", "suffix": ""}, {"first": "Mohammad", "middle": [], "last": "Arani", "suffix": ""}, {"first": "Wei-Mon", "middle": [], "last": "Rezaie", "suffix": ""}, {"first": "Arash", "middle": [], "last": "Yan", "suffix": ""}, {"first": "", "middle": [], "last": "Karimipour", "suffix": ""}], "year": 2015, "venue": "Int. Commun. Heat Mass Transf", "link": null}, "BIBREF13": {"title": "Thermal conductivity of Cu/TiO 2 -water/EG hybrid nanofluid: Experimental data and modeling using artificial neural network and correlation", "authors": [{"first": "Somchai", "middle": [], "last": "Mohammd Hemmat Esfe", "suffix": ""}, {"first": "Ali", "middle": [], "last": "Wongwises", "suffix": ""}, {"first": "Amin", "middle": [], "last": "Naderi", "suffix": ""}, {"first": "Mohammad", "middle": ["Reza"], "last": "Asadi", "suffix": ""}, {"first": "Hadi", "middle": [], "last": "Safaei", "suffix": ""}, {"first": "Mahidzal", "middle": [], "last": "Rostamian", "suffix": ""}, {"first": "Arash", "middle": [], "last": "Dahari", "suffix": ""}, {"first": "", "middle": [], "last": "Karimipour", "suffix": ""}], "year": 2015, "venue": "Int. Commun. Heat Mass Transf", "link": null}, "BIBREF14": {"title": "Physicochemical properties of oil-based nanofluids containing hybrid structures of silver nanoparticles supported on silica", "authors": [{"first": "S", "middle": [], "last": "Subelia", "suffix": ""}, {"first": "Patrick", "middle": [], "last": "Botha", "suffix": ""}, {"first": "Bernard", "middle": ["J"], "last": "Ndungu", "suffix": ""}, {"first": "", "middle": [], "last": "Bladergroen", "suffix": ""}], "year": 2011, "venue": "Ind. Eng. Chem. Res", "link": null}, "BIBREF15": {"title": "Experimental study on thermal conductivity of ethylene glycol containing hybrid nano-additives and development of a new correlation", "authors": [{"first": "Masoud", "middle": [], "last": "Afrand", "suffix": ""}], "year": 2017, "venue": "Appl. Therm. Eng", "link": "100112183"}, "BIBREF16": {"title": "Effects of temperature and solid volume fraction on viscosity of SiO2-MWCNTs/SAE40 hybrid nanofluid as a coolant and lubricant in heat engines", "authors": [{"first": "Masoud", "middle": [], "last": "Afrand", "suffix": ""}, {"first": "Karim", "middle": ["Nazari"], "last": "Najafabadi", "suffix": ""}, {"first": "Mohammad", "middle": [], "last": "Akbari", "suffix": ""}], "year": 2016, "venue": "Appl. Therm. Eng", "link": "113032111"}, "BIBREF17": {"title": "Effects of temperature and nanoparticles concentration on rheological behavior of Fe3O4-Ag/EG hybrid nanofluid: an experimental study", "authors": [{"first": "Masoud", "middle": [], "last": "Afranda", "suffix": ""}, {"first": "Davood", "middle": [], "last": "Toghraieb", "suffix": ""}, {"first": "Behrooz", "middle": [], "last": "Ruhania", "suffix": ""}], "year": 2016, "venue": "Exp. Therm. Fluid Sci", "link": null}, "BIBREF18": {"title": "Effect of suspending hybrid nano-additives on rheological behavior of engine oil and pumping power", "authors": [{"first": "", "middle": [], "last": "Ebrahim Dardan", "suffix": ""}, {"first": "A", "middle": ["H"], "last": "Masoud Afrand", "suffix": ""}, {"first": "", "middle": [], "last": "Meghdadi Isfahani", "suffix": ""}], "year": 2016, "venue": "Appl. Therm. Eng", "link": "115062329"}, "BIBREF19": {"title": "An experimental study on rheological behavior of non-Newtonian hybrid nano-coolant for application in cooling and heating systems", "authors": [{"first": "Hamed", "middle": [], "last": "Eshgarf", "suffix": ""}, {"first": "Masoud", "middle": [], "last": "Afrand", "suffix": ""}], "year": 2016, "venue": "Exp. Therm. Fluid Sci", "link": "67757032"}, "BIBREF20": {"title": "Thermal conductivity enhancement of COOH-functionalized MWCNTs/ethylene glycol-water nanofluid for application in heating and cooling systems", "authors": [{"first": "Mehdi", "middle": [], "last": "Soltanimehr", "suffix": ""}, {"first": "Masoud", "middle": [], "last": "Afrand", "suffix": ""}], "year": 2016, "venue": "Appl. Therm. Eng", "link": "111707623"}, "BIBREF21": {"title": "Study on thermal conductivity of water-based nanofluids with hybrid suspensions of CNTs/Al 2 O 3 nanoparticles", "authors": [{"first": "Mohammad", "middle": [], "last": "Hemmat Esfe", "suffix": ""}, {"first": "Seyfolah", "middle": [], "last": "Saedodin", "suffix": ""}, {"first": "Wei-Mon", "middle": [], "last": "Yan", "suffix": ""}, {"first": "Masoud", "middle": [], "last": "Afrand", "suffix": ""}, {"first": "Nima", "middle": [], "last": "Sina", "suffix": ""}], "year": 2016, "venue": "J. Therm. Anal. Calorim", "link": null}, "BIBREF22": {"title": "Measurement of thermal conductivity of ZnO-TiO 2 /EG hybrid nanofluid", "authors": [{"first": "Davood", "middle": [], "last": "Toghraie", "suffix": ""}, {"first": "Masoud", "middle": [], "last": "Vahid Avalin Chaharsoghi", "suffix": ""}, {"first": "", "middle": [], "last": "Afrand", "suffix": ""}], "year": 2016, "venue": "J. Therm. Anal. Calorim", "link": null}, "BIBREF23": {"title": "An empirical investigation on Cu/Ethylene Glycol nanofluid through a concentric annular tube and proposing a correlation for predicting Nusselt number, Alexandria Eng", "authors": [{"first": "A", "middle": [], "last": "Jafarimoghaddam", "suffix": ""}, {"first": "S", "middle": [], "last": "Aberoumand", "suffix": ""}], "year": 2016, "venue": "J", "link": "101599125"}, "BIBREF24": {"title": "Optimal synthesis and characterization of Ag nanofluids by electrical explosion of wires in liquids", "authors": [{"first": "E", "middle": ["J"], "last": "Park", "suffix": ""}, {"first": "S", "middle": ["W"], "last": "Lee", "suffix": ""}, {"first": "I", "middle": ["C"], "last": "Bang", "suffix": ""}, {"first": "H", "middle": ["W"], "last": "Park", "suffix": ""}], "year": 2011, "venue": "Nanoscale Res. Lett", "link": "1911663"}, "BIBREF25": {"title": "Ag-Au alloy nanoparticles prepared by electro-exploding wire technique", "authors": [{"first": "A", "middle": [], "last": "Alqudami", "suffix": ""}, {"first": "S", "middle": ["A"], "last": "Govind", "suffix": ""}, {"first": "S", "middle": ["M"], "last": "Shivaprasad", "suffix": ""}], "year": 2007, "venue": "J. Nanopart. Res", "link": "95446088"}, "BIBREF26": {"title": "Novel technique for preparing a nano-silver water suspension by the arc discharge method, Rev", "authors": [{"first": "D", "middle": ["C"], "last": "Tien", "suffix": ""}], "year": 2008, "venue": "Adv. Mater. Sci", "link": "56394380"}, "BIBREF27": {"title": "Sample Preparation Dispersing Procedures for Powders in Liquids", "authors": [], "year": 2000, "venue": "International Organization for Standardization", "link": null}, "BIBREF28": {"title": "The effects of graphene oxide nanosheets and ultrasonic oscillation on the supercooling and nucleation behavior of nanofluids PCMs", "authors": [{"first": "Y", "middle": [], "last": "Liu", "suffix": ""}, {"first": "Y", "middle": [], "last": "Liu", "suffix": ""}, {"first": "P", "middle": [], "last": "Hu", "suffix": ""}, {"first": "X", "middle": [], "last": "Li", "suffix": ""}, {"first": "R", "middle": [], "last": "Gao", "suffix": ""}, {"first": "Q", "middle": [], "last": "Peng", "suffix": ""}, {"first": "L", "middle": [], "last": "Wei", "suffix": ""}], "year": 2015, "venue": "Microfluid. Nanofluid", "link": null}, "BIBREF29": {"title": "Effective viscosities and thermal conductivities of aqueous nanofluids containing low volume concentrations of Al2O3 nanoparticles", "authors": [{"first": "J.-H", "middle": [], "last": "Lee", "suffix": ""}, {"first": "K", "middle": ["S"], "last": "Hwang", "suffix": ""}, {"first": "S", "middle": ["P"], "last": "Jang", "suffix": ""}, {"first": "B", "middle": ["H"], "last": "Lee", "suffix": ""}, {"first": "J", "middle": ["H"], "last": "Kim", "suffix": ""}, {"first": "S", "middle": ["U"], "last": "Choi", "suffix": ""}, {"first": "C", "middle": ["J"], "last": "Choi", "suffix": ""}], "year": 2008, "venue": "Int. J. Heat Mass Transf", "link": "94820113"}}, "ref_entries": {"FIGREF0": {"text": "PNC1K device (left) and a schematic of EEW method (right).", "type": "figure"}, "FIGREF1": {"text": "Absolute zeta potential of Ag-WO 3 /Transformer oil nanofluids as a function of Weight concentration.", "type": "figure"}, "FIGREF2": {"text": "Used KD2 Pro in this study.", "type": "figure"}, "FIGREF3": {"text": "Certificate quality assurance of the utilized KD2 Pro.", "type": "figure"}, "FIGREF4": {"text": "Thermal conductivity of hybrid nanofluids versus temperature (including error bars).", "type": "figure"}, "TABREF0": {"text": "Operational characteristics of the PNC1K in this study.", "type": "table"}, "TABREF1": {"text": "Dielectric strength of transformer oil-based nanofluid containing WO 3 and silver.", "type": "table"}}}
{"paper_id": "138418763", "_pdf_hash": "71c60de1e30a40cbf78d4d14640982d6a72ab077", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Advanced Steels for Transport Applications", "authors": [{"first": "A", "middle": [], "last": "Ramazani", "suffix": ""}, {"first": "B", "middle": [], "last": "Berme", "suffix": ""}, {"first": "U", "middle": [], "last": "Prahl", "suffix": ""}], "year": 2013, "venue": "Materials for Transport Application", "link": null}, "BIBREF1": {"title": "New High Strength Steels Applied to the Body Structure of ULSAB-AVC", "authors": [{"first": "B", "middle": [], "last": "Zuidema", "suffix": ""}, {"first": "S", "middle": [], "last": "Denner", "suffix": ""}, {"first": "B", "middle": [], "last": "Engl", "suffix": ""}, {"first": "J", "middle": [], "last": "Sperle", "suffix": ""}], "year": 2001, "venue": "", "link": "137948862"}, "BIBREF2": {"title": "Fundamental of Dual-phase Steels", "authors": [{"first": "G", "middle": ["R"], "last": "Speich", "suffix": ""}], "year": 1981, "venue": "", "link": null}, "BIBREF3": {"title": "Influence of martensite transformation strain on the ductility of dual-phase steels", "authors": [{"first": "D", "middle": ["L"], "last": "Bourell", "suffix": ""}, {"first": "A", "middle": [], "last": "Rizk", "suffix": ""}], "year": 1983, "venue": "Acta Metall", "link": "137624465"}, "BIBREF4": {"title": "Modelling the effect of microstructural banding on the flow curve behaviour of dual-phase (DP) steels", "authors": [{"first": "A", "middle": [], "last": "Ramazani", "suffix": ""}, {"first": "K", "middle": [], "last": "Mukherjee", "suffix": ""}, {"first": "U", "middle": [], "last": "Prahl", "suffix": ""}, {"first": "W", "middle": [], "last": "Bleck", "suffix": ""}], "year": 2012, "venue": "Comput. Mater. Sci", "link": "137592652"}, "BIBREF5": {"title": "Void formation during tensile testing of dual phase steels", "authors": [{"first": "D", "middle": ["L"], "last": "Steinbrunner", "suffix": ""}, {"first": "D", "middle": ["K"], "last": "Matlock", "suffix": ""}, {"first": "G", "middle": [], "last": "Krauss", "suffix": ""}], "year": 1988, "venue": "Metall. Trans. A Phys. Metall. Mater. Sci", "link": "137473655"}, "BIBREF6": {"title": "Initiation and growth of damage in a dual-phase steel observed by X-ray microtomography", "authors": [{"first": "E", "middle": [], "last": "Maire", "suffix": ""}, {"first": "O", "middle": [], "last": "Bouaziz", "suffix": ""}, {"first": "M", "middle": ["Di"], "last": "Michiel", "suffix": ""}, {"first": "C", "middle": [], "last": "Verdu", "suffix": ""}], "year": 2008, "venue": "Acta Mater", "link": "136602050"}, "BIBREF7": {"title": "Deformation and fracture mechanisms in fine-and ultrafine-grained ferrite/martensite dual-phase steels and the effect of aging", "authors": [{"first": "M", "middle": [], "last": "Calcagnotto", "suffix": ""}, {"first": "Y", "middle": [], "last": "Adachi", "suffix": ""}, {"first": "D", "middle": [], "last": "Ponge", "suffix": ""}, {"first": "D", "middle": [], "last": "Raabe", "suffix": ""}], "year": 2011, "venue": "Acta Mater", "link": "52083048"}, "BIBREF8": {"title": "Effect of microvoid formation on the tensile properties of dual-phase steel", "authors": [{"first": "E", "middle": [], "last": "Ahmad", "suffix": ""}, {"first": "T", "middle": [], "last": "Manzoor", "suffix": ""}, {"first": "K", "middle": ["L"], "last": "Ali", "suffix": ""}, {"first": "J", "middle": ["I"], "last": "Akhter", "suffix": ""}], "year": 2000, "venue": "J. Mater. Eng. Perform", "link": "136905808"}, "BIBREF9": {"title": "Predicting failure modes and ductility of dual phase steels using plastic strain localization", "authors": [{"first": "X", "middle": [], "last": "Sun", "suffix": ""}, {"first": "K", "middle": ["S"], "last": "Choi", "suffix": ""}, {"first": "W", "middle": ["N"], "last": "Liu", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Khaleel", "suffix": ""}], "year": 2009, "venue": "Int. J. Plast", "link": "136605856"}, "BIBREF10": {"title": "Experimental and numerical investigation of failure mode in geometrically imperfect DP590 steel", "authors": [{"first": "X", "middle": [], "last": "Zhuang", "suffix": ""}, {"first": "C", "middle": [], "last": "Xu", "suffix": ""}, {"first": "Z", "middle": [], "last": "Zhao", "suffix": ""}], "year": 2015, "venue": "Sci. China Technol. Sci", "link": "195307261"}, "BIBREF11": {"title": "Characterization and modelling of failure initiation in DP steel", "authors": [{"first": "A", "middle": [], "last": "Ramazani", "suffix": ""}, {"first": "A", "middle": [], "last": "Schwedt", "suffix": ""}, {"first": "A", "middle": [], "last": "Aretz", "suffix": ""}, {"first": "U", "middle": [], "last": "Prahl", "suffix": ""}, {"first": "W", "middle": [], "last": "Bleck", "suffix": ""}], "year": 2013, "venue": "Comput. Mater. Sci", "link": "136749195"}, "BIBREF12": {"title": "Study the effect of martensite banding on the failure initiation in dual-phase steel", "authors": [{"first": "A", "middle": [], "last": "Ramazani", "suffix": ""}, {"first": "Z", "middle": [], "last": "Ebrahimi", "suffix": ""}, {"first": "U", "middle": [], "last": "Prahl", "suffix": ""}], "year": 2014, "venue": "Comput. Mater. Sci", "link": "135875809"}, "BIBREF13": {"title": "Characterization and modeling of failure initiation in bainite-aided DP steel", "authors": [{"first": "A", "middle": [], "last": "Ramazani", "suffix": ""}, {"first": "Y", "middle": [], "last": "Chang", "suffix": ""}, {"first": "U", "middle": [], "last": "Prahl", "suffix": ""}], "year": 2014, "venue": "Adv. Eng. Mater", "link": "51998525"}, "BIBREF14": {"title": "An overview of dualphase steels: advances in microstructure-oriented processing and micromechanically guided design", "authors": [{"first": "C", "middle": ["C"], "last": "Tasan", "suffix": ""}, {"first": "M", "middle": [], "last": "Diehl", "suffix": ""}, {"first": "D", "middle": [], "last": "Yan", "suffix": ""}, {"first": "M", "middle": [], "last": "Bechtold", "suffix": ""}, {"first": "F", "middle": [], "last": "Roters", "suffix": ""}, {"first": "L", "middle": [], "last": "Schemmann", "suffix": ""}, {"first": "C", "middle": [], "last": "Zheng", "suffix": ""}, {"first": "N", "middle": [], "last": "Peranio", "suffix": ""}, {"first": "D", "middle": [], "last": "Ponge", "suffix": ""}, {"first": "M", "middle": [], "last": "Koyama", "suffix": ""}, {"first": "K", "middle": [], "last": "Tsuzaki", "suffix": ""}, {"first": "D", "middle": [], "last": "Raabe", "suffix": ""}], "year": 2015, "venue": "Annu. Rev. Mater. Res", "link": "52087438"}, "BIBREF15": {"title": "Development and application of a microstructure-based approach to characterize and model failure initiation in DP steels using XFEM", "authors": [{"first": "A", "middle": [], "last": "Ramazani", "suffix": ""}, {"first": "M", "middle": [], "last": "Abbasi", "suffix": ""}, {"first": "S", "middle": [], "last": "Kazemiabnavi", "suffix": ""}, {"first": "S", "middle": [], "last": "Schmauder", "suffix": ""}, {"first": "R", "middle": [], "last": "Larson", "suffix": ""}, {"first": "U", "middle": [], "last": "Prahl", "suffix": ""}], "year": 2016, "venue": "Mater. Sci. Eng. A", "link": "138664251"}, "BIBREF16": {"title": "Surface energies, work functions, and surface relaxations of low-index metallic surfaces from first principles", "authors": [{"first": "N", "middle": ["E"], "last": "Singh-Miller", "suffix": ""}, {"first": "N", "middle": [], "last": "Marzari", "suffix": ""}], "year": 2009, "venue": "Phys. Rev. B", "link": "118480618"}, "BIBREF17": {"title": "First principles calculations of solid-solid interfaces: an application to conversion materials for lithium-ion batteries", "authors": [{"first": "L", "middle": [], "last": "Martin", "suffix": ""}, {"first": "G", "middle": [], "last": "Vallverdu", "suffix": ""}, {"first": "H", "middle": [], "last": "Martinez", "suffix": ""}, {"first": "F", "middle": ["Le"], "last": "Cras", "suffix": ""}, {"first": "I", "middle": [], "last": "Baraille", "suffix": ""}], "year": 2012, "venue": "J. Mater. Chem", "link": "97261031"}, "BIBREF18": {"title": "Structure, magnetism, and adhesion at Cr/ Fe interfaces from density functional theory", "authors": [{"first": "D", "middle": ["F"], "last": "Johnson", "suffix": ""}, {"first": "D", "middle": ["E"], "last": "Jiang", "suffix": ""}, {"first": "E", "middle": ["A"], "last": "Carter", "suffix": ""}], "year": 2007, "venue": "Surf. Sci", "link": "16302446"}, "BIBREF19": {"title": "A density functional theory based study of the electron transfer reaction at the cathodeeelectrolyte interface in lithiumeair batteries", "authors": [{"first": "S", "middle": [], "last": "Kazemiabnavi", "suffix": ""}, {"first": "P", "middle": [], "last": "Dutta", "suffix": ""}, {"first": "S", "middle": [], "last": "Banerjee", "suffix": ""}], "year": 2015, "venue": "Phys. Chem. Chem. Phys", "link": null}, "BIBREF20": {"title": "Density functional theory based study of the electron transfer reaction at the lithium metal anode in a lithiumeair battery with ionic liquid electrolytes", "authors": [{"first": "S", "middle": [], "last": "Kazemiabnavi", "suffix": ""}, {"first": "P", "middle": [], "last": "Dutta", "suffix": ""}, {"first": "S", "middle": [], "last": "Banerjee", "suffix": ""}], "year": 2014, "venue": "J. Phys. Chem. C", "link": "34100393"}, "BIBREF21": {"title": "Ab initio modeling of the electron transfer reaction rate at the electrode-electrolyte interface in lithium-air batteries", "authors": [{"first": "S", "middle": [], "last": "Kazemiabnavi", "suffix": ""}, {"first": "P", "middle": [], "last": "Dutta", "suffix": ""}, {"first": "S", "middle": [], "last": "Banerjee", "suffix": ""}], "year": 2014, "venue": "International Mechanical Engineering Congress and Exposition, Energy", "link": "101294347"}, "BIBREF22": {"title": "Effects of operating temperature on the electrical performance of a Li-air battery operated with ionic liquid electrolyte", "authors": [{"first": "K", "middle": [], "last": "Yoo", "suffix": ""}, {"first": "A", "middle": ["M"], "last": "Dive", "suffix": ""}, {"first": "S", "middle": [], "last": "Kazemiabnavi", "suffix": ""}, {"first": "S", "middle": [], "last": "Banerjee", "suffix": ""}, {"first": "P", "middle": [], "last": "Dutta", "suffix": ""}], "year": 2016, "venue": "Electrochimica Acta", "link": "101749171"}, "BIBREF23": {"title": "A comparative study of hydrogen storage and hydrocarbon fuel processing for automotive fuel cells", "authors": [{"first": "S", "middle": [], "last": "Kazemiabnavi", "suffix": ""}, {"first": "A", "middle": [], "last": "Soundararaj", "suffix": ""}, {"first": "H", "middle": [], "last": "Zamani", "suffix": ""}, {"first": "B", "middle": [], "last": "Scharf", "suffix": ""}, {"first": "P", "middle": [], "last": "Thyagarajan", "suffix": ""}, {"first": "X", "middle": [], "last": "Zhou", "suffix": ""}], "year": 2015, "venue": "International Mechanical Engineering Congress and Exposition, Energy", "link": "112025924"}, "BIBREF24": {"title": "Modeling the electron transfer reaction at the lithium metal anode-liquid electrolyte interface in lithium-air batteries", "authors": [{"first": "S", "middle": [], "last": "Kazemiabnavi", "suffix": ""}, {"first": "P", "middle": [], "last": "Dutta", "suffix": ""}, {"first": "S", "middle": [], "last": "Banerjee", "suffix": ""}], "year": 2015, "venue": "Proc. 249th ACS National Meeting", "link": null}, "BIBREF25": {"title": "Surface relaxation of Fe(001) by ab initio molecular dynamics", "authors": [{"first": "T", "middle": [], "last": "Kishi", "suffix": ""}, {"first": "S", "middle": [], "last": "Itoh", "suffix": ""}], "year": 1996, "venue": "Surf. Sci", "link": "93515661"}, "BIBREF26": {"title": "Surface magnetic moments and electronic structure of Cr(100), Fe(100), and Ni(100) near the fermi level", "authors": [{"first": "A", "middle": ["A"], "last": "Ostroukhov", "suffix": ""}, {"first": "V", "middle": ["M"], "last": "Floka", "suffix": ""}, {"first": "V", "middle": ["T"], "last": "Cherepin", "suffix": ""}], "year": 1995, "venue": "Surf. Sci", "link": "97004896"}, "BIBREF27": {"title": "First-principles study of metallic iron interfaces", "authors": [{"first": "A", "middle": [], "last": "Hung", "suffix": ""}, {"first": "I", "middle": [], "last": "Yarovsky", "suffix": ""}, {"first": "J", "middle": [], "last": "Muscat", "suffix": ""}, {"first": "S", "middle": [], "last": "Russo", "suffix": ""}, {"first": "I", "middle": [], "last": "Snook", "suffix": ""}, {"first": "R", "middle": ["O"], "last": "Watts", "suffix": ""}], "year": 2002, "venue": "Surf. Sci", "link": "97283282"}, "BIBREF28": {"title": "Detection, distribution, and quantification of carbon in steel microstructures by PEELS", "authors": [{"first": "E", "middle": ["S K"], "last": "Menon", "suffix": ""}, {"first": "A", "middle": ["G"], "last": "Fox", "suffix": ""}], "year": 2002, "venue": "Microsc. Microanal", "link": "21001282"}, "BIBREF29": {"title": "A quantitative analysis of Mn segregation at partitioned ferrite/austenite interface in a Fe-C-Mn-Si alloy", "authors": [{"first": "H", "middle": [], "last": "Guo", "suffix": ""}, {"first": "S", "middle": ["W"], "last": "Yang", "suffix": ""}, {"first": "C", "middle": ["J"], "last": "Shang", "suffix": ""}, {"first": "X", "middle": ["M"], "last": "Wang", "suffix": ""}, {"first": "X", "middle": ["L"], "last": "He", "suffix": ""}], "year": 2009, "venue": "J. Mater. Sci. Technol", "link": null}, "BIBREF30": {"title": "Growth and overall transformation kinetics above the bay temperature in Fe-C-Mo alloys", "authors": [{"first": "G", "middle": ["J"], "last": "Shiflet", "suffix": ""}, {"first": "H", "middle": ["I"], "last": "Aaronson", "suffix": ""}], "year": 1990, "venue": "Metall. Trans. A Phys. Metall. Mater. Sci", "link": "137419713"}, "BIBREF31": {"title": "An investigation of the generality of incomplete transformation to bainite in Fe-C-X alloys", "authors": [{"first": "W", "middle": ["T"], "last": "Reynolds", "suffix": ""}, {"first": "S", "middle": ["K"], "last": "Liu", "suffix": ""}, {"first": "F", "middle": ["Z"], "last": "Li", "suffix": ""}, {"first": "S", "middle": [], "last": "Hartfield", "suffix": ""}, {"first": "H", "middle": ["I"], "last": "Aaronson", "suffix": ""}], "year": 1990, "venue": "Metallurgical Trans. A Phys. Metall. Mater. Sci", "link": "131768749"}, "BIBREF32": {"title": "The incomplete transformation phenomenon in Fe-C-Mo alloys", "authors": [{"first": "W", "middle": ["T"], "last": "Reynolds", "suffix": ""}, {"first": "F", "middle": ["Z"], "last": "Li", "suffix": ""}, {"first": "C", "middle": ["K"], "last": "Shui", "suffix": ""}, {"first": "H", "middle": ["I"], "last": "Aaronson", "suffix": ""}], "year": 1990, "venue": "Metallurgical Trans. A Phys. Metall. Mater. Sci", "link": "136800205"}, "BIBREF33": {"title": "Heavily doped transparent-emitter regions in junction solar cells, diodes, and transistors", "authors": [{"first": "M", "middle": ["A"], "last": "Shibib", "suffix": ""}, {"first": "F", "middle": ["A"], "last": "Lindholm", "suffix": ""}, {"first": "F", "middle": [], "last": "Therez", "suffix": ""}], "year": 1979, "venue": "IEEE Trans. Electron Devices", "link": "19288569"}, "BIBREF34": {"title": "Intrinsic concentration, effective densities of states, and effective mass in silicon", "authors": [{"first": "M", "middle": ["A"], "last": "Green", "suffix": ""}], "year": 1990, "venue": "J. Appl. Phys", "link": "96876887"}, "BIBREF35": {"title": "Insight into insulator-to-metal transition of sulfurdoped silicon by DFT calculations", "authors": [{"first": "Z.-Y", "middle": [], "last": "Zhao", "suffix": ""}, {"first": "P.-Z", "middle": [], "last": "Yang", "suffix": ""}], "year": 2014, "venue": "Phys. Chem. Chem. Phys", "link": "46134209"}, "BIBREF36": {"title": "The c/a Ratio in Quenched Fe-C and Fe-N Steels -a Heuristic Story", "authors": [{"first": "O", "middle": ["D"], "last": "Sherby", "suffix": ""}, {"first": "J", "middle": [], "last": "Wadsworth", "suffix": ""}, {"first": "D", "middle": ["R"], "last": "Lesuer", "suffix": ""}, {"first": "C", "middle": ["K"], "last": "Syn", "suffix": ""}], "year": 2007, "venue": "", "link": "102488918"}, "BIBREF37": {"title": "Revisiting the structure of martensite in iron-carbon steels", "authors": [{"first": "O", "middle": ["D"], "last": "Sherby", "suffix": ""}, {"first": "J", "middle": [], "last": "Wadsworth", "suffix": ""}, {"first": "D", "middle": ["R"], "last": "Lesuer", "suffix": ""}, {"first": "C", "middle": ["K"], "last": "Syn", "suffix": ""}], "year": 2008, "venue": "Mater. Trans", "link": "54634909"}, "BIBREF38": {"title": "X-Ray studies of the structure of quenched carbon steel", "authors": [{"first": "G", "middle": [], "last": "Kurdjumov", "suffix": ""}, {"first": "E", "middle": [], "last": "Kaminsky", "suffix": ""}], "year": 1928, "venue": "Nature", "link": null}, "BIBREF39": {"title": "Lattice-parameter variation with carbon content of martensite .1. X-Ray-diffraction experimental study", "authors": [{"first": "X", "middle": [], "last": "Liu", "suffix": ""}, {"first": "F", "middle": [], "last": "Zhong", "suffix": ""}, {"first": "J", "middle": ["X"], "last": "Zhang", "suffix": ""}, {"first": "M", "middle": ["X"], "last": "Zhang", "suffix": ""}, {"first": "M", "middle": ["K"], "last": "Kang", "suffix": ""}, {"first": "Z", "middle": ["Q"], "last": "Guo", "suffix": ""}], "year": 1995, "venue": "Phys. Rev. B", "link": "36667515"}, "BIBREF40": {"title": "On the effective lattice parameter of binary alloys", "authors": [{"first": "V", "middle": ["A"], "last": "Lubarda", "suffix": ""}], "year": 2003, "venue": "Mech. Mater", "link": "32486618"}, "BIBREF41": {"title": "Self-consistent equations including exchange and correlation effects", "authors": [{"first": "W", "middle": [], "last": "Kohn", "suffix": ""}, {"first": "L", "middle": ["J"], "last": "Sham", "suffix": ""}], "year": 1965, "venue": "Phys. Rev", "link": "55364462"}, "BIBREF42": {"title": "QUANTUM ESPRESSO: a modular and opensource software project for quantum simulations of materials", "authors": [{"first": "P", "middle": [], "last": "Giannozzi", "suffix": ""}, {"first": "S", "middle": [], "last": "Baroni", "suffix": ""}, {"first": "N", "middle": [], "last": "Bonini", "suffix": ""}, {"first": "M", "middle": [], "last": "Calandra", "suffix": ""}, {"first": "R", "middle": [], "last": "Car", "suffix": ""}, {"first": "C", "middle": [], "last": "Cavazzoni", "suffix": ""}, {"first": "D", "middle": [], "last": "Ceresoli", "suffix": ""}, {"first": "G", "middle": ["L"], "last": "Chiarotti", "suffix": ""}, {"first": "M", "middle": [], "last": "Cococcioni", "suffix": ""}, {"first": "I", "middle": [], "last": "Dabo", "suffix": ""}, {"first": "A", "middle": [], "last": "Corso", "suffix": ""}, {"first": "S", "middle": [], "last": "De Gironcoli", "suffix": ""}, {"first": "S", "middle": [], "last": "Fabris", "suffix": ""}, {"first": "G", "middle": [], "last": "Fratesi", "suffix": ""}, {"first": "R", "middle": [], "last": "Gebauer", "suffix": ""}, {"first": "U", "middle": [], "last": "Gerstmann", "suffix": ""}, {"first": "C", "middle": [], "last": "Gougoussis", "suffix": ""}, {"first": "A", "middle": [], "last": "Kokalj", "suffix": ""}, {"first": "M", "middle": [], "last": "Lazzeri", "suffix": ""}, {"first": "L", "middle": [], "last": "Martin-Samos", "suffix": ""}, {"first": "N", "middle": [], "last": "Marzari", "suffix": ""}, {"first": "F", "middle": [], "last": "Mauri", "suffix": ""}, {"first": "R", "middle": [], "last": "Mazzarello", "suffix": ""}, {"first": "S", "middle": [], "last": "Paolini", "suffix": ""}, {"first": "A", "middle": [], "last": "Pasquarello", "suffix": ""}, {"first": "L", "middle": [], "last": "Paulatto", "suffix": ""}, {"first": "C", "middle": [], "last": "Sbraccia", "suffix": ""}, {"first": "S", "middle": [], "last": "Scandolo", "suffix": ""}, {"first": "G", "middle": [], "last": "Sclauzero", "suffix": ""}, {"first": "A", "middle": ["P"], "last": "Seitsonen", "suffix": ""}, {"first": "A", "middle": [], "last": "Smogunov", "suffix": ""}, {"first": "P", "middle": [], "last": "Umari", "suffix": ""}, {"first": "R", "middle": ["M"], "last": "Wentzcovitch", "suffix": ""}], "year": 2009, "venue": "J. Phys. Condens. Matter", "link": "5846317"}, "BIBREF43": {"title": "Efficiency of ab-initio total energy calculations for metals and semiconductors using a plane-wave basis set", "authors": [{"first": "G", "middle": [], "last": "Kresse", "suffix": ""}, {"first": "J", "middle": [], "last": "Furthmuller", "suffix": ""}], "year": 1996, "venue": "Comput. Mater. Sci", "link": "137317947"}, "BIBREF44": {"title": "Iterative minimization techniques for ab initio total-energy calculations: molecular dynamics and conjugate gradients", "authors": [{"first": "M", "middle": ["C"], "last": "Payne", "suffix": ""}, {"first": "M", "middle": ["P"], "last": "Teter", "suffix": ""}, {"first": "D", "middle": ["C"], "last": "Allan", "suffix": ""}, {"first": "T", "middle": ["A"], "last": "Arias", "suffix": ""}, {"first": "J", "middle": ["D"], "last": "Joannopoulos", "suffix": ""}], "year": 1992, "venue": "Rev. Mod. Phys", "link": "91720571"}, "BIBREF45": {"title": "Band theory and mott insulators: hubbard U instead of stoner I", "authors": [{"first": "V", "middle": ["I"], "last": "Anisimov", "suffix": ""}, {"first": "J", "middle": [], "last": "Zaanen", "suffix": ""}, {"first": "O", "middle": ["K"], "last": "Andersen", "suffix": ""}], "year": 1991, "venue": "Phys. Rev. B", "link": null}, "BIBREF46": {"title": "Ab initio DFT plus U predictions of tensile properties of iron oxides", "authors": [{"first": "P", "middle": [], "last": "Liao", "suffix": ""}, {"first": "E", "middle": ["A"], "last": "Carter", "suffix": ""}], "year": 2010, "venue": "J. Mater. Chem", "link": null}, "BIBREF47": {"title": "Linear response approach to the calculation of the effective interaction parameters in the LDA\u00feU method", "authors": [{"first": "M", "middle": [], "last": "Cococcioni", "suffix": ""}, {"first": "S", "middle": [], "last": "De Gironcoli", "suffix": ""}], "year": 2005, "venue": "Phys. Rev. B", "link": null}, "BIBREF48": {"title": "Generalized gradient approximation made simple", "authors": [{"first": "J", "middle": ["P"], "last": "Perdew", "suffix": ""}, {"first": "K", "middle": [], "last": "Burke", "suffix": ""}, {"first": "M", "middle": [], "last": "Ernzerhof", "suffix": ""}], "year": 1996, "venue": "Phys. Rev. Lett", "link": "6425905"}, "BIBREF49": {"title": "Microscopic properties of lithium, sodium, and magnesium battery anode materials related to possible dendrite growth", "authors": [{"first": "M", "middle": [], "last": "Jaeckle", "suffix": ""}, {"first": "A", "middle": [], "last": "Gross", "suffix": ""}], "year": 2014, "venue": "J. Chem. Phys", "link": null}, "BIBREF50": {"title": "Adsorption at nanostructured surfaces from first principles", "authors": [{"first": "A", "middle": [], "last": "Gross", "suffix": ""}], "year": 2008, "venue": "J. Comput. Theor. Nanosci", "link": "53387292"}, "BIBREF51": {"title": "Tailoring the reactivity of bimetallic overlayer and surface alloy systems", "authors": [{"first": "A", "middle": [], "last": "Gross", "suffix": ""}], "year": 2009, "venue": "J. Phys. Condens. Matter", "link": "14974490"}, "BIBREF52": {"title": "Ab initio full-potential study of the structural and magnetic phase stability of iron", "authors": [{"first": "H", "middle": ["C"], "last": "Herper", "suffix": ""}, {"first": "E", "middle": [], "last": "Hoffmann", "suffix": ""}, {"first": "P", "middle": [], "last": "Entel", "suffix": ""}], "year": 1999, "venue": "Phys. Rev. B", "link": "121352240"}, "BIBREF53": {"title": "Surface energy and work function of elemental metals", "authors": [{"first": "H", "middle": ["L"], "last": "Skriver", "suffix": ""}, {"first": "N", "middle": ["M"], "last": "Rosengaard", "suffix": ""}], "year": 1992, "venue": "Phys. Rev. B", "link": "42350219"}, "BIBREF54": {"title": "Diatomic molecules according to the wave mechanics. II. Vibrational levels", "authors": [{"first": "P", "middle": ["M"], "last": "Morse", "suffix": ""}], "year": 1929, "venue": "Phys. Rev", "link": null}}, "ref_entries": {}}
{"paper_id": "102801740", "_pdf_hash": "c1a049ffe44fb4d73449df0c312596da01d7e3f8", "abstract": [{"section": "Abstract", "text": "Abstract: Studies of the volume change behaviour of saturated and unsaturated fine-grained 5 soils upon exposure to various types of fluid are of significant interest while dealing with 6 contaminated soils. In this study, the one-dimensional volume change behaviour of two clays 7 (Spergau kaolin and Calcigel bentonite) with dominant minerals as kaolinite and 8 montmorillonite was studied by inundating several initially unsaturated and saturated clay 9 specimens with water and a non-polar organic liquid (heptane). For both cases, applied 10 vertical pressures of 25 and 100 kPa were considered under oedometric conditions. The 11 magnitude of compression and swelling deformations of the clays were found to be strongly ", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "1", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Introduction 27 28", "text": "Studies of the volume change behaviour of fine-grained soils upon exposure to 29 various types of fluid are of great interest, particularly while dealing with contaminated soils. 30", "cite_spans": [], "ref_spans": []}, {"section": "Introduction 27 28", "text": "Contamination of soils in vadose zone may occur due to industrial activity, agricultural 31 chemicals, gasoline spillage, and improper disposal of waste. Similarly, mitigation strategies 32 adopted for soils contaminated with various organic contaminants demands understanding of 33 the soil-contaminant interaction at various stress states of soils. 34", "cite_spans": [], "ref_spans": []}, {"section": "35", "text": "The physico-chemical interaction between soil particles and their influence on the 36 volume change behaviour of fine grained soils depends upon the clay mineralogy and the 37 pore fluid characteristics (e.g., Sridharan and Rao, 1973; Lagaly 1989; Mitchell and Soga 38 2005) . Organic fluids, chemicals, and petroleum products usually possess dielectric constant 39 values far lower than that of water. A review of the literature suggests that the influence of 40 organic fluids on the plasticity properties, compressibility, shear strength, and hydraulic 41 conductivity of saturated clays has been studied in detail by several researchers in the past 42 (Mesri and Olson 1971; Sridharan and Rao 1973; Sridharan and Rao 1979; Fernandez and 43 Quigley 1985; Lagaly 1989; Shang et al. 1994; Kaya and de Brito Galvao 1998; Kaya and 44 Fang 2005) . However, studies concerning the volume change behaviour of compacted 45 unsaturated clays upon exposure to organic fluids, particularly in the context of the influence 46 of mineralogy, compaction conditions, and applied external stress are scarce in the literature. 47 until the equilibrium conditions were attained. At each compaction conditions (see Tables 2  145   and 3 ), four specimens were tested. In total, thirty-six clay specimens were tested, sixteen for 146 Spergau kaolin and twenty for Calcigel bentonite. 147", "cite_spans": [], "ref_spans": [{"start": 1199, "end": 1220, "text": "Tables 2  145   and 3", "ref_id": "TABREF1"}]}, {"section": "148", "text": "The dielectric constant of water is 80.4, whereas that of heptane is 1.92 as against the 149 dielectric constant of air of 1.0. Additionally, water is a polar liquid, whereas heptane is a 150 non-polar organic liquid. Heptane is a highly flammable solvent. Extreme care was exercised 151 while handling the solvent by wearing gloves and a medical mask. The oedometer tests were 152 6 carried out in an isolated room with appropriate ventilation system. Similarly, appropriate 153 disposal methods were undertaken after completion of the laboratory tests. 154", "cite_spans": [], "ref_spans": []}, {"section": "155", "text": "Prior to testing for the clay specimens, the pressure-deformation characteristics of the 156 oedometers used were studied using a steel dummy following the procedure suggested by 157 ASTM (1998). Based on the pressure-deformation characteristics of the oedometers used, the 158 measured heights of the specimens at each loading steps were corrected for calculating the 159 actual vertical deformations. The vertical deformation at equilibrium under any given applied 160 vertical pressure is defined as the ratio of the change in height of a specimen upon either 161 swelling or compression to the height of the specimens prior to inundation and is expressed 162 as a percentage. The void ratio changes during swelling or compression of the specimens 163", "cite_spans": [], "ref_spans": []}, {"section": "155", "text": "were calculated based on height of solids method. 164 pressure (25 or 100 kPa), the compression deformation was significantly smaller for the 183 specimens that were inundated with heptane than that occurred with water, (ii) the vertical 184 deformation decreased with an increase in the initial compaction dry density and with an 185 increase in the water content for both inundating fluid types, and (iii) the vertical deformation 186 increased with an increase in the applied stress for both fluid types. 187", "cite_spans": [], "ref_spans": []}, {"section": "188", "text": "For the saturated clay specimens with an initial water content of 61.5% (Fig. 2b) Table 3 ), such as (i) the swelling deformation was significantly greater for the 207 specimens that were inundated with water as against their counterparts that were inundated 208 with heptane, (ii) with an increase in the applied stress during inundation with any fluid, the 209 deformation behaviour of the specimens was accompanied by either a decrease in the 210 swelling deformation or an increase in the compression deformation, or even specimens that 211 exhibited swelling at 25 kPa, underwent compression at 100 kPa, (iii) for the specimens with 212 an initial water content of 0%, an increase in the compaction dry density caused an increase 213 in swelling deformation, whereas swelling deformation decreased with an increase in the 214 initial water content for the same compaction dry density (see results for dry density of 1.10 215 Mg/m 3 in Table 3 ). 216", "cite_spans": [], "ref_spans": [{"start": 82, "end": 89, "text": "Table 3", "ref_id": "TABREF1"}, {"start": 940, "end": 947, "text": "Table 3", "ref_id": "TABREF1"}]}, {"section": "217", "text": "The test results presented in Figs. 3, 4, and 5 clearly indicated that unlike the 218 deformation behaviour of the unsaturated specimens of Spergau kaolin, in which case the 219 compression deformation invariably increased with an increase in applied vertical pressure 220 and for both inundation fluids used (Figs. 1 and 2, Table 2), the deformation behaviour was 221 found to be reversed in the case of Calcigel bentonite. In the latter case, the swelling 222 deformation decreased with an increase in the vertical pressure. Additionally, the influence of 223 fluid type and applied vertical pressure was found to be quite significant on the volume 224 change behaviour of the specimens that were initially saturated ( Table 4 summarises the influence of a decrease in the dielectric constant of the 230 inundating fluid, an increase in the applied stress during the inundation process, an increase 231 in the compaction water content, and an increase in the compaction dry density on the vertical 232 deformation of clay specimens observed in this study. The possible reasons for the volume 233 change of clays are presented in Table 4 . 234", "cite_spans": [], "ref_spans": []}, {"section": "217", "text": "Further, the results can also be explained by the changes in the effective stress that has 235 been brought out by changes in normal stress, repulsive and attractive forces. It has been now 236 widely accepted that Terzaghi's concept of effective stress provides a satisfactory basis for 237 understanding the strength and deformation characteristics of saturated soils, which can be 238 It may be noted that \u03c3' is the contact stress at mineral to mineral contact zone, which 246 is also called inter-granular stress. While one can discuss at greater length the nature of this 247 contact, for purpose of brevity, it can be said that the role of contact is to transfer the stress. It 248 has been brought out earlier that both electrical attractive and repulsive forces exist between 249 clay particles. Since the fine grained soils are normally composed of clays, the existence of 250 attractive and repulsive forces in the soil-water system is inevitable. The studies of Sridharan 251 10 (1968) and Sridharan and Rao (1973, 1979) other. If the pore water pressure is negative (i.e., capillary pressure operative in partly 271 saturated soils), its role is to bring the particles closer to each other. The average contact 272 stress or the intergranular stress ( c ) between particles, is defined as the modified effective 273 stress and it is hypothesised that c is the stress controlling the shearing resistance and 274 volume changes that take place in soil-water system. In fine-grained soils / clayey soils, the 275 attractive and repulsive forces cannot be neglected, especially when the water content and the 276 soil plasticity are high. Since the clay-water system is complex, quantitative determination of 277 R and A becomes difficult for real systems. However, qualitative evaluation could be done. 278", "cite_spans": [], "ref_spans": []}, {"section": "217", "text": "The validity of eqns. (2) caused an increase in the modified effective stress and two distinct effects, such as that (i) the 305 interparticle shearing resistance did not decrease as that occurred with water as the inundating 306 fluid thereby causing a lesser compression of the specimens of Spergau kaolin and (ii) since 307 the electrical double layer thickness was reduced in case of Calcigel bentonite, the clay 308 exhibited a lesser swelling as compared to that occurred with water as the inundating fluid. 309", "cite_spans": [], "ref_spans": []}, {"section": "217", "text": "The magnitude of applied stress on the clays can be considered to have two effects, such as 310 an increase in the applied stress acts against the interparticle shearing resistance to cause a 311 greater deformation in case of Spergau kaolin and it acts as a restraint against the expansion 312 of the electrical double layer thereby causing a reduction in the swelling deformation in case 313 of Calcigel bentonite. 314 315 An increase in the initial compaction water content and its influence on the 316 deformation behaviour of the clays can be considered separately for the two inundating fluids 317 considered in this study (i.e., water and heptane). An increase in the compaction water 318 content causes a reduction in the inter-particle shearing resistance since the attractive pressure 319 is inversely proportional to the dielectric constant of the pore fluid. Additionally, an increase 320 in the compaction water content causes the hydration of the surfaces and the ions. A further 321 increase in the compaction water content above that is required for surface and ion hydration 322 aids in the formation of the electrical double layer. The increased volume of the clay due to 323 the expansion of the electrical double layer depends upon the volume of water available and 324 the type of clay mineral present. With the inundating fluid as water, the changes in the 325 vertical deformation in case Spergau kaolin was found to be minor since the pore fluid 326 13 remained unchanged. The swelling deformation in the case of Calcigel bentonite also reduced 327 since a part of the swelling process was already completed during the specimen preparation 328 stage. The clay specimens of Calcigel bentonite exhibited further swelling primarily due to 329 the available of water which caused a further expansion of the electrical double layer. 330 331 Replacement of water by heptane can be considered when the inundating fluid used 332 was heptane. This would tend to cause an increase in the inter-particle shearing resistance 333 primarily due to an increase in the attractive pressure and a decrease in thickness of the 334 electrical double layer. A replacement of molecules of water by heptane for kaolinite is 335 expected to cause no significant change in terms of the deformation, but due to a change in 336 the magnitude of the attractive pressure the clay may tend to flocculate causing an increase in 337 the volume (see test results for specimens at water content = 12% in Table 2 ). A decrease in 338 the thickness of electrical double layer in case of Calcigel bentonite reduced the swelling 339 deformation of the clay. Saturated specimens exhibited slight swelling deformation which 340 indicated that replacement of water with heptane will increase the electrical attractive forces 341 resulting in a relatively flocculent fabric which tend to get eliminated as the applied stress 342 increased (see test results of initially saturated specimens in Table 3) . 343 344 An increase in the compaction dry density is associated with an increase in the applied 345 stress that overcomes the inter-particle shearing resistance and tends to produce a more 346 Thus it can be seen that the volume change (compression or swelling) behaviour of 359 both the clays in this study can be explained by the changes in the intrinsic effective stress, 360 defined by equations (2) and (3), brought out by the changes in the electrical attractive and 361 repulsive pressures (influenced by the fluid types by their di-electric constant values), the 362 negative pore pressures and the externally applied stress. 363 364", "cite_spans": [], "ref_spans": [{"start": 2494, "end": 2501, "text": "Table 2", "ref_id": "TABREF3"}, {"start": 2975, "end": 2983, "text": "Table 3)", "ref_id": "TABREF1"}]}, {"section": "Conclusions 365 366", "text": "The one-dimensional volume change behaviour of kaolinite and montmorillonite-rich 367 clays is presented in this paper. Several initially unsaturated and saturated clay specimens 368 were inundated either with water or heptane at applied vertical pressures of 25 and 100 kPa. 369", "cite_spans": [], "ref_spans": []}, {"section": "370", "text": "The test results clearly showed that the physico-chemical forces within the clay-fluid 371 systems are significantly influenced by the mineralogy of clays, the properties of the 372 hydrating and the inundating fluids, the compaction dry density and water content, and the 373 applied stress during the inundation process. The kaolinite-rich clay in this study exhibited 374 low compression with both water and heptane, whereas the montmorillonite clay exhibited 375 significant swelling (up to 23%) with water, whereas in the kaolinite clay exhibited swelling 376 ", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Snehasis Tripathy 2 , Reader, TripathyS@cf.ac.uk and Prof. Asuri Sridharan 3 , Honorary Research Scientist, sridharanasuri@yahoo.com Address: \u2020 Deceased 12", "authors": [{"first": "", "middle": ["Tom"], "last": "Prof", "suffix": ""}, {"first": "\u2020", "middle": [], "last": "Schanz", "suffix": ""}, {"first": "", "middle": [], "last": "Professor", "suffix": ""}, {"first": "", "middle": [], "last": "De Dr", "suffix": ""}], "year": 2017, "venue": "Formerly", "link": null}}, "ref_entries": {"FIGREF0": {"text": "time versus void ratio plots for Spergau kaolin specimens at four 170 different initial placement conditions, two different applied vertical pressures (i.e., 25 and 171 100 kPa), and with water and heptane as the inundating fluids are shown in Figs. 1 and 2. The 172 vertical deformations of the specimens at equilibrium are shown in", "type": "figure"}, "FIGREF1": {"text": "at any given applied pressure and with both water and heptane as the 190 inundating fluids were very nearly similar clearly indicating that the pore-fluid type has 191 limited impact on the volume change behaviour of saturated kaolinites.time versus void ratio plots for the specimens of Calcigel bentonite at 196 five different initial placement conditions, two different applied vertical pressures (i.e., 25 197 and 100 kPa), and with water and heptane as the inundating fluids are shown in Figs. 3, 4, 198 and 5. The initial compaction conditions of the specimens, the inundation fluids used, and the 199 applied vertical pressures are shown in Figs. 3 to 5. The vertical deformations of the 200 specimens at equilibrium are given in", "type": "figure"}, "FIGREF2": {"text": "Table 3). This was 225 not evident in the case of saturated Spergau kaolin specimens (Figs. 2b and Table 2). 226 227 9 5. Influence of physico-chemical forces on the volume change of clays 228 229", "type": "figure"}, "FIGREF4": {"text": "saturated system, where c is the average contact stress, \uf073 is actual contact stress at 257 mineral -to -mineral level, a m is area fraction over which \uf073 acts or percentage area through 258 which \uf073 acts (non-dimensional), \u03c3 = the external applied stress, u = pore water pressure, R = 259 average repulsive pressure acting throughout the area, A = average attractive pressure'' is the intrinsic effective stress and \u03c3' is the conventional effective stress. 267 268 It may further be stated that the effect of \u03c3 and A is to bring the particles closer to each 269 other. The effect of positive pore water pressure and R is to keep the particles away from each 270", "type": "figure"}, "FIGREF5": {"text": "and (3) have been qualitatively studied extensively considering the 279 volume change behaviour (Sridharan and Rao 1973; Sridharan et al. 1973; Sridharan 2003:), 280 the strength behaviour (Sridharan et al. 1971; Sridharan and Rao 1979; Allam and Sridharan 281 1981; Sridharan et al. 1983; Sridharan and Prakash, 1999b), the shrinkage phenomena 282 (Sridharan and Rao 1971), the secondary compression behaviour (Sridharan and Rao 1982) 283 and the sediment formation (Sridharan and Prakash 1999a). 284 285 The thickness of the electrical double layer that is formed around the clay particles 286 are influenced by several factors (Mitchell and Soga 2005), such as the characteristics of the 287 hydrating fluid, the type and amount of exchangeable cation present in the clay, the specific 288 surface area, the applied external stress, and the temperature (Verwey and Overbeek 1948; 289 van Olphen 1977; Sridharan and Rao 1979; and Sridharan and Jayadeva 1982). The thickness 290 of the electrical double layer controls the swelling, compressibility, shear strength, and 291 hydraulic conductivity in clays. The factors that cause an increase in the thickness of 292 electrical double layer are also responsible for a higher magnitude of swelling deformation in 293 expansive clays resulting in a decrease in the modified effective stress. Similarly, the factors 294 that cause a decrease in the thickness of electrical double layer aid in an increasing the 295 modified effective stress and increasing the shearing resistance and cause a decrease in the 296 compressibility and the hydraulic conductivity. 297 298 The attractive force varies inversely and the repulsive force varies directly with the 299 dielectric constant of the pore fluid (Sridharan and Rao 1973 and 1979). Therefore, a 300 decrease in the dielectric constant of the pore fluid caused two opposite effects for both clays12 in this study when the inundating fluid was heptane, such as an increase in the attractive 302 pressure and a decrease in the repulsive pressure and thus an increase in the modified 303 effective stress. A greater mobilised attractive pressure with heptane as the inundating fluid 304", "type": "figure"}, "FIGREF6": {"text": "oriented fabric perpendicular to the direction of the applied load. A decrease in the void ratio 347 brings the clay particles closer towards each other which in turn, causes an increase in the 348 attractive pressure. Ignoring the orientation of clay particles and the difference in the 349 magnitude of the attractive pressure, under any given applied stress, clay specimens with 350 different initial compaction dry densities but with same initial water content may exhibit 351 14 different vertical deformations, but should attain the same void ratio upon saturation. A 352 decrease in the compression deformation in case of Spergau kaolin is attributed due to an 353 increase in the attractive pressure, whereas an increase in the swelling deformation due to an 354 increase in the compaction dry density in the case of Calcigel bentonite is attributed due to 355 expansion of the electrical double layer in response to the applied stress during the", "type": "figure"}, "FIGREF7": {"text": "Figure captions 497", "type": "figure"}, "FIGREF8": {"text": "Fig. 4 Time-deformation behaviour of Spergau kaolin specimens (initial water content = 9%) 520 521", "type": "figure"}, "TABREF0": {"text": "Following inundation of the specimens either with water or heptane, except two 175 specimens that exhibited a small volume increase upon inundated with heptane (water 176, Figs. 1 and 2). The compression deformation of the specimens occurred within 178 about 15 to 25 minutes following the inundation process in all cases. 179 180 The test results of the initially unsaturated specimens showed three distinct trends in 181 terms of the volume change (Table 2, Figs. 1a, 1b and 2a), such as (i) at any applied vertical 182", "type": "table"}, "TABREF1": {"text": "Following inundation either with water or heptane, except four specimens with high 203 initial void ratios of 1.94 and 1.8 that underwent slight compression at an applied stress of 204 100 kPa, all other specimens (Table 3) exhibited swelling. The test results of the initially 205 unsaturated specimens showed three distinct trends in terms of the volume change (Figs.", "type": "table"}, "TABREF2": {"text": "Properties of the clays used in the study 482", "type": "table"}, "TABREF3": {"text": "", "type": "table"}, "TABREF4": {"text": "", "type": "table"}, "TABREF5": {"text": "", "type": "table"}, "TABREF6": {"text": "Initial compaction conditions: Water content = 0%, Dry density = 0.95 Mg/m 3 Void ratio = 1.94, Degree of saturation = 0.0%", "type": "table"}, "TABREF7": {"text": "Fig. 5 Time-deformation behaviour of Calcigel bentonite specimens with initial water 525 contents of (a) 55.2% and (b) 64.3% 526Initial compaction conditions: Water content = 55.2% Dry density = 1.0 Mg/m 3 Void ratio = 1.54 Degree of saturation = 100.0%Water content = 64.3%, Dry density = 1.0 Mg/m 3 Void ratio = 1.80, Degree of saturation = 100.0%", "type": "table"}}}
{"paper_id": "102803056", "_pdf_hash": "d2cd40f569f0f651ac3ed423f1e06805429af4a1", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "149771561", "_pdf_hash": "c64b564cbd34bfbc82e0b41049da107b9bcb83d7", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Integrating soft skills assessment through soft skills workshop program for engineering students at University of Pahang: an analysis", "authors": [{"first": "R", "middle": [], "last": "Abbas", "suffix": ""}, {"first": "F", "middle": ["A A"], "last": "Kadir", "suffix": ""}, {"first": "I", "middle": ["A G"], "last": "Azmie", "suffix": ""}], "year": 2013, "venue": "International Journal", "link": "53443688"}, "BIBREF1": {"title": "University-industry cooperation in the education domain to foster competitiveness and employment", "authors": [{"first": "A", "middle": [], "last": "Afonso", "suffix": ""}, {"first": "J", "middle": ["J"], "last": "Ram\u00edrez", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "D\u00edaz-Puente", "suffix": ""}], "year": 2012, "venue": "Procedia-Social and Behavioral Sciences", "link": "143939324"}, "BIBREF2": {"title": "Employability skills development: strategy, evaluation and impact", "authors": [{"first": "G", "middle": [], "last": "Andrews", "suffix": ""}, {"first": "M", "middle": [], "last": "Russell", "suffix": ""}], "year": 2012, "venue": "Higher Education, Skills and Work-Based Learning", "link": "110959766"}, "BIBREF3": {"title": "Graduate employability, 'soft skills' versus 'hard' business knowledge: A European study", "authors": [{"first": "J", "middle": [], "last": "Andrews", "suffix": ""}, {"first": "H", "middle": [], "last": "Higson", "suffix": ""}], "year": 2008, "venue": "Europe", "link": "145408312"}, "BIBREF4": {"title": "Measurement Matters Assessing Personal Qualities Other Than Cognitive Ability for Educational Purposes", "authors": [{"first": "L", "middle": ["D"], "last": "Angela", "suffix": ""}, {"first": "", "middle": ["S Y"], "last": "David", "suffix": ""}], "year": 2015, "venue": "", "link": "8769528"}, "BIBREF5": {"title": "Employability skills in higher education and the case of Greece", "authors": [{"first": "S", "middle": [], "last": "Asonitou", "suffix": ""}], "year": 2015, "venue": "Procedia Social and Behavioral Sciences", "link": "169427037"}, "BIBREF6": {"title": "Competency development in business graduates: An industry-driven approach for examining the alignment of undergraduate business education with industry requirements", "authors": [{"first": "A", "middle": [], "last": "Azevedo", "suffix": ""}, {"first": "G", "middle": [], "last": "Apfelthaler", "suffix": ""}, {"first": "D", "middle": [], "last": "Hurst", "suffix": ""}], "year": 2012, "venue": "The International Journal of Management Education", "link": "144421247"}, "BIBREF7": {"title": "Essential research skills", "authors": [{"first": "V", "middle": [], "last": "Bailey", "suffix": ""}, {"first": "G", "middle": [], "last": "Bemrose", "suffix": ""}, {"first": "S", "middle": [], "last": "Goddard", "suffix": ""}, {"first": "R", "middle": [], "last": "Impey", "suffix": ""}, {"first": "E", "middle": [], "last": "Joslyn", "suffix": ""}, {"first": "J", "middle": [], "last": "Mackness", "suffix": ""}], "year": 1996, "venue": "", "link": null}, "BIBREF8": {"title": "Defining the content domain of intercultural competence for global leaders", "authors": [{"first": "A", "middle": [], "last": "Bird", "suffix": ""}, {"first": "M", "middle": [], "last": "Mendenhall", "suffix": ""}], "year": 2010, "venue": "Journal of Managerial Psychology", "link": "143174885"}, "BIBREF9": {"title": "Growing an achievement gap. Education Week", "authors": [{"first": "G", "middle": ["W"], "last": "Bracey", "suffix": ""}], "year": 2007, "venue": "", "link": null}, "BIBREF10": {"title": "Confederation of British Industry (Great Britain) (CBI) Education Development International (Great Britain)(EDI)", "authors": [{"first": "J", "middle": [], "last": "Bryson", "suffix": ""}], "year": 2011, "venue": "Journal of Education and Work", "link": null}, "BIBREF11": {"title": "Defining and developing your approach to employability: A framework for higher education institutions. Heslington: The Higher Education Academy", "authors": [{"first": "D", "middle": [], "last": "Cole", "suffix": ""}, {"first": "M", "middle": [], "last": "Tibby", "suffix": ""}], "year": 2013, "venue": "", "link": null}, "BIBREF12": {"title": "Global graduates into global leaders. Paper presented by The Association of Graduate Recruiters, The Council for Industry and Higher Education and CFE Research and Consulting", "authors": [{"first": "A", "middle": [], "last": "Diamond", "suffix": ""}, {"first": "L", "middle": [], "last": "Walkley", "suffix": ""}, {"first": "P", "middle": [], "last": "Forbes", "suffix": ""}, {"first": "T", "middle": [], "last": "Hughes", "suffix": ""}, {"first": "J", "middle": [], "last": "Sheen", "suffix": ""}], "year": 2011, "venue": "", "link": null}, "BIBREF13": {"title": "Modernisation of Higher Education in Europe: Funding and the Social Dimension. Education, Audiovisual and Culture Executive Agency", "authors": [{"first": "D", "middle": [], "last": "Crosier", "suffix": ""}, {"first": "S", "middle": [], "last": "Dalferth", "suffix": ""}, {"first": "V", "middle": [], "last": "Kerpanova", "suffix": ""}, {"first": "T", "middle": [], "last": "Parveva", "suffix": ""}], "year": 2011, "venue": "", "link": null}, "BIBREF14": {"title": "Is mass higher education working? Evidence from the labour market experiences of recent graduates", "authors": [{"first": "P", "middle": [], "last": "Elias", "suffix": ""}, {"first": "K", "middle": [], "last": "Purcell", "suffix": ""}], "year": 2004, "venue": "National Institute Economic Review", "link": "153536117"}, "BIBREF15": {"title": "The Erasmus impact study: Effects of mobility on the skills and employability of students and the internationalization of higher education institutions. The European Union", "authors": [{"first": "European", "middle": [], "last": "Union", "suffix": ""}], "year": 2014, "venue": "", "link": null}, "BIBREF16": {"title": "Employer and university engagement in the use and development of graduate level skills", "authors": [{"first": "T", "middle": [], "last": "Hogarth", "suffix": ""}, {"first": "M", "middle": [], "last": "Winterbotham", "suffix": ""}, {"first": "C", "middle": [], "last": "Hasluck", "suffix": ""}, {"first": "K", "middle": [], "last": "Carter", "suffix": ""}, {"first": "W", "middle": ["W"], "last": "Daniel", "suffix": ""}, {"first": "A", "middle": ["E"], "last": "Green", "suffix": ""}, {"first": "J", "middle": [], "last": "Morrison", "suffix": ""}], "year": 2007, "venue": "", "link": "154234957"}, "BIBREF17": {"title": "Chinese international students' perspective and strategies in preparing for their future employability", "authors": [{"first": "R", "middle": [], "last": "Huang", "suffix": ""}, {"first": "R", "middle": [], "last": "Turner", "suffix": ""}, {"first": "Q", "middle": [], "last": "Chen", "suffix": ""}], "year": 2014, "venue": "Training", "link": "42924881"}, "BIBREF18": {"title": "Student perceptions of the importance of employability skill provision in business undergraduate programs", "authors": [{"first": "D", "middle": [], "last": "Jackson", "suffix": ""}], "year": 2013, "venue": "Journal of Education for Business", "link": null}, "BIBREF19": {"title": "Employability skills initiatives in higher education: What effects do they have on graduate labour market outcomes? Education Economics", "authors": [{"first": "G", "middle": [], "last": "Mason", "suffix": ""}, {"first": "G", "middle": [], "last": "Williams", "suffix": ""}, {"first": "S", "middle": [], "last": "Cranmer", "suffix": ""}], "year": 2009, "venue": "", "link": "153712945"}, "BIBREF20": {"title": "Education to employment: Designing a system that works. McKinsey Center for Government. Retrieved from mckinseyonsociety", "authors": [{"first": "M", "middle": [], "last": "Mourshed", "suffix": ""}, {"first": "D", "middle": [], "last": "Farrell", "suffix": ""}, {"first": "D", "middle": [], "last": "Barton", "suffix": ""}], "year": 2012, "venue": "", "link": null}, "BIBREF21": {"title": "Generational Differences in Work Ethic: An Examination of Measurement Equivalence Across Three Cohorts", "authors": [{"first": "J", "middle": [], "last": "Meriac", "suffix": ""}, {"first": "D", "middle": [], "last": "Woehr", "suffix": ""}, {"first": "C", "middle": [], "last": "Banister", "suffix": ""}], "year": 2010, "venue": "Journal of Business and Psycholo gy", "link": "144303965"}, "BIBREF22": {"title": "Problems of educational processes development and labor market needs analysis in Russia", "authors": [{"first": "C", "middle": [], "last": "Natalia", "suffix": ""}, {"first": "S", "middle": [], "last": "Maria", "suffix": ""}, {"first": "S", "middle": [], "last": "Vladislav", "suffix": ""}, {"first": "P", "middle": [], "last": "Paquet", "suffix": ""}], "year": 2015, "venue": "Procedia -Social and Behavioral Sciences", "link": "154681581"}, "BIBREF23": {"title": "Enhancing Individual Employability: The Perspective of Engineering Graduates", "authors": [{"first": "S", "middle": [], "last": "Nilsson", "suffix": ""}], "year": 2010, "venue": "Education + Training", "link": "167769131"}, "BIBREF24": {"title": "Towards an OECD Skills Strategy", "authors": [{"first": "", "middle": [], "last": "Oecd", "suffix": ""}], "year": 2011, "venue": "", "link": null}, "BIBREF25": {"title": "Global competency is not enough: Attaining global citizenship", "authors": [{"first": "G", "middle": [], "last": "Ouyang", "suffix": ""}, {"first": "S", "middle": [], "last": "Mcalpine", "suffix": ""}], "year": 2013, "venue": "EAIE Summer Forum: Discussing International Education-Social Responsibility", "link": null}, "BIBREF26": {"title": "Determinants of knowledge sharing using Web 2.0 technologies", "authors": [{"first": "S", "middle": [], "last": "Paroutis", "suffix": ""}, {"first": "A", "middle": [], "last": "Saleh", "suffix": ""}], "year": 2009, "venue": "Journal of knowledge management", "link": "16280433"}, "BIBREF27": {"title": "Employability skills assessment: Measuring work ethic for research and learning. Career and Technical Education Research", "authors": [{"first": "H", "middle": [], "last": "Park", "suffix": ""}, {"first": "R", "middle": ["B"], "last": "Hill", "suffix": ""}], "year": 2016, "venue": "", "link": null}, "BIBREF28": {"title": "Effective education for employment: A global perspective", "authors": [{"first": "J", "middle": [], "last": "Playfoot", "suffix": ""}, {"first": "R", "middle": [], "last": "Hall", "suffix": ""}], "year": 2009, "venue": "", "link": null}, "BIBREF29": {"title": "Real estate graduates' employability skills: the perspective of human resource managers of surveying firms. Property management", "authors": [{"first": "J", "middle": [], "last": "Poon", "suffix": ""}], "year": 2012, "venue": "", "link": "154055444"}, "BIBREF30": {"title": "Employer engagement: Emerging practice from QAA reviews. The Quality Assurance Agency (QAA)", "authors": [{"first": "", "middle": [], "last": "Qaa", "suffix": ""}], "year": 2014, "venue": "", "link": null}, "BIBREF31": {"title": "Why Technical People Need Nontechnical Skills on Their Resumes", "authors": [{"first": "Robins", "middle": [], "last": "Resumes", "suffix": ""}], "year": 2015, "venue": "", "link": null}, "BIBREF32": {"title": "A Framework for 21st-Century Career-Technical and Workforce Education Curricula", "authors": [{"first": "J", "middle": ["W"], "last": "Rojewski", "suffix": ""}, {"first": "R", "middle": ["B"], "last": "Hill", "suffix": ""}], "year": 2017, "venue": "Peabody Journal of Education", "link": "152240316"}, "BIBREF33": {"title": "Beyond Empty Promises: Policies To Improve Transitions into College and Jobs", "authors": [{"first": "J", "middle": ["E"], "last": "Rosenbaum", "suffix": ""}], "year": 2002, "venue": "", "link": "150548110"}, "BIBREF34": {"title": "Fostering Integrity in Research: Definitions, Current Knowledge, and Future Directions", "authors": [{"first": "J", "middle": [], "last": "Schermerhorn", "suffix": ""}], "year": 2006, "venue": "Science and Engineering Ethics", "link": "38008107"}, "BIBREF35": {"title": "Millennial behaviors & demographics", "authors": [{"first": "R", "middle": [], "last": "Sweeney", "suffix": ""}], "year": 2006, "venue": "New Jersey Institute of Technology", "link": null}, "BIBREF36": {"title": "The effectiveness of access restriction to higher education in decreasing over education", "authors": [{"first": "A", "middle": [], "last": "Tarvid", "suffix": ""}], "year": 2015, "venue": "Economic Analysis and Policy", "link": "153801838"}, "BIBREF37": {"title": "Is graduate employability the 'whole-of-higher-education-issue'?", "authors": [{"first": "T", "middle": ["T"], "last": "Tran", "suffix": ""}], "year": 2015, "venue": "Journal of Education and Work", "link": "153464029"}, "BIBREF38": {"title": "Secretary's Commission on Achieving Necessary Skills(SCANS) Blueprint for Action: Building Community Coalitions", "authors": [], "year": 1991, "venue": "", "link": null}, "BIBREF39": {"title": "How does social software change knowledge management? Toward a strategic research agenda", "authors": [{"first": "Von", "middle": [], "last": "Krogh", "suffix": ""}, {"first": "G", "middle": [], "last": "", "suffix": ""}], "year": 2012, "venue": "Journal of Strategic Information Systems", "link": "7563397"}, "BIBREF40": {"title": "Employability skills initiatives in higher education: what effects do they have on graduate labour market outcomes?", "authors": [{"first": "G", "middle": [], "last": "Williams", "suffix": ""}, {"first": "S", "middle": [], "last": "Cranmer", "suffix": ""}], "year": 2009, "venue": "Education Economics", "link": "153712945"}, "BIBREF41": {"title": "Business graduates and management jobs: an employability match made in heaven?", "authors": [{"first": "N", "middle": [], "last": "Wilton", "suffix": ""}], "year": 2008, "venue": "Journal of Education and Work", "link": "155044569"}, "BIBREF42": {"title": "Embedding Employability into the Curriculum: Learning & Employability Series 1.The Higher Education Academy", "authors": [{"first": "M", "middle": [], "last": "Yorke", "suffix": ""}, {"first": "P", "middle": ["T"], "last": "Knight", "suffix": ""}], "year": 2006, "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "149771692", "_pdf_hash": "69e0594f83f39f9d1c0790b2243b52323779a3c8", "abstract": [], "body_text": [{"section": "", "text": "whether the signaler repeated the scratch gesture in the same location (persistence) or presented the same body part to the groomer (elaboration) in the 30 seconds after the first scratch ended. Such persistence and elaboration behaviours would have indicated that the signaler's goal was to request grooming in a specific location.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "We found little evidence of chimpanzees in Sonso and Kanyawara communities using 'big loud scratch' gestures to request grooming in a specific location. Very few scratches elicited grooming in the scratched location, and when the groomer failed to groom the scratched location, very few instances of persistence or elaboration to reach the goal were shown. This indicates that in these two communities of wild chimpanzees the signaler's goal is not to elicit grooming in a specific location. In contrast, we found 'present groom' gestures were highly successful in eliciting grooming on the presented body part and that big loud scratches were frequently used to initiate grooming bouts.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "These findings show that the habitual use of referential gestures with conspecifics is not a universal aspect of chimpanzee communication and it highlights the importance of replicating important findings in multiple populations. Our findings raise the intriguing possibility that the referential use of the big loud scratch gesture is culturally specific to the Ngogo community, and thus more detailed analysis of this behavior and examination of the signaler's goals and circumstances that have given rise to this form of communication are required in this community. For now, it seems that when not faced with the 'referential problem space' that captivity brings (Leavens et al., 2005) , not all wild chimpanzees habitually produce referential gestures and referential gesturing is not a ubiquitous feature of chimpanzee communication.", "cite_spans": [{"start": 667, "end": 689, "text": "(Leavens et al., 2005)", "ref_id": "BIBREF1"}], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Referential communication by chimpanzees (Pan troglodytes)", "authors": [{"first": "D", "middle": ["A"], "last": "Leavens", "suffix": ""}, {"first": "W", "middle": ["D"], "last": "Hopkins", "suffix": ""}, {"first": "R", "middle": ["K"], "last": "Thomas", "suffix": ""}], "year": 2004, "venue": "Journal of Comparative Psychology", "link": "34722049"}, "BIBREF1": {"title": "Understanding the point of chimpanzee pointing: epigenesis and ecological validity", "authors": [{"first": "D", "middle": ["A"], "last": "Leavens", "suffix": ""}, {"first": "W", "middle": ["D"], "last": "Hopkins", "suffix": ""}, {"first": "K", "middle": ["A"], "last": "Bard", "suffix": ""}], "year": 2005, "venue": "Current Directions in Psychological Science", "link": "16579742"}, "BIBREF2": {"title": "Referential gestural communication in wild chimpanzees (Pan troglodytes)", "authors": [{"first": "S", "middle": [], "last": "Pika", "suffix": ""}, {"first": "J", "middle": [], "last": "Mitani", "suffix": ""}], "year": 2006, "venue": "Current Biology", "link": "2273018"}, "BIBREF3": {"title": "Origins of human communication", "authors": [{"first": "M", "middle": [], "last": "Tomasello", "suffix": ""}], "year": 2008, "venue": "", "link": "13224707"}}, "ref_entries": {}}
{"paper_id": "149771926", "_pdf_hash": "4ec9b9c3e0e2fb805b718ce0af5e576951b46ffd", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Patterns of attachment: A psychological study of the strange situation", "authors": [{"first": "M", "middle": ["D"], "last": "Ainsworth", "suffix": ""}, {"first": "M", "middle": ["C"], "last": "Blehar", "suffix": ""}, {"first": "E", "middle": [], "last": "Waters", "suffix": ""}, {"first": "S", "middle": [], "last": "Wall", "suffix": ""}], "year": 1978, "venue": "", "link": "147960125"}, "BIBREF1": {"title": "Meeting of minds. Mutuality in psychoanalysis", "authors": [{"first": "L", "middle": [], "last": "Aron", "suffix": ""}], "year": 1996, "venue": "", "link": "143394584"}, "BIBREF2": {"title": "The practice of psychoanalytic parent-infant psychotherapy: Claiming the baby", "authors": [{"first": "T", "middle": [], "last": "Baradon", "suffix": ""}, {"first": "C", "middle": [], "last": "Broughton", "suffix": ""}, {"first": "I", "middle": [], "last": "Gibbs", "suffix": ""}, {"first": "J", "middle": [], "last": "James", "suffix": ""}, {"first": "A", "middle": [], "last": "Joyce", "suffix": ""}, {"first": "J", "middle": [], "last": "Woodhead", "suffix": ""}], "year": 2005, "venue": "", "link": null}, "BIBREF3": {"title": "Psychotherapy of Borderline Personality Disorder: Mentalization based treatment", "authors": [{"first": "A", "middle": ["W"], "last": "Bateman", "suffix": ""}, {"first": "P", "middle": [], "last": "Fonagy", "suffix": ""}], "year": 2004, "venue": "", "link": null}, "BIBREF4": {"title": "Infant research and adult treatment: Co-constructing interactions", "authors": [{"first": "B", "middle": [], "last": "Beebe", "suffix": ""}, {"first": "F", "middle": [], "last": "Lachmann", "suffix": ""}], "year": 2002, "venue": "", "link": "149512988"}, "BIBREF5": {"title": "Relatedness, self-definition and mental representation", "authors": [{"first": "B", "middle": [], "last": "Beebe", "suffix": ""}, {"first": "F", "middle": [], "last": "Lachmann", "suffix": ""}], "year": 2005, "venue": "", "link": null}, "BIBREF6": {"title": "Attacks on linking", "authors": [{"first": "W", "middle": ["R"], "last": "Bion", "suffix": ""}], "year": 1959, "venue": "International Journal of Psycho-Analysis", "link": "6324667"}, "BIBREF7": {"title": "Attachment and loss", "authors": [{"first": "J", "middle": [], "last": "Bowlby", "suffix": ""}], "year": 1969, "venue": "", "link": "143387931"}, "BIBREF8": {"title": "Momentos clave en la vida de tu hijo", "authors": [{"first": "T", "middle": ["B"], "last": "Brazelton", "suffix": ""}], "year": 2001, "venue": "", "link": null}, "BIBREF9": {"title": "The origins of reciprocity: The early motherinfant interaction", "authors": [{"first": "T", "middle": ["B"], "last": "Brazelton", "suffix": ""}, {"first": "B", "middle": [], "last": "Kowslowski", "suffix": ""}, {"first": "M", "middle": [], "last": "Main", "suffix": ""}], "year": 1974, "venue": "The effect of the infant on Its caregiver", "link": null}, "BIBREF10": {"title": "From pain to violence: The traumatic roots of destructiveness", "authors": [{"first": "F", "middle": [], "last": "De Zulueta", "suffix": ""}], "year": 2006, "venue": "", "link": "148302277"}, "BIBREF11": {"title": "Measuring the ghost in the nursery: A summary of the main findings of the Anna Freud Centre-University College London. Parent-Child Study Bulletin of the Anna Freud Centre", "authors": [{"first": "P", "middle": [], "last": "Fonagy", "suffix": ""}], "year": 1991, "venue": "", "link": "162598433"}, "BIBREF12": {"title": "Attachment, the reflective self, and borderline states: The predictive specificity of the Adult Attachment Interview and pathological emotional development", "authors": [{"first": "P", "middle": [], "last": "Fonagy", "suffix": ""}, {"first": "M", "middle": [], "last": "Steele", "suffix": ""}, {"first": "H", "middle": [], "last": "Steele", "suffix": ""}, {"first": "T", "middle": [], "last": "Leigh", "suffix": ""}, {"first": "R", "middle": [], "last": "Kennedy", "suffix": ""}, {"first": "G", "middle": [], "last": "Mattoon", "suffix": ""}], "year": 1995, "venue": "Attachment theory: Social, developmental and clinical perspectives", "link": "199142856"}, "BIBREF13": {"title": "Pathological defences in infancy", "authors": [{"first": "S", "middle": [], "last": "Fraiberg", "suffix": ""}], "year": 1982, "venue": "The Psychoanalytic Quarterly", "link": null}, "BIBREF14": {"title": "Ghosts in the nursery. A psychoanalytic approach to the problems of impaired infant-mother relationships", "authors": [{"first": "S", "middle": [], "last": "Fraiberg", "suffix": ""}, {"first": "E", "middle": [], "last": "Adelson", "suffix": ""}, {"first": "V", "middle": [], "last": "Shapiro", "suffix": ""}], "year": 1975, "venue": "Journal of the American Academy of Child & Adolescent Psychiatry", "link": "44691214"}, "BIBREF15": {"title": "The ego and mechanisms of defence", "authors": [{"first": "A", "middle": [], "last": "Freud", "suffix": ""}], "year": 1936, "venue": "", "link": null}, "BIBREF16": {"title": "Angels in the nursery: The intergenerational transmission of benevolent parental influences", "authors": [{"first": "A", "middle": [], "last": "Lieberman", "suffix": ""}, {"first": "E", "middle": [], "last": "Padr\u00f3n", "suffix": ""}, {"first": "P", "middle": [], "last": "Van Horn", "suffix": ""}, {"first": "W", "middle": [], "last": "Harris", "suffix": ""}], "year": 2005, "venue": "Infant Mental Health Journal", "link": null}, "BIBREF17": {"title": "Predictability of attachment behavior and representational processes at 1, 6 and 18 years of age: The Berkley Longitudinal Study", "authors": [{"first": "M", "middle": [], "last": "Main", "suffix": ""}, {"first": "E", "middle": [], "last": "Hesse", "suffix": ""}, {"first": "N", "middle": [], "last": "Kaplan", "suffix": ""}], "year": 2005, "venue": "", "link": null}, "BIBREF18": {"title": "Attachment from infancy to adulthood", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF19": {"title": "The impact of postnatal depression and associated adversity on early mother-infant interactions and later infant outcome", "authors": [{"first": "L", "middle": [], "last": "Murray", "suffix": ""}, {"first": "A", "middle": [], "last": "Fiori-Cowley", "suffix": ""}, {"first": "R", "middle": [], "last": "Hooper", "suffix": ""}, {"first": "P", "middle": ["J"], "last": "Cooper", "suffix": ""}], "year": 1996, "venue": "Child Development", "link": "28873478"}, "BIBREF20": {"title": "Effects of a secure attachment relationship on right brain development, affect regulation, and infant mental health", "authors": [{"first": "A", "middle": ["N"], "last": "Schore", "suffix": ""}], "year": 2001, "venue": "Infant Mental Health Journal", "link": "5530099"}, "BIBREF21": {"title": "Financial cost of social exclusion: Follow up study of antisocial children into adulthood", "authors": [{"first": "S", "middle": [], "last": "Scott", "suffix": ""}, {"first": "M", "middle": [], "last": "Knapp", "suffix": ""}, {"first": "J", "middle": [], "last": "Henderson", "suffix": ""}, {"first": "B", "middle": [], "last": "Maughan", "suffix": ""}], "year": 2001, "venue": "British Medical Journal", "link": "24825816"}, "BIBREF22": {"title": "Multicentre controlled trial of parenting groups for childhood antisocial behaviour in clinical practice", "authors": [{"first": "S", "middle": [], "last": "Scott", "suffix": ""}, {"first": "Q", "middle": [], "last": "Spender", "suffix": ""}, {"first": "M", "middle": [], "last": "Doolan", "suffix": ""}, {"first": "B", "middle": [], "last": "Jacobs", "suffix": ""}, {"first": "H", "middle": [], "last": "Aspland", "suffix": ""}], "year": 2001, "venue": "British Medical Journal", "link": "42641617"}, "BIBREF23": {"title": "The first relationship: Mother and infant", "authors": [{"first": "D", "middle": ["N"], "last": "Stern", "suffix": ""}], "year": 1977, "venue": "", "link": "142117966"}, "BIBREF24": {"title": "The motherhood constellation: A unified view of parent-infant psychotherapy", "authors": [{"first": "D", "middle": ["N"], "last": "Stern", "suffix": ""}], "year": 1998, "venue": "", "link": "143101639"}, "BIBREF25": {"title": "Three realms of the unconscious", "authors": [{"first": "R", "middle": [], "last": "Stolorow", "suffix": ""}, {"first": "G", "middle": [], "last": "Atwood", "suffix": ""}], "year": 2014, "venue": "Contexts of being: The intersubjective foundations of psychological life", "link": null}, "BIBREF26": {"title": "The neurobehavioral and social-emotional development of infants and children", "authors": [{"first": "E", "middle": [], "last": "Tronick", "suffix": ""}], "year": 2007, "venue": "", "link": "144700359"}, "BIBREF27": {"title": "Preocupaci\u00f3n maternal primaria (primary maternal preoccupation)", "authors": [{"first": "D", "middle": [], "last": "Winnicott", "suffix": ""}], "year": 1955, "venue": "", "link": null}, "BIBREF28": {"title": "Escritos de pediatr\u00eda y psicoan\u00e1lisis. Barcelona: Paid\u00f3s. Barcelona: Paid\u00f3s Ib\u00e9rica", "authors": [], "year": "", "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "149773830", "_pdf_hash": "c3126b0be10463cddefbf6bee03afe345b834775", "abstract": [], "body_text": [{"section": "", "text": "Complete or partial loss of teeth is very common clinical condition. The etiologies of missing teeth are several but commonest causes are dental caries, periodontal diseases & injury. 1 Loss of teeth may not only affect the oral impairments & loss of alveolar bone but also reduced self-confidence & general health.", "cite_spans": [{"start": 184, "end": 185, "text": "1", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "", "text": "2 Traditionally partial edentulous conditions are rehabilitated by removable partial dentures, fixed partial dentures & complete edentulous condition by complete denture. But in these above treatment options are several short & long term problems like pain, discomfort during speech & mastication, bone loss under pontic area, dental caries in abutment teeth. Due to several modern development of in the field of dental implant, it is one of the most predictable treatment options for partial or complete edentulism. In today's era patients need the immediate replacement of missing teeth in shorter duration of time & in more predictable way. In traditional Implantology technique required 4 to 6 months to rehabilitate the edentulous state with prosthesis. But due to several development in the field implant dentistry like several modification in implant thread design, surface treatments, immediate surgical protocol, advancement in imaging & lab technology, immediate bone augmentations material & techniques, implant placement with temporization, one piece compressive & Basal implants all these developments make the treatment in shorter duration of time with less surgical steps in minimal invasive way.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "3 But the biological principle is very much essential to determine the treatment option is suitable for particular clinical scenario. As modern Implantology is prosthetic driven, recent developments affect the immediate rehabilitation of esthetics & rapid restoration of implant fixtures. As for professionals and publically, the fast & fixed methodology of implant treatment has both risks and benefits.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "The usefulness of the implant dentistry trends discussed above is yet to be determined. However, with time some of these innovations becomes trends & others as historical sidenotes.so as a clinician, we always rely on biologic principles as well as long term clinical investigations to select the implants, surgical & prosthetic techniques. The most of newer materials & techniques are good enough but long term multicentric studies are required to establish the facts.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Permanent tooth mortality: a clinical study of causes of loss", "authors": [{"first": "H", "middle": ["W"], "last": "Krogh", "suffix": ""}], "year": 1958, "venue": "J Am Dent Assoc", "link": "31624081"}, "BIBREF1": {"title": "A 15-year study of osseointegrated implants in the treatment of the edentulous jaw", "authors": [{"first": "R", "middle": [], "last": "Adell", "suffix": ""}, {"first": "U", "middle": [], "last": "Lekholm", "suffix": ""}, {"first": "B", "middle": [], "last": "Rockler", "suffix": ""}, {"first": "P", "middle": ["I"], "last": "Branemark", "suffix": ""}], "year": 1981, "venue": "International journal of oral surgery", "link": "21034842"}, "BIBREF2": {"title": "Recent advances in dental implants. Maxillofacial plastic and reconstructive surgery", "authors": [{"first": "Dgk", "middle": [], "last": "Hong", "suffix": ""}, {"first": "J", "middle": ["H"], "last": "Oh", "suffix": ""}], "year": 2017, "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "149775112", "_pdf_hash": "40715f7aaaada0d81acc8c400a1146b0e28b36ef", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Randomized multicenter trial of sentinel node biopsy versus standard axillary treatment in operable breast cancer: the ALMANAC trial", "authors": [{"first": "R", "middle": ["E"], "last": "Mansel", "suffix": ""}, {"first": "L", "middle": [], "last": "Fallowfield", "suffix": ""}, {"first": "M", "middle": [], "last": "Kissin", "suffix": ""}, {"first": "D", "middle": [], "last": "England", "suffix": ""}], "year": 2006, "venue": "J Natl Cancer Inst", "link": "12609575"}, "BIBREF1": {"title": "Twenty-five-year follow-up of a randomized trial comparing radical mastectomy, total mastectomy, and total mastectomy followed by irradiation", "authors": [{"first": "B", "middle": [], "last": "Fisher", "suffix": ""}, {"first": "J", "middle": ["H"], "last": "Jeong", "suffix": ""}, {"first": "S", "middle": [], "last": "Anderson", "suffix": ""}, {"first": "J", "middle": [], "last": "Bryant", "suffix": ""}, {"first": "E", "middle": ["R"], "last": "Fisher", "suffix": ""}, {"first": "N", "middle": [], "last": "Wolmark", "suffix": ""}], "year": 2002, "venue": "N Engl J Med", "link": "32331059"}, "BIBREF2": {"title": "Lymphatic mapping and sentinel lymphadenectomy for breast cancer", "authors": [{"first": "A", "middle": ["E"], "last": "Giuliano", "suffix": ""}, {"first": "D", "middle": ["M"], "last": "Kirgan", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Guenther", "suffix": ""}, {"first": "D", "middle": ["L"], "last": "Morton", "suffix": ""}], "year": 1994, "venue": "Ann Surg", "link": "21005574"}, "BIBREF3": {"title": "Technical outcomes of sentinel-lymph-node resection and conventional axillary-lymph-node dissection in patients with clinically node-negative breast cancer: results from the NSABP B-32 randomised phase III trial", "authors": [{"first": "D", "middle": ["N"], "last": "Krag", "suffix": ""}, {"first": "S", "middle": ["J"], "last": "Anderson", "suffix": ""}, {"first": "T", "middle": ["B"], "last": "Julian", "suffix": ""}, {"first": "A", "middle": ["M"], "last": "Brown", "suffix": ""}, {"first": "S", "middle": ["P"], "last": "Harlow", "suffix": ""}, {"first": "T", "middle": [], "last": "Ashikaga", "suffix": ""}, {"first": "D", "middle": ["L"], "last": "Weaver", "suffix": ""}, {"first": "B", "middle": ["J"], "last": "Miller", "suffix": ""}, {"first": "L", "middle": ["M"], "last": "Jalovec", "suffix": ""}, {"first": "T", "middle": ["G"], "last": "Frazier", "suffix": ""}, {"first": "R", "middle": ["D"], "last": "Noyes", "suffix": ""}, {"first": "A", "middle": [], "last": "Robidoux", "suffix": ""}, {"first": "H", "middle": ["M"], "last": "Scarth", "suffix": ""}, {"first": "D", "middle": ["M"], "last": "Mammolito", "suffix": ""}, {"first": "D", "middle": [], "last": "Mccready", "suffix": ""}, {"first": "E", "middle": ["P"], "last": "Mamounas", "suffix": ""}, {"first": "J", "middle": ["P"], "last": "Costantino", "suffix": ""}, {"first": "N", "middle": [], "last": "Wolmark", "suffix": ""}], "year": 2007, "venue": "National Surgical Adjuvant Breast and Bowel Project", "link": "34628402"}, "BIBREF4": {"title": "Evolution of axillary nodal staging in breast cancer: clinical implications of the ACOSOG Z0011 trial", "authors": [{"first": "M", "middle": [], "last": "Shah-Khan", "suffix": ""}, {"first": "J", "middle": ["C"], "last": "Boughey", "suffix": ""}], "year": 2012, "venue": "Cancer Control", "link": "2875162"}, "BIBREF5": {"title": "An update on the medical management of breast cancer", "authors": [{"first": "B", "middle": [], "last": "Yeo", "suffix": ""}, {"first": "N", "middle": ["C"], "last": "Turner", "suffix": ""}, {"first": "A", "middle": [], "last": "Jones", "suffix": ""}], "year": 2014, "venue": "Bmj", "link": "44332825"}, "BIBREF6": {"title": "POSNOC: a randomised trial looking at axillary treatment in women with one or two sentinel nodes with macrometastases", "authors": [{"first": "A", "middle": [], "last": "Goyal", "suffix": ""}, {"first": "D", "middle": ["P"], "last": "Dodwell", "suffix": ""}], "year": 2015, "venue": "Clin Oncol", "link": "42439548"}, "BIBREF7": {"title": "Survival and axillary recurrence following sentinel node-positive breast cancer without completion axillary lymph node dissection: the randomized controlled SENOMAC trial", "authors": [{"first": "J", "middle": [], "last": "De Boniface", "suffix": ""}, {"first": "J", "middle": [], "last": "Frisell", "suffix": ""}, {"first": "Y", "middle": [], "last": "Andersson", "suffix": ""}], "year": 2017, "venue": "BMC Cancer", "link": "4536438"}, "BIBREF8": {"title": "SINODAR ONE, an ongoing randomized clinical trial to assess the role of axillary surgery in breast cancer patients with one or two macrometastatic sentinel nodes", "authors": [{"first": "C", "middle": [], "last": "Tinterri", "suffix": ""}, {"first": "G", "middle": [], "last": "Canavese", "suffix": ""}, {"first": "P", "middle": [], "last": "Bruzzi", "suffix": ""}, {"first": "B", "middle": [], "last": "Dozin", "suffix": ""}], "year": 2016, "venue": "Breast", "link": "1588935"}, "BIBREF9": {"title": "The value of completion axillary treatment in sentinel node positive breast cancer patients undergoing a mastectomy: a Dutch randomized controlled multicentre trial (BOOG 2013-07)", "authors": [{"first": "L", "middle": ["M"], "last": "Van Roozendaal", "suffix": ""}, {"first": "J", "middle": ["H"], "last": "De Wilt", "suffix": ""}, {"first": "T", "middle": [], "last": "Van Dalen", "suffix": ""}], "year": 2015, "venue": "BMC Cancer", "link": "215208675"}, "BIBREF10": {"title": "Abandoning sentinel lymph node biopsy in early breast cancer? A new trial in progress at the European Institute of Oncology of Milan (SOUND: sentinel node vs observation after axillary UltraSouND)", "authors": [{"first": "O", "middle": [], "last": "Gentilini", "suffix": ""}, {"first": "U", "middle": [], "last": "Veronesi", "suffix": ""}], "year": 2012, "venue": "Breast", "link": "24572536"}, "BIBREF11": {"title": "Comparison of quality of life and arm complaints after axillary lymph node dissection vs sentinel lymph node biopsy in breast cancer patients", "authors": [{"first": "F", "middle": [], "last": "Peintinger", "suffix": ""}, {"first": "R", "middle": [], "last": "Reitsamer", "suffix": ""}, {"first": "H", "middle": [], "last": "Stranzl", "suffix": ""}, {"first": "G", "middle": [], "last": "Ralph", "suffix": ""}], "year": 2003, "venue": "Br J Cancer", "link": "2460830"}, "BIBREF12": {"title": "Use of axillary ultrasound, ultrasound-fine needle aspiration biopsy and magnetic resonance imaging in the preoperative triage of breast cancer patients considered for sentinel node biopsy", "authors": [{"first": "A", "middle": ["G"], "last": "Fern\u00e1ndez", "suffix": ""}, {"first": "M", "middle": [], "last": "Fraile", "suffix": ""}, {"first": "N", "middle": [], "last": "Gim\u00e9nez", "suffix": ""}], "year": 2011, "venue": "Ultrasound Med Biol", "link": "205533805"}, "BIBREF13": {"title": "Axillary lymph node metastases in breast cancer: preoperative detection with dynamic contrast-enhanced MRI", "authors": [{"first": "K", "middle": ["A"], "last": "Kvistad", "suffix": ""}, {"first": "J", "middle": [], "last": "Rydland", "suffix": ""}, {"first": "H", "middle": ["B"], "last": "Smethurst", "suffix": ""}], "year": 2000, "venue": "Eur Radiol", "link": "6661626"}, "BIBREF14": {"title": "Impact of preoperative ultrasonography and fine-needle aspiration of axillary lymph nodes on surgical management of primary breast cancer", "authors": [{"first": "S", "middle": ["H"], "last": "Park", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Kim", "suffix": ""}, {"first": "B", "middle": ["W"], "last": "Park", "suffix": ""}, {"first": "H", "middle": ["J"], "last": "Moon", "suffix": ""}, {"first": "J", "middle": ["Y"], "last": "Kwak", "suffix": ""}, {"first": "E", "middle": ["K"], "last": "Kim", "suffix": ""}], "year": 2011, "venue": "Ann Surg Oncol", "link": "33158922"}, "BIBREF15": {"title": "The risk of nodal metastases in breast cancer patients with clinically negative lymph nodes: a population-based analysis", "authors": [{"first": "A", "middle": ["C"], "last": "Voogd", "suffix": ""}, {"first": "J", "middle": ["W"], "last": "Coebergh", "suffix": ""}, {"first": "O", "middle": ["J"], "last": "Van Driel", "suffix": ""}], "year": 2000, "venue": "Breast Cancer Res Treat", "link": null}, "BIBREF16": {"title": "Ultrasonography and fine-needle aspiration cytology in the preoperative evaluation of melanoma patients eligible for sentinel node biopsy", "authors": [{"first": "M", "middle": ["C"], "last": "Van Rijk", "suffix": ""}, {"first": "H", "middle": ["J"], "last": "Teertstra", "suffix": ""}, {"first": "J", "middle": ["L"], "last": "Peterse", "suffix": ""}, {"first": "", "middle": [], "last": "Nieweg", "suffix": ""}], "year": 2006, "venue": "Ann Surg Oncol", "link": "20274773"}, "BIBREF17": {"title": "Role of sonography in the diagnosis of axillary lymph node metastases in breast cancer: a systematic review", "authors": [{"first": "S", "middle": [], "last": "Alvarez", "suffix": ""}, {"first": "E", "middle": [], "last": "A\u00f1orbe", "suffix": ""}, {"first": "P", "middle": [], "last": "Alcorta", "suffix": ""}, {"first": "F", "middle": [], "last": "L\u00f3pez", "suffix": ""}, {"first": "I", "middle": [], "last": "Alonso", "suffix": ""}, {"first": "J", "middle": [], "last": "Cort\u00e9s", "suffix": ""}], "year": 2006, "venue": "Am J Roentgenol", "link": "42834815"}, "BIBREF18": {"title": "Magnetic resonance for assessment of axillary lymph node status in early breast cancer: a systematic review and meta-analysis", "authors": [{"first": "S", "middle": ["E"], "last": "Harnan", "suffix": ""}, {"first": "K", "middle": ["L"], "last": "Cooper", "suffix": ""}, {"first": "Y", "middle": [], "last": "Meng", "suffix": ""}, {"first": "S", "middle": ["E"], "last": "Ward", "suffix": ""}, {"first": "P", "middle": [], "last": "Fitzgerald", "suffix": ""}, {"first": "D", "middle": [], "last": "Papaioannou", "suffix": ""}, {"first": "C", "middle": [], "last": "Ingram", "suffix": ""}, {"first": "E", "middle": [], "last": "Lorenz", "suffix": ""}, {"first": "I", "middle": ["D"], "last": "Wilkinson", "suffix": ""}, {"first": "L", "middle": [], "last": "Wyld", "suffix": ""}], "year": 2011, "venue": "", "link": "8432532"}, "BIBREF20": {"title": "Accuracy of axillary lymph node staging in breast cancer patients: an observer-performance study comparison of MRI and ultrasound", "authors": [{"first": "H", "middle": [], "last": "Abe", "suffix": ""}, {"first": "D", "middle": [], "last": "Schacht", "suffix": ""}, {"first": "K", "middle": [], "last": "Kulkarni", "suffix": ""}, {"first": "A", "middle": [], "last": "Shimauchi", "suffix": ""}, {"first": "K", "middle": [], "last": "Yamaguchi", "suffix": ""}, {"first": "C", "middle": ["A"], "last": "Sennett", "suffix": ""}, {"first": "Y", "middle": [], "last": "Jiang", "suffix": ""}], "year": 2013, "venue": "Acad Radiol", "link": "29404475"}, "BIBREF21": {"title": "Lymphatic mapping and sentinel lymph node biopsy in early-stage breast carcinoma", "authors": [{"first": "T", "middle": [], "last": "Kim", "suffix": ""}, {"first": "A", "middle": ["E"], "last": "Giuliano", "suffix": ""}, {"first": "G", "middle": ["H"], "last": "Lyman", "suffix": ""}], "year": 2006, "venue": "Cancer", "link": null}, "BIBREF22": {"title": "A four node axillary sampling trial on breast cancer patients", "authors": [{"first": "K", "middle": [], "last": "Tanaka", "suffix": ""}, {"first": "D", "middle": [], "last": "Yamamoto", "suffix": ""}, {"first": "S", "middle": [], "last": "Kanematsu", "suffix": ""}, {"first": "H", "middle": [], "last": "Okugawa", "suffix": ""}, {"first": "Y", "middle": [], "last": "Kamiyama", "suffix": ""}], "year": 2006, "venue": "Breast", "link": "22220781"}, "BIBREF23": {"title": "The false-negative rate of sentinel node biopsy in patients with breast cancer: a metaanalysis", "authors": [{"first": "S", "middle": [], "last": "Pesek", "suffix": ""}, {"first": "T", "middle": [], "last": "Ashikaga", "suffix": ""}, {"first": "L", "middle": ["E"], "last": "Krag", "suffix": ""}, {"first": "D", "middle": [], "last": "Krag", "suffix": ""}], "year": 2012, "venue": "World J Surg", "link": "25368392"}, "BIBREF24": {"title": "Accuracy of predicting axillary lymph node positivity by physical examination, mammography, ultrasonography, and magnetic resonance imaging", "authors": [{"first": "S", "middle": ["A"], "last": "Valente", "suffix": ""}, {"first": "G", "middle": ["M"], "last": "Levine", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Silverstein", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Rayhanabad", "suffix": ""}, {"first": "J", "middle": ["G"], "last": "Wenggrumley", "suffix": ""}, {"first": "Ji", "middle": ["L"], "last": "Holmes", "suffix": ""}, {"first": "D", "middle": ["R"], "last": "Sposto", "suffix": ""}, {"first": "R", "middle": [], "last": "Sener", "suffix": ""}, {"first": "S", "middle": ["F"], "last": "", "suffix": ""}], "year": 2012, "venue": "Ann Surg Oncol", "link": "1471004"}, "BIBREF25": {"title": "Diagnostic performance of 18F-FDG PET/CT, ultrasonography and MRI", "authors": [{"first": "Y", "middle": ["S"], "last": "An", "suffix": ""}, {"first": "D", "middle": ["H"], "last": "Lee", "suffix": ""}, {"first": "J", "middle": ["K"], "last": "Yoon", "suffix": ""}], "year": 2014, "venue": "Nuklearmedizin", "link": null}, "BIBREF26": {"title": "Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations", "authors": [], "year": "", "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "149775152", "_pdf_hash": "41f4ab1528ccfade4a0164d80ce77034f01ed16d", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Antenna/RF Training Guide: HFSS", "authors": [{"first": "", "middle": [], "last": "Ansoft", "suffix": ""}], "year": 2010, "venue": "", "link": null}, "BIBREF1": {"title": "Antenna Theory: Analysis and Design", "authors": [{"first": "C", "middle": [], "last": "Balanis", "suffix": ""}], "year": 1997, "venue": "", "link": "109557562"}, "BIBREF2": {"title": "Design of Circular Polarized Dual band Patch Antenna", "authors": [{"first": "T", "middle": [], "last": "Edling", "suffix": ""}], "year": 2012, "venue": "", "link": "106884268"}, "BIBREF4": {"title": "Antenna and Wave Propagation. S.K Patari and Sons", "authors": [{"first": "A", "middle": [], "last": "Gautam", "suffix": ""}], "year": 2008, "venue": "", "link": null}, "BIBREF5": {"title": "Antennas from Theory to Practice", "authors": [{"first": "Y", "middle": [], "last": "Huang", "suffix": ""}, {"first": "K", "middle": [], "last": "Boyle", "suffix": ""}], "year": 2008, "venue": "", "link": "107224988"}, "BIBREF6": {"title": "Monopole with Modified Ground Plane", "authors": [{"first": "R", "middle": ["S"], "last": "Kamal", "suffix": ""}, {"first": "P", "middle": [], "last": "Singhal", "suffix": ""}], "year": 2012, "venue": "International Journal of Engineering and Technology. Science Publishing Corporation", "link": null}, "BIBREF7": {"title": "Antennas", "authors": [{"first": "J", "middle": ["D"], "last": "Kraus", "suffix": ""}], "year": 1998, "venue": "", "link": null}, "BIBREF8": {"title": "Multiband Antenna for G.S.M and 3G Mobile System. M.Eng Project Report", "authors": [{"first": "A", "middle": ["M"], "last": "Owag", "suffix": ""}], "year": 2006, "venue": "", "link": null}, "BIBREF9": {"title": "Stepped and Tapped -Stepped Construction of Monopole Antenna for Handset Mobile Phones", "authors": [{"first": "I", "middle": ["Y"], "last": "Salah", "suffix": ""}, {"first": "M", "middle": ["M"], "last": "Abousetta", "suffix": ""}], "year": 2003, "venue": "Proceeding of 3G -2003 Conference (iee), Michael Faraday House", "link": null}, "BIBREF10": {"title": "Design and Performance Enhancement of Cellular Handset Antennas and Assessment of their EM Interaction with a Human", "authors": [{"first": "I", "middle": ["Y"], "last": "Salah", "suffix": ""}], "year": 2009, "venue": "", "link": null}, "BIBREF11": {"title": "Impedance Dynamics of Mobile Phones Influenced By User Interaction", "authors": [{"first": "C &amp;", "middle": [], "last": "Saisset", "suffix": ""}, {"first": "P", "middle": [], "last": "Travers", "suffix": ""}], "year": 2009, "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "149776812", "_pdf_hash": "5edf24b70629386a79932a17938c5aff52b3db3e", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "149777662", "_pdf_hash": "0e2805feeb8d2f94f7655449e572a0c6978c67b9", "abstract": [{"section": "Abstract", "text": "Pendahuluan. Pengalaman rasa takut pada anak usia 4-6 tahun yang menjalani hospitalisasi berasal dari prosedur tindakan pada pasien, kurangnya informasi yang adekuat, lingkungan asing, dan perkembangan anak, tim kesehatan (dokter, perawat, petugas laboratorium). Bermain adalah kegiatan anak, dimanapun mereka membutuhkan kegiatan bermain. Tujuan dari penelitian ini adalah untuk mengidentifikasi pengaruh normative play terhadap penurunan rasa takut pada anak pra sekolah yang menjalani hospitalisasi. Metode. Penelitian ini menggunakan quasi eksperimen dengan one group pre-post design dengan jumlah sampel 24 anak pra sekolah yang menjalani perawatan di Rumah Sakit Umum dr. Slamet Garut. Rasa takut yang dialami anak diukur menggunakan modifikasi instrumen Revised Child Medical Fear Scale. Hasil. Hasil penelitian menunjukkan rata-rata rasa takut sebelum normative play (16.58) lebih tinggi daripada setelah normative play (7.75) pada anak pra sekolah. Hasil hipotesi dengan menggunakan pair t test menghasilkan nilai p 0.0005 (<0.005). Normative play memiliki pengaruh signifikan terhadap penurunan rasa takut anak pra sekolah yang dirawat di rumah sakit dr. Slamet Garut. Diskusi. Ruang perawatan anak sebaiknya dilengkapi dengan tempat bermain untuk anak yang sedang dirawat dan terapi bermain harus dijadikan standar operasional dalam menurunkan rasa takut pada kegiatan keperawatan dan tindakan kesehatan lainnya. ", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "INTRODUCTION", "text": "Hospitalization is a stressor for a child, even Salmela (2009) states that hospital care cause fear and anxiety in 90% of children of school age. Unlike school-age children who have been able to express his fear to others, pre-school children only dared to express fear in parents. Based on the interviews with the parents, it is said that almost 83% of school-age children experience a variety of symptoms of anxiety associated with the fear in the hospital (Rossen & Mc Keever, 2007) .", "cite_spans": [{"start": 48, "end": 62, "text": "Salmela (2009)", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "INTRODUCTION", "text": "According to research conducted by Salmela (2009) , that the fear experienced by a child aged 4-6 years who were hospitalized from a few things, namely the procedure to the patient, lack of adequate information, the foreign environment and with the development of son, the team of health care providers (doctors, nurses, laboratory personal) and nursing interventions. Based on the turn out of fear caused by the presence of nursing interventions that will be experienced by a child who is admitted to cause fear the most. Nursing interventions afraid of children aged 4-6 were 50% for injection administration, 32% for blood sampling procedures, and 13% respectively for the administration of drugs and surgical procedures (Salmela et al, 2009) . While past studies stated that there are four main things that cause fear in children who were hospitalized, the fear of going to school, fear of injections, scared away from family and fear of blood taken (Mahat & Scoloveno, 2006) . The phenomenon of fear of a child being treated in the hospital will certainly be a barrier to the smooth implementation of nursing, especially obviously written that most of the fear that children face is afraid to face the various nursing interventions that they may live. This should be a concern for all parents or caregivers and families who keep the child while in hospital to find ways to overcome the fear of the child.", "cite_spans": [{"start": 35, "end": 49, "text": "Salmela (2009)", "ref_id": "BIBREF7"}, {"start": 724, "end": 745, "text": "(Salmela et al, 2009)", "ref_id": "BIBREF7"}, {"start": 954, "end": 979, "text": "(Mahat & Scoloveno, 2006)", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "INTRODUCTION", "text": "Mathison and Butterworth in the Rivchardson Glasper (2007) identified some of the games can be used in children, among others, educational play, normative therapeutic play and play. The essence of this play is the provision of educative information. Form of the game can be books, drawings and diagrams for parents and children to read together in order to learn more about the process of care in hospitals. Normative toy play is offered daily in the hospital environment to bridge the gap between home and hospital. It provides comfort and security and a sense of family and normality.", "cite_spans": [], "ref_spans": []}, {"section": "INTRODUCTION", "text": "A study was conducted by Dianawati (2009) have concluded that play therapy affects the child's response to hospitalization. Response hospitalization children here can vary depending on the age of children who were treated, ranging from anxiety due to separation, loss of control and depression. Furthermore, Li & Lopez (2008) also conducted research on play in children who will undergo a surgical procedure. The results of the research states that children who received play therapy before they undergo surgery have lower levels of anxiety than children who only receive information only. Psychologically, it can use play therapy to reduce stress in children being treated (Sikhan, 2009 ). In addition, the usefulness of their own play therapy is to help children who have emotional problems, stress anxiety, stress or depression (Widyasari, 2009) .", "cite_spans": [{"start": 25, "end": 41, "text": "Dianawati (2009)", "ref_id": "BIBREF0"}, {"start": 308, "end": 325, "text": "Li & Lopez (2008)", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "INTRODUCTION", "text": "Garut Hospital is the only hospital type B Garut government. Based on a preliminary study conducted by researchers, until now Garut Hospital does not have a special playroom for the children, and not implementing play therapy for young patients are treated. Related research on play has not been performed at this hospital. Research conducted by Ramdaniati (2011) deals with fear at school and pre-school children to explain that the average child's fears occur at pre-school age.", "cite_spans": [], "ref_spans": []}, {"section": "INTRODUCTION", "text": "As previously described, the various play therapy related research have been conducted, but research related to specific normative play yet. Other than that associated with fear as a distinct form of psychological disorder anxiously, not yet known whether the well can be dealt with normative play or not. The purpose of this study was to identify the effect of normative play to reduce the fear of pre-school children who were treated at the dr. Slamet Garut in 2012.", "cite_spans": [], "ref_spans": []}, {"section": "METHODS", "text": "The study used quasi experimental with one group pre post test design. The sample in this study were all pre-school age children (4 to 6 years) who were treated at the General Hospital with consecutive sampling technique. Data collected in the form of an interview with a child's fears were measured using a questionnaire adapted from the Child Medical Fear Scale Revised (CMFS-R). Once the sample set, pediatric patients who met the inclusion criteria then measured fear using existing instruments, further intervention is given in the form of a game for 30-45 minutes. Games made for 3 consecutive days and then on the 4 th day of fear measured with the same instrument. A game made for 30 -45 minutes / day for 3 days. Nurse measured fear of children after treatment on 3 rd day. Data were analyzed by paired t test. Table 1 show that the average (mean) scale normative fear before play (16.58) is higher than the average scale normative scared after play (7.75) at pre-schoolchildren. This shows a decrease in the scale of fear of preschool children after therapy normative play. Table 2 shows that the average deviation of the scale of fear before and after treatment normative play is 8.83 with a standard deviation 2.99. The results of hypothesis testing using T test for dependent yield p value 0.0005 <0.05. That mean the normative play has significant effect in reducing the fear of pre-school children who were treated in dr. Slamet Garut Hospital. Statistically significant results of this study with 95% confidence intervals in the range of 7.57 to 10.10 (do not exceed 1).", "cite_spans": [], "ref_spans": [{"start": 820, "end": 827, "text": "Table 1", "ref_id": "TABREF0"}, {"start": 1084, "end": 1091, "text": "Table 2", "ref_id": "TABREF1"}]}, {"section": "RESULT", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "The state of the hospital environment that is foreign to pre-school children is a stressor that can cause fear for the child. According to research conducted by Salmela (2009) , that the fear experienced by a child aged 4-6 (preschool) years who were admitted to hospital from a few things, namely the procedure to the patient, lack of adequate information, the foreign environment and do not fit a child's development, a team of health care providers (doctors, nurses, laboratory personnel) as well as nursing interventions. Based on the turn out of fear caused by the presence of nursing interventions that will be experienced by a child who is admitted to cause fear the most. Nursing interventions afraid of children aged 4-6 were 50% for injection administration, 32% for blood sampling procedures, and 13% respectively for the administration of drugs and surgical procedures.", "cite_spans": [{"start": 161, "end": 175, "text": "Salmela (2009)", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "DISCUSSION", "text": "The fear that occurs in children who are admitted to hospital may be one of the factors inhibiting the implementation of maintenance actions in the process of nursing care in children. Efforts should be made to overcome the fears that occur in pre-school children who were hospitalized. One of the intervention to minimize the effort to do with play therapy. Play is the work of a child, wherever they are playing is a necessity. Play as a job or course requirements can be applied anywhere in the hospital is no exception, as long as the types of games that do not conflict with medical procedures and treatments undertaken.", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "The research was conducted in the form of therapeutic intervention by providing normative play at pre-school age children are admitted to the child care dr. Slamet Garut Hospital. Normative play therapy is a form of playing the usual pre-school children in the home such as cars, drawing and coloring, puzzles and action figures. The results showed that the average (mean) scale normative fear before play (16.58) is higher than the average scale normative scared after play (7.75) at 2,99 0,61 7,57 -10,10 0,0005 pre-school age children. Higher average scale normative play scared before therapy can be described that hospitals dr.Slamet Garut Hospital a local hospital were still arranging the room conventional child. Child care room has not been set up with rooms that appeal to children such as the color of the room treatment, arrangement of the playground, as well as the appearance of health workers especially nurses who still use traditional white uniforms and white. It certainly makes the hospital environment as a stranger to the child being treated. This condition can lead to an increase in the scale of fear prior to therapy normative play. The results of hypothesis testing using T test for dependent yield p value 0.0005 <0.05. This proves that the normative therapy play a significant effect (significant) in reducing the fear of pre-school children who were treated in dr. Slamet Garut Hospital. This shows a decrease in the scale of fear of pre-school children after therapy normative play. Decrease scale normative scared after play therapy can be understood that the hospital environment such as home circumstances cause students to feel familiar with the hospital environment because they can play activities as children's needs generally healthy home environment.", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "According to Hockenberry and Wilson (2009) stated that the intervention to minimize the stress response to hospitalization can be done in several ways that minimize the effects of separation from parents, minimal control and autonomy, prevent or minimize physical injury, maintain activities that support the development of children, using play activities , maximizing the benefits of hospitalization for children, support families and prepare children to be hospitalized. The opinion is consistent with the results of this study show that normative play therapy can reduce the fear of pre-school children who were hospitalized.", "cite_spans": [{"start": 13, "end": 42, "text": "Hockenberry and Wilson (2009)", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "DISCUSSION", "text": "A study was conducted by Dianawati (2009) have concluded that play therapy affects the child's response to hospitalization. Response hospitalization children here can vary depending on the age of children who were treated, ranging from anxiety due to separation, loss of control and depression. Furthermore, Li & Lopez (2008) also conducted research on play in children who will undergo a surgical procedure. The results of the research states that children who received play therapy before they undergo surgery have lower levels of anxiety than children who only receive information only. Psychologically, it can use play therapy to reduce stress in children being treated (Sikhan, 2009 ). In addition, the utility of play therapy alone is to help children who have emotional problems, stress anxiety, stress or depression (Widyasari, 2009) .", "cite_spans": [{"start": 25, "end": 41, "text": "Dianawati (2009)", "ref_id": "BIBREF0"}, {"start": 308, "end": 325, "text": "Li & Lopez (2008)", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "CONCLUSION AND RECOMMENDATION", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Conclusion", "text": "Normative play can reducing fear scale in pre-school children were treated in hospital.", "cite_spans": [], "ref_spans": []}, {"section": "Recommendation", "text": "The child care room should be equipped with a playroom for the children who were treated and play therapy should be used as a standard operating procedure in reducing the fear of going to be the action of nursing and other health actions.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Pengaruh therapy bermain terhadap respon hospitalisasi anak usia toddler di ruang dahlia RSU Sunan kalijaga Demak. Skripsi. Tidak diterbitkan", "authors": [{"first": "A", "middle": [], "last": "Dianawati", "suffix": ""}], "year": 2009, "venue": "", "link": null}, "BIBREF1": {"title": "A textbook of children's and young people's nursing", "authors": [{"first": "A", "middle": [], "last": "Glasper", "suffix": ""}, {"first": "J", "middle": [], "last": "Richardson", "suffix": ""}], "year": 2006, "venue": "", "link": "26690832"}, "BIBREF2": {"title": "Wong's clinical manual of pediatric nursing", "authors": [{"first": "M", "middle": ["J"], "last": "Hockenberry", "suffix": ""}, {"first": "", "middle": [], "last": "Wilson", "suffix": ""}], "year": 2009, "venue": "", "link": "70848659"}, "BIBREF3": {"title": "Wong's clinical manual of pediatric nursing", "authors": [{"first": "M", "middle": ["J"], "last": "Hockenberry", "suffix": ""}], "year": 2010, "venue": "", "link": "70848659"}, "BIBREF4": {"title": "Effectiveness and Appropriateness of Therapeutic Play Intervention in Preparing Children for Surgery: A Randomized Controlled Trial Study", "authors": [{"first": "H", "middle": ["C W"], "last": "Li", "suffix": ""}, {"first": "V", "middle": [], "last": "Lopez", "suffix": ""}], "year": 2008, "venue": "Journal of specialist in pediatric nursing", "link": "31843389"}, "BIBREF5": {"title": "Nepalese school-age children's selfreported fears and coping strategies related to medical experiences", "authors": [{"first": "G", "middle": [], "last": "Mahat", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Scoloveno", "suffix": ""}], "year": 2006, "venue": "Journal of Cultural Diversity \u2022", "link": "23900467"}, "BIBREF6": {"title": "The behavior of preschoolers during and after brief surgical hospitalizations", "authors": [{"first": "B", "middle": [], "last": "Rossen", "suffix": ""}, {"first": "P", "middle": [], "last": "Mckeever", "suffix": ""}], "year": 2007, "venue": "Issues in Comprehensive Pediatric Nursing", "link": "25020640"}, "BIBREF7": {"title": "Child-reported hospital fears in 4 to 6 year old children. Pediatric Nursing", "authors": [{"first": "M", "middle": [], "last": "Salmela", "suffix": ""}, {"first": "S", "middle": [], "last": "Salantera", "suffix": ""}, {"first": "E", "middle": [], "last": "Aronen", "suffix": ""}], "year": 2007, "venue": "", "link": null}, "BIBREF8": {"title": "Therapi bermain. Diakses dari", "authors": [{"first": "", "middle": [], "last": "Sikhan", "suffix": ""}], "year": 2008, "venue": "", "link": null}}, "ref_entries": {"TABREF0": {"text": "Description of Measurement Scale Normative Fear Before and After Play In pre-school aged children who were treated at the dr. Slamet Garut in 2012", "type": "table"}, "TABREF1": {"text": "Normative Play to Reducing Fear in Pre-schools Children were Treated in dr.", "type": "table"}}}
{"paper_id": "149779937", "_pdf_hash": "647345c5326aadd8f2bba58d556b2d850ed4d315", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Historical Vision and Strategic Thinking Required to Understand Tortuous Sino-Japanese Relations", "authors": [{"first": "Z", "middle": [], "last": "Baijia", "suffix": ""}], "year": 2014, "venue": "Modern International Relations: English Edition", "link": "141811759"}, "BIBREF1": {"title": "China and Japan's Simmering Rivalry", "authors": [{"first": "K", "middle": ["E"], "last": "Calder", "suffix": ""}], "year": 2006, "venue": "Foreign Affairs", "link": "158033522"}, "BIBREF2": {"title": "Persistence and Change in Japan-China Relationship", "authors": [{"first": "W", "middle": [], "last": "Choi", "suffix": ""}], "year": 2003, "venue": "Journal of International and Area Studies", "link": "55627584"}, "BIBREF3": {"title": "Contentious integration: Post-Cold War Japan-China Relations in the AsiaPacific", "authors": [{"first": "C", "middle": [], "last": "Chung", "suffix": ""}], "year": 2014, "venue": "", "link": "128438332"}, "BIBREF4": {"title": "Diplomatic Bluebook", "authors": [], "year": 2017, "venue": "", "link": null}, "BIBREF5": {"title": "Abe Vows to Achieve Major Improvement in Sino-Japan Relations in 2018", "authors": [{"first": "C", "middle": [], "last": "Gao", "suffix": ""}], "year": 2018, "venue": "", "link": null}, "BIBREF6": {"title": "Japan's China Policy: A Relational Power Analysis", "authors": [{"first": "Linus", "middle": [], "last": "Hagstr\u00f6m", "suffix": ""}], "year": 2005, "venue": "", "link": "127701086"}, "BIBREF7": {"title": "Understanding Fluctuations in Sino-Japanese Relations: To Politicize or to De-politicize the China Issue in the Japanese Diet", "authors": [{"first": "L", "middle": [], "last": "Hagstr\u00f6m", "suffix": ""}, {"first": "B", "middle": [], "last": "Jerd\u00e9n", "suffix": ""}], "year": 2010, "venue": "Pacific Affairs", "link": "144528459"}, "BIBREF8": {"title": "Japans response to Chinas rise: regional engagement, global containment, dangers of collision", "authors": [{"first": "C", "middle": ["W"], "last": "Hughes", "suffix": ""}], "year": 2009, "venue": "International Affairs", "link": null}, "BIBREF10": {"title": "The \uff02Abe/Aso Regime \"and Sino-Japanese Relations", "authors": [{"first": "L", "middle": [], "last": "Jiangyong", "suffix": ""}], "year": 2013, "venue": "Modern International Relations: English Edition", "link": "162114130"}, "BIBREF11": {"title": "Secure a Decisive Victory in Building a Moderately Prosperous Society in All Respects and Strive for the Great Success of Socialism with Chinese Characteristics for a New Era. Speech presented at 19th National Congress of the Communist Party of China in Beijing", "authors": [{"first": "X", "middle": [], "last": "Jingping", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF12": {"title": "Anti-Japanese Popular Nationalism and China's Approach Towards Japan amid Sino-Japanese Political Tension", "authors": [{"first": "S", "middle": [], "last": "Kang", "suffix": ""}], "year": 2001, "venue": "East Asia", "link": "154446634"}, "BIBREF13": {"title": "Japanese foreign policy at the crossroads: challenges and options for the twenty-first century", "authors": [{"first": "Y", "middle": [], "last": "Kawashima", "suffix": ""}], "year": 2003, "venue": "", "link": "153959649"}, "BIBREF14": {"title": "Japan, China Agree to Implement East China Sea Crisis Management Hotline", "authors": [{"first": "A", "middle": [], "last": "Panda", "suffix": ""}], "year": 2017, "venue": "", "link": null}, "BIBREF15": {"title": "Japan, China, and the Strains of Historical Memory", "authors": [{"first": "J", "middle": [], "last": "Renouard", "suffix": ""}], "year": 2017, "venue": "", "link": null}, "BIBREF16": {"title": "CHINA-JAPAN: A BRIEF. The Advocate of Peace", "authors": [{"first": "L", "middle": [], "last": "Russel", "suffix": ""}], "year": 1919, "venue": "", "link": null}, "BIBREF17": {"title": "Post -War Sino -Japanese Relations: A Constructivist Reinterpretation", "authors": [{"first": "D", "middle": [], "last": "Santos", "suffix": ""}], "year": 2017, "venue": "ISA International Conference", "link": "201635755"}, "BIBREF18": {"title": "The Yasukuni Shrine Dispute and the Politics of Identity in Japan: Why All the Fuss?", "authors": [{"first": "D", "middle": [], "last": "Shibuichi", "suffix": ""}], "year": 2005, "venue": "Asian Survey", "link": "144767187"}, "BIBREF19": {"title": "Chevreaux 27", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF20": {"title": "Pew Research Center's Global Attitudes Project", "authors": [{"first": "B", "middle": [], "last": "Stokes", "suffix": ""}], "year": 2016, "venue": "", "link": null}, "BIBREF21": {"title": "How Japan Imagines China and Sees Itself", "authors": [{"first": "M", "middle": [], "last": "Tamamoto", "suffix": ""}], "year": 2005, "venue": "World Policy Journal", "link": "156252791"}, "BIBREF22": {"title": "History Education: The Source of Conflict Between China and Japan", "authors": [{"first": "Z", "middle": [], "last": "Wang", "suffix": ""}], "year": "", "venue": "The Diplomat", "link": "126548310"}, "BIBREF23": {"title": "Anarchy is what States Make of it: The Social Construction of Power Politics", "authors": [{"first": "A", "middle": [], "last": "Wendt", "suffix": ""}], "year": 1992, "venue": "International Organization", "link": "17475858"}, "BIBREF24": {"title": "The Security Dimension of Sino-Japanese Relations: Warily Watching One Another", "authors": [{"first": "W", "middle": [], "last": "Xinbo", "suffix": ""}], "year": 2000, "venue": "Asian Survey", "link": "154698584"}}, "ref_entries": {}}
{"paper_id": "191680764", "_pdf_hash": "52a2a078c04b55567387707f7fd6e74165295492", "abstract": [{"section": "Abstract", "text": "Abstract: How to ensure energy supply and reduce environment pollution have turned into governments' top priorities and key factors to maintain sustainable development. In this context, two major trade and investment agreements that could lead to profound influence on low-carbon energy systems development around the Asia-Pacific region are the Regional comprehensive economic partnership (RCEP) consisted of the Association of Southeast Asian Nations (ASEAN) plus Australia, China, India, Japan, New Zealand, and Republic of Korea and the Belt and road initiative (BRI) initiated by China. In order to have a smooth transition to low-carbon energy systems in Asia, besides RCEP and BRI, it is imperative to boost private sector investment. Success of encouraging private sector investment depends on appropriate government policies towards promoting innovations and reducing financial risks to private investors. The research questions that are examined in this study are: What type of policy measures affects trade in low-carbon transition, particularly renewable energy (RE) transition? How can investment signals and incentives be reframed to scale up private finance in RE? The objective is to investigate and to provide several feasible trade policy and investment policy tools for both national and regional markets that governments could adopt to accelerate the speed of private financing of the low-carbon energy industry, particularly the RE industry.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Recent decade witnessed the fact that the Asia-Pacific countries, especially the emerging economies in East, South and South East Asia have proven to be the new engine of global economic growth. According to the Asian Development Outlook 2017, [1] Asia-Pacific now accounts for 60 per cent of the world's economic growth. Along with this significant economic achievement, issues concerning energy security, tradeenvironment nexus, and environment-growth nexus have become increasingly crucial in policy making both at the public and private sectors. Now, how to ensure energy supply and reduce environment pollution have turned into governments' top priorities and key factors to maintain sustainable development.", "cite_spans": [{"start": 244, "end": 247, "text": "[1]", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "Introduction", "text": "Although it is unanimously accepted in the COP21 meeting in Paris that energy efficiency and renewable energy are explicit, and probably the only, solution to tackle the issues concerning energy, environment, and economic growth, only few countries are aware of the role that international and regional cooperation in trade and investment can play in increasing the pace of transition to low-carbon energy systems. In this, the launching of the Intended Nationally Determined Contributions, which is now ratified as NDCs, is the first international agreement that enhances the collaboration on controlling global climate change between developing and developed countries. However, as NDCs lacks enough binding force as well as the U.S. is threatening to withdraw from the Paris Agreement, it indicates that it may be still too early and immature to reach an effective and worldwide recognized protocol. In this case, seeking a deeper and stronger cooperation within the local region is a more practical way to solve the current dilemma.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "In fact, two major trade and investment regional agreements that could lead to profound influence on lowcarbon energy systems development are now in prearrangement and/or at the negotiation stage around the Asia-Pacific region. One is the Regional Comprehensive Economic Partnership, which is proposed by the ASEAN 10 countries plus Australia, China, India, Japan, South 81 Korea and New Zealand in 2012. A very broad trade deal is expected from RCEP, however, currently it does not put forward any specific target or issue that is related to low-carbon energy systems in negotiation. Unlike the former one, the second is China's national premier development strategy, the Belt and Road Initiative (BRI), which clearly regards developing 'low-carbon and green energy technology' as one of the goals. Nevertheless, in order to have a smooth transition to low-carbon energy systems in Asia, it is imperative to scale up private sector investment, which depends on appropriate government policies towards promoting innovations and reducing financial risks to private investors. The multilateral financial institutions like the Asian Development Bank need to play the middleman role between the national governments and the private sector effectively through feasible policy framework.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "Under this macroeconomic scenario, this study aims to analyze the possibility and challenges in encouraging private sector investment in low-carbon energy systems in Asia, particularly in the RCEP region, and to suggest an effective policy framework that governments could apply to properly improve the development and dissemination of low-carbon energy (LCE) goods and technologies. The three main sources of low-carbon energy are renewables (RE), improving energy efficiency (EE) that includes cleaner coal technology (CE), and nuclear. However, the latter source of LCE is controversial in many countries. Hence, renewable energy (RE), energy efficiency (EE), and cleaner coal technology (CCT) have become the main sources of LCE. Given the current status of growth, renewable energy (RE) is the central focus of this study.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "The cleaner coal technology, which reduces the emission and increases the amount of energy gained per tonne of coal, seems to be the energy source of choice in the Asia Pacific region in recent times. The Global Trends in Renewable Energy Investment 2018 report by the UN Environment-Bloomberg New Energy Finance revealed that more CE generation was added in 2017 than conventional fossil fuels. Nevertheless, the report also pointed out that the world spent more money adding solar, wind and other renewable sources than it did adding coal, natural gas or nuclear plants. To be specific, global investment in renewable energy edged up 2% in 2017 to $279.8 billion, taking cumulative investment since 2004 to $2.9 trillion. The latest rise in capital outlays took place in a context of further falls in the costs of wind and solar that made it possible to buy megawatts of equipment more cheaply than ever before (Figure 1-4) . It is worth noting that the renewable energy (RE) based power generation is being promoted vigorously in many RCEP countries after the COP21 commitments. The leading locations by far for renewable energy investment in 2018 were China, which accounted for $100.1 billion, and followed by Japan ($27.1 billion), and India ($11.1 billion). India has overtaken the European Union with its renewable capacity expecting to more than double by 2022. [2] Drawing on the investment climate with respect to the RE sector, it may be noted that the clean energy share prices rose in 2017, by about 28% on the WilderHill New Energy Global Innovation Index, or NEX. However, this has so far not produced a jump in equity issues by specialist companies. Instead, public markets investment in RE dipped 6% to $5.7 billion, a five-year low. Venture capital and private equity (VC/PE) investment was also weak, fading 33% to $1.8 billion. The characteristics of the above financial markets along with the record high of $87.2 billion for asset acquisitions and refinancing in 2017 need an interpretation. [3] It can be argued that RE has become a mature sector increasingly dominated by big industrial players, utilities and institutional investors. One uncertainty ahead for RE is how investors will behave in the coming periods, in which project revenues have no government price support. Hence, private sector power purchases agreements or even just merchant power prices will be crucial for the development of the RE sector. This necessitates unconditional support not only from the governments, but also from the private sector to sustain technological research and development in innovating and disseminating the RE systems around the world. The usual ways the private sector would enter into the RE systems markets are through investment and trade.", "cite_spans": [{"start": 2015, "end": 2018, "text": "[3]", "ref_id": "BIBREF2"}], "ref_spans": [{"start": 913, "end": 925, "text": "(Figure 1-4)", "ref_id": "FIGREF1"}]}, {"section": "Introduction", "text": "There are very few studies exploring the effect of RE goods and services trade on the environment and no study comparing this effect between RE exports and imports. While RE imports are supposed to benefit the environment of the importing countries through the use of environmentally-friendly use of these goods, it is crucial to explore the impact of RE exports on the exporting countries' environments. In the case of exports of RE goods, the impact on the environment of the exporting countries operates both in the production stage and in the final environmental goods consumption stage. In this context, the important question is about the necessity of increasing RE trade in general and RE exports in particular; because, in the case where there is no impact of RE trade on the environment, there is no reason for countries to concentrate on facilitating free trade in RE through trade agreements, such as the RCEP.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "The research questions that are examined in this study are: What type of policy measures affects trade in lowcarbon transition, particularly RE transition? How can investment signals and incentives be reframed to scale up private finance in RE? The objective is to investigate and to provide several feasible trade policy and investment policy tools for both national and regional markets that governments could adopt to accelerate the speed of private financing of the low-carbon energy industry, particularly the RE industry.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "The following section discusses what the important factors that determine private investment in the RE sector are. The third section describes some of the market based trade policy measures used by the emerging economies in Asia to boost private sector investment and trade in RE systems. A critical evaluation of some of the policies is done with case studies in the next section. Policy suggestions to increase private sector investment in RE production are made in the final section. 2 Determinants of private investment in the production of RE goods and technologies", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "The two core methods of financing of any businesses are borrowing from any banks as a loan, and/or through approaching equity capital, which are of many different categories, such as venture capital, private equity, and public market. Also, it is possible for companies to raise funds through 'balance sheet' from the company's own corporate funds as part of their corporate strategy. Such companies draw on monies raised from the financial markets through bond issuance or general corporate bank facilities that are available to the business as a whole, or following the sale of other parts of the business. Often a company will choose whether to use project finance or corporate facilities depending on which offers the cheaper source of funding to the project so that profit from the project is enhanced. [4] Profit (\u03c0) is the difference between total revenue (R) and total cost (C). In functional form, (\u03c0) can be written", "cite_spans": [{"start": 808, "end": 811, "text": "[4]", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "Introduction", "text": "Where, P = Price of the output (Q) which is mainly determined in the competitive market; and C = Total cost that includes input cost, operational cost and hidden cost, such as the difference between the government's announced business licence costs and the actual cost to the businesses.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "The theory of profits emphasises that profit will be larger in a country where investors can operate their businesses at a lower cost. This implies that the variables that determine profit can equivalently determine the inflow of investment in any country. Therefore, the investment function in the reduced form is as follows:", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "The above version of the theoretical I function can be transformed into an empirical I function applying the arguments developed in the theory of profits. Drawing on the theory of profits, it is logical to argue that businesses will prefer to invest in countries where they can produce large amount of production at a lower cost and therefore, the size of the economy, is an important factor for making investment decisions. Further, UNCTAD (2000) argued that investors who mainly make Greenfield investment in foreign countries preferred to invest in countries with large domestic market. It is rational to expect that not all market seeking foreign investors will invest in foreign countries fully to serve the host economies and some would also be keen to export their products to other countries as well besides serving the host economy. This means that a country with small domestic market, but with open trade regime can also provide scale economies similar to the countries with large domestic market, to foreign investors.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "Even projects with considerable expected returns in developing countries could not receive financial support because of their perceived high risks and limited liquidity of financial flows [5] The risks are perceived due to many factors. In this context, Srivastava and Venugopal (2012) have classified the risks into two categories: political and macroeconomic risks, and low carbon market risks. Though it is possible to some extent to include political and macroeconomic risks in empirical analyses, it is difficult to include low carbon market risks because of lack of full information. Thus, reducing, if not eliminating the low carbon market risks plays the crucial role in determining private financing in RE goods and technologies. Here, governments need to make full use of the power of the market, or at least change the preference of the markets, both domestically and internationally, from fossil energy to low-carbon energy. Governments could implement a series of policies to boost the market confidence in developing and producing the RE goods and technologies. However, sometimes it is not as satisfactory as expected, because the selected policy approaches may not be appropriate to exert significant impact on the supply side and the demand side of the RE market. Hence, it is imperative to gauge the effectiveness of such policies on improving market confidence in financing the production of the RE goods and technologies.", "cite_spans": [{"start": 188, "end": 191, "text": "[5]", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "Introduction", "text": "3 Scaling up private investment in the RE market: Market based trade policy measures Different countries have been using different policy measures, such as feed-in tariffs, renewable certificates and public tenders to encourage private financing in the production and the distribution of the RE goods and technologies. By way of boosting the renewable energy sector investment, India, which is a major emerging economy in Asia, has put in place many progressive policies, at the federal and state levels. Federal policy support has been in the form of accelerated depreciation, generationbased incentives and viability gap funding. The statelevel policy support has typically been in the form of feed-in tariffs, net metering, and tax/duty exemptions influencing the supply side of the RE market. In China, export tax rebate system is used as an effective tool to guide the market growth. Export tax rebate (ETR), also known as the Value-Added Tax rebate, is an important policy tool to promote exports by influencing the supply side of the market, which is allowed by WTO as long as the rebate rate is not larger than the domestic valueadded tax rate. The ETR system is firstly introduced in 1985 in China, and the rebate rates for different goods vary from 5 per cent to 17 per cent. Chinese government regards ETR not only as an international trade policy, but also as a powerful tool to regulate the direction of the market development since export is highly relevant to domestic production activities too. A few researchers have attempted to assess the impact of ETR on the value of exports, and all of them found a significant positive causality relationship at the country level.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "Besides carbon tax and emissions trading scheme, in the international trade arena, tariff and non-tariff measures are important policy instruments used by countries to influence the demand side and the supply side of the market for RE goods and technologies in the importing countries and exporting countries respectively, which bear implications for investment in both the exporting and importing countries. It is argued that the monetary value of the non-tariff measures (NTM) exceeds that of the tariffs in many cases. Among the NTMs, in 2014, technical measures were most frequently applied on RE goods exports of RCEP member countries. This necessitates that there is an urgent need to have 'regulatory convergence' concerning non-tariff measures across countries. The present study uses the definition of the United Nations Conference on Trade and Development (UNC-TAD) (2012): 'Non-tariff measures are policy measures other than ordinary customs tariffs that can potentially have an economic effect on international trade in goods, changing quantities traded, or prices'. UNCTAD (2012) also points out that 'though many NTMs aim primarily at protecting public health or the environment, they also substantially affect trade through information, compliance and procedural costs'. NTMs data are downloaded from UNCTAD, which is made publicly available through TRAINS.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "A regional cooperation agreement such as the RCEP is another powerful instrument to influence the supply side and demand side of the RE markets nationally and re-gionally. Building low-carbon innovation systems is intrinsically linked with capacity building and technological cooperation. Further, building low-carbon innovation systems is both resource-intensive and long term, which becomes feasible through the regional cooperation agreements. Thus, governments' financial support is required to complement and assist private sector innovation. Governments' financial support can be strengthened further by permanently phasing out fossil fuel subsidies and all subsidies for price-competitive mature technologies. Some RCEP countries have adopted this approach in recent times, though not consistently. Also, governments of few RCEP member countries have targeted their policies towards establishing tax regimes and investment protections for RE investment; encouraging local banks to become involved; developing green bonds linked to RE investment; and supporting RE infrastructure for adaption purposes too. For example, Australia is one of the few RCEP countries with a national green investment bank. Since 2012, the Clean Energy Finance Corporation (CEFC), an independent statutory authority, has financed projects related to renewable energy and energy efficiency. The government credited the CEFC with AUD 2 billion a year from 2013 to 2017. [6] As of June 2018, the CEFC had committed AUD 5.3 billion to projects with a total value of AUD 19 billion (1% of 2018 GDP). Through regional cooperation technology transfer agreements embedded in the RCEP and BRI, China's potential to deploy its solar energy innovation has been exploited by a few member countries in the region.", "cite_spans": [{"start": 1452, "end": 1455, "text": "[6]", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Introduction", "text": "The following section discusses through case studies how effective are the above discussed market based trade policy measures in influencing the demand and supply sides of the RE markets in the RCEP member countries.", "cite_spans": [], "ref_spans": []}, {"section": "Critical evaluation of market based trade policy measures: Empirical analyses", "text": "To estimate the effectiveness of ETR on China's RE goods exports, a Stochastic Frontier Gravity model was applied. A panel data for China's RE goods exports to other RCEP countries[ Due to the availability of the consistent data from 2006 to 2017 only 11 trading RCEP partners of China were included in the empirical analysis.] from 2006 to 2014 was used as the dependent variable in the gravity frontier model (See the Appendix for data sources). Specifically, because of the data limitation, a simple average ETR rate was used as the renewable energy goods' ETR rate. A positive coefficient of ETR variable is expected. The stochastic frontier gravity ", "cite_spans": [], "ref_spans": []}, {"section": "Critical evaluation of market based trade policy measures: Empirical analyses", "text": "Where lntv is the logarithm of the value of exports of RE goods lngdp is the real GDP of the RCEP importer countries; lnpop is the population of RCEP importer countries; lndist is the distance between exporter and importer countries; Ex represents the relative exchange rate, direct quotation and lnex = ln(1 + ex); similarly, lntar = ln(1+tarif f ), which is a market demand side factor; and lnetr = ln(1 + export tax rebate rate), which is a market supply side factor. u i,t is the negative influence of non-tariff barriers, which are not fully known to the researchers. It is proxied by as a truncated normal variable with mean \u00b5 and a constant variance \u03c3 u 2 . \u03b5 i,t is the 'statistical' error term following the normal distribution with mean 0 and variance \u03c3 v 2 . The software FRONTIER 4.1 was used to estimate the stochastic frontier gravity equation and the estimation results are presented in Table 1 .", "cite_spans": [], "ref_spans": [{"start": 902, "end": 909, "text": "Table 1", "ref_id": "TABREF0"}]}, {"section": "Critical evaluation of market based trade policy measures: Empirical analyses", "text": "It is worth noting that the coefficient of ETR rate in Ta-ble 1 is significant at the 5 per cent level, which implies that ETR has influenced China's RE exports in a positive way. Export of REs would increase by 1.3% for a 1% increase in ETR. The coefficient of tariff of the importing countries is negative and is significant at the 5 per cent level. Generally, changes in tariff always come with the implementation of trade agreements inducing trade policy changes, which means that tariff rate is a strong indicator of governments' preferences. A lower tariff rate of RE goods reveals a stronger support by the importing country's trade policy, which directly encourages and stimulates the production and consumption of RE goods in the exporting and the importing countries respectively. The coefficient of \u03b3, which is the ratio of the observation specific variance to the total variance, indicates the influence of non-tariff measures on the exports. The coefficient of \u03b3 is significant at the 1 per cent level and strongly confirms the influence of non-tariff barriers on the exports. Hence, the empirical results suggest that ETR can be used as a powerful instrument to promote investment in RE market. Also, the results indicate that regional cooperation agreements could be used effectively to eliminate tariff and non-tariff barriers applied on RE goods exports. Then, a challenging question is as to why some countries promote RE trade liberalization by reducing tariff and non-tariff barriers, whereas others prefer protection. Identifying the root cause of this issue would certainly contribute to the progress of reducing RE trade barriers, and scaling up private investment in RE goods and technologies. An attempt has been made in this study to explain the reasons for the variation in countries' RE trade protection preferences. Political scientists have argued that the pressure for protectionism is generated not from the point of view of the interests of the nation as a whole, but from domestic interests adversely affected by the reduction of tariff and non-tariff barriers. Studies in this field indicate that group interests and domestic political institutions help explain trade policy outcomes. Even though a large literature in political science has been devoted to examining countries' protection preferences, the results of empirical studies vary, and there is no study using domestic politics explicitly to explain variation in trade barriers on RE goods and technologies.", "cite_spans": [], "ref_spans": []}, {"section": "Critical evaluation of market based trade policy measures: Empirical analyses", "text": "Drawing on the society-centred approaches, the variation in RE liberalization trade preferences among countries can be explained by the different outcomes of domestic political competitions during trade policy making processes among interest groups. The groups who benefit from trade liberalization would lobby for low trade barriers, while the groups who are adversely affected by it would lobby for high trade barriers. The study focuses on examining the assumption of the society-centred approaches that the broader interest the governments represent, the more they liberalize trade. To be more precise, countries with proportional electoral systems and characterized by more democracy are associated with lower RE trade barriers. The environmental concerns will be added into the models to capture the environmental interest with the assumption that the more people prefer to protect the environment, the more they support RE free trade, and their trade preference is a combination of economic and environmental concern. Environmental performance is used to be a proxy of environmental interest/concerns. Countries with better environmental performance are likely to have better awareness of and more attention to environmental protection.", "cite_spans": [], "ref_spans": []}, {"section": "Critical evaluation of market based trade policy measures: Empirical analyses", "text": "Further, even though society-centred approaches do not explicitly discuss corruption and regulatory quality, these two variables are usually included in the empirical models to control for political institutional quality. It is likely that corruption seems to increase the possibility for group interests to be dominated in domestic politics, while the better regulatory quality facilitates the likelihood of the national interest to be represented by politicians. Therefore, this study also includes these two variables to examine how they affect tariffs and non-tariff measures (NTMs) on RE goods and technologies.", "cite_spans": [], "ref_spans": []}, {"section": "Critical evaluation of market based trade policy measures: Empirical analyses", "text": "Drawing on Ehrlich (2007), the following empirical model was estimated:", "cite_spans": [], "ref_spans": []}, {"section": "Critical evaluation of market based trade policy measures: Empirical analyses", "text": "Tarrifs ik(t+1) = \u03b1 + \u03b2 1 Democracy it + \u03b2 2 Corruption it + \u03b2 3 Regulatory quality it + \u03b2 4 Environmental performance it + \u03b2 5 Electional system it + \u03b2 6 Political party it + \u03b2 7 Ln(Import ijkt /GDP it ) + \u03b2 8 LnGDP it + \u03b2 9 Exchange rate it + \u03b2 10 Ln(Agriculral value added it )+ \u03b2 11 Ln(Manufacturing value added it )+ \u03b2 12 ASEAN membership it + e it (4) where Ln is natural log, i and j are country i and j, k is environmental good at HS 6-digits, t refers to year t.", "cite_spans": [], "ref_spans": []}, {"section": "Critical evaluation of market based trade policy measures: Empirical analyses", "text": "Similar to tariffs models, in the NTMs models, NTMs are on the left-hand side of the equation. They refer to NTMs applied on RE good k at HS-6 digits of the importing country i at time t+1. Following UNCTAD (2012), NTMs are grouped into 3 subgroups: technical measures, non-technical measures, and export-related measures. Different from the case of tariffs, the dataset for NTMs models is cross sectional as there are only data on NTMs in one year, either for 2015 or for 2016.", "cite_spans": [], "ref_spans": []}, {"section": "Critical evaluation of market based trade policy measures: Empirical analyses", "text": "Based on the Hausman test results, the fixed effect model was chosen for tariffs and the cross section model with heteroscedasticity corrected estimation was chosen Table 2 . The coefficient of democracy is statistically significant and negative in all cases, which suggests that the more democratic countries seem to apply lower tariffs and fewer NTMs on RE goods. This relieves the worry raised by Kono (2006) that democracies may reduce transparent trade barriers, but replace them with less transparent NTMs. As the results suggested, democratic countries have both lower tariffs and NTMs than non-democratic countries. Even though this does not necessarily mean that democratic countries do not substitute tariffs by NTMs, but at least both of their tariffs and NTMs are lower than the non-democratic countries. When corruption increases, both tariffs and NTMs tend to increase. This is expected as corruption tends to make politicians more receptive to protectionist pressures of interest groups rather than representing society's interest as a whole. In other words, corruption may facilitate the process for narrow interest for protection of some industries or producers to be reflected in trade policy outcomes. In contrast, an increase in regulatory quality is associated with a decrease in tariffs and technical measures and non-technical measures. This effect is expected as the better the regulatory quality is, the more likely those governments reflect the interest of mass public that prefers free trade.", "cite_spans": [], "ref_spans": [{"start": 165, "end": 172, "text": "Table 2", "ref_id": "TABREF1"}]}, {"section": "Critical evaluation of market based trade policy measures: Empirical analyses", "text": "The sign of the variable environmental performance is as expected in both tariffs and NTMs models. Countries with better environmental performance have lower tariffs and fewer numbers of NTMs on RE imports. It suggests that environmental interest is reflected in trade policies of these countries; thus, they would lower trade barriers to promote RE imports and consumption. This result implies that, in order to enhance RE free trade, there is a need to enhance individuals' environmental preference and voices of environmental groups. As a result, the environmental preference can be reflected in trade policy outcomes.", "cite_spans": [], "ref_spans": []}, {"section": "Critical evaluation of market based trade policy measures: Empirical analyses", "text": "In terms of export-related NTMs, there are a variety of reasons for governments to apply these measures, for instance: supply shortage in domestic market, regulating prices, avoiding antidumping and political issues. It is hard to know exactly what induces governments to increase or decrease export-related NTMs. However, the following conjectures can be made, which need further investigation: the governments inclined more towards socialism would have fewer export-related measures, which may come from those governments aim to promote RE exports in order to create more jobs. On the other hand, more export-related NTMs of countries inclined more towards capitalism might be a result of their interest in increasing the RE supply in domestic markets.", "cite_spans": [], "ref_spans": []}, {"section": "Critical evaluation of market based trade policy measures: Empirical analyses", "text": "The results further show that when countries are more dependent on the RE international market, they are likely to apply more non-technical measures and export-related measures on RE goods and technologies. These results are consistent with the results of Saksena and Anderson's (2008) and Treflers (1993), who argued that high level of imports would cause protection. In addition, the bigger the economy is, the higher the tariffs and the more technical measures, non-technical measures and exportrelated measures it has. This indicates that big countries use their economic power to increase trade barriers as they face less threat of tit for tat actions from their partner countries. This result conforms to the arguments of Mansfield and Busch (1995) and Scaperlanda (1973) . In the case of export-related measures, larger countries may use higher export-related measures to increase domestic supply and the use of RE.", "cite_spans": [], "ref_spans": []}, {"section": "Critical evaluation of market based trade policy measures: Empirical analyses", "text": "Interestingly, the variable 'developed countries' shows that these countries are associated with a greater number of non-technical measures and export-related measures. The results indicate that if both importer and exporter countries are ASEAN members, non-technical measures on RE are lower, but technical measures and export-related measures are higher than the non-ASEAN members.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions and Policy Suggestions", "text": "Given the constraints on government budgets in many RCEP member countries and the large capital outlay required to achieve the renewable energy targets agreed at the COP21 meeting, both public and private capital needs to be mobilized in the long run. Many governments have adopted conventional measures, such as feed-in-tariff, renewable certificates, carbon tax, emissions trading scheme, and public tenders, and some have used less conventional financial instruments, such as credit and risk guarantees, innovative currency hedging facilities, and government green bonds to encourage private financing in the production and the distribution of the RE goods and technologies. Though the above conventional and less conventional financial instruments are used at the national level, only a few countries are aware of the role that international and regional cooperation agreements, such as RCEP and BRI can play in increasing the pace of transition to renewable energy systems.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions and Policy Suggestions", "text": "The basic principle underlying any business investment is profit maximization. However, market demand and supply conditions determine how sustainable the profitable returns would be over a period of time. In other words, the perception of market risk plays a crucial role in scaling up investment in RE. The evidence based research asserts that trade and investment are the two important pillars of any regional cooperation agreements. Hence, scaling up private investment in RE sector through regional cooperation agreements should be effective by facilitating smooth functioning of trade and investment in RE to eliminate the market risk. It is in this context, the present study has gauged the influence of the market based trade policy measures -export tax rebate, tariff and non-tariff measures, and the regional cooperation agreements on both the national and regional RE markets in the RCEP region. Policy suggestions are made about what the governments could do to strengthen the positive influence of those market based trade policies to accelerate the speed of private financing of the low-carbon energy industry, particularly the RE industry.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions and Policy Suggestions", "text": "The empirical results of this study suggest a few policy prescriptions to scale up private financing in the RE sector. No doubts, reduction in corruption and enhancement of democracy and regulatory quality would help improving the demand side of the RE market towards reducing trade barriers on RE goods and technologies. There is a need to enhance individuals' environmental concerns and voices of environmental groups so that this interest can be reflected in trade policies and contribute to tariffs and NTMs reduction.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions and Policy Suggestions", "text": "Governments should continuously support R&D investment that improves power generation and its forecasting ability. Due to the lack of accurate forecasting ability, currently the renewable power supply curve could not match the demand curve especially during the peak period in many countries, which contributes to investors' aversion to renewable energy. An alternative solution for this issue is to facilitate energy storage technology, which could smooth and RE investment. Unfortunately, even China only accounts for 6 per cent of world investment in energy storage program.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions and Policy Suggestions", "text": "Fiscal risk may emerge in the public-private partnership due to a country's weak legal and institutional frameworks, which can be mitigated through regional knowledge and institutional-infrastructure sharing facilitated through regional cooperation agreements. Drawing on Mustapha et al., [7] [8] [9] [10] [11] [12] [13] innovations in RE generation in the form of 'hybrid' projects can be disseminated across countries through regional cooperation agreements too. Finally, IRENA (2017) [2] argued that the power generation cost of solar PV and onshore wind have already been lower than traditional fossil energy sources. However, the transformation from fossil energy to renewable energy is still under a slow paced process. It appears like that people still prefer electricity or gas water heater rather than solar water heater. Therefore, other than price, governments need to work on ways to educate and to create appropriate incentives to induce consumers to change their consumption patterns.", "cite_spans": [{"start": 289, "end": 292, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 293, "end": 296, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 297, "end": 300, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 301, "end": 305, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 306, "end": 310, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 311, "end": 315, "text": "[12]", "ref_id": "BIBREF12"}, {"start": 316, "end": 320, "text": "[13]", "ref_id": "BIBREF13"}], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Asian Development Outlook 2017: Transcending the Middle-Income Challenge, Asian Development Bank", "authors": [{"first": "", "middle": [], "last": "Adb", "suffix": ""}], "year": 2017, "venue": "", "link": "157891746"}, "BIBREF2": {"title": "Global Landscape of Renewable Energy Finance", "authors": [], "year": 2018, "venue": "International Renewable Energy Agency (IRENA) and Climate Policy Initiative (CPI)", "link": null}, "BIBREF3": {"title": "Financing for Low-carbon Energy Transition: Unlocking the Potential of Private Capital", "authors": [{"first": "K", "middle": [], "last": "Kalirajan", "suffix": ""}, {"first": "H", "middle": ["L"], "last": "Chen", "suffix": ""}], "year": 2018, "venue": "", "link": "169641559"}, "BIBREF4": {"title": "Game-Changer or Compelement? The Potential of Public Finance Instruments for Covering Risks and Facilitating Low-Carbon Investments in Developing Countries", "authors": [{"first": "M", "middle": [], "last": "Stadelmann", "suffix": ""}, {"first": "K", "middle": [], "last": "Newcombe", "suffix": ""}], "year": 2011, "venue": "", "link": null}, "BIBREF5": {"title": "ARENA Large Scale Solar PV Projects", "authors": [], "year": 2017, "venue": "Australian Renewable Energy Agency, Australian Government", "link": null}, "BIBREF6": {"title": "Topic Guide: Blended Finance for Infrastructure and Low-Carbon Development", "authors": [{"first": "S", "middle": [], "last": "Mustapha", "suffix": ""}, {"first": "A", "middle": [], "last": "Prizzon", "suffix": ""}, {"first": "M", "middle": [], "last": "Gavas", "suffix": ""}], "year": 2014, "venue": "", "link": null}, "BIBREF7": {"title": "Global Trends in Renewable Energy Investment", "authors": [{"first": "Frankfurt", "middle": [], "last": "School", "suffix": ""}, {"first": "-Unep", "middle": [], "last": "Centre", "suffix": ""}, {"first": "/", "middle": [], "last": "Bnef", "suffix": ""}], "year": 2017, "venue": "", "link": null}, "BIBREF8": {"title": "Renewable Energy Policies in a Time of Transition'. IRENA, OECD/ IEA and REN21", "authors": [{"first": "", "middle": [], "last": "Irena", "suffix": ""}], "year": 2018, "venue": "", "link": null}, "BIBREF9": {"title": "Regional Cooperation toward Green Asia: Trade in Low Carbon Goods", "authors": [{"first": "K", "middle": [], "last": "Kalirajan", "suffix": ""}, {"first": "V", "middle": [], "last": "Anbumozhi", "suffix": ""}], "year": 2014, "venue": "The International Trade Journal", "link": "155016766"}, "BIBREF10": {"title": "Investment Climate and I in Developing Countries: Firm Level Evidence", "authors": [{"first": "T", "middle": [], "last": "Kinda", "suffix": ""}], "year": 2010, "venue": "World Development", "link": null}, "BIBREF12": {"title": "Evaluating Methods to Estimate Private Climate Finance Mobilised from Public Interventions", "authors": [{"first": "A", "middle": [], "last": "Srivastava", "suffix": ""}, {"first": "S", "middle": [], "last": "Venugopal", "suffix": ""}], "year": 2014, "venue": "", "link": null}, "BIBREF13": {"title": "Regional Political Risk Index, The PRS Group", "authors": [{"first": "Prs", "middle": [], "last": "The", "suffix": ""}, {"first": "", "middle": [], "last": "Group", "suffix": ""}], "year": 2018, "venue": "A. Accessed on August", "link": null}}, "ref_entries": {"FIGREF0": {"text": "Figure 1. Sources of new investment in renewable energy, 2004-2016", "type": "figure"}, "FIGREF1": {"text": "Figure 4. Investment in renewable energy by developing and developed countries", "type": "figure"}, "FIGREF3": {"text": ": (Source: Authors' estimation) ** significant at the 5 per cent level; *** significant at the 1 per cent level for the non-tariff measures. The results are presented in", "type": "figure"}, "TABREF0": {"text": "The Impact of Export Tax Rebate on RE Exports of", "type": "table"}, "TABREF1": {"text": "Determinants of Tariffs and Non-tariffs Measures on RE Exports", "type": "table"}}}
{"paper_id": "191683697", "_pdf_hash": "2a05871471d8ebc213e4f072a4aebe24d35c7ff5", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "191688840", "_pdf_hash": "516d7cdc62d99cd37b57c5c130a4393d7b5e1de7", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "The Alishar Hiiyiik. Seasons of 1930 and 1932. Part Ill. DIP 30", "authors": [{"first": "H", "middle": ["H"], "last": "Von Der Osten", "suffix": ""}], "year": 1937, "venue": "", "link": null}, "BIBREF1": {"title": "Ali$ar Hoyiik in the Second", "authors": [{"first": "R", "middle": ["L"], "last": "Gomy", "suffix": ""}], "year": 1990, "venue": "", "link": null}, "BIBREF3": {"title": "Glyptik aus dem Stadtgebiet von Bogazkoy", "authors": [{"first": "R", "middle": ["M G"], "last": "Boehmer / H", "suffix": ""}, {"first": "", "middle": [], "last": "Giiterbock", "suffix": ""}], "year": 1931, "venue": "", "link": null}, "BIBREF4": {"title": "Kanis / NeJa, fig. 187-188, vases from level lb", "authors": [{"first": "Kiiltepe", "middle": [], "last": "Ozgii&lt;y", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF6": {"title": "Gods and Goddesses with Identical Attributes During the Period of Old Assyrian Trade Colonies", "authors": [{"first": "N", "middle": [], "last": "Ozgii&lt;", "suffix": ""}, {"first": "; N", "middle": [], "last": "Ozgii&lt;y", "suffix": ""}], "year": 1979, "venue": "Florilegium Anatolicum -Melanges Offerts it Emmanuel Laroche", "link": null}, "BIBREF7": {"title": "Glyptik aus dem Stadtgebiet, Taf. XV /147 d, C", "authors": [{"first": "/", "middle": [], "last": "Boehmer", "suffix": ""}, {"first": "", "middle": [], "last": "Giiterbock", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF9": {"title": "The Megiddo Ivories. DIP 52", "authors": [{"first": "G", "middle": [], "last": "Loud", "suffix": ""}], "year": 1939, "venue": "", "link": null}, "BIBREF10": {"title": "This still unpublished artefact is displayed at the Museum of Anatolian Civilizations", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF11": {"title": "Die Reliefkeramik von Bogazkoy", "authors": [{"first": "", "middle": [], "last": "Boehmer", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF12": {"title": "A Preliminary Report on the Eleventh Excavation at Kaman-Kalehoyiik (1996)", "authors": [{"first": "S", "middle": [], "last": "Omura", "suffix": ""}], "year": 1997, "venue": "Anatolian Archaeological Studies Vol VI. Kaman KalehOyiik", "link": null}, "BIBREF13": {"title": "Hitit Sanat!. istanbul. 1992, fig. 154", "authors": [{"first": "M", "middle": [], "last": "Darga", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF14": {"title": "A Group of Metal Hittite Vessels from Kmlk-Kastamonu", "authors": [{"first": "K", "middle": [], "last": "Emre / A. &lt;;Maroglu", "suffix": ""}], "year": 1993, "venue": "Aspects of A.rt and Iconography: Anatolia and its Neighbors. Studies in Honor of N. QZgiif", "link": null}, "BIBREF15": {"title": "Bogazkoy Metinlerine gore Hititler Devri Anadolu'sunun Faunas!. Ankara'", "authors": [{"first": "H", "middle": [], "last": "Ertem", "suffix": ""}], "year": 1965, "venue": "", "link": null}, "BIBREF16": {"title": "Geschichte der hethitischen Religion", "authors": [{"first": "V", "middle": [], "last": "Haas", "suffix": ""}], "year": 1994, "venue": "", "link": null}, "BIBREF17": {"title": "Hititlerde AN.TAH .SUM sAR Bitkisi ve Bayraml Dzerine Bir inceleme", "authors": [{"first": "S", "middle": [], "last": "Erkut", "suffix": ""}, {"first": "", "middle": [], "last": "Jil", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF18": {"title": "Uluslarasl Hititoloji Kongresi Bildirileri . <;orum 16-22 Eyliil", "authors": [], "year": 1996, "venue": "KUB XXV 1811 1 f", "link": null}, "BIBREF20": {"title": "Die Reliefkeramik von Bogazkoy", "authors": [{"first": "", "middle": [], "last": "Boehmer", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF21": {"title": "Hitit <;::iyi Yazlh Belgelerinde suhha-' (duz) Dam, <;::atl ' ye onun Dinsel ye Sosyal Hayattaki Yeri", "authors": [{"first": "Y", "middle": [], "last": "Ankan", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF24": {"title": "Kiiltepe, Kan is / Nda, p. 98, fig . 50. Premoyable hearth from leyellI. 63 Ozgtic;Jnandlktepe, fig", "authors": [{"first": "M", "middle": [], "last": "Popko", "suffix": ""}], "year": 1978, "venue": "", "link": null}, "BIBREF25": {"title": "Religions of Asia Minor", "authors": [{"first": "M", "middle": [], "last": "Popko", "suffix": ""}], "year": 1995, "venue": "", "link": "161813081"}, "BIBREF28": {"title": "Fragment einer Hethitischen Reliefvase van Bogazkoy", "authors": [{"first": "K", "middle": [], "last": "Bittel", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF29": {"title": "In my opinion, Bogazkoy wagon 69 (fig. 6/2) might have been used for carrying cult objects like in the Hiiseyindede and Ali~ar vases . The following scene on Hiiseyindede vase contains new figures of female dancers 70, a novelty on relief vases . In conclusion, Hiiseyindede cult vase contributes novelties to Old Hittite Representative Art with narrative presentation of the spring festivals organized in honor of the local Storm God in Hatti country where agriculture and husbandry depended on fertility and reproduction", "authors": [{"first": "Festschriftfor", "middle": [], "last": "Kurt Galling", "suffix": ""}, {"first": "", "middle": ["A"], "last": "Hg", "suffix": ""}, {"first": "E", "middle": [], "last": "Kurscke", "suffix": ""}, {"first": "", "middle": [], "last": "Kutsch", "suffix": ""}, {"first": "", "middle": [], "last": "Ttibingen", "suffix": ""}], "year": 1970, "venue": "", "link": null}, "BIBREF30": {"title": "Hiiseyindede vase, drawing by T. YIldmm. 112, Ozgii9, inandlktepe, fig. 65. 113, Ozgii9, The Bitik Vase, p. 60, fig. I 114, Boehmer, Die Reliefkeramik van Bagazkdy, Taf. V / lOa, b. 115, Hiiseyindede, drawing by", "authors": [{"first": "", "middle": [], "last": "Fig", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF31": {"title": "/6, Ozgii9, Kiiltepe, Kanis / NeSa, fig. 187. 117, Ko~ay, Alaca Hdyuk KaZlsl", "authors": [], "year": 1937, "venue": "", "link": null}, "BIBREF32": {"title": "Ozgii9, inandlktepe, PI. 73 / 1. 1110, Ozgii9, Ma~at Hdyuk ll, PI. 87 / la ,b. 1111,12 Boehmer, Die Reliefkeramik van Bagazkdy, Abb. 39a", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF33": {"title": "YIldmm 2/2, Hiiseyindede, drawing by T. Sipahi. 2/3, Ozgii9, inandlktepe, fig . 64/18. 2/4, Boehmer, Die Reliefkeramik van Bagazkdy, Abb. 15, Kabakh. 2/5, Ozgii9, inandlktepe", "authors": [], "year": "", "venue": "Fig. 2/1, Hiiseyindede bull, drawing by T", "link": null}, "BIBREF35": {"title": "The Alishar Hiiyiik, Seasons of 1930-32. Part 11, DIP 29", "authors": [{"first": "H", "middle": ["H"], "last": "Von Der Osten", "suffix": ""}], "year": 1937, "venue": "", "link": null}, "BIBREF37": {"title": "Ozgii9, Ma$at Hoyuk II, PI. 87 / fig. 164 b. 2112, Ozgii9, N., Collectanea Orientalia 1996, fig. 9 2/13, Ozgii9, N., Florilegium Anatolicum, fig. 1 / Kt. s/k1. 2/14, Boehmer / Giiterbock", "authors": [{"first": "T", "middle": [], "last": "Ylldmm", "suffix": ""}], "year": 1939, "venue": "Glyptik aus dem Stadtgebiet, Abb. 38. 2115, Boehmer / Giiterbock, Glyptik aus dem Stadtgebiet, Taf. XV /147 d. 2116, Ko~ay", "link": null}, "BIBREF38": {"title": "The first frieze of the Hiiseyindede vase", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF39": {"title": "The Bitik Vase", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF40": {"title": "The second frieze of the Hiiseyindede vase", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF41": {"title": "/3, Ozgii9, The Bitik Vase", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF42": {"title": "Anatolia XIV11970, fig. 2. 417, Boehmer, Die Reliefkeramik von Bogazkoy, Abb", "authors": [{"first": "Mellink", "middle": [], "last": "", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF43": {"title": "Emre/C;maroglu, Studies in Honor of N. Ozgu(:, fig. 23. 4/10, Boehmer / Giiterbock, Glyptik aus dem Stadtgebiet, Taf. XV / 148k. 4/11", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF44": {"title": "The third frieze of the Hiiseyindede vase", "authors": [{"first": "T", "middle": [], "last": "Ildmm", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF45": {"title": "/2, Ozgii9, jnandlktepe, fig", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF46": {"title": "The Bitik Vase", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF47": {"title": "The fourth frieze of the Hiiseyindede vase, drawing by T. YIldmm. 6/2, Boehmer, Die Reliefkeramik von Bogazkoy", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF49": {"title": "Boehmer, Die Reliefkeramik von Bogazkoy", "authors": [], "year": "", "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "128191503", "_pdf_hash": "daaa189cc869d38b2fe35e7487b961bca312f65b", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "128193678", "_pdf_hash": "a066e990cb9f1ccae52cbe877fe134be3b62ed44", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "128194094", "_pdf_hash": "7c4c51a4336308dcfad9327e684f6cc10b6629c2", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "128196503", "_pdf_hash": "678f3eafddcd15353a2263777bc3603cbea54145", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "128197553", "_pdf_hash": "3cde315d9e3e01f32952e2f8a214bae4e7db0a85", "abstract": [], "body_text": [{"section": "INTRODUCTION", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "SOURCE OF ARSENIC", "text": "Arsenic is a common, naturallyoccurring element in the Earth's crust. Arsenic in ground water is often a result of arsenic-bearing minerals dissolving naturally over time. Historical wellwater data for southeastern Michigan indicated that where arsenic concentrations of ground water were elevated, wells were commonly, though not exclusively, completed in the Marshall Sandstone. The Marshall Sandstone is a fluvial to marginal marine geologic unit that is present below glacial materials in part of the study area ( fig. 1 ). Drinking-water wells in the study area often draw water from one or more additional geologic units -the Saginaw Formation, the Michigan Formation, or the Coldwater Shale ( fig. 1 ), as well as from the glacial materials that overlie these bedrock units. Figure 1 shows the arsenic concentration of 3,022 wells in the study area. Data for figure 1 were taken from recent and historical USGS records, as well as from MDEQ records of well-water analyses for domestic and public water supplies from 1997 to 1999. The USGS collected water samples from 76 domestic and public drinking-water wells in southeastern Michigan as part of this study. The wells were chosen to represent various aquifers in the study area and to avoid any possible source of human contamination. The highest arsenic concentration measured by the USGS (220 |ig/L) occurred in a well drawing water from the Marshall Sandstone. However, the USGS measured arsenic concentrations exceeding the current USEPA standard of 50 |ig/L in well water from all aquifer units except the glacial sand and gravel deposits, and arsenic concentrations equal to or exceeding 40 jig/L were measured in wells completed in glacial sediments in three counties.", "cite_spans": [], "ref_spans": [{"start": 518, "end": 524, "text": "fig. 1", "ref_id": "FIGREF0"}, {"start": 700, "end": 706, "text": "fig. 1", "ref_id": "FIGREF0"}, {"start": 782, "end": 790, "text": "Figure 1", "ref_id": "FIGREF0"}]}, {"section": "DISTRIBUTION OF ARSENIC IN GROUND WATER IN SHIAWASSEE COUNTY", "text": "Information on ground-water arsenic concentrations in Shiawassee County was available from the MDEQ, the USGS, and the county. The USGS sampled six drinking water wells in Shiawassee County as part of this study. The 138 analyses shown in figure 2 represent recent (1997 or later) MDEQ well-water analyses for total arsenic, as well as USGS analyses for total or dissolved arsenic. Of these, none exceeded the USEPA standard of 50 |ig/L (table 1) . Eightyeight of the 138 wells (63.7 percent) had arsenic concentrations less than or equal to 10 |ig/L, and 71 wells had arsenic concentrations less than 5 |ig/L. Welldrilling records were available for 13 wells. The highest arsenic concentration recorded for a well of known construction was 40 jig/L for a well in Vernon Township completed in glacial materials at a depth of 61 ft. The second highest concentration (31 |ig/L) was recorded in Shiawassee Township in a well completed at 104 ft. depth in glacial materials.", "cite_spans": [], "ref_spans": [{"start": 437, "end": 446, "text": "(table 1)", "ref_id": "TABREF2"}]}, {"section": "HEALTH EFFECTS OF ARSENIC", "text": "The Agency for Toxic Substances and Disease Registry (ATSDR, 1998) Toxicological Profile for arsenic describes some possible health effects of arsenic exposure. Consumption of arsenic doses greater than 60,000 |ig/L in food or water can be lethal (ATSDR, 1998) . Doses between 300 and 30,000 |ig/L may cause stomach pain, nausea, vomiting or diarrhea (ATSDR, 1998). Long-term exposure to arsenic may produce other effects. Arsenic is classified as a known human carcinogen by the USEPA, and it has been linked to skin, bladder, lung and prostate cancer. In addition, non-cancer effects of long-term exposure may include darkening and thickening of the skin (especially on the palms of the hands, the soles of the feet, and the torso) as well as numbness of the feet and hands, anemia or cardiovascular changes. The concentrations of arsenic that result in these long-term effects have not been clearly established. Lansing, usgs.gov ", "cite_spans": [], "ref_spans": []}, {"section": "FOR MORE INFORMATION", "text": "", "cite_spans": [], "ref_spans": []}], "bib_entries": {}, "ref_entries": {"FIGREF0": {"text": "Figure 1. Locations of selected wells in southeastern Michigan and their concentrations of arsenic.", "type": "figure"}, "FIGREF1": {"text": "Figure 2. Location of wells and their concentration of arsenic, Shiawassee County, Michigan.", "type": "figure"}, "FIGREF2": {"text": "Sheridan K. Haack and Cynthia M. Rachol For more information contact: U.S. Geological Survey 6520 Mercantile Way, Suite 5", "type": "figure"}, "TABREF0": {"text": "jig/L]. This MCL was established in 1986. The Safe Drinking Water Act, as amended in 1996, requires USEPA to revise this standard in 2000. In June 2000, the USEPA proposed a revised MCLof5|ig/L. In 1996, the USGS. in cooperation with the MDEQ and the Health Departments of Genesee, Huron, Lapeer, Livingston, Oakland, Sanilac, Shiawassee, Tuscola and Washtenaw counties, began a study of the factors controlling arsenic occurrence and concentrations in ground water in southeastern Michigan. This study is one of four USGS Drinking Water Initiative projects throughout the United States.", "type": "table"}, "TABREF2": {"text": "Arsenic summary by township. [jjg/L = micrograms per liter; detection limit = 1ug/L]Median Arsenic Concentration (\\ig/L)Percent <5 \\ag/L (%)Percent >50 \\ig/L (%)", "type": "table"}}}
{"paper_id": "128199877", "_pdf_hash": "e3293ed92caea522acd2c59265255f163bfcfae5", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "119420300", "_pdf_hash": "df3b7d82d714e4949785db9ea512baa7604785d6", "abstract": [{"section": "Abstract", "text": "We broaden the investigation of the dynamical properties of tidally perturbed, rotating star clusters by relaxing the traditional assumptions of coplanarity, alignment, and synchronicity between the internal and orbital angular velocity vector of their initial conditions. We show that the interplay between the internal evolution of these systems and their interaction with the external tidal field naturally leads to the development of a number of evolutionary features in their three-dimensional velocity space, including a precession and nutation of the global rotation axis and a variation of its orientation with the distance from the cluster centre. In some cases, such a radial variation may manifest itself as a counter-rotation of the outermost regions relative to the inner ones. The projected morphology of these systems is characterized by a non-monotonic ellipticity profile and, depending on the initial inclination of the rotation axis, it may also show a twisting of the projected isodensity contours. These results provide guidance in the identification of non-trivial features which may emerge in upcoming investigations of star cluster kinematics and a dynamical framework to understand some of the complexities already hinted by recent observational studies.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "INTRODUCTION", "text": "Many recent observational studies are significantly enriching our knowledge of the internal structural and kinematical properties of globular clusters, and in particular revealing their deviations from the traditional picture of them being spherical and isotropic systems. A consistent finding in these studies is the presence of rotation in globular clusters (e.g., Bellazzini et al. 2012; Fabricius et al. 2014; Lardo et al. 2015) .", "cite_spans": [], "ref_spans": []}, {"section": "INTRODUCTION", "text": "In most cases, the depth of current kinematic information allows only a simplified description of the internal distribution of the angular momentum. Ordered motions are often described only by a single value of the rotational velocity, and the orientation of the projected rotation axis is determined by using all members in a given sample, often binning together stars that are at different distances from the centre of the cluster and thus have different kinematical properties. A few studies have gone further and constructed a rotational radial profile of the cluster, (e.g., Gebhardt et al. 2000; van den Bosch et al. 2006; Bianchini et al. 2013; Boberg et al. 2017; Bellini et al. 2017; Kamann et al. 2017) , and some of these studies have noted that the rotation axis' position angle varies significantly with radius, suggesting that the orientation of such an axis may change with the distance from the cluster's centre. This complex kinematical property is usually not addressed in theoretical star cluster studies.", "cite_spans": [], "ref_spans": []}, {"section": "INTRODUCTION", "text": "Indeed, only relatively few dynamical investigations have explored some fundamental aspects of the evolution of rotating clusters and shown that collisional systems gradually lose their rotation due to the effects two-body relaxation (e.g., Einsel & Spurzem 1999; Ernst et al. 2007; Hong et al. 2013; Tiongco et al. 2017) ; this implies that present-day clusters had stronger rotation in the past and that rotation is an essential ingredient for more realistic models of cluster dynamics. These studies have considered exclusively isolated or tidally limited rotating clusters with the rotation axis parallel or anti-parallel to the cluster's orbital angular velocity vector. In this contribution, we broaden the exploration of the dynamics of rotating clusters and focus our attention on more general initial configurations for which the internal rotation axis is not aligned with the cluster's axis of rotation about the host galaxy and the internal and orbital motions are not synchronous.", "cite_spans": [], "ref_spans": []}, {"section": "INTRODUCTION", "text": "By means of N-body simulations, we explore the effects of the interplay between internal angular momentum and the external tidal field on the cluster's internal kinematics and show a dynamical path to a number of complex features in the three-dimensional velocity space of star clusters, including the radial variation of the rotation axis hinted by some observational star cluster studies mentioned above. This investigation of the coupling between internal and orbital angular momenta may also help to interpret some kinematic features identified in more massive stellar systems, such as nuclear star clusters (e.g., see Feldmeier-Krause et al. 2017 ). Analogies to peculiar kinematic subsystems identified both in dwarf and massive early-type galaxies (e.g., see Franx & Illingworth 1988 and De Rijcke et al. 2004 ) may also be qualitatively drawn. . Time-evolution of the Cartesian components and the absolute value of the angular velocity vector, \u03c9, normalized to the angular speed of the cluster's orbit about the host galaxy, \u2126. All models are represented (see Table 1 ). Time is expressed in units of the initial half-mass relaxation time. The overall rotation of the systems decreases in magnitude (gray line), but in all cases, the tidal torque due to the host galaxy initiates a precession of the cluster's rotation axis leading to large scale oscillations of \u03c9 x and \u03c9 y (black and red lines).", "cite_spans": [], "ref_spans": [{"start": 1068, "end": 1075, "text": "Table 1", "ref_id": "TABREF0"}]}, {"section": "METHOD AND INITIAL CONDITIONS", "text": "The N-body simulations presented in this paper were carried out using the NBODY6 code (Aarseth 2003) accelerated by a GPU (Nitadori & Aarseth 2012) , and run on the BIG RED II cluster at Indiana University. The clusters are scaled to N-body units such that G = M = 1 and E = \u22120.25 (Heggie & Hut 2003) .", "cite_spans": [{"start": 86, "end": 100, "text": "(Aarseth 2003)", "ref_id": "BIBREF0"}, {"start": 281, "end": 300, "text": "(Heggie & Hut 2003)", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "METHOD AND INITIAL CONDITIONS", "text": "For the initial conditions, we sample a series of rotating equilibria introduced by Varri & Bertin (2012) . This family of distribution function-based models is characterized by differential rotation and an oblate structure flattened in a direction parallel to the rotation axis. The initial half-mass relaxation time, t rh,i , is 62 times the halfmass orbital time ( 3\u03c0/G\u03c1). For a complete description we refer the reader to Varri & Bertin (2012) , and the parameters defining the specific models explored here are the same as those of the rotating models studied in Tiongco et al. (2016a, see their \u00a72) . In that study, the rotation axis of our models was assumed to be parallel to the angular velocity vector associated with the cluster's orbital motion. In this Letter, we explore more general initial configurations in which the internal rotation axis is not aligned with the angular velocity vector of the cluster's orbit about the host galaxy.", "cite_spans": [], "ref_spans": []}, {"section": "METHOD AND INITIAL CONDITIONS", "text": "Clusters are assumed to be on circular orbits in the host galaxy tidal field modeled as a point-mass, and the equations of motion are solved in a frame of reference co-rotating with the cluster around the host galaxy centre (see e.g. Heggie & Hut 2003) with angular speed \u2126. When we present the results of our analysis in this paper, however, we use a non-rotating reference frame still centred on the cluster's centre with the z-axis perpendicular to the cluster's orbital plane. The three-dimensional direction of the angular velocity vector, \u03c9, is expressed by \u03b8 \u03c9 , i.e. the angle measured from the z-axis, up to 180 degrees, and \u03c6 \u03c9 , which is defined as the angle between the projection of the vector on the x \u2212 y plane and the x-axis, starting at 0 degrees at the x-axis and increasing towards the y-axis. We consider systems with N = 32 768 equal-mass particles; particles moving beyond a distance from the cluster's centre equal to two times the Jacobi radius, r J , are removed from the simulation. All the simulations are run until 75% of the initial cluster mass is lost. Table 1 lists the simulations presented in this Letter and the initial orientation of the rotation axis of the cluster. All models have their initial rotation axis in the x \u2212 z plane, therefore, only the \u03b8 \u03c9 values of the initial orientation of the rotation axis are reported (see Table 1 , Col. 2). For each orientation we run two models: one including only the intrinsic rotation of the Varri & Bertin (2012) model, and one in which we add also a positive solid body rotation about the z-axis with an angular speed, \u2126, equal to that of the cluster's orbital motion. This set-up is intended to generalize the usual initial condition in which a cluster model is assumed to be co-rotating with the orbital motion. We refer to such models as 'locked', indicating the the solid-body component of the rotation has been assumed to come from tidal locking. For simplicity, the models without such a initial solid-body component are defined as 'unlocked'. We initialize the ratio of the half-mass radius of the cluster to the Jacobi radius to be r h /r J = 0.17.", "cite_spans": [{"start": 234, "end": 252, "text": "Heggie & Hut 2003)", "ref_id": "BIBREF12"}], "ref_spans": [{"start": 1084, "end": 1091, "text": "Table 1", "ref_id": "TABREF0"}, {"start": 1365, "end": 1372, "text": "Table 1", "ref_id": "TABREF0"}]}, {"section": "RESULTS", "text": "We begin our analysis by presenting the evolution of the components of the angular velocity vector, \u03c9, calculated using all particles within the Jacobi radius, r J . We calculate the moment of inertia tensor, I, and the angular momentum vector, L, and solve the equation L = I\u03c9. The evolution of the absolute value \u03c9 and the Cartesian components (\u03c9 x , \u03c9 y , \u03c9 z ) for all models are plotted in Fig. 1 as a function of time, expressed in units of the initial half-mass relaxation time of the cluster, t rh,i . A number of interesting features are present in Fig. 1 . In agreement with previous findings (e.g., see Einsel & Spurzem 1999; Ernst et al. 2007; Hong et al. 2013; Tiongco et al. 2017) , the overall rotation in the system decreases in magnitude over time, as determined by a general redistribution and loss of angular momentum in the system due to relaxation effects. As the system evolves, it gradually loses its intrinsic differential rotation and evolves towards a configuration dominated by an approximately solid-body rotation about the z-axis with angular speed equal to about 0.5\u2126 (models XZRLOC and XZRUNL take longer to converge to this value than the time shown in Fig. 1) . Thus, the rotating models explored here extend the conclusions of Tiongco et al. (2016b) , namely that a variety of initially non-rotating models reach a condition of only partial . Time evolution of the three-dimensional orientation of the angular velocity vector, \u03c9, as expressed by \u03c6 \u03c9 , i.e. the angle between the projection of \u03c9 on the x \u2212 y plane and the x-axis, and \u03b8 \u03c9 , i.e. the angle between \u03c9 and the z-axis. All models are represented (see Table 1 ). All the systems are characterized by a precession and nutation of the angular velocity vector.", "cite_spans": [], "ref_spans": [{"start": 395, "end": 401, "text": "Fig. 1", "ref_id": "FIGREF0"}, {"start": 558, "end": 564, "text": "Fig. 1", "ref_id": "FIGREF0"}, {"start": 1185, "end": 1192, "text": "Fig. 1)", "ref_id": "FIGREF0"}, {"start": 1647, "end": 1654, "text": "Table 1", "ref_id": "TABREF0"}]}, {"section": "RESULTS", "text": "synchronization, as a result of the interaction with the external tidal field and the preferential loss of prograde orbiting stars. A prominent feature in Fig. 1 is that all models acquire a rotation about the y-axis. The initial rotation of the system in the x-z plane, the non-spherical symmetry induced by this rotation, and its orientation imply that the system is affected by a tidal torque due to the host galaxy that initiates a precession of the rotation axis and a rotation about the y-axis (see the large scale oscillations in Fig.  1 ). As the system loses its initial intrinsic rotation, the amplitudes of the oscillations of \u03c9 y and \u03c9 x are damped and eventually converge to zero leaving the system only with the rotation about the z-axis discussed above. The time evolution of \u03c9 presented in Fig. 1 also shows the presence of small scale and rapid nutation oscillations.", "cite_spans": [], "ref_spans": [{"start": 155, "end": 161, "text": "Fig. 1", "ref_id": "FIGREF0"}, {"start": 537, "end": 544, "text": "Fig.  1", "ref_id": "FIGREF0"}, {"start": 806, "end": 812, "text": "Fig. 1", "ref_id": "FIGREF0"}]}, {"section": "RESULTS", "text": "We further explore the evolution of the angular velocity vector in terms of the angles (\u03b8 \u03c9 , \u03c6 \u03c9 ) which define the direction of \u03c9 (see Fig. 2 ). The evolution of \u03c6 \u03c9 illustrates the gradual change in orientation of \u03c9 on the x \u2212 y plane. Meanwhile, the evolution of \u03b8 \u03c9 shows that, as the cluster loses its initial differential rotation about the x and y axis, the direction of \u03c9 gradually converges toward the z-axis. Both Figs. 1 and 2 indicate that all models are characterized by a precession and nutation oscillations of \u03c9.", "cite_spans": [], "ref_spans": [{"start": 137, "end": 143, "text": "Fig. 2", "ref_id": "FIGREF1"}, {"start": 425, "end": 438, "text": "Figs. 1 and 2", "ref_id": "FIGREF0"}]}, {"section": "RESULTS", "text": "We now turn our attention to the study of the rotational properties as a function of the distance from the cluster centre. The rotation curve of the Varri & Bertin (2012) models is characterized by a radial profile increasing with radius in the cluster's inner regions, reaching a peak in the intermediate parts, and then decreasing and vanishing at the edge of the system. The additional solid-body rotation about the z-axis (either added in the initial conditions as in the locked systems or developing during the cluster evolution for the initially unlocked systems) naturally introduces a radial variation in the rotation axis. We explore this feature by inspecting the time evolution of the radial profile of \u03b8 \u03c9 for models XLOC and XUNL (see Fig. 3, top row) . For model XLOC, a radial gradient is present in the initial conditions because of the added solid body rotation around the z-axis, and subsequently, the system is characterized by a radial gradient in the orientation of its rotation axis during its entire evolution. Model XUNL, on the other hand, starts its evolution with no radial gradient in \u03b8 \u03c9 , but as it evolves and interacts with the external tidal field, it develops a radial profile of \u03b8 \u03c9 similar to that of the XLOC model.", "cite_spans": [], "ref_spans": [{"start": 748, "end": 764, "text": "Fig. 3, top row)", "ref_id": "FIGREF2"}]}, {"section": "RESULTS", "text": "The radial profile of \u03b8 \u03c9 shows that in the cluster's innermost regions the orientation of the rotation axis is determined mainly by that of the cluster initial intrinsic rotation (in this case parallel to the x-axis); \u03b8 \u03c9 decreases as the distance from the cluster center increases until the outermost regions where the rotation axis is almost parallel to the z-axis (i.e. parallel to the cluster's orbital angular velocity around the host galaxy) and mainly determined by the rotation resulting from the interaction of the cluster with the external tidal field.", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS", "text": "The bottom panels of Fig. 3 show the radial profiles of \u03c9 x , \u03c9 y , and \u03c9 z , and further illustrate the radial variation of the cluster's rotational properties and the transition from the inner regions dominated by rotation around the x and y axes, to the outer regions that are most affected by the influence of the tidal field and are increasingly dominated by rotation around the z axis.", "cite_spans": [], "ref_spans": [{"start": 21, "end": 27, "text": "Fig. 3", "ref_id": "FIGREF2"}]}, {"section": "RESULTS", "text": "Although a detailed connection between our theoretical results and observations is beyond the scope of this paper, it is important to understand how and to what extent the kinematical features found in our simulations would appear when studied using the tools and diagnostics typically available in current observational studies. To explore this issue, in Fig. 4 , we concentrate on a representative snapshot of the model XZRLOC.", "cite_spans": [], "ref_spans": [{"start": 356, "end": 362, "text": "Fig. 4", "ref_id": "FIGREF3"}]}, {"section": "RESULTS", "text": "The top panels of Fig. 4 show colour maps representing the mean radial velocity along the line of sight adopted in each column; the arrows indicate the direction and relative magnitude of the velocity in the plane perpendicular to the line of sight. A rotation signature can be detected both in the radial velocity maps and in the tangential velocity vector fields. This may simply suggest that the three-dimensional rotation axis is inclined relative to the plane of the projection, but as we have seen in Fig. 3 , the kinematical properties of our systems are in general more complex, and the direction of the rotation axis changes with the distance from the cluster centre.", "cite_spans": [], "ref_spans": [{"start": 18, "end": 24, "text": "Fig. 4", "ref_id": "FIGREF3"}, {"start": 507, "end": 513, "text": "Fig. 3", "ref_id": "FIGREF2"}]}, {"section": "RESULTS", "text": "The ellipses shown in the top panels are meant to be an approximation of projected isodensity contours. They have been calculated by diagonalizing the moment of inertia tensor of particles within elliptical annuli. The minor and major axes of such annuli are the square roots of the inverse of the first and second eigenvalue, respectively, and they are scaled to the size of the annulus. The orientation of the ellipse is calculated from the eigenvectors (a more detailed outline of the method can be found in Zemp et al. 2011 ; here we use their method S1 adapted to two dimensions). The lines representing the minor axes show evidence of isodensity twisting. This feature is the morphological manifestation on the plane of projection of the radial variation of the rotation axis from the cluster's inner regions, where rotation is dominated by the remaining initial intrinsic rotation, to the outer regions, that are most affected by the tidal field and are dominated by rotation around the z-axis.", "cite_spans": [{"start": 511, "end": 527, "text": "Zemp et al. 2011", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "RESULTS", "text": "The second row shows a rotation curve calculated following the standard method adopted in many observational investigations to study the rotational properties from line-of-sight velocities (see e.g. Bellazzini et al. 2012) . Studies based on this method typically identify the orientation of a global rotation axis that maximizes Top panels: Time evolution of the radial profile of \u03b8 \u03c9 for models XLOC and XUNL. Bottom panels: Evolution of the radial profiles of \u03c9 x , \u03c9 y , and \u03c9 z of the same models. The radius is expressed in units of the half-mass radius of the cluster. As a result of the coupling with the orbital angular momentum, the orientation of the internal rotation axis of the models depends on the distance from the cluster's centre.", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS", "text": "the rotation signal, and either derive a single global value for the rotation amplitude or derive a rotation curve around that axis. The rotation present in our model is clearly evident in all projections. We wish to point out that the radial variation of the rotation axis might in some cases manifest itself as a counter-rotation of the outermost regions relative to the inner ones (see Boberg et al. 2017 for a possible observational evidence of this effect). We stress, however, that a radial variation of the orientation of the rotation axis does not necessarily imply the presence of counter-rotation. The third row shows the radial variation of the position angle of the rotation axis calculated following the method used for the rotation curves in the second row, but for individual circular annuli at different distances from the cluster centre. We note that, while in some projections the gradient is clearly visible, the strong intrinsic gradient may be significantly weaker in the projected kinematical data. In the same panels, we also plot the radial variation of the position angle of the minor axes of the ellipses approximating the isodensity contours, and show that in general they follow the kinematical position angle. It is important to remark here that the radial variation in the orientation of the rotation axis and the cluster's minor axis may appear misaligned if the measurements of the cluster morphological and kinematical properties are made at the different distances from a cluster's centre.", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS", "text": "Finally, in the fourth row of Fig. 4 , we show the radial variation of the minor-to-major axis ratio, b/a, of the isodensity ellipses shown in the top row of the figure; these plots illustrate the effect of rotation and external tidal field on the projected morphological properties as the distance from the cluster centre increases.", "cite_spans": [], "ref_spans": [{"start": 30, "end": 36, "text": "Fig. 4", "ref_id": "FIGREF3"}]}, {"section": "CONCLUSIONS", "text": "In this Letter, we have broadened the exploration of the effects of the interplay between the internal angular momentum and the external tidal field on the dynamics of collisional stellar systems.", "cite_spans": [], "ref_spans": []}, {"section": "CONCLUSIONS", "text": "While previous studies have explored the evolution of rotating clusters with an initial internal angular velocity vector aligned with the orbital angular velocity one, here we have studied more general configurations with initial internal rotation axes pointing in generic directions, differing from that of the external orbital rotation.", "cite_spans": [], "ref_spans": []}, {"section": "CONCLUSIONS", "text": "Our simulations show that such a generalization of the cluster's initial conditions has a number of major implications and leads to a variety of complex features in the evolution of the cluster's rotational properties. Specifically: 1) We have followed the evolution of the total angular velocity vector, \u03c9, and shown that for a system with a rotation axis initially not aligned with the cluster's orbital angular velocity, the tidal torque due to the host galaxy initiates a precession and nutation of the cluster's rotation axis leading to a time-varying orientation and amplitude of the three components of \u03c9 (Figs. 1 and 2) .", "cite_spans": [], "ref_spans": [{"start": 612, "end": 627, "text": "(Figs. 1 and 2)", "ref_id": "FIGREF0"}]}, {"section": "CONCLUSIONS", "text": "2) The effects of the external tidal field lead to an internal rotation about the z-axis (the axis parallel to the cluster's orbital angular velocity); this effect naturally results in a dependence of the orientation of the internal rotation axis on the distance from the cluster centre (Fig. 3) . The inner regions are dominated by the cluster intrinsic rotation with an orientation determined by the initial conditions and then evolving due to the effects of the axis precession mentioned above; the outer regions are dominated by an approximately solid-body rotation about the z-axis.", "cite_spans": [], "ref_spans": [{"start": 287, "end": 295, "text": "(Fig. 3)", "ref_id": "FIGREF2"}]}, {"section": "CONCLUSIONS", "text": "3) Depending on the direction of the initial intrinsic rotation, the radial variation of the rotation axis may lead to systems in which the outermost regions are in counter-rotation relative to the inner ones.", "cite_spans": [], "ref_spans": []}, {"section": "CONCLUSIONS", "text": "4) As the overall magnitude of rotation decreases with time due to redistribution and loss of angular momentum from the system, a cluster gradually loses its initial intrinsic rotation and is increasingly dominated by the rotation about the z-axis due to the effects of the external tidal field. The rotation axis precession mentioned above is therefore affected by the effects of internal relaxation leading to a gradual damping of the precession oscillations and a gradual convergence of the rotation axis toward the axis perpendicular to the cluster orbital plane (z-axis).", "cite_spans": [], "ref_spans": []}, {"section": "CONCLUSIONS", "text": "5) The radial variation of the orientation of the rotation axis (including its possible manifestation as counter-rotation) may be detected with radial velocity measurements, but projection effects play a significant role (Fig. 4) . Projected density maps show evidence of the radial variation of the cluster ellipticity and may also be characterized by a twisting in the isodensity contours.", "cite_spans": [], "ref_spans": [{"start": 221, "end": 229, "text": "(Fig. 4)", "ref_id": "FIGREF3"}]}, {"section": "CONCLUSIONS", "text": "The rich kinematics found in our simulations is the natural out- come of the evolution of rotating clusters starting from a general set of initial conditions. Such a degree of generality suggests that these properties might be widespread in globular clusters (with the exception of the dynamically oldest clusters that may have completely lost any memory of their initial rotation).", "cite_spans": [], "ref_spans": []}, {"section": "CONCLUSIONS", "text": "Our study provides guidance in the identification of non-trivial features which may emerge in upcoming investigations of star cluster kinematics and a dynamical framework to understand some of the complexities already hinted by recent observational studies.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Gravitational N-Body Simulations", "authors": [{"first": "S", "middle": ["J"], "last": "Aarseth", "suffix": ""}], "year": 2003, "venue": "", "link": "16499200"}, "BIBREF12": {"title": "The Gravitational Million-Body Problem. Cambridge University Press", "authors": [{"first": "D", "middle": [], "last": "Heggie", "suffix": ""}, {"first": "P", "middle": [], "last": "Hut", "suffix": ""}], "year": 2003, "venue": "MNRAS", "link": null}, "BIBREF20": {"title": "ApJS, 197, 30 van den", "authors": [{"first": "M", "middle": [], "last": "Zemp", "suffix": ""}, {"first": "O", "middle": ["Y"], "last": "Gnedin", "suffix": ""}, {"first": "N", "middle": ["Y"], "last": "Gnedin", "suffix": ""}, {"first": "A", "middle": ["V"], "last": "Kravtsov", "suffix": ""}, {"first": "R", "middle": [], "last": "Bosch", "suffix": ""}, {"first": "T", "middle": [], "last": "De Zeeuw", "suffix": ""}, {"first": "K", "middle": [], "last": "Gebhardt", "suffix": ""}, {"first": "E", "middle": [], "last": "Noyola", "suffix": ""}, {"first": "G", "middle": [], "last": "Van De Ven", "suffix": ""}], "year": 2006, "venue": "ApJ", "link": null}}, "ref_entries": {"FIGREF0": {"text": "Figure 1. Time-evolution of the Cartesian components and the absolute value of the angular velocity vector, \u03c9, normalized to the angular speed of the cluster's orbit about the host galaxy, \u2126. All models are represented (see Table 1). Time is expressed in units of the initial half-mass relaxation time. The overall rotation of the systems decreases in magnitude (gray line), but in all cases, the tidal torque due to the host galaxy initiates a precession of the cluster's rotation axis leading to large scale oscillations of \u03c9 x and \u03c9 y (black and red lines).", "type": "figure"}, "FIGREF1": {"text": "Figure 2. Time evolution of the three-dimensional orientation of the angular velocity vector, \u03c9, as expressed by \u03c6 \u03c9 , i.e. the angle between the projection of \u03c9 on the x \u2212 y plane and the x-axis, and \u03b8 \u03c9 , i.e. the angle between \u03c9 and the z-axis. All models are represented (see Table 1). All the systems are characterized by a precession and nutation of the angular velocity vector.", "type": "figure"}, "FIGREF2": {"text": "Figure 3. Top panels: Time evolution of the radial profile of \u03b8 \u03c9 for models XLOC and XUNL. Bottom panels: Evolution of the radial profiles of \u03c9 x , \u03c9 y , and \u03c9 z of the same models. The radius is expressed in units of the half-mass radius of the cluster. As a result of the coupling with the orbital angular momentum, the orientation of the internal rotation axis of the models depends on the distance from the cluster's centre.", "type": "figure"}, "FIGREF3": {"text": "Figure 4. Analysis of a snapshot of the model XZRLOC at t/t rh,i = 1.95. Each column presents a different projection of the cluster in the plane specified in the top panel. First row: Cluster map colour coded according to the mean radial velocity of stars in that area of the projection (yellow-green colors represent the lowest velocity, violet is the highest velocity), and superimposed arrows represent the mean tangential velocity of stars in that area of the projection. Each ellipse is an approximation of the isodensity contours, and the straight lines denote the minor axes. Second row: Rotation curve calculated in bins parallel to the position angle of the global rotation axis. The error bars represent the standard error of the mean velocity in each bin. Third row: Position angles of the projected rotation axes, P A k , and position angles of the projected minor axes, P A m expressed as functions of the projected radius. The error bars of P A k are from the error of the fitting procedure. Fourth row: Ratio of the projected minor to major axes versus the projected radius in units of the corresponding projected half-mass radius. The error bars of P A m and b/a are from the standard error of the mean from bootstrap statistics of the positions of the stars in each bin.", "type": "figure"}, "TABREF0": {"text": "Summary of simulations", "type": "table"}}}
{"paper_id": "119421162", "_pdf_hash": "354e90dfbe3dce270d95b3ef00b15d8c99685207", "abstract": [{"section": "Abstract", "text": "ABSTRACT GOES soft X-ray light curves are used to measure the timing and duration of solar flare emission. The timing and duration of the magnetic reconnection and subsequent energy release which drives solar flares are unknown, though the light curves are presumably related. It is therefore critical to understand the physics which connects the two: how does the time scale of reconnection produce an observed GOES light curve? In this work, we model the formation and expansion of an arcade of loops with a hydrodynamic model, which we then use to synthesize GOES light curves. We calculate the FWHM and the e-folding decay time of the light curves and compare them to the separation of the centroids of the two ribbons which the arcade spans, which is representative of the size scale of the loops. We reproduce a linear relation between the two, as found observationally in previous work. We show that this demonstrates a direct connection between the duration of energy release and the evolution of these light curves. We also show that the cooling processes of individual loops comprising the flare arcade directly affect the measured time scales. From the clear consistency between the observed and modeled linearity, we conclude that the primary factors that control the flare time scales are the duration of reconnection and the loop lengths.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "INTRODUCTION", "text": "The Geostationary Operational Environmental Satellites (GOES), first launched in 1975 and most recently with GOES-16 in November 2016, are a series of satellites maintained by the National Oceanic and Atmospheric Administration (NOAA). Since GOES-8 in 1986 and with previous NOAA satellites, they have carried two X-ray sensors (XRS) which continuously monitor the solar X-ray flux in the wavelength bands 1-8\u00c5 (\u2248 1.5-12 keV) and 0.5-4\u00c5 (\u2248 3-24 keV). The emission in these bands is primarily due to dense plasma at temperatures exceeding 10 MK, and therefore the light curves are used to track the timing and evolution of solar flares.", "cite_spans": [], "ref_spans": []}, {"section": "INTRODUCTION", "text": "Observational relationships between flare evolution and geometry are often discussed since they might be the key to accessing the physics behind flare eruptions (see reviews by Priest & Forbes 2002; Fletcher et al. 2011; Shibata & Magara 2011) . In a recent paper, measured the full-width-at-half-maximum (FWHM) and the e-folding decay time of 1-8\u00c5 GOES light curves in 51 flares larger than M5 and correlated them with the distance between the centroids of the two flare ribbons d ribbon , as measured in the 1600\u00c5 bandpass with the Atmospheric Imaging Assembly (AIA, Lemen et al. 2012 ) onboard the Solar Dynamics Observatory (SDO, Pesnell et al. 2012 ). The distance d ribbon was measured over the duration of each event, rather than at one single instant, as detailed in that paper (see Figure 1 of that work). For both time scales, there was a strong linear correlation with the separation of the ribbon centroids. They found similar correlations between the time scales and the magnetic flux as well as the ribbon area.", "cite_spans": [], "ref_spans": [{"start": 791, "end": 799, "text": "Figure 1", "ref_id": "FIGREF0"}]}, {"section": "INTRODUCTION", "text": "A few processes drive the thermal evolution of coronal loops. Initially, after heating begins, the temperature rises sharply while the density is approximately unchanged, driving a strong conductive flux out of the corona. As evaporation carries plasma into the loop and the density rises significantly, radiation comes to dominate the energy losses while conduction becomes significantly less efficient (Antiochos 1980; Cargill et al. 1995 ). An enthalpy flux of plasma flowing out of the corona begins to power the transition region at later times, which leads to a scaling law that relates the temperature and density in the cooling phase, T \u221d n \u03b4 (Bradshaw & Cargill 2005) , where \u03b4 relates the relative strength of radiation to enthalpy flux (Bradshaw & Cargill 2010) . Once it falls below a critical temperature, the loop is unable to sustain the cooling, and undergoes \"catastrophic cooling\" where the temperature falls drastically while the density remains nearly constant (Reale & Landi 2012; .", "cite_spans": [], "ref_spans": []}, {"section": "INTRODUCTION", "text": "Not much attention has been paid so far to the facts that the coronal flux system involved in a flare is composed of multiple individual, elementary loops, and that the loops start to get heated impulsively (probably due to magnetic reconnection) with a certain delay, as is obvious from the expansion of flare ribbons (Dodson 1949; Bruzek 1964; Grigis & Benz 2005) . One of the earliest attempts to model this was made by Hori et al. (1997 Hori et al. ( , 1998 , who found that single loops were unable to explain observed blue-shifted Ca XIX line profiles with a large stationary component, whereas a bundle of loops naturally does so. Reeves et al. (2007) employed a reconnection model to drive the heat input into a multi-threaded simulation in order to reproduce emissions seen by multiple instruments, and found that the reconnection model predicted the correct magnitude of energy release.", "cite_spans": [], "ref_spans": []}, {"section": "INTRODUCTION", "text": "In this work, we model the evolution of flare loops by introducing not only the thermal processes (radiation, conduction, and enthalpy drainage) but also the effect of successive reconnection, and synthesize the GOES light curves. With these simulations, we test the relation directly: why is the separation of the ribbon centroids d ribbon correlated with the FWHM and e-folding decay time? Assuming that the emission comes from many different loops of varying lengths, we synthesize a total GOES light curve, determine the time scales, and measure how they compare with d ribbon . We reproduce the linear correlations, and confirm that the loop lengths play an important role in determining the FWHM and decay time. Since the duration of reconnection and subsequent expansion of the arcade determine the separation of the ribbon centroids, this relation demonstrates the direct connection between the duration of energy release and light curves in flares.", "cite_spans": [], "ref_spans": []}, {"section": "OBSERVATIONS", "text": "To further motivate this work, we briefly present GOES observations that can be later contrasted with the model that we have developed. We employ two time scales to measure the rate of decay of the GOES SXR light curves. The first, \u03c4 FWHM , is the standard full-width-at-half-maximum of the light curve, and the time t end past the peak with flux at half maximum is referred to as the \"GOES end time.\" The second time scale, \u03c4 decay , measures the e-folding decay time at the GOES end time:", "cite_spans": [], "ref_spans": []}, {"section": "OBSERVATIONS", "text": "The GOES flux is primarily due to thermal emission (bremsstrahlung and spectral lines) from dense, hot plasma, which is most sensitive to temperatures exceeding 10 MK (Garcia 1994; White et al. 2005 ; see Figure 1 of Warren & Antiochos 2004 for a plot of the temperature dependence of each channel). These two time scales therefore contain information about the rates at which the flaring loops heat to and cool from high temperatures. The information is obscured, though, since many loops comprise the system at any given time, and because there is a finite non-thermal component that does not strongly depend on the plasma temperature. The FWHM \u03c4 FWHM measures both the rising and falling time of the light curve, and so is determined by the rate at which plasma heats and then cools. The e-folding decay time \u03c4 decay more directly measures the rate at which the light curve falls, and therefore is determined primarily by the cooling of the flaring loops.", "cite_spans": [], "ref_spans": [{"start": 205, "end": 213, "text": "Figure 1", "ref_id": "FIGREF0"}]}, {"section": "OBSERVATIONS", "text": "In Figure 1 , we show example GOES light curves for three flares: the X3.9 flare on 5 November 2013, the X5.4 on 6 March 2012, and the M6.6 on 22 June 2015. The top plots show the light curves in each channel, 1-8\u00c5 in red, 0.5-4\u00c5 in blue, with the calculated time scales (measured in seconds) shown at top right. The bottom plots show the time derivatives of each channel, calculated numerically (x marks), and with a Savitzky-Golay smoothing filter of degree 4 with 33 points (yellow/cyan lines, Savitzky & Golay 1964; Press et al. 1986 ). We have also marked the times of peak emission and the GOES end times t end with diamonds. Below t end , we have drawn thin dashed lines to show the times at which the derivatives are used to calculate \u03c4 decay . The total durations of these flares range from roughly 20 minutes to well over 3 hours, reflected in each respective FWHM. For each case, we note the value of d ribbon .", "cite_spans": [{"start": 520, "end": 537, "text": "Press et al. 1986", "ref_id": "BIBREF49"}], "ref_spans": [{"start": 3, "end": 11, "text": "Figure 1", "ref_id": "FIGREF0"}]}, {"section": "OBSERVATIONS", "text": "There are a few important features. The GOES class has no bearing on either of the two time scales or the separation of the ribbon centroids d ribbon . The time scales in the 1-8\u00c5 channel are systematically larger than those of the 0.5-4\u00c5 channel, likely due to the differences in sensitivity to different temperatures, and because non-thermal emission is a relatively larger component of the high energy channel. There is considerably more oscillatory behavior in the light curves for the longer duration events (particularly noticeable in the derivatives), which may be due to wave fluctuations (Mariska 2006) or due to the variations of plasma temperature and density on individual threads (Rubio da Costa et al. 2016) . These oscillations may be related to quasi-periodic pulsations (Nakariakov & Melnikov 2009) , which have been reported in GOES observations (Dennis et al. 2017) . Finally, there is generally a correlation between the magnitude of all of the time scales and d ribbon , though there is considerable scatter.", "cite_spans": [], "ref_spans": []}, {"section": "OBSERVATIONS", "text": "We present the empirical relationship in Figure 2 between the time scales of GOES 1-8\u00c5 light curves and separation of the ribbon centroids for 50 of the 51 flares studied by , excluding event 12 which does not have a well-defined FWHM. We use their values for d ribbon , and independently have recalculated all time scales. We have extended the analysis to include the high energy 0.5-4\u00c5 channel, and find similar results: there is an approximately linear correlation, though the magnitudes of the time scales are lower than those in the low energy channel. The fits, also shown on the plot, are: log \u03c4 FWHM, 1-8\u00c5 = (0.94 \u00b1 0.09) log d ribbon + (1.70 \u00b1 0.13) log \u03c4 decay, 1-8\u00c5 = (0.87 \u00b1 0.12) log d ribbon + (1.67 \u00b1 0.17) log \u03c4 FWHM, 0.5-4\u00c5 = (0.89 \u00b1 0.09) log d ribbon + (1.59 \u00b1 0.14) log \u03c4 decay, 0.5-4\u00c5 = (0.92 \u00b1 0.10) log d ribbon + (1.39 \u00b1 0.14)", "cite_spans": [], "ref_spans": [{"start": 41, "end": 49, "text": "Figure 2", "ref_id": "FIGREF1"}]}, {"section": "OBSERVATIONS", "text": "The trend is approximately linear in all four cases, though it is unclear why. We now turn our focus towards explaining this result: how does this correlation arise?", "cite_spans": [], "ref_spans": []}, {"section": "RIBBON EXPANSION MODEL", "text": "In order to test the relation between ribbon separation and the time scales, we synthesize GOES light curves for bundles of loops with varying separations between the ribbon centroids d ribbon . We first synthesize light curves of individual loops, which we then use to construct a composite light curve assuming a bundle of loops with ever-increasing lengths as the reconnection event proceeds. Figure 3 illustrates the scheme we use to construct the bundles and integrated light curves.", "cite_spans": [], "ref_spans": [{"start": 396, "end": 404, "text": "Figure 3", "ref_id": "FIGREF2"}]}, {"section": "RIBBON EXPANSION MODEL", "text": "The separation between centroids d ribbon for a bundle can be found from simple geometry since we assume that the loops are all semi-circular. We take the centroid of a bundle to be the the foot-point separation of a loop with the median length of the loops in the bundle. In other words, d ribbon is the diameter of a loop with length", "cite_spans": [], "ref_spans": []}, {"section": "RIBBON EXPANSION MODEL", "text": ", so it is straight-forward to find that d ribbon = (2L)max+(2L)min \u03c0 . We define a reconnection time scale \u03c4 rec as", "cite_spans": [], "ref_spans": []}, {"section": "RIBBON EXPANSION MODEL", "text": "which simply says that the time to expand outwards is determined by the distance \u03b6 ribbon = 1 \u03c0 (2L) max \u2212 (2L) min from the initial reconnection site to the maximum extent of the ribbon, as well as by the ribbon expansion speed V ribbon . Assuming that the reconnection starts from a low altitude, i.e. in the limit L min \u2192 0, we have", "cite_spans": [], "ref_spans": []}, {"section": "RIBBON EXPANSION MODEL", "text": "or that \u03c4 rec \u221d L max \u221d d ribbon , which demonstrates the relation between the duration of reconnection and d ribbon . Assuming a constant ribbon speed of V ribbon = 20 km s \u22121 = 0.02 Mm s \u22121 , we have , and with a Savitzky-Golay smoothing filter (yellow/cyan lines). On the light curves, we have marked the times of peak emission and tend with diamonds. We have drawn lines below tend to denote the times at which the derivative is used to calculate \u03c4decay. with distances measured in Mm and time scales in s. Observationally, we have found", "cite_spans": [], "ref_spans": []}, {"section": "RIBBON EXPANSION MODEL", "text": "The striking agreement between the ribbon expansion scenario and the observational results points to the possibility that the duration of reconnection is one of most important parameters controlling the flare time scales. We therefore test this directly with hydrodynamic simulations, from which we synthesize the SXR emission as might be seen by GOES.", "cite_spans": [], "ref_spans": []}, {"section": "Hydrodynamic modeling", "text": "To test the cause of the correlations, we have run numerical experiments with the HYDrodynamics and RADiation code (HYDRAD, Bradshaw & Mason 2003) . The code solves the equations of conservation for mass, momentum, electron and ion energy along a one-dimensional magnetic flux tube . HYDRAD employs adaptive mesh refinement to properly resolve the transition region (TR), which is vitally important for determining accurate coronal densities . The code accounts for radiative losses calculated with CHIANTI version 8 (Dere et al. 1997; Del Zanna et al. 2015) , which includes full non-equilibrium ionization of various ion species, which is important for cooling rates (Bradshaw et al. 2004; Bradshaw & Raymond 2013) . In this work, we assume all loops are semi-circular, oriented vertically relative to the solar surface. The intensity from each light curve contributes to the total observed light curve of the flare, which is then used to calculate the two time scales. We synthesize the light curves for many bundles with various separations between the ribbon centroids dribbon.", "cite_spans": [], "ref_spans": []}, {"section": "Hydrodynamic modeling", "text": "We assume that the primary heating mechanism is a beam of non-thermal electrons that deposit their energy through Coulomb collisions in the upper chromosphere (Emslie 1978) . We have assumed an injected electron spectrum of the form (electrons s \u22121 cm \u22122 keV \u22121 ):", "cite_spans": [], "ref_spans": []}, {"section": "Hydrodynamic modeling", "text": "where F 0 (t) is the initial energy flux of the beam, E c is the low-energy cut-off, \u03b4 is the spectral index.", "cite_spans": [], "ref_spans": []}, {"section": "Hydrodynamic modeling", "text": "We have run simulations of loops with coronal lengths 2L = [3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 50, 75, 100, 125, 150, 175, 200 ] Mm (and a chromospheric depth of 2.2 Mm). We heat each loop with the same energy flux carried by the electron beam, F 0 = 10 11 erg s \u22121 cm \u22122 , and a spectral index \u03b4 = 4. We have run three sets of simulations, one with a low energy cut-off E c = 20 keV and 30 seconds of total heating, one with E c = 10 keV for 30 seconds of heating, and one with E c = 20 keV for 60 seconds of heating. The cooling of individual loops depends only weakly on the heating rate (\u221d Q \u22121/6 , Cargill 1994), so the assumption of constant energy flux should not drastically affect the measured time scales. We also assume that the cross-sectional area of the loops grows with time (equivalently, that the ribbon area grows with time), reaching its maximum value at the time of peak SXR emission (see Fig. 2 of .", "cite_spans": [], "ref_spans": [{"start": 923, "end": 929, "text": "Fig. 2", "ref_id": "FIGREF1"}]}, {"section": "Hydrodynamic modeling", "text": "We calculate the X-ray emissions as a sum of thermal and non-thermal components for a given loop as follows. The thermal components are evaluated with CHIANTI version 8 (Dere et al. 1997; Del Zanna et al. 2015) , using the \"isothermal\" routine to generate tables of spectra as a function of temperature and emission measure, which includes contributions from continuum processes and line emission. In each grid cell, we calculate the local emission measure EM = n 2 A\u2206s, where n is the density, A the assumed crosssectional area, and \u2206s the width of the grid cell. We then use the local emission measure and temperature to calculate the spectrum of that grid cell, which we sum across all the grid cells and at each time step to create a composite spectrum since GOES XRS is not spatially resolved.", "cite_spans": [], "ref_spans": []}, {"section": "Hydrodynamic modeling", "text": "We then add the non-thermal emission to the spectra assuming a thick-target (Brown 1971) . Free-free emission can be written (Kontar et al. 2011; Reep et al. 2013 )", "cite_spans": [], "ref_spans": []}, {"section": "Hydrodynamic modeling", "text": "(8) where R = 1 AU = 1.497 \u00d7 10 13 cm, \u01eb is the photon energy (keV), n H the hydrogen density (cm \u22123 ), v the electron velocity (cm s \u22121 ), Q(\u01eb, E) the cross-section of the interaction (cm 2 keV \u22121 ), and dE dt the energy lost by the electron per unit time (keV s \u22121 ). The inner integral is analytic for the assumed form of the injected electron spectrum. For the outer integral, we use a fully relativistic Bethe-Heitler cross-section with the Elwert correction factor (Bethe & Heitler 1934; Elwert 1939; Koch & Motz 1959) , which is then evaluated using GaussLaguerre quadrature of at least 100th order.", "cite_spans": [], "ref_spans": []}, {"section": "Hydrodynamic modeling", "text": "Although expected to be small, we include non-thermal free-bound emission using the formulation of Brown & Mallik (2008 , with corrections given by Brown et al. (2010) and Reep & Brown (2016) . We assume only recombination onto iron ions of ionization stage above Fe XX, which are the most significant contribution to this emission process (Reep & Brown 2016) .", "cite_spans": [], "ref_spans": []}, {"section": "Hydrodynamic modeling", "text": "Once all the emission has been summed, we then fold the spectra through the GOES response at the appropriate energy ranges to calculate light curves. The observed flares were all measured with GOES-15, so we use the response functions for that satellite (White et al. 2005) .", "cite_spans": [], "ref_spans": []}, {"section": "Hydrodynamic modeling", "text": "In order to create composite light curves, we must add together the emission from many loops. We follow the basic scenario outlined in Figure 3 . Using a typical ribbon expansion speed of \u2248 [10, 20, 30] For all bundles, using the composite light curves, we calculate the FWHM and decay time for both GOES channels. We then plot these values against the separation distance of the ribbon centroids d ribbon for each bundle, and fit a linear regression to measure any correlation. Finally, we compare the measured correlations against the observations in Section 2.", "cite_spans": [], "ref_spans": [{"start": 135, "end": 143, "text": "Figure 3", "ref_id": "FIGREF2"}]}, {"section": "Hydrodynamic modeling", "text": "4. RESULTS", "cite_spans": [], "ref_spans": []}, {"section": "Synthesized light curves", "text": "We begin by showing a few example synthesized GOES light curves, along with the plasma evolution of the emitting threads. Figure 4 shows three bundles of loops, with minimum length (2L) min = 3 Mm, and (respectively) maximum lengths (2L) max = [10, 125, 200] Mm, corresponding to d ribbon =[4.1, 40.7, 64.6] Mm. The top row shows the synthesized GOES light curves in 1-8\u00c5 (red) and 0.5-4\u00c5 (blue), along with the measured FWHM \u03c4 FWHM and e-folding decay time \u03c4 decay for both channels (in seconds). The bottom row shows the apex electron temperature and electron number density in each individual thread as a function of time (excluding the interpolated loops). These light curves were synthesized assuming a ribbon speed of V ribbon = 20 km s \u22121 .", "cite_spans": [], "ref_spans": [{"start": 122, "end": 130, "text": "Figure 4", "ref_id": "FIGREF3"}]}, {"section": "Synthesized light curves", "text": "The evolution of the plasma follows a similar path for any individual loop. Shortly after the onset of heating, the temperature rises sharply to over 20 MK, causing the thermal emissions (primarily bremsstrahlung) to begin to rise, though the emission measure (EM) is initially small. As the nonthermal electrons deposit their energy in the chromosphere, the pressure there expands as the temperature rises, which causes an expansion of material back into the corona, thus raising the EM and significantly increasing the thermal emissions. As the coronal density rises, thermal conduction becomes significantly less effective, and radiative losses begin to dominate. The density remains approximately constant while the temperature slowly falls during this time, which causes a reduction in the thermal emissions. Eventually, the loop begins to catastrophically collapse, and the temperature plummets to chromospheric temperatures in a short time, so that the loop effectively disappears in SXRs.", "cite_spans": [], "ref_spans": []}, {"section": "Synthesized light curves", "text": "The total GOES emissions are spatially unresolved, so the light curves follow the evolution of many individual loops at any given time. Both GOES channels are sensitive to high temperature emission (with significant overlap), but the 0.5-4\u00c5 channel's sensitivity falls off more rapidly at lower temperatures (see Fig. 6 of White et al. 2005 and Fig. 1 of Warren & Antiochos 2004) . Therefore, as the temperature decreases on the hottest loop, the light curve in 0.5-4\u00c5 falls off more rapidly than in the 1-8\u00c5 channel. This in turn causes both the FWHM and decay time to be lower in the 0.5-4\u00c5 channel (which also remains true in the observed flares).", "cite_spans": [], "ref_spans": [{"start": 313, "end": 319, "text": "Fig. 6", "ref_id": "FIGREF5"}, {"start": 345, "end": 351, "text": "Fig. 1", "ref_id": "FIGREF0"}]}, {"section": "Synthesized light curves", "text": "All four time scales are higher for larger centroid separations d ribbon , though the shapes of the light curves are similar. After the reconnection ceases and new loops are no longer being heated, plasma above 10 MK becomes scarce, significantly reducing the thermal bremsstrahlung which dominates the emission in the two channels. The duration of reconnection, therefore, appears critical in determining the evolution of the GOES light curves.", "cite_spans": [], "ref_spans": []}, {"section": "Synthesized light curves", "text": "There is no late phase heating in these simulations, so the cooling proceeds rapidly once heating ceases, which causes the sharp decrease in intensity. There are, however, indications that late phase heating occurs in flares, both in the TR (Doschek et al. 1977 ) and corona (Petrasso et al. 1979) . This is clear from the sustained high temperatures (\u0160vestka et al. 1982) , high densities (Moore et al. 1980) , and evaporative up-flows (Czaykowska et al. 1999 (Czaykowska et al. , 2001 ). Modeling efforts were able to quantify the energy release, and show that the heating is consistent with sustained reconnection (Cargill & Priest 1982 , 1983 Pneuman 1982) . There have recently been efforts to include late phase heating into multi-threaded modeling of flares , though the magnitude, temporal envelope, and duration of that heating require further study, a point which we plan to address in future work.", "cite_spans": [{"start": 390, "end": 409, "text": "(Moore et al. 1980)", "ref_id": "BIBREF44"}], "ref_spans": []}, {"section": "Synthesized light curves", "text": "There is another important factor: the time scales also strongly depend on the lengths of the loops within a bundle. To show this, we examine bundles of loops with an equal reconnection time scale, but variable d ribbon . \u03c4 rec measures the duration of time between the formation of the first and last loop in the bundle, and therefore depends on the distance between them and the speed at which the ribbon spreads.", "cite_spans": [], "ref_spans": []}, {"section": "Synthesized light curves", "text": "In Figure 5 , we compare five bundles of loops with equal reconnection time scale \u03c4 rec = 318 s but variable d ribbon . The bundles consist of lengths (2L) min = [10, 15, 20, 25, 30] Mm and respectively (2L) max = [20, 25, 30, 35, 40] Mm, which corresponds to d ribbon = [9.5, 12.7, 15.9, 19.1, 22 .3]Mm, and we assume a slow ribbon speed V ribbon = 10 km s \u22121 in order to emphasize the differences. Respectively, from shortest to longest, the bundles are shown as solid, dotted, dashed, dotdashed, and triple dot-dashed lines.", "cite_spans": [], "ref_spans": [{"start": 3, "end": 11, "text": "Figure 5", "ref_id": "FIGREF4"}]}, {"section": "Synthesized light curves", "text": "The differences between the individual bundles clearly show that while the rising phase of the light curves are similar, the time scales differ in both GOES channels. The longer bundles take longer to decay in both channels (monotonically). In other words, the lengths of the loops which comprise the bundle influence the values of the time scales, as one might expect from many previous loop cooling studies. It is therefore clear that both the duration of reconnection and the lengths of the loops directly affect the GOES light curves.", "cite_spans": [], "ref_spans": []}, {"section": "The modeled correlation", "text": "In Figure 6 , we summarize the results of many numerical experiments for different loop bundles with 9 scatter plots, showing the time scales as a function of separation of the ribbon centroids d ribbon . We include the data from both GOES channels. The red plus signs (blue asterisks) show the FWHM \u03c4 FWHM for the 1-8 (0.5-4)\u00c5 channel, and the black diamonds (purple triangles) show the decay time \u03c4 decay . The lines show the linear fit to each. The top row synthesized the light curves with a ribbon speed V ribbon = 10 km s \u22121 , while the center and bottom used 20 and 30 km s \u22121 . The simulations in the first column used a cut-off energy E c = 10 keV, while the latter two columns used 20 keV. Finally, the third column assumed a heating duration of 60 s, and the first two columns 30 s.", "cite_spans": [], "ref_spans": [{"start": 3, "end": 11, "text": "Figure 6", "ref_id": "FIGREF5"}]}, {"section": "The modeled correlation", "text": "All 9 cases reproduce the approximately linear relation in all four time scales, though there is some variance. For example, we find that there is reasonably good agreement between the observations and the case with V ribbon = 20 km s \u22121 , E c = 20 keV, and heating duration of 60 s. For that case, the linear regression fits with 1-sigma uncertainties, also in- ", "cite_spans": [], "ref_spans": []}, {"section": "The modeled correlation", "text": "In both channels, there is an approximately linear relation between both time scales and d ribbon , with both the slopes and absolute values comparable to those measured from the observed light curves (Figure 2 ). d ribbon is directly related to the duration of the energy release due to reconnection \u03c4 rec in this model (see Section 5). The separation between the centroids continues to grow as reconnection proceeds, which further implies that the time scale of reconnection \u03c4 rec is also connected with the time scales of the GOES light curves. To wit, the longer new loops are energized in a flare, the longer the SXR emission lasts. There is little scatter in the calculated fits as compared to the observed trends, however. We have made a number of simplifying assumptions that effectively reduce the scatter. Though we have assumed it constant, the ribbon expansion speed generally varies with time (Asai et al. 2004) , with field strength (Xie et al. 2009) , and from flare to flare , which would affect the rate at which loops are energized in the arcade model. As each flare in the observational sample had different field strengths and occurred in different active regions of various sizes and types, it is clear that this assumption effectively reduces the variance in the calculated time scales. Due to the different sizes of the active regions, our assumption that (2L) min = 3 Mm for all bundles is perhaps flawed, though it is not clear what value(s) would be more appropriate.", "cite_spans": [], "ref_spans": [{"start": 201, "end": 210, "text": "(Figure 2", "ref_id": "FIGREF1"}]}, {"section": "The modeled correlation", "text": "We have also assumed that each loop has the same heating parameters, i.e. that the electron beam parameters do not vary from loop to loop, or evolve with time. We know from observational studies that the beam parameters do vary with time (e.g. Holman et al. 2003; Milligan et al. 2014 ), but because HXR spatial resolution is limited, it is not clear how they change amongst individual loops. How the parameters vary from loop to loop is an on-going area of research that is at present poorly understood, because of this difficulty of resolving individual loops in a flare, even with high-resolution extreme ultraviolet satellites (Warren 2006; Warren et al. 2016; ). Another potential issue is that we have assumed only one source of heating of the plasma, whereas there is good reason to suspect that other mechanisms contribute to energy transport, including shock heating (Longcope et al. 2009 , magnetic wave damping (Reep & Russell 2016; Kerr et al. 2016) , and in situ heating driving thermal conduction fronts (Longcope 2014).", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "A clear linear correlation has been found between the separation of ribbon centroids and the FWHM and e-folding decay times of GOES light curves, which has been tested for large (above M5) flares. It was not clear how the correlation arises, or what mechanisms are involved. Flare models consisting of a single loop cool significantly faster than the observed trends, and therefore we developed an expanding arcade model to examine them. The model reproduces the linear trend: the FWHM and decay times are longer for larger centroid separations d ribbon . d ribbon is determined primarily by the duration of reconnection, while the rate at which individual loops cool is determined primarily by their lengths (e.g. Cargill et al. 1995) .", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "As the reconnection event proceeds, forming new loops and causing the expansion of the arcade, the ribbons of the flare continue to separate. For a constant ribbon expansion speed, the duration of reconnection determines the centroid separation d ribbon , and therefore is connected directly to the time scales. In general, though, the ribbon expansion speed is not constant, which is one cause of scatter in the observed trends.", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "Coronal loops cool primarily through three processes: thermal conduction (\u03c4 C \u221d L 2 ), radiation (\u03c4 R independent of length), and a draining enthalpy flux (\u03c4 V \u221d L), each successively dominating the cooling of an individual loop (Bradshaw & Cargill 2010) , which causes the total cooling time to depend strongly on length (\u221d L 5/6 , Cargill et al. 1995) . In a flare bundle with many loops, however, it is unclear which of these dominates the apparent cooling in light curves. We have found numerically that the FWHM and decay times increase for bundles of longer loops, even when the reconnection time scale remains constant. This demonstrates that both the reconnection time scale and the cooling of the individual loops determine the total time scales, and therefore we conclude that both cause the observed linear relation.", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "There (where \u03c4 could be either time scale). This is a relation that should be carefully checked in the future, as there would be important implications regarding heating durations, the number of strands in a flare, and the reconnection process itself.", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "We plan a more extensive parameter survey, where we allow many other beam parameters to vary from loop to loop, as well as a time-varying ribbon expansion speed, as each parameter has an effect on the GOES light curve (e.g. Reep et al. 2013) . We also will examine two-phase heating, where it appears that all loops comprising the flare are heated both impulsively and by a gradual and significantly weaker heat source (e.g. .", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "To more accurately model a given flare, it is important to determine the loop lengths, as demonstrated in Section 4.1. We therefore would like to incorporate a method to obtain the loop length distribution more directly, rather than making assumptions. In practice, this could be accomplished with a loop tracing algorithm (Aschwanden 2010) , non-linear force-free field modeling (Wiegelmann & Sakurai 2012) , or flaring active region modeling (Toriumi & Takasao 2017) . It would also be an important test to confirm observationally that d ribbon , the distance between the centroids of the two ribbons, is representative of the distribution of loop lengths within a flare.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF44": {"title": "Skylab Solar Workshop II", "authors": [{"first": "R", "middle": [], "last": "Moore", "suffix": ""}], "year": 1980, "venue": "", "link": null}, "BIBREF49": {"title": "Numerical recipes. The art of scientific computing Priest", "authors": [{"first": "W", "middle": ["H"], "last": "Press", "suffix": ""}, {"first": "B", "middle": ["P"], "last": "Flannery", "suffix": ""}, {"first": "S", "middle": ["A E R"], "last": "Teukolsky", "suffix": ""}, {"first": "T", "middle": ["G"], "last": "Forbes", "suffix": ""}], "year": 1986, "venue": "A&A Rv", "link": null}}, "ref_entries": {"FIGREF0": {"text": "Figure 1. GOES light curves (top) and time derivatives (bottom) for three large flares. The 1-8\u00c5 channel is shown in red, 0.5-4\u00c5 channel in blue. The calculated time scales, measured in seconds, are shown at the top right. The derivatives have been calculated numerically (x marks), and with a Savitzky-Golay smoothing filter (yellow/cyan lines). On the light curves, we have marked the times of peak emission and tend with diamonds. We have drawn lines below tend to denote the times at which the derivative is used to calculate \u03c4decay.", "type": "figure"}, "FIGREF1": {"text": "Figure 2. The empirical results for 50 large flares. We show the time scales for both GOES channels. We have recalculated all time scales independently. The red plus signs (blue asterisks) show the measured FWHM for the 1-8 (0.5-4)\u00c5 channel, while the black diamonds (purple triangles) show the measured decay times. The lines show the linear fits to the data. The linear regression fits with 1-sigma uncertainties are shown for each time scale.", "type": "figure"}, "FIGREF2": {"text": "Figure 3. A schematic cartoon illustrating the method by which we create bundles of loops that are used to synthesize the integrated GOES light curves. (a) As the reconnection event proceeds and the ribbons expand, new loops of increasing lengths form and are energized successively. (b) The intensity from each light curve contributes to the total observed light curve of the flare, which is then used to calculate the two time scales. We synthesize the light curves for many bundles with various separations between the ribbon centroids dribbon.", "type": "figure"}, "FIGREF3": {"text": "Figure 4. At top, synthesized GOES light curves for three sets of loop bundles. Each bundle has a minimum length (2L)min = 3 Mm, and maximum lengths of (2L)max =[10, 125, 200] Mm, corresponding to dribbon =[4.1, 40.7, 64.6] Mm. These assume a ribbon speed Vribbon = 20 km s \u22121 . At bottom, the apex electron temperatures and densities in each loop comprising the arcade as a function of time.", "type": "figure"}, "FIGREF4": {"text": "Figure 5. Five bundles of loops with an equal reconnection time scale \u03c4rec = 318 s, but different dribbon. Respectively, from shortest to longest, the bundles are shown as solid, dotted, dashed, dotdashed, and triple dot-dashed lines. It is clear that the rising phase of each bundle is similar, but the cooling phase differs in each case in both GOES channels, where longer bundles take longer to decay.", "type": "figure"}, "FIGREF5": {"text": "Figure 6. 9 scatter plots showing the FWHM and decay times as a function of separation between the ribbon centroids dribbon as found from the numerical experiments, using a variety of parameters (see the text). Compare these results against Figure 2.", "type": "figure"}, "FIGREF6": {"text": "are still a few open questions. Saint-Hilaire et al. (2008) found a weak quadratic correlation between the HXR burst duration and the HXR foot-point separation in a sample of 53 large flares seen with RHESSI: \u03c4 HXR \u221d d 2 HXR . Under the presumption that the HXR separation d HXR is approxi- mately the same as d ribbon , then we would have \u03c4 HXR \u221d \u03c4 2", "type": "figure"}, "TABREF0": {"text": "km s \u22121 (e.g. Asai et al. 2004), we assume that each new loop reconnects and is energized with a given time lag past the previous one. We use a sub-set of the simulations to form the bundles, e.g. with lengths [3, 4, 5] Mm, [3, 4, 5, 6] Mm, [3, 4, 5, 6, 7] Mm, etc.. To reduce the number of required simulations, and to en- sure reasonably smooth light curves, at each time we lin- early interpolate the X-ray emission between these simula- tions as if a new loop were to form at regular intervals of 1 3 Mm. For example, between the loops with 2L = 3 and 4 Mm, we have 2 interpolated loops of lengths 3.33 and 3.66 Mm. For the first loop, we calculate its X-ray inten- sity I 3.33 Mm (t) =", "type": "table"}}}
{"paper_id": "119422566", "_pdf_hash": "4103ef0ddf0ee00b9db6faa5c2db591a3496a2a4", "abstract": [{"section": "Abstract", "text": "Quantum Zakharov equations are obtained to describe the nonlinear interaction between quantum Langmuir waves and quantum ion-acoustic waves. These quantum Zakharov equations are applied to two model cases, namely the four-wave interaction and the decay instability. In the case of the four-wave instability, sufficiently large quantum effects tend to suppress the instability.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "For the decay instability, the quantum Zakharov equations lead to results similar to those of the classical decay instability except for quantum correction terms in the dispersion relations. Some considerations regarding the nonlinear aspects of the quantum Zakharov equations are also offered.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "I. INTRODUCTION", "text": "between high frequency Langmuir waves and low frequency ion-acoustic waves was first derived by Zakharov. 16 Since then, this system have been the subject of a large number of studies. 17 In one-dimension, the Zakharov equations can be written (in normalized units) as", "cite_spans": [], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "where E is the envelope of the high frequency electric field and n is the plasma density measured from its equilibrium value. The system (1-2) can be derived from a hydrodynamic description of the plasma 17, 18 by distinguishing two different time scales, the slow time scale of the ions and the fast time scale of the electrons. The low mobility of the ions as compared to that of the electrons justifies this kind of treatment. Since the Landau damping of the Langmuir waves is neglected in the fluid description, the model (1-2) is restricted by the condition k \u226a k D , where k is the wavenumber and k D is the Debye wavenumber. Also, a weak turbulence condition is to be satisfied.", "cite_spans": [{"start": 208, "end": 210, "text": "18", "ref_id": "BIBREF25"}], "ref_spans": []}, {"section": "17", "text": "In this paper, modified Zakharov equations are obtained by use of a quantum fluid approach. Specifically, we assume a two species, one-dimensional quantum plasma in the electrostatic approximation. Pressure effects are neglected for the ions whereas the electrons are described by an isothermal equation of state. Contrary to the quantum degenerate case, 12 the present model is more suitable to investigate the classical limith \u2192 0.We do not include quantum statistical effects in the present investigation, and therefore, only quantum diffraction effects, responsible e.g. for tunnelling, are taken into account.", "cite_spans": [], "ref_spans": []}, {"section": "17", "text": "The paper is organized as follows. In Section II we write the quantum hydrodynamic model for a two-species plasma and derive the Langmuir mode for quantum plasmas. In Section III, we obtain the quantum Zakharov system through a procedure similar to the classical one where a two-time scale formalism is used. In Section IV we study the influence of quantum effects in two relevant parametric instabilities: the decay instability and the four-wave instability. Section VI is devoted to a preliminary discussion of the nonlinear aspects of the problem and some of the remaining open questions. Section V is reserved to the conclusions.", "cite_spans": [], "ref_spans": []}, {"section": "II. QUANTUM LANGMUIR WAVES", "text": "Before considering the nonlinear coupling between ion-acoustic and Langmuir waves, we examine the linear stability analysis of the Langmuir waves in the quantum regime. 19 For this purpose we consider a one-dimensional quantum system, composed of electrons and singly charged ions. The quantum hydrodynamic equations in this case become ", "cite_spans": [], "ref_spans": []}, {"section": "II. QUANTUM LANGMUIR WAVES", "text": "where E is the electric field, P e is the electron pressure, and n e , n i , u e , u i , m e and m i represent the density, fluid velocity and mass of electrons (e) and ions (i), respectively. In addition, \u03b5 0 andh are the vacuum dielectric and the scaled Planck's constants. Since we are interested in high frequency waves, the ion density n i can be assumed constant, at this stage. The pressure P e is obtained from an equation of state for the electrons, which basically depends on the thermodynamic properties of the system. In the present investigation, we consider the isothermal equation of state P e = \u03ba B n e T e , where T e is the electrons' temperature and \u03ba B is the Boltzmann's constant. In view of their large mass, ions are treated classically. Also, in a first approximation, we consider cold, zero temperature ions. The Bohm potential term proportional toh 2 in (5) is responsible for negative differential resistance in semiconductor devices 13 and is associated to tunnelling.", "cite_spans": [], "ref_spans": []}, {"section": "II. QUANTUM LANGMUIR WAVES", "text": "Linearization of the electron equations (3), (5) and (7) around the homogeneous equilibrium n e = n i = n 0 , u e = 0 and E = 0 produces the following dispersion relation:", "cite_spans": [], "ref_spans": []}, {"section": "II. QUANTUM LANGMUIR WAVES", "text": "In Eq. (8), \u03c9 is the wave frequency, k is the wavenumber, \u03c9 e = (n 0 e 2 /m e \u03b5 0 ) 1/2 is the electron plasma frequency and v e = (\u03ba B T e /m e ) 1/2 is the electron thermal velocity. Notice that both classical and quantum modes can be obtained from Eq. (8) . In fact, the classical limith \u2192 0 gives the classical Langmuir wave dispersion relation. 18 According to Eq. (8), the frequency \u03c9 is always real, and instability (or damping) of this wave cannot be observed. The main purpose of this paper is to obtain a model describing the exchange of energy between the quantum Langmuir modes shown above and the recently found quantum ion-acoustic plasma modes.", "cite_spans": [{"start": 350, "end": 352, "text": "18", "ref_id": "BIBREF25"}], "ref_spans": []}, {"section": "12", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "III. QUANTUM ZAKHAROV EQUATIONS", "text": "In order to obtain the set of equations describing the nonlinear interaction between Langmuir waves and ion-acoustic waves, in the quantum regime, we follow the derivation originally made by Zakharov. 16 A general discussion of the validity of the Zakharov equations can be found in the review paper by Thornhill and ter Haar.", "cite_spans": [], "ref_spans": []}, {"section": "17", "text": "We first separate all fluid variables into high frequency (subscript h) and low frequency (subscript l) components,", "cite_spans": [], "ref_spans": []}, {"section": "17", "text": "Notice that the high frequency portions of the ion quantities [Eqs. (10) and (12)] were ignored due to the large ion mass. Also, from the very beginning we assume that departures from the quasi-neutral regime (n i \u2248 n e and u i \u2248 u e ) are provided only by the high frequency components of the electrons motion. The high frequency term of the electric field can also be written as", "cite_spans": [], "ref_spans": []}, {"section": "17", "text": "where\u1ebc(x, t) is the slowly varying envelope of the high frequency term and c.c. refer to complex conjugate. Using the high frequency components of Eqs. (3-7), we obtain, by the same procedure used in the classical case,", "cite_spans": [], "ref_spans": []}, {"section": "17", "text": "where the term |\u2202 2 t\u1ebc | \u226a |\u03c9 e \u2202 t\u1ebc | has been neglected. Equation (15) describes the evolution of the slowly varying amplitude\u1ebc, as defined in (14) .", "cite_spans": [], "ref_spans": []}, {"section": "17", "text": "We next proceed with the derivation of the equation for the low frequency part, n l , of the departure from the equilibrium density n 0 . After averaging over the fast time scale, we get a set of equations describing the low frequency part of the electron continuity equation, electron force equation and ion force equation,", "cite_spans": [], "ref_spans": []}, {"section": "17", "text": "Convective terms were disregarded in view of a weak Langmuir turbulence assumption, as detailed by Thornhill and ter Haar. 17 Eliminating u l and E l from Eqs. (16) (17) (18) and assuming m e /m i \u226a 1, we obtain", "cite_spans": [{"start": 170, "end": 174, "text": "(18)", "ref_id": "BIBREF25"}], "ref_spans": []}, {"section": "17", "text": "where c s = (\u03ba B T e /m i ) 1/2 is the ion-acoustic velocity. We call Eqs. (15) and (19) the quantum", "cite_spans": [], "ref_spans": []}, {"section": "Zakharov equations.", "text": "For the following analysis, it is most convenient to normalize Eqs. (15) and (19) . Normalized quantities are expressed as", "cite_spans": [], "ref_spans": []}, {"section": "Zakharov equations.", "text": "where \u03bb e is the electron Debye length. In addition to (20-21), we introduce the dimensionless quantum parameter", "cite_spans": [], "ref_spans": []}, {"section": "Zakharov equations.", "text": "where \u03c9 i = (n 0 e 2 /m i \u03b5 0 ) 1/2 is the ion plasma frequency. The resulting system reads (we dropped bars for the sake of simplicity)", "cite_spans": [], "ref_spans": []}, {"section": "Zakharov equations.", "text": "The quantum parameter H given in (22) expresses the ratio between the ion plasmon energy and the electron thermal energy. This is to be compared with the dimensionless parameter characterizing quantum effects in the two-stream quantum instability, 6 given by the ratio between electron plasmon and thermal energies. Here, the presence of ion-acoustic modes forces the appearance of ionic (inertia) parameters. Notice that for dense plasmas, In the next section, the model (23-24) is used to investigate two parametric instabilities extensively studied in classical plasmas: the decay instability and the four-wave interaction.", "cite_spans": [], "ref_spans": []}, {"section": "IV. PARAMETRIC INSTABILITIES A. Decay instability", "text": "Following strictly the treatment for the classical decay instability, 17 consider the proposal", "cite_spans": [], "ref_spans": []}, {"section": "IV. PARAMETRIC INSTABILITIES A. Decay instability", "text": "now for the quantum Zakharov equations (23) (24) , where E 1 (t) and n 1 (t) are first-order quantities, and", "cite_spans": [], "ref_spans": []}, {"section": "IV. PARAMETRIC INSTABILITIES A. Decay instability", "text": "Notice that Eq. (29) is identical to the quantum dispersion relation obtained by Haas et al. 12 (Section V) except for the value of H which, due to the use of a quantum equation of state, has a different definition there.", "cite_spans": [], "ref_spans": []}, {"section": "IV. PARAMETRIC INSTABILITIES A. Decay instability", "text": "Also, there are the usual matching conditions", "cite_spans": [], "ref_spans": []}, {"section": "IV. PARAMETRIC INSTABILITIES A. Decay instability", "text": "corresponding to momentum and energy conservation respectively. These conditions describe the decay of one quantum Langmuir wave, with dispersion relation (27), into other quantum Langmuir wave, with dispersion relation (28), and a quantum ion-acoustic wave, with dispersion relation (29).", "cite_spans": [], "ref_spans": []}, {"section": "IV. PARAMETRIC INSTABILITIES A. Decay instability", "text": "Linearizing the quantum Zakharov equations, we obtain", "cite_spans": [], "ref_spans": []}, {"section": "IV. PARAMETRIC INSTABILITIES A. Decay instability", "text": "where use has been made of the notation", "cite_spans": [], "ref_spans": []}, {"section": "IV. PARAMETRIC INSTABILITIES A. Decay instability", "text": "The resonant part [satisfying (30)] of (31) gives", "cite_spans": [], "ref_spans": []}, {"section": "IV. PARAMETRIC INSTABILITIES A. Decay instability", "text": "while (32) givesn", "cite_spans": [], "ref_spans": []}, {"section": "IV. PARAMETRIC INSTABILITIES A. Decay instability", "text": "For\u0116 1 = i\u03c9E 1 , elimination of n 1 leaves us with", "cite_spans": [], "ref_spans": []}, {"section": "IV. PARAMETRIC INSTABILITIES A. Decay instability", "text": "which is formally identical to the dispersion relation for the classical decay instability. Hence, all conclusions valid for the classical case can be immediately extended to the quantum case.", "cite_spans": [], "ref_spans": []}, {"section": "IV. PARAMETRIC INSTABILITIES A. Decay instability", "text": "In particular, for \u2126 \u226b |\u03c9|, so that the cubic term can be neglected in (36), and for \u03c9 = i\u03b3, we obtain the growth rate", "cite_spans": [], "ref_spans": []}, {"section": "IV. PARAMETRIC INSTABILITIES A. Decay instability", "text": "In all situations, the discriminant 20 of the cubic equation (36) is positive and there are one real and two complex conjugate solutions for this equation, one of which is necessarily unstable.", "cite_spans": [], "ref_spans": []}, {"section": "IV. PARAMETRIC INSTABILITIES A. Decay instability", "text": "To conclude, there is a formal similarity between the classical and quantum decay instabilities. The only differences remain in the dispersion relations (27-29), for the quantum Langmuir and ion-acoustic modes. The quantum dispersion relations, however, produces a saturation effect not present in the classical case (see Fig. 1 ). Combining (29) and (37), we", "cite_spans": [], "ref_spans": [{"start": 322, "end": 328, "text": "Fig. 1", "ref_id": "FIGREF5"}]}, {"section": "IV. PARAMETRIC INSTABILITIES A. Decay instability", "text": "for which a maximum value \u03b3 max = |E 0 |/ \u221a 2H is obtained for K \u2192 \u221e. This is to be compared with the classical case (H = 0) where \u03b3 grows with no bound as K increases.", "cite_spans": [], "ref_spans": []}, {"section": "IV. PARAMETRIC INSTABILITIES A. Decay instability", "text": "Even if the quantum effects do not imply stabilization, they limit the instability to a fixed maximum growth rate.", "cite_spans": [], "ref_spans": []}, {"section": "IV. PARAMETRIC INSTABILITIES A. Decay instability", "text": "For ", "cite_spans": [], "ref_spans": []}, {"section": "B. Four-wave instability", "text": "The general instability involving the interaction between one single finite-amplitude Langmuir wave, two other Langmuir waves and one ion-acoustic wave can be obtained by", "cite_spans": [], "ref_spans": []}, {"section": "B. Four-wave instability", "text": "n(x, t) =\u00f1 exp(\u2212i\u03c9t + ikx) + c.c ,", "cite_spans": [], "ref_spans": []}, {"section": "B. Four-wave instability", "text": "where the amplitudes E + , E \u2212 and\u00f1 are all first order quantities. We choose the equilibrium solution E(x, t) = E 0 exp(\u2212i\u03c9 0 t + ik 0 x), n(x, t) = 0 to satisfy Eqs. (23) (24) with E 0 real.", "cite_spans": [], "ref_spans": []}, {"section": "B. Four-wave instability", "text": "This implies the relation", "cite_spans": [], "ref_spans": []}, {"section": "B. Four-wave instability", "text": "The last equation can be found also from the dispersion relation for quantum Langmuir modes [equation (8)] taking \u03c9 e = 0 and the recalling of variables. In fact, \u03c9 e is absorbed in the electric field through (14) . In conclusion, (41) shows a quantum Langmuir mode.", "cite_spans": [], "ref_spans": []}, {"section": "B. Four-wave instability", "text": "The forms (39-40) when inserted in Eq. (23) yield", "cite_spans": [], "ref_spans": []}, {"section": "B. Four-wave instability", "text": "When combined, Eqs. (24), (41-42) and the complex conjugate of (43) give the following dispersion relation:", "cite_spans": [], "ref_spans": []}, {"section": "B. Four-wave instability", "text": "in which", "cite_spans": [], "ref_spans": []}, {"section": "B. Four-wave instability", "text": "Notice that the limit H \u2192 0 recovers the classical dispersion relation for the four-wave interaction.", "cite_spans": [], "ref_spans": []}, {"section": "18", "text": "The dispersion relation (44) is a fourth order polynomial in \u03c9 that, in general, can only be analyzed numerically. However, the simplest case \u03c9 0 = k 0 = 0 can be investigated analytically. For a purely growing instability \u03c9 = i\u03b3 the dispersion relation (44) becomes", "cite_spans": [], "ref_spans": []}, {"section": "18", "text": "Solving for \u03b3 2 , there follows two roots,", "cite_spans": [], "ref_spans": []}, {"section": "18", "text": "one of them necessarily negative (stable mode). The other root is positive (unstable mode) provided", "cite_spans": [], "ref_spans": []}, {"section": "18", "text": "This recovers the classical instability condition for the four-wave interaction 18 when H \u2192 0.", "cite_spans": [{"start": 80, "end": 82, "text": "18", "ref_id": "BIBREF25"}], "ref_spans": []}, {"section": "18", "text": "However, there is a new, quantum effect of instability suppression provided", "cite_spans": [], "ref_spans": []}, {"section": "18", "text": "This is in agreement with the overall stabilization that quantum diffraction effects produce in high density plasmas. 6, 7 In fact, for sufficiently large H there is no transfer of energy from the original quantum Langmuir mode to the two new quantum Langmuir modes and to the quantum ion-acoustic mode.", "cite_spans": [], "ref_spans": []}, {"section": "18", "text": "Let us consider in more detail the potentially unstable mode described by the positive root in (49). In Fig. 2 , we show \u03b3 2 versus k 2 for H = 0, H = 0.5 and H = 0.9, with E 0 = 0.5. The instability region (\u03b3 2 > 0) in k-space becomes narrower for bigger H. Also, the maximum \u03b3 Denote the unstable interval in k by I k = (k a , k b ). For higher pump energy E 0 , the third column of Fig. 4 shows an overall contraction of I k . This results from the gradual shift of k a to the right and k b to the left, due to the quantum effects. For the relevant range of values 0 \u2264 H \u2264 1, less severe attenuations occur for the maximum growth rate, compared to those found for the unstable interval in k. Thus, the numerical results show that the quantum effect inhibits the spreading of energy among different modes. In fact, assume that for a specific k, N I = (k b \u2212 k a )/k represents a first estimation for the number of active modes at the beginning of the process. Then, the contraction of I k implies that the Langmuir fluctuations in quantum plasmas might represent more coherent configurations, i.e., having less effective modes when compared to the corresponding classical situation, an issue to be checked by a direct numerical simulation and, possibly, by an experiment.", "cite_spans": [], "ref_spans": []}, {"section": "V. NONLINEAR ANALYSIS AND OPEN QUESTIONS", "text": "An important regime of the classical Zakharov equations concerns its static limit. In this case, the classical Zakharov system do possess soliton solutions described by a nonlinear Sch\u00f6dinger equation. 17 The procedure for the static limit of the quantum Zakharov equations considers the approximation \u2202 2 n/\u2202t 2 \u2248 0 in (24) . This gives immediately", "cite_spans": [], "ref_spans": []}, {"section": "V. NONLINEAR ANALYSIS AND OPEN QUESTIONS", "text": "Equation (52), inserted in Eq. (23), yields", "cite_spans": [], "ref_spans": []}, {"section": "V. NONLINEAR ANALYSIS AND OPEN QUESTIONS", "text": "In the classical limit H \u2192 0, the right-hand side of Eq. (53) vanishes and we recover the nonlinear Schr\u00f6dinger equation with its soliton solutions. In the quantum case, however, equations (52-53) form a coupled, nonlinear system. We have not been able to find localized, analytical solutions for this system. In fact, the usual reduction procedure of searching for solutions in the form", "cite_spans": [], "ref_spans": []}, {"section": "V. NONLINEAR ANALYSIS AND OPEN QUESTIONS", "text": "for real F , G, k, M, u and \u03b4 produces a complicated fourth-order system of coupled, nonlinear equations. The existence of soliton solutions for this system remains an open question. It seems that a numerical analysis could help in this respect but we believe that this issue", "cite_spans": [], "ref_spans": []}, {"section": "V. NONLINEAR ANALYSIS AND OPEN QUESTIONS", "text": "should be more appropriately treated in a future work.", "cite_spans": [], "ref_spans": []}, {"section": "V. NONLINEAR ANALYSIS AND OPEN QUESTIONS", "text": "Another avenue in nonlinear studies of the quantum Zakharov equation concerns its simultaneous semiclassical and static limit. Substituting (52) into (53) and retaining only terms up to O(H 2 ) produces the decoupled equation", "cite_spans": [], "ref_spans": []}, {"section": "V. NONLINEAR ANALYSIS AND OPEN QUESTIONS", "text": "Equation (55) can be used to study perturbations of the classical NLS soliton solutions.", "cite_spans": [], "ref_spans": []}, {"section": "V. NONLINEAR ANALYSIS AND OPEN QUESTIONS", "text": "The terms proportional to H 2 , in Eq. (55), will probably modify the dispersion-nonlinearity equilibrium, which is the ultimate responsible for the soliton existence.", "cite_spans": [], "ref_spans": []}, {"section": "V. NONLINEAR ANALYSIS AND OPEN QUESTIONS", "text": "More formal aspects of the Zakharov equations have to do with its variational formulation and the associated Noether currents. 21 In particular the quantum Zakharov equations preserve the number of plasmons |E| 2 dx of the high frequency electric field, as a consequence of the associated conservation law", "cite_spans": [], "ref_spans": []}, {"section": "V. NONLINEAR ANALYSIS AND OPEN QUESTIONS", "text": "where E(x, t) = A(x, t) exp(i\u03b8(x, t)), with A = A(x, t) and \u03b8 = \u03b8(x, t) real amplitude and phase functions, and", "cite_spans": [], "ref_spans": []}, {"section": "V. NONLINEAR ANALYSIS AND OPEN QUESTIONS", "text": "Notice the extra contribution proportional to H 2 to the plasmons current.The conservation law (56) comes from the imaginary part of (23) To finalize, we can derive some exact solutions for the quantum Zakharov equations (23-24) if we consider pure ion-sound waves obtained by taking E = 0. With zero electric field, the density perturbation satisfies the undriven equation", "cite_spans": [], "ref_spans": []}, {"section": "V. NONLINEAR ANALYSIS AND OPEN QUESTIONS", "text": "This linear fourth-order evolution equation was investigated using the method of Lie symmetries 25 and we found time and space translation symmetries, as well as a scale symmetry resulting from the linearity. The H 2 term breaks down the Lorentz invariance endowed by the classical model for pure ion-sound waves, so that arbitrary waves travelling at the ion-sound velocity can not be constructed. Nevertheless, exact solutions for Eq. (59) can be found supposing n =n(x \u2212 ct), for constant c and forn a function to be determined. For c 2 > 1, corresponding to supersonic flow, and disregarding an integration constant associated to non-bound solutions, we get periodic solutions of the form", "cite_spans": [{"start": 96, "end": 98, "text": "25", "ref_id": "BIBREF34"}], "ref_spans": []}, {"section": "V. NONLINEAR ANALYSIS AND OPEN QUESTIONS", "text": "where a, b and \u03b4 are numerical constants. This similarity solution is an arbitrary amplitude solution. Notice that quantum effects increase the spatial frequency of oscillations in the reference frame of the travelling wave.", "cite_spans": [], "ref_spans": []}, {"section": "VI. CONCLUSION", "text": "We obtained a general model to analyze the coupling between Langmuir waves and ionacoustic waves, in a quantum setting. The model was shown to be appropriate to the four-wave interaction and quantum effects have been shown to provide stabilization of a classically unstable mode. In the case of the decay instability, a formal similarity with the classical case is identified, except for small differences in the dispersion relations, representing quantum corrections. We also identified a dimensionless quantum parameter given by the ratio of the ion plasmon and electron thermal energies. As pointed out before, this quantum parameter may not be small, at least for dense plasmas.", "cite_spans": [], "ref_spans": []}, {"section": "VI. CONCLUSION", "text": "The consequences of our results on todays laboratory or technological plasmas are not yet fully assessed since, for present conditions, H \u226a 1 in these applications. However quantum effects may imply important consequences in the behavior of high density astrophysical plasmas, where H \u223c 1 is easily found. In this case, as we pointed out, quantum effects cause an overall reduction in the wave-wave interaction level. Specifically and in contrast to the classical case, the decay instability growth rate is bounded for large wavenumbers. Growth rate reduction also occurs for the four-wave interaction. Besides, suppression is also verified in the length of the unstable spectral range, implying spectral focusing, i.e., a restriction on the range of possible unstable wave-numbers. This focusing effect may extend to quite long ", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Semiconductor Equations", "authors": [{"first": "P", "middle": ["A"], "last": "Markowich", "suffix": ""}, {"first": "C", "middle": ["A"], "last": "Ringhofer", "suffix": ""}, {"first": "C", "middle": [], "last": "Schmeiser", "suffix": ""}], "year": 1990, "venue": "", "link": "126055883"}, "BIBREF25": {"title": "Introduction to Plasma Theory", "authors": [{"first": "D", "middle": ["R"], "last": "Nicholson", "suffix": ""}], "year": 1983, "venue": "", "link": "117636709"}, "BIBREF27": {"title": "Plasma Physics", "authors": [{"first": "J", "middle": ["E"], "last": "Drummond", "suffix": ""}], "year": 1961, "venue": "", "link": null}, "BIBREF29": {"title": "Tables of Integrals, Series and Products", "authors": [{"first": "I", "middle": ["S"], "last": "Gradshteyn", "suffix": ""}, {"first": "I", "middle": ["M"], "last": "Rhyzik", "suffix": ""}], "year": 1965, "venue": "", "link": "124443655"}, "BIBREF34": {"title": "Applications of Lie Groups to Differential Equations", "authors": [{"first": "P", "middle": ["J"], "last": "Olver", "suffix": ""}], "year": 1986, "venue": "", "link": "117822940"}}, "ref_entries": {"FIGREF0": {"text": "7 K, the parameter H is not irrelevant at all. For a completely ionized hydrogen plasma in these ranges of densities and temperatures, H typically goes from negligible values of order 10 \u22125 up to values of order unity. The presence of large values of H points to the possible experimental manifestation of quantum effects in the coupling between Langmuir and ion-acoustic modes in dense plasmas, particularly in astrophysical plasmas.", "type": "figure"}, "FIGREF1": {"text": "For laser hydrogen plasmas, however, to the best of our knowledge, such high densities are not yet attainable. For today's typical values 3 of n 0 \u223c 10 28 m \u22123 and T \u223c 10 5 K, we obtain a modest value of H \u223c 10 \u22122 . The smallness of the quantum effects for modulational instabilities in laser plasmas follows from the fact that, in this respect, the relevant parameter H is defined as the ratio of the ion plasmon energy to the electron thermal energy. If the pertinent quantum parameter were the ratio between the electron plasmon energy and the electron thermal energy, as in the quantum two-stream instability, 6 the lower mass of the electrons would increase significantly H. For laser plasmas with the same typical values as before, we would have H \u223c 0.4. Of course, we are not saying that quantum effects are irrelevant for laser plasmas: they can show up when the Landau length becomes comparable to the de Broglie wavelength, in which cas\u0113 h\u03c9 c \u223c \u03ba B T e , where \u03c9 c is the cyclotron frequency associated with the laser field, or when the electrons are degenerated.", "type": "figure"}, "FIGREF3": {"text": "becomes smaller the larger the quantum effects. This latter result is analytically supported by an expansion of the positive root of Eq. (49). The wavenumber for maximum growth rate, k max can be calculated, in a O(k 5 ) approximation, by expanding Eq. (49) up to fifth order in k. This perturbation analysis is interesting since d\u03b3/dk = 0 is not soluble in closed form if we use the exact expression for (49). The result of the expansion procedure is shown in Fig. 3, where the wavenumber k max for maximum growth rate when E 0 = 0.5 is shown as a function of H. (Notice the extended domain of the function, beyond the reasonable limit of H \u223c = 1.) Using this k max we obtain a somewhat complicated expression which can be used to calculate the associated growth rate \u03b3. Using a computer algebra program, we can easily obtain \u03b3 max =. This is an approximate equation showing that quantum effects produce stabilization. The approximations adopted are justified in view of our assumptions of long wavelengths and weak turbulence (small electric field amplitudes). For dense astrophysical plasmas with H \u223c 1, as in the decay instability case, we would get \u03b3 max =, a significant difference in comparison with the classical case where \u03b3 max = E 2 0 (1 \u2212 E 2 0 ). In order to further assess the role of quantum effects in the four-wave interaction process, we performed a numerical study of (44) for general k 0 = 0. Figure 4 displays the real (solid lines) and imaginary (dashed lines) parts of \u03c9 as a function of k. Both uncoupled (i.e., E 0 \u2248 0) and coupled cases are considered, for three different values of H. Due to the symmetry (k, \u03c9) \u2194 (\u2212k, \u2212\u03c9) \u21d2 D 1 \u2194 D 2 , of the dispersion relation (44), we consider only positive values of the wavenumber, around the overlay region of the branches D s and D 2 , where instability occurs. In the uncoupled case, k = 2k 0 is a root of D 2 when \u03c9 = 0, for both classical and quantum cases. Also, the plots of D s and D 2 branches touch each other at isolated points while, when E 0 = 0, overlay occurs for a whole finite interval of k, signalizing wave instability. The first column of plots shows that, for a fixed k 0 , both uncoupled curves raise with H, implying reduction of the interval in k where instability settles down. This can be checked against the corresponding figures in the second and third columns, where a contraction of the unstable interval is clearly seen.", "type": "figure"}, "FIGREF4": {"text": "and hence contains no contribution from n. A proper formulation of the remaining conservation laws (momentum and energy) of the system is an open question to be tackled, preferably in accordance with symmetry principles of an associated action functional. Other important issues concern the search for coherent solutions of the quantum Zakharov equations, namely quantum solitons and quantum cavitons. Still another issue related to the nonlinear analysis of Eqs. (23-24) concerns thermaliza- tion and recurrence. For periodic boundary conditions, the classical NLS does not exhibit thermalization and, therefore, is generically recurrent. 22,23 The classical procedure to address such questions is based on estimations for the number of active modes N A , from the Rayleigh quotient. An upper bound estimation for this number is provided by two invariants: the number of plasmons and a momentum-like invariant which, in our case, is not yet known. For classical regimes, numerical simulations show that the conclusions can, in general, be extended to the non-integrable Zakharov system, when considered as a perturbation of the NLS regime. 24 In fact, it has been shown that, at least for some period of time, the constancy of the momentum-like quantity is approximately satisfied. Moreover, numerical simulations show that the elementary estimation presented in the last section, i.e., N A \u2248 N I , can yield quite good results when applied to the full Zakharov equations. Under this viewpoint, the contraction of the k-unstable interval due to H = 0, verified in subsection (IV B), suggests that the distribution of energy is less intense in quantum plasmas when compared with the classical case. Therefore, quantum effect would favor recurrence in Langmuir modulational regimes.", "type": "figure"}, "FIGREF5": {"text": "FIGURE CAPTIONS", "type": "figure"}}}
{"paper_id": "119422749", "_pdf_hash": "8a8208eb00e35e8bb2c637e73b4ed6c49c6d387c", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Synchronization and chaotization in interacting dynamical systems", "authors": [{"first": "I", "middle": [], "last": "Blekhman", "suffix": ""}, {"first": "P", "middle": ["S"], "last": "Landa", "suffix": ""}, {"first": "M", "middle": ["G"], "last": "Rosenblum", "suffix": ""}], "year": 1995, "venue": "Applied Mechanics Review", "link": "121610274"}, "BIBREF1": {"title": "Synchronization of chaos using continuous control", "authors": [{"first": "T", "middle": [], "last": "Kapitaniak", "suffix": ""}], "year": 1994, "venue": "Physical Review E", "link": "38613196"}, "BIBREF2": {"title": "Synchronization in chaotic systems", "authors": [{"first": "L", "middle": ["M"], "last": "Pecora", "suffix": ""}, {"first": "T", "middle": ["L"], "last": "Carroll", "suffix": ""}], "year": 1990, "venue": "Physical Review Letters", "link": "117301648"}, "BIBREF3": {"title": "Driving systems with chaotic signals", "authors": [{"first": "L", "middle": ["M"], "last": "Pecora", "suffix": ""}, {"first": "T", "middle": ["L"], "last": "Carroll", "suffix": ""}], "year": 1991, "venue": "Physical Review A", "link": "39501350"}, "BIBREF4": {"title": "Predictable chaos in slightly perturbed unpredictable chaotic systems", "authors": [{"first": "K", "middle": [], "last": "Pyragas", "suffix": ""}], "year": 1993, "venue": "Physics Letters A", "link": "122037482"}, "BIBREF5": {"title": "Ogorza\"ek, Monotone synchronization of chaos", "authors": [{"first": "T", "middle": [], "last": "Kapitaniak", "suffix": ""}, {"first": "M", "middle": [], "last": "Sekieta", "suffix": ""}, {"first": "M", "middle": [], "last": "", "suffix": ""}], "year": 1996, "venue": "International Journal of Bifurcation and Chaos", "link": null}, "BIBREF6": {"title": "Coupling of two chaotic lasers", "authors": [{"first": "Y", "middle": [], "last": "Liu", "suffix": ""}, {"first": "J", "middle": ["R"], "last": "Rios Leite", "suffix": ""}], "year": 1994, "venue": "Physics Letters A", "link": "120655208"}, "BIBREF7": {"title": "Steady state locking in coupled chaotic systems", "authors": [{"first": "A", "middle": [], "last": "Stefa ! Nski", "suffix": ""}, {"first": "T", "middle": [], "last": "Kapitaniak", "suffix": ""}], "year": 1996, "venue": "Physics Letters A", "link": "54914975"}, "BIBREF8": {"title": "Stability theory of synchronized motion in coupled oscillator systems", "authors": [{"first": "H", "middle": [], "last": "Fujisaka", "suffix": ""}, {"first": "T", "middle": [], "last": "Yamada", "suffix": ""}], "year": 1983, "venue": "Progress of Theoretical Physics", "link": "122885071"}, "BIBREF9": {"title": "Using chaos synchronization to estimate the largest Lyapunov exponent of nonsmooth systems", "authors": [{"first": "A", "middle": [], "last": "Stefa ! Nski", "suffix": ""}, {"first": "T", "middle": [], "last": "Kapitaniak", "suffix": ""}], "year": 2000, "venue": "Discrete Dynamics in Nature and Society", "link": "33366038"}, "BIBREF10": {"title": "Estimation of the largest Lyapunov exponent in systems with impacts", "authors": [{"first": "A", "middle": [], "last": "Stefa", "suffix": ""}, {"first": "", "middle": [], "last": "Nski", "suffix": ""}], "year": 2000, "venue": "Chaos Solitons and Fractals", "link": null}, "BIBREF11": {"title": "Estimation of the largest Lyapunov exponent of discontinuous systems using chaos synchronization", "authors": [{"first": "A", "middle": [], "last": "Stefa ! Nski", "suffix": ""}, {"first": "J", "middle": [], "last": "Wojewoda", "suffix": ""}, {"first": "T", "middle": [], "last": "Kapitaniak", "suffix": ""}, {"first": "J", "middle": [], "last": "Brindley", "suffix": ""}], "year": 1999, "venue": "ASME DETC Proceedings (on CD", "link": null}, "BIBREF12": {"title": "Symmetry breaking bifurcation for coupled chaotic attractors", "authors": [{"first": "A", "middle": [], "last": "Pikovski", "suffix": ""}, {"first": "P", "middle": [], "last": "Grassberger", "suffix": ""}], "year": 1991, "venue": "Journal of Physics A", "link": "120368576"}, "BIBREF13": {"title": "On-off intermittency: a mechanism of bursting", "authors": [{"first": "N", "middle": [], "last": "Platt", "suffix": ""}, {"first": "A", "middle": [], "last": "Spiegel", "suffix": ""}, {"first": "C", "middle": [], "last": "Tresser", "suffix": ""}], "year": 1993, "venue": "Physical Review Letters", "link": null}, "BIBREF14": {"title": "The effects of additive noise and drift in the dynamics of the driving on chaotic synchronization", "authors": [{"first": "R", "middle": [], "last": "Brown", "suffix": ""}, {"first": "H", "middle": ["F"], "last": "Rulkov", "suffix": ""}, {"first": "N", "middle": ["B"], "last": "Tufillaro", "suffix": ""}], "year": 1994, "venue": "Physics Letters A", "link": "122052088"}}, "ref_entries": {}}
{"paper_id": "119422967", "_pdf_hash": "c71ca7652829267f5fe4e46c3fee9dfca9180b34", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Omni Watch\u00ae Architecture", "authors": [{"first": "Richard", "middle": [], "last": "Porter", "suffix": ""}], "year": 2009, "venue": "", "link": null}, "BIBREF2": {"title": "OmniWatch\u00ae Design Review", "authors": [], "year": 2009, "venue": "", "link": null}, "BIBREF3": {"title": "Combining advanced image processing and low cost remote imaging capabilities", "authors": [{"first": "Matthew", "middle": ["J"], "last": "Rohrer", "suffix": ""}, {"first": "Brian", "middle": [], "last": "Mcquiddy", "suffix": ""}], "year": 2008, "venue": "", "link": "109412140"}, "BIBREF4": {"title": "OmniWatch\u00ae 1.5 Restreamer Design Review", "authors": [{"first": "", "middle": [], "last": "Roeder", "suffix": ""}, {"first": "", "middle": [], "last": "Brent", "suffix": ""}, {"first": "", "middle": [], "last": "Sheffel", "suffix": ""}, {"first": "", "middle": [], "last": "Peter", "suffix": ""}, {"first": "Robert", "middle": [], "last": "Fish", "suffix": ""}], "year": 2010, "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "119423095", "_pdf_hash": "e628af89f7c6620090ce8477d3baf6bb4de2c251", "abstract": [{"section": "Abstract", "text": "Transport processes and resultant entropy production in magnetically confined plasmas are studied in detail for toroidal systems with gyrokinetic electromagnetic turbulence. The kinetic equation including the turbulent fluctuations are double averaged over the ensemble and the gyrophase. The entropy balance equation is derived from the double-averaged kinetic equation with the nonlinear gyrokinetic equation for the fluctuating distribution function. The result clarifies the spatial transport and local production of the entropy due to the classical, neoclassical and anomalous transport processes, respectively. For the anomalous transport process due to the electromagnetic turbulence as well as the classical and neoclassical processes, the kinetic form of the entropy production is rewritten as the thermodynamic form, from which the conjugate pairs of the thermodynamic forces and the transport fluxes are identified. The Onsager symmetry for the anomalous transport equations is shown to be valid within the quasilinear framework. The complete energy balance equation, which takes account of the anomalous transport and exchange of energy due to the fluctuations, is derived from the ensemble-averaged kinetic equation. The intrinsic ambipolarity of the anomalous particle fluxes is shown to hold for the self-consistent turbulent electromagnetic fields satisfying Poisson's equation and Amp\u00e8re's law.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "I. INTRODUCTION", "text": "Plasma transport of particles and heat in magnetically confined toroidal systems consists of classical, neoclassical, and anomalous \u0351or turbulent\u0352 processes. Both the classical and neoclassical transport [1] [2] [3] are caused by Coulomb collisions of particles, while the anomalous transport 4 results from turbulent fluctuations driven by various instabilities existing in confined plasmas.", "cite_spans": [{"start": 212, "end": 215, "text": "[3]", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "On the collisional transport, the classical process involves particle gyromotion while the neoclassical process is concerned with guiding-center drift motion in toroidal magnetic configurations. For the entropy production due to the classical transport, its kinetic form defined by the collision operator is equivalent to its thermodynamic form written as an inner product of thermodynamic forces and their conjugate transport fluxes. 3, 5 Also, due to the spatial locality of the process, the Onsager symmetry 6 of the classical transport matrix is directly derived from the self-adjointness of the linearized collision operator. 3, 5 On the other hand, since the long mean-free path of the guiding-center motion is involved in the neoclassical process, the neoclassical fluxes are defined through magnetic surface average, and the neoclassical transport matrix contains parameters relating to both the collisionality and the magnetic geometry. Thus, only by taking a magnetic surface average of the kinetic form of the neoclassical entropy production, we can derive the thermodynamic form, from which conjugate pairs of the thermodynamic forces and the neoclassical fluxes are rigorously identified. 5 Then, the Onsager symmetry is shown to be robustly valid for the neoclassical transport equations connecting the conjugate pairs even in nonaxisymmetric magnetic configurations. 5 Compared to the classical and neoclassical processes, it is rather difficult to analyze the anomalous transport process because of its nonlinearity even for more simplified configurations, and extensive theoretical and experimental studies have been performed so far. 4 However, most theoretical works on the anomalous transport have been done separately from the neoclassical transport theory, except for works by Shaing, 7, 8 Balescu, 9 and by Sugama and Horton, 10 which synthesize both the neoclassical and anomalous transport theories. These synthesized theories depend on how to formulate the neoclassical and anomalous parts of the total transport fluxes. In the works by Shaing 7, 8 and by Balescu, 9 the separation of variables into the average and fluctuating parts is done at the level of the fluid momentum balance equations, while, in the theory by Sugama and Horton 10 as well as in the present work, the plasma kinetic equation is divided into the ensemble-averaged part and the fluctuating part, and the fluctuation-particle interaction operator D a \u0353de-fined by Eq. \u03516\u0352 in the next section\u0354 plays an important role in the linkage of these two parts. Shaing and Balescu define the anomalous fluxes from the fluctuating parts of the fluid variables and use Shaing's ansatz [7] [8] [9] for the kinetic distribution function including mixture of the potential fluctuations and the averaged flow. Owing to the use of the fluctuationparticle interaction operator and the standard drift or gyrokinetic equation 11 -15 without Shaing's ansatz in our formula-tion, we can define the anomalous fluxes in more compact forms analogous to the definition of the classical fluxes in terms of the collision term, and we succeed to define the entropy production rate kinetically even for the anomalous transport processes, which is not considered in the theories by Shaing and by Balescu. From the anomalous entropy production rate, we can clearly specify the conjugate pairs of the thermodynamic forces and the anomalous transport fluxes, which are shown to be connected with each other by the Onsager symmetric quasilinear transport matrix. In the present work, we extend the formalism by Sugama and Horton 10 to more general toroidal systems with nonaxisymmetric magnetic configurations 16 -18 and gyrokinetic electromagnetic fluctuations, and give the complete description of the entropy and energy balance including all the transport processes, and examine the Onsager symmetry of the transport equations for each process.", "cite_spans": [{"start": 435, "end": 437, "text": "3,", "ref_id": "BIBREF2"}, {"start": 631, "end": 633, "text": "3,", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "In terms of the ordering parameter \u2426\u03f5 a /L \u0351 a : the thermal gyroradius, L: the equilibrium scale length\u0352, the gyrokinetic ordering employed here for the turbulent fluctuations is written as", "cite_spans": [], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "Here f a / f a , e a /T a , and \u0349B \u0349/\u0349B\u0349 are normalized fluctuations of the distribution function, the electrostatic potential, and the magnetic field strength, respectively, where the caret (\u02c6) represents the fluctuating part. The subscript a denotes the particle species and \u2340 a \u03ede a B/m a c is the gyrofrequency of the particle with the mass m a and the charge e a . The characteristic parallel \u0351perpendicular\u0352 wave number and frequency for the turbulence are denoted by k \u0288 (k \u040c ) and , respectively. Assuming that k \u0288 \u03f3L \u03ea1 , we find from Eq. \u03511\u0352 that k \u040c a \u03f31 and \u03f3 * a \u03f3 Ta \u03f3v Ta /L, where * a , Ta , and v Ta are the drift frequency, the transit frequency, and the thermal velocity, respectively.", "cite_spans": [], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "According to the same formulation as in Ref. 10 , the magnetic-surface-averaged radial particle and heat fluxes are given up to O \u0351\u2426", "cite_spans": [], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "where \u0357-\u0358 denotes the magnetic surface average and the volume V inside the magnetic surface is used as a radial variable. Here the superscript ''cl,'' ''PS,'' ''bp,'' ''na,'' and ''anom'' represents the classical, Pfirsch-Schl\u00fcter, bananaplateau, nonaxisymmetric, and anomalous fluxes, respectively. In Appendix A, their definitions are given. Since, in the gyrokinetic ordering, the ensemble-averaged drift kinetic equation is not affected up to O \u0351\u2426\u0352, 10 all the neoclassical \u0351Pfirsch-Schl\u00fcter, banana-plateau, and nonaxisymmetric\u0352 fluxes as well as the classical fluxes are given in terms of the thermodynamic forces by the same transport equations as in Ref. 5 for the cases with no turbulence. The anomalous particle and heat fluxes are defined by", "cite_spans": [], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "respectively, where K a1 and K a2 are the anomalous forces given by", "cite_spans": [], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "Here x a 2 \u03f5m a v 2 /2T a is the normalized kinetic energy and D a is the fluctuation-particle interaction term contained in the ensemble-averaged kinetic equation \u0353see Eq. \u03516\u0352 in Sec. II\u0354.", "cite_spans": [], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "It is shown in Ref. 10 that the relative effects of the anomalous forces K a j \u0351j\u03ed1,2\u0352 on the parallel viscosities and accordingly on the neoclassical transport are measured by \u232c 2 /\u2426 if we represent the order of the normalized fluctuations by f a / f a \u03f3e a /T a \u03f3\u2022\u2022\u2022\u03f3\u232c instead of the gyrokinetic ordering in Eq. \u03511\u0352. Then, the neoclassical banana-plateau fluxes and the bootstrap current are significantly modified by this coupling to the anomalous forces in the case where \u232c\u03f3\u2426 1/2 , as assumed in Ref. 10 . On the other hand, in the present work, this modification of the expressions for the neoclassical transport fluxes does not occur in the dominant or lowest order since the gyrokinetic ordering \u232c\u03f3\u2426 in Eq. \u03511\u0352 assures that the coupling effect is smaller by the order of \u232c 2 /\u2426\u03f3\u2426\u04f61. Thus, the condition for the validity of the additive expressions for the neoclassical and anomalous transport without their coupling is estimated by \u232c\u04f6\u2426 1/2 . From a microscopic point of view, for a single realization in the ensemble of the turbulent systems, the collision is the only irreversible process producing the entropy. The irreversibility or the positive entropy production due to the turbulent process is observed macroscopically by taking the ensemble average or coarse graining. Besides the ensemble average, the gyrophase average is also utilized to coarse grain the microscopic phase space, when the gyrokinetic fluctuations with frequencies much lower than the gyrofrequency are considered. Then, as shown later, the fluctuationparticle interaction operator D a defines the anomalous transport fluxes and describes completely the entropy production due to the gyrokinetic electromagnetic turbulence. The entropy production allows the identification of the conjugate pairs of the anomalous fluxes and the forces.", "cite_spans": [], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "It is a formidable task to give analytically the complete expressions for the anomalous transport equations that give the anomalous fluxes as complicated nonlinear functions of the forces. In addition to the nonlinear gyrokinetic equation, 15 the Poisson's equation and the Amp\u00e8re's law are required for a self-consistent description of the fluctuations in the particle distributions. Such additional constraints are important for establishing the properties of the anomalous transport without obtaining directly the anomalous transport equations. The intrinsic ambipolarity for the anomalous particle fluxes will be derived from these properties. Then, we will find that the radial electric field in the axisymmetric configuration is not determined by the ambipolarity condition, even in the presence of the anomalous transport.", "cite_spans": [], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "Within the quasilinear framework, the anomalous transport coefficients are given as functionals of the turbulence spectrum. Thus, the quasilinear transport equations are also considered as implicitly nonlinear with respect to the forces. Since the Onsager symmetry is relevant to the linear thermodynamic transport equations, 6 its direct validity is questionable for the anomalous transport equations, even in the quasilinear version. However, as in Ref. 10 , we will find that the Onsager symmetric matrix connects the conjugate pairs of the anomalous \u0351quasilinear\u0352 fluxes and the forces in the gyrokinetic electromagnetic turbulence.", "cite_spans": [], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "The rest of this work is organized as follows. In Sec. II, the Hazeltine recursion technique 19, 20 is applied to the ensemble-averaged kinetic equation in order to obtain the gyrophase-averaged kinetic equation including effects of the electromagnetic fluctuations. The resultant equation contains O \u0351\u2426 2 \u0352 terms, which are not contained in the conventional drift kinetic equation but necessary for a proper description of the entropy variation due to the classical and anomalous transport processes. In Sec. III, using the kinetic definition of entropy, the entropy balance equation is derived from the gyrophase-averaged kinetic equation obtained in Sec. II and the nonlinear gyrokinetic equation for the fluctuating distribution function. There, the spatial transport and local production of the entropy due to the classical, neoclassical, and anomalous transport processes are clearly described. For each transport process, the kinetic form of the entropy production is rewritten in the thermodynamic form, from which the conjugate pairs of the thermodynamic forces and the transport fluxes are identified. The entropy production due to the anomalous transport process is shown to balance with the collisional dissipation for the fluctuating microscopic distribution function, which agrees with the argument by Krommes and Hu on the entropy paradox. 21 In Sec. IV, the Onsager symmetry for the anomalous transport equations is shown to be valid within the quasilinear framework. Using the Krook collision model, the detailed expressions for the quasilinear anomalous transport coefficients are derived and the results, especially on the magnetic fluctuation effects on the anomalous transport, are compared to those in previous works. In Sec. V, from the ensemble-averaged kinetic equation, we obtain the complete energy balance equation for the cases, in which all of the classical, neoclassical, and anomalous transport processes are involved. That equation elucidates how the fluctuation effects on the energy balance should be expressed, which has been somewhat obscure in previous literatures. In Sec. VI, Poisson's equation, and Amp\u00e8re's law are used for the self-consistent turbulent electromagnetic fields, and the intrinsic ambipolarity of the anomalous particle fluxes is shown to hold for the self-consistent fields. Finally, the conclusions and a discussion are given in Sec. VII.", "cite_spans": [{"start": 93, "end": 96, "text": "19,", "ref_id": "BIBREF18"}, {"start": 97, "end": 99, "text": "20", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "II. GYROPHASE AVERAGE OF ENSEMBLE-AVERAGED KINETIC EQUATION", "text": "We start from an ensemble-averaged kinetic equation for species a: \u202b\u202av\u202c\u05e5/\u05e5\u0351-\u202c 1 \u03ea\u202b\u05e5/\u05e5\u202cv 2 \u0352 f \u03511\u0352 f \u03512\u0352\u0351r 12 \u03f5r 1 \u03ear 2 \u0352 causes the collisional interaction part of the two-body correlation function g 2 \u03511,2\u0352. Substitution of this part of g 2 into the first equation in the BBGKY hierarchy for the one-body distribution function f \u03511\u0352 gives the collision operator. The residual part of g 2 resulting from plasma unstable modes describes the collective interaction and gives the term corresponding to our D a when it is substituted into the onebody equation. Thus, the collision term C a and the fluctuation-particle interaction term D a in Eq. \u03515\u0352 follow from the corresponding parts of the two-body correlation g 2 produced by the discreteness source term S\u03511,2\u0352 and by unstable modes in a turbulent plasma, respectively.", "cite_spans": [], "ref_spans": []}, {"section": "II. GYROPHASE AVERAGE OF ENSEMBLE-AVERAGED KINETIC EQUATION", "text": "Hereafter, we derive the gyrophase-averaged kinetic equation from Eq. \u03515\u0352 by applying the recursion technique proposed by Hazeltine. 19, 20 For this purpose, let us introduce the phase space variables \u0351x\u0408,\u2440,,\u0352 which is defined in terms of \u0351x,v\u0352 as", "cite_spans": [{"start": 137, "end": 139, "text": "20", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "II. GYROPHASE AVERAGE OF ENSEMBLE-AVERAGED KINETIC EQUATION", "text": "where \u0351e 1 ,e 2 ,n\u03f5B/B\u0352 are unit vectors that form a righthanded orthogonal system at each point, and v\u03edv \u0288 n\u03e9v \u040c with v \u0288 \u03edv-n. The differential operator on the left-hand side of Eq. \u03515\u0352 is written as", "cite_spans": [], "ref_spans": []}, {"section": "II. GYROPHASE AVERAGE OF ENSEMBLE-AVERAGED KINETIC EQUATION", "text": "where, in the last line, the partial differentials are taken with \u0351t,x\u0408,\u2440,,\u0352 as independent variables, and \"\u0408\u03f5\u202b\u05e5/\u05e5\u202cx\u0408 is defined. The fast gyrofrequency \u2340 a is contained in as \u03ed\u03ea\u2340 a \u03e9\u2426 (\u2426 /\u2340 a \u03f3\u2426), and we subtract the fast gyrofrequency from d/dt to define the following operator:", "cite_spans": [], "ref_spans": []}, {"section": "II. GYROPHASE AVERAGE OF ENSEMBLE-AVERAGED KINETIC EQUATION", "text": "Then, rewriting Eq. \u03515\u0352 in the phase space variables \u0351x\u0408,\u2440,,\u0352 and separating it into the average and oscillating parts with respect to the gyrophase angle , we obtain", "cite_spans": [], "ref_spans": []}, {"section": "\u035111\u0352", "text": "where the average and oscillating parts in are represented for an arbitrary function F\u0351\u0352 as", "cite_spans": [], "ref_spans": []}, {"section": "\u035112\u0352", "text": "From Eq. \u035111\u0352, the gyrophase-dependent part of the ensemble-averaged distribution function is given to the lowest order in \u2426 by", "cite_spans": [], "ref_spans": []}, {"section": "\u035112\u0352", "text": "where the integration constant related to \u0350 d is uniquely determined by the condition f a (1) \u03ed 0. Substituting Eq. \u035113\u0352 into Eq. \u035110\u0352 with D a dropped gives Hazeltine's original drift kinetic equation 19, 20 for the case of no turbulence. Since, here, we are concerned with entropy productions due to both collisional and turbulent dissipations, we need to retain D a in Eqs. \u035110\u0352 and \u035111\u0352 and also calculate f a up to O\u0351\u2426", "cite_spans": [{"start": 202, "end": 205, "text": "19,", "ref_id": "BIBREF18"}, {"start": 206, "end": 208, "text": "20", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "\u035114\u0352", "text": "Here f a C and f a A causes classical and turbulent \u0351or anomalous\u0352 dissipation terms, respectively, when they are substituted into Eq. \u035110\u0352. On the other hand, f a H gives only the higher-order small corrections to the drift orbit, and it is neglected hereafter since it is not related to any dissipations. Then, using Eqs. \u035110\u0352 and \u035114\u0352, the double-averaged kinetic equation over the statistical ensemble and the gyrophase angle is written as", "cite_spans": [], "ref_spans": []}, {"section": "\u035114\u0352", "text": "where detailed expressions for the guiding center motion \u0351v gc ,\u2440 gc , gc \u0352 are given in Ref. 19 . The terms in the last line, except for the first one, are O\u0351\u2426 2 \u0352 and not included in Ref. 19 , although they are necessary for deriving complete expressions for the collisional and anomalous entropy productions and transport.", "cite_spans": [{"start": 94, "end": 96, "text": "19", "ref_id": "BIBREF18"}, {"start": 190, "end": 192, "text": "19", "ref_id": "BIBREF18"}], "ref_spans": []}, {"section": "III. ENTROPY BALANCE EQUATION", "text": "Let us define the kinetic form of the entropy per unit volume for species a in terms of the ensemble-averaged distribution function f a as", "cite_spans": [], "ref_spans": []}, {"section": "III. ENTROPY BALANCE EQUATION", "text": "where f a / f a \u03edO \u0351\u2426\u0352 is used. If we use the total distribution function f a \u03e9 f a to define the entropy, only the collisional processes produce that entropy while it is preserved, even in the presence of the turbulent transport for the collisionless case. By using the definition of Eq. \u035116\u0352 in which the microscopic turbulent processes are coarse grained, we can formulate the positive definite entropy production caused by the turbulent or anomalous transport. In order to obtain the entropy balance equation, let us multiply Eq. \u035115\u0352 by \u03ea\u0351ln f a \u03e91\u0352 and integrate it over the velocity space. First, we consider the contribution from collisions to the entropy balance equation, which is represented by", "cite_spans": [], "ref_spans": []}, {"section": "III. ENTROPY BALANCE EQUATION", "text": "Here the first term on the right-hand side is rewritten as", "cite_spans": [], "ref_spans": []}, {"section": "III. ENTROPY BALANCE EQUATION", "text": "where", "cite_spans": [], "ref_spans": []}, {"section": "III. ENTROPY BALANCE EQUATION", "text": "represent the collisional heat and momentum generation rates, respectively. The energy conservation in collisions requires", "cite_spans": [], "ref_spans": []}, {"section": "III. ENTROPY BALANCE EQUATION", "text": "The entropy variation a ncl caused by the O\u0351\u2426\u0352 deviation f a (1) from f aM is related to the neoclassical transport processes, as shown in detail in Ref. 5 . Taking the species summation of the flux surface average of a ncl multiplied by T a , we obtain the thermodynamic form of the entropy production due to the neoclassical transport:", "cite_spans": [], "ref_spans": []}, {"section": "III. ENTROPY BALANCE EQUATION", "text": "where the thermodynamic forces (X a1 ,X a2 ,X E ) and the neoclassical transport fluxes (J a1 ncl ,J a2 ncl ,J E ) are defined in Appendix A. In Ref. 5 it is shown from the self-adjointness and the positive definiteness of the linearized collision operator that these fluxes and forces are connected to each other by the neoclassical transport matrix with the Onsager symmetry and that \u035a a T a \u0357 a ncl \u0358 \u0443 0 holds. After some calculations, we find that the entropy variation \u1e60 a cl defined from f a C is rewritten as", "cite_spans": [], "ref_spans": []}, {"section": "III. ENTROPY BALANCE EQUATION", "text": "where J Sa cl is the entropy flux due to the classical flows u a", "cite_spans": [], "ref_spans": []}, {"section": "III. ENTROPY BALANCE EQUATION", "text": "/n a and q a cl \u0351see Appendix A for their definitions\u0352, and is given by", "cite_spans": [], "ref_spans": []}, {"section": "III. ENTROPY BALANCE EQUATION", "text": "and a cl is given in the thermodynamic form of the entropy production due to the classical particle and heat transport as", "cite_spans": [], "ref_spans": []}, {"section": "III. ENTROPY BALANCE EQUATION", "text": "Thus, \u1e60 a cl consists of the entropy transport term and the entropy production term, both of which result from the classical particle and heat transport. The classical particle and heat fluxes (J a1 cl ,J a2 cl ) defined in Appendix A are also related to the thermodynamic forces, (X a1 ,X a2 ) with the classical transport matrix with the Onsager symmetry. It is also shown that \u035a a T a a cl \u0443 0. Next, let us consider the contribution from turbulent fluctuations to the entropy balance equation, which is represented by", "cite_spans": [], "ref_spans": []}, {"section": "III. ENTROPY BALANCE EQUATION", "text": "In order to rewrite \u1e60 a A in a physically understandable form, the information for the fluctuating part f a of the distribution function in the turbulent electromagnetic fields is required. We assume that any fluctuating field F oscillates rapidly in the directions perpendicular to the magnetic field lines, with a characteric scale length \u040c \u03f3 a . Then, it is useful to put fluctuating functions in the WKB \u0351or eikonal\u0352 form:", "cite_spans": [], "ref_spans": []}, {"section": "III. ENTROPY BALANCE EQUATION", "text": "where the rapid spatial variation in the perpendicular directions is included through the eikonal \u0350 x\u0408 k \u040c -dx\u0408. The fluctuating part of the distribution function is divided into the adiabatic and nonadiabatic parts as", "cite_spans": [], "ref_spans": []}, {"section": "III. ENTROPY BALANCE EQUATION", "text": "where L a \u0351k \u040c \u0352\u03f5k \u040c -v\u060bn/\u2340 a . The nonadiabatic part of the distribution function satisfies the following nonlinear gyrokinetic equation.", "cite_spans": [], "ref_spans": []}, {"section": "III. ENTROPY BALANCE EQUATION", "text": "where", "cite_spans": [], "ref_spans": []}, {"section": "III. ENTROPY BALANCE EQUATION", "text": "Here the gyrophase-averaged potential for the turbulent electromagnetic fields is defined by", "cite_spans": [], "ref_spans": []}, {"section": "III. ENTROPY BALANCE EQUATION", "text": "Appendix B shows that the entropy change \u1e60 a A given by Eq. \u035124\u0352 is rewritten as", "cite_spans": [], "ref_spans": []}, {"section": "III. ENTROPY BALANCE EQUATION", "text": "Here the anomalous entropy flux J Sa A is given by", "cite_spans": [], "ref_spans": []}, {"section": "III. ENTROPY BALANCE EQUATION", "text": "where u a A \u03f5\u232b a A /n a and q a A are defined by Eqs. \u035134\u0352. The anomalous entropy production a A is written in the thermodynamic form as", "cite_spans": [], "ref_spans": []}, {"section": "III. ENTROPY BALANCE EQUATION", "text": "and the residual term is defined by", "cite_spans": [], "ref_spans": []}, {"section": "III. ENTROPY BALANCE EQUATION", "text": "which vanishes when the magnetic surface average \u0357-\u0358 and the quasisteady state ordering \u202b\u0358-\u0357\u05e5\u202c ens /\u202b\u05e5\u202ct\u03edO \u0351\u2426 2 \u0352 are used. In Eq. \u035131\u0352, we defined conjugated pairs of the thermodynamic forces,", "cite_spans": [], "ref_spans": []}, {"section": "III. ENTROPY BALANCE EQUATION", "text": "and the anomalous fluxes", "cite_spans": [], "ref_spans": []}, {"section": "III. ENTROPY BALANCE EQUATION", "text": "where the guiding center velocity due to the turbulent electromagnetic fields v da \u0351k \u040c \u0352 is defined by", "cite_spans": [], "ref_spans": []}, {"section": "III. ENTROPY BALANCE EQUATION", "text": "Here v E \u0351k \u040c \u0352\u03f5\u03eai(c/B)\u0351k \u040c \u0352k \u040c \u060bn is the electric drift velocity due to the fluctuating electrostatic potential , n \u03f5(i/B)\u00c2 \u0288 \u0351k \u040c \u0352k \u040c \u060bn denotes the perturbation of the magnetic field direction due to \u00c2 \u0288 \u0351\u00c2 \u0288 gives the magnetic field fluctuation in the direction perpendicular to the equilibrium field\u0352, and v a \"B (k \u040c ) \u03f5 \u03eai(c/e a B)B \u0288 (k \u040c )k \u040c \u060bn represents the \"B drift velocity due to the parallel magnetic field fluctuation B \u0288 . The magnitudes of the drift velocities due to the perpendicular and parallel magnetic fluctuations are estimated as v \u0288 n \u03f3v Ta B \u040c /B\u03f3\u2426v Ta and v a \"B \u03f3 k \u040c a v Ta B \u0288 /B \u03f3 k \u040c a \u2426v Ta , and thus the latter is negligible compared to the former in the long-wavelength limit k \u040c a \u04f61. In Eq. \u035135\u0352,", "cite_spans": [], "ref_spans": []}, {"section": "III. ENTROPY BALANCE EQUATION", "text": "give finite gyroradius effects, and they both reduce to the unity in the long-wavelength limit. The radial particle flux J a1 A \u03ed\u232b a A -\"V is conjugate to the force X a1 A consisting of the radial pressure gradient and the radial electric field; J a2 A \u03edq a A -\"V/T a is the radial heat flux divided by the temperature conjugate to the radial temperature gradient X a2 A . The flux J a3 A is conjugate to the force X a3 \u03ed1/T a and represents the heating of the particles due to the electromagnetic fluctuations. It should be noted that \u232b a A is the same as the anomalous particle flux \u232b a anom defined in Eq.", "cite_spans": [], "ref_spans": []}, {"section": "III. ENTROPY BALANCE EQUATION", "text": "\u03513\u0352, while q a A is different from the anolamous flux q a anom defined in Eq. \u03513\u0352. The difference between q a A and q a anom is given by", "cite_spans": [], "ref_spans": []}, {"section": "III. ENTROPY BALANCE EQUATION", "text": "which is regarded as a residual microscopic entropy flux. Using the gyrokinetic equation \u035127\u0352, the anomalous entropy production a A defined in Eq. \u035131\u0352 is rewritten as", "cite_spans": [], "ref_spans": []}, {"section": "III. ENTROPY BALANCE EQUATION", "text": "If we use the quasisteady-state ordering \u202b\u0358-\u0357\u05e5\u202c ens /\u202b\u05e5\u202ct\u03edO \u0351\u2426 2 \u0352 and take the magnetic surface average of Eq. \u035137\u0352, we obtain the balance between the anomalous entropy production driven by the turbulent transport and the collisional dissipation of the fluctuating distribution function:", "cite_spans": [], "ref_spans": []}, {"section": "III. ENTROPY BALANCE EQUATION", "text": "where \u0357\u0357-\u0358\u0358 represents a double average over the magnetic surface and the ensemble. This balance equation is equivalent to Eq. \u035141\u0352 in Ref. 21 , where Krommes and Hu discussed the problem of the ''entropy paradox.'' Equation \u035138\u0352 shows that, if there are no collisions, then the anomalous entropy production from the turbulent transport should vanish. However, Krommes and Hu recognized the critical difference between the limiting behavior of a system with negligibly small collisional dissipation and the behavior in the no collision case, and argued that the dissipation plays an important role, even in the limit of vanishing dissipation. Here, following their argument ''forcing determines dissipation'' \u0353see Eq. \u035143\u0352 in Ref. 22\u0354, we consider that, in the collisionless limit, the turbulent transport and accordingly the anomalous entropy production \u0357 a A \u0358\u03ed\u035a l\u03ed1 3 \u0357J al A \u0358X al A achieve nonzero steady-state values independent of collisions, although the fluctuating distribution f a adjusts itself such that the balance equation \u035138\u0352 holds. From Eq. \u035138\u0352 and the positive definiteness of the collision operator C a L \u0353see Eq. \u035110\u0352 in Ref. 5\u0354 , we obtain the following inequality for the anomalous entropy production similar to those for the classical and neoclassical entropy productions,", "cite_spans": [], "ref_spans": []}, {"section": "III. ENTROPY BALANCE EQUATION", "text": "Up to this point, we have derived the physically understandable expressions of the entropy variations due to the classical, neoclassical, and anomalous transport processes separately from their kinetic definitions. The entropy production rates for all the transport processes or their magnetic surface averages have been shown to be written in the thermodynamic form, i.e., as the sum of the products of the thermodynamic forces and the conjugate transport fluxes. Using Eqs. \u035115\u0352-\u035118\u0352, \u035121\u0352, \u035122\u0352, \u035124\u0352, \u035129\u0352, and \u035130\u0352, we obtain the equation ) given by Eq. \u035136\u0352 is added to the heat flux q a given by Eq. \u03512\u0352 to define the total heat flux q a \u0408 . Definitions of the classical fluxes J a j cl , the Pfirsch-Schl\u00fcter fluxes J a j PS , the bananaplateau fluxes J a j bp , the nonaxisymmetric fluxes J a j na , and the particle flux J a1 (E) due to the inductive electric field are given in Appendix A. We obtain from Eqs. \u035119\u0352 and \u035141\u0352,", "cite_spans": [], "ref_spans": []}, {"section": "IV. ONSAGER SYMMETRY FOR ANOMALOUS TRANSPORT EQUATIONS", "text": "Here we examine whether the Onsager symmetry is valid or not for the anomalous transport matrix, which connects conjugate pairs of the thermodynamic forces and anomalous fluxes defined in the previous section. We treat the spectrum of the turbulent electromagnetic fields as given arbitrarily for the moment \u0351the conditions for the selfconsistent turbulent fields are discussed in the next section\u0352 and consider the anomalous transport matrix as a functional of the fluctuation spectra. It is still difficult to derive the rigorous expression for the response of the distribution function to the fluctuating fields by solving the nonlinear gyrokinetic equation \u035127\u0352, so we neglect the nonlinear term in Eq. \u035127\u0352 and use a linear response relation to give ''quasilinear'' transport fluxes.", "cite_spans": [], "ref_spans": []}, {"section": "IV. ONSAGER SYMMETRY FOR ANOMALOUS TRANSPORT EQUATIONS", "text": "The quasilinear anomalous transport equations are written as", "cite_spans": [], "ref_spans": []}, {"section": "IV. ONSAGER SYMMETRY FOR ANOMALOUS TRANSPORT EQUATIONS", "text": "where the anomalous transport coefficients (L A ) mn ab are defined by Eq. \u0351C4\u0352 in Appendix C. The anomalous transport coefficients (L A ) mn ab are functionals of the spectra of the electromagnetic fluctuations \u0351k \u040c \u0352\u03f5\u0353 \u0351k \u040c \u0352,\u00c2 \u0288 \u0351k \u040c \u0352,B \u0288 \u0351k \u040c \u0352/k \u040c \u0354 and that it also contains B as a parameter:", "cite_spans": [], "ref_spans": []}, {"section": "IV. ONSAGER SYMMETRY FOR ANOMALOUS TRANSPORT EQUATIONS", "text": "where the spectra of the electromagnetic fluctuations \u0355 \u0356 are assumed to be given a priori. It is shown in Appendix C that the quasilinear anomalous transport coefficients satisfy the following Onsager symmetry:", "cite_spans": [], "ref_spans": []}, {"section": "IV. ONSAGER SYMMETRY FOR ANOMALOUS TRANSPORT EQUATIONS", "text": "where T a and T b appear because we defined the conjugate pairs of the forces X and the fluxes J from the entropy production by a \u03edJ a -X a for the anomalous transport, but by \u035a a T a a \u03edJ-X for the classical and neoclassical transport.", "cite_spans": [], "ref_spans": []}, {"section": "IV. ONSAGER SYMMETRY FOR ANOMALOUS TRANSPORT EQUATIONS", "text": "Here it is noted that, as in the neoclassical case, the Onsager symmetry of the quasilinear anomalous transport coefficients is valid for their magnetic-surface-averaged values instead of their spatially local values. The global dependence of the anomalous fluxes arises from the fluctuations with large wavelengths k \u0288 \u03ea1 \u03f3L along the magnetic field lines. In order to obtain detailed expressions of the quasilinear anomalous transport coefficients, we assume that the parallel correlation length for the fluctuations is short enough for inhomogeneities of the equilibrium quantities to be ignorable, k \u0288 \u04f7L \u03ea1 . Then, we use the Fourier transform for spatial variation of the fluctuations along the magnetic field lines so that n-\" is replaced with ik \u0288 , where the parallel wave number k \u0288 is assumed to satisfy L \u03ea1 \u04f6k \u0288 \u04f6k \u040c . Similarly, the Fou-rier transform is used for temporal variation of the fluctuations to replace \u202b\u202at\u202c\u05e5/\u05e5\u202c with \u03eai. Furthermore, for simplicity, we employ the Krook collision operator model C a L (\u0125 a e iL a ) \u03ed \u03ea a h a e iL a where a is the collision frequency and the contribution of \u0125 b (b a) to C a L is neglected. \u0351The validity limits due to the Krook model will be discussed later.\u0352 Then the coefficients connecting the fluxes to the forces for different species vanish, and we have", "cite_spans": [], "ref_spans": []}, {"section": "\u035149\u0352", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Here the quasilinear anomalous transport coefficients (L", "text": "where the function \u232c a \u0351k \u040c ,k \u0288 ,\u0352 is defined by", "cite_spans": [], "ref_spans": []}, {"section": "Here the quasilinear anomalous transport coefficients (L", "text": "which, in the limit a \u2192\u03e90, reduces to \u2426(\u03ea E \u03ea Da \u03eak \u0288 v \u0288 ). We can directly confirm by Eq. \u035150\u0352 the positive definiteness of a A \u03ed \u035a m,n (L A ) mn a X am A X an A and the symmetry properties of (L A ) mn a \u0353B,\u0355 \u0356\u0354 with respect to the transformations \u0353B,\u0355 (t)\u0356\u0354\u2192\u0353\u03eaB,\u0355 \u0351\u03eat\u0352\u0356\u0354 and (m,n)\u2192(n,m):", "cite_spans": [], "ref_spans": []}, {"section": "Here the quasilinear anomalous transport coefficients (L", "text": "We see that, for k \u0288 \u04f7L \u03ea1 , the Onsager symmetry holds for the local values of the quasilinear transport coefficients as in the case of the classical transport coefficients. These expressions of the anomalous transport coefficients with the Onsager symmetry are consistent with results of previous works in Ref. 10 and Ref. 23 , where only the electrostatic fluctuations are considered. \u0353Note that the conjugate pairs of the forces and the anomalous fluxes \u0351and accordingly the transport coefficients\u0352 given in the present work are slightly different from those in Ref. 10 and Ref. 23 , although the transport equations for the former pairs are consistently transformed into those for the latter.\u0354 Now let us examine the effects of the magnetic fluctuations in more detail. Two physically distinct types of magnetic fluctuations \u00c2 \u0288 and B \u0288 are contained in the anomalous transport coefficients through a . The effects of \u00c2 \u0288 , which give the fluctuating magnetic field perpendicular to the equilibrium field line, have been thoroughly investigated in the literatures. 24 -26 On the other hand, the fluctuations of the parallel component B \u0288 , which gives the fluctuating \"B drift velocity v a \"B as shown in Eq. \u035135\u0352, have scarcely been taken into account. This is because B \u0288 /B\u03f3\u2424(e a /T a ) for low \u2424\u0351\u03f58p/B 2 \u0352 plasmas 27 and because the parallel \u0351B \u0288 \u0352 effects are negligible for fluctuations with low wave numbers k \u040c a \u04f61, as is expected from a factor J 1 (k \u040c v \u040c /\u2340 a ) multiplied by B \u0288 in Eq. \u035128\u0352. On the other hand, both the parallel and perpendicular effects are comparable to each other for gyrokinetic fluctuations with k \u040c a \u03f31 and \u2424\u03f31. In order to show these magnetic fluctuation effects on the anomalous transport more clearly, we assume that the temporal variation of the fluctuations is very slow \u03f30 and that the wave number spectral functions are written as", "cite_spans": [], "ref_spans": []}, {"section": "\u035153\u0352", "text": "where \u040c and \u0288 denote perpendicular and parallel correlation lengths, respectively. Here we do not consider the electrostatic fluctuations and the cross correlation ", "cite_spans": [], "ref_spans": []}, {"section": "\u035153\u0352", "text": "Here D B\u040c represents the perpendicular diffusion coefficient of the magnetic field line defined by", "cite_spans": [], "ref_spans": []}, {"section": "\u035153\u0352", "text": "where x(l) denotes the position at a distance l from x along the magnetic field line. In the limit of Ta / \u040c \u2192\u03e90, the results of Eq. \u035154\u0352 reduce to those in Ref. 26 26 confirmed that the guiding center motion in the stochastic magnetic field shows a ballistic behavior for a shorter time scale t\u03fdt min and a subdiffusive behavior for a longer time scale t\u03fet max . Thus, the diffusion coefficient in Eq. \u035154\u0352 obtained by the gyrokinetic equation with the Krook collision model is considered to correctly describe the particle transport only for a time scale t min \u03fdt\u03fdt max . Equation \u035154\u0352 shows that the finite gyroradius effect reduces the diffusivity by a factor \u03511\u03e92 Ta", "cite_spans": [], "ref_spans": []}, {"section": "\u035153\u0352", "text": ", which is in agreement with the result obtained by the stochastic Vlasov equation in Ref. 28 .", "cite_spans": [], "ref_spans": []}, {"section": "\u035153\u0352", "text": "The contribution of the parallel magnetic fluctuations to (L A ) 11 a is given by", "cite_spans": [], "ref_spans": []}, {"section": "\u035153\u0352", "text": "where", "cite_spans": [], "ref_spans": []}, {"section": "\u035153\u0352", "text": ". \u035157\u0352", "cite_spans": [], "ref_spans": []}, {"section": "\u035153\u0352", "text": "The anomalous diffusion described by Eqs. \u035156\u0352 and \u035157\u0352 results from the fluctuating magnetic drift v a \"B and accordingly the resultant quasilinear diffusion coefficient (L B\u0288 ) 11 a is proportional to the velocity correlation \u0357v a \"B v a \"B \u0358 ens and therefore to \u0357B \u0288 B \u0288 \u0358 ens . We see that (L B\u0288 ) 11 a vanishes in the both limits of Ta / \u040c \u2192\u03e90 and \u03e9\u03f1, while it has a maximum value at Ta / \u040c \u03ed1. Equation \u035156\u0352 shows that (L B\u0288 ) 11 a monotonically increases with decreasing the collision frequency a , even for a \u04f6v Ta / \u0288 , which is a contrast to (L B\u040c ) 11 a independent of a for the same collision frequency region. However, it should be recalled that a time scale for validity of Eq. \u035156\u0352, obtained by using the Krook model also has an upper limit, since the velocity-space diffusion, which is described not by the Krook model but by the Fokker-Planck collision operator, deforms the propagator and causes the subdiffusion in a longer time scale.", "cite_spans": [], "ref_spans": []}, {"section": "26", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "V. ENERGY BALANCE EQUATION", "text": "For transport analyses of toroidal plasmas, particle and energy balance equations are used generally in the magneticsurface-averaged forms. The fluctuation term in the ensemble-averaged kinetic equation \u03515\u0352 conserves the particle number and gives neither source nor sink terms in the continuity equation derived by taking the zeroth moment of the kinetic equation. Then, the magnetic-surface-averaged continuity equation has a well-known form:", "cite_spans": [], "ref_spans": []}, {"section": "V. ENERGY BALANCE EQUATION", "text": "where it should be noted that anomalous particle flux is also included in the total particle flux \u0357\u232b a -\"V\u0358 as given by Eq.", "cite_spans": [], "ref_spans": []}, {"section": "\u035144\u0352.", "text": "The energy balance equation is similarly derived from the kinetic equation and it is written in the magnetic-surfaceaveraged form as ", "cite_spans": [], "ref_spans": []}, {"section": "\u035144\u0352.", "text": "where u a and q a \u0408 are written as Eq. \u035144\u0352. On the right-hand side of Eq. \u035162\u0352, the parallel flow \u0357Bu\u0288 a \u0358 and the parallel viscosity \u0357B-\"-a \u0358 can be written in terms of the thermodynamic forces in the similar way as the other classical and neoclassical transport fluxes. From the species summation of the momentum balance equations multiplied by the flow velocities, we have the following relation:", "cite_spans": [], "ref_spans": []}, {"section": "\u035144\u0352.", "text": "shows that the species summation of the heating terms on the right-hand side of Eq. \u035162\u0352, except for the anomalous heating \u0357J a3 A \u0358, originates from the Ohmic power input due to the inductive electric field. \u0353The term (J a1 (E) /n a )(\u202b\u05e5\u202cp a /\u202b\u05e5\u202cV) on the right-hand side of Eq. \u035162\u0352 does not appear in Eq. \u035163\u0352 since its species summation cancels out with the residual Ohmic heating terms \u0357J \u040c -E \u040c (A) \u0358 and", "cite_spans": [], "ref_spans": []}, {"section": "\u035144\u0352.", "text": "Shaing et al. 29 presented energy balance equations for toroidal plasmas, including nonaxisymmetric systems from the neoclassical theory, although they did not give a clear theoretical foundation to treat the energy balance in the cases where the anomalous transport exists. Equation \u035162\u0352, which was rigorously derived based on the gyrokinetic ordering from the kinetic equation taking account of the electromagnetic turbulence, shows completely how the fluctuations affect the energy balance. The anomalous particle flow u a A \u03f5 u a anom and the anomalous heat flux q a A \u03ed q a anom \u03e9 (q a A \u03ea q a anom ) are naturally included in the radial derivative term of the total energy flux. We also find that the product of the anomalous radial current and the radial electric field change between different species of particles although they give no net heating of total particles. The summation of these two terms is written as", "cite_spans": [], "ref_spans": []}, {"section": "\u035164\u0352", "text": "The radial electric field \u03ea\u202b\u05e5\u202c\u233d/\u202b\u05e5\u202cV enters the nonlinear gyrokinetic equation \u035127\u0352 and Eq. \u035164\u0352 only in the form of the Doppler shift (\u202b\u05e5/\u05e5\u202ct\u03e9i E ), and does not appear explicitly in the self-consistent conditions given in the next section \u0353see Eqs. \u035166\u0352-\u035168\u0352\u0354. Thus, for the solutions of Eqs. \u035127\u0352 and \u035166\u0352-\u035168\u0352, e i E t \u0125 a (k \u040c ) and e i E t a (k \u040c ) are independent of the radial electric field. Then, the radial electric field does not affect the magnitude of the anomalous heating effect given by Eq. \u035164\u0352", "cite_spans": [], "ref_spans": []}, {"section": "\u035164\u0352", "text": "The entropy balance equation \u035140\u0352 can be derived also from substituting the continuity equation \u035158\u0352 and the energy balance equation into the temporal variation of the entropy,", "cite_spans": [], "ref_spans": []}, {"section": "\u035164\u0352", "text": "although the correspondence between the kinetic and thermodynamic forms of the entropy productions due to the classical, neoclassical, and anomalous transport processes is better understood by the derivation in Sec. III.", "cite_spans": [], "ref_spans": []}, {"section": "VI. SELF-CONSISTENT ELECTROMAGNETIC FLUCTUATIONS AND AMBIPOLARITY CONDITION", "text": "Up to this point, the turbulent fluctuations have been general prescribed fields. When the fluctuations are local, self-consistent fields not driven by external sources, there are additional properties of the transport that we now derive.", "cite_spans": [], "ref_spans": []}, {"section": "VI. SELF-CONSISTENT ELECTROMAGNETIC FLUCTUATIONS AND AMBIPOLARITY CONDITION", "text": "Here we impose the self-consistent constraints on the turbulent fields, which are given by Poisson's equation:", "cite_spans": [], "ref_spans": []}, {"section": "\u035166\u0352", "text": "and the parallel and perpendicular components of Amp\u00e8re's law:", "cite_spans": [], "ref_spans": []}, {"section": "\u035168\u0352", "text": "where the Debye length D \u03f5(4\u035a a n a e a 2 /T a ) \u03ea1/2 is used. The use of the Amp\u00e8re's law is justified since the displacement current is neglected due to the gyrokinetic ordering.", "cite_spans": [], "ref_spans": []}, {"section": "\u035168\u0352", "text": "Substituting Eqs. \u035166\u0352-\u035168\u0352 into the definition of the anomalous fluxes, we find that the anomalous particle fluxes are intrinsically ambipolar:", "cite_spans": [], "ref_spans": []}, {"section": "\u035168\u0352", "text": "It is proved from the momentum conservation by collisions \u035a a F a1 \u03ed0 and the charge neutrality condition \u035a a n a e a \u03ed0 that, even if particles of different species belong to different collisional regimes, the ambipolarity condition is automatically and separately satisfied by the classical (J a1 cl ), PfirschSchl\u00fcter (J a1 PS ), and banana-plateau (J a1 bp ) parts of multispecies particle fluxes, which is called the principle of detailed ambipolar balance. 2, 30, 31 Then, only the nonaxisymmetric particle fluxes J a1 na are nonambipolar and the nonintrinsic ambipolarity condition is written as", "cite_spans": [], "ref_spans": []}, {"section": "\u035168\u0352", "text": "which is used to determine the radial electric field \u03ea\u202b\u05e5\u202c\u233d/\u202b\u05e5\u202cV in the nonaxisymmetric systems. Equations \u035166\u0352-\u035168\u0352 and Eq. \u035134\u0352 with the quasisteadystate ordering \u202b\u0358-\u0357\u05e5\u202c ens /\u202b\u05e5\u202ct\u03edO \u0351\u2426 2 \u0352 show that the species summation of the anomalous heating J a3", "cite_spans": [], "ref_spans": []}, {"section": "\u035168\u0352", "text": "A vanishes:", "cite_spans": [], "ref_spans": []}, {"section": "\u035168\u0352", "text": "The self-consistent fluctuations cause no net heating of the total particles, since the source of the anomalous heating is the energy of the fluctuating electromagnetic fields, which cannot be a stationary energy supplier unless the fluctuations are externally driven.", "cite_spans": [], "ref_spans": []}, {"section": "\u035168\u0352", "text": "Furthermore, we find from Eqs. \u035126\u0352, \u035136\u0352, and the Amp\u00e8re's law that the species summation of (q \u0351v\u03eau a \u0352 and takes account of the heat flux due to the particles only.\u0354", "cite_spans": [], "ref_spans": []}, {"section": "VII. CONCLUSIONS AND DISCUSSION", "text": "In this work, we have investigated the entropy production mechanisms due to all transport processes in the magnetically confined toroidal plasmas with the gyrokinetic electromagnetic turbulence. The kinetic equation double averaged over the turbulent fluctuations and the gyrophase was derived up to O \u0351\u2426 2 \u0352. The kinetic equation is employed as the foundation on which the entropy productions by the classical, neoclassical, and anomalous transport processes are kinetically defined. The recursive technique was used to derive the double-averaged kinetic equation, from which the entropy balance equation \u035140\u0352 was obtained. We showed the correspondence between the kinetic and thermodynamic forms of the entropy productions and identified the conjugated pairs of the forces and fluxes for all the transport processes. For the fluctuating part of the kinetic distribution function, we used the nonlinear gyrokinetic equation \u035127\u0352 derived by the recursive technique instead of the noncanonical Hamiltonian formalism [32] [33] [34] since the latter is for the total distribution function and is not clearly given for the case with collisions. The collisions are not only the cause of the classical and neoclassical entropy productions but also in essence required for the balance between the anomalous entropy production and the microscopic dissipation in the stationary state as shown in Eq. \u035138\u0352. It would be interesting to monitor the spatiotemporal variation of the anomalous entropy production given by Eq. \u035131\u0352 in the gyrokinetic simulations and examine the validity of the minimum entropy production for the turbulent stationary states.", "cite_spans": [], "ref_spans": []}, {"section": "VII. CONCLUSIONS AND DISCUSSION", "text": "It was shown that the anomalous transport equations satisfy the Onsager symmetry within the quasilinear framework. For the gyrokinetic electromagnetic fluctuations with parallel wave numbers k \u0288 \u03f3L \u03ea1 , the magnetic surface average must be taken in order to show the positive definiteness of the anomalous entropy production \u0353see Eq. \u035139\u0352\u0354 and the Onsager symmetry of the quasilinear anomalous transport coefficients \u0353see Eq. \u035148\u0352\u0354. This need for the surface average implies that microscopic phenomena \u0351or individual realizations in the ensemble\u0352 occurring over the distance of O (L) along the magnetic field lines should be coarse grained, not only by the ensemble average but also by the magnetic surface average to be viewed as an irreversible macroscopic \u0351or thermodynamic\u0352 process.", "cite_spans": [], "ref_spans": []}, {"section": "VII. CONCLUSIONS AND DISCUSSION", "text": "In the strong turbulence regime defined by short lifetimes of the fluctuation components, the proof of the Onsager symmetry for the anomalous transport matrix breaks down due to the nonresonant nature of the fluctuationparticle interactions. Krommes and Hu 35 claim that, instead of the conventional Onsager symmetry for transport equations near thermal equilibria, the generalized Onsager symmetry is valid for transport near the turbulent steady states. The generalized Onsager symmetry is relevant to the incremental transport equations that connect the small deviations of the forces and fluxes from their steady-state values, although the anomalous transport equations considered here and in many other works relate the total anomalous fluxes at the steady state to the total forces. The transport equations for the total anomalous fluxes are generally nonlinear with respect to the forces, even for the quasilinear case, and it is beyond the scope of this work to obtain them for the strong turbulence.", "cite_spans": [], "ref_spans": []}, {"section": "VII. CONCLUSIONS AND DISCUSSION", "text": "Using the Krook collision model, we derived for k \u0288 L\u04f61 the locally symmetric quasilinear transport matrix as a functional of the gyrokinetic electromagnetic turbulence spectra. As for the magnetic fluctuations, the contribution of the perpendicular magnetic field fluctuations to the anomalous transport decreases monotonically with increasing the ratio of the thermal gyroradius to the characteristic perpendicular fluctuation length / \u040c . In contrast, the parallel magnetic fluctuations' contribution, which has not been considered in previous works, becomes negligible at the both limits / \u040c \u2192\u03e90,\u03e9\u03f1, and comparable to the perpendicular contribution at / \u040c \u03edO \u03511\u0352. At low plasma beta, the parallel magnetic fluctuations' effect is small since B \u0288 /B\u03f3\u2424(e a /T a ).", "cite_spans": [], "ref_spans": []}, {"section": "VII. CONCLUSIONS AND DISCUSSION", "text": "The complete energy balance equation \u035162\u0352 derived from the ensemble-averaged kinetic equation \u03515\u0352 shows how the turbulence effects should be included. The anomalous heat flux q a A occurring in the entropy and energy balance equations contains the contribution of the residual microscopic entropy flux given by Eq. \u035136\u0352. Besides the anomalous particle and heat fluxes included in the radial derivative term of the total energy flux, the energy balance is modified by the turbulence through the product of the anomalous radial current and the radial electric field \u03eae a \u0357J a1 A \u0358\u202b\u05e5\u202c\u233d/\u202b\u05e5\u202cV and the anomalous heating \u0357J a3 A \u0358. These anomalous terms can cause a large energy exchange between electrons and ions. 29 The self-consistent turbulent electromagnetic fields satisfy Poisson's equation \u035166\u0352 and Amp\u00e8re's law given by Eqs. \u035167\u0352 and \u035168\u0352, from which the intrinsic ambipolarity of the anomalous particle fluxes is derived. Then, as in the conventional neoclassical theory, the radial electric field is determined by the ambipolarity condition for the neoclassical nonaxisymmetric particle fluxes, although it is not for the axisymmetric system in which all the particle fluxes are intrinsically ambipolar. We also find for the self-consistent fluctuations that the species summation of the anomalous heating vanishes and that the residual anomalous heat fluxes sum up to the Poynting energy flux of the turbulent electromagnetic fields.", "cite_spans": [], "ref_spans": []}, {"section": "VII. CONCLUSIONS AND DISCUSSION", "text": "In some operational regions of tokamak plasmas such as high-confinement modes \u0351H modes\u0352 36 and reversed shear configurations, 37 there have been observed transport barriers with significant reduction of anomalous transport to the level of neoclassical transport. Generally, large radial electric field shear \u0351or sheared E\u060bB flow\u0352 is considered as a cause of such a reduction of the transport level. In the present work as well as in the conventional neoclassical theory, the E\u060bB flow velocities have been assumed to be O (\u2426v T ) \u0351v T : the ion thermal velocity, \u2426\u03ed/L\u0352. However, this assumption is not suitable to describing the effects of the large radial electric field shear since the radial electric field is undetermined for tokamak plasmas due to the intrinsic ambipolarity of particle fluxes in axisymmetric systems. In the H-mode theory by Shaing et al., 38 the drift kinetic equation with large flows but without fluctuations are used to obtain the neoclassical viscosities and accordingly the ambipolarity condition as the constraint on the radial electric field, which is different from that given in the present work. Such pure neoclassical models as by Shaing et al. do not treat interactions between the E\u060bB background flows and the fluctuations through the Reynolds stress, 39, 40 but they are considered as another important factor of transition processes occurring in the transport barriers for a self-consistent description of the radial electric field, fluctuations, and transport. As an important task for understanding the transport barrier physics, extension of our theory to that including the large radial electric field and the Reynolds stress is now under investigation.", "cite_spans": [], "ref_spans": []}, {"section": "ACKNOWLEDGMENTS", "text": "This work is supported in part by the Grant-in-Aid from the Japanese Ministry of Education, Science, and Culture, and in part by U.S. Department of Energy Grant No. DB-FG05-80ET-53088.", "cite_spans": [], "ref_spans": []}, {"section": "APPENDIX A: DEFINITIONS OF CLASSICAL AND NEOCLASSICAL TRANSPORT FLUXES", "text": "The radial components of the classical particle and heat fluxes are defined by", "cite_spans": [], "ref_spans": []}, {"section": "APPENDIX A: DEFINITIONS OF CLASSICAL AND NEOCLASSICAL TRANSPORT FLUXES", "text": "respectively, where the friction forces F a1 and F a2 are given by", "cite_spans": [], "ref_spans": []}, {"section": "APPENDIX A: DEFINITIONS OF CLASSICAL AND NEOCLASSICAL TRANSPORT FLUXES", "text": "The fluxes J a1 cl and J a2 cl are conjugate to the thermodynamic forces X a1 and X a2 , respectively, which are defined in terms of radial gradients of the pressure, electrostatic potential, and temperature as", "cite_spans": [], "ref_spans": []}, {"section": "APPENDIX A: DEFINITIONS OF CLASSICAL AND NEOCLASSICAL TRANSPORT FLUXES", "text": "The neoclassical particle and heat fluxes are given by", "cite_spans": [], "ref_spans": []}, {"section": "APPENDIX A: DEFINITIONS OF CLASSICAL AND NEOCLASSICAL TRANSPORT FLUXES", "text": "Here the Pfirsch-Schl\u00fcter (J a j PS ), the banana-plateau (J a j bp ), and nonaxisymmetric (J a j na ) parts are defined by", "cite_spans": [], "ref_spans": []}, {"section": "APPENDIX A: DEFINITIONS OF CLASSICAL AND NEOCLASSICAL TRANSPORT FLUXES", "text": "where the viscosities a and \u2330 a are defined by", "cite_spans": [], "ref_spans": []}, {"section": "APPENDIX A: DEFINITIONS OF CLASSICAL AND NEOCLASSICAL TRANSPORT FLUXES", "text": "The inductive electric field E (A) \u03f5\u03eac \u03ea1 \u202b\u05e5\u202cA/\u202b\u05e5\u202ct also produces the radial particle flux J a1", "cite_spans": [], "ref_spans": []}, {"section": "\u0351A7\u0352", "text": "Here we have used the Hamada coordinates \u0351V,,\u0352 with the normalization \u035bd\u03ed\u035bd\u03ed1 to define the contravariant and covariant components of the magnetic field B \u03f5B-\", B \u03f5B-\", B \u03f5B-\u202b\u05e5\u202cx/\u202b,\u05e5\u202c B \u03f5B-\u202b\u05e5\u202cx/\u202b,\u05e5\u202c and the toroidal magnetic field B t \u03f5B \u202b.\u05e5/\u202ax\u202c\u05e5\u202c Another pair of the flux and the force is (J E ,X E ), where J E is defined in terms of the total parallel current J \u0288 \u03f5 \u035a a n a e a u \u0288 a as and the velocity space variables \u0351\u2440\u03f5 1 2 m a v 2 \u03e9e a \u233d, \u03f5m a v \u040c 2 /2B, \u03f5v-n/\u0349v-n\u0349\u0352. We also note that \u011c abm depends on equilibrium parameters contained in Eq. \u0351C2\u0352 such as the equilibrium \u0351or ensemble-averaged\u0352 magnetic field B\u03edBn, and that they are functionals of the spectra of the electromagnetic fluctuations \u0351k \u040c \u0352\u03f5\u0353 \u0351k \u040c \u0352, \u00c2 \u0288 \u0351k \u040c \u0352, B \u0288 \u0351k \u040c \u0352/k \u040c \u0354:", "cite_spans": [], "ref_spans": []}, {"section": "\u0351A7\u0352", "text": "\u011c abm \u03ed\u011c abm \u0353k \u040c ,x\u0408,t;\u2440,,;B,\u0355 \u0356\u0354.", "cite_spans": [], "ref_spans": []}, {"section": "\u0351C5\u0352", "text": "Then, Eq. \u0351C4\u0352 shows that the anomalous transport coefficients (L A ) mn ab are also functionals of the fluctuation spectra and that it also contains B as a parameter:", "cite_spans": [], "ref_spans": []}, {"section": "\u0351C5\u0352", "text": "where the spectra of the electromagnetic fluctuations \u0355 \u0356 are assumed to be given a priori. Now let us divide the fluctuations into even and odd parts with respect to the time reversal: which is the same as given by Eq. \u035148\u0352. When the parallel correlation length for the fluctuations is much shorter than the equilibrium scale length, we can use the Fourier transform for spatial variation of the fluctuations along the magnetic field lines and a procedure similar to the above shows that, in this case, the Onsager symmetry is valid for the local quasilinear anomalous transport coefficients \u0351without taking the magnetic-surface-average\u0352, ", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF2": {"title": "Transport Processes in Plasmas \u03512 volumes\u0352 \u0351North-Holland", "authors": [{"first": "R", "middle": [], "last": "Balescu", "suffix": ""}], "year": 1988, "venue": "", "link": null}, "BIBREF18": {"title": "Plasma Phys. 15", "authors": [{"first": "R", "middle": ["D"], "last": "Hazeltine", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF19": {"title": "Plasma Confinement \u0351Addison-Wesley", "authors": [{"first": "R", "middle": ["D"], "last": "Hazeltine", "suffix": ""}, {"first": "J", "middle": ["D"], "last": "Meiss", "suffix": ""}], "year": 1992, "venue": "", "link": null}, "BIBREF21": {"title": "Methods in Nonlinear Plasma Theory \u0351Academic", "authors": [{"first": "R", "middle": ["C"], "last": "Davidson", "suffix": ""}], "year": 1972, "venue": "", "link": null}}, "ref_entries": {"FIGREF0": {"text": "ens for simplicity. Then the contri- bution of the perpendicular magnetic fluctuations to the par", "type": "figure"}, "TABREF0": {"text": "as turbulent or stochastic variables. It is shown in Ref. 22 that the averaged kinetic equation for the one-body distribution function f (1)\u03f5 f \u0351x 1 ,v 1 ,t\u0352 with the col- lision term and the collective interaction term similar to Eq. \u03515\u0352 also follows from an appropriate truncation of the Bogoliubov-Born-Green-Kirkwood-Yvon \u0351BBGKY\u0352 hier- archy describing a turbulent plasma. In the second equation in the BBGKY hierarchy, the particle discreteness source term", "type": "table"}, "TABREF1": {"text": "describing the temporal variation of the magnetic surface average of the entropy density \u0357S a \u0358 forsince \u0357Bu\u0288 a \u0358 and \u0357BF\u0288 a1 \u0358\u03ed\u0357B-\"-a \u0358\u03ean a e a \u0357BE\u0288\u0358, as well as", "type": "table"}, "TABREF2": {"text": "\u0356. By using both the Langevin equation and the Fokker-Planck equation, Balescu et al.", "type": "table"}, "TABREF3": {"text": "due to the fluctuations. The viscous heating term \u0357u a -\"-a \u0358 in Eq. \u035159\u0352 can be written in various forms: \u0357u a -\"-a \u0358\u03ed", "type": "table"}, "TABREF5": {"text": "\u0357\u0351\u00ca \u060bB \u0352-\"V\u0358 ens .", "type": "table"}, "TABREF6": {"text": "\u0352\u03ed\u03ea \u03ea \u0351\u03eat\u0352.According to this division, \u0174 am and \u011c abm are divided as \u0174 am \u03ed\u0174 am \u0353\u0355 \u03e9 \u0356\u0354\u03e9\u0174 am \u0353\u0355 \u03ea \u0356\u0354\u03f5\u0176 am \u03e9\u1e90 am , \u0351C8\u0352 \u011c abm \u03ed\u011c abm \u0353\u0355 \u03e9 \u0356\u0354\u03e9\u011c abm \u0353\u0355 \u03ea \u0356\u0354\u03f5\u0124 abm \u03e9\u00ce abm . The functions on the right-hand side of Eq. \u0351C8\u0352 satisfy \u0176 am \u0353\u0355 \u0351t\u0352\u0356\u0354\u03ed\u0176 am \u0353\u0355 \u0351\u03eat\u0352\u0356\u0354, Z am \u0353\u0355 \u0351t\u0352\u0356\u0354\u03ed\u03ea\u1e90 am \u0353\u0355 \u0351\u03eat\u0352\u0356\u0354, \u0351C9\u0352 \u0124 abm \u0353\u0355 \u0351t\u0352\u0356\u0354\u03ed\u0124 abm \u0353\u0355 \u0351\u03eat\u0352\u0356\u0354, \u00ce abm \u0353\u0355 \u0351t\u0352\u0356\u0354\u03ed\u03ea\u00ce abm \u0353\u0355 \u0351\u03eat\u0352\u0356\u0354. Then, Eq. \u0351C2\u0352 also separates into the two parts:\u202b\u05e5\u202c \u202b\u05e5\u202ct \u03e9i\u0351 E \u03e9 Da \u0352\u03e9v \u0288 n-\"\u0408 \u036c \u0124 abm\u03ed\u2426 ab f bM \u0176 bm , \u0351C10\u0352\u202b\u05e5\u202c \u202b\u05e5\u202ct \u03e9i\u0351 E \u03e9 Da \u0352\u03e9v \u0288 n-\"\u0408 \u036c \u00ce abm\u03ed\u2426 ab f bM \u1e90 bm . Next, we consider the transformation \u0351t,B\u0352\u2192\u0351\u03eat,\u03eaB\u0352. Noting that \u0176 am and \u1e90 am are odd and even with respect to this transformation, respectively: \u0176 am \u0351t,B\u0352\u03ed\u03ea\u0176 am \u0351\u03eat,\u03eaB\u0352, \u0351C11\u0352 \u1e90 am \u0351t,B\u0352\u03ed\u1e90 am \u0351\u03eat,\u03eaB\u0352, we find that Eqs. \u0351C10\u0352 are separated into even and odd parts as\u202b\u05e5\u202c \u202b\u05e5\u202ct \u03e9i\u0351 E \u03e9 Da \u0352\u03e9v \u0288 n-\"\u0408 \u036a \u0124 abm\u03e9i\u0351 E \u03e9 Da \u0352\u03e9v \u0288 n-\"\u0408 \u036a \u0124 abm\u03ed\u2426 ab f bM \u0176 bm , \u0351C12\u0352\u202b\u05e5\u202c \u202b\u05e5\u202ct \u03e9i\u0351 E \u03e9 Da \u0352\u03e9v \u0288 n-\"\u0408 \u036c I abme iL a\u0408 \u0354\u03ed\u2426 ab f bM \u1e90 bm ,\u202b\u05e5\u202c \u202b\u05e5\u202ct \u03e9i\u0351 E \u03e9 Da \u0352\u03e9v \u0288 n-\"\u0408 \u036c \u00ce abmwhere the superscripts \u03e9 and \u03ea represent even and odd parts of the functions:From Eqs. \u0351C12\u0352 and the self-adjointness of the linear- ized collision operator C ab L , we can derive the following equations: T a M mn ab \u03f5T a \u0373 \u0375 d\u0357\u0351\u0176 am \u03e9\u1e90 am \u0352\u0351\u0124 abn \u03ea *\u03e9\u00ce abn \u03e9 *\u0352 \u0358 ens\u0374\u0355\u0357\u0351\u0124 a \u0408 am \u03e9 * \u03e9\u00ce a \u0408 am \u03ea * \u0352e \u03eaiL a\u0408 C a \u0408 b \u0408\u0353\u0351\u0124 a \u0408 bn \u03e9 \u03e9\u00ce a \u0408 bn \u03ea \u0352e iL a\u0408 ,\u0351\u0124 b \u0408 bn \u03e9 \u03e9\u00ce b \u0408 bn \u03ea \u0352e iL b\u0408 \u0354\u0358 ens \u03e9\u0357\u0351\u0124 a \u0408 bn \u03ea * \u03e9\u00ce a \u0408 bn \u03e9 * \u0352e \u03eaiL a\u0408 C a \u0408 b \u0408\u0353\u0351\u0124 a \u0408 am \u03ea \u03e9\u00ce a \u0408 am \u03e9 \u0352e iL a\u0408 ,\u0351\u0124 b \u0408 am \u03ea \u03e9\u00ce b \u0408 am \u03e9 \u0352e iL b\u0408 \u0354\u0358 ens \u0356 \u0374\u0357\u0351\u0176 am \u03e9\u1e90 am \u0352\u0351\u0124 abn \u03e9 *\u03e9\u00ce abn \u03ea *\u0352 \u0358 ens\u0374\u036b \u0373 \u0351 \u0124 a \u0408 bn \u03e9 * \u03e9\u00ce a \u0408 bn \u03ea * \u0352\u202b\u05e5\u202c \u202b\u05e5\u202ct \u03e9i\u0351 E \u03e9 Da \u0352\u03e9v \u0288 n-\"\u0408 \u036aens \u03ea \u0373 \u0351 \u0124 a \u0408 am \u03ea * \u03e9\u00ce a \u0408 am \u03e9 * \u0352 \u0369 \u202b\u05e5\u202c \u202b\u05e5\u202ct \u03e9i\u0351 E \u03e9 Da \u0352\u03e9v \u0288 n-\"\u0408 \u036a \u0351 \u0124 a \u0408 bn \u03ea \u03e9\u00ce a \u0408 bn \u03e9 \u0352 \u0374 ens \u0374 . Using the self-adjointness of C ab L again, we find T a M mn ab \u03edT b M nm ba , T a N mn ab \u03ed\u03eaT b N nm ba . \u0351C15\u0352 From the symmetry properties given by Eqs. \u0351C9\u0352, \u0351C11\u0352, and \u0351C13\u0352, it is shown thatFinally, using Eqs. \u0351C15\u0352 and \u0351C16\u0352, and noting that \u0357(L A ) mn ab \u0358\u03f5M mn ab \u03e9N mn ab , we obtain the Onsager symmetry of the quasilinear anomalous transport matrix, T a \u0357\u0351L A \u0352 mn ab \u0353B,\u0355 \u0351t\u0352\u0356\u0354\u0358\u03edT b \u0357\u0351L A \u0352 nm ba \u0353\u03eaB,\u0355 \u0351\u03eat\u0352\u0356\u0354\u0358, \u0351C17\u0352", "type": "table"}, "TABREF7": {"text": "L A \u0352 mn ab \u0353B,\u0355 \u0351t\u0352\u0356\u0354\u03edT b \u0351L A \u0352 nm ba \u0353\u03eaB,\u0355 \u0351\u03eat\u0352\u0356\u0354. \u0351C18\u0352 Furthermore, if we use the simple Krook collision model C a L (\u0125 a e iL a ) \u03ed \u03ea a \u0125 a e iL a , we find that the quasilinear trans- port coefficients (L A ) mn ab \u03ed\u2426 ab (L A ) mn a are given by Eqs. \u035150\u0352 and that their antisymmetric parts that correspond to N mn ab vanish.", "type": "table"}}}
{"paper_id": "119423496", "_pdf_hash": "7e1006fcd82d741dc757c04544355e981a4efc53", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "119423515", "_pdf_hash": "134e9c18323af9a29abb51880955ce8cd644a40f", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "The influence of curvature on heat transfer to incompressible Fluids", "authors": [{"first": "F", "middle": [], "last": "Kreith", "suffix": ""}], "year": 1995, "venue": "Journal of Fiuids Engineering", "link": null}, "BIBREF1": {"title": "Effect of streamwise wall curvature heat Transfer in a Turbulent Boundary Layer", "authors": [{"first": "H", "middle": [], "last": "Thomann", "suffix": ""}], "year": 1968, "venue": "Journal of Fluid Mechanics", "link": "122714480"}, "BIBREF2": {"title": "Turbulent Boundary Layer heat Transfer on curved Surfaces", "authors": [{"first": "Blairransfer", "middle": [], "last": "Mayle", "suffix": ""}], "year": 1979, "venue": "Journal of Hear Transfer", "link": "121863115"}, "BIBREF3": {"title": "The Calculation of Turbulent Boundary bayers on Spinning and Curved Surfaces", "authors": [{"first": "B", "middle": ["E"], "last": "Launder", "suffix": ""}, {"first": "C", "middle": ["H"], "last": "Pridden", "suffix": ""}, {"first": "B", "middle": ["I"], "last": "Sharma", "suffix": ""}], "year": 1977, "venue": "J.Fluid Eng", "link": null}, "BIBREF4": {"title": "Computational Hydrodynamics Theory And Application", "authors": [{"first": "W", "middle": ["L"], "last": "Wei", "suffix": ""}], "year": 2001, "venue": "", "link": null}, "BIBREF5": {"title": "Turnulence of open channel flow over smooth and rough beds", "authors": [{"first": "N", "middle": [], "last": "Rajaratnam", "suffix": ""}, {"first": "B", "middle": [], "last": "Nwachukwu", "suffix": ""}], "year": 1975, "venue": "Proc.JSCE", "link": null}}, "ref_entries": {}}
{"paper_id": "119423823", "_pdf_hash": "778d8f203dce870bc9a6e3e926562db7a8fc1b9d", "abstract": [{"section": "Abstract", "text": "For the Many-Body-Localized phase of random Majorana models, a general Strong Disorder RealSpace Renormalization procedure known as RSRG-X [D. Pekker, G. Refael, E. Altman, E. Demler and V. Oganesyan, Phys. Rev. X 4, 011052 (2014)] is described to produce the whole set of excited states, via the iterative construction of the Local Integrals of Motion (LIOMs). The RG rules are then explicitly derived for arbitrary quadratic Hamiltonians (free-fermions models) and for the Kitaev chain with local interactions involving even numbers of consecutive Majorana fermions. The emphasis is put on the advantages of the Majorana language over the usual quantum spin language to formulate unified RSRG-X rules.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "INTRODUCTION", "text": "Strong Disorder Renormalization procedures introduced for ground-states of random quantum models by MaDasgupta-Hu [1, 2] and Daniel Fisher [3] [4] [5] (see the review [6] and references therein) are usually formulated in terms of quantum spins. Although one can indeed argue that the language of quantum spins S = 1/2 or q-bits is the most natural framework for quantum models or quantum information, another appealing point of view is that it is much more advantageous to use instead the language of Majorana fermions in order to reveal the true underlying structure of the model, that could be otherwise somewhat hidden in the spin formulation (see for instance the two recent works [7, 8] where the Majorana language is instrumental to classify possible phases).", "cite_spans": [], "ref_spans": []}, {"section": "INTRODUCTION", "text": "In the present paper, the goal is thus to formulate Strong Disorder Renormalization rules for generic random Majorana models. Besides the construction of the ground-state mentioned above, the Strong Disorder Renormalization approach has been recently extended to construct the whole set of excited eigenstates via the RSRG-X procedure [9] [10] [11] [12] [13] [14] , or to obtain the effective dynamics via the RSRG-t procedure [15, 16] . These two closely related procedures [17] actually identify iteratively the Local Integrals of Motion called LIOMs [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] that are known to characterize the Many-Body-Localized phase existing in some isolated random quantum interacting models (see the many recent reviews [38] [39] [40] [41] [42] [43] [44] [45] [46] and references therein).", "cite_spans": [], "ref_spans": []}, {"section": "INTRODUCTION", "text": "The paper is organized as follows. In section II, the notations for general random Majorana Models with parityinteractions are introduced. In section III, the general RSRG-X procedure is described with the simplest example of the random Kitaev chain. In section IV, the RSRG-X rules are given for arbitrary quadratic Hamiltonians (freefermions). In section V, the RSRG-X rules are derived for the random Majorana chain with local interactions involving only consecutive Majorana operators. The conclusions are summarized in section VI. The Appendix A contains a short reminder of the dictionary between Majorana fermions, Dirac fermions and quantum spin chains.", "cite_spans": [], "ref_spans": []}, {"section": "II. NOTATIONS FOR RANDOM MAJORANA MODELS WITH PARITY-INTERACTIONS", "text": "A.", "cite_spans": [], "ref_spans": []}, {"section": "Majorana operators", "text": "In the present paper, we wish to study models defined in terms of 2N Majorana operators \u03b3 j with j = 1, .., 2N (see Appendix A for the dictionary between Majorana fermions, Dirac fermions and quantum spin chains.). These Majorana operators are hermitian", "cite_spans": [], "ref_spans": []}, {"section": "Majorana operators", "text": "square to unity", "cite_spans": [], "ref_spans": []}, {"section": "Majorana operators", "text": "and anti-commute with each other", "cite_spans": [], "ref_spans": []}, {"section": "Majorana operators", "text": "So the first advantage of the Majorana formulation over Dirac fermions or quantum spins is clearly the symmetric role played by the 2N Majorana operators instead of the creation and annihilation operators for the Dirac fermions, or the three Pauli matrices for quantum spins (see Appendix A). One thus expects that the Majorana language is more appropriate to formulate unified renormalization rules.", "cite_spans": [], "ref_spans": []}, {"section": "B. Parity operators", "text": "It is convenient to associate to any even number (2k) with k = 1, 2, ..N of Majorana operators labelled by 1 \u2264 j 1 < j 2 < .. < j 2k \u2264 2N the parity operator", "cite_spans": [], "ref_spans": []}, {"section": "B. Parity operators", "text": "For k = 1 and k = 2, they represent the usual interactions between two and four Majorana operators respectively", "cite_spans": [], "ref_spans": []}, {"section": "B. Parity operators", "text": "while for k = N , the only possibility is j q = q leads to the standard total parity of the whole system", "cite_spans": [], "ref_spans": []}, {"section": "B. Parity operators", "text": "The parity operators of Eq. 4 are hermitian", "cite_spans": [], "ref_spans": []}, {"section": "B. Parity operators", "text": "square to unity", "cite_spans": [], "ref_spans": []}, {"section": "B. Parity operators", "text": "and they commute or anti-commute", "cite_spans": [], "ref_spans": []}, {"section": "B. Parity operators", "text": "l1,l2,..,l2q = (\u22121) pc P l1,l2,..,l2q P j1,j2,..,j 2k", "cite_spans": [], "ref_spans": []}, {"section": "B. Parity operators", "text": "depending on the parity (\u22121) pc of the number p c of common Majorana operators between the two sets {j 1 , , , , j 2k } and {l 1 , , , , l 2q }.", "cite_spans": [], "ref_spans": []}, {"section": "C.", "text": "General Hamiltonian commuting with the total parity", "cite_spans": [], "ref_spans": []}, {"section": "C.", "text": "The most general hermitian Hamiltonian commuting with the total parity P tot of Eq. 6 can be expanded into all the parity operators of Eq. 4", "cite_spans": [], "ref_spans": []}, {"section": "C.", "text": "are the real couplings defining the model. For instance, H (2) corresponds to the most general quadratic Hamiltonian", "cite_spans": [], "ref_spans": []}, {"section": "C.", "text": "while H (4) contains all the possible four-Majorana-interactions", "cite_spans": [], "ref_spans": []}, {"section": "C.", "text": "Before specializing to specific models, it is useful to define first a general RSRG-X procedure for the generic Hamiltonian of Eq. 10, as described in the following section.", "cite_spans": [], "ref_spans": []}, {"section": "III. GENERAL RSRG-X PROCEDURE FOR RANDOM MAJORANA MODELS", "text": "In this section, we consider the generic Majorana Hamiltonian of Eq. 10 with random coupling constants K (2k) j1....j 2k , and we describe the RSRG-X procedure based on the decimation of the strongest two-Majorana-coupling.", "cite_spans": [], "ref_spans": []}, {"section": "A.", "text": "Strongest two-Majorana-coupling", "cite_spans": [], "ref_spans": []}, {"section": "A.", "text": "Let us choose the biggest two-Majorana-coupling in absolute value |K (2) nm | with 1 \u2264 n < n \u2264 2N", "cite_spans": [], "ref_spans": []}, {"section": "A.", "text": "The corresponding elementary two-Majorana Hamiltonian involves only the parity P", "cite_spans": [], "ref_spans": []}, {"section": "A.", "text": "so the two eigenvalues labelled by \u01eb = \u00b11", "cite_spans": [], "ref_spans": []}, {"section": "A.", "text": "are associated to the two orthogonal projectors", "cite_spans": [], "ref_spans": []}, {"section": "B. Perturbation theory in the other couplings", "text": "The projection of the full Hamiltonian on the two energy branches labelled by \u01eb = \u00b11 (Eqs 15) reads at second-order perturbation theory in all the other couplings", "cite_spans": [], "ref_spans": []}, {"section": "B. Perturbation theory in the other couplings", "text": "To evaluate how the Hamiltonian H behaves between two equal \u01eb = \u01eb \u2032 or opposite \u01eb = \u2212\u01eb \u2032 projectors of Eq. 16, it is useful to decompose H into the four terms", "cite_spans": [], "ref_spans": []}, {"section": "B. Perturbation theory in the other couplings", "text": "where the H ", "cite_spans": [], "ref_spans": []}, {"section": "B. Perturbation theory in the other couplings", "text": "Between two orthogonal projectors, only the anticommuting part survives and yields", "cite_spans": [], "ref_spans": []}, {"section": "B. Perturbation theory in the other couplings", "text": "so that the the numerator of Eq. 17 becomes", "cite_spans": [], "ref_spans": []}, {"section": "B. Perturbation theory in the other couplings", "text": "nm and H", "cite_spans": [], "ref_spans": []}, {"section": "10", "text": "nm contain an odd number of the other Majorana operators (\u03b3 j ) with j = (n, m), one obtains that the square of Eq. 20 reads", "cite_spans": [], "ref_spans": []}, {"section": "10", "text": "so that its projection reads", "cite_spans": [], "ref_spans": []}, {"section": "10", "text": "Putting everything together, one obtains that the effective Hamitonian of Eq 17 for the remaining Majorana operators reads", "cite_spans": [], "ref_spans": []}, {"section": "10", "text": "(2) nm (26) in terms of the decomposition of Eq. 18. To see how this procedure works in practice, let us now describe the simplest possible case.", "cite_spans": [], "ref_spans": []}, {"section": "C.", "text": "Simplest application : the random Kitaev chain", "cite_spans": [], "ref_spans": []}, {"section": "C.", "text": "As recalled in Appendix A, the Kitaev chain [47] with random nearest-neighbor-two-Majorana couplings K", "cite_spans": [], "ref_spans": []}, {"section": "C.", "text": "j,j+1 \u03b3 j \u03b3 j+1 (27) corresponds to the Random Transverse Field Ising Chain (RTFIC) of Eq. A7. Since the RTFIC is one of the basic model where the Strong Disorder RG approach has been developed [4] , it is useful to mention how the RSRG-X procedure described above works for the random Kitaev chain of Eq. 27. One chooses the biggest coupling in absolute value (Eq. 13)", "cite_spans": [], "ref_spans": []}, {"section": "C.", "text": "and one computes the corresponding decomposition of Eq. 18 (29) in order to obtain the effective Hamiltonian via Eq. 26", "cite_spans": [], "ref_spans": []}, {"section": "C.", "text": "So besides the first term H 00 nm representing the part of the chain that is left unchanged by the decimation of the pair (\u03b3 n , \u03b3 n+1 ) and the second term proportional to \u01eb representing the direct energy contribution of the decimation, the third term means that the Majorana operators \u03b3 n\u22121 and \u03b3 n+2 that become nearest-neighbor after the decimation are now coupled by the renormalized coupling (31) that is independent of the energy branch \u01eb = \u00b11 chosen for the decimation. This independence is of course not surprising, since it is a direct consequence of the notion of 'free fermions', but it is nevertheless important to stress here the difference with the RSRG-X rules formulated in the spin language, where the choice \u01eb = \u00b11 of the energy branch explicitly appear in the renormalization of the couplings [9] .", "cite_spans": [], "ref_spans": []}, {"section": "C.", "text": "In the remainder of the paper, we analyze two different generalizations of this random Kitaev chain. We first describe how the RSRG-X procedure works for arbitrary quadratic Hamiltonians in section IV. We then consider the random Kitaev chain in the presence of local interactions involving even numbers of consecutive Majorana fermions in section V.", "cite_spans": [], "ref_spans": []}, {"section": "IV. APPLICATION TO ARBITRARY QUADRATIC HAMILTONIANS", "text": "In this section, the RSRG-X procedure described in the previous section is applied to any random quadratic Hamiltonians (free-fermions).", "cite_spans": [], "ref_spans": []}, {"section": "IV. APPLICATION TO ARBITRARY QUADRATIC HAMILTONIANS", "text": "A.", "cite_spans": [], "ref_spans": []}, {"section": "IV. APPLICATION TO ARBITRARY QUADRATIC HAMILTONIANS", "text": "Decomposition of Eq. 18", "cite_spans": [], "ref_spans": []}, {"section": "IV. APPLICATION TO ARBITRARY QUADRATIC HAMILTONIANS", "text": "When the Hamiltonian contains only pair-interaction between Majorana operators (only k = 1 in Eq. 10)", "cite_spans": [], "ref_spans": []}, {"section": "IV. APPLICATION TO ARBITRARY QUADRATIC HAMILTONIANS", "text": "the decomposition of Eq. 18 with respect to the pair (\u03b3 n \u03b3 m ) reads", "cite_spans": [], "ref_spans": []}, {"section": "IV. APPLICATION TO ARBITRARY QUADRATIC HAMILTONIANS", "text": "where we have introduced the notation for j 2 > j 1 ", "cite_spans": [], "ref_spans": []}, {"section": "IV. APPLICATION TO ARBITRARY QUADRATIC HAMILTONIANS", "text": "while their commutator is quadratic", "cite_spans": [], "ref_spans": []}, {"section": "IV. APPLICATION TO ARBITRARY QUADRATIC HAMILTONIANS", "text": "B.", "cite_spans": [], "ref_spans": []}, {"section": "RSRG-X rules", "text": "Putting everything together, Eq 26 becomes", "cite_spans": [], "ref_spans": []}, {"section": "RSRG-X rules", "text": "j1j2 \u03b3 j1 \u03b3 j2 (37) with the renormalized couplings between the remaining Majorana operators", "cite_spans": [], "ref_spans": []}, {"section": "RSRG-X rules", "text": "These RSRG-X rules are thus closed for any quadratic Hamiltonian, and represent a direct generalization of the rule discussed above for the Kitaev chain in Eq. 31. Again, the choice of the energy branch \u01eb = \u00b11 appears only in the constant energy contribution of the decimation (second term of Eq. 37) but not in the renormalized couplings of Eq. 38 as a consequence of the notion of 'free-fermions'.", "cite_spans": [], "ref_spans": []}, {"section": "V. APPLICATION TO THE MAJORANA CHAIN WITH CONSECUTIVE-PARITY-INTERACTIONS", "text": "After the free-fermion models considered in the previous section, let us now focus on the random Majorana chain with local interactions.", "cite_spans": [], "ref_spans": []}, {"section": "A. Majorana chain with consecutive-parity-interactions", "text": "In this section, we focus on the case where the parity operators appearing in the Hamiltonian (Eq. 10) are only those involving strings of (2k) consecutive operators (instead of the general case of Eq. 4), so that it is convenient to introduce the simplified notation", "cite_spans": [], "ref_spans": []}, {"section": "A. Majorana chain with consecutive-parity-interactions", "text": "The Hamiltonian of Eq. 10 is thus replaced by", "cite_spans": [], "ref_spans": []}, {"section": "A. Majorana chain with consecutive-parity-interactions", "text": "In particular, H (2) corresponds to the random Kitaev chain of Eq. 27", "cite_spans": [], "ref_spans": []}, {"section": "A. Majorana chain with consecutive-parity-interactions", "text": "while H (4) contains only four-Majorana-interactions between four consecutive operators", "cite_spans": [], "ref_spans": []}, {"section": "A. Majorana chain with consecutive-parity-interactions", "text": "The translation of this model in the quantum spin language is given in Eqs A7 A9 A10 of Appendix A.", "cite_spans": [], "ref_spans": []}, {"section": "B. Renormalized consecutive parities", "text": "After the elimination of the two Majorana operators (\u03b3 n , \u03b3 n+1 ) corresponding to the biggest coupling in absolute value (Eq. 13)", "cite_spans": [], "ref_spans": []}, {"section": "B. Renormalized consecutive parities", "text": "the operators \u03b3 n\u22121 and \u03b3 n+2 have become neighbors. One then needs to introduce the renormalized consecutiveparity-operators across the decimated pair like the one already encountered in Eq. 30 for the Kitaev chain", "cite_spans": [], "ref_spans": []}, {"section": "B. Renormalized consecutive parities", "text": "Here we will need more generally the other renormalized consecutive parities", "cite_spans": [], "ref_spans": []}, {"section": "B. Renormalized consecutive parities", "text": "for j \u2264 n \u2212 1 and j + 2k \u2212 1 \u2265 n + 2", "cite_spans": [], "ref_spans": []}, {"section": "C. Decomposition of Eq. 18", "text": "In the decomposition of Eq. 18 ", "cite_spans": [], "ref_spans": []}, {"section": "C. Decomposition of Eq. 18", "text": "while H 11 n,n+1 reads in terms of the renormalized consecutive-parity-operators of Eq. 45", "cite_spans": [], "ref_spans": []}, {"section": "C. Decomposition of Eq. 18", "text": "H 01 n,n+1 can be obtained from all the parity operators beginning exactly at j = n + 1, and it is thus convenient to factor out the common operator \u03b3 n+2 to rewrite", "cite_spans": [], "ref_spans": []}, {"section": "C. Decomposition of Eq. 18", "text": "Similarly, H 10 n,n+1 can be obtained from all the parity operators ending exactly at j + 2k \u2212 1 = n, and one can factor out the common operator \u03b3 n\u22121 to rewrite", "cite_spans": [], "ref_spans": []}, {"section": "C. Decomposition of Eq. 18", "text": "Then their squares simplify into", "cite_spans": [], "ref_spans": []}, {"section": "C. Decomposition of Eq. 18", "text": "and", "cite_spans": [], "ref_spans": []}, {"section": "C. Decomposition of Eq. 18", "text": "while their commutator reads in terms of the renormalized consecutive-parity-operators of Eq. 45", "cite_spans": [], "ref_spans": []}, {"section": "D. Renormalized Hamiltonian", "text": "Putting everything together, Eq 26 yields", "cite_spans": [], "ref_spans": []}, {"section": "2K", "text": "(2) n,n+1", "cite_spans": [], "ref_spans": []}, {"section": "2K", "text": "To clarify the meaning of the various terms, it is useful to distinguish four types of contributions", "cite_spans": [], "ref_spans": []}, {"section": "2K", "text": "The first term is simply the constant contribution produced directly by the decimation that depends on the energy", "cite_spans": [], "ref_spans": []}, {"section": "2K", "text": "The second term contains the parity-operators localized on the left [1, ..., n \u2212 1] of the decimated pair", "cite_spans": [], "ref_spans": []}, {"section": "2K", "text": "The third term contains the parity-operators localized on the right [n + 2, ..., 2N ] of the decimated pair", "cite_spans": [], "ref_spans": []}, {"section": "2K", "text": "Finally the fourth term contains the renormalized parity-operators of Eq. 45 that begin before the decimated pair and that end after the decimated pair", "cite_spans": [], "ref_spans": []}, {"section": "2K", "text": "E.", "cite_spans": [], "ref_spans": []}, {"section": "RSRG-X rules", "text": "The RSRG-X rules for the couplings between the surviving Majorana operators can be thus summarized as follows.", "cite_spans": [], "ref_spans": []}, {"section": "RSRG-X rules", "text": "(i) The coupling associated to the parity operator P", "cite_spans": [], "ref_spans": []}, {"section": "RSRG-X rules", "text": "[l+1\u22122k,l] living on the left of the decimated pair l \u2264 n \u2212 1 (Eq. 57) follows the RG rule", "cite_spans": [], "ref_spans": []}, {"section": "RSRG-X rules", "text": "Besides its initial value K [l+1\u22122k,n] of order 2k + n \u2212 l \u2265 2k + 2 and depend on the choice \u01eb = \u00b1 of the energy branch.", "cite_spans": [], "ref_spans": []}, {"section": "RSRG-X rules", "text": "(ii) The coupling associated to the parity operator P (2k)", "cite_spans": [], "ref_spans": []}, {"section": "RSRG-X rules", "text": "[j,j+2k\u22121] living on the right of the decimated pair j \u2265 n + 2 (Eq. 58) follows the RG rule", "cite_spans": [], "ref_spans": []}, {"section": "RSRG-X rules", "text": "Here again, besides its initial value K [n+1,j+2k\u22121] of order 2k + j \u2212 n \u2212 1 \u2265 2k + 2 and depend on the choice \u01eb = \u00b1 of the energy branch.", "cite_spans": [], "ref_spans": []}, {"section": "RSRG-X rules", "text": "(iii) The renormalized parity operator P R(2k)", "cite_spans": [], "ref_spans": []}, {"section": "RSRG-X rules", "text": "[j,j+2k+1] that begins before the decimated pair j \u2264 n \u2212 1 and that ends after the decimated pair n + 2 \u2264 j + 1 + 2k (Eq 59) is associated to the new renormalized couplings", "cite_spans": [], "ref_spans": []}, {"section": "RSRG-X rules", "text": "The first terms corresponds again to the 'degradation' of the higher-order coupling K (2k+2) [j,j+2k+1] and depends on the choice \u01eb = \u00b1 of the energy branch. The second term is the generalization of the basic rule of Eq. 31 concerning the Kitaev chain and does not depend on the choice \u01eb = \u00b1 of the energy branch. In the present procedure, this second term is the only mechanism where new higher order couplings can be generated from two couplings of smaller orders 2k 1 = n + 1 \u2212 j and 2k 2 = 2k + j + 1 \u2212 n = 2k + 2 \u2212 2k 1 .", "cite_spans": [], "ref_spans": []}, {"section": "RSRG-X rules", "text": "In conclusion, the Majorana chain with consecutive parity-interactions of Eq. 40 remains closed for the RSRG-X procedure with the renormalized rules described above. To see more clearly how it works in practice, it is now useful to consider the following simplest example. ", "cite_spans": [], "ref_spans": []}, {"section": "RSRG-X rules", "text": "The RSRG-X rules for the first decimation of the biggest coupling K representing the 'degradation' of the four-Majorana-couplings K (4) [n\u22122,n+1] and K (4) [n\u22123,n] into contributions of couplings of order 2k = 2 that were already existing.", "cite_spans": [], "ref_spans": []}, {"section": "RSRG-X rules", "text": "(ii) The RG rule of Eq. 61 for the right of the decimated pair gives new contributions only for", "cite_spans": [], "ref_spans": []}, {"section": "RSRG-X rules", "text": "[n+2,n+3] + \u01ebK ", "cite_spans": [], "ref_spans": []}, {"section": "RSRG-X rules", "text": "representing also the 'degradation' of the four-Majorana-couplings K", "cite_spans": [], "ref_spans": []}, {"section": "RSRG-X rules", "text": "[n,n+3] and K", "cite_spans": [], "ref_spans": []}, {"section": "RSRG-X rules", "text": "[n+1,n+4] into contributions of couplings of order 2k = 2 that were already existing.", "cite_spans": [], "ref_spans": []}, {"section": "RSRG-X rules", "text": "(iii) The RG rule of Eq. 62 for the renormalized parities across the decimated pair gives new couplings of various orders. The only renormalized coupling of order 2k = 2 is ", "cite_spans": [], "ref_spans": []}, {"section": "RSRG-X rules", "text": "Finally, there is one new renormalized coupling of order 2k = 6", "cite_spans": [], "ref_spans": []}, {"section": "RSRG-X rules", "text": "where the first term involves k consecutive Pauli matrices \u03c3 z , while the second term involves only two Pauli matrices \u03c3 x separated by the distance k. As a final remark, let us mention that the Jordan Wigner transformation of Eq. A5 is of course specific to one dimension, but for certain bidimensional quantum spin models, other relations have been introduced between quantum spins and Majorana fermions [50] [51] [52] .", "cite_spans": [], "ref_spans": []}], "bib_entries": {}, "ref_entries": {"FIGREF0": {"text": "the other Majorana fermions (\u03b3 j ) with j = (n, m). In particular, H 00 nm and H 11 nm contain an even number of these other Majorana operators, while H 10 nm and H 01 nm contain an odd number of these other Majorana operators. As a consequence, the part H comm nm of H that commutes with the parity Pidentical projectors \u01eb = \u01eb \u2032 , only the commuting part survives and gives the contribution", "type": "figure"}, "FIGREF2": {"text": "n+1 contains all the terms of the Hamiltonian included in [1, .., n \u2212 1] or included in [n + 2, .., 2N ]", "type": "figure"}, "FIGREF3": {"text": "2k,l] , the new contributions comes from the 'degradation' of the higher-order couplings K", "type": "figure"}, "FIGREF4": {"text": ", the new contributions comes from the 'degradation' of the higher-", "type": "figure"}, "FIGREF5": {"text": "step for the initial chain involving only two and four Majorana interactions Let us consider the case where the initial Hamiltonian of Eq. 40 contains only interactions between two and four consecutive Majorana operators (Eqs 41 and 42)", "type": "figure"}, "FIGREF6": {"text": "in absolute value are the following. (i) The RG rule of Eq. 60 for the left of the decimated pair gives new contributions", "type": "figure"}, "FIGREF9": {"text": "n+2] and the renormalized contribution already seen for the Kitaev chain (Eq. 31). The only renormalized couplings of order 2k =", "type": "figure"}}}
{"paper_id": "119424823", "_pdf_hash": "3817ddab8e2411f03ad5e813fd4095637fccf866", "abstract": [{"section": "Abstract", "text": "Abstract. We outline the most important results regarding the stability of doubly heavy tetraquarks QQqq with an adequate treatment of the four-body dynamics. We consider both color-mixing and spin-dependent effects. Our results are straightforwardly applied to the case of all-heavy tetraquarks QQQQ. We conclude that the stability is favored in the limit MQ/mq \u226b 1 pointing to the stability of the bb\u016bd state and the instability of all-heavy tetraquarks.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Despite the impression given by the recent flurry of studies dealing with multiquark states, flavorexotic multiquarks have already a long history [1] and have motivated an abundant literature (see Ref.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "[2] for a recent compendium). In the pioneering work of Ader, Richard and Taxil [1] it was shown that QQqq four-quark configurations become more and more bound when the mass ratio M Q /m q increases. The critical value of M Q /m q for binding is somewhat model dependent.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Currently, a broad theoretical consensus about the existence of a stable axial vector doubly bottom tetraquark has been reached. Lattice QCD calculations find unambiguous signals for a stable J P = 1 + bottom-light tetraquark [3] . Based on a diquark hypothesis, Ref.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "[4] uses the discovery of the \u039e ++ cc baryon to calibrate the binding energy in a QQ diquark. Assuming that the same relation is true for the bb binding energy in a tetraquark, it concludes that the axial vector bb\u016bd state is stable. The Heavy-Quark Symmetry analysis of Ref.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "[5] predicts the existence of narrow doubly heavy tetraquarks. Using as input for the doubly bottom baryons, not yet experimentally measured, the diquark-model calculations of Ref.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "[4] also leads to a bound axial vector bb\u016bd tetraquark. Other approaches, using Wilson twisted mass lattice QCD [6], also find a bound state. Few-body calculations using quark-quark Cornell-like interactions [7] , simple color magnetic models [8] , QCD sum rule analysis [9] , or phenomenological studies [10] come to similar conclusions. More doubtful has become the prediction about the stability of all-heavy tetraquarks [11] .", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "In the present note, we stress that a careful treatment of the few-body problem is required before drawing any conclusion about the existence of stable states in a particular model. There is, indeed, a dramatic spread of strategies: some authors use the full machinery of a variational method based on correlated Gaussians or hyperspherical expansion, and others use a crude trial wave function or a cluster approximation.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Despite the impression given by the recent flurry of studies dealing with multiquark states, flavorexotic multiquarks have already a long history [1] and have motivated an abundant literature (see Ref. [2] for a recent compendium). In the pioneering work of Ader, Richard and Taxil [1] it was shown that QQqq four-quark configurations become more and more bound when the mass ratio M Q /m q increases. The critical value of M Q /m q for binding is somewhat model dependent.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "Currently, a broad theoretical consensus about the existence of a stable axial vector doubly bottom tetraquark has been reached. Lattice QCD calculations find unambiguous signals for a stable J P = 1 + bottom-light tetraquark [3] . Based on a diquark hypothesis, Ref. [4] uses the discovery of the \u039e ++ cc baryon to calibrate the binding energy in a QQ diquark. Assuming that the same relation is true for the bb binding energy in a tetraquark, it concludes that the axial vector bb\u016bd state is stable. The Heavy-Quark Symmetry analysis of Ref. [5] predicts the existence of narrow doubly heavy tetraquarks. Using as input for the doubly bottom baryons, not yet experimentally measured, the diquark-model calculations of Ref. [4] also leads to a bound axial vector bb\u016bd tetraquark. Other approaches, using Wilson twisted mass lattice QCD [6] , also find a bound state. Few-body calculations using quark-quark Cornell-like interactions [7] , simple color magnetic models [8] , QCD sum rule analysis [9] , or phenomenological studies [10] come to similar conclusions. More doubtful has become the prediction about the stability of all-heavy tetraquarks [11] .", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "In the present note, we stress that a careful treatment of the few-body problem is required before drawing any conclusion about the existence of stable states in a particular model. There is, indeed, a dramatic spread of strategies: some authors use the full machinery of a variational method based on correlated Gaussians or hyperspherical expansion, and others use a crude trial wave function or a cluster approximation.", "cite_spans": [], "ref_spans": []}, {"section": "General results based on symmetry breaking", "text": "The analogy between the stability of few-charge systems and multiquarks in additive chromoelectric potentials offers a good guidance for identifying the favorable configurations. There are, however, some differences mainly due to the color algebra replacing the simpler algebra of electric charges. Unlike in the case of the positronium molecule, the equal-mass tetraquarks are unstable in the chromoelectric model with frozen color wave functions [12, 13] . In both the atom and quark cases, the four-body system and its threshold, after simple rescaling, are governed by a generic Hamiltonian", "cite_spans": [], "ref_spans": []}, {"section": "General results based on symmetry breaking", "text": "with v(r) = \u22121/r in the atomic case, and v(r) = \u2212a/r + b r in the quark case [14] . In quantum mechanics, the minimum of a Hamiltonian containing a symmetric and an antisymmetric term is always lower than the minimum of the symmetric part. From this result, one can analyze the effect of symmetry breaking in systems of four-charged particles. Let us first consider the hydrogen molecule, M + M + m \u2212 m \u2212 . The Hamiltonian for this system reads,", "cite_spans": [], "ref_spans": []}, {"section": "General results based on symmetry breaking", "text": "where 2 \u00b5 \u22121 = M \u22121 + m \u22121 . The C-parity breaking term, H 1 , lowers the ground state energy of H with respect to the C-parity even part, H 0 , which is simply a rescaled version of the Hamiltonian of the positronium molecule. Since H 0 and H have the same threshold, and since the positronium molecule is stable, the hydrogen molecule is even more stable, and stability improves when M/m increases. Clearly, the Coulomb character of V hardly matters in this reasoning. The key property is that the potential does not change when the masses are modified. One can use the same reasoning to study the stability of four-charged particles when C-parity is preserved but particle symmetry is broken, in other words the", "cite_spans": [], "ref_spans": []}, {"section": "General results based on symmetry breaking", "text": "The Hamiltonian is that of Eq. (2) by exchanging 2 \u2194 3. The same arguments used above lead to the conclusion that this configuration gains binding with respect to the threshold (M + m \u2212 ) + (M \u2212 m + ) that it shares with H 0 . However, there is another threshold that lies lower, (M + M \u2212 ) + (m + m \u2212 ). This threshold gains more from the symmetry breaking than the four-body molecule, and, indeed, it is found that the molecule becomes unstable for M/m \u2265 2.2.", "cite_spans": [], "ref_spans": []}, {"section": "General results based on symmetry breaking", "text": "The above arguments can be directly translated to four-quark systems: the QQqq configuration becomes more and more bound when the mass ratio M Q /m q increases. This has been first established in Ref. [1] , and discussed and confirmed in further studies. Arguments based on diquarks, as e.g. [4] , might considerably overestimate the binding, as analyzed in [2] . There are many variants of the so-called diquark model. An extreme point of view is that diquarks are almost-elementary objects, with their specific interaction with quarks and between them. In the case of doubly heavy baryons QQq there is obviously a QQ clustering which makes it tempting to use a two-step approach: first a (QQ) diquark and then a (QQ)q quasi-meson, as the diquark has the same color3 as an antiquark. The exercise can be repeated for the QQqq states. For simplicity, we consider only the case of a frozen33 color wave function, i.e., the Hamiltonian (1). In Fig. 2 , we compare the exact solution of (1) with the approximation consisting of first computing the QQ diquark with r 12 /2 alone and qq with r 34 alone, and then (QQ)(qq) as a meson with a potential r 12,34 and constituent masses 2 M and 2 m.", "cite_spans": [], "ref_spans": [{"start": 942, "end": 948, "text": "Fig. 2", "ref_id": "FIGREF1"}]}, {"section": "General results based on symmetry breaking", "text": "A remaining problem is to understand why the positronium molecule lies slightly below its dissociation threshold, while a chromoelectric model associated with the color additive rule does not bind (at least according to most computations). This is due to a larger disorder in the color coefficients than in the electrostatic strength factors entering the Coulomb potential [13] . An alternative proof is based on the so-called Hall-Post inequalities [15, 16] . The principle is rather simple. If a Hamiltonian is decomposed as a sum of Hamiltonians,", "cite_spans": [], "ref_spans": []}, {"section": "General results based on symmetry breaking", "text": "then for the lowest energy,", "cite_spans": [], "ref_spans": []}, {"section": "General results based on symmetry breaking", "text": "With a33 color wave function and a quark mass set to M = 1/2 for simplicity, the Hamiltonian of the all-heavy tetraquark QQQQ can be written as [13] ,", "cite_spans": [], "ref_spans": []}, {"section": "General results based on symmetry breaking", "text": "where V ij = v(r ij ) is the quarkonium potential. Now, we can rewrite this expression as,", "cite_spans": [], "ref_spans": []}, {"section": "General results based on symmetry breaking", "text": "where h ij = p 2 i + p 2 j + V ij is the quarkonium Hamiltonian. By using Eq.( 4) one gets,", "cite_spans": [], "ref_spans": []}, {"section": "General results based on symmetry breaking", "text": "that demonstrates the instability of all-heavy tetraquarks. The above reasoning on the ground state holds for a single color channel. It is observed in explicit computations than the mixing of color states does no help much [7, 17] . The lower bound (7) can even be significantly improved if one relates Hamiltonians that are free of center-of-mass motion [2] .", "cite_spans": [], "ref_spans": []}, {"section": "Color dynamics.", "text": "In the heavy-quark limit, the lowest lying tetraquark configuration resembles the helium atom [5] , a factorized system with separate dynamics for the compact color3 QQ nucleus and for the light quarks bound to the stationary color 3 state, to construct a QQqq color singlet. This argument has been mathematically proved and numerically checked time ago [18] , see the probabilities for the axial vector bb\u016bd tetraquark shown in Table II (note that the 66 probability in a compact QQqq tetraquark tends to zero for M Q \u2192 \u221e). The\u03bb i .\u03bb j model of Eq. (1), with a pairwise potential due to color-octet exchange, induces mixing between33 and 66 states in the QQ \u2212qq basis. If one starts from a33 state with QQ in a spin triplet, and, for instanceqq =\u016bd with spin and isospin S = I = 0, then its orbital wave function is mainly made of an s-wave in all coordinates. It can mix with a color 66 with orbital excitations in the x and y linking QQ andqq, respectively. A minimal wave function in this sector can be chosen as:", "cite_spans": [], "ref_spans": []}, {"section": "Color dynamics.", "text": "To illustrate the role of color-mixing we use the potential AL1 [19] . Its central part is a Coulombplus-linear potential. Its spin-spin part is a regularized Breit-Fermi interaction, with a smearing parameter that depends on the reduced mass.", "cite_spans": [], "ref_spans": []}, {"section": "Color dynamics.", "text": "The energy as a function of M/m without and with color-mixing is shown in the left panel of Fig. 2 . The ground state of the QQ\u016bd, candidate for stability with J P = 1 + , has its main component with color33, and spin {1, 0} in the QQ \u2212\u016bd basis. The main admixture consists of 66 with spin {1, 0} and an antisymmetric orbital wave function of which (8) is a prototype, and of 66 with spin {0, 1} with a symmetric orbital wave function. Note how the diquark hypothesis and color mixing have opposite effects that tend to cancel in the charm sector.", "cite_spans": [], "ref_spans": [{"start": 92, "end": 98, "text": "Fig. 2", "ref_id": "FIGREF1"}]}, {"section": "Spin-dependent corrections", "text": "In Ref. [20] it was acknowledged that, within current models, a pure additive interaction such as (1) will not bind ccqq, on the sole basis that this tetraquark configuration benefits from the strong cc chromoelectric attraction that is absent in the Qq + Qq threshold. When qq = ud, there is in addition a favorable chromomagnetic interaction in the tetraquark, while the threshold experiences only heavy-light spin-spin interaction, whose strength is suppressed by a factor m/M .", "cite_spans": [], "ref_spans": []}, {"section": "Spin-dependent corrections", "text": "For illustration, we use the again the potential AL1 [19] . The results are shown in the right panel of Fig. 2 for QQ\u016bd, as a function of the mass ratio M/m. The system bb\u016bd is barely bound without the spin-spin term, though the mass ratio m b /m q is very large. It acquires its binding energy of the order of 150 MeV when the spin-spin is restored. The system cc\u016bd is clearly unbound when the spin-spin interaction is switched off. This is shown here for the AL1 model, but this is true for any realistic interaction, including an early model by Bhaduri et al. [21] . The case of cc\u016bd is actually remarkable. Here the binding requires both the color mixing of33 with 66, and the spin-spin interaction. Moreover, the binding is so tiny that it cannot be obtained with a simple variational method. One needs either a fully converged expansion on a basis of correlated Gaussians, or a hyperspherical expansion up to a grand orbital momentum K max of the order of 12. Semay and Silvestre-Brac [19] , who used the AL1 potential, missed the binding, but their method of systematic expansion on the eigenstates of an harmonic oscillator is not very efficient to account for the short-range correlations. Janc and Rosina [22] were the first to obtain binding with such potentials, and their calculation was checked in Ref. [7] . The stability of cc\u016bd with J P = 1 + is with respect to the nominal DD * threshold. Depending on its binding energy, it decays into DD\u03c0 or DD\u03b3. The bb analog decays weakly.", "cite_spans": [], "ref_spans": [{"start": 104, "end": 110, "text": "Fig. 2", "ref_id": "FIGREF1"}]}, {"section": "Conclusions", "text": "The four-body problem of tetraquarks is rather delicate, especially for systems at the edge of stability. The analogy with atomic physics is a good guidance to indicate the most favorable configurations. However, unlike the positronium molecule, the all-heavy configuration QQQQ is not stable if one adopts a standard quark model and solve the four-body problem correctly. The mixing of the33 and 66 color configurations is important, especially for states very near the threshold. This mixing occurs by both the spin-independent and the spin-dependent parts of the potential.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "Approximations are welcome, especially if they shed some light on the four-body dynamics. The diquark-antidiquark approximation is not supported by a rigorous solution of the 4-body problem, but benefits of a stroke of luck, as the erroneous extra attraction introduced in the color33 channel is somewhat compensated by the neglect of the coupling to the color 66 channel.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "Finally, cc\u016bd with J P = 1 + is at the edge of binding within current quark models. For this state, all contributions should be added, in particular the mixing of states with different color structure, and the four-body problem should be solved with extreme accuracy. In comparison, achieving the binding of bb\u016bd looks easier. Still, with a typical quark model, the stability of the ground state cannot be reached if spin-effects and color mixing are both neglected.", "cite_spans": [], "ref_spans": []}], "bib_entries": {}, "ref_entries": {"FIGREF0": {"text": "Figure 1. Comparison of the variational upper bound (light grey solid curve) and Hall-Post lower bound (dotted dark curve) for the tetraquark Hamiltonian (1) with a potential \u2212r \u22121 ij . Also shown is the naive diquark-antidiquark approximation (dashed faint curve). The faint solid line at \u2212E 4 /E 2 = \u22122 stands for the threshold. Figures are colored online.", "type": "figure"}, "FIGREF1": {"text": "Figure 2. Left panel: Effect of color-mixing on the binding of QQ\u016bd. The tetraquark energy calculated with only the color33 configurations (dark curve) and with the 66 components (light grey curve). Right panel: Effect of the spin-spin interaction of the binding of QQ\u016bd. The tetraquark energy calculated with (light grey line) and without (dark line) the chromomagnetic term. The faint dotted solid lines stand for the threshold. Figures are colored online.", "type": "figure"}}}
{"paper_id": "119425264", "_pdf_hash": "9911851f12683fce885803eb05ff0adc9756a89f", "abstract": [{"section": "Abstract", "text": "In general, Whitham dynamics involves infinitely many parameters called Whitham times, but in the context of N = 2 supersymmetric Yang-Mills theory it can be regarded as a finite system by restricting the number of Whitham times appropriately.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "For example, in the case of SU(r + 1) gauge theory without hypermultiplets, there are r Whitham times and they play an essential role in the theory. In this situation, the generating meromorphic 1-form of the Whitham hierarchy on Seiberg-Witten curve is represented by a finite linear combination of meromorphic 1-forms associated with these Whitham times, but it turns out that there are various differential relations among these differentials. Since these relations can be written only in terms of the Seiberg-Witten 1-form, their consistency conditions are found to give the Picard-Fuchs equations for the Seiberg-Witten periods.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "I. INTRODUCTION", "text": "Thanks to the study of electro-magnetic duality initiated by Seiberg and Witten, 1 the prepotential of the low energy effective action of N = 2 supersymmetric Yang-Mills theory was turned out to be viewed as a function on a complex projective space having singularities when the masses of charged particles vanish. This complex projective space can be identified with the moduli space of a Riemann surface determined by several physical requirements, thus the effective theory can be considered to be controlled by the geometry of moduli space of a Riemann surface. [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] According to this observation, since the effective coupling constants of the theory is interpreted as the period matrix of a Riemann surface, determining the period matrix from calculation of periods becomes equivalent to evaluate effective coupling constants. It is interesting that the instanton contributions to prepotential 17 can be obtained from the evaluation of periods and the prepotentials obtained in this way [18] [19] [20] [21] [22] [23] [24] [25] [26] are known to be consistent to the instanton calculus. [26] [27] [28] [29] [30] [31] [32] [33] In these studies, the method based on Picard-Fuchs equations [18] [19] [20] [21] [22] [23] [24] [25] [34] [35] [36] [37] [38] played a crucial role.", "cite_spans": [], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "However, on the one hand, the theory of prepotential often shows unexpected aspects behind the effective theory. For example, it is known that the Seiberg-Witten solutions can be understood in the framework of Whitham theory. 39, 40 Gorsky et al. 41 noticed that the Whitham dynamics in N = 2", "cite_spans": [], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "Yang-Mills theory could be written essentially by only finite number of Whitham times and found that the second-order derivatives of prepotential over the Whitham times could be represented by an elliptic function associated with Seiberg-Witten curve.", "cite_spans": [], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "However, we can further learn more aspects of Whitham hierarchy in gauge theory from the basic idea of Gorsky et al.. 41 For instance, note that since the number of time variables of the hierarchy is restricted to be finite the generating meromorphic 1-form of the Whitham hierarchy is represented by a finite linear combination of meromorphic 1-forms associated with these Whitham times. Then we can expect that there must be closed differential relations among these meromorphic differentials associated with Whitham times. In fact, a detailed study supports this observation and the aim of the paper is to show the consequence of these relations, especially, a connection to Picard-Fuchs equations for the Seiberg-Witten periods.", "cite_spans": [], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "The paper is organized as follows. In Sec. II, we briefly summarize the Whitham dynamics in SU(r + 1) gauge theory. In addition, following to Gorsky et al., 41 we consider the situation that the number of Whitham times is finite. ", "cite_spans": [], "ref_spans": []}, {"section": "II. WHITHAM HIERARCHY IN GAUGE THEORY", "text": "In this section, we briefly sketch the relation between Seiberg-Witten solution and Whitham dynamics in the context of N = 2 supersymmetric Yang-Mills theory.", "cite_spans": [], "ref_spans": []}, {"section": "39-41", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "A. Seiberg-Witten solution", "text": "To begin with, let us recall that the Seiberg-Witten curve in SU(r + 1) gauge theory without matter hypermultiplets [2] [3] [4] is given by the characteristic equation", "cite_spans": [], "ref_spans": []}, {"section": "A. Seiberg-Witten solution", "text": "of the Lax operator L(\u03c9) for Toda chain with r + 1 sites, 39 where x is the eigenvalue of L(\u03c9) and \u03c9 is the spectral parameter. (2.1) can be rewritten in the form of spectral curve", "cite_spans": [], "ref_spans": []}, {"section": "A. Seiberg-Witten solution", "text": "where \u039b SU(r + 1) is the dynamical mass parameter and", "cite_spans": [], "ref_spans": []}, {"section": "A. Seiberg-Witten solution", "text": "represents the simple singularity of type A r with moduli u i . This spectral curve (2.2) can be further rewritten in the familiar hyperelliptic form For a study of Riemann surface, it is often useful to consider the periods of Abelian differentials over the 1-cycles on the surface. In the case at hand, we can take 2r 1-cycles", "cite_spans": [], "ref_spans": []}, {"section": "A. Seiberg-Witten solution", "text": "on (2.4) as a canonical basis (B i are symplectic duals of A i ), which can be expressed by using the branching points of (2.4).", "cite_spans": [], "ref_spans": []}, {"section": "A. Seiberg-Witten solution", "text": "On the other hand, in order to interpret the components of period matrix constructed from periods of Abelian differentials as the effective coupling constants, the combination of Abelian differentials must be fixed uniquely up to total derivatives. In addition, in general, there are three kinds of Abelian differentials on a Riemann surface, but that of the third kind is not required here because we are considering a pure gauge theory. Therefore, the expected meromorphic differential 1-form is expressed by the Abelian differentials of the first and second kinds, and the one satisfying these requirements is called Seiberg-Witten differential dS SW , given by", "cite_spans": [], "ref_spans": []}, {"section": "A. Seiberg-Witten solution", "text": "where we have ignored the numerical normalization for simplicity, and then the Seiberg-Witten periods are given by the loop integrals over the canonical cycles", "cite_spans": [], "ref_spans": []}, {"section": "A. Seiberg-Witten solution", "text": "Note that dS SW can be viewed as the canonical 1-form of the integrable system. In this way, we can see the relation between Seiberg-Witten solution and integrable system.", "cite_spans": [], "ref_spans": []}, {"section": "B. Whitham hierarchy", "text": "We have seen that the Seiberg-Witten solution has a connection to integrable system, but it can be also viewed as a part of Whitham theory of solitons on a Riemann surface.", "cite_spans": [], "ref_spans": []}, {"section": "B. Whitham hierarchy", "text": "To see this, let us recall that in general Whitham theory consists of the following three ingredients:", "cite_spans": [], "ref_spans": []}, {"section": "42", "text": "\u2022 Riemann surface of genus g.", "cite_spans": [], "ref_spans": []}, {"section": "42", "text": "\u2022 Punctures on the surface.", "cite_spans": [], "ref_spans": []}, {"section": "42", "text": "\u2022 Existence of local coordinates near the punctures.", "cite_spans": [], "ref_spans": []}, {"section": "42", "text": "Gorsky et al. 41 noticed that the meromorphic differentials of the second kind d\u2126 n of (n + 1)-th order punctures (n > 0) on a Riemann surface was defined up to a linear combination of g holomorphic differentials d\u03c9 i and considered how to fix this combination by taking two basic requirements. The first one was to require", "cite_spans": [], "ref_spans": []}, {"section": "42", "text": "and the second one was to introduce new meromorphic differentials d \u2126 n which enjoy the property that their differentiations over the moduli coincide with holomorphic differentials.", "cite_spans": [], "ref_spans": []}, {"section": "42", "text": "According to their result, 41 the differential", "cite_spans": [], "ref_spans": []}, {"section": "42", "text": "with infinitely many parameters T n called Whitham times is found to be the expected solution which is suitable for applications to gauge theory. For this new meromorphic differential dS, the periods", "cite_spans": [], "ref_spans": []}, {"section": "42", "text": "can be defined in a natural way.", "cite_spans": [], "ref_spans": []}, {"section": "42", "text": "Next, in order to make a contact with Seiberg-Witten solution, Gorsky et al. 41 regarded the Riemann surface used here as the Seiberg-Witten hyperelliptic curve (2.4).", "cite_spans": [], "ref_spans": []}, {"section": "42", "text": "In such a situation, they found that the Whitham hierarchy could be actually written by only first r time variables and gave an explicit expression of dS. In particular, in the case of SU(r + 1) gauge theory, n is restricted to n < r + 1. Namely, in this situation, the periods (2.10) reduce to", "cite_spans": [], "ref_spans": []}, {"section": "42", "text": "and d \u2126 n are given by", "cite_spans": [], "ref_spans": []}, {"section": "42", "text": "In this expression, P n/(r+1) + means the non-negative terms in the expansion of P n/(r+1) for a large", "cite_spans": [], "ref_spans": []}, {"section": "42", "text": "x, and in general, P n/(r+1) in SU(r + 1) gauge theory is easily found to give", "cite_spans": [], "ref_spans": []}, {"section": "42", "text": "Note that the periods are now represented by a finite linear combination of d \u2126 n because we are considering only for n < r + 1 case. In addition, from (2.12), it is immediate to see that the Seiberg-Witten solution is recovered at the point", "cite_spans": [], "ref_spans": []}, {"section": "42", "text": "In fact, we find d \u2126 1 = dS SW . Of course, in this case, we have dS = dS SW .", "cite_spans": [], "ref_spans": []}, {"section": "III. PICARD-FUCHS STRUCTURE BEHIND WHITHAM HIERARCHY", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "A. Relations among meromorphic differentials", "text": "We have seen that dS is represented by a linear combination of d \u2126 n and also seen that d ", "cite_spans": [], "ref_spans": []}, {"section": "A. Relations among meromorphic differentials", "text": "it is easy to see that", "cite_spans": [], "ref_spans": []}, {"section": "A. Relations among meromorphic differentials", "text": "Note that in the derivation of (3.1) and (3.2) we have used the general formulae", "cite_spans": [], "ref_spans": []}, {"section": "A. Relations among meromorphic differentials", "text": "In a similar way, we can obtain differential relations between d \u2126 n for n > 1 and d \u2126 1 , but we omit the derivations for them and show only the result for n = 3 and 4 cases here.", "cite_spans": [], "ref_spans": []}, {"section": "A. Relations among meromorphic differentials", "text": "\u2202d", "cite_spans": [], "ref_spans": []}, {"section": "A. Relations among meromorphic differentials", "text": "\u2202d ", "cite_spans": [], "ref_spans": []}, {"section": "A. Relations among meromorphic differentials", "text": "which are the Picard-Fuchs equations obtained by several authors. 26, 37 For other d \u2126 n , we can construct similar equations and, in fact, we can obtain the \"hierarchy\" of Picard-Fuchs equations as follows:", "cite_spans": [], "ref_spans": []}, {"section": "A. Relations among meromorphic differentials", "text": "Note that the equations in (3.8) are all second-order equations and in some cases we can simplify them by using (", "cite_spans": [], "ref_spans": []}, {"section": "A. Relations among meromorphic differentials", "text": "26,37", "cite_spans": [], "ref_spans": []}, {"section": "C. Picard-Fuchs equations as a complete system", "text": "Of course, as a complete Picard-Fuchs system, it is not necessary to consider all equations in (3.7) and (3.8). In general, since there are r moduli parameters in the SU(r + 1) gauge theory, it is sufficient to extract at least r independent equations from them.", "cite_spans": [], "ref_spans": []}, {"section": "C. Picard-Fuchs equations as a complete system", "text": "To see this, let us notice the equations in (3.7). Since the number of the equations is r \u2212 1, one more equation is necessary. However, we can not obtain the expected equation from (3.8) because the equations presented there do not have the instanton corrections. If the instanton correction terms are not included in any one of Picard-Fuchs equations, the prepotential obtained from them will not show the instanton corrections precisely. Therefore, we require that the remaining one must include instanton terms.", "cite_spans": [], "ref_spans": []}, {"section": "C. Picard-Fuchs equations as a complete system", "text": "Actually, such equation was recognized by Ito and Yang 43 as the scaling relation. There, the Picard-Fuchs system was realized by two kinds of equations, one of which is Gauss-Manin system and the other is the scaling relation. Since the Gauss-Manin system does not involve instanton corrections, the situation looks like our's. Therefore, also for our case, the scaling relation may be used as the remaining Picard-Fuchs equation.", "cite_spans": [], "ref_spans": []}, {"section": "C. Picard-Fuchs equations as a complete system", "text": "For this, let us consider the Eulerian operator 9) which acts as", "cite_spans": [], "ref_spans": []}, {"section": "C. Picard-Fuchs equations as a complete system", "text": "Ed \u2126 n = nd \u2126 n (3.10) for all n > 0. (3.10) indicates that the degree of d \u2126 n is n. Realizing (3.10) as an equation only in terms of moduli derivatives can be easily accomplished by considering the squaring equation", "cite_spans": [], "ref_spans": []}, {"section": "37,43", "text": "In this way, we can associate r independent Picard-Fuchs equations for d \u2126 1 .", "cite_spans": [], "ref_spans": []}, {"section": "IV. PICARD-FUCHS EQUATIONS WITH WHITHAM TIMES", "text": "A. The SU ( In this case, the Picard-Fuchs equations with the Whitham times are found to be in the form", "cite_spans": [], "ref_spans": []}, {"section": "IV. PICARD-FUCHS EQUATIONS WITH WHITHAM TIMES", "text": "where", "cite_spans": [], "ref_spans": []}, {"section": "IV. PICARD-FUCHS EQUATIONS WITH WHITHAM TIMES", "text": "Though the derivation of Picard-Fuchs equations for other higher r is straightforward, the result is turned out to be too lengthy and complicated, so we do not consider these cases in this paper.", "cite_spans": [], "ref_spans": []}, {"section": "B. Specializations of SU(3) Picard-Fuchs equations", "text": "It may be instructive to see specializations of (4.2). With the help of (2.14), it is straightforward to make sure that the equations in (4. ", "cite_spans": [], "ref_spans": []}, {"section": "B. Specializations of SU(3) Picard-Fuchs equations", "text": "Note that the consistency condition of (4.3) leads to [u\u2202 On the other hand, from (4.2) with (T 1 , T 2 ) = (0, 1), we can also consider Picard-Fuchs equations", "cite_spans": [], "ref_spans": []}, {"section": "B. Specializations of SU(3) Picard-Fuchs equations", "text": "where Finally, note that we have", "cite_spans": [], "ref_spans": []}, {"section": "B. Specializations of SU(3) Picard-Fuchs equations", "text": "d \u2126 2 (4.5) from (2.9), (4.3) and (4.4).", "cite_spans": [], "ref_spans": []}, {"section": "V. SUMMARY", "text": "In this paper, we have discussed the SU(r + 1) gauge theory in the standpoint of Whitham dynamics and realized r \u2212 1 Picard-Fuchs equations for Seiberg-Witten periods as consistency equations among meromorphic differentials associated with Whitham times. In addition, we have used the scaling relation as the remaining independent equation in order to include the instanton corrections. Though the generalization to other cases except SU(r + 1) group is straightforward, the case of exceptional gauge groups would be interesting because there are two types of SeibergWitten curves in these gauge theories. 7, [11] [12] [13] [14] [15] [16] In particular, it may be interesting to know how the differences of physics expected from these two curves 12, 16, 24, 25 are reflected in the Whitham theory and the Picard-Fuchs structure behind it.", "cite_spans": [], "ref_spans": []}, {"section": "V. SUMMARY", "text": "Of course, our construction of Picard-Fuchs equations may provide helpful informations not only for these cases but also when we consider the relation among flat coordinates, 48, 49 WittenDijkgraaf-Verlinde-Verlinde equations [50] [51] [52] [53] [54] [55] and Whitham hierarchy. [39] [40] [41] We are now planning a discussion respect to this point.", "cite_spans": [{"start": 246, "end": 250, "text": "[54]", "ref_id": "BIBREF61"}], "ref_spans": []}], "bib_entries": {"BIBREF50": {"title": "Higher transcendental functions", "authors": [{"first": "A", "middle": [], "last": "Erd\u00e9lyi", "suffix": ""}], "year": 1966, "venue": "", "link": "119551296"}, "BIBREF61": {"title": "More evidence for the WDVV equations in N = 2 SUSY Yang-Mills theories", "authors": [{"first": "A", "middle": [], "last": "Marshakov", "suffix": ""}, {"first": "A", "middle": [], "last": "Mironov", "suffix": ""}, {"first": "A", "middle": [], "last": "Morozov", "suffix": ""}], "year": "", "venue": "", "link": "18762679"}}, "ref_entries": {"FIGREF0": {"text": "the hyperelliptic curve (2.4) is a Riemann surface of genus r.", "type": "figure"}, "FIGREF1": {"text": "related to dS SW ? If we can find any relation among them, the role of the Seiberg-Witten solution in the Whitham dynamics will be clarified. To find an answer to this question, let us notice that any meromorphic differential on a Riemann surface must be always written in terms of the basis of Abelian differentials on the surface. Of course, this must be true also for d \u2126 n for all n. Therefore, if we consider a differentiation of d \u2126 n over moduli, it will be ultimately represented by a linear combination of various d \u2126 n and their derivatives. However, actually, in the case of Seiberg-Witten Riemann surface, we can show that the derivatives of d \u2126 n for n > 1 are obtained from the Seiberg-Witten differential d \u2126 1 . Thus as the", "type": "figure"}, "FIGREF2": {"text": "Picard-Fuchs equations Next, let us consider Picard-Fuchs equations for the periods (\u03b1 i , \u03b1 D i ) of Whitham hierarchy. In the case of r = 1, the resulting Picard-Fuchs equation takes the same form with the usual one 18 up to rescaling of T 1 . For this reason, we do not discuss this case, and instead, let us consider r = 2 case in order to find a non-trivial example of Picard-Fuchs equations with Whitham times.", "type": "figure"}, "FIGREF4": {"text": ", we can obtain a relation like that from (4.3), but the same equation is also available from (3.3), provided \u2202d \u2126 1 /\u2202u i are eliminated from (3.3).", "type": "figure"}, "TABREF0": {"text": "Since the meromorphic 1-forms on Seiberg-Witten curve consisting of the Whitham hierarchy must be always represented by simply a linear combination of Abelian differentials, we can expect the existence of differential relations among these meromorphic 1-forms. In Sec. III, it is shown that such relations can be in fact found and as a result Picard- Fuchs equations for the Seiberg-Witten periods are available from this view point. It should be noted that the generating meromorphic differential of the Whitham hierarchy can be written in terms of the Seiberg-Witten 1-form. This indicates that it is sufficient to consider only the Seiberg-Witten", "type": "table"}, "TABREF1": {"text": "be directly determined through the Seiberg-Witten periods themselves. To see this more concretely, let us consider the case of d \u2126 2 as an example. Since the differenti- ations of d \u2126 2 over moduli are", "type": "table"}, "TABREF2": {"text": "by using differentiations, the equations satisfied by d \u2126 1 will be obtained. Furthermore, since d \u2126 1 = dS SW , we can identify such equations as Picard-Fuchs equations for Seiberg-Witten periods. To see this, it is enough to consider the cross derivatives of d \u2126 n . For example, for d \u2126 2 , from", "type": "table"}, "TABREF3": {"text": "2) yield the usual SU(3) Picard-Fuchs equations 18 L j (a i , a D i ) = 0 for the Seiberg-Witten periods, which can be identified with Appell's F 4 system", "type": "table"}}}
{"paper_id": "119425642", "_pdf_hash": "48f2e774f1fc640806f3c467a24a8763cc372b44", "abstract": [{"section": "Abstract", "text": "We present NPTFit, an open-source code package, written in python and cython, for performing non-Poissonian template fits (NPTFs). The NPTF is a recently-developed statistical procedure for characterizing the contribution of unresolved point sources (PSs) to astrophysical data sets. The NPTF was first applied to Fermi gamma-ray data to give evidence that the excess of \u223cGeV gammarays observed in the inner regions of the Milky Way likely arises from a population of sub-threshold point sources, and the NPTF has since found additional applications studying sub-threshold extragalactic sources at high Galactic latitudes. The NPTF generalizes traditional astrophysical template fits to allow for the ability to search for populations of unresolved PSs that may follow a given spatial distribution. NPTFit builds upon the framework of the fluctuation analyses developed in X-ray astronomy, and thus likely has applications beyond those demonstrated with gamma-ray data. The NPTFit package utilizes novel computational methods to perform the NPTF efficiently. The code is available at https://github.com/bsafdi/NPTFit and up-to-date and extensive documentation may be found at http://nptfit.readthedocs.io.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "I. INTRODUCTION", "text": "Astrophysical point sources (PSs), which are defined as sources with angular extent smaller than the resolution of the detector, play an important role in virtually every analysis utilizing images of the cosmos. It is useful to distinguish between resolved and unresolved PSs; the former may be detected individually at high significance, while members of the latter population are by definition too dim to be detected individually. However, unresolved PSs -due to their potentially large number density -can be a leading and sometimes pesky source of flux across wavelengths. Recently, a novel analysis technique called the non-Poissonian template fit (NPTF) has been developed for characterizing populations of unresolved PSs at fluxes below the detection threshold for finding individually-significant sources [1, 2] . The technique expands upon the traditional fluctuation analysis technique (see, for example, [3, 4] ), which analyzes the aggregate photon-count statistics of a data set to characterize the contribution from unresolved PSs, by additionally incorporating spatial information both for the distribution of unresolved PSs and for the potential sources of non-PS emission. In this work, we present a code package called NPTFit for numerically implementing the NPTF in python and cython.", "cite_spans": [], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "The most up-to-date version of the open-source package NPTFit may be found at https://github.com/bsafdi/NPTFit and the latest documentation at http://nptfit.readthedocs.io. * smsharma@princeton.edu \u2020 nrodd@mit.edu \u2021 bsafdi@mit.edu", "cite_spans": [], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "In addition, the version used in this paper has been archived at https://zenodo.org/record/380469#.WN_pSFPyvMV.", "cite_spans": [], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "The NPTF generalizes traditional astrophysical template fits. Template fitting is useful for pixelated data sets consisting of some number of photon counts n p in each pixel p, and it typically proceeds as follows. Given a set of model parameters \u03b8, the mean number of predicted photon counts \u00b5 p (\u03b8) in the pixel p may be computed. More specifically, \u00b5 p (\u03b8) = T", "cite_spans": [], "ref_spans": []}, {"section": "(S)", "text": "p, (\u03b8), where is an index of the set of templates T (S) p, , whose normalizations and spatial morphologies may depend on the parameters \u03b8. These templates may, for example, trace the gas-distribution or other extended structures that are expected to produce photon counts. Then, the probability to detect n p photons in the pixel p is simply given by the Poisson distribution with mean \u00b5 p (\u03b8). By taking a product of the probabilities over all pixels, it is straightforward to write down a likelihood function as a function of \u03b8.", "cite_spans": [], "ref_spans": []}, {"section": "(S)", "text": "The NPTF modifies this procedure by allowing for nonPoissonian photon-count statistics in the individual pixels. That is, unresolved PS populations are allowed to be distributed according to spatial templates, but in the presence of unresolved PSs the photon-count statistics in individual pixels, as parameterized by \u03b8, no longer follow Poisson distributions. This is heuristically because we now have to ask two questions in each pixel: first, what is the probability, given the model parameters \u03b8 that now also characterize the intrinsic source-count distribution of the PS population, that there are PSs within the pixel p, then second, given that PS population, what is the probability to observe n p photons?", "cite_spans": [], "ref_spans": []}, {"section": "(S)", "text": "It is important to distinguish between resolved and unresolved PSs. Once a PS is resolved -that is once its location and flux is known -that PS may be accounted for by its own Poissonian template. Unresolved PSs are different because their locations and fluxes are not known. When we characterize unresolved PSs with the NPFT, we characterize the entire population of unresolved sources, following a given spatial distribution, based on how that population modifies the photon-count statistics.", "cite_spans": [], "ref_spans": []}, {"section": "(S)", "text": "The NPTF has played an important role recently in addressing various problems in gamma-ray astroparticle physics with data collected by the Fermi-LAT gammaray telescope. 1 The NPTF was developed to address the excess of gamma rays observed by Fermi at \u223cGeV energies originating from the inner regions of the Milky Way [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] . The GeV excess, as it is commonly referred to, has received a significant amount of attention due to the possibility that the excess emission arises from dark matter (DM) annihilation. However, it is well known that unresolved PSs may complicate searches for annihilating DM in the Inner Galaxy region due to, for example, the expected population of dim pulsars [12, [19] [20] [21] [22] [23] [24] [25] [26] . In [2] (see also [27] ) it was shown, using the NPTF, that indeed the photon-count statistics of the data prefer a PS over a smooth DM interpretation of the GeV excess. The same conclusion was also reached by [28] using an unrelated method that analyzes the statistics of peaks in the wavelet transformation of the Fermi data.", "cite_spans": [], "ref_spans": []}, {"section": "(S)", "text": "In the case of the GeV excess, there are multiple PS populations that may contribute to the observed gammaray flux and complicate the search for DM annihilation. These include isotropically distributed PSs of extragalactic origin, PSs distributed along the disk of the Milky Way such as supernova remnants and pulsars, and a potential spherical population of PSs such as millisecond pulsars. Additionally, there are various identified PSs that contribute significantly to the flux as well as a variety of smooth emission mechanisms such as gascorrelated emission from pion decay and bremsstrahlung. The power of the NPTF is that these different source classes may be given separate degrees of freedom and constrained by incorporating the spatial morphology of their various contributions along with the difference in photoncount statistics between smooth emission and emission from unresolved PSs. Although the origin of the GeV excess is still not completely settled, as even if the excess arises from PSs as the NPTF suggests the source class of the PSs remains a mystery at present, the NPTF has emerged as a powerful tool for analyzing populations of dim PSs in complicated data sets with characteristic spatial morphology.", "cite_spans": [], "ref_spans": []}, {"section": "(S)", "text": "The NPTF and related techniques utilizing photoncount statistics have also been used recently to study the contribution of various source classes to the extragalactic gamma-ray background (EGB) [4, [29] [30] [31] [32] .", "cite_spans": [], "ref_spans": []}, {"section": "(S)", "text": "2 In these works it was shown that unresolved blazars would predominantly show up as PS populations under the NPTF, while other source classes such as star-forming galaxies would show up predominantly as smooth emission. For example, in [32] it was shown using the NPTF that blazars likely account for the majority of the EGB from \u223c2 GeV to \u223c2 TeV. These results set strong constraints on the flux from more diffuse sources, such as star-forming galaxies, which has significant implications for, among other problems, the interpretation of the highenergy astrophysical neutrinos observed by IceCube [34] [35] [36] [37] (see, for example, [38, 39] ). This is because certain sources that contribute gamma-ray flux at Fermi energies, such as star forming galaxies and various types of active galactic nuclei, may also contribute neutrino flux observable by IceCube.", "cite_spans": [], "ref_spans": []}, {"section": "(S)", "text": "The NPTF originates from the older fluctuation analysis technique, which is sometimes referred to as the P (D) analysis. This technique has been used extensively to study the flux of unresolved X-ray sources [3, [40] [41] [42] [43] . In these early works, the photon-count probability distribution function (PDF) was computed numerically for different PS source-count distributions using Monte Carlo (MC) techniques. The fluctuation analysis was first applied to gamma-ray data in [4] , 3 and in that work the authors developed a semi-analytic technique utilizing probability generating functions for calculating the photoncount PDF. The code package NPTFit presented in this work uses this formalism for efficiently calculating the photon-count PDF. The specific form of the likelihood function for the NPTF, while reviewed in this work, was first presented in [2] . The works [2, 27, 32] utilized an early version of NPTFit to perform their numerical analyses.", "cite_spans": [], "ref_spans": []}, {"section": "(S)", "text": "The NPTFit code package has a python interface, though the likelihood evaluation is efficiently implemented in cython [46] . The user-friendly interface allows for an arbitrary number of PS and smooth templates. The PS templates are characterized by pixel-dependent source-count distributions", "cite_spans": [], "ref_spans": []}, {"section": "(S)", "text": "is the spatial template tracking the distribution of point sources on the sky and dN/dF is the pixelindependent source-count distribution. The distribution dN p /dF quantifies the number of sources dN p that contributes flux between F and F + dF in the pixel p. The dN/dF are parameterized as multiply broken power-laws, with an arbitrary number of breaks. The code is able to account for both an arbitrary exposure map (accounting for the pointing strategy of an instrument) as well as an arbitrary point spread function (PSF, accounting for the instrument's finite angular resolution) in translating between flux F and counts S.", "cite_spans": [], "ref_spans": []}, {"section": "(S)", "text": "NPTFit has a built-in interface with MultiNest [47, 48] , which efficiently implements nested sampling of the pos-terior distribution and Bayesian evidence for the userspecified model, given the specified data and instrument response function, in the Bayesian framework [49] [50] [51] . The interface handles the Message Passing Interface (MPI), so that inference may be performed efficiently using parallel computing. A basic analysis package is provided in order to facilitate easy extraction of the most relevant data from the posterior distribution and quick plotting of the MultiNest output. The preferred format of the data for NPTFit is HEALPix [52] (a nested equalarea pixilation scheme of the sky), although the the code is also able to handle non-HEALPix data arrays. Note that the code package may also be used to simply extract the NPTF likelihood function so that NPTFit may be interfaced with any numerical package for Bayesian or frequentist inference.", "cite_spans": [], "ref_spans": []}, {"section": "(S)", "text": "A large set of example Jupyter [53] notebooks and python files are provided to illustrate the code. The examples utilize 413 weeks of processed Fermi Pass 8 data in the UltracleanVeto event class collected between August 4, 2008 and July 7, 2016 in the energy range from 2 to 20 GeV. We restrict this dataset to the top quartile as graded by PSF reconstruction and further apply the standard quality cuts DATA_QUAL==1 && LAT_CONFIG==1, as well as restricting the zenith angle to be less than 90", "cite_spans": [], "ref_spans": []}, {"section": "(S)", "text": "\u2022 . This data is made available in the code release. Moreover, the example notebooks illustrate many of the main results in [2, 27, 32] .", "cite_spans": [], "ref_spans": []}, {"section": "(S)", "text": "In addition to the above, the base NPTFit code makes use of the python packages corner [54] , matplotlib [55] , mpmath [56] , GSL [57] and numpy [58] .", "cite_spans": [{"start": 119, "end": 123, "text": "[56]", "ref_id": "BIBREF55"}, {"start": 145, "end": 149, "text": "[58]", "ref_id": "BIBREF57"}], "ref_spans": []}, {"section": "(S)", "text": "The rest of this paper is organized as follows. Section II outlines in more detail the framework of the NPTF. Section III highlights the key classes and features in the NPTFit code package and usage instructions. In Sec. IV we present an example of how to perform an NPTF scan using NPTFit, looking at the Galactic Center with Fermi data to reproduce aspects of the main results of [2] . We conclude in Sec. V. Appendices A, B, and C describe further details behind the mathematical framework of the NPTF.", "cite_spans": [], "ref_spans": []}, {"section": "II. THE NON-POISSONIAN TEMPLATE FIT", "text": "In this section we review the NPTF, which was first presented in [2] and described in more detail in [27, 32] (see also [1, 4, 29, 31] ). The NPTF is used to fit a model M with parameters \u03b8 to a data set d consisting of counts n p in each pixel p. The likelihood function for the NPTF is then simply", "cite_spans": [], "ref_spans": []}, {"section": "II. THE NON-POISSONIAN TEMPLATE FIT", "text": "where", "cite_spans": [], "ref_spans": []}, {"section": "II. THE NON-POISSONIAN TEMPLATE FIT", "text": "np (\u03b8) gives the probability of drawing n p counts in the given pixel p, as a function of the parameters \u03b8. The main computational challange, of course, is in computing these probabilities.", "cite_spans": [], "ref_spans": []}, {"section": "II. THE NON-POISSONIAN TEMPLATE FIT", "text": "It is useful to divide the model parameters into two different categories: the first category describes smooth templates, while the second category describes PS templates. We describe each category in turn, starting with the smooth templates.", "cite_spans": [], "ref_spans": []}, {"section": "II. THE NON-POISSONIAN TEMPLATE FIT", "text": "For most applications, the data has the interpretation of being a two-dimensional pixelated map consisting of an integer number of counts in each pixel. The smooth templates may be used to predict the mean number of counts \u00b5 p (\u03b8) in each pixel p:", "cite_spans": [], "ref_spans": []}, {"section": "II. THE NON-POISSONIAN TEMPLATE FIT", "text": "Above, is an index over templates and \u00b5 p, (\u03b8) denotes the mean contribution of the th template to pixel p for parameters \u03b8. In principle, \u03b8 may describe both the spatial morphology as well as the normalization of the templates. However, in the current implementation of the code, the Poissonian model parameters simply characterize the overall normalization of the templates:", "cite_spans": [], "ref_spans": []}, {"section": "II. THE NON-POISSONIAN TEMPLATE FIT", "text": "Here, A is the normalization parameter and T", "cite_spans": [], "ref_spans": []}, {"section": "(S)", "text": "p, is the th template, which takes values over all pixels p and is independent of the model parameters. The superscript (S) implies that the template is a counts templates, which is to be contrasted with a flux template, for which we use the symbol (F ). The two are related by the exposure map of the instrument E p :", "cite_spans": [], "ref_spans": []}, {"section": "(S)", "text": "p . In the case where we only have smooth, Poissonian templates, the probabilities are then given by the Poisson distribution:", "cite_spans": [], "ref_spans": []}, {"section": "(S)", "text": "In the presence of unresolved PS templates, the probabilities p (p) np (\u03b8) are no longer Poissonian functions of the model parameters \u03b8. Each PS template is characterized by a pixel-dependent source-count distribution dN p /dF , which describes the differential number of sources per pixel per unit flux interval. In this work, we model the source-count distribution by a multiply broken powerlaw: To summarize, a PS template described by a broken power-law with k breaks has 2(k + 1) model parameters describing the locations of the breaks, the power-law indices, and the overall normalization. For example, if we take a single break then the PS model parameters may be denoted as {A, F b,1 , n 1 , n 2 }. Additionally, a spatial template T (PS) must be specified, which describes the distribution of the number of sources (and total flux) with pixel p.", "cite_spans": [], "ref_spans": []}, {"section": "(S)", "text": "Notice that when we discussed the Poissonian templates we used the counts templates T (S) and talked directly in terms of counts S, while so far in our discussion of the unresolved PS templates we have used the point source distribution template T (PS) and written the source-count distribution dN/dF in terms of flux F . Of course as the total flux from a distribution of point sources is also proportional to the template T (PS) , it can be thought of as a flux template, however conceptually it is being used to track the distribution of the sources rather than the flux they produce. For this reason we have chosen to distinguish the two. Moreover, in the presence of a non-trivial PSF, T (S) should also be smoothed by the PSF to account for the instrument 4 In principle, the breaks and indices could also vary between pixels. However, in the current version of NPTFit, only the number of sources (and, accordingly, the total flux) is allowed to vary between pixels.", "cite_spans": [], "ref_spans": []}, {"section": "(S)", "text": "response function. That is, T (S) is a template for the observed counts taking into account the details of the instrument, while T (PS) (T (F ) ) is a map of the physical point sources (flux), which is independent of the instrument. In photon-counting applications, the exposure map E p often has units of cm 2 s and flux has units of counts cm \u22122 s \u22121 . For the unresolved PS templates, we also need to convert the source-count distribution from flux to counts. This is done by a simple change of variables:", "cite_spans": [], "ref_spans": []}, {"section": "(S)", "text": "which implies that for a non-Poissonian template the spatial dependence of dN p /dS is given by T (PS) p /E p . This inverse exposure scaling may seem surprising, but it is straightforward to confirm that the mean number of counts in a given pixel, dSSdN p /dS, is given by", "cite_spans": [], "ref_spans": []}, {"section": "(S)", "text": ", as expected, up to pixel independent factors. As an important aside, the template T (S) used by the Poissonian models needs to be smoothed by the PSF. Incorporating the PSF into the unresolved PS models, on the other hand, is more complicated and is not accomplished simply by smoothing the spatial template. Indeed, T (PS) p should remain un-smoothed by the PSF when used for non-Poissonian scans.", "cite_spans": [], "ref_spans": []}, {"section": "(S)", "text": "In the remainder of this section we briefly overview the mathematic framework behind the computation of the p (p) np (\u03b8) with NPTFit; however, details of the algorithms used to calculate these probabilities in practice, along with more in-depth explanations, are given in Apps. A, B, and C. We use the probability generating function formalism, following [4] , to calculate the probabilities. For a discrete probability distribution p k , with k = 0, 1, 2, . . ., the generating function is defined as:", "cite_spans": [], "ref_spans": []}, {"section": "(S)", "text": "from which we can recover the probabilities:", "cite_spans": [], "ref_spans": []}, {"section": "(S)", "text": "The key feature of generating functions exploited here is that the generating function of a sum of two independent random variables is simply the product of the individual generating functions. The probability generating function for the smooth templates, as a function of \u03b8, is simply given by", "cite_spans": [], "ref_spans": []}, {"section": "(S)", "text": "The probability generating function for an unresolved PS template, on the other hand, takes a more complicated form:", "cite_spans": [], "ref_spans": []}, {"section": "(S)", "text": "where", "cite_spans": [], "ref_spans": []}, {"section": "(S)", "text": "Above, \u03c1(f ) is a function that takes into account the PSF, which we describe in more detail in App. A. In the presence of a non-trivial PSF, the flux from a single source is smeared among pixels. The distribution of flux fractions among pixels is described by the function \u03c1(f ), where f is the flux fraction. By definition \u03c1(f )df equals the number of pixels which, on average, contain between f and f + df of the flux from a PS; the distribution is normalized such that", "cite_spans": [], "ref_spans": []}, {"section": "(S)", "text": "Putting aside the PSF correction for the moment, the x p,m have the interpretation of being the average number of m-count PSs within the pixel p, given the distribution dN p (S; \u03b8)/dS. The generating function for x m m-count sources is simply e xm(t m \u22121) (see [4] or App. A), which then leads directly to (9) . The PSF correction, through the distribution \u03c1(f ), incorporates the fact that PSs only contribute some fraction of their flux within a given pixel.", "cite_spans": [], "ref_spans": []}, {"section": "III. NPTFIT: ORIENTATION", "text": "NPTFit implements the NPTF, as described above, in python. In this section we give a brief orientation to the code package and its main classes. A more thorough description of the code and its uses is available in the online documentation. If no work_dir is specified, the code will default to the current directory. This is the directory where all output is stored. Specifying a tag will create an additional folder, with that name, within the work_dir for the output. The data, exposure map, and templates are loaded into the nptfit.NPTF instance after initialization (see the example in Sec. IV). The data and exposure map are loaded by nptf . load_data ( data , exposure )", "cite_spans": [], "ref_spans": []}, {"section": "III. NPTFIT: ORIENTATION", "text": "Here, data and exposure are 1-D numpy arrays. The recommended format for these arrays is the HEALPix format, so that all pixels are equal area, although the code is able to handle arbitrary data and exposure arrays so long as they are of the same length. The templates are added by nptf . add_template ( template , key , units = ' counts ')", "cite_spans": [], "ref_spans": []}, {"section": "III. NPTFIT: ORIENTATION", "text": "Here, template is a 1-D numpy array of the same length as the data and exposure map, key is a string that will be used to refer to the template later on, and units specifies whether the template is a counts template (keyword ' counts') or a flux template (keyword 'flux') in units counts cm \u22122 s \u22121 . The default, if unspecified, is units = 'counts'. The template should be pre-smoothed by the PSF if it is going to be used for a Poissonian model. If the template is going to be used for a non-Poissonian model, either choice for units is acceptable, though in the case of 'counts' the template should simply be the product of the exposure map times the flux template and not smoothed by the PSF.", "cite_spans": [], "ref_spans": []}, {"section": "III. NPTFIT: ORIENTATION", "text": "The user also has the option of loading in a mask that reduces the region of interest (ROI) to a subset of the pixels in the data, exposure, and template arrays. This is done through the command nptf . load_mask ( mask ) where mask is a boolean numpy array of the same length as the data and exposure arrays. Pixels in mask should be either True or False; by convention, pixels that are True will be masked, while those that are False will not be masked. Note if performing an analysis with nonPoissonian templates, regions where the exposure map is identically zero should be explicitly masked.", "cite_spans": [], "ref_spans": []}, {"section": "III. NPTFIT: ORIENTATION", "text": "Afterwards, Poissonian and non-Poissonian models may be added to the instance using the available templates. An arbitrary number of Poissonian and nonPoissonian models may be added to the scan. Moreover, each non-Poissonian model may be specified in terms of a multiply broken power law with a user-specified number of breaks, as in (4) .", "cite_spans": [], "ref_spans": []}, {"section": "III. NPTFIT: ORIENTATION", "text": "Poissonian models are added sequentially using the syntax Any of the model parameters may be fixed to a user specified value instead of floated in the scan. For those parameters that are floated in the scan, a prior range needs to be specified along with whether or not the prior is flat or log-flat. Note that if log_prior = True, then the prior range is set with respect to log 10 of the linear prior range. 5 For example, if we want to scan the normalization of a template over the range from [0.1, 10] with a log-flat prior, then we would set log_prior = True and prior_range = [-1,1]. In this case, it might make sense to label the model with model_tag = '$\\log_{10}A$' to emphasize that the actual model parameter is the log of the normalization; this label will appear in various plots made using the provided analysis class for visualizing the posterior.", "cite_spans": [], "ref_spans": []}, {"section": "III. NPTFIT: ORIENTATION", "text": "The non-Poissonian models are added with a similar syntax:", "cite_spans": [], "ref_spans": []}, {"section": "III. NPTFIT: ORIENTATION", "text": "nptf . add_non_poiss_model ( template_name , model_tag , prior_range =[] , log_prior = False , dnds_model = ' specify_breaks ' , fixed_params = None , units = ' counts ')", "cite_spans": [], "ref_spans": []}, {"section": "III. NPTFIT: ORIENTATION", "text": "The template_name keyword is the same as for the Poissonian models. The units keyword determines whether the priors for the breaks in the source-count distribution (and also the fixed parameters, if any are given) will be specified in terms of 'flux' or 'counts'. The relation between flux and counts varies between pixels if the exposure map is non-trivial. For this reason, it is more appropriate to think of the breaks in the source-count distribution in terms of flux. The keyword 'counts' still 5 More complicated priors will be incorporated in future releases of NPTFit.", "cite_spans": [], "ref_spans": []}, {"section": "III. NPTFIT: ORIENTATION", "text": "specifies the breaks in the source-count distribution in terms of flux, with the relation between counts and flux given through the mean of the exposure map mean(E): If 'specify_breaks' is chosen, which is the default, then the breaks are the model parameters.", "cite_spans": [], "ref_spans": []}, {"section": "III. NPTFIT: ORIENTATION", "text": "If instead 'specify_relative_breaks' is chosen, the full set of model parameters is given by [A, n 1 , n 2 , . . . , n k+1 , S b,1 , \u03bb 2 , . . . , \u03bb k ]. Here, S b,1 is the highest break and the lower breaks are determined by S b,i = \u03bb i S b,i\u22121 . Note that the prior ranges for the \u03bb's should be between 0 and 1 (for linear flat), since", "cite_spans": [], "ref_spans": []}, {"section": "III. NPTFIT: ORIENTATION", "text": "After setting up a scan, the configuration is finished by executing the command For a purely Poissonian scan, none of the keywords above need to be specified. For non-Poissonian scans, f_ary and df_rho_div_f_ary incorporate the PSF correction.", "cite_spans": [], "ref_spans": []}, {"section": "III. NPTFIT: ORIENTATION", "text": "In particular, f_ary is a discretized list of f values between 0 and 1, while df_rho_div_f_ary is a discretized list of df \u03c1(f )/f at those f values. A class is provided for computing these lists; it is described later in this section. If no keywords are given for these two arrays they default to the case of a \u03b4-function PSF. The keyword nexp, which defaults to 1, is related to the exposure correction in the calculation of the source-count distribution dN p /dS from dN p /dF . In many applications, it is computationally too expensive to perform the mapping in (5) in each pixel. The overall pixel-dependent normalization factor T (PS) p /E p factorizes from many of the internal computations, and as a result this contribution to the exposure correction is performed in every pixel. However, it is useful to perform the mapping from flux to counts, which should be performed uniquely in each pixel F = S/E p , using the mean exposure within small sub-regions. Within a given sub-region, we map flux to counts using F = S/mean(E), where the mean is taken over all pixels in the sub-region. The number of sub-regions is given by nexp, and all sub-regions have approximately the same area. As nexp approaches the number of pixels, the approximation becomes exact; however, for many applications the approximation converges for a relatively small number of exposure regions. We recommend verifying, in any application, that results are stable as nexp is increased.", "cite_spans": [], "ref_spans": []}, {"section": "III. NPTFIT: ORIENTATION", "text": "After configuring the NPTF instance, the log-likelihood may be extracted, as a function of the model parameters, in addition to the prior range. The log-likelihood and prior range may then be used with any external package for performing Bayesian or frequentist inference. This is particularly useful if the user would like to combine likelihood functions between different energy bins or otherwise add to the default likelihood function, for example, incorporating nuisance parameters beyond those associated with individual templates. The package MultiNest, however, is already incorporated into the NPTF class and may be run immediately after configuring the NPTF instance. This is done simply by executing the command nptf . perform_scan ( run_tag = None , nlive =100)", "cite_spans": [], "ref_spans": []}, {"section": "III. NPTFIT: ORIENTATION", "text": "where nlive is an integer that specifies the number of live points used in the sampling of the posterior distribution. MultiNest recommends an nlive \u223c500-1000, though the parameter defaults to 100 if unspecified for quick test runs. Additional MultiNest arguments may be passed as a dictionary through the optional pymultinest_options keyword (see the online documentation for more details). The optional keyword run_tag is used to create a subfolder for the MultiNest output with that name.", "cite_spans": [], "ref_spans": []}, {"section": "III. NPTFIT: ORIENTATION", "text": "After a scan has been run (or if a scan has been run previously and saved), the results may be loaded through the command nptf . load_scan ( run_tag = None )", "cite_spans": [], "ref_spans": []}, {"section": "III. NPTFIT: ORIENTATION", "text": "The MultiNest chains, which give a discretized view of the posterior distribution, may then be accessed through, for example, nptf.samples. An instance of the PyMultiNest analyzer class may be accessed through nptf.a. A small analysis package, described later in this section, is also provided for performing a few common analyses. If True, PSF not Gaussian and will be specified later bool Note that the arrays f_ary and df_rho_div_f_ary depend both on the PSF of the detector as well as the pixelation of the data; at present the PSFCorrection class requires the pixelation to be in the HEALPix pixelation.", "cite_spans": [], "ref_spans": []}, {"section": "III. NPTFIT: ORIENTATION", "text": "The keyword psf_dir points to the directory where the f_ary and df_rho_div_f_ary will be stored; if unspecified, they will be stored to the current directory. The f_ary consists of num_f_bins entries linear spaced between 0 and 1. The PSF correction involves placing many (n_psf) PSFs at random positions on the HEALPix map, drawing n_pts_per_psf points from each PSF, and then looking at the distribution of points among pixels. The larger n_psf and n_pts_per_psf, the more accurate the computation of df_rho_div_f_ary will be. However, the computation time of the PSF arrays also increases as these parameters are increased.", "cite_spans": [], "ref_spans": []}, {"section": "III. NPTFIT: ORIENTATION", "text": "By default the PSFCorrection class assumes that the PSF is a 2-D Gaussian distribution:", "cite_spans": [], "ref_spans": []}, {"section": "III. NPTFIT: ORIENTATION", "text": "Here, PSF(r) describes the spread of arriving counts with angular distance r away from the arrival direction. The parameter psf_sigma_deg denotes \u03c3 in degrees. Upon initializing PSFCorrection with psf_sigma_deg specified, the class automatically computes the array df_rho_div_f_ary and stores it in the psf_dir with a unique name related to the keywords. If such a file already exists in the psf_dir, then the code will simply load this file instead of recomputing it. After initialization, the relevant arrays may be accessed by pc_inst.f_ary and pc_inst.", "cite_spans": [], "ref_spans": []}, {"section": "III. NPTFIT: ORIENTATION", "text": "df_rho_div_f_ary.", "cite_spans": [], "ref_spans": []}, {"section": "III. NPTFIT: ORIENTATION", "text": "The PSFCorrection class can also handle arbitrary PSF functions. In this case, the class should be initialized with delay_compute = True. Then, the user should manually set the function pc_inst.psf_r_func to the desired function PSF(r). This function will be discretized with pc_inst.psf_samples points out to pc_inst.sample_psf_max degrees from r = 0. These two quantities also need to be manually specified. The user also needs to set pc_inst.psf_tag to a string that will be used for saving the PSF arrays. After these four attributes have been set manually by the user, the PSF arrays are computed and stored by executing", "cite_spans": [], "ref_spans": []}, {"section": "pc_inst.make_or_load_psf_corr(). def NPTFit.create_mask.make_mask_total", "text": "This function is used to make masks that can then be used to reduce the data and templates to a smaller ROI when performing the scan. While these masks can always be made by hand, this function provides a simple masking interface for maps in the HEALPix format. The make_mask_total function can mask pixels by latitude, longitude, and radius from any point on the sphere. See the online documentation for more specific examples. The analysis class may be used to extract useful information from the results of an NPTF performed using MultiNest. The class also has built-in plotting features for making many of the most common types of visualizations for the parameter posterior distribution. An instance of the analysis class can be instantiated by an = Analysis ( nptf , mask = None , pixarea =0.)", "cite_spans": [], "ref_spans": []}, {"section": "pc_inst.make_or_load_psf_corr(). def NPTFit.create_mask.make_mask_total", "text": "where nptf is itself an instance of the NPTF class that already has the results of a scan loaded. The keyword arguments mask and pixarea are optional. The user should specify a mask if the desired ROI for the analysis is different that that used in the scan. The user should specify a pixarea if the data is not in the HEALPix format. The code will still assume the pixels are equal area with area pixarea, which should be specified in sr. After initialization, the intensities of Poissonian and non-Poissonian templates, respectively, may be extracted from the analysis class by the commands an . r e t ur n _ i n t e ns i t y _ a r r ay s _ p o i s s ( comp ) and an . r e t u r n _ i n t e n s i t y _ a r r a y s _ n o n _ p o i s s ( comp )", "cite_spans": [], "ref_spans": []}, {"section": "pc_inst.make_or_load_psf_corr(). def NPTFit.create_mask.make_mask_total", "text": "Here, comp refers to the template key used by the Poissonian or non-Poissonian model. The arrays returned give the mean intensities of that model in the ROI in units of counts cm \u22122 s \u22121 , assuming the exposure map was in units of cm 2 s. The arrays computed over the full set of entries in the discretized posterior distribution output by MultiNest. Thus, these intensity arrays may be interpreted as the 1-D posteriors for the intensities. For additional keywords that may be used to customize the computation of the intensity arrays, see the online documentation.", "cite_spans": [], "ref_spans": []}, {"section": "pc_inst.make_or_load_psf_corr(). def NPTFit.create_mask.make_mask_total", "text": "The source-count distributions may also be accessed from the analysis class. Executing for Poissonian models, and", "cite_spans": [], "ref_spans": []}, {"section": "A_non_poiss_post , n_non_poiss_post , Sb_non_poiss_post = an . r e t u r n _ n o n _ p o i s s _ p a r a m e t e r _ p o s t e r i o r s ( comp )", "text": "for non-Poissonian models.", "cite_spans": [], "ref_spans": []}, {"section": "A_non_poiss_post , n_non_poiss_post , Sb_non_poiss_post = an . r e t u r n _ n o n _ p o i s s _ p a r a m e t e r _ p o s t e r i o r s ( comp )", "text": "Here A_poiss_post is a 1-D array of the discretized posterior distribution for the Poissonian template normalization parameter.", "cite_spans": [], "ref_spans": []}, {"section": "A_non_poiss_post , n_non_poiss_post , Sb_non_poiss_post = an . r e t u r n _ n o n _ p o i s s _ p a r a m e t e r _ p o s t e r i o r s ( comp )", "text": "Similarly, A_non_poiss_post is the posterior array for the non-Poissonian normalization parameter.", "cite_spans": [], "ref_spans": []}, {"section": "A_non_poiss_post , n_non_poiss_post , Sb_non_poiss_post = an . r e t u r n _ n o n _ p o i s s _ p a r a m e t e r _ p o s t e r i o r s ( comp )", "text": "The arrays n_non_poiss_post and Sb_non_poiss_post are 2-D, where -for examplen_non_poiss_post = [n_1_array, n_2_array, ...] and n_1_array is a 1-D array for the posterior for n 1 .", "cite_spans": [], "ref_spans": []}, {"section": "A_non_poiss_post , n_non_poiss_post , Sb_non_poiss_post = an . r e t u r n _ n o n _ p o i s s _ p a r a m e t e r _ p o s t e r i o r s ( comp )", "text": "Another useful piece of information that may be extracted from the scan is the Bayesian evidence:", "cite_spans": [], "ref_spans": []}, {"section": "A_non_poiss_post , n_non_poiss_post , Sb_non_poiss_post = an . r e t u r n _ n o n _ p o i s s _ p a r a m e t e r _ p o s t e r i o r s ( comp )", "text": "l_be , l_be_err = an . get_log_evidence () returns the log of the Bayesian evidence along with the uncertainty on this estimate based on the resolution of the MCMC.", "cite_spans": [], "ref_spans": []}, {"section": "A_non_poiss_post , n_non_poiss_post , Sb_non_poiss_post = an . r e t u r n _ n o n _ p o i s s _ p a r a m e t e r _ p o s t e r i o r s ( comp )", "text": "For information on the plotting capabilities in the analysis class, see the online documentation or the example in the following section.", "cite_spans": [], "ref_spans": []}, {"section": "IV.", "text": "NPTFIT: AN EXAMPLE", "cite_spans": [], "ref_spans": []}, {"section": "IV.", "text": "In this section we give an example for how to perform an NPTF using NPTFit. Many more examples are available in the online documentation. This particular example reproduces aspects of the main results of [2] , which found evidence for a spherical population of unresolved gamma-ray PSs around the Galactic Center. The example uses the processed, public Fermi data made available with the release of the NPTFit package. The data set consists of 413 weeks of Fermi Pass 8 data in the UltracleanVeto event class (top quartile of events as ranked by PSF) from 2 to 20 GeV. The map is binned in HEALPix with nside = 128. The data, along with the exposure map and background templates, may be downloaded from http://hdl.handle.net/1721.1/105492.", "cite_spans": [], "ref_spans": []}, {"section": "IV.", "text": "In the example we will perform an NPTF on the subregion where we mask the Galactic plane at latitude |b| < 2", "cite_spans": [], "ref_spans": []}, {"section": "IV.", "text": "\u2022 and mask pixels with angular distance greater than 30", "cite_spans": [], "ref_spans": []}, {"section": "IV.", "text": "\u2022 from the Galactic Center. We also mask identified PSs in the 3FGL PS catalog [59] at 95% containment using the provided PS mask, which is added to the geometric mask. We include smooth templates for diffuse gammaray emission in the Milky Way (using the Fermi p6v11 diffuse model), isotropic emission (which can also absorb instrumental backgrounds), and emission following the Fermi bubbles, which are taken to be uniform in flux following the spatial template in [60] . We also include a dark matter template, which traces the line of sight integral of the square of a canonical NFW density profile. We additionally include point source (non-Poissonian) models for the DM template, as well as for a disk template which corresponds to a doubly exponential thindisk source distribution with scale height 0.3 kpc and radius 5 kpc. The source-count distributions for these are parameterized by singly-broken power laws, each described by four parameters {A, F b,1 , n 1 , n 2 }.", "cite_spans": [], "ref_spans": []}, {"section": "A. Setting up the scan", "text": "We begin the example by loading in the relevant modules, described in the previous section, that we will need to setup, perform, and analyze the scan.", "cite_spans": [], "ref_spans": []}, {"section": "A. Setting up the scan", "text": "import numpy as np # module for performing scan from NPTFit import nptfit # module for creating the mask from NPTFit import create_mask as cm # module for determining the PSF correction from NPTFit import psf_correction as pc # module for analyzing the output from NPTFit import dnds_analysis Next, we create an instance of the NPTF class, which is used to configure and perform a scan.", "cite_spans": [], "ref_spans": []}, {"section": "n = nptfit . NPTF ( tag = ' GCE_Example ')", "text": "We assume here that the supplementary Fermi data has been downloaded to a directory 'fermi_data'. Then, we may load in the data and exposure maps by fermi_data = np . load ( ' fermi_data / fermidata_counts . npy ') . astype ( int ) fermi_exposure = np . load ( ' fermi_data / fermidata_exposure . npy ') n . load_data ( fermi_data , fermi_exposure ) Importantly, note that the exposure map has units of cm 2 s. Next, we use the create_mask class to generate our ROI mask, which consists of both the geometric mask and the PS mask loaded in from the 'fermi_data' directory: The templates may also be loaded in from this directory, dif = np . load ( ' fermi_data / template_dif . npy ') iso = np . load ( ' fermi_data / template_iso . npy ') bub = np . load ( ' fermi_data / template_bub . npy ') gce = np . load ( ' fermi_data / template_gce . npy ') dsk = np . load ( ' fermi_data / template_dsk . npy ')", "cite_spans": [], "ref_spans": []}, {"section": "n = nptfit . NPTF ( tag = ' GCE_Example ')", "text": "These templates are counts map (i.e. flux maps times the exposure map) that have been pre-smoothed by the PSF (except for the disk-correlated template labeled dsk). We then add them to our NPTF instance with appropriately chosen keywords:", "cite_spans": [], "ref_spans": []}, {"section": "n = nptfit . NPTF ( tag = ' GCE_Example ')", "text": "n . add_template ( dif , ' dif ') n . add_template ( iso , ' iso ') n . add_template ( bub , ' bub ') n . add_template ( gce , ' gce ') n . add_template ( dsk , ' dsk ') # remove the exposure correction for PS templates rescale = fermi_exposure / np . mean ( fermi_exposure ) n . add_template ( gce / rescale , ' gce_np ' , units = ' PS ') n . add_template ( dsk / rescale , ' dsk_np ' , units = ' PS ') Note that templates 'gce_np' and 'dsk_np' intended to be used in non-Poissonian models should trace the underlying PS distribution, without exposure correction, and are added with the keyword units='PS'.", "cite_spans": [], "ref_spans": []}, {"section": "B. Adding models", "text": "Now that we have loaded in all of the external data and templates, we can add models to our NPTF instance. First, we add in the Poissonian models, All Poissonian models are taken to have linear priors, with prior ranges for the normalizations between 0 and 2. However, the normalization of the diffuse background has been fixed to the value 14.67, which is approximately the correct normalization in these units for this template, in order to provide an example of this syntax. Next, we add in the two non-Poissonian models: We have added in the models for disk-correlated and NFW-correlated (line of sight integral of the the NFW distribution squared) unresolved PS templates. Each of these models takes singly-broken power-law source-count distributions. In each case, the normalization parameter is taken to have a log-flat prior while the indices and breaks are taken to have linear priors. The units of the breaks are specified in terms of counts.", "cite_spans": [], "ref_spans": []}, {"section": "C. Configure scan with PSF correction", "text": "In this energy range and with this data set, the PSF may be modeled by a 2-D Gaussian distribution with \u03c3 = 0.1812", "cite_spans": [], "ref_spans": []}, {"section": "C. Configure scan with PSF correction", "text": "\u2022 . From this, we are able to construct the PSF-correction arrays: 6 pc_inst = pc . PSFCorrection ( psf_sigma_deg =0.1812) f_ary , df_rho_div_f_ary = pc_inst . f_ary , pc_inst . df_rho_div_f_ary 6 For an example of how to construct these arrays with a more complicated, non-Gaussian PSF function, see the online documentation.", "cite_spans": [], "ref_spans": []}, {"section": "C. Configure scan with PSF correction", "text": "These arrays are then passed into the NPTF instance when we configure the scan:", "cite_spans": [], "ref_spans": []}, {"section": "C. Configure scan with PSF correction", "text": "n . configure_for_scan ( f_ary , df_rho_div_f_ary , nexp =1)", "cite_spans": [], "ref_spans": []}, {"section": "C. Configure scan with PSF correction", "text": "Note that since our ROI is relatively small and the exposure map does not change significantly over the region, we have a single exposure region with nexp=1.", "cite_spans": [], "ref_spans": []}, {"section": "D. Performing the scan with MultiNest", "text": "We perform the scan using MultiNest with nlive=100 as an example to demonstrate the basic features and conclusions of this analysis while being able to perform the scan in a reasonable amount of time on a single processor, although ideally nlive should be set to a higher value for more reliable results: The chains, giving a discretized view of the posterior distribution, may be accessed simply through the attribute n.samples. However, we will analyze the results by using the analysis class provided with NPTFit. We make an instance of this class simply by an = dnds_analysis . Analysis ( n )", "cite_spans": [], "ref_spans": []}, {"section": "Make triangle plots", "text": "Triangle plots are a simple and quick way of visualizing correlations in the posterior distribution. Such plots may be generated through the command an . make_triangle () which leads to the plot in Fig. 1 .", "cite_spans": [], "ref_spans": [{"start": 198, "end": 204, "text": "Fig. 1", "ref_id": "FIGREF11"}]}, {"section": "Plot source-count distributions", "text": "The source-count distributions for NFW-and diskcorrelated point source models may be plotted with along with the following matplotlib plotting options.", "cite_spans": [], "ref_spans": []}, {"section": "Plot source-count distributions", "text": "plt . yscale ( ' log ') plt . xscale ( ' log ') plt . xlim ([5 e -11 ,5 e -9]) plt . ylim ([2 e -13 ,1 e -10]) plt . tick_params ( axis = 'x ' , length =5 , width =2 , labelsize =18) plt . tick_params ( axis = 'y ' , length =5 , width =2 , labelsize =18)", "cite_spans": [], "ref_spans": []}, {"section": "Plot source-count distributions", "text": "fontsize =18) plt . title ( ' Galactic Center NPTF ' , y =1.02) plt . legend ( fancybox = True ) plt . tight_layout () This is shown in Fig. 2 . Contribution from both NFW-and disk-correlated PSs may be seen, with NFWcorrelated sources contributing dominantly at lower flux values. In that figure, we also show a histogram of the detected 3FGL sources within the relevant energy range and region, with vertical error bars indicating the 68% confidence interval from Poisson counting uncertainties only. 7 Since we have explicitly masked all 3FGL sources, we see that the disk-and NFW-correlated PS templates contribute at fluxes near and below the 3FGL PS detection threshold, which is \u223c5 \u00d7 10 \u221210 counts cm \u22122 s \u22121 in this case. ", "cite_spans": [], "ref_spans": []}, {"section": "Plot source-count distributions", "text": "Resolved PS masked", "cite_spans": [], "ref_spans": []}, {"section": "Plot source-count distributions", "text": "The source-count distribution as constructed from the analysis class, for the example NPTF described in the main text. This scan looks for disk-correlated PSs along with PSs correlated with the expected DM template (GCE PSs). Since all resolved PSs are masked in this analysis, the sourcecount distributions are seen to contribute dominantly below the 3FGL detection threshold. A histogram of resolved 3FGL sources is also shown.", "cite_spans": [], "ref_spans": []}, {"section": "Plot source-count distributions", "text": "The intensity fractions for the smooth and PS NFWcorrelated models may be plotted with an . p l o t _ i n t e n s i t y _ f r a c t i o n _ n o n _ p o i s s ( ' gce ' , bins =800 , color = ' cornflowerblue ' , label = ' GCE PS ') an . p l o t_ i n t e n s it y _ f r a c t io n _ p o i s s ( ' gce ' , bins =800 , color = ' lightsalmon ' , label = ' GCE DM ') plt . xlabel ( ' Flux fraction (%) ') plt . legend ( fancybox = True ) plt . xlim (0 ,6) This is shown in Fig. 3 . We immediately see a preference for NFW-correlated point sources over the smooth NFW component. ", "cite_spans": [], "ref_spans": [{"start": 467, "end": 473, "text": "Fig. 3", "ref_id": "FIGREF14"}]}, {"section": "Further analyses", "text": "The example above may easily be pushed further in many directions, many of which are outline in [2] . For example, a natural method for performing model comparison in the Bayesian framework is to compute the Bayes factor between two models. Here, for example, we may compute the Bayes factor between the model with and without NFW-correlated PSs. This involves repeating the scan described above but only adding in diskcorrelated PSs. Then, by comparing the global Bayesian evidence between the two scans (see Sec. III for the syntax on how to extract the Bayesian evidence), we find a Bayes factor \u223c10 3 in preference for the model with spherical PSs.", "cite_spans": [], "ref_spans": []}, {"section": "Further analyses", "text": "Another straightforward generalization of the example described above is simply to leave out the PS mask, so that the NFW-and disk-correlated PS templates must account for both the resolved and unresolved PSs. The likelihood evaluations take longer, in this case, since there Resolved PS unmasked Fig. 2 , but in this case the resolved 3FGL sources were not masked. The disk-correlated template accounts for the majority of the resolved PS emission.", "cite_spans": [], "ref_spans": []}, {"section": "FIG. 4. As in", "text": "are pixels with higher photon counts compared to the 3FGL-masked scan. The result for the source-count distribution from this analysis is shown in Fig. 4 . In this case, the disk-correlated PS template accounts for the resolved 3FGL sources, while the NFW-correlated PS template contributes at roughly the same flux range as in the 3FGL masked case. The Bayes factor in preference for the model with NFW-correlated PSs over that withoutas described above -is found to be \u223c10 10 in this case.", "cite_spans": [], "ref_spans": []}, {"section": "V. CONCLUSION", "text": "We have presented an open-source code package for performing non-Poissonian template fits. We strongly recommend referring to the online documentationwhich will be kept up-to-date -in addition to this paper accompanying the initial release. There are many way in which NPTFit can be improved in the future. For one, the NPTFit package only handles a single energy bin at a time. In a later version of the code we plan to incorporate the ability to scan over multiple energy bins simultaneously. Additionally, there are a few areas -such as the evaluation of the incomplete gamma functions -where the cython code may still be sped up. Such improvements to the computational cost are relevant for analyses of large data sets with many model parameters. Of course, we welcome additional suggestions for how we may improve the code and better adapt it to applications beyond the gamma-ray applications it has been used for so far. The remainder of this section is divided as follows. Firstly we outline how to determine the generating functions for the Poissonian and non-Poissonian case. We then describe how we account for finite PSF corrections.", "cite_spans": [], "ref_spans": []}, {"section": "The (non-)Poissonian generating function", "text": "There are two reasons why the evaluation of the Poissonian likelihood for traditional template fitting can be evaluated rapidly. The first of these is that the functional form of the Poissonian likelihood is simple. Secondly, and more importantly, is the fact that if we have two discrete random variables X and Y that follow Poisson distributions with means \u00b5 1 and \u00b5 2 , then the random variable Z = X+Y again follows a Poisson distribution with mean \u00b5 1 +\u00b5 2 . This generalizes to combining an arbitrary number of random Poisson distributed variables and is why we were able to write \u00b5 p, (\u03b8) = A (\u03b8)T (S) p, in Sec. II. This fact is not true when combining arbitrary random variables, and in particular if we add in a template following non-Poissonian statistics.", "cite_spans": [], "ref_spans": []}, {"section": "The (non-)Poissonian generating function", "text": "An elegant solution to this problem was introduced in [4] , using the method of generating functions. As we are always dealing with pixelized maps containing discrete counts (of photons or otherwise), for any model of interest there will always be a discrete probability dis-tribution p k , the probability of observing k = 0, 1, 2, . . . counts. In terms of these, we then define the probability generating function as in (6) . The property of probability generating functions that make them so useful in the present context is as follows. Consider two random processes X and Y , with generating functions P X (t) and P Y (t), that follow arbitrary and potentially different statistical distributions. Then the generating function of Z = X + Y is simply given by the product P X (t) \u00b7 P Y (t). In this subsection we will derive the appropriate form of P (t) for Poissonian and non-Poissonian statistics.", "cite_spans": [], "ref_spans": []}, {"section": "The (non-)Poissonian generating function", "text": "To begin with, consider the purely Poissonian case. Here and throughout this section we consider only the likelihood in a single pixel; the likelihood over a full map is obtained from the product of the pixel-based likelihoods. Then for a Poisson distribution with an expected number of counts \u00b5 p in a pixel p:", "cite_spans": [], "ref_spans": []}, {"section": "The (non-)Poissonian generating function", "text": "Note that the variation of the \u00b5 p across the full map will be a function of the model parameters, such that \u00b5 p = \u00b5 p (\u03b8). In order to simplify the notation in this section however, we leave the \u03b8 dependence implicit. Given the p k values, we then have:", "cite_spans": [], "ref_spans": []}, {"section": "The (non-)Poissonian generating function", "text": "From this form, it is clear that if we have two Poisson distributions with means \u00b5 (1) p and \u00b5 (2) p , the product of their generating functions will again describe a Poisson distribution, but with mean \u00b5", "cite_spans": [], "ref_spans": []}, {"section": "The (non-)Poissonian generating function", "text": "Next we work towards the generating function in the non-Poissonian case. At the outset, we let x p,m denote the average number of sources in a pixel p that emit exactly m counts. In terms of this, the probability of finding n m m-count sources in this pixel is just a draw from a Poisson distribution with mean x p,m , i.e.", "cite_spans": [], "ref_spans": []}, {"section": "The (non-)Poissonian generating function", "text": "Given this, the probability to find k counts from a population of m-count sources is", "cite_spans": [], "ref_spans": []}, {"section": "The (non-)Poissonian generating function", "text": "We can then use this to derive the non-Poissonian mcount generating function as follows:", "cite_spans": [], "ref_spans": []}, {"section": "The (non-)Poissonian generating function", "text": "However this is just the generating function for m-count sources, to get the full non-Poissonian generating function we need to multiply this over all values of m. Doing so we arrive at", "cite_spans": [], "ref_spans": []}, {"section": "The (non-)Poissonian generating function", "text": "justifying the form given in Sec. II. Again recall for the full likelihood we can just multiply the pixel based likelihoods and that x p,m = x p,m (\u03b8). So far we have said nothing of how to determine x p,m , the average number of m-count source in pixel p. This value depends on the source-count distribution dN p /dS, which specifies the distribution of sources as a function of their expected number of counts, S. Of course the physical object is dN/dF , where F is the flux. This distinction was discussed in Sec. II, and can be implemented in NPTFit to arbitrary precision. Nevertheless dN p /dS does not fully determine x p,m -we need to account for the fact that a source that is expected to give S photons could Poisson fluctuate to give m. As such any source can in principle contribute to x p,m , and so integrating over the full distribution we arrive at:", "cite_spans": [], "ref_spans": []}, {"section": "The (non-)Poissonian generating function", "text": "An important part of implementing the NPTF in a rapid manner, which is a central feature of NPTFit, is the analytic evaluation of the integral in this equation. In order to do this, we need to have a specific form of the source-count distribution. For this purpose, we allow the source count distribution to be a multiply broken powerlaw and evaluate the integral for any number of breaks. The details of this calculation are presented in App. C.", "cite_spans": [], "ref_spans": []}, {"section": "The (non-)Poissonian generating function", "text": "Putting the evaluation of the integral aside for the moment then, we have arrived at the full non-Poissonian generating function:", "cite_spans": [], "ref_spans": []}, {"section": "The (non-)Poissonian generating function", "text": "Contrasting this with Eq. (A2), we see that whilst the Poissonian likelihood is specified by a single number \u00b5 p , the non-Poissonian likelihood is instead specified by a distribution dN p /dS. In the case of multiple PS templates, we should multiply the independent probability generating functions. However, this is equivalent to summing the x p,m parameters. This is how multiple PS templates are incorporated into the NPTFit code:", "cite_spans": [], "ref_spans": []}, {"section": "The (non-)Poissonian generating function", "text": "where the sum over is over the contributions from individual PS templates.", "cite_spans": [], "ref_spans": []}, {"section": "Correcting for a finite point spread function", "text": "The next factor to account for is the fact that in any realistic dataset there will be a non-zero PSF. Here, we closely follow the discussion in [4] . The PSF arises due to the inability of an instrument to perfectly reconstruct the original direction of the photon, neutrino, or quantity making up the counts. In practice, a finite PSF means that a source in one pixel can contribute counts to nearby pixels as well. To implement this correction, we modify the calculation of x p,m given in Eq. (A8), which accounts for the distribution of sources as a function of S and the fact that each one could Poisson fluctuate to give us m counts. The finite PSF means that in addition to this, we also need to draw from the distribution \u03c1(f ), that determines the probability that a given source contributes a fraction of its flux f in a given pixel. Once we know \u03c1(f ), this modifies our calculation of x p,m in Eq. (A8) -now a source that is expected to contribute S counts, will instead contribute f S, where f is drawn from \u03c1(f ). As such we arrive at the result in (10) .", "cite_spans": [], "ref_spans": []}, {"section": "Correcting for a finite point spread function", "text": "In NPTFit we determine \u03c1(f ) using Monte Carlo. To do this we place a number of PSs appropriately smeared by the PSF at random positions on a pixelized sphere. Then integrating over all pixels we can determine the fraction of the flux in each pixel f p , p = 1, . . . , N pix , defined such that f 1 + f 2 + . . . = 1. Note in practice one can truncate this sum at some minimal value of f without impacting the argument below. From the set {f p }, we then denote by \u2206n(f ) the number of fractions for n point sources that fall within some range \u2206f . From these quantities, we may determine \u03c1(f ) as", "cite_spans": [], "ref_spans": []}, {"section": "Correcting for a finite point spread function", "text": "which is normalized such that df f \u03c1(f ) = 1. From this definition we see that the case of a vanishing PSF is just \u03c1(f ) = \u03b4(f \u2212 1) -i.e. the flux is always completely in the pixel with the PS.", "cite_spans": [], "ref_spans": []}, {"section": "Correcting for a finite point spread function", "text": "Then, for example,", "cite_spans": [], "ref_spans": []}, {"section": "Correcting for a finite point spread function", "text": "From here to determine F (k) (t) we simply need k \u2212 1 more derivatives. Using the generalized Leibniz rule, we have", "cite_spans": [], "ref_spans": []}, {"section": "Correcting for a finite point spread function", "text": "Then setting t = 0 and recalling the definition of p k , this yields", "cite_spans": [], "ref_spans": []}, {"section": "Correcting for a finite point spread function", "text": "as claimed.", "cite_spans": [], "ref_spans": []}, {"section": "Correcting for a finite point spread function", "text": "To calculate the f (k) in a pixel p, we need to calculate the x p,k and the sum \u221e m=1 x p,m . We may calculate these expressions analytically using the general sourcecount distribution in (4) . To calculate the sums, we make use of the relation ", "cite_spans": [], "ref_spans": []}, {"section": "Correcting for a finite point spread function", "text": "Finiteness of the total flux, and also the probabilities, requires n 1 > 2 and n k+1 < 2. However, both the integral and x p,0 , appearing in the last line above, may be divergent individually if 1 < n k+1 < 2. In this case, we analytically continue in n k+1 , evaluate the contributions individually, and then sum the two expressions to get a result that is finite across the whole range of allowable parameter space. The expressions for the x p,m and the sums over these quantities are given in App. C in terms of incomplete gamma-functions. In this appendix we derive analytic expressions for x p,m and \u221e m=1 x p,m , which go into (B3) and are needed to evaluate the non-Poissonian likelihood. This is done by a straightforward application of (A7) and (B10). Recall that x p,m represents the average number of m-count source in pixel p. We begin by working explicitly through the 1-and 2-break source-count distributions before discussing the general case.", "cite_spans": [], "ref_spans": []}, {"section": "1 break", "text": "For a single break, the pixel-dependent source count distribution is given in terms of counts by", "cite_spans": [], "ref_spans": []}, {"section": "1 break", "text": "In the following, we will suppress the overall factor of T (PS) p /E p , since it does not play an important role in this discussion and may always be restored by simply rescaling A. In the same spirit, we also suppress the pixel index p in x p,m .", "cite_spans": [], "ref_spans": []}, {"section": "1 break", "text": "With this in mind, we may explicitly evaluate the expression for x p,m using (A7): (C3) This is useful because we already know x 0 from the general form of x m above.", "cite_spans": [], "ref_spans": []}, {"section": "2 breaks", "text": "For 2 breaks, the source-count distribution is given in terms of counts by The source-count distribution in the general k-break case is given in (4) in terms of flux. In terms of counts and again suppressing pixel-dependent prefactors the result for x m and \u221e m=1 x m is a simple generalization from the expressions for the 1-and 2-break cases: ", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF55": {"title": "mpmath: a Python library for arbitrary-precision floating-point arithmetic (version 0", "authors": [{"first": "F", "middle": [], "last": "Johansson", "suffix": ""}], "year": 2013, "venue": "", "link": "125610425"}, "BIBREF57": {"title": "A guide to NumPy", "authors": [{"first": "T", "middle": ["E"], "last": "Oliphant", "suffix": ""}], "year": 2006, "venue": "", "link": null}}, "ref_entries": {"FIGREF1": {"text": "class NPTFit.nptfit.NPTF This is the main class used to set up and perform non- Poissonian and Poissonian template scans. It is initial- ized by nptf = NPTF ( tag = ' Untagged ' , work_dir = None )", "type": "figure"}, "FIGREF4": {"text": "class NPTFit.psf_correction.PSFCorrection This is the class used to construct the arrays f_ary and df_rho_div_f_ary for the PSF correction. An instance of PSFCorrection is initialized through pc_inst = PSFCorrection . PSFCorrection ( psf_dir = None , num_f_bins =10 , n_psf =50000 , n_pts_per_psf =1000 , f_trunc =0.01 , nside =128 , psf_sigma_deg = None ,", "type": "figure"}, "FIGREF6": {"text": "an . return_dndf_arrays ( comp , flux ) will return the discretized 1-D posterior distribution for mean ROI dN p (F )/dF at flux F for the PS model with template key comp. Note that the mean is computed over pixels p in the ROI. The 1-D posterior distributions for the individual model parameters may be accessed by", "type": "figure"}, "FIGREF7": {"text": "pscmask = np . array ( np . load ( ' fermi_data / fermidata_pscmask . npy ') , dtype = bool ) mask = cm . make_mask_total ( band_mask = True , band_mask_range = 2 , mask_ring = True , inner = 0 , outer = 30 , custom_mask = pscmask ) n . load_mask ( mask )", "type": "figure"}, "FIGREF9": {"text": "we are ready to analyze the results of the scan. First we load in relevant modules: import corner import matplotlib . pyplot as plt and then we load in the results of the scan (configured as above), n . load_scan ()", "type": "figure"}, "FIGREF11": {"text": "FIG. 1. The triangle plot obtained by analyzing the results of an NPTF in the Galactic Center, showing the one and two dimensional posteriors of the 11 parameters floated in the fit corresponding to three Poissonian and two non-Poissonian templates. For this analysis 3FGL point sources have been masked at 95% containment. See text for details.", "type": "figure"}, "FIGREF12": {"text": "an . p l o t _ s o u rce_co unt_m edian ( ' dsk ' , smin =0.01 , smax =1000 , nsteps =1000 , color = ' cornflowerblue ' , spow =2 , label = ' Disk ') an . p lo t _ s ou rce_count_band ( ' dsk ' , smin =0.01 , smax =1000 , nsteps =1000 , qs =[0.16 ,0.5 ,0.84] , color = ' cornflowerblue ' , alpha =0.3 , spow =2) an . p l o t _ s o u rce_co unt_m edian ( ' gce ' , smin =0.01 , smax =1000 , nsteps =1000 , color = ' forestgreen ' , spow =2 , label = ' GCE ') an . plot_source_count_band ( ' gce ' , smin =0.01 , smax =1000 , nsteps =1000 , qs =[0.16 ,0.5 ,0.84] , color = ' forestgreen ' , alpha =0.3 , spow =2)", "type": "figure"}, "FIGREF14": {"text": "FIG. 3. Intensity fractions for the smooth (green) and point source (red) templates correlating with the DM template, obtained by analyzing the results of an NPTF in the Galactic Center with 3FGL point sources masked at 95% containment.", "type": "figure"}, "FIGREF16": {"text": "In this section we present the mathematical foundation of the NPTF and the evaluation of the non-Poissonian likelihood in more detail that what was shown in Sec. II. Note that many of the details presented in this section have appeared in the earlier works of [1, 2, 4], however we have reproduced these here in order to have a single clear picture of the method.", "type": "figure"}, "FIGREF20": {"text": "C4) Again suppressing the pixel-dependent pre-factors, an ex- plicit evaluation gives", "type": "figure"}, "FIGREF21": {"text": "{\u0393(1 \u2212 n i+1 + m, S b,i+1 ) \u2212 \u0393(1 \u2212 n i+1 + m, S b,{\u0393(1 \u2212 n k+1 + m) \u2212 \u0393(1 \u2212 n k+1 + m, S b,k", "type": "figure"}, "TABREF0": {"text": "PS p = dF F dN p /dF ) in pixel p, for a fixed set of model parameters \u03b8, follows the template T (PS) p . On the other hand, the locations of the flux breaks and the indices are taken to be fixed between pixels.", "type": "table"}, "TABREF2": {"text": "The rest of the keywords arePrior [[min, max], ...]Log/linear-flat prior [bool,bool, ...] dnds_model 'specify_breaks' How to specify multiple breaks str fixed_params None Fix certain parameters [[int,float], ...] units 'counts' 'flux' or 'counts' units for breaksThe syntax for adding non-Poissonian models is that the model parameters are specified by [A, n 1 , n 2 , . . . , n k+1 , S b,1 , S b,2 , . . . , S b,k ] for a broken power-law with k breaks. As such, the model_tag, prior_range, and log_prior are now arrays where each entry refers to the respective model parameter. The code automatically determines the number of breaks by the length of the model_tag array. The arrays prior_range and log_prior should only include entries for model parameters that will be floated in the scan. Any model parameter may be fixed using the fixed_params array, with the syntax such that fixed_params = [[i,c_i],[j, c_j]] would fix the i th model parameter to c i and the j th to c j , where the parameter indexing starts from 0.", "type": "table"}}}
{"paper_id": "119426774", "_pdf_hash": "d0280f8cdbcedc8ef1569155c9be224a23b057c4", "abstract": [{"section": "Abstract", "text": "We present 42 low-resolution spectra of supernova (SN) 1993J, our complete collection from the Lick and Keck observatories, from day 3 after explosion to day 2454, as well as one Keck high-dispersion spectrum from day 383. SN 1993J began as an apparent SN II, albeit an unusual one. After a few weeks, a dramatic transition took place, as prominent helium lines emerged in the spectrum. SN 1993J had metamorphosed from a SN II to a SN IIb. Nebular spectra of SN 1993J closely resemble those of SNe Ib and Ic, but with a persistent Ha line. At very late times, the Ha emission line dominated the spectrum, but with an unusual, boxlike pro\u00d0le. This is interpreted as an indication of circumstellar interaction.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "INTRODUCTION", "text": "Supernova 1993J was visually discovered in the nearby galaxy M81 (NGC 3031 ; d \\ 3.6 Mpc ; Freedman et al. 1994 ) by F. Garcia on 1993 March 28.906 UT (Ripero, Garcia, & Rodriguez 1993 ; note that all calendar dates used herein are UT). It reached a maximum brightness of m V \\ 10.8 mag (e.g., Richmond et al. 1994) , becoming the brightest supernova (SN) in the northern hemisphere since SN 1954A Wild 1960 Barbon, Ciatti, & Rosino (m pg \\ 9.95 ; 1973) . In terms of observational coverage, both in temporal consistency (almost nightly observations at early times) and in the details of individual observations (including observations with signal-to-noise ratios [S/N], spectral resolutions, and wavelength regions not typically found in studies of SNe), SN 1993J is surpassed only by SN 1987A. Early spectra showed an almost featureless blue continuum, possibly with broad, but weak, Ha and He I j5876 lines. This led to a classi\u00d0cation of the SN as Type II Garnavich & Ann 1993 ; see Filippenko 1997 for a general discussion of SN types). Wheeler & Filippenko (1996) present a thorough review of the early work on SN 1993J.", "cite_spans": [{"start": 1042, "end": 1069, "text": "Wheeler & Filippenko (1996)", "ref_id": "BIBREF96"}], "ref_spans": []}, {"section": "INTRODUCTION", "text": "Both the spectra and the light curve of SN 1993J quickly began to indicate that this was not a typical Type II SN. Indeed, the initially unusual light curve and the appearance of He I lines in the spectra was interpreted as evidence that SN 1993J was similar to a SN Ib, with a low-mass outer layer of hydrogen that gave the early impression of a SN II (see discussion and references below). Following Woosley et al. (1987) , it was described as a \"\" Type IIb \u00cf\u00cf SN. This transformation from SN II to nearly SN Ib indicates a common mechanism (core collapse) for these two observationally de\u00d0ned subclasses. SN 1993J is thus one of the most signi\u00d0-cant SNe ever studied, not only for its role in linking Types II and Ib (and possibly Ic), but also because it was observed with such great detail.", "cite_spans": [], "ref_spans": []}, {"section": "INTRODUCTION", "text": "In\u00b02 of this paper we review the study of SN 1993J ; we are presenting over six years of optical spectra and it is appropriate to provide such a summary. (Wheeler & Filippenko 1996 only cover the \u00d0rst few months of the development of SN 1993J in their review ; moreover, the interpretation to follow depends on the context of the previous observations and analyses.) We then present the collection of our spectra of SN 1993J from the Lick and Keck observatories14 (\u00b03), along with a general description of the spectra through the various phases of evolution for the SN in\u00b04. Detailed analysis of our spectra for individual phases is discussed elsewhere (Filippenko, Matheson, & Ho 1993, hereinafter FMH93 ; Filippenko, Matheson, & Barth 1994, hereinafter FMB94 ; Matheson et al. 2000 , hereinafter Paper II).", "cite_spans": [{"start": 154, "end": 180, "text": "(Wheeler & Filippenko 1996", "ref_id": "BIBREF96"}], "ref_spans": []}, {"section": "PREVIOUS STUDIES OF SUPERNOVA 1993J", "text": "The evolution of the light curve of SN 1993J did not follow either of the two typical paths for SNe II. SN 1993J did not remain at a relatively constant brightness after a \u00c8\u00c8\u00c8\u00c8\u00c8\u00c8\u00c8\u00c8\u00c8\u00c8\u00c8\u00c8\u00c8\u00c8\u00c8 14 Spectropolarimetry obtained at Lick on days 24, 34, and 45 is discussed by Tran et al. (1997) and is not duplicated here.", "cite_spans": [], "ref_spans": []}, {"section": "PREVIOUS STUDIES OF SUPERNOVA 1993J", "text": "slight decline from maximum, as a normal Type II plateau SN would, nor did the brightness decline in the pattern of a Type II linear SN (for examples of these Type II light curves, see, e.g., Doggett & Branch 1985) . Instead, SN 1993J rose quickly, then rapidly declined for D1 week, only to brighten a second time over the next two weeks. This led to another rapid decrease in brightness for D3 weeks, followed by an approximately exponential decline. For a complete discussion of the photometry of SN 1993J, see Okyudo et al. (1993) , Schmidt et al. (1993) , van Driel et al. (1993) , Wheeler et al. (1993) , Benson et al. (1994) , Lewis et al. (1994) , Richmond et al. (1994 Richmond et al. ( , 1996 , Barbon et al. (1995) , Doroshenko, E\u00d0mov, & Shakhovskoi (1995) , and Prabhu et al. (1995) .", "cite_spans": [], "ref_spans": []}, {"section": "PREVIOUS STUDIES OF SUPERNOVA 1993J", "text": "The unusual initial behavior of the light curve rapidly led many SN modelers to conclude that SN 1993J was the result of a core-collapse explosion in a progenitor that had lost a signi\u00d0cant fraction of its hydrogen envelope, leaving only D0.1\u00c80.5 of hydrogen. The original envelope M _ could have been lost through winds Langer, & (Ho \u00d1ich, Duschinger 1993 ) from a fairly massive star (25\u00c830 M _ ). Another possibility explored by Hashimoto, Iwamoto, & Nomoto (1993 ; see also Nomoto et al. 1993 ) is that SN 1993J was the result of the explosion of an asymptotic giant branch star having main-sequence mass M ms B 7\u00c810 M _ , with a helium-rich envelope.", "cite_spans": [], "ref_spans": []}, {"section": "PREVIOUS STUDIES OF SUPERNOVA 1993J", "text": "A more likely solution is that the progenitor of SN 1993J was a member of a binary system and the companion had stripped away a considerable amount of hydrogen. The progenitor was observed during prior studies of M81. Aldering, Humphreys, & Richmond (1994) analyzed several sets of preexisting images and deduced that the photometry was inconsistent with a single star at the position of SN 1993J. They found that the best \u00d0t for the progenitor itself was a K0 I star with mag and V [R B 0.7 mag. M bol B [7. 8 Cohen, Darling, & Porter (1995) derived a similar color from a 5 month series of images of M81 from 1984 ; there was no apparent variability.", "cite_spans": [], "ref_spans": []}, {"section": "PREVIOUS STUDIES OF SUPERNOVA 1993J", "text": "Using the scenario of a star that had been stripped of most of its hydrogen envelope, Nomoto et al. (1993) and Shigeyama et al. (1994) Later studies continued to con-(M env B 0.9 M _ ). clude that a low-mass envelope of hydrogen on a helium core was the most likely scenario for the progenitor (Young, Baron, & Branch 1995 ; Utrobin 1996) . Intercomparison of two methods also indicated that the results were robust (Blinnikov et al. 1998) . Houck & Fransson (1996) used a nonlocal thermodynamic equilibrium (NLTE) synthetic spectrum code to \u00d0t nebular spectra and found that the Nomoto et al. (1993) models could explain the late-time spectra. They found a best \u00d0t with a 3.2 helium core M _ with a 0.2\u00c80.4 hydrogen envelope. Patat, Chugai, & M _ Mazzali (1995) also used the late-time spectra, speci\u00d0cally the Ha line, to derive an ionized hydrogen mass of 0.05\u00c80.2 this is a lower limit to the envelope mass. M _ ; Woosley et al. (1987) had already considered such a possibility for core-collapse SNe, giving them a new name : SNe IIb. The low-mass outer layer of hydrogen would give the initial appearance of a SN II, but the spectrum would slowly change to one more similar to that of a SN Ib, dominated by helium lines with the hydrogen either appearing weakly or completely gone. Indeed, Nomoto et al. (1993) predicted that the spectrum of SN 1993J would show this behavior. This was \u00d0rst con\u00d0rmed by , followed rapidly by Schmidt et al. (1993) and Swartz et al. (1993) . A complete analysis of our optical spectra covering the transformation of SN 1993J from a Type II to a Type IIb is presented by FMH93. Other studies of the early optical spectra include those of Wheeler et al. (1993) , Taniguchi et al. (1993) , Garnavich & Ann (1994) , Ohta et al. (1994) , Prabhu et al. (1995) , and Metlova et al. (1995) .", "cite_spans": [], "ref_spans": []}, {"section": "PREVIOUS STUDIES OF SUPERNOVA 1993J", "text": "Je \u2020ery et al. (1994) present an early ultraviolet (UV) spectrum of SN 1993J taken with the Hubble Space T elescope (HST ) on 1993 April 15. The other core-collapse SNe that had been observed in the UV to that point were compared with SN 1993J, and there were striking di \u2020erences. SN 1993J had a relatively smooth UV spectrum and was more similar to SN 1979C and SN 1980K, both of which are radio sources and thus likely to have thick circumstellar envelopes (e.g., Weiler et al. 1986 ). The UV spectra of SN 1987A, in contrast, showed broad absorption features. The illumination from circumstellar interaction may reduce the relative strengths of line features compared to the continuum and thus produce the featureless UV spectra of SNe 1979C, 1980K, and 1993J (Branch et al. 2000 . SN 1993J then evolved fairly rapidly into the nebular phase ; our analysis of this transition is covered by FMB94. The nebular-phase spectra were similar to those of a typical SN Ib, but the hydrogen lines never faded completely. In fact, Ha began to dominate the spectrum at late times, most likely the result of circumstellar interaction. There were several other papers that considered the nebular-phase spectra (and some relatively late-time spectra). Lewis et al. (1994) present the complete La Palma archive covering days 2 through 125. Li et al. (1994) discuss the nebular-phase spectra observed from the Beijing Astronomical Observatory. Barbon et al. (1995) show the \u00d0rst year of observations from Asiago ; the transformation of the SN from Type II to IIb is evident, as is the return of Ha at late times (by D200 days). A longer baseline (D500 days) for the spectra is found in the work of Finn et al. (1995) ; all the features described above are evident in their spectra, but the very late-time observations show even more clearly the presence of circumstellar interaction.", "cite_spans": [], "ref_spans": []}, {"section": "PREVIOUS STUDIES OF SUPERNOVA 1993J", "text": "There were optical spectropolarimetric observations of SN 1993J. Trammell, Hines, & Wheeler (1993) found a continuum polarization of P \\ 1.6%^0.1% on day 24 (assuming 1993 March 27.5 as the explosion date ; see below). Trammell et al. (1993) , as well as later considerations of the same data 1995 ; et al. 1996) , (Ho \u00d1ich Ho \u00d1ich argued that this polarization implied an overall asymmetry, but the source of this asymmetry was undetermined. The presence of SN 1993J in a binary system was implicated as a potential source for the asymmetry. With more epochs of observation (days 7, 8, 11 [V band only], 24, 30, 31, 32, 34, 45 , and 48), Tran et al. (1997) also found a polarization in the continuum of D1%, but a di \u2020erent level for the interstellar polarization. Nevertheless, they also concluded that SN 1993J was asymmetric. It is interesting to note that a subsequent SN IIb, SN 1996cb, showed substantially similar polarization of its spectra (Wang et al. 2000) .", "cite_spans": [], "ref_spans": []}, {"section": "PREVIOUS STUDIES OF SUPERNOVA 1993J", "text": "The analysis of individual aspects of the spectra has yielded some interesting results. Both and Spyromilio (1994) found evidence for clumpy ejecta with blueshifted emission lines. Houck & Fransson (1996) argue that the lines are not actually blueshifted, but that contamination from other lines appears to shift them. Nonetheless, the lines do show substructure that indicates clumpy ejecta. The discussion of the clumpy nature of the ejecta based on analysis of our spectra is presented in Paper II.", "cite_spans": [], "ref_spans": []}, {"section": "PREVIOUS STUDIES OF SUPERNOVA 1993J", "text": "Models of the early spectra could reproduce their overall shape, but the line strengths were problematic. Baron et al. (1993) found a photospheric temperature of D8000 K for day 10, but the predicted hydrogen and helium lines were too weak, possibly indicating unusual abundances or nonthermal e \u2020ects. A later analysis including the HST UV spectrum was \u00d0t well by including enhanced helium abundance and NLTE e \u2020ects (Baron, Hauschildt, & Branch 1994) . Je \u2020ery et al. (1994) also had difficulties \u00d0tting line strengths for transitions that are susceptible to NLTE e \u2020ects. Clocchiatti et al. (1995) studied the early spectra to follow the evolution of color temperature and to calculate a distance to M81 (D3.5 Mpc) using the expanding photosphere method (e.g., Eastman, Schmidt, & Kirshner 1996) . The NLTE treatment of calcium is explored by Zhang & Wang (1996) , who found a best \u00d0t with a reduced calcium abundance.", "cite_spans": [], "ref_spans": []}, {"section": "PREVIOUS STUDIES OF SUPERNOVA 1993J", "text": "SN 1993J was also observed quite thoroughly at other wavelengths (see Wheeler & Filippenko 1996 for a summary of early results). Pooley & Green (1993) presented a light curve at 2 cm obtained with the Ryle Telescope. These data were merged by Van Dyk et al. (1994) with the VLA data, which included not only observations at 2 cm, but also at 1.3 cm, 3.6 cm, 6 cm, and 20 cm. Interpreting the data within the context of standard theories of radio emission from SNe (e.g., Chevalier 1982 Chevalier , 1984 Weiler et al. 1986 ; Weiler, Panagia, & Sramek 1990) , Van Dyk et al. (1994) concluded that the radio absorbing material around the SN is inhomogeneous and that the circumstellar density pro\u00d0le is \u00d1atter than that expected for a constant mass-loss rate, constantvelocity wind. The \u00d1atter pro\u00d0le could be the result of decreasing mass-loss rate or increasing wind velocity. SN 1993J was also observed using very long baseline interferometry (VLBI). Early studies indicated either a disklike structure or an optically thick shell (Marcaide et al. 1994) , and other observations found SN 1993J to be circularly symmetric and expanding linearly (Bartel et al. 1994) . Later measurements found a spherically symmetric shell (Marcaide et al. 1995) . After years of observation using VLBI, Marcaide et al. (1997) still observed a symmetric shell, but the SN expansion had apparently begun to decelerate. With an even longer baseline, Bartel et al. (2000) also found that the expansion had begun to decelerate, as well as revealing some structure in the ejecta. As these studies probe di \u2020erent regions than the polarimetric observations described above, the spherical symmetry revealed by the VLBI images is not inconsistent with the asymmetry deduced from polarimetry.", "cite_spans": [{"start": 70, "end": 95, "text": "Wheeler & Filippenko 1996", "ref_id": "BIBREF96"}], "ref_spans": []}, {"section": "PREVIOUS STUDIES OF SUPERNOVA 1993J", "text": "Soft X-rays were detected from SN 1993J six days after the explosion by ROSAT (Zimmerman et al. 1994 ) and two days later by ASCA (Kohmura et al. 1994 ). Both observatories followed the SN for several months, recording a gradual decrease in X-ray \u00d1ux as well as a softening of the energy spectrum. The Compton Gamma-Ray Observatory detected SN 1993J with OSSE, and hard X-rays ([50 keV) were observed on at least two epochs (Leising et al. 1994) . All three of these groups, as well as Suzuki & Nomoto (1995) and Fransson, Lundqvist, & Chevalier (1996) , interpreted these observations as indications of circumstellar interaction, with the X-rays coming from either the shocked wind material or the reverse-shocked SN ejecta. Both Patat et al. (1995) and Houck & Fransson (1996) concluded that the late-time optical spectra could only be powered by a circumstellar interaction ; radioactive decay alone was not enough.", "cite_spans": [], "ref_spans": []}, {"section": "PREVIOUS STUDIES OF SUPERNOVA 1993J", "text": "Although SN 1993J has provided the best observational evidence for the transformation of a SN from one type to another, there have been other examples. The early spectra of SN 1987K showed hydrogen lines, but the late-time spectra more closely resembled those of SNe Ib (Filippenko 1988) . The transition itself was not observed, occurring while SN 1987K was in conjunction with the Sun. SN 1996cb underwent a very similar metamorphosis from SN II to SN Ib ; Qiu et al. (1999) present a complete spectroscopic record of the transformation. In addition, there were some suggestions of hydrogen in spectra of the Type Ic SN 1987M (Je \u2020ery et al. 1991 ; Filippenko 1992 ) and the SN Ic 1991A (and perhaps SN Ic 1990aa ; Filippenko 1992) . SN 1993J is clearly a signi\u00d0cant object in the study of SNe. By providing a link between SNe II and SNe Ib, it has strengthened the argument that SNe Ib (and, by extension, SNe Ic) are also core-collapse events.", "cite_spans": [], "ref_spans": []}, {"section": "OBSERVATIONS AND REDUCTIONS", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "L ow-Dispersion Spectra", "text": "Low-dispersion spectra of SN 1993J were obtained with the Kast double spectrograph (Miller & Stone 1993) at the Cassegrain focus of the Shane 3 m re\u00d1ector at Lick Observatory and with the Low-Resolution Imaging Spectrometer (LRIS ; Oke et al. 1995) at the Cassegrain focus of the Keck 10 m telescopes (both Keck I and Keck II were used). The Kast spectrograph has Reticon 400 ] 1200 pixel CCDs in both cameras, while LRIS has a single Tektronix 2048 ] 2048 pixel CCD. The spatial scale for the Kast CCD was per pixel ; the LRIS CCD was binned in the spatial 0A .8 direction, yielding per pixel. At Lick, the slit width was 0A .43 generally 2A, but 8A observations were also taken on potentially photometric nights to provide an absolute \u00d1ux scale ; the 2A data were scaled to the \u00d1ux level of the 8A observation. The 8A observations were done only when SN 1993J was reasonably bright (until about day 200). The LRIS slit width was typically 1A, but widths were also used when 0A .7 conditions allowed or when attempting to obtain better spectral resolution. Various gratings and grisms were utilized, yielding resolutions (full width at half maximum, FWHM) ranging from 2.5 to 15 Details of the exposures A . are given in Table 1 . Most of the spectra were taken with the slit oriented at, or near (within 10\u00a1), the parallactic angle c Observed wavelength range of spectrum. In some cases, the extreme ends are very noisy, and are not shown in the \u00d0gures. d Approximate spectral resolution (full width at half maximum intensity). e Position angle of the spectrograph slit. Most observations taken within 10\u00a1 of the parallactic angle (Filippenko 1982) . On day 123, difficult conditions arising from observing under the pole with an equatorially mounted telescope required constant rotation of the slit to observe the supernova ; the orientation was within 10\u00a1 of the parallactic angle for the duration of the observation. For day 881, a speci\u00d0c position angle (197) going through a nearby star was used to ensure that SN 1993J was in the slit. On days 83 and 89, the position angle used to observe the standard stars was signi\u00d0cantly di \u2020erent from the optimal parallactic angle, but the air mass of the observations was low. i Estimation of the photometric conditions for the night : N \\ not photometric, P \\ possibly photometric, Y \\ photometric, S \\ 2A slit width observations scaled to 8A slit width observations. j Seeing is estimated from the data and observers\u00cf records. k The range of exposure times for the various observations. In some cases, multiple exposures were taken so the actual time of integration at any given wavelength may be 3\u00c84 times the longest exposure time listed. (Filippenko 1982) , but exceptions are noted in Table 1 . We follow Lewis et al. (1994) in adopting 1993 March 27.5 (JD 2,449,074) as the date of explosion. Standard CCD processing and spectrum extraction were accomplished with VISTA (Terndrup, Lauer, & Stover 1984) through day 553 and IRAF15 for day 670 and thereafter (day 56 was also processed using IRAF). Optimal extraction was used for the IRAF reductions (Horne 1986 ). The wavelength scale was established using low-order polynomial \u00d0ts to calibration lamps of He-Hg-Cd-Ne-Ar (Lick) or He-Ne-Kr-Ar (Keck). The typical root mean square (rms) deviation for the wavelength solution was 0.1\u00c80.5 A , depending on the resolution for the particular exposure. Final adjustments to the wavelength scale were obtained by using the background sky regions to provide an absolute scale. We employed our own routines to \u00d1ux calibrate the data ; comparison stars are listed in Table 1 . Particular care was taken to remove telluric absorption features through division by an intrinsically featureless spectrum, where possible (Wade & Horne 1988 ; see also Paper II). The \u00d1ux standard was routinely employed for this purpose.", "cite_spans": [], "ref_spans": [{"start": 1222, "end": 1229, "text": "Table 1", "ref_id": "TABREF1"}, {"start": 2740, "end": 2747, "text": "Table 1", "ref_id": "TABREF1"}, {"start": 3613, "end": 3620, "text": "Table 1", "ref_id": "TABREF1"}]}, {"section": "L ow-Dispersion Spectra", "text": "As most of the spectra were observed with the position angle oriented along or near the parallactic angle, the relative spectrophotometry is quite good. For the nights during which an 8A slit width exposure was taken to provide an absolute \u00d1ux scale, we checked our \u00d1uxes against the BV RI photometry of Richmond et al. (1996) . Days 16, 45, and 209 were not photometric. Days 17, 18, 19, 34, 56 , and 93 all agreed quite well with the photometry (within D5% in B and V , slightly larger deviations in R and I, probably due to the di \u2020erences between the observed passband and the assumed passband used to calculate \u00d1uxes from the spectra). The \u00d1ux of the day 109 spectrum has large deviations from the broadband photometry (D20%). That night was our \u00d0rst attempt to observe SN 1993J \"\" under the pole \u00cf\u00cf with the equatorially mounted Shane 3 m telescope, and we attribute the \u00d1uxing errors to the difficulties arising from this complication to the observing program. Subsequent uses of the telescope \"\" under the pole \u00cf\u00cf were more successful, and days 123 and 139 are in fairly good agreement with the photometry, although they do di \u2020er in B. This may be the result of difficulties aligning the slit along the parallactic angle for these observations. Day 167 agrees with the photometry to within D10%, but day 182 shows much larger di \u2020erences. The spectrum had become almost completely nebular by this stage, so the e \u2020ects of strong emission lines falling near the edges of passbands may explain the discrepancies. For all of the other spectra, we had no absolute calibrators.", "cite_spans": [], "ref_spans": []}, {"section": "High-Dispersion Spectrum", "text": "A single high-dispersion spectrum was obtained on 1994 April 14 UT (day 383) with the HIRES echelle spectrometer (Vogt 1992 (Vogt , 1994 ) on the Keck I 10 m telescope. The HIRES detector is a Tektronix 2048 ] 2048 pixel CCD. The setup for these observations encompassed the range 4240\u00c86720 A in 31 spectral orders. Beyond D5100 small gaps in the A , wavelength coverage appear because the CCD was too \u00c8\u00c8\u00c8\u00c8\u00c8\u00c8\u00c8\u00c8\u00c8\u00c8\u00c8\u00c8\u00c8\u00c8\u00c8 15 IRAF is distributed by the National Optical Astronomy Observatories, which are operated by the Association of Universities for Research in Astronomy, Inc., under cooperative agreement with the National Science Foundation.", "cite_spans": [{"start": 113, "end": 123, "text": "(Vogt 1992", "ref_id": "BIBREF88"}], "ref_spans": []}, {"section": "High-Dispersion Spectrum", "text": "small to span the progressively wider orders. A KV408 order-blocking \u00d0lter was used to eliminate second-order blue light. The \"\" C5 \u00cf\u00cf slit decker was utilized to (1A .15 ] 7A) prevent overlapping orders and to ensure adequate sky background, yielding a spectral resolution of R \\ 38,000. The HIRES chip was binned in the spatial direction, with per pixel. There were three exposures of SN 1993J, two 0A .41 with integration times of 2700 s and one with an integration time of 1800 s. The seeing was and the night was D1A .2 photometric. At the time, HIRES had neither an image rotator nor an atmospheric dispersion compensator, so differential light losses may a \u2020ect the spectrum ; the position angle of the slit was not at the parallactic angle (Filippenko 1982) . For all three observations, SN 1993J was at an air mass of D1.5, so the e \u2020ects are small, especially redward of 4500 A .", "cite_spans": [], "ref_spans": []}, {"section": "High-Dispersion Spectrum", "text": "Once again, IRAF was used for standard CCD processing and spectrum extraction. We extracted onedimensional spectra by summing the \u00d0ve pixels centered on a polynomial \u00d0t to the centroid of the light distribution along the dispersion, yielding an e \u2020ective aperture of 1A .15", "cite_spans": [], "ref_spans": []}, {"section": "High-Dispersion Spectrum", "text": "A third-order \u00d0t to the thorium-argon comparison ] 2A .05. lamp spectra provided a wavelength solution with a dispersion of D0.003", "cite_spans": [], "ref_spans": []}, {"section": "High-Dispersion Spectrum", "text": "No attempt was made to \u00d1ux calibrate A . the data. The sdG star HD 84937 (Oke & Gunn 1983) was observed for use in the identi\u00d0cation and removal of telluric lines. In order to preserve the large-scale shape of the lines, several di \u2020erent attempts were made using the observed spectrum of HD 84937 and featureless regions of the spectrum of SN 1994I (see Ho & Filippenko 1995 for a discussion of the SN 1994I spectrum observed on this night). The corrections to the continuum shape made with SN 1994I provided the best representation when compared with low-dispersion spectra taken on approximately the same date. Residual errors remain in the overall shape of individual orders, but the small-scale structure is reproduced accurately.", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS AND DISCUSSION", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Days 3 to 34", "text": "Spectra from days 3 to 34 are shown in Figure 1 . The \u00d0rst spectrum obtained at Lick Observatory was taken on 1993 March 30, day 3. It shows a blue, nearly featureless continuum. There are some broad undulations that may be incipient P-Cygni features of Ha and He I j5876, but the presence of reduction artifacts makes interpretation problematic. Clocchiatti et al. (1995) found a best-\u00d0t blackbody curve for this spectrum that indicated a temperature of D30,000 K, along with mag. The day 3 spectrum also con-A V B 0.7 tained narrow (unresolved) emission features of He II j4686, [Fe X] j6374, and Ha. Benetti et al. (1994) also observed [Fe XIV] j5303. In addition, there are narrow absorption components of Ca II H and K and Na I D. The observed wavelengths of the narrow emission features allowed us to derive a relative heliocentric velocity for the SN of [140 km s~1, well in agreement with other results (e.g., Vladilo et al. 1993, [135 km s~1) . All spectra presented herein have had this velocity removed. More detailed studies using high-resolution spectrographs that discuss the narrow lines in the spectra of SN 1993J include those of Benetti et al. (1994) , Vladilo et al. (1993 Vladilo et al. ( , 1994 , and Bowen et al. (1994) .", "cite_spans": [], "ref_spans": [{"start": 39, "end": 47, "text": "Figure 1", "ref_id": "FIGREF1"}]}, {"section": "Days 3 to 34", "text": "As the SN cools, line structure begins to appear in the spectra. By days 16 through 19, SN 1993J resembles a rela- Figure 2 shows the day 19 spectrum on a linear \u00d1ux-density scale with some line identi\u00d0cations. Overall, this spectrum is very much like that of most SNe II. The spectra from days 32 through 34 start to show that SN 1993J is not a typical SN II. A broad notch develops in the Ha pro\u00d0le, and the emission component begins to split in two. In addition, the pro\u00d0le associated with He I j5876 and Na I D strengthens, especially in the absorption component. As described above, this is interpreted as the onset of a phase wherein the He I lines grow in prominence, with the notch in Ha being the P-Cygni pro\u00d0le of He I j6678. Note that the narrow feature seen in the Ha emission pro\u00d0le of earlier spectra at the wavelength of the helium notch is most likely telluric absorption (see Paper II for details). Another indication of helium is the P-Cygni pro\u00d0le of He I j7065 that also appears on day 32 in our spectra. Other He I lines are blended with other lines or are weak, and so are less convincing than j6678 and j7065.", "cite_spans": [], "ref_spans": []}, {"section": "Days 3 to 34", "text": "The notch in Ha is not obvious in the day 22 spectra of Barbon et al. (1995) or Lewis et al. (1994) , or in the day 23 spectrum of Prabhu et al. (1995) . It does appear in the day 25 spectra of Prabhu et al. (1995) and Barbon et al. (1995) ; they also have a day 26 spectrum with the notch. The notch   FIG. 2 .\u00c8Spectrum of SN 1993J from day 19 (1993 April 15) with line identi\u00d0cations. The \u00d1ux-density scale is linear and has been scaled to match the V -band photometry of Richmond et al. (1996) . The identi\u00d0ca-tion of the line at D4430 is uncertain, but it may be Ba II j4554 (see, e.g., A Williams 1987 ; Turatto et al. 1998 ; Fassia et al. 1998) .", "cite_spans": [], "ref_spans": []}, {"section": "Days 3 to 34", "text": "is clearly present in the day 27 spectrum of Finn et al. (1995) . (Note that the day 26 spectrum of Lewis et al. 1994 appears to have some reduction and/or observation errors ; it is very di \u2020erent from the spectra of the other groups at similar times, including their own from day 22.)", "cite_spans": [], "ref_spans": []}, {"section": "Days 45 to 109", "text": "The helium features continue to strengthen and the metamorphosis of SN 1993J from a Type II to IIb becomes readily apparent in days 45 through 109, shown in Figure 3 . The day 45 spectrum (Fig. 4) exhibits almost the entire He I series of lines. The most obvious lines remain He I j5876, j6678, and j7065, although j5876 is probably contaminated by Na I D. Other He I lines are also blended with other features, including j7281 (contaminated by [Ca II] jj7291, 7324), j5015 (blended with Fe II j5018), j4921 (a \u2020ected by Hb and Fe II j4924), and j4471 (blended with Hc).", "cite_spans": [], "ref_spans": [{"start": 157, "end": 165, "text": "Figure 3", "ref_id": "FIGREF2"}]}, {"section": "Days 45 to 109", "text": "By day 89, the helium lines begin to weaken in comparison with the rest of the spectrum, and they are e \u2020ectively gone by day 109, although a strong absorption due to He I j5876 and Na I D remains. This is similar to the late-time behavior of a typical SN Ib (e.g., Gaskell et al. 1986 ; . Although not quite at the fully nebular phase, some nebular lines begin to appear at these times, including Mg I] j4571, [O I] jj6300, 6364, and [Ca II] jj7291, 7324.", "cite_spans": [], "ref_spans": []}, {"section": "Days 123 to 266", "text": "The spectra from days 123 through 226 (Fig. 5) show fairly little evolution. The nebular lines strengthen relative to the continuum over time, resulting in an almost purely emission-line spectrum. The most dramatic aspect of these spectra is the continuing weakness of Ha. Qualitatively following the relative strength of [O I] jj6300, 6364 and Ha over these days shows the oxygen lines evolving to dominate the hydrogen strength. (Blending of the lines makes a quantitative ratio of these features very difficult.) The spectrum from day 182 is shown in Figure 6 with some line identi\u00d0cations. Aside from the weak Ha, this could easily be the nebular spectrum of a SN Ib or SN Ic. 5, 3.0, 4.5, 6.5, 8.3, 11.3, and 13.5 . Telluric absorption features are indicated for the day 91 spectrum, from which they could not be properly removed.", "cite_spans": [], "ref_spans": []}, {"section": "Days 286 to 553", "text": "The nebular lines begin to fade away during days 286 through 553 (Fig. 7) . The most prominent lines in the spectra on day 286\u00c8Mg oxygen line is reduced to a small feature on the blue shoulder of the Ha line by day 553.", "cite_spans": [], "ref_spans": [{"start": 65, "end": 73, "text": "(Fig. 7)", "ref_id": "FIGREF5"}]}, {"section": "Days 286 to 553", "text": "The day 387 spectrum is shown in Figure 8 . Note the development of the box-like Ha pro\u00d0le in comparison with day 182 (Fig. 6) 1993J\u00c8one dominated by the e \u2020ects of circumstellar interaction. This pro\u00d0le for Ha is discernible as early as day 298, perhaps even day 226, but it does not dominate the emission until day 473 and beyond. These emission pro\u00d0les imply a roughly spherical distribution for the source material, probably a geometrically thin shell, similar to that discussed above in the context of late-time radio observations. The nature of the spectra is very similar to that described by Chevalier & Fransson (1994) . Another inter- FIG. 8 .\u00c8Spectrum of SN 1993J from day 387 (1994 April 18) with line identi\u00d0cations. The \u00d1ux-density scale is linear and has been scaled to match the V -band photometry of Richmond et al. (1996) . esting aspect of the day 387 spectrum (and earlier spectra) is the presence of small-scale features in some of the emission lines. They are even more evident in Figure 9 , wherein the region of the spectrum containing [O I] jj6300 6364 and Ha is shown in greater detail, along with the HIRES spectrum obtained four days earlier. A full exploration of the clumps exhibited in the spectra of SN 1993J is presented in Paper II.", "cite_spans": [], "ref_spans": []}, {"section": "Days 670 to 2454", "text": "Circumstellar interaction continues to dominate the spectra of SN 1993J up to the most recent observations. Spectra from days 670 through 2454 are shown in Figure  10 . The box-like pro\u00d0les are especially obvious in the day 976 spectrum (Fig. 11) . While these pro\u00d0les are present earlier, the high S/N ratio of this spectrum allows one to see clearly the \"\" double-box \u00cf\u00cf created by the overlapping lines of He I j5876 and Na I D.", "cite_spans": [], "ref_spans": [{"start": 156, "end": 166, "text": "Figure  10", "ref_id": "FIGREF1"}, {"start": 237, "end": 246, "text": "(Fig. 11)", "ref_id": "FIGREF1"}]}, {"section": "Days 670 to 2454", "text": "One striking change that occurs during this period is highlighted by the spectra from day 976 (Fig. 11 ) and day 1766 (Fig. 12) . There appear to be narrower emission features on top of the boxy pro\u00d0les for [O III] jj4959, 5007 and [O II] jj7319, 7330 on day 1766 that are not obvious in the day 976 spectrum. Unfortunately, there is a large gap in the coverage at this point, so it is not known when these features appeared. They do show up at the same relative velocity in each pro\u00d0le (including the [O I] jj6300, 6364 doublet), indicating that they are related to the underlying oxygen lines. We interpret these features as the blue and red peaks of a double-horned pro\u00d0le due to a somewhat \u00d1at-tened, perhaps even disk-like emission source, with the red peak attenuated by absorption (see Paper II for details). They are superposed on the box-like pro\u00d0le from a roughly spherically distributed source. This is especially intriguing in light of the polarization measurements done at early times (Trammell et al. 1993 ; Tran et al. 1997) .", "cite_spans": [], "ref_spans": [{"start": 94, "end": 102, "text": "(Fig. 11", "ref_id": "FIGREF1"}, {"start": 118, "end": 127, "text": "(Fig. 12)", "ref_id": "FIGREF1"}]}, {"section": "Days 670 to 2454", "text": "With the knowledge of the day 1766 spectrum, the incipient beginnings of these features are discernible in the day 976 spectrum. In fact, the day 976 spectrum shows the weak, narrow remnant of the once prominent [O I] j6300 line still FIG. 9 .\u00c8Low-resolution spectrum of SN 1993J on day 387 compared with a high-resolution spectrum on day 383 (1994 April 14). The highresolution spectrum has been binned to 0.25 pixel~1 for clarity. The A global shape of each order of the high-resolution spectrum is not necessarily accurate. The substructure seen in the low-dispersion spectrum is re\u00d1ec-ted in the high-dispersion spectrum, and there is no apparent structure hidden by the lower resolution of the low-dispersion spectrum. present, but fading in comparison with the blue component of the two-horned pro\u00d0le of [O I]. These features persist, being strongly evident in the day 2454 spectrum (Fig. 13) .", "cite_spans": [], "ref_spans": [{"start": 889, "end": 898, "text": "(Fig. 13)", "ref_id": "FIGREF1"}]}, {"section": "Days 670 to 2454", "text": "The only other signi\u00d0cant change in the later spectra is the strengthening of [O III] jj4959, 5007 relative to [O III] j4363, indicating a drop in the density of the oxygenemitting regions. The [O I] jj6300, 6364 doublet begins to grow again relative to Ha. These changes are especially clear when comparing the day 2454 spectrum (Fig. 13) with the day 976 spectrum (Fig. 11) . Note that there is very little   FIG. 11 .\u00c8Spectrum of SN 1993J from day 976 (1995 November 28) with line identi\u00d0cations. The \u00d1ux-density scale is linear. change between days 2176 and 2454 (see Fig. 10 ). The overall spectra exhibit almost solely the emission from circumstellar interaction. The line-intensity ratios are generally similar to the predictions of Chevalier & Fransson (1994) , although some di \u2020er. Details of this analysis of the late-time spectral lines is presented in Paper II.", "cite_spans": [], "ref_spans": [{"start": 330, "end": 339, "text": "(Fig. 13)", "ref_id": "FIGREF1"}, {"start": 366, "end": 375, "text": "(Fig. 11)", "ref_id": "FIGREF1"}, {"start": 402, "end": 418, "text": "little   FIG. 11", "ref_id": "FIGREF1"}, {"start": 572, "end": 579, "text": "Fig. 10", "ref_id": "FIGREF1"}]}, {"section": "CONCLUSIONS", "text": "We have presented the complete existing collection of low-dispersion spectra of SN 1993J obtained at Lick and Keck observatories, as well as one high-dispersion spectrum from Keck. These 42 low-dispersion spectra, representing coverage from day 3 after explosion to day 2454, document thoroughly the distinctive characteristics of SN 1993J. The early spectra show a slightly unusual Type II event, followed by the appearance of strong helium absorption lines. After SN 1993J underwent this metamorphosis from Type II to IIb, the nebular phase developed rapidly, appearing as a typical late-time SN Ib or SN Ic, but with a weak residual Ha line. As the nebular lines weakened, new line pro\u00d0les emerged with box-like shapes implying circumstellar inter- FIG. 13 .\u00c8Spectrum of SN 1993J from day 2454 (1999 December 15) with line identi\u00d0cations. The \u00d1ux-density scale is linear. There is some second-order contamination of the spectrum beyond D7600 although it A , is not signi\u00d0cant ; as Fig. 10 shows, there is little structure in this region of the spectrum on earlier days. action with a spherical shell-like distribution. At even later times, double-horned pro\u00d0les appeared on top of the box pro\u00d0les, indicating the presence of a somewhat \u00d1attened or disk-like morphology along with the shell. As SN 1993J appears to be fading slowly (see Paper II), we plan to continue monitoring it spectroscopically for years to come. The metamorphosis in our spectra was discussed by FMH93, while the nebular spectra were analyzed by FMB94. Our study of the detailed line structure at relatively early times and the circumstellar interaction phase is presented in Paper II. This research was supported by NSF grants AST 91-15174 and AST 94-17213 to A.V. F. We are grateful to the sta \u2020s of the Lick and Keck observatories for help with the observations ; we are especially thankful to the Lick sta \u2020 for their heroic e \u2020orts in recon\u00d0guring the hardware and software of the equatorial Shane 3 m telescope to allow us to observe \"\" under the pole \u00cf\u00cf during the summer months of 1993 and 1994. William and Marina Kast provided a generous gift that led to the construction of the double spectrograph on the 3 m telescope that was used for most of the observations reported here. The W. M. Keck Observatory is operated as a scienti\u00d0c partnership among the California Institute of Technology, the University of California, and", "cite_spans": [], "ref_spans": [{"start": 984, "end": 991, "text": "Fig. 10", "ref_id": "FIGREF1"}]}], "bib_entries": {"BIBREF47": {"title": "Highlights of Astronomy", "authors": [{"first": "J", "middle": [], "last": "Koorneef", "suffix": ""}, {"first": "R", "middle": [], "last": "Bohlin", "suffix": ""}, {"first": "R", "middle": [], "last": "Buser", "suffix": ""}, {"first": "K", "middle": [], "last": "Horne", "suffix": ""}, {"first": "D", "middle": [], "last": "Turnshek", "suffix": ""}], "year": 1986, "venue": "", "link": "116965732"}, "BIBREF88": {"title": "Proc. ESO Workshop 40, High Resolution Spectroscopy with the VLT", "authors": [{"first": "S", "middle": ["S"], "last": "Vogt", "suffix": ""}], "year": 1992, "venue": "", "link": null}, "BIBREF89": {"title": "UCO/Lick Obs", "authors": [{"first": "", "middle": [], "last": "\u00c8\u00e8\u00e8", "suffix": ""}], "year": 1994, "venue": "", "link": null}, "BIBREF96": {"title": "Supernovae and Supernova Remnants", "authors": [{"first": "J", "middle": ["C"], "last": "Wheeler", "suffix": ""}, {"first": "A", "middle": ["V"], "last": "Filippenko", "suffix": ""}], "year": 1996, "venue": "", "link": "120528047"}}, "ref_entries": {"FIGREF0": {"text": ".\u00c8For each day, multiple observations are combined into a one-line summary. For days 670 and 976, the exposures with di \u2020erent slit widths are listed separately. a Days since estimated date of explosion, 1993 March 27 UT (JD 2,449,074). Note that the data from days 523 and 525 are combined into one spectrum in the \u00d0gures. b L \\ Lick 3 m/Kast Double Spectrograph ; K-I \\ Keck I 10 m/Low Resolution Imaging Spectrometer (LRIS) ; K-II \\ Keck II 10 m/LRIS.", "type": "figure"}, "FIGREF1": {"text": "FIG. 1.\u00c8Spectra of SN 1993J from days 3 to 34, assuming explosion on 1993 March 27.5 (JD 2,449,074). The \u00d1ux units are [2.5 log f j [ 21.10, following the de\u00d0nition of space telescope (ST) magnitudes (e.g., Koorneef et al. 1986). ST magnitudes are analogous to AB magnitudes ([2.5 log f l Oke & Gunn 1983), with the zero point yielding monochromatic [ 48.60 ; magnitudes for Vega in the Johnson V passband of D0. The following constants have been added to the individual spectra (top to bottom): ]1.7, [0.5, 0.0, 1.0, 2.0, 2.3, 3.5, and 5.3. Telluric absorption features are indicated for the day 3 spectrum, from which they could not be properly removed. In this and all subsequent \u00d0gures the systemic heliocentric velocity of [140 km s~1 has been removed.", "type": "figure"}, "FIGREF2": {"text": "FIG. 3.\u00c8Spectra of SN 1993J from days 45 to 109, with date of explosion and \u00d1ux units as in Fig. 1. The following constants have been added to the individual spectra (top to bottom) : 0.0, 1.5, 3.0, 4.5, 6.5, 8.3, 11.3, and 13.5. Telluric absorption features are indicated for the day 91 spectrum, from which they could not be properly removed.", "type": "figure"}, "FIGREF3": {"text": "FIG. 4.\u00c8Spectrum of SN 1993J from day 45 (1993 May 11) with line identi\u00d0cations. The \u00d1ux-density scale is linear and has been scaled to match the V -band photometry of Richmond et al. (1996).", "type": "figure"}, "FIGREF4": {"text": "FIG. 6.\u00c8Spectrum of SN 1993J from day 182 (1993 September 25) with line identi\u00d0cations. The \u00d1ux-density scale is linear and has been scaled to match the V -band photometry of Richmond et al. (1996).", "type": "figure"}, "FIGREF5": {"text": "FIG. 7.\u00c8Spectra of SN 1993J from days 286 to 553, with date of explosion and \u00d1ux units as in Fig. 1. The following constants have been added to the individual spectra (top to bottom) : 0.0, 2.5, 5.5, 7.5, 12.5, 15.5, 19.0, 22.0, and 25.0. Noisy spectra have been clipped for clarity.", "type": "figure"}, "FIGREF6": {"text": "FIG. 10.\u00c8Spectra of SN 1993J from days 670 to 2454, with date of explosion and \u00d1ux units as in Fig. 1. The following constants have been added to the individual spectra (top to bottom) : 0.0, 3.5, 6.5, 7.5, 10.5, 15.0, 17.5, 20.0, and 22.5. Noisy spectra have been clipped for clarity.", "type": "figure"}, "FIGREF7": {"text": "FIG. 12.\u00c8Spectrum of SN 1993J from day 1766 (1998 January 26) with line identi\u00d0cations. The \u00d1ux-density scale is linear.", "type": "figure"}, "TABREF0": {"text": "found a best \u00d0t to the light curve from their model of a 4", "type": "table"}, "TABREF1": {"text": "JOURNAL OF OBSERVATIONS Rangec Res.d P.A.e Opt. P.A.f", "type": "table"}}}
{"paper_id": "119427288", "_pdf_hash": "4a56b532c02fd6969e140d67ca276d577066ac0e", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "119427537", "_pdf_hash": "cca7799fb80b7f5c7f52bc54c8d2fde7268ea71e", "abstract": [{"section": "Abstract", "text": "We can probe observationally and reproduce theoretically the most detailed properties of the Crab Nebula nearest to the pulsar -The Inner Knot. The tiny knot is indeed a bright spot on the surface of a quasi-stationary magnetic relativistic shock that efficiently accelerates particles. It required that the part of the wind that produces the Inner Knot has low magnetization; thus, it is not a site of gamma-ray flares.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "We develop a model of particle acceleration during explosive reconnection events in relativistic highly magnetized plasma and apply the model to explain the Crab gammaray flares. Particles are efficiently accelerated by charge-starved DC-type electric fields during initial stages of magnetic flux merges. Thus, magnetic reconnection is an important, and possibly dominant process of particle acceleration in high energy astrophysical sources.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Understanding the nature of the Crab Nebula was one of the major achievements of Iosif Shklovsky (Shklovskii, I.S., On the Nature of the Crab Nebulas Optical Emission, Doklady Akad. Nauk SSSR 90, 983 (1953) , in Russian; translated with commentary in Lang & Gingerich 1979) . One might argue that the idea that the continuum emission is generated by a population of relativistic electrons via synchrotron emission gave birth to a new field -relativistic astrophysics. Only few years before Shklovsky' paper Minkowski wrote \"The only physically justified assumption is that the continuous spectrum is produced by free-free and free-bound transitions\" (Minkowski 1942) .", "cite_spans": [{"start": 251, "end": 273, "text": "Lang & Gingerich 1979)", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "Introduction", "text": "The Crab pulsar and its pulsar wind nebula (PWN) remain the prime targets for high energy astrophysical research. In many ways, the Crab Nebula is the paragon of astrophysical high energy source -many of the current models of Active Galactic Nuclei and Gamma Ray Bursts are based on what we have learned from the studies of the Crab. The recent detection of flares from the Crab Nebula by AGILE and Fermi satellites (Tavani et al. 2011; Abdo et al. 2011) have brought this object into the \"focal point\" once again. Their extreme properties seem impossible to explain within the standard theories of non-thermal particle acceleration and require their overhaul with important implications to high energy astrophysics in general (e. ", "cite_spans": [], "ref_spans": []}, {"section": "Crab Inner knot", "text": "In the MHD models of the Crab Nebula, the super-fast-magnetosonic relativistic wind of the Crab pulsar terminates at a reverse shock (Rees & Gunn 1974; Kennel & Coroniti 1984) . However, finding the shock in the images of the Crab Nebula has not been a straight-forward matter -there seem to be no sharp feature which can be undoubtedly identified with the shock surface. In their seminal paper, Kennel & Coroniti (1984) discuss the under-luminous region hosting the Crab pulsar and surrounded by the optical wisps as an indicator of the shock presence. After the discovery of the inner X-ray ring by Chandra (Weisskopf et al. 2000; Hester et al. 2002) , the ring is often referred to as the termination shock and yet this feature looks much more like a collection of knots than a smooth surface.", "cite_spans": [], "ref_spans": []}, {"section": "Crab Inner knot", "text": "The wind from an oblique rotator should have the so-called striped zone where the orientation of magnetic field alternated on the scale of the pulsar period. The magnetic energy associated with these stripes can be dissipated at the termination shock and converted into the energy of the wind particles (Lyubarsky 2003; Sironi & Spitkovsky 2011) .", "cite_spans": [], "ref_spans": []}, {"section": "Crab Inner knot", "text": "Given the highly anisotropic nature of the wind, the termination shock is squashed along the polar direction, Fig. 1 and can be highly oblique with respect to the upstream flow (Lyubarsky 2002) . Downstream of the shock, the flow can still be relativistic and its emission subject to strong Doppler beaming. The computer simulations of the Crab nebula and its radiation (Komissarov & Lyubarsky 2004 ) (see also more advanced more advanced 2D (Camus et al. 2009 ) and 3D (Porth et al. 2014) simulations) revealed the presence of a very bright compact feature in the synthetic synchrotron maps, highly reminiscent of the HST knot 1 of the Crab Nebula located very close to the pulsar (also called the inner knot, Hester et al. 1995) . (In these simulations, the termination shock was treated as source of synchrotron electrons with power-law energy spectrum, which then were carried out into the nebula by the shocked wind plasma.)", "cite_spans": [], "ref_spans": [{"start": 110, "end": 116, "text": "Fig. 1", "ref_id": "FIGREF1"}]}, {"section": "Crab Inner knot", "text": "Recently, a targeted multi-wavelength study of the Crab's inner knot has been conducted by Rudy et al. (2015) in order to check if it shows any activity correlated with the gamma-ray flares. Although no such correlation has been found, the optical data reveal the structure and temporal evolution of the knot with unprecedented detail. Lyutikov et al. (2016a) investigated if the data are consistent with the MHD-shock model of the knot using simple analytical and semi-analytical tools. In particular, they combined the theoretical shape of the shock with the oblique shock jumps in order to obtain the Doppler-beaming of the post shock emission and use this to determine the location, the shape and the brightness distribution of the knot. The model, Fig. 2 , successfully explains a number of its observed properties: Location: The knot is located on the same side of the pulsar as the Crab jet, along the symmetry axis of the inner nebula, and on the opposite side as the brighter section of the Crab torus. This is a direct consequence of the termination shock geometry and the Doppler-boosting.", "cite_spans": [], "ref_spans": [{"start": 753, "end": 759, "text": "Fig. 2", "ref_id": "FIGREF2"}]}, {"section": "Crab Inner knot", "text": "Size: The knot size is comparable to its separation from the pulsar. This also follows from the shock geometry and the Doppler-beaming. The anisotropy of the proper synchrotron emissivity, which vanishes along the magnetic field direction in combination with the relativistic aberration of light is another significant factor. Only models with low magnetization of the post-shock flow, with the effective magnetization parameter of the wind \u03c3 1 < 1 agree with the observations.", "cite_spans": [], "ref_spans": []}, {"section": "Elongation:", "text": "The knot is elongated in the direction perpendicular to the symmetry axis. This is because the knot emission comes from the region where the shock surface is almost parallel to the line of sight.", "cite_spans": [], "ref_spans": []}, {"section": "Polarization:", "text": "The knot polarization degree is high, and the electric vector is aligned with the symmetry axis. This come due to the fact that the post-shock magnetic field is highly ordered in the vicinity of the termination shock and azimuthal. In the model, the relativistic aberration of light leads to a noticeable rotation of the polarization vector along the knot and this prediction could be tested in future polarization observations. Accordingly, the polarization degree of the integral knot emission depends on the integration area -the bigger the area the smaller the degree is.", "cite_spans": [], "ref_spans": []}, {"section": "Polarization:", "text": "Luminosity: Taking into account Doppler beaming, the observed radiative efficiency of the inner knot is consistent with efficient particle acceleration at the termination shock and the knot's magnetic field of one milli-Gauss strength, which is a reasonable value for the inner Crab Nebula.", "cite_spans": [], "ref_spans": []}, {"section": "Variability:", "text": "The knot flux is anti-correlated with its separation from the pulsar. In the numerical simulations, the termination shock is found to be highly unsteady, changing its size and shape. As the shock moves away from the pulsar, so does the knot region, which leads to lower magnetic field and hence lower emissivity. Another outcome of the shock variability in the MHD simulations is the emission of wisps and hence one expects both the processes to occur on the same time-scale, which is consistent with the observations.", "cite_spans": [], "ref_spans": []}, {"section": "Variability:", "text": "Relation to Crab \u03b3-ray flares: The model requires that the sector of the wind that produces the inner knot has low magnetization \u03c3 1. Thus, it is not a region where flares originate since flares require highly magnetized medium, \u00a73.", "cite_spans": [], "ref_spans": []}, {"section": "Variability:", "text": "Our results may have a number of important implications to the astrophysics of relativistic plasma in general and that of PWN in particular. They show that the termination shock of the relativistic wind from the Crab pulsar is a reality and that this shock is a location of efficient particle acceleration. The strong Doppler-beaming of the emission from the shock explains why this shock has been so elusive. Only the emission from a small patch on the shock surface, the inner knot, is strongly Doppler-boosted and hence prominent. For most of the shock, its emission is beamed away from the Earth and hence difficult to observe.", "cite_spans": [], "ref_spans": []}, {"section": "Variability:", "text": "The shock model of the inner knot allows us to constrain the parameters of the wind from the Crab pulsar. Taken directly, the model requires the wind to be particle-dominated, \u03c3 1 < 1 , at least at the polar latitudes of 40 \u2022 \u2212 60 \u2022 . However, in the case of a striped wind, its termination shock can mimic that of a low \u03c3 flow even when the actual wind magnetization is extremely high (Lyubarsky 2003) . In this context, the magnetic inclination angle of the Crab pulsar should be above 45 \u2022 , which means that most of the Poynting flux of the Crab wind is converted into particles, if not in the wind itself then at its termination shock (Komissarov 2013) . This is in agreement with the results of numerical simulations, which can reproduce the observed properties of the inner Crab Nebula extremely well in models with moderate wind magnetization (Porth et al. 2014) . However, the polar region of a pulsar wind is free of stripes and can still inject highly magnetized plasma into its PWN.", "cite_spans": [], "ref_spans": []}, {"section": "Crab gamma-ray flares", "text": "The detection of flares from Crab Nebula by AGILE and Fermi satellites (Tavani et al. 2011; Abdo et al. 2011; Buehler et al. 2012 ) is one of the most astounding discoveries in high energy astrophysics. The unusually short durations, high luminosities, and high photon energies of the Crab Nebula gamma-ray flares require reconsideration of our basic assumptions about the physical processes responsible for acceleration of the highest-energy emitting particles in the Crab Nebula, and, possibly in other high-energy astrophysical sources.", "cite_spans": [], "ref_spans": []}, {"section": "Crab gamma-ray flares", "text": "The Crab flares are characterized by an increase of gamma-ray flux above 100 MeV by a factor of few or more on the day time-scale. This energy corresponds to the high end of the Crab's synchrotron spectrum. Most interestingly, in the other energy bands nothing unusual has been observed during the flares so far (Weisskopf et al. 2013 ). This suggests that the physical processes behind the flares lead to a dramatic increase of the highest energy population of relativistic electrons in the nebula, whereas lower energy population remains largely unaffected. The short duration of flares indicate explosive and highly localised events.", "cite_spans": [], "ref_spans": []}, {"section": "Crab gamma-ray flares", "text": "Most importantly, the peak of the flare spectrum approaches and even exceeds the maximal rest-frame synchrotron photon energy (de Jager et al. 1996; Lyutikov 2010; Clausen-Brown & Lyutikov 2012) . Balancing the synchrotron energy losses in the magnetic field B against the energy gain via acceleration in the electric field of strength E = \u03b7B leads to the upper limit of the synchrotron photon energy max \u223c \u03b7 mc 3 e 2 \u2248 100 MeV The high conductivity of astrophysical plasma ensures that for typical accelerating electric field \u03b7 < 1. The fact that the flare spectrum extends beyond this limit pushes \u03b7 towards unity, which implies energy gain on the scale of the gyration period. This practically excludes stochastic acceleration mechanisms in general and the shock acceleration in particular. In principle, strong Doppler boosting could somewhat reduce this constraint but the lack of observational evidence for ultra-relativistic macroscopic motion inside the nebula makes this unlikely.", "cite_spans": [], "ref_spans": []}, {"section": "Crab gamma-ray flares", "text": "A widely discussed alternative to the shock acceleration mechanism is the particle acceleration accompanying magnetic reconnection. It is well known that magnetic reconnection can lead to explosive release of magnetic energy, e.g. in solar flares. However, properties of plasma in the Crab Nebula, as well as magnetospheres of pulsars and magnetars, pulsar winds, AGN and GRB jets and other targets of relativistic astrophysics, are very different from those of more conventional Solar and laboratory plasmas (Lyutikov & Lazarian 2013) . In particular, the energy density of magnetic field can exceed not only the thermal energy density but also the rest mass-energy density of plasma particles. In order to quantify such a strong magnetization, it is convenient to use the relativistic magnetization parameter", "cite_spans": [], "ref_spans": []}, {"section": "Crab gamma-ray flares", "text": "where w = \u03c1c 2 + (\u03b3/\u03b3 \u2212 1)p is the relativistic enthalpy, which includes the rest mass-energy density of plasma. In traditional plasmas this parameter is very small but in relativistic astrophysics \u03c3 1 is quite common. This parameter is uniquely related to the Alfv\u00e9n speed v A via", "cite_spans": [], "ref_spans": []}, {"section": "Crab gamma-ray flares", "text": "We developed a model of particle acceleration in explosive reconnection events in relativistic magnetically-dominated plasmas and apply it to explain gamma-ray flares from the Crab Nebula (Lyutikov et al. 2016b) . The model relies on development of current-driven instabilities on macroscopic scales (not related to plasma skin depths), driven by large-scales magnetic stresses (of the type \"parallel currents attract\"). Using analytical and numerical methods (fluid and particle-in-cell simulations), we study a number of model problems involving merger of both current-carrying and zero total current magnetic flux tubes in relativistic magnetically-dominated plasma: (i) we extend Syrovatsky's classical model of explosive X-point collapse to magnetically-dominated plasmas; (ii) we consider instability of two-dimensional force-free system of magnetic islands/flux tubes (2D \"ABC\" structures); (iii) we consider merger of two zero total poloidal current magnetic flux tubes. In all cases regimes of spontaneous and driven evolution are investigated.", "cite_spans": [], "ref_spans": []}, {"section": "Large scale dynamics of PWNe -formation of current-carrying flux tubes", "text": "The powerful Crab flares require that energy from a macroscopic scale is made available to the acceleration process. As we will discuss in the following, current-driven MHD instabilities like the coalescence of parallel currents and the \"X-point collapse\" can be a viable way to achieve this. One of the key questions is then how a violently unstable and highly magnetized configuration is setup in the first place. To locate potential sites for the flaring region, we need to identify regions of high sigma and analyze the flow structure in these candidate flaring regions. Here we use the result of simulations by Porth et al. (2014) . Although the scales required for the \"daily\" flare duration are not resolved by the simulation (its resolution is > 3 light-days), it is instructive to correlate the high-sigma region (that forms as a consequence of flow-expansion) with the current distribution in the simulations.", "cite_spans": [], "ref_spans": []}, {"section": "Large scale dynamics of PWNe -formation of current-carrying flux tubes", "text": "Importantly, highly magnetized regions in the bulk of the nebula can be achieved via flow expansion at intermediate latitude regions starting with only mildly magnetized wind. In Fig. 1 we show the magnetization in the xy-plane from simulations of (Porth et al. 2014) . One can clearly see that the magnetization rises well above the maximal injected value of \u03c3 = 1. The highest value of \u03c3 \u2248 8 in the snapshot is achieved at the point where radial expansion reverses and forms the plume-like polar flow.", "cite_spans": [], "ref_spans": [{"start": 179, "end": 185, "text": "Fig. 1", "ref_id": "FIGREF1"}]}, {"section": "Large scale dynamics of PWNe -formation of current-carrying flux tubes", "text": "To better understand the geometry of the current and magnetic field, we display a representative volume rendering of the polar region in Fig. 3 . In the rendering, one can see the violently unstable polar beam embedded into the more regular high-\u03c3 region comprised of toroidal field lines. The plume forms downstream of this structure and is also strongly perturbed. A part of the disrupted plume approaches the termination shock as a flux-tube. The presence of such a configuration where two flux tubes can come together very close to the high sigma region lets us speculate that Crab flares might originate when the right geometry (e.g. parallel flux tubes) coincides with high magnetization as present in the nebula even for moderate wind magnetization. For higher magnetizations of the polar beam, the mechanism described by Lyubarsky (2012) could directly act also without first having to rely on enhancement of \u03c3 via flow expansion. Extrapolating from the moderate sigma simulations where the polar beam is highly unstable and forms a filamented current, this seems feasible at the very least.", "cite_spans": [], "ref_spans": [{"start": 137, "end": 143, "text": "Fig. 3", "ref_id": "FIGREF3"}]}, {"section": "Large scale dynamics of PWNe -formation of current-carrying flux tubes", "text": "As an initial pre-flare state of plasma we consider a 2D force-fee lattice of magnetic flux tubes", "cite_spans": [], "ref_spans": []}, {"section": "Large scale dynamics of PWNe -formation of current-carrying flux tubes", "text": "This constitutes a lattice of force-free magnetic islands separated by 90 o X-points in equilibrium.", "cite_spans": [], "ref_spans": []}, {"section": "Large scale dynamics of PWNe -formation of current-carrying flux tubes", "text": "Islands have alternating out-of-the-plane poloidal fields and alternating toroidal fields. Each magnetic flux tube carries a magnetic flux \u221d B 0 /\u03b1 2 , energy per unit length \u221d B 2 0 /\u03b1 2 , helicity per unit length \u221d B 2 0 /(\u03b1 3 ) and axial current \u221d B 0 /(\u03b1). Helicity of both types of flux tubes is of the same sign. Previously, this configuration (called ABC) has been considered by Parker (1983) in the context of Solar magnetic fields", "cite_spans": [], "ref_spans": []}, {"section": "Large scale dynamics of PWNe -formation of current-carrying flux tubes", "text": "The configuration (2) is unstable, Fig. 4 . The instability of the 2D ABC configuration is of the kind \"parallel currents attract\". In the initial configuration the attraction of parallel currents is balanced by the repulsion of anti-parallel ones. Small amplitude fluctuations lead to fluctuating forces between the currents, that eventually lead to the disruption of the system. To identify the dominant instability mode let us consider a simplified model problem replacing each island by a solid tube carrying a given current. Such incompressible-type approximation is expected to be valid at early times, when the resulting motions are slow and the amount of the dissipated magnetic energy is small. We identify two stages of particle acceleration: (i) fast explosive prompt X-point collapse and (ii) ensuing island merger. The fastest acceleration occurs during the initial catastrophic Xpoint collapse, with the reconnection electric field of the order of the magnetic field. During the X-point collapse particles are accelerated by charge-starved electric fields, which can reach (and even exceed) values of the local magnetic field. The explosive stage of reconnection produces nonthermal power-law tails with slopes that depend on the average magnetization \u03c3. For plasma magnetization \u03c3 \u2264 10 2 the spectrum power law index is p < 2; in this case the maximal energy depends linearly on the size of the reconnecting islands. For higher magnetization, \u03c3 \u2265 10 2 , the spectra are soft, p < 2, yet the maximal energy \u03b3 max can still exceed the average magnetic energy per particle, \u223c \u03c3, by orders of magnitude (if p is not too close to unity). The X-point collapse stage is followed by magnetic island merger that dissipates a large fraction of the initial magnetic energy in a regime of forced magnetic reconnection, further accelerating the particles, but proceeds at a slower reconnection rate.", "cite_spans": [], "ref_spans": [{"start": 35, "end": 41, "text": "Fig. 4", "ref_id": "FIGREF4"}]}, {"section": "Large scale dynamics of PWNe -formation of current-carrying flux tubes", "text": "Our model of Crab flares has a number of key features, that are both required by observations Acceleration mechanism. We argued that the particles producing Crab flares are accelerated in explosive magnetic reconnection events. This is, arguably, the first solidly established case in high energy astrophysics of direct acceleration in reconnection events (as opposed to shock acceleration). In addition, since in our mode the maximal energy that particles can achieve grows with the size of the acceleration region, it is possible that smaller reconnection events are responsible for the acceleration of the majority of high-energy emitting particles in the Crab Nebula; shock acceleration does work -producing the Crab inner knot (Lyutikov et al. 2016a ) -but it may be subdominant for the acceleration of high energy particles.", "cite_spans": [], "ref_spans": []}, {"section": "Large scale dynamics of PWNe -formation of current-carrying flux tubes", "text": "Location of flares. The flare-producing region is located at polar intermediate latitudes, between 10 and \u223c 45 degrees, where the wind magnetization is expected to be high (the lower limit on the flare latitude comes from available required potential, while upper limit comes from modeling of the Crab inner knot Lyutikov et al. (2016a) ). The sectors of the wind that eventually become the acceleration sites for flare particle have mild magnetization, \u03c3 w \u223c 10 \u2212 100. Magnetization first increases at the oblique termination shock and later in the bulk, during the deceleration of the mildly relativistic post-shock flow. As the flow decelerates to subrelativistic velocities, large scale kink instabilities lead to formation of current-carrying flux tubes, Fig. 3 .", "cite_spans": [], "ref_spans": [{"start": 760, "end": 766, "text": "Fig. 3", "ref_id": "FIGREF3"}]}, {"section": "Large scale dynamics of PWNe -formation of current-carrying flux tubes", "text": "Size of the accelerating region. In our model the acceleration occurs on macroscopic scales, not related to the plasma microscopic scales, like the skin depth. (Previous models of reconnection in Crab flares, e.g., Cerutti et al. 2012a,b , were based on the development of the tearing mode and achieved acceleration on scale related to the skin depth -there is not enough potential on scales of few skin depths to account for Crab flares.)", "cite_spans": [], "ref_spans": []}, {"section": "Large scale dynamics of PWNe -formation of current-carrying flux tubes", "text": "Relativistic beaming motion of the flare producing region. The peak frequency of flares, the energy and the energetics of flares all require mildly relativistic \"bulk\" motion of the flare producing particles, with \u0393 \u223c few. This is achieved via \"kinetic beaming\", and not through a genuine, fluid-like bulk motion of the lower energy component.)", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF14": {"title": "A source book in astronomy and astrophysics", "authors": [{"first": "K", "middle": ["R"], "last": "Lang", "suffix": ""}, {"first": "O", "middle": [], "last": "Gingerich", "suffix": ""}], "year": 1979, "venue": "", "link": null}}, "ref_entries": {"FIGREF0": {"text": ". Lyutikov 2010; Clausen-Brown & Lyutikov 2012; Cerutti et al. 2012a; B\u00fchler & Blandford 2014; Lyutikov et al. 2016b)", "type": "figure"}, "FIGREF1": {"text": "Fig. 1.-Left Panel: Zoom-in on the central part of global PWN simulation (Lyutikov et al. 2016a). The dashed line is the line of view and the blue curves show the regions of enhanced observed emissivity.The dot-dashed line separates the high and low magnetization regions of the wind. The arrowed lines are the instantaneous stream lines. Red line if the position of the shock. There is a clearly visible region of high magnetization at intermediate latitudes. Right Panel: View of the polar region of the termination shock for f (\u03b8) = sin 2 \u03b8 and the viewing angle \u03b8 ob = 60 \u2022 ; the pulsar position is shown by the dot.", "type": "figure"}, "FIGREF2": {"text": "Fig. 2.-Left Panel: one of the images from Rudy et al. (2015). Right panel: theoretical emission map for magnetization parameters, \u03c3 = 0 Lyutikov et al. (2016a). The pulsar is located at the origin.", "type": "figure"}, "FIGREF3": {"text": "Fig. 3.-3D volume rendering showing current filamentation of the polar beam just downstream of the termination shock. The shock surface is indicated as the orange plane and we draw field-lines shaded from white (\u03c3 = 0) to black (\u03c3 = 5). One clearly sees two current filaments producing structures similar to magnetic flux tubes. As discussed in Porth et al. (2014), streamlines from intermediate latitudes reach the axis behind this inner violently unstable region and form a plumelike outflow of moderate velocity v \u2248 0.7c.", "type": "figure"}, "FIGREF4": {"text": "Fig. 4.-X-point collapse and island merging for a set of unstressed magnetic islands in force-free simulations. We plot 1 \u2212 E 2 /B 2 at times t = 8.0, 10.0, 15.0 and 20. Compare with results of PIC simulations, Fig. 5.", "type": "figure"}, "FIGREF5": {"text": "Fig. 5.-Physics of particle injection into the acceleration process, from a 2D PIC simulation of ABC instability with kT /mc 2 = 10 \u22124 , \u03c3 = 42, performed within a square domain of size 2L \u00d7 2L. We plot the 2D ABC structure at ct/L = 6.65. Left panel: 2D plot of the out-of-plane field B z , in units of B 0,in . Among the particles that exceed the threshold \u03b3 0 = 30 within the interval 6.5 \u2264 ct 0 /L \u2264 6.8 we select the 20 particles that at the final time reach the highest energies, and with open white circles we plot their locations at the injection time t 0 . Center panel: 2D plot of the mean kinetic energy per particle \u03b3 \u2212 1 . Right panel: 2D plot of E \u00b7 B/B 2 0,in , showing in red and yellow the regions of charge starvation. Comparison of the top panel with the bottom panel shows that particle injection is localized in the charge-starved regions.", "type": "figure"}}}
{"paper_id": "119429168", "_pdf_hash": "eafc02fe965cd649a414fa52126050b2304dacc7", "abstract": [{"section": "Abstract", "text": "Context. Galaxy clusters at high redshift are important to test cosmological models and models for the growth of structure. They are difficult to find in wide-angle optical surveys, however, leaving dedicated follow-up of X-ray selected candidates as one promising identification route. Aims. We aim to increase the number of galaxy clusters beyond the SDSS-limit, z \u223c 0.75. Methods. We compiled a list of extended X-ray sources from the 2XMMp catalogue within the footprint of the Sloan Digital Sky Survey. Fields without optical counterpart were selected for further investigation. Deep optical imaging and follow-up spectroscopy were obtained with the Large Binocular Telescope, Arizona (LBT), of those candidates not known to the literature. Results. From initially 19 candidates, selected by visually screening X-ray images of 478 XMM-Newton observations and the corresponding SDSS images, 6 clusters were found in the literature. Imaging data through r,z filters were obtained for the remaining candidates, and 7 were chosen for multi-object (MOS) spectroscopy. Spectroscopic redshifts, optical magnitudes, and X-ray parameters (flux, temperature, and luminosity) are presented for the clusters with spectroscopic redshifts. The distant clusters studied here constitute one additional redshift bin for studies of the L X \u2212 T relation, which does not seem to evolve from high to low redshifts. Conclusions. The selection method of distant galaxy clusters presented here was highly successful. It is based solely on archival optical (SDSS) and X-ray (XMM-Newton) data. Out of 19 selected candidates, 6 of the 7 candidates selected for spectroscopic follow-up were verified as distant clusters, a further candidate is most likely a group of galaxies at z \u223c 1.21. Out of the remaining 12 candidates, 6 were known previously as galaxy clusters, one object is a likely X-ray emission from an AGN radio jet, and for 5 we see no clear evidence for them to be high-redshift galaxy clusters.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Clusters of galaxies are considered the largest gravitationally bound structures in the Universe, and they emit radiation on a wide wavelength range. The multi-component nature of clusters gives rise to various detection methods, since distinct physical effects contribute to different parts of the spectrum they emit. Beneath the main component of galaxy clusters, which is thought to be composed of dark matter and is hence not directly observable, the next major fraction is the hot ionized intra-cluster medium (ICM). The ICM can be observed through thermal emission of its gravitationally heated gas, which mainly emits in the soft XThe catalogue, similar to Table A.1, is available in electronic form at the CDS via anonymous ftp to cdsarc.u-strasbg.fr (130.79.128.5) or via http://cdsweb.u-strasbg.fr/cgi-bin/qcat?J/A+A/ Based on observations obtained with XMM-Newton, an ESA science mission with instruments and contributions directly funded by ESA Member States and NASA The LBT is an international collaboration among institutions in the United States, Italy and Germany. LBT Corporation partners are: The University of Arizona on behalf of the Arizona Board of Regents; Istituto Nazionale di Astrofisica, Italy; LBT Beteiligungsgesellschaft, Germany, representing the Max-Planck Society, The Leibniz Institute for Astrophysics Potsdam, and Heidelberg University; The Ohio State University, and The Research Corporation, on behalf of The University of Notre Dame, University of Minnesota and University of Virginia. -http://www.lbto.org/for-investigators.html ray regime. Inverse-Compton scattering of the ICM and photons of the cosmic microwave background, the Sunyaev-Zel'dovich (SZ effect; Sunyaev & Zeldovich 1972) , can be investigated at millimeter wavelengths. Optical and near-infrared (near-IR) observations, however, allow redshift measurements with moderate effort, and for instance reveal the dynamical state of the galaxy population of the cluster, as well as the morphology and star formation history of the individual members. The suitability of different wavelength regimes for detecting galaxy clusters is proven by various campaigns, for example B\u00f6hringer et al. (2001) , Gladders & Yee (2005) , and Vale & White (2006) for the selection using X-ray, optical, and millimeter wavelength, respectively. Important properties of galaxy clusters such as their number density and masses deliver important constraints for cosmological models. Large-area X-ray surveys like the ROSAT All Sky Survey (Voges et al. 1999 ) detected large numbers of clusters, see for example the Meta-Catalog of X-ray detected Clusters of galaxies (MCXC; Piffaretti et al. 2011) . Observations with XMM-Newton increase the number of deeply exposed regions of the X-ray sky, allowing for different luminosity constraints of potential clusters. Many cluster surveys are based on X-ray selection and optical verification of sources, either working on complete sets of archival data for the lower redshift regime (e.g. XMM-Newton and SDSS; Takey et al. 2011 Takey et al. , 2013 Takey et al. , 2016 A&A proofs: manuscript no. aa31128-17_abridged troscopy for discovering low-luminosity and high-redshift clusters (e.g. Fassbender et al. 2011; Pacaud et al. 2016) .", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "Large samples of clusters were confirmed using the redsequence method from photometric data of optical sky surveys, for example the MaxBCG Catalog based on SDSS photometry (Koester et al. 2007 ) and redMaPPer using data from SDSS and the Dark Energy Survey (DES) (Rykoff et al. 2016) . Other cluster surveys make use of spectroscopically confirmed galaxies as verification, for instance spectra of BCGs from the SDSS (Takey et al. 2011) . However, redshifts from SDSS data alone (either photometric or spectroscopic) are limited to redshifts below z \u223c 0.75. Buddendiek et al. (2015) cross-matched ROSAT All Sky Surveys sources with red galaxies from the SDSS, and using follow-up observations with the William Herschel Telescope (WHT) and the Large Binocular Telescope, Arizona (LBT), they were able to identify clusters at 0.6 z 1.0. Bleem et al. (2015) conducted a study using the SZ effect to discover galaxy clusters. Since the dimming of the observed SZ flux caused by the luminosity distance to the cluster is partly compensated for by the higher energy density of the cosmic microwave background (CMB) at higher redshifts, current SZ surveys (e.g. from the SPT) allow probing high-mass galaxy clusters out to z > 1. Bleem et al. (2015) used IR imaging and spectroscopy of SPITZER and gound-based facilities to verify overdensities of galaxies and to determine their redshift. Another approach is to select clusters purely on their near-IR and IR colour, where the z-band and the 3.6\u00b5m band of SPITZER, for instance, allow for tracing the 4000\u00c5 break of galaxies out to z > 1 (e.g. Muzzin et al. 2009; Webb et al. 2015; Wilson et al. 2009 ).", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "Here we investigate galaxy clusters that were serendipitously found by XMM-Newton observations and are listed in the 2XMMp catalogue, the predecessor of the public 2XMM catalogue (Watson et al. 2009 ). By explicitly considering SDSS blank fields in our selection, we intend to increase the number of high-redshift (z \u223c 1) galaxy clusters. This is the redshift regime where existing large-area optical surveys lack sensitivity to unambiguously confirm these clusters. We carried out follow-up observations at the LBT using the LBC prime focus camera for imaging and MODS for multi-object spectroscopy, resulting in identifications of six new clusters and one high-redshift group. Furthermore, six of the selected X-ray sources were identified with clusters of galaxies that have been published previously.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "This new sample complements the cluster samples published by Takey et al. (2013) and Takey et al. (2014) , which were also selected from the 2XMM catalogue, adding 13 high-redshift objects to the cluster identifications in the 2XMM/SDSS footprint.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "The paper is organized as follows: In Section 2 we explain the sample definition based on archival XMM-Newton data. Details on data reduction and the analysis of optical pre-imaging and spectroscopic follow-up are outlined in Section 3 and Section 4, respectively. The treatment of archival X-ray data is described in Section 5. Section 6 presents the results of this work. We describe how we derive the spectroscopic properties and cluster mass (Sect. 6.1), the generation and treatment of X-ray spectra to measure fluxes and ICM temperatures (Sect. 6.2), and detail the properties of the individual clusters in the following subsections. An analysis of the L \u2212 T relation (Sect. 6.6), using our sample in comparison to data from the literature, concludes the results section. We summarize our findings in Section 7. In the appendix we list photometric and spectroscopic properties of the fields observed with LBC and MODS at the LBT (Appendix A), and present optical and IR images of the previously known clusters (Appendix B), as well as of the rejected or unclassified fields (Appendix C).", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "Throughout the paper we assume a standard cosmology with \u2126 M = 0.3, \u2126 \u039b = 0.7 and H 0 = 70 km s \u22121 Mpc \u22121 . The critical density of the Universe for the respective mean cluster redshifts can be derived using \u03c1 c = 3H(z) 2 \u00b7 (8\u03c0 G) \u22121 , with the gravitational constant G and the Hubble parameter H(z). All given optical magnitudes refer to the AB system.", "cite_spans": [], "ref_spans": []}, {"section": "Sample definition", "text": "The catalogue 2XMMp, a pre-release of the second XMMNewton catalogue (2XMM; Watson et al. 2009 ), lists all sources detected with the XMM-EPIC cameras in \u223c 2400 observations before April 2006, covering an area on the sky of \u223c 360 deg 2 . When this project started, the 2XMMp catalogue was the current and most complete catalogue of XMM-Newton serendipitous sources. Since then, the XMM-Newton catalogue was updated continuously through incremented observations and changes in the data reduction pipeline. In Sect. 5 we compare the initial sample parameters to the more recent 3XMM-DR6 catalogue (Rosen et al. 2016) .", "cite_spans": [], "ref_spans": []}, {"section": "Sample definition", "text": "For our cluster sample we selected only observations within the footprint of the Sloan Digital Sky Survey DR6 (AdelmanMcCarthy et al. 2008 ) and at Galactic latitudes |bII| > 20", "cite_spans": [], "ref_spans": []}, {"section": "Sample definition", "text": "\u2022 . Observations not suitable for the detection of extended sources (e.g. because of very extended or very bright targets, or observations with severe background contamination) were removed by means of visual screening of the EPIC images. This reduced the number of EPIC pointings used for the compilation of our input catalogue to 478. When we take repeated or overlapping pointings in the same sky area into account, the total survey area is \u223c 60 deg 2 . For the 2XMM data processing, the source detection pipeline of XMM-SAS version 7.1 was used in a configuration enabling the classification of sources as point-like or extended. Extended sources were fitted with radially symmetric \u03b2-profiles, convolved with the corresponding EPIC point-spread function (PSF), in order to determine the source parameters. Since the spurious detection rate of extended sources is relatively high (e.g. near bright point-sources or because of blending of multiple point-sources), another visual screening step was necessary to clean the sample. The final list of extended sources comprises 412 entries.", "cite_spans": [], "ref_spans": []}, {"section": "Sample definition", "text": "In order to identify candidates for distant galaxy clusters, we correlated the source positions with the SDSS DR6 photometric and spectroscopic catalogues and generated SDSS finding charts for each of the extended X-ray sources. This correlation yielded 393 extended X-ray sources with either a galaxy or cluster candidate detected in the SDSS.", "cite_spans": [], "ref_spans": []}, {"section": "Sample definition", "text": "Only 19 sources of our selection (see Table 1 ) have no plausible counterpart in the SDSS imaging and therefore are considered as candidates for distant clusters of galaxies, where the member galaxies are beyond the detection limit of the SDSS.", "cite_spans": [], "ref_spans": [{"start": 38, "end": 45, "text": "Table 1", "ref_id": "TABREF0"}]}, {"section": "Optical pre-imaging", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Imaging data -data description and reduction", "text": "Deep optical imaging for 13 of the initial 19 fields was carried out between March 2008 and November 2011 at the LBT. Our imaging strategy included binocular observation to efficiently use the telescope capabilities. LBC-blue and LBC-red were equipped with r-SLOAN and z-SLOAN filters, respectively. Dither patterns of at least nine positions with singleexposure times of 90s or 120s were used to cleanly bridge the chip gaps of the instruments in the reduced images. For details Notes. Summary of the observational state of our sample. The first column lists the extended X-ray emission in the 2XMMp catalogue, from which this sample is built. The coordinates based on a cross-correlation with the 3XMM-DR6 catalogue are given in Cols. 2 and 3. The next two columns state the exposure time spent at imaging in LBT/LBC r-SLOAN, z-SLOAN, and at spectroscopy with LBT/MODS, respectively, followed by the spectroscopic redshift (Col. 6) and its reference (Col. 7). A 1D . The X-ray properties flux and ICM temperature are based on measurements within a radius of 300kpc, the bolometric luminosity was extrapolated to r 500 (details see Sect. 6.2). The X-ray flux is in units of 10 \u221214 erg cm \u22122 s \u22121 , the luminosity in 10 42 erg s \u22121 . Note that two clusters (2XMMp J120815.5+250001 and 2XMMp J123759.3+180332) have extremely large dynamical mass estimates (> 10 15 M ) but, for this sample, an average ICM temperature. The dynamical mass estimates might be overestimated due to velocity measurements from galaxies not gravitationally bound to the cluster (see Sect. 6.3.4 and 6.3.5). on the individual target coordinates and the exposure times, we refer to Table 1 .", "cite_spans": [], "ref_spans": [{"start": 962, "end": 966, "text": "A 1D", "ref_id": "FIGREF12"}, {"start": 1656, "end": 1663, "text": "Table 1", "ref_id": "TABREF0"}]}, {"section": "Imaging data -data description and reduction", "text": "All imaging data were reduced with the code THELI (Schirmer 2013; Erben et al. 2005) . The reduction included subtracting a master-bias and flat-fielding the raw data using skyflats, applying a background-model correction to reduce the imprinted fringing pattern, weighting, astrometric calibration, and coaddition of the individual science exposures. The photometric zero-point (AB system) of the mosaic image was calculated using the SDSS-DR9 catalogue data as reference.", "cite_spans": [], "ref_spans": []}, {"section": "Imaging data -data description and reduction", "text": "We extracted AB magnitudes using SExtractor (Bertin & Arnouts 1996) with critical settings that affect background estimation and object detection fixed for all fields and filters. The dual-image mode of SExtractor was used to simultaneously measure isophotal object magnitudes in r-SLOAN and z-SLOAN images on fixed positions that were determined on the z-band images. The limiting magnitude of the coadded mosaics, taking the flux from the sky background within a given aperture into account, is given by", "cite_spans": [], "ref_spans": []}, {"section": "Imaging data -data description and reduction", "text": "where we use the zero-point (ZP), the number of pixels (N pix ) within the aperture with 2 radius, and the variation of the sky background as measured by SExtractor. The resulting 5\u03c3 detection limits for both filters are 25.42 < r lim < 26.49 and 24.41 < z lim < 25.49, depending on the total exposure times of 0.3 to 0.85 hours. False-colour images, created from the reduced r-SLOAN and z-SLOAN exposures, are shown in Section 6 and the respective sub-paragraphs for each of the seven spectroscopically confirmed galaxy clusters.", "cite_spans": [], "ref_spans": []}, {"section": "Target selection for spectroscopic follow-up", "text": "We inspected the colour-magnitude diagrams of all fields in order to select the tentative cluster galaxies using the red-sequence method (see Gladders & Yee 2000) . In these colour-magnitude plots, the colour of passive galaxies shows a clear dependency on redshift, which is due to the prominence of the Balmer break (4000\u00c5 at restframe). Hence, galaxies of the same cluster undergoing similar evolution will scatter little in colour, but vary in magnitude. Since the fraction of early-type cluster member Article number, page 3 of 18 A&A proofs: manuscript no. aa31128-17_abridged Histogram built from all spectra of our spectroscopic observations. The transparent region in the main plot marks the content of stars identified in the sample, the light shaded regions reflect the content of galaxies, where the fraction of all identified cluster member galaxies is plotted black. The inset details the mean cluster redshift as vertical blue dashed lines overplotted on the histogram of the identified member galaxies that match our selection criteria.", "cite_spans": [], "ref_spans": []}, {"section": "Target selection for spectroscopic follow-up", "text": "galaxies decreases with redshift, the red sequence for distant clusters may be only sparsely populated. For this reason, not only the colour was decisive for the selection of a possible BCG and cluster galaxies, but also the position with respect to the extended X-ray emission and the actual observability, such as brightness and typical constraints of multi-object spectroscopy (slit collision and possible spectral overlap). Wherever possible, we filled the remaining space on the slit-masks with less likely targets and objects of opportunity (e.g. isolated X-ray sources or possible lensing features). Colour-magnitude diagrams of the six spectroscopically confirmed clusters are shown in Figures 5 and 6.", "cite_spans": [], "ref_spans": []}, {"section": "Spectroscopic follow-up", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Spectroscopy -data description", "text": "The spectroscopic follow-up was executed in February and March 2012. The instrument of choice for this campaign was the Multi-Object Double Spectrograph (MODS; Pogge et al. 2010) at the LBT. For each of the seven follow-up fields, one multi-slit mask (MOS-mask) was cut, intended to cover the most probable cluster galaxy candidates (see Sect. 3.2) and a few objects of opportunity. We only observed using the red spectral arm of MODS with grating G670L, resulting in a spectral coverage of 5200 \u2212 10 000 \u00c5. Depending on the target brightness and observing conditions, we took up to five individual exposures of 30 minutes per field; the total exposure time per field is summarized in Table 1 .", "cite_spans": [{"start": 160, "end": 178, "text": "Pogge et al. 2010)", "ref_id": "BIBREF41"}], "ref_spans": [{"start": 685, "end": 692, "text": "Table 1", "ref_id": "TABREF0"}]}, {"section": "Spectroscopy -data reduction", "text": "Data reduction was performed as a two-stage process: prereduction, and pipeline reduction. During pre-reduction we made use of modsCCDRed 1 , a set of Python-scripts that subtracted the bias-pattern and applied a flat-field correction. The resulting prereduced data were further reduced with a set of scripts written mainly in ESO-Midas. These scripts were initially intended to reduce VLT/FORS2 data, but are perpetually generalised to suit different multi-object spectroscopy instruments, including MODS.", "cite_spans": [], "ref_spans": []}, {"section": "Spectroscopy -data reduction", "text": "The workflow of the pipeline reduction includes the following tasks: cosmic filtering of scientific frames, wavelength calibration, weighted extraction of 1D spectra (following Horne 1986), including generation of respective error spectra, creation of 2D sky-subtracted frames, and co-addition of single spectra. Spectrophotometric standard stars observed during our observation period were used to flux-calibrate the final spectra.", "cite_spans": [], "ref_spans": []}, {"section": "Spectroscopy -data analysis", "text": "We were able to extract a total of 215 spectra from our data. All 1D flux-and error-spectra were inspected with EZ (a tool for automatic redshift measurement, see Garilli et al. 2010 ) to obtain first impressions on quality and redshift of each individual spectrum. The first inspection revealed 194 preliminary redshifts, of which 176 were graded secure because they showed several spectral features. In these science-grade spectra, we identified 10 late-type stars. Spectra of obvious galaxy cluster candidates, primarily passive galaxies (see Sect. 3.2), were inspected in more detail. We measured their redshift by fitting a double-Gaussian to the prominent CaII H&K absorption lines, or alternatively, when the signal-to-noise ratio was found to be too low, by solely ftting the [OII] (3727\u00c5) emission. All galaxy redshifts were converted into the barycentre of the solar system. In Fig. 1 we show a histogram of all science-grade redshifts from our spectroscopic program, where the inset highlights the redshifts of the successfully identified clusters.", "cite_spans": [], "ref_spans": [{"start": 888, "end": 894, "text": "Fig. 1", "ref_id": "FIGREF12"}]}, {"section": "Archival X-ray data and data reduction", "text": "The whole sample of extended sources was initially selected from the 2XMMp (see Sect. 2). Since in the meantime the number of XMM-Newton observations (OBSIDs) and the knowledge on the instruments have vastly increased, we compared our initial targets with the recent 3XMM-DR6 catalogue (Rosen et al. 2016) to ensure that the detections are characterized as extended sources. For all initial targets, we found an extended detection in the 3XMM-DR6, with the exception of 2XMMp J145220.8+165458, which is now classified as a point source. The extents of all other sources agreed well and were mostly within the errors of the two catalogues. The number of observations covering our sample increased from 28 to 36 between 2XMMp and 3XMM-DR6. A comparison between 2XMMp and 3XMM-DR6, containing source-identifiers (SR-CID), extent parameters (EP_EXTENT), and OBSID, is listed in Table D. 1. The table also contains the flare-cleaned exposure time for the EPIC instruments for all OBSIDs from which we extracted spectra (see Sect. 6.2).", "cite_spans": [], "ref_spans": []}, {"section": "Archival X-ray data and data reduction", "text": "We downloaded all publicly available XMM-Newton observations until December 2015 that overlapped our sample from the XMM-Newton Science Archive (XSA; Arviset et al. 2002) . The data reduction and analysis was carried out using the XMMNewton Science Analysis Software (SAS) version 15. From background-flare-cleaned event file lists, we generated X-ray im- Fig. 2 : LBC colour images of the confirmed cluster fields of Section 6.3. We assigned r-SLOAN and z-SLOAN images from the LBC to the blue and red channel of the colour image. The green channel was created from the mean of both bands. Overplotted red squares and green circles show cluster galaxies and spectroscopic sources outside our membership criteria, respectively. In panel (f), which shows the cluster 2XMMp J133853.9+482033, we additionally highlight with purple squares the group of galaxies that was ruled out by the iterative sigma-clipping method (compare Sect. 6.3.6). North is up, east is left, and the images are centred on the respective X-ray position. Red squares and green circles are overplotted on the LBC images, referring to cluster galaxies and spectroscopic sources outside our membership criteria, respectively. North is up, east is left, and the images are centred on the respective X-ray position.", "cite_spans": [], "ref_spans": []}, {"section": "Archival X-ray data and data reduction", "text": "ages in the energy range between 0.5 and 3.0 keV for each EPIC camera and OBSIDs individually.", "cite_spans": [], "ref_spans": []}, {"section": "Results: galaxy and cluster properties", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Cluster redshifts and dynamical masses", "text": "In this section we describe our procedure of cluster member selection and the velocity dispersion and dynamical mass calculation for the seven fields of which we have dedicated spectroscopic data from LBT/MODS. We proceed with the analysis of A. Rabitz et al.: Distant clusters of galaxies in the 2XMM/SDSS footprint Red squares and green circles are overplotted on the LBC images, referring to cluster galaxies and spectroscopic sources outside our membership criteria, respectively, while purple squares in panel (i) are explained in Sect. 6.3.6. North is up, east is left, and the images are centred on the respective X-ray position.", "cite_spans": [], "ref_spans": []}, {"section": "Cluster redshifts and dynamical masses", "text": "the XMM-Newton data, from which we extract spectra and compute fluxes, luminosities, and temperatures. We give the results and further details for all selected fields, which are grouped according to their available data and properties: (i) the six fields of newly confirmed clusters with LBT/MODS spectroscopy, (ii) targets with no spectroscopy from this work, but published redshifts from the literature, and (iii) the remaining fields containing a high-redshift group of galaxies, and candidates that are not yet confimed or are rejected.", "cite_spans": [], "ref_spans": []}, {"section": "Cluster redshifts and dynamical masses", "text": "At this point, we also introduce images from the Wide-field Infrared Survey Explorer (WISE, see Wright et al. 2010) , whose imaging bands are centred at 3.4, 4.6, 12, and 22 \u00b5m (W1-W4). Especially the bands W1 and W2 are useful for colourselecting galaxies between 0.75 < z < 1.75 because of an apparently monotonical reddening. This method was introduced by Papovich (2008) and later adopted by Gettings et al. (2012) for their search for distant galaxy clusters using WISE data. Cutout IR images from WISE for our cluster candidates therefore allow high-redshift galaxies to be better recognized than from optical survey data (SDSS) alone. We did not use the IR colour as an excluding criterion for the decision between low and high redshift of clusters -a qualitative examination of this criterion is part of ongoing work comprising a larger sample of galaxy clusters, and will be presented in a future paper (Rabitz et al. in prep.) . As additional detail for the LBT/MODS confirmed clusters, we provide cutouts from the SDSS, WISE, and LBC pre-imaging of the respective cluster fields (Figs. 2, 3 , and 4) together with photometric and spectroscopic results from our observations (Figs. 5 and 6).", "cite_spans": [], "ref_spans": [{"start": 1090, "end": 1101, "text": "(Figs. 2, 3", "ref_id": "FIGREF2"}]}, {"section": "Cluster redshifts and dynamical masses", "text": "Since LBT imaging data are also available for groups (ii) and (iii) of our data, we present the respective LBC images and SDSS finding charts in Appendices B and C, while additional information for the high-redshift group of galaxies are given in Figs. 7, 8, and 9 .", "cite_spans": [], "ref_spans": []}, {"section": "Cluster redshifts and dynamical masses", "text": "We summarize the properties of the LBT/MODS-confirmed clusters in Table 2 , and those of the clusters with references in Table 3 . To evaluate cluster redshift and velocity dispersion, we adopted the bi-weight method outlined in Beers et al. (1990) . Our strategy to determine z cl was as follows. We selected all galaxies as preliminary cluster members fulfilling |z mem \u2212 z BCG | \u00b7 c \u2264 4000 km s \u22121 , where we used the redshift of an obvious brightest cluster galaxy z BCG and the speed of light c, and calculated the preliminary cluster redshift and its velocity dispersion. Using a conservative clipping based on the preliminary velocity dispersion, |z pre \u2212 z mem | \u00b7 c \u2264 3\u03c3 pre \u00b7 (1 + z pre ), we rejected further galaxies from the sample in order to derive updated bi-weight estimators and repeated this step when necessary. Errors were calculated from 10 5 bootstrap simulations and the 90% confidence interval of jackknife rebinning, for z cl and \u03c3, respectively, as recommended in Beers et al. (1990) .", "cite_spans": [], "ref_spans": [{"start": 66, "end": 73, "text": "Table 2", "ref_id": "TABREF1"}, {"start": 121, "end": 128, "text": "Table 3", "ref_id": "TABREF2"}]}, {"section": "Cluster redshifts and dynamical masses", "text": "For clusters with very few member galaxies, we were unable to calculate a statistically meaningful velocity dispersion. We therefore show the number of galaxies (n) taken into account for the calculation in Table 2 . All \u03c3 values were scaled to the cluster redshift (factorized with (1 + z cl ) \u22121 , as stated in Peebles (1993)). Munari et al. (2013) examined the relation between the velocity dispersion of different physical tracers in simulated galaxy clusters to the mass of their respective dark matter halos, where they used Navarro-Frenk-White (NFW; Navarro et al. 1997) profile fits. We averaged the best-fitting parameters they found for the two corresponding simulations (ceased star formation and AGN feedback; Table 1 in Munari et al. 2013 ) and galaxies as tracers. Accordingly, the parameters A 1D = 1169.75 \u00b1 11.45 and \u03b1 = 0.3593\u00b10.0068 were used to calculate M 200 , the mass within which the mean matter density is 200 times \u03c1 c (z), using", "cite_spans": [], "ref_spans": [{"start": 207, "end": 214, "text": "Table 2", "ref_id": "TABREF1"}, {"start": 722, "end": 729, "text": "Table 1", "ref_id": "TABREF0"}]}, {"section": "Cluster redshifts and dynamical masses", "text": "In Eq. 2, \u03c3 1D denotes the line-of-sight velocity dispersion, and h(z) is the Hubble parameter at the cluster redshift z normalized by 100 km s \u22121 Mpc \u22121 . The uncertainties for M 200 are based on the intrinsic error of the fitting parameters and our error of \u03c3 for each galaxy cluster.", "cite_spans": [], "ref_spans": []}, {"section": "Cluster redshifts and dynamical masses", "text": "To computate r 200 , the radius within which the mean density of the halo is 200 times \u03c1 c (z), we used", "cite_spans": [], "ref_spans": []}, {"section": "Cluster redshifts and dynamical masses", "text": "assuming a mean density and spherical symmetry. These equations are valid when we assume that the clusters are in hydrostatic equilibrium and are spherically symmetric. Such estimates are therefore only considered as proxies. The main results from the spectroscopy on clusters are summarized in Table 2 , while the individual galaxy redshifts are given in Appendix A.", "cite_spans": [], "ref_spans": [{"start": 295, "end": 302, "text": "Table 2", "ref_id": "TABREF1"}]}, {"section": "X-ray fluxes and temperatures", "text": "X-ray spectroscopy was carried out for all clusters with redshift known either from the literature or from this work. Source extraction regions were centred on the positions of the detected extended source in the 3XMM-DR6 catalogue (see Table 1 ) and set to the common radius of 300kpc for the respective cluster redshift. Using the [0.5-3.0 keV] EPIC images, we searched for suitable background regions at approximately the same offaxis distances as the source, with a strong preference for the same chip whenever possible, and a radius sufficiently large in order to increase the quality and statistics of the background. Obvious point sources contaminating the background region were excluded. Taking the source radius into account, the background and source spectra for the individual instruments were extracted and response matrix files were created using the SAS task especget.", "cite_spans": [], "ref_spans": [{"start": 237, "end": 244, "text": "Table 1", "ref_id": "TABREF0"}]}, {"section": "X-ray fluxes and temperatures", "text": "The photons of all spectra were binned to at least one count per bin with the FTOOL task grppha. We used the XSPEC version 12.9.0m (Arnaud 1996) , the abundance table of Wilms et al. (2000) , and the atomic cross-sections of Verner et al. (1996) . In order to derive the ICM temperature of the selected clusters, we fitted the extracted EPIC spectra using the APEC model (Smith et al. 2001 ), while we accounted for the Galactic absorption with the tbabs model (T\u00fcbingen-Boulder ISM absorption model; Wilms et al. 2000) , taking the column density of neutral hydrogen as a parameter (see below). For each fit we fixed the following parameters in order to reduce the number of free variables: (i) the metallicity, (ii) the column density of Galactic neutral hydrogen, and (iii) the redshift of the cluster. The value for (i) was fixed to Z = 0.23 \u00b1 0.01 Z for the whole sample of X-ray data. This value was computed by McDonald et al. (2016) in their analysis of 153 mass-selected galaxy clusters between 0 < z < 1.5. We used the nH tool provided by HEASARC 2 , which determines the weighted average column density of neutral Galactic hydrogen (ii) based on data by the Leiden/Argentine/Bonn (LAB) survey (Kalberla et al. 2005; Hartmann & Burton 1997) . For (iii) we queried the literature for existing redshifts of our cluster candidates in addition to the clusters with spectroscopic redshifts based on data of this work (see Table 1 ). The best-fitting parameters, cluster temperature, the normalization, and their respective 1\u03c3 errors were determined by minimizing the C-statistics. The spectral fit enabled calculating the X-ray flux and luminosity in the energy range [0.5-2.0 keV]. The luminosity was further converted into a bolometric luminosity ([0.1 -50 keV]) using a dummy response matrix. The derived fluxes, F 0.5\u22122 (300kpc), and (bolometric) luminosities, L 0.5\u22122 (300kpc) and L bol (300kpc), take into account photons emitted within the extraction region of 300 kpc. In order to derive L bol for the more physically motivated radius r 500 , we used the iterative procedure based on L \u2212 T and L \u2212 M relations published by Pratt et al. (2009) . The whole procedure is outlined in detail in Takey et al. (2011) , but can be summarized to work as follows. It calculates a M 500 from the input bolometric luminosity, used to derive a first guess of r 500 based on the L\u2212 M relation. The temperature from the L \u2212 T relation is then used to calculate the core radius of the \u03b2 model (see relations in Finoguenov et al. 2007) . The flux ratio between the input radius and the aperture extrapolated from the \u03b2 model is finally used to correct the bolometric luminosity for the next iteration.", "cite_spans": [{"start": 131, "end": 144, "text": "(Arnaud 1996)", "ref_id": "BIBREF2"}, {"start": 1227, "end": 1250, "text": "Hartmann & Burton 1997)", "ref_id": "BIBREF21"}], "ref_spans": [{"start": 1427, "end": 1434, "text": "Table 1", "ref_id": "TABREF0"}]}, {"section": "X-ray fluxes and temperatures", "text": "We present the X-ray properties of the ICM-temperature, F 0.5\u22122 (300kpc) and L bol (r 500 ), and their 1\u03c3 confidence interval in Tables 2 and 3. 6.3. Results of individual clusters with LBT follow-up 6.3.1. 2XMMp J083026.2+524133", "cite_spans": [], "ref_spans": [{"start": 129, "end": 144, "text": "Tables 2 and 3.", "ref_id": "TABREF1"}]}, {"section": "X-ray fluxes and temperatures", "text": "A redshift based on the X-ray spectrum (z = 0.99) for this source has been published by Lamer et al. (2008) .", "cite_spans": [], "ref_spans": []}, {"section": "X-ray fluxes and temperatures", "text": "In the follow-up imaging of the field, many faint galaxies of similar colour to the apparent BCG are visible (compare Fig. 2a) , the colour-magnitude diagram in Fig. 5b indicates no dominant red sequence, and the spectroscopic followup revealed only eight galaxies matching our criteria for cluster members (Fig. 5a ). Nevertheless, we were able to determine a mean cluster redshift of z = 0.9856, thus confirming the initial finding from Lamer et al. (2008) , and a velocity dispersion (see Table 2 ). The dynamical mass of 2XMMp J083026.2+524133 within the radius of r 200 = 2.44 The high cluster mass from the dynamical analysis and the large virial radius agree within their errors with X-ray estimates from Lamer et al. (2008) considering a typical scaling factor of 1.52 between r 500 and r 200 (Piffaretti et al. 2011) .", "cite_spans": [], "ref_spans": [{"start": 161, "end": 168, "text": "Fig. 5b", "ref_id": "FIGREF6"}, {"start": 307, "end": 315, "text": "(Fig. 5a", "ref_id": "FIGREF6"}, {"start": 492, "end": 499, "text": "Table 2", "ref_id": "TABREF1"}]}, {"section": "X-ray fluxes and temperatures", "text": "We also note an independent cluster mass proxy from Culverhouse et al. (2010), who reported the gas mass derived from SZ observations. Their analysis of XMM-Newton data results in a cluster gas mass within r 2500 that agrees excellently with their SZ proxy. Furthermore, Culverhouse et al. (2010) reported a cluster temperature of 7.6 \u00b1 0.8 keV, which exactly matches our results. Another and more recent approach using SZ measurements (Schammel et al. 2013 ) derived a much lower cluster mass, M 200 = 3.6 \u00d7 10 14 M / 4.7 \u00d7 10 14 M (computed based on different models), compared to our dynamical calculation.", "cite_spans": [], "ref_spans": []}, {"section": "2XMMp J093437.4+551340", "text": "The two-band photometry yields a tight red sequence within the field of view (compare Fig. 5d ). While the optical counterpart to the BCG is hardly visible in the SDSS, AllWISE W1-imaging shows clear detections of the brightest cluster galaxies that coincide with the extended X-ray contours, see Figures 3d, 3e , and 3f.", "cite_spans": [], "ref_spans": [{"start": 86, "end": 93, "text": "Fig. 5d", "ref_id": "FIGREF6"}, {"start": 297, "end": 311, "text": "Figures 3d, 3e", "ref_id": "FIGREF2"}]}, {"section": "2XMMp J093437.4+551340", "text": "Optical spectroscopy resulted in 23 galaxy redshifts for the observed field. The mean cluster redshift and its velocity dispersion were calculated using an iterative clipping of redshifts from the sample (see beginning of Sect. 6) from a final census of 11 member galaxies to z cl = 0.83858 \u00b1 0.00073 and \u03c3 = 430 +120 \u221296 km s \u22121 . In the redshift histogram (Fig. 5c) , the confirmed member galaxies of galaxy cluster 2XMMp J093437.4+551340 are visible as a compact overdensity. Based on 11 cluster galaxies, a dynamical cluster mass and radius for an overdensity of \u2206 = 200 were computed. For these values and for the X-ray parameters of this cluster, we refer to Table 2 .", "cite_spans": [], "ref_spans": [{"start": 358, "end": 367, "text": "(Fig. 5c)", "ref_id": "FIGREF6"}, {"start": 665, "end": 672, "text": "Table 2", "ref_id": "TABREF1"}]}, {"section": "2XMMp J093437.4+551340", "text": "The publicly available X-ray data with \u223c 10ksec exposure time were sufficient to determine the ICM temperature within reasonable accuracy, k B T = 2.96 +0.86 \u22120.65 keV, taking the spectroscopic redshift of the cluster into account. X-ray flux and luminosity were calculated to be F 0.5\u22122 (300kpc) = (7.4 \u00b1 0.83) \u00d7 10 \u221214 erg cm \u22122 s \u22121 and L 0.5\u22122 (300kpc) = (20.9 \u00b1 2.3) \u00d7 10 42 erg s \u22121 , respectively (see also Table 2 ).", "cite_spans": [], "ref_spans": [{"start": 414, "end": 421, "text": "Table 2", "ref_id": "TABREF1"}]}, {"section": "2XMMp J105319.8+440817", "text": "When we analysed the colour-magnitude diagram ( Fig. 5f ) from the optical pre-imaging, a tight red sequence of galaxies became visible. Using the spectroscopic follow-up, we confirm eight galaxies out of the 28 spectra of this mask. We note that the BCG is relatively faint (20.96 mag in z-SLOAN) in comparison to the other clusters in our sample. The BCG and cluster members are not detected by the SDSS (Fig. 3g) , but have IR counter-parts in the AllWISE survey (Fig. 3h) . Based on the eight identified galaxies within the redshift range of 0.890 z 0.903, we calculated a low-precision velocity dispersion of \u03c3 = 780 +660 \u2212360 km s \u22121 (see Tab. 2). We also note that a close galaxy pair (the double-member east of the X-ray centre; Fig. 3i ) might bias the \u03c3 by possible interaction. Spectra of both galaxies were taken from the same slit on the MOS-mask and appear only \u223c 1.8 and \u223c 2950km s \u22121 apart in projection and recessional velocity, respectively.", "cite_spans": [], "ref_spans": [{"start": 48, "end": 55, "text": "Fig. 5f", "ref_id": "FIGREF6"}, {"start": 406, "end": 415, "text": "(Fig. 3g)", "ref_id": "FIGREF2"}, {"start": 466, "end": 475, "text": "(Fig. 3h)", "ref_id": "FIGREF2"}, {"start": 737, "end": 744, "text": "Fig. 3i", "ref_id": "FIGREF2"}]}, {"section": "2XMMp J105319.8+440817", "text": "As a peculiarity within the cluster field, imaging revealed a slightly distorted blue object only \u223c 5 away from the BCG. We identified this object as a background galaxy and were able to assign a redshift of z = 3.8354. The object is not bent to an Einstein ring, nor were any possible multiple images to this galaxy identified. Based on its magnitude (22.3 mag in z) with respect to its high redshift and the apparent magnitudes of the cluster members at z = 0.8955 (compare Table A .1), the galaxy is most likely lensed by the BCG of the galaxy cluster.", "cite_spans": [], "ref_spans": []}, {"section": "2XMMp J105319.8+440817", "text": "In the XSA we found two observations covering the source 2XMMp J105319.8+440817 with cleaned exposure times between 4 and 11 ksec (Table D.1). Using our common procedure, we extracted an X-ray flux of F 0.5\u22122 (300kpc) = (2.37 \u00b1 0.27) \u00d7 10 \u221214 erg cm \u22122 s \u22121 and a model luminosity of L 0.5\u22122 (300kpc) = (76.7 \u00b1 8.7) \u00d7 10 42 erg s \u22121 . The best-fitting value for the gas temperature of the cluster was calculated to be k B T = 3.6 +1.2 \u22120.76 keV (Table 2 ).", "cite_spans": [], "ref_spans": [{"start": 445, "end": 453, "text": "(Table 2", "ref_id": "TABREF1"}]}, {"section": "2XMMp J120815.5+250001", "text": "In the LBC imaging data, very many galaxies around the centre of 2XMMp J120815.5+250001 are visible (compare Fig.2d ). The colour-magnitude diagram in Fig. 6b appears to Objects with spectra are plotted in green, while the confirmed cluster members are shown in red. Error bars plotted in the colour-magnitude diagrams indicate the photometric uncertainties and are visible when they exceed the symbol size. Galaxies excluded by the iterative sigma clipping method are shown in purple in panels (e) and (f). rich red sequence, which is not very tight in colour. Within the MODS field of view of 2XMMp J120815.5+250001, we spectroscopically identified 20 galaxies in the redshift range of 0.96 < z < 1.06. A cluster consisting of those 20 galaxies would exhibit line-of-sight velocities (|v los | > 6000 km s \u22121 ) that are too high for this to be considered a gravitationally bound system. We detect several bright galaxies with greatly different recessional velocities near the centre of the elongated X-ray emission (Fig. 4c) , imaged as the brightest four galaxies near the inner X-ray contour. When we consider each as a possible BCG, we obtain different samples of cluster members and velocity dispersions, regarding our member selection algorithm. All four bright galaxies appear related to red sources (W1-W2 between 0.22 and 0.35) in the AllWISE data, visible as bright sources in Fig. 4b , and thus give no clear indication of a single BCG.", "cite_spans": [], "ref_spans": [{"start": 151, "end": 169, "text": "Fig. 6b appears to", "ref_id": "FIGREF7"}, {"start": 1017, "end": 1026, "text": "(Fig. 4c)", "ref_id": "FIGREF3"}, {"start": 1388, "end": 1395, "text": "Fig. 4b", "ref_id": "FIGREF3"}]}, {"section": "2XMMp J120815.5+250001", "text": "In the following, we consider the galaxy at the position 12:08:15 +25:00:01 with a z-SLOAN magnitude of 20.262 mag and a distance of 5 with respect to the X-ray centre, as the proper BCG. Our algorithm estimates a cluster redshift of z = 0.9929 \u00b1 0.0026 and \u03c3 = 1200 +300 \u2212240 km s \u22121 , taking the 16 galaxies into account as cluster members. The respective radius and mass we determine are listed in Table 2 .", "cite_spans": [], "ref_spans": [{"start": 401, "end": 408, "text": "Table 2", "ref_id": "TABREF1"}]}, {"section": "2XMMp J120815.5+250001", "text": "We extracted source spectra for all EPIC instruments using the one XMM-Newton observation available for this cluster. The APEC model fit constrained the ICM temperature for 2XMMp J120815.5+250001 to be kT = 4.1 +2.2 1.1 keV. X-ray flux and luminosity were calculated to be F 0.5\u22122 (300kpc) = (2.79 \u00b1 0.42) \u00d7 10 \u221214 erg cm \u22122 s \u22121 and L 0.5\u22122 (300kpc) = (106 \u00b1 16) \u00d7 10 42 erg s \u22121 , respectively.", "cite_spans": [], "ref_spans": []}, {"section": "2XMMp J120815.5+250001", "text": "The velocity dispersion of this cluster may be contaminated by galaxies that are not bound to the cluster, but are part of a larger structure. This is further supported by the relatively low ICM temperature found from the analysis of EPIC spectra compared to the large \u03c3 from optical spectroscopy.", "cite_spans": [], "ref_spans": []}, {"section": "2XMMp J123759.3+180332", "text": "The source 2XMMp J123759.3+180332 appears very rich in red galaxies in the optical pre-imaging (Fig. 2e) , with an apparent concentration in the central part of the X-ray emission (Fig. 4f) , and bright and possibly blended IR emission in the AllWISE imaging data (Fig. 4e) . The optical richness is also recovered in the corresponding colour-magnitude plot (Fig. 6d) as a clearly visible red sequence, of which a considerable fraction of objects were confirmed as cluster members. Applying our clipping algorithm, we were able to identify 16 members within the redshift range of 0.865 z 0.9, and consequently fixed the cluster redshift to z = 0.8874 \u00b1 0.0024 with \u03c3 = 1200 +310 \u2212250 km s \u22121 . The dynamical cluster mass computed based on \u03c3 results in a high value and confidence interval. A high cluster mass, however, slightly contradicts the average X-ray temperature (compare Table 2 ). The population of cluster member galaxies might contain an unidentified fraction of interloping galaxies, which we cannot identify for statistical reasons.", "cite_spans": [], "ref_spans": [{"start": 180, "end": 189, "text": "(Fig. 4f)", "ref_id": "FIGREF3"}, {"start": 264, "end": 273, "text": "(Fig. 4e)", "ref_id": "FIGREF3"}, {"start": 358, "end": 367, "text": "(Fig. 6d)", "ref_id": "FIGREF7"}, {"start": 880, "end": 887, "text": "Table 2", "ref_id": "TABREF1"}]}, {"section": "2XMMp J123759.3+180332", "text": "The LBC data imaged two blue objects in the cluster field (highlighted as blue circles in Fig. 2e ) with an apparently bent morphology. The respective spectra of both sources show no clear emission or absorption feature, rendering no opportunity to determine redshifts. A clear similarity between both spectral shapes is obvious, on the other hand, substantiating the hypothesis that both objects are lensed images of a source with a redshift in the redshift desert between 1.4 < z < 2.0. X-ray source photons of 2XMMp J123759.3+180332 were extracted within a radius of \u223c 0.95 Mpc. The low number of photons from the source (63/102/73 counts for MOS1/MOS2/PN) resulted in large error margins for the ICM temperature: k B T = 5.0 +1.9 \u22121.1 keV. The extracted flux was derived to be F 0.5\u22122 (300kpc) = (4.75 \u00b1 0.47) \u00d7 10 \u221214 erg cm \u22122 s \u22121 , and using the cluster redshift from optical spectroscopy, we calculated the X-ray luminosity to be L 0.5\u22122 (300kpc) = (134\u00b113)\u00d710 42 erg s \u22121 .", "cite_spans": [], "ref_spans": []}, {"section": "2XMMp J133853.9+482033", "text": "The LBT imaging shows the field of 2XMMp J133853.9+482033 as a rich cluster of galaxies. However, the red sequence (Fig. 6f) is not very pronounced. We identified the brightest galaxy near the X-ray centre as BCG (magenta square in Fig. 4i) , and the initial sample of tentative cluster galaxies comprises 13 galaxies within 0.749 z 0.756. Our iterative member clipping, however, divides the sample into two groups, indicated by red and magenta bars in the redshift histogram in Fig. 6e . The method finally excludes the inital BCG and surrounding group of galaxies (magenta) from the sample of cluster member galaxies (red) during the iteration. We therefore note that the following estimates are most possibly biased by insufficient member statistics. With to the procedure we applied for the whole spectroscopic sample in this paper, we calculate a mean cluster redshift based on eight galaxies of z = 0.74969 \u00b1 0.00030 and a velocity dispersion of \u03c3 = 122 Table 2 .", "cite_spans": [], "ref_spans": [{"start": 115, "end": 124, "text": "(Fig. 6f)", "ref_id": "FIGREF7"}, {"start": 232, "end": 240, "text": "Fig. 4i)", "ref_id": "FIGREF3"}, {"start": 479, "end": 486, "text": "Fig. 6e", "ref_id": "FIGREF7"}, {"start": 960, "end": 967, "text": "Table 2", "ref_id": "TABREF1"}]}, {"section": "2XMMp J133853.9+482033", "text": "We were unable to constrain the gas temperature of 2XMMp J133853.9+482033 based on the publicly available X-ray data. The X-ray flux and luminosity were measured to be F 0.5\u22122 (300kpc) = (1.1 \u00b1 0.16) \u00d7 10 \u221214 erg cm \u22122 s \u22121 and L 0.5\u22122 (300kpc) = (18.8 \u00b1 2.8) \u00d7 10 42 erg s \u22121 .", "cite_spans": [], "ref_spans": []}, {"section": "Results: galaxy clusters with redshifts from the literature", "text": "This section summarizes results from the subsample of X-ray selected cluster candidates, which are known to be clusters in the literature. We queried the NED for publications on galaxy clusters and took advantage of their spectroscopic cluster redshifts for our APEC fit of the analysis of XMM-Newton data. Our goal was to calculate X-ray cluster properties such as ICM temperature, flux, and luminosity for this sample as well and compare our XMM-Newton based properties to the literature values. We refer to Section 7, where we show an L \u2212 T plot of all clusters within this sample. In Table D .1 we collect important data on the individual cluster detection, including available OBSIDs, cleaned exposure times based on our reduction, and the 2XMMp vs. 3XMM-DR6 cross-reference. The procedure of our X-ray data reduction and analysis is described in Sections 5 and 6.2, respectively.", "cite_spans": [], "ref_spans": []}, {"section": "2XMMp J030212.0-000133", "text": "The cluster was discovered in X-rays in the framework of the XMM-Newton Distant Cluster Project (XDCP; Fassbender et al. 2011) . From six member galaxy spectra, \u0160uhada et al. (2011) derived a cluster redshift of z = 1.185\u00b10.016, which we adopted for our X-ray analysis. Notes. The X-ray properties flux (Col. 3) and temperature (Col. 5) were measured within radii of 0.3 Mpc at the redshift of the cluster, where we used the spectroscopic redshifts available from the reference noted in Col. 6. The bolometric luminosity (Col. 4) was extrapolated to r 500 (for details, see Sect. 6.2). The X-ray flux is given in units of 10 \u221214 erg cm \u22122 s \u22121 , and the luminosity in 10 42 erg s \u22121 ).", "cite_spans": [], "ref_spans": []}, {"section": "2XMMp J030212.0-000133", "text": "We extracted the X-ray spectrum within 300 kpc in the available \u223c 47 and \u223c 37 ksec exposures of MOS1/MOS2 and PN, respectively. The X-ray flux and the luminosity were calculated to be F 0.5\u22122 (300kpc) = (0.884 \u00b1 0.097) \u00d7 10 \u221214 erg cm", "cite_spans": [], "ref_spans": []}, {"section": "2XMMp J030212.0-000133", "text": "and L 0.5\u22122 (300kpc) = (35.2 \u00b1 3.9) \u00d7 10 42 erg s \u22121 , and the cluster temperature was fitted to k B T = 4.7 +1.5 \u22120.9 keV. Flux and luminosity agree within 3\u03c3 with those derived by \u0160uhada et al. (2011) , which are based on an extraction radius of 55 . The ICM temperature is higher in our case but is based on the spectral fits, while \u0160uhada et al. (2011) estimated their T 500 according to scaling relations. Our X-ray properties are summarized in Table 3 .", "cite_spans": [], "ref_spans": [{"start": 450, "end": 457, "text": "Table 3", "ref_id": "TABREF2"}]}, {"section": "2XMMp J084836.4+445345 and 2XMMp J084858.3+445158", "text": "We now describe together the properties of two single extended X-ray detections. Numerous publications in addition to the initial discovery papers (Stanford et al. 1997; Rosati et al. 1999 ) are available for these two clusters, for which more recent work suggested the terminus supercluster because of their close neighbourhood in onsky projection and in redshift space (compare Mei et al. 2012 ). Since they were initially found as extended sources in the RDCS, first X-ray fluxes and luminosities are based on ROSAT data. Observations with Chandra (i.e. Stanford et al. 2001) helped to reject point-sources from the data analysis because of their increased spatial resolution, and this improved the quality of the parameters derived for the clusters. On the other hand, Chandra results show a large spread, at least partly caused by the different calibration of the low-energy QE degradation as summarized and detailed by Jee et al. (2006) .", "cite_spans": [], "ref_spans": []}, {"section": "2XMMp J084836.4+445345 and 2XMMp J084858.3+445158", "text": "Our X-ray analysis is based on XMM-Newton data and not directly comparable to previous results because of cross-calibration issues between XMM-Newton and Chandra. We used all observations included in Table D .1, covering the fields of 2XMMp J084836.4+445345 (Lynx-W) and 2XMMp J084858.3+445158 (Lynx-E). For Lynx-W, we extracted source photons within 0.3 Mpc for the MOS1/MOS2 and PN instruments, leading to F 0.5\u22122 (300kpc) = (0.406 \u00b1 0.059) \u00d7 10 \u221214 erg cm \u22122 s \u22121 and L 0.5\u22122 (300kpc) = (30.8 \u00b1 4.4) \u00d7 10 42 erg s \u22121 . The spectral model fits returned a best-fitting temperature of k B T = 2.5 +1.4 \u22120.6 keV, where the large uncertainties reflect the low number of photons received from this cluster in X-rays. Stanford et al. (2001) calculated flux and luminosity for this cluster from a smaller extraction radius, and thus their results are not directly comparable to ours. However, our cluster temperature is comparable to their work (k B T = 1.6 ", "cite_spans": [], "ref_spans": []}, {"section": "2XMMp J100451.6+411626", "text": "Hoeft et al. (2008) found the extended source 2XMMp J100451.6+411626 in the field of a lensed quasar (SDSS J1004+4112), and identified the cluster in deep SUBARU-imaging of the field. They noted clear visibility of extended X-ray emission in all EPIC instruments and a faint optical counter-part in the centre of the emission in the SDSS i-band, indicating a distant galaxy cluster. The cluster redshift they provided in their analysis (z = 0.82 \u00b1 0.02) was derived from the X-ray spectrum itself.", "cite_spans": [], "ref_spans": []}, {"section": "2XMMp J100451.6+411626", "text": "We extracted the source within 300 kpc, corresponding to 35.4 , in contrast to Hoeft et al. (2008) (50 ) . No redshift based on spectroscopic data was available, but the quality of the available X-ray data allowed for a precise determination of the galaxy clusters redshift. We measured a redshift of z = 0.836 ", "cite_spans": [], "ref_spans": []}, {"section": "2XMMp J105344.2+573517", "text": "The initial detection of galaxy cluster 2XMMp J105344.2+573517 was named RX J1053.7+5735 and is based on deep (\u223c 1.3Ms) ROSAT observations (Hasinger et al. 1998 ) in a field with very low column density of the neutral galactic hydrogen (Lockman et al. 1986 ). The structure of the source in the so-called Lockman-Hole was found to be double-lobed in the X-ray data. Follow-up imaging in the optical and NIR uncovered potential cluster galaxies for both sides of the lobe and the peculiarity of a bright lensing arc at redshift z = 2.57, lensed by the BCG of the eastern lobe r-and z-SLOAN filters) . North is up, east is left, and all images cover the same region. Blue dashed lines (middle and right images) indicate contours from the X-ray flux. Red squares overplotted on the LBC image refer to the z \u223c 1.2 group, and green circles to spectroscopic sources outside our membership criteria. Blue cycles show galaxies from the foreground population (z \u223c 1).", "cite_spans": [], "ref_spans": []}, {"section": "2XMMp J105344.2+573517", "text": "( Thompson et al. 2001) . Using the Deep Imaging Multi-Object Spectrograph (DEIMOS; Faber et al. 2003) at the Keck II telescope, Hashimoto et al. (2005) confirmed six galaxies at concordant redshifts in both lobes of RX J1053.7+5735, giving a mean cluster redshift of z = 1.134 -in good agreement with z \u223c 1.16 +0.02 \u22120.03 and z \u223c 1.14 0.02 \u22120.01 estimated from the X-ray Fe-K line for the eastern and western lobe and based on XMM-Newton data (Hashimoto et al. 2004) . The coinciding redshift measurements of both lobes with independent methods underlines the possibility that RX J1053.7+5735 is in fact a merging cluster system.", "cite_spans": [{"start": 84, "end": 102, "text": "Faber et al. 2003)", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "2XMMp J105344.2+573517", "text": "For the X-ray analysis in this work, we used all observations from the XSA noted in Table D ", "cite_spans": [], "ref_spans": []}, {"section": "2XMMp J123113.1+154550", "text": "The source 2XMMp J123113.1+154550 has previously been selected by the XDCP, and received deep imaging and spectroscopic follow-up with VLT/FORS2. We will present further details on the optical analysis for this cluster as part of a larger sample in an upcoming paper (Rabitz et al. in prep.) . However, we use the spectroscopic mean cluster redshift of z = 0.893 here to reduce the free parameter for the APEC model fit. We extracted photons of the cluster within 0.3 Mpc around the source position of 2XMMp J123113.1+154550. The best-fit parameter for the cluster temperature is k B T = 8.9", "cite_spans": [], "ref_spans": []}, {"section": "2XMMp J123113.1+154550", "text": "+4.1 \u22122.2 keV, and therefore larger than for the highly luminous cluster 2XMMp J083026.2+524133 (compare Sect. 6.3.1), but with significant uncertainties. Furthermore, flux and luminosity were computed to be F 0.5\u22122 (300kpc) = (3.89 \u00b1 0.3) \u00d7 10 \u221214 erg cm \u22122 s \u22121 and L 0.5\u22122 (300kpc) = (99.3 \u00b1 7.8) \u00d7 10 42 erg s \u22121 , which is almost a factor of two smaller than the F 0.5\u22122 (300kpc) and L 0.5\u22122 (300kpc) of the latter highly luminous cluster. We summarize all X-ray properties of our analysis in Table 3.", "cite_spans": [], "ref_spans": []}, {"section": "2XMMp J123113.1+154550", "text": "6.5. Results: rejected and as yet unclassified fields 6.5.1. 2XMMp J092120.2+371735", "cite_spans": [], "ref_spans": []}, {"section": "2XMMp J123113.1+154550", "text": "The SDSS field of this source is empty, while WISE data show a clear signal in the central region of the X-ray emission (compare cutouts in Fig. 7a-7c ). LBC pre-imaging (Fig. 8 ) reveals a field that has no obvious overdensity of red galaxies, but is dominated by very faint sources. However, the possibility exists that the 4000\u00c5 break is already redshifted out of the z-SLOAN band, causing no red ridge line to be present in our given filter set, which is also reflected by the colour-magnitude diagram (Fig. 9b) . Since the source was considered to contain a potential high-redshift (z > 1) cluster, an attempt to select possible member galaxies was made for the spectroscopic follow-up. Spectra of the brightest extragalactic sources near the centre of the extended X-ray emission, however, yielded two redshift overdensities, at z \u223c 1.0 and z \u223c 1.2 (corresponding to the blue and red colours; see Figs. 7c and 9).", "cite_spans": [], "ref_spans": [{"start": 140, "end": 150, "text": "Fig. 7a-7c", "ref_id": "FIGREF11"}, {"start": 506, "end": 515, "text": "(Fig. 9b)", "ref_id": "FIGREF13"}]}, {"section": "2XMMp J123113.1+154550", "text": "The possible low-redshift cluster, with galaxies in the range of 0.984 z 1.033, would result in a velocity dispersion that is too high. These galaxies are therefore not considered as a bound system. The four galaxies within the range of 1.209 z 1.214 are, however, much closer in redshift space, with their two brightest members in the very X-ray centre (Fig. 7c) . We furthermore note that in the WISE IR imaging in Fig. 7b , we clearly see counterparts to the high-redshift galaxies. The four members of the high mean redshift population (z = 1.2134 \u00b1 0.0014) do not form a typical red sequence (Fig. 9b ), but were found to be active and are hence relatively blue galaxies according to their [OII] emission line -an indication for ongoing star formation. The X-ray emission from 2XMMp J092120.2+371735 is clearly Fig. 8 : LBC colour image of 2XMMp J092120.2+371735, the high-redshift group at z \u223c 1.21. We assigned r-SLOAN and z-SLOAN images from the LBC to the blue and red channel of the colour image. The green channel was created from the mean of both bands. Overplotted red squares refer to the z \u223c 1.2 group, and green circles show spectroscopic sources outside our membership criteria, while blue cycles indicate galaxies of a foreground population (see Sect. 6.5.1). North is up, east is left, and the image is centred on the X-ray position.", "cite_spans": [], "ref_spans": [{"start": 354, "end": 363, "text": "(Fig. 7c)", "ref_id": "FIGREF11"}, {"start": 417, "end": 424, "text": "Fig. 7b", "ref_id": "FIGREF11"}, {"start": 597, "end": 605, "text": "(Fig. 9b", "ref_id": "FIGREF13"}]}, {"section": "2XMMp J123113.1+154550", "text": "extended (\u223c 13 in 3XMM-DR6; compare Table D.1), and a meaningful tbabs fit of the extracted spectra was not possible, given the quality of the archival data. Because only four galaxies with coinciding redshifts are confirmed and we lack a clear detection of a red-sequence or even a passive BCG, we cannot confirm the status of a galaxy cluster for this group of z \u223c 1.21 galaxies.", "cite_spans": [], "ref_spans": []}, {"section": "2XMMp J093607.2+613245", "text": "The X-ray source 2XMMp J093607.2+613245 is catalogued as an extended source in 2XMMp, and its extent is also confirmed by the 3XMM-DR6 catalogue. Deep imaging with the LBC shows only faint blue galaxies within the central X-ray emission region, with a WISE counterpart in the W1 band (see upper panel in Fig. C.2) , while survey data from the SDSS do not detect foreground sources. Spectroscopic follow-up with MODS revealed three galaxies within a relatively wide redshift range (z = 0.81 .. 0.84), including the galaxy closest to the X-ray position, an OII emitter at z = 0.811. An object at 12 angular distance from the X-ray position was identified as a QSO at z = 1.55. A re-inspection of the X-ray source showed that the 2XMMp source is a blend of two sources to which the QSO contributes part of its flux. Since it remains unclear whether the galaxies at z \u223c 0.83 form a cluster that could give rise to the remaining X-ray emission, we did not add this source to the sample of identified clusters. . Objects with spectra are marked green, while the members of the high-redshift group are shown in red. Blue refers to the foreground population of galaxies, which is unlikely to be responsible for the X-ray emission. Error bars plotted in panel (b) indicate the photometric uncertainties and are visible when they exceed the symbol size.", "cite_spans": [], "ref_spans": []}, {"section": "2XMMp J120735.1+250538", "text": "The X-ray emission related to 2XMMp J120735.1+250538 is of low extent (6.6 ) and blended with a point source. Because of the uncertain X-ray extent and the lack of obvious member galaxies, spectroscopic follow-up was not executed.", "cite_spans": [], "ref_spans": []}, {"section": "2XMMp J133038.6-013832", "text": "The X-ray emission of 2XMMp J133038.6-013832 is of relatively low extent (\u223c 6.8 ; see Table D .1) and well isolated. In the centre, LBC imaging detects a concentration of red galaxies with counterparts in WISE data (see Figs. C.2i and C.2h). We skipped further follow-up for this cluster candidate, since its BCG is already visible in newer releases of the SDSS, where it is listed with a photometric redshift of z \u223c 0.75 and has a magnitude of 19.92 in the z-band of the LBC pre-imaging. This renders a high-redshift nature unlikely.", "cite_spans": [], "ref_spans": []}, {"section": "2XMMp J144854.8+085400", "text": "This X-ray source is clearly extended in the softer XMM-EPIC images [0.2-2] keV. In the harder bands, at [2.0-12] keV, a point source is apparent near the centre of the soft extended emission. No obvious galaxy cluster can be found in the LBC imaging. However, the hard point source is identified with a galaxy that is also detected in the SDSS with m r = 22.64 and has a photometric redshift z ph = 0.75. A search in radio catalogues of the field revealed two 1.4 GHz NVSS (Condon et al. 1998 ) sources 1 arcmin east and west of the hard X-ray source, roughly corresponding to the elongation of the extended X-ray emission. The 5 GHz FIRST survey (Becker et al. 1994 ) also shows several compact and extended sources, and the low-frequency GLEAM survey (Hurley-Walker et al. 2017 ) detected one source near the position of the eastern NVSS source.", "cite_spans": [{"start": 648, "end": 667, "text": "(Becker et al. 1994", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "2XMMp J144854.8+085400", "text": "We therefore conclude that the extended X-ray emission is more likely associated with emission from the jets of a radioloud AGN in the galaxy at z ph = 0.75. The core of the AGN must be highly obscured, since it is not visible at soft X-rays below 2 keV.", "cite_spans": [], "ref_spans": []}, {"section": "2XMMp J144854.8+085400", "text": "6.5.6. 2XMMp J145220.8+165458", "cite_spans": [], "ref_spans": []}, {"section": "2XMMp J144854.8+085400", "text": "In the 2XMMp catalogue, 2XMMp J145220.8+165458 is listed as an extended source, but it has lost the extent flag in the more recent 3XMM-DR6 catalogue. The central part of the Xray emission harbours a galaxy that was also visible in the SDSS. Deep LBC imaging and IR data from WISE do not indicate an additional background overdensity of galaxies (compare Fig. C.1e and the middle panel of Fig. C.3) . Therefore the source 2XMMp J145220.8+165458 was rejected as highredshift galaxy cluster and excluded from the follow-up program.", "cite_spans": [], "ref_spans": [{"start": 355, "end": 364, "text": "Fig. C.1e", "ref_id": "FIGREF12"}, {"start": 389, "end": 398, "text": "Fig. C.3)", "ref_id": "FIGREF2"}]}, {"section": "2XMMp J151716.8+001302", "text": "The source of 2XMMp J151716.8+001302 is extended in both 2XMMp and 3XMM-DR6, considering the OBSID 0103860601. A following observation (0201902001), only present in the more recent catalogue, lists no extent for this source, hence it remains uncertain whether the source is extended at all. The deep imaging with the LBC and survey data of WISE do not indicate a population of high-redshift galaxies either. Therefore this source was removed from the list of tentative high-redshift galaxy clusters.", "cite_spans": [], "ref_spans": []}, {"section": "Results: L \u2212 T relation", "text": "Based on the X-ray properties derived for the confirmed clusters of galaxies, we analysed the relation between L bol (r 500 ) and k B T . The bolometric luminosities within the radius r 500 were calculated using an iterative method (Takey et al. 2013) , and the cluster temperatures were derived from spectral model fits to the innermost 300 kpc region of the cluster, which we described in Section 6.2. We note that the spatial resolution of XMM-Newton does not allow us to exclude the core of clusters at the high redshifts of our sample, and therefore ICM temperatures might be biased by a cool cluster core. When we analysed our combined sample of 11 clusters (Tables 2 and 3) using the BCES orthogonal regression method (Akritas & Bershady 1996) on the logarithm of luminosity and temperature, we found as the best-fitting linear relation log L bol (r 500 )", "cite_spans": [], "ref_spans": []}, {"section": "Results: L \u2212 T relation", "text": "with the intersect A LT = 44.33 \u00b1 0.1, the slope B LT = 3.3 \u00b1 0.6, and the Hubble parameter h(z) (compare right panel of Fig. 10 ). Slope and intercept of the L \u2212 T relation are in good agreement with Takey et al. (2013) . Larger cluster statistics enabled Takey et al. (2013) to analyse three redshift bins of their sample. Although our slope indeed matches the value derived for their highest redshift bin (0.5 \u2264 z \u2264 0.7) best, it does not contradict their intermediate bin (0.25 < z < 0.5) either, taking into account the uncertainties of the fits. We restricted the data from their work to L bol h(z) \u22121 > 10 43 erg s \u22121 , rendering the lowest luminosity of the sample of Takey et al. (2013) at similar values as our high-redshift sample. The slopes and intersects were again derived using the BCES method, as described above. The derived fitting parameters are displayed in Fig. 10 with the refitted sample of Takey et al. (2013) in panels a, b, and c for the lowest, medium, and highest of their redshift bins. In panel d we plot the data from our current sample, which only consists of clusters with z > 0.75 from either LBT/MODS spectroscopy or spectra from the literature, as black dots. We generated a combined sample, including the data from Takey et al. (2013) and our highredshift sample of confirmed clusters in this work, and applied the L bol h(z) \u22121 > 10 43 erg s \u22121 cut. The best-fitting parameters for this new sample are A LT = 44.535\u00b10.083 and B LT = 3.45\u00b10.29, the solution is plotted in Fig. 10 as a dashed blue line. It is apparent that using the cut in bolometric luminosity, the parameters of the L \u2212 T relation are in agreement across all analysed redshift bins. Hence, we see no evolution in the L \u2212 T relation with redshifts using the present cluster statistics.", "cite_spans": [], "ref_spans": [{"start": 121, "end": 128, "text": "Fig. 10", "ref_id": "FIGREF12"}, {"start": 879, "end": 886, "text": "Fig. 10", "ref_id": "FIGREF12"}, {"start": 1510, "end": 1517, "text": "Fig. 10", "ref_id": "FIGREF12"}]}, {"section": "Results: L \u2212 T relation", "text": "Additionally, we analysed the intrinsic scatter of the data with respect to the derived best-fitting L \u2212 T relation for each sample using the procedure described by Pratt et al. (2009) . We first computed the raw scatter of our data points as the error-weighted orthogonal distances to the regression line. The quadratic difference between the raw scatter and the statistical uncertainties now give the intrinsic scatter, \u03c3 log L bol , of our samples.", "cite_spans": [], "ref_spans": []}, {"section": "Results: L \u2212 T relation", "text": "We summarize the fitting parameters for the different samples in Table 4 .", "cite_spans": [], "ref_spans": [{"start": 65, "end": 72, "text": "Table 4", "ref_id": "TABREF3"}]}, {"section": "Conclusions", "text": "In the input sample of 19 extended X-ray sources with empty SDSS fields, we found 13 distant clusters of galaxies with redshifts in the range z = 0.75 \u2212 1.27. While 6 of these clusters are (X-ray selected) objects with identifications and spectroscopic redshifts that have previously been published in the literature, we identified 6 new clusters, measured their redshifts, and also detected a group of four galaxies at the redshift of z \u223c 1.21, using the LBT. The high fraction of confirmed high-redshift clusters demonstrates the efficiency of this selection method, which is based solely on public archival data, for the discovery of these cosmologically interesting objects. The high-redshift objects complement the samples published by Takey et al. (2013) , which comprise extended 2XMM sources that have been confirmed as galaxy clusters using SDSS imaging and spectra.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "Our spectroscopic LBT observations confirmed the redshift (z=0.99) of the cluster 2XMMp 083026.2+524133, which . In all panels we highlight the best-fitting solution of Eq. 6 for the combined sample of Takey et al. (2013) and our high-redshift extension, including the luminosity cut, as a blue dashed line (parameters are listed in Table 4 ). Notes. Summary of the BCES fit on the sample with L bol h(z) \u22121 > 10 43 erg s \u22121 . The first three columns give the origin of the data, their sample size, and the redshift range of the particular clusters. The resulting best-fitting values for slope and intersect of Eq. 6, their respective errors, and the intrinsic scatter are given in the last three column.", "cite_spans": [], "ref_spans": [{"start": 333, "end": 340, "text": "Table 4", "ref_id": "TABREF3"}]}, {"section": "Conclusions", "text": "was previously determined from its X-ray spectrum . The analysis of new XMM-Newton observations of this object also confirmed its high X-ray temperature (k B T = 7.82 +0.4 \u22120.39 keV) and luminosity (L bol (r 500 ) = (1168 \u00b1 4) \u00d7 10 42 erg s \u22121 ). However, this cluster optically appears surprisingly inconspicuous, and only eight of the galaxies targeted spectroscopically were found to be cluster members. The resulting constraints to its dynamical mass (M 200 = 5.1 +6.7 \u22122.9 \u00d7 10 14 M ) are not accurate enough to favour either the high-mass estimates based on the X-ray temperature (M 500 = 5.6 \u00d7 10 14 M ; Lamer et al. 2008) or the lower estimates from SZ measurements (M 200 = 3.6 \u00d7 10 14 M / 4.7 \u00d7 10 14 M , depending on the model; Schammel et al. 2013) .", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "We were able to determine meaningful X-ray temperatures and bolometric luminosities for 11 clusters in the new sample. The sample shows a tight L \u2212 T relation of the form log L bol (r 500 ) h(z) = (44.33 \u00b1 0.1) + (3.3 \u00b1 0.6) log k B T 5 .", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "We have re-analysed the L \u2212 T relation in the sample of Takey et al. (2013) using only clusters with L bol (r 500 )h(z) \u22121 > 10 43 erg s \u22121 and find that the L \u2212 T relation in our high-redshift sample and the L \u2212 T relations in all redshift bins of the sample of Takey et al. (2013) are consistent with each other. When we combine our sample with the sample of Takey et al. (2013) , the best-fitting L \u2212 T relation is log L bol (r 500 ) h(z) = (44.54 \u00b1 0.1) + (3.45 \u00b1 0.29) log k B T 5 .", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "When it is compared with the BCES fit to the XMM XXL data ) without bias correction, the slope for our combined 2XMM sample is somewhat steeper, but still consistent within the errors. It is worth noting that with an intrinsic scatter of \u03c3 log L bol = 0.232 \u00b1 0.07, the L \u2212 T relation in the highz sample is significantly tighter than those of the Takey et al. (2013) and XMM XXL samples. The low scatter might be an indication of a lower fraction of cool-core clusters in the highz sample. A decline of the cool-core fraction at high redshifts can be expected because of the cosmological evolution of clusters. On the other hand, at increasing distance, cool-core clusters might also become too compact to be detected as extended X-ray sources.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "Finally, we note that for 5 of the 12 clusters we measured X-ray fluxes F 0.5\u22122 above 3 \u00b7 10 \u221214 erg cm \u22122 s \u22121 , which is the approximate limit for the detection of extended sources in the eROSITA all-sky survey (Merloni et al. 2012) . Given the solid angle of 60 deg 2 covered by our survey, we expect several", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF2": {"title": "Astronomical Society of the Pacific Conference Series", "authors": [{"first": "K", "middle": ["A"], "last": "Arnaud", "suffix": ""}], "year": 1996, "venue": "", "link": "127184381"}, "BIBREF4": {"title": "Astronomical Society of the Pacific Conference Series", "authors": [{"first": "R", "middle": ["H"], "last": "Becker", "suffix": ""}, {"first": "R", "middle": ["L"], "last": "White", "suffix": ""}, {"first": "D", "middle": ["J. ; D R"], "last": "Helfand", "suffix": ""}, {"first": "R", "middle": ["J"], "last": "Crabtree", "suffix": ""}, {"first": "&amp;", "middle": ["J"], "last": "Hanisch", "suffix": ""}, {"first": "", "middle": [], "last": "Barnes", "suffix": ""}], "year": 1994, "venue": "", "link": "127184381"}, "BIBREF13": {"title": "Instrument Design and Performance for Optical/Infrared Ground-based Telescopes", "authors": [{"first": "S", "middle": ["M"], "last": "Faber", "suffix": ""}, {"first": "A", "middle": ["C"], "last": "Phillips", "suffix": ""}, {"first": "R", "middle": ["I"], "last": "Kibrick", "suffix": ""}], "year": 2003, "venue": "Proc. SPIE", "link": null}, "BIBREF21": {"title": "Atlas of Galactic Neutral Hydrogen", "authors": [{"first": "D", "middle": [], "last": "Hartmann", "suffix": ""}, {"first": "W", "middle": ["B"], "last": "Burton", "suffix": ""}], "year": 1997, "venue": "", "link": "120290958"}, "BIBREF31": {"title": "The X-ray Universe", "authors": [{"first": "G", "middle": [], "last": "Lamer", "suffix": ""}, {"first": "A", "middle": [], "last": "De Hoon", "suffix": ""}, {"first": "R", "middle": [], "last": "Fassbender", "suffix": ""}], "year": 2011, "venue": "", "link": null}, "BIBREF40": {"title": "Principles of Physical Cosmology Piffaretti", "authors": [{"first": "P", "middle": ["J E"], "last": "Peebles", "suffix": ""}, {"first": "", "middle": [], "last": "; R", "suffix": ""}, {"first": "M", "middle": [], "last": "Arnaud", "suffix": ""}, {"first": "G", "middle": ["W"], "last": "Pratt", "suffix": ""}, {"first": "E", "middle": [], "last": "Pointecouteau", "suffix": ""}, {"first": "J.-B", "middle": [], "last": "Melin", "suffix": ""}], "year": 1993, "venue": "", "link": null}, "BIBREF41": {"title": "Society of Photo-Optical Instrumentation Engineers (SPIE) Conference Series", "authors": [{"first": "R", "middle": ["W"], "last": "Pogge", "suffix": ""}, {"first": "B", "middle": [], "last": "Atwood", "suffix": ""}, {"first": "D", "middle": ["F"], "last": "Brewer", "suffix": ""}], "year": 2010, "venue": "", "link": "126763621"}, "BIBREF56": {"title": "Astronomical Society of the Pacific Conference Series", "authors": [{"first": "M", "middle": ["B"], "last": "Taylor", "suffix": ""}], "year": 2005, "venue": "", "link": "127184381"}, "BIBREF57": {"title": "Astronomical Society of the Pacific Conference Series", "authors": [{"first": "M", "middle": ["B"], "last": "Taylor", "suffix": ""}], "year": 2006, "venue": "", "link": "127184381"}}, "ref_entries": {"FIGREF0": {"text": "or on fields that require dedicated deep follow-up imaging and spec- Article number, page 1 of 18 arXiv:1709.02436v1 [astro-ph.CO] 7 Sep 2017", "type": "figure"}, "FIGREF1": {"text": "Fig. 1: Histogram built from all spectra of our spectroscopic observations. The transparent region in the main plot marks the content of stars identified in the sample, the light shaded regions reflect the content of galaxies, where the fraction of all identified cluster member galaxies is plotted black. The inset details the mean cluster redshift as vertical blue dashed lines overplotted on the histogram of the identified member galaxies that match our selection criteria.", "type": "figure"}, "FIGREF2": {"text": "Fig. 3: Optical and near-IR images of the fields of 2XMMp J083026.2+524133 (top row), 2XMMp J093437.4+551340 (middle), and 2XMMp J105319.8+440817 (bottom). The first column shows SDSS cutouts of the respective fields, the central column shows the W1-band (3.4\u00b5m) images from the AllWISE survey, and on the right side, we present LBC images (mean of the r-and z-SLOAN filters). Images of each row are centred at the respective X-ray positions and show the same region of the sky. Blue dashed lines (middle and right images) indicate contours from the X-ray flux, where the levels are chosen for illustration alone. Red squares and green circles are overplotted on the LBC images, referring to cluster galaxies and spectroscopic sources outside our membership criteria, respectively. North is up, east is left, and the images are centred on the respective X-ray position.", "type": "figure"}, "FIGREF3": {"text": "Fig. 4: Optical and near-IR images of the fields of 2XMMp J120815.5+250001 (top row), 2XMMp J123759.3+180332 (middle), and 2XMMp J133853.9+482033 (bottom). The first column shows SDSS cutouts of the respective fields, the central column the W1-band (3.4\u00b5m) images from the AllWISE survey, and on the right side we present LBC images (mean of the r-and z-SLOAN filters). Images of each row are centred at the respective X-ray positions and show the same region of the sky. Blue dashed lines (middle and right images) indicate contours from the X-ray flux, where the levels are chosen for illustration alone. Red squares and green circles are overplotted on the LBC images, referring to cluster galaxies and spectroscopic sources outside our membership criteria, respectively, while purple squares in panel (i) are explained in Sect. 6.3.6. North is up, east is left, and the images are centred on the respective X-ray position.", "type": "figure"}, "FIGREF4": {"text": ". The source spectrum was extracted from XMM-Newton ob- servations with a total exposure time of 216.7, 223.4, and 170.3 ksec for MOS1, MOS2, and PN, respectively. Owing to the high luminosity of the source (L 0.5\u22122 (300kpc) = (189.6 \u00b1 2.8) \u00d7 10 42 erg s \u22121 ), we were able to constrain the ICM temperature with good accuracy to k B T = 7.82 +0.4 \u22120.39 keV. The temperature is in good agreement with the result from Lamer et al. (2008), which was based on fewer observations.", "type": "figure"}, "FIGREF6": {"text": "Fig. 5: Redshift histograms (left side) and colour-magnitude diagrams (right side) of 2XMMp J083026.2+524133 (top), 2XMMp J093437.4+551340 (middle), and 2XMMp J105319.8+440817 (bottom). Objects with spectra are plotted in green, while the confirmed cluster members are shown in red. Error bars plotted in the colour-magnitude diagrams indicate the photometric uncertainties and are visible when they exceed the symbol size.", "type": "figure"}, "FIGREF7": {"text": "Fig. 6: Redshift histograms (left side) and colour-magnitude diagrams (right side) of 2XMMp J120815.5+250001 (top), 2XMMp J123759.3+180332 (middle), and 2XMMp J133853.9+482033 (bottom). Objects with spectra are plotted in green, while the confirmed cluster members are shown in red. Error bars plotted in the colour-magnitude diagrams indicate the photometric uncertainties and are visible when they exceed the symbol size. Galaxies excluded by the iterative sigma clipping method are shown in purple in panels (e) and (f).", "type": "figure"}, "FIGREF8": {"text": "The low-velocity dispersion shifts 2XMMp J133853.9+482033 more into the regime of galaxy groups than clusters, and results in a dynamical mass estimate of only M 200 = 1M . We summarize all properties in", "type": "figure"}, "FIGREF9": {"text": ".6 keV), as well as to an analysis of Chandra data by Jee et al.XMM-Newton spectral analysis for the cluster Lynx-E resulted in fluxes and luminosities of F 0.5\u22122 = (0.885 \u00b1 0.053) \u00d7 10 \u221214 erg cm \u22122 s \u22121 and L 0.5\u22122 = (50.2\u00b13)\u00d710 42 erg s \u22121 . The flux is in agreement with measurements from Stanford et al. (2001), where their aperture flux was extrapolated. Our best-fitting pa- rameter for the ICM temperature is k B T = 4.93 +0.77 \u22120.62 keV, which is also comparable with the results by Stanford et al.keV); a comparison with additional results based on Chandra data is summarized in Jee et al. (2006).", "type": "figure"}, "FIGREF10": {"text": "very well with the value given by Hoeft et al. (2008) (z = 0.82). The resulting X-ray flux and luminosity are F 0.5\u22122 (300kpc) = (6.66 \u00b1 0.17) \u00d7 10 \u221214 erg cm \u22122 s \u22121 and L 0.5\u22122 (300kpc) = (171.1 \u00b1 4.4) \u00d7 10 42 erg s \u22121 , respectively. The temperature derived in our APEC fit, k B T = 4.84 +0.31 \u22120.30 keV, is also in within the 1\u03c3 interval of the findings by Hoeft et al. (2008) (k B T = 4.2 \u00b1 0.4 keV).", "type": "figure"}, "FIGREF11": {"text": "Fig. 7: Optical and near-IR images of the field of 2XMMp J092120.2+371735. (a): SDSS DR6 image. (b): W1-band (3.4\u00b5m) image from the AllWISE survey. (c): LBC image (mean of the r-and z-SLOAN filters). North is up, east is left, and all images cover the same region. Blue dashed lines (middle and right images) indicate contours from the X-ray flux. Red squares overplotted on the LBC image refer to the z \u223c 1.2 group, and green circles to spectroscopic sources outside our membership criteria. Blue cycles show galaxies from the foreground population (z \u223c 1).", "type": "figure"}, "FIGREF12": {"text": "After cleaning for times of high background events, the summed exposure times are \u223c 135, \u223c 147, and \u223c 114 ksec for MOS1, MOS2, and PN. Our APEC model fits give a flux and rest frame luminos- ity of F 0.5\u22122 (300kpc) = (1.928 \u00b1 0.038) \u00d7 10 \u221214 erg cm \u22122 s \u22121 and L 0.5\u22122 (300kpc) = (106.4 \u00b1 2.1) \u00d7 10 42 erg s \u22121 . Owing to the differences in the extraction region, these results are not di- rectly comparable to values in the literature. The best-fitting ICM temperature according to our model, k B T = 4.52 +0.24 \u22120.22 keV, is in agreement with Hashimoto et al. (2004) and their results for the eastern and western lobe (3keV, see Hashimoto et al. 2002).", "type": "figure"}, "FIGREF13": {"text": "Fig. 9: Redshift histogram (top panel) and colour-magnitude diagram (bottom) of 2XMMp J092120.2+371735. Objects with spectra are marked green, while the members of the high-redshift group are shown in red. Blue refers to the foreground population of galaxies, which is unlikely to be responsible for the X-ray emission. Error bars plotted in panel (b) indicate the photometric uncertainties and are visible when they exceed the symbol size.", "type": "figure"}, "FIGREF14": {"text": "Fig. 10: Cluster temperature plotted against the bolometric luminosity of two samples of galaxy clusters. Panels (a), (b), and (c) show data from Takey et al. (2013), restricted to L bol h(z) \u22121 > 10 43 erg s \u22121 , and present their three redshift bins (see individual panel). The clusters from this work are plotted in panel (d). In all panels we highlight the best-fitting solution of Eq. 6 for the combined sample of Takey et al. (2013) and our high-redshift extension, including the luminosity cut, as a blue dashed line (parameters are listed in Table 4).", "type": "figure"}, "FIGREF15": {"text": ".03 \u2264 z < 1.27 3.45 \u00b1 0.29 44.535 \u00b1 0.083 0.676 \u00b1 0.043", "type": "figure"}, "TABREF0": {"text": "List of all X-ray selected galaxy cluster candidates within SDSS blank fields", "type": "table"}, "TABREF1": {"text": "Cluster properties from optical and X-ray spectroscopy.", "type": "table"}, "TABREF2": {"text": "", "type": "table"}, "TABREF3": {"text": "Best-fitting parameters of L \u2212 T relation from the BCES method.", "type": "table"}}}
{"paper_id": "119429301", "_pdf_hash": "1f9e47f7d77fe22832e121f78c9168dd82983f6f", "abstract": [{"section": "Abstract", "text": "The Chinese Space Station Optical Survey (CSS-OS) is a planned full sky survey operated by the Chinese Space Station Telescope (CSST). It can simultaneously perform the photometric imaging and spectroscopic slitless surveys, and will probe weak and strong gravitational lensing, galaxy clustering, individual galaxies and galaxy clusters, active galactic nucleus (AGNs), and so on. It aims to explore the properties of dark matter and dark energy and other important cosmological problems. In this work, we focus on two main CSS-OS scientific goals, i.e. the weak gravitational lensing (WL) and galaxy clustering surveys. We generate the mock CSS-OS data based on the observational COSMOS and zCOSMOS catalogs. We investigate the constraints on the cosmological parameters from the CSS-OS using the Markov Chain Monte Carlo (MCMC) method. The intrinsic alignments, galaxy bias, velocity dispersion, and systematics from instrumental effects in the CSST WL and galaxy clustering surveys are also included, and their impacts on the constraint results are discussed. We find that the CSS-OS can improve the constraints on the cosmological parameters by a factor of a few (even one order of magnitude in the optimistic case), compared to the current WL and galaxy clustering surveys. The constraints can be further enhanced when performing joint analysis with the WL, galaxy clustering, and galaxy-galaxy lensing data. The CSS-OS is expected to be a powerful survey for exploring the Universe.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "INTRODUCTION", "text": "Understanding the nature of dark matter and dark energy, and formation and evolution of the cosmic largescale structure (LSS) is essential for the study of cosmology. A number of powerful observational tools, such as weak gravitational lensing (WL) (e.g. Kaiser 1992 Kaiser , 1998 , baryon acoustic oscillations (BAO) (e.g. Eisenstein 2005; Eisenstein et al. 2005) , and redshift-space distortion (RSD) (e.g. Jackson 1972; Kaiser 1987) , have been applied for solving these issues. A few Stage IV ground-and space-borne telescopes, e.g. the Large Synoptic Survey Telescope (LSST) 1 (Ivezic et al. 2008; Abell et al. 2009 ), Euclid space telescope 2 (Laureijs et al. 2011) , and Wide Field Infrared Survey Telescope (WFIRST) 3 , have been planned to perform these measurements. These powerful surveys are expected to make great improvements on related scientific objectives. The Chinese Space Station Optical Survey (CSS-OS) is another this kind of sky survey. CSS-OS is expected to be a powerful survey for probing the Universe, which is comparable and even more robust in some aspects than other Stage IV surveys (Zhan 2011) .", "cite_spans": [], "ref_spans": []}, {"section": "INTRODUCTION", "text": "In this work, we predict the measurements of weak lensing and galaxy clustering for the CSS-OS, and investigate the constraint accuracy of the cosmological parameters. We make use of two catalogs from the real observations, i.e. COSMOS and zCOSMOS surveys, as the mock catalogs for the CSST photometric and spectroscopic surveys, respectively. These two catalogs have similar magnitude limits as the CSS-OS, and can well represent the CSST observations. For the weak lensing survey, we derive the galaxy redshift distribution from the mock catalog, and divide it into several photometric redshift (photo-z) bins to calculate the auto and cross convergence power spectra. The galaxy intrinsic alignments and systematics (multiplicative and additive) due to point spread function, photometry offsets, instrumental noise, etc., are included when estimating the errors. We also evaluate the redshift-space galaxy clustering power spectra in the CSST spectroscopic survey with slitless gratings. The multipole power spectra are calculated in the spectroscopic redshift (spec-z) bins, and the effects of frequency resolution, galaxy bias, velocity dispersion, and systematic errors are considered in the error estimate. Then we compute the observed CSS-OS angular cross power spectra of the weak lensing and galaxy clustering, i.e. galaxy-galaxy lensing power spectra. The mock data of weak lensing, galaxy clustering, and their cross correlation are used in the constraints on the cosmological parameters. The Markov Chain Monte Carlo (MCMC) technique is adopted to illustrate the probability distributions of the parameters.", "cite_spans": [], "ref_spans": []}, {"section": "INTRODUCTION", "text": "The paper is organized as follows: the weak lensing, galaxy clustering, and galaxy-galaxy lensing power spectra surveys are discussed in Section 2, 3, and 4, respectively. In section 5, we show the details of fitting process using the MCMC method. The constraint results are shown in Section 6. We finally summarize the conclusions in Section 7. Throughout the paper, we assume the flat \u039bCDM cosmology with \u2126 m = 0.3, \u2126 b = 0.05, \u03c3 8 = 0.8, n s = 0.96, and h = 0.7 as the fiducial model.", "cite_spans": [], "ref_spans": []}, {"section": "WEAK LENSING SURVEY", "text": "The CSS-OS covers 17500 deg 2 survey area in the photometric imaging survey with survey depth i 26 AB magnitude (5\u03c3 detection for point sources) (Cao et al. 2018) . It has seven filters, i.e. N U V , u, g, r, i, z, and y bands, which covers the wavelength range 2500-11000 A (see Figure 1) . The point spread function (PSF) of the CSS-OS has Gaussian-shape, that is expected to obtain excellent galaxy shape measurements for the weak -The intrinsic transmissions for the filters of the CSST photometric (solid) and spectroscopic (dashed) surveys. There are seven bands, i.e. N U V , u, g, r, i, z, and y, in the photometric imaging survey, and three wide bands, i.e. GU , GV , and GI, in the slitless spectroscopic survey.", "cite_spans": [], "ref_spans": [{"start": 280, "end": 289, "text": "Figure 1)", "ref_id": "FIGREF0"}]}, {"section": "WEAK LENSING SURVEY", "text": "lensing study. In this section, we discuss the predicated galaxy redshift distribution and shear power spectra for the CSS-OS.", "cite_spans": [], "ref_spans": []}, {"section": "Galaxy photometric redshift distribution", "text": "Following Cao et al. (2018) , we adopt a galaxy redshift distribution n(z) derived from the COSMOS catalog for the CSS-OS photometric survey (Capak et al. 2007; Ilbert et al. 2009 ). This catalog contains about 220,000 galaxies in 2 deg 2 , and has similar magnitude limit as the CSS-OS with i \u2264 25.2 for galaxy observation. Although the survey area of the CSS-OS is much larger, it can represent the redshift and magnitude distributions, and galaxy types observed by the CSS-OS. The CSS-OS redshift distribution derived from this catalog is shown in dotted line in Figure 2 . We can find that the redshift distribution has a peak around z = 0.6, and can extend to z \u223c 4.", "cite_spans": [], "ref_spans": [{"start": 566, "end": 574, "text": "Figure 2", "ref_id": "FIGREF1"}]}, {"section": "Galaxy photometric redshift distribution", "text": "In order to extract more information from the weak lensing data, we divide the redshift range into different photo-z tomographic bins, and study the auto and cross power spectra of these bins. As shown in Figure 2 , for instance, we divide the redshift range into four photo-z bins (gray vertical lines). The first three bins has equal interval with \u2206 z = 0.6, and the last bin occupies the rest of the redshift range of redshift distribution 4 . Note that the fitting results of the cosmological parameters also depends on the number of photo-z bins (e.g. Huterer 2002) . Under the assumptions of the systematics as discussed in Section 2.2, we find that although more number of bins -The mock galaxy redshift distributions in the photometric imaging survey of the CSS-OS. The black dotted line denotes the total redshift distribution n(z), which is obtained from the COSMOS catalog (Cao et al. 2018) . The solid blue, green, orange, and red lines are the redshift distribution n i (z) for the four photo-z bins (divided by the gray vertical dashed lines) with \u2206z = 0 and \u03c3z = 0.05 in Eq. (2). may further improve the constraint results, the improvement is not much significant (averagely a factor of \u223c1.3 and \u223c1.5 on the standard deviations of cosmological parameters for the five and six photo-z bins cases, respectively). Considering the purpose of this work, a four-bin division is adequate for our study. More number of bins can be used in the real data analysis, which may help to improve the constraints on the cosmological parameters.", "cite_spans": [], "ref_spans": [{"start": 205, "end": 213, "text": "Figure 2", "ref_id": "FIGREF1"}]}, {"section": "Galaxy photometric redshift distribution", "text": "The real galaxy redshift distribution in the ith photo-z bin can be expressed as (e.g. Ma et al. 2006 )", "cite_spans": [], "ref_spans": []}, {"section": "Galaxy photometric redshift distribution", "text": "where z i p,l and z i p,u are the lower and upper limits of the ith photo-z bin, n(z) is the total redshift distribution, and p(z p |z) is the photo-z distribution function given the real redshift z. We assume it takes the form as", "cite_spans": [], "ref_spans": []}, {"section": "Galaxy photometric redshift distribution", "text": "where \u2206z and \u03c3 z are the redshift bias and scatter, respectively, which vary as functions of redshift. In this work, we assume that they are constants in different photo-z bins, and treat them as free parameters when fitting the data. Then the n i (z) in Eq.", "cite_spans": [], "ref_spans": []}, {"section": "Galaxy photometric redshift distribution", "text": "(1) can be reduced to", "cite_spans": [], "ref_spans": []}, {"section": "Galaxy photometric redshift distribution", "text": "where erf(x) is the error function, and", "cite_spans": [], "ref_spans": []}, {"section": "Galaxy photometric redshift distribution", "text": "Fig. 3.-The components of the shear power spectrum measured by the CSS-OS for the one-bin case assumingN add = 10 \u22129 . The blue solid, light blue dash-dotted, orange dotted, and red dashed curves denote the signal, convergence, intrinsic-intrinsic, gravitational-intrinsic power spectra, respectively. The shot-noise and additive term are shown in black dotted and dashed curves, respectively. The black solid line is for the total power spectrum. The blue circles with error bars are the mock data for the signal power spectrum.", "cite_spans": [], "ref_spans": []}, {"section": "Galaxy photometric redshift distribution", "text": "Note that we always have n(z) = i n i (z), no matter what form n i (z) takes.", "cite_spans": [], "ref_spans": []}, {"section": "Galaxy photometric redshift distribution", "text": "In Figure 2 , the solid blue, green, orange, and red lines show the n i (z) for the four photo-z bins with \u2206z = 0 and \u03c3 z = 0.05. In the COSMOS catalog, we find that there are about 208,000 galaxies with \u03c3 z \u2264 0.05, which take about 95% of the whole sample (Cao et al. 2018 ). This number can be used, as a reference, to estimate the galaxy number density in the CSS-OS weak lensing survey. We will adopt the n i (z) shown in Figure 2 and the estimated number density in the following WL discussion.", "cite_spans": [], "ref_spans": [{"start": 3, "end": 11, "text": "Figure 2", "ref_id": "FIGREF1"}, {"start": 426, "end": 434, "text": "Figure 2", "ref_id": "FIGREF1"}]}, {"section": "Shear power spectra", "text": "Considering intrinsic alignments and systematics, the measured shear power spectrum at a given multipole for the ith and jth tomographic bins can be estimated by (e.g. Huterer et al. 2006; Amara & Refregier 2008) ", "cite_spans": [], "ref_spans": []}, {"section": "Shear power spectra", "text": "where C ij \u03b3 ( ) is named as signal power spectrum, which is composed of three components (e.g. Hildebrandt et al. 2016; Troxel et al. 2017; Joudaki et al. 2017 )", "cite_spans": [], "ref_spans": []}, {"section": "Shear power spectra", "text": "Here P ij \u03ba ( ) is the convergence power spectrum, which is the desired galaxy shear power spectrum for cosmological analysis. The C ij II ( ) and C ij IG ( ) are Intrinsic-Intrinsic (II), and Gravitational-Intrinsic (GI) power spectra, respectively. They are accounting for the intrinsic galaxy . Both auto and cross power spectra have been shown. To avoid the non-linear effect, we only consider the data points at < 3000 in the cosmological analysis. alignment effects, that \"II\" denotes the correlation of the intrinsic ellipticities between neighbouring galaxies, and \"GI\" means the correlation between the intrinsic ellipticity of a foreground galaxy and the gravitational shear of a background galaxy (see e.g. Joachimi et al. 2016) . Assuming Limber and flat-sky approximations (Limber 1954) , we have", "cite_spans": [], "ref_spans": []}, {"section": "Shear power spectra", "text": "where \u03c7 is the comoving radial distance, \u03c7 H = \u03c7(z = 5) denotes the horizon distance, and r(\u03c7) is the comoving angular diameter distance. P m is the matter power spectrum, which is calculated by the halo model (Cooray & Sheth 2002) . q i (\u03c7) is the lensing weighting function in the ith tomographic bin", "cite_spans": [], "ref_spans": []}, {"section": "Shear power spectra", "text": "where H 0 = 100 h is the Hubble constant, c is the speed of light, a = 1/(1 + z) is the scale factor. n i (\u03c7) is the normalized source galaxy distribution of the ith tomographic bin, and n i (\u03c7)d\u03c7 = 1. The intrinsic-intrinsic and gravitational-intrinsic power spectra are given by", "cite_spans": [], "ref_spans": []}, {"section": "Shear power spectra", "text": "and", "cite_spans": [], "ref_spans": []}, {"section": "Shear power spectra", "text": "Here F i (\u03c7) is written as", "cite_spans": [], "ref_spans": []}, {"section": "Shear power spectra", "text": "where C 1 = 5 \u00d7 10 \u221214 h \u22122 M \u22121 Mpc 3 , \u03c1 c is the present critical density, D(\u03c7) is the linear growth factor normalized to unity at z = 0, and z 0 = 0.6 and L 0 are pivot redshift and luminosity, respectively. A IA , \u03b7 IA , and \u03b2 IA are free parameters in this model. For simplicity, we fix \u03b2 IA = 0 here, i.e. we do not consider luminosity dependence, since the change of the average luminosity can be ignored across different tomographic bins (Hildebrandt et al. 2016; Joudaki et al. 2017 ). The fiducial values of A IA and \u03b7 IA are set to be -1 and 0, respectively, when producing mock data.", "cite_spans": [], "ref_spans": []}, {"section": "Shear power spectra", "text": "In the shot-noise term N shot \u03b3 of Eq. (5), \u03c3 2 \u03b3 = 0.04 is the shear variance per component caused by intrinsic ellipticity and measurement error, andn i is the average galaxy number density in a given tomographic bin per steradian. According to the mock CSS-OS catalog, we assume \u223c 100, 000 galaxies with \u03c3 z \u2264 0.05 per deg 2 can be observed by the CSS-OS. This corresponds to a total density \u223c28 arcmin \u22122 , andn i = 7.9, 11.5, 4.6, and 3.7 arcmin \u22122 for the four redshift bins. Besides, we also consider the systematic errors in the CSS-OS weak lensing measurements. In Eq. (5), m i accounts for the effect of the multiplicative error in the ith redshift bin, which is averaged over all directions and galaxies in that bin. We assume it varies independently in different tomographic bins, and treat it as a free parameter in a given photo-z bin in the fitting process (Troxel et al. 2017) . We set m i = 0 as fiducial value in each bin when generating mock data.", "cite_spans": [], "ref_spans": []}, {"section": "Shear power spectra", "text": "The N ij add in Eq. (5) is the additive error, which can be generated by the anisotropy of the PSF . In principle, N ij add ( ) could vary at different scales and in different redshift bins, and also can appear in the correlations between bins Amara & Refregier 2008; Amara et al. 2010 ). For simplicity, we adopt an average constantN add over all scales of all auto and cross shear power spectra for different tomographic bins (Zhan 2006) . Based on the estimates of STEP (the Shear Testing Programme) and GREAT10 (the Gravitational Lensing Accuracy Testing 2010), th\u0113 N add can be controlled within 10 \u221210 with S/N \u223c 10 in the Stage IV weak lensing surveys (Heymans et al. 2006; Massey et al. 2007; Kitching et al. 2012; Massey et al. 2013) . We find that the S/N of most CSS-OS galaxies is around 7 for the most important g, r, and i bands (Cao et al. 2018) . Although theN add are expected to achieve \u223c 10 \u221210 when adding up the flux of all seven CSST imaging bands, we would take a conservative estimate withN add = 10 \u22129 as a moderate value in this work. We will discussN add = 10 \u22128 and 10 \u221210 as pessimistic and optimistic cases.", "cite_spans": [], "ref_spans": []}, {"section": "Shear power spectra", "text": "The covariance matrix of the shear power spectra can be estimated by ( -The mock galaxy redshift distribution of the CSST spectroscopic survey. The zCOSMOS catalog, which has similar survey depth, is adopted to simulate the CSST survey result. We find that the distribution has a peak around z = 0.3 \u2212 0.4, and can reach up to z \u223c 2.5. We divide the redshift range into five bins (by the gray vertical lines) with \u2206z = 0.3 for tomographic study.", "cite_spans": [], "ref_spans": []}, {"section": "Shear power spectra", "text": "where C ij \u03b3 ( ) is the observed shear power spectrum given by Eq. (5), and f sky is the sky coverage fraction of the survey. The CSS-OS can cover 17500 deg 2 , but after removing masked area (covering image defects, reflections, ghosts, etc.), we assume an effective area of \u223c 15000 deg 2 can be used in the data analysis (Hildebrandt et al. 2016; Troxel et al. 2017; Abbott et al. 2017) .", "cite_spans": [], "ref_spans": []}, {"section": "Shear power spectra", "text": "In Figure 3 , we show the power spectra discussed above for the one photo-z bin case (i.e. no tomographic bins). We assume that the shot-noise and additive terms can be eliminated in the data analysis 5 , and thus the mock data points of the C ij \u03b3 can be derived as shown in blue circles with error bars. A random Gaussian distribution derived from the covariance matrix is added to each data point. The C ij \u03b3 for the four photo-z bins are shown in Figure 4 . To avoid the non-linear effects, we only take account of the data at < 3000.", "cite_spans": [], "ref_spans": [{"start": 451, "end": 459, "text": "Figure 4", "ref_id": "FIGREF2"}]}, {"section": "GALAXY CLUSTERING SURVEY", "text": "In addition to the photometric imaging survey, the CSS-OS also can simultaneously perform the spectroscopic survey using slitless gratings. The CSST spectroscopic survey covers the same survey area (17500 deg 2 ) and similar wavelength range (2550-10000\u00c5) as the photometric imaging survey. It contains three bands, i.e. GU , GV , and GI (see Figure 1 ), with AB magnitude 5\u03c3 limit \u223c23 for point sources with spectral resolution R = 200 \u223c 250. In this section, we will discuss the galaxy clustering power spectrum with the effect of redshiftspace distortion (RSD) measured by the CSST spectroscopic survey.", "cite_spans": [], "ref_spans": [{"start": 343, "end": 351, "text": "Figure 1", "ref_id": "FIGREF0"}]}, {"section": "GALAXY CLUSTERING SURVEY", "text": "3.1. Galaxy spectroscopic redshift distribution We adopt the zCOSMOS catalog (DR3 release) to simulate the CSST spectroscopic survey result. The zCOS-MOS redshift survey observes in the COSMOS field using the VIMOS spectrograph mounted at the Melipal Unit Telescope of the VLT (Lilly et al. 2007 (Lilly et al. , 2009 ). It covers 1.7 deg 2 with a magnitude limit I AB 22.5, which is close to survey depth of the CSS-OS. The spectral coverage is 5550-9450\u00c5 with a spectral resolution R \u223c 600. There are about 20,000 sources in this catalog, and after selecting high-quality data suggested by the zCOSMOS team, we obtain about 16,600 sources (80% of the total) with reliable spectroscopic redshifts. The redshift distribution of this mock CSST spectroscopic catalog is shown in Figure 5 . We can see that it has a peak at z = 0.3 \u2212 0.4, and can extend to z \u223c 2.5. Since there are not many galaxies at high redshifts, we only consider the sources at z < 1.5 in the galaxy clustering analysis (\u223c 40 galaxies are out of this range). In order to study the evolution of the equation of state of dark energy and other cosmological parameters, we divide the redshift range into five tomographic bins with \u2206 z = 0.3. The galaxy number fraction in the five spec-troscopic bins are 0.17, 0.37, 0.35, 0.10, and 0.01, respectively. Note that more number of redshift bins can be used in the real data analysis, depending on the number density of observed galaxies.", "cite_spans": [], "ref_spans": [{"start": 776, "end": 784, "text": "Figure 5", "ref_id": "FIGREF4"}]}, {"section": "GALAXY CLUSTERING SURVEY", "text": "3.2. Redshift-space galaxy power spectrum The redshift-space galaxy power spectrum in (k, \u00b5) dimensions can be measured by the CSST spectroscopic survey, which can be expanded in Legendre polynomials (Taylor & Hamilton 1996; Ballinger et al. 1996) ", "cite_spans": [], "ref_spans": []}, {"section": "GALAXY CLUSTERING SURVEY", "text": "where (s) denotes the redshift space, \u00b5 = k /k is the cosine of the angle between the direction of wavenumber k and the line of sight, L (\u00b5) is the Legendre polynomials that only the first few non-vanishing orders = (0, 2, 4) are considered in the linear regime, and P g (k) is the multipole moments of the power spectrum. Considering the Alcock-Paczynski effect (Alcock & Paczynski 1979) , the galaxy multipole power spectra are given by", "cite_spans": [], "ref_spans": []}, {"section": "GALAXY CLUSTERING SURVEY", "text": "Here", "cite_spans": [], "ref_spans": []}, {"section": "GALAXY CLUSTERING SURVEY", "text": "are the scaling factors in the transverse and radial directions, respectively, and the superscript \"fid\" means the quantities in the fiducial cosmology. The k = k 2 + k 2 \u22a5 and \u00b5 = k /k are the apparent wavenumber and cosine of angle, where k = k /\u03b1 and k \u22a5 = k \u22a5 /\u03b1 \u22a5 . Assuming there is no peculiar velocity bias, the apparent redshiftspace galaxy power spectrum can be written as", "cite_spans": [], "ref_spans": []}, {"section": "GALAXY CLUSTERING SURVEY", "text": "where", "cite_spans": [], "ref_spans": []}, {"section": "GALAXY CLUSTERING SURVEY", "text": "is the apparent real-space galaxy power spectrum, b g is the galaxy bias, P m is the matter power spectrum, and \u03b2 = f /b g where f = d lnD(a)/d ln a is the growth rate. D(k , \u00b5 ) is the damping term at small scales, which is given by", "cite_spans": [], "ref_spans": []}, {"section": "GALAXY CLUSTERING SURVEY", "text": "Here", "cite_spans": [], "ref_spans": []}, {"section": "GALAXY CLUSTERING SURVEY", "text": "is the velocity dispersion (Scoccimarro 2004; Taruya et al. 2010 ), and we assume \u03c3 v0 = 7 Mpc/h for the measurements of emission line galaxies in the CSS-OS (Blake et al. 2016; Joudaki et al. 2017 ). It will be set as a free parameter in the fitting process. The \u03c3 R = c \u03c3 z /H(z) is the smearing factor for the small scales below the spectral resolution of spectroscopic surveys, where H(z) is the Hubble parameter, and \u03c3 z = (1 + z)\u03c3 0 z (Wang et al. 2009 ). Based on the instrumental design of the CSST, we set \u03c3 0 z = 0.002 as the accuracy of the spectral calibration.", "cite_spans": [], "ref_spans": []}, {"section": "GALAXY CLUSTERING SURVEY", "text": "After adding the shot-noise term and systematics, we obtain the total multipole power spectra of the ath spec-z bin", "cite_spans": [], "ref_spans": []}, {"section": "GALAXY CLUSTERING SURVEY", "text": "wheren a g is the galaxy number density in the ath spec-z bin. We take an average valuen a g in a given redshift bin, \u22123 (Mpc/h) \u22123 , and 7.9\u00d710 \u22125 from the mock CSS-OS catalog for the five spec-z bins, respectively. Besides, we consider an effective redshift factor f zs eff to account for the fraction of galaxies that can achieve the required accuracy of the CSS-OS spec-z calibration with \u03c3 0 z = 0.002 in the slitless grating observations (Wang et al. 2010) . We assume the fraction decreases as the redshift increases, i.e. f 5 , 5 \u00d7 10 4 , and 10 4 (Mpc/h) 3 , as pessimistic, moderate, and optimistic cases in the CSST galaxy clustering surveys.", "cite_spans": [], "ref_spans": []}, {"section": "GALAXY CLUSTERING SURVEY", "text": "The errors of the multipole power spectra in the ath bin are then given by", "cite_spans": [], "ref_spans": []}, {"section": "GALAXY CLUSTERING SURVEY", "text": "where V a S is the survey volume of the ath bin. We assume a 15000 deg 2 sky coverage for the galaxy clustering spectroscopic survey, which is the same as the photometric imaging survey area used in the weak lensing, after masking the area with bad measurements. For a constant n g in a given redshift bin, the corresponding effective survey volume for a multipole component of power spectrum can be defined as", "cite_spans": [], "ref_spans": []}, {"section": "GALAXY CLUSTERING SURVEY", "text": "In Figure 6 , we show the mock multipole power spectra P g 0 , P g 2 , and P g 4 . In order to avoid the non-linear effect, we only consider the data at k < 0.2 h/Mpc. The errors of the mock data are generated by assuming f zs,0 eff = 0.5 andN g sys = 5\u00d710", "cite_spans": [], "ref_spans": [{"start": 3, "end": 11, "text": "Figure 6", "ref_id": "FIGREF5"}]}, {"section": "GALAXY CLUSTERING SURVEY", "text": "4 (Mpc/h) 3 . In Figure 7 , the V eff of the P g 0 for each redshift bin are shown. The dashed, solid, and dotted curves are for the optimistic, moderate, and pessimistic cases.", "cite_spans": [], "ref_spans": [{"start": 17, "end": 25, "text": "Figure 7", "ref_id": "FIGREF6"}]}, {"section": "GALAXY CLUSTERING SURVEY", "text": "In addition to the redshift-space power spectrum, the CSS-OS three-dimensional (3-d) galaxy clustering data also can be analyzed using other methods, such as topology (Park & Kim 2010) , tomographic Alcock-Paczynski (Li et al. 2016 ) and 3-point correlation function (Takada & Jain 2003) , that can extract more cosmological information. We will discuss these methods in the future work.", "cite_spans": [], "ref_spans": []}, {"section": "GALAXY-GALAXY LENSING SURVEY", "text": "We can also cross-correlate the WL and galaxy clustering surveys to get galaxy-galaxy lensing power spectra for the photo-z and spec-z bins in the CSS-OS. This can help us to derive more cosmological information.", "cite_spans": [], "ref_spans": []}, {"section": "Angular galaxy power spectrum", "text": "We first consider the two-dimensional (2-d) angular galaxy power spectrum for the ath and bth spec-z bins, which can be derived from the 3-d galaxy power spectrum by assuming Limber approximation (Limber 1954; Kaiser 1992; Hu & Jain 2004 )", "cite_spans": [], "ref_spans": []}, {"section": "Angular galaxy power spectrum", "text": "where b g (k, \u03c7) is the galaxy bias, which depends on the scales and redshifts. For simplicity, we assume it is a constant at different scales and only varies as a function of redshift b g (z) when producing mock data.n a g (\u03c7) is the normalized galaxy redshift distribution for the ath spec-z bin, that we have n a g (\u03c7)d\u03c7 = 1. Incorporating the shot-noise term and systematics, the total angular galaxy power spectrum can be written as", "cite_spans": [], "ref_spans": []}, {"section": "Angular galaxy power spectrum", "text": "wheren a g is the average galaxy number density in the ath spec-z bin per steradian, and it is found to be 0.46, 1.0, 0.94, 0.29, and 0.02 arcmin \u22122 for the five bins (\u223c 2.7 arcmin \u22122 totaly), respectively. N g, ab sys ( ) is the systematic noise for the angular galaxy power spectrum, and we assume it is a constant for different scales and redshift bins. We find that the result is not sensitive to the N g sys as long as it is less than 10 \u22128 , i.e. the shot-noise term (the second term) in Eq. (21) is relatively large and dominant.", "cite_spans": [], "ref_spans": []}, {"section": "Angular galaxy power spectrum", "text": "Note that the cross power spectra vanish in the spectroscopic surveys (e.g. the case we discuss here), since there is no overlapping region between spec-z bins. However, Fig. 8 .-The angular galaxy power spectra for the five spectroscopic redshift bins, which can be cross-correlate with the shear power spectra. Note that there is no cross power spectrum between spec-z bins.", "cite_spans": [], "ref_spans": []}, {"section": "Angular galaxy power spectrum", "text": "for the photometric surveys, both the auto and cross angular galaxy power spectra are important, and can be used to calibrate the galaxy bias and redshift distributions when cooperating with the weak lensing survey (Hu & Jain 2004; Zhan 2006) . The CSS-OS also can probe the angular galaxy power spectrum in the photometric imaging survey, and we will discuss it in our future work. In Figure 8 , we show the 2-d angular galaxy power spectra for the five spec-z bins.", "cite_spans": [], "ref_spans": []}, {"section": "Angular galaxy power spectrum", "text": "4.2. Galaxy-galaxy lensing power spectrum Then we can calculate the angular galaxy-galaxy lensing power spectrum, i.e. cross-correlating the galaxy clustering and weak lensing surveys, of the ath galaxy spec-z bin and the ith photo-z bin. Considering the intrinsic alignment effect, it can be expressed as (Joudaki et al. 2017 )", "cite_spans": [], "ref_spans": []}, {"section": "Angular galaxy power spectrum", "text": "where the C ai g\u03ba and C ai gI are given by", "cite_spans": [], "ref_spans": []}, {"section": "Angular galaxy power spectrum", "text": "and", "cite_spans": [], "ref_spans": []}, {"section": "Angular galaxy power spectrum", "text": "(24) The covariance matrix for the galaxy-galaxy lensing power spectra is given by (Hu & Jain 2004) ", "cite_spans": [], "ref_spans": []}, {"section": "Angular galaxy power spectrum", "text": "Fig. 9.-The angular galaxy-galaxy lensing power spectra for the first photometric and second spectroscopic redshift bins, considering the intrinsic alignment effect. For comparison, the corresponding convergence and angular galaxy power spectra are also shown. Fig. 10. -The coefficients of the cross power spectra for the four photometric and five spectroscopic bins. The solid blue, light blue dash-dotted, green long dashed, orange dashed, and red dotted curves are for the correlations between a given photo-z bin (from the top to bottom panels) and the 1st, 2nd, 3rd, 4th, and 5th spec-z bins, respectively.", "cite_spans": [], "ref_spans": [{"start": 261, "end": 269, "text": "Fig. 10.", "ref_id": "FIGREF0"}]}, {"section": "Angular galaxy power spectrum", "text": "In Figure 9 , we show the mock galaxy-galaxy lensing power spectra for the first photo-z and second specz bins. The green solid, light blue dash-dotted, red dashed curves denote the total, galaxy-galaxy lensing, and galaxy-Intrinsic power spectra, respectively. For comparison, the corresponding convergence (dark blue dash-dotted) and angular galaxy (orange dashed-dotted) \u22128 . We can define the coefficients of the cross power spectra of weak lensing and galaxy clustering between the photometric and spectroscopic redshift bins, which is given by", "cite_spans": [], "ref_spans": []}, {"section": "Angular galaxy power spectrum", "text": "In Figure 10 , we calculate the coefficients of the cross power spectra for the four photometric and five spectroscopic bins. For instance, in the top panel, we find that the z 1 p bin only have significant correlations with the z 1 s and z 2 s bins, since they cover similar redshift range (see Figure 2 and 5).", "cite_spans": [], "ref_spans": [{"start": 3, "end": 12, "text": "Figure 10", "ref_id": "FIGREF0"}, {"start": 296, "end": 304, "text": "Figure 2", "ref_id": "FIGREF1"}]}, {"section": "FITTING THE MOCK DATA", "text": "When generating the mock data, we assume the flat \u039bCDM cosmology with the equation of state (EoS) of dark energy w = \u22121. In order to explore the constraint of the CSS-OS on the evolution of the dark energy EoS, we adopt the wCDM model with w = w 0 + w a (1 \u2212 a) when fitting the mock data. The HMcode is used to calculate the non-linear matter power spectrum for the wCDM model (Mead et al. 2015 (Mead et al. , 2016 . The cosmological and systematical parameters for the weak lensing, galaxy clustering, and galaxy-galaxy lensing power spectra in the fitting process are shown in Table 2 . In the joint constraint case of the CSST WL and galaxy clustering surveys with four photo-z bins and five spec-z bins, we totally have 31 free parameters in the model. velocity dispersion for the five spec-z bins is assumed as \u03c3 v = \u03c3 v,0 /(1 + z c ) where \u03c3 v,0 = 7 Mpc/h. s i z is the stretch factor that adjusts the width of the n i (z) in a given photo-z bin, which can equally change the redshift variance \u03c3 z . We set the fiducial values of \u2206z i , log 10 (s i z ), and m i to be 0 in the four photometric bins.", "cite_spans": [], "ref_spans": [{"start": 580, "end": 587, "text": "Table 2", "ref_id": "TABREF1"}]}, {"section": "FITTING THE MOCK DATA", "text": "The \u03c7 2 statistic method is adopted to fit the mock data, which is defined by", "cite_spans": [], "ref_spans": []}, {"section": "FITTING THE MOCK DATA", "text": "where C i mock is the mock data, and C i th is the theoretical power spectrum of the ith redshift bin. Cov ij is the corresponding covariance matrix. The total \u03c7 2 for joint surveys of the WL and galaxy clustering is given by \u03c7", "cite_spans": [], "ref_spans": []}, {"section": "FITTING THE MOCK DATA", "text": "\u03b3 , and \u03c7 2 g\u03b3 are the chisquares for the galaxy clustering, WL, and galaxy-galaxy lensing power spectra, respectively. The likelihood function then can be calculated by L \u223c exp(\u2212\u03c7 2 /2). We make use of the Markov Chain Monte Carlo (MCMC) technique to constrain the free parameters in the model. The Metropolis-Hastings algorithm is adopted to find the accepting probability of new chain points (Metropolis et al. 1953; Hastings 1970) . The proposal density matrix is estimated by a Gaussian sampler with adaptive step size (Doran & Muller 2004) . We assume flat priors for the parameters as shown in Table 2 . We run sixteen parallel chains for each case of systematical assumption, and obtain about 100,000 points for one chain after reaching the convergence criterion (Gelman & Rubin 1992) . After the burn-in and thinning processes, we combine all chains together and obtain about 10,000 chain points to illustrate one-dimensional (1-d) and 2-d probability distribution functions (PDFs) of the free parameters.", "cite_spans": [], "ref_spans": [{"start": 601, "end": 608, "text": "Table 2", "ref_id": "TABREF1"}]}, {"section": "CONSTRAINT RESULTS", "text": "In this section, we show the constraint results of the cosmological and systematical parameters using the CSS-OS mock data. We compare the results in different cases for the cosmological parameters, and discuss the impact of the systematics on the constraint results.", "cite_spans": [], "ref_spans": []}, {"section": "CONSTRAINT RESULTS", "text": "6.1. Constraints on cosmological parameters In Figure 11 , the fitting results of \u2126 m vs. \u03c3 8 and w 0 vs. w a have been shown. We explore three cases, i.e. the moderate, optimistic, and pessimistic assumptions (in solid, dashed, and dotted curves), about the systematics of the CSST WL and galaxy clustering surveys. The top, middle, and bottom panels show the constraint results from the WL, galaxy clustering, and joint (WL+galaxy clustering+galaxy-galaxy lensing) surveys, respectively. The gray lines show the fiducial values of the parameters.", "cite_spans": [], "ref_spans": [{"start": 47, "end": 56, "text": "Figure 11", "ref_id": "FIGREF0"}]}, {"section": "CONSTRAINT RESULTS", "text": "For the CSST WL survey, we find that \u2126 m = 0.304 \u22120.008 in the moderate case (solid lines). This constraint result of the cosmological parameters is averagely improved by a factor of \u223c 6 than that from the Dark Energy Survey (DES) and Kilo Degree Survey (KiDS) (Hildebrandt et al. 2016; Troxel et al. 2017) . The improvement can be even larger in the optimistic case (N add = 10 \u221210 ), and at least a factor of \u223c 3 in the pessimistic case (N add = 10 \u22128 ). This enhancement is due to several advantages of the CSST WL survey, e.g the large survey area (17500 deg 2 ), excellent image quality (2-d Gaussian PSF shape), and accurate photo-z calibration, which can efficiently suppress both statistical and systematical errors.", "cite_spans": [], "ref_spans": []}, {"section": "CONSTRAINT RESULTS", "text": "In the CSST galaxy clustering survey, we find that \u2126 m = 0.286 . This leads to a factor of \u223c 5 improvement at least compared to the current galaxy clustering surveys, such as the SDSS-III Baryon Oscillation Spectroscopic Survey (BOSS) , WiggleZ, 2-degree Field Lensing Survey (2dFLenS), etc. Wang et al. 2016; Blake et al. 2016; Hinton et al. 2017) . The constraint results could be better or worse with an average factor of 2-3 in the optimistic (f 3 ) cases. The improvement is mainly caused by that the CSST spectroscopic survey has deep magnitude limit (\u223c23 mag) and large effective survey volume (see Figure 7) .", "cite_spans": [], "ref_spans": [{"start": 606, "end": 615, "text": "Figure 7)", "ref_id": "FIGREF6"}]}, {"section": "CONSTRAINT RESULTS", "text": "Since the CSST photometric and spectroscopic surveys are planned to perform simultaneously and cover the same sky area, their joint constraint would be convenient and powerful, which gives \u2126 m = 0.304 tighter or looser by a factor of \u223c 1.3 and 1.7, respectively. Comparing to current similar joint fitting results, e.g. KiDS-450+2dFLenS (Joudaki et al. 2017) , we find that the CSST joint survey can enhance the constraints of the cosmological parameters by one order of magnitude when assuming the moderate systematics.", "cite_spans": [], "ref_spans": []}, {"section": "CONSTRAINT RESULTS", "text": "Since the systematics have been included in the analysis, fitting biases with respect to the best-fits appear in the constraint results according to the fiducial values of the cosmological parameters (gray dashed lines), especially for the moderate and pessimistic cases. By comparing the results of the three systematical assumptions, we find that well-controlled systematics not only can shrink the probability contours but also efficiently suppress the fitting biases of the cosmological parameters (see dashed contours in each survey). Besides, it seems that the fitting biases are relatively larger or more apparent in the joint constraint results (e.g. see the result of w a ). It means that better controlling of the systematics may be required in the CSS-OS joint fits. The detailed discussion of the systematical parameters can be found in the next section.", "cite_spans": [], "ref_spans": []}, {"section": "CONSTRAINT RESULTS", "text": "In Figure 13 , we show the comparison of the results from the WL, galaxy clustering, and joint surveys. As can be seen, the CSST WL and galaxy clustering surveys have similar constraint strength on \u2126 m . On the other hand, the WL is more powerful to constrain \u03c3 8 than the galaxy clustering by a factor of \u223c2, since the WL survey explores 2-d power spectra integrating over large redshift range. On the other hand, the CSST galaxy clustering survey can provide comparable or even a bit more stringent fitting results on w 0 and w a than the WL survey. The joint CSST surveys of WL+galaxy clustering+galaxy-galaxy lensing can further improve the fitting results, which give at least \u223c 2\u03c3 enhancement on the constraints of cosmological parameters, compared to the WL only or galaxy clustering only survey.", "cite_spans": [], "ref_spans": [{"start": 3, "end": 12, "text": "Figure 13", "ref_id": "FIGREF0"}]}, {"section": "CONSTRAINT RESULTS", "text": "The constraint results of all cosmological parameters with the mild assumption of the systematics for the WL, galaxy clustering, and joint surveys can be found in Appendix.", "cite_spans": [], "ref_spans": []}, {"section": "Constraints on systematical parameters", "text": "In Figure 14 , the 1-d PDFs of the intrinsic alignment parameters A IA and \u03b7 IA are shown for the WL (in blue curves) and joint (in green curves) surveys. We can find that there is no significant improvement on the constraint of A IA for the joint constraints, while a factor of \u223c 1.3 tighter for \u03b7 IA compared to the WL survey. This indi- cates that the joint fitting can be helpful to extract the redshift evolution effect of intrinsic alignment.", "cite_spans": [], "ref_spans": [{"start": 3, "end": 12, "text": "Figure 14", "ref_id": "FIGREF0"}]}, {"section": "Constraints on systematical parameters", "text": "The 1-d PDFs of the redshift calibration bias \u2206z i , stretch factor s i z , and multiplicative error m i , are shown in Figure 15 . The top and bottom panels show the results from the WL and joint surveys, respectively. We can see that the best-fits of the WL systematic parameters are close to their fiducial values (in 1\u03c3 C.L.), that means our fitting process can correctly extract the systematics as free parameters. This is also useful to reduce the effect of the systematics on the constraints of cosmological parameters, and can help suppressing the fitting biases (see Figure 11) . In order to retain small fitting biases of the cosmological parameters (keeping the fiducial values in 1\u03c3 C.L.), as shown in the top panels of Figure 15 , we need to control the systematical parameters in 1\u03c3 C.L. of their PDFs at least. This requires |\u2206z i | < 0.02, |log 10 (s i z )| < 0.05 (about 10%) 6 , and |m i | < 0.02 for the CSST WL survey. When performing the joint fitting, the constraint results of the systematics can be improved by a factor of \u223c 1.5, which implies that it is helpful to include other surveys (here the galaxy clustering survey) to eliminate the WL systematics in the fitting process.", "cite_spans": [], "ref_spans": [{"start": 120, "end": 129, "text": "Figure 15", "ref_id": "FIGREF0"}, {"start": 576, "end": 586, "text": "Figure 11)", "ref_id": "FIGREF0"}, {"start": 732, "end": 741, "text": "Figure 15", "ref_id": "FIGREF0"}]}, {"section": "Constraints on systematical parameters", "text": "In Figure 16 , the 1-d PDFs of galaxy bias b g and velocity dispersion \u03c3 v0 assuming the moderate systematics for the five spec-z bins are shown. For the galaxy clustering survey (top panels), we find that the dispersions of the best-fits of b g and \u03c3 v0 from the fiducial values are within \u00b10.1, and the 1\u03c3 ranges 0.03-0.05 for b g and 0.1-0.2 for \u03c3 v0 . The dispersions and uncertainties of b g and \u03c3 v0 can be further suppressed in the joint fitting (bottom panel), especially for \u03c3 v0 . We find that the dispersions of b g and \u03c3 v0 can be restricted within \u00b10.05, and the 1\u03c3 within 0.01-0.02 for b g and 0.02-0.06 for \u03c3 v0 (a factor of \u223c2 and \u223c 4 improvement, respectively.). It indicates that the CSS-OS can provide accurate constraints on the galaxy bias and velocity dispersion.", "cite_spans": [], "ref_spans": [{"start": 3, "end": 12, "text": "Figure 16", "ref_id": "FIGREF0"}]}, {"section": "SUMMARY AND DISCUSSION", "text": "In this work, we predict the measurements of the CSS-OS on the weak gravitational lensing and galaxy clustering, and explore the constraints on the cosmological parameters with the systematics. We make use of two catalogs, i.e. COSMOS and zCOSMOS catalogs, to simulate the CSST photometric imaging and slitless spectroscopic surveys. We find that the peaks of galaxy redshift distributions are around 0.6 and 0.3 for the CSST photometric and spectroscopic surveys, respectively.", "cite_spans": [], "ref_spans": []}, {"section": "SUMMARY AND DISCUSSION", "text": "We divide the photometric redshift distribution into four bins, and calculate the auto and cross convergence power spectra of these photo-z bins. The effect of intrinsic alignment, and multiplicative and additive errors are included when generating the mock WL data. In addition to the photometric WL survey, the CSST can simultaneously perform spectroscopic survey to illustrate clustering of galaxies. We compute the galaxy redshiftspace power spectra in five spec-z bins, and obtain the mock data of the multipole power spectra, i.e. P g 0 , P g 2 , and P g 4 . We consider a number of effects when estimat- ing the errors, such as the frequency resolution of the slitless grating, the effective redshift factor accounting for the fraction of galaxies that can achieve the required redshift accuracy in the slitless observations, and the systematic error due to the instrument effect. The cross correlations of the CSST WL and galaxy clustering surveys, i.e. galaxy-galaxy lensing power spectra, are also explored, which can be helpful to further suppress the uncertainties in the joint surveys.", "cite_spans": [], "ref_spans": []}, {"section": "SUMMARY AND DISCUSSION", "text": "After obtaining the CSS-OS mock data, the MCMC technique is adopted to constrain the cosmological and systematical parameters. We study and compare three cases with different assumptions about the systematics of the WL and galaxy clustering surveys, i.e. the pessimistic, moderate, and optimistic cases, in the constraint process. We find that the CSST WL and galaxy clustering surveys can provide a factor of a few (and optimistically even one order of magnitude) improvement about the cosmological parameters, compared to the current corresponding surveys. The constraints can be further enhanced by \u223c 2\u03c3 in the joint fitting process (WL+galaxy clustering+galaxy-galaxy lensing). The CSS-OS also could provide good fitting about the intrinsic alignment and systematics (in the redshift and shape calibrations) in the WL survey, and galaxy bias and velocity dispersion in the galaxy clustering survey. The joint constraint can further improve the results by a factor of \u223c2-4. Particularly, the systematics should be well controlled to avoid large fitting bias on the cosmological parameters in the WL survey, which requires redshift bias |\u2206z i | < 0.02, the redshift stretching scale (or the uncertainty of the redshift variance) s i z < 10%, and the multiplicative error |m i | < 0.02.", "cite_spans": [], "ref_spans": []}, {"section": "SUMMARY AND DISCUSSION", "text": "Besides the WL and redshift-space 3-d galaxy clustering surveys discussed above, the CSS-OS also can perform 2-d angular galaxy clustering photometric survey, strong gravitational lensing survey, galaxy cluster survey, etc. These surveys can offer more valuable information about dark matter and dark energy, the evolution of the LSS, and other important issues in cosmology. Therefore, we can expect that the CSS-OS will be a powerful space sky survey for the studies of our Universe. ", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF54": {"title": "\u2126 b , \u03c3 8 , n s , w 0 , w a , and h, from the CSST WL, galaxy clustering, and joint surveys with moderate systematic assumption are shown in Figure 17, 18, and 19. Fig. 17.-The constraint results of the seven cosmological parameters from the CSST WL survey", "authors": [], "year": "", "venue": "The constraint results of seven cosmological parameters, i.e. \u2126 m", "link": null}, "BIBREF55": {"title": "3%), 2\u03c3 (95.5%), and 3\u03c3 (99.7%) C.L. are shown", "authors": [], "year": "", "venue": "", "link": null}}, "ref_entries": {"FIGREF0": {"text": "Fig. 1.-The intrinsic transmissions for the filters of the CSST photometric (solid) and spectroscopic (dashed) surveys. There are seven bands, i.e. N U V , u, g, r, i, z, and y, in the photometric imaging survey, and three wide bands, i.e. GU , GV , and GI, in the slitless spectroscopic survey.", "type": "figure"}, "FIGREF1": {"text": "Fig. 2.-The mock galaxy redshift distributions in the photometric imaging survey of the CSS-OS. The black dotted line denotes the total redshift distribution n(z), which is obtained from the COSMOS catalog (Cao et al. 2018). The solid blue, green, orange, and red lines are the redshift distribution n i (z) for the four photo-z bins (divided by the gray vertical dashed lines) with \u2206z = 0 and \u03c3z = 0.05 in Eq. (2).", "type": "figure"}, "FIGREF2": {"text": "Fig. 4.-The signal power spectra for the four tomographic bins assumingN add = 10 \u22129 . Both auto and cross power spectra have been shown. To avoid the non-linear effect, we only consider the data points at < 3000 in the cosmological analysis.", "type": "figure"}, "FIGREF3": {"text": "Hu & Jain 2004; Huterer et al. 2006;", "type": "figure"}, "FIGREF4": {"text": "Fig. 5.-The mock galaxy redshift distribution of the CSST spectroscopic survey. The zCOSMOS catalog, which has similar survey depth, is adopted to simulate the CSST survey result. We find that the distribution has a peak around z = 0.3 \u2212 0.4, and can reach up to z \u223c 2.5. We divide the redshift range into five bins (by the gray vertical lines) with \u2206z = 0.3 for tomographic study.", "type": "figure"}, "FIGREF5": {"text": "Fig. 6.-The mock galaxy multipole moments of power spectra P g 0 , P g 2 , and P g 4 . The multipole power spectra for the five spec-z bins (from low to high redshift) are shown from the top to the bottom panels. We only consider the P g at k < 0.2 h/Mpc to avoid the non-linear clustering effect. We assume f zs,0 eff = 0.5 and N g sys = 5 \u00d7 10 4 (Mpc/h) 3 as a moderate case when generating the error bars.", "type": "figure"}, "FIGREF6": {"text": "Fig. 7.-The V eff of the P g 0 for the five spectroscopic redshift bins. The blue, light blue, green, orange, and red curves are for the 1st, 2nd, 3rd, 4th, and 5th spec-z bin, respectively. The dotted, solid, and dashed curves denote the results for the pessimistic, moderate, and optimistic cases with f zs,0 eff = 0.3, 0.5, 0.7, and N g sys = 10 5 , 5 \u00d7 10 4 , 10 4 (Mpc/h) 3 , respectively. and find thatn a g,ori = 3.4 \u00d7 10 \u22122 , 1.1 \u00d7 10 \u22122 , 5.5 \u00d7 10 \u22123 , 1.2\u00d710 \u22123 (Mpc/h) \u22123 , and 7.9\u00d710 \u22125 from the mock CSS-OS catalog for the five spec-z bins, respectively. Besides, we consider an effective redshift factor f", "type": "figure"}, "FIGREF7": {"text": "0.7, respectively, as the pessimistic, moderate, and optimistic cases. So the final number density in the ath spec-z bin should bendue to instrumentation effects of the CSST slitless gratings are assumed to be a constant in differ- ent tomographic bins, or it can be seen as the average valueN g sys over all redshift bins and scales. Combining the three assumptions of f zs,0 eff , we jointly assume three values, i.e.N g sys = 10", "type": "figure"}, "FIGREF8": {"text": "are also shown. The data points with error bars are obtained by assumingN add = 10 \u22129 and N g sys = 10", "type": "figure"}, "FIGREF9": {"text": "The fiducial values of b g for the five bins are obtained by b g = b 0 (1 + z c ) b1 , where b 0 = 1 and b 1 = 1 with the central redshifts of the five spec-z bins z c = 0.15, 0.45, 0.75, 1.05, and 1.35, respectively. The fiducial galaxy", "type": "figure"}, "FIGREF10": {"text": "Fig. 11.-The constraint results of \u2126m vs. \u03c3 8 and w 0 vs. wa for the CSST WL and galaxy clustering surveys. The 1\u03c3 (68.3%) and 2\u03c3 (95.5%) C.L. are shown. T op : results from the WL mock data. The solid, dashed, and dotted contours are the corresponding results by assumingN add = 10 \u22129 , 10 \u221210 , and 10 \u22128 , respectively. M iddle : the results from the CSST galaxy clustering survey. The solid, dashed, and dotted contours are for f zs,0 eff = 0.5, 0.7, and 0.3, andN g sys = 5 \u00d7 10 4 , 10 4 , and 10 5 (Mpc/h) 3 , respectively. Bottom : Joint constraint results (WL+galaxy clustering+galaxy-galaxy lensing). The three cases (solid, dashed, and dotted) are derived from the moderate, optimistic, and pessimistic assumptions of the WL and galaxy clustering surveys.", "type": "figure"}, "FIGREF11": {"text": "Fig. 12.-The contour maps (1\u03c3 and 2\u03c3) of \u2126m vs. S 8 \u2261 \u03c3 8 (\u2126m/0.3) 0.5 forN add = 10 \u22129 (solid), 10 \u221210 (dashed), and 10 \u22128 (dotted), respectively.", "type": "figure"}, "FIGREF12": {"text": "in 1\u03c3 confidence level (C.L.) for the moder- ate systematic case withN add = 10 \u22129 . We also show the constraint results of \u2126 m vs. S 8 \u2261 \u03c3 8 (\u2126 m /0.3) 0.5 in Fig- ure 12. We find that S 8 = 0.801 +0.009", "type": "figure"}, "FIGREF15": {"text": ".010 , \u03c3 8 = 0.803 +0.005 \u22120.008 , w 0 = \u22120.996 +0.010 \u22120.023 , w a = 0.044 +0.034 \u22120.038 in 1\u03c3 C.L. for the moderate systematic case. For the optimistic and pessimistic cases, the constraints can be", "type": "figure"}, "FIGREF16": {"text": "Fig. 13.-Comparison of the constraint results of \u2126m vs. \u03c3 8 (left panel) and w 0 vs. wa (right panel) for the WL, galaxy clustering, and joint surveys. The 1\u03c3 (68.3%) and 2\u03c3 (95.5%) C.L. are shown. Here we assume the moderate systematics, i.e.N add = 10 \u22129 , f zs,0 eff = 0.5, andN g sys = 5 \u00d7 10 4 (Mpc/h) 3 .", "type": "figure"}, "FIGREF17": {"text": "Fig. 14.-The 1-d PDFs of the intrinsic alignment parameters A IA and \u03b7 IA assuming the moderate systematics. The blue and green curves denotes the fitting results of the WL only and joint surveys, respectively.", "type": "figure"}, "FIGREF18": {"text": "Fig. 15.-The 1-d PDFs of the systematical parameters \u2206z i , s i z , and m i from the CSST WL (top) and joint (bottom) surveys for the four photo-z bins assuming the moderate systematics.", "type": "figure"}, "FIGREF19": {"text": "Fig. 16.-The 1-d PDFs of galaxy bias b a g and velocity dispersion parameter \u03c3 a v0 , compared to their fiducial values, from the CSST galaxy clustering (top) and joint (bottom) surveys for the five spec-z bins assuming the moderate systematics.", "type": "figure"}, "FIGREF20": {"text": "YG acknowledges the support of NSFC-11822305, NSFC-11773031, and Bairen program from the National Astronomical Observatories, Chinese Academy of Sci- ences. XKL acknowledges the support from", "type": "figure"}, "FIGREF21": {"text": "Fig. 18.-The constraint results of the seven cosmological parameters from the CSST galaxy clustering survey, assuming f zs,0 eff = 0.5 andN g sys = 5 \u00d7 10 4 (Mpc/h) 3 . The 1\u03c3 (68.3%), 2\u03c3 (95.5%), and 3\u03c3 (99.7%) C.L. are shown.", "type": "figure"}, "FIGREF22": {"text": "Fig. 19.-The joint constraint results of the seven cosmological parameters from the CSST WL, galaxy clustering, and galaxy-galaxy lensing surveys, assumingN add = 10 \u22129 , f zs,0 eff = 0.5, andN g sys = 5 \u00d7 10 4 (Mpc/h) 3 . The 1\u03c3 (68.3%), 2\u03c3 (95.5%), and 3\u03c3 (99.7%) C.L. are shown.", "type": "figure"}, "TABREF0": {"text": "Design parameters of the CSST photometric and spectroscopic surveys.", "type": "table"}, "TABREF1": {"text": "The fiducial values and ranges of the free parameters in the model.", "type": "table"}}}
{"paper_id": "119429742", "_pdf_hash": "8d8bbc95c75cc4bf17cdcab1756866bac88a6e7c", "abstract": [{"section": "Abstract", "text": "T2K is a long-baseline neutrino oscillation experiment using a \u03bd \u00b5 beam produced at the J-PARC facility. Neutrinos are detected at a Near Detector complex (ND280) and at the Far Detector (Super-Kamiokande). The most recent oscillation results presented by T2K are described in these proceedings. With these data T2K has produced the first constraints on \u03b4 CP , excluding CP conserving values at 2\u03c3 and the world best measurement of the \u03b8 23 mixing angle.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "PRESENTED AT", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "NuPhys2017, Prospects in Neutrino Physics", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Neutrino oscillations", "text": "A large variety of experimental results using neutrinos from very different sources has contributed to establish the phenomenon of neutrino oscillations that are described within the PMNS [1] framework. The PMNS matrix is a 3\u00d73 unitary mixing matrix and is parametrized by three mixing angles, \u03b8 12 , \u03b8 23 , \u03b8 13 , and a CP violating phase, \u03b4 CP (two additional phases are present if neutrinos are Majorana particles but they do not affect oscillations). The additional parameters governing neutrino oscillations are the squared-mass differences \u2206m The original discovery of neutrino oscillations and the first measurements of the corresponding mixing angles (\u03b8 12 and \u03b8 23 ) and mass squared differences from SuperKamiokande [2] , SNO [3] , and KamLAND [4] started a broad program in which neutrino oscillations have been observed by several experiments using very different neutrino sources and detection techniques.", "cite_spans": [], "ref_spans": []}, {"section": "Neutrino oscillations", "text": "The last relevant milestones have been the discovery that also the last unknown mixing angle, \u03b8 13 , is different from zero. After first indications from T2K in the \u03bd \u00b5 \u2192 \u03bd e transition [5] , \u03b8 13 was measured to be different from zero in 2012 by Daya Bay [6] and RENO [7] . This discovery started the era of precision measurements of neutrino oscillations with the possibility of investigating sub-leading order effects to determine the mass ordering and to observe CP violation in the leptonic sector. Such measurement is today the main goal of the T2K experiment.", "cite_spans": [], "ref_spans": []}, {"section": "Neutrino oscillations", "text": "2 The T2K experiment T2K (Tokai to Kamioka) [8] is a long-baseline neutrino oscillation experiment originally intended to measure \u03b8 13 by observing electron neutrino appearance. A muon neutrino beam is produced at the J-PARC accelerator complex on the East Coast of Japan by striking a 30 GeV proton beam onto a 90-cm long carbon target. This produces hadrons that are focused and selected in charge by a system of magnetic horns and are directed towards a decay tunnel where they decay into neutrinos. By changing the direction of the current in the magnetic horns it is possible to select in charge different hadrons. If positively charged pions are focused they decay into \u00b5 + and \u03bd \u00b5 (\u03bd-mode) while if negatively charged pions are focused they decay into \u00b5 \u2212 and \u03bd \u00b5 (\u03bd-mode). The undecayed pions and other hadrons, as well as the muons, are stopped by a beam dump, installed 100 m downstream the target.", "cite_spans": [], "ref_spans": []}, {"section": "Neutrino oscillations", "text": "Neutrinos are then observed in a Near Detector, ND280, at 280 m from the target, where the effect of the oscillations is negligible, and at the first oscillation peak at the far detector, Super-Kamiokande, 295 km away from J-PARC. The neutrino energy, peaked at 600 MeV, and the distance are chosen to be at the expected maximum of the oscillations in order to maximize the sensitivity to \u03bd \u00b5 (\u03bd \u00b5 ) disappearance and to \u03bd e (\u03bd e ) appearance. A schematic view of T2K is shown in Fig. 1 . The near detector complex comprises an on-axis detector (INGRID) and an offaxis detector (ND280). INGRID is composed of 14 modules of iron and plastic scintillator spanning the neutrino beam in a transverse section of 10\u00d710 meters. Its goal is to measure, on a day-by-day basis the neutrino beam direction and profile.", "cite_spans": [], "ref_spans": [{"start": 480, "end": 486, "text": "Fig. 1", "ref_id": "FIGREF1"}]}, {"section": "Neutrino oscillations", "text": "The off-axis detector, ND280 (see Fig. 2 ), consists of several detectors installed in the ex-UA1 magnet, operated at 0.2 T : a \u03c0 0 detector (P0D) to measure interactions with \u03c0 0 production, an electromagnetic calorimeter (ECAL) to measure the electromagnetic activity and a Side Muon Range Detector (SMRD) embedded in the magnet yokes. Finally a Tracker system, composed of two Fine Grained Detectors (FGD) and three Time Projection Chambers (TPC).", "cite_spans": [], "ref_spans": [{"start": 34, "end": 40, "text": "Fig. 2", "ref_id": "FIGREF2"}]}, {"section": "Neutrino oscillations", "text": "Each FGD has a mass of \u223c 1 ton and acts as active target for the neutrino interactions. The first FGD is a fully active detector, while in the second FGD scintillator layers are interleaved with inactive water layers, allowing to select neutrino interactions on carbon and on oxygen.The three TPCs are used to do a 3D tracking of the charged particles produced in interactions in one of the FGDs, and to measure their charge and momentum from the curvature induced by the magnetic field. The particle identification is performed based on the measurement of the ionization.", "cite_spans": [], "ref_spans": []}, {"section": "Neutrino oscillations", "text": "The far detector of T2K is Super-Kamiokande, a 50 kton water Cherenkov detector located at a depth of 2700 meters water equivalent in the Kamioka mine (see Fig. 2 ). Super-Kamiokande has a cylindrical shape with two concentric optically separated regions instrumented with Hamamatsu PMTs. Neutrino interactions with water produce Cherenkov light which can be used to distinguish between electron-like and muon-like events by analyzing the sharpness of a Cherenkov ring. A muon makes a sharp edged ring whilst an electron makes a fuzzy one due to electromagnetic showers. The electron/muon misidentification probability, estimated using atmospheric neutrinos, is about 1% for the T2K neutrino energy.", "cite_spans": [], "ref_spans": [{"start": 156, "end": 162, "text": "Fig. 2", "ref_id": "FIGREF2"}]}, {"section": "Neutrino oscillations", "text": "T2K has started the data taking in 2010 and, up to the ", "cite_spans": [], "ref_spans": []}, {"section": "T2K oscillation analyses", "text": "For the T2K oscillation analyses, the expected event rates and spectra at SuperKamiokande are predicted based on a model of neutrino fluxes and of neutrino crosssections and measurements of neutrino interactions at ND280. More details on the oscillation analyses are given in [9] . The flux modelling is based on the NA61/SHINE hadroproduction measurements [10] , that allow reduction of the uncertainties on the fluxes below 10%. The cross-section model is based on external measurements from different experiments (mostly MiniBooNE and Minerva, see here for details [11] ). Uncertainties on event rates and spectra of the order of 15% would be expected if only those data were available.", "cite_spans": [], "ref_spans": []}, {"section": "T2K oscillation analyses", "text": "Crucial inputs to the T2K oscillation analyses are then the measurements at the Near Detector. In the ND280 tracker, a total of 14 samples of \u03bd \u00b5 and \u03bd \u00b5 charged current interactions are selected in the FGD1 and in the FGD2 with muons precisely measured in the TPCs. The samples are separated according to the number of pions observed in the final state (0, 1, more than 1). Examples of these distributions as a function of outgoing muon momentum are shown in Fig. 3 .", "cite_spans": [], "ref_spans": [{"start": 460, "end": 466, "text": "Fig. 3", "ref_id": "FIGREF3"}]}, {"section": "T2K oscillation analyses", "text": "The 14 event samples, selected in data and Monte Carlo, are binned in p \u00b5 and cos \u03b8 \u00b5 (where \u03b8 is the angle between the neutrino beam and the lepton candidate track) and fitted with a likelihood fit. The likelihood assumes that the observed number of events in each bin follows a Poisson distribution, with an expectation calculated according to the flux, cross-section and detector systematic parameters. The fitted neutrino cross-section and unoscillated SK flux parameters are passed to the oscillation analysis, using a covariance matrix to describe their uncertainties. The fit results for these parameters are shown in Fig. 4 . The flux parameters are well within the priors, while for the cross-section parameters the fit tends to increase the 2p2h component and the cross-section at low and intermediate values of Q 2 (BeRPA A and BeRPA B in the plot). A systematic uncertainty on the number of expected A major improvement of the new T2K oscillation analysis with respect to previous analyses is that a new reconstruction algorithm is used for the Super-Kamiokande event selection. This algorithm combines time and charge likelihood for a given ring hypothesis. The better performance of this algorithm allows for a new definition of the Fiducial Volume in which not only the distance of the vertex from the wall but also the direction of the lepton candidate with respect to the wall is used.", "cite_spans": [], "ref_spans": [{"start": 625, "end": 631, "text": "Fig. 4", "ref_id": "FIGREF4"}]}, {"section": "T2K oscillation analyses", "text": "This new Super-Kamiokande selection and the new definition of the fiducial volume, allow to increase by 30% the efficiency in selecting e-like samples while keeping the same purity of \u223c 80%. For the \u00b5-like sample the new selection allows to increase the purity in selecting charged-current interactions without pions in the final state from 70% to 80%.", "cite_spans": [], "ref_spans": []}, {"section": "T2K oscillation analyses", "text": "Five samples are selected at Super-Kamiokande and are used in the oscillation analyses: single-ring \u00b5-like events selected in \u03bd-mode and in \u03bd-mode, single-ring e-like events selected in \u03bd-mode and in \u03bd-mode, and a fifth sample, selected only in \u03bd-mode, where the e-like ring is accompanied by the presence of a delayed electron, due to the decay of a pion produced in the neutrino interaction. The number of events selected at Super-Kamiokande in the 5 samples are presented in Tab. 1 and compared with the expected numbers of events for different values of \u03b4 CP . The spectra are shown in Fig. 5 . Top: \u00b5-like, e-like, e-like+1\u03c0 in \u03bd-mode. Bottom: \u00b5-like and e-like in \u03bd-mode.", "cite_spans": [], "ref_spans": [{"start": 590, "end": 596, "text": "Fig. 5", "ref_id": "FIGREF5"}]}, {"section": "T2K oscillation analyses", "text": "As it is clear from Tab. 1, \u03b4 CP only affects the e-like samples and values of \u03b4 CP close to -\u03c0/2 tends to increase the \u03bd e appearance probability, while decreasing the \u03bd e probability. This is exactly what is observed in the data in \u03bd-mode (\u03bd-mode), where 74 (7) single-ring e-like events are observed while 62 (9) are expected if \u03b4 CP = 0 or \u03c0.", "cite_spans": [], "ref_spans": []}, {"section": "T2K oscillation analyses", "text": "The five samples are then fitted together in order to extract the oscillation parameters \u03b8 23 , \u2206m 2 32 , \u03b8 13 , and \u03b4 CP . The value of \u03b8 13 can either be a free parameter in the fit or it can be constrained to the precise measurement of the reactor experiments. The two cases are shown in Fig. 6 : both fits prefer values of \u03b4 CP close to -\u03c0/2 and, when the reactor constraint is included, the CP conserving values 0 and \u03c0 are excluded at more than 95% CL. \u03b8 23 and \u2206m 2 32 are also precisely determined by T2K: in particular the value of \u03b8 23 is compatible with maximal mixing as shown in Fig. 7 . It should be noticed that in Fig. 7 some tensions are observed between T2K and the first published NO\u03bdA results for \u03b8 23 [12] . In a recent update of the oscillation analysis of NO\u03bdA, \u03b8 23 is found to be compatible with maximal mixing and currently there is no tension between T2K and NO\u03bdA results. ", "cite_spans": [], "ref_spans": [{"start": 291, "end": 297, "text": "Fig. 6", "ref_id": "FIGREF6"}, {"start": 592, "end": 598, "text": "Fig. 7", "ref_id": "FIGREF8"}, {"start": 630, "end": 636, "text": "Fig. 7", "ref_id": "FIGREF8"}]}, {"section": "T2K phase II", "text": "T2K was originally approved to collect 7.8\u00d710 21 p.o.t. and such statistics was mainly driven by the sensitivity of the experiment to \u03b8 13 , corresponding to the value at which systematic uncertainties would have been dominant in case of small \u03b8 13 . Today we know that \u03b8 13 is large and an increased statistics would improve the sensitivity of the experiment to measure \u03b4 CP as shown in Fig. 8 . For this reason T2K has proposed an extension of the running time that will allow to collect a statistics of 20\u00d710 21 p.o.t.. By collecting this statistics T2K will be able to observe CP violation with more than 3\u03c3 significance if CP violation is large and to measure \u03b8 23 and \u2206m \u2022 or better and 1%, respectively. Such statistics will be obtained also thanks to an upgrade of the J-PARC Main Ring power supplies that will allow to reach \u223c1 MW of beam power (while currently T2K is stably running at \u223c 470 kW of beam power). In order to fully profit from the foreseen additional statistics a better understanding on systematic uncertainties will be necessary. For this reason the T2K collaboration has launched an upgrade project for the Near Detector, aimed at overcoming the known limitations of the current design of ND280, that concerns the angular acceptance of the near and far detectors.", "cite_spans": [], "ref_spans": [{"start": 388, "end": 394, "text": "Fig. 8", "ref_id": "FIGREF9"}]}, {"section": "T2K phase II", "text": "Thanks to the cylindrical shape of the tank and to its large size, in fact, Super-Kamiokande has an efficiency in selecting neutrino interactions that is independent on the lepton direction. The geometrical configuration of the ND280 tracker, instead, allows to select with excellent efficiency tracks emitted parallel to the beam but this efficiency rapidly degrades with the angle with respect to the beam, being close to zero for cos \u03b8 \u2264 0.4 (where \u03b8 is the angle between the emitted lepton and the beam). The baseline proposal for the upgrade, which achieves a much better uniformity of acceptance as function of polar angle, includes a fully active scintillator detector acting as neutrino target, disposed along the plane including both the beam direction and the magnetic field. The favoured option for this detector is the Super-FGD concept [13] , consisting of small scintillator cubes each read-out by three wave-length shifting fibers. Two new TPCs, with concept similar to the one of the three existing TPCs, will be installed above and below the Super-FGD covering the large polar angle regions. Time-of-flight detectors will also be used to reject out of fiducial volume events. The goal is to install these new detectors in ND280 by 2021.", "cite_spans": [], "ref_spans": []}], "bib_entries": {}, "ref_entries": {"FIGREF0": {"text": "where m i is the mass of the i-th neutrino mass eigenstates.", "type": "figure"}, "FIGREF1": {"text": "Figure 1: A schematic view of the T2K neutrino beamline and detectors.", "type": "figure"}, "FIGREF2": {"text": "Figure 2: A schematic view of ND280 (left) and Super-Kamiokande (right).", "type": "figure"}, "FIGREF3": {"text": "Figure 3: Momentum distribution of outgoing muons for \u03bd \u00b5 CC-0\u03c0 + (left) and CC-1\u03c0 + (right) samples at ND280.", "type": "figure"}, "FIGREF4": {"text": "Figure 4: Flux (left) and cross-section (right) parameters before (red) and after (blue) the Near Detector fit.", "type": "figure"}, "FIGREF5": {"text": "Figure 5: Observed spectra at SK in the five samples used for the oscillation analyses. Top: \u00b5-like, e-like, e-like+1\u03c0 in \u03bd-mode. Bottom: \u00b5-like and e-like in \u03bd-mode.", "type": "figure"}, "FIGREF6": {"text": "Figure 6: Measurement of the oscillation parameters \u03b8 13 and \u03b4 CP without reactor constraint and measurement of \u03b4 CP with reactor constraints. The bands on the right plot represent the 95% CL allowed regions for the two hierarchies.", "type": "figure"}, "FIGREF8": {"text": "Figure 7: Measurement of the oscillation parameters \u03b8 23 and \u2206m 2 32 from T2K, compared to other experiments.", "type": "figure"}, "FIGREF9": {"text": "Figure 8: Left: Expected T2K-II sensitivity to \u03b4 CP assuming the mass ordering is not known as a function of \u03b4 CP . Right: Expected T2K-II sensitivity to \u03b8 23 and \u2206m", "type": "figure"}, "TABREF0": {"text": "Summer 2017, has collected 2.25\u00d710 21 p.o.t. (protons-on-target), 1.49\u00d710 21 p.o.t. in \u03bd-mode and 0.76\u00d710 21 p.o.t. in \u03bd-mode. T2K is currently running in \u03bd-mode.", "type": "table"}, "TABREF1": {"text": "Table 1: Observed and expected numbers of events at SK for different values of \u03b4 CP .", "type": "table"}}}
{"paper_id": "17780032", "_pdf_hash": "fa0cba0e326d19eb3686705584dd7477e6389c27", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Dynamic Programming", "authors": [{"first": "R", "middle": [], "last": "Bellman", "suffix": ""}], "year": 1957, "venue": "", "link": null}, "BIBREF1": {"title": "Lower bounding klondike solitaire with Monte-Carlo planning", "authors": [{"first": "R", "middle": [], "last": "Bjarnason", "suffix": ""}, {"first": "A", "middle": [], "last": "Fern", "suffix": ""}, {"first": "P", "middle": [], "last": "Tadepalli", "suffix": ""}], "year": 2009, "venue": "ICAPS'09", "link": "15771929"}, "BIBREF2": {"title": "Labeled RTDP: Improving the convergence of real-time dynamic programming", "authors": [{"first": "B", "middle": [], "last": "Bonet", "suffix": ""}, {"first": "H", "middle": [], "last": "Geffner", "suffix": ""}], "year": 2003, "venue": "ICAPS'03", "link": "941659"}, "BIBREF3": {"title": "The factored policy gradient planner (ipc-06 version)", "authors": [{"first": "O", "middle": [], "last": "Buffet", "suffix": ""}, {"first": "Aberdeen", "middle": [], "last": "", "suffix": ""}, {"first": "D", "middle": [], "last": "", "suffix": ""}], "year": 2006, "venue": "Fifth International Planning Competition at ICAPS'06", "link": "10699234"}, "BIBREF4": {"title": "Achieving master level play in 9x9 computer Go", "authors": [{"first": "S", "middle": [], "last": "Gelly", "suffix": ""}, {"first": "D", "middle": [], "last": "Silver", "suffix": ""}], "year": 2008, "venue": "AAAI'08", "link": null}, "BIBREF5": {"title": "PROST: Probabilistic Planning Based on UCT", "authors": [{"first": "T", "middle": [], "last": "Keller", "suffix": ""}, {"first": "P", "middle": [], "last": "Eyerich", "suffix": ""}], "year": 2012, "venue": "ICAPS'12", "link": "5072261"}, "BIBREF6": {"title": "bandit based monte-carlo planning", "authors": [{"first": "L", "middle": [], "last": "Kocsis", "suffix": ""}, {"first": "C", "middle": [], "last": "Szepesv\u00e1ri", "suffix": ""}], "year": 2006, "venue": "ECML'06", "link": "15184765"}, "BIBREF7": {"title": "Reverse iterative deepening for finite-horizon MDPs with large branching factors", "authors": [{"first": "A", "middle": [], "last": "Kolobov", "suffix": ""}, {"first": "P", "middle": [], "last": "Dai", "suffix": ""}, {"first": "D", "middle": ["S"], "last": "Weld", "suffix": ""}], "year": 2012, "venue": "ICAPS'12", "link": "11638975"}, "BIBREF8": {"title": "ReTrASE: Integrating paradigms for approximate probabilistic planning", "authors": [{"first": "A", "middle": [], "last": "Kolobov", "suffix": ""}, {"first": "D", "middle": [], "last": "Weld", "suffix": ""}], "year": 2009, "venue": "IJCAI'09. Nilsson, N. 1980. Principles of Artificial Intelligence. Tioga Publishing", "link": "2263600"}, "BIBREF9": {"title": "Markov Decision Processes", "authors": [{"first": "M", "middle": [], "last": "Puterman", "suffix": ""}], "year": 1994, "venue": "", "link": "122678161"}, "BIBREF10": {"title": "Trade-offs in samplingbased adversarial planning", "authors": [{"first": "R", "middle": [], "last": "Ramanujan", "suffix": ""}, {"first": "B", "middle": [], "last": "Selman", "suffix": ""}], "year": 2011, "venue": "ICAPS'11", "link": null}, "BIBREF11": {"title": "ICAPS 2011 international probabilistic planning competition", "authors": [{"first": "S", "middle": [], "last": "Sanner", "suffix": ""}], "year": 2011, "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "17780059", "_pdf_hash": "af74f73a5e5b6c0477b7f0c8aeffe8f7b4b93054", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Bivariate normality via Gaussian conditional structure", "authors": [{"first": "M", "middle": [], "last": "Ahsanullah", "suffix": ""}, {"first": "J", "middle": [], "last": "Wesolowski", "suffix": ""}], "year": 1993, "venue": "", "link": null}, "BIBREF1": {"title": "Bivariate distributions with Pareto conditionals", "authors": [{"first": "B", "middle": ["C"], "last": "Arnold", "suffix": ""}], "year": 1987, "venue": "Statist. Probab. Lett", "link": "120154979"}, "BIBREF2": {"title": "Conditional characterizations of multivariate distributions", "authors": [{"first": "B", "middle": ["C"], "last": "Arnold", "suffix": ""}, {"first": "M", "middle": [], "last": "Pourahmadi", "suffix": ""}], "year": 1988, "venue": "Metrika", "link": "122678391"}, "BIBREF3": {"title": "Conditionally specified distributions", "authors": [{"first": "B", "middle": ["C"], "last": "Arnold", "suffix": ""}, {"first": "E", "middle": [], "last": "Castillo", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Sarabia", "suffix": ""}], "year": 1992, "venue": "Lecture Notes in Statist", "link": "59988376"}, "BIBREF4": {"title": "Conditionally specified models: structure and inference", "authors": [{"first": "B", "middle": ["C"], "last": "Arnold", "suffix": ""}, {"first": "E", "middle": [], "last": "Castillo", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Sarabia", "suffix": ""}], "year": 1993, "venue": "Multivariate Analysis: Future Directions", "link": "119056557"}, "BIBREF5": {"title": "Multivariate distributions with generalized Pareto conditionals", "authors": [{"first": "B", "middle": ["C"], "last": "Arnold", "suffix": ""}, {"first": "E", "middle": [], "last": "Castillo", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Sarabia", "suffix": ""}], "year": 1993, "venue": "Statist. Probab. Lett", "link": "122881658"}, "BIBREF6": {"title": "Characterizations of discrete distributions by a conditional distribution and a regression function", "authors": [{"first": "T", "middle": [], "last": "Cacoullos", "suffix": ""}, {"first": "H", "middle": [], "last": "Papageorgiou", "suffix": ""}], "year": 1983, "venue": "Ann. Inst. Statist. Math", "link": "121506131"}, "BIBREF7": {"title": "Bivariate distributions with second kind beta conditionals", "authors": [{"first": "E", "middle": [], "last": "Castillo", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Sarabia", "suffix": ""}], "year": 1990, "venue": "Comm. Statist. Theory Methods", "link": "121330725"}, "BIBREF8": {"title": "Non-existence of certain polynomial regression in random sum theory", "authors": [{"first": "N", "middle": ["L"], "last": "Johnson", "suffix": ""}, {"first": "S", "middle": [], "last": "Kotz", "suffix": ""}], "year": 1992, "venue": "Set. A", "link": "126312590"}, "BIBREF9": {"title": "On characterizing some discrete distributions by linear regression", "authors": [{"first": "R", "middle": ["M"], "last": "Korwar", "suffix": ""}], "year": 1975, "venue": "Comm. Statist", "link": "120186689"}, "BIBREF10": {"title": "Characterization of bivariate discrete distributions", "authors": [{"first": "A", "middle": [], "last": "Kyriakoussis", "suffix": ""}], "year": 1988, "venue": "Sankhy5, Ser. A", "link": null}, "BIBREF11": {"title": "Characterizations of logarithmic series distributions", "authors": [{"first": "A", "middle": [], "last": "Kyriakoussis", "suffix": ""}, {"first": "H", "middle": [], "last": "Papageorgiou", "suffix": ""}], "year": 1991, "venue": "Statist. Neerlandiea", "link": null}, "BIBREF13": {"title": "Multivariate Pareto distributions", "authors": [], "year": "", "venue": "Ann. Math. Statist", "link": null}, "BIBREF14": {"title": "On characterizing some discrete distributions by a conditional distributions and a regression function", "authors": [{"first": "H", "middle": [], "last": "Papageorgiou", "suffix": ""}], "year": 1985, "venue": "Biometrieal J", "link": "120004763"}, "BIBREF15": {"title": "Bivariate discrete measures via a power series conditional distribution and a regression function", "authors": [{"first": "J", "middle": [], "last": "Wesolowski", "suffix": ""}], "year": 1993, "venue": "", "link": "121195880"}, "BIBREF16": {"title": "A new conditional specification of the bivariate Poisson conditionals distribution", "authors": [{"first": "J", "middle": [], "last": "Wesolowski", "suffix": ""}], "year": 1993, "venue": "", "link": "119922492"}, "BIBREF17": {"title": "Conditional specifications of multivariate Pareto and Student distributions", "authors": [{"first": "J", "middle": [], "last": "Wesolowski", "suffix": ""}, {"first": "M", "middle": [], "last": "Ahsanullah", "suffix": ""}], "year": 1994, "venue": "", "link": "121008191"}}, "ref_entries": {}}
{"paper_id": "17780203", "_pdf_hash": "000e0104d2fbdc00f74ee17d401b7492a4425132", "abstract": [{"section": "Abstract", "text": "Consent processes have attracted significant research attention over the last decade, including in the global south. Although relevant studies suggest consent is a complex negotiated process involving multiple actors, most guidelines assume consent is a one-off encounter with a clear 'yes' or 'no' decision. In this paper we explore the concept of 'silent refusals', a situation where it is not clear whether potential participants want to join studies or those in studies want to withdraw from research, as they were not actively saying no. We draw on participant observation, in-depth interviews and group discussions conducted with a range of stakeholders in two large community based studies conducted by the KEMRI Wellcome Trust programme in coastal Kenya. We identified three broad inter-related rationales for silent refusals: 1) a strategy to avoid conflicts and safeguard relations within households, -for young women in particular-to appear to conform to the wishes of elders; 2) an approach to maintain friendly, appreciative and reciprocal relationships with fieldworkers, and the broader research programme; and 3) an effort to retain study benefits, either for individuals, whole households or wider communities. That refusals and underlying rationales were silent posed multiple dilemmas for fieldworkers, who are increasingly recognised to play a key interface role between researchers and communities in many settings. Silent refusals reflect and reinforce complex power relations embedded in decisions about research participation, with important implications for consent processes and broader research ethics practice. Fieldworkers need support to reflect upon and respond to the ethically charged environment they work in.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Background", "text": "Consent for participation in health research in low income countries is imbued with many widely documented complexities. These include difficulties in explaining and understanding research terminologies [1] [2] [3] , participants joining research primarily to access much needed health care [2, [4] [5] [6] , and involvement and influence of family and other community members in individual decision-making [7, 8] . Although consent remains a core theme in research ethics, the extent to which entirely autonomous individual informed consent is possible, or even desirable, is an area of on-going ethical debate particularly in highly communal and patriarchal communities [9, 10] .", "cite_spans": [{"start": 203, "end": 206, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 207, "end": 210, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 211, "end": 214, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 291, "end": 294, "text": "[2,", "ref_id": "BIBREF1"}, {"start": 295, "end": 298, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 299, "end": 302, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 303, "end": 306, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 407, "end": 410, "text": "[7,", "ref_id": "BIBREF6"}, {"start": 411, "end": 413, "text": "8]", "ref_id": "BIBREF7"}, {"start": 672, "end": 675, "text": "[9,", "ref_id": "BIBREF8"}, {"start": 676, "end": 679, "text": "10]", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "Background", "text": "Numerous guidelines and documents describe strategies to strengthen consent processes in an effort to meet key ethical principles of respect to persons and communities. A common recommendation is that consent be seen as a process [11, 12] , and that research involves several layers of communication and consultation with host communities in addition to individual consent processes [13, 14] . The relationship between community engagement (CE) and individual consent processes is far from straightforward. For example, while community engagement can facilitate improved knowledge of a study in the host population [14] [15] [16] , too much information has the potential to lead to key research information being crowded out [13, 17] , and for people to feel obliged to participate in research in order for the community to gain benefits provided in research [18] .", "cite_spans": [{"start": 230, "end": 234, "text": "[11,", "ref_id": "BIBREF10"}, {"start": 235, "end": 238, "text": "12]", "ref_id": "BIBREF12"}, {"start": 383, "end": 387, "text": "[13,", "ref_id": "BIBREF13"}, {"start": 388, "end": 391, "text": "14]", "ref_id": "BIBREF14"}, {"start": 615, "end": 619, "text": "[14]", "ref_id": "BIBREF14"}, {"start": 620, "end": 624, "text": "[15]", "ref_id": "BIBREF15"}, {"start": 625, "end": 629, "text": "[16]", "ref_id": "BIBREF16"}, {"start": 725, "end": 729, "text": "[13,", "ref_id": "BIBREF13"}, {"start": 730, "end": 733, "text": "17]", "ref_id": "BIBREF17"}, {"start": 859, "end": 863, "text": "[18]", "ref_id": "BIBREF18"}], "ref_spans": []}, {"section": "Background", "text": "In some situations, involving a potential participant's partner or other relative ('significant other') in decision-making is recommended [1, [19] [20] [21] . However there is relatively little research on the nature of consultations between individuals and their significant others, the influence of such consultations on decisions, or the ethical importance of such influences in low income settings. These are important areas to explore since the nature of negotiations between research staff, potential participants, and their significant others can vary considerably from simple information giving to interactions where clear power asymmetries and potential for coercion exist. A particular research gap concerns decision-making in research 'decliners', not least because this information is practically and ethically challenging to collect [22, 23] .", "cite_spans": [{"start": 138, "end": 141, "text": "[1,", "ref_id": "BIBREF0"}, {"start": 142, "end": 146, "text": "[19]", "ref_id": "BIBREF19"}, {"start": 147, "end": 151, "text": "[20]", "ref_id": "BIBREF20"}, {"start": 152, "end": 156, "text": "[21]", "ref_id": "BIBREF21"}, {"start": 846, "end": 850, "text": "[22,", "ref_id": "BIBREF22"}, {"start": 851, "end": 854, "text": "23]", "ref_id": "BIBREF23"}], "ref_spans": []}, {"section": "Background", "text": "Within these complex and negotiated processes, the staff who undertake informed consent, often called frontline research staff or fieldworkers (FWs), play a key role. It is widely recognised that employing fieldworkers from study communities is essential for many research studies [24, 25] . Beyond conducting consent processes in the first language of potential participants, FWs take on many other important roles-formally or informally-including: conducting relatively straightforward research procedures such as simple surveys and health checks [26, 27] ; providing access to hard-to-reach populations such as stigmatized or hidden populations [28] ; advising researchers on local priorities, concerns, and culturally appropriate conduct of research including consent [29] and acting as 'cultural brokers' between the often very different worlds of researchers and research communities. A growing body of literature about such frontline workers suggests that their roles are imbued with diverse and ever-changing ethical challenges with important implications for consent processes [30] [31] [32] [33] . For example, some frontline staff may be motivated by their wish to help their communities [24, 27] , with potentially positive and negative implications for consent processes, including excessively encouraging research participation in contexts of constrained public health care systems [33] . Where fieldworkers are already well known within communities, there is potential for them to exploit this trust to meet recruitment quotas, and for confidentiality to be compromised [26, 27] . Given their central role in ethical consent processes, there is increasing recognition of the need to appropriately support fieldworkers in their community interactions; and for research guidelines and ethics frameworks to build on their experiences.", "cite_spans": [{"start": 281, "end": 285, "text": "[24,", "ref_id": "BIBREF24"}, {"start": 286, "end": 289, "text": "25]", "ref_id": "BIBREF26"}, {"start": 549, "end": 553, "text": "[26,", "ref_id": "BIBREF28"}, {"start": 554, "end": 557, "text": "27]", "ref_id": "BIBREF29"}, {"start": 648, "end": 652, "text": "[28]", "ref_id": "BIBREF30"}, {"start": 772, "end": 776, "text": "[29]", "ref_id": "BIBREF31"}, {"start": 1086, "end": 1090, "text": "[30]", "ref_id": "BIBREF32"}, {"start": 1091, "end": 1095, "text": "[31]", "ref_id": "BIBREF33"}, {"start": 1096, "end": 1100, "text": "[32]", "ref_id": "BIBREF35"}, {"start": 1101, "end": 1105, "text": "[33]", "ref_id": "BIBREF36"}, {"start": 1199, "end": 1203, "text": "[24,", "ref_id": "BIBREF24"}, {"start": 1204, "end": 1207, "text": "27]", "ref_id": "BIBREF29"}, {"start": 1396, "end": 1400, "text": "[33]", "ref_id": "BIBREF36"}, {"start": 1585, "end": 1589, "text": "[26,", "ref_id": "BIBREF28"}, {"start": 1590, "end": 1593, "text": "27]", "ref_id": "BIBREF29"}], "ref_spans": []}, {"section": "Background", "text": "Many documents aimed at strengthening consent processes include a core assumption that potential participants will-at some point in the process-explicitly agree or refuse to join a proposed study. Those who agree can then later change their minds [34] . However, a clearly stated decision may not be a reality. For example, in a previous study in Kenya, community members were argued to exert agency during interactions with relatively well-resourced researchers and institutions through a number of strategies that included 'silent refusals'; that is, hesitating to participate without explicitly refusing [31, 35] . In this paper we present one theme-'silent refusal'-that emerged from a broader social science study which explored the nature of interactions between fieldworkers and participants in two community-based studies in coastal Kenya. We describe the nature of silent refusals as it emerged in the community based studies, how fieldworkers encountered the silent refusal, the challenges and dilemmas they faced in handling silent refusals. We further make some recommendations for consent processes and for support to fieldworkers.", "cite_spans": [{"start": 247, "end": 251, "text": "[34]", "ref_id": "BIBREF37"}, {"start": 607, "end": 611, "text": "[31,", "ref_id": "BIBREF33"}, {"start": 612, "end": 615, "text": "35]", "ref_id": "BIBREF38"}], "ref_spans": []}, {"section": "Study Site: KEMRI-Wellcome Trust Research Programme", "text": "The study was carried out in a long-standing international research centre, the KEMRI-Wellcome Trust Research Programme (KWTRP); established on the Kenyan Coast since 1989 and with branches in other parts of the country including Nairobi (http://www.kemri-wellcome. org/). At the Coast, KWTRP is hosted at the Kilifi County Hospital (KCH), with research and support for Ministry of Health (MOH) services conducted in tandem. The centre runs a Health and Demographic Surveillance System (KHDSS) including about 260,000 residents living around KCH, representing the geographic area in which most studies are conducted in Kilifi [36] .", "cite_spans": [{"start": 626, "end": 630, "text": "[36]", "ref_id": "BIBREF39"}], "ref_spans": []}, {"section": "Study Site: KEMRI-Wellcome Trust Research Programme", "text": "All studies conducted by the Programme are approved by the national scientific and ethics review committees in addition to institutional-and where necessary external-review committees [37] . A comprehensive community engagement includes programme-wide and study specific activities [38] . A group of staff, the Community Liaison Group (CLG), consisting of experienced community facilitators, coordinates centre-wide community engagement activities, and advises all studies on community engagement at every stage of a study. Issues arising from the community are fed back to relevant departments and study Principal Investigators (PIs).", "cite_spans": [{"start": 184, "end": 188, "text": "[37]", "ref_id": "BIBREF40"}, {"start": 282, "end": 286, "text": "[38]", "ref_id": "BIBREF41"}], "ref_spans": []}, {"section": "Study Site: KEMRI-Wellcome Trust Research Programme", "text": "Fieldworkers are the largest group of staff at the research centre, forming nearly a third of the staff [31] . They are often recruited from the community where a study is conducted. Their main roles include communicating about studies, undertaking consent processes and following-up participants at their homes.", "cite_spans": [{"start": 104, "end": 108, "text": "[31]", "ref_id": "BIBREF33"}], "ref_spans": []}, {"section": "Methods", "text": "The data presented in this paper were collected as part of a wider social science study aimed at exploring the nature of interactions between fieldworkers and research participants in community-based studies, the challenges that fieldworkers faced, and if and how these were resolved. We purposively selected two community based studies for this broader social science study using criteria presented in Table 1 . Fig 1shows the flowchart of the selections of the two studies from a total of 66 active studies at the research centre at the time, of which 16 were community-based studies. The two community-based studies selected were: study involving eleven sites in seven African countries; this qualitative research focused on the Kilifi site.", "cite_spans": [], "ref_spans": [{"start": 403, "end": 410, "text": "Table 1", "ref_id": "TABREF0"}, {"start": 413, "end": 423, "text": "Fig 1shows", "ref_id": "FIGREF0"}]}, {"section": "Methods", "text": "The key features of the two community-based studies are published elsewhere [39] and summarised in Table 2 , including the main research questions each for each study, type of participants, locality, study team composition, study benefits and risks.", "cite_spans": [{"start": 76, "end": 80, "text": "[39]", "ref_id": "BIBREF42"}], "ref_spans": [{"start": 99, "end": 106, "text": "Table 2", "ref_id": "TABREF1"}]}, {"section": "Methods", "text": "A total of 36 'Junior' FWs and 6 Senior FWs were employed across these case studies. All 'Junior' fieldworkers came from and resided within the study population, and most were male (7/10 and 25/26 in the RSV-and Malaria-study respectively). Their main roles included sharing initial study information with potential participants and carrying out follow-up activities.", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "The social scientists carrying out this study were independent of the case study research teams. DK had over 8 years of managing and coordinating community engagement activities, training and providing support to fieldworkers at the research centre, with support from SM and VM. This knowledge, experience and relationships were important in building trust and being aware of different perceptions informing the findings. The main data collection methods were participant observation, natural and focus group discussions and individual in-depth interviews. All the immediate study team members in the two community based studies, that is, 'Junior' fieldworkers (n = 36), senior fieldworkers (n = 6), study Principal Investigators (n = 2) and study coordinator (n = 1) and were interviewed. In addition, we interviewed purposively selected participants in each case study. Table 3 shows the demographic characteristic of the respondents interviewed in this social science study.", "cite_spans": [], "ref_spans": [{"start": 872, "end": 879, "text": "Table 3", "ref_id": "TABREF2"}]}, {"section": "Participant observation", "text": "Participant observation provided first-hand information of the context in which FWs worked and the type and nature of interactions between FWs and different householders. DK carried out participant observations for a total of 4 months in the RSV-study and 1 month in the Malaria-study, and attended 12 and 4 study meetings respectively. She visited 19 households in the RSV-study and 30 participant households in the Malaria-study; and accompanied all 10 RSV 'Junior' FWs and 9/26 Malaria-Study 'Junior' FWs during their daily work. Considerable time was spent the first study selected for the social science study-in the RSV-study-to get deeper understanding of the range and depth of issues in FW-participant interactions. Less time was spent in the Malaria-study as the aim was to explore the extent to which findings from RSV-study were generalisable to a different type of community-based study in the same context.", "cite_spans": [], "ref_spans": []}, {"section": "Group discussions and in-depth interviews", "text": "A total of 11 focus group discussions (FGDs) with 64 respondents, 5 natural group discussions with 16 respondents and 7 in-depth interviews with 4 respondents were held (Table 4) . Natural group discussions were held with adult household members all participating in case study A, as this approach was one way of exploring household decision-making dynamics [40] . The advantage of natural group discussions is that members already know one another, and have established some norms of working as a group, which the research can gather insights from. Because some of the topics we explored in these natural groups turned out to be sensitive (such as household decision-making dynamics), we used FGDs in subsequent interviews. Respondent-households in the RSV-study were selected from the 19 households DK had previously visited during her participant observation. In this way, DK was not a total stranger Participants Entire household in a defined locality with an infant born after previous RSV epidemic and at least one elder sibling to the infant. Household defined as all members of a homestead who share at least one meal a day.", "cite_spans": [{"start": 358, "end": 362, "text": "[40]", "ref_id": "BIBREF43"}], "ref_spans": [{"start": 169, "end": 178, "text": "(Table 4)", "ref_id": "TABREF3"}]}, {"section": "Group discussions and in-depth interviews", "text": "Children aged 6-12 weeks and 5-17 months at first vaccination; 16,000 children across the 11 sites, a minimum of 6,000 in each of the age category. For Kilifi site, allocated total of 900 children, 600 and 300 in the 5-17 months 6-12 weeks group respectively.", "cite_spans": [], "ref_spans": []}, {"section": "Group discussions and in-depth interviews", "text": "Study procedures Follow-up visits at home every 3-4 days; data from each HH member collected at each visit included:", "cite_spans": [], "ref_spans": []}, {"section": "Group discussions and in-depth interviews", "text": "Randomisation to one of three groups; Experimental malaria vaccine and its booster at 1. Flocked oral swab (taken at alternate visits (once a week).A demographic and risk assessment questionnaire administered at beginning and end of the study.", "cite_spans": [], "ref_spans": []}, {"section": "Group discussions and in-depth interviews", "text": "Procedures: Initial physical examination, medical history, anthropometric tests, temperature; three vaccine doses each a month apart, and booster dose at 34 months; 5 scheduled blood samples over 3 years; each 2.5mls; Monitoring of minor and serious adverse; immediate and over time; 6 consecutive followup visits post-vaccination days at home. Monitoring of minor and serious adverse events; Referral to nearest health facility for illnesses, and to KCH for serious illnesses.", "cite_spans": [], "ref_spans": []}, {"section": "Risks", "text": "Mild discomfort during NSF taking, and time inconveniences. Detailed side effects as is typical of vaccines trials provided in the study protocol and informed consent; includes severe (such as convulsions, diarrhoea) and mild events (e.g. pain, swelling at vaccination site).", "cite_spans": [], "ref_spans": []}, {"section": "Benefits", "text": "For participants: Free medical care for all common illnesses during study period; clinical visits to every participating household once a month at home.", "cite_spans": [], "ref_spans": []}, {"section": "Benefits", "text": "For participants: Free health care for all conditions (chronic, acute, vaccine related or otherwise, injuries), throughout the study period (about 3 years). This includes:", "cite_spans": [], "ref_spans": []}, {"section": "Benefits", "text": "Other benefits/token staggered throughout the study period included two chairs to each household, sweets, educational materials and token** at end of study.", "cite_spans": [], "ref_spans": []}, {"section": "Benefits", "text": "Free referral for specialized treatment where required, all costs at government facilities covered while transport is provided for first visit to non-government facilities.", "cite_spans": [], "ref_spans": []}, {"section": "Benefits", "text": "All transport to and from the hospital provided by the study team and meals provided for participant and accompanying parents/ guardian for al clinic visits.", "cite_spans": [], "ref_spans": []}, {"section": "Benefits", "text": "Community benefits: boosting local health services through provision of drugs, additional clinical staff. Water treatment for all communal water points", "cite_spans": [], "ref_spans": []}, {"section": "Benefits", "text": "Community benefits: Boosting of three health facilities where the study is based; renovation of existing buildings, providing equipment's; boosting of health staff, provision of essential drugs.", "cite_spans": [], "ref_spans": []}, {"section": "Benefits", "text": "Provision of emergency medical aid during cholera epidemic including drugs, staff, referrals.", "cite_spans": [], "ref_spans": []}, {"section": "Benefits", "text": "*These staff were shared with other studies within the department **Token given at the end of the study were said to be the study teams appreciation to participants for having persevered until the end of the study. They included educational materials, food items, clothes to family members and had some idea of the household dynamics. Within this group, households were purposively selected to reflect diversity based on gender and household arrangements (extended and nuclear families). Respondent-households in the Malaria-study were purposively selected from the geographical area surrounding each of the three health facilities in which the trial was being conducted. FGDs were held separately with male and female respondents to address sensitivities around gender roles and household decision-making for research, as noted above. In both case studies, discussions were held with the study team members separately; that is fieldworkers and senior fieldworkers, study coordinator and principal investigators. Written informed consent was sought from interviewees in their preferred language. One RSV household refused to participate and did not want to disclose the reason.", "cite_spans": [], "ref_spans": []}, {"section": "Data management and analysis", "text": "Data collection continued until a point of saturation where no new themes were emerging. Data analysis started as soon as the first interviews were transcribed and cleaned, and continued throughout the study. All cleaned transcripts were uploaded into Nvivo Version 8.0, the software we used to organize and manage the data. Immediately after each step of data collection, DK and SM printed and read the transcripts, identified emerging issues from each transcript, and DK made summaries. We chose the most informative fieldworker FGD for initial open coding in Nvivo Version 8.0, as it would provide the most variable themes and categories [41] . Data under each open code were grouped into descriptive themes, and codes were merged, deleted and created as more transcripts were added [42] . Through this iterative process of analysis further areas of enquiry were identified and incorporated into subsequent question guides. The descriptive codes were further grouped into broader analytical themes. DK and SM independently coded initial transcripts and compared these with those of another independent researcher. The framework so developed was discussed with ST, PWG, VM and MP. To safeguard participants' privacy and confidentiality, all individual identifiers were replaced with codes in transcripts and in write ups. Summary findings were presented to different cadres of staff in the case studies and to researchers at the centre, as part of validating the findings.", "cite_spans": [{"start": 641, "end": 645, "text": "[41]", "ref_id": "BIBREF44"}, {"start": 786, "end": 790, "text": "[42]", "ref_id": "BIBREF45"}], "ref_spans": []}, {"section": "Ethics Statement", "text": "This study was approved by the local and national Institutional review Boards (IRB); the KEMRI Scientific Steering (SSC) committee and the KEMRI Ethics Review Committee (ERC), SCC protocol number 1463. ", "cite_spans": [], "ref_spans": []}, {"section": "Findings", "text": "Setting the scene for silent refusals: How were consent processes negotiated in the two case studies?", "cite_spans": [], "ref_spans": []}, {"section": "Findings", "text": "Individual and household consent processes in the case studies changed over time in response to practical challenges the teams encountered. For example, the RSV study initially sought consent from all adults in a household and assent from minors, but over time, the importance of gaining initial permission specifically from male household heads was recognised (Fig 2) . For the Malaria study, the community facilitators in the CLG initially shared information about the trial to groups of potential participants as part of Community engagement activities for that trial. This was followed by parental consent by a clinician at the health facility (Fig 3) . Over time and once the FWs had been trained in the trial details the FWs took the role of explaining the trial to potential participant. Study benefits provided in case studies (See Table 2 ) were highly appreciated constantly discussed and negotiated, and ultimately contributed centrally to whether participants joined and remained in studies. Particularly appreciated were the high quality and prompt health care services given, and the respectful way research staff handled participants. Food and transport for participants and guardians during follow-up visits (Malaria-study) and provision of chairs, educational materials, and first aid to the whole community during a cholera epidemic (RSVstudy), were seen as responding appropriately to community needs. However, such provisions also seemed to contribute to expectations of ever-increasing benefits, and potential jealousies between participants and non-participants.", "cite_spans": [], "ref_spans": [{"start": 361, "end": 368, "text": "(Fig 2)", "ref_id": "FIGREF2"}, {"start": 648, "end": 655, "text": "(Fig 3)", "ref_id": "FIGREF3"}, {"start": 840, "end": 847, "text": "Table 2", "ref_id": "TABREF1"}]}, {"section": "Findings", "text": "Concerns and worries which fed into continuous negotiations in the two studies included the safety of Nasopharyngeal Flocked Swabs (NFS) which were taken twice a week from all household members for 6 months (RSV-study), the safety of the malaria vaccine, concerns over blood samples (Malaria-study), and about the nature and motivation of the work of KWTRP.", "cite_spans": [], "ref_spans": []}, {"section": "Findings", "text": "Across community engagement activities, consent, daily research activities and study completion, DK observed constant discussions around benefits, and of participants' concerns and worries of being involved in the studies. A particular challenge for FWs was how to handle (potential) participants who repeatedly postponed consent decisions or who participated inconsistently. These were often referred to as 'silent refusals' by study teams and across the research programme.", "cite_spans": [], "ref_spans": []}, {"section": "Findings", "text": "Silent refusals: What are they and how did they emerge?", "cite_spans": [], "ref_spans": []}, {"section": "Findings", "text": "Silent refusals were observed during consent processes and over the course of studies. During consent processes, 'silent refusal' was used to describe the behaviour of those who appeared positive about participation, but kept postponing their final decision, often with very 'good' reasons. For example, some mothers requested extended periods to consult their husbands, mothers-in-law, or other family members, even when these individuals had already agreed to research participation. The need to involve others was expected and encouraged, and to avoid putting undue pressure on individuals, FWs were trained to follow up to a maximum of 3 times before categorising this response as a refusal. However FWs found it difficult to adhere to this guidance where individuals really appeared interested to participate, but did not make a commitment. Post-consent, a 'silent refusal' was used to describe those who participated in some but not all study procedures, but who appeared reluctant to withdraw from studies. They often had credible reasons for their inconsistent participation that did not suggest a desire to withdraw: \". . . but the way they were telling you is that, even you (FW) go in the morning and you tell them (participants) 'the vehicle is coming, prepare yourself'. . .and she tells you 'there is no problem'. . . . and you go there with the vehicle, and when you arrive there she says 'aaah I have remembered I have a visitor, so I will not come to the dispensary'\" (FW1_male_FGD10).", "cite_spans": [], "ref_spans": []}, {"section": "Findings", "text": "Initially FWs found it difficult to discern a silent refusal, but over time, as they got to know individuals and households better, this pattern became easier to identify. As one FW pointed out using a popular Kiswahili proverb:", "cite_spans": [], "ref_spans": []}, {"section": "Findings", "text": "\". . .I have truly known that akufukuzae hakwambii toka [the one who chases you away does not tell you go]. . . you have to understand them according to their actions or words then you completely know that this person does not want to participate\" (FW1_male_FGD05).", "cite_spans": [], "ref_spans": []}, {"section": "Findings", "text": "Why silently refuse? The reasons for silent refusals appeared to fall under three broad inter-related categories: avoiding conflicts in the household and with significant others; safeguarding relationships between participants and FWs/KWTRP; and ensuring continued access to study benefits.", "cite_spans": [], "ref_spans": []}, {"section": "Findings", "text": "Avoiding conflicts and safeguarding relations within households. A silent refusal was described as a norm when politely refusing people who were strangers, or who are highly respected. An outright refusal is perceived as being rude. Being polite is seen as a good in itself, and as an investment in kindness and generosity for future situations of need, even from strangers. \". . . so you don't want to refuse someone's request because it's like you are unaweka akiba [investing] so that another day someone will be kind to you\" (FW3_male_FGD06).", "cite_spans": [], "ref_spans": []}, {"section": "Findings", "text": "Within households, showing respect-especially to household heads and elders-is highly valued. Children and women should show this through obeying. A silent refusal is a way to disagree with elders and household heads respectfully, without openly disobeying them. With regards to research consent, decisions about household and children's participation in research were often made by male household members, even where consultations did take place. Those most affected by participation, often women charged with taking children for follow up procedures, wanted to be actively involved in making decisions about joining studies. Where this did not happen, silent refusals appeared to be a subtle strategy to covertly exercise agency. As a mother narrated, women would often only cooperate in studies involving their children if they supported the decision or would use different tactics to avoid research participation.", "cite_spans": [], "ref_spans": []}, {"section": "Findings", "text": "\". . .the mother is the one who will get hold of the child as blood is being drawn. If the father agrees for the child to participate but the mother refuses then you (mother) won't send the child. You may go and stay outside and then go back (home) with your child and say the child has missed the vaccines or you say the child has been attended; but you will just be cheating. . . . you will hold the child during bleeding, you look at her as she cries, but you will only do so if you have decided. . .\" (Pax2_female_FGD12).", "cite_spans": [], "ref_spans": []}, {"section": "Findings", "text": "In these instances, silent refusal was used by women as a short term strategy to mask a genuine refusal to participate in ways that did not cause rifts within households. The same strategy was used by younger men towards older male household members or heads.", "cite_spans": [], "ref_spans": []}, {"section": "Findings", "text": "\". . . So the thing is if like that one (a silent refusal), he could not out rightly say that he had withdrawn because he is not the household head, his elder brother [the household head] fully participates in the study. . .\" (FW4_male_FGD06).", "cite_spans": [], "ref_spans": []}, {"section": "Findings", "text": "It seemed that male participants were aware that their wives (and minors) used silent refusals to delay, and sometimes influence, their decisions; but felt unable to do anything about it. Instead they seemed to blame women and minors for not understanding the importance of the health care 'assistance' provided by KWTRP.", "cite_spans": [], "ref_spans": []}, {"section": "Findings", "text": "\"Yes, as the husband you can consent, and the wife can go as if going to the dispensary and because of ignorance (not knowing) you can be saying the child has been sent (to the dispensary). . . but in fact he has not been enrolled in the study. And if she comes to the dispensary, she does other things. So because of that they (study researchers) keep waiting for her and they get tired. . .\" (Pax6_male_FGD13)", "cite_spans": [], "ref_spans": []}, {"section": "Findings", "text": "An additional concern was reported widespread jealousy of husbands toward male FWs, given the latters' relatively well-paid jobs at KWTRP. Some men felt uneasy with male FWs visiting their wives at home, especially in the evening. Similarly, some female participants described being careful in associating with male FWs given these potential conflicts, instead choosing to participate in studies when their husbands were away-in order to access study benefits-and refusing at other times.", "cite_spans": [], "ref_spans": []}, {"section": "Findings", "text": "Safeguarding relationships with FWs and with KWTRP. Similar views to those within household relations were raised with regards to research, KWTRP and FWs. Participants knew that health care provided in KWTRP studies was prompt and of 'high quality' and wanted to continue accessing it. Some participants also perceived KWTRP to have great influence on the general provision of health care in public health facilities, despite reassurances to the contrary. As a well-resourced powerful research institution in a relatively poor community, some participants found it difficult to decline research participation given concerns about offending individual FWs and KWTRP, and used silent refusals to respectfully avoid participation because of fears that lack of cooperation would affect access to health care: \". . .one knows KEMRI has a branch here (at the dispensary). So they fear that 'if I say I don't want KEMRI here. . .if my child or I become sick and I go there (at the dispensary) and I had refused KEMRI (research), then I may be denied services'\" (FW2_male_FGD10). Silent refusals were also described as a strategy to delay decision-making in situations where participants were unsure of the implications of their choices, or where they wanted to further investigate the credibility of study information given; for example, by waiting to see if participants developed side effects. They worried that openly requesting for additional time to make decisions might be considered impolite or as a refusal:", "cite_spans": [], "ref_spans": []}, {"section": "Findings", "text": "\"You see, silent refusal usually happened because someone sees like you have become a member of that family; you have become part of them. So, they start to blame themselves because you have that uhusiano (good relationship) between you and her. So she feels if she tells you openly that. . .'from now or from today I withdraw'. . .she feels guilty that 'this person has been like my child, has been like my grandchild, or has been like my uncle or has been like a brother, so when now I withdraw its like I will be chasing them away. . . So that is why you see them not showing the signs of wanting to withdraw\" (FW1_male_FGD06).", "cite_spans": [], "ref_spans": []}, {"section": "Findings", "text": "For FWs who come from the community where the studies were conducted, positive relationships with participants were consolidated over the course of the studies, with FWs becoming considered part of families in many households [31] . Being employed in KWTRP gave FWs recognition and high status in the community. In addition there may have been an expectation for mutual reciprocity between FWs and participants; that is, that FWs would help community members through enrolling them in studies and ensuring access to study benefits; in turn the community members would participate in research. Therefore, participants may not have wanted to offend FWs by declining participation, instead using silent refusals tactfully.", "cite_spans": [{"start": 226, "end": 230, "text": "[31]", "ref_id": "BIBREF33"}], "ref_spans": []}, {"section": "Findings", "text": "\"Somebody like me, I'm respected in the community. So, somebody coming to me and telling me that I don't want that (study) is hard. So he takes you round, like the saying 'the one who chases you doesn't tell you go away', so its upon you to understand that. . . because she respects, she can't tell you no\" (FW5_male_FGD10).", "cite_spans": [], "ref_spans": []}, {"section": "Findings", "text": "Silent refusals may also have been a strategy to avoid participation in studies participants had not intended to join initially but had done so under perceived pressure from peers, friends and community leaders. Rumours about KEMRI generally, and research in particular-especially blood sampling-may have contributed to this form of silent refusal.", "cite_spans": [], "ref_spans": []}, {"section": "Findings", "text": "Study-related concerns: not wanting to lose study benefits. Study benefits formed one of the most common reasons for joining and remaining in studies, as we have described in a separate paper [39] . Fear of losing study benefits may have contributed to reluctance to refuse or withdraw from studies. In this case, silent refusals seemed to be used to mask active participation within households, as a form of 'silent participation', when some household members wanted to access or continue accessing benefits in the absence of permission from recognised decision-makers. In this case, they 'covertly' consented to participate when key dissenting adults were absent. They hoped that over time, the dissenters' fears would ease, allowing them to participate openly. The extent to which FWs were aware of this, and might even have encouraged it, was difficult to know. That it happened, albeit in few cases, is a point of concern for consent processes.", "cite_spans": [{"start": 192, "end": 196, "text": "[39]", "ref_id": "BIBREF42"}], "ref_spans": []}, {"section": "Findings", "text": "\"Maybe the vehicle goes to pick her. . .when the father is around, he refuses the mother from going to the dispensary. But when the husband is not around. . . she comes to the dispensary\" (Pax9_male_FGD13).", "cite_spans": [], "ref_spans": []}, {"section": "Findings", "text": "FWs were aware that study benefits filled a livelihood need especially for the extremely poor households; allowing silent refusals to remain in the study was one way of helping such families. The flipside for FWs was that accommodating silent refusals was likely to encourage other participants to behave similarly. This could potentially affect the quality of the research data collected.", "cite_spans": [], "ref_spans": []}, {"section": "Handling silent refusals", "text": "Study team handling of silent refusals.. Protocols in both case studies stated that participants should be followed up to a maximum of three times, after which he/she is considered a refusal and dropped from the study. The Malaria-study protocol also stated that follow-up visits are made to withdrawers to know the reasons, to provide important information should the vaccine eventually be licensed. Consent forms clearly stated that participation is voluntary and that a participant can withdraw at any time without censure, and would continue receiving health care services normally. Each study also required a minimum number of participants to be scientifically valid, allowing for dropouts and withdrawals.", "cite_spans": [], "ref_spans": []}, {"section": "Handling silent refusals", "text": "When faced with silent refusals, FWs and researchers initially followed study protocols and dropped participants from the study. However, they worried that high levels of refusals would affect the eventual validity of the study, particularly for the RSV-study where NFS was unfamiliar and majority of the participants initially declined to have it taken. FWs responded by spending extra time with participants to reassure them, giving opportunities for extended discussion to address concerns and clarify information. This contributed to generally positive relations between FWs and participants, and to building of trust as we describe elsewhere [31] . The positive relationships developed between participants and FWs, and the mutual benefits of working with silent refusals-as described above-safeguarded against hasty decisions. In the RSVstudy, over time the team accepted some silent refusals as 'permanent' within a participating household if an individual repeatedly 'not available' had minimal contact with an index child.", "cite_spans": [{"start": 647, "end": 651, "text": "[31]", "ref_id": "BIBREF33"}], "ref_spans": []}, {"section": "Handling silent refusals", "text": "\". . .we accommodated those who rarely get in to contact with the infant. . .whenever we did our home visits, we would collect data on their illness history. . .I would say they were not actually refusals of study participation, it's refusals to be swabbed [taken the NFS] period; but they were happy to be in the study. . .\", (R1_male_IDI04).", "cite_spans": [], "ref_spans": []}, {"section": "Handling silent refusals", "text": "Participants' views on how study teams should handle silent refusals. Both men and women participants in the case studies suggested that FWs should find out underlying reasons for silent refusals and find ways to resolve them. This included providing more information and addressing misunderstandings about the study and KWTRP's work. Only one participant suggested that those reluctant to participate in research should be withdrawn from the study. \". . .every time I fail to get the mother at home [because she dodges], then I will want to know the reason, whether she is willing to participate or not\" (Pax9_ female_FGD12).", "cite_spans": [], "ref_spans": []}, {"section": "Handling silent refusals", "text": "The strategies suggested for addressing silent refusals differed between men and women participants, related to the gendered nature of household decision-making in this community [43] . Many women felt that community leaders such as village elders and chiefs should arbitrate between FWs and silent refusals, men saw such arbitration as challenging their decisionmaking authority:", "cite_spans": [{"start": 179, "end": 183, "text": "[43]", "ref_id": "BIBREF46"}], "ref_spans": []}, {"section": "Handling silent refusals", "text": "\"In their misunderstanding they think if they go to the village elder they have been sued [challenged] for a mistake they have done. Instead of them knowing that they are being assisted with their children getting treatment they think they are going to be arrested. So these advices we are getting here, if he is called by the village elder he will think he's been sued. . .,\" (Pax1_male_FGD15).", "cite_spans": [], "ref_spans": []}, {"section": "Handling silent refusals", "text": "Those suggesting arbitration appeared to base it on wanting to support participants' access to high quality free health care, arguably a misunderstanding on what research is and how it differs with treatment; and the place for personal choice in research.", "cite_spans": [], "ref_spans": []}, {"section": "FWs' dilemmas in handling silent refusals", "text": "FWs and researchers saw an importance in understanding the reasons behind silent refusals in order to address these. Some FWs felt frustrated when they encountered silent refusals, being confused as to whether repeated follow-up visits would be a nuisance, and concerned about the increased workload. The genuine nature of reasons given made it difficult to strictly adhere to the rule of a maximum of three follow-up visits. In addition, FWs worried that failing to give participants enough time to make decisions could lead to tensions between themselves and participants. In a few instances, FWs felt that their Principal Investigator (PIs) did not understand these dynamics well enough, instead tending to blame FWs for causing a rift with participants, leading to silent refusals.", "cite_spans": [], "ref_spans": []}, {"section": "FWs' dilemmas in handling silent refusals", "text": "\". . . so that is the problem for us (FWs) . . .it's better if you didn't consent the person in the study but . . . she is in the study . . . she has gotten one dose (of vaccine); its better if that person had relocated to another area, there would be no problem. But you know she is there (at home) and she doesn't want to tell you (why she is reluctant) and then when you reach here (office) there is pressure you are being asked, 'what have you done to this child? What have you done to the mother until she now wants to withdraw from the study?'\" (FW1_male_FGD10).", "cite_spans": [], "ref_spans": []}, {"section": "FWs' dilemmas in handling silent refusals", "text": "Participants were aware that silent refusal posed particular challenges for FWs, and that the complex nature of underlying reasons and the fact it is not an openly expressed choice made it difficult for FWs to know how to response appropriately [39] . The dilemma for FWs with silent refusals was whether to accept it as a refusal and drop participants from the study or retain them. Dropping participants risked annoying some, adversely impacting relationships between them and the FW [31] and creating difficulties where FWs were continuing to visit other participants in the same and neighbouring household. Dropping participants also meant they could no longer access study benefits, an issue FWs struggled with especially for the poorest households [39] . In addition, over time participants appeared to get used to 'unpopular' study procedures, so that a FW deciding to drop a participant might later be blamed by that participant for taking such action, as narrated by a FW.", "cite_spans": [{"start": 245, "end": 249, "text": "[39]", "ref_id": "BIBREF42"}, {"start": 486, "end": 490, "text": "[31]", "ref_id": "BIBREF33"}, {"start": 754, "end": 758, "text": "[39]", "ref_id": "BIBREF42"}], "ref_spans": []}, {"section": "FWs' dilemmas in handling silent refusals", "text": ". . ..you see silent refusal usually happened because someone sees like you have become a member of that family. . .so he/she feels if they tell you openly from now or from today I withdraw there may be a problem. . .because the family will not qualify to continue to be in the study, (FW1_male_FGD6) Finally, as FWs live and are embedded within communities beyond the study period, they were understandably careful that transient research activities should not spoil already established long-term relationships [31] . With regards to the science of the study, by retaining silent refusals FWs feared they might collect low quality data, requiring repeated explanation to PIs. Whichever course of action FWs took, there were likely to be strained relationships, even if temporarily, between the FWs, participants and researchers.", "cite_spans": [{"start": 512, "end": 516, "text": "[31]", "ref_id": "BIBREF33"}], "ref_spans": []}, {"section": "Discussion", "text": "This study showed the socially embedded processes of consent processes for community-based studies in a long-term well-resourced research centre operating in a relatively poor, largely patriarchal community on the Kenyan Coast. In particular, we have described situations in which research consent decisions are not stated with an outright yes or no response. The findings highlight that negotiations were taking place throughout the course of the research; within households, between participants and FWs, and with others. While consent is one of the most widely described areas in research ethics, there is surprisingly little detailed research on the nature of these negotiations, and on how negotiations occur in research consent decisions. This paper further highlights that while ethical principles such as respect for persons and autonomy maybe universal, the way these are interpreted and negotiated can be context-specific, with implications for how individual agency is exercised. Given the paucity of literature on silent refusals in research conduct, there is need for empirical research in this area and across different research types and settings.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "In focusing on research decision negotiations, and on silent refusals as a complex set of strategies within those negotiations, this study has illustrated that consent decisions are made in the lived social world of participants; with decisions not only about weighing up research importance, risks and benefits, but also about safeguarding important relations with significant others and researchers. In this context silent refusals emerged as a strategy used to, among others, maintain harmonious relationships within household and with FWs, to negotiate participants' favourable participation levels while accessing full study benefits. In other papers, we have described the centrality of social relations [31] , study benefits [39] and of gender roles and household dynamics (in preparation) in shaping research participation in community-bases studies in our setting. In this paper we focus on silent refusals in the context of complex and unequal power relations during research conduct.", "cite_spans": [{"start": 710, "end": 714, "text": "[31]", "ref_id": "BIBREF33"}, {"start": 732, "end": 736, "text": "[39]", "ref_id": "BIBREF42"}], "ref_spans": []}, {"section": "Discussion", "text": "Silent refusals highlight the interweaving of power relationships into research processes. They highlight agency and the ways in which normative power relations can be challenged and overturned; wives making decisions about areas they would otherwise not be expected to control; and participants, to some extent, determining how to participate in research. VeneKlasen and Miller, cited in [44] , describe power as \". . .both dynamic and multi-dimensional, changing according to context, circumstances and interests. Its' expressions can range from domination and resistance to collaboration and transformation\" (p3). Long's description of agency power appears to be reflected in the concept of silent refusal.", "cite_spans": [{"start": 389, "end": 393, "text": "[44]", "ref_id": "BIBREF47"}], "ref_spans": []}, {"section": "Discussion", "text": "\" [Power] is the outcome of complex struggles and negotiation over authority, status, reputations and resources . . . such struggles are founded upon [the] extent to which specific actors perceived themselves capable of manoeuvring within particular situations and developing strategies for doing so\" [45] p2.", "cite_spans": [{"start": 301, "end": 305, "text": "[45]", "ref_id": "BIBREF48"}], "ref_spans": []}, {"section": "Discussion", "text": "Thus power can be exerted both overtly such as directly influencing actions and choices of others, and/or covertly such as subtle strategies that can influence the dynamics of negotiations [46] . In this study, silent refusals illustrate complex power relations within households, and between FW and households.", "cite_spans": [{"start": 189, "end": 193, "text": "[46]", "ref_id": "BIBREF49"}], "ref_spans": []}, {"section": "Within household power relations", "text": "Authoritative power, or power over others, [44] in households was largely described as held by male household heads over other household members, from elders to younger members, and from older women (such as first wives) to younger female (and male) household members. This form of power appeared to work in practice in some households, and on certain occasions, but not in others. Thus, some female household members and minors appeared to challenge male dominance in situations where they felt their choices mattered, particularly where research decisions and participation was likely to affect their roles in the household. Kandiyoti's (1988) concept of bargaining with patriarchy appropriately frames some of the strategies women and minors used to resist male dominance in some aspects of the research [47] . Because of the covert nature of silent refusal (unexpressed refusal), those with authoritative power such as husbands, household heads and male household members expressed helplessness when they encountered it. The phenomenon of silent refusal suggests that, at least in the Kilifi setting, participants' choices about research participation are influenced by the way the research is likely to shape relationships with significant others in the household. It was used to circumvent unpopular research decisions, and to manoeuvre personal preferences into decision-making processes, while also maintaining harmony in key relationships. Strategies for negotiating favourable decisions in unequal power relations within households have been documented in household treatment seeking behaviours for seriously ill children ( [43] ; however there relatively little information with regards to research participation.", "cite_spans": [{"start": 43, "end": 47, "text": "[44]", "ref_id": "BIBREF47"}, {"start": 1634, "end": 1638, "text": "[43]", "ref_id": "BIBREF46"}], "ref_spans": []}, {"section": "Participant-FW (and study) relations", "text": "With regards to power in participant-FW relations, generally it seemed that FWs were respected in the community due to their being employed in a reputable organisation (KWTRP) and having access to resources, technical knowledge, information about the study and access to the PIs. Participants thus conceptualised FWs as community gatekeepers and expected them to put community interests over and above those of KWTRP and of research. FWs were likely to be aware of these expectations, and may have encouraged them to achieve their own goals such as attaining high recognition and meeting recruitment targets, as documented elsewhere [48] . FWs were also aware that entering people's homes put them in positions of vulnerability, since household members had control over if and how the FWs would be received. FWs thus used discretionary power [44] during research implementation to shape research conduct, and to influence perceptions of community members and PIs about them, and about the study. Thus, overall, one would expect FWs to have power over participants in their interactions.", "cite_spans": [{"start": 633, "end": 637, "text": "[48]", "ref_id": "BIBREF51"}, {"start": 842, "end": 846, "text": "[44]", "ref_id": "BIBREF47"}], "ref_spans": []}, {"section": "Participant-FW (and study) relations", "text": "Participants in the case studies were aware that it was important for them to follow study procedures consistently for the research to be successful. This was discussed in various forums including in community engagement meetings, during consent processes and at follow-up visits. They also knew that FWs' job performance might largely depend on their participating faithfully in the research. It, therefore, seems that participants had latent power [46] to influence research conduct, through their ability to determine whether the study would take place (and in what form), and whether FWs would be welcomed to their homes for follow-up visits. They exercised these powers in various ways; overtly through continuous discussions; and covertly particularly through silent refusals. Together, these factors contributed to participants' perceptions and understanding of their tacit power to control the direction of study implementation, while maintaining harmony in key relationships. We call this subtle power as it was not explicitly expressed and appeared scattered and fragmented across different participants and over time. The relational nature of this form of power made it difficult to detect in the first instance, and was frustrating to those who experienced it, especially the FWs. The practice of silent refusal showed that to some extent participants could exert agency in their participation levels (choosing what study procedures to participate in, when and how), and the overall research implementation. Exploring factors underpinning silent refusals shows an intricate interplay between multiple sources of power amongst participants and FWs that shaped decisions about research participation.", "cite_spans": [{"start": 450, "end": 454, "text": "[46]", "ref_id": "BIBREF49"}], "ref_spans": []}, {"section": "Participant-FW (and study) relations", "text": "Many of the findings serve to highlight the disconnect between universalist ethics approaches and individual/contextualised responses to medical research. This tension is constantly faced by FWs in their daily roles, as something they have to constantly negotiate although it is rarely acknowledged. There is now a growing body of literature that is drawing attention to the ethical challenges and dilemmas that fieldworkers face in undertaking their research roles in developing countries [25, 26, 32, 49] ; this paper adds to this body of literature by describing an area that has not been written about, silent refusals and subtle power negotiations in research participation.", "cite_spans": [{"start": 490, "end": 494, "text": "[25,", "ref_id": "BIBREF26"}, {"start": 495, "end": 498, "text": "26,", "ref_id": "BIBREF28"}, {"start": 499, "end": 502, "text": "32,", "ref_id": "BIBREF35"}, {"start": 503, "end": 506, "text": "49]", "ref_id": "BIBREF52"}], "ref_spans": []}, {"section": "Conclusion", "text": "While many communities exhibit some form of silent refusal, very little has been written about it with regards to research participation. Silent refusals illustrate the complexities inherent in negotiating decisions around research participation and the ongoing nature of informed consent processes. They illuminate the socially embedded nature of research participation, and the significance of taking account of the social worlds of participants and the ways in which agency is exercised to shape research implementation in otherwise unequal power relations. Exercising such agency calls us to take account of both individualism and the relational nature of those involved in research, and the sometimes conflicting ways these two play out; such as women subtly exercising their power to make decisions in areas they otherwise would not be involved in, but doing so in ways that avoid conflicts within and beyond the household. Recognising the centrality of negotiations for research participation is one way to take account of power relations embedded in such processes, and to start to unpack and understand the ethical issues around consent as a process. In this research, we support the call to consider consent as a process for community-based studies. We propose that this requires understanding the nature of consultations and negotiations that go on, and unpacking of ethical issues interwoven in such processes. Those involved in undertaking consent, often fieldworkers who are embedded in communities, play a critical interface role and mediate between researchers and the community; one which brings multiple dilemmas and challenges. The complexity of power relationships between participants and FWs is echoed in those between FWs and PIs. PIs need to be aware of the ethically charged, complex and fluid environments that FWs encounter in their daily work. Guidelines are unlikely to be adequate for all situations that FWs encounter, and PIs who are more removed from the messy realities of community-embedded consent processes will find it difficult to understand the issues. Providing constructive supportive supervision where there is 'space' for fieldworkers to air and discuss their own embedded knowledge and concerns-as much as possible throughout the entire research cycle-will be important, as will ensuring that FWs are trained in research ethics, communication skills, and how to recognise and respond to ethical dilemmas they may encounter.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Understanding of informed consent in a low-income setting: three case studies from the Kenyan Coast. Social science & medicine", "authors": [{"first": "C", "middle": ["S"], "last": "Molyneux", "suffix": ""}, {"first": "N", "middle": [], "last": "Peshu", "suffix": ""}, {"first": "K", "middle": [], "last": "Marsh", "suffix": ""}], "year": 2004, "venue": "", "link": null}, "BIBREF1": {"title": "Where techno-science meets poverty: medical research and the economy of blood in The Gambia", "authors": [{"first": "J", "middle": [], "last": "Fairhead", "suffix": ""}, {"first": "M", "middle": [], "last": "Leach", "suffix": ""}, {"first": "M", "middle": [], "last": "Small", "suffix": ""}], "year": 2006, "venue": "West Africa. Social science & medicine", "link": null}, "BIBREF2": {"title": "Reflections and recommendations on research ethics in developing countries. Social science & medicine", "authors": [{"first": "S", "middle": ["R"], "last": "Benatar", "suffix": ""}], "year": 2002, "venue": "", "link": null}, "BIBREF3": {"title": "The therapeutic misconception: problems and solutions", "authors": [{"first": "C", "middle": ["W"], "last": "Lidz", "suffix": ""}, {"first": "P", "middle": ["S"], "last": "Appelbaum", "suffix": ""}], "year": 2002, "venue": "Medical care", "link": "8571067"}, "BIBREF4": {"title": "Why mothers choose to enrol their children in malaria clinical studies and the involvement of relatives in decision making: evidence from Malawi. Malawi medical journal: the journal of", "authors": [{"first": "F", "middle": [], "last": "Masiye", "suffix": ""}, {"first": "N", "middle": [], "last": "Kass", "suffix": ""}, {"first": "A", "middle": [], "last": "Hyder", "suffix": ""}, {"first": "P", "middle": [], "last": "Ndebele", "suffix": ""}, {"first": "J", "middle": [], "last": "Mfutso-Bengo", "suffix": ""}], "year": 2008, "venue": "Medical Association of Malawi", "link": "11758576"}, "BIBREF5": {"title": "Why do individuals agree to enrol in clinical trials? A qualitative study of health research participation in", "authors": [{"first": "J", "middle": [], "last": "Mfutso-Bengo", "suffix": ""}, {"first": "P", "middle": [], "last": "Ndebele", "suffix": ""}, {"first": "V", "middle": [], "last": "Jumbe", "suffix": ""}, {"first": "M", "middle": [], "last": "Mkunthi", "suffix": ""}, {"first": "F", "middle": [], "last": "Masiye", "suffix": ""}, {"first": "S", "middle": [], "last": "Molyneux", "suffix": ""}], "year": 2008, "venue": "Medical Association of Malawi", "link": null}, "BIBREF6": {"title": "HIV/AIDS reduces the relevance of the principle of individual medical confidentiality among the Bantu people of Southern Africa. Theoretical medicine and bioethics", "authors": [{"first": "P", "middle": [], "last": "Ndebele", "suffix": ""}, {"first": "J", "middle": [], "last": "Mfutso-Bengo", "suffix": ""}, {"first": "F", "middle": [], "last": "Masiye", "suffix": ""}], "year": 2008, "venue": "", "link": null}, "BIBREF7": {"title": "Trust and informed consent: insights from community members on the Kenyan coast", "authors": [{"first": "C", "middle": ["S"], "last": "Molyneux", "suffix": ""}, {"first": "N", "middle": [], "last": "Peshu", "suffix": ""}, {"first": "K", "middle": [], "last": "Marsh", "suffix": ""}], "year": 2005, "venue": "Social science & medicine", "link": "38470770"}, "BIBREF8": {"title": "Local attitudes, moral obligation, customary obedience and other cultural practices: their influence on the process of gaining informed consent for surgery in a tertiary institution in a developing country", "authors": [{"first": "D", "middle": ["O"], "last": "Irabor", "suffix": ""}, {"first": "P", "middle": [], "last": "Omonzejele", "suffix": ""}], "year": 2009, "venue": "Developing world bioethics", "link": "205627019"}, "BIBREF9": {"title": "Relational autonomy or undue pressure? Family's role in medical decision-making", "authors": [{"first": "A", "middle": [], "last": "Ho", "suffix": ""}], "year": 2008, "venue": "Scandinavian journal of caring sciences", "link": "205624982"}, "BIBREF10": {"title": "Tailoring consent to context: designing an appropriate consent process for a biomedical study in a low income setting. PLoS neglected tropical diseases", "authors": [{"first": "F", "middle": [], "last": "Tekola", "suffix": ""}, {"first": "S", "middle": ["J"], "last": "Bull", "suffix": ""}, {"first": "B", "middle": [], "last": "Farsides", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Newport", "suffix": ""}, {"first": "A", "middle": [], "last": "Adeyemo", "suffix": ""}, {"first": "C", "middle": ["N"], "last": "Rotimi", "suffix": ""}], "year": 2009, "venue": "", "link": null}, "BIBREF12": {"title": "Consent and Community Engagement in diverse research contexts", "authors": [], "year": 2013, "venue": "Participants in the Community E, Consent Workshop KKM", "link": null}, "BIBREF13": {"title": "Working with Concepts: The Role of Community in International Collaborative Biomedical Research", "authors": [{"first": "V", "middle": ["M"], "last": "Marsh", "suffix": ""}, {"first": "D", "middle": ["K"], "last": "Kamuya", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Parker", "suffix": ""}, {"first": "C", "middle": ["S"], "last": "Molyneux", "suffix": ""}], "year": 2011, "venue": "Public health ethics", "link": "9294148"}, "BIBREF14": {"title": "Community engagement and informed consent in the International HapMap project", "authors": [{"first": "C", "middle": [], "last": "Rotimi", "suffix": ""}, {"first": "M", "middle": [], "last": "Leppert", "suffix": ""}, {"first": "I", "middle": [], "last": "Matsuda", "suffix": ""}, {"first": "C", "middle": [], "last": "Zeng", "suffix": ""}, {"first": "H", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "C", "middle": [], "last": "Adebamowo", "suffix": ""}], "year": 2007, "venue": "Community genetics", "link": "10844405"}, "BIBREF15": {"title": "It takes a village: medical research and ethics in Mali", "authors": [{"first": "O", "middle": ["K"], "last": "Doumbo", "suffix": ""}], "year": 2005, "venue": "Science", "link": null}, "BIBREF16": {"title": "Towards a framework for community engagement in global health research", "authors": [{"first": "J", "middle": ["V"], "last": "Lavery", "suffix": ""}, {"first": "P", "middle": ["O"], "last": "Tinadana", "suffix": ""}, {"first": "T", "middle": ["W"], "last": "Scott", "suffix": ""}, {"first": "L", "middle": ["C"], "last": "Harrington", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Ramsey", "suffix": ""}, {"first": "C", "middle": [], "last": "Ytuarte-Nunez", "suffix": ""}], "year": 2010, "venue": "Trends in parasitology", "link": "32893657"}, "BIBREF17": {"title": "Experiences with community engagement and informed consent in a genetic cohort study of severe childhood diseases in Kenya", "authors": [{"first": "V", "middle": ["M"], "last": "Marsh", "suffix": ""}, {"first": "D", "middle": ["M"], "last": "Kamuya", "suffix": ""}, {"first": "A", "middle": ["M"], "last": "Mlamba", "suffix": ""}, {"first": "T", "middle": ["N"], "last": "Williams", "suffix": ""}, {"first": "S", "middle": ["S"], "last": "Molyneux", "suffix": ""}], "year": 2010, "venue": "BMC medical ethics", "link": "6524563"}, "BIBREF18": {"title": "Benefits and payments for research participants: experiences and views from a research centre on the Kenyan coast", "authors": [{"first": "S", "middle": [], "last": "Molyneux", "suffix": ""}, {"first": "S", "middle": [], "last": "Mulupi", "suffix": ""}, {"first": "L", "middle": [], "last": "Mbaabu", "suffix": ""}, {"first": "V", "middle": [], "last": "Marsh", "suffix": ""}], "year": 2012, "venue": "BMC medical ethics", "link": "13924565"}, "BIBREF19": {"title": "The social dynamics of consent and refusal in HIV surveillance in rural South Africa", "authors": [{"first": "L", "middle": [], "last": "Reynolds", "suffix": ""}, {"first": "T", "middle": [], "last": "Cousins", "suffix": ""}, {"first": "M-L", "middle": [], "last": "Newell", "suffix": ""}, {"first": "J", "middle": [], "last": "Imrie", "suffix": ""}], "year": 2013, "venue": "Social Science & Medicine", "link": "13904694"}, "BIBREF20": {"title": "Ethical issues in identifying and recruiting participants for familial genetic research", "authors": [{"first": "L", "middle": ["M"], "last": "Beskow", "suffix": ""}, {"first": "J", "middle": ["R"], "last": "Botkin", "suffix": ""}, {"first": "M", "middle": [], "last": "Daly", "suffix": ""}, {"first": "E", "middle": ["T"], "last": "Juengst", "suffix": ""}, {"first": "L", "middle": ["S"], "last": "Lehmann", "suffix": ""}, {"first": "J", "middle": ["F"], "last": "Merz", "suffix": ""}], "year": 2004, "venue": "American journal of medical genetics Part A", "link": "24264212"}, "BIBREF21": {"title": "Voluntary participation and comprehension of informed consent in a genetic epidemiological study of breast cancer in Nigeria", "authors": [{"first": "P", "middle": ["A"], "last": "Marshall", "suffix": ""}, {"first": "C", "middle": ["A"], "last": "Adebamowo", "suffix": ""}, {"first": "A", "middle": ["A"], "last": "Adeyemo", "suffix": ""}, {"first": "T", "middle": ["O"], "last": "Ogundiran", "suffix": ""}, {"first": "T", "middle": [], "last": "Strenski", "suffix": ""}, {"first": "J", "middle": [], "last": "Zhou", "suffix": ""}], "year": 2014, "venue": "BMC medical ethics", "link": "1004834"}, "BIBREF22": {"title": "Rights of and duties to non-consenting patients-informed refusal in the developing world", "authors": [{"first": "L", "middle": ["J"], "last": "Van Bogaert", "suffix": ""}], "year": 2006, "venue": "Developing world bioethics", "link": "45006364"}, "BIBREF23": {"title": "When \"no\" might not quite mean \"no\"; the importance of informed and meaningful non-consent: results from a survey of individuals refusing participation in a health-related research project. BMC health services research", "authors": [{"first": "B", "middle": [], "last": "Williams", "suffix": ""}, {"first": "L", "middle": [], "last": "Irvine", "suffix": ""}, {"first": "A", "middle": ["R"], "last": "Mcginnis", "suffix": ""}, {"first": "M", "middle": ["E"], "last": "Mcmurdo", "suffix": ""}, {"first": "I", "middle": ["K"], "last": "Crombie", "suffix": ""}], "year": 2007, "venue": "", "link": "17244970"}, "BIBREF24": {"title": "Community researchers conducting health disparities research: Ethical and other insights from fieldwork journaling. Social science & medicine", "authors": [{"first": "M", "middle": [], "last": "Mosavel", "suffix": ""}, {"first": "R", "middle": [], "last": "Ahmed", "suffix": ""}, {"first": "D", "middle": [], "last": "Daniels", "suffix": ""}, {"first": "C", "middle": [], "last": "Simon", "suffix": ""}], "year": 2011, "venue": "", "link": null}, "BIBREF26": {"title": "Field workers at the interface", "authors": [{"first": "S", "middle": [], "last": "Molyneux", "suffix": ""}, {"first": "D", "middle": [], "last": "Kamuya", "suffix": ""}, {"first": "P", "middle": ["A"], "last": "Madiega", "suffix": ""}, {"first": "T", "middle": [], "last": "Chantler", "suffix": ""}, {"first": "V", "middle": [], "last": "Angwenyi", "suffix": ""}, {"first": "P", "middle": ["W"], "last": "Geissler", "suffix": ""}], "year": 2013, "venue": "Developing world bioethics", "link": "13766791"}, "BIBREF28": {"title": "Community members as recruiters of human subjects: ethical considerations", "authors": [{"first": "C", "middle": [], "last": "Simon", "suffix": ""}, {"first": "M", "middle": [], "last": "Mosavel", "suffix": ""}], "year": 2010, "venue": "The American journal of bioethics: AJOB", "link": "2443263"}, "BIBREF29": {"title": "She's my sister-in-law, my visitor, my friend'-challenges of staff identity in home follow-up in an HIV trial in Western Kenya", "authors": [{"first": "P", "middle": ["A"], "last": "Madiega", "suffix": ""}, {"first": "G", "middle": [], "last": "Jones", "suffix": ""}, {"first": "R", "middle": ["J"], "last": "Prince", "suffix": ""}, {"first": "P", "middle": ["W"], "last": "Geissler", "suffix": ""}], "year": 2013, "venue": "Developing world bioethics", "link": "16948649"}, "BIBREF30": {"title": "Respondent-driven sampling in a study of drug users in New York City: notes from the field", "authors": [{"first": "C", "middle": [], "last": "Mcknight", "suffix": ""}, {"first": "Des", "middle": [], "last": "Jarlais", "suffix": ""}, {"first": "D", "middle": [], "last": "Bramson", "suffix": ""}, {"first": "H", "middle": [], "last": "Tower", "suffix": ""}, {"first": "L", "middle": [], "last": "Abdul-Quader", "suffix": ""}, {"first": "A", "middle": ["S"], "last": "Nemeth", "suffix": ""}, {"first": "C", "middle": [], "last": "", "suffix": ""}], "year": 2006, "venue": "", "link": "23503374"}, "BIBREF31": {"title": "What we learned about voluntariness and consent: incorporating \"background situations\" and understanding into analyses", "authors": [{"first": "D", "middle": [], "last": "Kamuya", "suffix": ""}, {"first": "V", "middle": [], "last": "Marsh", "suffix": ""}, {"first": "S", "middle": [], "last": "Molyneux", "suffix": ""}], "year": 2011, "venue": "The American journal of bioethics: AJOB", "link": "6939212"}, "BIBREF32": {"title": "Experiencing everyday ethics in context: frontline data collectors perspectives and practices of bioethics", "authors": [{"first": "P", "middle": [], "last": "Kingori", "suffix": ""}], "year": 2013, "venue": "Social science & medicine", "link": "13928649"}, "BIBREF33": {"title": "Evolving friendships and shifting ethical dilemmas: fieldworkers' experiences in a short term community based study in Kenya", "authors": [{"first": "D", "middle": ["M"], "last": "Kamuya", "suffix": ""}, {"first": "S", "middle": ["J"], "last": "Theobald", "suffix": ""}, {"first": "P", "middle": ["K"], "last": "Munywoki", "suffix": ""}, {"first": "D", "middle": [], "last": "Koech", "suffix": ""}, {"first": "W", "middle": ["P"], "last": "Geissler", "suffix": ""}, {"first": "S", "middle": ["C"], "last": "Molyneux", "suffix": ""}], "year": 2013, "venue": "Developing world bioethics", "link": "13899136"}, "BIBREF35": {"title": "Ethical challenges that arise at the community interface of health research: village reporters' experiences in Western Kenya. Developing world bioethics", "authors": [{"first": "T", "middle": [], "last": "Chantler", "suffix": ""}, {"first": "F", "middle": [], "last": "Otewa", "suffix": ""}, {"first": "P", "middle": [], "last": "Onyango", "suffix": ""}, {"first": "B", "middle": [], "last": "Okoth", "suffix": ""}, {"first": "F", "middle": [], "last": "Odhiambo", "suffix": ""}, {"first": "M", "middle": [], "last": "Parker", "suffix": ""}], "year": 2013, "venue": "", "link": null}, "BIBREF36": {"title": "He is now like a brother, I can even give him some blood'-relational ethics and material exchanges in a malaria vaccine 'trial community' in The Gambia. Social science & medicine", "authors": [{"first": "P", "middle": ["W"], "last": "Geissler", "suffix": ""}, {"first": "A", "middle": [], "last": "Kelly", "suffix": ""}, {"first": "B", "middle": [], "last": "Imoukhuede", "suffix": ""}, {"first": "R", "middle": [], "last": "Pool", "suffix": ""}], "year": 2008, "venue": "", "link": null}, "BIBREF37": {"title": "Research participation and the right to withdraw", "authors": [{"first": "S", "middle": ["J"], "last": "Edwards", "suffix": ""}], "year": 2005, "venue": "Bioethics", "link": "23773466"}, "BIBREF38": {"title": "Taking social relationships seriously: lessons learned from the informed consent practices of a vaccine trial on the Kenyan Coast. Social science & medicine", "authors": [{"first": "C", "middle": [], "last": "Gikonyo", "suffix": ""}, {"first": "P", "middle": [], "last": "Bejon", "suffix": ""}, {"first": "V", "middle": [], "last": "Marsh", "suffix": ""}, {"first": "S", "middle": [], "last": "Molyneux", "suffix": ""}], "year": 2008, "venue": "", "link": null}, "BIBREF39": {"title": "Profile: The Kilifi Health and Demographic Surveillance System (KHDSS)", "authors": [{"first": "J", "middle": ["A"], "last": "Scott", "suffix": ""}, {"first": "E", "middle": [], "last": "Bauni", "suffix": ""}, {"first": "J", "middle": ["C"], "last": "Moisi", "suffix": ""}, {"first": "J", "middle": [], "last": "Ojal", "suffix": ""}, {"first": "H", "middle": [], "last": "Gatakaa", "suffix": ""}, {"first": "C", "middle": [], "last": "Nyundo", "suffix": ""}], "year": 2012, "venue": "International journal of epidemiology", "link": "11635838"}, "BIBREF40": {"title": "Strengthening the informed consent process in international health research through community engagement: The KEMRI-Wellcome Trust Research Programme Experience", "authors": [{"first": "M", "middle": [], "last": "Boga", "suffix": ""}, {"first": "A", "middle": [], "last": "Davies", "suffix": ""}, {"first": "D", "middle": [], "last": "Kamuya", "suffix": ""}, {"first": "S", "middle": ["M"], "last": "Kinyanjui", "suffix": ""}, {"first": "E", "middle": [], "last": "Kivaya", "suffix": ""}, {"first": "F", "middle": [], "last": "Kombe", "suffix": ""}], "year": 2011, "venue": "PLoS medicine", "link": "687541"}, "BIBREF41": {"title": "Beginning community engagement at a busy biomedical research programme: experiences from the KEMRI CGMRC-Wellcome Trust Research Programme", "authors": [{"first": "V", "middle": [], "last": "Marsh", "suffix": ""}, {"first": "D", "middle": [], "last": "Kamuya", "suffix": ""}, {"first": "Y", "middle": [], "last": "Rowa", "suffix": ""}, {"first": "C", "middle": [], "last": "Gikonyo", "suffix": ""}, {"first": "S", "middle": [], "last": "Molyneux", "suffix": ""}], "year": 2008, "venue": "", "link": "13954724"}, "BIBREF42": {"title": "When they see us, it's like they have seen the benefits!\": experiences of study benefits negotiations in community-based studies on the Kenyan Coast", "authors": [{"first": "D", "middle": ["M"], "last": "Kamuya", "suffix": ""}, {"first": "V", "middle": [], "last": "Marsh", "suffix": ""}, {"first": "P", "middle": [], "last": "Njunguna", "suffix": ""}, {"first": "P", "middle": [], "last": "Munywoki", "suffix": ""}, {"first": "M", "middle": [], "last": "Parker", "suffix": ""}, {"first": "S", "middle": [], "last": "Molyneux", "suffix": ""}], "year": 2014, "venue": "BMC medical ethics", "link": "215597794"}, "BIBREF43": {"title": "Qualitative Methods for Health Research", "authors": [{"first": "J", "middle": [], "last": "Green", "suffix": ""}, {"first": "N", "middle": [], "last": "Thorogood", "suffix": ""}], "year": 2007, "venue": "", "link": "56883052"}, "BIBREF44": {"title": "Within-case and across-case approaches to qualitative data analysis", "authors": [{"first": "L", "middle": [], "last": "Ayres", "suffix": ""}, {"first": "K", "middle": [], "last": "Kavanaugh", "suffix": ""}, {"first": "K", "middle": ["A"], "last": "Knafl", "suffix": ""}], "year": 2003, "venue": "Qual Health Res", "link": "2531182"}, "BIBREF45": {"title": "Qualitative Research practice: A guide for social science students and researchers", "authors": [{"first": "J", "middle": [], "last": "Ritchie", "suffix": ""}, {"first": "J", "middle": [], "last": "Lewis", "suffix": ""}], "year": 2003, "venue": "", "link": "15027803"}, "BIBREF46": {"title": "Intra-household relations and treatment decision-making for childhood illness: a Kenyan case study", "authors": [{"first": "C", "middle": ["S"], "last": "Molyneux", "suffix": ""}, {"first": "G", "middle": [], "last": "Murira", "suffix": ""}, {"first": "J", "middle": [], "last": "Masha", "suffix": ""}, {"first": "R", "middle": ["W"], "last": "Snow", "suffix": ""}], "year": 2002, "venue": "Journal of biosocial science", "link": "30892957"}, "BIBREF47": {"title": "Actor interfaces and practices of power in a community health worker programme: a South African study of unintended policy outcomes. Health policy and planning", "authors": [{"first": "U", "middle": [], "last": "Lehmann", "suffix": ""}, {"first": "L", "middle": [], "last": "Gilson", "suffix": ""}], "year": 2013, "venue": "", "link": "14441682"}, "BIBREF48": {"title": "The Multiple Optic of Interface Analysis (working title). UNESCO Background paper on Interface Analysis1999", "authors": [{"first": "N", "middle": [], "last": "Long", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF49": {"title": "A Radical View", "authors": [{"first": "S", "middle": [], "last": "Lukes", "suffix": ""}, {"first": "", "middle": [], "last": "Power", "suffix": ""}], "year": 2005, "venue": "", "link": null}, "BIBREF51": {"title": "Kachinja are coming!': Encounters Around Medical Research Work in Kenyan Vilages", "authors": [{"first": "P", "middle": ["W"], "last": "Geissler", "suffix": ""}], "year": 2005, "venue": "Africa", "link": null}, "BIBREF52": {"title": "Conducting health related social science research in low income settings: Ethical dilemmas faced in Kenya and South Africa", "authors": [{"first": "C", "middle": [], "last": "Molyneux", "suffix": ""}, {"first": "J", "middle": [], "last": "Goudge", "suffix": ""}, {"first": "S", "middle": [], "last": "Russell", "suffix": ""}, {"first": "J", "middle": [], "last": "Chuma", "suffix": ""}, {"first": "T", "middle": [], "last": "Gumede", "suffix": ""}, {"first": "L", "middle": [], "last": "Gilson", "suffix": ""}], "year": 2009, "venue": "Journal of International Development", "link": "145618796"}, "BIBREF53": {"title": "Silent Refusals and Complex Power Relations in Consent Processes PLOS ONE", "authors": [], "year": 2015, "venue": "", "link": null}}, "ref_entries": {"FIGREF0": {"text": "Fig 1. Flow-Chart showing selection of the community-based studies. doi:10.1371/journal.pone.0126671.g001", "type": "figure"}, "FIGREF1": {"text": ", a nasopharyngeal flocked swab (NFS); history of respiratory illness Experimental malaria vaccine and a different booster dose of either Meningitis and septicaemia vaccine; and In addition, respiratory rate taken for all children under 5 years. Three doses of rabies vaccine plus a different booster doses of Meningitis and septicaemia.", "type": "figure"}, "FIGREF2": {"text": "Fig 2. Consenting process for RSV-study.", "type": "figure"}, "FIGREF3": {"text": "Fig 3. Consenting process for Malaria-Study. doi:10.1371/journal.pone.0126671.g003", "type": "figure"}, "TABREF0": {"text": "Criteria considered in selecting the Community-based studies.", "type": "table"}, "TABREF1": {"text": "Key features of the two community based case studies.", "type": "table"}, "TABREF2": {"text": "Demographic characteristics of respondents.Respondent-participants in the two Community-Based studies*as at the time of collecting the data in early 2010. doi:10.1371/journal.pone.0126671.t003 Silent Refusals and Complex Power Relations in Consent Processes PLOS ONE | DOI:10.1371/journal.pone.0126671 May 15, 2015", "type": "table"}, "TABREF3": {"text": "Summary of interview methods and respondents.IDIs with RSV-study researchers, two each with PI, Study coordinator, Senior FW 1 IDI with one FW in the Malaria-study", "type": "table"}}}
{"paper_id": "17780357", "_pdf_hash": "0411bf4cef0916ca53bf87a9d50028cd9af535db", "abstract": [{"section": "Abstract", "text": "Abstract. In this study computations of the two-dimensional Direct Simulation Monte Carlo (DSMC) method using Graphics Processing Units (GPUs) are presented. An all-device (GPU) computational approach is adopted -where the entire computation is performed on the GPU device, leaving the CPU idle -which includes particle moving, indexing, collisions between particles and state sampling. The subsequent application to GPU computation requires various changes to the original DSMC method to ensure efficient performance on the GPU device. Communications between the host (CPU) and device (GPU) only occur during problem initialization and simulation conclusion when results are only copied from the device to the host. Several multi-dimensional benchmark tests are employed to demonstrate the correctness of the DSMC implementation. We demonstrate here the application of DSMC using a single-GPU, with speedups of 3~10 times as compared to a high-end Intel CPU (Intel Xeon X5472) depending upon the size and the level of rarefaction encountered in the simulation.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "INTRODUCTION", "text": "The Direct Simulation Monte Carlo (DSMC) method is a computational tool for simulating flows in which effects at the molecular scale become significant [1] . The Boltzmann equation, which is appropriate for modeling these rarefied flows, is extremely difficult to solve numerically due to its high dimensionality and the complexity of the collision term. DSMC provides a particle based alternative for obtaining realistic numerical solutions. In DSMC the movement and collision behavior of a large number of representative \"simulation particles\" within the flow field are decoupled over a time step which is a small fraction of the local mean collision time. The computational domain itself is divided into either a structured or unstructured grid of cells which are then used to select particles for collisions on a probabilistic basis and also are used for sampling the macroscopic flow properties. The method has been shown to provide a solution to the Boltzmann equation when the number of simulated particles is large enough [2] . The sizes of DSMC cells have to be much smaller than the local mean free path for a meaningful simulation in general.", "cite_spans": [{"start": 152, "end": 155, "text": "[1]", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "NUMERICAL METHOD", "text": "Since its introduction, the Direct Simulation Monte Carlo (DSMC) [1] has become the standard method for simulating rarefied gas dynamics. It is generally very computationally intensive, especially in the near-continuum (collision-dominated) regime. The general wisdom for accelerating the DMSC computation is to parallelize the code using the MPI protocol running on clusters with large numbers of processors such as PDSC by Wu et al. [3] . Such implementations rely upon the Multiple Instructions on Multiple Data (MIMD) parallelization philosophy and parallel efficiency over massive numbers of nodes is not optimal. Recently, Graphics Processing Units (GPUs) have become an alternative platform for parallelization, employing a Single Instruction on Multiple Data sets (SIMD) FIGURE 1. A flowchart describing the application of DSMC to GPU-accelerated computation.", "cite_spans": [{"start": 65, "end": 68, "text": "[1]", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "NUMERICAL METHOD", "text": "parallelization philosophy. The resulting parallelization is much more efficient at the cost of flexibility -as a result, the computational time of several scientific computations, especially those which are optimally applied to vectorized computation strategies, have been demonstrated to reduce significantly. The application of GPU computation also has significant advantages in lower power consumption and significantly reduced equipment costs.", "cite_spans": [], "ref_spans": []}, {"section": "NUMERICAL METHOD", "text": "Experience showed that the higher the locality of the numerical scheme/algorithm, the higher the speedup is. However, there seems no successful previous study applying GPUs to accelerate the DSMC computation, which employs a (generally) highly local algorithm. The DSMC method, which is a particle-based method developed by Bird [1] , is described in Figure 1 . Following initialization, the DSMC method generally involves:", "cite_spans": [{"start": 329, "end": 332, "text": "[1]", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "NUMERICAL METHOD", "text": "\uf0b7 Moving all the simulated particles, which includes treatment of boundary conditions, \uf0b7 Indexing all simulation particles (sorting particles into cells), \uf0b7 Performing collisions between particles -outcomes of collisions are stochastic in nature, hence the use of the term \"Monte Carlo\" in the DSMC name, \uf0b7 sampling the molecules within cells to obtain the macroscopic quantities.", "cite_spans": [], "ref_spans": []}, {"section": "NUMERICAL METHOD", "text": "In this study, an all-device (GPU) computational approach is adopted, which includes particle moving, indexing, colliding between particles and sampling. This required some changes of the original DSMC method in order to allow efficient all-device computation. Figure 1 shows the flowchart of DSMC computation using a single-GPU. During the initialization stage, input data is loaded into memory and initial states are determined on the host (CPU). This information (including particle and computational cell information) is transferred to the GPU device global memory. Following this, the unsteady phase of the DSMC simulation is performed -particle moving, indexing, particle selection and collisions and sampling are executed on GPU. During particle movement, each particle is tracked by a thread, with each thread tracking N p /N thread +1 particles, where N p is total simulated particles and N thread is number of threads employed by the GPU device. Each thread reads/writes particle data to/from the global memory of the GPU device [4] . The particle indexing phase of the computation is similar to Bird's DSMC implementation [1] . We use a function contained within the Software Development Kit (SDK) of CUDA, scanLargeArray, to scan through data elements of large arrays contained within global memory. This function is used to efficiently perform particle indexing. During the collision phase, a different parallelization philosophy employed -all particle collisions within a cell are handled by a single thread, allowing efficient recollection of data since all data is coalesced. During the sampling phase, shared memory of GPU [4] is used to store properties of all particles in each cell. After all particles within the same cell are sampled, we copy the sampled data from the (faster) shared to (larger) global memory. When our simulation is nearing completion (i.e. the flow has reached steady state and the sampled data is sufficient to remove undesired statistical scatter) we move the sampled data from device (GPU) global memory to CPU memory. Finally, calculation of the macroscopic properties is performed by the host and the data is written to file for further analysis.", "cite_spans": [{"start": 1039, "end": 1042, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 1133, "end": 1136, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 1640, "end": 1643, "text": "[4]", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "RESULTS AND DISCUSSION", "text": "In this study, we verify our DSMC implementation and demonstrate significant speedup of DSMC computations using a single GPU device through the simulation of several two dimensional benchmark problems: namely, (i) supersonic flow over a (fixed temperature) horizontal flat plate, and (ii) a supersonic lid-driven cavity problem. Approximately 50 particles per cell for all benchmark test cases are maintained throughout the simulations. The DSMC computation employs a VHS collision model [1] for each case. All benchmark simulations are performed on the latest high end computation equipment: single CPU computations employ an Intel Xeon X5472 CPU (3.0 GHz, 12 MB Cache) while GPU computations employ an Nvidia Tesla C1060 (240 microprocessors @ 1.4 GHz, 4 GB DDR3 global memory) hosted by the same Intel Xeon CPU employed for the single CPU test cases.", "cite_spans": [{"start": 488, "end": 491, "text": "[1]", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "Two Dimensional Supersonic Flow over a Horizontal Flat Plate", "text": "This benchmark involves the two dimensional supersonic flow over a flat plate. Ideal argon (\u03b3=5/3) with temperature 300 K is initially assumed to be moving with Mach Number M = 4.4 over a diffusely reflecting flat plate of fixed temperature 500 K. The length of the flat plate is L = 0.9m, with the initial flow-field density based on the Knudsen number (computed with characteristic length based on the plate length). The initial simulation conditions are summarized in Table 1 .", "cite_spans": [], "ref_spans": [{"start": 471, "end": 478, "text": "Table 1", "ref_id": "TABREF0"}]}, {"section": "Two Dimensional Supersonic Flow over a Horizontal Flat Plate", "text": "Following the initialization, the simulation is allowed to progress in an unsteady fashion until a steady solution is reached, after which samples are taken to eliminate statistical scatter. Figure 2a shows the resulting contours of temperature for Case III. The results show that the GPU code can reproduce the data simulated by the serial (CPU) code with allowances for statistical scatter. Figure 2b shows the speedup obtained using GPU as compared to using a single core of the Intel Xeon X5472 CPU for each case. We demonstrate a decrease in computational time of 3~10 times when the GPU device specified is employed for the simulation. Table 2 summarizes the computational time and speedup of each component of all cases using both CPU and GPU. We observe that the speedup using GPU computing increases with reduced rarefaction of the flow. This is also justified since (i) application of a GPU device requires significant overhead due to data transfer and device initialization, and (ii) the general ratio of memory bound communications to device computations is reduced for larger flow problems, resulting in more time spent in computation than in communication. In the current implementation, the sampling phase of the simulation performs best due to the ideal parallelization using the device shared memory. ", "cite_spans": [], "ref_spans": [{"start": 191, "end": 200, "text": "Figure 2a", "ref_id": "FIGREF0"}, {"start": 393, "end": 402, "text": "Figure 2b", "ref_id": "FIGREF0"}, {"start": 642, "end": 649, "text": "Table 2", "ref_id": "TABREF1"}]}, {"section": "Two Dimensional Supersonic Lid-driven Cavity Problem", "text": "The second test case is a two-dimensional supersonic lid driven cavity problem. Here the simulation domain is a square cavity (1x1m) with diffusely reflecting walls of fixed temperature (300K). All walls are stationary except the upper wall which is moving (with positive velocity) at Mach Number M = 2. The gas (ideal argon, \u03b3=5/3) is initially at rest with a temperature of 300 K and various density depending on the governing Knudsen number, computed with a characteristic length equal to the box width. These initial conditions are summarized in Table 3 .", "cite_spans": [], "ref_spans": []}, {"section": "Two Dimensional Supersonic Lid-driven Cavity Problem", "text": "Following initialization, the simulation is progressed in time until the flow is steady and samples are taken to reduce the statistical scatter. Figure 3a show the temperature contour of Case II. It is worth noting that the region in the central region of the lid-driven cavity is rarefied, with a low density and relatively high temperature (as also shown in Figure 3 ). The GPU results are almost identical to the equivalent CPU results which again validate the CUDA GPU implementation. Differences between the results are (probably) able to be explained by differences between the random numbers employed by the GPU and CPU solvers and general levels of statistical scatter. The random numbers employed by the GPU DSMC implementation are drawn from pre-computed (fixed-length) arrays to improve the efficiency of random number use on the GPU device. Figure 3b shows the speedup using GPU is about 3~9 times as compared to that using a single core of the CPU described above. All computational timings are summarized in the Table 4 for reference. The ratio of communication to computation, a critical factor in GPU efficiency, is minimal for larger DSMC problems. Hence, the speedup using GPU computing is shown to increase with reducing rarefaction of the flow (i.e. increasing collision dominance). The sampling phase of the DSMC simulation is shown to be the most efficient phase of the computation when applied to GPU computation due to the low number of communications required. ", "cite_spans": [], "ref_spans": [{"start": 145, "end": 154, "text": "Figure 3a", "ref_id": "FIGREF1"}, {"start": 360, "end": 368, "text": "Figure 3", "ref_id": "FIGREF1"}, {"start": 853, "end": 862, "text": "Figure 3b", "ref_id": "FIGREF1"}, {"start": 1026, "end": 1033, "text": "Table 4", "ref_id": "TABREF2"}]}, {"section": "CONCLUSION", "text": "Presented here is the application of DSMC to a novel (entire-device based) GPU acceleration. In the implementation discussed, the CPU is only employed during the initialization and concluding phases of the simulation -the main processes employed during the DSMC simulation are performed on the GPU device while the CPU remains idle. The resulting computations demonstrate a speedup of 3~10 times, depending on problem size, resulting from the lack of communication-bound processes. Efficient use of various memory (caches) on the GPU device for different phases of the DSMC simulation also allow high levels of parallelization. The GPU-DSMC code has been verified through comparison against a conventional serial DSMC computation, with results showing excellent comparison in a fraction of the time. The GPU device used for the benchmark problems (Nvidia Tesla C1060) is commonly available for a fraction of the price associated with a conventional computer cluster required to match its performance.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Molecular Gas Dynamics and the Direct Simulation of Gas Flows", "authors": [{"first": "G", "middle": ["A"], "last": "Bird", "suffix": ""}], "year": 1994, "venue": "", "link": "92471512"}, "BIBREF3": {"title": "CUDA Programming Guide Version 2.3.1", "authors": [{"first": "", "middle": [], "last": "Nvidia Inc", "suffix": ""}], "year": 2009, "venue": "", "link": null}}, "ref_entries": {"FIGREF0": {"text": "FIGURE 2. Contour of temperature of Case III (left a) and speedup ratio (right b) of each cases for the supersonic horizontal flat plate problem.", "type": "figure"}, "FIGREF1": {"text": "FIGURE 3. Contour of temperature of Case II [left] and speedup ratio [right] of each cases for the driven cavity problem.", "type": "figure"}, "TABREF0": {"text": "Simulation conditions for the Supersonic flow over a horizontal flat plate benchmark.", "type": "table"}, "TABREF1": {"text": "Computational time (unit: second) and speedup ratio using a single CPU (Intel Xeon X5472) and single-GPU device (Nvidia Tesla C1060) for the supersonic horizontal flat plate problem.", "type": "table"}, "TABREF2": {"text": "Computational time (unit: second) and speedup using CPU of Intel (Xeon X5472) and single-GPU of NVIDIA (Tesla C1060) for the driven cavity problem.", "type": "table"}}}
{"paper_id": "17780374", "_pdf_hash": "7493903eb252829fe550d18495f7e70488f95d8d", "abstract": [{"section": "Abstract", "text": "Comparing the gravitational acceleration induced on the Local Group by optical (SSRS2; da Costa et al 1994 and IRAS (1.2 Jy; Fisher et al 1995 and 0.6 Jy -QDOT; RowanRobinson et al 1990) galaxies we estimate, within the framework of linear theory, their relative bias factor. Using both IRAS samples we find b OI \u2248 1.14 \u2212 1.2, slightly lower than in Willmer, Da Costa & Pellegrini (1998) who use a \u03be(r) approach.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Using linear perturbation theory one can relate the gravitational acceleration induced on the observer by the surrounding mass distribution to her/his peculiar velocity:", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "where", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "is the luminosity function of the objects under study and L min (r) = 4\u03c0r 2 S lim , with S lim being the flux limit of the sample under study.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Different classes of extragalactic objects (QSOs, AGNs, galaxies, clusters of galaxies) trace differently the underlying matter distribution, usually assumed to be linearly related via Kaiser 1984) . Although this complicates the use of dipole as an estimator of the cosmological density parameter, \u2126 \u2022 , it does allow one in principle to study the relative bias displayed by such objects (Kolokotronis et al 1996; Plionis 1995).", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Using different tracers, ie. SSRS2 optical and IRAS galaxies, to determine the Local Group acceleration (dipole) we can write: u(r) = \u2126 0.6", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "\u2022 D I (r)/b I and therefore we can obtain an estimate of their relative bias factor from:", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "A statistically more reliable approach is to use the differential dipole, estimated in equal volume shells, to fit b OI according to:", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "where C is the zero-point offset of the relation and \u03c3 are the corresponding shot-noise errors estimated according to Strauss et al. (1992) .", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "In the figure and in table 1 we present the results of both methods used to estimate the optical (SSRS2) to infrared (IRAS 1.2 Jy and QDOT) bias factors. We construct the X-ray luminosity (LF) for different classes of galaxies (Seyferts, ellipticals, star-forming galaxies and Liners), by convolving the optical LF of the Ho et al.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "spectroscopic sample of nearby galaxies with the corresponding L x /L o relations from the Fabbiano et al. X-ray atlas of galaxies. From the derived LF we can easily assess the contribution of galaxies to the X-ray background. The Seyferts and Liners make the largest contribution (\u223c 40%) assuming no evolution while the contribution of star-forming galaxies is much smaller (\u223c 5%).", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "We have used the spectroscopic sample of nearby galaxies (B<12.5) of Ho et al. (1995) . The great advantage of this sample is that there is excellent spectroscopic infomation (high signalto-noise, medium resolution) available and thus bona-fide spectroscopic identifications exist for all (\u223c 500) galaxies in the sample. Hence, we can construct the X-ray LF separately for Seyferts, star-forming galaxies (HII), ellipticals and Liners instead of simply dividing them to early-type and late-type according to their morphology. The majority of galaxies in the Ho et al. sample are HII (50%), Liners are (30%), Seyferts (13%) while 15% of galaxies present no emission lines and thus can be classified as 'early-type' galaxies or 'ellipticals'on the basis of their spectra rather than their morphology (Ho et al. 1997) . We first derive the optical LF for different classes of objects (Seyferts, HII, Liners and no-emission-line or early-type galaxies) using the classical 1/V max method. ", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "", "text": "Different classes of extragalactic objects (QSOs, AGNs, galaxies, clusters of galaxies) trace differently the underlying matter distribution, usually assumed to be linearly related via (\u03b4\u03c1/\u03c1) tracer = b tracer,m (\u03b4\u03c1/\u03c1) mass (cf. Kaiser 1984) . Although this complicates the use of dipole as an estimator of the cosmological density parameter, \u2126 \u2022 , it does allow one in principle to study the relative bias displayed by such objects (Kolokotronis et al 1996; Plionis 1995).", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Using different tracers, ie. SSRS2 optical and IRAS galaxies, to determine the Local Group acceleration (dipole) we can write: u(r) = \u2126 0.6", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "\u2022 D I (r)/b I and therefore we can obtain an estimate of their relative bias factor from:", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "A statistically more reliable approach is to use the differential dipole, estimated in equal volume shells, to fit b OI according to:", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "where C is the zero-point offset of the relation and \u03c3 are the corresponding shot-noise errors estimated according to Strauss et al. (1992) .", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "In the figure and in table 1 we present the results of both methods used to estimate the optical (SSRS2) to infrared (IRAS 1.2 Jy and QDOT) bias factors. We construct the X-ray luminosity (LF) for different classes of galaxies (Seyferts, ellipticals, star-forming galaxies and Liners), by convolving the optical LF of the Ho et al.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "spectroscopic sample of nearby galaxies with the corresponding L x /L o relations from the Fabbiano et al. X-ray atlas of galaxies. From the derived LF we can easily assess the contribution of galaxies to the X-ray background. The Seyferts and Liners make the largest contribution (\u223c 40%) assuming no evolution while the contribution of star-forming galaxies is much smaller (\u223c 5%).", "cite_spans": [], "ref_spans": []}, {"section": "The Sample & Method", "text": "We have used the spectroscopic sample of nearby galaxies (B<12.5) of Ho et al. (1995) . The great advantage of this sample is that there is excellent spectroscopic infomation (high signalto-noise, medium resolution) available and thus bona-fide spectroscopic identifications exist for all (\u223c 500) galaxies in the sample. Hence, we can construct the X-ray LF separately for Seyferts, star-forming galaxies (HII), ellipticals and Liners instead of simply dividing them to early-type and late-type according to their morphology. The majority of galaxies in the Ho et al. sample are HII (50%), Liners are (30%), Seyferts (13%) while 15% of galaxies present no emission lines and thus can be classified as 'early-type' galaxies or 'ellipticals'on the basis of their spectra rather than their morphology (Ho et al. 1997) . We first derive the optical LF for different classes of objects (Seyferts, HII, Liners and no-emission-line or early-type galaxies) using the classical 1/V max method. ", "cite_spans": [], "ref_spans": []}, {"section": "The Sample & Method", "text": "is the conditional probability function and can be expressed as a Gaussian around the mean L x value for a given L B (we use H o = 100 throughout).", "cite_spans": [], "ref_spans": []}, {"section": "The Sample & Method", "text": "Although, our method provides only an indirect way of deriving the X-ray LF, it is currently the only feasible method at least for some classes of galaxies. Unfortunately, the galaxies in X-rays are faint (apart from Seyferts) and thus we cannot yet obtain large X-ray selected galaxy samples neither in deep X-ray surveys nor in the ROSAT all-sky survey. The X-ray LF is plotted on Fig. 2 . It is clear that although the HII galaxies are the most numerous, due to their low L * they contribute much less X-ray luminosity per h \u22123 Mpc 3 compared to Seyfert galaxies. Indeed, the HII emissivity is J \u223c 1 \u00d7 10 We estimate the dipole of the diffuse 1.5 keV X-ray background from the ROSAT all-sky survey map of Snowden et al (1995) . We first subtract the diffuse Galactic emission by fitting to the data a finite disk model, following Iwan et al (1982) . We further exclude regions of low galactic latitudes, of local X-ray emission (eg the North Polar Spur) and model them using two different methods. We find that the ROSAT X-ray background dipole points towards", "cite_spans": [], "ref_spans": [{"start": 383, "end": 389, "text": "Fig. 2", "ref_id": "FIGREF4"}]}, {"section": "The Sample & Method", "text": "\u2022 of the CMB; its direction is also in good agreement with the HEAO-1 X-ray dipole at harder energies. The normalised amplitude of the ROSAT XRB dipole is \u223c 1.6%.", "cite_spans": [], "ref_spans": []}, {"section": "Subtracting the Diffuse Galactic Emission", "text": "A major problem in extracting the X-ray background dipole at soft X-rays is the large contribution of our Galaxy at such energies (cf. Kneissl et al 1998) . We attempt to model the diffuse Galactic component using a finite radius disk with an exponential scale height, (Iwan et al. 1982 ) which provides a good description of the Galactic component at harder energies We obtain a fraction of the total X-ray emission which is due to the Galaxy consistent with \u223c 25% while the disk scale height and disk radius where found to be 16 & 27 kpc respectively.", "cite_spans": [], "ref_spans": []}, {"section": "Dipole Estimation", "text": "After excluding from the ROSAT counts our best fit Galactic model and after masking, using either of two methods; homogeneous filling procedure or a spherical harmonic extrapolation procedure, the following regions: ", "cite_spans": [], "ref_spans": []}, {"section": "Dipole Results", "text": "When using the raw ROSAT data, the dipole points towards the Galactic centre (in agreement with the analysis of Kneissl et al 1997). However, when we exclude both the Galaxy and the North Polar Spur, the measured dipole is in much better directional agreement with the CMB dipole. For the homogeneous filling method we find \u03b4\u03b8 cmb \u223c 20", "cite_spans": [], "ref_spans": []}, {"section": "Dipole Results", "text": "\u2022 while for the spherical harmonic method the misalignment angle is larger, \u03b4\u03b8 cmb \u223c 51", "cite_spans": [], "ref_spans": []}, {"section": "Dipole Results", "text": "\u2022 .", "cite_spans": [], "ref_spans": []}, {"section": "Dipole Results", "text": "However, it should be expected that many Galactic sources, probably dominating the higher ROSAT counts, are still present in the data and could affect the behaviour of the estimated extragalactic XRB dipole. Excluding the highest \u223c 3% of the counts (C up\u223c > 140) we find that both methods used to model the masked areas agree and the XRB-CMB dipole misalignment angle is reduced significantly", "cite_spans": [], "ref_spans": []}, {"section": "Dipole Results", "text": "The interpretation that the high intensity cells are associated with Galactic sources is supported by the fact that when we include these few cells the resulting dipole direction moves towards the Galactic centre.", "cite_spans": [], "ref_spans": []}, {"section": "Dipole Results", "text": "Therefore, taking into account the variations of our results due to (a) the uncertainties of the Galactic model subtracted from the raw counts, (b) to the different methods used to mask the excluded sky regions and (c) to the different galactic latitude limits, we conclude that the extragalactic ROSAT dipole has: Assuming that this sample is dominated by QSO's we find that the characteristic depth of the sample is \u223c 410 h \u22121 Mpc. We find a significant angular correlation function, between \u223c 2", "cite_spans": [], "ref_spans": []}, {"section": "Dipole Results", "text": "\u2022 and 15", "cite_spans": [], "ref_spans": []}, {"section": "Dipole Results", "text": "\u2022 which roughly corresponds to a spatial correlation length of r \u2022 \u2243 15.5 \u00b1 4.5 h", "cite_spans": [], "ref_spans": []}, {"section": "Dipole Results", "text": "Mpc, roughly consistent with that of optically selected QSO's at z \u2243 1.5.", "cite_spans": [], "ref_spans": []}, {"section": "Method", "text": "The original RASS sample contains 18811 sources which include stars and extragalactic sources over the entire 0.1 -2 keV energy range. To exclude the stellar objects we cross We are at the process of quantifying biases related to the above methods and applying our shape determination procedure to the real APM data.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF5": {"title": "Proc. of the Moriond Astrophysics Meeting on Clustering in the Universe, Editions Frontieres", "authors": [{"first": "M", "middle": [], "last": "Plionis", "suffix": ""}], "year": 1995, "venue": "", "link": null}, "BIBREF23": {"title": "Atlas of Galactic Neutral Hydrogen", "authors": [{"first": "D", "middle": ["B"], "last": "Hartmann &amp; W", "suffix": ""}, {"first": "", "middle": [], "last": "Burton", "suffix": ""}], "year": 1997, "venue": "", "link": "120290958"}}, "ref_entries": {"FIGREF0": {"text": "min (r) \u03a6(L) dL, where \u03a6(L) is the luminosity function of the objects under study and L min (r) = 4\u03c0r 2 S lim , with S lim being the flux limit of the sample under study.", "type": "figure"}, "FIGREF1": {"text": "Next, we derive the L x /L B relation for the different subclasses using the EINSTEIN X-ray fluxes (0.5-4.0 keV) from the Fabbiano et al. (1992) X-ray atlas of galaxies. There are 164 entries (95 detections and 69 3\u03c3 upper limits) of Ho et al. galaxies in the Fabbiano atlas. Finally, in order to derive the X-ray LF we convolve the optical LF with the L x /L B relation:", "type": "figure"}, "FIGREF2": {"text": "For example we note that there are only 5 HII galaxies from the Ho et al. sample detected by the RASS (Zezas et al. 1998). The Results In the figure we plot the X-ray luminosities vs. the Blue luminosities (log 10 (L x ) vs log 10 (L B )), for different subclasses (open symbols represent upper limits while filled symbols represent detections; the color coding is as in the table).", "type": "figure"}, "FIGREF3": {"text": "The total galaxy emissivity is comparable to the emissivity of local galaxies in the 2-10 keV band derived by Lahav et al. (1993) from the cross-correlation of optical galaxy catalogues with the fluctuations of the hard X", "type": "figure"}, "FIGREF4": {"text": "60 keV). The fit to the model is performed by excluding the regions of the most apparent extended Galactic emission features: the North Polar Spur and the |b| < 20 \u2022 strip as well as most apparent \"local\" extragalactic features; a 4 \u2022 radius region around the Virgo cluster (l, b \u2248 287 \u2022 , 75 \u2022 ) and a 10 \u2022 radius region around the Magellanic clouds (l, b \u2248 278 \u2022 , \u221232 \u2022 ).", "type": "figure"}, "FIGREF5": {"text": "(a) The Galactic plane, with |b| \u2264 20 \u2022 or 30 \u2022 , (b) the area dominated by the Galactic bulge and the North Polar Spur (ie., \u221240 \u2022 < b < 75 \u2022 and 300 \u2022 < l < 30 \u2022 ) , (c) the Large Maggelanic Clouds (ie., an area of 10 \u2022 radius centred on l, b \u2248 278 \u2022 , \u221232 \u2022 ), we measure the dipole by weighing the unit directional vector pointing to each 40 2 arcmin 2 ROSAT cell with the X-ray intensity C i of that cell. We normalize the dipole by the monopole term (the mean X-ray intensity over the sky): D \u2261 |D|/M = C iri / C i", "type": "figure"}, "FIGREF6": {"text": "Our results are consistent with the HEAO-1 (2-10 keV) dipole (Shafer & Fabian 1983) which points in a similar direction (282 \u2022 , 30 \u2022 ) but has a lower amplitude: D XRB,HEAO\u22121 \u223c 0.005. The Angular Correlation Function of RASS Extragalactic Sources T. Akylas, M. Plionis & I. Georgantopoulos Astronomical Institute, National Observatory of Athens, I.Metaxa & Bas.Pavlou, Lofos Koufou, 15236, Athens, Greece We investigate the clustering properties of a new homogeneous sample of 2000 extra- galactic sources selected from the ROSAT XRT/PSPC All-Sky survey (Voges et al 1996).", "type": "figure"}, "FIGREF7": {"text": "correlated this sample with star catalogs (SAO, GSC, RASSOB, RASSWD, XRBCAT and CVCAT). Furthermore, we have cross-correlated the remaining sources (for b > 0 \u2022 ) with the Hamburg identifications (Bade et al 1998) to find that most of them, after excluding those with extension flag > 40, are identified as QSO's. In order to produce a homogeneous sample in exposure time we have omitted sources with count rate < 0.1 which results in a homogeneous sample over 92% of the sky. Finally, we exclude regions heavily affected by Galactic absorption, ie., |b| < 30 \u2022 as well as \u03b4 < \u221230 \u2022 (see below). Our final catalogue contains 2000 extragalactic sources. We further need to estimate the various selection functions that could affect the clustering properties of our survey. For example the significant absorption due to the diffuse Galactic Neutral Hydrogen could artificially enhance the 2-point correlation function and also intro- duce large-scale modulations. Therefore, we have cross correlated our RASS catalogue with the recent Leiden/Dwingeloo Atlas of Galactic Neutral Hydrogen (Hartmann & Burton 1997) which covers regions with \u03b4 \u2265 \u221230 \u2022 , to derive the RASS surface density as a function of N H , which is used to produce a random catalogue with similar absorption selection function. Results The correlation function estimator we use is: w(\u03b8) = f N dd /N dr \u2212 1, where the normalization factor is f = 2 \u00d7 N r /N o . Assuming a 2-p correlation function of the form w(\u03b8) = (\u03b8/\u03b8 \u2022 ) b we find b = \u22120.9 \u00b1 0.15 and \u03b8 \u2022 = 0.08 \u2022 \u00b1 0.05 \u2022 . A preliminary calculation using the average flux limit (\u223c 10 \u221212 erg/sec cm 2 ) of the RASS over the area used and a QSO characteristic luminosity of L * \u2243 2 \u00d7 10 43 (Boyle et al 1993) gives a characteristic depth of D * \u223c 410 h \u22121 Mpc. Using Limber's equation to relate the angular and spatial 2-point correlation function with \u03b3 \u2243 2 we find a correlation length of r \u2022 \u2243 15.5\u00b14.5 h \u22121 Mpc, which is compatible only with comoving QSO clustering (cf. Shanks & Boyle 1994 and La Franca et al 1998 which find r \u2022 \u2243 10 \u00b1 2.5 h \u22121 Mpc at z \u2243 1.5 \u2212 1.Astronomical Institute, National Observatory of Athens, I.Metaxa & Bas.Pavlou, Lofos Koufou, 15236, Athens, Greece 2 Section of Astronomy & Astrophysics, Univ. of Athens, Panepistimioupolis, 15784 Zografos, Athens, Greece 3 Institute of Astronomy, Madingley Road, Cambridge, CB3 0EZ, UK We study the performance of two different methods used to define cluster shapes with final aim to study the projected and intrinsic shapes of APM clusters (Dalton et al 1997). The 1 st method defines the cluster ellipticity by fitting ellipses to the individual galaxy distribution as a function of radius from the cluster centre. The 2 nd method is based on smoothing the discrete galaxy distribution and then fits an ellipse using all cells that fall above an overdensity threshold. This latter method is free of the known aperture bias which tends to artificially sphericalize clusters. Using Monte-Carlo simulations we have studied the performance of both methods in the presence of the expected galaxy background at the different distances traced by the APM clusters. The Method In order to estimate the projected cluster shape we diagonalize the inertia tensor (det(I ij \u2212 \u03bb 2 M 2 ) = 0) where M 2 is the 2 \u00d7 2 unit matrix. The eigenvalues (a, b) with (a > b) define the ellipticity of the configuration under study: \u03b5 = 1 \u2212 b/a (cf. Plionis, Barrow & Frenk 1991). Initially all galaxy positions are transformed to the coordinate system of each cluster by : x i = (RA g \u2212 RA cl ) \u00d7 cos(\u03b4 cl ) and y i = \u03b4 g \u2212 \u03b4 cl . Then we use the following procedures: 1 st Method: All galaxies within an initial small radius are used to define the initial value of the cluster shape parameters. Then the next nearest galaxy is added to the initial group and the shape is recalculated. This method, although straight forward, suffers from the fact that implicitly we are assuming a spherical aperture within which the cluster shape parameters are estimated (cf. Binggeli 1982). with weight w i = \u03c1 i \u2212 \u03c1(z) / \u03c1(z) where \u03c1(z) = Mmax M min (z) \u03a6(M)dM with \u03a6(M) the APM luminosity function (with z evolution) from Maddox, Efstathiou & Sutherland (1996) and M min (z) = m lim \u2212 5 log(r) \u2212 25 \u2212 3z. This method is free of the aperture bias and we found that it performs significantly better than the previous method. Background Contamination A major problem in reliably determining cluster shapes is the significant galaxy background which contaminates the cluster galaxy counts, especially in deep galaxy catalogues like the APM which has m lim = 20.5. In order to assess the effects of such contamination on the determination of cluster shapes we have performed large sets of Monte-Carlo simulations in which we compared the determination of cluster shapes, defined to have the King's profile with core radii \u2264 0.1 h \u22121 Mpc (cf. Girardi et al 1998), with and without the expected background contamination. The background at each cluster distance was estimated by:i is the ancular radius of the cluster. In the figure we show an example of a simulated cluster at 200 h \u22121 Mpc with \u03b5 = 0.5. The performance of the two methods, described above, is shown in the same colour coding as in the text. It is evident that the 2 nd method performs equally well in the presence or not of the galaxy background. However, the presence of substructure can affect unexpectedly the performance of this method as well.", "type": "figure"}, "TABREF0": {"text": "Optical to Infrared galaxy bias factors from differential dipole fit.", "type": "table"}, "TABREF1": {"text": "", "type": "table"}}}
{"paper_id": "17780413", "_pdf_hash": "40d82c5efc7c79961df232dc49df3137f66832fc", "abstract": [{"section": "Abstract", "text": "Abstract. We study a nonlinear parabolic system governing the biological dynamic in the soil. We prove global existence (in time) and uniqueness of weak and positive solutions for this reaction-diffusion semilinear system in a bounded domain, completed with homogeneous Neumann boundary conditions and positive initial conditions.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Biological dynamic in the soil is modeled by reaction-diffusion equations. The model we consider here take into account six pools of biological elements: micro-organisms (FM), dissolved organic matter (DOM), fresh organic matter (FOM), soil organic matter (SOM), enzymes (ENZ) and inorganic carbon (C02).", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "To our knowledge it is the first time that diffusion is used to model biological dynamics and linking it to real soil structure described by a 3D computed tomography image, see [4] .", "cite_spans": [{"start": 177, "end": 180, "text": "[4]", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "Introduction", "text": "Let T > 0 be a fixed time, The set of equations describing the organic matter cycle of decomposition in the soil is given by the following system: Where u = (u 1 , u 2 , ..., u 6 ) T with u 1 : density of micro-organisms (FM), u 2 : density of DOM, u 3 : density of SOM, u 4 : density of FOM, u 5 : density of enzymes and u 6 : density of CO2, q 1 (u) = \u2212 k u 2 K s + u 2 + \u00b5 + r + \u03bd, q 2 (u) = k u 1 K s + u 2 , q 3 (u) = c 1 u 5 K m + u 5 , q 4 (u) = c 2 u 5 K m + u 5 , q 5 (u) = \u03b6, q 6 (u) = 0, f 1 (u) = 0, f 2 (u) = u 5 K m + u 5 (c 1 u 3 + c 2 u 4 ) + \u03b6u 5 + \u00b5u 1 2 , f 3 (u) = \u03b6u 5 + \u00b5u 1 2 , f 4 (u) = 0, f 5 (u) = \u03bdu 1 , f 6 (u) = ru 1 , with \u00b5 mortality rate, r breathing rate, \u03bd enzymes production rate, \u03b6 transformation rate of deteriorated enzymes, c 1 maximal tranformation rate of SOM, c 2 maximal transformation rate of FOM, k maximal growth rate, K m and K s represent half-saturation constants and D i , i = 1 to 6, are strictly positive constants.", "cite_spans": [{"start": 273, "end": 274, "text": "4", "ref_id": "BIBREF3"}, {"start": 295, "end": 296, "text": "5", "ref_id": "BIBREF4"}, {"start": 324, "end": 325, "text": "6", "ref_id": "BIBREF5"}, {"start": 370, "end": 371, "text": "2", "ref_id": "BIBREF1"}, {"start": 409, "end": 410, "text": "2", "ref_id": "BIBREF1"}, {"start": 439, "end": 440, "text": "5", "ref_id": "BIBREF4"}, {"start": 469, "end": 470, "text": "5", "ref_id": "BIBREF4"}, {"start": 534, "end": 535, "text": "5", "ref_id": "BIBREF4"}, {"start": 562, "end": 563, "text": "5", "ref_id": "BIBREF4"}, {"start": 569, "end": 570, "text": "1", "ref_id": "BIBREF0"}, {"start": 588, "end": 589, "text": "5", "ref_id": "BIBREF4"}, {"start": 633, "end": 634, "text": "6", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Introduction", "text": "System (1) operates in other situations. It comes in population dynamics as LotkaVoltera equation which corresponds to the case f = 0, u i denoting the densities of species present and q i growth rate. This system is also involved in biochemical reactions. In this case, the u i are the concentrations of various molecules, q i is the rate of loss and f i represents the gains.", "cite_spans": [{"start": 7, "end": 10, "text": "(1)", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "Introduction", "text": "For models in biology, interested reader can consult with profit [6] where the author present some models based on partial differential equations and originating from various questions in population biology, such as physiologically structured equations, adaptative dynamics and bacterial movement. He describes original mathematical methods like the generalized relative entropy method, the description of Dirac concentration effects using a new type of Hamilton-Jacobi equations, and a general point of view on chemotaxis including various scales of description leading to kinetic, parabolic or hyperbolic equations.", "cite_spans": [{"start": 65, "end": 68, "text": "[6]", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Introduction", "text": "Theoretical study of semi-linear equations is widely investigated. Some interesting mathematical difficulties arise with these equations because of explosion in finite time, non-existence and uniqueness of solution, singularity of the solutions and non-continuity of the solution regarding data.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "In [1] , they prove the explosion in finite time for the system in 1D:", "cite_spans": [{"start": 3, "end": 6, "text": "[1]", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "Introduction", "text": "A sufficient condition for the explosion of the solution of parabolic semi-linear second order equation is obtained in [2] with nonlinear boundary conditions, so the set in which the explosion takes place. He also gives a sufficient condition for the solution of this equation tends to zero, and its asymptotic behavior.", "cite_spans": [{"start": 119, "end": 122, "text": "[2]", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Introduction", "text": "Existence and uniqueness of weak solutions for the following system are considered in [5] ,", "cite_spans": [{"start": 86, "end": 89, "text": "[5]", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "Introduction", "text": "and", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "with obstacles, giving a probabilistic interpretation of solution. This problem is solved using a probabilistic method under monotony assumptions.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "By using bifurcation theory, in [8] , authors determine the overall behavior of the dynamic System:", "cite_spans": [{"start": 32, "end": 35, "text": "[8]", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "Introduction", "text": "A Cauchy problem for parabolic semilinear equations with initial data in H s p (IR n ) is studied in [7] . Particularly the author solves local existence using distributions data.", "cite_spans": [{"start": 101, "end": 104, "text": "[7]", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "Introduction", "text": "The aim of this paper is to study the global in time existence of solutions to system (1). In our work, we use an approach based both on variational method and semi-groups method to demonstrate existence and uniqueness of weak solution for system (1).", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "The work is organized as follows: In a first part, we recall some preliminary results concerning variational method and semi-groups techniques. In the second part, we prove, using these methods, existence, uniqueness and positivity of weak solution under assumptions of positive initial conditions.", "cite_spans": [], "ref_spans": []}, {"section": "Preliminary results", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Variational method (see [3])", "text": "We consider two Hilbert spaces H and V such that V is embedded continuously and densely in H. Then we have by duality H \u2192 V . Using Riesz theorem, we identify H and H . So we get V \u2192 H \u2192 V .", "cite_spans": [], "ref_spans": []}, {"section": "Variational method (see [3])", "text": "which makes it a Hilbert space.", "cite_spans": [], "ref_spans": []}, {"section": "Variational method (see [3])", "text": "We assume the two following lemmas, see [3] .", "cite_spans": [{"start": 40, "end": 43, "text": "[3]", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "Lemma 2. There exists a continuous prolongation operator", "text": "P from W (0, T, V, V ) to W (\u2212\u221e, +\u221e, V, V ) such that P u |]0,T [ = u, \u2200u \u2208 W (0, T, V, V ). Lemma 3. D(IR, V ) is dense in W (\u2212\u221e, +\u221e, V, V ). Corollary 4. C \u221e ([0, T ], V ) is dense in W (0, T, V, V ). Proof If u \u2208 W (0, T, V, V ), one takes a sequence u n of D(IR, V ) which converges in W (\u2212\u221e, +\u221e, V, V ) toward P u and then (u n ) |]0,T [ converges toward u and (u n ) |]0,T [ \u2208 C \u221e ([0, T ], V ), \u2200n \u2208 IN. Proposition 5. Every element u \u2208 W (0, T, V, V ) is almost everywhere equal to a conti- nuous function from ]0, T [ to H.", "cite_spans": [], "ref_spans": []}, {"section": "Furthermore the injection of", "text": "Proof See [3] .", "cite_spans": [{"start": 10, "end": 13, "text": "[3]", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "Application.", "text": "For all t \u2208 [0, T ], a bilinear form (u, v) \u2192 a(t; u, v) is given on V \u00d7 V such that for u and v fixed, t \u2192 a(t; u, v) is measurable and it exists M > 0 such that", "cite_spans": [], "ref_spans": []}, {"section": "Application.", "text": "For each fixed t, one defines a continuous linear application from V into V by", "cite_spans": [], "ref_spans": []}, {"section": "< A(t)u, v >= a(t; u, v).", "text": "Also we associate, for all fixed t, an unbounded operator in H whose domain is the set of u \u2208 V such that v \u2192 a(t; u, v) is continuous on V for the induced norm by H. It's exactly the set of u \u2208 V such that A(t)u \u2208 H and then", "cite_spans": [], "ref_spans": []}, {"section": "The unbounded operator is noted A H (t) or A(t).", "text": "where the bracket is the duality between V and", "cite_spans": [], "ref_spans": []}, {"section": "The unbounded operator is noted A H (t) or A(t).", "text": "The variational parabolic problem associated to the triple (H, V, a(t; ., .)) is the following:", "cite_spans": [], "ref_spans": []}, {"section": "The unbounded operator is noted A H (t) or A(t).", "text": "This problem is equivalent to:", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 7. If the form is coercive then the problem (2) admits a unique solution.", "text": "Proof See Dautray-Lions [3] .", "cite_spans": [{"start": 24, "end": 27, "text": "[3]", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "Definition 8. The form is H coercive if there exist two constants \u03bb and \u03b1 with", "text": "We set u(t) = e \u03bbt w(t), so that u is solution of (2) if and only if w is solution of", "cite_spans": [], "ref_spans": []}, {"section": "Definition 8. The form is H coercive if there exist two constants \u03bb and \u03b1 with", "text": "b is a coercive form and then (3) admits a unique solution, and therefore (2) too. We apply Theorem 7 in the following case:", "cite_spans": [], "ref_spans": []}, {"section": "Definition 8. The form is H coercive if there exist two constants \u03bb and \u03b1 with", "text": "and defining", "cite_spans": [], "ref_spans": []}, {"section": "Definition 8. The form is H coercive if there exist two constants \u03bb and \u03b1 with", "text": "we assume", "cite_spans": [], "ref_spans": []}, {"section": "Definition 8. The form is H coercive if there exist two constants \u03bb and \u03b1 with", "text": "and there exists \u03b1 > 0 such that", "cite_spans": [], "ref_spans": []}, {"section": "Definition 8. The form is H coercive if there exist two constants \u03bb and \u03b1 with", "text": "Then, we deduce that", "cite_spans": [], "ref_spans": []}, {"section": "Definition 8. The form is H coercive if there exist two constants \u03bb and \u03b1 with", "text": "The form is then H coercive, it suffices to take \u03bb = \u03b1.", "cite_spans": [], "ref_spans": []}, {"section": "Definition 8. The form is H coercive if there exist two constants \u03bb and \u03b1 with", "text": "is still H coercive. We have the theorem: Theorem 9. Under the previous hypothesis, problem (2) ", "cite_spans": [{"start": 92, "end": 95, "text": "(2)", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "associated to the triple (H, V, b) admits a unique solution for all", "text": "Proof It remains to show that the solution is non negative.", "cite_spans": [], "ref_spans": []}, {"section": "associated to the triple (H, V, b) admits a unique solution for all", "text": "Given u \u2208 L", "cite_spans": [], "ref_spans": []}, {"section": "2", "text": "(\u2126), we set u", "cite_spans": [], "ref_spans": []}, {"section": "2", "text": "and by linearity we obtain", "cite_spans": [], "ref_spans": []}, {"section": "2", "text": "By integration, we have", "cite_spans": [], "ref_spans": []}, {"section": "2", "text": "Instead of a 0 (t, x) \u2265 0, assume that it exists a constant C > 0 such that a 0 (t, x) \u2265 \u2212C for all t, x.", "cite_spans": [], "ref_spans": []}, {"section": "2", "text": "As previously, if we set", "cite_spans": [], "ref_spans": []}, {"section": "2", "text": "It suffices to take \u03bb \u2265 C to reduce to the previous case and", "cite_spans": [], "ref_spans": []}, {"section": "2", "text": "Then, we get ", "cite_spans": [], "ref_spans": []}, {"section": "Equivalence of the variational solution with the initial problem", "text": "The boundary of", "cite_spans": [], "ref_spans": []}, {"section": "Equivalence of the variational solution with the initial problem", "text": "For the sake of simplicity we set a ij = 0 if i = j and a ii = 1 for all i. ", "cite_spans": [], "ref_spans": []}, {"section": "Equivalence of the variational solution with the initial problem", "text": "Using Green formula with (u, \u2212grad(u)) ", "cite_spans": [], "ref_spans": []}, {"section": "Semigroup method", "text": "Consider the variational triple (H, V, a) where a is independent of t. We associate operators A \u2208 L(V, V ) and", "cite_spans": [], "ref_spans": []}, {"section": "Semigroup method", "text": "Assume that a is H coercive. Then A H is the infinitesimal generator of semigroup", "cite_spans": [], "ref_spans": []}, {"section": "Semigroup method", "text": "over H and G(t) operates over V and V . If we note G(t) the extension of G(t) by 0 for t < 0 then the Laplace transform of G(t) is the resolvent of A H .", "cite_spans": [], "ref_spans": []}, {"section": "admits a unique solution given by", "text": "Proof Note\u0169 andf the extensions by 0 of u and f outside ]0, T [. Then we have", "cite_spans": [], "ref_spans": []}, {"section": "admits a unique solution given by", "text": "with \u03b4(t) the Dirac mesure on IR.", "cite_spans": [], "ref_spans": []}, {"section": "=f + u(0)\u03b4(t) \u2212 u(T )\u03b4(T \u2212 t).", "text": "Hence an equation of the form dU dt", "cite_spans": [], "ref_spans": []}, {"section": "By Laplace tranform, one is reduced to (A + P I)L(U ) = L(F ) where L(U ) = (A + P I)", "text": "\u22121 L(F ) and therefore U =G * F .", "cite_spans": [], "ref_spans": []}, {"section": "But since supp(\u03b4(T \u2212 t)) = T and supp G * (U (T )\u03b4(T \u2212 t)) \u2282 [T, +\u221e[ we have", "text": "Hence the result.", "cite_spans": [], "ref_spans": []}, {"section": "System (1) resolution with u 0 \u2265 0", "text": "In this part, we go back to system (1) with assumptions and shall analyze this problem by using the framework described in the previous section. In the following H = L 2 (\u2126) and", "cite_spans": [], "ref_spans": []}, {"section": "System (1) resolution with u 0 \u2265 0", "text": "We'll make a resolution component by component by applying Theorem 7 with for each i, the form", "cite_spans": [], "ref_spans": []}, {"section": "System (1) resolution with u 0 \u2265 0", "text": "One approaches the solution by a sequence of solutions of linear equations.", "cite_spans": [], "ref_spans": []}, {"section": "Recursive sequence of solutions", "text": "For n = 0, we note u ) and", "cite_spans": [], "ref_spans": []}, {"section": "Recursive sequence of solutions", "text": "). So 0 \u2264 q 3 (u ", "cite_spans": [], "ref_spans": []}, {"section": "Boundedness of the solution", "text": "Let us show that the sequence is bounded.", "cite_spans": [], "ref_spans": []}, {"section": "Boundedness of the solution", "text": "We want to take v = u n i (t). We note that", "cite_spans": [], "ref_spans": []}, {"section": "By density", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "< \u2202u", "text": "We have seen that we can obtain problem (3) replacing u(t) by w(t) = e \u2212\u03bbt u(t) and since 0 \u2264 t \u2264 T , if w is bounded, u is also bounded.", "cite_spans": [], "ref_spans": []}, {"section": "< \u2202u", "text": "We take then \u03bb = \u03b2 + \u03b4 and one is reduced to", "cite_spans": [], "ref_spans": []}, {"section": "< \u2202u", "text": "The form D i a is H coercive, so we take \u03b2 for", "cite_spans": [], "ref_spans": []}, {"section": "< \u2202u", "text": "The q i are bounded so we can take \u03b4 for \u03b4 + q i (u) \u2265 l, for all i, for all u \u2265 0, therefore", "cite_spans": [], "ref_spans": []}, {"section": "< \u2202u", "text": "We take for \u03b1 \u2212 2 = \u03b3 > 0.", "cite_spans": [], "ref_spans": []}, {"section": "< \u2202u", "text": "We deduce that (u ", "cite_spans": [], "ref_spans": []}, {"section": "Convergence of the sequence", "text": "We deduce at this stage that the sequence (u n i ), (one can extract subsequence (u", "cite_spans": [], "ref_spans": []}, {"section": "Convergence of the sequence", "text": "But it is not enough to pass to the limit in the equation, we need the ponctual convergence for almost all t to deduce that u i \u2265 0 for all i and to pass to the limit in", "cite_spans": [], "ref_spans": []}, {"section": "Convergence of the sequence", "text": "). To pass to the limit, we need strong compactness. Using Proposition 11, for all n we have", "cite_spans": [], "ref_spans": []}, {"section": "Convergence of the sequence", "text": "where G i (t) is the semigroup generated by the unbounded operator", "cite_spans": [], "ref_spans": []}, {"section": "Convergence of the sequence", "text": "One takes the triple (L", "cite_spans": [], "ref_spans": []}, {"section": "Convergence of the sequence", "text": "where \u2126 is regular and bounded. The unbounded variational operator A H associated to a is a positive symmetric operator with compact resolvent. ", "cite_spans": [], "ref_spans": []}, {"section": "Convergence of the sequence", "text": "Which proves that the operator is compact for all t > 0 because lim k\u2192+\u221e e \u2212t\u03bb k = 0.", "cite_spans": [], "ref_spans": []}, {"section": "Convergence of the sequence", "text": "We have the same formula for G i (t), it suffices to replace \u03bb k by", "cite_spans": [], "ref_spans": []}, {"section": "Convergence of the sequence", "text": "is an operator with finite rank which converges to G(t).", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 12. Let t \u2192 G(t) be an application from [0, \u221e[ into L(H). We assume that there exists a sequence of operators (G N (t)) N of H with the following properties: i) For all N and all", "text": "To show that G is compact, it suffices to show that for all N , G N is compact. Let B be a bounded set of C But G N (B)(t 0 ) being bounded and embedded in a subspace of finite dimension of H is relatively compact in H. Then, let us show the equicontinuity on t 0 .", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 12. Let t \u2192 G(t) be an application from [0, \u221e[ into L(H). We assume that there exists a sequence of operators (G N (t)) N of H with the following properties: i) For all N and all", "text": "Let M and C N such that", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 12. Let t \u2192 G(t) be an application from [0, \u221e[ into L(H). We assume that there exists a sequence of operators (G N (t)) N of H with the following properties: i) For all N and all", "text": "For 0 \u2264 t 0 \u2264 t \u2264 T one has:", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 12. Let t \u2192 G(t) be an application from [0, \u221e[ into L(H). We assume that there exists a sequence of operators (G N (t)) N of H with the following properties: i) For all N and all", "text": "We have", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 12. Let t \u2192 G(t) be an application from [0, \u221e[ into L(H). We assume that there exists a sequence of operators (G N (t)) N of H with the following properties: i) For all N and all", "text": "which tend to 0 when t \u2192 t 0 using ii) and the continuity under the integral.", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 12. Let t \u2192 G(t) be an application from [0, \u221e[ into L(H). We assume that there exists a sequence of operators (G N (t)) N of H with the following properties: i) For all N and all", "text": "We apply Theorem 12 to the semigroup generated by the Laplacien, we obtain:", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 12. Let t \u2192 G(t) be an application from [0, \u221e[ into L(H). We assume that there exists a sequence of operators (G N (t)) N of H with the following properties: i) For all N and all", "text": "if we take an increasing sequence (\u03bb k ). Then one gets", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 12. Let t \u2192 G(t) be an application from [0, \u221e[ into L(H). We assume that there exists a sequence of operators (G N (t)) N of H with the following properties: i) For all N and all", "text": "Thus G i is compact for all i. We have", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 12. Let t \u2192 G(t) be an application from [0, \u221e[ into L(H). We assume that there exists a sequence of operators (G N (t)) N of H with the following properties: i) For all N and all", "text": "where (g Moreover we can assume that u", "cite_spans": [], "ref_spans": []}, {"section": "Thus the sequence (", "text": "Remark that for all T < \u221e, we have:", "cite_spans": [], "ref_spans": []}, {"section": "Conclusion.", "text": "One has:", "cite_spans": [], "ref_spans": []}, {"section": "Conclusion.", "text": "The second term in the left side and the right side of the egality converge due to the weak convergence in L We deduce that \u2202u", "cite_spans": [], "ref_spans": []}, {"section": "Conclusion.", "text": "This being true for all \u03c6, we have", "cite_spans": [], "ref_spans": []}, {"section": "Conclusion.", "text": "that to say", "cite_spans": [], "ref_spans": []}, {"section": "Conclusion.", "text": "and ", "cite_spans": [], "ref_spans": []}, {"section": "Main result", "text": "Theorem 13. Let u 0 \u2208 H 6 , u 0i \u2265 0, then system (1) admits an unique solution u such that u i \u2265 0 and u i \u2208 W (0, T, V, V ) for all i.", "cite_spans": [], "ref_spans": []}, {"section": "Main result", "text": "Moreover for all i, u i satisfies relation (R).", "cite_spans": [], "ref_spans": []}, {"section": "Main result", "text": "Proof We have already shown existence of solution, thus it remains to show uniqueness. Let v be another solution of system (1)", "cite_spans": [], "ref_spans": []}, {"section": "Main result", "text": "Consequently", "cite_spans": [], "ref_spans": []}, {"section": "Main result", "text": "(]0, T [, V ), thus by Proposition 11, we have", "cite_spans": [], "ref_spans": []}, {"section": "Main result", "text": "By subtraction, we have ", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Numerical blow-up time for a semilinear parabolic equation with nonlinear boundary conditions", "authors": [{"first": "A", "middle": ["L"], "last": "Assal\u00e9", "suffix": ""}, {"first": "K", "middle": ["T"], "last": "Boni", "suffix": ""}, {"first": "D", "middle": [], "last": "Nabongo", "suffix": ""}], "year": 2008, "venue": "Journal of Applied Mathematics", "link": "2652776"}, "BIBREF1": {"title": "Sur l'explosion et le comportement asymptotique de la solution d'un\u00e9 equation parabolique semi-lin\u00e9aire du second ordre", "authors": [{"first": "T", "middle": ["K"], "last": "Boni", "suffix": ""}], "year": 1998, "venue": "Comptes Rendus de l'Acad\u00e9mie des Sciences", "link": null}, "BIBREF2": {"title": "Analyse math\u00e9matique et calcul num\u00e9rique pour les sciences et les techniques -vol", "authors": [{"first": "R", "middle": [], "last": "Dautray", "suffix": ""}, {"first": "J", "middle": ["L"], "last": "Lions", "suffix": ""}], "year": 1988, "venue": "", "link": null}, "BIBREF3": {"title": "Simulating biological dynamics using partial differential equations: application to decomposition of organic matter in 3D soil structure", "authors": [{"first": "P", "middle": [], "last": "Garnier", "suffix": ""}, {"first": "O", "middle": [], "last": "Monga", "suffix": ""}, {"first": "B", "middle": [], "last": "L\u00e8ye", "suffix": ""}], "year": "", "venue": "", "link": "7442675"}, "BIBREF4": {"title": "Sobolev solution for semilinear PDE with obstacle under monotonicity condition", "authors": [{"first": "A", "middle": [], "last": "Matoussi", "suffix": ""}, {"first": "M", "middle": [], "last": "Xu", "suffix": ""}], "year": 2008, "venue": "Electronic Journal of Probability", "link": "15162596"}, "BIBREF5": {"title": "Transport equations in biology, Series: Frontiers in Mathematics", "authors": [{"first": "B", "middle": [], "last": "Perthame", "suffix": ""}], "year": 2007, "venue": "", "link": null}, "BIBREF6": {"title": "Probl\u00e8me de Cauchy pour les\u00e9quations aux d\u00e9riv\u00e9es partielles semi lin\u00e9aires", "authors": [{"first": "F", "middle": [], "last": "Ribaud", "suffix": ""}], "year": 2006, "venue": "Comptes Rendus de l'Acad\u00e9mie des Sciences", "link": null}, "BIBREF7": {"title": "Persistence in reaction diffusion models with weak allee effect", "authors": [{"first": "J", "middle": [], "last": "Shi", "suffix": ""}, {"first": "R", "middle": [], "last": "Shivaji", "suffix": ""}], "year": 2006, "venue": "", "link": "3201474"}, "BIBREF8": {"title": "Nonlinear Functional Analysis and its Applications", "authors": [{"first": "E", "middle": [], "last": "Zeidler", "suffix": ""}], "year": 1985, "venue": "", "link": "118087770"}}, "ref_entries": {"FIGREF0": {"text": "smooth bounded domain, Q T =]0, T [\u00d7\u2126 and \u0393 T =]0, T [\u00d7\u2202\u2126.", "type": "figure"}, "FIGREF1": {"text": "\u2202t \u2212 D i \u2206u i + q i (u)u i = f i (u) in Q T , \u2202u i \u2202n = 0 over \u0393 T , u i (0, x) = u i0 (x) in \u2126, for i = 1, \u00b7 \u00b7 \u00b7 , 6.", "type": "figure"}, "FIGREF2": {"text": "Consider the triple (H, V, a) satisfying assumptions of Theorem 9, if a 0 \u2208 L \u221e (]0, T [\u00d7\u2126) and there exists", "type": "figure"}, "FIGREF3": {"text": "Then we can define u(0, x), u(T, x), and \u2202u \u2202n |]0,T [\u00d7\u2202\u2126 . Let us show that \u2202u \u2202n |]0,T [\u00d7\u2202\u2126 = 0. Let \u03c6 \u2208 D(]0, T [), we multiply equation (4) 1 by \u03c6 and by integration over ]0, T [ one gets", "type": "figure"}, "FIGREF4": {"text": "a linear equation within the framework of Corollary 10 with a 0 = q i (u n\u22121", "type": "figure"}, "FIGREF5": {"text": "\u2265 0 and f i \u2208 L 2 (]0, T [; V ) therefore u n i \u2208 W (0, T, V, V ) and u n i \u2265 0.", "type": "figure"}, "FIGREF6": {"text": "T ], H) and L 2 (]0, T [, V ). f 5 (u) = \u03bdu 1 , thus f 5 (uIt is the same for u n 6 because f 6 (u) = ru 1 .", "type": "figure"}, "FIGREF7": {"text": "It admits a sequence (\u03bb k ) k of positive eigenvalues with lim k\u2192+\u221e \u03bb k = +\u221e and a Hilbert basis (e k ) k of H consisting of eigenvectors of A H . If (G(t)) is the semigroup generated by \u2212A H , then for all u 0 \u2208 H,", "type": "figure"}, "FIGREF8": {"text": "H), using Ascoli result it will be relatively compact if G N (B) is equicontinuous and if for all t 0 in [0, T ], G N (B) is relatively compact in H.", "type": "figure"}, "FIGREF9": {"text": "T ], H) then (u n i ) belongs to a relatively compact set of C 0 ([0, T ], H). Therefore, from the sequence (u n i ) we can extract a subsequence (u m i ) which converges uniformely to u i \u2208 C 0 ([0, T ], H) for each i.", "type": "figure"}, "FIGREF10": {"text": "T [, V ). The third term in the left hand side also passes to the limit, due to the convergence in C 0 ([0, T ], H).", "type": "figure"}, "FIGREF11": {"text": "T ], H), we have u i (t) = G i (t)u 0i + t 0 G i (t \u2212 s)(\u2212q i (u)u i + f i (u))(s)ds (R).", "type": "figure"}, "FIGREF12": {"text": "u i being positive, we have u j K + u i \u2264 1 K u j \u221e where we set u j \u221e = u j L \u221e (]0,T [,H) . If we set u \u221e = 6 j=1 u j \u221e , we can find M 1 > 0 such that q i (u) \u221e = M 1 u \u221e \u2200u. So the numerator of q i (u)\u2212q i (v) is the sum of terms of form (u k \u2212v k )v j or (u j \u2212v j )u k , we can find M 2 > 0 such that |q i (u) \u2212 q i (v)| H (s) \u2264 M 2 6 j=1 |u j (s) \u2212 v j (s)| H . Also we can find M 3 > 0 such that |f i (u) \u2212 f i (v)| H (s) \u2264 M 3 6 j=1 |u j (s) \u2212 v j (s)| H . Summing and noting that G i (t \u2212 s) \u2264 N i e \u03c9 i T , we can find M such that", "type": "figure"}, "FIGREF13": {"text": "(t) \u2212 v i (t)| H \u2264 M u \u2212 v \u221e . Replacing in (5), we obtain", "type": "figure"}, "FIGREF14": {"text": "i (t) \u2212 v i (t)| H \u2264 M 2 u \u2212 v", "type": "figure"}}}
{"paper_id": "17780534", "_pdf_hash": "711b384b42df0cfcb95aab87fd1e1e845c7f0ddf", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Low-Power Baseband processors for Communications", "authors": [{"first": "Dake", "middle": [], "last": "Liu", "suffix": ""}, {"first": "Eric", "middle": [], "last": "Tell", "suffix": ""}], "year": 2004, "venue": "", "link": "107988715"}, "BIBREF1": {"title": "An accelerator architecture for programmable multi-standard baseband processors", "authors": [{"first": "Anders", "middle": [], "last": "Nilsson", "suffix": ""}, {"first": "Eric", "middle": [], "last": "Tell", "suffix": ""}, {"first": "Dake", "middle": [], "last": "Liu", "suffix": ""}], "year": 2004, "venue": "Proc. of WNET2004", "link": "208346295"}, "BIBREF2": {"title": "A Hardware Architecture for a Multi-Standard Block Interleaver", "authors": [{"first": "Eric", "middle": [], "last": "Tell", "suffix": ""}, {"first": "Dake", "middle": [], "last": "Liu", "suffix": ""}], "year": 2004, "venue": "", "link": null}, "BIBREF3": {"title": "A Converged Hardware Solution for FFT, DCT and Walsh Transform", "authors": [{"first": "Eric", "middle": [], "last": "Tell", "suffix": ""}, {"first": "Dake", "middle": [], "last": "Liu", "suffix": ""}], "year": 2003, "venue": "Proc. of ISSPA2003", "link": "18268177"}, "BIBREF4": {"title": "OFDM Wireless LANs: A Theoretical and practical guide", "authors": [{"first": "H", "middle": [], "last": "Heiskala", "suffix": ""}, {"first": "J", "middle": ["T"], "last": "Terry", "suffix": ""}], "year": 2002, "venue": "", "link": "54100680"}, "BIBREF5": {"title": "802.11a-1999 and IEEE Std", "authors": [{"first": "", "middle": [], "last": "Ieee Std", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF6": {"title": "CMOS Circuits for Digital RF Systems, Link\u00f6ping studies in science and technology. Dissertation", "authors": [{"first": "Ingemar", "middle": [], "last": "S\u00f6derquist", "suffix": ""}], "year": 2002, "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "17780859", "_pdf_hash": "90b5f4be2e888693227f26274764ede57e1bdee2", "abstract": [{"section": "Abstract", "text": "Abstract. The purpose of this paper is to present three new methods for finding all simple zeros of polynomials simultaneously. First, we give a new method for finding simultaneously all simple zeros of polynomials constructed by applying the Weierstrass method to the zero in the trapezoidal Newton's method, and prove the convergence of the method. We also present two modified Newton's methods combined with the derivative-free method, which are constructed by applying the derivative-free method to the zero in the trapezoidal Newton's method and the midpoint Newton's method, respectively. Finally, we give a numerical comparison between various simultaneous methods for finding zeros of a polynomial.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "With a typical iteration method such as Newton's method, an initial approximation of a zero converges to a specific zero, but the Weierstrass method (or Durand-Kerner method) approximates all simple (real or complex) zeros of polynomial simultaneously (see [2, 4] ).", "cite_spans": [{"start": 257, "end": 260, "text": "[2,", "ref_id": "BIBREF1"}, {"start": 261, "end": 263, "text": "4]", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "Abstract", "text": "Let P (z) = z n + a 1 z n\u22121 + \u00b7 \u00b7 \u00b7 + a n\u22121 z + a n be a polynomial of degree n having simple zeros with constants a 1 , a 2 , . . . , a n . Let r 1 , . . . , r n be the distinct zeros of P (z) and let distinct complex numbers z 1 , . . . , z n be their approximations. The Weierstrass method (Durand-Kerner method) is defined as", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "2010 Mathematics Subject Classification. 65H04, 65H05.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "I. Introduction", "text": "With a typical iteration method such as Newton's method, an initial approximation of a zero converges to a specific zero, but the Weierstrass method (or Durand-Kerner method) approximates all simple (real or complex) zeros of polynomial simultaneously (see [2, 4] ).", "cite_spans": [{"start": 257, "end": 260, "text": "[2,", "ref_id": "BIBREF1"}, {"start": 261, "end": 263, "text": "4]", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "I. Introduction", "text": "Let P (z) = z n + a 1 z n\u22121 + \u00b7 \u00b7 \u00b7 + a n\u22121 z + a n be a polynomial of degree n having simple zeros with constants a 1 , a 2 , . . . , a n . Let r 1 , . . . , r n be the distinct zeros of P (z) and let distinct complex numbers z 1 , . . . , z n be their approximations. The Weierstrass method ", "cite_spans": [], "ref_spans": []}, {"section": "I. Introduction", "text": "for m \u2265 0, and this method is one of the most frequently used iterative methods which", "cite_spans": [], "ref_spans": []}, {"section": "I. Introduction", "text": "give simultaneous computation of all zeros of P . If a function W i (z) is defined by", "cite_spans": [], "ref_spans": []}, {"section": "I. Introduction", "text": ", then W i (z) has the same zeros as the polynomial P , and so the problem of finding the zeros of P reduces to that of zeros of the function W i (z). If we denote W i = W i (z i ) for i = 1, 2, . . . , n in the case of z = z i , (1) can be written a\u015d", "cite_spans": [], "ref_spans": []}, {"section": "I. Introduction", "text": "where z i is a current approximation and\u1e91 i is a new approximation to a zero of polynomial P (z). The method constructed by (2) is called the Weierstrass-like method (briefly, WLM).", "cite_spans": [], "ref_spans": []}, {"section": "I. Introduction", "text": "The aim of this paper is to present three new methods for finding all simple zeros of polynomials simultaneously. These new methods are based on the Frontini-Sormani's midpoint Newton's method ( [7] ) and the Weerakoon's trapezoidal Newton's method ( [8] )", "cite_spans": [{"start": 195, "end": 198, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 251, "end": 254, "text": "[8]", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "I. Introduction", "text": "which were modifications of the Newton's method through iterative approximations.", "cite_spans": [], "ref_spans": []}, {"section": "I. Introduction", "text": "It is well known that Newton's method is defined by", "cite_spans": [], "ref_spans": []}, {"section": "I. Introduction", "text": "with an approximation", "cite_spans": [], "ref_spans": []}, {"section": "I. Introduction", "text": "x and a new approximation x * of a zero, and is efficient to find a zero of an equation", "cite_spans": [], "ref_spans": []}, {"section": "I. Introduction", "text": "f (x) = 0 for a differentiable function f with proper conditions and a sufficiently close initial value (see [8] ).", "cite_spans": [{"start": 109, "end": 112, "text": "[8]", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "I. Introduction", "text": "In [8] , Weerakoon proposed the trapezoidal Newton's method defined b\u0177", "cite_spans": [{"start": 3, "end": 6, "text": "[8]", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "I. Introduction", "text": "He applied Newton's method to the x * of the denominator.", "cite_spans": [], "ref_spans": []}, {"section": "I. Introduction", "text": "Along with (3), the midpoint Newton's method that Frontini-Sormani proposed in [7] is constructed asx", "cite_spans": [{"start": 79, "end": 82, "text": "[7]", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "I. Introduction", "text": "They also applied Newton's method to the x * of the denominator, and so set", "cite_spans": [], "ref_spans": []}, {"section": "I. Introduction", "text": ".", "cite_spans": [], "ref_spans": []}, {"section": "I. Introduction", "text": "Both the trapezoidal Newton's method and the midpoint Newton's method are of cubic order, while the original Newton's method was of quadratic order. A variety of methods can be applied to the x * in addition to Newton's method. Petkovi\u0107 [5] derived the following simultaneous method for finding all simple zeros of polynomials by applying the Weierstrass method to the x * in the midpoint Newton's method:", "cite_spans": [{"start": 237, "end": 240, "text": "[5]", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "I. Introduction", "text": "which is called Newton-Weierstrss method (or NWM). Also, Petkovi\u0107 [6] found the following derivative-free method (or DFM) defined a\u015d", "cite_spans": [{"start": 66, "end": 69, "text": "[6]", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "I. Introduction", "text": "which has a similar form with the one above and this method is of cubic order.", "cite_spans": [], "ref_spans": []}, {"section": "I. Introduction", "text": "In this paper, we present three new methods for the simultaneous approximation of all simple zeros of polynomials by applying the Weierstrass-like method and the derivativefree method to x * in the trapezoidal Newton's method and the midpoint Newton's method.", "cite_spans": [], "ref_spans": []}, {"section": "I. Introduction", "text": "Throughout this paper, the convergence of zeros will be discussed and the order will be calculated for new constructed methods. We will use the notation a = O M (b) for two complex numbers a and b whose moduli are of the same order, that is, |a| = O (|b|). In addition, the error is defined as |e| = max i=1,...,n {|e i |} with e i = z i \u2212 r i for i = 1, . . . , n.", "cite_spans": [], "ref_spans": []}, {"section": "I. Introduction", "text": "In all discussions, the order related to e i , which is an error of the previously approximated zeros z i , is presumed to be the same. After that, we will show that the order related to e i , which is an error of the approximated zeros concerning each method, is identical. For the same being, the order related to the already approximated zeros\u00ea i is hypothesized to be identical as follows:", "cite_spans": [], "ref_spans": []}, {"section": "I. Introduction", "text": "In Section 2, we give a new method for finding simultaneously all simple zeros of polynomials constructed by applying the Weierstrass method to the x * in the trapezoidal Newton's method, and prove the convergence of the method. In Section 3, we present two modified Newton's methods combined with the derivative-free method. They are constructed by applying the derivative-free method to the x * in the trapezoidal Newton's method and the midpoint Newton's method, respectively. In Section 4, we give a numerical comparison between various simultaneous methods for finding zeros of a polynomial.", "cite_spans": [], "ref_spans": []}, {"section": "I. Introduction", "text": "Finally, we conclude that the convergence of all new constructed methods in this paper are similar or superior than other iterative methods of cubic order.", "cite_spans": [], "ref_spans": []}, {"section": "II. Weierstrass-like Trapezoidal Newton's method", "text": "In this section, we construct a new method for finding simultaneously all simple zeros of polynomials of cubic order. By applying the Weierstrass method (5) to the x * in the trapezoidal Newton's method (3), we derive a new method constructed as follows:", "cite_spans": [], "ref_spans": []}, {"section": "II. Weierstrass-like Trapezoidal Newton's method", "text": "We call (7) the Weierstrass-like trapezoidal Newton's method, and from this, simply, call it Method 1.", "cite_spans": [], "ref_spans": []}, {"section": "II. Weierstrass-like Trapezoidal Newton's method", "text": "The calculation and discussion of the order of Method 1 are similar to those of the Newton-Weierstrass method, which is an alteration of Petkovi\u0107's midpoint Newton's method (see [5] ). From (7), we have the following theorem.", "cite_spans": [{"start": 178, "end": 181, "text": "[5]", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "II. Weierstrass-like Trapezoidal Newton's method", "text": "Lemma 1. For a polynomial P (z), we have", "cite_spans": [], "ref_spans": []}, {"section": "II. Weierstrass-like Trapezoidal Newton's method", "text": "Proof. By the Taylor's expansion around r i , we have that", "cite_spans": [], "ref_spans": []}, {"section": "II. Weierstrass-like Trapezoidal Newton's method", "text": "From (8), we obtain", "cite_spans": [], "ref_spans": []}, {"section": "II. Weierstrass-like Trapezoidal Newton's method", "text": "From Lemma 1, we have the following theorem.", "cite_spans": [], "ref_spans": []}, {"section": "II. Weierstrass-like Trapezoidal Newton's method", "text": "Theorem 1. If the approximate zero x i grounded from Method 1 is close enough to r i and the order of e i is the same, then the order of\u00ea i is identical, and", "cite_spans": [], "ref_spans": []}, {"section": "II. Weierstrass-like Trapezoidal Newton's method", "text": "Proof. We easily see that the following equation is satisfied.", "cite_spans": [], "ref_spans": []}, {"section": "II. Weierstrass-like Trapezoidal Newton's method", "text": "That is,", "cite_spans": [], "ref_spans": []}, {"section": "II. Weierstrass-like Trapezoidal Newton's method", "text": "If", "cite_spans": [], "ref_spans": []}, {"section": "II. Weierstrass-like Trapezoidal Newton's method", "text": "is a polynomial of order n \u2212 1, and Q(z i ) = P (z i ) for all i. Therefore, Q(z) is the Lagrange interpolation of points z 1 , z 2 , . . . , z n , and so we have", "cite_spans": [], "ref_spans": []}, {"section": "II. Weierstrass-like Trapezoidal Newton's method", "text": "Therefore, we obtain", "cite_spans": [], "ref_spans": []}, {"section": "II. Weierstrass-like Trapezoidal Newton's method", "text": "From (10), it follows that", "cite_spans": [], "ref_spans": []}, {"section": "II. Weierstrass-like Trapezoidal Newton's method", "text": "Substituting z = z i in (11), we obtain", "cite_spans": [], "ref_spans": []}, {"section": "II. Weierstrass-like Trapezoidal Newton's method", "text": "Therefore, we have", "cite_spans": [], "ref_spans": []}, {"section": "II. Weierstrass-like Trapezoidal Newton's method", "text": "Now we will find the order of Method 1. If the Taylor's expansion is applied to P \u2032 (z i \u2212 W i ), then we hav\u00ea", "cite_spans": [], "ref_spans": []}, {"section": "II. Weierstrass-like Trapezoidal Newton's method", "text": "The Chebyshev's method is defined b\u0177", "cite_spans": [], "ref_spans": []}, {"section": "II. Weierstrass-like Trapezoidal Newton's method", "text": "and of cubic order (see [7, Section 5.2] ). According to the Chebyshev's method, we see", "cite_spans": [{"start": 24, "end": 27, "text": "[7,", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "II. Weierstrass-like Trapezoidal Newton's method", "text": "Therefore, the order of\u00ea i is calculated as follows:", "cite_spans": [], "ref_spans": []}, {"section": "III. Modified Newton's methods combined with Derivative-free method", "text": "In this section, we present two modified Newton's methods combined with the derivativefree method (6) for finding all simple zeros of a polynomials simultaneously. The one is a form that the derivative-free method is applied to the x * in the trapezoidal Newton's method (3) as follows:\u1e91", "cite_spans": [], "ref_spans": []}, {"section": "III. Modified Newton's methods combined with Derivative-free method", "text": "which is called the Derivative-free trapezoidal Newton's method, or simply, Method 2.", "cite_spans": [], "ref_spans": []}, {"section": "III. Modified Newton's methods combined with Derivative-free method", "text": "From (13), we have the following theorem.", "cite_spans": [], "ref_spans": []}, {"section": "III. Modified Newton's methods combined with Derivative-free method", "text": "Theorem 2. If the approximate zero x i grounded from Method 2 is close enough to r i and the order of e i is the same, then the order of\u00ea i is identical, and", "cite_spans": [], "ref_spans": []}, {"section": "III. Modified Newton's methods combined with Derivative-free method", "text": "Proof. Since Petkovi\u0107's derivative-free method (6) is of cubic order", "cite_spans": [], "ref_spans": []}, {"section": "III. Modified Newton's methods combined with Derivative-free method", "text": "(see [6] ). Using (14) and the Taylor's expansion,\u1e91 i is calculated as follows. (In this case,", "cite_spans": [{"start": 5, "end": 8, "text": "[6]", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "III. Modified Newton's methods combined with Derivative-free method", "text": ").", "cite_spans": [], "ref_spans": []}, {"section": "III. Modified Newton's methods combined with Derivative-free method", "text": "Therefore, the order of\u00ea i is calculated as follows.", "cite_spans": [], "ref_spans": []}, {"section": "III. Modified Newton's methods combined with Derivative-free method", "text": "Now we apply the derivative-free method to the x * in the midpoint Newton's method (4) and construct the iteration as follows:", "cite_spans": [], "ref_spans": []}, {"section": "III. Modified Newton's methods combined with Derivative-free method", "text": "which is called the Derivative-free midpoint Newton's method. From this, we call it Method 3 simply. From (15), we have the following theorem.", "cite_spans": [], "ref_spans": []}, {"section": "III. Modified Newton's methods combined with Derivative-free method", "text": "Theorem 3. If the approximate zero x i grounded from Method 3 is close enough to r i and the order of e i is the same, then the order of\u00ea i is identical, and", "cite_spans": [], "ref_spans": []}, {"section": "III. Modified Newton's methods combined with Derivative-free method", "text": "Proof. By using (14) and Taylor's expansion,\u1e91 i is calculated as follows: (In this case,", "cite_spans": [], "ref_spans": []}, {"section": "III. Modified Newton's methods combined with Derivative-free method", "text": ").", "cite_spans": [], "ref_spans": []}, {"section": "III. Modified Newton's methods combined with Derivative-free method", "text": "Therefore, the order of\u00ea i can be calculated as follows.", "cite_spans": [], "ref_spans": []}, {"section": "IV. Numerical comparison", "text": "In this section, we give numerical experiments and comparisons between various simultaneous methods for finding zeros of a polynomial. These methods are all of cubic order.", "cite_spans": [], "ref_spans": []}, {"section": "IV. Numerical comparison", "text": "They include Method 1, Method 2, Method 3, the derivative-free method (DFM), the Petkovi\u0107's Newton-Weierstrass method (NWM), and the Weierstrass-like method (WLM).", "cite_spans": [], "ref_spans": []}, {"section": "IV. Numerical comparison", "text": "For a polynomial P (z) = z n +a 1 z n\u22121 +\u00b7 \u00b7 \u00b7+a n\u22121 z +a n , we choose initial approximations as Aberth's approach (see [1] ):", "cite_spans": [{"start": 121, "end": 124, "text": "[1]", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "IV. Numerical comparison", "text": "In this case, R is a radius of a circle, where the initial zeros by Aberth's approach are located in complex number plane. We use the following Henrici's fomula to select R (see [3] ):", "cite_spans": [], "ref_spans": []}, {"section": "IV. Numerical comparison", "text": "According to Henrici's formula, a disk {z : |z| < R} centered at the origin contains all zeros of polynomial P (z).", "cite_spans": [], "ref_spans": []}, {"section": "IV. Numerical comparison", "text": "The polynomials that we used on numerical comparison are as follows:", "cite_spans": [], "ref_spans": []}, {"section": "IV. Numerical comparison", "text": "Here P 1 (x), P 2 (x) and P 3 (x) are Wilkinson's polynomials when n = 4, 5, 6, respectively.", "cite_spans": [], "ref_spans": []}, {"section": "IV. Numerical comparison", "text": "We approximated the zeros until it satisfy the following condition:", "cite_spans": [], "ref_spans": []}, {"section": "IV. Numerical comparison", "text": "In Table I , we give a numerical comparison between several methods to find all zeros of those polynomials (16). It contains the iteration number m and the value max ", "cite_spans": [], "ref_spans": [{"start": 3, "end": 10, "text": "Table I", "ref_id": "TABREF0"}]}, {"section": "IV. Numerical comparison", "text": "P 1 9(8e-14) 8(9e-14) 7(1e-14) 9(9e-14) 8(1e-10) 13(3e-12) P 2 12(7e-13) 11(4e-13) 9(4e-13) 11(2e-13) 11(1e-12) 17(2e-12) P 3 14(2e-11) 13(5e-12) 11(8e-12) 13(8e-11) 13(7e-12) 21(2e-11) P 4 14(2e-11) 13(2e-11) 10(2e-11) 14(2e-11) 13(2e-11) 21(2e-11)", "cite_spans": [], "ref_spans": []}, {"section": "IV. Numerical comparison", "text": "V. Conclusion", "cite_spans": [], "ref_spans": []}, {"section": "IV. Numerical comparison", "text": "In this paper, three new methods for the simultaneous approximation of all simple zeros of polynomials by utilizing the trapezoidal Newton's method and the midpoint Newton's method were proposed. It was proven that each method was of third order. By simultaneously approximating all simple zeros of polynomials and by comparing numerical experiments with various methods that are of third order, we obtained that the results of Method 1 and Method 2 are similar with that of previous methods. But we found out that the result of Method 3 are superior than that of any other methods. All methods we constructed in this paper are new and creative. It seems that these methods can be applied to various fields, and the study on the applications of Method 3 is now in progress.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Iteration methods for finding all zeros of a polynomial simultaneously", "authors": [{"first": "O", "middle": [], "last": "Aberth", "suffix": ""}], "year": 1973, "venue": "Math. Comput", "link": "120655175"}, "BIBREF1": {"title": "Solution num\u00e9riques des\u00e9quations alg\u00e9braiques, Tom. I:\u00c9quations du Type F (x) = 0, Racines d'un Polyn\u00f4me", "authors": [{"first": "E", "middle": [], "last": "Durand", "suffix": ""}], "year": 1960, "venue": "", "link": null}, "BIBREF3": {"title": "Ein Gesamtschrittverfahren zur Berechnung der Nullstellen von Polynomen", "authors": [{"first": "I", "middle": ["O"], "last": "Kerner", "suffix": ""}], "year": 1966, "venue": "Numer. Math", "link": null}, "BIBREF4": {"title": "On a simultaneous method of Newton-Weierstrass' type for finding all zeros for a polynomial", "authors": [{"first": "M", "middle": ["S"], "last": "Petkovi\u0107", "suffix": ""}, {"first": "D", "middle": [], "last": "Herceg", "suffix": ""}, {"first": "I", "middle": [], "last": "Petkovi\u0107", "suffix": ""}], "year": 2009, "venue": "Appl. Math. Comput", "link": "46467368"}, "BIBREF5": {"title": "On a cubically convergent derivative free root finding method", "authors": [{"first": "M", "middle": ["S"], "last": "Petkovi\u0107", "suffix": ""}, {"first": "L", "middle": ["D"], "last": "Petkovi\u0107", "suffix": ""}], "year": 2007, "venue": "Int. J. Comput. Math", "link": "121223532"}, "BIBREF6": {"title": "Iterative Methods for the Solution of Equations", "authors": [{"first": "J", "middle": ["F"], "last": "Traub", "suffix": ""}], "year": 1964, "venue": "", "link": null}, "BIBREF7": {"title": "A variant of Newton's method with accelerated third-order convergence", "authors": [{"first": "S", "middle": [], "last": "Weerakoon", "suffix": ""}, {"first": "T", "middle": ["G I"], "last": "Fernando", "suffix": ""}], "year": 2000, "venue": "Appl. Math. Lett", "link": "38900993"}, "BIBREF8": {"title": "E-mail address: junseopsong@yonsei.ac.kr", "authors": [], "year": "", "venue": "", "link": null}}, "ref_entries": {"FIGREF1": {"text": "methods, after we approximated (17) to a satisfying label. The smaller the m, the faster approximated on the zeros, When m is the same, it can beleads to a higher accuracy of approximation. All computations have been done using MATLAB.", "type": "figure"}, "TABREF0": {"text": "The number of iterations(the error) of iterative methods Poly. Method 1 Method 2 Method 3 DFM NWM WLM", "type": "table"}}}
{"paper_id": "17780889", "_pdf_hash": "2c52ad51c5aacccab8bbfb6e3c901b1166c67c5d", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "A hierarchical optimization algorithm on distributed computer control system", "authors": [{"first": "Ya-Hui", "middle": [], "last": "Zhi-Xin Chen", "suffix": ""}, {"first": "", "middle": [], "last": "Wang", "suffix": ""}], "year": 2001, "venue": "Journal of System Simulation", "link": "64024863"}, "BIBREF1": {"title": "Variational approach to the optimal microprocessor control of induction motors with variable frequency of the supply voltage /in Russian", "authors": [{"first": "A", "middle": [], "last": "Krumov", "suffix": ""}, {"first": "I", "middle": [], "last": "Vassilev", "suffix": ""}], "year": 1989, "venue": "", "link": null}, "BIBREF2": {"title": "The hierarchical optimization of the nonlinear dynamical input-output model", "authors": [{"first": "Qing-Li", "middle": [], "last": "Jian-Min He", "suffix": ""}, {"first": "Nan -Rong", "middle": [], "last": "Da", "suffix": ""}, {"first": "", "middle": [], "last": "Xu", "suffix": ""}], "year": 1986, "venue": "", "link": "65253998"}, "BIBREF3": {"title": "Systems: decomposition, optimization, and control", "authors": [{"first": "M", "middle": ["G"], "last": "Singh", "suffix": ""}, {"first": "A", "middle": [], "last": "Tutli", "suffix": ""}], "year": 1985, "venue": "", "link": null}, "BIBREF4": {"title": "Hierarchical optimization with overlapping systems application to an electric power network", "authors": [{"first": "J", "middle": ["L"], "last": "Calvet", "suffix": ""}, {"first": "J", "middle": ["L"], "last": "", "suffix": ""}, {"first": "A", "middle": [], "last": "Titli", "suffix": ""}], "year": 1983, "venue": "Proceedings of IFAC/IFORS Symposium on Large Scale Systems: Theory and Application", "link": "126144019"}, "BIBREF5": {"title": "Reliability optimization design of distribution systems via multi-level hierarchical procedures and generalized reduced gradient method", "authors": [{"first": "Su", "middle": [], "last": "Ching-Tzong", "suffix": ""}, {"first": "Lii", "middle": [], "last": "Guor-Rurng", "suffix": ""}], "year": 1995, "venue": "Proceedings of Energy Management and Power Delivery", "link": "57241830"}, "BIBREF6": {"title": "Sensivity coordination method for hierarchical optimization of economic dispatching of hydrothermal power systems", "authors": [{"first": "Xueqing", "middle": [], "last": "Chen", "suffix": ""}, {"first": "Qiantu", "middle": [], "last": "Ruan", "suffix": ""}, {"first": "Tongxin", "middle": [], "last": "Zheng", "suffix": ""}], "year": 1996, "venue": "Journal of Tsinghua University", "link": null}, "BIBREF7": {"title": "A decomposition algorithm for nonlinear inseparable hierarchical optimization problem", "authors": [{"first": "G", "middle": [], "last": "Feng", "suffix": ""}], "year": 1993, "venue": "Structural optimization", "link": "120550904"}, "BIBREF8": {"title": "Two -level multilayer hierarchical optimization method for scheduling parallel machines in manufacturing systems", "authors": [{"first": "Lin", "middle": [], "last": "Jian -Nan", "suffix": ""}, {"first": "Zheng", "middle": [], "last": "Ying-Ping", "suffix": ""}], "year": 1989, "venue": "", "link": "67168705"}, "BIBREF9": {"title": "Software design for algorithms of hierarchical optimization", "authors": [{"first": "A", "middle": [], "last": "Kalliauer", "suffix": ""}], "year": 1979, "venue": "Proceedings of the 9-th IFIP Conference on Optimization Techniques", "link": "56561314"}, "BIBREF10": {"title": "An algorithm for hierarchical optimization of largescale problems with nested structure", "authors": [{"first": "A", "middle": [], "last": "Kalliauer", "suffix": ""}], "year": 1983, "venue": "Mathematical Programming", "link": "5185721"}, "BIBREF11": {"title": "Hierarchical optimization of electric power system application of Dantzig-Wolfe decomposition principle", "authors": [{"first": "P", "middle": [], "last": "Karlik", "suffix": ""}], "year": 1983, "venue": "Bulletin EGU", "link": null}, "BIBREF12": {"title": "Multilevel hierarchical optimization of aircraft trajectories", "authors": [{"first": "L", "middle": [], "last": "Mikhailov", "suffix": ""}, {"first": "J", "middle": [], "last": "Zaprianov", "suffix": ""}], "year": 1989, "venue": "", "link": "115107678"}, "BIBREF13": {"title": "Optimization by sequentially applied criteria /in Russian", "authors": [{"first": "V", "middle": [], "last": "Podinovskii", "suffix": ""}, {"first": "V", "middle": [], "last": "Gavrilov", "suffix": ""}], "year": 1975, "venue": "Soviet radio", "link": null}, "BIBREF14": {"title": "Multiple-objective optimization decision-making method for large scale systems", "authors": [{"first": "Fucai", "middle": [], "last": "Qian", "suffix": ""}, {"first": "Li", "middle": [], "last": "Ding", "suffix": ""}, {"first": "", "middle": [], "last": "Qi", "suffix": ""}, {"first": "", "middle": [], "last": "Liu", "suffix": ""}], "year": 2002, "venue": "Proceedings of the 4th World Congress on", "link": null}, "BIBREF15": {"title": "Multiple-level optimization method on inter-connected systems", "authors": [{"first": "Fucai", "middle": [], "last": "Qian", "suffix": ""}, {"first": "Li", "middle": [], "last": "Ding", "suffix": ""}, {"first": "", "middle": [], "last": "Qi", "suffix": ""}, {"first": "", "middle": [], "last": "Liu", "suffix": ""}], "year": 2002, "venue": "Proceedings of the 4th World Congress on", "link": "62059601"}, "BIBREF16": {"title": "Tracking approach in hierarchical optimization of large-scale systems", "authors": [{"first": "H", "middle": [], "last": "Sidaoui", "suffix": ""}, {"first": "Z", "middle": [], "last": "Binder", "suffix": ""}, {"first": "P", "middle": [], "last": "Perret", "suffix": ""}], "year": 1994, "venue": "International Journal of System Science", "link": "121145499"}, "BIBREF17": {"title": "Parameter estimation in large-scale systems using sequential decomposition", "authors": [{"first": "M", "middle": ["A"], "last": "Sultan", "suffix": ""}, {"first": "M", "middle": ["F"], "last": "Hassan", "suffix": ""}, {"first": "J", "middle": ["L"], "last": "Calvet", "suffix": ""}], "year": 1988, "venue": "International Journal of System Science", "link": "120381306"}, "BIBREF18": {"title": "A discrete dynamic model with distributed transport delays and its hierarchical optimization for preserving stream quality", "authors": [{"first": "H", "middle": [], "last": "Tamura", "suffix": ""}], "year": 1974, "venue": "IEEE Transactions on System , Man and Cybernetics", "link": "9046137"}, "BIBREF19": {"title": "Adiabatic layering: Beyond hierarchical multi-scale optimization", "authors": [{"first": "B", "middle": [], "last": "Truyen", "suffix": ""}, {"first": "J", "middle": [], "last": "Cornelis", "suffix": ""}], "year": 1994, "venue": "Proceedings of EUSIPCO-94. Seventh European Signal Processing Conference", "link": null}, "BIBREF20": {"title": "Multilevel optimization of high speed VLSI interconnects using decomposition", "authors": [{"first": "Y", "middle": [], "last": "Wei", "suffix": ""}, {"first": "Q", "middle": ["J"], "last": "Zhang", "suffix": ""}, {"first": "M", "middle": ["S"], "last": "Nakhla", "suffix": ""}], "year": "", "venue": "Proceedings of the IEEE Custom Integrated Circuits Conference", "link": "61854778"}, "BIBREF21": {"title": "Multilevel optimization of high speed VLSI interconnect networks by decomposition", "authors": [{"first": "Y", "middle": [], "last": "Wei", "suffix": ""}, {"first": "Q", "middle": ["J"], "last": "Zhang", "suffix": ""}, {"first": "M", "middle": ["S"], "last": "Nakhla", "suffix": ""}], "year": 1994, "venue": "IEEE Transactions on", "link": "61900182"}, "BIBREF22": {"title": "Hierarchical optimization algorithm for timetable generation problem", "authors": [{"first": "W", "middle": [], "last": "Wrega", "suffix": ""}], "year": 1989, "venue": "", "link": "113863841"}, "BIBREF23": {"title": "Hierarchical multiobjective optimization for large-scale dynamic system and its application to educational planning", "authors": [{"first": "Nanrong", "middle": [], "last": "Xu", "suffix": ""}, {"first": "Guoqing", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "Qingli", "middle": [], "last": "Da", "suffix": ""}], "year": 1988, "venue": "Proceedings of the 1988 IEEE International Conference on System, Man and Cybernatics", "link": "61231120"}, "BIBREF24": {"title": "A neural network for hierarchical optimization of nonlinear large-scale systems", "authors": [{"first": "Hou", "middle": [], "last": "Zeng-Guang", "suffix": ""}, {"first": "Wu", "middle": [], "last": "Cang-Pu", "suffix": ""}, {"first": "P", "middle": [], "last": "Bao", "suffix": ""}], "year": 1998, "venue": "International Journal of System Science", "link": null}, "BIBREF25": {"title": "Convexification and hierarchical optimization algorithm for distribution of water supply systems", "authors": [{"first": "Weijun", "middle": [], "last": "Zhong", "suffix": ""}, {"first": "Nanrong", "middle": [], "last": "Xu", "suffix": ""}], "year": 1996, "venue": "Journal of System Science and System Engineering", "link": "124989809"}}, "ref_entries": {}}
{"paper_id": "17780975", "_pdf_hash": "79edc0f3319f36daa60a82e24498eed289258e42", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Symmetry breaking Hopf bifurcations in equations with O2 symmetry with application to the KuramotoSivashinsky equation", "authors": [{"first": "F", "middle": [], "last": "Amdjadi", "suffix": ""}, {"first": "P", "middle": ["J"], "last": "Aston", "suffix": ""}, {"first": "P", "middle": [], "last": "Plechac", "suffix": ""}], "year": 1997, "venue": "J. Comp. Physics", "link": null}, "BIBREF1": {"title": "Hopf bifurcation with D 3 D 3 -symmetry", "authors": [{"first": "G", "middle": [], "last": "Dangelmayr", "suffix": ""}, {"first": "W", "middle": [], "last": "Uttinger", "suffix": ""}, {"first": "M", "middle": [], "last": "Wegelin", "suffix": ""}], "year": 1993, "venue": "Physik ZAMP", "link": null}, "BIBREF2": {"title": "Synchronized patterns in hierarchical networks of neural oscillators", "authors": [{"first": "G", "middle": [], "last": "Dangelmayr", "suffix": ""}, {"first": "W", "middle": [], "last": "Uttinger", "suffix": ""}, {"first": "J", "middle": [], "last": "Ander", "suffix": ""}, {"first": "J", "middle": [], "last": "Tomes", "suffix": ""}, {"first": "M", "middle": [], "last": "Wegelin", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF3": {"title": "Parity-breaking bifurcation in inhomogenous systems", "authors": [{"first": "G", "middle": [], "last": "Dangelmayr", "suffix": ""}, {"first": "J", "middle": [], "last": "Hettel", "suffix": ""}, {"first": "E", "middle": [], "last": "Knobloch", "suffix": ""}], "year": 1997, "venue": "", "link": null}, "BIBREF4": {"title": "Meandering of the spiral tip: an alternative approach, preprint", "authors": [{"first": "M", "middle": [], "last": "Golubitsky", "suffix": ""}, {"first": "V", "middle": [], "last": "Leblanc", "suffix": ""}, {"first": "I", "middle": [], "last": "Melbourne", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF5": {"title": "Hopf bifurcation in the presence of symmetry", "authors": [{"first": "M", "middle": [], "last": "Golubitsky", "suffix": ""}, {"first": "I", "middle": [], "last": "Stewart", "suffix": ""}], "year": 1985, "venue": "Arch. Rat. Mech. Anal", "link": "120590047"}, "BIBREF6": {"title": "Hopf bifurcation with dihedral group symmetry", "authors": [{"first": "M", "middle": [], "last": "Golubitsky", "suffix": ""}, {"first": "I", "middle": [], "last": "Stewart", "suffix": ""}], "year": 1986, "venue": "Multiparameter Bifurcation Theory, Contemporary Mathematics", "link": "115764909"}, "BIBREF7": {"title": "Singularities and Groups in Bifurcation Theory", "authors": [{"first": "M", "middle": [], "last": "Golubitsky", "suffix": ""}, {"first": "I", "middle": [], "last": "Stewart", "suffix": ""}, {"first": "D", "middle": [], "last": "Schae Er", "suffix": ""}], "year": 1986, "venue": "", "link": "119815519"}, "BIBREF8": {"title": "Amplitude equations for travelling wave convection", "authors": [{"first": "E", "middle": [], "last": "Knobloch", "suffix": ""}, {"first": "J", "middle": [], "last": "Deluca", "suffix": ""}], "year": 1990, "venue": "Nonlinearity", "link": "54043904"}, "BIBREF9": {"title": "Bifurcations of relative equilibria", "authors": [{"first": "M", "middle": [], "last": "Krupa", "suffix": ""}], "year": 1990, "venue": "SIAM J. Math. Anal", "link": "119794826"}, "BIBREF10": {"title": "A spatial center manifold approach to steady state bifurcations from spatially periodic patterns", "authors": [{"first": "A", "middle": [], "last": "Mielke ; B. Fiedler", "suffix": ""}, {"first": "K", "middle": [], "last": "Assner", "suffix": ""}, {"first": "A", "middle": [], "last": "Mielke", "suffix": ""}], "year": 1996, "venue": "Dynamics of Nonlinear Waves in Dissipative Systems", "link": "115881803"}, "BIBREF11": {"title": "Symmetry breaking Hopf bifurcation in anisotropic systems", "authors": [{"first": "M", "middle": [], "last": "Silber", "suffix": ""}, {"first": "H", "middle": [], "last": "Riecke", "suffix": ""}, {"first": "L", "middle": [], "last": "Kramer", "suffix": ""}], "year": 1992, "venue": "P h ysica D", "link": "120272322"}, "BIBREF13": {"title": "Hopf bifurcation in symmetrically coupled lasers, i n P . Chossat", "authors": [{"first": "M", "middle": [], "last": "Wegelin", "suffix": ""}], "year": 1994, "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "17781182", "_pdf_hash": "2ea1f4517ebf96e744403057f070e02a40d0e36c", "abstract": [{"section": "Abstract", "text": "There are increasing reports of cognitive and psychological declines related to occupational stress in subjects without psychiatric premorbidity or major life trauma. The underlying neurobiology is unknown, and many question the notion that the described disabilities represent a medical condition. Using PET we recently found that persons suffering from chronic occupational stress had limbic reductions in the 5-HT1A receptor binding potential. Here we examine whether chronic work-related stress is also associated with changes in brain structure. We performed MRI-based voxel-based morphometry and structural volumetry in stressed subjects and unstressed controls focusing on gray (GM) and white matter (WM) volumes, and the volumes of hippocampus, caudate, and putamen -structures known to be susceptible to neurotoxic changes. Stressed subjects exhibited significant reductions in the GM volumes of the anterior cingulate cortex and the dorsolateral prefrontal cortex. Furthermore, their caudate and putamen volumes were reduced, and the volumes correlated inversely to the degree of perceived stress. Our results add to previous data on chronic psychosocial stress, and indicate a morphological involvement of the frontostriatal circuits. The present findings of morphological changes in these regions confirm our previous conclusion that symptoms from occupational stress merit careful investigations and targeted treatment.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Western societies are facing increasing reports of stress-related sickness among otherwise healthy and high-performing persons who report that they have not experienced any major negative life events or particular stress in early life [1, 2, 3, 4, 5] . These persons describe having stereotyped symptoms, including memory and concentration problems, sleeplessness, diffuse aches, profound fatigue, irritability, anxiety, and a feeling of being emotionally drained, which they often attribute to occupational stress. It has also been found that such stressed individuals can experience an acute phase with symptoms of hypertension, chest pain, dizziness and serious cognitive disabilities [6] . Even though many individuals recover from the acute symptoms, the cognitive and emotional dysfunction as well as the increased sensitivity to stress often last for months, or years, forcing the affected individuals to work part-time, change jobs or retire early. Many professionals are still not accepting the described disabilities as a medical condition, and when accepted, they tend to be misdiagnosed as depression. Only a minor portion of the affected individuals are helped by treatment with serotonin reuptake inhibitors or other antidepressants [7] . The major pathways of the physiological response to stress involve autonomic nervous system as well as hypothalamicpituitary-adrenal (HPA) axis [8] . Although subjects suffering from symptoms attributed to chronic occupational stress are believed to have an altered reactivity of the HPA system, it is unknown whether this is a consistent finding [9] , and both normal [10, 11] , reduced [12, 13, 14, 15] , and elevated [16, 17, 18] cortisol levels after awakening have been reported. Furthermore, in contrast to patients with major depression [19] , subjects with chronic occupational stress symptoms show reduced cortisol and ACTH responses to the Corticotropin Releasing Hormone after dexametasone pretreatment [5, 20] . Emotional reactions to chronic stress and major depression, thus, seem to represent at least partly separate constructs, even if some symptoms (such as anxiety and attention and memory deficits) may overlap.", "cite_spans": [{"start": 235, "end": 238, "text": "[1,", "ref_id": "BIBREF0"}, {"start": 242, "end": 244, "text": "3,", "ref_id": "BIBREF3"}, {"start": 245, "end": 247, "text": "4,", "ref_id": "BIBREF5"}, {"start": 248, "end": 250, "text": "5]", "ref_id": "BIBREF7"}, {"start": 688, "end": 691, "text": "[6]", "ref_id": "BIBREF8"}, {"start": 1397, "end": 1400, "text": "[8]", "ref_id": "BIBREF10"}, {"start": 1600, "end": 1603, "text": "[9]", "ref_id": "BIBREF11"}, {"start": 1622, "end": 1626, "text": "[10,", "ref_id": "BIBREF12"}, {"start": 1627, "end": 1630, "text": "11]", "ref_id": "BIBREF13"}, {"start": 1641, "end": 1645, "text": "[12,", "ref_id": "BIBREF14"}, {"start": 1646, "end": 1649, "text": "13,", "ref_id": "BIBREF15"}, {"start": 1650, "end": 1653, "text": "14,", "ref_id": "BIBREF16"}, {"start": 1654, "end": 1657, "text": "15]", "ref_id": "BIBREF17"}, {"start": 1673, "end": 1677, "text": "[16,", "ref_id": "BIBREF18"}, {"start": 1678, "end": 1681, "text": "17,", "ref_id": "BIBREF19"}, {"start": 1682, "end": 1685, "text": "18]", "ref_id": "BIBREF20"}, {"start": 1797, "end": 1801, "text": "[19]", "ref_id": "BIBREF21"}, {"start": 1967, "end": 1970, "text": "[5,", "ref_id": "BIBREF7"}, {"start": 1971, "end": 1974, "text": "20]", "ref_id": "BIBREF22"}], "ref_spans": []}, {"section": "Introduction", "text": "In a recent PET study, we found that patients suffering from chronic work-related psychosocial stress had significant reductions in the 5-HT 1A receptor binding in three limbic structures: the hippocampus, the anterior cingulate cortex (ACC), and the anterior insular cortex [21] . A functional disconnection was also found between the amygdala, the ACC, and the medial prefrontal cortex (mPFC), despite the absence of psychiatric co-morbidity and major negative life events [21] . The locations of changes, in several aspects, corresponded to the locations of structural changes detected through MRI in persons suffering from other stressrelated conditions, such as stress in early life, repeated stressful negative life events, and post-traumatic stress disorder (PTSD), [22, 23, 24, 25, 26, 27, 28, 29] .", "cite_spans": [{"start": 275, "end": 279, "text": "[21]", "ref_id": "BIBREF23"}, {"start": 475, "end": 479, "text": "[21]", "ref_id": "BIBREF23"}, {"start": 773, "end": 777, "text": "[22,", "ref_id": "BIBREF24"}, {"start": 778, "end": 781, "text": "23,", "ref_id": "BIBREF25"}, {"start": 782, "end": 785, "text": "24,", "ref_id": "BIBREF26"}, {"start": 786, "end": 789, "text": "25,", "ref_id": "BIBREF27"}, {"start": 790, "end": 793, "text": "26,", "ref_id": "BIBREF28"}, {"start": 794, "end": 797, "text": "27,", "ref_id": "BIBREF29"}, {"start": 798, "end": 801, "text": "28,", "ref_id": "BIBREF30"}, {"start": 802, "end": 805, "text": "29]", "ref_id": "BIBREF31"}], "ref_spans": []}, {"section": "Introduction", "text": "This similarity raises the question of whether certain changes in structural volumes also occur among persons with symptoms related to chronic work-related stress. This is of interest for a couple reasons. Firstly, since the pathophysiology of symptoms attributed to occupational stress is highly debated, there is a need for clarification on whether this condition is associated with any cerebral changes. Secondly, if structural changes similar to those described in other stress-related conditions are also linked to occupational stress, one may hypothesize that chronic psychosocial stress affects our brains in a rather stereotyped manner, regardless of the underlying cause, and that cerebral changes are not limited to exposure to extreme and life threatening situations, but can also be related to accumulated everyday stress.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "We therefore carried out comparative MRI studies of cerebral gray matter (GM) and white matter (WM) volumes between patients with chronic occupation-related stress and healthy controls. The study also included an analysis of the structural volumes of the hippocampus, caudate, and putamen. The two latter regions, to the best of our knowledge, have not been previously investigated in this population. They were, however, of interest because they have been shown to process stress stimuli [30, 31, 32, 33] Furthermore, magnetic resonance imaging (MRI) of a large sample of adults with no history of psychopathology revealed that people who have experienced significant early life stress have volumetric reductions in the caudate nucleus in addition to the anterior cingulate cortex [24] . Also, a recent study of effects of life traumas during youth, reveal reductions in the caudate and putamen volumes [34] , further emphasizing that volume changes in these structures may be related to stress. On the basis of these previous data, and assuming that a repetitive stressinduced activation could lead to neuronal and dendritic damage in the structures involved, it was hypothesized that the caudate and putamen volumes may be smaller in persons suffering from prolonged occupational stress than in controls. Given previous findings on the effects of stress on the brain [5, 6, 21, 35] , a further hypothesis was that our stressed subjects would have reductions in the GM and WM volumes in the ACC and mPFC, and in the grey matter volumes of the hippocampus, amygdala and the insular cortex. These hypotheses were tested in a magnetic resonance (MR) study, which combined two different analyses -voxel based morphometry (VBM) and structural volumetry. VBM was carried out in two ways: 1) exploratively, with the entire brain as search space, to investigate whether there were any regional GM and WM changes in the brain on pixel by pixel basis. 2) It was also used with the assumption that GM and WM would be changed in regions known to be consistently involved in the regulation of stress (such as the hippocampus, mesial prefrontal cortex, insular cortex and the amygdala), and therefore, restricting the search space to a mask covering these areas (see methods). Structural volumetry was carried out in addition to the VBM analyses because some subcortical structures, basal ganglia in particular, have a poor white and gray matter demarcation, and the volumes of these structures are better defined with manual delineation.", "cite_spans": [{"start": 489, "end": 493, "text": "[30,", "ref_id": "BIBREF32"}, {"start": 494, "end": 497, "text": "31,", "ref_id": "BIBREF33"}, {"start": 498, "end": 501, "text": "32,", "ref_id": "BIBREF34"}, {"start": 502, "end": 505, "text": "33]", "ref_id": "BIBREF35"}, {"start": 782, "end": 786, "text": "[24]", "ref_id": "BIBREF26"}, {"start": 904, "end": 908, "text": "[34]", "ref_id": "BIBREF36"}, {"start": 1370, "end": 1373, "text": "[5,", "ref_id": "BIBREF7"}, {"start": 1374, "end": 1376, "text": "6,", "ref_id": "BIBREF8"}, {"start": 1377, "end": 1380, "text": "21,", "ref_id": "BIBREF23"}, {"start": 1381, "end": 1384, "text": "35]", "ref_id": "BIBREF37"}], "ref_spans": []}, {"section": "Methods", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Subjects", "text": "Thirty right-handed [36] , non-smoking patients (23 women and 7 men, age 41.366.6, range 36-55 years, education 13.562 years), who had been diagnosed as having had a 'reaction to severe stress and an adjustment disorder' according to the International Classification of Diseases (ICD-10, F43), were recruited from the Stress Research Institute at Stockholm University. In order to compose a study group with a homogenous etiology and to reduce variability, the selection was limited to subjects who attributed their illness to prolonged work-related stress, after working 60 to 70 hours per week continuously over several years prior to the onset of symptoms. Inclusion criteria consisted of a characteristic symptom course of sleeplessness, diffuse aches, palpitations and fatigue, a subsequent onset of irritability, anxiety, memory and concentration problems, feeling of depersonalization, and reduced work capacity (confirmed by the employers) [5, 6] . All of the subjects attributed their symptoms to chronic stress and had no other known etiology for their distress.", "cite_spans": [{"start": 20, "end": 24, "text": "[36]", "ref_id": "BIBREF38"}, {"start": 948, "end": 951, "text": "[5,", "ref_id": "BIBREF7"}, {"start": 952, "end": 954, "text": "6]", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "Subjects", "text": "Subjects were also required to have had a symptom duration of at least one year, to have been on sick leave ($50%) for stressrelated symptoms for a minimum of 6 months before entering the study, and to have an average stress-burnout score of $3.0 on the Maslach Stress-Burnout Inventory -General Survey (MBI-GS), [37] . This 7-point rating scale, ranging from 0 (never) to 6 (daily), consists of three subscales: exhaustion (five items), cynicism (five items), and lack of professional efficacy (six items). When rating perceived stress, subjects were asked to take into consideration the last six months, and not only the actual time-point. The average scores for Scandinavian populations are around 2 for MBI-GS, [1, 38] .", "cite_spans": [{"start": 313, "end": 317, "text": "[37]", "ref_id": "BIBREF39"}, {"start": 715, "end": 718, "text": "[1,", "ref_id": "BIBREF0"}, {"start": 719, "end": 722, "text": "38]", "ref_id": "BIBREF40"}], "ref_spans": []}, {"section": "Subjects", "text": "Subjects were excluded if they had previous history of psychosis, personality disorder, major or bipolar depression, alcohol or substance abuse, chronic fatigue, chronic pain, fibromyalgia, or neurological or endocrine disease. Subjects, who had experienced prominent stress factors in their private life or a major traumatic event at any time in their life, including sexual abuse, were also excluded. No daily medication was allowed during the two months prior to the study, except contraceptives. Review of past history of pharmacological treatment revealed no drugs known to affect brain structure (for example, psychopharmaca).", "cite_spans": [], "ref_spans": []}, {"section": "Subjects", "text": "Sixty-eight healthy, right-handed, non-smoking volunteers (53 females and 15 males, age 37.567.2 years, range 27-51 years, education 13.062.35 years) with no history of chronic stress or heredity for neuropsychiatric disorders were used as the control group. The patient and control groups therefore had similar gender distributions, and both groups had a female dominance to accommodate with the female-dominated epidemiology of the condition studied [1] . The study was approved by the Ethics Committee at the Karolinska Institute, and written informed consent was received from each participant.", "cite_spans": [{"start": 452, "end": 455, "text": "[1]", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "Subjects", "text": "Before the interview, participants completed questionnaires in order to evaluate their stress symptoms and assess their previous life events. In addition, the occurrence of major life events among the subjects was assessed through a clinical psychiatric interview based on the non-work-related items of the Holmes and Rahe Scale [39] . The participants were asked to answer yes or no to whether they had experienced any non-work-related stressful life events (e.g., death of a relative or spouse, recent divorce, forced family relocation). Subjects were excluded if they answered positively to having experienced such an event in their lives. Patients also received a medical screening, (physical examination, test of thyroid and liver function). The possible presence of psychiatric disorders or personality disturbances were assessed according to the Diagnostic and Statistical Manual of the American Psychiatric Association, 4th Edition (DSM-IV), including the Structured Questionnaire for DSM-IVH Axis I and II (Structured Clinical Interview for DSM-IVH (SCID-I, and II) (American Psychiatric Publishing Inc, Arlington, 1997), along with a test for depression using the Montgomery-Asberg Depression scale [40] .", "cite_spans": [{"start": 329, "end": 333, "text": "[39]", "ref_id": "BIBREF41"}, {"start": 1209, "end": 1213, "text": "[40]", "ref_id": "BIBREF42"}], "ref_spans": []}, {"section": "Magnetic Resonance Imaging", "text": "Data acquisition. All magnetic resonance imaging data was acquired on a whole-body 1.5-Tesla MRI medical scanner (General Electric, Milwaukee, Wisconsin) equipped with an 8-channel phased array coil. The MRI protocol included the following scans: 1) 3D-weighted T1 SPGR images with 1 mm isotropic voxel size according to a previously described protocol [41] ; and 2) 2D T2-weighted fast spin echo (FSE) images in the axial plane (effective TE = 56 ms, TR = 2500 ms, FOV = 24 cm, 23 slices of 3 mm thickness). The 2D images were not used in the present analysis.", "cite_spans": [{"start": 353, "end": 357, "text": "[41]", "ref_id": "BIBREF43"}], "ref_spans": []}, {"section": "Magnetic Resonance Imaging", "text": "Voxel-Based Morphometry (VBM). We used a version of the VBM in the SPM5 package (www.fil.ion.ucl.ac.uk/spm) with the Gaser toolbox (http://dbm.neuro.uni-jena.de/vbm/) and voxel values in the segmented images were modulated (multiplied) by the Jacobian determinants derived from the spatial normalization step. The analyses of modulated data allowed direct comparisons of regional differences in the amount of each tissue type.", "cite_spans": [], "ref_spans": []}, {"section": "Magnetic Resonance Imaging", "text": "After pre-processing, visually checking for homogeneity across the sample, smoothed (8 mm), modulated, and normalized images were obtained and used for the statistical analyses. These modulated volume images of the respective tissue types are hereafter referred to as GM, WM, and cerebrospinal fluid (CSF).", "cite_spans": [], "ref_spans": []}, {"section": "Magnetic Resonance Imaging", "text": "Structural volumetry. In regions with poor white and gray matter demarcation, as in basal ganglia, volumetry is regarded as more reliable than VBM analysis [43] , and manual volumetry was, therefore, used in addition to VBM. Homologous VOIs were delineated manually for the hippocampus, caudate, and putamen in all the subjects.", "cite_spans": [{"start": 156, "end": 160, "text": "[43]", "ref_id": "BIBREF45"}], "ref_spans": []}, {"section": "Magnetic Resonance Imaging", "text": "All the volumes were delineated on original, un-reformatted T1 images using MRIcro software (www.sph.sc.edu/comd/rorden/ mricro.html) by two investigators who were uninformed about the identity of the subjects. Values presented in Results and Table 1b were generated by investigator 1, who analyzed all the data (investigator 2 analyzed structural volumes from 15 randomized subjects in each study group). Both raters analyzed 10 images twice to establish the intra-rater reliability. VOIs were outlined according to previously described protocols [43, 44, 45] . In summary.", "cite_spans": [{"start": 548, "end": 552, "text": "[43,", "ref_id": "BIBREF45"}, {"start": 553, "end": 556, "text": "44,", "ref_id": "BIBREF46"}, {"start": 557, "end": 560, "text": "45]", "ref_id": "BIBREF47"}], "ref_spans": [{"start": 243, "end": 251, "text": "Table 1b", "ref_id": "TABREF0"}]}, {"section": "Magnetic Resonance Imaging", "text": "The hippocampus: the hippocampus was traced according to the protocol of Watson et al. [46] . The posterior boundary of the hippocampus was defined as the first image in which the crus of the fornix became visible. The superior boundary consisted of the alveus; the lateral boundary was the inferior corn of the lateral ventricle; the ambient cistern was the medial boundary, whereas the WM of the parahippocampal gyrus represented the inferior boundary. The hippocampus VOI included the tail of the hippocampus.", "cite_spans": [{"start": 87, "end": 91, "text": "[46]", "ref_id": "BIBREF48"}], "ref_spans": []}, {"section": "Magnetic Resonance Imaging", "text": "The caudate nucleus: the caudate nuclei were traced separately, in accordance with Raz et al. [47] . The lateral ventricle was used as the medial boundary; the subcallosal fasciculus served as the anterior boundary; the stria terminalis was the posterior boundary (identified by a change in signal intensity relative to the caudate nucleus); and the anterior limb of the internal capsule served as the lateral boundary. The region of interest included the head, the body of the caudate, and the tail (excluding the portion that turned anterior). The nucleus accumbens was excluded as well.", "cite_spans": [{"start": 94, "end": 98, "text": "[47]", "ref_id": "BIBREF49"}], "ref_spans": []}, {"section": "Magnetic Resonance Imaging", "text": "The putamen: the delineation of the putamen started in the first slice where it became visible laterally to the caudate. The superior boundary was defined by the corona radiata, the internal capsule was the medial border, and the lateral border was the external capsule. The posterior limit was the point at which the putamen was no longer visible in the corona radiata. The lower limit was just above the amygdala, excluding nucleus accumbens, when the operator could see the most inferior aspect of the third ventricle and the chiasmatic cistern was no longer visible.", "cite_spans": [], "ref_spans": []}, {"section": "Magnetic Resonance Imaging", "text": "The hippocampus was delineated on coronal images, and the other structures on horizontal sections. All the volumes were then viewed and corrected on coronal, horizontal, as well as sagital images.", "cite_spans": [], "ref_spans": []}, {"section": "Statistical analysis", "text": "Group differences in age and education, as well as differences in the total intracranial volume (TIV), calculated as the total volume of GM + WM + CSF, and the total tissue volume (TV), calculated as the total volume of GM + WM, were tested with unpaired Students t-test (p,0.05). Group comparisons of the total GM and WM volumes were tested using analysis of covariance (ANCOVA, p,0.05), taking into consideration individual differences in TIV, which was used as the covariate in addition to age and sex (the latter was not strictly necessary as the groups were matched for sex). Group comparisons of relative structural volumes (VOI/TIV) were carried out with unpaired Students t-tests using the mean individual relative values of the two homologous VOIs for each type of structure as input values (p,0.016), after Bonferroni correction for the three separate regions). The aforementioned analyses were carried out with PASW Statistics 18 (SPSS Inc., Chicago, IL).", "cite_spans": [], "ref_spans": []}, {"section": "Statistical analysis", "text": "Group differences in GM and WM volumes within the regions that were expected to show changes in stressed subjects (the ACC and mPFC, the hippocampus, amygdala and the insular cortex) were tested with VBM by restricting the search space to a mask encompassing the amygdalae (both sides), hippocampi, the ACC, the medial and superior frontal gyrus, and the insular cortex (both sides). This mask was derived using the WFU Pick Atlas (maldjian@wfubmc.edu), by adding the respective regional areas as defined by the atlas into a confluent, large mask (Fig. 1) . In addition, we employed explorative analysis using also the entire brain as the search space to investigate possible differences between the two subject groups in other regions. Significant clusters were defined with flexible factorial design in SPM5 (voxel threshold p,0.001, with FDR correction at p,0.05) using age, sex, and the total brain volume (TIV) as covariates of no interest. We also implemented non-stationary cluster extent correction in the Gaser toolbox to correct for the non-uniform smoothness in the VBM images. The co-ordinates are reported in Montreal Neurological Institute (MNI) space.", "cite_spans": [], "ref_spans": [{"start": 547, "end": 555, "text": "(Fig. 1)", "ref_id": "FIGREF1"}]}, {"section": "Statistical analysis", "text": "We hypothesized that changes in regional GM and WM, and in the structural volumes would be related to the degree of perceived stress. To test this, correlation analyses were carried out between MBI-GS scores and the individual GM or WM volumes extracted from the clusters showing significant group differences in GM and WM volumes as well as the relative volumes (the VOI/TIV ratios) of structures showing a significant difference between patients and controls. For the correlation analyses between VOI/TIV and MBI-GS, we used the mean of the two homologous regions (provided that a possible difference from controls was bilateral) in order to reduce the number of comparisons. The significance value for these linear regressions was set at p,0.05, because each of the regions included in this calculation was assumed to be affected by stress.", "cite_spans": [], "ref_spans": []}, {"section": "Statistical analysis", "text": "Inter-and intra-rater reliability was tested with linear correlation analysis, Pearson's coefficient, p,0.05.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Clinical data", "text": "The groups did not differ in age or education. (Table 1) . No significant difference was detected between the two subject groups in respect to depression, as assessed by MADRAS scores (p = 0.12), although the mean value was higher among patients (Table 1) . However, the MBI-GS scores, indicating perceived work-related stress levels, were significantly higher among the patients (4.261.1 vs. 2.260.5; p,0.0001; F = 100.6, df = 1); among controls, the scores were below 3.0 and in the range reported in other studies [1, 38] , (Table 1) .", "cite_spans": [{"start": 517, "end": 520, "text": "[1,", "ref_id": "BIBREF0"}, {"start": 521, "end": 524, "text": "38]", "ref_id": "BIBREF40"}], "ref_spans": [{"start": 47, "end": 56, "text": "(Table 1)", "ref_id": "TABREF0"}, {"start": 246, "end": 255, "text": "(Table 1)", "ref_id": "TABREF0"}, {"start": 527, "end": 536, "text": "(Table 1)", "ref_id": "TABREF0"}]}, {"section": "Clinical data", "text": "No gross anatomical abnormalities were found, as judged by an experienced neuroradiologist, and none of the subjects had to be excluded due to either movement artifacts during scanning or segmentation errors.", "cite_spans": [], "ref_spans": []}, {"section": "Clinical data", "text": "We did not detect any group difference regarding total GM volume, WM volume, total TV, or the TIV (Table 2) .", "cite_spans": [], "ref_spans": [{"start": 98, "end": 107, "text": "(Table 2)", "ref_id": "TABREF1"}]}, {"section": "Structural volumetry", "text": "Patients showed a significantly lower structural volume relative to the TIV (VOI/TIV) bilaterally in the caudate and putamen ( Table 2) . The results remained when adding age and MADRAS as covariate (p,0.001 for both structures, post hoc analysis with ANCOVA). No significant group difference was detected in the volume of the hippocampus. The inter-rater correlation was 0.8 for the measurements of the hippocampus, and 0.9 for the caudate and putamen; the corresponding intra-rater values were 0.8, 1.0, respectively.", "cite_spans": [], "ref_spans": [{"start": 127, "end": 135, "text": "Table 2)", "ref_id": "TABREF1"}]}, {"section": "Voxel-based morphometry", "text": "Significant reductions in the GM volumes were detected in three clusters among the patients. They were located in the ACC (a region covered by the a priori hypothesis), and, in addition, in the left and right middle frontal gyrus (regions constituting portions of the dorsolateral prefrontal cortex -dlPFC), (Table 3 , Fig. 2 ). Contrary to the hypothesis, we found no changes in the hippocampus, the amygdala, or the anterior insular cortex, (Table 3) . No regional increases in GM were found in among patients. No group differences were detected in regional WM.", "cite_spans": [], "ref_spans": [{"start": 308, "end": 316, "text": "(Table 3", "ref_id": "TABREF2"}, {"start": 443, "end": 452, "text": "(Table 3)", "ref_id": "TABREF2"}]}, {"section": "Voxel-based morphometry", "text": "Post hoc group comparison when adding MADRAS as covariate of no interest did not alter the results.", "cite_spans": [], "ref_spans": []}, {"section": "Correlation analyses", "text": "No correlations were detected between stress scores (MBI-GS) and the individual GM volumes extracted from the clusters showing significant differences between controls and patients (the ACC, the left and right middle frontal gyrus). There was, however, a statistically significant, negative correlation between the relative structural volume of the caudate and putamen (mean of the right and left values for the respective structure) and the MBI-GS scores (r = 20.47 and p = 0.0001, r = 20.45 p = 0.0001, respectively), Fig. 3A . When estimating the regression lines separately for stressed subjects and controls, significant inverse correlations remained amongst the controls for both structures (r = 20.57, and r = 20.45; p,0.0001 for both), Fig. 3B , whereas amongst the stressed group there was only a tendency for an inverse correlation in the caudate (r = 20.36, p = 0.054), and no correlation with the relative volume of the putamen (Fig. 3C) .", "cite_spans": [], "ref_spans": [{"start": 520, "end": 527, "text": "Fig. 3A", "ref_id": "FIGREF2"}, {"start": 744, "end": 751, "text": "Fig. 3B", "ref_id": "FIGREF2"}, {"start": 940, "end": 949, "text": "(Fig. 3C)", "ref_id": "FIGREF2"}]}, {"section": "Discussion", "text": "The present study tests the hypothesis that perceived prolonged occupational stress is associated with regional morphological changes in the brain. Such changes have been found in patients with PTSD (thus, in relation to life threatening trauma), in persons having experienced early life traumas, and in those reporting negative major life events [23, 27] . However, to the best of our knowledge, the possibility of such changes has not been previously discussed in relation to subjects undergoing occupational stress who have not faced extreme life conditions or psychosocial trauma and who have no history of psychiatric disorders.", "cite_spans": [{"start": 347, "end": 351, "text": "[23,", "ref_id": "BIBREF25"}, {"start": 352, "end": 355, "text": "27]", "ref_id": "BIBREF29"}], "ref_spans": []}, {"section": "Discussion", "text": "The principal findings were the reductions in the GM volumes of the ACC and the dlPFC, and reductions in the volumes of the caudate and putamen. The basal ganglia volumes were also inversely correlated with the degree of perceived stress. All the structures in which we detected changes have been described to be sensitive to stress stimuli [21, 23, 48, 49] and are known to be involved in stress physiology [31, 33, 50, 51] . Decreased GM volume and density in the prefrontal cortex and the ACC in particular has been detected in several studies of persons suffering from PTSD [26, 27, 52, 53, 54] . Of particular interest is the data of Kasai et al., showing atrophy of the ACC, hippocampus and insular cortex in combat veterans with PTSD but not in their identical twins, suggesting that the detected abnormality was acquired [26] . Furthermore, measurements of cortical thickness in a separate group of patients with PTSD have shown dynamic, stress-related changes in the dlPFC which were characterized by an increase in cortical thickness that gradually normalized over time during recovery [55] .", "cite_spans": [{"start": 341, "end": 345, "text": "[21,", "ref_id": "BIBREF23"}, {"start": 346, "end": 349, "text": "23,", "ref_id": "BIBREF25"}, {"start": 350, "end": 353, "text": "48,", "ref_id": "BIBREF50"}, {"start": 354, "end": 357, "text": "49]", "ref_id": "BIBREF51"}, {"start": 408, "end": 412, "text": "[31,", "ref_id": "BIBREF33"}, {"start": 413, "end": 416, "text": "33,", "ref_id": "BIBREF35"}, {"start": 417, "end": 420, "text": "50,", "ref_id": "BIBREF52"}, {"start": 421, "end": 424, "text": "51]", "ref_id": "BIBREF53"}, {"start": 578, "end": 582, "text": "[26,", "ref_id": "BIBREF28"}, {"start": 583, "end": 586, "text": "27,", "ref_id": "BIBREF29"}, {"start": 587, "end": 590, "text": "52,", "ref_id": "BIBREF54"}, {"start": 591, "end": 594, "text": "53,", "ref_id": "BIBREF55"}, {"start": 595, "end": 598, "text": "54]", "ref_id": "BIBREF56"}, {"start": 829, "end": 833, "text": "[26]", "ref_id": "BIBREF28"}, {"start": 1096, "end": 1100, "text": "[55]", "ref_id": "BIBREF57"}], "ref_spans": []}, {"section": "Discussion", "text": "Data from studies on basal ganglia in corresponding populations are less abundant. There are reports about an affection of the caudate and putamen in relation to early life traumas [56] and PTSD, [57] , but in general, these structures have received relatively minor interest in the context of stress. The present finding of reduced structural volumes in the caudate and putamen, therefore, deserves particular consideration. This finding is in accordance with the reported activations of the basal ganglia occurring during acute stress [31, 58, 59] . It is also compatible with the notion that both the putamen and caudate receive powerful glutamatergic input from the prefrontal cortex [60] and are susceptible to excitotoxicity [61, 62] . The present findings are also congruent with the well-known phenomenon of stress-related freezing [63] and raises the question of whether and how motor performance may be affected in persons suffering from chronic psychosocial stress.", "cite_spans": [{"start": 181, "end": 185, "text": "[56]", "ref_id": "BIBREF58"}, {"start": 196, "end": 200, "text": "[57]", "ref_id": "BIBREF59"}, {"start": 537, "end": 541, "text": "[31,", "ref_id": "BIBREF33"}, {"start": 542, "end": 545, "text": "58,", "ref_id": "BIBREF60"}, {"start": 546, "end": 549, "text": "59]", "ref_id": "BIBREF61"}, {"start": 688, "end": 692, "text": "[60]", "ref_id": "BIBREF62"}, {"start": 731, "end": 735, "text": "[61,", "ref_id": "BIBREF63"}, {"start": 736, "end": 739, "text": "62]", "ref_id": "BIBREF64"}, {"start": 840, "end": 844, "text": "[63]", "ref_id": "BIBREF65"}], "ref_spans": []}, {"section": "Discussion", "text": "The regions showing changes in our stressed patients are part of a network believed to mediate the integration of cognitive, affective, and autonomic responses [64] .", "cite_spans": [{"start": 160, "end": 164, "text": "[64]", "ref_id": "BIBREF66"}], "ref_spans": []}, {"section": "Discussion", "text": "It is tenable that an affection of these structures could lead to poor attention, and working memory deficits, symptoms which individuals with chronic occupational stress have described experiencing [5, 6, 65] . The preset data is in line with results from a fMRI study by Sandstr\u00f6m et al., showing a decreased activation of the dlPFC among 10 patients suffering from occupational stress [6] , and with a fMRI study by Qin et al., which detected a reduced activation of the dlPFC in healthy subjects who performed a working memory task under acute stress [51] .", "cite_spans": [{"start": 199, "end": 202, "text": "[5,", "ref_id": "BIBREF7"}, {"start": 203, "end": 205, "text": "6,", "ref_id": "BIBREF8"}, {"start": 206, "end": 209, "text": "65]", "ref_id": "BIBREF67"}, {"start": 388, "end": 391, "text": "[6]", "ref_id": "BIBREF8"}, {"start": 555, "end": 559, "text": "[51]", "ref_id": "BIBREF53"}], "ref_spans": []}, {"section": "Discussion", "text": "Contrary to our hypothesis, but in accordance with the presently available reports from MRI studies of subjects with occupational stress [5, 21] , no changes were detected in the hippocampus or amygdala. Among studies of other chronic stress conditions, relatively few have examined amygdala volumes, and Figure 2 . Reductions in GM volumes in stressed subjects. Significant reductions in the GM (red) in stressed subjects compared with controls. Clusters calculated using peak threshold at p = 0.001, FDR corrected at p,0.05. All the clusters are superimposed on the GM template from the entire study group. The numbers indicate z-levels in MNI co-ordinates. R = right side. doi:10.1371/journal.pone.0064065.g002 # Cluster showing a significant group difference when using a limbic mask comprising the anterior cingulate cortex, the mPFC, the insular cortex, the hippocampus and the amygdala, using peak threshold at p = 0.001, FDR corrected at p,0.05. The other clusters were calculated with same level of significance, but using the entire brain as search space (no a priori hypothesis). No group differences were observed in white matter volumes and no significant clusters were detected when reversing the contrast (using the contrast: stressed patients -controls). doi:10.1371/journal.pone.0064065.t003", "cite_spans": [{"start": 137, "end": 140, "text": "[5,", "ref_id": "BIBREF7"}, {"start": 141, "end": 144, "text": "21]", "ref_id": "BIBREF23"}], "ref_spans": []}, {"section": "Discussion", "text": "the results are variable. Among persons with PTSD, smaller volumes have been reported in some studies [66, 67] , while others have detected normal values [68, 69, 70] . Similar inconsistency appears with regard to the hippocampus [5, 69, 71] . One possible explanation for the mixed findings could be that the small size of these structures, the amygdala in particular, may lead to greater variability in volume measures, which hampers the probability of detecting significant group differences, especially when the investigated study groups are undersized. Given the size of the present population and the use of 1.5 Tesla scanner, we did not try to specifically assess the structural volume of the amygdala in the present study. Another potential explanation may be associated with time of the stress exposure in relation to age as such exposure may have effects on these structures under sensitive developmental periods [72, 73] .", "cite_spans": [{"start": 102, "end": 106, "text": "[66,", "ref_id": "BIBREF68"}, {"start": 107, "end": 110, "text": "67]", "ref_id": "BIBREF69"}, {"start": 154, "end": 158, "text": "[68,", "ref_id": "BIBREF70"}, {"start": 159, "end": 162, "text": "69,", "ref_id": "BIBREF71"}, {"start": 163, "end": 166, "text": "70]", "ref_id": "BIBREF72"}, {"start": 230, "end": 233, "text": "[5,", "ref_id": "BIBREF7"}, {"start": 234, "end": 237, "text": "69,", "ref_id": "BIBREF71"}, {"start": 238, "end": 241, "text": "71]", "ref_id": "BIBREF73"}, {"start": 923, "end": 927, "text": "[72,", "ref_id": "BIBREF74"}, {"start": 928, "end": 931, "text": "73]", "ref_id": "BIBREF75"}], "ref_spans": []}, {"section": "Discussion", "text": "The fact that the presently detected volume reductions were confined to regions believed to be involved in the processing of stress stimuli [23] makes it highly unlikely that they were random findings. The threshold used in the SPM analysis was in accordance with other VBM studies of psychosocial stress in humans [27, 74, 75] and the detected differences in the structural volumes of the caudate and putamen were highly significant.", "cite_spans": [{"start": 140, "end": 144, "text": "[23]", "ref_id": "BIBREF25"}, {"start": 315, "end": 319, "text": "[27,", "ref_id": "BIBREF29"}, {"start": 320, "end": 323, "text": "74,", "ref_id": "BIBREF76"}, {"start": 324, "end": 327, "text": "75]", "ref_id": "BIBREF77"}], "ref_spans": []}, {"section": "Discussion", "text": "At present, we can only speculate about the underpinnings of the observed changes. Because the study was cross-sectional, it is difficult to state whether the detected reductions represent the neurotoxic effect of stress, effect of other factors, such as nitric oxide, or are associated with a pre-existing condition that could have rendered the brain more vulnerable to the development of pathological stress responses. Due to our strict selection criteria, it is, however, possible to exclude potential confounding factors such as major life traumas, psychiatric premorbidity, depression, chronic pain, and pharmacological treatment. Considering the congruence with data from animal experiments as well as with the longitudinal data from patients with PTSD, we find it probable that the present findings reflect effects of chronic psychosocial stress, in this case, occupational stress. The observed inverse correlation between the stress scores and the relative volumes of the caudate and putamen (Fig. 3) could be taken as an argument for this view. It should be notified, however, that this correlation is dominated by the data from controls (r = 20.57, p = 0,0001, and r = 20.45, p = 0.0001, whereas the corresponding regression line in stressed subjects only showed a non-significant trend for the caudate (r = 20.36 p = 0.054), and no trend for the putamen (r = 20.08; p = 0.69). The reason for that is not evident, one possibility could be that the control group was much larger, and that the spread of volumes was larger among the controls. Worth mentioning is that in our recent follow up investigation of two new cohorts of controls and subjects with occupational stress, shows very similar results (Osika&Savic, manuscript in preparation).", "cite_spans": [], "ref_spans": [{"start": 1000, "end": 1008, "text": "(Fig. 3)", "ref_id": "FIGREF2"}]}, {"section": "Discussion", "text": "The molecular underpinnings of the morphological changes after stress are just beginning to be studied in detail, please see Leuner and Shors 2012, and Conrad 2008, for a comprehensive review [76, 77] . The major mediators of stress-related neuronal modulation involving dendritic retraction and in some cases neurotoxicity are glucocorticoids and glutamate [23] . They have own neuronal effects, and are also reported to interact [78, 79] . Circulating glucocorticoids interact with various neurotransmitters, [80] and chronic stress in tree shrews is found to reduce the number of dopamine transporter (DAT) binding sites (B max ) in the caudate nucleus and the putamen [81] . Adrenal ectomy is reported to increase the proliferation of hippocampal neurons whereas excess in glucocorticoid is reported to decrease it sharply, as do psychosocial stressors [82] . Experiments with betamethasone infusion in fetal sheep show glucocorticoid-related loss of synaptic density in the frontal neocortex, caudate, putamen, and hippocampus [83, 84] . While these alterations were initially viewed as a neurodegenerative event, it is worth mentioning that more recent studies suggest that stress induced dendritic alterations are reversible if animals are given time to recover from chronic stress [77] .", "cite_spans": [{"start": 192, "end": 196, "text": "[76,", "ref_id": "BIBREF78"}, {"start": 197, "end": 200, "text": "77]", "ref_id": "BIBREF79"}, {"start": 358, "end": 362, "text": "[23]", "ref_id": "BIBREF25"}, {"start": 431, "end": 435, "text": "[78,", "ref_id": "BIBREF80"}, {"start": 436, "end": 439, "text": "79]", "ref_id": "BIBREF81"}, {"start": 511, "end": 515, "text": "[80]", "ref_id": "BIBREF82"}, {"start": 672, "end": 676, "text": "[81]", "ref_id": "BIBREF83"}, {"start": 857, "end": 861, "text": "[82]", "ref_id": "BIBREF84"}, {"start": 1032, "end": 1036, "text": "[83,", "ref_id": "BIBREF85"}, {"start": 1037, "end": 1040, "text": "84]", "ref_id": "BIBREF86"}, {"start": 1289, "end": 1293, "text": "[77]", "ref_id": "BIBREF79"}], "ref_spans": []}, {"section": "Discussion", "text": "The second stress-associated factor, which could have contributed to the observed changes, is glutamate. Data from animal experiments show that stress causes an enhanced release of glutamate, and that a stress-related elevation of extracellular glutamate levels induces retraction in the spines in stress-targeted regions, such as the mPFC, ACC, and the basal ganglia [79, 85, 86, 87, 88] . Medial prefrontal cortex is reported to be sensitive to repetitive stress [89] . See also the review by Leuner and Shors [77] . Via glutamatergic excitation the mPFC and ACC send inhibitory GABA-ergic impulses to the amygdala, which is the primary cerebral relay for the processing of psychosocial stress stimuli [90] . One possible scenario is that the absence of prefrontal inhibition of the amygdala, due to the stress-mediated neurotoxic damage of the mPFC (due to high glutamate, cortisol or the combination of both [79, 91] , may cause amygdala hyperactivity [92] , providing a context for a vicious circle with increased excitation and excitotoxic changes along the networks linked to the amygdala and mPFC. These networks primarily include the dlPFC, the basal ganglia, and the limbic brain (the hippocampus and insular cortex). Whereas the ACC, the dlPFC, and the basal ganglia showed distinct changes, neither the hippocampus nor the insular cortex was seemingly affected according to our results, even though these regions were included in the specific search space defined by our limbic mask. This was unexpected, especially when considering that both structures had significant reductions in 5-HT 1A receptor binding potential in our previous study of a similar population [21] . The underlying reasons are not clear, and a larger population of subjects needs to be investigated before this lack of significance can be taken as an argument for specificity of the previously detected 5-HT 1A receptor changes.", "cite_spans": [{"start": 368, "end": 372, "text": "[79,", "ref_id": "BIBREF81"}, {"start": 373, "end": 376, "text": "85,", "ref_id": "BIBREF87"}, {"start": 377, "end": 380, "text": "86,", "ref_id": "BIBREF88"}, {"start": 381, "end": 384, "text": "87,", "ref_id": "BIBREF89"}, {"start": 385, "end": 388, "text": "88]", "ref_id": "BIBREF90"}, {"start": 465, "end": 469, "text": "[89]", "ref_id": "BIBREF91"}, {"start": 512, "end": 516, "text": "[77]", "ref_id": "BIBREF79"}, {"start": 704, "end": 708, "text": "[90]", "ref_id": "BIBREF92"}, {"start": 912, "end": 916, "text": "[79,", "ref_id": "BIBREF81"}, {"start": 917, "end": 920, "text": "91]", "ref_id": "BIBREF93"}, {"start": 956, "end": 960, "text": "[92]", "ref_id": "BIBREF94"}, {"start": 1677, "end": 1681, "text": "[21]", "ref_id": "BIBREF23"}], "ref_spans": []}, {"section": "Methodological limitations and strengths", "text": "Several methodological limitations deserve comment. Firstly, the sample was rather small even though the sensitivity was enhanced by the use of a homogenous study group. Secondly, causality cannot be determined in the present study, and longitudinal studies would be needed to provide a better understanding of the temporal relationships between morphological brain alterations and periods of psychosocial stress. The issue of comorbidity with depression is always a problem in a study group like our -as some symptoms are overlapping and the condition of profound fatigue and inability to lead a normal life is perceived as extremely taxing by some subjects. The stressed subjects were not deemed as depressed by the experienced psychiatrist. We also re-run the comparisons between groups using MADRAs scores as covariate in addition to age and gender when comparing the mean relative caudate and putamen values between the groups. The results remained (p = 0.0061 for caudate and p = 0.0002 for putamen). Also in the VBM analysis, when controlling for depression by entering depression scores as covariate the results remained unchanged. Finally, neuropsychological data was not collected systematically, as we whished to investigate weather there are any anatomical changes in the brain that could be related to occupational stress, before designing a study to test possible behavioural correlates. Such study is on going.", "cite_spans": [], "ref_spans": []}, {"section": "Methodological limitations and strengths", "text": "The advantage of the present study is that it combines VBM analysis and investigations of structural volumes. In regions with poor white and gray matter demarcation, as in the basal ganglia, volumetry is regarded as more reliable than VBM [43] , and the two methods should, therefore, be used in tandem. Consequently, it is not surprising that structural volumetry showed reductions in the basal ganglia while the corresponding GM and VM volumes did not differ from controls.", "cite_spans": [{"start": 239, "end": 243, "text": "[43]", "ref_id": "BIBREF45"}], "ref_spans": []}, {"section": "Conclusions", "text": "By investigating the GM and WM volumes and structural volumes of subjects who are experiencing chronic psychosocial stress, but do not have a history of a particular psychosocial trauma, the present study expands upon the data from animal experiments and reports from PTSD patients, and focuses on the involvement of the frontostriatal circuits in chronic stress. The finding of GM atrophy in regions known to be associated with chronic psychosocial stress confirms our previous conclusion that subjects reporting stereotyped symptoms from occupational stress have a medical condition requiring careful investigations and a targeted treatment. Larger series and consecutive investigations before and after treatments, as well as parallel mapping of cognitive and motor functions are highly encouraged in the future, and might have important implications for the understanding of this increasingly common condition.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Burnout in the general population. Results from the Finnish Health", "authors": [{"first": "K", "middle": [], "last": "Ahola", "suffix": ""}, {"first": "T", "middle": [], "last": "Honkonen", "suffix": ""}, {"first": "E", "middle": [], "last": "Isometsa", "suffix": ""}, {"first": "R", "middle": [], "last": "Kalimo", "suffix": ""}, {"first": "E", "middle": [], "last": "Nykyri", "suffix": ""}], "year": 2000, "venue": "Study. Soc Psychiatry Psychiatr Epidemiol", "link": null}, "BIBREF2": {"title": "Giornale italiano di medicina del", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF3": {"title": "Biological risk and health care workers: analysis of the effects of work chronobiology on the immune system", "authors": [{"first": "A", "middle": [], "last": "Copertaro", "suffix": ""}, {"first": "M", "middle": [], "last": "Bracci", "suffix": ""}, {"first": "M", "middle": [], "last": "Amati", "suffix": ""}, {"first": "E", "middle": [], "last": "Mocchegiani", "suffix": ""}, {"first": "M", "middle": [], "last": "Barbaresi", "suffix": ""}], "year": 2010, "venue": "", "link": "27098360"}, "BIBREF5": {"title": "Prevalence of burnout among anesthesiologists at Hospital", "authors": [{"first": "Fernandez", "middle": [], "last": "Torres", "suffix": ""}, {"first": "B", "middle": [], "last": "", "suffix": ""}, {"first": "Roldan", "middle": [], "last": "Perez", "suffix": ""}, {"first": "L", "middle": ["M"], "last": "", "suffix": ""}, {"first": "Guerra", "middle": [], "last": "Velez", "suffix": ""}, {"first": "A", "middle": [], "last": "", "suffix": ""}, {"first": "Roldan", "middle": [], "last": "Rodriguez", "suffix": ""}, {"first": "T", "middle": [], "last": "", "suffix": ""}, {"first": "Gutierrez", "middle": [], "last": "Guillen", "suffix": ""}, {"first": "A", "middle": [], "last": "", "suffix": ""}], "year": 2006, "venue": "", "link": null}, "BIBREF7": {"title": "Neuroendocrine, cognitive and structural imaging characteristics of women on longterm sickleave with job stress-induced depression", "authors": [{"first": "I", "middle": [], "last": "Rydmark", "suffix": ""}, {"first": "K", "middle": [], "last": "Wahlberg", "suffix": ""}, {"first": "P", "middle": ["H"], "last": "Ghatan", "suffix": ""}, {"first": "S", "middle": [], "last": "Modell", "suffix": ""}, {"first": "A", "middle": [], "last": "Nygren", "suffix": ""}], "year": 2006, "venue": "Biological psychiatry", "link": "13334508"}, "BIBREF8": {"title": "Impaired cognitive performance in patients with chronic burnout syndrome", "authors": [{"first": "A", "middle": [], "last": "Sandstrom", "suffix": ""}, {"first": "I", "middle": ["N"], "last": "Rhodin", "suffix": ""}, {"first": "M", "middle": [], "last": "Lundberg", "suffix": ""}, {"first": "T", "middle": [], "last": "Olsson", "suffix": ""}, {"first": "L", "middle": [], "last": "Nyberg", "suffix": ""}], "year": 2005, "venue": "Biol Psychol", "link": "565283"}, "BIBREF10": {"title": "Neural regulation of endocrine and autonomic stress responses", "authors": [{"first": "Y", "middle": ["M"], "last": "Ulrich-Lai", "suffix": ""}, {"first": "J", "middle": ["P"], "last": "Herman", "suffix": ""}], "year": 2009, "venue": "Nat Rev Neneurosci", "link": "205504991"}, "BIBREF11": {"title": "The cortisol awakening response (CAR): facts and future directions", "authors": [{"first": "E", "middle": [], "last": "Fries", "suffix": ""}, {"first": "L", "middle": [], "last": "Dettenborn", "suffix": ""}, {"first": "C", "middle": [], "last": "Kirschbaum", "suffix": ""}], "year": 2009, "venue": "Int J Psychophysiol", "link": "205350209"}, "BIBREF12": {"title": "Is burnout related to allostatic load?", "authors": [{"first": "S", "middle": [], "last": "Langelaan", "suffix": ""}, {"first": "A", "middle": ["B"], "last": "Bakker", "suffix": ""}, {"first": "W", "middle": ["B"], "last": "Schaufeli", "suffix": ""}, {"first": "W", "middle": [], "last": "Van Rhenen", "suffix": ""}, {"first": "L", "middle": ["J"], "last": "Van Doornen", "suffix": ""}], "year": 2007, "venue": "Int J Behav Med", "link": "43448582"}, "BIBREF13": {"title": "Clinical burnout is not reflected in the cortisol awakening response, the day-curve or the response to a low-dose dexamethasone suppression test", "authors": [{"first": "P", "middle": ["M"], "last": "Mommersteeg", "suffix": ""}, {"first": "C", "middle": ["J"], "last": "Heijnen", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Verbraak", "suffix": ""}, {"first": "L", "middle": ["J"], "last": "Van Doornen", "suffix": ""}], "year": 2006, "venue": "Psychoneuroendocrinology", "link": "8444094"}, "BIBREF14": {"title": "Longitudinal changes in pituitary-adrenal hormones in South African women with burnout", "authors": [{"first": "S", "middle": ["L"], "last": "Moch", "suffix": ""}, {"first": "V", "middle": ["R"], "last": "Panz", "suffix": ""}, {"first": "B", "middle": ["I"], "last": "Joffe", "suffix": ""}, {"first": "I", "middle": [], "last": "Havlik", "suffix": ""}, {"first": "J", "middle": ["D"], "last": "Moch", "suffix": ""}], "year": 2003, "venue": "Endocrine", "link": "28957544"}, "BIBREF15": {"title": "Cortisol deviations in people with burnout before and after psychotherapy: a pilot study", "authors": [{"first": "P", "middle": ["M"], "last": "Mommersteeg", "suffix": ""}, {"first": "G", "middle": ["P"], "last": "Keijsers", "suffix": ""}, {"first": "C", "middle": ["J"], "last": "Heijnen", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Verbraak", "suffix": ""}, {"first": "L", "middle": ["J"], "last": "Van Doornen", "suffix": ""}], "year": 2006, "venue": "Health Psychol", "link": "35830145"}, "BIBREF16": {"title": "Burnout, perceived stress, and cortisol responses to awakening", "authors": [{"first": "J", "middle": ["C"], "last": "Pruessner", "suffix": ""}, {"first": "D", "middle": ["H"], "last": "Hellhammer", "suffix": ""}, {"first": "C", "middle": [], "last": "Kirschbaum", "suffix": ""}], "year": 1999, "venue": "Psychosomatic medicine", "link": "25646483"}, "BIBREF17": {"title": "Cortisol awakening response and psychosocial factors: a systematic review and meta-analysis", "authors": [{"first": "Y", "middle": [], "last": "Chida", "suffix": ""}, {"first": "A", "middle": [], "last": "Steptoe", "suffix": ""}], "year": 2009, "venue": "Biol Psychol", "link": "36502754"}, "BIBREF18": {"title": "The morning salivary cortisol response in burnout", "authors": [{"first": "G", "middle": [], "last": "Grossi", "suffix": ""}, {"first": "A", "middle": [], "last": "Perski", "suffix": ""}, {"first": "M", "middle": [], "last": "Ekstedt", "suffix": ""}, {"first": "T", "middle": [], "last": "Johansson", "suffix": ""}, {"first": "M", "middle": [], "last": "Lindstrom", "suffix": ""}], "year": 2005, "venue": "J Psychosom Res", "link": "40220652"}, "BIBREF19": {"title": "Physiological correlates of burnout among women", "authors": [{"first": "G", "middle": [], "last": "Grossi", "suffix": ""}, {"first": "A", "middle": [], "last": "Perski", "suffix": ""}, {"first": "B", "middle": [], "last": "Evengard", "suffix": ""}, {"first": "V", "middle": [], "last": "Blomkvist", "suffix": ""}, {"first": "K", "middle": [], "last": "Orth-Gomer", "suffix": ""}], "year": 2003, "venue": "J Psychosom Res", "link": "33908932"}, "BIBREF20": {"title": "Chronic burnout, somatic arousal and elevated salivary cortisol levels", "authors": [{"first": "S", "middle": [], "last": "Melamed", "suffix": ""}, {"first": "U", "middle": [], "last": "Ugarten", "suffix": ""}, {"first": "A", "middle": [], "last": "Shirom", "suffix": ""}, {"first": "L", "middle": [], "last": "Kahana", "suffix": ""}, {"first": "Y", "middle": [], "last": "Lerman", "suffix": ""}], "year": 1999, "venue": "J Psychosom Res", "link": "26298876"}, "BIBREF21": {"title": "Dex/CRHtest response and sleep in depressed patients and healthy controls with and without vulnerability for affective disorders", "authors": [{"first": "E", "middle": [], "last": "Friess", "suffix": ""}, {"first": "D", "middle": [], "last": "Schmid", "suffix": ""}, {"first": "S", "middle": [], "last": "Modell", "suffix": ""}, {"first": "H", "middle": [], "last": "Brunner", "suffix": ""}, {"first": "C", "middle": ["J"], "last": "Lauer", "suffix": ""}], "year": 2008, "venue": "J Psychiatr Res", "link": "22919293"}, "BIBREF22": {"title": "Suppressed neuroendocrine stress response in depressed women on job-stressrelated long-term sick leave: a stable marker potentially suggestive of preexisting vulnerability", "authors": [{"first": "K", "middle": [], "last": "Wahlberg", "suffix": ""}, {"first": "P", "middle": ["H"], "last": "Ghatan", "suffix": ""}, {"first": "S", "middle": [], "last": "Modell", "suffix": ""}, {"first": "A", "middle": [], "last": "Nygren", "suffix": ""}, {"first": "M", "middle": [], "last": "Ingvar", "suffix": ""}], "year": 2009, "venue": "Biol Psychiatry", "link": "23118169"}, "BIBREF23": {"title": "Chronic stress is linked to 5-HT(1A) receptor changes and functional disintegration of the limbic networks", "authors": [{"first": "H", "middle": [], "last": "Jovanovic", "suffix": ""}, {"first": "A", "middle": [], "last": "Perski", "suffix": ""}, {"first": "H", "middle": [], "last": "Berglund", "suffix": ""}, {"first": "I", "middle": [], "last": "Savic", "suffix": ""}], "year": 2011, "venue": "NeuroImage", "link": "16390559"}, "BIBREF24": {"title": "Neuroimaging in posttraumatic stress disorder and other stress-related disorders", "authors": [{"first": "J", "middle": ["D"], "last": "Bremner", "suffix": ""}], "year": 2007, "venue": "Neuroimaging Clin N Am", "link": "8547232"}, "BIBREF25": {"title": "Structural and functional plasticity of the human brain in posttraumatic stress disorder", "authors": [{"first": "J", "middle": ["D"], "last": "Bremner", "suffix": ""}, {"first": "B", "middle": [], "last": "Elzinga", "suffix": ""}, {"first": "C", "middle": [], "last": "Schmahl", "suffix": ""}, {"first": "E", "middle": [], "last": "Vermetten", "suffix": ""}], "year": 2008, "venue": "Prog Brain Res", "link": "36701432"}, "BIBREF26": {"title": "Early life stress and morphometry of the adult anterior cingulate cortex and caudate nuclei", "authors": [{"first": "R", "middle": ["A"], "last": "Cohen", "suffix": ""}, {"first": "S", "middle": [], "last": "Grieve", "suffix": ""}, {"first": "K", "middle": ["F"], "last": "Hoth", "suffix": ""}, {"first": "R", "middle": ["H"], "last": "Paul", "suffix": ""}, {"first": "L", "middle": [], "last": "Sweet", "suffix": ""}], "year": 2006, "venue": "Biological psychiatry", "link": "23397179"}, "BIBREF27": {"title": "Thinner prefrontal cortex in veterans with posttraumatic stress disorder", "authors": [{"first": "E", "middle": [], "last": "Geuze", "suffix": ""}, {"first": "H", "middle": ["G"], "last": "Westenberg", "suffix": ""}, {"first": "A", "middle": [], "last": "Heinecke", "suffix": ""}, {"first": "C", "middle": ["S"], "last": "De Kloet", "suffix": ""}, {"first": "R", "middle": [], "last": "Goebel", "suffix": ""}], "year": 2008, "venue": "NeuroImage", "link": "207168976"}, "BIBREF28": {"title": "Evidence for acquired pregenual anterior cingulate gray matter loss from a twin study of combat-related posttraumatic stress disorder", "authors": [{"first": "K", "middle": [], "last": "Kasai", "suffix": ""}, {"first": "H", "middle": [], "last": "Yamasue", "suffix": ""}, {"first": "M", "middle": ["W"], "last": "Gilbertson", "suffix": ""}, {"first": "M", "middle": ["E"], "last": "Shenton", "suffix": ""}, {"first": "S", "middle": ["L"], "last": "Rauch", "suffix": ""}], "year": 2008, "venue": "Biological psychiatry", "link": "6380372"}, "BIBREF29": {"title": "Effects of stressful life events on human brain structure: a longitudinal voxelbased morphometry study", "authors": [{"first": "S", "middle": ["A"], "last": "Papagni", "suffix": ""}, {"first": "S", "middle": [], "last": "Benetti", "suffix": ""}, {"first": "S", "middle": [], "last": "Arulanantham", "suffix": ""}, {"first": "E", "middle": [], "last": "Mccrory", "suffix": ""}, {"first": "P", "middle": [], "last": "Mcguire", "suffix": ""}], "year": 2011, "venue": "Stress", "link": "10469661"}, "BIBREF30": {"title": "Bilateral MR volumetry of the amygdala in chronic PTSD patients", "authors": [{"first": "G", "middle": [], "last": "Pavlisa", "suffix": ""}, {"first": "J", "middle": [], "last": "Papa", "suffix": ""}, {"first": "L", "middle": [], "last": "Pavic", "suffix": ""}, {"first": "G", "middle": [], "last": "Pavlisa", "suffix": ""}], "year": 2006, "venue": "Coll Antropol", "link": "22878501"}, "BIBREF31": {"title": "Reduced medial prefrontal cortex volume in adults reporting childhood emotional maltreatment", "authors": [{"first": "A", "middle": ["L"], "last": "Van Harmelen", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Van Tol", "suffix": ""}, {"first": "N", "middle": ["J"], "last": "Van Der Wee", "suffix": ""}, {"first": "D", "middle": ["J"], "last": "Veltman", "suffix": ""}, {"first": "A", "middle": [], "last": "Aleman", "suffix": ""}], "year": 2010, "venue": "Biological psychiatry", "link": "16178895"}, "BIBREF32": {"title": "Impact of acute stress on human brain microstructure: An MR diffusion study of earthquake survivors", "authors": [{"first": "L", "middle": [], "last": "Chen", "suffix": ""}, {"first": "S", "middle": [], "last": "Lui", "suffix": ""}, {"first": "Q", "middle": ["Z"], "last": "Wu", "suffix": ""}, {"first": "W", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "D", "middle": [], "last": "Zhou", "suffix": ""}], "year": 2011, "venue": "", "link": "31215283"}, "BIBREF33": {"title": "Sex differences in stress response circuitry activation dependent on female hormonal cycle", "authors": [{"first": "J", "middle": ["M"], "last": "Goldstein", "suffix": ""}, {"first": "M", "middle": [], "last": "Jerram", "suffix": ""}, {"first": "B", "middle": [], "last": "Abbs", "suffix": ""}, {"first": "S", "middle": [], "last": "Whitfield-Gabrieli", "suffix": ""}, {"first": "N", "middle": [], "last": "Makris", "suffix": ""}], "year": 2010, "venue": "J Neurosci", "link": "4176148"}, "BIBREF34": {"title": "Stress, adaptation, and disease. Allostasis and allostatic load", "authors": [{"first": "B", "middle": ["S"], "last": "Mcewen", "suffix": ""}], "year": 1998, "venue": "Annals of the New York Academy of Sciences", "link": "20043016"}, "BIBREF35": {"title": "Perfusion functional MRI reveals cerebral blood flow pattern under psychological stress", "authors": [{"first": "J", "middle": [], "last": "Wang", "suffix": ""}, {"first": "H", "middle": [], "last": "Rao", "suffix": ""}, {"first": "G", "middle": ["S"], "last": "Wetmore", "suffix": ""}, {"first": "P", "middle": ["M"], "last": "Furlan", "suffix": ""}, {"first": "M", "middle": [], "last": "Korczykowski", "suffix": ""}], "year": 2005, "venue": "Proceedings of the National Academy of Sciences of the United States of America", "link": "8076191"}, "BIBREF36": {"title": "Impact of early vs. late childhood early life stress on brain morphometrics", "authors": [{"first": "L", "middle": ["M"], "last": "Baker", "suffix": ""}, {"first": "L", "middle": ["M"], "last": "Williams", "suffix": ""}, {"first": "M", "middle": ["S"], "last": "Korgaonkar", "suffix": ""}, {"first": "R", "middle": ["A"], "last": "Cohen", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Heaps", "suffix": ""}], "year": 2012, "venue": "Brain Imaging Behav", "link": "90644"}, "BIBREF37": {"title": "Dynamics of central nervous 5-HT1A-receptors under psychosocial stress", "authors": [{"first": "G", "middle": [], "last": "Flugge", "suffix": ""}], "year": 1995, "venue": "J Neurosci", "link": "23496657"}, "BIBREF38": {"title": "The assessment and analysis of handedness: the Edinburgh inventory", "authors": [{"first": "R", "middle": ["C"], "last": "Oldfield", "suffix": ""}], "year": 1971, "venue": "Neuropsychologia", "link": null}, "BIBREF39": {"title": "A cautionary note about the crossnational and clinical validity of cut-off points for the Maslach Burnout Inventory", "authors": [{"first": "W", "middle": ["B"], "last": "Schaufeli", "suffix": ""}, {"first": "D", "middle": [], "last": "Van Dierendonck", "suffix": ""}], "year": 1995, "venue": "Psychological reports", "link": "9711078"}, "BIBREF40": {"title": "Patients with burnout in relation to gender and a general population", "authors": [{"first": "T", "middle": [], "last": "Stenlund", "suffix": ""}, {"first": "C", "middle": [], "last": "Ahlgren", "suffix": ""}, {"first": "B", "middle": [], "last": "Lindahl", "suffix": ""}, {"first": "G", "middle": [], "last": "Burell", "suffix": ""}, {"first": "A", "middle": [], "last": "Knutsson", "suffix": ""}], "year": 2007, "venue": "Scand J Public Health", "link": "3106561"}, "BIBREF41": {"title": "The Social Readjustment Rating Scale", "authors": [{"first": "T", "middle": ["H"], "last": "Holmes", "suffix": ""}, {"first": "R", "middle": ["H"], "last": "Rahe", "suffix": ""}], "year": 1967, "venue": "J Psychosom Res", "link": "30573353"}, "BIBREF42": {"title": "Cross cultural studies on the use of CPRS in English and Swedish depressed patients", "authors": [{"first": "S", "middle": [], "last": "Montgomery", "suffix": ""}, {"first": "M", "middle": [], "last": "Asberg", "suffix": ""}, {"first": "L", "middle": [], "last": "Traskman", "suffix": ""}, {"first": "D", "middle": [], "last": "Montgomery", "suffix": ""}], "year": 1978, "venue": "Acta Psychiatr Scand", "link": "29978882"}, "BIBREF43": {"title": "The dopamine system in idiopathic generalized epilepsies: identification of syndrome-related changes", "authors": [{"first": "C", "middle": [], "last": "Ciumas", "suffix": ""}, {"first": "T", "middle": ["B"], "last": "Wahlin", "suffix": ""}, {"first": "C", "middle": [], "last": "Espino", "suffix": ""}, {"first": "I", "middle": [], "last": "Savic", "suffix": ""}], "year": 2010, "venue": "Neuroimage", "link": "5392506"}, "BIBREF44": {"title": "A fast diffeomorphic image registration algorithm", "authors": [{"first": "J", "middle": [], "last": "Ashburner", "suffix": ""}], "year": 2007, "venue": "NeuroImage", "link": "545830"}, "BIBREF45": {"title": "Structural changes in patients with primary generalized tonic and clonic seizures", "authors": [{"first": "C", "middle": [], "last": "Ciumas", "suffix": ""}, {"first": "I", "middle": [], "last": "Savic", "suffix": ""}], "year": 2006, "venue": "Neurology", "link": "24150455"}, "BIBREF46": {"title": "Increased thalamus levels of glutamate and glutamine (Glx) in patients with idiopathic generalised epilepsy", "authors": [{"first": "G", "middle": [], "last": "Helms", "suffix": ""}, {"first": "C", "middle": [], "last": "Ciumas", "suffix": ""}, {"first": "S", "middle": [], "last": "Kyaga", "suffix": ""}, {"first": "I", "middle": [], "last": "Savic", "suffix": ""}], "year": 2006, "venue": "J Neurol Neurosurg Psychiatry", "link": "5779617"}, "BIBREF47": {"title": "PET and MRI show differences in cerebral asymmetry and functional connectivity between homo-and heterosexual subjects", "authors": [{"first": "I", "middle": [], "last": "Savic", "suffix": ""}, {"first": "P", "middle": [], "last": "Lindstrom", "suffix": ""}], "year": 2008, "venue": "Proc Natl Acad Sci U S A", "link": "14880188"}, "BIBREF48": {"title": "Anatomic basis of amygdaloid and hippocampal volume measurement by magnetic resonance imaging", "authors": [{"first": "C", "middle": [], "last": "Watson", "suffix": ""}, {"first": "F", "middle": [], "last": "Andermann", "suffix": ""}, {"first": "P", "middle": [], "last": "Gloor", "suffix": ""}, {"first": "M", "middle": [], "last": "Jones-Gotman", "suffix": ""}, {"first": "T", "middle": [], "last": "Peters", "suffix": ""}], "year": 1992, "venue": "Neurology", "link": "38435124"}, "BIBREF49": {"title": "Regional brain changes in aging healthy adults: general trends, individual differences and modifiers", "authors": [{"first": "N", "middle": [], "last": "Raz", "suffix": ""}, {"first": "U", "middle": [], "last": "Lindenberger", "suffix": ""}, {"first": "K", "middle": ["M"], "last": "Rodrigue", "suffix": ""}, {"first": "K", "middle": ["M"], "last": "Kennedy", "suffix": ""}, {"first": "D", "middle": [], "last": "Head", "suffix": ""}], "year": 2005, "venue": "Cereb Cortex", "link": "14037828"}, "BIBREF50": {"title": "Physiology and neurobiology of stress and adaptation: central role of the brain", "authors": [{"first": "B", "middle": ["S"], "last": "Mcewen", "suffix": ""}], "year": 2007, "venue": "Physiol Rev", "link": "16840184"}, "BIBREF51": {"title": "Neural circuits underlying emotional distress in humans", "authors": [{"first": "R", "middle": [], "last": "Sinha", "suffix": ""}, {"first": "C", "middle": [], "last": "Lacadie", "suffix": ""}, {"first": "P", "middle": [], "last": "Skudlarski", "suffix": ""}, {"first": "B", "middle": ["E"], "last": "Wexler", "suffix": ""}], "year": 2004, "venue": "Annals of the New York Academy of Sciences", "link": "36119493"}, "BIBREF52": {"title": "Neural correlates of processing stressful information: an event-related fMRI study", "authors": [{"first": "K", "middle": [], "last": "Dedovic", "suffix": ""}, {"first": "M", "middle": [], "last": "Rexroth", "suffix": ""}, {"first": "E", "middle": [], "last": "Wolff", "suffix": ""}, {"first": "A", "middle": [], "last": "Duchesne", "suffix": ""}, {"first": "C", "middle": [], "last": "Scherling", "suffix": ""}], "year": 2009, "venue": "Brain research", "link": "27118224"}, "BIBREF53": {"title": "Acute psychological stress reduces working memory-related activity in the dorsolateral prefrontal cortex", "authors": [{"first": "S", "middle": [], "last": "Qin", "suffix": ""}, {"first": "E", "middle": ["J"], "last": "Hermans", "suffix": ""}, {"first": "H", "middle": ["J"], "last": "Van Marle", "suffix": ""}, {"first": "J", "middle": [], "last": "Luo", "suffix": ""}, {"first": "G", "middle": [], "last": "Fernandez", "suffix": ""}], "year": 2009, "venue": "Biological psychiatry", "link": "147678393"}, "BIBREF54": {"title": "Gray matter density in limbic and paralimbic cortices is associated with trauma load and EMDR outcome in PTSD patients", "authors": [{"first": "D", "middle": [], "last": "Nardo", "suffix": ""}, {"first": "G", "middle": [], "last": "Hogberg", "suffix": ""}, {"first": "J", "middle": ["C"], "last": "Looi", "suffix": ""}, {"first": "S", "middle": [], "last": "Larsson", "suffix": ""}, {"first": "T", "middle": [], "last": "Hallstrom", "suffix": ""}], "year": 2010, "venue": "J Psychiatr Res", "link": "6574222"}, "BIBREF55": {"title": "Reduced anterior cingulate and orbitofrontal volumes in child abuserelated complex PTSD", "authors": [{"first": "K", "middle": [], "last": "Thomaes", "suffix": ""}, {"first": "E", "middle": [], "last": "Dorrepaal", "suffix": ""}, {"first": "N", "middle": [], "last": "Draijer", "suffix": ""}, {"first": "M", "middle": ["B"], "last": "De Ruiter", "suffix": ""}, {"first": "A", "middle": ["J"], "last": "Van Balkom", "suffix": ""}], "year": 2010, "venue": "J Clin Psychiatry", "link": "24917173"}, "BIBREF56": {"title": "Voxelbased analysis of MRI reveals anterior cingulate gray-matter volume reduction in posttraumatic stress disorder due to terrorism", "authors": [{"first": "H", "middle": [], "last": "Yamasue", "suffix": ""}, {"first": "K", "middle": [], "last": "Kasai", "suffix": ""}, {"first": "A", "middle": [], "last": "Iwanami", "suffix": ""}, {"first": "T", "middle": [], "last": "Ohtani", "suffix": ""}, {"first": "H", "middle": [], "last": "Yamada", "suffix": ""}], "year": 2003, "venue": "Proceedings of the National Academy of Sciences of the United States of America", "link": "22827617"}, "BIBREF57": {"title": "The neurobiological role of the dorsolateral prefrontal cortex in recovery from trauma. Longitudinal brain imaging study among survivors of the South Korean subway disaster", "authors": [{"first": "I", "middle": ["K"], "last": "Lyoo", "suffix": ""}, {"first": "J", "middle": ["E"], "last": "Kim", "suffix": ""}, {"first": "S", "middle": ["J"], "last": "Yoon", "suffix": ""}, {"first": "J", "middle": [], "last": "Hwang", "suffix": ""}, {"first": "S", "middle": [], "last": "Bae", "suffix": ""}], "year": 2011, "venue": "Archives of general psychiatry", "link": "6876606"}, "BIBREF58": {"title": "Harsh corporal punishment is associated with increased T2 relaxation time in dopamine-rich regions", "authors": [{"first": "Y", "middle": ["S"], "last": "Sheu", "suffix": ""}, {"first": "A", "middle": [], "last": "Polcari", "suffix": ""}, {"first": "C", "middle": ["M"], "last": "Anderson", "suffix": ""}, {"first": "M", "middle": ["H"], "last": "Teicher", "suffix": ""}], "year": 2010, "venue": "NeuroImage", "link": "36393321"}, "BIBREF59": {"title": "Volume changes of corpus striatum, thalamus, hippocampus and lateral ventricles in posttraumatic stress disorder (PTSD) patients suffering from headaches and without therapy", "authors": [{"first": "B", "middle": ["R"], "last": "Filipovic", "suffix": ""}, {"first": "B", "middle": [], "last": "Djurovic", "suffix": ""}, {"first": "S", "middle": [], "last": "Marinkovic", "suffix": ""}, {"first": "L", "middle": [], "last": "Stijak", "suffix": ""}, {"first": "M", "middle": [], "last": "Aksic", "suffix": ""}], "year": 2011, "venue": "Cent Eur Neurosurg", "link": "223012"}, "BIBREF60": {"title": "Psychosocial stress reversibly disrupts prefrontal processing and attentional control", "authors": [{"first": "C", "middle": [], "last": "Liston", "suffix": ""}, {"first": "B", "middle": ["S"], "last": "Mcewen", "suffix": ""}, {"first": "B", "middle": ["J"], "last": "Casey", "suffix": ""}], "year": 2009, "venue": "Proceedings of the National Academy of Sciences of the United States of America", "link": "15900285"}, "BIBREF61": {"title": "Gender difference in neural response to psychological stress", "authors": [{"first": "J", "middle": [], "last": "Wang", "suffix": ""}, {"first": "M", "middle": [], "last": "Korczykowski", "suffix": ""}, {"first": "H", "middle": [], "last": "Rao", "suffix": ""}, {"first": "Y", "middle": [], "last": "Fan", "suffix": ""}, {"first": "J", "middle": [], "last": "Pluta", "suffix": ""}], "year": 2007, "venue": "Soc Cogn Affect Neurosci", "link": "6229840"}, "BIBREF62": {"title": "Protective and damaging effects of stress mediators: central role of the brain", "authors": [{"first": "B", "middle": ["S"], "last": "Mcewen", "suffix": ""}], "year": 2000, "venue": "Prog Brain Res", "link": "27802404"}, "BIBREF63": {"title": "Differential vulnerability of hippocampus, basal ganglia, and prefrontal cortex to long-term NMDA excitotoxicity", "authors": [{"first": "F", "middle": [], "last": "Bernal", "suffix": ""}, {"first": "J", "middle": [], "last": "Saura", "suffix": ""}, {"first": "J", "middle": [], "last": "Ojuel", "suffix": ""}, {"first": "N", "middle": [], "last": "Mahy", "suffix": ""}], "year": 2000, "venue": "Exp Neurol", "link": "23993150"}, "BIBREF64": {"title": "Glutamatemediated excitotoxic death of cultured striatal neurons is mediated by non-NMDA receptors", "authors": [{"first": "Q", "middle": [], "last": "Chen", "suffix": ""}, {"first": "C", "middle": [], "last": "Harris", "suffix": ""}, {"first": "C", "middle": ["S"], "last": "Brown", "suffix": ""}, {"first": "A", "middle": [], "last": "Howe", "suffix": ""}, {"first": "D", "middle": ["J"], "last": "Surmeier", "suffix": ""}], "year": 1995, "venue": "Exp Neurol", "link": "3085123"}, "BIBREF65": {"title": "Locomotor activity and a conditioned fear response: correlation with cortical and subcortical binding of the dopamine D1 receptor antagonist", "authors": [{"first": "M", "middle": [], "last": "Siemiatkowski", "suffix": ""}, {"first": "D", "middle": [], "last": "Rokicki", "suffix": ""}, {"first": "A", "middle": ["I"], "last": "Czlonkowska", "suffix": ""}, {"first": "H", "middle": [], "last": "Sienkiewicz-Jarosz", "suffix": ""}, {"first": "A", "middle": [], "last": "Bidzinski", "suffix": ""}], "year": 2000, "venue": "Neuroreport", "link": "28644499"}, "BIBREF66": {"title": "Psychophysiology of neural, cognitive and affective integration: fMRI and autonomic indicants", "authors": [{"first": "H", "middle": ["D"], "last": "Critchley", "suffix": ""}], "year": 2009, "venue": "Int J Psychophysiol", "link": "12997723"}, "BIBREF67": {"title": "A PET study of 5-HT1A receptors at different phases of the menstrual cycle in women with premenstrual dysphoria", "authors": [{"first": "H", "middle": [], "last": "Jovanovic", "suffix": ""}, {"first": "A", "middle": [], "last": "Cerin", "suffix": ""}, {"first": "P", "middle": [], "last": "Karlsson", "suffix": ""}, {"first": "J", "middle": [], "last": "Lundberg", "suffix": ""}, {"first": "C", "middle": [], "last": "Halldin", "suffix": ""}], "year": 2006, "venue": "Psychiatry Res", "link": "906636"}, "BIBREF68": {"title": "A volumetric study of amygdala in cancer survivors with intrusive recollections", "authors": [{"first": "Y", "middle": [], "last": "Matsuoka", "suffix": ""}, {"first": "S", "middle": [], "last": "Yamawaki", "suffix": ""}, {"first": "M", "middle": [], "last": "Inagaki", "suffix": ""}, {"first": "T", "middle": [], "last": "Akechi", "suffix": ""}, {"first": "Y", "middle": [], "last": "Uchitomi", "suffix": ""}], "year": 2003, "venue": "Biological psychiatry", "link": "23840037"}, "BIBREF69": {"title": "Smaller amygdala volume and reduced anterior cingulate gray matter density associated with history of post-traumatic stress disorder", "authors": [{"first": "M", "middle": ["A"], "last": "Rogers", "suffix": ""}, {"first": "H", "middle": [], "last": "Yamasue", "suffix": ""}, {"first": "O", "middle": [], "last": "Abe", "suffix": ""}, {"first": "H", "middle": [], "last": "Yamada", "suffix": ""}, {"first": "T", "middle": [], "last": "Ohtani", "suffix": ""}], "year": 2009, "venue": "Psychiatry Res", "link": "9829532"}, "BIBREF70": {"title": "Longitudinal MRI study of hippocampal volume in trauma survivors with PTSD", "authors": [{"first": "O", "middle": [], "last": "Bonne", "suffix": ""}, {"first": "D", "middle": [], "last": "Brandes", "suffix": ""}, {"first": "A", "middle": [], "last": "Gilboa", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Gomori", "suffix": ""}, {"first": "M", "middle": ["E"], "last": "Shenton", "suffix": ""}], "year": 2001, "venue": "Am J Psychiatry", "link": "6608302"}, "BIBREF71": {"title": "Smaller hippocampal volume predicts pathologic vulnerability to psychological trauma", "authors": [{"first": "M", "middle": ["W"], "last": "Gilbertson", "suffix": ""}, {"first": "M", "middle": ["E"], "last": "Shenton", "suffix": ""}, {"first": "A", "middle": [], "last": "Ciszewski", "suffix": ""}, {"first": "K", "middle": [], "last": "Kasai", "suffix": ""}, {"first": "N", "middle": ["B"], "last": "Lasko", "suffix": ""}], "year": 2002, "venue": "Nat Neurosci", "link": "2083689"}, "BIBREF72": {"title": "Smaller hippocampal volume in patients with recent-onset posttraumatic stress disorder", "authors": [{"first": "E", "middle": ["L"], "last": "Wignall", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Dickson", "suffix": ""}, {"first": "P", "middle": [], "last": "Vaughan", "suffix": ""}, {"first": "T", "middle": ["F"], "last": "Farrow", "suffix": ""}, {"first": "I", "middle": ["D"], "last": "Wilkinson", "suffix": ""}], "year": 2004, "venue": "Biological psychiatry", "link": "22503007"}, "BIBREF73": {"title": "Reduced hippocampal volume and total white matter volume in posttraumatic stress disorder", "authors": [{"first": "G", "middle": [], "last": "Villarreal", "suffix": ""}, {"first": "D", "middle": ["A"], "last": "Hamilton", "suffix": ""}, {"first": "H", "middle": [], "last": "Petropoulos", "suffix": ""}, {"first": "I", "middle": [], "last": "Driscoll", "suffix": ""}, {"first": "L", "middle": ["M"], "last": "Rowland", "suffix": ""}], "year": 2002, "venue": "Biological psychiatry", "link": "5284014"}, "BIBREF74": {"title": "Stress, sensitive periods and maturational events in adolescent depression", "authors": [{"first": "S", "middle": ["L"], "last": "Andersen", "suffix": ""}, {"first": "M", "middle": ["H"], "last": "Teicher", "suffix": ""}], "year": 2008, "venue": "Trends Neurosci", "link": "7783104"}, "BIBREF75": {"title": "Preliminary evidence for sensitive periods in the effect of childhood sexual abuse on regional brain development", "authors": [{"first": "S", "middle": ["L"], "last": "Andersen", "suffix": ""}, {"first": "A", "middle": [], "last": "Tomada", "suffix": ""}, {"first": "E", "middle": ["S"], "last": "Vincow", "suffix": ""}, {"first": "E", "middle": [], "last": "Valente", "suffix": ""}, {"first": "A", "middle": [], "last": "Polcari", "suffix": ""}], "year": 2008, "venue": "J Neuropsychiatry Clin Neurosci", "link": "40246835"}, "BIBREF76": {"title": "Gray matter density reduction in the insula in fire survivors with posttraumatic stress disorder: a voxel-based morphometric study", "authors": [{"first": "S", "middle": [], "last": "Chen", "suffix": ""}, {"first": "W", "middle": [], "last": "Xia", "suffix": ""}, {"first": "L", "middle": [], "last": "Li", "suffix": ""}, {"first": "J", "middle": [], "last": "Liu", "suffix": ""}, {"first": "Z", "middle": [], "last": "He", "suffix": ""}], "year": 2006, "venue": "Psychiatry Res", "link": "6614728"}, "BIBREF77": {"title": "Decreased gray matter volume in the left hippocampus and bilateral calcarine cortex in coal mine flood disaster survivors with recent onset PTSD", "authors": [{"first": "J", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "Q", "middle": [], "last": "Tan", "suffix": ""}, {"first": "H", "middle": [], "last": "Yin", "suffix": ""}, {"first": "X", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "Y", "middle": [], "last": "Huan", "suffix": ""}], "year": 2011, "venue": "Psychiatry Res", "link": "207443835"}, "BIBREF78": {"title": "Chronic stress-induced hippocampal vulnerability: the glucocorticoid vulnerability hypothesis", "authors": [{"first": "C", "middle": ["D"], "last": "Conrad", "suffix": ""}], "year": 2008, "venue": "Rev Neurosci", "link": "9053414"}, "BIBREF79": {"title": "Stress, anxiety, and dendritic spines: What are the connections? Neuroscience", "authors": [{"first": "B", "middle": [], "last": "Leuner", "suffix": ""}, {"first": "T", "middle": ["J"], "last": "Shors", "suffix": ""}], "year": 2012, "venue": "", "link": null}, "BIBREF80": {"title": "Effects of lamotrigine on hippocampal activation in corticosteroid-treated patients", "authors": [{"first": "E", "middle": ["S"], "last": "Brown", "suffix": ""}, {"first": "L", "middle": [], "last": "Zaidel", "suffix": ""}, {"first": "G", "middle": [], "last": "Allen", "suffix": ""}, {"first": "R", "middle": [], "last": "Mccoll", "suffix": ""}, {"first": "M", "middle": [], "last": "Vazquez", "suffix": ""}], "year": 2010, "venue": "Journal of affective disorders", "link": "28746312"}, "BIBREF81": {"title": "Stress-induced atrophy of apical dendrites of hippocampal CA3c neurons: involvement of glucocorticoid secretion and excitatory amino acid receptors", "authors": [{"first": "A", "middle": ["M"], "last": "Magarinos", "suffix": ""}, {"first": "B", "middle": ["S"], "last": "Mcewen", "suffix": ""}], "year": 1995, "venue": "Neuroscience", "link": "22418609"}, "BIBREF82": {"title": "The neurobiology of stress: from serendipity to clinical relevance", "authors": [{"first": "B", "middle": ["S"], "last": "Mcewen", "suffix": ""}], "year": 2000, "venue": "Brain research", "link": null}, "BIBREF83": {"title": "Chronic psychosocial stress reduces the density of dopamine transporters", "authors": [{"first": "E", "middle": [], "last": "Isovich", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Mijnster", "suffix": ""}, {"first": "G", "middle": [], "last": "Flugge", "suffix": ""}, {"first": "E", "middle": [], "last": "Fuchs", "suffix": ""}], "year": 2000, "venue": "Eur J Neurosci", "link": "39688767"}, "BIBREF84": {"title": "The corticoid environment: a determining factor for neural progenitors' survival in the adult hippocampus", "authors": [{"first": "E", "middle": ["Y"], "last": "Wong", "suffix": ""}, {"first": "J", "middle": [], "last": "Herbert", "suffix": ""}], "year": 2004, "venue": "Eur J Neurosci", "link": "8113218"}, "BIBREF85": {"title": "Recovery of glucocorticoid-related loss of synaptic density in the fetal sheep brain at 0.75 of gestation", "authors": [{"first": "C", "middle": [], "last": "Colberg", "suffix": ""}, {"first": "I", "middle": [], "last": "Antonow-Schlorke", "suffix": ""}, {"first": "T", "middle": [], "last": "Muller", "suffix": ""}, {"first": "H", "middle": [], "last": "Schubert", "suffix": ""}, {"first": "O", "middle": ["W"], "last": "Witte", "suffix": ""}], "year": 2004, "venue": "Neurosci Lett", "link": "43912383"}, "BIBREF86": {"title": "Repeated restraint stress facilitates fear conditioning independently of causing hippocampal CA3 dendritic atrophy", "authors": [{"first": "C", "middle": ["D"], "last": "Conrad", "suffix": ""}, {"first": "J", "middle": ["E"], "last": "Ledoux", "suffix": ""}, {"first": "A", "middle": ["M"], "last": "Magarinos", "suffix": ""}, {"first": "B", "middle": ["S"], "last": "Mcewen", "suffix": ""}], "year": 1999, "venue": "Behav Neurosci", "link": "29265452"}, "BIBREF87": {"title": "Regulation of kainate receptor subunit mRNA by stress and corticosteroids in the rat hippocampus", "authors": [{"first": "R", "middle": ["G"], "last": "Hunter", "suffix": ""}, {"first": "R", "middle": [], "last": "Bellani", "suffix": ""}, {"first": "E", "middle": [], "last": "Bloss", "suffix": ""}, {"first": "A", "middle": [], "last": "Costa", "suffix": ""}, {"first": "K", "middle": [], "last": "Mccarthy", "suffix": ""}], "year": 2009, "venue": "PloS one", "link": "12656533"}, "BIBREF88": {"title": "Effects of metabotropic glutamate 2/3 receptor antagonists in the stress-induced hyperthermia test in singly housed mice", "authors": [{"first": "M", "middle": [], "last": "Iijima", "suffix": ""}, {"first": "T", "middle": [], "last": "Shimazaki", "suffix": ""}, {"first": "A", "middle": [], "last": "Ito", "suffix": ""}, {"first": "S", "middle": [], "last": "Chaki", "suffix": ""}], "year": 2007, "venue": "Psychopharmacology", "link": "2043084"}, "BIBREF89": {"title": "Adrenalectomy attenuates stressinduced elevations in extracellular glutamate concentrations in the hippocampus", "authors": [{"first": "M", "middle": ["T"], "last": "Lowy", "suffix": ""}, {"first": "L", "middle": [], "last": "Gault", "suffix": ""}, {"first": "B", "middle": ["K"], "last": "Yamamoto", "suffix": ""}], "year": 1993, "venue": "Journal of neurochemistry", "link": null}, "BIBREF90": {"title": "Prevention of stress-induced morphological and cognitive consequences", "authors": [{"first": "B", "middle": ["S"], "last": "Mcewen", "suffix": ""}, {"first": "C", "middle": ["D"], "last": "Conrad", "suffix": ""}, {"first": "Y", "middle": [], "last": "Kuroda", "suffix": ""}, {"first": "M", "middle": [], "last": "Frankfurt", "suffix": ""}, {"first": "A", "middle": ["M"], "last": "Magarinos", "suffix": ""}], "year": 1997, "venue": "Eur Neuropsychopharmacol", "link": "22484546"}, "BIBREF91": {"title": "Mild, short-term stress alters dendritic morphology in rat medial prefrontal cortex", "authors": [{"first": "S", "middle": ["M"], "last": "Brown", "suffix": ""}, {"first": "S", "middle": [], "last": "Henning", "suffix": ""}, {"first": "C", "middle": ["L"], "last": "Wellman", "suffix": ""}], "year": 2005, "venue": "Cereb Cortex", "link": "15331326"}, "BIBREF92": {"title": "Limbic system mechanisms of stress regulation: hypothalamo-pituitary-adrenocortical axis", "authors": [{"first": "J", "middle": ["P"], "last": "Herman", "suffix": ""}, {"first": "M", "middle": ["M"], "last": "Ostrander", "suffix": ""}, {"first": "N", "middle": ["K"], "last": "Mueller", "suffix": ""}, {"first": "H", "middle": [], "last": "Figueiredo", "suffix": ""}], "year": 2005, "venue": "Progress in neuro-psychopharmacology & biological psychiatry", "link": "207408045"}, "BIBREF93": {"title": "NMDA receptor blockade alters stress-induced dendritic remodeling in medial prefrontal cortex", "authors": [{"first": "K", "middle": ["P"], "last": "Martin", "suffix": ""}, {"first": "C", "middle": ["L"], "last": "Wellman", "suffix": ""}], "year": 2011, "venue": "Cereb Cortex", "link": "14811381"}, "BIBREF94": {"title": "The basolateral amygdala interacts with the medial prefrontal cortex in regulating glucocorticoid effects on working memory impairment", "authors": [{"first": "B", "middle": [], "last": "Roozendaal", "suffix": ""}, {"first": "J", "middle": ["R"], "last": "Mcreynolds", "suffix": ""}, {"first": "J", "middle": ["L"], "last": "Mcgaugh", "suffix": ""}], "year": 2004, "venue": "J Neurosci", "link": "8630001"}}, "ref_entries": {"FIGREF0": {"text": "Matlab 7.3 (Math Works, Natick, MA). The VBM pre-processing included five steps: 1) Check for scanner artifacts and gross anatomical abnormal- ities for each subject. 2) Set of image origin at the Anterior Commissure AC. 3) Using the Hidden Markov Random Field (HMRF) option in the segmentation of the VBM5 toolbox to minimize the noise level of the segmentation. 4) Using the Diffeomorphic Anatomical Registration Through Lie Algebra toolbox (DARTEL, Wellcome Department of Imaging Neuroscience, University College London, UK; http://www.fil.ion.ucl.ac.uk/spm) for a high-dimensional normalization protocol. We followed the standard version of John Ashburner's chapter including the MNI space transfor- mation [42]. 5) To restore the original volume information within each voxel,", "type": "figure"}, "FIGREF1": {"text": "Figure 1. Illustration of the limbic mask, constructed from the WFU-pick atlas (please see methods), superimposed on the mean grey matter images from the entire study population. doi:10.1371/journal.pone.0064065.g001", "type": "figure"}, "FIGREF2": {"text": "Figure 3. Correlation analysis between stress scores (MBI-GS) and the relative putamen volume (mean of the right and left putamen/TIV) -upper panel, and the relative volume of the caudate (mean of the right and left caudate/TIV) -lower panel. A = All subjects; B = Control subjets only; C = Stressed subjects only. doi:10.1371/journal.pone.0064065.g003", "type": "figure"}, "TABREF0": {"text": "Demographics.", "type": "table"}, "TABREF1": {"text": "Structural volumes.", "type": "table"}, "TABREF2": {"text": "Significant group difference in GM volume.", "type": "table"}}}
{"paper_id": "17781311", "_pdf_hash": "51e8f656c0881af5bb56040453f100a9d266432d", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Extremal equilibria of oligopolistic supergames", "authors": [{"first": "Dilip", "middle": [], "last": "Abreu", "suffix": ""}], "year": 1986, "venue": "Journal of Economic Theory", "link": "154410813"}, "BIBREF1": {"title": "An Exploratory Study of the Emerging Role of Electronic Intermediaries", "authors": [{"first": "Joseph", "middle": ["P"], "last": "Bailey", "suffix": ""}, {"first": "Yannis", "middle": [], "last": "Bakos", "suffix": ""}], "year": 1997, "venue": "International Journal of Electronic Commerce", "link": null}, "BIBREF2": {"title": "A Strategic Analysis of Electronic Marketplaces", "authors": [{"first": "Yannis", "middle": [], "last": "Bakos", "suffix": ""}], "year": 1991, "venue": "MIS Quarterly", "link": "11759651"}, "BIBREF3": {"title": "Reducing buyer search costs: Implications for electronic marketplaces", "authors": [{"first": "J", "middle": [], "last": "Bakos", "suffix": ""}, {"first": "", "middle": [], "last": "Yannis", "suffix": ""}], "year": 1997, "venue": "Management Science", "link": "15895959"}, "BIBREF4": {"title": "The Emerging Role of Electronic Marketplaces on the Internet", "authors": [{"first": "J", "middle": [], "last": "Bakos", "suffix": ""}, {"first": "", "middle": [], "last": "Yannis", "suffix": ""}], "year": 1998, "venue": "", "link": null}, "BIBREF5": {"title": "Avoiding misuse of new information technologies: Legal and societal considerations", "authors": [{"first": "Paul", "middle": ["N"], "last": "Bloom", "suffix": ""}, {"first": "R", "middle": [], "last": "George", "suffix": ""}, {"first": "Robert", "middle": [], "last": "Milne", "suffix": ""}, {"first": "", "middle": [], "last": "Adler", "suffix": ""}], "year": 1994, "venue": "Journal of Marketing", "link": "167436287"}, "BIBREF6": {"title": "Frictionless commerce? A comparison of Internet and conventional retailers", "authors": [{"first": "Erik", "middle": [], "last": "Brynjolfsson", "suffix": ""}, {"first": "Michael", "middle": [], "last": "Smith", "suffix": ""}], "year": 2000, "venue": "Management Science", "link": "12433451"}, "BIBREF7": {"title": "Equilibrium price dispersion", "authors": [{"first": "Kenneth", "middle": [], "last": "Burdett", "suffix": ""}, {"first": "Kenneth", "middle": [], "last": "Judd", "suffix": ""}], "year": 1983, "venue": "Econometrica", "link": "154342240"}, "BIBREF8": {"title": "Pricing and matching with frictions", "authors": [{"first": "Kenneth", "middle": [], "last": "Burdett", "suffix": ""}, {"first": "Shouyong", "middle": [], "last": "Shi", "suffix": ""}, {"first": "Randall", "middle": [], "last": "Wright", "suffix": ""}], "year": 2000, "venue": "", "link": "27665101"}, "BIBREF9": {"title": "Discrete equilibrium price dispersion", "authors": [{"first": "John", "middle": ["A"], "last": "Carlson", "suffix": ""}, {"first": "R", "middle": ["Preston"], "last": "Mcafee", "suffix": ""}], "year": 1983, "venue": "Journal of Political Economy", "link": "153525452"}, "BIBREF10": {"title": "Switching Cost and Brand Loyalty in Electronic Markets: Evidence From On-line Retail Brokers", "authors": [{"first": "Pei-Yu", "middle": [], "last": "Chen", "suffix": ""}, {"first": "Lorin", "middle": ["M"], "last": "Hitt", "suffix": ""}], "year": 2000, "venue": "Proceedings of The 21st Annual International Conference on Information Systems", "link": "3189132"}, "BIBREF11": {"title": "Forthcoming. Price Dispersion and Differentiation in On-Line Travel: An Empirical Investigation", "authors": [{"first": "Eric", "middle": ["K"], "last": "Clemons", "suffix": ""}, {"first": "", "middle": [], "last": "Il-Horn", "suffix": ""}, {"first": "Lorin", "middle": ["M"], "last": "Hann", "suffix": ""}, {"first": "", "middle": [], "last": "Hitt", "suffix": ""}], "year": "", "venue": "Management Science", "link": null}, "BIBREF12": {"title": "A model of price adjustment", "authors": [{"first": "Peter", "middle": ["A"], "last": "Diamond", "suffix": ""}], "year": 1971, "venue": "Journal of Economic Theory", "link": null}, "BIBREF13": {"title": "Theories of cartel stability and the JEC", "authors": [{"first": "Glen", "middle": [], "last": "Ellison", "suffix": ""}], "year": 1994, "venue": "RAND Journal of Economics", "link": null}, "BIBREF14": {"title": "E-Commerce Meets Antitrust: A Primer", "authors": [{"first": "Albert", "middle": ["A"], "last": "Foer", "suffix": ""}], "year": 2001, "venue": "Journal of Public Policy and Marketing", "link": "154814525"}, "BIBREF15": {"title": "Noncooperative collusion under imperfect price information", "authors": [{"first": "Edward", "middle": ["J"], "last": "Green", "suffix": ""}, {"first": "H", "middle": [], "last": "Robert", "suffix": ""}, {"first": "", "middle": [], "last": "Porter", "suffix": ""}], "year": 1984, "venue": "Econometrica", "link": null}, "BIBREF16": {"title": "Shopbots and pricebots", "authors": [{"first": "Amy", "middle": ["R"], "last": "Greenwald", "suffix": ""}, {"first": "O", "middle": [], "last": "Jeffrey", "suffix": ""}, {"first": "", "middle": [], "last": "Kephart", "suffix": ""}], "year": 1999, "venue": "The Proceedings of International Joint Conference on Artificial Intelligence", "link": "7490553"}, "BIBREF17": {"title": "What makes a web site \"sticky\"? Cognitive lock in and the power law of practice. Working Paper, Columbia School of Business", "authors": [{"first": "Eric", "middle": ["J"], "last": "Johnson", "suffix": ""}, {"first": "Steven", "middle": [], "last": "Bellman", "suffix": ""}, {"first": "Gerald", "middle": ["L"], "last": "Lohse", "suffix": ""}], "year": 2000, "venue": "", "link": null}, "BIBREF18": {"title": "Follow the leader? Strategic pricing in e-commerce", "authors": [{"first": "Robert", "middle": ["J"], "last": "Kauffman", "suffix": ""}, {"first": "Chuck", "middle": ["A"], "last": "Wood", "suffix": ""}], "year": 2000, "venue": "Proceedings of The 21st Annual International Conference on Information Systems", "link": "1884235"}, "BIBREF19": {"title": "The Value of Internet Commerce to the Consumer", "authors": [{"first": "Ralph", "middle": ["L"], "last": "Keeny", "suffix": ""}], "year": 1999, "venue": "Management Science", "link": null}, "BIBREF20": {"title": "The Net: A Market Too Perfect for Profits?", "authors": [{"first": "Robert", "middle": [], "last": "Kuttner", "suffix": ""}], "year": 1998, "venue": "Business Week", "link": "166896369"}, "BIBREF21": {"title": "Electronic Markets and Electronic Hierarchies", "authors": [{"first": "Thomas", "middle": [], "last": "Malone", "suffix": ""}, {"first": "Joanne", "middle": [], "last": "Yates", "suffix": ""}, {"first": "Robert", "middle": [], "last": "Benjamin", "suffix": ""}], "year": 1987, "venue": "Communications of the ACM", "link": "11591286"}, "BIBREF22": {"title": "Designing a better shopbot", "authors": [{"first": "Alan", "middle": ["L"], "last": "Montgomery", "suffix": ""}, {"first": "Kartik", "middle": [], "last": "Hosanagar", "suffix": ""}, {"first": "Ramayya", "middle": [], "last": "Krishnan", "suffix": ""}, {"first": "Karen", "middle": ["B"], "last": "Clay", "suffix": ""}], "year": 2001, "venue": "", "link": "1817350"}, "BIBREF23": {"title": "Research Report: Disruptive Technologies Explaining Entry in Next Generation Information Technology Markets", "authors": [{"first": "Barrie", "middle": ["R"], "last": "Nault", "suffix": ""}, {"first": "B", "middle": [], "last": "Mark", "suffix": ""}, {"first": "", "middle": [], "last": "Vandenbosch", "suffix": ""}], "year": 2000, "venue": "Information Systems Research", "link": "41020968"}, "BIBREF24": {"title": "A simple model of equilibrium price dispersion", "authors": [{"first": "Jennifer", "middle": ["F"], "last": "Reinganum", "suffix": ""}], "year": 1979, "venue": "Journal of Political Economy", "link": "154151133"}, "BIBREF25": {"title": "A supergame-theoretic model of price wars during booms", "authors": [{"first": "Julio", "middle": ["J"], "last": "Rotemberg", "suffix": ""}, {"first": "Garth", "middle": [], "last": "Saloner", "suffix": ""}], "year": 1986, "venue": "American Economic Review", "link": "15294223"}, "BIBREF26": {"title": "Bargains and ripoffs: A model of monopolistically competitive price dispersion", "authors": [{"first": "S", "middle": [], "last": "Salop", "suffix": ""}, {"first": "J", "middle": ["E"], "last": "Stiglitz", "suffix": ""}], "year": 1977, "venue": "Review of Economic Studies", "link": "154283245"}, "BIBREF27": {"title": "Monopolistic competition with outside goods", "authors": [{"first": "S", "middle": [], "last": "Salop", "suffix": ""}], "year": 1979, "venue": "Bell Journal of Economics", "link": "30311480"}, "BIBREF28": {"title": "The theory of sales: A simple model of equilibrium price dispersion with identical agents", "authors": [{"first": "S", "middle": [], "last": "Salop", "suffix": ""}, {"first": "J", "middle": ["E"], "last": "Stiglitz", "suffix": ""}], "year": 1982, "venue": "The American Economic Review", "link": "153018327"}, "BIBREF29": {"title": "Understanding digital markets", "authors": [{"first": "Michael", "middle": [], "last": "Smith", "suffix": ""}, {"first": "Joseph", "middle": [], "last": "Bailey", "suffix": ""}, {"first": "Erik", "middle": [], "last": "Brynjolfsson", "suffix": ""}], "year": 2000, "venue": "", "link": null}, "BIBREF30": {"title": "Empirical studies of oligopolistic pricing and heterogeneous consumer search", "authors": [{"first": "Alan", "middle": ["T"], "last": "Sorensen", "suffix": ""}], "year": 1999, "venue": "Economics", "link": null}, "BIBREF31": {"title": "Equilibrium price dispersion for prescription drugs", "authors": [{"first": "Alan", "middle": ["T"], "last": "Sorensen", "suffix": ""}], "year": 2000, "venue": "Journal of Political Economy forthcoming", "link": null}, "BIBREF32": {"title": "Oligopolistic pricing with sequential consumer search", "authors": [{"first": "Dale", "middle": ["O"], "last": "Stahl", "suffix": ""}], "year": 1989, "venue": "The American Economic Review", "link": "15102822"}, "BIBREF33": {"title": "Competition and the number of retailers in a market: Are duopolies more competitive than atomistic markets", "authors": [{"first": "Joseph", "middle": ["E"], "last": "Stiglitz", "suffix": ""}], "year": 1987, "venue": "Journal of Political Economy", "link": null}, "BIBREF34": {"title": "The Impact of E-Commerce Announcements on the Market Value of Firms", "authors": [{"first": "Mani", "middle": [], "last": "Subramani", "suffix": ""}, {"first": "Eric", "middle": [], "last": "Walden", "suffix": ""}], "year": 2001, "venue": "Information Systems Research", "link": null}, "BIBREF35": {"title": "The Theory of Industrial Organization", "authors": [{"first": "Jean", "middle": [], "last": "Tirole", "suffix": ""}], "year": 1995, "venue": "", "link": "152408219"}, "BIBREF36": {"title": "Can Online Auctions Beat Online Catalogs", "authors": [{"first": "Yaniv", "middle": [], "last": "Vakrat", "suffix": ""}, {"first": "Abraham", "middle": [], "last": "Seidmann", "suffix": ""}], "year": 1999, "venue": "Proceedings of The 20th Annual International Conference on Information Systems", "link": "203984"}, "BIBREF37": {"title": "A model of sales", "authors": [{"first": "Hal", "middle": ["R"], "last": "Varian", "suffix": ""}], "year": 1980, "venue": "The American Economic Review", "link": null}, "BIBREF38": {"title": "Market structure in the network age", "authors": [{"first": "Hal", "middle": ["R"], "last": "Varian", "suffix": ""}], "year": 2000, "venue": "Brynjolfsson and Kahin", "link": "17414194"}}, "ref_entries": {}}
{"paper_id": "17781384", "_pdf_hash": "946b7e2c18080908012124aac5ea149fce66b899", "abstract": [{"section": "Abstract", "text": "Background: Zygosaccharomyces bailii is considered the most problematic acidic food spoilage yeast species due to its exceptional capacity to tolerate high concentrations of weak acids used as fungistatic preservatives at low pH. However, the mechanisms underlying its intrinsic remarkable tolerance to weak acids remain poorly understood. The identification of genes and mechanisms involved in Z. bailii acetic acid tolerance was on the focus of this study. For this, a genomic library from the highly acetic acid tolerant hybrid strain ISA1307, derived from Z. bailii and a closely related species and isolated from a sparkling wine production plant, was screened for acetic acid tolerance genes. This screen was based on the transformation of an acetic acid susceptible Saccharomyces cerevisiae mutant deleted for the gene encoding the acetic acid resistance determinant transcription factor Haa1.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "(Continued from previous page)", "text": "Conclusions: ISA1307 genes homologous to S. cerevisiae genes GYP8, WSC4, PMT1, KTR7, RKR1, TIF3, ILV3 and MSN4 are proposed as strong candidate determinants of acetic acid tolerance. The ORF ZBAI_02295 that contains a functional domain associated to the uncharacterised integral membrane proteins of unknown function of the DUP family is also suggested as a relevant tolerance determinant. The genes ZbMSN4 and ZbTIF3, encoding a putative stress response transcription factor and a putative translation initiation factor, were confirmed as determinants of acetic acid tolerance in both Z. bailii and S. cerevisiae. This study provides valuable indications on the cellular components, pathways and processes to be targeted in order to control food spoilage by the highly acetic acid tolerant Z. bailii and Z. bailii-derived strains. Additionally, this information is essential to guide the improvement of yeast cells robustness against acetic acid if the objective is their use as cell factories.", "cite_spans": [], "ref_spans": []}, {"section": "(Continued from previous page)", "text": "Keywords: Yeast, Zygosaccharomyces bailii, Acetic acid tolerance genes, Yeast hybrid strains, Food spoilage yeasts, Weak acid food preservatives", "cite_spans": [], "ref_spans": []}, {"section": "Background", "text": "Zygosaccharomyces bailii is considered the most problematic spoilage yeast found in the food and beverage industry, particularly in acidic foods, soft drinks, fruit juices, dairy products and salad dressings [1, 2] . This yeast species ability to cause spoilage derives from its outstanding intrinsic capacity to resist to weak acids widely used as fungistatic preservatives, such as acetic, propionic, benzoic and sorbic acids [1] [2] [3] [4] . Understanding the mechanisms of weak acid resistance is central to the development and implementation of more effective food and beverage preservation strategies in order to minimise economic losses. Although Z. bailii is the spoilage yeast that exhibits the highest level of tolerance to acetic acid, most of the scientific contributions on the mechanisms underlying adaptation and resistance to acetic acid in yeast have been focused on the more susceptible experimental model Saccharomyces cerevisiae [5] [6] [7] [8] [9] . At a pH equal or below its pKa (4.75), acetic acid is mainly in the undissociated form that can diffuse across the plasma membrane. Once in the near neutral cytosol, acetic acid dissociates leading to the accumulation of protons and acetate. The acidification of the cytosol leads to the inhibition of metabolic activity and to the dissipation of the proton gradient across plasma membrane required for secondary transport [10, 11] . To counteract this effect, the plasma membrane protonpumping ATPase (PM H + -ATPase) is activated in acetic acid-stressed S. cerevisiae cells [12] . The involvement of Z. bailii PM H + -ATPase in the active export of protons from cells challenged by weak acid preservatives, namely benzoic acid, was also demonstrated, suggesting that both yeasts share this response mechanism [13] . Given that the charged acetate counterion is not able to easily cross the hydrophobic plasma membrane lipid bilayer, it accumulates in the cell interior leading to increased oxidative stress and turgor pressure, among other effects [3, 9] . To counteract these effects, the plasma membrane multidrug resistance (MDR) transporters of the Major Facilitator Superfamily (MFS) Tpo2 and Tpo3 were hypothesized to play a role in the extrusion of acetate from acetic acid-challenged S. cerevisiae cells [5] . To date, no acetate export system was described in Z. bailii. S. cerevisiae response to acetic acid-induced stress involves several transcriptional regulators [4, 9] . The expression of the transcription factor encoding gene HAA1 was found to markedly decrease the duration of the adaptation period of a yeast cell population suddenly exposed to toxic concentrations of acetic acid, by decreasing the loss of cell viability that occurs during this phase of growth latency [5] . Haa1 is considered one of the key players in the control of S. cerevisiae response to acetic acid due to its role in the direct, or indirect, regulation of approximately 80 % of acetic acid-responsive genes [6] , several of them required for maximal tolerance to acetic acid [8] . These genes code for protein kinases, MDR transporters, transcription factors and proteins involved in lipid metabolism and nucleic acid processing [6] .", "cite_spans": [{"start": 208, "end": 211, "text": "[1,", "ref_id": "BIBREF0"}, {"start": 212, "end": 214, "text": "2]", "ref_id": "BIBREF1"}, {"start": 428, "end": 431, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 432, "end": 435, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 436, "end": 439, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 440, "end": 443, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 950, "end": 953, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 954, "end": 957, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 958, "end": 961, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 962, "end": 965, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 966, "end": 969, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 1395, "end": 1399, "text": "[10,", "ref_id": "BIBREF9"}, {"start": 1400, "end": 1403, "text": "11]", "ref_id": "BIBREF10"}, {"start": 1548, "end": 1552, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 1783, "end": 1787, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 2022, "end": 2025, "text": "[3,", "ref_id": "BIBREF2"}, {"start": 2026, "end": 2028, "text": "9]", "ref_id": "BIBREF8"}, {"start": 2286, "end": 2289, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 2451, "end": 2454, "text": "[4,", "ref_id": "BIBREF3"}, {"start": 2455, "end": 2457, "text": "9]", "ref_id": "BIBREF8"}, {"start": 2764, "end": 2767, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 2977, "end": 2980, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 3045, "end": 3048, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 3199, "end": 3202, "text": "[6]", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Background", "text": "In order to identify determinants of Z. bailii tolerance to acetic acid at the genome level we used in this study a genomic library previously prepared from the highly acetic acid tolerant strain ISA1307, an interspecies hybrid between Z. bailii and a closely related species which was isolated from a continuous production plant of sparkling wine [14, 15] . This genomic library was used to rescue the high susceptibility phenotype of S. cerevisiae BY4741_haa1\u0394. This mutant, deleted for HAA1 gene, was chosen due to its very high susceptibility to acetic acid to avoid the use of the much higher concentrations required to inhibit the parental strain growth. With this approach we also expected to identify the functional homologue of S. cerevisiae HAA1 gene in this hybrid strain. During the development of this study, our laboratory carried out the genome sequencing, assembly and annotation of ISA1307 [14] . This hybrid strain has been on the focus of several physiological studies, some of them aiming at the understanding of the mechanisms underlying its remarkable intrinsic resistance to acetic acid. Differently from S. cerevisiae, the Z.bailii-derived hybrid strain ISA1307 co-consumes glucose and acetic acid when cultivated in glucose medium supplemented with a sublethal growth inhibitory concentration of acetic acid [16, 17] . Quantitative proteomic studies on the adaptive response of this strain indicate that in glucose and acetic acid cultures the acid is channelled through the TCA cycle [16] . After glucose exhaustion, acetic acid being present as the sole carbon source, the content of several proteins involved in gluconeogenesis and pentose phosphate pathway was however found to increase [16] .", "cite_spans": [{"start": 348, "end": 352, "text": "[14,", "ref_id": "BIBREF13"}, {"start": 353, "end": 356, "text": "15]", "ref_id": "BIBREF14"}, {"start": 907, "end": 911, "text": "[14]", "ref_id": "BIBREF13"}, {"start": 1333, "end": 1337, "text": "[16,", "ref_id": "BIBREF15"}, {"start": 1338, "end": 1341, "text": "17]", "ref_id": "BIBREF16"}, {"start": 1510, "end": 1514, "text": "[16]", "ref_id": "BIBREF15"}, {"start": 1716, "end": 1720, "text": "[16]", "ref_id": "BIBREF15"}], "ref_spans": []}, {"section": "Background", "text": "The screening of ISA1307 genomic library for genes required for tolerance to acetic acid successfully pointed out several strong candidates, but since this is a hybrid strain difficult to be genetically manipulated, in order to confirm the role of the selected genes in acetic acid tolerance we have explored another strain, Z. bailii IST302. This strain was isolated from spontaneous fermentation of wine must and, contrarily to ISA1307 and Z. bailii CLIB213 T [18] , does not flocculate and proved to be more susceptible to genetic engineering than these reference strains. The genome of Z. bailii IST302 was recently sequenced and annotated in our laboratory (unpublished data), rendering possible the work here reported.", "cite_spans": [{"start": 462, "end": 466, "text": "[18]", "ref_id": "BIBREF17"}], "ref_spans": []}, {"section": "Background", "text": "The knowledge gathered during the present study was based on the expression of ISA1307 genomic library in S. cerevisiae, the availability of the genome sequences of the hybrid strain ISA1307 and Z. bailii IST302 and the expression of selected ISA1307 and IST302 gene sequences in S. cerevisiae and Z. bailii strains and led to the identification of a number of Z. bailii genes involved in tolerance to acetic acid. Strong candidates for determinants of acetic acid tolerance in Z. bailii or S. cerevisiae are here proposed.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "Selection of S. cerevisiae transformants with increased tolerance to acetic acid through the expression of an ISA1307 genomic library", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "To search for genes involved in the remarkable tolerance to acetic acid in a Z. bailii-related strain we looked for suppressors of the susceptibility phenotype of S. cerevisiae BY4741_haa1\u0394 through the transformation of this strain with a previously constructed genomic library from the highly tolerant Z. bailii-derived interspecies hybrid strain ISA1307 [15] . This allowed the isolation of 1225 yeast clones, selected in a minimal medium without uracil (Fig. 1) . These yeast transformants were screened for their increased tolerance to acetic acid through growth in liquid medium in 96-well microplates. This selection methodology allowed the identification of 92 potential candidates out of the 1225 positive colonies initially obtained. Total DNA was extracted from each selected transformant and used to transform Escherichia coli XL1-Blue in order to isolate the plasmid insert of interest and to guarantee the identification of a single plasmid capable of suppressing S. cerevisiae haa1\u0394 susceptibility phenotype. The plasmids were extracted from E.coli transformants, purified and used to transform again the deletion mutant S. cerevisiae BY4741_haa1\u0394 and also the parental strain BY4741. Out of these 92 tested transformants, only 31 DNA inserts were confirmed to substantially increase the haa1\u0394 mutant tolerance to acetic acid and were hence sequenced. Both the parental and the deletion mutant haa1\u0394 cells transformed with each one of these 31 plasmids were grown in 96-well microplates with 60 mM of acetic acid supplemented medium or in control conditions in order to confirm the ability of the corresponding inserts to rescue the haa1\u0394 mutant susceptibility phenotype as well as their effect in the growth of the parental strain transformants (Additional file 1: Figure S1 ). Considering the haa1\u0394 transformants, the suppressors were able to rescue haa1\u0394 susceptibility phenotype by shortening the latency period by at least 20 h when compared with the haa1\u0394 strain transformed with the empty vector. At the concentration of acetic acid tested (60 mM, pH4.0) the protective effect of the expression of the DNA inserts in the candidate clones was not as evident for the parental strain compared with the haa1\u0394 mutant, since the parental strain is much less susceptible than the mutant to acetic acid. Nevertheless, a number of inserts clearly improve the tolerance of the parental strain transformed with the empty vector at the acetic acid concentration tested. Results obtained with the five best suppressors, or in other words those capable of diminishing at a greater extent the duration of the latency period of the parental or the haa1\u0394 strains transformed with the empty vector, are shown in Fig. 2a and b. Three of these suppressors, the inserts B02, B18 and S06, were identified by the transformation of both the parental and the haa1 deletion mutant strains.", "cite_spans": [{"start": 356, "end": 360, "text": "[15]", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "Results", "text": "In silico analysis of ISA1307 genomic DNA fragments whose expression was found to be required for increased acetic acid tolerance in S. cerevisiae", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "The in silico analysis of the 31 selected genomic DNA fragments from the Z. bailii-derived interspecies hybrid strain ISA1307 led to the identification of a number of ORFs which are putative candidate determinants of tolerance to the acid. Since we found that the expression of DNA inserts containing only one putative truncated ORF also led to the increase of haa1\u0394 tolerance to acetic acid, the incomplete ORFs were also considered for further analysis and the presence of conserved functional domains in the identified inserts was investigated. However, the truncated ORFs comprising less than 15 % of the complete sequence, which contained limited portions of conserved domains or no conserved domains, were disregarded at this phase, resulting in the selection of 32 complete and 33 truncated putative candidate ORFs (Additional file 2).", "cite_spans": [], "ref_spans": []}, {"section": "ORFs with homology to S. cerevisiae genes", "text": "For each ISA1307 selected ORF, the predicted S. cerevisiae homologous gene and the corresponding functional description were gathered (Additional file 2). References to previous studies in which the deletion of the gene was already described as leading to an increase or decrease of yeast susceptibility to acetic acid or other weak acids are also indicated. Since the strain ISA1307 is an interspecies hybrid between Z. bailii and a closely related species [14] , Additional file 2 also includes information regarding the nucleotide Fig. 1 Genomic library screening to search for determinants of acetic acid tolerance in the strain ISA1307. Schematic representation of the screening of the Z. bailii-derived interspecies hybrid strain ISA1307 genomic library carried out in this study to search for determinants of acetic acid tolerance, able to rescue the susceptibility phenotype of S. cerevisiae BY4741_haa1\u0394 sequence identity of each ORF present in the different DNA inserts with Z. bailii CLIB213 T genome [18] to identify the ORFs that likely are from Z. bailii. Interestingly, about one half of the selected DNA inserts that were able to rescue the haa1\u0394 mutant susceptibility phenotype to acetic acid is, presumably, derived from the parental Z. bailii species (99-100 % identity with CLIB213", "cite_spans": [{"start": 458, "end": 462, "text": "[14]", "ref_id": "BIBREF13"}, {"start": 1012, "end": 1016, "text": "[18]", "ref_id": "BIBREF17"}], "ref_spans": []}, {"section": "ORFs with homology to S. cerevisiae genes", "text": "T genome) while the other half is, apparently, derived from the other yeast species closely related to Z. bailii (93-98 % identity with CLIB213 T genome).", "cite_spans": [], "ref_spans": []}, {"section": "ORFs with homology to S. cerevisiae genes", "text": "ORFs with no homology with S. cerevisiae genes For 7 out of the 65 ORFs identified amongst the ISA1307 genomic DNA fragments resulting from the screening, no homology with S. cerevisiae genes could be found. In order to obtain additional information that could support the elucidation of their possible function and contribution to confer protection against acetic acid in the S. cerevisiae haa1\u0394 mutant, a prediction of conserved functional domains [19] and transmembrane helices (http://www.cbs.dtu.dk/services/TMHMM/) was attempted. The information gathered for these ORFs is summarised in Table 1 that also includes the detected similarities with other organisms (using the PEDANT database). The DNA inserts E13 and S06, each one holding two complete ORFs, were considered to deserve further attention. The ORF ZBAI_09903 from the E13 DNA insert has homology with pyruvate decarboxylases from different organisms and contains a pyrimidine binding domain (PYR) that can be found in many key metabolic enzymes. The DNA insert E13 also contains the ORF ZBAI_09904 whose encoded protein has a domain characteristic of DNA and RNA helicases, but shows weak similarities with yeast helicases. Moreover, the two ORFs present in the insert S06, which was found to be the best suppressor of the acetic acid susceptibility phenotype of mutant haa1\u0394 and among the best five genomic library inserts whose expression led to increased tolerance to acetic acid in the parental strain, encode two putative membrane proteins. Specifically, ZBAI_02295 holds a domain associated with the DUP family of proteins of unknown function that were suggested to be involved in membrane trafficking processes [20] and ZBAI_02296 contains a PRK15313 domain related to autotransport proteins. Both ORFs have homologues in Z. rouxii. These observations reinforce the idea that at least one of these two ORFs is a strong candidate to be considered as a determinant of acetic acid tolerance. Given the apparent relevance of the insert S06 and to test the proposed hypothesis, the individual subcloning of these two ORFs was performed.", "cite_spans": [{"start": 450, "end": 454, "text": "[19]", "ref_id": "BIBREF18"}, {"start": 1685, "end": 1689, "text": "[20]", "ref_id": "BIBREF19"}], "ref_spans": [{"start": 593, "end": 600, "text": "Table 1", "ref_id": "TABREF0"}]}, {"section": "ORFs with homology to S. cerevisiae genes", "text": "The ORF ZBAI_02295 is required for tolerance to acetic acid", "cite_spans": [], "ref_spans": []}, {"section": "ORFs with homology to S. cerevisiae genes", "text": "The two ORFs present in S06 genomic library DNA insert were subcloned by homologous recombination in the expression vector pGREG506 containing a galactose inducible promoter (GAL1) and then expressed in both S. cerevisiae BY4741_ haa1\u0394 and parental background strains to search for increased tolerance to acetic acid. The heterologous expression of pGREG506_ZBAI_02295 in haa1\u0394 mutant strain was found to lead to a considerable increase of tolerance to acetic acid up to the level of the parental strain with the empty plasmid, with a pronounced decrease in the duration of the latency phase and an increase in the specific growth rate compared with control cells (Fig. 3) . This effect was barely detected when the parental strain was used as host cell, even Fig. 2 Growth curves of the best strains considering acetic acid tolerance obtained by transformation of S. cerevisiae BY4741_haa1\u0394 and BY4741 parental with ISA1307 genomic library plasmids. a S. cerevisiae BY4741_haa1\u0394 transformed with the empty vector (\u25a1) and with plasmids holding DNA fragments from the strain ISA1307 genomic library B02 (\u25a0), B18 (\u25b2), L04 (\u2666), S06 (\u25bc) and X25 (\u2022) cloned in vector pRS316. S. cerevisiae BY4741 parental strain transformed with the empty vector (\u25cb) was included in the same 96-well microplate as a positive control. b S. cerevisiae BY4741 parental strain transformed with the empty vector (\u25cb) or with plasmids containing DNA fragments from the strain ISA1307 genomic library B02 (\u25a0), B18 (\u25b2), S06 (\u25bc), S07 (+) and W08 (\u00d7). The selected strains were those with a significant decreased duration of the latency period of the deletion mutant or in the parental strain when compared with the corresponding strain containing the empty vector. The growth curves were performed in MM4 medium (pH 4.0) without uracil, supplemented with 60 mM acetic acid (pH 4.0) and are representative of at least three independent growth assays that gave rise to similar growth curves though we have used increased concentrations of acetic acid (65 and 70 mM) in order to obtain an inhibitory effect equivalent to the one observed in the mutant haa1\u0394 (results not shown). On the other hand, the expression of the ORF ZBAI_02296 caused an increase in the duration of the lag phase for both strains (Fig. 3) , which indicates that it can be harmful in the context of acetic acid tolerance. For control purposes, Fig. 3 also shows the growth curves of both strains transformed with pGREG506 or pGREG506_noHIS3, that is the same cloning vector but with the HIS3 gene, controlled by the GAL1 promoter, removed. This new construction was needed to prepare the correct controls since the recombinant plasmids lose the HIS3 gene active mark and also because the auxotrophy of the host cells (his \u2212 ) implicates an alteration of the acetic acid tolerance depending on histidine availability. Although in the case of the parental strain the removal of the HIS3 gene from the expression vector had no detectable implications in the growth curve of the transformed cells, the expression of this gene in haa1\u0394 cells confers a significant advantage when acetic acid is present. Therefore pGREG506_noHIS3 plasmid was considered the correct empty cloning vector to be used to transform the control cells.", "cite_spans": [], "ref_spans": []}, {"section": "ORFs with homology to S. cerevisiae genes", "text": "The results of the expression experiments support the idea that the ORF ZBAI_02295 should be considered as a strong candidate determinant of tolerance to acetic acid in strain ISA1307. On the contrary, the expression of ORF ZBAI_02296 had a negative effect in S. cerevisiae tolerance to acetic acid and for this reason it was not considered as a candidate determinant.", "cite_spans": [], "ref_spans": []}, {"section": "Selection of strong candidate determinants of acetic acid tolerance", "text": "The next step was to narrow down the list of the remaining 63 selected ORFs in an attempt to identify the most promising candidate genes for determinants of tolerance to acetic acid. Although all the selected ORFs are potential candidates, it is essential to understand the relevance of each one when several ORFs are present in the same insert. Due to the difficult genetic engineering of Zygosaccharomyces genus in general, and of the Glutathione S-transferase from Macrophomina phaseolina (charcoal rot fungus) and putative uncharacterized proteins from Torulaspora delbrueckii and several fungi.", "cite_spans": [], "ref_spans": []}, {"section": "Selection of strong candidate determinants of acetic acid tolerance", "text": "Domains related with the Glutathione Stransferase family. In particular, the portion which is present in the DNA library fragment possesses a C-terminal alpha helical domain of the GST family. Percentage of nucleotides present in the truncated ORFs, compared with the total ORF sequence, is indicated in parentheses ISA1307 hybrid strain in particular, no deletion mutant could be constructed and, consequently, the direct confirmation of the role of each putative candidate ORF in acetic acid tolerance in this specific strain was limited. Therefore, the selection of strong candidate determinants of acetic acid tolerance among the ORFs present in each DNA insert able to rescue the susceptibility phenotype of the S. cerevisiae haa1\u0394 mutant was based on the presumption that sole ORFs present in DNA inserts that were able to suppress the acetic acid susceptibility phenotype of haa1\u0394 are the cause of the increased tolerance. Some of these ORFs homologues were already mentioned as contributing to S. cerevisiae tolerance to acetic acid and/or other weak acids, supporting the criterion used. The list of inserts containing the strong candidate determinants of acetic acid tolerance selected during this work is presented in Table 2 (a selection from Additional file 2). The strong candidate determinants of tolerance, according to the mentioned criterion, are represented in bold in both Table 2 and Additional file 2. The ORF ZBAI_02295, whose role in acetic acid tolerance was confirmed by subcloning experiments, is also included. It is important to refer that the expression of truncated ORFs was found to apparently confer tolerance to acetic acid, given that this was observed when a single incomplete ORF was present in the insert. This is for example the case of S. cerevisiae truncated MSN4 and WSC4 homologues that are present in the DNA inserts B02 and 23.1, respectively. For the inserts where several complete and/or truncated ORFs are present it is not possible, at this phase, to decide which of the various ORFs is indeed involved in conferring increased tolerance to acetic acid without the subcloning and functional expression of each single ORF. Nevertheless, previous reports from the literature on the role of a considerable number of these ORFs in S. cerevisiae tolerance to weak acids provide good indications of where to start. In summary, and taking into account the aforementioned criterion, the following S. cerevisiae gene homologues were selected and proposed herein as strong candidate determinants of acetic acid tolerance in the strain ISA1307: GYP8 and WSC4 (cellular transport and transport routes), PMT1, KTR7 and RKR1 (protein fate), TIF3 (protein synthesis), ILV3 (amino acid metabolism) and MSN4 (transcription).", "cite_spans": [], "ref_spans": [{"start": 1229, "end": 1236, "text": "Table 2", "ref_id": "TABREF2"}, {"start": 1393, "end": 1400, "text": "Table 2", "ref_id": "TABREF2"}]}, {"section": "Selection of strong candidate determinants of acetic acid tolerance", "text": "Complementation of acetic acid susceptibility of S. cerevisiae mutants deleted for genes homologous to ISA1307 tolerance candidate genes In order to confirm the hypothesized role of the strong candidate determinants of acetic acid tolerance proposed, plasmids from ISA1307 genomic library containing a single complete or incomplete ORF were expressed in the haploid S. cerevisiae mutant lacking the corresponding homologous gene (Fig. 4) . The expression of the library plasmids containing GYP8, KTR7, MSN4 or WSC4 homologues was confirmed to rescue the acetic acid susceptibility phenotype of the corresponding S. cerevisiae deletion mutant. Specifically, an increase of the maximum specific growth rate was clearly observed when these library plasmids were individually expressed, as well as a reduction of the duration of the latency period even when compared with the parental strain carrying the empty plasmid. Although the expression of the TIF3 homologue in Fig. 3 Effect of the expression of ZBAI_02295 or ZBAI_02296 in S. cerevisiae parental strain BY4741 and derived deletion mutant haa1\u0394. Growth curves of S. cerevisiae BY4741 parental (a) and haa1\u0394 (b) strains transformed with pGREG506_ZBAI_02295 (\u25b3,\u25b2), pGREG506_ZBAI_02296 (\u25bd,\u25bc), pGREG506_noHIS3 (\u25a1,\u25a0) and pGREG506 (\u25cb,\u2022). Growth was performed in MM4 medium (pH 4.0) without uracil and containing 1 % (w/v) galactose, supplemented with 60 mM acetic acid (open symbols) and in the same conditions without acetic acid (closed symbols). The growth curves are representative of at least three independent growth assays that gave rise to similar results the corresponding library plasmid also decreased the duration of the latency period in S. cerevisiae tif3\u0394, it did not fully complement the high acetic acid susceptibility phenotype of tif3\u0394 up to the parental strain level. Since at the concentration of acetic acid used in the complementation experiments S. cerevisiae BY4741_rkr1\u0394 is mildly susceptible to acetic acid, the effect of the expression in this mutant of the RKR1 homologue in the duration of the latency phase in the presence of acetic acid was barely detected. The expression of the library plasmid containing the essential ILV3 homologous gene in the diploid strain S. cerevisiae BY4743 lacking a copy of ILV3 gene also led to the decrease of the duration of the latency phase of both ilv3\u0394 and parental strains. In the case of pmt1\u0394, a slight complementation of the susceptibility phenotype was achieved with the expression of the corresponding genomic library plasmid.", "cite_spans": [], "ref_spans": []}, {"section": "Selection of strong candidate determinants of acetic acid tolerance", "text": "As previously mentioned, when expressed in the yeast host cell the inserts containing MSN4 and TIF3 homologues were among the best suppressors of the acetic acid susceptibility phenotype of haa1\u0394 mutant, also The putative function of each ORF was assigned based on the function of each S. cerevisiae homologous gene (www.yeastgenome.org). The functional category is provided in bold f List of the studies involving the S. cerevisiae corresponding deletion mutant susceptibility or resistance phenotypes under weak acid stress (S) -the single deletion mutant is susceptible to the acid; (R) -the single deletion mutant is resistant to the acid leading to a remarkable increase of acetic acid tolerance in the parental strain. Given that the role of these genes in the context of S. cerevisiae tolerance to weak acids was already reported in literature, they were selected for further experiments.", "cite_spans": [], "ref_spans": []}, {"section": "Selection of strong candidate determinants of acetic acid tolerance", "text": "Expression of Z. bailii genes ZbMSN4 and ZbTIF3 in Z. bailii and S. cerevisiae strains", "cite_spans": [], "ref_spans": []}, {"section": "Selection of strong candidate determinants of acetic acid tolerance", "text": "The involvement of Z. bailii MSN4 homologue in acetic acid tolerance was investigated based on the expression of this gene in S. cerevisiae BY4741 parental and derived Fig. 4 Expression of ISA1307 genomic library plasmids containing a single ORF in S. cerevisiae mutants deleted for the corresponding homologous gene. Growth curves of S. cerevisiae mutants gyp8\u0394, ktr7\u0394, rkr1\u0394, msn4\u0394, pmt1\u0394, wsc4\u0394, tif3\u0394 and ilv3\u0394 transformed with the corresponding plasmid from the strain ISA1307 genomic library, specifically 8.23, S07, Y08, B02, 18.22, 23.1, B18 and 23.17, respectively, which contained the putative ISA1307 homologue of the S. cerevisiae gene deleted in each mutant (\u25a0) or with the empty vector (\u25a1). Strains were cultivated in MM4 medium (pH 4.0) without uracil or in this same basal medium supplemented with 60 mM (a), 40 mM (b) and 65 mM (c) of acetic acid. S. cerevisiae BY4741 and BY4743 parental strains were also transformed with the empty vector (\u25cb) for control purposes. The growth curves shown are representative of three independent assays deletion mutant msn4\u0394, and in S. cerevisiae W303-1A parental and derived double deletion mutant msn2\u0394msn4\u0394 strains (Fig. 5) . Since ISA1307 hybrid genome contains two copies of the MSN4 homologue that have similar 5\u2032 and 3\u2032 ends, it would be very difficult to amplify only the desired Z. bailii copy and for this reason strain Z. bailii IST302 was used to amplify the MSN4 homologue ZbMSN4. Results of this heterologous expression show that ZbMSN4 under the control of S. cerevisiae MSN4 promoter increases the tolerance of the parental S. cerevisiae strains BY4741 and W303-1A and derived deletion mutant strains msn4\u0394 and msn2\u0394msn4\u0394. While in W303-1A_msn2\u0394msn4\u0394 strain the expression of ZbMSN4 nearly complemented the acetic acid susceptibility phenotype to the level of the parental strain, in BY4741_msn4\u0394 the expression of the gene significantly improved the acetic acid tolerance even above the level of tolerance exhibited by its parental strain, as in the case of the complementation with the library plasmid B02. These results show that IST302 ZbMSN4 under the influence of S. cerevisiae MSN4 promoter in the selected expression vector overcomes the effect of the native S. cerevisiae MSN4 and is effective enough to counteract the lack of the two transcription factors in the double deletion mutant. Extra copies of ZbMSN4 and ZbTIF3 from Z. bailii IST302 were also expressed in this same strain. Results confirm that Z. bailii IST302 containing the recombinant vector with the extra copy of either ZbMSN4 or ZbTIF3 is significantly more tolerant to acetic acid in comparison with the host strain with the empty expression vector (Fig. 6) . Fig. 5 Effect of the expression of ZbMSN4 in S. cerevisiae strains BY4741 parental and derived deletion mutant msn4\u0394 (a) and W303-1A parental and derived double deletion mutant msn2\u0394msn4\u0394 (b). Growth curves of S. cerevisiae parental strains BY4741 (a) and W303-1A (b) (filled symbols) and the corresponding derived deletion mutants msn4\u0394 (a) and msn2\u0394msn4\u0394 (b) (empty symbols) transformed either with the empty vector (\u25cb,\u2022) or with pGREG506_promMSN4Sc_ZbMSN4 (\u25a1,\u25a0). S. cerevisiae BY4741 background strains were cultivated in MM4 medium (pH 4.0) without uracil or in this same basal medium supplemented with 65 mM (a), and S. cerevisiae W303-1A background strains were cultivated in MM5 medium (pH 4.0) without uracil or in this same basal medium supplemented with 60 mM (b). The growth curves shown are representative of three independent assays", "cite_spans": [], "ref_spans": [{"start": 2695, "end": 2703, "text": "(Fig. 6)", "ref_id": "FIGREF0"}]}, {"section": "Discussion", "text": "In order to get clues on the genes/proteins involved in the high intrinsic tolerance to acetic acid of the Z. bailiiderived interspecies hybrid strain ISA1307, we have explored a previously constructed genomic library from this strain, as well as the available information on its full genome sequence which was released and annotated during the progress of this study [14] . Considering the experimental design of the screening carried out to search for genes required for maximal tolerance to acetic acid, it was not expected that the identification of ISA1307 HAA1 homologue would fail. Indeed, based on the information retrieved from the PEDANT database, two copies of a putative HAA1-homologue are present in the genome of this hybrid strain (ZBAI_01494 and ZBAI_05761) sharing, respectively, 50 and 47 % identity with S. cerevisiae HAA1 nucleotide sequence (pairwise alignment performed at http://www.ebi.ac.uk/Tools/psa/ (European Bioinformatics Institute)). The fact is that when the genomic library used in the screening was constructed [15] , it was assumed that the size of ISA1307 genome was similar to the size of S. cerevisiae genome (12 Mb). However, following genome sequencing, the genome size of this hybrid strain was found to have approximately 22 Mb [14] . This means that the genomic library tested is poorly representative of the full ISA1307 genome and thus a full functional HAA1 gene sequence may be missing in the library. Also, we cannot exclude at this time the possibility that ISA1307 Haa1 proteins do not have in this highly acetic acid tolerant strain the important role demonstrated for the S. cerevisiae homologue or that the HAA1 homologous genes in this strain are not functional.", "cite_spans": [{"start": 368, "end": 372, "text": "[14]", "ref_id": "BIBREF13"}, {"start": 1045, "end": 1049, "text": "[15]", "ref_id": "BIBREF14"}, {"start": 1270, "end": 1274, "text": "[14]", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "Discussion", "text": "The genes emerging from this study derive at similar proportions from each of the two parental strains of the hybrid strain ISA1307. Remarkably, the differences registered in the two alleles of ISA1307, at the nucleotide level, have apparently no impact in the amino acid sequence of the encoded proteins identified in our study as potential determinants of tolerance to acetic acid. In fact, only six gene pairs in ISA1307 whole genome exhibit nucleotide differences (rate of non-synonymous substitutions (dN) and synonymous substitutions (dS) above 1) with an impact in the amino acid sequence of the encoded proteins [14] .", "cite_spans": [{"start": 620, "end": 624, "text": "[14]", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "Discussion", "text": "The mechanisms behind yeast adaptation and tolerance to weak acids stress are multifactorial [9] . In other words, yeast tolerance does not rely in a single key cellular process, so it would be expectable that the candidate determinants of acetic acid tolerance emerging from this study are related to different functions in cell. Indeed, the genes identified in our screening as strong candidate determinants of acetic acid tolerance in the highly tolerant strain ISA1307 include genes presumably involved in functions such as cellular transport and transport routes, protein fate, protein synthesis, amino acid metabolism and transcription, as detailed below. The ORFs identified in this study that share poor or no homology with S. cerevisiae genes should also be considered as relevant, in particular ZBAI_09903 that holds a pyrimidine binding domain of pyruvate decarboxylase required for the conversion of pyruvate into acetaldehyde and ethanol. Interestingly, a pyruvate decarboxylase enzyme, involved in pyruvate fermentation to acetaldehyde and ethanol, was recently reported as being up-regulated in acetic acidgrown ISA1307 cells compared to cells grown on glucose [16] . Moreover, the deletion of PDC1, coding for S. cerevisiae pyruvate decarboxylase, was found to lead to a susceptibility phenotype in cells exposed to acetic and propionic acids [7, 8] .", "cite_spans": [{"start": 93, "end": 96, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 1176, "end": 1180, "text": "[16]", "ref_id": "BIBREF15"}, {"start": 1359, "end": 1362, "text": "[7,", "ref_id": "BIBREF6"}, {"start": 1363, "end": 1365, "text": "8]", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "Discussion", "text": "Among the strong candidate determinants of acetic acid tolerance we identified GYP8 and WSC4 homologues, putatively involved in cellular transport, in particular vesicular transport. The processes of transport vesicle formation, targeting, docking and tethering require complex molecular machinery. Different Ras-like GTPases contribute to these activities by acting as key regulators in assembling specific protein complexes at different donor and target membranes [21] [22] [23] . In S. cerevisiae, GYP8 encodes a GTPase-activating protein for Ypt/Rab GTPases, which plays an essential function in endoplasmic reticulum to Golgi vesicular protein transport. S. cerevisiae gyp8\u0394 was found to be sensitive to acetic acid and the expression of the Z. bailii GYP8 homologue, sharing 99 % identity with Z. bailii CLIB213 T , led to a suppression of the mutant phenotype providing evidences of a similar function in Z. bailii. To our best knowledge, this is the first time that this gene is related with increased tolerance to acetic acid in yeast. Also in the context of cellular transport, we found that the expression of WSC4 homologue (presumably derived from the non-Z. bailii parental strain) suppresses the susceptibility phenotype of S. cerevisiae wsc4\u0394 mutant. S. cerevisiae Wsc4 is specifically involved in the translocation of soluble secretory proteins and insertion of membrane proteins into the ER membrane. In addition to its role in protein trafficking activity, Wsc4 was also described to play a role in S. cerevisiae response to a number of stresses, namely to heat shock, exposure to ethanol or 4-nitroquinoline 1-oxide (4-NQO), a DNA-damaging agent [24] . To our knowledge, there is no published information about the increased susceptibility to weak acids of wsc4\u0394 mutant, but the WSC4 gene was found to be upregulated after exposure to acetic acid by two-fold in S. cerevisiae [6] . Moreover, it is known that this gene is coregulated by the weak acid-responsive transcription factors Haa1 and Rim101 in response to acetic acid stress [6] .", "cite_spans": [{"start": 466, "end": 470, "text": "[21]", "ref_id": "BIBREF20"}, {"start": 471, "end": 475, "text": "[22]", "ref_id": "BIBREF21"}, {"start": 476, "end": 480, "text": "[23]", "ref_id": "BIBREF22"}, {"start": 1665, "end": 1669, "text": "[24]", "ref_id": "BIBREF23"}, {"start": 1895, "end": 1898, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 2053, "end": 2056, "text": "[6]", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Discussion", "text": "Genes homologous to S. cerevisiae RKR1, PMT1 and KTR7, putatively involved in modification and degradation of proteins, were also considered strong candidate determinants of acetic acid tolerance. In S. cerevisiae, both PMT1 and KTR7 code for mannosyltransferases that have been described as key enzymes for protein glycosylation known to be essential for cell wall rigidity [25, 26] . The remodelling of cell wall is considered a common response to several environmental stresses [8] . In the specific case of weak acid stress, such remodelling is known to be an essential adaptive response that presumably leads to the reduction of the diffusion rate of the undissociated weak acid form into the cell interior, limiting the futile cycle resulting from the continuous uptake of the lipophilic form by passive diffusion followed by the active expulsion of the counterion through specific transporters [27, 28] . Remarkably, the family-related S. cerevisiae gene KTR4, encoding another mannosyltransferase involved in protein glycosylation, was previously identified as a determinant of acetic acid tolerance [8] .", "cite_spans": [{"start": 375, "end": 379, "text": "[25,", "ref_id": "BIBREF24"}, {"start": 380, "end": 383, "text": "26]", "ref_id": "BIBREF25"}, {"start": 481, "end": 484, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 901, "end": 905, "text": "[27,", "ref_id": "BIBREF26"}, {"start": 906, "end": 909, "text": "28]", "ref_id": "BIBREF27"}, {"start": 1108, "end": 1111, "text": "[8]", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "Discussion", "text": "The ILV3 homologue was also identified as a strong candidate determinant of acetic acid tolerance. In S. cerevisiae, ILV3 codes for a dihydroxyacid dehydratase that catalyzes the third step in the pathways leading to biosynthesis of branched-chain amino acids [29] . Interestingly, the content of Ilv3 was found to be higher in acetic acid-challenged yeast cells, compared with unstressed cells [30] .", "cite_spans": [{"start": 260, "end": 264, "text": "[29]", "ref_id": "BIBREF28"}, {"start": 395, "end": 399, "text": "[30]", "ref_id": "BIBREF29"}], "ref_spans": []}, {"section": "Discussion", "text": "Among the DNA inserts identified during the present work, the best inserts whose expression confers a high protective effect against acetic acid stress in both the parental and the deletion mutant strains are S06 and those containing MSN4 or TIF3 homologues.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "The ORF ZBAI_02295, one of two ORFs included in S06 insert and presumably involved in membrane trafficking, was identified as being responsible for the considerable increase in the acetic acid tolerance of the haa1\u0394 mutant, but not of the parental strain, thereby suggesting that the expression of ZBAI_02295 can support the function of Haa1 targets in S. cerevisiae but cannot, at least individually, further enhance the acetic acid tolerance of the parental strain. The contribution of the encoding protein, containing a functional domain associated to the uncharacterised DUP family to acetic acid tolerance, is still unclear. DUP proteins were previously suggested as being connected to membrane trafficking and hypothesized as being involved in the trafficking of membrane transporters [20, 31] . Results gathered from large-scale chemical genomics screenings suggest that intracellular trafficking processes are required for weak acid tolerance [9] . Moreover, the genes of the DUP240 family in S. cerevisiae YAR028W and YAR029W were found to be up-regulated, their transcription being Haa1 dependent, in cells exposed to acetic acid stress [6] , reinforcing the idea that this family of proteins is involved in yeast response and tolerance to acetic acid and that the expression of ZBAI_02295 in haa1\u0394 can compensate the abolishment of YAR028W and YAR029W transcription and therefore elevate the acetic acid susceptibility of the mutant up to the level of the parental strain. This increase of tolerance was not observed in the parental cells maybe because the putative membrane protein originated from the ORF ZBAI_02295 does not bring any advantage in cells where the Haa1 regulon is transcribed. The fact that the expression of S06 insert, which contains ZBAI_02295 and ZBAI_02296, leads to the increase of the acetic acid tolerance of the parental strain may be due to the conjugated effect of both ORFs and also to the different conditions used, namely the medium composition and the cloning vector. The expression of the genes from S06 DNA insert under the control of their native promoters compared with the individual expression of each gene under the GAL1 inducible promoter can be different and it is likely that the overproduction of the two putative membrane proteins encoded by these ORFs might be deleterious to the host cell.", "cite_spans": [{"start": 791, "end": 795, "text": "[20,", "ref_id": "BIBREF19"}, {"start": 796, "end": 799, "text": "31]", "ref_id": "BIBREF30"}, {"start": 951, "end": 954, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 1147, "end": 1150, "text": "[6]", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Discussion", "text": "The relevance of TIF3 homologue as a putative translation initiation factor in yeast tolerance to acetic acid may rely on the fact that stressed cells generate stressresponsive programmes consisting on a specific upregulation of translation initiation towards the induction of specific adaptation proteins, while a rapid inhibition of protein synthesis in general occurs, in order to rationalize the consumption of resources [32] . Using the nonflocculating Z. bailii strain IST302, it was possible to confirm that the increased expression of ZbTIF3 in this same strain enhances its tolerance to acetic acid. ISA1307 MSN4 gene is homologous to S. cerevisiae paralogous genes encoding the transcription factors Msn2 and Msn4. These transcription factors are involved in the regulation of genes of the general stress response and, despite their high homology, both proteins play non-redundant and condition-specific roles in gene expression regulation in S. cerevisiae [33] . Interestingly, it was found that both the Haa1 and Msn2/4 regulons share a total of 23 acetic acidactivated genes [6] . For this reason, it is likely that the strain ISA1307 Msn4 homologue has the ability to suppress haa1\u0394 susceptibility phenotype in S. cerevisiae. Remarkably, ISA1307 Msn4 homologue was indeed one of the best acetic acid susceptibility suppressors found in the screening. Moreover, the expression of ZbMSN4 from IST302 either in S. cerevisiae parental strains BY4741 and W303-1A or the derived deletion mutants msn4\u0394 and msn2\u0394msn4\u0394 confers increased protection against acetic acid, indicating that ZbMsn4 has a role similar to its homologous S. cerevisiae protein. In addition, the increased expression of ZbMSN4 in Z. bailii IST302 also elevated this strain's tolerance to acetic acid, confirming this putative transcription factor as an important determinant of acetic acid resistance in Z. bailii.", "cite_spans": [{"start": 425, "end": 429, "text": "[32]", "ref_id": "BIBREF31"}, {"start": 967, "end": 971, "text": "[33]", "ref_id": "BIBREF32"}, {"start": 1088, "end": 1091, "text": "[6]", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Conclusions", "text": "In the present study we have identified several strong candidate determinants of tolerance to acetic acid in the intrinsically highly acetic acid tolerant Z. bailii-derived hybrid strain ISA1307. Specifically, this is the case of the following S. cerevisiae homologues presumably involved in different cellular processes -GYP8 and WSC4 (cellular transport and transport routes), PMT1, KTR7 and RKR1 (protein fate), TIF3 (protein synthesis), ILV3 (amino acid metabolism), MSN4 (transcription) -and of ZBAI_02295 (homologous to membrane proteins of unknown function and presumably involved in cellular trafficking). The overexpression of ZbMSN4 and ZbTIF3 genes, which were confirmed as playing a relevant role in acetic acid tolerance in yeast through their homologous and heterologous expression in Z. bailii and S. cerevisiae strains, may be useful considering the improvement of yeast cell robustness against acetic acid if the objective is their use as cell factories.", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Strains and growth media", "text": "The Saccharomyces cerevisiae deletion mutant strain BY4741_haa1\u0394, derived from the parental strain BY4741 (MATa, his3\u03941, leu2\u03940, met15\u03940, ura3\u03940) and obtained from the EUROSCARF collection was used as the host strain for the screening of acetic acid determinants of tolerance in a Zygosaccharomyces bailii-derived interspecies hybrid strain ISA1307 using a previously constructed genomic library [15] . Strains gyp8\u0394, ktr7\u0394, rkr1\u0394, msn4\u0394, pmt1\u0394, tif3\u0394 and wsc4\u0394 derived from the same S. cerevisiae parental strain were used for phenotype complementation assays. Since the deletion of ILV3 gene in the haploid background strain BY4741 is lethal, the ilv3\u0394 mutant used in phenotype complementation assays was derived from the diploid parental strain BY4743 (MATa/a, his3\u03941/his3\u03941, leu2\u03940/leu2\u03940, lys2\u03940/LYS2, MET15/ met15\u03940, ura3\u03940/ura3\u03940) with one copy of ILV3 deleted. S. cerevisiae strains W303-1A (MATa, leu2\u03943, 112 trp1\u03941, can1\u0394100, ura3\u03941, ade2\u03941, his3\u039411,15) and derived double deletion mutant msn2\u0394msn4\u0394 [34] were used for complementation assays of MSN4 from Z. bailii IST302 (ZbMSN4). This strain was isolated from a spontaneous fermentation of grape must from Douro wine-producing areas and its genome was recently sequenced and annotated in our laboratory (unpublished results). The taxonomic identification of Z. bailii IST302 was confirmed by comparing the partial 26S ribosomal DNA sequence (Additional file 3) with other DNA sequences from Z. bailii strains using the Basic Local Alignment Search Tool (BLAST) of the National Center for Biotechnology Information (NCBI). Strain IST302 was used for the amplification of ZbMSN4 and ZbTIF3 genes that were cloned into pZ 3 bT. This strain was also used as a host cell for the expression of an extra copy of its ZbMSN4 and ZbTIF3 genes. Escherichia coli XL1-Blue was used for plasmid maintenance and general cloning procedures. E. coli cells were grown in Luria-Bertani medium (LB), supplemented with 150 \u03bcg/ml ampicillin when required. Yeast strains were batch-cultured at 30\u00b0C with orbital agitation Screening of the genomic library from Z. bailii-derived interspecies hybrid strain ISA1307 Transformation of S. cerevisiae BY4741_haa1\u0394 with strain ISA1307 genomic library", "cite_spans": [{"start": 396, "end": 400, "text": "[15]", "ref_id": "BIBREF14"}, {"start": 1010, "end": 1014, "text": "[34]", "ref_id": "BIBREF33"}, {"start": 1681, "end": 1682, "text": "3", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "Strains and growth media", "text": "The ISA1307 strain genomic library constructed by Rodrigues et al. [15] in the pRS316 vector [35] was used in this work. This plasmid is a shuttle vector for S. cerevisiae and E. coli, containing origins of replication for both species and Amp r and URA3 genes as selection markers. Moreover, this cloning vector is a centromeric plasmid, possessing an S. cerevisiae centromere (CEN6). The choice for a low copy plasmid is useful for isolation of genes that may have a toxic effect when present in multiple copies. For library plasmid DNA isolation, E. coli cells containing the genomic library were grown at 26\u00b0C on LB medium supplemented with ampicillin until late stationary-phase and plasmid DNA was extracted from these cells using the QIAprep\u00ae Spin Maxiprep Kit according to the manufacturer's instructions. S. cerevisiae BY4741_haa1\u0394 strain was transformed with library plasmid DNA, using the lithium acetate method [36] . The transformation mixture was plated onto solid MM4 medium without uracil and plates were incubated at 30\u00b0C for 3 days.", "cite_spans": [{"start": 67, "end": 71, "text": "[15]", "ref_id": "BIBREF14"}, {"start": 93, "end": 97, "text": "[35]", "ref_id": "BIBREF34"}, {"start": 923, "end": 927, "text": "[36]", "ref_id": "BIBREF35"}], "ref_spans": []}, {"section": "Screening of the transformants for acetic acid tolerance", "text": "Selection of the transformants showing more tolerance to acetic acid was performed in 96-well microplates containing liquid MM4 medium without uracil at pH 4.0. At the end of the day, a first plate containing 200 \u03bcl of liquid medium was inoculated with cells taken from the different yeast transformants under study, and incubated at 30\u00b0C overnight with orbital agitation at 250 rpm. On the next morning, each inoculum was diluted and used to inoculate a microplate containing the same liquid media supplemented with 60 mM of acetic acid, at an initial OD 600nm of about 0.05. This plate was incubated at 30\u00b0C for 24 h under stirring at 250 rpm and after that time period the culture OD 600 nm was measured (VersaMax microplate reader, Molecular Devices). The tolerance of transformants to acetic acid was based on these values of growth observed after 24 h of incubation. Candidates were considered susceptible to acetic acid when OD 600nm reached values below 0.250, while candidates with an intermediate tolerance phenotype to acetic acid exhibited an OD 600nm between 0.250 and 0.350 and the tolerant candidates an OD 600nm above 0.350. S. cerevisiae BY4741_haa1\u0394 was used as the negative control as it is particularly susceptible to 60 mM acetic acid, pH 4.0, being unable to grow within the period of incubation used.", "cite_spans": [], "ref_spans": []}, {"section": "Screening of the transformants for acetic acid tolerance", "text": "Comparison of the tolerance of the selected candidates to acetic acid A confirmation screening of acetic acid tolerance phenotype was performed with the isolation of total DNA from yeast transformants selected as the most tolerant to acetic acid. DNA was used to transform E. coli XL1-Blue strain competent cells by electroporation using Bio-Rad Gene Pulser II (400 \u03a9, 25 \u03bcF, 2.5 kV). The transformants obtained were selected for ampicillin resistance and cultivated for 12 h in 3 ml of LB liquid medium with ampicillin at 37\u00b0C with an orbital agitation of 250 rpm. For plasmid isolation from E. coli a QIAprep\u00ae Spin Miniprep Kit was used, according to the manufacturer's instructions. The extracted DNA was then used to transform the parental strain S. cerevisiae BY4741 and the derived deletion mutant BY4741_haa1\u0394, using the lithium acetate method [36] . Growth curves of these strains in liquid media, either in the absence or presence of acetic acid were determined. Cells were grown in MM4 medium without uracil at pH 4.0 until exponential phase (OD 600nm of 0.5 \u00b1 0.05) and then re-inoculated at an OD 600nm of 0.05, in 50 ml of fresh medium, either or not supplemented with 60 mM of acetic acid. Growth was followed by measuring culture OD 600nm during batch cultivation at 30\u00b0C with an orbital agitation of 250 rpm. The parental strain S. cerevisiae BY4741 and the mutant BY4741_haa1\u0394 both transformed with the empty vector were used as controls. The suppressors of acetic acid susceptibility phenotype of BY4741_haa1\u0394 were selected and submitted to further sequence analysis. Finally, an additional confirmation step of the phenotype of BY4741_haa1\u0394 cells transformed with the sequenced suppressors was performed by repeating their growth curves in control conditions and in the presence of 60 mM of acetic acid in 96-well microplates (FilterMax F5, Multi-mode microplate reader, Molecular Devices), at 30\u00b0C. Microplate reads were carried out every 10 min using a 595 nm absorbance filter. An orbital agitation of three seconds was performed prior to each read. The growth curves of S. cerevisiae BY4741 parental strain transformed with these same suppressors were repeated as well. The plates were inoculated with cells in exponential phase (OD 600nm of 0.5 \u00b1 0.05) at an initial OD 600nm of 0.05.", "cite_spans": [{"start": 851, "end": 855, "text": "[36]", "ref_id": "BIBREF35"}], "ref_spans": []}, {"section": "Screening of the transformants for acetic acid tolerance", "text": "In order to be comparable, all the growth curves must come from the same plate, since the level of inhibition of the acid is hardly reproducible from plate to plate due to the extremely small volume contained in each well. So, all the parental strain transformants were grown in the same plate, and the same was done for the transformants of the deletion mutant BY4741_haa1\u0394. For comparison purposes between the transformants from the two different backgrounds, the growth curve of the parental strain with the empty vector was included in the plates with the BY4741_haa1\u0394 transformants.", "cite_spans": [], "ref_spans": []}, {"section": "Screening of the transformants for acetic acid tolerance", "text": "In silico analysis of the selected plasmid DNA inserts from strain ISA1307 genomic library", "cite_spans": [], "ref_spans": []}, {"section": "Screening of the transformants for acetic acid tolerance", "text": "The complete DNA sequence of the selected plasmid inserts from strain ISA1307 genomic library was obtained in two steps. First, approximately 1000 bp of the DNA sequence ends of each plasmid insert were sequenced using vector specific primers (forward and reverse). Second, the complete sequence of the plasmid insert was acquired by alignment of the sequenced ends against the genome sequence of the strain ISA1307 available in the PEDANT database (http://pedant.helmholtz-muenchen.de/genomes.jsp?Category=fungal) [37] . This sequence was part of a high-throughput DNA sequencing project, based on Illumina paired-end sequencing, carried out by our group [14] . The in silico analysis of each DNA plasmid insert from the genomic library was performed also using the PEDANT database and the genomic browser GBrowse_syn (http://mips.helmholtzmuenchen.de/gbrowse2/cgi-bin/gbrowse_syn/zbailii) [38] that returns all the putative open reading frames (ORFs) present in the DNA fragment based on sequence homology with S. cerevisiae. Additionally, this tool provides the synteny alignments for the Z. bailii-derived interspecies hybrid strain ISA1307 genome versus the genomes of Z. bailii CLIB213 T , Z. rouxii and S. cerevisiae. When the plasmid DNA insert contained truncated ORFs, the presence of specific functional domains was assessed using the Conserved Domain Database of the NCBI [19] . The description of each gene was based on the information gathered in Saccharomyces Genome Database (www.yeastgenome.org) for the corresponding putative homologue.", "cite_spans": [{"start": 515, "end": 519, "text": "[37]", "ref_id": "BIBREF36"}, {"start": 656, "end": 660, "text": "[14]", "ref_id": "BIBREF13"}, {"start": 891, "end": 895, "text": "[38]", "ref_id": "BIBREF37"}, {"start": 1384, "end": 1388, "text": "[19]", "ref_id": "BIBREF18"}], "ref_spans": []}, {"section": "Screening of the transformants for acetic acid tolerance", "text": "Cloning and expression of ZBAI_02295 and ZBAI_02296 in S. cerevisiae", "cite_spans": [], "ref_spans": []}, {"section": "Screening of the transformants for acetic acid tolerance", "text": "The pGREG506 plasmid from the DRAG & DROP collection [39] was used to individually clone by homologous recombination and express the genes ZBAI_02295 and ZBAI_02296 identified in the S06 DNA fragment from ISA1307 genomic library. That cloning vector was acquired from Euroscarf and contains a HIS3 gene under the control of a galactose inducible promoter (GAL1) and the yeast selectable marker URA3. During homologous recombination the HIS3 gene is replaced by the gene of interest. ZBAI_02295 and ZBAI_02296 DNA fragments were generated by PCR using genomic DNA extracted from the strain ISA1307 and the specific primers ZBAI_02295_FWD, ZBAI_02295_REV, ZBAI_02296_FWD and ZBAI_02296_REV, whose sequences are listed in Additional file 4. The cDNA from each gene was co-transformed into the parental strain BY4741 and derived deletion mutant haa1\u0394 with the pGREG506 vector, previously cut with SalI restriction enzyme. The recombinant plasmids pGREG506_ ZBAI_02295 and pGREG506_ ZBAI_02296 were obtained through homologous recombination in yeast. Correct cloning of each ORF was confirmed by DNA sequencing. Additionally, S. cerevisiae BY4741 parental and derived deletion mutant haa1\u0394 strains were transformed with the cloning vector pGREG506. To have the adequate control cells, both strains were transformed as well with the empty vector pGREG506 with the HIS3 gene deleted (pGREG506_noHIS3, obtained by digestion of pGREG506 with the restriction enzyme SalI), since in the recombinant vector the HIS3 gene is substituted by the insert of interest. The susceptibility to acetic acid of the parental strain BY4741 and the derived deletion mutant haa1\u0394, harbouring each one of the four described plasmids (pGREG506_ ZBAI_02295, pGREG 506_ ZBAI_02296, pGREG506 and pGREG506_noHIS3) was assessed. This was possible by comparing their growth curves in liquid MM4-U medium supplemented with 1 % of galactose (w/v) pH 4.0, at 30\u00b0C with orbital agitation (250 rpm), either or not supplemented with 60 mM acetic acid, as previously described.", "cite_spans": [{"start": 53, "end": 57, "text": "[39]", "ref_id": "BIBREF38"}], "ref_spans": []}, {"section": "Screening of the transformants for acetic acid tolerance", "text": "Complementation of S. cerevisiae deletion mutants by the corresponding Z. bailii ISA1307 single genes present in genomic library plasmids", "cite_spans": [], "ref_spans": []}, {"section": "Screening of the transformants for acetic acid tolerance", "text": "The genomic library plasmids 8.23, 18.22, 23.1, B02, B18, S07 and Y08 carrying the single S. cerevisiae putative homologous genes GYP8, PMT1, WSC4, MSN4, TIF3, KTR7 or RKR1, respectively, were transformed in S. cerevisiae BY4741 EUROSCARF mutants lacking the respective gene. The complementation of library plasmid 23.17 carrying ILV3 was performed using the diploid BY4743 parental strain with one copy of the essential ILV3 gene deleted, because the haploid BY4741_ilv3\u0394 is unviable. Both S. cerevisiae parental strains transformed with the empty vector were used as control. The transformants were batch-cultivated in MM4-U medium at pH 4.0, either or not supplemented with 60 mM of acetic acid, as previously described. Since S. cerevisiae tif3\u0394 is highly susceptible to acetic acid, a growth medium containing a lower concentration of acetic acid (40 mM) was used. The complementation assays using the diploid strains derived from BY4743 were performed with a higher concentration (65 mM) of acetic acid.", "cite_spans": [], "ref_spans": []}, {"section": "Screening of the transformants for acetic acid tolerance", "text": "Cloning and expression of ZbMSN4 in S. cerevisiae", "cite_spans": [], "ref_spans": []}, {"section": "Screening of the transformants for acetic acid tolerance", "text": "The gene ZbMSN4 amplified from Z. bailii IST302 was cloned by homologous recombination into pGREG506 using the strategy above described for the cloning of ZBAI_02295 and ZBAI_02296. The primers ZbMSN4_pGREG_FWD and ZbMSN4_pGREG_REV (Additional file 4) were used for the amplification of ZbMSN4 coding region. This DNA fragment and the pGREG506 vector previously digested with SalI restriction enzyme were co-transformed into S. cerevisiae BY4741 parental strain. The obtained recombinant plasmid pGREG506_ZbMSN4 was digested with SpeI and AscI restriction enzymes to remove the GAL1 promoter from the vector. The digested vector and S. cerevisiae MSN4 promoter (approximately 1000 bp upstream the start codon) that was amplified with primers ZbMSN4prom_FWD and ZbMSN4prom_REV (Additional file 4) were co-transformed into S. cerevisiae BY4741 parental cells. The recombinant vector pGREG506_ promMSN4Sc_ZbMSN4 obtained by homologous recombination was sequenced to confirm the correct cloning of the promoter region and the gene and transformed afterwards into S. cerevisiae BY4741_msn4\u0394, W303-1A parental and derived double deletion mutant msn2\u0394msn4\u0394 strains. The susceptibility to acetic acid of the parental strains BY4741 and W303-1A and of the corresponding derived deletion mutants msn4\u0394 and msn2\u0394msn4\u0394, harbouring pGREG506_promMSN4Sc_ZbMSN4 and also pGREG506_ noHIS3 was assessed by comparing their growth curves in liquid MM4-U (BY4741 background strains) and MM5-U (W303-1A background strains), either or not supplemented with the appropriate acetic acid concentration.", "cite_spans": [], "ref_spans": []}, {"section": "Screening of the transformants for acetic acid tolerance", "text": "Cloning and expression of an extra copy of ZbMSN4 and ZbTIF3 in Z. bailii IST302", "cite_spans": [], "ref_spans": []}, {"section": "Screening of the transformants for acetic acid tolerance", "text": "The expression of an extra copy of ZbMSN4 and ZbTIF3 genes in the parental strain Z. bailii IST302 was performed by cloning these genes by homologous recombination into the centromeric expression vector pZ 3 bT [40] linearized with XbaI. The genes ZbMSN4 and ZbTIF3 and their corresponding promoters (approximately 1000 bp upstream the start codon) were amplified from strain IST302 genomic DNA using the primers ZbMSN4_FWD, ZbMSN4_REV, ZbTIF3_FWD and ZbTIF3_REV (Additional file 4) and cotransformed with the linearized pZ 3 bT into S. cerevisiae BY4741. Selection of the transformants holding the recombinant vectors pZ 3 bT_ ZbMSN4 and pZ 3 bT_ ZbTIF3 was performed in YPD plates containing G418 (200 mg/L). The correct recombination was confirmed by sequencing the obtained plasmids. The recombinant plasmids and the empty plasmid were used to transform Z. bailii IST302 using a commercial yeast transformation kit (MP Biomedicals, California) with minor modifications. The susceptibility to acetic acid of Z. bailii IST302 cells transformed with pZ 3 bT or with the recombinant vectors pZ 3 bT_ ZbMSN4 and pZ 3 bT_ ZbTIF3 was assessed by comparing their growth curves in liquid MM either or not supplemented with 180 or 220 mM acetic acid.", "cite_spans": [{"start": 206, "end": 207, "text": "3", "ref_id": "BIBREF2"}, {"start": 211, "end": 215, "text": "[40]", "ref_id": "BIBREF39"}, {"start": 642, "end": 643, "text": "3", "ref_id": "BIBREF2"}], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Food and beverage spoilage yeasts", "authors": [{"first": "M", "middle": [], "last": "Stratford", "suffix": ""}], "year": 2006, "venue": "Yeasts in food and beverages", "link": "67780256"}, "BIBREF1": {"title": "Encyclopedia of Food Microbiology", "authors": [{"first": "I", "middle": [], "last": "S\u00e1-Correia", "suffix": ""}, {"first": "J", "middle": ["F"], "last": "Guerreiro", "suffix": ""}, {"first": "M", "middle": ["C"], "last": "Loureiro-Dias", "suffix": ""}, {"first": "C", "middle": [], "last": "Le\u00e3o", "suffix": ""}, {"first": "M", "middle": [], "last": "C\u00f4rte-Real", "suffix": ""}, {"first": "", "middle": [], "last": "Zygosaccharomyces", "suffix": ""}], "year": 2014, "venue": "", "link": null}, "BIBREF2": {"title": "Weak acid adaptation: the stress response that confers yeasts with resistance to organic acid food preservatives", "authors": [{"first": "P", "middle": [], "last": "Piper", "suffix": ""}, {"first": "C", "middle": ["O"], "last": "Calderon", "suffix": ""}, {"first": "K", "middle": [], "last": "Hatzixanthis", "suffix": ""}, {"first": "M", "middle": [], "last": "Mollapour", "suffix": ""}], "year": 2001, "venue": "Microbiology", "link": "27917528"}, "BIBREF3": {"title": "S\u00e1-Correia I. A genome-wide perspective on the response and tolerance to food-relevant stresses in Saccharomyces cerevisiae", "authors": [{"first": "M", "middle": ["C"], "last": "Teixeira", "suffix": ""}, {"first": "N", "middle": ["P"], "last": "Mira", "suffix": ""}], "year": 2011, "venue": "Curr Opin Biotechnol", "link": null}, "BIBREF4": {"title": "S\u00e1-Correia I. Saccharomyces cerevisiae adaptation to weak acids involves the transcription factor Haa1p and Haa1p-regulated genes", "authors": [{"first": "A", "middle": ["R"], "last": "Fernandes", "suffix": ""}, {"first": "N", "middle": ["P"], "last": "Mira", "suffix": ""}, {"first": "R", "middle": ["C"], "last": "Vargas", "suffix": ""}, {"first": "I", "middle": [], "last": "Canelhas", "suffix": ""}], "year": 2005, "venue": "Biochem Biophys Res Commun", "link": "32360365"}, "BIBREF5": {"title": "Genomic expression program involving the Haa1p-regulon in Saccharomyces cerevisiae response to acetic acid", "authors": [{"first": "N", "middle": ["P"], "last": "Mira", "suffix": ""}, {"first": "J", "middle": ["D"], "last": "Becker", "suffix": ""}, {"first": "I", "middle": [], "last": "S\u00e1-Correia", "suffix": ""}], "year": 2010, "venue": "OMICS", "link": "20862468"}, "BIBREF6": {"title": "S\u00e1-Correia I. The RIM101 pathway has a role in Saccharomyces cerevisiae adaptive response and resistance to propionic acid and other weak acids", "authors": [{"first": "N", "middle": ["P"], "last": "Mira", "suffix": ""}, {"first": "A", "middle": ["B"], "last": "Louren\u00e7o", "suffix": ""}, {"first": "A", "middle": ["R"], "last": "Fernandes", "suffix": ""}, {"first": "J", "middle": ["D"], "last": "Becker", "suffix": ""}], "year": 2009, "venue": "FEMS Yeast Res", "link": "37412897"}, "BIBREF7": {"title": "Genome-wide identification of Saccharomyces cerevisiae genes required for tolerance to acetic acid", "authors": [{"first": "N", "middle": ["P"], "last": "Mira", "suffix": ""}, {"first": "M", "middle": [], "last": "Palma", "suffix": ""}, {"first": "J", "middle": ["F"], "last": "Guerreiro", "suffix": ""}, {"first": "I", "middle": [], "last": "S\u00e1-Correia", "suffix": ""}], "year": 2010, "venue": "Microb Cell Fact", "link": "1876122"}, "BIBREF8": {"title": "S\u00e1-Correia I. Adaptive response and tolerance to weak acids in Saccharomyces cerevisiae: a genome-wide view", "authors": [{"first": "N", "middle": ["P"], "last": "Mira", "suffix": ""}, {"first": "M", "middle": ["C"], "last": "Teixeira", "suffix": ""}], "year": 2010, "venue": "OMICS", "link": null}, "BIBREF9": {"title": "Activity of the plasma membrane H( + )-ATPase and optimal glycolytic flux are required for rapid adaptation and growth of Saccharomyces cerevisiae in the presence of the weak-acid preservative sorbic acid", "authors": [{"first": "C", "middle": ["D"], "last": "Holyoak", "suffix": ""}, {"first": "M", "middle": [], "last": "Stratford", "suffix": ""}, {"first": "Z", "middle": [], "last": "Mcmullin", "suffix": ""}, {"first": "M", "middle": ["B"], "last": "Cole", "suffix": ""}, {"first": "K", "middle": [], "last": "Crimmins", "suffix": ""}, {"first": "A", "middle": ["J"], "last": "Brown", "suffix": ""}], "year": 1996, "venue": "Appl Environ Microbiol", "link": "15452274"}, "BIBREF10": {"title": "Combined effect of acetic acid, pH and ethanol on intracellular pH of fermenting yeast", "authors": [{"first": "M", "middle": ["E"], "last": "Pampulha", "suffix": ""}, {"first": "M", "middle": ["C"], "last": "Loureiro", "suffix": ""}], "year": 1989, "venue": "Appl Microbiol Biotechnol", "link": null}, "BIBREF11": {"title": "Effect of extracellular acidification on the activity of plasma membrane ATPase and on the cytosolic and vacuolar pH of Saccharomyces cerevisiae", "authors": [{"first": "V", "middle": [], "last": "Carmelo", "suffix": ""}, {"first": "H", "middle": [], "last": "Santos", "suffix": ""}, {"first": "I", "middle": [], "last": "S\u00e1-Correia", "suffix": ""}], "year": 1997, "venue": "Biochim Biophys Acta", "link": "11037511"}, "BIBREF12": {"title": "Plasma membrane H + and K + transporters are involved in the weak-acid preservative response of disparate food spoilage yeasts", "authors": [{"first": "N", "middle": [], "last": "Macpherson", "suffix": ""}, {"first": "L", "middle": [], "last": "Shabala", "suffix": ""}, {"first": "H", "middle": [], "last": "Rooney", "suffix": ""}, {"first": "M", "middle": ["G"], "last": "Jarman", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Davies", "suffix": ""}], "year": 2005, "venue": "Microbiology", "link": "42123681"}, "BIBREF13": {"title": "The genome sequence of the highly acetic acid-tolerant Zygosaccharomyces bailii-derived interspecies hybrid strain ISA1307, isolated from a sparkling wine plant", "authors": [{"first": "N", "middle": ["P"], "last": "Mira", "suffix": ""}, {"first": "M", "middle": [], "last": "M\u00fcnsterk\u04e7tter", "suffix": ""}, {"first": "F", "middle": [], "last": "Dias-Valada", "suffix": ""}, {"first": "J", "middle": [], "last": "Santos", "suffix": ""}, {"first": "M", "middle": [], "last": "Palma", "suffix": ""}, {"first": "F", "middle": ["C"], "last": "Roque", "suffix": ""}], "year": 2014, "venue": "DNA Res", "link": "16381147"}, "BIBREF14": {"title": "Construction of a genomic library of the food spoilage yeast Zygosaccharomyces bailii and isolation of the beta-isopropylmalate dehydrogenase gene (ZbLEU2)", "authors": [{"first": "F", "middle": [], "last": "Rodrigues", "suffix": ""}, {"first": "A", "middle": ["M"], "last": "Zeeman", "suffix": ""}, {"first": "C", "middle": [], "last": "Alves", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Sousa", "suffix": ""}, {"first": "H", "middle": ["Y"], "last": "Steensma", "suffix": ""}, {"first": "M", "middle": [], "last": "C\u00f4rte-Real", "suffix": ""}], "year": 2001, "venue": "FEMS Yeast Res", "link": "35849065"}, "BIBREF15": {"title": "Adaptive response to acetic acid in the highly resistant yeast species Zygosaccharomyces bailii revealed by quantitative proteomics", "authors": [{"first": "J", "middle": ["F"], "last": "Guerreiro", "suffix": ""}, {"first": "N", "middle": ["P"], "last": "Mira", "suffix": ""}, {"first": "I", "middle": [], "last": "S\u00e1-Correia", "suffix": ""}], "year": 2012, "venue": "Proteomics", "link": "22358540"}, "BIBREF16": {"title": "Mechanisms underlying the transport and intracellular metabolism of acetic acid in the presence of glucose in the yeast Zygosaccharomyces bailii", "authors": [{"first": "M", "middle": ["J"], "last": "Sousa", "suffix": ""}, {"first": "F", "middle": [], "last": "Rodrigues", "suffix": ""}, {"first": "M", "middle": [], "last": "C\u00f4rte-Real", "suffix": ""}, {"first": "C", "middle": [], "last": "Le\u00e3o", "suffix": ""}], "year": 1998, "venue": "Microbiology", "link": "11530627"}, "BIBREF17": {"title": "Genome sequence of the food spoilage yeast Zygosaccharomyces bailii CLIB 213 T", "authors": [{"first": "V", "middle": [], "last": "Galeote", "suffix": ""}, {"first": "F", "middle": [], "last": "Bigey", "suffix": ""}, {"first": "H", "middle": [], "last": "Devillers", "suffix": ""}, {"first": "C", "middle": [], "last": "Neuv\u00e9glise", "suffix": ""}, {"first": "S", "middle": [], "last": "Dequin", "suffix": ""}], "year": 2013, "venue": "Genome Announc", "link": "9836487"}, "BIBREF18": {"title": "CDD: a conserved domain database for the functional annotation of proteins", "authors": [{"first": "A", "middle": [], "last": "Marchler-Bauer", "suffix": ""}, {"first": "S", "middle": [], "last": "Lu", "suffix": ""}, {"first": "J", "middle": ["B"], "last": "Anderson", "suffix": ""}, {"first": "F", "middle": [], "last": "Chitsaz", "suffix": ""}, {"first": "M", "middle": ["K"], "last": "Derbyshire", "suffix": ""}, {"first": "C", "middle": [], "last": "Deweesescott", "suffix": ""}], "year": 2011, "venue": "Nucleic Acids Res", "link": "2517364"}, "BIBREF19": {"title": "An evolutionary scenario for one of the largest yeast gene families", "authors": [{"first": "L", "middle": [], "last": "Despons", "suffix": ""}, {"first": "B", "middle": [], "last": "Wirth", "suffix": ""}, {"first": "V", "middle": ["L"], "last": "Louis", "suffix": ""}, {"first": "S", "middle": [], "last": "Potier", "suffix": ""}, {"first": "J-L", "middle": [], "last": "Souciet", "suffix": ""}], "year": 2006, "venue": "Trends Genet", "link": "19088767"}, "BIBREF20": {"title": "COPII: a membrane coat formed by Sec proteins that drive vesicle budding from the endoplasmic reticulum", "authors": [{"first": "C", "middle": [], "last": "Barlowe", "suffix": ""}, {"first": "L", "middle": [], "last": "Orci", "suffix": ""}, {"first": "T", "middle": [], "last": "Yeung", "suffix": ""}, {"first": "M", "middle": [], "last": "Hosobuchi", "suffix": ""}, {"first": "S", "middle": [], "last": "Hamamoto", "suffix": ""}, {"first": "N", "middle": [], "last": "Salama", "suffix": ""}], "year": 1994, "venue": "Cell", "link": "39030655"}, "BIBREF21": {"title": "Protein complexes in transport vesicle targeting", "authors": [{"first": "W", "middle": [], "last": "Guo", "suffix": ""}, {"first": "M", "middle": [], "last": "Sacher", "suffix": ""}, {"first": "J", "middle": [], "last": "Barrowman", "suffix": ""}, {"first": "S", "middle": [], "last": "Ferro-Novick", "suffix": ""}, {"first": "P", "middle": [], "last": "Novick", "suffix": ""}], "year": 2000, "venue": "Trends Cell Biol", "link": "37627005"}, "BIBREF22": {"title": "Rab proteins as membrane organizers", "authors": [{"first": "M", "middle": [], "last": "Zerial", "suffix": ""}, {"first": "H", "middle": [], "last": "Mcbride", "suffix": ""}], "year": 2001, "venue": "Nat Rev Mol Cell Biol", "link": "205012880"}, "BIBREF23": {"title": "Mutations in WSC genes for putative stress receptors result in sensitivity to multiple stress conditions and impairment of Rlm1-dependent gene expression in Saccharomyces cerevisiae", "authors": [{"first": "T", "middle": [], "last": "Zu", "suffix": ""}, {"first": "J", "middle": [], "last": "Verna", "suffix": ""}, {"first": "R", "middle": [], "last": "Ballester", "suffix": ""}], "year": 2001, "venue": "Mol Genet Genomics", "link": "10217516"}, "BIBREF24": {"title": "The PMT gene family: protein O-glycosylation in Saccharomyces cerevisiae is vital", "authors": [{"first": "M", "middle": [], "last": "Gentzsch", "suffix": ""}, {"first": "W", "middle": [], "last": "Tanner", "suffix": ""}], "year": 1996, "venue": "EMBO J", "link": "2723456"}, "BIBREF25": {"title": "Completion of the Saccharomyces cerevisiae genome sequence allows identification of KTR5, KTR6 and KTR7 and definition of the nine-membered KRE2/MNT1 mannosyltransferase gene family in this organism", "authors": [{"first": "M", "middle": [], "last": "Lussier", "suffix": ""}, {"first": "A", "middle": ["M"], "last": "Sdicu", "suffix": ""}, {"first": "E", "middle": [], "last": "Winnett", "suffix": ""}, {"first": "D", "middle": ["H"], "last": "Vo", "suffix": ""}, {"first": "J", "middle": [], "last": "Sheraton", "suffix": ""}, {"first": "A", "middle": [], "last": "D\u00fcsterh\u00f6ft", "suffix": ""}], "year": 1997, "venue": "Yeast", "link": "12979904"}, "BIBREF26": {"title": "S\u00e1-Correia I. The SPI1 gene, encoding a glycosylphosphatidylinositol-anchored cell wall protein, plays a prominent role in the development of yeast resistance to lipophilic weak-acid food preservatives", "authors": [{"first": "T", "middle": [], "last": "Sim\u00f5es", "suffix": ""}, {"first": "N", "middle": ["P"], "last": "Mira", "suffix": ""}, {"first": "A", "middle": ["R"], "last": "Fernandes", "suffix": ""}], "year": 2006, "venue": "Appl Environ Microbiol", "link": "19583074"}, "BIBREF27": {"title": "Presence of the Fps1p aquaglyceroporin channel is essential for Hog1p activation, but suppresses Slt2(Mpk1)p activation, with acetic acid stress of yeast", "authors": [{"first": "M", "middle": [], "last": "Mollapour", "suffix": ""}, {"first": "A", "middle": [], "last": "Shepherd", "suffix": ""}, {"first": "P", "middle": ["W"], "last": "Piper", "suffix": ""}], "year": 2009, "venue": "Microbiology", "link": "3175675"}, "BIBREF28": {"title": "Cloning of the dihydroxyacid dehydratase-encoding gene (ILV3) from Saccharomyces cerevisiae", "authors": [{"first": "J", "middle": ["A"], "last": "Velasco", "suffix": ""}, {"first": "J", "middle": [], "last": "Cansado", "suffix": ""}, {"first": "M", "middle": ["C"], "last": "Pe\u00f1a", "suffix": ""}, {"first": "T", "middle": [], "last": "Kawakami", "suffix": ""}, {"first": "J", "middle": [], "last": "Laborda", "suffix": ""}, {"first": "V", "middle": [], "last": "Notario", "suffix": ""}], "year": 1993, "venue": "Gene", "link": "29859369"}, "BIBREF29": {"title": "Yeast protein expression profile during acetic acid-induced apoptosis indicates causal involvement of the TOR pathway", "authors": [{"first": "B", "middle": [], "last": "Almeida", "suffix": ""}, {"first": "S", "middle": [], "last": "Ohlmeier", "suffix": ""}, {"first": "A", "middle": ["J"], "last": "Almeida", "suffix": ""}, {"first": "F", "middle": [], "last": "Madeo", "suffix": ""}, {"first": "C", "middle": [], "last": "Le\u00e3o", "suffix": ""}, {"first": "F", "middle": [], "last": "Rodrigues", "suffix": ""}], "year": 2009, "venue": "Proteomics", "link": "43602253"}, "BIBREF30": {"title": "Organization of physical interactomes as uncovered by network schemas", "authors": [{"first": "E", "middle": [], "last": "Banks", "suffix": ""}, {"first": "E", "middle": [], "last": "Nabieva", "suffix": ""}, {"first": "B", "middle": [], "last": "Chazelle", "suffix": ""}, {"first": "M", "middle": [], "last": "Singh", "suffix": ""}], "year": 2008, "venue": "PLoS Comput Biol", "link": null}, "BIBREF31": {"title": "Adaptation to stress in yeast: to translate or not?", "authors": [{"first": "C", "middle": ["E"], "last": "Simpson", "suffix": ""}, {"first": "M", "middle": ["P"], "last": "Ashe", "suffix": ""}], "year": 2012, "venue": "Biochem Soc Trans", "link": null}, "BIBREF32": {"title": "Stress-activated genomic expression changes serve a preparative role for impending stress in yeast", "authors": [{"first": "D", "middle": ["B"], "last": "Berry", "suffix": ""}, {"first": "A", "middle": ["P"], "last": "Gasch", "suffix": ""}], "year": 2008, "venue": "Mol Biol Cell", "link": "9126035"}, "BIBREF33": {"title": "Two homologous zinc finger genes identified by multicopy suppression in a SNF1 protein kinase mutant of Saccharomyces cerevisiae", "authors": [{"first": "F", "middle": [], "last": "Estruch", "suffix": ""}, {"first": "M", "middle": [], "last": "Carlson", "suffix": ""}], "year": 1993, "venue": "Mol Cell Biol", "link": "34471138"}, "BIBREF34": {"title": "A system of shuttle vectors and yeast host strains designed for efficient manipulation of DNA in Saccharomyces cerevisiae", "authors": [{"first": "R", "middle": ["S"], "last": "Sikorski", "suffix": ""}, {"first": "P", "middle": [], "last": "Hieter", "suffix": ""}], "year": 1989, "venue": "Genetics", "link": "9565525"}, "BIBREF35": {"title": "Improved method for high efficiency transformation of intact yeast cells", "authors": [{"first": "D", "middle": [], "last": "Gietz", "suffix": ""}, {"first": "A", "middle": [], "last": "St Jean", "suffix": ""}, {"first": "R", "middle": ["A"], "last": "Woods", "suffix": ""}, {"first": "R", "middle": ["H"], "last": "Schiestl", "suffix": ""}], "year": 1992, "venue": "Nucleic Acids Res", "link": null}, "BIBREF36": {"title": "PEDANT covers all complete RefSeq genomes", "authors": [{"first": "M", "middle": ["C"], "last": "Walter", "suffix": ""}, {"first": "T", "middle": [], "last": "Rattei", "suffix": ""}, {"first": "R", "middle": [], "last": "Arnold", "suffix": ""}, {"first": "U", "middle": [], "last": "Guldener", "suffix": ""}, {"first": "M", "middle": [], "last": "Munsterkotter", "suffix": ""}, {"first": "K", "middle": [], "last": "Nenova", "suffix": ""}], "year": 2009, "venue": "Nucleic Acids Res", "link": "16049873"}, "BIBREF37": {"title": "Using the Generic Synteny Browser (GBrowse_syn)", "authors": [{"first": "S", "middle": ["J"], "last": "Mckay", "suffix": ""}, {"first": "I", "middle": ["A"], "last": "Vergara", "suffix": ""}, {"first": "J", "middle": ["E"], "last": "Stajich", "suffix": ""}], "year": 2010, "venue": "Curr Protoc Bioinformatics", "link": "23675937"}, "BIBREF38": {"title": "Drag&Drop cloning in yeast", "authors": [{"first": "G", "middle": [], "last": "Jansen", "suffix": ""}, {"first": "C", "middle": [], "last": "Wu", "suffix": ""}, {"first": "B", "middle": [], "last": "Schade", "suffix": ""}, {"first": "D", "middle": ["Y"], "last": "Thomas", "suffix": ""}, {"first": "M", "middle": [], "last": "Whiteway", "suffix": ""}], "year": 2005, "venue": "Gene", "link": "23747972"}, "BIBREF39": {"title": "The yeast Zygosaccharomyces bailii: a new host for heterologous protein production, secretion and for metabolic engineering applications", "authors": [{"first": "P", "middle": [], "last": "Branduardi", "suffix": ""}, {"first": "M", "middle": [], "last": "Valli", "suffix": ""}, {"first": "L", "middle": [], "last": "Brambilla", "suffix": ""}, {"first": "M", "middle": [], "last": "Sauer", "suffix": ""}, {"first": "L", "middle": [], "last": "Alberghina", "suffix": ""}, {"first": "D", "middle": [], "last": "Porro", "suffix": ""}], "year": 2004, "venue": "FEMS Yeast Res", "link": null}, "BIBREF40": {"title": "Adaptation of Saccharomyces cerevisiae to the herbicide 2,4-dichlorophenoxyacetic acid, mediated by Msn2p-and Msn4p-regulated genes: important role of SPI1", "authors": [{"first": "T", "middle": [], "last": "Sim\u00f5es", "suffix": ""}, {"first": "M", "middle": ["C"], "last": "Teixeira", "suffix": ""}, {"first": "A", "middle": ["R"], "last": "Fernandes", "suffix": ""}, {"first": "I", "middle": [], "last": "S\u00e1-Correia", "suffix": ""}], "year": 2003, "venue": "Appl Environ Microbiol", "link": "45799355"}, "BIBREF41": {"title": "Yeast genes involved in response to lactic acid and acetic acid: acidic conditions caused by the organic acids in Saccharomyces cerevisiae cultures induce expression of intracellular metal metabolism genes regulated by Aft1p", "authors": [{"first": "M", "middle": [], "last": "Kawahata", "suffix": ""}, {"first": "K", "middle": [], "last": "Masaki", "suffix": ""}, {"first": "T", "middle": [], "last": "Fujii", "suffix": ""}, {"first": "H", "middle": [], "last": "Iefuji", "suffix": ""}], "year": 2006, "venue": "FEMS Yeast Res", "link": "13281198"}}, "ref_entries": {"FIGREF0": {"text": "Fig. 6 Effect of the expression of an extra copy of Z. bailii IST302 genes ZbMSN4 or ZbTIF3 in this same strain. Growth curves of Z. bailii IST302 transformed either with the empty plasmid pZ 3 bT (\u25cb), pZ 3 bT_ ZbMSN4 (\u2022) or pZ 3 bT_ ZbTIF3 (\u25a0). Yeast cells were cultivated in MM medium, pH4.0, either or not supplemented with acetic acid (180 mM or 220 mM). The growth curves shown are representative of three independent assays", "type": "figure"}, "FIGREF1": {"text": "(250 rpm) in liquid mineral medium (MM) that contains, per litre: 1.7 g yeast nitrogen base without amino acids or (NH 4 ) 2 SO 4 (Difco Laboratories, Detroit, Mich.), 20 g glu- cose (Merck) and 2.65 g (NH 4 ) 2 SO 4 (Merck). Supplemen- tation was needed for auxotrophic strains either with 20 mg methionine, 20 mg histidine, 60 mg leucine and 20 mg uracil for growth of BY4741 and BY4743 back- ground strains (MM4), or with 20 mg histidine, 60 mg leucine, 40 mg tryptophan, 80 mg adenine and 20 mg ura- cil for growth of W303-1A background strains (MM5) (all from Sigma, Spain). For transformants selection, yeast strains were grown in MM4 or MM5 media without uracil supplementation. YPD medium (2 % glucose (Merck), 1 % yeast extract (Difco) and 2 % peptone (Difco)) was used for yeast cells' maintenance and to grow cells for trans- formation experiments. Solid media were obtained by adding 20 g of agar to each litre of the corresponding li- quid media. All strains were maintained at -80\u00b0C in ap- propriate media supplemented with 15 % glycerol (v/v).", "type": "figure"}, "TABREF0": {"text": "Genomic DNA inserts from strain ISA1307 genomic library required for acetic acid tolerance containing the putative ORFs for which weak or no homology with S. cerevisiae genes was found. Information about other ORFs present in the same DNA insert is provided, as well as the best blast hits and the predicted functional and transmembrane domains of the corresponding protein", "type": "table"}, "TABREF2": {"text": "Genomic DNA inserts from strain ISA1307 genomic library containing the strong candidate determinants of tolerance to acetic acid proposed in this workPercentage of nucleotides present in the truncated ORFs, compared with the total ORF sequence, is indicated in parenthesesIdentity (%) between each ORF found in the DNA inserts and Z. bailii CLIB213 T genome was obtained using BLAST analysis (http://blast.ncbi.nlm.nih.gov/Blast.cgi)", "type": "table"}}}
{"paper_id": "17781516", "_pdf_hash": "b755379fb2c1f93d7d2d1bc4b056899ba96e4937", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "A Framework for Structure, Layout & Function in Documents", "authors": [{"first": "J", "middle": [], "last": "Lumley", "suffix": ""}, {"first": "R", "middle": [], "last": "Gimson", "suffix": ""}, {"first": "O", "middle": [], "last": "Rees", "suffix": ""}], "year": 2005, "venue": "Proceedings of the 2005 ACM symposium on Document engineering", "link": "15231713"}, "BIBREF1": {"title": "Extensible Layout in Functional Documents", "authors": [{"first": "J", "middle": [], "last": "Lumley", "suffix": ""}, {"first": "R", "middle": [], "last": "Gimson", "suffix": ""}, {"first": "O", "middle": [], "last": "Rees", "suffix": ""}], "year": 2006, "venue": "Digital Publishing, Proc. of SPIE-IS&T Electronic Imaging", "link": "18602021"}, "BIBREF2": {"title": "Resolving Layout Interdependency with Presentational Variables", "authors": [{"first": "J", "middle": [], "last": "Lumley", "suffix": ""}, {"first": "R", "middle": [], "last": "Gimson", "suffix": ""}, {"first": "O", "middle": [], "last": "Rees", "suffix": ""}], "year": 2006, "venue": "Proceedings of the 2006 ACM symposium on Document engineering", "link": null}, "BIBREF3": {"title": "Evaluating Invariances in Document Layout Functions", "authors": [{"first": "A", "middle": [], "last": "Macdonald", "suffix": ""}, {"first": "D", "middle": [], "last": "Brailsford", "suffix": ""}, {"first": "J", "middle": [], "last": "Lumley", "suffix": ""}], "year": 2006, "venue": "Proceedings of the 2006 ACM symposium on Document engineering", "link": "1899443"}, "BIBREF4": {"title": "Progressive Document Evaluation", "authors": [{"first": "A", "middle": [], "last": "Macdonald", "suffix": ""}], "year": 2008, "venue": "", "link": "5238764"}, "BIBREF5": {"title": "High performance XSL-FO rendering for variable data printing", "authors": [{"first": "F", "middle": [], "last": "Giannetti", "suffix": ""}], "year": 2006, "venue": "SAC '06: Proceedings of the 2006 ACM symposium on Applied computing pages", "link": "207159425"}, "BIBREF7": {"title": "Project Apache FOP (Formatting Objects Processor", "authors": [{"first": "Xml", "middle": [], "last": "Apache", "suffix": ""}, {"first": "", "middle": [], "last": "Graphics", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF8": {"title": "E-path_PRE: partial redundancy elimination made easy", "authors": [{"first": "D", "middle": [], "last": "Dhamdhere", "suffix": ""}], "year": 2002, "venue": "In SIGPLAN Not", "link": "14666614"}}, "ref_entries": {}}
{"paper_id": "17781743", "_pdf_hash": "6ea6d9dd53792d621cfc19962368ba508c3588d5", "abstract": [{"section": "Abstract", "text": "Abstract. Classification of homotopy n-types has focused on developing algebraic categories which are equivalent to categories of n-types. We expand this theory by providing algebraic models of homotopy-theoretic constructions for stable one-types. These include a model for the Postnikov one-truncation of the sphere spectrum, and for its action on the model of a stable one-type. We show that a bicategorical cokernel introduced by Vitale models the cofiber of a map between stable one-types, and apply this to develop an algebraic model for the Postnikov data of a stable one-type.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "The homotopy category of groupoids is equivalent to the homotopy category of unstable one-types, via the classifying space and fundamental groupoid functors. This is one of the well-known results from a large body of work around the \"algebraic homotopy\" outlined by J.H.C. Whitehead in his 1950 address to the International Congress of Mathematicians. Crossed modules classify unstable two-types, and Conduch\u00e9 gives a generalization to unstable three-types [Con84] .", "cite_spans": [{"start": 457, "end": 464, "text": "[Con84]", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "Introduction", "text": "A related body of work focuses on stable homotopy type. Stable one-types are classified by Picard groupoids, i.e., group-like symmetric monoidal groupoids. This is a well-known result for which we give a new proof in Section 1. Picard groupoids were first introduced in the thesis of S\u00ednh Hoang Xuan [S\u00edn75] , where the author gives a thorough algebraic classification theorem. Since then, various results have further established the link between Picard groupoids and stable one types. Garz\u00f3n and Miranda [GM97] develop a model structure for the categories of Picard groupoids, identifying the path and cylinder constructions therein. They use this setting to model homotopy classes of maps between spaces with nontrivial homotopy groups in degrees n and n + 1 for n \u2265 1. Garz\u00f3n-Miranda-del R\u00edo [GMdR02] give categorical models for the n th homotopy groupoid of a space for n \u2265 2, showing that the resulting monoidal categories are braided for n = 2 and symmetric for n \u2265 3. As a generalization of Eilenberg-Mac Lane cohomology, BullejosCarrasco-Cegarra [BCC93] define a cohomology of simplicial sets with coefficients in a Picard groupoid. Their work uses this to give alternate categorical models for spaces with homotopy groups in degrees n and n + 1 for n \u2265 3-the stable range.", "cite_spans": [{"start": 300, "end": 307, "text": "[S\u00edn75]", "ref_id": "BIBREF23"}, {"start": 506, "end": 512, "text": "[GM97]", "ref_id": "BIBREF11"}, {"start": 796, "end": 804, "text": "[GMdR02]", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "Introduction", "text": "Our proof that Picard groupoids classify stable one-types is given in Theorem 1.5 using the perspective of E \u221e action on the categorical and topological objects. Our main results go beyond the basic classification to describe the homotopical structure of stable one-types through corresponding structure of Picard groupoids.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "Specifically, we study the decomposition of stable one-types by their Postnikov data. This consists of abelian groups \u03c0 0 and \u03c0 1 , and a single k-invariant, which is a map of Eilenberg-Mac Lane spectra H\u03c0 0 \u2192 \u03a3 2 H\u03c0 1 . Using the isomorphism [H\u03c0 0 , \u03a3 2 H\u03c0 1 ] \u223c = Hom(\u03c0 0 /2\u03c0 0 , \u03c0 1 ) [EM54, (2.7)], this k-invariant can be identified with the quadratic map \u03b7 * : \u03c0 0 \u2192 \u03c0 1 , induced by precomposition with the Hopf map \u03b7 : S 3 \u2192 S 2 [BM08, \u00a78] . Our main results model the Postnikov data and sphere action on a stable one-type directly in terms of Picard groupoid data. Note, in particular, that the target of the Postnikov invariant is a stable two-type (of a special kind). Hence our algebraic models lead naturally toward models for stable two-types.", "cite_spans": [{"start": 437, "end": 443, "text": "[BM08,", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Introduction", "text": "Our main results are as follows. For Picard groupoids C and D and a symmetric monoidal functor F : C \u2192 D, we describe a symmetric monoidal bicategory Coker(F ) first introduced by Vitale [Vit02] . In Section 4 we apply a long exact sequence argument to prove the following result as Theorem 4.3 and Corollaries 4.5 and 4.8.", "cite_spans": [{"start": 187, "end": 194, "text": "[Vit02]", "ref_id": "BIBREF24"}], "ref_spans": []}, {"section": "Introduction", "text": "Theorem A. Let F : C \u2192 D be a functor of Picard groupoids. Then there is a bigroupoid Coker(F ) and a natural pseudofunctor", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "which models the stable cofiber in the following sense:", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "i. Coker(F ) is symmetric monoidal and C F is a symmetric monoidal pseudofunctor.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "ii. Taking classifying spaces yields a cofibration sequence of grouplike E \u221e spaces:", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "iii. When D = C 0 is the discrete category of isomorphism classes of objects in C and F = \u03b1 0 is the induced monoidal functor, we have an equivalence with the Postnikov tower of BC :", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "Our approach also reveals that the action of the truncated sphere spectrum on a stable one-type is present in the algebraic model. This is hinted at in the unstable literature [BCC93, GMdR02] but not described explicitly. We prove the following as Propositions 3.1, 3.3 and 3.4.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "Theorem C. There is a Picard groupoid S which models the one-type of the sphere spectrum in the following sense:", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "i. The Picard groupoid S is the free Picard groupoid on one object.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "ii. The classifying space BS is the Postnikov 1-truncation of QS 0 .", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "iii. Let C be a Picard groupoid. There is a natural action of S on C such that the induced action of BS on BC is equivalent to the action of the truncated sphere spectrum on BC .", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "This work is a proving ground for a larger project joint with J.P. May which models stable two-types via symmetric monoidal bicategories. The top Postnikov invariant in that case lands in a stable 3-type, which should be modeled by a symmetric monoidal tricategory; one purpose of our program is to use this approach as leverage to understand symmetric monoidal structure on higher weak n-categories. 1 0 the full subcategory of S whose objects are spectra with all homotopy groups equal to zero except at levels 0 and 1. The objects of this category are called stable one-types. A map between stable one-types is a stable equivalence if it induces isomorphisms of homotopy groups.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "1.1. Definition. Let (C , \u2295, I) be a symmetric monoidal category. An object x is invertible if there exists an object y and an isomorphism", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "If such a y exists it is unique up to isomorphism. When one exists, we will sometimes use x * to denote a specified inverse of x.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "1.2. Definition. A Picard groupoid C is a symmetric monoidal groupoid such that every object is invertible. The isomorphism classes of objects form an abelian group denoted \u03c0 0 C , and the endomorphisms of the identity object I form an abelian group denoted \u03c0 1 C . [BCC93, \u00a75] , where the authors prove that the homotopy category of spaces with nontrivial homotopy groups \u03c0 n and \u03c0 n+1 , n \u2265 3, is equivalent to the homotopy category of Picard groupoids. We give another proof of this result based on compatibility of the fundamental groupoid and classifying space functors with E \u221e actions. Proof. We first recall that the homotopy category of connective spectra is equivalent to the homotopy category of group-like E \u221e spaces, and this equivalence descends to the category of stable one-types and the subcategory of group-like E \u221e spaces with no higher homotopy groups. Thus we can work in the context of E \u221e spaces.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "It is a classical result that the classifying space and fundamental groupoid functors give an equivalence is the category of one-type spaces. Thus it suffices to show that \u03a0 1 and B induce an equivalence between the homotopy categories of group-like E \u221e one-types and Picard groupoids.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "Let O be the categorical Barrat-Eccles operad-its jth category O(j) is the translation groupoid of the action of \u03a3 j on itself and its algebras are permutative categories [May72] .", "cite_spans": [{"start": 171, "end": 178, "text": "[May72]", "ref_id": "BIBREF18"}], "ref_spans": []}, {"section": "Introduction", "text": "Then BO is an E \u221e operad in Top: If C is a symmetric monoidal category, then BC is an E \u221e space and if C is a Picard groupoid, then BC is a group-like E \u221e one-type. If F : C \u2192 D is a functor between Picard groupoids, then BF : BC \u2192 BD is an E \u221e map.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "The operad \u03a0 1 BO is an E \u221e operad in categories, and \u03a0 1 preserves products. If X is an E \u221e one-type, then \u03a0 1 X is a symmetric monoidal groupoid. Moreover, \u03c0 0 X \u223c = \u03c0 0 \u03a0 1 X, so \u03a0 1 X is a Picard category if X is group-like. If f : X \u2192 Y is a map of E \u221e spaces, then \u03a0 1 f is a symmetric monoidal functor. Now consider the equivalence C \u2192 \u03a0 1 BC . Since this functor is part of a natural transformation of functors from Gpd to itself, we have functors", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "j that commute with the structure maps of the algebras C and \u03a0 1 BC , thus showing that the equivalence C \u2192 \u03a0 1 BC is a symmetric monoidal functor. A similar argument shows that for a stable one-type X, the weak equivalence X \u2192 B\u03a0 1 X is an E \u221e map.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "1.6. Remark. One can actually show that the fundamental groupoid of an E 3 algebra is symmetric monoidal. Indeed, if O is an E 3 operad in Top, then \u03a0 1 O is an E \u221e operad in Cat . This is because the fundamental groupoid depends only on the homotopy onetype of a space, and thus the obstructions to lifting an E 3 structure to an E \u221e structure on a groupoid vanish. Alternatively, one can provide an explicit argument using specific points of the little 3-cubes operad C 3 to prove that if X is an algebra over C 3 then \u03a0 1 X is a symmetric monoidal category. An example of this strategy can be found in [Gur11, Theorem 15] , where the author proves that the fundamental 2-groupoid of an algebra over the little 2-cubes operad is braided monoidal.", "cite_spans": [{"start": 605, "end": 612, "text": "[Gur11,", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "Strictification", "text": "In this section we prove a strictification result for skeletal Picard groupoids. The result is an algebraic reflection of the fact that the first k-invariant of a connected double loop space is trivial [BC97, Theorem 5.8].", "cite_spans": [], "ref_spans": []}, {"section": "Strictification", "text": "2.1. Definition. A Picard groupoid is permutative if it is strictly associative and strictly unital.", "cite_spans": [], "ref_spans": []}, {"section": "Strictification", "text": "2.2. Theorem. Every Picard groupoid is equivalent to one which is both skeletal and permutative.", "cite_spans": [], "ref_spans": []}, {"section": "Strictification", "text": "The proof appears after Proposition 2.5, which classifies Picard groupoids by symmetric 3-cocycles. Analogous results for stable crossed modules appear in [BC97] .", "cite_spans": [{"start": 155, "end": 161, "text": "[BC97]", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "Definition.", "text": "[Symmetric 3-cocycle] Let G be an abelian group and M a trivial Gmodule. A symmetric 3-cocycle for G with coefficients in M is a pair (h, c) where h is a normalized 3-cocycle:", "cite_spans": [], "ref_spans": []}, {"section": "Definition.", "text": "We say two symmetric 3-cocycles (h, c) and (h , c ) are cohomologous if there exists a function k :", "cite_spans": [], "ref_spans": []}, {"section": "Definition.", "text": "We denote the group of cohomology classes of symmetric 3-cocycles by H 3 sym (G; M ).", "cite_spans": [], "ref_spans": []}, {"section": "Definition. [S\u00edn75, Chapter 2, \u00a72],[JS93, \u00a73]", "text": "Let G be an abelian group, M a trivial G module, and (h, c) a symmetric 3-cocycle for G with coefficients in M . We define a skeletal Picard groupoid T = T (G, M, (h, c)) whose objects are the elements of G and whose morphisms are given by", "cite_spans": [], "ref_spans": []}, {"section": "Definition. [S\u00edn75, Chapter 2, \u00a72],[JS93, \u00a73]", "text": "Composition is defined by the addition in M and the monoidal structure is addition in G. The associativity is determined by", "cite_spans": [], "ref_spans": []}, {"section": "Definition. [S\u00edn75, Chapter 2, \u00a72],[JS93, \u00a73]", "text": "and the symmetry isomorphism is determined by c(x, y) :", "cite_spans": [], "ref_spans": []}, {"section": "Definition. [S\u00edn75, Chapter 2, \u00a72],[JS93, \u00a73]", "text": "The axioms of a symmetric 3-cocycle are precisely the axioms for compatibility of the symmetry and associativity in a skeletal symmetric monoidal groupoid.", "cite_spans": [], "ref_spans": []}, {"section": "Definition. [S\u00edn75, Chapter 2, \u00a72],[JS93, \u00a73]", "text": "Proof of Theorem 2.2. By Proposition 2.5, it suffices to consider a skeletal Picard groupoid C = T (G, M, (h, c)). Moreover, any abelian group G is a filtered colimit of finitely generated abelian groups, and any finitely generated abelian group is a direct sum of cyclic groups. Thus, by making use of the K\u00fcnneth theorem and colimits over finitely generated abelian groups, it suffices to consider the case where G is cyclic. h \u00b5 (x, y, z) = 0 for y + z < n x\u00b5 for y + z \u2265 n where x, y, z are taken to be integers in {0, . . . , n \u2212 1} and addition is performed over the integers to determine the values of h \u00b5 .", "cite_spans": [], "ref_spans": []}, {"section": "Definition. [S\u00edn75, Chapter 2, \u00a72],[JS93, \u00a73]", "text": "A calculation shows", "cite_spans": [], "ref_spans": []}, {"section": "Definition. [S\u00edn75, Chapter 2, \u00a72],[JS93, \u00a73]", "text": "where \u03c1 c(1,1) denotes the symmetry given by", "cite_spans": [], "ref_spans": []}, {"section": "Definition. [S\u00edn75, Chapter 2, \u00a72],[JS93, \u00a73]", "text": "This equivalence of cocycles determines a symmetric monoidal equivalence of the corresponding symmetric monoidal categories. Since the braiding on C is a symmetry, we have c(x, y) = \u2212c(y, x). Now note that if (h, c) is a symmetric 3-cocycle, then nc(1, 1) = 0 by Lemma 2.6, so h nc(1,1) = h 0 = 0. Therefore Eq. (2.1) shows that C is equivalent (as a Picard groupoid) to one whose representing cocycle is (0, \u03c1 c (1, 1)) and thus is both skeletal and permutative.", "cite_spans": [], "ref_spans": []}, {"section": "Definition. [S\u00edn75, Chapter 2, \u00a72],[JS93, \u00a73]", "text": "2.6. Lemma. If (h, c) is a symmetric 3-cocycle of Z/n with coefficients in M , then nc(1, 1) = 0.", "cite_spans": [], "ref_spans": []}, {"section": "Definition. [S\u00edn75, Chapter 2, \u00a72],[JS93, \u00a73]", "text": "Proof. Since c is symmetric, c(1, 1) = \u2212c(1, 1), and thus 2c(1, 1) = 0. If n is even, then the result follows; if n is odd, we make use of the identity c(x, x) = x 2 c(1, 1) for all x \u2208 Z/n:", "cite_spans": [], "ref_spans": []}, {"section": "Definition. [S\u00edn75, Chapter 2, \u00a72],[JS93, \u00a73]", "text": "For n odd, n \u2212 1 is even and thus the last term is zero.", "cite_spans": [], "ref_spans": []}, {"section": "Definition. [S\u00edn75, Chapter 2, \u00a72],[JS93, \u00a73]", "text": "The calculation of Eq. (2.1) shows that the symmetry c completely determines the cohomology class of the symmetric 3-cocycle (h, c) of a skeletal Picard groupoid. But [JS93, \u00a73] shows that the symmetry determines and is determined by the quadratic map", "cite_spans": [{"start": 167, "end": 173, "text": "[JS93,", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "Definition. [S\u00edn75, Chapter 2, \u00a72],[JS93, \u00a73]", "text": "Eilenberg and Mac Lane [EM54] , and Loday [Lod82] show that the set of quadratic maps q : G \u2192 M is isomorphic to the set of homotopy classes of maps [K(G, n), K(M, n+ 2)] for n \u2265 3, which is the set of stable homotopy classes of maps [K(G, 0), K(M, 2)] stable . This is the set of possible Postnikov invariants of a stable one-type with \u03c0 0 = G and \u03c0 1 = M . Thus we have the following refinement of Theorem 1.5: 2.8. Corollary. The stable one-types with \u03c0 0 = G and \u03c0 1 = M are classified by the symmetric structures on a skeletal and permutative monoidal groupoid with objects G and each endomorphism group isomorphic to M . 2.9. Remark. The contrast between triviality of unstable k-invariants and non-triviality of stable k-invariants may be worth clarifying: When modeling connected spaces with nontrivial \u03c0 1 and \u03c0 2 , it is the associativity of a monoidal groupoid (with invertible objects) which gives the first k-invariant of the corresponding space. However when modeling spectra with nontrivial \u03c0 0 and \u03c0 1 it is the symmetry of a Picard groupoid which gives the first (stable) k-invariant. A consequence of Theorem 1.5, Corollary 2.8, and [BC97, Theorem 5.8] is that the first k-invariant of a stable one-type is unstably trivial.", "cite_spans": [{"start": 23, "end": 29, "text": "[EM54]", "ref_id": "BIBREF6"}, {"start": 42, "end": 49, "text": "[Lod82]", "ref_id": "BIBREF17"}], "ref_spans": []}, {"section": "The truncated sphere spectrum", "text": "We now define a skeletal and permutative Picard groupoid S and explain how it is an algebraic model of the truncated sphere spectrum. The objects of S are the integers under addition, and the morphisms are given by", "cite_spans": [], "ref_spans": []}, {"section": "The truncated sphere spectrum", "text": "We let \u03b7 n denote the nontrivial element of S(n, n) for each n. The monoidal structure is symmetric, with the symmetry isomorphism given by c m,n = 0 if mn is even \u03b7 m+n if mn is odd.", "cite_spans": [], "ref_spans": []}, {"section": "The truncated sphere spectrum", "text": "Note that this symmetry isomorphism gives rise to the stable quadratic map q : Z \u2192 Z/2 given by the mod 2 map.", "cite_spans": [], "ref_spans": []}, {"section": "The truncated sphere spectrum", "text": "The Picard groupoid S is closely related to the category of finite sets, as we now describe. Let E be the skeletal category whose objects are the finite sets 0 = \u2205, n = {1, 2, . . . , n} and whose morphism sets are given by the symmetric groups. This is a permutative category, with sum given by sum in N and with symmetry isomorphism c \u2295 m,n given by the permutation that sends (1, 2, . . . , m + n) to (m + 1, m + 2, . . . , m + n, 1, 2, . . . , m). Note that E is skeletal and is equivalent to the category of finite sets.", "cite_spans": [], "ref_spans": []}, {"section": "The truncated sphere spectrum", "text": "There is a symmetric monoidal functor", "cite_spans": [], "ref_spans": []}, {"section": "The truncated sphere spectrum", "text": "given on objects by the inclusion of N into Z and on morphisms by the sign homomorphism \u03a3 n \u2192 Z/2. This is the functor that first abelianizes the group of endomorphisms of each object n, and then includes into S. The next three results justify our notation for S by showing that it is the free Picard groupoid on one object, its classifying space is the Postnikov 1-truncation of QS 0 , and its natural action on a Picard groupoid C is a model for the action of the truncated sphere spectrum on BC .", "cite_spans": [], "ref_spans": []}, {"section": "The truncated sphere spectrum", "text": "3.1. Proposition. The Picard groupoid S is symmetric monoidally equivalent to the free Picard groupoid on one object, F P ic ( * ).", "cite_spans": [], "ref_spans": []}, {"section": "The truncated sphere spectrum", "text": "Proof. The free Picard groupoid functor F P ic is equal to the composite of the free symmetric monoidal groupoid functor, F symM on , with the functor that freely adjoins inverses for objects, F inv . The free symmetric monoidal category on one object, F symM on ( * ), is symmetric monoidally equivalent to the category E defined above.", "cite_spans": [], "ref_spans": []}, {"section": "The truncated sphere spectrum", "text": "We now show that S satisfies the universal property for F inv (E ): Let C be a Picard category and G : E \u2192 C a symmetric monoidal functor. We construct a symmetric monoidal functor H making the diagram commute:", "cite_spans": [], "ref_spans": []}, {"section": "The truncated sphere spectrum", "text": "For every object x \u2208 C fix an inverse x * . We define H on objects as", "cite_spans": [], "ref_spans": []}, {"section": "The truncated sphere spectrum", "text": "To define H on morphisms, note that C (x, x) is an abelian group for all x \u2208 C and therefore G factors through the abelianization of E (n, n) and hence through \u03be. This factorization determines H on the endomorphism group of n for n \u2265 0, and the values of H on endomorphisms of negative n are determined by translation. It is easy to see that H is a symmetric monoidal functor. Now let H be another symmetric monoidal functor making the diagram commute. Note that for n \u2265 0, we must have H(n) = G(n) = H (n). On the other hand we have natural isomorphisms", "cite_spans": [], "ref_spans": []}, {"section": "The truncated sphere spectrum", "text": "and hence natural isomorphisms", "cite_spans": [], "ref_spans": []}, {"section": "The truncated sphere spectrum", "text": "These assemble to form a monoidal natural isomorphism between H and H .", "cite_spans": [], "ref_spans": []}, {"section": "The truncated sphere spectrum", "text": "3.2. Remark. Although a model for one-types of ring spectra is beyond the scope of this paper, we do note that S has a second symmetric monoidal structure, so that it is a bipermutative groupoid. This second monoidal structure is given by: By [May09] , BS is an E \u221e ring space.", "cite_spans": [{"start": 243, "end": 250, "text": "[May09]", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "The truncated sphere spectrum", "text": "Furthermore, the category E described above is a bipermutative category, with second product given by multiplication in N. This models the cartesian product of finite sets. The map \u03be : E \u2192 S is a bipermutative functor, and B\u03be : BE \u2192 BS is therefore an E \u221e ring map.", "cite_spans": [], "ref_spans": []}, {"section": "Proposition. Let QS", "text": "0 be the zeroth space of the sphere spectrum. Then there is a map of E \u221e ring spaces B\u03be : QS 0 \u2212\u2192 BS which is the Postnikov 1-truncation of QS 0 .", "cite_spans": [], "ref_spans": []}, {"section": "Proposition. Let QS", "text": "Proof. By Remark 3.2, we have a map of E \u221e ring spaces B\u03be : BE \u2192 BS. Since BS is group-like, this map factors through the group completion of BE , which is equivalent to QS 0 :", "cite_spans": [], "ref_spans": []}, {"section": "Proposition. Let QS", "text": "The map B\u03be is an isomorphism on \u03c0 0 = Z, \u03c0 1 = Z/2, and thus it is the Postnikov 1-truncation.", "cite_spans": [], "ref_spans": []}, {"section": "Proposition. Let QS", "text": "Let (C , \u2295, I) be any Picard groupoid. By Theorem 2.2, we can assume without loss of generality that C is both skeletal and permutative. Then each object x in C has a strict inverse, x * , so that x \u2295 x * = I = x * \u2295 x. There is a natural action of S on C", "cite_spans": [], "ref_spans": []}, {"section": "Proposition. Let QS", "text": "defined on objects as follows:", "cite_spans": [], "ref_spans": []}, {"section": "Proposition. Let QS", "text": "Let c denote the symmetry of C . The action \u00b7 on morphisms is defined by:", "cite_spans": [], "ref_spans": []}, {"section": "Proposition. Let QS", "text": "for n = 2.", "cite_spans": [], "ref_spans": []}, {"section": "Proposition. Let QS", "text": "3.4. Proposition. Let X be a stable one-type modeled by a Picard groupoid C , so BC X. Then the action of the truncated sphere spectrum on X is modeled by the action of S on C .", "cite_spans": [], "ref_spans": []}, {"section": "Proposition. Let QS", "text": "Proof. The action of S on C passes to an action of BS on BC which is homotopic to that of the group completion QS 0 : The top triangle in the diagram below commutes because BC is group complete; the bottom commutes because the group completion abelianizes \u03c0 1 and hence the action of even permutations (the alternating group) is trivial.", "cite_spans": [], "ref_spans": []}, {"section": "Proposition. Let QS", "text": "3.5. Remark. An alternate argument for Proposition 3.4 notes that the action of the truncated sphere spectrum on BC determines and is determined by the unique nontrivial Postnikov invariant", "cite_spans": [], "ref_spans": []}, {"section": "Proposition. Let QS", "text": "which is given by precomposition with \u03b7. The discussion preceding Corollary 2.8 shows that this Postnikov invariant is modeled by the stable quadratic map q : \u03c0 0 C \u2192 \u03c0 1 C given by q(x) = c(x, x). This, in turn, determines and is determined by the action of S on C since \u03b7 2 acts by the symmetry c. In Section 4.6 we define the Postnikov invariant of a Picard groupoid and show that it models the Postnikov invariant of BC (Corollary 4.8).", "cite_spans": [], "ref_spans": []}, {"section": "Cokernels of Picard groupoid maps", "text": "Here we describe the cokernel of a map of Picard groupoids and the resulting exact sequence in homotopy groups.", "cite_spans": [], "ref_spans": []}, {"section": "Definition.", "text": "[Bigroupoid] A bigroupoid is a bicategory G in which the 1-cells are invertible up to 2-isomorphism and the 2-cells are isomorphisms. The set \u03c0 0 G is given by the equivalence classes of objects. For an object x \u2208 G , the group \u03c0 1 (G , x) is given by the isomorphism classes of 1-endomorphisms of x. The group \u03c0 2 (G , x) is given by the 2-endomorphisms of 1 x , the identity 1-cell of x.", "cite_spans": [], "ref_spans": []}, {"section": "Definition.", "text": "[Cokernel [Vit02] ] Let F : C \u2192 D be a map of Picard groupoids. The cokernel of F is a bigroupoid Coker(F ) defined as follows: The objects of Coker(F ) are the objects of D. The 1-cells between objects x and y are pairs (f, n), where", "cite_spans": [{"start": 10, "end": 17, "text": "[Vit02]", "ref_id": "BIBREF24"}], "ref_spans": []}, {"section": "Definition.", "text": "is a morphism of D. The 2-cells between (f, n) and (f , n ) are given by morphisms \u03b1 : n \u2192 n of C such that the following diagram commutes:", "cite_spans": [], "ref_spans": []}, {"section": "Definition.", "text": "The composite of two 1-cells", "cite_spans": [], "ref_spans": []}, {"section": "Definition.", "text": "is given by the following composite morphism in D:", "cite_spans": [], "ref_spans": []}, {"section": "Definition.", "text": "Further details of the definition can be found in [Vit02, \u00a72] ; note that the cokernel is denoted Cok (F ) there.", "cite_spans": [{"start": 50, "end": 57, "text": "[Vit02,", "ref_id": "BIBREF24"}], "ref_spans": []}, {"section": "Definition.", "text": "There is a natural pseudofunctor C F : D \u2192 Coker(F ) which is the identity on objects and which takes a morphism f : x \u2192 y to the 1-cell f = (f, I C ) determined by the morphism", "cite_spans": [], "ref_spans": []}, {"section": "Definition.", "text": "4.3. Theorem. The symmetric monoidal structure on D induces a symmetric monoidal structure on the bicategory Coker(F ). The pseudofunctor C F is symmetric monoidal.", "cite_spans": [], "ref_spans": []}, {"section": "Definition.", "text": "We prove Theorem 4.3 in Section 5. In the remainder of this section we apply this cokernel to model stable cofibers and Postnikov invariants.", "cite_spans": [], "ref_spans": []}, {"section": "Theorem.", "text": "A map of Picard groupoids F : C \u2192 D gives rise to a long exact sequence of homotopy groups between C , D, and Coker(F )", "cite_spans": [], "ref_spans": []}, {"section": "Theorem.", "text": "Proof. Exactness at most positions is verified by [Vit02] , noting that the Ker(F ) used there has \u03c0 0 Ker(F ) \u223c = \u03c0 1 Coker(F ) and \u03c0 1 Ker(F ) \u223c = \u03c0 2 Coker(F ). Exactness at the remaining positions, \u03c0 1 D and at \u03c0 1 Coker(F ), is straightforward from the definitions: An element in \u03c0 1 C is represented by a morphism f : I C \u2192 I C . The image of this element in \u03c0 1 D is represented by the composite", "cite_spans": [{"start": 50, "end": 57, "text": "[Vit02]", "ref_id": "BIBREF24"}], "ref_spans": []}, {"section": "Theorem.", "text": "This composite morphism maps to the trivial element in \u03c0 1 Coker(F ) because it factors through a morphism in the image of F (namely, F (f )). Likewise, if g : F (X) \u2192 I D represents an element of \u03c0 1 D whose image in \u03c0 1 Coker(F ) is trivial (factors through a morphism in the image of F ), then the trivialization provides an element of \u03c0 1 C whose image in \u03c0 1 D is the element represented by g. Exactness at \u03c0 1 Coker(F ) is similar, and left to the reader.", "cite_spans": [], "ref_spans": []}, {"section": "Theorem.", "text": "The two previous results, together with [Oso12, GO] show that the cokernel of Picard groupoids models the cofiber of stable one-types: 4.5. Corollary. Let F : C \u2192 D be a map of Picard groupoids. Then the following is a cofibration sequence of group-like E \u221e spaces:", "cite_spans": [{"start": 40, "end": 47, "text": "[Oso12,", "ref_id": "BIBREF20"}, {"start": 48, "end": 51, "text": "GO]", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "Theorem.", "text": "Proof. Note that since Coker(F ) is a group-like symmetric monoidal bicategory, [Oso12, Theorem 2.1] and the improved results of [GO] imply that B Coker(F ) is a group-like E \u221e space. Let C be the cofiber of the map on classifying spaces. Then the dashed arrow to B Coker(F ) exists by the universal property of C, and it is an equivalence by Theorem 4.4.", "cite_spans": [], "ref_spans": []}, {"section": "Theorem.", "text": "4.6. Modeling Postnikov invariants 4.7. Definition. Let C be a Picard groupoid, and let C 0 be the category of isomorphism classes of objects of C , with only identity morphisms. Let", "cite_spans": [], "ref_spans": []}, {"section": "Theorem.", "text": "be the monoidal functor which takes each object to its isomorphism class and takes morphisms to identity morphisms. Let k 0 = C \u03b1 0 be the natural pseudofunctor from C 0 to Coker(\u03b1 0 ). We call the sequence", "cite_spans": [], "ref_spans": []}, {"section": "Theorem.", "text": "the Postnikov tower of C .", "cite_spans": [], "ref_spans": []}, {"section": "Theorem.", "text": "By Theorem 4.4, Coker(\u03b1 0 ) has only one non-trivial homotopy group, which is \u03c0 1 C in degree two. We refer to k 0 as the Postnikov invariant of C . Our terminology is motivated by the following result. Proof. This follows immediately from Corollary 4.5 and the fact that BC 0 K(\u03c0 0 , 0).", "cite_spans": [], "ref_spans": []}, {"section": "Theorem.", "text": "5. Proof of Theorem 4.3 5.1. Proposition. The bicategory Coker(F ) is symmetric monoidal.", "cite_spans": [], "ref_spans": []}, {"section": "Theorem.", "text": "To prove this proposition we will construct a double category Coker(F ) and use the results of [Shu10] , which are analogous to those of [GG09, \u00a76] . The idea behind this method is that it is usually easier to construct symmetric monoidal double categories than symmetric monoidal bicategories, and for certain double categories the symmetric monoidal structure lifts to a symmetric monoidal structure in a related bicategory.", "cite_spans": [{"start": 95, "end": 102, "text": "[Shu10]", "ref_id": "BIBREF22"}], "ref_spans": []}, {"section": "Theorem.", "text": "The double category Coker(F ) is constructed as follows. The category of objects, Coker(F ) 0 , is D. The category of morphisms, Coker(F ) 1 , has as objects the quadruples (x, y, f, n), where x and y are objects of D, n is an object of C and f :", "cite_spans": [], "ref_spans": []}, {"section": "Theorem.", "text": "A morphism in Coker(F ) 1 from (x, y, f, n) to (z, v, g, m) is given by a triple (a, b, \u03b1), where a : x \u2192 z and b : y \u2192 v are morphisms in D, and \u03b1 : n \u2192 m is a morphism in C , such that the following diagram commutes", "cite_spans": [], "ref_spans": []}, {"section": "Theorem.", "text": "Composition of morphisms in the category Coker(F ) 1 is given by composition componentwise. We follow the notation from [Shu10, Def. 2.1] to define the rest of the structure of the double category. The unit functor U is defined as", "cite_spans": [], "ref_spans": []}, {"section": "Theorem.", "text": "where 1 x is given by the composition x \u2192 x \u2295 I D \u2192 x \u2295 F (I C ). The functors for source and target, S and T , are given by:", "cite_spans": [], "ref_spans": []}, {"section": "Theorem.", "text": "Finally, the composition functor is given by", "cite_spans": [], "ref_spans": []}, {"section": "Theorem.", "text": "where f \u2022 g denotes the composition", "cite_spans": [], "ref_spans": []}, {"section": "Theorem.", "text": "The associativity and unit constraints come from those in the monoidal structure of C .", "cite_spans": [], "ref_spans": []}, {"section": "Theorem.", "text": "5.2. Proposition. The double category Coker(F ) is symmetric monoidal.", "cite_spans": [], "ref_spans": []}, {"section": "Theorem.", "text": "Proof. The category Coker(F ) 0 = D is symmetric monoidal. We now give a symmetric monoidal structure to Coker(F ) 1 . On objects it is given by:", "cite_spans": [], "ref_spans": []}, {"section": "Theorem.", "text": "where f g is the composition", "cite_spans": [], "ref_spans": []}, {"section": "Theorem.", "text": "On morphisms it is defined by applying the sum componentwise. The associativity, unit, and symmetry constraints are inherited from those in C and D.", "cite_spans": [], "ref_spans": []}, {"section": "Theorem.", "text": "The globular isomorphism", "cite_spans": [], "ref_spans": []}, {"section": "Theorem.", "text": "is given by the structural isomorphism in C", "cite_spans": [], "ref_spans": []}, {"section": "Theorem.", "text": "The globular morphism u : U x\u2295y \u2192 U x \u2295 U y is given by the morphism I \u2192 I \u2295 I in C . It is clear that all the necessary diagrams commute since they all involve compositions of morphisms of the symmetric monoidal structures on C and D.", "cite_spans": [], "ref_spans": []}, {"section": "Theorem.", "text": "We recall that a double category is fibrant in the terminology of [Shu10] if every vertical 1-morphism has a companion and a conjoint. These are horizontal 1-morphisms that allow transport of vertical structure to horizontal structure [Shu10, \u00a73]:", "cite_spans": [{"start": 66, "end": 73, "text": "[Shu10]", "ref_id": "BIBREF22"}], "ref_spans": []}, {"section": "Theorem.", "text": "5.3. Definition. Let a : x \u2192 z be a morphism in D. A companion for a is given by (x, z,\u00e2, I C ), where\u00e2 is the composite", "cite_spans": [], "ref_spans": []}, {"section": "Theorem.", "text": "The following diagrams commute and therefore the equations of [Shu10, 3.1] are trivially satisfied.", "cite_spans": [], "ref_spans": []}, {"section": "Theorem.", "text": "A conjoint for a is given by (z, x,\u01ce, I C ), where\u01ce is the composite", "cite_spans": [], "ref_spans": []}, {"section": "Theorem.", "text": "This is the companion of a in the double category obtained from Coker(F ) by taking the same category of objects and the opposite category of morphisms.", "cite_spans": [], "ref_spans": []}, {"section": "Theorem.", "text": "Proof of Proposition 5.1. The horizontal bicategory H (Coker(F )) is precisely Coker(F ). Since every morphism in D has a companion and a conjoint, Coker(F ) is a fibrant double category. Therefore by [Shu10, Thm 5.1] Coker(F ) is symmetric monoidal.", "cite_spans": [], "ref_spans": []}, {"section": "Theorem.", "text": "5.4. Remark. Vitale [Vit02] points out that Coker(F ) is a bigroupoid. We note, moreover, that the objects are weakly invertible since they are the objects of D with the same monoidal structure. Thus Coker(F ) is what one might call a Picard bigroupoid.", "cite_spans": [{"start": 20, "end": 27, "text": "[Vit02]", "ref_id": "BIBREF24"}], "ref_spans": []}, {"section": "Theorem.", "text": "5.5. Proposition. The pseudofunctor C F : D \u2192 Coker(F ) is symmetric monoidal.", "cite_spans": [], "ref_spans": []}, {"section": "Theorem.", "text": "Proof. We need to specify transformations (\u03c7 x,y , \u03c7 f,g ) : C F (x) \u2295 C F (y) \u2192 C F (x \u2295 y) and \u03b9 : I \u2192 C F (I).", "cite_spans": [], "ref_spans": []}, {"section": "Theorem.", "text": "We let \u03c7 x,y : x \u2295 y \u2192 x \u2295 y be the identity 1-cell in Coker(F ), that is, 1 x\u2295y . The 2-cell", "cite_spans": [], "ref_spans": []}, {"section": "Theorem.", "text": "is given by the unique structural morphism in C , I \u2295 I \u2192 I \u2295 (I \u2295 I). It is an easy verification that this is a valid 2-cell in Coker(F ), and that these data forms a transformation. Similarly, we let \u03b9 : I \u2192 I be the identity 1-cell. The rest of the data for a symmetric monoidal pseudofunctor consists of four modifications, which are collections of 2-cells. In the four cases, the source and target of the modifications have products of copies of the unit I \u2208 C as their second component, and hence the modifications are given by the unique structural morphism connecting these two products in C . The coherence of the symmetric monoidal structure on C therefore implies that these modifications satisfy all of the necessary equations.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "On the 2-type of an iterated loop space", "authors": [{"first": "H.-J", "middle": [], "last": "Baues", "suffix": ""}, {"first": "D", "middle": [], "last": "Conduch\u00e9", "suffix": ""}], "year": 1997, "venue": "Forum Math", "link": "119484764"}, "BIBREF1": {"title": "Secondary homotopy groups", "authors": [{"first": "H.-J", "middle": [], "last": "Baues", "suffix": ""}, {"first": "F", "middle": [], "last": "Muro", "suffix": ""}], "year": 2008, "venue": "Forum Math", "link": "15201067"}, "BIBREF2": {"title": "Cohomology with coefficients in symmetric cat-groups. An extension of Eilenberg-MacLane's classification theorems", "authors": [{"first": "M", "middle": [], "last": "Bullejos", "suffix": ""}, {"first": "P", "middle": [], "last": "Carrasco", "suffix": ""}, {"first": "A", "middle": [], "last": "Cegarra", "suffix": ""}], "year": 1993, "venue": "Math. Proc. Camb. Phil. Soc", "link": "119691532"}, "BIBREF3": {"title": "Cohomology with coefficients in symmetric cat-groups. An extension of Eilenberg-MacLane's classification theorems", "authors": [{"first": "M", "middle": [], "last": "Bullejos", "suffix": ""}, {"first": "P", "middle": [], "last": "Carrasco", "suffix": ""}, {"first": "A", "middle": [], "last": "Cegarra", "suffix": ""}], "year": 1993, "venue": "Math. Proc. Camb. Phil. Soc", "link": "119691532"}, "BIBREF4": {"title": "Modules crois\u00e9s g\u00e9n\u00e9ralis\u00e9s de longueur 2", "authors": [{"first": "D", "middle": [], "last": "Conduch\u00e9", "suffix": ""}], "year": 1984, "venue": "Journal of Pure and Applied Algebra", "link": "120055564"}, "BIBREF5": {"title": "Infinite-dimensional vector bundles in algebraic geometry", "authors": [{"first": "V", "middle": [], "last": "Drinfeld", "suffix": ""}], "year": 2006, "venue": "The Unity of Mathematics", "link": "117441637"}, "BIBREF6": {"title": "II: Methods of computation", "authors": [{"first": "S", "middle": [], "last": "Eilenberg", "suffix": ""}, {"first": "S", "middle": [], "last": "Maclane", "suffix": ""}], "year": 1954, "venue": "On the groups h(\u03c0, n)", "link": null}, "BIBREF7": {"title": "The low-dimensional structures formed by tricategories", "authors": [{"first": "R", "middle": [], "last": "Garner", "suffix": ""}, {"first": "N", "middle": [], "last": "Gurski", "suffix": ""}], "year": 2009, "venue": "Math. Proc. Cambridge Philos. Soc", "link": "115160397"}, "BIBREF8": {"title": "Symmetric and exterior powers of categories", "authors": [{"first": "N", "middle": [], "last": "Ganter", "suffix": ""}, {"first": "M", "middle": [], "last": "Kapranov", "suffix": ""}], "year": 2011, "venue": "", "link": "119315328"}, "BIBREF9": {"title": "Symmetric and exterior powers of categories", "authors": [{"first": "N", "middle": [], "last": "Ganter", "suffix": ""}, {"first": "M", "middle": [], "last": "Kapranov", "suffix": ""}], "year": 2011, "venue": "", "link": "119315328"}, "BIBREF10": {"title": "The low-dimensional structures formed by tricategories", "authors": [{"first": "R", "middle": [], "last": "Garner", "suffix": ""}, {"first": "N", "middle": [], "last": "Gurski", "suffix": ""}], "year": 2009, "venue": "Math. Proc. Cambridge Philos. Soc", "link": "115160397"}, "BIBREF11": {"title": "Homotopy theory for (braided) cat-groups", "authors": [{"first": "A", "middle": [], "last": "Garz\u00f3n", "suffix": ""}, {"first": "J", "middle": [], "last": "Miranda", "suffix": ""}], "year": 1997, "venue": "Cahiers Topologie G\u00e9om\u00e9trie Diff\u00e9rentielle Cat\u00e9goriques", "link": null}, "BIBREF12": {"title": "Tensor structures on homotopy groupoids of topological spaces", "authors": [{"first": "A", "middle": [], "last": "Garz\u00f3n", "suffix": ""}, {"first": "J", "middle": [], "last": "Miranda", "suffix": ""}, {"first": "A", "middle": [], "last": "Del R\u0131o", "suffix": ""}], "year": 2002, "venue": "", "link": null}, "BIBREF13": {"title": "Loop spaces, and coherence for monoidal and braided monoidal bicategories", "authors": [{"first": "N", "middle": [], "last": "Gurski", "suffix": ""}], "year": 2011, "venue": "Adv. Math", "link": "119631561"}, "BIBREF14": {"title": "Coherence for symmetric monoidal bicategories", "authors": [{"first": "N", "middle": [], "last": "Gurski", "suffix": ""}, {"first": "A", "middle": [], "last": "Osorno", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF15": {"title": "Quadratic functions in geometry, topology, and M -theory", "authors": [{"first": "M", "middle": [], "last": "Hopkins", "suffix": ""}, {"first": "I", "middle": [], "last": "Singer", "suffix": ""}], "year": 2005, "venue": "", "link": null}, "BIBREF16": {"title": "Braided tensor categories", "authors": [{"first": "A", "middle": [], "last": "Joyal", "suffix": ""}, {"first": "R", "middle": [], "last": "Street", "suffix": ""}], "year": 1993, "venue": "Adv. Math", "link": "121498034"}, "BIBREF17": {"title": "Spaces with finitely many non-trivial homotopy groups", "authors": [{"first": "J.-L", "middle": [], "last": "Loday", "suffix": ""}], "year": 1982, "venue": "Journal of Pure and Applied Algebra", "link": "14863407"}, "BIBREF18": {"title": "The geometry of iterated loop spaces", "authors": [{"first": "J", "middle": ["P"], "last": "May", "suffix": ""}], "year": 1972, "venue": "Lectures Notes in Mathematics", "link": null}, "BIBREF19": {"title": "The construction of E \u221e ring spaces from bipermutative categories", "authors": [], "year": 2009, "venue": "Geometry & Topology Monographs", "link": null}, "BIBREF20": {"title": "Spectra associated to symmetric monoidal bicategories", "authors": [{"first": "A", "middle": [], "last": "Osorno", "suffix": ""}], "year": 2012, "venue": "Algebr. Geom. Topol", "link": "55544468"}, "BIBREF21": {"title": "De Rham E -factors", "authors": [{"first": "D", "middle": [], "last": "Patel", "suffix": ""}], "year": 2012, "venue": "To appear in Inventiones Mathematicae", "link": null}, "BIBREF22": {"title": "Constructing symmetric monoidal bicategories", "authors": [{"first": "M", "middle": ["A"], "last": "Shulman", "suffix": ""}], "year": 2010, "venue": "", "link": "115180961"}, "BIBREF23": {"title": "Gr-cat\u00e9gories", "authors": [{"first": "H", "middle": ["X"], "last": "S\u00ednh", "suffix": ""}], "year": 1975, "venue": "", "link": null}, "BIBREF24": {"title": "Brauer exact sequence of categorical groups", "authors": [{"first": "E", "middle": [], "last": "Vitale", "suffix": ""}, {"first": "", "middle": [], "last": "Picard", "suffix": ""}], "year": 2002, "venue": "Journal of Pure and Applied Algebra", "link": null}, "BIBREF26": {"title": "Universit\u00e9 de Paris 13: breen@math.univ-paris13.fr Ronald Brown, University of North Wales: ronnie.profbrown(at)btinternet.com Valeria de Paiva: valeria", "authors": [{"first": "Lawrence", "middle": [], "last": "Breen", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF27": {"title": "Northwestern University: getzler(at)northwestern", "authors": [{"first": "Ezra", "middle": [], "last": "Getzler", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF29": {"title": "University of Insubria: robert.walters@uninsubria.it R", "authors": [{"first": "F", "middle": ["C"], "last": "Robert", "suffix": ""}, {"first": "", "middle": [], "last": "Walters", "suffix": ""}], "year": "", "venue": "J. Wood", "link": null}}, "ref_entries": {"FIGREF0": {"text": "Theorem. There is an equivalence between the categories Ho(S 1 0 ) and Ho(Pic) induced by the fundamental groupoid and classifying space functors.", "type": "figure"}, "FIGREF1": {"text": "Ho", "type": "figure"}, "FIGREF3": {"text": "Corollary. The Postnikov tower of C models the Postnikov tower of BC .", "type": "figure"}, "TABREF0": {"text": "1.3. Definition. The category Pic has as objects the Picard groupoids and as morphismsThe classification of stable one-types by Picard groupoids appears explicitly and im- plicitly in various parts of the literature. For example, Patel [Pat12, \u00a75] shows that there is an equivalence between the homotopy categories of stable one-types and Picard group- oids, making precise a \"vauge idea\" of Drinfeld [Dri06, \u00a75.5]. This is also sketched by Hopkins-Singer in [HS05, \u00a7B] and Ganter-Kapranov in [GK11, \u00a73]. An equivalent result of Bullejos-Carrasco-Cegarra appears in", "type": "table"}, "TABREF1": {"text": "This strategy for studying Picard groupoids appears in [EM54, 26.4] and [JS93, 3.2]. Let G be a cyclic group. We now prove that there is some c such that [(h, c)] = [(0, c )] in H Following Joyal and Street [JS93, \u00a73] we have an explicit formula for cocycle representa- tives corresponding to \u00b5:", "type": "table"}}}
{"paper_id": "17781774", "_pdf_hash": "48b14393c6e7495d1ff8f910c9bb2d1185b1d300", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Fingerprint image enhancement:algorithm and performance evaluation", "authors": [{"first": "Lin", "middle": [], "last": "Hong", "suffix": ""}, {"first": "Wan", "middle": [], "last": "Yifei", "suffix": ""}, {"first": "Anil", "middle": [], "last": "Jain", "suffix": ""}], "year": "", "venue": "", "link": "8244281"}, "BIBREF2": {"title": "Fingerprint image enhancement using CNNgabor-Cpe filter", "authors": [{"first": "V", "middle": [], "last": "Esaatci", "suffix": ""}, {"first": "", "middle": [], "last": "Tavsanogh", "suffix": ""}], "year": 2002, "venue": "Proceedings of the 7th IEEE International-Workshop on Cellular Neural Networks and their Applications", "link": null}, "BIBREF3": {"title": "A combination model for orientation field offingerprints", "authors": [{"first": "J", "middle": [], "last": "Gu", "suffix": ""}, {"first": "J", "middle": [], "last": "Zhou", "suffix": ""}, {"first": "D", "middle": [], "last": "Zhang", "suffix": ""}], "year": 2004, "venue": "Pattern Recognition", "link": "35103380"}, "BIBREF4": {"title": "Soft-I-Robot using Neural Networks and Genetic Algorithm", "authors": [{"first": "S", "middle": [], "last": "Santhosh", "suffix": ""}], "year": 2012, "venue": "Indian journal of Innovations And Developments", "link": "62918106"}, "BIBREF5": {"title": "Fingerprint enhancement with dyadic scale-space", "authors": [{"first": "J", "middle": [], "last": "Cheng", "suffix": ""}, {"first": "J", "middle": [], "last": "Tian", "suffix": ""}], "year": 2004, "venue": "Pattern Recognition Letters", "link": "2612233"}, "BIBREF6": {"title": "A fingerprint matching algorithm with registrationpattern inspection", "authors": [{"first": "H", "middle": [], "last": "Chen", "suffix": ""}, {"first": "J", "middle": [], "last": "Tian", "suffix": ""}], "year": 2005, "venue": "Journal of Software", "link": null}, "BIBREF7": {"title": "Improved SVMRegression using Mixtures ofKernels", "authors": [{"first": "E", "middle": [], "last": "Smits G Fjordaan", "suffix": ""}], "year": 2002, "venue": "Proceedings of the 2002 International Joint Conferenceon-Neural Networks", "link": null}, "BIBREF8": {"title": "The embedded-monitoring system based ARM\". journal of 7instrument-technology", "authors": [{"first": "", "middle": [], "last": "Fu Zhenghua", "suffix": ""}, {"first": "Tian", "middle": [], "last": "Li Yongjun", "suffix": ""}, {"first": "", "middle": [], "last": "Mi", "suffix": ""}], "year": 2007, "venue": "", "link": null}, "BIBREF9": {"title": "A face and fingerprint-identity authentication system based on multi-route detection", "authors": [{"first": "Jun", "middle": [], "last": "Zhou", "suffix": ""}, {"first": "Guangda", "middle": [], "last": "Sua", "suffix": ""}, {"first": "Chun", "middle": [], "last": "Hongjiang", "suffix": ""}], "year": 2007, "venue": "Neurocomputing", "link": "39334900"}, "BIBREF10": {"title": "Image-enhancement and minutiae matching in fingerprint verification", "authors": [{"first": "Yuliang", "middle": [], "last": "He", "suffix": ""}, {"first": "Jie", "middle": [], "last": "Tian", "suffix": ""}, {"first": "Xiping", "middle": [], "last": "Luo", "suffix": ""}, {"first": "Tanghui", "middle": [], "last": "Zhang", "suffix": ""}], "year": 2003, "venue": "Pattern Recognition Letters", "link": "39548736"}, "BIBREF11": {"title": "Morphological Shared-Weight Networks with Applications to Automatic Target Recognition", "authors": [{"first": "Y", "middle": [], "last": "Won", "suffix": ""}], "year": 1997, "venue": "IEEE Transactions on Neural Networks", "link": "6250759"}, "BIBREF12": {"title": "Design andimplementation of Log-Gabor filter in fingerprint imageenhancement", "authors": [{"first": "Wei", "middle": [], "last": "Wang", "suffix": ""}, {"first": "Jianwei", "middle": [], "last": "Li", "suffix": ""}, {"first": "Feifei", "middle": [], "last": "Huang", "suffix": ""}, {"first": "Hailiang", "middle": [], "last": "Feng", "suffix": ""}], "year": 2008, "venue": "Pattern Recognition Letters", "link": null}, "BIBREF13": {"title": "A new algorithm for distorted fingerprints matching based on normalized fuzzy similarity measure", "authors": [{"first": "X", "middle": [], "last": "Chen", "suffix": ""}, {"first": "J", "middle": [], "last": "Tian", "suffix": ""}, {"first": "X", "middle": [], "last": "Yang", "suffix": ""}], "year": 2006, "venue": "IEEE Transactions on image processing", "link": "1066450"}}, "ref_entries": {}}
{"paper_id": "17781944", "_pdf_hash": "352835288caaf48871c3d52590995839c4c4f4f8", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "White-band disease and the changing face of Caribbean coral reefs", "authors": [{"first": "R", "middle": ["B"], "last": "Aronson", "suffix": ""}, {"first": "W", "middle": ["T"], "last": "Precht", "suffix": ""}], "year": 2001, "venue": "Hydrobiologia", "link": "34863063"}, "BIBREF1": {"title": "Taphonomy's contribution to paleobiology", "authors": [{"first": "A", "middle": ["K"], "last": "Behrensmeyer", "suffix": ""}, {"first": "S", "middle": ["M"], "last": "Kidwell", "suffix": ""}], "year": 1985, "venue": "Paleobiology", "link": null}, "BIBREF2": {"title": "Anatomy of a fringing reef around Grand Cayman: storm rubble, not coral framework", "authors": [{"first": "P", "middle": [], "last": "Blanchon", "suffix": ""}, {"first": "B", "middle": [], "last": "Jones", "suffix": ""}, {"first": "W", "middle": [], "last": "Kalbfleisch", "suffix": ""}], "year": 1997, "venue": "J Sediment Res", "link": "129106024"}, "BIBREF3": {"title": "Comparative taphonomy: a key to paleoenvironmental interpretation based on fossil preservation", "authors": [{"first": "C", "middle": ["E"], "last": "Brett", "suffix": ""}, {"first": "G", "middle": ["C"], "last": "Baird", "suffix": ""}], "year": 1986, "venue": "Palaios", "link": "128728334"}, "BIBREF4": {"title": "Fossil lagerstatten: a taphonomic consequence of event sedimentation", "authors": [{"first": "C", "middle": ["E"], "last": "Brett", "suffix": ""}, {"first": "A", "middle": [], "last": "Seilacher", "suffix": ""}], "year": 1991, "venue": "Einsele E (ed) Cycles and events in stratigraphy", "link": null}, "BIBREF5": {"title": "A temporal hierarchy of paleoecologic processes within a Middle Devonian epeiric sea", "authors": [{"first": "C", "middle": ["E"], "last": "Brett", "suffix": ""}, {"first": "K", "middle": ["B"], "last": "Miller", "suffix": ""}, {"first": "G", "middle": ["C"], "last": "Baird", "suffix": ""}], "year": 1990, "venue": "Miller W (ed) Paleocommunity temporal dynamics: the longterm development of multispecies assemblies", "link": null}, "BIBREF6": {"title": "Regional decline of coral cover in the Indo-Pacific: timing, extent, and subregional comparisons", "authors": [{"first": "J", "middle": ["F"], "last": "Bruno", "suffix": ""}, {"first": "E", "middle": ["R"], "last": "Selig", "suffix": ""}], "year": 2007, "venue": "PLoS ONE", "link": "11591672"}, "BIBREF7": {"title": "Reefs at risk in the Caribbean", "authors": [{"first": "L", "middle": [], "last": "Burke", "suffix": ""}, {"first": "J", "middle": [], "last": "Maidens", "suffix": ""}], "year": 2004, "venue": "World Resources Institute", "link": "135397721"}, "BIBREF8": {"title": "Onethird of reef-building corals face elevated extinction risk from climate change and local impacts", "authors": [{"first": "K", "middle": ["E"], "last": "Carpenter", "suffix": ""}, {"first": "M", "middle": [], "last": "Abrar", "suffix": ""}, {"first": "G", "middle": [], "last": "Aeby", "suffix": ""}, {"first": "R", "middle": ["B"], "last": "Aronson", "suffix": ""}, {"first": "S", "middle": [], "last": "Banks", "suffix": ""}, {"first": "A", "middle": [], "last": "Bruckner", "suffix": ""}, {"first": "A", "middle": [], "last": "Chiriboga", "suffix": ""}, {"first": "J", "middle": [], "last": "Cort\u00e9s", "suffix": ""}, {"first": "J", "middle": ["C"], "last": "Delbeek", "suffix": ""}, {"first": "L", "middle": [], "last": "Devantier", "suffix": ""}, {"first": "G", "middle": ["L"], "last": "Edgar", "suffix": ""}, {"first": "A", "middle": ["J"], "last": "Edwards", "suffix": ""}, {"first": "D", "middle": [], "last": "Fenner", "suffix": ""}, {"first": "M", "middle": [], "last": "H\u00e9ctor", "suffix": ""}, {"first": "H", "middle": ["M"], "last": "Guzm\u00e1n", "suffix": ""}, {"first": "B", "middle": ["W"], "last": "Hoeksema", "suffix": ""}, {"first": "G", "middle": [], "last": "Hodgson", "suffix": ""}, {"first": "Johan", "middle": ["O"], "last": "Wilfredo", "suffix": ""}, {"first": "Y", "middle": [], "last": "Licuanan", "suffix": ""}, {"first": "W", "middle": ["Y"], "last": "Livingstone", "suffix": ""}, {"first": "S", "middle": ["R"], "last": "Lovell", "suffix": ""}, {"first": "E", "middle": ["R"], "last": "Moore", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Obura", "suffix": ""}, {"first": "D", "middle": ["O"], "last": "Ochavillo", "suffix": ""}, {"first": "D", "middle": [], "last": "Polidoro", "suffix": ""}, {"first": "B", "middle": ["A"], "last": "Precht", "suffix": ""}, {"first": "W", "middle": ["F"], "last": "Quibilan", "suffix": ""}, {"first": "M", "middle": ["C"], "last": "Reboton", "suffix": ""}, {"first": "C", "middle": [], "last": "Richards", "suffix": ""}, {"first": "Z", "middle": ["T"], "last": "Rogers", "suffix": ""}, {"first": "A", "middle": ["D"], "last": "Sanciangco", "suffix": ""}, {"first": "J", "middle": [], "last": "Sheppard", "suffix": ""}, {"first": "A", "middle": [], "last": "Sheppard", "suffix": ""}, {"first": "C", "middle": [], "last": "Smith", "suffix": ""}, {"first": "J", "middle": [], "last": "Stuart", "suffix": ""}, {"first": "S", "middle": [], "last": "Turak", "suffix": ""}, {"first": "E", "middle": [], "last": "Veron", "suffix": ""}, {"first": "Jen", "middle": [], "last": "Wallace", "suffix": ""}, {"first": "C", "middle": [], "last": "Weil", "suffix": ""}, {"first": "E", "middle": [], "last": "Wood", "suffix": ""}, {"first": "E", "middle": [], "last": "", "suffix": ""}], "year": 2008, "venue": "Science", "link": "206513451"}, "BIBREF9": {"title": "Environmental factors controlling community structure, morphology and linear extension of Mid-Holocene reef corals from Canada Honda, Southwestern, Dominican Republic", "authors": [{"first": "D", "middle": [], "last": "Cuevas", "suffix": ""}, {"first": "C", "middle": [], "last": "Sherman", "suffix": ""}, {"first": "W", "middle": [], "last": "Ramirez", "suffix": ""}, {"first": "D", "middle": ["K"], "last": "Hubbard", "suffix": ""}], "year": 2008, "venue": "Proc 11th Int Coral Reef Symp", "link": "54718960"}, "BIBREF10": {"title": "Abrupt sea surface pH change at the end of the Younger Dryas in the central sub-equatorial Pacific inferred from boron isotope abundance in corals (Porites)", "authors": [{"first": "E", "middle": [], "last": "Douville", "suffix": ""}, {"first": "M", "middle": [], "last": "Paterne", "suffix": ""}, {"first": "G", "middle": [], "last": "Cabioch", "suffix": ""}, {"first": "P", "middle": [], "last": "Louvat", "suffix": ""}, {"first": "J", "middle": [], "last": "Gaillardet", "suffix": ""}, {"first": "A", "middle": [], "last": "Juilletleclerc", "suffix": ""}, {"first": "L", "middle": [], "last": "Ayliffe", "suffix": ""}], "year": 2010, "venue": "Bioscience", "link": "55317657"}, "BIBREF11": {"title": "Community structure of Quaternary coral reefs compared with recent life and death assemblages", "authors": [{"first": "E", "middle": ["N"], "last": "Edinger", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Pandolfi", "suffix": ""}, {"first": "R", "middle": ["A"], "last": "Kelley", "suffix": ""}], "year": 2001, "venue": "Paleobiology", "link": "115136427"}, "BIBREF12": {"title": "Age accuracy and resolution of Quaternary corals used as proxies for sea level", "authors": [{"first": "E", "middle": ["N"], "last": "Edinger", "suffix": ""}, {"first": "G", "middle": ["S"], "last": "Burr", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Pandolfi", "suffix": ""}, {"first": "J", "middle": ["C"], "last": "Ortiz", "suffix": ""}], "year": 2007, "venue": "Earth Planet Sci Lett", "link": "56291393"}, "BIBREF13": {"title": "Longterm region-wide declines in Caribbean corals", "authors": [{"first": "T", "middle": ["A"], "last": "Gardner", "suffix": ""}, {"first": "I", "middle": ["M"], "last": "Cote", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Gill", "suffix": ""}, {"first": "A", "middle": [], "last": "Grant", "suffix": ""}, {"first": "A", "middle": ["R"], "last": "Watkinson", "suffix": ""}], "year": 2003, "venue": "Science", "link": null}, "BIBREF14": {"title": "The coral reefs of the Dominican Republic", "authors": [{"first": "F", "middle": ["X"], "last": "Geraldes", "suffix": ""}], "year": 2003, "venue": "", "link": "128011532"}, "BIBREF15": {"title": "Taphonomy: detecting critical events in fossil reef-coral assemblages. In: Aronson R (ed) Geological approaches to coral reef ecology", "authors": [{"first": "B", "middle": ["J"], "last": "Greenstein", "suffix": ""}], "year": 2007, "venue": "", "link": null}, "BIBREF16": {"title": "Comparative taphonomy of modern and Pleistocene corals", "authors": [{"first": "B", "middle": ["J"], "last": "Greenstein", "suffix": ""}, {"first": "H", "middle": ["A"], "last": "Moffat", "suffix": ""}], "year": 1996, "venue": "Palaios", "link": null}, "BIBREF17": {"title": "Preservation of community structure in modern reef coral life and death assemblages of the Florida Keys: implications for the Quaternary record of coral reefs", "authors": [{"first": "B", "middle": ["J"], "last": "Greenstein", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Pandolfi", "suffix": ""}], "year": 1997, "venue": "Bull Mar Sci", "link": "81489806"}, "BIBREF18": {"title": "Taphonomic alteration of reef corals: effects of reef environment and coral growth form. II: The Florida Keys", "authors": [{"first": "B", "middle": ["J"], "last": "Greenstein", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Pandolfi", "suffix": ""}], "year": 2003, "venue": "Palaios", "link": "55570763"}, "BIBREF19": {"title": "Shifting ecological baselines and the demise of Acropora cervicornis in the western North Atlantic and Caribbean Province: a Pleistocene perspective", "authors": [{"first": "B", "middle": ["J"], "last": "Greenstein", "suffix": ""}, {"first": "H", "middle": ["A"], "last": "Curran", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Pandolfi", "suffix": ""}], "year": 1998, "venue": "Coral Reefs", "link": "33534115"}, "BIBREF20": {"title": "How vulnerable is Acropora cervicornis to environmental change? Lessons from the early to middle Holocene", "authors": [{"first": "L", "middle": [], "last": "Greer", "suffix": ""}, {"first": "J", "middle": [], "last": "Jackson", "suffix": ""}, {"first": "H", "middle": ["A"], "last": "Curran", "suffix": ""}, {"first": "T", "middle": [], "last": "Guilderson", "suffix": ""}, {"first": "T", "middle": [], "last": "Teneva", "suffix": ""}], "year": 2009, "venue": "Geology", "link": "40307350"}, "BIBREF21": {"title": "Resheeting of relict Acropora palmata framework may promote fast growth, but does it compromise the structural integrity of the colony", "authors": [{"first": "R", "middle": [], "last": "Grober-Dunsmore", "suffix": ""}], "year": 2006, "venue": "Coral Reefs", "link": "46689573"}, "BIBREF22": {"title": "Hurricane-induced sediment transport in openshelf tropical systems-an example from", "authors": [{"first": "D", "middle": ["K"], "last": "Hubbard", "suffix": ""}], "year": 1992, "venue": "J Sediment Petrol", "link": null}, "BIBREF23": {"title": "Production and cycling of calcium carbonate in a shelf-edge reef system", "authors": [{"first": "D", "middle": ["K"], "last": "Hubbard", "suffix": ""}, {"first": "L", "middle": ["G"], "last": "Ward", "suffix": ""}, {"first": "Dm ;", "middle": [], "last": "Fitzgerald", "suffix": ""}, {"first": "", "middle": [], "last": "Dk", "suffix": ""}, {"first": "A", "middle": ["I"], "last": "Miller", "suffix": ""}, {"first": "D", "middle": [], "last": "Scaturo", "suffix": ""}], "year": 1976, "venue": "AAPG Annual Meeting", "link": null}, "BIBREF24": {"title": "Where's the reef: the role of framework in the Holocene", "authors": [{"first": "D", "middle": ["K"], "last": "Hubbard", "suffix": ""}, {"first": "R", "middle": ["B"], "last": "Burke", "suffix": ""}, {"first": "I", "middle": ["P"], "last": "Gill", "suffix": ""}], "year": 1998, "venue": "Carbonates Evaporites", "link": "129666662"}, "BIBREF25": {"title": "Holocene reef accretion along the north side of Bahia Enriquillo (western Dominican Republic): unique insights into patterns of reef development in response to sea-level rise", "authors": [{"first": "D", "middle": ["K"], "last": "Hubbard", "suffix": ""}, {"first": "W", "middle": [], "last": "Ramirez", "suffix": ""}, {"first": "D", "middle": [], "last": "Cuevas", "suffix": ""}, {"first": "T", "middle": [], "last": "Erickson", "suffix": ""}, {"first": "A", "middle": [], "last": "Estep", "suffix": ""}], "year": 2008, "venue": "Proc 11th Int Coral Reef Symp", "link": "59058953"}, "BIBREF26": {"title": "Catastrophes, phase shifts and large-scale degradation of a Caribbean coral reef", "authors": [{"first": "T", "middle": ["P"], "last": "Hughes", "suffix": ""}], "year": 1994, "venue": "Science", "link": "43204708"}, "BIBREF27": {"title": "Reefs since Columbus", "authors": [{"first": "Jbc", "middle": [], "last": "Jackson", "suffix": ""}], "year": 1997, "venue": "Coral Reefs", "link": "19632871"}, "BIBREF28": {"title": "The quality of the fossil record", "authors": [{"first": "S", "middle": ["M"], "last": "Kidwell", "suffix": ""}, {"first": "K", "middle": [], "last": "Flessa", "suffix": ""}], "year": 1995, "venue": "Annu Rev Ecol Syst", "link": null}, "BIBREF29": {"title": "A possible signature for white band disease and/or bleaching in Acropora palmata", "authors": [{"first": "A", "middle": [], "last": "Lagomarcino", "suffix": ""}, {"first": "D", "middle": ["K"], "last": "Hubbard", "suffix": ""}], "year": 2008, "venue": "Proc 11th Int Coral Reef Symp 263", "link": null}, "BIBREF30": {"title": "Microbial endoliths in skeletons of live and dead corals: Porites lobata", "authors": [{"first": "Le", "middle": [], "last": "Campion-Alsumard", "suffix": ""}, {"first": "T", "middle": [], "last": "Golubic", "suffix": ""}, {"first": "S", "middle": [], "last": "Hutchings", "suffix": ""}, {"first": "P", "middle": [], "last": "", "suffix": ""}], "year": 1995, "venue": "", "link": null}, "BIBREF31": {"title": "Bioerosion and encrustation on Curacao Pleistocene reefs: evaluating grazing in the fossil record", "authors": [{"first": "H", "middle": ["L"], "last": "Lescinsky", "suffix": ""}], "year": 2008, "venue": "(eds) 13th symposium on the geology of the Bahamas and other Carbonate regions", "link": null}, "BIBREF32": {"title": "Mollusc shell encrustation and bioerosion rates in a modern epeiric sea: taphonomy experiments in the Java Sea", "authors": [{"first": "H", "middle": ["L"], "last": "Lescinsky", "suffix": ""}, {"first": "E", "middle": [], "last": "Edinger", "suffix": ""}, {"first": "M", "middle": [], "last": "Risk", "suffix": ""}], "year": 2002, "venue": "Indonesia. Palaios", "link": "73707997"}, "BIBREF33": {"title": "Subaerially exposed Holocene coral reef", "authors": [{"first": "P", "middle": [], "last": "Mann", "suffix": ""}, {"first": "F", "middle": ["W"], "last": "Taylor", "suffix": ""}, {"first": "K", "middle": [], "last": "Burke", "suffix": ""}, {"first": "R", "middle": [], "last": "Kulstad", "suffix": ""}], "year": 1984, "venue": "Geol Soc Am Bull", "link": null}, "BIBREF34": {"title": "Documenting loss of large trophy fish from the Florida Keys with historical photographs", "authors": [{"first": "L", "middle": [], "last": "Mcclenachan", "suffix": ""}], "year": 2009, "venue": "Conserv Biol", "link": "18866032"}, "BIBREF35": {"title": "Conservation implications of historic sea turtle nesting beach loss", "authors": [{"first": "L", "middle": [], "last": "Mcclenachan", "suffix": ""}, {"first": "Jbc", "middle": [], "last": "Jackson", "suffix": ""}, {"first": "Mjh", "middle": [], "last": "Newman", "suffix": ""}], "year": 2006, "venue": "Front Ecol Environ", "link": "30886489"}, "BIBREF36": {"title": "Past and present marine mammal hunting rates and abundances: dugong (Dugong dugon) evidence from Dabangai Bone Mound, Torres Strait", "authors": [{"first": "I", "middle": ["J"], "last": "Mcniven", "suffix": ""}, {"first": "A", "middle": ["C"], "last": "Bedingfield", "suffix": ""}], "year": 2008, "venue": "J Archaeol Sci", "link": "140683602"}, "BIBREF37": {"title": "Preservation of in situ reef framework in regions of low hurricane frequency: Pleistocene of Curacao and Bonaire, southern Caribbean", "authors": [{"first": "D", "middle": ["L"], "last": "Meyer", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Bries", "suffix": ""}, {"first": "B", "middle": ["J"], "last": "Greenstein", "suffix": ""}], "year": 2003, "venue": "Lethaia", "link": "129929377"}, "BIBREF38": {"title": "Limited membership in Pleistocene reef coral assemblages from the Huon Peninsula, Papua New Guinea: constancy during global change", "authors": [{"first": "J", "middle": ["M"], "last": "Pandolfi", "suffix": ""}], "year": 1996, "venue": "Paleobiology", "link": "20944646"}, "BIBREF39": {"title": "Community structure of Pleistocene coral reefs of Curacao", "authors": [{"first": "J", "middle": ["M"], "last": "Pandolfi", "suffix": ""}, {"first": "Jbc", "middle": [], "last": "Jackson", "suffix": ""}], "year": 2001, "venue": "Ecol Monogr", "link": null}, "BIBREF40": {"title": "Broad-scale patterns in Pleistocene coral reef communities from the Caribbean: implications for ecology and management. In: Aronson R (ed) Geological approaches to coral reef ecology", "authors": [{"first": "J", "middle": ["M"], "last": "Pandolfi", "suffix": ""}, {"first": "Jbc", "middle": [], "last": "Jackson", "suffix": ""}], "year": 2007, "venue": "", "link": null}, "BIBREF41": {"title": "Global trajectories of the longterm decline of coral reef ecosystems", "authors": [{"first": "J", "middle": ["M"], "last": "Pandolfi", "suffix": ""}, {"first": "R", "middle": ["H"], "last": "Bradbury", "suffix": ""}, {"first": "E", "middle": [], "last": "Sala", "suffix": ""}, {"first": "T", "middle": ["P"], "last": "Hughes", "suffix": ""}, {"first": "K", "middle": ["A"], "last": "Bjorndal", "suffix": ""}, {"first": "R", "middle": ["G"], "last": "Cooke", "suffix": ""}, {"first": "D", "middle": [], "last": "Mcardle", "suffix": ""}, {"first": "L", "middle": [], "last": "Mcclenachan", "suffix": ""}, {"first": "Mjh", "middle": [], "last": "Newman", "suffix": ""}, {"first": "G", "middle": [], "last": "Paredes", "suffix": ""}, {"first": "R", "middle": ["R"], "last": "Warner", "suffix": ""}, {"first": "Jbc", "middle": [], "last": "Jackson", "suffix": ""}], "year": 2003, "venue": "Science", "link": "31903371"}, "BIBREF42": {"title": "Are U.S. coral reefs on the slippery slope to slime", "authors": [{"first": "J", "middle": ["M"], "last": "Pandolfi", "suffix": ""}, {"first": "Jbc", "middle": [], "last": "Jackson", "suffix": ""}, {"first": "N", "middle": [], "last": "Baron", "suffix": ""}, {"first": "R", "middle": ["H"], "last": "Bradbury", "suffix": ""}, {"first": "H", "middle": ["M"], "last": "Guzman", "suffix": ""}, {"first": "T", "middle": ["P"], "last": "Hughes", "suffix": ""}, {"first": "C", "middle": ["V"], "last": "Kappel", "suffix": ""}, {"first": "F", "middle": [], "last": "Micheli", "suffix": ""}, {"first": "J", "middle": ["C"], "last": "Ogden", "suffix": ""}, {"first": "H", "middle": ["P"], "last": "Possingham", "suffix": ""}, {"first": "E", "middle": [], "last": "Sala", "suffix": ""}], "year": 2005, "venue": "Science", "link": null}, "BIBREF43": {"title": "Mass mortality following disturbance in Holocene coral reefs from Papua New Guinea", "authors": [{"first": "J", "middle": ["M"], "last": "Pandolfi", "suffix": ""}, {"first": "A", "middle": ["M"], "last": "Tudhope", "suffix": ""}, {"first": "G", "middle": [], "last": "Burr", "suffix": ""}, {"first": "J", "middle": [], "last": "Chappell", "suffix": ""}, {"first": "E", "middle": [], "last": "Edinger", "suffix": ""}, {"first": "M", "middle": [], "last": "Frey", "suffix": ""}, {"first": "R", "middle": [], "last": "Steneck", "suffix": ""}, {"first": "C", "middle": [], "last": "Sharma", "suffix": ""}, {"first": "A", "middle": [], "last": "Yeates", "suffix": ""}, {"first": "M", "middle": [], "last": "Jennions", "suffix": ""}, {"first": "H", "middle": [], "last": "Lescinsky", "suffix": ""}], "year": 2006, "venue": "Geology", "link": "44079008"}, "BIBREF44": {"title": "Macroboring of Pleistocene coral communities, Falmouth formation", "authors": [{"first": "C", "middle": ["T"], "last": "Perry", "suffix": ""}], "year": 2000, "venue": "Jamaica. Palaios", "link": null}, "BIBREF45": {"title": "Storm-induced coral rubble deposition: Pleistocene records of natural reef disturbance and community response", "authors": [{"first": "C", "middle": ["T"], "last": "Perry", "suffix": ""}], "year": 2001, "venue": "Coral Reefs", "link": "10069828"}, "BIBREF46": {"title": "Mid-Holocene coral community data as baselines for understanding contemporary reef ecological states", "authors": [{"first": "R", "middle": ["C"], "last": "Roche", "suffix": ""}, {"first": "C", "middle": ["T"], "last": "Perry", "suffix": ""}, {"first": "K", "middle": ["G"], "last": "Johnson", "suffix": ""}, {"first": "K", "middle": [], "last": "Sultana", "suffix": ""}, {"first": "S", "middle": ["G"], "last": "Smithers", "suffix": ""}, {"first": "A", "middle": ["A"], "last": "Thompson", "suffix": ""}], "year": 2011, "venue": "Palaeogeogr Palaeoclimatol Palaeoecol", "link": "140608306"}, "BIBREF47": {"title": "The taphonomic significance of endoliths in dead-versus live-coral skeletons", "authors": [{"first": "T", "middle": ["P"], "last": "Scoffin", "suffix": ""}, {"first": "C", "middle": [], "last": "Bradshaw", "suffix": ""}], "year": 2000, "venue": "Palaios", "link": "130619399"}, "BIBREF48": {"title": "Fringing and nearshore coral reefs of the Great Barrier Reef: episodic Holocene development and future prospects", "authors": [{"first": "S", "middle": ["G"], "last": "Smithers", "suffix": ""}, {"first": "D", "middle": [], "last": "Hopley", "suffix": ""}, {"first": "K", "middle": ["E"], "last": "Parnell", "suffix": ""}], "year": 2006, "venue": "J Coast Res", "link": "55546151"}, "BIBREF49": {"title": "Coral assemblages, biofacies, and ecological zones in the mid-Holocene reef deposits of the Enriquillo Valley", "authors": [{"first": "T", "middle": ["A"], "last": "Stemann", "suffix": ""}, {"first": "K", "middle": ["G"], "last": "Johnson", "suffix": ""}], "year": 1992, "venue": "Lethaia", "link": null}, "BIBREF51": {"title": "Stratigraphy and radiocarbon chronology of a subaerially exposed Holocene coral reef, Dominican Republic", "authors": [{"first": "F", "middle": ["W"], "last": "Taylor", "suffix": ""}, {"first": "P", "middle": [], "last": "Mann", "suffix": ""}, {"first": "S", "middle": [], "last": "Valastro", "suffix": ""}, {"first": "K", "middle": [], "last": "Burke", "suffix": ""}], "year": 1985, "venue": "J Geol", "link": "128893496"}, "BIBREF52": {"title": "Sedimentation as an important environmental influence on Dominican Republic reefs", "authors": [{"first": "R", "middle": [], "last": "Torres", "suffix": ""}, {"first": "M", "middle": [], "last": "Chiappone", "suffix": ""}, {"first": "F", "middle": [], "last": "Geraldes", "suffix": ""}, {"first": "Y", "middle": [], "last": "Rodriguez", "suffix": ""}, {"first": "M", "middle": [], "last": "Vega", "suffix": ""}], "year": 2001, "venue": "Bull Mar Sci", "link": "88749784"}, "BIBREF54": {"title": "Variability in the El Nino-Southern oscillation through a glacial-interglacial cycle", "authors": [{"first": "A", "middle": ["W"], "last": "Tudhope", "suffix": ""}, {"first": "C", "middle": ["P"], "last": "Chilcott", "suffix": ""}, {"first": "M", "middle": ["T"], "last": "Mcculloch", "suffix": ""}, {"first": "E", "middle": ["R"], "last": "Cook", "suffix": ""}, {"first": "J", "middle": [], "last": "Chappell", "suffix": ""}, {"first": "R", "middle": ["M"], "last": "Ellam", "suffix": ""}, {"first": "D", "middle": ["W"], "last": "Lea", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Lough", "suffix": ""}, {"first": "G", "middle": ["B"], "last": "Shimmield", "suffix": ""}], "year": 2001, "venue": "Science", "link": "7750125"}, "BIBREF55": {"title": "Experimental studies on microbial bioerosion at Lee Stocking Island, Bahamas and One Tree Island, Great Barrier Reef, Australia: implications for paleoecological reconstructions", "authors": [{"first": "K", "middle": [], "last": "Vogel", "suffix": ""}, {"first": "M", "middle": [], "last": "Gektidis", "suffix": ""}, {"first": "S", "middle": [], "last": "Golubic", "suffix": ""}, {"first": "W", "middle": ["E"], "last": "Kiene", "suffix": ""}, {"first": "G", "middle": [], "last": "Radtke", "suffix": ""}], "year": 2000, "venue": "Lethaia", "link": null}, "BIBREF56": {"title": "Diversity and relative abundance of corals, octocorals and sponges at Jaragua National Park, Dominican Republic", "authors": [{"first": "E", "middle": [], "last": "Weil", "suffix": ""}], "year": 2006, "venue": "Rev Biol Trop", "link": "28828047"}, "BIBREF57": {"title": "Prehistoric fisheries in the Caribbean", "authors": [{"first": "S", "middle": ["R"], "last": "Wing", "suffix": ""}, {"first": "E", "middle": ["S"], "last": "Wing", "suffix": ""}], "year": 2001, "venue": "Coral Reefs", "link": "33025654"}}, "ref_entries": {}}
{"paper_id": "17782013", "_pdf_hash": "9a65807bb8bf35982c33424bc04649045045032f", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Synthesis of Speech from Unrestricted Text", "authors": [{"first": "J", "middle": [], "last": "Allen", "suffix": ""}], "year": "", "venue": "Proceedings, IEEE", "link": "42813358"}, "BIBREF1": {"title": "The 0FS Users' Guide", "authors": [{"first": "C", "middle": ["K"], "last": "Cheung", "suffix": ""}, {"first": "J", "middle": [], "last": "Kornatowskl", "suffix": ""}], "year": 1980, "venue": "", "link": null}, "BIBREF2": {"title": "PARTS -A System for Assigning Word Classes to English Text", "authors": [{"first": "L", "middle": ["L"], "last": "Cherry", "suffix": ""}], "year": 1978, "venue": "", "link": "60684503"}, "BIBREF3": {"title": "Computer Science and Office Information Systems", "authors": [{"first": "C", "middle": ["A"], "last": "Ellis", "suffix": ""}, {"first": "G", "middle": ["J"], "last": "Nutt", "suffix": ""}], "year": 1980, "venue": "Computing Surveys", "link": "6205946"}, "BIBREF4": {"title": "Synthetic Voices for Computers", "authors": [{"first": "J", "middle": ["L"], "last": "Flanagan", "suffix": ""}], "year": 1970, "venue": "IEEE, Spectrum", "link": "51639692"}, "BIBREF5": {"title": "MRS: A Microcomputer Database Management System", "authors": [{"first": "R", "middle": [], "last": "Hudyma", "suffix": ""}], "year": 1981, "venue": "Proceedings, ACM Workshop on Small Database Systems", "link": "8318487"}, "BIBREF6": {"title": "The C Programming Language", "authors": [{"first": "B", "middle": [], "last": "Kernighan", "suffix": ""}, {"first": "D", "middle": [], "last": "Ritehie", "suffix": ""}], "year": 1978, "venue": "N.J", "link": null}, "BIBREF7": {"title": "New Text and Message Services", "authors": [{"first": "P", "middle": [], "last": "Kirstein", "suffix": ""}], "year": 1980, "venue": "Proceedings. IFIP Congress", "link": "34013902"}, "BIBREF8": {"title": "Computer Voice", "authors": [{"first": "J", "middle": [], "last": "Koekebakker", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF10": {"title": "The MRS Users' Manual", "authors": [{"first": "J", "middle": ["Z"], "last": "Kornatowski", "suffix": ""}], "year": 1979, "venue": "", "link": null}, "BIBREF11": {"title": "An Office Form Flow ModeL", "authors": [{"first": "I", "middle": [], "last": "Ladd", "suffix": ""}, {"first": "D", "middle": [], "last": "Tsichritzis", "suffix": ""}], "year": 1980, "venue": "Proceedings", "link": "6518351"}, "BIBREF12": {"title": "An Experimental Speech Storage and Editing Facility", "authors": [{"first": "N", "middle": ["F"], "last": "Maxemchuk", "suffix": ""}], "year": 1980, "venue": "The Bell System Technical Journal", "link": "41105047"}, "BIBREF13": {"title": "Linear Prediction: A Tutorial Review", "authors": [{"first": "J", "middle": [], "last": "", "suffix": ""}], "year": 1975, "venue": "Proceedings, IEEE", "link": "57009570"}, "BIBREF14": {"title": "Voice Electronic Mail for the Business Executive", "authors": [{"first": "R", "middle": ["J"], "last": "Nacon", "suffix": ""}], "year": 1980, "venue": "Proceedings, NEC", "link": null}, "BIBREF15": {"title": "Digital Representations of Speech Signals", "authors": [{"first": "R", "middle": ["W"], "last": "Schafer", "suffix": ""}, {"first": "L", "middle": ["R"], "last": "Rabiner", "suffix": ""}], "year": 1975, "venue": "Proceedings IEEE", "link": "36081950"}, "BIBREF16": {"title": "Phonemes, Allopones, and LPC team to Synthesize Speech", "authors": [{"first": "W", "middle": [], "last": "Smith", "suffix": ""}], "year": 1981, "venue": "Electronic Design", "link": null}, "BIBREF17": {"title": "The UN3X Time Sharing System", "authors": [{"first": "K", "middle": [], "last": "Thompson", "suffix": ""}, {"first": "D", "middle": [], "last": "Ritchie", "suffix": ""}], "year": 1978, "venue": "Bell System Technical Journal", "link": null}, "BIBREF18": {"title": "0FS: An Integrated Form Management System", "authors": [{"first": "D", "middle": [], "last": "Tsichritzis", "suffix": ""}], "year": 1980, "venue": "Proceedings, 6th International Conference on Very Large Data Bases", "link": "40358385"}, "BIBREF19": {"title": "Integrating Data Base and Message Systems", "authors": [{"first": "D", "middle": [], "last": "Tsichritzis", "suffix": ""}], "year": 1981, "venue": "Proceedings, 7th International Conference on Very Large Data Bases", "link": "62612493"}, "BIBREF20": {"title": "Form Management", "authors": [{"first": "D", "middle": [], "last": "Tsichritzis", "suffix": ""}], "year": 1982, "venue": "CACM", "link": null}, "BIBREF21": {"title": "Office Information Systems: Challenge for the 80's", "authors": [{"first": "D", "middle": [], "last": "Tsiehritzis", "suffix": ""}, {"first": "F", "middle": ["H"], "last": "Lochovsky", "suffix": ""}], "year": 1980, "venue": "", "link": "34367746"}, "BIBREF22": {"title": "Votrax Model SVA Synthesizer Interface Specification", "authors": [{"first": "", "middle": [], "last": "Votrax", "suffix": ""}], "year": 1980, "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "17782170", "_pdf_hash": "258279a52d09761c5af74cd9369cd683858f2916", "abstract": [], "body_text": [{"section": "I N E C O N O M I C S A N D F I N A N C E", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Explaining the Recent Divergence in Payroll and Household Employment Growth", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Chinhui Juhn and Simon Potter Each month, the government releases two estimates of U.S. employment growth-one based on a survey of firms, the other on a survey of households. Since 1994, these measures have diverged sharply. Evidence suggests that the household survey's estimate has risen more slowly because it undercounts working-age adults who have found employment during the current economic expansion.", "text": "In recent years, two prominent government surveys-the payroll survey and the household survey-have given strikingly different estimates of employment growth. 1 From 1994 through third-quarter 1999, the payroll survey showed an employment increase of nearly 16 million, while the household survey indicated a rise of just 12 million. Significantly, the difference in employment levels reported in the payroll and household surveys-the \"employment gap\"-has more than doubled over this period, from 3 1/2 million to 7 1/2 million.", "cite_spans": [], "ref_spans": []}, {"section": "Chinhui Juhn and Simon Potter Each month, the government releases two estimates of U.S. employment growth-one based on a survey of firms, the other on a survey of households. Since 1994, these measures have diverged sharply. Evidence suggests that the household survey's estimate has risen more slowly because it undercounts working-age adults who have found employment during the current economic expansion.", "text": "In this edition of Current Issues, we seek an explanation for the recent increase in the employment gap by investigating the historical behavior of the employment estimates and examining the design and construction of the surveys themselves. We consider three possible reasons for the growing divergence of the employment estimates: the surveys' differing treatment of multiple jobholding, upward adjustments to the data in the payroll survey, and an undercount of the working-age population in the calculation of the household survey estimates.", "cite_spans": [], "ref_spans": []}, {"section": "Chinhui Juhn and Simon Potter Each month, the government releases two estimates of U.S. employment growth-one based on a survey of firms, the other on a survey of households. Since 1994, these measures have diverged sharply. Evidence suggests that the household survey's estimate has risen more slowly because it undercounts working-age adults who have found employment during the current economic expansion.", "text": "We find that the third explanation-an underestimated working-age population-best accounts for the recent rise in the employment gap. Since the household survey calculates the level of employment by combining survey data with a census-based estimate of the U.S. working-age population, an undercount of that population will produce low employment numbers. Evidence suggests that the census has in fact historically underestimated this population. Significantly, the undercount appears to be highest among groups whose employment status is very sensitive to business cycle fluctuations. We contend that the steady expansion of the economy in the 1990s has enabled these cyclical workers to find employment. Their numbers, only partly captured in the census-and, by extension, in the household survey-have in recent years helped to boost the job count in the payroll survey, widening the gap between the surveys' employment estimates.", "cite_spans": [], "ref_spans": []}, {"section": "The Gap between Payroll and Household Employment", "text": "In assessing the employment gap, we focus on the two most comparable categories of employment across the surveys-private nonfarm payroll employment from the payroll survey and private nonagricultural wage and salary employment, excluding the domestic services", "cite_spans": [], "ref_spans": []}, {"section": "December 1999", "text": "Volume 5 Number 16", "cite_spans": [], "ref_spans": []}, {"section": "December 1999", "text": "The gap [between the surveys' employment estimates] soared to more than 7 million in 1999.", "cite_spans": [], "ref_spans": []}, {"section": "December 1999", "text": "sector, from the household survey (see the highlighted entries in the table). 2 The difference between the employment figures reported for these two categories since 1948 is plotted in Chart 1. Although the gap has averaged about 3 million over the period, it soared to more than 7 million in 1999.", "cite_spans": [], "ref_spans": []}, {"section": "December 1999", "text": "The chart does, however, give a somewhat misleading impression of the gap, because overall employment has also grown tremendously during this period. Private nonfarm payroll employment, for example, increased from 39.2 million in 1948 to 108.7 million by the third quarter of 1999. To understand how this employment increase affects the gap, we recalculate the difference between the two series in relation to total employment. 3 Computed in this way, the recent gap between the surveys is certainly less dramatic (Chart 2). The difference in the employment figures for our two categories is smaller than it was during the early 1950s and about the same size as it was in the 1960s. Nevertheless, the increase in the gap in the 1990s is still sufficiently pronounced to require explanation: Now more than 7 percentage points, the gap easily exceeds the mean difference of 4.6 percentage points observed for the 1948-99 period as a whole.", "cite_spans": [], "ref_spans": []}, {"section": "December 1999", "text": "Another pattern evident in the charts is the link between the size of the gap and changes in the business cycle. Payroll employment growth has outpaced household employment growth most markedly during periods of economic prosperity and low unemployment; the gap has narrowed during periods of recession or high unemployment. In keeping with this pattern, the recent rise in the employment gap has occurred during a period of steady economic expansion and low overall unemployment. 4 The correlation between the gap and unemployment suggests that the explanation we are seeking for the conflicting survey estimates of employment will also clarify the cyclical behavior of the gap.", "cite_spans": [], "ref_spans": []}, {"section": "December 1999", "text": "FRBNY 2", "cite_spans": [], "ref_spans": []}, {"section": "December 1999", "text": "The Gap between Payroll and Household Employment ", "cite_spans": [], "ref_spans": []}, {"section": "Multiple Jobholding", "text": "Multiple jobholding appears to offer a simple and reasonable explanation for the employment gap. The employment increases reported in the payroll survey are likely to exceed those reported in the household survey because the payroll survey counts the number of jobs in the economy while the household survey counts the number of employed people. Since many workers hold more than one job, the payroll survey would be expected to yield higher estimates of employment.", "cite_spans": [], "ref_spans": []}, {"section": "Multiple Jobholding", "text": "But can multiple jobholding explain the recent increase in the gap between the survey estimates? To explore the extent of this factor's role in the employment gap, we look at household survey data compiled since 1994 on the multiple jobholding of respondents. 5 We find that while multiple jobholding can indeed explain the employment gap on average, it offers a poor explanation for the recent increase (Chart 3). The share of workers who hold multiple jobs has averaged just under 6 percent since 1994, a fact that would more than account for the mean difference of 4.6 percentage points between the two employment series. However, the 6 percent share is quite consistent with the share of multiple jobholders in the years before 1994, when the difference in the survey estimates was not especially marked. 6 In addition, since 1997 multiple jobholders' share of total employment has actually declined, while the employment gap has continued to rise. The contrasting behavior of these trends confirms that multiple jobholding by itself cannot account for the recent increase in the employment gap. Further evidence that this explanation does not \"fit\" is the lack of correspondence between the change in the number of multiple jobholders over time and the gap's strong cyclical behavior.", "cite_spans": [], "ref_spans": []}, {"section": "Payroll Data and the Possibility of Overcounting", "text": "Another possible explanation for the rising employment gap is overestimation of employment in the payroll survey. Some commentators have suggested that the method used by the Bureau of Labor Statistics (BLS) to calculate the payroll job numbers may lead to overcounting. 7 A look at the construction of the survey suggests that the BLS takes great care to arrive at accurate estimates. When compiling the payroll data, the BLS collects information from nearly 400,000 establishments-a large sample encompassing roughly 37 percent of total nonfarm employment. The numbers from this sample are scaled up to provide prompt monthly estimates of the number of jobs held in the nation as a whole. Then, in March of each year, the BLS revises its estimates by comparing them with a complete set of administrative records from the state unemployment insurance system. The records cover a full 98 percent of U.S. nonfarm employment, and supplemental sources are used to estimate the remaining 2 percent. The rigor of the entire process-particularly the annual benchmarking of the survey findings against administrative records-makes persistent overestimation of payroll employment highly unlikely.", "cite_spans": [], "ref_spans": []}, {"section": "Payroll Data and the Possibility of Overcounting", "text": "Questions have been raised, however, about the use of a \"bias adjustment factor\" in the computation of preliminary survey estimates (Epstein 1993; Koretz 1994; Wall Street Journal 1996) . Because the payroll survey cannot capture the employment changes that result from the formation of new firms or the closing of existing firms, the BLS uses information on past growth to adjust the sample-based estimates of jobs held. 8 In the recent period, when employment has been rising fairly steadily, the estimates have most often been adjusted upward to compensate for the survey's inability to capture the jobs created at many new firms. Critics have suggested that this bias adjustment may overcorrect the sample-based estimates, leading to inflated measures of employment growth. Others have noted that an adjustment factor based on information about past employment growth is unlikely to anticipate economic downturns and the resulting job losses. 9 Our review of the data suggests that the bias-adjusted numbers have not, in fact, overstated employment increases in recent months. Under the latest benchmark revisions, preliminary estimates of payroll employment were actually raised by 60,000 jobs. 10 In addition, a comparison of the preliminary and revised estimates of payroll employment since 1979 shows no systematic bias in the initial estimates. Beginning in 1992, revised payroll employment was consistently higher than the original estimates. Although payroll employment was revised downward in the two most recent recessions, 1982-83 and 1990-91, the benchmark revisions as a group exhibit no clear cyclical pattern. For example, the payroll employment figures were revised downward even during the strong expansionary economy of the late 1980s. Accordingly, we find no consistent evidence that the bias adjustment factor has exaggerated employment growth or performed poorly as a predictor of economic slowdowns.", "cite_spans": [{"start": 132, "end": 146, "text": "(Epstein 1993;", "ref_id": "BIBREF1"}, {"start": 147, "end": 159, "text": "Koretz 1994;", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "Payroll Data and the Possibility of Overcounting", "text": "Household Data and the Undercount of the U.S. Working-Age Population A much more likely source of measurement problems is the household survey. This survey's sample of roughly 47,000 households is much smaller and less representative than the payroll survey's sample. 11 Moreover, because the Bureau of Labor Statistics benchmarks the household data to the U.S. census, the benchmarking process can occur only every ten years, compared with the payroll data's annual benchmarking.", "cite_spans": [], "ref_spans": []}, {"section": "The Census Link: A Key to the Employment Gap", "text": "The household survey's tie to census data may very well explain why this survey has provided much lower estimates of employment than the payroll survey. To calculate the level of household employment in the nation as a whole, the BLS multiplies the percentage of employed individuals in its sample by an estimate of the U.S. working-age population. This estimate is based on figures from the previous census. 12 Use of the census count of the working-age population poses two problems. First, because the census is conducted only at tenyear intervals, the BLS must rely on a base figure that becomes increasingly uncertain as the decade advances. Second, demographic analysis of births, deaths, and net migration records provides strong evidence that the census has repeatedly underestimated the working-age population in the past several decades. The undercount in the 1940 census was especially severe: as much as 5.4 percent of the population was overlooked. Although the estimated undercount of 1.2 percent in the 1980 census indicated a significant improvement in accuracy, the trend reversed itself when the 1990 census missed an estimated 1.8 percent of the population. 13 To gauge how increases in the estimated workingage population affect household employment and the gap, we examine the revisions to household employment following the 1980 and 1990 census counts of the U.S. population. Although the census in both years underestimated the number of working-age people, it produced an estimate of the increase in this population that exceeded the increase projected by the Bureau of Labor Statistics. Using the census findings, the BLS \"rebased\" its estimates of household employment (Chart 4).", "cite_spans": [], "ref_spans": []}, {"section": "The Census Link: A Key to the Employment Gap", "text": "As the chart shows, the BLS revised household employment upward by approximately 1.5 million following the 1980 census. As a result of the correction, the employment gap narrowed by roughly 2.1 percentage points-a substantial decrease.", "cite_spans": [], "ref_spans": []}, {"section": "The Census Link: A Key to the Employment Gap", "text": "After the release of the 1990 census figures, the BLS raised household employment by approximately 832,000. 14 Although the estimated undercount in the 1990 census was a sizable 1.8 percent, the BLS was able to make a partial adjustment for the undercount using a post-enumeration survey of census respondents that revealed that many working-age people had been missed. 15 The resulting decrease in the employment gap was slightly less than 1 percentage point. Although this decrease is more modest than that produced by the updating of the 1980 population, it provides additional evidence that the employment gap is very sensitive to upward revisions of the household survey estimates. 16 ", "cite_spans": [], "ref_spans": []}, {"section": "A Hidden Labor Force", "text": "The undercounting of the working-age population, when combined with multiple jobholding, can explain the difference in the levels of the payroll and household employment series. However, the mere fact that a portion of the adult population is overlooked in the household survey cannot explain the cyclical behavior of the employment gap or, more specifically, the dramatic increase in the employment gap in recent years. To understand these trends, we need to know more about the identity and employment behavior of the undercounted groups.", "cite_spans": [], "ref_spans": []}, {"section": "A Hidden Labor Force", "text": "Using the indirect evidence available to us, we conclude that the groups underrepresented in the censusand thus in the household survey-are also those whose employment is likely to fluctuate with changes in the business cycle. For example, estimates suggest that 10.9 percent of black males were undercounted in the 1940 census, double the 5.4 percent undercount of the overall population. 17 Despite advances in census accuracy, the net undercount for black males remained high in the 1990 census, at 8.5 percent. This group also typically experiences the largest employment swings over the business cycle. For example, since 1992-the first full year of the current expansion-employment of black males increased 5 percentage points, from 55 to 60 percent, while employment of white males rose just 2 percentage points. Furthermore, from second-quarter 1992 to second-quarter 1999, the employment-topopulation ratio among black males who were between sixteen and twenty-four years old and had no more than a high school education rose a full 13 percentage points, from 44 to 57 percent. 18 This evidence suggests that the groups not fully captured by the household survey are moving into the documented employment sector as labor market conditions improve. Their inclusion in their employers' payroll records means that they will be counted in the government's payroll survey. Thus, the surfacing of this hidden labor force when the economy is strong could very well explain why payroll employment growth has outpaced household employment growth most dramatically during expansions and why the gap has become particularly large in recent years.", "cite_spans": [], "ref_spans": []}, {"section": "FRBNY 4 C U R R E N T I S S U E S I N E C O N O M I C S A N D F I N A N C E", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Chart 4 Revisions to Household Employment following the 1980 and 1990 Census Counts", "text": "How much of the increase in the employment gap could potentially be explained by the 1990 census undercount of such workers? If we assume a 2 percent undercount for the working-age population of 200 million, we would have approximately 4 million undercounted people in 1994. If half of the undercounted group found formal employment over the 1994-99 period, they would account for 2 million of the 4 million difference in the household and payroll estimates of employment growth since 1994-or roughly one-half of the gap. 19", "cite_spans": [], "ref_spans": []}, {"section": "Conclusion", "text": "The increasing disparity between the employment estimates reported in the payroll and household surveys has puzzled many analysts. We argue that the household survey probably underreports employment because its estimates incorporate a census undercount of the workingage population. The higher figures in the payroll survey are more reliable, accurately capturing the effects of the current economic expansion on the employment status of many adults overlooked by the census. 2. Even within these categories, there are minor differences between the surveys. For a clear and useful description of the differences in survey design, see Schweitzer and Ransom (1999) .", "cite_spans": [{"start": 634, "end": 662, "text": "Schweitzer and Ransom (1999)", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Conclusion", "text": "3. More precisely, we take the natural logarithm of the ratio of payroll employment to household employment.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusion", "text": "4. Statistical tests of the relationship between the civilian unemployment rate and the gap indicate that the unemployment rate can explain a large share-about 50 percent-of the variation in the gap.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusion", "text": "5. Using the 1994-99 monthly samples for the household survey, we calculated the total number of private wage and salary workers (including the incorporated self-employed) who were sixteen years of age or older, did not cite agriculture as their industry of employment, and reported holding more than one job. Although the number of multiple jobholders may not be fully represented in the household survey (see our discussion of this survey's undercount problems), the ratio-the share of multiple jobholders-should still be informative.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusion", "text": "6. Cohany, Polivka, and Rothgeb (1994) report that in May 1991 and fourth-quarter 1993, 6.2 percent of employed people were multiple jobholders.", "cite_spans": [{"start": 3, "end": 38, "text": "Cohany, Polivka, and Rothgeb (1994)", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "Conclusion", "text": "7. See, for example, Epstein (1993) , Koretz (1994), and Wall Street Journal (1996) . 8. The bias adjustment factor is derived from the following components: (1) the difference between actual benchmarked employment levels and the employment levels derived from the payroll survey samples for the previous three years; (2) a cyclical component incorporating the previous two quarters' employment changes in the payroll survey, multiplied by a regression coefficient relating survey employment growth to employment growth in the universe of unemployment insurance (UI) records; and (3) an adjustment factor that incorporates information from the UI records, available with a three-quarter lag.", "cite_spans": [{"start": 21, "end": 35, "text": "Epstein (1993)", "ref_id": "BIBREF1"}, {"start": 38, "end": 56, "text": "Koretz (1994), and", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "Conclusion", "text": "9. Epstein (1993) , for example, questions whether past undercounts of employment should be used to predict current undercountsparticularly when evidence suggests that economic conditions are unstable.", "cite_spans": [{"start": 3, "end": 17, "text": "Epstein (1993)", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Conclusion", "text": "10. This information is available at the BLS web site, under Current Employment Statistics (http://stats.bls.gov:80/cesbm98.htm).", "cite_spans": [], "ref_spans": []}, {"section": "Conclusion", "text": "Groups not fully captured by the household survey are moving into the documented employment sector as labor market conditions improve.", "cite_spans": [], "ref_spans": []}, {"section": "C U R R E N T I S S U E S I N E C O N O M I C S A N D F I N A N C E", "text": "11. Coverage varies by state, but the 47,000-household figure corresponds to less than .05 percent of the civilian noninstitutional population.", "cite_spans": [], "ref_spans": []}, {"section": "C U R R E N T I S S U E S I N E C O N O M I C S A N D F I N A N C E", "text": "12. The census is the universe from which the Bureau of Labor Statistics selects a sample of households to be interviewed each month. The population estimates use the previous census as the base figure for resident population, and population levels are projected forward on an annual basis using administrative data on births, deaths, and net legal immigration. These estimates are derived by state of residence, age, sex, race, and Hispanic origin. For further details, see U.S. Department of Labor (1992) and Stinson (1994) .", "cite_spans": [{"start": 511, "end": 525, "text": "Stinson (1994)", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "C U R R E N T I S S U E S I N E C O N O M I C S A N D F I N A N C E", "text": "13. See Table 2 in Robinson et al. (1993) .", "cite_spans": [{"start": 19, "end": 41, "text": "Robinson et al. (1993)", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "C U R R E N T I S S U E S I N E C O N O M I C S A N D F I N A N C E", "text": "14. We were unable to find records of revisions to the disaggregated category-private nonagricultural wage and salary employment-that we are analyzing. Total employment, however, was revised upward by the BLS by approximately 350,000 following the 1950 census, revised downward by roughly 200,000 after the 1960 census, and revised upward by 333,000 or so after the 1970 census.", "cite_spans": [], "ref_spans": []}, {"section": "C U R R E N T I S S U E S I N E C O N O M I C S A N D F I N A N C E", "text": "15. In the post-enumeration survey, a subset of individuals first captured in the census were reinterviewed. By comparing the results of the survey and the census, the BLS estimated the share of the population missed in the census. Overall, the 1990 population estimates together with the post-enumeration survey adjustments increased the working-age population by 1.25 million.", "cite_spans": [], "ref_spans": []}, {"section": "C U R R E N T I S S U E S I N E C O N O M I C S A N D F I N A N C E", "text": "16. The undercount problems associated with the household survey do not extend to such employment measures as the total civilian unemployment rate or the total civilian labor force participation rate. The BLS calculates these measures as a ratio in which both the numerator and the denominator include estimates of the population; thus, any errors in the data would likely cancel each other out.", "cite_spans": [], "ref_spans": []}, {"section": "C U R R E N T I S S U E S I N E C O N O M I C S A N D F I N A N C E", "text": "17. Our example focuses on black males because data on this group are more readily available than data on other groups likely to be underrepresented.", "cite_spans": [], "ref_spans": []}, {"section": "C U R R E N T I S S U E S I N E C O N O M I C S A N D F I N A N C E", "text": "18. These figures are based on our calculations from the monthly outgoing Current Population Survey samples. Freeman and Rodgers (1999) report an even larger change.", "cite_spans": [{"start": 109, "end": 135, "text": "Freeman and Rodgers (1999)", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "C U R R E N T I S S U E S I N E C O N O M I C S A N D F I N A N C E", "text": "19. Although a 50-percentage-point change in the employment rate of this undercounted group seems large, it is unlikely that the change reflects only the movement from nonemployment to employment. Rather, a large portion of this change probably reflects movement from the informal, undocumented sector (\"off-thebooks\" employment) to the documented sector.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Revisions in the Current Population Survey Effective", "authors": [{"first": "Sharon", "middle": ["R"], "last": "Cohany", "suffix": ""}, {"first": "Anne", "middle": ["E"], "last": "Polivka", "suffix": ""}, {"first": "Jennifer", "middle": ["M"], "last": "Rothgeb", "suffix": ""}], "year": 1994, "venue": "U.S. Bureau of Labor Statistics Employment and Earnings", "link": null}, "BIBREF1": {"title": "Pulling the Plug on Employment Numbers", "authors": [{"first": "Gene", "middle": [], "last": "Epstein", "suffix": ""}], "year": 1993, "venue": "", "link": null}, "BIBREF2": {"title": "Area Economic Conditions and the Labor Market Outcomes of Young Men in the 1990s Expansion", "authors": [{"first": "Richard", "middle": ["B"], "last": "Freeman", "suffix": ""}, {"first": "William", "middle": ["M"], "last": "Rodgers", "suffix": ""}, {"first": "Iii", "middle": [], "last": "", "suffix": ""}], "year": 1999, "venue": "", "link": "153302826"}, "BIBREF3": {"title": "Too Much Fudge in Job Numbers?", "authors": [{"first": "Gene", "middle": [], "last": "Koretz", "suffix": ""}], "year": 1994, "venue": "Business Week", "link": null}, "BIBREF4": {"title": "Estimation of Population Coverage in the 1990 United States Census Based on Demographic Analysis", "authors": [{"first": "J", "middle": [], "last": "Robinson", "suffix": ""}, {"first": "", "middle": [], "last": "Gregory", "suffix": ""}], "year": 1993, "venue": "Journal of the American Statistical Association", "link": "41325298"}, "BIBREF5": {"title": "Measuring Total Employment: Are a Few Million Workers Important?\" Federal Reserve Bank of Cleveland Economic Commentary", "authors": [{"first": "Mark", "middle": [], "last": "Schweitzer", "suffix": ""}, {"first": "Jennifer", "middle": [], "last": "Ransom", "suffix": ""}], "year": 1999, "venue": "", "link": null}, "BIBREF6": {"title": "How the Government Measures Unemployment", "authors": [{"first": "John", "middle": [], "last": "Stinson", "suffix": ""}], "year": 1994, "venue": "U.S. Bureau of Labor Statistics Report", "link": null}}, "ref_entries": {"FIGREF0": {"text": "U.S. Department of Labor, Bureau of Labor Statistics.", "type": "figure"}, "FIGREF1": {"text": "The payroll survey-the headline source for job growth-is officially known as Current Employment Statistics (CES); the household survey is known as the Current Population Survey (CPS). Both surveys are produced by the U.S. Department of Labor's Bureau of Labor Statistics (BLS). Their results, available monthly, are released jointly as the Employment Situation Summary.", "type": "figure"}, "TABREF0": {"text": "Difference as a percentage of employment Source: U.S. Department of Labor, Bureau of Labor Statistics. Note: The shaded areas denote periods designated recessions by the NBER.", "type": "table"}, "TABREF1": {"text": "Multiple Jobholders as a Share of Private Nonfarm Employment", "type": "table"}}}
{"paper_id": "17782449", "_pdf_hash": "ca492a928121bcb2dd49c70e401303db2df0324f", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Methods to ensure quality of service in cloud computing environment", "authors": [{"first": "S", "middle": [], "last": "Dubey", "suffix": ""}, {"first": "S", "middle": [], "last": "", "suffix": ""}], "year": 2013, "venue": "International Journal of Advanced Research in Computer Science and Software Engineering", "link": null}, "BIBREF1": {"title": "Quality-of-Service in cloud computing: modeling techniques and their applications", "authors": [{"first": "D", "middle": [], "last": "Ardagna", "suffix": ""}, {"first": "G", "middle": [], "last": "Casale", "suffix": ""}, {"first": "M", "middle": [], "last": "Ciavotta", "suffix": ""}, {"first": "J", "middle": ["F"], "last": "Perez", "suffix": ""}, {"first": "W", "middle": [], "last": "Wang", "suffix": ""}], "year": 2014, "venue": "Journal of Internet Services and Applications", "link": "2493689"}, "BIBREF2": {"title": "Negotiating and enforcing QoS and SLAs in grid and cloud computing", "authors": [{"first": "V", "middle": [], "last": "Stantchev", "suffix": ""}, {"first": "C", "middle": [], "last": "Schropfer", "suffix": ""}], "year": 2009, "venue": "Proc. Int. Conf. on Advances in Grid and Pervasive Computing, GPC \"09", "link": "27353935"}, "BIBREF3": {"title": "An Adaptive QoS-aware cloud", "authors": [{"first": "Z", "middle": [], "last": "Yuchao", "suffix": ""}, {"first": "D", "middle": [], "last": "Bo", "suffix": ""}, {"first": "P", "middle": [], "last": "Fuyang", "suffix": ""}], "year": 2012, "venue": "Proc. of Int. Conf. on Cloud computing, Technologies, Applications and Management", "link": "14299125"}, "BIBREF4": {"title": "The NIST definition of cloud computing", "authors": [{"first": "P", "middle": [], "last": "Mell", "suffix": ""}, {"first": "T", "middle": [], "last": "Grance", "suffix": ""}], "year": 2011, "venue": "Natl. Inst. of Standards of Technology (NIST)", "link": "167781982"}, "BIBREF5": {"title": "Cloud computing-A potential area for research", "authors": [{"first": "E", "middle": ["B K"], "last": "Manash", "suffix": ""}, {"first": "T", "middle": ["U"], "last": "Rani", "suffix": ""}], "year": 2015, "venue": "International Journal of Computer Trends and Technology (IJCTT)", "link": "54683686"}, "BIBREF6": {"title": "System of systems for Quality-of-Service observation and response in cloud", "authors": [{"first": "P", "middle": ["C"], "last": "Hershey", "suffix": ""}, {"first": "S", "middle": [], "last": "Rao", "suffix": ""}, {"first": "C", "middle": ["B"], "last": "Silio", "suffix": ""}, {"first": "A", "middle": [], "last": "Narayan", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF8": {"title": "The Next Generation Enterprise: Business as a Service in cloud", "authors": [{"first": "K", "middle": [], "last": "Ashar", "suffix": ""}], "year": 2015, "venue": "", "link": null}, "BIBREF9": {"title": "Governance as a Service for collaborative environment", "authors": [{"first": "J", "middle": [], "last": "Li", "suffix": ""}, {"first": "F", "middle": [], "last": "Bennier", "suffix": ""}, {"first": "Y", "middle": [], "last": "Amghar", "suffix": ""}], "year": 2012, "venue": "Proc. IFIP Advances in Information and Communication Technology", "link": "3465082"}, "BIBREF10": {"title": "Quality-of-Service in cloud computing: modelling techniques and their applications", "authors": [{"first": "D", "middle": [], "last": "Ardagna", "suffix": ""}, {"first": "G", "middle": [], "last": "Casale", "suffix": ""}, {"first": "M", "middle": [], "last": "Ciavotta", "suffix": ""}, {"first": "J", "middle": ["F"], "last": "Perez", "suffix": ""}, {"first": "W", "middle": [], "last": "Wang", "suffix": ""}], "year": 2014, "venue": "Journal of Internet Services and Applications", "link": "2493689"}, "BIBREF11": {"title": "Energyaware autonomic resource allocation in multitier virtualized environment", "authors": [{"first": "D", "middle": [], "last": "Ardagna", "suffix": ""}, {"first": "B", "middle": [], "last": "Panicucci", "suffix": ""}, {"first": "M", "middle": [], "last": "Trubian", "suffix": ""}, {"first": "L", "middle": [], "last": "Zhang", "suffix": ""}], "year": 2012, "venue": "IEEE Transactions on Services Computing", "link": "12680475"}, "BIBREF12": {"title": "Novel sensing approach for predicting SLA violations", "authors": [{"first": "V", "middle": [], "last": "Rajesekaran", "suffix": ""}, {"first": "A", "middle": ["A"], "last": "Ashok", "suffix": ""}, {"first": "R", "middle": [], "last": "Manjula", "suffix": ""}], "year": 2014, "venue": "International Journal of Computer Trends and Technology (IJCTT)", "link": "17135857"}, "BIBREF13": {"title": "Portable cloud applications-From theory to practice", "authors": [{"first": "D", "middle": [], "last": "Petcu", "suffix": ""}, {"first": "G", "middle": [], "last": "Macariu", "suffix": ""}, {"first": "S", "middle": [], "last": "Panica", "suffix": ""}, {"first": "C", "middle": [], "last": "Crcium", "suffix": ""}], "year": 2013, "venue": "Future Generation Computer Systems", "link": "2972666"}, "BIBREF14": {"title": "A QoS-oriented inter-cloud federation framework", "authors": [{"first": "M", "middle": [], "last": "Salam", "suffix": ""}, {"first": "A", "middle": [], "last": "Shawish", "suffix": ""}], "year": 2015, "venue": "IEEE Systems Journal", "link": "28870693"}, "BIBREF15": {"title": "An approach of quality of service assurance for enterprise cloud computing (QoSAECC)", "authors": [{"first": "W", "middle": ["C"], "last": "Chu", "suffix": ""}, {"first": "C", "middle": [], "last": "Yang", "suffix": ""}, {"first": "C", "middle": [], "last": "Lu", "suffix": ""}, {"first": "C", "middle": [], "last": "Chang", "suffix": ""}, {"first": "N", "middle": [], "last": "Hsueh", "suffix": ""}, {"first": "T", "middle": [], "last": "Hsu", "suffix": ""}, {"first": "S", "middle": [], "last": "Hung", "suffix": ""}], "year": 2014, "venue": "Proc. Int. Conf. on Trustworthy Systems and their Applications", "link": "12955732"}, "BIBREF16": {"title": "QoSaware resource provisioning for big data processing in cloud computing environment", "authors": [{"first": "M", "middle": ["M"], "last": "Hassan", "suffix": ""}, {"first": "B", "middle": [], "last": "Song", "suffix": ""}, {"first": "M", "middle": ["S"], "last": "Shamin", "suffix": ""}, {"first": "A", "middle": [], "last": "Alamri", "suffix": ""}], "year": 2014, "venue": "Proc. Int. Conf. on Computational Sc. and Computational Intelligence", "link": null}, "BIBREF17": {"title": "An end-to-end QoS mapping approach for cloud service selection", "authors": [{"first": "R", "middle": [], "last": "Karim", "suffix": ""}, {"first": "C", "middle": [], "last": "Ding", "suffix": ""}, {"first": "A", "middle": [], "last": "Miri", "suffix": ""}], "year": 2013, "venue": "Proc. IEEE Ninth World Congress on Services", "link": "20247338"}, "BIBREF18": {"title": "A QoS assurance middleware model for enterprise cloud computing", "authors": [{"first": "S", "middle": [], "last": "Lee", "suffix": ""}, {"first": "D", "middle": [], "last": "Tang", "suffix": ""}, {"first": "T", "middle": [], "last": "Chen", "suffix": ""}, {"first": "W", "middle": ["C"], "last": "Chu", "suffix": ""}], "year": 2012, "venue": "Proc. IEEE 36th Int. Conf. on Computer Software and Application Workshops", "link": "14261816"}, "BIBREF19": {"title": "A QoS-aware dynamic data replica deletion strategy for distributed storage systems under cloud computing environments", "authors": [{"first": "L", "middle": [], "last": "Bin", "suffix": ""}, {"first": "Y", "middle": [], "last": "Jiong", "suffix": ""}, {"first": "S", "middle": [], "last": "Hua", "suffix": ""}, {"first": "N", "middle": [], "last": "Mei", "suffix": ""}], "year": 2012, "venue": "Proc. Second Int. Conf. on Cloud and Green Computing", "link": "15522260"}, "BIBREF20": {"title": "A QoS-aware system for mobile cloud computing", "authors": [{"first": "P", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "Z", "middle": [], "last": "Yan", "suffix": ""}], "year": 2011, "venue": "Proc. of IEEE", "link": "16097277"}, "BIBREF21": {"title": "Reputation-based QoS provisioning in cloud computing via Dirichletmultinomial model", "authors": [{"first": "Y", "middle": [], "last": "Xiao", "suffix": ""}, {"first": "C", "middle": [], "last": "Lin", "suffix": ""}, {"first": "Y", "middle": [], "last": "Yiang", "suffix": ""}, {"first": "X", "middle": [], "last": "Chu", "suffix": ""}, {"first": "X", "middle": [], "last": "Shen", "suffix": ""}], "year": 2010, "venue": "IEEE ICC Proceedings", "link": "14832632"}, "BIBREF22": {"title": "A Multiple QoSconstrained scheduling strategy of multiple workflows from cloud computing", "authors": [{"first": "M", "middle": [], "last": "Xu", "suffix": ""}, {"first": "L", "middle": [], "last": "Cui", "suffix": ""}, {"first": "H", "middle": [], "last": "Wang", "suffix": ""}, {"first": "Y", "middle": ["B"], "last": "Bi", "suffix": ""}], "year": 2009, "venue": "IEEE International Symposium on Parallel and Distributed Proceeding with Applications", "link": null}}, "ref_entries": {}}
{"paper_id": "17782677", "_pdf_hash": "716a794b5b949e013e47e95499825bdf66ec56f9", "abstract": [{"section": "Abstract", "text": "Nuage are amorphous ultrastructural granules in the cytoplasm of male germ cells as divergent as Drosophila, Xenopus, and Homo sapiens. Most nuage are cytoplasmic ribonucleoprotein structures implicated in diverse RNA metabolism including the regulation of PIWI-interacting RNA (piRNA) synthesis by the PIWI family (i.e., MILI, MIWI2, and MIWI). MILI is prominent in embryonic and early post-natal germ cells in nuage also called germinal granules that are often associated with mitochondria and called intermitochondrial cement. We find that GASZ (Germ cell protein with Ankyrin repeats, Sterile alpha motif, and leucine Zipper) co-localizes with MILI in intermitochondrial cement. Knockout of Gasz in mice results in a dramatic downregulation of MILI, and phenocopies the zygotene-pachytene spermatocyte block and male sterility defect observed in MILI null mice. In Gasz null testes, we observe increased hypomethylation and expression of retrotransposons similar to MILI null testes. We also find global shifts in the small RNAome, including down-regulation of repeat-associated, known, and novel piRNAs. These studies provide the first evidence for an essential structural role for GASZ in male fertility and epigenetic and post-transcriptional silencing of retrotransposons by stabilizing MILI in nuage.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "The differentiation program of the germline is distinct from somatic cells in that resetting of the epigenome by demethylation of DNA and histones must take place for proper post-fertilization development of the embryo [1] . DNA demethylation occurs during primordial germ cell (PGC) migration as part of their normal development [2] . Different elements within the genome are remethylated at distinct time windows in a sex-specific fashion. Remethylation of retrotransposons occurs in the male germline at embryonic day 17.5 (E17.5) and in the female germline during postnatal oocyte maturation [1] . The resetting of the epigenetic state of the germline followed by the acquisition of male-specific methylation imprints, while a necessary component for postfertilization development, exposes the germline to potential risk from retrotransposon mobilization [3] . Insects and mammals resolve this problem through the action of several classes of small RNAs including piRNAs (,27 nt PIWI family-interacting RNAs) [4] [5] [6] [7] [8] [9] . Two classes of piRNAs, repeat-associated piRNAs and nonrepeat-associated piRNAs based on their similarity to retrotransposons, are present in the germline of animals as primitive as sponges [10] . Repeat-associated piRNAs limit expression of retrotransposons at the post-transcriptional level and through epigenetic silencing by the recruitment of DNA methyltransferases including DNMT3A and DNMT3L [11] [12] [13] [14] [15] . In the absence of these small RNAs, retrotransposon expression is dramatically increased in the germline, leading to DNA damage and cell death.", "cite_spans": [{"start": 219, "end": 222, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 330, "end": 333, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 596, "end": 599, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 1013, "end": 1016, "text": "[4]", "ref_id": "BIBREF2"}, {"start": 1017, "end": 1020, "text": "[5]", "ref_id": "BIBREF3"}, {"start": 1021, "end": 1024, "text": "[6]", "ref_id": "BIBREF4"}, {"start": 1025, "end": 1028, "text": "[7]", "ref_id": "BIBREF5"}, {"start": 1029, "end": 1032, "text": "[8]", "ref_id": "BIBREF6"}, {"start": 1033, "end": 1036, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 1229, "end": 1233, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 1438, "end": 1442, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 1443, "end": 1447, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 1448, "end": 1452, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 1453, "end": 1457, "text": "[14]", "ref_id": "BIBREF13"}, {"start": 1458, "end": 1462, "text": "[15]", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "Introduction", "text": "Regulation of retrotransposon repression is coordinated by proteins in spatially specialized compartments of ribonucleoprotein-rich structures called nuage. According to the nomenclature proposed by Chuma et al. [16] , embryonic prospermatogonia, postnatal spermatogonia and spermatocytes possess a form of nuage appearing as perinuclear granules transiently associated with mitochondria and thus termed intermitochondrial cement. In contrast, a single large granule of nuage, present in post-meiotic spermatids is called the chromatoid body [17, 18] . Multiple proteins have been localized by electron microscopy to both intermitochondrial cement and the chromatoid body including mouse VASA homolog (MVH; also called DDX4 or DEAD-box polypeptide 4), tudor-domain containing 1 (TDRD1), tudordomain containing 6 (TDRD6), and tudor-domain containing 7 (TDRD7) [19] [20] [21] . The chromatoid body is not believed to arise merely by coalescence of intermitochondrial cement granules; however, to date there are no examples of proteins localized by electron microscopy specifically to the intermitochondrial cement but absent from the chromatoid body.", "cite_spans": [{"start": 212, "end": 216, "text": "[16]", "ref_id": "BIBREF15"}, {"start": 542, "end": 546, "text": "[17,", "ref_id": "BIBREF16"}, {"start": 547, "end": 550, "text": "18]", "ref_id": "BIBREF17"}, {"start": 859, "end": 863, "text": "[19]", "ref_id": "BIBREF18"}, {"start": 864, "end": 868, "text": "[20]", "ref_id": "BIBREF19"}, {"start": 869, "end": 873, "text": "[21]", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "Introduction", "text": "Nuage are proposed sites for multiple RNA processing events including translational repression, RNA-mediated gene silencing, mRNA degradation, and nonsense-mediated mRNA decay [22] . A number of germ cell-specific mRNAs display translational repression with a lag of up to a week between their transcription and translation [23, 24] . The evidence for nuage regulation of mRNA is strongest for the chromatoid body. Translationally regulated mRNAs such as transition protein 2 (Tnp2) have been localized to the chromatoid body [25] . DEAD box helicases, including MVH/DDX4 and DDX25, which can unwind RNA in vitro, are localized to the chromatoid body [26] [27] [28] [29] [30] . MicroRNAs (,22 nt non-coding RNAs) and components of the RNA-Induced Silencing Complex (RISC) machinery including Dicer, Argonaute 2 (AGO2), and Argonaute 3 (AGO3) with demonstrated in vitro endonuclease activity, localize to the chromatoid body where they may function in translational control and mRNA stability, but their potential association with the intermitochondrial cement is not described [22, 31] . The chromatoid body also contains MILI and MIWI RNA endonucleases that generate piRNAs [32, 33] . Most MIWI-associated mRNAs in spermatids are associated with the RNP fraction with a smaller number associated with polysomes suggestive of a function in translational control [34] .", "cite_spans": [{"start": 176, "end": 180, "text": "[22]", "ref_id": "BIBREF21"}, {"start": 324, "end": 328, "text": "[23,", "ref_id": "BIBREF22"}, {"start": 329, "end": 332, "text": "24]", "ref_id": "BIBREF23"}, {"start": 526, "end": 530, "text": "[25]", "ref_id": "BIBREF24"}, {"start": 651, "end": 655, "text": "[26]", "ref_id": "BIBREF25"}, {"start": 656, "end": 660, "text": "[27]", "ref_id": "BIBREF26"}, {"start": 661, "end": 665, "text": "[28]", "ref_id": "BIBREF27"}, {"start": 666, "end": 670, "text": "[29]", "ref_id": "BIBREF28"}, {"start": 671, "end": 675, "text": "[30]", "ref_id": "BIBREF29"}, {"start": 1077, "end": 1081, "text": "[22,", "ref_id": "BIBREF21"}, {"start": 1082, "end": 1085, "text": "31]", "ref_id": "BIBREF30"}, {"start": 1175, "end": 1179, "text": "[32,", "ref_id": "BIBREF31"}, {"start": 1180, "end": 1183, "text": "33]", "ref_id": "BIBREF32"}, {"start": 1362, "end": 1366, "text": "[34]", "ref_id": "BIBREF33"}], "ref_spans": []}, {"section": "Introduction", "text": "Prior to the meiotic divisions, the role of nuage in mRNA metabolism in primordial germ cells, spermatogonia, and spermatocytes is unknown. Whereas MILI is present throughout this period, MIWI2 is restricted to nuage granules in embryonic testes, and MIWI is present in those of pachytene spermatocytes [13, [35] [36] [37] . The localization of PIWI family proteins to the intermitochondrial cement has not been clearly defined, although MILI interacts with the intermitochondrial cement protein TDRD1, MVH and other nuage proteins [33, 38] . Maelstrom (MAEL), the putative 39-59 endonuclease for piRNA 39 end formation, is also associated with nuage in mammals [39] [40] [41] . Thus, multiple components necessary for piRNA generation are connected physically to nuage.", "cite_spans": [{"start": 303, "end": 307, "text": "[13,", "ref_id": "BIBREF12"}, {"start": 308, "end": 312, "text": "[35]", "ref_id": "BIBREF34"}, {"start": 313, "end": 317, "text": "[36]", "ref_id": "BIBREF35"}, {"start": 318, "end": 322, "text": "[37]", "ref_id": "BIBREF36"}, {"start": 532, "end": 536, "text": "[33,", "ref_id": "BIBREF32"}, {"start": 537, "end": 540, "text": "38]", "ref_id": "BIBREF37"}, {"start": 662, "end": 666, "text": "[39]", "ref_id": "BIBREF38"}, {"start": 667, "end": 671, "text": "[40]", "ref_id": "BIBREF39"}, {"start": 672, "end": 676, "text": "[41]", "ref_id": "BIBREF40"}], "ref_spans": []}, {"section": "Introduction", "text": "Genetic evidence supports a conserved requirement for proper nuage assembly in retrotransposon control in the germline. In Drosophila, mutants of PIWI, aubergine (AUB), AGO3, the RNA helicases VASA and armitage (ARMI), and TUDOR-domain containing proteins krimper (KRIMP) and spindle-E (SPN-E) have defects in piRNA synthesis and retrotransposon control. In Drosophila, the interaction of two PIWI family members with opposite strand polarity during nuage assembly has also been proposed to facilitate the ''ping-pong'' mechanism of amplification necessary for retrotransposon inhibition [42] . piRNA defects and derepression of retrotransposons in germ cells also occurs in zebrafish ZILI and ZIWI mutants [43, 44] . Consistent with a key role of these nuage-associated proteins in the mammalian male germline, knockouts of Mvh, Mael, Mili, and Miwi2 block at the spermatocyte stage, while knockouts of TDRD1, TDRD6, and MIWI disrupt spermatogenesis at the spermatid stage. With the exception of MVH, which has not been assessed for these defects, all other nuage mutants with a spermatocyte arrest have defects in retrotransposon regulation and piRNA production [7, 20, 35, 38, [45] [46] [47] [48] .", "cite_spans": [{"start": 588, "end": 592, "text": "[42]", "ref_id": "BIBREF41"}, {"start": 707, "end": 711, "text": "[43,", "ref_id": "BIBREF42"}, {"start": 712, "end": 715, "text": "44]", "ref_id": "BIBREF43"}, {"start": 1164, "end": 1167, "text": "[7,", "ref_id": "BIBREF5"}, {"start": 1168, "end": 1171, "text": "20,", "ref_id": "BIBREF19"}, {"start": 1172, "end": 1175, "text": "35,", "ref_id": "BIBREF34"}, {"start": 1176, "end": 1179, "text": "38,", "ref_id": "BIBREF37"}, {"start": 1180, "end": 1184, "text": "[45]", "ref_id": "BIBREF44"}, {"start": 1185, "end": 1189, "text": "[46]", "ref_id": "BIBREF45"}, {"start": 1190, "end": 1194, "text": "[47]", "ref_id": "BIBREF46"}, {"start": 1195, "end": 1199, "text": "[48]", "ref_id": "BIBREF47"}], "ref_spans": []}, {"section": "Introduction", "text": "GASZ is a 475 amino acid Germ cell-specific protein with four Ankyrin repeats, a Sterile alpha motif, and a basic leucine Zipper domain [49] that is conserved across vertebrate evolution in amphibians, fish, birds, and mammals [50] . Our previous studies have shown that GASZ localizes to the Balbiani body, a nuage structure in Xenopus laevis oocytes. The high degree of evolutionary conservation of GASZ in vertebrates and the potential localization of GASZ to a conserved germline-specific structure stimulated our interest to determine the expression and essential roles of GASZ in nuage and its germline function in mammals.", "cite_spans": [{"start": 136, "end": 140, "text": "[49]", "ref_id": "BIBREF48"}, {"start": 227, "end": 231, "text": "[50]", "ref_id": "BIBREF49"}], "ref_spans": []}, {"section": "Results", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Knockout of GASZ Results in Male Sterility", "text": "To define the roles of GASZ in mammals, a null mutation in Gasz was generated (Figure 1 ). Gasz +/2 mice were viable and produced pups (1.0060.01 litters/month; 8.2560.29 pups/litter, n = 10) whose genotypes were consistent with Mendelian ratios (25.9% WT, 48.5% Gasz +/2 , 25.7% Gasz 2/2 ; n = 495) indicating that GASZ is not essential for embryogenesis. Whereas Gasz 2/2 females were fertile (0.9560.02 litters/month; 6.1660.32 pups/ litter), Gasz 2/2 males were sterile. Furthermore, although GASZ is a maternal effect protein [49] , observed in early preimplantation embryos, the viability of offspring from Gasz null females (i.e., oocytes lacking Gasz mRNA) indicates that maternal GASZ is also not required.", "cite_spans": [{"start": 531, "end": 535, "text": "[49]", "ref_id": "BIBREF48"}], "ref_spans": [{"start": 78, "end": 87, "text": "(Figure 1", "ref_id": "FIGREF0"}]}, {"section": "Gasz", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "2/2 Males Demonstrate a Defect in Meiosis", "text": "To define the cause of the infertility in Gasz 2/2 males, postnatal testes were analyzed grossly and histologically ( Figure 2 ). Testes from Gasz 2/2 males were significantly smaller (P,0.0001) than Gasz +/2 or WT littermates ( Figure 1A ). Six-week-old Gasz Figure 2H ), the seminiferous tubules of 6-week-old Gasz 2/2 testes showed markedly reduced spermatocytes, no post-meiotic spermatids or spermatozoa, and significant vacuolization ( Figure 2I-2K) . The most mature meiotic cells in seminiferous tubules from stages VII-XII were early meiotic germ cells while those from stages I-VI showed a mixture of degenerating spermatocytes. Gasz 2/2 and Gasz +/2 testes at postnatal day 5 (P5) were similar at the gross and histologic levels ( Figure S1 ). At postnatal day 10 (P10),", "cite_spans": [], "ref_spans": [{"start": 118, "end": 126, "text": "Figure 2", "ref_id": "FIGREF1"}, {"start": 229, "end": 238, "text": "Figure 1A", "ref_id": "FIGREF0"}, {"start": 260, "end": 269, "text": "Figure 2H", "ref_id": "FIGREF1"}, {"start": 442, "end": 455, "text": "Figure 2I-2K)", "ref_id": "FIGREF1"}, {"start": 742, "end": 751, "text": "Figure S1", "ref_id": "FIGREF0"}]}, {"section": "Author Summary", "text": "Many aspects of RNA processing are essential for or prominent in the differentiation of germ cells. Some RNA metabolism in animal germ cells is associated with physical structures surrounding the cell nucleus called nuage. Nuage has a distinct granular appearance prior to the meiotic divisions with unclear functions. We have identified a protein called GASZ, which plays a structural role in this early nuage. In mice lacking GASZ, retrotransposonsendogenous viral-like particles-become released from their typical repressed state in the germline by the loss of small RNAs called piRNAs, resulting in DNA damage and delayed germ cell maturation. Protection of the germline from genetic intruders may require the association of piRNA-synthesizing enzymes and other components of this nuage structure through direct or indirect associations with GASZ. Mutations in GASZ and other nuage components may contribute to infertility in men who do not produce spermatozoa.", "cite_spans": [], "ref_spans": []}, {"section": "Author Summary", "text": "the composition of Gasz 2/2 testes ( Figure 2C ) had not changed substantially in composition, whereas Gasz +/2 testes ( Figure 2B ) had advanced to contain preleptotene and leptotene spermatocytes. At P12, Gasz 2/2 testes ( Figure 2E ) contained predominantly spermatogonia with only 25% of the tubules containing preleptotene spermatocytes but no leptotene spermatocytes as compared with Gasz +/2 testes where more advanced zygotene spermatocytes were present ( Figure 2D ). By P14, Gasz 2/2 testes displayed early pachytene germ cell loss due to apoptosis ( Figure S3 ), with the most advanced germ cells being zygotene spermatocytes ( Figure 2G ), while Gasz +/2 testes ( Figure 2F ) had advanced to the mid-pachytene stage. Thus, histological analysis supports a consistent delay in Gasz 2/2 spermatogenesis beginning at meiotic prophase. Gasz", "cite_spans": [], "ref_spans": [{"start": 37, "end": 46, "text": "Figure 2C", "ref_id": "FIGREF1"}, {"start": 121, "end": 130, "text": "Figure 2B", "ref_id": "FIGREF1"}, {"start": 225, "end": 234, "text": "Figure 2E", "ref_id": "FIGREF1"}, {"start": 464, "end": 473, "text": "Figure 2D", "ref_id": "FIGREF1"}, {"start": 561, "end": 570, "text": "Figure S3", "ref_id": "FIGREF3"}, {"start": 639, "end": 648, "text": "Figure 2G", "ref_id": "FIGREF1"}, {"start": 676, "end": 685, "text": "Figure 2F", "ref_id": "FIGREF1"}]}, {"section": "2/2", "text": "spermatogenesis fails at an identical point in juveniles and young adults. However, by 6 months of age, there are few germ cells in the To further confirm our histological findings, we analyzed several genes that are expressed in spermatocytes ( Figure S2 and Figure S3 ). cH2AX is expressed from late spermatogonia through pachytene spermatocytes [51] . cH2AX shifts from staining autosomes to the XY body in pachytene spermatocytes. XY body staining by cH2AX was absent from Gasz 2/2 testes, in contrast to Gasz +/2 testes ( Figure S2 ). Instead, cH2AX labeled autosomes similar to Gasz +/2 early spermatocytes or dying spermatocytes with increased intensity. Our findings are reminiscent of MILI, MIWI2, and MVH knockout mouse models that demonstrate male sterility due to a zygotene:pachytene block but normal female fertility [7, 38, 45] .", "cite_spans": [{"start": 348, "end": 352, "text": "[51]", "ref_id": "BIBREF50"}, {"start": 831, "end": 834, "text": "[7,", "ref_id": "BIBREF5"}, {"start": 835, "end": 838, "text": "38,", "ref_id": "BIBREF37"}, {"start": 839, "end": 842, "text": "45]", "ref_id": "BIBREF44"}], "ref_spans": [{"start": 246, "end": 255, "text": "Figure S2", "ref_id": "FIGREF1"}, {"start": 260, "end": 269, "text": "Figure S3", "ref_id": "FIGREF3"}, {"start": 527, "end": 536, "text": "Figure S2", "ref_id": "FIGREF1"}]}, {"section": "GASZ Is a Component of the Intermitochondrial Cement and Co-Localizes with MILI", "text": "GASZ is present at low levels in the cytoplasm of type A and B spermatogonia and pre-leptotene spermatocytes, showing peak intensity in middle to late pachytene spermatocytes, and localizing to finer granules in the cytoplasm of round spermatids ( Figure S4 and Figure S5 ). Using antibodies against mitochondrial cytochrome c, GASZ was confirmed to localize to the interstices of spermatocyte mitochondrial clusters (i.e., intermitochondrial cement) ( Figure 3A and inset), consistent with our previous findings that GASZ localizes to nuage in frog oocytes [50] . GASZ partially co-localizes with TDRD1 and MVH in the intermitochondrial cement ( Figure 3B-3I ) and displays a substantial overlap with MILI in spermatocytes ( Figure 3J-3L ). Whereas TDRD1 and MVH relocalize to the chromatoid body in spermatids ( Figure 3E and 3F), GASZ fails to do so and also shows no relationship with unclustered mitochondria ( Figure 3D ). In late pachytene spermatocytes MIWI and GASZ also overlap ( Figure S6 ). MVH shows intense granular distribution in Gasz +/2 testes but is dramatically reduced in the Gasz 2/2 spermatocytes ( Figure S7 ). We also analyzed the relationship of GASZ and MILI at earlier time points to assess their interaction in immature germ cells. MILI was present in perinuclear granules in cell cycle arrested gonocytes of newborn mice ( Figure 3N ) in a distribution similar to that described in embryonic male germ cells [13] . There is a significant overlap between GASZ and MILI in newborn gonocytes ( Figure 3M-3O) . We compared the immunostaining of nuage proteins in the newborn Gasz 2/2 testis versus controls. TDRD1 was reduced but also diffusely cytoplasmic, failing to localize in a perinuclear granular pattern ( Figure 4B ). MILI was strikingly absent from the same GASZ null gonocytes ( Figure 4F ). MVH immunostaining also showed reduced granular localization ( Figure 4J ). Analysis of TDRD1 ( Figure 4D ) and MVH ( Figure 4L ) at E16.5 revealed a similar delocalization of these proteins in GASZ null gonocytes. However, MILI staining of E16.5 gonocytes ( Figure 4H ) was variable; in most germ cells, MILI staining was absent, whereas in only 2.25% (5 out of 222 gonocytes) granular MILI staining remained.", "cite_spans": [{"start": 558, "end": 562, "text": "[50]", "ref_id": "BIBREF49"}, {"start": 1438, "end": 1442, "text": "[13]", "ref_id": "BIBREF12"}], "ref_spans": [{"start": 248, "end": 257, "text": "Figure S4", "ref_id": "FIGREF4"}, {"start": 262, "end": 271, "text": "Figure S5", "ref_id": "FIGREF5"}, {"start": 453, "end": 462, "text": "Figure 3A", "ref_id": "FIGREF3"}, {"start": 647, "end": 659, "text": "Figure 3B-3I", "ref_id": "FIGREF3"}, {"start": 726, "end": 738, "text": "Figure 3J-3L", "ref_id": "FIGREF3"}, {"start": 814, "end": 823, "text": "Figure 3E", "ref_id": "FIGREF3"}, {"start": 916, "end": 925, "text": "Figure 3D", "ref_id": "FIGREF3"}, {"start": 990, "end": 999, "text": "Figure S6", "ref_id": "FIGREF6"}, {"start": 1122, "end": 1131, "text": "Figure S7", "ref_id": "FIGREF7"}, {"start": 1353, "end": 1362, "text": "Figure 3N", "ref_id": "FIGREF3"}, {"start": 1521, "end": 1534, "text": "Figure 3M-3O)", "ref_id": "FIGREF3"}, {"start": 1740, "end": 1749, "text": "Figure 4B", "ref_id": "FIGREF4"}, {"start": 1816, "end": 1825, "text": "Figure 4F", "ref_id": "FIGREF4"}, {"start": 1892, "end": 1901, "text": "Figure 4J", "ref_id": "FIGREF4"}, {"start": 1925, "end": 1934, "text": "Figure 4D", "ref_id": "FIGREF4"}, {"start": 1947, "end": 1956, "text": "Figure 4L", "ref_id": "FIGREF4"}, {"start": 2088, "end": 2097, "text": "Figure 4H", "ref_id": "FIGREF4"}]}, {"section": "GASZ Interaction Affects the Level of Intermitochondrial Cement Proteins", "text": "To study GASZ protein:protein interactions, we screened a P17 testis library by yeast two-hybrid analysis using full-length GASZ as bait. We found GASZ interacts with itself and RANBP9 ( Figure 5A ), a known MVH interactor that also localizes to nuage and the chromatoid body [52] . MIWI, but not MILI, or MVH, also directly interacts with GASZ ( Figure 5B ). Antibodies to GASZ could co-immunoprecipitate MIWI, TDRD1, and MVH, but not MILI or MAEL from P21 testes ( Figure 5C ). Conversely, antibodies to MIWI could also co-immunoprecipitate GASZ ( Figure 5D ). We observed a striking reduction in the amount of multiple intermitochondrial cement proteins in Gasz 2/2 testis lysates at P21 as well as at times prior to the observed spermatocyte loss ( Figure 5E ). Multiple interactions between these nuage proteins suggest that GASZ is a component of this network. Quantitative RT-PCR showed relatively modest reduction (roughly 2-fold) in the intermitochondrial cement mRNAs in contrast to their change in protein abundance ( Figure S8 and Table S1 ). Our findings by Western blot analysis were consistent with reduced MVH immunostaining of spermatocytes ( Figure S7 ) and absence of MILI in gonocytes ( Figure 4 ). We also examined newborn testes by electron microscopy for the presence of intermitochondrial cement. Although we could find nuage material associated with clustered mitochondria in most neonatal gonocytes in controls, we failed to detect this structure in Gasz 2/2 germ cells ( Figure S9 ). Our results indicate that GASZ plays a key role in the formation and/or maintenance of this network of RNA processing proteins.", "cite_spans": [{"start": 276, "end": 280, "text": "[52]", "ref_id": "BIBREF51"}], "ref_spans": [{"start": 187, "end": 196, "text": "Figure 5A", "ref_id": "FIGREF5"}, {"start": 347, "end": 356, "text": "Figure 5B", "ref_id": "FIGREF5"}, {"start": 467, "end": 476, "text": "Figure 5C", "ref_id": "FIGREF5"}, {"start": 550, "end": 559, "text": "Figure 5D", "ref_id": "FIGREF5"}, {"start": 753, "end": 762, "text": "Figure 5E", "ref_id": "FIGREF5"}, {"start": 1029, "end": 1038, "text": "Figure S8", "ref_id": "FIGREF9"}, {"start": 1043, "end": 1051, "text": "Table S1", "ref_id": "TABREF5"}, {"start": 1160, "end": 1169, "text": "Figure S7", "ref_id": "FIGREF7"}, {"start": 1207, "end": 1215, "text": "Figure 4", "ref_id": "FIGREF4"}]}, {"section": "Absence of GASZ Causes Hypomethylation of Retrotransposons and Their Increased Expression", "text": "There is increased retrotransposon transcription in MILI and MIWI2 null testes [7, 38] , and dying Gasz 2/2 spermatocytes have a characteristic chromatin pattern similar to these knockouts. Because of these similarities and GASZ association with MIWI, we measured levels of the retrotransposons intracisternal A particle (IAP) and long interspersed nuclear element 1 (Line L1) in the testes of P14 Gasz 2/2 mice. Quantitative RT-PCR demonstrated up to a 15-fold increase (p,0.05) in Line L1 and up to a 4-fold increase in IAP mRNA (p,0.05) in the postnatal Gasz 2/2 testis as well as similar increases in embryonic testes compared to controls ( Figure 6A and 6B). The largest increases were seen in the Line L1 ORF2 (encoding the reverse transcriptase and endonuclease domains) and IAP GAG mRNAs at P14. We saw even more dramatic increases in IAP GAG protein and Line L1 ORF1p. At P14, levels of IAP GAG and Line L1 ORF1p proteins are essentially undetectable in the WT samples but significantly upregulated in the Gasz 2/2 testes ( Figure 6C ). Likewise, in gonocytes of control newborn (P0) mice, retrotransposon proteins IAP GAG and Line L1 ORF1p were undetectable but were dramatically elevated in the cytoplasm of the Gasz 2/2 gonocytes ( Figure 6D -6G).", "cite_spans": [{"start": 79, "end": 82, "text": "[7,", "ref_id": "BIBREF5"}, {"start": 83, "end": 86, "text": "38]", "ref_id": "BIBREF37"}], "ref_spans": [{"start": 645, "end": 654, "text": "Figure 6A", "ref_id": "FIGREF6"}, {"start": 1033, "end": 1042, "text": "Figure 6C", "ref_id": "FIGREF6"}, {"start": 1244, "end": 1253, "text": "Figure 6D", "ref_id": "FIGREF6"}]}, {"section": "Absence of GASZ Causes Hypomethylation of Retrotransposons and Their Increased Expression", "text": "Consistent with compromised transposable element DNA methylation seen in MILI and MIWI2 null testes, we found significant hypomethylation of presumed germ cell-derived Line L1 and IAP sequences in Gasz 2/2 testes compared to controls at P14 ( Figure 6H ). Sequences demonstrating appropriate methylation in the Gasz knockout may reflect the presence of admixed somatic cell DNA. Thus, the delayed meiotic initiation and spermatocyte apoptosis in the Gasz 2/2 testes are likely secondary to abnormal derepression of retrotransposons in the male germline at the transcriptional and post-transcriptional levels.", "cite_spans": [], "ref_spans": [{"start": 243, "end": 252, "text": "Figure 6H", "ref_id": "FIGREF6"}]}, {"section": "Suppression of PIWI-Interacting RNAs (piRNAs) in GASZ Null Testes", "text": "Since increased retrotransposon expression in MILI and MIWI2 null germ cells has been ascribed to the loss of repression by repeat-associated RNAs, we evaluated their abundance by small RNA sequencing of P7, P10 and P14 Gasz +/2 and Gasz 2/2 testes using the Illumina Next Generation Sequencing platform that yields over 2 million sequence reads per sample. Control testes showed an increase in pachytene piRNAs at P14, resulting in a proportional reduction in miRNA reads contributing to the overall small RNA pool. By contrast, Gasz 2/2 testes failed to induce piRNAs, and the small RNAome (17-40 nt) was dominated by miRNAs in Gasz 2/2 testes compared to controls (71% vs. 44%, Figure 7A ). However, the overall miRNA profiles (the subset of miRNAs expressed and relative abundance) were strikingly similar in both genotypes suggesting that miRNA biogenesis and function are likely intact in the absence of GASZ; the relative increase in miRNA read abundance is a consequence of reduced piRNA sequences within a fixed sample of small RNA reads. MicroRNAs have been shown to be present in the chromatoid body, but based on our analysis, they are clearly present prior to the appearance of this structure. This observation suggests that the formation of the intermitochondrial cement and chromatoid body are not required for microRNA biogenesis, but might be important for their action on target mRNAs.", "cite_spans": [], "ref_spans": [{"start": 681, "end": 690, "text": "Figure 7A", "ref_id": "FIGREF7"}]}, {"section": "Suppression of PIWI-Interacting RNAs (piRNAs) in GASZ Null Testes", "text": "After excluding potential contributions to the Gasz null phenotype by miRNAs, we analyzed the remaining small RNAs in greater detail. This analysis revealed that most non-repeatassociated piRNAs showed a skewed distribution with 6% contributing 95-99% of the reads. There was a similar low number of known non-repeat-associated piRNAs in the control and null samples at P10 (Figure 7A ), consistent with previous studies demonstrating a robust increase at P14 pachytene stage in wild-type testes [6] . Non-repeat-associated piRNAs contributed only 14% of the piRNA reads in control testes at this age. However, 99% of the 6500 non-repeat-associated piRNAs detected in control P10 testes were reduced in Gasz 2/2 testes, 87% to undetectable levels. The decline was even more dramatic in P14 Gasz 2/2 testes when many more piRNAs are produced in the control testes ( Figure 7B and Table S2 ). Although the delayed spermatogenic development and apoptotic loss of spermatocytes could preclude the expression of these piRNAs in Gasz 2/2 testes, the concurrent increase in miRNAs and expression of prepachytene piRNAs, normally abundant by P8 [6] , indicate that these two effects are unlikely to be the cause. Over 1500 of 1700 distinct non-repeat-associated RNAs (92%) with greater abundance at P7 versus P14 were substantially reduced, and 1418 of these (90%) displayed a sustained reduction at subsequent time-points (Table S2). Twenty-seven of the 100 small RNAs displaying a relative increase in Gasz 2/2 testes appeared to be variants of miRNAs or potential passenger strands, many mapping to a miRNA cluster on the X chromosome (Table S3) . Two additional 22-23 nt sequences, DQ712837 mapping to Small Cajal body specific RNA 15 (Scarna15) and DQ688886 mapping to an intron of 1700041C02Rik, contributed 40% of the ''piRNA'' reads remaining in Gasz 2/2 testes. The 127 nt Scarna15 is predicted to form two stem-loops and DQ712837 derives from the stem of the second stem-loop. If we exclude these two likely misannotated Dicerdependent small RNAs, the non-repeat-associated piRNAs reads are 99% reduced.", "cite_spans": [{"start": 496, "end": 499, "text": "[6]", "ref_id": "BIBREF4"}, {"start": 1137, "end": 1140, "text": "[6]", "ref_id": "BIBREF4"}], "ref_spans": [{"start": 374, "end": 384, "text": "(Figure 7A", "ref_id": "FIGREF7"}, {"start": 865, "end": 874, "text": "Figure 7B", "ref_id": "FIGREF7"}, {"start": 879, "end": 887, "text": "Table S2", "ref_id": "TABREF6"}]}, {"section": "Suppression of PIWI-Interacting RNAs (piRNAs) in GASZ Null Testes", "text": "Control testes express an abundance of repeat-associated small RNAs compared to the Gasz 2/2 testes ( Figure 7A and Table S4 ), which fall into two size categories that peak at 22 and 27 nt ( Figure  S10A ). While there is a small peak at 22 nt in Gasz 2/2 testes, the 27 nt peak is essentially absent. To analyze the repeat-associated piRNAs, we excluded all sequences whose length was not 25-29 nt. Many of the 19-23 nt sequences map to SINEs ( Figure  S10D and Figure S10E and Table S3 ) and typically show less than a two-fold change. These SINE-associated small RNAs belong to a novel small RNA class that are cleaved from their precursor RNA by a Dicer-dependent but DGCR8-independent mechanism [53] . We also excluded 19-23 nt sequences that did not map to SINEs as potential Dicer-dependent endo-siRNAs ( Figure S10F and Figure S10G ). All 25-29 nt repeat-associated RNAs were classified as repeat-associated piRNAs ( Figure 7C ). These repeat-associated piRNAs map to LTRs (e.g., ERV-K IAPLTR1a_I_MM and MaLR MTA_Mm_LTR) or LINEs (L1_MM), and are 10 to 100-fold less abundant in Gasz 2/2 testes ( Figure S10B and Figure  S10C and Table S4 ). The majority of the 25-29 nt repeatassociated piRNAs contained a U at position 1 and an A at position 10 ( Figure S10H ), characteristic of participation in the ''ping-pong'' synthesis reaction [54] . In contrast, the 19-23 nt repeat-associated small RNAs had an initial U but a variable position 10 ( Figure S10I ), suggesting a lack of amplification by the ''ping-pong'' mechanism and confirming that these sequences are unlikely to be synthesized by the piRNA machinery. Subsequent analysis showed that the biggest difference in repeat-associated piRNAs occurred at P7 when many more elements were affected. Thus, the defect in repeat-associated piRNA production preceding delayed meiotic prophase initiation in Gasz 2/2 testes is a cause rather than an effect of this process.", "cite_spans": [{"start": 701, "end": 705, "text": "[53]", "ref_id": "BIBREF52"}, {"start": 1345, "end": 1349, "text": "[54]", "ref_id": "BIBREF53"}], "ref_spans": [{"start": 102, "end": 111, "text": "Figure 7A", "ref_id": "FIGREF7"}, {"start": 192, "end": 204, "text": "Figure  S10A", "ref_id": "FIGREF0"}, {"start": 447, "end": 459, "text": "Figure  S10D", "ref_id": "FIGREF0"}, {"start": 464, "end": 475, "text": "Figure S10E", "ref_id": "FIGREF0"}, {"start": 813, "end": 824, "text": "Figure S10F", "ref_id": "FIGREF0"}, {"start": 829, "end": 840, "text": "Figure S10G", "ref_id": "FIGREF0"}, {"start": 926, "end": 935, "text": "Figure 7C", "ref_id": "FIGREF7"}, {"start": 1106, "end": 1117, "text": "Figure S10B", "ref_id": "FIGREF0"}, {"start": 1122, "end": 1134, "text": "Figure  S10C", "ref_id": "FIGREF0"}, {"start": 1258, "end": 1269, "text": "Figure S10H", "ref_id": "FIGREF0"}, {"start": 1453, "end": 1464, "text": "Figure S10I", "ref_id": "FIGREF0"}]}, {"section": "Suppression of PIWI-Interacting RNAs (piRNAs) in GASZ Null Testes", "text": "Initially, 25% of the small RNAs sequences (.1 million reads) in control testes were unclassified. The majority of the unclassified sequences were 25-29 nt ( Figure 7D and Figure S10J ), but a 19-23 nt class was also present ( Figure S10K ). The majority of these unclassified RNAs possess a 59 U but a variable 10 th position ( Figure S10L ). Because of their similarity to piRNAs, we term the 25-29 nt category of unclassified sequences as ''putative piRNAs'' while the smaller size category called ''unknown small RNAs'' may contain novel miRNAs or other Dicer-dependent small RNAs. ''Putative piRNA'' reads were reduced compared to controls at P7 (7.9% versus 0.29%), P10 (1.6% versus 16.9%) and P14 (5.10% versus 0.91%) ( Figure 7D ). These findings indicate that GASZ plays a major role prior to the pachytene stage in facilitating the production of multiple types of piRNAs, including those associated with repeats involved in regulation of retrotransposons.", "cite_spans": [], "ref_spans": [{"start": 158, "end": 167, "text": "Figure 7D", "ref_id": "FIGREF7"}, {"start": 172, "end": 183, "text": "Figure S10J", "ref_id": "FIGREF0"}, {"start": 227, "end": 238, "text": "Figure S10K", "ref_id": "FIGREF0"}, {"start": 329, "end": 340, "text": "Figure S10L", "ref_id": "FIGREF0"}, {"start": 727, "end": 736, "text": "Figure 7D", "ref_id": "FIGREF7"}]}, {"section": "Discussion", "text": "GASZ was initially identified by our group as a male and female germ cell and maternal effect gene product [49] . Herein, we show that GASZ is not essential for fertility in the female germline. In contrast, absence of GASZ leads to male sterility due to a block at the zygotene-pachytene transition, reminiscent of the defect that is observed in knockouts of two PIWI family members, MILI and MIWI2 [7, 11, 38] . In frog oocytes, GASZ is expressed in the Balbiani body, a nuage structure [50] . Similarly, we show here that GASZ localizes to nuage in testicular primordial germ cells, gonocytes, spermatogonia, and spermatocytes. Using various markers, GASZ appears to be a component of the nuage termed intermitochondrial cement. We show that many nuage proteins depend upon GASZ for their normal levels. Aside from MIWI, which is expressed in germ cell types absent in the Gasz knockout, the reduction of MILI, MAEL, MVH, TDRD1, TDRD6, and TDRD7 in Gasz 2/2 testicular lysates likely reflects destabilization of this entire ultrastructural feature. TDRD1 and MVH become mislocalized in gonocytes and they become subsequently lost during postnatal spermatogenesis, suggesting that the loss of nuage proteins may result secondary to degradation following persistent failure to localize to germinal granules. The lesser change in MVH protein in GASZ null testes at P10 may indicate that MVH is less dependent upon GASZ than are the remaining nuage proteins. Perhaps this effect is due to additional proteins functionally redundant with GASZ or that MVH has a greater intrinsic stability in the absence of GASZ than other nuage proteins. Protein-protein interaction motifs in GASZ, including ankyrin domains, a sterile alpha motif, and a leucine zipper, may serve to direct the association and/or stabilization of nuage proteins. GASZ self-interaction may suggest the protein forms multimeric complexes as part of this function. A model depicting direct interactions within the nuage and proposed GASZ placement within this protein complex is provided ( Figure S11 ).", "cite_spans": [{"start": 107, "end": 111, "text": "[49]", "ref_id": "BIBREF48"}, {"start": 400, "end": 403, "text": "[7,", "ref_id": "BIBREF5"}, {"start": 404, "end": 407, "text": "11,", "ref_id": "BIBREF10"}, {"start": 408, "end": 411, "text": "38]", "ref_id": "BIBREF37"}, {"start": 489, "end": 493, "text": "[50]", "ref_id": "BIBREF49"}], "ref_spans": [{"start": 2053, "end": 2063, "text": "Figure S11", "ref_id": "FIGREF0"}]}, {"section": "Discussion", "text": "The Gasz null mice phenocopy the loss of MILI. Since the TDRD1:MILI interaction is critical [33, 48] and absence of GASZ leads to disruption of the TDRD1 distribution in the cytoplasm (Figure 4 ), MILI could be physically dislodged from its granule position in Gasz null germ cells leading to a subsequent destabilization of MILI. Although formation of intermitochondrial cement is disrupted in both Tdrd1 2/2 and Gasz 2/2 germ cells, MILI is only unstable in Gasz null cells indicating a distinct role for GASZ in stabilization of MILI. As we have shown, that all but 2.2% of germ cells at E16.5 contain MILI, and at P0, MILI is absent. Similar to the Mili null mice [6, 11, 38] , the absence of MILI in the Gasz knockout, is believed to mechanistically disrupt piRNA synthesis, resulting in an increase in retrotransposons and subsequent catastrophe for the male germ line. The current model for maintenance of transposable element repression in the germline involves the production of piRNAs by PIWI family members MILI and MIWI2 in embryonic and postnatal germ cells [6, 7] . Repeat-associated piRNAs are abundant in embryonic germ cells coincident with DNA remethylation of retrotransposons in the male germline at E17.5. GASZ is expressed in embryonic testes and co-localizes with MILI in fetal and newborn gonocytes. Transcriptional regulation of retrotransposons by antisense repeatassociated piRNAs, bound to MIWI2, whose nuclear localization depends upon MILI, has been proposed [13] . Consistent with the proposed mechanism, we observe a similar reduction of promoter methylation of IAP and Line L1 in Gasz 2/2 testes as observed in Mili 2/2 and Miwi2 2/2 testes. Mechanistically, absence of Gasz and the consequent loss of MILI and MILI-mediated retrotransposon repression affects fetal gonocytes during the interval that retrotransposon remethylation normally occurs. Although there is a continuity of the cell cycle arrest in male gonocytes between E16.5 and P0, the shift in Gasz null testes at E16.5 from slightly detectable MILI to its absence suggests that nuage is changing during this interval despite a lack of cell cycle progression. However, both MVH and TDRD1 displayed similar behavior in Gasz null testes at E16.5 and P0. Although we can find a direct interaction between GASZ and MIWI, we could not find evidence for direct interaction between GASZ and MILI. We speculate that a GASZ-MILI interaction occurs indirectly though other mediators. MVH can interact with MILI and MIWI [38] , as can TDRD1 [33, 48] both of which co-immunoprecipitate with GASZ. As shown in Figure 5A , GASZ interacts with RANBP9 and MIWI, known MVH interactors. Thus a large complex of proteins may be required for co-localization of GASZ with MILI and its support of MILI function in retrotransposon control. The inability to co-immunoprecipitate GASZ and MILI may suggest that MILI is more weakly ''linked'' to GASZ in this complex.", "cite_spans": [{"start": 92, "end": 96, "text": "[33,", "ref_id": "BIBREF32"}, {"start": 97, "end": 100, "text": "48]", "ref_id": "BIBREF47"}, {"start": 668, "end": 671, "text": "[6,", "ref_id": "BIBREF4"}, {"start": 672, "end": 675, "text": "11,", "ref_id": "BIBREF10"}, {"start": 676, "end": 679, "text": "38]", "ref_id": "BIBREF37"}, {"start": 1071, "end": 1074, "text": "[6,", "ref_id": "BIBREF4"}, {"start": 1075, "end": 1077, "text": "7]", "ref_id": "BIBREF5"}, {"start": 1489, "end": 1493, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 2506, "end": 2510, "text": "[38]", "ref_id": "BIBREF37"}, {"start": 2526, "end": 2530, "text": "[33,", "ref_id": "BIBREF32"}, {"start": 2531, "end": 2534, "text": "48]", "ref_id": "BIBREF47"}], "ref_spans": [{"start": 184, "end": 193, "text": "(Figure 4", "ref_id": "FIGREF4"}, {"start": 2593, "end": 2602, "text": "Figure 5A", "ref_id": "FIGREF5"}]}, {"section": "Discussion", "text": "Most of the nuage protein mutants that block in meiotic prophase have defects in repeat-associated piRNAs. Nuage protein knockouts cause two types of spermatogenic defects -those that block during meiotic prophase (including MVH, MILI, MIWI2 and MAEL) and those that block during haploid differentiation (including DDX25, MIWI, TDRD1, and TDRD6). In the latter class, Tdrd1 2/2 and Miwi 2/2 testes do not have altered repeatassociated piRNAs, both of which block at the spermatid stage and do not appear to have defects in stem cell maintenance. Nearly all of the former class possesses some defect in piRNA biosynthesis, but repeat-associated piRNAs are not altered in all mutants of this class. Like GASZ, disruption of MILI and MIWI2 result in an absence of repeat-associated piRNAs and a meiotic block prior to the loss of all germ cells from seminiferous tubules by 6 months of age [6, 11, 38] . The Mael 2/2 testis phenotype is unique in showing isolated pachytene piRNA defects but blocking during meiotic prophase with elevated retrotransposons [46] . An important gap in our knowledge is whether Mvh 1098/1098 testes display repeatassociated piRNA defects and elevated retrotransposons similar to vasa mutants in Drosophila [55] and the majority of piRNA pathway mutants blocking during meiotic prophase.", "cite_spans": [{"start": 887, "end": 890, "text": "[6,", "ref_id": "BIBREF4"}, {"start": 891, "end": 894, "text": "11,", "ref_id": "BIBREF10"}, {"start": 895, "end": 898, "text": "38]", "ref_id": "BIBREF37"}, {"start": 1053, "end": 1057, "text": "[46]", "ref_id": "BIBREF45"}, {"start": 1233, "end": 1237, "text": "[55]", "ref_id": "BIBREF54"}], "ref_spans": []}, {"section": "Discussion", "text": "Germ cell apoptosis in Gasz null mice may depend upon retrotransposon expression combined with meiotic defects, representing distinct MILI-dependent functions. The GAG, POL, and PRT proteins are all required for efficient retrotransposition of IAP [56] , but their individual contribution to cellular toxicity has not been described. Line L1 proteins are toxic to cells by several mechanisms including activation of BAX and caspase 3 [57] . Expression of the reverse transcriptase of ORF2 alone causes cellular pathology in cell lines and could inhibit completion of meiotic recombination in nuage protein knockouts through its ability to bind random breaks in DNA [58, 59] . Alternatively, the cause of apoptosis in Gasz 2/2 spermatocytes and nuage knockouts in the meiotic class may be retrotransposon-independent. Two observations suggest MILI regulates meiosis independent of retrotransposons. TDRD1, by preventing the processing of mRNAs into piRNAs, confers specificity in non-repeat piRNA generation by MILI [48] . Line L1 dysregulation in the Tdrd1 2/2 mutant must depend upon the decreased mRNAs or increased unannotated RNAs that results from the shift of the substrate RNA used by MILI to generate piRNAs. Since TDRD1 deficient testes do not block during meiotic prophase despite elevated Line L1 expression, spermatocyte death is unlikely to be due to isolated retrotransposon dysfunction. Missense mutants of the zebrafish MILI ortholog ZILI have isolated meiotic defects but no alterations in retrotransposon expression [43] , indicating MILI's contribution to meiosis and retrotransposon control are separable. Knockout models suggest that homologous chromosome synapsis depends upon functional MILI [11, 38] , MIWI2 [7, 11] and MAEL [46] . Mvh null testes block at the zygotene-pachytene transition but their ability to complete synapsis has not been assessed [45] . Therefore, the apoptotic loss of Gasz 2/2 spermatocytes may not result from retrotransposon-induced DNA damage alone, but could also result from failed MILI-dependent meiotic functions including homologous chromosome synapsis or meiotic recombination. MILI has been proposed to cause general effects on germ cell mRNA translation not limited to control of retrotransposon mRNAs [37] . It is possible that this aspect of MILI function might contribute to the reduction of nuage protein levels in Gasz null testes. Translational control of mRNAs necessary for meiotic prophase by MILI may indirectly affect retrotransposon promoter methylation or post-transcriptional processing of retrotransposon mRNAs in addition to MILI's actions mediated by repeatassociated piRNAs.", "cite_spans": [{"start": 248, "end": 252, "text": "[56]", "ref_id": "BIBREF55"}, {"start": 434, "end": 438, "text": "[57]", "ref_id": "BIBREF56"}, {"start": 665, "end": 669, "text": "[58,", "ref_id": "BIBREF57"}, {"start": 670, "end": 673, "text": "59]", "ref_id": "BIBREF58"}, {"start": 1015, "end": 1019, "text": "[48]", "ref_id": "BIBREF47"}, {"start": 1534, "end": 1538, "text": "[43]", "ref_id": "BIBREF42"}, {"start": 1715, "end": 1719, "text": "[11,", "ref_id": "BIBREF10"}, {"start": 1720, "end": 1723, "text": "38]", "ref_id": "BIBREF37"}, {"start": 1732, "end": 1735, "text": "[7,", "ref_id": "BIBREF5"}, {"start": 1736, "end": 1739, "text": "11]", "ref_id": "BIBREF10"}, {"start": 1749, "end": 1753, "text": "[46]", "ref_id": "BIBREF45"}, {"start": 1876, "end": 1880, "text": "[45]", "ref_id": "BIBREF44"}, {"start": 2261, "end": 2265, "text": "[37]", "ref_id": "BIBREF36"}], "ref_spans": []}, {"section": "Discussion", "text": "The piRNA pathway in mammals is specialized to support male germ cell development. Zebrafish and Drosophila share the requirement for PIWI family-dependent piRNA production for fertility of both sexes [42] [43] [44] ; whereas, it is required only for male fertility in the mouse. GASZ is not correlated with this shift because GASZ orthologs are present in many vertebrates including zebrafish [50] . In the mammalian male germline, GASZ supports piRNA biosynthesis required for initiation of retrotransposon repression during the embryonic period and maintenance during meiotic prophase when alterations to chromatin and transcriptional increase would otherwise be favorable toward their expression. GASZ is the first mammalian germline-and intermitochondrial cement-specific protein lacking domains for RNA modification which impacts piRNA processing by localizing or stabilizing multiple proteins in the nuage including PIWI family members.", "cite_spans": [{"start": 201, "end": 205, "text": "[42]", "ref_id": "BIBREF41"}, {"start": 206, "end": 210, "text": "[43]", "ref_id": "BIBREF42"}, {"start": 211, "end": 215, "text": "[44]", "ref_id": "BIBREF43"}, {"start": 394, "end": 398, "text": "[50]", "ref_id": "BIBREF49"}], "ref_spans": []}, {"section": "Materials and Methods", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Generation of Gasz Mutant Mice and Fertility Studies", "text": "We electroporated the linearized Gasz targeting vector ( Figure  S1A ) into the HPRT-negative AB2.2 ES cell line; selected clones in hypoxanthine, aminopterine, thymidine, and 1-(2 -deoxy-2 fluoro-D-arabinofuranosyl)-5-iodouracil; and screened the ES cell DNA by Southern blot as described [60] to identify the mutant Gasz allele, Gasz tm1Zuk (herein called Gasz 2 ). Correctly targeted clones were identified by using 59 and 39 probes as shown. Targeted ES cell clones were injected into blastocysts to produce chimeric male mice [61] , which were bred to produce C57BL6/ J6129 hybrid F1 Gasz 2/2 offspring. Ten homozygous mutant and heterozygous sires were bred with WT females over a 6-month mating period. Similar mating trials were performed with homozygous mutant and heterozygous dams. Except for testis defects, Gasz 2/2 mice were grossly indistinguishable from their littermates and lived to become adults.", "cite_spans": [{"start": 290, "end": 294, "text": "[60]", "ref_id": "BIBREF59"}, {"start": 531, "end": 535, "text": "[61]", "ref_id": "BIBREF60"}], "ref_spans": [{"start": 57, "end": 68, "text": "Figure  S1A", "ref_id": "FIGREF0"}]}, {"section": "Generation of the Anti-GASZ Antibody and Western Blot Analysis", "text": "Full-length His-tagged GASZ was injected into guinea pigs to produce polyclonal antibodies (Cocalico Biologicals, Reamstown, PA). Membranes with 20 or 50 mg of total testis lysate per lane were probed with guinea pig anti-GASZ (1:1000), rabbit anti-IAP GAG (1:1000), rabbit anti-TDRD1 (1:1000), rabbit anti-TDRD6 (1:1000), rabbit anti-TDRD7 (1:500), rabbit anti-MVH (1:500), rabbit anti-MAELSTROM (1:250 Abcam ab28661), or rabbit anti-MILI (1:250 Abcam ab36764) polyclonal antibodies. After developing, the membrane was stripped and re-probed with antib-actin clone AC-15 (Sigma) at 1:5,000. Secondary anti-guinea pig and anti-mouse horseradish peroxidase-conjugated antibodies (Jackson ImmunoResearch, West Grove, PA) were used at 1:10,000.", "cite_spans": [], "ref_spans": []}, {"section": "Immunohistochemistry, Immunofluorescence, and CoImmunoprecipitation Western Analysis", "text": "Testes were fixed in Bouin's fixative (for histology), 4% paraformaldehyde (immunofluorescence) or 4% paraformaldehyde/6.6% acetic acid (for immunohistochemistry), and embedded in paraffin. Antigen retrieval was performed on 5 mm sections by boiling for 20 minutes in citrate buffer pH 6.0. Samples for immunofluorescence were incubated with rabbit anti-cH2AX (1:5,000; 05-636 Upstate, now Millipore, Billerica, MA), guinea pig anti-GASZ (1:300), rabbit anti-MVH (1:500), rabbit anti-TDRD1 (1:100), rabbit anti-MILI (1:500), rabbit anti-IAP GAG (1:500), rabbit anti-ORF1 (1:500), and mouse anti-cytochrome c (1:300, 556433 BD Biosciences San Jose, CA). Alexa594-conjugated anti-guinea pig, Alexa488-conjugated anti-rabbit, and Alexa488-conjugated anti-mouse antibodies (Jackson ImmunoResearch) were used at 1:500. Sections were mounted with Vectashield mounting medium with DAPI or propidium iodide (Vector Laboratories). Representative images for immunofluorescence were selected and captured on a Zeiss Axiovert s100 2TV. When required, deconvolution was performed with softWoRx v3.3.6 (Applied Precision, Issaquah, WA).", "cite_spans": [], "ref_spans": []}, {"section": "Immunohistochemistry, Immunofluorescence, and CoImmunoprecipitation Western Analysis", "text": "One mg of testicular lysates from WT mice were prepared with 0.5% NP-40 lysis buffer as described previously [62] . Pre-cleared lysates were incubated overnight at 4uC with anti-GASZ, anti-MIWI, or no primary antibody, followed by incubation with protein G beads in 5% BSA to precipitate immune complexes. Coimmunoprecipitating proteins were detected by western blotting with anti-MVH (1:500; ab13840 Abcam Inc, Cambridge, MA), anti-MIWI (1:1000), anti-TDRD1 (1:1000), anti-MVH (1:500; Abcam Cambridge, MA), anti-GASZ (1:500), or b actin as above. Secondary antibodies used were horseradish peroxidase-labeled donkey anti-rabbit, goat anti-mouse, or goat anti-guinea pig (Jackson ImmunoResearch, West Grove, PA). Ten mg of WT and age-matched Gasz 2/2 lysates were used as loading controls.", "cite_spans": [{"start": 109, "end": 113, "text": "[62]", "ref_id": "BIBREF61"}], "ref_spans": []}, {"section": "Meiotic Marker and Apoptosis Evaluation", "text": "To evaluate meiotic progression, slides were incubated with guinea pig anti-GASZ (1:500), rabbit anti-SYCP3 (1:500), or rabbit anti-H1.T (1:1000). Staining was visualized using biotinylated goat anti-rabbit or goat anti-mouse secondary antibodies at 1:200 and the Vectastain ABC Kit according to the manufacturer (Vector Laboratories, Burlingame, CA). TUNEL analysis was performed with three sections from five mice of each genotype for 10-, 21-day-old and 6-week-old mice by using the Chemicon ApopTag Fluorescein In Situ Apoptosis Detection Kit (S7110). Representative images were captured on a Ziess Axioskop (Carl Zeiss MicroImaging, Thornwood, NY).", "cite_spans": [], "ref_spans": []}, {"section": "Yeast Two-Hybrid Screening", "text": "Yeast two-hybrid screening was performed by using CLON-TECH Matchmaker Two-Hybrid Library Construction & Screening Kit. A yeast cDNA library was constructed from 17-day-old mouse testis cDNA. Full-length mouse Gasz cDNA, was subcloned into pGBKT7 vector, and was used as the bait construct for screening a yeast cDNA library constructed from 17-day-old mouse testis cDNA. After yeast mating, clones that grew on (SD Leu-Trp-Ade-His-X-a-Gal) selection plates were isolated, and candidate pGADT7-Rec-cDNAs were sequenced. Interactions were confirmed by mating mouse Gasz bait with prey constructs.", "cite_spans": [], "ref_spans": []}, {"section": "Yeast Two-Hybrid Screening", "text": "To analyze how GASZ interacts with itself and other interacting proteins we generated prey constructs, by using pGADT7, expressing full-length GASZ, MILI, MIWI, and MVH constructs, as well as a RANBP9 construct lacking its proline-rich amino terminus (aa 1-50). Using the CLONTECH Matchmaker BioSensor Kit All constructs were confirmed by DNA sequencing. We made the mating culture by using full-length mouse Gasz bait mated with the prey constructs. Protein-protein interactions were quantified from the resultant fluorescent signal of an equal number of mated cells on a 96 well oxygen biosensor plate post culture for 24 hours using the CLONTECH Matchmaker BioSensor Kit. We added an equal number of mated cells to a 96 well oxygen biosensor plate, cultured the cells at 30uC for 24 hours, and quantified the resultant fluorescent signal.", "cite_spans": [], "ref_spans": []}, {"section": "RT-PCR and QPCR", "text": "Using the Superscript III Reverse Transcriptase Kit (Invitrogen, Rockville, MD) cDNA was synthesized from total mouse testis RNA from mice on embryonic day 18.5 and postnatal days 0, 7, and 14 primed with random hexamers following treatment with Turbo DNA-free (Ambion, Austin, TX). Gasz was PCR amplified using ACCGGTCCTCTCAGAAATTAAAA (forward, 111-133 of NM_023729.2) and ATTGGCGTCATAAGTCTCCTACA (reverse, 455-477 of NM_023729.2) primers. QPCR was performed in duplicate with primers specific to IAP and LINE1 [7] on six 14-day-old animals of each genotype using SYBR Green PCR Master Mix on a 7500 Real Time PCR System machine (Applied Biosystems). Nuage protein mRNAs were similarly quantified using primers designed in Primer Express (Applied Biosystems, Foster City, CA) with the exception of those for Mvh [63] and are described in Table S1 . Relative quantification was performed using Actb or Gapdh as appropriate. Cycle conditions were as follows: one cycle at 50uC for 2 min, followed by 1 cycle at 95uC for 10 min, followed by 40 cycles at 95uC for 15 s and 60uC for 1 min. The relative amount of transcripts was calculated by the DDCT method. SEM was calculated for the duplicate measurements, and the relative amount of target gene transcripts was plotted. Significance was determined using Student t-test.", "cite_spans": [{"start": 512, "end": 515, "text": "[7]", "ref_id": "BIBREF5"}, {"start": 813, "end": 817, "text": "[63]", "ref_id": "BIBREF62"}], "ref_spans": [{"start": 839, "end": 847, "text": "Table S1", "ref_id": "TABREF5"}]}, {"section": "Electron Microscopic Analysis of Nuage", "text": "Testes were removed from newborn mice and drop fixed in a modified Karnovsky's mixture of 2.5% glutaraldehyde, 2% paraformaldehyde plus 2 mM CaCl 2 in 0.1 M cacodylate buffer pH 7.4 overnight at 4uC. After primary fixation, the tissue was rinsed 3 times for 5 minutes in 0.1 M cacodylate buffer pH 7.4. The tissue was then post-fixed in 1% OsO 4 in pH 7.4. The tissue was dehydrated in a gradient series from 30% to 100% ethanol. After ethanol dehydration, the tissue was given 3 changes of fresh propylene oxide for 20 minutes each. The tissue was infiltrated up to 1:1 propylene oxide plus Spurr's Low Viscosity embedding resin. The tissue was placed in individual 00 BEEM capsules and polymerized at 70uC overnight. Thick sections were cut with a HistoDiatome knife on an RCM MT-6000XL ultra-microtome, stained with toluidine blue and examined on a light microscope for orientation. Thin sections were cut at 80 nm using a Diatome Ultra knife on the same ultra-microtome and picked up on 200 mesh copper grids. Thin sections were stained for 15 minutes in a saturated aqueous solution of uranyl acetate, counterstained for 6 minutes with Reynold's lead citrate and examined on a Hitachi H7500 transmission electron microscope. Digital images were captured using Gatan Digital Micrograph software and a Gatan US1000 camera.", "cite_spans": [], "ref_spans": []}, {"section": "Methylation Analysis of LINE L1 and IAP", "text": "Total testicular genomic DNA was recovered from 3 pooled 14-day-old mice by phenol:chloroform extraction and ethanol precipitation. Aliquots of DNA were denatured for 15 minutes at 50uC in 0.3 M NaOH and bisulfite treatment was performed as described in [64] . Briefly, samples were incubated at 50uC overnight with sodium metabisulfite and hydroxyquinone and purified using a modified procedure for a Viral RNA Miniprep kit (Qiagen). Samples were desulfonated in NaOH for 15 minutes, neutralized with HCl, and purified as before. PCRs were performed using Platinum Taq Supermix (Invitrogen) or ExTaq (Takara) using primers described below from [11] to amplify twelve CG dinucleotides in IAP LTR1_Mm ERVK and from [7] to amplify eight CG dinucleotides in L1MD-A2. Each PCR was performed in 4 replicates, which were pooled and purified using a DNA clean-up and concentrator kit (Zymo Research). Amplicons were ligated into pGEM-T Easy vector (Promega) and sequenced. Capital letters in the reference sequences below denote sequences that are complementary to primer binding sites. These do not contain CG dinucleotides, and all cytosine residues are expected to convert during bisulfite treatment. Fifteen mg of total RNA from WT and Gasz 2/2 mouse testes were gel-fractionated to isolate 18-40 nt small RNAs, followed by 39 and 59 adapter ligation, and product amplification by RT-PCR as per the small RNA kit (FC-102-1009, Illumina) protocol. Finally, the small RNA library was sequenced using a Solexa/ Illumina GA-1 Genome analyzer. Small RNA sequences were analyzed through a high-throughput computational pipeline. For each sample, all sequence reads were aligned to a reference set of miRNAs (miRNA pipeline) and all currently identified piRNAs. The reads are also mapped to the reference mouse genome (NCBI Build 37, UCSC mm9) using the Pash software package [65, 66] , and uploaded to Genboree platform (www.genboree.com) to identify snoRNAs, scRNAs and repeat-associated small RNAs. We performed a local Smith-Waterman alignment of each unique sequence read against each of the mature microRNAs in miRBase version 11.0, allowing for a 3 base overhang on the 59 end and a 6 base overhang on the 39 end. The alignments were scored such that a matching or overhanging base counts as 2 points and mismatches as 21. Each unique sequence read which achieves a per-base alignment score of 2 (i.e., a perfect match) was associated with each mature microRNA for which it achieved that score. The read counts of all redundantly aligning reads to multiple hairpins in the genome were equally apportioned to each mature microRNA to which they align. For repeat-associated small RNAs, each mapping is associated with LINEs, SINEs, DNA and RNA repeat subtypes. Reads were also mapped to consensus mouse and mammalian repeats from Repbase [67] , and rasiRNAs [11] using Blat [68] with a sensitive setting only requiring one 8mer seed filtered such that$90% of the reads mapped. All sequences corresponding to repeat-associated piRNAs and putative novel piRNAs have been deposited at piRNABank (http:// pirnabank.ibab.ac.in/) [69] .", "cite_spans": [{"start": 254, "end": 258, "text": "[64]", "ref_id": "BIBREF63"}, {"start": 645, "end": 649, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 714, "end": 717, "text": "[7]", "ref_id": "BIBREF5"}, {"start": 1866, "end": 1870, "text": "[65,", "ref_id": "BIBREF64"}, {"start": 1871, "end": 1874, "text": "66]", "ref_id": "BIBREF65"}, {"start": 2833, "end": 2837, "text": "[67]", "ref_id": "BIBREF66"}, {"start": 2853, "end": 2857, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 2869, "end": 2873, "text": "[68]", "ref_id": "BIBREF67"}, {"start": 3119, "end": 3123, "text": "[69]", "ref_id": "BIBREF68"}], "ref_spans": []}, {"section": "Supporting Information", "text": "Figure S1 testes from 12-day-old mice. H1.T is a testis-specific histone H1 expressed at low levels in early spermatocytes, peaking in late pachytene spermatocytes, and continued expression in round spermatids [71] . While numerous H1.T-positive spermatocytes were detected in Gasz +/2 testes, few H1.T-positive cells were observed in Gasz 2/2 testes composed of predominantly early spermatocytes and rare atypical ''pachytene'' spermatocytes. (E-J) TUNEL analysis was performed on the Gasz +/2 and Gasz 2/2 testes. In Gasz +/2 testes, TUNEL-positive germ cells were rare, predominantly affecting spermatogonia with the exception of 21-day-old testes when there is a normal developmental peak in germ cell apoptosis [72] . In Gasz 2/2 testes at postnatal days 10 and 21 and in the adult, there is enhanced germ cell apoptosis. By their size, location, and abundance, the most dying cells appear to be spermatocytes. Consistent with pachytene spermatocyte loss being restricted to the stages I-VI of the cycle of the seminiferous epithelium ( Figure S5 ), after 14 days of age we observed more inter-tubule variation including tubules lacking TUNEL positive cells. testes. The average number of reads for piRNAs from two Gasz 2/2 (KO) and control testes from postnatal day 7, 10, and 14 (P7, P10, and P14) mice are shown along with their percentage of the total reads from each testis. All piRNAs that were absent or reduced greater than three-fold in Gasz 2/2 from controls are highlighted in gray. piRNAs with greater abundance on D7 and D14 were analyzed separately. piRNA ID is the accession assigned by piRNABank (http://pirnabank.ibab.in) followed by the Genbank accession. The fold-change represents the degree of reduction in Gasz 2/2 from controls and was calculated for age-matched samples. testes were compared to the map positions (UCSC mm9) of mouse pre-miRNAs. The majority of overlapping sequences mapped to a large microRNA cluster on the X chromosome. The ''piRNA'' reads observed and the similar pre-miRNA with mature miRNA sequences in bold are provided. Most of the sequences are identical with mature miRNAs or differ by 1-2 nt at the 39 end. We also observed several piRNAs mapping to the strand of the stem-loop opposite to known miRNAs to which we assigned putative designations. Novel testis piRNA t27 is described in [74] . Found at: doi:10.1371/journal.pgen.1000635.s014 (0.03 MB XLS) Table S4 A subset of repeat-associated small RNAs are reduced in Gasz 2/2 testes. The average number of individual small RNAs from two Gasz 2/2 (KO) and control testes from postnatal day 7 (P7), 10 (P10), and 14 (P14) mice that mapped with greater than 90% identity to individual repeat consensuses are shown along with their percentage of the total reads from each testis. Each repeat is classified according to a class of repeats (LINE, SINE, LTR) and families within that class. The fold reduction of piRNAs in the Gasz 2/2 as compared to controls is shown with those elements reduced 10-fold highlighted in gray. Among those repeats displaying the most dramatic sustained reduction in Gasz null mice included LTRs (LTR45, MER72B, MER87, RLTR10, LTR75, LTR90B, MT2_Mm, MamGyp-Int, MT-Int, MTB-Int, ORR1A0, ORR1A-Int, ORR1A1, and several IAPs) and LINE L1s (L1MD_A, L1Md_F3, L1Md_Gf, Lx2A1). SINE-associated small RNAs, processed by Dicer, are mostly unaffected in Gasz ", "cite_spans": [{"start": 210, "end": 214, "text": "[71]", "ref_id": "BIBREF70"}, {"start": 716, "end": 720, "text": "[72]", "ref_id": "BIBREF71"}, {"start": 2342, "end": 2346, "text": "[74]", "ref_id": "BIBREF73"}], "ref_spans": [{"start": 1042, "end": 1051, "text": "Figure S5", "ref_id": "FIGREF5"}]}], "bib_entries": {"BIBREF0": {"title": "DNA methylation reprogramming in the germ line", "authors": [{"first": "D", "middle": ["J"], "last": "Lees-Murdock", "suffix": ""}, {"first": "C", "middle": ["P"], "last": "Walsh", "suffix": ""}], "year": 2008, "venue": "Epigenetics: Official Journal of the DNA Methylation Society", "link": "23911745"}, "BIBREF1": {"title": "Cellular dynamics associated with the genome-wide epigenetic reprogramming in migrating primordial germ cells in mice", "authors": [{"first": "Y", "middle": [], "last": "Seki", "suffix": ""}, {"first": "M", "middle": [], "last": "Yamaji", "suffix": ""}, {"first": "Y", "middle": [], "last": "Yabuta", "suffix": ""}, {"first": "M", "middle": [], "last": "Sano", "suffix": ""}, {"first": "M", "middle": [], "last": "Shigeta", "suffix": ""}], "year": 2007, "venue": "Epigenetics: Official Journal of the DNA Methylation Society", "link": "6287420"}, "BIBREF2": {"title": "Pseudogene-derived small interfering RNAs regulate gene expression in mouse oocytes", "authors": [{"first": "O", "middle": ["H"], "last": "Tam", "suffix": ""}, {"first": "A", "middle": ["A"], "last": "Aravin", "suffix": ""}, {"first": "P", "middle": [], "last": "Stein", "suffix": ""}, {"first": "A", "middle": [], "last": "Girard", "suffix": ""}, {"first": "E", "middle": ["P"], "last": "Murchison", "suffix": ""}], "year": 2008, "venue": "Nature", "link": "4327043"}, "BIBREF3": {"title": "Endogenous siRNAs from naturally formed dsRNAs regulate transcripts in mouse oocytes", "authors": [{"first": "T", "middle": [], "last": "Watanabe", "suffix": ""}, {"first": "Y", "middle": [], "last": "Totoki", "suffix": ""}, {"first": "", "middle": [], "last": "At", "suffix": ""}, {"first": "M", "middle": [], "last": "Kaneda", "suffix": ""}, {"first": "S", "middle": [], "last": "Kuramochi-Miyagawa", "suffix": ""}], "year": 2008, "venue": "Nature", "link": "4427274"}, "BIBREF4": {"title": "Developmentally regulated piRNA clusters implicate MILI in transposon control", "authors": [{"first": "A", "middle": ["A"], "last": "Aravin", "suffix": ""}, {"first": "R", "middle": [], "last": "Sachidanandam", "suffix": ""}, {"first": "A", "middle": [], "last": "Girard", "suffix": ""}, {"first": "K", "middle": [], "last": "Fejes-Toth", "suffix": ""}, {"first": "G", "middle": ["J"], "last": "Hannon", "suffix": ""}], "year": 2007, "venue": "Science", "link": "39170151"}, "BIBREF5": {"title": "MIWI2 is essential for spermatogenesis and repression of transposons in the mouse male germline", "authors": [{"first": "M", "middle": ["A"], "last": "Carmell", "suffix": ""}, {"first": "A", "middle": [], "last": "Girard", "suffix": ""}, {"first": "H", "middle": ["J"], "last": "Van De Kant", "suffix": ""}, {"first": "D", "middle": [], "last": "Bourc&apos;his", "suffix": ""}, {"first": "T", "middle": ["H"], "last": "Bestor", "suffix": ""}], "year": 2007, "venue": "Dev Cell", "link": "5763615"}, "BIBREF6": {"title": "A distinct small RNA pathway silences selfish genetic elements in the germline", "authors": [{"first": "V", "middle": ["V"], "last": "Vagin", "suffix": ""}, {"first": "A", "middle": [], "last": "Sigova", "suffix": ""}, {"first": "C", "middle": [], "last": "Li", "suffix": ""}, {"first": "H", "middle": [], "last": "Seitz", "suffix": ""}, {"first": "V", "middle": [], "last": "Gvozdev", "suffix": ""}], "year": 2006, "venue": "", "link": "40471466"}, "BIBREF8": {"title": "Repeat-associated siRNAs cause chromatin silencing of retrotransposons in the Drosophila melanogaster germline", "authors": [{"first": "M", "middle": ["S"], "last": "Klenov", "suffix": ""}, {"first": "S", "middle": ["A"], "last": "Lavrov", "suffix": ""}, {"first": "A", "middle": ["D"], "last": "Stolyarenko", "suffix": ""}, {"first": "S", "middle": ["S"], "last": "Ryazansky", "suffix": ""}, {"first": "A", "middle": ["A"], "last": "Aravin", "suffix": ""}], "year": 2007, "venue": "Nucleic Acids Research", "link": "5866901"}, "BIBREF9": {"title": "Early origins and evolution of microRNAs and Piwi-interacting RNAs in animals", "authors": [{"first": "A", "middle": [], "last": "Grimson", "suffix": ""}, {"first": "M", "middle": [], "last": "Srivastava", "suffix": ""}, {"first": "B", "middle": [], "last": "Fahey", "suffix": ""}, {"first": "B", "middle": ["J"], "last": "Woodcroft", "suffix": ""}, {"first": "H", "middle": ["R"], "last": "Chiang", "suffix": ""}], "year": 2008, "venue": "Nature", "link": "4371350"}, "BIBREF10": {"title": "DNA methylation of retrotransposon genes is regulated by Piwi family members MILI and MIWI2 in murine fetal testes", "authors": [{"first": "S", "middle": [], "last": "Kuramochi-Miyagawa", "suffix": ""}, {"first": "T", "middle": [], "last": "Watanabe", "suffix": ""}, {"first": "K", "middle": [], "last": "Gotoh", "suffix": ""}, {"first": "Y", "middle": [], "last": "Totoki", "suffix": ""}, {"first": "A", "middle": [], "last": "Toyoda", "suffix": ""}], "year": 2008, "venue": "Genes & Development", "link": "31949928"}, "BIBREF11": {"title": "An epigenetic activation role of Piwi and a Piwi-associated piRNA in Drosophila melanogaster", "authors": [{"first": "H", "middle": [], "last": "Yin", "suffix": ""}, {"first": "H", "middle": [], "last": "Lin", "suffix": ""}], "year": 2007, "venue": "Nature", "link": "4334925"}, "BIBREF12": {"title": "A piRNA pathway primed by individual transposons is linked to de novo DNA methylation in mice", "authors": [{"first": "A", "middle": ["A"], "last": "Aravin", "suffix": ""}, {"first": "R", "middle": [], "last": "Sachidanandam", "suffix": ""}, {"first": "D", "middle": [], "last": "Bourc&apos;his", "suffix": ""}, {"first": "C", "middle": [], "last": "Schaefer", "suffix": ""}, {"first": "D", "middle": [], "last": "Pezic", "suffix": ""}], "year": 2008, "venue": "Molecular Cell", "link": null}, "BIBREF13": {"title": "Essential role for de novo DNA methyltransferase Dnmt3a in paternal and maternal imprinting", "authors": [{"first": "M", "middle": [], "last": "Kaneda", "suffix": ""}, {"first": "M", "middle": [], "last": "Okano", "suffix": ""}, {"first": "K", "middle": [], "last": "Hata", "suffix": ""}, {"first": "T", "middle": [], "last": "Sado", "suffix": ""}, {"first": "N", "middle": [], "last": "Tsujimoto", "suffix": ""}], "year": 2004, "venue": "Nature", "link": "4344982"}, "BIBREF14": {"title": "Meiotic catastrophe and retrotransposon reactivation in male germ cells lacking Dnmt3L", "authors": [{"first": "D", "middle": [], "last": "Bourc&apos;his", "suffix": ""}, {"first": "T", "middle": ["H"], "last": "Bestor", "suffix": ""}], "year": 2004, "venue": "Nature", "link": "4422237"}, "BIBREF15": {"title": "Ultrastructural characterization of spermatogenesis and its evolutionary conservation in the germline: Germinal granules in mammals", "authors": [{"first": "S", "middle": [], "last": "Chuma", "suffix": ""}, {"first": "M", "middle": [], "last": "Hosokawa", "suffix": ""}, {"first": "T", "middle": [], "last": "Tanaka", "suffix": ""}, {"first": "N", "middle": [], "last": "Nakatsuji", "suffix": ""}], "year": 2008, "venue": "Molecular and Cellular Endocrinology", "link": "19953847"}, "BIBREF16": {"title": "Observations on the fine structure and relationships of the chromatoid body in mammalian spermatogenesis", "authors": [{"first": "D", "middle": ["W"], "last": "Fawcett", "suffix": ""}, {"first": "E", "middle": ["M"], "last": "Eddy", "suffix": ""}, {"first": "D", "middle": ["M"], "last": "Phillips", "suffix": ""}], "year": 1970, "venue": "Biology of Reproduction", "link": "29275848"}, "BIBREF17": {"title": "Cytochemical observations on the chromatoid body of the male germ cells", "authors": [{"first": "E", "middle": ["M"], "last": "Eddy", "suffix": ""}], "year": 1970, "venue": "Biology of Reproduction", "link": "38445593"}, "BIBREF18": {"title": "Expression and intracellular localization of mouse Vasa-homologue protein during germ cell development", "authors": [{"first": "Y", "middle": [], "last": "Toyooka", "suffix": ""}, {"first": "N", "middle": [], "last": "Tsunekawa", "suffix": ""}, {"first": "Y", "middle": [], "last": "Takahashi", "suffix": ""}, {"first": "Y", "middle": [], "last": "Matsui", "suffix": ""}, {"first": "M", "middle": [], "last": "Satoh", "suffix": ""}], "year": 2000, "venue": "Mechanisms of Development", "link": "1538116"}, "BIBREF19": {"title": "Tdrd1/ Mtr-1, a tudor-related gene, is essential for male germ-cell differentiation and nuage/germinal granule formation in mice", "authors": [{"first": "S", "middle": [], "last": "Chuma", "suffix": ""}, {"first": "M", "middle": [], "last": "Hosokawa", "suffix": ""}, {"first": "K", "middle": [], "last": "Kitamura", "suffix": ""}, {"first": "S", "middle": [], "last": "Kasai", "suffix": ""}, {"first": "M", "middle": [], "last": "Fujioka", "suffix": ""}], "year": 2006, "venue": "Proc Natl Acad Sci U S A", "link": "11630986"}, "BIBREF20": {"title": "Tudorrelated proteins TDRD1/MTR-1, TDRD6 and TDRD7/TRAP: domain composition, intracellular localization, and function in male germ cells in mice", "authors": [{"first": "M", "middle": [], "last": "Hosokawa", "suffix": ""}, {"first": "M", "middle": [], "last": "Shoji", "suffix": ""}, {"first": "K", "middle": [], "last": "Kitamura", "suffix": ""}, {"first": "T", "middle": [], "last": "Tanaka", "suffix": ""}, {"first": "T", "middle": [], "last": "Noce", "suffix": ""}], "year": 2007, "venue": "Dev Biol", "link": "31511785"}, "BIBREF21": {"title": "The chromatoid body: a germ-cell-specific RNA-processing centre", "authors": [{"first": "N", "middle": [], "last": "Kotaja", "suffix": ""}, {"first": "P", "middle": [], "last": "Sassone-Corsi", "suffix": ""}], "year": 2007, "venue": "Nat Rev Mol Cell Biol", "link": null}, "BIBREF22": {"title": "Patterns, mechanisms, and functions of translation regulation in mammalian spermatogenic cells", "authors": [{"first": "K", "middle": ["C"], "last": "Kleene", "suffix": ""}], "year": 2003, "venue": "Cytogenetic & Genome Research", "link": "26046441"}, "BIBREF23": {"title": "Expression profiling reveals meiotic male germ cell mRNAs that are translationally up-and down-regulated", "authors": [{"first": "N", "middle": [], "last": "Iguchi", "suffix": ""}, {"first": "J", "middle": ["W"], "last": "Tobias", "suffix": ""}, {"first": "N", "middle": ["B"], "last": "Hecht", "suffix": ""}], "year": 2006, "venue": "Proceedings of the National Academy of Sciences of the United States of America", "link": "25289667"}, "BIBREF24": {"title": "Stage-specific expression of rat transition protein 2 mRNA and possible localization to the chromatoid body of step 7 spermatids by in situ hybridization using a nonradioactive riboprobe", "authors": [{"first": "P", "middle": ["T"], "last": "Saunders", "suffix": ""}, {"first": "M", "middle": ["R"], "last": "Millar", "suffix": ""}, {"first": "S", "middle": ["M"], "last": "Maguire", "suffix": ""}, {"first": "R", "middle": ["M"], "last": "Sharpe", "suffix": ""}], "year": 1992, "venue": "Molecular Reproduction & Development", "link": "23589411"}, "BIBREF25": {"title": "D-E-A-D protein family of putative RNA helicases", "authors": [{"first": "S", "middle": ["R"], "last": "Schmid", "suffix": ""}, {"first": "P", "middle": [], "last": "Linder", "suffix": ""}], "year": 1992, "venue": "Molecular Microbiology", "link": "45727289"}, "BIBREF26": {"title": "Unwinding RNA in Saccharomyces cerevisiae: DEAD-box proteins and related families", "authors": [{"first": "Cruz", "middle": ["J"], "last": "De La", "suffix": ""}, {"first": "D", "middle": [], "last": "Kressler", "suffix": ""}, {"first": "P", "middle": [], "last": "Linder", "suffix": ""}], "year": 1999, "venue": "Trends in Biochemical Sciences", "link": "29944906"}, "BIBREF27": {"title": "Gonadotropinregulated testicular RNA helicase (GRTH/Ddx25) is a transport protein involved in gene-specific mRNA export and protein translation during spermatogenesis", "authors": [{"first": "Y", "middle": [], "last": "Sheng", "suffix": ""}, {"first": "C", "middle": ["H"], "last": "Tsai-Morris", "suffix": ""}, {"first": "R", "middle": [], "last": "Gutti", "suffix": ""}, {"first": "Y", "middle": [], "last": "Maeda", "suffix": ""}, {"first": "M", "middle": ["L"], "last": "Dufau", "suffix": ""}], "year": 2006, "venue": "Journal of Biological Chemistry", "link": "27910641"}, "BIBREF28": {"title": "Structural basis for RNA unwinding by the DEAD-box protein Drosophila Vasa", "authors": [{"first": "T", "middle": [], "last": "Sengoku", "suffix": ""}, {"first": "O", "middle": [], "last": "Nureki", "suffix": ""}, {"first": "A", "middle": [], "last": "Nakamura", "suffix": ""}, {"first": "S", "middle": [], "last": "Kobayashi", "suffix": ""}, {"first": "S", "middle": [], "last": "Yokoyama", "suffix": ""}], "year": 2006, "venue": "Cell", "link": "14994628"}, "BIBREF29": {"title": "Gonadotropinregulated testicular RNA helicase (GRTH/Ddx25) is essential for spermatid development and completion of spermatogenesis", "authors": [{"first": "C", "middle": ["H"], "last": "Tsai-Morris", "suffix": ""}, {"first": "Y", "middle": [], "last": "Sheng", "suffix": ""}, {"first": "E", "middle": [], "last": "Lee", "suffix": ""}, {"first": "K", "middle": ["J"], "last": "Lei", "suffix": ""}, {"first": "M", "middle": ["L"], "last": "Dufau", "suffix": ""}], "year": 2004, "venue": "Proceedings of the National Academy of Sciences of the United States of America", "link": "20963716"}, "BIBREF30": {"title": "Repression of protein synthesis by miRNAs: how many mechanisms?", "authors": [{"first": "R", "middle": ["S"], "last": "Pillai", "suffix": ""}, {"first": "S", "middle": ["N"], "last": "Bhattacharyya", "suffix": ""}, {"first": "W", "middle": [], "last": "Filipowicz", "suffix": ""}], "year": 2007, "venue": "Trends in Cell Biology", "link": "41194177"}, "BIBREF31": {"title": "Interplay of PIWI/ Argonaute protein MIWI and kinesin KIF17b in chromatoid bodies of male germ cells", "authors": [{"first": "N", "middle": [], "last": "Kotaja", "suffix": ""}, {"first": "H", "middle": [], "last": "Lin", "suffix": ""}, {"first": "M", "middle": [], "last": "Parvinen", "suffix": ""}, {"first": "P", "middle": [], "last": "Sassone-Corsi", "suffix": ""}], "year": 2006, "venue": "J Cell Sci", "link": "1126929"}, "BIBREF32": {"title": "Mili Interacts with Tudor Domain-Containing Protein 1 in Regulating Spermatogenesis", "authors": [{"first": "J", "middle": [], "last": "Wang", "suffix": ""}, {"first": "J", "middle": [], "last": "Saxe", "suffix": ""}, {"first": "T", "middle": [], "last": "Tanaka", "suffix": ""}, {"first": "S", "middle": [], "last": "Chuma", "suffix": ""}, {"first": "H", "middle": [], "last": "Lin", "suffix": ""}], "year": 2009, "venue": "Current Biology", "link": "8627591"}, "BIBREF33": {"title": "MIWI associates with translational machinery and PIWI-interacting RNAs (piRNAs) in regulating spermatogenesis", "authors": [{"first": "S", "middle": ["T"], "last": "Grivna", "suffix": ""}, {"first": "B", "middle": [], "last": "Pyhtila", "suffix": ""}, {"first": "H", "middle": [], "last": "Lin", "suffix": ""}], "year": 2006, "venue": "Proceedings of the National Academy of Sciences of the United States of America", "link": "21054661"}, "BIBREF34": {"title": "miwi, a murine homolog of piwi, encodes a cytoplasmic protein essential for spermatogenesis", "authors": [{"first": "W", "middle": [], "last": "Deng", "suffix": ""}, {"first": "H", "middle": [], "last": "Lin", "suffix": ""}], "year": 2002, "venue": "Dev Cell", "link": "24594272"}, "BIBREF35": {"title": "Two mouse piwi-related genes: miwi and mili", "authors": [{"first": "S", "middle": [], "last": "Kuramochi-Miyagawa", "suffix": ""}, {"first": "T", "middle": [], "last": "Kimura", "suffix": ""}, {"first": "K", "middle": [], "last": "Yomogida", "suffix": ""}, {"first": "A", "middle": [], "last": "Kuroiwa", "suffix": ""}, {"first": "Y", "middle": [], "last": "Tadokoro", "suffix": ""}], "year": 2001, "venue": "Mechanisms of Development", "link": "6569767"}, "BIBREF36": {"title": "MILI, a PIWI-interacting RNA-binding protein, is required for germ line stem cell self-renewal and appears to positively regulate translation", "authors": [{"first": "Y", "middle": [], "last": "Unhavaithaya", "suffix": ""}, {"first": "Y", "middle": [], "last": "Hao", "suffix": ""}, {"first": "E", "middle": [], "last": "Beyret", "suffix": ""}, {"first": "H", "middle": [], "last": "Yin", "suffix": ""}, {"first": "S", "middle": [], "last": "Kuramochi-Miyagawa", "suffix": ""}], "year": 2009, "venue": "Journal of Biological Chemistry", "link": "30414732"}, "BIBREF37": {"title": "Mili, a mammalian member of piwi family gene, is essential for spermatogenesis", "authors": [{"first": "S", "middle": [], "last": "Kuramochi-Miyagawa", "suffix": ""}, {"first": "T", "middle": [], "last": "Kimura", "suffix": ""}, {"first": "T", "middle": ["W"], "last": "Ijiri", "suffix": ""}, {"first": "T", "middle": [], "last": "Isobe", "suffix": ""}, {"first": "N", "middle": [], "last": "Asada", "suffix": ""}], "year": 2004, "venue": "Development", "link": "14102094"}, "BIBREF38": {"title": "Maelstrom, a Drosophila spindle-class gene, encodes a protein that colocalizes with Vasa and RDE1/AGO1 homolog, Aubergine, in nuage", "authors": [{"first": "S", "middle": ["D"], "last": "Findley", "suffix": ""}, {"first": "M", "middle": [], "last": "Tamanaha", "suffix": ""}, {"first": "N", "middle": ["J"], "last": "Clegg", "suffix": ""}, {"first": "H", "middle": [], "last": "Ruohola-Baker", "suffix": ""}], "year": 2003, "venue": "Development", "link": "13344310"}, "BIBREF39": {"title": "Mouse MAELSTROM: the link between meiotic silencing of unsynapsed chromatin and microRNA pathway?", "authors": [{"first": "Y", "middle": [], "last": "Costa", "suffix": ""}, {"first": "R", "middle": ["M"], "last": "Speed", "suffix": ""}, {"first": "P", "middle": [], "last": "Gautier", "suffix": ""}, {"first": "C", "middle": ["A"], "last": "Semple", "suffix": ""}, {"first": "K", "middle": [], "last": "Maratou", "suffix": ""}], "year": 2006, "venue": "Hum Mol Genet", "link": "11950881"}, "BIBREF40": {"title": "Functional insight into Maelstrom in the germline piRNA pathway: a unique domain homologous to the DnaQ-H 39-59 exonuclease, its lineage-specific expansion/loss and evolutionarily active site switch", "authors": [{"first": "D", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "H", "middle": [], "last": "Xiong", "suffix": ""}, {"first": "J", "middle": [], "last": "Shan", "suffix": ""}, {"first": "X", "middle": [], "last": "Xia", "suffix": ""}, {"first": "V", "middle": ["L"], "last": "Trudeau", "suffix": ""}], "year": 2008, "venue": "Biology Direct [Electronic Resource", "link": "10849185"}, "BIBREF41": {"title": "Specialized piRNA pathways act in germline and somatic tissues of the Drosophila ovary", "authors": [{"first": "C", "middle": [], "last": "Malone", "suffix": ""}, {"first": "J", "middle": [], "last": "Brennecke", "suffix": ""}, {"first": "M", "middle": [], "last": "Dus", "suffix": ""}, {"first": "A", "middle": [], "last": "Stark", "suffix": ""}, {"first": "W", "middle": [], "last": "Mccombie", "suffix": ""}], "year": 2009, "venue": "Cell", "link": "5917663"}, "BIBREF42": {"title": "Zili is required for germ cell differentiation and meiosis in zebrafish", "authors": [{"first": "S", "middle": [], "last": "Houwing", "suffix": ""}, {"first": "E", "middle": [], "last": "Berezikov", "suffix": ""}, {"first": "R", "middle": ["F"], "last": "Ketting", "suffix": ""}], "year": 2008, "venue": "EMBO Journal", "link": "14180643"}, "BIBREF43": {"title": "A role for Piwi and piRNAs in germ cell maintenance and transposon silencing in Zebrafish", "authors": [{"first": "S", "middle": [], "last": "Houwing", "suffix": ""}, {"first": "L", "middle": ["M"], "last": "Kamminga", "suffix": ""}, {"first": "E", "middle": [], "last": "Berezikov", "suffix": ""}, {"first": "D", "middle": [], "last": "Cronembold", "suffix": ""}, {"first": "A", "middle": [], "last": "Girard", "suffix": ""}], "year": 2007, "venue": "Cell", "link": "13373509"}, "BIBREF44": {"title": "The mouse homolog of Drosophila Vasa is required for the development of male germ cells", "authors": [{"first": "S", "middle": ["S"], "last": "Tanaka", "suffix": ""}, {"first": "Y", "middle": [], "last": "Toyooka", "suffix": ""}, {"first": "R", "middle": [], "last": "Akasu", "suffix": ""}, {"first": "Y", "middle": [], "last": "Katoh-Fukui", "suffix": ""}, {"first": "Y", "middle": [], "last": "Nakahara", "suffix": ""}], "year": 2000, "venue": "Genes Dev", "link": "606853"}, "BIBREF45": {"title": "Mouse maelstrom, a component of nuage, is essential for spermatogenesis and transposon repression in meiosis", "authors": [{"first": "S", "middle": ["F"], "last": "Soper", "suffix": ""}, {"first": "G", "middle": ["W"], "last": "Van Der Heijden", "suffix": ""}, {"first": "T", "middle": ["C"], "last": "Hardiman", "suffix": ""}, {"first": "M", "middle": [], "last": "Goodheart", "suffix": ""}, {"first": "S", "middle": ["L"], "last": "Martin", "suffix": ""}], "year": 2008, "venue": "Developmental Cell", "link": "39631415"}, "BIBREF46": {"title": "Tdrd6 is Required for Spermiogenesis, Chromatoid Body Architecture, and Regulation of miRNA Expression", "authors": [{"first": "A", "middle": [], "last": "Vasileva", "suffix": ""}, {"first": "D", "middle": [], "last": "Tiedau", "suffix": ""}, {"first": "A", "middle": [], "last": "Firooznia", "suffix": ""}, {"first": "T", "middle": [], "last": "Muller-Richert", "suffix": ""}, {"first": "R", "middle": [], "last": "Jessberger", "suffix": ""}], "year": 2009, "venue": "Current Biology", "link": "14394505"}, "BIBREF47": {"title": "Loss of the Miliinteracting Tudor domain-containing protein-1 activates transposons and alters the Mili-associated small RNA profile", "authors": [{"first": "M", "middle": [], "last": "Reuter", "suffix": ""}, {"first": "S", "middle": [], "last": "Chuma", "suffix": ""}, {"first": "T", "middle": [], "last": "Tanaka", "suffix": ""}, {"first": "T", "middle": [], "last": "Franz", "suffix": ""}, {"first": "A", "middle": [], "last": "Stark", "suffix": ""}], "year": 2009, "venue": "Nat Struct Mol Biol", "link": "5481594"}, "BIBREF48": {"title": "Identification of Gasz, an evolutionarily conserved gene expressed exclusively in germ cells and encoding a protein with four ankyrin repeats, a sterile-alpha motif, and a basic leucine zipper", "authors": [{"first": "W", "middle": [], "last": "Yan", "suffix": ""}, {"first": "A", "middle": [], "last": "Rajkovic", "suffix": ""}, {"first": "M", "middle": ["M"], "last": "Viveiros", "suffix": ""}, {"first": "K", "middle": ["H"], "last": "Burns", "suffix": ""}, {"first": "J", "middle": ["J"], "last": "Eppig", "suffix": ""}], "year": 2002, "venue": "Mol Endocrinol", "link": "38510012"}, "BIBREF49": {"title": "Identification and characterization of evolutionarily conserved pufferfish, zebrafish, and frog orthologs of GASZ", "authors": [{"first": "W", "middle": [], "last": "Yan", "suffix": ""}, {"first": "L", "middle": [], "last": "Ma", "suffix": ""}, {"first": "C", "middle": ["A"], "last": "Zilinski", "suffix": ""}, {"first": "M", "middle": ["M"], "last": "Matzuk", "suffix": ""}], "year": 2004, "venue": "Biol Reprod", "link": "25786517"}, "BIBREF50": {"title": "DNA double-strand breaks and gamma-H2AX signaling in the testis", "authors": [{"first": "G", "middle": [], "last": "Hamer", "suffix": ""}, {"first": "H", "middle": ["L"], "last": "Roepers-Gajadien", "suffix": ""}, {"first": "A", "middle": [], "last": "Van Duyn-Goedhart", "suffix": ""}, {"first": "I", "middle": ["S"], "last": "Gademan", "suffix": ""}, {"first": "H", "middle": ["B"], "last": "Kal", "suffix": ""}], "year": 2003, "venue": "Biol Reprod", "link": "41689907"}, "BIBREF51": {"title": "Mouse RanBPM is a partner gene to a germline specific RNA helicase, mouse vasa homolog protein", "authors": [{"first": "N", "middle": [], "last": "Shibata", "suffix": ""}, {"first": "N", "middle": [], "last": "Tsunekawa", "suffix": ""}, {"first": "S", "middle": [], "last": "Okamoto-Ito", "suffix": ""}, {"first": "R", "middle": [], "last": "Akasu", "suffix": ""}, {"first": "A", "middle": [], "last": "Tokumasu", "suffix": ""}], "year": 2004, "venue": "Mol Reprod Dev", "link": "25522245"}, "BIBREF52": {"title": "Mouse ES cells express endogenous shRNAs, siRNAs, and other Microprocessor-independent, Dicer-dependent small RNAs", "authors": [{"first": "J", "middle": ["E"], "last": "Babiarz", "suffix": ""}, {"first": "J", "middle": ["G"], "last": "Ruby", "suffix": ""}, {"first": "Y", "middle": [], "last": "Wang", "suffix": ""}, {"first": "D", "middle": ["P"], "last": "Bartel", "suffix": ""}, {"first": "R", "middle": [], "last": "Blelloch", "suffix": ""}], "year": 2008, "venue": "Genes & Development", "link": "25460999"}, "BIBREF53": {"title": "The growing catalog of small RNAs and their association with distinct Argonaute/Piwi family members", "authors": [{"first": "T", "middle": ["A"], "last": "Farazi", "suffix": ""}, {"first": "S", "middle": ["A"], "last": "Juranek", "suffix": ""}, {"first": "T", "middle": [], "last": "Tuschl", "suffix": ""}], "year": 2008, "venue": "Development", "link": "3237558"}, "BIBREF54": {"title": "The RNA interference proteins and vasa locus are involved in the silencing of retrotransposons in the female germline of Drosophila melanogaster", "authors": [{"first": "V", "middle": ["V"], "last": "Vagin", "suffix": ""}, {"first": "M", "middle": ["S"], "last": "Klenov", "suffix": ""}, {"first": "A", "middle": ["I"], "last": "Kalmykova", "suffix": ""}, {"first": "A", "middle": ["D"], "last": "Stolyarenko", "suffix": ""}, {"first": "R", "middle": ["N"], "last": "Kotelnikov", "suffix": ""}], "year": 2004, "venue": "Rna Biology", "link": "41411552"}, "BIBREF55": {"title": "Identification of autonomous IAP LTR retrotransposons mobile in mammalian cells", "authors": [{"first": "M", "middle": [], "last": "Dewannieux", "suffix": ""}, {"first": "A", "middle": [], "last": "Dupressoir", "suffix": ""}, {"first": "F", "middle": [], "last": "Harper", "suffix": ""}, {"first": "G", "middle": [], "last": "Pierron", "suffix": ""}, {"first": "T", "middle": [], "last": "Heidmann", "suffix": ""}], "year": 2004, "venue": "Nature Genetics", "link": "23989180"}, "BIBREF56": {"title": "L1 mobile element expression causes multiple types of toxicity", "authors": [{"first": "N", "middle": ["A"], "last": "Wallace", "suffix": ""}, {"first": "V", "middle": ["P"], "last": "Belancio", "suffix": ""}, {"first": "P", "middle": ["L"], "last": "Deininger", "suffix": ""}], "year": 2008, "venue": "Gene", "link": "12686548"}, "BIBREF57": {"title": "DNA repair mediated by endonuclease-independent LINE-1 retrotransposition", "authors": [{"first": "T", "middle": ["A"], "last": "Morrish", "suffix": ""}, {"first": "N", "middle": [], "last": "Gilbert", "suffix": ""}, {"first": "J", "middle": ["S"], "last": "Myers", "suffix": ""}, {"first": "B", "middle": ["J"], "last": "Vincent", "suffix": ""}, {"first": "T", "middle": ["D"], "last": "Stamato", "suffix": ""}], "year": 2002, "venue": "Nature Genetics", "link": "19443787"}, "BIBREF58": {"title": "Endonuclease-independent insertion provides an alternative pathway for L1 retrotransposition in the human genome", "authors": [{"first": "S", "middle": ["K"], "last": "Sen", "suffix": ""}, {"first": "C", "middle": ["T"], "last": "Huang", "suffix": ""}, {"first": "K", "middle": [], "last": "Han", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Batzer", "suffix": ""}], "year": 2007, "venue": "Nucleic Acids Research", "link": "2334851"}, "BIBREF59": {"title": "Alpha-inhibin is a tumour-suppressor gene with gonadal specificity in mice", "authors": [{"first": "M", "middle": ["M"], "last": "Matzuk", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Finegold", "suffix": ""}, {"first": "J", "middle": ["G"], "last": "Su", "suffix": ""}, {"first": "A", "middle": ["J"], "last": "Hsueh", "suffix": ""}, {"first": "A", "middle": [], "last": "Bradley", "suffix": ""}], "year": 1992, "venue": "Nature", "link": "45689074"}, "BIBREF60": {"title": "Production and Analysis of Chimeric Mice", "authors": [{"first": "", "middle": [], "last": "Bradley A In", "suffix": ""}], "year": 1987, "venue": "IRL", "link": "82897526"}, "BIBREF61": {"title": ") p19Ink4d and p18Ink4c cyclin-dependent kinase inhibitors in the male reproductive axis", "authors": [{"first": "G", "middle": ["M"], "last": "Buchold", "suffix": ""}, {"first": "P", "middle": ["L"], "last": "Magyar", "suffix": ""}, {"first": "R", "middle": [], "last": "Arumugam", "suffix": ""}, {"first": "M", "middle": ["M"], "last": "Lee", "suffix": ""}, {"first": "D", "middle": ["A"], "last": "O&apos;brien", "suffix": ""}], "year": 2007, "venue": "Molecular Reproduction & Development", "link": "24609899"}, "BIBREF62": {"title": "Generation of functional multipotent adult stem cells from GPR125+ germline progenitors", "authors": [{"first": "M", "middle": [], "last": "Seandel", "suffix": ""}, {"first": "D", "middle": [], "last": "James", "suffix": ""}, {"first": "S", "middle": ["V"], "last": "Shmelkov", "suffix": ""}, {"first": "I", "middle": [], "last": "Falciatori", "suffix": ""}, {"first": "J", "middle": [], "last": "Kim", "suffix": ""}], "year": 2007, "venue": "Nature", "link": "205211488"}, "BIBREF63": {"title": "Analysis of repetitive element DNA methylation by MethyLight", "authors": [{"first": "D", "middle": ["J"], "last": "Weisenberger", "suffix": ""}, {"first": "M", "middle": [], "last": "Campan", "suffix": ""}, {"first": "T", "middle": ["I"], "last": "Long", "suffix": ""}, {"first": "M", "middle": [], "last": "Kim", "suffix": ""}, {"first": "C", "middle": [], "last": "Woods", "suffix": ""}], "year": 2005, "venue": "Nucleic Acids Research", "link": "15066176"}, "BIBREF64": {"title": "Pash: efficient genome-scale sequence anchoring by Positional Hashing", "authors": [{"first": "K", "middle": ["J"], "last": "Kalafus", "suffix": ""}, {"first": "A", "middle": ["R"], "last": "Jackson", "suffix": ""}, {"first": "A", "middle": [], "last": "Milosavljevic", "suffix": ""}], "year": 2004, "venue": "Genome Research", "link": "10055465"}, "BIBREF65": {"title": "Pash 2.0: scaleable sequence anchoring for next-generation sequencing technologies", "authors": [{"first": "C", "middle": [], "last": "Coarfa", "suffix": ""}, {"first": "A", "middle": [], "last": "Milosavljevic", "suffix": ""}], "year": 2008, "venue": "Pacific Symposium on Biocomputing", "link": "1163083"}, "BIBREF66": {"title": "Repbase Update, a database of eukaryotic repetitive elements", "authors": [{"first": "J", "middle": [], "last": "Jurka", "suffix": ""}, {"first": "V", "middle": ["V"], "last": "Kapitonov", "suffix": ""}, {"first": "A", "middle": [], "last": "Pavlicek", "suffix": ""}, {"first": "P", "middle": [], "last": "Klonowski", "suffix": ""}, {"first": "O", "middle": [], "last": "Kohany", "suffix": ""}], "year": 2005, "venue": "Cytogenetic & Genome Research", "link": "45324190"}, "BIBREF67": {"title": "BLAT-the BLAST-like alignment tool", "authors": [{"first": "W", "middle": ["J"], "last": "Kent", "suffix": ""}], "year": 2002, "venue": "Genome Research", "link": null}, "BIBREF68": {"title": "piRNABank: a web resource on classified and clustered Piwi-interacting RNAs", "authors": [{"first": "S", "middle": [], "last": "Sai Lakshmi", "suffix": ""}, {"first": "S", "middle": [], "last": "Agrawal", "suffix": ""}], "year": 2008, "venue": "Nucleic Acids Research", "link": "8830523"}, "BIBREF69": {"title": "The time course and chromosomal localization of recombination-related proteins at meiosis in the mouse are compatible with models that can resolve the early DNA-DNA interactions without reciprocal recombination", "authors": [{"first": "P", "middle": ["B"], "last": "Moens", "suffix": ""}, {"first": "N", "middle": ["K"], "last": "Kolas", "suffix": ""}, {"first": "M", "middle": [], "last": "Tarsounas", "suffix": ""}, {"first": "E", "middle": [], "last": "Marcon", "suffix": ""}, {"first": "P", "middle": ["E"], "last": "Cohen", "suffix": ""}], "year": 2002, "venue": "Journal of Cell Science", "link": null}, "BIBREF70": {"title": "Expression of the mouse histone gene H1t begins at premeiotic stages of spermatogenesis", "authors": [{"first": "B", "middle": [], "last": "Drabent", "suffix": ""}, {"first": "C", "middle": [], "last": "Bode", "suffix": ""}, {"first": "N", "middle": [], "last": "Miosge", "suffix": ""}, {"first": "R", "middle": [], "last": "Herken", "suffix": ""}, {"first": "D", "middle": [], "last": "Doenecke", "suffix": ""}], "year": 1998, "venue": "Cell & Tissue Research", "link": "19149733"}, "BIBREF71": {"title": "Baxdependent spermatogonia apoptosis is required for testicular development and spermatogenesis", "authors": [{"first": "L", "middle": ["D"], "last": "Russell", "suffix": ""}, {"first": "H", "middle": [], "last": "Chiarini-Garcia", "suffix": ""}, {"first": "S", "middle": ["J"], "last": "Korsmeyer", "suffix": ""}, {"first": "C", "middle": ["M"], "last": "Knudson", "suffix": ""}], "year": 2002, "venue": "Biology of Reproduction", "link": "40597478"}, "BIBREF72": {"title": "Histological and Histopathological Evaluation of the Testis", "authors": [{"first": "L", "middle": ["D"], "last": "Russell", "suffix": ""}, {"first": "R", "middle": ["A"], "last": "Ettlin", "suffix": ""}, {"first": "A", "middle": ["P"], "last": "Sinha Hikim", "suffix": ""}, {"first": "E", "middle": ["D"], "last": "Clegg", "suffix": ""}], "year": 1990, "venue": "", "link": null}, "BIBREF73": {"title": "Cloning and expression profiling of testis-expressed microRNAs", "authors": [{"first": "S", "middle": [], "last": "Ro", "suffix": ""}, {"first": "C", "middle": [], "last": "Park", "suffix": ""}, {"first": "K", "middle": ["M"], "last": "Sanders", "suffix": ""}, {"first": "J", "middle": ["R"], "last": "Mccarrey", "suffix": ""}, {"first": "W", "middle": [], "last": "Yan", "suffix": ""}], "year": 2007, "venue": "Developmental Biology", "link": "42520312"}}, "ref_entries": {"FIGREF0": {"text": "Figure 1. Targeting of the Gasz allele and generation of Gasz mutant mice. (A) Schematic representation of the Gasz gene, structure of the targeting vector, and the resultant mutant allele. Genomic DNA fragments used as 59 and 39 homology arms in the targeting vector are indicated by thick lines. Exons 1 and 2 (which encode the Gasz transcriptional start site and the initiation ATG codon) are replaced by a PgkHPRT expression cassette (shaded boxes). The 59 and 39 probes (filled boxes) used for Southern blots are indicated. (S) Sph I, (K) Kpn I. The MC1tk expression cassette was used for negative selection. (B) Southern blot analysis of genomic DNA derived from a litter from Gasz +/2 (+/2) intercrosses. Similar percentages of male and female mice were genotyped as Gasz homozygous null (2/2). The 59 probe hybridizes to 7.7 kb (wild-type, WT) and 4.8 kb (mutant, Mut) SphI fragments. (C) RT-PCR analysis of Gasz expression in Gasz +/2 (+/2) and Gasz", "type": "figure"}, "FIGREF1": {"text": "Figure 2. Gross and histological analysis of postnatal testes. (A) Gross analysis of testes from 7-week-old littermates. (B-M) Histological analysis of testes of Gasz +/2 and Gasz 2/2 mice. (M) is a higher power magnification of (L) to show the lack of germ cells attached to the base of the tubule and sloughing germ cells in the lumen. G, spermatogonia; L, leptotene spermatocytes; M, meiotically dividing spermatocytes; Mit, mitotically dividing spermatogonia; P, pachytene spermatocytes, PL, preleptotene spermatocytes; Ser, Sertoli cells; Z, zygotene spermatocytes; dying spermatocytes with compact chromatin (red arrowhead); and with diffuse chromatin (open arrowhead); sloughing germ cells (black arrowheads). [Scale bars: 100 mm (B-C), 20 mm (D-K).] doi:10.1371/journal.pgen.1000635.g002", "type": "figure"}, "FIGREF3": {"text": "Figure 3. GASZ co-immunolocalization with intermitochondrial cement markers. (A-F) Immunofluorescent analysis of spermatocytes (A-C) and spermatids (D-F). (A,D) GASZ (red) localizes between mitochondrial clusters in spermatocytes using antibodies to cytochrome c (green). (A inset) Higher magnification. (B,E) Staining is shown for GASZ (red), TDRD1 (green). (C,F) Staining for GASZ (red) and MVH (green). Arrows in (E,F) identify the chromatoid body. Note the presence of the GASZ (red) foci and corresponding TDRD1 and MVH (green) foci in spermatocytes (A-C) but not in spermatids (D-F). (G-I) Staining is shown for GASZ (G), TDRD1 (H), and merged (I). (J-L) Staining is shown for GASZ (J), MILI (K), and merged (L). (M-O) Staining of newborn testes is shown for GASZ (M), MILI (N), and merged (O). Note the presence of the GASZ (green) foci and corresponding MILI (red) foci in gonocytes (arrowheads). [Scaling: 10,0006(A-F), 40X(G-L), and 4006(M-O) magnification.] doi:10.1371/journal.pgen.1000635.g003", "type": "figure"}, "FIGREF4": {"text": "Figure 4. MILI is lost in embryonic and newborn testes in the absence of GASZ. Immunofluorescent analysis of Gasz +/2 (A,C,E,G,I,K) and Gasz 2/2 (B,D,F,H,J,L) testes. Staining is shown for TDRD1 (A-D), MILI (E-H), and MVH (I-L). TDRD1 immunostaining is diffusely cytoplasmic in Gasz 2/2 newborn (B) and embryonic (D) gonocytes versus controls (A,C). Staining of the identical germ cells shows MILI is undetectable in newborn gonocytes and present in only a subset of Gasz 2/2 E16.5 gonocytes [arrowheads in (F,H)]. MVH staining is less granular in Gasz 2/2 (J,L) versus controls (I,K). [Scaling: 5,0006magnification.] doi:10.1371/journal.pgen.1000635.g004", "type": "figure"}, "FIGREF5": {"text": "Figure 5. GASZ interactions and reduction of nuage proteins in Gasz null testes. Biosensor quantification of interaction for a full-length GASZ bait by (A) RANBP9 partial clone, and by (B) GASZ and MIWI. (C,D) GASZ co-immunoprecipitation with nuage proteins. Testicular protein lysates from 21-day-old mice were incubated with no primary antibody [lane 1, (C,D)], anti-GASZ antibody [lane 2, (C)] or anti-MIWI antibody [lane 2, (D)] to immunoprecipitate protein complexes. 10 mg of WT lysate [lane 3, (C,D)] and Gasz 2/2 lysate [(lane 4, (C)] were used as controls. Coimmunoprecipitating proteins were detected by western blot analysis using antibodies against MIWI, TDRD1, MVH, MILI, MAEL, TDRD6, TDRD7, or bactin. (E) Western blot analysis of testicular protein lysates prepared from 10-and 14-day-old Gasz +/2 (+/2, lanes 1 and 3) and Gasz 2/2 (2/2, lanes 2 and 4) mice. Antibodies against MIWI, TDRD1, MVH, MILI, TDRD6, TDRD7, or an antibody to b-actin show levels of nuage proteins are reduced in Gasz 2/2 testes prior to spermatocyte apoptosis. doi:10.1371/journal.pgen.1000635.g005", "type": "figure"}, "FIGREF6": {"text": "Figure 6. Dysregulation of transposable elements in Gasz null testes. (A-B) Quantitative RT-PCR analysis of transposable elements in testes from embryonic, newborn, 7-and 14-day-old mice (mean6SEM). (C) Western blot analysis of testis samples from 14-day-old mice by using anti-GAG (Upper), anti-ORF1 (Middle), or anti-b-actin control (Lower) demonstrated increased IAP GAG and LINE L1 ORF1p expression in Gasz 2/2 testes. (D-G) Immunofluorescent analysis of IAP GAG (D-E) and ORF1p (F-G). Robust staining of IAP GAG and ORF1p is detected in Gasz 2/2 gonocytes (E,G) but absent from Gasz +/2 controls (D,F). (H) CpG methylation analysis of IAP and LINE L1 using bisulfite-converted testicular genomic DNA. Methylated CpG dinucleotides remain unconverted as cytosine (filled circles) and unmethylated cytosines are converted to uracils and amplified as thymidines (open circles). Percentages of CG dinucleotide methylation are given. doi:10.1371/journal.pgen.1000635.g006", "type": "figure"}, "FIGREF7": {"text": "Figure 7. Repeat and non-repeat piRNAs regulated by GASZ. (A) Compositional analysis of small RNA populations at postnatal days 7 (P7), 10 (P10), and 14 (P14) in Gasz +/2 (Left) and Gasz 2/2 (Right) testes with annotation of small RNA populations as described in experimental procedures. (B-D) Comparison of the relative abundance of several classes of known and putative novel piRNAs between Gasz 2/2 and control testes at postnatal days 7, 10, and 14 including known nonrepeat-associated piRNAs (B), repeat-associated piRNAs (25-29 nt) (C) and unknown small RNAs (25-29 nt) (D). doi:10.1371/journal.pgen.1000635.g007", "type": "figure"}, "FIGREF8": {"text": "Figure S4 GASZ localizes to perinuclear cytoplasmic granules. Immunolocalization of GASZ in adult testes using anti-GASZ antibody. Immunostaining is detectable in spermatogonia [G in (B,F)], preleptotene spermatocytes [PL in (C)], pachytene spermatocytes [P in (A-D)], and round spermatids [R in (A-C)]. Staining of leptotene [L in (D)] and zygotene spermatocytes [Z in (E)] as well as elongating [E in (E-F)] and condensing [C in (A-C)] spermatids was negligible. The most intense staining was detected in middle to late pachytene spermatocytes where GASZ displays a granular distribution pattern in the perinuclear region of the cytoplasm. Only dying germ cells are immunoreactive in Gasz 2/2 seminiferous tubules (G). STAGE I, V, VIII, IX, X, XII in (A-F) designates the corresponding stage seminiferous tubule. Found at: doi:10.1371/journal.pgen.1000635.s004 (9.51 MB TIF) Figure S5 Diagramatic summary of Gasz 2/2 . Loss of pachytene spermatocytes in Gasz 2/2 testes correlates with the stages of the seminiferous epithelium where GASZ immunostaining is most intense (green bars). Pachytene spermatocytes in stages I-VI (yellow) can be seen undergoing apoptosis. The most mature germ cells in stage VII-XII seminiferous tubules are early spermatocytes. All germ cells absent from Gasz 2/2 testes are shown in red. The diagram is modified from [73]. Found at: doi:10.1371/journal.pgen.1000635.s005 (0.70 MB TIF)", "type": "figure"}, "FIGREF9": {"text": "Figure S8 Nuage marker mRNAs are modestly reduced in embryonic and juvenile Gasz 2/2 testes. Quantitative RT-PCR analysis of MIWI2, MILI, MVH, TDRD1, MAEL, and MIWI in testes from e18.5, 7-, and 14-day-old mice (mean6SEM). (A) Gasz 2/2 embryonic testes show no alteration of nuage mRNAs. (B) In the postnatal testis most nuage markers are not significantly reduced until post-natal day 14 (P14) with the exception of MIWI2 mRNA which was reduced at post-natal day 7 (P7). Found at: doi:10.1371/journal.pgen.1000635.s008 (0.43 MB TIF) Figure S9 Intermitochondrial cement is absent from Gasz 2/2 gonocytes. Electron micrographs depicting a nuage localized to clustered mitochondria in Gasz +/2 [arrowheads in (A,C,E)] and the lack of a corresponding structure in Gasz 2/2 newborn testes (B,D,F). Found at: doi:10.1371/journal.pgen.1000635.s009 (4.99 MB TIF) Figure S10 Length and nucleotide composition analysis of repeat-associated and unknown small RNAs. Comparison of small RNA length in control and Gasz 2/2 testes from 10-day-old mice that mapped with $90% identity using Blat to consensus elements including all repeats (A), LTRs (B), LINE L1s (C), and SINEs (D). Developmental abundance of small RNA classes in Gasz 2/2 testes and controls at postnatal days 7 (P7), 10 (P10), and 14 (P14) including SINE-associated small RNAs (E), repeat-associated small RNAs (19-23 nt), and other repeat-associated small RNAs. (H-I) Compositional analysis of the 1 st and 10 th nucleotides of repeatassociated piRNAs (25-29 nt) (H) and repeat-associated small RNAs (19-23 nt) (I). (E,F) Characterization of length of the unknown category of small RNAs (J), developmental abundance of the unknown small RNAs (19-23 nt) in Gasz 2/2 testes and controls, and comparison of the nucleotide composition for 25-29 nt versus the 19-23 nt classes (F). Found at: doi:10.1371/journal.pgen.1000635.s010 (1.22 MB TIF) Figure S11 Model for GASZ interaction with nuage proteins. A summary of reported interactions between nuage proteins suggests that they may form a protein network containing GASZ. Physical interactions between nuage proteins are depicted by connecting lines. Found at: doi:10.1371/journal.pgen.1000635.s011 (0.09 MB TIF)", "type": "figure"}, "FIGREF10": {"text": ". SR (Simple Repeat); LC (Low Complexity); UNK (Unknown classification). Found at: doi:10.1371/journal.pgen.1000635.s015 (0.56 MB XLS)", "type": "figure"}, "TABREF3": {"text": "Histological analysis of 5-day-old testes. Histological analysis of testes of Gasz +/2 and Gasz 2/2 mice. Seminiferous tubules for both genotypes contain spermatogonia and juvenile Sertoli cells. G, spermatogonia; Mit, mitotically dividing sper- matogonia; Ser, Sertoli cells. [Scale bar: 20 mm] Found at: doi:10.1371/journal.pgen.1000635.s001 (7.69 MB TIF) Figure S2 The XY body fails to appear in Gasz 2/2 testes due to elevated DNA damage. (A-C) cH2AX localizes in WT testes to perinuclear chromatin of early germ cells [arrow in (A)] and the XY body in pachytene spermatocytes [arrowhead in (B)] while there is increased non-XY body staining in Gasz 2/2 [arrow in (C)]. [Scaling: 5,0006magnification] Found at: doi:10.1371/journal.pgen.1000635.s002 (2.87 MB TIF) Figure S3 Immunohistochemical and TUNEL analysis of juvenile Gasz +/2 and Gasz 2/2 testes. (A-D) Immunohistochemical analysis of testes of Gasz +/2 and Gasz 2/2 mice using antibodies to SYCP3 and H1.T. SYCP3, a marker for all primary spermato- cytes [70], labeled fewer spermatocytes in Gasz 2/2 than Gasz", "type": "table"}, "TABREF4": {"text": "Diagramatic summary of Gasz 2/2 . Loss of pachytene spermatocytes in Gasz 2/2 testes correlates with the stages of the seminiferous epithelium where GASZ immunostaining is most intense (green bars). Pachytene spermatocytes in stages I-VI (yellow) can be seen undergoing apoptosis. The most mature germ cells in stage VII-XII seminiferous tubules are early spermato- cytes. All germ cells absent from Gasz 2/2 testes are shown in red. The diagram is modified from [73]. Found at: doi:10.1371/journal.pgen.1000635.s005 (0.70 MB TIF) Figure S6 IWI and GASZ co-localize in late pachytene spermatocytes. Staining is shown for GASZ [(A) in green], MIWI [(B) in red], and merge (C). GASZ and MIWI co-localize in some granules in pachytene spermatocytes (arrows). GASZ does not co- localize with MIWI in the chromatoid body (arrowheads). [Scaling: 5,0006magnification] Found at: doi:10.1371/journal.pgen.1000635.s006 (2.48 MB TIF) Figure S7 MVH levels are reduced in Gasz null spermatocytes. Immunofluorescent analysis of Gasz +/2 (A) and Gasz 2/2 (B) testes. MVH prominently stains spermatocytes in Gasz +/2 testes [asterisks in (A)] versus low level staining of spermatogonia in Gasz 2/2 testes [arrowheads in (B)]. [Scaling: 5,0006magnification] Found at: doi:10.1371/journal.pgen.1000635.s007 (1.67 MB TIF)", "type": "table"}, "TABREF5": {"text": "Primers for quantitative RT-PCR assessment of nuage components. Found at: doi:10.1371/journal.pgen.1000635.s012 (0.02 MB XLS)", "type": "table"}, "TABREF6": {"text": "Non-repeat-associated piRNAs are reduced in Gasz", "type": "table"}, "TABREF7": {"text": "Found at: doi:10.1371/journal.pgen.1000635.s013 (17.58 MB XLS) Table S3 miRNAs missannotated as piRNAs. Sequences annotated as piRNAs that increased in abundance in Gasz", "type": "table"}}}
{"paper_id": "17782793", "_pdf_hash": "86cf04147d0c8034206814ff68d9e504ca46d35c", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "The Investigation of Optimal Si-SiGe Hetero-Structure Thin-Film Solar Cell With Theoretical Calculation and Quantitative Analysis", "authors": [{"first": "M", "middle": ["H"], "last": "Liao", "suffix": ""}, {"first": "C", "middle": ["H"], "last": "Chen", "suffix": ""}], "year": 2011, "venue": "IEEE Transactions on", "link": "37529340"}, "BIBREF2": {"title": "Twodimensional computer modeling of single junction a-Si:H solar cells", "authors": [{"first": "H", "middle": [], "last": "Efstathiadis", "suffix": ""}, {"first": "J", "middle": ["E"], "last": "Raynolds", "suffix": ""}, {"first": "P", "middle": [], "last": "Haldar", "suffix": ""}], "year": 2009, "venue": "Photovoltaic Specialists Conference (PVSC), 2009 34th IEEE", "link": null}, "BIBREF3": {"title": "Modeling of multi-junction solar cells by Crosslight APSYS", "authors": [{"first": "Z", "middle": ["Q"], "last": "Li", "suffix": ""}, {"first": "*", "middle": [], "last": "", "suffix": ""}, {"first": "Y", "middle": ["G"], "last": "Xiao", "suffix": ""}, {"first": "Z", "middle": ["M"], "last": "Simon Li", "suffix": ""}], "year": 2006, "venue": "", "link": "120318400"}, "BIBREF4": {"title": "Optimization and characterization of advanced solar cells based on thin-film aSi:H/SiGe hetero-structure", "authors": [{"first": "Abdolnabi", "middle": [";"], "last": "Kosarian", "suffix": ""}, {"first": "", "middle": [], "last": "Jelodarian", "suffix": ""}, {"first": ";", "middle": [], "last": "Peyman", "suffix": ""}], "year": 2011, "venue": "19th Iranian Conference on Electrical Engineering (ICEE)", "link": "19122574"}, "BIBREF5": {"title": "Numerical evaluation and characterization of single junction solar cell based on thin-film aSi:H/a-SiGe:H hetero-structure", "authors": [{"first": "Abdolnabi", "middle": [";"], "last": "Kovsarian", "suffix": ""}, {"first": "", "middle": [], "last": "Jelodarian", "suffix": ""}, {"first": ";", "middle": [], "last": "Peyman", "suffix": ""}], "year": 2011, "venue": "19th Iranian Conference on Electrical Engineering (ICEE)", "link": "24886214"}, "BIBREF6": {"title": "Computer simulation model of the effects of interface states on highperformance amorphous silicon solar cell", "authors": [{"first": "H", "middle": [], "last": "Tasaki", "suffix": ""}, {"first": "W", "middle": ["Y"], "last": "Kim", "suffix": ""}, {"first": "M", "middle": [], "last": "Hallerdt", "suffix": ""}, {"first": "M", "middle": [], "last": "Konagai", "suffix": ""}, {"first": "K", "middle": [], "last": "Takahashi", "suffix": ""}], "year": 1988, "venue": "", "link": "122518756"}, "BIBREF7": {"title": "Simulations of the Amorphous Silicon Static Induction Transistor", "authors": [{"first": "A", "middle": ["M"], "last": "Kemp", "suffix": ""}, {"first": "M", "middle": [], "last": "Meunier", "suffix": ""}, {"first": "C", "middle": ["G"], "last": "Tannous", "suffix": ""}], "year": 1989, "venue": "Solid-State Elect", "link": "96084710"}, "BIBREF8": {"title": "Numerical Simulations of Amorphous and Polycrystalline Silicon Thin-Film Transistors", "authors": [{"first": "B", "middle": ["M"], "last": "Hack", "suffix": ""}, {"first": "J", "middle": ["G"], "last": "Shaw", "suffix": ""}], "year": 1990, "venue": "Extended Abstracts 22nd International Conference on Solid-State Devices and Materials", "link": "139072676"}, "BIBREF9": {"title": "Figure 6. I-V and P-V curves of The double-junction a-Si:H/aSiGe:H solar cell for different operating temperature", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF10": {"title": "Figure 7. I-V and P-V curves of the optimized single and doublejunction solar cells", "authors": [], "year": "", "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "17783165", "_pdf_hash": "b21df69f73d2356f0de7279e813e2093a9bc6617", "abstract": [{"section": "Abstract", "text": "OBJECTIVE-Treatment of diabetic patients by pancreatic islet transplantation often requires the use of islets from two to four donors to produce insulin independence in a single recipient. Following isolation and transplantation, islets are susceptible to apoptosis, which limits their function and probably long-term islet graft survival.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "we examined the effect of the cell-permeable apoptosis inhibitor pentapeptide Val-Pro-Met-Leu-Lys, V5, on pancreatic islets in a mouse model.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "treatment upregulated expression of anti-apoptotic proteins Bcl-2 and XIAP (X-linked inhibitor of apoptosis protein) by more than 3-and 11-fold and downregulated expression of apoptosis-inducing proteins Bax, Bad, and nuclear factor-B-p65 by 10, 30, and nearly 50%, respectively. Treatment improved the recovered islet mass following collagenase digestion and isolation by 44% and in vitro glucose-responsive insulin secretion nearly fourfold. Following transplantation in streptozotocin-induced diabetic mice, 150 V5-treated islet equivalents functioned as well as 450 control untreated islet equivalents in normalizing blood glucose.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "CONCLUSIONS-These studies indicate that inhibition of apoptosis by V5 significantly improves islet function following isolation and improves islet graft function following transplantation. Use of this reagent in clinical islet transplantation could have a dramatic impact on the number of patients that might benefit from this therapy and could affect long-term graft survival.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "", "text": "RESULTS-V5 treatment upregulated expression of anti-apoptotic proteins Bcl-2 and XIAP (X-linked inhibitor of apoptosis protein) by more than 3-and 11-fold and downregulated expression of apoptosis-inducing proteins Bax, Bad, and nuclear factor-B-p65 by 10, 30, and nearly 50%, respectively. Treatment improved the recovered islet mass following collagenase digestion and isolation by 44% and in vitro glucose-responsive insulin secretion nearly fourfold. Following transplantation in streptozotocin-induced diabetic mice, 150 V5-treated islet equivalents functioned as well as 450 control untreated islet equivalents in normalizing blood glucose.", "cite_spans": [], "ref_spans": []}, {"section": "CONCLUSIONS-These studies indicate that inhibition of apo-", "text": "ptosis by V5 significantly improves islet function following isolation and improves islet graft function following transplantation. Use of this reagent in clinical islet transplantation could have a dramatic impact on the number of patients that might benefit from this therapy and could affect long-term graft survival. Diabetes 56:1259-1267, 2007 P ancreatic islet transplantation holds great promise as a treatment for type 1 diabetes. Insulin independence has been accomplished using a glucocorticoid-free immunosuppression regimen but often requires transplantation of islets from two to four donors (1) (2) (3) . Since there is a considerable shortage of pancreas donors suitable for islet isolation, relatively few diabetic patients have benefited from this form of therapy. More effective recovery of islets from donor pancreata would dramatically increase the number of patients that could be treated by islet transplantation and could improve long-term graft survival (4 -6) .", "cite_spans": [{"start": 605, "end": 608, "text": "(1)", "ref_id": "BIBREF0"}, {"start": 609, "end": 612, "text": "(2)", "ref_id": "BIBREF1"}, {"start": 613, "end": 616, "text": "(3)", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "CONCLUSIONS-These studies indicate that inhibition of apo-", "text": "Following transplantation, islets undergo apoptosis and necrosis from transient local hypoxia, a lack of nutrient support (7, 8) , and hyperglycemia-induced toxicity (9, 10) . While use of fibroblast growth factor-2 (FGF-2) at the time of transplantation improves revascularization of islet grafts and facilitates their engraftment (11) , this approach addresses only part of the problem. Collagenase digestion of the pancreas has been shown to induce apoptosis of isolated islets from anoikis and loss of cell-matrix interactions (12, 13) . In addition, islets express proinflammatory nuclear factor-B (NF-B)-dependent genes after isolation, amplifying apoptosis signaling and potentially inducing immunological rejection (14 -16) . Optimization of the isolation process to reduce islet stress has failed to improve recovery, leaving uncontrolled apoptosis as the main cause of poor islet yield (3, 13, 17) .", "cite_spans": [{"start": 122, "end": 125, "text": "(7,", "ref_id": "BIBREF6"}, {"start": 126, "end": 128, "text": "8)", "ref_id": "BIBREF7"}, {"start": 166, "end": 169, "text": "(9,", "ref_id": "BIBREF8"}, {"start": 170, "end": 173, "text": "10)", "ref_id": "BIBREF9"}, {"start": 332, "end": 336, "text": "(11)", "ref_id": "BIBREF10"}, {"start": 531, "end": 535, "text": "(12,", "ref_id": "BIBREF11"}, {"start": 536, "end": 539, "text": "13)", "ref_id": "BIBREF12"}, {"start": 896, "end": 899, "text": "(3,", "ref_id": "BIBREF2"}, {"start": 900, "end": 903, "text": "13,", "ref_id": "BIBREF12"}, {"start": 904, "end": 907, "text": "17)", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "CONCLUSIONS-These studies indicate that inhibition of apo-", "text": "Investigators have attempted to prevent \u2424-cell apoptosis by transferring antiapoptosis molecules (A20, Bcl-2, the I\u2424 [inhibitor of \u2424] repressor, and X-linked inhibitor of apoptosis protein [XIAP] ) and growth factors (hepatocyte and vascular endothelial) into islet grafts (18 -27) . In most cases, these genes have been delivered by recombinant adenovirus. This approach, however, is not without potential risk (28) . Use of IGF-II (29) , leptin (30) , and 17 \u2424-estradiol (31) has improved islet mass recovery and viability but has not affected the number of islets that are needed following transplantation to correct diabetes in mice. The caspase-3 inhibitor Z-DEVD-fmk (32) improves islet recovery and viability but inhibits only caspase-3. Whereas these methods have helped reduce apoptosis during islet isolation, few methods have been developed to reduce apoptosis after islet transplantation.", "cite_spans": [{"start": 412, "end": 416, "text": "(28)", "ref_id": "BIBREF27"}, {"start": 433, "end": 437, "text": "(29)", "ref_id": "BIBREF28"}, {"start": 447, "end": 451, "text": "(30)", "ref_id": "BIBREF29"}], "ref_spans": []}, {"section": "CONCLUSIONS-These studies indicate that inhibition of apo-", "text": "We examined the efficacy of the cell-permeable pentapeptide apoptosis inhibitor V5, which inhibits a wide range of caspases, on improving pancreatic islet recovery. This molecule binds Bax and prevents mitochondrial cytochrome c translocation (33) , resulting in global inhibition of caspases through activation of NF-B-dependent and BH1-4 genes (14, 15, 22) . In this study, we demonstrate that culture of isolated islets with V5 improved islet recovery and their capacity for glucose-responsive insulin secretion. Use of FGF-2 and V5 decreased the number of islets needed to correct diabetes following transplantation threefold and allowed routine correction of glucose homeostasis in mice using islets from a single donor.", "cite_spans": [{"start": 243, "end": 247, "text": "(33)", "ref_id": "BIBREF32"}, {"start": 346, "end": 350, "text": "(14,", "ref_id": "BIBREF13"}, {"start": 351, "end": 354, "text": "15,", "ref_id": "BIBREF14"}, {"start": 355, "end": 358, "text": "22)", "ref_id": "BIBREF21"}], "ref_spans": []}, {"section": "RESEARCH DESIGN AND METHODS", "text": "Peptide synthesis and preparation. Synthesis of a V5 was carried out at Sigma Genosis (Ishikari, Japan). The purity of the material was 98.8%, and the total amount of the product was 48.9 mg. Dried peptide powders were stored at \u03ea80\u00b0C and dissolved in fresh pure water for the experiments. Islet isolation and culture. Male inbred Balb/C mice, 20 g and 10 -12 weeks old, were used as pancreas donors. All the experiments performed were approved by the institutional ethical committee and were conducted according to its guidelines. Mouse islet isolation was performed with Hank's balanced salt solution (HBSS) (GibcoBRL, Grand island, NY), containing 2 mg/ml type-V collagenase (Sigma-Aldrich, St. Louis, MO), 2 mg/ml soybean trypsin inhibitor (Sigma-Aldrich), and 0.2% BSA (Sigma-Aldrich), using a modified Gotoh's method with Histopaque 1077-RPMI 1640 medium gradient (Sigma-Aldrich).", "cite_spans": [], "ref_spans": []}, {"section": "RESEARCH DESIGN AND METHODS", "text": "Islets were handpicked up under a microscope and cultured with RPMI-1640 (GibcoBRL) at 37\u00b0C and 5% CO 2 for in vitro analyses. Freshly isolated islets were used immediately for transplantation experiments. Islet viability was evaluated using a Live & Dead detection kit (Molecular Probes, Eugene, OR) in accordance with the manufacturer's instructions. Purity of islets was assessed by dithizone staining, and islet equivalents' yield was determined using a phase-contrast microscopy with a squared calibrated grid. One islet equivalent was equal to a spherical islet of 150 m in diameter. ATP content of islets, directly after isolation and following 24 h of culture, was measured at SRL (Tokyo, Japan) using 500 islet-equivalent aliquots per experiment in three separate studies. Measurement of mitochondrial activity of islets. Islets of 50 islet equivalents were cultured for 24 h with or without 100 mol/l V5 in each well of six-well plates (BD Biosciences, San Jose, CA), and mitochondrial dehydrogenases activity of islets were comparatively measured using 0.5 mg/ml of MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide) (MTT reagent; Sigma). Freshly isolated islets were used as a positive control (34) . Three independent experiments were performed. Detection of apoptosis of islets by annexin-V expression. Expression of annexin-V was measured in islets treated with or without 100 mol/l V5 at 24 h of culture. Islets were washed twice with HBSS and dispersed to a single cell by gentle pipeting in trypsin-EDTA (Sigma-Aldrich). Single islet cells were washed twice with HBSS containing 10% newborn calf serum (Sigma-Aldrich) and labeled with an annexin V-enhanced green fluorescent protein apoptosis detection kit (MBL, Nagoya, Japan), according to the manufacturer's instructions, and analyzed by a MoFlo cell sorter (Dako-Cytomation, Tokyo, Japan). Apoptotic cells were identified by the fluorescence of enhanced green fluorescent protein. Freshly isolated islets were used as a control (3) . Three independent experiments were performed. Power blot analysis for apoptosis-associated molecules. Islets (1,000 islet equivalents) were cultured with RPMI-1640-S with or without V5 (100 mol/l) for 24 h. Then, islets were washed with HBSS twice, rinsed with ice-cold lysis buffer of PBS containing 1.0% Triton X-100 (Sigma-Aldrich), sonicated for 30 s, and placed on ice for 10 min. Lysates were centrifuged at 15,000 rpm for 10 min at 4\u00b0C to exclude cellular debris. Protein concentrates were collected and analyzed for 50 apoptosis-associated molecules according to the manufacture's protocol (Clonotech, Tokyo, Japan). Three independent experiments were performed.", "cite_spans": [{"start": 1223, "end": 1227, "text": "(34)", "ref_id": "BIBREF33"}, {"start": 2017, "end": 2020, "text": "(3)", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "RESEARCH DESIGN AND METHODS", "text": "Measurement of insulin secretion, insulin content, and stimulation index of islets. Islets (10 islet equivalents/well of six-well plates) were cultured in RPMI-1640-S supplemented with or without V5 (100 mol/l) in both standard and ultralow attachment plates (BD Bioscience, Tokyo, Japan). Islets were treated for 20 min in 2 ml of Krebs-Ringer balanced buffer (KRBB) (containing 143.0 mmol/l Na, 5.8 mmol/l K, 2.5 mmol/l Ca, 1.2 mmol/l Mg 2 , 124.1 mmol/l Cl, 1.2 mmol/l PO-4, 1.2 mmol/l SO-4, 25 mmol/l HCO-3, 10 mmol/l HEPES, 0.2% BSA, and 3.3 or 25 mmol/l glucose) at pH 7.4 for RPMI-1640-S equilibration. Insulin secretion of the islets was measured under static incubation using a Mercodia mouse insulin enzyme-linked immunosorbent assay kit (Uppsala, Sweden) at 0, 24, 72, 120, and 168 h, as previously reported (35, 36) . Briefly, islets were first incubated at 37\u00b0C and 5% CO 2 for 2 h in KRBB with 3.3 mmol/l glucose, then in KRBB with 25 mmol/l glucose for 2 h, and finally in KRBB with 3.3 mmol/l glucose. Amount of insulin content of islets was measured at the end of static incubation. Three independent experiments were performed. Transplantation experiments. Female inbred Balb/C mice, 20 g and 10 weeks old, received a single intraperitoneal injection of 220 mg streptozotocin per kg body wt. Mice with blood glucose levels \u03fe360 mg/dl on a minimum of two consecutive measurements were selected as recipients (34) . Gelatinized microspheres for islet transplantation (30 -50 m in size) containing both FGF-2 (100 ng) and V5 (100 mol/l) or FGF-2 (100 ng) only were prepared through glutaraldehyde cross-linking of an aqueous gelatin solution, as previously reported (37) . For transplantation, freshly isolated islets were suspended in 10 l RMPI-1640-S medium, embedded with the gelatinized microspheres, and then transplanted under the kidney capsule of diabetic mice.", "cite_spans": [{"start": 819, "end": 823, "text": "(35,", "ref_id": "BIBREF34"}, {"start": 824, "end": 827, "text": "36)", "ref_id": "BIBREF35"}, {"start": 1425, "end": 1429, "text": "(34)", "ref_id": "BIBREF33"}, {"start": 1681, "end": 1685, "text": "(37)", "ref_id": "BIBREF36"}], "ref_spans": []}, {"section": "RESEARCH DESIGN AND METHODS", "text": "Diabetic mice were divided into the following four groups: 1) n \u03ed 21, transplantation with 150 islet equivalents obtained from one mouse prepared with FGF-2 only; 2) n \u03ed 21, transplantation with 150 islet equivalents obtained from one mouse prepared with both FGF-2 and V5; 3) n \u03ed 21, transplantation with 450 islet equivalents obtained from three mice prepared with FGF-2 only; and 4) n \u03ed 5, animals received no islet transplants. Normal healthy mice were used as a positive control (group 5; n \u03ed 5). In vivo evaluation after islet transplantation in diabetic mice. Blood glucose levels were monitored at regular intervals for 27 weeks. Normoglycemia was defined to be \u03fd126 mg/dl in at least two consecutive measurements. An intraperitoneal glucose tolerance test was performed at 24 weeks. Mice were fasted overnight and then glucose (1g/kg body wt) was injected intraperitoneally, as previously described (34) . Nephrectomy was performed at 26 weeks in the mice of groups 1, 2, and 3, and total insulin content of the samples was measured per microgram graft (34) . Histological studies of kidneys bearing islet grafts. Kidneys bearing islet grafts were removed at 3 days and at 26 weeks after transplantation (n \u03ed 3 from groups 1, 2, and 3), fixed in 10% formalin for 24 h, and embedded in paraffin for hematoxylin-eosin staining, insulin staining, and transferasemediated dUTP nick-end labeling (TUNEL) staining. Serial-matched paraffin sections were used for these stainings. Polyclonal anti-insulin guinea pig primary antibodies (Dakocytomation) were applied. Then, secondary antibody phycoethrin-labeled anti-guinea pig (Amersham Biosciences) was added. Green fluorescent nuclear counterstaining was used for all the samples. Immunofluorescent stained slides were observed under a confocal laser-scanning microscope (LSM510; Carl Zeiss) (34) . An in situ cell death detection tetramethylrhodamine red kit (Roche, Mannheim, Germany) was used for TUNEL staining. PCR analysis. For detection of inflammatory molecules, total RNA was extracted from kidneys bearing islet grafts 2 days after transplantation using RNA Trizol (Invitrogen), as previously reported (38) . RT-PCR was performed at 22\u00b0C for 10 min and then at 42\u00b0C for 20 min using 1.0 g RNA per reaction to ensure that the amount of cDNA amplified was proportional to the mRNA present in the original samples. The following specific primers were used: interleukin (IL)-1\u2424 (NM_008361), 5\u0408-caggcaggcagtatcactca-3\u0408 forward and 5\u0408-agctcatatgggtccgacag-3\u0408 reverse; tumor necrosis factor (TNF)-\u2423 (NM_01369), 5\u0408-agtccgggcaggtctacttt-3\u0408 forward and 5\u0408-ggtcactgtcccagcatctt-3\u0408 reverse; Bcl-2 (NM_009741), 5\u0408-aggagcaggtgcctacaaga-3\u0408 forward and 5\u0408-gcattttcccaccactgtct-3\u0408 reverse; and GAPDH (NM_008084) 5\u0408-acccagaagactgtggatgg-3\u0408 forward and 5\u0408-cacattgggggtaggaacac-3\u0408 reverse. Immunoelectron microscopic examination of kidneys bearing islet grafts. At 26 weeks, kidneys bearing islet grafts were harvested (n \u03ed 3 each from groups 1, 2, and 3) and fixed with 4% paraformaldehyde and 0.1% glutaraldehyde in 0.1 mol/l phosphate buffer at pH 7.4. Samples were embedded in LR White (London Resin, London, U.K.). Ultrathin sections on nickel grids were incubated with 6 mol/l urea in 0.1 mol/l glycine-HCl buffer (pH 3.5) for 5 min to etch the surface of sections. The grids were incubated with polyclonal anti-insulin-guinea pig primary antibodies (DakoCytomation) at 4\u00b0C overnight. After washing, the grids were incubated for 1.5 h with 10 nm colloidal gold-conjugated goat anti-guinea pig IgG (British Biocell Interna-", "cite_spans": [{"start": 908, "end": 912, "text": "(34)", "ref_id": "BIBREF33"}, {"start": 1062, "end": 1066, "text": "(34)", "ref_id": "BIBREF33"}, {"start": 1845, "end": 1849, "text": "(34)", "ref_id": "BIBREF33"}, {"start": 2165, "end": 2169, "text": "(38)", "ref_id": "BIBREF37"}], "ref_spans": []}, {"section": "V5 ALLOWS SINGLE-DONOR ISLET TRANSPLANTATION", "text": "tional). The grids were washed, postfixed with 2% glutaraldehyde, rinsed with ddH2O, and dried. The sections were stained with 2% uranyl acetate for 15 min and 3% lead citrate for 1 min and observed with a Hitachi H-7100 transmission electron microscope (35) . Statistical analysis. Results were expressed as means \u03ee SE. For comparisons between two groups, the paired or unpaired Student's t test (two tailed) was used. For multiple comparisons, the one-way ANOVA was used. KaplanMeier method was used to calculate the survival data. A P value \u03fd0.05 was considered significant when determined by the Mann-Whitney U test.", "cite_spans": [{"start": 254, "end": 258, "text": "(35)", "ref_id": "BIBREF34"}], "ref_spans": []}, {"section": "RESULTS", "text": "Effect of treatment with V5 on islet viability and function, as well as parameters associated with apoptosis in vitro. Pancreatic islet yield following isolation was 152.5 \u03ee 3.46 islet equivalents per mouse. Islet viability immediately after isolation, and 12 and 24 h later in control culture, was 99.1 \u03ee 0.7%, 81.0 \u03ee 1.2%, and 72.0 \u03ee 0.9%, respectively, whereas viability at the same time points after culture in the presence of 100 mol/l V5 was 98.9 \u03ee 0.6%, 95.4 \u03ee 0.8%, and 93.5 \u03ee 0.6%. To assess the effect of V5 on islets recovered under clinically relevant donor recovery conditions, we also evaluated the effect of V5 on mouse islets isolated in association with 12 h of cold ischemia and 30 min of warm ischemia. We found that V5 was effective in protecting mouse islets under these conditions (Table 1) . Since apoptosis is often reflected in mitochondrial function, we assessed mitochondrial dehydrogenase activity 24 h after isolation. As shown in Fig. 1A , mitochondrial dehydrogenase activity was significantly greater in V5-treated islets (96.4 \u03ee 1.5%) than that in control untreated islets (54.0 \u03ee 5.7%). We also measured the expression of annexin-V, an early marker of apoptosis, 24 h after isolation. V5-treated islets expressed significantly less annexin-V (14.0%) than control untreated islets (58.5%) (Fig. 1B-D) . A power blot was then performed to identify proteins significantly (more than twofold) altered in isolated islets after treatment for 24 h in V5. Power blot analysis screened over 50 proteins associated with apoptosis (Fig. 1E) . Western blot analysis showed a 0.11-fold reduction in the expression of the pro-apoptotic protein Bax, a 0.34-fold reduction in Bad, and a 0.46-fold reduction in NF-B-p65. Treatment of islets with V5 also generated an 11.76-fold upregulation in XIAP and a 3.31-fold increase in Bcl-2 expression (Fig. 1E and F) .", "cite_spans": [], "ref_spans": [{"start": 803, "end": 812, "text": "(Table 1)", "ref_id": "TABREF0"}, {"start": 960, "end": 967, "text": "Fig. 1A", "ref_id": "FIGREF0"}, {"start": 1322, "end": 1333, "text": "(Fig. 1B-D)", "ref_id": "FIGREF0"}, {"start": 1554, "end": 1563, "text": "(Fig. 1E)", "ref_id": "FIGREF0"}, {"start": 1861, "end": 1876, "text": "(Fig. 1E and F)", "ref_id": "FIGREF0"}]}, {"section": "RESULTS", "text": "To further investigate the effect of V5 on recovered islets, we analyzed glucose-responsive insulin secretion, or insulin secretion index, immediately after isolation and 24, 72, 120, and 168 h later. Since islets adherent to culture plates lose function quickly, analysis was performed on islets under both adherent and nonadherent conditions. V5-treated islets had a 2.7-to 3.7-fold higher insulin secretion index than control untreated islets at all time points under both adherent and nonadherent conditions ( Fig. 2A and B) , and V5-treated islets maintained their insulin content (128 \u03ee 1 at 24 h and 76 \u03ee 6 at 168 h under adherent culture conditions; 128 \u03ee 3 at 24 h and 101 \u03ee 5 at 168 h under nonadherent culture conditions) significantly better than untreated control islets (116 \u03ee 5 at 24 h and 9 \u03ee 2 at 168 h under adherent culture conditions; 117 \u03ee 4 at 24 h and 80 \u03ee 4 at 168 h under nonadherent culture conditions) (Fig. 2C and D) , respectively.", "cite_spans": [], "ref_spans": [{"start": 514, "end": 528, "text": "Fig. 2A and B)", "ref_id": "FIGREF1"}, {"start": 929, "end": 944, "text": "(Fig. 2C and D)", "ref_id": "FIGREF1"}]}, {"section": "Effect of V5 on recovered islets after transplantation.", "text": "To investigate the effect of V5 treatment on recovered islets after transplantation, we transplanted V5-treated and control untreated islets into streptozotocin-induced diabetic mice. Transplantation procedures induce a meaningful grade of apoptosis, dramatically reducing the islet engraftment capacities and its survival by induction of the inflammatory reactions. We examined the potential prevention of apoptosis in vivo by microspheres containing V5 and FGF-2 within the islets grafts, 3 days after transplantation, by insulin staining and TUNEL assay. We found that the number of insulin-positive cells was significantly maintained by V5 treatment (150 control untreated islet equivalents: 51 \u03ee 9 cells/high power field vs. 150 V5-treated islet equivalents: 202 \u03ee 23 cells/high power field; Fig. 3A-F and J) . Notably, a significantly larger number of TUNEL-positive cells were observed in control untreated islet grafts than found in V5-treated islets (Fig. 3G-I and K). V5 treatment significantly reduced inflammatory molecule IL-1\u2424 and TNF-\u2423 gene expression and enhanced Bcl-2 gene expression in islet grafts (Fig. 3) .", "cite_spans": [], "ref_spans": []}, {"section": "Effect of V5 on recovered islets after transplantation.", "text": "In consistency with this, following transplantation of 150 V5-treated islet equivalents (recovered from one donor), normoglycemia was achieved in all diabetic recipients within 12 days and 100% 6-month survival obtained ( Fig. 4A and B) . In contrast, transplantation of 150 control untreated islet equivalents (recovered from one donor) failed to tightly control blood glucose levels, and 60% of diabetic recipients died 6 months after transplantation. Transplantation of 450 control untreated islet equivalents (recovered from three donors) corrected hyperglycemia to the same degree as transplantation of 150 V5-treated islet equivalents and produced a similar degree of blood glucose control to that after transplantation of 150 V5-treated islet equivalents following glucose challenge (Fig. 4C) . Removal of kidneys bearing islet grafts 26 weeks after transplantation produced hyperglycemia in all transplanted mice, indicating that the islet grafts were responsible for correction of diabetes. Histological analysis of V5-treated islet grafts showed a comparatively equal amount of both total insulin content (16.1 \u03ee 0.4 g/graft), compared with those (16.7 \u03ee 1.4 g/graft) of V5-untreated 450 islet equivalents (Fig. 4D) , and size of the functional islet grafts (Fig. 5B, C, E, and F) . Insulin immunoelectron microscopy 26 weeks after transplantation showed \u2424-cells with numerous secretory granules and well-preserved ultrastructure organelles following V5-treatment (Fig. 5H  and J) , whereas control untreated islet grafts showed fewer \u2424-cells, each containing fewer insulin secretory granules and organelles ( Fig. 5G and J) .", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "Type 1 diabetes results from the loss of insulin-producing pancreatic \u2424-cells by \u2424-cell-specific autoimmune responses. Pancreatic islet transplantation is one possible method for the cure of diabetes; however, the shortage of human donor pancreata limits the widespread application of this procedure (1, 5, 6) . Because a relatively large \u2424-cell mass from two to four donor pancreata is needed to achieve normoglycemia in the recipient, it is crucial to develop treatments that would reduce loss of transplanted islets due to apoptosis and maximize use of the limited amount of donor tissue. Isolation of human islets is very stressful on the cells as it disrupts cell-cell and cell-matrix interactions and results in islet apoptosis (9, 12, 13, 17, 32, 38, 39) . Alterations in islet fine structure can be seen shortly after isolation and culture in vitro. Prevention of apoptosis has been a target to maintain islet mass for transplantation; for example, overexpression of XIAP (26) or A20 (23) in mouse islets by adenoviral vector-mediated delivery prevented early posttransplant apoptosis and reduced the islet cell mass needed to achieve normoglycemia. Although ex vivo gene transfer procedures using viral vectors are attractive, adenovirally transduced islets should be cultured to eliminate the risk of viral gene transfer to recipients. Thus, it would be beneficial to develop a simple, efficient method to protect islets from apoptosis and reduce the number of islets required for transplantation.", "cite_spans": [{"start": 300, "end": 303, "text": "(1,", "ref_id": "BIBREF0"}, {"start": 304, "end": 306, "text": "5,", "ref_id": "BIBREF4"}, {"start": 307, "end": 309, "text": "6)", "ref_id": "BIBREF5"}, {"start": 734, "end": 737, "text": "(9,", "ref_id": "BIBREF8"}, {"start": 738, "end": 741, "text": "12,", "ref_id": "BIBREF11"}, {"start": 742, "end": 745, "text": "13,", "ref_id": "BIBREF12"}, {"start": 746, "end": 749, "text": "17,", "ref_id": "BIBREF16"}, {"start": 750, "end": 753, "text": "32,", "ref_id": "BIBREF31"}, {"start": 754, "end": 757, "text": "38,", "ref_id": "BIBREF37"}, {"start": 758, "end": 761, "text": "39)", "ref_id": "BIBREF38"}, {"start": 992, "end": 996, "text": "(23)", "ref_id": "BIBREF22"}], "ref_spans": []}, {"section": "DISCUSSION", "text": "Bax is a member of the Bcl-2 family of proteins and plays a key role in the induction of apoptosis. In response to apoptotic stimuli, Bax translocates from the cytosol to mitochondria and causes release of apoptogenic factors (40) . Inhibition of Bax would be extremely useful in islet culture immediately after isolation procedure. Ku70 plays an important role in DNA double-strand break repair in the nucleus (41) . Ku70 binds Bax in the cytosol and inhibits its translocation into mitochondria (33) . The Bax-binding ", "cite_spans": [{"start": 226, "end": 230, "text": "(40)", "ref_id": "BIBREF39"}, {"start": 411, "end": 415, "text": "(41)", "ref_id": "BIBREF40"}, {"start": 497, "end": 501, "text": "(33)", "ref_id": "BIBREF32"}], "ref_spans": []}, {"section": "V5 ALLOWS SINGLE-DONOR ISLET TRANSPLANTATION", "text": "domain of human Ku70 consists of residues 578 -583, and a pentapeptide (i.e.,V5) contained within these residues is cell permeable and suppressed Bax-mediated apoptotic cell death in several types of human cells, including hepatoma Hep3B cells and myeloid 32D (EpoR wt) cells (14) . We previously found that V5 treatment of monkey hepatocyte cultures improved differentiated function and prolonged cell survival (42) . In this study, we investigated the effect of V5 on islet viability and functionality during islet isolation and transplantation into diabetic mice.", "cite_spans": [{"start": 276, "end": 280, "text": "(14)", "ref_id": "BIBREF13"}, {"start": 412, "end": 416, "text": "(42)", "ref_id": "BIBREF41"}], "ref_spans": []}, {"section": "V5 ALLOWS SINGLE-DONOR ISLET TRANSPLANTATION", "text": "First, we examined the effect of V5 on apoptosis of islets in vitro. We found that fluorescein isothyocyanate-labeled V5 (100 mol/l) was uniformly taken up by islet cells within 3 h when added into the culture, and no cytotoxic effects were observed with a dose \u0545500 mol/l (data not shown). Treatment of islets isolated from Balb/c mice with V5 peptide significantly increased viability and inhibited apoptosis.", "cite_spans": [], "ref_spans": []}, {"section": "V5 ALLOWS SINGLE-DONOR ISLET TRANSPLANTATION", "text": "The mitochondrial metabolite, succinate, is a key metabolic mediator of glucose-stimulated preproinsulin gene transcription and translation (43) . Therefore, we examined mitochondrial function in V5-treated islets and found that mitochondrial function was increased by \u03f342% compared with untreated islets. Preservation of mitochondrial function in \u2424-cells is critical for preserving their capacity to produce, store, and secrete insulin. V5 treatment significantly enhanced ATP levels in both 12-h cold preserved and 30-min warm preserved islets (Table 1 ) and markedly reduced apoptosis. Consistent with these findings, glucose-responsive insulin secretion was also increased by 2.7-to 3.7-fold in V5-treated islets. Islets treated with V5 maintained the insulin content of freshly isolated islets, even after 1 week of culture. Since islet culture seems to be an important step in the islet transplantation, the use of V5 might constitute an important tool for maintaining more viable islets with enhanced insulin secretion over the conventional cultures, floating better than adherent culture with matrices. Second, we examined the expression of proteins involved in the regulation of apoptosis in V5-treated islets. We found that the expression of pro-apoptotic molecules Bax, Bad, and NF-B was markedly reduced, and the expression of anti-apoptotic molecules XIAP and Bcl-2 was upregulated. XIAP has previously been shown to improve \u2424-cell growth, survival, and metabolic function during stress (35, 44, 45) and affects Akt/protein kinase B phosphorylation (36, 45) , modulating Bad, caspase-9, Bcl-2, cyclic AMP-response element-binding ", "cite_spans": [{"start": 140, "end": 144, "text": "(43)", "ref_id": "BIBREF42"}, {"start": 1500, "end": 1504, "text": "(35,", "ref_id": "BIBREF34"}, {"start": 1505, "end": 1508, "text": "44,", "ref_id": "BIBREF43"}, {"start": 1509, "end": 1512, "text": "45)", "ref_id": "BIBREF44"}, {"start": 1562, "end": 1566, "text": "(36,", "ref_id": "BIBREF35"}, {"start": 1567, "end": 1570, "text": "45)", "ref_id": "BIBREF44"}], "ref_spans": [{"start": 546, "end": 554, "text": "(Table 1", "ref_id": "TABREF0"}]}, {"section": "V5 ALLOWS SINGLE-DONOR ISLET TRANSPLANTATION", "text": "protein, and insulin receptor substrate-1 downstream. These changes may help to protect V5-treated islets from apoptosis and increase graft survival. The beneficial effects of XIAP have been reported. Overexpression of XIAP markedly enhanced \u2424-cell survival and functional recovery of islets in hypoxia-and cytokineinduced injury in vitro (27) . Overexpression of XIAP in human islets reversed the negative effects of immunosuppressive drugs on insulin secretion and cell viability (46) . Recently, it was reported that XIAP overexpression in human islets prevented posttransplant apoptosis and reduced the islet mass required to treat diabetes (26) .", "cite_spans": [{"start": 339, "end": 343, "text": "(27)", "ref_id": "BIBREF26"}, {"start": 482, "end": 486, "text": "(46)", "ref_id": "BIBREF45"}, {"start": 645, "end": 649, "text": "(26)", "ref_id": "BIBREF25"}], "ref_spans": []}, {"section": "V5 ALLOWS SINGLE-DONOR ISLET TRANSPLANTATION", "text": "These promising in vitro results suggested that V5 treatment might preserve the islet mass in grafts and thus reduce the number of islets needed to obtain insulin independence. Local hypoxia and lack of nutrients can cause apoptosis in islet transplants (8) . Early vascularization of islet grafts can overcome these problems and facilitate islet engraftment. We have previously found that use of gelatinized microspheres containing slow-release, cross-linked FGF-2 that persists for \u03f32 weeks produced rapid islet revascularization at the site of implantation (37) . In those mouse islet transplantation studies, islet graft function was improved by improved vascularization. However, we also encountered considerable transplantation-associated apoptosis that resulted in loss of islet mass (11) . Therefore, in this study, we transplanted islets embedded in microspheres containing FGF-2, to enhance vascularization, and V5, to reduce apoptosis, and found that apoptosis was decreased and the number of insulinpositive cells was increased in grafts containing islets treated with V5. When we embedded 150 islet equivalents within FGF-2-conjugated microspheres along with V5, diabetes was remitted within 12 days in streptozotocininduced diabetic mice, similar to the results seen in mice transplanted with 450 islet equivalents with FGF-2 only, suggesting that normoglycemia could be achieved with islets from a single donor if V5 is provided. Interestingly, V5 treatment significantly depressed inflammatory molecule IL-1\u2424 and TNF-\u2423 gene expression in islet grafts. We found that V5 treatment similarly affected allogenic islets following transplantation in preliminary studies (supplementary Fig. 1 [ available in an online appendix at http:// dx.doi.org/10.2337/db06-1679]). We next plan to explore methods to protect transplanted islets from autoimmune attack and early recurrence of diabetes following allogeneic islet transplantation.", "cite_spans": [{"start": 254, "end": 257, "text": "(8)", "ref_id": "BIBREF7"}, {"start": 560, "end": 564, "text": "(37)", "ref_id": "BIBREF36"}, {"start": 791, "end": 795, "text": "(11)", "ref_id": "BIBREF10"}], "ref_spans": [{"start": 1695, "end": 1701, "text": "Fig. 1", "ref_id": "FIGREF0"}]}, {"section": "V5 ALLOWS SINGLE-DONOR ISLET TRANSPLANTATION", "text": "In conclusion, we have shown that treatment of islets with V5 increases islet viability, enhances islet function, and prevents apoptosis. Transplantation of islets along with FGF-2 and V5 allowed a smaller islet mass (singledonor pancreas) to be used for transplantation; normoglycemia was achieved and insulin content and islet function were preserved posttransplantation. Timed release of V5, perhaps by gelatinization, may result in long-term prevention of apoptosis and improve outcomes in human islet transplantation.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen", "authors": [{"first": "A", "middle": ["M"], "last": "Shapiro", "suffix": ""}, {"first": "J", "middle": ["R"], "last": "Lakey", "suffix": ""}, {"first": "E", "middle": ["A"], "last": "Ryan", "suffix": ""}, {"first": "G", "middle": ["S"], "last": "Korbutt", "suffix": ""}, {"first": "E", "middle": [], "last": "Toth", "suffix": ""}, {"first": "G", "middle": ["L"], "last": "Warnock", "suffix": ""}, {"first": "N", "middle": ["M"], "last": "Kneteman", "suffix": ""}, {"first": "R", "middle": ["V"], "last": "Rajotte", "suffix": ""}], "year": 2000, "venue": "N Engl J Med", "link": "45022604"}, "BIBREF1": {"title": "Clinical outcomes and insulin secretion after islet transplantation with the Edmonton protocol", "authors": [{"first": "E", "middle": ["A"], "last": "Ryan", "suffix": ""}, {"first": "J", "middle": ["R"], "last": "Lakey", "suffix": ""}, {"first": "R", "middle": ["V"], "last": "Rajotte", "suffix": ""}, {"first": "G", "middle": ["S"], "last": "Korbutt", "suffix": ""}, {"first": "T", "middle": [], "last": "Kin", "suffix": ""}, {"first": "S", "middle": [], "last": "Imes", "suffix": ""}, {"first": "A", "middle": [], "last": "Rabinovitch", "suffix": ""}, {"first": "J", "middle": ["F"], "last": "Elliott", "suffix": ""}, {"first": "D", "middle": [], "last": "Bigam", "suffix": ""}, {"first": "N", "middle": ["M"], "last": "Kneteman", "suffix": ""}, {"first": "G", "middle": ["L"], "last": "Warnock", "suffix": ""}, {"first": "I", "middle": [], "last": "Larsen", "suffix": ""}, {"first": "A", "middle": ["M"], "last": "Shapiro", "suffix": ""}], "year": 2001, "venue": "Diabetes", "link": "18253881"}, "BIBREF2": {"title": "Early assessment of apoptosis in isolated islets of Langerhans", "authors": [{"first": "P", "middle": [], "last": "Cattan", "suffix": ""}, {"first": "T", "middle": [], "last": "Berney", "suffix": ""}, {"first": "S", "middle": [], "last": "Schena", "suffix": ""}, {"first": "R", "middle": ["D"], "last": "Molano", "suffix": ""}, {"first": "A", "middle": [], "last": "Pileggi", "suffix": ""}, {"first": "C", "middle": [], "last": "Vizzardelli", "suffix": ""}, {"first": "C", "middle": [], "last": "Ricordi", "suffix": ""}, {"first": "L", "middle": [], "last": "Inverardi", "suffix": ""}], "year": 2001, "venue": "Transplantation", "link": "11424898"}, "BIBREF3": {"title": "Unraveling the secrets of single donor success in islet transplantation", "authors": [{"first": "A", "middle": ["M"], "last": "Shapiro", "suffix": ""}, {"first": "C", "middle": [], "last": "Ricordi", "suffix": ""}], "year": 2004, "venue": "Am J Transplant", "link": "39409921"}, "BIBREF4": {"title": "Insulin independence after living-donor distal pancreatectomy and islet allotransplantation", "authors": [{"first": "S", "middle": [], "last": "Matsumoto", "suffix": ""}, {"first": "T", "middle": [], "last": "Okitsu", "suffix": ""}, {"first": "Y", "middle": [], "last": "Iwanaga", "suffix": ""}, {"first": "H", "middle": [], "last": "Noguchi", "suffix": ""}, {"first": "H", "middle": [], "last": "Nagata", "suffix": ""}, {"first": "Y", "middle": [], "last": "Yonekawa", "suffix": ""}, {"first": "Y", "middle": [], "last": "Yamada", "suffix": ""}, {"first": "K", "middle": [], "last": "Fukuda", "suffix": ""}, {"first": "K", "middle": [], "last": "Tsukiyama", "suffix": ""}, {"first": "H", "middle": [], "last": "Suzuki", "suffix": ""}, {"first": "Y", "middle": [], "last": "Kawasaki", "suffix": ""}, {"first": "M", "middle": [], "last": "Shimodaira", "suffix": ""}, {"first": "K", "middle": [], "last": "Matsuoka", "suffix": ""}, {"first": "T", "middle": [], "last": "Shibata", "suffix": ""}, {"first": "Y", "middle": [], "last": "Kasai", "suffix": ""}, {"first": "T", "middle": [], "last": "Maekawa", "suffix": ""}, {"first": "J", "middle": [], "last": "Shapiro", "suffix": ""}, {"first": "K", "middle": [], "last": "Tanaka", "suffix": ""}], "year": 2005, "venue": "Lancet", "link": "40596317"}, "BIBREF5": {"title": "Single-donor, marginal-dose islet transplantation in patients with type 1 diabetes", "authors": [{"first": "B", "middle": ["J"], "last": "Hering", "suffix": ""}, {"first": "R", "middle": [], "last": "Kandaswamy", "suffix": ""}, {"first": "J", "middle": ["D"], "last": "Ansite", "suffix": ""}, {"first": "P", "middle": ["M"], "last": "Eckman", "suffix": ""}, {"first": "M", "middle": [], "last": "Nakano", "suffix": ""}, {"first": "T", "middle": [], "last": "Sawada", "suffix": ""}, {"first": "I", "middle": [], "last": "Matsumoto", "suffix": ""}, {"first": "S", "middle": ["H"], "last": "Ihm", "suffix": ""}, {"first": "H", "middle": ["J"], "last": "Zhang", "suffix": ""}, {"first": "J", "middle": [], "last": "Parkey", "suffix": ""}, {"first": "D", "middle": ["W"], "last": "Hunter", "suffix": ""}, {"first": "D", "middle": ["E"], "last": "Sutherland", "suffix": ""}], "year": 2005, "venue": "JAMA", "link": "75322670"}, "BIBREF6": {"title": "Activation and expression of ERK, JNK, and p38 MAP-kinases in isolated islets of Langerhans: implications for cultured islet survival", "authors": [{"first": "S", "middle": [], "last": "Paraskevas", "suffix": ""}, {"first": "R", "middle": [], "last": "Aikin", "suffix": ""}, {"first": "D", "middle": [], "last": "Maysinger", "suffix": ""}, {"first": "J", "middle": ["R"], "last": "Lakey", "suffix": ""}, {"first": "T", "middle": ["J"], "last": "Cavanagh", "suffix": ""}, {"first": "B", "middle": [], "last": "Hering", "suffix": ""}, {"first": "R", "middle": [], "last": "Wang", "suffix": ""}, {"first": "L", "middle": [], "last": "Rosenberg", "suffix": ""}], "year": 1999, "venue": "FEBS Lett", "link": "34465267"}, "BIBREF7": {"title": "Pancreatic islet cell survival following islet isolation: the role of cellular interactions in the pancreas", "authors": [{"first": "A", "middle": [], "last": "Ilieva", "suffix": ""}, {"first": "S", "middle": [], "last": "Yuan", "suffix": ""}, {"first": "R", "middle": ["N"], "last": "Wang", "suffix": ""}, {"first": "D", "middle": [], "last": "Agapitos", "suffix": ""}, {"first": "D", "middle": ["J"], "last": "Hill", "suffix": ""}, {"first": "L", "middle": [], "last": "Rosenberg", "suffix": ""}], "year": 1999, "venue": "J Endocrinol", "link": "5670184"}, "BIBREF8": {"title": "Vulnerability of islets in the immediate posttransplantation period: dynamic changes in structure and function", "authors": [{"first": "A", "middle": ["M"], "last": "Davalli", "suffix": ""}, {"first": "L", "middle": [], "last": "Scaglia", "suffix": ""}, {"first": "D", "middle": ["H"], "last": "Zangen", "suffix": ""}, {"first": "J", "middle": [], "last": "Hollister", "suffix": ""}, {"first": "S", "middle": [], "last": "Bonner-Weir", "suffix": ""}, {"first": "G", "middle": ["C"], "last": "Weir", "suffix": ""}], "year": 1996, "venue": "Diabetes", "link": "25023913"}, "BIBREF9": {"title": "\u2424-cell death and mass in syngeneically transplanted islets exposed to short-and long-term hyperglycemia", "authors": [{"first": "M", "middle": [], "last": "Biarnes", "suffix": ""}, {"first": "M", "middle": [], "last": "Montolio", "suffix": ""}, {"first": "V", "middle": [], "last": "Nacher", "suffix": ""}, {"first": "M", "middle": [], "last": "Raurell", "suffix": ""}, {"first": "J", "middle": [], "last": "Soler", "suffix": ""}, {"first": "E", "middle": [], "last": "Montanya", "suffix": ""}], "year": 2002, "venue": "Diabetes", "link": "20772389"}, "BIBREF10": {"title": "Amelioration of diabetes in mice after single-donor islet transplantation using the controlled release of gelatinized FGF-2", "authors": [{"first": "J", "middle": ["D"], "last": "Rivas-Carrillo", "suffix": ""}, {"first": "N", "middle": [], "last": "Navarro-Alvarez", "suffix": ""}, {"first": "A", "middle": [], "last": "Soto-Gutierrez", "suffix": ""}, {"first": "T", "middle": [], "last": "Okitsu", "suffix": ""}, {"first": "Y", "middle": [], "last": "Chen", "suffix": ""}, {"first": "Y", "middle": [], "last": "Tabata", "suffix": ""}, {"first": "H", "middle": [], "last": "Misawa", "suffix": ""}, {"first": "H", "middle": [], "last": "Noguchi", "suffix": ""}, {"first": "S", "middle": [], "last": "Matsumoto", "suffix": ""}, {"first": "N", "middle": [], "last": "Tanaka", "suffix": ""}, {"first": "N", "middle": [], "last": "Kobayashi", "suffix": ""}], "year": 2006, "venue": "Cell Transplant", "link": "25421669"}, "BIBREF11": {"title": "Anoikis, extracellular matrix, and apoptosis factors in isolated cell transplantation", "authors": [{"first": "F", "middle": ["T"], "last": "Thomas", "suffix": ""}, {"first": "J", "middle": ["L"], "last": "Contreras", "suffix": ""}, {"first": "G", "middle": [], "last": "Bilbao", "suffix": ""}, {"first": "C", "middle": [], "last": "Ricordi", "suffix": ""}, {"first": "D", "middle": [], "last": "Curiel", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Thomas", "suffix": ""}], "year": 1999, "venue": "Surgery", "link": "21982495"}, "BIBREF12": {"title": "A tripartite anoikis-like mechanism causes early isolated islet apoptosis", "authors": [{"first": "F", "middle": [], "last": "Thomas", "suffix": ""}, {"first": "J", "middle": [], "last": "Wu", "suffix": ""}, {"first": "J", "middle": ["L"], "last": "Contreras", "suffix": ""}, {"first": "C", "middle": [], "last": "Smyth", "suffix": ""}, {"first": "G", "middle": [], "last": "Bilbao", "suffix": ""}, {"first": "J", "middle": [], "last": "He", "suffix": ""}, {"first": "J", "middle": [], "last": "Thomas", "suffix": ""}], "year": 2001, "venue": "Surgery", "link": "26121285"}, "BIBREF13": {"title": "The biochemistry of apoptosis", "authors": [{"first": "M", "middle": ["O"], "last": "Hengartner", "suffix": ""}], "year": 2000, "venue": "Nature", "link": "4415642"}, "BIBREF14": {"title": "Signaling to NF-kappaB", "authors": [{"first": "M", "middle": ["S"], "last": "Hayden", "suffix": ""}, {"first": "S", "middle": [], "last": "Ghosh", "suffix": ""}], "year": 2004, "venue": "Genes Dev", "link": "45830250"}, "BIBREF15": {"title": "Insulin-secreting beta-cells possess specific receptors for interleukin-1 beta", "authors": [{"first": "P", "middle": [], "last": "Hammonds", "suffix": ""}, {"first": "M", "middle": [], "last": "Beggs", "suffix": ""}, {"first": "G", "middle": [], "last": "Beresford", "suffix": ""}, {"first": "J", "middle": [], "last": "Espinal", "suffix": ""}, {"first": "J", "middle": [], "last": "Clarke", "suffix": ""}, {"first": "R", "middle": ["J"], "last": "Mertz", "suffix": ""}], "year": 1990, "venue": "FEBS Lett", "link": "41300517"}, "BIBREF16": {"title": "Cell loss in isolated human islets occurs by apoptosis", "authors": [{"first": "S", "middle": [], "last": "Paraskevas", "suffix": ""}, {"first": "D", "middle": [], "last": "Maysinger", "suffix": ""}, {"first": "R", "middle": [], "last": "Wang", "suffix": ""}, {"first": "T", "middle": ["P"], "last": "Duguid", "suffix": ""}, {"first": "L", "middle": [], "last": "Rosenberg", "suffix": ""}], "year": 2000, "venue": "Pancreas", "link": "25399532"}, "BIBREF17": {"title": "Elevated vascular endothelial growth factor production in islets improves islet graft vascularization", "authors": [{"first": "N", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "A", "middle": [], "last": "Richter", "suffix": ""}, {"first": "J", "middle": [], "last": "Suriawinata", "suffix": ""}, {"first": "S", "middle": [], "last": "Harbaran", "suffix": ""}, {"first": "J", "middle": [], "last": "Altomonte", "suffix": ""}, {"first": "L", "middle": [], "last": "Cong", "suffix": ""}, {"first": "H", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "K", "middle": [], "last": "Song", "suffix": ""}, {"first": "M", "middle": [], "last": "Meseck", "suffix": ""}, {"first": "J", "middle": [], "last": "Bromberg", "suffix": ""}, {"first": "H", "middle": [], "last": "Dong", "suffix": ""}], "year": 2004, "venue": "Diabetes", "link": "7201239"}, "BIBREF18": {"title": "Transfection of human pancreatic islets with an anti-apoptotic gene (bcl-2) protects \u2424-cells from cytokine-induced destruction", "authors": [{"first": "A", "middle": [], "last": "Rabinovitch", "suffix": ""}, {"first": "W", "middle": [], "last": "Suarez-Pinzon", "suffix": ""}, {"first": "K", "middle": [], "last": "Strynadka", "suffix": ""}, {"first": "Q", "middle": [], "last": "Ju", "suffix": ""}, {"first": "D", "middle": [], "last": "Edelstein", "suffix": ""}, {"first": "M", "middle": [], "last": "Brownlee", "suffix": ""}, {"first": "G", "middle": ["S"], "last": "Korbutt", "suffix": ""}, {"first": "R", "middle": ["V"], "last": "Rajotte", "suffix": ""}], "year": 1999, "venue": "Diabetes", "link": "1023454"}, "BIBREF19": {"title": "The X-linked inhibitor of apoptosis protein enhances survival of murine islet allografts", "authors": [{"first": "A", "middle": [], "last": "Plesner", "suffix": ""}, {"first": "P", "middle": [], "last": "Liston", "suffix": ""}, {"first": "R", "middle": [], "last": "Tan", "suffix": ""}, {"first": "R", "middle": ["G"], "last": "Korneluk", "suffix": ""}, {"first": "C", "middle": ["B"], "last": "Verchere", "suffix": ""}], "year": 2005, "venue": "Diabetes", "link": "16111793"}, "BIBREF20": {"title": "Hepatocyte growth factor gene therapy for pancreatic islets in diabetes: reducing the minimal islet transplant mass required in a glucocorticoid-free rat model of allogeneic portal vein islet transplantation", "authors": [{"first": "J", "middle": ["C"], "last": "Lopez-Talavera", "suffix": ""}, {"first": "A", "middle": [], "last": "Garcia-Ocana", "suffix": ""}, {"first": "I", "middle": [], "last": "Sipula", "suffix": ""}, {"first": "K", "middle": ["K"], "last": "Takane", "suffix": ""}, {"first": "I", "middle": [], "last": "Cozar-Castellano", "suffix": ""}, {"first": "A", "middle": ["F"], "last": "Stewart", "suffix": ""}], "year": 2004, "venue": "Endocrinology", "link": "16153418"}, "BIBREF21": {"title": "Role of caspases in the regulation of apoptotic pancreatic islet beta-cells death", "authors": [{"first": "H", "middle": [], "last": "Hui", "suffix": ""}, {"first": "F", "middle": [], "last": "Dotta", "suffix": ""}, {"first": "Di", "middle": [], "last": "Mario", "suffix": ""}, {"first": "U", "middle": [], "last": "Perfetti", "suffix": ""}, {"first": "R", "middle": [], "last": "", "suffix": ""}], "year": 2004, "venue": "J Cell Physiol", "link": "25298689"}, "BIBREF22": {"title": "Genetic engineering of a suboptimal islet graft with A20 preserves beta cell mass and function", "authors": [{"first": "S", "middle": ["T"], "last": "Grey", "suffix": ""}, {"first": "C", "middle": [], "last": "Longo", "suffix": ""}, {"first": "T", "middle": [], "last": "Shukri", "suffix": ""}, {"first": "V", "middle": ["I"], "last": "Patel", "suffix": ""}, {"first": "E", "middle": [], "last": "Csizmadia", "suffix": ""}, {"first": "S", "middle": [], "last": "Daniel", "suffix": ""}, {"first": "M", "middle": ["B"], "last": "Arvelo", "suffix": ""}, {"first": "V", "middle": [], "last": "Tchipashvili", "suffix": ""}, {"first": "C", "middle": [], "last": "Ferran", "suffix": ""}], "year": 2003, "venue": "J Immunol", "link": "23854240"}, "BIBREF23": {"title": "Protection of human islets from the effects of interleukin-1beta by adenoviral gene transfer of an Ikappa B repressor", "authors": [{"first": "N", "middle": [], "last": "Giannoukakis", "suffix": ""}, {"first": "W", "middle": ["A"], "last": "Rudert", "suffix": ""}, {"first": "M", "middle": [], "last": "Trucco", "suffix": ""}, {"first": "P", "middle": ["D"], "last": "Robbins", "suffix": ""}], "year": 2000, "venue": "J Biol Chem", "link": "23973572"}, "BIBREF24": {"title": "Adenovirus-mediated hepatocyte growth factor expression in mouse islets improves pancreatic islet transplant performance and reduces beta cell death", "authors": [{"first": "A", "middle": [], "last": "Garcia-Ocana", "suffix": ""}, {"first": "K", "middle": ["K"], "last": "Takane", "suffix": ""}, {"first": "V", "middle": ["T"], "last": "Reddy", "suffix": ""}, {"first": "J", "middle": ["C"], "last": "Lopez-Talavera", "suffix": ""}, {"first": "R", "middle": ["C"], "last": "Vasavada", "suffix": ""}, {"first": "A", "middle": ["F"], "last": "Stewart", "suffix": ""}], "year": 2003, "venue": "J Biol Chem", "link": "23164927"}, "BIBREF25": {"title": "XIAP overexpression in human islets prevents early posttransplant apoptosis and reduces the islet mass needed to treat diabetes", "authors": [{"first": "J", "middle": ["A"], "last": "Emamaullee", "suffix": ""}, {"first": "R", "middle": ["V"], "last": "Rajotte", "suffix": ""}, {"first": "P", "middle": [], "last": "Liston", "suffix": ""}, {"first": "R", "middle": ["G"], "last": "Korneluk", "suffix": ""}, {"first": "J", "middle": ["R"], "last": "Lakey", "suffix": ""}, {"first": "A", "middle": ["M"], "last": "Shapiro", "suffix": ""}, {"first": "J", "middle": ["F"], "last": "Elliott", "suffix": ""}], "year": 2005, "venue": "Diabetes", "link": "17309633"}, "BIBREF26": {"title": "XIAP overexpression in islet beta-cells enhances engraftment and minimizes hypoxia-reperfusion injury", "authors": [{"first": "J", "middle": [], "last": "Emamaullee", "suffix": ""}, {"first": "P", "middle": [], "last": "Liston", "suffix": ""}, {"first": "R", "middle": ["G"], "last": "Korneluk", "suffix": ""}, {"first": "A", "middle": ["M"], "last": "Shapiro", "suffix": ""}, {"first": "J", "middle": ["F"], "last": "Elliott", "suffix": ""}], "year": 2005, "venue": "Am J Transplant", "link": "25672362"}, "BIBREF27": {"title": "Gene therapy death prompts review of adenovirus vector", "authors": [{"first": "E", "middle": [], "last": "Marshall", "suffix": ""}], "year": 1999, "venue": "Science", "link": "46362535"}, "BIBREF28": {"title": "Insulin-like growth factor II allows prolonged blood glucose normalization with a reduced islet cell mass transplantation", "authors": [{"first": "R", "middle": [], "last": "Robitaille", "suffix": ""}, {"first": "J", "middle": [], "last": "Dusseault", "suffix": ""}, {"first": "N", "middle": [], "last": "Henley", "suffix": ""}, {"first": "L", "middle": [], "last": "Rosenberg", "suffix": ""}, {"first": "J", "middle": ["P"], "last": "Halle", "suffix": ""}], "year": 2003, "venue": "Endocrinology", "link": "36648348"}, "BIBREF29": {"title": "Leptin increases the viability of isolated rat pancreatic islets by suppressing apoptosis", "authors": [{"first": "S", "middle": [], "last": "Okuya", "suffix": ""}, {"first": "K", "middle": [], "last": "Tanabe", "suffix": ""}, {"first": "Y", "middle": [], "last": "Tanizawa", "suffix": ""}, {"first": "Y", "middle": [], "last": "Oka", "suffix": ""}], "year": 2001, "venue": "Endocrinology", "link": "43875603"}, "BIBREF30": {"title": "Eckhoff DE: 17beta-Estradiol protects isolated human pancreatic islets against proinflammatory cytokine-induced cell death: molecular mechanisms and islet functionality", "authors": [{"first": "J", "middle": ["L"], "last": "Contreras", "suffix": ""}, {"first": "C", "middle": ["A"], "last": "Smyth", "suffix": ""}, {"first": "G", "middle": [], "last": "Bilbao", "suffix": ""}, {"first": "C", "middle": ["J"], "last": "Young", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Thompson", "suffix": ""}], "year": 2002, "venue": "Transplantation", "link": "208515125"}, "BIBREF31": {"title": "Caspase-3 inhibitor prevents apoptosis of human islets immediately after isolation and improves islet graft function", "authors": [{"first": "M", "middle": [], "last": "Nakano", "suffix": ""}, {"first": "I", "middle": [], "last": "Matsumoto", "suffix": ""}, {"first": "T", "middle": [], "last": "Sawada", "suffix": ""}, {"first": "J", "middle": [], "last": "Ansite", "suffix": ""}, {"first": "J", "middle": [], "last": "Oberbroeckling", "suffix": ""}, {"first": "H", "middle": ["J"], "last": "Zhang", "suffix": ""}, {"first": "N", "middle": [], "last": "Kirchhof", "suffix": ""}, {"first": "J", "middle": [], "last": "Shearer", "suffix": ""}, {"first": "D", "middle": ["E"], "last": "Sutherland", "suffix": ""}, {"first": "B", "middle": ["J"], "last": "Hering", "suffix": ""}], "year": 2004, "venue": "Pancreas", "link": "23875867"}, "BIBREF32": {"title": "Cytoprotective membrane-permeable peptides designed from the Bax-binding domain of Ku70", "authors": [{"first": "M", "middle": [], "last": "Sawada", "suffix": ""}, {"first": "P", "middle": [], "last": "Hayes", "suffix": ""}, {"first": "S", "middle": [], "last": "Matsuyama", "suffix": ""}], "year": 2003, "venue": "Nat Cell Biol", "link": "27967122"}, "BIBREF33": {"title": "A human beta-cell line for transplantation therapy to control type 1 diabetes", "authors": [{"first": "M", "middle": [], "last": "Narushima", "suffix": ""}, {"first": "N", "middle": [], "last": "Kobayashi", "suffix": ""}, {"first": "T", "middle": [], "last": "Okitsu", "suffix": ""}, {"first": "Y", "middle": [], "last": "Tanaka", "suffix": ""}, {"first": "S", "middle": ["A"], "last": "Li", "suffix": ""}, {"first": "Y", "middle": [], "last": "Chen", "suffix": ""}, {"first": "A", "middle": [], "last": "Miki", "suffix": ""}, {"first": "K", "middle": [], "last": "Tanaka", "suffix": ""}, {"first": "S", "middle": [], "last": "Nakaji", "suffix": ""}, {"first": "K", "middle": [], "last": "Takei", "suffix": ""}, {"first": "A", "middle": ["S"], "last": "Gutierrez", "suffix": ""}, {"first": "J", "middle": ["D"], "last": "Rivas-Carrillo", "suffix": ""}, {"first": "N", "middle": [], "last": "Navarroalvarez", "suffix": ""}, {"first": "H", "middle": ["S"], "last": "Jun", "suffix": ""}, {"first": "K", "middle": ["A"], "last": "Westerman", "suffix": ""}, {"first": "H", "middle": [], "last": "Noguchi", "suffix": ""}, {"first": "J", "middle": ["R"], "last": "Lakey", "suffix": ""}, {"first": "P", "middle": [], "last": "Leboulch", "suffix": ""}, {"first": "N", "middle": [], "last": "Tanaka", "suffix": ""}, {"first": "J", "middle": ["W"], "last": "Yoon", "suffix": ""}], "year": 2005, "venue": "Nat Biotechnol", "link": "23171356"}, "BIBREF34": {"title": "Oncogenic kinase signalling", "authors": [{"first": "P", "middle": [], "last": "Blume-Jensen", "suffix": ""}, {"first": "T", "middle": [], "last": "Hunter", "suffix": ""}], "year": 2001, "venue": "Nature", "link": "4428819"}, "BIBREF35": {"title": "XIAP regulates Akt activity and caspase-3-dependent cleavage during cisplatin-induced apoptosis in human ovarian epithelial cancer cells", "authors": [{"first": "E", "middle": [], "last": "Asselin", "suffix": ""}, {"first": "G", "middle": ["B"], "last": "Mills", "suffix": ""}, {"first": "B", "middle": ["K"], "last": "Tsang", "suffix": ""}], "year": 2001, "venue": "Cancer Res", "link": "18562503"}, "BIBREF36": {"title": "Neovascularization effect of biodegradable gelatin microspheres incorporating basic fibroblast growth factor", "authors": [{"first": "Y", "middle": [], "last": "Tabata", "suffix": ""}, {"first": "S", "middle": [], "last": "Hijikata", "suffix": ""}, {"first": "M", "middle": [], "last": "Muniruzzaman", "suffix": ""}, {"first": "Y", "middle": [], "last": "Ikada", "suffix": ""}], "year": 1999, "venue": "J Biomater Sci Polym Ed", "link": "22820886"}, "BIBREF37": {"title": "Endotoxin-mediated delayed islet graft function is associated with increased intra-islet cytokine production and islet cell apoptosis", "authors": [{"first": "T", "middle": [], "last": "Berney", "suffix": ""}, {"first": "R", "middle": ["D"], "last": "Molano", "suffix": ""}, {"first": "P", "middle": [], "last": "Cattan", "suffix": ""}, {"first": "A", "middle": [], "last": "Pileggi", "suffix": ""}, {"first": "C", "middle": [], "last": "Vizzardelli", "suffix": ""}, {"first": "R", "middle": [], "last": "Oliver", "suffix": ""}, {"first": "C", "middle": [], "last": "Ricordi", "suffix": ""}, {"first": "L", "middle": [], "last": "Inverardi", "suffix": ""}], "year": 2001, "venue": "Transplantation", "link": "45813515"}, "BIBREF38": {"title": "Inhibition of caspasemediated PARP-1 cleavage results in increased necrosis in isolated islets of Langerhans", "authors": [{"first": "R", "middle": [], "last": "Aikin", "suffix": ""}, {"first": "L", "middle": [], "last": "Rosenberg", "suffix": ""}, {"first": "S", "middle": [], "last": "Paraskevas", "suffix": ""}, {"first": "D", "middle": [], "last": "Maysinger", "suffix": ""}], "year": 2004, "venue": "J Mol Med", "link": "20162176"}, "BIBREF39": {"title": "Movement of Bax from the cytosol to mitochondria during apoptosis", "authors": [{"first": "K", "middle": ["G"], "last": "Wolter", "suffix": ""}, {"first": "Y", "middle": ["T"], "last": "Hsu", "suffix": ""}, {"first": "C", "middle": ["L"], "last": "Smith", "suffix": ""}, {"first": "A", "middle": [], "last": "Nechushtan", "suffix": ""}, {"first": "X", "middle": ["G"], "last": "Xi", "suffix": ""}, {"first": "R", "middle": ["J"], "last": "Youle", "suffix": ""}], "year": 1997, "venue": "J Cell Biol", "link": "9478967"}, "BIBREF40": {"title": "Structure of the Ku heterodimer bound to DNA and its implications for double-strand break repair", "authors": [{"first": "J", "middle": ["R"], "last": "Walker", "suffix": ""}, {"first": "R", "middle": ["A"], "last": "Corpina", "suffix": ""}, {"first": "J", "middle": [], "last": "Goldberg", "suffix": ""}], "year": 2001, "venue": "Nature", "link": "4371575"}, "BIBREF41": {"title": "Prolonged survival of mice with acute liver failure with transplantation of monkey hepatocytes cultured with an antiapoptotic pentapeptide V5", "authors": [{"first": "K", "middle": [], "last": "Tanaka", "suffix": ""}, {"first": "N", "middle": [], "last": "Kobayashi", "suffix": ""}, {"first": "A", "middle": ["S"], "last": "Gutierrez", "suffix": ""}, {"first": "J", "middle": ["D"], "last": "Rivas-Carrillo", "suffix": ""}, {"first": "N", "middle": [], "last": "Navarro-Alvarez", "suffix": ""}, {"first": "Y", "middle": [], "last": "Chen", "suffix": ""}, {"first": "M", "middle": [], "last": "Narushima", "suffix": ""}, {"first": "A", "middle": [], "last": "Miki", "suffix": ""}, {"first": "T", "middle": [], "last": "Okitsu", "suffix": ""}, {"first": "H", "middle": [], "last": "Noguchi", "suffix": ""}, {"first": "N", "middle": [], "last": "Tanaka", "suffix": ""}], "year": 2006, "venue": "Transplantation", "link": "23091874"}, "BIBREF42": {"title": "Mitochondrial regulation of insulin production in rat pancreatic islets", "authors": [{"first": "G", "middle": [], "last": "Leibowitz", "suffix": ""}, {"first": "M", "middle": ["Z"], "last": "Khaldi", "suffix": ""}, {"first": "A", "middle": [], "last": "Shauer", "suffix": ""}, {"first": "M", "middle": [], "last": "Parnes", "suffix": ""}, {"first": "A", "middle": ["I"], "last": "Oprescu", "suffix": ""}, {"first": "E", "middle": [], "last": "Cerasi", "suffix": ""}, {"first": "J", "middle": ["C"], "last": "Jonas", "suffix": ""}, {"first": "N", "middle": [], "last": "Kaiser", "suffix": ""}], "year": 2005, "venue": "Diabetologia", "link": "6220257"}, "BIBREF43": {"title": "The activation of Akt/PKB signaling pathway and cell survival", "authors": [{"first": "G", "middle": [], "last": "Song", "suffix": ""}, {"first": "G", "middle": [], "last": "Ouyang", "suffix": ""}, {"first": "S", "middle": [], "last": "Bao", "suffix": ""}], "year": 2005, "venue": "J Cell Mol Med", "link": "39272916"}, "BIBREF44": {"title": "Cellular survival: a play in three Akts", "authors": [{"first": "S", "middle": ["R"], "last": "Datta", "suffix": ""}, {"first": "A", "middle": [], "last": "Brunet", "suffix": ""}, {"first": "M", "middle": ["E"], "last": "Greenberg", "suffix": ""}], "year": 1999, "venue": "Genes Dev", "link": "33500799"}, "BIBREF45": {"title": "Adenovirus-mediated XIAP gene transfer reverses the negative effects of immunosuppressive drugs on insulin secretion and cell viability of isolated human islets", "authors": [{"first": "H", "middle": [], "last": "Hui", "suffix": ""}, {"first": "N", "middle": [], "last": "Khoury", "suffix": ""}, {"first": "X", "middle": [], "last": "Zhao", "suffix": ""}, {"first": "L", "middle": [], "last": "Balkir", "suffix": ""}, {"first": "D", "middle": [], "last": "&apos;amico", "suffix": ""}, {"first": "E", "middle": [], "last": "Bullotta", "suffix": ""}, {"first": "A", "middle": [], "last": "Nguyen", "suffix": ""}, {"first": "E", "middle": ["D"], "last": "Gambotto", "suffix": ""}, {"first": "A", "middle": [], "last": "Perfetti", "suffix": ""}, {"first": "R", "middle": [], "last": "", "suffix": ""}], "year": 2005, "venue": "Diabetes", "link": "17034861"}}, "ref_entries": {"FIGREF0": {"text": "FIG. 1. Mitochondrial function, annexin-V expression, and power blot assay of the islets treated with V5. A: Comparative measurements of mitochondrial function of the islets at 24 h by an MTT assay. V5-treated islets showed significantly better function than untreated islets [P < 0.01 for V5 (\u0609): 96.4 \u060e 1.5%] and V5 (\u060a): 54.0 \u060e 5.7%). The value for islets immediately after isolation was 100%. B-D: Detection of annexin-V expression. V5-untreated islets revealed the high expression of annexin-V (58.5%) 24 h after isolation. The significantly lower expression of annexin-V (14.0%) was observed in the V5-treated islets at 24 h, which was relatively comparable with that of normal islets immediately after isolation (8.7%). E: List of the molecules assessed by a power blot study. F: The differential expression of the molecules in V5-treated or -untreated islets at 24 h. The marked reduction of the expression of pro-apoptotic proteins of Bax, Bad, and NF-B p65 and the upregulated expression of XIAP and Bcl-2 were observed in V5-treated islets. The data are representative of three independent experiments.", "type": "figure"}, "FIGREF1": {"text": "FIG. 2. Insulin secretion index and insulin content of islets. A: V5-treated islets showed significantly better insulin secretion index than V5-untreated islets at days 1, 3, 5, and 7. C: The insulin content was significantly higher in V5-treated islets at days 1, 3, 5, and 7 compared with V5-untreated islets. These data are representative of three independent experiments. E: Treatment of V5 allowed significantly favorable maintenance of islet mass at days 1, 3, 5, and 7. B-F: These findings, observed in adherent culture, were also confirmed in islets in floating culture using ultralow attachment dishes. IEQ, islet equivalent.", "type": "figure"}, "TABREF0": {"text": "Effect of V5 on mouse islets isolated in association with 12 h of cold ischemia and 30 min of warm ischemia", "type": "table"}}}
{"paper_id": "17783411", "_pdf_hash": "dc2828bd8e2bdd71ce83ca6780b83d01967f9243", "abstract": [], "body_text": [{"section": "List of Figures", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Introduction to LIDAR", "text": "Light detection and ranging (LIDAR) is an application of lasers used to discover information about a distant object, usually some form of distance information. LIDAR data are usually collected via airplane, with the airplane traversing a subject area of interest and collecting data about this area through the use of laser pulses. These laser pulses are emitted from the airplane fuselage from a laser scanner device, and the round trip travel time from this emission and the returning light is measured. This time delay is then used to determine the elevation of the ground in this particular area. LIDAR equipment is usually paired with a global positioning system (GPS) in order to accurately pinpoint the x and y coordinates of a specific data measurement.", "cite_spans": [], "ref_spans": []}, {"section": "The LIDAR Collection Process", "text": "The way in which LIDAR data is collected is a very detailed one that needs to be explained more thoroughly in order to appreciate it fully. This information as released by the National Oceanic and Atmospheric Administration (NOAA) details in depth about how this data is so intricately extracted. Already discussed is the use of laser pulses, which scan the area of interest up to 5000 pulses per second.", "cite_spans": [], "ref_spans": []}, {"section": "The LIDAR Collection Process", "text": "The laser type used is generally the neodymium-doped yttrium aluminum garnet (Nd:YAG) laser with a wavelength around 1064 nanometers, placing the laser in the infrared range of light. This pulsed laser is emitted when the population inversion in the resonator has reached its maximum, achieved by what is known as Q-switching, which places a switch inside the resonator which releases the stored pulse when the maximum amount of atoms are in an excited state.", "cite_spans": [], "ref_spans": []}, {"section": "The LIDAR Collection Process", "text": "Of major interest is the mechanism which allows this technology to perform its task of collecting LIDAR data. Two mirrors, one a 45-degree angled folding mirror and the other a moving mirror, combine to direct the laser pulses towards the ground. The laser pulses encounter the folding mirror first, with the reflection directed towards the moving mirror below. The reflection from the moving mirror directs the laser pulses towards the ground, with an overall coverage angle of 30 degrees. Since these aircraft fly at heights of around 700 meters, the 30 degree angle allows an overall circular coverage area with a diameter of approximately 350 meters. Therefore, in order for the aircraft to cover a broad area of land, multiple paths are usually flown, resulting in some overlap between coverage areas, as illustrated in Figure 1 ", "cite_spans": [], "ref_spans": [{"start": 825, "end": 833, "text": "Figure 1", "ref_id": "FIGREF2"}]}, {"section": "LIDAR Data", "text": "With the LIDAR data collected, the real question becomes apparent: how is LIDAR data processed? LIDAR data in combination with a GPS allow for each measured elevation to be paired with its location, effectively creating a three-dimensional coordinate for each measured elevation. The x and y coordinates are usually latitudes and longitudes derived from the GPS system, while the z coordinate is the measured elevation using the LIDAR collection device, measured usually in either meters or feet. An ASCII file with each line containing a measurement point (x,y,z) having each coordinate separated by either a tab or comma is common when working with LIDAR data. The precision on this height measurement is usually in the range of 10-25 centimeters, allowing for a very accurate measurement of ground elevation.", "cite_spans": [], "ref_spans": []}, {"section": "LIDAR Processing Applications", "text": "LIDAR data is currently being used in a diverse array of applications, ranging from the study of seismology to traffic control analysis. LIDAR is used in seismology to detect faults, with one such example relating to a particular fault in Seattle. LIDAR allowed the detection of the Seattle fault from an earthquake that occurred over 1000 years ago, effectively painting a picture of the surface in the area by penetrating through tree canopies, allowing for a view of what is now known as the Seattle fault. LIDAR data is also used in traffic law enforcement, replacing radar as a speed detector in police laser systems. Other applications of LIDAR relate to its use in adaptive cruise control systems in cars and its use as a height measuring tool in the forestry industry.", "cite_spans": [], "ref_spans": []}, {"section": "LIDAR Processing Applications", "text": "One of the main uses of LIDAR data and an important idea in the development and identification of building footprints pertains to its ability to create topographic maps of areas. LIDAR data is able to be manipulated and processed in such a way to allow a visual representation of an area based on the time delay measurements translated into heights along with the paired GPS coordinates. The final result of such processing techniques on this data is known as a digital elevation model (DEM).", "cite_spans": [], "ref_spans": []}, {"section": "Creation of Digital Elevation Models", "text": "While the creation of DEMs is not directly considered here, it is important to note its use as it is the main scientific and image processing based application of LIDAR data. In the figure below, a DEM of Mount Saint Helens is shown as an example of this particular LIDAR application performed by LIDAR mapping company EarthData [9]. Colors gravitating towards the red end of the spectrum represent areas of higher elevation, whereas colors present on the blue end of the spectrum represent areas of lower elevation. This particular DEM is shown in three dimensions in order to enhance the view and appearance of the elevation data generated using LIDAR. LIDAR intensity images are also an important visualization of LIDAR data, allowing irregularly spaced LIDAR data to be represented as a digital grayscale image of varying intensities, with higher intensities representing higher elevations, and lower intensities representing lower intensities. This particular creation of grayscale intensity images will prove extremely important in the classification of particular areas of interest, in this case, the classification of buildings.", "cite_spans": [], "ref_spans": []}, {"section": "Building Identification and Modeling", "text": "LIDAR intensity images can be examined using image processing techniques. These techniques allow the visual representation of LIDAR data to be identified, classified, and separated into areas of interest to be analyzed. One such classification involves the identification of buildings, with this identification proving important in various real life applications, including the study of urban population and the development of ground plans. The identification of buildings can also be extended into the development of three-dimensional building models.", "cite_spans": [], "ref_spans": []}, {"section": "Building Identification and Modeling", "text": "Previous work has successfully identified building footprints through the use of filtering, region growing, and dominant direction estimation [1] . However, the use of dominant direction estimation as a means of cleaning building footprints assumes a particular relationship between perpendicular/parallel building edges and oblique building edges. Also, a visual comparison to aerial imagery was used to detect omission and commission errors. With a refined definition of what constitutes a building boundary along with a new method for confirming building boundaries through the use of a satellite image region growing algorithm, this work provides a new view of building footprint detection.", "cite_spans": [{"start": 142, "end": 145, "text": "[1]", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "Building Footprint Extraction", "text": "One of the major applications of LIDAR technology has been the ability to use the data for feature extraction and identification. Building footprint extraction is just one of the many feature extraction opportunities provided by airborne LIDAR data. The goal is to determine the location of buildings in the area of interest, effectively separating buildings by determining their boundary. There are many ways to accomplish this task, with commonalities along the way in each. One such method of extracting building footprints will be described in great detail here.", "cite_spans": [], "ref_spans": []}, {"section": "Pre-Processing Techniques", "text": "Before any analysis can be done on LIDAR data, the data must become useful in a way that allows understanding and interaction. Once the area of interest has been determined, the LIDAR XYZ files need to be interpreted in a way to allow such an understanding to be possible. A visual depiction of LIDAR data becomes a necessary means for understanding and future analysis, and the use of image processing provides such a means to the researcher. The LIDAR data will be visualized in a digital image, with the x and y values representing pixel coordinates of the image, and the elevation value z representing the intensity value of the grayscale image. This pre-processing stage sets up the ability for any application of LIDAR data and will help to extract building footprints.", "cite_spans": [], "ref_spans": []}, {"section": "Pre-Processing Techniques", "text": "First, the LIDAR data XYZ files are read into a three-dimensional array, with each coordinate (x,y,z) being read into a row of the array. The goal is to create an image using the LIDAR data points that maps each coordinate to a pixel or group of pixels. LIDAR data by its very nature has a randomness to its data points, which prohibits a one-to-one mapping of each LIDAR point to a pixel, as some areas have such a dense coverage but others are sparsely sampled. Upon reading the data into the array, the number of points read is determined and stored in order to find the minimum x and y values of the LIDAR data. The horizontal size of the image is determined by the user, and the vertical size is derived based on this horizontal size by manipulation of the maximum and minimum coordinates, as indicated in the following equation.", "cite_spans": [], "ref_spans": []}, {"section": "Pre-Processing Techniques", "text": "Basically, the user controls how large of an image the LIDAR data will be processed into, but only to an extent. The LIDAR data itself and its range determines the height to prohibit too small or too large an overall image size chosen. However, this can result in some information loss because of the lack of a one-to-one mapping as stated above. Also, each pixel could contain more than one LIDAR coordinate point, in which case the smallest elevation value is chosen as the pixel value at that location. This would seem to grid the LIDAR data into an image reasonably, but not all pixels have a corresponding LIDAR data point and elevation value. In this case, a value is used as a place holder if there is no corresponding LIDAR point for that pixel.", "cite_spans": [], "ref_spans": []}, {"section": "Pre-Processing Techniques", "text": "Once the above step is performed, the image is processed further by interpolation of pixel values. The image is interpolated in order to replace the place holder points described above with a minimum elevation value in a window. A window size w is specified for this interpolation with a value of 3. Each pixel value is scanned in a search for the place holder value, indicating that there is no data for this specific location in the area of interest. When a pixel of this value is found, the pixel values in the window are scanned. If less than 25% of the pixel values in the window contain the place holder value, the minimum pixel value in the window is determined and assigned to the pixel in question. However, if more than 25% of the pixel values in this window also contain the place holder value, then the pixel value in question remains the place holder value, but the window size is increased by two. This process continues up to a maximum window size specified by the user, in this case the maximum window size being 15. This progressive window operation allows stray place holder pixels to be replaced by surrounding values in order to have a more complete image, but place holder pixels that do not get replaced through this interpolation remain as such and are represented in the resulting pre-processed grayscale image as the highest intensity possible, resulting in a white color. The resulting image after interpolation is shown in Figure 3 below. This image represents a subset of Lenoir County, North Carolina. The pre-processed image above is of size 1201x401, obtained through the interpolation methods discussed above. Upon examination of this final pre-processed image, a few traits are immediately noticeable. First, the portions of the image that had no LIDAR data points corresponding to the actual pixel coordinate have a white intensity. Also, the overall intensity differences, ranging from light grey to a grayscale intensity that is close to black in color, indicate elevation differences of the LIDAR data coverage area. The lower intensities (dark grey / black) represent very low-lying areas relative to the rest of the coverage area, indicating that these points are most likely ground points. The higher intensities (lighter grey) indicate that the elevation is higher in those locations and could therefore correspond to buildings, but further detail will be necessary to make such a determination. This pre-processed image represents the starting point for all further analysis, as various image processing techniques will be employed in order to accomplish the task of identifying building footprints.", "cite_spans": [], "ref_spans": [{"start": 1450, "end": 1458, "text": "Figure 3", "ref_id": "FIGREF4"}]}, {"section": "The Progressive Morphological Filter", "text": "With the pre-processed image obtained, and the overall goal being to determine the locations of buildings and their boundaries, a method must be determined to perform such a separation of the building pixels from the rest of the image. However, one cannot simply separate the building objects from the rest of the image immediately. First, the pixels representing ground elevations must be separated from the pixels representing non-ground elevations. Non-ground elevations refer to any pixel whose intensity has a value greater than a predefined threshold for height, regardless of whether or not the point corresponds to a building, vegetation, or other object that is higher off the ground than this predefined threshold.", "cite_spans": [], "ref_spans": []}, {"section": "The Progressive Morphological Filter", "text": "There are many methods that have been employed in order to accomplish this task of separating non-ground points from ground points. One such way was formulated by Vosselman, who identified non-ground points and separated them from ground points by analyzing the slope between a given pixel and the eight neighbors of the pixel. Vosselman determined the slope from a given pixel to each of its neighbors, and then found the overall maximum slope. If the maximum slope was less than a predefined threshold, then the point was labeled a ground point; otherwise, the point was considered a non-ground point.", "cite_spans": [], "ref_spans": []}, {"section": "The Progressive Morphological Filter", "text": "The major pitfall with separating non-ground points from ground points arises in the derivation of a best-fit filtering threshold. Zhang [2] has identified the following two general problems with separating ground points from non-ground points: commission errors and omission errors. Commission errors refer to mistakenly identifying non-ground points as ground points, while omission errors refer to mistakenly including ground points as non-ground points. If one selects the best-fit threshold for the filtering method of choice, then these errors will be minimized, and the resulting separation will be as accurate as possible. Zhang proposed what is known as the progressive morphological filter to mathematically remove non-ground points from a processed grayscale image like the one in Figure 3 above.", "cite_spans": [{"start": 137, "end": 140, "text": "[2]", "ref_id": "BIBREF1"}], "ref_spans": [{"start": 792, "end": 800, "text": "Figure 3", "ref_id": "FIGREF4"}]}, {"section": "The Progressive Morphological Filter", "text": "A morphological filter is a filter that utilizes a combination of dilations and erosions in order to dilate and/or erode features of an image. When dealing with a grayscale image as in the preprocessed image of Figure 3 , these dilation and erosion operations actually become maximum and minimum operations. The progressive morphological filter combines the use of maximum filters and minimum filters in order to detect the non-ground elevations by effectively replacing all of these values with ground pixel values, removing the non-ground pixels from the image.", "cite_spans": [], "ref_spans": [{"start": 211, "end": 219, "text": "Figure 3", "ref_id": "FIGREF4"}]}, {"section": "The Progressive Morphological Filter", "text": "In order to implement progressive morphological filter, an initial window size w is chosen (3 in this case). A minimum filter of size w x w (3x3) was performed on the pre-processed image of Figure 3 . This minimum filter operates on the original image by sweeping the window over the entire image, and for each given pixel, replacing the pixel's value with the minimum pixel value included in the window neighborhood. This effectively removes any non-ground object smaller than the window size because it changes the appropriate pixel value to the minimum value in the region. This minimum filter is immediately followed by a maximum filter of the same window size, effectively repairing any damage done to non-ground objects that are larger than the window size by replacing the pixel value with the maximum value in the window area. This combination of a minimum filter following by a maximum filter is known as an opening operation of the morphological filter.", "cite_spans": [], "ref_spans": [{"start": 190, "end": 198, "text": "Figure 3", "ref_id": "FIGREF4"}]}, {"section": "The Progressive Morphological Filter", "text": "Once this initial opening operation is performed, the difference between the original image and the new image filtered using the opening operation is obtained. This image should therefore have pixel intensity values of zero for all ground pixels since the ground pixels were not removed in the opening operation performed. However, this image should have pixel values relating to the non-ground values in the original image, as the difference image was obtained by subtracting each intensity value of the filtered image from the original image. This difference image now becomes extremely important in the implementation of the progressive morphological filter as it relates directly the best-fit threshold described above. The height threshold was predefined to be 0.1 for this morphological operation. However, the best-fit threshold was determined to be dependent on the window size in the following way:", "cite_spans": [], "ref_spans": []}, {"section": "The Progressive Morphological Filter", "text": "Therefore, the actual filtering operation occurs by comparing each difference image pixel value with this best-fit threshold value. If the given difference image pixel value is greater than this best-fit threshold value, then the corresponding original pixel value is replaced with the pixel value of the image obtained after the opening operation. If the given difference image pixel value is less than the best-fit threshold value, then the corresponding original pixel value remains the same. This process repeats every pixel of the image is traversed.", "cite_spans": [], "ref_spans": []}, {"section": "The Progressive Morphological Filter", "text": "Upon initial viewing, one would think that the operation performed in equation (2) would simply set the best-fit threshold to a value of 0.3 since the window size above was chosen to be three. However, this is not the case, as this morphological operation is progressive in nature. The progressive nature of the morphological filter refers to the fact that the window size progresses to a higher value after each performance of this algorithm. A maximum window size is set by the user initially. A window step size is also set initially by the user, which indicates how much the window will increase after each traversal of the algorithm. In this particular case, a maximum window size of 40 and a window step size of 10 were chosen. The following table shows the progressive increasing nature of the window size for the morphological filtering operation. This table above shows that the initial window size was set by the user at a value of 3. The opening operation was performed with a window size of 3x3, and then the difference image values were compared to the best-fit threshold as described above. The window step size was then added to the initial window size to achieve a new window size of 13x13 for the opening operation. This process is repeated until the maximum window size of 40 was achieved. The best-fit threshold also progressively changes with respect to the window size according to equation (2) above. The grayscale image obtained after removal of all non-ground objects through the implementation of the progressive morphological filter is given in Figure 4 below. In comparison to the original pre-processed image in Figure 3 , one can see that the areas of higher intensity are now completely removed in Figure 4 . This proves that the progressive morphological filter performed well in separating ground pixel values from non-ground pixel values.", "cite_spans": [], "ref_spans": [{"start": 1571, "end": 1579, "text": "Figure 4", "ref_id": "FIGREF5"}, {"start": 1640, "end": 1648, "text": "Figure 3", "ref_id": "FIGREF4"}, {"start": 1728, "end": 1736, "text": "Figure 4", "ref_id": "FIGREF5"}]}, {"section": "The Region Growing Algorithm", "text": "With the non-ground pixel values successfully separated from the ground pixel values and identified, the algorithm to identify building areas and their boundaries becomes the focus. The algorithm proposed to accomplish the task of separating building areas from other non-building non-ground objects is the region growing algorithm. The region growing process will iteratively separate the non-ground pixels into distinct regions of interest which will allow a successful building footprint extraction.", "cite_spans": [], "ref_spans": []}, {"section": "The Region Growing Algorithm", "text": "Region growing is an image processing concept that allows an image to be separated into areas (regions) that have a predefined characteristic. This process starts from a single pixel that satisfies a given condition, effectively becoming the first pixel of the region. Then, the eight neighbors of the pixel are examined against the same condition that included the first pixel in the region. If any of these pixels also satisfy the criteria given for acceptance, these pixels are also considered part of the region and indicated as such. Then, the eight neighbors of each of these added pixels are examined, with the process continuing in this way until no new pixels are added to the region. Figure 5 below shows the beginning of the region growing process, the choice of a seed point that meets the specific condition under testing. The seed pixel is the first pixel in the scanned image containing a \"true\" output to the testing condition. The region will then grow outward from this pixel by testing each of the pixels eight neighbors individually, adding said pixels to the region if the condition is satisfied. Figure 6 below illustrates the region growing process after multiple iterations of the condition check. As can easily be seen, the highlighted area in the above figure indicates that these particular pixels satisfied the condition for inclusion and therefore are now members of the region. This process continues until no new neighboring pixels can be added to the region, creating an effective boundary for the region in question.", "cite_spans": [], "ref_spans": [{"start": 694, "end": 702, "text": "Figure 5", "ref_id": "FIGREF6"}, {"start": 1118, "end": 1126, "text": "Figure 6", "ref_id": "FIGREF7"}]}, {"section": "The Region Growing Algorithm", "text": "With the basics of the region growing process now explained, the detailed region-growing algorithm applied to the specific Lenoir County area of North Carolina is performed. The progressive morphological filter has effectively separated the ground and non-ground pixels by creating an output image that has removed all non-ground pixels and replaced them with average ground pixel values.", "cite_spans": [], "ref_spans": []}, {"section": "The Region Growing Algorithm", "text": "With this initial separation complete, the non-ground pixels must be further segmented into consolidated regions of interest, as each non-ground pixel should belong to an area of nonground pixels, representing anything from a car to a building to an area of vegetation. Zhang [2] referred to two different types of non-ground pixels as inside points and boundary points. An inside point is a non-ground pixel whose eight neighbors are also non-ground pixels. A boundary point is defined as a non-ground pixel with at least one of its eight neighbors being a ground pixel. Therefore, all non-ground pixels can be segmented further into two distinct subsets of pixels, classified based on whether the pixel is an inside point or a boundary point. This revelation allows the first region growing segmentation to take place. The desired outcome is a set of regions of inside points, along with a set of regions of boundary points corresponding to these inside point regions.", "cite_spans": [{"start": 276, "end": 279, "text": "[2]", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "The Region Growing Algorithm", "text": "The region growing process for segmenting regions of inside points is the first task after the progressive morphological filtering operation is performed. First, a testing condition must be established which will allow for a new region to begin from an initial seed point with properties that satisfy the condition. A height (pixel intensity value) threshold is chosen as this initial condition, given a value of 10, and this threshold will be the first testing condition upon which a region is initiated. This threshold is variable, allowing the algorithm to run with any threshold with value greater than zero desired. The image to be operated on is the difference image, which now contains intensity values near zero for ground pixels and intensity values equal to the height of non-ground objects for all pixels that are not considered part of the ground area. The difference image is scanned, starting from the upper left corner, until a pixel with intensity value greater than the threshold is found. This initial conditioning does not identify the point as an inside point, so the pixel cannot yet be added to a region.", "cite_spans": [], "ref_spans": []}, {"section": "The Region Growing Algorithm", "text": "Once a pixel satisfying the initial threshold condition is found, further conditioning is performed to determine whether or not this pixel is an inside point. Of note is the fact that each pixel will be identified as \"belonging to a region\" or \"not belonging to a region\" by a labeling scheme within the algorithm itself. Initially, all pixels will contain a label of \"not belonging to a region.\"", "cite_spans": [], "ref_spans": []}, {"section": "The Region Growing Algorithm", "text": "The second condition tests whether the pixel belongs to a region already by scanning the pixel's label for this information, represented in the algorithm as a Boolean '1' (belongs to a region) or '0' (does not belong to any region). If the pixel does not belong to any region as of yet, the second condition is satisfied and further conditioning is performed. The third and final condition does not test the pixel in question itself, but the pixel's eight neighbors. The third condition checks whether all of the eight neighbors satisfy the initial condition of having an intensity value greater than the threshold. This is accomplished by performing an AND operation of each neighbor condition, resulting in a satisfied condition only when all pixels are greater than the threshold. If all of the eight neighboring pixels have a value greater than this threshold, then the pixel in question is indeed an inside point. Therefore, the pixel is added to the region as the seed point and labeled as described above as \"belonging to a region\" to avoid placing the same pixel in multiple regions or in the same region more than once. The pixel is added to the region in the algorithm itself by utilizing linked lists, with each region being identified by its own linked list. This allows for each region to have varying size along with the possibility of adding pixels at a random rate based on condition testing. If the above process fails to produce a pixel that satisfies the conditions of an inside point, the difference image scan continues until the first inside point is found, making it the initial seed point for the region.", "cite_spans": [], "ref_spans": []}, {"section": "The Region Growing Algorithm", "text": "With the seed point for the inside point region determined, the region must then be grown. Since a seed inside point was found, the scanning of the difference image stops. The location of the scan is saved so that when the region is completely grown, the scan can begin again from the same location, looking for another region to grow. As shown in Figure 5 above, the region growing process grows outward from the seed point, so the conditioning moves on to the eight neighbors of the seed point.", "cite_spans": [], "ref_spans": [{"start": 348, "end": 356, "text": "Figure 5", "ref_id": "FIGREF6"}]}, {"section": "The Region Growing Algorithm", "text": "First, the upper-left neighbor of the seed point is identified for testing. Since the seed point itself was labeled as an inside point, by definition this already indicates that this upper-left neighbor passes the initial threshold test. Therefore, the upper-left neighbor is tested based on whether or not it already belongs to a region. If it already belongs to a region, then the testing of this pixel fails, and the upper neighbor of the seed point is identified for testing. However, if the upper-left neighbor is not already included in a region, then further testing is performed to determine whether this neighbor is also an inside point of the region in question. This further testing involves the eight neighbors of this upper-left neighbor. If all of the eight neighbors of the upper-left neighbor have intensity values greater than the threshold, then the upper-left neighbor is considered an inside point, labeled, and added to the region. This process continues, with each neighbor of the original seed point being checked for its possibility of belonging to the region.", "cite_spans": [], "ref_spans": []}, {"section": "The Region Growing Algorithm", "text": "Once all of the eight neighbors of the original seed point are tested, the linked list which contains the pixels in the region will now have a maximum of nine pixel members. The region growing implementation does not stop here, however, as some regions may have more than nine total pixels in the region. Assuming all of the eight neighbors of the original seed point have been added to the region, the region contains nine pixel members, and the next available pixels to undergo testing for inclusion in the region are the neighbors of these eight neighbors. Therefore, the linked list's link is incremented in order to get to the second pixel that was added to the region. Then, the algorithm tests all of its eight neighbors in the same way as the original seed point was tested, and if any of its neighbors meet the conditions for inclusion, these pixels are added to the list. This process continues until the end of the linked list is reached, successfully exhausting all possible pixel values to be included in the region, effectively creating a region of labeled pixels with a defined boundary.", "cite_spans": [], "ref_spans": []}, {"section": "The Region Growing Algorithm", "text": "With the end of the region determined, the difference image scan continues from the same pixel in which it left off, checking for the next seed point for a new region to begin. The image is scanned until the next pixel with intensity greater than the threshold and with property of not already belonging to a region is found. If a pixel value is found to successfully meet this condition, another region is grown as described above. This region growing process for inside points continues until the entire difference image is scanned, effectively segmenting the nonground pixels into regions of inside points with well defined boundaries.", "cite_spans": [], "ref_spans": []}, {"section": "The Region Growing Algorithm", "text": "With the inside points completely separated into regions, the determination of boundary points becomes the important priority. These inside point regions are incomplete in the sense that along their boundaries, there are still non-ground pixels that are not members of the region. This occurs due to the definition of an inside point, which states that all eight of its neighbors must be non-ground points as well. With this in mind, what if one or more of these eight neighbors already defined as non-ground points have neighbors that are ground points? These pixels are also part of the non-ground region of interest, just not part of the specific inside point regions. These pixels are the boundary points for the inside point regions, and they need to be separated as such in order to identify every non-ground point as either an inside point or a boundary point.", "cite_spans": [], "ref_spans": []}, {"section": "The Region Growing Algorithm", "text": "In order to determine these boundary point regions, a new scan of the difference image is performed after each inside point region is determined. The initial condition for inclusion in a boundary point region is threefold: the pixel must not already be included in an inside point region, the pixel must have an intensity value greater than the threshold, and the pixel must have at least one of its neighbors be an inside point. Once the seed point for the boundary point region is found, further conditioning is performed similar to the conditioning described above for determining inclusion in the inside point regions. If at least one of the eight neighbors of this new seed point is a ground point, and at least one of the eight neighbors of this new seed point is labeled as belonging to an inside point region, then the pixel is labeled as belonging to a boundary point region and added to the region as the initial seed point. The key element to this conditioning allowing the boundary point regions to be separated according to their relevance to other inside point regions is the fact that at least one of the eight neighbors already belongs to a ground point region. Otherwise, without this condition there would be no way to separate each boundary point region, resulting in one large region of boundary points. However, as will be described in the post-processing stages of the building footprint algorithm, the boundary point regions must be separated here as such.", "cite_spans": [], "ref_spans": []}, {"section": "The Region Growing Algorithm", "text": "The following table shows the pseudo code for the region growing separation algorithm, resulting in distinct regions of inside points and boundary points. Once this algorithm is performed, the non-ground pixels are successfully separated into regions of inside points and regions of boundary points. Figure 7 below shows the inside point regions, identified by the pixels that are shaded white in the image. In a direct comparison with Figure 3 , Figure 7 illustrates the algorithms ability to identify nonground pixels effectively. Moreover, it also illustrates the ability of the algorithm to identify regions of interest based upon a defined threshold that can be preset by the user. This allows for a height threshold specification for inclusion, allowing for the elimination of other non-ground objects that are not necessarily buildings, objects such as cars, shrubs, and other vegetation. The result of the figure above is an illustration of the automated determination of building ground plans and outlines found using the region growing algorithm for the segmentation of boundary points. The figure clearly defines non-ground regions, including those of smaller building areas. It can be noticed in this image as well that the effects of small distinct nonground pixels are not included in the region identification, having successfully been removed as not belonging to a building region. Further comparison of these two figures with the original pre-processed image will be performed after a discussion of a more advanced region growing algorithm implementation next.", "cite_spans": [], "ref_spans": [{"start": 300, "end": 308, "text": "Figure 7", "ref_id": "FIGREF8"}, {"start": 436, "end": 444, "text": "Figure 3", "ref_id": "FIGREF4"}, {"start": 447, "end": 455, "text": "Figure 7", "ref_id": "FIGREF8"}]}, {"section": "Plane-fitting techniques", "text": "The above algorithm successfully resolved the non-ground pixels into two distinct types, boundary points and inside points. The region growing process allowed these two distinct types of pixels to be represented as grown region areas with clearly defined boundaries. However, in order to reduce inclusion errors present in any region growing process, further segmentation of the inside point regions is necessary. The process involved in this further segmentation employs the use of a plane-fitting technique to separate inside point regions into smaller regions representing building surfaces. The overall goal is to segment each inside point region into smaller regions based on the formation of best-fit planes of pixels and their neighbors, resulting in a representation of planar surfaces within each inside point region.", "cite_spans": [], "ref_spans": []}, {"section": "Plane-fitting techniques", "text": "The plane-fitting process used is a least-squares method of determining a best-fit plane from a given number of three-dimensional points. The algorithm determines a plane that best fits nine distinct three-dimensional points, in this case an inside point pixel and its eight neighboring pixels. The solution provides the least squares solution to the following equation:", "cite_spans": [], "ref_spans": []}, {"section": "Plane-fitting techniques", "text": "with I(x,y) representing the intensity of the pixel located at coordinate (x,y) and A,B,C representing parameters of the best-fit plane determined from the nine pixels in question. The goal of this least squares solution is to minimize the sum of the squared errors between the pixel intensity values and the resulting intensity value when using the plane equation (3).", "cite_spans": [], "ref_spans": []}, {"section": "Plane-fitting techniques", "text": "Given a set of pixels", "cite_spans": [], "ref_spans": []}, {"section": "Plane-fitting techniques", "text": "under consideration, a function is defined as follows: . This condition results in the following system of three simultaneous equations which can be solved for the bestfit plane of the given nine pixels:", "cite_spans": [], "ref_spans": []}, {"section": "Plane-fitting techniques", "text": "Equation (5) The above matrix equation is solved for the parameters A, B, and C respectively which defines the best-fit plane of the nine pixels in question. With these parameters determined, a plane-fitted intensity value can be found for any of the pixels in question. This plane-fitted intensity value can then be used in comparison with the actual intensity value observed at the pixel in question in order to create a condition for a region growing procedure that will allow segmentation into surface regions.", "cite_spans": [], "ref_spans": []}, {"section": "Plane-fitting techniques", "text": "In order for this condition to be used in the region growing process, an initial seed point must be determined. Therefore, an additional detail is added to the region growing processes above -the calculation of the ABC parameters for each inside point pixel determined in the inside point segmentation process. Therefore, when a pixel meets all criteria for inclusion in an inside point region, a best-fit plane for the pixel and its eight neighbors is calculated. Along with these ABC parameters for the plane equation, the minimum sum of squared errors (SSE) is also calculated for each inside point according to the following equation:", "cite_spans": [], "ref_spans": []}, {"section": "Plane-fitting techniques", "text": "with x i and y i representing the coordinate of the pixel in question and I actual (x i ,y i ) representing the actual intensity value at the pixel in question. This equation represents the sum of squared error calculation, determined by the square of the difference between the calculated best-fit intensity value and the actual pixel intensity value at the specific coordinate being analyzed.", "cite_spans": [], "ref_spans": []}, {"section": "Plane-fitting techniques", "text": "This SSE calculation allows an initial seed point to be determined for the surface growing algorithm. Once an inside point region is completely grown, all best-fit plane parameters and the corresponding SSE for any inside point and its eight neighbors has been determined using the matrix equation (6). The linked list that houses the inside point region pixels and this best-fit plane data is now sorted in ascending order according to the SSE, effectively determining the minimum SSE value for the inside point region in question. The inside point with the minimum SSE determined through the plane-fitting algorithm is added to the surface region. The reason for this minimum SSE being the condition for initial inclusion in the surface algorithm is that the inside point with the smallest SSE value has the most accurate best-fit plane associated with it and its eight neighbors. This allows a fairly accurate plane representation, and therefore the best chance for a smooth surface to be determined from pixels in a particular area, for example a face on a roof of a building. The goal is to grow surfaces in this particular algorithm, so the condition must allow for the best possible surfaces to be grown, which is accomplished by selecting the inside point with this minimum SSE value.", "cite_spans": [], "ref_spans": []}, {"section": "Plane-fitting techniques", "text": "With the initial seed point selected, the conditional testing proceeds to the eight neighbors of this seed point. The testing first checks if the neighbor is an inside point, using the same conditions described above in the general region growing algorithm. If the neighbor is an inside point, then additional surface testing is performed. Using the ABC parameters of the initial seed point and the specific x and y coordinates of the neighbor in question, a calculated intensity value is determined using the plane equation (3). This calculated intensity value is then compared to the actual intensity value at this point, and the absolute value of the difference between the two values is calculated. If this difference is greater than a specific \u0394h threshold (usually 15-30 cm according to Zhang [1] ), then the pixel in question has an intensity that is not within the desired range and therefore is not a close enough fit to be included in the surface. However, if the calculated height difference is less than this \u0394h threshold, then the pixel is a close enough fit to the growing surface and is included in the surface region.", "cite_spans": [{"start": 799, "end": 802, "text": "[1]", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "Plane-fitting techniques", "text": "This testing continues until all eight neighbors have been tested for inclusion in this particular surface region. Once the eight neighbors have been completely checked, the pointer to the linked list containing the surface region values is incremented, and further testing is performed on the eight neighbors of this point. This process continues until the surface region has been fully traversed and no further growing can be performed, effectively ending the surface in question.", "cite_spans": [], "ref_spans": []}, {"section": "Plane-fitting techniques", "text": "However, testing does not stop here. Every point within the inside point region must be added to a surface, and thus far, only the initial surface determined from the minimum SSE inside point has been accounted for. Therefore, the linked list pointer to the inside point region is incremented, finding the second smallest SSE value. If this point does not already belong to a surface, then this inside point becomes the new initial seed point, and surface growing begins again in the same fashion. This process continues until the end of the inside point region is reached, completing the traversal of the entire inside point region.", "cite_spans": [], "ref_spans": []}, {"section": "Plane-fitting techniques", "text": "The fact that every inside point must belong to a surface results in surfaces of various sizes. If, for instance, an inside point on the outer edge of an inside point region becomes the seed point, the SSE may be the largest without regard to the plane-fitting algorithm's calculations on the \"smoothness\" of a group of pixels, and the surface grown would be extremely small because the surrounding pixels may not lie within the defined height threshold, possibly resulting in a surface of only one pixel if no other points fit the plane for that seed point. The process is rather complicated in this sense but works as desired for breaking up the larger inside point regions into sub-regions with conditions that define well defined surfaces. This further segmentation results in many more surfaces than inside point regions, separated by their relative fit to the region in general.", "cite_spans": [], "ref_spans": []}, {"section": "Plane-fitting techniques", "text": "For the test area in Lenoir County, North Carolina shown in figure 3 , there were 218 inside point regions found and 1655 surfaces determined from these points. This much greater number of surfaces shows that the conditioning performed in this surface growing algorithm vigorously separate the inside point regions, resulting in a much finer conditioning and therefore datasets that share very similar properties which can be used to refine the building footprint algorithm drastically.", "cite_spans": [], "ref_spans": [{"start": 60, "end": 68, "text": "figure 3", "ref_id": "FIGREF4"}]}, {"section": "Merging of Building Surfaces", "text": "With the non-ground points now completely segmented into surfaces, the next step is simply an adjustment phase, hoping to help eliminate any errors that may have become prevalent in the previous steps. Because the segmentation above relies on thresholds in order to separate pixels and determine building footprints from these separated pixels, the quality of the building footprints and the amount of errors present in them are all determined by how closely the thresholds chosen are to the optimum threshold. After much testing, the values for the thresholds were chosen as indicated above, with a summary of the threshold values given in Table 3 below. All of the above threshold values have been explained in the sections above relative to their use in the algorithms they are associated with. However, there is another threshold mentioned here that has not been discussed yet, which relates to the merging of building surfaces which allows the final building footprints to be determined. In order to eliminate small patches of vegetation, a minimum building area must be determined. This minimum area threshold is set to 60 square meters, encompassing an area of three pixels on average, so any inside point regions having less than three pixels are neglected in the building separation process.", "cite_spans": [], "ref_spans": [{"start": 641, "end": 648, "text": "Table 3", "ref_id": "TABREF2"}]}, {"section": "Building Footprint Post-Processing", "text": "The building footprints for the particular area of Lenoir County, North Carolina considered thus far have been determined using the region growing algorithm. Inside points and boundary points were identified, and the resulting images have been displayed. However, the building footprints that have been identified are noisy since LIDAR data is inherently irregularly spaced. Therefore, some simplification of these noisy footprints must be performed. In the boundary point figure above, the edges of identified buildings have a zigzag quality and need to be simplified into a line that represents the true building boundary. Many simplification algorithms exist, but the Douglas-Peucker algorithm was implemented to simplify the noisy building footprints.", "cite_spans": [], "ref_spans": []}, {"section": "The Douglas-Peucker Algorithm", "text": "One such technique to develop a cleaner building footprint is the Douglas-Peucker algorithm, an algorithm developed by cartographers D.H. Douglas and T.K. Peucker in [7] . The DouglasPeucker algorithm allows for a simplification of any polyline by a recursive threshold technique.", "cite_spans": [{"start": 166, "end": 169, "text": "[7]", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "The Douglas-Peucker Algorithm", "text": "The Douglas-Peucker algorithm operates on the boundary point regions identified by the conditioning described above. An initial simplification guess begins the process. For each boundary point region, the initial guess contains the first boundary pixel in the region and the last boundary pixel in the region connected together to form a line segment. The algorithm then determines whether the initial guess of a line segment is a good enough simplification for the polyline in question. This determination is performed based on a user-defined distance threshold.", "cite_spans": [], "ref_spans": []}, {"section": "The Douglas-Peucker Algorithm", "text": "Assuming the boundary point regions represent buildings, a line segment should never be a good enough simplification in this case. Therefore, further processing is necessary. The entire boundary point region is scanned, and the distance from each boundary pixel to the initial guess line segment is calculated. If the boundary point in question is within the outer limits of the initial guess line segment, a perpendicular distance is calculated. If the boundary point in question is on either side of the outer limits of the initial guess line segment, then the distance from either the left endpoint of the initial guess (the boundary point is on the left side of the initial guess line segment) or the right endpoint of the initial guess (the boundary point is on the right side of the initial guess line segment) is calculated. This distance calculation is measured in pixel units, with each side of a pixel considered to have unit length.", "cite_spans": [], "ref_spans": []}, {"section": "The Douglas-Peucker Algorithm", "text": "Once all boundary point pixels in the region have had distances from the initial guess line segment calculated, the boundary point pixel at which the maximum distance from the initial guess line segment is identified. This maximum distance value is compared to the distance threshold provided by the user, and if the maximum distance is less than this threshold value, then the initial guess line segment was an accurate enough simplification, and the new boundary point region contains only two points, the endpoints of the initial guess line segment. However, if the maximum distance is greater than the threshold value, then the initial guess line segment was not accurate enough, and further processing must be performed.", "cite_spans": [], "ref_spans": []}, {"section": "The Douglas-Peucker Algorithm", "text": "Assuming the initial guess line segment was not accurate enough, a new guess is determined. The pixel at which the distance threshold was exceeded becomes one of the endpoints of two new line segments representing the new guess. The first point of the boundary point region is connected to this maximum distance pixel to form a line segment, and this maximum distance pixel is connected to the last of the boundary point region to form another line segment. Each line segment is now assumed to be a new initial guess, and the process continues recursively until all boundary point calculated distances are less than the user-defined threshold. The figure below illustrates the process described above. The boundary points that remained after the Douglas-Peucker algorithm was performed are colored white above. The building footprint simplifications are obtained by connecting each consecutive Douglas boundary point together as line segments. While most buildings are identified fairly well, some of the smaller buildings were unsuccessfully simplified. This problem is due to the order that the boundary point regions were identified in. This problem is considered and eliminated in the next chapter containing improvements to the above algorithms.", "cite_spans": [], "ref_spans": []}, {"section": "Region Growing Algorithm Improvements", "text": "With the algorithms completed and the building footprints successfully extracted, ways to possibly improve results were considered. It was noted that the possible improvements could exist when the boundary point regions were initially identified. The resulting footprints were extremely noisy, and therefore simplification seemed to be a difficult process. Therefore, a new way of defining boundary points was considered, and a new method of growing the boundary point regions was developed.", "cite_spans": [], "ref_spans": []}, {"section": "Boundary Point Identification", "text": "Boundary points were initially identified as any pixel in the difference image which had a value greater than a height threshold that also had at least one neighboring pixel identified as a ground pixel. This definition is somewhat incomplete, considering that any boundary point should also have a neighboring pixel identified as an inside point. Therefore, the definition of what constitutes a boundary point was made more strict, requiring the intensity of the difference image to be greater than the given height threshold, at least one neighboring pixel identified as a ground pixel, and at least one neighboring pixel identified as an inside point. It was believed that this extra condition would obviously result in fewer pixels to pass the boundary pixel test, and therefore result in less overall boundary pixels and a better overall simplification of the building footprints and a less noisy one as well. The figure below shows the identification of boundary footprints with this new definition. The above image with boundary pixels colored white shows a definite improvement in the reduction of noisy edges from the original boundary point figure identified in Chapter 3. A visual comparison between specific buildings in the two images will be given in the next chapter.", "cite_spans": [], "ref_spans": []}, {"section": "Boundary Point Region Growing", "text": "While there is a noticeable improvement in the identification of boundary points via the new definition, the footprints are still noisy enough to require further processing improvements. The Douglas-Peucker algorithm result illustrated above was not an acceptable simplification in all cases. It was determined that the Douglas-Peucker algorithm is extremely order intensive, in the sense that the order that the boundary points were placed into regions was extremely important in the determining a successful resulting simplification.", "cite_spans": [], "ref_spans": []}, {"section": "Boundary Point Region Growing", "text": "Boundary points were initially sorted through by scanning the difference image from the left portion of the image to the right part of the image in a top-down manner. The entire difference image was scanned for each boundary point region, a fairly inefficient process. Also, because of the left-to-right, top-down identification of the boundary point regions, the order of the boundary points could become scattered and not representative of buildings. Initially, this did not seem to be causing a problem, but once the Douglas-Peucker algorithm was implemented on these unordered boundary point regions, the result was clear. Because the Douglas-Peucker algorithm only checks distances of points to the initial guess on points that exist between the endpoints of the initial guess, ordering is extremely important. The Douglas-Peucker algorithm approximates the polyline obtained by connecting every boundary point in the order that they are added to the region.", "cite_spans": [], "ref_spans": []}, {"section": "Boundary Point Region Growing", "text": "Therefore, the goal was set to develop a sorting algorithm that would order boundary points in a way that, if each boundary point in the region were connected to the adjacent boundary points in the region, the result would be exactly as shown in the boundary point region figure above, that is they would represent the buildings that are to be simplified. The sorting was performed by using a variation on the region growing algorithm. First, the definition condition of a boundary point must be satisfied. Once a pixel satisfied this condition, the pixel was labeled as a boundary point and added to the region.", "cite_spans": [], "ref_spans": []}, {"section": "Boundary Point Region Growing", "text": "The next step is key to the development of a successful sort. The region growing algorithm described above would check every neighbor and add any pixels that satisfied the condition to the region. However, this could in some cases add more than neighbor to the region if more than one neighbor satisfied the condition. This would cause a problem in the ordering, as it is desired for the sort to represent a point-to-point connection of the boundaries of buildings. If more than one neighbor were added to the boundary point region for satisfying the boundary condition, then the corners of buildings would not contain a point-to-point connection. Therefore, once a seed point for the boundary point region was determined, the region growing algorithm begins. However, if two or more neighbors satisfy the boundary condition, only the first point is added to the list, and the region growing process continues in whatever direction this point was from the seed point. All boundary points obtained via the new definition by the original left-to-right, topdown scan are contained in this new region growing scan.", "cite_spans": [], "ref_spans": []}, {"section": "Boundary Point Region Growing", "text": "Once the sorting was complete and all boundary points were identified, the Douglas-Peucker algorithm was run on this new boundary point data. The image below shows the result of the Douglas-Peucker algorithm with this new modified region growing algorithm sort. The resulting image shows that the Douglas-Peucker algorithm with this modified sorting mechanism improves upon the previous top-down sorting run. A comparison of particular problem areas will be shown in the next chapter.", "cite_spans": [], "ref_spans": []}, {"section": "Satellite Image Processing", "text": "The resulting images above show that the algorithms for identifying building footprints successfully identify buildings. However, it was desired that there be data available to use in the future for possible comparison purposes, that is the ability to compare the obtained LIDAR building footprints with some other form of data to determine how accurate the LIDAR building footprints were.", "cite_spans": [], "ref_spans": []}, {"section": "Satellite Image Processing", "text": "In [1] Zhang performs a visual comparison to aerial photos by overlaying the obtained footprints over the aerial image to determine how accurate the LIDAR building footprints were. Contrary to Zhang, this particular satellite comparison algorithm attempts to provide a tool to compare the obtained LIDAR footprints to satellite imagery automatically.", "cite_spans": [{"start": 3, "end": 6, "text": "[1]", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "Satellite Image Processing", "text": "The following image shown in Figure 13 was obtained by performing a screen capture of a satellite image of Lenoir County using Yahoo Maps. The image was resized to match the LIDAR data image as closely as possible (the LIDAR image has size 1201x401 and the satellite image has size 1203x420). The goal is to perform a region growing algorithm on the above satellite image. The condition to include a point in a particular region is the Euclidean distance between the associated RGB color intensities. This color region growing algorithm will provide regions that have similar color within a user-defined color threshold. The area of each region along with the average values of the x and y coordinates of the pixels in each region are calculated. The areas of the inside point and boundary point regions along with their average x and y coordinates were calculated with the region growing approach above. The claim is that with this data, buildings can be separated from vegetation based on color characteristics, which could prove helpful in removing false building identifications that could occur in dense forest areas. Also, if some areas and averages obtained from the inside/boundary region growing algorithm are similar to the areas and averages obtained from this color region growing algorithm, this algorithm could provide confirmation that the LIDAR building footprints were obtained accurately without visual inspection.", "cite_spans": [], "ref_spans": [{"start": 29, "end": 38, "text": "Figure 13", "ref_id": "FIGREF2"}]}, {"section": "Satellite Image Processing", "text": "Because all points must be grown into corresponding color regions, there is no initial condition for selection of a seed point. The seed point is selected on the condition that it has not already been placed in a region, and it is then added to a region, and its color is identified according to its red, green, and blue components. Then, a condition is placed on its eight neighbors according to the following equation: ", "cite_spans": [], "ref_spans": []}, {"section": "Satellite Image Processing", "text": "A user-defined color threshold is provided. If the above calculated distance is less than the color threshold, then the pixel is considered close enough in color to the seed point and added to the region. This process continues until all 8 neighbors of the original seed point have been tested. Once this process is complete, the neighbors of the neighbors that were just added to the color region are tested based on their distance away from the seed point color. This process continues until all neighbors fail the color threshold test, effectively ending the region. Then, another region is started by selecting a point that has not yet been included in a region, and the process continues until every point has been assigned to a region.", "cite_spans": [], "ref_spans": []}, {"section": "Satellite Image Processing", "text": "The threshold provided to the algorithm for testing was based upon the maximum value of D color . The satellite image was normalized so that the minimum possible color value was 0 and the maximum possible color value was 1. Therefore, the maximum color difference would result in a D color value of approximately 1.7. The user-defined threshold therefore is limited to a value between 0 and 1.7 for this particular algorithm. The algorithm successfully provides the area of each region along with x coordinate and y coordinate averages for each region. This data is available for comparison purposes to the LIDAR obtained building regions.", "cite_spans": [], "ref_spans": []}, {"section": "Chapter 5", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Comparative Results", "text": "In Chapter 4, the results of changing the original approach to the region growing algorithm were presented, and it was shown that there was visual confirmation of improvement in the identification of building footprints. However, a side-by-side comparison will further show the effect the above changes have had on the building footprint results.", "cite_spans": [], "ref_spans": []}, {"section": "Comparative Results", "text": "The figure below shows an enlarged section of the Lenoir County study area, comparing the old boundary point definition to the new boundary point definition. This building footprint comparison clearly shows that redefining what a boundary point really is results in a less noisy and simplified footprint that more accurately represents the actual building boundaries. The extreme jagged nature of the footprint on the left is replaced by a fairly smooth representation on the right, considering that LIDAR data is irregularly spaced and therefore noisy to begin with.", "cite_spans": [], "ref_spans": []}, {"section": "Comparative Results", "text": "Yet another comparison figure below shows a problematic area in the original Douglas-Peucker algorithm and its improved result. ", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "The goal of extracting building footprints from a LIDAR dataset was completed successfully.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "Redefining what constitutes a building boundary point helped to improve the Douglas-Peucker algorithm's identification of building corners and improved the simplification process. The additional ability to grow regions based on the RGB color attributes in a satellite image allows for confirmation or disconfirmation of building footprints. This ability to automatically prove or disprove the validity of the extraction of building footprints improves upon simple visual inspection of aerial or satellite imagery for such purposes.", "cite_spans": [], "ref_spans": []}, {"section": "Future Work", "text": "Even though the algorithms above successfully identify building footprints and provide a means for comparison with satellite imagery, future work is available. Actual comparisons could be performed by sorting the color regions and inside/boundary regions according to areas and attempting to find similarities between them, confirming building locations and possibly removing dense forestry areas misidentified as buildings. Also, with building footprints successfully identified, a next step would be to perform some three-dimensional modeling using the building footprints as a guide to the type of building model and the locations of these models.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Automatic Construction of Building Footprints From Airborne LIDAR Data", "authors": [{"first": "K", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "J", "middle": [], "last": "Yan", "suffix": ""}, {"first": "S.-C", "middle": [], "last": "Chen", "suffix": ""}], "year": 2006, "venue": "IEEE Transactions on Geoscience and Remote Sensing", "link": "18251335"}, "BIBREF1": {"title": "A Progressive Morphological Filter for Removing Non-Ground Measurements from Airborne LIDAR Data", "authors": [{"first": "K", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "S.-C", "middle": [], "last": "Chen", "suffix": ""}, {"first": "D", "middle": [], "last": "Whitman", "suffix": ""}, {"first": "M.-L", "middle": [], "last": "Shyu", "suffix": ""}, {"first": "J", "middle": [], "last": "Yan", "suffix": ""}, {"first": "C", "middle": [], "last": "Zhang", "suffix": ""}], "year": 2003, "venue": "IEEE Transactions on Geoscience and Remote Sensing", "link": "12370335"}, "BIBREF2": {"title": "Fundamentals of Photonics", "authors": [{"first": "Bahaa", "middle": ["E A"], "last": "Saleh", "suffix": ""}, {"first": "Malvin", "middle": [], "last": "Carl Teich", "suffix": ""}], "year": 1991, "venue": "", "link": "120755349"}, "BIBREF3": {"title": "LIDAR Accuracy: An Airborne 1 Perspective", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF4": {"title": "Digital Image Processing Using MATLAB", "authors": [{"first": "Rafael", "middle": ["C"], "last": "Gonzalez", "suffix": ""}, {"first": "C", "middle": [], "last": "Richard", "suffix": ""}, {"first": "Steven", "middle": ["L"], "last": "Woods", "suffix": ""}, {"first": "", "middle": [], "last": "Eddins", "suffix": ""}], "year": 2003, "venue": "", "link": null}, "BIBREF5": {"title": "Algorithms for the reduction of the number of points required to represent a line or its caricature. The Canadian Cartographer", "authors": [{"first": "D", "middle": ["H"], "last": "Douglas", "suffix": ""}, {"first": "T", "middle": ["K"], "last": "Peucker", "suffix": ""}], "year": 1973, "venue": "", "link": null}, "BIBREF6": {"title": "He is a graduate of the Jesuit High School class of 2001 with the distinction Summa Cum Laude. He received his Bachelor of Science in Electrical Engineering from the", "authors": [{"first": "Henry", "middle": [], "last": "Christopher", "suffix": ""}, {"first": "George", "middle": [], "last": "", "suffix": ""}], "year": "", "venue": "in 2005 with the distinction of Magna Cum Laude", "link": null}}, "ref_entries": {"FIGREF0": {"text": "Figure 1: Aircraft Emitting Laser Pulses for LIDAR Collection.........................................2 Figure 2: Mount Saint Helens Digital Elevation Model ......................................................3 Figure 3: Pre-Processed LIDAR Image After Interpolation ................................................6 Figure 4: Grayscale Image After Morphological Processing ..............................................9 Figure 5: Region Growing -A Graphical Example ..........................................................10 Figure 6: Region Growing -Example After Multiple Iterations.......................................10 Figure 7: Inside Point Region Identification......................................................................14 Figure 8: Boundary Point Region Identification................................................................14 Figure 9: Visualizing the Douglas-Peucker Algorithm .....................................................19 Figure 10: Douglas-Peucker Algorithm Resulting Image .................................................20 Figure 11: Boundary Point Region Identification -New Definition.................................21 Figure 12: Douglas-Peucker Algorithm -Improved Sort..................................................23 Figure 13: Satellite Image Data .........................................................................................24 Figure 14: Boundary Point Identification -Comparison...................................................26 Figure 15: Douglas-Peucker Algorithm -Comparison .....................................................26 Figure 16: Douglas-Peucker Algorithm -Example Simplification...................................27", "type": "figure"}, "FIGREF1": {"text": "below [8].", "type": "figure"}, "FIGREF2": {"text": "Figure 1: Aircraft Emitting Laser Pulses for LIDAR Collection", "type": "figure"}, "FIGREF3": {"text": "Figure 2: Mount Saint Helens Digital Elevation Model", "type": "figure"}, "FIGREF4": {"text": "Figure 3: Pre-Processed LIDAR Image After Interpolation", "type": "figure"}, "FIGREF5": {"text": "Figure 4: Grayscale Image After Morphological Processing", "type": "figure"}, "FIGREF6": {"text": "Figure 5: Region Growing -A Graphical Example", "type": "figure"}, "FIGREF7": {"text": "Figure 6: Region Growing -Example After Multiple Iterations", "type": "figure"}, "FIGREF8": {"text": "Figure 7: Inside Point Region Identification", "type": "figure"}, "FIGREF9": {"text": "Figure 8 below shows the boundary point regions, once again identified by the shade of white in the image.", "type": "figure"}, "FIGREF10": {"text": "Figure 8: Boundary Point Region Identification", "type": "figure"}, "FIGREF11": {"text": "is defined in such a way that all values are positive and the vertex of the resulting hyperparabaloid occurs when the gradient satisfies the condition", "type": "figure"}, "FIGREF13": {"text": "Figure 9: Visualizing the Douglas-Peucker Algorithm", "type": "figure"}, "FIGREF14": {"text": "Figure 10: Douglas-Peucker Algorithm Resulting Image", "type": "figure"}, "FIGREF15": {"text": "Figure 11: Boundary Point Region Identification -New Definition", "type": "figure"}, "FIGREF16": {"text": "Figure 12: Douglas-Peucker Algorithm -Improved Sort", "type": "figure"}, "FIGREF17": {"text": "Figure 13: Satellite Image Data", "type": "figure"}, "FIGREF19": {"text": "Figure 14: Boundary Point Identification -Comparison", "type": "figure"}, "FIGREF20": {"text": "Figure 15: Douglas-Peucker Algorithm -Comparison", "type": "figure"}, "FIGREF21": {"text": "Figure 16: Douglas-Peucker Algorithm -Example Simplification", "type": "figure"}, "TABREF0": {"text": "Progressive Morphological Filter Window Sizes", "type": "table"}, "TABREF1": {"text": "Pseudo Code for Inside Point / Boundary Point Region GrowingCheck for Initial Condition. if (intensity > threshold) AND if(\"not in a region\") 3. Check the Eight Neighbors. if(all 8 neighbors' intensity > threshold) 4. Seed Point Found. Add to Region and Check Neighbors.", "type": "table"}, "TABREF2": {"text": "Various Thresholds Used in Algorithms", "type": "table"}}}
{"paper_id": "17783439", "_pdf_hash": "c8fef886a5d994a25ba349089057c2c3323caf6a", "abstract": [{"section": "Abstract", "text": "abstract: There has been growing interest in the role of viral infections and their association with adverse pregnancy outcomes. However, little is known about the impact viral infections have on the fetal membranes (FM). Toll-like receptors (TLR) are thought to play a role in infectionassociated inflammation at the maternal-fetal interface. Therefore, the objective of this study was to characterize the cytokine profile and antiviral response in human FMs exposed to viral dsRNA, which activates TLR3, and viral ssRNA, which activates TLR8; and to determine the mechanisms involved. The viral dsRNA analog, Poly(I:C), induced up-regulated secretion of MIP-1a, MIP-1b, RANTES and TNF-a, and down-regulated interleukin (IL)-2 and VEGF secretion. In contrast, viral ssRNA induced a broader panel of cytokines in the FMs by up-regulating the secretion of IL-1b, IL-2, IL-6, G-CSF, MCP-1, MIP-1a, MIP-1b, RANTES, TNF-a and GRO-a. Using inhibitory peptides against TLR adapter proteins, FM secretion of MIP-1b and RANTES in response to Poly(I:C) was MyD88 dependent; MIP-1a secretion was dependent on MyD88 and TRIF; and TNF-a production was independent of MyD88 and TRIF. Viral ssRNA-induced FM secretion of IL-1b, IL-2, IL-6, G-CSF, MIP-1a, RANTES and GRO-a was dependent on MyD88 and TRIF; MIP-1b was dependent upon TRIF, but not MyD88; and TNF-a and MCP-1 secretion was dependent on neither. Poly(I:C), but not ssRNA, induced an FM antiviral response by up-regulating the expression of IFNb, myxovirus-resistance A, 2 \u2032 ,5 \u2032 -oligoadenylate synthetase and apolipoprotein B mRNA-editing enzyme-catalytic polypeptide-like 3G. These findings demonstrate that human FMs respond to two viral signatures by generating distinct inflammatory cytokine/chemokine profiles and antiviral responses through different mechanisms.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Bacterial infection and inflammation of the placental fetal membranes (FM) play a major role in chorioamnionitis, preterm premature rupture of membranes (PPROM) and preterm birth (ACOG Practice Bulletin No. 80, 2007 , Goldenberg et al., 2000 Lamont, 2003; Caughey et al., 2008; Goldenberg et al., 2008) . The FMs are likely the first tissues colonized by an ascending bacterial infection (Herve et al., 2008) . Although most normal term deliveries have evidence of bacteria in the chorioamnion, it is the association with inflammation that correlates with pathology and prematurity (Romero et al., 2007) . An intrauterine infection gaining access to the FMs is thought to trigger prematurity by activating innate immune responses (Romero et al., 2007) . Indeed, clinical and experimental studies have correlated bacteria/bacterial components and inflammation at the maternal-fetal interface with preterm birth (Elovitz and Mrinalini, 2004; Elovitz et al., 2006; Romero et al., 2006; Pettker et al., 2007; Koga et al., 2009; Pirianov et al., 2009; Burd et al., 2010; Cardenas et al., 2011) . However, in spite of this association, no single bacterium has been attributed to preterm birth, and antibiotic interventions have proved unsuccessful (Ganu et al., 2012) .", "cite_spans": [{"start": 216, "end": 241, "text": ", Goldenberg et al., 2000", "ref_id": "BIBREF25"}, {"start": 242, "end": 255, "text": "Lamont, 2003;", "ref_id": "BIBREF41"}, {"start": 256, "end": 277, "text": "Caughey et al., 2008;", "ref_id": "BIBREF12"}, {"start": 278, "end": 302, "text": "Goldenberg et al., 2008)", "ref_id": "BIBREF26"}, {"start": 388, "end": 408, "text": "(Herve et al., 2008)", "ref_id": "BIBREF30"}, {"start": 582, "end": 603, "text": "(Romero et al., 2007)", "ref_id": "BIBREF67"}, {"start": 730, "end": 751, "text": "(Romero et al., 2007)", "ref_id": "BIBREF67"}, {"start": 910, "end": 939, "text": "(Elovitz and Mrinalini, 2004;", "ref_id": "BIBREF19"}, {"start": 940, "end": 961, "text": "Elovitz et al., 2006;", "ref_id": "BIBREF20"}, {"start": 962, "end": 982, "text": "Romero et al., 2006;", "ref_id": "BIBREF66"}, {"start": 983, "end": 1004, "text": "Pettker et al., 2007;", "ref_id": "BIBREF58"}, {"start": 1005, "end": 1023, "text": "Koga et al., 2009;", "ref_id": "BIBREF37"}, {"start": 1024, "end": 1046, "text": "Pirianov et al., 2009;", "ref_id": "BIBREF60"}, {"start": 1047, "end": 1065, "text": "Burd et al., 2010;", "ref_id": "BIBREF10"}, {"start": 1066, "end": 1088, "text": "Cardenas et al., 2011)", "ref_id": "BIBREF11"}], "ref_spans": []}, {"section": "Introduction", "text": "More recently there has been growing interest in the role of viral infections and adverse pregnancy outcomes. The presence of a number of viral infections in the amniotic fluid or gestational tissues have been reported to be linked to increased risk for chorioamnionitis and spontaneous preterm birth, such as adenovirus (Srinivas et al., 2006; Tsekoura et al., 2010) ; Epstein -Barr virus, cytomegalovirus (CMV), herpes virus (Gibson et al., 2008 (Gibson et al., , 2011 , human papillomavirus (Gomez et al., 2008) , coxsackie virus, group B type 1 (Strong and Young, 1995) , the enterovirus herpangia (Chen et al., 2010) and hepatitis virus (Elefsiniotis et al., 2010; Connell et al., 2011) . Infection with adenovirus has also been associated with second trimester pregnancy loss (Srinivas et al., 2006) . Similarly, infection with Parvovirus B19 or herpes virus early in pregnancy has been linked to second trimester miscarriage or very preterm birth (Johansson et al., 2008) . In addition, women with H1N1 are more likely to have adverse pregnancy outcomes such as spontaneous miscarriages and preterm birth (Creanga et al., 2010; Investigators and Australasian Maternity Outcomes Surveillance, 2010; Siston et al., 2010) , and the rate of preterm birth correlates with maternal disease severity (Michaan et al., 2012) .", "cite_spans": [{"start": 321, "end": 344, "text": "(Srinivas et al., 2006;", "ref_id": "BIBREF72"}, {"start": 345, "end": 367, "text": "Tsekoura et al., 2010)", "ref_id": "BIBREF74"}, {"start": 427, "end": 447, "text": "(Gibson et al., 2008", "ref_id": "BIBREF23"}, {"start": 448, "end": 470, "text": "(Gibson et al., , 2011", "ref_id": "BIBREF24"}, {"start": 494, "end": 514, "text": "(Gomez et al., 2008)", "ref_id": "BIBREF27"}, {"start": 549, "end": 573, "text": "(Strong and Young, 1995)", "ref_id": "BIBREF73"}, {"start": 602, "end": 621, "text": "(Chen et al., 2010)", "ref_id": "BIBREF13"}, {"start": 642, "end": 669, "text": "(Elefsiniotis et al., 2010;", "ref_id": "BIBREF18"}, {"start": 670, "end": 691, "text": "Connell et al., 2011)", "ref_id": "BIBREF16"}, {"start": 782, "end": 805, "text": "(Srinivas et al., 2006)", "ref_id": "BIBREF72"}, {"start": 954, "end": 978, "text": "(Johansson et al., 2008)", "ref_id": "BIBREF34"}, {"start": 1112, "end": 1134, "text": "(Creanga et al., 2010;", "ref_id": "BIBREF17"}, {"start": 1205, "end": 1225, "text": "Siston et al., 2010)", "ref_id": "BIBREF71"}, {"start": 1300, "end": 1322, "text": "(Michaan et al., 2012)", "ref_id": "BIBREF54"}], "ref_spans": []}, {"section": "Introduction", "text": "While FMs are permissive to viral infections, including influenza virus (Uchide et al., 2002a (Uchide et al., , b, 2006 (Uchide et al., , 2009 (Uchide et al., , 2012 , CMV (Figueroa et al., 1978; Kumazaki et al., 2002; Matsunaga et al., 2013) , and herpes virus (Rokos et al., 1998) , and viral infections can trigger an inflammatory cytokine response in the chorioamnion (Uchide et al., 2002b (Uchide et al., , 2006 (Uchide et al., , 2012 , little is known about the mechanisms involved. One way in which infection-associated inflammation at the maternal -fetal interface arises is through activation of the innate immune Toll-like receptors (TLRs) (Abrahams, 2008) . We have previously shown that normal human FMs at term constitutively express TLRs 1-10, as well as the two major TLR adapter proteins, MyD88 and TRIF (Hoang et al., 2014) . Moreover, in response to bacterial agonists, TLR2, TLR4, TLR5 and TLR9 mediate distinct FM cytokine profiles (Hoang et al., 2014) . Thus, we hypothesized that this might also be the case for TLR3, which senses viral dsRNA and TLR8, which detects viral ssRNA (Kumar et al., 2011) . Therefore, the objective of this study was to characterize the cytokine profile and antiviral response in human FMs exposed to the viral signatures, dsRNA and ssRNA, and to determine the mechanisms involved.", "cite_spans": [{"start": 72, "end": 93, "text": "(Uchide et al., 2002a", "ref_id": "BIBREF76"}, {"start": 120, "end": 142, "text": "(Uchide et al., , 2009", "ref_id": "BIBREF79"}, {"start": 143, "end": 165, "text": "(Uchide et al., , 2012", "ref_id": "BIBREF80"}, {"start": 172, "end": 195, "text": "(Figueroa et al., 1978;", "ref_id": "BIBREF21"}, {"start": 196, "end": 218, "text": "Kumazaki et al., 2002;", "ref_id": "BIBREF40"}, {"start": 219, "end": 242, "text": "Matsunaga et al., 2013)", "ref_id": "BIBREF51"}, {"start": 262, "end": 282, "text": "(Rokos et al., 1998)", "ref_id": "BIBREF61"}, {"start": 372, "end": 393, "text": "(Uchide et al., 2002b", "ref_id": "BIBREF77"}, {"start": 394, "end": 416, "text": "(Uchide et al., , 2006", "ref_id": "BIBREF78"}, {"start": 417, "end": 439, "text": "(Uchide et al., , 2012", "ref_id": "BIBREF80"}, {"start": 650, "end": 666, "text": "(Abrahams, 2008)", "ref_id": "BIBREF0"}, {"start": 820, "end": 840, "text": "(Hoang et al., 2014)", "ref_id": "BIBREF31"}, {"start": 952, "end": 972, "text": "(Hoang et al., 2014)", "ref_id": "BIBREF31"}, {"start": 1101, "end": 1121, "text": "(Kumar et al., 2011)", "ref_id": "BIBREF39"}], "ref_spans": []}, {"section": "Materials and Methods", "text": "Fetal membrane collection, preparation and stimulation FM (n \u00bc 16) were collected from uncomplicated normal term pregnancies (39-41 weeks) delivered by elective repeat Cesarean section, without signs of labor, infection or PPROM. No patients received prostaglandins or any other induction agent prior to Cesarean section. Sample collection was approved by Yale University's Human Investigation Committee. After washing the FMs with sterile PBS supplemented with penicillin (100 U/ml) and streptomycin (100 mg/ml) (Gibco, Grand Island, NY, USA), adherent blood clots were removed and sections where both the chorion and amnion were intact were cut using a 6-mm biopsy punch. The FM explants were then placed in 0.4-mm cell culture inserts (BD Falcon, Franklin Lakes, NJ, USA), with 500-ml Dulbecco's Modified Eagle Medium (DMEM; Gibco) supplemented with 10% fetal bovine serum (FBS; Hyclone, Logan, UT, USA) and these were placed in a 24-well plate containing 500 ml of the DMEM media for 24 h, as previously described (Luo et al., 2010; Hoang et al., 2014) . The next day the media was removed and replaced with serumfree OptiMeM media (Gibco). FM explants were then treated with: no treatment (NT); the TLR3 agonist and synthetic analog of viral dsRNA, Poly(I:C), at 20 mg/ml (Invivogen, San Diego, CA, USA); or the TLR8 agonist, viral ssRNA at 5 mg/ml (Invivogen). To determine the involvement of caspase-1, FM explants were pretreated for 1 h with the specific caspase-1 inhibitor, Z-WEHD-FMK at 1 mM (R&D Systems, Minneapolis, MN, USA). To determine the involvement of MyD88 or TRIF, FM explants were pretreated for 1 h with either a MyD88 inhibitor peptide (Pepin-MYD; 10 mM); a TRIF inhibitor peptide (Pepin-TRIF; 10 mM) or a control peptide (Pepin-Control; 10 mM) (Invivogen). The optimal Poly(I:C) and viral ssRNA concentrations were determined in preliminary experiments (data not shown) and the time point determined from previous studies (Hoang et al., 2014) . After 24 h of treatment, cell-free culture supernatants were collected and the explants snap frozen. Supernatants and tissues were then stored at 2808C until further analysis was performed.", "cite_spans": [{"start": 1018, "end": 1036, "text": "(Luo et al., 2010;", "ref_id": "BIBREF46"}, {"start": 1037, "end": 1056, "text": "Hoang et al., 2014)", "ref_id": "BIBREF31"}, {"start": 1949, "end": 1969, "text": "(Hoang et al., 2014)", "ref_id": "BIBREF31"}], "ref_spans": []}, {"section": "Materials and Methods", "text": "Cytokine analysis FM supernatants were analyzed for the following cytokines/chemokines using multiplex analysis (BioRad): IL-1b, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-17, G-CSF (CSF3), GM-CSF (CSF2), IFNg, MCP-1 (CCL2), MIP-1a, MIP-1, b RANTES (CCL5), TNF-a, VEGF and GRO-a as previously described (Luo et al., 2010; Hoang et al., 2014) . FM supernatants were also analyzed for IL-1b by ELISA (R&D Systems).", "cite_spans": [{"start": 301, "end": 319, "text": "(Luo et al., 2010;", "ref_id": "BIBREF46"}, {"start": 320, "end": 339, "text": "Hoang et al., 2014)", "ref_id": "BIBREF31"}], "ref_spans": []}, {"section": "Quantitative real-time RT-PCR", "text": "FM explant biopsies were homogenized and total RNA extracted as previously described Krikun et al., 2013; Hoang et al., 2014) . Quantitative real-time PCR was performed using the KAPA SYBR Fast qPCR kit (Kapa Biosystems, Woburn, MA, USA), and PCR amplification performed on the BioRad CFX Connect Real-time System (BioRad, Hercules, CA, USA). Detection of human IFNb, 2 \u2032 ,5 \u2032 -oligoadenylate synthetase (OAS), myxovirus-resistance A (MxA) and apolipoprotein B mRNA-editing enzyme-catalytic polypeptide-like 3G (APOBEC3G) and secretory leukocyte protease inhibitor (SLPI) was performed using primer sequences as previously described (Krikun et al., 2013) . Data were normalized to the housekeeping gene, GAPDH, analyzed using the D-DCT method and presented as fold change (FC) in the expression of gene of interest relative to the NT control, as previously described Krikun et al., 2013) .", "cite_spans": [{"start": 85, "end": 105, "text": "Krikun et al., 2013;", "ref_id": "BIBREF38"}, {"start": 106, "end": 125, "text": "Hoang et al., 2014)", "ref_id": "BIBREF31"}, {"start": 633, "end": 654, "text": "(Krikun et al., 2013)", "ref_id": "BIBREF38"}, {"start": 867, "end": 887, "text": "Krikun et al., 2013)", "ref_id": "BIBREF38"}], "ref_spans": []}, {"section": "Statistical analysis", "text": "Experiments were performed at least three times and data presented as mean + SEM. Prism from Graphpad Software, Inc. (La Jolla, CA, USA) was used to calculate significance (P , 0.05). Statistical analysis was performed using either the paired t-test, or for multiple comparisons, one-way ANOVA.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Viral signatures induce distinct FM cytokine profiles", "text": "In a previous study we established that human FMs from normal term pregnancies constitutively express the viral sensors, TLR3 and TLR8, as well as the TLR adapter proteins MyD88 and TRIF (Hoang et al., 2014) . Therefore, in this study, FMs were treated with the TLR3 agonist, Poly(I:C), and the TLR8 agonist, viral ssRNA (Kumar et al., 2011) . After treatment with Poly(I:C), FMs secreted significantly higher levels of TNF-a (2.1-fold), MIP-1a (8-fold), MIP-1b (4.8-fold), and RANTES (16.4-fold) compared with the NT control. In parallel, FM secretion of IL-2, and VEGF was significantly dampened by 4-fold and 4.1-fold, respectively, after exposure to Poly(I:C) (Fig. 1) . FM secretion of IL-1b, IL-6, G-CSF, MCP-1, GRO-a, IL-8, GM-CSF and IFNg were not significantly changed after Poly(I:C) treatment (Fig. 1) . After treatment with viral ssRNA, FMs secreted significantly higher levels of IL-1b (13.8-fold), IL-2 (1.3-fold), IL-6 (4.1-fold), TNF-a (4.2-fold), MCP-1 (1.9-fold), G-CSF (3.8-fold), MIP-1a (4.8-fold), , RANTES (4.3-fold) and GRO-a (6.6-fold) (Fig. 1) . FM secretion of IL-8, GM-CSF, IFNg and VEGF were not significantly changed after ssRNA treatment (Fig. 1) . Levels of IL-4, IL-10, IL-12 and IL-17 were below the assay's detection limit.", "cite_spans": [{"start": 187, "end": 207, "text": "(Hoang et al., 2014)", "ref_id": "BIBREF31"}, {"start": 321, "end": 341, "text": "(Kumar et al., 2011)", "ref_id": "BIBREF39"}], "ref_spans": []}, {"section": "Viral signatures induce distinct FM cytokine profiles", "text": "Role of MyD88 and TRIF in viral dsRNA-and ssRNA-induced FM cytokine secretion Having established that human FMs respond to the viral TLR agonists, Poly(I:C) and ssRNA by secreting cytokines and chemokines, we next sought to determine the role of the adapter proteins MyD88 and TRIF. Typically, TLR3 utilizes the adapter protein TRIF (Yamamoto et al., 2002; Oshiumi et al., 2003) , while TLR8 signals through MyD88 (Han et al., 2012; Heil et al., 2004) . As shown in Fig. 2A , the Poly(I:C)-induced up-regulation of FM MIP-1a, MIP-1b and RANTES in the presence of the control peptide was significantly reduced by the presence of the MyD88 inhibitor. The TRIF inhibitor also significantly reduced Poly(I:C)-induced secretion of MIP-1a, but not MIP-1b or RANTES (Fig. 2A) . Neither the MyD88 nor the TRIF inhibitor had any significant effect on the FMs Poly(I:C)-induced TNF-a response ( Fig. 2A) . As shown in Fig. 2B , the ssRNA-induced up-regulation of IL-1b, IL-2, IL-6, G-CSF, MIP-1a, RANTES and GRO-a secretion by the FMs was significantly reduced by both the MyD88 inhibitor and the TRIF inhibitor, when compared with the control peptide. Viral ssRNA-induced up-regulation of MIP-1b secretion by the FMs was significantly inhibited by the presence of the TRIF inhibitor, but not the MyD88 inhibitor (Fig. 2B) . ssRNA-induced TNF-a and MCP-1 secretion was not significantly altered by ether inhibitor (Fig. 2B) .", "cite_spans": [{"start": 333, "end": 356, "text": "(Yamamoto et al., 2002;", "ref_id": "BIBREF82"}, {"start": 357, "end": 378, "text": "Oshiumi et al., 2003)", "ref_id": "BIBREF57"}, {"start": 414, "end": 432, "text": "(Han et al., 2012;", "ref_id": "BIBREF28"}, {"start": 433, "end": 451, "text": "Heil et al., 2004)", "ref_id": "BIBREF29"}], "ref_spans": [{"start": 466, "end": 473, "text": "Fig. 2A", "ref_id": "FIGREF0"}, {"start": 759, "end": 768, "text": "(Fig. 2A)", "ref_id": "FIGREF0"}, {"start": 885, "end": 893, "text": "Fig. 2A)", "ref_id": "FIGREF0"}, {"start": 908, "end": 915, "text": "Fig. 2B", "ref_id": "FIGREF0"}, {"start": 1303, "end": 1312, "text": "(Fig. 2B)", "ref_id": "FIGREF0"}, {"start": 1404, "end": 1413, "text": "(Fig. 2B)", "ref_id": "FIGREF0"}]}, {"section": "Viral signatures induce distinct FM cytokine profiles", "text": "FM IL-1b secretion in response to viral ssRNA is caspase-1 dependent Since viral ssRNA, but not Poly(I:C), induced the FMs to produce IL-1b, we further examined the mechanism involved. We previously demonstrated that human FMs express the inflammasome components Nalp1, Nalp3, ASC (apoptosis-associated speck-like protein containing a CARD) and caspase-1 (Hoang et al., 2014) , which mediate the processing of intracellular pro-IL-1b into its active, secreted form (Agostini et al., 2004; Martinon and Tschopp, 2004) . In the presence of a caspase-1 inhibitor, IL-1b secretion induced by viral ssRNA was significantly reduced by 54.7% (Fig. 3) .", "cite_spans": [{"start": 355, "end": 375, "text": "(Hoang et al., 2014)", "ref_id": "BIBREF31"}, {"start": 465, "end": 488, "text": "(Agostini et al., 2004;", "ref_id": "BIBREF5"}, {"start": 489, "end": 516, "text": "Martinon and Tschopp, 2004)", "ref_id": "BIBREF49"}], "ref_spans": [{"start": 635, "end": 643, "text": "(Fig. 3)", "ref_id": "FIGREF1"}]}, {"section": "Viral signatures induce distinct FM cytokine profiles", "text": "Poly(I:C), but not viral ssRNA, induces an FM antiviral response TLR3 and TLR8 activation can induce a type I interferon (IFN) response (Arpaia and Barton, 2011) , and the subsequent production of antiviral factors, such as IFN-inducible OAS, MxA and APOBEC3G (Samuel, 2001; Turelli et al., 2004; Abrahams et al., 2006; Bonvin et al., 2006; Krikun et al., 2013) and SLPI (Schaefer et al., 2005; Abrahams et al., 2006; Krikun et al., 2013) . As shown in Fig. 4 , Poly(I:C), but not ssRNA, significantly induced FMs to express elevated levels of IFNb, Figure 1 Cytokine profile of FM after exposure to Poly(I:C) and viral ssRNA. FM explants were treated with NT, Poly(I:C) or viral ssRNA. Bar charts show levels of IL-1b, IL-2, IL-6, TNFa, MCP-1, G-CSF, MIP-1a, MIP-1b, RANTES, GROa, VEGF, IL-8, GM-CSF and IFNg (*P , 0.05, **P , 0.001; n \u00bc 6).", "cite_spans": [{"start": 136, "end": 161, "text": "(Arpaia and Barton, 2011)", "ref_id": "BIBREF8"}, {"start": 260, "end": 274, "text": "(Samuel, 2001;", "ref_id": "BIBREF69"}, {"start": 275, "end": 296, "text": "Turelli et al., 2004;", "ref_id": "BIBREF75"}, {"start": 297, "end": 319, "text": "Abrahams et al., 2006;", "ref_id": "BIBREF1"}, {"start": 320, "end": 340, "text": "Bonvin et al., 2006;", "ref_id": "BIBREF9"}, {"start": 341, "end": 361, "text": "Krikun et al., 2013)", "ref_id": "BIBREF38"}, {"start": 371, "end": 394, "text": "(Schaefer et al., 2005;", "ref_id": "BIBREF70"}, {"start": 395, "end": 417, "text": "Abrahams et al., 2006;", "ref_id": "BIBREF1"}, {"start": 418, "end": 438, "text": "Krikun et al., 2013)", "ref_id": "BIBREF38"}], "ref_spans": [{"start": 453, "end": 459, "text": "Fig. 4", "ref_id": "FIGREF2"}]}, {"section": "Effect of viral products on human fetal membranes", "text": "MxA, OAS and APOBEC3G mRNA. In contrast, neither Poly(I:C) nor ssRNA induced a significant increase in SLPI mRNA levels (Fig. 4) .", "cite_spans": [], "ref_spans": [{"start": 120, "end": 128, "text": "(Fig. 4)", "ref_id": "FIGREF2"}]}, {"section": "Discussion", "text": "Infection-associated pregnancy complications such as chorioamnionitis, PPROM and preterm birth have been strongly associated with bacterial infection and inflammation of the FMs (ACOG Practice Bulletin No. 80, 2007 , Goldenberg et al., 2000 Lamont, 2003; Caughey et al., 2008; Goldenberg et al., 2008) . Although, much less is known about the role of viral infections, there is growing evidence to suggest an association with pregnancy mortality and morbidity and gestational tissues including the FMs may be a target (Figueroa et al., 1978; Rokos et al., 1998; Kumazaki et al., 2002; Uchide et al., 2002a Uchide et al., , b, 2006 Uchide et al., , 2009 Uchide et al., , 2012 Matsunaga et al., 2013) . The functional role of innate immune pattern recognition receptors, such as the TLRs and Nod proteins, in response to bacterial components in the FMs has been described (Kim et al., 2004; Adams et al., 2007; Leroy et al., 2007; Abrahams et al., 2013; Lappas, 2013 Lappas, , 2014 Hoang et al., 2014) , however, little is known about this tissue's response to viral components or the mechanisms involved. In this current study we have demonstrated that FMs exposed to the TLR3 agonist, viral dsRNA, and the TLR8 agonist, viral ssRNA, generate distinct cytokine/ chemokine and antiviral profiles. Furthermore, we have demonstrated a differential role for the TLR adapter proteins, MyD88 and TRIF, in mediating FM cytokine/chemokine production in response to these two viral signatures. We have also demonstrated a role for the inflammasome component, caspase-1, in mediating FM IL-1b production following exposure to viral ssRNA.", "cite_spans": [{"start": 215, "end": 240, "text": ", Goldenberg et al., 2000", "ref_id": "BIBREF25"}, {"start": 241, "end": 254, "text": "Lamont, 2003;", "ref_id": "BIBREF41"}, {"start": 255, "end": 276, "text": "Caughey et al., 2008;", "ref_id": "BIBREF12"}, {"start": 277, "end": 301, "text": "Goldenberg et al., 2008)", "ref_id": "BIBREF26"}, {"start": 518, "end": 541, "text": "(Figueroa et al., 1978;", "ref_id": "BIBREF21"}, {"start": 542, "end": 561, "text": "Rokos et al., 1998;", "ref_id": "BIBREF61"}, {"start": 562, "end": 584, "text": "Kumazaki et al., 2002;", "ref_id": "BIBREF40"}, {"start": 585, "end": 605, "text": "Uchide et al., 2002a", "ref_id": "BIBREF76"}, {"start": 631, "end": 652, "text": "Uchide et al., , 2009", "ref_id": "BIBREF79"}, {"start": 653, "end": 674, "text": "Uchide et al., , 2012", "ref_id": "BIBREF80"}, {"start": 675, "end": 698, "text": "Matsunaga et al., 2013)", "ref_id": "BIBREF51"}, {"start": 870, "end": 888, "text": "(Kim et al., 2004;", "ref_id": "BIBREF36"}, {"start": 889, "end": 908, "text": "Adams et al., 2007;", "ref_id": "BIBREF4"}, {"start": 909, "end": 928, "text": "Leroy et al., 2007;", "ref_id": "BIBREF44"}, {"start": 929, "end": 951, "text": "Abrahams et al., 2013;", "ref_id": "BIBREF2"}, {"start": 952, "end": 964, "text": "Lappas, 2013", "ref_id": "BIBREF42"}, {"start": 965, "end": 979, "text": "Lappas, , 2014", "ref_id": "BIBREF43"}, {"start": 980, "end": 999, "text": "Hoang et al., 2014)", "ref_id": "BIBREF31"}], "ref_spans": []}, {"section": "Discussion", "text": "When we compared the cytokine profile generated by human FMs after exposure to the viral TLR3 and TLR8 agonists, Poly(I:C) and viral ssRNA, respectively, these two viral signatures induced quite different cytokine/chemokine responses. Poly(I:C) up-regulated the secretion of the pro-inflammatory cytokine, TNF-a, and the inflammatory chemokines MIP-1a, MIP-1b and RANTES, while down-regulating the constitutive of IL-2 and VEGF. In contrast viral ssRNA triggered a much broader response by increasing the tissue's section of the pro-inflammatory cytokines, IL-1b, TNF-a, IL-6 and IL-2; the inflammatory chemokines, MCP-1, MIP-1a, MIP-1b, RANTES and GRO-a and the growth factor, G-CSF. So while both viral components triggered distinct profiles, both responses were a combination of pro-inflammatory cytokines and chemokines.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "The production of the chemokines, MCP-1, MIP-1a, MIP-1b, RANTES and GRO-a by FMs exposed to viral RNA, suggests that in the context of a viral infection, the chorioamnion may play a role in immune cell recruitment. Although histologic chorioamnionitis is characterized by a neutrophil infiltrate, and the classic chemokine for this, IL-8, is often elevated in these cases , in our studies FMs treated with Poly(I:C) or ssRNA did not produce elevated levels of IL-8. Interestingly, basal IL-8 levels produced by the FMs were much higher than the other chemokines detected. Neutrophil chemotaxis can, however, be regulated by a number of other chemokines. In mice, for example, it has been shown that neutrophils express two major chemokine receptors, CCR1 and CXCR2 (Chou et al., 2010; McDonald and Kubes, 2010) . CCR1 can be ligated by MIP-1a, MIP-1b and RANTES, while CXCR2 can be activated by GRO-a (Chou et al., 2010; McDonald and Kubes, 2010) . Thus, it seems that after TLR3 and TLR8 stimulation, human FMs are producing mostly CCR1 ligands and may recruit neutrophils preferentially through this receptor.", "cite_spans": [{"start": 765, "end": 784, "text": "(Chou et al., 2010;", "ref_id": "BIBREF14"}, {"start": 785, "end": 810, "text": "McDonald and Kubes, 2010)", "ref_id": "BIBREF52"}, {"start": 901, "end": 920, "text": "(Chou et al., 2010;", "ref_id": "BIBREF14"}, {"start": 921, "end": 946, "text": "McDonald and Kubes, 2010)", "ref_id": "BIBREF52"}], "ref_spans": []}, {"section": "Discussion", "text": "The production of the pro-inflammatory cytokine, TNF-a by the FMs in response to TLR3 and TLR8 activation, and IL-1b and IL-6 in response to viral ssRNA also suggests a role for the FMs in contributing to preterm birth. Levels of IL-1b, IL-6 and TNF-a are elevated in the amniotic fluids of patients with preterm birth and intra-amniotic infection (Romero et al., 1989 (Romero et al., , 1990 (Romero et al., , 1992a and IL-1b plays a role in promoting preterm labor (Sadowsky et al., 2006; Christiaens et al., 2008; Kemp et al., 2010) . These findings are also in keeping with previous reports that infection of human chorion cells with influenza virus, which is an ssRNA virus, induces the production of the pro-inflammatory cytokines, IL-1b, IL-6 and TNFa (Uchide et al., 2002b (Uchide et al., , 2006 .", "cite_spans": [{"start": 348, "end": 368, "text": "(Romero et al., 1989", "ref_id": "BIBREF62"}, {"start": 369, "end": 391, "text": "(Romero et al., , 1990", "ref_id": "BIBREF63"}, {"start": 392, "end": 415, "text": "(Romero et al., , 1992a", "ref_id": "BIBREF64"}, {"start": 466, "end": 489, "text": "(Sadowsky et al., 2006;", "ref_id": "BIBREF68"}, {"start": 490, "end": 515, "text": "Christiaens et al., 2008;", "ref_id": "BIBREF15"}, {"start": 516, "end": 534, "text": "Kemp et al., 2010)", "ref_id": "BIBREF35"}, {"start": 758, "end": 779, "text": "(Uchide et al., 2002b", "ref_id": "BIBREF77"}, {"start": 780, "end": 802, "text": "(Uchide et al., , 2006", "ref_id": "BIBREF78"}], "ref_spans": []}, {"section": "Discussion", "text": "In order to achieve IL-1b secretion, intracellular pro-IL-1b must be processed into its active, secreted form (Agostini et al., 2004; Martinon and Tschopp, 2004) , and this is often mediated by caspase-1 (Netea et al., 2010) that associates with the other inflammasome components, Nalp1 or Nalp3 and ASC (Agostini et al., 2004; Martinon and Tschopp, 2007) . We have previously reported that normal human FMs at term express all these components and in response to the bacterial TLR agonists, lipopolysaccharide (LPS), peptidoglycan and flagellin induce IL-1b processing and secretion via caspase-1 (Hoang et al., 2014) . A recent study by Lappas, also showed LPS-induced IL-1b by FMs to be mediated by caspase-1 (Lappas, 2014) . In this current study we demonstrated that human FMs exposed to viral ssRNA secrete IL-1b in a caspase-1 dependent manner, suggesting that TLR8 activation may induce inflammasome activity. Indeed, the TLR8 agonist, imidazoquinoline, can activate monocyte IL-1b production via caspase-1 (Philbin et al., 2012) , and viral ssRNA-mediated IL-1b release by monocytes is dependent on the Nalp3 inflammasome (Allen et al., 2011) .", "cite_spans": [{"start": 110, "end": 133, "text": "(Agostini et al., 2004;", "ref_id": "BIBREF5"}, {"start": 134, "end": 161, "text": "Martinon and Tschopp, 2004)", "ref_id": "BIBREF49"}, {"start": 204, "end": 224, "text": "(Netea et al., 2010)", "ref_id": "BIBREF56"}, {"start": 304, "end": 327, "text": "(Agostini et al., 2004;", "ref_id": "BIBREF5"}, {"start": 328, "end": 355, "text": "Martinon and Tschopp, 2007)", "ref_id": "BIBREF50"}, {"start": 598, "end": 618, "text": "(Hoang et al., 2014)", "ref_id": "BIBREF31"}, {"start": 712, "end": 726, "text": "(Lappas, 2014)", "ref_id": "BIBREF43"}, {"start": 1015, "end": 1037, "text": "(Philbin et al., 2012)", "ref_id": "BIBREF59"}, {"start": 1131, "end": 1151, "text": "(Allen et al., 2011)", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "Discussion", "text": "To further explore the mechanisms by which viral dsRNA and ssRNA induce FM cytokine/chemokine production, we determined the functional role of the TLR adapter proteins, MyD88 and TRIF in this response. TLR3 is known to signal through TRIF (Yamamoto et al., 2002; Oshiumi et al., 2003) , while TLR8 signals through MyD88 (Heil et al., 2004; Han et al., 2012) . In this study we found that Poly(I:C) induced MIP-1a, MIP-1b and RANTES production via MyD88, MIP-1a production was also mediated by TRIF, but TNFa production was dependent upon neither adapter protein. This suggests that in FMs, Poly(I:C), in addition Effect of viral products on human fetal membranes to activating the TLR3/TRIF pathway, may also be activating another receptor utilizing MyD88. Alternatively, in human FMs, TLR3 may be able to signal through both adapter proteins, similarly to TLR4 (Yamamoto et al., 2003) . Indeed an early study reported that TLR3 could indeed utilize MyD88 (Alexopoulou et al., 2001) . The lack of dependency for either MyD88 or TRIF for Poly(I:C)-induced TNFa could again suggest activation of an alternative, TLR3-independent pathway (Hoebe et al., 2003) , such as the cytosolic RIG-like receptors (RLR) and non-RLR helicases (Vabret and Blander, 2013) . We found a similar differential usage of MyD88 and TRIF in FMs exposed to viral ssRNA. Both adapter proteins played a role in the secretion of the majority of cytokines and chemokines induced by ssRNA, except for MIP-1b, which was only dependent upon TRIF. This suggests that in the FMs, TLR8 can also utilize both MyD88 and TRIF, or that an additional TRIF-dependent pathway is activated. Indeed, Marshall-Clarke et al. (2007) , reported that TLR3 can sense both dsRNA and ssRNA. However, similarly to the Poly(I:C) response, TNFa was dependent upon neither adapter protein, as was MCP-1 production, again suggesting activation of a TLR-independent pathway (Vabret and Blander, 2013) .", "cite_spans": [{"start": 239, "end": 262, "text": "(Yamamoto et al., 2002;", "ref_id": "BIBREF82"}, {"start": 263, "end": 284, "text": "Oshiumi et al., 2003)", "ref_id": "BIBREF57"}, {"start": 320, "end": 339, "text": "(Heil et al., 2004;", "ref_id": "BIBREF29"}, {"start": 340, "end": 357, "text": "Han et al., 2012)", "ref_id": "BIBREF28"}, {"start": 862, "end": 885, "text": "(Yamamoto et al., 2003)", "ref_id": "BIBREF83"}, {"start": 956, "end": 982, "text": "(Alexopoulou et al., 2001)", "ref_id": "BIBREF6"}, {"start": 1135, "end": 1155, "text": "(Hoebe et al., 2003)", "ref_id": "BIBREF32"}, {"start": 1227, "end": 1253, "text": "(Vabret and Blander, 2013)", "ref_id": "BIBREF81"}, {"start": 1914, "end": 1940, "text": "(Vabret and Blander, 2013)", "ref_id": "BIBREF81"}], "ref_spans": []}, {"section": "Discussion", "text": "Our last observation in this study was that Poly(I:C) triggered the expression of the type interferon, IFNb, and the IFN-inducible antiviral factors, OAS, MxA and APOBEC3G (Samuel, 2001; Turelli et al., 2004; Abrahams et al., 2006; Bonvin et al., 2006) . However, the antimicrobial peptide SLPI, which is not regulated by type I IFNs, but has been shown to be regulated by TLR3 in other tissues (Schaefer et al., 2005; Abrahams et al., 2006) , was not induced in Poly(I:C)-treated FMs. Furthermore, and in contrast to the Poly(I:C)-induced response, treatment of FMs with viral ssRNA did not induce the expression of IFNb or the antiviral factors. That FMs can generate this antiviral response to viral dsRNA is in keeping with observations that infection of human chorion cells with influenza induces IFNb (Uchide et al., 2002b) , and treatment of FM explants with Poly(I:C) elevates the production of IL-29 (IFN-lambda3) (Nace et al., 2010) , a virally induced type III IFN (Li et al., 2013) .", "cite_spans": [{"start": 172, "end": 186, "text": "(Samuel, 2001;", "ref_id": "BIBREF69"}, {"start": 187, "end": 208, "text": "Turelli et al., 2004;", "ref_id": "BIBREF75"}, {"start": 209, "end": 231, "text": "Abrahams et al., 2006;", "ref_id": "BIBREF1"}, {"start": 232, "end": 252, "text": "Bonvin et al., 2006)", "ref_id": "BIBREF9"}, {"start": 395, "end": 418, "text": "(Schaefer et al., 2005;", "ref_id": "BIBREF70"}, {"start": 419, "end": 441, "text": "Abrahams et al., 2006)", "ref_id": "BIBREF1"}, {"start": 807, "end": 829, "text": "(Uchide et al., 2002b)", "ref_id": "BIBREF77"}, {"start": 923, "end": 942, "text": "(Nace et al., 2010)", "ref_id": "BIBREF55"}, {"start": 976, "end": 993, "text": "(Li et al., 2013)", "ref_id": "BIBREF45"}], "ref_spans": []}, {"section": "Discussion", "text": "In summary, we have demonstrated that viral dsRNA and ssRNA induce distinct pro-inflammatory cytokine and chemokine responses in an MyD88/TRIF-dependent and independent manner. Thus, FM inflammatory responses to viral dsRNA and ssRNA may be both TLR dependent and TLR independent. The FM response to viral dsRNA [Poly(I:C)] appears more protective since a strong type I IFN and antiviral response is also generated, while the ssRNA-induced response is predominantly pro-inflammatory, and FM sensing of viral ssRNA may activate the inflammasome giving rise to IL-1b secretion. Together these findings provide further evidence of how different pattern recognition receptors can generate distinct responses in the FMs through distinct mechanisms, and suggest a role for viruses in promoting inflammation of the chorioamnion.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Pattern recognition at the maternal-fetal interface", "authors": [{"first": "V", "middle": ["M"], "last": "Abrahams", "suffix": ""}], "year": 2008, "venue": "Immunol Invest", "link": "19120175"}, "BIBREF1": {"title": "Expression and secretion of anti-viral factors by trophoblast cells following stimulation by the TLR-3 agonist, Poly(I:C)", "authors": [{"first": "V", "middle": ["M"], "last": "Abrahams", "suffix": ""}, {"first": "T", "middle": ["M"], "last": "Schaefer", "suffix": ""}, {"first": "J", "middle": ["V"], "last": "Fahey", "suffix": ""}, {"first": "I", "middle": [], "last": "Visintin", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Wright", "suffix": ""}, {"first": "P", "middle": [], "last": "Bole-Aldo", "suffix": ""}, {"first": "R", "middle": [], "last": "Romero", "suffix": ""}, {"first": "C", "middle": ["R"], "last": "Wira", "suffix": ""}, {"first": "G", "middle": [], "last": "Mor", "suffix": ""}], "year": 2006, "venue": "Hum Reprod", "link": "7729852"}, "BIBREF2": {"title": "Bacterial modulation of human fetal membrane Toll-like receptor expression", "authors": [{"first": "V", "middle": ["M"], "last": "Abrahams", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Potter", "suffix": ""}, {"first": "G", "middle": [], "last": "Bhat", "suffix": ""}, {"first": "M", "middle": ["R"], "last": "Peltier", "suffix": ""}, {"first": "G", "middle": [], "last": "Saade", "suffix": ""}, {"first": "R", "middle": [], "last": "Menon", "suffix": ""}], "year": 2013, "venue": "Am J Reprod Immunol", "link": "26527172"}, "BIBREF3": {"title": "Premature Rupture of Membranes. Clinical management guidelines for obstetrician-gynecologists", "authors": [{"first": "", "middle": [], "last": "Acog Practice Bulletin", "suffix": ""}, {"first": "", "middle": [], "last": "No", "suffix": ""}], "year": 2007, "venue": "Obstet Gynecol", "link": null}, "BIBREF4": {"title": "LPS induces translocation of TLR4 in amniotic epithelium", "authors": [{"first": "K", "middle": ["M"], "last": "Adams", "suffix": ""}, {"first": "J", "middle": [], "last": "Lucas", "suffix": ""}, {"first": "R", "middle": ["P"], "last": "Kapur", "suffix": ""}, {"first": "A", "middle": ["M"], "last": "Stevens", "suffix": ""}], "year": 2007, "venue": "Placenta", "link": "20739702"}, "BIBREF5": {"title": "NALP3 forms an IL-1beta-processing inflammasome with increased activity in Muckle-Wells autoinflammatory disorder", "authors": [{"first": "L", "middle": [], "last": "Agostini", "suffix": ""}, {"first": "F", "middle": [], "last": "Martinon", "suffix": ""}, {"first": "K", "middle": [], "last": "Burns", "suffix": ""}, {"first": "M", "middle": ["F"], "last": "Mcdermott", "suffix": ""}, {"first": "P", "middle": ["N"], "last": "Hawkins", "suffix": ""}, {"first": "J", "middle": [], "last": "Tschopp", "suffix": ""}], "year": 2004, "venue": "Immunity", "link": "32726434"}, "BIBREF6": {"title": "Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3", "authors": [{"first": "L", "middle": [], "last": "Alexopoulou", "suffix": ""}, {"first": "A", "middle": ["C"], "last": "Holt", "suffix": ""}, {"first": "R", "middle": [], "last": "Medzhitov", "suffix": ""}, {"first": "R", "middle": ["A"], "last": "Flavell", "suffix": ""}], "year": 2001, "venue": "Nature", "link": "4346537"}, "BIBREF7": {"title": "Outcomes of preterm infants: morbidity replaces mortality", "authors": [{"first": "M", "middle": ["C"], "last": "Allen", "suffix": ""}, {"first": "E", "middle": ["A"], "last": "Cristofalo", "suffix": ""}, {"first": "C", "middle": [], "last": "Kim", "suffix": ""}], "year": 2011, "venue": "Clin Perinatol", "link": "36293033"}, "BIBREF8": {"title": "Toll-like receptors: key players in antiviral immunity", "authors": [{"first": "N", "middle": [], "last": "Arpaia", "suffix": ""}, {"first": "G", "middle": ["M"], "last": "Barton", "suffix": ""}], "year": 2011, "venue": "Curr Opin Virol", "link": "23520186"}, "BIBREF9": {"title": "Interferon-inducible expression of APOBEC3 editing enzymes in human hepatocytes and inhibition of hepatitis B virus replication", "authors": [{"first": "M", "middle": [], "last": "Bonvin", "suffix": ""}, {"first": "F", "middle": [], "last": "Achermann", "suffix": ""}, {"first": "I", "middle": [], "last": "Greeve", "suffix": ""}, {"first": "D", "middle": [], "last": "Stroka", "suffix": ""}, {"first": "A", "middle": [], "last": "Keogh", "suffix": ""}, {"first": "D", "middle": [], "last": "Inderbitzin", "suffix": ""}, {"first": "D", "middle": [], "last": "Candinas", "suffix": ""}, {"first": "P", "middle": [], "last": "Sommer", "suffix": ""}, {"first": "S", "middle": [], "last": "Wain-Hobson", "suffix": ""}, {"first": "J", "middle": ["P"], "last": "Vartanian", "suffix": ""}], "year": 2006, "venue": "Hepatology", "link": "28537090"}, "BIBREF10": {"title": "Inflammation-induced preterm birth alters neuronal morphology in the mouse fetal brain", "authors": [{"first": "I", "middle": [], "last": "Burd", "suffix": ""}, {"first": "A", "middle": ["I"], "last": "Bentz", "suffix": ""}, {"first": "J", "middle": [], "last": "Chai", "suffix": ""}, {"first": "J", "middle": [], "last": "Gonzalez", "suffix": ""}, {"first": "H", "middle": [], "last": "Monnerie", "suffix": ""}, {"first": "Le", "middle": [], "last": "Roux", "suffix": ""}, {"first": "P", "middle": ["D"], "last": "Cohen", "suffix": ""}, {"first": "A", "middle": ["S"], "last": "Yudkoff", "suffix": ""}, {"first": "M", "middle": [], "last": "Elovitz", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "", "suffix": ""}], "year": 2010, "venue": "J Neurosci Res", "link": "9752404"}, "BIBREF11": {"title": "Nod1 activation by bacterial iE-DAP induces maternal-fetal inflammation and preterm labor", "authors": [{"first": "I", "middle": [], "last": "Cardenas", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Mulla", "suffix": ""}, {"first": "K", "middle": [], "last": "Myrtolli", "suffix": ""}, {"first": "A", "middle": ["K"], "last": "Sfakianaki", "suffix": ""}, {"first": "E", "middle": ["R"], "last": "Norwitz", "suffix": ""}, {"first": "S", "middle": [], "last": "Tadesse", "suffix": ""}, {"first": "S", "middle": [], "last": "Guller", "suffix": ""}, {"first": "V", "middle": ["M"], "last": "Abrahams", "suffix": ""}], "year": 2011, "venue": "J Immunol", "link": "44709284"}, "BIBREF12": {"title": "Contemporary diagnosis and management of preterm premature rupture of membranes", "authors": [{"first": "A", "middle": ["B"], "last": "Caughey", "suffix": ""}, {"first": "J", "middle": ["N"], "last": "Robinson", "suffix": ""}, {"first": "E", "middle": ["R"], "last": "Norwitz", "suffix": ""}], "year": 2008, "venue": "Rev Obstet Gynecol", "link": "41033774"}, "BIBREF13": {"title": "Increased risk of adverse pregnancy outcomes among women affected by herpangina", "authors": [{"first": "Y", "middle": ["H"], "last": "Chen", "suffix": ""}, {"first": "H", "middle": ["C"], "last": "Lin", "suffix": ""}, {"first": "H", "middle": ["C"], "last": "Lin", "suffix": ""}], "year": 2010, "venue": "Am J Obstet Gynecol", "link": null}, "BIBREF14": {"title": "Lipid-cytokine-chemokine cascade drives neutrophil recruitment in a murine model of inflammatory arthritis", "authors": [{"first": "R", "middle": ["C"], "last": "Chou", "suffix": ""}, {"first": "N", "middle": ["D"], "last": "Kim", "suffix": ""}, {"first": "C", "middle": ["D"], "last": "Sadik", "suffix": ""}, {"first": "E", "middle": [], "last": "Seung", "suffix": ""}, {"first": "Y", "middle": [], "last": "Lan", "suffix": ""}, {"first": "M", "middle": ["H"], "last": "Byrne", "suffix": ""}, {"first": "B", "middle": [], "last": "Haribabu", "suffix": ""}, {"first": "Y", "middle": [], "last": "Iwakura", "suffix": ""}, {"first": "A", "middle": ["D"], "last": "Luster", "suffix": ""}], "year": 2010, "venue": "Immunity", "link": "6000205"}, "BIBREF15": {"title": "Inflammatory processes in preterm and term parturition", "authors": [{"first": "I", "middle": [], "last": "Christiaens", "suffix": ""}, {"first": "D", "middle": ["B"], "last": "Zaragoza", "suffix": ""}, {"first": "L", "middle": [], "last": "Guilbert", "suffix": ""}, {"first": "S", "middle": ["A"], "last": "Robertson", "suffix": ""}, {"first": "B", "middle": ["F"], "last": "Mitchell", "suffix": ""}, {"first": "D", "middle": ["M"], "last": "Olson", "suffix": ""}], "year": 2008, "venue": "J Reprod Immunol", "link": "16493465"}, "BIBREF16": {"title": "Maternal hepatitis B and hepatitis C carrier status and perinatal outcomes", "authors": [{"first": "L", "middle": ["E"], "last": "Connell", "suffix": ""}, {"first": "H", "middle": ["M"], "last": "Salihu", "suffix": ""}, {"first": "J", "middle": ["L"], "last": "Salemi", "suffix": ""}, {"first": "E", "middle": ["M"], "last": "August", "suffix": ""}, {"first": "H", "middle": [], "last": "Weldeselasse", "suffix": ""}, {"first": "A", "middle": ["K"], "last": "Mbah", "suffix": ""}], "year": 2011, "venue": "Liver Int", "link": "205652195"}, "BIBREF17": {"title": "Severity of 2009 pandemic influenza A (H1N1) virus infection in pregnant women", "authors": [{"first": "A", "middle": ["A"], "last": "Creanga", "suffix": ""}, {"first": "T", "middle": ["F"], "last": "Johnson", "suffix": ""}, {"first": "S", "middle": ["B"], "last": "Graitcer", "suffix": ""}, {"first": "L", "middle": ["K"], "last": "Hartman", "suffix": ""}, {"first": "T", "middle": [], "last": "Al-Samarrai", "suffix": ""}, {"first": "A", "middle": ["G"], "last": "Schwarz", "suffix": ""}, {"first": "S", "middle": ["Y"], "last": "Chu", "suffix": ""}, {"first": "J", "middle": ["E"], "last": "Sackoff", "suffix": ""}, {"first": "D", "middle": ["J"], "last": "Jamieson", "suffix": ""}, {"first": "A", "middle": ["D"], "last": "Fine", "suffix": ""}], "year": 2010, "venue": "Obstet Gynecol", "link": "205472453"}, "BIBREF18": {"title": "Spontaneous preterm birth in women with chronic hepatitis B virus infection", "authors": [{"first": "I", "middle": [], "last": "Elefsiniotis", "suffix": ""}, {"first": "K", "middle": [], "last": "Tsoumakas", "suffix": ""}, {"first": "E", "middle": [], "last": "Vezali", "suffix": ""}, {"first": "I", "middle": [], "last": "Glynou", "suffix": ""}, {"first": "N", "middle": [], "last": "Drakoulis", "suffix": ""}, {"first": "G", "middle": [], "last": "Saroglou", "suffix": ""}], "year": 2010, "venue": "Int J Gynaecol Obstet", "link": "205260124"}, "BIBREF19": {"title": "Animal models of preterm birth", "authors": [{"first": "M", "middle": ["A"], "last": "Elovitz", "suffix": ""}, {"first": "C", "middle": [], "last": "Mrinalini", "suffix": ""}], "year": 2004, "venue": "Trends Endocrinol Metab", "link": "46335482"}, "BIBREF20": {"title": "Elucidating the early signal transduction pathways leading to fetal brain injury in preterm birth", "authors": [{"first": "M", "middle": ["A"], "last": "Elovitz", "suffix": ""}, {"first": "C", "middle": [], "last": "Mrinalini", "suffix": ""}, {"first": "M", "middle": ["D"], "last": "Sammel", "suffix": ""}], "year": 2006, "venue": "Pediatric Res", "link": "22111884"}, "BIBREF21": {"title": "Infection of human amnion cells with cytomegalovirus", "authors": [{"first": "M", "middle": ["E"], "last": "Figueroa", "suffix": ""}, {"first": "L", "middle": [], "last": "Geder", "suffix": ""}, {"first": "F", "middle": [], "last": "Rapp", "suffix": ""}], "year": 1978, "venue": "J Med Virol", "link": "3113565"}, "BIBREF22": {"title": "The role of microbial communities in parturition: is there evidence of association with preterm birth and perinatal morbidity and mortality?", "authors": [{"first": "R", "middle": ["S"], "last": "Ganu", "suffix": ""}, {"first": "J", "middle": [], "last": "Ma", "suffix": ""}, {"first": "K", "middle": ["M"], "last": "Aagaard", "suffix": ""}], "year": 2013, "venue": "Am J Perinatol", "link": "12429034"}, "BIBREF23": {"title": "Fetal exposure to herpesviruses may be associated with pregnancyinduced hypertensive disorders and preterm birth in a Caucasian population", "authors": [{"first": "C", "middle": ["S"], "last": "Gibson", "suffix": ""}, {"first": "P", "middle": ["N"], "last": "Goldwater", "suffix": ""}, {"first": "A", "middle": ["H"], "last": "Maclennan", "suffix": ""}, {"first": "E", "middle": ["A"], "last": "Haan", "suffix": ""}, {"first": "K", "middle": [], "last": "Priest", "suffix": ""}, {"first": "G", "middle": ["A"], "last": "Dekker", "suffix": ""}], "year": 2008, "venue": "BJOG", "link": "27972091"}, "BIBREF24": {"title": "Fetal MBL2 haplotypes combined with viral exposure are associated with adverse pregnancy outcomes", "authors": [{"first": "C", "middle": ["S"], "last": "Gibson", "suffix": ""}, {"first": "A", "middle": ["H"], "last": "Maclennan", "suffix": ""}, {"first": "E", "middle": ["A"], "last": "Haan", "suffix": ""}, {"first": "K", "middle": [], "last": "Priest", "suffix": ""}, {"first": "G", "middle": ["A"], "last": "Dekker", "suffix": ""}], "year": 2011, "venue": "J Matern Fetal Neonatal Med", "link": "23708672"}, "BIBREF25": {"title": "Intrauterine infection and preterm delivery", "authors": [{"first": "R", "middle": ["L"], "last": "Goldenberg", "suffix": ""}, {"first": "J", "middle": ["C"], "last": "Hauth", "suffix": ""}, {"first": "W", "middle": ["W"], "last": "Andrews", "suffix": ""}], "year": 2000, "venue": "N Engl J Med", "link": "27350577"}, "BIBREF26": {"title": "Epidemiology and causes of preterm birth", "authors": [{"first": "R", "middle": ["L"], "last": "Goldenberg", "suffix": ""}, {"first": "J", "middle": ["F"], "last": "Culhane", "suffix": ""}, {"first": "J", "middle": ["D"], "last": "Iams", "suffix": ""}, {"first": "R", "middle": [], "last": "Romero", "suffix": ""}], "year": 2008, "venue": "Lancet", "link": "33175"}, "BIBREF27": {"title": "Placental infection with human papillomavirus is associated with spontaneous preterm delivery", "authors": [{"first": "L", "middle": ["M"], "last": "Gomez", "suffix": ""}, {"first": "Y", "middle": [], "last": "Ma", "suffix": ""}, {"first": "C", "middle": [], "last": "Ho", "suffix": ""}, {"first": "C", "middle": ["M"], "last": "Mcgrath", "suffix": ""}, {"first": "D", "middle": ["B"], "last": "Nelson", "suffix": ""}, {"first": "S", "middle": [], "last": "Parry", "suffix": ""}], "year": 2008, "venue": "Hum Reprod", "link": "25525654"}, "BIBREF28": {"title": "Epigenetic regulation of tumor necrosis factor alpha (TNFalpha) release in human macrophages by HIV-1 single-stranded RNA (ssRNA) is dependent on TLR8 signaling", "authors": [{"first": "X", "middle": [], "last": "Han", "suffix": ""}, {"first": "X", "middle": [], "last": "Li", "suffix": ""}, {"first": "S", "middle": ["C"], "last": "Yue", "suffix": ""}, {"first": "A", "middle": [], "last": "Anandaiah", "suffix": ""}, {"first": "F", "middle": [], "last": "Hashem", "suffix": ""}, {"first": "P", "middle": ["S"], "last": "Reinach", "suffix": ""}, {"first": "H", "middle": [], "last": "Koziel", "suffix": ""}, {"first": "S", "middle": ["D"], "last": "Tachado", "suffix": ""}], "year": 2012, "venue": "J Biol Chem", "link": "205319877"}, "BIBREF29": {"title": "Species-specific recognition of singlestranded RNA via toll-like receptor 7 and 8", "authors": [{"first": "F", "middle": [], "last": "Heil", "suffix": ""}, {"first": "H", "middle": [], "last": "Hemmi", "suffix": ""}, {"first": "H", "middle": [], "last": "Hochrein", "suffix": ""}, {"first": "F", "middle": [], "last": "Ampenberger", "suffix": ""}, {"first": "C", "middle": [], "last": "Kirschning", "suffix": ""}, {"first": "S", "middle": [], "last": "Akira", "suffix": ""}, {"first": "G", "middle": [], "last": "Lipford", "suffix": ""}, {"first": "H", "middle": [], "last": "Wagner", "suffix": ""}, {"first": "S", "middle": [], "last": "Bauer", "suffix": ""}], "year": 2004, "venue": "Science", "link": "1680581"}, "BIBREF30": {"title": "The PDE4 inhibitor rolipram prevents NF-kappaB binding activity and proinflammatory cytokine release in human chorionic cells", "authors": [{"first": "R", "middle": [], "last": "Herve", "suffix": ""}, {"first": "T", "middle": [], "last": "Schmitz", "suffix": ""}, {"first": "D", "middle": [], "last": "Evain-Brion", "suffix": ""}, {"first": "D", "middle": [], "last": "Cabrol", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Leroy", "suffix": ""}, {"first": "C", "middle": [], "last": "Mehats", "suffix": ""}], "year": 2008, "venue": "J Immunol", "link": "29306738"}, "BIBREF31": {"title": "Human fetal membranes generate distinct cytokine profiles in response to bacterial Toll-like receptor and nod-like receptor agonists", "authors": [{"first": "M", "middle": [], "last": "Hoang", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Potter", "suffix": ""}, {"first": "S", "middle": ["M"], "last": "Gysler", "suffix": ""}, {"first": "C", "middle": ["S"], "last": "Han", "suffix": ""}, {"first": "S", "middle": [], "last": "Guller", "suffix": ""}, {"first": "E", "middle": ["R"], "last": "Norwitz", "suffix": ""}, {"first": "V", "middle": ["M"], "last": "Abrahams", "suffix": ""}], "year": 2014, "venue": "Biol Reprod", "link": "43611588"}, "BIBREF32": {"title": "Upregulation of costimulatory molecules induced by lipopolysaccharide and double-stranded RNA occurs by Trif-dependent and Trif-independent pathways", "authors": [{"first": "K", "middle": [], "last": "Hoebe", "suffix": ""}, {"first": "E", "middle": ["M"], "last": "Janssen", "suffix": ""}, {"first": "S", "middle": ["O"], "last": "Kim", "suffix": ""}, {"first": "L", "middle": [], "last": "Alexopoulou", "suffix": ""}, {"first": "R", "middle": ["A"], "last": "Flavell", "suffix": ""}, {"first": "J", "middle": [], "last": "Han", "suffix": ""}, {"first": "B", "middle": [], "last": "Beutler", "suffix": ""}], "year": 2003, "venue": "Nat Immunol", "link": "8505015"}, "BIBREF33": {"title": "Australasian Maternity Outcomes Surveillance S. Critical illness due to 2009 A/H1N1 influenza in pregnant and postpartum women: population based cohort study", "authors": [{"first": "A", "middle": ["I"], "last": "Investigators", "suffix": ""}], "year": 2010, "venue": "BMJ", "link": null}, "BIBREF34": {"title": "Infection with parvovirus B19 and herpes viruses in early pregnancy and risk of second trimester miscarriage or very preterm birth", "authors": [{"first": "S", "middle": [], "last": "Johansson", "suffix": ""}, {"first": "S", "middle": [], "last": "Buchmayer", "suffix": ""}, {"first": "S", "middle": [], "last": "Harlid", "suffix": ""}, {"first": "A", "middle": [], "last": "Iliadou", "suffix": ""}, {"first": "M", "middle": [], "last": "Sjoholm", "suffix": ""}, {"first": "L", "middle": [], "last": "Grillner", "suffix": ""}, {"first": "M", "middle": [], "last": "Norman", "suffix": ""}, {"first": "P", "middle": [], "last": "Sparen", "suffix": ""}, {"first": "J", "middle": [], "last": "Dillner", "suffix": ""}, {"first": "S", "middle": [], "last": "Cnattingius", "suffix": ""}], "year": 2008, "venue": "Reprod Toxicol", "link": "29842817"}, "BIBREF35": {"title": "Preterm birth, infection, and inflammation advances from the study of animal models", "authors": [{"first": "M", "middle": ["W"], "last": "Kemp", "suffix": ""}, {"first": "M", "middle": [], "last": "Saito", "suffix": ""}, {"first": "J", "middle": ["P"], "last": "Newnham", "suffix": ""}, {"first": "I", "middle": [], "last": "Nitsos", "suffix": ""}, {"first": "K", "middle": [], "last": "Okamura", "suffix": ""}, {"first": "S", "middle": ["G"], "last": "Kallapur", "suffix": ""}], "year": 2010, "venue": "Reprod Sci", "link": "32162187"}, "BIBREF36": {"title": "Toll-like receptor-2 and -4 in the chorioamniotic membranes in spontaneous labor at term and in preterm parturition that are associated with chorioamnionitis", "authors": [{"first": "Y", "middle": ["M"], "last": "Kim", "suffix": ""}, {"first": "R", "middle": [], "last": "Romero", "suffix": ""}, {"first": "T", "middle": [], "last": "Chaiworapongsa", "suffix": ""}, {"first": "G", "middle": ["J"], "last": "Kim", "suffix": ""}, {"first": "M", "middle": ["R"], "last": "Kim", "suffix": ""}, {"first": "H", "middle": [], "last": "Kuivaniemi", "suffix": ""}, {"first": "G", "middle": [], "last": "Tromp", "suffix": ""}, {"first": "J", "middle": [], "last": "Espinoza", "suffix": ""}, {"first": "E", "middle": [], "last": "Bujold", "suffix": ""}, {"first": "V", "middle": ["M"], "last": "Abrahams", "suffix": ""}], "year": 2004, "venue": "Am J Obstet Gynecol", "link": "21190262"}, "BIBREF37": {"title": "Activation of TLR3 in the trophoblast is associated with preterm delivery", "authors": [{"first": "K", "middle": [], "last": "Koga", "suffix": ""}, {"first": "I", "middle": [], "last": "Cardenas", "suffix": ""}, {"first": "Aldo", "middle": ["P"], "last": "Abrahams", "suffix": ""}, {"first": "V", "middle": ["M"], "last": "Peng", "suffix": ""}, {"first": "B", "middle": [], "last": "Fill", "suffix": ""}, {"first": "S", "middle": [], "last": "Romero", "suffix": ""}, {"first": "R", "middle": [], "last": "Mor", "suffix": ""}, {"first": "G", "middle": [], "last": "", "suffix": ""}], "year": 2009, "venue": "Am J Reprod Immunol", "link": null}, "BIBREF38": {"title": "Human endometrial endothelial cells generate distinct inflammatory and antiviral responses to the TLR3 agonist, Poly(I:C) and the TLR8 agonist, viral ssRNA", "authors": [{"first": "G", "middle": [], "last": "Krikun", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Potter", "suffix": ""}, {"first": "V", "middle": ["M"], "last": "Abrahams", "suffix": ""}], "year": 2013, "venue": "Am J Reprod Immunol", "link": "3233543"}, "BIBREF39": {"title": "Pathogen recognition by the innate immune system", "authors": [{"first": "H", "middle": [], "last": "Kumar", "suffix": ""}, {"first": "T", "middle": [], "last": "Kawai", "suffix": ""}, {"first": "S", "middle": [], "last": "Akira", "suffix": ""}], "year": 2011, "venue": "Int Rev Immunol", "link": "42000671"}, "BIBREF40": {"title": "Detection of cytomegalovirus DNA in human placenta", "authors": [{"first": "K", "middle": [], "last": "Kumazaki", "suffix": ""}, {"first": "K", "middle": [], "last": "Ozono", "suffix": ""}, {"first": "T", "middle": [], "last": "Yahara", "suffix": ""}, {"first": "Y", "middle": [], "last": "Wada", "suffix": ""}, {"first": "N", "middle": [], "last": "Suehara", "suffix": ""}, {"first": "M", "middle": [], "last": "Takeuchi", "suffix": ""}, {"first": "M", "middle": [], "last": "Nakayama", "suffix": ""}], "year": 2002, "venue": "J Med Virol", "link": "19130726"}, "BIBREF41": {"title": "The role of infection in preterm labour and birth", "authors": [{"first": "R", "middle": ["F"], "last": "Lamont", "suffix": ""}], "year": 2003, "venue": "Hosp Med", "link": "37222049"}, "BIBREF42": {"title": "NOD1 and NOD2 regulate proinflammatory and prolabor mediators in human fetal membranes and myometrium via nuclear factor-kappa B", "authors": [{"first": "M", "middle": [], "last": "Lappas", "suffix": ""}], "year": 2013, "venue": "Biol Reprod", "link": "19045715"}, "BIBREF43": {"title": "Caspase-1 Activation is increased with human labour in foetal membranes and myometrium and mediates infection-induced interleukin-1beta secretion", "authors": [{"first": "M", "middle": [], "last": "Lappas", "suffix": ""}], "year": 2014, "venue": "Am J Reprod Immunol", "link": "206986854"}, "BIBREF44": {"title": "Inflammation of choriodecidua inducestumor necrosis factor alpha-mediated apoptosis of human myometrial cells", "authors": [{"first": "M", "middle": ["J"], "last": "Leroy", "suffix": ""}, {"first": "E", "middle": [], "last": "Dallot", "suffix": ""}, {"first": "I", "middle": [], "last": "Czerkiewicz", "suffix": ""}, {"first": "T", "middle": [], "last": "Schmitz", "suffix": ""}, {"first": "M", "middle": [], "last": "Breuiller-Fouche", "suffix": ""}], "year": 2007, "venue": "Biol Reprod", "link": "11542353"}, "BIBREF45": {"title": "Novel type III interferons produce anti-tumor effects through multiple functions", "authors": [{"first": "Q", "middle": [], "last": "Li", "suffix": ""}, {"first": "K", "middle": [], "last": "Kawamura", "suffix": ""}, {"first": "Y", "middle": [], "last": "Tada", "suffix": ""}, {"first": "H", "middle": [], "last": "Shimada", "suffix": ""}, {"first": "K", "middle": [], "last": "Hiroshima", "suffix": ""}, {"first": "M", "middle": [], "last": "Tagawa", "suffix": ""}], "year": 2013, "venue": "Front Biosci", "link": "30909318"}, "BIBREF46": {"title": "Progesterone inhibits basal and TNF-alpha-induced apoptosis in fetal membranes: a novel mechanism to explain progesterone-mediated prevention of preterm birth", "authors": [{"first": "G", "middle": [], "last": "Luo", "suffix": ""}, {"first": "V", "middle": ["M"], "last": "Abrahams", "suffix": ""}, {"first": "S", "middle": [], "last": "Tadesse", "suffix": ""}, {"first": "E", "middle": ["F"], "last": "Funai", "suffix": ""}, {"first": "E", "middle": ["J"], "last": "Hodgson", "suffix": ""}, {"first": "J", "middle": [], "last": "Gao", "suffix": ""}, {"first": "E", "middle": ["R"], "last": "Norwitz", "suffix": ""}], "year": 2010, "venue": "Reprod Sci", "link": "21538840"}, "BIBREF49": {"title": "Inflammatory caspases: linking an intracellular innate immune system to autoinflammatory diseases", "authors": [{"first": "F", "middle": [], "last": "Martinon", "suffix": ""}, {"first": "J", "middle": [], "last": "Tschopp", "suffix": ""}], "year": 2004, "venue": "Cell", "link": "15140093"}, "BIBREF50": {"title": "Inflammatory caspases and inflammasomes: master switches of inflammation", "authors": [{"first": "F", "middle": [], "last": "Martinon", "suffix": ""}, {"first": "J", "middle": [], "last": "Tschopp", "suffix": ""}], "year": 2007, "venue": "Cell Death Differ", "link": "11911521"}, "BIBREF51": {"title": "Differences in permissive cytomegalovirus infection between primary cultured human fetal membrane chorion and amnion cells", "authors": [{"first": "S", "middle": [], "last": "Matsunaga", "suffix": ""}, {"first": "N", "middle": [], "last": "Uchide", "suffix": ""}, {"first": "M", "middle": [], "last": "Shono", "suffix": ""}, {"first": "K", "middle": [], "last": "Ohyama", "suffix": ""}, {"first": "M", "middle": [], "last": "Takeichi", "suffix": ""}, {"first": "H", "middle": [], "last": "Toyoda", "suffix": ""}], "year": 2013, "venue": "Biol Pharm Bull", "link": "6379454"}, "BIBREF52": {"title": "Chemokines: sirens of neutrophil recruitment-but is it just one song?", "authors": [{"first": "B", "middle": [], "last": "Mcdonald", "suffix": ""}, {"first": "P", "middle": [], "last": "Kubes", "suffix": ""}], "year": 2010, "venue": "Immunity", "link": "29264097"}, "BIBREF53": {"title": "Chorioamnionitis-a complex pathophysiologic syndrome", "authors": [{"first": "R", "middle": [], "last": "Menon", "suffix": ""}, {"first": "R", "middle": ["N"], "last": "Taylor", "suffix": ""}, {"first": "S", "middle": ["J"], "last": "Fortunato", "suffix": ""}], "year": 2010, "venue": "Placenta", "link": "38481875"}, "BIBREF54": {"title": "Maternal and neonatal outcome of pregnant women infected with H1N1 influenza virus (swine flu)", "authors": [{"first": "N", "middle": [], "last": "Michaan", "suffix": ""}, {"first": "S", "middle": [], "last": "Amzallag", "suffix": ""}, {"first": "I", "middle": [], "last": "Laskov", "suffix": ""}, {"first": "Y", "middle": [], "last": "Cohen", "suffix": ""}, {"first": "M", "middle": [], "last": "Fried", "suffix": ""}, {"first": "J", "middle": ["B"], "last": "Lessing", "suffix": ""}, {"first": "A", "middle": [], "last": "Many", "suffix": ""}], "year": 2012, "venue": "J Matern Fetal Neonatal Med", "link": "2568402"}, "BIBREF55": {"title": "The expression pattern of two novel cytokines (IL-24 and IL-29) in human fetal membranes", "authors": [{"first": "J", "middle": [], "last": "Nace", "suffix": ""}, {"first": "S", "middle": ["J"], "last": "Fortunato", "suffix": ""}, {"first": "H", "middle": [], "last": "Maul", "suffix": ""}, {"first": "R", "middle": [], "last": "Menon", "suffix": ""}], "year": 2010, "venue": "J Perinat Med", "link": "207463085"}, "BIBREF56": {"title": "IL-1beta processing in host defense: beyond the inflammasomes", "authors": [{"first": "M", "middle": ["G"], "last": "Netea", "suffix": ""}, {"first": "A", "middle": [], "last": "Simon", "suffix": ""}, {"first": "F", "middle": [], "last": "Van De Veerdonk", "suffix": ""}, {"first": "B", "middle": ["J"], "last": "Kullberg", "suffix": ""}, {"first": "J", "middle": ["W"], "last": "Van Der Meer", "suffix": ""}, {"first": "L", "middle": ["A"], "last": "Joosten", "suffix": ""}], "year": 2010, "venue": "PLoS Pathog", "link": null}, "BIBREF57": {"title": "TICAM-1, an adaptor molecule that participates in Toll-like receptor 3-mediated interferon-beta induction", "authors": [{"first": "H", "middle": [], "last": "Oshiumi", "suffix": ""}, {"first": "M", "middle": [], "last": "Matsumoto", "suffix": ""}, {"first": "K", "middle": [], "last": "Funami", "suffix": ""}, {"first": "T", "middle": [], "last": "Akazawa", "suffix": ""}, {"first": "T", "middle": [], "last": "Seya", "suffix": ""}], "year": 2003, "venue": "Nat Immunol", "link": "42514812"}, "BIBREF58": {"title": "Value of placental microbial evaluation in diagnosing intra-amniotic infection", "authors": [{"first": "C", "middle": ["M"], "last": "Pettker", "suffix": ""}, {"first": "I", "middle": ["A"], "last": "Buhimschi", "suffix": ""}, {"first": "L", "middle": ["K"], "last": "Magloire", "suffix": ""}, {"first": "A", "middle": ["K"], "last": "Sfakianaki", "suffix": ""}, {"first": "B", "middle": ["D"], "last": "Hamar", "suffix": ""}, {"first": "C", "middle": ["S"], "last": "Buhimschi", "suffix": ""}], "year": 2007, "venue": "Obstet Gynecol", "link": "25906731"}, "BIBREF59": {"title": "Imidazoquinoline Toll-like receptor 8 agonists activate human newborn monocytes and dendritic cells through adenosine-refractory and caspase-1-dependent pathways", "authors": [{"first": "V", "middle": ["J"], "last": "Philbin", "suffix": ""}, {"first": "D", "middle": ["J"], "last": "Dowling", "suffix": ""}, {"first": "L", "middle": ["C"], "last": "Gallington", "suffix": ""}, {"first": "G", "middle": [], "last": "Cortes", "suffix": ""}, {"first": "Z", "middle": [], "last": "Tan", "suffix": ""}, {"first": "E", "middle": ["E"], "last": "Suter", "suffix": ""}, {"first": "K", "middle": ["W"], "last": "Chi", "suffix": ""}, {"first": "A", "middle": [], "last": "Shuckett", "suffix": ""}, {"first": "L", "middle": [], "last": "Stoler-Barak", "suffix": ""}, {"first": "M", "middle": [], "last": "Tomai", "suffix": ""}], "year": 2012, "venue": "J Allergy Clin Immunol", "link": "25917359"}, "BIBREF60": {"title": "The cyclopentenone 15-deoxy-delta 12,14-prostaglandin J(2) delays lipopolysaccharide-induced preterm delivery and reduces mortality in the newborn mouse", "authors": [{"first": "G", "middle": [], "last": "Pirianov", "suffix": ""}, {"first": "S", "middle": ["N"], "last": "Waddington", "suffix": ""}, {"first": "T", "middle": ["M"], "last": "Lindstrom", "suffix": ""}, {"first": "V", "middle": [], "last": "Terzidou", "suffix": ""}, {"first": "H", "middle": [], "last": "Mehmet", "suffix": ""}, {"first": "P", "middle": ["R"], "last": "Bennett", "suffix": ""}], "year": 2009, "venue": "Endocrinology", "link": "207059132"}, "BIBREF61": {"title": "Transport of viruses through fetal membranes: an in vitro model of perinatal transmission", "authors": [{"first": "K", "middle": [], "last": "Rokos", "suffix": ""}, {"first": "H", "middle": [], "last": "Wang", "suffix": ""}, {"first": "J", "middle": [], "last": "Seeger", "suffix": ""}, {"first": "A", "middle": [], "last": "Schafer", "suffix": ""}, {"first": "G", "middle": [], "last": "Pauli", "suffix": ""}], "year": 1998, "venue": "J Med Virol", "link": "24946038"}, "BIBREF62": {"title": "Infection and labor. III. Interleukin-1: a signal for the onset of parturition", "authors": [{"first": "R", "middle": [], "last": "Romero", "suffix": ""}, {"first": "D", "middle": ["T"], "last": "Brody", "suffix": ""}, {"first": "E", "middle": [], "last": "Oyarzun", "suffix": ""}, {"first": "M", "middle": [], "last": "Mazor", "suffix": ""}, {"first": "Y", "middle": ["K"], "last": "Wu", "suffix": ""}, {"first": "J", "middle": ["C"], "last": "Hobbins", "suffix": ""}, {"first": "S", "middle": ["K"], "last": "Durum", "suffix": ""}], "year": 1989, "venue": "Am J Obstet Gynecol", "link": "71698558"}, "BIBREF63": {"title": "Amniotic fluid interleukin 6 in preterm labor. Association with infection", "authors": [{"first": "R", "middle": [], "last": "Romero", "suffix": ""}, {"first": "C", "middle": [], "last": "Avila", "suffix": ""}, {"first": "U", "middle": [], "last": "Santhanam", "suffix": ""}, {"first": "P", "middle": ["B"], "last": "Sehgal", "suffix": ""}], "year": 1990, "venue": "J Clin Invest", "link": "2232362"}, "BIBREF64": {"title": "Interleukin-1 alpha and interleukin-1 beta in preterm and term human parturition", "authors": [{"first": "R", "middle": [], "last": "Romero", "suffix": ""}, {"first": "M", "middle": [], "last": "Mazor", "suffix": ""}, {"first": "F", "middle": [], "last": "Brandt", "suffix": ""}, {"first": "W", "middle": [], "last": "Sepulveda", "suffix": ""}, {"first": "C", "middle": [], "last": "Avila", "suffix": ""}, {"first": "D", "middle": ["B"], "last": "Cotton", "suffix": ""}, {"first": "C", "middle": ["A"], "last": "Dinarello", "suffix": ""}], "year": 1992, "venue": "Am J Reprod Immunol", "link": "10952264"}, "BIBREF65": {"title": "Tumor necrosis factor in preterm and term labor", "authors": [{"first": "R", "middle": [], "last": "Romero", "suffix": ""}, {"first": "M", "middle": [], "last": "Mazor", "suffix": ""}, {"first": "W", "middle": [], "last": "Sepulveda", "suffix": ""}, {"first": "C", "middle": [], "last": "Avila", "suffix": ""}, {"first": "D", "middle": [], "last": "Copeland", "suffix": ""}, {"first": "J", "middle": [], "last": "Williams", "suffix": ""}], "year": 1992, "venue": "Am J Obstet Gynecol", "link": "35792893"}, "BIBREF66": {"title": "The preterm parturition syndrome", "authors": [{"first": "R", "middle": [], "last": "Romero", "suffix": ""}, {"first": "J", "middle": [], "last": "Espinoza", "suffix": ""}, {"first": "J", "middle": ["P"], "last": "Kusanovic", "suffix": ""}, {"first": "F", "middle": [], "last": "Gotsch", "suffix": ""}, {"first": "S", "middle": [], "last": "Hassan", "suffix": ""}, {"first": "O", "middle": [], "last": "Erez", "suffix": ""}, {"first": "T", "middle": [], "last": "Chaiworapongsa", "suffix": ""}, {"first": "M", "middle": [], "last": "Mazor", "suffix": ""}], "year": 2006, "venue": "BJOG", "link": "8240175"}, "BIBREF67": {"title": "The role of inflammation and infection in preterm birth", "authors": [{"first": "R", "middle": [], "last": "Romero", "suffix": ""}, {"first": "J", "middle": [], "last": "Espinoza", "suffix": ""}, {"first": "L", "middle": ["F"], "last": "Goncalves", "suffix": ""}, {"first": "J", "middle": ["P"], "last": "Kusanovic", "suffix": ""}, {"first": "L", "middle": [], "last": "Friel", "suffix": ""}, {"first": "S", "middle": [], "last": "Hassan", "suffix": ""}], "year": 2007, "venue": "Semin Reprod Med", "link": "23971547"}, "BIBREF68": {"title": "Preterm labor is induced by intraamniotic infusions of interleukin-1beta and tumor necrosis factor-alpha but not by interleukin-6 or interleukin-8 in a nonhuman primate model", "authors": [{"first": "D", "middle": ["W"], "last": "Sadowsky", "suffix": ""}, {"first": "K", "middle": ["M"], "last": "Adams", "suffix": ""}, {"first": "M", "middle": ["G"], "last": "Gravett", "suffix": ""}, {"first": "S", "middle": ["S"], "last": "Witkin", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Novy", "suffix": ""}], "year": 2006, "venue": "Am J Obstet Gynecol", "link": null}, "BIBREF69": {"title": "Antiviral actions of interferons", "authors": [{"first": "C", "middle": ["E"], "last": "Samuel", "suffix": ""}], "year": 2001, "venue": "Clin Microbiol Rev", "link": null}, "BIBREF70": {"title": "Innate immunity in the human female reproductive tract: antiviral response of uterine epithelial cells to the TLR3 agonist poly(I:C)", "authors": [{"first": "T", "middle": ["M"], "last": "Schaefer", "suffix": ""}, {"first": "J", "middle": ["V"], "last": "Fahey", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Wright", "suffix": ""}, {"first": "C", "middle": ["R"], "last": "Wira", "suffix": ""}], "year": 2005, "venue": "J Immunol", "link": "14832486"}, "BIBREF71": {"title": "Pandemic 2009 influenza A(H1N1) virus illness among pregnant women in the United States", "authors": [{"first": "A", "middle": ["M"], "last": "Siston", "suffix": ""}, {"first": "S", "middle": ["A"], "last": "Rasmussen", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Honein", "suffix": ""}, {"first": "A", "middle": ["M"], "last": "Fry", "suffix": ""}, {"first": "K", "middle": [], "last": "Seib", "suffix": ""}, {"first": "W", "middle": ["M"], "last": "Callaghan", "suffix": ""}, {"first": "J", "middle": [], "last": "Louie", "suffix": ""}, {"first": "T", "middle": ["J"], "last": "Doyle", "suffix": ""}, {"first": "M", "middle": [], "last": "Crockett", "suffix": ""}, {"first": "R", "middle": [], "last": "Lynfield", "suffix": ""}], "year": 2010, "venue": "JAMA", "link": "205023171"}, "BIBREF72": {"title": "Placental inflammation and viral infection are implicated in second trimester pregnancy loss", "authors": [{"first": "S", "middle": ["K"], "last": "Srinivas", "suffix": ""}, {"first": "Y", "middle": [], "last": "Ma", "suffix": ""}, {"first": "M", "middle": ["D"], "last": "Sammel", "suffix": ""}, {"first": "D", "middle": [], "last": "Chou", "suffix": ""}, {"first": "C", "middle": [], "last": "Mcgrath", "suffix": ""}, {"first": "S", "middle": [], "last": "Parry", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Elovitz", "suffix": ""}], "year": 2006, "venue": "Am J Obstet Gynecol", "link": "30619278"}, "BIBREF73": {"title": "Intrauterine coxsackie virus, group B type 1, infection: viral cultivation from amniotic fluid in the third trimester", "authors": [{"first": "B", "middle": ["S"], "last": "Strong", "suffix": ""}, {"first": "S", "middle": ["A"], "last": "Young", "suffix": ""}], "year": 1995, "venue": "Am J Perinatol", "link": "37722482"}, "BIBREF74": {"title": "Adenovirus genome in the placenta: association with histological chorioamnionitis and preterm birth", "authors": [{"first": "E", "middle": ["A"], "last": "Tsekoura", "suffix": ""}, {"first": "A", "middle": [], "last": "Konstantinidou", "suffix": ""}, {"first": "S", "middle": [], "last": "Papadopoulou", "suffix": ""}, {"first": "S", "middle": [], "last": "Athanasiou", "suffix": ""}, {"first": "N", "middle": [], "last": "Spanakis", "suffix": ""}, {"first": "D", "middle": [], "last": "Kafetzis", "suffix": ""}, {"first": "A", "middle": [], "last": "Antsaklis", "suffix": ""}, {"first": "A", "middle": [], "last": "Tsakris", "suffix": ""}], "year": 2010, "venue": "J Med Virol", "link": "9051744"}, "BIBREF75": {"title": "Inhibition of hepatitis B virus replication by APOBEC3G", "authors": [{"first": "P", "middle": [], "last": "Turelli", "suffix": ""}, {"first": "B", "middle": [], "last": "Mangeat", "suffix": ""}, {"first": "S", "middle": [], "last": "Jost", "suffix": ""}, {"first": "S", "middle": [], "last": "Vianin", "suffix": ""}, {"first": "D", "middle": [], "last": "Trono", "suffix": ""}], "year": 2004, "venue": "Science", "link": "85976209"}, "BIBREF76": {"title": "Apoptosis in cultured human fetal membrane cells infected with influenza virus", "authors": [{"first": "N", "middle": [], "last": "Uchide", "suffix": ""}, {"first": "K", "middle": [], "last": "Ohyama", "suffix": ""}, {"first": "T", "middle": [], "last": "Bessho", "suffix": ""}, {"first": "B", "middle": [], "last": "Yuan", "suffix": ""}, {"first": "T", "middle": [], "last": "Yamakawa", "suffix": ""}], "year": 2002, "venue": "Biol Pharm Bull", "link": "25432404"}, "BIBREF77": {"title": "Differential mRNA expression of inflammatory cytokines in cultured human fetal membrane cells responding to influenza virus infection", "authors": [{"first": "N", "middle": [], "last": "Uchide", "suffix": ""}, {"first": "K", "middle": [], "last": "Ohyama", "suffix": ""}, {"first": "B", "middle": [], "last": "Yuan", "suffix": ""}, {"first": "T", "middle": [], "last": "Sano", "suffix": ""}, {"first": "T", "middle": [], "last": "Bessho", "suffix": ""}, {"first": "T", "middle": [], "last": "Yamakawa", "suffix": ""}], "year": 2002, "venue": "Biol Pharm Bull", "link": "34511832"}, "BIBREF78": {"title": "Secretion of bioactive interleukin-6 and tumor necrosis factor-alpha proteins from primary cultured human fetal membrane chorion cells infected with influenza virus", "authors": [{"first": "N", "middle": [], "last": "Uchide", "suffix": ""}, {"first": "A", "middle": [], "last": "Suzuki", "suffix": ""}, {"first": "K", "middle": [], "last": "Ohyama", "suffix": ""}, {"first": "T", "middle": [], "last": "Bessho", "suffix": ""}, {"first": "H", "middle": [], "last": "Toyoda", "suffix": ""}], "year": 2006, "venue": "Placenta", "link": "40484868"}, "BIBREF79": {"title": "Lactate dehydrogenase leakage as a marker for apoptotic cell degradation induced by influenza virus infection in human fetal membrane cells", "authors": [{"first": "N", "middle": [], "last": "Uchide", "suffix": ""}, {"first": "K", "middle": [], "last": "Ohyama", "suffix": ""}, {"first": "T", "middle": [], "last": "Bessho", "suffix": ""}, {"first": "H", "middle": [], "last": "Toyoda", "suffix": ""}], "year": 2009, "venue": "Intervirology", "link": "6208772"}, "BIBREF80": {"title": "Possible roles of proinflammatory and chemoattractive cytokines produced by human fetal membrane cells in the pathology of adverse pregnancy outcomes associated with influenza virus infection", "authors": [{"first": "N", "middle": [], "last": "Uchide", "suffix": ""}, {"first": "K", "middle": [], "last": "Ohyama", "suffix": ""}, {"first": "T", "middle": [], "last": "Bessho", "suffix": ""}, {"first": "M", "middle": [], "last": "Takeichi", "suffix": ""}, {"first": "H", "middle": [], "last": "Toyoda", "suffix": ""}], "year": 2012, "venue": "Mediators Inflamm", "link": "936936"}, "BIBREF81": {"title": "Sensing microbial RNA in the cytosol", "authors": [{"first": "N", "middle": [], "last": "Vabret", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Blander", "suffix": ""}], "year": 2013, "venue": "Front Immunol", "link": "14175882"}, "BIBREF82": {"title": "Cutting edge: a novel Toll/IL-1 receptor domain-containing adapter that preferentially activates the IFN-beta promoter in the Toll-like receptor signaling", "authors": [{"first": "M", "middle": [], "last": "Yamamoto", "suffix": ""}, {"first": "S", "middle": [], "last": "Sato", "suffix": ""}, {"first": "K", "middle": [], "last": "Mori", "suffix": ""}, {"first": "K", "middle": [], "last": "Hoshino", "suffix": ""}, {"first": "O", "middle": [], "last": "Takeuchi", "suffix": ""}, {"first": "K", "middle": [], "last": "Takeda", "suffix": ""}, {"first": "S", "middle": [], "last": "Akira", "suffix": ""}], "year": 2002, "venue": "J Immunol", "link": "23986310"}, "BIBREF83": {"title": "Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway", "authors": [{"first": "M", "middle": [], "last": "Yamamoto", "suffix": ""}, {"first": "S", "middle": [], "last": "Sato", "suffix": ""}, {"first": "H", "middle": [], "last": "Hemmi", "suffix": ""}, {"first": "K", "middle": [], "last": "Hoshino", "suffix": ""}, {"first": "T", "middle": [], "last": "Kaisho", "suffix": ""}, {"first": "H", "middle": [], "last": "Sanjo", "suffix": ""}, {"first": "O", "middle": [], "last": "Takeuchi", "suffix": ""}, {"first": "M", "middle": [], "last": "Sugiyama", "suffix": ""}, {"first": "M", "middle": [], "last": "Okabe", "suffix": ""}, {"first": "K", "middle": [], "last": "Takeda", "suffix": ""}], "year": 2003, "venue": "Science", "link": "19276476"}}, "ref_entries": {"FIGREF0": {"text": "Figure 2 FM cytokine responses to Poly(I:C) and viral ssRNA are regulated by MyD88 and TRIF. FM explants were treated with NT, or either (A) Poly(I:C) or (B) viral ssRNA all in the presence of either a control peptide (Control), a MyD88 inhibitor peptide (MyD88) or a TRIF inhibitor peptide (TRIF) (10 mM). Bar charts show cytokine secretion as FC relative to the NT controls (*P , 0.05 relative to the control; n \u00bc 5).", "type": "figure"}, "FIGREF1": {"text": "Figure 3 Viral ssRNA induces FM IL-1b secretion in a caspase-1 dependent manner. FM explants (n \u00bc 10) were treated with NT or ssRNA in the presence of media or a caspase-1 inhibitor after which supernatants were measured for IL-1b (*P , 0.05, **P , 0.001 relative to NT unless otherwise indicated).", "type": "figure"}, "FIGREF2": {"text": "Figure 4 Poly(I:C) and viral ssRNA trigger distinct FM antiviral responses. FMs explants were incubated with NT, Poly(I:C) or viral ssRNA and then analyzed for IFNB, MxA, OAS, APOBEC3G and SLPI mRNA levels by qRT -PCR. Bar charts show mRNA expression as FC relative to the NT control (*P , 0.05; n \u00bc 3 -6).", "type": "figure"}}}
{"paper_id": "17783639", "_pdf_hash": "ed094deccf8b76ae477bef43e3605ebf96110939", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Coartaci\u00f3n a\u00f3rtica abdominal. Tratamiento mediante implantaci\u00f3n de stent", "authors": [{"first": "J", "middle": ["M"], "last": "Gu\u00eda", "suffix": ""}, {"first": "F", "middle": ["J"], "last": "Castro", "suffix": ""}, {"first": "M", "middle": [], "last": "Graci\u00e1n", "suffix": ""}, {"first": "A", "middle": [], "last": "Gilabert", "suffix": ""}, {"first": "E", "middle": [], "last": "Garc\u00eda", "suffix": ""}], "year": 2001, "venue": "Rev Esp Cardiol", "link": null}, "BIBREF1": {"title": "Coartaci\u00f3n de aorta: diferentes formas anatomocl\u00ednicas seg\u00fan la edad de presentaci\u00f3n", "authors": [{"first": "L", "middle": ["F"], "last": "Valenzuela Garc\u00eda", "suffix": ""}, {"first": "V\u00e1zquez", "middle": [], "last": "Garc\u00eda", "suffix": ""}, {"first": "R", "middle": [], "last": "", "suffix": ""}, {"first": "Pastor", "middle": [], "last": "Morales", "suffix": ""}, {"first": "L", "middle": [], "last": "", "suffix": ""}, {"first": "Calvo", "middle": [], "last": "Jambrina", "suffix": ""}, {"first": "R", "middle": [], "last": "", "suffix": ""}, {"first": "Rodr\u00edguez", "middle": [], "last": "Hern\u00e1ndez", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "", "suffix": ""}, {"first": "Font", "middle": [], "last": "Cabrera", "suffix": ""}, {"first": "I", "middle": [], "last": "", "suffix": ""}], "year": 1998, "venue": "Rev Esp Cardiol", "link": null}, "BIBREF2": {"title": "Utilidad de la ecocardiograf\u00eda transesof\u00e1gica en el diagn\u00f3stico de un hematoma a\u00f3rtico tras la angioplastia de una recoartaci\u00f3n a\u00f3rtica", "authors": [{"first": "J", "middle": [], "last": "Merc\u00e9", "suffix": ""}, {"first": "A", "middle": [], "last": "Evangelista", "suffix": ""}, {"first": "Jaume", "middle": [], "last": "Sagrist\u00e0", "suffix": ""}, {"first": "J", "middle": [], "last": "", "suffix": ""}, {"first": "Garc\u00eda", "middle": [], "last": "Del Castillo", "suffix": ""}, {"first": "H", "middle": [], "last": "", "suffix": ""}, {"first": "Soler", "middle": [], "last": "Soler", "suffix": ""}, {"first": "J", "middle": [], "last": "", "suffix": ""}], "year": 1997, "venue": "Rev Esp Cardiol", "link": null}, "BIBREF3": {"title": "Self-and balloonexpandable stent implantation for severe native coarctation of aorta in adults", "authors": [{"first": "S", "middle": [], "last": "Tyagi", "suffix": ""}, {"first": "S", "middle": [], "last": "Singh", "suffix": ""}, {"first": "S", "middle": [], "last": "Mukhopadhyay", "suffix": ""}, {"first": "A", "middle": [], "last": "Kaul", "suffix": ""}], "year": 2003, "venue": "Am Heart J", "link": "10928004"}, "BIBREF4": {"title": "Implantaci\u00f3n primaria de stent en la coartaci\u00f3n de aorta: seguimiento a medio plazo", "authors": [{"first": "J", "middle": [], "last": "Alc\u00edbar", "suffix": ""}, {"first": "N", "middle": [], "last": "Pe\u00f1a", "suffix": ""}, {"first": "A", "middle": [], "last": "O\u00f1ate", "suffix": ""}, {"first": "A", "middle": [], "last": "Cabrera", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Galdeano", "suffix": ""}, {"first": "E", "middle": [], "last": "Pastor", "suffix": ""}], "year": 2000, "venue": "Rev Esp Cardiol", "link": null}}, "ref_entries": {}}
{"paper_id": "17783872", "_pdf_hash": "ddd7108273522be291eddef7687d43dbf9cb0402", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "An Introduction to Biometric Recognition", "authors": [{"first": "A", "middle": ["K"], "last": "Jain", "suffix": ""}, {"first": "A", "middle": [], "last": "Ross", "suffix": ""}, {"first": "S", "middle": [], "last": "Prabhaker", "suffix": ""}], "year": 2004, "venue": "IEEE transactions on circuits and systems for video technology", "link": null}, "BIBREF1": {"title": "Argus: The Digital Doorman", "authors": [{"first": "R", "middle": [], "last": "Sukthankar", "suffix": ""}, {"first": "R", "middle": [], "last": "Stockton", "suffix": ""}], "year": 2001, "venue": "", "link": "402622"}, "BIBREF2": {"title": "Facial Features Detection on Uneven Illumination Images", "authors": [{"first": "S", "middle": ["S"], "last": "Hao", "suffix": ""}, {"first": "M", "middle": ["S"], "last": "Ye", "suffix": ""}], "year": 2005, "venue": "International Workshop on Nonlinear Signal and Image Processing 2005 (NSIP 2005) 19PM2A-01", "link": "61812659"}, "BIBREF3": {"title": "Automatic Facial Feature Detection on Security System", "authors": [{"first": "R", "middle": ["F"], "last": "Hwu", "suffix": ""}, {"first": "M", "middle": ["S"], "last": "Ye", "suffix": ""}, {"first": "S", "middle": ["S"], "last": "Hao", "suffix": ""}], "year": 2005, "venue": "Lung-Tang", "link": null}, "BIBREF4": {"title": "Shape Measures for Content Based Image Retrival: A Comparison", "authors": [{"first": "B", "middle": ["M"], "last": "Mehtre", "suffix": ""}, {"first": "M", "middle": ["S"], "last": "Kankanhalli", "suffix": ""}, {"first": "W", "middle": ["F"], "last": "Lee", "suffix": ""}], "year": 1997, "venue": "Information Processing and Management", "link": "6901546"}, "BIBREF5": {"title": "Visual Pattern Recognition by Moment Invariants", "authors": [{"first": "M", "middle": ["K"], "last": "Hu", "suffix": ""}], "year": 1962, "venue": "IRE Transactions on Information Theory", "link": "6431165"}, "BIBREF6": {"title": "Pattern Recognition", "authors": [{"first": "S", "middle": [], "last": "Theodoridis", "suffix": ""}, {"first": "K", "middle": [], "last": "Koutroumbas", "suffix": ""}], "year": 2003, "venue": "", "link": null}, "BIBREF7": {"title": "Color Object segmentation using Fuzzy C-Means with Eigen-subspace Projections", "authors": [{"first": "J", "middle": ["F"], "last": "Yang", "suffix": ""}, {"first": "S", "middle": ["S"], "last": "Hao", "suffix": ""}, {"first": "P", "middle": ["C"], "last": "Chung", "suffix": ""}], "year": 2002, "venue": "Signal Processing", "link": null}, "BIBREF8": {"title": "Fundamentals of Wavelets,Theory, Algorithms, and Applications", "authors": [{"first": "J", "middle": ["C"], "last": "Goswami", "suffix": ""}, {"first": "A", "middle": ["K"], "last": "Chan", "suffix": ""}], "year": 1999, "venue": "", "link": "122474759"}}, "ref_entries": {}}
{"paper_id": "17783980", "_pdf_hash": "b3cbddce0057bbc3524250cf36fedf8c96dedbda", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "A study on radiation shielding and safety analysis for a synchrotron radiation beamline", "authors": [{"first": "Y", "middle": [], "last": "Asano", "suffix": ""}], "year": 2001, "venue": "JAERI-Research", "link": null}, "BIBREF1": {"title": "Measurements of photoneutron spectrum due to gas bremsstrahlung at SPring8 insertion device beamlines", "authors": [{"first": "Y", "middle": [], "last": "Asano", "suffix": ""}], "year": 2001, "venue": "Proceedings of the 1 st International Workshop on Radiation Safety at Synchrotron Radiation Sources", "link": null}, "BIBREF2": {"title": "Measurements of Photoneutron Spectrum Due to Gas Bremsstrahlung at SPring8 Insertion Device Beamlines", "authors": [{"first": "Y", "middle": [], "last": "Asano", "suffix": ""}], "year": 2001, "venue": "Proceedings of the 1 st International Workshop on Radiation Safety at Synchrotron Radiation Sources", "link": null}, "BIBREF3": {"title": "Comparison of design and practices for radiation safety among five synchrotron radiation facilities", "authors": [{"first": "P", "middle": [], "last": "Berkvens", "suffix": ""}], "year": "", "venue": "Proceedings of the 3 rd International Workshop on", "link": "96878143"}, "BIBREF4": {"title": "Synchrotron Radiation Sources", "authors": [], "year": 2004, "venue": "Radiation Measurements", "link": null}, "BIBREF6": {"title": "Radiation physics for personnel and environmental protection. FERMILAB-TM-1834 Revision 9b", "authors": [{"first": "J", "middle": [], "last": "Cossairt", "suffix": ""}], "year": 2007, "venue": "", "link": null}, "BIBREF7": {"title": "Attenuation of scattered monochromatic synchrotron radiation in iron and lead", "authors": [{"first": "A", "middle": [], "last": "Fasso", "suffix": ""}, {"first": "J", "middle": [], "last": "Liu", "suffix": ""}], "year": "", "venue": "", "link": "139315148"}, "BIBREF9": {"title": "Synchrotron Radiation Sources for the Future", "authors": [{"first": "S", "middle": [], "last": "Gruner", "suffix": ""}, {"first": "D", "middle": [], "last": "Bilderback", "suffix": ""}, {"first": "M", "middle": ["White"], "last": "Tigner", "suffix": ""}, {"first": "", "middle": [], "last": "Paper", "suffix": ""}], "year": "", "venue": "", "link": "2246425"}, "BIBREF10": {"title": "Primary gas bremsstrahlung shielding requirements for SPEAR3 beamlines", "authors": [{"first": "H", "middle": [], "last": "Khater", "suffix": ""}, {"first": "J", "middle": [], "last": "Liu", "suffix": ""}, {"first": "A", "middle": [], "last": "Prinz", "suffix": ""}, {"first": "A", "middle": [], "last": "Fasso", "suffix": ""}, {"first": "S", "middle": [], "last": "Rokni", "suffix": ""}], "year": 2003, "venue": "Stanford Linear Accelerator Center", "link": null}, "BIBREF11": {"title": "Gas Bremsstrahlung and Associated Photon-Neutron Shielding Calculations for Electron Storage Rings", "authors": [{"first": "J", "middle": [], "last": "Liu", "suffix": ""}, {"first": "", "middle": ["W"], "last": "Nelson", "suffix": ""}, {"first": "R", "middle": [], "last": "Kase", "suffix": ""}], "year": 1995, "venue": "Health Phys", "link": null}, "BIBREF12": {"title": "Radiation protection at synchrotron radiation facilities", "authors": [{"first": "J", "middle": [], "last": "Liu", "suffix": ""}, {"first": "V", "middle": [], "last": "Vylet", "suffix": ""}], "year": 2001, "venue": "Rad. Prot. Dosim", "link": "25064553"}, "BIBREF13": {"title": "Radiation safety design for SPEAR3 beamline frontend", "authors": [{"first": "J", "middle": [], "last": "Liu", "suffix": ""}, {"first": "", "middle": ["S"], "last": "Mao", "suffix": ""}, {"first": "S", "middle": [], "last": "Roesler", "suffix": ""}, {"first": "S", "middle": [], "last": "Rokni", "suffix": ""}], "year": 2003, "venue": "Stanford Linear Accelerator Center", "link": null}, "BIBREF14": {"title": "Radiation safety design for SSRL SPEAR3 storage ring", "authors": [{"first": "J", "middle": [], "last": "Liu", "suffix": ""}, {"first": "S", "middle": [], "last": "Rokni", "suffix": ""}, {"first": "H", "middle": [], "last": "Khater", "suffix": ""}, {"first": "S", "middle": [], "last": "Mao", "suffix": ""}], "year": 2003, "venue": "Stanford Linear Accelerator Center", "link": null}, "BIBREF15": {"title": "Synchrotron radiation shielding design for SPEAR3 white light hutches", "authors": [{"first": "J", "middle": [], "last": "Liu", "suffix": ""}, {"first": "H", "middle": [], "last": "Khater", "suffix": ""}, {"first": "A", "middle": [], "last": "Prinz", "suffix": ""}, {"first": "", "middle": [], "last": "Roknis", "suffix": ""}], "year": "", "venue": "Stanford Linear Accelerator Center", "link": null}, "BIBREF16": {"title": "Generic radiation safety design for SSRL synchrotron radiation beamlines", "authors": [{"first": "J", "middle": [], "last": "Liu", "suffix": ""}, {"first": "A", "middle": [], "last": "Fasso", "suffix": ""}, {"first": "H", "middle": [], "last": "Khater", "suffix": ""}, {"first": "A", "middle": [], "last": "Prinz", "suffix": ""}, {"first": "", "middle": [], "last": "Roknis", "suffix": ""}], "year": 2004, "venue": "Stanford Linear Accelerator Center", "link": "122071193"}, "BIBREF17": {"title": "Comparison of design and practices for radiation safety among five synchrotron radiation facilities", "authors": [{"first": "J", "middle": [], "last": "Liu", "suffix": ""}, {"first": "S", "middle": [], "last": "Rokni", "suffix": ""}, {"first": "Y", "middle": [], "last": "Asano", "suffix": ""}, {"first": "W", "middle": [], "last": "Casey", "suffix": ""}, {"first": "R", "middle": [], "last": "Donahue", "suffix": ""}, {"first": "P", "middle": [], "last": "Job", "suffix": ""}], "year": 2004, "venue": "Proceedings of the 3 rd International Workshop on \"Radiation Safety of Synchrotron Radiation Sources", "link": "96878143"}, "BIBREF18": {"title": "Gamma-ray production in a storage ring free-electron laser", "authors": [{"first": "V", "middle": ["N"], "last": "Litvinenko", "suffix": ""}], "year": 1997, "venue": "Phys. Rev. Letters", "link": "124976886"}, "BIBREF19": {"title": "National Council on Radiation Protection and Measurements; Report No. 144. Radiation protection for particle accelerator facilities", "authors": [], "year": 2003, "venue": "", "link": null}, "BIBREF20": {"title": "Dose Measurements of Bremsstrahlung-Produced Neutrons from Thick Targets", "authors": [{"first": "M", "middle": [], "last": "Pisharody", "suffix": ""}, {"first": "E", "middle": [], "last": "Semones", "suffix": ""}, {"first": "P", "middle": [], "last": "Job", "suffix": ""}], "year": 1999, "venue": "Nucl. Instru. Meth", "link": "117846104"}, "BIBREF21": {"title": "Generic synchrotron radiation shielding design for SPEAR3 pink-light hutches and VUV beampipes", "authors": [{"first": "A", "middle": [], "last": "Prinz", "suffix": ""}, {"first": "J", "middle": [], "last": "Liu", "suffix": ""}, {"first": "H", "middle": [], "last": "Khater", "suffix": ""}], "year": 2003, "venue": "Stanford Linear Accelerator Center", "link": null}, "BIBREF22": {"title": "Shielding for scattered gas bremsstrahlung for SPEAR3 beamlines", "authors": [{"first": "A", "middle": [], "last": "Prinz", "suffix": ""}, {"first": "J", "middle": [], "last": "Liu", "suffix": ""}, {"first": "H", "middle": [], "last": "Khater", "suffix": ""}, {"first": "S", "middle": [], "last": "Rokni", "suffix": ""}], "year": "", "venue": "Stanford Linear Accelerator Center", "link": null}, "BIBREF23": {"title": "Synchrotron radiation shielding design for SPEAR3 VUV beamlines", "authors": [{"first": "A", "middle": [], "last": "Prinz", "suffix": ""}, {"first": "J", "middle": [], "last": "Liu", "suffix": ""}], "year": 2007, "venue": "Stanford Linear Accelerator Center", "link": null}, "BIBREF24": {"title": "SPEAR3 beamline in alcove radiation shielding", "authors": [{"first": "T", "middle": [], "last": "Rabedeau", "suffix": ""}], "year": 2003, "venue": "SSRL M417, Rev", "link": null}, "BIBREF25": {"title": "Wiggler and Undulator Insertion Devices", "authors": [{"first": "", "middle": ["R D"], "last": "Schlueter", "suffix": ""}], "year": 1994, "venue": "", "link": "56313720"}, "BIBREF26": {"title": "Stanford Linear Accelerator Center (SLAC)", "authors": [], "year": 1998, "venue": "", "link": null}, "BIBREF27": {"title": "to operate in quasi-continuous mode (500 fs bunches at 74.5 MHz bunch rep rate), with a high average current of 10 mA", "authors": [{"first": "H", "middle": [], "last": "Winick", "suffix": ""}, {"first": "", "middle": [], "last": "Editor", "suffix": ""}], "year": 1994, "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "17784023", "_pdf_hash": "f78c9c3aaa40d3e438dbd9aa3bced6a059b9fa87", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Face recognition base on fitting a 3D morphable model", "authors": [{"first": "V", "middle": [], "last": "Blanz", "suffix": ""}, {"first": "T", "middle": [], "last": "Vetter", "suffix": ""}], "year": 2003, "venue": "IEEE Trans. PAMI", "link": null}, "BIBREF1": {"title": "On optimally combining pieces of information with application to estimating 3-d complexobject position from range data", "authors": [{"first": "R", "middle": [], "last": "Bolle", "suffix": ""}, {"first": "D", "middle": [], "last": "Cooper", "suffix": ""}], "year": 1986, "venue": "IEEE Trans. on Pattern Analysis and Machine Intelligence", "link": "7955943"}, "BIBREF2": {"title": "View-base active appearance models", "authors": [{"first": "T", "middle": [], "last": "Cootes", "suffix": ""}, {"first": "K", "middle": [], "last": "Walker", "suffix": ""}, {"first": "C", "middle": [], "last": "Taylor", "suffix": ""}], "year": 2000, "venue": "Proc. Intl. Conf. on Automatic Face and Gesture Recognition", "link": null}, "BIBREF3": {"title": "Elements of Information Theory", "authors": [{"first": "T", "middle": ["M"], "last": "Cover", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Thomas", "suffix": ""}], "year": 1991, "venue": "", "link": "190432"}, "BIBREF4": {"title": "Sequential Monte Carlo Methods in Practice", "authors": [{"first": "A", "middle": [], "last": "Doucet", "suffix": ""}, {"first": "N", "middle": ["D"], "last": "Freitas", "suffix": ""}, {"first": "N", "middle": [], "last": "Gordon", "suffix": ""}], "year": 2001, "venue": "", "link": "30176573"}, "BIBREF5": {"title": "Joint manifold distance: a new approach to appearance based clustering", "authors": [{"first": "A", "middle": [], "last": "Fitzgibbon", "suffix": ""}, {"first": "A", "middle": [], "last": "Zisserman", "suffix": ""}], "year": 2003, "venue": "Proc. IEEE Conference on Computer Vision and Pattern Recognition", "link": "15081966"}, "BIBREF6": {"title": "Learning bilinear models for two-factor problems in vision", "authors": [{"first": "W", "middle": ["T"], "last": "Freeman", "suffix": ""}, {"first": "J", "middle": ["B"], "last": "Tenenbaum", "suffix": ""}], "year": 1997, "venue": "Proc. of IEEE Conf. on Computer Vision and Pattern Recognition", "link": "5258674"}, "BIBREF7": {"title": "Eigen light-fields and face recognition across pose", "authors": [{"first": "R", "middle": [], "last": "Gross", "suffix": ""}, {"first": "I", "middle": [], "last": "Matthews", "suffix": ""}, {"first": "S", "middle": [], "last": "Baker", "suffix": ""}], "year": 2002, "venue": "Proc. of Intl. Conf. on Automatic Face and Gesture Recognition", "link": "15170260"}, "BIBREF8": {"title": "Probabilistic modeling in computer vision. Handbook of Computer Vision and Applications", "authors": [{"first": "J", "middle": [], "last": "Hornegger", "suffix": ""}, {"first": "D", "middle": [], "last": "Paulus", "suffix": ""}, {"first": "N", "middle": ["H"], "last": "", "suffix": ""}], "year": 1999, "venue": "", "link": null}, "BIBREF9": {"title": "Video-based face recognition using probabilistic appearance manifolds", "authors": [{"first": "K", "middle": [], "last": "Lee", "suffix": ""}, {"first": "J", "middle": [], "last": "Ho", "suffix": ""}, {"first": "M", "middle": [], "last": "Yang", "suffix": ""}, {"first": "D", "middle": [], "last": "Kriegman", "suffix": ""}], "year": 2003, "venue": "Proc. IEEE Conference on Computer Vision and Pattern Recognition", "link": "9388942"}, "BIBREF10": {"title": "Constructing facial identity surfaces in a nonlinear discriminating space", "authors": [{"first": "Y", "middle": [], "last": "Li", "suffix": ""}, {"first": "S", "middle": [], "last": "Gong", "suffix": ""}, {"first": "H", "middle": [], "last": "Liddell", "suffix": ""}], "year": 2001, "venue": "Proc. IEEE Conference on Computer Vision and Pattern Recognition", "link": "7500278"}, "BIBREF11": {"title": "Video-based face recognition using adaptive hidden markov models", "authors": [{"first": "X", "middle": [], "last": "Liu", "suffix": ""}, {"first": "T", "middle": [], "last": "Chen", "suffix": ""}], "year": 2003, "venue": "Proc. IEEE Conference on Computer Vision and Pattern Recognition", "link": "296341"}, "BIBREF12": {"title": "Monte Carlo Statistical Methods", "authors": [{"first": "C", "middle": [], "last": "Robert", "suffix": ""}, {"first": "G", "middle": [], "last": "Casella", "suffix": ""}], "year": 1999, "venue": "", "link": "61502973"}, "BIBREF13": {"title": "Face recognition from long-term observations", "authors": [{"first": "G", "middle": [], "last": "Shakhnarovich", "suffix": ""}, {"first": "J", "middle": [], "last": "Fisher", "suffix": ""}, {"first": "T", "middle": [], "last": "Darrell", "suffix": ""}], "year": 2002, "venue": "Proc. European Conference on Computer Vision", "link": "15164089"}, "BIBREF14": {"title": "The CMU pose, illuminatin, and expression (PIE) database", "authors": [{"first": "T", "middle": [], "last": "Sim", "suffix": ""}, {"first": "S", "middle": [], "last": "Baker", "suffix": ""}, {"first": "M", "middle": [], "last": "Bsat", "suffix": ""}], "year": 2002, "venue": "Proc. Intl. Conf. on Face and Gesture Recognition", "link": "2091854"}, "BIBREF15": {"title": "Eigenfaces for recognition", "authors": [{"first": "M", "middle": [], "last": "Turk", "suffix": ""}, {"first": "A", "middle": [], "last": "Pentland", "suffix": ""}], "year": 1991, "venue": "Journal of Cognitive Neuroscience", "link": "26127529"}, "BIBREF16": {"title": "Kernel principal angles for classification machines with applications to image sequence interpretation", "authors": [{"first": "L", "middle": [], "last": "Wolf", "suffix": ""}, {"first": "A", "middle": [], "last": "Shashua", "suffix": ""}], "year": 2003, "venue": "Proc. IEEE Conference on Computer Vision and Pattern Recognition", "link": "14334740"}, "BIBREF17": {"title": "Real-time kernel-based tracking in joint feature-spatial spaces", "authors": [{"first": "C", "middle": [], "last": "Yang", "suffix": ""}, {"first": "R", "middle": [], "last": "Duraiswami", "suffix": ""}, {"first": "A", "middle": [], "last": "Elgammal", "suffix": ""}, {"first": "D", "middle": ["L"], "last": "", "suffix": ""}], "year": 2004, "venue": "", "link": "5375335"}, "BIBREF18": {"title": "Rank constrained recognition under unknown illuminations", "authors": [{"first": "S", "middle": [], "last": "Zhou", "suffix": ""}, {"first": "R", "middle": [], "last": "Chellappa", "suffix": ""}], "year": 2003, "venue": "IEEE Intl. Workshop on Analysis and Modeling of Faces and Gestures", "link": "11791304"}, "BIBREF19": {"title": "Probabilistic recognition of human faces from video", "authors": [{"first": "S", "middle": [], "last": "Zhou", "suffix": ""}, {"first": "V", "middle": [], "last": "Krueger", "suffix": ""}, {"first": "R", "middle": [], "last": "Chellappa", "suffix": ""}], "year": 2003, "venue": "Computer Vision and Image Understanding", "link": "10785532"}}, "ref_entries": {}}
{"paper_id": "17784191", "_pdf_hash": "12b849996eeb722c51f7d3dcd209a39f9dd89ce0", "abstract": [], "body_text": [{"section": "", "text": "( 732 km ) ( 3000 km ) ", "cite_spans": [], "ref_spans": []}], "bib_entries": {}, "ref_entries": {"FIGREF0": {"text": "\u00d7\u00b8L = 3000 km \u00d2 L = 7500 km\u00b8\u00db \u00d3\u00d6 \u00d3\u00d8 \u00d6 \u00d6 \u00d7\u00d3\u00d2\u00d7 \u00d6 \u00d0\u00d7\u00d3 \u00d0\u00d0 \u00d1 \u00d3\u00d6 \u00d9\u00d8\u00d9\u00d6 N eutrino F actory \u00dc\u00d4 \u00d6 \u00d1 \u00d2\u00d8\u00d7\u00ba \u00c8 \u00cb \u00d2\u00d9\u00d1 \u00d6\u00d7 \u00bd\u00bf\u00ba\u00bd \u00ba\u00b7 \u00b8\u00bd \u00ba \u00bc\u00ba\u00c8\u00d5\u00b8\u00bd \u00ba \u00bc\u00ba\u00cb\u00d8 \u00c3 \u00dd\u00db\u00d3\u00d6 \u00d7 AE \u00db \u00cb\u00d8 \u00d2 \u00d6 \u00c5\u00d3 \u00d0 AE \u00d9\u00d8\u00d6 \u00d2\u00d3 \u00c7\u00d7 \u00d0\u00d0 \u00d8 \u00d3\u00d2\u00d7 AE \u00d9\u00d8\u00d6 \u00d2\u00d3Beam\u00b8 \u00d2 N eutrino F actory\u00b8\u00d7 \u00d3\u00d9\u00d0 \u00d6 \u00d2 \u00d8 \u00d2 \u00d9\u00d8\u00d6 \u00d2\u00d3 \u00d3\u00d7 \u00d0\u00d0 \u00b9 \u00d8 \u00d3\u00d2 \u00d4 \u00d6 \u00d1 \u00d8 \u00d6 \u00d6\u00d6\u00d3\u00d6\u00d7 \u00d3\u00db\u00d2 \u00d8\u00d3 \u00d3\u00d9\u00d8 1 3% \u00bf\u2104 \u00d2 \u00d8 \u00d6 \u00b9 \u00d3\u00d6 \u00da \u00d2 \u00d3\u00d6 \u00d7\u00d3\u00da \u00d6\u00dd \u00d3 \u00d8\u00d7\u00b8\u00db \u00d4\u00d3\u00d7\u00d7 \u00d0\u00dd * \u00d0 \u00d8\u00d6\u00d3\u00d2 \u00d6 \u00d7\u00d7 \u00c5 \u00d6 \u00ba \u00d6 \u00d0", "type": "figure"}, "FIGREF1": {"text": "\u00dc U \u2113 i \u00d2 \u00d5\u00ba\u00b4 \u00b5 \u00d6 6 \u00d1\u00d3 \u00d9\u00d0 \u00d2 3 \u00c8 \u00d4 \u00d7 \u00d7 3 \u00d7\u00d8 \u00d2 \u00d6 \u00d1 \u00dc \u00d2 \u00d2 \u00d0 \u00d7\u00b4\u03b8 12 , \u03b8 13 , \u03b8 23 \u00b5 \u00b7 1 \u00d7\u00d8 \u00d2\u00b9 \u00d6 \u00d6 \u00d4 \u00d7 \u00b4\u03b4 13 \u00b5 \u00b7 3 \u00d2 \u00db \u00d7\u00d1 \u00d0\u00d0 AE\u00c8 \u00d1 \u00dc \u00d2 \u00d2 \u00d0 \u00d7 \u03b8 14 , \u03b8 24 , \u03b8 34 \u00b5 \u00b7 2 \u00d2 \u00db AE\u00c8 \u00d6 \u00d4 \u00d7 \u00d7\u00b4\u03b4 24 , \u03b4 34 \u00b5\u00ba \u00cc \u00d2 V = \uf8eb \uf8ed sin(\u03b8 14 ) cos(\u03b8 14 ) sin(\u03b8 24 ) e \u2212i\u03b424 cos(\u03b8 14 ) cos(\u03b8 24 ) sin(\u03b8 34 )14 ) cos(\u03b8 24 ) sin(\u03b8 34 ) e \u2212i\u03b434 sin(\u03b8 24 ) sin(\u03b8 34 ) e \u2212i(\u03b434\u2212\u03b424) 1 \u2212 cos(\u03b8 34 ) \uf8f6 \uf8f8 .\u00b4\u00bf \u00b5 \u00cc\u00db\u00d3 \u00d7 \u00d8\u00d7 \u00d3 V \u00d4 \u00d6 \u00d1 \u00d8 \u00d6\u00d7\u00b8 \u00d3\u00d8 \u00d7 \u00d8 \u00d7 \u00dd \u00d2 \u00d4\u00d6 \u00d7 \u00d2\u00d8 \u00dc\u00b9 \u00d4 \u00d6 \u00d1 \u00d2\u00d8 \u00d0 \u00d3\u00d2\u00d7\u00d8\u00d6 \u00d2\u00d8\u00d7 \u00da \u00d2 \u00dd \u00d5\u00ba\u00b4\u00bf \u00b5", "type": "figure"}, "FIGREF2": {"text": "A e\u00b8 \u00d2 \u00d8\u00d3 \u00d8 \u03b5 \u00b5\u03c4 AE\u00c8 \u00d4 \u00d6 \u00d1 \u00d8 \u00d6\u00b4\u00d8 \u00d9\u00d7\u00b8 \u00d7 \u00d8\u00d2 \u00db \u03bd e \u00d3\u00d6 \u03bd\u0113 \u00d6 \u00d2\u00da\u00d3\u00d0\u00da \u00b5\u00ba \u00c1\u00d2 \u00d8 \u00d6\u00d2 \u00d7\u00ba \u00c5\u00d3\u00d6 \u00d3\u00da \u00d6\u00b8\u00d8 \u00d7 \u00d3\u00d7 \u00d0\u00d0 \u00d8 \u00d3\u00d2 \u00d2\u00d2 \u00d0\u00d7 \u00d6 \u00d7 \u00d2\u00d7 \u00d8 \u00da \u00d8\u00d3 \u00d8 \u00b4\u00d2\u00d3\u00d8 \u00d7\u00d3 \u00da \u00d6\u00dd \u00db \u00d0\u00d0 \u00d2\u00d3\u00db\u00d2\u00b5 \u00da \u00d0\u00d9 \u00d3 \u00d8 sin 2 (\u03b8 13 )\u00ba \u00c1\u00d2 \u00d8 \u00d3\u00d8 \u00d6 \u00d2\u00d2 \u00d0\u00d7\u00b8\u00db \u00d8 \u00d3\u00d9\u00d8 \u03bd e \u00d2 \u03bd\u0113\u00d8 \u00d4 \u00d2 \u00d2 \u00d3\u00d2 \u00d8 sin 2 (\u03b8 13 ) \u00d7 \u00d7\u00d1 \u00d0\u00d0\u00b8 \u00da", "type": "figure"}, "FIGREF3": {"text": "\u00d6\u00d3\u00db \u00d3\u00d6\u00d6 \u00d7\u00d4\u00d3\u00d2 \u00d7 \u00d8\u00d3 \u00b13%\u00b4\u00b12\u03c3\u00b5 \u00da \u00d8 \u00d3\u00d2\u00d7 \u00d3 \u00d8 \u03bdSM \u00d2 \u00d9\u00d8\u00d6 \u00d2\u00d3 \u00d3\u00d7 \u00d0\u00d0 \u00d8 \u00d3\u00d2 \u00d4 \u00d6 \u00d1 \u00d8 \u00d6\u00d7 \u00db \u00d8 \u00d2\u00dd \u00d7 \u00d0 \u03b413 \u00da \u00d0\u00d9 \u00ba \u00cc \u00d0 \u00d8 \u00d6 \u00dd \u00d2 \u00d2 \u00d8 \u00d1 \u00d0 \u00b4 \u00d3\u00d8\u00d8\u00d3\u00d1\u00b5 \u00d6\u00d3\u00db \u00d3\u00d6\u00d6 \u00d7\u00d4\u00d3\u00d2 \u00d7 \u00d8\u00d3 \u00d8 \u00d9\u00d6\u00d6 \u00d2\u00d8 \u00d0\u00d3 \u00d0 \u00d7\u00d8 \u00d8 \u00d4 \u00d6 \u00d1 \u00d8 \u00d6\u00d7 \u00db \u00d8 AE\u00c8 V \u00d4 \u00d6 \u00d1 \u00d8 \u00d6\u00d7 \u00d7 \u00d8 \u00d5\u00ba\u00b4 \u00bc\u00ba \u00b5\u00b4 \u00d5\u00ba\u00b4 \u00bc\u00ba \u00b5\u00b5\u00b8\u00db \u00d8 \u00d2\u00dd \u00d7 \u00d0 \u00da \u00d0\u00d9 \u00d7 \u00d3 \u03b413, \u03b424, \u03b434\u00ba \u00d9\u00d6\u00da \u00d7 \u00d4\u00d6 \u00d7 \u00d2\u00d8 \u00d2 \u00d0\u00d0 \u00d6 \u00d4 \u00d7 \u00d3\u00d6\u00d6 \u00d7\u00d4\u00d3\u00d2 \u00d8\u00d3 \u00d8 \u00d9\u00d6\u00d6 \u00d2\u00d8 \u00d0\u00d3 \u00d0 \u00d7\u00d8 \u00d8 \u00d4 \u00d6 \u00d1 \u00d8 \u00d6\u00d7 \u00db \u00d8 \u00d0\u00d0 \u00d7 \u00d0 \u00c8 \u00d4 \u00d7 \u00d7 \u00d5\u00d9 \u00d0 \u00d8\u00d3 0\u00b4\u00d7\u00d3\u00d0 \u00d9\u00d6\u00da \u00d7\u00b5 \u00d2 \u00db \u00d8 \u00dc \u00d8\u00d0\u00dd \u00d3\u00d2 \u00d3 \u00d8 \u00d1 \u00d5\u00d9 \u00d0 \u00d8\u00d3 \u03c0/2\u00b4", "type": "figure"}, "FIGREF4": {"text": "\u03b413 \u00da \u00d0\u00d9 \u00d2 \u03bdSM \u00d3\u00d2\u00d0\u00dd\u00b4\u00d2\u00d3 AE\u00c8\u00b5\u00ba \u00cc \u00d6 \u00b4\u00d0 \u00d8\u00b5 \u00d6 \u00dd \u00d2 \u00d2 \u00d8 \u00d9\u00d4\u00d4 \u00d6 \u00d6\u00d3\u00db \u00d3\u00d6\u00d6 \u00d7\u00d4\u00d3\u00d2 \u00d7 \u00d8\u00d3 \u00b13%\u00b4\u00b12\u03c3\u00b5 \u00da \u00d8 \u00d3\u00d2\u00d7 \u00d3 \u00d8 \u03bdSM \u00d2 \u00d9\u00d8\u00d6 \u00d2\u00d3 \u00d3\u00d7 \u00d0\u00d0 \u00d8 \u00d3\u00d2 \u00d4 \u00d6 \u00d1 \u00d8 \u00d6\u00d7 \u00db \u00d8 \u00d2\u00dd \u00d7 \u00d0 \u03b413 \u00da \u00d0\u00d9 \u00ba \u00cc \u00d0 \u00d8 \u00d6 \u00dd \u00d2 \u00d2 \u00d8 \u00d1 \u00d0 \u00b4 \u00d3\u00d8\u00d8\u00d3\u00d1\u00b5 \u00d6\u00d3\u00db \u00d3\u00d6\u00d6 \u00d7\u00d4\u00d3\u00d2 \u00d7 \u00d8\u00d3 \u00d8 \u00d9\u00d6\u00d6 \u00d2\u00d8 \u00d0\u00d3 \u00d0 \u00d7\u00d8 \u00d8 \u00d4 \u00d6 \u00d1 \u00d8 \u00d6\u00d7 \u00db \u00d8 AE\u00c8 V \u00d4 \u00d6 \u00d1 \u00d8 \u00d6\u00d7 \u00d7 \u00d8 \u00d5\u00ba\u00b4 \u00bc\u00ba \u00b5\u00b4 \u00d5\u00ba\u00b4 \u00bc\u00ba \u00b5\u00b5\u00b8\u00db \u00d8 \u00d2\u00dd \u00d7 \u00d0 \u00da \u00d0\u00d9 \u00d7 \u00d3 \u03b413, \u03b424, \u03b434\u00ba \u00d9\u00d6\u00da \u00d7 \u00d4\u00d6 \u00d7 \u00d2\u00d8 \u00d2 \u00d0\u00d0 \u00d6 \u00d4 \u00d7 \u00d3\u00d6\u00d6 \u00d7\u00d4\u00d3\u00d2 \u00d8\u00d3 \u00d8 \u00d9\u00d6\u00d6 \u00d2\u00d8 \u00d0\u00d3 \u00d0 \u00d7\u00d8 \u00d8 \u00d4 \u00d6 \u00d1 \u00d8 \u00d6\u00d7 \u00db \u00d8 \u00d0\u00d0 \u00d7 \u00d0 \u00c8 \u00d4 \u00d7 \u00d7 \u00d5\u00d9 \u00d0 \u00d8\u00d3 0\u00b4\u00d7\u00d3\u00d0 \u00d9\u00d6\u00da \u00d7\u00b5 \u00d2 \u00db \u00d8 \u00dc \u00d8\u00d0\u00dd \u00d3\u00d2 \u00d3 \u00d8 \u00d1 \u00d5\u00d9 \u00d0 \u00d8\u00d3 \u03c0/2\u00b4\u00d2\u00b8\u00db \u00d3\u00d0\u00d0 \u00d8 \u00d0\u00d0 \u00d3\u00d6\u00d1\u00d9\u00d0 \u00d7 \u00d3\u00d6 \u00d8 \u00da\u00d3\u00d6 \u00d8\u00d6 \u00d2\u00d7 \u00d8 \u00d3\u00d2 \u00d4\u00d6\u00d3 \u00d0 \u00d8 \u00d7\u00b8 \u00d2 \u00d3\u00d2\u00d7\u00d8 \u00d2\u00d8 \u00d2\u00d7 \u00d8\u00dd \u00d1 \u00d8\u00d8 \u00d6\u00b8 \u00d3\u00d6 \u00d0\u00d0 \u00dc\u00d4 \u00d6 \u00d12\u00b8\u00db \u00d6 \u00d8 \u00d9\u00d4\u00d4 \u00d6\u00b4\u00d0\u00d3\u00db \u00d6\u00b5 \u00d7 \u00d2 \u00d6 \u00d6\u00d7 \u00d8\u00d3 \u00d8 \u00d2\u00d3\u00d6\u00d1 \u00d0\u00b4 \u00d2\u00da \u00d6\u00d8 \u00b5 \u00d1 \u00d7\u00d7 \u00d6 \u00d6 \u00dd \u00be \u2104\u00ba", "type": "figure"}, "FIGREF5": {"text": "\u03b8 12 ) cos(2 \u03b8 23 ) (2 \u2206 cos(\u2206) \u2212 sin(\u2206)) sin(\u2206) sin(2 \u03b8 23 ) (\u03b5 \u00b5\u00b5 \u2212 \u03b5 \u03c4 \u03c4 ) + 2 cos(2 \u03b8 23 ) cos(\u03c7 \u00b5\u03c4 )cos(\u03b8 23 ) 2 cos(\u03b4 13 + \u03c7 e\u00b5 ) sin(\u2206)\u00b4 \u00bd\u00bc\u00b5 \u2212 A e \u2212 (1 \u2212 4 A e + 2 A 2 e ) cos(2 \u03b8 23 ) sin(\u2206) \u2212 A e \u2212 cos(2 \u03b8 23 ) sin(\u2206 \u2212 2 A e \u2206) + \u22121 + A e sin(\u03b4 13 + \u03c7 e\u00b5 ) sin(2 \u2206) \u2212 sin(2 (1 \u2212 A e ) \u2206) \u2212 sin(2 A e \u2206) +\u03b5 e\u03c4 sin(\u03b8 23 ) 2 cos(\u03b4 13 + \u03c7 e\u03c4 ) sin(\u2206) \u2212 A e + (1 \u2212 4 A e + 2 A 2 e ) cos(2 \u03b8 23 ) sin(\u2206) \u2212 A e + cos(2 \u03b8 23 ) sin(\u2206 \u2212 2 A e \u2206) \u2212 \u22121 + A e sin(\u03b4 13 + \u03c7 e\u03c4 ) sin(2 \u2206) \u2212 sin(2 (1 \u2212 A e ) \u2206) \u2212 sin(2 A e \u2206) .C s .\u00b4 \u00bd\u00bd\u00b5 \u00d0\u00d7\u00d3 \u00d3\u00d6 \u00d8 \u03bd \u00b5 \u2192 \u03bd \u00b5 \u00d8\u00d6 \u00d2\u00d7 \u00d8 \u00d3\u00d2\u00b8 \u00d0\u00d0 \u00d8 \u00d6\u00d1\u00d7 \u00d3\u00d2\u00d8\u00d6 \u00d9\u00d8 \u00ba \u00cc \u00d1\u00d3 \u00d9\u00d0\u00d9\u00d7 \u00d3 \u00d8 \u00d6\u00d7\u00d8 \u00d2\u00d8 \u00d6 \u00d8 \u00d3\u00d2 \u00d3\u00d6\u00d6 \u00d8 \u00d3\u00d2 \u00d8 \u00d6\u00d1 \u00d7", "type": "figure"}, "TABREF0": {"text": "e \u03b5 e\u00b5 sin(2 \u03b8 12 ) sin(\u03b8 23 ) cos(\u03c7 e\u00b5 ) cos(2 (\u22121 + A e ) \u2206)\u00b4 \u00b5 \u2212 cos(2 A e \u2206) 1 \u2212 A e + cos(2 \u03b8 23 ) + 2 (2 \u2212 A e \u2212 2 A(\u2206) \u2212 A e sin(\u03c7 e\u00b5 ) sin(2 \u2206) + sin(2 (1 \u2212 A e ) \u2206) + sin(2 A e \u2206) +\u03b5 e\u03c4 cos(\u03b8 23 ) sin(2 \u03b8 12 ) cos(\u03c7 e\u03c4 ) cos(2 (\u22121 + A e ) \u2206) \u2212 cos(2 A e \u2206)23 ) + A e sin(\u03c7 e\u03c4 ) \u2212 sin(2 \u2206) + sin(2 (1 \u2212 A e ) \u2206) + sin(2 A e \u2206) \u22124 \u22121 + A e A", "type": "table"}, "TABREF1": {"text": "+ A e A e \u03b5 e\u00b5 cos(\u03c7 e\u00b5 ) cos(\u03b8 23 ) sin(2 \u03b8 12 ) \u22121 + A e \u00b4 \u00bd\u00be\u00b5 cos(2 A e \u2206) cos 4 (\u03b8 23 ) + A e sin 2 (\u03b8 23 ) \u22121 + cos(2 (\u22121 + A e ) \u2206) sin 2 (\u03b8 23 )23 ) (\u03b5 \u00b5\u00b5 \u2212 \u03b5 \u03c4 \u03c4 ) + 2 cos(2 \u03b8 23 ) cos(\u03c7 \u00b5\u03c4 ) \u03b5 \u00b5\u03c4 ] ,\u03b5 e\u00b5 cos(\u03b4 13 + \u03c7 e\u00b5 ) sin(\u03b8 23 ) 2 \u22121 + 2 A e \u2212 cos(2 \u03b8 23 ) \u00b4 \u00bd\u00bf\u00b5 \u22121 + cos(2 A e \u2206) cos 2 (\u03b8 23 ) + cos(2 (\u22121 + A e ) \u2206) sin 2 (\u03b8 23 ) + cos(\u03b8 23 ) sin 2 (\u2206) (\u22121 + A e ) A e cos 2 (\u03b8 23 ) \u2212 (1 + (\u22123 + A e ) A e ) sin 2 (\u03b8 23 ) sin(2 \u03b8 23 ) + \u03b5 e\u03c4 cos(\u03b4 13 + \u03c7 e\u03c4 ) sin(\u03b8 23 )\u2212 A e ) A e cos(2 \u03b8 23 ) + sin 2 (\u03b8 23 ) sin(2 \u03b8 23 ) .\u00d3\u00d4\u00d4\u00d3\u00d7 \u00d8 \u00d7 \u00d2\u00b8 \u00d2 \u00d3\u00d1\u00d4 \u00d6 \u00d7\u00d3\u00d2 \u00d8\u00d3 \u00d8 \u00d4\u00d6 \u00da \u00d3\u00d9\u00d7\u00d0\u00dd \u00d7\u00d9\u00d7\u00d7 \u00d8\u00d6 \u00d2\u00d7 \u00d8 \u00d3\u00d2 \u03bd \u00b5 \u2192 \u03bd \u03c4\u22121 + A e A e [cos(\u03b4 13 ) cos(\u2206) + sin(\u03b4 13 ) sin(\u2206)] sin( A e \u2206) sin(\u2206 \u2212 A e \u2206) sin(2 \u03b8 12 ) sin(2 \u03b8 23 ) ,", "type": "table"}}}
{"paper_id": "17784239", "_pdf_hash": "de1b454a8fb612329cb4b93dba549db904c2fe2b", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Link Stability and Route Lifetime in Ad-hoc Wireless Networks", "authors": [{"first": "G", "middle": [], "last": "Lim", "suffix": ""}, {"first": "K", "middle": [], "last": "Shin", "suffix": ""}, {"first": "S", "middle": [], "last": "Lee", "suffix": ""}, {"first": "H", "middle": [], "last": "Yoon", "suffix": ""}, {"first": "J", "middle": ["S"], "last": "Ma", "suffix": ""}], "year": 2002, "venue": "Proc. IEEE ICPPW'02", "link": "9663441"}, "BIBREF1": {"title": "Signal Stability based Adaptive Routing (SSA) for Ad-Hoc Mobile Networks", "authors": [{"first": "R", "middle": [], "last": "Dube", "suffix": ""}, {"first": "C", "middle": ["D"], "last": "Rais", "suffix": ""}, {"first": "K.-Y", "middle": [], "last": "Wang", "suffix": ""}, {"first": "S", "middle": ["K"], "last": "Tripathi", "suffix": ""}], "year": 1997, "venue": "", "link": "702617"}, "BIBREF2": {"title": "A Novel Distributed Routing Protocol To Support Ad-Hoc Mobile Computing", "authors": [{"first": "C.-K", "middle": [], "last": "Toh", "suffix": ""}], "year": 1996, "venue": "Proc. IEEE Phoenix Conf. Computer and Communications", "link": "1546614"}, "BIBREF3": {"title": "Link life Based Routing Protocol for Ad hoc Wireless Networks", "authors": [{"first": "B", "middle": ["S"], "last": "Manoj", "suffix": ""}, {"first": "R", "middle": [], "last": "Ananthapadmanabha", "suffix": ""}, {"first": "C", "middle": [], "last": "Siva Ram", "suffix": ""}, {"first": "", "middle": [], "last": "Murthy", "suffix": ""}], "year": 2001, "venue": "Proc. IEEE Conf. on Computer Communications", "link": null}, "BIBREF4": {"title": "Link Stability Models for QoS Ad Hoc Routing Algorithms", "authors": [{"first": "I", "middle": [], "last": "Rubin", "suffix": ""}, {"first": "Y", "middle": [], "last": "", "suffix": ""}, {"first": "-", "middle": ["C"], "last": "Liu", "suffix": ""}], "year": 2003, "venue": "Proc. IEEE VTC2003 Fall", "link": "62494118"}, "BIBREF5": {"title": "A Highly Adaptive Distributed Routing Algorithm for Mobile Wireless Networks", "authors": [{"first": "V", "middle": ["D"], "last": "Park", "suffix": ""}, {"first": "M", "middle": ["S"], "last": "Corson", "suffix": ""}], "year": 1997, "venue": "Proc. IEEE INFOCOM", "link": "18280369"}, "BIBREF6": {"title": "A Pseudo-Distance Routing(PDR) Algorithm for Mobile Ad-hoc Networks", "authors": [{"first": "M.-G", "middle": [], "last": "Lee", "suffix": ""}, {"first": "S", "middle": [], "last": "Lee", "suffix": ""}], "year": 2006, "venue": "IEICE Trans. Fundamentals", "link": "45978815"}}, "ref_entries": {}}
{"paper_id": "17784253", "_pdf_hash": "2dac2006aaab6ba73588ba8b863bb48d66f0bf30", "abstract": [], "body_text": [], "bib_entries": {"BIBREF1": {"title": "Amphibian oocyte maturation induced by extracts of Physarum polycephalum in mitosis", "authors": [], "year": "", "venue": "J Cell Biol", "link": "15762717"}, "BIBREF2": {"title": "Control of cell cycle length in amphibian egg evidence for a temporal relationship between the nucleus and egg cytoplasm Development", "authors": [{"first": "C", "middle": [], "last": "Aimar", "suffix": ""}], "year": 1988, "venue": "", "link": null}, "BIBREF3": {"title": "Cell cleavage. Ultrastrucrural evidence against equatorial stimulation by aster microtubules", "authors": [{"first": "C", "middle": [], "last": "Asnes", "suffix": ""}, {"first": "T", "middle": ["E"], "last": "Schroeder", "suffix": ""}], "year": 1979, "venue": "Expl Cell Res", "link": "37813319"}, "BIBREF4": {"title": "Factors affecting the transplantabihty of nuclei of frog embryonic cells", "authors": [{"first": "R And", "middle": [], "last": "Briggs", "suffix": ""}, {"first": "T", "middle": [], "last": "King", "suffix": ""}], "year": 1953, "venue": "J exp Zool", "link": null}, "BIBREF5": {"title": "1987) pl3sucl acts in the fission yeast cell division cycle as a component of the p34cdc2 protein kinase", "authors": [{"first": "L", "middle": [], "last": "Brizuella", "suffix": ""}, {"first": "G", "middle": [], "last": "Draetta", "suffix": ""}, {"first": "D", "middle": [], "last": "Beach", "suffix": ""}], "year": "", "venue": "EMBO J", "link": null}, "BIBREF6": {"title": "Mechanism of action of cytochalasin' Evidence that it binds to actin filament ends", "authors": [{"first": "S", "middle": ["S"], "last": "Brown", "suffix": ""}, {"first": "J", "middle": [], "last": "Spudich", "suffix": ""}], "year": 1981, "venue": "J Cell Bwl", "link": null}, "BIBREF7": {"title": "Polarized bundles of actin filaments within microvilli of fertilized sea-urchin eggs", "authors": [{"first": "D", "middle": [], "last": "Burgess", "suffix": ""}, {"first": "T", "middle": ["E"], "last": "Schroeder", "suffix": ""}], "year": 1977, "venue": "Cell Bwl", "link": "29352668"}, "BIBREF8": {"title": "Early events in anuran amphibian fertilization: an ultrastructural study of changes occurring in the course of monospermic fertilization and artificial activation Devi", "authors": [{"first": "M", "middle": [], "last": "Charbonneau", "suffix": ""}, {"first": "B", "middle": [], "last": "Picheral", "suffix": ""}], "year": 1983, "venue": "Growth and Differ", "link": "83361875"}, "BIBREF9": {"title": "Role of nuclear material in the early cycle of Xenopus embryos", "authors": [{"first": "M C", "middle": [], "last": "Dabauvalle", "suffix": ""}, {"first": "M", "middle": [], "last": "Doree", "suffix": ""}, {"first": "", "middle": [], "last": "Bravo", "suffix": ""}, {"first": "E", "middle": [], "last": "Karsenti", "suffix": ""}], "year": 1988, "venue": "Cell", "link": "29350765"}, "BIBREF10": {"title": "Morphological changes of the surface of the eggs of Xenopus laevis in the course of development 2 Cytokinesis and early cleavage", "authors": [{"first": "S", "middle": [], "last": "Denis-Donini", "suffix": ""}, {"first": "B", "middle": [], "last": "Baccetti", "suffix": ""}, {"first": "A", "middle": [], "last": "Monroy", "suffix": ""}], "year": 1976, "venue": "J Ultrastruct Res", "link": "29696338"}, "BIBREF11": {"title": "The amphibian egg cortex in fertilization and early development In The Cell Surface", "authors": [{"first": "R P ; R P And", "middle": [], "last": "Eunson", "suffix": ""}, {"first": "M", "middle": ["E"], "last": "Manes", "suffix": ""}], "year": 1978, "venue": "", "link": null}, "BIBREF12": {"title": "Ca 2+ -Ionophore-mduced microvilli and cortical contractions in Xenopus eggs Evidence for involvement of actomyosin Roux's Arch devl Bwl 194", "authors": [{"first": "R M", "middle": [], "last": "Ezzell", "suffix": ""}, {"first": "W", "middle": ["D"], "last": "Cande", "suffix": ""}, {"first": "A", "middle": [], "last": "Brothers", "suffix": ""}], "year": 1985, "venue": "", "link": null}, "BIBREF13": {"title": "Distribution and modification of arrangement of microfilamentous structures and actin in the cortex of the amphibian oocyte", "authors": [{"first": "W", "middle": ["W"], "last": "Franke", "suffix": ""}, {"first": "P", "middle": ["C"], "last": "Rathke", "suffix": ""}, {"first": "E", "middle": [], "last": "Sejb", "suffix": ""}, {"first": "M", "middle": ["F"], "last": "Trendelenburg", "suffix": ""}, {"first": "", "middle": [], "last": "Osborn", "suffix": ""}, {"first": "K", "middle": [], "last": "Weber", "suffix": ""}], "year": 1976, "venue": "Cytobwlogie", "link": null}, "BIBREF14": {"title": "Dephosphorylation and activation of Xenopus p34 cdc2 protein kinase during the cell cycle", "authors": [{"first": "J", "middle": [], "last": "Gautier", "suffix": ""}, {"first": "T", "middle": [], "last": "Matsukawa", "suffix": ""}, {"first": "P", "middle": [], "last": "Nurse", "suffix": ""}, {"first": "J", "middle": [], "last": "Maller", "suffix": ""}], "year": 1989, "venue": "Nature", "link": null}, "BIBREF15": {"title": "Cychn is a component of maturation promoting factor from Xenopus", "authors": [{"first": "J", "middle": [], "last": "Gautier", "suffix": ""}, {"first": "J", "middle": [], "last": "Minshull", "suffix": ""}, {"first": "M", "middle": [], "last": "Lohka", "suffix": ""}, {"first": "M", "middle": [], "last": "Glotzer", "suffix": ""}, {"first": "T", "middle": [], "last": "Hunt", "suffix": ""}, {"first": "J", "middle": [], "last": "Maller", "suffix": ""}], "year": 1990, "venue": "Cell", "link": null}, "BIBREF16": {"title": "Cell cycle dynamics of an M phase specific cytoplasmic factor in Xenopus laevis oocytes and eggs", "authors": [{"first": "J C", "middle": [], "last": "Gerhart", "suffix": ""}, {"first": "M", "middle": [], "last": "Wu", "suffix": ""}, {"first": "M", "middle": [], "last": "Kirschner", "suffix": ""}], "year": 1984, "venue": "Cell Bwl", "link": "195692100"}, "BIBREF17": {"title": "Tyrosine dephosphorylation of the fission yeast cdc2 protein kinase regulates entry in mitosis", "authors": [{"first": "K", "middle": ["L"], "last": "Gould", "suffix": ""}, {"first": "P", "middle": [], "last": "Nurse", "suffix": ""}], "year": 1989, "venue": "Nature", "link": null}, "BIBREF18": {"title": "A (1973) Sequence of events in plasma membrane assembly during the cell cycle", "authors": [{"first": "J", "middle": ["M"], "last": "Graham", "suffix": ""}, {"first": "M", "middle": ["C B"], "last": "Sumner", "suffix": ""}, {"first": "D", "middle": ["H"], "last": "Curtis", "suffix": ""}, {"first": "C", "middle": [], "last": "Pasternak", "suffix": ""}], "year": "", "venue": "Nature", "link": null}, "BIBREF19": {"title": "Effects of polyamines on the first division cycle of Xenopus laevis eggs", "authors": [{"first": "N", "middle": ["J"], "last": "Grant", "suffix": ""}, {"first": "", "middle": [], "last": "Aimar", "suffix": ""}, {"first": "C", "middle": [], "last": "Oriol-Audit", "suffix": ""}], "year": 1984, "venue": "Expl Cell Res", "link": "28725679"}, "BIBREF20": {"title": "Formation and structure of the fertilization envelope in Xenopus laevis Devi Bwl", "authors": [{"first": "R", "middle": ["D"], "last": "Grey", "suffix": ""}, {"first": "", "middle": [], "last": "Wolf", "suffix": ""}, {"first": "J", "middle": [], "last": "Hedrick", "suffix": ""}], "year": 1974, "venue": "", "link": "28166828"}, "BIBREF21": {"title": "A cytoplasmic clock with the same period as the division cycle in Xenopus egg", "authors": [{"first": "K", "middle": [], "last": "Hara", "suffix": ""}, {"first": "", "middle": [], "last": "Tydeman", "suffix": ""}, {"first": "M", "middle": [], "last": "Kirschner", "suffix": ""}], "year": 1980, "venue": "Proc natn Acad Sci U.S A", "link": "41333370"}, "BIBREF22": {"title": "Cell division and the mitotic spindle", "authors": [{"first": "S", "middle": [], "last": "Inoue", "suffix": ""}], "year": 1981, "venue": "J. Cell Bwl", "link": "34239199"}, "BIBREF23": {"title": "Direct activation of cdc2 with phosphatase identification of pl3sucl-sensitive and insensitive steps", "authors": [{"first": "C", "middle": [], "last": "Jessus", "suffix": ""}, {"first": "", "middle": [], "last": "Ducommun", "suffix": ""}, {"first": "D", "middle": [], "last": "Beach", "suffix": ""}], "year": 1990, "venue": "FEBS Lett", "link": "37368822"}, "BIBREF25": {"title": "Phosphorylation changes associated with the early cell cycle in Xenopus laevis Devi Bwl", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF26": {"title": "Interconversion of metaphase and interphase microtubules arrays as studied by the injection of centrosomes and nuclei into Xenopus eggs", "authors": [{"first": "E", "middle": [], "last": "Karsenti", "suffix": ""}, {"first": "J", "middle": [], "last": "Newport", "suffix": ""}, {"first": "", "middle": [], "last": "Hubble", "suffix": ""}, {"first": "M", "middle": [], "last": "Kirschner", "suffix": ""}], "year": 1984, "venue": "J Cell Bwl", "link": "12650410"}, "BIBREF28": {"title": "An M-phase-specific protein kinase of Xenopus oocytes. Partial purification and possible mechanism of its periodic activation Devi Bwl", "authors": [], "year": "", "venue": "", "link": "30418801"}, "BIBREF29": {"title": "Cleavage of structural proteins during the assembly of the head of bactenophage T4", "authors": [{"first": "U", "middle": [], "last": "Laemmli", "suffix": ""}], "year": 1970, "venue": "Nature", "link": null}, "BIBREF30": {"title": "The effect of injected cytochalasin B on filament organisation in the cleaving egg of Xenopus laevis", "authors": [{"first": "D", "middle": [], "last": "Luchtel", "suffix": ""}, {"first": "J G And", "middle": [], "last": "Bluemink", "suffix": ""}, {"first": "S", "middle": [], "last": "De Laat", "suffix": ""}], "year": 1976, "venue": "J Ultrastruct Res", "link": null}, "BIBREF31": {"title": "Mitogenic signalling and protein phosphorylation in Xenopus oocytes J Cyclic Nucl Prot Phosphor Res", "authors": [{"first": "J", "middle": [], "last": "Maller", "suffix": ""}], "year": 1987, "venue": "", "link": null}, "BIBREF32": {"title": "Cytoplasmic control of nuclear behavior during meiotic maturation of frog oocytes", "authors": [{"first": "Y", "middle": [], "last": "Masui", "suffix": ""}, {"first": "C", "middle": [], "last": "Markert", "suffix": ""}], "year": 1971, "venue": "J exp Zool", "link": "22938637"}, "BIBREF33": {"title": "Development of cytoplasmic activities that control chromosome cycles during maturation of amphibians oocytes In Molecular Regulation of Nuclear Events in Mitosis and Meiosis", "authors": [{"first": "Y", "middle": [], "last": "Masui", "suffix": ""}, {"first": "E", "middle": ["K"], "last": "Shibuya", "suffix": ""}, {"first": "M", "middle": ["S"], "last": "Schleger", "suffix": ""}, {"first": "P N", "middle": [], "last": "Halleck", "suffix": ""}, {"first": "", "middle": [], "last": "Rao", "suffix": ""}], "year": 1987, "venue": "", "link": null}, "BIBREF34": {"title": "A AND BACCETTI, B (1975) Morphological changes of the surface of the egg of Xenopus laevis in the course of development. I Fertilization and early cleavage", "authors": [{"first": "J", "middle": [], "last": "Mrrchinson", "suffix": ""}], "year": 1984, "venue": "Cell Cycle Clocks", "link": null}, "BIBREF35": {"title": "Regulation of the cell cycle during early Xenopus development", "authors": [{"first": "J", "middle": [], "last": "Newport", "suffix": ""}, {"first": "M", "middle": [], "last": "Kirschner", "suffix": ""}], "year": 1984, "venue": "Cell", "link": "22558952"}, "BIBREF36": {"title": "Cell surface changes during cleavage of newt eggs, scanning electron microscopic studies", "authors": [{"first": "H", "middle": [], "last": "Oshima", "suffix": ""}, {"first": "T", "middle": [], "last": "Kubota", "suffix": ""}], "year": 1985, "venue": "Embryol exp Morph", "link": "161018"}, "BIBREF37": {"title": "La F^condation chez le tnton Pleurodele II La penetration des spermatozoides et la reaction locale de l'oeuf", "authors": [{"first": "B", "middle": [], "last": "Picheral", "suffix": ""}], "year": 1977, "venue": "J Ultrastruct Res", "link": null}, "BIBREF38": {"title": "Surface and shape changes during cell division", "authors": [{"first": "J", "middle": [], "last": "Sanger", "suffix": ""}, {"first": "J", "middle": [], "last": "Sanger", "suffix": ""}], "year": 1980, "venue": "Cell Tissue Res", "link": "13135535"}, "BIBREF39": {"title": "Cyclic changes in the cortical layer of nonnucleate fragments of the newt's egg", "authors": [{"first": "T", "middle": [], "last": "Sawai", "suffix": ""}], "year": 1979, "venue": "J Embryol exp Morph", "link": null}, "BIBREF40": {"title": "Interrelation between the cell surface and the cytoskeleton in cleaving sea urchin eggs", "authors": [{"first": "T E ; G L", "middle": [], "last": "Schroeder", "suffix": ""}, {"first": "", "middle": [], "last": "Nicholson", "suffix": ""}], "year": 1981, "venue": "Cytoskeleton Elements and Plasma Membrane Organization Cell surface Rev. 7", "link": null}, "BIBREF42": {"title": "Nuclear and mitotic abnormalities produced by cycloheximide in the newt egg during cleavage and their relationship to the cell cycle", "authors": [{"first": "P", "middle": [], "last": "Sentein", "suffix": ""}], "year": 1981, "venue": "Expl Cell Bwl", "link": "19945335"}, "BIBREF43": {"title": "The role of spindle microtubules in the timing of the cell cycle in echinoderm eggs", "authors": [{"first": "G", "middle": [], "last": "Sluder", "suffix": ""}, {"first": "", "middle": [], "last": "Miller", "suffix": ""}, {"first": "K", "middle": [], "last": "Spanjian", "suffix": ""}], "year": 1986, "venue": "exp Zool", "link": "10194410"}, "BIBREF44": {"title": "A non-nutnent medium for cultunng amphibian embryonic tissues In Carnegie Institution of Washington Year Book 56", "authors": [{"first": "M", "middle": [], "last": "Steinberg", "suffix": ""}], "year": 1957, "venue": "", "link": null}, "BIBREF45": {"title": "Mitosis-specific phosphorylation causes 83K non-muscle caldesmon to dissociate from microfilaments", "authors": [{"first": "S", "middle": [], "last": "Yamashtro", "suffix": ""}, {"first": "Yamaktta", "middle": [], "last": "", "suffix": ""}, {"first": "Y", "middle": [], "last": "Ishikawa", "suffix": ""}, {"first": "R", "middle": [], "last": "Matsumura", "suffix": ""}, {"first": "F", "middle": [], "last": "", "suffix": ""}], "year": 1990, "venue": "Nature", "link": "4362644"}}, "ref_entries": {}}
{"paper_id": "17784298", "_pdf_hash": "3cef374069758e3cc1f72366bda8ec89384fe63d", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "The prevalence of age-related maculopathy in the Rotterdam Study", "authors": [{"first": "J", "middle": ["R"], "last": "Vingerling", "suffix": ""}, {"first": "I", "middle": [], "last": "Dielemans", "suffix": ""}, {"first": "A", "middle": [], "last": "Hofman", "suffix": ""}], "year": 1995, "venue": "Ophthalmology", "link": "43170040"}, "BIBREF1": {"title": "Mutation of the Stargardt disease gene (ABCR) in age-related macular degeneration", "authors": [{"first": "R", "middle": [], "last": "Allikmets", "suffix": ""}, {"first": "N", "middle": ["F"], "last": "Shroyer", "suffix": ""}, {"first": "N", "middle": [], "last": "Singh", "suffix": ""}], "year": 1997, "venue": "Science", "link": "73353125"}, "BIBREF2": {"title": "Genetic association of apolipoprotein E with age-related macular degeneration", "authors": [{"first": "C", "middle": ["C"], "last": "Klaver", "suffix": ""}, {"first": "M", "middle": [], "last": "Kliffen", "suffix": ""}, {"first": "C", "middle": ["M"], "last": "Van Duijn", "suffix": ""}], "year": 1998, "venue": "Am J Hum Genet", "link": "9863807"}, "BIBREF3": {"title": "Relation of smoking to the incidence of age-related maculopathy: the Beaver Dam Eye Study", "authors": [{"first": "R", "middle": [], "last": "Klein", "suffix": ""}, {"first": "B", "middle": ["E"], "last": "Klein", "suffix": ""}, {"first": "S", "middle": ["E"], "last": "Moss", "suffix": ""}], "year": 1998, "venue": "Am J Epidemiol", "link": "32772741"}, "BIBREF4": {"title": "Risk factors for neovascular age-related macular degeneration", "authors": [], "year": 1992, "venue": "Arch Ophthalmol", "link": null}, "BIBREF5": {"title": "Sunlight and age-related macular degeneration: the Beaver Dam Eye Study", "authors": [{"first": "K", "middle": ["J"], "last": "Cruickshanks", "suffix": ""}, {"first": "R", "middle": [], "last": "Klein", "suffix": ""}, {"first": "B", "middle": ["E"], "last": "Klein", "suffix": ""}], "year": 1993, "venue": "Arch Ophthalmol", "link": "714347"}, "BIBREF6": {"title": "Sun exposure and agerelated macular degeneration: an Australian case-control study", "authors": [{"first": "P", "middle": [], "last": "Darzins", "suffix": ""}, {"first": "P", "middle": [], "last": "Mitchell", "suffix": ""}, {"first": "R", "middle": ["F"], "last": "Heller", "suffix": ""}], "year": 1997, "venue": "Ophthalmology", "link": "24661081"}, "BIBREF7": {"title": "Dietary carotenoids, vitamins A, C, and E, and advanced age-related macular degeneration", "authors": [{"first": "J", "middle": ["M"], "last": "Seddon", "suffix": ""}, {"first": "U", "middle": ["A"], "last": "Ajani", "suffix": ""}, {"first": "R", "middle": ["D"], "last": "Sperduto", "suffix": ""}], "year": 1994, "venue": "JAMA", "link": "73033937"}, "BIBREF8": {"title": "Body mass index and the incidence of visually significant age-related maculopathy in men", "authors": [{"first": "D", "middle": ["A"], "last": "Schaumberg", "suffix": ""}, {"first": "W", "middle": ["G"], "last": "Christen", "suffix": ""}, {"first": "S", "middle": ["E"], "last": "Hankinson", "suffix": ""}, {"first": "R", "middle": ["J"], "last": "Glynn", "suffix": ""}], "year": 2001, "venue": "Arch Ophthalmol", "link": "8623516"}, "BIBREF9": {"title": "Plasma fibrinogen levels, other cardiovascular risk factors, and age-related maculopathy: the Blue Mountains Eye Study", "authors": [{"first": "W", "middle": [], "last": "Smith", "suffix": ""}, {"first": "P", "middle": [], "last": "Mitchell", "suffix": ""}, {"first": "S", "middle": ["R"], "last": "Leeder", "suffix": ""}, {"first": "J", "middle": ["J"], "last": "Wang", "suffix": ""}], "year": 1998, "venue": "Arch Ophthalmol", "link": "71593758"}, "BIBREF10": {"title": "Dietary fat and age-related maculopathy", "authors": [{"first": "J", "middle": ["A"], "last": "Mares-Perlman", "suffix": ""}, {"first": "W", "middle": ["E"], "last": "Brady", "suffix": ""}, {"first": "R", "middle": [], "last": "Klein", "suffix": ""}], "year": 1995, "venue": "Arch Ophthalmol", "link": "24628005"}, "BIBREF11": {"title": "Multivariable Adjusted* 2-Year Incident Odds Ratios and 95% Confidence Intervals of Myocardial Infarction, Stratified by Type of Age-Related Macular Degeneration (AMD) and Age Group", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF12": {"title": "Adjusted for age within each age group, gender, race, hypertension, and diabetes. Persons without AMD during baseline period were the referent group", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF13": {"title": "Dietary fat and fish intake and age-related maculopathy", "authors": [{"first": "W", "middle": [], "last": "Smith", "suffix": ""}, {"first": "P", "middle": [], "last": "Mitchell", "suffix": ""}, {"first": "S", "middle": ["R"], "last": "Leeder", "suffix": ""}], "year": 2000, "venue": "Arch Ophthalmol", "link": "71803595"}, "BIBREF14": {"title": "Incidence of exudative age-related macular degeneration among elderly Americans", "authors": [{"first": "J", "middle": ["C"], "last": "Javitt", "suffix": ""}, {"first": "Z", "middle": [], "last": "Zhou", "suffix": ""}, {"first": "M", "middle": ["G"], "last": "Maguire", "suffix": ""}], "year": 2003, "venue": "Ophthalmology", "link": "17993893"}, "BIBREF15": {"title": "Longitudinal prevalence of major eye diseases", "authors": [{"first": "P", "middle": ["P"], "last": "Lee", "suffix": ""}, {"first": "Z", "middle": ["W"], "last": "Feldman", "suffix": ""}, {"first": "J", "middle": [], "last": "Ostermann", "suffix": ""}], "year": 2003, "venue": "Arch Ophthalmol", "link": "25314638"}, "BIBREF16": {"title": "The Framingham Eye Study monograph: an ophthalmological and epidemiological study of cataract, glaucoma, diabetic retinopathy, macular degeneration, and visual acuity in a general population of 2631 adults", "authors": [{"first": "H", "middle": ["M"], "last": "Leibowitz", "suffix": ""}, {"first": "D", "middle": ["E"], "last": "Krueger", "suffix": ""}, {"first": "L", "middle": ["R"], "last": "Maunder", "suffix": ""}], "year": 1973, "venue": "Surv Ophthalmol", "link": "22188566"}, "BIBREF17": {"title": "Eye Diseases Prevalence Research Group. Prevalence of agerelated macular degeneration in the United States", "authors": [], "year": 2004, "venue": "Arch Ophthalmol", "link": null}, "BIBREF18": {"title": "Hypertension, cardiovascular disease, and age-related macular degeneration", "authors": [{"first": "L", "middle": [], "last": "Hyman", "suffix": ""}, {"first": "A", "middle": ["P"], "last": "Schachat", "suffix": ""}, {"first": "Q", "middle": [], "last": "He", "suffix": ""}], "year": 2000, "venue": "Arch Ophthalmol", "link": "71244446"}, "BIBREF19": {"title": "The Framingham Eye Study. II. Association of ophthalmic pathology with single variables previously measured in the Framingham Heart Study", "authors": [{"first": "H", "middle": ["A"], "last": "Kahn", "suffix": ""}, {"first": "H", "middle": ["M"], "last": "Leibowitz", "suffix": ""}, {"first": "J", "middle": ["P"], "last": "Ganley", "suffix": ""}], "year": 1977, "venue": "Am J Epidemiol", "link": "33383258"}, "BIBREF20": {"title": "Systemic hypertension and age-related maculopathy in the Framingham Study", "authors": [{"first": "R", "middle": ["D"], "last": "Sperduto", "suffix": ""}, {"first": "R", "middle": [], "last": "Hiller", "suffix": ""}], "year": 1986, "venue": "Arch Ophthalmol", "link": "35728641"}, "BIBREF21": {"title": "Factors associated with age-related macular degeneration: an analysis of data from the first National Health and Nutrition Examination Survey", "authors": [{"first": "J", "middle": [], "last": "Goldberg", "suffix": ""}, {"first": "G", "middle": [], "last": "Flowerdew", "suffix": ""}, {"first": "E", "middle": [], "last": "Smith", "suffix": ""}], "year": 1988, "venue": "Am J Epidemiol", "link": "9197801"}, "BIBREF22": {"title": "Risk factors associated with age-related macular degeneration: a casecontrol study in the Age-Related Eye Disease Study. AgeRelated Eye Disease Study report number 3", "authors": [], "year": 2000, "venue": "Ophthalmology", "link": null}, "BIBREF23": {"title": "Blood pressure, atherosclerosis, and the incidence of age-related maculopathy: the Rotterdam Study", "authors": [{"first": "R", "middle": [], "last": "Van Leeuwen", "suffix": ""}, {"first": "M", "middle": ["K"], "last": "Ikram", "suffix": ""}, {"first": "J", "middle": ["R"], "last": "Vingerling", "suffix": ""}], "year": 2003, "venue": "Invest Ophthalmol Vis Sci", "link": "13484210"}, "BIBREF24": {"title": "The pathogenesis of diabetic retinopathy: old concepts and new questions", "authors": [{"first": "J", "middle": [], "last": "Cai", "suffix": ""}, {"first": "M", "middle": [], "last": "Boulton", "suffix": ""}], "year": 2002, "venue": "Eye", "link": "24164131"}, "BIBREF25": {"title": "Risk factor analysis for atrophic and exudative age-related macular degeneration: an epidemiological study of 1000 aged individuals", "authors": [{"first": "T", "middle": [], "last": "Vinding", "suffix": ""}, {"first": "M", "middle": [], "last": "Appleyard", "suffix": ""}, {"first": "J", "middle": [], "last": "Nyboe", "suffix": ""}, {"first": "G", "middle": [], "last": "Jensen", "suffix": ""}], "year": 1992, "venue": "Acta Ophthalmol (Copenh)", "link": "2292584"}, "BIBREF26": {"title": "Early age-related maculopathy in the Cardiovascular Health Study", "authors": [{"first": "R", "middle": [], "last": "Klein", "suffix": ""}, {"first": "B", "middle": ["E"], "last": "Klein", "suffix": ""}, {"first": "E", "middle": ["K"], "last": "Marino", "suffix": ""}], "year": 2003, "venue": "Ophthalmology", "link": "44537050"}, "BIBREF27": {"title": "Senile macular degeneration: a case-control study", "authors": [{"first": "L", "middle": ["G"], "last": "Hyman", "suffix": ""}, {"first": "A", "middle": ["M"], "last": "Lilienfeld", "suffix": ""}, {"first": "F", "middle": ["L"], "last": "Ferris", "suffix": ""}, {"first": "", "middle": [], "last": "Iii", "suffix": ""}, {"first": "S", "middle": ["L"], "last": "Fine", "suffix": ""}], "year": 1983, "venue": "Am J Epidemiol", "link": "37538967"}, "BIBREF28": {"title": "Risk factors for neovascular age-related macular degeneration", "authors": [], "year": 1992, "venue": "Arch Ophthalmol", "link": null}, "BIBREF29": {"title": "The relation of cardiovascular disease and its risk factors to the 5-year incidence of agerelated maculopathy: the Beaver Dam Eye Study", "authors": [{"first": "R", "middle": [], "last": "Klein", "suffix": ""}, {"first": "B", "middle": ["E"], "last": "Klein", "suffix": ""}, {"first": "S", "middle": ["C"], "last": "Jensen", "suffix": ""}], "year": 1997, "venue": "Ophthalmology", "link": "8933063"}, "BIBREF30": {"title": "Prevalence of age-related maculopathy in the Atherosclerosis Risk in Communities Study", "authors": [{"first": "R", "middle": [], "last": "Klein", "suffix": ""}, {"first": "L", "middle": [], "last": "Clegg", "suffix": ""}, {"first": "L", "middle": ["S"], "last": "Cooper", "suffix": ""}], "year": 1999, "venue": "Arch Ophthalmol", "link": "28412675"}, "BIBREF31": {"title": "Biomarkers of cardiovascular disease as risk factors for age-related macular degeneration", "authors": [{"first": "A", "middle": ["K"], "last": "Vine", "suffix": ""}, {"first": "J", "middle": [], "last": "Stader", "suffix": ""}, {"first": "K", "middle": [], "last": "Branham", "suffix": ""}], "year": 2005, "venue": "Ophthalmology", "link": "17782759"}, "BIBREF32": {"title": "Age-related macular degeneration is associated with atherosclerosis: the Rotterdam Study", "authors": [{"first": "J", "middle": ["R"], "last": "Vingerling", "suffix": ""}, {"first": "I", "middle": [], "last": "Dielemans", "suffix": ""}, {"first": "M", "middle": ["L"], "last": "Bots", "suffix": ""}], "year": 1995, "venue": "Am J Epidemiol", "link": "43416568"}, "BIBREF33": {"title": "Accuracy of ICD-9-CM codes for identifying cardiovascular and stroke risk factors", "authors": [{"first": "E", "middle": [], "last": "Birman-Deych", "suffix": ""}, {"first": "A", "middle": ["D"], "last": "Waterman", "suffix": ""}, {"first": "Y", "middle": [], "last": "Yan", "suffix": ""}], "year": 2005, "venue": "Med Care", "link": "23983289"}, "BIBREF34": {"title": "Specificity and sensitivity of claims-based algorithms for identifying members of Medicare\u03e9Choice health plans that have chronic medical conditions", "authors": [{"first": "T", "middle": ["S"], "last": "Rector", "suffix": ""}, {"first": "S", "middle": ["L"], "last": "Wickstrom", "suffix": ""}, {"first": "M", "middle": [], "last": "Shah", "suffix": ""}], "year": 2004, "venue": "Health Serv Res", "link": "20847705"}}, "ref_entries": {}}
{"paper_id": "17784629", "_pdf_hash": "0cfc285a5cff2b8e12e66e8ebd37a94961f4c768", "abstract": [{"section": "Abstract", "text": "A new approach to the generalised Brownian motion introduced by M. Bo\u017cejko and R. Speicher is described, based on symmetry rather than deformation. The symmetrisation principle is provided by Joyal's notions of tensorial and combinatorial species. Any such species V gives rise to an endofunctor FV of the category of Hilbert spaces with contractions mapping a Hilbert space H to a symmetric Hilbert space FV (H) with the same symmetry as the species V . A general framework for annihilation and creation operators on these spaces is developed and shown to give vacuum expectations as prescribed by Bo\u017cejko and Speicher. The existence of the second quantisation as functor from Hilbert spaces to von Neumann algebras with completely positive maps is investigated. For a certain one parameter interpolation between the classical and the free Brownian motion it is shown that the \"field algebras\" \u0393(K) are type II1 factors when K is infinite dimensional.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "In non-commutative probability theory one is interested in finding generalisations of classical probabilistic concepts such as independence and processes with independent stationary increments. Motivated by a central limit theorem result and by the analogy with classical Brownian motion, M. Bo\u017cejko and R. Speicher proposed in [3] a class of operator algebras called \"generalised Brownian motions\" and investigated an example of interpolation between the classical [18] and the free motion of Voiculescu [23] . A better known interpolation is provided by the \"q-deformed commutation relations\" [2, 4, 5, 6, 7, 8, 16, 24] .", "cite_spans": [{"start": 328, "end": 331, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 466, "end": 470, "text": "[18]", "ref_id": "BIBREF17"}, {"start": 505, "end": 509, "text": "[23]", "ref_id": "BIBREF22"}, {"start": 595, "end": 598, "text": "[2,", "ref_id": "BIBREF1"}, {"start": 599, "end": 601, "text": "4,", "ref_id": "BIBREF3"}, {"start": 602, "end": 604, "text": "5,", "ref_id": "BIBREF4"}, {"start": 605, "end": 607, "text": "6,", "ref_id": "BIBREF5"}, {"start": 611, "end": 613, "text": "8,", "ref_id": "BIBREF7"}, {"start": 614, "end": 617, "text": "16,", "ref_id": "BIBREF15"}, {"start": 618, "end": 621, "text": "24]", "ref_id": "BIBREF23"}], "ref_spans": []}, {"section": "Introduction", "text": "Such an operator algebra is obtained by performing the GNS representation of the free tensor algebra A(K) over an arbitrary infinite dimensional real Hilbert space K, with respect to a \"Gaussian state\"\u03c1 t defined by the following \"pairing prescription\":", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "where f i \u2208 K, \u03c9(f i ) \u2208 A(K) and the sum runs over all pair partitions of the ordered set {1, 2, . . . , n}. The functional is uniquely determined by the complex valued function t on pair partitions. Classical Brownian motion is obtained by taking K = L 2 (R + ) and B s := \u03c9(1 [0,s) ) with the constant function t(V) = 1 on all pair partitions; the free Brownian motion [23] requires t to be 0 on crossing partitions and 1 on non-crossing partitions.", "cite_spans": [{"start": 372, "end": 376, "text": "[23]", "ref_id": "BIBREF22"}], "ref_spans": []}, {"section": "Introduction", "text": "If one considers complex Hilbert spaces, the analogue of a Gaussian state is called a Fock state. We show that the GNS representation of the free algebra C(H) of creation and annihilation operators with respect to a Fock state \u03c1 t can be described in a functorial way inspired by the notions of tensorial species of Joyal [12, 13] : the representation space has the form", "cite_spans": [{"start": 322, "end": 326, "text": "[12,", "ref_id": "BIBREF11"}, {"start": 327, "end": 330, "text": "13]", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "Introduction", "text": "where V n are Hilbert spaces carrying unitary representations of the symmetric groups S(n) and \u2297 s means the subspace of the tensor product containing vectors which are invariant under the double action of S(n). The creation operators have the expression:", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "where j n : V n \u2192 V n+1 is an operator which intertwines the action of S(n) and S(n + 1). In Section 3 we connect these Fock representations with positive functionals on a certain algebraic object BP 2 (\u221e) which we call the * -semigroup of \"broken pair partitions\". The elements of this * -semigroup can be described graphically as segments located between two vertical lines which cut through the graphical representation of a pair partition. In particular, the pair partitions are elements of BP 2 (\u221e). We show that if \u03c1 t is a Fock state then the function t has a natural extension to a positive functionalt on BP 2 (\u221e). The GNS-like representation with respect tot provides the combinatorial data (V n , j n ) \u221e n=0 associated to \u03c1 t . The representation of A(K) with respect to a Gaussian state\u03c1 t is a * -algebra generated by \"fields\" \u03c9 t (f ). Monomials of such fields can be seen as moments, with the corresponding cumulants being a generalisation of the Wick products known from the q-deformed Brownian motion [2] . Using generalised Wick products we prove that any Gaussian state\u03c1 t extends to a Fock state \u03c1 t on the algebra of creation and annihilation operators C(K C ) (see section 4).", "cite_spans": [{"start": 1019, "end": 1022, "text": "[2]", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Introduction", "text": "Second quantisation is a functor from the category of real Hilbert spaces with contractions to the category of (non-commutative) probability spaces. For any real Hilbert space K we consider first the * -algebra\u0393 t (K) of generalised Wick products. In a standard manner we associate to it a von Neumann algebra \u0393 t (K) and investigate the possibility of making \u0393 t into a functor of second quantisation. A necessary condition is that the function t has the multiplicative property, a form of statistical independence. A sufficient condition is the separating property of the vacuum. By modifying the definition of the \"field algebras\" we obtain another second quantisation functor denoted \u2206 t this time for all multiplicative (positive definite) functions t.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "In the last section we develop a useful criterion, in terms of the spectrum of a characteristic contraction, for factoriality of the algebras \u0393 t (\u2113 2 (Z)) in the case when the vacuum state \u03c1 t is tracial. We then apply it to a particular example of positive definite function t q where 0 \u2264 q < 1, which interpolates between the bosonic and free cases and has been introduced in [3] (see [10] for another proof of the positivity). We conclude that that \u0393 t (\u2113 2 (Z)) is a type II 1 factor. Further generalisation of this criterion to factors of type III will be investigated in a forthcoming paper [11] .", "cite_spans": [{"start": 379, "end": 382, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 388, "end": 392, "text": "[10]", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "Definitions and description of the Fock representation", "text": "The generalised Brownian motions [3] are representations with respect to special gaussian states on free algebras over real Hilbert spaces. We start by giving all necessary definitions and subsequently we will analyse the structure of the Fock representations which are intimately connected with the generalised Brownian motion (see section 4) .", "cite_spans": [{"start": 33, "end": 36, "text": "[3]", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "Definitions and description of the Fock representation", "text": "Definition 2.1 Let K be a real Hilbert space. The algebra A(K) is the free unital * -algebra with generators \u03c9(h) for all h \u2208 K, divided by the relations:", "cite_spans": [], "ref_spans": []}, {"section": "Definitions and description of the Fock representation", "text": "for all f, g \u2208 K and a, b \u2208 R. Definition 2.2 Let H be a complex Hilbert space. The algebra C(H) is the free unital * -algebra with generators a(h) and a * (h) for all h \u2208 H, divided by the relations:", "cite_spans": [], "ref_spans": []}, {"section": "Definitions and description of the Fock representation", "text": "for all f, g \u2208 H and \u03bb, \u00b5 \u2208 C.", "cite_spans": [], "ref_spans": []}, {"section": "Definitions and description of the Fock representation", "text": "We notice the existence of the canonical injection from", "cite_spans": [], "ref_spans": []}, {"section": "Definitions and description of the Fock representation", "text": "where K C is the complexification of the real Hilbert space K. On the algebras defined above we would like to define positive linear functionals by certain pairing prescriptions for which we need some notions of pair partitions.", "cite_spans": [], "ref_spans": []}, {"section": "Definitions and description of the Fock representation", "text": "Definition 2.3 Let S be a finite ordered set. We denote by P 2 (S) is the set of pair partitions of S, that is V \u2208 P 2 (S) if V consists of 1 2 n disjoint ordered pairs (l, r) with l < r having S as their reunion. The set of all pair partitions is", "cite_spans": [], "ref_spans": []}, {"section": "Definitions and description of the Fock representation", "text": "Note that P 2 (n) = \u2205 if n is odd. In this paper the symbol t will always stand for a function t :", "cite_spans": [], "ref_spans": []}, {"section": "Definitions and description of the Fock representation", "text": "Definition 2.4 A Fock state on the algebra C(H) is a positive normalised linear functional \u03c1 t : C(H) \u2192 C of the form", "cite_spans": [], "ref_spans": []}, {"section": "Definitions and description of the Fock representation", "text": "the symbols \u266f i standing for creation or annihilation and the two by two covariance matrix Q is given by", "cite_spans": [], "ref_spans": []}, {"section": "Definitions and description of the Fock representation", "text": "where a i = a(e i ) and e i is an arbitrary normalized vector in H. Note that the l.h.s. of (2.5) is zero for odd values of n.", "cite_spans": [], "ref_spans": []}, {"section": "Definitions and description of the Fock representation", "text": "Definition 2.5 A Gaussian state on A(K) is a positive normalised linear functional\u03c1 t with moments", "cite_spans": [], "ref_spans": []}, {"section": "Definitions and description of the Fock representation", "text": "Remark. The restriction of a Fock state \u03c1 t on C(K C ) to the subalgebra A(K) is the Gaussian state\u03c1 t . If \u03c1 t is a Fock state for all choices of K then we call the function", "cite_spans": [], "ref_spans": []}, {"section": "Definitions and description of the Fock representation", "text": "The GNS representations associated to pairs (C(H), \u03c1 t ) have been studied in a number of cases. One obtains a representation \u03c0 t of C(H) as * -algebra of creation and annihilation operators acting on a Hilbert space F t (H) which has a Fock-type structure", "cite_spans": [], "ref_spans": []}, {"section": "Definitions and description of the Fock representation", "text": "H n with H n being a (symmetric) subspace of H \u2297n in the case of bosonic or fermionic algebras [18] , the full tensor product in models of free probablity [23] , a deformation of it in the case of q-deformations [2, 4, 5, 6, 7, 8, 16, 24] , or even \"larger\" spaces containing more copies of H \u2297n with a deformed inner product in the case of another deformation depending on a parameter \u22121 \u2264 q \u2264 1 constructed in [3] . The action of the creation operators is a * (f )\u2126 t = f \u2208 H,", "cite_spans": [{"start": 95, "end": 99, "text": "[18]", "ref_id": "BIBREF17"}, {"start": 155, "end": 159, "text": "[23]", "ref_id": "BIBREF22"}, {"start": 212, "end": 215, "text": "[2,", "ref_id": "BIBREF1"}, {"start": 216, "end": 218, "text": "4,", "ref_id": "BIBREF3"}, {"start": 219, "end": 221, "text": "5,", "ref_id": "BIBREF4"}, {"start": 222, "end": 224, "text": "6,", "ref_id": "BIBREF5"}, {"start": 228, "end": 230, "text": "8,", "ref_id": "BIBREF7"}, {"start": 231, "end": 234, "text": "16,", "ref_id": "BIBREF15"}, {"start": 235, "end": 238, "text": "24]", "ref_id": "BIBREF23"}, {"start": 412, "end": 415, "text": "[3]", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "Definitions and description of the Fock representation", "text": "while that of the annihilation operator is less transparent, depending on the inner product on H n . Proving the positivity of this inner product is in general nontrivial.", "cite_spans": [], "ref_spans": []}, {"section": "Definitions and description of the Fock representation", "text": "In [10] we have followed a different, more combinatorial approach to the study of the representations \u03c0 t (C(H)) for various examples of positive definite functions t. We give here a brief description of our construction. The representation space is denoted by F V (H) and has certain symmetry properties encoded by a sequence (V n ) \u221e n=0 of (not necessarily finite dimensional) Hilbert spaces such that each V n carries a unitary representation of the symmetric group S(n)", "cite_spans": [{"start": 3, "end": 7, "text": "[10]", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "Definitions and description of the Fock representation", "text": "In concrete examples we have realised V n as \u2113 2 (F [n]) where F [ ] is a species of structures [1, 12, 13] , i.e., a functor from the category of finite sets with bijections as morphisms to the category of finite sets with maps as morphisms. For each finite set A, the rule F prescribes a finite set F [A] whose elemens are called F -structures over the set A. Moreover for any bijection \u03c3 :", "cite_spans": [{"start": 96, "end": 99, "text": "[1,", "ref_id": "BIBREF0"}, {"start": 100, "end": 103, "text": "12,", "ref_id": "BIBREF11"}, {"start": 104, "end": 107, "text": "13]", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "Definitions and description of the Fock representation", "text": "In particular for n := {0, 1, . . . n \u2212 1} there is an action of the symmetric group S(n) on the set of structures:", "cite_spans": [], "ref_spans": []}, {"section": "Definitions and description of the Fock representation", "text": "which gives a unitary representation U (\u00b7) of S(n) on", "cite_spans": [], "ref_spans": []}, {"section": "Definitions and description of the Fock representation", "text": "Simple examples are such species as sets, ordered sequences, trees, graphs, etc. We define", "cite_spans": [], "ref_spans": []}, {"section": "Definitions and description of the Fock representation", "text": "where V n \u2297 s H \u2297n is the subspace of V n \u2297H \u2297n spanned by the vectors \u03c8 invariant under the action of S(n): ", "cite_spans": [], "ref_spans": []}, {"section": "Definitions and description of the Fock representation", "text": "The creation and annihilation operators are defined with the help of a sequence of densely defined linear maps (j n ) \u221e n=0 with j n : V n \u2192 V n+1 satisfying the intertwining relations", "cite_spans": [], "ref_spans": []}, {"section": "Definitions and description of the Fock representation", "text": "with \u03b9 n : S(n) \u2192 S(n + 1) being the canonical embedding associated to the inclusion of sets", "cite_spans": [], "ref_spans": []}, {"section": "Definitions and description of the Fock representation", "text": "In the examples using species of structures the map j n :", "cite_spans": [], "ref_spans": []}, {"section": "Definitions and description of the Fock representation", "text": ") is constructed by giving the matrix elements j n (s, t) := \u03b4 t , V n \u03b4 s which can be seen as \"transition coefficients\" between s \u2208 F [n] and t \u2208 F [n + 1]. For example [10] if the species F [\u00b7] is that of rooted trees one can choose j n (s, t) = 1 if the tree s is obtained by removing the leaf with label n from the tree t; otherwise we choose j n (s, t) = 0. Notice that there is no canonical manner of defining j n but certain species of structures offer rather natural definitions, for example the species of sets, ordered sequences, rooted trees, oriented graphs, sequences of non empty sets, etc [10] . Let h \u2208 H; the creation operator a * V,j (h) has the action:", "cite_spans": [{"start": 171, "end": 175, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 605, "end": 609, "text": "[10]", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "Definitions and description of the Fock representation", "text": "The annihilation operator a V,j (h) is the adjoint of a * V,j (h). Its action on the n + 1-th level is given by the restriction of the operator", "cite_spans": [], "ref_spans": []}, {"section": "Definitions and description of the Fock representation", "text": "to the subspace V n+1 \u2297 s H \u2297n+1 . Note that due to condition (2.11) the operators a * V,j (h), a V,j (h) are well defined. Let us denote by C V,j (H) the * -algebra generated by all operators a * V,j (h), a V,j (h) and by \u2126 V \u2208 V 0 the normalised vacuum vector in F V (H). The following theorem is a generalisation of Proposition 5.1 in [10] : ", "cite_spans": [{"start": 338, "end": 342, "text": "[10]", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "Definitions and description of the Fock representation", "text": "Sketch of the proof. Let A \u2208 B(H). On F V (H) we define the operator", "cite_spans": [], "ref_spans": []}, {"section": "Definitions and description of the Fock representation", "text": "for v n \u2208 V n , f i \u2208 H. Then the following commutation relations hold:", "cite_spans": [], "ref_spans": []}, {"section": "Definitions and description of the Fock representation", "text": "In particular by choosing an orthonormal basis {e i } i\u2208I in H and denoting a", "cite_spans": [], "ref_spans": []}, {"section": "Definitions and description of the Fock representation", "text": "(2.17)", "cite_spans": [], "ref_spans": []}, {"section": "Definitions and description of the Fock representation", "text": ". . , n. By using (2.16), it follows that", "cite_spans": [], "ref_spans": []}, {"section": "Definitions and description of the Fock representation", "text": "We then apply (2.17) repatedly to obtain", "cite_spans": [], "ref_spans": []}, {"section": "Definitions and description of the Fock representation", "text": "The vacuum expectation of a monomial n k=1 a", "cite_spans": [], "ref_spans": []}, {"section": "Definitions and description of the Fock representation", "text": "can be different from zero only if the number of creators is equal to the number of annihilators, a \u266f1 i1 is an annihilator and a \u266fn in a creator. We will therefore assume that this is the case. We put the monomial in the form a i1 n k=2 a \u266f k i k and apply (2.19) . We obtain a sum over all pairs (a i1 , a * i k ) of the same color (i 1 = i k ) and replace i 1 by a new color i 0 . We pass now to the next annihilator in each term of the sum and repeat the procedure, the new color which we add this time being different from all the colors used previously. After n 2 steps we obtain a sum containing all possible pairings of annihilators and creators of the same color in", "cite_spans": [], "ref_spans": []}, {"section": "Definitions and description of the Fock representation", "text": ", where the indices j k , \u266f k satisfy the following conditions: if k = l then j k = j l if and only if (k, l) \u2208 V, in which case a", "cite_spans": [], "ref_spans": []}, {"section": "Definitions and description of the Fock representation", "text": "We prove now that the converse is also true.", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 2.7 Let t be a positive definite function on pair partitions. Then for any complex Hilbert space H the GNS-representation of", "text": "Proof. We first consider H := \u2113 2 (N * ) with the orthonormal basis (e i )", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 2.7 Let t be a positive definite function on pair partitions. Then for any complex Hilbert space H the GNS-representation of", "text": ". We split the proof in 3 steps. 1. Identify the spaces V n and the maps j n . Let (F t (H), C t (H), \u2126 t ) be the triple obtained from the GNS-construction. Let V n be the closure of the subspace of F t (H) spanned by vectors of the form", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 2.7 Let t be a positive definite function on pair partitions. Then for any complex Hilbert space H the GNS-representation of", "text": ")\u2126 t for which the following conditions hold: (i) in the sequence (a", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 2.7 Let t be a positive definite function on pair partitions. Then for any complex Hilbert space H the GNS-representation of", "text": "k=1 each creation operator a * t (e j ) appears exactly once for 1 \u2264 j \u2264 n;", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 2.7 Let t be a positive definite function on pair partitions. Then for any complex Hilbert space H the GNS-representation of", "text": "(ii) the rest of the sequence contains p creation operators (a * t (e lq )) p q=1 and p annihilation operators (a t (e lq )) p q=1 for p vectors (e lq ) p q=1 different among each other and with l q / \u2208 {1, . . . , n} for all 1 \u2264 q \u2264 p. The vector v n does not depend in fact on the colours (l q ) p q=1 but only on the positions of the creation and annihilation operators in the monomial. Thus when necessary we can consider l q > N for all 1 \u2264 q \u2264 n and some fixed big enough N \u2208 N . The map j n is defined as the restriction of a * t (e n+1 ) to V n :", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 2.7 Let t be a positive definite function on pair partitions. Then for any complex Hilbert space H the GNS-representation of", "text": "Obviously, the image of j n lies in V n+1 . The state \u03c1 t is invariant under unitary transformations U \u2208 U(H):", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 2.7 Let t be a positive definite function on pair partitions. Then for any complex Hilbert space H the GNS-representation of", "text": "is unitary and", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 2.7 Let t be a positive definite function on pair partitions. Then for any complex Hilbert space H the GNS-representation of", "text": "The action on the algebra of creation and annihilation operators is", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 2.7 Let t be a positive definite function on pair partitions. Then for any complex Hilbert space H the GNS-representation of", "text": "Considering unitaries which act by permuting the basis vectors {e 1 , . . . , e n } and leave all the others invariant we obtain a unitary representation of S(n) on V n . The intertwining property (2.11) follows immediately from the definition of j n . Having the \"combinatorial data\" (V n , j n ), we can construct the triple (F V (H), C V,j (H), \u2126 V ) according to equations (2.8, 2.13, 2.14). Similarly to F t (U ) we have the unitary", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 2.7 Let t be a positive definite function on pair partitions. Then for any complex Hilbert space H the GNS-representation of", "text": "We call F V (U ) the second quantisation of U at the Hilbert space level. Its action on operators is:", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 2.7 Let t be a positive definite function on pair partitions. Then for any complex Hilbert space H the GNS-representation of", "text": "Analogously to V n we define for any finite subset {i 1 , . . . , i n } \u2282 N the linear subspace V (i 1 , . . . , i n ) of F t (H) spanned by applying to the vacuum \u2126 t monomials", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 2.7 Let t be a positive definite function on pair partitions. Then for any complex Hilbert space H the GNS-representation of", "text": "t (e j k ) for which the colours (j k ) 2p+n k=1 satisfy conditions similar to i), ii) but now with {i 1 , . . . , i n } instead of {1, . . . , n}. For a unitary U which permutes the basis vectors, U e i = e u(i) we get", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 2.7 Let t be a positive definite function on pair partitions. Then for any complex Hilbert space H the GNS-representation of", "text": "One can check by calculating inner products that any two such spaces are either orthogonal or coincide. Similarly, we define the following subspaces of F V (H)", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 2.7 Let t be a positive definite function on pair partitions. Then for any complex Hilbert space H the GNS-representation of", "text": "which are also orthogonal for different sets of \"colours\" {i 1 , . . . , i n }.", "cite_spans": [], "ref_spans": []}, {"section": "2.", "text": "We proceed by proving the equality of the states \u03c1 t and \u03c1 V,j . As \u03c1 V,j is a Fock state by Theorem 2.6, we need only verify that the positive definite function t we have started with and the one derived from \u03c1 V,j coincide. By definition there is an isometry", "cite_spans": [], "ref_spans": []}, {"section": "2.", "text": "Furthermore for any unitary U \u2208 U(H) which permutes the basis vectors such that U e k = e i k , the operator", "cite_spans": [], "ref_spans": []}, {"section": "2.", "text": "depends only on the set {i 1 , . . . , i n }. Finally, the definitions of j n , a \u266f V,j (f ) amounts to the fact that the following diagram commutes", "cite_spans": [], "ref_spans": []}, {"section": "2.", "text": "and by acting from the left and from the right with the appropriate second quantisation operators and using (2.28, 2.22, 2.24) we obtain", "cite_spans": [], "ref_spans": []}, {"section": "2.", "text": "with a similar diagram for the annihilation operators. This is sufficient for proving the equality \u03c1 t (", "cite_spans": [], "ref_spans": []}, {"section": "2.", "text": ") for monomials containing n pairs of creation and annihilation operators of n different colours. 3. Finally we prove that \u2126 V,j is cyclic vector for C V,j (H). The space F V (H) has a decomposition with respect to occupation numbers", "cite_spans": [], "ref_spans": []}, {"section": "2.", "text": "with monomials satisfying the conditions i) and ii). By replacing the creation operators (a * (e k )) n k=1 appearing in the monomial, with the sequence containing n i times the creator a * (e i ) for i \u2208 {1, . . . p} and p i=1 n i = n we obtain a set of vectors which are dense in F V (n 1 , . . . , n p ) and this completes the proof of the cyclicity of the vacuum. Putting together 1., 2. and 3. we conclude that the representations (F t (H), C t (H), \u2126 t ) and (F V (H), C V,j (H), \u2126 V ) are unitarily equivalent for infinite dimensional H. The case H finite dimensional follows by restriction of the previous representations to the appropriate subspaces.", "cite_spans": [], "ref_spans": []}, {"section": "2.", "text": "3 The * -semigroup of broken pair partitions", "cite_spans": [], "ref_spans": []}, {"section": "2.", "text": "The content of the last two theorems can be summarised by the following fact: there exist a bijective correspondence between positive definite functions on pair partitions t, and \"combinatorial data\" (V n , j n ) \u221e n=0 . This suggests that the positivity of t can be characterised in a simpler way by regarding t as a positive functional on an algebraic object containing P 2 (\u221e) as a subset. Theorem 1 of [3] shows that a positive definite function on pair partitions t restricts to positive definite functions on the symmetric groups S(n) for all n \u2208 N through the embedding", "cite_spans": [{"start": 406, "end": 409, "text": "[3]", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "2.", "text": "given by", "cite_spans": [], "ref_spans": []}, {"section": "2.", "text": "However t is not determined completely by its restriction and thus one would like to find another algebraic object which completely encodes the positivity requirement. We will show that this is the * -semigroup of broken pair partitions which we denote by BP 2 (\u221e) and will be described below. Pictorially, the elements of the semigroup are segments obtained by sectioning pair partitions with vertical lines. Definition 3.1 Let X be an arbitrary finite ordered set and (L, P, R) a disjoint partition of X. We consider all the triples (V, f l , f r ) where V \u2208 P 2 (P ) and", "cite_spans": [], "ref_spans": []}, {"section": "2.", "text": "are bijections. Any order preserving bijection \u03b1 : X \u2192 Y induces an obvious map", "cite_spans": [], "ref_spans": []}, {"section": "2.", "text": "where", "cite_spans": [], "ref_spans": []}, {"section": "2.", "text": "We have the following pictorial representation: an element d is given by a diagram containing a sequence of l + r + 2n points displayed horizontally with 2n of them connected into n pairs, l points are connected with other l points vertically ordered on the left side (left legs) and r points are connected with r points vertically ordered on the right (right legs). An example is given in Figure  1 . In this case we have X = {1, . . . , 5}, V = {(1, 4)}, the left legs are connecting the points labeled 2 and 5 on the horizontal to the the points on the left side which are ordered vertically and labeled by 1 and 2. Similarly for the right legs. Usually we will label the ordered set of horizontal points will be of the form {n, n + 1, . . . n + m}. The product of two diagrams is calculated by drawing the diagrams next to each other and joining the right legs of the left diagram with the left legs of the right diagram which are situated at the same level on the vertical. Figure 2 illustrates an example. More formally if d i = (V i , f l,i , f r,i ) for i = 1, 2 with the notations from Definition 3.1, then", "cite_spans": [], "ref_spans": [{"start": 390, "end": 399, "text": "Figure  1", "ref_id": "FIGREF1"}, {"start": 979, "end": 987, "text": "Figure 2", "ref_id": "FIGREF0"}]}, {"section": "2.", "text": "and similarly for f r . The product does not depend on the chosen representatives for d i in their equivlence class and is associative. The diagrams with no legs are the pair partitions, thus", "cite_spans": [], "ref_spans": []}, {"section": "2.", "text": "The involution is given by mirror reflection (see Figure 3) .", "cite_spans": [], "ref_spans": []}, {"section": "2.", "text": "with the underlying set X * obtained by reversing the order on X and", "cite_spans": [], "ref_spans": []}, {"section": "2.", "text": "is the adjoint of V. It is easy to check that", "cite_spans": [], "ref_spans": []}, {"section": "2.", "text": "Let t be a linear functional on pair partitions. We extend it to a functiont on BP 2 (\u221e) defined ast", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 3.2 The function t on pair partitions is positive definite if and only ift is postive on the", "text": "Proof. The main ideas are already present in the proof of Proposition 2.7. A GNS-type of construction associates to the pair (BP 2 (\u221e),t) a cyclic representation \u03c7 t of BP 2 (\u221e) on a Hilbert space V with cyclic vector \u03be \u2208 V . We have", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 3.2 The function t on pair partitions is positive definite if and only ift is postive on the", "text": "the set of diagrams with n left legs and no right legs. Then using", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 3.2 The function t on pair partitions is positive definite if and only ift is postive on the", "text": "we obtain: 1. the representation space V is of the form", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 3.2 The function t on pair partitions is positive definite if and only ift is postive on the", "text": "there is an obvious action of S(n) by permutations of the positions of the left ends of the legs. Figure 4 shows the action of the transposition \u03c4 1,2 . This induces a unitary representation of S(n) on V n as", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 3.2 The function t on pair partitions is positive definite if and only ift is postive on the", "text": "and \u03c4 \u2208 S(n). 3. let d 0 \u2208 BP (1,0) 2 be the \"left hook\" (the diagram with no pairs). Then j := \u03c7 t (d 0 ) is an operator on V whose restriction j n to V n maps it into V n+1 and satisfies the intertwining condition (2.11) with respect ot the representations of the symmetric groups on V n and V n+1 . Using the data (V n , j n ) we construct the triple (F V (H), C V,j (H), \u2126 V ). According to Proposition 2.6 there exists a positive definite function on pair partitions t \u2032 such that \u03c1 V,j = \u03c1 t \u2032 . We have to prove that t, which is the restriction oft to P 2 (\u221e) coincides with t \u2032 . Any pair partition V can be written in a \"standard form\" (see Figure 5 ):", "cite_spans": [], "ref_spans": [{"start": 650, "end": 658, "text": "Figure 5", "ref_id": "FIGREF6"}]}, {"section": "Theorem 3.2 The function t on pair partitions is positive definite if and only ift is postive on the", "text": "where the permutations \u03c0 i are uniquely defined by the requirement that any two lines connecting two pairs in the associated graphic intersect minimally and at the rightmost possible position. Let", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 3.2 The function t on pair partitions is positive definite if and only ift is postive on the", "text": "be a monomial containing n creation operators and n annihilation operators such that by pairing creators with annihilators of the same colour on their right side, we generate a pair partition V. The definitions (2.13), (2.14) of the creation and annihilation operators give their expressions in terms of the operator j, j * and the unitary representations of the permutation groups on the spaces V n . By using the intertwining property (2.11) we can pass all permutations to the left of the j-terms and obtain:", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 3.2 The function t on pair partitions is positive definite if and only ift is postive on the", "text": "Conversely, starting from a positive definite function t we construct the representation (V, \u03c7 t (BP 2 (\u221e)), \u03be) through applying Theorem 2.7 and thust is positive on BP 2 (\u221e).", "cite_spans": [], "ref_spans": []}, {"section": "Generalised Wick products", "text": "As argued in the introduction, the representations of the \"field algebras\" A(K) with respect to Gaussian states\u03c1 t give rise to (noncommutative) processes called generalised Brownian motions [3] for K (infinite dimensional) real Hilbert space. In all known examples such representations appear as restrictions to the subalgebra A(K) of Fock representations of the algebra of creation and annihilation operators C(K C ) with respect to the state \u03c1 t . We will prove that this is always the case, thus answering a question put in [3] . Let", "cite_spans": [{"start": 191, "end": 194, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 528, "end": 531, "text": "[3]", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "Generalised Wick products", "text": "be such that\u03c1 t is a Gaussian state on A(K) for K infinite dimensional Hilbert space. Let (F t (K),\u03c0 t (A(K)),\u03a9 t ) be the GNS-triple associated to (A(K),\u03c1 t ). The * -algebra\u03c0 t (A(K)) is generated by the operators \u03c9 t (f ) :=\u03c0 t (\u03c9(f )) for all f \u2208 K.", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 4.1 The operators \u03c9 t (f ) are essentially selfadjoint.", "text": "Proof. By definition \u03c9 t (f ) is symmetric as operator defined on the dense domain D :=\u03c0 t (A(K))\u03a9 t . By Theorem VIII.3 in [17] , \u03c9 t (f ) is essentially selfadjoint if and only if Ran(\u03c9 t (f ) \u00b1 i) is dense inF t (K). Let B \u2208 A(K) such that for all A \u2208 A(K) we have", "cite_spans": [{"start": 124, "end": 128, "text": "[17]", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "Lemma 4.1 The operators \u03c9 t (f ) are essentially selfadjoint.", "text": "By choosing A = \u03c9 t (f )B we get \u03c1 t (B * \u03c9(f )B) = 0 and \u03c1 t (B * \u03c9(f ) 2 B) = 0. Choose now A = B, then \u03c1 t (B * B) = 0 thus \u03c0 t (B)\u2126 t = 0.", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 4.1 The operators \u03c9 t (f ) are essentially selfadjoint.", "text": "In analogy to (2.21) for any orthogonal operator O \u2208 O(K) there exists a unitaryF", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 4.1 The operators \u03c9 t (f ) are essentially selfadjoint.", "text": "This induces an action on the", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 4.1 The operators \u03c9 t (f ) are essentially selfadjoint.", "text": "Certain operators play a similar role to that of the Wick products in quantum field theory [18, 21] or for the q-deformed Brownian motion [2, 4] . r 1 ) , . . . , (l p , r p )} \u2208 P 2 (P ) and f : F \u2192 K.", "cite_spans": [{"start": 91, "end": 95, "text": "[18,", "ref_id": "BIBREF17"}, {"start": 96, "end": 99, "text": "21]", "ref_id": "BIBREF20"}, {"start": 138, "end": 141, "text": "[2,", "ref_id": "BIBREF1"}, {"start": 142, "end": 144, "text": "4]", "ref_id": "BIBREF3"}], "ref_spans": [{"start": 147, "end": 152, "text": "r 1 )", "ref_id": "FIGREF1"}]}, {"section": "Lemma 4.1 The operators \u03c9 t (f ) are essentially selfadjoint.", "text": "The generalised Wick product associated to (V, f ) is the operator \u03a8(V, f ) determined recursively by", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 4.1 The operators \u03c9 t (f ) are essentially selfadjoint.", "text": "where f k,n := f (k) for k \u2208 F and f li,n = f ri,n = e np+i for i = 1, . . . , p with (e l ) l\u2208N a set of normalised vectors, orthogonal to each other and to the vectors (f (k)) ", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 4.1 The operators \u03c9 t (f ) are essentially selfadjoint.", "text": "for n 0 \u2208 N large enough such that the subspaces K 1 and K 2 of K spanned by (e n0+j ) j\u22650 respectively by (g ", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 4.1 The operators \u03c9 t (f ) are essentially selfadjoint.", "text": "3) The dense domain D is spanned by the vectors of the form", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 4.1 The operators \u03c9 t (f ) are essentially selfadjoint.", "text": "with F = {1, . . . , n}.", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 4.1 The operators \u03c9 t (f ) are essentially selfadjoint.", "text": "4) The choice for {1, . . . , 2p + n} as the underlying ordered set is not essential. It is useful to think of \u03a8(V, f ) in terms of an arbitrary underlying finite ordered set X, where V \u2208 P 2 (A), A \u2282 X, f : X \\ A \u2192 K. For example we can consider the set X = {0} and f (0) = h, then \u03a8(\u2205, f ) = \u03c9 t (h). The relation between M (V, f ) and \u03a8(V, f ) is similar to the one between moments and cumulants.", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 4.3 Let \u03a8(V, f ), M (V, f ) be as in Definition 4.2. The equations (4.6) can be inverted into:", "text": "Proof. Direct application of the definition.", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 4.3 Let \u03a8(V, f ), M (V, f ) be as in Definition 4.2. The equations (4.6) can be inverted into:", "text": "Let X be an ordered set. Let {P, F } be a partition of X into disjoint sets and consider a pair (V \u2208 P 2 (P ), f : F \u2192 K). Then for X * as underlying set we define the pair (V * , f * ) where V * \u2208 P 2 (X * ) contains the same pairs as V but with the reversed order and f * = f . For two ordered sets X and Y we define their concatenation X +Y as the disjoint union with the original order on X and Y and with x < y for any x \u2208 X, y \u2208 Y . If f X : X \u2192 K and f Y : Y \u2192 K then we denote by f X \u2295f Y the function on X +Y which restricts to f X and f Y on X respectively Y . Finally if |X| = |Y | = m we identify the subset of P 2 (X + Y ):", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 4.4 With the above notations the following relation holds:", "text": "with the convention \u03b7 f * 1 \u2295f2 (V) = 1 for", "cite_spans": [], "ref_spans": []}, {"section": "Proof. From Definitions 2.5, 4.2 it follows that", "text": "We apply Lemma 4.3 and obtain:", "cite_spans": [], "ref_spans": []}, {"section": "Proof. From Definitions 2.5, 4.2 it follows that", "text": "where the sum runs over all", "cite_spans": [], "ref_spans": []}, {"section": "Proof. From Definitions 2.5, 4.2 it follows that", "text": "Substituting in the last expression the result from equation (4.13) it becomes:", "cite_spans": [], "ref_spans": []}, {"section": "Proof. From Definitions 2.5, 4.2 it follows that", "text": "with the second sum running over all V \u2208 P 2 ((", "cite_spans": [], "ref_spans": []}, {"section": "Proof. From Definitions 2.5, 4.2 it follows that", "text": "). We make the notation\u1e7c := V \u2032 * 1 \u222a V \u2032 2 \u222a V and by grouping together all terms containing\u1e7c the initial expression looks like:", "cite_spans": [], "ref_spans": []}, {"section": "Proof. From Definitions 2.5, 4.2 it follows that", "text": "where the symbol m(\u1e7c) stands for total contribution from the terms of the form", "cite_spans": [], "ref_spans": []}, {"section": "Proof. From Definitions 2.5, 4.2 it follows that", "text": ". We calculate now m(\u1e7c): 16) this sum running over all V \u2208 P 2 ((", "cite_spans": [{"start": 25, "end": 28, "text": "16)", "ref_id": "BIBREF15"}], "ref_spans": []}, {"section": "Proof. From Definitions 2.5, 4.2 it follows that", "text": "Otherwise\u1e7c can be written in a unique way as", "cite_spans": [], "ref_spans": []}, {"section": "Proof. From Definitions 2.5, 4.2 it follows that", "text": "(4.17)", "cite_spans": [], "ref_spans": []}, {"section": "Proof. From Definitions 2.5, 4.2 it follows that", "text": ". Then one has the inclusions V ", "cite_spans": [], "ref_spans": []}, {"section": "Proof. From Definitions 2.5, 4.2 it follows that", "text": "(\u22121)", "cite_spans": [], "ref_spans": []}, {"section": "Proof. From Definitions 2.5, 4.2 it follows that", "text": "In conclusion", "cite_spans": [], "ref_spans": []}, {"section": "Proof. From Definitions 2.5, 4.2 it follows that", "text": "A similar result holds for algebras of creation and annihilation operators. Suppose that t is a function (not neccesarily positive definite) on pair partitions. Let P, F, V, f be as in Definition 4.2 and define in the representation space", "cite_spans": [], "ref_spans": []}, {"section": "Proof. From Definitions 2.5, 4.2 it follows that", "text": "..,p a set of normalised vectors, orthogonal to each other and to the vectors (f (k)) n k=1 .", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 4.6 Let t be a function on pair partitions. Then", "text": "Proof. The equation follows then directly from Definition 2.4.", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 4.6 Let t be a function on pair partitions. Then", "text": "Now we are ready for the main result of this section.", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 4.7 Let t be a function on pair partitions. If\u03c1 t is a Gaussian state on A(K) for any real Hilbert space K then \u03c1 t is a Fock state on C(K C ).", "text": "Proof. Suppose that \u03c1 t is not a Fock state. Then in the representation space F t (K C ) there exists a vector of the form", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 4.7 Let t be a function on pair partitions. If\u03c1 t is a Gaussian state on A(K) for any real Hilbert space K then \u03c1 t is a Fock state on C(K C ).", "text": "with all f a taking values in the real subspace K of K C and c a \u2208 C, such that \u03c8, \u03c8 < 0. But from lemmas 4.5 and 4.6 it results that m a=1 c a \u00b7 \u03a8(V a , f a )\u03a9 t 2 < 0 which is a contradiction. Thus \u03c1 t is a positive functional and t is a positive definite function on pair partitions.", "cite_spans": [], "ref_spans": []}, {"section": "Second Quantisation", "text": "This section is dedicated to the description of functorial properties of the generalised Brownian motion which go by the name of second quantisation and appear at two different levels depending on the categories with which we work. Let H, H \u2032 be Hilbert spaces and T a contraction from H to H \u2032 . Define the second quantisation of T at the Hilbert space level by", "cite_spans": [], "ref_spans": []}, {"section": "Second Quantisation", "text": "for all v \u2208 V n , h i \u2208 H when n \u2265 1, and equal to the identity on V 0 . Clearly F t (T ) is a contraction, satisfies the equation", "cite_spans": [], "ref_spans": []}, {"section": "Second Quantisation", "text": "and for T unitary it coincides with the operator defined in the equations (2.23) and (2.24).", "cite_spans": [], "ref_spans": []}, {"section": "Second Quantisation", "text": "Definition 5.1 We call F t the functor of second quantisation at the Hilbert space level .", "cite_spans": [], "ref_spans": []}, {"section": "Second Quantisation", "text": "There is however a more interesting notion of second quantisation.", "cite_spans": [], "ref_spans": []}, {"section": "Second Quantisation", "text": "Definition 5.2 [14] i) The category of non-commutative probability spaces has as objects pairs (A, \u03c1 A ) of von Neumann algebras and normal states and as morphisms between two objects (A, \u03c1 A ) and (B, \u03c1 B ) all completely positive maps", "cite_spans": [{"start": 15, "end": 19, "text": "[14]", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "Second Quantisation", "text": "ii) A functor \u0393 from the category of (real) Hilbert spaces with contractions to the category of non-commutative probability spaces such that \u0393({0}) = C where {0} stands for the zero dimensional Hilbert space is called functor of white noise.", "cite_spans": [], "ref_spans": []}, {"section": "Second Quantisation", "text": "From Lemmas 4.3 and 4.4 we know that the generalised Wick products \u03a8(V, f ) acting on F t (K) form a * -algebra of operators which contains \u03c0 t (A(K)) and will be denoted by\u0393 t (K). In general this is not an algebra of bounded operators. However in a standard manner we construct the von Neumann algebra \u0393 t (K) generated by all the spectral projections of selfadjoint operators in\u0393 t (K). Any X \u2208\u0393 t (K) is affiliated to \u0393 t (K). The pair (\u0393 t (K), \u2126 t , \u00b7\u2126 t ) makes up a noncommutative probability space. Let us first note that Theorem 4.7 implies that the representations of\u0393 t (K) on F t (K C ) andF t (K) are unitarily equivalent, thus:", "cite_spans": [], "ref_spans": []}, {"section": "Second Quantisation", "text": "The vacuum vector \u2126 t is cyclic for the field algebra \u0393 t (K) for any real Hilbert space K.", "cite_spans": [], "ref_spans": []}, {"section": "Second Quantisation", "text": "Our task is to find for which functions t, the map K \u2192 \u0393 t (K) can be enriched with the morphisms", "cite_spans": [], "ref_spans": []}, {"section": "Second Quantisation", "text": "for all contractions T : K \u2192 K \u2032 such that \u0393 t is a functor of white noise and moreover the following continuity requirement is satisfied: for any pair of Hilbert spaces K, K \u2032 , any X \u2208 \u0393 t (K) and any sequence of contractions T n : K \u2192 K \u2032 converging weakly to T we have", "cite_spans": [], "ref_spans": []}, {"section": "Second Quantisation", "text": "When this is true we call \u0393 t a functor of second quantisation at algebraic level and the completely positive map \u0393 t (T ) the second quantisation of the contraction T . The existence of the second quantisation at algebraic level turns out to be connected to a property of the functions on pair partitions.", "cite_spans": [], "ref_spans": []}, {"section": "Definition 5.4 [3]", "text": "A function t on pair partitions is called multiplicative if for all k, l, n \u2208 N with 0 \u2264 k < l \u2264 n and all V 1 \u2208 P 2 ({1, . . . , k, l + 1, . . . , n}) and V 2 \u2208 P 2 ({k + 1, . . . , l}) we have", "cite_spans": [], "ref_spans": []}, {"section": "Proposition 5.5 If \u0393 is a functor of second quantisation then \u0393(T ) is an automorphism (injective * -homomorphism) if T is a unitary (isometry), and \u0393(P ) is a conditional expectation if P is an orthogonal projection.", "text": "Proof. For separating vacuum the proof has been given in [15] . Here we do not assume this property. 1. Let O : K \u2192 K \u2032 be an orthogonal operator and X \u2208 \u0393(K). As \u0393(O * ) and \u0393(O) are completely positive we have the inequalities", "cite_spans": [{"start": 57, "end": 61, "text": "[15]", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "Proposition 5.5 If \u0393 is a functor of second quantisation then \u0393(T ) is an automorphism (injective * -homomorphism) if T is a unitary (isometry), and \u0393(P ) is a conditional expectation if P is an orthogonal projection.", "text": "which by applying the positive operator \u0393(O * ) becomes", "cite_spans": [], "ref_spans": []}, {"section": "Proposition 5.5 If \u0393 is a functor of second quantisation then \u0393(T ) is an automorphism (injective * -homomorphism) if T is a unitary (isometry), and \u0393(P ) is a conditional expectation if P is an orthogonal projection.", "text": "and by reapeating the argument for X + Y and X + iY we obtain that \u0393(O) is a * -isomorphism. 2. Let K be a real Hilbert space and I : K \u2192 K \u2295 \u2113 2 (Z) the natural isometry. Let S be the shift operator on \u2113 2 (Z). The operator O := 1 \u2295 S is orthogonal and w\u2212lim n\u2192\u221e O n = P where P is the projection on K. By the continuity assumption 5.2 we have then", "cite_spans": [], "ref_spans": []}, {"section": "Proposition 5.5 If \u0393 is a functor of second quantisation then \u0393(T ) is an automorphism (injective * -homomorphism) if T is a unitary (isometry), and \u0393(P ) is a conditional expectation if P is an orthogonal projection.", "text": ") of operators invariant under the action of the group of automor-", "cite_spans": [], "ref_spans": []}, {"section": "Proposition 5.5 If \u0393 is a functor of second quantisation then \u0393(T ) is an automorphism (injective * -homomorphism) if T is a unitary (isometry), and \u0393(P ) is a conditional expectation if P is an orthogonal projection.", "text": "We show now that \u0393(I) is an injective * -homomorphism. By a similar argument to that used in (5.4, 5.6) we have:", "cite_spans": [], "ref_spans": []}, {"section": "Proposition 5.5 If \u0393 is a functor of second quantisation then \u0393(T ) is an automorphism (injective * -homomorphism) if T is a unitary (isometry), and \u0393(P ) is a conditional expectation if P is an orthogonal projection.", "text": "for all X, Y \u2208 \u0393(K). Now for any Z \u2208 \u0393(K)", "cite_spans": [], "ref_spans": []}, {"section": "Proposition 5.5 If \u0393 is a functor of second quantisation then \u0393(T ) is an automorphism (injective * -homomorphism) if T is a unitary (isometry), and \u0393(P ) is a conditional expectation if P is an orthogonal projection.", "text": "which together with (5.9) implies", "cite_spans": [], "ref_spans": []}, {"section": "Proposition 5.5 If \u0393 is a functor of second quantisation then \u0393(T ) is an automorphism (injective * -homomorphism) if T is a unitary (isometry), and \u0393(P ) is a conditional expectation if P is an orthogonal projection.", "text": "and thus \u0393(I) is an injective * -homomorphism. 3. Let I : K \u2192 K \u2032 be an isometry. We consider the natural isometries I", "cite_spans": [], "ref_spans": []}, {"section": "Proposition 5.5 If \u0393 is a functor of second quantisation then \u0393(T ) is an automorphism (injective * -homomorphism) if T is a unitary (isometry), and \u0393(P ) is a conditional expectation if P is an orthogonal projection.", "text": "From the previous argument we know that Thus \u0393(I) is a * -homomorphism. The injectivity follows from I * I = 1 K . 4. Using the previous step of the proof we see that \u0393(P ) is a norm one projection from \u0393(K \u2032 ) onto its von Neumann subalgebra \u0393(I)(\u0393(K)). Thus \u0393(P ) is a conditional expectation [22] .", "cite_spans": [{"start": 295, "end": 299, "text": "[22]", "ref_id": "BIBREF21"}], "ref_spans": []}, {"section": "Corollary 5.6 If \u0393 is a functor of second quantisation then for any infinite dimensional real Hilbert space", "text": "Proof. We can choose K = \u2113 2 (Z). Let S be the right shift. Then S n converges weakly to 0 as n \u2192 \u221e. By the previous proposition we have that \u0393(K)", "cite_spans": [], "ref_spans": []}, {"section": "Corollary 5.6 If \u0393 is a functor of second quantisation then for any infinite dimensional real Hilbert space", "text": "Z is isomorphic with \u0393(I)({0}) where I is the trivial isometry from {0} to \u2113 2 (Z).", "cite_spans": [], "ref_spans": []}, {"section": "Corollary 5.6 If \u0393 is a functor of second quantisation then for any infinite dimensional real Hilbert space", "text": "Corollary 5.7 Let t be a positive definite function on pair partitions and suppose that the functor of second quantisation \u0393 t exists and", "cite_spans": [], "ref_spans": []}, {"section": "Corollary 5.6 If \u0393 is a functor of second quantisation then for any infinite dimensional real Hilbert space", "text": ". Then the function t is multiplicative.", "cite_spans": [], "ref_spans": []}, {"section": "Corollary 5.6 If \u0393 is a functor of second quantisation then for any infinite dimensional real Hilbert space", "text": "with the two right shifts S 1 , S 2 acting separately on the two \u2113 2 (Z). Let V 1 \u222a V 2 be a pair partition as in Definition 5.4. For any pair partition V the operator \u03a8(V, \u2205) on F t (K) commutes with F t (O) for all O \u2208 O(K) and is affiliated to \u0393 t (K). By corollary 5.6 we have", "cite_spans": [], "ref_spans": []}, {"section": "Corollary 5.6 If \u0393 is a functor of second quantisation then for any infinite dimensional real Hilbert space", "text": "(5.14)", "cite_spans": [], "ref_spans": []}, {"section": "Corollary 5.6 If \u0393 is a functor of second quantisation then for any infinite dimensional real Hilbert space", "text": "We consider the monomial of fields M (V 1 \u222a V 2 ) containing |V 1 | + |V 2 | pairs of different colours arranged according to the pair partition V 1 \u222a V 2 and such that the colours for the pairs in V 1 belong to the first \u2113 2 (Z) in K, and those for the pairs in V 2 belong to the second term. Then", "cite_spans": [], "ref_spans": []}, {"section": "Corollary 5.6 If \u0393 is a functor of second quantisation then for any infinite dimensional real Hilbert space", "text": "(5.15)", "cite_spans": [], "ref_spans": []}, {"section": "Corollary 5.6 If \u0393 is a functor of second quantisation then for any infinite dimensional real Hilbert space", "text": "Lemma 5.8 Let \u03c8(V, f ) as defined in equation (4.20) . Then", "cite_spans": [], "ref_spans": []}, {"section": "Corollary 5.6 If \u0393 is a functor of second quantisation then for any infinite dimensional real Hilbert space", "text": "Proof. We use the representation \u03c7 t of the * -semigroup of broken pair partitions BP 2 (\u221e) with respect to the statet (see equation 3.7). Let {F, P } be a partition of {1, . . . , 2p + n} and V \u2208 P 2 (P ), f : F \u2192 H. Then using (4.20) and the equations (2.13, 2.14) we obtain", "cite_spans": [], "ref_spans": []}, {"section": "Corollary 5.6 If \u0393 is a functor of second quantisation then for any infinite dimensional real Hilbert space", "text": "for\u1e7c \u2208 BP n,0 2 the diagram with the set of pairs V and n legs to the left which do not intersect each other.", "cite_spans": [], "ref_spans": []}, {"section": "Corollary 5.6 If \u0393 is a functor of second quantisation then for any infinite dimensional real Hilbert space", "text": "Lemma 5.9 Let P : K \u2192 K \u2032 be a coisometry i.e. P P * = 1 K \u2032 and t a positive definite function on pair partitions. Then the map\u0393 t (P )", "cite_spans": [], "ref_spans": []}, {"section": "Corollary 5.6 If \u0393 is a functor of second quantisation then for any infinite dimensional real Hilbert space", "text": "is well defined.", "cite_spans": [], "ref_spans": []}, {"section": "Corollary 5.6 If \u0393 is a functor of second quantisation then for any infinite dimensional real Hilbert space", "text": "Proof. It is enough to show that", "cite_spans": [], "ref_spans": []}, {"section": "Corollary 5.6 If \u0393 is a functor of second quantisation then for any infinite dimensional real Hilbert space", "text": "For this we prove the equality of the matrix elements", "cite_spans": [], "ref_spans": []}, {"section": "Corollary 5.6 If \u0393 is a functor of second quantisation then for any infinite dimensional real Hilbert space", "text": "From Lemma 5.9 we deduce that if P : K \u2192 K \u2032 is a coisometry then \u0393 t (P )(\u00b7) := F t (P ) \u00b7 F t (P * ) is well defined from \u0393 t (K) to \u0393 t (K \u2032 ) and completely positive. ", "cite_spans": [], "ref_spans": []}, {"section": "Corollary 5.6 If \u0393 is a functor of second quantisation then for any infinite dimensional real Hilbert space", "text": "Proof. The contraction T can be written as T = P I where I : K 1 \u2192 K \u2032 is an isometry and P : K \u2032 \u2192 K 2 is a coisometry. The faithfulness of the vacuum and the fact that the isometry F t (I) has the action", "cite_spans": [], "ref_spans": []}, {"section": "Corollary 5.6 If \u0393 is a functor of second quantisation then for any infinite dimensional real Hilbert space", "text": "is an injective * -homomorphism from\u0393 t (K 1 ) to\u0393 t (K \u2032 ). On the level of von Neumann algebras we obtain the homomorphism (and thus completely positive map) \u0393 t (I) from \u0393 t (K 1 ) to \u0393 t (K 2 ). By Lemma 5.9, \u0393 t (P ) is a conditional expectation and \u0393 t (I)\u0393 t (P ) depends only on T = P I:", "cite_spans": [], "ref_spans": []}, {"section": "Corollary 5.6 If \u0393 is a functor of second quantisation then for any infinite dimensional real Hilbert space", "text": "(5.24)", "cite_spans": [], "ref_spans": []}, {"section": "Corollary 5.6 If \u0393 is a functor of second quantisation then for any infinite dimensional real Hilbert space", "text": "5.1 A second definition for the functor of second quantisation Theorem 5.10 points out that a separating vacuum insures the existence of the injective * -homomorphism \u0393 t (I) and thus of the functor of second quatisation \u0393 t . We will show here that this condition can be removed if one uses a different definition for the \"field algebra\" \u0393 t (K). Let K be a real Hilbert space and define the von Neumann algebra", "cite_spans": [], "ref_spans": []}, {"section": "Corollary 5.6 If \u0393 is a functor of second quantisation then for any infinite dimensional real Hilbert space", "text": "Similarly to \u0393 t (K), this von Neumann algebra is generated by the spectral projections of the selfadjoint operators in the * -algebr\u00e3 \u2206 t (K) of generalised Wick products \u03a8(V, f ) with Im(f ) \u2282 K. The subrepresentation of \u2206 t (K) for which \u2126 t is cyclic, is unitarily equivalent to \u0393 t (K). ", "cite_spans": [], "ref_spans": []}, {"section": "The corresponding map\u2206 t (I) acts as follows", "text": "where Im(f ) \u2282 K.", "cite_spans": [], "ref_spans": []}, {"section": "The corresponding map\u2206 t (I) acts as follows", "text": "Proof. We have", "cite_spans": [], "ref_spans": []}, {"section": "The corresponding map\u2206 t (I) acts as follows", "text": "Then we have the injective * -homomorphism:", "cite_spans": [], "ref_spans": []}, {"section": "The corresponding map\u2206 t (I) acts as follows", "text": "Thus we have shown the existence of the injective * -homomorphism \u2206 t (I). This does not depend on the choice of O K . The action on\u2206 t (K) is obvious. Now let P : K \u2192 K \u2032 be a coisometry. We define the second quantisation of P (for the functor \u2206 t ) in a similar manner to \u0393 t (P ) (see 5.18) by the completely positive map:", "cite_spans": [], "ref_spans": []}, {"section": "The corresponding map\u2206 t (I) acts as follows", "text": "According to Lemma 5.9, on the * -algebra\u2206 t (K) we have:", "cite_spans": [], "ref_spans": []}, {"section": "The corresponding map\u2206 t (I) acts as follows", "text": "Finally let T be an arbitrary contraction. Independent of the choice of the decomposition T = P I we hav\u1ebd", "cite_spans": [], "ref_spans": []}, {"section": "The corresponding map\u2206 t (I) acts as follows", "text": "which is implemented by a compression of the type F t (P \u2032 ) \u00b7 F t (P \u2032 * ) where ", "cite_spans": [], "ref_spans": []}, {"section": "An Example", "text": "In [3] and [10] it has been proved that for all 0 \u2264 q \u2264 1, the following function on pair partitions is positive definite:", "cite_spans": [{"start": 3, "end": 6, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 11, "end": 15, "text": "[10]", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "An Example", "text": "where |B(V)| is the number of blocks of the pair partition V. A block is a subpartition whose graphical representation is connected and does not intersect other pairs from the rest of the partition. The corresponding vacuum state \u03c1 tq (\u00b7) = \u2126 tq , \u00b7\u2126 tq is tracial for any von Neumann algebra \u0393 tq (K) associated to a real Hilbert space K. Indeed for any pair partition V we have t q (V) = \u2126 tq , M V \u2126 tq with M V a monomial of fields containing |V| pairs of different colours arranged according to the pair partition V. The trace property for the vacuum is equivalent with the invariance under circular permutations of the fields in the monomial M V which is equivalent to the invariance of t q under transformations described as follows:", "cite_spans": [], "ref_spans": []}, {"section": "An Example", "text": "Under such transformations the number of blocks remains unchanged thus t q (V) is equal to t q (\u1e7c) and \u03c1 tq is tracial. Thus the assumption of Theorem 5.10 is satisfied and we have second quantisation at algebraic level. Next, we want to investigate the type of the von Neumann algebras \u0393 tq (K) for dim K = \u221e. Inspired by [2] , we will find a sufficient condition for \u0393 t (K) to be a type II 1 factor, and we will apply it to t q . Let t be a multiplicative positive definite function such that \u03c1 t is trace state on \u0393 t (K) for K infinite dimensional. Let I be the natural isometry from K to K \u2295 R, and e 0 a unit vector in the orthogonal complement of its image. The function t being multiplicative implies that the map \u03c6 : F t (K) \u2192 F t (K \u2295 R) (6.4) defined by \u03c6 = \u03c9 t (e 0 )F t (I) is an isometry.", "cite_spans": [{"start": 323, "end": 326, "text": "[2]", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "An Example", "text": "Definition 6.1 Let (P, L, R) be a disjoint partition of the ordered set {1, . . . , 2n + l + r} and d = (V, f l , f r ) an element of the * \u2212semigroup of broken pair partitions with V \u2208 P 2 (P ), f l : L \u2192 {1, . . . l} the left legs and f r : R \u2192 {1, . . . r} the right legs. We denote by d := (V, f l , f r ) the element obtained by adding to V one pair which embraces all other pairs V := V \u222a {(0, 2n + l + r + 1)} \u2208 P 2 ({0} \u222a P \u222a {2n + l + r + 1}).", "cite_spans": [], "ref_spans": []}, {"section": "An Example", "text": "(6.5)", "cite_spans": [], "ref_spans": []}, {"section": "An Example", "text": "Then the map\u03a6(\u00b7) := \u03c6 * \u0393 t (I)(\u00b7)\u03c6 has the following action on\u0393 t (K):", "cite_spans": [], "ref_spans": []}, {"section": "An Example", "text": "\u03a6(\u03a8(V, f )) = \u03a8(V, f ) (6.6) which on the level of von Neumann algebras gives the completely positive contraction \u03a6(\u00b7) := \u03c6 * \u0393 t (I)(\u00b7)\u03c6 from \u0393 t (K) to itself. We fix an orthonormal basis (e n ) \u221e n=1 in K. Then by direct computation one can check that: \u03a6(X) = w\u2212lim n\u2192\u221e \u03c9 t (e n )X\u03c9 t (e n ).", "cite_spans": [], "ref_spans": []}, {"section": "An Example", "text": "(6.7)", "cite_spans": [], "ref_spans": []}, {"section": "An Example", "text": "Let now \u03c4 be a tracial normal state on \u0393 t (K). Then using the fact that w\u2212lim n\u2192\u221e \u03c9 t (e n ) 2 = 1 we get:", "cite_spans": [], "ref_spans": []}, {"section": "An Example", "text": "\u03c4 (\u03a6(X)) = lim n\u2192\u221e \u03c4 (\u03c9 t (e n )X\u03c9 t (e n )) = lim n\u2192\u221e \u03c4 (\u03c9 t (e n ) 2 X) = \u03c4 (X). for all X \u2208 \u0393 t (K) which by the faithfulness of the vacuum state is equivalent to lim k\u2192\u221e \u03a6 k (X)\u2126 t = \u03c1 t (X)\u2126 t . Then by equation (6.8) we conclude that \u03c1 t is the only trace state on \u0393 t (K) which is thus a type II 1 factor. Let us take a closer look at the contraction \u0398 : X\u2126 t \u2192 \u03a6(X)\u2126 t .", "cite_spans": [], "ref_spans": []}, {"section": "An Example", "text": "(6.10)", "cite_spans": [], "ref_spans": []}, {"section": "An Example", "text": "From equation (6.6) the operator \u0398 commutes with the orthogonal projectors on the spaces with definite \"occupation numbers\" F t (n 1 , . . . , n k ) (see 2.31). Thus be two diagrams with n left legs and no right legs. Then", "cite_spans": [], "ref_spans": []}, {"section": "An Example", "text": "(6.14)", "cite_spans": [], "ref_spans": []}, {"section": "An Example", "text": "But if \u03c1 t is a trace thent", "cite_spans": [], "ref_spans": []}, {"section": "An Example", "text": "which implies that", "cite_spans": [], "ref_spans": []}, {"section": "An Example", "text": "Thus \u03b8 is a selfadjoint contraction. be two diagrams with n \u2265 1 left legs and no right legs. Then", "cite_spans": [], "ref_spans": []}, {"section": "An Example", "text": "( 6.18) where we have used the selfadjointness of \u03b8 in the first step and", "cite_spans": [], "ref_spans": []}, {"section": "An Example", "text": "in the second equality. Thus the restriction of \u03b8 to V \u2296 C\u03be has norm q < 1 and we can apply Theorem 6.3.", "cite_spans": [], "ref_spans": []}, {"section": "An Example", "text": "Remark. If \u03c1 t is a faithful, multiplicative but non-tracial state for \u0393 t (K) then the operators \u03c6, \u03a6, \u0398, \u03b8 can still be defined in the same way. If moreover, \u03be is the only eigenvector with eigenvalue 1 of the operator \u03b8, then by a similar argument it can be shown that the algebra \u0393 t (K) is a factor. Indeed if X is an element in the center of \u0393 t (K) then \u03a6(X) = w\u2212lim k\u2192\u221e \u03c9 t (e n ) 2 X = X. which contradicts the assumption on \u03b8. The factor must be infinite; otherwise by a limit argument it would result that \u03c1 t is tracial. Examples of such positive definite multplicative functions on pair partitions will be given in a forthcoming paper [11] . ", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Combinatorial Species and Tree-like Structures", "authors": [{"first": "F", "middle": [], "last": "Bergeron", "suffix": ""}, {"first": "G", "middle": [], "last": "Labelle", "suffix": ""}, {"first": "P", "middle": [], "last": "Leroux", "suffix": ""}], "year": 1998, "venue": "", "link": "117739580"}, "BIBREF1": {"title": "Speicher, R: q-Gaussian Processes: Noncommutative and Classical Aspects", "authors": [{"first": "M", "middle": [], "last": "Bo\u017cejko", "suffix": ""}, {"first": "B", "middle": [], "last": "K\u00fcmmerer", "suffix": ""}], "year": 1997, "venue": "", "link": null}, "BIBREF2": {"title": "Interpolations Between Bosonic and Fermionic Relations given by Generalized Brownian Motion", "authors": [{"first": "M", "middle": [], "last": "Bo\u017cejko", "suffix": ""}, {"first": "R", "middle": [], "last": "Speicher", "suffix": ""}], "year": 1996, "venue": "Math. Z", "link": "186226377"}, "BIBREF3": {"title": "An Example of a Generalized Brownian Motion", "authors": [{"first": "M", "middle": [], "last": "Bo\u017cejko", "suffix": ""}, {"first": "R", "middle": [], "last": "Speicher", "suffix": ""}], "year": 1991, "venue": "Comm. Math. Phys", "link": "123190397"}, "BIBREF4": {"title": "An Example of a Generalized Brownian Motion I, in Accardi", "authors": [{"first": "M", "middle": [], "last": "Bo\u017cejko", "suffix": ""}, {"first": "R", "middle": [], "last": "Speicher", "suffix": ""}], "year": 1992, "venue": "", "link": null}, "BIBREF5": {"title": "Interpolation Between Fermi and Bose Statistics using Generalized Commutators", "authors": [{"first": "D", "middle": [], "last": "Fivel", "suffix": ""}], "year": 1990, "venue": "Phys. Rev. Lett", "link": "24586937"}, "BIBREF7": {"title": "Particles with Small Violations of Fermi or Bose Statistics", "authors": [{"first": "O", "middle": ["W"], "last": "Greenberg", "suffix": ""}], "year": 1991, "venue": "Phys. Rev. D", "link": "33587120"}, "BIBREF8": {"title": "A Generalized Method of Field Quantisation", "authors": [{"first": "H", "middle": ["S"], "last": "Green", "suffix": ""}], "year": 1953, "venue": "Phys. Rev", "link": null}, "BIBREF9": {"title": "Symmetric Hilbert Spaces arising from Species of Structures", "authors": [{"first": "M", "middle": [], "last": "Gu\u0163\u0203", "suffix": ""}, {"first": "H", "middle": [], "last": "Maassen", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF11": {"title": "Une Th\u00e9orie Combinatoire des S\u00e9ries Formelles", "authors": [{"first": "A", "middle": [], "last": "Joyal", "suffix": ""}], "year": 1981, "venue": "Adv. Math", "link": "121273355"}, "BIBREF12": {"title": "Foncteurs Analytiques et Especes de Structures, in \"Combinatoire enumerative", "authors": [{"first": "A", "middle": [], "last": "Joyal", "suffix": ""}], "year": 1986, "venue": "Proc. Colloq., Montreal/Can. 1985", "link": null}, "BIBREF13": {"title": "Infinite dimensional harmonic analysis", "authors": [{"first": "B", "middle": [], "last": "K\u00fcmmerer", "suffix": ""}], "year": 1996, "venue": "Quantum White Noise", "link": null}, "BIBREF14": {"title": "Survey on a Theory of Non-commutative Markov Processes", "authors": [{"first": "B", "middle": [], "last": "K\u00fcmmerer", "suffix": ""}], "year": 1988, "venue": "", "link": null}, "BIBREF15": {"title": "A q-deformation of the Gaussian Distribution", "authors": [{"first": "H", "middle": [], "last": "Maassen", "suffix": ""}, {"first": "H", "middle": [], "last": "Van Leeuwen", "suffix": ""}], "year": 1995, "venue": "J. Math. Phys", "link": null}, "BIBREF16": {"title": "Methods of Modern Mathematical Physics I", "authors": [{"first": "M", "middle": [], "last": "Reed", "suffix": ""}, {"first": "B", "middle": [], "last": "Simon", "suffix": ""}], "year": 1972, "venue": "", "link": "115957504"}, "BIBREF17": {"title": "The P (\u03a6) 2 Quantum Euclidian Field Theory", "authors": [{"first": "B", "middle": [], "last": "Simon", "suffix": ""}], "year": 1974, "venue": "", "link": null}, "BIBREF18": {"title": "Generalized Statistics of Macroscopic Fields", "authors": [{"first": "R", "middle": [], "last": "Speicher", "suffix": ""}], "year": 1993, "venue": "Lett. Math. Phys", "link": "120654349"}, "BIBREF19": {"title": "Free Probability theory", "authors": [{"first": "R", "middle": [], "last": "Speicher", "suffix": ""}], "year": 1997, "venue": "Fields Institute Communications", "link": "3018645"}, "BIBREF20": {"title": "PCT, Spin and Statistics, and all that", "authors": [{"first": "R", "middle": ["F"], "last": "Streater", "suffix": ""}, {"first": "A", "middle": ["S"], "last": "Wightman", "suffix": ""}], "year": 1964, "venue": "", "link": "63949752"}, "BIBREF21": {"title": "Theory of Operator Algebras I", "authors": [{"first": "M", "middle": [], "last": "Takesaki", "suffix": ""}], "year": 1979, "venue": "", "link": "195895026"}, "BIBREF22": {"title": "Free Random Variables", "authors": [{"first": "D", "middle": [], "last": "Voiculescu", "suffix": ""}, {"first": "K", "middle": [], "last": "Dykema", "suffix": ""}, {"first": "A", "middle": [], "last": "Nica", "suffix": ""}], "year": 1992, "venue": "", "link": "125816404"}, "BIBREF23": {"title": "Realizability of a Model in Infinite Statistics", "authors": [{"first": "D", "middle": [], "last": "Zagier", "suffix": ""}], "year": 1992, "venue": "Comm. Math. Phys", "link": "53385666"}}, "ref_entries": {"FIGREF0": {"text": "Let {P, F } be a partition of the ordered set {1, . . . , 2p+n} with |P | = 2p and |F | = n. Let V = {(l 1 ,", "type": "figure"}, "FIGREF1": {"text": "The right side of the last equation needs some clarifications. All operators appearing in (4.6) are defined on the domain D. The operator M (V, f ) is defined on D by its matrix elements. If \u03c8 i = mi a=1 \u03c9 t (g (i) a )\u03a9 t for i = 1, 2 are vectors in D then from the definition of the Gaussian state", "type": "figure"}, "FIGREF2": {"text": "i = 1, 2 are orthogonal to each other. The limit does not depend on the choice of the vectors (e i ) i\u2208N (as long as they are normal and orthogonal to each other) but depends only on their positions in the monomial which are determined by the pair partition V. Thus M (V, f ) is well defined. 2) If the vectors (f (k)) n k=1 are orthogonal on each other then \u03b7 f", "type": "figure"}, "FIGREF4": {"text": "\u2282\u1e7c i for i = 1, 2 and V c \u2282 V. The calculation of m(\u1e7c) reduces then to", "type": "figure"}, "FIGREF6": {"text": "10 Let t be a positive definite function on pair partitions such that the vacuum \u2126 t \u2208 F t (K) is separating vector for the von Neumann algebra \u0393 t (K) for any real Hilbert space K. Let T : K 1 \u2192 K 2 be a contraction between real Hilbert spaces. Then the second quantisation of T is the completely positive map", "type": "figure"}, "FIGREF8": {"text": ": v \u2297 s e(n) \u2192 \u03b8(v) \u2297 s e(n) (6.11) where e(n) := e 1 \u2297 . . . \u2297 e 1 n1times \u2297 . . . \u2297 e k \u2297 . . .\u2208 V n and \u03b8 : V \u2192 V is the linear operator defined by \u03b8 : \u03c7 t (d)\u03be \u2192 \u03c7 t (d)\u03be, (d \u2208 BP 2 (\u221e)). (6.13) Lemma 6.2 Let t be a multiplicative positive definite function such that \u03c1 t is trace. Then the operator \u03b8 : V \u2192 V defined by 6.13 is a selfadjoint contraction. Proof. Let d 1 , d", "type": "figure"}, "FIGREF9": {"text": "Figure 1: Diagram corresponding to an element of the semigroup", "type": "figure"}, "TABREF1": {"text": "Fock state, i.e. there exists a positive definite function t on pair partitions depending on", "type": "table"}, "TABREF2": {"text": "Lemma 5.11 Let K, K \u2032 be real Hilbert spaces and I : K \u2192 K \u2032 an isometry. Then there exists an injective * -homomorphism \u2206 t", "type": "table"}, "TABREF3": {"text": "This leads us to the result of this subsection: Theorem 5.12 If t is positive definite and multiplicative then \u2206 t is a functor of second quantisation.", "type": "table"}, "TABREF4": {"text": "Theorem 6.3 If \u03be is the only eigenvector of \u03b8 with eigenvalue 1 then \u0393 t (K) is a II 1 factor for any infinite dimensional real Hilbert space K. Proof. The operator \u03b8 is a selfadjoint contraction, thus w\u2212limwhere P \u03be is the projection on the subspace C\u03be. This implies 6.9 and thus \u0393 t (K) is a II 1 factor . Corollary 6.4 Let K be an infinite dimensional real Hilbert space and t the function given by 6.1 with 0 \u2264 q < 1. Then the von Neumann algebra \u0393 t (K) is a type II 1 factor. Proof. Let d 1 , d 2 \u2208 BP", "type": "table"}}}
{"paper_id": "17784659", "_pdf_hash": "eab613d41820c3b3c5efc817187347b45b51407b", "abstract": [{"section": "Abstract", "text": "We propose a new method for calculating optical defect levels and thermodynamic chargetransition levels of point defects in semiconductors, which includes quasiparticle corrections to the Kohn-Sham eigenvalues of density-functional theory. Its applicability is demonstrated for anion vacancies at the (110) surfaces of III-V semiconductors. We find the (+/0) charge-transition level to be 0.49 eV above the surface valence-band maximum for GaAs(110) and 0.82 eV for InP(110). The results show a clear improvement over the local-density approximation and agree closely with an experimental analysis.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "", "text": "The electrical and optical properties of semiconductors depend sensitively on the electronic structure in the gap region and can hence be modified dramatically by the presence of native defects and impurities that introduce unwanted additional states inside the fundamental band gap. Most importantly, such electrically active defects can trap charge carriers (electrons or holes), counteracting the effect of intentional doping. If their concentration is sufficiently high, this process can lead to a full compensation of implanted acceptors and donors and thus eventually to Fermi-level pinning. Besides, electron-hole recombination at deep defects drastically reduces the lifetime of minority carriers, and transitions involving defect states inside the band gap may dominate optical absorption. This is especially relevant at surfaces and interfaces, where the crystal termination and the contact with other phases naturally give rise to a high number of structural defects that have been linked to the formation of Schottky barriers [1] . The central quantities are the optical defect levels inside the band gap and the charge-transition levels. The former can, in principle, be probed by direct (filled states) or inverse (empty states) photoemission. The Franck-Condon principle is well justified, as the rearrangement of the atoms happens on a much slower time scale than the electron emission or absorption, but the coupling to the atomic lattice may be visible in the line widths and shapes. The optical defect levels contain the full electronic relaxation in response to the created hole or the injected electron, however. The charge-transition levels, on the other hand, are thermodynamic quantities and specify the values of the Fermi energy where the charge state of the defect changes. Therefore, they are affected noticeably by the atomic relaxation taking place upon the addition or removal of an electron.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Despite considerable efforts, a reliable determination of the optical defect levels and the related charge-transition levels of deep defects still poses a very difficult challenge. Experimental investigations are thwarted by the fact that many traditional spectroscopic techniques are not applicable due to the low concentration of native point defects, while capacitance methods like deep-level transient spectroscopy [2] are very sensitive but provide no elemental or structural information to identify the type of defect. For surfaces, at least, Ebert et al. [3] now demonstrated how the electronic structure of individual defects can be deduced using a combination of scanning tunneling microscopy (STM) and photoelectron spectroscopy, providing the first reliable experimental analysis of a chargetransition level for the P vacancy at InP(110). Theoretical approaches, on the other hand, must include accurate exchange-correlation contributions, the coupling between electronic and lattice degrees of freedom, and, in general, require the treatment of open systems in which the number of particles is not constant [4] . Previous studies that employed density-functional theory (DFT) in the localdensity approximation (LDA) [5] indeed suffered from fundamental limitations [3, 6, 7, 8] . For example, Ebert et al. [3] noted \"that the systematic error for the calculated energies of the charge transfer levels is too large to identify the symmetry of the vacancy on the position of the defect level only.\" In order to overcome this problem we here propose a new computational approach, broadly applicable to defects in the bulk as well as at surfaces, that combines DFT with many-body perturbation theory. As an example, we examine the optical defect levels and the thermodynamic charge-transition levels of anion vacancies at GaAs(110) and InP(110). The results are in close agreement with the experimental analysis [3] .", "cite_spans": [{"start": 1119, "end": 1122, "text": "[4]", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "", "text": "The geometry of anion vacancies at the (110) surfaces of III-V semiconductors is now well understood thanks to a combination of experimental and theoretical studies. For p-doped materials STM images of the filled states under negative bias feature a localized hole at the position of the missing anion surrounded by a voltage-dependent depression [9] . The latter is due to a downward local band bending, indicating a positive charge of the va-cancy. The charge state is, in fact, established as +1 [10] , which is also predicted by electronic-structure calculations [3, 6, 7, 8] . STM images acquired under positive bias probe the empty p z -like orbitals of the cation sublattice and show an enhancement of the cations surrounding the vacancy, initially wrongly interpreted as an upward relaxation of those atoms [9] but now understood as arising from the local depression of the electron density. DFT-LDA calculations actually show that an inward relaxation of the two Ga atoms enclosing the As vacancy V + As at GaAs (110) is consistent with the observations [6, 7] . The symmetry of the positively charged anion vacancies was initially a matter of controversy [6, 7] . In STM images they appear symmetric, but in a combined experimental and theoretical study of V + P at InP(110) Ebert et al. [3] explained the observed features as resulting from the thermal flip motion between two degenerate asymmetric configurations. This interpretation later received further confirmation [11] . In n-doped materials, on the other hand, the vacancy is in a charge state of \u22121 [12] , and DFT-LDA calculations predict a symmetric relaxation for this configuration as well as the neutral vacancy [6, 7] .", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "The anion vacancies at GaAs(110) or InP(110) give rise to three nondegenerate electronic states, labeled 1a \u2032 , 1a", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "\u2032\u2032 , and 2a \u2032 . While the 1a \u2032 state is located several eV below the valence-band maximum and always filled with two electrons, and the 2a \u2032 state is too high in energy to become populated, the 1a \u2032\u2032 state lies inside the band gap. It is this state, therefore, that is relevant for the discussion of charge-transition levels. Depending on the level of doping it may be occupied by zero, one, or two electrons, which corresponds to the positive, neutral, and negative charge state, respectively.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "The formation energy of a surface vacancy with charge state q, relative to that of the neutral defect, is given by", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "where E vac (q, Q) denotes the total energy of a surface featuring a single vacancy with the actual electron population q \u2208 {+, 0, \u2212} and geometry optimized for charge state Q \u2208 {Q + , Q 0 , Q \u2212 }. The final term accounts for the transfer of the charge q between the defect level and the electron reservoir, i.e., the Fermi energy \u01eb F . The charge-transition levels \u01eb q/q \u2032 are defined as the values of \u01eb F where the charge state of the vacancy changes, i.e., where E form (q/0) = E form (q \u2032 /0), and conventionally given relative to the surface valence-band maximum. For the systems considered here the interesting transitions are \u01eb +/0 and \u01eb 0/\u2212 . For example, the former is", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "All previous DFT-LDA calculations for surface point defects evaluated this energy difference directly [3, 6, 7, 8] , but this approach leads to systematic errors that arise because the total energies E vac (0, Q 0 ) and E vac (+, Q + ) refer to systems with different electron numbers. As is well known, the exact exchange-correlation potential in DFT exhibits a discontinuity upon addition or removal of an electron [13] , which is not contained in the LDA or other jellium-based functionals. Besides, aspects like the self-interaction are treated inappropriately. As a consequence, the band gaps of semiconductors and the energies of localized defect states are not given correctly: for the P vacancy at InP(110) the experimentally determined \u01eb +/0 level of 0.75\u00b10.1 eV [3] contrasts noticeably with the calculated values 0.52 eV [3] and 0.388 eV [8] .", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "The variation between the two theoretical results can be traced to differences in the pseudopotentials and parallels the variation of the corresponding band gaps.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "To arrive at a more accurate quantitative method that corrects the above-mentioned severe shortcomings of the LDA we rewrite Eq. (2) as", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "by adding and subtracting the total energy E vac (+, Q 0 ) of a system with the geometry of the relaxed neutral vacancy but a charge state q = +1. In this way the chargetransition level is decomposed into two separate contributions. The first describes the structural relaxation energy for the positive charge state and two different geometries: that of the neutral and that of the positive charge state. It is always positive. As the electron number remains constant, the problem of the discontinuity does not arise, and DFT-LDA is perfectly applicable. The second term equals the ionization energy of the neutral defect, where the removed electron is transfered to the reservoir, i.e., the Fermi energy. Determining the ionization potential from the quasiparticle band structure requires a correction of the Kohn-Sham eigenvalues, for which we employ many-body perturbation theory. Specifically, we use the G 0 W 0 approximation for the electronic self-energy [14] . This approach is known to yield reliable band gaps for III-V semiconductors [15] and their surfaces [16] .", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "In the same spirit, \u01eb 0/\u2212 can be written as", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "The first term in this case describes the energy difference of the vacancy with q = \u22121 between its own equilibrium geometry and that of the neutral charge state. It is always negative. The second term equals the electron affinity of the neutral charge state. In principle, the self-energy of the neutral charge state yields both the ionization potential and the electron affinity, which correspond to the energy of the highest occupied and the lowest unoccupied quasiparticle state, respectively. From a computational point of view, however, this procedure is inconvenient, because the neutral defect has an odd number of electrons and requires a spin-polarized calculation. Instead, we follow an equivalent approach and extract the energy levels from two separate calculations for nonspin-polarized systems with an even number of electrons. In practice, we thus determine E vac (0, Q 0 ) \u2212 E vac (+, Q 0 ) as the electron affinity of the positive charge state and E vac (\u2212, Q 0 ) \u2212 E vac (0, Q 0 ) as the ionization potential of the negative charge state, both in the Q 0 geometry.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "In the following we apply the expressions derived above to anion vacancies at the (110) surfaces of GaAs and InP. To determine the defect geometries we use DFT together with norm-conserving pseudopotentials [17] and the LDA exchange-correlation functional [18] . The surfaces are simulated using a supercell with a (2\u00d74) periodicity in the [001] and [110] directions, consisting of six atomic layers separated by a vacuum buffer equivalent to four layers. A single vacancy is created at one side of the slab, while the dangling bonds at the other are passivated by pseudoatoms with noninteger nuclear charges of 0.75 and 1.25 for anion and cation termination, respectively. This mimics the continuation of the substrate by a III-V bulk layer. We use the theoretical lattice constants 5.55\u00c5 for GaAs and 5.81\u00c5 for InP to prevent errors resulting from a nonequilibrium unit-cell volume during the surface relaxation. The integration in reciprocal space is carried out with a mesh corresponding to eight k-points in the two-dimensional Brillouin zone of the (1\u00d71) unit cell of the defect-free surface. In the case of charged defects we apply a uniform compensating background in order to ensure overall charge neutrality. For GaAs we thus obtain the relaxation energies E vac (+, Before presenting our quasiparticle results, we first calculate the charge-transition levels strictly within the LDA by invoking the Slater-Janak transition-state approach [19] , where the ionization potential and the electron affinity equal the eigenvalue of the 1a \u2032\u2032 level determined self-consistently with the noninteger occupancy 0.5 and 1.5, respectively. The transition state corrects, at least partially, the erroneous self-interaction of the LDA but not the discontinuity problem. The resulting energy contributions are displayed in Fig. 1 relative to the surface valence-band maximum. The occurrence of slightly negative values in some cases implies that the defect level actually falls below the valence-band maximum. This is an artefact of the constrained nonequilibrium geometry: if the atomic structure is allowed to relax, then the defect level always lies inside the band gap. For all systems studied here we find that the transition-state approach yields the same results, with a deviation of less than 0.01 eV, as a straightforward evaluation of Eq. (110) as a function of the occupation number. The geometry is identical in all calculations for the same material and optimized for the neutral charge state. The Slater-Janak transition-state approach (filled circles) yields the ionization potentials and electron affinities in the LDA. More accurate results are obtained by calculating the quasiparticle corrections within the G0W0 approximation (filled squares). In either case the energy zero is set to the respective surface valence-band maximum. experimentally derived charge-transition level as earlier studies at this level of approximation [3, 8] .", "cite_spans": [], "ref_spans": [{"start": 1819, "end": 1825, "text": "Fig. 1", "ref_id": "FIGREF1"}]}, {"section": "", "text": "In order to determine the electronic contribution to the charge-transition levels more accurately we employ many-body perturbation theory. The energies derived within this framework correspond directly to the values measured in direct or inverse photoemission. We follow the usual approach to calculate the quasiparticle energies", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "as a first-order correction of the Kohn-Sham eigenvalues \u01eb KS 1a \u2032\u2032 . Here \u03a3 is the complex, nonlocal, and frequencydependent self-energy, which we evaluate in the G 0 W 0 approximation using the Green function G 0 of the underlying Kohn-Sham system. Our numerical implementation is based on the space-time method [20] . The local exchange-correlation potential V xc must be subtracted from the self-energy to avoid double counting. A more detailed discussion of our computational method can be found in Ref. [21] . The quasiparticle corrections, but not the Kohn-Sham eigenvalues, are obtained from a smaller (2\u00d72) surface cell, which reduces the computational effort considerably. Although we investigate charged systems, the relative self-energy shifts are insensitive to the size of the supercell, because they only include exchangecorrelation effects and no electrostatic Hartree contribution. Keeping the atomic positions fixed at the optimized geometry for the neutral vacancy, we performed separate G 0 W 0 calculations for the positive and negative charge states. The calculated 1a", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "\u2032\u2032 single-particle energies \u01eb 1a \u2032\u2032 (+, Q 0 ) and \u01eb 1a \u2032\u2032 (\u2212, Q 0 ) are shown in Fig. 1 with and without the self-energy correction.", "cite_spans": [], "ref_spans": [{"start": 81, "end": 87, "text": "Fig. 1", "ref_id": "FIGREF1"}]}, {"section": "", "text": "In Table I we summarize the results for the As vacancy at GaAs(110). Values in brackets refer to the constrained symmetric relaxation of V + As and are included for the purpose of comparison with earlier studies. In contrast to Refs. [6, 7] , which found a stable neutral charge state within a narrow energy window, our own calculation at the level of the LDA indicates \u01eb +/0 > \u01eb 0/\u2212 and hence a direct transition from the positive to the negative charge state, but the small energetic separation is within the uncertainty of the calculation. With the G 0 W 0 approximation we find a reversed ordering, which implies the existence of a stable neutral charge state, and a slightly increased splitting of the charge-transition levels.", "cite_spans": [], "ref_spans": [{"start": 3, "end": 10, "text": "Table I", "ref_id": "TABREF0"}]}, {"section": "", "text": "The charge-transition levels for the P vacancy at InP(110) are listed in Table II . Our LDA results are similar to those reported previously [3, 8] and well below the experimentally deduced value of 0.75\u00b10.1 eV [3] . The G 0 W 0 approximation, on the other hand, yields a value for \u01eb +/0 that lies within the experimental error bar. In conclusion, we have developed a general computational scheme for the optical defect levels and thermodynamic charge-transition levels of point defects in semiconductors. The method is broadly applicable to the bulk as well as to surfaces. It relies on a separation of structural and electronic energy contributions that can be accurately evaluated within DFT and many-body perturbation theory, respectively. In this way the discontinuity of the exchange-correlation potential as well as other shortcomings of the LDA are treated appropriately. Our calculated (+/0) charge-transition level for the P vacancy at InP(110) is in close agreement with the experimental analysis, confirming the accuracy of this method.", "cite_spans": [], "ref_spans": [{"start": 73, "end": 81, "text": "Table II", "ref_id": "TABREF0"}]}], "bib_entries": {"BIBREF0": {"title": "* Electronic address: A.Schindlmayr@fz-juelich.de \u2020 Present address: Lehrstuhl f\u00fcr Theoretische Festk\u00f6rper-physik", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF4": {"title": "Semiconductors and Semimetals", "authors": [{"first": "U", "middle": [], "last": "Scherz", "suffix": ""}, {"first": "M", "middle": [], "last": "Scheffler", "suffix": ""}], "year": 1993, "venue": "", "link": null}}, "ref_entries": {"FIGREF0": {"text": "0 )\u2212E vac (+, Q + ) = 0.30 eV and E vac (\u2212, Q \u2212 ) \u2212 E vac (\u2212, Q 0 ) = \u22120.13 eV. The cor- responding values for InP are 0.20 eV and \u22120.17 eV.", "type": "figure"}, "FIGREF1": {"text": "FIG. 1: Position of the optical 1a \u2032\u2032 defect level of the anion vacancies at GaAs(110) and InP(110) as a function of the occupation number. The geometry is identical in all calculations for the same material and optimized for the neutral charge state. The Slater-Janak transition-state approach (filled circles) yields the ionization potentials and electron affinities in the LDA. More accurate results are obtained by calculating the quasiparticle corrections within the G0W0 approximation (filled squares). In either case the energy zero is set to the respective surface valence-band maximum.", "type": "figure"}, "TABREF0": {"text": "The charge-transition levels associated with the As vacancy at GaAs(110), given in eV. Values in brackets refer to the constrained symmetric relaxation of the positively charged vacancy. The quasiparticle band gap of 1.55 eV in this work, calculated at the theoretical lattice constant 5.55\u00c5, is close to the experimental value 1.52 eV.TABLE II: The charge-transition levels associated with the P vacancy at InP(110), given in eV. The quasiparticle band gap of 1.52 eV in this work, calculated at the theoretical lattice constant 5.81\u00c5, is close to the experimental value 1.42 eV.", "type": "table"}}}
{"paper_id": "17784755", "_pdf_hash": "caaa5916e349dbd7909cac467288ee6a3745eb49", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "System-Level Power Optimization: Techniques and Tools", "authors": [{"first": "Luca", "middle": [], "last": "Benini", "suffix": ""}], "year": 2000, "venue": "ACM Trans. Design Automation of Electronic Systems", "link": "52804399"}, "BIBREF1": {"title": "Energy-Aware Design of Embedded Memories: A Survey of Technologies, Architectures, and Optimization Techniques", "authors": [{"first": "Luca", "middle": [], "last": "Benini", "suffix": ""}], "year": 2003, "venue": "ACM Trans. Embedded Computing Systems", "link": "10641732"}, "BIBREF2": {"title": "Data and Memory Optimization Techniques for Embedded Systems", "authors": [{"first": "P", "middle": ["R"], "last": "Panda", "suffix": ""}], "year": 2001, "venue": "ACM Trans. Design Automation of Electronic Systems", "link": "10911530"}, "BIBREF3": {"title": "A 160MHz, 32-b, 0.5-W CMOS RISC microprocessor", "authors": [{"first": "J", "middle": [], "last": "Montanaro", "suffix": ""}], "year": 1997, "venue": "Digital Tech. Journal", "link": null}, "BIBREF4": {"title": "A 32b 66 MHz 1.8 W Microprocessor", "authors": [{"first": "R", "middle": [], "last": "Bechade", "suffix": ""}], "year": 1994, "venue": "Proc. Int. Solid-State Circuits Conference", "link": null}, "BIBREF5": {"title": "Low-Complexity Algorithms for Static Cache Locking in Multitasking Hard Real-Time Systems", "authors": [{"first": "I", "middle": [], "last": "Puant", "suffix": ""}], "year": 2002, "venue": "RTSS", "link": "17603106"}, "BIBREF6": {"title": "Explicit reservation of cache memory in a predictable, preemptive multitasking real-time system", "authors": [{"first": "Jack", "middle": [], "last": "Whitham", "suffix": ""}], "year": 2014, "venue": "ACM Trans. Embedd. Comput. Syst", "link": null}, "BIBREF7": {"title": "Cooperative cache partitioning for chip multiprocessors", "authors": [{"first": "Jichuan", "middle": [], "last": "Chang", "suffix": ""}, {"first": "Gurindar", "middle": ["S"], "last": "Sohi", "suffix": ""}], "year": 2007, "venue": "Proc. 21st annual int. conf. Supercomputing (ICS '07)", "link": "192698"}, "BIBREF8": {"title": "SACR: Scheduling-Aware Cache Reconfiguration for Real-Time Embedded Systems", "authors": [{"first": "W", "middle": [], "last": "Wang", "suffix": ""}, {"first": "P", "middle": [], "last": "Mishra", "suffix": ""}, {"first": "A", "middle": [], "last": "Gordon-Ross", "suffix": ""}], "year": 2009, "venue": "", "link": "12902255"}, "BIBREF9": {"title": "Conference on VLSI Design", "authors": [{"first": "", "middle": [], "last": "Int", "suffix": ""}], "year": 2009, "venue": "", "link": null}, "BIBREF10": {"title": "A survey of Web cache replacement strategies", "authors": [{"first": "Stefan", "middle": [], "last": "Podlipnig", "suffix": ""}], "year": 2003, "venue": "ACM Computing Surveys", "link": null}, "BIBREF11": {"title": "Optimal Replacements in Caches with Two Miss Costs", "authors": [{"first": "Jaeheon", "middle": [], "last": "Jeong", "suffix": ""}, {"first": "Michel", "middle": [], "last": "Duhois", "suffix": ""}], "year": 1999, "venue": "Proc. 11 th Annual ACM Symp.Parallel Algorithms and Architectures", "link": "5334735"}, "BIBREF12": {"title": "A New Cache Replacement Algorithm for Last-level Caches by Exploiting Tag-distance Correlation of Cache Lines", "authors": [{"first": "", "middle": [], "last": "Do", "suffix": ""}], "year": 2015, "venue": "In Journal of Microprocessor and Microsystems", "link": "12176020"}, "BIBREF13": {"title": "Cache Operations by MRU Change", "authors": [{"first": "Kimming", "middle": [], "last": "So", "suffix": ""}, {"first": "Rudolph", "middle": ["N"], "last": "Rechtshaffen", "suffix": ""}], "year": 1988, "venue": "IEEE Trans. on Computers", "link": "34939432"}, "BIBREF14": {"title": "An Adaptive CoherenceReplacement Protocol for Web Proxy Cache Systems", "authors": [{"first": "Jose", "middle": [], "last": "Aguilar", "suffix": ""}, {"first": "Ernst", "middle": ["L"], "last": "Leiss", "suffix": ""}], "year": 2004, "venue": "Communication and Systems", "link": "9976013"}, "BIBREF15": {"title": "Cache memories", "authors": [{"first": "Alan", "middle": ["J"], "last": "Smith", "suffix": ""}], "year": 1982, "venue": "Computer Survey", "link": null}, "BIBREF16": {"title": "Operating Systems Theory", "authors": [{"first": "G", "middle": [], "last": "Edward", "suffix": ""}], "year": "", "venue": "", "link": "5193639"}, "BIBREF17": {"title": "Self-Correcting LRU Replacement Policies", "authors": [{"first": "Martin", "middle": [], "last": "Kampe", "suffix": ""}], "year": 2004, "venue": "Proc. 1st Conference on Computing frontiers", "link": "5051017"}, "BIBREF18": {"title": "LLRU: Late LRU Replacement Strategy for Power Efficient Embedded Cache", "authors": [{"first": "K", "middle": [], "last": "Biju", "suffix": ""}, {"first": "", "middle": [], "last": "Raveendran", "suffix": ""}], "year": 2007, "venue": "Proc. 15th IEEE Int. Conference on Advanced Computing and Communications", "link": "15964074"}, "BIBREF19": {"title": "Embedded Intel486 Processor Family Developer's Manual", "authors": [{"first": "Intel", "middle": [], "last": "Corp", "suffix": ""}], "year": 1997, "venue": "", "link": null}, "BIBREF20": {"title": "Performance Evaluation of Cache Replacement Policies for the SPEC CPU2000 Benchmark Suite", "authors": [{"first": "Hussein", "middle": [], "last": "Al-Zoubi", "suffix": ""}], "year": 2004, "venue": "Proc. 42 nd Annual Southeast regional conference", "link": null}, "BIBREF21": {"title": "Intel Itanium 2 Processor Reference Manual for Software Development and Optimization", "authors": [{"first": "Intel", "middle": [], "last": "Corp", "suffix": ""}], "year": 2004, "venue": "", "link": null}, "BIBREF22": {"title": "A Data-Replace-Controlled Cache Memory System and its Performance Evaluations", "authors": [{"first": "N", "middle": [], "last": "Maki", "suffix": ""}], "year": 1999, "venue": "Proc. IEEE Region 10 Conf", "link": "60672032"}, "BIBREF23": {"title": "Software-Assisted Cache Replacement Mechanisms for Embedded Systems", "authors": [{"first": "Prabhat", "middle": [], "last": "Jain", "suffix": ""}], "year": 2001, "venue": "Proc. Int. Conference on Computer-Aided Design", "link": "2773693"}, "BIBREF24": {"title": "Using the Compiler to Improve Cache Replacement Decisions", "authors": [{"first": "Zhenlin", "middle": [], "last": "Wang", "suffix": ""}], "year": 2002, "venue": "Proc. Int. Conference on Parallel Architectures and Compilation Techniques", "link": "9720590"}, "BIBREF25": {"title": "Cooperative Hardware/Software Caching for NextGeneration Memory Systems", "authors": [{"first": "Zhenlin", "middle": [], "last": "Wang", "suffix": ""}], "year": 2004, "venue": "", "link": null}, "BIBREF26": {"title": "The Alpha 21264 microprocessor architecture", "authors": [{"first": "R", "middle": ["E"], "last": "Kessler", "suffix": ""}], "year": "", "venue": "", "link": "9857122"}, "BIBREF27": {"title": "Cache Memory Design with Late Replacements for Embedded Systems", "authors": [{"first": "", "middle": [], "last": "Biju Raveendran", "suffix": ""}], "year": "", "venue": "Int. Journal of Lateral Computing", "link": "62261937"}, "BIBREF28": {"title": "General Adaptive Replacement Policies", "authors": [{"first": "Yannis", "middle": [], "last": "Smaragdakis", "suffix": ""}], "year": 2004, "venue": "Proc. 4 th Int. Symp. Memory Management", "link": "1743984"}, "BIBREF29": {"title": "SFLRU Cache Replacement Algorithm", "authors": [{"first": "J", "middle": [], "last": "Alghazo", "suffix": ""}], "year": 2004, "venue": "Proc. Int. Workshop Memory Technology, Design and Testing", "link": null}}, "ref_entries": {}}
{"paper_id": "17784895", "_pdf_hash": "1cc1865f152c7f91e3d7f1832ee1491631e388e6", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "17784985", "_pdf_hash": "935119e04cce0817be27451ccf5d98b1ddbde08d", "abstract": [{"section": "Abstract", "text": "Background: Treatment failure after radiotherapy of head and neck squamous cell carcinoma (HNSCC) could be a significant problem. Our objective is to sensitize SCCVII cells to ionizing radiation in vitro and in vivo through inhibiting ATM expression using antisense oligodeoxynucleotides (AS-ODNs), and investigate the potential mechanism of radiosensitization.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Background", "text": "Despite advances in surgical treatments, radiotherapy is superior in its ability to preserve function and appearance in the treatment of head and neck squamous cell carcinoma (HNSCC). But some kinds of HNSCC are refractory to ionizing radiation, which results in the low effectiveness of radiotherapy alone [1, 2] . SCCVII cell line, is a spontaneously arising head and neck squamous carcinoma cell line from syngeneic C3H/HeJ mice [3] . An oral cancer murine model using the SCCVII cell line shares characteristics such as initial locoregional tumor invasion, direct extension into the neck, and early cervical metastases with human head and neck tumors [4] . So SCCVII cell line could be a good object to study the biological behavior of HNSCC.", "cite_spans": [{"start": 307, "end": 310, "text": "[1,", "ref_id": "BIBREF0"}, {"start": 311, "end": 313, "text": "2]", "ref_id": "BIBREF1"}, {"start": 432, "end": 435, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 655, "end": 658, "text": "[4]", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "Background", "text": "One strategy to improve the effectiveness of radiotherapy is augmenting of tumour radiosensitivity [5] . In the latter study, SCCVII cells were found to be resistant to ionizing radiation. The cytotoxicity of ionizing radiation is mainly mediated through the generation of DNA-double strand break (DSB) as evidenced by the pronounced radiosensitivity of cells and organisms defective in the machinery of DSB repair [6] [7] [8] . Thus, inhibition of DSB repair provides a mechanism to enhance the cytotoxicity of IR in tumour cells. The ataxia-telangiectasia mutated (ATM) protein kinase is a critical component in these pathways and integrates the cellular response to damage by phosphorylating key proteins involved in cell cycle regulation and DSB repair [9, 10] . Lack of the normal ATM function in the inherited ataxia telangiectasia (AT) syndrome results in the profound hypersensitivity to ionizing radiation [11] [12] [13] . As mentioned elsewhere p53-wild-type cell lines with dysfunctional ATM, when irradiated, either show a lack of or delayed activation of p53, resulting in a defective G1/S cell-cycle checkpoint [14] . However, in p53 mutated cell lines, disruption of ATM resulted in defective G2/M checkpoint control, radio-resistant DNA synthesis, retarded cell proliferation and enhanced radiosensitivity [15, 16] . Therefore, we manage to examine whether reduction of ATM expression after antisense oligodeoxynucleotides (AS-ODNs) treatment would result in enhanced radiosensitivity of p53-mutated SCCVII cells from C3H/He mice through the aberrant G2/M checkpoint.", "cite_spans": [{"start": 99, "end": 102, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 415, "end": 418, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 419, "end": 422, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 423, "end": 426, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 757, "end": 760, "text": "[9,", "ref_id": "BIBREF8"}, {"start": 761, "end": 764, "text": "10]", "ref_id": "BIBREF9"}, {"start": 915, "end": 919, "text": "[11]", "ref_id": "BIBREF11"}, {"start": 920, "end": 924, "text": "[12]", "ref_id": "BIBREF12"}, {"start": 925, "end": 929, "text": "[13]", "ref_id": "BIBREF13"}, {"start": 1125, "end": 1129, "text": "[14]", "ref_id": "BIBREF14"}, {"start": 1322, "end": 1326, "text": "[15,", "ref_id": "BIBREF15"}, {"start": 1327, "end": 1330, "text": "16]", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "Methods", "text": "Reagents RPMI-1640 media and 10% heat-inactivated fetal bovine serum (FBS) were purchased from Gibco Company (Eggenstein, Germany). Lipofectamine 2000, Opti-MEM medium and Trizol kit were bought from Invitrogen Company(Carlsbad, CA, USA). SYBR ExScript RT-PCR Kit and SYBR Green Master Mix were purchased from Takara Biotechnology Company (Dalian, China). ATM monoclonal antibodies was bought from Santa Cruz Biotechnology (Santa Cruz, CA, USA), and \u03b2-actin monoclonal antibodies from Sigma (St Louis, MO, USA). BCIP/NBT alkaline phosphatase substrate kit IV was purchased from Vector laboratories (Burlingame, CA, USA). TUNEL apoptosis detection kit was bought from Roche Company (Shanghai, China)", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "Cell lines and mice SCCVII cell line was generously obtained from the laboratory of gene therapy at Johns Hopkins University. SCCVII cells were cultured in complete RPMI-1640 media containing 10% heat-inactivated FBS, 2 mM L-glutamine, 100 IU/mL penicillin, 100 \u03bcg/mL streptomycin. Cells were cultured as a monolayer at 37\u00b0C in a humidified atmosphere containing 5% CO2. Female C3H/He mice, aged 6-8 weeks, weighing 18-22 g, were obtained from Vital River Laboratories (Beijing, China) and were maintained in the animal facility at West China Medical School, Sichuan University in accordance with nation's related regulations and animal welfare requirements.", "cite_spans": [], "ref_spans": []}, {"section": "Synthesis of oligodeoxynucleotides(ODNs) and selection of target sequences", "text": "A 25-mer AS-ODN which was previously reported to inhibit ATM expression in mouse cerebrovascular endothelial cells [17] , and its associated controls, sense (Sen) and mismatch (Mis) ODNs, were synthesized by Shanghai Sangon Biological Engineering Technology & Services (Shangai, China). The sequences were as follows: AS, 5'-GTGCTAGACTCATGGTTTAAGATTT-3'; Sen, 5'-AAATCTTAAACCATGAGTCTAGCAC-3' and Mis, 5'-CCCCAGCAGCTCCCATTGGGCGTAA-3'. All the ODNs were chemically modified to phosphorothioate ODNs by substituting the oxygen molecules of the phosphate backbone with sulfur.", "cite_spans": [{"start": 115, "end": 119, "text": "[17]", "ref_id": "BIBREF17"}], "ref_spans": []}, {"section": "Transfection of ODNs in SCCVII cells", "text": "SCCVII cells at a density of 5 \u00d7 10 4 cells/ml were plated for overnight incubation. Cells were maintained in RPMI-1640 medium supplemented with 10% FBS at 37\u00b0C and 5% CO2. After grew to 80%-90% fill, cells were replenished with incompleted RPMI-1640 medium, then treated with ATM AS-ODNs, ATM Sen-ODNs and Mis-ODNs. The procedures were as follows: 200 nM of ATM AS-ODNs, Sen-ODNs, Mis-ODNs and 2 mg/ml Lipofectamine 2000 were added to Opti-MEM medium separately, and incubated for 5 min at room temperature. Then liposome and ODNs were mixed together respectively and incubated at room temperature for 20 min. SCCVII cells were washed again with Opti-MEM medium before transfection. The liposome ODNs complexes were carefully plated on the cells, and incubated at 37\u00b0C, 5% CO2. After 6 hours transfected cells were washed twice with PBS, the medium was replaced with fresh RPMI-1640 medium supplemented with 10% FBS, cells were incubated at 37\u00b0C overnight. A second ODNs incubation was performed before cells were exposed to radiation.", "cite_spans": [], "ref_spans": []}, {"section": "Real-time quantitative PCR analysis", "text": "Total RNAs were extracted from cultured SCCVII cells using Trizol reagent according to the manufacture's protocol. RNA concentration and purity were determined on a UV spectrophotometer (BioRad Inc., Hercules, CA, USA) by the 260 nm absorbance and 260-280 nm absorbance ratio, respectively. Synthesis of cDNA was conducted using SYBR ExScript RT-PCR Kit according to manufacturer's instructions. Real-time quantitative RT-PCR for the ATM mRNA was performed on an ABI PRISM 7300 Sequence Detection System (Applied Biosystems, Foster City, CA, USA) using SYBR Green Master Mix. For normalization the gene GAPDH was used. Final reaction volume is 25 \u03bcl. Cycling conditions were as follows: initial denaturation at 95\u00b0C for 10 s, followed by 40 cycles of 95\u00b0C for 5 s and 59\u00b0C for 31 s. Each measurement was performed in triplicate. The gene expression levels obtained were normalized by mRNA expression of GAPDH. The relative mRNA expression was then presented in relation to the untreated control group. All oligonucleotide primers were designed and synthesized by Sangon (Shanghai, China). The primer sequences are listed as follows: ATM, forward, 5'-CCAGGGGAAGATGATGAAGA-3' reverse 5'-CTACAATGAGCTGCGTGTGG-3'; GAPDH, forward,5'-CCTCAAGATTGTCAGCAAT-3' reverse, 5'-CCATC-CACAGTCTTCTGAGT-3'.", "cite_spans": [], "ref_spans": []}, {"section": "Western blot analysis", "text": "Total proteins extracted from SCCVII cells were separated on 10% or 15% SDS-polyacrylamide gels. Fifty micrograms each of the preparations were fractionated by 12.5% SDS-PAGE and transferred to nitrocellulose membrane (Millipore, Bedford, MA). The membrane was blocked with 3% milk powder in PBS at room temperature for 3 hours, washed with TBS (PBS containing 0.1% Tween-20) for 10 min three times, then incubated with the ATM monoclonal antibodies (1:1000 dilution) or \u03b2-actin monoclonal antibodies (1:2000 dilution) in TBS containing 1% milk powder at 4\u00b0C overnight. After three washes with TBS, the membrane was incubated with alkaline phosphatase-labeled anti-mouse IgG antibody in TBS containing 1% milk powder at room temperature for 3 hours and washed again with TBS three times. The membrane was briefly equilibrated with PBS and visualized with the BCIP/NBT alkaline phosphatases substrate kit IV. Reactive bands were scanned by Gel Doc 1000 (Bio-Rad). The experiment was repeated three times.", "cite_spans": [], "ref_spans": []}, {"section": "Irradiation", "text": "ELEKTA Precise radiation system (Elekta, Sweden) was used to irradiate cells and solid tumor. X-ray irradiation was performed at room temperature at a dose rate of 200 cGy/min and equipped with an external 0.5-mm copper filter.", "cite_spans": [], "ref_spans": []}, {"section": "Clonogenic survival assay", "text": "The SCCVII cells were seeded in triplicate at limiting dilutions in 6-well plates for about 24 hours in RPMI-1640 medium supplemented with 10% FBS until attached. Then the cells were transfected with ATM AS-ODNs, ATM Sen-ODNs and Mis-ODNs respectively. About 18 hours after transfection, they were irradiated with different doses of X-ray radiation(0, 2, 4, 6, and 8 Gy) respectively. The medium was replaced with a fresh one 24 hours after irradiation. After 7 days of incubation, the colonies were fixed with methanol, stained with 0.5% crystal violet in absolute ethanol and colonies with >50 cells were counted under dissection microscope. In each irradiation dose group, surviving fraction (SF) of cells was calculated as plating efficiency of the irradiated cells divided by the plating efficiency of the irradiated cells by that of the untreated control.", "cite_spans": [], "ref_spans": []}, {"section": "Cell cycle and apoptosis analyzed by flow cytometry", "text": "After 48 hours exposed to 2 Gy radiation, cells were harvested, and centrifuged at 1500 rpm for 2 min. Then cells were washed with PBS twice, and fixed with 70% icy-cold ethanol at 4\u00b0C overnight. Cells were stained with PI at 4\u00b0C for 30 min. Cell cycle progression and apoptotic rate were analyzed by flow cytometry (Elite ESP, Beckman Coulter, USA).", "cite_spans": [], "ref_spans": []}, {"section": "Animal experiment of radiosensitization", "text": "Female C3H/He mice were used to investigate the effect of ATM AS-ODNs on radiosensitivity of SCCVII cells solid tumor. All surgical procedures and care administered to the animals were in accordance with institutional guidelines. Animal surgeries and radiotherapy were performed under general anesthesia, 50 mg/kg ip injection of pentobarbital sodium. About 5 \u00d7 10 6 SCCVII cells were subcutaneously inoculated in submental space of the mice. Tumor growth rates were determined by measuring two orthogonal dimensional diameters of each tumor twice a week. Tumour volumes were estimated according to the formula V = \u03c0/6 \u00d7 a2 \u00d7 b, where a is the short axis, and b the long axis. When tumors reached an average volume of about 200 mm 3 , the tumor-bearing C3H/He mice were divided into four groups: (a) control group, no treatment; (b) ATM AS-ODNs group, tumors were treated with ATM AS-ODNs alone but not exposed to irradiation for each time; (c) irradiation group, tumors were exposed to X-ray of 2 Gy alone for each time; and (d) combination group, 2.5 mg/kg of ATM AS-ODNs was injected into the solid tumor the day before X-ray exposure, another dosage of ATM AS-ODNs was injected right before exposure to 2 Gy of X-ray for each time. The same treatment for each group were repeated 3 times (the interval time was 5 days). C3H/ He mice were killed 3 weeks later. The ATM protein expression of the tumor in the different groups were ananlysed by western blot using the procedures described as above. The tumor inhibition rate was evaluated using the following formula: (1-average tumor volume of experimental group/average tumor volume of control group) \u00d7 100%.", "cite_spans": [], "ref_spans": []}, {"section": "Animal experiment of radiosensitization", "text": "Terminal deoxynucleotidyltransferase-mediated dUTPdigoxigenin nick-end-labeling (TUNEL) assay TUNEL staining of tumour sections was performed using an in situ apoptosis detection kit (Roche, Shanghai, China) according to the manufacture's protocol. The total number of apoptotic cells in 10 randomly selected fields was counted. The apoptotic index (AI) was calculated as the percentage of positive staining cells, namely AI = number of apoptotic cells \u00d7 100/total number of nucleated cells.", "cite_spans": [], "ref_spans": []}, {"section": "Statistics", "text": "Results were expressed as mean \u00b1 standard deviation(SD). SPSS12.0 software package was used to perform statistical analysis. One-way ANOVA test was used to determine statistical difference between the experimental groups with others. Differences were considered statistically significant at P < 0.05.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Expression of ATM in ATM AS-ODNs transfected SCCVII cells", "text": "We analyzed the expression of ATM in mRNA and protein level in SCCVII cells using real-time fluorescent quantitative PCR and western blot assay respectively. After 48 hours treatment, there were no significant difference among the group treated with liposome alone, the group treated with Sen-ODNs and the group treated with MisODNs (P > 0.05; Figure. 1 ). However when incubating with liposome formulations of ATM AS-ODNs, the relative ATM mRNA expression was only about 25.7 \u00b1 3.1% to the untreated SCCVII cells, which demonstrated a significantly reduced expression of ATM mRNA (P < 0.05; Figure. 1 ). As shown in Figure. 2, ATM protein expression was also significantly reduced by ATM AS-ODNs compared with Sen-ODNs and Mis-ODNs after 72 hours treatment ( Figure. 2A) . The relative ATM protein expression of SCCVII cells treated with ATM AS-ODNs was only about 24.1 \u00b1 2.8% to the untreated cells (P < 0.05; Figure. 2B ). But there was no significant difference among the group treated with liposome alone, the group treated with SenODNs and the group treated with Mis-ODNs (P > 0.05; Figure. 2B).", "cite_spans": [], "ref_spans": []}, {"section": "Effect of ATM AS-ODNs on clonogenic survival ability of SCCVII cells after irradiation", "text": "Cellular response to ionizing radiation was evaluated by clonogenic survival assay. Compared with untreated cells or cells treated with control ODNs, cloning efficiency declined notably in cells which transfected with ATM ASODNs at the same dose of radiation ( Figure. 3) . The survival fraction after 2 Gy (SF2) reflect the cellular intrinsic radiosensitivity. The SF2 of cells transfected with ATM ASODNs was 53.3 \u00b1 3.1%, definitely lower than that of other cells, which indicated a significant increase in the radiosensitivity (P < 0.05; Figure. 3). There were no obvious differences among the other groups about clonogenic survival ability (P > 0.05; Figure. 3).", "cite_spans": [], "ref_spans": []}, {"section": "Effect of ATM AS-ODNs on apoptosis and cell cycle of SCCVII cells after irradiation in vitro", "text": "After 2 Gy irradiation, the apoptotic rate in ATM AS-ODNs transfected cells was 24.7 \u00b1 2.5%, which was higher than that in Sen-ODNs and Mis-ODNs transfected cells (P < 0.05; Figure. ", "cite_spans": [], "ref_spans": []}, {"section": "Inhibitory effect of ATM AS-ODNs on tumor growth in vivo after irradiation", "text": "In the group treated with ATM AS-ODNs alone and the group irradiated in combination with the treatment of ATM AS-ODNs, the relative ATM protein expression were only 63.4 \u00b1 5.6% and 62.1 \u00b1 6.1% to the untreated group respectively (P < 0.05; Figure. 6 ). Tumor growth of the mice in four groups were shown in Figure. 7. The inhibition rate in SCCVII cells solid tumor exposed to X-ray alone was 23.2 \u00b1 2.7%, while it was 56.1 \u00b1 3.8% in solid tumor irradiated in combination with the treatment of ATM AS-ODNs at the experimental endpoint(P < 0.05; Figure. 7).", "cite_spans": [], "ref_spans": [{"start": 240, "end": 249, "text": "Figure. 6", "ref_id": "FIGREF4"}]}, {"section": "Enhancement of tumour apoptosis by irradiation combined with ATM AS-ODNs treatment in vivo", "text": "Only small numbers of apoptotic cells were detected by TUNEL analysis in tumors treated with irradiation alone. In contrast with irradiation alone, tumor cell apoptosis was doubled following irradiation in combination with ATM AS-ODNs treatment ( Figure. 8A) . Accordingly, the AI for tumors from ATM AS-ODNs treated mice was 19.6 \u00b1 3.2, significantly higher than that of the other groups (P < 0.05; Figure. ", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "Damage to cellular DNA evokes a wide range of cellular responses that lead to activation of a variety of genes necessary for cellular survival, delay in cell-cycle progression, and induction of DNA repair [18] [19] [20] . ATM protein is a key mediator of the radioprotective machinery inducing a signaling network that is responsible for repair of radiationinduced damaged DNA and for cellular recovery and survival [21] [22] [23] . Rasheed had found that disruption of the ATM gene in mice resulted in exquisite sensitivity to low doses of ionizing radiation [24] . Yin demonstrated that treatment of mouse cerebrovascular endothelial cells with ATM AS-ODNs led to specific inhibition of ATM induction, and increased radiation-induced apoptosis in vitro [17] . Therefore we designed the experiment to test the hypothesis whether ATM AS-ODNs could inhibit the expression of ATM in SCCVII cells and furthermore increase the radiosensitivity by enhancing radiationinduced apoptosis in vitro and in vivo.", "cite_spans": [{"start": 205, "end": 209, "text": "[18]", "ref_id": "BIBREF18"}, {"start": 210, "end": 214, "text": "[19]", "ref_id": "BIBREF19"}, {"start": 215, "end": 219, "text": "[20]", "ref_id": "BIBREF20"}, {"start": 416, "end": 420, "text": "[21]", "ref_id": "BIBREF21"}, {"start": 421, "end": 425, "text": "[22]", "ref_id": "BIBREF22"}, {"start": 426, "end": 430, "text": "[23]", "ref_id": "BIBREF23"}, {"start": 560, "end": 564, "text": "[24]", "ref_id": "BIBREF24"}, {"start": 755, "end": 759, "text": "[17]", "ref_id": "BIBREF17"}], "ref_spans": []}, {"section": "Discussion", "text": "In the present study, we successfully transfected ATM ASODNs into SCCVII cells using liposome as delivery carrier, and detected the inhibitory expression of ATM at mRNA and protein level in SCCVII cells. We found that expression of ATM was dramatically reduced after cells were transfected with ATM AS-ODNs compared with that Sen-ODNs and Mis-ODNs treated groups, which indicated that the inhibition was specific for the ATM antisense sequence. Then we investigated whether the reduction of ATM expression resulted in radiosensitization in SCCVII cells. The results of clonogenic survival assay in vitro demonstrated that the cloning efficiency declined notably in cells which transfected with ATM ASODNs at the same dose of radiation (P < 0.05) compared with untreated cells or cells treated with control ODNs. While the SF2 of cells transfected with ATM AS-ODNs was 53.3 \u00b1 3.1%, definitely lower than that of other cells, which means the increase of cell intrinsic radiosensitivity. Furthermore we investigated whether the increased radioSurvival curves for SCCVII cells after irradiation Figure 3 Survival curves for SCCVII cells after irradiation. Survival fractions at each dose point were normalized to untreated cells. * P < 0.05, The mean of SF2 in the cells transfected with ATM AS-ODNs was significantly lower than that of other cells. sensitivity in SCCVII cells was due to the enhanced radiation-induced apoptosis and defective cell-cycle checkpoint. As we known, in p53 mutated cell lines, ATM mainly regulates the G2/M checkpoint to arrest cells in G2 phase at the time of irradiation where the radiationinduced DSBs can be repaired [15, 16] . From flow cytometry, we found that the cells did not accumulate in the G2/ M phase following irradiation in cells transfected with ATM AS-ODNs, which mean the reduced ATM expression resulted in the defective G2/M checkpoint control. Moreover, we found that radiation-induced apoptosis increased among the cells lack of ATM expression compared with those cells that have impact ATM expression.", "cite_spans": [{"start": 1647, "end": 1651, "text": "[15,", "ref_id": "BIBREF15"}, {"start": 1652, "end": 1655, "text": "16]", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "Discussion", "text": "In our study, we also investigated the effects of ATM ASODNs on the apoptotic responses to ionizing radiation in vivo. It was found that the tumors irradiated in combination with the treatment of ATM AS-ODNs were effective in controlling tumor growth and showed higher apoptotic rate. The inhibition rate in the tumors injected with ATM AS-ODNs before exposure to X-ray was 56.1 \u00b1 3.8%, whereas it was 23.2 \u00b1 2.7% in tumors exposed to radiation alone, and a significant difference was found between these two groups (P < 0.05). The results of TUNEL assay demonstrated that the apoptotic rate of the tumors irradiated in combination with the treatment of ATM AS-ODNs was obviously higher than that of control groups. The results of in vivo experiments indicated that the radiosensitivity of SCCVII cells solid tumors were enhanced by the The apoptotic rate of SCCVII cells after 2 Gy irradiation Figure 4 The apoptotic rate of SCCVII cells after 2 Gy irradiation. The apoptotic rate (Apo) in ATM AS-ODNs transfected cells was higher than that in Sen-ODNs and Mis-ODNs transfected cells after 2 Gy irradiation. * P > 0.05, no significant difference among these groups. ** P < 0.05, compared with other groups. treatment of ATM AS-ODNs and related with the increased radiation-induced apoptosis.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusion", "text": "We had demonstrated that the ATM AS-ODNs used in our study could specificly reduce the ATM expression and further result in an increased radiosensitivity in SCCVII cells in vitro and in vivo. The potential mechanism of radiosensitization related with reduced ATM expression should be the defective G2/M cell-cycle checkpoint control and enhanced radiation-induced apoptosis. formed the rest of the experiments and wrote the manuscript. All authors read and approved the final manuscript.", "cite_spans": [], "ref_spans": []}, {"section": "Effect of ATM AS-ODNs on the ATM protein expression in vivo", "text": "", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Combination radiation and adenovirus-mediated P16(INK4A) gene therapy in a murine model for head and neck cancer. ORL; journal for oto-rhino-laryngology and its related specialties", "authors": [{"first": "J", "middle": ["G"], "last": "Rhee", "suffix": ""}, {"first": "D", "middle": [], "last": "Li", "suffix": ""}, {"first": "", "middle": [], "last": "O&apos;malley", "suffix": ""}, {"first": "", "middle": [], "last": "Bw", "suffix": ""}, {"first": "M", "middle": [], "last": "Suntharalingam", "suffix": ""}], "year": 2003, "venue": "", "link": null}, "BIBREF1": {"title": "Radiosensitization of head/neck squamous cell carcinoma by adenovirus-mediated expression of the Nbs1 protein. International journal of radiation oncology, biology", "authors": [{"first": "J", "middle": ["G"], "last": "Rhee", "suffix": ""}, {"first": "D", "middle": [], "last": "Li", "suffix": ""}, {"first": "M", "middle": [], "last": "Suntharalingam", "suffix": ""}, {"first": "C", "middle": [], "last": "Guo", "suffix": ""}, {"first": "", "middle": [], "last": "O&apos;malley", "suffix": ""}, {"first": "", "middle": [], "last": "Bw", "suffix": ""}, {"first": "J", "middle": ["P"], "last": "Carney", "suffix": ""}], "year": 2007, "venue": "", "link": null}, "BIBREF2": {"title": "A new immunocompetent murine model for oral cancer", "authors": [{"first": "", "middle": [], "last": "O&apos;malley", "suffix": ""}, {"first": "", "middle": [], "last": "Bw", "suffix": ""}, {"first": "K", "middle": ["A"], "last": "Cope", "suffix": ""}, {"first": "C", "middle": ["S"], "last": "Johnson", "suffix": ""}, {"first": "M", "middle": ["R"], "last": "Schwartz", "suffix": ""}], "year": 1997, "venue": "Arch Otolaryngol Head Neck Surg", "link": "40826827"}, "BIBREF3": {"title": "Characterization of a spontaneously arising murine squamous cell carcinoma (SCC VII) as a prerequisite for head and neck cancer immunotherapy", "authors": [{"first": "D", "middle": [], "last": "Khurana", "suffix": ""}, {"first": "E", "middle": ["A"], "last": "Martin", "suffix": ""}, {"first": "J", "middle": ["L"], "last": "Kasperbauer", "suffix": ""}], "year": 2001, "venue": "Head & neck", "link": "27292031"}, "BIBREF4": {"title": "Relationship between clonogenic radiosensitivity, radiation-induced apoptosis and DNA damage/repair in human colon cancer cells", "authors": [{"first": "A", "middle": ["L"], "last": "Dunne", "suffix": ""}, {"first": "M", "middle": ["E"], "last": "Price", "suffix": ""}, {"first": "C", "middle": [], "last": "Mothersill", "suffix": ""}, {"first": "S", "middle": ["R"], "last": "Mckeown", "suffix": ""}, {"first": "T", "middle": [], "last": "Robson", "suffix": ""}, {"first": "D", "middle": ["G"], "last": "Hirst", "suffix": ""}], "year": 2003, "venue": "British journal of cancer", "link": "16104931"}, "BIBREF5": {"title": "Expression of ATM in ataxia telangiectasia fibroblasts rescues defects in DNA double-strand break repair in nuclear extracts", "authors": [{"first": "Y", "middle": [], "last": "Li", "suffix": ""}, {"first": "M", "middle": ["P"], "last": "Carty", "suffix": ""}, {"first": "G", "middle": ["G"], "last": "Oakley", "suffix": ""}, {"first": "M", "middle": ["M"], "last": "Seidman", "suffix": ""}, {"first": "M", "middle": [], "last": "Medvedovic", "suffix": ""}, {"first": "K", "middle": [], "last": "Dixon", "suffix": ""}], "year": 2001, "venue": "Environmental and molecular mutagenesis", "link": "8603270"}, "BIBREF6": {"title": "Radiosensitivity of human tumour cells is correlated with the induction but not with the repair of DNA double-strand breaks", "authors": [{"first": "R", "middle": ["A"], "last": "El-Awady", "suffix": ""}, {"first": "E", "middle": [], "last": "Dikomey", "suffix": ""}, {"first": "J", "middle": [], "last": "Dahm-Daphi", "suffix": ""}], "year": 2003, "venue": "British journal of cancer", "link": "1077807"}, "BIBREF7": {"title": "Ability to repair DNA double-strand breaks related to cancer susceptibility and radiosensitivity. Radiation medicine", "authors": [{"first": "K", "middle": [], "last": "Sakata", "suffix": ""}, {"first": "M", "middle": [], "last": "Someya", "suffix": ""}, {"first": "Y", "middle": [], "last": "Matsumoto", "suffix": ""}, {"first": "M", "middle": [], "last": "Hareyama", "suffix": ""}], "year": 2007, "venue": "", "link": null}, "BIBREF8": {"title": "ATM and related protein kinases: safeguarding genome integrity", "authors": [{"first": "Y", "middle": [], "last": "Shiloh", "suffix": ""}], "year": 2003, "venue": "Nature reviews", "link": "22770833"}, "BIBREF9": {"title": "Maintaining integrity", "authors": [{"first": "Y", "middle": [], "last": "Shiloh", "suffix": ""}, {"first": "A", "middle": ["R"], "last": "Lehmann", "suffix": ""}], "year": 2004, "venue": "Nature cell biology", "link": "41175805"}, "BIBREF11": {"title": "Roles of ATM and NBS1 in chromatin structure modulation and DNA double-strand break repair", "authors": [{"first": "E", "middle": [], "last": "Berkovich", "suffix": ""}, {"first": "R", "middle": ["J"], "last": "Monnat", "suffix": ""}, {"first": "M", "middle": ["B"], "last": "Kastan", "suffix": ""}], "year": 2007, "venue": "Nature cell biology", "link": "25031230"}, "BIBREF12": {"title": "Deficiency in the catalytic subunit of DNA-dependent protein kinase causes down-regulation of ATM", "authors": [{"first": "Y", "middle": [], "last": "Peng", "suffix": ""}, {"first": "R", "middle": ["G"], "last": "Woods", "suffix": ""}, {"first": "H", "middle": [], "last": "Beamish", "suffix": ""}], "year": 2005, "venue": "Cancer research", "link": "3254605"}, "BIBREF13": {"title": "The Rad50S allele promotes ATM-dependent DNA damage responses and suppresses ATM deficiency: implications for the Mre11 complex as a DNA damage sensor", "authors": [{"first": "M", "middle": [], "last": "Morales", "suffix": ""}, {"first": "J", "middle": ["W"], "last": "Theunissen", "suffix": ""}, {"first": "C", "middle": ["F"], "last": "Kim", "suffix": ""}, {"first": "R", "middle": [], "last": "Kitagawa", "suffix": ""}, {"first": "M", "middle": ["B"], "last": "Kastan", "suffix": ""}, {"first": "J", "middle": ["H"], "last": "Petrini", "suffix": ""}], "year": 2005, "venue": "Genes & development", "link": "40378041"}, "BIBREF14": {"title": "Relationship between DNA double-strand break rejoining and cell survival after exposure to ionizing radiation in human fibroblast strains with differing ATM/p53 status: implications for evaluation of clinical radiosensitivity", "authors": [{"first": "R", "middle": [], "last": "Mirzayans", "suffix": ""}, {"first": "D", "middle": [], "last": "Severin", "suffix": ""}, {"first": "D", "middle": [], "last": "Murray", "suffix": ""}], "year": 2006, "venue": "International journal of radiation oncology", "link": "19719595"}, "BIBREF15": {"title": "DNA damage-induced cell-cycle phase regulation of p53 and p21waf1 in normal and ATM-defective cells", "authors": [{"first": "D", "middle": [], "last": "Delia", "suffix": ""}, {"first": "E", "middle": [], "last": "Fontanella", "suffix": ""}, {"first": "C", "middle": [], "last": "Ferrario", "suffix": ""}, {"first": "L", "middle": [], "last": "Chessa", "suffix": ""}, {"first": "S", "middle": [], "last": "Mizutani", "suffix": ""}], "year": 2003, "venue": "Oncogene", "link": "745275"}, "BIBREF16": {"title": "Bendamustine induces G2 cell cycle arrest and apoptosis in myeloma cells: the role of ATM-Chk2-Cdc25A and ATMp53-p21-pathways", "authors": [{"first": "L", "middle": [], "last": "Gaul", "suffix": ""}, {"first": "S", "middle": [], "last": "Mandl-Weber", "suffix": ""}, {"first": "P", "middle": [], "last": "Baumann", "suffix": ""}, {"first": "B", "middle": [], "last": "Emmerich", "suffix": ""}, {"first": "R", "middle": [], "last": "Schmidmaier", "suffix": ""}], "year": 2008, "venue": "Journal of cancer research and clinical oncology", "link": "206987203"}, "BIBREF17": {"title": "ATM gene regulates oxygen-glucose deprivation-induced nuclear factor-kappaB DNA-binding activity and downstream apoptotic cascade in mouse cerebrovascular endothelial cells. Stroke; a journal of cerebral circulation", "authors": [{"first": "K", "middle": ["J"], "last": "Yin", "suffix": ""}, {"first": "S", "middle": ["D"], "last": "Chen", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Lee", "suffix": ""}, {"first": "J", "middle": [], "last": "Xu", "suffix": ""}, {"first": "C", "middle": ["Y"], "last": "Hsu", "suffix": ""}], "year": 2002, "venue": "", "link": null}, "BIBREF18": {"title": "Relationships between clonogenic cell survival, DNA damage and chromosomal radiosensitivity in nine human cervix carcinoma cell lines", "authors": [{"first": "A", "middle": ["M"], "last": "Eastham", "suffix": ""}, {"first": "J", "middle": [], "last": "Atkinson", "suffix": ""}, {"first": "C", "middle": ["M"], "last": "West", "suffix": ""}], "year": 2001, "venue": "International journal of radiation biology", "link": "44480439"}, "BIBREF19": {"title": "The relationship between cellular radiosensitivity and radiation-induced DNA damage measured by the comet assay. The Journal of veterinary medical science/the", "authors": [{"first": "S", "middle": [], "last": "Wada", "suffix": ""}, {"first": "H", "middle": [], "last": "Kurahayashi", "suffix": ""}, {"first": "Y", "middle": [], "last": "Kobayashi", "suffix": ""}], "year": 2003, "venue": "", "link": null}, "BIBREF20": {"title": "Prediction of cellular radiosensitivity from DNA damage induced by gamma-rays and carbon ion irradiation in canine tumor cells. The Journal of veterinary medical science/the", "authors": [{"first": "S", "middle": [], "last": "Wada", "suffix": ""}, {"first": "T", "middle": [], "last": "Van Khoa", "suffix": ""}, {"first": "Y", "middle": [], "last": "Kobayashi", "suffix": ""}], "year": 2005, "venue": "", "link": null}, "BIBREF21": {"title": "A single ataxia telangiectasia gene with a product similar to PI-3 kinase", "authors": [{"first": "K", "middle": [], "last": "Savitsky", "suffix": ""}, {"first": "A", "middle": [], "last": "Bar-Shira", "suffix": ""}, {"first": "S", "middle": [], "last": "Gilad", "suffix": ""}], "year": 1995, "venue": "Science", "link": "70672519"}, "BIBREF22": {"title": "A pathway of double-strand break rejoining dependent upon ATM, Artemis, and proteins locating to gamma-H2AX foci", "authors": [{"first": "E", "middle": [], "last": "Riballo", "suffix": ""}, {"first": "M", "middle": [], "last": "Kuhne", "suffix": ""}, {"first": "N", "middle": [], "last": "Rief", "suffix": ""}], "year": 2004, "venue": "Molecular cell", "link": "12614156"}, "BIBREF23": {"title": "The Mre11 complex and ATM: a two-way functional interaction in recognising and signaling DNA double strand breaks", "authors": [{"first": "M", "middle": ["F"], "last": "Lavin", "suffix": ""}], "year": 2004, "venue": "DNA repair", "link": "25921356"}, "BIBREF24": {"title": "Atm-deficient mice: an osteoporosis model with defective osteoblast differentiation and increased osteoclastogenesis", "authors": [{"first": "N", "middle": [], "last": "Rasheed", "suffix": ""}, {"first": "X", "middle": [], "last": "Wang", "suffix": ""}, {"first": "Q", "middle": ["T"], "last": "Niu", "suffix": ""}, {"first": "J", "middle": [], "last": "Yeh", "suffix": ""}, {"first": "B", "middle": [], "last": "Li", "suffix": ""}], "year": 2006, "venue": "Human molecular genetics", "link": "21304881"}}, "ref_entries": {"FIGREF0": {"text": "4). It was also found that cell percentage of G2/M phase was decreased dramatically in ATM AS-ODNs transfected cells at 48 hours after 2 Gy irradiation com- pared with that of other groups(P < 0.05; Figure.", "type": "figure"}, "FIGREF1": {"text": "5).", "type": "figure"}, "FIGREF2": {"text": "8B).", "type": "figure"}, "FIGREF3": {"text": "Real-time quantitative PCR analysis of ATM mRNA expression Figure 1 Real-time quantitative PCR analysis of ATM mRNA expression. Reduced expression of ATM mRNA in the presence of liposome formulations of ATM AS-ODNs(AS-Lipo) was observed. *P > 0.05, no significantly difference among liposome- treated group(Lipo), and Sen-ODNs (Sen-Lipo) treated group and Mis-ODNs (Mis-Lipo)treated group. **P < 0.05, compared with other groups. Effect of ATM AS-ODNs on the expression of ATM protein in vitro Figure 2 Effect of ATM AS-ODNs on the expression of ATM protein in vitro. (A) Liposome formulations of ATM AS-ODNs significantly reduced the expression of ATM protein compared with other groups. (B) *P > 0.05, no significantly difference among liposome-treated group(Lipo), and Sen-ODNs (Sen-Lipo) treated group and Mis-ODNs (Mis-Lipo) treated group. **P < 0.05, compared with other groups.", "type": "figure"}, "FIGREF4": {"text": "Effect of ATM AS-ODNs on the ATM protein expression in vivo. (A) In the group treated with ATM AS-ODNs alone (ATM AS-ODNs treated alone) and the group irradiated in combination with ATM AS-ODNs (ATM AS-ODNs + irradiation), the expression of ATM protein were decreased. (B) * P < 0.05, compared with the untreated group and the group irradiated alone. Tumor growth in ATM AS-ODNs treated SCCVII cells in C3H/He mice with or without irradiation Figure 7 Tumor growth in ATM AS-ODNs treated SCCVII cells in C3H/He mice with or without irradiation. The apoptosis of SCCVII cells in vivo after irradiation Figure 8 The apoptosis of SCCVII cells in vivo after irradiation. (A) Apoptotic cells are detected by TUNEL. The nuclei of apop- totic cells were stained brown as observed under light microscopy (magnification, \u00d7 400). (B) The treatment by irradiation in combination with ATM AS-ODNs injection enhanced the apoptotic rate of tumor cells. * P < 0.05, there was a significant dif- ference in the AI of tumors treated with irradiation alone compared with the untreated group and the group treated with ATM AS-ODNs alone. ** P < 0.05, compared with the other groups.", "type": "figure"}}}
{"paper_id": "17785049", "_pdf_hash": "2f6c3b3e54c93c67e57d7461ecf3c5387f7a868e", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Analysis of jackknifing in articulated steer vehicles", "authors": [{"first": "N", "middle": ["L"], "last": "Azad", "suffix": ""}, {"first": "A", "middle": [], "last": "Khajepour", "suffix": ""}, {"first": "J", "middle": [], "last": "Mcphee", "suffix": ""}], "year": 2005, "venue": "Proceedings of the IEEE vehicle power and propulsion (VPP) conference", "link": "37289049"}, "BIBREF1": {"title": "Electrical sensors and transducers", "authors": [{"first": "J", "middle": ["R"], "last": "Carstens", "suffix": ""}], "year": 1993, "venue": "", "link": "106475190"}, "BIBREF2": {"title": "Electric machinery fundamentals", "authors": [{"first": "S", "middle": ["J"], "last": "Chapman", "suffix": ""}], "year": 2005, "venue": "", "link": "106620724"}, "BIBREF3": {"title": "The battery charging circuit", "authors": [{"first": "T.-L", "middle": [], "last": "Chen", "suffix": ""}, {"first": "J.-W", "middle": [], "last": "Lin", "suffix": ""}], "year": 1997, "venue": "Journal of the Power Electrics", "link": null}, "BIBREF4": {"title": "Advanced electronic circuit design", "authors": [{"first": "D", "middle": ["J"], "last": "Comer", "suffix": ""}, {"first": "D", "middle": ["T"], "last": "Comer", "suffix": ""}], "year": 2003, "venue": "", "link": "108001245"}, "BIBREF5": {"title": "Technical Company. Home service station AC air compressor", "authors": [{"first": "", "middle": [], "last": "Dai-Dai", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF6": {"title": "Quartz crystals as remote sensors for tire pressure", "authors": [{"first": "R", "middle": [], "last": "Grossmann", "suffix": ""}], "year": 1999, "venue": "Proceedings of the 16th IEEE instrumentation and measurement technology conference", "link": "108746313"}, "BIBREF7": {"title": "Electromechanics: Principles, concepts and devices", "authors": [{"first": "J", "middle": ["H"], "last": "Harter", "suffix": ""}], "year": 2000, "venue": "", "link": "106740835"}, "BIBREF8": {"title": "Half-tone images in laser image projection using saturated laser Fourier-amplifiers", "authors": [{"first": "A", "middle": ["F"], "last": "Kornev", "suffix": ""}, {"first": "I", "middle": ["G"], "last": "Kuchma", "suffix": ""}, {"first": "V", "middle": ["P"], "last": "Pokrovski", "suffix": ""}, {"first": "L", "middle": ["N"], "last": "Soms", "suffix": ""}], "year": 2005, "venue": "Proceedings of the CAOL second international conference on advanced optoelectronics and lasers", "link": "27241917"}, "BIBREF9": {"title": "Monitoring and managing tire pressure", "authors": [{"first": "M", "middle": [], "last": "Kowalewski", "suffix": ""}], "year": 2004, "venue": "IEEE Potentials", "link": "13217369"}, "BIBREF10": {"title": "Design of analog integrated circuits and systems", "authors": [{"first": "K", "middle": ["R"], "last": "Laker", "suffix": ""}, {"first": "W", "middle": ["M C"], "last": "Sansen", "suffix": ""}], "year": 1994, "venue": "", "link": "108532106"}, "BIBREF11": {"title": "Automatic tire pressure fault monitor using wavelet-based probability density estimation", "authors": [{"first": "L", "middle": [], "last": "Li", "suffix": ""}, {"first": "F. -Y", "middle": [], "last": "Wang", "suffix": ""}, {"first": "Z", "middle": [], "last": "Qunzhi", "suffix": ""}, {"first": "G", "middle": [], "last": "Shan", "suffix": ""}], "year": 2003, "venue": "Proceedings of the IEEE intelligent vehicles symposium", "link": "110588844"}, "BIBREF12": {"title": "The development of the battery charging device for the motorcycle", "authors": [{"first": "J.-S", "middle": [], "last": "Li", "suffix": ""}, {"first": "Y.-H", "middle": [], "last": "Liu", "suffix": ""}], "year": 2001, "venue": "Journal of the Power Electrics", "link": null}, "BIBREF13": {"title": "The development of the photo-element used in lighting service of the car", "authors": [{"first": "S.-K", "middle": [], "last": "Lie", "suffix": ""}, {"first": "L.-B", "middle": [], "last": "Yu", "suffix": ""}], "year": 2000, "venue": "Journal of the Technology Development", "link": null}, "BIBREF14": {"title": "The development of the efficiency battery charging device", "authors": [{"first": "Y.-H", "middle": [], "last": "Liu", "suffix": ""}], "year": 2001, "venue": "Journal of the Power Electrics", "link": null}, "BIBREF15": {"title": "The research of the lighting device of the technical company in Taiwan. The IEK-IT IS Project", "authors": [{"first": "J. -Y", "middle": [], "last": "Liu", "suffix": ""}], "year": 2005, "venue": "", "link": null}, "BIBREF16": {"title": "Upper Saddler River", "authors": [{"first": "I", "middle": ["S"], "last": "Mackenzie", "suffix": ""}], "year": 1999, "venue": "The 8051 microcontroller", "link": null}, "BIBREF17": {"title": "A passive telemetry LC pressure sensor optimized for TPMS", "authors": [{"first": "R", "middle": [], "last": "Mihali", "suffix": ""}, {"first": "T", "middle": [], "last": "Sobh", "suffix": ""}, {"first": "Usa", "middle": [], "last": "Detroit", "suffix": ""}, {"first": "M", "middle": [], "last": "Nabipoor", "suffix": ""}, {"first": "B", "middle": ["Y"], "last": "Majlis", "suffix": ""}], "year": 1999, "venue": "Proceedings of the IEEE international conference on robotics and automation", "link": "24774939"}, "BIBREF19": {"title": "The An-Hun Technical Company. The potable pneumatic tire machine-AH-C010. <http://www.szanhang.com.cn/>. The Audi-Tai Car Technical Company. The pneumatic tire machine with the digital player", "authors": [{"first": "A", "middle": [], "last": "Pohl", "suffix": ""}, {"first": "G", "middle": [], "last": "Ostermayer", "suffix": ""}, {"first": "L", "middle": [], "last": "Reindl", "suffix": ""}, {"first": "F", "middle": [], "last": "Seifert", "suffix": ""}], "year": 1997, "venue": "Proceedings of the IEEE ultrasonics symposium", "link": null}, "BIBREF20": {"title": "The automated wingmanUsing JACK intelligent agents for unmanned autonomous vehicles", "authors": [{"first": "P", "middle": [], "last": "Wallis", "suffix": ""}, {"first": "R", "middle": [], "last": "Ronnquist", "suffix": ""}, {"first": "D", "middle": [], "last": "Jarvis", "suffix": ""}, {"first": "A", "middle": [], "last": "Lucas", "suffix": ""}], "year": 2002, "venue": "Proceedings of the IEEE aerospace conference", "link": "111335905"}, "BIBREF21": {"title": "Fuzzy control of plural hydraulic jacks in an elasticplastic structural test", "authors": [{"first": "T", "middle": [], "last": "Yamada", "suffix": ""}, {"first": "K", "middle": [], "last": "Suzuki", "suffix": ""}], "year": 1990, "venue": "Proceedings of the first international symposium on uncertainty modeling and analysis", "link": "110266865"}, "BIBREF22": {"title": "The power bank and battery charging device", "authors": [{"first": "J.-L", "middle": [], "last": "Yeh", "suffix": ""}], "year": 1997, "venue": "Journal of the Taiwan Power Company", "link": null}}, "ref_entries": {}}
{"paper_id": "17785392", "_pdf_hash": "4c44fd7dc7fa9f1497b6de64528ba33cb52b9a00", "abstract": [{"section": "Abstract", "text": "We describe an improved synthetic strategy for the preparation of nucleic acid encoded peptide and protein libraries. A solid-phase format was used to prepare and purify a novel type of mRNA-template for in vitro mRNA-protein fusion synthesis. The present protocol simplifies and accelerates the preparation of fusion libraries and should prove most useful for in vitro protein evolution procedures which involve repetitive cycles of fusion library preparation and selection.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Combinatorial library technologies have emerged during the past 15 years as powerful tools for basic research and drug discovery and development. As first developed for peptides, the general concept of combinatorial libraries involves the generation of sequence permutations for a peptide of a given length, in connection with a screening and selection process that enables the isolation and identification of rare, functional peptides in the presence of large numbers of less active or inactive compounds. Since the individual synthesis of such large numbers of compounds (>10 4 ) is impractical, a variety of approaches have been developed to generate and screen mixtures of peptides, proteins and organic compounds. Whereas combinatorial chemistry technologies allow for easy incorporation of non-proteinogenic building blocks and are focused on the preparation of low molecular weight compound libraries for the discovery of drug candidates [1] , nucleic acid-encoded libraries like phage display or yeast display are usually employed to discover novel polypeptide binding motifs or to identify protein binding partners within a cell's proteome [2] . Common for the biosynthetic approaches are the iterative process of randomization, selection and amplification. While the last step is not readily available for chemical libraries, it is an important advantage of nucleic acid-encoded libraries that allows the handling of minimal amounts of material with maximum diversity, and eliminating virtually any worries about detection limits. Until recently, the limitations of nucleic acid-encoded library technologies were largely due to necessary in vivo steps, which limit library size and provide selection pressure that cannot be controlled by the experimenter. A lately introduced method for the preparation of a minimal genetic unit which consists of a mRNA covalently linked to a polypeptide (PROfusion TM ) circumvents the in vivo step and allows the selection for peptides and proteins with desired properties totally in vitro [3] [4] [5] . RNAprotein fusion libraries with up to 10 14 different sequences have been generated and have been successfully used for the isolation of peptide and protein binders to a variety of different targets [6] . The originally described method for RNA-protein fusion preparation involved translation of an enzymatically linked mRNA-puromycin conjugate [3] . Recently, we developed a simplified method for fusion synthesis from psoralen-crosslinked mRNA-puromycin templates [7] . Here we report a further improvement of this method in which the mRNA-puromycin template is prepared in an integrated affinity purification and crosslink formation process on solid phase. This novel synthesis protocol further simplifies mRNA-protein fusion preparation and should prove most useful in an automated fusion synthesis process.", "cite_spans": [{"start": 578, "end": 579, "text": "4", "ref_id": "BIBREF3"}, {"start": 945, "end": 948, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 1149, "end": 1152, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 2036, "end": 2039, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 2040, "end": 2043, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 2044, "end": 2047, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 2250, "end": 2253, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 2396, "end": 2399, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 2517, "end": 2520, "text": "[7]", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "Results and Discussion", "text": "The preparation of the mRNA template coding for the 10th fibronection type III domain (21 out of 94 amino acids were randomized) began with the in vitro transcription from a PCR-DNA library (10 12 different sequences) according to the method described in reference [5] (Fig. 1) . The freshly transcribed mRNA was annealed to a limiting amount of puromycin-linker carrying a photo-cleavable biotin group for affinity purification on solid-phase (Fig. 2) . The hybridized mRNA template-linker complex was then incubated with neutravidin agarose beads followed by washing to remove excess mRNA and transcription buffer components. UV-irradiation of the beads led to psoralen interstrandcrosslink formation and simultaneous cleavage of the biotin-tag. A planned quantity of pure mRNApuromycin template could be eluted from the solid phase. Polyacrylamide gel analysis indicated a ligation yield of > 80 % for the mRNA-puromycin template which was directly used for in vitro translation and fusion formation in rabbit reticulocyte lysate to produce the mRNA-protein fusion library [7] .", "cite_spans": [{"start": 265, "end": 268, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 1076, "end": 1079, "text": "[7]", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "Figure 1:", "text": "Schematic outline of mRNA-protein fusion synthesis. A double stranded DNA template library was in vitro transcribed to produce the mRNA template (a) which was annealed with a limiting amount of biotinylated puromycin-linker (b) and subsequently captured on neutravidin beads (c) After a washing step to remove unbound mRNA (d) the beads were irradiated with UV light (e) Elution yielded the photo-ligated mRNA-puromycin template which was directly subjected to in vitro translation to form the mRNA-protein fusions library (f) T7, transcription promoter sequence; TMV, a portion of the tobacco mosaic virus 5'-UTR with good initiation codon context; random 10 Fn3, a sequence coding for a randomized 10th fibronection type III domain; const, a constant sequence which codes for the linker hybridization and crosslinking sites as detailed in Fig. 2 ; Pu, puromycin; Pso, psoralen; PCbiotin, a photo-cleavable biotin-tag described in Fig. 2 .", "cite_spans": [], "ref_spans": []}, {"section": "Figure 1:", "text": "T TE EG G 6 6 d dC Cd dC C P Pu u PC-Biot in Figure 2 : Sequence design of the mRNA template 3'-end and the puromycin-linker. The mRNA template 3'-constant region codes for a linker hybridization sequence, a UAA stop codon and a dA 18 tag sequence. The biotinylated puromycin-linker sequence shown in red carries a 5'-terminal psoralen moiety (Pso), followed by a hybridization region and a flexible tether with puromycin (Pu) at the 3'-end and carrying a photo-cleavable biotin-tag. A 10 base complementary region between mRNA 3'-end and the photo-linker was found to be sufficient to achieve efficient hybridization and photo-crosslink formation. The use of 2'-OMe RNA in the linker hybridization sequence was intended to increase the stability of the 10 base-pair duplex; also, it protected the mRNA from cleavage by any RNase H activity during translation in rabbit reticulocyte lysate. The hydroxymethyl trioxsalen moiety (psoralen) was tethered to the 5'-phosphate through a hexamethylene spacer [8] (psoralen C6, Glen Research).", "cite_spans": [{"start": 1002, "end": 1005, "text": "[8]", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "Figure 1:", "text": "We found the above protocol to be useful for efficient synthesis of mRNA-peptide and mRNAprotein fusion libraries from a number of template libraries different in length and complexity. Efficient mRNA affinity purification on neutravidin agarose carrying the biotinylated puromycin-linker replaced the laborious mRNA gel purification step used in previous protocols [3, 5] . Crosslinkformation of the hybridized mRNA on solid-phase and simultaneous biotin-tag cleavage yielded pure mRNA-puromycin template for direct use in an in vitro translation system. The ease with which the amount of synthesized mRNA-puromycin template can be controlled by hybridization with limiting amounts of linker allowed us to keep the reaction volumes and stoichiometry of the subsequent fusion preparation synthesis constant and independent from the yield of the preceding transcription reaction. This feature of the present protocol should prove most useful in an automated in vitro protein evolution process which involves repetitive cycles of fusion library synthesis and selection and where manual quantification and adjustments only will lead to a time-lag in the production process.", "cite_spans": [{"start": 366, "end": 369, "text": "[3,", "ref_id": "BIBREF2"}, {"start": 370, "end": 372, "text": "5]", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "Experimental", "text": "Freshly transcribed mRNA (0.5 -2.5 nmol) was hybridized to biotinylated puromycin-linker (0.5 nmol, see Fig. 2 ) in 300 \u00b5l binding buffer (30 mM Tris, pH 7.0, 250 mM NaCl) by heating to 85\u00b0 C for 30 sec followed by cooling to 4\u00b0 C in 5 min. 100 \u00b5l pre-washed Neutravidin beads (Pierce) were added to the hybridization mixture and incubated for 30 min at 4 \u00b0C under rocking. Subsequently, the beads were washed 3x 100 \u00b5l binding buffer followed by centrifugation to remove the liquid phase. The moist beads were then irradiated for 15 min at room temperature with a 25W UV-lamp (Pyrex-filter, \u03bb > 300nm). Subsequently, the beads were washed with 100 \u00b5l plain water to yield 170 -200 pmol photo-crosslinked mRNA-puromycin template which was directly used for mRNA-peptide fusion formation in rabbit reticulocyte lysate to produce the mRNA-protein fusions library according to reference [7] .", "cite_spans": [{"start": 884, "end": 887, "text": "[7]", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "Experimental", "text": "The puromycin-linker was prepared according to Kurz et al. [7] and biotinylated by carbamate bond formation between the puromycin amino group (50 \u00b5M) and the photo-cleavable biotin-reagent [9] (NHS-PC-Biotin, 5 mM, EZ-Link TM -Biotin, Pierce Chemicals) in 25% DMSO/water for 2 h at room temperature followed by NaCl/EtOH precipitation. Photo-cleavage of the 1-(2-nitrophenyl)ethyl carbamate moiety restored the primary amino group on the 3'-terminal puromycin which acts as the peptidyl-acceptor in the fusion formation process (see Fig. 1 ).", "cite_spans": [{"start": 59, "end": 62, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 189, "end": 192, "text": "[9]", "ref_id": "BIBREF8"}], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "The challenge of preparing and testing combinatorial compound libraries in the fast lane, at the front end of drug development", "authors": [{"first": "E", "middle": [], "last": "Felder", "suffix": ""}], "year": 1994, "venue": "Chimia", "link": null}, "BIBREF1": {"title": "Biosynthetic polypeptide libraries", "authors": [{"first": "E", "middle": ["V"], "last": "Shusta", "suffix": ""}, {"first": "J", "middle": [], "last": "Vanantwerp", "suffix": ""}, {"first": "K", "middle": ["D"], "last": "Wittrup", "suffix": ""}], "year": 1999, "venue": "Curr Opin Biotechnol", "link": "41680809"}, "BIBREF2": {"title": "RNA-peptide fusions for the in vitro selection of peptides and proteins", "authors": [{"first": "R", "middle": ["W"], "last": "Roberts", "suffix": ""}, {"first": "J", "middle": ["W"], "last": "Szostak", "suffix": ""}], "year": 1997, "venue": "Proc Natl Acad Sci", "link": "9892255"}, "BIBREF3": {"title": "In vitro virus: Bonding of mRNA bearing puromycin at the 3'-terminal end to the C-terminal end of its encoded protein on the ribosome in vitro", "authors": [{"first": "N", "middle": [], "last": "Nemoto", "suffix": ""}, {"first": "E", "middle": [], "last": "Miyamoto-Sato", "suffix": ""}, {"first": "Y", "middle": [], "last": "Husimi", "suffix": ""}, {"first": "H", "middle": [], "last": "Yanagawa", "suffix": ""}], "year": 1997, "venue": "FEBS Lett", "link": "7601102"}, "BIBREF4": {"title": "Optimized synthesis of RNA-protein fusions for in vitro protein selection", "authors": [{"first": "R", "middle": [], "last": "Liu", "suffix": ""}, {"first": "J", "middle": ["E"], "last": "Barrick", "suffix": ""}, {"first": "J", "middle": ["W"], "last": "Szostak", "suffix": ""}, {"first": "R", "middle": ["W"], "last": "Roberts", "suffix": ""}], "year": 2000, "venue": "Methods in Enzymology", "link": "7963710"}, "BIBREF5": {"title": "Totally in vitro protein selection using mRNA-protein fusions and ribosome display", "authors": [{"first": "R", "middle": ["W"], "last": "Roberts", "suffix": ""}], "year": 1999, "venue": "Curr Opin Chem Biol", "link": "10221998"}, "BIBREF6": {"title": "Psoralen photo-crosslinked mRNA-puromycin conjugates: a novel template for the rapid and facile preparation of mRNA-protein fusions", "authors": [{"first": "M", "middle": [], "last": "Kurz", "suffix": ""}, {"first": "K", "middle": [], "last": "Gu", "suffix": ""}, {"first": "P", "middle": ["A"], "last": "Lohse", "suffix": ""}], "year": 2000, "venue": "Nucleic Acids Res", "link": "205225912"}, "BIBREF7": {"title": "Psoralen covalently linked to oligodeoxyribonucleotides: synthesis, sequence specific recognition of DNA and photo-cross-linking to pyrimidine residues of DNA", "authors": [{"first": "U", "middle": [], "last": "Pieles", "suffix": ""}, {"first": "U", "middle": [], "last": "Englisch", "suffix": ""}], "year": 1989, "venue": "Nucleic Acids Res", "link": "30811121"}, "BIBREF8": {"title": "Photocleavable biotin derivatives: a versatile approach for the isolation of biomolecules", "authors": [{"first": "J", "middle": [], "last": "Olejnik", "suffix": ""}, {"first": "S", "middle": [], "last": "Sonar", "suffix": ""}, {"first": "E", "middle": [], "last": "Krzymanska-Olejnik", "suffix": ""}, {"first": "K", "middle": ["J"], "last": "Rothschild", "suffix": ""}], "year": 1995, "venue": "Proc Natl Acad Sci", "link": "39421718"}}, "ref_entries": {}}
{"paper_id": "17785740", "_pdf_hash": "da48bda29865c64f70ef42d7c4d6b3a3aaee4c4b", "abstract": [{"section": "Abstract", "text": "We construct and analyze D-branes in superstring theories in even dimensions less than ten. The backgrounds under study are supersymmetric", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "where the level of the supercoset is tuned such as to provide bona fide string theory backgrounds.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "We provide exact boundary states for D-branes that are localized at the tip of the cigar pure Yang-Mills theory with minimal supersymmetry. In the case with four macroscopic flat directions d = 4, we realize an N = 1 super Yang-Mills theory, and we interpret the backreaction for the dilaton as the running of the gauge coupling, and study the relation between R-symmetry breaking in the gauge theory and the backreaction on the RR axion.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Non-critical Superstrings and Holography", "text": "It has been proven useful to study the physics of gauge theories using the geometrical pictures and intuition provided by brane set-ups in string theory (see e.g. [1] ). One spectacular outcome of the study of D-branes and their associated geometry [2] has been the impressive list of concrete examples of holography [3] , in which gravitational theories are dual to theories without a massless spin two particle.", "cite_spans": [{"start": 163, "end": 166, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 249, "end": 252, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 317, "end": 320, "text": "[3]", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "Non-critical Superstrings and Holography", "text": "In this paper, we concentrate on backgrounds of string theory with d flat directions, supplemented with a cigar superconformal field theory R 1,d\u22121 times SL(2, R)/U (1) [4, 5, 6, 7] . The background can arise from taking a double scaling limit of string theory near a singularity in a Calabi-Yau manifold, or in the presence of NS5-branes [8] . It can also be thought of as providing a d-dimensional string theory background per se. By dialing the level k the background becomes critical. For even dimension d, the background comes equipped with an N = 2 superconformal worldsheet supersymmetry that can be used to GSO project and that provides us with a target-space supersymmetric superstring theory.", "cite_spans": [{"start": 169, "end": 172, "text": "[4,", "ref_id": "BIBREF3"}, {"start": 173, "end": 175, "text": "5,", "ref_id": "BIBREF4"}, {"start": 176, "end": 178, "text": "6,", "ref_id": "BIBREF5"}, {"start": 179, "end": 181, "text": "7]", "ref_id": "BIBREF6"}, {"start": 339, "end": 342, "text": "[8]", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "Non-critical Superstrings and Holography", "text": "These backgrounds and their D-branes are appropriate examples to further study the interplay between holography and D-branes. Indeed, these solutions are of linear dilaton type and can be argued to interpolate between two-dimensional string theories and their ten-dimensional cousins. The dilaton gradient provided by the cigar conformal field theory takes values intermediate between the two-dimensional (strong) gradient and the tendimensional (zero) gradient. This mechanism for achieving criticality allows us to interpolate in the dimension of space-time. Since two-dimensional (or generally low-dimensional) examples of holography seem to be under more control than their ten-dimensional counterparts (see e.g. [9] and follow-ups) it may be worthwhile to lay out the playground in between. In the process, we should learn more about linear dilaton holography [10] .", "cite_spans": [{"start": 717, "end": 720, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 865, "end": 869, "text": "[10]", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "Gauge Theory Physics", "text": "Constructing string duals to N = 1 SYM theories has proven to be difficult. Previous approaches [11, 12] start from bulk theories with a larger number of supersymmetries, which are then broken through various mechanisms. An unwanted feature in these constructions is the existence of (extra) matter fields (e.g. massive scalars and/or fermions) in the theory. When one goes to the deep infrared (where the extra matter fields are absent), the supergravity backgrounds typically are not under control, either because of strong curvature [11] or strong coupling [12] .", "cite_spans": [{"start": 96, "end": 100, "text": "[11,", "ref_id": "BIBREF13"}, {"start": 101, "end": 104, "text": "12]", "ref_id": "BIBREF14"}, {"start": 536, "end": 540, "text": "[11]", "ref_id": "BIBREF13"}, {"start": 560, "end": 564, "text": "[12]", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "Gauge Theory Physics", "text": "Non-critical superstrings seem to be free of most of these problems. The target-space has reduced space-time supersymmetry, and the branes living in them are likewise less supersymmetric. Thus, we need only carefully construct the bulk, and then the corresponding branes to study gauge theories with less supersymmetry. In this sense, the occurrence of gauge theories with less supersymmetry is natural in the context of lower-dimensional superstring backgrounds. One must keep in mind however that the curvatures in these backgrounds are of string scale; gravity is not a priori a good approximation, and one necessarily has to work with the full sigma model which (after backreaction) involves the difficult problem of dealing with background fluxes.", "cite_spans": [], "ref_spans": []}, {"section": "Gauge Theory Physics", "text": "In this paper, we present a boundary state description of the branes in these backgrounds. Though it is a closed string description in principle, the boundary states are in practice more useful to describe open string physics by channel duality, and less so to compute the exact string background; we only compute the linear backreaction to the closed string background. Nevertheless, we consider this an important first step. This approach to N = 1 gauge theories through lower-dimensional superstrings may provide us with a new window to gauge theory physics.", "cite_spans": [], "ref_spans": []}, {"section": "Summary of Results", "text": "In this paper, we present the exact conformal field theory description of branes in lower-dimensional superstring theories, and compute the spectrum and low energy theory on these branes for d = 2, 4, 6. In the d = 4 case, we present evidence that our closed string background is dual to a non-gravitational theory which in the IR flows arbitrarily close to 4d N = 1 SYM, and in the UV is completed to a theory which is asymptotically free. In this sense, it is similar to the holographic descriptions in [13] and [12] 1 .", "cite_spans": [{"start": 505, "end": 509, "text": "[13]", "ref_id": "BIBREF15"}, {"start": 514, "end": 518, "text": "[12]", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "Summary of Results", "text": "Furthermore, it is possible to understand instantons and the anomalous breaking of the chiral U (1) R symmetry to Z 2N along the lines of [14] by studying the large distance behavior of the Ramond-Ramond fields: the background value of the RR axion potential spontaneously breaks a U (1) isometry of the solution.", "cite_spans": [{"start": 138, "end": 142, "text": "[14]", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "Organization", "text": "In section 2 we briefly review the bulk physics of noncritical superstring theories. The boundary states that describe the D-branes that we concentrate on are presented in section 3. We analyze the spectrum encoded in the one-loop partition function in some detail and argue for the low-energy effective action for these branes in section 4. We follow up by laying bare the physics encoded in the one-point function of the boundary states, in the case of N = 1 SYM in four dimensions. In the conclusions we summarize our results and indicate possible further developments. Various technicalities, and a generic proof of the vanishing of open string partition functions in Gepner-like (compact or non-compact) models are presented in the appendices.", "cite_spans": [], "ref_spans": []}, {"section": "Note added in publication", "text": "Very recently the interesting paper [15] appeared with some overlap with our paper. In particular, we note the overlap in the construction 2 of the open string spectrum for d = 4.", "cite_spans": [{"start": 36, "end": 40, "text": "[15]", "ref_id": "BIBREF17"}, {"start": 139, "end": 140, "text": "2", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Note added in publication", "text": "However, it is mostly usefully complementary in both subject matter and techniques. In [15] one finds an explicit analysis of the relation to brane set-ups and an analysis of flavor physics in this context. In our work, we focus on pure Yang-Mills, providing many details of the open string theory. We moreover compute properties of the dual closed string background using the boundary states.", "cite_spans": [{"start": 87, "end": 91, "text": "[15]", "ref_id": "BIBREF17"}], "ref_spans": []}, {"section": "Superstrings in dimensions less than ten", "text": "In this section, we briefly review salient features of the closed string background in which we will embed D-branes in section 3. The closed string background we shall study is the type IIB d dimensional superstring [4] which consists of d-dimensional flat space tensored with a non-trivially curved space: IR d\u22121,1 \u00d7 SL(2, R)/U (1). The factor SL(2)/U (1) is a Kazama-Suzuki supersymmetric coset conformal field theory [17] , at (supersymmetric) level k. One can write an effective target space action for this coset as:", "cite_spans": [{"start": 216, "end": 219, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 420, "end": 424, "text": "[17]", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "Superstrings in dimensions less than ten", "text": "This SCFT is known to have a mirror description as the N = 2 Liouville theory. The level k of the coset is tuned to make the total central charge c = 15. The matter worldsheet theory 2 Following prior work in [16] .", "cite_spans": [{"start": 183, "end": 184, "text": "2", "ref_id": "BIBREF1"}, {"start": 209, "end": 213, "text": "[16]", "ref_id": "BIBREF18"}], "ref_spans": []}, {"section": "Superstrings in dimensions less than ten", "text": "is tensored with the standard N = 2 superconformal ghosts of central charge c = \u221215, such that the total worldsheet central charge vanishes. From the formula for the flat space and coset central charge, we derive a relation between the dimension d and the level k:", "cite_spans": [], "ref_spans": []}, {"section": "Superstrings in dimensions less than ten", "text": "For future reference we note that we have the following correspondences:", "cite_spans": [], "ref_spans": []}, {"section": "Superstrings in dimensions less than ten", "text": "For d = 8 we obtain the familiar superstring in ten dimensional flat space, while for d = 0 we obtain a critical two-dimensional black hole background. The supercoset theory asymptotes to a N = 2 linear dilaton with slope Q = 2 k", "cite_spans": [], "ref_spans": []}, {"section": "Superstrings in dimensions less than ten", "text": ". The short calculation above illustrates how the level of the coset (i.e. dilaton gradient) allows us to interpolate in the dimension of space-time.", "cite_spans": [], "ref_spans": []}, {"section": "Superstrings in dimensions less than ten", "text": "We will now discuss briefly the two-dimensional conformal field theories on the worldsheet. In the d + 2 dimensional theory, the free scalar fields X \u00b5 parameterize the flat space directions. Far from the tip of the cigar, the cigar can be approximated by a cylinder with a dilaton varying linearly along its length. The cylinder directions will be labeled by the fields (\u03c1, \u03b8). 3 For each worldsheet boson there is a corresponding worldsheet fermion.", "cite_spans": [{"start": 379, "end": 380, "text": "3", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "Superstrings in dimensions less than ten", "text": "In the flat directions, we have worldsheet fermions \u03c8 \u00b5 , while the fermions in the cigar directions are named \u03c8 ", "cite_spans": [], "ref_spans": []}, {"section": "Superstrings in dimensions less than ten", "text": "Here, (j, m, m) label the primaries of the SL(2)/U (1) supercoset. We review the construction of these states in more detail in appendix B. Here, we note that the quantum number j governs the radial behavior of the wavefunctions, asymptotically \u03c6 \u223c e 2j\u03c1 ; the quantum numbers m, m are related to the momentum and winding around the cigar. The bulk superstring theories have an interesting physical spectrum that depends strongly on the dimension -this was analyzed in [5, 6, 7 ] to which we refer for details. Below we explicitly write down the vertex operators necessary for the analysis of one point functions we carry out in section 5.", "cite_spans": [{"start": 469, "end": 472, "text": "[5,", "ref_id": "BIBREF4"}, {"start": 473, "end": 475, "text": "6,", "ref_id": "BIBREF5"}, {"start": 476, "end": 477, "text": "7", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "Closed String Vertex Operators for d = 4", "text": "a) The Graviton", "cite_spans": [], "ref_spans": []}, {"section": "Closed String Vertex Operators for d = 4", "text": "In the NSNS sector, we shall first consider states in the (\u22121, \u22121) picture with m = m = 0. The worldsheet states which give us the second rank tensor in spacetime are:", "cite_spans": [], "ref_spans": []}, {"section": "Closed String Vertex Operators for d = 4", "text": "Physical states obey the condition L 0 \u2212 1 =", "cite_spans": [], "ref_spans": []}, {"section": "Closed String Vertex Operators for d = 4", "text": "We will be interested in the graviton modes which propagate in the radial direction of the cigar.", "cite_spans": [], "ref_spans": []}, {"section": "Closed String Vertex Operators for d = 4", "text": "These have k \u00b5 k \u00b5 = 0 and are in the continuous representation on the cigar j = \u2212 1 2 + iP . The on-shell condition becomes P 2 = \u22121/4.", "cite_spans": [], "ref_spans": []}, {"section": "b) The Tachyon", "text": "As mentioned in section 2, the non-trivial part of the closed string background can be thought of as a supercoset or equivalently as an N = 2 Liouville theory with winding condensate. It is immediate from the second description (but it is also seen easily from the first) that there is a stable scalar field (called the tachyon) in the spectrum with asymptotic winding number one. This mode of the tachyon has the form in the (\u22121, \u22121) picture", "cite_spans": [], "ref_spans": []}, {"section": "b) The Tachyon", "text": "The mass shell condition for this mode is", "cite_spans": [], "ref_spans": []}, {"section": "b) The Tachyon", "text": ", and j = \u2212 1 2 + iP , the on-shell state becomes P 2 = 0.", "cite_spans": [], "ref_spans": []}, {"section": "c) The Ramond-Ramond Axion", "text": "We are interested in the zero mode of the axion field and so we restrict to operators with m = m = 0. As we will see below, the calculation of the one point function on the disk forces the Ramond sector vertex operator to be in the (\u2212 ", "cite_spans": [], "ref_spans": []}, {"section": "c) The Ramond-Ramond Axion", "text": "The symmetry of the backreaction problem tells us that the components of the one form field strength along the flat directions vanish: \u2202 \u00b5 \u03c7 = 0. The remaining modes \u2202 \u03b8\u00b1\u03c1 \u03c7 are constructed [7] from the spin fields such that there is zero spin in the flat four directions and the U (1) R charge of the N = 2 algebra on the cigar is Q = ", "cite_spans": [{"start": 190, "end": 193, "text": "[7]", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "c) The Ramond-Ramond Axion", "text": "where the 4-dimensional spinorial index \u03b1 is contracted to get a scalar.", "cite_spans": [], "ref_spans": []}, {"section": "c) The Ramond-Ramond Axion", "text": "We note that the behavior of the graviton which had an effective mass in the six dimensions is different from that of the tachyon and axion which are effectively massless.", "cite_spans": [], "ref_spans": []}, {"section": "c) The Ramond-Ramond Axion", "text": "We shall see later that this difference manifests itself in the difference in the falloff rates in the weak coupling region of the backreaction onto these fields.", "cite_spans": [], "ref_spans": []}, {"section": "General remarks about non-critical strings", "text": "The string coupling at the tip of the cigar g . The parameters are related as", "cite_spans": [], "ref_spans": []}, {"section": "General remarks about non-critical strings", "text": "All the bulk amplitudes of the theory depend on this parameter. This will also be true of the localized branes that we discuss in this paper.", "cite_spans": [], "ref_spans": []}, {"section": "General remarks about non-critical strings", "text": "The various theories have a bosonic Poincare symmetry generated by the momenta There is another conserved charge, the U (1) momentum around the cigar, which acts as an R-symmetry in the d-dimensional superalgebra. We have (in the case of even {S a , S\u03b2} = 2\u03b3", "cite_spans": [], "ref_spans": []}, {"section": "General remarks about non-critical strings", "text": "We have set up the discussion of lower-dimensional string theories without referring explicitly to their ten-dimensional origins since we believe they deserve study in their own right, and exhibit physics that are very particular to their precise form (a simple example being the dimension of space-time). However, it is often helpful to realize their roots in ten dimensions. They arise from NS5-branes or singularities inside a Calabi-Yau manifold, in a double scaling limit [8] [18] in which the string coupling is taken to zero while keeping ", "cite_spans": [{"start": 477, "end": 480, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 481, "end": 485, "text": "[18]", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "The boundary state", "text": "In this section we review the ingredients that are necessary to construct boundary states in the full lower-dimensional string theory that are consistent with the bulk spectrum and the GSO projection [16] . To that end, we need aspects of boundary states in flat space, as well as boundary states in the supersymmetric cigar conformal field theory [21, 22] . We add to this a careful analysis of the Ramond ground state to complete the construction of the full boundary state. We will then use the boundary states assembled in this section to analyze the physics of the spectrum as well as of the one-point function in sections 4, 5 and 6. We assemble some of the details of the set-up in appendix A.", "cite_spans": [{"start": 200, "end": 204, "text": "[16]", "ref_id": "BIBREF18"}, {"start": 348, "end": 352, "text": "[21,", "ref_id": "BIBREF23"}, {"start": 353, "end": 356, "text": "22]", "ref_id": "BIBREF24"}], "ref_spans": []}, {"section": "The terms and factors in the boundary state", "text": "We first recall the different ingredients in the boundary state. The branes we focus on are of the form:", "cite_spans": [], "ref_spans": []}, {"section": "The terms and factors in the boundary state", "text": "where the |B X,\u03c8 refers to that part of the boundary state coming from the flat space IR 1,d\u22121 directions and |B Cig refers to a boundary state in the cigar conformal field theory.", "cite_spans": [], "ref_spans": []}, {"section": "The terms and factors in the boundary state", "text": "The part of the boundary state |B gh in the ghost sector is identical to the one constructed for Dp-branes in ten dimensional superstring theory [23, 24] . The sum denoted by \u03b1 above will run over the periodicity (namely the NS-NS and R-R sectors) and spin structures (which encode how the left and right fermions are glued together for a given periodicity).", "cite_spans": [{"start": 150, "end": 153, "text": "24]", "ref_id": "BIBREF27"}], "ref_spans": []}, {"section": "The terms and factors in the boundary state", "text": "The building blocks that constitute the boundary states are the Ishibashi states which satisfy the gluing conditions for a fixed label \u03b1. They can be solved for separately in the NS-NS and R-R sectors of the theory. In appendix A, we give a detailed construction of the D-branes that are extended in all of the flat spacetime directions, and that are point-like in the cigar directions.", "cite_spans": [], "ref_spans": []}, {"section": "The terms and factors in the boundary state", "text": "We briefly recall the solution to the bosonic part of the conditions on the boundary state:", "cite_spans": [], "ref_spans": []}, {"section": "The terms and factors in the boundary state", "text": "The ket |0, k \u00b5 = 0 denotes the vacuum of the worldsheet bosons. In the fermionic sector, we need to account for the different periodicities and spin structures. The solution to the non-zero modes of the fermionic equations is", "cite_spans": [], "ref_spans": []}, {"section": "The terms and factors in the boundary state", "text": "Here |0, \u03b7 NS/R is the fermionic vacuum. There is a unique NS sector vacuum. However in the R sector, we also need to solve the zero mode fermionic constraints in order to specify the vacuum. Since the total dimension of space-time differs from ten, leading to a different Clifford algebra satisfied by the fermion zeromodes, this calculation differs slightly from the usual one. We give the relevant technical details in the appendix A.", "cite_spans": [], "ref_spans": []}, {"section": "Assembling the full boundary state", "text": "In order to describe the full boundary state, we must be more specific about the sum over periodicities and spin structures in the boundary state (3.1). To construct a", "cite_spans": [], "ref_spans": []}, {"section": "Assembling the full boundary state", "text": "GSO invariant boundary state, we need to sum over NS and R sectors, and then insert a projection operator (1 + (\u2212) F )(1 + (\u2212)F ) in the type IIB superstring theory. The sum over the label \u03b1 is then a sum over four terms, either NS or R and either with or without the insertion of the operator (\u2212) F . 4 This sum is equivalent to a sum over NS and R-sector and the two values of the spin structure \u03b7. 5 We index this sum by the label \u03b1 = (N S, N S, R, R).", "cite_spans": [{"start": 302, "end": 303, "text": "4", "ref_id": "BIBREF3"}, {"start": 401, "end": 402, "text": "5", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "Assembling the full boundary state", "text": "The boundary states of flat space to be tensored with the cigar part are:", "cite_spans": [], "ref_spans": []}, {"section": "Assembling the full boundary state", "text": "where the right hand side of the equation is given by equations (3.2) and (3.3). Finally, in the cigar sector, we read off from [25, 22] (see also [26, 27] ) the expression for the boundary state corresponding to a point-like brane on the cigar:", "cite_spans": [{"start": 128, "end": 132, "text": "[25,", "ref_id": "BIBREF28"}, {"start": 133, "end": 136, "text": "22]", "ref_id": "BIBREF24"}, {"start": 147, "end": 151, "text": "[26,", "ref_id": "BIBREF29"}, {"start": 152, "end": 155, "text": "27]", "ref_id": "BIBREF30"}], "ref_spans": []}, {"section": "Assembling the full boundary state", "text": "As explained in Appendix B, one can separate the supercoset into a bosonic part and free fermions. The wavefunctions in the different sectors are 6 determined by the purely bosonic part of the CFT:", "cite_spans": [], "ref_spans": []}, {"section": "Assembling the full boundary state", "text": "The full GSO projected boundary state can now be written down using the factors (3.4) and (3.5):", "cite_spans": [], "ref_spans": []}, {"section": "Assembling the full boundary state", "text": "The explicit form of the ghost part of the boundary state will not play a role in the computations that follow and so have not been written out. We have used the notation 4 We note here that the raising operators in the Ishibashi states do not change the relative (\u2212) F between the left and right movers. In the NS sector, the vacuum and hence all the boundary states that we have been considering have (\u2212) F = (\u2212)F . In the R sector, the vacuum has to be chosen with a certain value of (\u2212) F + F , and all the states then retain that choice. In either case, the sum over eight terms thus reduces to four terms. 5 In both the NS and R sector, the boundary state satisfies (\u2212) F |\u03b7 = \u00b1| \u2212 \u03b7 , and this facilitates the solution of the GSO projected state as (|\u03b7 = + \u00b1 |\u03b7 = \u2212 ). In the boundary state \u03b7 actually labels whether (\u2212) F is present or not in the sum. 6 We choose u = 1 in the notation of that paper, i.e. the D0-brane on the cigar with only the ", "cite_spans": [{"start": 171, "end": 172, "text": "4", "ref_id": "BIBREF3"}, {"start": 612, "end": 613, "text": "5", "ref_id": "BIBREF4"}, {"start": 860, "end": 861, "text": "6", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "The open string theory on the branes", "text": "In this section we discuss the physics associated to the D-branes we constructed above.", "cite_spans": [], "ref_spans": []}, {"section": "The open string theory on the branes", "text": "In particular, we study in some detail the low-energy spectrum for the open strings living on the D-branes, and the low-energy effective action that describes their dynamics. The Dbranes presented in the previous section break half of the bulk space-time supersymmetry, which will be indicated by the presences of massless fermions (goldstinos). The other half of the bulk supersymmetry is linearly realized on the brane -in appendix C, we exhibit the explicit form of the supercharges preserved by the D-brane in the four-dimensional case d = 4, using a worldsheet analysis.", "cite_spans": [], "ref_spans": []}, {"section": "The open string theory on the branes", "text": "In the following we present for each D-brane, as a function of the dimension d:", "cite_spans": [], "ref_spans": []}, {"section": "The open string theory on the branes", "text": "1. The spectrum of excitations on the D-brane and information on the low energy limit of the worldvolume theory. In every case, the theory is a pure gauge theory with minimal supersymmetry, and the spectrum consists of gauge bosons and gauginos which are the realization of the goldstinos.", "cite_spans": [], "ref_spans": []}, {"section": "The open string theory on the branes", "text": "2. The exact form of the full partition function and a proof that it vanishes for d = 4, 6, consistent with supersymmetry. The case d = 2 is a little subtle, because of the potential existence of unpaired fermion zero modes, on which we shall comment briefly.", "cite_spans": [], "ref_spans": []}, {"section": "The open string theory on the branes", "text": "3. A considerably more general proof of supersymmetry following arguments used for supersymmetric bulk partition functions [28] is presented in appendix D.", "cite_spans": [{"start": 123, "end": 127, "text": "[28]", "ref_id": "BIBREF31"}], "ref_spans": []}, {"section": "The open string theory on the branes", "text": "We first summarize the parts of the analysis that are common to all space-time dimensions. In all dimensions d, the partition function for the branes filling the flat space", "cite_spans": [], "ref_spans": []}, {"section": "The open string theory on the branes", "text": "is given by the following sum over sectors labeled by \u03b1:", "cite_spans": [], "ref_spans": []}, {"section": "The open string theory on the branes", "text": "where the individual terms are given by the expressions [29, 16] :", "cite_spans": [{"start": 56, "end": 60, "text": "[29,", "ref_id": "BIBREF32"}, {"start": 61, "end": 64, "text": "16]", "ref_id": "BIBREF18"}], "ref_spans": []}, {"section": "The open string theory on the branes", "text": "The worldvolume theory on the branes has a bosonic Poincare symmetry in the d flat directions. We show in appendix C that exactly half of the supercharges (2.7) are preserved by the brane. These are of the form", "cite_spans": [], "ref_spans": []}, {"section": "The open string theory on the branes", "text": ". In the free theory, the U (1) R symmetry is preserved. The superalgebra is of the form:", "cite_spans": [], "ref_spans": []}, {"section": "The open string theory on the branes", "text": "In all the open string theories, we can write down the following massless states:", "cite_spans": [], "ref_spans": []}, {"section": "The open string theory on the branes", "text": "Here, \u03a3 \u03b1 is the spin field on the worldsheet which transforms under Spin(d). These states are BRST invariant on the worldsheet when k \u00b5 k \u00b5 = 0, and when the polarizations \u01eb \u00b5 and , there is a sensible low energy limit in which one can write down a low energy action for these massless modes. In the following, we will turn to the individual cases d = 4, 6, 2 and discuss some features of the theories which are typical to the bulk theory in which they are embedded. We start out with the four-dimensional theory.", "cite_spans": [], "ref_spans": []}, {"section": "d = 4 and N = 1 SYM The low energy theory", "text": "Writing the partition function (4.2) in the N S sector as", "cite_spans": [], "ref_spans": []}, {"section": "d = 4 and N = 1 SYM The low energy theory", "text": "the masses of the excitations in sector \u03b1 are obtained by expanding A \u03b1 in powers of", "cite_spans": [], "ref_spans": []}, {"section": "d = 4 and N = 1 SYM The low energy theory", "text": "The coefficients in the expansion give the degeneracy of states with a given mass. We find:", "cite_spans": [], "ref_spans": []}, {"section": "d = 4 and N = 1 SYM The low energy theory", "text": "The first state with negative conformal dimension is the N S sector vacuum and will be projected out by the GSO projection. The lowest lying physical states in the N S sector are therefore two massless gauge bosons from the first excited level. In the R-sector, one finds the expansion", "cite_spans": [], "ref_spans": []}, {"section": "d = 4 and N = 1 SYM The low energy theory", "text": "The partition function in the twisted R sector vanishes, and thus, the (GSO projected)", "cite_spans": [], "ref_spans": []}, {"section": "d = 4 and N = 1 SYM The low energy theory", "text": "Ramond sector gives rise to two physical massless fermionic states in spacetime.", "cite_spans": [], "ref_spans": []}, {"section": "d = 4 and N = 1 SYM The low energy theory", "text": "To summarize, we see that the modes on the brane with k 2 \u00b5 = 0 are two physical states each from the NS / R sector. Analyzing (4.4) for this case, we find that the spectrum consists of a massless gauge boson A \u00b5 and a massless gaugino \u03bb \u03b1 transforming in the 2 of Spin (4), which are the physical degrees of freedom corresponding to the N = 1 SYM multiplet in four dimensions.", "cite_spans": [], "ref_spans": []}, {"section": "d = 4 and N = 1 SYM The low energy theory", "text": "In appendix C, we have shown that the D-brane boundary state (3.7) preserves N = 1 supersymmetry in d = 4. We deduce that the low energy (\u03b1 \u2032 \u2192 0) effective action is indeed that of pure super Yang-Mills theory", "cite_spans": [], "ref_spans": []}, {"section": "Full partition function", "text": "Using the identities in Appendix E, we can rewrite (4.1) as:", "cite_spans": [], "ref_spans": []}, {"section": "Full partition function", "text": "Now we use the following identities of theta functions [30, 6, 31] , (4.10) and plugging into (4.9), we find that The D5-branes preserve eight supercharges, and the low energy theory is then determined to be the (0, 1) supersymmetric Yang-Mills theory in six dimensions.", "cite_spans": [{"start": 55, "end": 59, "text": "[30,", "ref_id": "BIBREF33"}, {"start": 60, "end": 62, "text": "6,", "ref_id": "BIBREF5"}, {"start": 63, "end": 66, "text": "31]", "ref_id": "BIBREF34"}], "ref_spans": []}, {"section": "Full partition function", "text": "As sketched in Appendix E, one can rewrite the partition function as:", "cite_spans": [], "ref_spans": []}, {"section": "Full partition function", "text": "Using the commonly encountered Jacobi identity, we again get the result that the partition function vanishes.", "cite_spans": [], "ref_spans": []}, {"section": "Low energy theory", "text": "For d = 2, we find the q-expansion of the partition functions to be", "cite_spans": [], "ref_spans": []}, {"section": "Low energy theory", "text": "(4.15)", "cite_spans": [], "ref_spans": []}, {"section": "Low energy theory", "text": "By the now familiar argument of low energy spectrum, and exact supersymmetry, we find that in this case, the low energy theory on the D-strings is d = 2, N = (0, 2) SYM.", "cite_spans": [], "ref_spans": []}, {"section": "Low energy theory", "text": "As this case has new features, we present below the full partition function.", "cite_spans": [], "ref_spans": []}, {"section": "Full partition function", "text": "We have:", "cite_spans": [], "ref_spans": []}, {"section": "Full partition function", "text": "At this point, we would like to make a couple of", "cite_spans": [], "ref_spans": []}, {"section": "Comments on fermion zero modes and vanishing of partition function:", "text": "1. Note here that in d = 2, we find two fermionic modes with L 0 = 0, both having", "cite_spans": [], "ref_spans": []}, {"section": "Comments on fermion zero modes and vanishing of partition function:", "text": "F does not vanish due to the presence of poles for two terms that come with the same sign. The usual free fermion degeneracy in the R sector is lifted in the coset for very particular states. This is seen as the fact that an operator G \u00b1 0 annihilates a particular state, instead of giving rise to a degenerate state, or as the presence of a pole in the partition function. Whenever the coset is combined with SCFT's with fermion zero modes (like for d = 4, 6), we will not notice this subtlety (since the extra excitations re-introduce the degeneracy, and make for the vanishing of the total twisted R-sector partition function).", "cite_spans": [], "ref_spans": []}, {"section": "Comments on fermion zero modes and vanishing of partition function:", "text": "2. It is still true that the partition function vanishes and two parallel D-strings do not feel any force. However, the fermion zero modes which are projected out need to be understood better, and may lead to interesting physics.", "cite_spans": [], "ref_spans": []}, {"section": "Backreaction on the NSNS closed string background", "text": "In this section, we concentrate on the case of d = 4 and compute the backreaction on the cigar background by N D3\u2212branes. To first order, this is given by the appropriately transformed one-point function of closed string fields in the presence of the boundary state (3.7) multiplied by a factor of N . In particular, we shall compute the shift in the background value of the fields in the gravity multiplet, and the tachyon multiplet. We assume that the dilaton (the trace of the second rank tensor) couples to the kinetic term in the gauge theory and interpret the profile of the dilaton in the radial direction of the cigar as the running gauge theory coupling (See also e.g. [32, 33, 34, 20] for similar phenomena in related contexts). In order to get a \"geometric interpretation\", we use the following strategy: We use as an input the exact form of the one point functions and reflection amplitudes. As a tool during the computation, we approximate the exact closed string vertex operators with their mini-superspace approximate wavefunction. Even though we work in a strongly curved string background, where the curvature is of order the string length, we can have some faith in our calculations. First of all, the mini-superspace approximation will not be as bad as it looks, since it is known that for N = 2 supersymmetric coset models the background metric and dilaton do not receive further curvature corrections [35, 36] .", "cite_spans": [{"start": 678, "end": 682, "text": "[32,", "ref_id": "BIBREF35"}, {"start": 683, "end": 686, "text": "33,", "ref_id": "BIBREF36"}, {"start": 691, "end": 694, "text": "20]", "ref_id": "BIBREF22"}, {"start": 1422, "end": 1426, "text": "[35,", "ref_id": "BIBREF38"}, {"start": 1427, "end": 1430, "text": "36]", "ref_id": "BIBREF39"}], "ref_spans": []}, {"section": "Backreaction on the NSNS closed string background", "text": "Moreover, at appropriate intuitively understandable junctions in the calculation, we replace semi-classical approximations by their known exact counterparts.", "cite_spans": [], "ref_spans": []}, {"section": "Bulk graviton", "text": "The notation is as discussed in Section 2 and the Appendices: the primary vertex operators in the cigar SCFT are denoted \u03a6 ", "cite_spans": [], "ref_spans": []}, {"section": "Bulk graviton", "text": "where V is the vertex operator for the graviton introduced in section 2. To get the profile in position space, we fold this with the solution of the Laplacian in the six-dimensional background, which factorizes as", "cite_spans": [], "ref_spans": []}, {"section": "Bulk graviton", "text": "The delta functions in the flat directions reduce the expression to a one dimensional integral:", "cite_spans": [], "ref_spans": []}, {"section": "Bulk graviton", "text": "with a = 1/2. The exact one point function of the operator \u03a6 is (3.6) denoted:", "cite_spans": [], "ref_spans": []}, {"section": "Bulk graviton", "text": "3)", "cite_spans": [], "ref_spans": []}, {"section": "Bulk graviton", "text": "The delta-function normalized minisuperspace field \u03c6", "cite_spans": [], "ref_spans": []}, {"section": "Bulk graviton", "text": "where F (a, b; c; z) is the hypergeometric function 2 F 1 . The exact reflection amplitude", "cite_spans": [], "ref_spans": []}, {"section": "Bulk graviton", "text": "is obtained by putting m bos = m bos = 0 in the expression for R(P ) in Appendix B; it obeys R grav (P )R grav (\u2212P ) = 1. Using this, the closed string field configuration can be written as: by the quantum one, we recover (5.6).", "cite_spans": [], "ref_spans": []}, {"section": "Bulk graviton", "text": "The expression for the linear backreaction on the graviton field is now:", "cite_spans": [], "ref_spans": []}, {"section": "Bulk graviton", "text": "In fact the above integral needs a more precise contour prescription for it to be welldefined 8 . First of all, we note that if we had taken only the semi-classical one-point function and reflection amplitude, the above integral (without the factor \u0393(1 \u2212 2iP ) in the denominator) would allow for closing the contour in the P upper half-plane, leading to the evaluation of the integral as the residue of the pole on the positive imaginary axis 9 . For the above approximation to the exact result, a contour prescription will be more subtle,", "cite_spans": [{"start": 94, "end": 95, "text": "8", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "Bulk graviton", "text": "since the behaviour of the extra \u0393 function factor does not allow for the naive semi-classical contour. Although this subtlety is important, we believe that a good approximation to the exact result is given by evaluating the above integral at the pole in the propagator on the positive imaginary axis. (One can dictate a corresponding contour prescription.) We will indeed see in the following in various instances that this prescription captures a lot of the expected physics. The caveat that we described will be present in further backreaction computations as well.", "cite_spans": [], "ref_spans": []}, {"section": "Bulk graviton", "text": "The poles of the integrand are only at P = \u00b1ia, and we prescribed to pick up the pole on the positive imaginary axis, P = +ia, a > 0. We have, with a = ", "cite_spans": [], "ref_spans": []}, {"section": "Bulk graviton", "text": "(5.8)", "cite_spans": [], "ref_spans": []}, {"section": "Bulk graviton", "text": "After multiplying by N , we get the expression for the graviton field:", "cite_spans": [], "ref_spans": []}, {"section": "Bulk graviton", "text": "In the two limits of large and small radial distance, we find that", "cite_spans": [], "ref_spans": []}, {"section": "Bulk graviton", "text": "as \u03c1 \u2192 \u221e and", "cite_spans": [], "ref_spans": []}, {"section": "Bulk graviton", "text": "(5.10)", "cite_spans": [], "ref_spans": []}, {"section": "Comments:", "text": "1. We would like to point out here that the \"Fourier Transform\" we performed in order to convert the momentum space one-point function into the position space profile used only the continuous series j = \u2212 1 2 + iP . However, our result (5.8) is simply the profile of an on-shell mode in the discrete series with asymptotic behavior e \u22122\u03c1 . The graviton mode with polarization in the cigar directions is precisely the interaction operator in the worldsheet theory which is the first correction from the cylinder towards the cigar.", "cite_spans": [], "ref_spans": []}, {"section": "10", "text": "2. This mode is normalizable at the weak coupling end. In this respect, our result is similar to the ones by [38] , in that the the localized branes sources the normalizable mode on the cigar. ", "cite_spans": [], "ref_spans": []}, {"section": "Relation to gauge theory", "text": "The following is a short note on understanding the physics of the calculation above from the point of view of the holographic theory. The cigar background had a metric which was asymptotically flat and a dilaton which behaved as \u03a6(\u03c1) = \u2212 log cosh \u03c1. The one-point function calculation tells us that in the presence of the D-branes, the fields (2.4) whose behaviour in the radial direction is e \u03a6 shift from the background value by (5.7), (5.8). The trace of this second rank tensor gives us the change in the dilaton:", "cite_spans": [], "ref_spans": []}, {"section": "Relation to gauge theory", "text": "To connect with the gauge theory on the D-branes, we use the expansion of this equation near the tip of the cigar where we get:", "cite_spans": [], "ref_spans": []}, {"section": "Relation to gauge theory", "text": "This can be understood semiclassically -notice that the region near the tip cigar behaves like flat space 12 with a constant dilaton. In such a region, a pointlike source has a propagator which is logarithmic in two dimensions. If we use a Born-Infeld type action for the world-volume theory on the D-brane using the background closed string fields,", "cite_spans": [], "ref_spans": []}, {"section": "Relation to gauge theory", "text": "The metric on the cigar (2.1) asymptotically looks like ds 2 = d\u03c1 2 + d\u03b8 2 + e \u22122\u03c1 d\u03b8 2 . 11 Our branes can be thought of as the analog of the ZZ branes of Liouville theory. 12 Note that this is a space of size string scale -there is an overall factor of \u03b1 \u2032 which multiplies the metric.", "cite_spans": [{"start": 174, "end": 176, "text": "12", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "Relation to gauge theory", "text": "and add this as a source to the closed string equations of motion, we recover (5.11). Here \u03c4 3 is a dimensionful quantity entering the tension of the brane.", "cite_spans": [], "ref_spans": []}, {"section": "Relation to gauge theory", "text": "From the Born-Infeld action (5.13), it is clear that e \u2212\u03a6 acts as the coupling constant", "cite_spans": [], "ref_spans": []}, {"section": "Relation to gauge theory", "text": "Y M of the gauge theory. Also, in a putative holographic duality between N = 1 SYM and the closed string theory in the background of these D-branes, it is reasonable to expect that the closed string field e \u2212\u03a6 couples to the operator T rF 2 in the action. Putting all of these facts together, we get:", "cite_spans": [], "ref_spans": []}, {"section": "Relation to gauge theory", "text": "\u223c N log(\u03c1/\u039b) (5.14)", "cite_spans": [], "ref_spans": []}, {"section": "Relation to gauge theory", "text": "Comments;", "cite_spans": [], "ref_spans": []}, {"section": "Relation to gauge theory", "text": "1. We see here that the radial coordinate on the cigar \u03c1 plays the role of the scale in the gauge theory. The constant \u039b, the strong coupling scale in the gauge theory is related to where the RG flow in the IR theory is matched to the full stringy UV complete theory.", "cite_spans": [], "ref_spans": []}, {"section": "Relation to gauge theory", "text": "2. There is a factor of \u03bd \u2212 1 2 present in (5.9). We shall see in the next section that this should be interpreted as the renormalized string coupling at the tip (g tip s,ren ) \u22121 . This renormalization is a redefinition of the zero mode of the dilaton. In the gauge theory, such a redefinition would be a change in the strong coupling scale \u039b.", "cite_spans": [], "ref_spans": []}, {"section": "Bulk tachyon winding mode", "text": "This state has m = m = 1 2 , and possesses the following reflection amplitude (with k = 1):", "cite_spans": [], "ref_spans": []}, {"section": "Bulk tachyon winding mode", "text": "The (generalized) wavefunction for this mode is", "cite_spans": [], "ref_spans": []}, {"section": "Bulk tachyon winding mode", "text": "In the second line, we rewrote the wavefunction in variables suited to the asymptotic region consistent with the above reflection amplitude as in the graviton case. We can now see easily that the asymptotic behavior is \u03a6 tach (\u03c1) \u2261 T (\u03c1) = \u00b5e Liouville theory, and we can extend the understanding gained in that case [39] to this one.", "cite_spans": [{"start": 317, "end": 321, "text": "[39]", "ref_id": "BIBREF42"}], "ref_spans": []}, {"section": "Bulk tachyon winding mode", "text": "First, we note that objects in the theory are singular in the limit k \u2192 1, and we regularize as k = 1 + \u01eb. In order to keep quantities like the two and three point functions in the bulk theory finite, we need to keep\u03bc 2. Keeping track of all the terms in the above computation tells us that the full tachyon winding mode has also a normalizable piece which behaves as \u03a6 \u223c \u00b5 ren log \u00b5 ren e (\u03b8\u2212\u03b8)\u2212\u03c1 . We will see below that this is the mode that is sourced by the brane.", "cite_spans": [], "ref_spans": []}, {"section": "Backreaction on the tachyon winding mode", "text": "The one point function of this mode on our brane is given by:", "cite_spans": [], "ref_spans": []}, {"section": "Backreaction on the tachyon winding mode", "text": "We can collect the above pieces as before to get the expression for the backreaction:", "cite_spans": [], "ref_spans": []}, {"section": "Backreaction on the tachyon winding mode", "text": "We can compute the integral using the principal value prescription 13 :", "cite_spans": [], "ref_spans": []}, {"section": "Backreaction on the tachyon winding mode", "text": "From the discussion of the bulk tachyon field above, it is clear now that the one-point function for the bare tachyon field 14 must diverge, and must be interpreted as \u03b4T \u223c (\u03b4\u00b5)e \u2212\u03c1 . The physical statement to be inferred from the above is:", "cite_spans": [], "ref_spans": []}, {"section": "Backreaction on the RR fields", "text": "We shall now repeat the analysis for the Ramond-Ramond fields which the Dp-brane source. We shall focus on the case of the D3-brane which is charged under the dual of the axion field. The quantum numbers of the RR scalar has been discussed earlier in section 2. The reflection amplitude is given by", "cite_spans": [], "ref_spans": []}, {"section": "Backreaction on the RR fields", "text": "We now compute the profile of the RR field in spacetime following the procedure outlined in the NSNS case. We need to compute the overlap of the RR vertex operator with the boundary state in Appendix A in the (\u2212 ", "cite_spans": [], "ref_spans": []}, {"section": "Backreaction on the RR fields", "text": "where j = \u2212 1 2", "cite_spans": [], "ref_spans": []}, {"section": "Backreaction on the RR fields", "text": "+ iP , and N\u03b1 \u03b2 is the result of the zero mode overlap between the Ramond sector ground state of the boundary state and the spin fields. In this picture, we actually compute the background value of the gauge potential [41] , by taking the trace of (6.2) with the appropriate \u0393-matrices:", "cite_spans": [{"start": 218, "end": 222, "text": "[41]", "ref_id": "BIBREF44"}], "ref_spans": []}, {"section": "Backreaction on the RR fields", "text": "In position space, we thus get the profile of the gauge field to be", "cite_spans": [], "ref_spans": []}, {"section": "Backreaction on the RR fields", "text": "where \u03a8 R P is given by (3.6) with m bos = m bos = 1 2", "cite_spans": [], "ref_spans": []}, {"section": "Backreaction on the RR fields", "text": "The Ramond sector of our boundary state (3.7) tells us that the only non-zero gauge potential is A 0123 .", "cite_spans": [], "ref_spans": []}, {"section": "Backreaction on the RR fields", "text": "It now remains to obtain the solution to the Laplace equation \u03c6 R P (\u03c1) that implements the generalized Fourier transform. For modes with m = m, this solution should have, in the semiclassical limit, the correct reflection amplitude obtained from the coset algebra.", "cite_spans": [], "ref_spans": []}, {"section": "Backreaction on the RR fields", "text": "The required wavefunction in the minisuperspace approximation is given by", "cite_spans": [], "ref_spans": []}, {"section": "Backreaction on the RR fields", "text": "which has an asymptotic expansion: 5) where the quantum reflection amplitude is given by (6.1). Indeed, as for the NS-NS case, we can use the connection formula for the hypergeometric function to check that it reproduces the classical reflection amplitude in the Ramond-Ramond sector [22] with k \u2192 \u221e.", "cite_spans": [{"start": 35, "end": 37, "text": "5)", "ref_id": "BIBREF4"}, {"start": 284, "end": 288, "text": "[22]", "ref_id": "BIBREF24"}], "ref_spans": []}, {"section": "Backreaction on the RR fields", "text": "We can now repeat the analysis of the NS-NS sector. Substituting the above expressions in (6.3) , we get", "cite_spans": [], "ref_spans": []}, {"section": "Backreaction on the RR fields", "text": "This integral is divergent, with a behavior ", "cite_spans": [], "ref_spans": []}, {"section": "Backreaction on the RR fields", "text": "Let us write the vertex operators asymptotically with \u03c1 dependence e ", "cite_spans": [], "ref_spans": []}, {"section": "Backreaction on the RR fields", "text": "We use again the principal value of the integral and evaluating the pole as P \u2192 0, we get:", "cite_spans": [], "ref_spans": []}, {"section": "Backreaction on the RR fields", "text": "(6.9)", "cite_spans": [], "ref_spans": []}, {"section": "Backreaction on the RR fields", "text": "Dualizing, we get \u03c7 \u223c N \u03b8. We shall fix the coefficient in the next section. For now, we note that we can integrate to get an expression for the (non-normalizable) vertex operator for the potential g s A 0123 (\u03c1) = (cosh \u03c1) \u22121 log sinh \u03c1.", "cite_spans": [], "ref_spans": []}, {"section": "A short note on instantons and the chiral U (1) R symmetry breaking.", "text": "The U (1) R symmetry of the Super Yang-Mills theory is realized in the string theory dual as the conserved U (1) momentum around the cigar. Adding the D3-branes at the tip sources a constant RR axion field strength, and the axion field hence depends linearly on the angular coordinate with a coefficient proportional to N which can be determined by channel duality of the annulus amplitude. We shall proceed to fix this coefficient using electric-magnetic duality of the action that describes the massless RR fields.", "cite_spans": [], "ref_spans": []}, {"section": "A short note on instantons and the chiral U (1) R symmetry breaking.", "text": "In the ten dimensional superstring, we know that the shift symmetry of the RR axion is non-perturbatively broken. This is also the case in the non-critical superstring theories, where the shift is realized as translation around the angular direction of the cigar \u03b8. To test this, as usual, we consider a D-instanton in the theory which is charged under this axion field. At all orders in perturbation theory, the zero mode of \u03c7 is a modulus, but this mode multiplies the action of a D-instanton, and for the string theory path integral to be well-defined even after summing over instanton configurations, we deduce that the zero mode is only defined upto periodic identifications.", "cite_spans": [], "ref_spans": []}, {"section": "A short note on instantons and the chiral U (1) R symmetry breaking.", "text": "The type IIB theory contains odd dimensional D-branes with a Chern-Simons coupling \u00b5 p C p+1 for p = \u22121, 1, 3, 5 where the RR potentials C p are canonically normalized.", "cite_spans": [], "ref_spans": []}, {"section": "A short note on instantons and the chiral U (1) R symmetry breaking.", "text": "The action at tree level has a symmetry which exchanges electric and magnetic states under the various gauge potentials. The Dirac quantization condition then implies \u00b5 p \u00b5 2\u2212p = 2\u03c0.", "cite_spans": [], "ref_spans": []}, {"section": "A short note on instantons and the chiral U (1) R symmetry breaking.", "text": "In the presence of N D3-branes, we have \u03c7 = \u00b5 3 N Putting the above facts together tells us that the modification of the closed string background shows a breaking of the chiral U (1) R symmetry of the theory to Z 2N as expected. It is not clear from our construction how the chiral symmetry is broken further to Z 2 . This is expected to involve the exact form of the axion field in the deep IR which is beyond the scope of this work.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "We have taken an exact conformal field theory approach towards the construction of interesting gauge theory physics in lower-dimensional superstring theory backgrounds. The construction and explicit analysis of the full open string spectrum was done using known boundary conformal field theory results for the free scalar conformal field theory and the conformal field theory of the cigar SL(2, R)/U (1). We concentrated on the branes that are localized at the tip of the cigar, and analyzed them in different target space dimensions. We analyzed some of the information encoded in the exact boundary states. We made a first analysis of the resulting backreaction on the closed string background and the physics of the gauge theories that is reflected in it, e.g. the logarithmic running of the coupling constant of N = 1 super Yang-Mills theory, and the breaking of the U (1) R symmetry to Z 2N .", "cite_spans": [], "ref_spans": []}, {"section": "15", "text": "Clearly, there is room for further analysis of the closed string backreaction. In particular, one would like to go beyond the linear approximation for the pure N = 1 super Yang-Mills theory. Since the compactification is at string scale, an exact conformal field 15 It would be desirable to investigate the further breaking to Z 2 . theory approach to this problem would be most convincing -however, supersymmetry may validate a low-energy approach. In particular, it would be desirable to have an analytic solution to the six dimensional non-critical supergravity (along the lines of [42, 43] ) that corresponds to these D-branes.", "cite_spans": [{"start": 263, "end": 265, "text": "15", "ref_id": "BIBREF17"}, {"start": 585, "end": 589, "text": "[42,", "ref_id": "BIBREF45"}, {"start": 590, "end": 593, "text": "43]", "ref_id": "BIBREF46"}], "ref_spans": []}, {"section": "15", "text": "It is interesting to include flavors in the construction presented here [42, 43, 15] , to for instance compare the relative normalizations of the running of the gauge coupling.", "cite_spans": [{"start": 72, "end": 76, "text": "[42,", "ref_id": "BIBREF45"}, {"start": 77, "end": 80, "text": "43,", "ref_id": "BIBREF46"}, {"start": 81, "end": 84, "text": "15]", "ref_id": "BIBREF17"}], "ref_spans": []}, {"section": "15", "text": "Moreover, it will be interesting to study chiral matter in the N = 1 gauge theory, following the techniques for obtaining chiral matter in brane set-ups (see e.g. [44] and references therein). This should allow for a splitting of the multiplets analyzed in [19, 15] .", "cite_spans": [{"start": 163, "end": 167, "text": "[44]", "ref_id": "BIBREF47"}, {"start": 257, "end": 261, "text": "[19,", "ref_id": "BIBREF21"}, {"start": 262, "end": 265, "text": "15]", "ref_id": "BIBREF17"}], "ref_spans": []}, {"section": "15", "text": "A closer analysis of the gauge theory physics, for every individual even dimension d is equally desirable. We believe that the economical brane construction and tools provided in this paper may serve a further analysis well. Finally, we may hope that the exact conformal field theory treatment of this background allows for a continuous interpolation between the more familiar gauge theory physics and the highly stringy physics at the typical length scale of the cigar (i.e. the string scale). We already saw an example of the convincing simplicity of this interpolation in the analysis of the linear backreaction on the dilatonone may hope that this gives us a privileged window on little string theory and holography at the string scale.", "cite_spans": [], "ref_spans": []}, {"section": "Acknowledgments", "text": "We would like to thank Bobby Acharya, Costas Bachas, Matteo Bertolini, Justin David, Eleonora Dell'Aquila, Angelos Fotopoulos, Edi Gava, Dan Israel, Sunil Mukhi, Vasilis Niarchos, Ari Pakman, Nikolaos Prezas and Ashoke Sen for discussions on related topics and useful correspondence. S.A. would like to thank the kind hospitality of the Harish-Chandra Research Institute, Allahabad, where part of this research was done. We would also like to thank the developers of Skype softphone that facilitated free intercontinental communication.", "cite_spans": [], "ref_spans": []}, {"section": "Appendix A. A few details of the construction of the full boundary states", "text": "In the following, we will construct D-branes that are extended in all of the flat spacetime directions, and that are point-like in the cigar directions. 16 The notion of being point-like is of course a semiclassical statement. The defining feature of the branes we shall study is that they are BPS (B branes), preserve the momentum around the cigar and localized near the tip.", "cite_spans": [{"start": 153, "end": 155, "text": "16", "ref_id": "BIBREF18"}], "ref_spans": []}, {"section": "Appendix A. A few details of the construction of the full boundary states", "text": "We will denote the boundary state by |Bp with p = d \u2212 1. In the IR", "cite_spans": [], "ref_spans": []}, {"section": "Appendix A. A few details of the construction of the full boundary states", "text": "we have the worldsheet equations", "cite_spans": [], "ref_spans": []}, {"section": "Appendix A. A few details of the construction of the full boundary states", "text": "We will follow the conventions that the left-movers are holomorphic and the right movers (indicated by variables with tildes) are anti-holomorphic. In terms of the worldsheet modes, the equations become There is another Z Z 2 ambiguity in the choice relating the left and right moving N = 2 currents which tells us whether we have A or B branes. We shall be interested in B-type boundary conditions J R = \u2212J R , G \u00b1 = i\u03b7G \u00b1 which leads to branes of the type (A.1) extended along the flat directions and localized on the cigar. This leads also to Neumann boundary conditions on the angular direction of the cigar [22] . These imply that the one point functions have a delta function in the momentum n around the cigar. 18 In the conventions introduced earlier, this means that m = m.", "cite_spans": [{"start": 612, "end": 616, "text": "[22]", "ref_id": "BIBREF24"}, {"start": 718, "end": 720, "text": "18", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "A.1. Ramond ground state", "text": "We need to solve for the zero mode factor of the boundary state that solves the conditions in equation (A.2). The R sector ground state of the theory also includes the solution of the zero modes equations of the two fermions of the coset. The fact that the worldsheet fermions are free facilitates this analysis. We can treat this part of the problem as one in flat space R 1,d+1 with the understanding that the Ramond ground states in the cigar have charges and conformal weights different from those of two dimensional flat space in such a way that the ground states we write down are weight one states of the full string theory. The full set of zero mode equations we wish to solve is then:", "cite_spans": [], "ref_spans": []}, {"section": "A.1. Ramond ground state", "text": "We choose the following representation of the gamma matrices for even dimension d [46] for IR", "cite_spans": [{"start": 82, "end": 86, "text": "[46]", "ref_id": "BIBREF49"}], "ref_spans": []}, {"section": "A.1. Ramond ground state", "text": "We further define the parity and charge conjugation matrices:", "cite_spans": [], "ref_spans": []}, {"section": "A.1. Ramond ground state", "text": "18 We note that the conventions of [25] are opposite to ours (the BPS localized D-branes in IIB theory are the A branes in [16] ) because they consider the theory on the T-dual circle with a condensate of momentum. Indeed, in the exact conformal field theory, the choice of A-or Btype boundary condition is arbitrary, since they are related by an automorphism of the N = 2 superconformal algebra. It is only after we specify a specific semi-classical picture, i.e. give a geometrical interpretation to the N = 2 currents and the branes in the conformal field theory that the distinction between A-type and B-type branes becomes meaningful.", "cite_spans": [{"start": 35, "end": 39, "text": "[25]", "ref_id": "BIBREF28"}, {"start": 123, "end": 127, "text": "[16]", "ref_id": "BIBREF18"}], "ref_spans": []}, {"section": "A.1. Ramond ground state", "text": "The operator \u0393 is defined to have eigenvalues \u00b11. The gamma matrices obey the relations:", "cite_spans": [], "ref_spans": []}, {"section": "A.1. Ramond ground state", "text": "Denoting the vacuum by |B 0 = |A | B where A and B are the 2 d+1 2 dimensional spinor indices of Spin(d + 2), the action of \u03c8 I ,\u03c8 I are those of the gamma matrices as implied by the fermion zeromode commutation relations: ", "cite_spans": [], "ref_spans": []}, {"section": "A.1. Ramond ground state", "text": "A solution to the equation is:", "cite_spans": [], "ref_spans": []}, {"section": "A.1. Ramond ground state", "text": "It is also useful to decompose the spinors into d dimensional spinors with specific chirality under \u0393. Since \u0393 has eigenvalues \u00b11, we can always choose a basis where the top half of the 2 d 2 spinor and the bottom half have eigenvalues \u00b11. We can then decompose the matrix M AB = M \u03b1\u03b2 M \u03b1\u03b2 M\u03b1 \u03b2 M\u03b1\u03b2 . The vacuum solution can be written as a superposition:", "cite_spans": [], "ref_spans": []}, {"section": "A.1. Ramond ground state", "text": "where the two terms are given by:", "cite_spans": [], "ref_spans": []}, {"section": "A.1. Ramond ground state", "text": "Here, we have chosen the (\u2212 2 ) picture for the superghosts (which is a useful to compute one point functions [24] [41]). Notice that the two terms have definite fermion number eigenvalue:", "cite_spans": [{"start": 110, "end": 114, "text": "[24]", "ref_id": "BIBREF27"}], "ref_spans": []}, {"section": "A.1. Ramond ground state", "text": "(\u2212)", "cite_spans": [], "ref_spans": []}, {"section": "A.1. Ramond ground state", "text": "which implies the relations:", "cite_spans": [], "ref_spans": []}, {"section": "A.1. Ramond ground state", "text": "This completes the discussion of the solution to the zero-mode conditions on the boundary state in the R-sector.", "cite_spans": [], "ref_spans": []}, {"section": "A.2. Spectral flowed extended characters", "text": "The open string partition function for the point-like brane in the cigar supercoset conformal field theory is most easily encoded in characters of the N = 2 superconformal algebra that are extended, i.e. summed over spectral flow orbits. Below, the character Ch t denotes the extended character of the N = 2 superconformal algebra associated to the trivial representation of SL(2, R). The trivial representation is a finite, one-dimensional representation. We can associate a spin j = 0 to this representation (or u = 1 in the notation of [22] ). We recall the trivial unextended characters:", "cite_spans": [{"start": 539, "end": 543, "text": "[22]", "ref_id": "BIBREF24"}], "ref_spans": []}, {"section": "A.2. Spectral flowed extended characters", "text": "in the notation of [22] (brought slightly closer to more standard notation). In the R-sector r \u2032 = r + 1/2, i.e. it takes values in a range which is shifted compared to the NS-sector range. To define the extended characters, we perform a sum over spectral flow orbits. Suppose we have a rational level k = N K , where K, N are strictly positive integers (and let's suppose they have greatest common divisor one). We define the extended characters by a sum over spectral flow orbits, determined by the integer N :", "cite_spans": [{"start": 19, "end": 23, "text": "[22]", "ref_id": "BIBREF24"}], "ref_spans": []}, {"section": "A.2. Spectral flowed extended characters", "text": "(A.14)", "cite_spans": [], "ref_spans": []}, {"section": "A.2. Spectral flowed extended characters", "text": "We compute and find the following characters:", "cite_spans": [], "ref_spans": []}, {"section": "A.2. Spectral flowed extended characters", "text": "(A.15)", "cite_spans": [], "ref_spans": []}, {"section": "A.2. Spectral flowed extended characters", "text": "Again r \u2032 = r + 1/2, i.e. r \u2032 takes values in a shifted range compared to the NS-sector where r \u2208 Z N . For the twisted R-sector, generically, we need to be careful. Indeed, although the \u03b8 1 function may be zero, there may appear a pole in the denominator of the other factors,", "cite_spans": [], "ref_spans": []}, {"section": "A.2. Spectral flowed extended characters", "text": "for particular values of z and r \u2032 . We therefore note that generically we have: ", "cite_spans": [], "ref_spans": []}, {"section": "Appendix B. Closed String Vertex Operators on the Cigar", "text": "In this section, we construct the primaries of the supersymmetric coset SL(2, IR)/U (1) at level k. We follow the conventions of [48, 22] and references therein. This theory has an N = 2 superconformal symmetry. The parent supersymmetric SL(2, IR) k theory has currents J a and \u03c8 a which have coupled OPEs", "cite_spans": [{"start": 129, "end": 133, "text": "[48,", "ref_id": "BIBREF51"}, {"start": 134, "end": 137, "text": "22]", "ref_id": "BIBREF24"}], "ref_spans": []}, {"section": "Appendix B. Closed String Vertex Operators on the Cigar", "text": "with the fermions satisfying the usual OPEs. This theory is a product of a bosonic SL(2, IR)", "cite_spans": [], "ref_spans": []}, {"section": "Appendix B. Closed String Vertex Operators on the Cigar", "text": "at level k + 2, generated by the currents", "cite_spans": [], "ref_spans": []}, {"section": "Appendix B. Closed String Vertex Operators on the Cigar", "text": "and three free fermions. The U (1) symmetry to be gauged is generated by J 3 , \u03c8 3 cig . The currents that make up the N = 2 chiral algebra on the coset are: As these fields are independent of the free fermions, they are also primary fields of the superconformal SL(2, IR) at level k. In order to obtain the primaries of the coset, it is useful to bosonize the various currents we have as follows:", "cite_spans": [], "ref_spans": []}, {"section": "Appendix B. Closed String Vertex Operators on the Cigar", "text": "where the normalizations ensure that the scalars have canonical OPEs. These scalars are not all independent and using the definition of the bosonic currents and the N = 2 (B.2), we can rewrite all scalars in terms of X 3 and X R :", "cite_spans": [], "ref_spans": []}, {"section": "Appendix B. Closed String Vertex Operators on the Cigar", "text": "Given these expressions, and knowing that the currents that are gauged in the coset are ", "cite_spans": [], "ref_spans": []}, {"section": "Appendix B. Closed String Vertex Operators on the Cigar", "text": "In the supersymmetric coset, we also gauge the fermionic current \u03c8 3 and the primary we start with in the parent theory is of the form V In terms of m and n, the conformal dimension is read off to be", "cite_spans": [], "ref_spans": []}, {"section": "Appendix B. Closed String Vertex Operators on the Cigar", "text": "while the R-charge is given by", "cite_spans": [], "ref_spans": []}, {"section": "Appendix B. Closed String Vertex Operators on the Cigar", "text": "In the NSNS sector, we have n \u2208 Z Z, while in the RR sector, we have n \u2208 Z Z + ", "cite_spans": [], "ref_spans": []}, {"section": "Appendix B. Closed String Vertex Operators on the Cigar", "text": "In the full theory, we tensor together these operators with the flat space operators as in (2.3). The physical operators are obtained by imposing BRST invariance and a GSO projection which tie together the two Hilbert spaces. 19 The negative sign follows from the axial gauging of the coset.", "cite_spans": [{"start": 226, "end": 228, "text": "19", "ref_id": "BIBREF21"}], "ref_spans": []}, {"section": "B.1. Reflection Amplitude", "text": "For completeness, we also write down the reflection amplitude for the bulk fields. It is defined by the two point function of the fields \u03a6 j,n,n m bos ,m bos", "cite_spans": [], "ref_spans": []}, {"section": "B.1. Reflection Amplitude", "text": "Note that irrespective of whether the operators are in the NSNS or RR sector, the reflection amplitude is determined by the quantum numbers m bos , m bos from the k + 2-level bosonic current algebra.", "cite_spans": [], "ref_spans": []}, {"section": "Appendix C. The construction of the conserved space-time supercharges", "text": "In this appendix, we show that a combination of the supercurrents S \u03b1 (z) andS \u03b1 (z) is conserved on the open string worldsheet; in other words, the supercharges dz S \u03b1 (z) + dzS \u03b1 (z) annihilate the boundary state. This construction is subtle at the quantum mechanical level [49, 23, 24] . We shall prove it at the classical level by studying the boundary conditions on the worldsheet fields.", "cite_spans": [{"start": 276, "end": 280, "text": "[49,", "ref_id": "BIBREF52"}, {"start": 285, "end": 288, "text": "24]", "ref_id": "BIBREF27"}], "ref_spans": []}, {"section": "Appendix C. The construction of the conserved space-time supercharges", "text": "As already discussed in Appendix B, the supersymmetric coset SL 2 /U (1) is described as a product of the bosonic SL(2, IR) k+2 and the two free fermions \u03c8 \u00b1 cig which have OPE's which do not mix [17] . Also, the fermions \u03c8 a cig have conformal weight 1 2 and can be bosonized as", "cite_spans": [{"start": 196, "end": 200, "text": "[17]", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "Appendix C. The construction of the conserved space-time supercharges", "text": "We have already exhibited the N = 2 algebra of the coset in (B.2). The N = 2 supersymmetry in the IR 1,3 factor can be seen by forming the linear combinations", "cite_spans": [], "ref_spans": []}, {"section": "Appendix C. The construction of the conserved space-time supercharges", "text": "in terms of which", "cite_spans": [], "ref_spans": []}, {"section": "Appendix C. The construction of the conserved space-time supercharges", "text": "We bosonize the fermions and denote them", "cite_spans": [], "ref_spans": []}, {"section": "Appendix C. The construction of the conserved space-time supercharges", "text": "Denoting the bosonized superghost by \u03d5, the dimension one operator which is the spacetime supercharge is [4] ", "cite_spans": [{"start": 105, "end": 108, "text": "[4]", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "Appendix C. The construction of the conserved space-time supercharges", "text": "In order to verify that the boundary state we have constructed is supersymmetric (at least at the classical level), we will begin with the boundary conditions (A.3)", "cite_spans": [], "ref_spans": []}, {"section": "Appendix C. The construction of the conserved space-time supercharges", "text": "and construct the linear combination of (C.5) and its right-moving counterpart that is preserved by the D-brane. Rewriting this in the bosonized variables, we get the boundary conditions:", "cite_spans": [], "ref_spans": []}, {"section": "Appendix C. The construction of the conserved space-time supercharges", "text": "The superconformal ghosts obey the boundary condition [23] ", "cite_spans": [], "ref_spans": []}, {"section": "Appendix C. The construction of the conserved space-time supercharges", "text": "We need to supplement these standard boundary conditions with boundary conditions for the chiral boson \u03b8 which preserve the Neumann condition on the boson:", "cite_spans": [], "ref_spans": []}, {"section": "Appendix C. The construction of the conserved space-time supercharges", "text": "We note as a check that for the case d = 6, when the chiral boson is at the free fermion radius, the boundary condition (C.9) is the same as the one for the other fermions (C.7).", "cite_spans": [], "ref_spans": []}, {"section": "Appendix C. The construction of the conserved space-time supercharges", "text": "Using (C.7), (C.9) and (C.8), one can check that the combination of supercharges that preserve the boundary condition is S +S . Other supercharges, which are local with respect to this one are obtained by flipping the signs in front of two of the three bosonized fields H a . One can show that for all of these supercharges, the same left-right combination preserves the boundary condition.", "cite_spans": [], "ref_spans": []}, {"section": "Appendix D. A generic proof of the vanishing of supersymmetric open string partition functions", "text": "We sketch a generic proof of the vanishing of the GSO projected open string partition function. Our aim in this section is to clarify conceptually the mechanism underlying the delicate cancellation of the bosonic and fermionic contributions to the partition functions.", "cite_spans": [], "ref_spans": []}, {"section": "Appendix D. A generic proof of the vanishing of supersymmetric open string partition functions", "text": "To lay bare the generic mechanism, we export some important lessons from the construction of bulk supersymmetric partition functions to our context (see especially [28] for a nice summary of the relevant techniques in the bulk). The basic differences with the bulk analysis is that for the annulus amplitude, we needn't worry about modular invariance, and on the other hand that we wish to prove the supersymmetry of the open string spectrum -we therefore apply the relevant part of the strategy of [28] in the open string channel directly.", "cite_spans": [{"start": 164, "end": 168, "text": "[28]", "ref_id": "BIBREF31"}, {"start": 499, "end": 503, "text": "[28]", "ref_id": "BIBREF31"}], "ref_spans": []}, {"section": "Appendix D. A generic proof of the vanishing of supersymmetric open string partition functions", "text": "Let's assume then, following [28] that we are in light-cone gauge -which most straight- We observe that the degrees of freedom associated to the U (1) R scalar \u03c6 may be fermionized using one (chiral) complex fermion. The complex fermion will be in the R-sector, provided that all total light-cone U (1) R charges are odd. That is the second assumption. (The assumption is realized by performing a GSO projection.)", "cite_spans": [{"start": 29, "end": 33, "text": "[28]", "ref_id": "BIBREF31"}], "ref_spans": []}, {"section": "Appendix D. A generic proof of the vanishing of supersymmetric open string partition functions", "text": "We expect that the operators O 1/2 = e i\u03c6 and O \u2020 1/2 = e \u2212i\u03c6 , leave the total partition function invariant (up to a minus sign). For the first operator, this is manifest, while for the second it follows from the bijective character of spectral flow (see also [28] for a slightly different argument).", "cite_spans": [{"start": 261, "end": 265, "text": "[28]", "ref_id": "BIBREF31"}], "ref_spans": []}, {"section": "Appendix D. A generic proof of the vanishing of supersymmetric open string partition functions", "text": "The vanishing of the partition function can now be argued for as follows. We concentrate on the fermionized U The first term in the third expression corresponds to R-charges that are one modulo four, while the second term corresponds to R-charges that are three modulo four. The relative sign is necessary for the partition function to change sign under the action of O 1/2 . The partition function is zero -it has a factor that is zero, corresponding to a twisted R-sector partition function for a chiral complex fermion.", "cite_spans": [], "ref_spans": []}, {"section": "Appendix D. A generic proof of the vanishing of supersymmetric open string partition functions", "text": "In summary, the proof of the vanishing of the open string partition function is generic, provided we can show that it is of the form we assumed above. It is more straightforward then its closed string counterpart because we needn't worry about modular invariance.", "cite_spans": [], "ref_spans": []}, {"section": "Appendix D. A generic proof of the vanishing of supersymmetric open string partition functions", "text": "The adaptation from the proof in [28] is conceptual, in that we thought of it as applying to the open string channel. Note that the above proof provides the rationale for the thetafunction identities proven in the bulk of the paper and a lot of other identities that may be difficult to prove otherwise, and that it explains the generic logic for the implementation of the GSO projection in the open string channel. We note for instance that some identities for which numerical evidence was provided in [50] (referred to in [25] in a context very close to that of our paper) can be proven in the above fashion. Note that the proof equally well applies to the case of D-branes in compact Gepner models [51] [52] . In all these cases, the conditions on the proof are met. To prove the vanishing of the exact partition function, we use the identity (where the sum is a formal sum over any set), (E.2) 20 We also plugged the modular functions into a symbolic manipulation program and got the expansion to high order.", "cite_spans": [{"start": 33, "end": 37, "text": "[28]", "ref_id": "BIBREF31"}, {"start": 503, "end": 507, "text": "[50]", "ref_id": "BIBREF53"}, {"start": 524, "end": 528, "text": "[25]", "ref_id": "BIBREF28"}, {"start": 706, "end": 710, "text": "[52]", "ref_id": "BIBREF55"}, {"start": 898, "end": 900, "text": "20", "ref_id": "BIBREF22"}], "ref_spans": []}, {"section": "E.2. d=6", "text": "We use a formal power series expansion to re-express the first term Z NS as 21 : Using similar manipulations, we get the other the equations in (4.13). 21 It is dangerous to use the formal power series expansion for s < 0. In a more careful analysis, one splits the sum over s into two sums, both containing positive powers of q as we did previously.", "cite_spans": [{"start": 152, "end": 154, "text": "21", "ref_id": "BIBREF23"}], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Type IIB superstrings, BPS monopoles, and threedimensional gauge dynamics", "authors": [{"first": "A", "middle": [], "last": "Hanany", "suffix": ""}, {"first": "E", "middle": [], "last": "Witten", "suffix": ""}], "year": 1997, "venue": "Nucl. Phys. B", "link": "122644424"}, "BIBREF1": {"title": "Dirichlet-Branes and Ramond-Ramond Charges", "authors": [{"first": "J", "middle": [], "last": "Polchinski", "suffix": ""}], "year": 1995, "venue": "Phys. Rev. Lett", "link": null}, "BIBREF2": {"title": "The large N limit of superconformal field theories and supergravity", "authors": [{"first": "J", "middle": ["M"], "last": "Maldacena", "suffix": ""}], "year": 1998, "venue": "Adv. Theor. Math. Phys", "link": "12613310"}, "BIBREF3": {"title": "Noncritical Superstrings", "authors": [{"first": "D", "middle": [], "last": "Kutasov", "suffix": ""}, {"first": "N", "middle": [], "last": "Seiberg", "suffix": ""}], "year": 1990, "venue": "Phys. Lett. B", "link": null}, "BIBREF4": {"title": "Modular invariance in superstring on Calabi-Yau n-fold with A-D-E singularity", "authors": [{"first": "T", "middle": [], "last": "Eguchi", "suffix": ""}, {"first": "Y", "middle": [], "last": "Sugawara", "suffix": ""}], "year": 2000, "venue": "Nucl. Phys. B", "link": null}, "BIBREF5": {"title": "Modular invariant critical superstrings on four-dimensional Minkowski space \u00d7 two-dimensional black hole", "authors": [{"first": "S", "middle": [], "last": "Mizoguchi", "suffix": ""}], "year": 2000, "venue": "JHEP", "link": null}, "BIBREF6": {"title": "Notes on non-critical superstrings in various dimensions", "authors": [{"first": "S", "middle": [], "last": "Murthy", "suffix": ""}], "year": 2003, "venue": "JHEP", "link": "15621068"}, "BIBREF7": {"title": "Holography for non-critical superstrings", "authors": [{"first": "A", "middle": [], "last": "Giveon", "suffix": ""}, {"first": "D", "middle": [], "last": "Kutasov", "suffix": ""}, {"first": "O", "middle": [], "last": "Pelc", "suffix": ""}], "year": 1999, "venue": "JHEP", "link": "3240821"}, "BIBREF8": {"title": "Strings from tachyons: The c = 1 matrix reloaded", "authors": [{"first": "J", "middle": [], "last": "Mcgreevy", "suffix": ""}, {"first": "H", "middle": [], "last": "Verlinde", "suffix": ""}], "year": 2003, "venue": "JHEP", "link": null}, "BIBREF9": {"title": "D-brane decay in two-dimensional string theory", "authors": [{"first": "I", "middle": ["R"], "last": "Klebanov", "suffix": ""}, {"first": "J", "middle": [], "last": "Maldacena", "suffix": ""}, {"first": "N", "middle": [], "last": "Seiberg", "suffix": ""}], "year": 2003, "venue": "JHEP", "link": "30161331"}, "BIBREF10": {"title": "A new hat for the c = 1 matrix model", "authors": [{"first": "M", "middle": ["R"], "last": "Douglas", "suffix": ""}, {"first": "I", "middle": ["R"], "last": "Klebanov", "suffix": ""}, {"first": "D", "middle": [], "last": "Kutasov", "suffix": ""}, {"first": "J", "middle": [], "last": "Maldacena", "suffix": ""}, {"first": "E", "middle": [], "last": "Martinec", "suffix": ""}, {"first": "N", "middle": [], "last": "Seiberg", "suffix": ""}], "year": "", "venue": "", "link": "8840778"}, "BIBREF11": {"title": "A matrix model dual of type 0B string theory in two dimensions", "authors": [{"first": "T", "middle": [], "last": "Takayanagi", "suffix": ""}, {"first": "N", "middle": [], "last": "Toumbas", "suffix": ""}], "year": 2003, "venue": "JHEP", "link": null}, "BIBREF12": {"title": "Linear dilatons, NS5-branes and holography", "authors": [{"first": "O", "middle": [], "last": "Aharony", "suffix": ""}, {"first": "M", "middle": [], "last": "Berkooz", "suffix": ""}, {"first": "D", "middle": [], "last": "Kutasov", "suffix": ""}, {"first": "N", "middle": [], "last": "Seiberg", "suffix": ""}], "year": 1998, "venue": "JHEP", "link": null}, "BIBREF13": {"title": "Supergravity and a confining gauge theory: Duality cascades and chiSB-resolution of naked singularities", "authors": [{"first": "I", "middle": ["R"], "last": "Klebanov", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Strassler", "suffix": ""}], "year": 2000, "venue": "JHEP", "link": "2484915"}, "BIBREF14": {"title": "Towards the large N limit of pure N = 1 super Yang Mills", "authors": [{"first": "J", "middle": ["M"], "last": "Maldacena", "suffix": ""}, {"first": "C", "middle": [], "last": "Nunez", "suffix": ""}], "year": 2001, "venue": "Phys. Rev. Lett", "link": null}, "BIBREF15": {"title": "The string dual of a confining four-dimensional gauge theory", "authors": [{"first": "J", "middle": [], "last": "Polchinski", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Strassler", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF16": {"title": "A gravity dual of the chiral anomaly", "authors": [{"first": "I", "middle": ["R"], "last": "Klebanov", "suffix": ""}, {"first": "P", "middle": [], "last": "Ouyang", "suffix": ""}, {"first": "E", "middle": [], "last": "Witten", "suffix": ""}], "year": 2002, "venue": "Phys. Rev. D", "link": null}, "BIBREF17": {"title": "D-branes and SQCD in Non-Critical Superstring Theory", "authors": [{"first": "A", "middle": [], "last": "Fotopoulos", "suffix": ""}, {"first": "V", "middle": [], "last": "Niarchos", "suffix": ""}, {"first": "N", "middle": [], "last": "Prezas", "suffix": ""}], "year": "", "venue": "", "link": "8735717"}, "BIBREF18": {"title": "Modular bootstrap for boundary N = 2 Liouville theory", "authors": [{"first": "T", "middle": [], "last": "Eguchi", "suffix": ""}, {"first": "Y", "middle": [], "last": "Sugawara", "suffix": ""}], "year": 2004, "venue": "JHEP", "link": "119348791"}, "BIBREF19": {"title": "New N=2 Superconformal Field Theories And Superstring Compactification", "authors": [{"first": "Y", "middle": [], "last": "Kazama", "suffix": ""}, {"first": "H", "middle": [], "last": "Suzuki", "suffix": ""}], "year": 1989, "venue": "", "link": "123032075"}, "BIBREF20": {"title": "Little string theory in a double scaling limit", "authors": [{"first": "A", "middle": [], "last": "Giveon", "suffix": ""}, {"first": "D", "middle": [], "last": "Kutasov", "suffix": ""}], "year": 1999, "venue": "JHEP", "link": "2452099"}, "BIBREF21": {"title": "D-branes in the background of NS fivebranes", "authors": [{"first": "S", "middle": [], "last": "Elitzur", "suffix": ""}, {"first": "A", "middle": [], "last": "Giveon", "suffix": ""}, {"first": "D", "middle": [], "last": "Kutasov", "suffix": ""}, {"first": "E", "middle": [], "last": "Rabinovici", "suffix": ""}, {"first": "G", "middle": [], "last": "Sarkissian", "suffix": ""}], "year": 2000, "venue": "JHEP", "link": "122184756"}, "BIBREF22": {"title": "D-branes in little string theory", "authors": [{"first": "D", "middle": [], "last": "Israel", "suffix": ""}, {"first": "A", "middle": [], "last": "Pakman", "suffix": ""}, {"first": "J", "middle": [], "last": "Troost", "suffix": ""}], "year": "", "venue": "", "link": "13885443"}, "BIBREF23": {"title": "Branes in the 2-D black hole", "authors": [{"first": "S", "middle": [], "last": "Ribault", "suffix": ""}, {"first": "V", "middle": [], "last": "Schomerus", "suffix": ""}], "year": 2004, "venue": "JHEP", "link": null}, "BIBREF24": {"title": "D-branes in N = 2 Liouville theory and its mirror", "authors": [{"first": "D", "middle": [], "last": "Israel", "suffix": ""}, {"first": "A", "middle": [], "last": "Pakman", "suffix": ""}, {"first": "J", "middle": [], "last": "Troost", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF26": {"title": "Adding Holes And Crosscaps To The Superstring", "authors": [{"first": "C", "middle": [], "last": "Callan", "suffix": ""}, {"first": "C", "middle": ["R"], "last": "Lovelace", "suffix": ""}, {"first": "S", "middle": ["A"], "last": "Nappi", "suffix": ""}, {"first": "", "middle": [], "last": "Yost", "suffix": ""}], "year": 1987, "venue": "Nucl. Phys. B", "link": "120177121"}, "BIBREF27": {"title": "Bosonized Superstring Boundary States And Partition Functions", "authors": [{"first": "S", "middle": ["A"], "last": "Yost", "suffix": ""}], "year": 1989, "venue": "Nucl. Phys. B", "link": "121813948"}, "BIBREF28": {"title": "Modular bootstrap for boundary N = 2 Liouville theory", "authors": [{"first": "T", "middle": [], "last": "Eguchi", "suffix": ""}, {"first": "Y", "middle": [], "last": "Sugawara", "suffix": ""}], "year": 2004, "venue": "JHEP", "link": "119348791"}, "BIBREF29": {"title": "ZZ-branes of N = 2 super-Liouville theory", "authors": [{"first": "C", "middle": [], "last": "Ahn", "suffix": ""}, {"first": "M", "middle": [], "last": "Stanishkov", "suffix": ""}, {"first": "M", "middle": [], "last": "Yamamoto", "suffix": ""}], "year": 2004, "venue": "JHEP", "link": "16326310"}, "BIBREF30": {"title": "N = 2 Liouville theory with boundary", "authors": [{"first": "K", "middle": [], "last": "Hosomichi", "suffix": ""}], "year": "", "venue": "", "link": "119380415"}, "BIBREF31": {"title": "PUPT-1121 Lectures at Spring School on Superstrings", "authors": [{"first": "D", "middle": [], "last": "Gepner", "suffix": ""}], "year": 1989, "venue": "", "link": null}, "BIBREF32": {"title": "Lectures on non-BPS Dirichlet branes", "authors": [{"first": "M", "middle": ["R"], "last": "Gaberdiel", "suffix": ""}], "year": 2000, "venue": "Class. Quant. Grav", "link": "16438195"}, "BIBREF33": {"title": "Theta constants, Riemann surfaces and the modular group", "authors": [{"first": "H", "middle": ["M"], "last": "Farkas", "suffix": ""}, {"first": "I", "middle": [], "last": "Kra", "suffix": ""}], "year": "", "venue": "Graduate studies in mathematics", "link": null}, "BIBREF34": {"title": "New critical dimensions for string theories", "authors": [{"first": "A", "middle": [], "last": "Bilal", "suffix": ""}, {"first": "J", "middle": ["L"], "last": "Gervais", "suffix": ""}], "year": 1987, "venue": "Nucl. Phys. B", "link": "119799581"}, "BIBREF35": {"title": "Solutions of four-dimensional field theories via M-theory", "authors": [{"first": "E", "middle": [], "last": "Witten", "suffix": ""}], "year": 1997, "venue": "Nucl. Phys. B", "link": null}, "BIBREF36": {"title": "Gauge theories from D branes", "authors": [{"first": "P", "middle": [], "last": "", "suffix": ""}, {"first": "Di", "middle": [], "last": "Vecchia", "suffix": ""}, {"first": "A", "middle": [], "last": "Liccardo", "suffix": ""}], "year": "", "venue": "", "link": "18988713"}, "BIBREF38": {"title": "Conformally exact metric and dilaton in string theory on curved space-time", "authors": [{"first": "I", "middle": [], "last": "Bars", "suffix": ""}, {"first": "K", "middle": [], "last": "Sfetsos", "suffix": ""}], "year": 1992, "venue": "Phys. Rev. D", "link": null}, "BIBREF39": {"title": "Conformal sigma models corresponding to gauged Wess-ZuminoWitten theories", "authors": [{"first": "A", "middle": ["A"], "last": "Tseytlin", "suffix": ""}], "year": 1994, "venue": "Nucl. Phys. B", "link": "14763241"}, "BIBREF40": {"title": "Handbook of Mathematical Functions", "authors": [{"first": "M", "middle": [], "last": "Abramowitz", "suffix": ""}, {"first": "I", "middle": [], "last": "Stegun", "suffix": ""}], "year": "", "venue": "", "link": "117843805"}, "BIBREF42": {"title": "Classical and quantum D-branes in 2D string theory", "authors": [{"first": "J", "middle": [], "last": "Mcgreevy", "suffix": ""}, {"first": "J", "middle": [], "last": "Teschner", "suffix": ""}, {"first": "H", "middle": [], "last": "Verlinde", "suffix": ""}], "year": 2004, "venue": "JHEP", "link": "119327007"}, "BIBREF44": {"title": "Classical pbranes from boundary state", "authors": [{"first": "P", "middle": ["Di"], "last": "Vecchia", "suffix": ""}, {"first": "M", "middle": [], "last": "Frau", "suffix": ""}, {"first": "I", "middle": [], "last": "Pesando", "suffix": ""}, {"first": "S", "middle": [], "last": "Sciuto", "suffix": ""}, {"first": "A", "middle": [], "last": "Lerda", "suffix": ""}, {"first": "R", "middle": [], "last": "Russo", "suffix": ""}], "year": 1997, "venue": "Nucl. Phys. B", "link": null}, "BIBREF45": {"title": "Non-critical supergravity (d \u00bf 1) and holography", "authors": [{"first": "S", "middle": [], "last": "Kuperstein", "suffix": ""}, {"first": "J", "middle": [], "last": "Sonnenschein", "suffix": ""}], "year": 2004, "venue": "JHEP", "link": "10606319"}, "BIBREF46": {"title": "Superconformal gauge theories and non-critical superstrings", "authors": [{"first": "I", "middle": ["R"], "last": "Klebanov", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Maldacena", "suffix": ""}], "year": "", "venue": "", "link": "11192821"}, "BIBREF47": {"title": "On the realization of chiral four-dimensional gauge theories using branes", "authors": [{"first": "A", "middle": [], "last": "Hanany", "suffix": ""}, {"first": "A", "middle": [], "last": "Zaffaroni", "suffix": ""}], "year": 1998, "venue": "JHEP", "link": null}, "BIBREF48": {"title": "D-branes on Calabi-Yau spaces and their mirrors", "authors": [{"first": "H", "middle": [], "last": "Ooguri", "suffix": ""}, {"first": "Y", "middle": [], "last": "Oz", "suffix": ""}, {"first": "Z", "middle": [], "last": "Yin", "suffix": ""}], "year": 1996, "venue": "Nucl. Phys. B", "link": null}, "BIBREF49": {"title": "String theory", "authors": [{"first": "J", "middle": [], "last": "Polchinski", "suffix": ""}], "year": 1998, "venue": "", "link": "115912490"}, "BIBREF50": {"title": "SL(2,R)/U(1) supercoset and elliptic genera of noncompact Calabi-Yau manifolds", "authors": [{"first": "T", "middle": [], "last": "Eguchi", "suffix": ""}, {"first": "Y", "middle": [], "last": "Sugawara", "suffix": ""}], "year": 2004, "venue": "JHEP", "link": "119034880"}, "BIBREF51": {"title": "Type 0 strings in a 2-d black hole", "authors": [{"first": "A", "middle": [], "last": "Giveon", "suffix": ""}, {"first": "A", "middle": [], "last": "Konechny", "suffix": ""}, {"first": "A", "middle": [], "last": "Pakman", "suffix": ""}, {"first": "A", "middle": [], "last": "Sever", "suffix": ""}], "year": 2003, "venue": "JHEP", "link": "5390853"}, "BIBREF52": {"title": "Boundary States of D-Branes and Dy-Strings", "authors": [{"first": "M", "middle": [], "last": "Li", "suffix": ""}], "year": 1996, "venue": "Nucl. Phys. B", "link": "14431485"}, "BIBREF53": {"title": "Superstring vacua of 4-dimensional pp-waves with enhanced supersymmetry", "authors": [{"first": "Y", "middle": [], "last": "Hikida", "suffix": ""}, {"first": "Y", "middle": [], "last": "Sugawara", "suffix": ""}], "year": 2002, "venue": "JHEP", "link": "12186604"}, "BIBREF54": {"title": "D-branes in Gepner models", "authors": [{"first": "A", "middle": [], "last": "Recknagel", "suffix": ""}, {"first": "V", "middle": [], "last": "Schomerus", "suffix": ""}], "year": 1998, "venue": "Nucl. Phys. B", "link": "5876504"}, "BIBREF55": {"title": "D-branes in Gepner models and supersymmetry", "authors": [{"first": "M", "middle": [], "last": "Gutperle", "suffix": ""}, {"first": "Y", "middle": [], "last": "Satoh", "suffix": ""}], "year": 1999, "venue": "Nucl. Phys. B", "link": "119086986"}}, "ref_entries": {"FIGREF0": {"text": "The superconformal field theory on IR d\u22121,1 and the cigar CFT are essentially decou- pled: the N=2 worldsheet currents are the sums of the respective currents of the two theories, and states are built in the product state space of the two conformal field theories. The closed string vertex operators are the operators on the cigar \u03a6", "type": "figure"}, "FIGREF1": {"text": "The capital letters I, J = 0, 1..d \u2212 1, \u03c1, \u03b8 label all the d + 2 dimensions in the theory while the Greek indices \u00b5, \u03bd = 0, 1..d \u2212 1 run over the flat space directions only.", "type": "figure"}, "FIGREF2": {"text": ") picture. The full vertex operator is obtained by tensoring with the ghost contributions and four dimensional spin fields. For propagating states with m = m = 0 and k \u00b5 k \u00b5 = 0, the on-shell condition", "type": "figure"}, "FIGREF4": {"text": "\u03a6 0 is a modulus of the theory and is related to the parameter multiplying the Sine-Liouville interaction in the mirror description. Starting from the linear dilaton theory, one can obtain one or the other description by turning on the operator\u03bc\u03a6", "type": "figure"}, "FIGREF5": {"text": "and Lorentz rotations in flat space The theory with d flat directions has 2 d 2 left moving conserved supercharges. For d 2 even, there are two sets of conjugate spinors S \u03b1 ,S\u03b1 and for d 2 odd, there are two sets of the same spinor S \u03b1 ,S \u03b1 . There are an equal number of right moving supercharges, which for the type IIB theory obey exactly the same condition.", "type": "figure"}, "FIGREF7": {"text": "fixed the mass of the relevant non-abelian degrees of freedom (leading to the Higgsed phase of little string theories). From the perspective of the exact description of the near-horizon geometry in terms of coset conformal field theories, one can lose dimensions of space-time by tuning the value of the level of any number of SU (2)/U (1) factors such that they become of central charge zero. (This has its well-known analogue in the Landau-Ginzburg worldsheet description of the strings near singularities in Calabi-Yau manifolds embedded in weighted projective spaces.) The analysis of the exact description of branes in NS5-brane backgrounds [19][16][20] is thus technically close to the analysis that follows in section 3.", "type": "figure"}, "FIGREF8": {"text": "extended trivial representation in the open string channel. for the tensor product which is correct only in the NS sector. The GSO projection ties together the R sector vacua of the factors, and the equation should be read as representing the tensor product of the raising operators acting on the total vacuum. A Cardy type check can be performed on these D-branes. It consists of a combination of Cardy checks which have already been performed on the individual factors that comprise the full boundary state. The calculation is therefore a combination of the usual Cardy check performed on D-branes in flat space, and the D-branes of the cigar conformal field theory. Note that for the branes that are localized on the cigar, the spectrum in the open string channel is discrete, indeed allowing for a standard Cardy check in terms of the demand that open string degeneracies are positive integers -this is not always the case in non-rational conformal field theories where open string partition functions can depend on continuous quantum numbers, and where volume divergences can spoil this approach tailored on rational conformal field theories. However, for the localized branes on which we concentrated in this paper, no such complication arises. The Cardy check is thus straightforward.", "type": "figure"}, "FIGREF9": {"text": "The physical interpretation of these modes are clear as a gauge boson and a gaugino in each of the cases. Since the other modes on the brane have masses of order \u03b1", "type": "figure"}, "FIGREF13": {"text": "Indeed, earlier work on holography in asymptotically linear dilaton backgrounds leads us to expect that closed string dynamics in the background of N D3\u2212branes in the six dimensional theory is dual to an open string theory which flows at low energies (\u03c1 \u2192 0) arbitrarily close to the flow of pure N = 1 SYM. Our first interest therefore is the backreaction on the dilaton near the tip of the cigar where one might expect agreement with the familiar logarithmic running of the coupling in the four dimensional supersymmetric gauge theory.", "type": "figure"}, "FIGREF14": {"text": "behavior of the closed string field perturbation (2.4) in the presence of the D-branes (3.7) is given (in momentum space) by the amplitude with the insertion of a closed string propagator (we are omitting to explicitly show that n = n = 0 to avoid cluttering the equations):", "type": "figure"}, "FIGREF16": {"text": ", we have written the minisuperspace solution in terms of the basis of incoming and outgoing modes propagating on the cigar, which is better suited to the asymptotic description. If we rewrite the solution (5.4) in the above asymptotic basis by using the connection formula (Eg: (15.3.7) of [37]), and replace the semiclassical reflection amplitude", "type": "figure"}, "FIGREF19": {"text": "the edge of the Seiberg window of operators non-normalizable at the weak coupling end. In this respect, the N = 2 Liouville theory with k = 1 is similar to the c = 1 bosonic", "type": "figure"}, "FIGREF20": {"text": "finite. Using the relation between the mirror parameters, this means that the bare N = 2 Liouville interaction diverges. To see what this implies, let us look at the full wavefunction of the tachyon winding mode including the reflected piece. The reflection amplitude for the mode in the action j = k 2 has the value R = \u22121. The asymptotic behavior is (keeping only the leading behavior):", "type": "figure"}, "FIGREF21": {"text": "It is clear that we should keep the quantity \u00b5 ren defined above finite and the rela- tions between the various parameters (g tip s,ren ) \u22122 = \u00b5 2 ren =\u03bc ren \u2261 \u03bd \u22121 where all the quantities are now finite and tunable.", "type": "figure"}, "FIGREF25": {"text": "(p\u22121)\u03c1 . BRST invari- ance of the vertex then implies pF (p) = 0 and pA(p) = F (p). In position space, these are g s d * g \u22121 s (g s F ) = 0 and g s dg \u22121 s A = g s F . This shows us the meaning of the divergence -for a constant field strength, we have A(p \u2192 0) = F (p \u2192 0)/p, and in position space, this will translate to A = \u03c1e \u2212\u03c1 . To keep all our calculations finite, it is also clear what to do: compute the field strength from the beginning:", "type": "figure"}, "FIGREF26": {"text": "The Chern-Simons coupling of the D-instanton is then \u03b4S D(\u22121) = \u00b5 \u22121 \u00b5 3 N \u03b8 2\u03c0 = N \u03b8; it follows that the geometric U (1) isometry of the cigar is broken to Z N . Let us remind ourselves that the normalization of the U (1) R charge (4.3) was defined such that the fermions in spacetime have a half- integer charge. This normalization is sensible from the geometric point of view as smooth boundary conditions at the tip of the cigar enforce antiperiodicity of the fermions. On the other hand, the normalization of the U (1) R current in the gauge theory is such that a rotation of 2\u03c0 gives the gluini a phase of unity. This makes it clear that \u03b8 cig = 2\u03b8 SY M .", "type": "figure"}, "FIGREF27": {"text": ", we argued that the low-energy spectrum and effective action are those of N = 1 super Yang-Mills theory. Supersymmetry of the open string spectrum was shown directly in the open string channel, in several complementary ways: technically and precisely, using non-trivial theta- function identities, and conceptually (and very generically), following the techniques ap- plied previously to supersymmetric bulk compactifications. The conceptual proof applies to generic compact and non-compact Gepner models.", "type": "figure"}, "FIGREF28": {"text": "(A.1) and (A.2) are written in worldsheet coordinates suited to the closed string channel. Later on we rewrite these conditions in terms of the open string variables to derive the supersymmetries that are left unbroken by the D-brane. The zero mode of the bosonic oscillators is the momentum kthe NS sector and r \u2208 Z Z in the R sector. The variable \u03b7 = \u00b1 denotes the spin structure related to the Z Z 2 automorphism of the gauged N = 1 algebra implemented by the map G \u2192 \u03b7G. In the R sector, there are fermion zero modes, and in that sector \u03b7 indicates the choice of the eigenvalue of the operator (\u2212) F acting on the ground state. In the cigar part, the conditions on the boundary state can be written down in terms of the current algebra [45][22]. The fermionic part involves the conditions like those in equation (A.2) for the fermions \u03c8 \u00b1 cig . The same spin structure \u03b7 as the flat space part must be imposed on the fermionic modes of the cigar.", "type": "figure"}, "FIGREF30": {"text": "the gamma-matrix \u0393 in the action of the right movers ensures that the left and right movers anti-commute. If we denote the solution of the zero-mode equation (A.3) by M AB |A | B , we can translate the equation into one for the matrix of coefficients M:", "type": "figure"}, "FIGREF33": {"text": "of these characters in the paper are as follows. First of all it is important to realize in the light of the proof of the vanishing of the GSO projected open string partition function given in appendix C that the open string partition function can indeed be written as a trivial, extended N = 2 character, and in particular that it corresponds to a sum over spectral flow orbits. This is manifest from the papers [25][47][22]. Secondly, it is important to have the twisted R-sector partition function at generic values of z, since it allows for the evaluation of possible singular terms in the limit z \u2192 1 (as in the case of d = 2 in the bulk of the paper). Moreover, as observed in [25][47][22] , the powerful formalism allows for easier generalization (to orbifolds, other levels, other backgrounds, etc). The above character formulas can easily be evaluated at the levels k = 2, 1, 2/3, 1/2 and yield (the coset factors in) the open string partition functions recorded in the bulk of the paper.", "type": "figure"}, "FIGREF34": {"text": "the primaries of the bosonic SL(2, IR) (at level k + 2) are denoted V j m bos m bos , where m bos is the charge under the purely bosonic jThey have (left and right) conformal dimensions \u2206(V j,m bos ,m bos ) = \u2212 j(j + 1) k .", "type": "figure"}, "FIGREF35": {"text": "is a primary of the bosonic Euclidean coset CFT (at level k + 2).", "type": "figure"}, "FIGREF36": {"text": "These two equations lead to the decomposition of the primary in the parent theory ofIt is clear from equation (B.5) that the J 3 eigenvalue of the operator is given by m = m bos + n .", "type": "figure"}, "FIGREF37": {"text": "string field is obtained by putting together the left and right moving pieces and yields \u03a6 j,n,n m bos ,m bos . The axial gauging of the coset is done such that the J 3 and J 3 eigenvalues m and m are are related to the asymptotic momentum and winding of the circle direction of the cylinder at infinity", "type": "figure"}, "FIGREF38": {"text": "forwardly encodes the physical spectrum. The (open string channel) N = 2 superconformal field theory has central charge c = 12. The (total transverse) U (1) R current can then be written as J = i2\u2202\u03c6, where \u03c6 is a canonically normalized scalar. We define an associated operator (in the open string channel): O 1/2 = e i\u03c6 , which is the operator that implements spectral flow by half a unit. The proof of the vanishing of the partition functions is based on two assumptions. Firstly, we assume that the partition function in the open string channel consists of (supersymmetric) characters which are of the following form:\u03c7 n (\u03c4 ) , namely, it is an alternating sum (over bosons and fermions) of contributions that are related by half a unit of spectral flow, implemented by the operator O 1/2 .", "type": "figure"}, "FIGREF39": {"text": "R scalar. Decompose the c = 12 theory into a c = 1 theory of a complex fermion in the R-sector and a theory with central charge c = 11. The action of the operators O 1/2 , O \u2020 1/2 is on the first theory only, and it generates all states, starting from a ground state (typically denoted |s = \u2212 1 2 ). The partition function in the open string sector will therefore be of the form:", "type": "figure"}, "FIGREF40": {"text": "the D3-brane in d = 4, the sum over s in (4.5) can be simplified as followsMultiplying the two contributions leads to 20 formula (4.6).", "type": "figure"}}}
{"paper_id": "17785939", "_pdf_hash": "f7291493b4d13bb7ebf5634a555ea9ab1a001258", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "People-to-People-to-Geographical-Places: The P3 Framework for Location-Based Community Systems", "authors": [{"first": "Q", "middle": [], "last": "Jones", "suffix": ""}, {"first": "S", "middle": ["A"], "last": "Grandhi", "suffix": ""}, {"first": "L", "middle": [], "last": "Terveen", "suffix": ""}, {"first": "S", "middle": [], "last": "Whittaker", "suffix": ""}], "year": 2004, "venue": "Computer Supported Cooperative Work", "link": "12745299"}, "BIBREF1": {"title": "Workspace Challenges for the Oil & Gas Exploration & Production Industry", "authors": [{"first": "E", "middle": ["E R"], "last": "Russo", "suffix": ""}, {"first": "A", "middle": ["B"], "last": "Raposo", "suffix": ""}, {"first": "T", "middle": [], "last": "Fernando", "suffix": ""}, {"first": "M", "middle": [], "last": "Gattass", "suffix": ""}], "year": 2004, "venue": "Proceedings of CONVR 2004 -4 th Conference of Construction Applications of Virtual Reality", "link": "158736"}, "BIBREF2": {"title": "Architectures for Collaborative Applications", "authors": [{"first": "P", "middle": [], "last": "Dewan", "suffix": ""}], "year": 1999, "venue": "Computer Supported Cooperative Work", "link": "109812991"}, "BIBREF3": {"title": "Clover Architecture for Groupware", "authors": [{"first": "Y", "middle": [], "last": "Laurillau", "suffix": ""}, {"first": "L", "middle": [], "last": "Nigay", "suffix": ""}], "year": 2002, "venue": "Proc. of CSCW\u00b402", "link": "7593298"}, "BIBREF4": {"title": "Activity, Consciousness and Personality", "authors": [{"first": "A", "middle": ["N"], "last": "Leontjev", "suffix": ""}], "year": 1978, "venue": "", "link": null}, "BIBREF5": {"title": "Remote Concept Design from An Activity Theory Perspective", "authors": [{"first": "T", "middle": [], "last": "Tuikka", "suffix": ""}], "year": 2002, "venue": "Proceedings of CSCW\u00b402", "link": "623966"}, "BIBREF6": {"title": "Modelling Shared Contexts in Cooperative Environments: Concept, Implementation, and Evaluation", "authors": [{"first": "T", "middle": [], "last": "Gross", "suffix": ""}, {"first": "W", "middle": [], "last": "Prinz", "suffix": ""}], "year": 2004, "venue": "", "link": "20245118"}, "BIBREF7": {"title": "DCWPL: A Programming Language For Describing Collaborative Work", "authors": [{"first": "M", "middle": [], "last": "Cort\u00e9s", "suffix": ""}, {"first": "P", "middle": [], "last": "Mishra", "suffix": ""}], "year": 1996, "venue": "Proceedings of CSCW\u00b496", "link": "8790054"}, "BIBREF8": {"title": "COCA: Collaboration Objects Coordination Architecture", "authors": [{"first": "D", "middle": [], "last": "Li", "suffix": ""}, {"first": "R", "middle": [], "last": "Muntz", "suffix": ""}], "year": 1998, "venue": "Proceedings of CSCW\u00b498", "link": null}, "BIBREF9": {"title": "Equilibrium, Ballast Control and FreeSurface Effect Computations Using The Sstab System. 8 th Int. Conf. Stability of Ships and Ocean Vehicles -Stab", "authors": [{"first": "L", "middle": ["C G"], "last": "Coelho", "suffix": ""}, {"first": "C", "middle": ["G"], "last": "Jordani", "suffix": ""}, {"first": "M", "middle": ["C"], "last": "Oliveira", "suffix": ""}, {"first": "I", "middle": ["Q"], "last": "Masetti", "suffix": ""}], "year": 2003, "venue": "", "link": null}, "BIBREF10": {"title": "Dynamic Simulation of Anchoring Systems Using Computer Graphics. OMAE Conference", "authors": [{"first": "L", "middle": ["C G"], "last": "Coelho", "suffix": ""}, {"first": "K", "middle": [], "last": "Nishimoto", "suffix": ""}, {"first": "I", "middle": ["Q"], "last": "Masetti", "suffix": ""}], "year": 2001, "venue": "", "link": null}, "BIBREF11": {"title": "The Institute of Electrical and Electronic Engineers", "authors": [], "year": "", "venue": "IEEE Standard for Modeling and Simulation (M&S) High Level Architecture (HLA)-Framework and Rules", "link": null}, "BIBREF12": {"title": "The Extensible Run-Time Infrastructure (XRTI): An Experimental Implementation of Proposed Improvements to the High Level Architecture", "authors": [{"first": "A", "middle": [], "last": "Kapolka", "suffix": ""}], "year": 2003, "venue": "", "link": "60008762"}, "BIBREF13": {"title": "Using Metalevel Techniques in a Flexible Toolkit for CSCW Applications", "authors": [{"first": "P", "middle": [], "last": "Dourish", "suffix": ""}], "year": 1998, "venue": "", "link": "2864452"}}, "ref_entries": {}}
{"paper_id": "17786002", "_pdf_hash": "e4c4b0461e46fc3e5bebc173b372eceac4094082", "abstract": [{"section": "Abstract", "text": "Predicting protein function has been a major goal of bioinformatics for several decades, and it has gained fresh momentum thanks to recent community-wide blind tests aimed at benchmarking available tools on a genomic scale. Sequence-based predictors, especially those performing homology-based transfers, remain the most popular but increasing understanding of their limitations has stimulated the development of complementary approaches, which mostly exploit machine learning. Here we present Thanks to a combination of experimental assays and computational studies, knowledge about protein function has been steadily accumulating in public databases, where it is commonly described through the Gene Ontology 1 (GO). On the one hand, hypothesis-driven research has traditionally led to the thorough characterization of one or few proteins at a time. On the other hand, high-throughput technologies have opened the way to very large-scale exploratory surveys to study biological processes, identify binding partners, or establish subcellular locations. Meanwhile, some homology-based approaches for annotation transfers have developed enough to produce fairly confident results. The GO consortium, for instance, makes wide use of a semi-automated tool for phylogenetic analysis and functional inference 2 , and of mappings between protein domain families to GO terms that are valid for all their members 3 . Despite these multi-pronged efforts, however, a substantial fraction of deposited sequences still have no functional annotation at all, and the remaining ones usually lack assignments for at least one GO domain. When available, this information may not be at the finest level of detail possible, not only because of the way some electronically inferred annotations are generated, but also because of the varying levels of resolution characterizing experimental results 4, 5 . Finally, nature can still spring surprises: protein moonlighting demonstrates that novel functions can still await discovery even for well-researched proteins 6 . One way to fill in some of these gaps employs machine learning to examine diverse biological data types separately or in combination, and to provide functional hypotheses that complement homology-based annotation transfers 7-9 . In particular, over the years several supervised methods have been devised for function prediction from amino acid sequences, which are easier to collect than structural data or genome-wide measurements of gene expression or protein-protein interactions. GOStruct 10 and FANN-GO 11 , for instance, make GO term assignments by analysing the patterns of BLAST 12 E-values to experimentally characterized proteins using structured Support Vector Machines (SVM) and multioutput neural networks, respectively. Given the computational complexity of training classifiers with multiple correlated outputs, it is difficult to learn the relationship between the input features and the whole GO; the proponents have therefore adopted workarounds such as reducing the number of output terms and ensemble modelling. Rather than tackling this complex structured learning problem,", "cite_spans": [{"start": 1877, "end": 1879, "text": "4,", "ref_id": "BIBREF3"}, {"start": 1880, "end": 1881, "text": "5", "ref_id": "BIBREF4"}, {"start": 2043, "end": 2044, "text": "6", "ref_id": "BIBREF5"}], "ref_spans": []}], "body_text": [{"section": "", "text": "Thanks to a combination of experimental assays and computational studies, knowledge about protein function has been steadily accumulating in public databases, where it is commonly described through the Gene Ontology 1 (GO). On the one hand, hypothesis-driven research has traditionally led to the thorough characterization of one or few proteins at a time. On the other hand, high-throughput technologies have opened the way to very large-scale exploratory surveys to study biological processes, identify binding partners, or establish subcellular locations. Meanwhile, some homology-based approaches for annotation transfers have developed enough to produce fairly confident results. The GO consortium, for instance, makes wide use of a semi-automated tool for phylogenetic analysis and functional inference 2 , and of mappings between protein domain families to GO terms that are valid for all their members 3 . Despite these multi-pronged efforts, however, a substantial fraction of deposited sequences still have no functional annotation at all, and the remaining ones usually lack assignments for at least one GO domain. When available, this information may not be at the finest level of detail possible, not only because of the way some electronically inferred annotations are generated, but also because of the varying levels of resolution characterizing experimental results 4, 5 . Finally, nature can still spring surprises: protein moonlighting demonstrates that novel functions can still await discovery even for well-researched proteins 6 . One way to fill in some of these gaps employs machine learning to examine diverse biological data types separately or in combination, and to provide functional hypotheses that complement homology-based annotation transfers [7] [8] [9] . In particular, over the years several supervised methods have been devised for function prediction from amino acid sequences, which are easier to collect than structural data or genome-wide measurements of gene expression or protein-protein interactions. GOStruct 10 and FANN-GO 11 , for instance, make GO term assignments by analysing the patterns of BLAST 12 E-values to experimentally characterized proteins using structured Support Vector Machines (SVM) and multioutput neural networks, respectively. Given the computational complexity of training classifiers with multiple correlated outputs, it is difficult to learn the relationship between the input features and the whole GO; the proponents have therefore adopted workarounds such as reducing the number of output terms and ensemble modelling. Rather than tackling this complex structured learning problem, other researchers have tested with success the possibility of converting it into a set of simpler binary classification tasks. This approach has recently allowed our group to train GO term-specific neural networks from features describing the results of profile-profile comparisons 13 . Alignment-derived features, such as similarity scores, sequence coverage and E-values, can help learn which sequence similarity patterns correlate with the conservation of individual annotations, thus allowing more effective control on homology-based annotation transfers. Complementary efforts have investigated the usefulness of biophysical attributes to make homology-free inferences, under the assumption that proteins with similar functions would have similar biological features despite the lack of significant sequence similarities. For example, the occurrence of signal peptides gives useful hints about protein subcellular location, and also limits the number of their molecular functions and of the biological processes they partake. The idea was first implemented in ProtFun, which is based on neural networks trained for the functional classification of protein sequences from similarities in amino acid composition, and content of signal peptides, trans-membrane helices, post-translationally modified residues as well as other biological features 14, 15 . The observation that the length and position of intrinsically disordered protein regions strongly correlates with some molecular activities and biological processes led to an expanded set of sequence-derived features, which FFPred scans through a library of GO term-specific SVMs to annotate protein chains 16, 17 . A more recent study has confirmed the effectiveness of this feature-based approach with the use of random forests for supervised learning 18 . In this paper, we describe the latest FFPred release, which updates the previous one with an extended vocabulary spanning all three GO domains, reflecting the increasing attention in cellular component annotations, as evidenced from recent experiments in the Critical Assessment of Functional Annotation initiative. We evaluate FFPred 3 prediction accuracy using two complementary approaches and describe its improvements over the previous version. Finally, we show how its predictions can help get a glimpse into the effects of alternative splicing on human protein function. The results show patterns of functional conservation and variation consistent with the presence or absence of particular biophysical attributes and with general biological knowledge.", "cite_spans": [{"start": 809, "end": 810, "text": "2", "ref_id": "BIBREF1"}, {"start": 910, "end": 911, "text": "3", "ref_id": "BIBREF2"}, {"start": 1383, "end": 1385, "text": "4,", "ref_id": "BIBREF3"}, {"start": 1386, "end": 1387, "text": "5", "ref_id": "BIBREF4"}, {"start": 1549, "end": 1550, "text": "6", "ref_id": "BIBREF5"}, {"start": 1776, "end": 1779, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 1780, "end": 1783, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 1784, "end": 1787, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 2054, "end": 2056, "text": "10", "ref_id": "BIBREF9"}, {"start": 2069, "end": 2071, "text": "11", "ref_id": "BIBREF10"}, {"start": 2148, "end": 2150, "text": "12", "ref_id": "BIBREF11"}, {"start": 2938, "end": 2940, "text": "13", "ref_id": "BIBREF12"}, {"start": 4004, "end": 4007, "text": "14,", "ref_id": "BIBREF13"}, {"start": 4008, "end": 4010, "text": "15", "ref_id": "BIBREF14"}, {"start": 4320, "end": 4323, "text": "16,", "ref_id": "BIBREF15"}, {"start": 4324, "end": 4326, "text": "17", "ref_id": "BIBREF16"}, {"start": 4467, "end": 4469, "text": "18", "ref_id": "BIBREF17"}], "ref_spans": []}, {"section": "Results and Discussion", "text": "Summary of tool updates. Thanks to the continued growth of annotation databases, the latest FFPred release features a GO term vocabulary, which spans all three GO domains for the first time and is almost twice the size of that in the previous update. Supplementary Data file 1 lists the 868 GO terms, for which a dedicated SVM is available along with the classification accuracy estimated from the validation experiments following the training procedures. The new release makes still use of SVMs, which are known to successfully handle imbalanced classification tasks-typical in computational biology-where it is extremely important to allow for error control and avoid overfitting to known observations. Subcellular localization prediction has been the focus of many previous studies, which mostly focused on the well-known compartments of eukaryotic cells-such as nucleus, cytosol, endoplasmic reticulum, Golgi apparatus, mitochondrion and other organelles. The newly added cellular component terms in FFPred 3 also include some of the numerous macromolecular complexes found in them. The extensions to the other two sub-ontologies provide more specific descriptions for functional categories previously covered, and they reflect the increasing body of knowledge in areas such as organelle localization, immune system and reproductive processes, response to stimuli and chromosome segregation. A small fraction of molecular function and biological process terms have been removed (Fig. 1a,b) , because they no longer occur in curated databases-mostly after the GO consortium made them obsolete. The majority of functional categories that have been retained can be predicted with negligible changes in expected accuracy-though some exceptions exist. As a consequence of the extended knowledge about human protein function since the last update, the patterns of biophysical attrbutes linked to terms such as sulfur compound metabolic process (GO:0006790), neurotrophin TRK receptor signaling pathway (GO:0048011), growth factor activity (GO:0008083) and protein kinase binding (GO:0019901) can be more easily identified and modelled. For other functions, such as calcium ion transport (GO:0006816), single organismal cell-cell adhesion (GO:0016337), ATPase activity (GO:0016887), and nuclease activity (GO:0004518), SVM performance has dropped, suggesting that their relationships to sequence-derived features are more complex than previously appreciated (Fig. 1c,d) .", "cite_spans": [], "ref_spans": [{"start": 1482, "end": 1493, "text": "(Fig. 1a,b)", "ref_id": "FIGREF0"}, {"start": 2455, "end": 2466, "text": "(Fig. 1c,d)", "ref_id": "FIGREF0"}]}, {"section": "Results and Discussion", "text": "The tool is designed with a focus on the function of human proteins, and so annotations curated for other organisms are never used for training. To learn effectively the relationship between biophysical attributes and GO terms, sufficiently large numbers of positive instances are needed, thus limiting the specificity of the functional categories that can be currently predicted. While this feature may not be desirable for all applications, its benefits to overcome some well-known limitations of homology-based annotation transfers have already been reported 15, 17 . Interestingly, previous work showed that the tool can also help annotate protein function for other eukaryotic organisms. The updated tool is publicly available on the web at http://bioinf.cs.ucl.ac.uk/ffpred.", "cite_spans": [{"start": 562, "end": 565, "text": "15,", "ref_id": "BIBREF14"}, {"start": 566, "end": 568, "text": "17", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "Results and Discussion", "text": "Performance evaluation. The accuracy estimates in Supplementary Data file 1 are GO term-specific and point out the usefulness of FFPred 3 to prioritize human genes for downstream experimental screening when homology offers little or no help. To complement this analysis and gauge how well protein function as a whole can be predicted for such difficult cases, a timed experiment similar to the Critical Assessment of Functional Annotation challenge was conducted, by training a separate SVM library using the public databases released in November 2013. The resulting 597 classifiers were then used to assign GO terms to human proteins with no experimentally verified biological roles at that time, and their accuracy was finally measured against the UniProtKB-GOA data as of March 2016. For comparison purposes under difficult working conditions with limited or completely missing homology information, additional predictions were generated by a baseline method (Na\u00efve), which ranks GO terms by prevalence in UniProtKB-GOA, and by a sequence similarity-based approach (BLAST), which can transfer annotations only from distantly related and experimentally characterized proteins as detailed in Methods. Other machine-learning based tools for GO term prediction from patterns of biological features could not be included in the study: ProtFun 15 has not been updated in a very long time and only covers a handful of currently valid GO terms, whereas ProFET 18 requires training from scratch classifiers for all GO categories of interest.", "cite_spans": [{"start": 1341, "end": 1343, "text": "15", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "Results and Discussion", "text": "The precision-recall plots in Fig. 2 and the data in Table 1 provide graphical and numerical reports on the evaluation results for the three separate GO domains, according to standard practice in the field. At high levels of recall (i.e. above roughly 40% for molecular function and 20% for the other two sub-ontologies), FFPred 3 predictions achieve higher precision values than the baseline approaches do, and the maximum F-scores in Table 1 clearly back up this observation. However, the highest scoring predictions made by BLAST for subcellular locations and by Na\u00efve for all sub-ontologies attain higher precision than the corresponding ones by FFPred 3. This result surprisingly suggests that these less sophisticated approaches are more useful than FFPred 3, when only a handful of assays can be run on each protein. Or are they?", "cite_spans": [], "ref_spans": [{"start": 30, "end": 36, "text": "Fig. 2", "ref_id": "FIGREF1"}]}, {"section": "Results and Discussion", "text": "It is widely accepted that an obvious pitfall of precision-recall analysis is the total disregard of how informative predictions are. The most confident GO term assignments made by Na\u00efve for each test protein-GO:0043226 (binding), GO:0005488 (organelle) and GO:0009987 (cellular process)-are far from useful in cutting down the options for the design of experiments, indeed. Nonetheless, their very shallow nature guarantees that they will be eventually confirmed for most, if not all, proteins. Furthermore, comparing the precision values achieved by different methods and plotted against the same level of recall could be more ambiguous than it looks at first sight. If the recall is less than 1.0, the predictors are evaluated on non-identical sets of target proteins, which can even be disjoint. Another confounding aspect is the number of GO term predictions above a given decision threshold made for individual proteins: predictors based on high-throughput functional data aim at high recall and generally produce longer lists of assignments than those generated by methods based on homology transfers, which tend to achieve higher precision. Finally, correctly assigning the term t to distinct proteins p and q can pose prediction challenges of diverse nature, depending on how many proteins are annotated with t, and on how closely p and q follow the patterns of features used to build the classifiers-e.g. sequence similarity, domain architecture, biological attributes, gene expression and so on. Therefore, it is useful to look at method performance from a different angle, by considering both the accuracy and the informativeness of equal numbers of high scoring predictions for each target and sub-ontology-thus reducing the above biases and yielding results that can be interpreted more clearly and more easily by non-specialists, too.", "cite_spans": [], "ref_spans": []}, {"section": "Results and Discussion", "text": "The top row panels in Fig. 3 summarize prediction quality in terms of F 1 measure and the underlying precision and recall values are plotted in Figure S1 . It is quite clear that FFPred 3 is superior to both Na\u00efve and BLAST across all three GO domains, because it achieves higher recall than the other predictors do, in combination with intermediate values of precision. The data also clearly confirm the expectation that Na\u00efve predictions Table 1 . Performance comparison between FFPred 3 and the baseline prediction methods. For each method, the table reports the total numbers of true positives (TP), false positives (FP) and false negatives (FN) each method achieves at the decision threshold that maximises the F 1 score for each GO domain. NP is the number of proteins with at least one prediction with a confidence score greater than or equal to the corresponding threshold value, which is used to calculate the average precision of each method according to equation (4) in the main text. The average recall is calculated using equation (5) using the number of proteins with annotations in the GO domain under consideration, which can be found in the section \"Methods\". The latter two values are used to locate the full triangles in the precision-recall space shown in Fig. 2 . generally are highly precise, but not deep enough in the GO graph to outperform the other approaches in terms of recall. The results for the CC sub-ontology are an interesting exception: the low numbers of false negatives most likely arise from the relatively shorter distances between nodes associated with experimental annotations and nodes associated with the most frequent terms in UniProtKB-GOA. The plots also clearly illustrate the limits of homology-based transfers in such challenging situations. When the evolutionary distances from previously annotated proteins are large, only the most general functional aspects are retained (e.g. catalytic or transporter activity), while the finer details diverge (e.g. the nature of the substrates and the chemistry of the reactions), thus resulting in high numbers of both false positives and false negatives, and ultimately affecting negatively precision, recall and F-measure values.", "cite_spans": [], "ref_spans": [{"start": 22, "end": 28, "text": "Fig. 3", "ref_id": "FIGREF2"}, {"start": 144, "end": 153, "text": "Figure S1", "ref_id": "FIGREF0"}, {"start": 1276, "end": 1282, "text": "Fig. 2", "ref_id": "FIGREF1"}]}, {"section": "Results and Discussion", "text": "As mentioned above, the design and implementation of FFPred 3 produced a list of GO terms with varying levels of detail, so it could be questioned how informative its predictions are and how helpful they can be to experimenters. In Fig. 3 , the plots in the bottom row show the average amount of useful information the highest scoring predictions would actually provide. For this purpose, the analysis only considers true positive predictions, which are not regarded as equally valuable as in the standard precision-recall analysis, however. They are rather weighted according to their information content, which estimates their specificity and informativeness from their occurrence in the UniProtKB/SwissProt database -so that more frequent functional categories are down-weighted, and vice versa. The plots undoubtedly prove that FFPred 3 correct predictions are consistently more specific than those generated by BLAST, which in turn are more specific than those made by Na\u00efve. Therefore, despite the relatively low levels of term specificity, FFPred 3 can give useful hints to drive the experimental characterization of proteins, when routes alternative to homology transfers are needed. Table S1 gives some clear examples of how well FFPred 3 top-ranked predictions compare with the validated GO term assignments, which some proteins with no prior experimental functional data have recently acquired.", "cite_spans": [], "ref_spans": [{"start": 229, "end": 238, "text": "In Fig. 3", "ref_id": "FIGREF2"}]}, {"section": "Results and Discussion", "text": "Insights into the functional consequences of alternative splicing in humans. Experimentally supported functional information for individual splice variants is generally scarce-only a handful of isoform-level GO term annotations have been reviewed and included in public databases. Even when some isoforms encoded by the same gene have been assayed, the data are still largely incomplete, because the experiments are usually focussed on a particular functional aspect. Within this active area of research, FFPred 3 and similar methods for protein function prediction have the opportunity to help investigate the functional ramifications of alternative splicing. Indeed, very often comparative sequence analysis can only suggest that the relatively small sequence changes between splice isoforms cause more or less pronounced structural and functional differences. In other words, this approach is typically unable to put forward more detailed testable hypotheses. This opens up the possibility that alternative splicing products may not encode biochemically active molecules, but rather constitute a reservoir for natural selection [19] [20] [21] -a conjecture that is also hard to verify. Notwithstanding, experimental evidence shows that the functional divergence between alternative splice variants can vary from subtle modulations of biochemical activities to completely antagonistic regulatory roles 22 . It is therefore interesting to investigate: i) which functional aspects tend to be more robust to splicing, and consequently conserved across splice variants of the same gene; and ii) whether canonical isoforms tend to be enriched in functions that are different from those over-represented in their alternative variants-see Methods for further details on the conservation and primarity scores.", "cite_spans": [{"start": 1131, "end": 1135, "text": "[19]", "ref_id": "BIBREF18"}, {"start": 1136, "end": 1140, "text": "[20]", "ref_id": "BIBREF19"}, {"start": 1141, "end": 1145, "text": "[21]", "ref_id": "BIBREF20"}, {"start": 1404, "end": 1406, "text": "22", "ref_id": "BIBREF21"}], "ref_spans": []}, {"section": "Results and Discussion", "text": "To examine these patterns, a large-scale survey was carried out on 9,214 human proteins and their recorded splice variants using FFPred 3, under the assumption that eventually they all fulfil a physiological role in the cell. The analysis was restricted to the GO term predictions compatible with the manually curated assignments existing in UniProtKB/SwissProt, as to reduce the effects of spurious results on the biological interpretation. The summary data in Supplementary Data file 2 indicate that the GO terms used in this study display varying levels of conservation across sets of alternatively spliced transcripts, even though it is difficult to assess the statistical significance of the observed differences. Only five predicted (and admittedly broad) functions appear to be consistently assigned to all the variants of a gene, and very few of them are highly conserved, when the focus is on the most reliably predicted GO terms-i.e. the SVM Matthews correlation coefficient value is in the top 50% of the distribution recorded for the corresponding sub-ontology. For instance, only six of such terms annotate all isoforms of a gene in 90% or more of the cases examined. Therefore, despite the use of a consolidated set of predictions, the findings support the expectation that alternative splicing plays a role in diversifying the cellular functional repertoire. Support for this theory is strengthened by the differential associations of individual biological roles with canonical or alternative splice isoforms -as gauged by the GO term primarity scores. The Supplementary Data file 3 indicate that there are many more GO categories preferentially associated with principal variants than with alternative ones, partly because these analyses are restricted to predicted functions in line with available annotations in UniProtKB/SwissProt. Nevertheless, the GO terms with high primarity scores tend to represent more constitutive cellular functions, and those with negative scores appear to be mostly associated with larger sets of alternatively spliced genes or to be induced by changes in the environment or in the cellular conditions. As mentioned above, it is difficult to draw statistically sound conclusions from this initial study: identifying the canonical isoform of each gene is still an open question, and here a rather simple and pragmatic approach was taken just like in previous studies.", "cite_spans": [], "ref_spans": []}, {"section": "Results and Discussion", "text": "To emphasize the unique advantages that analyzing biological features can offer, Fig. 4 gives some insight into their relationship with some of the most conserved functions in each GO domain-see Methods for more details. The heatmap allows to link the over-and under-representation of specific biophysical attributes with the conservation of particular functional aspects. Similarly, Figs 5 and 6 show the extent of positive or negative correlation between sequence-derived feature groups and the GO terms that are preferentially associated with principal or alternative splice variants, respectively. The results generally reflect well-established trends between functional categories and the occurrence or lack of intrinsically disordered residues, transmembrane helices and signal peptides, and these interpretable patterns of association also apply to extended lists of GO terms, which are either expected to be predicted with lower confidence or to be less conserved ( Figures S2, S3 and S4 ).", "cite_spans": [], "ref_spans": [{"start": 81, "end": 87, "text": "Fig. 4", "ref_id": "FIGREF3"}, {"start": 384, "end": 396, "text": "Figs 5 and 6", "ref_id": "FIGREF4"}, {"start": 974, "end": 995, "text": "Figures S2, S3 and S4", "ref_id": "FIGREF1"}]}, {"section": "Results and Discussion", "text": "The figures above provide a general overview across the whole human isoform proteome; however, the online server allows to study how alternative splicing is likely to preserve or abolish individual functions, by providing a detailed graphical view of the biological features detected in the input sequences. The following showcases how functional conservation and variation are consistent with the presence or absence of particular biophysical attributes and, most importantly, with independent biological knowledge.", "cite_spans": [], "ref_spans": []}, {"section": "Results and Discussion", "text": "Protein intrinsic disorder has long been linked to binding activities and regulatory processes in the light of both experimental and computational investigations [23] [24] [25] , and its enrichment in DNA binding proteins has a two-fold explanation. Basic leucine zipper (bZIP) and AT hook domains-both well known examples of disordered regions-are frequently found in many transcription factors and regulators, and some are conserved in their splice isoforms, too. The proto-oncogene c-Fos (UniProt accession P01100) and the high mobility group protein HMGI-C (UniProt accession P52926) include one bZIP and three AT hook motifs, respectively, which are all conserved across their known splice isoforms. Most often, however, DNA binding proteins usually include additional disordered segments that are not directly involved in DNA binding, but rather in the establishment of transient and highly specific protein-protein interactions for transactivation purposes. These regions are either maintained upon splicing-like the C-terminal domain of c-Fos-or swapped with other disordered segments to rewire cellular and signaling networks 26 . Signal peptides and transmembrane helices provide useful hints about protein subcellular localization and transmembrane transporter activities. They are unsurprisingly over and under-represented accordingly in those splice isoforms that need to retain the corresponding roles. The main and alternative isoforms of both the calcium-transporting ATPase type 2C member 1 (UniProt accession P98194) and of the 5-hydroxytryptamine receptor 3E (UniProt accession A5X5Y0) clearly illustrate this point. Alternative splicing hardly affects the transmembrane segments of these channels-only the isoform P98194-2 loses one helix-therefore they still localize in the membrane, and likely act as transporters of possibly different molecules.", "cite_spans": [{"start": 162, "end": 166, "text": "[23]", "ref_id": "BIBREF22"}, {"start": 167, "end": 171, "text": "[24]", "ref_id": "BIBREF23"}, {"start": 172, "end": 176, "text": "[25]", "ref_id": "BIBREF24"}, {"start": 1135, "end": 1137, "text": "26", "ref_id": "BIBREF25"}], "ref_spans": []}, {"section": "Results and Discussion", "text": "Some associations-such as those between beta strands and several functional categories-may not look blatantly obvious, but brief scrutiny reveals their consistency with known biological facts. Nucleotides such as FAD, NAD and NADP are commonly bound by \u03b2 \u03b1 \u03b2 super-secondary structure motifs, which usually occur in tandem in the Rossman fold where they can form relatively large beta sheets. Mitochondrial glutathione reductase (UniProt accession P00390) has five known isoforms that all preserve the nucleotide binding site, for instance, thus suggesting that the sequence differences do not impact this functional aspect, but something else. It is known that the isoform P00390-1 is indeed found in the mithocondrion, while isoform P00390-2 is cytoplasmatic, for instance. The enrichment of residues in beta strands in isoforms at the cell periphery is also easily explained by the abundance of immunoglobulin-like (Ig-like) domains, which fold into a beta sandwich structure and are involved in a wide range of functions such as cell surface recognition, immune response and muscle structural organization. Both the mucosal addressin cell adhesion molecule 1(UniProt accession Q13477) and the leukocyte Ig-like receptor subfamily A member 5 (UniProt accession A6NI73) exemplify well this over-representation. Both proteins include a signal peptide followed by two Ig-like domains, one transmembrane helix and a C-terminal cytosolic region. All recorded splicing events cause the removal or replacement of sequence regions outside the signal peptide and the core of the Ig-like domains, thus proving that the alternative variants are still secreted. Based on these examples, we would expect that this updated version of FFPred 3 will assist experimentalists narrow down the number of assays to functionally characterize individual variants of their own interest. In turn, those efforts will definitely stimulate further bio-curation work to interpret this information and make it available in machine-readable format. Initial computational studies have been carried out to advance this area of functional genomics using gene expression profile data 27, 28 ; their integration with other complementary sources of biological information that are tissue and condition-specific will undoubtedly be the focus of many more investigations in the near future. , and the following is a brief overview of the procedure, which is also graphically summarised in Supplementary Figure S5 . Candidate functional classes were identified based on the availability of sufficiently large and confident positive and negative instances, which were split into training (70%) and validation (30%) data. The training subset was then encoded through 258 sequence-derived features covering a range of 14 different functional and structural aspects; the resulting vectors were fed into SVM-Light 32 to perform feature selection and parameter optimization. Based on the number of training instances available for each function, the number of folds k ranges between 3 and 5, within the constraint that the partitions are equally sized. Feature selection was performed using a backward elimination approach, which involves first using all feature groups to estimate classification accuracy, and then iteratively testing if the removal of each feature group improves it. At each step, a grid search of the SVM hyper-parameter space was conducted with k-fold cross-validation to estimate SVM performance using the highest average Matthews correlation coefficient (MCC)", "cite_spans": [{"start": 2152, "end": 2155, "text": "27,", "ref_id": "BIBREF26"}, {"start": 2156, "end": 2158, "text": "28", "ref_id": "BIBREF27"}], "ref_spans": [{"start": 2467, "end": 2476, "text": "Figure S5", "ref_id": "FIGREF4"}]}, {"section": "Methods", "text": "where TP is the number of proteins correctly labelled as positives (true positives); TN is the number of proteins correctly labelled as negatives (true negatives); FP is the number of misclassified negative cases (false positives); and FN is the number of misclassified positive instances (false negatives). These parameters were used to build a binary classifier from all training examples, the performance of which was tested against the proteins in the unseen validation set. Only GO terms corresponding to predictors achieving MCC \u2265 0.05 were retained, and for them FFPred 3 makes predictions with SVMs trained on the joint training and validation sets to make the most of available annotations. Platt scaling 33 is applied to estimate the posterior probability that the input protein performs the function associated with a SVM given the raw output score.", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "Datasets and procedures for performance evaluation. Only for the purpose of estimating prediction accuracy, an intermediate version of the SVM library was trained using the GO OBO flat file released on 2013-11-05, the UniProt-GOA gene association file for human submitted to the GO Consortium on 2013-10-28, UniProtKB and UniRef90 release 2013_10. The training procedures outlined above produced a vocabulary consisting of 400 terms in the biological process (BP) domain, 108 in the molecular function (MF) domain, and 89 in the cellular component (CC) domain, which allowed to make predictions for all human protein sequences released as targets of the second Critical Assessment of Functional Annotation challenge 34 . The benchmark set was collated from the UniProt-GOA gene association file, by selecting those human proteins that received GO term assignments supported by evidence code EXP, IDA, IMP, IGI, IEP, TAS or IC between 2014-01-20 (end of the CAFA2 prediction stage) and 2016-03-14 (the database release date). Annotations to the term \"protein binding\" (GO:0005515) were discarded because they convey limited functional information unless the context is quoted (e.g. where and when the activity takes place and the requirement or absence of other molecules), and because these qualifiers are neglected by current function prediction evaluation protocols. This resulted in 3,881 annotations for 1,365 proteins in total-602 MF annotations for 454 proteins, 1,802 BP annotations for 661 proteins, and 1,477 CC annotations for 991 proteins.", "cite_spans": [{"start": 716, "end": 718, "text": "34", "ref_id": "BIBREF34"}], "ref_spans": []}, {"section": "Methods", "text": "Prediction accuracy was measured separately for each GO domain by precision-recall analysis as in similar studies following the lead of the CAFA experiments 34, 35 . For each protein x in the benchmark set and decision threshold v, the set of predicted terms P x,v was built by collecting all terms with confidence scores greater than or equal to v and their ancestors in GO linked by \"is a\" relationships and different from the root; the set of reference terms R x was generated in a similar way by up-propagating the validated annotations for x. These sets were used to calculate the number of true positives tp x,v , false positives fp x,v and false negatives fn x,v respectively as the sizes of the intersection P x,v \u2229 R x , of the set difference P x,v \\R x and of the set difference R x \\P x,v . These data were combined into precision", "cite_spans": [{"start": 157, "end": 160, "text": "34,", "ref_id": "BIBREF34"}, {"start": 161, "end": 163, "text": "35", "ref_id": "BIBREF35"}], "ref_spans": []}, {"section": "Methods", "text": "Scientific RepoRts | 6:31865 | DOI: 10.1038/srep31865", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "and then averaged across the test set using the formulas", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "where m is the number of target proteins in the GO domain at hand and n is the number of those with at least one prediction scoring at least v. Finally, the average F-measure for the threshold v was calculated as", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "that is by taking the harmonic mean of p v and r v .", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "A complementary evaluation of function prediction quality was carried out on the top-ranked predictions for each target t and GO domain d. To this end, after ranking based on confidence scores, the initial predictions were trimmed to the same length l \u2208 {1, 2, 3, 4, 5, n t,d }, where n t,d is the number of experimental annotations for t in the sub-ontology d. To handle ties in confidence scores, first 1,000 prediction lists of the desired length l were randomly sampled without replacement for each protein. Then, the average values of precision, recall, F-measure were calculated for each list of top l predictions; finally the average of such statistics over all replicates were analysed.", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "Along with the above statistics, the average sum of true positive information content was also calculated from all replicates. The information content of a GO term t was estimated in a Bayesian framework as proposed by Clark and Radivojac 36 using the equation", "cite_spans": [{"start": 239, "end": 241, "text": "36", "ref_id": "BIBREF36"}], "ref_spans": []}, {"section": "Methods", "text": "where P(t) represents the set of parent nodes of t, and the function N(\u00b7) returns for any set of GO terms the number of human proteins annotated in UniProtKB-SwissProt with evidence code EXP, IDA, IMP, IGI, IEP, TAS or IC. The Supplementary Data file 4 includes the complete sets of reference annotations and of predictions used in these performance comparison experiments.", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "Baseline function prediction methods. Na\u00efve predictions were generated based on the frequency of the GO term annotations for human sequences recorded in UniProt-GOA as of 2013-10-28. To this end, initial counts were obtained for all GO terms except \"protein binding\" (GO:0005515) supported by the evidence codes EXP, IDA, IPI, IMP, IGI, IEP, IC and TAS. The data were then propagated following \"is a\" links in the GO released on 2013-11-05, and finally scaled between 0 and 1 for each domain separately, by dividing the final counts by the number of occurrences of the root node and rounding the result to three decimals like FFPred does. The resulting 6,504 pairs of GO terms (469 for CC, 1,268 for MF and 4,767 for BP) and scores were used to annotate all proteins in the benchmark set.", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "BLAST predictions were obtained by first collecting all BLAST 12 hits in the UniRef90 31 sequence database released in October 2013 with an E-value greater than 1e-03. Then the annotations in UniProtKB release 2013_10 supported by evidence code EXP, IDA, IPI, IMP, IGI, IEP, IC and TAS were transferred to the target sequences. GO term confidence scores were calculated by dividing the local alignment sequence identity by 100. When multiple BLAST hits were annotated with the same function, the highest score was retained.", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "Annotation and functional analysis of human splice variants. The sequences of the human isoform proteome and the classification between main and alternative splice variants were obtained from the release 2015_03 of UniProtKB/SwissProt and the accompanying \"varsplic\" file. Individual isoforms were discarded if a) their amino acid sequence is unknown; or b) it is shorter than 15 amino acids; or c) it is longer than 1500 amino acids, or d) it includes non-standard amino acid symbols; or e) it is recorded in a separate database entry due to substantial differences from the canonical sequence. When these filters led to the exclusion of main variants, associated alternative sequences were removed from the dataset as well. This initial screening yielded 28,310 splice variants for 9,267 UniProtKB/SwissProt entries.", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "FFPred 3 was run to make isoform-specific GO term predictions, which were then screened for consistency with the UniProtKB/SwissProt data. Only functional classes that were either explicitly assigned by the curators or implied by the GO data released on 2015-02-27 were retained. Removal of principal isoforms at this stage also led to the elimination of all related alternative variants, hence producing a final dataset P as consisting of 28,142 sequences for 9,214 UniProtKB/SwissProt entries.", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "Patterns of conservation and variation were analysed for all GO terms predicted to the splice isoforms of at least 20 distinct UniProtKB/SwissProt entries. For each functional class G, the survey aimed at quantifying its tendency to be conserved upon splicing, as well as its preference for principal rather than alternative splice variants. The average conservation of G across splice variants of the same gene was measured as the ratio between the number of UniProtKB/SwissProt entries where G was assigned to all isoforms, and the number of database records where it was predicted for at least one isoform. The primarity of G-that is its enrichment among main isoforms rather than alternative variants-was taken as where m G and a G are respectively the numbers of main and alternative isoforms annotated with G, while n = 9214 is the number of genes in the dataset, and m = 28142 is the total number of splice variants. Therefore, \u03b4 G > 0 if G is preferentially found among canonical isoform predictions; \u03b4 G < 0 if G is assigned more often to alternative variants than to main ones; and \u03b4 G = 0 if G is equally associated with the two sets of protein products.", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "To investigate further and interpret the conservation of each GO term g in the light of current biological knowledge, the biological attributes associated with the set of canonical and splicing variants annotated with g (V g ) were compared with those previously observed in the positive training set (T g ) of the corresponding SVM. In particular, for each sequence-derived feature f, the median value m g,f,T observed during the training process was compared to m g,f,V -the median value in V g -by first mapping the latter to the lowest percentile p g f T , , seen in T g and then by calculating", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "Therefore, E g,f = 0 if the two median values are identical, E g,f > 0 if on average f takes higher values in V g than in T g , while E g,f < 0 if f typically has lower values in V g than T g . Similarly, the association between a feature f and a functional class g that is over-represented in either set of canonical or alternative protein isoforms was estimated using Pearson's correlation coefficient between the values f takes on V g and the correspondin g SVM output scores.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Gene ontology: tool for the unification of biology. The Gene Ontology Consortium", "authors": [{"first": "M", "middle": [], "last": "Ashburner", "suffix": ""}], "year": 2000, "venue": "Nat Genet", "link": null}, "BIBREF1": {"title": "Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium", "authors": [{"first": "P", "middle": [], "last": "Gaudet", "suffix": ""}, {"first": "M", "middle": ["S"], "last": "Livstone", "suffix": ""}, {"first": "S", "middle": ["E"], "last": "Lewis", "suffix": ""}, {"first": "P", "middle": ["D"], "last": "Thomas", "suffix": ""}], "year": 2011, "venue": "Brief Bioinform", "link": "5913602"}, "BIBREF2": {"title": "The InterPro protein families database: the classification resource after 15 years", "authors": [{"first": "A", "middle": [], "last": "Mitchell", "suffix": ""}], "year": 2015, "venue": "Nucleic Acids Res", "link": null}, "BIBREF3": {"title": "Understanding how and why the Gene Ontology and its annotations evolve: the GO within UniProt", "authors": [{"first": "R", "middle": ["P"], "last": "Huntley", "suffix": ""}, {"first": "T", "middle": [], "last": "Sawford", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Martin", "suffix": ""}, {"first": "C", "middle": [], "last": "O&apos;donovan", "suffix": ""}], "year": 2014, "venue": "Gigascience", "link": "2682835"}, "BIBREF4": {"title": "A guide to best practices for Gene Ontology (GO) manual annotation. Database (Oxford)", "authors": [{"first": "R", "middle": [], "last": "Balakrishnan", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Harris", "suffix": ""}, {"first": "R", "middle": [], "last": "Huntley", "suffix": ""}, {"first": "K", "middle": [], "last": "Van Auken", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Cherry", "suffix": ""}], "year": 2013, "venue": "", "link": null}, "BIBREF5": {"title": "An introduction to protein moonlighting", "authors": [{"first": "C", "middle": ["J"], "last": "Jeffery", "suffix": ""}], "year": 2014, "venue": "Biochem Soc Trans", "link": null}, "BIBREF6": {"title": "Machine learning applications in genetics and genomics", "authors": [{"first": "M", "middle": ["W"], "last": "Libbrecht", "suffix": ""}, {"first": "W", "middle": ["S"], "last": "Noble", "suffix": ""}], "year": 2015, "venue": "Nat Rev Genet", "link": "26580409"}, "BIBREF7": {"title": "Integrated protein function prediction by mining function associations, sequences, and protein-protein and gene-gene interaction networks", "authors": [{"first": "R", "middle": [], "last": "Cao", "suffix": ""}, {"first": "J", "middle": [], "last": "Cheng", "suffix": ""}], "year": 2016, "venue": "Methods", "link": "1298380"}, "BIBREF8": {"title": "Computational protein function predictions", "authors": [{"first": "D", "middle": [], "last": "Kihara", "suffix": ""}], "year": 2016, "venue": "Methods", "link": "13621547"}, "BIBREF9": {"title": "Hierarchical classification of gene ontology terms using the GOstruct method", "authors": [{"first": "A", "middle": [], "last": "Sokolov", "suffix": ""}, {"first": "A", "middle": [], "last": "Ben-Hur", "suffix": ""}], "year": 2010, "venue": "J Bioinform Comput Biol", "link": "12808000"}, "BIBREF10": {"title": "Analysis of protein function and its prediction from amino acid sequence", "authors": [{"first": "W", "middle": ["T"], "last": "Clark", "suffix": ""}, {"first": "P", "middle": [], "last": "Radivojac", "suffix": ""}], "year": 2011, "venue": "Proteins", "link": "18136627"}, "BIBREF11": {"title": "Basic local alignment search tool", "authors": [{"first": "S", "middle": ["F"], "last": "Altschul", "suffix": ""}, {"first": "W", "middle": [], "last": "Gish", "suffix": ""}, {"first": "W", "middle": [], "last": "Miller", "suffix": ""}, {"first": "E", "middle": ["W"], "last": "Myers", "suffix": ""}, {"first": "D", "middle": ["J"], "last": "Lipman", "suffix": ""}], "year": 1990, "venue": "J Mol Biol", "link": "14441902"}, "BIBREF12": {"title": "Protein function prediction by massive integration of evolutionary analyses and multiple data sources", "authors": [{"first": "D", "middle": [], "last": "Cozzetto", "suffix": ""}, {"first": "D", "middle": ["W"], "last": "Buchan", "suffix": ""}, {"first": "K", "middle": [], "last": "Bryson", "suffix": ""}, {"first": "D", "middle": ["T"], "last": "Jones", "suffix": ""}], "year": 2013, "venue": "BMC Bioinformatics", "link": "17813466"}, "BIBREF13": {"title": "Prediction of human protein function from post-translational modifications and localization features", "authors": [{"first": "L", "middle": ["J"], "last": "Jensen", "suffix": ""}], "year": 2002, "venue": "J Mol Biol", "link": null}, "BIBREF14": {"title": "Prediction of human protein function according to Gene Ontology categories", "authors": [{"first": "L", "middle": ["J"], "last": "Jensen", "suffix": ""}, {"first": "R", "middle": [], "last": "Gupta", "suffix": ""}, {"first": "H", "middle": ["H"], "last": "Staerfeldt", "suffix": ""}, {"first": "S", "middle": [], "last": "Brunak", "suffix": ""}], "year": 2003, "venue": "Bioinformatics", "link": null}, "BIBREF15": {"title": "Inferring function using patterns of native disorder in proteins", "authors": [{"first": "A", "middle": [], "last": "Lobley", "suffix": ""}, {"first": "M", "middle": ["B"], "last": "Swindells", "suffix": ""}, {"first": "C", "middle": ["A"], "last": "Orengo", "suffix": ""}, {"first": "D", "middle": ["T"], "last": "Jones", "suffix": ""}], "year": 2007, "venue": "PLoS Comput Biol", "link": "16004480"}, "BIBREF16": {"title": "FFPred 2.0: improved homology-independent prediction of gene ontology terms for eukaryotic protein sequences", "authors": [{"first": "F", "middle": [], "last": "Minneci", "suffix": ""}, {"first": "D", "middle": [], "last": "Piovesan", "suffix": ""}, {"first": "D", "middle": [], "last": "Cozzetto", "suffix": ""}, {"first": "D", "middle": ["T"], "last": "Jones", "suffix": ""}], "year": 2013, "venue": "PLoS One", "link": "5992983"}, "BIBREF17": {"title": "ProFET: Feature engineering captures high-level protein functions", "authors": [{"first": "D", "middle": [], "last": "Ofer", "suffix": ""}, {"first": "M", "middle": [], "last": "Linial", "suffix": ""}], "year": 2015, "venue": "Bioinformatics", "link": "7378275"}, "BIBREF18": {"title": "Alternative splicing in human transcriptome: functional and structural influence on proteins", "authors": [{"first": "K", "middle": [], "last": "Yura", "suffix": ""}], "year": 2006, "venue": "Gene", "link": "38906665"}, "BIBREF19": {"title": "The implications of alternative splicing in the ENCODE protein complement", "authors": [{"first": "M", "middle": ["L"], "last": "Tress", "suffix": ""}], "year": 2007, "venue": "Proc Natl Acad Sci", "link": null}, "BIBREF20": {"title": "Stochastic noise in splicing machinery", "authors": [{"first": "E", "middle": [], "last": "Melamud", "suffix": ""}, {"first": "J", "middle": [], "last": "Moult", "suffix": ""}], "year": 2009, "venue": "Nucleic Acids Res", "link": "14188227"}, "BIBREF21": {"title": "Function of alternative splicing", "authors": [{"first": "O", "middle": [], "last": "Kelemen", "suffix": ""}], "year": 2013, "venue": "Gene", "link": "39665876"}, "BIBREF22": {"title": "Intrinsically unstructured proteins: re-assessing the protein structure-function paradigm", "authors": [{"first": "P", "middle": ["E"], "last": "Wright", "suffix": ""}, {"first": "H", "middle": ["J"], "last": "Dyson", "suffix": ""}], "year": 1999, "venue": "J Mol Biol", "link": "9392184"}, "BIBREF23": {"title": "The contribution of intrinsic disorder prediction to the elucidation of protein function", "authors": [{"first": "D", "middle": [], "last": "Cozzetto", "suffix": ""}, {"first": "D", "middle": ["T"], "last": "Jones", "suffix": ""}], "year": 2013, "venue": "Curr Opin Struct Biol", "link": "24404250"}, "BIBREF24": {"title": "Intrinsically disordered proteins in cellular signalling and regulation", "authors": [{"first": "P", "middle": ["E"], "last": "Wright", "suffix": ""}, {"first": "H", "middle": ["J"], "last": "Dyson", "suffix": ""}], "year": 2015, "venue": "Nat Rev Mol Cell Biol", "link": "19812614"}, "BIBREF25": {"title": "Alternative splicing of intrinsically disordered regions and rewiring of protein interactions", "authors": [{"first": "M", "middle": [], "last": "Buljan", "suffix": ""}], "year": 2013, "venue": "Curr Opin Struct Biol", "link": "8686751"}, "BIBREF26": {"title": "Systematically differentiating functions for alternatively spliced isoforms through integrating RNA-seq data", "authors": [{"first": "R", "middle": [], "last": "Eksi", "suffix": ""}], "year": 2013, "venue": "PLoS Comput Biol", "link": "2672792"}, "BIBREF27": {"title": "Semi-supervised Learning Predicts Approximately One Third of the Alternative Splicing Isoforms as Functional Proteins", "authors": [{"first": "Y", "middle": [], "last": "Hao", "suffix": ""}], "year": 2015, "venue": "Cell Rep", "link": null}, "BIBREF28": {"title": "The GOA database: gene Ontology annotation updates for 2015", "authors": [{"first": "R", "middle": ["P"], "last": "Huntley", "suffix": ""}], "year": 2015, "venue": "Nucleic Acids Res", "link": "16437496"}, "BIBREF29": {"title": "UniProt: a hub for protein information", "authors": [{"first": "C", "middle": [], "last": "Uniprot", "suffix": ""}], "year": 2015, "venue": "Nucleic Acids Res", "link": "196106903"}, "BIBREF31": {"title": "UniRef clusters: a comprehensive and scalable alternative for improving sequence similarity searches", "authors": [{"first": "B", "middle": ["E"], "last": "Suzek", "suffix": ""}], "year": 2015, "venue": "Bioinformatics", "link": "12423917"}, "BIBREF32": {"title": "Making large scale SVM learning practical", "authors": [{"first": "T", "middle": [], "last": "Joachims", "suffix": ""}], "year": 1999, "venue": "", "link": null}, "BIBREF33": {"title": "Probabilistic outputs for support vector machines and comparisons to regularized likelihood methods", "authors": [{"first": "J", "middle": [], "last": "Platt", "suffix": ""}], "year": 1999, "venue": "Advances in large margin classifiers", "link": "56563878"}, "BIBREF34": {"title": "An expanded evaluation of protein function prediction methods shows an improvement in accuracy", "authors": [{"first": "Y", "middle": [], "last": "Jiang", "suffix": ""}], "year": 2016, "venue": "", "link": null}, "BIBREF35": {"title": "A large-scale evaluation of computational protein function prediction", "authors": [{"first": "P", "middle": [], "last": "Radivojac", "suffix": ""}], "year": 2013, "venue": "Nat Methods", "link": null}, "BIBREF36": {"title": "Information-theoretic evaluation of predicted ontological annotations", "authors": [{"first": "W", "middle": ["T"], "last": "Clark", "suffix": ""}, {"first": "P", "middle": [], "last": "Radivojac", "suffix": ""}], "year": 2013, "venue": "Bioinformatics", "link": "3256456"}}, "ref_entries": {"FIGREF0": {"text": "Figure 1. Comparison between FFPred 2 and FFPred 3. Extent of the overlap between FFPred 2 and FFPred 3 GO term lists in the MF (a) and BP (b) domains. Most common terms in the MF (c) and BP (d) sub-ontologies are expected to be predicted with similar accuracy, as measured by the MCC.", "type": "figure"}, "FIGREF1": {"text": "Figure 2. Graphical summary of the precision-recall analysis. The three panels show the evaluation results for the MF (left), BP (centre) and CC (right) domains, respectively. The full triangles mark the points associated with the maximum F-measure.", "type": "figure"}, "FIGREF2": {"text": "Figure 3. Comparison of the prediction accuracy and informativeness against number of top ranked predictions. The graphs on the top row compare the average F-measure of the highest scoring GO term assignments made by FFPred 3, Na\u00efve and BLAST for the MF (left), BP (centre) and CC (right) domains, respectively. The bottom row shows the average information content of the true positives for the same predictions in the top row. Data are plotted only when there are at least 25 targets with x \u2208 {1, 2, 3, 4, 5} predictions and x validated annotations or more. The label n represents the case where for each protein the number of predictions assessed equals the number of experimentally supported functions.", "type": "figure"}, "FIGREF3": {"text": "Figure 4. Enrichment of biological features for the most conserved functions in human alternative isoforms. The heatmaps compare the feature values calculated for the annotated splice variants with those used to train the classifiers for each of the five most conserved and confidently predicted functions in the MF (top), BP (centre) and CC (bottom) domain, respectively. The classifiers are in the top 50% of the corresponding subontology. Warmer (colder) colours represent median feature group values that are higher (lower) in the human isoform proteome than in the positive training set for the corresponding GO term. Grey cells indicate feature groups not used by FFPred 3 to make predictions.", "type": "figure"}, "FIGREF4": {"text": "Figure 5. Relationship between biological features and GO terms preferentially associated with main splice isoforms. For each function, the heatmaps report the correlation between the feature values calculated for the annotated splice variants with the estimated probability produced by the corresponding classifier. Only the five GO terms with highest expected accuracy and propensity for the canonical splice variants are listed for the MF (top), BP (centre) and CC (bottom) domain, respectively. The classifiers are in the top 50% of the corresponding sub-ontology. Warmer (colder) colours represent higher (lower) values of median correlation across each feature group. Grey cells indicate feature groups not used by FFPred 3 to make predictions.", "type": "figure"}, "FIGREF5": {"text": "Figure 6. Relationship between biological features and GO terms preferentially associated with alternative splice isoforms. For each function, the heatmaps report the correlation between the feature values calculated for the annotated splice variants with the estimated probability produced by the corresponding classifier. Only the five GO terms with highest expected accuracy and propensity for alternative variants are listed for the MF (top), BP (centre) and CC (bottom) domain, respectively. The classifiers are in the top 50% of the corresponding sub-ontology. Warmer (colder) colours represent higher (lower) values of median correlation in each feature group. Grey cells indicate feature groups not used by FFPred 3 to make predictions. Some GO names have been abbreviated: RNA polymerase II core promoter proximal region sequence-specific DNA binding transcription factor activity involved in positive regulation of transcription (transcription factor activity (A); RNA polymerase II core promoter proximal region sequence-specific DNA binding transcription factor activity (transcription factor activity (B); RNA polymerase II transcription regulatory region sequence-specific DNA binding transcription factor activity involved in positive regulation of transcription (transcriptional activator activity (C); sequence-specific DNA binding RNA polymerase II transcription factor activity (transcription factor activity (D).", "type": "figure"}, "FIGREF6": {"text": "Datasets and procedures for training and testing. Training procedures employed the term defini- tions and relationships defined in the GO 1 OBO flat file released on 2015-02-03, the annotations for human proteins in UniProt-GOA 29 released on 2015-04-02 and in UniProtKB 30 release 2015_02, and the UniRef90 31 release 2015_02 for sequence similarity searches. GO term-specific Support Vector Machines (SVM) were trained as detailed before 17", "type": "figure"}}}
{"paper_id": "17786238", "_pdf_hash": "04cc19f72fa69cdc0ca5bc5590f52dd12ee20f37", "abstract": [{"section": "Abstract", "text": "The star HDE 226868 known as an optical counterpart of the black hole candidate Cyg X-1 has been observed in H\u03b1 region using spectrograph at Ond\u0159ejov 2-m telescope. The orbital parameters are determined from He Iline by means of the author's method of Fourier disentangling. Preliminary results are also presented of disentangling the H\u03b1-line into a P-Cyg profile of the (optical) primary and an emission profile of the circumstellar matter (and a telluric component).", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "INTRODUCTION", "text": "The bright X-ray source Cyg X-1 has been identified with the star denoted as HDE 226868, V1357 Cyg or BD+34", "cite_spans": [], "ref_spans": []}, {"section": "INTRODUCTION", "text": "\u2022 3815 etc. An improvement of instrumentation of the Ond\u0159ejov 2-m telescope enabled to start with systematic observations of this target of magnitude V\u22438.9, B\u22439.6. With coordinates \u03b1 2000 = 19 h 58 m 21.7 s , \u03b4 2000 = +35", "cite_spans": [], "ref_spans": []}, {"section": "INTRODUCTION", "text": "\u2022 12 \u2032 6 \u2032\u2032 it is well observable from Ond\u0159ejov mainly at summer. It is known to be an interacting binary with period P \u2243 5.6d. The primary component is a supergiant of spectral type classified as B0 (or O9.7) Iab with temperature T eff = 30400 \u00b1 500 K and log g = 3.31 \u00b1 0.07. This primary, which nearly fills its Roche lobe, shows signs of variable strong stellar wind and an overabundace of He and heavier elements (cf. e.g. Karitskaya et al. 2007 ).", "cite_spans": [], "ref_spans": []}, {"section": "INTRODUCTION", "text": "The secondary component invisible in optical radiation is a compact object, most probably a black hole. This companion, or its neighborhood emits a variable Xradiation, which is supposed to originate from an accretion disk fed by the stellar wind from the primary.", "cite_spans": [], "ref_spans": []}, {"section": "INTRODUCTION", "text": "The X-radiation switches chaotically between two states. In the low/hard state the total X-ray flux is low and the spectrum is flat, so that the hard tail of Xradiation prevails. In the high/soft state the soft radiation is enhanced more, and consequently the spectrum has a steeper decrease toward the higher energies and hence the radiation is softer in the mean. Some intermediate states may also appear temporarily.", "cite_spans": [], "ref_spans": []}, {"section": "INTRODUCTION", "text": "The X-ray flux is anticorrelated with the strength of emission in the H \u03b1 -line of the primary: in the X-low/hard state the H \u03b1 emission is strong, while in the X-high/soft state the H \u03b1 emission is weak.", "cite_spans": [], "ref_spans": []}, {"section": "INTRODUCTION", "text": "The aim of the observational campaign at Ond\u0159ejov observatory was to improve orbital parameters of the system, to check a possible spectroscopic features connected with the circumstellar matter (either accretion disk around the black hole, gaseous streams or stellar wind) or with a possible third body, and to get lineprofiles enabling a quantitative comparison with a model of the atmosphere and stellar wind of the primary. The first part of obtained spectra was provided for a study on Cyg X-1 organized in a wide international collaboration, the results of which should appear in Gies et al. (2007) . In the present contribution, results obtained using the author's method of spectra disentangling from the same set of Ond\u0159ejov spectra are given. A more detailed study taking into account also recently obtained spectra is in progress. The observational period covers a transition of Cyg X-1 from the low to high state and back, as it can be seen from the RXTE X-ray light-curve in Fig. 1 .", "cite_spans": [{"start": 585, "end": 603, "text": "Gies et al. (2007)", "ref_id": "BIBREF0"}], "ref_spans": [{"start": 987, "end": 993, "text": "Fig. 1", "ref_id": "FIGREF0"}]}, {"section": "INTRODUCTION", "text": "Examples of obtained spectra in both states are given in Fig. 2 . It is obvious here that the upper spectrum taken at April before the high-state episode has a strong emission in the whole H \u03b1 line profile, while in August the emission remains in the long-wavelength wing of the line only and the short-wavelength side of the line-profiles reveals an absorption, as it is typical in the P-Cyg line-profiles of stars losing mass via a stellar wind. The strength of the emission can be quantified by the equivalent width of the line, i.e. by an integral across the line of the intensity rectified to the continuum. These values are plotted for each exposure in Fig. 1 which confirms the above mentioned anticorrelation with the X-ray flux. The He I-line 6678\u00c5 is practically free of emission in both states. It means that this line may enable to measure reliably radial velocities of the primary component to get a constraint on the orbital parameters of the system.", "cite_spans": [], "ref_spans": [{"start": 57, "end": 63, "text": "Fig. 2", "ref_id": "FIGREF1"}, {"start": 659, "end": 665, "text": "Fig. 1", "ref_id": "FIGREF0"}]}, {"section": "SPECTRA DISENTANGLING", "text": "Despite the radial velocities of the He I-line 6678\u00c5 could be measured using some standard method, it is advantageous to use the author's method of Fourier spectra disentangling (cf. Hadrava 1994 Hadrava , 1997 Hadrava , 2004 , which makes the procedure efficient and provides directly the orbital parameters. The principle of the method (in the version of 1997 used here) consists in least-squares fitting of all the spectra I observed at various times t as a superposition of unknown spectra I j of the components in the form", "cite_spans": [{"start": 196, "end": 210, "text": "Hadrava , 1997", "ref_id": "BIBREF2"}, {"start": 211, "end": 225, "text": "Hadrava , 2004", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "SPECTRA DISENTANGLING", "text": "Here x = c ln\u03bb is a logarithmic wavelength, v j are instantaneous radial velocities of each component (or logarithms of redshift g-factors for a general relativistic case), s j are factors fitting possibly variable strengths of lines, p are the orbital parameters to be found. Fourier transform", "cite_spans": [], "ref_spans": []}, {"section": "SPECTRA DISENTANGLING", "text": "of Eq. (1) separates the solving for I j into individual modes; similarly for s j one gets a set of linear equations, while p can be found by some numerical method of optimization (e.g. simplex method in the author's code KOREL). Here \u2206 j = s j \u03b4(x \u2212 v j ) in the present calculation, but generally it could also characterize some general broadening function. The method can generally provide intrinsic spectra of n sources, if more than n observed spectra taken at different values v j are on input. Karas & Kraus (1996) suggested a possibility to disentangle in this way contributions of several spots to a line-profile of an accretion disk. The author's code KOREL should be modified for such a purpose, because it is designed for applications to systems of binary or multiple stars. A hierarchical structure of the system is supposed (cf. Fig. 3, left) , in which two pairs of close binaries (denoted 1 + 2 and 3 + 4) are orbiting around their common centre of mass, which may be on an even wider orbit with respect to another component (Nr. 5). To be able to treat simpler systems, spectrum of each component can be switched on or off, and the higher orbits (denoted by numbers in parenthesis in Fig. 3 ) may be chosen degenerated. At the same time, this model is general enough to enable solving some more complicated cases, e.g. just like a presence of circumstellar matter in a binary.", "cite_spans": [{"start": 501, "end": 521, "text": "Karas & Kraus (1996)", "ref_id": "BIBREF7"}], "ref_spans": [{"start": 843, "end": 856, "text": "Fig. 3, left)", "ref_id": "FIGREF2"}, {"start": 1201, "end": 1207, "text": "Fig. 3", "ref_id": "FIGREF2"}]}, {"section": "SPECTRA DISENTANGLING", "text": "As already mentioned, there are seen no traces of the companion or of the circumstellar matter in the He I-line for Cyg X-1. Consequently, one could take the extremally simple case n = 1 of the disentangling (with only the component 1 and orbit (0) switched on -cf. Fig. 3, right) for the spectral region around 6678\u00c5. However, because some weak telluric lines are also present in this region, n = 2 was used instead, with the component 5 corresponding to the telluric lines and orbit (3) to the annual motion. Results of the disentangling are shown on Fig. 4 . In the upper part of this standard output from the KOREL-code, we can see superimposed the 24 observed line-profiles (rectified to the continuum) and their reconstructions from the disentangled line-profiles, which are plotted as the two bottom curves.", "cite_spans": [], "ref_spans": [{"start": 266, "end": 280, "text": "Fig. 3, right)", "ref_id": "FIGREF2"}, {"start": 553, "end": 559, "text": "Fig. 4", "ref_id": "FIGREF4"}]}, {"section": "SPECTRA DISENTANGLING", "text": "The disentangled values of orbital parameters (the epoch and the amplitude of the radial-velocity curve) are given in Tab. 1. ", "cite_spans": [], "ref_spans": []}, {"section": "DOPPLER MAPPING AND DISENTANGLING OF CIRCUMSTELLAR MATTER", "text": "Unlike the He I-line, the H \u03b1 shows the above mentioned irregular emission, revealing a presence of strongly variable circumstellar matter in the system. The variability of line-profile of the emission component, which is frequent in many emission-line systems, obviously violates the assumption on constancy of component spectra I j in Eq. (1) and makes the use of disentangling for such systems questionable. On the other hand, one can always try, if a violation of underlying assumptions is not an effect of second order, and if a mean behaviour of the system cannot be approximated neglecting this effect, or if the effect cannot be modelled as some additional perturbation. Several attempts have been done by the author to fit discrepancies between observed spectra of different binaries with circumstellar matter (e.g. Be-stars or algols) and their reconstructions from disentangled spectra. The method consists in fixing the period of orbit (1) equal to that of orbit (0) but converging either epochs or periastron longitudes of both orbits together with the radial-velocity amplitudes (K) as independent quantities. If the component 1 and 2 correspond to the primary and secondary star, the component 3 may also be switched on, to correspond to (either emission or absorption) features of the circumstellar matter. The amplitude and phase-shift of this component are then correspond to the absolute value and orientation of the superposition of the orbital and intrinsic velocity of the circumstellar matter with respect to the center of mass of the system. In principle, up to five component spectra corresponding to different features corotating in the orbital plane of a binary may be treated using KOREL, if the periods of all four orbits are fixed equal. Such a disentangling always improved formally the fit, but usually it did not provide a fully satisfactory explanation of a long-lasting series of line-profiles. This may be explained by variations of the motion and emissivity of the circumstellar matter on time-scales shorter then the orbital period. Sowers et al. (1998) used the method of Doppler mapping to interpret the lineprofiles of the H \u03b1 line of Cyg X-1. They found a good agreement with observations if an emission source attributed to a focused stellar wind is involved. Recently Jingzhi Yan (2007) suggested to disentangle this focused stellar wind and the primary component from the H \u03b1 line of Cyg X-1. The preliminary results reported here are obtained by switching on the components 1, 3 and 5 for the primary, the focused wind and telluric water-vapor lines (which are quite strong here), resp. The period of orbit (1) is set equal to that of orbit (0), orbit (3) is the annual motion and orbit (2) is degenerated (cf. Fig. 3, right) .", "cite_spans": [{"start": 2071, "end": 2091, "text": "Sowers et al. (1998)", "ref_id": "BIBREF9"}], "ref_spans": [{"start": 2757, "end": 2771, "text": "Fig. 3, right)", "ref_id": "FIGREF2"}]}, {"section": "DOPPLER MAPPING AND DISENTANGLING OF CIRCUMSTELLAR MATTER", "text": "The results are shown in Fig. 5 and Tab. 1. The profiles reconstructed from the disentangled components are again superimposed on the observed 24 line-profiles plotted in the chronological order from the top. The agreement of these curves is surprisingly better than the one obtained for some other interacting binaries with much less pronounced variability. The agreement is a bit worse for the first two exposures taken before the X-high episode, also compared to the last exposures, where X-emission was low again and H \u03b1 emission high (cf. Fig. 4 ), but still with the P-Cyg profile. The mean line-profile of the primary has a P-Cyg shape, the component attributed to the focused stellar wind is a broad emission. The disen-tangled spectrum of telluric lines is partly contamined with the H \u03b1 emission, but again much less than for many other emission-line binaries. Both the primary and wind components are varying in strength, but the analysis of this variability is postponed to a next study based on more spectra disentangled with constrained telluric component as described by Hadrava (2006) . and \u03c6 0 = 0.86 using the tomographic method. Such a disagreement is not surprising, because in spite of some similarities, both methods are different, particularly in taking into account the line-strength variability or the telluric lines. Also the long-term stability of the focused-wind component should be tested by additional spectra. However, the present results indicate, that the velocity-distribution of this component does not vary substantially before and during the episode od high X-ray state.", "cite_spans": [{"start": 1086, "end": 1100, "text": "Hadrava (2006)", "ref_id": "BIBREF5"}], "ref_spans": [{"start": 25, "end": 31, "text": "Fig. 5", "ref_id": "FIGREF5"}, {"start": 544, "end": 550, "text": "Fig. 4", "ref_id": "FIGREF4"}]}], "bib_entries": {"BIBREF0": {"title": "Stellar wind variations during the X-ray high and low states of Cygnus X-1", "authors": [{"first": "D", "middle": ["R"], "last": "Gies", "suffix": ""}, {"first": "C", "middle": ["T"], "last": "Bolton", "suffix": ""}, {"first": "M", "middle": [], "last": "Blake", "suffix": ""}, {"first": "S", "middle": ["M"], "last": "Caballero-Nieves", "suffix": ""}, {"first": "D", "middle": ["M"], "last": "Crenshaw", "suffix": ""}, {"first": "P", "middle": [], "last": "Hadrava", "suffix": ""}, {"first": "A", "middle": [], "last": "Herrero", "suffix": ""}, {"first": "T", "middle": ["C"], "last": "Hillwig", "suffix": ""}, {"first": "S", "middle": ["B"], "last": "Howell", "suffix": ""}, {"first": "W", "middle": [], "last": "Huang", "suffix": ""}, {"first": "L", "middle": [], "last": "Kaper", "suffix": ""}, {"first": "P", "middle": [], "last": "Koubsk\u00fd", "suffix": ""}, {"first": "M", "middle": ["V"], "last": "Mcswain", "suffix": ""}, {"first": "L", "middle": [], "last": "Melymuk", "suffix": ""}], "year": 2007, "venue": "", "link": "9961956"}, "BIBREF1": {"title": "Orbital elements of multiple spectroscopic stars", "authors": [{"first": "P", "middle": [], "last": "Hadrava", "suffix": ""}], "year": 1995, "venue": "A&AS", "link": "117101684"}, "BIBREF2": {"title": "Relative line photometry of eclipsing binaries", "authors": [{"first": "P", "middle": [], "last": "Hadrava", "suffix": ""}], "year": 1997, "venue": "A&AS", "link": "59046002"}, "BIBREF3": {"title": "The method of spectra disentangling and its links to Doppler tomography", "authors": [{"first": "P", "middle": [], "last": "Hadrava", "suffix": ""}], "year": 2001, "venue": "Lecture notes in physics", "link": "115392510"}, "BIBREF4": {"title": "KOREL -User's guide", "authors": [{"first": "P", "middle": [], "last": "Hadrava", "suffix": ""}], "year": 2004, "venue": "Publ. Astron. Inst. ASCR", "link": "59045937"}, "BIBREF5": {"title": "Disentangling of the spectra of binary stars -Principles, results and future development", "authors": [{"first": "P", "middle": [], "last": "Hadrava", "suffix": ""}], "year": 2006, "venue": "Astrophys. & Sp. Sc", "link": "121876078"}, "BIBREF7": {"title": "Doppler tomography of relativistic accretion disks", "authors": [{"first": "V", "middle": [], "last": "Karas", "suffix": ""}, {"first": "P", "middle": [], "last": "Kraus", "suffix": ""}], "year": 1996, "venue": "PASJ", "link": "119362453"}, "BIBREF9": {"title": "Tomographic analysis of H\u03b1 profiles in HDE 226868/Cygnus X-1", "authors": [{"first": "J", "middle": ["W"], "last": "Sowers", "suffix": ""}, {"first": "D", "middle": ["R"], "last": "Gies", "suffix": ""}, {"first": "W", "middle": ["G"], "last": "Bagnuolo", "suffix": ""}, {"first": "", "middle": [], "last": "Jr", "suffix": ""}, {"first": "A", "middle": ["W"], "last": "Shafter", "suffix": ""}, {"first": "R", "middle": [], "last": "Wiemker", "suffix": ""}, {"first": "M", "middle": ["S"], "last": "Wiggs", "suffix": ""}], "year": 1998, "venue": "ApJ", "link": "122273384"}, "BIBREF10": {"title": "Reduction of spectra exposed by the 700mm CCD camera of the Ond\u0159ejov telescope coud\u00e9 spectrograph", "authors": [{"first": "P", "middle": [], "last": "\u0160koda", "suffix": ""}, {"first": "M", "middle": [], "last": "\u0160lechta", "suffix": ""}], "year": 2002, "venue": "Publ. Astron. Inst. ASCR", "link": "116004480"}}, "ref_entries": {"FIGREF0": {"text": "Figure 1. The equivalent width of H\u03b1 emission (in\u00c5, crosses) in 2003 and ASM/RXTE one-day averages of sum-band intensity (in counts/s, error-bars)", "type": "figure"}, "FIGREF1": {"text": "Figure 2. Spectra of Cyg X-1 taken with Ond\u0159ejov 2-m telescope on April 1st (upper curve) and August 5th (lower curve) 2003", "type": "figure"}, "FIGREF2": {"text": "Figure 3. Hierarchical structure of a multiple stellar system supposed in KOREL-code (left) and its use for H\u03b1-line of Cyg X-1 (right)", "type": "figure"}, "FIGREF4": {"text": "Figure 4. Disentangled line He I 6678\u00c5", "type": "figure"}, "FIGREF5": {"text": "Figure 5. Disentangled H\u03b1-line", "type": "figure"}}}
{"paper_id": "17786441", "_pdf_hash": "437c0c524a3e5a0868939448f4d4011592d485b7", "abstract": [], "body_text": [{"section": "Introduction", "text": "In science policy it was assumed into the 1990s that society can benefit most from a science which pursues research at a high level. Correspondingly, indicators were (and are) used in scientometrics, such as citation counts, which measure the impact of research on science itself. Since the 1990s a trend can be observed in science policy no longer to assume that society benefits from a science pursued at a high level (Bornmann, 2012 (Bornmann, , 2013 . It is now expected that the benefit for society be demonstrated. Thus, for example, organizations which support research (such as, for example, the US National Science Foundation) now expect that supported projects lead to an outcome which is of interest not solely to science. For these organizations the consequence for the peer review procedure is that not only the possible scientific yield of the project has to be assessed, but also the returns for other sections of society.", "cite_spans": [{"start": 420, "end": 435, "text": "(Bornmann, 2012", "ref_id": "BIBREF2"}, {"start": 436, "end": 453, "text": "(Bornmann, , 2013", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "Introduction", "text": "These days, scientific work is not assessed solely on the basis of the peer review procedure, but also with indicators. A good example of these quantitative assessments is university ranking (Hazelkorn, 2011) . The most important indicators in this connection (not only with university ranking) are bibliometric indicators based on publications and their citations (Vinkler, 2010) . The impact of research is generally measured with citations. Since the impact of one publication on another publication is measured here, citations measure the impact of research on research itself. Citations allow a determination as to whether research (for example in institutions or countries) is being pursued at the highest level on average or not. But citations cannot be used to measure the impact of research on other sections of society. This is why scientometrics has taken up the wish in science policy to measure the impact of research beyond the confines of science, and is seeking new possibilities for impact measurement (Bornmann, 2014) . With societal impact assessments the (1) social, (2) cultural, (3) environmental and (4) economic returns (impact and effects) from results (research output) or products (research outcome) of publicly funded research are measured (Bornmann, 2013) . Currently the most favored procedure for measuring societal impact involves case studies, which, however, are seen as too time-consuming and therefore less practicable.", "cite_spans": [{"start": 191, "end": 208, "text": "(Hazelkorn, 2011)", "ref_id": "BIBREF15"}, {"start": 365, "end": 380, "text": "(Vinkler, 2010)", "ref_id": "BIBREF33"}, {"start": 1019, "end": 1035, "text": "(Bornmann, 2014)", "ref_id": "BIBREF4"}, {"start": 1268, "end": 1284, "text": "(Bornmann, 2013)", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "Introduction", "text": "An attractive possibility for measuring societal impact is seen in altmetrics (short for alternative metrics) (Mohammadi & Thelwall, 2014) . \"Altmetrics refers to data sources, tools, and metrics (other than citations) that provide potentially relevant information on the impact of scientific outputs (e.g., the number of times a publication has been tweeted, shared on Facebook, or read in Mendeley). Altmetrics opens the door to a broader interpretation of the concept of impact and to more diverse forms of impact analysis\" (Waltman & Costas, 2014, p. 433 ). An overview of various altmetrics may be obtained from Priem and Hemminger (2010) . Twitter (www.twitter.com), for example, is the best known microblogging application. This application allows the user to post short messages (tweets) of up to 140", "cite_spans": [{"start": 110, "end": 138, "text": "(Mohammadi & Thelwall, 2014)", "ref_id": "BIBREF24"}, {"start": 617, "end": 643, "text": "Priem and Hemminger (2010)", "ref_id": "BIBREF28"}], "ref_spans": []}, {"section": "Introduction", "text": "characters. \"These tweets can be categorized, shared, sent directly to other users and linked to websites or scientific papers \u2026 Currently there are more than 200 million active Twitter users who post over 400 million tweets per day\" (Darling, Shiffman, C\u00f4t\u00e9, & Drew, 2013) . Priem and Costello (2010) define tweets as Twitter citations if they contain a direct or indirect link to a peer-reviewed scholarly article. These Twitter citations can be counted and assessed as an alternative metric for papers.", "cite_spans": [{"start": 234, "end": 273, "text": "(Darling, Shiffman, C\u00f4t\u00e9, & Drew, 2013)", "ref_id": "BIBREF9"}, {"start": 276, "end": 301, "text": "Priem and Costello (2010)", "ref_id": "BIBREF27"}], "ref_spans": []}, {"section": "Introduction", "text": "There are already a number of studies concerning altmetrics. An overview of these studies can be found in Bar-Ilan, Shema, and Thelwall (2014) , Haustein (2014), and Priem (2014) . Many of these studies have measured the correlation between citations and altmetrics.", "cite_spans": [{"start": 106, "end": 142, "text": "Bar-Ilan, Shema, and Thelwall (2014)", "ref_id": "BIBREF1"}, {"start": 145, "end": 165, "text": "Haustein (2014), and", "ref_id": "BIBREF13"}, {"start": 166, "end": 178, "text": "Priem (2014)", "ref_id": "BIBREF26"}], "ref_spans": []}, {"section": "Introduction", "text": "Since the correlations were often at a moderate level, the results are difficult to interpret: Both metrics seem to measure something similar but not identical. The studies published so far cannot yet provide a satisfactory answer to the question whether altmetrics is appropriate for the measurement of societal impact or not. That is the reason for this investigation of the question.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "In January 2002, a new type of peer-review system has been launched, in which about 5000 Faculty members are asked \"to identify, evaluate and comment on the most interesting papers they read for themselves each month -regardless of the journal in which they appear\" (Wets, Weedon, & Velterop, 2003, p. 251) . What is known as the Faculty of 1000 (F1000) peer review system is accordingly not an ex-ante assessment of manuscripts provided for publication in a journal, but an ex-post assessment of papers which have already been published in journals. The Faculty members also attach tags to the papers indicating their relevance for science (e.g. \"new finding\"), but which can also serve other purposes. One example of the tags which the members can attach is \"good for teaching\". Papers can be marked in this way if they represent a key paper in a field, are well written, provide a good overview of a topic, and/or are well suited as literature for students. Papers marked with this tag can be expected to have an impact beyond science itself (that means societal impact), unlike papers without this tag. If altmetrics indicate a greater impact for papers with this tag than those without, this would suggest that altmetrics measure societal impact.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "This study is essentially based on a dataset with papers (and their evaluations and tags from Faculty members) extracted from F1000 (see also Mohammadi & Thelwall, 2013) . This dataset was extended with further data -bibliometric (e.g. citation counts) and altmetric (e.g.", "cite_spans": [{"start": 142, "end": 169, "text": "Mohammadi & Thelwall, 2013)", "ref_id": "BIBREF23"}], "ref_spans": []}, {"section": "Twitter counts", "text": "). There follows in the next sections a comparison of altmetric counts with citation counts, to investigate the differences between the two metrics in relation to tags and recommendations.", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Peer ratings provided by F1000", "text": "F1000 is a post-publication peer review system of the biomedical literature (papers from medical and biological journals). This service is part of the Science Navigation Group, a group of independent companies that publish and develop information services for the professional biomedical community and the consumer market. F1000 Biology was launched in 2002 and F1000 Medicine in 2006. The two services were merged in 2009 today constitute the F1000 database. Papers for F1000 are selected by a peer-nominated global \"Faculty\" of leading scientists and clinicians who then rate them and explain their importance (F1000, 2012) . This means that only a restricted set of papers from the medical and biological journals covered is reviewed, and most of the papers are actually not (Kreiman & Maunsell, 2011; Wouters & Costas, 2012) .", "cite_spans": [{"start": 778, "end": 804, "text": "(Kreiman & Maunsell, 2011;", "ref_id": "BIBREF18"}, {"start": 805, "end": 828, "text": "Wouters & Costas, 2012)", "ref_id": "BIBREF39"}], "ref_spans": []}, {"section": "Peer ratings provided by F1000", "text": "The Faculty nowadays numbers more than 5,000 experts worldwide, assisted by 5,000", "cite_spans": [], "ref_spans": []}, {"section": "Peer ratings provided by F1000", "text": "associates, which are organized into more than 40 subjects (which are further subdivided into over 300 sections). On average, 1,500 new recommendations are contributed by the Faculty each month (F1000, 2012) . Faculty members can choose and evaluate any paper that interests them; however, \"the great majority pick papers published within the past month, including advance online papers, meaning that users can be made aware of important papers rapidly\" (Wets, et al., 2003, p. 254) . Although many papers published in popular and high-profile journals (e.g. Nature, New England Journal of Medicine, Science) are evaluated, 85% of the papers selected come from specialized or less well-known journals (Wouters & Costas, 2012) .", "cite_spans": [{"start": 701, "end": 725, "text": "(Wouters & Costas, 2012)", "ref_id": "BIBREF39"}], "ref_spans": []}, {"section": "Peer ratings provided by F1000", "text": "\"Less than 18 months since Faculty of 1000 was launched, the reaction from scientists has been such that two-thirds of top institutions worldwide already subscribe, and it was the recipient of the Association of Learned and Professional Society Publishers (ALPSP) award for Publishing Innovation in 2002 (http://www.alpsp.org/about.htm)\" (Wets, et al., 2003, p. 249 ). The F1000 data base is regarded as a significant aid for scientists seeking the most relevant papers in their subject area: \"The aim of Faculty of 1000 is not to provide an evaluation for all papers, as this would simply exacerbate the 'noise', but to take advantage of electronic developments to create the optimal human filter for effectively reducing the noise,\" (Wets, et al., 2003, p. 253) .", "cite_spans": [], "ref_spans": []}, {"section": "Peer ratings provided by F1000", "text": "The papers selected for F1000 are rated by the members as \"Good,\" \"Very good\" or \"Exceptional\" which is equivalent to scores of 1, 2, or 3, respectively. In many cases a paper is assessed not just by one member but by several. The FFa (F1000 Article Factor), given as a total score in the F1000 database, is calculated from the different recommendations for a publication. Besides making recommendations, Faculty members also tag publications with classifications, as for example (see http://f1000.com/prime/my/about/evaluating):", "cite_spans": [], "ref_spans": []}, {"section": "Peer ratings provided by F1000", "text": "investigates the effects of an intervention (but neither randomized nor controlled) in human subjects. The classifications, recommendations and bibliographic information for publications form the fully searchable F1000 database containing more than 100,000 records (end of 2013). Overall, the F1000 database is regarded simply as an aid for scientists to receive pointers to the most relevant papers in their subject area, but also as an important tool for research evaluation purposes. So, for example, Wouters and Costas (2012) write that \"the data and indicators provided by F1000 are without doubt rich and valuable, and the tool has a strong potential for research evaluation, being in fact a good complement to alternative metrics for research assessments at different levels (papers, individuals, journals, etc.)\" (p.", "cite_spans": [{"start": 504, "end": 529, "text": "Wouters and Costas (2012)", "ref_id": "BIBREF39"}], "ref_spans": []}, {"section": "Peer ratings provided by F1000", "text": "14).", "cite_spans": [], "ref_spans": []}, {"section": "Formation of the dataset, to which bibliometric data and altmetrics are attached", "text": "In January 2014, F1000 provided me with data on all recommendations (and classifications) made and the bibliographic information for the corresponding papers in their system (n=149,227 records (Bornmann, in press ). In addition, Altmetric can only reliably provide data for papers published after 2011. For this reason the dataset is reduced in what follows -where altmetric data is statistically evaluated -to papers from the period after 2011.", "cite_spans": [], "ref_spans": []}, {"section": "Formation of the dataset, to which bibliometric data and altmetrics are attached", "text": "Since Altmetric could not add altmetric data for all the papers, but only for 69%, the question arises how the remaining papers should be treated in the statistical evaluation. One could perhaps argue that these papers should be set to zero counts for all altmetrics.", "cite_spans": [], "ref_spans": []}, {"section": "Formation of the dataset, to which bibliometric data and altmetrics are attached", "text": "Apparently, not even a mention is available for these papers in any of the social media platforms. On the other hand, the dataset from Altmetric should have at least a mention for all papers under F1000 since the data to which Altmetric attaches altmetric data originate from F1000, and F1000 recommendations are also evaluated by Altmetric. But since this is not the case in the current dataset, the 31% of the papers for which Altmetric was not able to supply any altmetric data were recorded as missing and excluded from the statistical analysis. As the following analyses shows, only a few papers published after 2011 are affected by this problem -that is those papers which were used in the current study for the analysis of alternative metrics. the fraction of papers with 0 counts is also provided. As the results show, the counts in the altmetrics are generally low. For example, the papers in the dataset have an average of 0.46 blogs mentioning a paper with a minimum of 0 and a maximum of 111. An important reason for the generally low averages in the altmetrics is the large fraction with 0 counts: For almost all altmetrics in the table, (significantly) more than two thirds of the papers show zero counts.", "cite_spans": [], "ref_spans": []}, {"section": "Formation of the dataset, to which bibliometric data and altmetrics are attached", "text": "Since the total altmetric counts and the unique tweeters mentioning papers (Twitter counts) are the only altmetrics with significantly higher average counts and significantly lower share of 0 counts than with the other altmetrics, these are the only ones included in the following statistical analysis.", "cite_spans": [], "ref_spans": []}, {"section": "Formation of the dataset, to which bibliometric data and altmetrics are attached", "text": "On the one hand, the analysis of Twitter counts in this study has the further advantage that the data evaluated originates only from one service (which represents the standard in the area of microblogging). This facilitates the collection of data for Altmetric and ensures the reliability of the counts. Blogs, for example, do not have this advantage: \"While most other Web 2.0 applications are closely identified with a few 'name-brand' services (for instance, Twitter for microblogging and delicious for social bookmarking), blogging is not\" (Priem & Hemminger, 2010) . Blogs are distributed over the whole Web, and there is no standard service aggregating these blogs. On the other hand, Twitter is particularly in use by people who operate outside the area of science: Although Twitter is one of the most often used social media platforms, it is generally assumed that only few scientists actually tweet (Darling, et al., 2013; Mahrt, Weller, & Peters, 2012) .", "cite_spans": [{"start": 544, "end": 569, "text": "(Priem & Hemminger, 2010)", "ref_id": "BIBREF28"}, {"start": 908, "end": 931, "text": "(Darling, et al., 2013;", "ref_id": "BIBREF9"}, {"start": 932, "end": 962, "text": "Mahrt, Weller, & Peters, 2012)", "ref_id": "BIBREF22"}], "ref_spans": []}, {"section": "Statistical procedure and software used", "text": "The statistical software package Stata 13.1 (http://www.stata.com/) is used for this study; in particular, the Stata commands nbreg, margins, and coefplot are used.", "cite_spans": [], "ref_spans": []}, {"section": "Statistical procedure and software used", "text": "A series of regression models has been estimated. The outcome variables (number of citations, number of tweeds, number of total altmetric counts) in the models are count variables. They indicate \"how many times something has happened\" (Long & Freese, 2006, p. 350) . The Poisson distribution is often used to model information on counts. However, this distribution rarely fits in the statistical analysis of bibliometric and altmetric data, due to overdispersion. \"That is, the [Poisson] model underfits the amount of dispersion in the outcome\" (Long & Freese, 2006, p. 372) . Since the standard model to account for overdispersion is the negative binomial (Hausman, Hall, & Griliches, 1984) , negative binomial regression models are calculated in the present study (Hilbe, 2007) .", "cite_spans": [{"start": 657, "end": 691, "text": "(Hausman, Hall, & Griliches, 1984)", "ref_id": "BIBREF12"}, {"start": 766, "end": 779, "text": "(Hilbe, 2007)", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "Statistical procedure and software used", "text": "The violation of the assumption of independent observations by including several different items of information about the same paper (such as several F1000 recommendation scores or several subject categories associated with a paper) is considered by using the cluster option in Stata (StataCorp., 2013) . This option specifies that the information items are independent across papers but are not necessarily independent within the same paper (Hosmer & Lemeshow, 2000, section 8.3 ).", "cite_spans": [], "ref_spans": []}, {"section": "Statistical procedure and software used", "text": "The publication years of the papers were included in the models predicting different counts (e.g. citations) as exposure time (Long & Freese, 2006, pp. 370-372) . The exposure option provided in Stata takes into account the time that a paper is available for citations or other mentions (e.g. in Twitter).", "cite_spans": [], "ref_spans": []}, {"section": "Statistical procedure and software used", "text": "In this study, adjusted predictions are used to make the results easy to understand and interpret. Such predictions are referred to as margins, predictive margins, or adjusted predictions (Bornmann & Williams, 2013; Williams, 2012; Williams & Bornmann, in preparation) . The predictions allow a determination of the meaning of the empirical results which goes beyond the statistical significance test. Whereas the regression models illustrate which effects are statistically significant and what the direction of the effects is, adjusted predictions can provide us a practical feel for the substantive significance of the findings. Table 2 shows the distribution of the tags over the records in the dataset (in which papers appear more than once) and total tag mentions (\"total\" line). It is very clear that the tags are applied very differently: Whereas, for example, \"new finding\" makes up about half of the tag mentions, for \"review\" it is only about 2%. In order to be able to make a reliable statement about the validity of the altmetrics, the following statistical analysis does not include all tags, but only those with more than 5% of mentions or allocated to more than 10% of records. What expectations are there in the current study in relation to the connection between altmetrics counts or citation counts and the categorization of papers with the five selected tags (which are described in further detail in section 2.1)? In connection with \"new finding\", \"confirmation\" and \"interesting hypothesis\", it is expected that the citation counts for such papers would be higher for those where a Faculty member has used this tag than for those where this did not happen. Since these tags particularly relate to aspects which are relevant in a scientific context, it would not be expected that the altmetric tags show this difference between tagged and untagged papers. In contrast to this, we could expect that papers tagged with \"good for teaching\" would (also) be interesting for a group of people outside science or research. These are papers which are well written, provide an overview of a topic and are well suited for teaching. Therefore, a higher altmetrics count would be expected for papers with this tag than for papers without it. The \"technical advance\" tag is used on papers that present a new technique or tool (whether that's a lab technique/tool or a clinical one) that make an advance on an existing technique. The tag can be used both for research papers and outside,", "cite_spans": [{"start": 188, "end": 215, "text": "(Bornmann & Williams, 2013;", "ref_id": "BIBREF8"}, {"start": 216, "end": 231, "text": "Williams, 2012;", "ref_id": "BIBREF37"}], "ref_spans": [{"start": 632, "end": 639, "text": "Table 2", "ref_id": "TABREF3"}]}, {"section": "Results", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "The distribution and selection of the tags in the dataset", "text": "i.e. clinical or fieldwork. Thus, a similar effect of this tag on altmetric or citation counts would be expected in the statistical analysis.", "cite_spans": [], "ref_spans": []}, {"section": "How do the counts differ for differently tagged papers?", "text": "In order to ascertain how total altmetric counts, Twitter counts, and citation counts differ with differently tagged papers, three regression models were calculated with the three counts as dependent variables and the tags as independent variables (see Table 3 ). Each model includes the individual recommendation scores of the Faculty members alongside the tags.", "cite_spans": [], "ref_spans": [{"start": 253, "end": 260, "text": "Table 3", "ref_id": "TABREF4"}]}, {"section": "How do the counts differ for differently tagged papers?", "text": "This enables us to ascertain the influence of the tags on the different counts, controlling for the effect of the recommendations. Since the recommendations reflect the quality of the papers, the results of the tags are adjusted for the quality of the papers. In other words: the different results for the tags can hardly be traced back to the differing quality of the papers. As Table 3 shows, the three models involve papers from different years: The models with altmetrics as dependent variables can only take into account papers published after 2011 (see above). The model with citation counts as dependent variable only involves papers published before 2011. Since the citation window for the papers extends from the publication year to the end of 2012 in this study, the citation window for papers published after 2011 is too narrow to measure the citation impact reliably (Wang, 2013) . The inclusion of papers from before 2011 leads, however, to a shortage of records tagged with \"good for teaching\" (0.1%, n=181) (see Table 3 ). The \"good for teaching\" tag is relatively new for F1000Prime; it was introduced only in 2011. Therefore, it cannot be included in the analysis of the citations. The results of the regression models are shown in Table 4 . These are the test statistics depend on the models with all independent variables, they are calculated for the different tags under control of the recommendation scores (and adjusted for quality). In all the models in Table 4 , a statistically significant result is seen for the recommendation scores of the Faculty members. Since the coefficients have a positive sign, higher total altmetric counts, Twitter counts, and citation counts are to be expected with better scores. Thus the quality of the papers does not only play an important role for the citation impact, but also for the altmetric counts. The relation between the different recommendation scores and the predicted numbers of counts is presented in Figure 1 : It is very clear that citation counts in particular separate the differently evaluated papers.", "cite_spans": [{"start": 879, "end": 891, "text": "(Wang, 2013)", "ref_id": "BIBREF35"}], "ref_spans": [{"start": 380, "end": 387, "text": "Table 3", "ref_id": "TABREF4"}, {"start": 1027, "end": 1034, "text": "Table 3", "ref_id": "TABREF4"}, {"start": 1249, "end": 1256, "text": "Table 4", "ref_id": "TABREF5"}, {"start": 1477, "end": 1484, "text": "Table 4", "ref_id": "TABREF5"}]}, {"section": "How do the counts differ for differently tagged papers?", "text": "In the two models for the altmetrics (models 1 and 2), the coefficient for \"good for teaching\" is statistically significant. Correspondingly, Figure 2 and Figure 3 show higher predicted numbers of counts for papers where this tag is set, than for those papers where this was not the case. For example, we can expect a paper with this tag to have around seven", "cite_spans": [], "ref_spans": []}, {"section": "How do the counts differ for differently tagged papers?", "text": "Twitter citations more than one without -if the paper is rated as \"very good\" by Faculty members and has no other tags. These results for \"good for teaching\" correspond to the expectations (see above) and indicate that altmetric data (and especially tweets) can indicate papers which are of interest outside of science.", "cite_spans": [], "ref_spans": []}, {"section": "How do the counts differ for differently tagged papers?", "text": "Unfortunately, the \"good for teaching\" tag could not be included in the model for the citation counts (see above). Therefore, there is a lack of results which could be included in a comparison. Model 3 for the citation counts provides two statistically significant results (see Table 4 ): Citations are particularly to be expected if a paper presents original data, models or hypotheses (tag: \"new finding\") or introduces a new practical/ theoretical technique (tag:", "cite_spans": [], "ref_spans": [{"start": 278, "end": 285, "text": "Table 4", "ref_id": "TABREF5"}]}, {"section": "How do the counts differ for differently tagged papers?", "text": "\"technical advance\"). Whereas the results for \"new finding\" correspond with the expectations (see above), the results for \"technical advance\" can clarify the unspecific expectations formulated above: Papers tagged with \"technical advance\" seem to involve techniques with relevance for research rather than for areas outside research. For both tags, Figure 4 shows a clear citation impact advantage for papers with this tag than for those without.", "cite_spans": [], "ref_spans": [{"start": 349, "end": 357, "text": "Figure 4", "ref_id": "FIGREF2"}]}, {"section": "How do the counts differ for differently tagged papers?", "text": "The results in Figure 4 also show that confirmatory results (tag: \"confirmation\") and interesting hypotheses (tag: \"hypothesis\") can hardly be associated with higher or lower citation counts (against the expectation). ", "cite_spans": [], "ref_spans": [{"start": 15, "end": 23, "text": "Figure 4", "ref_id": "FIGREF2"}]}, {"section": "Is normalization of impact necessary for altmetric counts, as with citation counts?", "text": "If altmetric data is to be used for the measurement of societal impact in the evaluation of research, the question arises of its normalization (Torres-Salinas, Cabezas-Clavijo, & Jimenez-Contreras, 2013). With citation counts, there is a consensus in the bibliometric community that the impact of papers should be normalized in relation to the subject category (the field) and the publication year (the time) (Bornmann, Leydesdorff, & Wang, 2013) . Is this also necessary for the Twitter counts and total altmetric counts investigated here? The following statistical analysis will focus on the question of taking into account the subject categories, since, for the papers in this study, only the publication year is available and not the publication month or day. Unlike citations which arise only a long time after the appearance of a paper, altmetric data generally appears relatively quickly (Priem, Taraborelli, Groth, & Neylon, 2010; Rodgers & Barbrow, 2013) . The temporal aspect in the normalization of altmetric data can therefore only be clarified with data on the month or day level. Other empirical studies have already indicated subject area differences with altmetric data. Thus, for example Loach (2014) shows from Twitter counts in the Altmetric database \"that medical articles receive a disproportionate amount of online attention. In fact, 60% of tracked tweets from the last week pointed to articles from journals publishing Medical and Health Science research. Interestingly, 63% of these were directed to articles from journals tagged as relating to Clinical Medicine or Public Health specifically.\" An important disadvantage of the studies which have so far appeared on subject area difference is that the quality of the papers is not controlled in the analyses of the subject area differences. Therefore, it is not known whether the differences between the subject areas depend on aspects specific to the subject or quality differences between the papers. Thus, medical papers could receive more online attention just because these papers are generally of a higher quality than papers from other subject categories. The quality of the papers should therefore be controlled in the analysis of subject area differences.", "cite_spans": [{"start": 409, "end": 446, "text": "(Bornmann, Leydesdorff, & Wang, 2013)", "ref_id": "BIBREF6"}, {"start": 895, "end": 938, "text": "(Priem, Taraborelli, Groth, & Neylon, 2010;", "ref_id": "BIBREF29"}, {"start": 939, "end": 963, "text": "Rodgers & Barbrow, 2013)", "ref_id": "BIBREF30"}, {"start": 1205, "end": 1217, "text": "Loach (2014)", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "Is normalization of impact necessary for altmetric counts, as with citation counts?", "text": "In the current study, WoS subject categories are used to determine subject area differences in the counts. Most bibliometric studies use these categories, which, however, are not applied on the level of individual papers, but on the level of journals: A set of journals is combined in a subject category by Thomson Reuters. Table 5 shows the distribution of the papers over the subject categories published after 2011 in the dataset. Since the evaluation of the altmetric data could only include papers after 2011, the table refers to this part of the data.", "cite_spans": [], "ref_spans": [{"start": 324, "end": 331, "text": "Table 5", "ref_id": "TABREF6"}]}, {"section": "Is normalization of impact necessary for altmetric counts, as with citation counts?", "text": "As the table shows, around 14% of the category classifications relate to \"multidisciplinary sciences\" -that corresponds to around 20% of the papers. This journal set includes the two multi-disciplinary journals Nature and Science. Around 13% of the papers in the dataset were published in a journal belonging to the category \"cell biology\". The subject categories in Table 5 are included as independent variables in two negative binomial regression models, where one includes the total altmetrics counts and the other the Twitter counts as dependent variable. With the help of this model, the predicted numbers of counts could be determined for the individual subject categories, where the quality of the papers is controlled for by the individual recommendation scores (which are included as mean scores per paper in the model alongside subject categories). The model also takes into account that the papers appeared in different publication years and have different numbers of subject categories. The results of the regression models will not be presented in", "cite_spans": [], "ref_spans": [{"start": 367, "end": 374, "text": "Table 5", "ref_id": "TABREF6"}]}, {"section": "Is normalization of impact necessary for altmetric counts, as with citation counts?", "text": "table form in what follows, since the tables are very extensive given the large number of different subject categories. But the predicted numbers of counts with 95% confidence intervals for the individual subject categories are presented as the results of the models (see Figure 5 and Figure 6 ). Figure 5 . Predicted numbers of total altmetric counts with 95% confidence intervals. The graphic is based on 13,278 papers published after 2011 with 18,254 subject category instances (only subject categories with more than 100 instances). The results arise from a negative binomial regression model, in which the quality of the papers is controlled by the individual recommendation scores of the Faculty members. Predicted number of count Figure 6 . Predicted numbers of Twitter counts with 95% confidence intervals. The graphic is based on 13,278 papers published after 2011 with 18,254 subject category instances (only subject categories with more than 100 instances). The results arise from a negative binomial regression model, where the quality of the papers is controlled for with the individual recommendation scores of the Faculty members.", "cite_spans": [], "ref_spans": []}, {"section": "Is normalization of impact necessary for altmetric counts, as with citation counts?", "text": "In order to determine whether the predicted numbers of counts for the subject categories with the altmetric data follows a similar (or different) pattern to that with the citation counts, Figure 7 shows the predicted numbers of citation counts with 95% confidence intervals. As with the evaluations described in section 3.2, these predicted numbers arise from a negative binomial regression model based on papers from the time period before (and not after) 2011. Even if the analysis underlying Figure 7 only took into account subject categories with more than 100 instances in the dataset (similarly to Figure 5 and Figure 6 ), the subject Predicted number of count categories in Figure 7 do not coincide with those shown in Figure 5 and Figure 6 . The reason for the discrepancies lies in the different publication years involved. Figure 7 . Predicted numbers of citation counts with 95% confidence intervals. The graphic is based on 42,858 papers published before 2011 with 60,468 subject category instances (only subject categories with more than 100 instances). The results arise from a negative binomial regression model, where the quality of the papers is controlled for with the individual recommendation scores of the Faculty members.", "cite_spans": [], "ref_spans": []}, {"section": "Is normalization of impact necessary for altmetric counts, as with citation counts?", "text": "As the results in the three figures show, the predicted numbers of counts for the altmetric data on the one hand is very different from that for the bibliometric data, on the other. With the altmetric data (total altmetric counts and Twitter counts), the predicted Predicted number of count number of counts is relatively low for almost all subject categories. Only for \"biology\", \"ecology\", \"evolutionary biology\", \"multidisciplinary sciences\" and especially for \"medicine, general & internal\" are they higher. Particularly in the journals of the subject category \"medicine, general & internal\" an especially large number of contributions seem to be published which are not only of scientific interest.", "cite_spans": [], "ref_spans": []}, {"section": "Is normalization of impact necessary for altmetric counts, as with citation counts?", "text": "The predicted numbers of citation counts shown in Figure 7 , shows a different pattern from the predicted numbers of altmetrics data. In Figure 7 there are quite a few subject categories which stand out with relatively high counts (and many categories with hardly any), but the individual subject categories are distributed over a large bandwidth of different predicted numbers of counts. This difference between the altmetric data and citations in the distribution over the predicted numbers of counts is visualized in Figure 8 . Box plots are used to represent the distribution of the counts which are visualized in Figure 5 , Figure 6 and Figure 7 . In Figure 8 it can clearly be seen that the predicted numbers of citation counts are distributed over a greater area than the predicted numbers of total altmetric counts and Twitter counts. Correspondingly, the citation counts show a significantly greater standard deviation than the altmetric data (see Figure 8 ). Twitter count (n=45) Citation count (n=58) Figure 8 . Distribution of the predicted number of total altmetrics counts, Twitter counts and citation counts. Whereas the standard deviations for the total altmetrics counts and Twitter counts are std=11.3 and std=9.5, for the citation counts it is std=23.5.", "cite_spans": [], "ref_spans": []}, {"section": "Is normalization of impact necessary for altmetric counts, as with citation counts?", "text": "The results for the differences in the distribution of the predicted numbers of counts between the altmetric and the bibliometric data indicate that the subject categories have a different meaning in this area. Whereas the evaluation of the bibliometric data indicates different citation practices in the fields (which should be taken into account with a normalization), the evaluation of the altmetric data gives the impression that only papers from a few specific subject areas receive a larger number of mentions. With the altmetric data, it does not therefore appear a matter of different habits in the mentioning of papers between the fields, but of a particularly large (or small) interest among people outside science for papers from a few specific areas (or for the bulk of scientific papers). Therefore, a normalization of the counts on the level of subject categories (journal sets) is not regarded as reasonable.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "Can altmetric data be validly used for the measurement of societal impact? The current study has sought to answer this question with a comprehensive dataset from very disparate sources (F1000, Altmetric, and an in-house database based on WoS). In the F1000 peer review system, experts attach particular tags to papers which indicate whether a paper could be of interest for science or rather for other segments of society. In this study, these tags were", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "used in an attempt to analyze the validity of altmetric data. A \"good for teaching\" tag indicates that a paper could be of interest outside the science. If papers with this tag receive more altmetric counts than those without, this would be an indication of the validity of measuring societal impact with altmetric data. Conversely, papers with tags for specifically scientific aspects (such as \"new finding\" or \"hypothesis\") should show no effect on the altmetric counts. For contrast with the altmetric data results, this study analyzed citation counts.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "First of all, the results of the regression model in relation to all counts (bibliometric and altmetric) show a correlation with the quality of the papers: With better recommendation scores of the Faculty members, the higher the counts are. For example, for recommendation scores \"good\", \"very good\", and \"exceptional\" the corresponding predicted probabilities of citations are 69, 113, and 178. The effect of the recommendation scores occurs -as expected -more strongly with the citation counts than with the altmetric data, and is in agreement with the results of Bornmann (in press). In the study of Bornmann (in press), it is shown that the recommendations of the Faculty members are correlated with field-und time-normalized citation impact scores. The further results of the regression models show substantial differences between altmetrics counts and citation counts (see Bar-Ilan, 2012 ). With regard to a possible societal impact measurement with altmetrics, the results of the present study indicate that with altmetric data impact measurement beyond the science seems possible:", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "Papers with the tag \"good for teaching\" do really achieve higher altmetric counts than papers without this tag -if the quality of the papers is controlled. At the same time, a higher citation count is shown especially by papers with a tag that is specifically scientifically oriented (\"new finding\"). Although the tag \"good for teaching\" could not be included in the model with the citation counts (so the contrasting comparison was absent), no (statistically) significant effect was demonstrated for the tag \"new finding\" in the models with the altmetric data.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "The results of this study possibly indicate that papers tailored for a readership outside the area of research or science lead to societal impact. This result is in agreement with the proposal of Bornmann and Marx (2014) . To produce societal impact, the authors suggest that scientists write assessment reports summarizing the status of the research on a certain subject and representing knowledge which is available for society to access. An assessment report should be couched in generally understandable terms so that readers who are not familiar with the subject area or the scientific discipline can make sense of it. In the view of Bornmann and Marx (2014) , these reports could be seen as part of the secondary literature of science, which has up to now drawn on review journals, monographs, handbooks and textbooks (primary literature is made up of the publications of the original research literature). With the help of these assessment reports it should be possible to reach people from other segments of society (besides science) and to achieve a correspondingly high impact that would then have an effect on the altmetric data.", "cite_spans": [{"start": 196, "end": 220, "text": "Bornmann and Marx (2014)", "ref_id": "BIBREF7"}, {"start": 639, "end": 663, "text": "Bornmann and Marx (2014)", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "Discussion", "text": "If altmetric data is to be used for the measurement of societal impact, the question arises of its normalization. Bibliometric data -citations -are normalized for subject area and time. This study has therefore taken a second analytic step involving a possible subject area normalization of altmetric data. In this analysis too, additional citation data was considered to be able to determine common factors and differences in the results. In contrast to the predicted numbers of citation counts, where the subject categories each showed very different clustering, the predicted numbers of altmetric counts (total Altmetric counts and Twitter counts) showed very few subject categories producing high levels of clustering (and the great bulk of the categories low clustering): \"biology\", \"ecology\", \"evolutionary biology\", \"multidisciplinary sciences\" and especially \"medicine, general & internal\".", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "In comparison with the other subject categories (which obtained relatively low counts), these categories are of the sort which appeal to a wider audience public. This wider audience is generally especially interested in topics like ecology and evolution, as well as research results from (internal) medicine (or particular diseases). In addition, there is a special interest in contributions from the best-known scientific journals Nature, Science, and", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "Proceedings of the National Academy of Sciences (PNAS), which publish research from all disciplines. There are obviously -as the results of this study show -particular topics in the biomedical area which are of especially great interest for a wide audience. Since these more or less interesting topics are not completely reflected in Thomson Reuters' journal sets, a normalization of altmetric data (especially Twitter) should not be based on the level of subject categories, but on the level of topics: Thus, for example, Twitter's homepage includes a current list of trending topics as a main feature. \"These terms reflect the topics that are being discussed most at that moment on the site's fast-flowing stream of tweets. In order to avoid topics that are popular regularly (e.g., good morning or good night on certain times of the day), Twitter focuses on topics that are being discussed much more than usual, that is, topics that recently experienced an increase of use, therefore trending\" (Zubiaga, Spina, Mart\u00ednez, & Fresno, 2014) . The comparison of Twitter citations of papers published on a particular topic would then show a greater or lesser interest in papers on this topic. A normalization of Twitter citations could then be performed on the level of papers on a topic.", "cite_spans": [{"start": 997, "end": 1039, "text": "(Zubiaga, Spina, Mart\u00ednez, & Fresno, 2014)", "ref_id": "BIBREF40"}], "ref_spans": []}, {"section": "Conclusions", "text": "In relation to the measurement of societal impact, the results of this study are promising: Altmetric data (Twitter counts) seem able to indicate papers which produce societal impact. However, it is not clear which kind of impact is measured: Does it measure social, cultural, environmental and/ or economic impact? With evaluating citations in university text books (impact on education), patents (impact on industry) and clinical guidelines (impact on clinical praxis), there are already some approved instruments available for the reliable societal impact measurements which could be complemented by altmetrics.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "In a bid to measure the influence of research on industry, Narin, Hamilton, and Olivastro (1997) studied the frequency with which scientific publications were cited in US patents. They evaluated 400,000 US patents issued between 1987 and 1994. Their results", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "show that the knowledge flow from US science to US industry tripled in these years. Grant (1999) and Lewison and Sullivan (2008) pursued a similar objective to Narin, et al. (1997) with their evaluation of clinical guidelines: how does knowledge flow from clinical research to clinical practice? The pilot study by Grant (1999) examined three guidelines and was able to ascertain that they contained citations of a total of 284 publications (which can be categorised by author, research institution, country, etc.). For Grant (1999) , the study results demonstrate the usefulness of his approach to tracing the flow of knowledge from research funding into clinical practice.", "cite_spans": [{"start": 84, "end": 96, "text": "Grant (1999)", "ref_id": "BIBREF11"}, {"start": 101, "end": 128, "text": "Lewison and Sullivan (2008)", "ref_id": "BIBREF19"}, {"start": 160, "end": 180, "text": "Narin, et al. (1997)", "ref_id": "BIBREF25"}, {"start": 315, "end": 327, "text": "Grant (1999)", "ref_id": "BIBREF11"}, {"start": 520, "end": 532, "text": "Grant (1999)", "ref_id": "BIBREF11"}], "ref_spans": []}, {"section": "Conclusions", "text": "As most of the former empirical studies on altmetrics have pointed out, we need further studies (including a broad range of altmetrics) dealing with the question of the specific impacts of altmetrics. For this, datasets are required which contain information about the importance of individual publications outside the area of science. This information should be produced by experts (and thus be reliable and valid). Unfortunately, the F1000 dataset does not contain this information. It would be particularly interesting to have information on the importance of publications for very specific segments of society (such as the economy, politics or culture). With this data, one could determine which specific altmetric impact one could measure in which segment of society.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF1": {"title": "Bibliographic References in Web 2.0", "authors": [{"first": "J", "middle": [], "last": "Bar-Ilan", "suffix": ""}, {"first": "H", "middle": [], "last": "Shema", "suffix": ""}, {"first": "M", "middle": [], "last": "Thelwall", "suffix": ""}], "year": 2014, "venue": "Beyond bibliometrics: harnessing multi-dimensional indicators of performance", "link": "63674152"}, "BIBREF2": {"title": "Measuring the societal impact of research", "authors": [{"first": "L", "middle": [], "last": "Bornmann", "suffix": ""}], "year": 2012, "venue": "EMBO Reports", "link": null}, "BIBREF3": {"title": "What is societal impact of research and how can it be assessed? A literature survey", "authors": [{"first": "L", "middle": [], "last": "Bornmann", "suffix": ""}], "year": 2013, "venue": "Journal of the American Society of Information Science and Technology", "link": "10221141"}, "BIBREF4": {"title": "Is there currently a scientific revolution in scientometrics", "authors": [{"first": "L", "middle": [], "last": "Bornmann", "suffix": ""}], "year": 2014, "venue": "Journal of the Association for Information Science and Technology", "link": "20103460"}, "BIBREF5": {"title": "Inter-rater reliability and convergent validity of F1000Prime peer review", "authors": [{"first": "L", "middle": [], "last": "Bornmann", "suffix": ""}], "year": "", "venue": "Journal of the Association for Information Science and Technology", "link": "25137203"}, "BIBREF6": {"title": "Which percentile-based approach should be preferred for calculating normalized citation impact values? An empirical comparison of five approaches including a newly developed citation-rank approach (P100)", "authors": [{"first": "L", "middle": [], "last": "Bornmann", "suffix": ""}, {"first": "L", "middle": [], "last": "Leydesdorff", "suffix": ""}, {"first": "J", "middle": [], "last": "Wang", "suffix": ""}], "year": 2013, "venue": "Journal of Informetrics", "link": "13062228"}, "BIBREF7": {"title": "How should the societal impact of research be generated and measured? A proposal for a simple and practicable approach to allow interdisciplinary comparisons", "authors": [{"first": "L", "middle": [], "last": "Bornmann", "suffix": ""}, {"first": "W", "middle": [], "last": "Marx", "suffix": ""}], "year": 2014, "venue": "Scientometrics", "link": "12288156"}, "BIBREF8": {"title": "How to calculate the practical significance of citation impact differences? An empirical example from evaluative institutional bibliometrics using adjusted predictions and marginal effects", "authors": [{"first": "L", "middle": [], "last": "Bornmann", "suffix": ""}, {"first": "R", "middle": [], "last": "Williams", "suffix": ""}], "year": 2013, "venue": "Journal of Informetrics", "link": "18825774"}, "BIBREF9": {"title": "The role of Twitter in the life cycle of a scientific publication", "authors": [{"first": "E", "middle": ["S"], "last": "Darling", "suffix": ""}, {"first": "D", "middle": [], "last": "Shiffman", "suffix": ""}, {"first": "I", "middle": ["M"], "last": "C\u00f4t\u00e9", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Drew", "suffix": ""}], "year": 2013, "venue": "PeerJ PrePrints", "link": null}, "BIBREF10": {"title": "What is F1000?", "authors": [{"first": "", "middle": [], "last": "F1000", "suffix": ""}], "year": 2012, "venue": "", "link": null}, "BIBREF11": {"title": "Evaluating the outcomes of biomedical research on healthcare", "authors": [{"first": "J", "middle": [], "last": "Grant", "suffix": ""}], "year": 1999, "venue": "Research Evaluation", "link": "154559501"}, "BIBREF12": {"title": "Econometric models for count data with an application to the patents R and D relationship", "authors": [{"first": "J", "middle": [], "last": "Hausman", "suffix": ""}, {"first": "B", "middle": ["H"], "last": "Hall", "suffix": ""}, {"first": "Z", "middle": [], "last": "Griliches", "suffix": ""}], "year": 1984, "venue": "Econometrica", "link": "154594979"}, "BIBREF13": {"title": "Readership metrics", "authors": [{"first": "S", "middle": [], "last": "Haustein", "suffix": ""}], "year": 2014, "venue": "Beyond bibliometrics: harnessing multi-dimensional indicators of performance", "link": null}, "BIBREF15": {"title": "Rankings and the reshaping of higher education. The battle for worldclass excellence", "authors": [{"first": "E", "middle": [], "last": "Hazelkorn", "suffix": ""}], "year": 2011, "venue": "", "link": "152732460"}, "BIBREF16": {"title": "Negative binomial regression", "authors": [{"first": "J", "middle": ["M"], "last": "Hilbe", "suffix": ""}], "year": 2007, "venue": "", "link": "198472171"}, "BIBREF17": {"title": "Applied logistic regression", "authors": [{"first": "D", "middle": ["W"], "last": "Hosmer", "suffix": ""}, {"first": "S", "middle": [], "last": "Lemeshow", "suffix": ""}], "year": 2000, "venue": "", "link": "150290167"}, "BIBREF18": {"title": "Nine criteria for a measure of scientific output", "authors": [{"first": "G", "middle": [], "last": "Kreiman", "suffix": ""}, {"first": "J", "middle": ["H R"], "last": "Maunsell", "suffix": ""}], "year": 2011, "venue": "Frontiers in Computational Neuroscience", "link": "6295095"}, "BIBREF19": {"title": "The impact of cancer research: how publications influence UK cancer clinical guidelines", "authors": [{"first": "G", "middle": [], "last": "Lewison", "suffix": ""}, {"first": "R", "middle": [], "last": "Sullivan", "suffix": ""}], "year": 2008, "venue": "British Journal of Cancer", "link": "10009609"}, "BIBREF20": {"title": "Analysing Attention", "authors": [{"first": "T", "middle": [], "last": "Loach", "suffix": ""}], "year": 2014, "venue": "", "link": null}, "BIBREF21": {"title": "Regression models for categorical dependent variables using Stata", "authors": [{"first": "J", "middle": ["S"], "last": "Long", "suffix": ""}, {"first": "J", "middle": [], "last": "Freese", "suffix": ""}], "year": 2006, "venue": "", "link": "41874930"}, "BIBREF22": {"title": "Twitter in scholarly communication", "authors": [{"first": "M", "middle": [], "last": "Mahrt", "suffix": ""}, {"first": "K", "middle": [], "last": "Weller", "suffix": ""}, {"first": "I", "middle": [], "last": "Peters", "suffix": ""}], "year": 2012, "venue": "", "link": null}, "BIBREF23": {"title": "Assessing non-standard article impact using F1000 labels", "authors": [{"first": "E", "middle": [], "last": "Mohammadi", "suffix": ""}, {"first": "M", "middle": [], "last": "Thelwall", "suffix": ""}], "year": 2013, "venue": "Scientometrics", "link": "16323114"}, "BIBREF24": {"title": "Mendeley readership altmetrics for the social sciences and humanities: Research evaluation and knowledge flows", "authors": [{"first": "E", "middle": [], "last": "Mohammadi", "suffix": ""}, {"first": "M", "middle": [], "last": "Thelwall", "suffix": ""}], "year": 2014, "venue": "Journal of the Association for Information Science and Technology", "link": "10431919"}, "BIBREF25": {"title": "The increasing linkage between US technology and public science", "authors": [{"first": "F", "middle": [], "last": "Narin", "suffix": ""}, {"first": "K", "middle": ["S"], "last": "Hamilton", "suffix": ""}, {"first": "D", "middle": [], "last": "Olivastro", "suffix": ""}], "year": 1997, "venue": "Research Policy", "link": "145695615"}, "BIBREF26": {"title": "Beyond bibliometrics: harnessing multi-dimensional indicators of performance", "authors": [{"first": "J", "middle": [], "last": "Priem", "suffix": ""}], "year": 2014, "venue": "", "link": null}, "BIBREF27": {"title": "How and why scholars cite on Twitter", "authors": [{"first": "J", "middle": [], "last": "Priem", "suffix": ""}, {"first": "K", "middle": ["L"], "last": "Costello", "suffix": ""}], "year": 2010, "venue": "Proceedings of the American Society for Information Science and Technology", "link": "17919203"}, "BIBREF28": {"title": "Scientometrics 2.0: toward new metrics of scholarly impact on the social Web", "authors": [{"first": "J", "middle": [], "last": "Priem", "suffix": ""}, {"first": "B", "middle": ["M"], "last": "Hemminger", "suffix": ""}], "year": 2010, "venue": "First Monday", "link": null}, "BIBREF29": {"title": "Altmetrics: a manifesto", "authors": [{"first": "J", "middle": [], "last": "Priem", "suffix": ""}, {"first": "D", "middle": [], "last": "Taraborelli", "suffix": ""}, {"first": "P", "middle": [], "last": "Groth", "suffix": ""}, {"first": "C", "middle": [], "last": "Neylon", "suffix": ""}], "year": 2010, "venue": "", "link": null}, "BIBREF30": {"title": "A look at altmetrics and its growing significance to research libraries", "authors": [{"first": "E", "middle": ["P"], "last": "Rodgers", "suffix": ""}, {"first": "S", "middle": [], "last": "Barbrow", "suffix": ""}], "year": 2013, "venue": "", "link": "108875658"}, "BIBREF31": {"title": "Stata statistical software: release 13", "authors": [{"first": "", "middle": [], "last": "Statacorp", "suffix": ""}], "year": 2013, "venue": "", "link": null}, "BIBREF32": {"title": "Altmetrics: new indicators for scientific communication in Web 2.0. Comunicar", "authors": [{"first": "D", "middle": [], "last": "Torres-Salinas", "suffix": ""}, {"first": "A", "middle": [], "last": "Cabezas-Clavijo", "suffix": ""}, {"first": "E", "middle": [], "last": "Jimenez-Contreras", "suffix": ""}], "year": 2013, "venue": "", "link": "10444280"}, "BIBREF33": {"title": "The evaluation of research by scientometric indicators", "authors": [{"first": "P", "middle": [], "last": "Vinkler", "suffix": ""}], "year": 2010, "venue": "", "link": "143277501"}, "BIBREF34": {"title": "F1000 Recommendations as a Potential New Data Source for Research Evaluation: A Comparison With Citations", "authors": [{"first": "L", "middle": [], "last": "Waltman", "suffix": ""}, {"first": "R", "middle": [], "last": "Costas", "suffix": ""}], "year": 2014, "venue": "Journal of the Association for Information Science and Technology", "link": "38110817"}, "BIBREF35": {"title": "Citation time window choice for research impact evaluation", "authors": [{"first": "J", "middle": [], "last": "Wang", "suffix": ""}], "year": 2013, "venue": "Scientometrics", "link": "16996855"}, "BIBREF36": {"title": "Post-publication filtering and evaluation: Faculty of 1000", "authors": [{"first": "K", "middle": [], "last": "Wets", "suffix": ""}, {"first": "D", "middle": [], "last": "Weedon", "suffix": ""}, {"first": "J", "middle": [], "last": "Velterop", "suffix": ""}], "year": 2003, "venue": "Learned Publishing", "link": "23919491"}, "BIBREF37": {"title": "Using the margins command to estimate and interpret adjusted predictions and marginal effects", "authors": [{"first": "R", "middle": [], "last": "Williams", "suffix": ""}], "year": 2012, "venue": "The Stata Journal", "link": "54728443"}, "BIBREF38": {"title": "The substantive and practical significance of citation impact differences between institutions: guidelines for the analysis of percentiles using effect sizes and confidence intervals", "authors": [{"first": "R", "middle": [], "last": "Williams", "suffix": ""}, {"first": "L", "middle": [], "last": "Bornmann", "suffix": ""}], "year": "", "venue": "Measuring scholarly impact: methods and practice", "link": "2093455"}, "BIBREF39": {"title": "Users, narcissism and control -tracking the impact of scholarly publications in the 21st century", "authors": [{"first": "P", "middle": [], "last": "Wouters", "suffix": ""}, {"first": "R", "middle": [], "last": "Costas", "suffix": ""}], "year": 2012, "venue": "", "link": null}, "BIBREF40": {"title": "Real-time classification of twitter trends", "authors": [{"first": "A", "middle": [], "last": "Zubiaga", "suffix": ""}, {"first": "D", "middle": [], "last": "Spina", "suffix": ""}, {"first": "R", "middle": [], "last": "Mart\u00ednez", "suffix": ""}, {"first": "V", "middle": [], "last": "Fresno", "suffix": ""}], "year": 2014, "venue": "Journal of the Association for Information Science and Technology", "link": "4252868"}}, "ref_entries": {"FIGREF0": {"text": "and p-values, respectively, for the null hypothesis that an individual coefficient is zero, given that the other variables are in the model. The constant is the negative binomial regression estimate when all variables in the model are evaluated at zero (see the annotated Stata output at http://www.ats.ucla.edu/stat/stata/output/stata_nbreg_output.htm). The predicted numbers of count for the different tags and recommendation scores, resulting from the models, are shown inSince the predicted numbers of counts", "type": "figure"}, "FIGREF1": {"text": "Figure 1. Predicted numbers of total altmetric counts, Twitter counts und citation counts with 95% confidence intervals for three individual recommendation scores. Whereas papers published before 2011 are included in the evaluation of the citation counts, the evaluation of the altmetric data involves papers after 2011.", "type": "figure"}, "FIGREF2": {"text": "Figure 4. Predicted numbers of citation counts with 95% confidence intervals for papers tagged differently (papers published after 2011)", "type": "figure"}, "FIGREF4": {"text": "count (n=45)", "type": "figure"}, "TABREF2": {"text": "Altmetric data made available by Altmetric for papers published after 2011 (n=13,678)Table 1 displays the arithmetic mean for the counts, as well as the minimum and maximum for all papers published after 2011 for which Altmetric provides data. In addition,", "type": "table"}, "TABREF3": {"text": "Tags, allocated by Faculty members (n=17,805 records, n=25,557 tag mentions). This assessment applies only to papers with a publication year later than 2011, since only these papers are included in the statistical analysis of the altmetrics.", "type": "table"}, "TABREF4": {"text": "Dependent and independent variables included in the three negative binomial regression models", "type": "table"}, "TABREF5": {"text": "", "type": "table"}, "TABREF6": {"text": "Distribution of the papers over subject categories published after 2011 (n=17,805). Subject categories are only listed if they appear more than 100 times in the dataset.", "type": "table"}}}
{"paper_id": "17786458", "_pdf_hash": "33cd117078f9ead4a04a109edb5affff89c8df0a", "abstract": [{"section": "Abstract", "text": "ABSTRACT Ascites, also called pulmonary hypertension syndrome, is a metabolic disorder in chickens that have an insufficient pulmonary vascular capacity. The tendency of broilers to develop ascites is heritable, and successful selection against this susceptibility would benefit from good and easy-to-measure indicator traits. Blood gas parameters have been suggested as indicator traits for ascites susceptibility. Therefore, the aim of the present study was to estimate the heritability of blood gas parameters and the genetic and phenotypic correlations between blood gas parameters, heart ratio (postmortem indicator for ascites), and BW at 2 different ages. For this purpose, blood gas parameters, including the partial pressure of carbon dioxide in venous blood (pvCO 2 ), the partial pressure of oxygen in venous blood (pvO 2 ), and blood oxygen saturation, were measured at an average age of 22 d in nearly 3,000 broilers. To challenge the resistance of the birds to ascites, they were kept under cold conditions. Heritability for heart ratio was 0.43, and the heritability estimates were low: 0.02 for pvCO 2 , 0.03 for pvO 2 , and 0.07 for blood oxygen saturation. The estimated heritability for pH was 0.15, for bicarbonate was 0.19, and for total carbon dioxide content was 0.19. The genetic correlations between heart ratio and total carbon dioxide content (0.31 \u00b1 0.15) and between heart ratio and bicarbonate (0.31 \u00b1 0.15) were moderate and positive. For pvO 2 , the genetic correlation with heart ratio was stronger and negative (\u22120.62 \u00b1 0.21); however, this correlation could not be estimated accurately because of the low heritability of pvO 2 . For pvCO 2 , the genetic correlation with the heart ratio was close to zero (\u22120.04 \u00b1 0.45). Phenotypic correlations between traits were, in general, similar to the genetic correlations. Heritabilities for blood gas parameters and the genetic correlations between blood gas parameters and the heart ratio estimated in the present study do not support the suggestion that blood gas parameters measured during wk 3 or 4 are useful traits to select against the susceptibility for ascites.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "INTRODUCTION", "text": "Ascites, also called pulmonary hypertension syndrome, is a metabolic disorder in chickens. The disorder is associated with an insufficient pulmonary vascular capacity and results in right ventricular failure (Julian et al., 1987; Julian, 1998; Balog et al., 2000) . In most cases, ascites is caused by a disproportion between the oxygen requirement and the cardiovascular ability to supply oxygen (Julian and Mirsalimi, 1992; Scheele et al., 1992; Decuypere et al., 2000) . Oxygen shortage puts pressure on the pulmonary vascular system and can lead to oxygen deficiency in the tissues, which will increase pulmonary arterial pressure. The high blood pressure and high work load of the heart lead to fluid accumulation in the abdominal cavity and eventually death (Shlosberg et al., 1992; Decuypere et al., 2000; Havenstein et al., 2003) . Mortality caused by ascites ranges from 5 to 8% in populations worldwide and can be as great as 20 to 30% in heavier broiler flocks (Balog, 2003; Pavlidis et al., 2007) .", "cite_spans": [{"start": 208, "end": 229, "text": "(Julian et al., 1987;", "ref_id": "BIBREF17"}, {"start": 230, "end": 243, "text": "Julian, 1998;", "ref_id": "BIBREF15"}, {"start": 244, "end": 263, "text": "Balog et al., 2000)", "ref_id": "BIBREF1"}, {"start": 397, "end": 425, "text": "(Julian and Mirsalimi, 1992;", "ref_id": "BIBREF18"}, {"start": 426, "end": 447, "text": "Scheele et al., 1992;", "ref_id": "BIBREF33"}, {"start": 448, "end": 471, "text": "Decuypere et al., 2000)", "ref_id": "BIBREF8"}, {"start": 764, "end": 788, "text": "(Shlosberg et al., 1992;", "ref_id": "BIBREF36"}, {"start": 789, "end": 812, "text": "Decuypere et al., 2000;", "ref_id": "BIBREF8"}, {"start": 813, "end": 837, "text": "Havenstein et al., 2003)", "ref_id": "BIBREF13"}, {"start": 972, "end": 985, "text": "(Balog, 2003;", "ref_id": "BIBREF0"}, {"start": 986, "end": 1008, "text": "Pavlidis et al., 2007)", "ref_id": "BIBREF32"}], "ref_spans": []}, {"section": "INTRODUCTION", "text": "The increase in the occurrence of ascites has been linked to genetic selection for increased growth rate, greater meat yield, and lower feed conversion ratio (Decuypere et al., 2000; Balog, 2003) . It has been shown that fast-growing broilers are more susceptible to ascites than slow-growing broilers (Julian, 1993) . Ascites in broiler flocks can be reduced by management measures, such as avoiding low temperatures, maintaining good air quality and high oxygen concentrations, and restricting feeding to restrict growth (Decuypere et al., 2000; Julian, 2000; Balog, 2003) . A variety of physiological studies have evaluated specific traits as indicators for ascites susceptibility. Two of the most common clinical signs associated with ascites are right ventricular hypertrophy and fluid accumulation in the abdominal cavity (Decuypere et al., 2000; Moghadam et al., 2001; Balog et al., 2003; Pakdel et al., 2005a; Zerehdaran et al., 2006) . The ratio of right to total ventricular weight (RATIO), which measures right ventricular hypertrophy, has been suggested as a good indicator for ascites (Julian, 1993; McGovern et al., 1999; Pakdel et al., 2005c) .", "cite_spans": [{"start": 158, "end": 182, "text": "(Decuypere et al., 2000;", "ref_id": "BIBREF8"}, {"start": 183, "end": 195, "text": "Balog, 2003)", "ref_id": "BIBREF0"}, {"start": 302, "end": 316, "text": "(Julian, 1993)", "ref_id": "BIBREF14"}, {"start": 523, "end": 547, "text": "(Decuypere et al., 2000;", "ref_id": "BIBREF8"}, {"start": 548, "end": 561, "text": "Julian, 2000;", "ref_id": "BIBREF16"}, {"start": 562, "end": 574, "text": "Balog, 2003)", "ref_id": "BIBREF0"}, {"start": 828, "end": 852, "text": "(Decuypere et al., 2000;", "ref_id": "BIBREF8"}, {"start": 853, "end": 875, "text": "Moghadam et al., 2001;", "ref_id": "BIBREF25"}, {"start": 876, "end": 895, "text": "Balog et al., 2003;", "ref_id": "BIBREF2"}, {"start": 896, "end": 917, "text": "Pakdel et al., 2005a;", "ref_id": "BIBREF28"}, {"start": 918, "end": 942, "text": "Zerehdaran et al., 2006)", "ref_id": "BIBREF42"}, {"start": 1098, "end": 1112, "text": "(Julian, 1993;", "ref_id": "BIBREF14"}, {"start": 1113, "end": 1135, "text": "McGovern et al., 1999;", "ref_id": "BIBREF23"}, {"start": 1136, "end": 1157, "text": "Pakdel et al., 2005c)", "ref_id": "BIBREF31"}], "ref_spans": []}, {"section": "INTRODUCTION", "text": "Studies have shown genetic variation within lines (Wideman and French, 1999; Deeb et al., 2002; Pakdel et al., 2002) and between lines (Lubritz et al., 1995; Buys et al., 1999a,b; Wideman and French, 2000; De Greef et al., 2001; Druyan et al., 2007 Druyan et al., , 2008 for susceptibility to ascites. However, current indicator traits, such as RATIO and fluid accumulation in the abdominal cavity, can only be measured postmortem. Therefore, selection against ascites susceptibility by using these indicators is complicated, and information for selection relies heavily on information from relatives (McMillan and Quinton, 2002; Pakdel et al., 2005a) . Thus, there is a need for alternative indicator traits that can be measured on living birds; blood gas parameters might be a good alternative. It has been shown that broilers with right ventricular failure have significantly lower blood oxygen saturation (sO 2 ) compared with broilers with a normal heart (Julian and Mirsalimi, 1992) . Wideman et al. (2003) found that chickens with an elevated RATIO had a greater partial pressure of carbon dioxide in venous blood (pvCO 2 ), a lower partial pressure of oxygen in arterial blood, and greater bicarbonate (HCO 3 ) concentrations in arterial blood compared with chickens with a normal RATIO. Furthermore, by comparing 2 different broiler lines, Scheele et al. (2003) observed a relationship between ascites susceptibility and high pvCO 2 at d 11 in juvenile chickens and suggested that ascites could be eliminated by selecting for low pvCO 2 . Navarro et al. (2006) demonstrated that sO 2 is heritable and suggested that ascites susceptibility could be decreased by selecting for increased sO 2 values. Druyan et al. (2007) reported a moderate heritability for sO 2 and indicated that sO 2 might serve as an indicator in selection against ascites susceptibility, although with limited efficacy.", "cite_spans": [{"start": 50, "end": 76, "text": "(Wideman and French, 1999;", "ref_id": "BIBREF38"}, {"start": 77, "end": 95, "text": "Deeb et al., 2002;", "ref_id": "BIBREF9"}, {"start": 96, "end": 116, "text": "Pakdel et al., 2002)", "ref_id": "BIBREF29"}, {"start": 135, "end": 157, "text": "(Lubritz et al., 1995;", "ref_id": "BIBREF21"}, {"start": 180, "end": 205, "text": "Wideman and French, 2000;", "ref_id": "BIBREF39"}, {"start": 206, "end": 228, "text": "De Greef et al., 2001;", "ref_id": "BIBREF6"}, {"start": 229, "end": 248, "text": "Druyan et al., 2007", "ref_id": "BIBREF11"}, {"start": 249, "end": 270, "text": "Druyan et al., , 2008", "ref_id": "BIBREF10"}, {"start": 601, "end": 629, "text": "(McMillan and Quinton, 2002;", "ref_id": "BIBREF24"}, {"start": 630, "end": 651, "text": "Pakdel et al., 2005a)", "ref_id": "BIBREF28"}, {"start": 960, "end": 988, "text": "(Julian and Mirsalimi, 1992)", "ref_id": "BIBREF18"}, {"start": 991, "end": 1012, "text": "Wideman et al. (2003)", "ref_id": "BIBREF40"}, {"start": 1349, "end": 1370, "text": "Scheele et al. (2003)", "ref_id": "BIBREF34"}, {"start": 1548, "end": 1569, "text": "Navarro et al. (2006)", "ref_id": "BIBREF26"}, {"start": 1707, "end": 1727, "text": "Druyan et al. (2007)", "ref_id": "BIBREF11"}], "ref_spans": []}, {"section": "INTRODUCTION", "text": "In addition to the studies by Navarro et al. (2006) and Druyan et al. (2007) , to our knowledge, no other studies have reported heritability estimates for blood gas parameters. Furthermore, to our knowledge, only Druyan et al. (2007) reported genetic correlations between blood gas parameters and other ascites indicator traits such as RATIO.", "cite_spans": [{"start": 30, "end": 51, "text": "Navarro et al. (2006)", "ref_id": "BIBREF26"}, {"start": 56, "end": 76, "text": "Druyan et al. (2007)", "ref_id": "BIBREF11"}, {"start": 213, "end": 233, "text": "Druyan et al. (2007)", "ref_id": "BIBREF11"}], "ref_spans": []}, {"section": "INTRODUCTION", "text": "The objective of the present study was to estimate heritability, heart ratio, and genetic and phenotypic correlations between blood gas parameters measured during wk 3 and 4 and BW at 2 different ages in broilers.", "cite_spans": [], "ref_spans": []}, {"section": "MATERIALS AND METHODS", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Experimental Population and Phenotyping", "text": "Animal Material. The experiment was carried out by licensed and authorized personnel under approval of Hendrix Genetics. The experimental population consisted of 5,987 broilers. The chickens were from generations 7 and 8 of an advanced intercross line, which was a cross between 2 genetically different dam lines originating from the White Plymouth Rock breed. The data consisted of 2,413 males, 2,452 females, and 1,122 chickens of unknown gender. Birds from generations 3 of this population have been used in previous studies on ascites and meat quality traits (van Kaam et al., 1998; Pakdel et al., 2002) . The chickens in the experiment were kept under a cold temperature regimen to induce ascites. The temperature was 30\u00b0C at the time of hatching and was gradually reduced to 10\u00b0C at 22 d of age. The temperature remained at 10\u00b0C until the end of the experiment when the chickens were 5 wk of age. The chickens were group housed with 20 birds/m 2 , they had ad libitum access to a commercial broiler feed containing 12,970 KJ/kg, and they were exposed to 23 h of light per day during the entire experiment. Except for the temperature schedule applied, the chickens were kept under conditions that closely resemble commercial practice.", "cite_spans": [{"start": 563, "end": 586, "text": "(van Kaam et al., 1998;", "ref_id": "BIBREF37"}, {"start": 587, "end": 607, "text": "Pakdel et al., 2002)", "ref_id": "BIBREF29"}], "ref_spans": []}, {"section": "Experimental Population and Phenotyping", "text": "Venous blood samples were taken when the chickens were, on average, 22 d old (ranging from 19 to 27 d old). The blood gas parameters measured (GEM Premier 3000, Instrumentation Laboratories, Lexington, MA) were blood pH, pvCO 2 , and partial pressure of oxygen in venous blood (pvO 2 ). Bicarbonate and total carbon dioxide content (TCO 2 ) were calculated from the pH and pvCO 2 by the following equations:", "cite_spans": [], "ref_spans": []}, {"section": "Experimental Population and Phenotyping", "text": "Log HCO 3 = pH + log pvCO 2 \u2212 7.608, and TCO 2 = HCO 3 + 0.03 pvCO 2 .", "cite_spans": [], "ref_spans": []}, {"section": "Experimental Population and Phenotyping", "text": "Blood sO 2 is an indicator of the percentage of hemoglobin saturated with oxygen at the time of the measurement; pvO 2 , pH, and HCO 3 were used to calculate sO 2 with the following equation: ", "cite_spans": [], "ref_spans": []}, {"section": "Experimental Population and Phenotyping", "text": ". The weight of the heart ventricles was determined at 5 wk of age. The RATIO was the weight of the right ventricle as a percentage of the total ventricle weight (TV). The chickens were weighed at 2 wk (BW 2 ) and 5 wk of age (BW 5 ). No postmortem dissection was performed on the animals that died before the end of the experiment; therefore, the cause of death was unknown.", "cite_spans": [], "ref_spans": []}, {"section": "Experimental Population and Phenotyping", "text": "Animals that died before the end of the experiment were assigned a total mortality (MORT-TOT) score of 1 and birds that survived got a score of 0.", "cite_spans": [], "ref_spans": []}, {"section": "Experimental Population and Phenotyping", "text": "Statistical Analysis. Genetic parameter estimates were obtained by using ASREML software (Gilmour et al., 2006) . To determine the importance of maternal effects, a model without a maternal effect and a model with a maternal environmental effect were used. The following model without a maternal environmental effect was used:", "cite_spans": [{"start": 89, "end": 111, "text": "(Gilmour et al., 2006)", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "Experimental Population and Phenotyping", "text": "where y ijkl is the dependent variable of chicken ijkl of sex i , which is the fixed effect of sex (i = female, male, or unknown); IHD j is the fixed effect of individual hatching day (j = 1, 2, . . ., 34 d at hatching); date k is the fixed effect for date of blood gas measurement (k = 1, 2, . . ., 37); a l is the random direct genetic effect of individual l with a~N(0,A ); a 2 and e ijkl is the random residual effect with e~N(0,I ).", "cite_spans": [], "ref_spans": []}, {"section": "Experimental Population and Phenotyping", "text": "The effect date k was used only in the model for the blood gas parameters.", "cite_spans": [], "ref_spans": []}, {"section": "Experimental Population and Phenotyping", "text": "The second model with a maternal environmental effect was", "cite_spans": [], "ref_spans": []}, {"section": "Experimental Population and Phenotyping", "text": "This model is identical to the first model, except for the random maternal environmental effect of dam m (d m ) with d~N(0,I ). To test the significance of the maternal environmental effect, a likelihood ratio test with 1 df was used: Some of the animals died before the end of the experiment and had an observation for only BW 2 . The animals that died might have been the ones that were most susceptible to ascites, and this selection might have had an impact on the estimated genetic parameters. Selection related to BW 2 can be accounted for by performing a multivariate analysis including BW 2 (Ouweltjes et al., 1988) . Therefore, we also estimated heritabilities by using a bivariate analysis with BW 2 as a permanent trait. The effect of selection on genetic correlations was studied by performing a trivariate analysis with BW 2 as a permanent trait.", "cite_spans": [{"start": 599, "end": 623, "text": "(Ouweltjes et al., 1988)", "ref_id": "BIBREF27"}], "ref_spans": []}, {"section": "RESULTS", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Data Description", "text": "Means, SD, and CV of the traits measured under cold stress conditions are presented in Table 1 . Of the 5,987 chickens retained for measurement of BW 2 , 5,222 also had measurements for BW 5 , 5,155 had measurements for RATIO, and 2,956 chickens were used for measuring blood gas parameters. Mortality recordings were missing for 210 chickens because of the loss of wing bands or because the trait was not recorded.", "cite_spans": [], "ref_spans": [{"start": 87, "end": 94, "text": "Table 1", "ref_id": "TABREF1"}]}, {"section": "Data Description", "text": "The average venous blood pH was 7.38, the average sO 2 was 84%, the average pvCO 2 was 45.4 mmHg, and the average HCO 3 concentration was 26.88 mmol/L (Table 1 ). The average BW of broilers under cold stress conditions was 360 g at 2 wk and 1,146 g at 5 wk, and the average RATIO was 25%. The MORT-TOT was 10%. Coefficients of variation were moderate to high for most of the traits (e.g., 14.6% for pvCO 2 , 20% for pvO 2 , 29.4% for BW 2 , 18.9% for BW 5 , and 21.2% for RATIO). However, the CV for pH was very low (0.7%). ", "cite_spans": [], "ref_spans": [{"start": 151, "end": 159, "text": "(Table 1", "ref_id": "TABREF1"}]}, {"section": "Genetic Analyses", "text": "Phenotypic variance, heritability, and maternal environmental effects for the ascites-related traits obtained from the univariate models are given in Table 2 . The heritability for RATIO was 0.43. For some of the blood gas parameters, the heritabilities were close to zero: 0.02 for pvCO 2 , 0.03 for pvO 2 , and 0.07 for sO 2 . However, for pH, HCO 3 , and TCO 2, moderate heritabilities were found: 0.15, 0.19, and 0.19, respectively. The estimated heritabilities for the 2 BW measurements were 0.15 for BW 2 and 0.17 for BW 5 .", "cite_spans": [], "ref_spans": [{"start": 150, "end": 157, "text": "Table 2", "ref_id": "TABREF2"}]}, {"section": "Genetic Analyses", "text": "The traits BW 2 , BW 5 , TV, pvCO 2 , and MORT-TOT were significantly affected by maternal environmental effects. The fraction of the total variation explained by maternal environmental effects was 0.05 for pvCO 2 , 0.12 for BW 2 , and 0.07 for BW 5 . No significant evidence for the presence of maternal environmental effects was found for the traits RATIO, pH, pvO 2 , HCO 3 , TCO 2 , and sO 2 . Using a model without a maternal effect gave a heritability estimate of 0.51 for BW 2 , of 0.37 for BW 5 , and of 0.15 for pvCO 2 (Table 2) . Bivariate analysis with BW 2 as a permanent trait resulted in slightly greater heritability estimates; they were at maximum 0.03 greater than the heritabilities estimated by using a univariate model (results not shown). The heritability estimates for MORT-TOT were also analyzed by using a binary model (results not shown), and the results increased compared with heritabilities estimated from the linear model. These results were in agreement with heritabilities estimated by transforming the heritabilities from the linear model to the underlying scale (Lynch and Walsh, 1998) .", "cite_spans": [{"start": 1095, "end": 1118, "text": "(Lynch and Walsh, 1998)", "ref_id": "BIBREF22"}], "ref_spans": [{"start": 528, "end": 537, "text": "(Table 2)", "ref_id": "TABREF2"}]}, {"section": "Genetic Analyses", "text": "The estimates for genetic correlations (above the diagonal) and the phenotypic correlations (below the diagonal) of the blood gas parameters RATIO, BW, and MORT-TOT are presented in Table 3 . The greatest genetic correlation between RATIO as a postmortem indicator for ascites and blood gas parameters was found for pvO 2 (\u22120.62 \u00b1 0.21). However, genetic correlations between pvO 2 and other traits have high SE, mainly because of the low heritability for pvO 2 . The genetic correlations between RATIO and the blood gas parameters TCO 2 (0.31 \u00b1 0.15) and HCO 3 (0.31 \u00b1 0.15) were positive and moderate. For pvCO 2 and RATIO, the genetic correlation was close to zero (\u22120.04 \u00b1 0.45). The genetic correlation between BW 2 and RATIO was 0.19, whereas the genetic correlation between BW 5 and RA-TIO was \u22120.18. The genetic correlation between BW 2 and BW 5 was high (0.88). Phenotypic correlations between traits were, in general, similar to the genetic correlations. A trivariate model with BW 2 as a permanent trait had hardly any effect on the estimated genetic correlation between the traits: genetic correlations between RATIO and the blood gas parameters increased from 0.01 to 0.02 when using a trivariate model instead of a bivariate model (results not shown).", "cite_spans": [], "ref_spans": [{"start": 182, "end": 189, "text": "Table 3", "ref_id": "TABREF4"}]}, {"section": "DISCUSSION", "text": "The objective of the present study was to estimate the heritability and genetic and phenotypic correlations between blood gas parameters measured at an average age of 22 d, BW at 2 different ages, and heart ratio in broilers. Body weight and RATIO were measured on 5,987 birds, and the blood gas parameters were measured on a subset of 2,956 birds. The study was performed under cold stress conditions to stimulate the metabolic rate resulting in an increased requirement for oxygen, which is known to increase the incidence of ascites in chickens (Decuypere et al., 2000) . To evaluate whether specific blood gas parameters could be used in selecting against ascites susceptibility, we studied the heritability and genetic correlations with RATIO.", "cite_spans": [{"start": 548, "end": 572, "text": "(Decuypere et al., 2000)", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "Severity of the Challenge", "text": "Previous studies have indicated that correlations between BW and ascites traits are dependent on the frequency of ascitic birds in the population, and there- 1 BW 2 = BW at 2 wk; BW 5 = BW at 5 wk; RATIO = ratio of right to total ventricular weight; RV = right ventricular weight; TV = total ventricular weight; pvCO 2 = partial pressure of carbon dioxide in venous blood; pvO 2 = partial pressure of oxygen in venous blood; HCO 3 = bicarbonate; TCO 2 = total carbon dioxide in venous blood; sO 2 = oxygen saturation in venous blood; MORT-TOT = total mortality. fore on the severity of the challenge (De Greef et al., 2001; Zerehdaran et al., 2006 ). In the current study, the average MORT-TOT was 10%. In comparison with the MORT-TOT of 16% found by Pakdel et al. (2002) under cold conditions, the mortality in the present study was not very high. However, mortality was much greater than the 4 to 5% mortality found in chickens reared under normal commercial conditions (Pakdel et al., 2002) . In the study by Pakdel et al. (2002) , an average RATIO of 28% was found, which is greater than the average value of 25% that was obtained in the current study. Julian et al. (1987) suggested that a RATIO of greater than 25% indicates susceptibility to ascites. This threshold would imply that, in our experiment, 45% of the birds showed signs of ascites. The BW 5 in the present study was also lower than under commercial conditions. This suppressed growth rate was likely due to the cold stress conditions under which the birds were kept.", "cite_spans": [{"start": 600, "end": 623, "text": "(De Greef et al., 2001;", "ref_id": "BIBREF6"}, {"start": 624, "end": 647, "text": "Zerehdaran et al., 2006", "ref_id": "BIBREF42"}, {"start": 751, "end": 771, "text": "Pakdel et al. (2002)", "ref_id": "BIBREF29"}, {"start": 972, "end": 993, "text": "(Pakdel et al., 2002)", "ref_id": "BIBREF29"}, {"start": 1012, "end": 1032, "text": "Pakdel et al. (2002)", "ref_id": "BIBREF29"}, {"start": 1157, "end": 1177, "text": "Julian et al. (1987)", "ref_id": "BIBREF17"}], "ref_spans": []}, {"section": "Severity of the Challenge", "text": "In the current study, the average pvCO 2 was 45.4 mmHg. Scheele et al. (2003) found an average pvCO 2 at 3 wk of age of 53.8 mmHg in a high-risk broiler line and an average pvCO 2 of 43.9 mmHg in a low-risk line. Interestingly, however, the pvO 2 was lower (44.6 mmHg for the high-risk line and 46.9 mmHg for the low-risk line) than in the current study (52.46 mmHg). However, it should be noted that Scheele et al. (2003) used only male broilers, whereas in the current study, the average measurements were based on results from both males and females. In addition, the previous study compared ascites susceptibility between 2 genetically different stocks (high-and low-risk lines), whereas the current study investigated ascites susceptibility within one crossed line.", "cite_spans": [{"start": 56, "end": 77, "text": "Scheele et al. (2003)", "ref_id": "BIBREF34"}, {"start": 401, "end": 422, "text": "Scheele et al. (2003)", "ref_id": "BIBREF34"}], "ref_spans": []}, {"section": "Severity of the Challenge", "text": "It can be concluded that birds in the current study were kept under circumstances that caused a mild increase in ascites. Because estimates of genetic parameters depend on the severity of the challenge (De Greef et al., 2001; Zerehdaran et al., 2006) , the estimates presented in this study should be interpreted in this context. Pakdel et al. (2005c) found a negative genetic correlation between BW 5 and RATIO (\u22120.27). This is consistent with the negative genetic correlation (\u22120.18) found between RATIO and BW 5 in the present study. A positive genetic correlation (0.19) was observed between RATIO and BW 2 . These results suggest that susceptible chickens tend to have a greater BW early in life (BW 2 ) and a lower BW later in life (BW 5 ). These results are in agreement with the general finding that correlations between traits are dependent on the frequency of ascitic birds in the population.", "cite_spans": [{"start": 202, "end": 225, "text": "(De Greef et al., 2001;", "ref_id": "BIBREF6"}, {"start": 226, "end": 250, "text": "Zerehdaran et al., 2006)", "ref_id": "BIBREF42"}, {"start": 330, "end": 351, "text": "Pakdel et al. (2005c)", "ref_id": "BIBREF31"}], "ref_spans": []}, {"section": "Correlations Between BW and RATIO", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Maternal Effects", "text": "A maternal environmental effect may influence the phenotype of the individual, which, in case these effects play a role, should be accounted for in the statistical analysis (Cl\u00e9ment et al., 2001 ). In the current study, noticeable changes were found in the heritabilities for TV, pvCO 2 , and MORT-TOT when the maternal environmental effect was included in the model. De Smit et al. (2008) showed that ascites resistance is related to several physiological variables at the embryonic stage, which suggests that maternal effects might play a role in susceptibility. Several studies have reported a maternal effect for BW (Koerhuis and Thompson, 1997; van Kaam et al., 1998; Pakdel et al., 2002) . Pakdel et al. (2002) found a significant maternal effect for RATIO, which could not be confirmed in the present study. Navarro et al. (2006) found little evidence for maternal (environmental) effects on sO 2 ; of the 4 broiler lines investigated, one of them exhibited significant evidence for the presence of maternal effects. In that line, maternal environmental effects explained approximately 2% of the total variance. In the present study, we did not find significant maternal effects on sO 2 ; however, a significant maternal effect was found for pvCO 2 , which explains 5% of the phenotypic variation.", "cite_spans": [{"start": 173, "end": 194, "text": "(Cl\u00e9ment et al., 2001", "ref_id": "BIBREF5"}, {"start": 368, "end": 389, "text": "De Smit et al. (2008)", "ref_id": "BIBREF7"}, {"start": 620, "end": 649, "text": "(Koerhuis and Thompson, 1997;", "ref_id": "BIBREF19"}, {"start": 650, "end": 672, "text": "van Kaam et al., 1998;", "ref_id": "BIBREF37"}, {"start": 673, "end": 693, "text": "Pakdel et al., 2002)", "ref_id": "BIBREF29"}, {"start": 696, "end": 716, "text": "Pakdel et al. (2002)", "ref_id": "BIBREF29"}, {"start": 815, "end": 836, "text": "Navarro et al. (2006)", "ref_id": "BIBREF26"}], "ref_spans": []}, {"section": "Blood Gas Parameters as Indicator Traits for Ascites Susceptibility", "text": "In the present study, we evaluated the suitability of blood gas parameters as indicator traits for ascites based on heritabilities and correlations with RATIO. For some of the blood gas parameters, heritabilities were close to zero (pvCO 2 , pvO 2 , and sO 2 ), whereas for others, they were moderate (pH, HCO 3 , and TCO 2 ). The heritability estimate for sO 2 was in agreement with results by Navarro et al. (2006) ; however, in that study, sO 2 was measured on 6-wk-old chickens that were not cold stressed. This might have affected the heritability estimates. Druyan et al. (2007) reported a considerably greater heritability estimate (0.49 \u00b1 0.23) for sO 2 in chickens that were 7 d old. However, this estimate is not significantly different from the heritability estimate reported in the present study. The low heritabilities indicate that accurate estimates of breeding values for these traits cannot be obtained based on single observations. Accuracies might be improved by using repeated observations, but this will depend on the repeatability of the traits. Repeatability could not be estimated based on the present data; therefore, this is still an option that can be explored. In addition to high heritability, a suitable indicator trait should also have a high genetic correlation with ascites susceptibility. This was evaluated by studying correlations with RATIO. Several authors have suggested that RATIO is a good indicator trait for ascites susceptibility (Lubritz et al., 1995; Pakdel et al., 2002 Pakdel et al., , 2005b . Julian et al. (1987) recommended the use of RATIO as an objective method for assessing right ventricular failure, and therefore of diagnosing ascites. However, others have questioned whether RATIO is a good indicator trait for birds kept under normal conditions (i.e., conditions that do not stimulate ascites; Pavlidis et al., 2007) . In the present study, birds were kept under cold stress conditions. Genetic correlations between RATIO and both HCO 3 and TCO 2 were moderate, and correlations between RATIO and pH or pvCO 2 were close to zero. The correlation between RATIO and pvO 2 was \u22120.62; however, the estimated heritability for pvO 2 was very low, resulting in very high SE for the genetic correlations with this trait. Therefore, results from the present study suggest that blood gas parameters are not useful as indicators for ascites susceptibility when measured at an average age of 22 d.", "cite_spans": [{"start": 395, "end": 416, "text": "Navarro et al. (2006)", "ref_id": "BIBREF26"}, {"start": 564, "end": 584, "text": "Druyan et al. (2007)", "ref_id": "BIBREF11"}, {"start": 1474, "end": 1496, "text": "(Lubritz et al., 1995;", "ref_id": "BIBREF21"}, {"start": 1497, "end": 1516, "text": "Pakdel et al., 2002", "ref_id": "BIBREF29"}, {"start": 1517, "end": 1539, "text": "Pakdel et al., , 2005b", "ref_id": "BIBREF30"}, {"start": 1542, "end": 1562, "text": "Julian et al. (1987)", "ref_id": "BIBREF17"}, {"start": 1853, "end": 1875, "text": "Pavlidis et al., 2007)", "ref_id": "BIBREF32"}], "ref_spans": []}, {"section": "Blood Gas Parameters as Indicator Traits for Ascites Susceptibility", "text": "Experimental results from juvenile chickens (Korte et al., 1999; Scheele et al., 2003) showed that at the age of 11 d, a high pvCO 2 is associated with a greater incidence of ascites at the age of 5 to 7 wk. Scheele et al. (2005) stated that genetic selection for low pvCO 2 values at 11 d of age will be an effective method of reducing the occurrence of the ascites syndrome. However, results from the present study do not confirm this. The first explanation for the discrepancy between results from the present study and results by Scheele et al. (2003 Scheele et al. ( , 2005 may be the different ages of the chickens at which the blood gas parameters were measured. The pulmonary pressure index values are known to change rapidly over the first 2 wk of the life of a chicken. Particularly during the period of juvenile growth, the metabolic rate is high and these conditions impose greater metabolic demands. The increased metabolism requires high O 2 intake and, at the same time, high maintenance requirements. These factors lead to the maximal potential delivery capacity of oxygen in the respiratory and cardiovascular systems, which is then exceeded and triggers the events that lead to ascites (Decuypere et al., 2000) . In the current study, the blood gas parameters were measured when the chickens were, on average, 22 d old. However, in the study by Scheele et al. (2005) , the differences in pvCO 2 values between the lines remained consistent until the end of the experiment, but did increase as the chickens became older. The pvO 2 values decreased as the chickens aged, and the differences between the mean pvO 2 values in the 2 lines became greater (Scheele et al., 2003) . It should be mentioned that the severity of the challenge differed between the study by Scheele et al. (2003 Scheele et al. ( , 2005 and the current study. In the current study, the temperature was gradually reduced to 10\u00b0C at 22 d of age, whereas Scheele et al. (2003 Scheele et al. ( , 2005 gradually reduced the temperature to 15\u00b0C at 16 d of age. Although this did not result in a greater mortality, it is possible that even ascites-resistant broilers experienced problems with breathing because of the low temperature. This might have had an effect on the blood gas parameter values. The second explanation could be the lines that were used. Scheele et al. (2003) compared ascites susceptibility between 2 genetically different stocks (high-and low-risk lines), and several different lines were compared in the other study (Scheele et al., 2005) , whereas in the current study, ascites susceptibility was investigated within one crossed line. A third explanation could be the fact that only males were used by Scheele et al. (2003 Scheele et al. ( , 2005 , whereas both males and females were used in the current study. The female growth rate is slower than the male growth rate; thus, ascites-susceptible females will have a lower pvCO 2 , on average. Therefore, differences in pvCO 2 between healthy and affected chickens will be smaller. Although previous studies (Scheele et al., 2003 (Scheele et al., , 2005 reported the use of pvCO 2 as an indicator trait for ascites susceptibility in male broilers, the results from the current study do not support this. It might be concluded that the severity of the challenge, the genetic lines used, the sex of the chickens, and the time of measurement are critical factors.", "cite_spans": [{"start": 44, "end": 64, "text": "(Korte et al., 1999;", "ref_id": "BIBREF20"}, {"start": 65, "end": 86, "text": "Scheele et al., 2003)", "ref_id": "BIBREF34"}, {"start": 208, "end": 229, "text": "Scheele et al. (2005)", "ref_id": "BIBREF35"}, {"start": 534, "end": 554, "text": "Scheele et al. (2003", "ref_id": "BIBREF34"}, {"start": 555, "end": 578, "text": "Scheele et al. ( , 2005", "ref_id": "BIBREF35"}, {"start": 1204, "end": 1228, "text": "(Decuypere et al., 2000)", "ref_id": "BIBREF8"}, {"start": 1363, "end": 1384, "text": "Scheele et al. (2005)", "ref_id": "BIBREF35"}, {"start": 1667, "end": 1689, "text": "(Scheele et al., 2003)", "ref_id": "BIBREF34"}, {"start": 1780, "end": 1800, "text": "Scheele et al. (2003", "ref_id": "BIBREF34"}, {"start": 1801, "end": 1824, "text": "Scheele et al. ( , 2005", "ref_id": "BIBREF35"}, {"start": 1940, "end": 1960, "text": "Scheele et al. (2003", "ref_id": "BIBREF34"}, {"start": 1961, "end": 1984, "text": "Scheele et al. ( , 2005", "ref_id": "BIBREF35"}, {"start": 2339, "end": 2360, "text": "Scheele et al. (2003)", "ref_id": "BIBREF34"}, {"start": 2520, "end": 2542, "text": "(Scheele et al., 2005)", "ref_id": "BIBREF35"}, {"start": 2707, "end": 2727, "text": "Scheele et al. (2003", "ref_id": "BIBREF34"}, {"start": 2728, "end": 2751, "text": "Scheele et al. ( , 2005", "ref_id": "BIBREF35"}, {"start": 3064, "end": 3085, "text": "(Scheele et al., 2003", "ref_id": "BIBREF34"}, {"start": 3086, "end": 3109, "text": "(Scheele et al., , 2005", "ref_id": "BIBREF35"}], "ref_spans": []}, {"section": "Conclusion", "text": "The estimated heritabilities for the blood gas parameters pvCO 2 and pvO 2 were almost zero. This indicates that selection based on single measurements of these blood gas parameters is not feasible. The heritabilities of HCO 3 and TCO 2 showed enough variation in the population to be used for selection. However, the low genetic correlation between RATIO and these 2 blood gas parameters suggests that they are not useful as indicators for ascites susceptibility. Therefore, the current data suggest that blood gas parameters measured at an average age of 22 d will not be very effective when used for selecting against susceptibility.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Ascites syndrome (pulmonary hypertension syndrome) in broiler chickens: Are we seeing the light at the end of the tunnel? Avian Poult", "authors": [{"first": "J", "middle": ["M"], "last": "Balog", "suffix": ""}], "year": 2003, "venue": "Biol. Rev", "link": "83676413"}, "BIBREF1": {"title": "Ascites syndrome and related pathologies in feed restricted broilers raised in a hypobaric chamber", "authors": [{"first": "J", "middle": ["M"], "last": "Balog", "suffix": ""}, {"first": "N", "middle": ["B"], "last": "Anthony", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Cooper", "suffix": ""}, {"first": "B", "middle": ["D"], "last": "Kidd", "suffix": ""}, {"first": "G", "middle": ["R"], "last": "Huff", "suffix": ""}, {"first": "W", "middle": ["E"], "last": "Huff", "suffix": ""}, {"first": "N", "middle": ["C"], "last": "Rath", "suffix": ""}], "year": 2000, "venue": "Poult. Sci", "link": "3626135"}, "BIBREF2": {"title": "Effect of cold stress on broilers selected for resistance or susceptibility to ascites syndrome", "authors": [{"first": "J", "middle": ["M"], "last": "Balog", "suffix": ""}, {"first": "B", "middle": ["D"], "last": "Kidd", "suffix": ""}, {"first": "W", "middle": ["E"], "last": "Huff", "suffix": ""}, {"first": "G", "middle": ["R"], "last": "Huff", "suffix": ""}, {"first": "N", "middle": ["C"], "last": "Rath", "suffix": ""}, {"first": "N", "middle": ["B"], "last": "Anthony", "suffix": ""}], "year": 2003, "venue": "Poult. Sci", "link": "3632314"}, "BIBREF3": {"title": "Performance and physiological variables in broiler chicken lines differing in susceptibility to the ascites syndrome: 2. Effect of ambient temperature on partial efficiencies of protein and fat retention and plasma hormone concentrations", "authors": [{"first": "N", "middle": [], "last": "Buys", "suffix": ""}, {"first": "C", "middle": ["W"], "last": "Scheele", "suffix": ""}, {"first": "C", "middle": [], "last": "Kwakernaak", "suffix": ""}, {"first": "E", "middle": [], "last": "Decuypere", "suffix": ""}], "year": 1999, "venue": "Br. Poult. Sci", "link": "29407130"}, "BIBREF4": {"title": "Performance and physiological variables in broiler chicken lines differing in susceptibility to the ascites syndrome: 1. Changes in blood gases as a function of ambient temperature", "authors": [{"first": "N", "middle": [], "last": "Buys", "suffix": ""}, {"first": "C", "middle": ["W"], "last": "Scheele", "suffix": ""}, {"first": "C", "middle": [], "last": "Kwakernaak", "suffix": ""}, {"first": "J", "middle": ["D"], "last": "Van Der Klis", "suffix": ""}, {"first": "E", "middle": [], "last": "Decuypere", "suffix": ""}], "year": 1999, "venue": "Br. Poult. Sci", "link": "35193857"}, "BIBREF5": {"title": "Simulation analysis to test the influence of model adequacy and data structure on the estimation of genetic parameters for traits with direct and maternal effects", "authors": [{"first": "V", "middle": [], "last": "Cl\u00e9ment", "suffix": ""}, {"first": "B", "middle": [], "last": "Bib\u00e9", "suffix": ""}, {"first": "E", "middle": [], "last": "Verrier", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Elsen", "suffix": ""}, {"first": "E", "middle": [], "last": "Manfredi", "suffix": ""}, {"first": "J", "middle": [], "last": "Bouix", "suffix": ""}, {"first": "E", "middle": [], "last": "Hanocq", "suffix": ""}], "year": 2001, "venue": "Genet. Sel. Evol", "link": "11076040"}, "BIBREF6": {"title": "Disease-induced variability of genetic correlations: Ascites in broilers as a case study", "authors": [{"first": "K", "middle": ["H"], "last": "De Greef", "suffix": ""}, {"first": "L", "middle": ["L"], "last": "Janss", "suffix": ""}, {"first": "A", "middle": ["L"], "last": "Vereijken", "suffix": ""}, {"first": "R", "middle": [], "last": "Pit", "suffix": ""}, {"first": "C", "middle": ["L"], "last": "Gerritsen", "suffix": ""}], "year": 2001, "venue": "J. Anim. Sci", "link": "43728905"}, "BIBREF7": {"title": "The effect of nonventilation during early incubation on the embryonic development of chicks of two commercial broiler strains differing in ascites susceptibility", "authors": [{"first": "De", "middle": [], "last": "Smit", "suffix": ""}, {"first": "L", "middle": [], "last": "", "suffix": ""}, {"first": "V", "middle": [], "last": "Bruggeman", "suffix": ""}, {"first": "M", "middle": [], "last": "Debonne", "suffix": ""}, {"first": "J", "middle": ["K"], "last": "Tona", "suffix": ""}, {"first": "B", "middle": [], "last": "Kamers", "suffix": ""}, {"first": "N", "middle": [], "last": "Everaert", "suffix": ""}, {"first": "A", "middle": [], "last": "Witters", "suffix": ""}, {"first": "O", "middle": [], "last": "Onagbesan", "suffix": ""}, {"first": "L", "middle": [], "last": "Arckens", "suffix": ""}, {"first": "J", "middle": ["De"], "last": "Baerdemaeker", "suffix": ""}, {"first": "E", "middle": [], "last": "Decuypere", "suffix": ""}], "year": 2008, "venue": "Poult. Sci", "link": null}, "BIBREF8": {"title": "Ascites in broiler chickens: Exogenous and endogenous structural and functional causal factors", "authors": [{"first": "E", "middle": [], "last": "Decuypere", "suffix": ""}, {"first": "J", "middle": [], "last": "Buyse", "suffix": ""}, {"first": "N", "middle": [], "last": "Buys", "suffix": ""}], "year": 2000, "venue": "World's Poult. Sci. J", "link": "84473034"}, "BIBREF9": {"title": "Genotype-by-environment interaction with broiler genotypes differing in growth rate. 4. Association between responses to heat stress and to coldinduced ascites", "authors": [{"first": "N", "middle": [], "last": "Deeb", "suffix": ""}, {"first": "A", "middle": [], "last": "Shlosberg", "suffix": ""}, {"first": "A", "middle": [], "last": "Cahaner", "suffix": ""}], "year": 2002, "venue": "Poult. Sci", "link": "3627772"}, "BIBREF10": {"title": "Growth rate of ascites-resistant versus ascites-susceptible broilers in commercial and experimental lines", "authors": [{"first": "S", "middle": [], "last": "Druyan", "suffix": ""}, {"first": "Y", "middle": [], "last": "Hadad", "suffix": ""}, {"first": "A", "middle": [], "last": "Cahaner", "suffix": ""}], "year": 2008, "venue": "Poult. Sci", "link": "207745203"}, "BIBREF11": {"title": "Evaluation of growth rate, body weight, heart rate, and blood parameters as potential indicators for selection against susceptibility to the ascites syndrome in young broilers", "authors": [{"first": "S", "middle": [], "last": "Druyan", "suffix": ""}, {"first": "A", "middle": [], "last": "Shlosberg", "suffix": ""}, {"first": "A", "middle": [], "last": "Cahaner", "suffix": ""}], "year": 2007, "venue": "Poult. Sci", "link": "3656655"}, "BIBREF12": {"title": "ASReml User Guide", "authors": [{"first": "A", "middle": ["R"], "last": "Gilmour", "suffix": ""}, {"first": "B", "middle": ["J"], "last": "Gogel", "suffix": ""}, {"first": "B", "middle": ["R"], "last": "Cullis", "suffix": ""}, {"first": "R", "middle": [], "last": "Thompson", "suffix": ""}], "year": 2006, "venue": "New South Wales Department of Primary Industries", "link": null}, "BIBREF13": {"title": "Growth, livability, and feed conversion of 1957 versus 2001 broilers when fed representative 1957 and 2001 broiler diets", "authors": [{"first": "G", "middle": ["B"], "last": "Havenstein", "suffix": ""}, {"first": "P", "middle": ["R"], "last": "Ferket", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Qureshi", "suffix": ""}], "year": 2003, "venue": "Poult. Sci", "link": "3614111"}, "BIBREF14": {"title": "Ascites in poultry", "authors": [{"first": "R", "middle": ["J"], "last": "Julian", "suffix": ""}], "year": 1993, "venue": "Avian Pathol", "link": "12016135"}, "BIBREF15": {"title": "Rapid growth problems: Ascites and skeletal deformities in broilers", "authors": [{"first": "R", "middle": ["J"], "last": "Julian", "suffix": ""}], "year": 1998, "venue": "Poult. Sci", "link": "3628310"}, "BIBREF16": {"title": "Physiological, management, and environmental triggers of the ascites syndrome: A review", "authors": [{"first": "R", "middle": ["J"], "last": "Julian", "suffix": ""}], "year": 2000, "venue": "Avian Pathol", "link": "34095373"}, "BIBREF17": {"title": "The relationship of right ventricular hypertrophy, right ventricular failure, and ascites to weight gain in broiler and roaster chickens", "authors": [{"first": "R", "middle": ["J"], "last": "Julian", "suffix": ""}, {"first": "G", "middle": ["W"], "last": "Friars", "suffix": ""}, {"first": "H", "middle": [], "last": "French", "suffix": ""}, {"first": "M", "middle": [], "last": "Quinton", "suffix": ""}], "year": 1987, "venue": "Avian Dis", "link": "37043034"}, "BIBREF18": {"title": "Blood oxygen concentration of fast-growing and slow-growing broiler chickens, and chickens with ascites from right ventricular failure", "authors": [{"first": "R", "middle": ["J"], "last": "Julian", "suffix": ""}, {"first": "S", "middle": ["M"], "last": "Mirsalimi", "suffix": ""}], "year": 1992, "venue": "Avian Dis", "link": "208530486"}, "BIBREF19": {"title": "Models to estimate maternal effects for juvenile body weight in broiler chickens", "authors": [{"first": "A", "middle": ["N M"], "last": "Koerhuis", "suffix": ""}, {"first": "R", "middle": [], "last": "Thompson", "suffix": ""}], "year": 1997, "venue": "Genet. Sel. Evol", "link": null}, "BIBREF20": {"title": "High carbon dioxide tension (PCO 2 ) and the incidence of cardiac arrhythmias in rapidly growing broiler chickens", "authors": [{"first": "S", "middle": ["M"], "last": "Korte", "suffix": ""}, {"first": "A", "middle": [], "last": "Sgoifo", "suffix": ""}, {"first": "W", "middle": [], "last": "Ruesink", "suffix": ""}, {"first": "C", "middle": [], "last": "Kwakernaak", "suffix": ""}, {"first": "S", "middle": [], "last": "Van Voorst", "suffix": ""}, {"first": "C", "middle": ["W"], "last": "Scheele", "suffix": ""}, {"first": "H", "middle": ["J"], "last": "Blokhuis", "suffix": ""}], "year": 1999, "venue": "Vet. Rec", "link": "26890928"}, "BIBREF21": {"title": "Heritability of ascites and the ratio of right to total ventricle weight in broiler breeder male lines", "authors": [{"first": "D", "middle": ["L"], "last": "Lubritz", "suffix": ""}, {"first": "J", "middle": ["L"], "last": "Smith", "suffix": ""}, {"first": "B", "middle": ["N"], "last": "Mcpherson", "suffix": ""}], "year": 1995, "venue": "Poult. Sci", "link": "3627475"}, "BIBREF22": {"title": "Genetics and Analysis of Quantitative Traits. 5th rev", "authors": [{"first": "M", "middle": [], "last": "Lynch", "suffix": ""}, {"first": "B", "middle": [], "last": "Walsh", "suffix": ""}], "year": 1998, "venue": "", "link": null}, "BIBREF23": {"title": "Growth performance, carcass characteristics, and the incidence of ascites in broilers in response to feed restriction and litter oiling", "authors": [{"first": "R", "middle": ["H"], "last": "Mcgovern", "suffix": ""}, {"first": "J", "middle": ["J"], "last": "Feddes", "suffix": ""}, {"first": "F", "middle": ["E"], "last": "Robinson", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Hanson", "suffix": ""}], "year": 1999, "venue": "Poult. Sci", "link": "3619371"}, "BIBREF24": {"title": "Selection strategies for limiting the increase in ascites while increasing growth in broilers", "authors": [{"first": "I", "middle": [], "last": "Mcmillan", "suffix": ""}, {"first": "V", "middle": ["M"], "last": "Quinton", "suffix": ""}], "year": 2002, "venue": "Poult. Sci", "link": "3611683"}, "BIBREF25": {"title": "Estimation of genetic parameters for ascites syndrome in broiler chickens", "authors": [{"first": "H", "middle": ["K"], "last": "Moghadam", "suffix": ""}, {"first": "I", "middle": [], "last": "Mcmillan", "suffix": ""}, {"first": "J", "middle": ["R"], "last": "Chambers", "suffix": ""}, {"first": "R", "middle": ["J"], "last": "Julian", "suffix": ""}], "year": 2001, "venue": "Poult. Sci", "link": "3624293"}, "BIBREF26": {"title": "Genetic parameters for blood oxygen saturation, body weight and breast conformation in 4 meat-type chicken lines", "authors": [{"first": "P", "middle": [], "last": "Navarro", "suffix": ""}, {"first": "P", "middle": ["M"], "last": "Visscher", "suffix": ""}, {"first": "D", "middle": [], "last": "Chatziplis", "suffix": ""}, {"first": "A", "middle": ["N M"], "last": "Koerhuis", "suffix": ""}, {"first": "C", "middle": ["S"], "last": "Haley", "suffix": ""}], "year": 2006, "venue": "Br. Poult. Sci", "link": "14739513"}, "BIBREF27": {"title": "Sensitivity of methods of variance component estimation to culling type of selection", "authors": [{"first": "W", "middle": [], "last": "Ouweltjes", "suffix": ""}, {"first": "L", "middle": ["R"], "last": "Schaeffer", "suffix": ""}, {"first": "B", "middle": ["W"], "last": "Kennedy", "suffix": ""}], "year": 1988, "venue": "J. Dairy Sci", "link": "119602766"}, "BIBREF28": {"title": "Selection strategies for body weight and reduced ascites susceptibility in broilers", "authors": [{"first": "A", "middle": [], "last": "Pakdel", "suffix": ""}, {"first": "P", "middle": [], "last": "Bijma", "suffix": ""}, {"first": "B", "middle": ["J"], "last": "Ducro", "suffix": ""}, {"first": "H", "middle": [], "last": "Bovenhuis", "suffix": ""}], "year": 2005, "venue": "Poult. Sci", "link": "3617059"}, "BIBREF29": {"title": "Direct and maternal genetic effects for ascites-related traits in broilers", "authors": [{"first": "A", "middle": [], "last": "Pakdel", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Van Arendonk", "suffix": ""}, {"first": "A", "middle": ["L"], "last": "Vereijken", "suffix": ""}, {"first": "H", "middle": [], "last": "Bovenhuis", "suffix": ""}], "year": 2002, "venue": "Poult. Sci", "link": "3636804"}, "BIBREF30": {"title": "Genetic parameters of ascites-related traits in broilers: Correlations with feed efficiency and carcass traits", "authors": [{"first": "A", "middle": [], "last": "Pakdel", "suffix": ""}, {"first": "J", "middle": ["A M"], "last": "Van Arendonk", "suffix": ""}, {"first": "A", "middle": ["L J"], "last": "Vereijken", "suffix": ""}, {"first": "H", "middle": [], "last": "Bovenhuis", "suffix": ""}], "year": 2005, "venue": "Br. Poult. Sci", "link": "36959670"}, "BIBREF31": {"title": "Genetic parameters of ascites-related traits in broilers: Effect of cold and normal temperature conditions", "authors": [{"first": "A", "middle": [], "last": "Pakdel", "suffix": ""}, {"first": "J", "middle": ["A M"], "last": "Van Arendonk", "suffix": ""}, {"first": "A", "middle": ["L J"], "last": "Vereijken", "suffix": ""}, {"first": "H", "middle": [], "last": "Bovenhuis", "suffix": ""}], "year": 2005, "venue": "Br. Poult. Sci", "link": "25338765"}, "BIBREF32": {"title": "Divergent selection for ascites incidence in chickens", "authors": [{"first": "H", "middle": ["O"], "last": "Pavlidis", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Balog", "suffix": ""}, {"first": "L", "middle": ["K"], "last": "Stamps", "suffix": ""}, {"first": "J", "middle": ["D"], "last": "Hughes", "suffix": ""}, {"first": "W", "middle": ["E"], "last": "Huff", "suffix": ""}, {"first": "N", "middle": ["B"], "last": "Anthony", "suffix": ""}], "year": 2007, "venue": "Poult. Sci", "link": "6793029"}, "BIBREF33": {"title": "Ascites in broilers. 2. Disturbances in the hormonal regulation of metabolic rate and fat metabolism", "authors": [{"first": "C", "middle": ["W"], "last": "Scheele", "suffix": ""}, {"first": "E", "middle": [], "last": "Decuypere", "suffix": ""}, {"first": "P", "middle": ["F G"], "last": "Vereijken", "suffix": ""}, {"first": "F", "middle": ["J G"], "last": "Schreurs", "suffix": ""}], "year": 1992, "venue": "Poult. Sci", "link": "3601876"}, "BIBREF34": {"title": "Haematological characteristics predicting susceptibility for ascites. 1. High carbon dioxide tensions in juvenile chickens", "authors": [{"first": "C", "middle": ["W"], "last": "Scheele", "suffix": ""}, {"first": "J", "middle": ["D"], "last": "Van Der Klis", "suffix": ""}, {"first": "C", "middle": [], "last": "Kwakernaak", "suffix": ""}, {"first": "N", "middle": [], "last": "Buys", "suffix": ""}, {"first": "E", "middle": [], "last": "Decuypere", "suffix": ""}], "year": 2003, "venue": "Br. Poult. Sci", "link": "23434808"}, "BIBREF35": {"title": "Ascites and venous carbon dioxide tensions in juvenile chickens of highly selected genotypes and native strains", "authors": [{"first": "C", "middle": ["W"], "last": "Scheele", "suffix": ""}, {"first": "J", "middle": ["D"], "last": "Van Der Klis", "suffix": ""}, {"first": "C", "middle": [], "last": "Kwakernaak", "suffix": ""}, {"first": "R", "middle": ["A"], "last": "Dekker", "suffix": ""}, {"first": "J", "middle": ["H"], "last": "Van Middelkoop", "suffix": ""}, {"first": "J", "middle": [], "last": "Buyse", "suffix": ""}, {"first": "E", "middle": [], "last": "Decuypere", "suffix": ""}], "year": 2005, "venue": "World's Poult. Sci. J", "link": "55477638"}, "BIBREF36": {"title": "The effects of poor ventilation, low temperatures, type of feed and sex of bird on the development of ascites in broilers. physiopathological factors", "authors": [{"first": "A", "middle": [], "last": "Shlosberg", "suffix": ""}, {"first": "I", "middle": [], "last": "Zadikov", "suffix": ""}, {"first": "U", "middle": [], "last": "Bendheim", "suffix": ""}, {"first": "V", "middle": [], "last": "Handji", "suffix": ""}, {"first": "E", "middle": [], "last": "Berman", "suffix": ""}], "year": 1992, "venue": "Avian Pathol", "link": "42273732"}, "BIBREF37": {"title": "Whole genome scan for quantitative trait loci affecting body weight in chickens using a three generation design", "authors": [{"first": "J", "middle": ["B C H M"], "last": "Kaam", "suffix": ""}, {"first": "J", "middle": ["A M"], "last": "Van Arendonk", "suffix": ""}, {"first": "M", "middle": ["A M"], "last": "Groenen", "suffix": ""}, {"first": "H", "middle": [], "last": "Bovenhuis", "suffix": ""}, {"first": "A", "middle": ["L J"], "last": "Vereijken", "suffix": ""}, {"first": "R", "middle": ["P M A"], "last": "Crooijmans", "suffix": ""}, {"first": "J", "middle": ["J"], "last": "Van Der Poel", "suffix": ""}, {"first": "A", "middle": [], "last": "Veenendaal", "suffix": ""}], "year": 1998, "venue": "Livest. Prod. Sci", "link": "85568800"}, "BIBREF38": {"title": "Broiler breeder survivors of chronic unilateral pulmonary artery occlusion produce progeny resistant to pulmonary hypertension syndrome (ascites) induced by cool temperatures", "authors": [{"first": "R", "middle": ["F"], "last": "Wideman", "suffix": ""}, {"first": "H", "middle": [], "last": "French", "suffix": ""}], "year": 1999, "venue": "Poult. Sci", "link": "3644533"}, "BIBREF39": {"title": "Ascites resistance of progeny from broiler breeders selected for two generations using chronic unilateral pulmonary artery occlusion", "authors": [{"first": "R", "middle": ["F"], "last": "Wideman", "suffix": ""}, {"first": "H", "middle": [], "last": "French", "suffix": ""}], "year": 2000, "venue": "Poult. Sci", "link": "3655682"}, "BIBREF40": {"title": "Dietary sodium bicarbonate, cool temperatures, and feed withdrawal: Impact on arterial and venous blood-gas values in broilers", "authors": [{"first": "R", "middle": ["F"], "last": "Wideman", "suffix": ""}, {"first": "D", "middle": ["M"], "last": "Hooge", "suffix": ""}, {"first": "K", "middle": ["R"], "last": "Cummings", "suffix": ""}], "year": 2003, "venue": "Poult. Sci", "link": "3643072"}, "BIBREF41": {"title": "Venous blood pressure in broilers during acute inhalation of five percent carbon dioxide or unilateral pulmonary artery occlusion", "authors": [{"first": "R", "middle": ["F"], "last": "Wideman", "suffix": ""}, {"first": "P", "middle": [], "last": "Maynard", "suffix": ""}, {"first": "W", "middle": ["G"], "last": "Bottje", "suffix": ""}], "year": 1999, "venue": "Poult. Sci", "link": "3621987"}, "BIBREF42": {"title": "A bivariate mixture model analysis of body weight and ascites traits in broilers", "authors": [{"first": "S", "middle": [], "last": "Zerehdaran", "suffix": ""}, {"first": "E", "middle": ["M"], "last": "Van Grevehof", "suffix": ""}, {"first": "E", "middle": ["H"], "last": "Van Der Waaij", "suffix": ""}, {"first": "H", "middle": [], "last": "Bovenhuis", "suffix": ""}], "year": 2006, "venue": "Poult. Sci", "link": "3636635"}}, "ref_entries": {"FIGREF2": {"text": "BW at 2 wk; BW 5 = BW at 5 wk; RATIO = ratio of right to total ventricular weight; RV = right ventricular weight; TV = total ventricular weight; pvCO 2 = partial pressure of carbon dioxide in venous blood; pvO 2 = partial pressure of oxygen in venous blood; HCO", "type": "figure"}, "TABREF1": {"text": "The mean, SD, and CV for BW, heart ratio, blood gas parameters, and mortality of the broiler chickens", "type": "table"}, "TABREF2": {"text": "Phenotypic", "type": "table"}, "TABREF4": {"text": "The genetic correlations (above the diagonal) and the phenotypic correlations (below the diagonal)", "type": "table"}}}
{"paper_id": "17786462", "_pdf_hash": "e78aec139cf2539f86526efe006bb95e54f50168", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Robust uncertainty principles: exact signal reconstruction from highly incomplete frequency information", "authors": [{"first": "E", "middle": [], "last": "Cand\u00e8s", "suffix": ""}, {"first": "J", "middle": [], "last": "Romberg", "suffix": ""}, {"first": "T", "middle": [], "last": "Tao", "suffix": ""}], "year": 2006, "venue": "IEEE Trans. Inf. Theory", "link": "7033413"}, "BIBREF1": {"title": "Compressed sensing", "authors": [{"first": "D", "middle": [], "last": "Donoho", "suffix": ""}], "year": 2006, "venue": "IEEE Trans. Inf. Theory", "link": "206737254"}, "BIBREF2": {"title": "Cognitive radio: brain-empowered wireless communications", "authors": [{"first": "S", "middle": [], "last": "Haykin", "suffix": ""}], "year": 2005, "venue": "IEEE Journal on Selected Areas in Communications", "link": "15310505"}, "BIBREF3": {"title": "Random sampling for analog-to-information conversion of wideband signals", "authors": [{"first": "J", "middle": [], "last": "Laska", "suffix": ""}, {"first": "S", "middle": [], "last": "Kirolos", "suffix": ""}, {"first": "Y", "middle": [], "last": "Massoud", "suffix": ""}, {"first": "R", "middle": [], "last": "Baraniuk", "suffix": ""}, {"first": "A", "middle": [], "last": "Gilbert", "suffix": ""}, {"first": "M", "middle": [], "last": "Iwen", "suffix": ""}, {"first": "M", "middle": [], "last": "Strauss", "suffix": ""}], "year": 2006, "venue": "IEEE Dallas/CAS Workshop on Design, Applications, Integration and Software", "link": "12879662"}, "BIBREF4": {"title": "Recovery of signals from nonuniform samples using iterative methods", "authors": [{"first": "F", "middle": [], "last": "Marvasti", "suffix": ""}, {"first": "M", "middle": [], "last": "Analoui", "suffix": ""}, {"first": "M", "middle": [], "last": "Gamshadzahi", "suffix": ""}], "year": 1991, "venue": "IEEE Transactions on Signal Processing", "link": "109553763"}, "BIBREF5": {"title": "From theory to practice: SubNyquist sampling of sparse wideband analog signals", "authors": [{"first": "M", "middle": [], "last": "Mishali", "suffix": ""}, {"first": "Y", "middle": [], "last": "Eldar", "suffix": ""}], "year": 2010, "venue": "IEEE Journal of Selected Topics in Signal Processing", "link": "2477322"}, "BIBREF6": {"title": "A 9-bit, 14 \u00b5W and 0.06 mm 2 pulse position modulation ADC in 90 nm digital CMOS", "authors": [{"first": "S", "middle": [], "last": "Naraghi", "suffix": ""}, {"first": "M", "middle": [], "last": "Courcy", "suffix": ""}, {"first": "M", "middle": [], "last": "Flynn", "suffix": ""}], "year": 2010, "venue": "IEEE Journal of Solid-State Circuits", "link": "424905"}, "BIBREF7": {"title": "CoSaMP: Iterative signal recovery from incomplete and inaccurate samples", "authors": [{"first": "D", "middle": [], "last": "Needell", "suffix": ""}, {"first": "J", "middle": [], "last": "Tropp", "suffix": ""}], "year": 2009, "venue": "Applied and Computational Harmonic Analysis", "link": "123799335"}, "BIBREF8": {"title": "Implementation models for analog-to-information conversion via random sampling", "authors": [{"first": "T", "middle": [], "last": "Ragheb", "suffix": ""}, {"first": "S", "middle": [], "last": "Kirolos", "suffix": ""}, {"first": "J", "middle": [], "last": "Laska", "suffix": ""}, {"first": "A", "middle": [], "last": "Gilbert", "suffix": ""}, {"first": "M", "middle": [], "last": "Strauss", "suffix": ""}, {"first": "R", "middle": [], "last": "Baraniuk", "suffix": ""}, {"first": "Y", "middle": [], "last": "Massoud", "suffix": ""}], "year": 2007, "venue": "50th Midwest Symposium on Circuits and Systems (MWSCAS)", "link": "6681250"}, "BIBREF9": {"title": "Beyond Nyquist: Efficient sampling of sparse bandlimited signals", "authors": [{"first": "J", "middle": [], "last": "Tropp", "suffix": ""}, {"first": "J", "middle": [], "last": "Laska", "suffix": ""}, {"first": "M", "middle": [], "last": "Duarte", "suffix": ""}, {"first": "J", "middle": [], "last": "Romberg", "suffix": ""}, {"first": "R", "middle": [], "last": "Baraniuk", "suffix": ""}], "year": 2010, "venue": "IEEE Trans. Inf. Theory", "link": "568192"}, "BIBREF10": {"title": "Mixed-signal parallel compressed sensing and reception for cognitive radio", "authors": [{"first": "Z", "middle": [], "last": "Yu", "suffix": ""}, {"first": "S", "middle": [], "last": "Hoyos", "suffix": ""}, {"first": "B", "middle": [], "last": "Sadler", "suffix": ""}], "year": 2008, "venue": "IEEE International Conference on Acoustics, Speech and Signal Processing (ICASSP)", "link": "10277365"}}, "ref_entries": {}}
{"paper_id": "17786614", "_pdf_hash": "0dc93c5f3209e9567928c98dcd971c583bdbaa2d", "abstract": [{"section": "Abstract", "text": "Background: The occurrence of HIV-1 and syphilis infections during pregnancy poses major health risks to the foetus due to mother-to-child transmission. We conducted surveillance of HIV and syphilis infections among pregnant women attending antenatal clinics (ANCs) in Mainland Tanzania in 2011. Methods: This surveillance was carried out in 133 ANCs selected from 21 regions in Tanzania. In each region, six ANC sites were selected, with urban, semi-urban, and rural areas contributing two each. All pregnant women who were attending selected sentinel ANC sites for the first time at any pregnancy between September and December 2011 were enrolled. Serial ELISA assays were performed to detect HIV infection in an unlinked anonymous manner using dried blood spot (DBS) after routine syphilis testing. Data analysis was conducted using Stata v.12 software. Results: A total of 39,698 pregnant women representing 2.4 % of all pregnant women (1.68 million) attending ANCs in the Mainland Tanzania were enrolled. The overall HIV prevalence was found to be 5.6 % (95 % CI: 5.4-5.8 %). The risk for HIV infection was significantly higher among women aged 25-34 (cOR = 1.97, 95 % CI: 1.79-2.16; p < 0.05), older than 35 years (cOR = 1.88, 95 % CI: 1.62-2.17; p < 0.05) and those having 1-2 and 3-4 previous pregnancies. HIV infection was less prevalent among women attending rural ANC clinics (cOR = 0.46, 95 % CI 0.4-0.52; p < 0.05). The overall syphilis prevalence was 2.5 % (95 % CI: 2.3, 3.6). The risk for syphilis infection was significantly higher among women attending semi-urban and rural clinics and those having 3-4, and 5 previous pregnancies (p < 0.05). Marital status and level of education were not statistically significant with either of the two infections. HIV and syphilis co-infections occurred in 109 of 38,928 (0.3 %). Conclusion: The overall prevalence of HIV infection (5.6 %) and syphilis (2.5 %) found among pregnant women attending ANC clinics in Tanzania calls for further strengthening of current intervention measures, which include scaling up the integration of prevention of mother to child transmission (PMTCT) services in Reproductive and Child Health (RCH) clinics.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Background", "text": "In many developing countries, including Tanzania, estimates on the magnitude of and trends on the HIV epidemic are obtained through HIV seroprevalence surveys conducted over a period of time [1] . These surveys are primarily conducted using sentinel and general population. HIV seroprevalence targeting the general population allows more accurate estimation of the national HIV prevalence than traditional sentinel surveillance, and have been of useful value in assessing the scale of epidemics worldwide [2] [3] [4] . Despite that sentinel surveillance remains the main instrument in estimating HIV prevalence in many developing countries due to financial and logistical reasons. In Tanzania the most frequently used sentinel populations are women attending antenatal clinics (ANCs) and persons attending clinics for routine diagnosis and treatment of sexually transmitted infections (STIs) [5] [6] [7] . Apart from these surveys, the country has also conducted household surveys to monitor HIV infection and behavioral risks factors in general population [8] [9] [10] . Results from various surveys have reported varying trends of both HIV and other sexual transmission diseases [8, 11, 12] .", "cite_spans": [{"start": 191, "end": 194, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 505, "end": 508, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 509, "end": 512, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 513, "end": 516, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 892, "end": 895, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 896, "end": 899, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 900, "end": 903, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 1057, "end": 1060, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 1061, "end": 1064, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 1065, "end": 1069, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 1181, "end": 1184, "text": "[8,", "ref_id": "BIBREF7"}, {"start": 1185, "end": 1188, "text": "11,", "ref_id": "BIBREF11"}, {"start": 1189, "end": 1192, "text": "12]", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "Background", "text": "In Tanzania the last round of ANC HIV and syphilis surveillance was conducted in 2007 (reference). This has left a gap regarding the dynamics of HIV and syphilis infections among pregnant women attending ANC clinics in Tanzania. Therefore, in 2011 the National AIDS Control Programme (NACP) decided to conduct a country-wide surveillance to estimate the prevalence of HIV and syphilis among pregnant women attending ANC in Tanzania. The ultimate goal was to provide important information for program planning and evaluation of various interventions taken by the Government of the United Republic of Tanzania and other stakeholders, including development partners.", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Selection of surveillance sites", "text": "A total of 133 ANC (44 health centres, 48 dispensaries, 24 hospitals and 17 reproductive and child health clinics) were selected from all 21 regions of mainland Tanzania. In most regions two sites were purposively selected from urban, semi-urban and rural settings except for Dar es Salaam (the capital city), in which all the selected sites were classified as urban. ANC sites were considered for selection if they could enroll at least 120 pregnant women during the three consecutive months of data collection. In total, 46 sites were located in urban (city and/or town at the regional headquarters), 40 in semi-urban (district headquarters, country borders, or towns situated along major roads), and 47 in rural (remote areas where communities either farm or keep livestock) areas.", "cite_spans": [], "ref_spans": []}, {"section": "Surveillance target population", "text": "The surveillance population included all pregnant women of all ages attending a selected sentinel ANC site for the first time at any pregnancy during survey period between September and December 2011.", "cite_spans": [], "ref_spans": []}, {"section": "Specimen collection and preparation for testing", "text": "About 3-5 ml of whole blood was collected from each woman in an Ethylenediamine Tetra acetate (EDTA) vacutainer tube for routine syphilis testing. In addition, a drop of blood (\u2248100 \u03bcl) was used to prepare DBS specimens for HIV surveillance purposes. The DBS cards were left overnight to dry at room temperature. The same surveillance number was also written on the surveillance data collection form. At this point, the upper part of the surveillance data collection form that contained the woman's clinic card number was torn up and discarded in order to ensure de-linking of the client identifier from the respective HIV data that was documented on the surveillance data collection form.", "cite_spans": [], "ref_spans": []}, {"section": "Storage and transportation of DBS", "text": "Dried DBS cards were stacked between weighing paper and stored in zip-locked plastic bags with desiccant (drying) packets and a humidity indicator card together with their completed data collection forms. Desiccant packs were changed when humidity indicator cards changed color from blue to pink. On weekly basis using courier service, ANC survey staff mailed completed data collection forms and DBS samples to their assigned zonal laboratory. From zonal laboratory specimens were transported to the Department of Microbiology and Immunology at Muhimbili University of Health and Allied Sciences (MUHAS) for testing.", "cite_spans": [], "ref_spans": []}, {"section": "Social-demographic information", "text": "Surveillance staff recorded social and demographic details of the women at the site. The recorded information included age, marital status, parity, educational level and duration of stay at present residence.", "cite_spans": [], "ref_spans": []}, {"section": "Syphilis testing and treatment", "text": "Testing for syphilis infection was done on site using rapid plasma reagin (RPR), which is a routine test for syphilis infection among ANC attendees in Tanzania. In the majority of rural sites nurses at ANC clinics performed the test, whereas in most of the urban and semiurban sites laboratory staff performed tests. Results were recorded directly on the data collection form and on the woman's clinic card or laboratory investigation request form. Women whose RPR test results positive were offered treatment based on the National sexual transmitted infections (STIs) Treatment Guidelines [13] .", "cite_spans": [{"start": 590, "end": 594, "text": "[13]", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "Syphilis testing and treatment", "text": "HIV testing and quality assurance ", "cite_spans": [], "ref_spans": []}, {"section": "Ethical considerations", "text": "Because syphilis screening is already routinely conducted as per the guidelines of the Ministry of Health and Social Welfare (MOHSW) and HIV testing was performed on non-linked samples, informed consent was not warranted. There were no direct benefits or risks to participating in the survey, and data was de-identified before analysis to protect client confidentiality. Before actual protocol implementation, the National Institute for Medical Research (NIMR) approved the ANC surveillance protocol (reference number NIMR/HQ/R.8C/Vol 1/43).", "cite_spans": [], "ref_spans": []}, {"section": "Data analysis", "text": "Data analysis was performed using Stata v.12 software (Stata Corporation, College Station, Texas, USA). Association between HIV and syphilis infections with variables were determined through univariate and multivariate logistic regression and expressed through odds ratio and 95 % confidence interval. Factors that were found to be significant in the univariate logistic regression analysis were used in the multivariate logistic regression and a p-value less than 0.05 was considered to be significant.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Distribution of ANC attendees by region and locality", "text": "A total of 39,698 pregnant women, equivalent to 2.4 % of estimated 1.68 million women attending ANC in Mainland Tanzania were enrolled. The number of women enrolled varied by region, ranging from 867 in Mtwara to 3780 in Dar es Salaam (Table 1) , while the percentage of those enrolled ranged from 1.2 % in Kagera to 5.1 % in Arusha.", "cite_spans": [], "ref_spans": [{"start": 235, "end": 244, "text": "(Table 1)", "ref_id": "TABREF1"}]}, {"section": "Distribution of ANC attendees by region and locality", "text": "HIV prevalence in association with socio-demographic characteristics of the ANC attendees Among 39,698 pregnant women enrolled in the surveillance, majority (87 %) were married and nearly half (48.7 %) were aged between 15-24 years. About 41.3 % had 1-2 previous pregnancies and most women (51.4 %) were from urban areas, and over two thirds (68.6 %) had primary education.", "cite_spans": [], "ref_spans": []}, {"section": "Distribution of ANC attendees by region and locality", "text": "The overall prevalence of HIV was 5.6 % (95 % CI: 5.4, 5.8). Single women (6.8 %) were at more risk of being HIV infected than married women (5.4 %) (cOR = 1.28, 95 % CI: 1.13-1.45; p < 0.05) and divorced women (5.1 %) ( Table 2) . Women aged 25-34 (cOR = 1.97, 95 % CI: 1.79-2.16; p < 0.05) and those older than 35 (cOR = 1.88, 95 % CI: 1.62-2.17; p < 0.05) had increased risk of being HIV infected compared to age group 15-24 years. Women with 1-2 previous pregnancies (cOR = 1.94, 95 % CI 1.71-2.19); p < 0.05) and those with 3-4 previous pregnancies (cOR = 2.19, 95 % CI 1.92-2.59; p < 0.05) had significantly greater likelihood of being HIV infected compared to those who had more than 5 pregnancies (cOR = 1.23, 95 % CI 1.02-1.48); p = 0.07). The likelihood of being HIV infected was significantly less frequent among women residing in rural areas (3.13 %) (cOR = 0.46, 95 % CI 0.4-0.52; p < 0.05) and semi-urban areas (5.82 %) (cOR = 0.88, 95 % CI 0.8-0.96, p < 0.05) compared to urban areas (6.59 %). There was no statistically significant difference in the risk of HIV with education and duration of stay in residence.", "cite_spans": [], "ref_spans": [{"start": 221, "end": 229, "text": "Table 2)", "ref_id": "TABREF2"}]}, {"section": "Distribution of ANC attendees by region and locality", "text": "On performing multivariate analysis after adjusting for potential confounding, the risk of HIV infection remained significantly high in the 25-34 year-old age group (aOR = 1.90, 95 % CI 1.70-2.13: P < 0.05) and in women older than 35 years (aOR = 2.30, 95 % CI 1.93-2.76; p < 0.05 compared to 15-24 years. Other independent factors of HIV infection were being single and having 1-2 (aOR = 1.50, 95 % CI 1.17-1.92; P < 0.05) and 3-4 previous pregnancies (aOR = 1.7, 95 % 1.27-2.29; p < 0.05) ( Table 2) , while those attending rural ANC clinics had a decreased risk of HIV infection (adOR = 0.48, 95 % CI 0.42-0.56; p < 0.05).", "cite_spans": [], "ref_spans": [{"start": 493, "end": 501, "text": "Table 2)", "ref_id": "TABREF2"}]}, {"section": "Syphilis prevalence in association with demographic characteristics of ANC attendees", "text": "The overall syphilis prevalence was 2.5 % (956/38,920) (95 % CI: 2.3-3.6). The risk of syphilis infection was higher among women having 3-4 pregnancies (cOR = 1.94, 95 % CI: 1.60-2.35; p < 0.05) and >5 pregnancies (cOR = 2.48; 95 % CI 2-3.08; p < 0.05) as compared to 1-2 previous pregnancies (cOR = 1.23, 95 % CI 1.03-1.48; p = 0.06). Other characteristics significantly associated with syphilis were (Table 3) . After adjusting for potential confounding, the likelihood of syphilis remained significantly higher among women having more than three previous pregnancies, and those who were attending semi-urban and rural ANC clinics.", "cite_spans": [], "ref_spans": [{"start": 402, "end": 411, "text": "(Table 3)", "ref_id": "TABREF3"}]}, {"section": "HIV and syphilis prevalence by location of ANC attendees", "text": "The prevalence of HIV infection ranged from 1. (Table 4) , whereas syphilis infection ranged from 0.4 % in Arusha to 6.7 % in Mwanza. In almost all regions, the 2011 HIV prevalence among ANC attendees is comparable to that of women from 2011/2012THMIS with minor variations, and both were higher than that of men and close to the general HIV prevalence (including men and women aged 15-49 years), Table 5 .", "cite_spans": [], "ref_spans": [{"start": 47, "end": 56, "text": "(Table 4)", "ref_id": "TABREF5"}, {"start": 397, "end": 404, "text": "Table 5", "ref_id": "TABREF4"}]}, {"section": "HIV and syphilis prevalence by location of ANC attendees", "text": "Apparently, there was no clear association in the occurrence of the two infections. For example, while the prevalence of HIV infection in Iringa region was 14.82 % that of syphilis was only 1.91 %. Similarly, the prevalence of HIV infection in Mbeya region was 11.31 %, while that of syphilis was 2.2 %. ", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Overall prevalence of HIV and syphilis infections", "text": "The 2011 ANC surveillance results shows that the overall prevalence of HIV infection was 5.6 % (95 % CI: 5.4, 5.8 %) while that of syphilis was 2.5 % (95 % CI: 2.3, 3.6 %). The observed HIV prevalence in this study was lower than the previous 2007/08 Tanzania ANC surveillance data (7 %) [14] and 2011/2012 Tanzania HIV-AIDS malaria indicator survey (THMS) (6 %) [8, 11, 14, 15] and a recent THMS survey [9] ( Table 5 ). The NACP needs to investigate the possible reasons for persistently high prevalence of HIV infection in these regions. Our survey also showed HIV prevalence varied by residence with 3.1 %, 5.8 % and 6.6 % for rural, semi-urban and urban clinic attendees respectively, an observation which is in consistent with previous and recent reports from Tanzania [11, 13, 16] . These observed differences are probably due to differences in social-economic activities and level of wealth in urban versus semi-urban and rural areas [17, 18] as well as round sexual networks and prevalence of sex work in urban and semi-urban areas.", "cite_spans": [{"start": 288, "end": 292, "text": "[14]", "ref_id": "BIBREF14"}, {"start": 363, "end": 366, "text": "[8,", "ref_id": "BIBREF7"}, {"start": 367, "end": 370, "text": "11,", "ref_id": "BIBREF11"}, {"start": 371, "end": 374, "text": "14,", "ref_id": "BIBREF14"}, {"start": 375, "end": 378, "text": "15]", "ref_id": "BIBREF15"}, {"start": 404, "end": 407, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 774, "end": 778, "text": "[11,", "ref_id": "BIBREF11"}, {"start": 779, "end": 782, "text": "13,", "ref_id": "BIBREF13"}, {"start": 783, "end": 786, "text": "16]", "ref_id": "BIBREF16"}, {"start": 941, "end": 945, "text": "[17,", "ref_id": "BIBREF17"}, {"start": 946, "end": 949, "text": "18]", "ref_id": "BIBREF18"}], "ref_spans": [{"start": 410, "end": 417, "text": "Table 5", "ref_id": "TABREF4"}]}, {"section": "Factors associated with HIV infection", "text": "In this survey, the risk of HIV infection significantly increased with age above 25 years, being highest (7.3 %) in women aged 25-34 years, followed by 35 years and above (7 %); finding which is in agreement with previous studies in Tanzania [11, 12] , and elsewhere in Africa [19] . We also found relatively low risk of HIV infection among young women with no history of previous pregnancies compare to those 1-4 previous pregnancies ( Table 2 ). The relatively low HIV prevalence (3.9 %) among women aged between 15-24years may signify a reduction in the number of new infections [20] , however this need to be substantiated by trend analysis studies. Women who reported single marital status (6.8 %) had significantly increased risk of HIV as compared to married women (5.4 %), an observation which is in keeping with the previous studies and ANC surveillance reports [11, 14, 15, 21] . Other reports in Tanzania have found highest HIV prevalence among married women or formerly married women [8, 13] . Such variations may imply that marital status per se is not an indicator of sexual activity and hence risk for HIV infection, which underlines the need to involve men in the control of HIV infection [22] . Notably, the risk of HIV infection decreased significantly with being in rural area as compared to semiurban and urban areas is consistent with past and recent studies [11, 14, 23] . However these geographical differences seem to be decreasing.", "cite_spans": [{"start": 242, "end": 246, "text": "[11,", "ref_id": "BIBREF11"}, {"start": 247, "end": 250, "text": "12]", "ref_id": "BIBREF12"}, {"start": 277, "end": 281, "text": "[19]", "ref_id": "BIBREF19"}, {"start": 582, "end": 586, "text": "[20]", "ref_id": "BIBREF20"}, {"start": 871, "end": 875, "text": "[11,", "ref_id": "BIBREF11"}, {"start": 876, "end": 879, "text": "14,", "ref_id": "BIBREF14"}, {"start": 880, "end": 883, "text": "15,", "ref_id": "BIBREF15"}, {"start": 884, "end": 887, "text": "21]", "ref_id": "BIBREF21"}, {"start": 996, "end": 999, "text": "[8,", "ref_id": "BIBREF7"}, {"start": 1000, "end": 1003, "text": "13]", "ref_id": "BIBREF13"}, {"start": 1205, "end": 1209, "text": "[22]", "ref_id": "BIBREF22"}, {"start": 1380, "end": 1384, "text": "[11,", "ref_id": "BIBREF11"}, {"start": 1385, "end": 1388, "text": "14,", "ref_id": "BIBREF14"}, {"start": 1389, "end": 1392, "text": "23]", "ref_id": "BIBREF23"}], "ref_spans": [{"start": 437, "end": 444, "text": "Table 2", "ref_id": "TABREF2"}]}, {"section": "Factors associated with HIV infection", "text": "In general, our results show significant regional and rural/semi-urban/urban variations in HIV prevalence. Therefore there is a need for national-wide scaling PMTCT services within RCH clinics. All ANC clinics should be able to provide PMTCT option B+ which require women and their infants to receive a cascade of interventions including uptake of antenatal services and HIV testing during pregnancy, use of antiretroviral treatment (ART) by pregnant women living with HIV, safe childbirth practices and appropriate infant feeding, uptake of infant HIV testing and other post-natal healthcare services [24] . The issues and challenges which have been identified to hamper the promotion of PMTCT such as stigma, male involvement, infant feeding options and decision making, home deliveries, and access to upto-date information on PMTCT should be addressed in order to ensure uptake and utilization of PMTCT services [25, 26] .", "cite_spans": [{"start": 602, "end": 606, "text": "[24]", "ref_id": "BIBREF24"}, {"start": 915, "end": 919, "text": "[25,", "ref_id": "BIBREF25"}, {"start": 920, "end": 923, "text": "26]", "ref_id": "BIBREF26"}], "ref_spans": []}, {"section": "Factors associated with syphilis infection", "text": "The only factors that were associated with risk for syphilis were living in a rural or semi-urban area and having 1 to 4 previous numbers of pregnancies. Our finding of high burden of syphilis in rural and semi-urban areas is similar to what has been reported in studies from SubSaharan Africa and China [12, [27] [28] [29] . The high burden of syphilis among the rural and semi-urban population in Tanzania may be partially explained by the relatively poor treatment access as well as data quality. In rural settings syphilis testing was done by ANC nurses, whom may be less skilled than laboratory technicians who performed the test in urban testing. The RPR is a macroscopic flocculation tests and requires no microscope, but has the potential for false-negative results due to prozone reactions. For many years surveillance of syphilis in Tanzania has based on RPR, which is (non-treponemal) which are not specific and may therefore provide some false positive or negative results. We are therefore advocating use of rapid point-of-care (RPOC) tests as a new approach to ensuring that diagnosis and treatment of syphilis is timely across the diverse geographic and social settings in the country. The RPOC tests should be able to detect recent, as distinct from past treated infections.", "cite_spans": [{"start": 304, "end": 308, "text": "[12,", "ref_id": "BIBREF12"}, {"start": 309, "end": 313, "text": "[27]", "ref_id": "BIBREF27"}, {"start": 314, "end": 318, "text": "[28]", "ref_id": "BIBREF28"}, {"start": 319, "end": 323, "text": "[29]", "ref_id": "BIBREF29"}], "ref_spans": []}, {"section": "Association between occurrence of syphilis and HIV infections", "text": "Apparently, there was no clear correlation in the occurrence of the two infections in the different regions. For example, while the prevalence of HIV infection in Iringa region was 14.82 % that of syphilis was only 1.91 %. Similarly, the prevalence of HIV infection in Mbeya region was 11.31 %, while that of syphilis was 2.2 %. On the other hand, Mwanza region which had the highest prevalence of syphilis (6.7 %), had a rather modest prevalence of HIV infection (4.2 %). Tabora region which had syphilis prevalence of 3.07 % had a HIV prevalence of 4.74 %.", "cite_spans": [], "ref_spans": []}, {"section": "Association between occurrence of syphilis and HIV infections", "text": "Possible explanations for lack of correlation could be part to the use of non-treponemal test for diagnosis of syphilis where my overestimate or underestimate the true case of syphilis.", "cite_spans": [], "ref_spans": []}, {"section": "Association between occurrence of syphilis and HIV infections", "text": "The strength of our study is in Tanzania~94 % of pregnant women make at least one antenatal care (ANC) visit [30] , therefore there was a good representation data of ANC attendees which can provide a reasonable estimate of HIV and syphilis prevalence within the general population.", "cite_spans": [{"start": 109, "end": 113, "text": "[30]", "ref_id": "BIBREF30"}], "ref_spans": []}, {"section": "Association between occurrence of syphilis and HIV infections", "text": "However, compared to population survey ANC surveillance have several limitations including is limited by geographical coverage because sampling is often not representative of smaller and more remote areas in a country, only women of certain social economic status attend the clinics, and do not provide information on women who are not pregnant or sexually active and who do not attend public health clinics and it lacks information on men [3, 31, 32] . In our study, these limitations were minimized by selecting 133 health facilities from all regions in Tanzania mainland and from each region at least 2 ANC clinics were selected from rural, semi-urban and urban areas.", "cite_spans": [{"start": 440, "end": 443, "text": "[3,", "ref_id": "BIBREF2"}, {"start": 444, "end": 447, "text": "31,", "ref_id": "BIBREF31"}, {"start": 448, "end": 451, "text": "32]", "ref_id": "BIBREF32"}], "ref_spans": []}, {"section": "Association between occurrence of syphilis and HIV infections", "text": "Fortunately, Tanzania has opportunity of both ANC sentinel surveillance and population surveys that can complement information thereby providing clear picture of HIV infection. We therefore advocate use of both datasets for in-depth analysis of national HIV epidemic.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "The overall prevalence of HIV infection (5.6 %) and syphilis (2.5 %) found among pregnant women attending ANC clinics in Tanzania calls for further strengthening of current intervention measures, which include scaling up the integration of prevention of mother to child transmission (PMTCT) services in Reproductive and Child Health (RCH) clinics. The issues and challenges which have been identified to hamper the promotion of PMTCT such as stigma, male involvement, infant feeding options and decision making, home deliveries, and access to up-to-date information on PMTCT should be addressed in order to ensure uptake and utilization of PMTCT services.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Estimates of HIV-1 prevalence from national population-based surveys as a new gold standard", "authors": [{"first": "J", "middle": ["T"], "last": "Boerma", "suffix": ""}, {"first": "P", "middle": ["D"], "last": "Ghys", "suffix": ""}, {"first": "N", "middle": [], "last": "Walker", "suffix": ""}], "year": 2003, "venue": "Lancet", "link": "28441270"}, "BIBREF1": {"title": "HIV testing in national population-based surveys: experience from the Demographic and Health Surveys", "authors": [{"first": "V", "middle": [], "last": "Mishra", "suffix": ""}, {"first": "M", "middle": [], "last": "Vaessen", "suffix": ""}, {"first": "J", "middle": ["T"], "last": "Boerma", "suffix": ""}, {"first": "F", "middle": [], "last": "Arnold", "suffix": ""}, {"first": "A", "middle": [], "last": "Way", "suffix": ""}, {"first": "B", "middle": [], "last": "Barrere", "suffix": ""}], "year": 2006, "venue": "Bull World Health Organ", "link": "14703531"}, "BIBREF2": {"title": "Comparison of adult HIV prevalence from national population-based surveys and antenatal clinic surveillance in countries with generalised epidemics: implications for calibrating surveillance data", "authors": [{"first": "E", "middle": [], "last": "Gouws", "suffix": ""}, {"first": "V", "middle": [], "last": "Mishra", "suffix": ""}, {"first": "T", "middle": ["B"], "last": "Fowler", "suffix": ""}], "year": 2008, "venue": "Sex Transm Infect", "link": "8328053"}, "BIBREF3": {"title": "Lessons learned in the conduct, validation, and interpretation of national population based HIV surveys", "authors": [{"first": "J", "middle": ["M"], "last": "Calleja", "suffix": ""}, {"first": "L", "middle": ["H"], "last": "Marum", "suffix": ""}, {"first": "C", "middle": ["P"], "last": "Carcamo", "suffix": ""}, {"first": "L", "middle": [], "last": "Kaetano", "suffix": ""}, {"first": "J", "middle": [], "last": "Muttunga", "suffix": ""}, {"first": "A", "middle": [], "last": "Way", "suffix": ""}], "year": 2005, "venue": "AIDS", "link": "1337365"}, "BIBREF4": {"title": "Global surveillance and forecasting of AIDS", "authors": [{"first": "J", "middle": [], "last": "Chin", "suffix": ""}, {"first": "J", "middle": [], "last": "Mann", "suffix": ""}], "year": 1989, "venue": "Bull World Health Organ", "link": "33598350"}, "BIBREF5": {"title": "STI surveillance", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF6": {"title": "Guidelines for conducting HIV sentinel serosurveys among pregnant women and other groups. Geneva: World Health Organization", "authors": [{"first": "Sti", "middle": [], "last": "Surveillance", "suffix": ""}], "year": 2003, "venue": "UNAIDS/WHO Working Group on Global HIV/AIDS", "link": null}, "BIBREF7": {"title": "Office of the Chief Government Statistician (OCGS), and Macro International Inc. Tanzania HIV/AIDS and Malaria Indicator Survey 2007-08", "authors": [], "year": 2008, "venue": "", "link": null}, "BIBREF8": {"title": "Office of the Chief Government Statistician (OCGS), and Macro International Inc. Tanzania HIV/AIDS and Malaria Indicator Survey", "authors": [], "year": 2011, "venue": "Tanzania Commission for AIDS (TACAIDS), Zanzibar AIDS Commission (ZAC)", "link": null}, "BIBREF9": {"title": "Tanzania Commission for AIDS (TACAIDS), National Bureau of Statistics (NBS), and ORC Macro. Tanzania HIV/AIDS Indicator Survey", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF11": {"title": "Surveillance of HIV and syphilis infections among antenatal clinic attendees in Tanzania", "authors": [{"first": "R", "middle": ["O"], "last": "Swai", "suffix": ""}, {"first": "G", "middle": ["G"], "last": "Somi", "suffix": ""}, {"first": "M", "middle": ["I"], "last": "Matee", "suffix": ""}, {"first": "J", "middle": [], "last": "Killewo", "suffix": ""}, {"first": "E", "middle": ["F"], "last": "Lyamuya", "suffix": ""}, {"first": "G", "middle": [], "last": "Kwesigabo", "suffix": ""}], "year": 2003, "venue": "BMC Public Health", "link": "11370057"}, "BIBREF12": {"title": "Trends in HIV & syphilis prevalence and correlates of HIV infection: results from cross-sectional surveys among women attending ante-natal clinics in Northern Tanzania", "authors": [{"first": "Y", "middle": [], "last": "Kumogola", "suffix": ""}, {"first": "E", "middle": [], "last": "Slaymaker", "suffix": ""}, {"first": "B", "middle": [], "last": "Zaba", "suffix": ""}, {"first": "J", "middle": [], "last": "Mngara", "suffix": ""}, {"first": "R", "middle": [], "last": "Isingo", "suffix": ""}, {"first": "J", "middle": [], "last": "Changalucha", "suffix": ""}], "year": 2010, "venue": "BMC Public Health", "link": "7384446"}, "BIBREF13": {"title": "Reproductive and Child Health Section. National guidelines for management of sexually transmitted and reproductive tract infections", "authors": [], "year": 2007, "venue": "National AIDS Control Programme", "link": null}, "BIBREF14": {"title": "The United Republic of Tanzania. Ministry of Health and Social welfare. National AIDS Control Programme. Surveillance of HIV and syphilis among antenatal clinic attendees", "authors": [], "year": 2007, "venue": "", "link": null}, "BIBREF15": {"title": "The United Republic of Tanzania, Ministry of Health and Social Welfare. National AIDS Control Programme. Surveillance of HIV and syphilis among antenatal clinic enrolees", "authors": [], "year": 2003, "venue": "", "link": null}, "BIBREF16": {"title": "Community effects on the risk of HIV infection in rural Tanzania", "authors": [{"first": "S", "middle": ["S"], "last": "Bloom", "suffix": ""}, {"first": "M", "middle": [], "last": "Urassa", "suffix": ""}, {"first": "R", "middle": [], "last": "Isingo", "suffix": ""}, {"first": "J", "middle": [], "last": "Ng&apos;weshemi", "suffix": ""}, {"first": "J", "middle": ["T"], "last": "Boerma", "suffix": ""}], "year": 2002, "venue": "Sex Transm Infect", "link": "12325380"}, "BIBREF17": {"title": "Are poor more affected by HIV/AIDS in sub-Saharan Africa? The 2006 HIV/AIDS Implementers Meeting of the President's Emergency Plan for AIDS Relief", "authors": [{"first": "V", "middle": [], "last": "Mishra", "suffix": ""}, {"first": "S", "middle": [], "last": "Rutstein", "suffix": ""}, {"first": "R", "middle": [], "last": "Greener", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF18": {"title": "Why do some communities have more HIV than others? The association between structural factors and HIV prevalence in rural South Africa", "authors": [{"first": "P", "middle": ["M"], "last": "Pronyk", "suffix": ""}, {"first": "L", "middle": ["A"], "last": "Marison", "suffix": ""}, {"first": "R", "middle": [], "last": "Auripidou", "suffix": ""}, {"first": "G", "middle": [], "last": "Phetla", "suffix": ""}], "year": 2005, "venue": "", "link": null}, "BIBREF19": {"title": "Seroprevalence of syphilis and HIV-1 during pregnancy in a teaching hospital in northwest Ethiopia", "authors": [{"first": "A", "middle": [], "last": "Mulu", "suffix": ""}, {"first": "A", "middle": [], "last": "Kassu", "suffix": ""}, {"first": "B", "middle": [], "last": "Tessema", "suffix": ""}, {"first": "G", "middle": [], "last": "Yismaw", "suffix": ""}, {"first": "M", "middle": [], "last": "Tiruneh", "suffix": ""}, {"first": "F", "middle": [], "last": "Moges", "suffix": ""}], "year": 2007, "venue": "Jpn J Infect Dis", "link": "21876519"}, "BIBREF20": {"title": "Measuring trends in prevalence and incidence of HIV infection in countries with generalised epidemics", "authors": [{"first": "P", "middle": ["D"], "last": "Ghys", "suffix": ""}, {"first": "E", "middle": [], "last": "Kufa", "suffix": ""}, {"first": "M", "middle": ["V"], "last": "George", "suffix": ""}], "year": 2006, "venue": "Sex Transm Infect", "link": "20776436"}, "BIBREF21": {"title": "HIV-1 and HIV-2 prevalence and associated risk factors among postnatal women in Harare", "authors": [{"first": "J", "middle": ["H"], "last": "Humphrey", "suffix": ""}, {"first": "K", "middle": ["J"], "last": "Nathoo", "suffix": ""}, {"first": "J", "middle": ["W"], "last": "Hargrove", "suffix": ""}, {"first": "P", "middle": ["J"], "last": "Iliff", "suffix": ""}, {"first": "K", "middle": ["E"], "last": "Mutasa", "suffix": ""}, {"first": "L", "middle": ["H"], "last": "Moulton", "suffix": ""}], "year": 2007, "venue": "Zimbabwe. Epidemiol Infect", "link": "538837"}, "BIBREF22": {"title": "Risk factors for HIV infection among women in", "authors": [{"first": "S", "middle": ["H"], "last": "Kapiga", "suffix": ""}, {"first": "J", "middle": ["F"], "last": "Shao", "suffix": ""}, {"first": "G", "middle": ["K"], "last": "Lwihula", "suffix": ""}, {"first": "D", "middle": ["J"], "last": "Hunter", "suffix": ""}], "year": 1994, "venue": "J Acquir Immune Defic Syndr", "link": null}, "BIBREF23": {"title": "Prevalence of HIV-1 infection in urban, semi-urban and rural areas in Arusha region", "authors": [{"first": "K", "middle": ["S"], "last": "Mnyika", "suffix": ""}, {"first": "K", "middle": ["I"], "last": "Klepp", "suffix": ""}, {"first": "G", "middle": [], "last": "Kvale", "suffix": ""}, {"first": "S", "middle": [], "last": "Nilssen", "suffix": ""}, {"first": "P", "middle": ["E"], "last": "Kissila", "suffix": ""}, {"first": "Ole-King&apos;ori", "middle": [], "last": "", "suffix": ""}, {"first": "N", "middle": [], "last": "", "suffix": ""}], "year": 1994, "venue": "Tanzania. AIDS", "link": "23942128"}, "BIBREF24": {"title": "HIV prevention transformed: the new prevention research agenda", "authors": [{"first": "N", "middle": ["S"], "last": "Padian", "suffix": ""}, {"first": "S", "middle": ["I"], "last": "Mccoy", "suffix": ""}, {"first": "S", "middle": ["S"], "last": "Karim", "suffix": ""}, {"first": "N", "middle": [], "last": "Hasen", "suffix": ""}, {"first": "J", "middle": [], "last": "Kim", "suffix": ""}, {"first": "M", "middle": [], "last": "Bartos", "suffix": ""}], "year": 2011, "venue": "Lancet", "link": "7055653"}, "BIBREF25": {"title": "Women's preferences regarding infant or maternal antiretroviral prophylaxis for prevention of mother-to-child transmission of HIV during breastfeeding and their views on Option B+ in Dar es Salaam", "authors": [{"first": "M", "middle": [], "last": "Ngarina", "suffix": ""}, {"first": "E", "middle": ["A"], "last": "Tarimo", "suffix": ""}, {"first": "H", "middle": [], "last": "Naburi", "suffix": ""}, {"first": "C", "middle": [], "last": "Kilewo", "suffix": ""}, {"first": "M", "middle": [], "last": "Mwanyika-Sando", "suffix": ""}, {"first": "G", "middle": [], "last": "Chalamilla", "suffix": ""}], "year": 2014, "venue": "PLoS One", "link": "4079539"}, "BIBREF26": {"title": "Conversations with mothers: exploring reasons for prevention of mother-to-child transmission (PMTCT) failures in the era of programmatic scale", "authors": [{"first": "F", "middle": [], "last": "Laher", "suffix": ""}, {"first": "A", "middle": [], "last": "Cescon", "suffix": ""}, {"first": "Lazarus", "middle": ["E"], "last": "Kaida", "suffix": ""}, {"first": "A", "middle": [], "last": "Makongoza", "suffix": ""}, {"first": "M", "middle": [], "last": "Hogg", "suffix": ""}, {"first": "R", "middle": ["S"], "last": "", "suffix": ""}], "year": 2011, "venue": "AIDS Behav", "link": null}, "BIBREF27": {"title": "Risk factors for active syphilis and TPHA seroconversion in a rural African population", "authors": [{"first": "J", "middle": [], "last": "Todd", "suffix": ""}, {"first": "K", "middle": [], "last": "Munguti", "suffix": ""}, {"first": "H", "middle": [], "last": "Grosskurth", "suffix": ""}, {"first": "J", "middle": [], "last": "Mngara", "suffix": ""}, {"first": "J", "middle": [], "last": "Changalucha", "suffix": ""}, {"first": "P", "middle": [], "last": "Mayaud", "suffix": ""}], "year": 2001, "venue": "Sex Transm Infect", "link": null}, "BIBREF28": {"title": "Syphilis screening among 27,150 pregnant women in south Chinese rural areas using point-of-care tests", "authors": [{"first": "L-G", "middle": [], "last": "Yang", "suffix": ""}, {"first": "J", "middle": ["D"], "last": "Tucker", "suffix": ""}, {"first": "F-Y", "middle": [], "last": "Liu", "suffix": ""}, {"first": "X-Q", "middle": [], "last": "Ren", "suffix": ""}, {"first": "X", "middle": [], "last": "Hong", "suffix": ""}, {"first": "C", "middle": [], "last": "Wang", "suffix": ""}], "year": 2013, "venue": "PLoS ONE", "link": "1100561"}, "BIBREF29": {"title": "Low seroprevalence of syphilis in Burkina Faso", "authors": [{"first": "F", "middle": [], "last": "Kirakoya-Samadoulougou", "suffix": ""}, {"first": "M", "middle": ["C"], "last": "Defer", "suffix": ""}, {"first": "S", "middle": [], "last": "Yaro", "suffix": ""}, {"first": "P", "middle": [], "last": "Fao", "suffix": ""}, {"first": "F", "middle": [], "last": "Ilboudo", "suffix": ""}, {"first": "Y", "middle": [], "last": "Langani", "suffix": ""}], "year": 2010, "venue": "Sex Transm Infect", "link": "20188924"}, "BIBREF30": {"title": "Tanzania Demographic and Health Survey2004-05", "authors": [{"first": "]", "middle": [], "last": "Tanzania", "suffix": ""}, {"first": "", "middle": [], "last": "Macro", "suffix": ""}], "year": 2005, "venue": "", "link": null}, "BIBREF31": {"title": "Epidemiological analysis of the quality of HIV sero-surveillance in the world: how well do we track the epidemic?", "authors": [{"first": "N", "middle": [], "last": "Walker", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Garcia-Calleja", "suffix": ""}, {"first": "L", "middle": [], "last": "Heaton", "suffix": ""}, {"first": "E", "middle": [], "last": "Asamoah-Odei", "suffix": ""}, {"first": "G", "middle": [], "last": "Poumerol", "suffix": ""}, {"first": "S", "middle": [], "last": "Lazzari", "suffix": ""}], "year": 2001, "venue": "AIDS", "link": "22155074"}, "BIBREF32": {"title": "Submit your next manuscript to BioMed Central and take full advantage of: \u2022 Convenient online submission \u2022 Thorough peer review \u2022 No space constraints or color figure charges \u2022 Immediate publication on acceptance \u2022 Inclusion in PubMed, CAS, Scopus and Google Scholar \u2022 Research which is freely available for redistribution", "authors": [{"first": "M", "middle": [], "last": "Fabiani", "suffix": ""}, {"first": "S", "middle": [], "last": "Accorsi", "suffix": ""}, {"first": "M", "middle": [], "last": "Lukwiya", "suffix": ""}, {"first": "T", "middle": [], "last": "Rosolen", "suffix": ""}, {"first": "E", "middle": ["O"], "last": "Ayella", "suffix": ""}, {"first": "P", "middle": ["A"], "last": "Onek", "suffix": ""}], "year": 2001, "venue": "AIDS", "link": null}}, "ref_entries": {"TABREF0": {"text": "The Department of Microbiology and Immunology at Muhimbili University of Health and Allied Sciences (MUHAS) collaborated with the Centers for Disease Control and Prevention (CDC) in developing a DBS HIV testing protocol and algorithm. At the laboratory, the DBS cards were eluted and tested for the presence of IgG antibodies to HIV using screening test, Vironostika\u00ae HIV Uni-Form II Ag/Ab ELISA test (Biomerieux, The Netherlands). Specimens with negative results under- went no further testing and were considered negative. Reactive samples underwent a second ELISA test, Enzyg- nostic Intergral II (Siemens Health care Diagnostic Prod- ucts, GMBH, Marbug-Germany). Specimens that were reactive on both ELISA tests were considered HIV anti- body positive. All discordant specimens were sent to the Tanzania's National Health Laboratory Quality Assur- ance and Training Center (NHLQATC) for resolution.", "type": "table"}, "TABREF1": {"text": "The 2011 ANC attendees, estimated number of pregnant women and percentage enrolment, Tanzania**Estimated number of pregnant women attended ANC clinic in 2011", "type": "table"}, "TABREF2": {"text": "Socio-demographical characteristics of the ANC attendees in association with HIV infection in Tanzania 2011", "type": "table"}, "TABREF3": {"text": "Prevalence of syphilis in association with social-demographic characteristics of the ANC attendees, Tanzania 2011cOR crude odd ratio, aOR adjusted odd ratio, CI confidence interval", "type": "table"}, "TABREF4": {"text": "", "type": "table"}, "TABREF5": {"text": "Prevalence of HIV and syphilis infection by region, Tanzania 2011", "type": "table"}, "TABREF6": {"text": "Comparison of HIV prevalence according to 2011 ANC and 2011/12 THMIS data by region, Tanzania 2011/12", "type": "table"}}}
{"paper_id": "17787145", "_pdf_hash": "6027865627979e4d36127545cb46ec94c56bd58b", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Software and the concurrency revolution", "authors": [{"first": "H", "middle": [], "last": "Sutter", "suffix": ""}, {"first": "J", "middle": [], "last": "Larus", "suffix": ""}], "year": 2005, "venue": "Queue", "link": null}, "BIBREF1": {"title": "A Pattern Language", "authors": [{"first": "C", "middle": [], "last": "Alexander", "suffix": ""}, {"first": "S", "middle": [], "last": "Ishikawa", "suffix": ""}, {"first": "M", "middle": [], "last": "Silverstein", "suffix": ""}, {"first": "M", "middle": [], "last": "Jacobson", "suffix": ""}, {"first": "I", "middle": [], "last": "Fiksdahl-King", "suffix": ""}, {"first": "S", "middle": [], "last": "Angel", "suffix": ""}], "year": 1977, "venue": "", "link": "67422904"}, "BIBREF2": {"title": "Design Patterns: Elements of Reusable Object-Oriented Software, ser", "authors": [{"first": "E", "middle": [], "last": "Gamma", "suffix": ""}, {"first": "R", "middle": [], "last": "Helm", "suffix": ""}, {"first": "R", "middle": [], "last": "Johnson", "suffix": ""}, {"first": "J", "middle": [], "last": "Vlissides", "suffix": ""}], "year": 1995, "venue": "", "link": null}, "BIBREF3": {"title": "Pattern-based reengineering of software systems", "authors": [{"first": "M", "middle": [], "last": "Meyer", "suffix": ""}], "year": 2006, "venue": "13 th Working Conference on Reverse Engineering (WCRE '06", "link": "24630713"}, "BIBREF4": {"title": "Concurrent Programming in Java: Design Principles and Patterns, Second Edition", "authors": [{"first": "D", "middle": [], "last": "Lea", "suffix": ""}], "year": 2000, "venue": "", "link": null}, "BIBREF5": {"title": "Antipattern-based detection of deficiencies in java multithreaded software", "authors": [{"first": "H", "middle": [], "last": "Hallal", "suffix": ""}, {"first": "E", "middle": [], "last": "Alikacem", "suffix": ""}, {"first": "W", "middle": [], "last": "Tunney", "suffix": ""}, {"first": "S", "middle": [], "last": "Boroday", "suffix": ""}, {"first": "A", "middle": [], "last": "Petrenko", "suffix": ""}], "year": 2004, "venue": "4 th International Conference on Quality Software", "link": "58160685"}, "BIBREF6": {"title": "Concurrent bug patterns and how to test them", "authors": [{"first": "E", "middle": [], "last": "Farchi", "suffix": ""}, {"first": "Y", "middle": [], "last": "Nir", "suffix": ""}, {"first": "S", "middle": [], "last": "Ur", "suffix": ""}], "year": 2003, "venue": "Proc. of the 1 st International Workshop on Parallel and Distributed Systems: Testing and Debugging", "link": "18313533"}, "BIBREF7": {"title": "Compiling a benchmark of documented multi-threaded bugs", "authors": [{"first": "Y", "middle": [], "last": "Eytani", "suffix": ""}, {"first": "S", "middle": [], "last": "Ur", "suffix": ""}], "year": 2004, "venue": "Proc. of the 2 nd International Workshop on Parallel and Distributed Systems: Testing and Debugging", "link": "12139145"}, "BIBREF8": {"title": "Mutation operators for concurrent Java (J2SE 5.0)", "authors": [{"first": "J", "middle": ["S"], "last": "Bradbury", "suffix": ""}, {"first": "J", "middle": ["R"], "last": "Cordy", "suffix": ""}, {"first": "J", "middle": [], "last": "Dingel", "suffix": ""}], "year": 2006, "venue": "Proc. of the 2 nd Workshop on Mutation Analysis", "link": "14201937"}, "BIBREF9": {"title": "Multithreaded Java program test generation", "authors": [{"first": "O", "middle": [], "last": "Edelstein", "suffix": ""}, {"first": "E", "middle": [], "last": "Farchi", "suffix": ""}, {"first": "Y", "middle": [], "last": "Nir", "suffix": ""}, {"first": "G", "middle": [], "last": "Ratsaby", "suffix": ""}, {"first": "S", "middle": [], "last": "Ur", "suffix": ""}], "year": 2002, "venue": "IBM Systems Journal", "link": "2958623"}, "BIBREF10": {"title": "Findbugs -find bugs in Java programs", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF11": {"title": "Jlint Manual: Java program checker", "authors": [], "year": 2002, "venue": "", "link": null}, "BIBREF12": {"title": "Finding synchronization defects in java programs: extended static analyses and code patterns", "authors": [{"first": "F", "middle": [], "last": "Otto", "suffix": ""}, {"first": "T", "middle": [], "last": "Moschny", "suffix": ""}], "year": 2008, "venue": "IWMSE '08: Proceedings of the 1st international workshop on Multicore software engineering", "link": "17966580"}, "BIBREF13": {"title": "Tool support for continuous quality control", "authors": [{"first": "F", "middle": [], "last": "Deissenboeck", "suffix": ""}, {"first": "E", "middle": [], "last": "Juergens", "suffix": ""}, {"first": "B", "middle": [], "last": "Hummel", "suffix": ""}, {"first": "S", "middle": [], "last": "Wagner", "suffix": ""}, {"first": "B", "middle": ["M"], "last": "Parareda", "suffix": ""}, {"first": "M", "middle": [], "last": "Pizka", "suffix": ""}], "year": 2008, "venue": "IEEE Software", "link": "11027661"}, "BIBREF14": {"title": "Mutation-based exploration of a method for verifying concurrent Java components", "authors": [{"first": "B", "middle": [], "last": "Long", "suffix": ""}, {"first": "R", "middle": [], "last": "Duke", "suffix": ""}, {"first": "D", "middle": [], "last": "Goldson", "suffix": ""}, {"first": "P", "middle": ["A"], "last": "Strooper", "suffix": ""}, {"first": "L", "middle": [], "last": "Wildman", "suffix": ""}], "year": 2004, "venue": "Proc. of the 2 nd International Workshop on Parallel and Distributed Systems: Testing and Debugging", "link": "245431"}, "BIBREF15": {"title": "A method for verifying concurrent Java components based on an analysis of concurrency failures", "authors": [{"first": "B", "middle": [], "last": "Long", "suffix": ""}, {"first": "P", "middle": [], "last": "Strooper", "suffix": ""}, {"first": "L", "middle": [], "last": "Wildman", "suffix": ""}], "year": 2007, "venue": "Concurrency and Computation: Practice and Experience", "link": "13449195"}, "BIBREF16": {"title": "High-level data races", "authors": [{"first": "C", "middle": [], "last": "Artho", "suffix": ""}, {"first": "K", "middle": [], "last": "Havelund", "suffix": ""}, {"first": "A", "middle": [], "last": "Biere", "suffix": ""}], "year": 2003, "venue": "Proc. of the 1 st International Workshop on Verification and Validation of Enterprise Information Systems (VVEIS'03)", "link": "4695489"}, "BIBREF17": {"title": "What are race conditions?: Some issues and formalizations", "authors": [{"first": "R", "middle": ["H B"], "last": "Netzer", "suffix": ""}, {"first": "B", "middle": ["P"], "last": "Miller", "suffix": ""}], "year": 1992, "venue": "ACM Lett. Program. Lang. Syst", "link": "3877497"}}, "ref_entries": {}}
{"paper_id": "17787381", "_pdf_hash": "51e9dea6492e7e999e10a421cd6bef2605df38b9", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Obtaining steady high-voltage direct current from a thermionic rectifier without a filter", "authors": [{"first": "F", "middle": ["W"], "last": "Maxstadt", "suffix": ""}], "year": 1924, "venue": "Trans. AIEE", "link": "51671385"}, "BIBREF1": {"title": "The rated output ofcommutatorless inverter motors having a simple six-phase connection", "authors": [{"first": "M", "middle": [], "last": "Stohr", "suffix": ""}], "year": 1938, "venue": "Archiv. Elektrotechnik", "link": null}, "BIBREF2": {"title": "The rating of brushless converter motors with improved motor connections", "authors": [], "year": 1938, "venue": "Archiv. Elektrotechnik", "link": null}, "BIBREF3": {"title": "The unit capacity of converter-fed synchronous machines in connection with various number of phases of types of circuits", "authors": [{"first": "W", "middle": [], "last": "Leitgeb", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF5": {"title": "Optimization of magnetic materials utilization in semiconductor commutated electric machines", "authors": [{"first": "H", "middle": [], "last": "Boenig", "suffix": ""}], "year": 1971, "venue": "", "link": null}, "BIBREF6": {"title": "Analysis and Testing ofa direct-voltage induced e.m.f. commutated thyristor motor", "authors": [{"first": "C", "middle": ["J"], "last": "St", "suffix": ""}, {"first": "", "middle": [], "last": "Lamb", "suffix": ""}], "year": 1970, "venue": "Proc. Inst. Elec. Eng", "link": "110823422"}, "BIBREF7": {"title": "Selected harmonic reduction in static dc-ac inverters", "authors": [{"first": "F", "middle": ["G"], "last": "Turnbull", "suffix": ""}], "year": 1964, "venue": "IEEE Trans. Commun. Electron", "link": null}, "BIBREF8": {"title": "Generalized techniques of harmonic elimination and voltage control in thyristor inverters. Part 1, harmonic elimination", "authors": [{"first": "H", "middle": ["S"], "last": "Patel", "suffix": ""}, {"first": "R", "middle": ["G"], "last": "Hoft", "suffix": ""}], "year": 1974, "venue": "IEEE Trans. Ind. Appl", "link": "110122659"}, "BIBREF9": {"title": "Generalized techniques of harmonic elimination and voltage control in thyristor inverters. Part 11, Voltage control", "authors": [], "year": 1974, "venue": "IEEE Trans. Ind. Appl", "link": "110122659"}, "BIBREF10": {"title": "Optimal pulsewidth modulation for feeding ac motors", "authors": [{"first": "G", "middle": ["S"], "last": "Buja", "suffix": ""}, {"first": "G", "middle": ["B"], "last": "Indri", "suffix": ""}], "year": 1977, "venue": "IEEE Trans. Ind. Appl", "link": "6038952"}, "BIBREF11": {"title": "From 1981 to 1983, he was a Visiting Scholar at the _ 5-_ University of Wisconsin-Madison, working with T. A. Lipo and D. W. Novotny. His areas of interest include design and control of electrical machines, ac drives and electromagnetic field in electrical machines", "authors": [{"first": "X", "middle": [], "last": "Feng", "suffix": ""}], "year": 1938, "venue": "Wang was born in Shandong Province, the People's Republic of China on February", "link": null}}, "ref_entries": {}}
{"paper_id": "17787429", "_pdf_hash": "c4b83b6e7ce767f6d6353ca5b768c94517afc129", "abstract": [], "body_text": [{"section": "", "text": "There are at least two distinct patterns of reaction in the peripheral nerves in cases of peripheral neuropathy. Axonal degeneration or segmental demyelination (or both) may occur and their histological appearances are now well known. Disorders associated with primary destruction of axis cylinders include the classical example of Wallerian degeneration, and the latter, sometimes termed 'Schwann cell diseases', includes the neuropathies of diabetes mellitus and metachromatic leucodystrophy (Dayan, 1967) .", "cite_spans": [{"start": 494, "end": 507, "text": "(Dayan, 1967)", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "", "text": "We have recently studied one family in which peripheral neuropathy has occurred in members of three generations, and another unrelated family only one member of which was definitely affected. Nerve biopsies from both families have shown both axonal destruction and segmental demyelination associated with unique features of Schwann cell dysfunction.", "cite_spans": [], "ref_spans": []}, {"section": "MATERIAL AND METHODS", "text": "Under local anaesthesia, a sural nerve and peroneus brevis muscle were biopsied. For light microscopy they were fixed in buffered formol saline and paraffin and frozen sections cut and stained by conventional methods. Isolated fibres were 'teased' from the nerve by freehand dissection after post-fixation in 10% osmic acid and maceration in 60% glycerine (Dayan, 1967) . The internodal lengths and diameters of such fibres were measured directly with a micrometer eyepiece at magnifications of x 100 and x 950 respectively. Part of the sural nerve of Case 1 was post-fixed in 1 % osmic acid and the number of myelinated fibres and their diameters were measured directly in transverse sections at a magnification of x 950, with the aid of a Fleming Particle Size Micrometer and Analyser, Type 526 (Fleming Instrument Co. Ltd., Stevenage, U.K.).", "cite_spans": [{"start": 356, "end": 369, "text": "(Dayan, 1967)", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "MATERIAL AND METHODS", "text": "For electron microscopy, small pieces of nerve were post-fixed in buffered osmic acid and embedded in Epikote. Ultra-thin sections stained with lead citrate and uranyl acetate were examined in an AEI 'EM6' electron microscope. FAMILY HISTORY This is shown in Figure 1 . The index patient (III.9), of our study, had three live children, one of whom (IV.7), was also affected and forms Case 2 of this report.", "cite_spans": [], "ref_spans": []}, {"section": "MATERIAL AND METHODS", "text": "The mother (II.8) of the propositus was 85 years old when examined and considered herself to be in good health, although for many years her feet 'turned in' when she walked.", "cite_spans": [], "ref_spans": []}, {"section": "MATERIAL AND METHODS", "text": "On examination of the cranial nerves she had bilateral nerve deafness. A semi-quantitative analysis of the relationship between internodal lengths and diameter of individual fibres is shown in Fig. 6 , displayed by the convention of Fullerton, Gilliatt, Lascelles, and Morgan-Hughes (1965 It shows a wide scatter of segmental lengths most of which are much shorter than the normal value for fibres of that particular diameter. Some fibres contained some short segments and others of normal length. These changes are characteristic of segmental de-and remyelination and of regeneration after axonal degeneration Thomas and Lascelles, 1966) . and their associated myelin sheaths were seen, in many fields the sheaths were abnormal (Fig. 7b) develop normally for the first few months of his life. However, motor development was retarded and when he began to walk at the age of 13 months it was noticed that his right foot would frequently 'turn in' when he stood on it. He has needed calipers for walking since the age of 18 months. Examination showed a young child of normal habitus except for marked wasting of the legs below the knees. His hands, arms, trunk, and girdle muscles appeared normal. He had weakness of all muscle groups in his legs which were flaccid. The motor weakness was most severe distally with, for example, foot drop and only slight weakness of the quadriceps. There was pes cavus deformity of both feet. Tendon reflexes seemed normal in the arms, but could not be elicited in the legs. Sensation appeared normal in the arms, but there was undoubted hypoaesthesia in the legs below knee level, with diminished perception of vibration, joint position, heat and cold. Peripheral nerves did not feel thickened.", "cite_spans": [{"start": 611, "end": 638, "text": "Thomas and Lascelles, 1966)", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "MATERIAL AND METHODS", "text": "Conduction velocities in the right median nerve (15 m/sec) in the forearm and in the right lateral popliteal nerve (10 m/sec) were very slow.", "cite_spans": [], "ref_spans": []}, {"section": "MATERIAL AND METHODS", "text": "Laboratory investigations were all normal including full blood count, liver function tests, and estimation of serum proteins. Phytanic acid was not detected in his serum (Professor J. N. Cumings).", "cite_spans": [], "ref_spans": []}, {"section": "MATERIAL AND METHODS", "text": "Biopsy was attempted of the right sural nerve but only a small fascicle of it was obtained. The peroneus brevis muscle was also biopsied.", "cite_spans": [], "ref_spans": []}, {"section": "MATERIAL AND METHODS", "text": "HISTOLOGICAL FINDINGS (a) Nerve It was only possible to prepare paraffin sections in which the myelin sheaths appeared normal and one degenerating axis cylinder was found (Fig. 8) .", "cite_spans": [], "ref_spans": []}, {"section": "MATERIAL AND METHODS", "text": "(b) Peroneus brevis muscle This appeared normal. FAMILY HISTORY Both parents of the patient were said to be normal and so were his brother (his only sib), his wife, and both of his children, although the youngest, now aged 2 years, has not yet learned to walk.", "cite_spans": [], "ref_spans": []}, {"section": "MATERIAL AND METHODS", "text": "PAST HISTORY His birth was difficult and he was cyanosed for a while. There appeared to be no immediate sequelae of this, but he did not learn to walk until he was 5 years old and his hands were weak and clumsy. These symptoms were unchanged when he was examined at the age of 11 years. At that time there was generalized weakness of the thighs and lower legs and he walked with a steppage gait. Hand muscles also were weak and wasted, but other muscle groups appeared normal. All tendon reflexes were absent and the plantar responses were flexor. No sensory abnormalities were found. PRESENT CONDITION The patient was not seen again until February 1968, aged 26 years, when he thought his condition has been unchanged for some time. Although his hands and legs were still weak, he could run, swim, ride a bicycle, and was employed as an engineeringfitter. In September 1966 he had first noticed tingling and numbness of the tips of his fingers which made him drop things. The numbness had developed over a few weeks and had since persisted unchanged. There had been no sensory symptoms in the feet.", "cite_spans": [], "ref_spans": []}, {"section": "MATERIAL AND METHODS", "text": "On examination in May 1967, there was impaired sensation to touch and pain in all the fingers to the level of the palms, and wasting of the small muscles of the hands. The hip flexors were weak and so were the extensors and flexors of the toes. The tendon reflexes and plantar responses could not be elicited. The calf and hand muscles were tender.", "cite_spans": [], "ref_spans": []}, {"section": "MATERIAL AND METHODS", "text": "Electrophysiological studies showed very slow conduction velocities in both the right and left ulnar nerves (21 and 23 m/sec respectively). The left median nerve was inexcitable. In the hand muscles and anterior tibial muscles electromyography showed fibrillation potentials at rest and a reduced interference pattern on volition.", "cite_spans": [], "ref_spans": []}, {"section": "MATERIAL AND METHODS", "text": "Lumbar cerebrospinal fluid contained protein 70 mg/ 100 ml. Glucose and pyruvate tolerance tests, serum W.R., serum B12, and the serum creatine phosphokinase (32 i.u./l.) were all normal. The right sural nerve and peroneus brevis muscle were biopsied. PROGRESS He was considered to have polyneuritis and was treated with prednisone 20 mg daily for four weeks.", "cite_spans": [], "ref_spans": []}, {"section": "MATERIAL AND METHODS", "text": "By the end of the course of steroid the paraesthesiae and numbness in the fingers had disappeared, but the patient thought that his hands were weaker than before. When last seen in August 1967 his condition was unchanged.", "cite_spans": [], "ref_spans": []}, {"section": "MATERIAL AND METHODS", "text": "HISTOLOGICAL FINDINGS (a) Sural nerve biopsy The lesions observed were very similar to those seen in Case 1, with severe loss of nerve fibres, marked endoneurial fibrosis and the presence in the nerve of occasional ovoids of myelin-like material. Isolated, teased fibres had a bizarre 'beaded' appearance due to the presence on them of osmiophilic globules (Fig. 9) . There was extensive segmental de-and remyelination, and osmiophilic globules of various sizes were present along the internodes. FIG. 9. Case 3. Consecutive lengths ofa singlefibre from the sural nerve. There is veryextensive demyelination, sometimes extending over several segments, and densely-stained globules are also present. (Osmic-acid, x 100.)", "cite_spans": [], "ref_spans": []}, {"section": "MATERIAL AND METHODS", "text": "There was no inflammatory infiltration in the nerve and its blood vessels appeared normal.", "cite_spans": [], "ref_spans": []}, {"section": "MATERIAL AND METHODS", "text": "The relationship between fibre diameter and internodal length was measured, and the results, plotted according to the convention of Fullerton et al. (1965) , are shown in Figure 10 . Large numbers of fibres bore inappropriately short segments which are typical of regeneration after axonal degeneration, and the wide scatter of intemodal lengths confirms the many observations of demyelinated and healing segments.", "cite_spans": [{"start": 132, "end": 155, "text": "Fullerton et al. (1965)", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "MATERIAL AND METHODS", "text": "Electron microscopy There was severe endoneurial fibrosis and many nerve fibres were represented by thick bundles of collagen fibres with a central core of an abnormal nerve fibre. No true coils or whorls of Schwann cells were found (Fig. 11) .", "cite_spans": [], "ref_spans": []}, {"section": "MATERIAL AND METHODS", "text": "The majority of axis cylinders appeared normal but a few showed focal collections of mitochondria and small vesicles. Some large axons had very thin myelin sheaths and were probably undergoing remyelination. As in Case 1, Schwann cells appeared normal apart from their enveloped multi-layered globular inclusions, apparently derived from nearby degenerating myelin. The globules appeared to lie outside the main bulk of the Schwann cell cytoplasm, but were almost certainly connected to it by continuity of plasma membrane until degeneration was well established. This was shown in a few instances by finding globules which were enclosed by a few of the outer turns of the myelin sheath. Many Schwann cells, whether bearing normal or abnormally thin myelin sheaths, contained large cytoplasmic multilaminated osmiophilic ovoids typical of 'myelin figures'.", "cite_spans": [], "ref_spans": []}, {"section": "MATERIAL AND METHODS", "text": "(b) Peroneus brevis muscle biposy There was marked neurogenic atrophy of the muscle. No intra-muscular nerves were found.", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "Members of three generations of family A and one member of the unrelated family B have suffered from a peripheral sensori-motor neuropathy. In ave not examined personally, also has a internodes of normal length and the short segments of Although the main clinical signs were healed demyelination implying that Schwann cell ,tor system, there were also sensory damage may occur independently of lesions to the s, and pathological lesions were demon-axis cylinders which they envelop. both motor and sensory nerves in the The multi-lamellated, myelin-like structure of the nerve biopsies.", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "globules suggests that they consist of complex ological position of this disorder is not phospholipids and this is supported by their staining we suggest it be given the description of reactions. The electron microscope evidence, which uropathy' until its relationship with other showed apparent continuity of globules and normal s has been clarified. Clinically it appears myelin sheath, suggests two possible ways at least y to resemble the variety of peroneal in which they could arise. Firstly, as the globules trophy with sensory loss as described, appear to be breakdown products of myelin there , by England and Denny-Brown (1952) c. Globule lying within myelin sheath (x 7,500).", "cite_spans": [{"start": 607, "end": 637, "text": "England and Denny-Brown (1952)", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "DISCUSSION", "text": "Insert shows myelin-like lamination ofglobule at higher magnification (x 50,800).", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "sheaths by the chronic degeneration of nerve fibres. If this hypothesis is applicable to GN, the metabolic defect in this disease, either sporadic or inherited in its expression, has at least two effects on nerve fibres because it appears to have caused both destruction of axis cylinders and the defective removal of myelin debris which has resulted in the formation of 'globules'. The three patients described seem to be examples of a disease of the peripheral nervous system in which both axons and their Schwann cell-myelin sheaths are damaged. Such effects of disease are perhaps more commonly recognized in the central nervous system where they sometimes appear to be due to a single genetic metabolic defect. It will be of great theoretical and practical interest ifa comparable enzymatic failure can be found also in globular neuropathy.", "cite_spans": [], "ref_spans": []}, {"section": "SUMMARY", "text": "Members of three generations of one family and one member of another suffered from a progressive peripheral sensorimotor neuropathy.", "cite_spans": [], "ref_spans": []}, {"section": "SUMMARY", "text": "Study of sural nerve biopsies from two cases showed axonal degeneration, segmental de-and remyelination and incorporation of bizarre globules of complex phospholipids into the myelin sheaths.", "cite_spans": [], "ref_spans": []}, {"section": "SUMMARY", "text": "It is suggested tentatively that the families have a metabolic disorder, possibly inherited, which has produced chronic axonal degeneration and damage to myelin sheaths. There also appears to be either defective degradation of myelin by the Schwann cells of demyelinating segments or an abnormal myelin formed initially may resist breakdown along the usual paths.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Cellulo-radiculopathies chroniques", "authors": [{"first": "Th", "middle": [], "last": "Alajouanine", "suffix": ""}, {"first": "J", "middle": [], "last": "Nick", "suffix": ""}, {"first": "F", "middle": [], "last": "Contamin", "suffix": ""}, {"first": "H.-P", "middle": [], "last": "Cathala", "suffix": ""}, {"first": "M.-H", "middle": [], "last": "Nicolle", "suffix": ""}, {"first": "Ph", "middle": [], "last": "Penther", "suffix": ""}], "year": 1962, "venue": "Rev. neurol", "link": null}, "BIBREF1": {"title": "The significance of the 'dying back' process in experimental and human neurological disease", "authors": [{"first": "J", "middle": ["B"], "last": "Cavanagh", "suffix": ""}], "year": 1964, "venue": "Int. Rev. exp. Path", "link": "45370130"}, "BIBREF2": {"title": "Changes in nerve conduction in experimental allergic neuritis", "authors": [{"first": "B", "middle": ["G"], "last": "Cragg", "suffix": ""}, {"first": "P", "middle": ["K"], "last": "Thomas", "suffix": ""}], "year": 1964, "venue": "J. Neurol. Neurosurg. Psychiat", "link": "10822512"}, "BIBREF3": {"title": "Peripheral neuropathy of metachromatic leucodystrophy: observations on segmental demyelination and remyelination and the intracellular distribution of sulphatide", "authors": [{"first": "A", "middle": ["D"], "last": "Dayan", "suffix": ""}], "year": 1967, "venue": "Ibid", "link": "25799491"}, "BIBREF4": {"title": "Histologic and teased-fiber measurements of sural nerve in disorders of lower motor and primary sensory neurons", "authors": [{"first": "P", "middle": ["J"], "last": "Dyck", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Gutrecht", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Bastron", "suffix": ""}, {"first": "W", "middle": ["E"], "last": "Karnes", "suffix": ""}, {"first": "A", "middle": ["J D"], "last": "Dale", "suffix": ""}], "year": 1968, "venue": "Mayo Clin. Proc", "link": "39989011"}, "BIBREF5": {"title": "Severe sensory changes and trophic disorder in personeal muscle atrophy (CharcotMarie-Tooth type)", "authors": [{"first": "A", "middle": ["C"], "last": "England", "suffix": ""}, {"first": "D", "middle": [], "last": "Denny-Brown", "suffix": ""}], "year": 1952, "venue": "Arch. Neurol", "link": null}, "BIBREF6": {"title": "The relation between fibre diameter and internodal length in chronic neuropathy", "authors": [{"first": "P", "middle": ["M"], "last": "Fullerton", "suffix": ""}, {"first": "R", "middle": ["W"], "last": "Gilliatt", "suffix": ""}, {"first": "R", "middle": ["G"], "last": "Lascelles", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Morganhughes", "suffix": ""}], "year": 1965, "venue": "J. Physiol", "link": null}, "BIBREF7": {"title": "Changes due to age in internodal length in the sural nerve in man", "authors": [{"first": "R", "middle": ["G"], "last": "Lascelles", "suffix": ""}, {"first": "P", "middle": ["K"], "last": "Thomas", "suffix": ""}], "year": 1966, "venue": "J. Neurol. Neurosurg., Psychiat", "link": "5348431"}, "BIBREF8": {"title": "The pathology of diabetic neuropathy. Quart", "authors": [{"first": "P", "middle": ["K"], "last": "Thomas", "suffix": ""}, {"first": "R", "middle": ["G"], "last": "Lascelles", "suffix": ""}], "year": 1966, "venue": "J. Med", "link": null}, "BIBREF9": {"title": "Diphtheritic neuropathy in the chicken: An electron-microscope study", "authors": [{"first": "R", "middle": [], "last": "Weller", "suffix": ""}], "year": 1965, "venue": "Acid phosphatase and lysosome activity in diphtheritic neuropathy and Wallerian degeneration", "link": "35691834"}}, "ref_entries": {"FIGREF0": {"text": "FIG. 7B. Case 1. Longitudinal section of sural nerve. There is a node of Ranvier on the left. On the right several coiled, multilamellated accumulations of osmiophilic, myelin-like material lie within the myelin sheath. (x 2,500.)", "type": "figure"}, "FIGREF1": {"text": "FIG. 10. Cas sural nerve.", "type": "figure"}, "TABREF0": {"text": "5This work forms part of an M.D. thesis submitted by A.D.D. to the University of London. 'Present address: National Hospital for Nevrous Diseases, London.A male clerical worker (Neurological Centre No. 2515) aged 52 years had for 15 years noticed progressive weakness of his left foot. The right foot and both hands had been affected for about five years. On examination, the patient had normal facies, moderate thoracic kyphosis, marked wasting of all distal muscle groups in the lower forearms, calves and feet, and relatively good preservation of proximal limb and girdle muscles. He had mild pes cavus. His hand grip and small hand muscles were weak, and he had difficulty in walking both on the level and up stairs. He had considerable weakness of dorsiflexion and eversion of the feet and of dorsiflexion of the toes. Distal to the elbow and knees there was severe diminution of all modalities of sensation, including joint position and vibration senses and per- ception of pain and temperature. The tendon reflexes and plantar responses were absent. Peripheral nerves did not feel thickened. There was no nystagmus or cerebellar ataxia. The feet were not ulcerated. General physical examination and the ECG were normal. Conduction velocities in the right median and left ulnar nerves were reduced to 18 m/sec. Laboratory investigations were all normal including blood count, liver function tests and electrophoresis of serum proteins. Phytanic acid was not detected in his serum (Professor J. N. Cumings).", "type": "table"}, "TABREF1": {"text": "III.13, and IV.8 all of whom seemed normal. Conduction velocity in the right lateral popliteal nerve of 11.7 was normal. The right sural nerve and peroneus brevis muscle of Case 1 were biopsied. HISTOLOGICAL FINDINGS (a) Sural nerve There was severe loss of normal myelinated axons, marked endo- neurial fibrosis, and an excess of fine, unmyelinated fibres. In frozen sections there was a small number of what appeared to be ovoids of myelin-like material (Fig. 2) which stained magenta by the periodic acid-Schiff technique, black with Sudan black B, weak orange with Sudan m, and showed birefringence in polarized light. The fibre spectrum in a transverse section showed a severe loss of nerve fibres and a relative excess of small ones (Fig. 3). Teased fibres presented a bizarre appearance. Instead of normal myelinated segments of constant thickness", "type": "table"}, "TABREF3": {"text": "thin sheath of Schwann cell cytoplasm and lacked a recognizable myelin sheath. A very few hemi-nodes of Ranvier were also found in which the other half of the node was lacking, although a virtually normal axis cylinder was still present. These changes were interpreted as evidence of segmental demyelination. Although in some areas normal appearing Schwann cells mm4labk.-,.", "type": "table"}, "TABREF4": {"text": ". They had ..:.. .. expanded into swellings containing electron dense whorls and dense droplets of such complexity as to make their exact morphological relationships difficult to determine. Schwann cells generally had nuclei of normal appearance -;. i .... .: - which were surrounded by a variable amount of cytoplasm ..... .... containing the usual organelles and a small amount of ...-. X W ; .........endoplasmic reticulum. There was no obvious increase in lysosome-like structures. The complex globules of.....ll altered myelin impinged closely on perinuclear Schwann cell cytoplasm, axis cylinder, and the surrounding fibrous . ....:::. .... 4 , ,tissue. Sometimes their myelin lamellae appeared to run Ill ...... .. -; 4 t 4 4 ,through an area of debris to join a normal myelin sheath .............. ,on the other side. The swellings were considered to be the globules seen .__No definite lesion was seen in the few small intramuscular Fibre diameter (Is) nerves present in the biopsy. FIG. 6. Case 1. Graphical analysis of fibres from the sural nerve by the method ofFullerton et al. (1965). Shaded area encloses normal mean and 950% confidence limits (Thomas and Lascelles, 1966). Each vertical line represents one nerve fibre. The very wide scatter of points shows the effects ofsegmental demyelination and axonal degeneration and healing.This patient (Neurological Centre No. 3069) was the 4-year-old son of Case 1 (IV.7 of Fig. 1). After an uneventful pregnancy and birth the child seemed to", "type": "table"}, "TABREF6": {"text": "case and GN which it resembles superficially, but they may not be the same disease because of the ... relatively short duration of the illness in their .'I| patient and because the illustrations of teased . ........ ..... fibres (their Fig. 7) show only a few small masses of the myelin debris such as may be found in any ;i', .. active demyelinating neuropathy. We have not ;. ........seen histological appearances like those of GN in .........appeared to be inherited perhaps by an devoid of any stainable myelin sheath. The majority lominant gene with variable expression. of naked segments were very short suggesting that ir yet whether Case 3 is the only affected they were on fibres which had regenerated after family B, or whether one of his children, axonal degeneration. Some fibres carried both", "type": "table"}, "TABREF7": {"text": ", might be a defect in the early stages of its degrada- ith more prominent hypoaesthesia. The tion. No numerical increase was seen in structures otor involvement and the lesser degree of with the morphological appearance of lysosomes the sensory systems make globular which are involved in myelin degradation in other (GN) unlike any of the variants of demyelinating diseases of peripheral nerves (Weller, ensory neuropathy including the forms 1965; Weller and Mellick, 1966), but it is still signs described by Alajouanine, Nick, possible that the enzymatic degradation of myelin Cathala, Nicolle, and Penther (1962). is abnormal. Or, perhaps the myelin being broken *echt, Bastron, Karnes, and Dale (1968) down has an abnormal composition which slows its fibres from the sural nerve of a 51-year-removal. eir Case 73-67) who had had a peripheral The concurrence of segmental de-and remyelin- for five years. The nerve fibres showed ation in conditions of chronic axonal degeneration healed Schwann cell damage and some has been reviewed by Dayan, Graveson, Illis, and amps of osmiophilic debris attached to Robinson (in preparation). They concluded that in sheaths. Insufficient information is given such disorders there is circumstantial evidence of an efinitely the relationship between their immune reaction against myelin-Schwann cell FIG. 1 1. Case 3. Sural nerve. Electron micrographs. a. Transverse section showing loss of myelinated nerve fibres, endoneurial fibrosis and one fibre partly enveloped by a globule (approximately x 1,200). .4i- b. Laminated debris are partly enclosed by the normal myelin sheath which forms decompacted loops at the node ofRanvier on the left. The axis cylinder appears normal ( x 8,000).", "type": "table"}}}
{"paper_id": "17787510", "_pdf_hash": "ffe8650fe1c99a2793f8475c569c6efcdc099d3a", "abstract": [], "body_text": [], "bib_entries": {"BIBREF1": {"title": "Impact of Human Mobility on the Design of Opportunistic Forwarding Algorithms, INFOCOM", "authors": [{"first": "Augustin", "middle": [], "last": "Chaintreau", "suffix": ""}, {"first": "Pan", "middle": [], "last": "Hui", "suffix": ""}, {"first": "Jon", "middle": [], "last": "Crowcroft", "suffix": ""}, {"first": "Christophe", "middle": [], "last": "Diot", "suffix": ""}, {"first": "Richard", "middle": [], "last": "Gass", "suffix": ""}, {"first": "James", "middle": [], "last": "Scott", "suffix": ""}], "year": 2006, "venue": "", "link": "9434270"}, "BIBREF3": {"title": "Multi-hop Ad Hoc Networking: the theory", "authors": [{"first": "M", "middle": [], "last": "Conti", "suffix": ""}, {"first": "S", "middle": [], "last": "Giordano", "suffix": ""}], "year": 2007, "venue": "", "link": null}, "BIBREF4": {"title": "Multi-hop Ad Hoc Networking: the reality, IEEE Communication Magazine", "authors": [{"first": "M", "middle": [], "last": "Conti", "suffix": ""}, {"first": "S", "middle": [], "last": "Giordano", "suffix": ""}], "year": 2007, "venue": "", "link": null}, "BIBREF5": {"title": "Haggle: A Networking Architecture Designed Around Mobile Users", "authors": [{"first": "Pan", "middle": [], "last": "Ames Scott", "suffix": ""}, {"first": "Jon", "middle": [], "last": "Hui", "suffix": ""}, {"first": "Christophe", "middle": [], "last": "Crowcroft", "suffix": ""}, {"first": "", "middle": [], "last": "Diot", "suffix": ""}], "year": 2006, "venue": "", "link": null}, "BIBREF6": {"title": "Uppsala team, Haggle mailing list", "authors": [], "year": 2007, "venue": "", "link": null}, "BIBREF7": {"title": "Mobility Increases the Capacity of Ad hoc Wireless Networks", "authors": [{"first": "Matthias", "middle": [], "last": "Grossglauser", "suffix": ""}, {"first": "N", "middle": ["C"], "last": "David", "suffix": ""}, {"first": "", "middle": [], "last": "Tse", "suffix": ""}], "year": 2002, "venue": "IEEE/ACM Transactions on Networking", "link": "8878742"}, "BIBREF8": {"title": "Enhanced DHCP Client", "authors": [{"first": "S", "middle": [], "last": "Giordano", "suffix": ""}, {"first": "D", "middle": [], "last": "Lenzarini", "suffix": ""}, {"first": "A", "middle": [], "last": "Puiatti", "suffix": ""}, {"first": "S", "middle": [], "last": "Vanini", "suffix": ""}], "year": 2007, "venue": "ACM Mobicom/CHANTS", "link": "12271132"}, "BIBREF9": {"title": "RFC 2131 -Dynamic Host Configuration Protocol", "authors": [{"first": "R", "middle": [], "last": "Droms", "suffix": ""}], "year": 1997, "venue": "", "link": "59924905"}, "BIBREF10": {"title": "Probabilistic Routing Protocol for Intermittently Connected Mobile Ad hoc Networks (PROPICMAN)", "authors": [{"first": "H", "middle": ["A"], "last": "Nguyen", "suffix": ""}, {"first": "S", "middle": [], "last": "Giordano", "suffix": ""}, {"first": "A", "middle": [], "last": "Puiatti", "suffix": ""}], "year": 2007, "venue": "IEEE AOC", "link": "12415538"}}, "ref_entries": {}}
{"paper_id": "17787527", "_pdf_hash": "ce71771aa44ada303e62b2362f89652b1cad68f5", "abstract": [{"section": "Abstract", "text": "In recent years there has been an increased focus upon developing platforms for community decision-making, and an awareness of the importance of handing over civic platforms to community organisations to oversee the process of decision-making at a local level. In this paper, we detail fieldwork from working with two community organisations who used our distributed situated devices as part of consultation processes. We focus on some of the mundane and often-untold aspects of this type of work: how questions for consultations were formed, how locations for devices were determined, and the ways in which the data collected fed into decision-making processes. We highlight a number of challenges for HCI and civic technology research going forward, related to the role of the researcher, the messiness of decision making in communities, and the ability of community organisations to influence how citizens participate in democratic processes.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "INTRODUCTION", "text": "It is well acknowledged that HCI research has a significant role to play in understanding how digital technology can facilitate and support new forms of civic engagement. Over the last five years, we have seen a wealth of work where technology has been used as a means for collecting community opinion [28, 45] to support community activists and community organisations to gather data [47] and facilitate discussion around political decision making [11] .", "cite_spans": [{"start": 302, "end": 306, "text": "[28,", "ref_id": "BIBREF32"}, {"start": 385, "end": 389, "text": "[47]", "ref_id": "BIBREF54"}, {"start": 449, "end": 453, "text": "[11]", "ref_id": "BIBREF11"}], "ref_spans": []}, {"section": "INTRODUCTION", "text": "These emerging landscapes for HCI research typically require extensive working with and within communities [13, 44] , and often come laden with ideals around supporting new forms of democracy and participation in civic life. Furthermore, it involves placing greater emphasis not on just designing systems to collect public opinion, but to design systems for citizens, civic groups and local government to collect public opinion from others.", "cite_spans": [{"start": 107, "end": 111, "text": "[13,", "ref_id": "BIBREF15"}, {"start": 112, "end": 115, "text": "44]", "ref_id": "BIBREF51"}], "ref_spans": []}, {"section": "INTRODUCTION", "text": "In this paper, we build on this prior work by detailing our experiences of collaborating with community organisations who used our 'Viewpoint' situated consultation technologies. We discuss fieldwork from two collaborative projects where our voting devices have been deployed to collect opinion on specific issues at different stages of campaigns and participatory governance exercises. Rather than focusing primarily on an evaluation of Viewpoint 'in use', we highlight the various trade-offs and decisions made before, and the making sense and use of collected data following deployment of the devices. Following [13, 14, 15] we highlight some of the human work that goes into planning and overseeing the use of consultation technologies for community organisations, and the ways in which the research team guided and influenced this process. Our reflections on this fieldwork highlight specific issues related to: the forming of the right questions to be posed on the devices; the identification of and gaining access to the right locations for promoting engagement and discussion; and the difficulties community organisations face in using and responding to the data and insights collected through novel consultation technologies.", "cite_spans": [{"start": 615, "end": 619, "text": "[13,", "ref_id": "BIBREF15"}, {"start": 620, "end": 623, "text": "14,", "ref_id": "BIBREF17"}, {"start": 624, "end": 627, "text": "15]", "ref_id": "BIBREF18"}], "ref_spans": []}, {"section": "INTRODUCTION", "text": "Our contributions to the developing HCI discourse surrounding civics technology are two-fold. First, through rich ethnographic insights we highlight stakeholder (researcher and community partner) influence and responsibilities in deployments of community consultation technologies. Second, based on our two case studies, we highlight challenges and opportunities for HCI researchers working with communities and civic organisations, while problematising the perceived neutrality of community consultation technologies in contexts where only a privileged few set the questions, situate the devices and have access to the data.", "cite_spans": [], "ref_spans": []}, {"section": "HCI AND THE CIVIC TURN", "text": "The field of HCI has for many years dealt with issues to do with civic action, engagement and participation. A huge amount of work within the CSCW and CHI communities has examined how social media services are appropriated for civic discourse [11] , information sharing [42] , activism [30] , protest [46] , and action [25, 39] . Alongside studying the role of technology in relation to issues of civic importance, there has been increased attention paid to conducting in-the-wild studies of systems in community and civic contexts. Going back over 15 years, projects such as Civic Nexus [34] and CiVicinity [5] have highlighted the benefits of closely collaborating with communities to create Participatory design and systems that connect local actors and transform practices in voluntary and community sector organisations. More recently, a number of studies have explored how technology can support new forms of community engagement and participation in local decisionmaking. Much of this work has focused upon the evaluation of situated displays in public places to engage citizens in voting, consultation, and other forms of sharing and contributing to such processes (e.g. [8, 20, 22, 24, 43] ). For example, ongoing work in Oulu, Finland, has articulated the value of interactive public displays in engaging members of the public in commentating and giving feedback on planning proposals [23] . Taking a different approach, in the Bespoke project, Taylor et al. [45] deployed their Viewpoint technology as a simple means for local government representatives to set questions for community members to respond to. The ambition here was to promote wider participation, and a sense of increased efficacy, for community residents. Koeman et al. [28] took an approach to distributing voting boxes at multiple locations around communities. Again, like Taylor et al. [45] , they harness lightweight forms of engagement to promote participation in opinion sharing-however, they took a further step in visualising the results on a location-by-location basis, as well as in a 'neutral' ground, which promoted wider discussion around the contrasts and divisions within the community itself.", "cite_spans": [{"start": 243, "end": 247, "text": "[11]", "ref_id": "BIBREF11"}, {"start": 270, "end": 274, "text": "[42]", "ref_id": "BIBREF49"}, {"start": 286, "end": 290, "text": "[30]", "ref_id": "BIBREF34"}, {"start": 301, "end": 305, "text": "[46]", "ref_id": "BIBREF53"}, {"start": 319, "end": 323, "text": "[25,", "ref_id": "BIBREF29"}, {"start": 324, "end": 327, "text": "39]", "ref_id": "BIBREF43"}, {"start": 588, "end": 592, "text": "[34]", "ref_id": "BIBREF38"}, {"start": 608, "end": 611, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 1179, "end": 1182, "text": "[8,", "ref_id": "BIBREF8"}, {"start": 1183, "end": 1186, "text": "20,", "ref_id": "BIBREF23"}, {"start": 1187, "end": 1190, "text": "22,", "ref_id": "BIBREF26"}, {"start": 1191, "end": 1194, "text": "24,", "ref_id": "BIBREF28"}, {"start": 1195, "end": 1198, "text": "43]", "ref_id": "BIBREF50"}, {"start": 1395, "end": 1399, "text": "[23]", "ref_id": "BIBREF27"}, {"start": 1747, "end": 1751, "text": "[28]", "ref_id": "BIBREF32"}], "ref_spans": []}, {"section": "HCI AND THE CIVIC TURN", "text": "For a long time, the participatory design and community informatics literature-along with wider participatory research scholarship-has discussed, articulated and debated the challenges involved in working with community organisations and facilitating new practices and processes [2, 6, 34] . Issues such as these are becoming of increasing importance to the HCI scholarship on civic and community technology. This is especially so, given that HCI researchers are no longer just deploying technologies for opinion gathering and consultation-rather, in many respects, they are aiming to support others in developing such practices. This is particularly recognisable in Vlachokyriakos et al's [47] work on PosterVote, where the ambition was to build platforms to be appropriated and deployed by activists, rather than deploying it and evaluating it on their behalf. Beyond the technical and design features of the system under study, PosterVote raised questions related to the governance and ownership of the data collected and the influence of activists groups on the way people voted. In their work on crowdsourced cycling data, LeDantec et al. [12] noted issues of the provenance, legibility and meaningfulness of data generated by publics to those making planning decisions. Taylor et al. [43] -also raising issues of who owns and accesses communitygenerated data-note the ways in which residents make data meanigful by placing it into context. They also note the important role the research team played as a percieved neutral party to support dialogue and sensemaking around community-generated data, as well as providing the necessary skills and expertise to install and maintain devices and related infrastructures and archives. This is echoed by [44] who discuss the critical importance of building relationships with local residents and lead community members through the duration of projects and ensure skills and infrastructure are in place to sustain endeavours beyond the completion of the research project. In a similar vein, Hosio et al. [27] discuss the percieved value of situated displays in civic and community contexts, highlighting the range of additional costs and burdens they bring to the local government organisations who use them.", "cite_spans": [{"start": 279, "end": 282, "text": "[2,", "ref_id": "BIBREF1"}, {"start": 283, "end": 285, "text": "6,", "ref_id": "BIBREF5"}, {"start": 286, "end": 289, "text": "34]", "ref_id": "BIBREF38"}, {"start": 690, "end": 694, "text": "[47]", "ref_id": "BIBREF54"}, {"start": 1144, "end": 1148, "text": "[12]", "ref_id": "BIBREF13"}, {"start": 1290, "end": 1294, "text": "[43]", "ref_id": "BIBREF50"}, {"start": 1751, "end": 1755, "text": "[44]", "ref_id": "BIBREF51"}, {"start": 2050, "end": 2054, "text": "[27]", "ref_id": "BIBREF31"}], "ref_spans": []}, {"section": "HCI AND THE CIVIC TURN", "text": "These examples in different ways pose questions about the responsibilities of different stakeholders in civic technology contexts where decision-making is a primary concern. They also raise issues related to the role of the researcher in these contexts, and whether they have a responsibility to not just to provide new tools with which to consult but also help organisations and individuals develop the skills, resources, capacity and practices to use these in a meaningful and sustainable manner. We build on the above by discussing our experiences of conducting field trials of distributed, multi-site community consultation technologies with two communty organisations. These deployments were intended to be led by our partners, as we will highlight, however, our community partners faced a number of conceptual and practical challenges in planning, overseeing and making sense of the insights from these deployments. Through our discussion of these projects we will highlight the ways in which the research team played an important role in carefully guiding and, at times, explicitly directing and managing parts of these deployments.", "cite_spans": [], "ref_spans": []}, {"section": "OUR CONTEXT", "text": "Our work built on the prior work of Taylor et al [45] and their original Viewpoint system. In the following, we provide an overview of this original work, followed by how our projects and version of the technology builds upon it.", "cite_spans": [], "ref_spans": []}, {"section": "Viewpoint and the Bespoke Project", "text": "The original Viewpoint technology was developed as part of the Bespoke project. The overarching project explored issues to do with community cohesion and political disengagement in a small city in North West England. Viewpoint allowed local councillors and community As noted in [45] , the choice of a simple interface situated in a public space proved to be successful in gathering high quantities of feedback. Across a two-month deployment, eight different polls received an average of over two hundred votes each, an order of magnitude higher than original expectations. However, Viewpoint was less successful in creating the kind of positive feedback loop that had been intended. Community members remained sceptical of whether any change would occur, and few meaningful responses or promises of action were given by the local government collaborators. Having to work closely with councillors to help them formulate a question that was capable of being answered through a binary choice, the rapid turnover on questions, and the lack of actionable issues with a burning need for input made this difficult to achieve. As since discussed extensively by Harding et al. [26] , this exposed a failure to integrate with existing council processes that might have created avenues for change. This was compounded by the way that Viewpoint placed the agenda firmly in the hands of those in positions of power, with community members acting as passive respondents.", "cite_spans": [{"start": 1169, "end": 1173, "text": "[26]", "ref_id": "BIBREF30"}], "ref_spans": []}, {"section": "From Viewpoint 1 to Viewpoint 2", "text": "Findings from the original Viewpoint suggest a number of future possibilities that we chose to take forward. First, the use of short-term, targeted deployments would allow the device to be deployed only when specific input was needed and actionable. This might also take advantage of the novelty effects that had been observed. Second, situated voting technologies might be more closely tied into existing practices. This could mean integrating with council feedback schemes, but it may also mean putting Viewpoint in the hands of community organisations who are already engaged with local authorities. For the most part, this repositioning only requires a change in how the device is used. However, to better support new deployment contexts, we redesigned Viewpoint with a focus on flexibility and portability. The redesigned device ( Figure 1 ) allowed greater flexibility in how questions could be presented and responded to. It made use of a physical rotary control rather than buttons to allow voters to respond through multiplechoice answers or points on a sliding scale. It also supported voice and video input if required, along with a touch-screen display to be enabled as and when deemed appropriate. Additionally, the devices were made considerably smaller, with the intention that they might be more easily moved between different locations, and a 3G modem was added as a backup in situations where Wi-Fi could not be provided.", "cite_spans": [], "ref_spans": [{"start": 836, "end": 844, "text": "Figure 1", "ref_id": "FIGREF0"}]}, {"section": "From Viewpoint 1 to Viewpoint 2", "text": "We deployed the second generation of Viewpoint in two case studies, where the technology was used by community groups to elicit feedback on issues related to local planning and transportation developments. In the following sections we provide an overview of these case study contexts.", "cite_spans": [], "ref_spans": []}, {"section": "Case Study 1: Acorn Road", "text": "Our first case study involved working with the local chapter of an international movement that champions sustainable communities. When we approached them, the group were beginning to collect evidence to support the pedestrianisation of Acorn Road, a small shopping street that formed the centre of their neighbourhood. The group felt that the street was overly congested, making it dangerous for local pedestrians and cyclists who they felt most used the street, and that many of the cars could easily be re-routed to create a more pleasant environment.", "cite_spans": [], "ref_spans": []}, {"section": "Case Study 1: Acorn Road", "text": "The campaigners used the Viewpoint boxes to contribute to their ongoing consultations with people on Acorn Road. They developed two questions (discussed in the Findings) that were displayed on the devices for two weeks each, during the summer and during the autumn (to collect data from the student population). Three devices were deployed in the community: two in local supermarkets, with a third inside the neighbourhood's library. Simultaneously, the group carried out a street survey in which they stopped passers-by to ask a number of questions, one of which related to means of travel, and a traffic observation survey. Across the entire deployment, shoppers placed 2,040 votes in total. By contrast, the group's past attempts to collect feedback online had returned only a few dozen results.", "cite_spans": [], "ref_spans": []}, {"section": "Case Study 2: Ambit", "text": "Our second study was conducted in a small coastal town in Northern England comprised of approximately 6,000 residents. The town attracts large numbers visitors in the summer season and is currently experiencing major redevelopment, particularly in its harbour area. Beside this regeneration, which is primarily funded by the local Civic Tech, Participation and Society #chi4good, CHI 2016, San Jose, CA, USA government, there is significant private investment. The development within the town is primarily driven by a Local Development Trust (henceforth 'the Trust'). The Trust was set up two decades ago as a response to the perceived lack of opportunities for development and employment in the town. It is responsible for attracting funding grants for community projects. One requirement the Trust has is to carry out public consultation as part of its applications to receive grants, along with further consultation to then allocate the budgets associated with community projects.", "cite_spans": [], "ref_spans": []}, {"section": "Case Study 2: Ambit", "text": "Significantly, there is a feeling amongst many residents in the town that regeneration is often focused on tourism, excluding the needs of those who live there. This is further compounded by high-levels of unemployment and closure of local industry over the last several decades. As such, this has led to a lack of trust that local and central government will act in their interests. These issues were echoed by the Trust, which has noted a substantial decline in levels of engagement in recent years which they put down to a feeling of disfranchisement from some residents. This is problematised further by a feeling that the consultations they perform tend to attract the same group of people every time, and the setting of consultation events at a fixed time and place leaves many people unable to attend.", "cite_spans": [], "ref_spans": []}, {"section": "Case Study 2: Ambit", "text": "These were important motivators for the Trust in using Viewpoint devices in their application scoping and project allocation processes. They developed three questions (again, discussed in the Findings) that were displayed on four boxes during the summer of 2015. Four devices were deployed in different locations around the town in areas where they expected to capture feedback from local people who would normally not engage in their consultations. Across the deployment of the Viewpoint devices, people registered 699 responses in total, with a significant number of these votes coming from devices located in parts of the town rarely engaged with by the Trust.", "cite_spans": [], "ref_spans": []}, {"section": "METHOD", "text": "Initial contact with each group came via community engagement activities conducted by our research lab. The research team then met with each of the organisations to discuss their projects, modes of engagement and consultation, and the challenges they faced.", "cite_spans": [], "ref_spans": []}, {"section": "METHOD", "text": "During the Acorn Road deployments, the devices and the progress of the campaign were monitored by both a researcher and the campaign group, although the primary source of data collected was automated interaction logs. The researcher and campaign group maintained regular contact through the deployment. For Ambit, we expanded on this approach to place more focus on in-situ observations. Semi-structured interviews were conducted with four 'custodians' (people working in locations where devices were deployed). These interviews were audiorecorded and focused on the use of the device by others as perceived by the custodians. These were supplemented by observations where the researcher would 'hang around' [48] and note interactions with the device and events that occur in these spaces. The researcher talked with users of the devices to ask them about why they participated and their response to the ongoing results presented on Viewpoint.", "cite_spans": [{"start": 708, "end": 712, "text": "[48]", "ref_id": "BIBREF55"}], "ref_spans": []}, {"section": "METHOD", "text": "Overall, 84 hours of fieldwork observations were conducted and 22 conversations documented.", "cite_spans": [], "ref_spans": []}, {"section": "METHOD", "text": "Each trial ended with a semi-structured interview with the representatives of each community partner, as well as device custodians for Ambit, where we discussed consultation results and how they may use the data gathered. The data collected (transcriptions of interviews and field notes) was then used as a corpus for thematic analysis [3, 9] . Data coding was driven by questions related to how choices and decisions that impacted on the consultation process were made during the projects. Coding of data was shared between the first and second authors and checked by the third author. Codes were then clustered into the themes presented in this paper.", "cite_spans": [{"start": 336, "end": 339, "text": "[3,", "ref_id": "BIBREF2"}, {"start": 340, "end": 342, "text": "9]", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "FINDINGS", "text": "Our analysis generated five themes. We organise our themes to present a comparative narrative of how the two field trials played out over time.", "cite_spans": [], "ref_spans": []}, {"section": "Asking the Right Questions", "text": "A critical aspect of our engagements across each study was working with the community organisations to establish the types of questions to be posed on the devices. Learning from our prior projects with the older Viewpoint boxes, each of our case studies was tied in one form or another to pre-existing campaigns and consultation processes. However, the stages within these processes at which the Viewpoints were used were rather different-this shaped the discussions around what questions may be asked, and how they should be asked and responded to. As such, what was initially assumed to be a simple endeavour in setting questions to ask the public, became complex decisionmaking processes in their own right.", "cite_spans": [], "ref_spans": []}, {"section": "Asking the Right Questions", "text": "In Acorn Road, the choice of overriding topic was determined by the pre-existing campaign. As noted, the ambitions behind the campaign were to advocate for the pedestrianisation of a local street. Initially the organisation considered using Viewpoint to directly ask residents whether they thought the street should be pedestrianised, with the intention that this could be presented to the council like a petition. However, prior to deployment concerns were raised about this direct line of questioning:", "cite_spans": [], "ref_spans": []}, {"section": "Asking the Right Questions", "text": "\" This was a concern raised all the more by the fact that local businesses-who were opposed to pedestrianisation-were envisaged as being the most likely deployment locations, so some sensitivity was required. Instead, the group developed a new set of questions and possible responses that, as they articulated it, were more \"objective\" (Acorn Road campaigner). Two questions were asked: \"What has been your main means of travel today?\" followed by \"How far do you live from here?\" These questions sought to ascertain what percentage of the street's users were travelling by car and what proportion were local and might reasonably travel by foot or bicycle instead. The questions themselves were carefully chosen and reflected the many stakeholders that existed in this community issue. The decision to collect \"objective\" data about usage of the street rather subjective opinions about its future meant that data was felt to be unbiased (or, at least, less biased), and was envisaged as being taken more seriously by the complex range of actors involved in future decision making.", "cite_spans": [], "ref_spans": []}, {"section": "Asking the Right Questions", "text": "A similarly complex set of trade-offs around question setting occurred in the Ambit project. The Ambit project differed significantly from Acorn Road in that it occurred at a much earlier stage in a consultation process. As such, there was not a specific campaign for the organisation facilitating the trial to push-rather the Viewpoint devices were to be used as part of a scoping exercise for future project development. The main ambition here was to capture views from people about the locations and places in the town they felt needed investment. This initial broad consultation process would identify specific locations in the area to be targeted in a more focused piece of consultation work. Like Acorn Road, however, the language used in the questions posed was very carefully considered. While the Trust did have money for projects, they \"did not want to raise expectations\" (Trust representative) that this scoping process would lead to money being committed before current projects were complete. Initial questions suggested for the devices included words such as \"funding\", \"investment\" and \"projects\"-however, these were iterated to instead focus on the locations in the town people wished to \"change\" or where they \"like to visit\". These changes to how the questions were posed made them much more ambiguousat the same time it allowed the Trust to distance themselves from acting on the results of the consultation, should they feel unable to commit to working in the locations most identified in the responses.", "cite_spans": [], "ref_spans": []}, {"section": "Asking the Right Questions", "text": "Across both deployments the community groups had an agenda that in some way they wanted to obfuscate. As researchers, we had to find ways to fulfil the broad goals of each consultation, yet also encourage flexibility against some of the more conservative plans for using the technologies made by the community organisation. This continued when designing how citizens would respond to the questions posed on Viewpoint, which we discuss next.", "cite_spans": [], "ref_spans": []}, {"section": "Considering Forms of Response", "text": "While in both studies the same system was used, the process of providing responses to questions was very different. The way in which people were invited to respond represented the types of questions our collaborators defined and, again, the stage in their consultation process they found themselves to be in. In Acorn Road, the campaign group were very clear about the form of data they required and, as noted, had a strong desire for it to look objective. It needed to carefully compliment previous surveys they had conducted, and the data was to be used in a public report handed to the local council. The campaigners had a preference for collecting detailed information using a multistage questionnaire presented on Viewpoint. Ultimately, they had to be convinced by us that this was at odds with the design intent underpinning Viewpoint-that it offered lightweight and quick engagement-and that based on previous work it was unlikely people would stand and complete a longer questionnaire in a public place. This demonstrated a tension between the insights gained from our previous research experience and their desire for it to fit in with familiar frameworks of data.", "cite_spans": [], "ref_spans": []}, {"section": "Considering Forms of Response", "text": "The process of determining the form of response was rather more complex in Ambit, perhaps in part due to the scoping nature of the Trust's exercise. Initially, much like the campaign group, the organisation envisaged appropriating Viewpoint in relation to traditional consultation methods. They imagined using the box as an \"interactive questionnaire\" (Trust representative) where passers-by could switch through different questions and respond to them through scaled answers. However, when iterating imagined answers to these questions it was thought such an approach would lead to a very restrictive set of responses. Through a series of meetings, we came to an agreement that the Viewpoint boxes should represent the local area cartographically, where respondents could simply touch those parts of the town that correspond with their response to the question. Again, however, this process was not as Civic Tech, Participation and Society #chi4good, CHI 2016, San Jose, CA, USA simple as may appear-there was anxiety among the Trust that capturing just a location on a map was \"not enough\" and that they needed to \"know more\" (Trust representative). There was a desire to capture additional comments from people who provided their response to the question. Ideas suggested at this stage included supporting video or audio feedback via the cameras and microphones built into the system. These were discounted by the Trust however due to perceived privacy concerns.", "cite_spans": [], "ref_spans": []}, {"section": "Considering Forms of Response", "text": "The issues encountered in both of the projects around defining the ways people responded to consultation questions highlighted issues around the legibility of even relatively simple civic technologies to community groups. Furthermore, it highlights the significant agency the research team had in advising and, in some respects, pushing ideas around what the technology was for and how it would best work. This is an issue we return to in more detail in the following section.", "cite_spans": [], "ref_spans": []}, {"section": "Locating the Devices", "text": "Through the two projects, the Viewpoint boxes were deployed across seven different locations for at least twoweeks at a time. Strategic selection of locations was important in both of the projects. Prior to each of the projects, it was assumed that good places for locating these boxes would be busy places. For the campaign group there was a concern for making sure the Viewpoint boxes were placed in carefully chosen locations in and around Acorn Road where they captured \"a lot of footfall\" but also a broad audience of passers-by. Two of the devices were located in local supermarkets-one a branch of the country's largest retailer and the other a newly opened branch of an upmarket chain. Both shops were heavily trafficked and the location of the devices, both just past the check-outs (see Figure 1) , helped to secure a large number of votes. In the Ambit project, the Trust wished to locate one of the boxes in a newly opened seafood centre, where again it was assumed they \"would get a lot of people coming\" (Trust representative). Indeed, these assumptions were confirmed as the seafood centre did capture the largest number of responses overall. The other locations where the devices were deployed blurred notions of public and private. In both projects, local libraries were used as locations for a device. Libraries were chosen as a legitimate space for the type of consultation processes both groups were engaging in-indeed, historically libraries in the UK often act as venues where redevelopment plans are displayed. Unlike shops and busy tourist destinations, libraries are also almost exclusively used by local residents, which has implications in terms of demographics that can be reached. In both projects, libraries were the locations with the fewest responses, yet they were appreciated for being able to reach parts of the community busier locations might not.", "cite_spans": [], "ref_spans": [{"start": 797, "end": 806, "text": "Figure 1)", "ref_id": "FIGREF0"}]}, {"section": "Locating the Devices", "text": "Another location used in the Ambit project was a local pub. Like libraries, community pubs are almost exclusively used by local residents, and they are places that have a unique social mix, considered to contribute to social capital and a healthy community [36] . Pubs are places void of institutional influence where citizens share information, often through vernacular, rather than formal interactions, but this sharing is a by-product of the focal activity of socialisation [17, 18] . While this may appear to be an unorthodox location for these devices, it was chosen due to being embedded in a different part of the town to the other devices in Ambit. We also assumed the chatter, gossip and complaints that may occur in such spaces might be usefully harnessed for the purposes of the consultation. During the deployment, the pub received the second highest quantity of responses-this was despite being deployed for the shortest period of time. More significantly, however, votes made at the pub were dramatically different to the three other locations in Ambit. In response to the 'place you would change' question, places where factories had closed down and job losses occurred were dominant. Our interviews and observations highlighted how bringing a Viewpoint to this location engendered conversations-and that the space was formed of regulars and hangers-around meant discussions were deeper and more heated than the impromptu and fleeting conversations seen at the other places the boxes were located.", "cite_spans": [{"start": 257, "end": 261, "text": "[36]", "ref_id": "BIBREF40"}, {"start": 477, "end": 481, "text": "[17,", "ref_id": "BIBREF20"}, {"start": 482, "end": 485, "text": "18]", "ref_id": "BIBREF21"}], "ref_spans": []}, {"section": "Locating the Devices", "text": "It's worth noting that in all cases gaining access to the 'right' locations was not a simple affair. In the Ambit project a key criteria for the Trust was to elicit feedback from people who were not the \"usual suspects\". One of the core benefits seen in using the Viewpoint boxes was that they could be situated around the town in different locations, perhaps where dwellers and passers-by might not be those who would normally interact with the Trust. However, while the Trust desired to connect with the wider community, they were limited in brokering locations where the devices could be located. Indeed, early in the project, suggested locations were primarily based on their existing social networks. While in many cases the proprietors of these venues were happy to engage, the locations were not fitting with the stated aims of the consultation.", "cite_spans": [], "ref_spans": []}, {"section": "Locating the Devices", "text": "Again, the research team found themselves conflicted in the Ambit collaboration-should we let the Trust continue in their planned process of consultation, or should we push back and direct them to using other locations? It became clear at this stage that our collaborators simply did not have the social capital within the town with which to access certain places. What then followed involved the lead author taking ownership of a small number of boxes as a seemingly neutral party, in an attempt to engage new stakeholders across the town in the project. This process of wider engagement was, in itself, an incredibly time consuming and intensive process. It literally involved the researcher walking from one end of the town, visiting venues, and if appropriate spending time in each, before approaching staff or managers to explain the project, often with positive and supportive reactions.", "cite_spans": [], "ref_spans": []}, {"section": "Civic Tech, Participation and Society #chi4good, CHI 2016, San Jose, CA, USA", "text": "Overall, the locating of the devices for the Acorn Road project was a simpler process-the campaign group used their existing links with local supermarkets and the local council to have the boxes installed. However, the ease of gaining initial consent masks a variety of issue that needed to be taken into account: health and safety regulations, pressure from managers regarding the appearance of a store, and local politics. As previously discussed, the choice of location even influenced the questions that could be asked, as it became increasingly important not to alienate traders who were also hosting the devices. These were issues experienced in Ambit as well, where despite the initial good will reported above, sometimes practical and infrastructural problems in specific shops, cafes and pubs meant Viewpoints could not be installed.", "cite_spans": [], "ref_spans": []}, {"section": "Making Sense of the Data", "text": "A further set of issues encountered during both studies related to the expectations our collaborators set around the value and validity of the data they would be collecting, and how they were able to use this going forward. In the case of the Acorn Road deployment, there was a very clear trajectory for the organisation from the collection of the data through to presenting it to the local authority alongside data collected by traditional methods. The Viewpoint devices were unique in capturing data over longer periods of time, while expending less human resource from the campaign. That the types of data collected were comparable to one another was of huge value here. On its own the data from Viewpoint wasn't seen as entirely \"legitimate\", but as one feature in a set of tools it was seen to be \"very useful\" (Acorn Road campaigner) in gathering a wider picture of the issue at hand. This was aided all the more that many of the results were \"as expected\":", "cite_spans": [], "ref_spans": []}, {"section": "\"I think that was what I expected, I mean I suppose I might have hoped that it would have been only 10% car, but that would have been very unlikely considering how many cars go up and down. So I think it was really matched pretty much with what I did expect.\" (Acorn Road campaigner)", "text": "In particular, the campaign group felt the devices validated their intuition that more people travelled via public transport to the local area, and that the majority of shoppers were likely to be students:", "cite_spans": [], "ref_spans": []}, {"section": "\"The findings [\u2026] from the Viewpoint [show] that the majority of people come by foot or bicycle or public transport depending on the time of year. But during the student time it's more, and that's most of the year actually.\" (Acorn Road campaigner)", "text": "This is not to say that the trial did not process some unexpected results. One of the results that did surprise the campaigners was that despite a significant number of people travelling by car, the vast majority travelled from less than three miles away: In making sense of the data, the campaign group were not only forced to readdress their assumptions, but also change the focus of their campaign-softening their plans for full pedestrianisation, to a semi-pedestrianised space that still acknowledged the need for some parking and other access.", "cite_spans": [], "ref_spans": []}, {"section": "\"The findings [\u2026] from the Viewpoint [show] that the majority of people come by foot or bicycle or public transport depending on the time of year. But during the student time it's more, and that's most of the year actually.\" (Acorn Road campaigner)", "text": "Compared to the Acorn Road campaign, the Viewpoint data in Ambit was somewhat more challenging for the Trust to make sense of. This was, in part, a result of the more ambiguous framing of the questions and the form of response determined at the start of the project. In this case, contributions on Viewpoints located where there would likely be many tourists were interpreted, perhaps unsurprisingly, as highlighting places that were primarily visitor attractions. Locations identified on boxes in primarily residential areas-such as the pub-instead were contextualised in the history of the town and ongoing concerns around employment opportunities. The data was used to construct a narrative about the different priorities people who used Viewpoint would have. These narratives were often based on ideas of who was living in specific parts of the town, what their imagined concerns and aspirations were and why they would choose specific places to change. Because the Viewpoints had not captured the provenance of these responses, the Trust's representatives made sense of these through relying on their own prior assumptions and knowledge.", "cite_spans": [], "ref_spans": []}, {"section": "\"The findings [\u2026] from the Viewpoint [show] that the majority of people come by foot or bicycle or public transport depending on the time of year. But during the student time it's more, and that's most of the year actually.\" (Acorn Road campaigner)", "text": "While much of the data was used to reinforce what was already 'expected' by our partners-for Acorn Road judgements were made about the mode of travel of shoppers; for Ambit this was much more determined by the Civic Tech, Participation and Society #chi4good, CHI 2016, San Jose, CA, USA imagined social class and background of the people responding in a particular place-it did leave space for ambiguity and interpretation, and even the groups reassessing their interpretations.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion, Decisions and Divisions", "text": "Throughout both of the studies, the Viewpoint deployments caused a significant amount of discussion and debate. This was somewhat a novelty effect-across many of the periods spent observing Viewpoint at a distance, members of the public would be seen staring at it, asking questions of staff in venues about what it was, what it was doing here, and how to use it. The leader of the campaign group noted that \"it stimulated discussion, for sure\" and that people \"asked what's going to be done\". All of the custodians interviewed at the end of the Ambit project reported how conversations that were born from curiosity typically then opened a debate about specific issues around the places displayed on the devices. In some cases these individuals saw it as a catalyst to discuss wider issues and in turn contest future decisions: ", "cite_spans": [], "ref_spans": []}, {"section": "decision, it would give them access to data that states look, 'this is what we want' this is, is a community project, the community answers.\" (Ambit custodian 4)", "text": "Custodians of the devices also explained how people that may not normally be engaged in such processes were seemingly empowered by the boxes. For instance, our custodian in the public house explained how many people she knew well, but rarely discussed politics with, were suddenly inspired to comment on recent redevelopments based on the presence of the Viewpoint box. She remarked in surprise that older, opinionated, but \"technophobic\" regulars were seen to participate in giving their response. Another one of the locations hosting a device in Ambit regularly runs training sessions and courses for young people. The assumptions of the custodians in this space was that such a group would be reluctant to get involved in activities beyond their own training: \"But they actually took", "cite_spans": [], "ref_spans": []}, {"section": "part\u2026which they wouldn't have done if we'd asked them direct.\" (Ambit custodian 1).", "text": "Clearly, the hope of promoting discussion and gathering data, from our collaborators perspectives, was to inform either their own decision making, or to put pressure on and influence the decisions of others. In Acorn Road, the Viewpoint consultation was a key step in a much longer process. Combined results of the Viewpoint survey and a street survey asking similar questions were presented to the city council as a report. The group's recommendation was softened based on the results, from full pedestrianisation of the street to a one-way street with shared space for cars, bikes and pedestrians. What followed was a period of consultation and protest lasting three years. After proposals were unveiled, local businesses complained about the loss of parking spaces, leading the council to launch a consultation on two different proposals. After the more radical proposal was chosen, concerns were raised about the validity of the vote and who was able to contributeconcerns that are echoed in our own findings around Viewpoint, which on its own lacked legitimacy. Interestingly, part of this consultation took place through the city's recently-launched online consultation platform, as well as through more traditional means. Two further petitions-one from each side of the argument-led to a reopened consultation and a revised plan that retained more parking spaces. At the time of writing, work is just beginning on the site, three years after the Viewpoint data was collected. Despite Viewpoint's role being dwarfed by the scale of the process, it is notable that there were clear points where Viewpoint and other technologies empowered citizens to drive or shift the agenda. There was similar hope that the Ambit deployment would also lead to some decision being made-even if this was just to determine more focused consultations in the next round. However, the discussions promoted around Viewpoint were in many respects born from a suspicion of the local council, or of those running the consultation. For example, early in the deployment one of the custodians commented on how some people were suspicious of places \"missing\" from the maps on the devices:", "cite_spans": [], "ref_spans": []}, {"section": "part\u2026which they wouldn't have done if we'd asked them direct.\" (Ambit custodian 1).", "text": "\"People asked where places were, they were concerned about as they could not identify them on the map, so they had these preconceived ideas already [of deception and mistrust] and saw this as an opportunity to say something.\" (Ambit custodian 4)", "cite_spans": [], "ref_spans": []}, {"section": "part\u2026which they wouldn't have done if we'd asked them direct.\" (Ambit custodian 1).", "text": "Fears were raised that places that were missing had already been determined as not worthy of changing. Furthermore, as time went on, the data being captured by the Viewpoint boxes themselves appeared to reaffirm these divisions within the town: different Viewpoint sites captured very different impressions of what were important places to change; these would then be viewable and made visible to people interacting with the devices; this, in turn, promoted even further discourse around mistrust and division in the town. Critically, the Trust themselves-and not just local governors-were open for critique. They were described as a \"very closed group\", and indistinguishable from other institutions of power in the town: \"the same people's on the development trust's as is on the harbour commissioners; they've all got their finger in little pies.\" (Ambit custodian 4). The lack of visibility with what was happening to the data they collect, coupled with the feeling some groups are excluded from any development has left people concerned about whose interests are being served.", "cite_spans": [], "ref_spans": []}, {"section": "part\u2026which they wouldn't have done if we'd asked them direct.\" (Ambit custodian 1).", "text": "The community groups in our studies were sometimes discussed as an extension of the civic authority, warranting the same distrust. Despite the studies being designed to support consultation, there were many unexpected results around broader issues of division and decision-making that were equally, if not more, interesting.", "cite_spans": [], "ref_spans": []}, {"section": "part\u2026which they wouldn't have done if we'd asked them direct.\" (Ambit custodian 1).", "text": "Civic Tech, Participation and Society #chi4good, CHI 2016, San Jose, CA, USA", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "Our two case studies highlight some of the challenges for researchers and community organisations engaging in the use and deployment of situated consultation technologies. Some challenges were practical and technical in naturesuch as gaining access to appropriate locations that had the required space and infrastructure for the boxes to work, but most were conceptual, social and political. In the following sections we examine some of these issues. We draw out a number of key reflections on our experiences with Viewpoint and ask questions for the HCI and civic technology communities going forward.", "cite_spans": [], "ref_spans": []}, {"section": "The Researcher as an Agent", "text": "One issue that was apparent in both of the case studies was the important role the researcher plays as an agent and as part of the infrastructure of civic technology deployments.", "cite_spans": [], "ref_spans": []}, {"section": "The Researcher as an Agent", "text": "There is very often a tendency for the voice of the researcher to be 'written out' in the aid of objectivity, a criticism that HCI scholarship has faced in recent years [1, 7] . In our case it would be impossible not to acknowledge how critical the research team were in shaping the work conducted. We acted as critical friends to bounce ideas off-helping our collaborators to think through the questions they wished to pose, the places they wished to pose them in, and supporting them in understanding the particular affordances offered by the boxes. On other occasions we were more direct in our guidance. This was, we felt, to ensure that they maximised the potential of the technology. However, with it we also invoked a particular stance on what we saw as the 'right' and 'wrong' way to motivate people to participate in local decision making.", "cite_spans": [{"start": 169, "end": 172, "text": "[1,", "ref_id": "BIBREF0"}, {"start": 173, "end": 175, "text": "7]", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "The Researcher as an Agent", "text": "The participatory research literature highlights the importance of capacity building [29] and the negotiation of power and control in community research contexts [10] . In our examples we could see how a mutual exchange of skills and expertise informally supported the development of reflective practices around setting questions and inviting responses. Control over this had to be continually negotiated however, and a balance had to be found between offering our expertise and not taking ownership of the consultation. Often community partners have more at stake and more to lose than the research team, so in our case it was not surprising they resisted some of the ideas we brought. At different moments the social capital of the researchers or the community groups was more appropriate, and understanding this dynamic was an important element in maintaining positive and successful partnerships. Greater honesty and critical reflection on these issues is therefore needed, not just in civic technologies research, but in a broader range of participatory projects in HCI where such issues might arise.", "cite_spans": [{"start": 85, "end": 89, "text": "[29]", "ref_id": "BIBREF33"}, {"start": 162, "end": 166, "text": "[10]", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "The Mess of Making Decisions", "text": "The rhetoric underpinning much of the civic technology and digital democracy literature is that digital systems can support new relationships between citizens and states (e.g. [21, 41] ), and provide new mechanisms for decision-making (e.g. [19, 31, 37, 38, 40] ). In many respects it was this rhetoric that motivated our collaborators' use of the Viewpoints. In using the devices, both hoped to come to some agreement about the issues that faced them, to determine what 'should' be done about a busy road, or where the focus 'should' be of future community projects. However, in practice the results of both case studies raised more questions than answers. In the case of Ambit there were some occasions where people at different sites found commonalities with the views seemingly expressed elsewhere. Primarily however Viewpoint provided a platform for community members to express their concerns around the ongoing regeneration of the town, and a recent history of political dissatisfaction and economic disadvantage. The maps on the devices made visible social divisions and perceived and actual inequalities within this small community. In the Acorn Road trial the questions raised by the system were perhaps less divisive but equally as complex to deal withthey required the campaigners to re-evaluate their own perceptions of the problem at hand, to soften their political stance, and to find common solutions to the very different challenges and positions of a myriad of stakeholders.", "cite_spans": [{"start": 176, "end": 180, "text": "[21,", "ref_id": "BIBREF24"}, {"start": 181, "end": 184, "text": "41]", "ref_id": "BIBREF48"}, {"start": 241, "end": 245, "text": "[19,", "ref_id": "BIBREF22"}, {"start": 246, "end": 249, "text": "31,", "ref_id": "BIBREF35"}, {"start": 250, "end": 253, "text": "37,", "ref_id": "BIBREF41"}, {"start": 254, "end": 257, "text": "38,", "ref_id": "BIBREF42"}, {"start": 258, "end": 261, "text": "40]", "ref_id": "BIBREF45"}], "ref_spans": []}, {"section": "The Mess of Making Decisions", "text": "Viewpoint was somewhat predicated on the idea that technology can provide lower barriers of entry to having a say and thus support the conditions for democratic processes to occur. This simplistic view ignores how such interventions fit into the much wider, complex network of processes and actors of varying degrees of power and influence at play. It also ignores pre-existing issues around trust between different parties, an issue that has been argued to be oft-discounted in digital voting and consultation literature [33] . As noted by Harding et al. [26] , this is not just mistrust of decision-makers and authorities by certain groups of citizens, but also mistrust from certain decisionmakers as to the legitimacy and value of contributions in certain formats or from specific groups of people. In our case it was clear that Viewpoint in some cases reaffirmed these issues of mistrust. Perhaps revealing these issues could be productively channelled in the long-term, but only if technologies like Viewpoint are designed in ways to account for this bigger picture and embedded as an actor in a carefully designed process of decision-making.", "cite_spans": [{"start": 522, "end": 526, "text": "[33]", "ref_id": "BIBREF37"}, {"start": 556, "end": 560, "text": "[26]", "ref_id": "BIBREF30"}], "ref_spans": []}, {"section": "Ownership, Power and Feedback", "text": "As with prior work [12, 43, 47] our studies also raised questions around who owned the data generated by the Viewpoint devices, and the subtle ways ownership and power over the data were deployed by our partnering organisations. Burgess [4] warns that the ongoing appropriation of deliberative engagement by institutional authorities can often serve to legitimise policy decisions set independently of public participation. It would be unfair to claim that this was the case in our studies-there was great will and desire from both of our partners to reach into new parts of the community, to consult a wide number of people, and to use the insights gathered in a meaningful and honest manner. However, because both of the projects had Civic Tech, Participation and Society #chi4good, CHI 2016, San Jose, CA, USA very specific agendas involved it was hard for our collaborators not to let these shape the ways in which the consultations with the devices happened.", "cite_spans": [{"start": 19, "end": 23, "text": "[12,", "ref_id": "BIBREF13"}, {"start": 24, "end": 27, "text": "43,", "ref_id": "BIBREF50"}, {"start": 28, "end": 31, "text": "47]", "ref_id": "BIBREF54"}, {"start": 237, "end": 240, "text": "[4]", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "Ownership, Power and Feedback", "text": "One observation here is that our desire to seek case studies where there were the results would the \"actioned\" (at least envisioned to be) meant our partners very carefully thought through the types of questions they would ask. While in part this was a process of ensuring they would ask good quality questions, as we saw it also involved them thinking through the potentially negative consequences of asking the wrong questions. In Ambit, the wrong question was one that would be seen to commit the Trust to spend project funds on a particular site in town; for the campaign group it was to make known their own values and opinions from the consultation. It could be argued that by choosing not to expose their ultimate intentions, the campaign group prevented citizens and local businesses from making their voices heard. We can imagine that these other stakeholders might want to collect their own data if they are in opposition to those conducting the polls, or to verify the data being collected; indeed, this was a desire and even an expectation expressed by the custodians of our devices in the Ambit project.", "cite_spans": [], "ref_spans": []}, {"section": "Ownership, Power and Feedback", "text": "That the systems were deployed in clear decision-making processes also raised further questions around power, the use of citizen voice, and potentially on efficacy. Where the first generation Viewpoint device was designed with inbuilt mechanisms to support accountability and a sense of efficacy, the timescales and number of actors involved in these actionable contexts make this impossible. The slow timescales of decision-making processes and eventual outcomes are juxtaposed sharply against the quick, straightforward, lightweight interactions afforded by civic technologies, leaving a gap between engagement and action that may cause citizens to question 'what' is happening with the data. Fundamentally the length of these consultation processes means the rhetoric around feedback and voter efficacy become highly problematic.", "cite_spans": [], "ref_spans": []}, {"section": "CONCLUSION", "text": "In this paper we have reported on our experiences of working with community organisations that used our distributed, situated technologies as platforms for consulting their local communities. We have highlighted the diverse ways the Viewpoints promoted discussion and debate, facilitated the making of decisions, and exposed mistrust and contestation in the places they were deployed. In some cases this was promoted by the fact the boxes were installed in highly public locations, seen and engaged with, by a large number of people; it was also because they were distributed in a range of other locations as well, where existing practices of sociality and conviviality could be harnessed further. This is in keeping with recent work on similar systems (e.g. [28] ) that highlights the potential of these technologies to create a buzz and dialogue around local matters of concern. It also overlaps with scholarship on deliberative democracy [16, 32] , which states that political discourse are acts of everyday talk, and we should take the processes of decision-making to those sites where such talk occurs in civil society [35] .", "cite_spans": [{"start": 759, "end": 763, "text": "[28]", "ref_id": "BIBREF32"}, {"start": 941, "end": 945, "text": "[16,", "ref_id": "BIBREF19"}, {"start": 946, "end": 949, "text": "32]", "ref_id": "BIBREF36"}, {"start": 1124, "end": 1128, "text": "[35]", "ref_id": "BIBREF39"}], "ref_spans": []}, {"section": "CONCLUSION", "text": "However, it's critical to note that while we (the researchers) captured the buzz around the deployments, our collaborating community partners did not. The design of Viewpoint was such that it followed a simple framework of participation in the aid of lowering the barrier to entry. In doing so it purposely designed out the collection of \"noise\", privileging the idea that participation in local matters of concern can be captured at the press of a button or the tap of a map. If it were not for the performance of fieldwork around our systems then the richness and detail of conversations would be missed. While this may appear to be a moot point, it's a critical one in a context where the ambition is to create platforms that enable people to ask questions of others. In this context, it is critical to understand 'why' people say what they do, and to capture the wider discourse the questions posed provoke. Such additional layers of study would be practically difficult for our collaborators to conduct. Further, the perceived lack of objectivity of our collaborators from some of those being consulted may, in some respects, have made any such attempts meaningless. In this regard, the perceived neutrality of the researchers [43] eased people into sharing their views in a more candid manner.", "cite_spans": [{"start": 1232, "end": 1236, "text": "[43]", "ref_id": "BIBREF50"}], "ref_spans": []}, {"section": "CONCLUSION", "text": "One might argue that there were opportunities in our work to design in the capturing of such 'noise'. We could have invited people to give video or audio responses to questions. But beyond the privacy concerns bound up in this, there is a more poignant concern that such interactions lose the richness and discursive, dialogic element of debate.", "cite_spans": [], "ref_spans": []}, {"section": "CONCLUSION", "text": "In future work, we should perhaps look to designing systems that adapt to the conversations already taking place in society, rather than asking citizens to adapt to artificial interactions to express their views. With this comes an appreciation that it is the researcher's duty to proactively capture and convey this richness, so that community organisations-and the authorities and institutions to which they lobby-can acknowledge and use them appropriately in their decision-making processes.", "cite_spans": [], "ref_spans": []}, {"section": "ACKNOWLEDGMENTS", "text": "We'd like to thank our community partners and the Viewpoint 'custodians' for giving their time to these projects. ", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Understanding sustained community engagement", "authors": [{"first": "Mara", "middle": [], "last": "Balestrini", "suffix": ""}, {"first": "Jon", "middle": [], "last": "Bird", "suffix": ""}, {"first": "Paul", "middle": [], "last": "Marshall", "suffix": ""}, {"first": "Alberto", "middle": [], "last": "Zaro", "suffix": ""}, {"first": "Yvonne", "middle": [], "last": "Rogers", "suffix": ""}], "year": 2014, "venue": "Proceedings of the 32nd annual ACM conference on Human factors in computing systems -CHI '14", "link": null}, "BIBREF1": {"title": "Communities and Technologies", "authors": [{"first": "", "middle": [], "last": "Peter Van Den", "suffix": ""}, {"first": "", "middle": [], "last": "Besselaar", "suffix": ""}], "year": 2005, "venue": "Proceedings of the Second Communities and Technologies Conference", "link": null}, "BIBREF2": {"title": "Using thematic analysis in psychology", "authors": [{"first": "Virginia", "middle": [], "last": "Braun", "suffix": ""}, {"first": "Victoria", "middle": [], "last": "Clarke", "suffix": ""}], "year": 2008, "venue": "Qualitative Research in Psychology", "link": null}, "BIBREF3": {"title": "From \"trust us\" to participatory governance: Deliberative publics and science policy", "authors": [{"first": "M", "middle": [], "last": "Michael", "suffix": ""}, {"first": "", "middle": [], "last": "Burgess", "suffix": ""}], "year": 2014, "venue": "", "link": "206607489"}, "BIBREF4": {"title": "Community Network 2.0: Visions, Participation, and Engagement in New Information Infrastructures", "authors": [{"first": "John", "middle": ["M"], "last": "Carroll", "suffix": ""}, {"first": "Michael", "middle": [], "last": "Horning", "suffix": ""}, {"first": "Blaine", "middle": [], "last": "Hoffman", "suffix": ""}, {"first": "Craig", "middle": [], "last": "Ganoe", "suffix": ""}, {"first": "Harold", "middle": [], "last": "Robinson", "suffix": ""}, {"first": "Mary", "middle": ["Beth"], "last": "Rosson", "suffix": ""}], "year": 2011, "venue": "", "link": "34090137"}, "BIBREF5": {"title": "Participatory design in community informatics", "authors": [{"first": "John", "middle": ["M"], "last": "Carroll", "suffix": ""}, {"first": "Mary", "middle": ["Beth"], "last": "Rosson", "suffix": ""}], "year": 2007, "venue": "Design Studies", "link": "12769729"}, "BIBREF6": {"title": "Community engagement for research", "authors": [{"first": "Alan", "middle": [], "last": "Chamberlain", "suffix": ""}, {"first": "Andy", "middle": [], "last": "Crabtree", "suffix": ""}, {"first": "Mark", "middle": [], "last": "Davies", "suffix": ""}], "year": 2013, "venue": "Proceedings of the 6th International Conference on Communities and Technologies -C&T '13", "link": null}, "BIBREF8": {"title": "Controlling In-the-Wild Evaluation Studies of Public Displays", "authors": [{"first": "Sandy", "middle": [], "last": "Claes", "suffix": ""}, {"first": "Niels", "middle": [], "last": "Wouters", "suffix": ""}, {"first": "Karin", "middle": [], "last": "Slegers", "suffix": ""}, {"first": "Andrew", "middle": [], "last": "Vande Moere", "suffix": ""}], "year": 2015, "venue": "Proceedings of the 33rd Annual ACM Conference on Human Factors in Computing Systems -CHI '15", "link": "16664515"}, "BIBREF9": {"title": "Teaching thematic analysis: Overcoming challenges and developing strategies for effective learning", "authors": [{"first": "V", "middle": [], "last": "Clarke", "suffix": ""}, {"first": "V", "middle": [], "last": "Braun", "suffix": ""}], "year": 2013, "venue": "The Psychologist", "link": "30997001"}, "BIBREF10": {"title": "What is participatory research? Social science & medicine", "authors": [{"first": "A", "middle": [], "last": "Cornwall", "suffix": ""}, {"first": "", "middle": [], "last": "Jewkes", "suffix": ""}], "year": 1982, "venue": "", "link": null}, "BIBREF11": {"title": "A pool of dreams", "authors": [{"first": "Clara", "middle": [], "last": "Crivellaro", "suffix": ""}, {"first": "Rob", "middle": [], "last": "Comber", "suffix": ""}, {"first": "John", "middle": [], "last": "Bowers", "suffix": ""}, {"first": "Peter", "middle": ["C"], "last": "Wright", "suffix": ""}, {"first": "Patrick", "middle": [], "last": "Olivier", "suffix": ""}], "year": 2014, "venue": "Proceedings of the 32nd annual ACM conference on Human factors in computing systems -CHI '14", "link": null}, "BIBREF13": {"title": "Planning with Crowdsourced Data", "authors": [{"first": "A", "middle": ["Le"], "last": "Christopher", "suffix": ""}, {"first": "Mariam", "middle": [], "last": "Dantec", "suffix": ""}, {"first": "Aditi", "middle": [], "last": "Asad", "suffix": ""}, {"first": "Kari", "middle": ["E"], "last": "Misra", "suffix": ""}, {"first": "", "middle": [], "last": "Watkins", "suffix": ""}], "year": 2015, "venue": "Proceedings of the 18th ACM Conference on Computer Supported Cooperative Work & Social Computing -CSCW '15", "link": null}, "BIBREF15": {"title": "Strangers at the Gate. Proceedings of the 18th ACM Conference on Computer Supported Cooperative Work & Social Computing -CSCW '15", "authors": [{"first": "A", "middle": ["Le"], "last": "Christopher", "suffix": ""}, {"first": "Sarah", "middle": [], "last": "Dantec", "suffix": ""}, {"first": "", "middle": [], "last": "Fox", "suffix": ""}], "year": 2015, "venue": "", "link": null}, "BIBREF17": {"title": "Participation and publics", "authors": [{"first": "Christopher", "middle": [], "last": "Le", "suffix": ""}, {"first": "Dantec", "middle": [], "last": "", "suffix": ""}], "year": 2012, "venue": "Proceedings of the 2012 ACM annual conference on Human Factors in Computing Systems -CHI '12", "link": null}, "BIBREF18": {"title": "Lost in translation", "authors": [{"first": "Rog\u00e9rio", "middle": [], "last": "Depaula", "suffix": ""}], "year": 2004, "venue": "Proceedings of the eighth conference on Participatory design Artful integration: interweaving media, materials and practices -PDC 04", "link": null}, "BIBREF19": {"title": "Deliberative Democracy and Beyond: Liberals, Critics, Contestations", "authors": [{"first": "S", "middle": [], "last": "John", "suffix": ""}, {"first": "", "middle": [], "last": "Dryzek", "suffix": ""}], "year": 2000, "venue": "", "link": "142806383"}, "BIBREF20": {"title": "Information grounds and the use of need-based services by immigrants in Queens", "authors": [{"first": "Karen", "middle": ["E"], "last": "Fisher", "suffix": ""}, {"first": "Joan", "middle": ["C"], "last": "Durrance", "suffix": ""}, {"first": "Marian", "middle": ["Bouch"], "last": "Hinton", "suffix": ""}], "year": 2004, "venue": "Journal of the American Society for Information Science and Technology", "link": "14369519"}, "BIBREF21": {"title": "Information Grounds: Theoretical Basis and Emperical Findings on Information Flow in Social Settings", "authors": [{"first": "Karen", "middle": ["E"], "last": "Fisher", "suffix": ""}, {"first": "Charles", "middle": ["M"], "last": "Naumer", "suffix": ""}], "year": 2006, "venue": "New Directions in Human Information Behaviour", "link": "151191943"}, "BIBREF22": {"title": "Experimenting with a Democratic Ideal: Deliberative Polling and Public Opinion", "authors": [{"first": "", "middle": [], "last": "Js Fishkin", "suffix": ""}, {"first": "", "middle": [], "last": "Luskin", "suffix": ""}], "year": 2005, "venue": "Acta Politica", "link": null}, "BIBREF23": {"title": "Getting quizzical about physical", "authors": [{"first": "Sarah", "middle": [], "last": "Gallacher", "suffix": ""}, {"first": "Connie", "middle": [], "last": "Golsteijn", "suffix": ""}, {"first": "Lorna", "middle": [], "last": "Wall", "suffix": ""}, {"first": "Lisa", "middle": [], "last": "Koeman", "suffix": ""}, {"first": "Sami", "middle": [], "last": "Andberg", "suffix": ""}], "year": 2015, "venue": "Proceedings of the 2015 ACM International Joint Conference on Pervasive and Ubiquitous ComputingUbiComp '15", "link": null}, "BIBREF24": {"title": "Closing the Feedback Loop: Can Civic Tech, Participation and Society #chi4good", "authors": [{"first": "Samantha", "middle": [], "last": "Bjo\u0308rn-So\u0308ren Gigler", "suffix": ""}, {"first": "Savita", "middle": [], "last": "Custer", "suffix": ""}, {"first": "Elizabeth", "middle": [], "last": "Bailur", "suffix": ""}, {"first": "Saher", "middle": [], "last": "Dodds", "suffix": ""}, {"first": "Elena", "middle": [], "last": "Asad", "suffix": ""}, {"first": "", "middle": [], "last": "Gagievapetrova", "suffix": ""}], "year": 2014, "venue": "CHI", "link": null}, "BIBREF25": {"title": "Technology Amplify Citezen Voices? In Closing the feedback Loop: Can Technology Briidge the Accountability Gap?, Bjo\u0308rn", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF26": {"title": "Yvonne Rogers and Licia Capra", "authors": [{"first": "Connie", "middle": [], "last": "Golsteijn", "suffix": ""}, {"first": "Sarah", "middle": [], "last": "Gallacher", "suffix": ""}, {"first": "Lisa", "middle": [], "last": "Koeman", "suffix": ""}, {"first": "Lorna", "middle": [], "last": "Wall", "suffix": ""}, {"first": "Sami", "middle": [], "last": "Andberg", "suffix": ""}], "year": 2015, "venue": "VoxBox. Proceedings of the Ninth International Conference on Tangible, Embedded, and Embodied Interaction -TEI '14", "link": null}, "BIBREF27": {"title": "Hannu Kukka and Vassilis Kostakos", "authors": [{"first": "Jorge", "middle": [], "last": "Goncalves", "suffix": ""}, {"first": "Denzil", "middle": [], "last": "Ferreira", "suffix": ""}, {"first": "Simo", "middle": [], "last": "Hosio", "suffix": ""}, {"first": "Yong", "middle": [], "last": "Liu", "suffix": ""}, {"first": "Jakob", "middle": [], "last": "Rogstadius", "suffix": ""}], "year": 2013, "venue": "Proceedings of the 2013 ACM international joint conference on Pervasive and ubiquitous computingUbiComp '13", "link": null}, "BIBREF28": {"title": "Eliciting situated feedback: A comparison of paper, web forms and public displays", "authors": [{"first": "Jorge", "middle": [], "last": "Goncalves", "suffix": ""}, {"first": "Simo", "middle": [], "last": "Hosio", "suffix": ""}, {"first": "Yong", "middle": [], "last": "Liu", "suffix": ""}, {"first": "Vassilis", "middle": [], "last": "Kostakos", "suffix": ""}], "year": 2014, "venue": "Displays", "link": "14745507"}, "BIBREF29": {"title": "Civic action brokering platforms", "authors": [{"first": "Derek", "middle": ["L"], "last": "Hansen", "suffix": ""}, {"first": "Jes", "middle": ["A"], "last": "Koepfler", "suffix": ""}, {"first": "Paul", "middle": ["T"], "last": "Jaeger", "suffix": ""}, {"first": "John", "middle": ["C"], "last": "Bertot", "suffix": ""}, {"first": "Tracy", "middle": [], "last": "Viselli", "suffix": ""}], "year": 2014, "venue": "Proceedings of the 17th ACM conference on Computer supported cooperative work & social computing -CSCW '14", "link": null}, "BIBREF30": {"title": "HCI, Civic Engagement & Trust. Proceedings of the 33rd Annual ACM Conference on Human Factors in Computing Systems -CHI '15", "authors": [{"first": "Mike", "middle": [], "last": "Harding", "suffix": ""}, {"first": "Bran", "middle": [], "last": "Knowles", "suffix": ""}, {"first": "Nigel", "middle": [], "last": "Davies", "suffix": ""}, {"first": "Mark", "middle": [], "last": "Rouncefield", "suffix": ""}], "year": 2015, "venue": "", "link": null}, "BIBREF31": {"title": "What's in it for me", "authors": [{"first": "Simo", "middle": [], "last": "Hosio", "suffix": ""}, {"first": "Jorge", "middle": [], "last": "Goncalves", "suffix": ""}, {"first": "Hannu", "middle": [], "last": "Kukka", "suffix": ""}, {"first": "Alan", "middle": [], "last": "Chamberlain", "suffix": ""}, {"first": "Alessio", "middle": [], "last": "Malizia", "suffix": ""}], "year": 2014, "venue": "Proceedings of The International Symposium on Pervasive Displays -PerDis '14", "link": null}, "BIBREF32": {"title": "Everyone Is Talking about It", "authors": [{"first": "Lisa", "middle": [], "last": "Koeman", "suffix": ""}, {"first": "Vaiva", "middle": [], "last": "Kalnikait\u00e9", "suffix": ""}, {"first": "Yvonne", "middle": [], "last": "Rogers", "suffix": ""}], "year": 2015, "venue": "Proceedings of the 33rd Annual ACM Conference on Human Factors in Computing Systems -CHI '15", "link": null}, "BIBREF33": {"title": "Participatory Research: Strategies and Tools", "authors": [{"first": "Ajit", "middle": [], "last": "Krishnaswamy", "suffix": ""}], "year": 2004, "venue": "", "link": "151222757"}, "BIBREF34": {"title": "Does slacktivism hurt activism?", "authors": [{"first": "Yu-Hao", "middle": [], "last": "Lee", "suffix": ""}, {"first": "Gary", "middle": [], "last": "Hsieh", "suffix": ""}], "year": 2013, "venue": "Proceedings of the SIGCHI Conference on Human Factors in Computing Systems -CHI '13", "link": null}, "BIBREF35": {"title": "Democratic citizenship community: a social network to promote e-deliberative process", "authors": [{"first": "Cristiano", "middle": [], "last": "Maciel", "suffix": ""}, {"first": "Lic\u00ednio", "middle": [], "last": "Roque", "suffix": ""}, {"first": "Ana Cristina Bicharra", "middle": [], "last": "Garcia", "suffix": ""}], "year": 2009, "venue": "Proceedings from the 10th Digital Government Society of North America", "link": "11880790"}, "BIBREF36": {"title": "Everyday talk in the deliberative system", "authors": [{"first": "Jane", "middle": [], "last": "Mansbridge", "suffix": ""}], "year": 1999, "venue": "Deliberative Politics: Essays on Democracy and Disagreement., Stephen Macedo", "link": null}, "BIBREF37": {"title": "Big Data: A Revolution that Will Transform how We Live, Work, and Think", "authors": [{"first": "Viktor", "middle": [], "last": "Mayer", "suffix": ""}, {"first": "-", "middle": [], "last": "Sch\u00f6nberger", "suffix": ""}, {"first": "Kenneth", "middle": [], "last": "Cukier", "suffix": ""}], "year": 2013, "venue": "", "link": "116895975"}, "BIBREF38": {"title": "Participatory design in community computing contexts", "authors": [{"first": "Cecelia", "middle": ["B"], "last": "Merkel", "suffix": ""}, {"first": "Lu", "middle": [], "last": "Xiao", "suffix": ""}, {"first": "Umer", "middle": [], "last": "Farooq", "suffix": ""}, {"first": "Craig", "middle": ["H"], "last": "Ganoe", "suffix": ""}, {"first": "Roderick", "middle": [], "last": "Lee", "suffix": ""}, {"first": "John", "middle": ["M"], "last": "Carroll", "suffix": ""}, {"first": "Mary", "middle": ["Beth"], "last": "Rosson", "suffix": ""}], "year": 2004, "venue": "Proceedings of the eighth conference on Participatory design Artful integration: interweaving media, materials and practices -PDC 04", "link": null}, "BIBREF39": {"title": "Deliberative Manoeuvres in the Digital Darkness: e-Democracy Policy in the UK", "authors": [{"first": "Giles", "middle": [], "last": "Moss", "suffix": ""}, {"first": "Stephen", "middle": [], "last": "Coleman", "suffix": ""}], "year": 2013, "venue": "The British Journal of Politics & International Relations", "link": "155078322"}, "BIBREF40": {"title": "Celebrating the Third Place: Inspiring Stories about the \"great Good Places\" at the Heart of Our Communities", "authors": [{"first": "Ray", "middle": [], "last": "Oldenburg", "suffix": ""}], "year": 2001, "venue": "", "link": "106849173"}, "BIBREF41": {"title": "Voting in online deliberative assemblies", "authors": [{"first": "Jeremy", "middle": [], "last": "Pitt", "suffix": ""}, {"first": "Lloyd", "middle": [], "last": "Kamara", "suffix": ""}, {"first": "Marek", "middle": [], "last": "Sergot", "suffix": ""}, {"first": "Alexander", "middle": [], "last": "Artikis", "suffix": ""}], "year": "", "venue": "Proceedings of the 10th international conference on Artificial intelligence and law -ICAIL '05", "link": "2292133"}, "BIBREF42": {"title": "Social media supporting political deliberation across multiple public spheres", "authors": [{"first": "C", "middle": [], "last": "Bryan", "suffix": ""}, {"first": "Scott", "middle": ["P"], "last": "Semaan", "suffix": ""}, {"first": "Sara", "middle": [], "last": "Robertson", "suffix": ""}, {"first": "Misa", "middle": [], "last": "Douglas", "suffix": ""}, {"first": "", "middle": [], "last": "Maruyama", "suffix": ""}], "year": 2014, "venue": "Proceedings of the 17th ACM conference on Computer supported cooperative work & social computing -CSCW '14", "link": null}, "BIBREF43": {"title": "Navigating Imagined Audiences", "authors": [{"first": "Bryan", "middle": [], "last": "Semaan", "suffix": ""}, {"first": "Heather", "middle": [], "last": "Faucett", "suffix": ""}, {"first": "Scott", "middle": [], "last": "Robertson", "suffix": ""}, {"first": "Misa", "middle": [], "last": "Maruyama", "suffix": ""}, {"first": "Sara", "middle": [], "last": "Douglas", "suffix": ""}], "year": 2015, "venue": "Proceedings of the 18th ACM Conference on Computer Supported Cooperative Work & Social Computing -CSCW '15", "link": null}, "BIBREF45": {"title": "Designing Political Deliberation Environments to Support Interactions in the Public Sphere", "authors": [{"first": "Bryan", "middle": [], "last": "Semaan", "suffix": ""}, {"first": "Heather", "middle": [], "last": "Faucett", "suffix": ""}, {"first": "Scott", "middle": ["P"], "last": "Robertson", "suffix": ""}, {"first": "Misa", "middle": [], "last": "Maruyama", "suffix": ""}, {"first": "Sara", "middle": [], "last": "Douglas", "suffix": ""}], "year": 2015, "venue": "Proceedings of the Civic Tech, Participation and Society #chi4good, CHI 2016", "link": "5174753"}, "BIBREF46": {"title": "33rd Annual ACM Conference on Human Factors in Computing Systems -CHI '15", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF48": {"title": "Bridging the Digital Divide : Technology", "authors": [{"first": "Lisa", "middle": ["J"], "last": "Servon", "suffix": ""}], "year": 2008, "venue": "", "link": null}, "BIBREF49": {"title": "How) will the revolution be retweeted?", "authors": [{"first": "Kate", "middle": [], "last": "Starbird", "suffix": ""}, {"first": "Leysia", "middle": [], "last": "Palen", "suffix": ""}], "year": 2012, "venue": "Proceedings of the ACM 2012 conference on Computer Supported Cooperative Work -CSCW '12", "link": null}, "BIBREF50": {"title": "Data-in-Place", "authors": [{"first": "Alex", "middle": ["S"], "last": "Taylor", "suffix": ""}, {"first": "Si\u00e2n", "middle": [], "last": "Lindley", "suffix": ""}, {"first": "Tim", "middle": [], "last": "Regan", "suffix": ""}, {"first": "David", "middle": [], "last": "Sweeney", "suffix": ""}, {"first": "Vasilis", "middle": [], "last": "Vlachokyriakos", "suffix": ""}, {"first": "Lillie", "middle": [], "last": "Grainger", "suffix": ""}, {"first": "Jessa", "middle": [], "last": "Lingel", "suffix": ""}], "year": 2015, "venue": "Proceedings of the 33rd Annual ACM Conference on Human Factors in Computing Systems -CHI '15", "link": null}, "BIBREF51": {"title": "Leaving the wild", "authors": [{"first": "Nick", "middle": [], "last": "Taylor", "suffix": ""}, {"first": "Keith", "middle": [], "last": "Cheverst", "suffix": ""}, {"first": "Peter", "middle": [], "last": "Wright", "suffix": ""}, {"first": "Patrick", "middle": [], "last": "Olivier", "suffix": ""}], "year": "", "venue": "Proceedings of the SIGCHI Conference on Human Factors in Computing Systems -CHI '13", "link": null}, "BIBREF52": {"title": "Proceedings of the 2012 ACM annual conference on Human Factors in Computing Systems -CHI '12", "authors": [{"first": "Justin", "middle": [], "last": "Taylor", "suffix": ""}, {"first": "Alicia", "middle": [], "last": "Marshall", "suffix": ""}, {"first": "Justin", "middle": [], "last": "Blum-Ross", "suffix": ""}, {"first": "Alicia", "middle": [], "last": "Marshall", "suffix": ""}, {"first": "John", "middle": [], "last": "Blum-Ross", "suffix": ""}, {"first": "Jon", "middle": [], "last": "Mills", "suffix": ""}, {"first": "Paul", "middle": [], "last": "Rogers", "suffix": ""}, {"first": "David", "middle": ["M"], "last": "Egglestone", "suffix": ""}, {"first": "Peter", "middle": [], "last": "Frohlich", "suffix": ""}, {"first": "Patrick", "middle": [], "last": "Wright", "suffix": ""}, {"first": "", "middle": [], "last": "Olivier", "suffix": ""}], "year": 2012, "venue": "", "link": null}, "BIBREF53": {"title": "Time, place, technology: Twitter as an information source in the Wisconsin labor protests", "authors": [{"first": "Aaron", "middle": ["S"], "last": "Veenstra", "suffix": ""}, {"first": "Narayanan", "middle": [], "last": "Iyer", "suffix": ""}], "year": 2014, "venue": "Computers in Human Behavior", "link": "46021870"}, "BIBREF54": {"title": "PosterVote. Proceedings of the 2014 conference on Designing interactive systems -DIS '14", "authors": [{"first": "Vasilis", "middle": [], "last": "Vlachokyriakos", "suffix": ""}, {"first": "Rob", "middle": [], "last": "Comber", "suffix": ""}, {"first": "Karim", "middle": [], "last": "Ladha", "suffix": ""}, {"first": "Nick", "middle": [], "last": "Taylor", "suffix": ""}, {"first": "Paul", "middle": [], "last": "Dunphy", "suffix": ""}, {"first": "Patrick", "middle": [], "last": "Mccorry", "suffix": ""}, {"first": "Patrick", "middle": [], "last": "Olivier", "suffix": ""}], "year": 2014, "venue": "", "link": null}, "BIBREF55": {"title": "Encounters with participatory action research", "authors": [{"first": "", "middle": [], "last": "William Foote Whyte", "suffix": ""}], "year": 1995, "venue": "Qualitative Sociology", "link": null}, "BIBREF56": {"title": "Civic Tech, Participation and Society #chi4good", "authors": [], "year": 2016, "venue": "", "link": null}}, "ref_entries": {"FIGREF0": {"text": "Figure 1. The second generation of Viewpoint while deployed at a supermarket for the Acorn Road case study.", "type": "figure"}, "FIGREF1": {"text": "Figure 2. Viewpoint in different locations during the Ambit case study.", "type": "figure"}, "TABREF1": {"text": "At first we thought we'd do a poll, \"Are you in favour of pedestrianisation\", but [\u2026] what would that mean? It might mean different things to different people and it also might lead to resistance and people would be saying, oh well come out and vote against it and it wouldn't really be a very easy thing to get a fair result from.\" (Acorn Road campaigner)", "type": "table"}, "TABREF5": {"text": "This research was funded through the EPSRC Centre for Doctoral Training in Digital Civics (EP/L016176/1) and EPSRC Additional Sponsorship for Newcastle University (EP/J501359/1). Data supporting this publication is openly available under an 'Open Data Commons Open Database License'. Additional metadata are available at: 10.17634/154300-8. Please contact Newcastle Research Data Service at rdm@ncl.ac.uk for access instructions.", "type": "table"}}}
{"paper_id": "17787669", "_pdf_hash": "29c5fa16a20f7454aa1fdb324e2fd7292fa4c862", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "17787826", "_pdf_hash": "29a2b8c9ea7b410600b562ece647a2103b84ad74", "abstract": [{"section": "Abstract", "text": "Oxidative damage to mitochondrial DNA has been implicated in human degenerative diseases and aging. Although removal of oxidative lesions from mitochondrial DNA occurs, the responsible DNA repair enzymes are poorly understood. By expressing the epitope-tagged proteins in COS-7 cells, we examined subcellular localizations of gene products of human DNA glycosylases: hOGG1, hMYH and hNTH1. A gene encoding for hOGG1 which excises 7,8-dihydro-8-oxoguanine (8-oxoG) from DNA generates four isoforms by alternative splicing (types 1a, 1b, 1c and 2). Three tagged isoforms (types 1b, 1c and 2) were localized in the mitochondria. Type 1a protein, which exclusively contains a putative nuclear localization signal, was sorted to the nucleus and lesser amount to the mitochondria. hMYH, a human homolog gene product of Escherichia coli mutY was mainly transported into the mitochondria. hNTH1 protein excising several pyrimidine lesions was transported into both the nucleus and mitochondria. In contrast to the three DNA glycosylases, translocation of the human major AP endonuclease (hAPE) into the mitochondria was hardly observed in COS-7 cells. These results suggest that the previously observed removal of oxidative base lesions in mitochondrial DNA is initiated by the above DNA glycosylases.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "INTRODUCTION", "text": "A variety of DNA base modifications are generated by reactive oxygen species (ROS) and most of these lesions are excised by DNA glycosylases in living cells (1) . Escherichia coli, the best characterized organism for the repair of oxidized DNA, uses different DNA glycosylases for purine and pyrimidine base lesions (2) . A wide variety of oxidized pyrimidines are excised by E.coli endonuclease III. The general importance of this DNA glycosylase for life is suggested by the fact that many organisms whose complete genome sequences have been analyzed possess E.coli nth-like gene(s) and putative homologs are found in the database of various eukaryotic sequences from yeast to man (3) .", "cite_spans": [{"start": 157, "end": 160, "text": "(1)", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "INTRODUCTION", "text": "A gene product of the human homolog, termed hNTH1, was characterized as possessing a substrate specificity similar to that of E.coli endonuclease III (3, 4) . MutM/Fpg, another E.coli DNA glycosylase, acts on oxidized purines representing 7,8-dihydro-8-oxoguanine (8-oxoG) and 2,6-diamino-4-hydroxy-5-N-methylformamidopyrimidine (Fapy). The biological significance of the 8-oxoG is widely recognized because of its strong mutagenic potential and abundant production by ROS in cells. To counteract the 8-oxoG-induced mutations, E.coli provides two additional enzymes, namely, MutY that excises mispaired adenine opposite 8-oxoG, and MutT that acts as 8-oxo-dGTPase to sanitize the nucleotide pool. Human homologs of mutY and mutT have been cloned as hMYH (5) and hMTH1 (6) , suggesting that the repair of 8-oxoG is also crucial for human. Although a homolog of the mutM gene has not been identified in human, a gene encoding for a DNA glycosylase functionally similar to MutM, termed OGG1, was cloned initially from Saccharomyces cerevisiae (7, 8) and recently from human as hMMH/hOGG1/hOGH1 (9) (10) (11) (12) (13) (14) . It is, therefore, reasonable to suppose that hOGG1, hMYH and hMTH1 cooperatively protect against the 8-oxoG-induced mutagenesis in human, as MutM, MutY and MutT in E.coli (15) .", "cite_spans": [{"start": 154, "end": 156, "text": "4)", "ref_id": "BIBREF3"}, {"start": 1040, "end": 1043, "text": "(7,", "ref_id": "BIBREF6"}, {"start": 1100, "end": 1104, "text": "(11)", "ref_id": "BIBREF10"}, {"start": 1105, "end": 1109, "text": "(12)", "ref_id": "BIBREF11"}, {"start": 1110, "end": 1114, "text": "(13)", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "INTRODUCTION", "text": "The apurinic/apyrimidinic (AP) site in DNA is generated by spontaneous base loss or by the action of DNA glycosylase. The AP site is toxic because it blocks DNA replication and is mutagenic when translesional DNA synthesis takes place (1) . A major AP endonuclease, APE (APEX/HAP1/Ref-1), initiates the repair by nicking 5\u2032-adjacent to the AP site. The incision leaves a 5\u2032-terminal deoxyribose 5-phosphate (dRP) which disturbs the following repair synthesis. Experiments of in vitro reconstitution have shown that dRPase activity associated by DNA polymerase \u03b2 (pol\u03b2) or nuclease activity of FEN-1 is required for the removal of the 5\u2032-lesion and the subsequent repair synthesis (16, 17) . This base excision repair (BER) model appears to be limited to the APE-initiated repair and to the event in the nucleus. On the other hand, hNTH1 and hOGG1 are able to incise DNA strand at the glycosylitically produced AP site without APE due to the associated AP lyase activity. Thus, the process of repair initiated by the action of the DNA glycosylase/AP lyase remains to be established.", "cite_spans": [{"start": 235, "end": 238, "text": "(1)", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "INTRODUCTION", "text": "Mitochondrial oxidative energy metabolism is the major intracellular source of ROS. Mitochondrial biomolecules including mitochondrial DNA (mtDNA) are constantly exposed to a high *To whom correspondence should be addressed. Tel: +81 22 717 8465; Fax: +81 22 717 8470; Email: ayasui@idac.tohoku.ac.jp extent of ROS. The accumulation of oxidative DNA lesions or the resulting mtDNA alteration has been implicated in the cause of aging and several human diseases such as Parkinson's disease and Alzheimer's disease (reviewed in [18] [19] [20] . While the mitochondrial antioxidants such as superoxide dismutase, catalase and glutathione are well known to defend against ROS, the DNA repair mechanism and responsible enzymes in mitochondria are poorly understood. Nonetheless, observations that MutM-and endonuclease IIIsensitive DNA lesions are efficiently removed from mtDNA (21, 22) , suggests the presence of DNA repair enzymes in this organella. Biochemical studies have shown that mitochondria contain endonuclease III-like AP nicking activity (23) and OGG1/MutM-like DNA glycosylase/AP lyase activity (24) . Additionally, mitochondrial localization of hMTH1 has been documented, suggesting the existence of a repair and protection system against 8-oxoG-induced mutations (25) . These studies prompted us to examine localization of products of DNA glycosylase genes recently isolated from human.", "cite_spans": [], "ref_spans": []}, {"section": "INTRODUCTION", "text": "Among eukaryotic DNA glycosylases whose genes have been cloned so far, uracil DNA glycosylase (UNG) is the only protein for which mitochondrial localization has been demonstrated (26, 27) . It was revealed that two alternative forms are transcribed from the UNG gene, which have distinct N-terminal sequences: one containing a nuclear localization signal (NLS), and the other containing a mitochondrial targeting signal (MTS) (27) . While single coding sequences for hMYH, hNTH1 and hAPE have been reported, we have previously identified four distinct hOGG1 transcripts generated by alternative splicing. All the isoforms (types 1a, 1b, 1c and 2) are equally able to reduce the mutation frequency of E.coli (mutM mutY) host cells (9) . Here, we present the subcellular localization of the recombinant proteins of four hOGG1 isoforms, hMYH, hNTH1 and APE to assess the possibility that these gene products may be involved in the presumed mitochondrial base excision repair for oxidative damage.", "cite_spans": [], "ref_spans": []}, {"section": "MATERIALS AND METHODS", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Plasmid constructs", "text": "Four hOGG1 cDNAs were cloned previously (9) . The other cDNA encoding for hMYH, hNTH1 or hAPE was amplified by polymerase chain reaction (PCR) from human testis or brain cDNA library (Gibco-BRL) based on the database sequences (MYH, U63329; APE, D90373; NTH1, U81285). In order to tag the C-terminus of the protein, PCR was performed using a C-terminal primer containing a FLAG sequence and stop codon (GAC TAC AAG GAC GAC GAT GAC AAG TGA). The 5\u2032-sequence was modified by introducing a translation signal (CCACC) in front of the initiation codon. The FLAG-tagged cDNA was cloned behind the CMV promoter of the expression vector, pTargeT (Promega). A fusion construct with green fluorescent protein (GFP) was obtained by subcloning a PCR product having appropriate restriction sites on the ends into pEGFP-C1 (Clontech). observed under a microscope. Transfectants with FLAG-tagged constructs were subsequently washed once, treated with 0.2% Triton X-100 in PBS for 2 min, washed twice, and incubated with a blocking reagent (NEN) in TN buffer (0.1 M Tris-HCl, 0.15 M NaCl, pH 7.5). The cells were then incubated with anti-FLAG M2 antibody (Kodak) at 40 \u00b5g/ml in TNT buffer (TN buffer containing 0.05% Tween 20) at room temperature for 1 h or at 4_C overnight. Indirect immunofluorescence was performed with a combination of a biotin-labeled second antibody (Zymed), a tyramide signal amplification system (TSA-Indirect, NEN) and a fluorescent conjugate (Streptavidin-Fluorescein, NEN) according to the manufacturer's instructions. For detection of mitochondria, MitoTracker Red CMXros (Molecular Probes) was added to the culture medium of the transfected cells 20 min before the fixation. The transfectants were visualized with a fluorescence microscope (Leica model DM LB) equipped with photographic system (MPS60). Filter L4 or TX (Leica) was used for the fluorescein and GFP or CMXros, respectively.", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Structure and MTS prediction of hOGG1, hMYH, hNTH1 and APE", "text": "A putative NLS has been suggested for hOGG1 (9) (10) (11) (12) 14) , for hNTH1 (4) and for hAPE (29) . We re-evaluated possible targeting signals for nucleus and mitochondria by using the PSORT program (30; Fig. 1 ). Four isoforms of hOGG1 (types 1a, 1b, 1c and 2) with a variable C-terminus of 8-108 residues are generated by alternative splicing (9) . The putative NLS is exclusively found in the C-terminal segment of type 1a sequence. Human MYH, NTH1 and APE are homologs of E.coli mutY, nth and xth, respectively. Their deduced sequences have 'extended' segments which are not included in the E.coli counterparts. The predicted NLSs reside mostly in the extended segments. For mitochondrial targeting, it is known that regular MTS is located at the N-terminal end composed of typically 20-60 residues with abundant positive charges, very little if any negative charges, and frequent hydroxylated residues which can form an amphipathic \u03b1-helix (31). Mitochondrial targeting is predicted for hOGG1, hMYH and hNTH1.", "cite_spans": [{"start": 53, "end": 57, "text": "(11)", "ref_id": "BIBREF10"}, {"start": 58, "end": 62, "text": "(12)", "ref_id": "BIBREF11"}, {"start": 96, "end": 100, "text": "(29)", "ref_id": "BIBREF28"}], "ref_spans": [{"start": 207, "end": 213, "text": "Fig. 1", "ref_id": "FIGREF1"}]}, {"section": "Subcellular localization of hOGG1 isoforms", "text": "To access the actual localization of the hOGG1 isoforms in vivo, we transiently expressed a construct in COS-7 cells, in which a FLAG epitope was added at the C-terminus of the respective cDNA. The protein expression and its subcellular localization was detected by immunofluorescence staining using anti-FLAG M2 antibody. Cells were also treated with CMXros prior to fixation in order to visualize mitochondria.", "cite_spans": [], "ref_spans": []}, {"section": "Subcellular localization of hOGG1 isoforms", "text": "As expected, the tagged type 1a protein was mainly detected in the nucleus. We observed, in addition to the nucleus, cytosolic fluorescence forming dots or lines characteristic of mitochondria ( Fig. 2A) . In sharp contrast to the nuclear translocation of the type 1a protein, the other three proteins were detected not in nuclei at all but in mitochondria (Fig. 2B-D) . Therefore, the sequence PAKRRK at 333 in the C-terminal segment of type 1a is actually utilized for nuclear targeting and the common N-terminal domain contains a MTS. Similar localization for the each isoform was obtained in HeLa transfectants (not shown).", "cite_spans": [], "ref_spans": [{"start": 195, "end": 203, "text": "Fig. 2A)", "ref_id": "FIGREF2"}, {"start": 357, "end": 368, "text": "(Fig. 2B-D)", "ref_id": "FIGREF2"}]}, {"section": "Subcellular localization of hOGG1 isoforms", "text": "To confirm whether the common N-terminal region of hOGG1 protein possesses a regular MTS, a truncated protein with a deletion of N-terminal 31 amino acids, which retains the core domain homologous to S.cerevisiae OGG1, was expressed in COS-7 cells. The epitope-tagged \u2206N31-type 1a protein was targeted to the nucleus without mitochondrial localization (Fig. 2E) . The same N-terminal deletion from the type 2 protein (\u2206N31-type 2) resulted in no mitochondrial localization, weak fluorescence from the nucleus and several bright granular dots in the cytosol (Fig. 2F) , probably suggesting rapid transport and degradation in lysosome.", "cite_spans": [], "ref_spans": [{"start": 352, "end": 361, "text": "(Fig. 2E)", "ref_id": "FIGREF2"}, {"start": 557, "end": 566, "text": "(Fig. 2F)", "ref_id": "FIGREF2"}]}, {"section": "Subcellular localization of hMYH", "text": "In the bacterial repair and protection system against 8-oxoGinduced mutations, MutY and MutT also play substantial roles. However, in a mutT -background E.coli (mutY + ) is more mutagenic than E.coli (mutY -) because MutY excises adenine opposite 8-oxoG that has been misincorporated by DNA ", "cite_spans": [], "ref_spans": []}, {"section": "hMYH-FLAG protein was transiently expressed in COS-7 cells (A), HeLa cells (B) or CHO-9 cells (C). The N-terminal truncated protein (\u2206N64) or the GFP-fusion protein with the hMYH C-terminal segment (GFP-C55) was expressed in COS-7 cells [(D) or (E), respectively].", "text": "polymerase (32) . In human cells, hMTH1 has been found in the mitochondrial matrix as well as in cytosol (25) . This situation could allow hMYH protein to work in the mitochondria for cooperative DNA repair with hOGG1. Figure 4 shows the immunofluorescence staining of transiently expressed hMYH-FLAG protein. The protein was clearly co-localized with mitochondria in COS-7 cells (Fig. 3A) . Unexpectedly, hMYH-FLAG protein was hardly detected in nucleus, although some transfectants which appeared to strongly express the recombinant protein showed both mitochondrial and nuclear localization of the protein (not shown). We further examined the localization of the hMYH-FLAG protein in different cell lines, HeLa cells (Fig. 3B ) and CHO-9 cells (Fig. 3C) . The results indicated mitochondrial localization of the protein and very little if any nuclear immunofluorescence in either type of cells.", "cite_spans": [], "ref_spans": [{"start": 219, "end": 227, "text": "Figure 4", "ref_id": "FIGREF4"}, {"start": 380, "end": 389, "text": "(Fig. 3A)", "ref_id": "FIGREF3"}, {"start": 720, "end": 728, "text": "(Fig. 3B", "ref_id": "FIGREF3"}, {"start": 747, "end": 756, "text": "(Fig. 3C)", "ref_id": "FIGREF3"}]}, {"section": "hMYH-FLAG protein was transiently expressed in COS-7 cells (A), HeLa cells (B) or CHO-9 cells (C). The N-terminal truncated protein (\u2206N64) or the GFP-fusion protein with the hMYH C-terminal segment (GFP-C55) was expressed in COS-7 cells [(D) or (E), respectively].", "text": "According to the alignment (5), the human sequence, relative to E.coli MutY, has extended segments composed of 63 residues toward the N-terminus and \u223c50 residues toward the C-terminus. One NLS-like sequence (PWRRR at 98) is found in the core domain, but this is in the conserved block. A more likely NLS (RKKPR at 505) is located in the extended C-terminal segment (Fig. 1) . To determine whether the latter C-terminal NLS is active or not, we expressed a GFP protein fused at its C-terminus with the C-terminal extended segment (55 residues) of the hMYH sequence (GFP-C55). The COS-7 transfectants showed nuclear localization of the protein (Fig. 3E) . Furthermore, a construct in which the extended N-terminal segment (64 residues) was deleted from the hMYH-FLAG resulted in the nuclear localization of the \u2206N64 protein (Fig. 3D) . These results indicate that the C-terminal segment has a potential NLS. ", "cite_spans": [], "ref_spans": [{"start": 365, "end": 373, "text": "(Fig. 1)", "ref_id": "FIGREF1"}, {"start": 642, "end": 651, "text": "(Fig. 3E)", "ref_id": "FIGREF3"}, {"start": 822, "end": 831, "text": "(Fig. 3D)", "ref_id": "FIGREF3"}]}, {"section": "Subcellular localization of hNTH1", "text": "We studied subcellular localization for another DNA glycosylase, hNTH1, to link the gene product to the observed mitochondrial repair activity for oxidative pyrimidines (21, 22) . The hNTH1 sequence has an extended N-terminal segment composed of \u223c95 residues (3, 4) . N-terminal MTS and three putative NLSs appear within or near this segment (PLRRR at 30, PVKRPRK at 46, PKVRR at 117; Fig. 1 ). The expression of hNTH1-FLAG protein in COS-7 cells (Fig. 4A ) and HeLa cells (Fig. 4B ) resulted in the protein being transported into both the nucleus and mitochondria. Therefore, the hNTH1 protein has dual transport signals to repair nuclear and mitochondrial DNA lesions.", "cite_spans": [{"start": 263, "end": 265, "text": "4)", "ref_id": "BIBREF3"}], "ref_spans": [{"start": 385, "end": 391, "text": "Fig. 1", "ref_id": "FIGREF1"}, {"start": 447, "end": 455, "text": "(Fig. 4A", "ref_id": "FIGREF4"}, {"start": 473, "end": 481, "text": "(Fig. 4B", "ref_id": "FIGREF4"}]}, {"section": "Subcellular localization of hAPE", "text": "In contrast to the above DNA glycosylases, N-terminal MTS is not predicted in the hAPE sequence while the NLS of hAPE is located near the end of the N-terminus (PKRGKK at 2). The extended N-terminal segment of mammalian APE is a domain, apart from the AP endonuclease activity, for the redox function to facilitate DNA binding of several transcription factors such as AP-1 (31). Although activity of hAPE protein is found mostly in nuclear extracts, immunohistochemical studies have shown differential nuclear and cytosolic localization of the protein depending on the tissues and cell types (34) and colorectal adenomas and carcinomas (35) . We examined subcellular localization of hAPE-FLAG protein in COS-7 cells. As shown in Figure 5 , the recombinant protein was predominantly localized in the nucleus. Mitochondrial and other cytosolic hAPE-FLAG protein was below the detection limit in the transfectants.", "cite_spans": [], "ref_spans": [{"start": 729, "end": 737, "text": "Figure 5", "ref_id": "FIGREF5"}]}, {"section": "DISCUSSION", "text": "We used an epitope-tagging strategy to demonstrate the subcellular localization of hOGG1, hMYH, hNTH1 and hAPE proteins. Results of the nuclear localizations of hOGG1 type 1a and hNTH1, together with recent evidence that the nucleotide excision repair (NER) removes thymine glycol and 8-oxoG in vitro (36) , indicate that the nucleus has two distinct pathways for repair of the same lesions. More importantly, the mitochondrial localizations of four hOGG1 isoforms and hNTH1 imply that these DNA glycosylases are the requisite enzymes for the repair of mtDNA. Although the specific contribution of hOGG1 and hNTH1 to the repair is uncertain, the substrates characterized to date for hOGG1 9, (11) (12) (13) (14) , and hNTH1 (thymine glycol and urea; 3,4) are the most abundant DNA lesions generated by ROS and are included in the MutM-and endonuclease III-sensitive lesions, efficient removal of which from mtDNA has been observed previously (21, 22, 37) . Since mitochondria do not appear to possess NER for the removal of these lesions, our results underscore the importance of mitochondrial BER for these oxidative lesions initiated by hOGG1 and hNTH1 DNA glycosylases. In addition, we showed that hMYH is also targeted to mitochondria. Together with the previously demonstrated mitochondrial localization of hMTH1 (25) , hOGG1, hMYH and hMTH1 can constitute mitochondrial repair and protection system against the 8-oxoG-induced mutagenesis.", "cite_spans": [{"start": 301, "end": 305, "text": "(36)", "ref_id": "BIBREF35"}, {"start": 692, "end": 696, "text": "(11)", "ref_id": "BIBREF10"}, {"start": 697, "end": 701, "text": "(12)", "ref_id": "BIBREF11"}, {"start": 702, "end": 706, "text": "(13)", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "DISCUSSION", "text": "The molecular weight of the hOGG1 isoform varies with the length of the each C-terminal segment. Type 1a (39 kDa) and type 1b (36 kDa) are small, consisting of a core domain conserved between yeast and human, while type 1c (46 kDa) and type 2 (47 kDa) have a relatively long C-terminal segment with sequences unrelated to each other (Fig. 1 ). An 8-oxoG DNA glycosylase/AP lyase purified from rat liver mitochondria has a molecular mass of 25-30 kDa as estimated by gel-filtration (38) . When considering that a presequence (usually 20-60 residues) is processed in the mitochondrial matrix, the purified protein could be a mitochondrial form of a rat OGG1 protein, presumably corresponding to the small human isoform (type 1a and/or type 1b).", "cite_spans": [], "ref_spans": [{"start": 333, "end": 340, "text": "(Fig. 1", "ref_id": "FIGREF1"}]}, {"section": "DISCUSSION", "text": "hOGG1 splicing variants were obtained from human colon cDNA (9) . These transcripts seem to be ubiquitously expressed when analyzed by RT-PCR and at least type 1a and type 1b are expressed at similar level by RNase protection assay (9; H.Aburatani and Y.Hippo, unpublished). Also, partial sequences for all the isoforms from various sources have been entered in the EST database. It is an interesting question why human cells express four isoforms all directed to mitochondria. Recently, a limited substrate specificity of S.cerevisiae OGG1 (a counterpart of human type 1a) has been reported, where the enzyme does not excise several purine lesions including adenine lesions 8-hydroxyadenine and 4,6-diamino-5-formamidopyrimidine (39) . The variable C-terminal domain in type 1c and type 2 might provide different or additional substrate specificity in order to manage the repair for such minor purine lesions in mitochondria in the absence of NER.", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "The hMYH gene encoding for a 59 kDa protein with a 41% amino acid sequence similarity to E.coli MutY was cloned from a database search with the bacterial sequence (5) . While the activity of the gene product has not been published, a 65 kDa protein with the adenine DNA glycosylase activity and the cross-reactivity to anti-MutY antibodies has been purified from calf thymus and HeLa cells, which is also termed MYH (40) . We presumed that the hMYH gene encodes for the latter purified protein and used the nucleotide sequence of the gene to amplify the cDNA. We thus initially expected nuclear localization of the recombinant protein because the protein had been obtained from the nuclear extracts (40) . However, translocation of the fulllength hMYH-FLAG protein into nuclei was relatively weak in COS-7 cells and almost undetectable in HeLa and CHO-9 cells. The results of the GFP-fusion and the N-terminal truncated protein indicate that the C-terminal sequence of hMYH contains a potential NLS. Therefore, we conclude that the NLS of hMYH protein is less effective than the N-terminal MTS as a protein transport signal. However, a discrepancy remains between calf thymus nuclear extracts containing MYH protein activity and the apparent absence of the recombinant hMYH protein in HeLa/ CHO-9 transfectants (Fig. 3B and C) . It is possible to consider the existence of a second, yet similar, hMYH protein in the nucleus. With regard to this, the exclusive localization of UNG protein has been found to be originated by alternative splicing (28) . The second hMYH, if present, might be an isoform derived from an alternative splicing of the hMYH gene where the N-terminal MTS is deleted or replaced. Further work is needed to identify the gene providing the nuclear MYH activity.", "cite_spans": [], "ref_spans": [{"start": 1311, "end": 1326, "text": "(Fig. 3B and C)", "ref_id": "FIGREF3"}]}, {"section": "DISCUSSION", "text": "A BER repair model for AP sites has been proposed, which includes APE incision and pol\u03b2-or PCNA-dependent processing (16, 17) . Although the model is not fully applicable to mitochondrial BER, incision at AP sites is expected to initiate the repair. Recently, a class II mitochondrial AP endonuclease of Xenopus laevis has been revealed to initiate the AP-DNA repair in vitro (41) . Our result showing apparent nuclear localization of hAPE suggests that the mitochondrial AP endonuclease might be an alternative form of Xenopus APE or encoded by a distinct gene. On the other hand, an early study showed other AP nicking activities in mouse plasmacytoma mitochondria (23) . The enzymes are EDTA resistant and incise UV-irradiated DNA in addition to AP-DNA. These properties and the mitochondrial localization of hNTH1 shown here suggest that at least one of the mitochondrial AP nicking activities is an AP lyase function of NTH1 protein. The contribution of the mitochondrial AP lyase to the AP-DNA repair and the processing of 3\u2032-unsaturated sugarphosphate generated by it remain to be established.", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "MtDNA alterations including deletion, rearrangement, point mutation and fragmentation are age-associated events (18) (19) (20) . Oxidative damage is thought to be a primary cause of these mutations which lead to mitochondrial dysfunction and then increased ROS production (20) . Normal mitochondrial function seems to be required for maintenance of the mitochondrial DNA repair capacity because oxidative lesions in mtDNA are accumulated in aged cells, and are unrepaired in cells under strong oxidative stress which does not affect the nuclear DNA repair capacity (42) . Elucidation and characterization of the mitochondrial DNA repair enzymes involved in BER and also mismatch repair is an important step toward understanding the molecular basis of age-associated mitochondrial genome instability.", "cite_spans": [{"start": 565, "end": 569, "text": "(42)", "ref_id": "BIBREF41"}], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "DNA Repair and Mutagenesis", "authors": [{"first": "E", "middle": ["C"], "last": "Friedberg", "suffix": ""}, {"first": "G", "middle": ["C"], "last": "Walker", "suffix": ""}, {"first": "W", "middle": [], "last": "Siede", "suffix": ""}], "year": 1995, "venue": "", "link": "82247704"}, "BIBREF3": {"title": "Proc. Natl. Acad. Sci. USA", "authors": [{"first": "R", "middle": [], "last": "Aspinwall", "suffix": ""}, {"first": "D", "middle": ["G"], "last": "Rothwell", "suffix": ""}, {"first": "T", "middle": [], "last": "Roldan-Arjona", "suffix": ""}, {"first": "C", "middle": [], "last": "Anselmino", "suffix": ""}, {"first": "C", "middle": ["J"], "last": "Ward", "suffix": ""}, {"first": "J", "middle": ["P"], "last": "Cheadle", "suffix": ""}, {"first": "J", "middle": ["R"], "last": "Sampson", "suffix": ""}, {"first": "T", "middle": [], "last": "Lindahl", "suffix": ""}, {"first": "P", "middle": ["C"], "last": "Harris", "suffix": ""}, {"first": "I", "middle": ["D"], "last": "Hickson", "suffix": ""}], "year": 1997, "venue": "", "link": null}, "BIBREF6": {"title": "Proc. Natl. Acad. Sci. USA", "authors": [{"first": "P", "middle": ["A"], "last": "Van Der Kemp", "suffix": ""}, {"first": "D", "middle": [], "last": "Thomas", "suffix": ""}, {"first": "R", "middle": [], "last": "Barbey", "suffix": ""}, {"first": "R", "middle": [], "last": "De Oliveira", "suffix": ""}, {"first": "S", "middle": [], "last": "Boiteux", "suffix": ""}], "year": 1996, "venue": "", "link": null}, "BIBREF10": {"title": "Proc. Natl. Acad. Sci. USA", "authors": [{"first": "T", "middle": ["A"], "last": "Rosenquist", "suffix": ""}, {"first": "D", "middle": ["O"], "last": "Zharkov", "suffix": ""}, {"first": "A", "middle": ["P"], "last": "Grollman", "suffix": ""}], "year": 1997, "venue": "", "link": null}, "BIBREF11": {"title": "Proc. Natl. Acad. Sci. USA", "authors": [{"first": "J", "middle": ["P"], "last": "Radicella", "suffix": ""}, {"first": "C", "middle": [], "last": "Dherin", "suffix": ""}, {"first": "C", "middle": [], "last": "Desmaze", "suffix": ""}, {"first": "M", "middle": ["S"], "last": "Fox", "suffix": ""}, {"first": "S", "middle": [], "last": "Boiteux", "suffix": ""}], "year": 1997, "venue": "", "link": null}, "BIBREF12": {"title": "Proc. Natl. Acad. Sci. USA", "authors": [{"first": "T", "middle": [], "last": "Roldan-Arjona", "suffix": ""}, {"first": "Y.-F", "middle": [], "last": "Wei", "suffix": ""}, {"first": "K", "middle": ["C"], "last": "Carter", "suffix": ""}, {"first": "A", "middle": [], "last": "Klungland", "suffix": ""}, {"first": "C", "middle": [], "last": "Anselmino", "suffix": ""}, {"first": "R.-P", "middle": [], "last": "Wang", "suffix": ""}, {"first": "M", "middle": [], "last": "Augustus", "suffix": ""}, {"first": "T", "middle": [], "last": "Lindahl", "suffix": ""}], "year": 1997, "venue": "", "link": null}, "BIBREF28": {"title": "Proc. Natl. Acad. Sci. USA", "authors": [{"first": "B", "middle": [], "last": "Demple", "suffix": ""}, {"first": "T", "middle": [], "last": "Herman", "suffix": ""}, {"first": "D", "middle": ["S"], "last": "Chen", "suffix": ""}], "year": 1991, "venue": "", "link": null}, "BIBREF35": {"title": "Proc. Natl. Acad. Sci. USA", "authors": [{"first": "J", "middle": ["T"], "last": "Reardon", "suffix": ""}, {"first": "T", "middle": [], "last": "Bessho", "suffix": ""}, {"first": "H", "middle": ["C"], "last": "Kung", "suffix": ""}, {"first": "P", "middle": ["H"], "last": "Bolton", "suffix": ""}, {"first": "A", "middle": [], "last": "Sancar", "suffix": ""}], "year": 1997, "venue": "", "link": null}, "BIBREF41": {"title": "Proc. Natl. Acad. Sci. USA", "authors": [{"first": "F", "middle": ["M"], "last": "Yakes", "suffix": ""}, {"first": "B", "middle": [], "last": "Van Houten", "suffix": ""}], "year": 1997, "venue": "", "link": null}}, "ref_entries": {"FIGREF0": {"text": "Transfection COS-7 cells, HeLa cells or CHO-9 cells grown in 35 mm tissue culture dishes were transfected with the above plasmid DNA using Lipofectamine (Gibco-BRL). The cells were washed in PBS and fixed with 4% paraformaldehyde in PBS at 44-48 h following the start of transfection. GFP fluorescence was then", "type": "figure"}, "FIGREF1": {"text": "Figure 1. Schematic representation of possible NLS and MTS in human OGG1, MYH, NTH and APE proteins. PSORT (version II, http://psort.nibb.ac.jp/ ) was employed to predict nuclear and/or mitochondrial localizations. Scores of discriminant analysis for mitochondrial localization (MITDISC; 30) are shown in parentheses. Positions of the predicted NLSs are shown by filled boxes. The arrow represents a position used for construction of N-terminal truncated protein (\u2206N31 or \u2206N64) or that of GFP-fusion protein (GFP-C55).", "type": "figure"}, "FIGREF2": {"text": "Figure 2. Subcellular localization of hOGG1 isoforms in COS-7 cells. COS-7 cells were transfected with the constructs expressing C-terminal FLAG-tagged hOGG1 type 1a (A), type 1b (B) type 1c (C) and type 2 (D). The 31 amino acids of the N-terminal sequence are truncated from the type 1a construct (E) or from the type 2 constructs (F). Representative immunofluorescence staining with anti-FLAG M2 antibody (E) and (F) and left images in (A)-(D) and mitochondrial staining with CMXros [right images in (A)-(D)] are shown (magnification \u00d7400).", "type": "figure"}, "FIGREF3": {"text": "Figure 3. Mitochondrial and possible nuclear localization of hMYH protein. The hMYH-FLAG protein was transiently expressed in COS-7 cells (A), HeLa cells (B) or CHO-9 cells (C). The N-terminal truncated protein (\u2206N64) or the GFP-fusion protein with the hMYH C-terminal segment (GFP-C55) was expressed in COS-7 cells [(D) or (E), respectively].", "type": "figure"}, "FIGREF4": {"text": "Figure 4. Dual localization of hNTH1 protein in nucleus and mitochondria. The hNTH1-FLAG protein was transiently expressed in COS-7 cells (A) or in HeLa cells (B) and visualized by immunofluorescence staining (left). Mitochondria were stained by CMXros (right).", "type": "figure"}, "FIGREF5": {"text": "Figure 5. Nuclear localization of hAPE protein in COS-7 cells. The hAPE-FLAG protein was transiently expressed in COS-7 cells and visualized by immunofluorescence staining.", "type": "figure"}}}
{"paper_id": "17788241", "_pdf_hash": "f174c2d4f32f1692f51f3f01cf3ff0c9783aa611", "abstract": [], "body_text": [], "bib_entries": {"BIBREF1": {"title": "Constrained and restrained refinement in EXAFS data analysis with curved wave theory", "authors": [{"first": "N", "middle": [], "last": "Binsted", "suffix": ""}, {"first": "R", "middle": ["W"], "last": "Strange", "suffix": ""}, {"first": "S", "middle": ["S"], "last": "Hasnain", "suffix": ""}], "year": 1992, "venue": "Biochemistry", "link": "121295216"}, "BIBREF2": {"title": "A new species of Beauveria isolated from Scottish moorland soil", "authors": [{"first": "J", "middle": [], "last": "Bisset", "suffix": ""}, {"first": "P", "middle": [], "last": "Widden", "suffix": ""}], "year": 1986, "venue": "Can. J. Bot", "link": null}, "BIBREF3": {"title": "Dissolution of poorly crystalline iron oxides by EDTA and oxalate", "authors": [{"first": "O", "middle": ["K"], "last": "Borggaard", "suffix": ""}], "year": 1992, "venue": "Z. Pflanzenernaehr Bodenkd", "link": null}, "BIBREF4": {"title": "Rainfall and crop residue effects on soil dispersion and Beauveria bassiana spread to corn", "authors": [{"first": "D", "middle": ["J"], "last": "Bruck", "suffix": ""}, {"first": "L", "middle": ["C"], "last": "Lewis", "suffix": ""}], "year": 2002, "venue": "Appl. Soil Ecol", "link": "43200843"}, "BIBREF5": {"title": "Elemental composition and function of polyphosphates in ectomycorrhizal fungi-an X-ray microanalytical study", "authors": [{"first": "H", "middle": [], "last": "Bucking", "suffix": ""}, {"first": "W", "middle": [], "last": "Heyser", "suffix": ""}], "year": 1999, "venue": "Mycol. Res", "link": "86440848"}, "BIBREF6": {"title": "Fungal involvement in bioweathering and biotransformation of rocks and minerals", "authors": [{"first": "E", "middle": ["P"], "last": "Burford", "suffix": ""}, {"first": "M", "middle": [], "last": "Fomina", "suffix": ""}, {"first": "G", "middle": ["M"], "last": "Gadd", "suffix": ""}], "year": 2003, "venue": "Miner. Mag", "link": "129340140"}, "BIBREF7": {"title": "Leaching of metals with fungi", "authors": [{"first": "W", "middle": [], "last": "Burgstaller", "suffix": ""}, {"first": "F", "middle": [], "last": "Schinner", "suffix": ""}], "year": 1993, "venue": "J. Biotechnol", "link": "85122270"}, "BIBREF8": {"title": "Oxalic acid, a pathogenicity factor for Sclerotinia sclerotiorum, suppresses the oxidative burst of the host plant", "authors": [{"first": "S", "middle": ["G"], "last": "Cessna", "suffix": ""}, {"first": "V", "middle": ["E"], "last": "Sears", "suffix": ""}, {"first": "M", "middle": ["B"], "last": "Dickman", "suffix": ""}, {"first": "P", "middle": ["S"], "last": "Low", "suffix": ""}], "year": 2000, "venue": "Plant Cell", "link": null}, "BIBREF9": {"title": "Oxalic acid overproduction by coppertolerant brown-rot basidiomycetes on southern yellow pine treated with copper-based preservatives", "authors": [{"first": "C", "middle": ["A"], "last": "Clausen", "suffix": ""}, {"first": "F", "middle": [], "last": "Green", "suffix": ""}], "year": 2003, "venue": "Int. Biodeterior. Biodegrad", "link": "9049059"}, "BIBREF10": {"title": "Genetic variation and heavy metal tolerance in the ectomycorrhizal basidiomycete Suillus luteus", "authors": [{"first": "J", "middle": ["V"], "last": "Colpaert", "suffix": ""}, {"first": "P", "middle": [], "last": "Vandenkoornhuyse", "suffix": ""}, {"first": "K", "middle": [], "last": "Adriaensen", "suffix": ""}, {"first": "J", "middle": [], "last": "Vangronsveld", "suffix": ""}], "year": 2000, "venue": "New Phytol", "link": "86057326"}, "BIBREF11": {"title": "Calcium translocation, calcium oxalate accumulation, and hyphal sheath morphology in the white rot fungus Resinicium bicolor", "authors": [{"first": "J", "middle": ["H"], "last": "Connolly", "suffix": ""}, {"first": "J", "middle": [], "last": "Jellison", "suffix": ""}], "year": 1995, "venue": "Can. J. Bot", "link": "86390399"}, "BIBREF12": {"title": "Oxalate production by fungi: its role in pathogenicity and ecology in the soil environment", "authors": [{"first": "M", "middle": ["V"], "last": "Dutton", "suffix": ""}, {"first": "C", "middle": ["S"], "last": "Evans", "suffix": ""}], "year": 1996, "venue": "Can. J. Microbiol", "link": "83553167"}, "BIBREF13": {"title": "Activity of exoglycans as sorbents of ions of heavy metals", "authors": [{"first": "N", "middle": ["P"], "last": "Elinov", "suffix": ""}, {"first": "E", "middle": ["P"], "last": "Anan&apos;eva", "suffix": ""}, {"first": "G", "middle": ["A"], "last": "Yaskovich", "suffix": ""}], "year": 1999, "venue": "Appl. Biochem. Microbiol", "link": "89529376"}, "BIBREF14": {"title": "Can plants use entomopathogens as bodyguards?", "authors": [{"first": "S", "middle": ["L"], "last": "Elliot", "suffix": ""}, {"first": "M", "middle": ["W"], "last": "Sabelis", "suffix": ""}, {"first": "A", "middle": [], "last": "Janssen", "suffix": ""}, {"first": "L", "middle": ["P S"], "last": "Van Der Geest", "suffix": ""}, {"first": "E", "middle": ["A M"], "last": "Beerling", "suffix": ""}, {"first": "J", "middle": [], "last": "Fransen", "suffix": ""}], "year": 2000, "venue": "Ecol. Lett", "link": "84643303"}, "BIBREF15": {"title": "Nutritional influence on the ability of fungal mycelia to penetrate toxic metal-containing domains", "authors": [{"first": "M", "middle": [], "last": "Fomina", "suffix": ""}, {"first": "K", "middle": [], "last": "Ritz", "suffix": ""}, {"first": "G", "middle": ["M"], "last": "Gadd", "suffix": ""}], "year": 2003, "venue": "Mycol. Res", "link": "25586409"}, "BIBREF16": {"title": "The fungal community: its organization and role in the ecosystem", "authors": [{"first": "M", "middle": [], "last": "Fomina", "suffix": ""}, {"first": "E", "middle": ["P"], "last": "Burford", "suffix": ""}, {"first": "G", "middle": ["M"], "last": "Gadd", "suffix": ""}], "year": "", "venue": "", "link": "82319362"}, "BIBREF17": {"title": "Interactions of fungi with toxic metals", "authors": [{"first": "G", "middle": ["M"], "last": "Gadd", "suffix": ""}], "year": 1993, "venue": "New Phytol", "link": null}, "BIBREF18": {"title": "Fungal production of citric and oxalic acid: importance in metal speciation, physiology and biogeochemical processes", "authors": [{"first": "G", "middle": ["M"], "last": "Gadd", "suffix": ""}], "year": 1999, "venue": "Adv. Microb. Physiol", "link": "28899255"}, "BIBREF19": {"title": "Brown-rot fungal degradation of wood: our evolving view", "authors": [{"first": "B", "middle": [], "last": "Goodell", "suffix": ""}], "year": 2003, "venue": "Wood Deterior. Preserv", "link": "136575160"}, "BIBREF20": {"title": "Copper tolerance of brown-rot fungi: time course of oxalic acid production", "authors": [{"first": "F", "middle": [], "last": "Green", "suffix": ""}, {"first": "C", "middle": ["A"], "last": "Clausen", "suffix": ""}], "year": 2003, "venue": "Int. Biodeterior. Biodegrad", "link": "96785162"}, "BIBREF21": {"title": "A rapid, exact, curved-wave theory for EXAFS calculations", "authors": [{"first": "S", "middle": ["J"], "last": "Gurman", "suffix": ""}, {"first": "N", "middle": [], "last": "Binsted", "suffix": ""}, {"first": "I", "middle": [], "last": "Ross", "suffix": ""}], "year": 1984, "venue": "J. Phys. C", "link": "121674145"}, "BIBREF22": {"title": "A rapid, exact, curved-wave theory for EXAFS calculations. 2. The multiple-scattering contributions", "authors": [{"first": "S", "middle": ["J"], "last": "Gurman", "suffix": ""}, {"first": "N", "middle": [], "last": "Binsted", "suffix": ""}, {"first": "I", "middle": [], "last": "Ross", "suffix": ""}], "year": 1986, "venue": "J. Phys. C", "link": "120625028"}, "BIBREF23": {"title": "Hyphal-sheath polysaccharides in fungal deterioration", "authors": [{"first": "A", "middle": [], "last": "Gutierrez", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Martinez", "suffix": ""}, {"first": "G", "middle": [], "last": "Almendros", "suffix": ""}, {"first": "F", "middle": ["J"], "last": "Gonzalezvila", "suffix": ""}, {"first": "A", "middle": ["T"], "last": "Martinez", "suffix": ""}], "year": 1995, "venue": "Sci. Total Environ", "link": "29756057"}, "BIBREF24": {"title": "Effects of electron-electron and electronphonon interactions on the one-electron states of solids", "authors": [{"first": "L", "middle": [], "last": "Hedin", "suffix": ""}, {"first": "S", "middle": [], "last": "Lundqvist", "suffix": ""}], "year": 1969, "venue": "Solid State Phys", "link": "118610356"}, "BIBREF25": {"title": "Crystals in gels and Liesegang rings", "authors": [{"first": "H", "middle": ["K"], "last": "Henisch", "suffix": ""}], "year": 2002, "venue": "", "link": "136546140"}, "BIBREF26": {"title": "A novel Antarctic microbial endolithic community within gypsum crusts", "authors": [{"first": "K", "middle": ["A"], "last": "Hughes", "suffix": ""}, {"first": "B", "middle": [], "last": "Lawley", "suffix": ""}], "year": 2003, "venue": "Environ. Microbiol", "link": "22411520"}, "BIBREF27": {"title": "Hyphal sheath and iron-binding compound formation in liquid cultures of wood decay fungi Gloeophyllum trabeum and Postia placenta", "authors": [{"first": "J", "middle": [], "last": "Jellison", "suffix": ""}, {"first": "Y", "middle": [], "last": "Chen", "suffix": ""}, {"first": "F", "middle": ["A"], "last": "Fekete", "suffix": ""}], "year": 1997, "venue": "Holzforschung", "link": "96546632"}, "BIBREF28": {"title": "The influence of oxalic acid on release rates of metals from contaminated river sediment", "authors": [{"first": "D", "middle": [], "last": "Klarup", "suffix": ""}], "year": 1997, "venue": "Sci. Total Environ", "link": "97328887"}, "BIBREF29": {"title": "Commercial fermentations and nutritional needs of their microorganisms", "authors": [{"first": "C", "middle": ["P"], "last": "Kubicek", "suffix": ""}], "year": 1998, "venue": "", "link": null}, "BIBREF30": {"title": "Citric acid fermentation", "authors": [{"first": "C", "middle": ["P"], "last": "Kubicek", "suffix": ""}, {"first": "M", "middle": [], "last": "Roehr", "suffix": ""}], "year": 1986, "venue": "Crit. Rev. Biotechnol", "link": "86777944"}, "BIBREF31": {"title": "Oxalic acid synthesis by the mycorrhizal fungus Paxillus involutus (Batsch, ex Fr.)", "authors": [{"first": "F", "middle": [], "last": "Lapeyrie", "suffix": ""}, {"first": "G", "middle": ["A"], "last": "Chilvers", "suffix": ""}, {"first": "C", "middle": ["A"], "last": "Bhem", "suffix": ""}], "year": 1987, "venue": "New Phytol", "link": "85200466"}, "BIBREF32": {"title": "Phosphate-solubilizing activity of ectomycorrhizal fungi in vitro", "authors": [{"first": "F", "middle": [], "last": "Lapeyrie", "suffix": ""}, {"first": "J", "middle": [], "last": "Ranger", "suffix": ""}, {"first": "D", "middle": [], "last": "Vairelles", "suffix": ""}], "year": 1991, "venue": "Can. J. Bot", "link": "84446202"}, "BIBREF33": {"title": "Bioavailability of heavy metals in the mycorrhizosphere", "authors": [{"first": "C", "middle": [], "last": "Leyval", "suffix": ""}, {"first": "E", "middle": ["J"], "last": "Joner", "suffix": ""}], "year": 2001, "venue": "Trace elements in the rhizosphere", "link": "89470778"}, "BIBREF34": {"title": "Detection of metal-chelating compounds from wood-rotting fungi Trametes versicolor and Wolfiporia cocos", "authors": [{"first": "A", "middle": [], "last": "Machuca", "suffix": ""}, {"first": "D", "middle": [], "last": "Napoleao", "suffix": ""}, {"first": "A", "middle": ["M F"], "last": "Milagres", "suffix": ""}], "year": 2001, "venue": "World J. Microbiol. Biotechnol", "link": "94864079"}, "BIBREF35": {"title": "Dissolution of feldspars by low-molecularweight aliphatic and aromatic acids", "authors": [{"first": "E", "middle": [], "last": "Manley", "suffix": ""}, {"first": "L", "middle": [], "last": "Evans", "suffix": ""}], "year": 1986, "venue": "Soil Sci", "link": "93518318"}, "BIBREF36": {"title": "Solubilization of insoluble inorganic zinc compounds by ericoid mycorrhizal fungi derived from heavy metal polluted sites", "authors": [{"first": "E", "middle": [], "last": "Martino", "suffix": ""}, {"first": "S", "middle": [], "last": "Perotto", "suffix": ""}, {"first": "R", "middle": [], "last": "Parsons", "suffix": ""}, {"first": "G", "middle": ["M"], "last": "Gadd", "suffix": ""}], "year": 2003, "venue": "Soil Biol. Biochem", "link": "85356463"}, "BIBREF37": {"title": "Dissolution of dental zinc phosphate cement in organic acid solution", "authors": [{"first": "S", "middle": [], "last": "Matsuya", "suffix": ""}, {"first": "Y", "middle": [], "last": "Matsuya", "suffix": ""}], "year": 1994, "venue": "J. Ceramic Soc. Jpn", "link": "101594032"}, "BIBREF38": {"title": "Leaching of zinc from an industrial filter dust with Penicillium, Pseudomonas and Corynebacterium: citric acid is the leaching agent rather than amino acids", "authors": [{"first": "B", "middle": [], "last": "Muller", "suffix": ""}, {"first": "W", "middle": [], "last": "Burgstaller", "suffix": ""}, {"first": "H", "middle": [], "last": "Strasser", "suffix": ""}, {"first": "A", "middle": [], "last": "Zanella", "suffix": ""}, {"first": "F", "middle": [], "last": "Schinner", "suffix": ""}], "year": 1995, "venue": "J. Ind. Microbiol", "link": "24485015"}, "BIBREF39": {"title": "Mechanisms of dissolution of iron oxides in aqueous oxalic acid solutions", "authors": [{"first": "D", "middle": [], "last": "Panias", "suffix": ""}, {"first": "M", "middle": [], "last": "Taxiarchou", "suffix": ""}, {"first": "A", "middle": [], "last": "Kontopoulos", "suffix": ""}], "year": 1996, "venue": "Hydrometallurgy", "link": null}, "BIBREF40": {"title": "pH signaling in Sclerotinia sclerotiorum: identification of a pacC/RIM1 homolog", "authors": [{"first": "J", "middle": ["A"], "last": "Rollings", "suffix": ""}, {"first": "M", "middle": ["B"], "last": "Dickman", "suffix": ""}], "year": 2001, "venue": "Appl. Environ. Microbiol", "link": "32673310"}, "BIBREF41": {"title": "Solubilization of insoluble compounds by soil fungi: development of a screening method for solubilizing ability and metal tolerance", "authors": [{"first": "J", "middle": ["A"], "last": "Sayer", "suffix": ""}, {"first": "S", "middle": ["L"], "last": "Raggett", "suffix": ""}, {"first": "G", "middle": ["M"], "last": "Gadd", "suffix": ""}], "year": 1995, "venue": "Mycol. Res", "link": "84721283"}, "BIBREF42": {"title": "Solubilisation and transformation of insoluble metal compounds to insoluble metal oxalates by Aspergillus niger", "authors": [{"first": "J", "middle": ["A"], "last": "Sayer", "suffix": ""}, {"first": "G", "middle": ["M"], "last": "Gadd", "suffix": ""}], "year": 1997, "venue": "Mycol. Res", "link": null}, "BIBREF43": {"title": "Lead mineral transformation by fungi", "authors": [{"first": "J", "middle": ["A"], "last": "Sayer", "suffix": ""}, {"first": "J", "middle": ["D"], "last": "Cotter-Howells", "suffix": ""}, {"first": "C", "middle": [], "last": "Watson", "suffix": ""}, {"first": "S", "middle": [], "last": "Hillier", "suffix": ""}, {"first": "G", "middle": ["M"], "last": "Gadd", "suffix": ""}], "year": 1999, "venue": "Curr. Biol", "link": "19743818"}, "BIBREF44": {"title": "Binding of cobalt and zinc by organic acids and culture filtrates of Aspergillus niger grown in the absence or presence of insoluble cobalt or zinc phosphate", "authors": [{"first": "J", "middle": ["A"], "last": "Sayer", "suffix": ""}, {"first": "G", "middle": ["M"], "last": "Gadd", "suffix": ""}], "year": 2001, "venue": "Mycol. Res", "link": "43035725"}, "BIBREF45": {"title": "High yield production of oxalic acid for metal leaching purposes by Aspergillus niger", "authors": [{"first": "H", "middle": [], "last": "Strasser", "suffix": ""}, {"first": "W", "middle": [], "last": "Burgstaller", "suffix": ""}, {"first": "F", "middle": [], "last": "Schinner", "suffix": ""}], "year": 1994, "venue": "FEMS Microbiol. Lett", "link": null}, "BIBREF46": {"title": "Occurrence of crystalline hyphal sheaths in Poria placenta (Fr.)", "authors": [{"first": "H", "middle": ["P"], "last": "Sutter", "suffix": ""}, {"first": "E", "middle": ["B G"], "last": "Jones", "suffix": ""}, {"first": "O", "middle": [], "last": "Walchi", "suffix": ""}], "year": 1984, "venue": "Cke. J. Inst. Wood Sci", "link": "89387467"}, "BIBREF47": {"title": "Colonization of corn, Zea mays, by the entopathogenic fungus Beauveria bassiana", "authors": [{"first": "B", "middle": ["L"], "last": "Wagner", "suffix": ""}, {"first": "L", "middle": ["C"], "last": "Lewis", "suffix": ""}], "year": 2000, "venue": "Appl. Environ. Microbiol", "link": "46127631"}, "BIBREF48": {"title": "Apatite as a source in mycorrhizal and non-mycorrhizal Pinus sylvestris seedlings", "authors": [{"first": "H", "middle": [], "last": "Wallander", "suffix": ""}, {"first": "T", "middle": [], "last": "Wickman", "suffix": ""}, {"first": "G", "middle": [], "last": "Jacks", "suffix": ""}], "year": 1997, "venue": "Plant Soil", "link": "28780508"}, "BIBREF49": {"title": "Microbial extracellular polysaccharides and plagioclase dissolution", "authors": [{"first": "S", "middle": ["A"], "last": "Welch", "suffix": ""}, {"first": "W", "middle": ["W"], "last": "Barker", "suffix": ""}, {"first": "J", "middle": ["F"], "last": "Banfield", "suffix": ""}], "year": 1999, "venue": "Geochim. Cosmochim. Acta", "link": "95901189"}, "BIBREF50": {"title": "Clavicipitalean fungal epibionts and endophytes-development of symbiotic interactions with plants", "authors": [{"first": "J", "middle": ["F"], "last": "White", "suffix": ""}, {"first": "F", "middle": [], "last": "Belanger", "suffix": ""}, {"first": "W", "middle": ["M"], "last": "Meyer", "suffix": ""}, {"first": "R", "middle": ["F"], "last": "Sullivan", "suffix": ""}, {"first": "J", "middle": ["F"], "last": "Bischoff", "suffix": ""}, {"first": "E", "middle": ["A"], "last": "Lewis", "suffix": ""}], "year": 2002, "venue": "Symbiosis", "link": "88883676"}, "BIBREF51": {"title": "Analysis of phylogenetic relationships by amplification and direct sequencing of ribosomal RNA genes", "authors": [{"first": "T", "middle": ["J"], "last": "White", "suffix": ""}, {"first": "T", "middle": ["D"], "last": "Bruns", "suffix": ""}, {"first": "S", "middle": [], "last": "Lee", "suffix": ""}, {"first": "J", "middle": [], "last": "Taylor", "suffix": ""}], "year": 1990, "venue": "PCR protocols: a guide to methods and applications", "link": "88956749"}, "BIBREF52": {"title": "Reductive dissolution of manganese(III, IV) (hydr)-oxides by oxalate: the effect of pH and light", "authors": [{"first": "A", "middle": ["G"], "last": "Xyla", "suffix": ""}, {"first": "B", "middle": [], "last": "Sulzberger", "suffix": ""}, {"first": "G", "middle": ["W"], "last": "Lither", "suffix": ""}, {"first": "Iii", "middle": [], "last": "", "suffix": ""}, {"first": "J", "middle": ["G"], "last": "Hering", "suffix": ""}, {"first": "P", "middle": [], "last": "Van Cappellen", "suffix": ""}, {"first": "W", "middle": [], "last": "Stumm", "suffix": ""}], "year": 1992, "venue": "Langmuir", "link": "96070144"}}, "ref_entries": {}}
{"paper_id": "17788292", "_pdf_hash": "8b54011536136781ace396a334514f00f7f62bee", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Estimation of monthly rainfall over Japan and surrounding waters from a combination of low-orbit microwave and geosynchronous IR data", "authors": [{"first": "R", "middle": ["F"], "last": "Adler", "suffix": ""}, {"first": "P", "middle": ["R"], "last": "Keehn", "suffix": ""}, {"first": "I", "middle": ["M"], "last": "Hakkainen", "suffix": ""}], "year": 1993, "venue": "Journal of Applied Meteorology", "link": "119557499"}, "BIBREF1": {"title": "Adequacy of satellite derived rainfall data for stream flow modelling", "authors": [{"first": "G", "middle": [], "last": "Artan", "suffix": ""}, {"first": "H", "middle": [], "last": "Gadain", "suffix": ""}, {"first": "J", "middle": ["L"], "last": "Smith", "suffix": ""}, {"first": "K", "middle": [], "last": "Asante", "suffix": ""}, {"first": "C", "middle": ["J"], "last": "Bandaragoda", "suffix": ""}, {"first": "J", "middle": [], "last": "Verdin", "suffix": ""}], "year": 2007, "venue": "Natural Hazards", "link": "129125923"}, "BIBREF2": {"title": "Assessment of methods for extracting low-resolution river networks from high-resolution digital data", "authors": [{"first": "H", "middle": ["N"], "last": "Davies", "suffix": ""}, {"first": "V", "middle": ["A"], "last": "Bell", "suffix": ""}], "year": 2009, "venue": "Hydrological Sciences Journal", "link": "129430035"}, "BIBREF3": {"title": "Scaling gridded river networks for macroscale hydrology: development, analysis, and control of error", "authors": [{"first": "B", "middle": ["M"], "last": "Fekete", "suffix": ""}, {"first": "", "middle": [], "last": "V\u00f6", "suffix": ""}, {"first": "C", "middle": ["J"], "last": "Smarty", "suffix": ""}, {"first": "R", "middle": ["B"], "last": "Lammers", "suffix": ""}], "year": 2001, "venue": "Water Resources Research", "link": "129775250"}, "BIBREF4": {"title": "Large-scale runoff routing with an aggregated network-response function", "authors": [{"first": "L", "middle": [], "last": "Gong", "suffix": ""}, {"first": "E", "middle": [], "last": "Wid\u00e9 N-Nilsson", "suffix": ""}, {"first": "S", "middle": [], "last": "Halldin", "suffix": ""}, {"first": "C.-Y", "middle": [], "last": "Xu", "suffix": ""}], "year": 2009, "venue": "Journal of Hydrology", "link": "54605935"}, "BIBREF5": {"title": "Investigating the optimal configuration of conceptual hydrologic models for satellite-rainfall-based flood prediction", "authors": [{"first": "A", "middle": [], "last": "Harris", "suffix": ""}, {"first": "F", "middle": [], "last": "Hossain", "suffix": ""}], "year": 2008, "venue": "IEEE Geoscience and Remote Sensing Letters", "link": "16380531"}, "BIBREF6": {"title": "Estimation of Global NRCS-CN (Natural Resource Conservation Service Curve Numbers) using satellite remote sensing and geospatial data", "authors": [{"first": "Y", "middle": [], "last": "Hong", "suffix": ""}, {"first": "R", "middle": ["F"], "last": "Adler", "suffix": ""}], "year": 2008, "venue": "International Journal of Remote Sensing", "link": null}, "BIBREF7": {"title": "Precipitation estimation from remotely sensed imagery using artificial neural network -cloud classification system (PERSIANN-CCS)", "authors": [{"first": "Y", "middle": [], "last": "Hong", "suffix": ""}, {"first": "K", "middle": ["L"], "last": "Hsu", "suffix": ""}, {"first": "X", "middle": [], "last": "Gao", "suffix": ""}, {"first": "S", "middle": [], "last": "Sorooshian", "suffix": ""}], "year": 2004, "venue": "Journal of Applied Meteorology", "link": null}, "BIBREF8": {"title": "Uncertainty quantification of satellite precipitation estimation and Monte Carlo assessment of the error propagation into hydrologic response", "authors": [{"first": "Y", "middle": [], "last": "Hong", "suffix": ""}, {"first": "K.-L", "middle": [], "last": "Hsu", "suffix": ""}, {"first": "H", "middle": [], "last": "Moradkhani", "suffix": ""}, {"first": "S", "middle": [], "last": "Sorooshian", "suffix": ""}], "year": 2006, "venue": "Water Resources Research", "link": "18226424"}, "BIBREF9": {"title": "A first approach to global runoff simulation using satellite rainfall estimation", "authors": [{"first": "Y", "middle": [], "last": "Hong", "suffix": ""}, {"first": "R", "middle": ["F"], "last": "Adler", "suffix": ""}, {"first": "F", "middle": [], "last": "Hossain", "suffix": ""}, {"first": "S", "middle": [], "last": "Curtis", "suffix": ""}, {"first": "G", "middle": ["J"], "last": "Huffman", "suffix": ""}], "year": 2007, "venue": "Water Resources Research", "link": null}, "BIBREF10": {"title": "The TRMM Multisatellite Precipitation Analysis (TMPA): Quasi-global, multiyear, combined sensor precipitation estimates at fine scales", "authors": [{"first": "G", "middle": ["J"], "last": "Huffman", "suffix": ""}, {"first": "R", "middle": ["F"], "last": "Adler", "suffix": ""}, {"first": "D", "middle": ["T"], "last": "Bolvin", "suffix": ""}, {"first": "G", "middle": ["J"], "last": "Gu", "suffix": ""}, {"first": "E", "middle": ["J"], "last": "Nelkin", "suffix": ""}, {"first": "K", "middle": ["P"], "last": "Bowman", "suffix": ""}, {"first": "Y", "middle": [], "last": "Hong", "suffix": ""}, {"first": "E", "middle": ["F"], "last": "Stocker", "suffix": ""}, {"first": "D", "middle": ["B"], "last": "Wolff", "suffix": ""}], "year": 2007, "venue": "Journal of Hydrometeorology", "link": "18674044"}, "BIBREF11": {"title": "The TRMM Multi-satellite Precipitation Analysis (TMPA)", "authors": [{"first": "G", "middle": ["J"], "last": "Huffman", "suffix": ""}, {"first": "R", "middle": ["F"], "last": "Adler", "suffix": ""}, {"first": "D", "middle": ["T"], "last": "Bolvin", "suffix": ""}, {"first": "E", "middle": ["J"], "last": "Nelkin", "suffix": ""}], "year": 2010, "venue": "Satellite Applications for Surface Hydrology, F. Hossain and M. Gebremichael (Eds)", "link": "129382382"}, "BIBREF12": {"title": "Good practices for substantial human loss reduction from floods", "authors": [], "year": 2006, "venue": "", "link": null}, "BIBREF13": {"title": "CMORPH: a method that produces global precipitation estimates from passive microwave and infrared data at high spatial and temporal resolution", "authors": [{"first": "R", "middle": ["J"], "last": "Joyce", "suffix": ""}, {"first": "J", "middle": ["E"], "last": "Janowiak", "suffix": ""}, {"first": "P", "middle": ["A"], "last": "Arkin", "suffix": ""}, {"first": "P", "middle": [], "last": "Xie", "suffix": ""}], "year": 2004, "venue": "Journal of Hydrometeorology", "link": "54609580"}, "BIBREF14": {"title": "The NCEP stage II/IV hourly precipitation analyses: development and applications", "authors": [{"first": "Y", "middle": [], "last": "Lin", "suffix": ""}, {"first": "K", "middle": ["E"], "last": "Mitchell", "suffix": ""}], "year": 2005, "venue": "Preprints, 19th Conference on Hydrology 9-13", "link": null}, "BIBREF15": {"title": "River routing at the continental scale: use of globally-available data and an a priori method of parameter estimation", "authors": [{"first": "P", "middle": [], "last": "Naden", "suffix": ""}, {"first": "P", "middle": [], "last": "Broadhurst", "suffix": ""}, {"first": "N", "middle": [], "last": "Tauveron", "suffix": ""}, {"first": "A", "middle": [], "last": "Walker", "suffix": ""}], "year": 1999, "venue": "Hydrology and Earth System Sciences", "link": "128897920"}, "BIBREF16": {"title": "Design of total runoff integrating pathways TRIP -a global river channel network", "authors": [{"first": "T", "middle": [], "last": "Oki", "suffix": ""}, {"first": "Y", "middle": ["C"], "last": "Sud", "suffix": ""}], "year": 1998, "venue": "Earth Interactions", "link": "130269024"}, "BIBREF17": {"title": "Real-time estimation of precipitation fields using radar precipitation and rain gauge data", "authors": [{"first": "D", "middle": ["J"], "last": "Seo", "suffix": ""}], "year": 1998, "venue": "Journal of Hydrology", "link": null}, "BIBREF18": {"title": "Evaluation of PERSIANN system satellite-based estimates of tropical rainfall", "authors": [{"first": "S", "middle": [], "last": "Sorooshian", "suffix": ""}, {"first": "K.-L", "middle": [], "last": "Hsu", "suffix": ""}, {"first": "X", "middle": [], "last": "Gao", "suffix": ""}, {"first": "H", "middle": [], "last": "Gupta", "suffix": ""}, {"first": "B", "middle": [], "last": "Imam", "suffix": ""}, {"first": "D", "middle": [], "last": "Braithwaite", "suffix": ""}], "year": 2000, "venue": "Bulletin of the American Meteorological Society", "link": "124631220"}, "BIBREF19": {"title": "An examination of radar and rain gauge-derived mean areal precipitation over Georgia watersheds", "authors": [{"first": "K", "middle": ["M"], "last": "Stellman", "suffix": ""}, {"first": "H", "middle": ["E"], "last": "Fuelberg", "suffix": ""}, {"first": "R", "middle": [], "last": "Garza", "suffix": ""}, {"first": "M", "middle": [], "last": "Mullusky", "suffix": ""}], "year": 2001, "venue": "", "link": "122987778"}, "BIBREF20": {"title": "Evaluation of TRMM Multisatellite Precipitation Analysis (TMPA) and its utility in hydrologic prediction in the La Plata Basin", "authors": [{"first": "F", "middle": [], "last": "Su", "suffix": ""}, {"first": "Y", "middle": [], "last": "Hong", "suffix": ""}, {"first": "D", "middle": ["P"], "last": "Lettenmaier", "suffix": ""}], "year": 2008, "venue": "Journal of Hydrometeorology", "link": "15937849"}, "BIBREF21": {"title": "Multitemporal analysis of TRMM-based satellite precipitation products for land data assimilation applications", "authors": [{"first": "Y", "middle": [], "last": "Tian", "suffix": ""}, {"first": "C", "middle": ["D"], "last": "Peters-Lidard", "suffix": ""}, {"first": "B", "middle": ["J"], "last": "Choudhury", "suffix": ""}, {"first": "Garcia", "middle": [], "last": "", "suffix": ""}, {"first": "M", "middle": [], "last": "", "suffix": ""}], "year": 2007, "venue": "Journal of Hydrometeorology", "link": "129391993"}, "BIBREF22": {"title": "Intercomparison of rain gauge, radar, and satellite-based precipitation estimates with emphasis on hydrologic forecasting", "authors": [{"first": "K", "middle": ["K"], "last": "Yilmaz", "suffix": ""}, {"first": "T", "middle": ["S"], "last": "Hogue", "suffix": ""}, {"first": "K.-L", "middle": [], "last": "Hsu", "suffix": ""}, {"first": "S", "middle": [], "last": "Sorooshian", "suffix": ""}, {"first": "H", "middle": ["V"], "last": "Gupta", "suffix": ""}, {"first": "T", "middle": [], "last": "Wagener", "suffix": ""}], "year": 2005, "venue": "Journal of Hydrometeorology", "link": "17757895"}}, "ref_entries": {}}
{"paper_id": "17788621", "_pdf_hash": "5d1ecf78392e60a5a050c4151d88c03c0a825f69", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Automating bug report assignment", "authors": [{"first": "J", "middle": [], "last": "Anvik", "suffix": ""}], "year": 2006, "venue": "Proc. of the 28th Int. Conf. on Software Engineering", "link": "18239576"}, "BIBREF1": {"title": "Coping with an open bug repository", "authors": [{"first": "J", "middle": [], "last": "Anvik", "suffix": ""}, {"first": "L", "middle": [], "last": "Hiew", "suffix": ""}, {"first": "G", "middle": ["C"], "last": "Murphy", "suffix": ""}], "year": 2005, "venue": "Proc. of the 2005 OOPSLA Workshop on Eclipse Technology Exchange", "link": "164909"}, "BIBREF2": {"title": "Who should fix this bug?", "authors": [{"first": "J", "middle": [], "last": "Anvik", "suffix": ""}, {"first": "L", "middle": [], "last": "Hiew", "suffix": ""}, {"first": "G", "middle": ["C"], "last": "Murphy", "suffix": ""}], "year": 2006, "venue": "Proc. of the 28th international Conference on Software Engineering", "link": "1384439"}, "BIBREF3": {"title": "ICSE '06", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF4": {"title": "What makes a good bug report", "authors": [{"first": "N", "middle": [], "last": "Bettenburg", "suffix": ""}, {"first": "S", "middle": [], "last": "Just", "suffix": ""}, {"first": "A", "middle": [], "last": "Schr\u00f6ter", "suffix": ""}, {"first": "C", "middle": [], "last": "Weiss", "suffix": ""}, {"first": "R", "middle": [], "last": "Premraj", "suffix": ""}, {"first": "T", "middle": [], "last": "Zimmermann", "suffix": ""}], "year": 2008, "venue": "Proc. of the 16th ACM SIGSOFT Int. Symp. on Foundations of Software Engineering", "link": "5913612"}, "BIBREF5": {"title": "Quality of bug reports in Eclipse", "authors": [{"first": "N", "middle": [], "last": "Bettenburg", "suffix": ""}, {"first": "S", "middle": [], "last": "Just", "suffix": ""}, {"first": "A", "middle": [], "last": "Schr\u00f6ter", "suffix": ""}, {"first": "C", "middle": [], "last": "Wei\u00df", "suffix": ""}, {"first": "R", "middle": [], "last": "Premraj", "suffix": ""}, {"first": "T", "middle": [], "last": "Zimmermann", "suffix": ""}], "year": 2007, "venue": "Proc of the 2007 OOPSLA Workshop on Eclipse Technology Exchange", "link": "11540279"}, "BIBREF6": {"title": "Duplicate bug reports considered harmful \u2026 really", "authors": [{"first": "N", "middle": [], "last": "Bettenburg", "suffix": ""}, {"first": "R", "middle": [], "last": "Premraj", "suffix": ""}, {"first": "T", "middle": [], "last": "Zimmermann", "suffix": ""}, {"first": "S", "middle": [], "last": "Kim", "suffix": ""}], "year": 2008, "venue": "IEEE International Conference on Software Maintenance", "link": "7998134"}, "BIBREF7": {"title": "One Step More to Understand the Bug Report Duplication Problem", "authors": [{"first": "Y", "middle": ["C"], "last": "Cavalcanti", "suffix": ""}, {"first": "P", "middle": ["M S N"], "last": "Anselmo", "suffix": ""}, {"first": "E", "middle": ["S"], "last": "Almeida", "suffix": ""}, {"first": "C", "middle": ["E.A"], "last": "Cunha", "suffix": ""}, {"first": "D", "middle": [], "last": "Lucredio", "suffix": ""}, {"first": "S", "middle": ["R L"], "last": "Meira", "suffix": ""}], "year": "", "venue": "Proceedings of the 2010 Brazilian Symposium on Software Engineering (SBES '10", "link": "16011740"}, "BIBREF8": {"title": "An Initial Study on the Bug Report Duplication Problem", "authors": [{"first": "Y", "middle": ["C"], "last": "Cavalcanti", "suffix": ""}, {"first": "E", "middle": ["S"], "last": "Almeida", "suffix": ""}, {"first": "C", "middle": ["E.A"], "last": "Cunha", "suffix": ""}, {"first": "D", "middle": [], "last": "Lucredio", "suffix": ""}, {"first": "S", "middle": ["R"], "last": "Meira", "suffix": ""}], "year": 2010, "venue": "14th European Conference on Software Maintenance and Reengineering", "link": "8056171"}, "BIBREF9": {"title": "Drawing and sketching in Open Source design", "authors": [{"first": "E", "middle": [], "last": "Chung", "suffix": ""}, {"first": "C", "middle": [], "last": "Jensen", "suffix": ""}, {"first": "K", "middle": [], "last": "Yatani", "suffix": ""}, {"first": "V", "middle": [], "last": "Kuechler", "suffix": ""}, {"first": "K", "middle": ["N"], "last": "Truong", "suffix": ""}], "year": 2010, "venue": "IEEE Symposium on Visual Languages and Human-Centric Computing, 2010. VL/HCC", "link": null}, "BIBREF10": {"title": "Socialization in an Open Source Software Community: A Socio-Technical Analysis", "authors": [{"first": "N", "middle": [], "last": "Ducheneaut", "suffix": ""}], "year": 2005, "venue": "Computer Supported Coop. Work", "link": "6165778"}, "BIBREF11": {"title": "The Orbiten Free Software Survey", "authors": [{"first": "R", "middle": ["A"], "last": "Ghosh", "suffix": ""}, {"first": "V", "middle": ["V"], "last": "Prakash", "suffix": ""}], "year": 2000, "venue": "First Monday", "link": null}, "BIBREF12": {"title": "Leveraging open-source software in the design and development process", "authors": [{"first": "C", "middle": [], "last": "Green", "suffix": ""}, {"first": "I", "middle": [], "last": "Tollinger", "suffix": ""}, {"first": "C", "middle": [], "last": "Ratterman", "suffix": ""}, {"first": "G", "middle": [], "last": "Pyrzak", "suffix": ""}, {"first": "A", "middle": [], "last": "Eiser", "suffix": ""}, {"first": "L", "middle": [], "last": "Castro", "suffix": ""}, {"first": "A", "middle": [], "last": "Vera", "suffix": ""}], "year": "", "venue": "Proc. of the", "link": "9373916"}, "BIBREF13": {"title": "on Human Factors in Computing Systems", "authors": [{"first": "", "middle": [], "last": "Int", "suffix": ""}, {"first": "", "middle": [], "last": "Conf", "suffix": ""}], "year": 2009, "venue": "", "link": null}, "BIBREF14": {"title": "Working for free? Motivations of participating in open source projects", "authors": [{"first": "A", "middle": [], "last": "Hars", "suffix": ""}, {"first": "S", "middle": [], "last": "Ou", "suffix": ""}], "year": 2001, "venue": "Proceedings of the 34th Annual Hawaii International Conference on", "link": "1074342"}, "BIBREF15": {"title": "Automated duplicate detection for bug tracking systems", "authors": [{"first": "N", "middle": [], "last": "Jalbert", "suffix": ""}, {"first": "W", "middle": [], "last": "Weimer", "suffix": ""}], "year": 2008, "venue": "IEEE Int. Conf. on Dependable Sys. and Networks With FTCS and DCC", "link": "11545475"}, "BIBREF16": {"title": "Role Migration and Advancement Processes in OSSD Projects: A Comparative Case Study", "authors": [{"first": "C", "middle": [], "last": "Jensen", "suffix": ""}, {"first": "W", "middle": [], "last": "Scacchi", "suffix": ""}], "year": 2007, "venue": "Int Conf. on Software Engineering, ICSE'07", "link": "5718724"}, "BIBREF17": {"title": "Improving bug triage with bug tossing graphs", "authors": [{"first": "G", "middle": [], "last": "Jeong", "suffix": ""}, {"first": "S", "middle": [], "last": "Kim", "suffix": ""}, {"first": "T", "middle": [], "last": "Zimmermann", "suffix": ""}], "year": 2009, "venue": "Proc. of the the 7th Joint Meeting of the European Software Engineering Conf. and the ACM SIGSOFT Symposium on the Foundations of Software Engineering", "link": "14428047"}, "BIBREF18": {"title": "How power users help and hinder open bug reporting", "authors": [{"first": "A", "middle": ["J"], "last": "Ko", "suffix": ""}, {"first": "P", "middle": ["K"], "last": "Chilana", "suffix": ""}], "year": 2010, "venue": "Proc. of the 28th Int. Conf on Human Factors in Computing Systems", "link": "8442975"}, "BIBREF19": {"title": "Cave or Community?: An Empirical Examination of 100 Mature Open Source Projects", "authors": [{"first": "S", "middle": [], "last": "Krishnamurthy", "suffix": ""}], "year": 2002, "venue": "First Monday", "link": "38700379"}, "BIBREF20": {"title": "Two case studies of open source software development: Apache and Mozilla", "authors": [{"first": "A", "middle": [], "last": "Mockus", "suffix": ""}, {"first": "R", "middle": ["T"], "last": "Fielding", "suffix": ""}, {"first": "J", "middle": ["D"], "last": "Herbsleb", "suffix": ""}], "year": 2002, "venue": "ACM Transactions on Software Engineering Methodology", "link": "1938015"}, "BIBREF21": {"title": "Predicting Eclipse Bug Lifetimes", "authors": [{"first": "L", "middle": ["D"], "last": "Panjer", "suffix": ""}], "year": 2007, "venue": "Proceedings of the 4th int. Workshop on Mining Software Repositories. Int. Conference on Software Engineering", "link": "15400066"}, "BIBREF22": {"title": "Supporting the Learning Process of Open Source Novices: An Evaluation of Code and Project History Visualization Tools", "authors": [{"first": "Y", "middle": [], "last": "Park", "suffix": ""}], "year": 2008, "venue": "", "link": null}, "BIBREF23": {"title": "The Cathedral and the Bazaar", "authors": [{"first": "Eric", "middle": ["S"], "last": "Raymond", "suffix": ""}], "year": 2000, "venue": "Computers & Mathematics with Applications", "link": "908300"}, "BIBREF24": {"title": "Community, joining, and specialization in open source software innovation: a case study", "authors": [{"first": "G", "middle": [], "last": "Von Krogh", "suffix": ""}, {"first": "S", "middle": [], "last": "Spaeth", "suffix": ""}, {"first": "K", "middle": ["R"], "last": "Lakhani", "suffix": ""}], "year": 2003, "venue": "Open Source Software Development", "link": "14150967"}, "BIBREF25": {"title": "An approach to detecting duplicate bug reports using natural language and execution information", "authors": [{"first": "X", "middle": [], "last": "Wang", "suffix": ""}, {"first": "L", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "T", "middle": [], "last": "Xie", "suffix": ""}, {"first": "J", "middle": [], "last": "Anvik", "suffix": ""}, {"first": "J", "middle": [], "last": "Sun", "suffix": ""}], "year": 2008, "venue": "Proc. of the 30th Int Conf on Software Engineering", "link": "5637463"}, "BIBREF26": {"title": "How Long Will It Take to Fix This Bug?", "authors": [{"first": "C", "middle": [], "last": "Weiss", "suffix": ""}, {"first": "R", "middle": [], "last": "Premraj", "suffix": ""}, {"first": "T", "middle": [], "last": "Zimmermann", "suffix": ""}, {"first": "A", "middle": [], "last": "Zeller", "suffix": ""}], "year": 2007, "venue": "4 th Int. Workshop on Mining Software Repositories, MSR '07", "link": "1986915"}, "BIBREF27": {"title": "Toward an understanding of the motivation of open source software developers", "authors": [{"first": "Y", "middle": [], "last": "Yunwen", "suffix": ""}, {"first": "K", "middle": [], "last": "Kishida", "suffix": ""}], "year": 2003, "venue": "Proc. of the 25 th Int. Conf. on Software Engineering", "link": null}}, "ref_entries": {}}
{"paper_id": "17788658", "_pdf_hash": "3e95f47c8c397c4e9b17bc7227dee630b7787519", "abstract": [{"section": "Abstract", "text": "Macrophages are divided into two subpopulations: classically activated macrophages (M1) and alternatively activated macrophages (M2). BCG (Bacilli Calmette-Gu\u00e9rin) activates disabled na\u00efve macrophages to M1 macrophages, which act as inflammatory, microbicidal and tumoricidal cells through cell-cell contact and/or the release of soluble factors. Various transcription factors and signaling pathways are involved in the regulation of macrophage activation and polarization. We discovered that BCG-activated macrophages (BAM) expressed a new molecule, and we named it Novel Macrophage Activated Associated Protein 1 (NMAAP1).", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "The current study found that the overexpression of NMAAP1 in macrophages results in M1 polarization with increased expression levels of M1 genes, such as inducible nitric oxide synthase (iNOS), tumor necrosis factor alpha (TNF-\u03b1), Interleukin 6 (IL-6), Interleukin 12 (IL-12), Monocyte chemoattractant protein-1 (MCP-1) and Interleukin-1 beta (IL-1\u03b2), and decreased expression of some M2 genes, such as Kruppel-like factor 4 (KLF4) and suppressor of cytokine signaling 1 (SOCS1), but not other M2 genes, including arginase-1 (Arg-1), Interleukin (IL-10), transforming growth factor beta (TGF-\u03b2) and found in inflammatory zone 1 (Fizz1). Moreover, NMAAP1 overexpression in the RAW264.7 cell line increased cytotoxicity against MCA207 tumor cells, which depends on increased inflammatory cytokines rather than cell-cell contact. NMAAP1 also substantially enhanced the phagocytic ability of macrophages, which implies that NMAAP1 promoted macrophage adhesive and clearance activities. Our results indicate that NMAAP1 is an essential molecule that modulates macrophages phenotype and plays an important role in macrophage tumoricidal functions.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "INTRODUCTION", "text": "Activated macrophages produce various cytokines, chemokines, and enzymes (Chan et al., 2011) , and exhibit diverse and opposing functions, including pro-and anti-inflammatory responses, tissue repair and destruction, and tumoricidal, proangiogenesis and pro-tumoral functions (Labonte et al., 2014; Villalta et al., 2009; Wang et al., 2014) . The paradoxical plasticity of macrophage function is closely related to the polarized activation state.", "cite_spans": [{"start": 73, "end": 92, "text": "(Chan et al., 2011)", "ref_id": "BIBREF6"}, {"start": 276, "end": 298, "text": "(Labonte et al., 2014;", "ref_id": "BIBREF19"}, {"start": 299, "end": 321, "text": "Villalta et al., 2009;", "ref_id": "BIBREF42"}, {"start": 322, "end": 340, "text": "Wang et al., 2014)", "ref_id": "BIBREF43"}], "ref_spans": []}, {"section": "INTRODUCTION", "text": "Heterogenic macrophages are divided into two subpopulations: classically activated macrophages (M1) and alternatively activated macrophages (M2). LPS and IFN gamma activate classical or M1 macrophages, which exhibit the following characteristics: high endocytic and phagocytic capacities; high production of interleukin-12 (IL-12), interleukin-23 (IL-23) and toxic intermediates (e.g., nitric oxide and reactive oxygen intermediates); great antigen presentation abilities; and high antimicrobial and anti-proliferative activities (Sica and Mantovani, 2012) . Therefore, M1 macrophages are generally considered potent effector cells that exhibit anti-microbial and tumoricidal abilities and secrete large amounts of pro-inflammatory cytokines (Sica et al., 2014) . In contrast, interleukin-4 (IL-4), interleukin-13 (IL-13), glucocorticoids, interleukin-10 (IL-10) or immunoglobulin complexes activate alternatively activated or M2 macrophages. M2 cells produce small amounts of inflammatory cytokines (e.g., , promote tissue remodeling and repair, contribute to angiogenesis and tumor progression, and exhibit low antigen presentation capacity (Gordon et al., 2010) . These seemingly opposing effects may be explained by the existence of phenotypically and functionally heterogeneous macrophages. Several molecules, including miR223, suppressor of cytokine signaling 3 (SOCS3), Kruppel-like factor 4 (KLF4) and peroxisome proliferator-activated receptors \u03b3 (PPAR\u03b3), and cells, such as Th1, Th2, Tregs and B cells, regulate macrophage polarization and contribute to different macrophage functions (Wang et al., 2014; Wong et al., 2010) .", "cite_spans": [{"start": 530, "end": 556, "text": "(Sica and Mantovani, 2012)", "ref_id": "BIBREF35"}, {"start": 742, "end": 761, "text": "(Sica et al., 2014)", "ref_id": "BIBREF36"}, {"start": 1143, "end": 1164, "text": "(Gordon et al., 2010)", "ref_id": "BIBREF13"}, {"start": 1595, "end": 1614, "text": "(Wang et al., 2014;", "ref_id": "BIBREF43"}, {"start": 1615, "end": 1633, "text": "Wong et al., 2010)", "ref_id": "BIBREF44"}], "ref_spans": []}, {"section": "INTRODUCTION", "text": "Macrophages obtain surprisingly high tumoricidal activities after activation by select stimuli. Bacilli Calmette-Gu\u00e9rin (BCG) is a strong stimulus that is used for the treatment of superficial bladder cancer (Huang et al., 2015; Liu et al., 2014) . However, the mechanism of action of BCG is not clear. Several studies suggest that the tumoricidal effect is related to the ability of BCG to activate macrophages (Lodillinsky et al., 2010; Luo et al., 2006; Svatek et al., 2015; Thompson et al., 2015) . Stimulation of macrophages with BCG in vitro induces cytotoxicity against bladder cancer cells via interleukin-6 (IL-6), interleukin-12 (IL-12), and tumor necrosis factor alpha (TNF-\u03b1) secretion, and this activation process is inhibited by IL-10 and direct contact with cancer cells (Benoit et al., 2008; Svatek et al., 2015) . The cytotoxicity of BCG-activated macrophages requires direct cell-to-cell contact and soluble factors, such as IL-6, Interferon gamma (FN-\u03b3) and TNF-\u03b1. Neutralizing endogenous cytokines, including IL-12, IL-18, IFN-\u03b3 and TNF-\u03b1, reduce the cytotoxicity of BCG-activated macrophage by 38%, 22%, 15% and 94%, respectively (Luo et al., 2006) .", "cite_spans": [{"start": 208, "end": 228, "text": "(Huang et al., 2015;", "ref_id": "BIBREF17"}, {"start": 229, "end": 246, "text": "Liu et al., 2014)", "ref_id": "BIBREF21"}, {"start": 412, "end": 438, "text": "(Lodillinsky et al., 2010;", "ref_id": "BIBREF22"}, {"start": 439, "end": 456, "text": "Luo et al., 2006;", "ref_id": "BIBREF24"}, {"start": 457, "end": 477, "text": "Svatek et al., 2015;", "ref_id": "BIBREF37"}, {"start": 478, "end": 500, "text": "Thompson et al., 2015)", "ref_id": "BIBREF39"}, {"start": 786, "end": 807, "text": "(Benoit et al., 2008;", "ref_id": "BIBREF2"}, {"start": 808, "end": 828, "text": "Svatek et al., 2015)", "ref_id": "BIBREF37"}, {"start": 1151, "end": 1169, "text": "(Luo et al., 2006)", "ref_id": "BIBREF24"}], "ref_spans": []}, {"section": "INTRODUCTION", "text": "Novel macrophage activated-associated protein 1 (NMAAP1, accession number: NP 001001738) was identified using capillary liquid chromatography tandem-mass spectrometry (LC-MS/MS) in BCG-activated macrophage (Zhang et al., 2007) . NMAAP1 is a novel membrane-associated protein in BCGactivated macrophages that contains a partial male abnormal 21 (MAB-21) domain, and it is expressed in a wide range of tissues (Kang et al., 2010) . MAB-21 is a conserved sequence that acts as part of the mechanism required for correct cell fate choice, and the MAB-21 gene in vertebrates exhibits an amino acid homology up to 90% (Baldessari et al., 2004; Yamada et al., 2004; Zhao et al., 2011) . DANGER1A has an MAB-21 domain that binds the inositol trisphosphate receptor (IP3R) to promote the differentiation and outgrowth of neuronal processes (Ho et al., 2001) . Whether NMAAP1 has the same effect as DANGER1A is not known.", "cite_spans": [{"start": 206, "end": 226, "text": "(Zhang et al., 2007)", "ref_id": "BIBREF47"}, {"start": 408, "end": 427, "text": "(Kang et al., 2010)", "ref_id": "BIBREF18"}, {"start": 612, "end": 637, "text": "(Baldessari et al., 2004;", "ref_id": "BIBREF1"}, {"start": 638, "end": 658, "text": "Yamada et al., 2004;", "ref_id": "BIBREF46"}, {"start": 659, "end": 677, "text": "Zhao et al., 2011)", "ref_id": "BIBREF48"}, {"start": 831, "end": 848, "text": "(Ho et al., 2001)", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "INTRODUCTION", "text": "This study investigated the relationship between macrophage polarization state and NMAAP1 expression after BCG treatment in a mouse model to clarify the physiological function of NMAAP1 in BCG-activated macrophage polarization. NMAAP1 overexpression in RAW264.7 cells was established to investigate the effect of NMAAP1 on macrophage phenotype, phagocytic ability and tumoricidal activities. Our results demonstrate that NMAAP1 is a modulatory protein in macrophage polarization and cytotoxicity.", "cite_spans": [], "ref_spans": []}, {"section": "MATERIALS AND METHODS", "text": "Cells and animals RAW264.7 cells (murine macrophage cell line ATCC TIB-71) and transfected RAW264.7 cells were cultured in Dulbecco\u2032s Modified Eagle\u2032s Medium (DMEM) with 10% heat-inactivated fetal bovine serum (Sigma, USA), 100 \u03bcg/ml streptomycin and 100 IU/ml penicillin (Invitrogen). Cells were maintained at 37\u00b0C in a 5% CO 2 incubator. The MCA207 cell line was kindly provided by Prof. Kangla Tsung (Stanford University, USA). This cell line is a methylcholan-threne-induced transplantable tumor in C57BL/6 mice, and these cells were maintained in the same conditions. ICR mice were purchased from the Experimental Animal Center of Jilin University. All mice were housed under specific pathogen-free conditions in the animal facilities of Jilin University. The Institutional Animal Care and Use Committee of Jilin University approved the experimental procedures. Transfection RAW264.7 cells were seeded at 2 x 10 5 per well in a 24-well plate and grown until 70-80% confluency before transfection. pIRES2-EGFP/NMAAP1 or pIRES2-EGFP/CONTROL plasmids were directly transfected into the cells using Lipofectamine\u2122 2000 Transfection Reagent (Invitrogen, USA) according to the manufacturer's protocol. Fluorescein-labeled pIRES2-EGFP/NMAAP1 or pIRES2-EGFP/CONTROL transfected cells were examined under fluorescence optics to determine transfection efficiency after 24 and 48 h. 3-5% and 7-8% initial transfection efficiency was observed in RAW264.7 cells 24 and 48 h post-transfection, respectively. Selection was performed 72 h later using media that contained G418 (400 \u03bcg/ml). Culture continued for 14 days to generate stable transfectants, and G418-resistant clones were isolated. GFP signals from transfected RAW264.7 cells were assessed using fluorescence microscopy. Clones were further expanded and analyzed usingby regular PCR and Western blotting. Transfected cells were used for subsequent experiments.", "cite_spans": [], "ref_spans": []}, {"section": "MATERIALS AND METHODS", "text": "BCG treatment and peritoneal macrophage preparation ICR mice (n = 6/group/treatment/experiment) were injected intraperitoneally with 2 mg BCG (Shanghai Institute of Biological Products) or PBS on day 2 and day 10. Peritoneal exudate cells were harvested from these mice, and peritoneal macrophages were purified on days 4, 8, and 12 by washing cells from peritoneal cavity lavage with 5 ml of ice-cold, sterile PBS, according to a previously described protocol (Park et al., 2014) . The cells were distributed in DMEM supplemented with 10% FBS in six-well tissue culture plates (5 x 10 6 cells/ml) and incubated for 4 h. Non-adherent cells were removed by washing twice with Opti-MEM at 37\u00b0C in a 5% CO 2 incubator.", "cite_spans": [{"start": 461, "end": 480, "text": "(Park et al., 2014)", "ref_id": "BIBREF28"}], "ref_spans": []}, {"section": "Reverse transcription and quantitative real-time PCR (qRT-PCR)", "text": "Total RNA was directly isolated from adherent macrophages using Trizol reagent (Invitrogen, USA), according to the manufacturer\u2032s protocol. RNA quantity and quality were determined using an absorbance microplate reader TQuant (BioTEK, USA). cDNA for reverse transcription was prepared from 2 \u03bcg of total RNA using oligo(dT) primers and reverse transcriptase M-MLV in a total volume of 20 \u03bcl, according to the manufacturer\u2032s instructions (Takara, Japan). The resulting cDNA was used for real-time PCR for NMAAP1, iNOSII and cytokines (ARG-1, TNF-\u03b1, IL-10, and TGF-\u03b2) using an ABI PRISM 7300 sequence detection system (Applied Biosystems, USA). Quantitative PCR was performed using SYBR green PCR master mix (Applied Biosystem, USA). Expression of each gene was normalized to the expression of the housekeeping gene, glyceraldehyde-3-phosphate dehydrogenase (GAPDH). The following forward and reverse specific primer sequences were used:", "cite_spans": [], "ref_spans": []}, {"section": "Reverse transcription and quantitative real-time PCR (qRT-PCR)", "text": "Reverse 5\u2032-CGTCCGGAGTAATTTGGTGC-3\u2032 IL-6: Forward 5\u2032-TAGTCCTTCCTACCCCAATTT-3\u2032", "cite_spans": [], "ref_spans": []}, {"section": "Reverse transcription and quantitative real-time PCR (qRT-PCR)", "text": "Reverse 5\u2032-TTGGTCCTTAGCCACTCCTTC-3\u2032 KLF4: Forward 5\u2032-TATACATTCCGCCACAGCAG-3\u2032", "cite_spans": [], "ref_spans": []}, {"section": "Reverse transcription and quantitative real-time PCR (qRT-PCR)", "text": "Reverse 5\u2032-CGCCTCTTGCTTAATCTTGG-3\u2032 MCP-1: Forward 5\u2032-TTAAAAACCTGGATCGGAACC-3\u2032", "cite_spans": [], "ref_spans": []}, {"section": "Reverse transcription and quantitative real-time PCR (qRT-PCR)", "text": "Reverse 5\u2032-GCATTAGCTTCAGATTTACGG-3\u2032 Fizz1: Forward 5\u2032-CCCTTCTCATCTGCATCT-3\u2032", "cite_spans": [], "ref_spans": []}, {"section": "Reverse transcription and quantitative real-time PCR (qRT-PCR)", "text": "Reverse 5\u2032-CTGGATTGGCAAGAAGTTCC-3\u2032 SOCS1: Forward 5\u2032-CTGCGGCTTCTATTGGGGAC-3\u2032", "cite_spans": [], "ref_spans": []}, {"section": "Reverse transcription and quantitative real-time PCR (qRT-PCR)", "text": "Reverse 5\u2032-AAAAGGCAGTCGAAGTCTCG-3\u2032 SOCS3: Forward 5\u2032-CCCTTGCAGTTCTAAGTTCAA-3\u2032", "cite_spans": [], "ref_spans": []}, {"section": "Reverse transcription and quantitative real-time PCR (qRT-PCR)", "text": "Reverse 5\u2032-ACCTTTGACAAGCGGACTCTC-3\u2032 ARG-1: Forward 5\u2032-CAGTCTGGCAGTTGGAAGC-3\u2032", "cite_spans": [], "ref_spans": []}, {"section": "Reverse transcription and quantitative real-time PCR (qRT-PCR)", "text": "Reverse 5\u2032-GGTTGTCAGGGGAGTGTTG-3\u2032 TNF-\u03b1: Forward 5\u2032-ACTGAACTTCGGGGTGATCG-3\u2032", "cite_spans": [], "ref_spans": []}, {"section": "Reverse transcription and quantitative real-time PCR (qRT-PCR)", "text": "Reverse 5\u2032-CCACTTGGTGGTTTGCTACG-3\u2032 IL-10: Forward 5\u2032-GTTGCCAAGCCTTATCGG-3\u2032 Reverse 5\u2032-GCTCTTATTTTCACAGGGGAG-3\u2032 TGF-\u03b2: Forward 5\u2032-GAGGCGGTGCTCGCTTTGTA-3\u2032", "cite_spans": [], "ref_spans": []}, {"section": "Reverse transcription and quantitative real-time PCR (qRT-PCR)", "text": "Reverse 5\u2032-CGTTGTTGCGGTCCACCATTA-3\u2032 GAPDH: Forward 5\u2032-GACTTCAACAGCAACTCCCACTC-3\u2032", "cite_spans": [], "ref_spans": []}, {"section": "Reverse transcription and quantitative real-time PCR (qRT-PCR)", "text": "Reverse 5\u2032-TAGCCGTATTCATTGTCATACCAG-3\u2032", "cite_spans": [], "ref_spans": []}, {"section": "Reverse transcription and quantitative real-time PCR (qRT-PCR)", "text": "Each reaction for real-time quantitative PCR contained 1x SYBR Green PCR master mixture (Power SYBR Green PCR Master Mix; Applied Biosystems, UK), 10 pmol of each primer, and 1 \u03bcl of cDNA in a final volume of 20 \u03bcl. The following reaction conditions were used: initial activation step (5 min at 95\u00b0C) and cycling step (denaturation for 30 s at 94\u00b0C, annealing for 30 s at 60\u00b0C and extension for 1 min at 72\u00b0C \u00d7 40 cycles) followed by melt curve analysis. Detection of the dequenched probe, calculation of threshold cycles (Ct values), and further data analyses were performed using the Sequence Detector software. Relative changes in NMAAP1, iNOSII and cytokines (ARG-1, TNF-\u03b1, IL-10, and TGF-\u03b2) mRNA expression were compared with control, normalized to GAPDH, and were quantified using the 2-(\u25b3\u25b3Ct) method. Therefore, all values for experimental samples are expressed as fold differences between the sample mRNA and the calibrator (GAPDH) mRNA.", "cite_spans": [], "ref_spans": []}, {"section": "Flow cytometric analysis", "text": "Cells were washed twice in phosphate-buffered saline, counted, and re-suspended in FACS buffer (3% FBS in PBS containing 0.01% NaN 3 ). Cells (1 x 10 6 cells/samples) for phenotypic analyses were stained using the indicated fluorochromeconjugated antibody for 30 min on ice. Cells were washed with FACS buffer, and appropriate isotype controls were used in all cases. Typical forward-and side-scatter gates for flow cytometric analyses were set to exclude dead and aggregated cells. A total of 10 4 events in the gate were collected and analyzed using Accuri C6 and software (BD Biosciences, USA). The anti-CD23, anti-CD16/32 and anti-F4/80 antibodies (Abs) used in flow cytometric analyses were obtained from eBioscience (USA).", "cite_spans": [], "ref_spans": []}, {"section": "Flow cytometric analysis", "text": "Cytokines measurement using ELISA Blood was extracted from mouse eye sockets. Serum was prepared using routine methods and stored in a -80\u00b0C refrigerator for subsequent tests. Serum and supernatant cytokine levels of were measured using an enzyme-linked immunoassay (ELISA) kit according to the manufacturer\u2032s instructions (eBioscience, USA). Briefly, 100 \u03bcl of sera were added to each well of a 96-well plate precoated with 100 \u03bcl/well capture antibody and incubated for 2 h at 37\u00b0C. The wells were washed and a detection antibody (biotin-conjugated antibody) was added for 1 h at 37\u00b0C. Wells were washed, and an avidin-horseradish peroxidase (HRP)-labeled Ab was added for 30 min at 37\u00b0C. A final wash was performed, and the presence of HRP-labeled Abs was revealed by the addition of tetramethylbenidine (TMB). The reaction was stopped with sulfuric acid (2 N). Coloration was evaluated using an optical density at 450-570 nm.", "cite_spans": [], "ref_spans": []}, {"section": "Phagocytic function of ON/RAW264.7 cells using fluorescence and FACS", "text": "Microsphere pellets were resuspended in 3% (w/v) BSA and incubated at 37\u00b0C for 30 min. Microspheres were sonicated in a bath sonicator at 80 W for 5 min. The coating of microspheres in BSA ensures that beads remain in a monodispersed state and do not aggregate. OV/RAW264.7 and ON/RAW264.7 cells were plated at 5 \u00d7 10 5 cells/well in 6-well culture plates (USA) for 24 h (37\u00b0C, 5% CO 2 , humidified), and microspheres were added to each well at a final cell to particle ratio of 1:15 (1 \u03bcm) for approximately 90 min at 37\u00b0C. The culture media were aspirated, and cells were washed three times with ice-cold PBS to remove excess beads. Cells were observed under fluorescence microscopy to analyze the phagocytosis rate and phagocytosis index or lifted from culture plates by gentle scraping for flow cytometry analyses. Mean fluorescence represents the average fluorescent intensity of all intact cells counted per experiment. ", "cite_spans": [], "ref_spans": []}, {"section": "Protein preparation and Western blot analysis", "text": "Various cells were harvested and lysed in lysis buffer (50 mM Tris-HCl, 1% NP40, 150 mM NaCl, 1 mM EDTA and 1 mM PMSF) for 30 min at 4\u00b0C. Total cell extracts were separated using 12% SDS/PAGE gels and transferred to PVDF membranes. Membranes were blocked with 3% BSA and incubated with primary antibodies diluted in blocking solution. The signals were visualized using the chemiluminescent substrate method and the SuperSignal West Pico Kit (Pierce). The \u03b2-actin was used as an internal control to normalize the loading materials.", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "NMAAP1 expression coincides with M1 markers in BCG-activated macrophages", "text": "We examined the phenotype of BCG-activated macrophages to delineate the effect of BCG on macrophage biological functions. We detected the expression of M1 and M2 cell markers and NMAAP1 levels. CD16/32 (M1) and CD23 (M2) were used to detect the phenotypes of BCG-activated macrophages. The percentage of BCG-activated macrophages that expressed M1 markers increased on day 4 and decreased on day 8. Mice were challenged with i.p. BCG on day 10. Therefore, there was an increase in these markers on day 12 (Figs. 1A and 1B) . We next examined whether NMAAP1 was critical in macrophage polarization. We performed quantitative RT-PCR (qPCR) analysis of BCG-activated macrophages (BAMs). NMAAP1 mRNA increased in BAMs with a peak of a ~70-fold increase on day 4 and decreased in the following 4 days. NMAAP1 mRNA expression increased from day 8 to day 12 and decreased subsequently. NMAAP1 mRNA expression increased slightly on day 12. There was a similar pattern of changes in the percentage of M1 BAMs. IL-10 mRNA expression increased slowly from day 4 to day 8 and declined rapidly until day 12. Therefore, the change in IL-10 mRNA expression was opposite to NMAAP1 mRNA expression (Fig. 1C) . We performed ELISAs to measure IL-10 and TNF-\u03b1 release in BCG-stimulated mice sera on day 4, 8 and 12 (Fig. 1D) . ", "cite_spans": [], "ref_spans": [{"start": 505, "end": 522, "text": "(Figs. 1A and 1B)", "ref_id": "FIGREF0"}, {"start": 1181, "end": 1190, "text": "(Fig. 1C)", "ref_id": "FIGREF0"}, {"start": 1295, "end": 1304, "text": "(Fig. 1D)", "ref_id": "FIGREF0"}]}, {"section": "NMAAP1 overexpression in RAW264.7 cells", "text": "Some morphological changes in RAW264.7 were observed after gene transfection. EGFP expression was observed 24 and 48 hours after transfection using fluorescent microscopy, and the transfection efficiency reached peak levels at 72 h. RAW264.7 cells were transfected with pIRES2-EGFP/NMAAP1 or pIRES2-EGFP/CONTROL expression plasmids and selected with G418 as indicated. Stably transfected cells were observed in the same field ( Fig. 2A) . The results of RT-PCR and Western blot analyses verified that RAW264.7 cells transfected with pIRES2-EGFP/NMAAP1 overexpressed NMAAP1 (ON/RAW264.7) compared to cells transfected with empty pIRES2-EGFP/CONTROL (OV/RAW264.7) (Figs. 2B-2E ). The molecular weight of the expressed full-length NMAAP1 was approximately 63 kDa, which is consistent with the previously reported molecular weight of NMAAP1 (Zhao et al., 2011) .", "cite_spans": [{"start": 837, "end": 856, "text": "(Zhao et al., 2011)", "ref_id": "BIBREF48"}], "ref_spans": [{"start": 428, "end": 436, "text": "Fig. 2A)", "ref_id": "FIGREF1"}, {"start": 662, "end": 674, "text": "(Figs. 2B-2E", "ref_id": "FIGREF1"}]}, {"section": "NMAAP1 overexpression contributes to M1 polarization of RAW264.7", "text": "Classically activated macrophages exhibit a TNF-\u03b1 high iN-OS-II high cytokine profile and exhibit an increased expression of CD16/32 (Herder et al., 2014; Liu et al., 2013) . Therefore, we evaluated whether NMAAP1 played a regulatory role in macrophage polarization. We characterized ON/RAW264.7 cells along an M1/M2 spectrum using functional and phenotypic readouts. Cells were stained and analyzed using flow cytometry of CD16/32 and CD23 expression (Fig. 3A) . A significantly higher percentage of ON/RAW264.7 cells expressed CD16/32 compared to control cells, but lower CD23 expression was observed (30.17% vs. 5.4%, respectively; p < 0.01) (Fig. 3B) . We quantified the expression of phenotypespecific markers of OV/RAW264.7 and ON/RAW264.7 cells using quantitative real-time RT-PCR analyses to determine the influence of NMAAP1 on M1 and M2 gene transcription (Fig. 3C) . The M1 markers iNOS, TNF-\u03b1, IL-6, IL-12 and MCP-1 were expressed at higher levels in ON/RAW264.7 cells than OV/RAW264.7 cells, which is consistent with the peritoneal macrophage results. The M2 markers TGF-\u03b2, Arg-1, Fizz1 and SOCS3 and the anti-inflammatory cytokine IL-10 were not significantly altered. The expression levels of KLF4 and SOCS1 were markedly lower in ON/RAW264.7 cells than OV/RAW264.7 cells.", "cite_spans": [{"start": 133, "end": 154, "text": "(Herder et al., 2014;", "ref_id": "BIBREF15"}, {"start": 155, "end": 172, "text": "Liu et al., 2013)", "ref_id": "BIBREF20"}], "ref_spans": [{"start": 452, "end": 461, "text": "(Fig. 3A)", "ref_id": "FIGREF2"}, {"start": 645, "end": 654, "text": "(Fig. 3B)", "ref_id": "FIGREF2"}, {"start": 866, "end": 875, "text": "(Fig. 3C)", "ref_id": "FIGREF2"}]}, {"section": "NMAAP1 overexpression contributes to M1 polarization of RAW264.7", "text": "TNF-\u03b1 concentrations in the supernatant of ON/RAW264.7 cells was higher than OV/RAW264.7 cells at 6 h, 12 h and 24 h. ON/RAW264.7 cells produced more IL-1\u03b2 than OV/RARW 264.7 cells at 24 h and 48 h. ON/RAW264.7 cells produced slightly higher IL-12 than OV/RARW264.7 cells (Fig. 3D ). There were no differences in the levels of the antiinflammatory molecular markers Arg-1 and IL-10 in the supernatants of ON/ RAW264.7 and OV/RAW264.7 cells (Fig.  3E) . These results indicate that NMAAP1 regulates some, but not all, M1 genes.", "cite_spans": [], "ref_spans": [{"start": 272, "end": 280, "text": "(Fig. 3D", "ref_id": "FIGREF2"}, {"start": 440, "end": 450, "text": "(Fig.  3E)", "ref_id": "FIGREF2"}]}, {"section": "NMAAP1 modulates macrophage-mediated phagocytosis", "text": "Phagocytosis is the process by which invading pathogens and dead cells are efficiently removed by phagocytic cells, primarily macrophages. Macrophage phagocytosis plays an important role in host defense (Das et al., 2014) . The phagocytic activities of OV/RAW264.7 and ON/RAW264.7 cells were measured using fluorescent microspheres after co-incubation for 2 h. Phagocytosis rates and phagocytosis index of OV/RAW264.7 and ON/RAW264.7 cells were quantified using fluorescence microscopy (Figs. 4A and 4B) and flow cytometry (Figs. 4C and 4D ). OV/RAW264.7 and ON/RAW264.7 cells efficiently phagocytize fluorescent microspheres. However, ON/RAW264.7 cells exhibited a significantly higher phagocytosis rate and phagocytosis index against xenogeneic target microspheres than OV/RAW264.7 cells.", "cite_spans": [{"start": 203, "end": 221, "text": "(Das et al., 2014)", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "NMAAP1 promotes tumoricidal activities of RAW264.7", "text": "Cytotoxicity assays were performed via the culture of tumor cells with supernatants collected from OV/RAW264.7 and ON/RAW264.7 cultures to determine the influence of NMAAP1 on the tumoricidal activity of macrophages. ON/RAW264.7 cells presented a more prominent cytotoxicity effect for the inhibition of MCA207 tumor cell viability than OV/RAW264.7 cells (Fig. 5A) .", "cite_spans": [], "ref_spans": []}, {"section": "NMAAP1 promotes tumoricidal activities of RAW264.7", "text": "We measured the contact-dependent tumoricidal function and excluded the possible effect of soluble factors using paraformaldehyde (PFA)-fixed macrophages. PFA-fixed OV/RAW264.7 and ON/RAW264.7 cells did not significantly alter the cytotoxicity of cells co-cultured with MCA207 cells at 24 h, 48 h and 72 h (Fig.  5B ). Tumor cell death was measured using morphological analyses (Hoechst 33342) and flow cytometry to further confirm these results. Figure 5C shows that most cells from the control M. from at least three independent experiments. *P < 0.05, **P < 0.01 and ***P < 0.001 (unpaired Student t test. compared with the corresponding control values).", "cite_spans": [], "ref_spans": []}, {"section": "A C B D E", "text": "h group (MAC207 alone and OV/RAW264.7 + MCA207) contained large and regular nuclei. Clear evidence of chromatin condensation and a clear decrease in cell size was observed in cells cultured for 48 h in the supernatant of ON/RAW264.7 cells cultured for 24 h (white arrow). Cell death was also measured using the fluorescent dye Annexin V-FITC, which binds phosphatidylserine residues that are redistributed from the inner to the outer leaflet of the cell membrane as an early event in apoptosis. After the loss of membrane integrity, 7AAD enters the cell and intercalates into DNA. Figures 5D and 5E show the percentages of Annexin V-stained and 7AAD-stained cells in response to the supernatants of OV/RAW264.7 and ON/RAW264.7 cells (24 h). The supernatant of ON/RAW264.7 cell culture (48 h) on MCA207 culture for 24 h induced a greater population of apoptotic cells than the OV/RAW264.7 group (33.6% vs. 8.1%). These data suggest that NMAAP1 exerts prominent effect on the modulation of macrophage-mediated cytotoxicity, which may occur via NMAAP1 induction of macrophage secretion of more inflammatory cytokines.", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "Macrophages (M\u0444) are a heterogeneous cell population that are involved in diverse physiological processes, including antimicrobial defense, wound resolution, inflammation, tissue remodeling and the promotion of tumor growth (Epelman et al., 2014; Wynn et al., 2013) . Macrophages achieve high tumoricidal activity after activation by some stimuli, such as BCG. BCG is the attenuated (virulence-reduced) live bovine tuberculosis bacillus, Mycobacterium bovis, which has lost its virulence in humans. Macrophages recognize BCG through Toll-like receptor 2 (TLR2), Toll-like receptor 9 (TLR9) and possibly Tolllike receptor 4 (TLR4) and become activated. Activated macrophages have been used for the treatment of some bladder cancers for more than two decades (Huang et al., 2015; Liu et al., 2014) , and they exhibit antitumor effects via direct cell-tocell contact (Zhang et al., 2007) . Macrophages with strong microbicidal and tumoricidal activities are generally regarded as M1 macrophages, with characteristics of TNF-\u03b1, IL-1\u03b2, inducible nitric oxide synthase (iNOS or NOS2), and reactive nitrogen and oxygen intermediates production and promotion of Th1 responses (Biswas et al., 2012; Sica and Mantovani, 2012) . Our results demonstrated that macrophages from BCGinjected mice exhibited an M1 polarized phenotype. However, previous reports demonstrated that some components of Mycobacterium tuberculosis, such as lipoproteins, DnaK and PPE18, interact with TLR2 and activate IL-10 induction in macrophages and polarize macrophages to the M2-like phenotype (Lopes et al., 2014; Nair et al., 2009; Pecora et al., 2006) . One reason for these differences may be that the pathogenic mycobacterium bovis strains differ in their ability to modulate the polarization of macrophages. The B2 and H37Rv strains synergistically induce M1 polarization, and the MP287/03 strain expresses high levels of Arg-1, which lead to lower levels of NO production (Andrade et al., 2012) . Another reason may be that different components of attenuated and viable M. tuberculosis induce the absolute opposite polarization of macrophages. Lipoproteins and the MHC class II inhibition of M. tuberculosis may be destroyed after attenuation, but other components that promote M1 polarization of macrophages remain (Pai et al., 2014) . The components of BCG that promote M1 polarization require more experiments to support these hypotheses. The expression of many proteins was upregulated in BCGactivated macrophages, which would play important roles in the tumoricidal effect or modulatory activities. The novel protein NMAAP1 was specifically expressed on BCG-stimulated macrophages, and it played a crucial role in the regulation of M1 macrophage polarization. BCG-activated macrophages maintained NMAAP1 expression during a state of high activity in M1-polarized cells, which facilitated M1 gene expression. Upregulated NMAAP1 expression in RAW264.7 cells increased the expression of M1 markers (e.g., CD16/32, iNOS, TNF-\u03b1, IL-6, IL-12, MCP-1 and IL-1\u03b2), and decreased or did not affect M2 markers (e.g., KLF4, SOCS1, IL-10, SOCS3, Fizz1 and Arg-1) (Labonte et al., 2014) .", "cite_spans": [{"start": 224, "end": 246, "text": "(Epelman et al., 2014;", "ref_id": "BIBREF11"}, {"start": 247, "end": 265, "text": "Wynn et al., 2013)", "ref_id": "BIBREF45"}, {"start": 757, "end": 777, "text": "(Huang et al., 2015;", "ref_id": "BIBREF17"}, {"start": 778, "end": 795, "text": "Liu et al., 2014)", "ref_id": "BIBREF21"}, {"start": 864, "end": 884, "text": "(Zhang et al., 2007)", "ref_id": "BIBREF47"}, {"start": 1168, "end": 1189, "text": "(Biswas et al., 2012;", "ref_id": "BIBREF3"}, {"start": 1190, "end": 1215, "text": "Sica and Mantovani, 2012)", "ref_id": "BIBREF35"}, {"start": 1561, "end": 1581, "text": "(Lopes et al., 2014;", "ref_id": "BIBREF23"}, {"start": 1582, "end": 1600, "text": "Nair et al., 2009;", "ref_id": "BIBREF25"}, {"start": 1601, "end": 1621, "text": "Pecora et al., 2006)", "ref_id": "BIBREF29"}, {"start": 1946, "end": 1968, "text": "(Andrade et al., 2012)", "ref_id": "BIBREF0"}, {"start": 2290, "end": 2308, "text": "(Pai et al., 2014)", "ref_id": "BIBREF27"}, {"start": 3128, "end": 3150, "text": "(Labonte et al., 2014)", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "DISCUSSION", "text": "BCG-activated macrophages kill tumor cells through cell-tocell contact and the secretion of tumoricidal mediators, such as iNOS, TNF-\u03b1, INF-\u03b3, IL-2, IL-6 and IL-12, which induce macrophage activation and cytotoxic activity, and IL-10 plays a negative role in BCG-induced macrophage cytotoxicity (Luo and Knudson, 2010) . However, knowledge of the mechanism of cell-cell contact-mediated killing is limited. BCG infection may upregulate adhesion molecules, such as lymphocyte function-associated antigen-1 (LFA-1) or apoptosis-inducing molecules, such as Fas ligand and TRAIL on macrophages (DesJardin et al., 2002; Diehl et al., 2004) . Soluble factors released from BCG-activated human monocytes/macrophages contributed to the total killing of bladder cancer UCRU-BL-17 cells more than effector-target cell contact (Pryor et al., 1995) . NMAAP1-transfected RAW264.7 cells exhibited profound toxic effects on tumor cells, especially the induction of tumor cell apoptosis. Cytotoxicity was also enhanced through the secretion of iNOS, TNF-\u03b1, and IL-6. However, tumoricidal effects on tumor cells through cell-to-cell contact were not detected. This result may be because NMAAP1 could not regulate the tumoricidal membrane protein expression on macrophages. Activated macrophages engulf tumor cells via antibody-mediated phagocytosis (Overdijk et al., 2015) . The effect of increased phagocytic ability suggests that NMAAP1 plays an important role in the clearing of tumor cells and invading pathogens (Das et al., 2014) , and it may enhance the expression of some adhesive molecules and IgG receptors (DesJardin et al., 2002; Shi et al., 2015) .", "cite_spans": [{"start": 590, "end": 614, "text": "(DesJardin et al., 2002;", "ref_id": "BIBREF9"}, {"start": 615, "end": 634, "text": "Diehl et al., 2004)", "ref_id": "BIBREF10"}, {"start": 816, "end": 836, "text": "(Pryor et al., 1995)", "ref_id": "BIBREF30"}, {"start": 1332, "end": 1355, "text": "(Overdijk et al., 2015)", "ref_id": "BIBREF26"}, {"start": 1500, "end": 1518, "text": "(Das et al., 2014)", "ref_id": "BIBREF8"}, {"start": 1600, "end": 1624, "text": "(DesJardin et al., 2002;", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "DISCUSSION", "text": "NMAAP1 is a membrane-associated protein that contains an open-reading frame (ORF) that encodes a peptide of 555 amino acids and a small portion of the MAB-21 domain that is expressed in a wide range of tissues (Zhao et al., 2011) . Members of the MAB-21 family control cellular differentiation in C. elegans, Danio rerio, and Mus musculus (Heanue and Pachnis, 2006; Yamada et al., 2004) .", "cite_spans": [{"start": 210, "end": 229, "text": "(Zhao et al., 2011)", "ref_id": "BIBREF48"}, {"start": 339, "end": 365, "text": "(Heanue and Pachnis, 2006;", "ref_id": "BIBREF14"}, {"start": 366, "end": 386, "text": "Yamada et al., 2004)", "ref_id": "BIBREF46"}], "ref_spans": []}, {"section": "DISCUSSION", "text": "NMAAP1 bears a similar amino acid sequence to the human protein kiaa1754, which is a regulatory protein for inositol 1,4,5-trisphosphate-receptor activity. The kiaa1754 protein is a membrane-associated IP3R-binding protein that physiologically binds IP3R to regulate calcium release and neuronal process outgrowth in neuronal cell lineages (van Rossum et al., 2006) . We hypothesized that NMAAP1 shared a regulatory activity on IP3R and played an important role via IP3R-mediated calcium signaling to trigger the differentiation of certain macrophage subpopulations and prompt phagocytic and tumoricidal activities of macrophage.", "cite_spans": [{"start": 340, "end": 365, "text": "(van Rossum et al., 2006)", "ref_id": "BIBREF41"}], "ref_spans": []}, {"section": "DISCUSSION", "text": "Various factors, including cytokines/chemokines, hormones, and external biomechanical stimuli affect macrophage phenotype. The mechanism of actions of these factors is related to calcium signaling (Collins and Meyer, 2009; Evans and Fake, 2007; Trav\u00e9s et al., 2013) . Ca 2+ is a highly versatile intracellular signaling messenger that regulates many different cellular processes during the entire cell lifespan, such as cell differentiation, proliferation, secretion and synaptic plasticity. Recent reports demonstrate that several molecules, such as DANGER (van Rossum et al., 2006) , cytochrome c (Boehning et al., 2003; 2005) , polyglutamine expanded huntingtin (Htt exp ) and huntingtin-associated protein-1A (Tang et al., 2003) , strictly regulate Ca 2+ release activity via binding to IP3R in physiological and pathological situations.", "cite_spans": [{"start": 197, "end": 222, "text": "(Collins and Meyer, 2009;", "ref_id": "BIBREF7"}, {"start": 245, "end": 265, "text": "Trav\u00e9s et al., 2013)", "ref_id": "BIBREF40"}, {"start": 558, "end": 583, "text": "(van Rossum et al., 2006)", "ref_id": "BIBREF41"}, {"start": 599, "end": 622, "text": "(Boehning et al., 2003;", "ref_id": "BIBREF4"}, {"start": 623, "end": 628, "text": "2005)", "ref_id": "BIBREF5"}, {"start": 713, "end": 732, "text": "(Tang et al., 2003)", "ref_id": "BIBREF38"}], "ref_spans": []}, {"section": "DISCUSSION", "text": "These results demonstrated that BCG increased NMAAP1 expression in macrophages, and NMAAP1 may promote the polarization of M1 macrophages, which exhibit tumoricidal activities through the secretion of inducible mediators.", "cite_spans": [], "ref_spans": []}, {"section": "Note: Supplementary information is available on the Molecules and Cells website (www.molcells.org).", "text": "", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Pathogenic Mycobacterium bovis strains differ in their ability to modulate the proinflammatory activation phenotype of macrophages", "authors": [{"first": "M", "middle": ["R"], "last": "Andrade", "suffix": ""}, {"first": "E", "middle": ["P"], "last": "Amaral", "suffix": ""}, {"first": "S", "middle": ["C"], "last": "Ribeiro", "suffix": ""}, {"first": "F", "middle": ["M"], "last": "Almeida", "suffix": ""}, {"first": "T", "middle": ["V"], "last": "Peres", "suffix": ""}, {"first": "V", "middle": [], "last": "Lanes", "suffix": ""}, {"first": "M", "middle": ["R"], "last": "D&apos;imp\u00e9rio-Lima", "suffix": ""}, {"first": "E", "middle": ["B"], "last": "Lasunskaia", "suffix": ""}], "year": 2012, "venue": "BMC Microbiol", "link": "5352924"}, "BIBREF1": {"title": "MAB21L2, a vertebrate member of the Male-abnormal 21 family, modulates BMP signaling and interacts with SMAD1", "authors": [{"first": "D", "middle": [], "last": "Baldessari", "suffix": ""}, {"first": "A", "middle": [], "last": "Badaloni", "suffix": ""}, {"first": "R", "middle": [], "last": "Longhi", "suffix": ""}, {"first": "V", "middle": [], "last": "Zappavigna", "suffix": ""}, {"first": "G", "middle": ["G"], "last": "Consalez", "suffix": ""}], "year": 2004, "venue": "BMC Cell Biol", "link": "16958148"}, "BIBREF2": {"title": "Macrophage polarization in bacterial infections", "authors": [{"first": "M", "middle": [], "last": "Benoit", "suffix": ""}, {"first": "B", "middle": [], "last": "Desnues", "suffix": ""}, {"first": "J", "middle": ["L"], "last": "Mege", "suffix": ""}], "year": 2008, "venue": "J. Immunol", "link": "17130960"}, "BIBREF3": {"title": "Orchestration of metabolism by macrophages", "authors": [{"first": "S", "middle": ["K"], "last": "Biswas", "suffix": ""}, {"first": "A", "middle": [], "last": "Mantovani", "suffix": ""}], "year": 2012, "venue": "Cell Metab", "link": "12116499"}, "BIBREF4": {"title": "Cytochrome c binds to inositol (1,4,5) trisphosphate receptors, amplifying calcium-dependent apoptosis", "authors": [{"first": "D", "middle": [], "last": "Boehning", "suffix": ""}, {"first": "R", "middle": ["L"], "last": "Patterson", "suffix": ""}, {"first": "L", "middle": [], "last": "Sedaghat", "suffix": ""}, {"first": "N", "middle": ["O"], "last": "Glebova", "suffix": ""}, {"first": "T", "middle": [], "last": "Kurosaki", "suffix": ""}, {"first": "S", "middle": ["H"], "last": "Snyder", "suffix": ""}], "year": 2003, "venue": "Nat Cell Biol", "link": "27761335"}, "BIBREF5": {"title": "A peptide inhibitor of cytochrome c/inositol 1,4,5-trisphosphate receptor binding blocks intrinsic and extrinsic cell death pathways", "authors": [{"first": "D", "middle": [], "last": "Boehning", "suffix": ""}, {"first": "D", "middle": ["B"], "last": "Van Rossum", "suffix": ""}, {"first": "R", "middle": ["L"], "last": "Patterson", "suffix": ""}, {"first": "S", "middle": ["H"], "last": "Snyder", "suffix": ""}], "year": 2005, "venue": "Proc. Natl. Acad. Sci. USA", "link": "1680817"}, "BIBREF6": {"title": "CD4(+) T-cells are important in regulating macrophage polarization in C57BL/6 wild-type mice", "authors": [{"first": "T", "middle": [], "last": "Chan", "suffix": ""}, {"first": "E", "middle": ["A"], "last": "Pek", "suffix": ""}, {"first": "K", "middle": [], "last": "Huth", "suffix": ""}, {"first": "A", "middle": ["A"], "last": "Ashkar", "suffix": ""}], "year": 2011, "venue": "Cell Immunol", "link": "25065253"}, "BIBREF7": {"title": "Calcium flickers lighting the way in chemotaxis?", "authors": [{"first": "S", "middle": ["R"], "last": "Collins", "suffix": ""}, {"first": "T", "middle": [], "last": "Meyer", "suffix": ""}], "year": 2009, "venue": "Dev. Cell", "link": "3328493"}, "BIBREF8": {"title": "Plasminogen promotes macrophage phagocytosis in mice", "authors": [{"first": "R", "middle": [], "last": "Das", "suffix": ""}, {"first": "S", "middle": [], "last": "Ganapathy", "suffix": ""}, {"first": "M", "middle": [], "last": "Settle", "suffix": ""}, {"first": "E", "middle": ["F"], "last": "Plow", "suffix": ""}], "year": 2014, "venue": "Blood", "link": "24728922"}, "BIBREF9": {"title": "Mycobacterium tuberculosis-infected human macrophages exhibit enhanced cellular adhesion with increased expression of LFA-1 and ICAM-1 and reduced expression and/or function of complement receptors, FcgammaRII and the mannose receptor", "authors": [{"first": "L", "middle": ["E"], "last": "Desjardin", "suffix": ""}, {"first": "T", "middle": ["M"], "last": "Kaufman", "suffix": ""}, {"first": "B", "middle": [], "last": "Potts", "suffix": ""}, {"first": "B", "middle": [], "last": "Kutzbach", "suffix": ""}, {"first": "H", "middle": [], "last": "Yi", "suffix": ""}, {"first": "L", "middle": ["S"], "last": "Schlesinger", "suffix": ""}], "year": 2002, "venue": "Microbiology", "link": "22400969"}, "BIBREF10": {"title": "TRAIL-R as a negative regulator of innate immune cell responses", "authors": [{"first": "G", "middle": ["E"], "last": "Diehl", "suffix": ""}, {"first": "H", "middle": ["H"], "last": "Yue", "suffix": ""}, {"first": "K", "middle": [], "last": "Hsieh", "suffix": ""}, {"first": "A", "middle": ["A"], "last": "Kuang", "suffix": ""}, {"first": "M", "middle": [], "last": "Ho", "suffix": ""}, {"first": "L", "middle": ["A"], "last": "Morici", "suffix": ""}, {"first": "L", "middle": ["L"], "last": "Lenz", "suffix": ""}, {"first": "D", "middle": [], "last": "Cado", "suffix": ""}, {"first": "L", "middle": ["W"], "last": "Riley", "suffix": ""}, {"first": "A", "middle": [], "last": "Winoto", "suffix": ""}], "year": 2004, "venue": "Immunity", "link": "28717723"}, "BIBREF11": {"title": "Origin and functions of tissue macrophages", "authors": [{"first": "S", "middle": [], "last": "Epelman", "suffix": ""}, {"first": "K", "middle": ["J"], "last": "Lavine", "suffix": ""}, {"first": "G", "middle": ["J"], "last": "Randolph", "suffix": ""}], "year": 2014, "venue": "Immunity", "link": "205420665"}, "BIBREF12": {"title": "Ca 2+ influx is an essential component of the positive-feedback loop that maintains leadingedge structure and activity in macrophages", "authors": [{"first": "J", "middle": ["H"], "last": "Evans", "suffix": ""}, {"first": "J", "middle": ["J"], "last": "Falke", "suffix": ""}], "year": 2007, "venue": "Proc. Natl. Acad. Sci. USA", "link": "21357195"}, "BIBREF13": {"title": "Alternative activation of macrophages: mechanism and functions", "authors": [{"first": "S", "middle": [], "last": "Gordon", "suffix": ""}, {"first": "F", "middle": ["O"], "last": "Martinez", "suffix": ""}], "year": 2010, "venue": "Immunity", "link": "205412983"}, "BIBREF14": {"title": "Expression profiling the developing mammalian enteric nervous system identifies marker and candidate Hirschsprung disease genes", "authors": [{"first": "T", "middle": ["A"], "last": "Heanue", "suffix": ""}, {"first": "V", "middle": [], "last": "Pachnis", "suffix": ""}], "year": 2006, "venue": "Proc. Natl. Acad. Sci. USA", "link": "24267774"}, "BIBREF15": {"title": "Dynamic changes of microglia/macrophage M1 and M2 polarization in theiler's murine encephalomyelitis", "authors": [{"first": "V", "middle": [], "last": "Herder", "suffix": ""}, {"first": "C", "middle": ["D"], "last": "Iskandar", "suffix": ""}, {"first": "K", "middle": [], "last": "Kegler", "suffix": ""}, {"first": "F", "middle": [], "last": "Hansmann", "suffix": ""}, {"first": "S", "middle": ["A"], "last": "Elmarabet", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Khan", "suffix": ""}, {"first": "A", "middle": [], "last": "Kalkuhl", "suffix": ""}, {"first": "U", "middle": [], "last": "Deschl", "suffix": ""}, {"first": "W", "middle": [], "last": "Baumg\u00e4rtner", "suffix": ""}, {"first": "R", "middle": [], "last": "Ulrich", "suffix": ""}], "year": 2014, "venue": "Brain Pathol", "link": "207095045"}, "BIBREF16": {"title": "Postembryonic expression of Caenorhabditis elegans mab-21 and its requirement in sensory ray differentiation", "authors": [{"first": "S", "middle": ["H"], "last": "Ho", "suffix": ""}, {"first": "G", "middle": ["M"], "last": "So", "suffix": ""}, {"first": "K", "middle": ["L"], "last": "Chow", "suffix": ""}], "year": 2001, "venue": "Dev. Dyn", "link": "23197295"}, "BIBREF17": {"title": "Efficacy of intravesical Bacillus Calmette-Gu\u00e9rin therapy against tumor immune escape in an orthotopic model of bladder cancer", "authors": [{"first": "P", "middle": [], "last": "Huang", "suffix": ""}, {"first": "C", "middle": [], "last": "Ma", "suffix": ""}, {"first": "P", "middle": [], "last": "Xu", "suffix": ""}, {"first": "K", "middle": [], "last": "Guo", "suffix": ""}, {"first": "A", "middle": [], "last": "Xu", "suffix": ""}, {"first": "C", "middle": [], "last": "Liu", "suffix": ""}], "year": 2015, "venue": "Exp. Ther. Med", "link": "2352257"}, "BIBREF18": {"title": "Death-associated protein kinase-mediated cell death modulated by interaction with DANGER", "authors": [{"first": "B", "middle": ["N"], "last": "Kang", "suffix": ""}, {"first": "A", "middle": ["S"], "last": "Ahmad", "suffix": ""}, {"first": "S", "middle": [], "last": "Saleem", "suffix": ""}, {"first": "R", "middle": ["L"], "last": "Patterson", "suffix": ""}, {"first": "L", "middle": [], "last": "Hester", "suffix": ""}, {"first": "S", "middle": [], "last": "Dor\u00e9", "suffix": ""}, {"first": "S", "middle": ["H"], "last": "Snyder", "suffix": ""}], "year": 2010, "venue": "J. Neurosci", "link": "16124505"}, "BIBREF19": {"title": "The role of macrophage polarization in infectious and inflammatory diseases", "authors": [{"first": "A", "middle": ["C"], "last": "Labonte", "suffix": ""}, {"first": "A", "middle": ["C"], "last": "Tosello-Trampont", "suffix": ""}, {"first": "Y", "middle": ["S"], "last": "Hahn", "suffix": ""}], "year": 2014, "venue": "Mol. Cells", "link": "17571090"}, "BIBREF20": {"title": "Targeting the shift from M1 to M2 macrophages in experimental autoimmune encephalomyelitis mice treated with fasudil", "authors": [{"first": "C", "middle": [], "last": "Liu", "suffix": ""}, {"first": "Y", "middle": [], "last": "Li", "suffix": ""}, {"first": "J", "middle": [], "last": "Yu", "suffix": ""}, {"first": "L", "middle": [], "last": "Feng", "suffix": ""}, {"first": "S", "middle": [], "last": "Hou", "suffix": ""}, {"first": "Y", "middle": [], "last": "Liu", "suffix": ""}, {"first": "M", "middle": [], "last": "Guo", "suffix": ""}, {"first": "Y", "middle": [], "last": "Xie", "suffix": ""}, {"first": "J", "middle": [], "last": "Meng", "suffix": ""}, {"first": "H", "middle": [], "last": "Zhang", "suffix": ""}], "year": 2013, "venue": "PLoS One", "link": "17595817"}, "BIBREF21": {"title": "Cytokines as effectors and predictors of responses in the treatment of bladder cancer by bacillus Calmette-Gu\u00e9rin", "authors": [{"first": "X", "middle": [], "last": "Liu", "suffix": ""}, {"first": "A", "middle": ["C"], "last": "Dowell", "suffix": ""}, {"first": "P", "middle": [], "last": "Patel", "suffix": ""}, {"first": "R", "middle": ["P"], "last": "Viney", "suffix": ""}, {"first": "M", "middle": ["C"], "last": "Foster", "suffix": ""}, {"first": "E", "middle": [], "last": "Porfiri", "suffix": ""}, {"first": "N", "middle": ["D"], "last": "James", "suffix": ""}, {"first": "R", "middle": ["T"], "last": "Bryan", "suffix": ""}], "year": 2014, "venue": "Future Oncol", "link": "9407789"}, "BIBREF22": {"title": "Cytokines as effectors and predictors of responses in the treatment of bladder cancer by bacillus Calmette-Gu\u00e9rin", "authors": [{"first": "C", "middle": [], "last": "Lodillinsky", "suffix": ""}, {"first": "Y", "middle": [], "last": "Langle", "suffix": ""}, {"first": "A", "middle": [], "last": "Guionet", "suffix": ""}, {"first": "A", "middle": [], "last": "G\u00f3ngora", "suffix": ""}, {"first": "A", "middle": [], "last": "Baldi", "suffix": ""}, {"first": "E", "middle": ["O"], "last": "Sandes", "suffix": ""}, {"first": "A", "middle": [], "last": "Casab\u00e9", "suffix": ""}, {"first": "A", "middle": ["M"], "last": "Eij\u00e1n", "suffix": ""}], "year": 2010, "venue": "PLoS One", "link": "9407789"}, "BIBREF23": {"title": "Mycobacterium bovis bacillus Calmette-Gu\u00e9rin-induced macrophage cytotoxicity against bladder cancer cells", "authors": [{"first": "R", "middle": ["L"], "last": "Lopes", "suffix": ""}, {"first": "T", "middle": ["J"], "last": "Borges", "suffix": ""}, {"first": "J", "middle": ["F"], "last": "Ara\u00fajo", "suffix": ""}, {"first": "N", "middle": ["G"], "last": "Pinho", "suffix": ""}, {"first": "L", "middle": ["S"], "last": "Bergamin", "suffix": ""}, {"first": "A", "middle": ["M"], "last": "Battastini", "suffix": ""}, {"first": "S", "middle": ["P"], "last": "Muraro", "suffix": ""}, {"first": "A", "middle": ["P"], "last": "Souza", "suffix": ""}, {"first": "R", "middle": ["F"], "last": "Zanin", "suffix": ""}, {"first": "C", "middle": [], "last": "Bonorino", "suffix": ""}], "year": 2010, "venue": "Clin. Dev. Immunol", "link": "17976448"}, "BIBREF24": {"title": "Role of Th1-stimulating cytokines in bacillus Calmette-Gu\u00e9rin(BCG)-induced macrophage cytotoxicity against mouse bladder cancer MBT-2 cells", "authors": [{"first": "Y", "middle": [], "last": "Luo", "suffix": ""}, {"first": "H", "middle": [], "last": "Yamada", "suffix": ""}, {"first": "D", "middle": ["P"], "last": "Evanoff", "suffix": ""}, {"first": "Chen", "middle": [], "last": "", "suffix": ""}, {"first": "X", "middle": [], "last": "", "suffix": ""}], "year": 2006, "venue": "Clin. ExpImmunol", "link": "46468372"}, "BIBREF25": {"title": "The PPE18 of Mycobacterium tuberculosis interacts with TLR2 and activates IL-10 induction in macrophage", "authors": [{"first": "S", "middle": [], "last": "Nair", "suffix": ""}, {"first": "P", "middle": ["A"], "last": "Ramaswamy", "suffix": ""}, {"first": "S", "middle": [], "last": "Ghosh", "suffix": ""}, {"first": "D", "middle": ["C"], "last": "Joshi", "suffix": ""}, {"first": "N", "middle": [], "last": "Pathak", "suffix": ""}, {"first": "I", "middle": [], "last": "Siddiqui", "suffix": ""}, {"first": "P", "middle": [], "last": "Sharma", "suffix": ""}, {"first": "S", "middle": ["E"], "last": "Hasnain", "suffix": ""}, {"first": "S", "middle": ["C"], "last": "Mande", "suffix": ""}, {"first": "S", "middle": [], "last": "Mukhopadhyay", "suffix": ""}], "year": 2009, "venue": "J. Immunol", "link": "17309991"}, "BIBREF26": {"title": "Antibody-mediated phagocytosis contributes to the anti-tumor activity of the therapeutic antibody daratumumab in lymphoma and multiple myeloma", "authors": [{"first": "M", "middle": ["B"], "last": "Overdijk", "suffix": ""}, {"first": "S", "middle": [], "last": "Verploegen", "suffix": ""}, {"first": "M", "middle": [], "last": "B\u00f6gels", "suffix": ""}, {"first": "M", "middle": [], "last": "Van Egmond", "suffix": ""}, {"first": "J", "middle": ["J"], "last": "Lammerts Van Bueren", "suffix": ""}, {"first": "T", "middle": [], "last": "Mutis", "suffix": ""}, {"first": "R", "middle": ["W"], "last": "Groen", "suffix": ""}, {"first": "E", "middle": [], "last": "Breij", "suffix": ""}, {"first": "A", "middle": ["C"], "last": "Martens", "suffix": ""}, {"first": "W", "middle": ["K"], "last": "Bleeker", "suffix": ""}], "year": 2015, "venue": "MAbs", "link": "215569634"}, "BIBREF27": {"title": "Prolonged toll-like receptor signaling by Mycobacterium tuberculosis and its 19-kilodalton lipoprotein inhibits gamma interferon-induced regulation of selected genes in macrophages", "authors": [{"first": "R", "middle": ["K"], "last": "Pai", "suffix": ""}, {"first": "M", "middle": ["E"], "last": "Pennini", "suffix": ""}, {"first": "A", "middle": ["A"], "last": "Tobian", "suffix": ""}, {"first": "D", "middle": ["H"], "last": "Canaday", "suffix": ""}, {"first": "W", "middle": ["H"], "last": "Boom", "suffix": ""}, {"first": "C", "middle": ["V"], "last": "Harding", "suffix": ""}], "year": 2014, "venue": "Infect. Immun", "link": "24229443"}, "BIBREF28": {"title": "Exercise training is more effective than resveratrol supplementation on alleviation of inflammation in peritoneal macrophages of high fat diet mice", "authors": [{"first": "H", "middle": ["G"], "last": "Park", "suffix": ""}, {"first": "Y", "middle": ["R"], "last": "Lee", "suffix": ""}, {"first": "J", "middle": ["K"], "last": "Jun", "suffix": ""}, {"first": "W", "middle": ["L"], "last": "Lee", "suffix": ""}], "year": 2014, "venue": "J. Exerc. Nutrition Biochem", "link": "18244488"}, "BIBREF29": {"title": "Mycobacterium tuberculosis LprA is a lipoprotein agonist of TLR2 that regulates innate immunity and APC function", "authors": [{"first": "N", "middle": ["D"], "last": "Pecora", "suffix": ""}, {"first": "A", "middle": ["J"], "last": "Gehring", "suffix": ""}, {"first": "D", "middle": ["H"], "last": "Canaday", "suffix": ""}, {"first": "W", "middle": ["H"], "last": "Boom", "suffix": ""}, {"first": "C", "middle": ["V"], "last": "Harding", "suffix": ""}], "year": 2006, "venue": "J. Immunol", "link": "24729216"}, "BIBREF30": {"title": "Bacillus Calmette-Guerin (BCG) enhances monocyte-and lymphocyte-mediated bladder tumour cell killing", "authors": [{"first": "K", "middle": [], "last": "Pryor", "suffix": ""}, {"first": "J", "middle": [], "last": "Goddard", "suffix": ""}, {"first": "D", "middle": [], "last": "Goldstein", "suffix": ""}, {"first": "P", "middle": [], "last": "Stricker", "suffix": ""}, {"first": "P", "middle": [], "last": "Russell", "suffix": ""}, {"first": "D", "middle": [], "last": "Golovsky", "suffix": ""}, {"first": "R", "middle": [], "last": "Penny", "suffix": ""}], "year": 1995, "venue": "Br J. Cancer", "link": "17523523"}, "BIBREF32": {"title": "NMAAP1 Promotes M1 Macrophage Polarization Qihui", "authors": [{"first": "", "middle": [], "last": "Liu", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF34": {"title": "Trastuzumab triggers phagocytic killing of high HER2 cancer cells in vitro and in vivo by interaction with Fc\u03b3 receptors on macrophages", "authors": [], "year": "", "venue": "J. Immunol", "link": "21298426"}, "BIBREF35": {"title": "Macrophage plasticity and polarization: in vivo veritas", "authors": [{"first": "A", "middle": [], "last": "Sica", "suffix": ""}, {"first": "A", "middle": [], "last": "Mantovani", "suffix": ""}], "year": 2012, "venue": "J. Clin. Invest", "link": "24128924"}, "BIBREF36": {"title": "Macrophage plasticity and polarization in liver homeostasis and pathology", "authors": [{"first": "A", "middle": [], "last": "Sica", "suffix": ""}, {"first": "P", "middle": [], "last": "Invernizzi", "suffix": ""}, {"first": "A", "middle": [], "last": "Mantovani", "suffix": ""}], "year": 2014, "venue": "Hepatology", "link": "24492548"}, "BIBREF37": {"title": "Sequential intravesical mitomycin plus Bacillus Calmette-Gu\u00e9rin for non-muscle-invasive urothelial bladder carcinoma: translational and phase I clinical trial", "authors": [{"first": "R", "middle": ["S"], "last": "Svatek", "suffix": ""}, {"first": "X", "middle": ["R"], "last": "Zhao", "suffix": ""}, {"first": "E", "middle": ["E"], "last": "Morales", "suffix": ""}, {"first": "M", "middle": ["K"], "last": "Jha", "suffix": ""}, {"first": "T", "middle": ["Y"], "last": "Tseng", "suffix": ""}, {"first": "C", "middle": ["M"], "last": "Hugen", "suffix": ""}, {"first": "V", "middle": [], "last": "Hurez", "suffix": ""}, {"first": "J", "middle": [], "last": "Hernandez", "suffix": ""}, {"first": "T", "middle": ["J"], "last": "Curiel", "suffix": ""}], "year": 2015, "venue": "Clin. Cancer Res", "link": "22052458"}, "BIBREF38": {"title": "Huntingtin and huntingtin-associated protein 1 influence neuronal calcium signaling mediated by inositol-(1,4,5) triphosphate receptor type 1", "authors": [{"first": "T", "middle": ["S"], "last": "Tang", "suffix": ""}, {"first": "H", "middle": [], "last": "Tu", "suffix": ""}, {"first": "E", "middle": ["Y"], "last": "Chan", "suffix": ""}, {"first": "A", "middle": [], "last": "Maximov", "suffix": ""}, {"first": "Z", "middle": [], "last": "Wang", "suffix": ""}, {"first": "C", "middle": ["L"], "last": "Wellington", "suffix": ""}, {"first": "M", "middle": ["R"], "last": "Hayden", "suffix": ""}, {"first": "I", "middle": [], "last": "Bezprozvanny", "suffix": ""}], "year": 2003, "venue": "Neuron", "link": "1847245"}, "BIBREF39": {"title": "Immunological basis in the pathogenesis and treatment of bladder cancer", "authors": [{"first": "D", "middle": ["B"], "last": "Thompson", "suffix": ""}, {"first": "L", "middle": ["E"], "last": "Siref", "suffix": ""}, {"first": "M", "middle": ["P"], "last": "Feloney", "suffix": ""}, {"first": "R", "middle": ["J"], "last": "Hauke", "suffix": ""}, {"first": "D", "middle": ["K"], "last": "Agrawal", "suffix": ""}], "year": 2015, "venue": "Exp. Rev. Clin. Immunol", "link": "37704319"}, "BIBREF40": {"title": "Selective impairment of P2Y signaling by prostaglandin E2 in macrophages: implications for Ca2+-dependent responses", "authors": [{"first": "P", "middle": ["G"], "last": "Trav\u00e9s", "suffix": ""}, {"first": "M", "middle": [], "last": "Pimentel-Santillana", "suffix": ""}, {"first": "L", "middle": ["M"], "last": "Carrasquero", "suffix": ""}, {"first": "R", "middle": [], "last": "P\u00e9rez-Sen", "suffix": ""}, {"first": "E", "middle": ["G"], "last": "Delicado", "suffix": ""}, {"first": "A", "middle": [], "last": "Luque", "suffix": ""}, {"first": "M", "middle": [], "last": "Izquierdo", "suffix": ""}, {"first": "P", "middle": [], "last": "Mart\u00edn-Sanz", "suffix": ""}, {"first": "M", "middle": ["T"], "last": "Miras-Portugal", "suffix": ""}, {"first": "L", "middle": [], "last": "Bosc\u00e1", "suffix": ""}], "year": 2013, "venue": "J. Immunol", "link": "24487531"}, "BIBREF41": {"title": "DANGER, a novel regulatory protein of inositol 1,4,5-trisphosphate-receptor activity", "authors": [{"first": "D", "middle": ["B"], "last": "Van Rossum", "suffix": ""}, {"first": "R", "middle": ["L"], "last": "Patterson", "suffix": ""}, {"first": "K", "middle": ["H"], "last": "Cheung", "suffix": ""}, {"first": "R", "middle": ["K"], "last": "Barrow", "suffix": ""}, {"first": "V", "middle": [], "last": "Syrovatkina", "suffix": ""}, {"first": "G", "middle": ["S"], "last": "Gessell", "suffix": ""}, {"first": "S", "middle": ["G"], "last": "Burkholder", "suffix": ""}, {"first": "D", "middle": ["N"], "last": "Watkins", "suffix": ""}, {"first": "J", "middle": ["K"], "last": "Foskett", "suffix": ""}, {"first": "S", "middle": ["H"], "last": "Snyder", "suffix": ""}], "year": 2006, "venue": "J. Biol. Chem", "link": "32761655"}, "BIBREF42": {"title": "Shifts in macrophage phenotypes and macrophage competition for arginine metabolism affect the severity of muscle pathology in muscular dystrophy", "authors": [{"first": "S", "middle": ["A"], "last": "Villalta", "suffix": ""}, {"first": "H", "middle": ["X"], "last": "Nguyen", "suffix": ""}, {"first": "B", "middle": [], "last": "Deng", "suffix": ""}, {"first": "T", "middle": [], "last": "Gotoh", "suffix": ""}, {"first": "J", "middle": ["G"], "last": "Tidball", "suffix": ""}], "year": 2009, "venue": "Hum. Mol. Genet", "link": "18708303"}, "BIBREF43": {"title": "Molecular mechanisms that influence the macrophage m1-m2 polarization balance", "authors": [{"first": "N", "middle": [], "last": "Wang", "suffix": ""}, {"first": "H", "middle": [], "last": "Liang", "suffix": ""}, {"first": "K", "middle": [], "last": "Zen", "suffix": ""}], "year": 2014, "venue": "Front Immunol", "link": "414934"}, "BIBREF44": {"title": "Macrophage polarization to a unique phenotype driven by B cells", "authors": [{"first": "S", "middle": ["C"], "last": "Wong", "suffix": ""}, {"first": "A", "middle": ["L"], "last": "Puaux", "suffix": ""}, {"first": "M", "middle": [], "last": "Chittezhath", "suffix": ""}, {"first": "I", "middle": [], "last": "Shalova", "suffix": ""}, {"first": "T", "middle": ["S"], "last": "Kajiji", "suffix": ""}, {"first": "X", "middle": [], "last": "Wang", "suffix": ""}, {"first": "J", "middle": ["P"], "last": "Abastado", "suffix": ""}, {"first": "K", "middle": ["P"], "last": "Lam", "suffix": ""}, {"first": "S", "middle": ["K"], "last": "Biswas", "suffix": ""}], "year": 2010, "venue": "Eur. J. Immunol", "link": "25241170"}, "BIBREF45": {"title": "Macrophage biology in development, homeostasis and disease", "authors": [{"first": "T", "middle": ["A"], "last": "Wynn", "suffix": ""}, {"first": "A", "middle": [], "last": "Chawla", "suffix": ""}, {"first": "J", "middle": ["W"], "last": "Pollard", "suffix": ""}], "year": 2013, "venue": "Nature", "link": "205233375"}, "BIBREF46": {"title": "Requirement for Mab21l2 during development of murine retina and ventral body wall", "authors": [{"first": "R", "middle": [], "last": "Yamada", "suffix": ""}, {"first": "Y", "middle": [], "last": "Mizutani-Koseki", "suffix": ""}, {"first": "H", "middle": [], "last": "Koseki", "suffix": ""}, {"first": "N", "middle": [], "last": "Takahashi", "suffix": ""}], "year": 2004, "venue": "Dev Biol", "link": "12660189"}, "BIBREF47": {"title": "Proteomic analysis of macrophages: a new way to identify novel cell-surface antigens", "authors": [{"first": "L", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "Y", "middle": [], "last": "Lun", "suffix": ""}, {"first": "D", "middle": [], "last": "Yan", "suffix": ""}, {"first": "L", "middle": [], "last": "Yu", "suffix": ""}, {"first": "W", "middle": [], "last": "Ma", "suffix": ""}, {"first": "B", "middle": [], "last": "Du", "suffix": ""}, {"first": "X", "middle": [], "last": "Zhu", "suffix": ""}], "year": 2007, "venue": "J. Immunol. Methods", "link": "23471742"}, "BIBREF48": {"title": "Phylogenetic analysis and prokaryotic expression of NMAAP1 derived from BCG-activated murine macrophages", "authors": [{"first": "X", "middle": [], "last": "Zhao", "suffix": ""}, {"first": "L", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "D", "middle": [], "last": "Yan", "suffix": ""}, {"first": "X", "middle": [], "last": "Feng", "suffix": ""}, {"first": "D", "middle": [], "last": "Chu", "suffix": ""}, {"first": "B", "middle": [], "last": "Li", "suffix": ""}, {"first": "B", "middle": [], "last": "Du", "suffix": ""}, {"first": "X", "middle": [], "last": "Zhu", "suffix": ""}], "year": 2011, "venue": "Comp. Immunol. Microbiol. Infect. Dis", "link": "46114342"}}, "ref_entries": {"FIGREF0": {"text": "Fig. 1. NMAAP1 expression was associated with the percent of M1 macrophages in BCG-activated peritoneal macrophages. (A) The percent of M1 macrophages in peritoneal macrophages on day 4, day 8 and day 12 were assessed using FACS. (B) Linear graphs analysis of the percent of M1 macrophages in BCG-activated macrophage. (C) IL-10 and NMAAP1 expression after BCG stimulation on day 4, day 8 and day 12 was determined using quantitative RT-PCR (qPCR). (D) Determination of IL-10 and TNF-\u03b1 release using ELISA in BCG-stimulated mice sera after day 4, day 8 and day 12. Data are represented as mean \u00b1 S.E.M. from at least three independent experiments.", "type": "figure"}, "FIGREF1": {"text": "Fig. 2. pIRES2-EGFP/NMAAP1 transfection and transgene expression in RAW264.7 cells, Identification of stable transfectants expressing NMAAP1. (A) RAW264.7 cells were stably transfected with pIRES2-EGFP/NMAAP1 or pIRES2-EGFP/CONTROL. Bright field, DAPI, GFP and DAPI merged with GFP images were taken by a laser-scanning confocal microscope. (B, C) RT-PCR analysis. Expression in OV/RAW264.7 and ON/RAW264.7 cells were detected using RT-PCR. Bar graph displays means \u00b1 SEM of the percentage of NMAAP1/GAPDH ratio for the respective groups. (D, E) Protein expression of NMAAP1 in RAW264.7 cells normalized to \u03b2-Actin as an internal standard: lane 1, pIRES2-EGFP/CONTROL transfected cells; lane 2, pIRES2-EGFP/NMAAP1 transfected cells. Bar graph displays the densitometry results (arbitrary units [AU]) of the Western blots for the respective groups. Data are represented as mean\u00b1S.E.M. from at least three independent experiments. ***P < 0.001 (unpaired Student t test. compared with the corresponding control values).", "type": "figure"}, "FIGREF2": {"text": "Fig. 3. NMAAP1 altered the gene and protein expression of phenotype-related molecules. The highly expression of NMAAP1 regulated phenotype-specific markers for M1/M2 macrophages. (A, B) The percent of CD16/32 cells in ON/RAW264.7 cells using FACS. (C) M1/M2 genes were evaluated using quantitative real-time RT-PCR. (D, E) Release of M1/M2 cytokines was detected using ELISA in 6 h, 12 h, 24 h and 48 h culture supernatants of OV/RAW264.7 and ON/RAW264.7 cells. Data are represented as mean \u00b1 S.E.M. from at least three independent experiments. *P < 0.05, **P < 0.01 and ***P < 0.001 (unpaired Student t test. compared with the corresponding control values).", "type": "figure"}, "FIGREF3": {"text": "Fig. 4. Macrophage-mediated phagocytosis is modulated by NMAAP1. (A) The images show phagocytosis of fluorescent microspheres by OV/RAW264.7 and ON/RAW264.7 cells incubated with red carboxylatemodified fluorescent beads for 60 min. The cellular uptake of fluorescent beads was determined using fluorescence microscopy (x 40). (B) The phagocytosis rates and phagocytosis index of ON/RAW264.7 cells were obviously increased compared to the OV/RAW264.7 cells (**p < 0.01) (C, D) Relative phagocytosis was assayed using flow cytometry as the intensity of fluorescence. Data are represented as mean \u00b1 S.E.M. from at least three independent experiments. **P < 0.01 (unpaired Student t test. compared with the corresponding control values).", "type": "figure"}}}
{"paper_id": "17788790", "_pdf_hash": "df8e6302b05ffc81252f89e7618ff38c5a1870a7", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Hard and Soft Law in International Governance", "authors": [{"first": "Kenneth", "middle": ["W"], "last": "Abbott", "suffix": ""}, {"first": "Duncan", "middle": [], "last": "Snidal", "suffix": ""}], "year": 2000, "venue": "International Organization", "link": "154998967"}, "BIBREF1": {"title": "Product Standards to Protect the Local Environment: The GATT and the Uruguay Round Sanitary and Phytosanitary Agreement", "authors": [{"first": "Iii", "middle": [], "last": "Barcel\u00f3", "suffix": ""}, {"first": "John", "middle": ["J"], "last": "", "suffix": ""}], "year": 1994, "venue": "Cornell International Law Journal", "link": "54962899"}, "BIBREF2": {"title": "National Politics as International Process: The Case of Anti-Female-Genital-Cutting Laws", "authors": [{"first": "Elizabeth", "middle": [], "last": "Boyle", "suffix": ""}, {"first": "Sharon", "middle": ["E"], "last": "Heger", "suffix": ""}, {"first": "", "middle": [], "last": "Preves", "suffix": ""}], "year": 2000, "venue": "Law and Society Review", "link": "143632129"}, "BIBREF3": {"title": "Harmonizing Phyto-sanitary and Sanitary Regulations", "authors": [{"first": "Maury", "middle": ["E"], "last": "Bredahl", "suffix": ""}, {"first": "Kenneth", "middle": ["W"], "last": "Forsythe", "suffix": ""}], "year": 1989, "venue": "World Economy", "link": "154500962"}, "BIBREF4": {"title": "Future Activities of the Committee in Regard to the Establishment and Regular Review of Provisions Relating to Food Additives in Codex Standards and Possible Mechanisms for the Establishment of General Provisions for the Use of Food Additives in Non-Standardized Foods", "authors": [{"first": "Dr", "middle": ["W H B"], "last": "Denner", "suffix": ""}], "year": 1989, "venue": "Codex Committee on Food Additives and Contaminants", "link": null}, "BIBREF5": {"title": "Social Norms: Internalization, Persuasion, and History", "authors": [{"first": "Amitai", "middle": [], "last": "Etzioni", "suffix": ""}], "year": 2000, "venue": "Law and Society Review", "link": "144249151"}, "BIBREF6": {"title": "Dueling Risk Assessments: Why the WTO and Codex Threaten U.S. Food Standards", "authors": [{"first": "John", "middle": [], "last": "Ewers", "suffix": ""}], "year": 2000, "venue": "Environmental Law", "link": "158417561"}, "BIBREF7": {"title": "Informe taller nacional sobre analisis de la legislacion alimentaria y procedimientos para su armonizacion con las normas del Codex", "authors": [{"first": "", "middle": [], "last": "Fao", "suffix": ""}], "year": 2001, "venue": "", "link": null}, "BIBREF8": {"title": "Public Health Law: Power", "authors": [{"first": "Lawrence", "middle": [], "last": "Gostin", "suffix": ""}], "year": 2000, "venue": "", "link": null}, "BIBREF9": {"title": "When Knowledge is Power: Three Models of Change in International Organizations", "authors": [{"first": "Ernst", "middle": ["B"], "last": "Haas", "suffix": ""}], "year": 1990, "venue": "", "link": "147828104"}, "BIBREF10": {"title": "Saving the Mediterranean: The Politics of International Environmental Cooperation", "authors": [{"first": "Peter", "middle": ["M"], "last": "Haas", "suffix": ""}], "year": 1990, "venue": "", "link": "154955901"}, "BIBREF11": {"title": "Policy Paradigms, Social Learning, and the State: The Case of Economic Policymaking in Britain", "authors": [{"first": "Peter", "middle": ["A"], "last": "Hall", "suffix": ""}], "year": 1993, "venue": "Comparative Politics", "link": "150898353"}, "BIBREF12": {"title": "Risk Analysis and the Law: International Law, the World Trade Organization, Codex Alimentarius, and National Legislation", "authors": [{"first": "Linda", "middle": ["R"], "last": "Horton", "suffix": ""}], "year": 2001, "venue": "Food Additives and Contaminants", "link": "39791020"}, "BIBREF13": {"title": "Treating International Institutions as Social Environments", "authors": [{"first": "Alastair", "middle": [], "last": "Johnston", "suffix": ""}, {"first": "", "middle": [], "last": "Iain", "suffix": ""}], "year": 2001, "venue": "International Studies Quarterly", "link": "15463844"}, "BIBREF14": {"title": "The International Regulation of Pesticide Residues in Food: A Report to the National Science Foundation on the Application of International Regulatory Techniques to Scientific/Technical Problems", "authors": [{"first": "David", "middle": ["A"], "last": "Kay", "suffix": ""}], "year": 1976, "venue": "Studies in Transnational Legal Policy", "link": null}, "BIBREF15": {"title": "Resolving International Sanitary and Phytosanitary Disputes in the WTO: Lessons and Future Directions", "authors": [{"first": "Kevin", "middle": ["C"], "last": "Kennedy", "suffix": ""}], "year": 2000, "venue": "Food and Drug Law Journal", "link": "35495924"}, "BIBREF16": {"title": "Standards as Public, Collective and Private Goods", "authors": [{"first": "Charles", "middle": ["P"], "last": "Kindleberger", "suffix": ""}], "year": 1983, "venue": "Kyklos", "link": "154445810"}, "BIBREF17": {"title": "How Nations Choose Product Standards and Standards Change Nations", "authors": [{"first": "Samuel", "middle": [], "last": "Krislov", "suffix": ""}], "year": 1997, "venue": "", "link": "153955420"}, "BIBREF18": {"title": "International Regulatory Regimes: Case Studies in Health, Meteorology, and Food. 2 vols", "authors": [{"first": "David", "middle": ["M"], "last": "Leive", "suffix": ""}], "year": 1976, "venue": "", "link": "126748492"}, "BIBREF19": {"title": "Challenges in the Application of Science to Global Affairs: Contingency, Trust, and Moral Order", "authors": [{"first": "Clark", "middle": ["A"], "last": "Miller", "suffix": ""}], "year": 2001, "venue": "Changing the Atmosphere: Expert Knowledge and Environmental Governance", "link": null}, "BIBREF20": {"title": "Internationalization and Domestic Politics: An Introduction", "authors": [{"first": "Helen", "middle": ["V"], "last": "Milner", "suffix": ""}, {"first": "Robert", "middle": ["O"], "last": "Keohane", "suffix": ""}], "year": 1996, "venue": "Internationalization and Domestic Politics", "link": "156632204"}, "BIBREF21": {"title": "Regulatory Reform and International Standardisation. Paris: Organization for Economic Cooperation and Development, Working Party of the Trade Committee", "authors": [], "year": 1999, "venue": "OECD Working Papers", "link": null}, "BIBREF22": {"title": "Waste Trading Among Rich Nations: Building a New Theory of Environmental Regulation", "authors": [{"first": "Kate", "middle": [], "last": "O&apos;neill", "suffix": ""}], "year": 2000, "venue": "", "link": "152735496"}, "BIBREF23": {"title": "Qualitative Research and Evaluation Methods", "authors": [{"first": "Michael", "middle": [], "last": "Patton", "suffix": ""}, {"first": "", "middle": [], "last": "Quinn", "suffix": ""}], "year": 2002, "venue": "", "link": "150930396"}, "BIBREF24": {"title": "The Path to European Integration: A Historical Institutionalist Analysis", "authors": [{"first": "Paul", "middle": [], "last": "Pierson", "suffix": ""}], "year": 1996, "venue": "Comparative Political Studies", "link": null}, "BIBREF25": {"title": "The Effectiveness of the International Food Safety Regime. Paper read at International Studies Association", "authors": [{"first": "Diahanna", "middle": ["L"], "last": "Post", "suffix": ""}], "year": 2002, "venue": "", "link": null}, "BIBREF26": {"title": "Let's Argue!\": Communicative Action in World Politics", "authors": [{"first": "Thomas", "middle": [], "last": "Risse", "suffix": ""}], "year": 2000, "venue": "International Organization", "link": "59059368"}, "BIBREF27": {"title": "The Power of Human Rights: International Norms and Domestic Change, Cambridge Studies in International Relations", "authors": [{"first": "", "middle": [], "last": "Risse", "suffix": ""}, {"first": "Stephen", "middle": ["C"], "last": "Thomas", "suffix": ""}, {"first": "Kathryn", "middle": [], "last": "Ropp", "suffix": ""}, {"first": "", "middle": [], "last": "Sikkink", "suffix": ""}], "year": 1999, "venue": "", "link": null}, "BIBREF28": {"title": "Sanitary and Phytosanitary Risk Management in the Post-Uruguay Round Era: An Economic Perspective. In Incorporating Science, Economics, and Sociology in Developing Sanitary and Phytosanitary Standards in International Trade", "authors": [{"first": "Donna", "middle": [], "last": "Roberts", "suffix": ""}], "year": 2000, "venue": "Board on Agriculture and Natural Resources", "link": null}, "BIBREF29": {"title": "Do We Really Know that the WTO Increases Trade? Cambridge", "authors": [{"first": "Andrew", "middle": ["K"], "last": "Rose", "suffix": ""}], "year": 2002, "venue": "", "link": null}, "BIBREF30": {"title": "FDA's Consideration of Codex Alimentarius Standards in Light of International Trade Agreements", "authors": [{"first": "Lucinda", "middle": [], "last": "Sikes", "suffix": ""}], "year": 1998, "venue": "Food and Drug Law Journal", "link": "14212806"}, "BIBREF31": {"title": "The Impact of International Trade Agreements on US Food Safety and Labeling Standards", "authors": [{"first": "Bruce", "middle": ["A"], "last": "Silverglade", "suffix": ""}], "year": 1998, "venue": "Food and Drug Law Journal", "link": "28356893"}, "BIBREF32": {"title": "The WTO Agreement on Sanitary and Phytosanitary Measures: Weakening Food Safety Regulations to Facilitate Trade?", "authors": [], "year": 2000, "venue": "Food and Drug Law Journal", "link": "8315748"}, "BIBREF33": {"title": "Internationalization, Democracy, and Food Safety Measures: The (Il)Legitimacy of Consumer Preferences?", "authors": [{"first": "Grace", "middle": [], "last": "Skogstad", "suffix": ""}], "year": 2001, "venue": "Global Governance", "link": null}, "BIBREF34": {"title": "Product Standards for Internationally Integrated Goods Markets", "authors": [{"first": "Alan", "middle": ["O"], "last": "Sykes", "suffix": ""}], "year": 1995, "venue": "", "link": "144659047"}, "BIBREF35": {"title": "Historical Institutionalism in Comparative Politics", "authors": [{"first": "Kathleen", "middle": [], "last": "Thelen", "suffix": ""}, {"first": "Sven", "middle": [], "last": "Steinmo", "suffix": ""}], "year": 1992, "venue": "Structuring Politics: Historical Institutionalism in Comparative Analysis", "link": "25750240"}, "BIBREF36": {"title": "Standardization: A New Discipline", "authors": [{"first": "Lal", "middle": ["C"], "last": "Verman", "suffix": ""}], "year": 1973, "venue": "", "link": "166700267"}, "BIBREF37": {"title": "Effective Multilateral Regulation of Industrial Activity: Institutions for Policing and Adjusting Binding and Nonbinding Legal Commitments. PhD, Political Science", "authors": [{"first": "David", "middle": ["G"], "last": "Victor", "suffix": ""}, {"first": "", "middle": [], "last": "; R. Kagan", "suffix": ""}, {"first": "", "middle": [], "last": "Berkeley", "suffix": ""}], "year": 1998, "venue": "Dynamics of Regulatory Change: How Globalization Affects National Regulatory Policies", "link": null}, "BIBREF38": {"title": "Trade and Environment in the World Trading System: A Decade of Stalemate?", "authors": [{"first": "Marc", "middle": [], "last": "Williams", "suffix": ""}], "year": 2001, "venue": "Global Environmental Politics", "link": "57568363"}, "BIBREF39": {"title": "The Role of Science in the Uruguay Round and NAFTA Trade Disciplines", "authors": [{"first": "David", "middle": ["A"], "last": "Wirth", "suffix": ""}], "year": 1994, "venue": "Cornell International Law Journal", "link": null}}, "ref_entries": {}}
{"paper_id": "17788967", "_pdf_hash": "19f57b5e385ec29b1bf8463244d86f8bf21ff5f8", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Modal mu-calculi", "authors": [{"first": "J", "middle": [], "last": "Bradfield", "suffix": ""}, {"first": "C", "middle": [], "last": "Stirling", "suffix": ""}], "year": 2007, "venue": "Handbook of Modal Logic", "link": null}, "BIBREF1": {"title": "Cut-free sequent systems for temporal logics", "authors": [{"first": "K", "middle": [], "last": "Br\u00fcnnler", "suffix": ""}, {"first": "M", "middle": [], "last": "Lange", "suffix": ""}], "year": "", "venue": "", "link": "6453609"}, "BIBREF2": {"title": "A proof system for the linear time \u00b5-calculus", "authors": [{"first": "C", "middle": [], "last": "Dax", "suffix": ""}, {"first": "M", "middle": [], "last": "Hofmann", "suffix": ""}, {"first": "M", "middle": [], "last": "Lange", "suffix": ""}], "year": 2006, "venue": "Proc. 26th Conf. on Foundations of Software Technology and Theoretical Computer Science, FSTTCS'06", "link": "8804987"}, "BIBREF3": {"title": "Propositional dynamic logic of regular programs", "authors": [{"first": "M", "middle": ["J"], "last": "Fischer", "suffix": ""}, {"first": "R", "middle": ["E"], "last": "Ladner", "suffix": ""}], "year": 1979, "venue": "Journal of Computing and System Science", "link": "10368524"}, "BIBREF4": {"title": "Die Grundlegung der elementaren Zahlenlehre", "authors": [{"first": "D", "middle": [], "last": "Hilbert", "suffix": ""}], "year": 1931, "venue": "Mathematische Annalen", "link": null}, "BIBREF5": {"title": "Cut-free systems for the propositional modal mu-calculus", "authors": [{"first": "G", "middle": [], "last": "J\u00e4ger", "suffix": ""}, {"first": "M", "middle": [], "last": "Kretz", "suffix": ""}, {"first": "T", "middle": [], "last": "Studer", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF6": {"title": "Cut-free common knowledge", "authors": [{"first": "G", "middle": [], "last": "J\u00e4ger", "suffix": ""}, {"first": "M", "middle": [], "last": "Kretz", "suffix": ""}, {"first": "T", "middle": [], "last": "Studer", "suffix": ""}], "year": "", "venue": "Journal of Applied Logic", "link": "7962388"}, "BIBREF7": {"title": "Automata for the modal mu-calculus and related results", "authors": [{"first": "D", "middle": [], "last": "Janin", "suffix": ""}, {"first": "I", "middle": [], "last": "Walukiewicz", "suffix": ""}], "year": 1995, "venue": "MFCS '95: Proceedings of the 20th International Symposium on Mathematical Foundations of Computer Science", "link": null}, "BIBREF8": {"title": "Results on the propositional modal \u00b5-calculus", "authors": [{"first": "D", "middle": [], "last": "Kozen", "suffix": ""}], "year": 1983, "venue": "Theoretical Computer Science", "link": null}, "BIBREF9": {"title": "A finite model theorem for the propositional \u00b5-calculus", "authors": [{"first": "D", "middle": [], "last": "Kozen", "suffix": ""}], "year": 1988, "venue": "Studia Logica", "link": "8492026"}, "BIBREF10": {"title": "A proof theoretic methodology for propositional dynamic logic", "authors": [{"first": "D", "middle": [], "last": "Leivant", "suffix": ""}], "year": 1981, "venue": "Proceedings of the International Colloquium on Formalization of Programming Concepts", "link": "11699246"}, "BIBREF11": {"title": "Proof Theory", "authors": [{"first": "K", "middle": [], "last": "Sch\u00fctte", "suffix": ""}], "year": 1977, "venue": "", "link": null}, "BIBREF12": {"title": "On the structure of inductive reasoning: Circular and tree-shaped proofs in the mu-calculus", "authors": [{"first": "C", "middle": [], "last": "Sprenger", "suffix": ""}, {"first": "M", "middle": [], "last": "Dam", "suffix": ""}], "year": 2003, "venue": "Proc. FOSSACS'03, Springer LNCS", "link": "28388732"}, "BIBREF13": {"title": "An automata theoretic decision procedure for the propositional modal mu-calculus. Information and Computation", "authors": [{"first": "R", "middle": ["S"], "last": "Streett", "suffix": ""}, {"first": "E", "middle": ["A"], "last": "Emerson", "suffix": ""}], "year": 1989, "venue": "", "link": null}, "BIBREF14": {"title": "Normal derivability in classical logic", "authors": [{"first": "W", "middle": [], "last": "Tait", "suffix": ""}], "year": 1968, "venue": "The Syntax and Semantics of Infinitary Languages", "link": "116945481"}, "BIBREF15": {"title": "Completeness of Kozen's axiomatization of the propositional \u00b5-calculus. Information and Computation", "authors": [{"first": "I", "middle": [], "last": "Walukiewicz", "suffix": ""}], "year": 2000, "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "17789310", "_pdf_hash": "d12352a7f72b8efe35b15745fba2a3fbd22bf6c2", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Behavior-based robotics", "authors": [{"first": "R", "middle": ["C"], "last": "Arkin", "suffix": ""}], "year": 1998, "venue": "", "link": null}, "BIBREF1": {"title": "Intelligent behavior in animals and robots", "authors": [{"first": "D", "middle": [], "last": "Mcfarland", "suffix": ""}, {"first": "T", "middle": [], "last": "B\u00f6sser", "suffix": ""}], "year": 1993, "venue": "", "link": null}, "BIBREF2": {"title": "A method for behavioural organization for autonomous robots based on evolutionary optimization of utility functions", "authors": [{"first": "M", "middle": [], "last": "Wahde", "suffix": ""}], "year": 2003, "venue": "Journal of Systems and Control Engineering", "link": "109651682"}, "BIBREF3": {"title": "How to do the right thing", "authors": [{"first": "P", "middle": [], "last": "Maes", "suffix": ""}], "year": 1989, "venue": "Journal of Connection Science", "link": "4842002"}, "BIBREF4": {"title": "Action selection in Hamsterdam: Lessons from ethology", "authors": [{"first": "B", "middle": ["M"], "last": "Blumberg", "suffix": ""}], "year": 1994, "venue": "From Animals to animats 3, Proc. of the 3 rd Int. conf. on simulation of adaptive behavior (SAB94)", "link": "10916409"}}, "ref_entries": {}}
{"paper_id": "17789598", "_pdf_hash": "85968a682f064cf7645483d24bc5a1de7291c8f8", "abstract": [], "body_text": [{"section": "INTRODUCTION", "text": "Yolk sac tumours (YST), or perhaps more correctly they should be named as endodermal primitive tumours, are rare and malignant germ cell neoplasms that usually occur in gonads (1, 2) . YST usually presents in young patients. The median age at the time of diagnosis is 18 years (3). YST arising in the pelvis outside of the ovary are uncommon. We present a case of widely spread YST that originated from a broad uterine in a young female, that was diagnosed and successfully treated at the Vilnius University Hospital Santariskiu Clinics (Santari\u0161ki\u0173 Klinikos).", "cite_spans": [{"start": 176, "end": 179, "text": "(1,", "ref_id": "BIBREF0"}, {"start": 180, "end": 182, "text": "2)", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "CASE PRESENTATION", "text": "A 22 year-old woman was admitted to the emergency room with severe lower abdominal pain, nausea, diarrhea, and fever.", "cite_spans": [], "ref_spans": []}, {"section": "CASE PRESENTATION", "text": "On physical examination, a bulky and painful, fixed to the left pelvic sidewall, tumour was palpated in the left lower quadrant. Bimanual examination revealed the presence of a bulky mass, consisting of the uterus and adnexa.", "cite_spans": [], "ref_spans": []}, {"section": "CASE PRESENTATION", "text": "On ultrasound examination, a non-homogenous tumour of the pelvis, up to 9 \u00d7 6 cm in size, was seen.", "cite_spans": [], "ref_spans": []}, {"section": "CASE PRESENTATION", "text": "Apart from the pelvic lesion, multiple liver foci were suspected as metastasis. About 1,000 ml of ascites was present.", "cite_spans": [], "ref_spans": []}, {"section": "CASE PRESENTATION", "text": "Contrast enhanced CT scan revealed a nonhomogenous pelvic mass, approximately 113 \u00d7 105 \u00d7 154 mm in size, displacing the uterus and bladder, deforming and possibly infiltrating the front wall of the rectum (Fig. 1) . Blood test showed a high level of alpha-fetoprotein (AFP) 13,675 kU/l, serum hCG level was 2.75 U/l, LDH 356 U/l, CRP 69.9 mg/l, WBC 10.78*10e9/l (without shift to the left).", "cite_spans": [], "ref_spans": [{"start": 206, "end": 214, "text": "(Fig. 1)", "ref_id": "FIGREF0"}]}, {"section": "CASE PRESENTATION", "text": "Diagnostic laparoscopy was performed in order to verify the tumour's histology. The intraoperative findings revealed that the uterus was normal in appearance, displaced by the left broad ligament tumour to the right. Ovaries and fallopian tubes were normal. The rectum was fixed in the rectouterine excavation. Multiple peritoneal and bulky intrahepatic liver metastases were observed. Biopsies from a bulky tumour, peritoneal lesions, and liver metastasis were conducted.", "cite_spans": [], "ref_spans": []}, {"section": "CASE PRESENTATION", "text": "Microscopic examination revealed tubulo-papillary structures, covered by cuboid epithelium with slightly irregular nuclei with nucleoli, positive for placental alkaline phosphatase and alpha-fetoprotein ( Fig. 3) , hence the diagnosis of yolk sac tumour was made. Multiple liver metastases were observed (Fig. 2) . The multidisciplinary team decision was to start chemotherapy followed by debulking surgery. A standard BEP chemotherapeutic regimen has been chosen: bleomycin (30 mg/day) given on days 2, 9 and 16; etoposide (100 mg/m 2 /day) given on days 1-5; and cisplatin (20 mg/m 2 /day) given on days 1-5 for 4 cycles. The cycles were repeated every 3 weeks. After the fourth cycle, the serum AFP level reduced to 6.05 kU/l.", "cite_spans": [], "ref_spans": [{"start": 205, "end": 212, "text": "Fig. 3)", "ref_id": "FIGREF2"}, {"start": 304, "end": 312, "text": "(Fig. 2)", "ref_id": "FIGREF1"}]}, {"section": "CASE PRESENTATION", "text": "On the fourth month following the treatment, a PET CT scan was performed. Two metabolically active lesions in the pouch of Douglas and omentum were detected (Fig. 4) .", "cite_spans": [], "ref_spans": [{"start": 157, "end": 165, "text": "(Fig. 4)", "ref_id": "FIGREF3"}]}, {"section": "CASE PRESENTATION", "text": "A laparoscopic removal of the above-mentioned lesions was performed. After the surgery, the serum AFP level decreased to 0.575 kU/l. According to the histologic analysis, there was the same YST with 90% of tumour necrosis. The surgical margins were free from a tumour but not from the signs of necrosis.", "cite_spans": [], "ref_spans": []}, {"section": "CASE PRESENTATION", "text": "Four months after the laparoscopy, the AFP level raised up to 12.7 kU/l. PET CT was performed and a metabolically active lesion in the area of the pouch of Douglas was observed.", "cite_spans": [], "ref_spans": []}, {"section": "CASE PRESENTATION", "text": "The multidisciplinary team decision was to perform a laparotomy and completely resect the residual tumour. If extensive tumour deposits were found, a high dose chemotherapy with bone marrow transplantation would be considered as postoperative treatment.", "cite_spans": [], "ref_spans": []}, {"section": "CASE PRESENTATION", "text": "During the surgery, the residual tumour was seen at the area of the rectovaginal septum and in the area of the left mesovarium. Excision of the rectovaginal area with a part of the posterior uterine wall and anterior resection of the rectum with left salpingectomy were performed, and endto-end rectum anastomosis was conducted. The postoperative period was uneventful.", "cite_spans": [], "ref_spans": []}, {"section": "CASE PRESENTATION", "text": "The post-surgical specimen was free from a tumour macroscopically and microscopically at the margins; hence, no chemotherapy was administered. Two years after the treatment, a PET-CT scan showed no signs of the primary tumour or metastases. Serum AFP levels were normal.", "cite_spans": [], "ref_spans": []}, {"section": "CASE PRESENTATION", "text": "The menstrual cycle came back 4 months following the last cycle of chemotherapy.", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "Primary germ cell tumours of extragonadal origin are rare and the exact incidence of this type of cancer is unknown. They have been estimated to represent 3-5% of all adult germ cell malignancies (4). The most common extragonadal site is the vagina, where extraovarian yolk sac tumours arise in young children (5) . Rare cases have been reported in the vulva (6), the cervix and the endometrium (7). Yolk sac tumours arising in the pelvis outside of the ovary are distinctly uncommon (1, 8) .", "cite_spans": [{"start": 310, "end": 313, "text": "(5)", "ref_id": "BIBREF4"}, {"start": 484, "end": 487, "text": "(1,", "ref_id": "BIBREF0"}, {"start": 488, "end": 490, "text": "8)", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "DISCUSSION", "text": "The pathogenesis of YST is not known. The classical theory suggests that it arises from local The majority of adults with YST present with advanced local disease and distant metastases; therefore, the complete local excision is rarely feasible. This tumour most commonly spreads to the regional lymph nodes, lung, liver, and bone. Extragonadal germ cell tumours may reach a large size with no or relatively few symptoms (10) . The most common presenting symptoms for patients with endodermal primitive tumours are rapidly enlarging pelvic mass and pain (11) . In the presented case the patient's major concern was fever lasting for two months. According to the literature, fever is present in 10-25% of YST cases (12) . During further investigation, our patient was also diagnosed with high value of alpha-fetoprotein (AFP 13,675 ng/mL) that significantly decreased during the treatment the patient received: after 4 cycles of BEP chemotherapy the AFP value was 6.05 ng/mL and 0.575 ng/mL after the laparoscopic tumour debulking surgery, respectively. The decreasing ratio of post-operative serum AFP is an effective indicator to determine whether residual disease remains after surgery (13) . Response to chemotherapy can also be evaluated by normalization of AFP [14] . According to the literature, in order to detect a relapse, the AFP is more sensitive than the CT scan (15) . Yet despite its significance, the prognostic value of high levels of AFP in yolk sac tumours at the time of diagnosis remains controversial. In two studies AFP > 1,000 kU/L was associated with a higher risk of relapse after treatment (14, 16) . Two other studies found that pre-operative serum AFP levels before initial surgery had no significant correlation with prognosis (17) .", "cite_spans": [{"start": 420, "end": 424, "text": "(10)", "ref_id": "BIBREF9"}, {"start": 553, "end": 557, "text": "(11)", "ref_id": "BIBREF10"}, {"start": 713, "end": 717, "text": "(12)", "ref_id": "BIBREF11"}, {"start": 1187, "end": 1191, "text": "(13)", "ref_id": "BIBREF12"}, {"start": 1265, "end": 1269, "text": "[14]", "ref_id": "BIBREF13"}, {"start": 1374, "end": 1378, "text": "(15)", "ref_id": "BIBREF14"}, {"start": 1615, "end": 1619, "text": "(14,", "ref_id": "BIBREF13"}, {"start": 1620, "end": 1623, "text": "16)", "ref_id": "BIBREF16"}, {"start": 1755, "end": 1759, "text": "(17)", "ref_id": "BIBREF17"}], "ref_spans": []}, {"section": "DISCUSSION", "text": "In order to confirm diagnosis morphologically, laparoscopic surgery has been made in our case. In the past after the laparoscopic diagnosis of YST, conversion to laparotomy was recommended in order to achieve an optimal staging and to avoid an uncertain tumour cell spread. Today, advancement in technologies enabled us to achieve the same or even better surgical prognosis and a potentially faster recovery with less traumatic minimally invasive laparoscopic surgery compared to a conventional laparotomy (18, 19) .", "cite_spans": [{"start": 506, "end": 510, "text": "(18,", "ref_id": "BIBREF18"}, {"start": 511, "end": 514, "text": "19)", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "DISCUSSION", "text": "Extragonadal germ cell tumours have been managed under the same principle as their primary gonadal counterparts, using the treatment comprised of systemic chemotherapy together with local treatment, including surgery and radiotherapy (20) (21) (22) (23) (24) . The aim of surgery is removing the primary tumour without excessive morbidity. Neoadjuvant chemotherapy can be considered for patients with extensive intra-abdominal disease when initial debulking surgery is not an option (25) . In our case neoadjuvant chemotherapy with 4 BEP cycles was chosen as an option to reduce the tumour size and also to minimize the extent of surgical procedure causing as minimal as possible impact on the patient's fertility. Before the introduction of effective chemotherapy, the prognosis for patients with YST was poor, with a 3-year survival rate of 13% for malignant endodermal primitive tumours. The establishment of BEP chemotherapy for malignant germ cell tumours has significantly improved outcomes. BEP chemotherapy is regarded to be a gold-standard regimen for the first-line treatment of germ cell tumours at all stages of disease (26) . As our experience showed, in stage IV of YST neoadjuvant chemotherapy with following surgery is a considerably better choice for the patient as our patient had her menstrual cycle restored; hence, it is likely that the fertility of our patient is also preserved.", "cite_spans": [{"start": 234, "end": 238, "text": "(20)", "ref_id": "BIBREF20"}, {"start": 239, "end": 243, "text": "(21)", "ref_id": "BIBREF21"}, {"start": 244, "end": 248, "text": "(22)", "ref_id": "BIBREF22"}, {"start": 249, "end": 253, "text": "(23)", "ref_id": "BIBREF23"}, {"start": 254, "end": 258, "text": "(24)", "ref_id": "BIBREF24"}, {"start": 483, "end": 487, "text": "(25)", "ref_id": "BIBREF25"}, {"start": 1132, "end": 1136, "text": "(26)", "ref_id": "BIBREF26"}], "ref_spans": []}, {"section": "DISCUSSION", "text": "The possibility of a residual tumour and its management is a subject of consideration in IV stage disease. Patients who have a residual tumour after treatment with chemotherapy ought to undergo secondary surgery so that all residual tumour lesions would be excised (27) . In the presented case, surgical management of the residual tumour in the front rectum wall and the rectovaginal portion of the peritoneum after initial laparoscopic debulking was chosen as a treatment option and rectum resection was made. High-dose chemotherapy (HDCT) along with an autologous stem cell transplant (ASCT) is also a way to manage a residual germ cell tumour and must be taken into consideration if a residual tumour is present (28) . Despite risks of chemotherapy concerning the reproductive function of female patients, studies have shown that most of the women can anticipate a normal menstrual and reproductive function after treatment (29) (30) (31) .", "cite_spans": [{"start": 265, "end": 269, "text": "(27)", "ref_id": "BIBREF27"}, {"start": 715, "end": 719, "text": "(28)", "ref_id": "BIBREF28"}, {"start": 927, "end": 931, "text": "(29)", "ref_id": "BIBREF29"}, {"start": 932, "end": 936, "text": "(30)", "ref_id": "BIBREF30"}, {"start": 937, "end": 941, "text": "(31)", "ref_id": "BIBREF31"}], "ref_spans": []}, {"section": "DISCUSSION", "text": "After the treatment a follow-up is required involving an abdominal/pelvic exam, CT, AFP levels and CXR as an option (32) . Two studies reported specifically on the prognostic factors of ovarian yolk sac tumours. In the study of Nawa et al., the 5-year survival rate was 95.2, 75, 30, and 25% for patients with stage I, II, III, and IV, respectively. The respective numbers in the study by Kawai et al. were 92, 44, and 29% for stage I, II, and III. According to these two studies, other than the stage of ovarian YST significant prognostic factors were the presence and quantity of ascites before initial surgery and the amount of residual disease after surgery (16, 32) . In contrast to the study by Murugaesu et al. (33) , there was no correlation between the pre-operative serum AFP levels and prognosis. In the study by Mitchell et al. (14) the amount of residual disease after initial surgery and the extent of initial surgery did not significantly affect the outcome.", "cite_spans": [{"start": 116, "end": 120, "text": "(32)", "ref_id": "BIBREF32"}, {"start": 662, "end": 666, "text": "(16,", "ref_id": "BIBREF16"}, {"start": 667, "end": 670, "text": "32)", "ref_id": "BIBREF32"}, {"start": 718, "end": 722, "text": "(33)", "ref_id": "BIBREF33"}, {"start": 840, "end": 844, "text": "(14)", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "CONCLUSIONS", "text": "Our case illustrates that even at stage IV of YST, positive treatment results can be achieved through neoadjuvant chemotherapy and laparoscopic surgery. In order to achieve the results reported in our case, patients with late stage YST must be admitted to tertiary care hospitals where highly specialized medical treatment facilities can be provided. Highly qualified specialists who employ multidisciplinary approaches from the very beginning can be of crucial importance in order to avoid more complex surgical procedures. Another important aspect to successful treatment is an early preoperative histological verification of malignant pathology. Our patient has been disease free for a 24-month period after the latest surgical intervention.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Extragonadal yolk sac tumor in pelvic localization. A case report and literature review", "authors": [{"first": "M", "middle": [], "last": "Dede", "suffix": ""}, {"first": "R", "middle": [], "last": "Pabuccu", "suffix": ""}, {"first": "G", "middle": [], "last": "Yagci", "suffix": ""}, {"first": "M", "middle": ["C"], "last": "Yenen", "suffix": ""}, {"first": "U", "middle": [], "last": "Goktolga", "suffix": ""}, {"first": "O", "middle": [], "last": "Gunhan", "suffix": ""}], "year": 2004, "venue": "Gynecol Oncol", "link": "40843245"}, "BIBREF1": {"title": "Long-term outcome and prognostic factors for yolk sac tumor of the ovary. Nagoya", "authors": [{"first": "T", "middle": [], "last": "Umezu", "suffix": ""}, {"first": "H", "middle": [], "last": "Kajiyama", "suffix": ""}, {"first": "M", "middle": [], "last": "Terauchi", "suffix": ""}, {"first": "K", "middle": [], "last": "Shibata", "suffix": ""}, {"first": "K", "middle": [], "last": "Ino", "suffix": ""}, {"first": "A", "middle": [], "last": "Nawa", "suffix": ""}], "year": 2008, "venue": "J Med Sci", "link": "21652775"}, "BIBREF2": {"title": "Yolk sac tumor of the ovary associated with endometrioid carcinoma with metastasis to the vagina: a case report", "authors": [{"first": "W", "middle": ["C"], "last": "Mcbee", "suffix": ""}, {"first": "J", "middle": [], "last": "Brainard", "suffix": ""}, {"first": "J", "middle": [], "last": "Sawady", "suffix": ""}, {"first": "P", "middle": ["G"], "last": "Rose", "suffix": ""}], "year": 2007, "venue": "Gynecol Oncol", "link": "20006784"}, "BIBREF3": {"title": "Treatment and surgical staging of testicular and primary extragonadal germ cell cancer", "authors": [{"first": "M", "middle": ["B"], "last": "Garnick", "suffix": ""}, {"first": "G", "middle": ["P"], "last": "Canellos", "suffix": ""}, {"first": "J", "middle": ["P"], "last": "Richie", "suffix": ""}], "year": 1983, "venue": "JAMA", "link": "26865640"}, "BIBREF4": {"title": "Endodermal sinus tumor of the vagina: a report of nine cases and review of the literature", "authors": [{"first": "R", "middle": ["H"], "last": "Young", "suffix": ""}, {"first": "R", "middle": ["E"], "last": "Scully", "suffix": ""}], "year": 1984, "venue": "Gynecol Oncol", "link": "34412276"}, "BIBREF5": {"title": "Endodermal sinus tumor of the vulva: successfully treated with high-dose chemotherapy", "authors": [{"first": "K", "middle": [], "last": "Traen", "suffix": ""}, {"first": "H", "middle": [], "last": "Logghe", "suffix": ""}, {"first": "J", "middle": [], "last": "Maertens", "suffix": ""}, {"first": "C", "middle": [], "last": "Mattelaere", "suffix": ""}, {"first": "P", "middle": [], "last": "Moerman", "suffix": ""}, {"first": "I", "middle": [], "last": "Vergote", "suffix": ""}], "year": 2004, "venue": "Int J Gynecol Cancer", "link": "36610050"}, "BIBREF6": {"title": "Tumor del seno endodermal extragonadal en la infancia. reporte de dos casos", "authors": [{"first": "J", "middle": [], "last": "S\u00e1nchez Lihon", "suffix": ""}, {"first": "Casavilca", "middle": [], "last": "Zambrano", "suffix": ""}, {"first": "S", "middle": [], "last": "", "suffix": ""}, {"first": "Garcia", "middle": [], "last": "Madrid", "suffix": ""}, {"first": "J", "middle": [], "last": "", "suffix": ""}, {"first": "Klinge", "middle": [], "last": "Castro", "suffix": ""}, {"first": "G", "middle": [], "last": "", "suffix": ""}], "year": 2003, "venue": "Rev Medica Hered", "link": null}, "BIBREF7": {"title": "Extraovarian pelvic yolk sac tumors. Cancer", "authors": [{"first": "P", "middle": ["B"], "last": "Clement", "suffix": ""}, {"first": "R", "middle": ["H"], "last": "Young", "suffix": ""}, {"first": "R", "middle": ["E"], "last": "Scully", "suffix": ""}], "year": 1988, "venue": "", "link": null}, "BIBREF8": {"title": "Yolk sac tumor: histopathologic report of 2 cases", "authors": [{"first": "H", "middle": ["M"], "last": "Alkatan", "suffix": ""}, {"first": "A", "middle": [], "last": "Al-Kofide", "suffix": ""}, {"first": "H", "middle": [], "last": "Al-Hussain", "suffix": ""}], "year": 2008, "venue": "Can J Ophthalmol", "link": "28396356"}, "BIBREF9": {"title": "Extragonadal seminoma: an international multicenter analysis of prognostic factors and long term treatment outcome", "authors": [{"first": "C", "middle": [], "last": "Bokemeyer", "suffix": ""}, {"first": "J", "middle": ["P"], "last": "Droz", "suffix": ""}, {"first": "A", "middle": [], "last": "Horwich", "suffix": ""}, {"first": "A", "middle": [], "last": "Gerl", "suffix": ""}, {"first": "S", "middle": ["D"], "last": "Fossa", "suffix": ""}, {"first": "J", "middle": [], "last": "Beyer", "suffix": ""}], "year": 2001, "venue": "Cancer", "link": null}, "BIBREF10": {"title": "Management of germ cell tumours of the ovary", "authors": [{"first": "J", "middle": [], "last": "Bailey", "suffix": ""}, {"first": "D", "middle": [], "last": "Church", "suffix": ""}], "year": 2005, "venue": "Rev Gynaecol Pract", "link": "72061208"}, "BIBREF11": {"title": "Malignant germ cell tumors of the ovary", "authors": [{"first": "K", "middle": [], "last": "Tewari", "suffix": ""}, {"first": "F", "middle": [], "last": "Cappuccini", "suffix": ""}, {"first": "P", "middle": ["J"], "last": "Disaia", "suffix": ""}, {"first": "M", "middle": ["L"], "last": "Berman", "suffix": ""}, {"first": "A", "middle": [], "last": "Manetta", "suffix": ""}, {"first": "M", "middle": ["F"], "last": "Kohler", "suffix": ""}], "year": 2000, "venue": "Obstet Gynecol", "link": "11238650"}, "BIBREF12": {"title": "Serum alpha-fetoprotein as a marker for the effect of post-operative radiation therapy and/or chemotherapy in eight cases of ovarian endodermal sinus tumour", "authors": [{"first": "A", "middle": [], "last": "Sell", "suffix": ""}, {"first": "H", "middle": [], "last": "Sogaard", "suffix": ""}, {"first": "B", "middle": [], "last": "Norgaard-Pedersen", "suffix": ""}], "year": 1976, "venue": "Int J Cancer", "link": "24894144"}, "BIBREF13": {"title": "Treatment of nondysgerminomatous ovarian germ cell tumors: an analysis of 69 cases. Cancer", "authors": [{"first": "P", "middle": ["L"], "last": "Mitchell", "suffix": ""}, {"first": "N", "middle": [], "last": "Al-Nasiri", "suffix": ""}, {"first": "A", "middle": [], "last": "&apos;hern", "suffix": ""}, {"first": "R", "middle": [], "last": "Fisher", "suffix": ""}, {"first": "C", "middle": [], "last": "Horwich", "suffix": ""}, {"first": "A", "middle": [], "last": "Pinkerton", "suffix": ""}, {"first": "C", "middle": ["R"], "last": "", "suffix": ""}], "year": 1999, "venue": "", "link": null}, "BIBREF14": {"title": "Endodermal sinus tumor in children", "authors": [{"first": "A", "middle": ["M"], "last": "Davidoff", "suffix": ""}, {"first": "A", "middle": [], "last": "Hebra", "suffix": ""}, {"first": "N", "middle": [], "last": "Bunin", "suffix": ""}, {"first": "S", "middle": ["J"], "last": "Shochat", "suffix": ""}, {"first": "L", "middle": [], "last": "Schnaufer", "suffix": ""}], "year": "", "venue": "", "link": "25737839"}, "BIBREF16": {"title": "Prognostic factors of patients with yolk sac tumors of the ovary", "authors": [{"first": "A", "middle": [], "last": "Nawa", "suffix": ""}, {"first": "N", "middle": [], "last": "Obata", "suffix": ""}, {"first": "F", "middle": [], "last": "Kikkawa", "suffix": ""}, {"first": "M", "middle": [], "last": "Kawai", "suffix": ""}, {"first": "T", "middle": [], "last": "Nagasaka", "suffix": ""}, {"first": "S", "middle": [], "last": "Goto", "suffix": ""}], "year": 2001, "venue": "Am J Obstet Gynecol", "link": "25986817"}, "BIBREF17": {"title": "Prognostic factors for women with ovarian germ cell tumors", "authors": [{"first": "J", "middle": ["I"], "last": "Mayordomo", "suffix": ""}, {"first": "L", "middle": [], "last": "Paz-Ares", "suffix": ""}, {"first": "M", "middle": ["T"], "last": "Diaz-Puente", "suffix": ""}, {"first": "P", "middle": [], "last": "Lianes", "suffix": ""}, {"first": "M", "middle": ["D"], "last": "Garcia-Prats", "suffix": ""}, {"first": "H", "middle": [], "last": "Cortes-Funes", "suffix": ""}], "year": 1994, "venue": "J Clin Oncol", "link": "12885042"}, "BIBREF18": {"title": "Laparoscopic treatment of early ovarian cancer: surgical and survival outcomes", "authors": [{"first": "R", "middle": [], "last": "Tozzi", "suffix": ""}, {"first": "C", "middle": [], "last": "K\u00f6hler", "suffix": ""}, {"first": "A", "middle": [], "last": "Ferrara", "suffix": ""}, {"first": "A", "middle": [], "last": "Schneider", "suffix": ""}], "year": 2004, "venue": "Gynecol Oncol", "link": "22425771"}, "BIBREF19": {"title": "Endodermal sinus tumour of the ovary: the place of alphafetoprotein detection, surgery and chemotherapy", "authors": [{"first": "S", "middle": ["K"], "last": "Khoo", "suffix": ""}, {"first": "D", "middle": ["W"], "last": "Buntine", "suffix": ""}, {"first": "P", "middle": ["F"], "last": "Massey", "suffix": ""}, {"first": "Isc", "middle": [], "last": "Jones", "suffix": ""}], "year": 1981, "venue": "Aust N Z J Obstet Gynaecol", "link": "43577690"}, "BIBREF20": {"title": "Prognosis of malignant sacrococcygeal germ cell tumours according to their natural history and surgical management", "authors": [{"first": "F", "middle": [], "last": "De Corti", "suffix": ""}, {"first": "S", "middle": [], "last": "Sarnacki", "suffix": ""}, {"first": "C", "middle": [], "last": "Patte", "suffix": ""}, {"first": "V", "middle": [], "last": "Mosseri", "suffix": ""}, {"first": "M", "middle": ["C"], "last": "Baranzelli", "suffix": ""}, {"first": "H", "middle": [], "last": "Martelli", "suffix": ""}], "year": 2012, "venue": "Surg Oncol", "link": "7723984"}, "BIBREF21": {"title": "First-line chemotherapy of non-seminomatous germ cell tumors(NSGCTs)", "authors": [{"first": "K", "middle": [], "last": "Pliarchopoulou", "suffix": ""}, {"first": "D", "middle": [], "last": "Pectasides", "suffix": ""}], "year": 2009, "venue": "Cancer Treat Rev", "link": "37902365"}, "BIBREF22": {"title": "Survival and reproductive function of 52 women treated with surgery and bleomycin, etoposide, cisplatin (BEP) chemotherapy for ovarian yolk sac tumor", "authors": [{"first": "T", "middle": [], "last": "De La Motte Rouge", "suffix": ""}, {"first": "P", "middle": [], "last": "Pautier", "suffix": ""}, {"first": "P", "middle": [], "last": "Duvillard", "suffix": ""}, {"first": "A", "middle": [], "last": "Rey", "suffix": ""}, {"first": "P", "middle": [], "last": "Morice", "suffix": ""}, {"first": "C", "middle": [], "last": "Haie-Meder", "suffix": ""}], "year": 2008, "venue": "Ann Oncol", "link": "18739392"}, "BIBREF23": {"title": "Extragonadal germ cell tumors: relation to testicular neoplasia and management options", "authors": [{"first": "C", "middle": [], "last": "Bokemeyer", "suffix": ""}, {"first": "J", "middle": ["T"], "last": "Hartmann", "suffix": ""}, {"first": "S", "middle": ["D"], "last": "Fossa", "suffix": ""}, {"first": "J-P", "middle": [], "last": "Droz", "suffix": ""}, {"first": "H-J", "middle": [], "last": "Schmol", "suffix": ""}, {"first": "A", "middle": [], "last": "Horwich", "suffix": ""}], "year": 2003, "venue": "APMIS", "link": "23802184"}, "BIBREF24": {"title": "Primary yolk sac tumor of the omentum: a case report and review of the literature", "authors": [{"first": "S", "middle": ["W"], "last": "Kim", "suffix": ""}, {"first": "J", "middle": ["H"], "last": "Park", "suffix": ""}, {"first": "M", "middle": ["C"], "last": "Lim", "suffix": ""}, {"first": "J", "middle": ["Y"], "last": "Park", "suffix": ""}, {"first": "C", "middle": ["W"], "last": "Yoo", "suffix": ""}, {"first": "S", "middle": ["Y"], "last": "Park", "suffix": ""}], "year": 2009, "venue": "Arch Gynecol Obstet", "link": "21152110"}, "BIBREF25": {"title": "National Guideline Clearinghouse | Ovarian germ cell tumours", "authors": [], "year": 2016, "venue": "", "link": null}, "BIBREF26": {"title": "Adjuvant therapy of ovarian germ cell tumors with cisplatin, etoposide, and bleomycin: a trial of the Gynecologic Oncology Group", "authors": [{"first": "S", "middle": [], "last": "Williams", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Blessing", "suffix": ""}, {"first": "S", "middle": ["Y"], "last": "Liao", "suffix": ""}, {"first": "H", "middle": [], "last": "Ball", "suffix": ""}, {"first": "P", "middle": [], "last": "Hanjani", "suffix": ""}], "year": 1994, "venue": "J Clin Oncol", "link": "24946664"}, "BIBREF27": {"title": "WHO | Medicines for treatment of the following cancers -review -EML and EMLc", "authors": [], "year": 2016, "venue": "", "link": null}, "BIBREF28": {"title": "Salvage high-dose chemotherapy for germ cell tumors", "authors": [{"first": "D", "middle": ["R"], "last": "Feldman", "suffix": ""}, {"first": "T", "middle": [], "last": "Powles", "suffix": ""}], "year": 2015, "venue": "Urol Oncol", "link": "205571856"}, "BIBREF29": {"title": "Survival and reproductive function after treatment of malignant germ cell ovarian tumors", "authors": [{"first": "G", "middle": [], "last": "Zanetta", "suffix": ""}, {"first": "C", "middle": [], "last": "Bonazzi", "suffix": ""}, {"first": "M", "middle": [], "last": "Cant\u00f9", "suffix": ""}, {"first": "S", "middle": [], "last": "Binidagger", "suffix": ""}, {"first": "A", "middle": [], "last": "Locatelli", "suffix": ""}, {"first": "G", "middle": [], "last": "Bratina", "suffix": ""}], "year": 2001, "venue": "J Clin Oncol", "link": "46036544"}, "BIBREF30": {"title": "Effects of treatment on fertility in long-term survivors of childhood or adolescent cancer", "authors": [{"first": "J", "middle": [], "last": "Byrne", "suffix": ""}, {"first": "J", "middle": ["J"], "last": "Mulvihill", "suffix": ""}, {"first": "M", "middle": ["H"], "last": "Myers", "suffix": ""}, {"first": "R", "middle": ["R"], "last": "Connelly", "suffix": ""}, {"first": "M", "middle": ["D"], "last": "Naughton", "suffix": ""}, {"first": "M", "middle": ["R"], "last": "Krauss", "suffix": ""}], "year": 1987, "venue": "N Engl J Med", "link": "72792150"}, "BIBREF31": {"title": "Gonadal effects of cancer therapy in girls. Cancer", "authors": [{"first": "S", "middle": ["V"], "last": "Nicosia", "suffix": ""}, {"first": "M", "middle": [], "last": "Matus-Ridley", "suffix": ""}, {"first": "A", "middle": ["T"], "last": "Meadows", "suffix": ""}], "year": 1985, "venue": "", "link": "41028275"}, "BIBREF32": {"title": "Prognostic factors in yolk sac tumors of the ovary. A clinicopathologic analysis of 29 cases", "authors": [{"first": "M", "middle": [], "last": "Kawai", "suffix": ""}, {"first": "T", "middle": [], "last": "Kano", "suffix": ""}, {"first": "Y", "middle": [], "last": "Furuhashi", "suffix": ""}, {"first": "K", "middle": [], "last": "Mizuno", "suffix": ""}, {"first": "N", "middle": [], "last": "Nakashima", "suffix": ""}, {"first": "S", "middle": ["E"], "last": "Hattori", "suffix": ""}], "year": 1991, "venue": "Cancer", "link": "37936303"}, "BIBREF33": {"title": "Malignant ovarian germ cell tumors: identification of novel prognostic markers and long-term outcome after multimodality treatment", "authors": [{"first": "N", "middle": [], "last": "Murugaesu", "suffix": ""}, {"first": "P", "middle": [], "last": "Schmid", "suffix": ""}, {"first": "G", "middle": [], "last": "Dancey", "suffix": ""}, {"first": "R", "middle": [], "last": "Agarwal", "suffix": ""}, {"first": "L", "middle": [], "last": "Holden", "suffix": ""}, {"first": "I", "middle": [], "last": "Mcneish", "suffix": ""}], "year": 2006, "venue": "J Clin Oncol", "link": "26078934"}}, "ref_entries": {"FIGREF0": {"text": "Fig. 1. Contrast enhanced CT scan revealed non-homogenous pelvic mass, approximately 113 \u00d7 105 \u00d7 154 mm in size", "type": "figure"}, "FIGREF1": {"text": "Fig. 2. CT scan revealed multiple liver metastases", "type": "figure"}, "FIGREF2": {"text": "Fig. 3. Primary biopsy: HE (left) and immunohistochemical stains, PLAP (placental alkaline phosphatase) (in between) and AFP (alpha-fetoprotein); magnification 200x: tubulopapillary structures with focal positivity to PLAP and AFP", "type": "figure"}, "FIGREF3": {"text": "Fig. 4. PET CT scan showed metabolically active lesions in the rectouterine pouch and large omentum", "type": "figure"}}}
{"paper_id": "17789698", "_pdf_hash": "e91f25fb7afa483426c8abcfff8b7e44594859e3", "abstract": [{"section": "Abstract", "text": "ABSTRACT. The eastern syntaxis of the Himalayas is expressed in the crust as a pronounced southward bend in the orogen. The change in strike of geologic features coincides with the high topography of the Namche Barwa region, the exposure of granulite-grade metamorphic rocks, and a 180-degree bend in the Yalu Tsangpo. We have conducted a geochronologic and geochemical investigation of several suites of granitoids collected from the Namche Barwa massif and subjacent terranes of southeastern Tibet, ranging from cm-scale dikes and sills to larger, outcrop-scale intrusions. U-Pb SHRIMP-RG zircon ages establish at least five magmatic episodes: \u03f3400 to 500 Ma, \u03f3120 Ma, 40 to 70 Ma, 18 to 25 Ma, and 3 to 10 Ma. These episodes broadly correlate to spatial patterns in sample localities, as follows: 400 to 500 Ma ages occur in zircon cores collected from within the massif proper; \u03f3120 Ma granites, related to early Gangdese arc plutonism, are primarily located northeast of Namche Barwa; later (40 -70 Ma) Gangdese activity is expressed in granites west of Namche Barwa. 18 to 25 Ma granites occur both along the suture zone west of Gyala Peri, and directly north of Namche Barwa along the area of the Jiali fault zone, and are attributed both to shearing within the Jiali fault zone and to an early Miocene Gangdese Thrust event. Exceptionally young (<10 Ma) zircon ages are clustered near the core of the massif, along the Yalu Tsangpo gorge. Trace-element geochemical data indicates the presence of both fluid-present and fluid absent melts, with a fluid-absent (decompression) melting regime dominating near the core of Namche Barwa.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "", "text": "this zone of highly strained rocks. Medium to high-grade metamorphic rocks (presumably derived from Indian Basement rocks) make up the core of the syntaxis and were once structurally below the Transhimalayan Plutonic Belt. They are dominantly migmatitic gneisses of Proterozoic initial age (Zhang and others, 1992; Burg and others, 1997) . According to Liu and Zhong (1997) , they can be divided into a granulite group in the north and an amphibolite group in the south, with the former thrust over the latter by the Namula thrust system.", "cite_spans": [{"start": 353, "end": 373, "text": "Liu and Zhong (1997)", "ref_id": "BIBREF54"}], "ref_spans": []}, {"section": "", "text": "A number of granitoids with distinctly different means of formation occur within or near the eastern syntaxis. We briefly review the main types of granitoids that have been reported from the region to date.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Namche Barwa Massif.-In the core of this massif, granitic dikes and sills intrude Indian Basement gneisses on a range of scales. Burg and others (1998) reported leucogranite and pegmatite dikes in the Namche Barwa syntaxis, including leucosomes that crosscut metamorphic layering in the pelitic gneisses. This structural relationship indicates that anatexis has outlasted the main fabric development in the core of Namche Barwa. Single crystal U-Th-Pb analyses on zircon, xenotime and thorite by Burg and others (1997) provide leucosome crystallization ages ranging between 2.9 and 3.9 Ma, with a protolith age of 484 \u03ee 3 Ma. Ding and others (2001) reported U-Pb zircon ages as young as \u03f311 Ma from mafic granulites and two-mica-bearing leucosomes within the massif's core. A cluster of ages at \u03f365 Ma likely crystallized during Andean-type Gangdese magmatism, while a younger (\u03f340 Ma) cluster is interpreted to have crystallized during fluid-present, high-grade metamorphism during the early stages of India-Asia collision. The youngest, 11 to 25 Ma, zircon ages are attributed to a later high-grade metamorphic event, possibly related to decompression melting during rapid exhumation.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Nanga Parbat massif.-In the western Himalayan syntaxis, decompression melting has been invoked for the formation of leucogranites that intrude the Nanga Parbat massif (Zeitler and Chamberlain, 1991) , due to the temporal coincidence of exhumation and melting. In addition to fluid-absent (decompression) melting, fluid-present melts have been documented at Nanga Parbat. The concurrence of both types of melt Ding and others (2001) . Location of fig. 2 shown in box. GTS \u03ed Gangdese Thrust System, RZTS \u03ed Renbu Zedong Thrust System, STDS \u03ed South Tibetan Detachment System, ITSZ \u03ed Indus Tsangpo Suture Zone, MCT \u03ed Main Central Thrust, MBT \u03ed Main Boundary Thrust, NB \u03ed Namche Barwa. Regional geographic location of Namche Barwa shown in inset. NBS \u03ed Namche Barwa Syntaxis, NPS \u03ed Nanga Parbat Syntaxis. of southeastern Tibet, Namche Barwa Area reaction is attributed to a change from fluid-absent anatexis in the mid-crust (\u03f320 km depth) to fluid infiltration in the upper crust (\u03f310 km depth) (Whittington and others, 1999) . These granites are among the youngest documented in the Himalayan system, at 1 to 3 Ma (Zeitler and Chamberlain, 1991) .", "cite_spans": [{"start": 167, "end": 198, "text": "(Zeitler and Chamberlain, 1991)", "ref_id": "BIBREF89"}, {"start": 1110, "end": 1141, "text": "(Zeitler and Chamberlain, 1991)", "ref_id": "BIBREF89"}], "ref_spans": [{"start": 446, "end": 452, "text": "fig. 2", "ref_id": "FIGREF2"}]}, {"section": "", "text": "Himalayan leucogranites.-Tertiary magmatism within the Himalaya proper is largely confined to two parallel granite belts, the High Himalayan Leucogranites and the North Himalayan Granites (Harrison and others, 1997b) . A commonly prescribed model for Himalayan leucogranite genesis involves fluid advection from the dehydrating footwall into the relatively hot hanging wall, along major fault systems such as the Main Central Thrust (Le Fort, 1981; Le Fort and others, 1987) . Improved knowledge of granite crystallization ages (Edwards and Harrison, 1997; Harrison and others, 1997a ) suggests a different model, relating the formation of Miocene leucogranites to syn-orogenic extension on the South Tibetan Detachment System (STDS) around 20 Ma. This model assumes that the primary cause of melting is decompression during exhumation south of the STDS (Hodges and others, 1992; Harris and Massey, 1994) . In southeastern Tibet, Miocene partial melts and late Eocene K-rich magmas have been attributed to simultaneous shear heating and rapid erosion (for example, Harrison and others, 1998) during coeval slip along the MCT and STDS. An alternative slab break-off model (Chemenda and others, 2000; Yin and Harrison, 2000; Kohn and Parkinson, 2002) has been proposed to explain the Miocene leucogranites, based on the occurrence of rare Eocene eclogites in southeastern Tibet. This model assumes subduction of Greater Himalayan crustal rocks to \u03f3100 km depth in the Eocene followed by buoyant rise after decoupling from the mantle lithosphere.", "cite_spans": [{"start": 528, "end": 556, "text": "(Edwards and Harrison, 1997;", "ref_id": "BIBREF19"}, {"start": 880, "end": 904, "text": "Harris and Massey, 1994)", "ref_id": "BIBREF27"}, {"start": 1199, "end": 1222, "text": "Yin and Harrison, 2000;", "ref_id": "BIBREF86"}, {"start": 1223, "end": 1248, "text": "Kohn and Parkinson, 2002)", "ref_id": "BIBREF39"}], "ref_spans": []}, {"section": "", "text": "Gangdese Arc.-Just to the north of the ITSZ is the Transhimalayan plutonic belt, a semi-continuous 2600-km-long batholith with rocks ranging in composition from gabbro to granite (Debon and others, 1986) . In the proximity of the Namche Barwa syntaxis, this belt is represented by the Gangdese batholith, forming the root of the Gangdese magmatic arc that developed as a consequence of northward subduction of Neo-Tethys oceanic crust (Hodges, 2000 , and references therein). Diorites and granodiorites from the eastern section of the Gangdese batholith yield geochronologic ages between 113 \u03ee 2 Ma (   40   Ar/   39 Ar method on amphiboles; Maluski and others, 1988) and 41.1 \u03ee 0.4 Ma (U/Pb method on zircons; Sch\u00e4rer and others, 1984) . There is a wide variety in composition (that is, Debon and others, 1986) , but no clear relationship between chemistry and age of plutonism (Sch\u00e4rer and others, 1984) .", "cite_spans": [{"start": 435, "end": 448, "text": "(Hodges, 2000", "ref_id": "BIBREF34"}], "ref_spans": []}, {"section": "", "text": "Red River shear zone.-East of the Namche Barwa syntaxis, documented magmatism is associated with ductile deformation and high-grade metamorphism along the Red River shear zone others, 1990, 1994; Harrison and others, 1992; Leloup and Kienast, 1993; others, 1993, 1995; Chung and others, 1998; Wang and others, 2001) . Partial melts in the Red River shear zone coeval with ductile deformation yield ages of 22 to 23 Ma and geochemical data indicate anatexis at 20 to 15 km depth, with crustally derived mantle affinities (Zhang and Sch\u00e4rer, 1999) .", "cite_spans": [{"start": 223, "end": 248, "text": "Leloup and Kienast, 1993;", "ref_id": "BIBREF49"}, {"start": 520, "end": 545, "text": "(Zhang and Sch\u00e4rer, 1999)", "ref_id": "BIBREF93"}], "ref_spans": []}, {"section": "", "text": "Early Miocene melts, southern Tibet.-Two types of magmatism are documented in areas of southern Tibet from circa 25 to 10 Ma, those of ultrapotassic composition and of calc-alkaline composition (Coulon and others, 1986; Yin and others, 1994; Turner and others, 1996; Miller and others, 1999; Williams and others, 2001) . These \"postcollisional\" magmas occur as small intrusive and extrusive bodies located west of Lhasa city. Recently, calc-alkaline magmas emplaced from circa 26 to 10 Ma have also been reported in the areas around Xigaze and east of Lhasa city (Chung and others, 2003) , which exhibit geochemical signatures characteristic of adakites, lavas previously found only in subduction zones. Chung and others (2003) believe them to represent the first example of adakites produced in a modern continental collision setting, resulting from melting of thickened Tibetan lower crust, induced by removal of lithospheric mantle in late Oligocene time. Murphy and Yin (2003) , however, suggest that postcollision (Oligocene/Miocene) high-K, calc-alkaline magmatism along the southern margin of the Lhasa block may be attributed to late subduction of remnant Neo-Tethyan oceanic crust, producing magmatism.", "cite_spans": [{"start": 959, "end": 980, "text": "Murphy and Yin (2003)", "ref_id": "BIBREF63"}], "ref_spans": []}, {"section": "", "text": "Himalayan Paleozoic ages.-Le Fort and others (1980) first reported Paleozoic ages (516 \u03ee 6 Ma; whole rock Rb/Sr method) on the Manshera granite in Pakistan. Recent work in the central Himalayas (Gehrels and others, 2003) also documents the existence of \u03f3470 to 485 Ma granitic intrusions (U-Pb method on zircons) within Greater Himalayan metasediments, reflecting initiation of the Himalayan orogen along an early Paleozoic thrust belt. This age range is also supported by numerous \u03f3480 to 500 Ma U-Pb zircon ages (Ferrara and others, 1983; Trivedi and others, 1984; Le Fort and others, 1986; Hodges and others, 1996; others, 1998, 2000; Miller and others, 2001 ) from cross-cutting granitic plutons and orthogneisses within Greater Himalayan rocks. Group A samples, collected from within the Namche Barwa massif proper, are 20 to 300 cm-thick dikes and sills that intrude amphibolite to granulite grade Precambrian gneisses. Samples IG-2d, IG-4, and IG-6b were collected along the upper inner gorge of the Yalu Tsangpo ( fig. 2) , along a traverse from Jiala to Zhibei. Sample IG-2d ( fig. 3 ) represents a deformed felsic melt pod within a 100-meter amphibolite section near Jiala. Sample IG-4 was collected from an \u03f33-meter leucocratic pegmatite dike that locally crosscuts and elsewhere is sheared concordantly into the foliation. Sample IG-6b was collected from a felsic crosscutting dikelet (\u03f320 cm) within a small biotite gneiss outcrop exposed along the trail from Zhibei to Jiala, just northeast of Zhibei. Sample IG-15a was collected from a granitic sweat within the gneisses, along a road cut just to the east-northeast of Pai. Sample IG-16 was collected from a K-feldspar-bearing banded migmatite exposed along a jeep road from Pai to Duoxiong La, on the northwest side of Duoxiong La pass. Sample IG-18 was collected as float from an \u03f34 m, coarse-grained granitic boulder halfway to the top of Duoxiong La pass. The source of this boulder, however, was clearly from a large granite sill visible in the headwall above. We therefore justify the sampling of float in the case of IG-18, by asserting that the source rock is very well constrained.", "cite_spans": [], "ref_spans": [{"start": 1022, "end": 1029, "text": "fig. 2)", "ref_id": "FIGREF2"}, {"start": 1086, "end": 1092, "text": "fig. 3", "ref_id": "FIGREF3"}]}, {"section": "", "text": "Group B samples were collected along the northwestern margin of the NB-GP massif, and represent granite and pegmatite dikes intruding basement gneisses of both Lhasa block and Indian Plate origin. Samples BT-14, BT-15, BT-17 ( fig. 4) , were collected from a section within the De'u Gungbu Valley ( fig. 5 ), along an E-W traverse across the brittle-faulted western margin of the NB-GP massif (including the modified and very narrow Indus-Tsangpo suture zone). Within this group, BT-14 is a granitic gneiss, BT-15 represents a leucocratic pegmatite dike cross-cutting the Lhasa Block basement gneisses, BT-17 is a medium-grained granite dike from the westernmost edge of the Gyala Peri massif, cross-cutting the amphibolites near a brittle fault zone, BT-19 is a syntectonic foliated muscovite-bearing granite east of the S/C mylonite zone, and BT-20 is a S/C mylonite with coarse augen. North of this traverse, BT-07 and NB-35-02 were collected near Dongjiu, from a garnet granite cutting Lhasa block gneisses and a granite cutting Lhasa metasediments, respectively. Group C samples were collected from a large area west of the NB-GP massif. Sample NB-159-02 was collected from Lhasa block basement granitic gneiss near Loulan. Samples NB-120-02, BT19E, BT20E, BT-4-01 are spread out to the west of the NB-GP massif, in the general vicinity of Bayi and along the Nyang River. These, along with samples BT-36 and BT-37 (located considerably west, off the map, along the road to Lhasa from Bayi) most likely represent outcrops of Gangdese Arc granitoids.", "cite_spans": [], "ref_spans": [{"start": 227, "end": 234, "text": "fig. 4)", "ref_id": "FIGREF4"}, {"start": 299, "end": 305, "text": "fig. 5", "ref_id": "FIGREF5"}]}, {"section": "", "text": "Group D consists of two samples, BT-33 and BT-17-01 (2001 field season), collected from roughly north of the Namche Barwa massif, near Tungmai, in the area of the Jiali fault zone. Both represent granitic dikes intruding Lhasa Block metasediments of medium grade.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Group E samples were collected from northeast of Namche Barwa, in the vicinity of Bomi. Samples BM-02 and BM-03 represent Gangdese plutonic rock and were collected from a granodiorite and a granite pegmatite dike, respectively, between Medog and Bomi. Samples BC-01, BC-02, and BC-03 are also Gangdese granitoids, collected along the main road to Qamdo and Chengdu, east of Bomi.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Mapping procedures.-The map ( fig. 2 ) is based on the work of our Chengdu colleagues (Geng and others, 2002) , modified and extended using observations made during our field work. Portions of original maps by Zhang and others (1992) and others (1997, 1998) for the eastern part of the syntaxis are also incorporated into figure 2.", "cite_spans": [], "ref_spans": [{"start": 30, "end": 36, "text": "fig. 2", "ref_id": "FIGREF2"}]}, {"section": "", "text": "Analytical techniques and considerations.-At the Stanford -U.S. Geological Survey Mass Analysis Center, we determined SHRIMP-RG (Sensitive High-Resolution Ion Microprobe -Reverse Geometry), U-Pb ages for all of the samples in this study. Zircons were separated using standard techniques of crushing, grinding, and heavy liquid and magnetic separation. Analyzed zircon fractions were primarily composed of clear, euhedral grains, and consistently exhibited one of two morphologies: elongate prisms 897 of southeastern Tibet, Namche Barwa Area or stubby prisms. Mineral coloring was honey yellow to light pink, with occasional inclusions of quartz, feldspar and biotite. Zircons from all sample groups were strongly zoned, and exhibited distinct cores with complicated overgrowths ( fig. 6 ).", "cite_spans": [], "ref_spans": [{"start": 781, "end": 787, "text": "fig. 6", "ref_id": "FIGREF6"}]}, {"section": "", "text": "For each sample, separates were mounted in epoxy and polished to approximately half the mean grain thickness, then imaged with reflected light and cathodoluminescence to illuminate internal zoning. The mounts were coated with gold for analysis and each sample was sputtered by using a primary beam of O -ions with a spot size of \u03f325 m. 248 ThO, and 254 UO were measured from the secondary beam. Analytical and data reduction procedures followed those given in Williams (1998) . For age standardization, concentrations of uranium and thorium from standard zircons SL13 and CZ3 were used. U/Pb ratios were determined through replicate analyses of standard zircons R33 (418 Ma) and AS57 (1099 Ma), and ages were based on the measured 206 Pb/ 238 U ratio calibrated to the 206 Pb/ 238 U ratio in the AS57 standard. The Pb/U ratio in the standard typically exhibited a calculated external spot-to-spot error of \u03f32.0% (2). All reported ages were determined using the data-reduction program Squid (Ludwig, 2001) . Common Pb corrections were made using the two-stage average crustal Pb model of Stacey and Kramers (1975) . Analyses yielding ages greater than 1000 Ma we corrected by using Pb, while younger ages were corrected using measured 207 Pb. Because our samples are primarily young (Mesozoic and younger), Tera-Wasserburg concordia plots are chosen as the most appropriate to display the analytical data (figs. 6-10).", "cite_spans": [{"start": 460, "end": 475, "text": "Williams (1998)", "ref_id": "BIBREF83"}, {"start": 990, "end": 1004, "text": "(Ludwig, 2001)", "ref_id": "BIBREF55"}, {"start": 1087, "end": 1112, "text": "Stacey and Kramers (1975)", "ref_id": "BIBREF74"}], "ref_spans": []}, {"section": "", "text": "Major and trace element analyses for 37 Namche Barwa area granites were obtained by employing conventional XRF (X-ray fluorescence) spectrometry at the Washington State University GeoAnalytical Laboratory. Of these, three samples (BT14-02, BT19E-02, NB02-159) included weathered pieces in those that were ground for analysis. All had good XRF totals, however, indicating that the amount of latealteration hydrous material was not significant.", "cite_spans": [], "ref_spans": []}, {"section": "results", "text": "Geochronology.-Our new U-Pb zircon ages place significant constraints on the timing of granitic melt generation in the Namche Barwa and adjacent regions. Analytical results (table 1) are shown on Tera-Wasserburg concordia plots in figures 7, 8, 9, 10 and 11. The majority of the ages are concordant, with some older, slightly discordant ages resulting from inheritance, as would be expected from crustallyderived partial melts.", "cite_spans": [], "ref_spans": []}, {"section": "results", "text": "As the scope of our study is focused primarily on correlations between age and location, we emphasize that the procedures used for age assignments are not statistically rigorous, such as a more precise age-focused study would be. The wide range of the determined ages allows us to make groupings based on spatial trends; these groups are distinct from each other, and do not overlap within a 95 percent confidence interval.", "cite_spans": [], "ref_spans": []}, {"section": "results", "text": "Final ages were assigned using the weighted mean 207-corrected 206 Pb/ 238 U age of a coherent group, discounting points that showed abnormally high U, high 204 Pb, or discordance. The assigned age for each sample is presented with its concordia diagram, along with the age error (2), number of analyses, and mean square of weighted deviates (MSWD) for the coherent group. Values of MSWD greater than one are indicative of errors beyond those strictly associated with analytical errors, and suggest geologic errors such as outliers or samples from more than one population are contributing to the overall age range. In samples where distinct core and rim populations were present, the final age always represents the rim age; core ages are plotted separately on a collective diagram, one per sampling group. Coherent age groups were extracted using a minimum 5 percent probability-of-fit, and a minimum 30 percent fraction of the total analyses to constitute a valid age group. In cases where no coherent age group was apparent, the age we present is an inferred age, chosen to be the most likely crystallization age for that sample based on the available data points. Because we are focusing primarily on the broad tectonic implications of these zircon ages, inferred ages are treated with equal consideration in our conclusions. The ages exhibit ranges that are geographically distinct, as can be seen in figure 2, and correspond to the five principle sampling groups previously outlined:", "cite_spans": [], "ref_spans": []}, {"section": "results", "text": "[A] For samples from within the Namche Barwa massif, five U-Pb SHRIMP ages fell between 2.9 and 9.7 Ma ( fig. 7) . Concordant core ages cluster around 400 to 500 Ma and 800 to 900 Ma. Details of each sample are as follows:", "cite_spans": [], "ref_spans": [{"start": 105, "end": 112, "text": "fig. 7)", "ref_id": "FIGREF8"}]}, {"section": "results", "text": "For sample IG-2d, 11 rim spots and 11 core spots were analyzed. Of the 11 rim ages, no coherent age group was apparent; several of these ages are a likely reflection of mixing between rim and core compositions; however, six ages fall between 13 and 15 Ma. The age presented (\u03f314 Ma) is an average of these six ages, and is therefore approximate. In sample IG-4, 9 spots were analyzed; all were rim ages. The coherent age group was comprised of 4 spots, yielding a final (weighted mean) age of 3.0 Ma. In sample IG-6b, 10 rim spots and 7 core spots were analyzed. 9 rim ages comprised a coherent group, with a weighted mean of 9.7 Ma. In sample IG-15a, 10 rim spots and 4 core spots were analyzed. Both core and rim spots, however, yielded the same age U age-concordance; For ages \u03fe 1000 Ma, the value in this column is a 204-corrected age 911 of southeastern Tibet, Namche Barwa Area range (5 -8 Ma). 13 analyses comprised a coherent age group, with a weighted mean of 6.2 Ma. In sample IG-16, 9 rim spots and 4 core spots were analyzed. Of the 9 rim ages, 6 comprised a coherent group with a weighted mean of 4.3 Ma. In sample IG-18, 9 rim spots and 10 core spots were analyzed. Some rim spots yielded ages as old as the cores, and many were discordant. Five rim ages, however, formed a coherent (young) age group with a weighted mean of 2.9 Ma.", "cite_spans": [], "ref_spans": []}, {"section": "results", "text": "[B] Along the northwestern margin of the NB-GP massif, the zircons are primarily Oligocene-Miocene in age ( fig. 8 ), and were obtained from granitic bodies intruding both Lhasa block basement and Indian plate gneisses. Zircon core ages from this group show mostly Gangdese inheritance, except for sample BT-17, which exhibits protolith ages upwards of 1 Ga (Lhasa block material). Sample BT-20 also exhibited a Pan-African zircon rim age of 465 Ma.", "cite_spans": [], "ref_spans": [{"start": 108, "end": 114, "text": "fig. 8", "ref_id": "FIGREF11"}]}, {"section": "results", "text": "Rim age populations for samples BT-14, BT-15, BT-17, BT-19, BT-20 and NB-35 all contained a coherent group, from which the final age (weighted mean) was extracted. BT-07 did not yield a coherent group, so the final age is approximate and equals the average (40 Ma) of the three youngest analyses, which clustered between 38 and 42 Ma.", "cite_spans": [], "ref_spans": []}, {"section": "results", "text": "[C] West of the NB-GP massif, our results fall primarily into the age range of \u03f340 to 70 Ma ( fig. 9) , with one 26 Ma age observed in sample BT-4, collected near Nyingchi. Another anomalous age (250 Ma -late Permian) was observed in sample BT-36, farther to the west, between Bayi and Lhasa (not shown on map; 29\u00b058\u040823.0\u0408\u0408N 93\u00b06\u040831.6\u0408\u0408E). Sample BT-37 is also off the map (29\u00b043\u040800.4\u0408\u0408N 93\u00b02\u040822.4\u0408\u0408E), but yields a more-expected age of 72 Ma. Limited core ages for group C samples (660 Ma and 300 Ma for BT-4; 520 Ma and 97 Ma for BT-19E) suggest a Gondwanan protolith, plus some mixing between core and rim compositions.", "cite_spans": [], "ref_spans": [{"start": 94, "end": 101, "text": "fig. 9)", "ref_id": "FIGREF12"}]}, {"section": "results", "text": "All Group C samples had rim age populations that yielded coherent groups. Final ages, presented on figure 9, represent the weighted means of each of these groups.", "cite_spans": [], "ref_spans": []}, {"section": "results", "text": "[D] Two samples, BT-17-01 and BT-33, collected north of Namche Barwa along the Jiali fault zone yield 21 Ma ages ( fig. 10 ). Core ages show evidence for a Gangdese protolith (74 Ma for BT-33; 100 Ma for BT-17-01). Rim ages for both samples exhibit a fair amount of scatter and did not possess a coherent age group; consequently these final ages are approximate. However, sample BT-17-01 shows a distinct cluster (N\u03ed11) of ages between 19 and 23 Ma, and BT-33 has a cluster (N\u03ed 5) between 20 and 22 Ma, allowing us to place reasonably good constraints on these approximations.", "cite_spans": [], "ref_spans": [{"start": 115, "end": 122, "text": "fig. 10", "ref_id": "FIGREF0"}]}, {"section": "results", "text": "[E] Northeast of Namche Barwa, in the vicinity of Bomi, the zircon populations are as old as Mesozoic (113 -118 Ma) in age ( fig. 11) , with one 63 Ma age. These samples (BM-02, BM-03, BC-01, BC-02, and BC-03) exhibited no distinct evidence of inheritance, and each age population yielded a coherent group. Final ages represent the weighted means of these coherent groups, and are expressed on figure 11.", "cite_spans": [], "ref_spans": [{"start": 125, "end": 133, "text": "fig. 11)", "ref_id": "FIGREF0"}]}, {"section": "results", "text": "Geochemistry.-All samples have bulk compositions within the range typical of peraluminous granites, consisting of quartz (20 -35%), plagioclase (15 -25%), K-feldspar (25 -40%), and muscovite \u03ee biotite (2 -10%). Namche Barwa (Group A) fig. 12 ), relative to granitoids outside the massif, with an average ratio of 3.8. Granitic bodies outside of the massif, north and west of Gyala Peri and northeast of Namche Barwa (Groups B, C, D, and E), are predominantly peraluminous and have notably lower Rb/Sr ratios.", "cite_spans": [], "ref_spans": [{"start": 234, "end": 241, "text": "fig. 12", "ref_id": "FIGREF0"}]}, {"section": "results", "text": "Bulk geochemical abundances of the trace elements Rb, Y, and Nb indicate that the majority of the granites are calc-alkaline to alkaline, plotting in the field of volcanic arc granites ( fig. 13 ) of Pearce and others (1984) and in the \"post\"-collision granite field of Pearce (1996) . Lhasa block gneisses and metasediments north of Namche Barwa, near the Jiali fault zone; and [E] Gangdese Arc granitoids intruded into Lhasa block gneisses and metasediments northeast of Namche Barwa. We interpret the emplacement of these five groups of granites to be related to a series of different tectonic events impacting southeastern Tibet during Mesozoic-Cenozoic time.", "cite_spans": [{"start": 270, "end": 283, "text": "Pearce (1996)", "ref_id": "BIBREF66"}], "ref_spans": [{"start": 187, "end": 194, "text": "fig. 13", "ref_id": "FIGREF0"}]}, {"section": "results", "text": "Geochronology.-Our results for granite emplacement ages from Group A samples (Namche Barwa massif) are in good agreement with those reported by both Burg and others (1997) and Ding and others (2001) , and support the evidence for exceptionally recent granitic activity near the massif core. Previously determined ages (Burg and others, 1997; Ding and others, 2001 ) combined with the results of this study define a distinct group of young crystallization ages for Namche Barwa massif samples. Also apparent is a well-defined population of 400 to 500 Ma core ages, possibly reflecting an event of regional high-grade metamorphism and melting during early Paleozoic time. Such evidence lends additional support to the concept of an early Paleozoic thrust event within Greater Himalayan rocks, as suggested by the studies of DeCelles and others (2000) and Gehrels and others (2003) , and could indicate that Namche Barwa massif rocks may have undergone a similar history.", "cite_spans": [], "ref_spans": []}, {"section": "results", "text": "Group B samples (northwest margin of the NB-GP massif) contain protolith ages that help to delineate the ITSZ west of Gyala Peri. Within this transect across the suture ( fig. 5) , younger granitoids are present with ages of 24 Ma, but core ages indicate Fig. 8. (continued) inherited signatures that jump sharply from Gangdese in the west (67 Ma for BT-14 and 82 Ma for BT-15) to Indian in the east (\"Pan-African\" age of 465 for .", "cite_spans": [], "ref_spans": [{"start": 171, "end": 178, "text": "fig. 5)", "ref_id": "FIGREF5"}]}, {"section": "results", "text": "Group C samples (west of Namche Barwa) exhibit a cluster of crystallization ages between 40 to 70 Ma, corresponding to Gangdese plutonism. Sample BT-36, however, yielded a crystallization age of 250 Ma, which is not a surprising result, considering Permian rift-related rocks have been documented in the southern Lhasa block (Dewey and others, 1988) .", "cite_spans": [], "ref_spans": []}, {"section": "results", "text": "Group E samples (northeast of Namche Barwa) contain numerous ages that correspond to Gangdese plutonism. Two isolated 21 Ma ages (Group D) in the north, however, are too young to be related to this subduction-related magmatism. Considering the widespread documentation of magmatism along the Red River shear zone (for example, Leloup and Kienast, 1993; Zhang and Sch\u00e4rer, 1999) , and partial melts with emplacement ages around 22 to 23 Ma, the 21 Ma granitoids may be analogous to these melts. However, because these and similar other dikes consistently cut the ductile foliation of the gneisses in and near the Jiali fault zone, these granitic bodies are not likely to be a product of the shearing related to movement within this zone. Instead, we suggest they are perhaps related to the Gangdese Thrust event, which is of this age (\u03f327 -18 Ma) and involved underthrusting of part of the Gangdese belt (Copeland and others, 1995; Yin and others, 1999; Harrison and others, 2000) . The role of the Gangdese Thrust, however, is controversial (that is, Aitchison and others, 2003) . Therefore, an alternative means of production for the \u03f321 Ma granites might be slab break-off or slab detachment. Both of these mechanisms are suggested to have occurred at \u03f325 Ma (Kosarev and others, 1999; Miller and others, 1999; Chemenda and others, 2000; Yin and Harrison, 2000; Maheo and others, 2002; Kohn and Parkinson, 2002; Tilman and others, 2003) .", "cite_spans": [{"start": 327, "end": 352, "text": "Leloup and Kienast, 1993;", "ref_id": "BIBREF49"}, {"start": 353, "end": 377, "text": "Zhang and Sch\u00e4rer, 1999)", "ref_id": "BIBREF93"}, {"start": 1340, "end": 1363, "text": "Yin and Harrison, 2000;", "ref_id": "BIBREF86"}, {"start": 1388, "end": 1413, "text": "Kohn and Parkinson, 2002;", "ref_id": "BIBREF39"}], "ref_spans": []}, {"section": "results", "text": "Overall, in addition to the expected evidence for activity related to the Gangdese Arc, there is clear evidence in our results for a widespread partial-melting event around 20 to 25 Ma, and a much-younger (3 -10 Ma) melting episode observed only at Namche Barwa. Geochemical data from the granites provides some insight as to the nature of these two young events.", "cite_spans": [], "ref_spans": []}, {"section": "results", "text": "Geochemistry.-Granitoids from within Namche Barwa exhibit a high Rb/Sr ratio (greater than 1.4), with notably greater frequency than outside the massif ( fig. 12) . It has been shown (Harris and others, 1993; Whittington and others, 1999 ) that trace element abundances in granitic rocks can provide information regarding the conditions prevalent during melting. A study by Harris and Inger (1992) predicted the consequences of fluid-present and fluid-absent melting for the composition of pelitederived granites, in terms of the trace elements Rb, Sr and Ba. For granite systems, only these three elements reside predominantly in the major reactants and products of melting reactions (micas and feldspars). Concentration ratios (C l /C o ) in the liquid relative to the source are calculated from appropriate partition coefficients (K D ) for granitic melts, using a range of values from Nash and Crecraft (1985) , Blundy and Fig. 9. (continued) Wood (1991), and Harris and others (1993) . Simple melts have well-defined C l /C o ratios for Rb, Sr and Ba, whether controlled by mineral fractionation or by partial melting (Whittington and others, 1999) . Fluid-present melting results in low Rb/Sr ratios and depleted Ba relative to the source, whereas fluid-absent melting results in high Rb/Sr ratios and enrichment of Ba. Geochemical modeling of Rb and Sr during anatexis suggests that fluid-absent breakdown of muscovite would produce melts with Rb/Sr ratios \u03fe1.5 (Harris and Inger, 1992) .", "cite_spans": [{"start": 374, "end": 397, "text": "Harris and Inger (1992)", "ref_id": "BIBREF26"}, {"start": 889, "end": 913, "text": "Nash and Crecraft (1985)", "ref_id": "BIBREF65"}, {"start": 1469, "end": 1493, "text": "(Harris and Inger, 1992)", "ref_id": "BIBREF26"}], "ref_spans": [{"start": 154, "end": 162, "text": "fig. 12)", "ref_id": "FIGREF0"}]}, {"section": "results", "text": "The majority of the Namche Barwa samples (group A) exhibit relatively high Rb/Sr ratios (\u03fe1.4) suggesting that a fluid-absent melting (decompression) regime dominates near the massif core. Meanwhile, granitoids from groups B, C, D and E exhibit Rb/Sr ratios consistently below 1.5 (table 2) and imply fluid-present melting in these surrounding regions.", "cite_spans": [], "ref_spans": []}, {"section": "results", "text": "A particularly interesting result is that the Namche Barwa granites with the youngest U-Pb zircon ages (3.0 Ma and 2.9 Ma, samples IG-4 and IG-18) exhibit a low Rb/Sr ratio, implying a fluid-present melting history. This result has implications for both the rate of melt emplacement and the degree of meteoric water circulation at Namche Barwa. Moreover, the presence of both fluid-absent and fluid-present melts is significant, as it resembles conditions at Nanga Parbat in the western Himalayan syntaxis. At Namche Barwa, the predominance of fluid-absent \"decompression\" melts could be a reflection of numerous varying parameters: (1) the sample locality bias-it is considerably more difficult to collect samples from the core of the massif as opposed to the lower-elevation flanks; (2) the uplift rate-if it were sufficiently rapid everywhere, only rarely could assemblages be preserved that were allowed to cool above the wet pelite solidus; (3) the degree of meteoric fluid circulation-how deep and how Fig. 11 . Tera-Wasserburg concordia diagrams showing U-Pb SHRIMP ages for group E samples -from the area of Bomi, northeast of the Namche Barwa-Gyala Peri massif. Error ellipses are shown at 2 uncertainty. Table   2 Major and trace-element geochemistry of southeastern Tibet granitoids, grouped by geographical location as in table 1 and figures 7-11. Table   2 (continued) 921 of southeastern Tibet, Namche Barwa Area extensively meteoric water has pervaded the crust; (4) the level of metamorphism previously experienced by rocks entering the massif-if they were low-grade and fertile, fluid-present melting would dominate, as opposed to Nanga Parbat, where rocks had undergone earlier high-grade metamorphism and were entering the massif relatively dry; or (5) deformation coeval with emplacement of melts, enhancing fluid infiltration-some samples show clear evidence of syn-kinematic emplacement and foliation.", "cite_spans": [], "ref_spans": [{"start": 1008, "end": 1015, "text": "Fig. 11", "ref_id": "FIGREF0"}]}, {"section": "results", "text": "Tectonic discrimination of granites.-Southeastern Tibet is tectonically complex, but trace-element modeling provides constraints on the dominant tectonic regime that is reflected in the geochemistry of granitic melts. Trace-element geochemical analyses indicate that the majority of the granites are calc-alkaline to alkaline, plotting in the field of volcanic arc granites ( fig. 13 ) of Pearce and others (1984) and in the \"post\"-collision granite field of Pearce (1996) . Pearce (1996) emphasized that the collisional granites are the most difficult to classify on the basis of chemistry, as they have the greatest range of sources. Unlike granites from other settings, collisional granites cannot be explained and modeled by their trace element geochemical behavior, in terms of a single, well-defined mantle or crustal source. They can result from melting of the upper mantle due to adiabatic decompression that accompanies collisional uplift and erosion (England and Thompson, 1984) , and might plot in either the volcanic arc or the within-plate field. In southeastern Tibet, volcanic arc activity is clearly present north of the Namche Barwa syntaxis, but within the massif itself the source of the melts is more ambiguous. Young zircon ages (\u03fd10 Ma) in the context of a 60 \u03ee 10 Ma Himalayan orogeny require that these melts are not related to early thrusting and crustal thickening/shortening. The presence of decompression melts in a region that is being exhumed rapidly is also characteristic of later stages of collisional Pearce and others (1984) and Pearce (1996) tectonic settings. Hence, the distribution of Namche Barwa granites on Pearce and others' (1984) tectonic discrimination diagram, spanning the volcanic arc and within plate fields, is in accordance with our other data sets, specifically zircon ages, Rb/Sr geochemistry and geological and tectonic settings. Zircon core ages provide further constraints on the source area for these granitoids. For group A samples, U-Pb ages of predominantly 400 to 500 Ma, with some 700 to 800 Ma ages (table 1) imply an Indian plate precursor for the youngest melts. Outside of Namche Barwa, most core ages are greater than 500 Ma, with the oldest protolith ages (0.9 -2.4 Ga) present in the northern and western granite groups. Lhasa block material is the most likely source for these granites, but older metasediments or Indian continental basement cannot be ruled out on this basis alone.", "cite_spans": [{"start": 459, "end": 472, "text": "Pearce (1996)", "ref_id": "BIBREF66"}, {"start": 475, "end": 488, "text": "Pearce (1996)", "ref_id": "BIBREF66"}, {"start": 960, "end": 988, "text": "(England and Thompson, 1984)", "ref_id": "BIBREF20"}, {"start": 1564, "end": 1577, "text": "Pearce (1996)", "ref_id": "BIBREF66"}], "ref_spans": [{"start": 376, "end": 383, "text": "fig. 13", "ref_id": "FIGREF0"}]}, {"section": "results", "text": "discussion Namche Barwa granites.-The granites from Namche Barwa exhibit zircon U-Pb ages consistently under 10 Ma and thus are distinct from those reported elsewhere in the Himalayas. The young ages correspond to a period of rapid denudation at Namche Barwa, estimated at \u03f310 mm/yr over the last 4 Myr (Burg and others, 1997) . Coincidence of young granites with a period of rapid erosion suggests a cause-effect relationship, in particular a scenario involving decompression melting that mimics Nanga Parbat in the western Himalayan syntaxis. Relatively high Rb/Sr ratios in the Namche Barwa granites support a decompression melting regime similar to Nanga Parbat, where rapid exhumation has led to leucogranite emplacement by fluid-absent breakdown of muscovite (Zeitler and Chamberlain, 1991; Butler and others, 1997; Whittington and others, 1999) . Young activity and decompression melts are evidence in favor of a \"tectonic aneurysm\" model (Zeitler and others, 2001a; Koons and others, 2002) , attributing anatexis and high-grade metamorphism to rapid exhumation by the Yalu Tsangpo.", "cite_spans": [{"start": 765, "end": 796, "text": "(Zeitler and Chamberlain, 1991;", "ref_id": "BIBREF89"}], "ref_spans": []}, {"section": "results", "text": "Coupled thermal-mechanical-erosional modeling (Koons and others, 1998; Zeitler and others, 2001b; Koons and others, 2002) shows that in a deforming orogen, local rheological variations will arise from deep and rapid incision. The crust will weaken as the strong upper crust is stripped from above by erosion and the local geotherm is steepened from below by rapid uplift of hot rock. If this process occurs where the crust is already weak, it will focus local upward movement of material from below. Provided that efficient erosion continues, a positive feedback develops in which flow of material into this weakened zone maintains local elevation and relief, reinforcing the concentrated exhumation and bowing up isotherms, further weakening the upper crust. This focusing of strain and rapid exhumation leads to metamorphic and structural overprinting of the crust as high-temperature lower crustal rocks are isothermally decompressed, and also leads to development of large mountains of limited spatial extent perched atop hot, weak crust. It is this concentration of exhumation and redirection of strain, with associated thermal, petrological, and geophysical anomalies, that Zeitler and others (2001a) dubbed a \"tectonic aneurysm,\" in the sense of self-sustained failure of a normally strong boundary. Inherent in this model is the notion that feedback can amplify rather local geomorphic processes to the point where they exert a profound influence on the metamorphic and structural evolution of rocks at considerable depth. The emplacement of young melts near the core of Namche Barwa seems to support this model.", "cite_spans": [], "ref_spans": []}, {"section": "results", "text": "Granites outside Namche Barwa.-Zircon core and rim ages from the E-W transect across the western margin of Gyala Peri confirm the location of the suture zone between Indian and Asian plate components. Paralleling the trend of several other geological units and foliations, the attenuated suture wraps around just to the west of the Gyala Peri massif. West of Gyala Peri, U-Pb ages of samples intruding Lhasa Block basement exhibit a distinct cluster within 40 to 70 Ma, corresponding to Gangdese plutonism. However, the younger (\u03fd26 Ma) group in this area must be associated with a more recent metamorphic event, possibly related to slip along the Gangdese thrust, slab break-off, or slab detachment. Neogene magmatism in the Gangdese belt is uncommon but has been identified in several places, with calc-alkaline magmatism of Gangdese geochemical affinity documented at 18 to 16 Ma in southwestern Tibet (Miller and others, 1999) and at 16 to 10 Ma in south-central Tibet (Coulon and others, 1986) . Samples BT-4, NB-35-02, BT-15, and BT-17 all yield U-Pb zircon ages between 24 to 26 Ma, but do not exhibit a decompression melt signature and are therefore unlikely to be related to an eastward continuation of the STDS. These samples do, however, show volcanic arc affinity as per Pearce and others (1984) and might represent young Gangdese-related magmatism. Harrison and others (2000) proposed that a continuous process produced calc-alkaline Gangdese magmatism through the Tertiary, caused by an input of heat from the asthenosphere. Through such a mechanism, our 24 to 26 Ma granites could have been produced as collisional melts, representing continued subduction of Indian lithosphere (Chung and others, 2003) . Alternatively, slab break-off of the subducting Indian continental margin, or slab detachment, whereby the mantle lithosphere peels off from the overlying crust and passively sinks into the asthenosphere, might explain the origin of these magmas. Yet another possibility is that processes related to underthrusting on the Gangdese Thrust structure, such as dewatering or shear heating, contributed to production of these \u03f325 Ma granites.", "cite_spans": [], "ref_spans": []}, {"section": "results", "text": "The two 21 Ma samples from north of Namche Barwa (BT-33, BT-17) along the Jiali fault zone are distinct from the 24 to 26 Ma group north and west of Gyala Peri, based on their tectonic setting and geochemistry. These granites might be related to Miocene shearing as reported for the Red River fault others, 1990, 1994; Harrison and others, 1992; Leloup and Kienast, 1993; others, 1993, 1995) . Although the Red River fault is located considerably southeast of the eastern Himalayan syntaxis, it was at that time a left-lateral fault, possibly related to the ductile sinistral shear seen near Tungmai on the Jiali fault zone. An eastern extension of the Jiali-Parlung fault is reported to have been dextrally active during \u03f318 to 12 Ma (Lee and others, 2003) , and perhaps the associated shear produced the 21 Ma granites that we observe. Common syntectonic emplacement of granitic melts in ductile strike-slip shear zones can be explained by partial melting of the lower crust, induced by shear heating in the upper mantle (for example, Leloup and others, 1999) . If this is the case, samples BT-33 and BT-17 represent westward manifestations of the early Miocene oblique-slip tectonics and shear heating regime more prominent in easterly parts of the Tibetan-Himalayan orogen.", "cite_spans": [{"start": 346, "end": 371, "text": "Leloup and Kienast, 1993;", "ref_id": "BIBREF49"}], "ref_spans": []}, {"section": "results", "text": "Another possible cause of Oligo-Miocene igneous activity in southern Tibet suggested by Yin (2000) is lithospheric-scale rifting, whereby large, deep cracks in the mantle lithosphere allow asthenosphere to flow upward, providing the necessary heat for melt production. Alternatively, the \u03f321 Ma granites could be related to slab break-off, slab detachment, or a Gangdese Thrust event, similar to the 24 to 26 Ma granites further southeast.", "cite_spans": [{"start": 88, "end": 98, "text": "Yin (2000)", "ref_id": "BIBREF85"}], "ref_spans": []}, {"section": "results", "text": "conclusion Our U-Pb SHRIMP ages establish a complex tectonic history for southeastern Tibet, with the presence of at least five magmatic episodes: 400 to 500 Ma, \u03f3120 Ma, 40 to 70 Ma, 18 to 25 Ma, and 3 to 10 Ma. The oldest age group is attributed to early Paleozoic tectonism. Later melting episodes are primarily related to the CretaceousTertiary India-Asia convergence and collision, including the subduction of Neo-Tethys oceanic crust and Gangdese plutonism. Less expected, however, is the widespread occurrence of 20 to 25 Ma granitoids in the areas surrounding the Namche Barwa massif. These could be a product of slab break-off, slab delamination, Gangdese thrusting, or early Miocene shearing accompanying dextral motion along the Jiali fault.", "cite_spans": [], "ref_spans": []}, {"section": "results", "text": "The youngest group (3 -10 Ma) of granitoids, present within the core of the Namche Barwa massif along and near the Yalu Tsangpo gorge, provides solid evidence for a tectonic-surficial feedback relationship at Namche Barwa. Geochemical data indicates the presence of young granites produced by both fluid-absent and fluidpresent melting in the Namche Barwa and adjacent regions, with a decompression melting regime dominating in the core of the Namche Barwa massif. Taken together, our geochronologic and geochemical data appear to support a tectonic aneurysm model for the development of Namche Barwa. Surrounding the Namche Barwa-Gyala Peri massif, however, granite emplacement results from distinctly different modes of production. This mode of production reflects the complex deformation at the eastern edge of the Indian plate, and the recent (Miocene and younger) activity along warped eastward expressions of dominant Himalayan structures.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "The Gangdese thrust: a phantom structure that did not raise Tibet: Terra Nova", "authors": [{"first": "J", "middle": ["C"], "last": "Aitchison", "suffix": ""}, {"first": "A", "middle": ["M"], "last": "Davis", "suffix": ""}, {"first": "", "middle": [], "last": "Badengzhu", "suffix": ""}, {"first": "H", "middle": [], "last": "Luo", "suffix": ""}], "year": 2003, "venue": "", "link": null}, "BIBREF1": {"title": "Crystal-chemical controls on the partitioning of Sr and Ba between plagioclase feldspar, silicate melts, and hydrothermal solutions: Geochimica et Cosmochimica Acta", "authors": [{"first": "J", "middle": ["D"], "last": "Blundy", "suffix": ""}, {"first": "B", "middle": ["J"], "last": "Wood", "suffix": ""}], "year": 1991, "venue": "", "link": null}, "BIBREF2": {"title": "Tectonic interpretation of GPS results from the SE part of the Tibetan Plateau and within the European/Asian framework", "authors": [{"first": "B", "middle": ["C"], "last": "Burchfiel", "suffix": ""}, {"first": "R", "middle": [], "last": "King", "suffix": ""}, {"first": "L", "middle": ["H"], "last": "Royden", "suffix": ""}, {"first": "E", "middle": [], "last": "Wang", "suffix": ""}, {"first": "Z", "middle": [], "last": "Chen", "suffix": ""}, {"first": "X", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "J", "middle": [], "last": "Zhao", "suffix": ""}], "year": 1998, "venue": "", "link": null}, "BIBREF3": {"title": "Exhumation during crustal folding in the Namche Barwa syntaxis", "authors": [{"first": "J", "middle": ["P"], "last": "Burg", "suffix": ""}, {"first": "P", "middle": [], "last": "Davy", "suffix": ""}, {"first": "P", "middle": [], "last": "Nievergelt", "suffix": ""}, {"first": "F", "middle": [], "last": "Oberli", "suffix": ""}, {"first": "D", "middle": [], "last": "Seward", "suffix": ""}, {"first": "Z", "middle": [], "last": "Diao", "suffix": ""}, {"first": "M", "middle": [], "last": "Meier", "suffix": ""}], "year": 1997, "venue": "", "link": "126486103"}, "BIBREF4": {"title": "The Namche-Barwa syntaxis: Evidence for exhumation related to compressional crustal folding", "authors": [{"first": "J", "middle": ["P"], "last": "Burg", "suffix": ""}, {"first": "P", "middle": [], "last": "Nievergelt", "suffix": ""}, {"first": "F", "middle": [], "last": "Oberli", "suffix": ""}, {"first": "D", "middle": [], "last": "Seward", "suffix": ""}, {"first": "P", "middle": [], "last": "Davy", "suffix": ""}, {"first": "J", "middle": ["C"], "last": "Maurin", "suffix": ""}, {"first": "Z", "middle": [], "last": "Diao", "suffix": ""}, {"first": "M", "middle": [], "last": "Meier", "suffix": ""}], "year": 1998, "venue": "Journal of Asian Earth Sciences", "link": "129527350"}, "BIBREF5": {"title": "Interactions between deformation, magmatism and hydrothermal activity during active crustal thickening: a field example from Nanga Parbat", "authors": [{"first": "R", "middle": ["W H"], "last": "Butler", "suffix": ""}, {"first": "N", "middle": ["B W"], "last": "Harris", "suffix": ""}, {"first": "A", "middle": ["G"], "last": "Whittington", "suffix": ""}], "year": 1997, "venue": "", "link": null}, "BIBREF6": {"title": "Evolutionary model of the Himalaya-Tibet system: geopoem: based on new modelling, geological and geophysical data: Earth and Planetary Science Letters", "authors": [{"first": "A", "middle": ["I"], "last": "Chemenda", "suffix": ""}, {"first": "J", "middle": ["P"], "last": "Burg", "suffix": ""}, {"first": "M", "middle": [], "last": "Mattauer", "suffix": ""}], "year": 2000, "venue": "", "link": null}, "BIBREF7": {"title": "Diachronous uplift of the Tibet Plateau starting 40 Myr ago: Nature, v", "authors": [{"first": "S", "middle": ["L"], "last": "Chung", "suffix": ""}, {"first": "C", "middle": ["H"], "last": "Lo", "suffix": ""}, {"first": "T", "middle": ["Y"], "last": "Lee", "suffix": ""}, {"first": "Z", "middle": [], "last": "Yuquan", "suffix": ""}, {"first": "X", "middle": [], "last": "Yingwen", "suffix": ""}, {"first": "L", "middle": [], "last": "Xianhua", "suffix": ""}, {"first": "K", "middle": ["L"], "last": "Wang", "suffix": ""}, {"first": "P", "middle": ["L"], "last": "Wang", "suffix": ""}], "year": 1998, "venue": "", "link": "126560834"}, "BIBREF8": {"title": "Adakites from continental collision zones: Melting of thickened lower crust beneath southern Tibet: Geology, v. 31", "authors": [{"first": "S", "middle": ["L"], "last": "Chung", "suffix": ""}, {"first": "D", "middle": [], "last": "Liu", "suffix": ""}, {"first": "J", "middle": [], "last": "Ji", "suffix": ""}, {"first": "M", "middle": ["F"], "last": "Chu", "suffix": ""}, {"first": "H", "middle": ["Y"], "last": "Lee", "suffix": ""}, {"first": "D", "middle": ["J"], "last": "Wen", "suffix": ""}, {"first": "C", "middle": ["H"], "last": "Lo", "suffix": ""}, {"first": "T", "middle": ["Y"], "last": "Lee", "suffix": ""}, {"first": "Q", "middle": [], "last": "Qian", "suffix": ""}, {"first": "Q", "middle": [], "last": "Zhang", "suffix": ""}], "year": 2003, "venue": "", "link": null}, "BIBREF9": {"title": "Thermal evolution of the Gangdese Batholith, southern Tibet; a history of episodic unroofing: Tectonics, v. 14", "authors": [{"first": "P", "middle": [], "last": "Copeland", "suffix": ""}, {"first": "T", "middle": ["M"], "last": "Harrison", "suffix": ""}, {"first": "P", "middle": [], "last": "Yun", "suffix": ""}, {"first": "W", "middle": ["S F"], "last": "Kidd", "suffix": ""}, {"first": "M", "middle": [], "last": "Roden", "suffix": ""}, {"first": "Y", "middle": [], "last": "Zhang", "suffix": ""}], "year": 1995, "venue": "", "link": null}, "BIBREF10": {"title": "Mesozoic and Cenozoic volcanic rocks from central and southern Tibet", "authors": [{"first": "C", "middle": [], "last": "Coulon", "suffix": ""}, {"first": "H", "middle": [], "last": "Maluski", "suffix": ""}, {"first": "C", "middle": [], "last": "Bollinger", "suffix": ""}, {"first": "Wang", "middle": [], "last": "", "suffix": ""}, {"first": "S", "middle": [], "last": "", "suffix": ""}], "year": 1986, "venue": "", "link": "129733287"}, "BIBREF11": {"title": "Ar-40 Ar dating, petrological characteristics and geodynamical significance: Earth and Planetary Science Letters, v. 79", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF12": {"title": "Neogene foreland basin deposits, erosional unroofing, and the kinematic history of the Himalayan fold-thrust belt", "authors": [{"first": "P", "middle": ["G"], "last": "Decelles", "suffix": ""}, {"first": "G", "middle": ["E"], "last": "Gehrels", "suffix": ""}, {"first": "J", "middle": [], "last": "Quade", "suffix": ""}, {"first": "T", "middle": ["P"], "last": "Ojha", "suffix": ""}, {"first": "P", "middle": ["A"], "last": "Kapp", "suffix": ""}, {"first": "B", "middle": ["N"], "last": "Upreti", "suffix": ""}], "year": 1998, "venue": "", "link": null}, "BIBREF13": {"title": "Tectonic implications of U-Pb zircon ages of the Himalayan orogenic belt in Nepal: Science, v. 288", "authors": [{"first": "P", "middle": ["G"], "last": "Decelles", "suffix": ""}, {"first": "G", "middle": ["E"], "last": "Gehrels", "suffix": ""}, {"first": "J", "middle": [], "last": "Quade", "suffix": ""}, {"first": "B", "middle": [], "last": "Lareau", "suffix": ""}, {"first": "M", "middle": [], "last": "Spurlin", "suffix": ""}], "year": 2000, "venue": "", "link": null}, "BIBREF14": {"title": "Time relationship between magmatism, tectonics and metamorphism in southern Tibet: new K-Ar data: Geology Rundsch", "authors": [{"first": "F", "middle": [], "last": "Debon", "suffix": ""}, {"first": "J", "middle": [], "last": "Zimmerman", "suffix": ""}, {"first": "G", "middle": ["H"], "last": "Liu", "suffix": ""}, {"first": "C", "middle": ["W"], "last": "Jin", "suffix": ""}, {"first": "R", "middle": ["H"], "last": "Xu", "suffix": ""}], "year": 1985, "venue": "", "link": null}, "BIBREF15": {"title": "The four plutonic belts of the TranshimalayaHimalaya; a chemical, mineralogical, isotopic, and chronological synthesis along a Tibet-Nepal section", "authors": [{"first": "F", "middle": [], "last": "Debon", "suffix": ""}, {"first": "P", "middle": [], "last": "Le Fort", "suffix": ""}, {"first": "S", "middle": ["M F"], "last": "Sheppard", "suffix": ""}, {"first": "J", "middle": [], "last": "Sonet", "suffix": ""}], "year": 1986, "venue": "Journal of Petrology", "link": "131636003"}, "BIBREF16": {"title": "The tectonic evolution of the Tibetan Plateau: Philosophical Transactions of the", "authors": [{"first": "J", "middle": ["F"], "last": "Dewey", "suffix": ""}, {"first": "R", "middle": ["M"], "last": "Shackleton", "suffix": ""}, {"first": "C", "middle": [], "last": "Chengfa", "suffix": ""}, {"first": "Yiyin", "middle": [], "last": "", "suffix": ""}, {"first": "S", "middle": [], "last": "", "suffix": ""}], "year": 1988, "venue": "Royal Society of London, Series A: Mathematical and Physical Sciences", "link": null}, "BIBREF17": {"title": "Cenozoic structural and metamorphic evolution of the eastern Himalayan syntaxis", "authors": [{"first": "L", "middle": [], "last": "Ding", "suffix": ""}, {"first": "D", "middle": [], "last": "Zhong", "suffix": ""}, {"first": "A", "middle": [], "last": "Yin", "suffix": ""}, {"first": "P", "middle": [], "last": "Kapp", "suffix": ""}, {"first": "T", "middle": ["M"], "last": "Harrison", "suffix": ""}], "year": 2001, "venue": "Earth and Planetary Science Letters", "link": null}, "BIBREF18": {"title": "Cenozoic Volcanism in Tibet: Evidence for a Transition from Oceanic to Continental Subduction", "authors": [{"first": "L", "middle": [], "last": "Ding", "suffix": ""}, {"first": "P", "middle": [], "last": "Kapp", "suffix": ""}, {"first": "D", "middle": [], "last": "Zhong", "suffix": ""}, {"first": "W", "middle": [], "last": "Deng", "suffix": ""}], "year": 2003, "venue": "Journal of Petrology", "link": null}, "BIBREF19": {"title": "When did the roof collapse? Late Miocene north-south extension in the high Himalaya revealed by Th-Pb monazite dating of the Khula Kangri Granite: Geology, v. 25", "authors": [{"first": "M", "middle": ["A"], "last": "Edwards", "suffix": ""}, {"first": "T", "middle": ["M"], "last": "Harrison", "suffix": ""}], "year": 1997, "venue": "", "link": "42834431"}, "BIBREF20": {"title": "Pressure-temperature-time paths of regional metamorphism; II, Their inference and interpretation using mineral assemblages in metamorphic rocks", "authors": [{"first": "P", "middle": ["C"], "last": "England", "suffix": ""}, {"first": "A", "middle": ["B"], "last": "Thompson", "suffix": ""}], "year": 1984, "venue": "Journal of Petrology", "link": "130241804"}, "BIBREF21": {"title": "Rb/Sr geochronology of granites and gneisses from the Mount Everest region", "authors": [{"first": "G", "middle": [], "last": "Ferrara", "suffix": ""}, {"first": "B", "middle": [], "last": "Lombardo", "suffix": ""}, {"first": "S", "middle": [], "last": "Tonarini", "suffix": ""}], "year": 1983, "venue": "Geologische Rundschau", "link": null}, "BIBREF22": {"title": "Tibet uplift and erosion: Tectonophysics, v. 260", "authors": [{"first": "E", "middle": [], "last": "Fielding", "suffix": ""}], "year": 1996, "venue": "", "link": null}, "BIBREF23": {"title": "Initiation of the Himalayan orogen as an early Paleozoic thin-skinned thrust belt: GSA Today", "authors": [{"first": "G", "middle": ["E"], "last": "Gehrels", "suffix": ""}, {"first": "P", "middle": ["G"], "last": "Decelles", "suffix": ""}, {"first": "A", "middle": [], "last": "Martin", "suffix": ""}, {"first": "T", "middle": ["P"], "last": "Ojha", "suffix": ""}, {"first": "G", "middle": [], "last": "Pinhassi", "suffix": ""}], "year": 2003, "venue": "", "link": null}, "BIBREF24": {"title": "Ophiolitic Melanges in the Yarlung-Tsangpo", "authors": [{"first": "Q", "middle": [], "last": "Geng", "suffix": ""}, {"first": "L", "middle": [], "last": "Zheng", "suffix": ""}, {"first": "G", "middle": [], "last": "Pan", "suffix": ""}, {"first": "C", "middle": [], "last": "Ou", "suffix": ""}, {"first": "Z", "middle": [], "last": "Sun", "suffix": ""}, {"first": "H", "middle": [], "last": "Dong", "suffix": ""}, {"first": "X", "middle": [], "last": "Wang", "suffix": ""}, {"first": "Y", "middle": [], "last": "Liu", "suffix": ""}, {"first": "Li", "middle": [], "last": "", "suffix": ""}, {"first": "S", "middle": [], "last": "", "suffix": ""}], "year": 2002, "venue": "Transactions of the American Geophysical Union", "link": "126848082"}, "BIBREF25": {"title": "Distorted drainage basins as markers of crustal strain east of the Himalaya", "authors": [{"first": "B", "middle": [], "last": "Hallet", "suffix": ""}, {"first": "P", "middle": [], "last": "Molnar", "suffix": ""}], "year": 2001, "venue": "Journal of Geophysical Research", "link": "131619686"}, "BIBREF26": {"title": "Trace element modelling of pelite-derived granites: Contributions to Mineralogy and Petrology", "authors": [{"first": "N", "middle": ["B W"], "last": "Harris", "suffix": ""}, {"first": "S", "middle": [], "last": "Inger", "suffix": ""}], "year": 1992, "venue": "", "link": "127403049"}, "BIBREF27": {"title": "Decompression and anatexis of Himalayan metapelites: Tectonics, v", "authors": [{"first": "N", "middle": ["B W"], "last": "Harris", "suffix": ""}, {"first": "J", "middle": [], "last": "Massey", "suffix": ""}], "year": 1994, "venue": "", "link": "126713112"}, "BIBREF28": {"title": "The role of fluids in the formation of High Himalayan leucogranites, in Treloar", "authors": [{"first": "N", "middle": ["B W"], "last": "Harris", "suffix": ""}, {"first": "S", "middle": [], "last": "Inger", "suffix": ""}, {"first": "J", "middle": ["; P J"], "last": "Massey", "suffix": ""}, {"first": "M", "middle": ["P"], "last": "Searle", "suffix": ""}, {"first": "", "middle": [], "last": "Himalayan Tectonics", "suffix": ""}], "year": 1993, "venue": "", "link": null}, "BIBREF30": {"title": "A Late Miocene-Pliocene origin for the Central Himalayan inverted metamorphism: Earth and Planetary Science Letters", "authors": [{"first": "T", "middle": ["M"], "last": "Harrison", "suffix": ""}, {"first": "F", "middle": ["J"], "last": "Ryerson", "suffix": ""}, {"first": "Le", "middle": [], "last": "Fort", "suffix": ""}, {"first": "P", "middle": [], "last": "Yin", "suffix": ""}, {"first": "A", "middle": [], "last": "Lovera", "suffix": ""}, {"first": "O", "middle": ["M"], "last": "Catlos", "suffix": ""}, {"first": "E", "middle": ["J"], "last": "", "suffix": ""}], "year": 1997, "venue": "", "link": null}, "BIBREF31": {"title": "New insights into the origin of two contrasting Himalayan granite belts: Geology, v. 25", "authors": [{"first": "T", "middle": ["M"], "last": "Harrison", "suffix": ""}, {"first": "O", "middle": ["M"], "last": "Lovera", "suffix": ""}, {"first": "M", "middle": [], "last": "Grove", "suffix": ""}], "year": 1997, "venue": "", "link": "127142626"}, "BIBREF32": {"title": "A model for the origin of Himalayan anatexis and inverted metamorphism", "authors": [{"first": "T", "middle": ["M"], "last": "Harrison", "suffix": ""}, {"first": "M", "middle": [], "last": "Grove", "suffix": ""}, {"first": "O", "middle": ["M"], "last": "Lovera", "suffix": ""}, {"first": "E", "middle": ["J"], "last": "Catlos", "suffix": ""}], "year": 1998, "venue": "Journal of Geophysical Research", "link": "128474805"}, "BIBREF33": {"title": "The Zedong Window; a record of superposed Tertiary convergence in southeastern Tibet", "authors": [{"first": "T", "middle": ["M"], "last": "Harrison", "suffix": ""}, {"first": "A", "middle": [], "last": "Yin", "suffix": ""}, {"first": "M", "middle": [], "last": "Grove", "suffix": ""}, {"first": "O", "middle": ["M"], "last": "Lovera", "suffix": ""}, {"first": "F", "middle": ["J"], "last": "Ryerson", "suffix": ""}, {"first": "Z", "middle": [], "last": "Xinhua", "suffix": ""}], "year": 2000, "venue": "Journal of Geophysical Research", "link": "27995541"}, "BIBREF34": {"title": "Tectonics of the Himalaya and southern Tibet from two perspectives: GSA Bulletin", "authors": [{"first": "K", "middle": ["V"], "last": "Hodges", "suffix": ""}], "year": 2000, "venue": "", "link": null}, "BIBREF35": {"title": "Simultaneous Miocene extension and shortening in the Himalayan Orogen: Science, v. 258", "authors": [{"first": "K", "middle": ["V"], "last": "Hodges", "suffix": ""}, {"first": "R", "middle": ["R"], "last": "Parrish", "suffix": ""}, {"first": "T", "middle": ["B"], "last": "Housh", "suffix": ""}, {"first": "D", "middle": ["R"], "last": "Lux", "suffix": ""}, {"first": "B", "middle": ["C"], "last": "Burchfiel", "suffix": ""}, {"first": "L", "middle": ["H"], "last": "Royden", "suffix": ""}, {"first": "Chen", "middle": [], "last": "", "suffix": ""}, {"first": "Z", "middle": [], "last": "", "suffix": ""}], "year": 1992, "venue": "", "link": null}, "BIBREF36": {"title": "Tectonic evolution of the central Annapurna Range", "authors": [{"first": "K", "middle": ["V"], "last": "Hodges", "suffix": ""}, {"first": "R", "middle": ["R"], "last": "Parrish", "suffix": ""}, {"first": "M", "middle": ["P"], "last": "Searle", "suffix": ""}], "year": 1996, "venue": "Nepalese Himalayas: Tectonics, v. 15", "link": "126877038"}, "BIBREF37": {"title": "Mesozoic and Cenozoic tectonic evolution of the Shiquanhe area of western Tibet: Tectonics", "authors": [{"first": "P", "middle": [], "last": "Kapp", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Murphy", "suffix": ""}, {"first": "A", "middle": [], "last": "Yin", "suffix": ""}, {"first": "T", "middle": ["M"], "last": "Harrison", "suffix": ""}, {"first": "L", "middle": [], "last": "Ding", "suffix": ""}, {"first": "J", "middle": [], "last": "Guo", "suffix": ""}], "year": 2003, "venue": "", "link": "197523097"}, "BIBREF38": {"title": "Tectonic evolution of the early Mesozoic blueschist-bearing Qiangtang metamorphic belt, central Tibet: Tectonics, v", "authors": [{"first": "P", "middle": [], "last": "Kapp", "suffix": ""}, {"first": "A", "middle": [], "last": "Yin", "suffix": ""}, {"first": "C", "middle": ["E"], "last": "Manning", "suffix": ""}, {"first": "T", "middle": ["M"], "last": "Harrison", "suffix": ""}, {"first": "M", "middle": ["H"], "last": "Taylor", "suffix": ""}, {"first": "L", "middle": [], "last": "Ding", "suffix": ""}], "year": 2003, "venue": "", "link": "17284370"}, "BIBREF39": {"title": "Petrologic case for Eocene slab breakoff during the Indo-Asian collision: Geology, v. 30", "authors": [{"first": "M", "middle": ["J"], "last": "Kohn", "suffix": ""}, {"first": "C", "middle": ["D"], "last": "Parkinson", "suffix": ""}], "year": 2002, "venue": "", "link": null}, "BIBREF40": {"title": "Fluid flow during active oblique convergence; a Southern Alps model from mechanical and geochemical observations: Geology, v. 26", "authors": [{"first": "P", "middle": ["O"], "last": "Koons", "suffix": ""}, {"first": "D", "middle": [], "last": "Craw", "suffix": ""}, {"first": "S", "middle": ["C"], "last": "Cox", "suffix": ""}, {"first": "P", "middle": [], "last": "Upton", "suffix": ""}, {"first": "A", "middle": ["S"], "last": "Templeton", "suffix": ""}, {"first": "C", "middle": ["P"], "last": "Chamberlain", "suffix": ""}], "year": 1998, "venue": "", "link": "130084033"}, "BIBREF42": {"title": "Seismic evidence for a detached Indian lithospheric mantle beneath Tibet: Science, v. 283", "authors": [{"first": "G", "middle": [], "last": "Kosarev", "suffix": ""}, {"first": "R", "middle": [], "last": "Kind", "suffix": ""}, {"first": "S", "middle": ["V"], "last": "Sobolev", "suffix": ""}, {"first": "X", "middle": [], "last": "Yuan", "suffix": ""}, {"first": "W", "middle": [], "last": "Hanka", "suffix": ""}, {"first": "S", "middle": [], "last": "Oreshin", "suffix": ""}], "year": 1999, "venue": "", "link": null}, "BIBREF43": {"title": "Miocene Jiali faulting and its implications for Tibetan tectonic evolution: Earth and Planetary Science Letters, v. 205", "authors": [{"first": "H", "middle": ["Y"], "last": "Lee", "suffix": ""}, {"first": "S", "middle": ["L"], "last": "Chung", "suffix": ""}, {"first": "J", "middle": ["R"], "last": "Wang", "suffix": ""}, {"first": "D", "middle": ["J"], "last": "Wen", "suffix": ""}, {"first": "C", "middle": ["H"], "last": "Lo", "suffix": ""}, {"first": "T", "middle": ["F"], "last": "Yang", "suffix": ""}, {"first": "Y", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "Y", "middle": [], "last": "Xie", "suffix": ""}, {"first": "T", "middle": ["Y"], "last": "Lee", "suffix": ""}, {"first": "G", "middle": [], "last": "Wu", "suffix": ""}, {"first": "Ji", "middle": [], "last": "", "suffix": ""}, {"first": "J", "middle": [], "last": "", "suffix": ""}], "year": 2003, "venue": "", "link": null}, "BIBREF44": {"title": "Himalaya: the collided range", "authors": [{"first": "Le", "middle": [], "last": "Fort", "suffix": ""}, {"first": "P", "middle": [], "last": "", "suffix": ""}], "year": 1975, "venue": "", "link": null}, "BIBREF45": {"title": "Manaslu leucogranite: A collision signature of the Himalaya, a model for its genesis and emplacement", "authors": [], "year": "", "venue": "Journal of Geophysical Research", "link": "130784184"}, "BIBREF46": {"title": "The \"Lesser Himalayan\" cordierite granite belt, typology and age of the pluton of Manserah (Pakistan)", "authors": [{"first": "Le", "middle": [], "last": "Fort", "suffix": ""}, {"first": "P", "middle": [], "last": "Debon", "suffix": ""}, {"first": "F", "middle": [], "last": "Sunet", "suffix": ""}, {"first": "J", "middle": [], "last": "", "suffix": ""}], "year": 1980, "venue": "Proceedings of the International Committee on Geodynamics Group 6 meeting: Geological Bulletin", "link": null}, "BIBREF47": {"title": "The 500 Ma magmatic event in Alpine southern Asia, a thermal episode at Gondwana Scale: Sciences de la Terre", "authors": [{"first": "Le", "middle": [], "last": "Fort", "suffix": ""}, {"first": "P", "middle": [], "last": "Debon", "suffix": ""}, {"first": "F", "middle": [], "last": "Pecher", "suffix": ""}, {"first": "A", "middle": [], "last": "Sonet", "suffix": ""}, {"first": "J", "middle": [], "last": "Vidal", "suffix": ""}, {"first": "P", "middle": [], "last": "", "suffix": ""}], "year": 1986, "venue": "M\u00e9mories", "link": null}, "BIBREF49": {"title": "High-temperature metamorphism in a major strike-slip shear zone", "authors": [{"first": "P", "middle": ["H"], "last": "Leloup", "suffix": ""}, {"first": "J", "middle": ["R"], "last": "Kienast", "suffix": ""}], "year": 1993, "venue": "", "link": null}, "BIBREF50": {"title": "People's Republic of China: Earth and Planetary Science Letters, v. 118", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF51": {"title": "Structural, petrological and thermal evolution of a Tertiary ductile strike-slip shear zone", "authors": [{"first": "P", "middle": ["H"], "last": "Leloup", "suffix": ""}, {"first": "T", "middle": ["M"], "last": "Harrison", "suffix": ""}, {"first": "F", "middle": ["J"], "last": "Ryerson", "suffix": ""}, {"first": "", "middle": [], "last": "Wenji", "suffix": ""}, {"first": "", "middle": [], "last": "Chen", "suffix": ""}, {"first": "", "middle": [], "last": "Qi", "suffix": ""}, {"first": "", "middle": [], "last": "Li", "suffix": ""}, {"first": "P", "middle": [], "last": "Tapponnier", "suffix": ""}, {"first": "R", "middle": [], "last": "Lacassin", "suffix": ""}], "year": 1993, "venue": "Journal of Geophysical Research", "link": null}, "BIBREF52": {"title": "The Ailao Shan-Red River shear zone", "authors": [{"first": "P", "middle": ["H"], "last": "Leloup", "suffix": ""}, {"first": "R", "middle": [], "last": "Lacassin", "suffix": ""}, {"first": "P", "middle": [], "last": "Tapponnier", "suffix": ""}, {"first": "U", "middle": [], "last": "Schaerer", "suffix": ""}, {"first": "Z", "middle": [], "last": "Dalai", "suffix": ""}, {"first": "L", "middle": [], "last": "Xiaohan", "suffix": ""}, {"first": "L", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "J", "middle": [], "last": "Shaocheng", "suffix": ""}, {"first": "Trinh", "middle": [], "last": "", "suffix": ""}, {"first": "P", "middle": ["T"], "last": "", "suffix": ""}], "year": 1995, "venue": "Tertiary transform boundary of Indochina: Tectonophysics, v. 251", "link": null}, "BIBREF53": {"title": "Shear heating in continental strike-slip shear zones; model and field examples", "authors": [{"first": "P", "middle": ["H"], "last": "Leloup", "suffix": ""}, {"first": "Y", "middle": [], "last": "Ricard", "suffix": ""}, {"first": "J", "middle": [], "last": "Battaglia", "suffix": ""}, {"first": "R", "middle": [], "last": "Lacassin", "suffix": ""}], "year": 1999, "venue": "Geophysical Journal International, v", "link": "55576185"}, "BIBREF54": {"title": "Petrology of high-pressure granulites from the eastern Himalayan syntaxis", "authors": [{"first": "Y", "middle": [], "last": "Liu", "suffix": ""}, {"first": "D", "middle": [], "last": "Zhong", "suffix": ""}], "year": 1997, "venue": "Journal of Metamorphic Geology", "link": "128894979"}, "BIBREF55": {"title": "User's Manual for Isoplot/Ex, Version 2.49, A Geochronological Toolkit for Microsoft Excel", "authors": [{"first": "K", "middle": ["R"], "last": "Ludwig", "suffix": ""}], "year": 2001, "venue": "Berkeley Geochronology Center Special Publication", "link": null}, "BIBREF56": {"title": "A slab breakoff model for the Neogene thermal evolution of South Karakorum and South Tibet: Earth and Planetary Science Letters, v. 195", "authors": [{"first": "G", "middle": [], "last": "Maheo", "suffix": ""}, {"first": "S", "middle": [], "last": "Guillot", "suffix": ""}, {"first": "J", "middle": [], "last": "Blichert-Toft", "suffix": ""}, {"first": "Y", "middle": [], "last": "Rolland", "suffix": ""}, {"first": "A", "middle": [], "last": "Pecher", "suffix": ""}], "year": 2002, "venue": "", "link": null}, "BIBREF57": {"title": "Argon 39-Argon 40 dating of metamorphic and plutonic events in the North and High Himalaya belts", "authors": [{"first": "H", "middle": [], "last": "Maluski", "suffix": ""}, {"first": "P", "middle": [], "last": "Matte", "suffix": ""}, {"first": "M", "middle": [], "last": "Brunel", "suffix": ""}], "year": 1988, "venue": "Tectonics, v. 7", "link": null}, "BIBREF58": {"title": "Crustal thickening in Gansu-Qinghai, lithospheric mantle subduction, and oblique, strike-slip controlled growth of the Tibet Plateau", "authors": [{"first": "B", "middle": [], "last": "Meyer", "suffix": ""}, {"first": "T", "middle": [], "last": "Tapponnier", "suffix": ""}, {"first": "L", "middle": [], "last": "Bourjot", "suffix": ""}, {"first": "F", "middle": [], "last": "Metivier", "suffix": ""}, {"first": "Y", "middle": [], "last": "Gaudemer", "suffix": ""}, {"first": "G", "middle": [], "last": "Peltzer", "suffix": ""}, {"first": "G", "middle": [], "last": "Shunmin", "suffix": ""}, {"first": "C", "middle": [], "last": "Zhitai", "suffix": ""}], "year": 1998, "venue": "Geophysical Journal International, v", "link": "54801321"}, "BIBREF59": {"title": "Post-collisional potassic and ultrapotassic magmatism in SW Tibet; geochemical and Sr-Nd-Pb-O isotopic constraints for mantle source characteristics and petrogenesis", "authors": [{"first": "C", "middle": [], "last": "Miller", "suffix": ""}, {"first": "R", "middle": [], "last": "Schuster", "suffix": ""}, {"first": "U", "middle": ["S"], "last": "Kloetzli", "suffix": ""}, {"first": "W", "middle": [], "last": "Frank", "suffix": ""}, {"first": "F", "middle": [], "last": "Purtscheller", "suffix": ""}], "year": 1999, "venue": "Journal of Petrology", "link": "130293467"}, "BIBREF60": {"title": "The early Paleozoic magmatic event in the northwest Himalaya, India: source, tectonic setting and age of emplacement: Geological Magazine", "authors": [{"first": "C", "middle": [], "last": "Miller", "suffix": ""}, {"first": "M", "middle": [], "last": "Thoni", "suffix": ""}, {"first": "W", "middle": [], "last": "Frank", "suffix": ""}, {"first": "B", "middle": [], "last": "Grazemann", "suffix": ""}, {"first": "U", "middle": ["S"], "last": "Kloetzli", "suffix": ""}, {"first": "P", "middle": [], "last": "Guntli", "suffix": ""}, {"first": "E", "middle": [], "last": "Dragnitis", "suffix": ""}], "year": 2001, "venue": "", "link": null}, "BIBREF61": {"title": "Mantle dynamics, the uplift of the Tibetan plateau, and the Indian monsoon: Reviews of Geophysics", "authors": [{"first": "P", "middle": [], "last": "Molnar", "suffix": ""}, {"first": "P", "middle": [], "last": "England", "suffix": ""}, {"first": "J", "middle": [], "last": "Martinod", "suffix": ""}], "year": 1993, "venue": "", "link": null}, "BIBREF62": {"title": "Relationship between leucogranites and the Qomolangma detachment in the Rongbuk Valley, south Tibet: Geology, v", "authors": [{"first": "M", "middle": ["A"], "last": "Murphy", "suffix": ""}, {"first": "T", "middle": ["M"], "last": "Harrison", "suffix": ""}], "year": 1999, "venue": "", "link": "31715789"}, "BIBREF63": {"title": "Structural evolution and sequence of thrusting in the Tethyan fold-thrust belt and Indus-Yalu suture zone", "authors": [{"first": "M", "middle": ["A"], "last": "Murphy", "suffix": ""}, {"first": "Yin", "middle": [], "last": "", "suffix": ""}, {"first": "A", "middle": [], "last": "", "suffix": ""}], "year": 2003, "venue": "", "link": null}, "BIBREF65": {"title": "Partition coefficients for trace elements in silicic magmas: Geochimica et Cosmochimica Acta", "authors": [{"first": "W", "middle": ["P"], "last": "Nash", "suffix": ""}, {"first": "H", "middle": ["R"], "last": "Crecraft", "suffix": ""}], "year": 1985, "venue": "", "link": null}, "BIBREF66": {"title": "A user's guide to basalt discrimination diagrams", "authors": [{"first": "J", "middle": ["A"], "last": "Pearce", "suffix": ""}], "year": 1996, "venue": "Trace Element Geochemistry of Volcanic Rocks: Applications for Massive Sulphide Exploration: Geological Association of Canada", "link": null}, "BIBREF67": {"title": "Trace element discrimination diagrams for the tectonic interpretation of granitic rocks", "authors": [{"first": "J", "middle": ["A"], "last": "Pearce", "suffix": ""}, {"first": "N", "middle": [], "last": "Harris", "suffix": ""}, {"first": "A", "middle": [], "last": "Tindle", "suffix": ""}], "year": 1984, "venue": "Journal of Petrology", "link": "128902434"}, "BIBREF68": {"title": "Thermal evolution and slip history of the Renbu Zedong Thrust, southeastern Tibet", "authors": [{"first": "X", "middle": [], "last": "Quidelleur", "suffix": ""}, {"first": "M", "middle": [], "last": "Grove", "suffix": ""}, {"first": "O", "middle": ["M"], "last": "Lovera", "suffix": ""}, {"first": "T", "middle": ["M"], "last": "Harrison", "suffix": ""}, {"first": "A", "middle": [], "last": "Yin", "suffix": ""}, {"first": "F", "middle": ["J"], "last": "Ryerson", "suffix": ""}], "year": 1997, "venue": "Journal of Geophysical Research", "link": "128449997"}, "BIBREF69": {"title": "Distributed deformation in southern and western Tibet during and after the India-Asia collision", "authors": [{"first": "L", "middle": [], "last": "Ratschbacher", "suffix": ""}, {"first": "W", "middle": [], "last": "Frisch", "suffix": ""}, {"first": "G", "middle": [], "last": "Liu", "suffix": ""}, {"first": "Chen", "middle": [], "last": "", "suffix": ""}, {"first": "C", "middle": ["C"], "last": "", "suffix": ""}], "year": 1994, "venue": "Journal of Geophysical Research", "link": null}, "BIBREF70": {"title": "The Gangotri granite (Garhwal Himalaya): laccolith emplacement in an extending collisional belt", "authors": [{"first": "B", "middle": [], "last": "Scaillet", "suffix": ""}, {"first": "A", "middle": [], "last": "Pecher", "suffix": ""}, {"first": "P", "middle": [], "last": "Rochette", "suffix": ""}, {"first": "M", "middle": [], "last": "Champenois", "suffix": ""}], "year": 1995, "venue": "Journal of Geophysical Research", "link": "129851711"}, "BIBREF71": {"title": "U-Pb geochronology of Gangdese (Transhimalaya) plutonism in the Lhasa-Xigaze region", "authors": [{"first": "U", "middle": [], "last": "Sch\u00e4rer", "suffix": ""}, {"first": "R", "middle": ["H"], "last": "Xu", "suffix": ""}, {"first": "Allegre", "middle": [], "last": "", "suffix": ""}, {"first": "C", "middle": ["J"], "last": "", "suffix": ""}], "year": 1984, "venue": "Tibet: Earth and Planetary Science Letters", "link": null}, "BIBREF72": {"title": "Intraplate tectonics in Asia: A precise age for large-scale Miocene movement along the Ailao Shan -Red River shear zone, China: Earth and Planetary Science Letters", "authors": [{"first": "U", "middle": [], "last": "Sch\u00e4rer", "suffix": ""}, {"first": "P", "middle": [], "last": "Tapponnier", "suffix": ""}, {"first": "R", "middle": [], "last": "Lacassin", "suffix": ""}, {"first": "P", "middle": ["H"], "last": "Leloup", "suffix": ""}, {"first": "Ji", "middle": [], "last": "Zhong Dalai", "suffix": ""}, {"first": "S", "middle": [], "last": "", "suffix": ""}], "year": 1990, "venue": "", "link": null}, "BIBREF73": {"title": "Duration of strike-slip movements in large shear zones: The Red River belt, China: Earth and Planetary Science Letters", "authors": [{"first": "U", "middle": [], "last": "Sch\u00e4rer", "suffix": ""}, {"first": "L", "middle": ["S"], "last": "Zhang", "suffix": ""}, {"first": "P", "middle": [], "last": "Tapponnier", "suffix": ""}], "year": 1994, "venue": "", "link": null}, "BIBREF74": {"title": "Approximation of terrestrial lead isotopic evolution by a two-stage model: Earth and Planetary Science Letters", "authors": [{"first": "J", "middle": ["S"], "last": "Stacey", "suffix": ""}, {"first": "J", "middle": ["D"], "last": "Kramers", "suffix": ""}], "year": 1975, "venue": "", "link": null}, "BIBREF75": {"title": "Seismic imaging of the downwelling Indian lithosphere beneath central Tibet: Science, v. 300", "authors": [{"first": "F", "middle": [], "last": "Tilmann", "suffix": ""}, {"first": "J", "middle": [], "last": "Ni", "suffix": ""}, {"first": "T", "middle": [], "last": "Hearn", "suffix": ""}, {"first": "Y", "middle": ["S"], "last": "Ma", "suffix": ""}, {"first": "R", "middle": [], "last": "Rapine", "suffix": ""}, {"first": "R", "middle": [], "last": "Kind", "suffix": ""}, {"first": "J", "middle": [], "last": "Mechie", "suffix": ""}, {"first": "J", "middle": [], "last": "Saul", "suffix": ""}, {"first": "S", "middle": [], "last": "Haines", "suffix": ""}, {"first": "S", "middle": [], "last": "Klemperer", "suffix": ""}, {"first": "L", "middle": [], "last": "Brown", "suffix": ""}, {"first": "P", "middle": [], "last": "Pananont", "suffix": ""}, {"first": "A", "middle": [], "last": "Ross", "suffix": ""}, {"first": "K", "middle": ["D"], "last": "Nelson", "suffix": ""}, {"first": "J", "middle": [], "last": "Guo", "suffix": ""}, {"first": "W", "middle": [], "last": "Zhao", "suffix": ""}], "year": 2003, "venue": "", "link": null}, "BIBREF76": {"title": "Rb-Sr ages of granitic rocks within the Lesser Himalayan nappes", "authors": [{"first": "J", "middle": ["R"], "last": "Trivedi", "suffix": ""}, {"first": "K", "middle": [], "last": "Gopalan", "suffix": ""}, {"first": "K", "middle": ["S"], "last": "Valdiya", "suffix": ""}], "year": 1984, "venue": "Journal of the Geological Society of India", "link": null}, "BIBREF77": {"title": "Postcollision, shoshonitic volcanism on the Tibetan Plateau: Implications for convective thinning of the lithosphere and the source of ocean island basalts", "authors": [{"first": "S", "middle": [], "last": "Turner", "suffix": ""}, {"first": "N", "middle": [], "last": "Arnaud", "suffix": ""}, {"first": "J", "middle": [], "last": "Liu", "suffix": ""}, {"first": "N", "middle": [], "last": "Rogers", "suffix": ""}, {"first": "C", "middle": [], "last": "Hawkesworth", "suffix": ""}, {"first": "N", "middle": [], "last": "Harris", "suffix": ""}, {"first": "S", "middle": [], "last": "Kelley", "suffix": ""}, {"first": "P", "middle": [], "last": "Van Calsteren", "suffix": ""}, {"first": "W", "middle": [], "last": "Deng", "suffix": ""}], "year": 1996, "venue": "", "link": "129607579"}, "BIBREF78": {"title": "Interpretation of Cenozoic tectonics in the right-lateral accommodation zone between the Ailao Shan shear zone and the eastern Himalayan syntaxis: International Geology Review", "authors": [{"first": "E", "middle": [], "last": "Wang", "suffix": ""}, {"first": "B", "middle": ["C"], "last": "Burchfiel", "suffix": ""}], "year": 1997, "venue": "", "link": null}, "BIBREF79": {"title": "A tectonic model for Cenozoic igneous activities in the eastern Indo-Asian collision zone: Earth and Planetary Science Letters", "authors": [{"first": "J", "middle": [], "last": "Wang", "suffix": ""}, {"first": "A", "middle": [], "last": "Yin", "suffix": ""}, {"first": "T", "middle": ["M"], "last": "Harrison", "suffix": ""}, {"first": "M", "middle": [], "last": "Grove", "suffix": ""}, {"first": "Z", "middle": [], "last": "Yuquan", "suffix": ""}, {"first": "X", "middle": [], "last": "Guanghong", "suffix": ""}], "year": 2001, "venue": "", "link": null}, "BIBREF80": {"title": "Crustal anatexis and its relation to the exhumation of collisional orogenic belts, with particular reference to the Himalaya: Mineralogical Magazine", "authors": [{"first": "A", "middle": ["G"], "last": "Whittington", "suffix": ""}, {"first": "P", "middle": ["J"], "last": "Treloar", "suffix": ""}], "year": 2002, "venue": "", "link": null}, "BIBREF81": {"title": "Contrasting anatectic styles at Nanga Parbat, northern Pakistan", "authors": [{"first": "A", "middle": ["G"], "last": "Whittington", "suffix": ""}, {"first": "N", "middle": ["B W"], "last": "Harris", "suffix": ""}, {"first": "R", "middle": ["W H"], "last": "Butler", "suffix": ""}], "year": 1999, "venue": "", "link": "133209246"}, "BIBREF82": {"title": "Age and composition of dikes in southern Tibet: New constraints on the timing of east-west extension and its relationship to postcollisional magmatism: Geology, v", "authors": [{"first": "H", "middle": [], "last": "Williams", "suffix": ""}, {"first": "S", "middle": [], "last": "Turner", "suffix": ""}, {"first": "S", "middle": [], "last": "Kelley", "suffix": ""}, {"first": "N", "middle": [], "last": "Harris", "suffix": ""}], "year": 2001, "venue": "", "link": null}, "BIBREF83": {"title": "Applications of Microanalytical Techniques to Understanding Mineralizing Processes", "authors": [{"first": "I", "middle": ["S"], "last": "Williams", "suffix": ""}], "year": 1998, "venue": "", "link": null}, "BIBREF84": {"title": "Metamorphism and melting of the lithosphere due to rapid denudation", "authors": [{"first": "D", "middle": ["M"], "last": "Winslow", "suffix": ""}, {"first": "C", "middle": ["P"], "last": "Chamberlain", "suffix": ""}, {"first": "P", "middle": ["K"], "last": "Zeitler", "suffix": ""}], "year": 1995, "venue": "Journal of Geology", "link": null}, "BIBREF85": {"title": "Mode of Cenozoic east-west extension in Tibet suggesting a common origin of rifts in Asia during the Indo-Asian collision", "authors": [{"first": "A", "middle": [], "last": "Yin", "suffix": ""}], "year": 2000, "venue": "Journal of Geophysical Research", "link": "140171054"}, "BIBREF86": {"title": "Geologic evolution of the Himalayan-Tibetan orogen: Annual Review of Earth and Planetary Sciences", "authors": [{"first": "A", "middle": [], "last": "Yin", "suffix": ""}, {"first": "T", "middle": ["M"], "last": "Harrison", "suffix": ""}], "year": 2000, "venue": "", "link": null}, "BIBREF87": {"title": "Tertiary structural evolution of the Gangdese thrust system, southwestern Tibet", "authors": [{"first": "A", "middle": [], "last": "Yin", "suffix": ""}, {"first": "T", "middle": ["M"], "last": "Harrison", "suffix": ""}, {"first": "F", "middle": ["J"], "last": "Ryerson", "suffix": ""}, {"first": "W", "middle": [], "last": "Chen", "suffix": ""}, {"first": "W", "middle": ["S F"], "last": "Kidd", "suffix": ""}, {"first": "P", "middle": [], "last": "Copeland", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF88": {"title": "Tertiary deformation history of southeastern and southwestern Tibet during the Indo-Asian collision", "authors": [{"first": "A", "middle": [], "last": "Yin", "suffix": ""}, {"first": "T", "middle": ["M"], "last": "Harrison", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Murphy", "suffix": ""}, {"first": "M", "middle": [], "last": "Grove", "suffix": ""}, {"first": "S", "middle": [], "last": "Nie", "suffix": ""}, {"first": "F", "middle": ["J"], "last": "Ryerson", "suffix": ""}, {"first": "W", "middle": ["X"], "last": "Feng", "suffix": ""}, {"first": "C", "middle": ["Z"], "last": "Le", "suffix": ""}], "year": 1999, "venue": "", "link": "41864555"}, "BIBREF89": {"title": "Petrogenetic and tectonic significance of young leucogranites from the NW Himalaya", "authors": [{"first": "P", "middle": ["K"], "last": "Zeitler", "suffix": ""}, {"first": "C", "middle": ["P"], "last": "Chamberlain", "suffix": ""}], "year": 1991, "venue": "", "link": "127042902"}, "BIBREF90": {"title": "Synchronous anatexis, metamorphism, and rapid denudation at Nanga Parbat", "authors": [{"first": "P", "middle": ["K"], "last": "Zeitler", "suffix": ""}, {"first": "C", "middle": ["P"], "last": "Chamberlain", "suffix": ""}, {"first": "H", "middle": [], "last": "Smith", "suffix": ""}], "year": 1993, "venue": "Geology, v", "link": null}, "BIBREF91": {"title": "Erosion, Himalayan geodynamics, and the geomorphology of metamorphism: GSA Today", "authors": [{"first": "P", "middle": ["K"], "last": "Zeitler", "suffix": ""}, {"first": "A", "middle": ["S"], "last": "Meltzer", "suffix": ""}, {"first": "P", "middle": ["O"], "last": "Koons", "suffix": ""}, {"first": "D", "middle": [], "last": "Craw", "suffix": ""}, {"first": "B", "middle": [], "last": "Hallet", "suffix": ""}, {"first": "C", "middle": ["P"], "last": "Chamberlain", "suffix": ""}, {"first": "W", "middle": ["S F"], "last": "Kidd", "suffix": ""}, {"first": "S", "middle": ["K"], "last": "Park", "suffix": ""}, {"first": "L", "middle": [], "last": "Seeber", "suffix": ""}, {"first": "M", "middle": [], "last": "Bishop", "suffix": ""}, {"first": "J", "middle": [], "last": "Shroder", "suffix": ""}], "year": 2001, "venue": "", "link": null}, "BIBREF92": {"title": "Crustal reworking at", "authors": [{"first": "P", "middle": ["K"], "last": "Zeitler", "suffix": ""}, {"first": "P", "middle": ["O"], "last": "Koons", "suffix": ""}, {"first": "M", "middle": ["P"], "last": "Bishop", "suffix": ""}, {"first": "C", "middle": ["P"], "last": "Chamberlain", "suffix": ""}, {"first": "D", "middle": [], "last": "Craw", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Edwards", "suffix": ""}, {"first": "S", "middle": [], "last": "Hamidullah", "suffix": ""}, {"first": "M", "middle": ["Q"], "last": "Jan", "suffix": ""}, {"first": "M", "middle": [], "last": "Khan", "suffix": ""}, {"first": "M", "middle": [], "last": "Khattak", "suffix": ""}, {"first": "W", "middle": ["S F"], "last": "Kidd", "suffix": ""}, {"first": "R", "middle": ["L"], "last": "Mackie", "suffix": ""}, {"first": "A", "middle": ["S"], "last": "Meltzer", "suffix": ""}, {"first": "S", "middle": ["K"], "last": "Park", "suffix": ""}, {"first": "A", "middle": [], "last": "Pecher", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Poage", "suffix": ""}, {"first": "G", "middle": [], "last": "Sarker", "suffix": ""}, {"first": "D", "middle": ["A"], "last": "Schneider", "suffix": ""}, {"first": "L", "middle": [], "last": "Seeber", "suffix": ""}, {"first": "J", "middle": ["F"], "last": "Shroder", "suffix": ""}], "year": 2001, "venue": "", "link": null}, "BIBREF93": {"title": "Age and origin of magmatism along the Cenozoic Red River shear belt, China: Contributions to Mineralogy and Petrology", "authors": [{"first": "L", "middle": ["S"], "last": "Zhang", "suffix": ""}, {"first": "U", "middle": [], "last": "Sch\u00e4rer", "suffix": ""}], "year": 1999, "venue": "", "link": null}, "BIBREF94": {"title": "Geology of the Namche Barwa Region: Beijing", "authors": [{"first": "Z", "middle": ["G"], "last": "Zhang", "suffix": ""}, {"first": "Y", "middle": ["H"], "last": "Liu", "suffix": ""}, {"first": "H", "middle": ["X"], "last": "Qnag", "suffix": ""}, {"first": "B", "middle": ["C"], "last": "Xu", "suffix": ""}], "year": 1992, "venue": "", "link": "128188219"}}, "ref_entries": {"FIGREF0": {"text": "Fig. 1. Tectonic sketch map of southeastern Tibet, after Ding and others (2001). Location of fig. 2 shown in box. GTS \u03ed Gangdese Thrust System, RZTS \u03ed Renbu Zedong Thrust System, STDS \u03ed South Tibetan Detachment System, ITSZ \u03ed Indus Tsangpo Suture Zone, MCT \u03ed Main Central Thrust, MBT \u03ed Main Boundary Thrust, NB \u03ed Namche Barwa. Regional geographic location of Namche Barwa shown in inset. NBS \u03ed Namche Barwa Syntaxis, NPS \u03ed Nanga Parbat Syntaxis.", "type": "figure"}, "FIGREF1": {"text": "methods Samples.-During September-October 2001 and May-June 2002 field seasons, our samples were gathered from five principal areas, and can be grouped as follows: [A] within the Namche Barwa massif (fig. 2) -from granitic dikes and migmatites intruding Indian plate gneisses and metasediments; [B] along the northwest margin of the Namche Barwa-Gyala Peri (NB-GP) massif -from granitic intrusions into both Lhasa block and Indian plate gneisses and metasediments; [C] substantially west of the NB-GP massif, spread out from Loulan toward Bayi, and along the Nyang River - intruding Lhasa block gneisses and metasediments; [D] north of Namche Barwa, along the inferred location of the Jiali Fault zone -from intrusions into Lhasa block gneisses and metasediments; and [E] northeast of Namche Barwa near the Jiali Fault zone - from presumed Gangdese plutonic rock of granodioritic compositions.", "type": "figure"}, "FIGREF2": {"text": "Fig. 2. Geological map of Namche Barwa syntaxis, showing major lithological units and faults, town names referred to in text, sample localities, and distribution of U-Pb zircon ages. Location of cross section (fig. 5) is shown.", "type": "figure"}, "FIGREF3": {"text": "Fig. 3. Sample IG-2d -Deformed felsic melt pod (\u03f350 cm across) within amphibolite section near Jiala.", "type": "figure"}, "FIGREF4": {"text": "Fig. 4. Sample BT-17-02 -Pegmatite dike cross-cutting basement gneisses, De'u Gungbu section, western margin of Gyala Peri massif.", "type": "figure"}, "FIGREF5": {"text": "Fig. 5. Detailed cross-section (for location, see fig. 2) through the structural western margin of the Namche Barwa/Gyala Peri massif, on the western flank of the Gyala Peri massif (De'u Gungbu Valley). This section crosses the attenuated remnants of the Indus-Tsangpo suture. U-Pb zircon ages of samples are shown.", "type": "figure"}, "FIGREF6": {"text": "Fig. 6. Cathodoluminescence (CL) images of representative zircons from each sample group: (A) Namche Barwa (IG-16), (B) Northwest margin of NB-GP massif (BT-20), (C) Western Gangdese and related granitoids (NB-120), (D) North of Namche Barwa group (BT-33), and (E) Northeastern granites (BM-03), all showing strong zoning patterns.", "type": "figure"}, "FIGREF8": {"text": "Fig. 7. Tera-Wasserburg concordia diagrams showing U-Pb SHRIMP ages for group A samples -from within the Namche Barwa massif. Error ellipses are shown at 2 uncertainty. Older zircon core ages are shown, where applicable, for all samples on composite Concordia plot.", "type": "figure"}, "FIGREF9": {"text": "Fig. 7. (continued)", "type": "figure"}, "FIGREF10": {"text": "interpretation Our study encompasses a series of granitic bodies that vary in their geochemistry and emplacement age, and occur within differing tectonic terranes. These granitoids are grouped as follows: [A] those intruded into Indian gneisses of Namche Barwa; [B] intruded into Lhasa block and Indian plate metasediments along the northwest margin of the NB-GP massif; [C] Gangdese Arc and related granitoids intruded into Lhasa block metasediments considerably west of the NB-GP massif; [D] intruded into", "type": "figure"}, "FIGREF11": {"text": "Fig. 8. Tera-Wasserburg concordia diagrams showing U-Pb SHRIMP ages for group B samples -from the northwest margin of the Namche Barwa-Gyala Peri massif. Error ellipses are shown at 2 uncertainty. Older zircon core ages are shown, where applicable, for all samples on composite Concordia plot.", "type": "figure"}, "FIGREF12": {"text": "Fig. 9. Tera-Wasserburg concordia diagrams showing U-Pb SHRIMP ages from group C samples -from western Gangdese and Gandgese-related samples. Error ellipses are shown at 2 uncertainty. Older zircon core ages are shown, where applicable, for all samples on composite Concordia plot.", "type": "figure"}, "FIGREF13": {"text": "Fig. 10. Tera-Wasserburg concordia diagrams showing U-Pb SHRIMP ages for group D samples -from north of the Namche Barwa-Gyala Peri massif. Error ellipses are shown at 2 uncertainty. Older zircon core ages are shown, where applicable, for all samples on composite Concordia plot.", "type": "figure"}, "FIGREF14": {"text": "Fig. 12. Rb/Sr ratio vs. Ba (ppm) plot, showing the geochemical variation among sample groups. Fields labeled by geographic grouping: (A) Namche Barwa massif granitoids (green horizontal lines), (B) NW margin of NB-GP massif granites (blue vertical lines), (C) western Gangdese and related samples (purple diagonal dashes), (D) Northern granites (orange crosshatch pattern), and (E) northeastern/Bomi region granitoids (red wavy lines), data from table 2. Note the higher frequency of decompression melts (Rb/Sr ratios \u03fe 1.4) among the group A (Namche Barwa) granite suite.", "type": "figure"}, "FIGREF15": {"text": "Fig. 13. Rb vs. Y \u03e9 Nb diagram after Pearce and others (1984) and Pearce (1996) for granitoid groups: (A) Within the", "type": "figure"}, "FIGREF16": {"text": "Fig. 13. Rb vs. Y \u03e9 Nb diagram after Pearce and others (1984) and Pearce (1996) for granitoid groups: (A) Within the Namche Barwa massif (squares), (B) Northwest margin of NB-GP massif (circles), (C) Western Gangdese and related granites (asterisks), (D) north of NB-GP massif (diamonds), and (E) Northeastern/Bomi region (triangles). Syn-COLG and post-COLG: Syn-and \"Post\"-Collision Granites; WPG: Within Plate Granites; VAG: Volcanic Arc Granites; ORG: Ocean Ridge Granites.", "type": "figure"}, "TABREF1": {"text": "Summary of U-Pb isotopic data for all granitoids, with samples grouped by geographic location as in figures 7-11: Namche Barwa, Northwest margin of NB-GP massif, western Gangdese/related, north of NB-GP massif, and Bomi region/Northeast of NB-GP massif.", "type": "table"}, "TABREF2": {"text": "", "type": "table"}}}
{"paper_id": "17789708", "_pdf_hash": "f5516674e6d61d3add88accdd9e776d4a2883961", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Survey of interconnection Networks", "authors": [{"first": "T", "middle": ["Y"], "last": "Feng", "suffix": ""}], "year": 1981, "venue": "IEEE Computer", "link": null}, "BIBREF1": {"title": "A Survey of Faulttolerant Multistage Networks and comparison to Extra Stage Cube", "authors": [{"first": "George", "middle": ["B"], "last": "Adams", "suffix": ""}, {"first": "Howard", "middle": ["Jay"], "last": "Siegel", "suffix": ""}], "year": 1984, "venue": "17th Annual Hawaii International Conference on System Sciences", "link": null}, "BIBREF2": {"title": "A Survey and Comparison of Fult-tolerent Multistage Interconnection Networks", "authors": [{"first": "George", "middle": ["B"], "last": "Adams", "suffix": ""}, {"first": "P", "middle": [], "last": "Dharma", "suffix": ""}, {"first": "Howard", "middle": ["Jay"], "last": "Agrawal", "suffix": ""}, {"first": "", "middle": [], "last": "Siegel", "suffix": ""}], "year": 1987, "venue": "IEEE Computer", "link": null}, "BIBREF3": {"title": "Performance of Multiprocessor Interconnection Networks", "authors": [{"first": "N", "middle": [], "last": "Laxmi", "suffix": ""}, {"first": "Qing", "middle": [], "last": "Bhuyan", "suffix": ""}, {"first": "Dharma", "middle": ["P"], "last": "Yang", "suffix": ""}], "year": 1989, "venue": "IEEE", "link": "645393"}, "BIBREF4": {"title": "Network reliability optimization problem of interconnection network under node-edge failure model", "authors": [{"first": "R", "middle": ["K"], "last": "Dash", "suffix": ""}, {"first": "N", "middle": ["K"], "last": "Barpanda", "suffix": ""}, {"first": "P", "middle": ["K"], "last": "Tripathy", "suffix": ""}, {"first": "C", "middle": ["R"], "last": "Tripathy", "suffix": ""}], "year": 2012, "venue": "Journal of Applied Soft Computing", "link": "205702536"}, "BIBREF5": {"title": "Using the Multistage Cube Network Topology in Parallel Supercomputers", "authors": [{"first": "Howard", "middle": ["Jay"], "last": "Siegal", "suffix": ""}, {"first": "Wayne", "middle": ["G"], "last": "Nation", "suffix": ""}, {"first": "Clyde", "middle": ["P"], "last": "Kruskal", "suffix": ""}, {"first": "Leonard", "middle": ["M"], "last": "Napolitano", "suffix": ""}], "year": 1979, "venue": "Proceedings of IEEE", "link": "17685037"}, "BIBREF6": {"title": "A study Communication Problem in the Self-Repairable Multiprocessor", "authors": [{"first": "N", "middle": [], "last": "Levitt", "suffix": ""}, {"first": "M", "middle": ["W"], "last": "Green", "suffix": ""}, {"first": "J", "middle": [], "last": "Goldberg", "suffix": ""}], "year": 1968, "venue": "Proc. AFIPS Conference", "link": null}, "BIBREF7": {"title": "Design of Fault-Tolerant Packet Communication Computer Architecture", "authors": [{"first": "C", "middle": ["K C"], "last": "Leung", "suffix": ""}, {"first": "J", "middle": ["B"], "last": "Dennis", "suffix": ""}], "year": 1980, "venue": "Proc. International Symposium on Fault -Tolerant Computing", "link": null}, "BIBREF8": {"title": "Graph Theoretical Analysis and Design of Multistage Interconnection Networks", "authors": [{"first": "P", "middle": [], "last": "Dharma", "suffix": ""}], "year": 1983, "venue": "IEEE Trans. On Computer", "link": "5891604"}, "BIBREF9": {"title": "Parallel Processing with the Perfect Shuffle", "authors": [{"first": "H", "middle": ["S"], "last": "Stone", "suffix": ""}], "year": 1971, "venue": "IEEE Trans. On Computers", "link": "1491411"}, "BIBREF10": {"title": "Access and Alignment of Data in an Array Processor", "authors": [{"first": "D", "middle": ["H"], "last": "Lawrie", "suffix": ""}], "year": 1975, "venue": "IEEE Trans. On Computers", "link": "1277225"}, "BIBREF11": {"title": "Processor-Memory Interconnection for Multiprocessors", "authors": [{"first": "J", "middle": ["H"], "last": "Patel", "suffix": ""}], "year": 1979, "venue": "Proc. of the 6th Annual Symposium on Computer Architecture", "link": null}, "BIBREF12": {"title": "Advanced Parallel Processing with Super Computers", "authors": [{"first": "K", "middle": [], "last": "Hwang", "suffix": ""}], "year": 1987, "venue": "Proc. IEEE, OC-79", "link": null}, "BIBREF13": {"title": "Fault-tolerant Routing in Unique-Path Multistage Interconnection Networks", "authors": [{"first": "H", "middle": [], "last": "Sadawarti", "suffix": ""}, {"first": "P", "middle": ["K"], "last": "Bansal", "suffix": ""}], "year": 2004, "venue": "Proceedings of the IEEE First India Annual Conference INDICON", "link": "33885179"}, "BIBREF14": {"title": "The Indirect Binary n-Cube Multiprocessor Array", "authors": [{"first": "M", "middle": ["C"], "last": "Pease", "suffix": ""}], "year": 1977, "venue": "IEEE Trans. On Computers", "link": "62632189"}, "BIBREF15": {"title": "Design and Performance of Generalized Interconnection Network", "authors": [{"first": "L", "middle": ["N"], "last": "Bhuyan", "suffix": ""}, {"first": "D", "middle": ["P"], "last": "", "suffix": ""}], "year": 1983, "venue": "IEEE Trans. On Computers", "link": null}, "BIBREF16": {"title": "Mathematical Theory of Connecting Networks and Telephone Traffic", "authors": [{"first": "V", "middle": ["E"], "last": "Benes", "suffix": ""}], "year": 1965, "venue": "", "link": "123463071"}, "BIBREF17": {"title": "A Study of Non-Bocking Switching Networks", "authors": [{"first": "", "middle": [], "last": "Clos", "suffix": ""}], "year": 1953, "venue": "Bell System Technical Journal", "link": null}, "BIBREF18": {"title": "Fault-Tolerant Computing: Fundamental Concepts", "authors": [{"first": "V", "middle": ["P"], "last": "Nelson", "suffix": ""}], "year": 1990, "venue": "IEEE Computer", "link": "5820457"}, "BIBREF19": {"title": "Fault-Tolerant Analysis of One Sided Cross-Point Switching Network", "authors": [{"first": "Anujan", "middle": [], "last": "Varma", "suffix": ""}, {"first": "Suresh", "middle": [], "last": "Chalasani", "suffix": ""}], "year": 1992, "venue": "IEEE Trans. On Computers", "link": null}, "BIBREF20": {"title": "Interconnection Networks for Large Scale Parallel Processing: Theory and Case Studies", "authors": [{"first": "H", "middle": ["J"], "last": "Siegal", "suffix": ""}], "year": 1985, "venue": "", "link": "62639562"}, "BIBREF21": {"title": "INDRA: A Class of Interconnection Networks with Redundant Paths", "authors": [{"first": "C", "middle": ["S"], "last": "Raghavandera", "suffix": ""}, {"first": "A", "middle": [], "last": "Varma", "suffix": ""}], "year": 1984, "venue": "Proc. Real-Time Systems Symposium", "link": "54136838"}, "BIBREF22": {"title": "Reliability and Performance Analysis of a Modular Network", "authors": [{"first": "P", "middle": ["K"], "last": "Bansal", "suffix": ""}, {"first": "Kuldip", "middle": [], "last": "Singh", "suffix": ""}, {"first": "R", "middle": ["C"], "last": "Joshi", "suffix": ""}], "year": 1991, "venue": "Journal of Microelectronics and Reliability", "link": null}, "BIBREF23": {"title": "Extra Group Network: A Cost-Effective Fault-Tolerant Multistage Interconnection Network", "authors": [{"first": "S", "middle": [], "last": "Wei", "suffix": ""}, {"first": "G", "middle": [], "last": "Lee", "suffix": ""}], "year": 1988, "venue": "Proc. 15th Annual Symposium on Parallel Architecture", "link": "18886889"}, "BIBREF24": {"title": "The Extra Cube: A Fault-Tolerant Symposium Interconnection Network for Supersystems", "authors": [{"first": "G", "middle": ["B"], "last": "Adams", "suffix": ""}, {"first": "H", "middle": ["J"], "last": "Siegal", "suffix": ""}], "year": 1982, "venue": "Trans. On Computers", "link": null}, "BIBREF25": {"title": "Reliability analysis of shuffle-exchange network systems", "authors": [{"first": "Indra", "middle": [], "last": "Gunawan", "suffix": ""}], "year": 2008, "venue": "Elsevier Journal of Reliability Engineering and System Safety", "link": "34652905"}, "BIBREF26": {"title": "Redundant paths and reliability bounds in gamma networks", "authors": [{"first": "Indra", "middle": [], "last": "Gunawan", "suffix": ""}], "year": 2008, "venue": "Elsevier Journal of Applied Mathematical Modelling", "link": "122175627"}, "BIBREF27": {"title": "Tighter Bounds on Full Access Probability in Fault-Tolerant Multistage sParallel and Distributed Systems", "authors": [{"first": "Suresh", "middle": [], "last": "Rai", "suffix": ""}], "year": 1999, "venue": "", "link": null}, "BIBREF28": {"title": "Thesis on Multistage interconnection Networks", "authors": [{"first": "Himanshu", "middle": [], "last": "Agarwal", "suffix": ""}], "year": 2000, "venue": "Thapar Institute of Engg. And Technology", "link": null}, "BIBREF29": {"title": "Thesis on Fault tolerant Multistage interconnection Networks", "authors": [{"first": "", "middle": [], "last": "Sheetal", "suffix": ""}], "year": 2008, "venue": "Thapar Institute of Engg. And Technology", "link": null}, "BIBREF30": {"title": "Thesis on Fast Packet Switching for Integrated Services", "authors": [{"first": "Peter", "middle": [], "last": "Newman", "suffix": ""}], "year": 1988, "venue": "", "link": null}, "BIBREF31": {"title": "Thesis on Performance Prediction of Packet Switched Multistage Interconnection Network in an Execution-driven environment", "authors": [{"first": "Grant", "middle": [], "last": "Lauderdale", "suffix": ""}, {"first": "", "middle": [], "last": "Matthew", "suffix": ""}], "year": 1990, "venue": "", "link": null}, "BIBREF32": {"title": "thesis onQuality of Service in Interconnection Networks\" the Faculty of Mathematics and Natural Sciences at the University of Oslo", "authors": [{"first": "Sven-Arne", "middle": [], "last": "Reinemo", "suffix": ""}], "year": 2007, "venue": "", "link": null}, "BIBREF33": {"title": "The augmented data vortex switch fabric: An all-optical packet switched interconnection network with enhanced fault tolerance", "authors": [{"first": "Neha", "middle": [], "last": "Sharma", "suffix": ""}, {"first": "D", "middle": [], "last": "Chadha", "suffix": ""}, {"first": "Vinod", "middle": [], "last": "Chandra", "suffix": ""}], "year": 2007, "venue": "Elsevier Journal of Optical Switching and Networking", "link": "22902341"}, "BIBREF34": {"title": "Permutation and Reliability Measures of Regular and Irregular MINs", "authors": [{"first": "J", "middle": [], "last": "Sengupta", "suffix": ""}, {"first": "P", "middle": ["K"], "last": "Bansal", "suffix": ""}, {"first": "Ajay", "middle": [], "last": "Gupta", "suffix": ""}], "year": 2000, "venue": "", "link": "61103907"}, "BIBREF35": {"title": "3-Disjoint gamma interconnection networks", "authors": [{"first": "Ching-Wen", "middle": [], "last": "Chen", "suffix": ""}, {"first": "Neng-Pin", "middle": [], "last": "Lu", "suffix": ""}, {"first": "Chung-Ping", "middle": [], "last": "Chung", "suffix": ""}], "year": 2003, "venue": "Elsevier Journal of Systems and Software", "link": "44531197"}, "BIBREF36": {"title": "Irregular Class of Multistage Interconnection Networks in Parallel Processing", "authors": [{"first": "S", "middle": [], "last": "Sharma", "suffix": ""}, {"first": "K", "middle": ["S"], "last": "Kahlon", "suffix": ""}, {"first": "P", "middle": ["K"], "last": "Bansal", "suffix": ""}, {"first": "K", "middle": [], "last": "Singh", "suffix": ""}], "year": 2008, "venue": "Journal of Computer Science", "link": "61968523"}, "BIBREF37": {"title": "On a class of Multistage Interconnection Networks in Parallel Processing", "authors": [{"first": "S", "middle": [], "last": "Kahlon", "suffix": ""}, {"first": "K", "middle": ["S"], "last": "Bansal", "suffix": ""}, {"first": "P", "middle": ["K"], "last": "", "suffix": ""}], "year": 2008, "venue": "International Journal of Computer Science and Network Security", "link": null}, "BIBREF38": {"title": "Permutation Capability and Connectivity of Enhanced Multistage Interconnection Network (E-MIN)", "authors": [{"first": "A", "middle": [], "last": "Subramanyam", "suffix": ""}, {"first": "E", "middle": ["V"], "last": "Prasad", "suffix": ""}, {"first": "R", "middle": [], "last": "Nadamuni", "suffix": ""}], "year": 2006, "venue": "Proceedings of IEEE International Conference on Advanced Computing and Communications ADCOM-06", "link": "17051956"}, "BIBREF39": {"title": "Performance Evaluation of Single Stage and Multistage Interconnection Networks Connectivity in Multiprocessors", "authors": [{"first": "A", "middle": [], "last": "Subramanyam", "suffix": ""}, {"first": "E", "middle": ["V"], "last": "Prasad", "suffix": ""}, {"first": "C", "middle": ["N"], "last": "Reddy", "suffix": ""}], "year": 2008, "venue": "IE(I) Journal CP", "link": null}, "BIBREF41": {"title": "Permutation and Reliability Measures of Regular and Irregular MINs", "authors": [{"first": "J", "middle": [], "last": "Sengupta", "suffix": ""}, {"first": "P", "middle": ["K"], "last": "Bansal", "suffix": ""}, {"first": "Ajay", "middle": [], "last": "Gupta", "suffix": ""}], "year": 2000, "venue": "", "link": "61103907"}, "BIBREF42": {"title": "3-Disjoint gamma interconnection networks", "authors": [{"first": "Ching-Wen", "middle": [], "last": "Chen", "suffix": ""}, {"first": "Neng-Pin", "middle": [], "last": "Lu", "suffix": ""}, {"first": "Chung-Ping", "middle": [], "last": "Chung", "suffix": ""}], "year": 2003, "venue": "Elsevier Journal of Systems and Software", "link": "44531197"}, "BIBREF43": {"title": "Permutation and Reliability Measures of Regular and Irregular MINs", "authors": [{"first": "J", "middle": [], "last": "Sengupta", "suffix": ""}, {"first": "P", "middle": ["K"], "last": "Bansal", "suffix": ""}, {"first": "Ajay", "middle": [], "last": "Gupta", "suffix": ""}], "year": 2000, "venue": "", "link": "61103907"}, "BIBREF44": {"title": "Routing and Path Length Algorithm for Cost-effective Modified Four Tree Network", "authors": [{"first": "H", "middle": [], "last": "Aggarwal", "suffix": ""}, {"first": "P", "middle": ["K"], "last": "Bansal", "suffix": ""}], "year": 2002, "venue": "Proceedings of IEEE Region 10 Conference on Computers", "link": "64299609"}, "BIBREF45": {"title": "On the Scalability of Multistage Interconnection Networks", "authors": [{"first": "A", "middle": ["C"], "last": "Aljundi", "suffix": ""}, {"first": "J", "middle": ["L"], "last": "Dekeyser", "suffix": ""}, {"first": "M", "middle": ["T"], "last": "Kechadi", "suffix": ""}], "year": 2001, "venue": "Proceedings of IEEE International Conference on Information and Communication Technologies: From Theory to Applications", "link": "36275336"}, "BIBREF46": {"title": "A Study of an Evaluation methodology for Unbuffered Multistage Interconnection Networks", "authors": [{"first": "A", "middle": ["C"], "last": "Aljundi", "suffix": ""}, {"first": "J", "middle": ["L"], "last": "Dekeyser", "suffix": ""}, {"first": "M", "middle": ["T"], "last": "Kechadi", "suffix": ""}], "year": 2003, "venue": "proceedings of IEEE International Symposium on Parallel and Distributed Processing", "link": "5812309"}, "BIBREF47": {"title": "A Universal Performance Factor for Multi-criteria Evaluation of Multistage Interconnection Networks", "authors": [{"first": "A", "middle": ["C"], "last": "Aljundia", "suffix": ""}, {"first": "J", "middle": ["L"], "last": "Dekeyser", "suffix": ""}, {"first": "M", "middle": ["T"], "last": "Kechadi", "suffix": ""}, {"first": "I", "middle": ["D"], "last": "Scherson", "suffix": ""}], "year": 2006, "venue": "Future Generation Computer Systems", "link": "1138808"}, "BIBREF48": {"title": "Reliable Omega IN for Large-scale Multiprocessor Systems", "authors": [{"first": "S", "middle": ["M"], "last": "Bataineh", "suffix": ""}, {"first": "G", "middle": ["E"], "last": "Qanzu", "suffix": ""}], "year": 2003, "venue": "The Computer Journal", "link": null}, "BIBREF49": {"title": "Fault-tolerant Multistage Interconnection Network", "authors": [{"first": "S", "middle": ["M"], "last": "Bataineh", "suffix": ""}, {"first": "B", "middle": ["Y"], "last": "Allosl", "suffix": ""}], "year": 2001, "venue": "Telecommunication Systems", "link": "2408884"}, "BIBREF50": {"title": "Performance Analysis and Fault Tolerance of Randomized Routing on Clos Networks", "authors": [{"first": "M", "middle": [], "last": "Bhatia", "suffix": ""}, {"first": "A", "middle": [], "last": "Youssef", "suffix": ""}], "year": 1998, "venue": "Telecommunication Systems", "link": "62606605"}}, "ref_entries": {}}
{"paper_id": "42950429", "_pdf_hash": "2abd8d5eb9efb5b62ce1c79dc33911cf843a47e8", "abstract": [{"section": "Abstract", "text": "Objectives: To investigate the in vitro activity of cethromycin, a new ketolide, against Chlamydia pneumoniae.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Methods: The in vitro activity of cethromycin against 20 isolates of C. pneumoniae was compared with the activities of telithromycin, erythromycin A, azithromycin and clarithromycin against those isolates.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Results: The MIC at which 90% of the isolates were inhibited and the minimal chlamydiacidal concentration at which 90% of the isolates were killed by cethromycin were both 0.016 mg/L (range 0.016-0.031 mg/L). Cethromycin was the most active antibiotic tested in this study.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Our results appear to indicate that cethromycin is an effective antibiotic that should play some role in the treatment of respiratory tract infections caused by C. pneumoniae.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "The ketolide class of antibacterial agents includes 14-membered ring macrolides that differ from erythromycin A in that they have a 3-keto group instead of the L-cladinose moiety in the lactone ring. Telithromycin was the first ketolide to be developed for clinical use. Another ketolide, cethromycin (formerly ABT-773), has a cyclic carbamate group at the 11, 12-position in addition to the 3-keto group. This antimicrobial agent exhibits good antibacterial activity against a broad range of respiratory pathogens, including multiresistant Streptococcus pneumoniae and staphylococci, Haemophilus influenzae, Moraxella catarrhalis, Legionella spp. and Mycoplasma pneumoniae. 1, 2 Chlamydia pneumoniae is recognized as an important pathogen of respiratory tract infections worldwide, is a common cause of pneumonia, bronchitis, pharyngitis and sinusitis, and is responsible for almost 10% of cases of community-acquired pneumonia (CAP). 3 The in vitro activity of macrolides and telithromycin against C. pneumoniae is variable, with clarithromycin showing the lowest MICs followed by telithromycin, azithromycin and erythromycin A. [4] [5] [6] [7] [8] However, the available data on the activity of cethromycin against C. pneumoniae are limited. 4 Therefore, we compared the in vitro activities of cethromycin and other macrolides and telithromycin against five standard strains and 15 wild-type Japanese isolates of C. pneumoniae.", "cite_spans": [{"start": 675, "end": 677, "text": "1,", "ref_id": "BIBREF0"}, {"start": 678, "end": 679, "text": "2", "ref_id": "BIBREF1"}, {"start": 936, "end": 937, "text": "3", "ref_id": "BIBREF2"}, {"start": 1131, "end": 1134, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 1139, "end": 1142, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 1143, "end": 1146, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 1147, "end": 1150, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 1245, "end": 1246, "text": "4", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "Materials and methods", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Antimicrobial agents", "text": "The antimicrobial agents tested were erythromycin A (Shionogi Co., Osaka, Japan), clarithromycin (Taisho Pharmaceutical Co., Osaka, Japan), azithromycin (Pfizer Pharmaceutical Co., Tokyo, Japan), telithromycin (Aventis Pharma Co., Tokyo, Japan) and cethromycin (Dainabbott Laboratories, Osaka, Japan). Solutions of the agents were prepared following the manufacturers' instructions.", "cite_spans": [], "ref_spans": []}, {"section": "Isolates", "text": "Twenty C. pneumoniae isolates were used in this study. TW-183, AR-39 and AR-388 were obtained from the Washington Research Foundation, Seattle, WA, USA. IOL-207 and Kajaani-6 were acquired from P. Saikku, National Public Health Institute, Oulu, Finland. Fifteen wild-type isolates (designated KKpn-1 to KKpn-15) were also tested, which were isolated from nasopharyngeal swab specimens collected from patients with acute respiratory tract infections at Kawasaki Medical School Hospital, Japan. The organisms from these clinical samples were positively stained with C. pneumoniae-specific monoclonal antibody. These clinical isolates were morphologically different from TWAR (TW-183, AR-39 and AR-388) strains from the United States (examples are given in Figure 1 ). 3 KKpn-15 elementary bodies (EBs) have a narrow periplasmic space and ", "cite_spans": [{"start": 766, "end": 767, "text": "3", "ref_id": "BIBREF2"}], "ref_spans": [{"start": 754, "end": 762, "text": "Figure 1", "ref_id": "FIGREF1"}]}, {"section": "Measurement of MICs and minimal chlamydiacidal concentrations (MCCs)", "text": "One millilitre of culture medium [Eagle's minimal essential medium (Nissui Pharmaceuticals Co., Tokyo, Japan) and 10% heat-inactivated fetal calf serum (GIBCO BRL Life Technologies Inc., Grand Island, NY, USA)] containing 10 5 HEp-2 cells per mL were dispensed into each well of plastic 24-well culture plates, which were then incubated in 5% CO 2 at 35\u00b0C for 48 h. After confirming growth of a confluent monolayer, the culture fluid was removed from the wells by aspiration. Next, 10 4 inclusion-forming units per mL of each chlamydial strain were inoculated into each well. Then the plates were centrifuged at 900g for 60 min, and 1 mL of each preparation of the culture medium containing 1 mg/L cycloheximide (Nakarai Tesque Inc., Tokyo, Japan) and one concentration (final concentrations; range from 0.008 to 2 mg/L) of the test antibiotic were dispensed into each well. After incubation in 5% CO 2 at 35\u00b0C for 72 h, the cultures were fixed and stained for inclusions with the fluorescein isothiocyanate-conjugated monoclonal antibody specific for the chlamydial genus-specific antigen (Chlamydia FA Seiken; Denka Seiken, Tokyo, Japan). The MIC was defined as the lowest concentration at which no inclusions were found. The MCCs were determined by aspirating the antibiotic-containing medium, washing the wells twice with phosphate-buffered saline, and adding antibiotic-free medium. The infected cells were frozen at -70\u00b0C, thawed, passed onto new cells, incubated for 72 h, and then fixed and stained as described above. The MCC was the lowest antibiotic concentration resulting in no inclusions after passage. All tests were run in triplicate. Antichlamydial activity was determined when the same results were observed in at least two out of three experiments.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "The MIC and MCC ranges of cethromycin and the other antimicrobial agents for C. pneumoniae used in this study are shown in Table 1 . The MICs and MCCs of cethromycin for the 20 C. pneumoniae isolates both ranged between 0.016 and 0.031 mg/L. The MICs of cethromycin, telithromycin, clarithromycin, azithromycin and erythromycin A at which 90% of the isolates were inhibited (MIC 90 ) were 0.016, 0.063, 0.063, 0.25 and 0.25 mg/L, respectively. The MCC 90 of cethromycin was also 0.016 mg/L. Cethromycin was the most active antibiotic tested in this study.", "cite_spans": [], "ref_spans": [{"start": 123, "end": 130, "text": "Table 1", "ref_id": "TABREF0"}]}, {"section": "Discussion", "text": "C. pneumoniae is a well-known respiratory pathogen that causes upper and lower respiratory tract infections and pneumonia. Macrolides and ketolides have been demonstrated to be active in vitro against C. pneumoniae. [4] [5] [6] [7] [8] We have previously reported on the experimental effectiveness of macrolides against acute chlamydial respiratory tract infections. 6, 7 The therapeutic effect of a 7 day course of clarithromycin at doses of 5 and 10 mg/kg body weight administered orally twice daily and of azithromycin at a dose of 10 mg/kg body weight administered orally once daily to mice with experimental Chlamydia psittaci pneumonia was excellent, with a 100% survival rate at 14 or 21 days after infection. This finding was the same as that for treatment with minocycline administered at 10 mg/kg twice daily. 6, 7 Recently, Hammerschlag et al. 9 reported a study assessing the efficacy of cethromycin for treatment of C. pneumoniae pneumonia. They found a 100% efficacy in eradication of the organism from the nasopharynx of patients with CAP. Telithromycin (given at a dosage of 800 mg once daily for 7-10 days) also showed good clinical efficacy against CAP due to C. pneumoniae. 10, 11 However, the diagnosis of C. pneumoniae infection in these telithromycin studies was based entirely on serology, not culture. Clinical studies on erythromycin A, clarithromycin and azithromycin in which cultures were carried out demonstrated that these macrolides are effective drugs for the treatment of respiratory infection associated with C. pneumoniae. 12, 13 The available data on the activity of cethromycin against C. pneumoniae are limited. Strigl et al. 4 found that both the MIC 50 and MIC 90 values of cethromycin against 20 isolates of C. pneumoniae including two reference strains, TW-183 and AR-39, were 0.015 mg/L.The MIC 90 and MCC 90 against 20 isolates of C. pneumoniae found in our study are also consistent with their report. Based on the above ", "cite_spans": [{"start": 216, "end": 219, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 224, "end": 227, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 228, "end": 231, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 232, "end": 235, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 367, "end": 369, "text": "6,", "ref_id": "BIBREF5"}, {"start": 370, "end": 371, "text": "7", "ref_id": "BIBREF6"}, {"start": 820, "end": 822, "text": "6,", "ref_id": "BIBREF5"}, {"start": 823, "end": 824, "text": "7", "ref_id": "BIBREF6"}, {"start": 1193, "end": 1196, "text": "10,", "ref_id": "BIBREF10"}, {"start": 1562, "end": 1564, "text": "13", "ref_id": "BIBREF11"}, {"start": 1664, "end": 1665, "text": "4", "ref_id": "BIBREF3"}], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "The in vitro activity of ABT 773, a new ketolide antimicrobial agent", "authors": [{"first": "J", "middle": ["M"], "last": "Andrews", "suffix": ""}, {"first": "T", "middle": ["M A"], "last": "Weller", "suffix": ""}, {"first": "J", "middle": ["P"], "last": "Ashby", "suffix": ""}], "year": 2000, "venue": "Journal of Antimicrobial Chemotherapy", "link": "23314996"}, "BIBREF1": {"title": "Comparative in vitro activity of ABT-773, a novel antibacterial ketolide", "authors": [{"first": "A", "middle": ["M"], "last": "Nilius", "suffix": ""}, {"first": "M", "middle": ["H"], "last": "Bui", "suffix": ""}, {"first": "L", "middle": [], "last": "Almer", "suffix": ""}], "year": 2001, "venue": "Antimicrobial Agents and Chemotherapy", "link": "29063766"}, "BIBREF2": {"title": "Chlamydia pneumoniae (TWAR)", "authors": [{"first": "C", "middle": ["C"], "last": "Kuo", "suffix": ""}, {"first": "L", "middle": ["A"], "last": "Jackson", "suffix": ""}, {"first": "L", "middle": ["A"], "last": "Campbell", "suffix": ""}], "year": 1995, "venue": "Clinical Microbiology Reviews", "link": "33373857"}, "BIBREF3": {"title": "In vitro activity of ABT 773, a new ketolide antibiotic, against Chlamydia pneumoniae", "authors": [{"first": "S", "middle": [], "last": "Strigl", "suffix": ""}, {"first": "P", "middle": ["M"], "last": "Roblin", "suffix": ""}, {"first": "T", "middle": [], "last": "Reznik", "suffix": ""}], "year": 2000, "venue": "Antimicrobial Agents and Chemotherapy", "link": "23200363"}, "BIBREF5": {"title": "In vitro and in vivo activities of azithromycin, a new azalide antibiotic, against Chlamydia", "authors": [{"first": "Y", "middle": [], "last": "Niki", "suffix": ""}, {"first": "M", "middle": [], "last": "Kimura", "suffix": ""}, {"first": "N", "middle": [], "last": "Miyashita", "suffix": ""}], "year": 1994, "venue": "Antimicrobial Agents and Chemotherapy", "link": "9064331"}, "BIBREF6": {"title": "In vitro and in vivo activities of AM-1155, a new fluoroquinolone, against Chlamydia spp", "authors": [{"first": "N", "middle": [], "last": "Miyashita", "suffix": ""}, {"first": "Y", "middle": [], "last": "Niki", "suffix": ""}, {"first": "T", "middle": [], "last": "Kishimoto", "suffix": ""}], "year": 1997, "venue": "Antimicrobial Agents and Chemotherapy", "link": "30139781"}, "BIBREF7": {"title": "In vitro activity of telithromycin, a new ketolide, against Chlamydia pneumoniae", "authors": [{"first": "N", "middle": [], "last": "Miyashita", "suffix": ""}, {"first": "H", "middle": [], "last": "Fukano", "suffix": ""}, {"first": "Y", "middle": [], "last": "Niki", "suffix": ""}], "year": 2001, "venue": "Journal of Antimicrobial Chemotherapy", "link": null}, "BIBREF9": {"title": "Microbiological efficacy of ABT-773 (cethromycin) for the treatment of community-acquired pneumonia due to Chlamydia pneumoniae", "authors": [], "year": "", "venue": "Journal of Antimicrobial Chemotherapy", "link": "28538008"}, "BIBREF10": {"title": "Oral telithromycin (HMR 3647; 800 mg OD) for 7-10 days is well tolerated and as effective as oral trovafloxacin (200 mg OD) for 7-10 days in community-acquired pneumonia (CAP) in adults", "authors": [{"first": "G", "middle": [], "last": "Tellier", "suffix": ""}, {"first": "J", "middle": [], "last": "Hassman", "suffix": ""}, {"first": "B", "middle": [], "last": "Leroy", "suffix": ""}], "year": 1995, "venue": "Program and Abstracts of the Fortieth Interscience Conference on Antimicrobial Agents and Chemotherapy", "link": null}, "BIBREF11": {"title": "Microbiologic efficacy of azithromycin and susceptibilities to azithromycin of isolates of Chlamydia pneumoniae from adults and children with communityacquired pneumonia", "authors": [{"first": "P", "middle": ["M"], "last": "Roblin", "suffix": ""}, {"first": "M", "middle": ["R"], "last": "Hammerschlag", "suffix": ""}], "year": 1998, "venue": "Antimicrobial Agents and Chemotherapy", "link": "22436206"}}, "ref_entries": {"FIGREF0": {"text": ". . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . *Corresponding author. Tel: +81-86-462-1111; Fax: +81-86-462-1199; E-mail: nao@med.kawasaki-m.ac.jp Downloaded from https://academic.oup.com/jac/article-abstract/52/3/497/776045 by guest on 21 April 2019 are round in shape, whereas TW-183 EBs are enclosed by a wavy outer membrane and are 'pear-shaped' in profile.", "type": "figure"}, "FIGREF1": {"text": "Figure 1. Thin sections of TW-183 (a) and KKpn-15 (b) isolates in HEp-2 cells at 60 h post-inoculation. Bar, 500 nm. EB, elementary body; RB, reticulate body.", "type": "figure"}, "TABREF0": {"text": "In vitro activities of cethromycin and other antimicrobial agents against 20 isolates of Chlamydophila pneumoniae MIC (mg/L) MCC (mg/L)findings and previous reports of the potent and broad antibacterial activity of cethromycin, we can conclude that cethromycin, like telithromycin, could be a useful oral agent for the acute treatment of respiratory tract infections. Prospective studies of cethromycin for the treatment of CAP should be able to determine the role of this drug in the treatment of such infections.", "type": "table"}}}
{"paper_id": "42951068", "_pdf_hash": "08ec3b1b24ece15f5796a674fd0e70aff206799a", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "42951367", "_pdf_hash": "ec0a017d5025b80a6b53217622ba81d5e075da39", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Mortality, symptoms and functional impairment in late-life depression", "authors": [{"first": "C", "middle": ["M"], "last": "Callahan", "suffix": ""}, {"first": "F", "middle": ["D"], "last": "Wolinsky", "suffix": ""}, {"first": "T", "middle": ["E"], "last": "Stump", "suffix": ""}, {"first": "N", "middle": ["A"], "last": "Nienaber", "suffix": ""}, {"first": "S", "middle": ["L"], "last": "Hui", "suffix": ""}, {"first": "W", "middle": ["M"], "last": "Tierney", "suffix": ""}], "year": 1998, "venue": "J Gen Intern Med", "link": "21414445"}, "BIBREF1": {"title": "Depressive disorders in primary care: prevalence, functional disability, and identification", "authors": [{"first": "J", "middle": ["W"], "last": "Williams", "suffix": ""}, {"first": "C", "middle": ["A"], "last": "Kerber", "suffix": ""}, {"first": "C", "middle": ["D"], "last": "Mulrow", "suffix": ""}, {"first": "A", "middle": [], "last": "Medina", "suffix": ""}, {"first": "C", "middle": [], "last": "Aguilar", "suffix": ""}], "year": 1995, "venue": "J Gen Intern Med", "link": "35615841"}, "BIBREF2": {"title": "Diagnosis and treatment of depression in late life", "authors": [], "year": 1992, "venue": "NIH Consensus Development Conference", "link": null}, "BIBREF3": {"title": "Antidepressant use in the elderly population in Canada: results from a national survey", "authors": [{"first": "S", "middle": ["C"], "last": "Newman", "suffix": ""}, {"first": "A", "middle": ["I"], "last": "Hassan", "suffix": ""}], "year": 1999, "venue": "J Gerontol A Biol Sci Med Sci", "link": "33291917"}, "BIBREF4": {"title": "Prevalence of depressive symptoms and depressive disorder in primary care patients over 65 years of age", "authors": [{"first": "H", "middle": [], "last": "Van Marwijk", "suffix": ""}, {"first": "H", "middle": ["L"], "last": "Hoeksuma", "suffix": ""}, {"first": "J", "middle": [], "last": "Hermans", "suffix": ""}, {"first": "A", "middle": ["A"], "last": "Kaptein", "suffix": ""}, {"first": "J", "middle": ["D"], "last": "Mulder", "suffix": ""}], "year": 1994, "venue": "Fam Pract", "link": null}, "BIBREF5": {"title": "Psychiatric disorders in older primary care patients", "authors": [{"first": "J", "middle": ["M"], "last": "Lyness", "suffix": ""}, {"first": "E", "middle": ["D"], "last": "Caine", "suffix": ""}, {"first": "D", "middle": ["A"], "last": "King", "suffix": ""}, {"first": "C", "middle": [], "last": "Cox", "suffix": ""}, {"first": "Z", "middle": [], "last": "Yoediono", "suffix": ""}], "year": 1999, "venue": "J Gen Intern Med", "link": "5658177"}, "BIBREF6": {"title": "Prognosis of depression in elderly community and primary care populations: a systematic review and meta-analysis", "authors": [{"first": "M", "middle": ["G"], "last": "Cole", "suffix": ""}, {"first": "F", "middle": [], "last": "Bellavance", "suffix": ""}, {"first": "A", "middle": [], "last": "Mansour", "suffix": ""}], "year": 1999, "venue": "Am J Psychiatry", "link": "24530494"}, "BIBREF7": {"title": "Long-term follow-up of depression among patients in the community and in family practice settings", "authors": [{"first": "E", "middle": ["M"], "last": "Van Weel-Baumgarten", "suffix": ""}, {"first": "H", "middle": ["J"], "last": "Schers", "suffix": ""}, {"first": "", "middle": [], "last": "Van Den", "suffix": ""}, {"first": "W", "middle": ["J"], "last": "Bosch", "suffix": ""}, {"first": "H", "middle": [], "last": "Van Den Hoogen", "suffix": ""}, {"first": "F", "middle": ["G"], "last": "Zitman", "suffix": ""}], "year": 2000, "venue": "J Fam Pract", "link": null}, "BIBREF8": {"title": "Late-life depression in primary care. How well are we doing?", "authors": [{"first": "D", "middle": ["A"], "last": "Banazak", "suffix": ""}], "year": 1996, "venue": "J Gen Intern Med", "link": null}, "BIBREF9": {"title": "How do general practitioners select antidepressants for depressed elderly people?", "authors": [{"first": "R", "middle": [], "last": "Butler", "suffix": ""}, {"first": "E", "middle": [], "last": "Collins", "suffix": ""}, {"first": "C", "middle": [], "last": "Katona", "suffix": ""}, {"first": "M", "middle": [], "last": "Orrell", "suffix": ""}], "year": 2000, "venue": "Int J Geriatr Psychiatry", "link": "40419287"}, "BIBREF10": {"title": "Depression of elderly outpatients: primary care physicians' attitudes and practice patterns", "authors": [{"first": "C", "middle": ["M"], "last": "Callahan", "suffix": ""}, {"first": "N", "middle": ["A"], "last": "Nienaber", "suffix": ""}, {"first": "H", "middle": ["C"], "last": "Hendrie", "suffix": ""}, {"first": "W", "middle": ["M"], "last": "Tierney", "suffix": ""}], "year": 1992, "venue": "J Gen Intern Med", "link": "20682787"}, "BIBREF11": {"title": "Improving treatment of late life depression in primary care; a randomized clinical trial", "authors": [{"first": "C", "middle": ["M"], "last": "Callahan", "suffix": ""}, {"first": "H", "middle": ["C"], "last": "Hendrie", "suffix": ""}, {"first": "R", "middle": ["S"], "last": "Dittus", "suffix": ""}, {"first": "D", "middle": ["C"], "last": "Brater", "suffix": ""}, {"first": "S", "middle": ["L"], "last": "Hui", "suffix": ""}, {"first": "W", "middle": ["M"], "last": "Tierney", "suffix": ""}], "year": 1994, "venue": "J Am Geriatr Soc", "link": "41968533"}, "BIBREF12": {"title": "Primary care physicians' medical decision making for late life depression", "authors": [{"first": "C", "middle": ["M"], "last": "Callahan", "suffix": ""}, {"first": "R", "middle": ["S"], "last": "Dittus", "suffix": ""}, {"first": "W", "middle": ["M"], "last": "Tierney", "suffix": ""}], "year": 1996, "venue": "J Gen Intern Med", "link": "19389909"}, "BIBREF13": {"title": "Quality improvement research on late life depression in primary care", "authors": [{"first": "C", "middle": ["M"], "last": "Callahan", "suffix": ""}], "year": 2001, "venue": "Med Care", "link": "12793337"}, "BIBREF14": {"title": "Management of depression in the elderly by general practitioners. II. Attitudes to aging and factors affecting practice", "authors": [{"first": "E", "middle": [], "last": "Collins", "suffix": ""}, {"first": "C", "middle": [], "last": "Katona", "suffix": ""}, {"first": "M", "middle": [], "last": "Orrell", "suffix": ""}], "year": 1995, "venue": "Fam Pract", "link": "9469662"}, "BIBREF15": {"title": "The treatment of depression: prescribing patterns of antidepressants in primary care in the UK", "authors": [{"first": "J", "middle": ["M"], "last": "Donoghue", "suffix": ""}, {"first": "A", "middle": [], "last": "Tylee", "suffix": ""}], "year": 1996, "venue": "Br J Psychiatry", "link": "21608158"}, "BIBREF16": {"title": "Cross-sectional database analysis of antidepressant prescribing in general practice in the United Kingdom", "authors": [{"first": "J", "middle": ["M"], "last": "Donoghue", "suffix": ""}, {"first": "A", "middle": [], "last": "Tylee", "suffix": ""}, {"first": "H", "middle": [], "last": "Wildgust", "suffix": ""}], "year": 1996, "venue": "BMJ", "link": "35806999"}, "BIBREF17": {"title": "Attitudes, knowledge, and behaviour of family physicians regarding depression in late life", "authors": [{"first": "J", "middle": ["J"], "last": "Gallo", "suffix": ""}, {"first": "S", "middle": ["D"], "last": "Ryan", "suffix": ""}, {"first": "D", "middle": ["E"], "last": "Ford", "suffix": ""}], "year": 1999, "venue": "Arch Fam Med", "link": "37529101"}, "BIBREF18": {"title": "Assessment and treatment of geriatric depression in primary care settings", "authors": [{"first": "M", "middle": [], "last": "Glasser", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Gravdal", "suffix": ""}], "year": 1997, "venue": "Arch Fam Med", "link": "35113281"}, "BIBREF19": {"title": "Inadequate dosaging in general practice of tricyclic vs. other antidepressants for depression", "authors": [{"first": "E", "middle": [], "last": "Isometsa", "suffix": ""}, {"first": "I", "middle": [], "last": "Seppala", "suffix": ""}, {"first": "M", "middle": [], "last": "Henriksson", "suffix": ""}, {"first": "P", "middle": [], "last": "Kekki", "suffix": ""}, {"first": "J", "middle": [], "last": "Lonnqvist", "suffix": ""}], "year": 1998, "venue": "Acta Psychiatr Scand", "link": "20655409"}, "BIBREF20": {"title": "Managing depression and suicidal geriatric patients: differences among primary care physicians", "authors": [{"first": "M", "middle": ["S"], "last": "Kaplan", "suffix": ""}, {"first": "M", "middle": ["E"], "last": "Adamek", "suffix": ""}, {"first": "A", "middle": [], "last": "Calderon", "suffix": ""}], "year": 1999, "venue": "Gerontologist", "link": null}, "BIBREF21": {"title": "The treatment of depression: prescribing practices of primary care physicians and psychiatrists", "authors": [{"first": "M", "middle": [], "last": "Olfson", "suffix": ""}, {"first": "G", "middle": ["L"], "last": "Klerman", "suffix": ""}], "year": 1992, "venue": "J Fam Pract", "link": "40519338"}, "BIBREF22": {"title": "The management of depression in the elderly by general practitioners: I. Use of antidepressants", "authors": [{"first": "M", "middle": [], "last": "Orrell", "suffix": ""}, {"first": "E", "middle": [], "last": "Collins", "suffix": ""}, {"first": "S", "middle": [], "last": "Shergill", "suffix": ""}, {"first": "C", "middle": [], "last": "Katona", "suffix": ""}], "year": 1995, "venue": "Fam Pract", "link": "40541244"}, "BIBREF23": {"title": "Depression in medical outpatients: under-recognition and misdiagnosis", "authors": [{"first": "E", "middle": [], "last": "P\u00e9rez-Stable", "suffix": ""}, {"first": "J", "middle": [], "last": "Miranda", "suffix": ""}, {"first": "R", "middle": [], "last": "Mu\u00f1oz", "suffix": ""}, {"first": "Y", "middle": [], "last": "Ying", "suffix": ""}], "year": 1990, "venue": "Arch Intern Med", "link": "9822553"}, "BIBREF24": {"title": "An examination of the attitudes and practice of general practitioners in the diagnosis and treatment of depression in older people", "authors": [{"first": "I", "middle": [], "last": "Rothera", "suffix": ""}, {"first": "R", "middle": [], "last": "Jones", "suffix": ""}, {"first": "C", "middle": [], "last": "Gordon", "suffix": ""}], "year": 2002, "venue": "Int J Geriatr Psychiatry", "link": "13289947"}, "BIBREF25": {"title": "A survey of general practitioners' confidence in their management of elderly patients", "authors": [{"first": "S", "middle": [], "last": "Shah", "suffix": ""}, {"first": "M", "middle": [], "last": "Harris", "suffix": ""}], "year": 1997, "venue": "Aust Fam Physician", "link": "26096000"}, "BIBREF26": {"title": "Affective disorders among elderly general practice patients. A two-phase survey in", "authors": [{"first": "C", "middle": [], "last": "Turrina", "suffix": ""}, {"first": "R", "middle": [], "last": "Caruso", "suffix": ""}, {"first": "R", "middle": [], "last": "Este", "suffix": ""}, {"first": "F", "middle": [], "last": "Lucchi", "suffix": ""}, {"first": "G", "middle": [], "last": "Fazzari", "suffix": ""}, {"first": "M", "middle": ["E"], "last": "Dewey", "suffix": ""}], "year": 1994, "venue": "Br J Psychiatry", "link": null}, "BIBREF27": {"title": "Patterns of care for depressed older adults in a large staff model HMO", "authors": [{"first": "J", "middle": [], "last": "Un\u00fctzer", "suffix": ""}, {"first": "W", "middle": [], "last": "Katon", "suffix": ""}, {"first": "J", "middle": [], "last": "Russo", "suffix": ""}, {"first": "G", "middle": [], "last": "Simon", "suffix": ""}, {"first": "T", "middle": [], "last": "Bush", "suffix": ""}, {"first": "E", "middle": [], "last": "Walker", "suffix": ""}], "year": 1999, "venue": "Am J Geriatr Psychiatry", "link": "2982396"}, "BIBREF28": {"title": "Treating depressed older adults in primary care: narrowing the gap between efficacy and effectiveness", "authors": [{"first": "J", "middle": [], "last": "Un\u00fctzer", "suffix": ""}, {"first": "W", "middle": [], "last": "Katon", "suffix": ""}, {"first": "M", "middle": [], "last": "Sullivan", "suffix": ""}, {"first": "J", "middle": [], "last": "Miranda", "suffix": ""}], "year": 1999, "venue": "Milbank Q", "link": "33403934"}, "BIBREF29": {"title": "Care for depression in HMO patients aged 65 and older", "authors": [{"first": "J", "middle": [], "last": "Un\u00fctzer", "suffix": ""}, {"first": "G", "middle": [], "last": "Simon", "suffix": ""}, {"first": "T", "middle": ["R"], "last": "Belin", "suffix": ""}, {"first": "M", "middle": [], "last": "Datt", "suffix": ""}, {"first": "W", "middle": [], "last": "Katon", "suffix": ""}, {"first": "D", "middle": [], "last": "Patrick", "suffix": ""}], "year": 2000, "venue": "J Am Geriatr Soc", "link": "36681605"}, "BIBREF30": {"title": "Two-year effects of quality improvement programs on medication management for depression", "authors": [{"first": "J", "middle": [], "last": "Un\u00fctzer", "suffix": ""}, {"first": "L", "middle": [], "last": "Rubenstein", "suffix": ""}, {"first": "W", "middle": ["J"], "last": "Katon", "suffix": ""}, {"first": "L", "middle": [], "last": "Tang", "suffix": ""}, {"first": "N", "middle": [], "last": "Duan", "suffix": ""}, {"first": "I", "middle": ["T"], "last": "Lagomasino", "suffix": ""}], "year": 2001, "venue": "Arch Gen Psychiatry", "link": "7492269"}, "BIBREF31": {"title": "Depression treatment in a sample of 1,801 depressed older adults in primary care", "authors": [{"first": "J", "middle": [], "last": "Un\u00fctzer", "suffix": ""}, {"first": "W", "middle": [], "last": "Katon", "suffix": ""}, {"first": "C", "middle": ["M"], "last": "Callahan", "suffix": ""}, {"first": "J", "middle": ["W"], "last": "Williams", "suffix": ""}, {"first": "E", "middle": [], "last": "Hunkeler", "suffix": ""}, {"first": "L", "middle": [], "last": "Harpole", "suffix": ""}], "year": 2003, "venue": "J Am Geriatr Soc", "link": "26053509"}, "BIBREF32": {"title": "Management of depression in elderly general practice patients", "authors": [{"first": "H", "middle": [], "last": "Van Marwijk", "suffix": ""}, {"first": "G", "middle": ["H"], "last": "De Bock", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "De Jong", "suffix": ""}, {"first": "A", "middle": ["A"], "last": "Kaptein", "suffix": ""}, {"first": "J", "middle": ["D"], "last": "Mulder", "suffix": ""}], "year": 1994, "venue": "Scand J Prim Health Care", "link": "37144114"}, "BIBREF33": {"title": "Treatment of depression related to recurrence: 10-year follow-up in general practice", "authors": [{"first": "", "middle": [], "last": "Van Weel-Baumgarten", "suffix": ""}, {"first": "", "middle": [], "last": "Van Den", "suffix": ""}, {"first": "W", "middle": ["J"], "last": "Bosch", "suffix": ""}, {"first": "Y", "middle": ["A"], "last": "Hekster", "suffix": ""}, {"first": "H", "middle": ["J"], "last": "Van Den Hoogen", "suffix": ""}, {"first": "F", "middle": ["G"], "last": "Zitman", "suffix": ""}], "year": 2000, "venue": "J Clin Pharm Ther", "link": "42058583"}, "BIBREF34": {"title": "The quality of care for depressive and anxiety disorders in the United States", "authors": [{"first": "A", "middle": ["S"], "last": "Young", "suffix": ""}, {"first": "R", "middle": [], "last": "Klap", "suffix": ""}, {"first": "C", "middle": ["D"], "last": "Sherbourne", "suffix": ""}, {"first": "K", "middle": ["B"], "last": "Wells", "suffix": ""}], "year": 2001, "venue": "Arch Gen Psychiatry", "link": "2200193"}, "BIBREF35": {"title": "Canadian medical directory. Don Mills, Ont: Canadian Information Products Group", "authors": [], "year": 2000, "venue": "", "link": null}, "BIBREF36": {"title": "Clinical guidelines for the treatment of depressive disorders. VI. Special populations", "authors": [{"first": "L", "middle": [], "last": "Thorpe", "suffix": ""}, {"first": "D", "middle": ["K"], "last": "Whitney", "suffix": ""}, {"first": "S", "middle": ["P"], "last": "Kutcher", "suffix": ""}, {"first": "S", "middle": ["A"], "last": "Kennedy", "suffix": ""}], "year": 2001, "venue": "Can J Psychiatry", "link": "21587265"}, "BIBREF37": {"title": "Expert consensus guideline series: pharmacotherapy of depressive disorders in older patients", "authors": [{"first": "G", "middle": [], "last": "Alexopoulos", "suffix": ""}, {"first": "I", "middle": [], "last": "Katz", "suffix": ""}, {"first": "C", "middle": [], "last": "Reynolds", "suffix": ""}, {"first": "D", "middle": [], "last": "Carpenter", "suffix": ""}, {"first": "J", "middle": [], "last": "Docherty", "suffix": ""}], "year": 2001, "venue": "Postgrad Med", "link": null}, "BIBREF38": {"title": "Canadian Pharmacists Association. Compendium of pharmaceuticals and specialties", "authors": [], "year": 2001, "venue": "", "link": null}, "BIBREF39": {"title": "Pharmacologic treatment of depression in late life", "authors": [{"first": "A", "middle": ["J"], "last": "Flint", "suffix": ""}], "year": 1997, "venue": "CMAJ", "link": null}, "BIBREF40": {"title": "Helping your elderly patient cope with depression", "authors": [{"first": "A", "middle": [], "last": "Mithani", "suffix": ""}, {"first": "R", "middle": ["J"], "last": "Ancill", "suffix": ""}], "year": 1996, "venue": "Med North Am", "link": null}, "BIBREF41": {"title": "sertraline and fluvoxamine: new selective serotonin reuptake inhibitors", "authors": [{"first": "S", "middle": ["R"], "last": "Grimsley", "suffix": ""}, {"first": "Jann", "middle": ["Mw"], "last": "Paroxetine", "suffix": ""}], "year": 1992, "venue": "Clin Pharm", "link": null}, "BIBREF42": {"title": "Pharmacotherapy of affective disorders in old age", "authors": [{"first": "M-F", "middle": [], "last": "Tourigny-Rivard", "suffix": ""}], "year": 1997, "venue": "Can J Psychiatry", "link": null}, "BIBREF43": {"title": "Clinical overview of serotonin reuptake inhibitors", "authors": [{"first": "K", "middle": [], "last": "Rickels", "suffix": ""}, {"first": "E", "middle": [], "last": "Schweizer", "suffix": ""}], "year": 1990, "venue": "J Clin Psychiatry", "link": "25952125"}, "BIBREF44": {"title": "Diagnosis and treatment of depression in late life. Consensus statement update", "authors": [{"first": "B", "middle": ["D"], "last": "Lebowitz", "suffix": ""}, {"first": "J", "middle": ["L"], "last": "Pearson", "suffix": ""}, {"first": "L", "middle": ["S"], "last": "Schneider", "suffix": ""}, {"first": "C", "middle": ["F"], "last": "Reynolds", "suffix": ""}, {"first": "", "middle": [], "last": "Iii", "suffix": ""}, {"first": "G", "middle": ["S"], "last": "Alexopoulos", "suffix": ""}, {"first": "M", "middle": ["L"], "last": "Bruce", "suffix": ""}], "year": 1997, "venue": "JAMA", "link": "29142479"}, "BIBREF45": {"title": "The effect of treatment on the two-year course of late-life depression", "authors": [{"first": "A", "middle": ["J"], "last": "Flint", "suffix": ""}, {"first": "S", "middle": ["L"], "last": "Rifat", "suffix": ""}], "year": 1997, "venue": "Br J Psychiatry", "link": "19212456"}, "BIBREF46": {"title": "How long should the elderly take antidepressants? A double-blind placebo-controlled study of continuation/prophylaxis therapy with dothiepin", "authors": [], "year": 1993, "venue": "Br J Psychiatry", "link": null}, "BIBREF47": {"title": "The optimum duration of antidepressant treatment in the elderly", "authors": [{"first": "A", "middle": ["J"], "last": "Flint", "suffix": ""}], "year": 1992, "venue": "Int J Geriatr Psychiatry", "link": "145435393"}, "BIBREF48": {"title": "Relapse prevention with antidepressant drug treatment in depressive disorders: a systematic review", "authors": [{"first": "J", "middle": ["R"], "last": "Geddes", "suffix": ""}, {"first": "S", "middle": ["M"], "last": "Carney", "suffix": ""}, {"first": "C", "middle": [], "last": "Davies", "suffix": ""}, {"first": "T", "middle": ["A"], "last": "Furukawa", "suffix": ""}, {"first": "D", "middle": ["J"], "last": "Kupfer", "suffix": ""}, {"first": "E", "middle": [], "last": "Frank", "suffix": ""}], "year": 2003, "venue": "Lancet", "link": "20198748"}}, "ref_entries": {}}
{"paper_id": "42951531", "_pdf_hash": "f246896226aba71c586595d8237c06aab76e96bc", "abstract": [], "body_text": [{"section": "", "text": "on results of serial measurements of copeptin level it has been suggested that the increased copept in concentration or trend to elevation of one area independent risk factor for long-term HF-related clinical outcomes and sudden death in patients with established CV disease [11] [12] [13] .Being able to better predict all-cause mortality rate and HF-related risks including death and admission to the hospital copeptin might be considered as much more accurate biomarker than natriuretic peptides for optimize medical care in HF patients [14, 15] . Unfortunately, there are large body of evidence regarding that the level of copeptin might relate closely to some metabolic abnormalities including hyperglycemia that sufficiently limits the predictive power of the biomarker in serial measurements especially in patients with diabetes and obesity [14, 16] . However, the improvement of diagnostic reliability of copeptin may achieve by means use of combined biomarker strategy, in particular it might be based on copeptin and natriuretic peptides (N-terminal pro-brain natriuretic peptide, midregional pro-atrial natriuretic peptide) [17, 18] . Finally, circulating level of copeptinare now recognized a promising biomarker with better discriminative value for both all-cause mortality and HF-related outcomes general population and individuals with established CV disease.", "cite_spans": [{"start": 275, "end": 279, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 280, "end": 284, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 285, "end": 289, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 540, "end": 544, "text": "[14,", "ref_id": "BIBREF13"}, {"start": 848, "end": 852, "text": "[14,", "ref_id": "BIBREF13"}, {"start": 853, "end": 856, "text": "16]", "ref_id": "BIBREF15"}, {"start": 1135, "end": 1139, "text": "[17,", "ref_id": "BIBREF16"}, {"start": 1140, "end": 1143, "text": "18]", "ref_id": "BIBREF17"}], "ref_spans": []}, {"section": "", "text": "The main biological role of heart type of FABP (hFABP) is to facilitate the long-chain fatty acids reuptake, attenuate calcium transport in cardiomyocytes and regulate inflammatory response in reply to some lipid signals [19] . hFABP is predominantly expressed in cardiomyocytes and is powerful biomarker of myocardial injury. Recent studies have shown that the hFABP has better predicted CV outcomes to other biomarkers of cardiac damage, i.e. myoglobin and high-sensitive troponins [3, 14, 20] , whereas elevated intestinal FABP would identify patients with advanced HF who had severe fluid retention and intestinal congestion [21] . Overall, the H-FABP may better provide prognostic information on survival and more precise reflecta risk of major CV events during hospitalization period and short-time after discharge than natriuretic peptides, cardiac troponins and galectin-3. However, the role of several types of FABP in HF is not fully clear. Large clinical studies are required to more accurately explain the predictive value of these biomarkers.", "cite_spans": [{"start": 221, "end": 225, "text": "[19]", "ref_id": "BIBREF18"}, {"start": 484, "end": 487, "text": "[3,", "ref_id": "BIBREF2"}, {"start": 488, "end": 491, "text": "14,", "ref_id": "BIBREF13"}, {"start": 492, "end": 495, "text": "20]", "ref_id": "BIBREF19"}, {"start": 629, "end": 633, "text": "[21]", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "", "text": "Growth differentiation factor (GDF)-15 belongs to the super family of transforming growth factor-\u03b2 [22] . GDF-15 is widely expressed on the surfaces of various cells. In HF GDF-15 is secreted by injured cardiomyocytesin response to ischemia, reperfusion, inflammatory cytokine stimulation and exposure to biomechanical stress [14] . Elevated level of circulating GDF-15 was found in HF individuals irrespectively etiology of cardiac dysfunction [23] . There is strong evidence regarding being tight interrelationship between circulating level of GDF-15 and HF signs and symptoms, reduced left ventricular ejection fraction [24] . Although serial biomarker evaluation has not showed superiority of incremental predictive ability in GDF-15 versus natriuretic peptides in acute HF [25] , in chronic HF multiple marker strategy based on GDF-15, galectin-3 and natriuretic peptides might exhibit several advantages before conventional approach in ability to predict all-cause mortality, CV mortality and HF-related outcomes in outpatients with HF [26, 27] . Finally, there are several controversies regarding importance of predictive value for survival and incremental prognostication in diagnosis of HF. There is need in larger clinical studies with higher statistical power and head-to-head comparison of biomarkers to clear their role in diagnosis and guided therapy of HF.", "cite_spans": [{"start": 99, "end": 103, "text": "[22]", "ref_id": "BIBREF21"}, {"start": 326, "end": 330, "text": "[14]", "ref_id": "BIBREF13"}, {"start": 445, "end": 449, "text": "[23]", "ref_id": "BIBREF22"}, {"start": 623, "end": 627, "text": "[24]", "ref_id": "BIBREF23"}, {"start": 778, "end": 782, "text": "[25]", "ref_id": "BIBREF24"}, {"start": 1042, "end": 1046, "text": "[26,", "ref_id": "BIBREF25"}, {"start": 1047, "end": 1050, "text": "27]", "ref_id": "BIBREF26"}], "ref_spans": []}, {"section": "Conclusions:", "text": "Although recent clinical trials have been exhibited much more information regarding biomarker use in prognostication of HF, there is considerable limitation in head-to-head comparison of several biomarkers and biomarker-based strategy to treat of HF. All these are a cause of some speculations around advantages and shortcomings of biomarker-based management of HF including new biological indicators, such as procalcitonin, copeptin, hFABP and GDF-15. Novel biomarkers are needed to be investigated in details, while there is suggestion that multiple biomarker models would be better in prediction HF evolution and outcomes than even single brand new biomarker.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Authors/Task Force Members. 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) developed with the special contribution of the Heart Failure Association (HFA) of the ESC", "authors": [{"first": "P", "middle": [], "last": "Ponikowski", "suffix": ""}, {"first": "A", "middle": ["A"], "last": "Voors", "suffix": ""}, {"first": "S", "middle": ["D"], "last": "Anker", "suffix": ""}, {"first": "H", "middle": [], "last": "Bueno", "suffix": ""}, {"first": "J", "middle": ["G"], "last": "Cleland", "suffix": ""}, {"first": "A", "middle": ["J"], "last": "Coats", "suffix": ""}], "year": 2016, "venue": "Eur Heart J", "link": null}, "BIBREF1": {"title": "Biomarkers for Heart Failure: An Update for Practitioners of Internal Medicine", "authors": [{"first": "N", "middle": [], "last": "Wettersten", "suffix": ""}, {"first": "A", "middle": ["S"], "last": "Maisel", "suffix": ""}], "year": 2016, "venue": "Am J Med", "link": "5754976"}, "BIBREF2": {"title": "Prognostication in different heart failure phenotypes: the role of circulating biomarkers", "authors": [{"first": "A", "middle": ["E"], "last": "Berezin", "suffix": ""}], "year": 2016, "venue": "Journal of Circulating Biomarkers", "link": "29088529"}, "BIBREF3": {"title": "Which biomarkers do clinicians need for diagnosis and management of heart failure with reduced ejection fraction?", "authors": [{"first": "A", "middle": ["C"], "last": "Pouleur", "suffix": ""}], "year": 2015, "venue": "ClinChim Acta", "link": "25943004"}, "BIBREF4": {"title": "Clinical Usefulness of Procalcitonin and C-Reactive Protein as Outcome Predictors in Critically Ill Patients with Severe Sepsis and Septic Shock", "authors": [{"first": "J", "middle": ["A"], "last": "Ryu", "suffix": ""}, {"first": "J", "middle": ["H"], "last": "Yang", "suffix": ""}, {"first": "D", "middle": [], "last": "Lee", "suffix": ""}, {"first": "C", "middle": ["M"], "last": "Park", "suffix": ""}, {"first": "G", "middle": ["Y"], "last": "Suh", "suffix": ""}, {"first": "K", "middle": [], "last": "Jeon", "suffix": ""}], "year": "", "venue": "PLoS One. 2015", "link": "215073736"}, "BIBREF5": {"title": "Procalcitonin as a Biomarker for Predicting Amputation Level in Lower Extremity Infections", "authors": [{"first": "M", "middle": ["M"], "last": "Reiner", "suffix": ""}, {"first": "W", "middle": ["E"], "last": "Khoury", "suffix": ""}, {"first": "M", "middle": ["B"], "last": "Canales", "suffix": ""}, {"first": "R", "middle": ["A"], "last": "Chmielewski", "suffix": ""}, {"first": "K", "middle": [], "last": "Patel", "suffix": ""}, {"first": "M", "middle": ["C"], "last": "Razzante", "suffix": ""}], "year": 2017, "venue": "J Foot Ankle Surg", "link": "3822581"}, "BIBREF6": {"title": "Head-to-head comparison of procalcitonin and presepsin for the diagnosis of sepsis in critically ill adult patients: a protocol for a systematic review and meta-analysis", "authors": [{"first": "K", "middle": [], "last": "Hayashida", "suffix": ""}, {"first": "Y", "middle": [], "last": "Kondo", "suffix": ""}, {"first": "Y", "middle": [], "last": "Hara", "suffix": ""}, {"first": "M", "middle": [], "last": "Aihara", "suffix": ""}, {"first": "K", "middle": [], "last": "Yamakawa", "suffix": ""}], "year": 2017, "venue": "BMJ Open", "link": "298594"}, "BIBREF7": {"title": "Serum procalcitonin and C-reactive protein levels as markers of bacterial infection: a systematic review and meta-analysis", "authors": [{"first": "L", "middle": [], "last": "Simon", "suffix": ""}, {"first": "F", "middle": [], "last": "Gauvin", "suffix": ""}, {"first": "D", "middle": ["K"], "last": "Amre", "suffix": ""}, {"first": "P", "middle": [], "last": "Saint-Louis", "suffix": ""}, {"first": "J", "middle": [], "last": "Lacroix", "suffix": ""}], "year": 2004, "venue": "Clin Infect Dis", "link": "1614119"}, "BIBREF8": {"title": "Assay for the measurement of copeptin, a stable peptide derived from the precursor of vasopressin", "authors": [{"first": "N", "middle": ["G"], "last": "Morgenthaler", "suffix": ""}], "year": 2006, "venue": "Clin Chem", "link": "14448176"}, "BIBREF9": {"title": "The cardiovascular markers copeptin and high-sensitive C-reactive protein decrease following specific therapy for primary aldosteronism", "authors": [{"first": "H", "middle": [], "last": "Remde", "suffix": ""}, {"first": "A", "middle": [], "last": "Dietz", "suffix": ""}, {"first": "R", "middle": [], "last": "Emeny", "suffix": ""}, {"first": "A", "middle": [], "last": "Riester", "suffix": ""}, {"first": "A", "middle": [], "last": "Peters", "suffix": ""}, {"first": "T", "middle": [], "last": "De Las Heras Gala", "suffix": ""}], "year": 2016, "venue": "J Hypertens", "link": "3275471"}, "BIBREF10": {"title": "Advances in heart failure: a review of biomarkers, emerging pharmacological therapies, durable mechanical support and telemonitoring. ClinSci (Lond)", "authors": [{"first": "Y", "middle": [], "last": "Moayedi", "suffix": ""}, {"first": "H", "middle": ["J"], "last": "Ross", "suffix": ""}], "year": 2017, "venue": "", "link": "23448444"}, "BIBREF11": {"title": "Copeptin Associates with Cause-Specific Mortality in Patients with Impaired Renal Function: Results from the LURIC and the 4D Study", "authors": [{"first": "V", "middle": [], "last": "Krane", "suffix": ""}, {"first": "B", "middle": [], "last": "Genser", "suffix": ""}, {"first": "M", "middle": ["E"], "last": "Kleber", "suffix": ""}, {"first": "C", "middle": [], "last": "Drechsler", "suffix": ""}, {"first": "W", "middle": [], "last": "M\u00e4rz", "suffix": ""}, {"first": "G", "middle": [], "last": "Delgado", "suffix": ""}], "year": 2017, "venue": "Clin Chem", "link": "9664129"}, "BIBREF12": {"title": "Predictive value of plasma copeptin level for the risk and mortality of heart failure: a meta-analysis", "authors": [{"first": "J", "middle": ["J"], "last": "Yan", "suffix": ""}, {"first": "Y", "middle": [], "last": "Lu", "suffix": ""}, {"first": "Z", "middle": ["P"], "last": "Kuai", "suffix": ""}, {"first": "Y", "middle": ["H"], "last": "Yong", "suffix": ""}], "year": 2017, "venue": "J Cell Mol Med", "link": "1989338"}, "BIBREF13": {"title": "Biological markers of cardiovascular diseases. Part 4. Diagnostic and prognostic value of biological markers at risk stratification among patients with heart failure", "authors": [{"first": "A", "middle": ["E"], "last": "Berezin", "suffix": ""}], "year": 2015, "venue": "", "link": null}, "BIBREF15": {"title": "Copeptin in patients with acute myocardial infarction and newly detected glucose abnormalities -A marker of increased stress susceptibility? A report from the Glucose in Acute Myocardial Infarction cohort", "authors": [{"first": "M", "middle": ["I"], "last": "Smaradottir", "suffix": ""}, {"first": "V", "middle": [], "last": "Ritsinger", "suffix": ""}, {"first": "V", "middle": [], "last": "Gyberg", "suffix": ""}, {"first": "A", "middle": [], "last": "Norhammar", "suffix": ""}, {"first": "P", "middle": [], "last": "N\u00e4sman", "suffix": ""}, {"first": "L", "middle": ["G"], "last": "Mellbin", "suffix": ""}], "year": 2017, "venue": "DiabVasc Dis Res", "link": "24287171"}, "BIBREF16": {"title": "Higher copeptin levels are associated with worse outcome in patients with hypertrophic cardiomyopathy", "authors": [{"first": "I", "middle": [], "last": "Sahin", "suffix": ""}, {"first": "B", "middle": [], "last": "Gungor", "suffix": ""}, {"first": "B", "middle": [], "last": "Ozkaynak", "suffix": ""}, {"first": "F", "middle": [], "last": "Uzun", "suffix": ""}, {"first": "S", "middle": ["H"], "last": "K\u00fc\u00e7\u00fck", "suffix": ""}, {"first": "I", "middle": ["I"], "last": "Avci", "suffix": ""}], "year": 2017, "venue": "ClinCardiol", "link": "5285551"}, "BIBREF17": {"title": "Predictive capacity of a multimarker strategy to determine short-term mortality in patients attending a hospital emergency Department for acute heart failure. BIO-EAHFE study", "authors": [{"first": "P", "middle": [], "last": "Herrero-Puente", "suffix": ""}, {"first": "B", "middle": [], "last": "Prieto-Garc\u00eda", "suffix": ""}, {"first": "M", "middle": [], "last": "Garc\u00eda-Garc\u00eda", "suffix": ""}, {"first": "J", "middle": [], "last": "Jacob", "suffix": ""}, {"first": "F", "middle": ["J"], "last": "Mart\u00edn-S\u00e1nchez", "suffix": ""}, {"first": "D", "middle": [], "last": "Pascual-Figal", "suffix": ""}], "year": 2017, "venue": "ClinChimActa", "link": "38619062"}, "BIBREF18": {"title": "The multigene family of fatty acidbinding proteins (FABPs): function, structure, and polymorphism", "authors": [{"first": "A", "middle": [], "last": "Chmurzynska", "suffix": ""}], "year": 2006, "venue": "J Appl Genet", "link": "2622822"}, "BIBREF19": {"title": "Heart-type Fatty Acid Binding Protein in the Assessment of Acute Pulmonary Embolism", "authors": [{"first": "H", "middle": ["Y"], "last": "Qian", "suffix": ""}, {"first": "J", "middle": [], "last": "Huang", "suffix": ""}, {"first": "Y", "middle": ["J"], "last": "Yang", "suffix": ""}, {"first": "Y", "middle": ["M"], "last": "Yang", "suffix": ""}, {"first": "Z", "middle": ["Z"], "last": "Li", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Zhang", "suffix": ""}], "year": 2016, "venue": "Am J Med Sci", "link": "10263069"}, "BIBREF20": {"title": "Circulating intestinal fatty acid-binding protein (I-FABP) levels in acute decompensated heart failure", "authors": [{"first": "T", "middle": [], "last": "Kitai", "suffix": ""}, {"first": "Y", "middle": ["H"], "last": "Kim", "suffix": ""}, {"first": "K", "middle": [], "last": "Kiefer", "suffix": ""}, {"first": "R", "middle": [], "last": "Morales", "suffix": ""}, {"first": "A", "middle": ["G"], "last": "Borowski", "suffix": ""}, {"first": "J", "middle": ["L"], "last": "Grodin", "suffix": ""}], "year": 2017, "venue": "ClinBiochem", "link": "25543028"}, "BIBREF21": {"title": "Growth Differentiation Factor-15: a New Biomarker in Cardiovascular Disease", "authors": [{"first": "T", "middle": [], "last": "Kempf", "suffix": ""}, {"first": "K", "middle": ["C"], "last": "Wollert", "suffix": ""}], "year": 2009, "venue": "Herz", "link": null}, "BIBREF22": {"title": "Growth differentiation factor 15 in heart failure with preserved vs. reduced ejection fraction", "authors": [{"first": "M", "middle": ["M"], "last": "Chan", "suffix": ""}, {"first": "R", "middle": [], "last": "Santhanakrishnan", "suffix": ""}, {"first": "J", "middle": ["P"], "last": "Chong", "suffix": ""}, {"first": "Z", "middle": [], "last": "Chen", "suffix": ""}, {"first": "B", "middle": ["C"], "last": "Tai", "suffix": ""}, {"first": "O", "middle": ["W"], "last": "Liew", "suffix": ""}], "year": 2016, "venue": "Eur J Heart Fail", "link": "9948829"}, "BIBREF23": {"title": "Inflammatory Biomarkers Predict Heart Failure Severity and Prognosis in Patients With Heart Failure With Preserved Ejection Fraction: A Holistic Proteomic Approach", "authors": [{"first": "C", "middle": [], "last": "Hage", "suffix": ""}, {"first": "E", "middle": [], "last": "Micha\u00eblsson", "suffix": ""}, {"first": "C", "middle": [], "last": "Linde", "suffix": ""}, {"first": "Donal", "middle": ["E"], "last": "Daubert", "suffix": ""}, {"first": "J", "middle": ["C"], "last": "Gan", "suffix": ""}, {"first": "L", "middle": ["M"], "last": "", "suffix": ""}], "year": 2017, "venue": "CircCardiovasc Genet", "link": "7952647"}, "BIBREF24": {"title": "A multimarker multi-time point-based risk stratification strategy in acute heart failure: results from the RELAX-AHF trial", "authors": [{"first": "B", "middle": ["G"], "last": "Demissei", "suffix": ""}, {"first": "G", "middle": [], "last": "Cotter", "suffix": ""}, {"first": "M", "middle": ["F"], "last": "Prescott", "suffix": ""}, {"first": "G", "middle": ["M"], "last": "Felker", "suffix": ""}, {"first": "G", "middle": [], "last": "Filippatos", "suffix": ""}, {"first": "B", "middle": ["H"], "last": "Greenberg", "suffix": ""}], "year": 2017, "venue": "Eur J Heart Fail", "link": "205783200"}, "BIBREF25": {"title": "The utility of biomarker risk prediction score in patients with chronic heart failure", "authors": [{"first": "A", "middle": ["E"], "last": "Berezin", "suffix": ""}, {"first": "A", "middle": ["A"], "last": "Kremzer", "suffix": ""}, {"first": "Y", "middle": ["V"], "last": "Martovitskaya", "suffix": ""}, {"first": "T", "middle": ["A"], "last": "Samura", "suffix": ""}, {"first": "T", "middle": ["A"], "last": "Berezina", "suffix": ""}, {"first": "A", "middle": [], "last": "Zulli", "suffix": ""}], "year": 2015, "venue": "Int J ClinExp Med", "link": "214981041"}, "BIBREF26": {"title": "The risk stratification in heart failure patients: The controversial role of highsensitive ST2", "authors": [{"first": "A", "middle": ["E"], "last": "Berezin", "suffix": ""}], "year": 2015, "venue": "J IntegrCardiol", "link": "77757881"}, "BIBREF27": {"title": "Are Novel Cardiac Biomarkers Required in Prediction of Heart Failure Development and Outcomes?", "authors": [{"first": "Alexander", "middle": ["E"], "last": "Berezin", "suffix": ""}], "year": 2017, "venue": "ARC Journal of Cardiology", "link": "42951531"}, "BIBREF28": {"title": "This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium", "authors": [{"first": "Alexander", "middle": ["E"], "last": "Berezin", "suffix": ""}], "year": 2017, "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "42951639", "_pdf_hash": "70c230750d9fb1b8619ad1b105476ff2e223c95a", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Generic, configurable, cooperation protocols for multi-agent systems", "authors": [{"first": "B", "middle": [], "last": "Burmeister", "suffix": ""}, {"first": "A", "middle": [], "last": "Haddadi", "suffix": ""}, {"first": "K", "middle": [], "last": "Sundermeyer", "suffix": ""}], "year": 1995, "venue": "From Reaction to Cognition", "link": "5884547"}, "BIBREF1": {"title": "Strategies of cooperation in distributed problem solving", "authors": [{"first": "S", "middle": [], "last": "Cammarata", "suffix": ""}, {"first": "D", "middle": ["M"], "last": "Arthur", "suffix": ""}, {"first": "R", "middle": [], "last": "Steeb", "suffix": ""}], "year": 1988, "venue": "Readings in Distributed Artificial Intelligence", "link": "5700373"}, "BIBREF2": {"title": "Collective Robotics Workshop 98, number n \u2022 1456 in LNAI", "authors": [{"first": "A", "middle": [], "last": "Drogoul", "suffix": ""}, {"first": "M", "middle": [], "last": "Tambe", "suffix": ""}, {"first": "T", "middle": [], "last": "Fukuda", "suffix": ""}], "year": 1998, "venue": "", "link": null}, "BIBREF3": {"title": "The Semantics of Programming Languages: An Introduction Using Structured Operational Semantics", "authors": [{"first": "M", "middle": [], "last": "Hennessy", "suffix": ""}], "year": 1990, "venue": "", "link": null}, "BIBREF4": {"title": "Modeling and implementing conversation policies using POS", "authors": [{"first": "J.-L", "middle": [], "last": "Koning", "suffix": ""}, {"first": "P.-Y", "middle": [], "last": "Oudeyer", "suffix": ""}], "year": 2000, "venue": "International Conference on Communications in Computing (CIC-00)", "link": null}, "BIBREF5": {"title": "The Objective Caml system", "authors": [{"first": "X", "middle": [], "last": "Leroy", "suffix": ""}], "year": 2000, "venue": "", "link": "60980868"}, "BIBREF6": {"title": "A proposal for standard ML", "authors": [{"first": "R", "middle": [], "last": "Milner", "suffix": ""}], "year": 1987, "venue": "ACM Conference on Lisp and Functional Programming", "link": null}, "BIBREF7": {"title": "Pizza into Java: Translating theory into practice", "authors": [{"first": "M", "middle": [], "last": "Odersky", "suffix": ""}, {"first": "P", "middle": [], "last": "Wadler", "suffix": ""}], "year": 1997, "venue": "4th ACM Symposium on Principles of Programming Languages", "link": "12393192"}, "BIBREF8": {"title": "Modeling soccer-robots strategies through conversation policies", "authors": [{"first": "P.-Y", "middle": [], "last": "Oudeyer", "suffix": ""}, {"first": "J.-L", "middle": [], "last": "Koning", "suffix": ""}], "year": 2000, "venue": "2nd IEEE International Symposium on Agent Systems and Application (ASA/MA-00)", "link": "19885128"}, "BIBREF9": {"title": "A structural approach to operationnal semantics", "authors": [{"first": "G", "middle": [], "last": "Plotkin", "suffix": ""}], "year": 1981, "venue": "Computer Science Department", "link": null}, "BIBREF10": {"title": "Adaptation based on cooperative learning in multi-agent systems", "authors": [{"first": "S", "middle": ["S"], "last": "Sian", "suffix": ""}], "year": 1991, "venue": "", "link": "60157248"}}, "ref_entries": {}}
{"paper_id": "42951889", "_pdf_hash": "aba603a859e5bea445c4b5eb9e1caac07337b4e9", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "EEG changes in acute cerebral anoxia from cardiac or respiratory arrest", "authors": [{"first": "J", "middle": ["M"], "last": "Hockaday", "suffix": ""}, {"first": "F", "middle": [], "last": "Potts", "suffix": ""}, {"first": "E", "middle": [], "last": "Epstein", "suffix": ""}, {"first": "A", "middle": [], "last": "Bonazzi", "suffix": ""}, {"first": "R", "middle": ["S"], "last": "Schwab", "suffix": ""}], "year": 1965, "venue": "Electroenceph. clin. Neurophysiol", "link": null}, "BIBREF1": {"title": "Prediction of death in serious brain damage", "authors": [{"first": "P", "middle": [], "last": "L1ngren", "suffix": ""}], "year": 1968, "venue": "Acta Chir Scand", "link": "36418513"}, "BIBREF2": {"title": "Alpha coma: Electroencephalographic, clinical, pathological and etiologic correlation", "authors": [{"first": "B", "middle": ["F"], "last": "Westmoreland", "suffix": ""}, {"first": "D", "middle": ["W"], "last": "Klass", "suffix": ""}, {"first": "F", "middle": ["W"], "last": "Shar-Brough", "suffix": ""}, {"first": "Reagon", "middle": [], "last": "", "suffix": ""}, {"first": "T", "middle": ["J"], "last": "", "suffix": ""}], "year": 1975, "venue": "Arch. Neurol", "link": "23761703"}, "BIBREF3": {"title": "Electroencephalographic rhythms of alpha frequency in comatose patients after cardiopulmonary arrest", "authors": [{"first": "V", "middle": [], "last": "Vignaendra", "suffix": ""}, {"first": "R", "middle": ["J"], "last": "Wilkus", "suffix": ""}, {"first": "M", "middle": ["K"], "last": "Copass", "suffix": ""}, {"first": "Chatrian", "middle": [], "last": "", "suffix": ""}, {"first": "G", "middle": ["E"], "last": "", "suffix": ""}], "year": 1974, "venue": "Neurology (Minneap", "link": "43148278"}, "BIBREF4": {"title": "Alpha-like\" rhythms in electroencephalograms in coma after cardiac arrest", "authors": [{"first": "S", "middle": [], "last": "Chokroverty", "suffix": ""}], "year": 1975, "venue": "Neurology (Minneap.)", "link": "37194479"}, "BIBREF5": {"title": "Alpha-pattern coma\" and survival after cardiac arrest", "authors": [{"first": "M", "middle": [], "last": "Moller", "suffix": ""}], "year": 1978, "venue": "Electroenceph. clin. Neurophysiol", "link": "36855969"}, "BIBREF6": {"title": "Alpha-pattern coma: 24 cases with 9 survivors", "authors": [{"first": "A", "middle": ["B"], "last": "Grindal", "suffix": ""}, {"first": "C", "middle": [], "last": "Suter", "suffix": ""}, {"first": "A", "middle": ["J"], "last": "Martinez", "suffix": ""}], "year": 1977, "venue": "Ann. NeuroL", "link": "28191563"}, "BIBREF7": {"title": "Electroencephalogram in a case of pontomesencephalic hemorrhage", "authors": [{"first": "C", "middle": [], "last": "Loeb", "suffix": ""}, {"first": "Poggio", "middle": [], "last": "", "suffix": ""}, {"first": "G", "middle": [], "last": "", "suffix": ""}], "year": 1953, "venue": "Electroenceph. clin. Neurophysiol", "link": null}, "BIBREF8": {"title": "Clinical and electroencephalographic manifestations of vascular lesions of the pons", "authors": [{"first": "T", "middle": ["N"], "last": "Chase", "suffix": ""}, {"first": "L", "middle": [], "last": "Moretti", "suffix": ""}, {"first": "Prensky", "middle": [], "last": "", "suffix": ""}, {"first": "A", "middle": [], "last": "", "suffix": ""}], "year": 1968, "venue": "Neurology (Minneap)", "link": "34931504"}, "BIBREF9": {"title": "Alternating 'waking' and 'sleep' EEG pattern in a deeply comatose patient", "authors": [{"first": "J", "middle": ["R"], "last": "Hughes", "suffix": ""}, {"first": "J", "middle": [], "last": "Cayaffa", "suffix": ""}, {"first": "J", "middle": [], "last": "Leestma", "suffix": ""}, {"first": "Mizuna", "middle": [], "last": "", "suffix": ""}, {"first": "Y", "middle": [], "last": "", "suffix": ""}], "year": 1972, "venue": "Clin. Electroenceph", "link": "147384213"}, "BIBREF10": {"title": "Alpha and beta coma in drug intoxication uncomplicated by cerebral hypoxia", "authors": [{"first": "W", "middle": ["M"], "last": "Carrol", "suffix": ""}, {"first": "F", "middle": ["L"], "last": "Mastaglla", "suffix": ""}], "year": 1979, "venue": "Electroenceph. clin. Neurolphysiol", "link": "4552497"}, "BIBREF11": {"title": "Alpha-pattern coma in high voltage electrical injury", "authors": [{"first": "A", "middle": ["B"], "last": "Grindal", "suffix": ""}, {"first": "C", "middle": [], "last": "Suter", "suffix": ""}], "year": 1975, "venue": "Electroenceph. clin. NeurophysioL", "link": "4548136"}}, "ref_entries": {}}
{"paper_id": "42952567", "_pdf_hash": "ccca091fb3419d81ebad8762925f33cc74c09761", "abstract": [], "body_text": [{"section": "", "text": "(Periodic acid-Schiff, tartrazine, ", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Regeneration of Epiphyseal Cartilage", "authors": [{"first": "S", "middle": ["W"], "last": "", "suffix": ""}, {"first": "Compere", "middle": [], "last": "", "suffix": ""}, {"first": "E", "middle": ["L"], "last": "", "suffix": ""}], "year": 1941, "venue": "An Experimental Study. Annals ofSurgery", "link": null}, "BIBREF1": {"title": "Dyschondroplasia and Hemangiomata (Maffucci's Syndrome)", "authors": [{"first": "W", "middle": ["B"], "last": "Bean", "suffix": ""}], "year": 1955, "venue": "", "link": "32354475"}}, "ref_entries": {"FIGREF0": {"text": "FIG. 4", "type": "figure"}}}
{"paper_id": "42952780", "_pdf_hash": "ed1d3817b2676f3d4325a684ce028783800a4d99", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "42954506", "_pdf_hash": "817fdd303ab743ad84addd90a85b4070424f8a29", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Static var compensator models for power flow and dynamic performance simulation", "authors": [], "year": 1994, "venue": "IEEE Special Stability Controls Working Group", "link": "52137"}, "BIBREF1": {"title": "Voltage and reactive power control", "authors": [], "year": 1992, "venue": "Cigre Meeting", "link": null}, "BIBREF2": {"title": "Interaction between multiple SVS adaptive voltage regulators", "authors": [{"first": "G", "middle": [], "last": "Fusco", "suffix": ""}, {"first": "M", "middle": [], "last": "Russo", "suffix": ""}], "year": 2004, "venue": "Bulk Power System Dynamics and Control-VI", "link": null}, "BIBREF3": {"title": "Advanced static Var compensator using gate turn-off thyristor for utility applications", "authors": [{"first": "L", "middle": [], "last": "Gyugyi", "suffix": ""}, {"first": "N", "middle": ["G"], "last": "Hingorani", "suffix": ""}, {"first": "P", "middle": ["R"], "last": "Nannery", "suffix": ""}, {"first": "N", "middle": [], "last": "Tai", "suffix": ""}], "year": 1990, "venue": "", "link": null}, "BIBREF4": {"title": "Application of static VAr compensators to increase power system damping", "authors": [{"first": "E", "middle": ["Z"], "last": "Zhou", "suffix": ""}], "year": 1993, "venue": "IEEE Transactions on Power Systems", "link": null}, "BIBREF5": {"title": "Comparison of thyristor regulated three-phase reactors schemes", "authors": [{"first": "J", "middle": [], "last": "Zakis", "suffix": ""}, {"first": "O", "middle": [], "last": "Plataiskalns", "suffix": ""}, {"first": "I", "middle": [], "last": "Rankis", "suffix": ""}], "year": 2005, "venue": "Elektronika ir Elektrotehniks", "link": "111616203"}, "BIBREF6": {"title": "Adaptive control for static variable compensator", "authors": [{"first": "N", "middle": [], "last": "Djagarov", "suffix": ""}, {"first": "Z", "middle": [], "last": "Grozdev", "suffix": ""}], "year": 2006, "venue": "International conference, Electroenergetica", "link": null}, "BIBREF7": {"title": "Power system stability improving by using of power system stabilizers and adaptive static compensators", "authors": [{"first": "N", "middle": [], "last": "Djagarov", "suffix": ""}, {"first": "", "middle": [], "last": "Zh", "suffix": ""}, {"first": "M", "middle": [], "last": "Grozdev", "suffix": ""}, {"first": "", "middle": [], "last": "Bonev", "suffix": ""}], "year": 2009, "venue": "Proceedings of IV th International Scientific Symposium Transactions of Conference Elektroenergetika", "link": null}, "BIBREF8": {"title": "Sim Power Systems Toolbox 4, Reference, The MathWorks", "authors": [{"first": "&amp;", "middle": [], "last": "Matlab", "suffix": ""}, {"first": "", "middle": [], "last": "Simulink", "suffix": ""}], "year": 2000, "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "42955080", "_pdf_hash": "1923b02fddc9d43bbc7b3ab1df8b988512293e6d", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Three biologically active phenylpropanoid glucosides from Myriophyllum verticillatum", "authors": [{"first": "G", "middle": [], "last": "Aliotta", "suffix": ""}, {"first": "A", "middle": [], "last": "Molinario", "suffix": ""}, {"first": "P", "middle": [], "last": "Monaco", "suffix": ""}, {"first": "G", "middle": [], "last": "Pinto", "suffix": ""}, {"first": "L", "middle": [], "last": "Previtera", "suffix": ""}], "year": 1992, "venue": "Phytochemistry", "link": "85426072"}, "BIBREF1": {"title": "Estimation of total tobacco phenols by their bonding to polyvinylpyrrolidone", "authors": [{"first": "R", "middle": ["A"], "last": "Andersen", "suffix": ""}, {"first": "J", "middle": ["R"], "last": "Todd", "suffix": ""}], "year": 1968, "venue": "Tob Sci", "link": null}, "BIBREF2": {"title": "Distribution and production of sago pondweed (Potamogeton pectinatus L.) on a northern prairie marsh", "authors": [{"first": "M", "middle": ["G"], "last": "Anderson", "suffix": ""}], "year": 1978, "venue": "Ecology", "link": "84189642"}, "BIBREF3": {"title": "Sediment-related mechanisms of growth limitation in submersed macrophytes", "authors": [{"first": "J", "middle": ["W"], "last": "Barko", "suffix": ""}, {"first": "R", "middle": ["M"], "last": "Smart", "suffix": ""}], "year": 1986, "venue": "Ecology", "link": "84749858"}, "BIBREF4": {"title": "Photoreversible control of heterophylly in Hippuris vulgaris L", "authors": [{"first": "P", "middle": ["C"], "last": "Bodkin", "suffix": ""}, {"first": "Dhn", "middle": [], "last": "Spence", "suffix": ""}, {"first": "D", "middle": ["C"], "last": "Weeks", "suffix": ""}], "year": 1980, "venue": "New Phytol", "link": "86256221"}, "BIBREF5": {"title": "Carbon/nutrient balance of boreal plants in relation to vertebrate herbivory", "authors": [{"first": "J", "middle": ["P"], "last": "Bryant", "suffix": ""}, {"first": "F", "middle": ["S"], "last": "Chapin", "suffix": ""}, {"first": "D", "middle": ["R"], "last": "Klein", "suffix": ""}], "year": 1983, "venue": "Oikos", "link": "85157419"}, "BIBREF6": {"title": "Response of winter chemical defense in Alaska paper birch and green alder to manipulation of plant carbon/nitrogen balance", "authors": [{"first": "J", "middle": ["P"], "last": "Bryant", "suffix": ""}, {"first": "F", "middle": ["S"], "last": "Chapin", "suffix": ""}, {"first": "P", "middle": ["B"], "last": "Reichardt", "suffix": ""}, {"first": "T", "middle": ["P"], "last": "Clausen", "suffix": ""}], "year": 1987, "venue": "Oecologia", "link": null}, "BIBREF7": {"title": "Effects of submersed macrophytes on ecosystem processes", "authors": [{"first": "S", "middle": ["R"], "last": "Carpenter", "suffix": ""}, {"first": "D", "middle": ["M"], "last": "Lodge", "suffix": ""}], "year": 1986, "venue": "Aquat Bot", "link": "84759529"}, "BIBREF8": {"title": "Comparison of herbivory and plant defenses in temperate and tropical broad-leaved forests", "authors": [{"first": "P", "middle": ["D"], "last": "Coley", "suffix": ""}, {"first": "T", "middle": ["M"], "last": "Aide", "suffix": ""}], "year": 1991, "venue": "", "link": null}, "BIBREF9": {"title": "Resource availability and plant antiherbivore defense", "authors": [{"first": "P", "middle": ["D"], "last": "Coley", "suffix": ""}, {"first": "J", "middle": ["P"], "last": "Bryant", "suffix": ""}, {"first": "F", "middle": ["S"], "last": "Chapin", "suffix": ""}], "year": 1985, "venue": "Science", "link": "18179626"}, "BIBREF10": {"title": "Influence of macrophyte structure, nutritive value, and chemistry on the feeding choices of a generalist crayfish", "authors": [{"first": "G", "middle": [], "last": "Cronin", "suffix": ""}], "year": 1998, "venue": "The structuring role of submerged macrophytes in lakes", "link": "82748412"}, "BIBREF11": {"title": "Resource allocation in seaweeds and marine invertebrates: chemical defense patterns in relation to defense theories", "authors": [{"first": "G", "middle": [], "last": "Cronin", "suffix": ""}], "year": 2001, "venue": "Marine chemical ecology", "link": "89419428"}, "BIBREF12": {"title": "Effects of light and nutrient availability on the growth, secondary chemistry, and resistance to herbivory of two brown seaweeds", "authors": [{"first": "G", "middle": [], "last": "Cronin", "suffix": ""}, {"first": "M", "middle": ["E"], "last": "Hay", "suffix": ""}], "year": 1996, "venue": "Oikos", "link": "88113928"}, "BIBREF13": {"title": "Seaweed-herbivore interactions depend on recent history of both the plant and animal", "authors": [{"first": "G", "middle": [], "last": "Cronin", "suffix": ""}, {"first": "M", "middle": ["E"], "last": "Hay", "suffix": ""}], "year": 1996, "venue": "Ecology", "link": null}, "BIBREF14": {"title": "Intraspecific variation in feeding preference and performance of Galerucella nymphaeae (Chrysomelidae: Coleoptera) on aquatic macrophytes", "authors": [{"first": "G", "middle": [], "last": "Cronin", "suffix": ""}, {"first": "T", "middle": [], "last": "Schlacher", "suffix": ""}, {"first": "D", "middle": ["M"], "last": "Lodge", "suffix": ""}, {"first": "E", "middle": ["L"], "last": "Siska", "suffix": ""}], "year": 1999, "venue": "J N Am Benthol Soc", "link": "84550197"}, "BIBREF15": {"title": "Comparative feeding selectivity of herbivorous insects on water lilies: aquatic vs. semi-terrestrial insects and submersed vs. floating leaves", "authors": [{"first": "G", "middle": [], "last": "Cronin", "suffix": ""}, {"first": "K", "middle": ["D"], "last": "Wissing", "suffix": ""}, {"first": "D", "middle": ["M"], "last": "Lodge", "suffix": ""}], "year": 1998, "venue": "Freshw Biol", "link": "84037141"}, "BIBREF16": {"title": "Crayfish feeding preferences for freshwater macrophytes: the influence of plant structure and chemistry", "authors": [{"first": "G", "middle": [], "last": "Cronin", "suffix": ""}, {"first": "D", "middle": ["M"], "last": "Lodge", "suffix": ""}, {"first": "M", "middle": ["E"], "last": "Hay", "suffix": ""}, {"first": "M", "middle": [], "last": "Miller", "suffix": ""}, {"first": "A", "middle": ["M"], "last": "Hill", "suffix": ""}, {"first": "T", "middle": [], "last": "Horvath", "suffix": ""}, {"first": "R", "middle": ["C"], "last": "Bolser", "suffix": ""}, {"first": "N", "middle": [], "last": "Lindquist", "suffix": ""}, {"first": "M", "middle": [], "last": "Wahl", "suffix": ""}], "year": 2002, "venue": "J Crustac Biol", "link": "56303546"}, "BIBREF17": {"title": "Leaf quality and enemy avoidance by the larvae of a pyralid moth", "authors": [{"first": "H", "middle": [], "last": "Damman", "suffix": ""}], "year": 1987, "venue": "Ecology", "link": "84452660"}, "BIBREF18": {"title": "Variable plants and herbivores in natural and managed systems", "authors": [{"first": "R", "middle": ["F"], "last": "Denno", "suffix": ""}, {"first": "M", "middle": ["S"], "last": "Mcclure", "suffix": ""}], "year": 1972, "venue": "J Ecol", "link": "87445339"}, "BIBREF19": {"title": "Solute movement in submerged angiosperms", "authors": [{"first": "P", "middle": [], "last": "Denny", "suffix": ""}], "year": 1980, "venue": "Biol Rev", "link": "84147572"}, "BIBREF20": {"title": "Feeding preferences and performance of an aquatic lepidopteran on macrophytes: plant hosts as food and habitat", "authors": [{"first": "N", "middle": ["J"], "last": "Dorn", "suffix": ""}, {"first": "G", "middle": [], "last": "Cronin", "suffix": ""}, {"first": "D", "middle": ["M"], "last": "Lodge", "suffix": ""}], "year": 2001, "venue": "Oecologia", "link": "23267740"}, "BIBREF21": {"title": "Leaf decomposition in two Mediterranean ecosystems of southwest Spain: influence of substrate quality", "authors": [{"first": "A", "middle": [], "last": "Gallardo", "suffix": ""}, {"first": "J", "middle": [], "last": "Merino", "suffix": ""}], "year": 1993, "venue": "Ecology", "link": "84616183"}, "BIBREF22": {"title": "On the economy of plant form and function", "authors": [{"first": "T", "middle": ["J"], "last": "Givnish", "suffix": ""}, {"first": "", "middle": [], "last": "Jp", "suffix": ""}, {"first": "J", "middle": ["C"], "last": "Crick", "suffix": ""}, {"first": "J", "middle": ["E"], "last": "Rincon", "suffix": ""}], "year": 1986, "venue": "Plasticity in plants. The Company of Biologists", "link": null}, "BIBREF23": {"title": "Polyphenols with algicidal activity in the submerged macrophyte Myriophyllum spicatum L", "authors": [{"first": "E", "middle": ["M"], "last": "Gross", "suffix": ""}, {"first": "R", "middle": [], "last": "S\u00fctfeld", "suffix": ""}], "year": 1994, "venue": "Acta Hortic", "link": "83467636"}, "BIBREF24": {"title": "Release and ecological impact of algicidal hydrolysable polyphenols in Myriophyllum spicatum", "authors": [{"first": "E", "middle": ["M"], "last": "Gross", "suffix": ""}, {"first": "H", "middle": [], "last": "Meyer", "suffix": ""}, {"first": "G", "middle": [], "last": "Schilling", "suffix": ""}], "year": 1996, "venue": "Phytochemistry", "link": "85726591"}, "BIBREF25": {"title": "Tannins and lignins", "authors": [{"first": "A", "middle": ["E"], "last": "Hagerman", "suffix": ""}, {"first": "L", "middle": ["G"], "last": "Butler", "suffix": ""}], "year": 1991, "venue": "Herbivores: their interactions with secondary plant metabolites", "link": null}, "BIBREF26": {"title": "The dilemma of plants: to grow or defend", "authors": [{"first": "D", "middle": ["A"], "last": "Herms", "suffix": ""}, {"first": "W", "middle": ["J"], "last": "Mattson", "suffix": ""}], "year": 1992, "venue": "Q Rev Biol", "link": "19279900"}, "BIBREF27": {"title": "Ecological studies on the productivity of aquatic plant communities: IV. Light conditions and community photosynthesis production", "authors": [{"first": "I", "middle": [], "last": "Ikusima", "suffix": ""}], "year": 1970, "venue": "Bot Mag (Tokyo)", "link": "140566166"}, "BIBREF28": {"title": "Herbivory modifies the production of different leaf types in the yellow water-lily, Nuphar lutea (Nymphaeaceae)", "authors": [{"first": "E", "middle": [], "last": "Jeppesen", "suffix": ""}, {"first": "Sondergaard", "middle": [], "last": "Ma", "suffix": ""}, {"first": "Sondergaard", "middle": [], "last": "Mo", "suffix": ""}], "year": 1993, "venue": "Funct Ecol", "link": "87651862"}, "BIBREF29": {"title": "Herbivory on freshwater macrophytes", "authors": [{"first": "D", "middle": ["M"], "last": "Lodge", "suffix": ""}], "year": 1991, "venue": "Aquat Botany", "link": "30677326"}, "BIBREF30": {"title": "Impact of herbivory on plant standing crop: comparisons among biomes, between vascular and nonvascular plants, and among freshwater herbivore taxa", "authors": [{"first": "D", "middle": ["M"], "last": "Lodge", "suffix": ""}, {"first": "G", "middle": [], "last": "Cronin", "suffix": ""}, {"first": "E", "middle": [], "last": "Van Donk", "suffix": ""}, {"first": "A", "middle": ["J"], "last": "Froelich", "suffix": ""}], "year": 1998, "venue": "The structuring role of submerged macrophytes in lakes", "link": "83135052"}, "BIBREF31": {"title": "Growth correlation. In: Loomis WE (ed) Growth and differentiation in plants: a monograph of the American Society of Plant Physiologists", "authors": [{"first": "W", "middle": ["E"], "last": "Loomis", "suffix": ""}], "year": 1953, "venue": "", "link": null}, "BIBREF32": {"title": "Growth and differentiation: an introduction and summary. In: Loomis WE (ed) Growth and differentiation in plants: a monograph of the American Society of Plant Physiologists", "authors": [{"first": "W", "middle": ["E"], "last": "Loomis", "suffix": ""}], "year": 1953, "venue": "", "link": null}, "BIBREF33": {"title": "Terpenes and phenolics in response to nitrogen fertilization: a test of the carbon/nutrient balance hypothesis", "authors": [], "year": 1993, "venue": "Chemoecology", "link": "24462002"}, "BIBREF34": {"title": "Herbivory and detritivory on freshwater macrophytes by invertebrates: a review", "authors": [{"first": "R", "middle": ["M"], "last": "Newman", "suffix": ""}], "year": 1991, "venue": "J N Am Benthol Soc", "link": "85317265"}, "BIBREF35": {"title": "The watercress glucosinolate-myrosinase system: a feeding deterrent to caddisflies, snails, and amphipods", "authors": [{"first": "R", "middle": ["M"], "last": "Newman", "suffix": ""}, {"first": "Z", "middle": [], "last": "Hanscom", "suffix": ""}, {"first": "W", "middle": ["C"], "last": "Kerfoot", "suffix": ""}], "year": 1992, "venue": "Oecologia", "link": "23148764"}, "BIBREF36": {"title": "Watercress allelochemical defends high-nitrogen foliage against consumption: effects on freshwater invertebrate herbivores", "authors": [{"first": "R", "middle": ["M"], "last": "Newman", "suffix": ""}, {"first": "W", "middle": ["C"], "last": "Kerfoot", "suffix": ""}, {"first": "Z", "middle": [], "last": "Hanscom", "suffix": ""}], "year": 1996, "venue": "Ecology", "link": null}, "BIBREF37": {"title": "Importance of hybridization of indigenous and nonindigenous freshwater species: an overlooked threat to North American biodiversity", "authors": [{"first": "W", "middle": ["L"], "last": "Perry", "suffix": ""}, {"first": "D", "middle": ["M"], "last": "Lodge", "suffix": ""}, {"first": "J", "middle": ["L"], "last": "Feder", "suffix": ""}], "year": 2002, "venue": "Syst Biol", "link": "435468"}, "BIBREF38": {"title": "Ecological significance of phenolic compounds of Myriophyllum spicatum", "authors": [{"first": "D", "middle": [], "last": "Planas", "suffix": ""}, {"first": "F", "middle": [], "last": "Sarhan", "suffix": ""}, {"first": "L", "middle": [], "last": "Dube", "suffix": ""}, {"first": "H", "middle": [], "last": "Godmaire", "suffix": ""}, {"first": "C", "middle": [], "last": "Cadieux", "suffix": ""}], "year": 1981, "venue": "Verh Int Verein Limnol", "link": "90515730"}, "BIBREF39": {"title": "Intraspecific variation in the red alga Portieria hornemannii: monoterpene concentrations are not influenced by nitrogen or phosphorus enrichment", "authors": [{"first": "M", "middle": ["P"], "last": "Puglisi", "suffix": ""}, {"first": "V", "middle": ["J"], "last": "Paul", "suffix": ""}], "year": 1997, "venue": "Mar Biol", "link": "85181823"}, "BIBREF40": {"title": "Phlorotannins, brown algal polyphenols", "authors": [{"first": "M", "middle": ["A"], "last": "Ragan", "suffix": ""}, {"first": "K", "middle": ["W"], "last": "Glombitza", "suffix": ""}], "year": 1986, "venue": "Progress in phycological research", "link": "80798728"}, "BIBREF41": {"title": "Carbon/nutrient balance as a predictor of plant defense in Alaskan balsam poplar: potential importance of metabolite turnover", "authors": [{"first": "P", "middle": ["B"], "last": "Reichardt", "suffix": ""}, {"first": "F", "middle": ["S"], "last": "Chapin", "suffix": ""}, {"first": "J", "middle": ["P"], "last": "Bryant", "suffix": ""}, {"first": "B", "middle": ["R"], "last": "Mattes", "suffix": ""}, {"first": "T", "middle": ["P"], "last": "Clausen", "suffix": ""}], "year": 1991, "venue": "Oecologia", "link": "21440757"}, "BIBREF42": {"title": "Herbivore population dynamics and plant chemistry", "authors": [{"first": "D", "middle": ["F"], "last": "Rhoades", "suffix": ""}], "year": 1983, "venue": "Variable plants and herbivores in natural and managed systems", "link": null}, "BIBREF43": {"title": "Heads I win, tails you lose': testing directional alternative hypotheses in ecological and evolutionary research", "authors": [{"first": "W", "middle": ["R"], "last": "Rice", "suffix": ""}, {"first": "S", "middle": ["D"], "last": "Gaines", "suffix": ""}], "year": 1994, "venue": "Trends Ecol Evol", "link": "32303567"}, "BIBREF44": {"title": "Inhibitory substances from Myriophyllum brasiliense on growth of bluegreen algae", "authors": [], "year": 1989, "venue": "J Nat Prod", "link": "84065365"}, "BIBREF45": {"title": "Alternative equilibria in shallow lakes", "authors": [{"first": "M", "middle": [], "last": "Scheffer", "suffix": ""}, {"first": "S", "middle": ["H"], "last": "Hosper", "suffix": ""}, {"first": "M", "middle": ["L"], "last": "Meijer", "suffix": ""}, {"first": "B", "middle": [], "last": "Moss", "suffix": ""}, {"first": "E", "middle": [], "last": "Jeppesen", "suffix": ""}], "year": 1993, "venue": "Trends Ecol Evol", "link": "12095685"}, "BIBREF46": {"title": "Determination of total dissolved phosphorus and particulate phosphorus in natural waters", "authors": [{"first": "L", "middle": [], "last": "Solorzano", "suffix": ""}, {"first": "J", "middle": [], "last": "Sharp", "suffix": ""}], "year": 1980, "venue": "Limnol Oceanogr", "link": "83515836"}, "BIBREF47": {"title": "Effects of condensed tannins on leaf processing in mid-latitude and tropical streams: a theoretical approach", "authors": [{"first": "R", "middle": ["J"], "last": "Stout", "suffix": ""}], "year": 1989, "venue": "Can J Fish Aquat Sci", "link": null}, "BIBREF48": {"title": "Heterophylly in a water lily: interacting effects of [CO 2 ] with sediment and water depth", "authors": [{"first": "J", "middle": ["E"], "last": "Titus", "suffix": ""}], "year": 1996, "venue": "Suppl Ecol Soc Am", "link": null}, "BIBREF49": {"title": "The ecology and evolution of inducible defenses", "authors": [], "year": 1992, "venue": "Trends Ecol Evol", "link": null}, "BIBREF50": {"title": "Extrinsic factors influencing the production of secondary metabolites in plants", "authors": [{"first": "P", "middle": ["G"], "last": "Waterman", "suffix": ""}, {"first": "S", "middle": [], "last": "Mole", "suffix": ""}], "year": 1989, "venue": "Bernays EA (ed) Insect-plant interactions", "link": "209587340"}, "BIBREF51": {"title": "An index to measure weather-induced stress of trees associated with outbreaks of psyllids in Australia", "authors": [{"first": "Tcr", "middle": [], "last": "White", "suffix": ""}], "year": 1969, "venue": "Ecology", "link": "86137120"}, "BIBREF52": {"title": "The abundance of invertebrate herbivores in relation to the availability of nitrogen in stressed food plants", "authors": [{"first": "Tcr", "middle": [], "last": "White", "suffix": ""}], "year": 1984, "venue": "Oecologia", "link": "20266301"}, "BIBREF53": {"title": "A review of evidence on the control of shoot:root ratio, in relation to models", "authors": [{"first": "J", "middle": ["B"], "last": "Wilson", "suffix": ""}], "year": 1988, "venue": "Ann Bot", "link": null}, "BIBREF54": {"title": "Effects of nutrient availability and herbivory on polyphenolics in the seaweed Fucus vesiculosus", "authors": [{"first": "J", "middle": ["L"], "last": "Yates", "suffix": ""}, {"first": "P", "middle": [], "last": "Peckol", "suffix": ""}], "year": 1993, "venue": "Ecology", "link": "84992301"}, "BIBREF55": {"title": "Furanocoumarins in wild parsnip: effects of photosynthetically active radiation, ultraviolet light, and nutrients", "authors": [{"first": "A", "middle": ["R"], "last": "Zangerl", "suffix": ""}, {"first": "M", "middle": ["R"], "last": "Berenbaum", "suffix": ""}], "year": 1987, "venue": "Ecology", "link": "84767363"}}, "ref_entries": {}}
{"paper_id": "42955338", "_pdf_hash": "5d5218cfa101fdf64b63d5929ee9aca220024753", "abstract": [], "body_text": [{"section": "28", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Communication Research 38(1)", "text": "The recent widespread adoption of social network sites (SNS; boyd & Ellison, 2007) influences communication behavior in a variety of contexts, including political participation (Smith & Rainie, 2008) , identity construction (Liu, 2007) , collegiate teacher-student relationships (Mazer, Murphy, & Simonds, 2007) , and adolescent friendships (Lenhart & Madden, 2007) . Though users appropriate these sites for varied purposes, the maintenance of networked interpersonal relationships is their central attraction and function (Donath, 2007; Ellison, Steinfeld, & Lampe, 2007; Tufekci, 2008) . Accordingly, such sites are now receiving attention from interpersonal communication researchers, though a theoretical understanding of how SNS may contribute to relational closeness remains in infancy (Baym & Ledbetter, 2009) . Of the hundreds of SNS available on the Internet, Facebook is one of the most popular across a variety of demographic categories (Boyd & Ellison, 2007) . This article explores motivations toward self-disclosure and social connection as distinct yet related predictors of Facebook use within specific relationships. Though any number of specific interpersonal communication motivations might merit research attention, Facebook itself explicitly calls attention to these motivations in the site's slogan, prominently featured on the opening page: \"Facebook helps you connect and share with the people in your life\" (Facebook.com, 2009, emphasis added) . Facebook creator Zuckerberg (2008) acknowledged that the site's features are designed with these two motivations in mind. Separately, Ledbetter (2009b) identifies self-disclosure and social connection as fundamental motivations that foster online interpersonal communication more generally. Given decades of debate regarding interpersonal outcomes associated with online communication (for a review, see Walther & Parks, 2002) and that interpersonal communication scholars identify relational closeness as an outcome of practical and theoretical interest (Vangelisti & Caughlin, 1997) , the chief goal of this study is to test a theoretical model that elaborates how these two motivations might contribute to Facebook communication behavior (within specific interpersonal relationships) and, in turn, how such communication is associated with relational closeness.", "cite_spans": [{"start": 61, "end": 82, "text": "boyd & Ellison, 2007)", "ref_id": "BIBREF6"}, {"start": 177, "end": 199, "text": "(Smith & Rainie, 2008)", "ref_id": "BIBREF62"}, {"start": 224, "end": 235, "text": "(Liu, 2007)", "ref_id": "BIBREF40"}, {"start": 279, "end": 311, "text": "(Mazer, Murphy, & Simonds, 2007)", "ref_id": "BIBREF42"}, {"start": 341, "end": 365, "text": "(Lenhart & Madden, 2007)", "ref_id": "BIBREF34"}, {"start": 524, "end": 538, "text": "(Donath, 2007;", "ref_id": "BIBREF12"}, {"start": 574, "end": 588, "text": "Tufekci, 2008)", "ref_id": "BIBREF70"}, {"start": 793, "end": 817, "text": "(Baym & Ledbetter, 2009)", "ref_id": "BIBREF4"}, {"start": 949, "end": 971, "text": "(Boyd & Ellison, 2007)", "ref_id": "BIBREF6"}, {"start": 1606, "end": 1623, "text": "Ledbetter (2009b)", "ref_id": "BIBREF30"}, {"start": 1876, "end": 1898, "text": "Walther & Parks, 2002)", "ref_id": "BIBREF80"}, {"start": 2027, "end": 2056, "text": "(Vangelisti & Caughlin, 1997)", "ref_id": "BIBREF75"}], "ref_spans": []}, {"section": "Theoretical Background", "text": "Online communication's integration with offline social networks is seen clearly in the recent emergence of social network sites (SNSs), or \"web-based services that allow individuals to (1) construct a public or semi-public profile within a bounded system, (2) articulate a list of other users with whom they share a connection, and (3) view and traverse their list of connections and those made by others within the system\" (boyd & Ellison, 2007, p. 211) . Though Facebook originated in 2004 as an SNS exclusively for college student use, the site soon opened to corporate networks in early 2006 and then to the general public by the end of that year (boyd & Ellison, 2007) . As of this writing, Facebook remains one of the most popular SNSs across a variety of demographic categories (Hargittai, 2007 ). Yet before further considering the nature of interpersonal relationships on Facebook, we must address the ambiguous nature of the term friend when discussing SNS communication (boyd & Ellison, 2007) . Though colloquial and 30 Communication Research 38(1) affective components. These affective/cognitive orientations, in turn, influence behavior toward the attitude object. Given the diverse manifestations of online communication, some may question whether research can speak meaningfully about an attitude toward online communication as a whole. Without denying the value of examining attitudes toward specific technologies, a robust research tradition examines trait-like orientations toward tech nology at a more abstract level, identifying constructs such as online communication apprehension (Scott & Timmerman, 2005) , generalized problematic Internet use (Caplan, 2003) , and information reception apprehension from technology sources (Wheeless, Eddleman-Spears, Magness, & Preiss, 2005 ) that significantly predict technology use and related outcomes. This investigation follows this tradition, with the hope that such knowledge will help build theory that explains both current and future communication technologies (Sawhney, 2007) .", "cite_spans": [{"start": 651, "end": 673, "text": "(boyd & Ellison, 2007)", "ref_id": "BIBREF6"}, {"start": 785, "end": 801, "text": "(Hargittai, 2007", "ref_id": "BIBREF17"}, {"start": 981, "end": 1003, "text": "(boyd & Ellison, 2007)", "ref_id": "BIBREF6"}, {"start": 1602, "end": 1627, "text": "(Scott & Timmerman, 2005)", "ref_id": "BIBREF60"}, {"start": 1667, "end": 1681, "text": "(Caplan, 2003)", "ref_id": "BIBREF9"}, {"start": 1747, "end": 1798, "text": "(Wheeless, Eddleman-Spears, Magness, & Preiss, 2005", "ref_id": "BIBREF83"}, {"start": 2030, "end": 2045, "text": "(Sawhney, 2007)", "ref_id": "BIBREF59"}], "ref_spans": []}, {"section": "Theoretical Background", "text": "With this theoretical background in mind, Ledbetter (2009b) validates attitude toward online self-disclosure (OSD) and attitude toward online social connection (OSC) as two fundamental orientations influencing media-use patterns in interpersonal relationships, with similar concepts echoing in related lines of research (e.g., \"disposition toward social grooming and privacy concerns, \" Tufekci, 2008, p. 561) . Specifically, Ledbetter argues that these orientations address an individual's attitude toward the medium itself, which then influences both the formation and interpretation of online messages. That previous research recognizes both self-disclosure (Acquisti & Gross, 2006; Mazer et al., 2007) and social connection (Donath, 2007; Ellison et al., 2007) as core SNS behaviors further supports this line of argumentation; also, that Facebook's basic site structure aims to gratify both of these attitudinal orientations (Zuckerberg, 2008) further merits considering theoretical links between these motivations, communication behavior, and subsequent relational outcomes. We will review each of these orientations in turn.", "cite_spans": [{"start": 42, "end": 59, "text": "Ledbetter (2009b)", "ref_id": "BIBREF30"}, {"start": 661, "end": 685, "text": "(Acquisti & Gross, 2006;", "ref_id": "BIBREF0"}, {"start": 686, "end": 705, "text": "Mazer et al., 2007)", "ref_id": "BIBREF42"}, {"start": 728, "end": 742, "text": "(Donath, 2007;", "ref_id": "BIBREF12"}, {"start": 743, "end": 764, "text": "Ellison et al., 2007)", "ref_id": "BIBREF14"}, {"start": 930, "end": 948, "text": "(Zuckerberg, 2008)", "ref_id": "BIBREF88"}], "ref_spans": []}, {"section": "Theoretical Background", "text": "OSD. Mazer and his colleagues (2007) provided perhaps the earliest peer-reviewed article on Facebook self-disclosure. Conceptualizing self-disclosure as \"any message about the self that a person communicates to another\" (Wheeless & Grotz, 1976, p. 47 ), Mazer and his colleagues identify several Facebook features that foster self-disclosure: \"users post personal information such as pictures, hobbies, and messages to communicate with fellow students and instructors as well as friends and family\" (p. 2). Building from Mazer and his colleagues' work and Petronio's (2002) treatment of self-disclosure as coordinating boundaries around private information, Walther and his colleagues (Walther, Van Der Heide, Kim, Westerman, & Tong, 2008) noted that self-disclosure occurs alongside information about the self provided by other users (e.g., through \"wall\" posts or comments on status messages). Wright and his colleagues (Wright, Craig, Cunningham, Igiel, & Ploeger, 2008) further validate the importance of self-disclosure behavior via Facebook, finding that breadth and depth of self-disclosure is associated with increased interdependence and predictability. Thus, as Facebook's own slogan claims, the site is indeed a location where users share information about the self with a proscribed set of others.", "cite_spans": [{"start": 556, "end": 573, "text": "Petronio's (2002)", "ref_id": "BIBREF50"}, {"start": 685, "end": 739, "text": "(Walther, Van Der Heide, Kim, Westerman, & Tong, 2008)", "ref_id": "BIBREF81"}, {"start": 922, "end": 973, "text": "(Wright, Craig, Cunningham, Igiel, & Ploeger, 2008)", "ref_id": "BIBREF85"}], "ref_spans": []}, {"section": "Theoretical Background", "text": "Communication researchers have long recognized the role of self-disclosure in healthy relational development (Petronio, 2002) , and Mazer et al. (2007) likewise report that Facebook self-disclosure can enhance the quality of teacher-student relationships. However, evidence from other studies of online communication suggests that generalized attraction to OSD may be associated with negative psychological and relational outcomes. Online communication scholars have long considered the antecedents and outcomes of identity formation and self presentation enacted via OSD (O'Sullivan, 2000; Turkle, 1995) , with several studies reporting that communicators often self-disclose more online than they do when face to face (Ho & McLeod, 2008; Joinson, 2001; Postmes, Spears, & Lea, 1998) . McKenna, Green, and Gleason (2002) focused on self-disclosure in online-only relationships, arguing that lack of social competence may account for heightened selfdisclosure online because those with poor social skills may prefer the greater control over communication behavior that online contexts afford:", "cite_spans": [{"start": 109, "end": 125, "text": "(Petronio, 2002)", "ref_id": "BIBREF50"}, {"start": 132, "end": 151, "text": "Mazer et al. (2007)", "ref_id": "BIBREF42"}, {"start": 572, "end": 590, "text": "(O'Sullivan, 2000;", "ref_id": "BIBREF48"}, {"start": 591, "end": 604, "text": "Turkle, 1995)", "ref_id": "BIBREF71"}, {"start": 720, "end": 739, "text": "(Ho & McLeod, 2008;", "ref_id": "BIBREF20"}, {"start": 740, "end": 754, "text": "Joinson, 2001;", "ref_id": "BIBREF22"}, {"start": 755, "end": 784, "text": "Postmes, Spears, & Lea, 1998)", "ref_id": "BIBREF51"}, {"start": 787, "end": 821, "text": "McKenna, Green, and Gleason (2002)", "ref_id": "BIBREF44"}], "ref_spans": []}, {"section": "Theoretical Background", "text": "Logically, those individuals . . . who have the social skills needed to communicate themselves well and effectively have little need to express their true selves or \"Real Me\" over the Internet. The rest of us should be glad that the Internet exists. . . . Thus we would expect people who are lonely or are socially anxious in traditional, faceto-face interaction settings to be likely to feel better able to express their true self over the Internet and so to develop close and meaningful relationships there. (p. 12) Thus, they argue that motivation to self-disclose online may produce beneficial relational outcomes, as online communication may provide the socially anxious with opportunities to build social skills and meaningful relationships (see also Valkenburg & Peter, 2008) .", "cite_spans": [{"start": 757, "end": 782, "text": "Valkenburg & Peter, 2008)", "ref_id": "BIBREF73"}], "ref_spans": []}, {"section": "Theoretical Background", "text": "Like McKenna et al. (2002) , Caplan (2003) agreed that poor social skills are associated with a preference for online communication (and particularly online self disclosure). Caplan (2007) identified lack of communication competence as a theoretical motivator, arguing that those with high social anxiety prefer online communication's \"greater control over self presentation\" and \"less perceived social risk, than in traditional FtF communication\" (p. 235 ). Yet Caplan (2003) challenged the claim that such use generates positive outcomes, demonstrating that preference for online communication is associated with depression, loneliness, and other negative psychosocial outcomes. Though Caplan's (2002) research initially focused on online and offline social life as separate social spheres, his recent research identifies communication competence as a more general influence on online communication behavior; in other words, Caplan (2007) does not theorize or test whether relational medium of origin or degree of multimodality influences online communication frequency. Relatedly, Spitzberg's (2006) overview of communication competence in online contexts concludes that loneliness and depression are related to online communication use in complex ways. Following these lines of theoretical development, Ledbetter (2009b) directly tested the association between OSD and generalized communication competence, finding a significant moderate inverse association between the two constructs.", "cite_spans": [{"start": 5, "end": 26, "text": "McKenna et al. (2002)", "ref_id": "BIBREF44"}, {"start": 29, "end": 42, "text": "Caplan (2003)", "ref_id": "BIBREF9"}, {"start": 175, "end": 188, "text": "Caplan (2007)", "ref_id": "BIBREF10"}, {"start": 463, "end": 476, "text": "Caplan (2003)", "ref_id": "BIBREF9"}, {"start": 927, "end": 940, "text": "Caplan (2007)", "ref_id": "BIBREF10"}, {"start": 1084, "end": 1102, "text": "Spitzberg's (2006)", "ref_id": "BIBREF64"}, {"start": 1307, "end": 1324, "text": "Ledbetter (2009b)", "ref_id": "BIBREF30"}], "ref_spans": []}, {"section": "Theoretical Background", "text": "To summarize, self-disclosure is an important Facebook communication behavior, and thus we would expect those with high OSD to use it more. Moreover, Caplan's (2003 Caplan's ( , 2007 OSC. In contrast to OSD, we argue that maintaining existing social connections (i.e., OSC) is a relationally healthier motivation for using online communication. Ledbetter (2009b) reports that both OSC and OSD exhibit similar patterns of association with online communication behavior, yet differ in their association with generalized communication competence: Though OSD is inversely associated with communication competence, OSC yields a positive association of nearly equivalent magnitude. This may suggest that communicatively competent people do not seek online communication because they wish to avoid discomfort attendant with face-to-face communication, but rather because they perceive online communication as a useful method for sustaining preexisting weak and strong social ties (Haythornthwaite, 2005) .", "cite_spans": [{"start": 150, "end": 164, "text": "Caplan's (2003", "ref_id": "BIBREF9"}, {"start": 165, "end": 182, "text": "Caplan's ( , 2007", "ref_id": "BIBREF10"}, {"start": 345, "end": 362, "text": "Ledbetter (2009b)", "ref_id": "BIBREF30"}, {"start": 973, "end": 996, "text": "(Haythornthwaite, 2005)", "ref_id": "BIBREF18"}], "ref_spans": []}, {"section": "Theoretical Background", "text": "Other research supports our assertion that OSC is associated with positive relational outcomes. When countering claims that online communication (i.e., more generally than just SNS use) produces negative relational outcomes (Kraut et al., 1998; Nie et al., 2002) , scholars frequently provide empirical evidence demonstrating beneficial outcomes for the strength of both local and long distance social ties (Baym, Zhang, & Lin, 2004; QuanHaase, Wellman, Witte, & Hampton, 2002) . That SNSs likewise maintain social networks may sound tautological; nevertheless, recent research elaborates mechanisms via which SNSs foster such connections. For example, Ellison and her colleagues (2007) reported that Facebook social connections develop several types of social capital, Stern and Taylor (2007) reported that college students use Facebook to maintain social connections developed on campus and with old friends, and Baym and Ledbetter (2009) suggested that shared interests may motivate the formation of some SNS relationships.", "cite_spans": [{"start": 224, "end": 244, "text": "(Kraut et al., 1998;", "ref_id": "BIBREF26"}, {"start": 245, "end": 262, "text": "Nie et al., 2002)", "ref_id": "BIBREF47"}, {"start": 407, "end": 433, "text": "(Baym, Zhang, & Lin, 2004;", "ref_id": "BIBREF5"}, {"start": 770, "end": 793, "text": "Stern and Taylor (2007)", "ref_id": "BIBREF67"}, {"start": 915, "end": 940, "text": "Baym and Ledbetter (2009)", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "Theoretical Background", "text": "In addition to Ledbetter (2009b) , other empirical evidence suggests that internal attitudinal factors influence attraction to online communication as a space for building social connections. Both Donath (2007) and Tufekci (2008) conceptualized SNS use as analogous to social grooming among primates (Dunbar, 1998) , advancing the claim that resources devoted to regular, brief contacts facilitate relational ties with other individuals in a social network. Tufekci noted that this desire for social grooming varies in magnitude across individuals, with some people valuing such behaviors and others considering them unnecessary; in Tufekci's study, those who generally desire social grooming were also more likely to use an SNS. Donath claims that this motivation arises from the nature of SNSs as \"more temporally efficient and cognitively effective\" for the purpose of \"maintaining ties\" (p. 231). Donath noted that this increased efficiency may facilitate formation of social supernets or social networks that are larger than those sustainable through other communication media. This line of theoretical development resonates with Parks' (2006) recent argument that all dyadic relationships are intimately constituted in webs of network ties, with individuals sustaining ties using several communication media (Sawhney, 2007; Walther & Parks, 2002) . Taken as a whole, then, this research indicates that many people use SNSs because they wish to maintain existing social ties and that this motivation, in contrast to OSD, is associated with positive relational and psychosocial outcomes. What remains less clear, however, is the extent to which OSC is associated with offline communication between Facebook Friends. Some research suggests that those who engage in social networking behavior when online are also likely to do so when communicating offline (Quan-Haase et al., 2002; Tufekci, 2008 We also expect a significantly positive association between Facebook communication frequency and offline communication frequency. Though media multiplexity theory (Haythornthwaite, 2005) suggests that tie strength is a moderator (i.e., such that strong ties communicate across many media whereas weak ties use fewer media), most studies find a significantly positive association between offline and online frequency with a specific relational partner (Baym et al., 2004; Ramirez & Broneck, 2009 ", "cite_spans": [{"start": 15, "end": 32, "text": "Ledbetter (2009b)", "ref_id": "BIBREF30"}, {"start": 197, "end": 210, "text": "Donath (2007)", "ref_id": "BIBREF12"}, {"start": 215, "end": 229, "text": "Tufekci (2008)", "ref_id": "BIBREF70"}, {"start": 300, "end": 314, "text": "(Dunbar, 1998)", "ref_id": "BIBREF13"}, {"start": 1135, "end": 1148, "text": "Parks' (2006)", "ref_id": "BIBREF49"}, {"start": 1314, "end": 1329, "text": "(Sawhney, 2007;", "ref_id": "BIBREF59"}, {"start": 1330, "end": 1352, "text": "Walther & Parks, 2002)", "ref_id": "BIBREF80"}, {"start": 1859, "end": 1884, "text": "(Quan-Haase et al., 2002;", "ref_id": "BIBREF54"}, {"start": 1885, "end": 1898, "text": "Tufekci, 2008", "ref_id": "BIBREF70"}, {"start": 2062, "end": 2085, "text": "(Haythornthwaite, 2005)", "ref_id": "BIBREF18"}, {"start": 2350, "end": 2369, "text": "(Baym et al., 2004;", "ref_id": "BIBREF5"}, {"start": 2370, "end": 2393, "text": "Ramirez & Broneck, 2009", "ref_id": "BIBREF55"}], "ref_spans": []}, {"section": "Facebook Communication and Relational Closeness", "text": "Thus far, we have considered relational outcomes associated with Facebook communication but have not specified these in testable hypotheses. In this investigation, relational closeness is our chief outcome of interest, as Vangelisti and Caughlin (1997) noted that relational closeness is a variable of interest in a wide variety of relationship types (including friendship, family, and romantic relationships). Though we acknowledge that closeness is not the only possible relational outcome worthy of investigation, it is also worth acknowledging that close relationships are important sources of social support (Burleson & MacGeorge, 2002) and that ongoing closeness promotes relational longevity (Ledbetter, Griffin, & Sparks, 2007) . Closeness has also received attention as an outcome variable associated with several forms of online communication behavior across diverse samples, including online relational maintenance (among U.S. college students; Ledbetter, 2009a) , duration of Internet use (among Israeli adolescents; Mesch & Talmud, 2006) , and both frequency of online communication and depth of online self-disclosure (among Dutch adolescents; Valkenburg & Peter, 2007) . Though scholars have not devoted as much attention to closeness across SNSs, Baym and Ledbetter (2009) reported that though relational quality (a variable conceptually similar to closeness) with SNS Friends tends to be low, frequency of SNS contact between Friends is positively associated with relational quality (even after controlling for contact across other media). In this study, we conceptualize 34", "cite_spans": [{"start": 222, "end": 252, "text": "Vangelisti and Caughlin (1997)", "ref_id": "BIBREF75"}, {"start": 613, "end": 641, "text": "(Burleson & MacGeorge, 2002)", "ref_id": "BIBREF7"}, {"start": 699, "end": 735, "text": "(Ledbetter, Griffin, & Sparks, 2007)", "ref_id": "BIBREF32"}, {"start": 956, "end": 973, "text": "Ledbetter, 2009a)", "ref_id": "BIBREF29"}, {"start": 1029, "end": 1050, "text": "Mesch & Talmud, 2006)", "ref_id": "BIBREF45"}, {"start": 1158, "end": 1183, "text": "Valkenburg & Peter, 2007)", "ref_id": "BIBREF72"}, {"start": 1263, "end": 1288, "text": "Baym and Ledbetter (2009)", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "Communication Research 38(1)", "text": "closeness as a subjective experience of intimacy, emotional affinity, and psychological bonding with another person (see Aron, Mashek, & Aron, 2004) ; given the foregoing literature, we predict that frequency of Facebook communication will uniquely and positively predict Friend closeness. Our conceptualization of closeness bears strong resemblance to Haythornthwaite's approach to strong and weak social ties in her theory of media multiplexity. Strong social ties include relationships such as those with friends, romantic partners, and family members; such relationships exhibit behavior that reflects emotionality, interdependence, and intimacy (i.e., a high level of closeness). By contrast, weak ties are \"casual contacts\" that are more loosely connected to an individual's social network and are not characterized by intimacy (Haythornthwaite, 2005, p. 128) . According to media multiplexity theory, the number of different communication media that dyad members use is strongly associated with whether a tie is weak or strong. Specifically, strong ties employ several media types, but weak ties use only one or two media. As Baym and Ledbetter (2009) As we argued earlier, previous research and theory (e.g., Caplan, 2007) suggests that online communication motivated by OSD is associated with negative outcomes. Nevertheless, some interpersonal communication theory (Altman & Taylor, 1973) and empirical research (Laurenceau, Barrett, & Pietromonaco, 1998) suggests that self-disclosure is positively associated with relational closeness. Thus, the computer-mediated communication and traditional interpersonal communication literatures offer divergent predictions regarding this association. Thus, we advance a research question:", "cite_spans": [{"start": 121, "end": 148, "text": "Aron, Mashek, & Aron, 2004)", "ref_id": "BIBREF2"}, {"start": 1133, "end": 1158, "text": "Baym and Ledbetter (2009)", "ref_id": "BIBREF4"}, {"start": 1217, "end": 1230, "text": "Caplan, 2007)", "ref_id": "BIBREF10"}, {"start": 1375, "end": 1398, "text": "(Altman & Taylor, 1973)", "ref_id": "BIBREF1"}, {"start": 1422, "end": 1465, "text": "(Laurenceau, Barrett, & Pietromonaco, 1998)", "ref_id": "BIBREF28"}], "ref_spans": []}, {"section": "Communication Research 38(1)", "text": "Research Question 1: Does OSD indirectly (i.e., mediated via Facebook and offline communication constructs) predict relational closeness (with specific Facebook Friends)?", "cite_spans": [], "ref_spans": []}, {"section": "Communication Research 38(1)", "text": "Though earlier online research characterizes online communication as reducing a sense of social connection, work countering this claim demonstrates that those who build social connections offline also tend to do so online and, consequently, experience positive relational outcomes (e.g., Quan-Haase et al., 2002 That extant literature suggests divergent outcomes from OSC and OSD implies that these motivations are inversely associated with each other. However, previous research reports a positive association between the two constructs (Ledbetter, 2009b) ; as such, it is theoretically unclear what outcomes arise from an individual who possesses high levels of both motivations. Following Caplan (2007) , one might speculate that problematic Internet use driven by OSD would reduce beneficial outcomes from increased social connections. Alternatively, following theoretical arguments that online social ties may enhance the social skills of the lonely and socially anxious (McKenna et al., 2002; Valkenburg & Peter, 2008) , it could stand to reason that OSC is associated with positive social outcomes regardless of an individual's level of OSD. In any case, the extant literature at least suggests the possibility of a meaningful interaction effect between these two constructs on online communication and relational closeness, though the available evidence does not permit a prediction of the nature of this association in advance. Thus, ", "cite_spans": [{"start": 288, "end": 311, "text": "Quan-Haase et al., 2002", "ref_id": "BIBREF54"}, {"start": 538, "end": 556, "text": "(Ledbetter, 2009b)", "ref_id": "BIBREF30"}, {"start": 692, "end": 705, "text": "Caplan (2007)", "ref_id": "BIBREF10"}, {"start": 976, "end": 998, "text": "(McKenna et al., 2002;", "ref_id": "BIBREF44"}, {"start": 999, "end": 1024, "text": "Valkenburg & Peter, 2008)", "ref_id": "BIBREF73"}], "ref_spans": []}, {"section": "Method", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Sampling and Participants", "text": "In order to capture a diverse sample of Facebook users, we recruited participants via three approaches. First, with the consent of the computing services department at a large Midwestern university, a random sample was drawn from the list of all students enrolled in undergraduate courses. Second, other participants were recruited through announcements on the Facebook pages of various members of the research team. Third, we posted a call for participants on the listserv of a professional organization interested in technology and communication. After discarding participants that indicated no Facebook usage (n = 27), these sampling techniques resulted in a group of 325 participants (75 men, 250 women) with 226 (69.5%) identifying themselves as undergraduate students. Participants' age ranged from 18 to 59 years (M = 23.4, SD = 6.0), and most participants (90.5%) reported their ethnic identity as White.", "cite_spans": [], "ref_spans": []}, {"section": "36", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Communication Research 38(1) Procedures", "text": "Recruitment procedures directed participants to a Web link containing an informed consent form, and upon acceptance, participants were taken to the secure online questionnaire. If the participants were Facebook users, the questionnaire instructed them to open their Facebook account in a separate window and load their profile. At the time of data collection (early 2008), Facebook profiles included a box at the left side of the screen that displayed Friends selected from a person's primary network. Although Facebook has not publicly discussed the algorithm behind Friend selection for this window, tests of the feature at the time seemed to indicate that Friend selection was at least pseudorandom (although it is worth noting that Facebook's recent site redesign seems to have altered this algorithm since data collection). This method of Friend selection was designed to move beyond the practice of participant friend selection common in friendship research (e.g., Johnson, Wittenberg, Villagran, Mazur, & Villagran, 2003; Ledbetter, 2009a) . The survey directed participants to complete several measures based on the first Friend who appeared in this box. At the end of the survey, participants had the option of entering their e-mail addresses for a chance to win one of four US$20 gift certificates from Amazon.com. These e-mail addresses were removed from the data set before analysis.", "cite_spans": [{"start": 971, "end": 1028, "text": "Johnson, Wittenberg, Villagran, Mazur, & Villagran, 2003;", "ref_id": "BIBREF21"}, {"start": 1029, "end": 1046, "text": "Ledbetter, 2009a)", "ref_id": "BIBREF29"}], "ref_spans": []}, {"section": "Measurement", "text": "Online communication attitude. The self-disclosure and social connection subscales of Ledbetter's (2009b) generalized measure of online communication attitude assessed OSD and OSC, respectively. The self-disclosure subscale contains 7 items: \"I feel less nervous when sharing personal information online\"; \"I feel like I can be more open when I am communicating online\"; \"I feel like I can sometimes be more personal during Internet conversations\"; \"When online, I feel more comfortable disclosing personal information to a member of the opposite sex\"; \"I feel less shy when I am communicating online\"; \"I feel less embarrassed sharing personal information with another person online\"; and \"It is easier to disclose personal information online.\" The social connection subscale contains 6 items: (Wheeless et al., 2005) . Participants responded on a 7-point Likert-type scale with response options ranging from 1 (strongly disagree) to 7 (strongly agree). Cronbach's alpha reliability was acceptable for both the OSD (.92) and OSC (.87) dimensions. Friend demographic information. Participants reported basic demographic information about the randomly chosen Friend. Most reported that their Friend was a member of the participant's sex (n = 193, 59.4%), though others reported on cross-sex relationships (n = 132, 40.6%). Age of the Friend ranged from 17 to 60 (M = 22.8, SD = 5.2), with length of relationship ranging from 1 month to 43 years (M = 4.3 years, SD = 5.2). Most participants reported that their Facebook Friend was, indeed, a friend (n = 204, 62.8%) or an acquaintance (n = 73, 22.5%), though a small number reported on a romantic partner (n = 11, 3.4%), a family member (n = 6, 1.8%) or did not specify the type of relationship (n = 31, 9.5%). Though most participants reported on local relationships (n = 221, 68.0%), some reported on long-distance relationships (n = 104, 32.0%).", "cite_spans": [{"start": 86, "end": 105, "text": "Ledbetter's (2009b)", "ref_id": "BIBREF30"}, {"start": 795, "end": 818, "text": "(Wheeless et al., 2005)", "ref_id": "BIBREF83"}], "ref_spans": []}, {"section": "Measurement", "text": "Facebook communication. Informed by Lenhart and Madden's (2007) description of the methods of communication possible within Facebook, a 6-point Likert-type scale assessed frequency of Facebook communication with the Friend. This measure contains 7 items: \"I write on my friend's wall,\" \"I send my friend a private message,\" \"I communicate with the friend in a Facebook group,\" \"I 'poke' my friend,\" \"I comment on one of my friend's photographs,\" \"I comment on one of my friend's notes,\" and \"I communicate with the friend through an application on Facebook.\" Participants responded on a 6-point Likert-type scale with response options ranging from 0 (never) to 5 (very frequently). Following Baym and Ledbetter's (2009) evidence that communication frequency on another SNS (Last.fm) exhibits unidimensional structure, we submitted all items to an exploratory factor analysis using the principal components extraction method with varimax (i.e., orthogonal) rotation. Using the criterion of eigenvalue >1.0 produced a unidimensional solution with all items loading above 0.60 (McCroskey & Young, 1979) . The 7 items also demonstrated strong internal reliability (a = .87), and thus were averaged to form a single measure of Facebook communication frequency with the Friend.", "cite_spans": [{"start": 36, "end": 63, "text": "Lenhart and Madden's (2007)", "ref_id": "BIBREF34"}, {"start": 692, "end": 719, "text": "Baym and Ledbetter's (2009)", "ref_id": "BIBREF4"}, {"start": 1074, "end": 1099, "text": "(McCroskey & Young, 1979)", "ref_id": "BIBREF43"}], "ref_spans": []}, {"section": "Measurement", "text": "Offline communication. Several theorists in the field of computer-mediated communication urge examination of online communication alongside offline communication media (Baym et al., 2004; Sawhney, 2007; Walther & Parks, 2002) . Following this line of theoretical development, Ledbetter (2009b) factor-analyzed media use via a 6-point Likerttype scale structure (0 = never to 6 = very frequently) adopted from Scott and Timmerman (2005) , finding that face-to-face and telephone communication load onto the same factor of offline media use. We used the same instrument in this study to measure frequency of offline communication with the Friend, with an additional item measuring cellular-phone text messaging. These 3 items demonstrated good internal reliability (a = .85), and thus were treated as separate manifest indicators of a single latent construct in the confirmatory and structural models.", "cite_spans": [{"start": 168, "end": 187, "text": "(Baym et al., 2004;", "ref_id": "BIBREF5"}, {"start": 188, "end": 202, "text": "Sawhney, 2007;", "ref_id": "BIBREF59"}, {"start": 203, "end": 225, "text": "Walther & Parks, 2002)", "ref_id": "BIBREF80"}, {"start": 276, "end": 293, "text": "Ledbetter (2009b)", "ref_id": "BIBREF30"}, {"start": 409, "end": 435, "text": "Scott and Timmerman (2005)", "ref_id": "BIBREF60"}], "ref_spans": []}, {"section": "Measurement", "text": "Relational closeness. Vangelisti and Caughlin's (1997) 7-item measure assessed relational closeness with the Facebook Friend. Sample items include the following: \"How often do you talk about personal things with this person?\" and \"How close are you to this person?\" Participants responded on a 7-point Likert-type scale with response options ranging from 1 (not at all) to 7 (very much). The measure demonstrated strong internal reliability (a = .93).", "cite_spans": [{"start": 22, "end": 54, "text": "Vangelisti and Caughlin's (1997)", "ref_id": "BIBREF75"}], "ref_spans": []}, {"section": "Data Analysis", "text": "All hypotheses and research questions were addressed via structural equation modeling (SEM) using the LISREL 8.80 for Windows software package. Two chief advantages of SEM are holistic assessment of an a priori specified model, which is clearly advantageous for the model specified in this study ( Figure 1 ); in addition, SEM corrects for error variance and thus more accurately identifies parameters of interest. We assessed model fit using four frequently reported fit indices: (1) model chi-square, (2) the root mean square error of approximation (RMSEA), (3) the non-normed fit index (NNFI), and (4) the comparative fit index (CFI; Kline, 2005) . For the RMSEA statistic, lower values indicate better model fit, with 0.08 the traditional threshold for acceptable fit (and 0.05 for close fit). For the NNFI and CFI statistics, better fitting models achieve higher values, with 0.90 and 0.95 as traditional thresholds for acceptable and close model fit, respectively (Kline, 2005) .", "cite_spans": [{"start": 637, "end": 649, "text": "Kline, 2005)", "ref_id": "BIBREF25"}, {"start": 970, "end": 983, "text": "(Kline, 2005)", "ref_id": "BIBREF25"}], "ref_spans": [{"start": 298, "end": 306, "text": "Figure 1", "ref_id": "FIGREF3"}]}, {"section": "Data Analysis", "text": "As shown in Figure 1 , the hypothesized model contained 6 latent constructs: (1) attitude toward online self-disclosure (i.e., OSD), (2) attitude toward online social connection (i.e., OSC), (3) an interaction term for OSD and OSC, (4) Facebook communication frequency, (5) offline communication frequency, and (6) relational closeness. The OSD, OSC, Facebook communication, and relational closeness constructs were identified by creating three parcels (\"aggregate-level [indicators] comprised of the sum (or average) of two or more items, responses, or behaviors\"; Little, Cunningham, Shahar, & Widaman, 2002, p. 152) per latent construct. Given the unidimensional nature of these constructs, items were assigned to parcels by thirds (e.g., for the 6-item OSD measure, the first parcel contained Items 1 and 4, the second parcel contained Items 2 and 5, and the third parcel contained Items 3 and 6). Offline communication was identified by single-item indicators of face-to-face, telephone, and text messaging communication. The interaction effect was modeled by creating an orthogonalized interaction term, a method that more effectively removes multicollinearity than Baron and Kenny's (1986) method of mean-centering predictors prior to computing the interaction term. As described by Little, Card, Bovaird, Preacher, and Crandall (2007) , this necessitates forming a series of nine product terms between the mean-centered parcels for each construct (i.e., all possible multiplicative interactions between one of the three OSD parcels and one of the three OSC parcels). These product terms were then regressed onto the firstorder parcels, and their unstandardized residuals were saved. These unstandardized residuals were then combined into three parcels such that each interaction-term parcel contains only one instance of each of the first-order parcels (see Marsh et al., 2007) , resulting in indicators that are entirely orthogonal to the first-order indicators (e.g., Soliz & Harwood, 2006) . Table 1 presents the correlation matrix between the continuous study variables at the manifest level of measurement. Before latent variable analyses, an EM (expectation-maximization) algorithm imputed the trivial amount of missing data (less than 1%) in the data set (Vriens & Melton, 2002) . Consistent with standard two-step procedures for SEM (Kline, 2005) , confirmatory factor analysis (CFA) first evaluated the fit between the manifest indicators and their respective latent constructs. To evaluate potential covariates, a series of three metric invariance tests (Little, 1997) compared (1) male and female participants, (2) undergraduatestudent status (i.e., undergraduate versus nonundergraduate participants), and (3) local and long-distance friends. Specifically, this procedure invokes a sequential series of model constraints that evaluate equality of indicator loadings (i.e., weak metric invariance), equality of indicator means (i.e., strong metric invariance), and homogeneity of the variance/covariance matrix among latent constructs. These tests indicated both weak and strong metric invariance Thus, any apparent differences between groups are likely due to chance variation, and thus all groups should be analyzed in a single structural model (Ledbetter, 2009a) To further probe the nature of the association between the two components of online communication attitude and Facebook communication, the interaction effect was decomposed using the method described by Cohen, Cohen, West, and Aiken (2003) . To do this, we recomputed the structural model as a mean and covariance structures (MACS) model. As Kline noted, standard SEM lacks a mean structure (i.e., all latent variables are assumed to be standardized with a mean of 0), and thus information about means is lost. A mean structure is added to a structural model \"by regressing exogenous or endogenous variables on a constant that equals 1.0\" (2005, p. 287) . From the standpoint of regression analysis, this essentially adds intercept terms to both the manifest and latent variables. By identifying the model and mean structure via the contrast coding method described by Little, Slegers, and Card (2005) , we obtained intercepts and predicted values that reflect the original measurement metric of the manifest indicators, thus aiding interpretation of the interaction effect decomposition. Using these values to generate linear regression equations, we plotted the relationship between OSC and Facebook communication at three different levels of OSD (i.e., at the minimum value of 1, at the latent mean value of 3.63, and at the maximum value of 7). Figure 3 presents results of this decomposition.", "cite_spans": [{"start": 1172, "end": 1196, "text": "Baron and Kenny's (1986)", "ref_id": "BIBREF3"}, {"start": 1290, "end": 1342, "text": "Little, Card, Bovaird, Preacher, and Crandall (2007)", "ref_id": "BIBREF37"}, {"start": 1866, "end": 1885, "text": "Marsh et al., 2007)", "ref_id": "BIBREF41"}, {"start": 1978, "end": 2000, "text": "Soliz & Harwood, 2006)", "ref_id": "BIBREF63"}, {"start": 2270, "end": 2293, "text": "(Vriens & Melton, 2002)", "ref_id": "BIBREF76"}, {"start": 2349, "end": 2362, "text": "(Kline, 2005)", "ref_id": "BIBREF25"}, {"start": 3266, "end": 3284, "text": "(Ledbetter, 2009a)", "ref_id": "BIBREF29"}, {"start": 3488, "end": 3524, "text": "Cohen, Cohen, West, and Aiken (2003)", "ref_id": "BIBREF11"}], "ref_spans": [{"start": 12, "end": 20, "text": "Figure 1", "ref_id": "FIGREF3"}, {"start": 2003, "end": 2010, "text": "Table 1", "ref_id": "TABREF5"}, {"start": 4634, "end": 4642, "text": "Figure 3", "ref_id": "FIGREF6"}]}, {"section": "Results", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Structural Model", "text": "Though OSC positively predicts Facebook communication when OSD is low, increased levels of OSD weaken the strength of this association. Specifically, OSC significantly predicts Facebook communication at both the minimum, B = 0.29 (95% CI = 0.15-0.44), b = .39 (95% CI = 0.20-0.58, p < .01), and mean, B = 0.17 (95% CI = 0.09-0.26), b = .23 (95% CI = 0.11-0.34, p < .01), levels of OSD, but the association is nonsignificant at a maximum OSD score: B = 0.02 (95% CI = -0.15 to 0.19) and b = .02 (95% CI = -0.20 to 0.25, p > .05). Examination of the graph indicates that the regression lines converge at an OSC value between the minimum and the mean. Solving the regression equations for this point of convergence reveals that it occurs when an individual's OSC score is 1.88. In other words, when an individual's OSC is slightly below a mean response of 2 (i.e., disagree), that individual's Facebook communication with a specific Friend will tend to be 0.77 (i.e., slightly below a mean response of 1, or very rarely) regardless of that individual's level of OSD. Taken as a whole, these results suggest that OSD has a moderate inverse association with Facebook communication when OSC is high, and OSC has a moderate positive association with Facebook communication when OSD is low. At low levels of OSC or high levels of OSD, the effect of the other independent variable becomes much weaker. 42", "cite_spans": [], "ref_spans": []}, {"section": "Communication Research 38(1)", "text": "The initially hypothesized model also predicted that both offline and Facebook communication are positively associated with relational closeness. When controlling for the significantly positive covariance between these two latent constructs, Y = .72 (95% CI = 0.65-0.79, p < .01), both offline communication, B = 1.30 (95% CI = 1.02-1.57) and b = .70 (95% CI = 0.55-0.85, p < .01), and Facebook communication, B = 0.33 (95% CI = 0.13-0.53) and \u03b2 = .18 (95% CI = 0.07-0.30, p < .01), emerged as separate predictors of relational closeness. Offline communication appeared to be a much stronger predictor than Facebook communication, and thus we formally tested the significance of this difference by creating a nested model with the relevant regression paths constrained to equality; this produced a significant decline in model fit, Dc 2 (1) = 24.28, p < .01, demonstrating that offline communication is indeed a stronger predictor of closeness.", "cite_spans": [], "ref_spans": []}, {"section": "Communication Research 38(1)", "text": "In addition to direct effects on relational closeness, the model also leaves the possibility that online communication attitude (i.e., OSC and OSD) indirectly predicts relational closeness via Facebook communication. This possibility was tested via Preacher and Hayes's (2004) procedure for generating robust estimates of unstandardized regression weights with nonparametric bootstrapping, a technique in which \"cases from the original data file are randomly selected with replacement to generate other data sets, usually with the same number of cases as the original\" (Kline, 2005, p. 42) . After computing the structural model across these data sets, the unstandardized regression weight is defined as the mean of the products of the indirect path's component parameter estimates; statistical significance is then determined by (a) sorting these estimates in ascending order, and (b) when a = .05 and k represents the number of bootstrapped samples, obtaining the values that appear at .025 \u00d7 k and .975 \u00d7 k in the ordered list. These represent the boundaries of the confidence interval; if this interval does not contain zero, then the bootstrapped estimate is statistically significant. As bootstrapping does not assume normal distribution of unstandardized regression weights, the boundaries of the confidence interval are not necessarily symmetrical around the estimate. Standardized regression weight estimates were obtained via the covariance matrix of latent constructs from computation of a model based on bootstrapped estimates of the covariance matrix of manifest indicators.", "cite_spans": [{"start": 249, "end": 276, "text": "Preacher and Hayes's (2004)", "ref_id": "BIBREF52"}], "ref_spans": []}, {"section": "Communication Research 38(1)", "text": "Bootstrap analyses revealed that OSC, B = 0.08 (95% CI = 0.01-0.15) and b = .04 (95% CI = 0.01-0.08, p < .05); OSD, B = -0.04 (95% CI = -0.10 to -0.001) and b = -.02 (95% CI = -0.06 to -0.001, p < .05); and the interaction effect, B = -0.03 (95% CI = -0.07 to -0.001) and b = -.02 (95% CI = -0.04 to -0.001, p < .05), significantly and indirectly predicted relational closeness. As the contrast coding method of identification is not amenable to bootstrapping in LISREL, we could not decompose the interaction effect in the metric of the original variables. Rather, we conducted decomposition using information from bootstrapped models with latent construct variance fixed to 1.0, thus expressing the interaction effect in terms of construct standard deviations. The pattern of results from this decomposition was almost identical to the decomposition for Facebook communication (Figure 3) , such that OSC is a significant positive predictor of relational closeness at low, that is, two standard deviations below the mean, B = 0.14 (95% CI = 0.04-0.23) and b = .07 (95% CI = 0.02-0.13, p < .01), and mean, B = 0.08 (95% CI = 0.01-0.15) and b = .04 (95% CI = 0.01-0.07, p < .05), levels of OSD but not when OSD is high, that is, two standard deviations above the mean, B = 0.01 (95% CI = -0.08-0.11) and b = .01 (95% CI = -0.04-0.06, p > .05). Together, the direct and indirect effects explained 70.7% of the variance in relational closeness.", "cite_spans": [], "ref_spans": [{"start": 879, "end": 889, "text": "(Figure 3)", "ref_id": "FIGREF6"}]}, {"section": "Discussion", "text": "The overarching goal of this investigation was to test a theoretical model whereby trait-like attitudes toward online communication predict Facebook and offline communication, with these constructs then predicting relational closeness. Results generally supported the hypothesized model, with the exception of the speculated paths between online communication attitude and offline communication. More important, OSD functioned somewhat differently than predicted by some previous online communication research (e.g., Caplan, 2007; McKenna et al., 2002) , not only yielding an inverse main association with Facebook communication but also reducing the positive contribution of OSC to this dependent variable and, indirectly, to relational closeness. Taken as a whole, these results support media multiplexity theory (Haythornthwaite, 2005) yet suggest that the theoretical expectation that social anxiety fosters online communication (Caplan, 2007) ", "cite_spans": [{"start": 517, "end": 530, "text": "Caplan, 2007;", "ref_id": "BIBREF10"}, {"start": 531, "end": 552, "text": "McKenna et al., 2002)", "ref_id": "BIBREF44"}, {"start": 815, "end": 838, "text": "(Haythornthwaite, 2005)", "ref_id": "BIBREF18"}, {"start": 933, "end": 947, "text": "(Caplan, 2007)", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "Online Communication Attitude and Communication Frequency", "text": "One of Facebook's core functions is building connections within a social network (Zuckerberg, 2008) , and, as expected (Hypothesis 3), those who use online communication for that purpose (i.e., possess high OSC) are more likely to communicate with their Facebook Friends (Tufekci, 2008) . As the OSC variable addresses orientation toward a preexisting social network rather than just a dyad, this calls attention to the need to understand broader network-level forces when examining dyadic relationships. In other words, traditional interpersonal communication theory considers closeness as an outcome of dyad-and individual-level variables, whereas OSC is an individual-level variable that may bespeak group-and network-level realities. Though network forces no doubt operate offline as well (Parks, 2006) , Donath (2007) argues that SNSs facilitate creation of social supernets, or social networks, \"with many more ties than is feasible without socially assistive tools\" (p. 231); this may only augment group-and network-level effects on specific dyads. The social-relationships model (Kenny, Kashy, & Cook, 2006) permits statistical isolation of individual, dyadic, and group effects and thus may be an invaluable tool for identifying which effects are truly individual, truly unique to the dyad, or truly a reflection of broader social forces.", "cite_spans": [{"start": 81, "end": 99, "text": "(Zuckerberg, 2008)", "ref_id": "BIBREF88"}, {"start": 271, "end": 286, "text": "(Tufekci, 2008)", "ref_id": "BIBREF70"}, {"start": 793, "end": 806, "text": "(Parks, 2006)", "ref_id": "BIBREF49"}, {"start": 809, "end": 822, "text": "Donath (2007)", "ref_id": "BIBREF12"}, {"start": 1087, "end": 1115, "text": "(Kenny, Kashy, & Cook, 2006)", "ref_id": "BIBREF24"}], "ref_spans": []}, {"section": "Online Communication Attitude and Communication Frequency", "text": "Similarly, drawing from previous research and theory indicating that social anxiety produces attraction to OSD (e.g., Caplan, 2007; McKenna et al., 2002) , we predicted that OSD would positively predict Facebook communication with a specific Friend (Hypothesis 1). Instead, OSD inversely predicted Facebook communication in the final model. This differs both from the positive zero-order association with SNS use reported in Ledbetter (2009b) and the nonsignificant zero-order association reported here (see Table 1 ). This suggests that, when examined in the context of a structural model that controls for the shared variance between Facebook and offline communication, OSD may not foster Facebook use as it does other forms of online communication. Interpreting this unexpected finding requires reconsidering the theoretical mechanisms that underlie the association between preference for OSD and online communication use. One approach is to consider the role of moderating variables. McKenna et al. examined how individuals selfdisclose within completely online relationships, whereas most Facebook friendships exist between individuals who also know each other offline ; thus, considering the moderating influence of a relationship's medium of origin (as well as current degree of multimodality) in future research might further explain this unexpected finding.", "cite_spans": [{"start": 118, "end": 131, "text": "Caplan, 2007;", "ref_id": "BIBREF10"}, {"start": 132, "end": 153, "text": "McKenna et al., 2002)", "ref_id": "BIBREF44"}, {"start": 425, "end": 442, "text": "Ledbetter (2009b)", "ref_id": "BIBREF30"}], "ref_spans": [{"start": 508, "end": 515, "text": "Table 1", "ref_id": "TABREF5"}]}, {"section": "Online Communication Attitude and Communication Frequency", "text": "Alternatively (yet not necessarily in contradiction), as Caplan notes, the logic of the expectation that OSD positively predicts communication frequency rests in the communicator's desire to manage self-presentation and identity:", "cite_spans": [], "ref_spans": []}, {"section": "Online Communication Attitude and Communication Frequency", "text": "In almost all social interactions, people are motivated to engage in strategic self presentation and identity management and to avoid making undesired impressions on others. Social anxiety arises from the desire to create a positive impression of one's self in others along with a lack of self-presentational confidence. Most importantly . . . the self-presentational theory of social anxiety posits that, in order to increase their perceived self-presentational efficacy, socially anxious individuals are highly motivated to seek low-risk communicative encounters. (p. 235) Traditional forms of online communication (e.g., e-mail) provide such low-risk encounters, as the private and/or asynchronous nature of the communication medium permits almost complete control over self-presentation (Walther, 1996) . Yet Donath (2007 ) argued (and Tong, Van Der Heide, Langwell, & Walther, 2008 , empirically confirm) that users of an SNS are evaluated, in part, in terms of the nature of their social connections with others; thus, it stands to reason that identity management partially lies within the control of social network members (and outside the control of the individual). Recent empirical evidence supports this theoretical claim, finding that wall posts written by friends and the physical attractiveness of those friends influences perception of a Facebook profile's owner . Walther and his colleagues explained these findings in terms of the information's level of warrant, or \"degree to which that information is perceived to be immune to manipulation from the target to whom the information pertains\" (p. 32); a wall post by a Facebook Friend is an example of such high-warrant information. Because the information target cannot favorably alter that information, Walther, Van Der Heide, Hamel, and Shulman (2009) argue that others perceive that information as more trustworthy than low-warrant information. Recent empirical evidence supports this expectation. Taken together with Caplan's findings (2007) and results of the current study, it is possible that those who are socially anxious may prefer traditional forms of online communication because they wish to control their own self-presentation by avoiding high-warrant information. As Facebook's site design encourages proliferation of high-warrant information (Zuckerberg, 2006) , those with high OSD may avoid it in favor of other low-warrant forms of online communication.", "cite_spans": [{"start": 791, "end": 806, "text": "(Walther, 1996)", "ref_id": "BIBREF77"}, {"start": 813, "end": 825, "text": "Donath (2007", "ref_id": "BIBREF12"}, {"start": 1771, "end": 1820, "text": "Walther, Van Der Heide, Hamel, and Shulman (2009)", "ref_id": "BIBREF82"}, {"start": 2325, "end": 2343, "text": "(Zuckerberg, 2006)", "ref_id": "BIBREF87"}], "ref_spans": []}, {"section": "Online Communication Attitude and Communication Frequency", "text": "This line of argument is further supported by decomposition of the interaction effect between OSD and OSC on Facebook communication (Research Question 1). Though OSC is a positive predictor of Facebook communication when OSD is low, this association is nonsignificant at high levels of OSD. That is, high levels of OSD tend to weaken the association between OSC and Facebook communication. As noted in the theoretical warrant, such a finding supports Caplan's argument that OSD is socially debilitating, perhaps reducing beneficial outcomes that might otherwise accrue from the desire to maintain preexisting relationships online. In other words, if preference for OSD does reflect a desire for greater control over self-presentation (Caplan, 2007) , such a motivation may override a person's desire to build online social connections. Following Walther and his colleagues' (2008) recent research, perhaps those who possess both high OSC and high OSD seek out forms of online communication that do not provide high-warrant information. In terms of theoretical development, this suggests that social anxiety is not necessarily associated with online communication as a whole but rather encourages use of media that lack high-warrant information, online or otherwise. Testing this theoretical claim via experiment is a clear direction for future research.", "cite_spans": [{"start": 734, "end": 748, "text": "(Caplan, 2007)", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "Online Communication Attitude and Communication Frequency", "text": "The expectations that self-disclosure (Hypothesis 2), social connection (Hypothesis 4), and the interaction between them (Research Question 3) would predict offline 46", "cite_spans": [], "ref_spans": []}, {"section": "Communication Research 38(1)", "text": "communication were not supported in the final model. Though previous research reports significant zero-order associations between these constructs and face-to-face communication frequency (Ledbetter, 2009b) , a significant association did not emerge when modeling offline communication as a latent construct and controlling for variance shared with Facebook communication. Perhaps other structural/contextual variables (such as temporal ability to synchronize schedules for offline contact; Ling & Yttri, 2002) influence frequency of offline communication with specific Facebook Friends, and thus the hypothesized associations did not emerge.", "cite_spans": [{"start": 188, "end": 206, "text": "(Ledbetter, 2009b)", "ref_id": "BIBREF30"}, {"start": 491, "end": 510, "text": "Ling & Yttri, 2002)", "ref_id": "BIBREF35"}], "ref_spans": []}, {"section": "Relational Closeness", "text": "As predicted by media multiplexity theory (Haythornthwaite, 2005) , both offline communication (Hypothesis 6) and Facebook communication (Hypothesis 7) positively predicted relational closeness. This replicates the pattern of results obtained by Baym and Ledbetter's (2009) study of Last.fm, a music-oriented SNS, suggesting that the predictions of media multiplexity theory apply across many types of SNSs. What remains unanswered is whether use of multiple SNSs with the same friend also additively contributes to relational outcomes; indeed, we are not aware of any study that examines SNS use as a multimodal phenomenon. But if researchers cannot fully understand online communication use apart from patterns of offline communication behavior (Baym et al., 2004 , and as our final model indicates), then one might expect that continually examining single SNSs in isolation may yield an incomplete theoretical picture of their role in interpersonal relationships. The measures employed here offer at least some of the tools necessary for such future research. It is important to note that our Facebook communication scale was developed and used in the present study before some recent alterations were made to Facebook's status message feature; when these data were collected, the status-message feature forced users to include the word \"is\" (e.g., \"John is tired\" was possible, whereas \"John stayed up too late last night\" was not), and the feature did not include the ability to attach direct comments to a status message. Even though the instrument demonstrated strong internal reliability and unidimensional structure (as did Baym & Ledbetter's measure of Last.fm communication), scholars should consider the status message as a possible scale item in future investigations, as well as any other new forms of communication developed on such a continuously evolving website.", "cite_spans": [{"start": 42, "end": 65, "text": "(Haythornthwaite, 2005)", "ref_id": "BIBREF18"}, {"start": 246, "end": 273, "text": "Baym and Ledbetter's (2009)", "ref_id": "BIBREF4"}, {"start": 747, "end": 765, "text": "(Baym et al., 2004", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Relational Closeness", "text": "Both dimensions of online communication attitude and the interaction effect between them produced significant indirect effects on relational closeness. OSD inversely predicted relational closeness (thus answering Research Question 1), and OSC emerged as a positive predictor (Hypothesis 8). This pattern of results supports our chief contention that OSC is a healthy, communicatively competent motivation for using online communication; however, motivation arising from OSD is associated with negative relational outcomes (Ledbetter, 2009b) . As such, this investigation provides empirical evidence consistent with the theoretical expectation that attraction to OSD produces not only negative psychosocial outcomes but also negative relational outcomes (Caplan, 2003) . These results are also consistent with the finding that Facebook communication better supports and facilitates the concept of bridging (versus bonding) of social capital . As with decomposition of the interaction effect's association with Facebook communication, OSD and OSC interact in such a way that high OSD reduces the positive indirect association between OSC and relational closeness to nonsignificance. This is consistent with media multiplexity theory (Haythornthwaite, 2005) as, to the extent that high OSD reduces OSC's association with Facebook communication, the theory suggests that losses in closeness would occur unless dyad members compensate with the addition of another medium. Such an interpretation also follows Haythornthwaite's finding that different social networks enact different hierarchies of media use.", "cite_spans": [{"start": 522, "end": 540, "text": "(Ledbetter, 2009b)", "ref_id": "BIBREF30"}, {"start": 753, "end": 767, "text": "(Caplan, 2003)", "ref_id": "BIBREF9"}, {"start": 1231, "end": 1254, "text": "(Haythornthwaite, 2005)", "ref_id": "BIBREF18"}], "ref_spans": []}, {"section": "Relational Closeness", "text": "The direct and indirect effects in the model explained a large amount of the variance in relational closeness (approximately 71%). Along with other recent empirical evidence (Baym & Ledbetter, 2009; Ledbetter, 2009c) , this suggests that media multiplexity is a parsimonious yet robust account of how media use is associated with strength of a relational tie. In turn, this further supports the importance of studying individual attitudinal factors that may foster or inhibit use of particular communication media. On a more practical level, these results refute some popular claims that SNSs reduce relational closeness (Henry, 2007; Tilsner, 2008) , as Facebook communication positively predicted relational closeness even when controlling for the contribution of offline communication. However, this finding must be interpreted in light of the significantly stronger association between offline communication and relational closeness (perhaps reflecting that relational maintenance is more temporally efficient via media with multiple nonverbal cues; Walther, 1996) .", "cite_spans": [{"start": 174, "end": 198, "text": "(Baym & Ledbetter, 2009;", "ref_id": "BIBREF4"}, {"start": 199, "end": 216, "text": "Ledbetter, 2009c)", "ref_id": "BIBREF31"}, {"start": 621, "end": 634, "text": "(Henry, 2007;", "ref_id": "BIBREF19"}, {"start": 635, "end": 649, "text": "Tilsner, 2008)", "ref_id": "BIBREF68"}, {"start": 1054, "end": 1068, "text": "Walther, 1996)", "ref_id": "BIBREF77"}], "ref_spans": []}, {"section": "Conclusion", "text": "Of course, any study must be interpreted within the limitations imposed by the research design. Though it is tempting to make causal inferences from analytic methods that model endogenous and exogenous variables, the cross-sectional nature of the data necessitates caution. Future longitudinal research might test the extent to which closeness predicts communication frequency or vice versa. Though a particular strength of the study is the inclusion of data beyond a college-student sample and establishment of metric invariance across groups, the sample is relatively homogeneous regarding racial and ethnic identity. Future research may consider cultural dimensions such as individualism and collectivism that have demonstrated associations with online communication in previous research (Lee & Choi, 2005; Zhang, Lowry, Zhou, & Fu, 2007) . Our sample also contained more women than men, even though our recruitment procedures were not sex specific in any respect. We do not possess an explanation for why more women completed our questionnaire, and nonsignificant metric invariance tests suggest this probably does not influence study results greatly. The study also explained a relatively small amount of variance in Facebook communication; this is perhaps to be expected when global trait-like constructs predict variables located within specific relational contexts. Future research might address this by more explicitly examining the degree of variance that exists within individual SNS networks; dyadic data analyses (Kenny et al., 2006) may also yield higher effect sizes by accounting for the attitudes of both friends.", "cite_spans": [{"start": 791, "end": 809, "text": "(Lee & Choi, 2005;", "ref_id": "BIBREF33"}, {"start": 810, "end": 841, "text": "Zhang, Lowry, Zhou, & Fu, 2007)", "ref_id": "BIBREF86"}, {"start": 1526, "end": 1546, "text": "(Kenny et al., 2006)", "ref_id": "BIBREF24"}], "ref_spans": []}, {"section": "Conclusion", "text": "It is also worth noting that this investigation did not directly measure participant social anxiety. Though multiple studies establish preference for OSD as positively associated with social anxiety and related constructs (Caplan, 2007; Ho & McLeod, 2008; Kelly & Keaten, 2007; McKenna et al., 2002; Morahan-Martin & Schumacher, 2003; Valkenburg & Peter, 2008 ) and thus warrants use as an interpretive heuristic in this investigation, it remains possible that other forces foster a positive attitude toward OSD, such as the desire to create a sense of relational immediacy (e.g., in teacher-student relationships; Mazer et al., 2007) or finding others who share rare or stigmatized conditions (Walther & Boyd, 2002) . To the extent that social anxiety is not perfectly associated with OSD, it remains possible that OSD is positively associated with relational outcomes if shared variance with social anxiety were controlled. Of course, verifying this speculation requires further empirical investigation.", "cite_spans": [{"start": 222, "end": 236, "text": "(Caplan, 2007;", "ref_id": "BIBREF10"}, {"start": 237, "end": 255, "text": "Ho & McLeod, 2008;", "ref_id": "BIBREF20"}, {"start": 256, "end": 277, "text": "Kelly & Keaten, 2007;", "ref_id": "BIBREF23"}, {"start": 278, "end": 299, "text": "McKenna et al., 2002;", "ref_id": "BIBREF44"}, {"start": 300, "end": 334, "text": "Morahan-Martin & Schumacher, 2003;", "ref_id": "BIBREF46"}, {"start": 335, "end": 359, "text": "Valkenburg & Peter, 2008", "ref_id": "BIBREF73"}, {"start": 615, "end": 634, "text": "Mazer et al., 2007)", "ref_id": "BIBREF42"}, {"start": 694, "end": 716, "text": "(Walther & Boyd, 2002)", "ref_id": "BIBREF78"}], "ref_spans": []}, {"section": "Conclusion", "text": "Given their widespread proliferation and adoption, especially among younger users (Lenhart & Madden, 2007) , it stands to reason that SNSs will remain an important medium for maintaining social connections. The existence of these sites raises important questions regarding individual traits that might influence online communication frequency and the integration of dyads into larger social structures (Parks, 2006) . These results inform these broader projects by further identifying attitude toward online self-disclosure and social connection as two such traits that may produce divergent effects on both media use and, to some degree, subsequent outcomes in interpersonal relationships.", "cite_spans": [{"start": 82, "end": 106, "text": "(Lenhart & Madden, 2007)", "ref_id": "BIBREF34"}, {"start": 402, "end": 415, "text": "(Parks, 2006)", "ref_id": "BIBREF49"}], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Imagined communities: Awareness, information sharing, and privacy on the Facebook", "authors": [{"first": "A", "middle": [], "last": "Acquisti", "suffix": ""}, {"first": "R", "middle": [], "last": "Gross", "suffix": ""}], "year": 2006, "venue": "Proceedings of the 6 th workshop on privacy enhancing technologies", "link": "600035"}, "BIBREF1": {"title": "Social penetration: The development of interpersonal relationships", "authors": [{"first": "I", "middle": [], "last": "Altman", "suffix": ""}, {"first": "D", "middle": [], "last": "Taylor", "suffix": ""}], "year": 1973, "venue": "", "link": "142635962"}, "BIBREF2": {"title": "Closeness as including other in the self", "authors": [{"first": "A", "middle": ["P"], "last": "Aron", "suffix": ""}, {"first": "D", "middle": ["J"], "last": "Mashek", "suffix": ""}, {"first": "E", "middle": ["N"], "last": "Aron", "suffix": ""}], "year": 2004, "venue": "Handbook of closeness and intimacy", "link": "150001319"}, "BIBREF3": {"title": "The moderator-mediator variable distinction in social psychological research: Conceptual, strategic, and statistical considerations", "authors": [{"first": "R", "middle": ["M"], "last": "Baron", "suffix": ""}, {"first": "D", "middle": ["A"], "last": "Kenny", "suffix": ""}], "year": 1986, "venue": "Journal of Personality and Social Psychology", "link": "1925599"}, "BIBREF4": {"title": "Tunes that bind? Predicting friendship strength in a music-based social network. Information", "authors": [{"first": "N", "middle": ["K"], "last": "Baym", "suffix": ""}, {"first": "A", "middle": ["M"], "last": "Ledbetter", "suffix": ""}], "year": 2009, "venue": "Communication & Society", "link": null}, "BIBREF5": {"title": "Social interactions across media: Interpersonal communication on the internet, telephone, and face-to-face", "authors": [{"first": "N", "middle": ["K"], "last": "Baym", "suffix": ""}, {"first": "Y", "middle": ["B"], "last": "Zhang", "suffix": ""}, {"first": "M.-C", "middle": [], "last": "Lin", "suffix": ""}], "year": 2004, "venue": "New Media & Society", "link": "206726065"}, "BIBREF6": {"title": "Social network sites: Definition, history, and scholarship", "authors": [{"first": "D", "middle": ["M"], "last": "Boyd", "suffix": ""}, {"first": "N", "middle": ["B"], "last": "Ellison", "suffix": ""}], "year": 2007, "venue": "Journal of Computer Mediated Communication", "link": "154752238"}, "BIBREF7": {"title": "Handbook of Interpersonal Communication", "authors": [{"first": "B", "middle": ["R"], "last": "Burleson", "suffix": ""}, {"first": "E", "middle": ["L"], "last": "Macgeorge", "suffix": ""}], "year": 2002, "venue": "", "link": null}, "BIBREF8": {"title": "Problematic Internet use and psychosocial well-being: Development of a theory-based cognitive-behavioral measure", "authors": [{"first": "S", "middle": ["E"], "last": "Caplan", "suffix": ""}], "year": 2002, "venue": "Computers in Human Behavior", "link": "10994348"}, "BIBREF9": {"title": "Preference for online social interaction: A theory of problematic Internet use and psychosocial well-being", "authors": [{"first": "S", "middle": ["E"], "last": "Caplan", "suffix": ""}], "year": 2003, "venue": "Communication Research", "link": "27459923"}, "BIBREF10": {"title": "Relations among loneliness, social anxiety, and problematic Internet use", "authors": [{"first": "S", "middle": ["E"], "last": "Caplan", "suffix": ""}], "year": 2007, "venue": "CyberPsychology & Behavior", "link": "30216573"}, "BIBREF11": {"title": "Applied multiple regression/correlation analysis for the behavioral sciences", "authors": [{"first": "J", "middle": [], "last": "Cohen", "suffix": ""}, {"first": "P", "middle": [], "last": "Cohen", "suffix": ""}, {"first": "S", "middle": ["G"], "last": "West", "suffix": ""}, {"first": "L", "middle": ["S"], "last": "Aiken", "suffix": ""}], "year": 2003, "venue": "", "link": "122050980"}, "BIBREF12": {"title": "Signals in social supernets", "authors": [{"first": "J", "middle": [], "last": "Donath", "suffix": ""}], "year": 2007, "venue": "Journal of Computer-Mediated Communication", "link": "16784421"}, "BIBREF13": {"title": "Grooming, gossip, and the evolution of language", "authors": [{"first": "R", "middle": [], "last": "Dunbar", "suffix": ""}], "year": 1998, "venue": "", "link": "144730829"}, "BIBREF14": {"title": "The benefits of Facebook \"friends\": Social capital and college students' use of online social network sites", "authors": [{"first": "N", "middle": ["B"], "last": "Ellison", "suffix": ""}, {"first": "C", "middle": [], "last": "Steinfield", "suffix": ""}, {"first": "C", "middle": [], "last": "Lampe", "suffix": ""}], "year": 2007, "venue": "Journal of Computer-Mediated Communication", "link": "11940919"}, "BIBREF16": {"title": "America calling: A social history of the telephone to 1940", "authors": [{"first": "C", "middle": ["S"], "last": "Fischer", "suffix": ""}], "year": 1992, "venue": "", "link": "164267293"}, "BIBREF17": {"title": "Whose space? Differences among users and non-users of social network sites", "authors": [{"first": "E", "middle": [], "last": "Hargittai", "suffix": ""}], "year": 2007, "venue": "", "link": "16068354"}, "BIBREF18": {"title": "Social networks and internet connectivity effects. Information, Communication & Society", "authors": [{"first": "C", "middle": [], "last": "Haythornthwaite", "suffix": ""}], "year": 2005, "venue": "", "link": null}, "BIBREF19": {"title": "How do you define a friend? Newhouse News Service", "authors": [{"first": "F", "middle": [], "last": "Henry", "suffix": ""}], "year": 2007, "venue": "", "link": null}, "BIBREF20": {"title": "Social-psychological influences on opinion expression in face-to-face and computer-mediated communication", "authors": [{"first": "S", "middle": ["S"], "last": "Ho", "suffix": ""}, {"first": "D", "middle": ["M"], "last": "Mcleod", "suffix": ""}], "year": 2008, "venue": "Communication Research", "link": "32599085"}, "BIBREF21": {"title": "Relational progression as a dialectic: Examining turning points in communication among friends. Communication Monographs", "authors": [{"first": "A", "middle": ["J"], "last": "Johnson", "suffix": ""}, {"first": "E", "middle": [], "last": "Wittenberg", "suffix": ""}, {"first": "M", "middle": ["M"], "last": "Villagran", "suffix": ""}, {"first": "M", "middle": [], "last": "Mazur", "suffix": ""}, {"first": "P", "middle": [], "last": "Villagran", "suffix": ""}], "year": 2003, "venue": "", "link": "144247540"}, "BIBREF22": {"title": "Self-disclosure in computer-mediated communication: The role of self-awareness and visual anonymity", "authors": [{"first": "A", "middle": ["N"], "last": "Joinson", "suffix": ""}], "year": 2001, "venue": "European Journal of Social Psychology", "link": "8531351"}, "BIBREF23": {"title": "Development of the affect for communication channels scale", "authors": [{"first": "L", "middle": [], "last": "Kelly", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Keaten", "suffix": ""}], "year": 2007, "venue": "Journal of Communication", "link": "145697413"}, "BIBREF24": {"title": "Dyadic data analysis", "authors": [{"first": "D", "middle": ["A"], "last": "Kenny", "suffix": ""}, {"first": "D", "middle": ["A"], "last": "Kashy", "suffix": ""}, {"first": "W", "middle": ["L"], "last": "Cook", "suffix": ""}], "year": 2006, "venue": "", "link": "142666556"}, "BIBREF25": {"title": "Principles and practice of structural equation modeling", "authors": [{"first": "R", "middle": ["B"], "last": "Kline", "suffix": ""}], "year": 2005, "venue": "", "link": null}, "BIBREF26": {"title": "Internet paradox: A social technology that reduces social involvement and psychological well-being?", "authors": [{"first": "R", "middle": [], "last": "Kraut", "suffix": ""}, {"first": "M", "middle": [], "last": "Patterson", "suffix": ""}, {"first": "V", "middle": [], "last": "Lundmark", "suffix": ""}, {"first": "S", "middle": [], "last": "Kiesler", "suffix": ""}, {"first": "T", "middle": [], "last": "Mukhopadhyay", "suffix": ""}, {"first": "W", "middle": [], "last": "Scherlis", "suffix": ""}], "year": 1998, "venue": "American Psychologist", "link": "513632"}, "BIBREF28": {"title": "Intimacy as an interpersonal process: The importance of self-disclosure, partner disclosure, and perceived partner responsiveness in interpersonal exchanges", "authors": [{"first": "J.-P", "middle": [], "last": "Laurenceau", "suffix": ""}, {"first": "L", "middle": ["F"], "last": "Barrett", "suffix": ""}, {"first": "P", "middle": ["R"], "last": "Pietromonaco", "suffix": ""}], "year": 1998, "venue": "Journal of Personality and Social Psychology", "link": "1209571"}, "BIBREF29": {"title": "Family communication patterns and relational maintenance behavior: Direct and mediated associations with friendship closeness", "authors": [{"first": "A", "middle": ["M"], "last": "Ledbetter", "suffix": ""}], "year": 2009, "venue": "Human Communication Research", "link": null}, "BIBREF30": {"title": "Measuring online communication attitude: Instrument development and validation", "authors": [{"first": "A", "middle": ["M"], "last": "Ledbetter", "suffix": ""}], "year": 2009, "venue": "Communication Monographs", "link": "143642549"}, "BIBREF31": {"title": "Patterns of media use and multiplexity: Associations with sex, geographic distance, and friendship interdependence", "authors": [{"first": "A", "middle": ["M"], "last": "Ledbetter", "suffix": ""}], "year": 2009, "venue": "New Media & Society", "link": "21015401"}, "BIBREF32": {"title": "Forecasting \"friends forever\": A longitudinal investigation of sustained closeness between college best friends", "authors": [{"first": "A", "middle": ["M"], "last": "Ledbetter", "suffix": ""}, {"first": "E", "middle": [], "last": "Griffin", "suffix": ""}, {"first": "G", "middle": ["G"], "last": "Sparks", "suffix": ""}], "year": 2007, "venue": "Personal Relationships", "link": null}, "BIBREF33": {"title": "The role of horizontal and vertical individualism and collectivism in online consumers' response toward persuasive communication on the Web", "authors": [{"first": "W.-N", "middle": [], "last": "Lee", "suffix": ""}, {"first": "S", "middle": ["M"], "last": "Choi", "suffix": ""}], "year": 2005, "venue": "Journal of ComputerMediated Communication", "link": null}, "BIBREF34": {"title": "Teens, privacy and online social networks: How teens manage their online identities and personal information in the age of MySpace. Pew Internet & American Life Project", "authors": [{"first": "A", "middle": [], "last": "Lenhart", "suffix": ""}, {"first": "M", "middle": [], "last": "Madden", "suffix": ""}], "year": 2007, "venue": "", "link": null}, "BIBREF35": {"title": "Hyper-coordination via mobile phones in Norway", "authors": [{"first": "R", "middle": [], "last": "Ling", "suffix": ""}, {"first": "B", "middle": [], "last": "Yttri", "suffix": ""}], "year": 2002, "venue": "", "link": "142708339"}, "BIBREF36": {"title": "Mean and covariance structures (MACS) analyses of cross-cultural data: Practical and theoretical issues", "authors": [{"first": "T", "middle": ["D"], "last": "Little", "suffix": ""}], "year": 1997, "venue": "Multivariate Behavioral Research", "link": "207055455"}, "BIBREF37": {"title": "Structural equation modeling of mediation and moderation with contextual factors", "authors": [{"first": "T", "middle": ["D"], "last": "Little", "suffix": ""}, {"first": "N", "middle": ["A"], "last": "Card", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Bovaird", "suffix": ""}, {"first": "K", "middle": [], "last": "Preacher", "suffix": ""}, {"first": "C", "middle": ["S"], "last": "Crandall", "suffix": ""}], "year": 2007, "venue": "Modeling contextual effects in longitudinal studies", "link": "12915719"}, "BIBREF38": {"title": "To parcel or not to parcel: Exploring the question, weighing the merits", "authors": [{"first": "T", "middle": ["D"], "last": "Little", "suffix": ""}, {"first": "W", "middle": ["A"], "last": "Cunningham", "suffix": ""}, {"first": "G", "middle": [], "last": "Shahar", "suffix": ""}, {"first": "K", "middle": ["F"], "last": "Widaman", "suffix": ""}], "year": 2002, "venue": "Structural Equation Modeling", "link": null}, "BIBREF39": {"title": "A non-arbitrary method of identifying and scaling latent variables in SEM and MACS models", "authors": [{"first": "T", "middle": ["D"], "last": "Little", "suffix": ""}, {"first": "D", "middle": ["W"], "last": "Slegers", "suffix": ""}, {"first": "N", "middle": ["A"], "last": "Card", "suffix": ""}], "year": 2006, "venue": "Structural Equation Modeling", "link": "53601677"}, "BIBREF40": {"title": "Social network profiles as taste performances", "authors": [{"first": "H", "middle": [], "last": "Liu", "suffix": ""}], "year": 2007, "venue": "Journal of Computer-Mediated Communication", "link": "38752485"}, "BIBREF41": {"title": "Unconstrained structural equation models of latent interactions: Contrasting residual-and mean-centered approaches", "authors": [{"first": "H", "middle": ["W"], "last": "Marsh", "suffix": ""}, {"first": "Z", "middle": [], "last": "Wen", "suffix": ""}, {"first": "K.-T", "middle": [], "last": "Hau", "suffix": ""}, {"first": "T", "middle": ["D"], "last": "Little", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Bovaird", "suffix": ""}, {"first": "K", "middle": ["F"], "last": "Widaman", "suffix": ""}], "year": 2007, "venue": "Structural Equation Modeling", "link": "121649724"}, "BIBREF42": {"title": "I'll see you on \"Facebook\": The effects of computermediated teacher self-disclosure on student motivation, affective learning, and classroom climate. Communication Education", "authors": [{"first": "J", "middle": ["P"], "last": "Mazer", "suffix": ""}, {"first": "R", "middle": ["E"], "last": "Murphy", "suffix": ""}, {"first": "C", "middle": ["J"], "last": "Simonds", "suffix": ""}], "year": 2007, "venue": "", "link": null}, "BIBREF43": {"title": "The use and abuse of factor analysis in communication research", "authors": [{"first": "J", "middle": ["C"], "last": "Mccroskey", "suffix": ""}, {"first": "T", "middle": ["J"], "last": "Young", "suffix": ""}], "year": 1979, "venue": "Human Communication Research", "link": "39654298"}, "BIBREF44": {"title": "Relationship formation on the Internet: What's the big attraction", "authors": [{"first": "K", "middle": ["Y A"], "last": "Mckenna", "suffix": ""}, {"first": "A", "middle": ["S"], "last": "Green", "suffix": ""}, {"first": "M", "middle": ["E J"], "last": "Gleason", "suffix": ""}], "year": 2002, "venue": "Journal of Social Issues", "link": "12086933"}, "BIBREF45": {"title": "The quality of online and offline relationships: The role of multiplexity and duration of social relationships", "authors": [{"first": "G", "middle": [], "last": "Mesch", "suffix": ""}, {"first": "I", "middle": [], "last": "Talmud", "suffix": ""}], "year": 2006, "venue": "", "link": "12742621"}, "BIBREF46": {"title": "Loneliness and social uses of the Internet", "authors": [{"first": "J", "middle": [], "last": "Morahan-Martin", "suffix": ""}, {"first": "P", "middle": [], "last": "Schumacher", "suffix": ""}], "year": 2003, "venue": "Computers in Human Behavior", "link": "16933593"}, "BIBREF47": {"title": "Internet use, interpersonal relations, and sociability", "authors": [{"first": "N", "middle": ["H"], "last": "Nie", "suffix": ""}, {"first": "D", "middle": ["S"], "last": "Hillygus", "suffix": ""}, {"first": "L", "middle": [], "last": "Erbring", "suffix": ""}], "year": 2002, "venue": "The Internet in everyday life", "link": null}, "BIBREF48": {"title": "What you don't know won't hurt me: Impression management functions of communication channels in relationships", "authors": [{"first": "P", "middle": ["B"], "last": "O&apos;sullivan", "suffix": ""}], "year": 2000, "venue": "Human Communication Research", "link": "146399183"}, "BIBREF49": {"title": "Personal relationships and personal networks", "authors": [{"first": "M", "middle": ["R"], "last": "Parks", "suffix": ""}], "year": 2006, "venue": "", "link": "142442947"}, "BIBREF50": {"title": "Boundaries of privacy: Dialectics of disclosure", "authors": [{"first": "S", "middle": [], "last": "Petronio", "suffix": ""}], "year": 2002, "venue": "", "link": "153086513"}, "BIBREF51": {"title": "Breaching or building social boundaries? SIDE-effects of computer-mediated communication", "authors": [{"first": "T", "middle": [], "last": "Postmes", "suffix": ""}, {"first": "R", "middle": [], "last": "Spears", "suffix": ""}, {"first": "M", "middle": [], "last": "Lea", "suffix": ""}], "year": 1998, "venue": "Communication Research", "link": "145640433"}, "BIBREF52": {"title": "SPSS and SAS procedures for estimating indirect effects in simple mediation models", "authors": [{"first": "K", "middle": ["J"], "last": "Preacher", "suffix": ""}, {"first": "A", "middle": ["F"], "last": "Hayes", "suffix": ""}], "year": 2004, "venue": "Behavior Research Methods, Instruments, & Computers", "link": "18785280"}, "BIBREF53": {"title": "University students' local and distant social ties: Using and integrating modes of communication on campus", "authors": [{"first": "A", "middle": [], "last": "Quan-Haase", "suffix": ""}], "year": 2007, "venue": "", "link": "58514728"}, "BIBREF54": {"title": "Capitalizing on the net: Social contact, civic engagement, and sense of community", "authors": [{"first": "A", "middle": [], "last": "Quan-Haase", "suffix": ""}, {"first": "B", "middle": [], "last": "Wellman", "suffix": ""}, {"first": "J", "middle": ["C"], "last": "Witte", "suffix": ""}, {"first": "K", "middle": ["N"], "last": "Hampton", "suffix": ""}], "year": 2002, "venue": "The Internet in everyday life", "link": "154586210"}, "BIBREF55": {"title": "IM me\": Instant messaging as relational maintenance and everyday communication", "authors": [{"first": "A", "middle": [], "last": "Ramirez", "suffix": ""}, {"first": "", "middle": [], "last": "Jr", "suffix": ""}, {"first": "K", "middle": [], "last": "Broneck", "suffix": ""}], "year": 2009, "venue": "Journal of Social and Personal Relationships", "link": "146661561"}, "BIBREF56": {"title": "Friendship matters: Communication, dialectics, and the life course", "authors": [{"first": "W", "middle": ["K"], "last": "Rawlins", "suffix": ""}], "year": 1992, "venue": "", "link": "143192259"}, "BIBREF57": {"title": "Doesn't anybody stay in one place anymore?\" An exploration of the under-studied phenomenon of long-distance relationships", "authors": [{"first": "M", "middle": ["E"], "last": "Rohlfing", "suffix": ""}], "year": 1995, "venue": "Under-studied relationships: Off the beaten track", "link": null}, "BIBREF58": {"title": "Beliefs, attitudes, and values: A theory of organization and change", "authors": [{"first": "M", "middle": [], "last": "Rokeach", "suffix": ""}], "year": 1968, "venue": "", "link": "142245534"}, "BIBREF59": {"title": "Strategies for increasing the conceptual yield of new technologies research", "authors": [{"first": "H", "middle": [], "last": "Sawhney", "suffix": ""}], "year": 2007, "venue": "Communication Monographs", "link": "145495595"}, "BIBREF60": {"title": "Relating computer, communication, and computer-mediated communication apprehensions to new communication technology use in the workplace", "authors": [{"first": "C", "middle": ["R"], "last": "Scott", "suffix": ""}, {"first": "C", "middle": ["E"], "last": "Timmerman", "suffix": ""}], "year": 2005, "venue": "Communication Research", "link": "8578162"}, "BIBREF61": {"title": "The social psychology of telecommunications", "authors": [{"first": "J", "middle": [], "last": "Short", "suffix": ""}, {"first": "E", "middle": [], "last": "Williams", "suffix": ""}, {"first": "B", "middle": [], "last": "Christie", "suffix": ""}], "year": 1976, "venue": "", "link": "144403490"}, "BIBREF62": {"title": "The Internet and the 2008 election. Pew Internet & American Life Project", "authors": [{"first": "A", "middle": [], "last": "Smith", "suffix": ""}, {"first": "L", "middle": [], "last": "Rainie", "suffix": ""}], "year": 2008, "venue": "", "link": null}, "BIBREF63": {"title": "Shared family identity, age salience and intergroup contact: Investigation of the grandparent-grandchild relationship", "authors": [{"first": "J", "middle": [], "last": "Soliz", "suffix": ""}, {"first": "J", "middle": [], "last": "Harwood", "suffix": ""}], "year": 2006, "venue": "Communication Monographs", "link": "14875966"}, "BIBREF64": {"title": "Preliminary development of a model and measure of computer-mediated communication (CMC) competence", "authors": [{"first": "B", "middle": ["H"], "last": "Spitzberg", "suffix": ""}], "year": 2006, "venue": "Journal of Computer-Mediated Communication", "link": "36591686"}, "BIBREF66": {"title": "Reducing social context cues: Electronic mail in organizational communication", "authors": [{"first": "L", "middle": [], "last": "Sproull", "suffix": ""}, {"first": "S", "middle": [], "last": "Kiesler", "suffix": ""}], "year": 1986, "venue": "Management Science", "link": "61012784"}, "BIBREF67": {"title": "Social networking on Facebook", "authors": [{"first": "L", "middle": ["A"], "last": "Stern", "suffix": ""}, {"first": "K", "middle": [], "last": "Taylor", "suffix": ""}], "year": 2007, "venue": "Journal of the Communication, Speech & Theater Association of North Dakota", "link": null}, "BIBREF68": {"title": "Overrated: Social networking can't replace a face to face", "authors": [{"first": "J", "middle": [], "last": "Tilsner", "suffix": ""}], "year": 2008, "venue": "", "link": null}, "BIBREF69": {"title": "Too much of a good thing? The relationship between number of friends and interpersonal impressions on Facebook", "authors": [{"first": "S", "middle": ["T"], "last": "Tong", "suffix": ""}, {"first": "B", "middle": [], "last": "Van Der Heide", "suffix": ""}, {"first": "L", "middle": [], "last": "Langwell", "suffix": ""}, {"first": "J", "middle": ["B"], "last": "Walther", "suffix": ""}], "year": 2008, "venue": "Journal of ComputerMediated Communication", "link": "6256236"}, "BIBREF70": {"title": "Grooming, gossip, Facebook and MySpace: What can we learn about these sites from those who won't assimilate? Information", "authors": [{"first": "Z", "middle": [], "last": "Tufekci", "suffix": ""}], "year": 2008, "venue": "", "link": "149494772"}, "BIBREF71": {"title": "Life on the screen: Identity in the age of the Internet", "authors": [{"first": "S", "middle": [], "last": "Turkle", "suffix": ""}], "year": 1995, "venue": "", "link": "141688633"}, "BIBREF72": {"title": "Preadolescents' and adolescents' online communication and their closeness to friends", "authors": [{"first": "P", "middle": ["M"], "last": "Valkenburg", "suffix": ""}, {"first": "J", "middle": [], "last": "Peter", "suffix": ""}], "year": 2007, "venue": "Developmental Psychology", "link": "28034644"}, "BIBREF73": {"title": "Adolescents' identity experiments on the Internet", "authors": [{"first": "P", "middle": ["M"], "last": "Valkenburg", "suffix": ""}, {"first": "J", "middle": [], "last": "Peter", "suffix": ""}], "year": 2008, "venue": "Communication Research", "link": "15349483"}, "BIBREF74": {"title": "A review and synthesis of the measurement invariance literature: Suggestions, practices, and recommendations for organizational research", "authors": [{"first": "R", "middle": ["J"], "last": "Vanderberg", "suffix": ""}, {"first": "C", "middle": ["E"], "last": "Lance", "suffix": ""}], "year": 2000, "venue": "Organizational Research Methods", "link": null}, "BIBREF75": {"title": "Revealing family secrets: The influence of topic, function, and relationships", "authors": [{"first": "A", "middle": ["L"], "last": "Vangelisti", "suffix": ""}, {"first": "J", "middle": ["P"], "last": "Caughlin", "suffix": ""}], "year": 1997, "venue": "Journal of Social and Personal Relationships", "link": "145658541"}, "BIBREF76": {"title": "Managing missing data", "authors": [{"first": "M", "middle": [], "last": "Vriens", "suffix": ""}, {"first": "E", "middle": [], "last": "Melton", "suffix": ""}], "year": 2002, "venue": "Marketing Research", "link": null}, "BIBREF77": {"title": "Computer-mediated communication: Impersonal, interpersonal, and hyperpersonal interaction", "authors": [{"first": "J", "middle": ["B"], "last": "Walther", "suffix": ""}], "year": 1996, "venue": "Communication Research", "link": "152119884"}, "BIBREF78": {"title": "Attraction to computer-mediated social support", "authors": [{"first": "J", "middle": ["B"], "last": "Walther", "suffix": ""}, {"first": "S", "middle": [], "last": "Boyd", "suffix": ""}], "year": 2002, "venue": "Communication technology and society: Audience adoption and uses", "link": null}, "BIBREF79": {"title": "Relational communication in computer-mediated interaction", "authors": [{"first": "J", "middle": ["B"], "last": "Walther", "suffix": ""}, {"first": "J", "middle": ["K"], "last": "Burgoon", "suffix": ""}], "year": 1992, "venue": "Human Communication Research", "link": "143857783"}, "BIBREF80": {"title": "Cues filtered out, cues filtered in: Computer-mediated communication and relationships", "authors": [{"first": "J", "middle": ["B"], "last": "Walther", "suffix": ""}, {"first": "M", "middle": ["R"], "last": "Parks", "suffix": ""}], "year": 2002, "venue": "Handbook of interpersonal communication", "link": "140993772"}, "BIBREF81": {"title": "The role of friends' behavior on evaluations of individuals' Facebook profiles: Are we known by the company we keep?", "authors": [{"first": "J", "middle": ["B"], "last": "Walther", "suffix": ""}, {"first": "B", "middle": [], "last": "Van Der Heide", "suffix": ""}, {"first": "S", "middle": [], "last": "Kim", "suffix": ""}, {"first": "D", "middle": [], "last": "Westerman", "suffix": ""}, {"first": "S", "middle": ["T"], "last": "Tong", "suffix": ""}], "year": 2008, "venue": "Human Communication Research", "link": null}, "BIBREF82": {"title": "Self-generated versus othergenerated statements and impressions in computer-mediated communication: A test of warranting theory using Facebook", "authors": [{"first": "J", "middle": ["B"], "last": "Walther", "suffix": ""}, {"first": "B", "middle": [], "last": "Van Der Heide", "suffix": ""}, {"first": "L", "middle": ["M"], "last": "Hamel", "suffix": ""}, {"first": "H", "middle": ["C"], "last": "Shulman", "suffix": ""}], "year": 2009, "venue": "Communication Research", "link": "39327673"}, "BIBREF83": {"title": "Informational reception apprehension and information from technology aversion: Development and test of a new construct", "authors": [{"first": "L", "middle": ["R"], "last": "Wheeless", "suffix": ""}, {"first": "L", "middle": [], "last": "Eddleman-Spears", "suffix": ""}, {"first": "L", "middle": ["D"], "last": "Magness", "suffix": ""}, {"first": "R", "middle": ["W"], "last": "Preiss", "suffix": ""}], "year": 2005, "venue": "Communication Quarterly", "link": "143731951"}, "BIBREF84": {"title": "Conceptualization and measurement of reported self-disclosure", "authors": [{"first": "L", "middle": ["R"], "last": "Wheeless", "suffix": ""}, {"first": "J", "middle": [], "last": "Grotz", "suffix": ""}], "year": 1976, "venue": "Human Communication Research", "link": "143858612"}, "BIBREF85": {"title": "Will you (still) be my friend?: Computer-mediated relational maintenance on Facebook.com. Paper presented at the annual meeting of the National Communication Association", "authors": [{"first": "K", "middle": [], "last": "Wright", "suffix": ""}, {"first": "E", "middle": [], "last": "Craig", "suffix": ""}, {"first": "C", "middle": [], "last": "Cunningham", "suffix": ""}, {"first": "M", "middle": [], "last": "Igiel", "suffix": ""}, {"first": "N", "middle": [], "last": "Ploeger", "suffix": ""}], "year": 2008, "venue": "", "link": null}, "BIBREF86": {"title": "The impact of individualism-collectivism, social presence, and group diversity on group decision making under majority influence", "authors": [{"first": "D", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "P", "middle": ["B"], "last": "Lowry", "suffix": ""}, {"first": "L", "middle": [], "last": "Zhou", "suffix": ""}, {"first": "X", "middle": [], "last": "Fu", "suffix": ""}], "year": 2007, "venue": "Journal of Management Information Systems", "link": "35256490"}, "BIBREF87": {"title": "An open letter from Mark Zuckerberg", "authors": [{"first": "M", "middle": [], "last": "Zuckerberg", "suffix": ""}], "year": 2006, "venue": "", "link": "166495458"}, "BIBREF88": {"title": "Thoughts on the evolution of Facebook", "authors": [{"first": "M", "middle": [], "last": "Zuckerberg", "suffix": ""}], "year": 2008, "venue": "", "link": null}, "BIBREF89": {"title": "University of Kansas, 2007) is an assistant professor in the Department of Communication Studies at Texas Christian University", "authors": [{"first": "Bios", "middle": [], "last": "Andrew", "suffix": ""}, {"first": "M", "middle": [], "last": "Ledbetter", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF90": {"title": "Illinois State University) is an assistant professor in the Department of", "authors": [{"first": "Joseph", "middle": ["P"], "last": "Mazer", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF91": {"title": "2009) is an assistant professor in the Department of Speech", "authors": [{"first": "Jocelyn", "middle": ["M"], "last": "Degroot", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF92": {"title": "2009) is an assistant professor in the School of Communication at", "authors": [{"first": "Kevin", "middle": ["R"], "last": "Meyer", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF93": {"title": "Bowling Green State University) is an academic developer in the communication and technology graduate program at the University of Alberta", "authors": [{"first": "Yuping", "middle": [], "last": "Mao", "suffix": ""}, {"first": "(", "middle": [], "last": "Ma", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF94": {"title": "2007) is a doctoral student in the School of Communication Studies at Ohio University", "authors": [{"first": "Brian", "middle": [], "last": "Swafford", "suffix": ""}, {"first": "(", "middle": [], "last": "Ma", "suffix": ""}, {"first": "Ohio", "middle": [], "last": "University", "suffix": ""}], "year": "", "venue": "", "link": null}}, "ref_entries": {"FIGREF0": {"text": "report that SNS com- munication explains variance in relational development beyond that explained by other communication media, we expect that Facebook communication will function similarly: Hypothesis 6: Offline communication positively predicts relational closeness (with specific Facebook Friends). Hypothesis 7: Facebook communication positively predicts relational closeness (with specific Facebook Friends).", "type": "figure"}, "FIGREF1": {"text": "Figure 1 depicts all hypotheses and research questions together in a structural model. The overarching goal of this investigation is to evaluate this model's fit.", "type": "figure"}, "FIGREF3": {"text": "Figure 1. Hypothesized structural model predicting communication frequency and relational closeness Note: Research Question 1, Hypothesis 8, and Research Question 4 are not depicted. These address indirect predictors of relational closeness, respectively: OSD (no direction predicted), OSC (positive predictor), and the interaction effect (no direction predicted).", "type": "figure"}, "FIGREF4": {"text": ". A combined groups confirmatory model produced close model fit, c 2 (120) = 209.00, RMSEA = 0.045 (90% CI = 0.033-0.056), NNFI = 0.98, CFI = 0.99, and examination of the modi- fication indices did not suggest any alterations to the model. After establishing close fit for the measurement model, we tested the hypothesized reg- ression paths in a structural equation model (see Figure 1). The initial structural model not only demonstrated close fit, c 2 (125) = 215.41, RMSEA = 0.044 (90% CI = 0.033-0.055), NNFI = 0.98, CFI = 0.99, but also revealed the presence of nonsignificant regression paths. Specifically, the paths between online communication attitude and offline communication were weak. As the hypothesized predictive association between online communication atti- tude and Facebook communication holds greater face validity than that between online communication attitude and offline communication, these paths were removed from the model (these paths also would be removed if trimming proceeded through iterations using param- eter z scores as the removal criterion; Kline, 2005). This trimmed model (see Figure 2) also demonstrated close fit, c 2 (128) = 218.30, RMSEA = 0.044 (90% CI = 0.032-0.054), NNFI = 0.98, CFI = 0.99, with a chi-square difference test indicating a nonsignificant decline in fit relative to the initial structural model, Dc 2 (3) = 2.89, p > .05. The final model revealed significant main effects between online communication attitude and Facebook communication frequency. As expected, OSC positively predicted Facebook communication, B = 0.23 (95% CI = 0.11-0.35) and b = .23 (95% CI = 0.11-0.35, p < .01), with OSD emerging as an inverse predictor, b = -.13 (95% CI = -0.02 to -0.24) and b = -.13 (95% CI = -0.02 to -0.24, p < .05). In addition to these main effects, the interaction effect between OSD and OSC significantly predicted Facebook communication: B = -0.10 (95% CI = -0.004 to -0.19) and b = -.09 (95% CI = -0.004 to -0.18, p < .05). Together, the main and interaction effects explained 4.7% of the variance in Facebook communica- tion with a specific Facebook friend.", "type": "figure"}, "FIGREF5": {"text": "Figure 2. Structural model predicting communication frequency and relational closeness Note: Dc 2 (128) = 218.30, RMSEA = 0.044 (90% CI: 0.032-0.054), NNFI = 0.98, CFI = 0.99.", "type": "figure"}, "FIGREF6": {"text": "Figure 3. Decomposition of the interaction effect between attitudes toward online selfdisclosure (OSD) and social connection (OSC) on Facebook communication Note: Possible Facebook communication scale scores range from 0 (never) to 5 (very frequently).", "type": "figure"}, "TABREF0": {"text": "research also suggests that high OSD may be associated with avoidance of face-to- face communication, even in relationships where dyads have previously communicated face to face. Thus, we hypothesize:", "type": "table"}, "TABREF1": {"text": "). Thus, we argue that OSC may positively predict not just frequency of Facebook communication but also that of offline communication. We hypothesize:", "type": "table"}, "TABREF2": {"text": "). Thus, Hypothesis 5: Facebook communication is positively associated with offline com- munication (with specific Facebook Friends).", "type": "table"}, "TABREF3": {"text": "). This resonates with Ellison and her colleagues' (2007) work demonstrating increased social capital associated with Facebook use. Thus, to the extent that high OSC fosters Facebook use, we predict that OSC will indirectly predict relational closeness: Hypothesis 8: OSC positively and indirectly (i.e., mediated via Facebook and offline communication constructs) predicts relational closeness (with specific Facebook Friends).", "type": "table"}, "TABREF4": {"text": "communicate online, I would feel 'out of the loop' with my friends\"; \"If I lost Internet access, I think I would probably lose contact with many of my friends\"; \"Without the Internet, my social life would be drastically different\"; \"I would communicate less with my friends if I couldn't talk with them online\"; \"Losing Internet access would not changefirst establishes face validity by developing scale items from analysis of open- ended descriptions of online social life and then demonstrates evidence for the convergent and discriminant validity of these constructs via associations with usage experience and information reception apprehension from technology sources", "type": "table"}, "TABREF5": {"text": "Descriptive Statistics and Bivariate Correlations Among Manifest Indicatorsregardless of participant sex or student status. When comparing local and long-distance friendships, the initial test of strong metric invariance failed, but examination of the model results indicated a large amount of misfit for the face-to-face frequency intercept. As both theory and intuition suggest that long-distance friends would score lower on this measure", "type": "table"}, "TABREF6": {"text": "may not necessarily describe Facebook communication with specific Friends. We will elaborate subsequent theoretical implications by addressing each component of the model in turn.", "type": "table"}}}
{"paper_id": "42955561", "_pdf_hash": "5d09fd29298e1e83ce5b60eaffd465449a18510d", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Production and control of extracellular a-amylase in Micrococcus varians", "authors": [{"first": "A", "middle": ["I"], "last": "Adeteye", "suffix": ""}], "year": 1990, "venue": "J.Basic Microbial", "link": null}, "BIBREF1": {"title": "Purification and properties of a-amylase from Micrococcus varians", "authors": [{"first": "", "middle": ["I"], "last": "Adex.M&apos;e A", "suffix": ""}], "year": 1990, "venue": "Jd~asic Microbiol", "link": null}, "BIBREF2": {"title": "Characteristics of glucoamylase fromAspergillus terreus", "authors": [{"first": "S", "middle": [], "last": "All", "suffix": ""}, {"first": "", "middle": [], "last": "Hossain Z", "suffix": ""}], "year": 1991, "venue": "J.Appl.Bacteriol", "link": "83546790"}, "BIBREF3": {"title": "Extraceilular amylase production by cassava fermenting bacteria", "authors": [{"first": "", "middle": ["O"], "last": "Amund O", "suffix": ""}, {"first": "O", "middle": ["A"], "last": "Oounslna", "suffix": ""}], "year": 1987, "venue": "Zlndustr.Microbiol", "link": null}, "BIBREF4": {"title": "Estimation of the molecular weights of proteins by Sephadex gel filtration", "authors": [{"first": "", "middle": [], "last": "Andrews P", "suffix": ""}], "year": "", "venue": "Biochem2", "link": null}, "BIBREF5": {"title": "Bergey's Manual of Dewrminative Bacteriology", "authors": [{"first": "", "middle": ["E"], "last": "Buchanan R", "suffix": ""}, {"first": "N", "middle": ["E"], "last": "Gmnons", "suffix": ""}], "year": 1974, "venue": "", "link": null}, "BIBREF6": {"title": "Amylase production by three Lactobacillus strains isolated from chicken crop", "authors": [{"first": "M", "middle": [], "last": "~p", "suffix": ""}, {"first": "P", "middle": [], "last": "Szvlrr", "suffix": ""}, {"first": "P", "middle": [], "last": "R~naud", "suffix": ""}, {"first": "D~", "middle": ["X ~ N"], "last": "Arr-Abd~", "suffix": ""}], "year": 1983, "venue": "J,4ppl.BacterioL", "link": null}, "BIBREF7": {"title": "Production of extracellular thermostable a-amylase by Bacillus licheniformis", "authors": [{"first": "A", "middle": ["K"], "last": "Cg_And~", "suffix": ""}, {"first": "S", "middle": [], "last": "M~da", "suffix": ""}, {"first": "D~", "middle": ["A I C"], "last": "Bi~", "suffix": ""}], "year": 1980, "venue": "J.Ferment.Technol", "link": "83213285"}, "BIBREF9": {"title": "Bacillus subtilis a-amylase properties", "authors": [{"first": "", "middle": ["H"], "last": "Fisher E", "suffix": ""}, {"first": "", "middle": ["W"], "last": "Sijmmerwell N", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Junge", "suffix": ""}, {"first": "E", "middle": ["A"], "last": "Ste~n", "suffix": ""}], "year": 1960, "venue": "Proc.Internat.Congr.Biochem. S", "link": null}, "BIBREF10": {"title": "Purification and characterization of glucoamylase of Aspergillus terreus NA-170 mutant", "authors": [{"first": "H", "middle": [], "last": "Ghosh", "suffix": ""}, {"first": "B", "middle": [], "last": "Chatmmee", "suffix": ""}, {"first": "", "middle": [], "last": "Das A", "suffix": ""}], "year": 1991, "venue": "J.Appl.BacterioL", "link": null}, "BIBREF11": {"title": "Phytocheraical methods", "authors": [{"first": "J", "middle": ["B"], "last": "Harborne", "suffix": ""}], "year": 1984, "venue": "", "link": null}, "BIBREF12": {"title": "Studies on a-amylase from a thermophilic bacteria. I. Purification and characterization", "authors": [{"first": "", "middle": [], "last": "Haseg^wa A", "suffix": ""}, {"first": "", "middle": [], "last": "Mwcaa", "suffix": ""}, {"first": "T", "middle": [], "last": "Osmna", "suffix": ""}, {"first": "I", "middle": ["C"], "last": "Imahopa", "suffix": ""}], "year": 1976, "venue": "J.Biochem", "link": null}, "BIBREF13": {"title": "Action of the amylases", "authors": [{"first": "R", "middle": ["H"], "last": "Hoemns", "suffix": ""}], "year": 1946, "venue": "Adv.Enzymol", "link": null}, "BIBREF15": {"title": "A Biologist's Physical Chemistry", "authors": [{"first": "J", "middle": ["G"], "last": "Morris", "suffix": ""}], "year": 1971, "venue": "", "link": "82732377"}, "BIBREF16": {"title": "Microorganisms asociated with cassava fermentation for gari production", "authors": [{"first": "", "middle": [], "last": "Okafor N", "suffix": ""}], "year": 1977, "venue": "J.AppLBacteriol", "link": null}, "BIBREF17": {"title": "Extracellular 0vamylase activity in avocado fruit pulp", "authors": [{"first": "", "middle": ["L"], "last": "Pv&apos; Xjeller S", "suffix": ""}, {"first": "", "middle": ["H"], "last": "Elliot W", "suffix": ""}], "year": 1969, "venue": "J.Amer.Soc.Hortic.Sci", "link": null}, "BIBREF18": {"title": "Amylases from Lactobacillus cellobiosus isolated from vegetable wastes", "authors": [{"first": "", "middle": [], "last": "Sen S", "suffix": ""}, {"first": "", "middle": [], "last": "Chakrabarty S.L", "suffix": ""}], "year": 1984, "venue": "ZFerment.Technol", "link": null}, "BIBREF19": {"title": "Purification and properties of heat stable a-amylase from Bacillus brevis", "authors": [{"first": "", "middle": ["T"], "last": "Tsvetkov V", "suffix": ""}, {"first": "E", "middle": ["I"], "last": "Emanuilova", "suffix": ""}], "year": 1989, "venue": "Appl.Microbiol. Biotech", "link": null}, "BIBREF20": {"title": "L: Effect of carbon sources on formation of a-amylase by Bacillus stearothermoplu'lus", "authors": [{"first": "", "middle": ["E"], "last": "Welker N", "suffix": ""}, {"first": "L", "middle": [], "last": "Campnell", "suffix": ""}], "year": 1978, "venue": "J.Bacteriol", "link": null}}, "ref_entries": {}}
{"paper_id": "42956853", "_pdf_hash": "876aa7925cddb6f41325761ce2645b563bb7acde", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Improving the accuracy of the second-kind Fredholm integral equations by using the Buffa-Christiansen functions", "authors": [{"first": "S", "middle": [], "last": "Van", "suffix": ""}, {"first": "J-M", "middle": [], "last": "Jin", "suffix": ""}, {"first": "Z", "middle": [], "last": "Nie", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF2": {"title": "Accuracy improvement of the second-kind integral equations for generally shaped objects", "authors": [], "year": 2013, "venue": "IEEE Trans. Anlennas Propag", "link": "24996487"}, "BIBREF3": {"title": "Fast and Effi cient Algorithms in Computational Electromagnetic", "authors": [], "year": 2001, "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "42957420", "_pdf_hash": "dcd58b1276a73003be78b126a559a824106dd625", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Optimal Planning of Substation Locating and Sizing Based on Refined Multi-team PSO Algorithm", "authors": [{"first": "Zhang", "middle": [], "last": "Liu Zi-Fa", "suffix": ""}, {"first": "", "middle": [], "last": "Jian-Hua", "suffix": ""}], "year": 2006, "venue": "Proceedings of the CSEE", "link": null}, "BIBREF1": {"title": "Intelligent Locating and Sizing of Substation Based on GIS A nd PSO", "authors": [{"first": "Liu", "middle": [], "last": "Wenxia", "suffix": ""}, {"first": "Zhang", "middle": [], "last": "Linfeng", "suffix": ""}, {"first": "Zhang", "middle": [], "last": "Jianhua", "suffix": ""}], "year": 2006, "venue": "presented at the Chinese Int Conf. Electricity Distribution", "link": null}, "BIBREF2": {"title": "Substation Locating and Sizing Based on Hybrid Genetic Algorithm", "authors": [{"first": "Wang", "middle": [], "last": "Chengshan", "suffix": ""}, {"first": "Wei", "middle": [], "last": "Haiyang", "suffix": ""}, {"first": "Xiao", "middle": [], "last": "Jun", "suffix": ""}], "year": 2005, "venue": "Automation of Electric Power Systems", "link": "113345339"}, "BIBREF3": {"title": "Optimal Location and Sizing of HV/MV Substations in Uncertainty Load Environment Using Genetic Algorithm", "authors": [{"first": "M", "middle": ["R"], "last": "Haghifam", "suffix": ""}, {"first": "Shahabi", "middle": [], "last": "", "suffix": ""}, {"first": "M", "middle": [], "last": "", "suffix": ""}], "year": 2002, "venue": "Electric Power Systems Research", "link": "109652092"}, "BIBREF4": {"title": "Application Of GIS And Fuzzy Patten Recognition Theory In Substation Locating", "authors": [{"first": "Yang", "middle": [], "last": "Litu", "suffix": ""}, {"first": "Wang", "middle": [], "last": "Jiayao", "suffix": ""}, {"first": "Jia", "middle": [], "last": "Defeng", "suffix": ""}], "year": 2003, "venue": "Automation of Electric Power Systems", "link": null}, "BIBREF5": {"title": "Optimization Based on Bacterial Chemotaxis", "authors": [{"first": "Sibylle", "middle": ["D"], "last": "M\u00fcller", "suffix": ""}, {"first": "Jarno", "middle": [], "last": "Marchetto", "suffix": ""}, {"first": "Stefano", "middle": [], "last": "Airaghi", "suffix": ""}, {"first": "Petros", "middle": [], "last": "Koumoutsakos", "suffix": ""}], "year": 2002, "venue": "IEEE Trans. Evolutionary computation", "link": "16968815"}, "BIBREF6": {"title": "Function optimization method based on bacterial colony chemotaxis", "authors": [{"first": "Wang", "middle": [], "last": "Li Wei-Wu", "suffix": ""}, {"first": "Zou", "middle": [], "last": "Hui", "suffix": ""}, {"first": "", "middle": [], "last": "Zhi-Jun", "suffix": ""}], "year": 2005, "venue": "Journal of Circutis and Systems", "link": "63613452"}, "BIBREF7": {"title": "Reactive Optimization kkkower Systems based on Bacterial Colony Chemotaxis", "authors": [{"first": "Huang", "middle": [], "last": "Wei", "suffix": ""}, {"first": "Zhang", "middle": [], "last": "Jian-Hua", "suffix": ""}, {"first": "Zhang", "middle": [], "last": "Cong", "suffix": ""}], "year": 2007, "venue": "Automation of Electric Power System", "link": null}, "BIBREF8": {"title": "An Intelligent Distribution Network Planning Method Based on Geographical Differential Evolution Algorithm", "authors": [{"first": "Liu", "middle": [], "last": "Liu Jun", "suffix": ""}, {"first": "Huang", "middle": [], "last": "Zifa", "suffix": ""}, {"first": "", "middle": [], "last": "Wei", "suffix": ""}], "year": 2007, "venue": "Computer Engineering and Applications", "link": "64026350"}, "BIBREF10": {"title": "At the same time she is working toward the Ph.D. degree at Electrical Power deparment of NCEPU, She has been with Key laboratory of Power System Protection and Dynamic", "authors": [], "year": 1990, "venue": "WenXia Liu was born in Jilin, China, in 1967. He received the B.S. degrees in electronic engineering from", "link": null}, "BIBREF11": {"title": "man, full professor (doctor tutor), power system voltage stabilization", "authors": [{"first": "Jianhua", "middle": [], "last": "Zhang", "suffix": ""}], "year": "", "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "42958394", "_pdf_hash": "32bf826b0c99bccd15e10ffbe5568ca66c1edd83", "abstract": [], "body_text": [], "bib_entries": {"BIBREF1": {"title": "Inactivated virus vaccines: Protective efficacy in poliomyelitis", "authors": [{"first": "A", "middle": ["D"], "last": "Langmuir", "suffix": ""}], "year": 1961, "venue": "Fifth International Conference on Poliomyelitis", "link": null}, "BIBREF2": {"title": "Persistence of immunity following administration of formalin-treated poliovirus vaccine", "authors": [{"first": "J", "middle": ["E"], "last": "Salk", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF3": {"title": "Antibody response and survival following booster injections of poliomyelitis (killedvirus) vaccine. Pediatrics 29: 116", "authors": [{"first": "R", "middle": [], "last": "Batson", "suffix": ""}, {"first": "A", "middle": [], "last": "Christie", "suffix": ""}, {"first": "W", "middle": ["J"], "last": "Cheatham", "suffix": ""}, {"first": "M", "middle": ["L"], "last": "Michal", "suffix": ""}, {"first": "G", "middle": ["W"], "last": "Sleight", "suffix": ""}, {"first": "M", "middle": ["L"], "last": "Lepow", "suffix": ""}, {"first": "P", "middle": ["H"], "last": "Carver", "suffix": ""}, {"first": "F", "middle": ["C"], "last": "Robbins", "suffix": ""}], "year": 1962, "venue": "Amer. J. Dis. Child", "link": null}, "BIBREF4": {"title": "Prevention of viral diseases", "authors": [{"first": "R", "middle": ["J"], "last": "Warren", "suffix": ""}, {"first": "F", "middle": ["C"], "last": "Robbins", "suffix": ""}], "year": 1962, "venue": "Pediatrics", "link": "5388674"}, "BIBREF5": {"title": "A comparison of the response of 100 infants to primary poliomyelitis immunization with two and with three doses of vaccine", "authors": [{"first": "F", "middle": ["T"], "last": "Perkins", "suffix": ""}, {"first": "R", "middle": [], "last": "Yetts", "suffix": ""}, {"first": "W", "middle": [], "last": "Gaisford", "suffix": ""}], "year": 1959, "venue": "Brit. Med. J", "link": "45646961"}, "BIBREF6": {"title": "Serologic response of infants to a multiple vaccine for simultaneous immunization against diptheria, pertussis, tetanus and poliomyelitis, in relation to the presence of specific maternal antibody", "authors": [{"first": "G", "middle": ["C"], "last": "Brown", "suffix": ""}, {"first": "P", "middle": ["L"], "last": "Kendrick", "suffix": ""}], "year": 1960, "venue": "Amer. J. Public Health", "link": "22958906"}, "BIBREF7": {"title": "Multiple antigen immunization of infants against poliomyelitis, diptheria, pertussis and tetanus", "authors": [{"first": "C", "middle": ["D"], "last": "Barrett", "suffix": ""}, {"first": "", "middle": [], "last": "Jr", "suffix": ""}, {"first": "I", "middle": ["W"], "last": "Mclean", "suffix": ""}, {"first": "", "middle": [], "last": "Jr", "suffix": ""}, {"first": "J", "middle": ["G"], "last": "Molner", "suffix": ""}, {"first": "E", "middle": ["A"], "last": "Timm", "suffix": ""}, {"first": "C", "middle": ["F"], "last": "Weiss", "suffix": ""}], "year": 1962, "venue": "Pediatrics", "link": "57316451"}, "BIBREF8": {"title": "Progress in the Development of a Purified Poliomyelitis Vaccine", "authors": [{"first": "M", "middle": ["R"], "last": "Hilleman", "suffix": ""}, {"first": "J", "middle": [], "last": "Charney", "suffix": ""}, {"first": "A", "middle": ["A"], "last": "Tytell", "suffix": ""}, {"first": "C", "middle": [], "last": "Weihl", "suffix": ""}, {"first": "D", "middle": [], "last": "Cornfeld", "suffix": ""}, {"first": "J", "middle": ["T"], "last": "Ichter", "suffix": ""}, {"first": "N", "middle": ["D"], "last": "Riley", "suffix": ""}, {"first": "Jr", "middle": [], "last": "Huang", "suffix": ""}, {"first": "N", "middle": [], "last": "", "suffix": ""}], "year": 1961, "venue": "Fifth International Conference on Poliomyelitis", "link": null}, "BIBREF9": {"title": "Concentration and partial purification of poliomyelitis viruses", "authors": [{"first": "K", "middle": ["H"], "last": "Fantes", "suffix": ""}], "year": 1962, "venue": "J. Hyg", "link": "24098633"}, "BIBREF10": {"title": "Exit Poliomyelitis&mdash;What Next? in \"Virology and Epidemiology", "authors": [{"first": "S", "middle": [], "last": "Gard", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF12": {"title": "New quadruple vaccine", "authors": [{"first": "D", "middle": ["S"], "last": "Dane", "suffix": ""}, {"first": "G", "middle": ["W A"], "last": "Dick", "suffix": ""}, {"first": "D", "middle": ["I H"], "last": "Simpson", "suffix": ""}, {"first": "E", "middle": ["M"], "last": "Briggs", "suffix": ""}, {"first": "J", "middle": [], "last": "Mcalister", "suffix": ""}, {"first": "R", "middle": [], "last": "Nelson", "suffix": ""}, {"first": "C", "middle": ["M B"], "last": "Field", "suffix": ""}], "year": 1962, "venue": "Lancet", "link": "10439150"}, "BIBREF13": {"title": "Limitation of fecal and pharyngeal poliovirus excretion in Salk-vaccinated children", "authors": [{"first": "W", "middle": ["M"], "last": "Marine", "suffix": ""}, {"first": "T", "middle": ["D"], "last": "Chin", "suffix": ""}, {"first": "C", "middle": ["R"], "last": "Gravelle", "suffix": ""}], "year": 1962, "venue": "Am. J. Hyg", "link": null}, "BIBREF14": {"title": "Studies on the develop", "authors": [{"first": "H", "middle": ["M"], "last": "Gelfand", "suffix": ""}, {"first": "D", "middle": ["R"], "last": "Leblanc", "suffix": ""}, {"first": "L", "middle": [], "last": "Potash", "suffix": ""}, {"first": "J", "middle": ["P"], "last": "Fox", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF15": {"title": "Day by day response of vaccinated chimpanzees to poliomyelitis infection", "authors": [{"first": "H", "middle": ["A"], "last": "Howe", "suffix": ""}], "year": 1957, "venue": "Am. J. Pub. Health", "link": null}, "BIBREF16": {"title": "Intrafamilial and interfamilial spread of living vaccine strains of polioviruses", "authors": [{"first": "H", "middle": ["M"], "last": "Gelfand", "suffix": ""}, {"first": "L", "middle": [], "last": "Potash", "suffix": ""}, {"first": "D", "middle": ["R"], "last": "Lebanc", "suffix": ""}, {"first": "J", "middle": ["P"], "last": "Fox", "suffix": ""}], "year": 1959, "venue": "J. A. M. A", "link": null}, "BIBREF17": {"title": "Clinical trials in infants of orally administered attenuated poliomyelitis viruses", "authors": [{"first": "S", "middle": ["A"], "last": "Plotkin", "suffix": ""}, {"first": "H", "middle": [], "last": "Koprowski", "suffix": ""}, {"first": "J", "middle": [], "last": "Stokes", "suffix": ""}, {"first": "", "middle": [], "last": "Jr", "suffix": ""}], "year": 1959, "venue": "Pediatrics", "link": "45415756"}, "BIBREF18": {"title": "Effect of Sabin type I poliomyelitis vaccine administered by mouth to newborn infants", "authors": [{"first": "M", "middle": ["L"], "last": "Lepow", "suffix": ""}, {"first": "R", "middle": ["J"], "last": "Warren", "suffix": ""}, {"first": "N", "middle": [], "last": "Gray", "suffix": ""}, {"first": "V", "middle": ["G"], "last": "Ingram", "suffix": ""}, {"first": "F", "middle": ["C"], "last": "Robbins", "suffix": ""}], "year": 1961, "venue": "New Eng. J. Med", "link": "30751091"}, "BIBREF19": {"title": "Variation in the responses of infants to living attenuated poliovirus vaccines. New Eng", "authors": [{"first": "J", "middle": ["S"], "last": "Pagano", "suffix": ""}, {"first": "S", "middle": ["A"], "last": "Plotkin", "suffix": ""}, {"first": "H", "middle": [], "last": "Koprowski", "suffix": ""}], "year": 1961, "venue": "J. Med", "link": null}, "BIBREF20": {"title": "Immunological Problems of the Vaccination of Newborn and Very Young Infants with Live Avirulent Poliovirus. European Association against Poliomyelitis and Allied Diseases VIIth Symposium", "authors": [{"first": "F", "middle": [], "last": "Buser", "suffix": ""}, {"first": "V", "middle": [], "last": "Dostal", "suffix": ""}, {"first": "S", "middle": [], "last": "Barandun", "suffix": ""}, {"first": "J", "middle": [], "last": "Haenzel", "suffix": ""}, {"first": "H", "middle": ["P"], "last": "Witschi", "suffix": ""}], "year": 1961, "venue": "", "link": null}, "BIBREF21": {"title": "Further Experiences with Oral Poliomyelitis Vaccines in Minnesota", "authors": [{"first": "H", "middle": [], "last": "Kleinman", "suffix": ""}, {"first": "R", "middle": ["N"], "last": "Barr", "suffix": ""}, {"first": "H", "middle": [], "last": "Bauer", "suffix": ""}, {"first": "A", "middle": ["C"], "last": "Kimball", "suffix": ""}, {"first": "M", "middle": ["R"], "last": "Cooney", "suffix": ""}, {"first": "J", "middle": ["E"], "last": "Bearman", "suffix": ""}, {"first": "W", "middle": ["E"], "last": "Mathey", "suffix": ""}], "year": 1963, "venue": "Live Poliovirus Vaccines, Second Int. Conf. Pan Amer", "link": "78831624"}, "BIBREF22": {"title": "Immunization with oral poliovirus vaccine (Sabin)", "authors": [{"first": "D", "middle": ["M"], "last": "Horstmann", "suffix": ""}, {"first": "J", "middle": ["R"], "last": "Paul", "suffix": ""}, {"first": "M", "middle": [], "last": "Godenne-Mccrea", "suffix": ""}, {"first": "R", "middle": ["M"], "last": "Green", "suffix": ""}, {"first": "E", "middle": ["M"], "last": "Opton", "suffix": ""}, {"first": "A", "middle": ["I"], "last": "Holtz", "suffix": ""}, {"first": "J", "middle": ["C"], "last": "Niederman", "suffix": ""}], "year": 1961, "venue": "J. A. M. A", "link": null}, "BIBREF23": {"title": "Studies on live poliovirus vaccine", "authors": [{"first": "J", "middle": ["L"], "last": "Melnick", "suffix": ""}, {"first": "M", "middle": [], "last": "Benyesh-Melnick", "suffix": ""}, {"first": "J", "middle": ["T"], "last": "Brennan", "suffix": ""}], "year": 1959, "venue": "J. A. M. A", "link": null}, "BIBREF24": {"title": "The polioviruses of man", "authors": [{"first": "S", "middle": ["A"], "last": "Plotkin", "suffix": ""}], "year": 1962, "venue": "Ann. N. Y. Acad. Sci", "link": null}, "BIBREF25": {"title": "Immune responses in human volunteers upon oral administration of a rodentadapted strain of poliomyelitis virus", "authors": [{"first": "H", "middle": [], "last": "Koprowski", "suffix": ""}, {"first": "G", "middle": ["A"], "last": "Jervis", "suffix": ""}, {"first": "T", "middle": ["W"], "last": "Norton", "suffix": ""}], "year": 1952, "venue": "Am. J. Hyg", "link": "11036753"}, "BIBREF26": {"title": "Tin anniv. of develop. of live virus vaccine", "authors": [{"first": "H", "middle": [], "last": "Koprowski", "suffix": ""}], "year": 1960, "venue": "J. A. M. A", "link": null}, "BIBREF27": {"title": "Antibodies of three different antigenic types of poliomyelitis in sera from North Alaskan eskimos", "authors": [{"first": "J", "middle": ["R"], "last": "Paul", "suffix": ""}, {"first": "J", "middle": ["T"], "last": "Riordan", "suffix": ""}, {"first": "J", "middle": ["L"], "last": "Melnick", "suffix": ""}], "year": 1951, "venue": "Am. J. Hyg", "link": null}, "BIBREF28": {"title": "An outbreak of poliomyelitis in Israel in 1961 and the use of attenuated Type 1 vaccine in its control", "authors": [{"first": "J", "middle": [], "last": "Yafe", "suffix": ""}, {"first": "N", "middle": [], "last": "Goldblum", "suffix": ""}, {"first": "E", "middle": [], "last": "Eylan", "suffix": ""}, {"first": "J", "middle": ["L"], "last": "Melnick", "suffix": ""}], "year": 1962, "venue": "Am. J. Hyg", "link": null}, "BIBREF29": {"title": "Oral poliovirus vaccine: Recent results and recommendations for optimum use", "authors": [{"first": "A", "middle": ["B"], "last": "Sabin", "suffix": ""}], "year": "", "venue": "", "link": "41250987"}, "BIBREF31": {"title": "Routine immunization with orally administered attenuated poliovirus: A study of 850 children in an American city", "authors": [{"first": "J", "middle": ["S"], "last": "Pagano", "suffix": ""}, {"first": "S", "middle": ["A"], "last": "Plotkin", "suffix": ""}, {"first": "C", "middle": ["G"], "last": "Janowsky", "suffix": ""}, {"first": "S", "middle": ["M"], "last": "Richardson", "suffix": ""}, {"first": "H", "middle": [], "last": "Koprowski", "suffix": ""}], "year": 1960, "venue": "J. A. M. A", "link": "39014444"}, "BIBREF32": {"title": "Viremia after administration of live poliovirus vaccine", "authors": [{"first": "J", "middle": ["L"], "last": "Melnick", "suffix": ""}, {"first": "R", "middle": [], "last": "Proctor", "suffix": ""}, {"first": "A", "middle": ["R"], "last": "Ocampo", "suffix": ""}, {"first": "A", "middle": ["R"], "last": "Diwan", "suffix": ""}, {"first": "E", "middle": [], "last": "Ben-Porath", "suffix": ""}], "year": 1961, "venue": "Bact. Proc", "link": null}, "BIBREF36": {"title": "Problems Associated with Live Poliovirus Vaccine and Its Progeny After Multiplication in Man", "authors": [{"first": "J", "middle": ["L"], "last": "Welnick", "suffix": ""}, {"first": "M", "middle": [], "last": "Benyesh-Melnick", "suffix": ""}], "year": 1960, "venue": "Live Poliovirus Vaccines Second Intern. Conf. Pan Am. Health Organization", "link": "88992039"}, "BIBREF37": {"title": "A Type 3 attenuated poliovirus genetically stable after human intestinal passage", "authors": [{"first": "S", "middle": ["A"], "last": "Plotkin", "suffix": ""}, {"first": "T", "middle": ["W"], "last": "Norton", "suffix": ""}, {"first": "B", "middle": ["J"], "last": "Cohen", "suffix": ""}, {"first": "H", "middle": [], "last": "Koprowski", "suffix": ""}], "year": 1961, "venue": "Proc. Soc. Exptl. Biol. Med", "link": "6652318"}, "BIBREF38": {"title": "Vaccination against poliomyelitis", "authors": [{"first": "A", "middle": ["E"], "last": "Duxbury", "suffix": ""}, {"first": "G", "middle": [], "last": "Goulding", "suffix": ""}, {"first": "J", "middle": ["J"], "last": "Graydon", "suffix": ""}], "year": 1963, "venue": "", "link": "20209812"}}, "ref_entries": {}}
{"paper_id": "42959141", "_pdf_hash": "41836bfc60e8f50417c09a49b25c4fa4698e0209", "abstract": [], "body_text": [], "bib_entries": {"BIBREF1": {"title": "Terrigenous fluxes at the Celtic margin during the last 605 glacial cycle", "authors": [{"first": "F", "middle": [], "last": "Eynaud", "suffix": ""}, {"first": "M", "middle": [], "last": "Siegert", "suffix": ""}], "year": 2002, "venue": "Marine Geology", "link": "55733838"}, "BIBREF2": {"title": "Geochemical and geophysical implications of the radiocarbon calibration", "authors": [{"first": "E", "middle": [], "last": "Bard", "suffix": ""}], "year": 1998, "venue": "", "link": "127226445"}, "BIBREF4": {"title": "Hydrological impact of Heinrich 609 eventsin the subtropical Northeast Atlantic", "authors": [{"first": "E", "middle": [], "last": "Bard", "suffix": ""}, {"first": "F", "middle": [], "last": "Rostek", "suffix": ""}, {"first": "J", "middle": ["L"], "last": "Turon", "suffix": ""}, {"first": "S", "middle": [], "last": "Gendreau", "suffix": ""}], "year": 2000, "venue": "Science", "link": null}, "BIBREF5": {"title": "611 Correlations between climate records from North atlantic sediments and Greeland ice. 612", "authors": [{"first": "G", "middle": [], "last": "Bond", "suffix": ""}, {"first": "W", "middle": [], "last": "Broecker", "suffix": ""}, {"first": "S", "middle": [], "last": "Johnsen", "suffix": ""}, {"first": "J", "middle": [], "last": "Mcmanus", "suffix": ""}, {"first": "L", "middle": [], "last": "Labeyrie", "suffix": ""}, {"first": "J", "middle": [], "last": "Jouzel", "suffix": ""}, {"first": "G", "middle": [], "last": "Bonani", "suffix": ""}], "year": 1993, "venue": "Nature", "link": null}, "BIBREF7": {"title": "615 Evidence for massive discharges of icebergs into the North Atlantic ocean during the 616 last glacial period", "authors": [{"first": "R", "middle": [], "last": "Jantschik", "suffix": ""}, {"first": "S", "middle": [], "last": "Clasen", "suffix": ""}, {"first": "C", "middle": [], "last": "Simet", "suffix": ""}, {"first": "K", "middle": [], "last": "Tedesco", "suffix": ""}, {"first": "M", "middle": [], "last": "Klas", "suffix": ""}, {"first": "G", "middle": [], "last": "Bonani", "suffix": ""}, {"first": "S", "middle": [], "last": "Ivy", "suffix": ""}], "year": 1992, "venue": "Nature", "link": null}, "BIBREF8": {"title": "Glaciology of the British Isles Ice Sheet during the last 618 glacial cycle: form, flow, streams and lobes", "authors": [{"first": "G", "middle": [], "last": "Boulton", "suffix": ""}, {"first": "M", "middle": [], "last": "Hagdorn", "suffix": ""}], "year": 2006, "venue": "Quaternary Science Reviews", "link": "129027043"}, "BIBREF9": {"title": "Sedimentology of some flysch deposits: a graphic approach to facies 621 interpretation", "authors": [{"first": "A", "middle": ["H"], "last": "Bouma", "suffix": ""}], "year": 1962, "venue": "", "link": "128452131"}, "BIBREF10": {"title": "The \"Fleuve Manche\": the 623 submarine sedimentary features from the outer shelf to the deep-sea fans", "authors": [{"first": "J", "middle": ["F"], "last": "Bourillet", "suffix": ""}, {"first": "J", "middle": ["Y"], "last": "Reynaud", "suffix": ""}, {"first": "A", "middle": [], "last": "Baltzer", "suffix": ""}, {"first": "S", "middle": [], "last": "Zaragosi", "suffix": ""}], "year": 2003, "venue": "Journal of 624 Quaternary Science", "link": "54198082"}, "BIBREF12": {"title": "New data for 627 the Last Glacial Maximum in Great Britain and Ireland", "authors": [{"first": "D", "middle": ["Q"], "last": "Bowen", "suffix": ""}, {"first": "F", "middle": ["M"], "last": "Phillips", "suffix": ""}, {"first": "A", "middle": ["M"], "last": "Mccabe", "suffix": ""}, {"first": "P", "middle": ["C"], "last": "Knutz", "suffix": ""}, {"first": "G", "middle": ["A"], "last": "Sykes", "suffix": ""}], "year": 2002, "venue": "Quaternary Science Reviews", "link": "128773893"}, "BIBREF13": {"title": "Correlation of Quaternary 630 glaciations in england, Ireland, Scotland and Wales", "authors": [{"first": "D", "middle": ["Q"], "last": "Bowen", "suffix": ""}, {"first": "J", "middle": [], "last": "Rose", "suffix": ""}, {"first": "A", "middle": ["M"], "last": "Mccabe", "suffix": ""}, {"first": "D", "middle": ["G"], "last": "Sutherland", "suffix": ""}], "year": 1986, "venue": "Quaternary Science Reviews", "link": "140654297"}, "BIBREF14": {"title": "Expansion and retreat of the Jura ice sheet (France) 633 during the last glacial maximum", "authors": [{"first": "J", "middle": ["F"], "last": "Buoncristiani", "suffix": ""}, {"first": "M", "middle": [], "last": "Campy", "suffix": ""}], "year": 2004, "venue": "Sedimentary Geology", "link": "128424112"}, "BIBREF15": {"title": "Sea surface temperature variability 635 during the last glacial-interglacial cycle: Assessing the magnitude and pattern of 636 climate change in the North Atlantic", "authors": [{"first": "M", "middle": ["R"], "last": "Chapman", "suffix": ""}, {"first": "N", "middle": ["J"], "last": "Shackleton", "suffix": ""}, {"first": "J", "middle": ["C"], "last": "Duplessy", "suffix": ""}], "year": 2000, "venue": "Palaeogeography, Palaeoclimatology, 637 Palaeoecology", "link": "131181461"}, "BIBREF16": {"title": "Sea level changes forced ice breakouts in the Last Glacial cycle: new 639 results from coral terraces", "authors": [{"first": "J", "middle": [], "last": "Chappell", "suffix": ""}], "year": 2002, "venue": "Quaternary Science Reviews", "link": "129789843"}, "BIBREF17": {"title": "Rapid sea level rise at 19,000 641 years ago and its global implications", "authors": [{"first": "P", "middle": ["U"], "last": "Clark", "suffix": ""}, {"first": "A", "middle": ["M"], "last": "Mccabe", "suffix": ""}, {"first": "A", "middle": ["C"], "last": "Mix", "suffix": ""}, {"first": "A", "middle": ["J"], "last": "Weaver", "suffix": ""}], "year": 2004, "venue": "Science", "link": null}, "BIBREF18": {"title": "A 644 glaciological perspective on Heinrich events", "authors": [{"first": "G", "middle": ["K C"], "last": "Clarke", "suffix": ""}, {"first": "S", "middle": ["J"], "last": "Marshall", "suffix": ""}, {"first": "C", "middle": [], "last": "Hillaire-Marcel", "suffix": ""}, {"first": "G", "middle": [], "last": "Bilodeau", "suffix": ""}, {"first": "C", "middle": [], "last": "Veiga-Pires", "suffix": ""}], "year": 1999, "venue": "Mechanisms of Global Climate 645 Change at Millennial Time Scales", "link": null}, "BIBREF19": {"title": "Sedimentary environment and glacial history during the 648 last 40 ka of the Voring continental margin, mid-Norway", "authors": [{"first": "K", "middle": ["I T"], "last": "Dahlgren", "suffix": ""}, {"first": "T", "middle": ["O"], "last": "Vorren", "suffix": ""}], "year": 2003, "venue": "Marine Geology", "link": null}, "BIBREF21": {"title": "Evidence for general instability of past climate from 250-kyr ice-core record. 653", "authors": [{"first": "C", "middle": ["U"], "last": "Hvidberg", "suffix": ""}, {"first": "C", "middle": ["S"], "last": "Steffensen", "suffix": ""}, {"first": "J", "middle": ["P"], "last": "Sveinbj\u00f6rnsdottir", "suffix": ""}, {"first": "A", "middle": ["E"], "last": "Jouzel", "suffix": ""}, {"first": "J", "middle": [], "last": "Bond", "suffix": ""}, {"first": "G", "middle": [], "last": "", "suffix": ""}], "year": 1993, "venue": "Nature", "link": null}, "BIBREF23": {"title": "On the architecture of high-latitude continental margins: the influence of ice-sheet and 656 sea-ice processes in the Polar North Atlantic", "authors": [], "year": "", "venue": "Glacier-Influenced Sedimentation on High-Latitude Continental Margins. 658 Geological Society", "link": "130950072"}, "BIBREF24": {"title": "L'\u00e9ventail profond de la marge 660", "authors": [{"first": "L", "middle": [], "last": "Droz", "suffix": ""}, {"first": "G", "middle": ["A"], "last": "Auffret", "suffix": ""}, {"first": "B", "middle": [], "last": "Savoye", "suffix": ""}, {"first": "J", "middle": ["F"], "last": "Bourillet", "suffix": ""}], "year": 1999, "venue": "", "link": null}, "BIBREF25": {"title": "Celtique : stratigraphie et \u00e9volution s\u00e9dimentaire", "authors": [], "year": "", "venue": "C.R. Acad. Sci. Paris", "link": null}, "BIBREF26": {"title": "Coherent patterns of ice-rafted debris 662 deposits in the Nordic regions during the last glacial (10-60 ka). Earth and Planetary 663", "authors": [{"first": "M", "middle": [], "last": "Elliot", "suffix": ""}, {"first": "L", "middle": [], "last": "Labeyrie", "suffix": ""}, {"first": "T", "middle": [], "last": "Dokken", "suffix": ""}, {"first": "S", "middle": [], "last": "Manthe", "suffix": ""}], "year": 2001, "venue": "Science Letters", "link": null}, "BIBREF27": {"title": "Late Cenozoic erosion and sediment yield from 665 the Svalbard-Barents Sea region: implications for the understanding of glacierized 666 basins", "authors": [{"first": "A", "middle": [], "last": "Elverhoi", "suffix": ""}, {"first": "R", "middle": ["L"], "last": "Hooke", "suffix": ""}, {"first": "A", "middle": [], "last": "Solheim", "suffix": ""}], "year": 1998, "venue": "Quaternary Sciences Reviews", "link": null}, "BIBREF28": {"title": "Depositional evidence for marginal oscillations of the 668", "authors": [{"first": "D", "middle": ["J A"], "last": "Evans", "suffix": ""}, {"first": "C", "middle": [], "last": "O&apos;cofaigh", "suffix": ""}], "year": 2003, "venue": "", "link": null}, "BIBREF29": {"title": "Irish Sea ice stream in southeast Ireland during the last glaciation", "authors": [], "year": "", "venue": "Boreas", "link": null}, "BIBREF30": {"title": "Cosmogenic 10BE age 670 constraints for the Wester Ross Readvance moraine: Insights into British Ice-Sheet 671 behaviour", "authors": [{"first": "J", "middle": ["D"], "last": "Everest", "suffix": ""}, {"first": "T", "middle": [], "last": "Bradwell", "suffix": ""}, {"first": "C", "middle": ["J"], "last": "Fogwill", "suffix": ""}, {"first": "P", "middle": ["W"], "last": "Kubik", "suffix": ""}], "year": 2006, "venue": "Geografiska Annaler, Series A: Physical Geography", "link": null}, "BIBREF31": {"title": "The Late Devensian (<22,000 BP) Irish Sea Basin: The 673 sedimentary record of a collapsed ice sheet margin", "authors": [{"first": "N", "middle": [], "last": "Eyles", "suffix": ""}, {"first": "A", "middle": [], "last": "Mccabe", "suffix": ""}], "year": 1989, "venue": "Quaternary Science Reviews", "link": "128565331"}, "BIBREF32": {"title": "Kystes de dinoflagell\u00e9s et \u00e9volution pal\u00e9oclimatique et pal\u00e9ohydrologique 676 de l'Atlantique", "authors": [{"first": "F", "middle": [], "last": "Eynaud", "suffix": ""}], "year": 1999, "venue": "", "link": null}, "BIBREF34": {"title": "Deglacial laminated facies on the NW European 680 continental margin: the hydrographic significance of British Ice sheet deglaciation and 681", "authors": [{"first": "M", "middle": [], "last": "Locascio", "suffix": ""}, {"first": "A", "middle": [], "last": "Reijonen", "suffix": ""}], "year": 2007, "venue": "", "link": null}, "BIBREF35": {"title": "Fleuve Manche paleoriver discharges", "authors": [], "year": "", "venue": "Geochemistry, Geophysics, Geosystems", "link": null}, "BIBREF36": {"title": "A 17,000-year glacioeustatic sea level record: Influence of glacial 684 melting on the Younger Dryas event and deep-ocean circulation", "authors": [{"first": "R", "middle": ["G"], "last": "Fairbanks", "suffix": ""}], "year": 1989, "venue": "Nature", "link": null}, "BIBREF37": {"title": "Simulation of the Eurasian ice sheet dynamics during the 686 last glaciation", "authors": [{"first": "P", "middle": ["L"], "last": "Forsstr\u00f6m", "suffix": ""}, {"first": "R", "middle": [], "last": "Greve", "suffix": ""}], "year": 2004, "venue": "Global and Planetary Change", "link": "55061179"}, "BIBREF38": {"title": "Glacimarine 688 sedimentation in Kangerdluk (Disko Fjord), West Greenland, in response to a surging 689 glacier", "authors": [{"first": "R", "middle": [], "last": "Gilbert", "suffix": ""}, {"first": "N", "middle": [], "last": "Nielsen", "suffix": ""}, {"first": "H", "middle": [], "last": "Moller", "suffix": ""}, {"first": "J", "middle": ["R"], "last": "Desloges", "suffix": ""}, {"first": "M", "middle": [], "last": "Rasch", "suffix": ""}], "year": 2002, "venue": "Marine Geology", "link": null}, "BIBREF40": {"title": "Atlantic Heinrich events triggered by the behavior of the European ice sheets?", "authors": [], "year": "", "venue": "Geology", "link": null}, "BIBREF41": {"title": "Fine-grained sediment lofting from meltwater-694 generated turbidity currents during Heinrich events", "authors": [{"first": "R", "middle": [], "last": "Hesse", "suffix": ""}, {"first": "H", "middle": [], "last": "Rashid", "suffix": ""}, {"first": "S", "middle": [], "last": "Khodabakhsh", "suffix": ""}], "year": 2004, "venue": "Geology", "link": "129652416"}, "BIBREF42": {"title": "696 New evidence for a grounded Irish Sea glaciation of the Isles of Scilly", "authors": [{"first": "J", "middle": ["F"], "last": "Hiemstra", "suffix": ""}, {"first": "D", "middle": ["J A"], "last": "Evans", "suffix": ""}, {"first": "J", "middle": ["D"], "last": "Scourse", "suffix": ""}, {"first": "D", "middle": [], "last": "Mccarroll", "suffix": ""}, {"first": "M", "middle": ["F A"], "last": "Furze", "suffix": ""}, {"first": "E", "middle": [], "last": "Rhodes", "suffix": ""}], "year": 2006, "venue": "", "link": null}, "BIBREF44": {"title": "Late Quaternary denudation of the Alps, valley and lake fillings and 699 modern river loads", "authors": [{"first": "M", "middle": [], "last": "Hinderer", "suffix": ""}], "year": 2001, "venue": "Geodinamica Acta", "link": "131363340"}, "BIBREF45": {"title": "Marine04 Marine Radiocarbon Age Calibration", "authors": [{"first": "K", "middle": ["A"], "last": "Hughen", "suffix": ""}], "year": 2004, "venue": "Cal Kyr BP. 701 Radiocarbon", "link": null}, "BIBREF46": {"title": "Glacier response in the 703", "authors": [{"first": "S", "middle": [], "last": "Ivy-Ochs", "suffix": ""}, {"first": "H", "middle": [], "last": "Kerschner", "suffix": ""}, {"first": "P", "middle": ["W"], "last": "Kubik", "suffix": ""}, {"first": "C", "middle": [], "last": "Schl\u00fcchter", "suffix": ""}], "year": 2006, "venue": "", "link": null}, "BIBREF47": {"title": "European Alps to Heinrich Event 1 cooling: the Gschnitz stadial", "authors": [], "year": "", "venue": "Journal of 704 Quaternary Science", "link": null}, "BIBREF48": {"title": "Timing of 706 deglaciation on the northern Alpine foreland (Switzerland)", "authors": [{"first": "S", "middle": [], "last": "Ivy-Ochs", "suffix": ""}, {"first": "J", "middle": [], "last": "Sch\u00e4fer", "suffix": ""}, {"first": "P", "middle": ["W"], "last": "Kubik", "suffix": ""}, {"first": "H.-A", "middle": [], "last": "Synal", "suffix": ""}, {"first": "C", "middle": [], "last": "Schl\u00fcchter", "suffix": ""}], "year": 2004, "venue": "Eclogae Geologicae", "link": "129102959"}, "BIBREF50": {"title": "Re-advance of the Fennoscandian Ice Sheet during Heinrich Event 1", "authors": [{"first": "R", "middle": ["S"], "last": "", "suffix": ""}], "year": 2007, "venue": "", "link": "128483812"}, "BIBREF53": {"title": "Multidecadal ocean variability and NW European ice sheet surges during 713 the last deglaciation", "authors": [{"first": "N", "middle": ["J"], "last": "", "suffix": ""}], "year": 2002, "venue": "Geochemistry, Geophysics, Geosystems", "link": "13818876"}, "BIBREF54": {"title": "Glacimarine slope 716 sedimentation, contourite drifts and bottom current pathways on the Barra Fan, UK 717 North Atlantic margin", "authors": [{"first": "P", "middle": ["C"], "last": "Knutz", "suffix": ""}, {"first": "E", "middle": ["J W"], "last": "Jones", "suffix": ""}, {"first": "W", "middle": ["E N"], "last": "Austin", "suffix": ""}, {"first": "T", "middle": ["C E"], "last": "Van Weering", "suffix": ""}], "year": 2002, "venue": "Marine Geology", "link": "128906734"}, "BIBREF55": {"title": "Centennial-scale variability if the British Ice Sheet: 719 Implications for climate forcing and atlantic meridional overturning circulation during 720 the last deglaciation", "authors": [{"first": "P", "middle": ["C"], "last": "Knutz", "suffix": ""}, {"first": "R", "middle": [], "last": "Zahn", "suffix": ""}, {"first": "I", "middle": ["R"], "last": "Hall", "suffix": ""}], "year": 2007, "venue": "Paleoceanography", "link": null}, "BIBREF56": {"title": "Multiproxy 722 approach for the reconstruction of the glacial ocean surface (MARGO)", "authors": [{"first": "M", "middle": [], "last": "Kucera", "suffix": ""}, {"first": "A", "middle": [], "last": "Rosell-Mele", "suffix": ""}, {"first": "R", "middle": [], "last": "Schneider", "suffix": ""}, {"first": "C", "middle": [], "last": "Waelbroeck", "suffix": ""}, {"first": "M", "middle": [], "last": "Weinelt", "suffix": ""}], "year": 2005, "venue": "Science Reviews", "link": "56372006"}, "BIBREF57": {"title": "Into and out of the Last Glacial Maximum: 725 sea-level change during Oxygen Isotope Stages 3 and 2", "authors": [{"first": "K", "middle": [], "last": "Lambeck", "suffix": ""}, {"first": "Y", "middle": [], "last": "Yokoyama", "suffix": ""}, {"first": "T", "middle": [], "last": "Purcell", "suffix": ""}], "year": 2002, "venue": "Quaternary Science Reviews", "link": "55391260"}, "BIBREF58": {"title": "Carte des pal\u00e9o-vall\u00e9es et des bancs de la 728 Manche orientale (1/50 000)", "authors": [{"first": "C", "middle": [], "last": "Larsonneur", "suffix": ""}, {"first": "J", "middle": ["P"], "last": "Auffret", "suffix": ""}, {"first": "A", "middle": ["J"], "last": "Smith", "suffix": ""}], "year": 1982, "venue": "", "link": null}, "BIBREF59": {"title": "Synth\u00e8se bathym\u00e9trique et imagerie acoustique. zone \u00e9conomique 730 exclusive (ZEE)", "authors": [{"first": "Le", "middle": [], "last": "Suav\u00e9", "suffix": ""}, {"first": "R", "middle": [], "last": "", "suffix": ""}], "year": 2000, "venue": "", "link": null}, "BIBREF60": {"title": "732 Laminated sediments preceding Heinrich event 1 in the Northern North Sea", "authors": [{"first": "W", "middle": ["A H"], "last": "Lekens", "suffix": ""}, {"first": "H", "middle": ["P"], "last": "Sejrup", "suffix": ""}, {"first": "H", "middle": [], "last": "Haflidason", "suffix": ""}, {"first": "G", "middle": ["O"], "last": "Petersen", "suffix": ""}, {"first": "B", "middle": [], "last": "Hjelstuen", "suffix": ""}, {"first": "G", "middle": [], "last": "Knorr", "suffix": ""}], "year": 2005, "venue": "", "link": null}, "BIBREF61": {"title": "Southern Norwegian Sea: Origin, processes and regional linkage", "authors": [], "year": "", "venue": "Marine Geology", "link": null}, "BIBREF62": {"title": "Evolution du Fleuve Manche depuis l'Oligoc\u00e8ne: stratigraphie et 736 g\u00e9omorphologie d'une plate-forme continentale en r\u00e9gime p\u00e9riglaciaire", "authors": [{"first": "G", "middle": [], "last": "Lericolais", "suffix": ""}], "year": 1997, "venue": "", "link": null}, "BIBREF63": {"title": "Faci\u00e8s sismique et architecture du syst\u00e8me turbiditique armoricain. Rapport 739 de Dipl\u00f4me d'Etudes Approfondi", "authors": [{"first": "S", "middle": [], "last": "Mansor", "suffix": ""}], "year": 2004, "venue": "", "link": null}, "BIBREF64": {"title": "Last Glacial Maximum in Poland", "authors": [{"first": "L", "middle": [], "last": "Marks", "suffix": ""}], "year": 2002, "venue": "Quaternary Science Reviews", "link": "129194061"}, "BIBREF65": {"title": "Ice-sheet variability around the North Atlantic Ocean 744 during the last deglaciation", "authors": [{"first": "A", "middle": ["M"], "last": "Mccabe", "suffix": ""}, {"first": "P", "middle": ["U"], "last": "Clark", "suffix": ""}], "year": 1998, "venue": "Nature", "link": "1125814"}, "BIBREF66": {"title": "AMS 14C dating of deglacial events in the Irish 746 Sea Basin and other sectors of the British-Irish ice sheet", "authors": [{"first": "A", "middle": ["M"], "last": "Mccabe", "suffix": ""}, {"first": "P", "middle": ["U"], "last": "Clark", "suffix": ""}, {"first": "J", "middle": [], "last": "Clark", "suffix": ""}], "year": 2005, "venue": "Quaternary Science Reviews", "link": null}, "BIBREF67": {"title": "Radiocarbon constraints on the history of the 749 western Irish ice sheet prior to the Last Glacial Maximum", "authors": [{"first": "A", "middle": ["M"], "last": "Mccabe", "suffix": ""}, {"first": "P", "middle": ["U"], "last": "Clark", "suffix": ""}, {"first": "J", "middle": [], "last": "Clark", "suffix": ""}], "year": 2007, "venue": "Geology", "link": "16969907"}, "BIBREF68": {"title": "Radiocarbon constraints on 751 readvances of the British-Irish Ice Sheet in the northern Irish Sea Basin during the last 752 deglaciation", "authors": [{"first": "A", "middle": ["M"], "last": "Mccabe", "suffix": ""}, {"first": "P", "middle": ["U"], "last": "Clark", "suffix": ""}, {"first": "J", "middle": [], "last": "Clark", "suffix": ""}, {"first": "P", "middle": [], "last": "Dunlop", "suffix": ""}], "year": 2007, "venue": "Quaternary Science Reviews", "link": "32346105"}, "BIBREF70": {"title": "Early reactivation of European Rivers during the last deglaciation", "authors": [{"first": "J", "middle": ["S"], "last": "", "suffix": ""}], "year": 2006, "venue": "Science", "link": "45157193"}, "BIBREF71": {"title": "SCOPIX: A new X-ray imaging 757 system for core analysis", "authors": [{"first": "S", "middle": [], "last": "Migeon", "suffix": ""}, {"first": "O", "middle": [], "last": "Weber", "suffix": ""}, {"first": "J.-C", "middle": [], "last": "Faug\u00e8res", "suffix": ""}, {"first": "J", "middle": [], "last": "Saint-Paul", "suffix": ""}], "year": 1999, "venue": "", "link": null}, "BIBREF72": {"title": "Environmental processes of the ice age: land, 759 oceans, glaciers (EPILOG)", "authors": [{"first": "A", "middle": ["C"], "last": "Mix", "suffix": ""}, {"first": "E", "middle": [], "last": "Bard", "suffix": ""}, {"first": "R", "middle": [], "last": "Schneider", "suffix": ""}], "year": 2001, "venue": "Quaternary Science Reviews", "link": "54990029"}, "BIBREF73": {"title": "761 Palaeoclimatology and palaeohydrography of the glacial stages on Celtic and 762 Armorican margins over the last 360 000 yrs", "authors": [{"first": "M", "middle": [], "last": "Mojtahid", "suffix": ""}, {"first": "F", "middle": [], "last": "Eynaud", "suffix": ""}, {"first": "S", "middle": [], "last": "Zaragosi", "suffix": ""}, {"first": "J", "middle": [], "last": "Scourse", "suffix": ""}, {"first": "J", "middle": ["F"], "last": "Bourillet", "suffix": ""}, {"first": "T", "middle": [], "last": "Garlan", "suffix": ""}], "year": 2005, "venue": "Marine Geology", "link": null}, "BIBREF75": {"title": "Present-day and past (last 25 000 years) 765 marine pollen signal off western Iberia", "authors": [{"first": "E", "middle": [], "last": "Cortijo", "suffix": ""}, {"first": "T", "middle": [], "last": "Drago", "suffix": ""}, {"first": "M", "middle": ["C"], "last": "Freitas", "suffix": ""}], "year": 2007, "venue": "Marine Micropaleontology", "link": null}, "BIBREF77": {"title": "Wet to dry trend in north western Iberia within Heinrich 768 events", "authors": [{"first": "F", "middle": [], "last": "Rostek", "suffix": ""}, {"first": "J", "middle": ["L"], "last": "Turon", "suffix": ""}], "year": "", "venue": "Earth and Planetary Science Letters", "link": null}, "BIBREF78": {"title": "Deglaciation history 770 of the southwestern Fennoscandian Ice Sheet between 15 and 13 14 C ka BP", "authors": [{"first": "A", "middle": [], "last": "Nygard", "suffix": ""}, {"first": "H", "middle": ["P"], "last": "Sejrup", "suffix": ""}, {"first": "H", "middle": [], "last": "Haflidason", "suffix": ""}, {"first": "M", "middle": [], "last": "Cecchi", "suffix": ""}, {"first": "D", "middle": [], "last": "Ottesen", "suffix": ""}], "year": 2004, "venue": "Boreas", "link": null}, "BIBREF79": {"title": "Radiocarbon constraints on the age of the maximum 773 advance of the British-Irish Ice Sheet in the Celtic Sea", "authors": [{"first": "C", "middle": [], "last": "O&apos;cofaigh", "suffix": ""}, {"first": "D", "middle": ["J A"], "last": "Evans", "suffix": ""}], "year": 2007, "venue": "Quaternary Science Reviews", "link": "129497522"}, "BIBREF80": {"title": "High resolution evidence for linkages between NW European ice sheet 777 instability and Atlantic Meridional Overturning Circulation. Earth and Planetary 778", "authors": [{"first": "V", "middle": ["L"], "last": "Peck", "suffix": ""}, {"first": "I", "middle": ["R"], "last": "Hall", "suffix": ""}, {"first": "R", "middle": [], "last": "Zahn", "suffix": ""}, {"first": "H", "middle": [], "last": "Elderfield", "suffix": ""}, {"first": "F", "middle": [], "last": "Grousset", "suffix": ""}, {"first": "S", "middle": ["R"], "last": "Hemming", "suffix": ""}, {"first": "J", "middle": ["D"], "last": "Scourse", "suffix": ""}], "year": 2006, "venue": "Science Letters", "link": null}, "BIBREF81": {"title": "The 780 relationship of Heinrich events and their European precursors over the past 60 ka BP: 781 a multi-proxy ice", "authors": [{"first": "V", "middle": ["L"], "last": "Peck", "suffix": ""}, {"first": "I", "middle": ["R"], "last": "Hall", "suffix": ""}, {"first": "R", "middle": [], "last": "Zahn", "suffix": ""}, {"first": "F", "middle": [], "last": "Grousset", "suffix": ""}, {"first": "S", "middle": ["R"], "last": "Hemming", "suffix": ""}, {"first": "J", "middle": ["D"], "last": "Scourse", "suffix": ""}], "year": 2007, "venue": "", "link": null}, "BIBREF83": {"title": "Eustatic controls on clastic deposition II -Sequence 784 and systems tract models", "authors": [{"first": "H", "middle": ["W"], "last": "Posamentier", "suffix": ""}, {"first": "P", "middle": ["R"], "last": "Vail", "suffix": ""}], "year": 1988, "venue": "Sea-level Changes: an 785 Integrated Approach", "link": "131329156"}, "BIBREF84": {"title": "Origin of unusually thick Heinrich layers in ice-787 proximal regions of the northwest Labrador Sea", "authors": [{"first": "H", "middle": [], "last": "Rashid", "suffix": ""}, {"first": "R", "middle": [], "last": "Hesse", "suffix": ""}, {"first": "D", "middle": ["J W"], "last": "Piper", "suffix": ""}], "year": 2003, "venue": "Earth and Planetary Science Letters", "link": "54534623"}, "BIBREF86": {"title": "Eustatic and hydrodynamic controls on the architecture of a 791 deep shelf sand bank (Celtic Sea)", "authors": [{"first": "J", "middle": ["F"], "last": "Lericolais", "suffix": ""}, {"first": "G", "middle": [], "last": "", "suffix": ""}], "year": 1999, "venue": "Sedimentology", "link": "128675216"}, "BIBREF88": {"title": "The 794", "authors": [{"first": "V", "middle": [], "last": "Zelcs", "suffix": ""}, {"first": "J", "middle": ["P"], "last": "Lunkka", "suffix": ""}, {"first": "I", "middle": ["E"], "last": "Pavlovskaya", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Piotrowski", "suffix": ""}, {"first": "A", "middle": [], "last": "Raukas", "suffix": ""}], "year": 2006, "venue": "", "link": null}, "BIBREF89": {"title": "Last Deglaciation of the Southeastern Sector of the Scandinavian Ice Sheet", "authors": [], "year": "", "venue": "Science", "link": null}, "BIBREF90": {"title": "Late Pleistocene stratigraphy and palaeobotany of the Isles of Scilly", "authors": [{"first": "J", "middle": ["D"], "last": "Scourse", "suffix": ""}], "year": 1991, "venue": "Philosophical Transactions of the Royal Society of London", "link": "83568925"}, "BIBREF92": {"title": "Sedimentology and micropaleontology of glacimarine sediments 800 from the Central and Southwestern Celtic Sea", "authors": [{"first": "J", "middle": ["R"], "last": "Young", "suffix": ""}], "year": 1990, "venue": "Special Publication of the Geological 801 Society of London", "link": null}, "BIBREF93": {"title": "A critical review of the glaciomarine model for Irish sea 803 deglaciation: evidence from southern Britain, the Celtic shelf and adjacent continental 804 slope", "authors": [{"first": "J", "middle": ["D"], "last": "Scourse", "suffix": ""}, {"first": "M", "middle": ["F A"], "last": "Furze", "suffix": ""}], "year": 2001, "venue": "Journal of Quaternary Science", "link": "128473338"}, "BIBREF95": {"title": "Sea-level fluctuations during the last glacial cycle", "authors": [{"first": "D", "middle": ["A"], "last": "Smeed", "suffix": ""}], "year": 2003, "venue": "Nature", "link": "4420155"}, "BIBREF96": {"title": "Analysis and modelling of gravity-and piston coring 809 based on soil mechanics", "authors": [{"first": "L", "middle": ["C"], "last": "Skinner", "suffix": ""}, {"first": "I", "middle": ["N"], "last": "Mccave", "suffix": ""}], "year": 2003, "venue": "Marine Geology", "link": "128829268"}, "BIBREF97": {"title": "Deep-water fine-grained sediments: facies model. Fine-811 grained sediments: deep-water processes and facies", "authors": [{"first": "D", "middle": ["A V"], "last": "Stow", "suffix": ""}, {"first": "D", "middle": ["J W"], "last": "Piper", "suffix": ""}], "year": 1984, "venue": "", "link": null}, "BIBREF98": {"title": "Extended 14C data base and revised CALIB radiocarbon 814 calibration program", "authors": [{"first": "M", "middle": [], "last": "Stuiver", "suffix": ""}, {"first": "P", "middle": ["J"], "last": "Reimer", "suffix": ""}], "year": 1993, "venue": "Radiocarbon", "link": null}, "BIBREF101": {"title": "Tidal evolution 819 of the northwest European shelf seas from the Last Glacial Maximum to the present", "authors": [{"first": "K", "middle": [], "last": "Uehara", "suffix": ""}, {"first": "J", "middle": ["D"], "last": "Scourse", "suffix": ""}, {"first": "K", "middle": ["J"], "last": "Horsburgh", "suffix": ""}, {"first": "K", "middle": [], "last": "Lambeck", "suffix": ""}, {"first": "A", "middle": ["P"], "last": "Purcell", "suffix": ""}], "year": 2006, "venue": "Journal of Geophysical Research", "link": "129622290"}, "BIBREF102": {"title": "regional variation in the response of vegetation to Lateglacial climatic 822 events in Europe", "authors": [{"first": "W", "middle": ["A"], "last": "Watts", "suffix": ""}], "year": 1980, "venue": "Studies in the 823 Lateglacial of North West Europe", "link": null}, "BIBREF103": {"title": "The North Atlantic deep-sea floor -glacial versus 825 interglacial controls and comparisons between the eastern and western North Atlantic", "authors": [{"first": "P", "middle": ["P E"], "last": "Weaver", "suffix": ""}, {"first": "S", "middle": [], "last": "Benetti", "suffix": ""}], "year": 2006, "venue": "", "link": null}, "BIBREF105": {"title": "Continental margin 828 sedimentation, with special reference to the north-east Atlantic margin", "authors": [{"first": "P", "middle": ["P E"], "last": "Weaver", "suffix": ""}, {"first": "R", "middle": ["B"], "last": "Wynn", "suffix": ""}, {"first": "N", "middle": ["H"], "last": "Kenyon", "suffix": ""}, {"first": "J", "middle": [], "last": "Evans", "suffix": ""}], "year": 2000, "venue": "Sedimentology", "link": "128852542"}, "BIBREF106": {"title": "The last British Ice Sheet: growth, maximum 831 extent and deglaciation", "authors": [{"first": "L", "middle": ["J"], "last": "Wilson", "suffix": ""}, {"first": "W", "middle": ["E N"], "last": "Austin", "suffix": ""}, {"first": "E", "middle": [], "last": "Jansen", "suffix": ""}], "year": 2002, "venue": "Polar Research", "link": "128701238"}, "BIBREF107": {"title": "Timing of the 833 Last Glacial Maximum from observed sea-level minima", "authors": [{"first": "Y", "middle": [], "last": "Yokoyama", "suffix": ""}, {"first": "K", "middle": [], "last": "Lambeck", "suffix": ""}, {"first": "P", "middle": [], "last": "De Deckker", "suffix": ""}, {"first": "P", "middle": [], "last": "Johnston", "suffix": ""}, {"first": "L", "middle": ["K"], "last": "Fifield", "suffix": ""}], "year": 2000, "venue": "Nature", "link": "7378990"}, "BIBREF108": {"title": "The deep-sea Armorican 835 depositional system (Bay of Biscay), a multiple source, ramp model", "authors": [{"first": "Le", "middle": [], "last": "Zaragosi", "suffix": ""}, {"first": "S", "middle": [], "last": "Bourillet", "suffix": ""}, {"first": "", "middle": [], "last": "Auffret", "suffix": ""}, {"first": "", "middle": [], "last": "Faug\u00e8res", "suffix": ""}, {"first": "Garlan", "middle": [], "last": "Pujol", "suffix": ""}], "year": 2001, "venue": "Geo-Marine", "link": "129256442"}, "BIBREF109": {"title": "838 Physiography and recent sediment distribution of the Celtic Deep-Sea Fan", "authors": [{"first": "S", "middle": [], "last": "Zaragosi", "suffix": ""}, {"first": "G", "middle": ["A"], "last": "Auffret", "suffix": ""}, {"first": "J", "middle": ["C"], "last": "Faugeres", "suffix": ""}, {"first": "T", "middle": [], "last": "Garlan", "suffix": ""}, {"first": "C", "middle": [], "last": "Pujol", "suffix": ""}, {"first": "E", "middle": [], "last": "Cortijo", "suffix": ""}], "year": 2000, "venue": "", "link": null}, "BIBREF111": {"title": "The impact of the last European deglaciation on the deep-sea turbidite 842 systems of the Celtic-Armorican margin", "authors": [{"first": "S", "middle": [], "last": "Zaragosi", "suffix": ""}, {"first": "J", "middle": ["F"], "last": "Bourillet", "suffix": ""}, {"first": "F", "middle": [], "last": "Eynaud", "suffix": ""}, {"first": "S", "middle": [], "last": "Toucanne", "suffix": ""}, {"first": "B", "middle": [], "last": "Denhard", "suffix": ""}, {"first": "A", "middle": [], "last": "Van Toer", "suffix": ""}], "year": 2006, "venue": "Geo-Marine Letters", "link": null}, "BIBREF112": {"title": "Initiation of 845 the European deglaciation as recorded in the northwestern Bay of Biscay slope 846 environments (Meriadzek Terrace and Trevelyan Escarpment): a multi-proxy 847 approach", "authors": [{"first": "S", "middle": [], "last": "Zaragosi", "suffix": ""}, {"first": "F", "middle": [], "last": "Eynaud", "suffix": ""}, {"first": "C", "middle": [], "last": "Pujol", "suffix": ""}, {"first": "G", "middle": ["A"], "last": "Auffret", "suffix": ""}, {"first": "J", "middle": ["L"], "last": "Turon", "suffix": ""}, {"first": "T", "middle": [], "last": "Garlan", "suffix": ""}], "year": 2001, "venue": "Earth and Planetary Science Letters", "link": null}}, "ref_entries": {}}
{"paper_id": "8330197", "_pdf_hash": "b2c5bb9faa0fa1f7b952f3afaea05fa09874fa8e", "abstract": [{"section": "Abstract", "text": "Rising levels of atmospheric CO 2 have often been reported to reduce plant water use. Such behavior is also predicted by standard equations relating photosynthesis, stomatal conductance, and atmospheric CO 2 concentration, which form the core of dynamic global vegetation models (DGVMs). Here, we provide first results from a free air CO 2 enrichment (FACE) experiment with naturally growing, mature (35 m) Picea abies (L.) (Norway spruce) and compare them to simulations by the DGVM LPJ-GUESS. We monitored sap flow, stem water deficit, stomatal conductance, leaf water potential, and soil moisture in five 35-40 m tall CO 2 -treated (550 ppm) trees over two seasons. Using LPJ-GUESS, we simulated this experiment using climate data from a nearby weather station. While the model predicted a stable reduction of transpiration of between 9% and 18% (at concentrations of 550-700 ppm atmospheric CO 2 ), the combined evidence from various methods characterizing water use in our experimental trees suggest no changes in response to future CO 2 concentrations. The discrepancy between the modeled and the experimental results may be a scaling issue: while dynamic vegetation models correctly predict leaf-level responses, they may not sufficiently account for the processes involved at the canopy and ecosystem scale, which could offset the first-order stomatal response.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "INTRODUCTION", "text": "Whether and if so how plants respond to increasing atmospheric CO 2 is critical for future ecosystem carbon and water cycling and largely depends on the response of the stomata that control both carbon (C) uptake and water loss. Several authors have suggested that water-related effects of elevated CO 2 (eCO 2 ) on stomatal closure might be or become more important than immediate effects on carbon uptake (Morgan et al., 2003; Holtum and Winter, 2010; Hartmann, 2011) . One reason for this may be that while stimulated growth and biomass accumulation rarely persist over many years (K\u00f6rner et al., 2005; Norby et al., 2010; Leuzinger et al., 2011b) , but see McCarthy et al. (2010) , stomatal responses tend to be sustained (see Holtum and Winter, 2010 for a review). For grassland, there is compelling experimental evidence that stimulated biomass production under eCO 2 is in fact a consequence of soil water savings resulting from reduced stomatal conductance (Niklaus et al., 1998; Morgan et al., 2004) . Such a water-mediated CO 2 -effect is expected to be more pronounced in water-limited ecosystems, although under extremely dry conditions it has not been observed (Housman et al., 2006) . The experimental conditions (species composition tested, CO 2 -administration method, laboratory vs. field experiment, ontogenetic stage of test plants) and particularly the experimental duration are fundamental for the interpretation of net water use under eCO 2 (Norby et al., 1999) . For example, initial CO 2 -induced increases in total leaf area per unit land area leaf area index, (LAI) in young, rapidly expanding systems will inevitably lead to increased stand transpiration, irrespective of the leaf-level stomatal response (Uddling et al., 2008; Tricker et al., 2009) . Similarly, the long-term response (>10 years) often differs from measurements over only a few years (K\u00f6rner, 2006) . The scaling from first-order stomatal responses to stand water use therefore requires careful consideration of the interactions between the water-and the carbon cycle across temporal and spatial scales.", "cite_spans": [{"start": 407, "end": 428, "text": "(Morgan et al., 2003;", "ref_id": "BIBREF54"}, {"start": 429, "end": 453, "text": "Holtum and Winter, 2010;", "ref_id": "BIBREF25"}, {"start": 454, "end": 469, "text": "Hartmann, 2011)", "ref_id": "BIBREF20"}, {"start": 584, "end": 605, "text": "(K\u00f6rner et al., 2005;", "ref_id": "BIBREF34"}, {"start": 606, "end": 625, "text": "Norby et al., 2010;", "ref_id": "BIBREF58"}, {"start": 626, "end": 650, "text": "Leuzinger et al., 2011b)", "ref_id": "BIBREF39"}, {"start": 731, "end": 754, "text": "Holtum and Winter, 2010", "ref_id": "BIBREF25"}, {"start": 965, "end": 987, "text": "(Niklaus et al., 1998;", "ref_id": "BIBREF56"}, {"start": 988, "end": 1008, "text": "Morgan et al., 2004)", "ref_id": "BIBREF55"}, {"start": 1174, "end": 1196, "text": "(Housman et al., 2006)", "ref_id": "BIBREF26"}, {"start": 1463, "end": 1483, "text": "(Norby et al., 1999)", "ref_id": "BIBREF60"}, {"start": 1732, "end": 1754, "text": "(Uddling et al., 2008;", "ref_id": "BIBREF77"}, {"start": 1755, "end": 1776, "text": "Tricker et al., 2009)", "ref_id": "BIBREF75"}, {"start": 1879, "end": 1893, "text": "(K\u00f6rner, 2006)", "ref_id": "BIBREF32"}], "ref_spans": []}, {"section": "INTRODUCTION", "text": "Overall, there is a striking lack of data from mature forests as most of the evidence for water savings under eCO 2 still comes from grass-or shrub ecosystems, or from branch bag experiments on mature trees (Roberntz and Stockfors, 1998; Pataki et al., 2000; Morgan et al., 2004) . No eCO 2 experiments on tall trees exist in the tropical forests (K\u00f6rner, 2009) . Worldwide, there are only five experiments testing the effect of future CO 2 concentrations on entire tree crowns using the free air CO 2 enrichment (FACE) method (K\u00f6rner et al., 2005; Norby et al., 2005) , excluding whole tree chamber and agricultural experiments (Medhurst et al., 2006; Kimball et al., 2007) . Although those five studies were conducted with different species and in a variety of biomes, three of them roughly agree on reduced total stand water use under eCO 2 of c. 10% (Warren et al., 2011) . The remaining two were young, expanding systems where the transpiration response to CO 2 was dominated by a stimulation of LAI and therefore increased stand water use (Uddling et al., 2008; Tricker et al., 2009 ). Responses in leaf-level stomatal conductance (g s ) to eCO 2 are less consistent in the five large forest FACE experiments mentioned (\u22124% to \u221244%), but approximately match findings from meta-analyses including experiments with woody plants in branch bag and greenhouse experiments (\u221221% Medlyn et al., 2001, \u221218% Ainsworth and Rogers, 2007 , and no significant response from a much earlier review predominantly on seedlings and saplings, Curtis and Wang, 1998) . At the Swiss Canopy Crane (SCC), where the present study was conducted, stomatal conductance was reduced around 10% in six deciduous tree species, and sap flow by 2-22%, resulting in a reduction of yearly stand transpiration of c. 10% (Cech et al., 2003; Keel et al., 2007; Leuzinger and K\u00f6rner, 2007) . Overall, water savings under eCO 2 tend to decline with the duration of the experiment (Medlyn et al., 2001; Leuzinger and K\u00f6rner, 2010; Leuzinger et al., 2011b) , with increasing woodiness (Ainsworth and Rogers, 2007) , with increasing age of the studied plants (Medlyn et al., 2001) , and from deciduous to coniferous trees (Ellsworth, 1999; K\u00f6rner et al., 2007) . Because the number of short-term experiments with herbaceous or young trees is disproportionately larger than the number of experiments with mature trees, we can assume that water savings under eCO 2 tend to be overestimated, particularly because the response is likely to diminish further when scaling up from the individual plant to the landscape level (McNaughton and Jarvis, 1991; Field et al., 1995; Leuzinger and K\u00f6rner, 2010) . A way to circumvent the necessity of scaling up CO 2 -experiments with young, disturbed systems is 13 C analysis of tree rings to infer intrinsic water use efficiency (iWUE, Francey and Farquhar, 1982; Bert et al., 1997) . Penuelas et al. (2011) in a recent review report that iWUE has increased by c. 20% over the past 40 years, with slightly larger responses in broad-leaved relative to coniferous trees. On the other hand, in a study on various species of oak, hornbeam and maple, no change in iWUE was reported based on only 2-3 leaf samples during the twentieth century (MillerRushing et al., 2009 ). Changes in iWUE may originate either from changes in the nominator (leaf-level photosynthesis) or the denominator (stomatal conductance), and thus cannot be used to fill in the lack of FACE experiments to estimate changes in stand transpiration under future CO 2 concentrations. Experimental estimates of leaf-level and whole tree responses are also key to algorithms and their parameterization in dynamic global vegetation models (DGVMs) and earth system models, and therefore predictions of future vegetation responses and climate feedbacks (Moorcroft, 2006) . Stomatal conductance models used in DGVMs predict substantial decreases of g s with a doubling of atmospheric CO 2 , fundamentally because the substomatal CO 2 concentration (C i ) is held approximately constant (Jarvis, 1976; Leuning, 1995; Haxeltine and Prentice, 1996) . It is therefore little surprising that DGVMs predict global water savings by the vegetation of around 10-20% (Luo et al., 2008) , which lead to increased runoff of mostly a few percent (e.g., Betts et al., 2007; Boucher et al., 2009; Long et al., 2010) , matching estimates based on experimental data (Leuzinger and K\u00f6rner, 2010) . However, it is important to note that few of these model results can be validated due to a lack of data, and net responses largely hinge on the way the leaf-level response is scaled up to the canopy and landscape scale. The aim of the present study is to (1) provide novel data on water relations of fully grown Norway spruce (Picea abies) trees under approximately double pre-industrial CO 2 -conditions, and (2) to discuss these findings in context of simulations of the experiment by the DGVM LPJ-GUESS (Smith et al., 2001; Sitch et al., 2003) .", "cite_spans": [{"start": 207, "end": 237, "text": "(Roberntz and Stockfors, 1998;", "ref_id": "BIBREF66"}, {"start": 238, "end": 258, "text": "Pataki et al., 2000;", "ref_id": "BIBREF61"}, {"start": 259, "end": 279, "text": "Morgan et al., 2004)", "ref_id": "BIBREF55"}, {"start": 347, "end": 361, "text": "(K\u00f6rner, 2009)", "ref_id": "BIBREF33"}, {"start": 527, "end": 548, "text": "(K\u00f6rner et al., 2005;", "ref_id": "BIBREF34"}, {"start": 549, "end": 568, "text": "Norby et al., 2005)", "ref_id": "BIBREF57"}, {"start": 629, "end": 652, "text": "(Medhurst et al., 2006;", "ref_id": "BIBREF50"}, {"start": 653, "end": 674, "text": "Kimball et al., 2007)", "ref_id": "BIBREF30"}, {"start": 854, "end": 875, "text": "(Warren et al., 2011)", "ref_id": "BIBREF80"}, {"start": 1045, "end": 1067, "text": "(Uddling et al., 2008;", "ref_id": "BIBREF77"}, {"start": 1068, "end": 1088, "text": "Tricker et al., 2009", "ref_id": "BIBREF75"}, {"start": 1419, "end": 1431, "text": "Rogers, 2007", "ref_id": "BIBREF1"}, {"start": 1530, "end": 1552, "text": "Curtis and Wang, 1998)", "ref_id": "BIBREF12"}, {"start": 1790, "end": 1809, "text": "(Cech et al., 2003;", "ref_id": "BIBREF10"}, {"start": 1810, "end": 1828, "text": "Keel et al., 2007;", "ref_id": "BIBREF29"}, {"start": 1829, "end": 1856, "text": "Leuzinger and K\u00f6rner, 2007)", "ref_id": "BIBREF40"}, {"start": 1946, "end": 1967, "text": "(Medlyn et al., 2001;", "ref_id": "BIBREF51"}, {"start": 1968, "end": 1995, "text": "Leuzinger and K\u00f6rner, 2010;", "ref_id": "BIBREF41"}, {"start": 1996, "end": 2020, "text": "Leuzinger et al., 2011b)", "ref_id": "BIBREF39"}, {"start": 2049, "end": 2077, "text": "(Ainsworth and Rogers, 2007)", "ref_id": "BIBREF1"}, {"start": 2122, "end": 2143, "text": "(Medlyn et al., 2001)", "ref_id": "BIBREF51"}, {"start": 2185, "end": 2202, "text": "(Ellsworth, 1999;", "ref_id": "BIBREF14"}, {"start": 2203, "end": 2223, "text": "K\u00f6rner et al., 2007)", "ref_id": "BIBREF35"}, {"start": 2581, "end": 2610, "text": "(McNaughton and Jarvis, 1991;", "ref_id": "BIBREF49"}, {"start": 2611, "end": 2630, "text": "Field et al., 1995;", "ref_id": "BIBREF16"}, {"start": 2631, "end": 2658, "text": "Leuzinger and K\u00f6rner, 2010)", "ref_id": "BIBREF41"}, {"start": 2835, "end": 2862, "text": "Francey and Farquhar, 1982;", "ref_id": "BIBREF17"}, {"start": 2863, "end": 2881, "text": "Bert et al., 1997)", "ref_id": "BIBREF6"}, {"start": 2884, "end": 2906, "text": "Penuelas et al. (2011)", "ref_id": "BIBREF63"}, {"start": 3810, "end": 3827, "text": "(Moorcroft, 2006)", "ref_id": "BIBREF53"}, {"start": 4042, "end": 4056, "text": "(Jarvis, 1976;", "ref_id": "BIBREF27"}, {"start": 4057, "end": 4071, "text": "Leuning, 1995;", "ref_id": "BIBREF37"}, {"start": 4072, "end": 4101, "text": "Haxeltine and Prentice, 1996)", "ref_id": "BIBREF22"}, {"start": 4213, "end": 4231, "text": "(Luo et al., 2008)", "ref_id": "BIBREF45"}, {"start": 4296, "end": 4315, "text": "Betts et al., 2007;", "ref_id": "BIBREF7"}, {"start": 4316, "end": 4337, "text": "Boucher et al., 2009;", "ref_id": "BIBREF9"}, {"start": 4338, "end": 4356, "text": "Long et al., 2010)", "ref_id": "BIBREF43"}, {"start": 4405, "end": 4433, "text": "(Leuzinger and K\u00f6rner, 2010)", "ref_id": "BIBREF41"}, {"start": 4942, "end": 4962, "text": "(Smith et al., 2001;", "ref_id": "BIBREF71"}, {"start": 4963, "end": 4982, "text": "Sitch et al., 2003)", "ref_id": "BIBREF70"}], "ref_spans": []}, {"section": "MATERIALS AND METHODS", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "STUDY SITE", "text": "The SCC is located in a mature, mixed deciduous forest 15 km south of Basel, Switzerland (47 \u2022 28 N, 7 \u2022 30 E, 550 m a.s.l.). The crane gondola allows access to all tree crowns located within the 30 m radius of the jib. The site has a mean January temperature of 2 \u2022 C and mean July temperature of 19 \u2022 C, long-term average annual precipitation amounts to 990 mm, two-thirds of which fall during the growing season. The oldest trees are c. 110 years old and reach heights of 35-40 m. Stand density is 415 trees ha \u22121 (trees >0.1 m breast height diameter), at a stem basal area of 46 m 2 ha \u22121 and a LAI of c. 5. The soil type is a Rendzic Leptosol (WRB) (Rendzina, FAO; Lithic Rendoll, USDA) with an accessible profile depth of at most 25 cm followed by rocky subsoil blending into the calcareous bedrock at 40-90 cm. The soil texture is a loamy clay (pH 5.8 in the top 10 cm). The species mixture includes deciduous trees (Fagus sylvatica L., Quercus petraea (Matt.) Liebl., Carpinus betulus L., and, less abundant, Tilia platyphyllos Scop., Acer campestre L., Prunus avium L.) as well as conifers (Picea abies (L.) Karst., Larix decidua Mill., Pinus sylvestris L., Abies alba Mill.). For more information on the site see (Pepin and K\u00f6rner, 2002) .", "cite_spans": [{"start": 1223, "end": 1247, "text": "(Pepin and K\u00f6rner, 2002)", "ref_id": "BIBREF64"}], "ref_spans": []}, {"section": "EXPERIMENTAL SET-UP AND FREE AIR CO 2 ENRICHMENT", "text": "Five Norway spruce (P. abies) individuals were selected for CO 2 enrichment (550 ppm), together with five control trees, only three of which were accessible with the crane gondola. The treatment was initiated on July 30, 2009. To simulate future atmospheric conditions, pure CO 2 was released through laser-punched irrigation tubes woven into the spruce trees with a central supply pipe running up the stem. Sample lines were connected to two infrared gas analyzers (LI-800, Li-Cor, Lincoln, NE, USA), in order to monitor and automatically adjust the amount of CO 2 supplied. CO 2 enrichment was discontinued when daily temperature maxima did not reach 6 \u2022 C, or when above-canopy incoming radiation was less than 100 \u00b5mol m \u22122 s \u22121 (i.e., no night-time CO 2 enrichment). On average, the target CO 2 concentration of 550 ppm was achieved well: the mean across all sample lines during times of fumigation reached 563 ppm \u00b1 94 s.e. in 2009 and 617 ppm \u00b1 88 in 2010.", "cite_spans": [], "ref_spans": []}, {"section": "CONTINUOUS MEASUREMENTS AND MEASURING CAMPAIGNS", "text": "We continuously measured sap flow, stem radius changes, microclimate, and soil moisture. One heat dissipation sap flow sensor (TDP-30, Dynamax, Huston, TX, USA) was used per tree (5 treated, 5 controls), inserted directly into the stem after removing loose bits of bark. The sensors were oriented toward north, water-proofed with silicon paste and insulated with styrofoam and reflecting foil. They remained in the same position for both the 2009 and 2010 growing seasons. Stem radius changes (\u00b5m) were recorded with high-precision point dendrometers (ZB06, Natkon, Hombrechtikon, Switzerland), and, together with the sap flow signals, logged to two central data loggers (DL2e, Delta-T Devices Ltd., Cambridge, UK) in 10 min intervals (average over 30 s readings). Soil moisture was logged every 6 h at 0-10 cm depth using \"ECH 2 O Probes\" (EC-10, Decagon Devices Ltd., Pullman, Washington, DC). Eleven sensors were distributed around the treated trees, 18 sensors around control trees, logging onto self-contained data loggers (Em50, Decagon). Measurements took place from day of year 134 to 297 (May 14-October 24) in 2009 and from day of year 134 to 267 (May 14-September 24) in 2010. Microclimate (temperature, relative humidity, incoming radiation, and precipitation) was logged above the canopy in 10-min intervals to a DL2e logger (Delta-T Devices Ltd.). Data gaps resulting from occasional logger failure were filled by interpolation based on climate recordings from a nearby weather station (2 km air-line distance).", "cite_spans": [], "ref_spans": []}, {"section": "CONTINUOUS MEASUREMENTS AND MEASURING CAMPAIGNS", "text": "On three cloudless days (July 29, August 6 2009, and July 14 2010), we measured daily courses (five measurements per tree pre-dawn to dusk) of leaf water potential and stomatal conductance on the five treated trees and the three controls that were accessible with the crane gondola. Two twigs per tree and time window were cut off with a razor blade, needles, bark, and phloem around the cut were removed, and their leaf water potential was measured subsequently using a pressure chamber (SKPM 1400, Skye Instruments, Powys, UK). Only plant material from the fully light-exposed top crown was selected to ensure comparable conditions. Stomatal conductance was measured on current and previous year's needles, removing the needles on two c. 2 cm wide bands to allow the gas-exchange chamber to close. A portable photosynthesis system (LI-6400 XT, LI-COR Biosciences, Lincoln, NE, USA) with a conifer chamber was used for this purpose. Readings were taken as soon as rates of net photosynthesis and stomatal conductance remained stable (<5 min). All measurements were taken at full sunlight (>1000 \u00b5mol m \u22122 s \u22121 ). Treated trees were measured at their target CO 2 concentration of 560 ppm, control trees at ambient CO 2 (390 ppm). Vapor pressure deficit (VPD) inside the cuvette was adjusted to ambient conditions. Stomatal conductance was calculated by multiplying the readings with the total leaf area of the samples (harvested at the end of the experiment). Because there were no systematic differences between current year and previous year needles, all analyzes presented here are based on the average values.", "cite_spans": [], "ref_spans": []}, {"section": "MODEL SPECIFICATION AND MODEL RUNS", "text": "We used the DGVM LPJ-GUESS, featuring an accurate representation of detailed plant physiological processes (Smith et al., 2001; Sitch et al., 2003) , to simulate our experimental results. The model was run in cohort mode using daily climate data from an official Swiss weather station 11 km north of the study site (Basel-Binningen, Tank et al., 2002) . Relative humidity, radiation and temperature data correlated well with weather data recorded at the experimental site (R 2 -values equal to 0.86, 0.89, and 0.98 respectively), and specific correction factors were applied to simulate long climate time series at the experimental site as closely as possible. A 700-years spin-up period was allowed in order to equilibrate the various carbon pools with the background climate (data from 1901 to 1930 used repeatedly, CO 2 concentration at 296 ppm). Thereafter, we considered the period from 1901 to 2110. Atmospheric CO 2 concentration was altered in four different ways, all based on the actually measured mean values until 2010: (1) step change to 550 ppm in 2010, (2) step change to 700 ppm in 2010, (3) gradual change to 550 ppm until 2057, and (4) gradual change to 700 ppm until 2100. Because we only considered Norway spruce, only the plant functional type (PFT) \"needle-leaved evergreen\" was allowed to grow, all other PFTs were suppressed. Soil water storage capacity was set to 80 mm, which is the best estimate determined for a nearby site (see Walthert et al., 2004) . Only one patch with a size of 1000 m 2 was computed, hence no competition took place in order to simulate the responses of mature coniferous trees. Because forest fires are extremely rare in this region, fire disturbance was suppressed. No further parameter changes or adjustments were made relative to the default version of LPJ-GUESS (Sitch et al., 2003) .", "cite_spans": [{"start": 107, "end": 127, "text": "(Smith et al., 2001;", "ref_id": "BIBREF71"}, {"start": 128, "end": 147, "text": "Sitch et al., 2003)", "ref_id": "BIBREF70"}, {"start": 1457, "end": 1479, "text": "Walthert et al., 2004)", "ref_id": "BIBREF79"}, {"start": 1818, "end": 1838, "text": "(Sitch et al., 2003)", "ref_id": "BIBREF70"}], "ref_spans": []}, {"section": "MODEL SPECIFICATION AND MODEL RUNS", "text": "Daily transpiration in LPJ is equal to the lower value out of daily water supply and daily water demand. If water supply < water demand, then the available soil water is transpired up to a maximum rate of 5 mm d \u22121 and thus independent of CO 2 . On the other hand, if water supply > water demand, stomatal conductance decreases with increasing CO 2 because C i /C a (intercellular to ambient CO 2 concentration) is held constant and photosynthesis is stimulated (Haxeltine and Prentice, 1996) . As a result, at a leaf temperature of 20 \u2022 C, stomatal conductance is reduced c. 35% at 2\u00d7 pre-industrial CO 2 concentration. Transpiration is then calculated from potential evapotranspiration, stomatal conductance and two (constant) scaling parameters.", "cite_spans": [{"start": 462, "end": 492, "text": "(Haxeltine and Prentice, 1996)", "ref_id": "BIBREF22"}], "ref_spans": []}, {"section": "DATA PROCESSING AND STATISTICAL ANALYSES", "text": "Stem water deficit was related to the individual's stem radius at the beginning of the experiment and expressed in per mille change from the initial value. The resulting time series were decomposed into radius changes due to changes in stem water storage and a growth component according to the method outlined in (Zweifel et al., 2005) . Essentially, this method considers periods between stem radius peaks as stem water deficits (see Figure 1 of Zweifel et al., 2005) .", "cite_spans": [{"start": 314, "end": 336, "text": "(Zweifel et al., 2005)", "ref_id": "BIBREF84"}, {"start": 448, "end": 469, "text": "Zweifel et al., 2005)", "ref_id": "BIBREF84"}], "ref_spans": [{"start": 436, "end": 444, "text": "Figure 1", "ref_id": "FIGREF0"}]}, {"section": "DATA PROCESSING AND STATISTICAL ANALYSES", "text": "Millivolt signals of sap flow sensors were processed as follows to achieve most realistic conditions of zero-flow (R. Zweifel, personal communication): the maximum mV values were converted to temperature differences ( T) using a constant factor of 25. Then, T maxima between 3 h and 8 h every night were connected with a straight line. This linearly changing baseline ( T max ) was used as the pre-nightly maximum value as in the standard transformation outlined in (Granier, 1985) . Because sap flow signals are difficult to interpret as absolute mass flow densities, particularly when exact estimates of the sap wood width and the radial flow distribution are lacking Leuzinger et al., 2011a) , we chose to use only relative sap flow values (Figure 1) . Each sap flow time series was therefore standardized to its own pre-treatment maximum (mean of 20 largest values) resulting in time series between 0 and approximately 1, spanning both growing seasons (henceforth called \"relative sap flow\"). To test treatment-specific differences in daily courses of leaf water potential and stomatal conductance, we used mixed effects models (R package \"nlme\") with treatment and time of day as fixed effects and tree as a random effect. Additionally, we used an autoregressive moving average (ARMA) correlation structure to model dependence among observations. The relationship between stem water deficit ( W) and soil moisture (sm) was modeled individually for the pre-treatment and the two FACE periods (season 2009 and 2010) using a 2-parameter Michaelis-Menten-type hyperbola: W = a \u00d7 sm/ (b + sm), where \"a\" is the asymptote and \"b\" the soil moisture level at which stem water deficit reaches half of its asymptotic value (Figure 3) .", "cite_spans": [{"start": 466, "end": 481, "text": "(Granier, 1985)", "ref_id": "BIBREF18"}, {"start": 670, "end": 694, "text": "Leuzinger et al., 2011a)", "ref_id": "BIBREF38"}], "ref_spans": [{"start": 743, "end": 753, "text": "(Figure 1)", "ref_id": "FIGREF0"}]}, {"section": "DATA PROCESSING AND STATISTICAL ANALYSES", "text": "Generally, we tested statistically significant differences between treatments by fitting models with common parameter estimates and varying parameter estimates for each treatment, followed by a comparison of the two models (Figures 2, 4, and 5) . The CO 2 -treatment was considered to affect the variable of interest statistically significantly, if the Akaike information criterion (AIC) was significantly lower in the more complex model (i.e., AIC > 2). To determine the envelope curves for the sap flow-VPD relationships, we calculated the 95th percentiles of relative sap flow (SF 95 ) for every 2 kPa VPDVPD bin and fitted the poly-", "cite_spans": [], "ref_spans": [{"start": 223, "end": 244, "text": "(Figures 2, 4, and 5)", "ref_id": "FIGREF1"}]}, {"section": "DATA PROCESSING AND STATISTICAL ANALYSES", "text": ", since all other attempts to fit a non-linear model failed. The factor CO 2 is the CO 2 -treatment with the levels 1 (elevated) and 0 (ambient). The interaction term VPD \u00d7CO 2 was not significant and was therefore dropped. All analyzes were carried out using R version 2.13.0 (R Development Core Team, 2011).", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS WATER RELATIONS OF P. abies UNDER ELEVATED CO 2", "text": "A comparison of the seasonal relative sap flow sums (median of both treated and control groups) did not show any change when the pre-treatment period was compared to the CO 2 enrichment period. (Table 1, Figure 1) . The pattern did not differ when wet and dry periods were considered separately (both by soil moisture and VPD conditions). Before the treatment was initiated, the trees designated to be treated with eCO 2 tended to show less transpiration (Wilcoxon rank sum test, p = 0.055, Table 1) .", "cite_spans": [], "ref_spans": [{"start": 194, "end": 213, "text": "(Table 1, Figure 1)", "ref_id": "FIGREF0"}, {"start": 491, "end": 499, "text": "Table 1)", "ref_id": "TABREF0"}]}, {"section": "RESULTS WATER RELATIONS OF P. abies UNDER ELEVATED CO 2", "text": "A more detailed look at the daily courses of sap flow, leaf water potential, and stomatal conductance during bright sunny days before and after the start of the treatment confirmed that water consumption in P. abies remained unaffected by CO 2 enrichment. Daily courses of sap flow were not significantly different between treatments, neither before nor after treatment initiation (daily sums of relative sap flow, Wilcoxon rank-sum test, n = 5, p-values = 0.90, 0.90, 0.79 for left, center and right panel of Figure 2A ). Similarly, leaf water potential and stomatal conductance differed with time of day (p-values < 0.0001 for both years and measurements) but not with the treatment: we employed linear mixed effects models with treatment, time and their interaction as fixed factors and tree individuals as random factors. Except for the leaf water potential measurements during the pretreatment period (left panel of Figure 2B ), where the interaction term was significant (p = 0.022), the treatment differences were not significantly different during any day (Figures 2B,C, p-values > 0.1). In both summers, low soil water availability resulted in low pre-dawn leaf water potentials around \u22121 MPa. During daytime, high VPD values exceeding 2 kPa caused leaf water potentials to drop to values between \u22121.5 and \u22122.0 MPa. Stomatal conductance peaked with light intensity and reached values about 100 mmol m \u22122 s \u22121 and declined in the course of the afternoon to values below 50 mmol m \u22122 s \u22121 .", "cite_spans": [], "ref_spans": [{"start": 510, "end": 519, "text": "Figure 2A", "ref_id": "FIGREF1"}, {"start": 921, "end": 930, "text": "Figure 2B", "ref_id": "FIGREF1"}, {"start": 1064, "end": 1078, "text": "(Figures 2B,C,", "ref_id": "FIGREF1"}]}, {"section": "RESULTS WATER RELATIONS OF P. abies UNDER ELEVATED CO 2", "text": "Overall, sap flow was lower on July 14 2010 because of the very high VPD values (maximum of c. 3.5 kPa). All 3 days were cloudless, except for some haziness in the afternoon of July 14 2010. The dent in photoactive radiation (PAR) around 10 am is due to passing shadow from the crane top.", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS WATER RELATIONS OF P. abies UNDER ELEVATED CO 2", "text": "Point dendrometer data showed that growth was initiated in mid-April (day of year 135) and ended in mid-August (day of year 230) in 2009, with no systematic difference between treatments (defined as the day when 10% of the yearly growth increment was reached, Wilcoxon rank-sum test, p = 0.4). Stem water deficit derived from dendrometer readings did not differ systematically between the two groups ( Figure 3A) . Soil moisture under CO 2 -enriched trees tended to be higher than under control trees, but this difference was already present before the onset of the treatment in the first year and disappeared in the second year ( Figure 3B) . Decreasing mean daily soil moisture generally increased mean daily stem water deficit sharply, but as judged by the AIC the pattern did not change between the two groups, neither before nor after the start of the CO 2 -treatment (Figure 4) . Stem storage saturation occurred at a wide spectrum of soil moisture contents, but depleted stem water reservoirs only occurred at low soil moisture values (<25 Vol. %, Figure 4) . We also looked at the relative sap flow response to VPD according to experimental period (before and after treatment initiation). The 95th percentiles per 2 kPa bin did not differ between treatments, both before and after CO 2 enrichment, because the interaction between VPD and CO 2 in the polynomial model fits was statistically not significant ( Figure 5 ).", "cite_spans": [], "ref_spans": [{"start": 1416, "end": 1424, "text": "Figure 5", "ref_id": "FIGREF3"}]}, {"section": "COMPARISON TO MODELING THE CO 2 -RESPONSE WITH LPJ-GUESS", "text": "Given the commonly implemented algorithms controlling leaf gas exchange in dynamic vegetation models, it can be expected that any PFT will show less water use under eCO 2 (Farquhar et al., 1980) . To see whether and to what extent this is the case in the commonly used DGVM LPJ-GUESS, we simulated our experiment with local climate data. We suppressed all other plant functional types but \"needle-leaved evergreen.\" The CO 2 concentration for the 700-years spin-up was kept at 296 ppm. After 1901, the four CO 2 -scenarios outlined in the section \"materials and methods\" were imposed. The daily transpiration rates were sensitive to the final CO 2 concentrations reached (550 ppm or 700 ppm), but only little to whether a step or gradual change in the CO 2 concentration was used. Overall, there was c. 10% less transpiration in the 550 ppm scenario and c. 17% less transpiration in the 700 ppm scenario, regardless of how the concentration was reached or how long the new atmospheric conditions lasted ( Table 1) .", "cite_spans": [{"start": 171, "end": 194, "text": "(Farquhar et al., 1980)", "ref_id": "BIBREF15"}], "ref_spans": [{"start": 1005, "end": 1013, "text": "Table 1)", "ref_id": "TABREF0"}]}, {"section": "DISCUSSION", "text": "We aimed to assess the response of whole-tree water relations to future levels of atmospheric CO 2 in Norway spruce, one of the most abundant and economically important coniferous tree species in Europe. Using five different, fully independent approaches (sap flow-, dendrometer-, leaf water potential-, and soil moisture measurements), our experimental data shows that this species is unlikely to adjust its water use under atmospheric CO 2 concentrations anticipated to occur in c. 2050. This stands in contrast to the model results of the DGVM LPJ-GUESS, which predicts a c. 10% reduction in transpiration when simulating needle-leaved evergreen trees under CO 2 concentrations and site conditions matching those of the field experiment. Because of the wide distribution across Europe and Asia and its importance as a timber species the lack of a water use response of Norway spruce to elevated atmospheric CO 2 is fundamental for the parameterization and validation of DGVMs and fully coupled earth system models predicting the future water and carbon cycle. Further, it is central to our understanding of plant responses to eCO 2 and how they are scaled with ontogeny and the successional stage of the tested species or community. Critical to the estimates of net plant water use under eCO 2 seem to be the developmental stage of the tested individuals, the species and PFT tested, the duration of the treatment, the method of CO 2 administration, and the nature and timing of the measured traits used as a proxy to estimate plant water use ( Table 2 ). All these factors will have an impact on the net response of plant water use to eCO 2 . Despite the large range of responses reported, the majority of studies tend to predict a decrease in stomatal conductance and therefore net water use under eCO 2 (e.g., Curtis and Wang, 1998; Medlyn et al., 2001 ). However, there are numerous examples that show no response or even an increase in water www.frontiersin.org", "cite_spans": [{"start": 1816, "end": 1838, "text": "Curtis and Wang, 1998;", "ref_id": "BIBREF12"}, {"start": 1839, "end": 1858, "text": "Medlyn et al., 2001", "ref_id": "BIBREF51"}], "ref_spans": [{"start": 1548, "end": 1555, "text": "Table 2", "ref_id": "TABREF1"}]}, {"section": "DISCUSSION", "text": "October 2012 | Volume 3 | Article 229 | 7 Plant functional type Decrease from herbaceous to woody plants and from deciduous to coniferous trees Saxe et al., 1998; Medlyn et al., 2001; Ainsworth and Rogers, 2007 Combination with other global change drivers Trend for decrease Leuzinger et al., 2011b Scaling from plant to canopy/landscape Decrease with increasing scale Field et al., 1995; Wullschleger et al., 2002 Upscaling from experimental period to yearly average response", "cite_spans": [{"start": 144, "end": 162, "text": "Saxe et al., 1998;", "ref_id": "BIBREF67"}, {"start": 163, "end": 183, "text": "Medlyn et al., 2001;", "ref_id": "BIBREF51"}, {"start": 184, "end": 210, "text": "Ainsworth and Rogers, 2007", "ref_id": "BIBREF1"}, {"start": 275, "end": 298, "text": "Leuzinger et al., 2011b", "ref_id": "BIBREF39"}, {"start": 369, "end": 388, "text": "Field et al., 1995;", "ref_id": "BIBREF16"}, {"start": 389, "end": 414, "text": "Wullschleger et al., 2002", "ref_id": "BIBREF81"}], "ref_spans": []}, {"section": "DISCUSSION", "text": "Responses-dependent on weather conditions, average water use often lower than if extrapolated linearly from experimental period Wullschleger and Norby, 2001; Cech et al., 2003; Leuzinger and K\u00f6rner, 2007 Soil feedback Decrease (through wetter soils) Sch\u00e4fer et al., 2002 The circumstances that lead to this decline can generally be associated with a more realistic scenario (young vs. mature stands, local vs. global scale response etc.) use under eCO 2 . For P. abies, the species tested in the present study, Roberntz and Stockfors (1998) found no effect on g s using branch bags, and Barton et al. (1993) , Kupper et al. (2006) and Uddling et al. (2009) all report an increase in water use under eCO 2 from glasshouse and branch bag experiments. For Pinus taeda, both a branch-bag and an open-top chamber experiment suggest that this species does not respond to eCO 2 in its water use (Teskey, 1995; Pataki et al., 1998) . Contrary to grassland experiments, Domec et al. (2009) found reduced stomatal conductance under eCO 2 in tall, 28 years old Pinus taeda individuals only at high soil moisture, and no response during dry conditions. In trees that are in an early (expanding) successional stage, increased LAI under eCO 2 may periodically (over-) compensate reductions in stomatal conductance (Li et al., 2003) or lead to an increase in total water use (Bobich et al., 2010) . Increasing LAI following CO 2 -treatment has been reported for a closedcanopy Pinus taeda stand growing at the Duke experimental forest (McCarthy et al., 2007) . However, this canopy response to eCO 2 was determined by nitrogen availability patterns and additional N fertilization trials suggested that LAI stimulation is unlikely to occur at high fertility sites (McCarthy et al., 2007) . Most other eCO 2 studies suggest that CO 2 will not cause an increase in LAI in mature systems (Bader et al., in preparation; K\u00f6rner et al., 2005; Norby et al., 2005; Warren et al., 2011) . H\u00e4ttenschwiler and K\u00f6rner (1997) even found a lower LAI under eCO 2 in a young, closed-canopy Norway spruce stand, similar to what tropical tree model ecosystems revealed after stand closure (K\u00f6rner and Arnone, 1992) . Furthermore, a LAI beyond c. 2.7 will not affect canopy conductance (Schulze et al., 1994) . Given the age of our study trees (>100 years) and the nutrient-rich soil they thrive on, it seems improbable that CO 2 enrichment will enhance LAI in this stand.", "cite_spans": [{"start": 128, "end": 157, "text": "Wullschleger and Norby, 2001;", "ref_id": "BIBREF82"}, {"start": 158, "end": 176, "text": "Cech et al., 2003;", "ref_id": "BIBREF10"}, {"start": 177, "end": 203, "text": "Leuzinger and K\u00f6rner, 2007", "ref_id": "BIBREF40"}, {"start": 250, "end": 270, "text": "Sch\u00e4fer et al., 2002", "ref_id": "BIBREF68"}, {"start": 511, "end": 540, "text": "Roberntz and Stockfors (1998)", "ref_id": "BIBREF66"}, {"start": 587, "end": 607, "text": "Barton et al. (1993)", "ref_id": "BIBREF2"}, {"start": 610, "end": 630, "text": "Kupper et al. (2006)", "ref_id": "BIBREF36"}, {"start": 635, "end": 656, "text": "Uddling et al. (2009)", "ref_id": "BIBREF78"}, {"start": 888, "end": 902, "text": "(Teskey, 1995;", "ref_id": "BIBREF74"}, {"start": 903, "end": 923, "text": "Pataki et al., 1998)", "ref_id": "BIBREF62"}, {"start": 961, "end": 980, "text": "Domec et al. (2009)", "ref_id": "BIBREF13"}, {"start": 1300, "end": 1317, "text": "(Li et al., 2003)", "ref_id": "BIBREF42"}, {"start": 1360, "end": 1381, "text": "(Bobich et al., 2010)", "ref_id": "BIBREF8"}, {"start": 1520, "end": 1543, "text": "(McCarthy et al., 2007)", "ref_id": "BIBREF46"}, {"start": 1748, "end": 1771, "text": "(McCarthy et al., 2007)", "ref_id": "BIBREF46"}, {"start": 1900, "end": 1920, "text": "K\u00f6rner et al., 2005;", "ref_id": "BIBREF34"}, {"start": 1921, "end": 1940, "text": "Norby et al., 2005;", "ref_id": "BIBREF57"}, {"start": 1941, "end": 1961, "text": "Warren et al., 2011)", "ref_id": "BIBREF80"}, {"start": 1964, "end": 1996, "text": "H\u00e4ttenschwiler and K\u00f6rner (1997)", "ref_id": "BIBREF21"}, {"start": 2155, "end": 2180, "text": "(K\u00f6rner and Arnone, 1992)", "ref_id": "BIBREF31"}, {"start": 2251, "end": 2273, "text": "(Schulze et al., 1994)", "ref_id": "BIBREF69"}], "ref_spans": []}, {"section": "DISCUSSION", "text": "We argue that the majority of the evidence underlying the existing reviews on plant water savings under eCO 2 experiments (Curtis and Wang, 1998; Medlyn et al., 2001; Ainsworth and Long, 2005; Ainsworth and Rogers, 2007) rests on short-term (sub-seasonal) experiments, predominantly on grasslands, tree seedlings or juveniles tested under relatively confined conditions (e.g., glasshouses). However, these test conditions tend to overestimate the effects of eCO 2 on stomatal conductance and/or water use and potential long-term alterations such as structural changes in the hydraulic pathway as have been reported for Pinus taeda at the Duke FACE site may remain undetected ( Table 2 ; Domec et al., 2009) .", "cite_spans": [{"start": 122, "end": 145, "text": "(Curtis and Wang, 1998;", "ref_id": "BIBREF12"}, {"start": 146, "end": 166, "text": "Medlyn et al., 2001;", "ref_id": "BIBREF51"}, {"start": 167, "end": 192, "text": "Ainsworth and Long, 2005;", "ref_id": "BIBREF0"}, {"start": 193, "end": 220, "text": "Ainsworth and Rogers, 2007)", "ref_id": "BIBREF1"}, {"start": 687, "end": 706, "text": "Domec et al., 2009)", "ref_id": "BIBREF13"}], "ref_spans": [{"start": 677, "end": 684, "text": "Table 2", "ref_id": "TABREF1"}]}, {"section": "DISCUSSION", "text": "Another source for overestimating water use under eCO 2 is temporal upscaling from an experimental period shorter than or non-representative of a whole year K\u00f6rner, 2007, 2010) . Often, the response strongly depends on the weather and soil moisture conditions (Wullschleger and Norby, 2001; Cech et al., 2003) . Our study, together with others (Ellsworth, 1999; Sch\u00e4fer et al., 2002; Bernacchi et al., 2003; Keel et al., 2007; Uddling et al., 2009) , supports the view that near-natural conditions tend to yield a smaller or no response in annual water use to elevated CO 2 .", "cite_spans": [{"start": 260, "end": 290, "text": "(Wullschleger and Norby, 2001;", "ref_id": "BIBREF82"}, {"start": 291, "end": 309, "text": "Cech et al., 2003)", "ref_id": "BIBREF10"}, {"start": 344, "end": 361, "text": "(Ellsworth, 1999;", "ref_id": "BIBREF14"}, {"start": 362, "end": 383, "text": "Sch\u00e4fer et al., 2002;", "ref_id": "BIBREF68"}, {"start": 384, "end": 407, "text": "Bernacchi et al., 2003;", "ref_id": "BIBREF5"}, {"start": 408, "end": 426, "text": "Keel et al., 2007;", "ref_id": "BIBREF29"}, {"start": 427, "end": 448, "text": "Uddling et al., 2009)", "ref_id": "BIBREF78"}], "ref_spans": []}, {"section": "DISCUSSION", "text": "Apart from the obvious absence of a CO 2 -response in the water flux of our experimental trees, the patterns found (Figure 2 ) match with earlier reports on water relations of P. abies (e.g., Gross and Koch, 1991; Zweifel et al., 2001) . The low pre-dawn shoot water potentials around \u22121 MPa resulted from a combination of soil water deficits and the hydrostatic water potential of c. 0.4 MPa. The diurnal courses of water relations also showed tight stomatal control over transpiration, preventing midday shoot water potentials from dropping below \u22121.9 MPa. This rather isohydric behavior allowed the maintenance of an adequate hydraulic safety margin from the critical threshold of \u22122.5 MPa that has been reported as turgor loss point (Gross and Koch, 1991) and as the level at which significant xylem cavitation occurs in branches of adult Norway spruce trees (Cochard, 1992; Lu et al., 1995) . Compared to the first day of measurements (Figure 2 , left panels), stomatal conductance decreased due to lower soil moisture or higher VPD, causing considerably less sap flow (Figure 2 , middle and right panels). The incomplete night-time recovery of stem radius during times of low soil moisture (<30 vol. %) and high VPD suggests that internal water storage tissues could not be replenished and is thus indicative of a tree water deficit (Zweifel et al., 2005 Figure 3) . We have no explanation for the high predawn stomatal conductance measured in the morning of July 14 (Figure 2) . The modeled reduction in water use by coniferous trees for this site stands in contrast to our in situ measurements. The LPJ-GUESS dynamic vegetation model consistently predicted between 9% and 18% reduced transpiration, with the ambient CO 2 concentration (C a , 550 ppm vs. 700 ppm) causing most of the sensitivity of the response and the mode of increase (step vs. gradual) as well as the duration of the new conditions (immediately after the increase vs. 100 years later) being rather insignificant. In LPJ-GUESS, but also in other dynamic vegetation models, the first-order response originates from the photosynthesis model through stomatal closure due to increased intercellular CO 2 concentrations (C i ). Because C i /C a is assumed constant, changes in C a will result in proportional changes in stomatal conductance. However, in LPJ-GUESS this effect only manifests itself during ample water supply (see section \"Materials and Methods\"). Therefore, the CO 2 -response does not increase with dry conditions, which has been found earlier (Hickler et al., 2008) , although a carry-over effect from wet to dry periods (higher available soil moisture under eCO 2 ) is possible. This behavior certainly does not mirror observations from grassland (Niklaus et al., 1998; Morgan et al., 2004 ) and the drought \u00d7 eCO 2 interactions in trees do not seem to be uniform (Beerling et al., 1996; Heath, 1998; Cech et al., 2003; Leuzinger and K\u00f6rner, 2007 and others) .", "cite_spans": [{"start": 192, "end": 213, "text": "Gross and Koch, 1991;", "ref_id": "BIBREF19"}, {"start": 214, "end": 235, "text": "Zweifel et al., 2001)", "ref_id": "BIBREF83"}, {"start": 737, "end": 759, "text": "(Gross and Koch, 1991)", "ref_id": "BIBREF19"}, {"start": 863, "end": 878, "text": "(Cochard, 1992;", "ref_id": "BIBREF11"}, {"start": 879, "end": 895, "text": "Lu et al., 1995)", "ref_id": "BIBREF44"}, {"start": 1339, "end": 1360, "text": "(Zweifel et al., 2005", "ref_id": "BIBREF84"}, {"start": 2532, "end": 2554, "text": "(Hickler et al., 2008)", "ref_id": "BIBREF24"}, {"start": 2737, "end": 2759, "text": "(Niklaus et al., 1998;", "ref_id": "BIBREF56"}, {"start": 2760, "end": 2779, "text": "Morgan et al., 2004", "ref_id": "BIBREF55"}, {"start": 2878, "end": 2890, "text": "Heath, 1998;", "ref_id": "BIBREF23"}, {"start": 2891, "end": 2909, "text": "Cech et al., 2003;", "ref_id": "BIBREF10"}], "ref_spans": [{"start": 115, "end": 124, "text": "(Figure 2", "ref_id": "FIGREF1"}, {"start": 940, "end": 949, "text": "(Figure 2", "ref_id": "FIGREF1"}, {"start": 1074, "end": 1083, "text": "(Figure 2", "ref_id": "FIGREF1"}, {"start": 1473, "end": 1483, "text": "(Figure 2)", "ref_id": "FIGREF1"}]}, {"section": "Frontiers in Plant Science", "text": "The key difference between photosynthesis models that are employed in dynamic vegetation models is essentially the formulation of C i /C a (Katul et al., 2000) . Therefore, the range of modeled responses is relatively narrow (Luo et al., 2008) and foreseeable, unless model-specific feedback mechanisms dampen or enhance the initial signal. For example, increased LAI through altered carbon allocation patterns, soil moisture, or atmospheric feedback (in a fully coupled model) could all contribute to changing the initial response largely prescribed by the photosynthesis model. The fact that our modeled water relations response to eCO 2 seems largely-independent of the time the eCO 2 -conditions are in place suggests that very little feedback mechanisms contribute to altering the first-order response, which seems to be stable across models and ecosystem types (Luo et al., 2008) . Another important component potentially responsible for mitigating the CO 2 -response are the leaf and canopy boundary layer resistances, which are in series with the stomatal resistance but not explicitly considered in LPJ-GUESS (McNaughton and Jarvis, 1991).", "cite_spans": [{"start": 139, "end": 159, "text": "(Katul et al., 2000)", "ref_id": "BIBREF28"}, {"start": 225, "end": 243, "text": "(Luo et al., 2008)", "ref_id": "BIBREF45"}, {"start": 867, "end": 885, "text": "(Luo et al., 2008)", "ref_id": "BIBREF45"}], "ref_spans": []}, {"section": "Frontiers in Plant Science", "text": "Clearly, there are limitations as to what conclusions can be drawn from a sample of five adult Norway spruce individuals treated with elevated atmospheric CO 2 over two seasons only. Such experiments struggle with the inherent trade-off between sample size and the realism of the experimental setting. While it may be more satisfying to get statistically more robust results on CO 2 -responses with young trees, we make little progress if young trees respond differently to mature trees (Medlyn et al., 2001; Uddling et al., 2009; Leuzinger et al., 2011a,b) . More data on water use under eCO 2 are needed from large-scale studies in mature systems to confirm our results. Equally important is the continuation of large-scale experiments over many years in order to alleviate some of the statistical shortcomings from originating from low replication.", "cite_spans": [{"start": 487, "end": 508, "text": "(Medlyn et al., 2001;", "ref_id": "BIBREF51"}, {"start": 509, "end": 530, "text": "Uddling et al., 2009;", "ref_id": "BIBREF78"}], "ref_spans": []}, {"section": "Frontiers in Plant Science", "text": "In conclusion, we find a contrasting response between our experimental results with mature P. abies trees, and the model output from the global dynamic vegetation model LPJ-GUESS. Our experimental results are corroborated by evidence from studies on other plant functional types, and we argue that the more realistic the testing conditions, the smaller the water savings in response to eCO 2 . The modeled water relations response to eCO 2 was strikingly robust both in this and previous studies. Because the modeled responses are closer to the leaf-level than to the ecosystem response in experiments, one explanation for the apparent discrepancy is that the propagation of the response from the leaf to the ecosystem is not captured appropriately in the currently available models. Attempts should be made to account for such processes in models potentially mitigating first-order CO 2 -effects on plant water use.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "What have we learnt from 15 years of free-air CO 2 enrichment (FACE)? A meta-analytic review of the responses of photosynthesis, canopy properties and plant production to rising CO 2 . Tansley Rev", "authors": [{"first": "E", "middle": ["A"], "last": "Ainsworth", "suffix": ""}, {"first": "S", "middle": ["P"], "last": "Long", "suffix": ""}], "year": 2005, "venue": "New Phytol", "link": "16605259"}, "BIBREF1": {"title": "The response of photosynthesis and stomatal conductance to rising [CO 2 ]: mechanisms and environmental interactions", "authors": [{"first": "E", "middle": ["A"], "last": "Ainsworth", "suffix": ""}, {"first": "Rogers", "middle": [], "last": "", "suffix": ""}, {"first": "A", "middle": [], "last": "", "suffix": ""}], "year": 2007, "venue": "Plant Cell Environ", "link": null}, "BIBREF2": {"title": "A branch bag and CO 2 control-system for long-term CO 2 enrichment of mature Sitka spruce Picea-sitchensis (Bong) carr", "authors": [{"first": "C", "middle": ["V M"], "last": "Barton", "suffix": ""}, {"first": "H", "middle": ["S J"], "last": "Lee", "suffix": ""}, {"first": "Jarvis", "middle": [], "last": "", "suffix": ""}, {"first": "P", "middle": ["G"], "last": "", "suffix": ""}], "year": 1993, "venue": "Plant Cell Environ", "link": "86072367"}, "BIBREF4": {"title": "Drought-CO 2 interactions in trees: observations and mechanisms", "authors": [], "year": "", "venue": "New Phytol", "link": null}, "BIBREF5": {"title": "Photosynthesis and stomatal conductance responses of poplars to free-air CO 2 enrichment (PopFACE) during the first growth cycle and immediately following coppice", "authors": [{"first": "C", "middle": ["J"], "last": "Bernacchi", "suffix": ""}, {"first": "C", "middle": [], "last": "Calfapietra", "suffix": ""}, {"first": "P", "middle": ["A"], "last": "Davey", "suffix": ""}, {"first": "V", "middle": ["E"], "last": "Wittig", "suffix": ""}, {"first": "G", "middle": ["E"], "last": "Scarasciamugnozza", "suffix": ""}, {"first": "C", "middle": ["A"], "last": "Raines", "suffix": ""}], "year": 2003, "venue": "New Phytol", "link": "59152996"}, "BIBREF6": {"title": "Variations of wood delta C-13 and water-use efficiency of Abies alba during the last century", "authors": [{"first": "D", "middle": [], "last": "Bert", "suffix": ""}, {"first": "S", "middle": ["W"], "last": "Leavitt", "suffix": ""}, {"first": "J", "middle": ["L"], "last": "Dupouey", "suffix": ""}], "year": 1997, "venue": "Ecology", "link": null}, "BIBREF7": {"title": "Projected increase in continental runoff due to plant responses to increasing carbon dioxide", "authors": [{"first": "R", "middle": ["A"], "last": "Betts", "suffix": ""}, {"first": "O", "middle": [], "last": "Boucher", "suffix": ""}, {"first": "M", "middle": [], "last": "Collins", "suffix": ""}, {"first": "P", "middle": ["M"], "last": "Cox", "suffix": ""}, {"first": "P", "middle": ["D"], "last": "Falloon", "suffix": ""}, {"first": "N", "middle": [], "last": "Gedney", "suffix": ""}], "year": 2007, "venue": "Nature", "link": "4418252"}, "BIBREF8": {"title": "Effects of drought and changes in vapour pressure deficit on water relations of Populus deltoides growing in ambient and elevated CO(2)", "authors": [{"first": "E", "middle": ["G"], "last": "Bobich", "suffix": ""}, {"first": "G", "middle": ["A"], "last": "Barron-Gafford", "suffix": ""}, {"first": "K", "middle": ["G"], "last": "Rascher", "suffix": ""}, {"first": "R", "middle": [], "last": "Murthy", "suffix": ""}], "year": 2010, "venue": "Tree Physiol", "link": "205333571"}, "BIBREF9": {"title": "Article 229 | 9 dioxide on plants in the Met Office Unified Model HadCM3", "authors": [{"first": "O", "middle": [], "last": "Boucher", "suffix": ""}, {"first": "A", "middle": [], "last": "Jones", "suffix": ""}, {"first": "R", "middle": ["A"], "last": "Betts", "suffix": ""}], "year": 2009, "venue": "Clim. Dynam", "link": null}, "BIBREF10": {"title": "Elevated CO 2 reduces sap flux in mature deciduous forest trees", "authors": [{"first": "P", "middle": ["G"], "last": "Cech", "suffix": ""}, {"first": "S", "middle": [], "last": "Pepin", "suffix": ""}, {"first": "C", "middle": [], "last": "K\u00f6rner", "suffix": ""}], "year": 2003, "venue": "Oecologia", "link": "24820472"}, "BIBREF11": {"title": "Vulnerability of several conifers to air embolism", "authors": [{"first": "H", "middle": [], "last": "Cochard", "suffix": ""}], "year": 1992, "venue": "Tree Physiol", "link": "46256537"}, "BIBREF12": {"title": "A meta-analysis of elevated CO 2 effects on woody plant mass, form, and physiology", "authors": [{"first": "P", "middle": ["S"], "last": "Curtis", "suffix": ""}, {"first": "X", "middle": ["Z"], "last": "Wang", "suffix": ""}], "year": 1998, "venue": "Oecologia", "link": "206990070"}, "BIBREF13": {"title": "Acclimation of leaf hydraulic conductance and stomatal conductance of Pinus taeda (loblolly pine) to long-term growth in elevated CO(2) (free-air CO(2) enrichment) and N-fertilization", "authors": [{"first": "J.-C", "middle": [], "last": "Domec", "suffix": ""}, {"first": "S", "middle": [], "last": "Palmroth", "suffix": ""}, {"first": "E", "middle": [], "last": "Ward", "suffix": ""}, {"first": "C", "middle": ["A"], "last": "Maier", "suffix": ""}, {"first": "M", "middle": [], "last": "Therezien", "suffix": ""}, {"first": "Oren", "middle": [], "last": "", "suffix": ""}, {"first": "R", "middle": [], "last": "", "suffix": ""}], "year": 2009, "venue": "Plant Cell Environ", "link": "18635869"}, "BIBREF14": {"title": "CO 2 enrichment in a maturing pine forest: are CO 2 exchange and water status in the canopy affected?", "authors": [{"first": "D", "middle": ["S"], "last": "Ellsworth", "suffix": ""}], "year": 1999, "venue": "Plant Cell Environ", "link": null}, "BIBREF15": {"title": "A biochemicalmodel of photosynthetic CO 2 assimilation in leaves of C-3 species", "authors": [{"first": "G", "middle": ["D"], "last": "Farquhar", "suffix": ""}, {"first": "S", "middle": ["V"], "last": "Caemmerer", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Berry", "suffix": ""}], "year": 1980, "venue": "Planta", "link": null}, "BIBREF16": {"title": "Stomatal responses to increased CO 2 , implications from the plant to the global scale", "authors": [{"first": "C", "middle": ["B"], "last": "Field", "suffix": ""}, {"first": "R", "middle": ["B"], "last": "Jackson", "suffix": ""}, {"first": "H", "middle": ["A"], "last": "Mooney", "suffix": ""}], "year": 1995, "venue": "Plant Cell Environ", "link": "85870252"}, "BIBREF17": {"title": "An explanation of C-13/C-12 variations in tree rings", "authors": [{"first": "R", "middle": ["J"], "last": "Francey", "suffix": ""}, {"first": "G", "middle": ["D"], "last": "Farquhar", "suffix": ""}], "year": 1982, "venue": "Nature", "link": null}, "BIBREF18": {"title": "A new method of sap flow measurement in tree stems", "authors": [{"first": "A", "middle": [], "last": "Granier", "suffix": ""}], "year": 1985, "venue": "Ann. Sci. For", "link": "131235208"}, "BIBREF19": {"title": "Water relations of picea-abies.1. Comparison of water relations parameters of spruce shoots examined at the end of the vegetation period and in winter", "authors": [{"first": "K", "middle": [], "last": "Gross", "suffix": ""}, {"first": "W", "middle": [], "last": "Koch", "suffix": ""}], "year": 1991, "venue": "Physiol. Plantarum", "link": "96188105"}, "BIBREF20": {"title": "Will a 385 million year-struggle for light become a struggle for water and for carbon? -How trees may cope with more frequent climate change-type drought events", "authors": [{"first": "H", "middle": [], "last": "Hartmann", "suffix": ""}], "year": 2011, "venue": "Glob. Change Biol", "link": "84089204"}, "BIBREF21": {"title": "Annual CO 2 budget of spruce model ecosystems in the third year of exposure to elevated CO2", "authors": [{"first": "S", "middle": [], "last": "H\u00e4ttenschwiler", "suffix": ""}, {"first": "C", "middle": [], "last": "K\u00f6rner", "suffix": ""}], "year": 1997, "venue": "Acta Oecol", "link": null}, "BIBREF22": {"title": "A general model for the light-use efficiency of primary production", "authors": [{"first": "A", "middle": [], "last": "Haxeltine", "suffix": ""}, {"first": "Prentice", "middle": [], "last": "", "suffix": ""}, {"first": "I", "middle": ["C"], "last": "", "suffix": ""}], "year": 1996, "venue": "Funct. Ecol", "link": null}, "BIBREF23": {"title": "Stomata of trees growing in CO 2 -enriched air show reduced sensitivity to vapour pressure deficit and drought", "authors": [{"first": "J", "middle": [], "last": "Heath", "suffix": ""}], "year": 1998, "venue": "Plant Cell Environ", "link": "84693964"}, "BIBREF24": {"title": "CO 2 fertilization in temperate FACE experiments not representative of boreal and tropical forests", "authors": [{"first": "T", "middle": [], "last": "Hickler", "suffix": ""}, {"first": "B", "middle": [], "last": "Smith", "suffix": ""}, {"first": "I", "middle": ["C"], "last": "Prentice", "suffix": ""}, {"first": "K", "middle": [], "last": "Mjofors", "suffix": ""}, {"first": "P", "middle": [], "last": "Miller", "suffix": ""}, {"first": "A", "middle": [], "last": "Arneth", "suffix": ""}], "year": 2008, "venue": "Glob. Change Biol", "link": null}, "BIBREF25": {"title": "Elevated CO 2 and forest vegetation: more a water issue than a carbon issue?", "authors": [{"first": "J", "middle": ["A M"], "last": "Holtum", "suffix": ""}, {"first": "K", "middle": [], "last": "Winter", "suffix": ""}], "year": 2010, "venue": "Funct. Plant Biol", "link": "824378"}, "BIBREF26": {"title": "Increases in desert shrub productivity under elevated carbon dioxide vary with water availability", "authors": [{"first": "D", "middle": ["C"], "last": "Housman", "suffix": ""}, {"first": "E", "middle": [], "last": "Naumburg", "suffix": ""}, {"first": "T", "middle": ["E"], "last": "Huxman", "suffix": ""}, {"first": "T", "middle": ["N"], "last": "Charlet", "suffix": ""}, {"first": "R", "middle": ["S"], "last": "Nowak", "suffix": ""}, {"first": "S", "middle": ["D"], "last": "Smith", "suffix": ""}], "year": 2006, "venue": "Ecosystems", "link": "133567"}, "BIBREF27": {"title": "Interpretation of variations in leaf water potential and stomatal conductance found in canopies in field", "authors": [{"first": "P", "middle": ["G"], "last": "Jarvis", "suffix": ""}], "year": 1976, "venue": "Philos. Trans. R. Soc. Lond. B Biol. Sci", "link": null}, "BIBREF28": {"title": "Modelling assimilation and intercellular CO 2 from measured conductance: a synthesis of approaches", "authors": [{"first": "G", "middle": ["G"], "last": "Katul", "suffix": ""}, {"first": "D", "middle": ["S"], "last": "Ellsworth", "suffix": ""}, {"first": "C", "middle": ["T"], "last": "Lai", "suffix": ""}], "year": 2000, "venue": "Plant Cell Environ", "link": "53120160"}, "BIBREF29": {"title": "Stomatal conductance in mature deciduous forest trees exposed to elevated CO 2", "authors": [{"first": "S", "middle": ["G"], "last": "Keel", "suffix": ""}, {"first": "S", "middle": [], "last": "Pepin", "suffix": ""}, {"first": "S", "middle": [], "last": "Leuzinger", "suffix": ""}, {"first": "C", "middle": [], "last": "K\u00f6rner", "suffix": ""}], "year": 2007, "venue": "Trees", "link": "11186815"}, "BIBREF30": {"title": "Seventeen years of carbon dioxide enrichment of sour orange trees: final results", "authors": [{"first": "B", "middle": ["A"], "last": "Kimball", "suffix": ""}, {"first": "S", "middle": ["B"], "last": "Idso", "suffix": ""}, {"first": "S", "middle": [], "last": "Johnson", "suffix": ""}, {"first": "M", "middle": ["C"], "last": "Rillig", "suffix": ""}], "year": 2007, "venue": "Glob. Change Biol", "link": "9633643"}, "BIBREF31": {"title": "Responses to elevated carbon dioxide in artificial tropical ecosystems", "authors": [{"first": "C", "middle": [], "last": "K\u00f6rner", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Arnone", "suffix": ""}], "year": 1992, "venue": "Science", "link": "46642325"}, "BIBREF32": {"title": "Plant CO 2 responses: an issue of definition, time and resource supply", "authors": [{"first": "C", "middle": [], "last": "K\u00f6rner", "suffix": ""}], "year": 2006, "venue": "New Phytol", "link": "13786073"}, "BIBREF33": {"title": "Responses of humid tropical trees to rising CO(2)", "authors": [{"first": "C", "middle": [], "last": "K\u00f6rner", "suffix": ""}], "year": 2009, "venue": "Annu. Rev. Ecol. Evol. Syst", "link": "85748315"}, "BIBREF34": {"title": "Carbon flux and growth in mature deciduous forest trees exposed to elevated CO 2", "authors": [{"first": "C", "middle": [], "last": "K\u00f6rner", "suffix": ""}, {"first": "R", "middle": [], "last": "Asshoff", "suffix": ""}, {"first": "O", "middle": [], "last": "Bignucolo", "suffix": ""}, {"first": "S", "middle": [], "last": "Hattenschwiler", "suffix": ""}, {"first": "S", "middle": ["G"], "last": "Keel", "suffix": ""}, {"first": "S", "middle": [], "last": "Pelaez-Riedl", "suffix": ""}], "year": 2005, "venue": "Science", "link": "52819766"}, "BIBREF35": {"title": "Terrestrial Ecosystems in a Changing World. CO 2 Fertilization: When", "authors": [{"first": "C", "middle": [], "last": "K\u00f6rner", "suffix": ""}, {"first": "J", "middle": [], "last": "Morgan", "suffix": ""}, {"first": "R", "middle": [], "last": "Norby", "suffix": ""}], "year": 2007, "venue": "", "link": null}, "BIBREF36": {"title": "Water relations in Norway spruce trees growing at ambient and elevated CO 2 concentrations", "authors": [{"first": "P", "middle": [], "last": "Kupper", "suffix": ""}, {"first": "A", "middle": [], "last": "Sellin", "suffix": ""}, {"first": "Z", "middle": [], "last": "Klimankova", "suffix": ""}, {"first": "R", "middle": [], "last": "Pokorny", "suffix": ""}, {"first": "J", "middle": [], "last": "Puertolas", "suffix": ""}], "year": 2006, "venue": "Biol. Plantarum", "link": "24930169"}, "BIBREF37": {"title": "A criticalappraisal of a combined stomatalphotosynthesis model for C-3 plants", "authors": [{"first": "R", "middle": [], "last": "Leuning", "suffix": ""}], "year": 1995, "venue": "Plant Cell Environ", "link": null}, "BIBREF38": {"title": "Water relations of climbing ivy in a temperate forest", "authors": [{"first": "S", "middle": [], "last": "Leuzinger", "suffix": ""}, {"first": "A", "middle": [], "last": "Hartmann", "suffix": ""}, {"first": "C", "middle": [], "last": "K\u00f6rner", "suffix": ""}], "year": 2011, "venue": "Planta", "link": "31830033"}, "BIBREF39": {"title": "Do global change experiments overestimate impacts on terrestrial ecosystems?", "authors": [{"first": "S", "middle": [], "last": "Leuzinger", "suffix": ""}, {"first": "Y", "middle": ["Q"], "last": "Luo", "suffix": ""}, {"first": "C", "middle": [], "last": "Beier", "suffix": ""}, {"first": "W", "middle": [], "last": "Dieleman", "suffix": ""}, {"first": "S", "middle": [], "last": "Vicca", "suffix": ""}, {"first": "C", "middle": [], "last": "K\u00f6rner", "suffix": ""}], "year": 2011, "venue": "Trends Ecol. Evol", "link": "13178825"}, "BIBREF40": {"title": "Water savings in mature deciduous forest trees under elevated CO 2 . Glob", "authors": [{"first": "S", "middle": [], "last": "Leuzinger", "suffix": ""}, {"first": "C", "middle": [], "last": "K\u00f6rner", "suffix": ""}], "year": 2007, "venue": "Change Biol", "link": null}, "BIBREF41": {"title": "Rainfall distribution is the main driver of runoff under future CO 2 -concentration in a temperate deciduous forest", "authors": [{"first": "S", "middle": [], "last": "Leuzinger", "suffix": ""}, {"first": "C", "middle": [], "last": "K\u00f6rner", "suffix": ""}], "year": 2010, "venue": "Glob. Change Biol", "link": "86019303"}, "BIBREF42": {"title": "Direct and indirect effects of elevated CO 2 on transpiration from Quercus myrtifolia in a scrub-oak ecosystem", "authors": [{"first": "J", "middle": ["H"], "last": "Li", "suffix": ""}, {"first": "W", "middle": ["A"], "last": "Dugas", "suffix": ""}, {"first": "G", "middle": ["J"], "last": "Hymus", "suffix": ""}, {"first": "D", "middle": ["P"], "last": "Johnson", "suffix": ""}, {"first": "B", "middle": ["G"], "last": "Drake", "suffix": ""}, {"first": "B", "middle": ["A"], "last": "Hungate", "suffix": ""}], "year": 2003, "venue": "Glob. Change Biol", "link": "85945401"}, "BIBREF43": {"title": "Importance of carbon dioxide physiological forcing to future climate change", "authors": [{"first": "C", "middle": [], "last": "Long", "suffix": ""}, {"first": "G", "middle": [], "last": "Bala", "suffix": ""}, {"first": "K", "middle": [], "last": "Caldeira", "suffix": ""}, {"first": "R", "middle": [], "last": "Nemani", "suffix": ""}, {"first": "G", "middle": [], "last": "Ban-Weiss", "suffix": ""}], "year": 2010, "venue": "Trends Plant Sci", "link": null}, "BIBREF44": {"title": "Water relations of adult Norway spruce (Picea abies (L) Karst) under soil drought in the Vosges mountains: water potential, stomatal conductance and transpiration", "authors": [{"first": "B", "middle": [], "last": "Lu", "suffix": ""}, {"first": "P", "middle": [], "last": "Biron", "suffix": ""}, {"first": "N", "middle": [], "last": "Br\u00e9da", "suffix": ""}, {"first": "A", "middle": [], "last": "Granier", "suffix": ""}], "year": 1995, "venue": "Ann. For. Sci", "link": null}, "BIBREF45": {"title": "Modeled interactive effects of precipitation, temperature, and [CO2] on ecosystem carbon and water dynamics in different climatic zones", "authors": [{"first": "Y", "middle": ["Q"], "last": "Luo", "suffix": ""}, {"first": "D", "middle": [], "last": "Gerten", "suffix": ""}, {"first": "G", "middle": [], "last": "Le Maire", "suffix": ""}, {"first": "W", "middle": ["J"], "last": "Parton", "suffix": ""}, {"first": "E", "middle": ["S"], "last": "Weng", "suffix": ""}, {"first": "X", "middle": ["H"], "last": "Zhou", "suffix": ""}], "year": 1986, "venue": "Glob. Change Biol", "link": "9556910"}, "BIBREF46": {"title": "Temporal dynamics and spatial variability in the enhancement of canopy leaf area under elevated atmospheric CO 2", "authors": [{"first": "H", "middle": ["R"], "last": "Mccarthy", "suffix": ""}, {"first": "R", "middle": [], "last": "Oren", "suffix": ""}, {"first": "A", "middle": ["C"], "last": "Finzi", "suffix": ""}, {"first": "D", "middle": ["S"], "last": "Ellsworth", "suffix": ""}, {"first": "H.-S", "middle": [], "last": "Kim", "suffix": ""}, {"first": "K", "middle": ["H"], "last": "Johnsen", "suffix": ""}], "year": 2007, "venue": "Glob. Change Biol", "link": "210249768"}, "BIBREF48": {"title": "Re-assessment of plant carbon dynamics at the Duke free-air CO 2 enrichment site: interactions of atmospheric CO 2 with nitrogen and water availability over stand development", "authors": [], "year": "", "venue": "New Phytol", "link": "3513357"}, "BIBREF49": {"title": "Effects of spatial scale on stomatal control of transpiration", "authors": [{"first": "K", "middle": ["G"], "last": "Mcnaughton", "suffix": ""}, {"first": "Jarvis", "middle": [], "last": "", "suffix": ""}, {"first": "P", "middle": ["G"], "last": "", "suffix": ""}], "year": 1991, "venue": "Agric. For. Meteorol", "link": null}, "BIBREF50": {"title": "A whole-tree chamber system for examining tree-level physiological responses of fieldgrown trees to environmental variation and climate change", "authors": [{"first": "J", "middle": [], "last": "Medhurst", "suffix": ""}, {"first": "J", "middle": [], "last": "Parsby", "suffix": ""}, {"first": "S", "middle": [], "last": "Linder", "suffix": ""}, {"first": "G", "middle": [], "last": "Wallin", "suffix": ""}, {"first": "E", "middle": [], "last": "Ceschia", "suffix": ""}, {"first": "M", "middle": [], "last": "Slaney", "suffix": ""}], "year": 2006, "venue": "Plant Cell Environ", "link": "10774377"}, "BIBREF51": {"title": "Stomatal conductance of forest species after long-term exposure to elevated CO 2 concentration: a synthesis", "authors": [{"first": "B", "middle": ["E"], "last": "Medlyn", "suffix": ""}, {"first": "C", "middle": ["V M"], "last": "Barton", "suffix": ""}, {"first": "M", "middle": ["S J"], "last": "Broadmeadow", "suffix": ""}, {"first": "R", "middle": [], "last": "Ceulemans", "suffix": ""}, {"first": "P", "middle": [], "last": "De Angelis", "suffix": ""}, {"first": "M", "middle": [], "last": "Forstreuter", "suffix": ""}], "year": 2001, "venue": "New Phytol", "link": "84864802"}, "BIBREF52": {"title": "Long-term relationships among atmospheric CO(2), stomata, and intrinsic water use efficiency in individual trees", "authors": [{"first": "A", "middle": ["J"], "last": "Miller-Rushing", "suffix": ""}, {"first": "R", "middle": ["B"], "last": "Primack", "suffix": ""}, {"first": "P", "middle": ["H"], "last": "Templer", "suffix": ""}, {"first": "S", "middle": [], "last": "Rathbone", "suffix": ""}, {"first": "S", "middle": [], "last": "Mukunda", "suffix": ""}], "year": 2009, "venue": "Am. J. Bot", "link": "36366896"}, "BIBREF53": {"title": "How close are we to a predictive science of the biosphere?", "authors": [{"first": "P", "middle": ["R"], "last": "Moorcroft", "suffix": ""}], "year": 2006, "venue": "Trends Ecol. Evol", "link": "3070981"}, "BIBREF54": {"title": "Grassland productivity responses to rising atmospheric carbon dioxide are driven primarily by water relations", "authors": [{"first": "J", "middle": ["A"], "last": "Morgan", "suffix": ""}, {"first": "D", "middle": ["E"], "last": "Pataki", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Gruenzweig", "suffix": ""}, {"first": "C", "middle": [], "last": "K\u00f6rner", "suffix": ""}, {"first": "P", "middle": ["A"], "last": "Niklaus", "suffix": ""}, {"first": "H", "middle": ["W"], "last": "Polley", "suffix": ""}], "year": 2003, "venue": "Ecol. Soc. Am. Ann. Meet. Abstr", "link": null}, "BIBREF55": {"title": "Water relations in grassland and desert ecosystems exposed to elevated atmospheric CO 2", "authors": [{"first": "J", "middle": ["A"], "last": "Morgan", "suffix": ""}, {"first": "D", "middle": ["E"], "last": "Pataki", "suffix": ""}, {"first": "C", "middle": [], "last": "K\u00f6rner", "suffix": ""}, {"first": "H", "middle": [], "last": "Clark", "suffix": ""}, {"first": "S", "middle": ["J"], "last": "Del Grosso", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Grunzweig", "suffix": ""}], "year": 2004, "venue": "Oecologia", "link": "26030169"}, "BIBREF56": {"title": "Soil moisture dynamics of calcareous grassland under elevated CO 2", "authors": [{"first": "P", "middle": ["A"], "last": "Niklaus", "suffix": ""}, {"first": "D", "middle": [], "last": "Spinnler", "suffix": ""}, {"first": "C", "middle": [], "last": "K\u00f6rner", "suffix": ""}], "year": 1998, "venue": "Oecologia", "link": "26041893"}, "BIBREF57": {"title": "Forest response to elevated CO 2 is conserved across a broad range of productivity", "authors": [{"first": "R", "middle": ["J"], "last": "Norby", "suffix": ""}, {"first": "E", "middle": ["H"], "last": "Delucia", "suffix": ""}, {"first": "B", "middle": [], "last": "Gielen", "suffix": ""}, {"first": "C", "middle": [], "last": "Calfapietra", "suffix": ""}, {"first": "C", "middle": ["P"], "last": "Giardina", "suffix": ""}, {"first": "J", "middle": ["S"], "last": "King", "suffix": ""}], "year": 2005, "venue": "Proc. Natl. Acad. Sci. U.S.A", "link": "13581899"}, "BIBREF58": {"title": "CO(2) enhancement of forest productivity constrained by limited nitrogen availability", "authors": [{"first": "R", "middle": ["J"], "last": "Norby", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Warren", "suffix": ""}, {"first": "C", "middle": ["M"], "last": "Iversen", "suffix": ""}, {"first": "B", "middle": ["E"], "last": "Medlyn", "suffix": ""}, {"first": "R", "middle": ["E"], "last": "Mcmurtrie", "suffix": ""}], "year": 2010, "venue": "", "link": "81212951"}, "BIBREF60": {"title": "Tree responses to rising CO 2 in field experiments: implications for the future forest", "authors": [{"first": "R", "middle": ["J"], "last": "Norby", "suffix": ""}, {"first": "S", "middle": ["D"], "last": "Wullschleger", "suffix": ""}, {"first": "C", "middle": ["A"], "last": "Gunderson", "suffix": ""}, {"first": "D", "middle": ["W"], "last": "Johnson", "suffix": ""}, {"first": "R", "middle": [], "last": "Ceulemans", "suffix": ""}], "year": 1999, "venue": "Plant Cell Environ", "link": null}, "BIBREF61": {"title": "Water use of two Mojave Desert shrubs under elevated CO 2 . Glob", "authors": [{"first": "D", "middle": ["E"], "last": "Pataki", "suffix": ""}, {"first": "T", "middle": ["E"], "last": "Huxman", "suffix": ""}, {"first": "D", "middle": ["N"], "last": "Jordan", "suffix": ""}, {"first": "S", "middle": ["F"], "last": "Zitzer", "suffix": ""}, {"first": "J", "middle": ["S"], "last": "Coleman", "suffix": ""}, {"first": "S", "middle": ["D"], "last": "Smith", "suffix": ""}], "year": 2000, "venue": "Change Biol", "link": null}, "BIBREF62": {"title": "Responses of sap flux and stomatal conductance of Pinus taeda L. Trees to stepwise reductions in leaf area", "authors": [{"first": "D", "middle": ["E"], "last": "Pataki", "suffix": ""}, {"first": "R", "middle": [], "last": "Oren", "suffix": ""}, {"first": "N", "middle": [], "last": "Phillips", "suffix": ""}], "year": 1998, "venue": "J. Exp. Bot", "link": "86796921"}, "BIBREF63": {"title": "Increased water-use efficiency during the 20th century did not translate into enhanced tree growth", "authors": [{"first": "J", "middle": [], "last": "Penuelas", "suffix": ""}, {"first": "J", "middle": ["G"], "last": "Canadell", "suffix": ""}, {"first": "R", "middle": [], "last": "Ogaya", "suffix": ""}], "year": 2011, "venue": "Glob. Ecol. Biogeogr", "link": "85758857"}, "BIBREF64": {"title": "Web-FACE: a new canopy free-air CO 2 enrichment system for tall trees in mature forests", "authors": [{"first": "S", "middle": [], "last": "Pepin", "suffix": ""}, {"first": "C", "middle": [], "last": "K\u00f6rner", "suffix": ""}], "year": 2002, "venue": "Oecologia", "link": "42056301"}, "BIBREF65": {"title": "R: A Language and Environment for Statistical Computing. Vienna: R Foundation for Statistical Computing", "authors": [{"first": "R", "middle": [], "last": "Development Core", "suffix": ""}, {"first": "", "middle": [], "last": "Team", "suffix": ""}], "year": 2011, "venue": "", "link": null}, "BIBREF66": {"title": "Effects of elevated CO 2 concentration and nutrition on net photosynthesis, stomatal conductance and needle respiration of field-grown Norway spruce trees", "authors": [{"first": "P", "middle": [], "last": "Roberntz", "suffix": ""}, {"first": "J", "middle": [], "last": "Stockfors", "suffix": ""}], "year": 1998, "venue": "Tree Physiol", "link": "22379430"}, "BIBREF67": {"title": "Tree and forest functioning in an enriched CO 2 atmosphere", "authors": [{"first": "H", "middle": [], "last": "Saxe", "suffix": ""}, {"first": "D", "middle": ["S"], "last": "Ellsworth", "suffix": ""}, {"first": "J", "middle": [], "last": "Heath", "suffix": ""}], "year": 1998, "venue": "Tansley Rev. New Phytol", "link": null}, "BIBREF68": {"title": "Hydrologic balance in an intact temperate forest ecosystem under ambient and elevated atmospheric CO 2 concentration", "authors": [{"first": "K", "middle": ["V R"], "last": "Sch\u00e4fer", "suffix": ""}, {"first": "R", "middle": [], "last": "Oren", "suffix": ""}, {"first": "C", "middle": ["T"], "last": "Lai", "suffix": ""}, {"first": "G", "middle": ["G"], "last": "Katul", "suffix": ""}], "year": 2002, "venue": "Glob. Change Biol", "link": "85868349"}, "BIBREF69": {"title": "Relationships among maximum stomatal conductance, ecosystem surface conductance, carbon assimilation rate, and plant nitrogen nutrition -a global ecology scaling exercise", "authors": [{"first": "E", "middle": ["D"], "last": "Schulze", "suffix": ""}, {"first": "F", "middle": ["M"], "last": "Kelliher", "suffix": ""}, {"first": "C", "middle": [], "last": "K\u00f6rner", "suffix": ""}, {"first": "J", "middle": [], "last": "Lloyd", "suffix": ""}, {"first": "R", "middle": [], "last": "Leuning", "suffix": ""}], "year": 1994, "venue": "Ann. Rev. Ecol. Syst", "link": "85754957"}, "BIBREF70": {"title": "Evaluation of ecosystem dynamics, plant geography and terrestrial carbon cycling in the LPJ dynamic global vegetation model", "authors": [{"first": "S", "middle": [], "last": "Sitch", "suffix": ""}, {"first": "B", "middle": [], "last": "Smith", "suffix": ""}, {"first": "I", "middle": ["C"], "last": "Prentice", "suffix": ""}, {"first": "A", "middle": [], "last": "Arneth", "suffix": ""}, {"first": "A", "middle": [], "last": "Bondeau", "suffix": ""}, {"first": "W", "middle": [], "last": "Cramer", "suffix": ""}], "year": 2003, "venue": "Glob. Change Biol", "link": "85742875"}, "BIBREF71": {"title": "Representation of vegetation dynamics in the modelling of terrestrial ecosystems: comparing two contrasting approaches within European climate space", "authors": [{"first": "B", "middle": [], "last": "Smith", "suffix": ""}, {"first": "I", "middle": ["C"], "last": "Prentice", "suffix": ""}, {"first": "M", "middle": ["T"], "last": "Sykes", "suffix": ""}], "year": 2001, "venue": "Glob. Ecol. Biogeogr", "link": "203412778"}, "BIBREF73": {"title": "Daily dataset of 20th-century surface air temperature and precipitation series for the European Climate Assessment", "authors": [], "year": "", "venue": "Int. J. Climatol", "link": "55560519"}, "BIBREF74": {"title": "A field-study of the effects of elevated CO 2 on carbon assimilation, stomatal conductance and leaf and branch growth of Pinus taeda trees", "authors": [{"first": "R", "middle": ["O"], "last": "Teskey", "suffix": ""}], "year": 1995, "venue": "Plant Cell Environ", "link": "85162710"}, "BIBREF75": {"title": "Water use of a bioenergy plantation", "authors": [{"first": "P", "middle": ["J"], "last": "Tricker", "suffix": ""}, {"first": "M", "middle": [], "last": "Pecchiari", "suffix": ""}, {"first": "S", "middle": ["M"], "last": "Bunn", "suffix": ""}, {"first": "F", "middle": ["P"], "last": "Vaccari", "suffix": ""}, {"first": "A", "middle": [], "last": "Peressotti", "suffix": ""}, {"first": "F", "middle": [], "last": "Miglietta", "suffix": ""}], "year": 2009, "venue": "", "link": null}, "BIBREF77": {"title": "Sap flux in pure aspen and mixed aspen-birch forests exposed to elevated concentrations of carbon dioxide and ozone", "authors": [{"first": "J", "middle": [], "last": "Uddling", "suffix": ""}, {"first": "R", "middle": ["M"], "last": "Teclaw", "suffix": ""}, {"first": "M", "middle": ["E"], "last": "Kubiske", "suffix": ""}, {"first": "K", "middle": ["S"], "last": "Pregitzer", "suffix": ""}, {"first": "D", "middle": ["S"], "last": "Ellsworth", "suffix": ""}], "year": 2008, "venue": "Tree Physiol", "link": null}, "BIBREF78": {"title": "Leaf and canopy conductance in aspen and aspen-birch forests under free-air enrichment of carbon dioxide and ozone", "authors": [{"first": "J", "middle": [], "last": "Uddling", "suffix": ""}, {"first": "R", "middle": ["M"], "last": "Teclaw", "suffix": ""}, {"first": "K", "middle": ["S"], "last": "Pregitzer", "suffix": ""}, {"first": "D", "middle": ["S"], "last": "Ellsworth", "suffix": ""}], "year": 2009, "venue": "Tree Physiol", "link": null}, "BIBREF79": {"title": "Waldb\u00f6den der Schweiz. Band 1. Grundlagen und Region Jura", "authors": [{"first": "L", "middle": [], "last": "Walthert", "suffix": ""}, {"first": "S", "middle": [], "last": "Zimmermann", "suffix": ""}, {"first": "P", "middle": [], "last": "Blaser", "suffix": ""}, {"first": "J", "middle": [], "last": "Luster", "suffix": ""}, {"first": "P", "middle": [], "last": "L\u00fcscher", "suffix": ""}], "year": 2004, "venue": "", "link": null}, "BIBREF80": {"title": "Ecohydrologic impact of reduced stomatal conductance in forests exposed to elevated CO(2)", "authors": [{"first": "J", "middle": ["M"], "last": "Warren", "suffix": ""}, {"first": "E", "middle": [], "last": "Poetzelsberger", "suffix": ""}, {"first": "S", "middle": ["D"], "last": "Wullschleger", "suffix": ""}, {"first": "P", "middle": ["E"], "last": "Thornton", "suffix": ""}, {"first": "H", "middle": [], "last": "Hasenauer", "suffix": ""}, {"first": "R", "middle": ["J"], "last": "Norby", "suffix": ""}], "year": 2011, "venue": "Ecohydrology", "link": null}, "BIBREF81": {"title": "Sensitivity of stomatal and canopy conductance to elevated CO 2 concentrationinteracting variables and perspectives of scale", "authors": [{"first": "S", "middle": ["D"], "last": "Wullschleger", "suffix": ""}, {"first": "C", "middle": ["A"], "last": "Gunderson", "suffix": ""}, {"first": "P", "middle": ["J"], "last": "Hanson", "suffix": ""}, {"first": "K", "middle": ["B"], "last": "Wilson", "suffix": ""}, {"first": "R", "middle": ["J"], "last": "Norby", "suffix": ""}], "year": 2002, "venue": "New Phytol", "link": null}, "BIBREF82": {"title": "Sap velocity and canopy transpiration in a sweetgum stand exposed to free-air CO2 enrichment (FACE)", "authors": [{"first": "S", "middle": ["D"], "last": "Wullschleger", "suffix": ""}, {"first": "R", "middle": ["J"], "last": "Norby", "suffix": ""}], "year": 2001, "venue": "New Phytol", "link": "83887915"}, "BIBREF83": {"title": "Link between diurnal stem radius changes and tree water relations", "authors": [{"first": "R", "middle": [], "last": "Zweifel", "suffix": ""}, {"first": "H", "middle": [], "last": "Item", "suffix": ""}, {"first": "R", "middle": [], "last": "H\u00e4sler", "suffix": ""}], "year": 2001, "venue": "Tree Physiol", "link": "20111484"}, "BIBREF84": {"title": "Modeling tree water deficit from microclimate: an approach to quantifying drought stress", "authors": [{"first": "R", "middle": [], "last": "Zweifel", "suffix": ""}, {"first": "L", "middle": [], "last": "Zimmermann", "suffix": ""}, {"first": "D", "middle": ["M"], "last": "Newbery", "suffix": ""}], "year": 2005, "venue": "Tree Physiol", "link": "17621496"}}, "ref_entries": {"FIGREF0": {"text": "FIGURE 1 | Daily relative sap flow sums of the control and CO 2 -treated trees, both before (A) and after the CO 2 -treatment was initiated (B and C). Shown are the medians of each group (n = 5). The bold dotted line represents the 1:1 line, the solid line the linear fit (with dashed lines as 95% confidence intervals). The 1:1 line lies within the confidence intervals where data points are available, suggesting that there was no significant difference between treated and control trees in any of the three periods shown.", "type": "figure"}, "FIGREF1": {"text": "FIGURE 2 | Diurnal water relations data of mature P. abies trees under elevated (bold/filled symbols) and ambient (open symbols) atmospheric CO 2 , before and after the treatment was initiated, on three cloudless summer days in 2009 and 2010. Panels (A) show relative sap flow (each tree standardized to its pre-treatment maximum, n = 5), panels (B) and (C) show mean leaf water potentials and stomatal conductance from pre-dawn to dusk, and (D) the photosynthetically active radiation (above the canopy, thin line, left hand side axis) and vapor pressure deficit (at canopy height, bold line, and font, right hand side axis). Shaded areas and bars represent one standard error. None of the differences between control and treated trees is significant on any of the 3 days (see text).", "type": "figure"}, "FIGREF2": {"text": "FIGURE 3 | Stem water deficit in control and CO 2 -treated P. abies trees. (A) Standardized time series of stem water deficit in CO 2 -treated (bold) and control (dashed line) trees, growth-trend corrected (see section \"Materials and Methods\").", "type": "figure"}, "FIGREF3": {"text": "FIGURE 5 | Relative sap flow plotted against the vapor pressure deficit (VPD), according to treatment (open symbols, ambient; closed symbols, treated), before and after the initialization of the CO 2 -treatment. Shown are 95 percentile values for 2 kPa bins, with non-linear fits (solid lines) and their 95% confidence intervals (gray-shaded area around the regression line). The merged model fits (treated and control trees) are shown. (A) 2009, before the start of the CO 2 treatment. (B) 2010, during the CO 2 treatment.", "type": "figure"}, "TABREF0": {"text": "Comparison of measured and modeled transpiration under control and elevated CO 2 conditions, estimated from relative sap flow in P. abies in the experiment, and from total stand transpiration of evergreen needle-leaved trees in the dynamic global vegetation model LPJ-GUESS.", "type": "table"}, "TABREF1": {"text": "", "type": "table"}}}
{"paper_id": "8330274", "_pdf_hash": "7a66064b1e995106484c9294b6cc39d1d7fbde9c", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Draw the obtained feedback, that is, u as a piecewise constant function of w 0 and graphically compare it to the optimal feedback defined at \u00a72", "authors": [], "year": "", "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "8330482", "_pdf_hash": "d8ddabae2c022355e4bb81669b7d08611c662e59", "abstract": [], "body_text": [{"section": "", "text": "Detailed information on sulphur metabolism in moulds was initiated by Steinberg's (1941) investigations into the utilization of various sulphurcontaining compounds by Aspergillus niger. He concluded that the reduction of such compounds is a normal preliminary process in inorganic sulphur utilization in this mould. Hockenhull (1948) obtained similar results for PeniciElium notatum and described two parathiotrophic mutants of this mould. Parathiotrophic mutants of Ophiostoma multiannulutum had previously been produced by Fries (1945) and parathiotrophy had been observed in the Saprolegniaceae by Volkonsky (1983) and in Staphylococcus uweus by Fildes & Richardson (1937). Hockenhull (1949) obtained a number of parafhiotrophic mutants of Aspergillus niduhns and, from their growth behaviour on a number of compounds, postulated that sulphate was metabolized to cysteine with the intermediate formation of sulphite, sulphoxylate, thiosulphate and cysteine-S-sulphonic acid. Phinney (1948) and Phinney, Fling, Sheng & Horowitz (1950) obtained evidence that in Newospora mama sulphite, thiosulphate, cysteic acid and cysteine sulphinic acid were intermediates between, sulphate and cysteine. In Escherichia coEi, the work of Lampen, Roepke dz Jones (1947) and of Cowie, Bolton & Sands (1950) indicated that suIphite, thiosulphate and possibly sulphide, were intermediates between sulphate and cysteine.", "cite_spans": [{"start": 70, "end": 88, "text": "Steinberg's (1941)", "ref_id": "BIBREF22"}, {"start": 525, "end": 537, "text": "Fries (1945)", "ref_id": "BIBREF4"}, {"start": 677, "end": 694, "text": "Hockenhull (1949)", "ref_id": "BIBREF7"}, {"start": 997, "end": 1036, "text": "Phinney, Fling, Sheng & Horowitz (1950)", "ref_id": "BIBREF17"}, {"start": 1265, "end": 1293, "text": "Cowie, Bolton & Sands (1950)", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "", "text": "Kearney & Singer (1952 & Singer ( , 1953 and Singer & Kearney (1954) obtained evidence that in Prdeus vulgaris oxidation of cysteine to sulphate occurs with the intermediate formation of cysteine sulphinic acid, P-sulphinyl pyruvic acid and sulphite, while Chapeville & Fromageot (1954) have shown the formation of cysteine sulphinic acid from sulphite in rabbit kidney.", "cite_spans": [{"start": 8, "end": 22, "text": "& Singer (1952", "ref_id": "BIBREF10"}, {"start": 45, "end": 68, "text": "Singer & Kearney (1954)", "ref_id": "BIBREF21"}, {"start": 257, "end": 286, "text": "Chapeville & Fromageot (1954)", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "", "text": "No experimental approach, using both metabolic studies and mutant studies simultaneously, has been made, and Aspergillus niddans appears to offer reasonable material for this purpose, as the starvation method of Pontecorvo (1958) enables large numbers of parathiotrophic mutants to be produced with relative ease. It was hoped that information gained by the above approach would make it possible to reconcile and amplify previous studies with both A. nidulans and other organisms. For growth studies, the mutants were grown on the above minimal medium supplemented with various sulphur compounds and biotin where necessary.", "cite_spans": [], "ref_spans": []}, {"section": "METHODS", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Organisms", "text": "Enzyme preparations. The mycelium from the aerated shake culture was washed on a sintered-glass funnel with a large volume of distilled water, resuspended in 800 ml, distilled water and aerated for 5 hr. It was then filtered off and suspended in a large volume of ice-cold acetone. After standing overnight at O\", the mycelium was again filtered on a sintered-glass funnel, washed with ice-cold acetone and ether and dried in wamo over sulphuric acid.", "cite_spans": [], "ref_spans": []}, {"section": "Organisms", "text": "On a suggestion by Dr E. E. Snell, the mycelium was constantly aerated during all stages of manipulation until it was plunged into the ice-cold acetone. Lack of aeration during the filtration steps resulted in low and fluctuating activities in the acetone powders. Considerable endogenous production of cysteine was observed when mycelium was not starved in distilled water, Reaction mixture. The total reaction mixture volume was 10 ml. consisting of 5 ml. 0.067 M-phosphate buffer (pH 7-2) in which 100-200 mg. of acetone powder were suspended. Amino and keto acids and sulphur sources were added to a final concentration of 0.1 M, as sodium salts, and pyridoxal to a final concentration of 0.01 M.", "cite_spans": [], "ref_spans": []}, {"section": "Organisms", "text": "Estimdioru. At the end of each experiment, the digest was centrifuged, the precipitate washed twice with 5 ml. distilIed water, and the washings and supernatant fluid combined. The precipitate was suspended in 10 ml. distilled water and heated for 10 min, in a boiling water bath. After cooling, solid material was removed by centrifugation. Cysteine and cystine were estimated directly on samples from the original supernatant fluid and on samples from the hot water extract by the method of Kassell & Brand (1988). The results were expressed as pg. cysteine, although the experimental manipulations led to the oxidation of varying proportions of the cysteine to cystine.", "cite_spans": [], "ref_spans": []}, {"section": "Organisms", "text": "Chromatogruphy of amino acids. For the production of satisfactory chromatograms it was found necessary to treat the extracts in the following manner in order to remove inorganic sulphur compounds. To a sample of the hot water extract 0 . 1~ iodine solution was added until a faint yellow colour persisted; excess of saturated barium hydroxide solution was then added and carbon dioxide bubbled through the solution to remove excess barium hydroxide. The mixture was centrifuged and the supernatant fluid freeze-dried. After redissolving in 1-2 ml. water, 5-20 pl. samples were chromatographed on Whatman no. 1 paper, using n-butanol +acetic acid +water (4 : 1 : 5 ) or methanol + pyridine +water (6 : 2 : 2) as solvents. The chromatograms were dipped in 0.2 yo (w/v) ninhydrin in acetone and the colour developed by heating at 90\" for 15 min.", "cite_spans": [], "ref_spans": []}, {"section": "Organisms", "text": "Semi-quantitative measurements of the amount of amino acid present were made by cutting out the coloured spots, eluting with 4 ml. of acetone+water (8: 1) and measuring the colour in a Beckman Model DU spectrophotometer at a wavelength of 570 mp.", "cite_spans": [], "ref_spans": []}, {"section": "Organisms", "text": "Reagents. Analytical grade reagents were used wherever possible. Cysteine, cystine, methionine, taurine, isethionic acid and pyridoxal were obtained from L, Light and Co. ; glutamic acid, aspartic acid and serine from Roche Products Ltd, ; and sodium formaldehyde sulphoxylate from Brotherton and Co. Ltd. All amino acids were used in the form of their L-isomers.", "cite_spans": [], "ref_spans": []}, {"section": "Organisms", "text": "Cysteine sulphinic acid was prepared according to Levine (1986) , cysteic acid according to Shinohara (1932) , cystine disulphoxide according to Levine ( 1 9SS), cysteine-S-sulphonic acid according to Clarke (1932) (Hughes, 1951) , or by grinding with powdered alumina (McIlwain, Roper & Hughes, 1948) showed negligible activities. Acetone powders of mycelium when prepared at a low temperature, showed a high activity which varied within the range of 38-82 pg. cysteine produced/hr./lOO mg. acetone powder with sulphite as the inorganic sulphur source, and 25-74 pg. cysteine produced/hr./100 mg. acetone powder with thiosulphate as the inorganic sulphur source.", "cite_spans": [{"start": 50, "end": 63, "text": "Levine (1986)", "ref_id": "BIBREF14"}, {"start": 201, "end": 214, "text": "Clarke (1932)", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Organisms", "text": "Cysteine synthesis from sulphate and mlphite The mycelial acetone powders, when incubated alone in buffer, showed a small endogenous production of cysteine, possibly due to autolysis. As shown in Table 1 , there was a considerable synthesis of cysteine when pyridoxal, glutamate and pyruvate were added to this system. The omission of glutamate, or pyruvate, caused only a 5 0 % decrease of synthesis, as it was impossible to decrease significantly the amount of free internal amino acids in the mycelium by starvation. (After 6 hr, starvation approximately 80% of the original amount of glutamic acid still remained.) Other amino acids, such as alanine and aspartic acid, and a-ketoglutaric acid and oxalacetic acid were less effective in the system. With sulphate as the inorganic sulphur source, the rate of synthesis was markedly lower, but the pattern followed was identical with that found with sulphite. Acetone powder preparations of mycelium were incubated in a tots1 volume of 10 ml, at 87' for 5 hr. Cysteine and cystine were determined in the supernatant after incubation, the results being expressed as pg. cysteine formed/hr./100 mg. acetone powder. Four experiments recorded. Additions Cysteine synthesis from thiosulphate There was a considerable synthesis of cysteine with the acetone powder, buffer and thiosulphate alone; this was markedly increased by the addition of serine. The rate of synthesis was not increased by the further addition of pyridoxal and a slight inhibition was noted upon the addition of other amino acids and keto acids ( Table 2) . Cysteine sulphinic acid as an intermediate i n the synthesis The production of cysteine sulphinic acid and the utilization of glutamic acid were demonstrated with sulphite as the inorganic sulphur source. With thiosulphate as the sulphur source, formation of cysteine sulphinic acid was not observed. The results obtained by a semi-quantitative estimation of changes in free internal amino acids, other than cysteine, are shown in Table 3 . Table 3 . Formation and utilization of amino acids during cysteiw synthesis Acetone powder preparations of mycelium were incubated in a total volume of 10 ml. at 3 ' 7 ' for 5 hr. Amino acids were determined after incubation of hot water extracts of the acetone powders by the chromatographic method described in the text, the results being expressed in arbitrary units.", "cite_spans": [], "ref_spans": [{"start": 196, "end": 203, "text": "Table 1", "ref_id": "TABREF2"}, {"start": 1563, "end": 1571, "text": "Table 2)", "ref_id": "TABREF3"}]}, {"section": "Organisms", "text": "Additions ", "cite_spans": [], "ref_spans": []}, {"section": "C . J . Shepherd", "text": "Growth studies with mutant organisms The results of growth studies with various mutants, by the colony diameter method, are shown in Table 4 , Auxanographic tests gave results similar to those obtained by this method. In addition t o the various mutants mentioned in the text, forty-two other mutants were obtained, the metabolic block in all cases being between sulphate and sulphite. Mutants 1 and 7 made relatively poor growth on all media, whereas the growth of the other mutants, where it occurred, was more like that of the wild type. Studies with mutant no. 7 Mutant no. 7 was studied in greatest detail because of the interest aroused by its poor growth on thiosulphate. The results of the metabolic experiments indicate that sulphite and thiosulphate may be metabolized by different paths, and it might be expected that mutants would be found which could utilize sulphite but not thiosulphate, and vice versa. That mutant no. 7 does not utilize either sulphite or thiosulphate to any large extent may indicate that these compounds are on the same pathway, or that some type of double block in two separate pathways is present. The response of this mutant to cysteine is shown in Fig, 1 , and the quantitative response to various other sulphur compounds is shown in Fig. 2 , as measuredin spore germination tests. Table 5 illustrates ' leakiness ', i.e. some growth and germination on sulphate, but much less than that of the wild type. Such 'leakiness' may be due to a slight ability of the mutant t o convert sulphate to cysteine. Many of the 'leaky' mutants gave a negative auxanographic test for growth on sulphate, while showing some response in the spore germination tests. ", "cite_spans": [], "ref_spans": [{"start": 133, "end": 140, "text": "Table 4", "ref_id": "TABREF4"}, {"start": 1274, "end": 1280, "text": "Fig. 2", "ref_id": "FIGREF6"}, {"start": 1322, "end": 1329, "text": "Table 5", "ref_id": "TABREF5"}]}, {"section": "Apparent ' leakiness' of the mutants", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "The evidence presented suggests that inorganic sulphur compounds may be synthesized biologically into cysteine via at least two different pathways in Aspergillus niduluns. The pathway proposed by Kearney & Singer (1952) for the metabolism of cysteine sulphinic acid in Prokw vulgaris and shown to be reversible in rabbit kidney by Chapeville & Fromageot (1954) suggests the pathway starting with sulphate shown in Fig. 3 . The latter part of this pathway is taken from the suggestion of Medes & Floyd (1942) that cysteine is oxidized via cysteine sulphenic acid to cysteine sulphinic acid. This would explain the experimental data obtained with the wild-type Aspergillus nidulans preparations which use sulphate and sulphite as the inorganic sulphur sources, and also the growth behaviour of mutants 1, 2, 8, 4, 6, 8 and 9. This pathway, however, provides no explanation for the metabolism of thiosulphate.", "cite_spans": [{"start": 196, "end": 219, "text": "Kearney & Singer (1952)", "ref_id": "BIBREF10"}, {"start": 331, "end": 360, "text": "Chapeville & Fromageot (1954)", "ref_id": "BIBREF0"}, {"start": 487, "end": 507, "text": "Medes & Floyd (1942)", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "DISCUSSION", "text": "The stimulation of cysteine synthesis by serine, when thiosulphate is the inorganic sulphur source, and the complete lack of any stimulating effect of glutamic acid, keto acids or pyridoxal on this system, together with the evidence that there is no intermediate production of cysteine sulphinic acid, leads to the conclusion that thiosulphate is metabolized by an alternative pathway. The suggestion by Hockenhull (1949) that thiosulphate and serine combine to give cysteine-S-sulphonic acid, which gives rise to cysteine, would provide an alternative pathway for the metabolism of thiosulphate which would agree with the experimental data. The pathway in mutant no. 7 is not entirely clear, but a block in the production of some unknown cofactor or energy-providing system common to both pathways, or a permeability change in the mycelium, are possible explanations of the behaviour of this mutant, which is apparently blocked in both metabolic pathways simultaneously.", "cite_spans": [{"start": 404, "end": 421, "text": "Hockenhull (1949)", "ref_id": "BIBREF7"}], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "La formation enzymatique de I'acide cysteinesulphinique a partir de sulfite", "authors": [{"first": "F", "middle": [], "last": "Chapeville", "suffix": ""}, {"first": "P", "middle": [], "last": "Fromageot", "suffix": ""}], "year": 1954, "venue": "Biochim. biophys. Acta", "link": null}, "BIBREF1": {"title": "The action of sdphite upon cysteine", "authors": [{"first": "H", "middle": ["J"], "last": "Clarke", "suffix": ""}], "year": 1932, "venue": "J . Mol. Chem", "link": null}, "BIBREF2": {"title": "Sulphur metabolism in Ed~erichia coli. I. Sulphate metabolism of normal and mutant cells", "authors": [{"first": "D", "middle": ["B"], "last": "Cowie", "suffix": ""}, {"first": "E", "middle": ["T"], "last": "Bolton", "suffix": ""}, {"first": "M", "middle": ["K"], "last": "Sands", "suffix": ""}], "year": 1950, "venue": "J . Bact", "link": null}, "BIBREF3": {"title": "T h e nutrition of StaphyZococcw QUT~US: sulphur requirements", "authors": [{"first": "P", "middle": [], "last": "Fixdes", "suffix": ""}, {"first": "G", "middle": ["M"], "last": "Richardson", "suffix": ""}], "year": 1937, "venue": "Bdt. J . exp. Path", "link": null}, "BIBREF4": {"title": "X-ray induced mutations in the physiology of Ophiostoma", "authors": [{"first": "N", "middle": [], "last": "Fries", "suffix": ""}], "year": 1945, "venue": "Nature", "link": null}, "BIBREF5": {"title": "Sur la dkgradation anaerobie de la cysteine par la desulphurase du foie", "authors": [{"first": "C", "middle": [], "last": "Froma~eot", "suffix": ""}, {"first": "E", "middle": [], "last": "Wookey", "suffix": ""}, {"first": "P", "middle": [], "last": "Chaix", "suffix": ""}], "year": "", "venue": "Enzymologia", "link": null}, "BIBREF6": {"title": "Studies in penicillin production by PeniciZZiurn notatum in surface culture: 11. Further studies in the metabolism of sulphur", "authors": [{"first": "D", "middle": ["J"], "last": "Hockenhull", "suffix": ""}, {"first": "D", "middle": [], "last": "", "suffix": ""}], "year": 1948, "venue": "Biochem. J", "link": null}, "BIBREF7": {"title": "The sulphur metabolism of mould fungi: the use of 'biochemical mutant' strains of Aspergillus niduluns in elucidating the biosynthesk of cystine", "authors": [{"first": "D", "middle": ["J D"], "last": "Hockenhull", "suffix": ""}], "year": 1949, "venue": "Biochim. biophys. Acta", "link": null}, "BIBREF8": {"title": "A press for disrupting bacteria and other microorganisms", "authors": [{"first": "D", "middle": ["E"], "last": "Hughes", "suffix": ""}], "year": 1951, "venue": "Brit. J. exp. Path", "link": null}, "BIBREF9": {"title": "The photometric determination of cystine, cysteine, ascorbic acid and related compounds with phosphotungstic acid", "authors": [{"first": "B", "middle": [], "last": "Elassell", "suffix": ""}, {"first": "E", "middle": [], "last": "Brand", "suffix": ""}], "year": 1938, "venue": "J. Iriol. Chem", "link": "82154663"}, "BIBREF10": {"title": "Intermediary metabolism of cysteine sulphinic acid in cell-free extracts of Proteus vulgurb", "authors": [{"first": "E", "middle": ["B"], "last": "Kearney", "suffix": ""}, {"first": "T", "middle": ["P"], "last": "Singer", "suffix": ""}], "year": 1952, "venue": "Biochim. w h y s . Actu", "link": null}, "BIBREF11": {"title": "The oxidation of cysteine sulphinic and cysteic acids in P T o t w vulgaria", "authors": [{"first": "E", "middle": ["B"], "last": "Kearney", "suffix": ""}, {"first": "T", "middle": ["P"], "last": "Sinueei", "suffix": ""}], "year": 1958, "venue": "Biochim, hhphys. Acta", "link": null}, "BIBREF12": {"title": "90). Chlorinations with sulfuryl chloride. 111. (a) The peroxide catalysed chlorination of aliphatic acids and acid chlorides. ( b ) The photochemical sulphonation of aliphatic acids", "authors": [{"first": "M", "middle": ["S"], "last": "Kharaech", "suffix": ""}, {"first": "H", "middle": ["C"], "last": "Brown", "suffix": ""}], "year": "", "venue": "J . A M . chem. Soc", "link": null}, "BIBREF13": {"title": "Studies on the sulphur metabolism of Escherichia c o k 111. Mutant strains of Escherichia coli unable to utilize sulphate for their complete sulphur requirements", "authors": [{"first": "J", "middle": ["O"], "last": "Lampen", "suffix": ""}, {"first": "R", "middle": ["R"], "last": "Roepke", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Jones", "suffix": ""}], "year": 1947, "venue": "Arch. Biochem", "link": null}, "BIBREF14": {"title": "The oxidation of cysthe in non-aqueous media. VI. A study of the reactions of the disulphoxide of L-cystine, especially of its dismutative decompositions", "authors": [{"first": "T", "middle": ["F"], "last": "Levine", "suffix": ""}], "year": 1986, "venue": "J . biol. Chern", "link": null}, "BIBREF15": {"title": "Relationships in streptococci between growth and metabolism of glutamine", "authors": [{"first": "H", "middle": [], "last": "Mcilwain", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Rorer", "suffix": ""}, {"first": "D", "middle": ["E"], "last": "Hughes", "suffix": ""}], "year": 1948, "venue": "BWch~?m. J", "link": "31987509"}, "BIBREF16": {"title": "Metabolism of sulphur. 11. Further investigations of the enzymic oxidation of sulphur-containing amino acids", "authors": [{"first": "G", "middle": [], "last": "Medes", "suffix": ""}, {"first": "N", "middle": [], "last": "Floyd", "suffix": ""}], "year": 1942, "venue": "J . R. micr, SOC", "link": "6289187"}, "BIBREF17": {"title": "Unpublished experiments quoted in ' Biochemical genetics of Neurospora", "authors": [{"first": "B", "middle": ["O"], "last": "Phinney", "suffix": ""}, {"first": "M", "middle": [], "last": "Fling", "suffix": ""}, {"first": "T", "middle": ["C"], "last": "Sheng", "suffix": ""}, {"first": "N", "middle": ["H"], "last": "Horowitz", "suffix": ""}], "year": 1950, "venue": "", "link": null}, "BIBREF18": {"title": "Auxanographic techniques in biochemical genetics", "authors": [{"first": "G", "middle": [], "last": "Pontecorvo", "suffix": ""}], "year": 1949, "venue": "J . gen. Microbiol", "link": "29140338"}, "BIBREF19": {"title": "The genetics of Aspergillus nidulans", "authors": [{"first": "G", "middle": [], "last": "Pontecorvo", "suffix": ""}], "year": 1953, "venue": "Advanc. Genet", "link": null}, "BIBREF20": {"title": "Oxidation of cystine by iodine in aqueous media", "authors": [{"first": "W", "middle": ["B"], "last": "Robertbon", "suffix": ""}], "year": 1932, "venue": "J . biol. Chem", "link": "83143778"}, "BIBREF21": {"title": "Pathways of L-cysteine-sulphinate metabolism in animal tissues", "authors": [{"first": "T", "middle": ["P"], "last": "Singer", "suffix": ""}, {"first": "E", "middle": [], "last": "Kearney", "suffix": ""}], "year": 1954, "venue": "Biochirn. Mophys. Acta", "link": null}, "BIBREF22": {"title": "Sulphur and trace element nutrition of Aspergillus niger", "authors": [{"first": "R", "middle": ["A"], "last": "Steinberg", "suffix": ""}], "year": 1941, "venue": "J . agm'c. R e g", "link": null}, "BIBREF23": {"title": "Sur l'assimilation des sulfates per les Champignons: euthiotrophie et parathiotrophie", "authors": [{"first": "M", "middle": [], "last": "Volkonsky", "suffix": ""}], "year": "", "venue": "C.R. Acad. S&", "link": null}, "BIBREF24": {"title": "The availability of disulphide acids as supplementing agents in diets deficient in cystine, 11. a-hydroxy-8-dithiolpropionic acid", "authors": [{"first": "B", "middle": ["D"], "last": "Westerman", "suffix": ""}, {"first": "W", "middle": ["C"], "last": "Rose", "suffix": ""}], "year": 1926, "venue": "J. bid. Chem", "link": null}, "BIBREF25": {"title": "Uberfiihrung der Weinsiiure in Oxalessigsaure durch Wasserabspaltung bei niederer Temperatur", "authors": [{"first": "A", "middle": [], "last": "Wohl", "suffix": ""}, {"first": "C", "middle": [], "last": "Oesterlin", "suffix": ""}], "year": "", "venue": "Ber. dtsch. chem. Ges", "link": null}}, "ref_entries": {"FIGREF0": {"text": "B signifies acetone powder suspended in buffer and heated for 10 min, at lOO\".)", "type": "figure"}, "FIGREF1": {"text": "signifies acetone powder suspended in buffer and heated \u20acor 10 min. at looo.)", "type": "figure"}, "FIGREF2": {"text": "min. at looo.) G. Microb. xv Downloaded from www.microbiologyresearch.", "type": "figure"}, "FIGREF4": {"text": "pg. cysteine per ml.", "type": "figure"}, "FIGREF5": {"text": "Fig. 1.", "type": "figure"}, "FIGREF6": {"text": "Fig. 2. Response of mutant no. 7 to various sulphur sources. Sulphur compounds were added to liquid medium at a concentration of 100 pg./ml. and the percentage germination estimated after incubation at 8 7 ' for 6 hr.", "type": "figure"}, "FIGREF7": {"text": "Fig. 8. Scheme for cysteine synthesis in dSpt?T@lW niduluns. The positions of the postulated metabolic blocks in the various mutants is shown.", "type": "figure"}, "TABREF0": {"text": ". AspergiZEus nidulum (Eidam) Wint. (Commonwealth Myco- logical Institute Culture Collection No. 186418) was used for the metabolic experiments and as the wild-type mould for the production of mutants. For the isolation of mutants, approximately 20 x 108 conidia were suspended in 2 ml. 1 : 5000 Teepol solution, uv-irradiated in a rocked quartz dish until only 0.2 % remained viable and plated out on minimal medium + cysteine. For the production of mutants by the starvation method of Pontecorvo (1958), a biotinless mutant derived from the wild type was used as the parent strain. The requirements of the parathiotrophic mutants produced were determined by the auxanographic method of Pontecorvo (19169). CuEtivdiun. The mould was grown in the following medium: 6.0 g. NaNO,; 0.5 g. KC1; 0.5 g. MgS0,.7H20; 1.5 g. KH,PO,; 20.0 g. glucose; 95 pug. Na4B,0,. lOH,O ; 398 pg. CuSO, .5H,O; 997 pug. FeSO, .7H20; 158 pug. MnSO, .4H,O ; 62 ,ug* (NH,),MoO, ; 8.8 mg. ZnSO, .7H,O and 1000 ml. water. The pH value was adjusted to 6-8 beford autoclaving at 15 1b.lsq.in. for 15 min. The medium was dispensed in 200 ml. amounts in 1 1. flat-bottorn flasks and aerated vigorously with a fast stream of air passed through a sin- tered-glass distributor, while being shaken with a frequency of 150 strokeslmin. at an amplitude of 4 cm. Incubation was for 72 hr, at 20' and resulted in a dense suspension of short pieces of vegative mycelium.", "type": "table"}, "TABREF1": {"text": ", /3-sulphonyl propionic acid according to Kharasch & Brown (1940), a-dihydroxy-p- dithiolpropionic acid according to Westerman & Rose (1928) and oxalacetic acid according to Wohl & Oesterlin (1901). Sodium pyruvate was prepared from pyruvic acid (L. Light and Co.) by the method of Robertson (1942). A sample of a-ketoglutaric acid was kindly provided by Mr B. Slater and a sample of p-sulphonyl lactic acid by Dr P. Aichenegg. Memurement of response of parathiotrophic mutants. The qualitative response of the parathiotrophic mutants was tested auxanographically on the basal medium solidified with 2 % agar. The quantitative response of the mutants was estimated by a spore gemination method (Shepherd, unpublished) and by measurement of growth rates on agar supplemented with the compounds under test. Preliminary experiments indicated that fresh mycelium showed very low and variable activities in synthesizing cysteine from sulphate, sulphite or thio- sulphate. The activity of freeze-dried mycelium was very variable, while mycelium broken by ultrasonic disintegration, by shaking with glass beads (Mickle, 1948), by treating in the Hughes press", "type": "table"}, "TABREF2": {"text": "Cysteine synthesis by Aspergillus nidulans in the presence of sulphate and sulphite", "type": "table"}, "TABREF3": {"text": "Cysteine synthesis by Aspergillus nidulans in the presence of thiosulphate Acetone powder preparations of mycelium were incubated in a total volume of 10 ml. at 87' for 5 hr. Cysteine and cystine were determined in the supernatant after incubation, the results being expressed as p g . cysteine formed/hr./100 mg. acetone powder. Two experi- ments recorded. Additions", "type": "table"}, "TABREF4": {"text": "Growth rates of purathiotrophic mutants on various sulphur sources", "type": "table"}, "TABREF5": {"text": "Incompleteness of the blocked reaction in the mutants Growth ability was tested by measurement of colony diameter after growth on a minimal medium with 100 ,ug./ml. sulphate as the sulphur source for 88 hr. at 37O, and by estimating spore germination in a sulphate-containing liquid medium.", "type": "table"}}}
{"paper_id": "8330661", "_pdf_hash": "443b5458b1c67491a1ea993d79ca0483de954d08", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Gossip and mixing times of random walks on random graphs", "authors": [{"first": "S", "middle": [], "last": "Boyd", "suffix": ""}, {"first": "A", "middle": [], "last": "Ghosh", "suffix": ""}, {"first": "B", "middle": [], "last": "Prabhakar", "suffix": ""}, {"first": "D", "middle": [], "last": "Shah", "suffix": ""}], "year": "", "venue": "", "link": "14813508"}, "BIBREF1": {"title": "Algebraic gossip: A network coding approach to optimal multiple rumor mongering", "authors": [{"first": "S", "middle": [], "last": "Deb", "suffix": ""}, {"first": "M", "middle": [], "last": "M\u00e9dard", "suffix": ""}], "year": 2004, "venue": "The Forty-Second Annual Allerton Conferenc e on Communication, Control, and Computing", "link": "10549775"}, "BIBREF2": {"title": "Algebraic gossip: A network coding approach to optimal multiple rumor mongering", "authors": [{"first": "S", "middle": [], "last": "Deb", "suffix": ""}, {"first": "M", "middle": [], "last": "M\u00e9dard", "suffix": ""}], "year": 2004, "venue": "M.I.T. LIDS Technical Report", "link": "10549775"}, "BIBREF3": {"title": "Epidemic algorithms for replicated database maintenance", "authors": [{"first": "A", "middle": [], "last": "Demers", "suffix": ""}], "year": 1987, "venue": "Proc. ACM Symposium on Principles of Distributed Computing", "link": "1889203"}, "BIBREF4": {"title": "The benefits of coding over routing in a randomized setting", "authors": [{"first": "T", "middle": [], "last": "Ho", "suffix": ""}, {"first": "M", "middle": [], "last": "M\u00e9dard", "suffix": ""}, {"first": "M", "middle": [], "last": "Effros", "suffix": ""}, {"first": "D", "middle": [], "last": "Karger", "suffix": ""}], "year": 2003, "venue": "Proc. IEEE Symposium on Information Theory", "link": null}, "BIBREF5": {"title": "On randomized network coding", "authors": [{"first": "T", "middle": [], "last": "Ho", "suffix": ""}, {"first": "M", "middle": [], "last": "M\u00e9dard", "suffix": ""}, {"first": "M", "middle": [], "last": "Effros", "suffix": ""}, {"first": "D", "middle": [], "last": "Karger", "suffix": ""}], "year": 2003, "venue": "Proc. 41st Allerton Annual Conference on Communication, Control and Computing", "link": "16128810"}, "BIBREF6": {"title": "Randomized rumor spreading", "authors": [{"first": "R", "middle": [], "last": "Karp", "suffix": ""}, {"first": "C", "middle": [], "last": "Schindelhauer", "suffix": ""}, {"first": "S", "middle": [], "last": "Shenker", "suffix": ""}, {"first": "B", "middle": [], "last": "Vocking", "suffix": ""}], "year": 2000, "venue": "Proc. Foundations of Computer Science", "link": "1135881"}, "BIBREF7": {"title": "Spatial gossip and resource location protocols", "authors": [{"first": "David", "middle": [], "last": "Kempe", "suffix": ""}, {"first": "Jon", "middle": ["M"], "last": "Kleinberg", "suffix": ""}, {"first": "Alan", "middle": ["J"], "last": "Demers", "suffix": ""}], "year": 2001, "venue": "Proc. ACM Symposium on Theory of Computing", "link": "53246907"}, "BIBREF8": {"title": "Spreading rumors cheaply, quickly, and reliably", "authors": [{"first": "Y", "middle": [], "last": "Minski", "suffix": ""}], "year": 2002, "venue": "", "link": "17131796"}}, "ref_entries": {}}
{"paper_id": "8330818", "_pdf_hash": "9d9d2575ce691af901208d7f5a03bbbd78ed11b2", "abstract": [{"section": "Abstract", "text": "Valid fish species identification is essential for biodiversity conservation and fisheries management. Here, we provide a sequence reference library based on mitochondrial cytochrome c oxidase subunit I for a valid identification of 79 freshwater fish species from the Lower Paran\u00e1 River. Neighbour-joining analysis based on K2P genetic distances formed non-overlapping clusters for almost all species with a !99% bootstrap support each. Identification was successful for 97.8% of species as the minimum genetic distance to the nearest neighbour exceeded the maximum intraspecific distance in all these cases. A barcoding gap of 2.5% was apparent for the whole data set with the exception of four cases. Withinspecies distances ranged from 0.00% to 7.59%, while interspecific distances varied between 4.06% and 19.98%, without considering Odontesthes species with a minimum genetic distance of 0%. Sequence library validation was performed by applying BOLDs BIN analysis tool, Poisson Tree Processes model and Automatic Barcode Gap Discovery, along with a reliable taxonomic assignment by experts. Exhaustive revision of vouchers was performed when a conflicting assignment was detected after sequence analysis and BIN discordance evaluation. Thus, the sequence library presented here can be confidently used as a benchmark for identification of half of the fish species recorded for the Lower Paran\u00e1 River.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Reliable species identification is necessary for conservation and sustainable exploitation of natural resources. DNA sequences of highly conserved genes have been used as a tool to identify biological species. This approach became especially relevant when identification based on morphological characters is not possible (e.g. larvae, eggs and fragmented tissue). A short Given the great power of DNA barcoding to identify fish species and considering the unique assemblage of Lower Paran\u00e1 River fish along with future changing scenarios, the present study aimed to group the first comprehensive reference COI sequence library for fishes of this region. Also, to test the effectiveness of the barcoding methodology for their identification in future studies.", "cite_spans": [], "ref_spans": []}, {"section": "Materials and Methods", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Specimen collection and sampling area", "text": "Several fishing techniques were used for sampling. Sampling methods included gill nets, lift nets, slat traps, hoop nets and angling. Animals were handled with maximum care to prevent or minimize injuries during studies. All sampling procedures and methods were in accordance with the FishBol international project recommendations and the Guidelines for the use of fishes in research by the American Fisheries Society.", "cite_spans": [], "ref_spans": []}, {"section": "Specimen collection and sampling area", "text": "A total of 308 specimens were sampled between 2012 and 2013 from a wide area of the Lower Paran\u00e1 River near the city of Rosario (50 sampling points, site 1) with the exception of 8 specimens obtained at one sampling point at site 2 (Fig 1) . The locations involved in the study were not part of any protected area, reserve forests or national parks. The General Direction of Natural Resources of the Production Ministry from Entre Rios Province in compliance with the law N\u00b04892/70, issued the permission to conduct this study in Paran\u00e1 River and Delta from Diamante to Gualeguay city. No specific permissions were required for sampling point 2 since tissue samples and photograph of Specimens were obtained from sport and commercial fishermen. The selected area encompasses a variety of environments, such as lagoons, streams, wetlands, the main river channel and its coasts. Collected specimens were anesthetized by immersion in 1% benzocaine in water and euthanized by benzocaine excess. A small piece (5-7 mm\u00b3) of muscle or fin tissue was removed from the right side of each fresh fish and preserved in 96% ethanol at -20\u00b0C. Specimens were photographed, labeled and fixed in 10% formaldehyde solution for 7 days. Occasionally, tissues were collected through the support of fisherman. Tissues and vouchers specimens were stored in 96% ethanol and deposited in the Fish Collection of the Angel Gallardo Natural Sciences Provincial Museum, Rosario, Argentina. Some tissue samples lack morphological vouchers, but have a \"photographic voucher\" according to the Fish-BOL collaborator's protocol [28] . All specimens for this study were obtained in compliance with animal welfare laws, local guidelines and national policy in the realm of the Argentine Republic.", "cite_spans": [{"start": 1594, "end": 1598, "text": "[28]", "ref_id": "BIBREF28"}], "ref_spans": [{"start": 232, "end": 239, "text": "(Fig 1)", "ref_id": "FIGREF0"}]}, {"section": "Fish identification", "text": "Taxonomic determination was performed following the identification reliability levels 1 and 2 according to the Fish-BOL collaborator's protocol [28] . Fish identification was determined to the species level whenever possible; using the following references [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] [44] [45] [46] [47] . Fish classification follows Eschmeyer (2014) [48] .", "cite_spans": [{"start": 144, "end": 148, "text": "[28]", "ref_id": "BIBREF28"}, {"start": 257, "end": 261, "text": "[29]", "ref_id": "BIBREF29"}, {"start": 262, "end": 266, "text": "[30]", "ref_id": "BIBREF30"}, {"start": 267, "end": 271, "text": "[31]", "ref_id": "BIBREF31"}, {"start": 272, "end": 276, "text": "[32]", "ref_id": "BIBREF32"}, {"start": 277, "end": 281, "text": "[33]", "ref_id": "BIBREF33"}, {"start": 282, "end": 286, "text": "[34]", "ref_id": "BIBREF34"}, {"start": 287, "end": 291, "text": "[35]", "ref_id": "BIBREF35"}, {"start": 292, "end": 296, "text": "[36]", "ref_id": "BIBREF36"}, {"start": 297, "end": 301, "text": "[37]", "ref_id": "BIBREF37"}, {"start": 302, "end": 306, "text": "[38]", "ref_id": "BIBREF38"}, {"start": 307, "end": 311, "text": "[39]", "ref_id": "BIBREF39"}, {"start": 312, "end": 316, "text": "[40]", "ref_id": "BIBREF40"}, {"start": 317, "end": 321, "text": "[41]", "ref_id": "BIBREF41"}, {"start": 322, "end": 326, "text": "[42]", "ref_id": "BIBREF42"}, {"start": 327, "end": 331, "text": "[43]", "ref_id": "BIBREF43"}, {"start": 332, "end": 336, "text": "[44]", "ref_id": "BIBREF44"}, {"start": 337, "end": 341, "text": "[45]", "ref_id": "BIBREF45"}, {"start": 342, "end": 346, "text": "[46]", "ref_id": "BIBREF46"}, {"start": 347, "end": 351, "text": "[47]", "ref_id": "BIBREF47"}, {"start": 382, "end": 398, "text": "Eschmeyer (2014)", "ref_id": "BIBREF48"}, {"start": 399, "end": 403, "text": "[48]", "ref_id": "BIBREF48"}], "ref_spans": []}, {"section": "Fish identification", "text": "Extraction, PCR amplification, and DNA sequencing Total genomic DNA was extracted from muscle or fin tissue from each specimen using an automated Glass Fiber protocol [49] . A 648-bp DNA sequence from the 5' region of COI [50] was subsequently amplified by PCR, with the following thermal cycling: initial denaturation at 95\u00b0C for 2 min, 35 cycles at 94\u00b0C for 30 s, 52\u00b0C for 30 s, and 72\u00b0C for 1min, with a final extension step at 72\u00b0C for 10 min. The 12.5 \u03bcl PCR reaction mixes included 6.25 \u03bcl of 10% trehalose, 2 \u03bcl of ultrapure water, ", "cite_spans": [{"start": 167, "end": 171, "text": "[49]", "ref_id": "BIBREF49"}, {"start": 222, "end": 226, "text": "[50]", "ref_id": "BIBREF50"}], "ref_spans": []}, {"section": "Sequence alignment and data analysis", "text": "Bidirectional sequences were assembled in SEQSCAPE version 2.1.1 (Applied Biosystems, Foster City, CA, USA), and manually edited. Assembled DNA sequences were submitted to GenBank (accession numbers: KU288760-KU289067).", "cite_spans": [], "ref_spans": []}, {"section": "Sequence alignment and data analysis", "text": "The COI assemble sequences were analyzed using Alignment Browser and Sequence Composition tools, both available in the Sequence Analysis Module of BOLD. Genetic distances among and within species were estimated using MEGA, version 6.0 [52] . The applied model of nucleotide substitution was estimated using the best fit substitution model tool [53] available in the same software. General time reversible substitution model (GTR) with a Gamma distribution of variable sites and invariable sites was the model that best fit the substitution pattern of the dataset with ti/tv = 3.48, \u03b1 = 0.83, and I = 0.56.", "cite_spans": [{"start": 235, "end": 239, "text": "[52]", "ref_id": "BIBREF52"}, {"start": 344, "end": 348, "text": "[53]", "ref_id": "BIBREF53"}], "ref_spans": []}, {"section": "Sequence alignment and data analysis", "text": "Genetic distances among and within species were also estimated using the Kimura two-parameter (K2P) substitution model [54] , implemented in the Distance Summary tool in BOLD. This is the standard model for DNA barcoding data sets and one of the most commonly used models to describe distance between species using COI. Since no significant differences were found in estimated distances and tree topologies between GTR and K2P models, the latter was chosen for comparison purposes. Haplotype identification was performed using DnaSP 5.10.01 [55] .", "cite_spans": [{"start": 119, "end": 123, "text": "[54]", "ref_id": "BIBREF54"}, {"start": 541, "end": 545, "text": "[55]", "ref_id": "BIBREF55"}], "ref_spans": []}, {"section": "Sequence alignment and data analysis", "text": "Neighbour Joining (NJ) and Maximum Likelihood (ML) trees based on K2P genetic distance were created to provide a graphic representation for the patterning of distance between species using the MEGA 6 software [52] . Node robustness was inferred with 1000 bootstrap replicates. Comparisons at the species level of the maximum intraspecific genetic distance with the minimum distance to the nearest neighbour were performed applying the BOLD's 'Barcoding Gap Analysis' tool.", "cite_spans": [{"start": 209, "end": 213, "text": "[52]", "ref_id": "BIBREF52"}], "ref_spans": []}, {"section": "Sequence alignment and data analysis", "text": "Three different clustering methods, Barcode Index Number (BIN) system [5] , Poisson Tree Processes (PTP) model [6] and Automatic Barcode Gap Discovery (ABGD) [7] , were used to confirm the concordance between sequence clusters and species designations by taxonomy. These methods were selected based on their general popularity and strong performance in previous studies [56, 57] . The three methods clustered COI sequence data into operational taxonomic units (OTUs) independent of prior taxonomic assignment. PTP reports were generated with default settings using the ML solution. ABGD clustering was carried out using the K2P distance model applying the following parameters: Pmin = 0.001, Pmax = 0.1; Steps 20; Nb bins = 20. We implemented a range of values for the gap width (X), between 0.1 and 1.5 to assess the consistency of inferred groups under varying gap width values.", "cite_spans": [{"start": 70, "end": 73, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 111, "end": 114, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 158, "end": 161, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 370, "end": 374, "text": "[56,", "ref_id": "BIBREF56"}, {"start": 375, "end": 378, "text": "57]", "ref_id": "BIBREF57"}], "ref_spans": []}, {"section": "Sequence alignment and data analysis", "text": "Sequence comparisons with previously known sequences and close species were performed by BLAST (Basic Local Alignment Search Tool; http://www.ncbi.nlm.nih.gov/BLAST) and the BOLD Identification System (IDS) (www.boldsystems.org).", "cite_spans": [], "ref_spans": []}, {"section": "Sequence alignment and data analysis", "text": "Diagnostic characters among sets of sequences were examined using BOLD's Diagnostic Character analysis tool. Concordance between BINs assignment and species identification by classical taxonomy was analyzed by the 'BIN Discordance Report' sequence analysis tool [5] available on BOLD. The BIN Discordance Report facilitates this check by comparing the taxonomy on selected records against all others in the BINs they are associated with. Specimens corresponding to discordant BINs were re-evaluated by a specialist in order to verify our data and correct potential misidentifications.", "cite_spans": [{"start": 262, "end": 265, "text": "[5]", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "Results", "text": "Taxonomic identification of the 308 fish specimens resulted in 79 species (71 Genera, 35 Families and 10 Orders) from the Lower Paran\u00e1 River (Fig 2; S1 Table) . All collected species belong to the Class Actinopterygii with the exception of Potamotrygon motoro that belongs to the Class Chondrichthyes. Eight out of 71 genera (11.3%) were represented by more than one species (Astyanax, Characidium, Odontesthes, Pimelodus, Ageneiosus, Brycon, Crenicichla, and Cnesterodon). The number of individuals per species ranged from 1 to 10 (mean 4) with 33 species represented by more than 4 individuals and 16 species represented by one specimen.", "cite_spans": [], "ref_spans": [{"start": 141, "end": 158, "text": "(Fig 2; S1 Table)", "ref_id": "FIGREF0"}]}, {"section": "Results", "text": "Most species of commercial interest were represented in this study, such as the large migratory species Prochilodus lineatus, Salminus brasiliensis, Pseudoplatystoma corruscans, Brycon orbignyanus and Leporinus obtusidens. Recreational interest species such as P. motoro, Hoplias malabaricus, Odontesthes bonariensis, Gymnotus inaequilabiatus, Eigenmannia trilineata, and Hoplosternum littorale were also included. G. inaequilabiatus and E. trilineata are widely used as live bait for sport fishing [22] . Most species belong to the orders Siluriformes and Characiformes in agreement with previous reports for Neotropics [58, 59] . In addition, species belonging to the orders Clupeiformes (Lysengraulis grossidens, Ramnogaster melanostoma, and Pellona flavipinnis) and Atheriniformes (O. bonariensis) that migrate from estuarine or marine environments to freshwater habitats were identified. Cyprinus carpio, an exotic species, was also reported.", "cite_spans": [{"start": 499, "end": 503, "text": "[22]", "ref_id": "BIBREF22"}, {"start": 621, "end": 625, "text": "[58,", "ref_id": "BIBREF58"}, {"start": 626, "end": 629, "text": "59]", "ref_id": "BIBREF59"}], "ref_spans": []}, {"section": "DNA barcoding-specimen identification", "text": "COI amplified DNA fragments (~648 pb) were obtained from all 308 specimens. No stop codons, insertions, or deletions were found in any of the amplified sequences, suggesting that all of them constitute functional mitochondrial COI sequences. No NUMTs (nuclear DNA sequences originating from mitochondrial DNA sequences) amplifications were detected. Average nucleotide frequencies were C (27.53%), T (29.40%), A (24.82%), and G (18.04%), similar to those previously reported in other studies [60] .", "cite_spans": [{"start": 492, "end": 496, "text": "[60]", "ref_id": "BIBREF60"}], "ref_spans": []}, {"section": "DNA barcoding-specimen identification", "text": "Relationships among sequences were represented by ML (Fig 3) and NJ (S1 Fig) trees. Both K2P ML and NJ trees grouped sequences of the same taxonomically identified species in no overlapping clusters, with the exception of two species of the genera Odontesthes (O. bonariensis and O. perugiae) which were present in the same COI cluster. Species clusters were supported with boostrap values of 100%. Deep intraspecific divergences were observed in the NJ and K2P ML analysis among some sequences of H. malabaricus, B. orbignyanus, P. motoro and Megalonema argentinum species (Fig 3) .", "cite_spans": [], "ref_spans": [{"start": 53, "end": 60, "text": "(Fig 3)", "ref_id": "FIGREF2"}, {"start": 574, "end": 581, "text": "(Fig 3)", "ref_id": "FIGREF2"}]}, {"section": "DNA barcoding-specimen identification", "text": "Genetic distances increased from lower to higher taxonomic levels. The average K2P genetic distance between specimens was 0.53% within species, 12.26% within genera and 19.61% within families (Table 1 ). The average K2P genetic distance within conspecific specimens was 23-fold lower than the average value found in congeneric species.", "cite_spans": [], "ref_spans": [{"start": 192, "end": 200, "text": "(Table 1", "ref_id": "TABREF1"}]}, {"section": "DNA barcoding-specimen identification", "text": "Distances between species ranged from 0.00% to 19.98% (Table 1) , considering the two species of the genus Odontesthes with a very low genetic distance value ranging from 0% to 0.62% (Table 2 ). For the other congeneric species, minimum interspecific distances ranged from 4.06% in Pimelodus genus to 19.48% in Crenicichla genus (Table 2) .", "cite_spans": [], "ref_spans": [{"start": 54, "end": 63, "text": "(Table 1)", "ref_id": "TABREF1"}]}, {"section": "DNA barcoding-specimen identification", "text": "A barcode gap of 2.5% between conspecifics and congenerics K2P distances was observed for most analyzed data (Fig 4) . In 95% of species analysed the maximum intraspecific distance was 1.56%. The remaining 5% presented intraspecific distances higher than 2%: H. malabaricus (7.59%), B. orbignyanus (6.68%), P. motoro (3.32%), and M. argentinum (2.19%) (Fig 4A and  4A' ). The minimum genetic distance between species was 4.06% in 99% of species analysed. Only Odontesthes genus presented an intraspecific distance lower than 0.62% ( Fig 4B and 4B' ).", "cite_spans": [], "ref_spans": [{"start": 109, "end": 116, "text": "(Fig 4)", "ref_id": "FIGREF3"}, {"start": 352, "end": 368, "text": "(Fig 4A and  4A'", "ref_id": "FIGREF3"}, {"start": 533, "end": 547, "text": "Fig 4B and 4B'", "ref_id": "FIGREF3"}]}, {"section": "DNA barcoding-specimen identification", "text": "The species discrimination power of DNA barcoding was analysed by plotting the maximum intraspecific distance of each species against its minimum distance to the nearest neighbour (Fig 5) . For whole data set, with the exception of Odontesthes species sequences, genetic The K2P/ML tree of 308 COI sequences for 79 morphologically identified freshwater fish species from Lower Paran\u00e1 River in Argentina. NJ tree was divided into two parts from top to bottom in order from left to right. Bootstrap values >90 for 1000 replicates are shown at each branch. The number of specimens analyzed for each species is shown between brackets. Solid triangles represent clusters of multiple specimens, with height proportional to specimen number and the horizontal width proportional to the genetic variation within each cluster. In gray are shown branches of species with high intraspecific genetic divergence and species with overlapping clusters. Columns next to the tree represent presence of recognition for each clustering method while boxes highlights the differences among methods. Specimens of Brycon orbignyanus with high genetic divergence that were re-classified as B. cf. hilarii are highlighted with \"*\".", "cite_spans": [], "ref_spans": []}, {"section": "DNA barcoding-specimen identification", "text": "distances of each species to their nearest neighbours were higher than the maximum intraspecific genetic distance, showing that COI barcode could discriminate 97% of species analysed from Lower Paran\u00e1 River (Fig 5) .", "cite_spans": [], "ref_spans": []}, {"section": "Species delimitation", "text": "For reliable COI species assignment, all data set was analyzed by three clustering methods (BIN, ABGD and PTP) in order to confirm the concordance between sequence clusters and species designations through taxonomy.", "cite_spans": [], "ref_spans": []}, {"section": "Species delimitation", "text": "Congruent results were obtained among the three clustering methods tested in most cases. Records were assigned to 79 BINs corresponding to 79 species identified by taxonomy experts (Fig 3) . One species (Hoplosternum littorale) had no BIN, since it did not meet BOLD minimum requirements to be included in this analysis. Two species shared one same BIN (O. bonariensis and O. perugiae). New BINs for G. inaequilabiatus, P. motoro, Crenicichla vittata, Serrapinus piaba, M. argentinum, and Pachyurus bonariensis were generated. G. inaequilabiatus and P. motoro have already had records with a different BIN number. The description of new BINs for species that already had records with a different BIN number could reveal possible cryptic fish species or misidentification.", "cite_spans": [], "ref_spans": [{"start": 181, "end": 188, "text": "(Fig 3)", "ref_id": "FIGREF2"}]}, {"section": "Species delimitation", "text": "Differences between clustering methods were found in C. decemmaculatus-C. cf. raddai cluster, in which BIN and ABGD reported two groups while PTP reported only one (Fig 3) .", "cite_spans": [], "ref_spans": [{"start": 164, "end": 171, "text": "(Fig 3)", "ref_id": "FIGREF2"}]}, {"section": "Species delimitation", "text": "At least two clustering methods separated three of the four taxonomic identified species with higher intraspecific divergence into two different clusters, suggesting that these three groups deserved further investigation (H. malabaricus, B. orbignyanus, and P. motoro). In the case of M. argentinum, only one cluster was defined by the three clustering methods. Little information is available about M. argentinum biology, geographical distribution and conservation status, and no molecular data has been reported until now.", "cite_spans": [], "ref_spans": []}, {"section": "Special cases", "text": "Two clusters for one taxonomic identified species. For further analyses of H. malabaricus, B. orbignyanus, and P. motoro cases, K2P-NJ trees were performed (Fig 6) using COI and Amazonas River (AMAZ, [61] ). NJ tree was rooted using an H. intermedius sequence from BSB-BOLD project. Results showed that the six sequences that grouped together in the general tree (Fig 3 and Fig 6I-a cluster A) clustered with sequences of H. malabaricus from Salado River basin (Fig 6I-b) . This cluster presented a maximum divergence of 0.3% and conformed only one BIN (BOLD:AAZ3734). The sequence in a separated branch at the main tree (Fig 3  and Fig 6I-a cluster B) , clustered with H. malabaricus sequences from Upper Parana River and Amazonas River basins with a maximum divergence of 0.5%, conforming another BIN (BOLD: AAB1732) (Fig 6I-b) . In addition, this sequence belonged to a specimen with different phenotypic characteristics easily recognized by fishermen (H. malabaricus of \"small head\", Fig 6I-a,  photographs) . For sampling areas covered in this work only H. malabaricus has been cited. Our results showed that deep genetic divergence for H. malabaricus also occurred in a smaller geographic scale since all individuals were sampled in the same area. Genetic and/or morphological-morphometric studies have not been reported yet for H. malabaricus from Lower Paran\u00e1 River. Therefore, information obtained in this work would provide the kickoff for future research on this species complex.", "cite_spans": [{"start": 200, "end": 204, "text": "[61]", "ref_id": "BIBREF61"}], "ref_spans": [{"start": 156, "end": 163, "text": "(Fig 6)", "ref_id": "FIGREF4"}, {"start": 363, "end": 393, "text": "(Fig 3 and Fig 6I-a cluster A)", "ref_id": "FIGREF2"}, {"start": 461, "end": 471, "text": "(Fig 6I-b)", "ref_id": "FIGREF4"}, {"start": 621, "end": 652, "text": "(Fig 3  and Fig 6I-a cluster B)", "ref_id": "FIGREF2"}, {"start": 819, "end": 829, "text": "(Fig 6I-b)", "ref_id": "FIGREF4"}, {"start": 988, "end": 1011, "text": "Fig 6I-a,  photographs)", "ref_id": "FIGREF4"}]}, {"section": "Special cases", "text": "The Brycon genus case. Only published sequences (n = 33) of six South American species were used: B. orbignyanus from Upper Paran\u00e1 River (BOLD project code FUPR), Brycon melanopterus from Amazonas River and Brycon orthotaenia, Brycon opalinus, Brycon insignis and Brycon nattereri from Sao Francisco River (BOLD project code BSB). Comparative NJ sub-tree showed that seven COI sequences of B. orbignyanus specimens that grouped together in the general tree (Fig 3 and Fig 6II-a-cluster A) clustered with B. orbignyanus sequences from Upper Paran\u00e1 River (Fig 6II-b) . This group presented a mean K2P distance of 0.07% and a maximum distance of 0.16%, and belonged to the same BIN (BOLD:AAE8065). Interestingly, the other two specimens that conformed cluster B at the NJ tree in Fig 6II-a, conformed a cohesive separate cluster with a different BIN number (BOLD:AAE0479) (Fig 6II-b) . In order to determine species-specific status, both sequences were compared by BLAST against the NCBI nr database and by IDS tool against BOLD database. Both sequences displayed a 99% identity with B. hilarii sequences and over 99.6% of similarity by IDS tool, showing that the vouchers might be misidentified. Only photographic vouchers were available for these two individuals, which were revised and compared with all B. orbignyanus photographic vouchers. Taking into account sequence comparison results and differences found between photographic vouchers, both BOLD records were re classified as Brycon cf. hilarii in BOLD database and in NJ tree (Fig  3) . Although B. hilarii distribution corresponds to Paraguay River Basin [62] , our result showed that B. hilarii could reach the Paran\u00e1 River near the mouth of the Paraguay River (Fig  1, sampling site 2 ). However, a higher sampling effort is necessary to confirm this observation.", "cite_spans": [{"start": 1614, "end": 1618, "text": "[62]", "ref_id": "BIBREF62"}], "ref_spans": [{"start": 457, "end": 488, "text": "(Fig 3 and Fig 6II-a-cluster A)", "ref_id": "FIGREF2"}, {"start": 553, "end": 564, "text": "(Fig 6II-b)", "ref_id": "FIGREF4"}, {"start": 777, "end": 787, "text": "Fig 6II-a,", "ref_id": "FIGREF4"}, {"start": 869, "end": 880, "text": "(Fig 6II-b)", "ref_id": "FIGREF4"}, {"start": 1534, "end": 1542, "text": "(Fig  3)", "ref_id": "FIGREF2"}, {"start": 1721, "end": 1745, "text": "(Fig  1, sampling site 2", "ref_id": "FIGREF0"}]}, {"section": "Special cases", "text": "The P. motoro case. Two clusters were observed at the main tree with deep intraspecific divergences between them (Fig 3 and Fig 6III-a) . One cluster (A) grouped three sequences (BIN BOLD:ACG6814) while the other one (B), included only one sequence (BIN BOLD: AAB5375). Comparison analysis of COI sequences was performed using sequences of three different species from Upper Paran\u00e1 River (P. motoro and Potamotrygon falkneri of BOLD project code FUPR, and Potamotrygon hystrix [63] ). Comparison analysis (Fig 6III-b) revealed that the sequence at cluster B grouped with P. motoro and P. falkneri sequences from the Upper Paran\u00e1 River conforming a single BIN (BOLD:AAB5375). The other three P. motoro sequences (cluster A) were displayed in a separated branch, without genetic divergence among them, and constituted a new exclusive BIN (BOLD:ACG6814). Interestingly, the three P. motoro sequences in cluster A did not cluster to any other known species of the genus with reported COI sequences. A possible explanation for this result could be the presence of a new species that share some morphological characters and pattern coloration with P. motoro, which has led to misidentification. Vouchers revision was not possible in this case since only photographic vouchers were available for these individuals. More than one species for one cluster: Species with interspecific genetic divergence values in the same range than intraspecific genetic divergence values: O. perugiae and O. bonariensis. COI interspecific genetic K2P distance between O. perugiae and O. bonariensis was in the same range as intraspecific distances recorded for O. bonariensis. BOLD's Diagnostic Character analysis showed that there was not any exclusive nucleotide for species. Six haplotypes were observed among O. perugiae and O. bonariensis sequences, two of them were shared between specimens from both species (data not shown). Moreover, COI haplotypes were shared also with other Odontesthes species, such as O. argentinensis and O. mirinensis (Villanova GV not published results).", "cite_spans": [{"start": 477, "end": 481, "text": "[63]", "ref_id": "BIBREF63"}], "ref_spans": [{"start": 113, "end": 135, "text": "(Fig 3 and Fig 6III-a)", "ref_id": "FIGREF2"}, {"start": 505, "end": 517, "text": "(Fig 6III-b)", "ref_id": "FIGREF4"}]}, {"section": "Special cases", "text": "Barcode Index Numbers (BINs) and taxonomic concordance. To check the correlation degree between species designations by taxonomy and assigned BINs, all sequences were analyzed by the 'BIN Discordance Report' tool available within the \"Sequence Analysis\" module of BOLD. As a result 79 BINS were identified from 291 records that met the minimum requirements to be included in the analysis. Taxonomic concordance was found in 113 records of 27 BINs (34.2%), 1 record (Xyliphius sp.) was singleton (BINs with single specimens) (1.2%) and 177 records of 51 BINs (64.6%) were conflictive, indicating that at least two different taxonomic assignments were found in BOLD database within a single BIN.", "cite_spans": [], "ref_spans": []}, {"section": "Special cases", "text": "Among the 51 discordant BINS, 6 were at the Family level (17 conflicting records), 16 at the Genus level (60 conflicting records) and 29 at the species level (100 conflicting records). After an exhaustive revision by two independent groups of fish taxonomists, who worked with identification reliability level 2 according to the Fish-BOL collaborator's protocol [28] , the 17 conflicting records at the Family level as well as the 60 records at the Genus level were resolved. In most of these cases, the discordant entries were caused by misidentifications in previous BOLD data projects. Out of 29 discordant BINS at the species level, 15 were shown to exhibit 'no true' : values obtained using individuals grouped in the same BIN *: the discordance was probably caused by misidentifications **: the discordance was probably caused by COI lower species-specific power of discrimination ***: the discordance COI sequences were not published or available in public BOLD projects ****: the discordance was probably caused by a combination of tree previous cases.", "cite_spans": [{"start": 362, "end": 366, "text": "[28]", "ref_id": "BIBREF28"}], "ref_spans": []}, {"section": "Special cases", "text": "doi:10.1371/journal.pone.0157419.t003", "cite_spans": [], "ref_spans": []}, {"section": "Special cases", "text": "discordances, as the discordant BINS were caused by lack of taxonomic determination at species level in previous BOLD projects (S2 Table) such as species identified as sp. or cf. (e.g. Potamotrygon sp., Pimelodella cf. cristata, etc.). There were 28 conflicting taxa within the 14 \"true\" discordant BINS. Among these conflicting taxa common characteristics were found and records were classified in four groups in order to explain the discordance among records within a BIN (Table 3) : Group I ( \u00c3 ): the discordance was probably caused by misidentifications,; Group II ( \u00c3\u00c3 ): the discordance was probably caused by COI lower species-specific power of discrimination; Group III ( \u00c3\u00c3\u00c3 ): the discordance could not be analyzed comparing involved records since COI sequences were not available in public BOLD projects. BIN discordance analysis in BOLD is performed using all record uploaded to BOLD database. However a high proportion of these records belonged to projects that are not public and sequences were not available to be used. Group IV ( \u00c3\u00c3\u00c3\u00c3 ): the discordance was probably caused by a combination of tree previous cases. For each conflicting sequence data, the maximum intraspecific distance and nearest neighbour distance were calculated and geographic distribution of specimens and references were added when available (Table 3) .", "cite_spans": [], "ref_spans": [{"start": 474, "end": 483, "text": "(Table 3)", "ref_id": "TABREF2"}, {"start": 1332, "end": 1341, "text": "(Table 3)", "ref_id": "TABREF2"}]}, {"section": "Discussion", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Barcoding success", "text": "The present study represents the first molecular survey of Lower Paran\u00e1 River fish diversity corresponding to the Southernmost Neotropical region. Seventy nine (43%) of the 185 fish species described for the Lower Paran\u00e1 River were assessed in this work using COI barcodes from a subarea of this river. The observed COI genetic distances between conspecifics and congenerics (means: 0.53% and 12.26% respectively) for Lower Paran\u00e1 River fish were within the range of previously reported values from fishes of freshwater ecosystems [8, 10, 27, 70] . All sequences of the same species formed high bootstrap-supported clusters without any overlap between species, even in species within the same genera, with the exception of Odontesthes species. Nine new records not previously studied by COI barcodes were generated and incorporated to the BOLD data system (C. cf. raddai, Schizodon platae \u00c3 , Otocinclus arnoldi, Parastegophilus maculatus \u00c3 , Pseudohemiodon laticeps, M. argentinum \u00c3 , Auchenipterus nigripinnis, B. cf. hilarii and Xyliphius sp.), three of which are endemic species of Argentina ( \u00c3 ). Our study included species that migrate from estuarine or marine environments to freshwater habitats. Reproductive activity was reported for some of them in the Lower Paran\u00e1 River (e.g. L. grossidens [71] ). In this regards, COI barcode reference library will contribute to future freshwater ichthyoplankton identification and life cycle monitoring.", "cite_spans": [{"start": 531, "end": 534, "text": "[8,", "ref_id": "BIBREF7"}, {"start": 535, "end": 538, "text": "10,", "ref_id": "BIBREF9"}, {"start": 539, "end": 542, "text": "27,", "ref_id": "BIBREF27"}, {"start": 543, "end": 546, "text": "70]", "ref_id": "BIBREF70"}, {"start": 1303, "end": 1307, "text": "[71]", "ref_id": "BIBREF71"}], "ref_spans": []}, {"section": "Species delimitation and data reliability", "text": "Molecular data provide a valuable resource for preliminary species delimitations or validating traditional phenotype-based species circumscriptions [7, 72] . In our study, all data set was analyzed by three clustering methods and numerous experts in order to confirm the concordance between sequence clusters and species designations by taxonomy. Analysis of the results obtained by distinct clustering methods offer an additional level of confidence in the inferred OTUs in Lower Paran\u00e1 River fish. Two species (H. malabaricus and P. motoro) displayed a deep intra-specific genetic distance (>2%) and the corresponding sequences grouped into two different clusters in each one. The genus Hoplias is distributed throughout many hydrographic systems of South America and has 11 recognized species. At least 3 of them are present in Argentina [73, 74] . Only H. malabaricus was described in the Lower Parana River. H. malabaricus is considered by many authors as a complex of cryptic species that require a profound taxonomic revision [61, 75] . Based on COI sequence analysis, a strong geographic structure for H. malabaricus from distant hydrographic basins in South America was previously proposed [27] . However, specimens obtained in this study from the same Paran\u00e1 River area also present high COI divergence supporting the hypothesis of the existence of a cryptic species in the Lower Paran\u00e1 River.", "cite_spans": [{"start": 148, "end": 151, "text": "[7,", "ref_id": "BIBREF6"}, {"start": 152, "end": 155, "text": "72]", "ref_id": "BIBREF72"}, {"start": 841, "end": 845, "text": "[73,", "ref_id": "BIBREF73"}, {"start": 846, "end": 849, "text": "74]", "ref_id": "BIBREF74"}, {"start": 1033, "end": 1037, "text": "[61,", "ref_id": "BIBREF61"}, {"start": 1038, "end": 1041, "text": "75]", "ref_id": "BIBREF75"}, {"start": 1199, "end": 1203, "text": "[27]", "ref_id": "BIBREF27"}], "ref_spans": []}, {"section": "Species delimitation and data reliability", "text": "At least six freshwater stingrays species of the genera Potamotrygon are present in the Lower Parana River (P. schuhmacheri, P. hystrix, P amandae, P. brachyura, P. falknerii, and P. motoro). Recently, a new Potamotrygon sp. was described by Almir\u00f3n et al. [18] , in the Paran\u00e1 Delta area, which could not be assigned to previously described species. Among them, P. motoro is the most widely distributed species of the family Potamotrygonidae, present in most freshwater systems in South America [63, 76, 77] . The widespread distribution of the genera Potamotrygon, together with significant variation in some morphological characters (e.g., dorsal disc coloration) among populations of different basins, and even in closely adjacent areas, has led some authors to indicate that a taxonomic subdivision of P. motoro may be necessary [77, 78] . In the case of Lower Paran\u00e1 River stingrays, only COI sequences for P. motoro are available. Although low intra and interspecific variation have been reported among Potamotrygonidae family members in the Upper Paran\u00e1 River basin [10, 79, 80] , our results showed a high COI divergence between P. motoro specimens. This scenario claims a more extensive and profound taxonomic revision along with DNA sequences analysis for Potamotrygon genera that inhabits the Lower Parana River.", "cite_spans": [{"start": 257, "end": 261, "text": "[18]", "ref_id": "BIBREF17"}, {"start": 496, "end": 500, "text": "[63,", "ref_id": "BIBREF63"}, {"start": 501, "end": 504, "text": "76,", "ref_id": "BIBREF76"}, {"start": 505, "end": 508, "text": "77]", "ref_id": "BIBREF77"}, {"start": 834, "end": 838, "text": "[77,", "ref_id": "BIBREF77"}, {"start": 839, "end": 842, "text": "78]", "ref_id": "BIBREF78"}, {"start": 1074, "end": 1078, "text": "[10,", "ref_id": "BIBREF9"}, {"start": 1079, "end": 1082, "text": "79,", "ref_id": "BIBREF79"}, {"start": 1083, "end": 1086, "text": "80]", "ref_id": "BIBREF80"}], "ref_spans": []}, {"section": "Species delimitation and data reliability", "text": "Results obtained in this work, and previous reports [10, 11, 22] state the existence of hidden diversity in many species and suggest that Neotropical species richness is still underestimated.", "cite_spans": [{"start": 52, "end": 56, "text": "[10,", "ref_id": "BIBREF9"}, {"start": 57, "end": 60, "text": "11,", "ref_id": "BIBREF10"}, {"start": 61, "end": 64, "text": "22]", "ref_id": "BIBREF22"}], "ref_spans": []}, {"section": "Importance of reference libraries", "text": "The success of using barcoding for species identification strongly depends on the presence of high-quality reference sequences available in public sequence libraries and the existence of specimen vouchers correctly identified. DNA barcode databases such as BOLD, have implemented minimal quality criteria for barcode data acquisition and generation [24] . However, reference specimen misidentification appears to be the single largest factor contributing to errors in the FISH-BOL data set [81] . Barcoding methodology and a careful examination of specimens allowed us to resolve apparent outliers and cluster conflicts in the FISH-BOL data set. This situation also highlights the importance of checking the taxonomic identity in the light of COI information previous to its upload in public sequence databases. This was the case for Brycon cf. hilarii, previously characterized as B. Orbignyanus, as well as for several detected BIN discordances based in misidentification. In these cases, the analyses of COI sequences correctly separates species pairs obtained in previous barcode studies on these species (e.g. Ageneiosus inermis vs. Ageneiosus ucayalensis [64] ). COI sequence comparisons was not able to discriminate between two species of the genera Odontesthes (O. bonariensis and O. perugie). Moreover, shared haplotypes between specimens of both species were found (data not shown). This result is consistent with a recent radiation process in the genera Odontesthes as proposed by Garcia et al. (2014) [67] and Campanella et al. (2015) [82] , and states that COI information could be used only for genera identification.", "cite_spans": [{"start": 349, "end": 353, "text": "[24]", "ref_id": "BIBREF24"}, {"start": 490, "end": 494, "text": "[81]", "ref_id": "BIBREF81"}, {"start": 1161, "end": 1165, "text": "[64]", "ref_id": "BIBREF64"}, {"start": 1513, "end": 1517, "text": "[67]", "ref_id": "BIBREF67"}, {"start": 1522, "end": 1546, "text": "Campanella et al. (2015)", "ref_id": "BIBREF82"}, {"start": 1547, "end": 1551, "text": "[82]", "ref_id": "BIBREF82"}], "ref_spans": []}, {"section": "Importance of reference libraries", "text": "The current COI reference library provides highly reliable DNA and vouchers exemplars for 97.5% of the fish species investigated and it can be confidently used as a benchmark for identification of almost 50% of Lower Parana River fish species. This COI barcode library will be especially important for fish biodiversity monitoring, for sustainable exploitation of fishing resources, for reproductive biology studies and ecological monitoring, among other applications.", "cite_spans": [], "ref_spans": []}, {"section": "Importance of reference libraries", "text": "Supporting Information ", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Barcoding animal life: cytochrome c oxidase subunit 1 divergences among closely related species", "authors": [{"first": "Pdn", "middle": [], "last": "Hebert", "suffix": ""}, {"first": "S", "middle": [], "last": "Ratnasingham", "suffix": ""}], "year": 2003, "venue": "Proceedings of the Royal Society", "link": "6517747"}, "BIBREF1": {"title": "Biological identifications through DNA barcodes. Proceedings of the Royal Society", "authors": [{"first": "Pdn", "middle": [], "last": "Hebert", "suffix": ""}, {"first": "A", "middle": [], "last": "Cywinska", "suffix": ""}, {"first": "S", "middle": ["L"], "last": "Ball", "suffix": ""}, {"first": "J", "middle": ["R"], "last": "De Waard", "suffix": ""}], "year": 2003, "venue": "", "link": null}, "BIBREF2": {"title": "Error Rates Based on Comprehensive Sampling", "authors": [{"first": "C", "middle": ["P"], "last": "Meyer", "suffix": ""}, {"first": "G", "middle": [], "last": "Paulay", "suffix": ""}, {"first": "", "middle": [], "last": "Barcoding", "suffix": ""}], "year": 2005, "venue": "PLoS Biology", "link": null}, "BIBREF3": {"title": "Ten species in one: DNA barcoding reveals cryptic species in the Neotropical skipper butterfly Astraptes fulgerator", "authors": [{"first": "Pdn", "middle": [], "last": "Hebert", "suffix": ""}, {"first": "E", "middle": ["H"], "last": "Penton", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Burns", "suffix": ""}, {"first": "D", "middle": ["H"], "last": "Janzen", "suffix": ""}, {"first": "W", "middle": [], "last": "Hallwachs", "suffix": ""}], "year": 2004, "venue": "Proceedings of the National Academy of Sciences USA", "link": "3905370"}, "BIBREF4": {"title": "A DNA-Based Registry for All Animal Species: The Barcode Index Number (BIN) System", "authors": [{"first": "S", "middle": [], "last": "Ratnasingham", "suffix": ""}, {"first": "Pdn", "middle": [], "last": "Hebert", "suffix": ""}], "year": 2013, "venue": "PLoS ONE", "link": "3894046"}, "BIBREF5": {"title": "A general species delimitation method with applications to phylogenetic placements", "authors": [{"first": "J", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "P", "middle": [], "last": "Kapli", "suffix": ""}, {"first": "P", "middle": [], "last": "Pavlidis", "suffix": ""}, {"first": "A", "middle": [], "last": "Stamatakis", "suffix": ""}], "year": 2013, "venue": "Bioinformatics", "link": "15141910"}, "BIBREF6": {"title": "Automatic Barcode Gap Discovery for primary species delimitation", "authors": [{"first": "N", "middle": [], "last": "Puillandre", "suffix": ""}, {"first": "A", "middle": [], "last": "Lambert", "suffix": ""}, {"first": "S", "middle": [], "last": "Brouillet", "suffix": ""}, {"first": "Achaz", "middle": ["G"], "last": "Abgd", "suffix": ""}], "year": 2012, "venue": "Molecular Ecology", "link": "135371"}, "BIBREF7": {"title": "Identifying Canadian freshwater fishes through DNA barcodes", "authors": [{"first": "N", "middle": [], "last": "Hubert", "suffix": ""}, {"first": "R", "middle": [], "last": "Hanner", "suffix": ""}, {"first": "E", "middle": [], "last": "Holm", "suffix": ""}, {"first": "N", "middle": ["E"], "last": "Mandrak", "suffix": ""}, {"first": "E", "middle": [], "last": "Taylor", "suffix": ""}, {"first": "M", "middle": [], "last": "Burridge", "suffix": ""}], "year": 2008, "venue": "PLoS ONE", "link": "7776879"}, "BIBREF8": {"title": "Deep barcode divergence in Brazilian freshwater fishes: the case of Sao Francisco River Basin", "authors": [{"first": "D", "middle": ["C"], "last": "Carvalho", "suffix": ""}, {"first": "Daa", "middle": [], "last": "Oliveira", "suffix": ""}, {"first": "P", "middle": ["S"], "last": "Pompeu", "suffix": ""}, {"first": "C", "middle": ["G"], "last": "Leal", "suffix": ""}, {"first": "C", "middle": [], "last": "Oliveira", "suffix": ""}, {"first": "R", "middle": [], "last": "Hanner", "suffix": ""}], "year": 2011, "venue": "Mitochondrial DNA", "link": "3917577"}, "BIBREF9": {"title": "Can DNA barcoding accurately discriminate megadiverse Neotropical freshwaterfish fauna?", "authors": [{"first": "Lhg", "middle": [], "last": "Pereira", "suffix": ""}, {"first": "R", "middle": [], "last": "Hanner", "suffix": ""}, {"first": "F", "middle": [], "last": "Foresti", "suffix": ""}, {"first": "C", "middle": [], "last": "Oliveira", "suffix": ""}], "year": 2013, "venue": "BMC Genetics", "link": "7444914"}, "BIBREF10": {"title": "DNA Barcoding in Pencilfishes (Lebiasinidae: Nannostomus) Reveals Cryptic Diversity across the Brazilian Amazon", "authors": [{"first": "D", "middle": ["C"], "last": "Benzaquem", "suffix": ""}, {"first": "C", "middle": [], "last": "Oliveira", "suffix": ""}, {"first": "Silva", "middle": [], "last": "Da", "suffix": ""}, {"first": "J", "middle": [], "last": "Batista", "suffix": ""}, {"first": "J", "middle": [], "last": "Zuanon", "suffix": ""}, {"first": "Rebelo", "middle": [], "last": "Porto", "suffix": ""}, {"first": "J", "middle": ["I"], "last": "", "suffix": ""}], "year": 2015, "venue": "Plos ONE", "link": "5045428"}, "BIBREF11": {"title": "Current state of knowledge regarding the world's wetlands and their future under global climate change: a synthesis", "authors": [{"first": "W", "middle": ["J"], "last": "Junk", "suffix": ""}, {"first": "S", "middle": [], "last": "An", "suffix": ""}, {"first": "C", "middle": ["M"], "last": "Finlayson", "suffix": ""}, {"first": "B", "middle": [], "last": "Gopal", "suffix": ""}, {"first": "J", "middle": [], "last": "Kvet", "suffix": ""}, {"first": "S", "middle": ["A"], "last": "Mitchell", "suffix": ""}], "year": 2013, "venue": "Aquatic Science", "link": "18008349"}, "BIBREF12": {"title": "Menu-Marque S. Peces de la regi\u00f3n sureste de los Andes y sus probables relaciones biogeogr\u00e1ficas actuales", "authors": [{"first": "G", "middle": [], "last": "Arratia", "suffix": ""}, {"first": "M", "middle": ["B"], "last": "Pe\u00f1afort", "suffix": ""}], "year": 1983, "venue": "Deserta", "link": null}, "BIBREF13": {"title": "Panorama sin\u00f3ptico sobre la ictiofauna, la pesca y la piscicultura en los r\u00edos de la Cuenca del Plata, con especial referencia al Paran\u00e1", "authors": [{"first": "A", "middle": ["A"], "last": "Bonetto", "suffix": ""}], "year": 1998, "venue": "Revista de Ictiolog\u00eda", "link": null}, "BIBREF14": {"title": "Do aquatic plant assemblages in the Paran\u00e1 River change along the river's length?", "authors": [{"first": "J", "middle": ["J"], "last": "Neiff", "suffix": ""}, {"first": "S", "middle": [], "last": "Casco", "suffix": ""}, {"first": "Eka", "middle": [], "last": "Mari", "suffix": ""}, {"first": "Di", "middle": [], "last": "Rienzo", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Poi", "suffix": ""}], "year": 2014, "venue": "Aquatic Botany", "link": "84058877"}, "BIBREF15": {"title": "Temperate freshwater wetlands: types, status, and threats", "authors": [{"first": "M", "middle": ["M"], "last": "Brinson", "suffix": ""}, {"first": "A", "middle": ["I"], "last": "Malv\u00e1rez", "suffix": ""}], "year": 2002, "venue": "Environmental Conservation", "link": "86552762"}, "BIBREF16": {"title": "Ichthyological ecoregions of Argentina. Probiota, Serie Documentos N\u00b01", "authors": [{"first": "H", "middle": ["L"], "last": "L\u00f3pez", "suffix": ""}, {"first": "C", "middle": ["C"], "last": "Morgan", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Montenegro", "suffix": ""}], "year": 2002, "venue": "", "link": null}, "BIBREF17": {"title": "Gu\u00eda de los peces del Parque Nacional Pre-Delta", "authors": [{"first": "A", "middle": [], "last": "Almir\u00f3n", "suffix": ""}, {"first": "J", "middle": [], "last": "Casciotta", "suffix": ""}, {"first": "L", "middle": [], "last": "Ciotec", "suffix": ""}, {"first": "P", "middle": [], "last": "Giorgis", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF18": {"title": "Buenos Aires: Administraci\u00f3n de Parques Nacionales", "authors": [], "year": 2005, "venue": "", "link": null}, "BIBREF19": {"title": "Biogeograf\u00eda de los peces continentales de la Argentina", "authors": [{"first": "H", "middle": ["L"], "last": "L\u00f3pez", "suffix": ""}, {"first": "A", "middle": ["M"], "last": "Miquelarena", "suffix": ""}], "year": 2005, "venue": "Mexico: Facultad de Ciencias", "link": null}, "BIBREF20": {"title": "Proceedings of International Large River Symposium).Ontario: Canadian Special Publication of Fisheries and Aquatic Sciences 116", "authors": [{"first": "R", "middle": [], "last": "Quir\u00f3s", "suffix": ""}, {"first": "S", "middle": [], "last": "Cuch", "suffix": ""}], "year": 1989, "venue": "", "link": null}, "BIBREF21": {"title": "Los peces del corredor fluvial Paran\u00e1-Paraguay", "authors": [{"first": "S", "middle": [], "last": "Sverlij", "suffix": ""}, {"first": "J", "middle": [], "last": "Liotta", "suffix": ""}, {"first": "P", "middle": [], "last": "Minotti", "suffix": ""}, {"first": "F", "middle": [], "last": "Brancolini", "suffix": ""}, {"first": "C", "middle": [], "last": "Baig\u00fan", "suffix": ""}, {"first": "Firpo", "middle": [], "last": "Lacoste", "suffix": ""}, {"first": "F", "middle": [], "last": "Benzaquen", "suffix": ""}, {"first": "L", "middle": [], "last": "Blanco", "suffix": ""}, {"first": "D", "middle": ["E"], "last": "B\u00f3", "suffix": ""}, {"first": "R", "middle": ["F"], "last": "Kandus", "suffix": ""}, {"first": "P", "middle": [], "last": "Lingua", "suffix": ""}, {"first": "G", "middle": ["F"], "last": "Minotti", "suffix": ""}, {"first": "P", "middle": [], "last": "Quintana", "suffix": ""}, {"first": "R", "middle": ["D"], "last": "Sverlij", "suffix": ""}, {"first": "S", "middle": [], "last": "Vidal", "suffix": ""}, {"first": "L", "middle": [], "last": "", "suffix": ""}], "year": 2013, "venue": "Inventario de los humedales de Argentina: sistemas de paisajes de humedales del corredor fluvial Paran\u00e1 Paraguay", "link": null}, "BIBREF22": {"title": "La pesca artesanal en la Cuenca del Plata (Argentina) y sus implicancias en la conservaci\u00f3n de la biodiversidad en la Cuenca del Plata. Revista del Museo Argentino de Ciencias Naturales", "authors": [{"first": "J", "middle": ["M"], "last": "Iwaszkiw", "suffix": ""}, {"first": "F", "middle": ["F"], "last": "Lacoste", "suffix": ""}], "year": 2011, "venue": "", "link": null}, "BIBREF23": {"title": "Assessment of s\u00e1balo (Prochilodus lineatus) fisheries in the lower Paran\u00e1 River basin (Argentina) based on hydrological, biological, and fishery indicators", "authors": [{"first": "C", "middle": [], "last": "Baig\u00fan", "suffix": ""}, {"first": "P", "middle": [], "last": "Minotti", "suffix": ""}, {"first": "N", "middle": [], "last": "Oldani", "suffix": ""}], "year": 2013, "venue": "Neotropical Ichthyology", "link": "55744423"}, "BIBREF24": {"title": "The Parana River Basin development and the changes in the lower basin fisheries", "authors": [{"first": "R", "middle": [], "last": "Quir\u00f3s", "suffix": ""}], "year": 1990, "venue": "Interciencia", "link": null}, "BIBREF25": {"title": "Resource use in the Paran\u00e1 River delta (Argentina): moving away from an ecohydrological approach?", "authors": [{"first": "C", "middle": [], "last": "Baig\u00fan", "suffix": ""}, {"first": "A", "middle": [], "last": "Puig", "suffix": ""}, {"first": "P", "middle": ["G"], "last": "Minotti", "suffix": ""}, {"first": "P", "middle": [], "last": "Kandus", "suffix": ""}, {"first": "R", "middle": [], "last": "Quintana", "suffix": ""}, {"first": "R", "middle": [], "last": "Vicari", "suffix": ""}], "year": 2008, "venue": "Ecohydrology and Hydrobiology", "link": "83895149"}, "BIBREF26": {"title": "Effects of decadal changes in the hydrological regime of the middle reach of the Paran\u00e1 River (Argentina) on fish densities", "authors": [{"first": "L", "middle": ["A"], "last": "Esp\u00edndola", "suffix": ""}, {"first": "M", "middle": ["L"], "last": "Amsler", "suffix": ""}, {"first": "A", "middle": ["R"], "last": "Paira", "suffix": ""}, {"first": "E", "middle": ["E"], "last": "Drago", "suffix": ""}, {"first": "Mcm", "middle": [], "last": "Blettler", "suffix": ""}, {"first": "A", "middle": ["A"], "last": "Agostinho", "suffix": ""}], "year": 2014, "venue": "Environmental Biology of Fishes", "link": null}, "BIBREF27": {"title": "DNA barcoding Neotropical fishes: recent advances from the Pampa Plain", "authors": [{"first": "J", "middle": ["J"], "last": "Rosso", "suffix": ""}, {"first": "E", "middle": [], "last": "Mabraga\u00f1a", "suffix": ""}, {"first": "Gonzalez", "middle": [], "last": "Castro", "suffix": ""}, {"first": "M", "middle": [], "last": "", "suffix": ""}, {"first": "Diaz", "middle": [], "last": "De Astarloa", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "", "suffix": ""}], "year": 2012, "venue": "Argentina. Molecular Ecology Resources", "link": null}, "BIBREF28": {"title": "The FISH-BOL collaborators' protocol", "authors": [{"first": "D", "middle": [], "last": "Steinke", "suffix": ""}, {"first": "R", "middle": [], "last": "Hanner", "suffix": ""}], "year": 2011, "venue": "Mitochondrial DNA", "link": "3945361"}, "BIBREF29": {"title": "Comunicaciones del Museo Argentino de Ciencias Naturales Bernardino Rivadavia", "authors": [{"first": "R", "middle": ["B"], "last": "L\u00f3pez", "suffix": ""}, {"first": "H", "middle": ["P"], "last": "Castello", "suffix": ""}], "year": 1966, "venue": "Ciencias Zool\u00f3gicas", "link": null}, "BIBREF30": {"title": "Los peces argentinos de agua dulce", "authors": [{"first": "R", "middle": ["A"], "last": "Ringuelet", "suffix": ""}, {"first": "R", "middle": ["H"], "last": "Ar\u00e1mburu", "suffix": ""}, {"first": "De", "middle": [], "last": "Ar\u00e1mburu", "suffix": ""}, {"first": "A", "middle": ["A"], "last": "", "suffix": ""}], "year": 1967, "venue": "Consejo de Investigaciones Cient\u00edficas de", "link": null}, "BIBREF31": {"title": "Characoids of the world", "authors": [{"first": "J", "middle": [], "last": "G\u00e9ry", "suffix": ""}], "year": 1977, "venue": "", "link": "83080111"}, "BIBREF32": {"title": "Review of the genus Hypostomus Lac\u00e9p\u00e8de, 1803 from southern Brazil, with descriptions of three new species (Pisces, Siluriformes, Loricariidae)", "authors": [{"first": "R", "middle": ["E"], "last": "Reis", "suffix": ""}, {"first": "C", "middle": [], "last": "Weber", "suffix": ""}, {"first": "", "middle": [], "last": "Malabarba", "suffix": ""}], "year": 1990, "venue": "", "link": "87124391"}, "BIBREF33": {"title": "Una nueva cita y ampliaci\u00f3n de la distribuci\u00f3n de dos especies para la ictiofauna argentina", "authors": [{"first": "M", "middle": ["M"], "last": "Azpelicueta", "suffix": ""}, {"first": "L", "middle": [], "last": "Braga", "suffix": ""}], "year": 1981, "venue": "Neotropica", "link": null}, "BIBREF34": {"title": "A check-list of fishes from El Bagual ecological reserve", "authors": [{"first": "M", "middle": ["M"], "last": "Azpelicueta", "suffix": ""}, {"first": "A", "middle": ["A"], "last": "Yanosky", "suffix": ""}], "year": 1992, "venue": "Argentina. Ichthyological Exploration of Freshwaters", "link": null}, "BIBREF35": {"title": "Los Hypostominae (Pisces:Loricariidae) de Argentina", "authors": [{"first": "H", "middle": ["L"], "last": "L\u00f3pez", "suffix": ""}, {"first": "A", "middle": ["M"], "last": "Miquelarena", "suffix": ""}], "year": 1991, "venue": "", "link": null}, "BIBREF36": {"title": "The Crenicichla (Teleostei: Cichlidae) species of the Uruguai River drainage in Brazil", "authors": [{"first": "Cas", "middle": [], "last": "Lucena", "suffix": ""}, {"first": "S", "middle": ["O"], "last": "Kullander", "suffix": ""}], "year": 1992, "venue": "Ichthyological Exploration of Freshwaters", "link": null}, "BIBREF37": {"title": "Electric fishes of the continental waters of America: classification and catalogue of the electric fishes of the order Gymnotiformes (Teleostei: ostariophysi) with descriptions of new genera and species. Caracas: Fundaci\u00f3n para el Desarrollo de las Ciencias F\u00edsicas", "authors": [{"first": "F", "middle": [], "last": "Mago-Leccia", "suffix": ""}], "year": 2003, "venue": "", "link": null}, "BIBREF38": {"title": "Revis\u00e3o taxonomica e relac\u00f5es filogeneticas das especies de Roeboides grupo-microlepis (Ostariophysi, Characiformes, Characidae). Iheringia, S\u00e9rie Zoologia", "authors": [{"first": "Cas", "middle": [], "last": "Lucena", "suffix": ""}], "year": 2003, "venue": "", "link": null}, "BIBREF39": {"title": "Description of a new genus with six new species from southern Brazil, Uruguay and Argentina, with a discussion of a putative characid clade (Teleostei: Characiformes: Characidae)", "authors": [{"first": "L", "middle": ["R"], "last": "Malabarba", "suffix": ""}, {"first": "S", "middle": ["H"], "last": "Weitzman", "suffix": ""}], "year": 2003, "venue": "Comunica\u00e7\u00f5es do Museu de Ci\u00eancias e Tecnologia da PUCRS", "link": null}, "BIBREF40": {"title": "Revision of the Neotropical genus Triportheus Cope, 1872 (Characiformes: Characidae)", "authors": [{"first": "Mcsl", "middle": [], "last": "Malabarba", "suffix": ""}], "year": 2004, "venue": "Neotropical Ichthyology", "link": "85570089"}, "BIBREF41": {"title": "Historia natural y paisaje de la Reserva El Bagual, provincia de Formosa, Argentina. Inventario de la fauna de vertebrados y de la flora vascular del Chaco H\u00famedo", "authors": [{"first": "M", "middle": ["M"], "last": "Azpelicueta", "suffix": ""}, {"first": "", "middle": [], "last": "Peces De La Reserva El", "suffix": ""}, {"first": "", "middle": [], "last": "Bagual", "suffix": ""}], "year": 2005, "venue": "Temas de Naturaleza y Conservaci\u00f3n 4. Buenos Aires: Aves Argentinas", "link": null}, "BIBREF42": {"title": "Astyanax tumbayaensis, a new species from northwestern Argentina highlands (Characiformes: Characidae) with a key to the Argentinean species of the genus and comments on their distribution. Revue suisse zoologie", "authors": [{"first": "A", "middle": ["M"], "last": "Miquelarena", "suffix": ""}, {"first": "R", "middle": ["C"], "last": "Menni", "suffix": ""}], "year": 2005, "venue": "", "link": null}, "BIBREF43": {"title": "A review of the species of Crenicichla (Teleostei: Cichlidae) from the Atlantic coastal rivers of southeastern Brazil from Bahia to Rio Grande do Sul states, with descriptions of three new species", "authors": [{"first": "S", "middle": ["O"], "last": "Kullander", "suffix": ""}, {"first": "Cas", "middle": [], "last": "De Lucena", "suffix": ""}], "year": 2006, "venue": "Neotropical Ichthyology", "link": null}, "BIBREF44": {"title": "Astyanax endy (Characiformes: Characidae), a new fish species from the upper R\u00edo Bermejo basin, northwestern Argentina", "authors": [{"first": "J", "middle": ["M"], "last": "Mirande", "suffix": ""}, {"first": "G", "middle": [], "last": "Aguilera", "suffix": ""}, {"first": "M", "middle": ["M"], "last": "Azpelicueta", "suffix": ""}], "year": 2006, "venue": "Zootaxa", "link": null}, "BIBREF45": {"title": "Revis\u00e3o taxon\u00f4mica das esp\u00e9cies do g\u00eanero Roeboides grupo-affinis (Ostariophysi, Characiformes, Characidae)", "authors": [{"first": "Cas", "middle": [], "last": "Lucena", "suffix": ""}], "year": 2007, "venue": "Iheringia", "link": null}, "BIBREF46": {"title": "Peces de la Mesopotamia Argentina (Characiformes: Characidae: Cheirodontinae)", "authors": [{"first": "A", "middle": ["M"], "last": "Miquelarena", "suffix": ""}, {"first": "J", "middle": ["E"], "last": "Mantinian", "suffix": ""}, {"first": "H", "middle": ["L"], "last": "L\u00f3pez", "suffix": ""}], "year": 2008, "venue": "Miscel\u00e1nea", "link": null}, "BIBREF47": {"title": "Actinopterygii: Characiformes: Characidae) for the R\u00edo Pilcomayo National Park and Ramsar Site in the province of Formosa", "authors": [{"first": "F", "middle": [], "last": "Brancolini", "suffix": ""}, {"first": "L", "middle": [], "last": "Protogino", "suffix": ""}, {"first": "P", "middle": [], "last": "Minotti", "suffix": ""}, {"first": "C", "middle": [], "last": "Baig\u00fan", "suffix": ""}, {"first": "H", "middle": [], "last": "L\u00f3pez", "suffix": ""}, {"first": "D", "middle": [], "last": "Colautti", "suffix": ""}], "year": 2004, "venue": "Argentina. Check List", "link": null}, "BIBREF48": {"title": "Catalog of Fishes website", "authors": [{"first": "W", "middle": ["N"], "last": "Eschmeyer", "suffix": ""}], "year": 2014, "venue": "", "link": null}, "BIBREF49": {"title": "An inexpensive, automation friendly protocol for recovering high-quality DNA", "authors": [{"first": "N", "middle": ["V"], "last": "Ivanova", "suffix": ""}, {"first": "J", "middle": ["R"], "last": "De Waard", "suffix": ""}, {"first": "Pdn", "middle": [], "last": "Hebert", "suffix": ""}], "year": 2006, "venue": "Molecular Ecology Notes", "link": "3938638"}, "BIBREF50": {"title": "The complete sequence of the zebrafish (Danio rerio) mitochondrial genome and evolutionary patterns in vertebrate mitochondrial DNA", "authors": [{"first": "R", "middle": ["E"], "last": "Broughton", "suffix": ""}, {"first": "J", "middle": ["E"], "last": "Milam", "suffix": ""}, {"first": "B", "middle": ["A"], "last": "Roe", "suffix": ""}], "year": 2001, "venue": "Genome Research", "link": "1204860"}, "BIBREF51": {"title": "Universal primer cocktails for fish DNA barcoding", "authors": [{"first": "N", "middle": ["V"], "last": "Ivanova", "suffix": ""}, {"first": "T", "middle": ["S"], "last": "Zemlak", "suffix": ""}, {"first": "R", "middle": ["H"], "last": "Hanner", "suffix": ""}, {"first": "Pdn", "middle": [], "last": "Hebert", "suffix": ""}], "year": 2007, "venue": "Molecular Ecology Notes", "link": "40048219"}, "BIBREF52": {"title": "MEGA6: Molecular Evolutionary Genetics Analysis Version 6.0", "authors": [{"first": "K", "middle": [], "last": "Tamura", "suffix": ""}, {"first": "G", "middle": [], "last": "Stecher", "suffix": ""}, {"first": "D", "middle": [], "last": "Peterson", "suffix": ""}, {"first": "A", "middle": [], "last": "Filipski", "suffix": ""}, {"first": "S", "middle": [], "last": "Kumar", "suffix": ""}], "year": 2013, "venue": "Molecular Biology and Evolution", "link": null}, "BIBREF53": {"title": "Barcoding Fishes from the Lower Paran\u00e1 River PLOS ONE | DOI", "authors": [{"first": "M", "middle": [], "last": "Nei", "suffix": ""}, {"first": "S", "middle": [], "last": "Kumar", "suffix": ""}], "year": 2000, "venue": "", "link": null}, "BIBREF54": {"title": "A simple method for estimating evolutionary rate of base substitutions through comparative studies of nucleotide sequences", "authors": [{"first": "M", "middle": [], "last": "Kimura", "suffix": ""}], "year": 1980, "venue": "Journal of Molecular Evolution", "link": null}, "BIBREF55": {"title": "DnaSP v5: a software for comprehensive analysis of DNA polymorphism data", "authors": [{"first": "P", "middle": [], "last": "Librado", "suffix": ""}, {"first": "J", "middle": [], "last": "Rozas", "suffix": ""}], "year": 2009, "venue": "Bioinformatics", "link": "60509238"}, "BIBREF56": {"title": "Effects of phylogenetic reconstruction method on the robustness of species delimitation using single-locus data", "authors": [{"first": "C", "middle": ["Q"], "last": "Tang", "suffix": ""}, {"first": "A", "middle": ["M"], "last": "Humphreys", "suffix": ""}, {"first": "D", "middle": [], "last": "Fontaneto", "suffix": ""}, {"first": "T", "middle": ["G"], "last": "Barraclough", "suffix": ""}], "year": 2014, "venue": "Methods in Ecology and Evolution", "link": "215642934"}, "BIBREF57": {"title": "Delineating Species with DNA Barcodes: A Case of Taxon Dependent Method Performance in Moths", "authors": [{"first": "M", "middle": [], "last": "Kekkonen", "suffix": ""}, {"first": "M", "middle": [], "last": "Mutanen", "suffix": ""}, {"first": "L", "middle": [], "last": "Kaila", "suffix": ""}, {"first": "M", "middle": [], "last": "Nieminen", "suffix": ""}, {"first": "Pdn", "middle": [], "last": "Hebert", "suffix": ""}], "year": 2015, "venue": "PLoS ONE", "link": "215210982"}, "BIBREF58": {"title": "Fish diversity and ecology, habitats and fisheries for the undammed riverine axis Paraguay-Parana-R\u00edo de la PLata (Southern South America)", "authors": [{"first": "R", "middle": [], "last": "Quir\u00f3s", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Bechara", "suffix": ""}, {"first": "E", "middle": ["K"], "last": "De Resende", "suffix": ""}], "year": 2007, "venue": "", "link": "885379"}, "BIBREF59": {"title": "Ichthyofauna diversity of the upper rio Paran\u00e1: present composition and future perspectives", "authors": [{"first": "F", "middle": [], "last": "Langeani", "suffix": ""}, {"first": "R", "middle": ["M"], "last": "Corr\u00eaa E Castro", "suffix": ""}, {"first": "O", "middle": ["T"], "last": "Oyakawa", "suffix": ""}, {"first": "O", "middle": ["A"], "last": "Shibatta", "suffix": ""}, {"first": "Simone", "middle": [], "last": "Pavanelli", "suffix": ""}, {"first": "C", "middle": [], "last": "Casatti", "suffix": ""}, {"first": "L", "middle": [], "last": "", "suffix": ""}], "year": 2007, "venue": "Biota Neotropica", "link": null}, "BIBREF60": {"title": "DNA Barcoding Identifies Argentine Fishes from Marine and Brackish Waters", "authors": [{"first": "E", "middle": [], "last": "Mabraga\u00f1a", "suffix": ""}, {"first": "D\u00edaz", "middle": [], "last": "De Astarloa", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Hanner", "suffix": ""}, {"first": "R", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "J", "middle": [], "last": "", "suffix": ""}, {"first": "Gonz\u00e1lez", "middle": [], "last": "Castro", "suffix": ""}, {"first": "M", "middle": [], "last": "", "suffix": ""}], "year": 2011, "venue": "PLoS ONE", "link": null}, "BIBREF61": {"title": "Cytogenetic and DNA barcoding reveals high divergence within the trahira, Hoplias malabaricus (Characiformes: Erythrinidae) from the lower Amazon River", "authors": [{"first": "D", "middle": ["F"], "last": "Marques", "suffix": ""}, {"first": "F", "middle": [], "last": "Araujo Dos Santos", "suffix": ""}, {"first": "Santos", "middle": [], "last": "Da Silva", "suffix": ""}, {"first": "S", "middle": [], "last": "Sampaio", "suffix": ""}, {"first": "I", "middle": [], "last": "", "suffix": ""}, {"first": "Ribeiro", "middle": [], "last": "Rodrigues", "suffix": ""}, {"first": "L", "middle": ["R"], "last": "", "suffix": ""}], "year": 2013, "venue": "Neotropical Ichthyology", "link": "8649693"}, "BIBREF62": {"title": "Checklist of the Freshwater Fishes of South and Central America", "authors": [{"first": "Fct", "middle": [], "last": "Lima", "suffix": ""}, {"first": "S", "middle": ["O"], "last": "Kullander", "suffix": ""}, {"first": "Ferraris", "middle": [], "last": "Cj", "suffix": ""}], "year": 2003, "venue": "Porto Alegre: EDIPUCRS", "link": null}, "BIBREF63": {"title": "Body plan convergence in the evolution of skates and rays (Chondrichthyes: Batoidea)", "authors": [{"first": "N", "middle": ["C"], "last": "Aschliman", "suffix": ""}, {"first": "M", "middle": [], "last": "Nishida", "suffix": ""}, {"first": "M", "middle": [], "last": "Miya", "suffix": ""}, {"first": "J", "middle": ["G"], "last": "Inoue", "suffix": ""}, {"first": "K", "middle": ["M"], "last": "Rosana", "suffix": ""}, {"first": "G", "middle": ["J"], "last": "Naylor", "suffix": ""}], "year": 2012, "venue": "Molecular Phylogenetics and Evolution", "link": "16496631"}, "BIBREF64": {"title": "Molecular phylogeny of thorny catfishes (Siluriformes: Doradidae). Molecular phylogenetics and evolution", "authors": [{"first": "M", "middle": [], "last": "Arce", "suffix": ""}, {"first": "R", "middle": ["E"], "last": "Reis", "suffix": ""}, {"first": "A", "middle": ["J"], "last": "Geneva", "suffix": ""}, {"first": "Mhs", "middle": [], "last": "P\u00e9rez", "suffix": ""}], "year": 2013, "venue": "", "link": null}, "BIBREF65": {"title": "DNA barcoding of freshwater ichthyoplankton in the Neotropics as a tool for ecological monitoring", "authors": [{"first": "W", "middle": [], "last": "Frantine-Silva", "suffix": ""}, {"first": "S", "middle": ["H"], "last": "Sofia", "suffix": ""}, {"first": "M", "middle": ["L"], "last": "Orsi", "suffix": ""}, {"first": "F", "middle": ["S"], "last": "Almeida", "suffix": ""}], "year": 2015, "venue": "Molecular Ecology Resources", "link": "24676270"}, "BIBREF66": {"title": "Molecular comparison of the piranhas genera Serrasalmus and Pygocentrus (Characiformes, Serrasalmidae) from upper Paran\u00e1, upper Paraguai, Tocantins and S\u00e3o Francisco River basins", "authors": [{"first": "Souto", "middle": [], "last": "Bignoto", "suffix": ""}, {"first": "T", "middle": [], "last": "", "suffix": ""}], "year": 2010, "venue": "", "link": null}, "BIBREF67": {"title": "Promiscuous Speciation with Gene Flow in Silverside Fish Genus Odontesthes (Atheriniformes, Atherinopsidae) from South Western Atlantic Ocean Basins", "authors": [{"first": "G", "middle": [], "last": "Garc\u00eda", "suffix": ""}, {"first": "N", "middle": [], "last": "R\u00edos", "suffix": ""}, {"first": "V", "middle": [], "last": "Guti\u00e9rrez", "suffix": ""}, {"first": "J", "middle": ["G"], "last": "Varela", "suffix": ""}, {"first": "Bouza", "middle": [], "last": "Fern\u00e1ndez", "suffix": ""}, {"first": "C", "middle": [], "last": "", "suffix": ""}, {"first": "G\u00f3mez", "middle": [], "last": "Pardo", "suffix": ""}, {"first": "B", "middle": [], "last": "", "suffix": ""}], "year": 2014, "venue": "PLoS ONE", "link": "4642033"}, "BIBREF68": {"title": "Description and comparison of two economically important fish species mitogenomes: Prochilodus argenteus and Prochilodus costatus (Characiformes, Prochilodontidae)", "authors": [{"first": "A", "middle": ["T"], "last": "Chagas", "suffix": ""}, {"first": "A", "middle": ["O"], "last": "Carmo", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Costa", "suffix": ""}, {"first": "L", "middle": ["C"], "last": "Resende", "suffix": ""}, {"first": "Brand\u00e3o", "middle": [], "last": "Dias", "suffix": ""}, {"first": "P", "middle": ["F"], "last": "Martins", "suffix": ""}, {"first": "A", "middle": ["P"], "last": "", "suffix": ""}], "year": 2015, "venue": "Mitochondrial DNA", "link": "28067390"}, "BIBREF69": {"title": "First identification of interspecies hybridization in the freshwater stingrays Potamotrygon motoro and P. falkneri (Myliobatiformes, Potamotrygonidae)", "authors": [{"first": "V", "middle": ["P"], "last": "Cruz", "suffix": ""}, {"first": "M", "middle": [], "last": "Vera", "suffix": ""}, {"first": "F", "middle": ["F"], "last": "Mendon\u00e7a", "suffix": ""}, {"first": "B", "middle": ["G"], "last": "Pardo", "suffix": ""}, {"first": "P", "middle": [], "last": "Martinez", "suffix": ""}, {"first": "C", "middle": [], "last": "Oliveira", "suffix": ""}], "year": 2014, "venue": "Conservation Genetics", "link": "2392000"}, "BIBREF70": {"title": "DNA barcodes discriminate freshwater fishes from the Para\u00edba do Sul River Basin", "authors": [{"first": "L", "middle": ["H"], "last": "Pereira", "suffix": ""}, {"first": "G", "middle": ["M"], "last": "Maia", "suffix": ""}, {"first": "R", "middle": [], "last": "Hanner", "suffix": ""}, {"first": "F", "middle": [], "last": "Foresti", "suffix": ""}, {"first": "C", "middle": [], "last": "Oliveira", "suffix": ""}], "year": 2011, "venue": "Brazil. Mitochondrial DNA", "link": null}, "BIBREF71": {"title": "Review and consideration on habitat use, distribution and life history of Lycengraulis grossidens (Agassiz, 1829) (Actinopterygii, Clupeiformes, Engraulididae)", "authors": [{"first": "Acg", "middle": [], "last": "Mai", "suffix": ""}, {"first": "J", "middle": ["P"], "last": "Vieira", "suffix": ""}], "year": 2013, "venue": "Biota Neotropica", "link": "52083031"}, "BIBREF72": {"title": "Delimiting species using single-locus data and the generalized mixed yule coalescent (GMYC) approach: a revised method and evaluation on simulated datasets", "authors": [{"first": "T", "middle": [], "last": "Fujisawa", "suffix": ""}, {"first": "T", "middle": ["G"], "last": "Barraclough", "suffix": ""}], "year": 2013, "venue": "Systematic Biology", "link": "15397507"}, "BIBREF73": {"title": "Revision of the Neotropical trahiras of the Hoplias lacerdae species-group (Ostariophysi: Characiformes: Erythrinidae) with descriptions of two new species", "authors": [{"first": "O", "middle": ["T"], "last": "Oyakawa", "suffix": ""}, {"first": "Jmt", "middle": [], "last": "Mattox", "suffix": ""}], "year": 2009, "venue": "Neotropical Ichthyology", "link": null}, "BIBREF74": {"title": "Fish diversity and community structure of Yabot\u00ed stream", "authors": [{"first": "P", "middle": ["R"], "last": "Araya", "suffix": ""}, {"first": "L", "middle": ["H"], "last": "Hirt", "suffix": ""}, {"first": "S", "middle": ["A"], "last": "Flores", "suffix": ""}], "year": 2015, "venue": "Revista Mexicana de Biodiversidad", "link": null}, "BIBREF75": {"title": "Dispersal and vicariance of Hoplias malabaricus (Bloch, 1794) (Teleostei, Erythrinidae) populations of the Brazilian continental margin", "authors": [{"first": "T", "middle": ["L"], "last": "Pereira", "suffix": ""}, {"first": "U", "middle": [], "last": "Santos", "suffix": ""}, {"first": "C", "middle": [], "last": "Schaefer", "suffix": ""}, {"first": "G", "middle": ["O"], "last": "Souza", "suffix": ""}, {"first": "S", "middle": ["R"], "last": "Paiva", "suffix": ""}, {"first": "L", "middle": ["R"], "last": "Malabarba", "suffix": ""}], "year": 2013, "venue": "Journal of Biogeography", "link": "86156270"}, "BIBREF76": {"title": "Checklist of the Freshwater Fishes of South and Central America", "authors": [{"first": "", "middle": [], "last": "Carvalho Mr De", "suffix": ""}, {"first": "N", "middle": ["R"], "last": "Lovejoy", "suffix": ""}, {"first": "R", "middle": ["S"], "last": "Rosa", "suffix": ""}], "year": 2003, "venue": "Reis RE, Kullander SO and Ferraris CJ Jr", "link": null}, "BIBREF77": {"title": "Estado actual de los estudios sobre la raya fluvial neotropical", "authors": [{"first": "M", "middle": ["N"], "last": "Castex", "suffix": ""}], "year": 1964, "venue": "Museo Provincial de Ciencias Naturales \"Florentino Ameghino\" publications. Cincuentenario del Museo Provincial de Ciencias Naturales Florentino Ameghino. Santa F\u00e9: Museo Provincial de Ciencias Naturales", "link": null}, "BIBREF78": {"title": "Systematic revision of the Potamotrygon motoro (M\u00fcller and Henle, 1841) species complex in the Paran\u00e1-Paraguay basin, with description of two new ocellated species (Chondrichthyes: Myliobatiformes: Potamotrygonidae)", "authors": [{"first": "T", "middle": ["S"], "last": "Loboda", "suffix": ""}, {"first": "Mrd", "middle": [], "last": "Carvalho", "suffix": ""}], "year": 2013, "venue": "Neotropical Ichthyology", "link": "84962231"}, "BIBREF79": {"title": "A test of the utility of DNA barcoding in the radiation of the freshwater stingray genus Potamotrygon (Potamotrygonidae, Myliobatiformes)", "authors": [{"first": "D", "middle": [], "last": "Toffoli", "suffix": ""}, {"first": "T", "middle": [], "last": "Hrbek", "suffix": ""}, {"first": "Mlgd", "middle": [], "last": "Ara\u00fajo", "suffix": ""}, {"first": "Mpd", "middle": [], "last": "Almeida", "suffix": ""}, {"first": "P", "middle": [], "last": "Charvet-Almeida", "suffix": ""}, {"first": "I", "middle": ["P"], "last": "Farias", "suffix": ""}], "year": 2008, "venue": "Genetics and Molecular Biology", "link": "55494031"}, "BIBREF80": {"title": "Estudos gen\u00e9ticos em raias do g\u00eanero Potamotrygon (Chondrichthyes: Myliobatiformes: Potamotrygonidae) na Bacia do Rio Paran\u00e1", "authors": [{"first": "V", "middle": ["P"], "last": "Cruz", "suffix": ""}], "year": 2013, "venue": "", "link": null}, "BIBREF81": {"title": "Five years of FISH-BOL: Brief status report", "authors": [{"first": "S", "middle": [], "last": "Becker", "suffix": ""}, {"first": "R", "middle": [], "last": "Hanner", "suffix": ""}, {"first": "D", "middle": [], "last": "Steinke", "suffix": ""}], "year": 2011, "venue": "Mitochondrial DNA", "link": "3955416"}, "BIBREF82": {"title": "Multi-locus fossil-calibrated phylogeny of Atheriniformes (Teleostei, Ovalentaria)", "authors": [{"first": "D", "middle": [], "last": "Campanella", "suffix": ""}, {"first": "L", "middle": ["C"], "last": "Hughes", "suffix": ""}, {"first": "P", "middle": ["J"], "last": "Unmack", "suffix": ""}, {"first": "D", "middle": ["D"], "last": "Bloom", "suffix": ""}, {"first": "K", "middle": ["R"], "last": "Piller", "suffix": ""}, {"first": "G", "middle": [], "last": "Ort\u00ed", "suffix": ""}], "year": 2015, "venue": "", "link": "5087966"}}, "ref_entries": {"FIGREF0": {"text": "Fig 1. Sample sites map. Map of the Lower Parana River Basin showing the 50 sampling points at sites 1 and 2.", "type": "figure"}, "FIGREF1": {"text": "Fig 2. 3D histogram showing the number of Families, Genus and species by Order. doi:10.1371/journal.pone.0157419.g002", "type": "figure"}, "FIGREF2": {"text": "Fig 3. The K2P/ML tree of 308 COI sequences for 79 morphologically identified freshwater fish species from Lower Paran\u00e1 River in Argentina. NJ tree was divided into two parts from top to bottom in order from left to right. Bootstrap values >90 for 1000 replicates are shown at each branch. The number of specimens analyzed for each species is shown between brackets. Solid triangles represent clusters of multiple specimens, with height proportional to specimen number and the horizontal width proportional to the genetic variation within each cluster. In gray are shown branches of species with high intraspecific genetic divergence and species with overlapping clusters. Columns next to the tree represent presence of recognition for each clustering method while boxes highlights the differences among methods. Specimens of Brycon orbignyanus with high genetic divergence that were re-classified as B. cf. hilarii are highlighted with \"*\".", "type": "figure"}, "FIGREF3": {"text": "Fig 4. Box plots of K2P distances at different taxonomic levels. (A) within-species variation; (A') within-species variation excluding the four species with high genetic divergence (H. malabaricus, B. orbignyanus, P. motoro and Megalonema argentinum); (B) variation at genus level; (B') variation at genus level excluding genus with low genetic divergence (Odontesthes), (C) variation at Family level. The box comprise 25-75th percentiles of the data set. Whiskers show the lowest and highest values. Points represent outliers. Grey bar indicates 'barcoding gap' between intra and interspecific distances. doi:10.1371/journal.pone.0157419.g004", "type": "figure"}, "FIGREF4": {"text": "Fig 6. K2P-NJ trees of species with high conspecific genetic divergence. On the left, K2P-NJ trees calculated with specimens of this project. On the right, K2P-NJ trees calculated with all the South American published sequences of each genus. Specimens of this project are shown in bold and clusters indicated with A and B. BIN numbers are shown in brackets. Pictures represent morphology of typical specimens for each branch. Specimen number on collapsed branches is shown in brackets. Bootstrap values >50 for 1000 replicates are shown at each branch. Specimens of Brycon orbignyanus with high", "type": "figure"}, "FIGREF5": {"text": "genetic divergence that were re-classified as B. cf. hilarii are highlighted with \"*\". LPR: Lower Paran\u00e1 River, UPR: Upper Paran\u00e1 River, AMAZ: Amazonas River, SR: Salado River and SFR: Sao Francisco River. doi:10.1371/journal.pone.0157419.g006", "type": "figure"}, "FIGREF6": {"text": "Fig. The K2P/NJ tree of 308 COI sequences for 79 morphologically identified freshwater fish species from the Lower Paran\u00e1 River in Argentina. Bootstrap values for 1000 replicates are shown at each branch. Before and after of the species name voucher and BIN numbers are respectively shown. Specimens of Brycon orbignyanus with high genetic divergence that were re-classified as B. cf. hilarii are highlighted with \"Prochilodus genus K2P/NJ tree showing that COI clearly separates P. lineatus and P. nigricans species. Bootstrap values for 1000 replicates are shown at each branch. The num- ber of specimens analyzed for each species is shown between brackets. Solid triangles represent clusters of multiple specimens, with height proportional to specimen number and the horizon- tal depth proportional to the genetic variation within each cluster. (TIF) S1", "type": "figure"}, "TABREF0": {"text": "1.25 \u03bcl 10X PCR buffer [200 mMTris-HCl (pH 8.4), 500 mMKCl], 0.625 \u03bcl MgCl 2 (50 mM), 0.125 \u03bcl of C_FishF1t1 and C_FishR1t1 primer combination (0.01 mM) [51], 0.062 \u03bcl of each dNTP (10 mM), 0.060 \u03bcl of PlatinumTaq Polymerase (Invitro- gen), and 2 \u03bcl of DNA template. PCR products were sent to the Biodiversity Institute of Ontario facility for sequencing on an ABI 3730 capillary sequencer (Applied Biosystems, Inc.) following the manufacturer's instructions.", "type": "table"}, "TABREF1": {"text": "K2P genetic divergence values within different taxonomic levels from 308 specimens of Lower Paran\u00e1 River analyzed.", "type": "table"}, "TABREF2": {"text": "List of species with \"true\" discordance BINs found by the 'BIN Discordance Report' sequence analysis tool. Only BINs with species level conflicts are shown.", "type": "table"}, "TABREF3": {"text": "(Continued)", "type": "table"}, "TABREF4": {"text": "Taxonomic classification of the 79 morphologically identified freshwater fish spe- cies from the Lower Paran\u00e1 River in Argentina. (DOCX) S2 Table. List of species with \"no true\" discordance BINs found by the 'BIN Discordance Report' sequence analysis tool. Only BINs with species level conflicts are shown. (DOCX)", "type": "table"}}}
{"paper_id": "8331057", "_pdf_hash": "b726e53bec31787316d1d000b4559e4283b60a09", "abstract": [{"section": "Abstract", "text": "The rapidly expanding field of big data analytics has started to play a pivotal role in the evolution of healthcare practices and research. It has provided tools to accumulate, manage, analyze, and assimilate large volumes of disparate, structured, and unstructured data produced by current healthcare systems. Big data analytics has been recently applied towards aiding the process of care delivery and disease exploration. However, the adoption rate and research development in this space is still hindered by some fundamental problems inherent within the big data paradigm. In this paper, we discuss some of these major challenges with a focus on three upcoming and promising areas of medical research: image, signal, and genomics based analytics. Recent research which targets utilization of large volumes of medical data while combining multimodal data from disparate sources is discussed. Potential areas of research within this field which have the ability to provide meaningful impact on healthcare delivery are also examined.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "The concept of \"big data\" is not new; however the way it is defined is constantly changing. Various attempts at defining big data essentially characterize it as a collection of data elements whose size, speed, type, and/or complexity require one to seek, adopt, and invent new hardware and software mechanisms in order to successfully store, analyze, and visualize the data [1] [2] [3] . Healthcare is a prime example of how the three Vs of data, velocity (speed of generation of data), variety, and volume [4] , are an innate aspect of the data it produces. This data is spread among multiple healthcare systems, health insurers, researchers, government entities, and so forth. Furthermore, each of these data repositories is siloed and inherently incapable of providing a platform for global data transparency. To add to the three Vs, the veracity of healthcare data is also critical for its meaningful use towards developing translational research.", "cite_spans": [{"start": 374, "end": 377, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 378, "end": 381, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 382, "end": 385, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 507, "end": 510, "text": "[4]", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "Introduction", "text": "Despite the inherent complexities of healthcare data, there is potential and benefit in developing and implementing big data solutions within this realm. A report by McKinsey Global Institute suggests that if US healthcare were to use big data creatively and effectively, the sector could create more than $300 billion in value every year. Two-thirds of the value would be in the form of reducing US healthcare expenditure [5] . Historical approaches to medical research have generally focused on the investigation of disease states based on the changes in physiology in the form of a confined view of certain singular modality of data [6] . Although this approach to understanding diseases is essential, research at this level mutes the variation and interconnectedness that define the true underlying medical mechanisms [7] . After decades of technological laggard, the field of medicine has begun to acclimatize to today's digital data age. New technologies make it possible to capture vast amounts of information about each individual patient over a large timescale. However, despite the advent of medical electronics, the data captured and gathered from these patients has remained vastly underutilized and thus wasted.", "cite_spans": [{"start": 423, "end": 426, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 636, "end": 639, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 822, "end": 825, "text": "[7]", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "Introduction", "text": "Important physiological and pathophysiological phenomena are concurrently manifest as changes across multiple clinical streams. This results from strong coupling among different systems within the body (e.g., interactions between heart rate, respiration, and blood pressure) thereby producing potential markers for clinical assessment. Thus, understanding and predicting diseases require an aggregated approach where structured and unstructured data stemming from a myriad of clinical and nonclinical modalities are utilized for a more comprehensive perspective of the disease states. An aspect of healthcare research that has recently gained traction is in addressing some of the growing pains in introducing concepts of big data analytics to medicine. Researchers are studying the complex nature of healthcare data in terms of both characteristics of the data itself and the taxonomy of analytics that can be meaningfully performed on them.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "In this paper, three areas of big data analytics in medicine are discussed. These three areas do not comprehensively reflect the application of big data analytics in medicine; instead they are intended to provide a perspective of broad, popular areas of research where the concepts of big data analytics are currently being applied.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "Image Processing. Medical images are an important source of data frequently used for diagnosis, therapy assessment and planning [8] . Computed tomography (CT), magnetic resonance imaging (MRI), X-ray, molecular imaging, ultrasound, photoacoustic imaging, fluoroscopy, positron emission tomography-computed tomography (PET-CT), and mammography are some of the examples of imaging techniques that are well established within clinical settings. Medical image data can range anywhere from a few megabytes for a single study (e.g., histology images) to hundreds of megabytes per study (e.g., thin-slice CT studies comprising upto 2500+ scans per study [9] ). Such data requires large storage capacities if stored for long term. It also demands fast and accurate algorithms if any decision assisting automation were to be performed using the data. In addition, if other sources of data acquired for each patient are also utilized during the diagnoses, prognosis, and treatment processes, then the problem of providing cohesive storage and developing efficient methods capable of encapsulating the broad range of data becomes a challenge.", "cite_spans": [{"start": 128, "end": 131, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 647, "end": 650, "text": "[9]", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "Introduction", "text": "Signal Processing. Similar to medical images, medical signals also pose volume and velocity obstacles especially during continuous, high-resolution acquisition and storage from a multitude of monitors connected to each patient. However, in addition to the data size issues, physiological signals also pose complexity of a spatiotemporal nature. Analysis of physiological signals is often more meaningful when presented along with situational context awareness which needs to be embedded into the development of continuous monitoring and predictive systems to ensure its effectiveness and robustness.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "Currently healthcare systems use numerous disparate and continuous monitoring devices that utilize singular physiological waveform data or discretized vital information to provide alert mechanisms in case of overt events. However, such uncompounded approaches towards development and implementation of alarm systems tend to be unreliable and their sheer numbers could cause \"alarm fatigue\" for both care givers and patients [10] [11] [12] . In this setting, the ability to discover new medical knowledge is constrained by prior knowledge that has typically fallen short of maximally utilizing high-dimensional time series data. The reason that these alarm mechanisms tend to fail is primarily because these systems tend to rely on single sources of information while lacking context of the patients' true physiological conditions from a broader and more comprehensive viewpoint. Therefore, there is a need to develop improved and more comprehensive approaches towards studying interactions and correlations among multimodal clinical time series data. This is important because studies continue to show that humans are poor in reasoning about changes affecting more than two signals [13] [14] [15] .", "cite_spans": [{"start": 424, "end": 428, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 429, "end": 433, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 434, "end": 438, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 1182, "end": 1186, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 1187, "end": 1191, "text": "[14]", "ref_id": "BIBREF13"}, {"start": 1192, "end": 1196, "text": "[15]", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "Introduction", "text": "Genomics. The cost to sequence the human genome (encompassing 30,000 to 35,000 genes) is rapidly decreasing with the development of high-throughput sequencing technology [16, 17] . With implications for current public health policies and delivery of care [18, 19] , analyzing genome-scale data for developing actionable recommendations in a timely manner is a significant challenge to the field of computational biology. Cost and time to deliver recommendations are crucial in a clinical setting. Initiatives tackling this complex problem include tracking of 100,000 subjects over 20 to 30 years using the predictive, preventive, participatory, and personalized health, refered to as P4, medicine paradigm [20] [21] [22] as well as an integrative personal omics profile [23] . The P4 initiative is using a system approach for (i) analyzing genome-scale datasets to determine disease states, (ii) moving towards blood based diagnostic tools for continuous monitoring of a subject, (iii) exploring new approaches to drug target discovery, developing tools to deal with big data challenges of capturing, validating, storing, mining, integrating, and finally (iv) modeling data for each individual. The integrative personal omics profile (iPOP) combines physiological monitoring and multiple high-throughput methods for genome sequencing to generate a detailed health and disease states of a subject [23] . Ultimately, realizing actionable recommendations at the clinical level remains a grand challenge for this field [24, 25] . Utilizing such high density data for exploration, discovery, and clinical translation demands novel big data approaches and analytics.", "cite_spans": [{"start": 170, "end": 174, "text": "[16,", "ref_id": "BIBREF15"}, {"start": 175, "end": 178, "text": "17]", "ref_id": "BIBREF16"}, {"start": 255, "end": 259, "text": "[18,", "ref_id": "BIBREF17"}, {"start": 260, "end": 263, "text": "19]", "ref_id": "BIBREF18"}, {"start": 706, "end": 710, "text": "[20]", "ref_id": "BIBREF19"}, {"start": 711, "end": 715, "text": "[21]", "ref_id": "BIBREF20"}, {"start": 716, "end": 720, "text": "[22]", "ref_id": "BIBREF21"}, {"start": 770, "end": 774, "text": "[23]", "ref_id": "BIBREF22"}, {"start": 1396, "end": 1400, "text": "[23]", "ref_id": "BIBREF22"}, {"start": 1515, "end": 1519, "text": "[24,", "ref_id": "BIBREF23"}, {"start": 1520, "end": 1523, "text": "25]", "ref_id": "BIBREF24"}], "ref_spans": []}, {"section": "Introduction", "text": "Despite the enormous expenditure consumed by the current healthcare systems, clinical outcomes remain suboptimal, particularly in the USA, where 96 people per 100,000 die annually from conditions considered treatable [26] . A key factor attributed to such inefficiencies is the inability to effectively gather, share, and use information in a more comprehensive manner within the healthcare systems [27] . This is an opportunity for big data analytics to play a more significant role in aiding the exploration and discovery process, improving the delivery of care, helping to design and plan healthcare policy, providing a means for comprehensively measuring, and evaluating the complicated and convoluted healthcare data. More importantly, adoption of insights gained from big data analytics has the potential to save lives, improve care delivery, expand access to healthcare, align payment with performance, and help curb the vexing growth of healthcare costs.", "cite_spans": [{"start": 217, "end": 221, "text": "[26]", "ref_id": "BIBREF25"}, {"start": 399, "end": 403, "text": "[27]", "ref_id": "BIBREF26"}], "ref_spans": []}, {"section": "Medical Image Processing from Big Data Point of View", "text": "Medical imaging provides important information on anatomy and organ function in addition to detecting diseases states. Moreover, it is utilized for organ delineation, identifying tumors in lungs, spinal deformity diagnosis, artery stenosis detection, aneurysm detection, and so forth. In these applications, image processing techniques such as enhancement, segmentation, and denoising in addition to machine learning methods are employed. As the size and dimensionality of data increase, understanding the dependencies among the data and designing efficient, accurate, and computationally effective methods demand new computer-aided techniques and platforms. The rapid growth in the number of healthcare organizations as well as the number of patients has resulted in the greater use of computer-aided medical diagnostics and decision support systems in clinical settings. Many areas in health care such as diagnosis, prognosis, and screening can be improved by utilizing computational intelligence [28] .", "cite_spans": [{"start": 999, "end": 1003, "text": "[28]", "ref_id": "BIBREF27"}], "ref_spans": []}, {"section": "Medical Image Processing from Big Data Point of View", "text": "The integration of computer analysis with appropriate care has potential to help clinicians improve diagnostic accuracy [29] . The integration of medical images with other types of electronic health record (EHR) data and genomic data can also improve the accuracy and reduce the time taken for a diagnosis.", "cite_spans": [{"start": 120, "end": 124, "text": "[29]", "ref_id": "BIBREF28"}], "ref_spans": []}, {"section": "Medical Image Processing from Big Data Point of View", "text": "In the following, data produced by imaging techniques are reviewed and applications of medical imaging from a big data point of view are discussed.", "cite_spans": [], "ref_spans": []}, {"section": "Data Produced by Imaging Techniques.", "text": "Medical imaging encompasses a wide spectrum of different image acquisition methodologies typically utilized for a variety of clinical applications. For example, visualizing blood vessel structure can be performed using magnetic resonance imaging (MRI), computed tomography (CT), ultrasound, and photoacoustic imaging [30] . From a data dimension point of view, medical images might have 2, 3, and four dimensions. Positron emission tomography (PET), CT, 3D ultrasound, and functional MRI (fMRI) are considered as multidimensional medical data. Modern medical image technologies can produce highresolution images such as respiration-correlated or \"fourdimensional\" computed tomography (4D CT) [31] . Higher resolution and dimensions of these images generate large volumes of data requiring high performance computing (HPC) and advanced analytical methods. For instance, microscopic scans of a human brain with high resolution can require 66TB of storage space [32] . Although the volume and variety of medical data make its analysis a big challenge, advances in medical imaging could make individualized care more practical [33] and provide quantitative information in variety of applications such as disease stratification, predictive modeling, and decision making systems. In the following we refer to two medical imaging techniques and one of their associated challenges.", "cite_spans": [{"start": 317, "end": 321, "text": "[30]", "ref_id": "BIBREF29"}, {"start": 692, "end": 696, "text": "[31]", "ref_id": "BIBREF30"}, {"start": 959, "end": 963, "text": "[32]", "ref_id": "BIBREF31"}, {"start": 1123, "end": 1127, "text": "[33]", "ref_id": "BIBREF32"}], "ref_spans": []}, {"section": "Data Produced by Imaging Techniques.", "text": "Molecular imaging is a noninvasive technique of cellular and subcellular events [34] which has the potential for clinical diagnosis of disease states such as cancer. However, in order to make it clinically applicable for patients, the interaction of radiology, nuclear medicine, and biology is crucial [35] that could complicate its automated analysis.", "cite_spans": [{"start": 80, "end": 84, "text": "[34]", "ref_id": "BIBREF33"}, {"start": 302, "end": 306, "text": "[35]", "ref_id": "BIBREF34"}], "ref_spans": []}, {"section": "Data Produced by Imaging Techniques.", "text": "Microwave imaging is an emerging methodology that could create a map of electromagnetic wave scattering arising from the contrast in the dielectric properties of different tissues [36] . It has both functional and physiological information encoded in the dielectric properties which can help differentiate and characterize different tissues and/or pathologies [37] . However, microwaves have scattering behavior that makes retrieval of information a challenging task.", "cite_spans": [{"start": 180, "end": 184, "text": "[36]", "ref_id": "BIBREF35"}, {"start": 360, "end": 364, "text": "[37]", "ref_id": "BIBREF36"}], "ref_spans": []}, {"section": "Data Produced by Imaging Techniques.", "text": "The integration of images from different modalities and/or other clinical and physiological information could improve the accuracy of diagnosis and outcome prediction of disease. Liebeskind and Feldmann explored advances in neurovascular imaging and the role of multimodal CT or MRI including angiography and perfusion imaging on evaluating the brain vascular disorder and achieving precision medicine [33] . Delayed enhanced MRI has been used for exact assessment of myocardial infarction scar [38] . For this kind of disease, electroanatomic mapping (EAM) can help in identifying the subendocardial extension of infarct. The role of evaluating both MRI and CT images to increase the accuracy of diagnosis in detecting the presence of erosions and osteophytes in the temporomandibular joint (TMJ) has been investigated by Hussain et al. [39] . According to this study simultaneous evaluation of all the available imaging techniques is an unmet need.", "cite_spans": [{"start": 402, "end": 406, "text": "[33]", "ref_id": "BIBREF32"}, {"start": 495, "end": 499, "text": "[38]", "ref_id": "BIBREF37"}, {"start": 838, "end": 842, "text": "[39]", "ref_id": "BIBREF38"}], "ref_spans": []}, {"section": "Data Produced by Imaging Techniques.", "text": "Advanced Multimodal Image-Guided Operating (AMIGO) suite has been designed which has angiographic X-ray system, MRI, 3D ultrasound, and PET/CT imaging in the operating room (OR). This system has been used for cancer therapy and showed the improvement in localization and targeting an individual's diseased tissue [40] .", "cite_spans": [{"start": 313, "end": 317, "text": "[40]", "ref_id": "BIBREF39"}], "ref_spans": []}, {"section": "Data Produced by Imaging Techniques.", "text": "Besides the huge space required for storing all the data and their analysis, finding the map and dependencies among different data types are challenges for which there is no optimal solution yet.", "cite_spans": [], "ref_spans": []}, {"section": "Methods.", "text": "The volume of medical images is growing exponentially. For instance, ImageCLEF medical image dataset contained around 66,000 images between 2005 and 2007 while just in the year of 2013 around 300,000 images were stored everyday [41] . In addition to the growing volume of images, they differ in modality, resolution, dimension, and quality which introduce new challenges such as data integration and mining specially if multiple datasets are involved. Compared to the volume of research that exists on single modal medical image analysis, there is considerably lesser number of research initiatives on multimodal image analysis.", "cite_spans": [{"start": 228, "end": 232, "text": "[41]", "ref_id": "BIBREF40"}], "ref_spans": []}, {"section": "Methods.", "text": "When utilizing data at a local/institutional level, an important aspect of a research project is on how the developed system is evaluated and validated. Having annotated data or a structured method to annotate new data is a real challenge. This becomes even more challenging when large-scale data integration from multiple institutions are taken into account. As an example, for the same applications (e.g., traumatic brain injury) and the same modality (e.g., CT), different institutes might use different settings in image acquisitions which makes it hard to develop unified annotation or analytical methods for such data. In order to benefit the multimodal images and their integration with other medical data, new analytical methods with real-time feasibility and scalability are required. In the following we look at analytical methods that deal with some aspects of big data.", "cite_spans": [], "ref_spans": []}, {"section": "Analytical Methods.", "text": "The goal of medical image analytics is to improve the interpretability of depicted contents [8] . Many methods and frameworks have been developed for medical image processing. However, these methods are not necessarily applicable for big data applications.", "cite_spans": [{"start": 92, "end": 95, "text": "[8]", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "Analytical Methods.", "text": "One of the frameworks developed for analyzing and transformation of very large datasets is Hadoop that employs MapReduce [42, 43] . MapReduce is a programming paradigm that provides scalability across many servers in a Hadoop cluster with a broad variety of real-world applications [44] [45] [46] . However, it does not perform well with inputoutput intensive tasks [47] . MapReduce framework has been used in [47] to increase the speed of three large-scale medical image processing use-cases, (i) finding optimal parameters for lung texture classification by employing a well-known machine learning method, support vector machines (SVM), (ii) content-based medical image indexing, and (iii) wavelet analysis for solid texture classification. In this framework, a cluster of heterogeneous computing nodes with a maximum of 42 concurrent map tasks was set up and the speedup around 100 was achieved. In other words, total execution time for finding optimal SVM parameters was reduced from about 1000 h to around 10 h. Designing a fast method is crucial in some applications such as trauma assessment in critical care where the end goal is to utilize such imaging techniques and their analysis within what is considered as a goldenhour of care [48] . Therefore, execution time or real-time feasibility of developed methods is of importance. Accuracy is another factor that should be considered in designing an analytical method. Finding dependencies among different types of data could help improve the accuracy. For instance, a hybrid machine learning method has been developed in [49] that classifies schizophrenia patients and healthy controls using fMRI images and single nucleotide polymorphism (SNP) data [49] . The authors reported an accuracy of 87% classification, which would not have been as high if they had used just fMRI images or SNP alone. del Toro and Muller have compared some organ segmentation methods when data is considered as big data. They have proposed a method that incorporates both local contrast of the image and atlas probabilistic information [50] . An average of 33% improvement has been achieved compared to using only atlas information. Tsymbal et al. have designed a clinical decision support system that exploits discriminative distance learning with significantly lower computational complexity compared to classical alternatives and hence this system is more scalable to retrieval [51] . A computer-aided decision support system was developed by Chen et al. [52] that could assist physicians to provide accurate treatment planning for patients suffering from traumatic brain injury (TBI). In this method, patient's demographic information, medical records, and features extracted from CT scans were combined to predict the level of intracranial pressure (ICP). The accuracy, sensitivity, and specificity were reported to be around 70.3%, 65.2%, and 73.7%, respectively. In [53] , molecular imaging and its impact on cancer detection and cancer drug improvement are discussed. The proposed technology is designed to aid in early detection of cancer by integrating molecular and physiological information with anatomical information. Using this imaging technique for patients with advanced ovarian cancer, the accuracy of the predictor of response to a special treatment has been increased compared to other clinical or histopathologic criteria. A hybrid digital-optical correlator (HDOC) has been designed to speed up the correlation of images [54] . HDOC can be employed to compare images in the absence of coordinate matching or georegistration. In this multichannel method, the computation is performed in the storage medium which is a volume holographic memory which could help HDOC to be applicable in the area of big data analytics [54] .", "cite_spans": [{"start": 121, "end": 125, "text": "[42,", "ref_id": "BIBREF41"}, {"start": 126, "end": 129, "text": "43]", "ref_id": "BIBREF42"}, {"start": 282, "end": 286, "text": "[44]", "ref_id": "BIBREF43"}, {"start": 287, "end": 291, "text": "[45]", "ref_id": "BIBREF44"}, {"start": 292, "end": 296, "text": "[46]", "ref_id": "BIBREF45"}, {"start": 366, "end": 370, "text": "[47]", "ref_id": "BIBREF46"}, {"start": 410, "end": 414, "text": "[47]", "ref_id": "BIBREF46"}, {"start": 1242, "end": 1246, "text": "[48]", "ref_id": "BIBREF47"}, {"start": 1580, "end": 1584, "text": "[49]", "ref_id": "BIBREF48"}, {"start": 1709, "end": 1713, "text": "[49]", "ref_id": "BIBREF48"}, {"start": 2072, "end": 2076, "text": "[50]", "ref_id": "BIBREF49"}, {"start": 2417, "end": 2421, "text": "[51]", "ref_id": "BIBREF50"}, {"start": 2494, "end": 2498, "text": "[52]", "ref_id": "BIBREF51"}, {"start": 2909, "end": 2913, "text": "[53]", "ref_id": "BIBREF52"}, {"start": 3479, "end": 3483, "text": "[54]", "ref_id": "BIBREF53"}, {"start": 3773, "end": 3777, "text": "[54]", "ref_id": "BIBREF53"}], "ref_spans": []}, {"section": "Collecting, Sharing, and Compressing Methods.", "text": "In addition to developing analytical methods, efforts have been made for collecting, compressing, sharing, and anonymizing medical data. One example is iDASH (integrating data for analysis, anonymization, and sharing) which is a center for biomedical computing [55] . It focuses on algorithms and tools for sharing data in a privacy-preserving manner. The goal of iDASH is to bring together a multi-institutional team of quantitative scientists to develop algorithms and tools, services, and a biomedical cyber infrastructure to be used by biomedical and behavioral researchers [55] . Another example of a similar approach is Health-e-Child consortium of 14 academic, industry, and clinical partners with the aim of developing an integrated healthcare platform for European paediatrics [51] .", "cite_spans": [{"start": 261, "end": 265, "text": "[55]", "ref_id": "BIBREF54"}, {"start": 578, "end": 582, "text": "[55]", "ref_id": "BIBREF54"}, {"start": 786, "end": 790, "text": "[51]", "ref_id": "BIBREF50"}], "ref_spans": []}, {"section": "Collecting, Sharing, and Compressing Methods.", "text": "Based on the Hadoop platform, a system has been designed for exchanging, storing, and sharing electronic medical records (EMR) among different healthcare systems [56] . This system can also help users retrieve medical images from a database. Medical data has been investigated from an acquisition point of view where patients' vital data is collected through a network of sensors [57] . This system delivers data to a cloud for storage, distribution, and processing. A prototype system has been implemented in [58] to handle standard store/query/retrieve requests on a database of Digital Imaging and Communications in Medicine (DICOM) images. This system uses Microsoft Windows Azure as a cloud computing platform.", "cite_spans": [{"start": 162, "end": 166, "text": "[56]", "ref_id": "BIBREF55"}, {"start": 380, "end": 384, "text": "[57]", "ref_id": "BIBREF56"}, {"start": 510, "end": 514, "text": "[58]", "ref_id": "BIBREF57"}], "ref_spans": []}, {"section": "Collecting, Sharing, and Compressing Methods.", "text": "When dealing with a very large volume of data, compression techniques can help overcome data storage and network bandwidth limitations. Many methods have been developed for medical image compression. However, there are a few methods developed for big data compression. A method has been designed to compress both high-throughput sequencing dataset and the data generated from calculation of log-odds of probability error for each nucleotide and the maximum compression ratios of 400 and 5 have been achieved, respectively [55] . This dataset has medical and biomedical data including genotyping, gene expression, proteomic measurements with Medical images suffer from different types of noise/artifacts and missing data. Noise reduction, artifact removal, missing data handling, contrast adjusting, and so forth could enhance the quality of images and increase the performance of processing methods. Employing multimodal data could be beneficial for this purpose [63] [64] [65] .", "cite_spans": [{"start": 522, "end": 526, "text": "[55]", "ref_id": "BIBREF54"}, {"start": 963, "end": 967, "text": "[63]", "ref_id": "BIBREF62"}, {"start": 968, "end": 972, "text": "[64]", "ref_id": "BIBREF63"}, {"start": 973, "end": 977, "text": "[65]", "ref_id": "BIBREF64"}], "ref_spans": []}, {"section": "Collecting, Sharing, and Compressing Methods.", "text": "Compression Reducing the volume of data while maintaining important data such as anatomically relevant data [55, 61, 66] . Parallelization/real-time realization", "cite_spans": [{"start": 108, "end": 112, "text": "[55,", "ref_id": "BIBREF54"}, {"start": 113, "end": 116, "text": "61,", "ref_id": "BIBREF60"}, {"start": 117, "end": 120, "text": "66]", "ref_id": "BIBREF65"}], "ref_spans": []}, {"section": "Collecting, Sharing, and Compressing Methods.", "text": "Developing scalable/parallel methods and frameworks to speed up the analysis/processing [61] .", "cite_spans": [{"start": 88, "end": 92, "text": "[61]", "ref_id": "BIBREF60"}], "ref_spans": []}, {"section": "Collecting, Sharing, and Compressing Methods.", "text": "Registration/mapping Aligning consecutive slices/frames from one scan or corresponding images from different modalities [67, 68] .", "cite_spans": [{"start": 120, "end": 124, "text": "[67,", "ref_id": "BIBREF66"}, {"start": 125, "end": 128, "text": "68]", "ref_id": "BIBREF67"}], "ref_spans": []}, {"section": "Collecting, Sharing, and Compressing Methods.", "text": "Sharing/security/anonymization Integrity, privacy, and confidentiality of data must be protected [55, [69] [70] [71] .", "cite_spans": [{"start": 97, "end": 101, "text": "[55,", "ref_id": "BIBREF54"}, {"start": 102, "end": 106, "text": "[69]", "ref_id": "BIBREF68"}, {"start": 107, "end": 111, "text": "[70]", "ref_id": "BIBREF69"}, {"start": 112, "end": 116, "text": "[71]", "ref_id": "BIBREF70"}], "ref_spans": []}, {"section": "Segmentation", "text": "Delineation of anatomical structure such as vessels and bones [50, 68, 72] .", "cite_spans": [{"start": 62, "end": 66, "text": "[50,", "ref_id": "BIBREF49"}, {"start": 67, "end": 70, "text": "68,", "ref_id": "BIBREF67"}, {"start": 71, "end": 74, "text": "72]", "ref_id": "BIBREF71"}], "ref_spans": []}, {"section": "Data integration/mining", "text": "Finding dependencies/patterns among multimodal data and/or the data captured at different time points in order to increase the accuracy of diagnosis, prediction, and overall performance of the system [47, 49, 52, 73] .", "cite_spans": [{"start": 200, "end": 204, "text": "[47,", "ref_id": "BIBREF46"}, {"start": 205, "end": 208, "text": "49,", "ref_id": "BIBREF48"}, {"start": 209, "end": 212, "text": "52,", "ref_id": "BIBREF51"}, {"start": 213, "end": 216, "text": "73]", "ref_id": "BIBREF72"}], "ref_spans": []}, {"section": "Validation", "text": "Assessing the performance or accuracy of the system/method. Validation can be objective or subjective. For the former, annotated data is usually required [74] [75] [76] .", "cite_spans": [{"start": 154, "end": 158, "text": "[74]", "ref_id": "BIBREF73"}, {"start": 159, "end": 163, "text": "[75]", "ref_id": "BIBREF74"}, {"start": 164, "end": 168, "text": "[76]", "ref_id": "BIBREF75"}], "ref_spans": []}, {"section": "Validation", "text": "demographics, laboratory values, images, therapeutic interventions, and clinical phenotypes for Kawasaki Disease (KD). By illustrating the data with a graph model, a framework for analyzing large-scale data has been presented [59] . For this model, the fundamental signal processing techniques such as filtering and Fourier transform were implemented. In [60] , the application of simplicity and power (SP) theory of intelligence in big data has been investigated. The goal of SP theory is to simplify and integrate concepts from multiple fields such as artificial intelligence, mainstream computing, mathematics, and human perception and cognition that can be observed as a brain-like system [60] . The proposed SP system performs lossless compression through the matching and unification of patterns. However, this system is still in the design stage and cannot be supported by today's technologies. There are some limitations in implementing the application-specific compression methods on both generalpurpose processors and parallel processors such as graphics processing units (GPUs) as these algorithms need highly variable control and complex bit manipulations which are not well suited to GPUs and pipeline architectures. To overcome this limitation, an FPGA implementation was proposed for LZ-factorization which decreases the computational burden of the compression algorithm [61] . A lossy image compression has been introduced in [62] that reshapes the image in such a way that if the image is uniformly sampled, sharp features have a higher sampling density than the coarse ones. This method is claimed to be applicable for big data compression. However, for medical applications lossy methods are not applicable in most cases as fidelity is important and information must be preserved.", "cite_spans": [{"start": 226, "end": 230, "text": "[59]", "ref_id": "BIBREF58"}, {"start": 355, "end": 359, "text": "[60]", "ref_id": "BIBREF59"}, {"start": 693, "end": 697, "text": "[60]", "ref_id": "BIBREF59"}, {"start": 1386, "end": 1390, "text": "[61]", "ref_id": "BIBREF60"}, {"start": 1442, "end": 1446, "text": "[62]", "ref_id": "BIBREF61"}], "ref_spans": []}, {"section": "Validation", "text": "These techniques are among a few techniques that have been either designed as prototypes or developed with limited applications. Developing methods for processing/analyzing a broad range and large volume of data with acceptable accuracy and speed is still critical. In Table 1 , we summarize the challenges facing medical image processing. When dealing with big data, these challenges seemed to be more serious and on the other hand analytical methods could benefit the big data to handle them.", "cite_spans": [], "ref_spans": [{"start": 269, "end": 276, "text": "Table 1", "ref_id": "TABREF0"}]}, {"section": "Medical Signal Analytics", "text": "Telemetry and physiological signal monitoring devices are ubiquitous. However, continuous data generated from these monitors have not been typically stored for more than a brief period of time, thereby neglecting extensive investigation into generated data. However, in the recent past, there has been an increase in the attempts towards utilizing telemetry and continuous physiological time series monitoring to improve patient care and management [77] [78] [79] [80] .", "cite_spans": [{"start": 449, "end": 453, "text": "[77]", "ref_id": "BIBREF76"}, {"start": 454, "end": 458, "text": "[78]", "ref_id": "BIBREF77"}, {"start": 459, "end": 463, "text": "[79]", "ref_id": "BIBREF78"}, {"start": 464, "end": 468, "text": "[80]", "ref_id": "BIBREF79"}], "ref_spans": []}, {"section": "Medical Signal Analytics", "text": "Streaming data analytics in healthcare can be defined as a systematic use of continuous waveform (signal varying against time) and related medical record information developed through applied analytical disciplines (e.g., statistical, quantitative, contextual, cognitive, and predictive) to drive decision making for patient care. The analytics workflow of real-time streaming waveforms in clinical settings can be broadly described using Figure 1 . Firstly, a platform for streaming data acquisition and ingestion is required which has the bandwidth to handle multiple waveforms at different fidelities. Integrating these dynamic waveform data with static data from the EHR is a key component to provide situational and contextual awareness for the analytics engine. Enriching the data consumed by analytics not only makes the system more robust, but also helps balance the sensitivity and specificity of the predictive analytics. The specifics of the signal processing will largely depend on the type of disease cohort under investigation. A variety of signal processing mechanisms can be utilized to extract a multitude of target features which are then consumed by a pretrained machine learning model to produce an actionable insight. These actionable insights could either be diagnostic, predictive, or prescriptive. These insights could further be designed to trigger other mechanisms such as alarms and notification to physicians.", "cite_spans": [], "ref_spans": [{"start": 439, "end": 447, "text": "Figure 1", "ref_id": "FIGREF1"}]}, {"section": "Medical Signal Analytics", "text": "Harmonizing such continuous waveform data with discrete data from other sources for finding necessary patient information and conducting research towards development of next generation diagnoses and treatments can be a daunting task [81] . For bed-side implementation of such systems in clinical environments, there are several technical considerations and requirements that need to be designed and implemented at system, analytic, and clinical levels. The following subsections provide an overview of different challenges and existing approaches in the development of monitoring systems that consume both high fidelity waveform data and discrete data from noncontinuous sources.", "cite_spans": [{"start": 233, "end": 237, "text": "[81]", "ref_id": "BIBREF80"}], "ref_spans": []}, {"section": "Data Acquisition.", "text": "Historically streaming data from continuous physiological signal acquisition devices was rarely stored. Even if the option to store this data were available, the length of these data captures was typically short and downloaded only using proprietary software and data formats provided by the device manufacturers. Although most major medical device manufactures are now taking steps to provide interfaces to access live streaming data from their devices, such data in motion very quickly poses archetypal big data challenges. The fact that there are also governance challenges such as lack of data protocols, lack of data standards, and data privacy issues is adding to this. On the other side there are many challenges within the healthcare systems such as network bandwidth, scalability, and cost that have stalled the widespread adoption of such streaming data collection [82] [83] [84] . This has allowed way for system-wide projects which especially cater to medical research communities [77, 79, 80, [85] [86] [87] [88] [89] [90] [91] [92] [93] .", "cite_spans": [{"start": 875, "end": 879, "text": "[82]", "ref_id": "BIBREF81"}, {"start": 880, "end": 884, "text": "[83]", "ref_id": "BIBREF82"}, {"start": 885, "end": 889, "text": "[84]", "ref_id": "BIBREF83"}, {"start": 993, "end": 997, "text": "[77,", "ref_id": "BIBREF76"}, {"start": 998, "end": 1001, "text": "79,", "ref_id": "BIBREF78"}, {"start": 1002, "end": 1005, "text": "80,", "ref_id": "BIBREF79"}, {"start": 1006, "end": 1010, "text": "[85]", "ref_id": "BIBREF84"}, {"start": 1011, "end": 1015, "text": "[86]", "ref_id": "BIBREF85"}, {"start": 1016, "end": 1020, "text": "[87]", "ref_id": "BIBREF86"}, {"start": 1021, "end": 1025, "text": "[88]", "ref_id": "BIBREF87"}, {"start": 1026, "end": 1030, "text": "[89]", "ref_id": "BIBREF88"}, {"start": 1031, "end": 1035, "text": "[90]", "ref_id": "BIBREF89"}, {"start": 1036, "end": 1040, "text": "[91]", "ref_id": "BIBREF90"}, {"start": 1041, "end": 1045, "text": "[92]", "ref_id": "BIBREF91"}, {"start": 1046, "end": 1050, "text": "[93]", "ref_id": "BIBREF92"}], "ref_spans": []}, {"section": "Data Acquisition.", "text": "Research community has interest in consuming data captured from live monitors for developing continuous monitoring technologies [94, 95] . There have been several indigenous and off-the-shelf efforts in developing and implementing systems that enable such data capture [85, [96] [97] [98] [99] . There are also products being developed in the industry that facilitate device manufacturer agnostic data acquisition from patient monitors across healthcare systems.", "cite_spans": [{"start": 128, "end": 132, "text": "[94,", "ref_id": "BIBREF93"}, {"start": 133, "end": 136, "text": "95]", "ref_id": "BIBREF94"}, {"start": 269, "end": 273, "text": "[85,", "ref_id": "BIBREF84"}, {"start": 274, "end": 278, "text": "[96]", "ref_id": "BIBREF95"}, {"start": 279, "end": 283, "text": "[97]", "ref_id": "BIBREF96"}, {"start": 284, "end": 288, "text": "[98]", "ref_id": "BIBREF97"}, {"start": 289, "end": 293, "text": "[99]", "ref_id": "BIBREF98"}], "ref_spans": []}, {"section": "Data Storage and Retrieval.", "text": "With large volumes of streaming data and other patient information that can be gathered from clinical settings, sophisticated storage mechanisms of such data are imperative. Since storing and retrieving can be computational and time expensive, it is key to have a storage infrastructure that facilitates rapid data pull and commits based on analytic demands.", "cite_spans": [], "ref_spans": []}, {"section": "Data Storage and Retrieval.", "text": "With its capability to store and compute large volumes of data, usage of systems such as Hadoop, MapReduce, and MongoDB [100, 101] is becoming much more common with the healthcare research communities. MongoDB is a free cross-platform document-oriented database which eschews traditional table-based relational database. Typically each health system has its own custom relational database schemas and data models which inhibit interoperability of healthcare data for multi-institutional data sharing or research studies. Furthermore, given the nature of traditional databases integrating data of different types such as streaming waveforms and static EHR data is not feasible. This is where MongoDB and other document-based databases can provide high performance, high availability, and easy scalability for the healthcare data needs [102, 103] . Apache Hadoop is an open source framework that allows for the distributed processing of large datasets across clusters of computers using simple programming models. It is a highly scalable platform which provides a variety of computing modules such as MapReduce and Spark. For performing analytics on continuous telemetry waveforms, a module like Spark is especially useful since it provides capabilities to ingest and compute on streaming data along with machine learning and graphing tools. Such technologies allow researchers to utilize data for both realtime as well as retrospective analysis, with the end goal to translate scientific discovery into applications for clinical settings in an effective manner.", "cite_spans": [{"start": 120, "end": 125, "text": "[100,", "ref_id": "BIBREF99"}, {"start": 126, "end": 130, "text": "101]", "ref_id": "BIBREF100"}, {"start": 834, "end": 839, "text": "[102,", "ref_id": "BIBREF101"}, {"start": 840, "end": 844, "text": "103]", "ref_id": "BIBREF102"}], "ref_spans": []}, {"section": "Data Aggregation.", "text": "Integration of disparate sources of data, developing consistency within the data, standardization of data from similar sources, and improving the confidence in the data especially towards utilizing automated analytics are among challenges facing data aggregation in healthcare systems [104] . Medical data can be complex in nature as well as being interconnected and interdependent; hence simplification of this complexity is important. Medical data is also subject to the highest level of scrutiny for privacy and provenance from governing bodies, therefore developing secure storage, access, and use of the data is very important [105] .", "cite_spans": [{"start": 285, "end": 290, "text": "[104]", "ref_id": "BIBREF103"}, {"start": 632, "end": 637, "text": "[105]", "ref_id": "BIBREF105"}], "ref_spans": []}, {"section": "Data Aggregation.", "text": "Analysis of continuous data heavily utilizes the information in time domain. However, static data does not always provide true time context and, hence, when combining the waveform data with static electronic health record data, the temporal nature of the time context during integration can also add significantly to the challenges. There are considerable efforts in compiling waveforms and other associated electronic medical information into one cohesive database that are made publicly available for researchers worldwide [106, 107] . For example, MIMIC II [108, 109] and some other datasets included in Physionet [96] provide waveforms and other clinical data from a wide variety of actual patient cohorts.", "cite_spans": [{"start": 525, "end": 530, "text": "[106,", "ref_id": "BIBREF106"}, {"start": 531, "end": 535, "text": "107]", "ref_id": "BIBREF107"}, {"start": 560, "end": 565, "text": "[108,", "ref_id": "BIBREF108"}, {"start": 566, "end": 570, "text": "109]", "ref_id": "BIBREF109"}, {"start": 617, "end": 621, "text": "[96]", "ref_id": "BIBREF95"}], "ref_spans": []}, {"section": "Signal Analytics Using Big Data.", "text": "Research in signal processing for developing big data based clinical decision support systems (CDSSs) is getting more prevalent [110] . In fact organizations such as the Institution of Medicine have long advocated use of health information technology including CDSS to improve care quality [111] . CDSSs provide medical practitioners with knowledge and patient-specific information, intelligently filtered and presented at appropriate times, to improve the delivery of care [112] .", "cite_spans": [{"start": 128, "end": 133, "text": "[110]", "ref_id": "BIBREF110"}, {"start": 290, "end": 295, "text": "[111]", "ref_id": "BIBREF111"}, {"start": 474, "end": 479, "text": "[112]", "ref_id": "BIBREF112"}], "ref_spans": []}, {"section": "Signal Analytics Using Big Data.", "text": "A vast amount of data in short periods of time is produced in intensive care units (ICU) where a large volume of physiological data is acquired from each patient. Hence, the potential for developing CDSS in an ICU environment has been recognized by many researchers. A scalable infrastructure for developing a patient care management system has been proposed which combines static data and stream data monitored from critically ill patients in the ICU for data mining and alerting medical staff of critical events in real time [113] . Similarly, Bressan et al. developed an architecture specialized for a neonatal ICU which utilized streaming data from infusion pumps, EEG monitors, cerebral oxygenation monitors, and so forth to provide clinical decision support [114] . A clinical trial is currently underway which extracts biomarkers through signal processing from heart and respiratory waveforms in real time to test whether maintaining stable heart rate and respiratory rate variability throughout the spontaneous breathing trials, administered to patients before extubation, may predict subsequent successful extubation [115] . An animal study shows how acquisition of noninvasive continuous data such as tissue oxygenation, fluid content, and blood flow can be used as indicators of soft tissue healing in wound care [78] . Electrocardiogrpah parameters from telemetry along with demographic information including medical history, ejection fraction, laboratory values, and medications have been used to develop an inhospital early detection system for cardiac arrest [116] .", "cite_spans": [{"start": 527, "end": 532, "text": "[113]", "ref_id": "BIBREF113"}, {"start": 764, "end": 769, "text": "[114]", "ref_id": "BIBREF114"}, {"start": 1126, "end": 1131, "text": "[115]", "ref_id": "BIBREF115"}, {"start": 1324, "end": 1328, "text": "[78]", "ref_id": "BIBREF77"}, {"start": 1574, "end": 1579, "text": "[116]", "ref_id": "BIBREF116"}], "ref_spans": []}, {"section": "Signal Analytics Using Big Data.", "text": "A study presented by Lee and Mark uses the MIMIC II database to prompt therapeutic intervention to hypotensive episodes using cardiac and blood pressure time series data [117] . Another study shows the use of physiological waveform data along with clinical data from the MIMIC II database for finding similarities among patients within the selected cohorts [118] . This similarity can potentially help care givers in the decision making process while utilizing outcomes and treatments knowledge gathered from similar disease cases from the past. A combination of multiple waveform information available in the MIMIC II database is utilized to develop early detection of cardiovascular instability in patients [119] . Many types of physiological data captured in the operative and preoperative care settings and how analytics can consume these data to help continuously monitor the status of the patients during, before and after surgery, are described in [120] . The potential of developing data fusion based machine learning models which utilizes biomarkers from breathomics (metabolomics study of exhaled air) as a diagnostic tool is demonstrated in [121] .", "cite_spans": [{"start": 170, "end": 175, "text": "[117]", "ref_id": "BIBREF117"}, {"start": 357, "end": 362, "text": "[118]", "ref_id": "BIBREF118"}, {"start": 709, "end": 714, "text": "[119]", "ref_id": "BIBREF119"}, {"start": 955, "end": 960, "text": "[120]", "ref_id": "BIBREF120"}, {"start": 1152, "end": 1157, "text": "[121]", "ref_id": "BIBREF121"}], "ref_spans": []}, {"section": "Signal Analytics Using Big Data.", "text": "Research in neurology has shown interest in electrophysiologic monitoring of patients to not only examine complex diseases under a new light but also develop next generation diagnostics and therapeutic devices. An article focusing on neurocritical care explores the different physiological monitoring systems specifically developed for the care of patients with disorders who require neurocritical care [122] . The authors of this article do not make specific recommendations about treatment, imaging, and intraoperative monitoring; instead they examine the potentials and implications of neuromonitoring with differeing quality of data and also provide guidance on developing research and application in this area. The development of multimodal monitoring for traumatic brain injury patients and individually tailored, patient specific care are examined in [123] . Zanatta et al. have investigated whether multimodal brain monitoring performed with TCD, EEG, and SEPs reduces the incidence of major neurologic complications in patients who underwent cardiac surgery. The authors evaluated whether the use of multimodal brain monitoring shortened the duration of mechanical ventilation required by patients as well as ICU and healthcare stays. The concepts of multimodal monitoring for secondary brain injury in neurocritical care as well as outline initial and future approaches using informatics tools for understanding and applying such data towards clinical care are described in [124] .", "cite_spans": [{"start": 403, "end": 408, "text": "[122]", "ref_id": "BIBREF122"}, {"start": 858, "end": 863, "text": "[123]", "ref_id": "BIBREF123"}, {"start": 1484, "end": 1489, "text": "[124]", "ref_id": "BIBREF124"}], "ref_spans": []}, {"section": "Signal Analytics Using Big Data.", "text": "As complex physiological monitoring devices are getting smaller, cheaper, and more portable, personal monitoring devices are being used outside of clinical environments by both patients and enthusiasts alike. However, similar to clinical applications, combining information simultaneously collected from multiple portable devices can become challenging. Pantelopoulos and Bourbakis discussed the research and development of wearable biosensor systems and identified the advantages and shortcomings in this area of study [125] . Similarly, portable and connected electrocardiogram, blood pressure and body weight devices are used to set up a network based study of telemedicine [126] . The variety of fixed as well as mobile sensors available for data mining in the healthcare sector and how such data can be leveraged for developing patient care technologies are surveyed in [127] .", "cite_spans": [{"start": 520, "end": 525, "text": "[125]", "ref_id": "BIBREF125"}, {"start": 677, "end": 682, "text": "[126]", "ref_id": "BIBREF126"}, {"start": 875, "end": 880, "text": "[127]", "ref_id": "BIBREF127"}], "ref_spans": []}, {"section": "Big Data Applications in Genomics", "text": "The advent of high-throughput sequencing methods has enabled researchers to study genetic markers over a wide range of population [22, 128] , improve efficiency by more than five orders of magnitude since sequencing of the human genome was completed [129] , and associate genetic causes of the phenotype in disease states [130] . Genome-wide analysis utilizing microarrays has been successful in analyzing traits across a population and contributed successfully in treatments of complex diseases such as Crohn's disease and agerelated muscular degeneration [130] .", "cite_spans": [{"start": 130, "end": 134, "text": "[22,", "ref_id": "BIBREF21"}, {"start": 135, "end": 139, "text": "128]", "ref_id": "BIBREF128"}, {"start": 250, "end": 255, "text": "[129]", "ref_id": "BIBREF129"}, {"start": 322, "end": 327, "text": "[130]", "ref_id": "BIBREF130"}, {"start": 557, "end": 562, "text": "[130]", "ref_id": "BIBREF130"}], "ref_spans": []}, {"section": "Big Data Applications in Genomics", "text": "Analytics of high-throughput sequencing techniques in genomics is an inherently big data problem as the human genome consists of 30,000 to 35,000 genes [16, 17] . Initiatives are currently being pursued over the timescale of years to integrate clinical data from the genomic level to the physiological level of a human being [22, 23] . These initiatives will help in delivering personalized care to each patient. Delivering recommendations in a clinical setting requires fast analysis of genome-scale big data in a reliable manner. This field is still in a nascent stage with applications in specific focus areas, such as cancer [131] [132] [133] [134] , because of cost, time, and labor intensive nature of analyzing this big data problem.", "cite_spans": [{"start": 152, "end": 156, "text": "[16,", "ref_id": "BIBREF15"}, {"start": 157, "end": 160, "text": "17]", "ref_id": "BIBREF16"}, {"start": 325, "end": 329, "text": "[22,", "ref_id": "BIBREF21"}, {"start": 330, "end": 333, "text": "23]", "ref_id": "BIBREF22"}, {"start": 629, "end": 634, "text": "[131]", "ref_id": "BIBREF131"}, {"start": 635, "end": 640, "text": "[132]", "ref_id": "BIBREF132"}, {"start": 641, "end": 646, "text": "[133]", "ref_id": "BIBREF133"}, {"start": 647, "end": 652, "text": "[134]", "ref_id": "BIBREF134"}], "ref_spans": []}, {"section": "Big Data Applications in Genomics", "text": "Big data applications in genomics cover a wide variety of topics. Here we focus on pathway analysis, in which functional effects of genes differentially expressed in an experiment or gene set of particular interest are analyzed, and the reconstruction of networks, where the signals measured using high-throughput techniques are analyzed to reconstruct underlying regulatory networks. These networks influence numerous cellular processes which affect the physiological state of a human being [135] .", "cite_spans": [{"start": 492, "end": 497, "text": "[135]", "ref_id": "BIBREF135"}], "ref_spans": []}, {"section": "Pathway Analysis.", "text": "Resources for inferring functional effects for \"-omics\" big data are largely based on statistical associations between observed gene expression changes and predicted functional effects. Experiment and analytical practices lead to error as well as batch effects [136, 137] . Interpretation of functional effects has to incorporate continuous increases in available genomic data and corresponding annotation of genes [25] . There are variety of tools, but no \"gold standard\" for functional pathway analysis of high-throughput genome-scale data [138] . Three generations of methods used for pathway analysis [25] are described as follows.", "cite_spans": [{"start": 261, "end": 266, "text": "[136,", "ref_id": "BIBREF136"}, {"start": 267, "end": 271, "text": "137]", "ref_id": "BIBREF137"}, {"start": 415, "end": 419, "text": "[25]", "ref_id": "BIBREF24"}, {"start": 542, "end": 547, "text": "[138]", "ref_id": "BIBREF138"}, {"start": 605, "end": 609, "text": "[25]", "ref_id": "BIBREF24"}], "ref_spans": []}, {"section": "Pathway Analysis.", "text": "The first generation encompasses overrepresentation analysis approaches that determine the fraction of genes in a particular pathway found among the genes which are differentially expressed [25] . Examples of the first generation tools are Onto-Express [139, 140] , GoMiner [142] , and ClueGo [144] . The second generation includes functional class scoring approaches which incorporate expression level changes in individual genes as well as functionally similar genes [25] . GSEA [146] is a popular tool that belongs to the second generation of pathway analysis. The third generation includes pathway topology based tools which are publicly available pathway knowledge databases with detailed information of gene products interactions: how specific gene products interact with each other and the location where they interact [25] . Pathway-Express [148] is an example of a third generation tool that combines the knowledge of differentially expressed genes with biologically meaningful changes on a given pathway to perform pathway analysis.", "cite_spans": [{"start": 190, "end": 194, "text": "[25]", "ref_id": "BIBREF24"}, {"start": 253, "end": 258, "text": "[139,", "ref_id": "BIBREF139"}, {"start": 259, "end": 263, "text": "140]", "ref_id": "BIBREF140"}, {"start": 274, "end": 279, "text": "[142]", "ref_id": "BIBREF142"}, {"start": 293, "end": 298, "text": "[144]", "ref_id": "BIBREF144"}, {"start": 469, "end": 473, "text": "[25]", "ref_id": "BIBREF24"}, {"start": 481, "end": 486, "text": "[146]", "ref_id": "BIBREF146"}, {"start": 826, "end": 830, "text": "[25]", "ref_id": "BIBREF24"}, {"start": 849, "end": 854, "text": "[148]", "ref_id": "BIBREF148"}], "ref_spans": []}, {"section": "Reconstruction of Regulatory Networks.", "text": "Pathway analysis approaches do not attempt to make sense of high-throughput big data in biology as arising from the integrated operation of a dynamical system [25] . There are multiple approaches to analyzing genome-scale data using a dynamical system framework [135, 152, 159] . Due to the breadth of the field, in this section we mainly focus on techniques to infer network models from biological big data. Applications developed for network inference in systems biology for big data applications can be split into two broad categories consisting of reconstruction of metabolic networks and gene regulatory networks [135] . Various approaches of network inference vary in performance, and combining different approaches has shown to produce superior predictions [152, 160] .", "cite_spans": [{"start": 159, "end": 163, "text": "[25]", "ref_id": "BIBREF24"}, {"start": 262, "end": 267, "text": "[135,", "ref_id": "BIBREF135"}, {"start": 268, "end": 272, "text": "152,", "ref_id": "BIBREF152"}, {"start": 273, "end": 277, "text": "159]", "ref_id": "BIBREF159"}, {"start": 618, "end": 623, "text": "[135]", "ref_id": "BIBREF135"}, {"start": 764, "end": 769, "text": "[152,", "ref_id": "BIBREF152"}, {"start": 770, "end": 774, "text": "160]", "ref_id": "BIBREF160"}], "ref_spans": []}, {"section": "Reconstruction of Regulatory Networks.", "text": "Reconstruction of metabolic networks has advanced in last two decades. One objective is to develop an understanding of organism-specific metabolism through reconstruction of metabolic networks by integrating genomics, transcriptomics, and proteomics high-throughput sequencing techniques [150, [161] [162] [163] [164] [165] [166] [167] . Constraint-based methods are widely applied to probe the genotype-phenotype relationship and attempt to overcome the limited availability of kinetic constants [168, 169] . There are multitude of challenges in terms of analyzing genome-scale data including the experiment and inherent biological noise, differences among experimental platforms, and connecting gene expression to reaction flux used in constraint-based methods [170, 171] .", "cite_spans": [{"start": 288, "end": 293, "text": "[150,", "ref_id": "BIBREF150"}, {"start": 294, "end": 299, "text": "[161]", "ref_id": "BIBREF161"}, {"start": 300, "end": 305, "text": "[162]", "ref_id": "BIBREF162"}, {"start": 306, "end": 311, "text": "[163]", "ref_id": "BIBREF163"}, {"start": 312, "end": 317, "text": "[164]", "ref_id": "BIBREF164"}, {"start": 318, "end": 323, "text": "[165]", "ref_id": "BIBREF165"}, {"start": 324, "end": 329, "text": "[166]", "ref_id": "BIBREF166"}, {"start": 330, "end": 335, "text": "[167]", "ref_id": "BIBREF167"}, {"start": 497, "end": 502, "text": "[168,", "ref_id": "BIBREF168"}, {"start": 503, "end": 507, "text": "169]", "ref_id": "BIBREF169"}, {"start": 763, "end": 768, "text": "[170,", "ref_id": "BIBREF170"}, {"start": 769, "end": 773, "text": "171]", "ref_id": "BIBREF171"}], "ref_spans": []}, {"section": "Reconstruction of Regulatory Networks.", "text": "Available reconstructed metabolic networks include Recon 1 [161] , Recon 2 [150] , SEED [163] , IOMA [165] , and MADE [172] . Recon 2 (an improvement over Recon 1) is a model to represent human metabolism and incorporates [139, 140] Pathway analysis Breast cancer [141] GoMiner [142] Pathway analysis Pancreatic cancer [143] ClueGo [144] Pathway analysis Colorectal tumors [145] GSEA [146] Pathway analysis Diabetes [147] Pathway-Express [148] P a t h w a y a n a l y s i s L e u k e m i a [ 149] Recon 2 [150] Reconstruction of metabolic networks Drug target prediction studies [151] Boolean methods [135, 152, 153] Reconstruction of gene regulatory networks Cardiac differentiation [154] ODE models [155] [156] [157] [158] Reconstruction of gene regulatory networks Cardiac development [158] 7,440 reactions involving 5,063 metabolites. Recon 2 has been expanded to account for known drugs for drug target prediction studies [151] and to study off-target effects of drugs [173] . Reconstruction of gene regulatory networks from gene expression data is another well developed field. Network inference methods can be split into five categories based on the underlying model in each case: regression, mutual information, correlation, Boolean regulatory networks, and other techniques [152] . Over 30 inference techniques were assessed after DREAM5 challenge in 2010 [152] . Performance varied within each category and there was no category found to be consistently better than the others. Different methods utilize different information available in experiments which can be in the form of time series, drug perturbation experiments, gene knockouts, and combinations of experimental conditions. A tree-based method (using ensembles of regression trees) [174] and two-way ANOVA (analysis of variance) method [175] gave the highest performance in a recent DREAM challenge [160] .", "cite_spans": [{"start": 59, "end": 64, "text": "[161]", "ref_id": "BIBREF161"}, {"start": 75, "end": 80, "text": "[150]", "ref_id": "BIBREF150"}, {"start": 88, "end": 93, "text": "[163]", "ref_id": "BIBREF163"}, {"start": 101, "end": 106, "text": "[165]", "ref_id": "BIBREF165"}, {"start": 118, "end": 123, "text": "[172]", "ref_id": "BIBREF172"}, {"start": 222, "end": 227, "text": "[139,", "ref_id": "BIBREF139"}, {"start": 228, "end": 232, "text": "140]", "ref_id": "BIBREF140"}, {"start": 264, "end": 269, "text": "[141]", "ref_id": "BIBREF141"}, {"start": 278, "end": 283, "text": "[142]", "ref_id": "BIBREF142"}, {"start": 319, "end": 324, "text": "[143]", "ref_id": "BIBREF143"}, {"start": 332, "end": 337, "text": "[144]", "ref_id": "BIBREF144"}, {"start": 373, "end": 378, "text": "[145]", "ref_id": "BIBREF145"}, {"start": 384, "end": 389, "text": "[146]", "ref_id": "BIBREF146"}, {"start": 416, "end": 421, "text": "[147]", "ref_id": "BIBREF147"}, {"start": 438, "end": 443, "text": "[148]", "ref_id": "BIBREF148"}, {"start": 505, "end": 510, "text": "[150]", "ref_id": "BIBREF150"}, {"start": 579, "end": 584, "text": "[151]", "ref_id": "BIBREF151"}, {"start": 601, "end": 606, "text": "[135,", "ref_id": "BIBREF135"}, {"start": 607, "end": 611, "text": "152,", "ref_id": "BIBREF152"}, {"start": 612, "end": 616, "text": "153]", "ref_id": "BIBREF153"}, {"start": 684, "end": 689, "text": "[154]", "ref_id": "BIBREF154"}, {"start": 701, "end": 706, "text": "[155]", "ref_id": "BIBREF155"}, {"start": 707, "end": 712, "text": "[156]", "ref_id": "BIBREF156"}, {"start": 713, "end": 718, "text": "[157]", "ref_id": "BIBREF157"}, {"start": 719, "end": 724, "text": "[158]", "ref_id": "BIBREF158"}, {"start": 788, "end": 793, "text": "[158]", "ref_id": "BIBREF158"}, {"start": 927, "end": 932, "text": "[151]", "ref_id": "BIBREF151"}, {"start": 974, "end": 979, "text": "[173]", "ref_id": "BIBREF173"}, {"start": 1283, "end": 1288, "text": "[152]", "ref_id": "BIBREF152"}, {"start": 1365, "end": 1370, "text": "[152]", "ref_id": "BIBREF152"}, {"start": 1752, "end": 1757, "text": "[174]", "ref_id": "BIBREF174"}, {"start": 1806, "end": 1811, "text": "[175]", "ref_id": "BIBREF175"}, {"start": 1869, "end": 1874, "text": "[160]", "ref_id": "BIBREF160"}], "ref_spans": []}, {"section": "Reconstruction of Regulatory Networks.", "text": "Boolean regulatory networks [135] are a special case of discrete dynamical models where the state of a node or a set of nodes exists in a binary state. The actual state of each node or set of nodes is determined by using Boolean operations on the state of other nodes in the network [153] . Boolean networks are extremely useful when amount of quantitative data is small [135, 153] but yield high number of false positives (i.e., when a given condition is satisfied while actually that is not the case) that may be reduced by using prior knowledge [176, 177] . Another bottleneck is that Boolean networks are prohibitively expensive when the number of nodes in network is large. This is due to the number of global states rising exponentially in the number of entities [135] . A method to overcome this bottleneck is to use clustering to break down the problem size. For example, Martin et al. [178] broke down a 34,000-probe microarray gene expression dataset into 23 sets of metagenes using clustering techniques. This Boolean model successfully captured the network dynamics for two different immunology microarray datasets. The dynamics of gene regulatory network can be captured using ordinary differential equations (ODEs) [155] [156] [157] [158] . This approach has been applied to determine regulatory network for yeast [155] . The study successfully captured the regulatory network which has been characterized using experiments by molecular biologists. Reconstruction of a gene regulatory network on a genome-scale system as a dynamical model is computationally intensive [135] . A parallelizeable dynamical ODE model has been developed to address this bottleneck [179] . It reduces the computational time to O( 2 ) from time taken in other approaches which is O( 3 ) or O( 2 log ) [179] . Determining connections in the regulatory network for a problem of the size of the human genome, consisting of 30,000 to 35,000 genes [16, 17] , will require exploring close to a billion possible connections. The dynamical ODE model has been applied to reconstruct the cardiogenic gene regulatory network of the mammalian heart [158] . A summary of methods and toolkits with their applications is presented in Table 2 .", "cite_spans": [{"start": 28, "end": 33, "text": "[135]", "ref_id": "BIBREF135"}, {"start": 283, "end": 288, "text": "[153]", "ref_id": "BIBREF153"}, {"start": 371, "end": 376, "text": "[135,", "ref_id": "BIBREF135"}, {"start": 377, "end": 381, "text": "153]", "ref_id": "BIBREF153"}, {"start": 548, "end": 553, "text": "[176,", "ref_id": "BIBREF176"}, {"start": 554, "end": 558, "text": "177]", "ref_id": "BIBREF177"}, {"start": 769, "end": 774, "text": "[135]", "ref_id": "BIBREF135"}, {"start": 894, "end": 899, "text": "[178]", "ref_id": "BIBREF178"}, {"start": 1229, "end": 1234, "text": "[155]", "ref_id": "BIBREF155"}, {"start": 1235, "end": 1240, "text": "[156]", "ref_id": "BIBREF156"}, {"start": 1241, "end": 1246, "text": "[157]", "ref_id": "BIBREF157"}, {"start": 1247, "end": 1252, "text": "[158]", "ref_id": "BIBREF158"}, {"start": 1328, "end": 1333, "text": "[155]", "ref_id": "BIBREF155"}, {"start": 1582, "end": 1587, "text": "[135]", "ref_id": "BIBREF135"}, {"start": 1674, "end": 1679, "text": "[179]", "ref_id": "BIBREF179"}, {"start": 1792, "end": 1797, "text": "[179]", "ref_id": "BIBREF179"}, {"start": 1934, "end": 1938, "text": "[16,", "ref_id": "BIBREF15"}, {"start": 1939, "end": 1942, "text": "17]", "ref_id": "BIBREF16"}, {"start": 2128, "end": 2133, "text": "[158]", "ref_id": "BIBREF158"}], "ref_spans": [{"start": 2210, "end": 2217, "text": "Table 2", "ref_id": "TABREF2"}]}, {"section": "Conclusion", "text": "Big data analytics which leverages legions of disparate, structured, and unstructured data sources is going to play a vital role in how healthcare is practiced in the future. One can already see a spectrum of analytics being utilized, aiding in the decision making and performance of healthcare personnel and patients. Here we focused on three areas of interest: medical image analysis, physiological signal processing, and genomic data processing. The exponential growth of the volume of medical images forces computational scientists to come up with innovative solutions to process this large volume of data in tractable timescales. The trend of adoption of computational systems for physiological signal processing from both research and practicing medical professionals is growing steadily with the development of some very imaginative and incredible systems that help save lives. Developing a detailed model of a human being by combining physiological data and high-throughput \"-omics\" techniques has the potential to enhance our knowledge of disease states and help in the development of blood based diagnostic tools [20] [21] [22] . Medical image analysis, signal processing of physiological data, and integration of physiological and \"-omics\" data face similar challenges and opportunities in dealing with disparate structured and unstructured big data sources.", "cite_spans": [{"start": 1123, "end": 1127, "text": "[20]", "ref_id": "BIBREF19"}, {"start": 1128, "end": 1132, "text": "[21]", "ref_id": "BIBREF20"}, {"start": 1133, "end": 1137, "text": "[22]", "ref_id": "BIBREF21"}], "ref_spans": []}, {"section": "Conclusion", "text": "Medical image analysis covers many areas such as image acquisition, formation/reconstruction, enhancement, transmission, and compression. New technological advances have resulted in higher resolution, dimension, and availability of multimodal images which lead to the increase in accuracy of diagnosis and improvement of treatment. However, integrating medical images with different modalities or with other medical data is a potential opportunity. New analytical frameworks and methods are required to analyze these data in a clinical setting. These methods address some concerns, opportunities, and challenges such as features from images which can improve the accuracy of diagnosis and the ability to utilize disparate sources of data to increase the accuracy of diagnosis and reducing cost and improve the accuracy of processing methods such as medical image enhancement, registration, and segmentation to deliver better recommendations at the clinical level.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusion", "text": "Although there are some very real challenges for signal processing of physiological data to deal with, given the current state of data competency and nonstandardized structure, there are opportunities in each step of the process towards providing systemic improvements within the healthcare research and practice communities. Apart from the obvious need for further research in the area of data wrangling, aggregating, and harmonizing continuous and discrete medical data formats, there is also an equal need for developing novel signal processing techniques specialized towards physiological signals. Research pertaining to mining for biomarkers and clandestine patterns within biosignals to understand and predict disease cases has shown potential in providing actionable information. However, there are opportunities for developing algorithms to address data filtering, interpolation, transformation, feature extraction, feature selection, and so forth. Furthermore, with the notoriety and improvement of machine learning algorithms, there are opportunities in improving and developing robust CDSS for clinical prediction, prescription, and diagnostics [180, 181] .", "cite_spans": [{"start": 1156, "end": 1161, "text": "[180,", "ref_id": "BIBREF180"}, {"start": 1162, "end": 1166, "text": "181]", "ref_id": "BIBREF181"}], "ref_spans": []}, {"section": "Conclusion", "text": "Integration of physiological data and high-throughput \"-omics\" techniques to deliver clinical recommendations is the grand challenge for systems biologists. Although associating functional effects with changes in gene expression has progressed, the continuous increase in available genomic data and its corresponding effects of annotation of genes and errors from experiment and analytical practices make analyzing functional effect from high-throughput sequencing techniques a challenging task.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusion", "text": "Reconstruction of networks on the genome-scale is an ill-posed problem. Robust applications have been developed for reconstruction of metabolic networks and gene regulatory networks. Limited availability of kinetic constants is a bottleneck and hence various models attempt to overcome this limitation. There is an incomplete understanding for this largescale problem as gene regulation, effect of different network architectures, and evolutionary effects on these networks are still being analyzed [135] . To address these concerns, the combination of careful design of experiments and model development for reconstruction of networks will help in saving time and resources spent in building understanding of regulation in genome-scale networks. The opportunity of addressing the grand challenge requires close cooperation among experimentalists, computational scientists, and clinicians.", "cite_spans": [{"start": 499, "end": 504, "text": "[135]", "ref_id": "BIBREF135"}], "ref_spans": []}, {"section": "Conflict of Interests", "text": "Ashwin Belle and Kayvan Najarian have patents and pending patents pertinent to some of the methodologies surveyed and cited in this paper. Raghuram Thiagarajan, S. M. Reza Soroushmehr, Fatemeh Navidi, and Daniel A. Beard have no conflict of interests.", "cite_spans": [], "ref_spans": []}, {"section": "Authors' Contribution", "text": "Ashwin Belle is the primary author for the section on signal processing and contributed to the whole paper, Raghuram Thiagarajan is the primary author for the section on genomics and contributed to the whole papaer, and S. M. Reza Soroushmehr is the primary author for the image processing section and contributed to the whole paper. Fatemeh Navidi contributed to the section on image processing. Daniel A. Beard contributed to and supervised the whole paper. Kayvan Najarian contributed to and supervised the whole paper. All authors have read and approved the final version of this paper. Ashwin Belle, Raghuram Thiagarajan, and S. M. Reza Soroushmehr contributed equally to this work.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Big data: the management revolution", "authors": [{"first": "A", "middle": [], "last": "Mcafee", "suffix": ""}, {"first": "E", "middle": [], "last": "Brynjolfsson", "suffix": ""}, {"first": "T", "middle": ["H"], "last": "Davenport", "suffix": ""}, {"first": "D", "middle": ["J"], "last": "Patil", "suffix": ""}, {"first": "D", "middle": [], "last": "Barton", "suffix": ""}], "year": 2012, "venue": "Harvard Business Review", "link": "12289690"}, "BIBREF1": {"title": "Big data: how do your data grow?", "authors": [{"first": "C", "middle": [], "last": "Lynch", "suffix": ""}], "year": 2008, "venue": "Nature", "link": null}, "BIBREF2": {"title": "The pathologies of big data", "authors": [{"first": "A", "middle": [], "last": "Jacobs", "suffix": ""}], "year": 2009, "venue": "Communications of the ACM", "link": null}, "BIBREF3": {"title": "Understanding Big Data: Analytics for Enterprise Class Hadoop and Streaming Data", "authors": [{"first": "P", "middle": [], "last": "Zikopoulos", "suffix": ""}, {"first": "C", "middle": [], "last": "Eaton", "suffix": ""}, {"first": "D", "middle": [], "last": "", "suffix": ""}, {"first": "T", "middle": [], "last": "Deutsch", "suffix": ""}, {"first": "G", "middle": [], "last": "Lapis", "suffix": ""}], "year": 2011, "venue": "", "link": "57105873"}, "BIBREF4": {"title": "Big Data: The Next Frontier for Innovation, Competition, and Productivity", "authors": [{"first": "J", "middle": [], "last": "Manyika", "suffix": ""}, {"first": "M", "middle": [], "last": "Chui", "suffix": ""}, {"first": "B", "middle": [], "last": "Brown", "suffix": ""}], "year": 2011, "venue": "", "link": "166449414"}, "BIBREF5": {"title": "Clinical practice as natural laboratory for psychotherapy research: a guide to case-based time-series analysis", "authors": [{"first": "J", "middle": ["J"], "last": "Borckardt", "suffix": ""}, {"first": "M", "middle": ["R"], "last": "Nash", "suffix": ""}, {"first": "M", "middle": ["D"], "last": "Murphy", "suffix": ""}, {"first": "M", "middle": [], "last": "Moore", "suffix": ""}, {"first": "D", "middle": [], "last": "Shaw", "suffix": ""}, {"first": "P", "middle": [], "last": "O&apos;neil", "suffix": ""}], "year": 2008, "venue": "The American Psychologist", "link": "12685571"}, "BIBREF6": {"title": "Big data' in the intensive care unit: closing the data loop", "authors": [{"first": "L", "middle": ["A"], "last": "Celi", "suffix": ""}, {"first": "R", "middle": ["G"], "last": "Mark", "suffix": ""}, {"first": "D", "middle": ["J"], "last": "Stone", "suffix": ""}, {"first": "R", "middle": ["A"], "last": "Montgomery", "suffix": ""}], "year": 2013, "venue": "American Journal of Respiratory and Critical Care Medicine", "link": null}, "BIBREF7": {"title": "Medical image analysis", "authors": [{"first": "F", "middle": [], "last": "Ritter", "suffix": ""}, {"first": "T", "middle": [], "last": "Boskamp", "suffix": ""}, {"first": "A", "middle": [], "last": "Homeyer", "suffix": ""}], "year": 2011, "venue": "IEEE Pulse", "link": "128365360"}, "BIBREF8": {"title": "Modalities and data acquisition", "authors": [{"first": "J", "middle": ["A"], "last": "Seibert", "suffix": ""}], "year": 2010, "venue": "Practical Imaging Informatics", "link": "59826133"}, "BIBREF9": {"title": "Insights into the problem of alarm fatigue with physiologic monitor devices: a comprehensive observational study of consecutive intensive care unit patients", "authors": [{"first": "B", "middle": ["J"], "last": "Drew", "suffix": ""}, {"first": "P", "middle": [], "last": "Harris", "suffix": ""}, {"first": "J", "middle": ["K"], "last": "Z\u00e8gre-Hemsey", "suffix": ""}], "year": 2014, "venue": "PLoS ONE", "link": "12020480"}, "BIBREF10": {"title": "Monitor alarm fatigue: standardizing use of physiological monitors and decreasing nuisance alarms", "authors": [{"first": "K", "middle": ["C"], "last": "Graham", "suffix": ""}, {"first": "M", "middle": [], "last": "Cvach", "suffix": ""}], "year": 2010, "venue": "The American Journal of Critical Care", "link": "26098336"}, "BIBREF11": {"title": "Monitor alarm fatigue: an integrative review", "authors": [{"first": "M", "middle": [], "last": "Cvach", "suffix": ""}], "year": 2012, "venue": "Biomedical Instrumentation & Technology", "link": "207374908"}, "BIBREF12": {"title": "The Critical Care Safety Study: the incidence and nature of adverse events and serious medical errors in intensive care", "authors": [{"first": "J", "middle": ["M"], "last": "Rothschild", "suffix": ""}, {"first": "C", "middle": ["P"], "last": "Landrigan", "suffix": ""}, {"first": "J", "middle": ["W"], "last": "Cronin", "suffix": ""}], "year": 2005, "venue": "Critical Care Medicine", "link": "3147928"}, "BIBREF13": {"title": "A human factors engineering conceptual framework of nursing workload and patient safety in intensive care units", "authors": [{"first": "P", "middle": [], "last": "Carayon", "suffix": ""}, {"first": "A", "middle": ["P"], "last": "G\u00fcrses", "suffix": ""}], "year": 2005, "venue": "Intensive and Critical Care Nursing", "link": "23060333"}, "BIBREF14": {"title": "Human factors of complex sociotechnical systems", "authors": [{"first": "P", "middle": [], "last": "Carayon", "suffix": ""}], "year": 2006, "venue": "Applied Ergonomics", "link": "31815529"}, "BIBREF15": {"title": "Initial sequencing and analysis of the human genome", "authors": [{"first": "E", "middle": ["S"], "last": "Lander", "suffix": ""}, {"first": "L", "middle": ["M"], "last": "Linton", "suffix": ""}, {"first": "B", "middle": [], "last": "Birren", "suffix": ""}], "year": 2001, "venue": "Nature", "link": "186242719"}, "BIBREF16": {"title": "Human genome sequencing using unchained base reads on self-assembling DNA nanoarrays", "authors": [{"first": "R", "middle": [], "last": "Drmanac", "suffix": ""}, {"first": "A", "middle": ["B"], "last": "Sparks", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Callow", "suffix": ""}], "year": 2010, "venue": "Science", "link": null}, "BIBREF17": {"title": "Reflections on the cost of 'Low-Cost' whole genome sequencing: framing the health policy debate", "authors": [{"first": "T", "middle": [], "last": "Caulfield", "suffix": ""}, {"first": "J", "middle": [], "last": "Evans", "suffix": ""}, {"first": "A", "middle": [], "last": "Mcguire", "suffix": ""}], "year": 2013, "venue": "PLoS Biology", "link": "229700"}, "BIBREF18": {"title": "Clinical interpretation and implications of whole-genome sequencing", "authors": [{"first": "F", "middle": ["E"], "last": "Dewey", "suffix": ""}, {"first": "M", "middle": ["E"], "last": "Grove", "suffix": ""}, {"first": "C", "middle": [], "last": "Pan", "suffix": ""}], "year": 2014, "venue": "JAMA", "link": "4103489"}, "BIBREF19": {"title": "Predictive, personalized, preventive, participatory (P4) cancer medicine", "authors": [{"first": "L", "middle": [], "last": "Hood", "suffix": ""}, {"first": "S", "middle": ["H"], "last": "Friend", "suffix": ""}], "year": 2011, "venue": "Nature Reviews Clinical Oncology", "link": "9074524"}, "BIBREF20": {"title": "A personal view on systems medicine and the emergence of proactive P4 medicine: predictive, preventive, personalized and participatory", "authors": [{"first": "L", "middle": [], "last": "Hood", "suffix": ""}, {"first": "M", "middle": [], "last": "Flores", "suffix": ""}], "year": 2012, "venue": "New Biotechnology", "link": "873920"}, "BIBREF21": {"title": "Demystifying disease, democratizing health care", "authors": [{"first": "L", "middle": [], "last": "Hood", "suffix": ""}, {"first": "N", "middle": ["D"], "last": "Price", "suffix": ""}], "year": 2014, "venue": "Article ID 225ed5", "link": "26137749"}, "BIBREF22": {"title": "Personal omics profiling reveals dynamic molecular and medical phenotypes", "authors": [{"first": "R", "middle": [], "last": "Chen", "suffix": ""}, {"first": "G", "middle": ["I"], "last": "Mias", "suffix": ""}, {"first": "J", "middle": [], "last": "Li-Pook-Than", "suffix": ""}], "year": 2012, "venue": "Cell", "link": "8381898"}, "BIBREF23": {"title": "Bioinformatics challenges for personalized medicine", "authors": [{"first": "G", "middle": ["H"], "last": "Fernald", "suffix": ""}, {"first": "E", "middle": [], "last": "Capriotti", "suffix": ""}, {"first": "R", "middle": [], "last": "Daneshjou", "suffix": ""}, {"first": "K", "middle": ["J"], "last": "Karczewski", "suffix": ""}, {"first": "R", "middle": ["B"], "last": "Altman", "suffix": ""}], "year": 2011, "venue": "Article ID btr295", "link": "340024"}, "BIBREF24": {"title": "Ten years of pathway analysis: current approaches and outstanding challenges", "authors": [{"first": "P", "middle": [], "last": "Khatri", "suffix": ""}, {"first": "M", "middle": [], "last": "Sirota", "suffix": ""}, {"first": "A", "middle": ["J"], "last": "Butte", "suffix": ""}], "year": 2012, "venue": "PLoS Computational Biology", "link": "8079962"}, "BIBREF25": {"title": "Bioinformatics, healthcare informatics and analytics: an imperative for improved healthcare system", "authors": [{"first": "J", "middle": [], "last": "Oyelade", "suffix": ""}, {"first": "J", "middle": [], "last": "Soyemi", "suffix": ""}, {"first": "I", "middle": [], "last": "Isewon", "suffix": ""}, {"first": "O", "middle": [], "last": "Obembe", "suffix": ""}], "year": 2015, "venue": "International Journal of Applied Information Systems", "link": "55237079"}, "BIBREF26": {"title": "Sub-optimal patterns of information use: a rational analysis of information seeking behavior in critical care", "authors": [{"first": "T", "middle": ["G"], "last": "Kannampallil", "suffix": ""}, {"first": "A", "middle": [], "last": "Franklin", "suffix": ""}, {"first": "T", "middle": [], "last": "Cohen", "suffix": ""}, {"first": "T", "middle": ["G"], "last": "Buchman", "suffix": ""}], "year": 2014, "venue": "Cognitive Informatics in Health and Biomedicine", "link": "140290016"}, "BIBREF27": {"title": "Hybrid system for lymphatic diseases diagnosis", "authors": [{"first": "H", "middle": [], "last": "Elshazly", "suffix": ""}, {"first": "A", "middle": ["T"], "last": "Azar", "suffix": ""}, {"first": "A", "middle": [], "last": "El-Korany", "suffix": ""}, {"first": "A", "middle": ["E"], "last": "Hassanien", "suffix": ""}], "year": 2013, "venue": "Proceedings of the International Conference on Advances in Computing, Communications and Informatics (ICACCI '13)", "link": "1636050"}, "BIBREF28": {"title": "Digital Image Processing for Medical Applications", "authors": [{"first": "G", "middle": [], "last": "Dougherty", "suffix": ""}], "year": 2009, "venue": "", "link": null}, "BIBREF29": {"title": "Acoustic angiography: a new imaging modality for assessing microvasculature architecture", "authors": [{"first": "R", "middle": ["C"], "last": "Gessner", "suffix": ""}, {"first": "C", "middle": ["B"], "last": "Frederick", "suffix": ""}, {"first": "F", "middle": ["S"], "last": "Foster", "suffix": ""}, {"first": "P", "middle": ["A"], "last": "Dayton", "suffix": ""}], "year": 2013, "venue": "International Journal of Biomedical Imaging", "link": "14870625"}, "BIBREF30": {"title": "Quantifying the impact of respiratory-gated 4D CT acquisition on thoracic image quality: a digital phantom study", "authors": [{"first": "K", "middle": [], "last": "Bernatowicz", "suffix": ""}, {"first": "P", "middle": [], "last": "Keall", "suffix": ""}, {"first": "P", "middle": [], "last": "Mishra", "suffix": ""}, {"first": "A", "middle": [], "last": "Knopf", "suffix": ""}, {"first": "A", "middle": [], "last": "Lomax", "suffix": ""}, {"first": "J", "middle": [], "last": "Kipritidis", "suffix": ""}], "year": 2015, "venue": "Medical Physics", "link": "40887844"}, "BIBREF31": {"title": "Challenges of medical image processing", "authors": [{"first": "I", "middle": [], "last": "Scholl", "suffix": ""}, {"first": "T", "middle": [], "last": "Aach", "suffix": ""}, {"first": "T", "middle": ["M"], "last": "Deserno", "suffix": ""}, {"first": "T", "middle": [], "last": "Kuhlen", "suffix": ""}], "year": 2011, "venue": "Computer Science-Research and Development", "link": "14976328"}, "BIBREF32": {"title": "Imaging of cerebrovascular disorders: precision medicine and the collaterome", "authors": [{"first": "D", "middle": ["S"], "last": "Liebeskind", "suffix": ""}, {"first": "E", "middle": [], "last": "Feldmann", "suffix": ""}], "year": 2015, "venue": "Annals of the New York Academy of Sciences", "link": "5043940"}, "BIBREF33": {"title": "Molecular imaging for cancer diagnosis and surgery", "authors": [{"first": "T", "middle": [], "last": "Hussain", "suffix": ""}, {"first": "Q", "middle": ["T"], "last": "Nguyen", "suffix": ""}], "year": 2014, "venue": "Advanced Drug Delivery Reviews", "link": "20120970"}, "BIBREF34": {"title": "Molecular imaging is the key driver for clinical cancer diagnosis in the next century!", "authors": [{"first": "G", "middle": [], "last": "Baio", "suffix": ""}], "year": 2013, "venue": "Journal of Molecular Imaging & Dynamics", "link": "74790696"}, "BIBREF35": {"title": "Novel preprocessing techniques for accurate microwave imaging of human brain", "authors": [{"first": "S", "middle": [], "last": "Mustafa", "suffix": ""}, {"first": "B", "middle": [], "last": "Mohammed", "suffix": ""}, {"first": "A", "middle": [], "last": "Abbosh", "suffix": ""}], "year": 2013, "venue": "IEEE Antennas and Wireless Propagation Letters", "link": "24418642"}, "BIBREF36": {"title": "Tomographic microwave imaging with incorporated prior spatial information", "authors": [{"first": "A", "middle": ["H"], "last": "Golnabi", "suffix": ""}, {"first": "P", "middle": ["M"], "last": "Meaney", "suffix": ""}, {"first": "K", "middle": ["D"], "last": "Paulsen", "suffix": ""}], "year": 2013, "venue": "IEEE Transactions on Microwave Theory and Techniques", "link": "14354679"}, "BIBREF37": {"title": "Infarct architecture and characteristics on delayed enhanced magnetic resonance imaging and electroanatomic mapping in patients with postinfarction ventricular arrhythmia", "authors": [{"first": "B", "middle": [], "last": "Desjardins", "suffix": ""}, {"first": "T", "middle": [], "last": "Crawford", "suffix": ""}, {"first": "E", "middle": [], "last": "Good", "suffix": ""}], "year": 2009, "venue": "Heart Rhythm", "link": "5564111"}, "BIBREF38": {"title": "Role of different imaging modalities in assessment of temporomandibular joint erosions and osteophytes: a systematic review", "authors": [{"first": "A", "middle": ["M"], "last": "Hussain", "suffix": ""}, {"first": "G", "middle": [], "last": "Packota", "suffix": ""}, {"first": "P", "middle": ["W"], "last": "Major", "suffix": ""}, {"first": "C", "middle": [], "last": "Flores-Mir", "suffix": ""}], "year": 2014, "venue": "Dentomaxillofacial Radiology", "link": "26081753"}, "BIBREF39": {"title": "Multimodal imaging for improved diagnosis and treatment of cancers", "authors": [{"first": "C", "middle": ["M C"], "last": "Tempany", "suffix": ""}, {"first": "J", "middle": [], "last": "Jayender", "suffix": ""}, {"first": "T", "middle": [], "last": "Kapur", "suffix": ""}], "year": 2015, "venue": "Cancer", "link": "23610030"}, "BIBREF40": {"title": "Gesture interaction for content-based medical image retrieval", "authors": [{"first": "A", "middle": [], "last": "Widmer", "suffix": ""}, {"first": "R", "middle": [], "last": "Schaer", "suffix": ""}, {"first": "D", "middle": [], "last": "Markonis", "suffix": ""}, {"first": "H", "middle": [], "last": "M\u00fcller", "suffix": ""}], "year": 2014, "venue": "Proceedings of the 4th ACM International Conference on Multimedia Retrieval", "link": "7003067"}, "BIBREF41": {"title": "The Hadoop distributed file system", "authors": [{"first": "K", "middle": [], "last": "Shvachko", "suffix": ""}, {"first": "H", "middle": [], "last": "Kuang", "suffix": ""}, {"first": "S", "middle": [], "last": "Radia", "suffix": ""}, {"first": "R", "middle": [], "last": "Chansler", "suffix": ""}], "year": 2010, "venue": "Proceedings of the IEEE 26th Symposium on Mass Storage Systems and Technologies (MSST '10)", "link": "13925042"}, "BIBREF42": {"title": "MedCloud: healthcare cloud computing system", "authors": [{"first": "D", "middle": [], "last": "Sobhy", "suffix": ""}, {"first": "Y", "middle": [], "last": "El-Sonbaty", "suffix": ""}, {"first": "M", "middle": [], "last": "Abou Elnasr", "suffix": ""}], "year": 2012, "venue": "Proceedings of the International Conference for Internet Technology and Secured Transactions", "link": "2144794"}, "BIBREF43": {"title": "MapReduce: simplified data processing on large clusters", "authors": [{"first": "J", "middle": [], "last": "Dean", "suffix": ""}, {"first": "S", "middle": [], "last": "Ghemawat", "suffix": ""}], "year": 2008, "venue": "Communications of the ACM", "link": "207166250"}, "BIBREF44": {"title": "Largescale multimodal mining for healthcare with mapreduce", "authors": [{"first": "F", "middle": [], "last": "Wang", "suffix": ""}, {"first": "V", "middle": [], "last": "Ercegovac", "suffix": ""}, {"first": "T", "middle": [], "last": "Syeda-Mahmood", "suffix": ""}], "year": 2010, "venue": "Proceedings of the 1st ACM International Health Informatics Symposium", "link": null}, "BIBREF45": {"title": "Xbase: cloud-enabled information appliance for healthcare", "authors": [{"first": "W.-S", "middle": [], "last": "Li", "suffix": ""}, {"first": "J", "middle": [], "last": "Yan", "suffix": ""}, {"first": "Y", "middle": [], "last": "Yan", "suffix": ""}, {"first": "J", "middle": [], "last": "Zhang", "suffix": ""}], "year": 2010, "venue": "Proceedings of the 13th International Conference on Extending Database Technology (EDBT '10)", "link": "35759200"}, "BIBREF46": {"title": "Using MapReduce for large-scale medical image analysis", "authors": [{"first": "D", "middle": [], "last": "Markonis", "suffix": ""}, {"first": "R", "middle": [], "last": "Schaer", "suffix": ""}, {"first": "I", "middle": [], "last": "Eggel", "suffix": ""}, {"first": "H", "middle": [], "last": "Muller", "suffix": ""}, {"first": "A", "middle": [], "last": "Depeursinge", "suffix": ""}], "year": 2012, "venue": "Proceedings of the 2nd IEEE International Conference on Healthcare Informatics, Imaging and Systems Biology (HISB '12)", "link": "7868077"}, "BIBREF47": {"title": "System & method for delineation and quantification of fluid accumulation in efast trauma ultrasound images", "authors": [{"first": "K", "middle": [], "last": "Shackelford", "suffix": ""}], "year": 2014, "venue": "US Patent Application", "link": null}, "BIBREF48": {"title": "A hybrid machine learning method for fusing fMRI and genetic data: combining both improves classification of schizophrenia", "authors": [{"first": "H", "middle": [], "last": "Yang", "suffix": ""}, {"first": "J", "middle": [], "last": "Liu", "suffix": ""}, {"first": "J", "middle": [], "last": "Sui", "suffix": ""}, {"first": "G", "middle": [], "last": "Pearlson", "suffix": ""}, {"first": "V", "middle": ["D"], "last": "Calhoun", "suffix": ""}], "year": 2010, "venue": "Frontiers in Human Neuroscience", "link": "2125207"}, "BIBREF49": {"title": "Multi atlas-based segmentation with data driven refinement", "authors": [{"first": "O", "middle": ["A J"], "last": "Toro", "suffix": ""}, {"first": "H", "middle": [], "last": "Muller", "suffix": ""}], "year": 2014, "venue": "Proceedings of the IEEE-EMBS International Conference on Biomedical and Health Informatics (BHI '14)", "link": "9994132"}, "BIBREF50": {"title": "Towards cloud-based image-integrated similarity search in big data", "authors": [{"first": "A", "middle": [], "last": "Tsymbal", "suffix": ""}, {"first": "E", "middle": [], "last": "Meissner", "suffix": ""}, {"first": "M", "middle": [], "last": "Kelm", "suffix": ""}, {"first": "M", "middle": [], "last": "Kramer", "suffix": ""}], "year": 2014, "venue": "Proceedings of the IEEE-EMBS International Conference on Biomedical and Health Informatics (BHI '14)", "link": "14936386"}, "BIBREF51": {"title": "Intracranial pressure level prediction in traumatic brain injury by extracting features from multiple sources and using machine learning methods", "authors": [{"first": "W", "middle": [], "last": "Chen", "suffix": ""}, {"first": "C", "middle": [], "last": "Cockrell", "suffix": ""}, {"first": "K", "middle": ["R"], "last": "Ward", "suffix": ""}, {"first": "K", "middle": [], "last": "Najarian", "suffix": ""}], "year": 2010, "venue": "Proceedings of the IEEE International Conference on Bioinformatics and Biomedicine (BIBM '10)", "link": "22420509"}, "BIBREF52": {"title": "Molecular imaging in cancer", "authors": [{"first": "R", "middle": [], "last": "Weissleder", "suffix": ""}], "year": 2006, "venue": "Science", "link": null}, "BIBREF53": {"title": "Full-range in-plane rotation measurement for image recognition with hybrid digitaloptical correlator", "authors": [{"first": "T", "middle": [], "last": "Zheng", "suffix": ""}, {"first": "L", "middle": [], "last": "Cao", "suffix": ""}, {"first": "Q", "middle": [], "last": "He", "suffix": ""}, {"first": "G", "middle": [], "last": "Jin", "suffix": ""}], "year": 2014, "venue": "Optical Engineering", "link": "122154933"}, "BIBREF54": {"title": "iDASH: integrating data for analysis, anonymization, and sharing", "authors": [{"first": "L", "middle": [], "last": "Ohno-Machado", "suffix": ""}, {"first": "V", "middle": [], "last": "Bafna", "suffix": ""}, {"first": "A", "middle": ["A"], "last": "Boxwala", "suffix": ""}], "year": 2012, "venue": "Journal of the American Medical Informatics Association", "link": "206847275"}, "BIBREF55": {"title": "Implementation of a medical image file accessing system on cloud computing", "authors": [{"first": "C.-T", "middle": [], "last": "Yang", "suffix": ""}, {"first": "L.-T", "middle": [], "last": "Chen", "suffix": ""}, {"first": "W.-L", "middle": [], "last": "Chou", "suffix": ""}, {"first": "K.-C", "middle": [], "last": "Wang", "suffix": ""}], "year": 2010, "venue": "Proceedings of the 13th IEEE International Conference on Computational Science and Engineering (CSE' 10)", "link": "8472784"}, "BIBREF56": {"title": "A cloud computing solution for patient's data collection in health care institutions", "authors": [{"first": "C", "middle": ["O"], "last": "Rolim", "suffix": ""}, {"first": "F", "middle": ["L"], "last": "Koch", "suffix": ""}, {"first": "C", "middle": ["B"], "last": "Westphall", "suffix": ""}, {"first": "J", "middle": [], "last": "Werner", "suffix": ""}, {"first": "A", "middle": [], "last": "Fracalossi", "suffix": ""}, {"first": "G", "middle": ["S"], "last": "Salvador", "suffix": ""}], "year": 2010, "venue": "Proceedings of the 2nd International Conference on eHealth, Telemedicine, and Social Medicine (ETELEMED '10)", "link": "8917447"}, "BIBREF57": {"title": "A medical image archive solution in the cloud", "authors": [{"first": "C.-C", "middle": [], "last": "Teng", "suffix": ""}, {"first": "J", "middle": [], "last": "Mitchell", "suffix": ""}, {"first": "C", "middle": [], "last": "Walker", "suffix": ""}], "year": 2010, "venue": "Proceedings of the IEEE International Conference on Software Engineering and Service Sciences (ICSESS '10)", "link": "8213047"}, "BIBREF58": {"title": "Big data analysis with signal processing on graphs: representation and processing of massive data sets with irregular structure", "authors": [{"first": "A", "middle": [], "last": "Sandryhaila", "suffix": ""}, {"first": "J", "middle": ["M F"], "last": "Moura", "suffix": ""}], "year": 2014, "venue": "IEEE Signal Processing Magazine", "link": "11496360"}, "BIBREF59": {"title": "Big data and the SP theory of intelligence", "authors": [{"first": "J", "middle": ["G"], "last": "Wolff", "suffix": ""}], "year": 2014, "venue": "IEEE Access", "link": "62101047"}, "BIBREF60": {"title": "ZIP-IO: architecture for application-specific compression of Big Data", "authors": [{"first": "S", "middle": ["W"], "last": "Jun", "suffix": ""}, {"first": "K", "middle": ["E"], "last": "Fleming", "suffix": ""}, {"first": "M", "middle": [], "last": "Adler", "suffix": ""}, {"first": "J", "middle": [], "last": "Emer", "suffix": ""}], "year": 2012, "venue": "Proceedings of the International Conference on FieldProgrammable Technology (FPT '12)", "link": "1364828"}, "BIBREF61": {"title": "The anamorphic stretch transform: putting the squeeze on 'big data", "authors": [{"first": "B", "middle": [], "last": "Jalali", "suffix": ""}, {"first": "M", "middle": ["H"], "last": "Asghari", "suffix": ""}], "year": 2014, "venue": "Optics and Photonics News", "link": "123116261"}, "BIBREF62": {"title": "The single pixel GPS: learning big data signals from tiny coresets", "authors": [{"first": "D", "middle": [], "last": "Feldman", "suffix": ""}, {"first": "C", "middle": [], "last": "Sung", "suffix": ""}, {"first": "D", "middle": [], "last": "Rus", "suffix": ""}], "year": 2012, "venue": "Proceedings of the 20th International Conference on Advances in Geographic Information Systems (SIGSPATIAL '12)", "link": "8492022"}, "BIBREF63": {"title": "Efficient denoising algorithms for large experimental datasets and their applications in Fourier transform ion cyclotron resonance mass spectrometry", "authors": [{"first": "L", "middle": [], "last": "Chiron", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Van Agthoven", "suffix": ""}, {"first": "B", "middle": [], "last": "Kieffer", "suffix": ""}, {"first": "C", "middle": [], "last": "Rolando", "suffix": ""}, {"first": "M.-A", "middle": [], "last": "Delsuc", "suffix": ""}], "year": 2014, "venue": "Proceedings of the National Academy of Sciences of the United States of America", "link": "23516269"}, "BIBREF64": {"title": "Recent developments in the sparse fourier transform: a compressed fourier transform for big data", "authors": [{"first": "A", "middle": ["C"], "last": "Gilbert", "suffix": ""}, {"first": "P", "middle": [], "last": "Indyk", "suffix": ""}, {"first": "M", "middle": [], "last": "Iwen", "suffix": ""}, {"first": "L", "middle": [], "last": "Schmidt", "suffix": ""}], "year": 2014, "venue": "IEEE Signal Processing Magazine", "link": "14585685"}, "BIBREF65": {"title": "Segmentation-based compression: new frontiers of telemedicine in telecommunication", "authors": [{"first": "W.-Y", "middle": [], "last": "Hsu", "suffix": ""}], "year": 2015, "venue": "Telematics and Informatics", "link": null}, "BIBREF66": {"title": "Medical image registration: a review", "authors": [{"first": "F", "middle": ["P M"], "last": "Oliveira", "suffix": ""}, {"first": "J", "middle": ["M R S"], "last": "Tavares", "suffix": ""}], "year": 2014, "venue": "Computer Methods in Biomechanics and Biomedical Engineering", "link": "28012712"}, "BIBREF67": {"title": "3D registration of biological images and models: registration of microscopic images and its uses in segmentation and annotation", "authors": [{"first": "L", "middle": [], "last": "Qu", "suffix": ""}, {"first": "F", "middle": [], "last": "Long", "suffix": ""}, {"first": "H", "middle": [], "last": "Peng", "suffix": ""}], "year": 2015, "venue": "IEEE Signal Processing Magazine", "link": "4988177"}, "BIBREF68": {"title": "Medical image security and EPR hiding using shamir's secret sharing scheme", "authors": [{"first": "M", "middle": [], "last": "Ulutas", "suffix": ""}, {"first": "G", "middle": [], "last": "Ulutas", "suffix": ""}, {"first": "V", "middle": ["V"], "last": "Nabiyev", "suffix": ""}], "year": 2011, "venue": "Journal of Systems and Software", "link": "43011981"}, "BIBREF69": {"title": "Teleradiology network system on cloud using the web medical image conference system with a new information security solution", "authors": [{"first": "H", "middle": [], "last": "Satoh", "suffix": ""}, {"first": "N", "middle": [], "last": "Niki", "suffix": ""}, {"first": "K", "middle": [], "last": "Eguchi", "suffix": ""}], "year": 2013, "venue": "Medical Imaging : Advanced PACS-based Imaging Informatics and Therapeutic Applications", "link": "62228361"}, "BIBREF70": {"title": "Security protection of DICOM medical images using duallayer reversible watermarking with tamper detection capability", "authors": [{"first": "C", "middle": ["K"], "last": "Tan", "suffix": ""}, {"first": "J", "middle": ["C"], "last": "Ng", "suffix": ""}, {"first": "X", "middle": [], "last": "Xu", "suffix": ""}, {"first": "C", "middle": ["L"], "last": "Poh", "suffix": ""}, {"first": "Y", "middle": ["L"], "last": "Guan", "suffix": ""}, {"first": "K", "middle": [], "last": "Sheah", "suffix": ""}], "year": 2011, "venue": "Journal of Digital Imaging", "link": "2567813"}, "BIBREF71": {"title": "Hadoopgis: a high performance query system for analytical medical imaging with mapreduce", "authors": [{"first": "F", "middle": [], "last": "Wang", "suffix": ""}, {"first": "R", "middle": [], "last": "Lee", "suffix": ""}, {"first": "Q", "middle": [], "last": "Liu", "suffix": ""}, {"first": "A", "middle": [], "last": "Aji", "suffix": ""}, {"first": "X", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "J", "middle": [], "last": "Saltz", "suffix": ""}], "year": 2011, "venue": "Tech. Rep", "link": null}, "BIBREF72": {"title": "Disease prediction in the at-risk mental state for psychosis using neuroanatomical biomarkers: results from the fepsy study", "authors": [{"first": "N", "middle": [], "last": "Koutsouleris", "suffix": ""}, {"first": "S", "middle": [], "last": "Borgwardt", "suffix": ""}, {"first": "E", "middle": ["M"], "last": "Meisenzahl", "suffix": ""}, {"first": "R", "middle": [], "last": "Bottlender", "suffix": ""}, {"first": "H.-J", "middle": [], "last": "M\u00f6ller", "suffix": ""}, {"first": "A", "middle": [], "last": "Riecher-R\u00f6ssler", "suffix": ""}], "year": 2012, "venue": "Schizophrenia Bulletin", "link": "16274020"}, "BIBREF73": {"title": "Validation of medical image analysis techniques", "authors": [{"first": "K", "middle": ["W"], "last": "Bowyer", "suffix": ""}], "year": 2000, "venue": "Handbook of Medical Imaging", "link": null}, "BIBREF74": {"title": "Guest editorial: validation in medical image processing", "authors": [{"first": "P", "middle": [], "last": "Jannin", "suffix": ""}, {"first": "E", "middle": [], "last": "Krupinski", "suffix": ""}, {"first": "S", "middle": [], "last": "Warfield", "suffix": ""}], "year": 2006, "venue": "IEEE Transactions on Medical Imaging", "link": "10072232"}, "BIBREF75": {"title": "Statistical validation metric for accuracy assessment in medical image segmentation", "authors": [{"first": "A", "middle": [], "last": "Popovic", "suffix": ""}, {"first": "M", "middle": [], "last": "De La Fuente", "suffix": ""}, {"first": "M", "middle": [], "last": "Engelhardt", "suffix": ""}, {"first": "K", "middle": [], "last": "Radermacher", "suffix": ""}], "year": 2007, "venue": "International Journal of Computer Assisted Radiology and Surgery", "link": "24166228"}, "BIBREF76": {"title": "Automatic pre-hospital vital signs waveform and trend data capture fills quality management, triage and outcome prediction gaps", "authors": [{"first": "C", "middle": ["F"], "last": "Mackenzie", "suffix": ""}, {"first": "P", "middle": [], "last": "Hu", "suffix": ""}, {"first": "A", "middle": [], "last": "Sen", "suffix": ""}], "year": 2008, "venue": "AMIA Annual Symposium Proceedings", "link": "38807290"}, "BIBREF77": {"title": "Multimodal noninvasive monitoring of soft tissue wound healing", "authors": [{"first": "M", "middle": [], "last": "Bodo", "suffix": ""}, {"first": "T", "middle": [], "last": "Settle", "suffix": ""}, {"first": "J", "middle": [], "last": "Royal", "suffix": ""}, {"first": "E", "middle": [], "last": "Lombardini", "suffix": ""}, {"first": "E", "middle": [], "last": "Sawyer", "suffix": ""}, {"first": "S", "middle": ["W"], "last": "Rothwell", "suffix": ""}], "year": 2013, "venue": "Journal of Clinical Monitoring and Computing", "link": "11203567"}, "BIBREF78": {"title": "Identification of dynamic prehospital changes with continuous vital signs acquisition", "authors": [{"first": "P", "middle": [], "last": "Hu", "suffix": ""}, {"first": "S", "middle": ["M"], "last": "Galvagno", "suffix": ""}, {"first": "A", "middle": [], "last": "Sen", "suffix": ""}], "year": 2014, "venue": "Air Medical Journal", "link": "12801622"}, "BIBREF79": {"title": "Real-time analysis of physiological data to support medical applications", "authors": [{"first": "D", "middle": [], "last": "Apiletti", "suffix": ""}, {"first": "E", "middle": [], "last": "Baralis", "suffix": ""}, {"first": "G", "middle": [], "last": "Bruno", "suffix": ""}, {"first": "T", "middle": [], "last": "Cerquitelli", "suffix": ""}], "year": 2009, "venue": "IEEE Transactions on Information Technology in Biomedicine", "link": "18802441"}, "BIBREF80": {"title": "Grand challenges for multimodal bio-medical systems", "authors": [{"first": "J", "middle": [], "last": "Chen", "suffix": ""}, {"first": "E", "middle": [], "last": "Dougherty", "suffix": ""}, {"first": "S", "middle": ["S"], "last": "Demir", "suffix": ""}, {"first": "C", "middle": ["P"], "last": "Friedman", "suffix": ""}, {"first": "C", "middle": ["S"], "last": "Li", "suffix": ""}, {"first": "S", "middle": [], "last": "Wong", "suffix": ""}], "year": 2005, "venue": "IEEE Circuits and Systems Magazine", "link": "50227363"}, "BIBREF81": {"title": "Hospital quality of care: does information technology matter? The relationship between information technology adoption and quality of care", "authors": [{"first": "N", "middle": [], "last": "Menachemi", "suffix": ""}, {"first": "A", "middle": [], "last": "Chukmaitov", "suffix": ""}, {"first": "C", "middle": [], "last": "Saunders", "suffix": ""}, {"first": "R", "middle": ["G"], "last": "Brooks", "suffix": ""}], "year": 2008, "venue": "Health Care Management Review", "link": "9548357"}, "BIBREF82": {"title": "Electronic health records in ambulatory care-a national survey of physicians", "authors": [{"first": "C", "middle": ["M"], "last": "Desroches", "suffix": ""}, {"first": "E", "middle": ["G"], "last": "Campbell", "suffix": ""}, {"first": "S", "middle": ["R"], "last": "Rao", "suffix": ""}], "year": 2008, "venue": "The New England Journal of Medicine", "link": "13140755"}, "BIBREF83": {"title": "The effect of health information technology on quality in U.S. hospitals", "authors": [{"first": "J", "middle": ["S"], "last": "Mccullough", "suffix": ""}, {"first": "M", "middle": [], "last": "Casey", "suffix": ""}, {"first": "I", "middle": [], "last": "Moscovice", "suffix": ""}, {"first": "S", "middle": [], "last": "Prasad", "suffix": ""}], "year": 2010, "venue": "Health Affairs", "link": "5676009"}, "BIBREF84": {"title": "Design and implementation of a hospital wide waveform capture system", "authors": [{"first": "J", "middle": ["M"], "last": "Blum", "suffix": ""}, {"first": "H", "middle": [], "last": "Joo", "suffix": ""}, {"first": "H", "middle": [], "last": "Lee", "suffix": ""}, {"first": "M", "middle": [], "last": "Saeed", "suffix": ""}], "year": 2015, "venue": "Journal of Clinical Monitoring and Computing", "link": "2660052"}, "BIBREF85": {"title": "The future of patient monitoring", "authors": [{"first": "D", "middle": [], "last": "Freeman", "suffix": ""}], "year": 2009, "venue": "Health Management Technology", "link": null}, "BIBREF86": {"title": "Systems and methods for storing, analyzing, retrieving and displaying streaming medical data", "authors": [{"first": "B", "middle": [], "last": "Muhsin", "suffix": ""}, {"first": "A", "middle": [], "last": "Sampath", "suffix": ""}], "year": 2012, "venue": "", "link": null}, "BIBREF87": {"title": "Codeblue: an ad hoc sensor network infrastructure for emergency medical care", "authors": [{"first": "D", "middle": [], "last": "Malan", "suffix": ""}, {"first": "T", "middle": [], "last": "Fulford-Jones", "suffix": ""}, {"first": "M", "middle": [], "last": "Welsh", "suffix": ""}, {"first": "S", "middle": [], "last": "Moulton", "suffix": ""}], "year": 2004, "venue": "Proceedings of the International Workshop on Wearable and Implantable Body Sensor Networks", "link": "7229038"}, "BIBREF88": {"title": "Cloud-based secure health monitoring: optimizing fully-homomorphic encryption for streaming algorithms", "authors": [{"first": "A", "middle": [], "last": "Page", "suffix": ""}, {"first": "O", "middle": [], "last": "Kocabas", "suffix": ""}, {"first": "S", "middle": [], "last": "Ames", "suffix": ""}, {"first": "M", "middle": [], "last": "Venkitasubramaniam", "suffix": ""}, {"first": "T", "middle": [], "last": "Soyata", "suffix": ""}], "year": 2014, "venue": "Proceedings of the IEEE Globecom Workshops (GC Wkshps '14)", "link": "15949934"}, "BIBREF89": {"title": "Medical data transport over wireless life critical network", "authors": [{"first": "J", "middle": [], "last": "Bange", "suffix": ""}, {"first": "M", "middle": [], "last": "Gryzwa", "suffix": ""}, {"first": "K", "middle": [], "last": "Hoyme", "suffix": ""}, {"first": "D", "middle": ["C"], "last": "Johnson", "suffix": ""}, {"first": "J", "middle": [], "last": "Lalonde", "suffix": ""}, {"first": "W", "middle": [], "last": "Mass", "suffix": ""}], "year": 2011, "venue": "", "link": null}, "BIBREF90": {"title": "Reasoning with contextual data in telehealth applications", "authors": [{"first": "N", "middle": [], "last": "Kara", "suffix": ""}, {"first": "O", "middle": ["A"], "last": "Dragoi", "suffix": ""}], "year": 2007, "venue": "Proceedings of the 3rd IEEE International Conference on Wireless and Mobile Computing, Networking and Communications (WiMoB '07)", "link": "6004405"}, "BIBREF91": {"title": "A multiple biomedical signals synchronous acquisition circuit based on over-sampling and shaped signal for the application of the ubiquitous health care", "authors": [{"first": "G", "middle": [], "last": "Li", "suffix": ""}, {"first": "J", "middle": [], "last": "Liu", "suffix": ""}, {"first": "X", "middle": [], "last": "Li", "suffix": ""}, {"first": "L", "middle": [], "last": "Lin", "suffix": ""}, {"first": "R", "middle": [], "last": "Wei", "suffix": ""}], "year": 2014, "venue": "Circuits, Systems, and Signal Processing", "link": "11993570"}, "BIBREF92": {"title": "BioStream: a system architecture for real-time processing of physiological signals", "authors": [{"first": "A", "middle": [], "last": "Bar-Or", "suffix": ""}, {"first": "J", "middle": [], "last": "Healey", "suffix": ""}, {"first": "L", "middle": [], "last": "Kontothanassis", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Van Thong", "suffix": ""}], "year": 2004, "venue": "Proceedings of the 26th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC' 04)", "link": "15834394"}, "BIBREF93": {"title": "Big data analytics in healthcare: promise and potential", "authors": [{"first": "W", "middle": [], "last": "Raghupathi", "suffix": ""}, {"first": "V", "middle": [], "last": "Raghupathi", "suffix": ""}], "year": 2014, "venue": "Health Information Science and Systems", "link": "388276"}, "BIBREF94": {"title": "Continuous multiparameter heart rate variability analysis heralds onset of sepsis in adults", "authors": [{"first": "S", "middle": [], "last": "Ahmad", "suffix": ""}, {"first": "T", "middle": [], "last": "Ramsay", "suffix": ""}, {"first": "L", "middle": [], "last": "Huebsch", "suffix": ""}], "year": 2009, "venue": "PLoS ONE", "link": "5619301"}, "BIBREF95": {"title": "Physiobank, physiotoolkit, and physionet components of a new research resource for complex physiologic signals", "authors": [{"first": "A", "middle": ["L"], "last": "Goldberger", "suffix": ""}, {"first": "L", "middle": ["A"], "last": "Amaral", "suffix": ""}, {"first": "L", "middle": [], "last": "Glass", "suffix": ""}], "year": 2000, "venue": "Circulation", "link": "642375"}, "BIBREF96": {"title": "ICASP: an intensive-care acquisition and signal processing integrated framework", "authors": [{"first": "E", "middle": ["J"], "last": "Siachalou", "suffix": ""}, {"first": "I", "middle": ["K"], "last": "Kitsas", "suffix": ""}, {"first": "K", "middle": ["J"], "last": "Panoulas", "suffix": ""}], "year": 2005, "venue": "Journal of Medical Systems", "link": "1643937"}, "BIBREF97": {"title": "Mimic ii: a massive temporal icu patient database to support research in intelligent patient monitoring", "authors": [{"first": "M", "middle": [], "last": "Saeed", "suffix": ""}, {"first": "C", "middle": [], "last": "Lieu", "suffix": ""}, {"first": "G", "middle": [], "last": "Raber", "suffix": ""}, {"first": "R", "middle": ["G"], "last": "Mark", "suffix": ""}], "year": 2002, "venue": "Proceedings of the Computers in Cardiology", "link": "39447008"}, "BIBREF98": {"title": "Using 'off-theshelf ' tools for terabyte-scale waveform recording in intensive care: computer system design, database description and lessons learned", "authors": [{"first": "A", "middle": [], "last": "Burykin", "suffix": ""}, {"first": "T", "middle": [], "last": "Peck", "suffix": ""}, {"first": "T", "middle": ["G"], "last": "Buchman", "suffix": ""}], "year": 2011, "venue": "Computer Methods and Programs in Biomedicine", "link": "19990252"}, "BIBREF99": {"title": "Mongodb: an open source alternative for HL7-CDA clinical documents management", "authors": [{"first": "G", "middle": [], "last": "Adri\u00e1n", "suffix": ""}, {"first": "G", "middle": ["E"], "last": "Francisco", "suffix": ""}, {"first": "M", "middle": [], "last": "Marcela", "suffix": ""}, {"first": "A", "middle": [], "last": "Baum", "suffix": ""}, {"first": "L", "middle": [], "last": "Daniel", "suffix": ""}, {"first": "G", "middle": ["B"], "last": "De Quir\u00f3s Fern\u00e1n", "suffix": ""}], "year": 2013, "venue": "Proceedings of the Open Source International Conference (CISL '13)", "link": "11082671"}, "BIBREF100": {"title": "Managing data in healthcare information systems: many models, one solution", "authors": [{"first": "K", "middle": [], "last": "Kaur", "suffix": ""}, {"first": "R", "middle": [], "last": "Rani", "suffix": ""}], "year": 2015, "venue": "Computer", "link": "7490665"}, "BIBREF101": {"title": "NextGen data persistence pattern in healthcare: polyglot persistence", "authors": [{"first": "S", "middle": [], "last": "Prasad", "suffix": ""}, {"first": "M", "middle": ["S N"], "last": "Sha", "suffix": ""}], "year": 2013, "venue": "Proceedings of the 4th International Conference on Computing, Communications and Networking Technologies (ICCCNT '13)", "link": "18474977"}, "BIBREF102": {"title": "A distributed storage solution for cloud based e-Healthcare Information System", "authors": [{"first": "W", "middle": ["D"], "last": "Yu", "suffix": ""}, {"first": "M", "middle": [], "last": "Kollipara", "suffix": ""}, {"first": "R", "middle": [], "last": "Penmetsa", "suffix": ""}, {"first": "S", "middle": [], "last": "Elliadka", "suffix": ""}], "year": 2013, "venue": "Proceedings of the IEEE 15th International Conference on e-Health Networking, Applications & Services (Healthcom '13)", "link": "16633072"}, "BIBREF103": {"title": "Enabling ubiquitous Data Mining in intensive care: features selection and data pre-processing", "authors": [{"first": "M", "middle": [], "last": "Santos", "suffix": ""}, {"first": "F", "middle": [], "last": "Portela", "suffix": ""}], "year": 2011, "venue": "Proceedings of the 13th International Conference on Enterprise Information Systems (ICEIS' 11)", "link": "906434"}, "BIBREF104": {"title": "BioMed Research International", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF105": {"title": "Healthcare data warehousing and quality assurance", "authors": [{"first": "D", "middle": ["J"], "last": "Berndt", "suffix": ""}, {"first": "J", "middle": ["W"], "last": "Fisher", "suffix": ""}, {"first": "A", "middle": ["R"], "last": "Hevner", "suffix": ""}, {"first": "J", "middle": [], "last": "Studnicki", "suffix": ""}], "year": 2001, "venue": "Computer", "link": "195913977"}, "BIBREF106": {"title": "2010 i2b2/VA challenge on concepts, assertions, and relations in clinical text", "authors": [{"first": "\u00d6", "middle": [], "last": "Uzuner", "suffix": ""}, {"first": "B", "middle": ["R"], "last": "South", "suffix": ""}, {"first": "S", "middle": [], "last": "Shen", "suffix": ""}, {"first": "S", "middle": ["L"], "last": "Duvall", "suffix": ""}], "year": 2011, "venue": "Journal of the American Medical Informatics Association", "link": "30029552"}, "BIBREF107": {"title": "tranS-MART: an open source and community-driven informatics and data sharing platform for clinical and translational research", "authors": [{"first": "B", "middle": ["D"], "last": "Athey", "suffix": ""}, {"first": "M", "middle": [], "last": "Braxenthaler", "suffix": ""}, {"first": "M", "middle": [], "last": "Haas", "suffix": ""}, {"first": "Y", "middle": [], "last": "Guo", "suffix": ""}], "year": 2013, "venue": "AMIA Summits on Translational Science Proceedings", "link": "38002171"}, "BIBREF108": {"title": "Multiparameter intelligent monitoring in intensive care II: a public-access intensive care unit database", "authors": [{"first": "M", "middle": [], "last": "Saeed", "suffix": ""}, {"first": "M", "middle": [], "last": "Villarroel", "suffix": ""}, {"first": "A", "middle": ["T"], "last": "Reisner", "suffix": ""}], "year": 2011, "venue": "Critical Care Medicine", "link": "13019290"}, "BIBREF109": {"title": "Accessing the public MIMIC-II intensive care relational database for clinical research", "authors": [{"first": "D", "middle": ["J"], "last": "Scott", "suffix": ""}, {"first": "J", "middle": [], "last": "Lee", "suffix": ""}, {"first": "I", "middle": [], "last": "Silva", "suffix": ""}], "year": 2013, "venue": "BMC Medical Informatics and Decision Making", "link": "5546932"}, "BIBREF110": {"title": "Biomedical informatics for computer-aided decision support systems: a survey", "authors": [{"first": "A", "middle": [], "last": "Belle", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Kon", "suffix": ""}, {"first": "K", "middle": [], "last": "Najarian", "suffix": ""}], "year": 2013, "venue": "The Scientific World Journal", "link": "5180067"}, "BIBREF111": {"title": "Crossing the quality chasm: a new health system for the 21st century (committee on quality of health care in America, institute of medicine)", "authors": [{"first": "B", "middle": ["S"], "last": "Bloom", "suffix": ""}], "year": 2002, "venue": "The Journal of the American Medical Association", "link": null}, "BIBREF112": {"title": "Clinical decision support systems: state of the art", "authors": [{"first": "S", "middle": ["Eta"], "last": "Berner", "suffix": ""}], "year": 2009, "venue": "", "link": "5605457"}, "BIBREF113": {"title": "An infrastructure of stream data mining, fusion and management for monitored patients", "authors": [{"first": "H", "middle": [], "last": "Han", "suffix": ""}, {"first": "H", "middle": ["C"], "last": "Ryoo", "suffix": ""}, {"first": "H", "middle": [], "last": "Patrick", "suffix": ""}], "year": 2006, "venue": "Proceedings of the 19th IEEE International Symposium on Computer-Based Medical Systems (CBMS '06)", "link": "6134049"}, "BIBREF114": {"title": "Trends and opportunities for integrated real time neonatal clinical decision support", "authors": [{"first": "N", "middle": [], "last": "Bressan", "suffix": ""}, {"first": "A", "middle": [], "last": "James", "suffix": ""}, {"first": "C", "middle": [], "last": "Mcgregor", "suffix": ""}], "year": 2012, "venue": "Proceedings of the IEEE-EMBS International Conference on Biomedical and Health Informatics (BHI '12)", "link": "3091655"}, "BIBREF115": {"title": "Do heart and respiratory rate variability improve prediction of extubation outcomes in critically ill patients?", "authors": [{"first": "A", "middle": ["J E"], "last": "Seely", "suffix": ""}, {"first": "A", "middle": [], "last": "Bravi", "suffix": ""}, {"first": "C", "middle": [], "last": "Herry", "suffix": ""}], "year": 2014, "venue": "Critical Care", "link": "195644"}, "BIBREF116": {"title": "Electrocardiogram characteristics prior to in-hospital cardiac arrest", "authors": [{"first": "M", "middle": [], "last": "Attin", "suffix": ""}, {"first": "G", "middle": [], "last": "Feld", "suffix": ""}, {"first": "H", "middle": [], "last": "Lemus", "suffix": ""}], "year": 2015, "venue": "Journal of Clinical Monitoring and Computing", "link": "4854157"}, "BIBREF117": {"title": "A hypotensive episode predictor for intensive care based on heart rate and blood pressure time series", "authors": [{"first": "J", "middle": [], "last": "Lee", "suffix": ""}, {"first": "R", "middle": ["G"], "last": "Mark", "suffix": ""}], "year": 2010, "venue": "", "link": "4525317"}, "BIBREF118": {"title": "A system for mining temporal physiological data streams for advanced prognostic decision support", "authors": [{"first": "J", "middle": [], "last": "Sun", "suffix": ""}, {"first": "D", "middle": [], "last": "Sow", "suffix": ""}, {"first": "J", "middle": [], "last": "Hu", "suffix": ""}, {"first": "S", "middle": [], "last": "Ebadollahi", "suffix": ""}], "year": 2010, "venue": "Proceedings of the 10th IEEE International Conference on Data Mining (ICDM' 10)", "link": "12341181"}, "BIBREF119": {"title": "Predicting icu hemodynamic instability using continuous multiparameter trends", "authors": [{"first": "H", "middle": [], "last": "Cao", "suffix": ""}, {"first": "L", "middle": [], "last": "Eshelman", "suffix": ""}, {"first": "N", "middle": [], "last": "Chbat", "suffix": ""}, {"first": "L", "middle": [], "last": "Nielsen", "suffix": ""}, {"first": "B", "middle": [], "last": "Gross", "suffix": ""}, {"first": "M", "middle": [], "last": "Saeed", "suffix": ""}], "year": 2008, "venue": "Proceedings of the IEEE International Conference on Engineering in Medicine and Biology Society (EMBS '08)", "link": "21871805"}, "BIBREF120": {"title": "Monitoring in Anesthesia and Perioperative Care", "authors": [{"first": "D", "middle": ["L"], "last": "Reich", "suffix": ""}], "year": 2011, "venue": "", "link": "71155532"}, "BIBREF121": {"title": "Current breathomics-a review on data pre-processing techniques and machine learning in metabolomics breath analysis", "authors": [{"first": "A", "middle": [], "last": "Smolinska", "suffix": ""}, {"first": "A", "middle": [], "last": "Ch", "suffix": ""}, {"first": "R", "middle": ["R R"], "last": "Hauschild", "suffix": ""}, {"first": "J", "middle": ["W"], "last": "Fijten", "suffix": ""}, {"first": "J", "middle": [], "last": "Dallinga", "suffix": ""}, {"first": "F", "middle": ["J"], "last": "Baumbach", "suffix": ""}, {"first": "", "middle": [], "last": "Van Schooten", "suffix": ""}], "year": 2014, "venue": "Journal of Breath Research", "link": "9834888"}, "BIBREF122": {"title": "Consensus summary statement of the international multidisciplinary consensus conference on multimodality monitoring in neurocritical care", "authors": [{"first": "P", "middle": ["Le"], "last": "Roux", "suffix": ""}, {"first": "D", "middle": ["K"], "last": "Menon", "suffix": ""}, {"first": "G", "middle": [], "last": "Citerio", "suffix": ""}], "year": 2014, "venue": "Intensive Care Medicine", "link": "4673528"}, "BIBREF123": {"title": "Multimodal monitoring in traumatic brain injury: current status and future directions", "authors": [{"first": "M", "middle": ["M"], "last": "Tisdall", "suffix": ""}, {"first": "M", "middle": [], "last": "Smith", "suffix": ""}], "year": 2007, "venue": "British Journal of Anaesthesia", "link": "8476395"}, "BIBREF124": {"title": "Multimodal monitoring and neurocritical care bioinformatics", "authors": [{"first": "J", "middle": ["C"], "last": "Hemphill", "suffix": ""}, {"first": "P", "middle": [], "last": "Andrews", "suffix": ""}, {"first": "M", "middle": [], "last": "De Georgia", "suffix": ""}], "year": 2011, "venue": "Nature Reviews Neurology", "link": "17056153"}, "BIBREF125": {"title": "A survey on wearable sensor-based systems for health monitoring and prognosis", "authors": [{"first": "A", "middle": [], "last": "Pantelopoulos", "suffix": ""}, {"first": "N", "middle": ["G"], "last": "Bourbakis", "suffix": ""}], "year": 2010, "venue": "IEEE Transactions on Systems, Man and Cybernetics Part C: Applications and Reviews", "link": "20905429"}, "BIBREF126": {"title": "A new telemonitoring system intended for chronic heart failure patients using mobile telephone technology-feasibility study", "authors": [{"first": "S", "middle": [], "last": "Winkler", "suffix": ""}, {"first": "M", "middle": [], "last": "Schieber", "suffix": ""}, {"first": "S", "middle": [], "last": "L\u00fccke", "suffix": ""}], "year": 2011, "venue": "International Journal of Cardiology", "link": "25618032"}, "BIBREF127": {"title": "Mining of sensor data in healthcare: a survey", "authors": [{"first": "D", "middle": [], "last": "Sow", "suffix": ""}, {"first": "D", "middle": ["S"], "last": "Turaga", "suffix": ""}, {"first": "M", "middle": [], "last": "Schmidt", "suffix": ""}], "year": 2013, "venue": "Managing and Mining Sensor Data", "link": "10317010"}, "BIBREF128": {"title": "Genome-wide genetic marker discovery and genotyping using next-generation sequencing", "authors": [{"first": "J", "middle": ["W"], "last": "Davey", "suffix": ""}, {"first": "P", "middle": ["A"], "last": "Hohenlohe", "suffix": ""}, {"first": "P", "middle": ["D"], "last": "Etter", "suffix": ""}, {"first": "J", "middle": ["Q"], "last": "Boone", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Catchen", "suffix": ""}, {"first": "M", "middle": ["L"], "last": "Blaxter", "suffix": ""}], "year": 2011, "venue": "Nature Reviews Genetics", "link": "15080731"}, "BIBREF129": {"title": "Repetitive DNA and nextgeneration sequencing: computational challenges and solutions", "authors": [{"first": "T", "middle": ["J"], "last": "Treangen", "suffix": ""}, {"first": "S", "middle": ["L"], "last": "Salzberg", "suffix": ""}], "year": 2012, "venue": "Nature Reviews Genetics", "link": "26127200"}, "BIBREF130": {"title": "The next-generation sequencing revolution and its impact on genomics", "authors": [{"first": "D", "middle": ["C"], "last": "Koboldt", "suffix": ""}, {"first": "K", "middle": ["M"], "last": "Steinberg", "suffix": ""}, {"first": "D", "middle": ["E"], "last": "Larson", "suffix": ""}, {"first": "R", "middle": ["K"], "last": "Wilson", "suffix": ""}, {"first": "E", "middle": ["R"], "last": "Mardis", "suffix": ""}], "year": 2013, "venue": "Cell", "link": "1154964"}, "BIBREF131": {"title": "Informatics Needs and Challenges in Cancer Research: Workshop Summary", "authors": [], "year": 2012, "venue": "", "link": "78276775"}, "BIBREF132": {"title": "Clinical analysis and interpretation of cancer genome data", "authors": [{"first": "E", "middle": ["M"], "last": "Van Allen", "suffix": ""}, {"first": "N", "middle": [], "last": "Wagle", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Levy", "suffix": ""}], "year": 2013, "venue": "Journal of Clinical Oncology", "link": "9595857"}, "BIBREF133": {"title": "Incorporating genomics into breast cancer clinical trials and care", "authors": [{"first": "A", "middle": [], "last": "Tabchy", "suffix": ""}, {"first": "C", "middle": ["X"], "last": "Ma", "suffix": ""}, {"first": "R", "middle": [], "last": "Bose", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Ellis", "suffix": ""}], "year": 2013, "venue": "Clinical Cancer Research", "link": "6736402"}, "BIBREF134": {"title": "Prioritizing targets for precision cancer medicine", "authors": [{"first": "F", "middle": [], "last": "Andre", "suffix": ""}, {"first": "E", "middle": [], "last": "Mardis", "suffix": ""}, {"first": "M", "middle": [], "last": "Salm", "suffix": ""}, {"first": "J", "middle": ["C"], "last": "Soria", "suffix": ""}, {"first": "L", "middle": ["L"], "last": "Siu", "suffix": ""}, {"first": "C", "middle": [], "last": "Swanton", "suffix": ""}], "year": 2014, "venue": "Annals of Oncology", "link": "5172955"}, "BIBREF135": {"title": "Modelling and analysis of gene regulatory networks", "authors": [{"first": "G", "middle": [], "last": "Karlebach", "suffix": ""}, {"first": "R", "middle": [], "last": "Shamir", "suffix": ""}], "year": 2008, "venue": "Nature Reviews Molecular Cell Biology", "link": "14052800"}, "BIBREF136": {"title": "Revisiting global gene expression analysis", "authors": [{"first": "J", "middle": [], "last": "Lov\u00e9n", "suffix": ""}, {"first": "D", "middle": ["A"], "last": "Orlando", "suffix": ""}, {"first": "A", "middle": ["A"], "last": "Sigova", "suffix": ""}], "year": 2012, "venue": "Cell", "link": "10962764"}, "BIBREF137": {"title": "Tackling the widespread and critical impact of batch effects in highthroughput data", "authors": [{"first": "J", "middle": ["T"], "last": "Leek", "suffix": ""}, {"first": "R", "middle": ["B"], "last": "Scharpf", "suffix": ""}, {"first": "H", "middle": ["C"], "last": "Bravo", "suffix": ""}], "year": 2010, "venue": "Nature Reviews Genetics", "link": "18681700"}, "BIBREF138": {"title": "Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists", "authors": [{"first": "D", "middle": ["W"], "last": "Huang", "suffix": ""}, {"first": "B", "middle": ["T"], "last": "Sherman", "suffix": ""}, {"first": "R", "middle": ["A"], "last": "Lempicki", "suffix": ""}], "year": 2009, "venue": "Nucleic Acids Research", "link": "14847796"}, "BIBREF139": {"title": "Profiling gene expression using Onto-Express", "authors": [{"first": "P", "middle": [], "last": "Khatri", "suffix": ""}, {"first": "S", "middle": [], "last": "Draghici", "suffix": ""}, {"first": "G", "middle": ["C"], "last": "Ostermeier", "suffix": ""}, {"first": "S", "middle": ["A"], "last": "Krawetz", "suffix": ""}], "year": 2001, "venue": "Genomics", "link": null}, "BIBREF140": {"title": "Global functional profiling of gene expression", "authors": [{"first": "S", "middle": [], "last": "Draghici", "suffix": ""}, {"first": "P", "middle": [], "last": "Khatri", "suffix": ""}, {"first": "R", "middle": ["P"], "last": "Martins", "suffix": ""}, {"first": "G", "middle": ["C"], "last": "Ostermeier", "suffix": ""}, {"first": "S", "middle": ["A"], "last": "Krawetz", "suffix": ""}], "year": 2003, "venue": "Genomics", "link": "15432928"}, "BIBREF141": {"title": "Global functional profiling of gene expression", "authors": [{"first": "S", "middle": [], "last": "Dr\u01ceghici", "suffix": ""}, {"first": "P", "middle": [], "last": "Khatri", "suffix": ""}, {"first": "R", "middle": ["P"], "last": "Martins", "suffix": ""}, {"first": "G", "middle": ["C"], "last": "Ostermeier", "suffix": ""}, {"first": "S", "middle": ["A"], "last": "Krawetz", "suffix": ""}], "year": 2003, "venue": "Genomics", "link": "15432928"}, "BIBREF142": {"title": "GoMiner: a resource for biological interpretation of genomic and proteomic data", "authors": [{"first": "B", "middle": ["R"], "last": "Zeeberg", "suffix": ""}, {"first": "W", "middle": [], "last": "Feng", "suffix": ""}, {"first": "G", "middle": [], "last": "Wang", "suffix": ""}], "year": 2003, "venue": "Genome Biology", "link": "14676993"}, "BIBREF143": {"title": "A new microarray, enriched in pancreas and pancreatic cancer cdnas to identify genes relevant to pancreatic cancer", "authors": [{"first": "K", "middle": ["L"], "last": "Poguegeile", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Mackey", "suffix": ""}, {"first": "R", "middle": ["D"], "last": "George", "suffix": ""}], "year": 2004, "venue": "Cancer Genomics and Proteomics", "link": "86233639"}, "BIBREF144": {"title": "Cluego: a cytoscape plug-in to decipher functionally grouped gene ontology and pathway annotation networks", "authors": [{"first": "G", "middle": [], "last": "Bindea", "suffix": ""}, {"first": "B", "middle": [], "last": "Mlecnik", "suffix": ""}, {"first": "H", "middle": [], "last": "Hackl", "suffix": ""}], "year": 2009, "venue": "Bioinformatics", "link": "16214239"}, "BIBREF145": {"title": "CluePedia Cytoscape plugin: pathway insights using integrated experimental and in silico data", "authors": [{"first": "G", "middle": [], "last": "Bindea", "suffix": ""}, {"first": "J", "middle": [], "last": "Galon", "suffix": ""}, {"first": "B", "middle": [], "last": "Mlecnik", "suffix": ""}], "year": 2013, "venue": "Bioinformatics", "link": "5091042"}, "BIBREF146": {"title": "Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles", "authors": [{"first": "A", "middle": [], "last": "Subramanian", "suffix": ""}, {"first": "P", "middle": [], "last": "Tamayo", "suffix": ""}, {"first": "V", "middle": ["K"], "last": "Mootha", "suffix": ""}], "year": 2005, "venue": "Proceedings of the National Academy of Sciences of the United States of America", "link": "2374637"}, "BIBREF147": {"title": "PGC-1 -responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes", "authors": [{"first": "V", "middle": ["K"], "last": "Mootha", "suffix": ""}, {"first": "C", "middle": ["M"], "last": "Lindgren", "suffix": ""}, {"first": "K.-F", "middle": [], "last": "Eriksson", "suffix": ""}], "year": 2003, "venue": "Nature Genetics", "link": "13940856"}, "BIBREF148": {"title": "A systems biology approach for pathway level analysis", "authors": [{"first": "S", "middle": [], "last": "Draghici", "suffix": ""}, {"first": "P", "middle": [], "last": "Khatri", "suffix": ""}, {"first": "A", "middle": ["L"], "last": "Tarca", "suffix": ""}], "year": 2007, "venue": "Genome Research", "link": "6058434"}, "BIBREF149": {"title": "Gene expression profiling related to antiinflammatory properties of curcumin in K562 leukemia cells", "authors": [{"first": "M.-H", "middle": [], "last": "Teiten", "suffix": ""}, {"first": "S", "middle": [], "last": "Eifes", "suffix": ""}, {"first": "S", "middle": [], "last": "Reuter", "suffix": ""}, {"first": "A", "middle": [], "last": "Duvoix", "suffix": ""}, {"first": "M", "middle": [], "last": "Dicato", "suffix": ""}, {"first": "M", "middle": [], "last": "Diederich", "suffix": ""}], "year": 2009, "venue": "Annals of the New York Academy of Sciences", "link": "205932630"}, "BIBREF150": {"title": "A communitydriven global reconstruction of human metabolism", "authors": [{"first": "I", "middle": [], "last": "Thiele", "suffix": ""}, {"first": "N", "middle": [], "last": "Swainston", "suffix": ""}, {"first": "R", "middle": ["M T"], "last": "Fleming", "suffix": ""}], "year": 2013, "venue": "Nature Biotechnology", "link": "18461025"}, "BIBREF151": {"title": "Predicting selective drug targets in cancer through metabolic networks", "authors": [{"first": "O", "middle": [], "last": "Folger", "suffix": ""}, {"first": "L", "middle": [], "last": "Jerby", "suffix": ""}, {"first": "C", "middle": [], "last": "Frezza", "suffix": ""}, {"first": "E", "middle": [], "last": "Gottlieb", "suffix": ""}, {"first": "E", "middle": [], "last": "Ruppin", "suffix": ""}, {"first": "T", "middle": [], "last": "Shlomi", "suffix": ""}], "year": 2011, "venue": "Molecular Systems Biology", "link": "215528143"}, "BIBREF152": {"title": "Wisdom of crowds for robust gene network inference", "authors": [{"first": "D", "middle": [], "last": "Marbach", "suffix": ""}, {"first": "J", "middle": ["C"], "last": "Costello", "suffix": ""}, {"first": "R", "middle": [], "last": "K\u00fcffner", "suffix": ""}], "year": 2012, "venue": "Nature Methods", "link": "5964780"}, "BIBREF153": {"title": "Boolean modeling in systems biology: an overview of methodology and applications", "authors": [{"first": "R.-S", "middle": [], "last": "Wang", "suffix": ""}, {"first": "A", "middle": [], "last": "Saadatpour", "suffix": ""}, {"first": "R", "middle": [], "last": "Albert", "suffix": ""}], "year": 2012, "venue": "Physical Biology", "link": "15339922"}, "BIBREF154": {"title": "Inferring dynamic gene regulatory networks in cardiac differentiation through the integration of multi-dimensional data", "authors": [{"first": "W", "middle": [], "last": "Gong", "suffix": ""}, {"first": "N", "middle": [], "last": "Koyano-Nakagawa", "suffix": ""}, {"first": "T", "middle": [], "last": "Li", "suffix": ""}, {"first": "D", "middle": ["J"], "last": "Garry", "suffix": ""}], "year": 2015, "venue": "BMC Bioinformatics", "link": "215223426"}, "BIBREF155": {"title": "Integrative analysis of cell cycle control in budding yeast", "authors": [{"first": "K", "middle": ["C"], "last": "Chen", "suffix": ""}, {"first": "L", "middle": [], "last": "Calzone", "suffix": ""}, {"first": "A", "middle": [], "last": "Csikasz-Nagy", "suffix": ""}, {"first": "F", "middle": ["R"], "last": "Cross", "suffix": ""}, {"first": "B", "middle": [], "last": "Novak", "suffix": ""}, {"first": "J", "middle": ["J"], "last": "Tyson", "suffix": ""}], "year": 2004, "venue": "Molecular Biology of the Cell", "link": null}, "BIBREF156": {"title": "Inference of S-system models of genetic networks using a cooperative coevolutionary algorithm", "authors": [{"first": "S", "middle": [], "last": "Kimura", "suffix": ""}, {"first": "K", "middle": [], "last": "Ide", "suffix": ""}, {"first": "A", "middle": [], "last": "Kashihara", "suffix": ""}], "year": 2005, "venue": "Bioinformatics", "link": null}, "BIBREF157": {"title": "Modeling gene regulatory networks with piecewise linear differential equations", "authors": [{"first": "J", "middle": [], "last": "Gebert", "suffix": ""}, {"first": "N", "middle": [], "last": "Radde", "suffix": ""}, {"first": "G.-W", "middle": [], "last": "Weber", "suffix": ""}], "year": 2007, "venue": "European Journal of Operational Research", "link": "15574046"}, "BIBREF158": {"title": "The inferred cardiogenic gene regulatory network in the mammalian heart", "authors": [{"first": "J", "middle": ["N"], "last": "Bazil", "suffix": ""}, {"first": "K", "middle": ["D"], "last": "Stamm", "suffix": ""}, {"first": "X", "middle": [], "last": "Li", "suffix": ""}], "year": 2014, "venue": "PLoS ONE", "link": "2695949"}, "BIBREF159": {"title": "Systems Biology", "authors": [{"first": "B", "middle": ["O"], "last": "Palsson", "suffix": ""}], "year": 2006, "venue": "", "link": "61067196"}, "BIBREF160": {"title": "Revealing strengths and weaknesses of methods for gene network inference", "authors": [{"first": "D", "middle": [], "last": "Marbach", "suffix": ""}, {"first": "R", "middle": ["J"], "last": "Prill", "suffix": ""}, {"first": "T", "middle": [], "last": "Schaffter", "suffix": ""}, {"first": "C", "middle": [], "last": "Mattiussi", "suffix": ""}, {"first": "D", "middle": [], "last": "Floreano", "suffix": ""}, {"first": "G", "middle": [], "last": "Stolovitzky", "suffix": ""}], "year": 2010, "venue": "Proceedings of the National Academy of Sciences of the United States of America", "link": "12836883"}, "BIBREF161": {"title": "Global reconstruction of the human metabolic network based on genomic and bibliomic data", "authors": [{"first": "N", "middle": ["C"], "last": "Duarte", "suffix": ""}, {"first": "S", "middle": ["A"], "last": "Becker", "suffix": ""}, {"first": "N", "middle": [], "last": "Jamshidi", "suffix": ""}], "year": 2007, "venue": "Proceedings of the National Academy of Sciences of the United States of America", "link": "22176006"}, "BIBREF162": {"title": "Flux balance analysis of biological systems: applications and challenges", "authors": [{"first": "K", "middle": [], "last": "Raman", "suffix": ""}, {"first": "N", "middle": [], "last": "Chandra", "suffix": ""}], "year": 2009, "venue": "Briefings in Bioinformatics", "link": "277052"}, "BIBREF163": {"title": "High-throughput generation, optimization and analysis of genome-scale metabolic models", "authors": [{"first": "C", "middle": ["S"], "last": "Henry", "suffix": ""}, {"first": "M", "middle": [], "last": "Dejongh", "suffix": ""}, {"first": "A", "middle": ["A"], "last": "Best", "suffix": ""}, {"first": "P", "middle": ["M"], "last": "Frybarger", "suffix": ""}, {"first": "B", "middle": [], "last": "Linsay", "suffix": ""}, {"first": "R", "middle": ["L"], "last": "Stevens", "suffix": ""}], "year": 2010, "venue": "Nature Biotechnology", "link": "6641097"}, "BIBREF164": {"title": "Integration of metabolic databases for the reconstruction of genome-scale metabolic networks", "authors": [{"first": "K", "middle": [], "last": "Radrich", "suffix": ""}, {"first": "Y", "middle": [], "last": "Tsuruoka", "suffix": ""}, {"first": "P", "middle": [], "last": "Dobson", "suffix": ""}], "year": 2010, "venue": "BMC Systems Biology", "link": "10027997"}, "BIBREF165": {"title": "Integrating quantitative proteomics and metabolomics with a genome-scale metabolic network model", "authors": [{"first": "K", "middle": [], "last": "Yizhak", "suffix": ""}, {"first": "T", "middle": [], "last": "Benyamini", "suffix": ""}, {"first": "W", "middle": [], "last": "Liebermeister", "suffix": ""}, {"first": "E", "middle": [], "last": "Ruppin", "suffix": ""}, {"first": "T", "middle": [], "last": "Shlomi", "suffix": ""}], "year": 2010, "venue": "Article ID btq183", "link": "6097071"}, "BIBREF166": {"title": "Whole-genome metabolic network reconstruction and constraint-based modeling", "authors": [{"first": "C", "middle": ["R"], "last": "Haggart", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Bartell", "suffix": ""}, {"first": "J", "middle": ["J"], "last": "Saucerman", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Papin", "suffix": ""}], "year": 2011, "venue": "Methods in Systems Biology", "link": "205136042"}, "BIBREF167": {"title": "Basic and applied uses of genome-scale metabolic network reconstructions of Escherichia coli", "authors": [{"first": "D", "middle": [], "last": "Mccloskey", "suffix": ""}, {"first": "B", "middle": ["\u00d8"], "last": "Palsson", "suffix": ""}, {"first": "A", "middle": ["M"], "last": "Feist", "suffix": ""}], "year": 2013, "venue": "Molecular Systems Biology", "link": "215520553"}, "BIBREF168": {"title": "The application of flux balance analysis in systems biology", "authors": [{"first": "E", "middle": ["P"], "last": "Gianchandani", "suffix": ""}, {"first": "A", "middle": ["K"], "last": "Chavali", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Papin", "suffix": ""}], "year": 2010, "venue": "Wiley Interdisciplinary Reviews: Systems Biology and Medicine", "link": "3232402"}, "BIBREF169": {"title": "Constraining the metabolic genotype-phenotype relationship using a phylogeny of in silico methods", "authors": [{"first": "N", "middle": ["E"], "last": "Lewis", "suffix": ""}, {"first": "H", "middle": [], "last": "Nagarajan", "suffix": ""}, {"first": "B", "middle": ["O"], "last": "Palsson", "suffix": ""}], "year": 2012, "venue": "Nature Reviews Microbiology", "link": "26271079"}, "BIBREF170": {"title": "Integrating multiple 'omics' analysis for microbial biology: application and methodologies", "authors": [{"first": "W", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "F", "middle": [], "last": "Li", "suffix": ""}, {"first": "L", "middle": [], "last": "Nie", "suffix": ""}], "year": 2010, "venue": "Microbiology", "link": "1786640"}, "BIBREF171": {"title": "Integration of expression data in genome-scale metabolic network reconstructions", "authors": [{"first": "A", "middle": ["S"], "last": "Blazier", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Papin", "suffix": ""}], "year": 2012, "venue": "Frontiers in Physiology", "link": "215535891"}, "BIBREF172": {"title": "Functional integration of a metabolic network model and expression data without arbitrary thresholding", "authors": [{"first": "P", "middle": ["A"], "last": "Jensen", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Papin", "suffix": ""}], "year": 2011, "venue": "Bioinformatics", "link": "20593895"}, "BIBREF173": {"title": "Drug off-target effects predicted using structural analysis in the context of a metabolic network model", "authors": [{"first": "R", "middle": ["L"], "last": "Chang", "suffix": ""}, {"first": "L", "middle": [], "last": "Xie", "suffix": ""}, {"first": "L", "middle": [], "last": "Xie", "suffix": ""}, {"first": "P", "middle": ["E"], "last": "Bourne", "suffix": ""}, {"first": "B", "middle": ["\u00d8"], "last": "Palsson", "suffix": ""}], "year": 2010, "venue": "PLoS Computational Biology", "link": "4917823"}, "BIBREF174": {"title": "Inferring regulatory networks from expression data using treebased methods", "authors": [{"first": "V", "middle": ["A"], "last": "Huynh-Thu", "suffix": ""}, {"first": "A", "middle": [], "last": "Irrthum", "suffix": ""}, {"first": "L", "middle": [], "last": "Wehenkel", "suffix": ""}, {"first": "P", "middle": [], "last": "Geurts", "suffix": ""}], "year": 2010, "venue": "PLoS ONE", "link": "10420934"}, "BIBREF175": {"title": "Inferring gene regulatory networks by ANOVA", "authors": [{"first": "R", "middle": [], "last": "K\u00fcffner", "suffix": ""}, {"first": "T", "middle": [], "last": "Petri", "suffix": ""}, {"first": "P", "middle": [], "last": "Tavakkolkhah", "suffix": ""}, {"first": "L", "middle": [], "last": "Windhager", "suffix": ""}, {"first": "R", "middle": [], "last": "Zimmer", "suffix": ""}], "year": 2012, "venue": "Article ID bts143", "link": "9924271"}, "BIBREF176": {"title": "Crowdsourcing network inference: the dream predictive signaling network challenge", "authors": [{"first": "R", "middle": ["J"], "last": "Prill", "suffix": ""}, {"first": "J", "middle": [], "last": "Saez-Rodriguez", "suffix": ""}, {"first": "L", "middle": ["G"], "last": "Alexopoulos", "suffix": ""}, {"first": "P", "middle": ["K"], "last": "Sorger", "suffix": ""}, {"first": "G", "middle": [], "last": "Stolovitzky", "suffix": ""}], "year": 2011, "venue": "Science Signaling", "link": "206671090"}, "BIBREF177": {"title": "Analysis and practical guideline of constraint-based boolean method in genetic network inference", "authors": [{"first": "T", "middle": [], "last": "Saithong", "suffix": ""}, {"first": "S", "middle": [], "last": "Bumee", "suffix": ""}, {"first": "C", "middle": [], "last": "Liamwirat", "suffix": ""}, {"first": "A", "middle": [], "last": "Meechai", "suffix": ""}], "year": 2012, "venue": "Article ID e30232", "link": "3830174"}, "BIBREF178": {"title": "Boolean dynamics of genetic regulatory networks inferred from microarray time series data", "authors": [{"first": "S", "middle": [], "last": "Martin", "suffix": ""}, {"first": "Z", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "A", "middle": [], "last": "Martino", "suffix": ""}, {"first": "J.-L", "middle": [], "last": "Faulon", "suffix": ""}], "year": 2007, "venue": "Bioinformatics", "link": "14230470"}, "BIBREF179": {"title": "A parallel algorithm for reverse engineering of biological networks", "authors": [{"first": "J", "middle": ["N"], "last": "Bazil", "suffix": ""}, {"first": "F", "middle": [], "last": "Qi", "suffix": ""}, {"first": "D", "middle": ["A"], "last": "Beard", "suffix": ""}], "year": 2011, "venue": "Integrative Biology", "link": "13115155"}, "BIBREF180": {"title": "Rulebased computer aided decision making for traumatic brain injuries", "authors": [{"first": "A", "middle": [], "last": "Belle", "suffix": ""}, {"first": "S.-Y", "middle": [], "last": "Ji", "suffix": ""}, {"first": "W", "middle": [], "last": "Chen", "suffix": ""}, {"first": "T", "middle": [], "last": "Huynh", "suffix": ""}, {"first": "K", "middle": [], "last": "Najarian", "suffix": ""}], "year": 2014, "venue": "Machine Learning in Healthcare Informatics", "link": "6886447"}, "BIBREF181": {"title": "Data mining in healthcare and biomedicine: a survey of the literature", "authors": [{"first": "I", "middle": [], "last": "Yoo", "suffix": ""}, {"first": "P", "middle": [], "last": "Alafaireet", "suffix": ""}, {"first": "M", "middle": [], "last": "Marinov", "suffix": ""}], "year": 2012, "venue": "Journal of Medical Systems", "link": "16522754"}}, "ref_entries": {"FIGREF0": {"text": "", "type": "figure"}, "FIGREF1": {"text": "Figure 1: Generalized analytic workflow using streaming healthcare data.", "type": "figure"}, "TABREF0": {"text": "Challenges facing medical image analysis.", "type": "table"}, "TABREF2": {"text": "Summary of popular methods and toolkits with their applications.", "type": "table"}}}
{"paper_id": "8331508", "_pdf_hash": "34b5aa670f7b1c6c857771e1e48ec2a32f1b907d", "abstract": [], "body_text": [{"section": "Introduction", "text": "The watercolor effect (WCE), first described by Pinna (1987) , has provoked great interest over the last decade (Pinna, Brelstaff, & Spillmann, 2001) . In its classic configuration, it is generated by two adjacent and thin, parallel, wavy contours of different chromaticity separating two regions in the visual field. The color of one of the contours appears to diffuse into the region it borders, filling it with a washed-out shade of the contour. The fill-in can occur over a large region of the visual field, raising the possibility that the phenomenon relates to high-level processes (Spillmann & Werner, 1996) , such as surface perception (Pinna et al., 2001) , figure-ground segregation (Pinna, Werner, & Spillmann, 2003; von der Heydt & Pierson, 2006; , or other aspects of perceptual organization (Pinna, 2005) .", "cite_spans": [{"start": 48, "end": 60, "text": "Pinna (1987)", "ref_id": "BIBREF20"}, {"start": 112, "end": 149, "text": "(Pinna, Brelstaff, & Spillmann, 2001)", "ref_id": "BIBREF23"}, {"start": 588, "end": 614, "text": "(Spillmann & Werner, 1996)", "ref_id": "BIBREF34"}, {"start": 644, "end": 664, "text": "(Pinna et al., 2001)", "ref_id": "BIBREF23"}, {"start": 693, "end": 727, "text": "(Pinna, Werner, & Spillmann, 2003;", "ref_id": "BIBREF26"}, {"start": 728, "end": 758, "text": "von der Heydt & Pierson, 2006;", "ref_id": "BIBREF36"}, {"start": 805, "end": 818, "text": "(Pinna, 2005)", "ref_id": "BIBREF22"}], "ref_spans": []}, {"section": "Introduction", "text": "The strength of the WCE is influenced by several factors, including the relative luminances of the contours (Devinck, Delahunt, Hardy, Spillmann, & Werner, 2006; Devinck & Knoblauch, 2012) , the width of the inducing contours (Pinna et al., 2001; Devinck, Gerardin, Dojat, & Knoblauch, 2014) , and the continuity and contiguity of the contour pairs (Devinck & Spillmann, 2009 ). Most studies have assessed the strength of the effect with matching or hue cancellation Citation: Gerardin, P., Devinck, F., Dojat, M., & Knoblauch, K. (2014) . Contributions of contour frequency, amplitude, and luminance to the watercolor effect estimated by conjoint measurement. Journal of Vision, 14(4):9, 1-15, http://www. journalofvision.org/content/14/4/9, doi:10.1167/14.4.9.", "cite_spans": [{"start": 108, "end": 161, "text": "(Devinck, Delahunt, Hardy, Spillmann, & Werner, 2006;", "ref_id": "BIBREF4"}, {"start": 162, "end": 188, "text": "Devinck & Knoblauch, 2012)", "ref_id": "BIBREF6"}, {"start": 226, "end": 246, "text": "(Pinna et al., 2001;", "ref_id": "BIBREF23"}, {"start": 247, "end": 291, "text": "Devinck, Gerardin, Dojat, & Knoblauch, 2014)", "ref_id": "BIBREF5"}, {"start": 349, "end": 375, "text": "(Devinck & Spillmann, 2009", "ref_id": "BIBREF7"}, {"start": 491, "end": 537, "text": "Devinck, F., Dojat, M., & Knoblauch, K. (2014)", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Introduction", "text": "techniques (Devinck, Delahunt, Hardy, Spillmann, & Werner, 2005; von der Heydt & Pierson, 2006) . More recently, paired comparisons have been used to quantify the phenomenon. Cao, Yazdanbakhsh, and Mingolla (2011) judged which of a pair of stimuli showed a more salient brightness filling-in for an achromatic version of the WCE. The strength of the WCE was related to the probability of distinguishing two patterns. Devinck and Knoblauch used maximum likelihood difference scaling (MLDS) to estimate the strength of the WCE as a function of the luminance of the interior inducing contour. MLDS involves comparisons between large stimulus differences or intervals and leads to an interval scale that describes changes in stimulus appearance along a single dimension (Maloney & Yang, 2003; Knoblauch & Maloney, 2012b) .", "cite_spans": [{"start": 11, "end": 64, "text": "(Devinck, Delahunt, Hardy, Spillmann, & Werner, 2005;", "ref_id": "BIBREF3"}, {"start": 65, "end": 95, "text": "von der Heydt & Pierson, 2006)", "ref_id": "BIBREF36"}, {"start": 175, "end": 213, "text": "Cao, Yazdanbakhsh, and Mingolla (2011)", "ref_id": "BIBREF1"}, {"start": 766, "end": 788, "text": "(Maloney & Yang, 2003;", "ref_id": "BIBREF17"}, {"start": 789, "end": 816, "text": "Knoblauch & Maloney, 2012b)", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "Introduction", "text": "MLDS is a promising technique because it is based on a Gaussian, equal-variance signal-detection model (Knoblauch & Maloney, 2012b) . The estimated perceptual scales have been shown to predict discrimination behavior, thus yielding an integrated description of performance from threshold to perception (Devinck & Knoblauch, 2012) . A disadvantage is that the method only permits evaluation of one stimulus dimension at a time. This difficulty, however, is overcome by the paradigm of conjoint measurement (Luce & Tukey, 1964; Krantz, Luce, Suppes, & Tversky, 1971; Falmagne, 1985; Roberts, 1985; Knoblauch & Maloney, 2012b) , which permits estimating interval scales for two or more dimensions from the same experimental data. In this paradigm, the observer judges one pair of stimuli in each trial, but the levels of the dimensions being studied vary independently across the two stimuli from trial to trial. In this way, the influence on judgments of varying one dimension while the other is fixed can be evaluated. Ho et al. (2008) recently developed a Gaussian, equal-variance, signal-detection model of conjoint measurement and used maximum likelihood to estimate the underlying perceptual scales and to test several hypotheses on how observers combine information across dimensions (maximum likelihood conjoint measurement or MLCM). We used this procedure to study the joint influences of luminance contrast, contour frequency, and amplitude on the WCE.", "cite_spans": [{"start": 103, "end": 131, "text": "(Knoblauch & Maloney, 2012b)", "ref_id": "BIBREF14"}, {"start": 302, "end": 329, "text": "(Devinck & Knoblauch, 2012)", "ref_id": "BIBREF6"}, {"start": 505, "end": 525, "text": "(Luce & Tukey, 1964;", "ref_id": "BIBREF16"}, {"start": 526, "end": 564, "text": "Krantz, Luce, Suppes, & Tversky, 1971;", "ref_id": "BIBREF15"}, {"start": 565, "end": 580, "text": "Falmagne, 1985;", "ref_id": "BIBREF8"}, {"start": 581, "end": 595, "text": "Roberts, 1985;", "ref_id": "BIBREF30"}, {"start": 596, "end": 623, "text": "Knoblauch & Maloney, 2012b)", "ref_id": "BIBREF14"}, {"start": 1018, "end": 1034, "text": "Ho et al. (2008)", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "Material and methods", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Observers", "text": "Six observers (two male and four female) with normal or corrected-to-normal vision volunteered for the experiments (mean age 6 SD: 33 6 8 years). Three participated in all three conditions, two in only one condition, and one in two of the conditions. All observers but one (author PG) were naive, and all had normal color vision as assessed by a Farnsworth Panel D15. Observers who required optical corrections wore their glasses while performing the experiments.", "cite_spans": [], "ref_spans": []}, {"section": "Observers", "text": "All experiments were in accordance with the principles of the Declaration of Helsinki.", "cite_spans": [], "ref_spans": []}, {"section": "Apparatus", "text": "The experiments were performed in a dark room. Stimuli were displayed on an Eizo FlexScan T562-T color monitor (42 cm) driven by a MacBook Pro (2.2 GHz). The screen had a resolution of 800 \u00b7 600 pixels and was run at a field rate of 100 Hz, noninterlaced. The voltage-phosphor luminance relationship was linearized with look-up tables. Calibration of the screen was performed with a Minolta CS-100 chroma meter. Observers were placed at a distance of 57.3 cm from the screen.", "cite_spans": [], "ref_spans": []}, {"section": "Stimuli", "text": "Each stimulus was generated with Matlab R2009b (http://www.mathworks.com/) and displayed with the Psychophysics Toolbox extensions (Brainard, 1997; Pelli, 1997) . All stimuli were displayed on a white background (128 cd/m 2 , CIE xy \u00bc 0.29, 0.30). The contour pairs that defined the stimuli were each of width 16 min, that is, 8 min for the interior and exterior contours, each. The outer contour was purple (CIE xy \u00bc 0.32, 0.19) and the inner orange (CIE xy \u00bc 0.48, 0.34). The stimuli were also specified in the DKL color space (Derrington, Krauskopf, & Lennie, 1984) with purple and orange contours at azimuths of 3208 and 458, respectively. Control stimuli were identical except that the contours were interlaced and generated little fillingin (Figure 1c) .", "cite_spans": [{"start": 131, "end": 147, "text": "(Brainard, 1997;", "ref_id": "BIBREF0"}, {"start": 148, "end": 160, "text": "Pelli, 1997)", "ref_id": "BIBREF19"}, {"start": 529, "end": 568, "text": "(Derrington, Krauskopf, & Lennie, 1984)", "ref_id": "BIBREF2"}], "ref_spans": [{"start": 747, "end": 758, "text": "(Figure 1c)", "ref_id": "FIGREF0"}]}, {"section": "Stimuli", "text": "For independent control of the frequency and the amplitude of the WCE contours, they were constructed as Fourier descriptors (Zahn & Roskies, 1972) . Each stimulus was defined by a circle of 48 diameter whose radius was modulated sinusoidally as a function of angle according to the equation", "cite_spans": [{"start": 125, "end": 147, "text": "(Zahn & Roskies, 1972)", "ref_id": "BIBREF37"}], "ref_spans": []}, {"section": "Stimuli", "text": "where R is the stimulus radius at angle h, r the average radius of the stimulus, A the modulation, and f the frequency in cycles per revolution (cpr). The stimuli are then plotted by transforming the polar coordinates (R, h) to rectangular coordinates (x, y) with the equations x\u00f0R; h\u00de \u00bc R\u00f0h\u00desin\u00f02ph\u00de \u00f0 2\u00de y\u00f0R; h\u00de \u00bc R\u00f0h\u00decos\u00f02ph\u00de:", "cite_spans": [], "ref_spans": []}, {"section": "Stimuli", "text": "For each condition, a factorial design was defined in which five levels along each of two dimensions (frequency, amplitude, or luminance) were chosen, and all levels crossed, creating a table of 25 stimuli. Figure  1a shows an example for frequency and amplitude with frequency varying across columns and amplitude across rows. The five frequencies were equally spaced, ranging from 4 to 20 cpr. The five amplitudes evaluated ranged from 0.04 to 0.2, and the five luminances of the orange contour ranged from 0.1 to 0.9 equally spaced in elevation in DKL space. In two other conditions, the dimensions of frequency/luminance and amplitude/ luminance were similarly crossed.", "cite_spans": [], "ref_spans": [{"start": 207, "end": 217, "text": "Figure  1a", "ref_id": "FIGREF0"}]}, {"section": "Procedure", "text": "Observers were run in three conditions (luminance/ frequency, luminance/amplitude, frequency/amplitude) with a single condition tested within a session. In each trial, a pair of different stimuli from the stimulus table for that condition (e.g., Figure 1a ) was chosen at random and presented to the observer. Observers judged which of the two patterns evoked the most salient fill-in color. To test that observers responded according to the fill-in appearance and not on the basis of some other stimulus feature(s), an equal number of test and control stimuli were interleaved in each session (e.g., Figure 1b and c). There are 25 \u00b7 24/2 \u00bc 300 such pairs. In each trial, either a pair of test or control stimuli were presented. A session consisted of a random presentation of all 600 test and control pairs. Each condition was repeated in five sessions, yielding 1,500 test and 1,500 control trials per condition for a given observer.", "cite_spans": [], "ref_spans": [{"start": 246, "end": 255, "text": "Figure 1a", "ref_id": "FIGREF0"}, {"start": 601, "end": 610, "text": "Figure 1b", "ref_id": "FIGREF0"}]}, {"section": "Model", "text": "We modeled the data following the framework described by Ho et al. (2008) for analyzing conjoint measurement experiments (see also chapter 8, Knoblauch & Maloney, 2012b) . They define three nested models that can be fit to describe the choices of the observers in order of complexity: an independence model, an additive model, and a saturated model. We begin the description with the additive model and then describe the simpler and more complex models with respect to it.", "cite_spans": [{"start": 57, "end": 73, "text": "Ho et al. (2008)", "ref_id": "BIBREF12"}, {"start": 142, "end": 169, "text": "Knoblauch & Maloney, 2012b)", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "Model", "text": "We represent the stimulus levels along the two dimensions of a condition by a variable / ij , i, j \u00bc 1, . . . 5, where the indices refer to two of the dimensions in the set (luminance, frequency, amplitude), for example, a row and column, respectively, of Figure 1a . In the additive model, we suppose that each of the two dimensions contributes to a filling-in response, w 1 i , w 2 j , respectively, which depends on its physical intensity level, and that the filling-in response, w ij , to a stimulus, / ij , is the sum of the component responses", "cite_spans": [], "ref_spans": [{"start": 256, "end": 265, "text": "Figure 1a", "ref_id": "FIGREF0"}]}, {"section": "Model", "text": "We assume that the observer judges the stimulus / ij to display stronger filling-in than the stimulus / kl when", "cite_spans": [], "ref_spans": []}, {"section": "Model", "text": "This representation yields an interval scale (Krantz et al., 1971) . Note, for example, that by rearranging Equation 5 as follows,", "cite_spans": [{"start": 45, "end": 66, "text": "(Krantz et al., 1971)", "ref_id": "BIBREF15"}], "ref_spans": []}, {"section": "Model", "text": "the decision rule is equivalent to a comparison of intervals across dimensions. It is unlikely, however, that the observer would make the same response in every trial when the two stimuli are very similar. To incorporate this inherent variability of human responses, we suppose that the decision variable, D ijkl , is contaminated by internal noise so that the observer chooses the first stimulus exactly when", "cite_spans": [], "ref_spans": []}, {"section": "Model", "text": "where each ijkl is a draw from a distribution of independent and identically distributed normal variables with l \u00bc 0 and variance \u00bc 4r 2 . This is an equalvariance, Gaussian signal-detection model. The coefficient of four on the variance parameterizes the estimated scale values so that variance of the response along each dimension is equal to r 2 . As a result, the estimated response values w k i /r are distributed as normal variables with r 2 \u00bc 1 and are, thus, on the same scale as the sensitivity measure d 0 from signal detection theory (Green & Swets, 1966) .", "cite_spans": [], "ref_spans": []}, {"section": "1", "text": "With p intensity levels sampled along each dimension and the estimate of the variance of , there are 2p \u00fe 1 parameters in the model. The reparameterizations of the scale described above suggest that we may multiply the estimated values by any constant without changing the model predictions of the observer's responses. In fact, we may similarly add any constant to the scales with similar results. To fix the estimated scales, we set the lowest value of each scale to zero.", "cite_spans": [], "ref_spans": []}, {"section": "1", "text": "This eliminates two parameters from the fit. In addition, by making r 2 \u00bc 1, we eliminate one more so that the fitting process requires estimating 2p -2 parameters. The parameterization that we propose is slightly different from that used by Ho et al. (2008) , who estimated r but normalized the estimated functions so that the maximum scale value was unity.", "cite_spans": [{"start": 242, "end": 258, "text": "Ho et al. (2008)", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "1", "text": "Both parameterizations yield identical predictions of performance.", "cite_spans": [], "ref_spans": []}, {"section": "1", "text": "The additive model implies that there are component functions representing the internal response to each physical dimension and that the overall response to a stimulus is the simple sum of these component responses. We illustrate this in Figure 2c and d. In Figure 2c , we show two hypothetical component responses, w 1 and w 2 , each of which, for simplicity, is a linear function of the stimulus level. Stimulus level here and elsewhere is indicated by an index, not physical units. This convention, as used elsewhere (Ho et al., 2008; Knoblauch & Maloney, 2012b) , allows the scales for both dimensions to be plotted together. The response to any stimulus with levels i and j, respectively, along the two stimulus dimensions is represented by the sum of their component responses. As an example, consider a stimulus of level three along the first dimension and level four along the second. The component responses to the level along each dimension are indicated by the two black points. Figure 2d shows the set of summed responses for all pairings of the two dimensions with the base dimension corresponding to w 2 and the parameter indicated along each curve corresponding to w 1 . Each curve has the shape of the component curve for w 2 but is displaced vertically by the value of w 1 , resulting in a set of parallel contours. Analogous to a linear model, we could say that each dimension shows a main effect but no interaction. The summed response to the stimulus with the levels. indicated in Figure 2c is indicated by the black point.", "cite_spans": [{"start": 520, "end": 537, "text": "(Ho et al., 2008;", "ref_id": "BIBREF12"}, {"start": 538, "end": 565, "text": "Knoblauch & Maloney, 2012b)", "ref_id": "BIBREF14"}], "ref_spans": [{"start": 238, "end": 247, "text": "Figure 2c", "ref_id": "FIGREF1"}, {"start": 258, "end": 267, "text": "Figure 2c", "ref_id": "FIGREF1"}, {"start": 990, "end": 999, "text": "Figure 2d", "ref_id": "FIGREF1"}, {"start": 1501, "end": 1510, "text": "Figure 2c", "ref_id": "FIGREF1"}]}, {"section": "1", "text": "A simpler model than the additive model is obtained by assuming that the observer's judgments depend on only one of the component dimensions. In that case, the decision variable reduces to", "cite_spans": [], "ref_spans": []}, {"section": "1", "text": "where we assume that only the first dimension contributes to the judgments. Ho et al. (2008) call this the independent-property model, but we will refer to it as just the independence model. The independence model requires estimating only p -1 parameters. The independence model is illustrated in Figure 2a and b. In Figure 2a , the component w 1 increases with stimulus level along the first dimension, but w 2 is flat or independent of the level of the second dimension. The summed responses are indicated in Figure 2b by a set of lines of zero slope that are vertically displaced by the responses along the w 1 curve. In analogy to a linear model, there is a significant main effect of the first dimension but not of the second.", "cite_spans": [{"start": 76, "end": 92, "text": "Ho et al. (2008)", "ref_id": "BIBREF12"}], "ref_spans": [{"start": 297, "end": 306, "text": "Figure 2a", "ref_id": "FIGREF1"}, {"start": 317, "end": 326, "text": "Figure 2a", "ref_id": "FIGREF1"}, {"start": 511, "end": 520, "text": "Figure 2b", "ref_id": "FIGREF1"}]}, {"section": "1", "text": "Finally, the additive model may not suffice to provide a satisfactory description of the observer's responses. Ho et al. (2008) describe the full model, which includes interaction terms, w variable is", "cite_spans": [{"start": 111, "end": 127, "text": "Ho et al. (2008)", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "1", "text": "This model requires the estimation of p 2 -1 parameters, one less than the number of stimuli tested, and will be referred to as the saturated model. An example of response curves that might result from a saturated model are shown in Figure 2e . The important feature is that the curves are not parallel and, thus, the curves cannot be explained by a simple additive combination of component curves as in the previous two cases.", "cite_spans": [], "ref_spans": [{"start": 233, "end": 242, "text": "Figure 2e", "ref_id": "FIGREF1"}]}, {"section": "Analyses", "text": "The three models described above form a nested sequence. The estimated scale values with the above constraints that best predict the observers' responses are fitted by maximum likelihood (Ho et al., 2008) . Because the decision variable is linear in the estimated coefficients, however, the fitting procedure is simply implemented as a generalized linear model with a binomial family (McCullagh & Nelder, 1989) . Standard errors and confidence intervals of estimated scale values for comparing model fits were estimated using a bootstrap procedure (Knoblauch & Maloney, 2012a , 2012b . All analyses were performed using the open source software R (R Development Core Team, 2012) with functions from the MLCM package (Knoblauch & Maloney, 2012a , 2012b .", "cite_spans": [{"start": 187, "end": 204, "text": "(Ho et al., 2008)", "ref_id": "BIBREF12"}, {"start": 384, "end": 410, "text": "(McCullagh & Nelder, 1989)", "ref_id": "BIBREF18"}, {"start": 548, "end": 575, "text": "(Knoblauch & Maloney, 2012a", "ref_id": "BIBREF13"}, {"start": 576, "end": 583, "text": ", 2012b", "ref_id": "BIBREF14"}, {"start": 716, "end": 743, "text": "(Knoblauch & Maloney, 2012a", "ref_id": "BIBREF13"}, {"start": 744, "end": 751, "text": ", 2012b", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "Results", "text": "Judgments from the observers for test and control conditions for each of the pairings of the three dimensions are shown in Figure 3a through c in a format introduced by Ho et al. (2008) and termed a conjoint proportion plot (CPP) by Knoblauch and Maloney (2012a) . Each CPP summarizes the proportion of times that the ordinate stimulus, S kl , was judged to show a greater fill-in than the abscissa stimulus, S ij , coded according to the grey levels shown in the color bar at the right of each set of graphs, for every stimulus pair presented. The levels along the two dimensions are represented along each axis using a scheme in which a 5 \u00b7 5 outer grid demarcates the stimulus levels along one dimension (e.g., amplitude in Figure 3a) , and the levels of the second dimension are represented as an inner subgrid nested within each square of the outer grid (e.g., frequency in the same figure) . As the responses are combined across random left/right orders in the presentation-only the upper left triangle of a CPP is unique and displayed.", "cite_spans": [{"start": 169, "end": 185, "text": "Ho et al. (2008)", "ref_id": "BIBREF12"}, {"start": 233, "end": 262, "text": "Knoblauch and Maloney (2012a)", "ref_id": "BIBREF13"}], "ref_spans": [{"start": 123, "end": 132, "text": "Figure 3a", "ref_id": "FIGREF2"}, {"start": 727, "end": 737, "text": "Figure 3a)", "ref_id": "FIGREF2"}]}, {"section": "Results", "text": "In Figure 3a through c, the set of results from each observer is indicated by his/her initials above the pair of CPPs for test (upper) and control (lower) stimuli. Figure 3d shows the expected pattern of responses for an ideal observer for whom the judgments are based on the level of only one of the two stimulus dimensions. The left CPP shows the results when the judgments depend solely on the outer dimensions (Dim 1) and the right on the inner (Dim 2). In general, the CPP for the test stimuli resemble more closely the ideal pattern displayed for the inner dimension, suggesting that the contribution of frequency dominated when both frequency and amplitude covaried but that luminance contributed more strongly to the judgments when paired with the other two dimensions. The patterns do, however, deviate from the ideal, indicating contributions from both dimensions.", "cite_spans": [], "ref_spans": [{"start": 3, "end": 12, "text": "Figure 3a", "ref_id": "FIGREF2"}, {"start": 164, "end": 173, "text": "Figure 3d", "ref_id": "FIGREF2"}]}, {"section": "Results", "text": "There is an important difference in the procedure used here from that reported by Ho et al. (2008) . They tested stimuli that varied along the dimensions of roughness and glossiness and asked different observers to judge which member of a pair appeared rougher or shinier. Thereby, they could estimate the contamination of the one dimension to judgments along the other. In our experiments, the task is not necessarily related to the stimulus dimensions. Thus, one cannot be sure a priori that the observer is actually basing his/her judgments on the stated criterion. Instead, the observer may simply be judging the variation along the two dimensions manipulated, that is, which stimulus has a higher frequency contour, amplitude, or luminance. If observers were performing in this manner, then we would expect to see the same pattern of responses in the CPPs for control and test stimuli. By and large, however, the patterns are quite different with the control CPP patterns appearing to be random. The principal exception to this is evident in the control data of observer OH for the amplitude/luminance condition ( Figure 3b ) and, to a lesser extent, for observer DL in the same condition. In these two cases, then, we cannot exclude that either the observers perceived a small amount of filling-in or, alternatively, that they showed a tendency to base their judgments on the physical dimensions of the stimulus for a subset of the trials rather than on the perceived filling-in per se. For example, Figure 4a indicates that the contribution of the frequency dimension to the filling-in strength increases with the frequency of the contour while the amplitude dimension shows a smaller effect that increases between the first and second levels tested for all observers but one (SJ shows a relatively flat amplitude contribution) and then remains approximately constant. These results contrast with the scales estimated for the control stimuli that show no difference and very little effect of either dimension on the strength of filling-in.", "cite_spans": [{"start": 82, "end": 98, "text": "Ho et al. (2008)", "ref_id": "BIBREF12"}], "ref_spans": [{"start": 1119, "end": 1128, "text": "Figure 3b", "ref_id": "FIGREF2"}, {"start": 1506, "end": 1515, "text": "Figure 4a", "ref_id": "FIGREF4"}]}, {"section": "Results", "text": "Similarly, Figure 4b shows that the contribution of luminance to the filling-in increases with the luminance of the orange contour while the amplitude contributions are similar to those obtained in Figure 4a with the exception of observer SJ who shows a stronger luminance contribution than in the previous condition. The controls show little influence of either dimension. The exception is again shown by observer OH, consistent with the CPP plots in Figure 3b . Note also, that, for this condition, the responses of observers PG and OH to the test stimuli result mostly from the luminance dimension, again, as suggested by comparison of their CPP plots to the ideal cases. Figure 4c shows the contributions of luminance and frequency when these two dimensions are varied. The luminance scales are similar to those in Figure 4b , and the frequency scales resemble those obtained in Figure  4a . As in the preceding figures, the control stimuli provide little evidence for filling-in in that the contributions of each dimension to the judgments remain low as the scale value is increased.", "cite_spans": [], "ref_spans": [{"start": 11, "end": 20, "text": "Figure 4b", "ref_id": "FIGREF4"}, {"start": 198, "end": 207, "text": "Figure 4a", "ref_id": "FIGREF4"}, {"start": 452, "end": 461, "text": "Figure 3b", "ref_id": "FIGREF2"}, {"start": 675, "end": 684, "text": "Figure 4c", "ref_id": "FIGREF4"}, {"start": 819, "end": 828, "text": "Figure 4b", "ref_id": "FIGREF4"}, {"start": 883, "end": 893, "text": "Figure  4a", "ref_id": "FIGREF4"}]}, {"section": "Results", "text": "Finally, Figure 4d shows the means and 95% confidence intervals across observers for each pairing of the three dimensions. The scales for the control conditions show little effect with confidence intervals overlapping zero, and confidence intervals for test conditions exclude zero with the exception of the highest amplitude in the amplitude/luminance condition. The large confidence intervals for some of the test conditions reflect the individual differences shown in the previous graphs. Interestingly, the average scale for each dimension tends to be similar, independently of the other dimension with which it is paired, a point we will examine in more detail below.", "cite_spans": [], "ref_spans": [{"start": 9, "end": 18, "text": "Figure 4d", "ref_id": "FIGREF4"}]}, {"section": "Comparisons of independence and additive models", "text": "We consider the possibility that the contribution of only one dimension independently of the other suffices to account for observers' judgments, that is, the independence model. We chose to model the data based on the dimension that generated the strongest contributions under the additive model. We will refer to this dimension as the primary dimension and the other as the secondary dimension. Specifically, luminance was the primary dimension when paired with frequency or amplitude, and frequency was the primary dimension when paired with amplitude.", "cite_spans": [], "ref_spans": []}, {"section": "Comparisons of independence and additive models", "text": "We compare the models by plotting the estimated scales from both models in the same graph for each observer. For reference, we are comparing the two models shown in Figure 2a and c. Comparisions between additive (solid) and independence (grey dashed) model fits are displayed in Figure 5 with 95% confidence intervals of the additive estimates displayed. By construction, the contribution of the secondary dimension is fixed at zero for the independence model.", "cite_spans": [], "ref_spans": [{"start": 165, "end": 174, "text": "Figure 2a", "ref_id": "FIGREF1"}, {"start": 279, "end": 287, "text": "Figure 5", "ref_id": "FIGREF5"}]}, {"section": "Comparisons of independence and additive models", "text": "The comparisons in Figure 5 indicate that scale estimates of the primary dimension under the independent model tend to correspond closely to those under the additive model. For observer SJ in the amplitude/luminance condition and for all observers in the frequency/luminance condition, however, the estimate of the primary dimension contribution for the independence model falls outside the confidence limits for the additive model. This is sufficient to reject the independence model for these conditions. Moreover, in all cases but one (observer SJ for the amplitude/ frequency experiment), the secondary dimension of the additive model differs significantly from zero, the prediction along the secondary dimension for independence, thus leading to rejection of the independence model in nearly every case. Thus, although the contribution of amplitude to the judgments is small, it is significant.", "cite_spans": [], "ref_spans": [{"start": 19, "end": 27, "text": "Figure 5", "ref_id": "FIGREF5"}]}, {"section": "Comparisons of additive and saturated models", "text": "To compare the additive and saturated model fits, we adopt the format of Figure 2d and e in which the estimated scale values are plotted as a function of the stimulus index along one dimension with the other dimension treated as a parameter. The comparisons are shown for each pair of dimensions and for each observer in the panels of Figure 6 . The results are noisier than for the preceding comparison. However, for most of the comparisons, the confidence intervals for the saturated model (solid) overlap the curves for the additive model (dashed), suggesting that the simpler additive model suffices to describe the data. Most of the exceptions concern the amplitude dimension that, as we saw above, only weakly contributes to the judgments compared to the frequency or the luminance and displays more variability across conditions. In addition, the deviations that occur are not systematic across observers.", "cite_spans": [], "ref_spans": [{"start": 73, "end": 82, "text": "Figure 2d", "ref_id": "FIGREF1"}, {"start": 335, "end": 343, "text": "Figure 6", "ref_id": "FIGREF6"}]}, {"section": "Comparisons of additive and saturated models", "text": "Residual differences between the two models are shown as grey level plots in Figure 7a through c. The differences have been normalized with respect to the standard errors of the saturated model fits. In general, there is no obvious pattern in the residuals although the frequency/amplitude condition appears noisier than the other two. For this condition, eight of the 125 residuals (6.4%) exceed a magnitude of two whereas none of the residuals exceed a value of two for the other two conditions.", "cite_spans": [], "ref_spans": [{"start": 77, "end": 86, "text": "Figure 7a", "ref_id": "FIGREF7"}]}, {"section": "Comparisons of estimated scales across experiments", "text": "To what extent are the estimated contributions from each dimension invariant with respect to the context of the judgments? For example, does the estimated scale for the contribution of luminance depend on whether either frequency or amplitude is the covarying dimension? The same question can be posed for each dimension with respect to the other two. Figure 8a shows the estimated contribution of luminance to the fill-in color when the contour frequency (red) or its amplitude (blue) is the covarying dimension as a function of the luminance index for the four observers who performed both experiments. The scales obtained under the different conditions agree very well for all of the observers, and the overlap in the confidence intervals lends no support to the importance of the differences in the means.", "cite_spans": [], "ref_spans": [{"start": 352, "end": 361, "text": "Figure 8a", "ref_id": "FIGREF8"}]}, {"section": "Comparisons of estimated scales across experiments", "text": "Similarly, Figure 8b and c shows the comparisons of the scales obtained for the frequency and amplitude dimensions, respectively. There is good agreement across conditions for the frequency scales for observers PG and SJ. For OH, the scales agree in form although the sensitivity to frequency is higher when paired with the luminance than with the amplitude dimension.", "cite_spans": [], "ref_spans": [{"start": 11, "end": 20, "text": "Figure 8b", "ref_id": "FIGREF8"}]}, {"section": "Comparisons of estimated scales across experiments", "text": "There seems to be less agreement between the scales based on the amplitude dimension. This is most marked for observer SJ, for whom the contribution of amplitude to the judgments is insignificant when paired with frequency but significantly higher, based on the nonoverlap of confidence intervals, when paired with the luminance dimension. As noted previously (see Figure 4a and b) , however, the amplitude contributions tended to be small and more variable. This is borne out by the averages across observers shown in Figure 8d that show good agreement in the scales measured along each dimension and agrees with the averages based on all observers from Figure 4d . The average data show the amplitude contribution asymptotes by the second stimulus level, which corresponds to an amplitude of 0.08. The frequency contribution asymptotes by the third level, which corresponds to a value of 12 cpr.", "cite_spans": [], "ref_spans": [{"start": 365, "end": 381, "text": "Figure 4a and b)", "ref_id": "FIGREF4"}, {"start": 519, "end": 528, "text": "Figure 8d", "ref_id": "FIGREF8"}, {"start": 655, "end": 664, "text": "Figure 4d", "ref_id": "FIGREF4"}]}, {"section": "Discussion", "text": "We used the MLCM technique to quantify the contributions to the filling-in strength of the WCE of three stimulus dimensions. An important difference from the previous use of this technique by Ho et al. (2008) is that the perceptual judgment required of the observers in our experiments is not directly linked to either of the stimulus dimensions whereas in Ho et al. (2008) it was. Thus, in theory, the observers could have simply based their judgments directly on the stimulus dimensions manipulated (luminance, frequency, and/or amplitude) rather than the perceptual criterion of filling-in strength. To evaluate this possibility, we included control stimuli during the sessions for which very little, if any, filling-in was expected to occur. If the observers based their judgments on the manipulated dimensions rather than the perceived filling-in, then the estimated contributions to the judgments for control and test stimuli would be the same. In fact, the model estimates for the control conditions were severely attenuated in all conditions, thus supporting that the test conditions do reflect judgments with respect to filling-in.", "cite_spans": [{"start": 192, "end": 208, "text": "Ho et al. (2008)", "ref_id": "BIBREF12"}, {"start": 357, "end": 373, "text": "Ho et al. (2008)", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "Discussion", "text": "As shown previously using a difference scaling technique (Devinck & Knoblauch, 2012) , the strength of the WCE depends importantly on the luminance of the interior contour. We show here, as well, that the filling-in is stronger for higher frequencies of the contour modulation although the influence of contour frequency asymptotes at about 12 cpr. Probably because of its small value, the estimates of the contribution of amplitude to the phenomenon were found to be more variable across conditions and observers. In addition, the results are best supported by a model in which the responses to the separate dimensions contribute in an additive fashion.", "cite_spans": [{"start": 57, "end": 84, "text": "(Devinck & Knoblauch, 2012)", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "Discussion", "text": "It has previously been reported that the WCE is present although weaker with straight contours (Pinna et al., 2001) . Our results confirm this observation in that, for nearly all conditions, the amplitude contribution was greater for higher amplitudes than for the lowest value tested. We did not test a frequency of zero cpr or a zero amplitude because it would have led to a singular set of conditions, a row and column of identical stimuli in the frequency/amplitude matrix of stimuli (Figure 1) . Additionally, because we fix the lowest perceptual scale values at zero in order to make the estimated coefficients identifiable, our measurements of the strength of the phenomenon are only in reference to this value. A measure of the strength at this lowest value could have been obtained by including paired comparisons between test and control stimuli in the experiment, but this would have quadrupled the number of stimulus pairs to evaluate.", "cite_spans": [{"start": 95, "end": 115, "text": "(Pinna et al., 2001)", "ref_id": "BIBREF23"}], "ref_spans": [{"start": 488, "end": 498, "text": "(Figure 1)", "ref_id": "FIGREF0"}]}, {"section": "Discussion", "text": "We performed the experiments analyzing dimensions pairwise, that is, two-way experiments. Following the logic of factorial design, it might be argued that it would be more efficient to perform an experiment with all three attributes permitted to covary simultaneously, that is, a three-way experiment. Employing five levels along each dimension, as here, would generate 5 3 \u00bc 125 different stimuli and 125 \u00b7 124/2 \u00bc 7,750 paired comparisons, which could be reasonably argued is excessive. Simulation results for two-way experiments suggest that it is the number of total judgments and not the number of conditions that determines the precision of the estimates (Knoblauch & Maloney, 2012b) . Similar results have been obtained for the MLDS technique (Maloney & Yang, 2003) . This raises the possibility of obtaining good scale estimates for a threeway experiment by subsampling from the full set of stimulus pairs although it will be necessary to verify such a conjecture via simulation.", "cite_spans": [{"start": 661, "end": 689, "text": "(Knoblauch & Maloney, 2012b)", "ref_id": "BIBREF14"}, {"start": 750, "end": 772, "text": "(Maloney & Yang, 2003)", "ref_id": "BIBREF17"}], "ref_spans": []}, {"section": "Discussion", "text": "Comparing the dimensions pairwise permitted us to evaluate whether the estimated contributions of each dimension to the observer's judgments were independent of the contributions of the second, covarying dimension. The results support such an invariance for the luminance and frequency dimensions but are more equivocal for the amplitude although all three dimensions are consistent with invariance for the average data. We suspect that the failures of invariance along the amplitude dimension stem more from its weak contribution to the WCE, rendering it difficult to estimate with the number of trials that we employed and possible criterion shifts of the observers. These hypotheses remain to be tested, however. ", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "The Psychophysics Toolbox", "authors": [{"first": "D", "middle": ["H"], "last": "Brainard", "suffix": ""}], "year": 1997, "venue": "Spatial Vision", "link": "27687210"}, "BIBREF1": {"title": "The effect of contrast intensity and polarity in the achromatic watercolor effect", "authors": [{"first": "B", "middle": [], "last": "Cao", "suffix": ""}, {"first": "A", "middle": [], "last": "Yazdanbakhsh", "suffix": ""}, {"first": "E", "middle": [], "last": "Mingolla", "suffix": ""}], "year": 2011, "venue": "Journal of Vision", "link": "14015923"}, "BIBREF2": {"title": "Chromatic mechanisms in lateral geniculate nucleus of macaque", "authors": [{"first": "A", "middle": ["M"], "last": "Derrington", "suffix": ""}, {"first": "J", "middle": [], "last": "Krauskopf", "suffix": ""}, {"first": "P", "middle": [], "last": "Lennie", "suffix": ""}], "year": 1984, "venue": "The Journal of Physiology", "link": "8300574"}, "BIBREF3": {"title": "The watercolor effect: Quantitative evidence for luminance-dependent mechanisms of long-range color assimilation", "authors": [{"first": "F", "middle": [], "last": "Devinck", "suffix": ""}, {"first": "P", "middle": ["B"], "last": "Delahunt", "suffix": ""}, {"first": "J", "middle": ["L"], "last": "Hardy", "suffix": ""}, {"first": "L", "middle": [], "last": "Spillmann", "suffix": ""}, {"first": "J", "middle": ["S"], "last": "Werner", "suffix": ""}], "year": 2005, "venue": "", "link": "16603734"}, "BIBREF4": {"title": "Spatial dependence of color assimilation by the watercolor effect. Perception", "authors": [{"first": "F", "middle": [], "last": "Devinck", "suffix": ""}, {"first": "P", "middle": ["B"], "last": "Delahunt", "suffix": ""}, {"first": "J", "middle": ["L"], "last": "Hardy", "suffix": ""}, {"first": "L", "middle": [], "last": "Spillmann", "suffix": ""}, {"first": "J", "middle": ["S"], "last": "Werner", "suffix": ""}], "year": 2006, "venue": "", "link": null}, "BIBREF5": {"title": "Spatial selectivity of the watercolor effect", "authors": [{"first": "F", "middle": [], "last": "Devinck", "suffix": ""}, {"first": "P", "middle": [], "last": "Gerardin", "suffix": ""}, {"first": "M", "middle": [], "last": "Dojat", "suffix": ""}, {"first": "K", "middle": [], "last": "Knoblauch", "suffix": ""}], "year": 2014, "venue": "Journal of the Optical Society of America A", "link": "11609653"}, "BIBREF6": {"title": "A common signal detection model accounts for both perception and discrimination of the watercolor effect", "authors": [{"first": "F", "middle": [], "last": "Devinck", "suffix": ""}, {"first": "K", "middle": [], "last": "Knoblauch", "suffix": ""}], "year": 2012, "venue": "Journal of Vision", "link": "14406839"}, "BIBREF7": {"title": "The watercolor effect: Spacing constraints", "authors": [{"first": "F", "middle": [], "last": "Devinck", "suffix": ""}, {"first": "L", "middle": [], "last": "Spillmann", "suffix": ""}], "year": 2009, "venue": "Vision Research", "link": "440763"}, "BIBREF8": {"title": "Elements of psychophysical theory", "authors": [{"first": "J.-C", "middle": [], "last": "Falmagne", "suffix": ""}], "year": 1985, "venue": "", "link": "120324522"}, "BIBREF9": {"title": "Signal detection theory and psychophysics", "authors": [{"first": "D", "middle": ["M"], "last": "Green", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Swets", "suffix": ""}], "year": 1966, "venue": "Journal of Vision", "link": "60579107"}, "BIBREF10": {"title": "Curvature population coding for complex shapes in human vision", "authors": [{"first": "Devinck", "middle": [], "last": "Gerardin", "suffix": ""}, {"first": "", "middle": [], "last": "Dojat", "suffix": ""}, {"first": "C", "middle": [], "last": "Knoblauch Habak", "suffix": ""}, {"first": "F", "middle": [], "last": "Wilkinson", "suffix": ""}, {"first": "B", "middle": [], "last": "Zakher", "suffix": ""}, {"first": "H", "middle": ["R"], "last": "Wilson", "suffix": ""}], "year": 2004, "venue": "Vision Research", "link": "18571128"}, "BIBREF11": {"title": "Selectivity for complex shapes in primate visual area V2", "authors": [{"first": "J", "middle": [], "last": "Hegd\u00e9", "suffix": ""}, {"first": "D", "middle": ["C"], "last": "Van Essen", "suffix": ""}], "year": 2000, "venue": "The Journal of Neuroscience", "link": "14987632"}, "BIBREF12": {"title": "Conjoint measurement of gloss and surface texture", "authors": [{"first": "Y", "middle": ["X"], "last": "Ho", "suffix": ""}, {"first": "M", "middle": ["S"], "last": "Landy", "suffix": ""}, {"first": "L", "middle": ["T"], "last": "Maloney", "suffix": ""}], "year": 2008, "venue": "Psychological Science", "link": "1080419"}, "BIBREF13": {"title": "MLCM: Maximum likelihood conjoint measurement", "authors": [{"first": "K", "middle": [], "last": "Knoblauch", "suffix": ""}, {"first": "L", "middle": ["T"], "last": "Maloney", "suffix": ""}], "year": 2012, "venue": "", "link": null}, "BIBREF14": {"title": "Modeling psychophysical data in R", "authors": [{"first": "K", "middle": [], "last": "Knoblauch", "suffix": ""}, {"first": "L", "middle": ["T"], "last": "Maloney", "suffix": ""}], "year": 2012, "venue": "", "link": "64150849"}, "BIBREF15": {"title": "Additive and polynomial representations", "authors": [{"first": "D", "middle": ["H"], "last": "Krantz", "suffix": ""}, {"first": "R", "middle": ["D"], "last": "Luce", "suffix": ""}, {"first": "P", "middle": [], "last": "Suppes", "suffix": ""}, {"first": "A", "middle": [], "last": "Tversky", "suffix": ""}], "year": 1971, "venue": "", "link": "117989280"}, "BIBREF16": {"title": "Simultaneous conjoint measurement: A new scale type of fundamental measurement", "authors": [{"first": "R", "middle": ["D"], "last": "Luce", "suffix": ""}, {"first": "J", "middle": ["W"], "last": "Tukey", "suffix": ""}], "year": 1964, "venue": "Journal of Mathematical Psychology", "link": null}, "BIBREF17": {"title": "Maximum likelihood difference scaling", "authors": [{"first": "L", "middle": ["T"], "last": "Maloney", "suffix": ""}, {"first": "J", "middle": ["N"], "last": "Yang", "suffix": ""}], "year": 2003, "venue": "Journal of Vision", "link": "8216028"}, "BIBREF18": {"title": "Generalized linear models", "authors": [{"first": "P", "middle": [], "last": "Mccullagh", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Nelder", "suffix": ""}], "year": 1989, "venue": "", "link": "14154576"}, "BIBREF19": {"title": "The VideoToolbox software for visual psychophysics: Transforming numbers into movies", "authors": [{"first": "D", "middle": ["G"], "last": "Pelli", "suffix": ""}], "year": 1997, "venue": "Spatial Vision", "link": "35717021"}, "BIBREF20": {"title": "Un effeto di colorazione", "authors": [{"first": "B", "middle": [], "last": "Pinna", "suffix": ""}], "year": 1987, "venue": "", "link": null}, "BIBREF21": {"title": "l laboratorio e la citt. xxi congresso degli psicologi italiani", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF22": {"title": "The role of the Gestalt principle of similarity in the watercolor illusion", "authors": [{"first": "B", "middle": [], "last": "Pinna", "suffix": ""}], "year": 2005, "venue": "Spatial Vision", "link": "20481018"}, "BIBREF23": {"title": "Surface color from boundaries: A new 'watercolor' illusion", "authors": [{"first": "B", "middle": [], "last": "Pinna", "suffix": ""}, {"first": "G", "middle": [], "last": "Brelstaff", "suffix": ""}, {"first": "L", "middle": [], "last": "Spillmann", "suffix": ""}], "year": 2001, "venue": "Vision Research", "link": "35097897"}, "BIBREF24": {"title": "The watercolor illusion and neon color spreading: A unified analysis of new cases and neural mechanisms", "authors": [{"first": "B", "middle": [], "last": "Pinna", "suffix": ""}, {"first": "S", "middle": [], "last": "Grossberg", "suffix": ""}], "year": 2005, "venue": "Journal of the Optical Society of America A", "link": "922382"}, "BIBREF25": {"title": "Perceptual organization reconsidered in the light of the watercolor illusion: The problem of perception of holes and the objecthole effect", "authors": [{"first": "B", "middle": [], "last": "Pinna", "suffix": ""}, {"first": "M", "middle": [], "last": "Tanca", "suffix": ""}], "year": 2008, "venue": "Journal of Vision", "link": "2920546"}, "BIBREF26": {"title": "The watercolor effect: A new principle of grouping and figure-ground organization", "authors": [{"first": "B", "middle": [], "last": "Pinna", "suffix": ""}, {"first": "J", "middle": ["S"], "last": "Werner", "suffix": ""}, {"first": "L", "middle": [], "last": "Spillmann", "suffix": ""}], "year": 2003, "venue": "Vision Research", "link": "9337784"}, "BIBREF27": {"title": "A biologically plausible model of human radial frequency perception", "authors": [{"first": "F", "middle": ["J"], "last": "Poirier", "suffix": ""}, {"first": "H", "middle": ["R"], "last": "Wilson", "suffix": ""}], "year": 2006, "venue": "Vision Research", "link": "6334306"}, "BIBREF28": {"title": "R: A language and environment for statistical computing", "authors": [], "year": 2012, "venue": "", "link": null}, "BIBREF30": {"title": "Measurement theory", "authors": [{"first": "F", "middle": ["S"], "last": "Roberts", "suffix": ""}], "year": 1985, "venue": "", "link": null}, "BIBREF31": {"title": "Toward a unified theory of visual area V4", "authors": [{"first": "A", "middle": ["W"], "last": "Roe", "suffix": ""}, {"first": "L", "middle": [], "last": "Chelazzi", "suffix": ""}, {"first": "C", "middle": ["E"], "last": "Connor", "suffix": ""}, {"first": "B", "middle": ["R"], "last": "Conway", "suffix": ""}, {"first": "I", "middle": [], "last": "Fujita", "suffix": ""}, {"first": "J", "middle": ["L"], "last": "Gallant", "suffix": ""}, {"first": ".", "middle": ["."], "last": "Vanduffel", "suffix": ""}, {"first": "W", "middle": [], "last": "", "suffix": ""}], "year": 2012, "venue": "Neuron", "link": "9011736"}, "BIBREF32": {"title": "Shape recognition and inferior temporal neurons", "authors": [{"first": "E", "middle": ["L"], "last": "Schwartz", "suffix": ""}, {"first": "R", "middle": [], "last": "Desimone", "suffix": ""}, {"first": "T", "middle": ["D"], "last": "Albright", "suffix": ""}, {"first": "C", "middle": ["G"], "last": "Gross", "suffix": ""}], "year": 1983, "venue": "Proceedings of the National Academy of Sciences", "link": "43828795"}, "BIBREF33": {"title": "Color in the cortex: Single-and double-opponent cells", "authors": [{"first": "R", "middle": [], "last": "Shapley", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Hawken", "suffix": ""}], "year": 2011, "venue": "Vision Research", "link": "6568169"}, "BIBREF34": {"title": "Long-range interactions in visual perception", "authors": [{"first": "L", "middle": [], "last": "Spillmann", "suffix": ""}, {"first": "J", "middle": ["S"], "last": "Werner", "suffix": ""}], "year": 1996, "venue": "Trends in Neuroscience", "link": "11537730"}, "BIBREF35": {"title": "The phenomenal dissociation between coloration and object-hole effects in the watercolor illusion", "authors": [{"first": "M", "middle": [], "last": "Tanca", "suffix": ""}, {"first": "B", "middle": [], "last": "Pinna", "suffix": ""}], "year": 2008, "venue": "Visual Neuroscience", "link": "206287984"}, "BIBREF36": {"title": "Dissociation of color and figure-ground effects in the watercolor illusion", "authors": [{"first": "R", "middle": [], "last": "Von Der Heydt", "suffix": ""}, {"first": "R", "middle": [], "last": "Pierson", "suffix": ""}], "year": 2006, "venue": "Spatial Vision", "link": "16209905"}, "BIBREF37": {"title": "Fourier descriptors for plane close curves", "authors": [{"first": "C", "middle": ["T"], "last": "Zahn", "suffix": ""}, {"first": "R", "middle": ["Z"], "last": "Roskies", "suffix": ""}], "year": 1972, "venue": "IEEE Transactions on Computers, C", "link": null}}, "ref_entries": {"FIGREF0": {"text": "Figure 1. (a) Example of stimulus set for a conjoint measurement experiment. The table shows the set of stimuli used in the frequency/amplitude condition. Each column corresponds to a different frequency and each row to a different amplitude. (b) In each trial, a pair of stimuli were chosen from the table. The test stimuli contained a continuous interior orange contour. (c) For the control stimuli, the interior contour was braided with the exterior contour. Observers were asked to judge which member of the pair evoked the most salient filling-in.", "type": "figure"}, "FIGREF1": {"text": "Figure 2. Schematic examples of the three models. (a) Illustrative component curves for an independence model. (b) Predicted responses for each combination of stimulus attributes for the independence model. (c) Illustrative component curves for the additive model. (d) Predicted responses for each combination of stimulus attributes for the additive model. (e) Predicted responses for a saturated model. Filled black points in c and d are described in the text.", "type": "figure"}, "FIGREF2": {"text": "Figure 3. Conjoint proportion plots. Each plot shows the proportion of stimulus, S kl , judged to show a greater fill-in than the stimulus represented on the abscissa, S ij , as grey level coded according to the color bar at the right. Levels i and k along one dimension are indicated by the exterior axis numbers. Each of the squares (i, k) is subdivided in a 5 \u00b7 5 grid indicating the pairings (j, l) along the second dimension. Interior axis labels are shown for the extreme levels in the two lower right squares of each plot. In each set of plots, the top row indicates the results for the test stimuli and the bottom for the control with observers' initials indicated in the upper strips. (a) Outer/inner dimensions: ampitude/frequency. (b) Amplitude/luminance. (c) Frequency/luminance. (d) Expected response patterns for an observer who judges the stimuli based on the contributions along only one of the dimensions. Dim 1 shows the expected pattern for the outer dimension and Dim 2 for the inner dimension.", "type": "figure"}, "FIGREF3": {"text": "Figure 4a through c shows the average estimated scales under the additive model for each observer for each pairing of frequency, luminance, and amplitude. A different color is used to indicate the contributions to the judgment of each dimension: red \u00bc frequency, blue \u00bc amplitude, green \u00bc luminance. The top row of graphs in each subfigure shows the scale values estimated for the test stimulus and the bottom row for the control.", "type": "figure"}, "FIGREF4": {"text": "Figure 4. (a) Results for Experiment 1. Additive model average estimates for perceived WCE for test and control patterns as a function of frequency (red circles) and amplitude (blue circles) of the contour for four observers. Means of five sessions; error bars are 95% confidence intervals. (b) Results for Experiment 2. Additive model average estimates for perceived WCE for test and control patterns as a function of luminance (green circles) and amplitude (blue circles) of the contour for four observers. Means of five sessions, error bars are 95% confidence intervals. (c) Results for Experiment 3. Additive model average estimates for perceived WCE for test and control patterns as a function of luminance (green circles) and frequency (red circles) of the contour for four observers. Means of five sessions; error bars are 95% confidence intervals. (d) Mean estimated scales for each pairing of dimensions. Error bars indicate 95% confidence intervals for observer differences. Color codes correspond to those used in previous three figures.", "type": "figure"}, "FIGREF5": {"text": "Figure 5. Comparisons of additive and independent model fits for each observer in the three experiments. The solid lines indicate the estimated contributions of each dimension under the additive model, and the dashed grey lines indicate the estimates under the independence model. The color codes correspond to those of the points from Figure 4 with red \u00bc frequency, green \u00bc luminance, and blue \u00bc amplitude. The error bars are bootstrap estimated 95% confidence intervals (n \u00bc 10,000) under the additive model. (a) Amplitude/frequency. (b) Amplitude/luminance. (c) Frequency/luminance.", "type": "figure"}, "FIGREF6": {"text": "Figure 6. Comparisons of additive and saturated model fits for each observer in the three experiments. The solid lines indicate the estimated contributions for each combination of the two dimensions under the saturated model, and the dashed lines indicate the contributions under the additive model. Color is used to code the index of the secondary dimension (black, red, blue, green, and gray for indices 1 to 5, respectively). The error bars are bootstrap estimated 95% confidence intervals (n \u00bc 10,000) under the saturated model. (a) The estimated contributions as a function of the index of the frequency variable for each amplitude tested. (b) Estimated contributions as in panel (a) but as a function of the amplitude index with the curves parameterized by luminance. (c) The estimated contributions as in the previous panels but as a function of the frequency index with the curves parameterized by luminance.", "type": "figure"}, "FIGREF7": {"text": "Figure 7. Residual differences between additive and saturated model fits shown in Figure 6 for all observers and conditions plotted as grey levels according to color bars at the right of each plot. (a) Residuals for model fits of frequency/amplitude pairing for each observer. (b) Residuals for models fits of amplitude/luminance pairing. (c) Residuals for models fits of frequency/luminance pairing. The residuals have been normalized with respect to the estimated standard errors for the saturated model fits.", "type": "figure"}, "FIGREF8": {"text": "Figure 8. (a) Comparison of the average perceptual scales as a function of contour luminance for four observers. Red symbols correspond to the experiment frequency \u00b7 luminance and blue symbols to the experiment amplitude \u00b7 luminance. Each point is the mean of five sessions, and the error bars are 95% confidence intervals. (b) Comparison of the average perceptual scales as a function of contour frequency for three observers. Green symbols correspond to the experiment frequency \u00b7 luminance and blue symbols to the experiment amplitude \u00b7 frequency. Each point is the mean of five sessions, and the error bars are 95% confidence intervals. (c) Comparison of the average perceptual scales as a function of contour amplitude for three observers. Red symbols correspond to the experiment amplitude \u00b7 luminance and green symbols to the experiment amplitude \u00b7 frequency. Each point is the mean of five sessions, and the error bars are 95% confidence intervals. (d) Mean comparison of the average perceptual scales as a function of the indices of contour amplitude (left, n \u00bc 3), of contour frequency (middle, n \u00bc 3), and of contour luminance (right, n \u00bc 4). Blue symbols correspond to experiments with amplitude, green symbols to experiments with luminance, and red symbols to experiments with frequency. The error bars are 95% confidence intervals based on interindividual differences.", "type": "figure"}}}
{"paper_id": "8331565", "_pdf_hash": "597f1241d65ef23e28b86936df622d0122993fb3", "abstract": [{"section": "Abstract", "text": "ABSTRACT. Objective. To determine the efficacy and safety of topical ciprofloxacin/dexamethasone otic suspension compared with ofloxacin otic solution in the treatment of acute otitis media with otorrhea through tympanostomy tubes (AOMT) in pediatric patients.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Methods. This multicenter, prospective, randomized, observer-masked, parallel-group study was conducted at 39 sites in 599 children aged >6 months to 12 years with an AOMT episode of <3 weeks' duration. The mean age of patients was 2.5 years (standard deviation: 2.37 years). Patients received either ciprofloxacin 0.3%/dexamethasone 0.1% otic suspension 4 drops twice daily for 7 days or ofloxacin 0.3% otic solution 5 drops twice daily for 10 days. Clinical signs and symptoms of AOMT were evaluated at clinic visits on days 1 (baseline), 3 (on therapy), 11 (end of therapy), and 18 (test of cure). A patient diary was used to measure time to cessation of otorrhea. Principal pretherapy pathogens included Streptococcus pneumoniae (16.8%), Staphylococcus aureus (13.0%), Pseudomonas aeruginosa (12.7%), Haemophilus influenzae (12.4%), S epidermidis (10.2%), and Moraxella catarrhalis (4.1%).", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Results. Ciprofloxacin/dexamethasone is superior to ofloxacin for clinical cure (90% vs 78%) and microbiologic success (92% vs 81.8%) at the test-of-cure visit, produces fewer treatment failures (4.4% vs 14.1%), and results in a shorter median time to cessation of otorrhea (4 days vs 6 days). Ciprofloxacin/dexamethasone treatment is also superior to improvement in clinical response by visit, absence of otorrhea by visit, and reduction of otorrhea volume by visit. Both topical otic preparations are safe and well tolerated in pediatric patients. No change in speech recognition threshold or decrease in hearing from baseline, based on audiometric testing, was noted with either regimen.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Conclusion. Topical ciprofloxacin/dexamethasone treatment is superior to topical ofloxacin in the treatment of AOMT. Pediatrics 2004;113:e40 -e46. URL: http://www. pediatrics.org/cgi/content/full/113/1/e40; ciprofloxacin, dexamethasone, ofloxacin, otorrhea, AOM, tympanostomy tubes.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "ABBREVIATIONS. AOMT, acute otitis media with otorrhea through tympanostomy tubes; CSOM, chronic suppurative otitis media; TOC, test of cure; ITT, intention-to-treat. T he most common surgery performed in children for treatment of recurrent otitis media with effusion is the insertion of a tympanostomy tube into the eardrum. 1 However, otorrhea is a common complication after their insertion. The vast majority (90%-95%) of cases of acute otitis media with otorrhea through tympanostomy tubes (AOMT) occur in children aged 1 to 12 years, and typically 2 to 6 episodes of AOMT are experienced. 2,3 Topical ciprofloxacin is an effective and safe therapy for AOMT 4,5 and chronic suppurative otitis media (CSOM). 6 -8 Bacteria commonly isolated from patients with AOMT include Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus, and Pseudomonas aeruginosa. 3 Because of the inflammatory response induced by these microorganisms, topical corticosteroids have often been given empirically together with topical antibiotics in an effort to reduce the sequelae. Although several studies demonstrated the efficacy and safety of antibiotic-corticosteroid combinations in the treatment or prophylaxis of AOMT, 9 -14 definitive evidence of the benefit of adding a topical corticosteroid has not been shown in randomized, controlled trials.", "cite_spans": [{"start": 898, "end": 899, "text": "3", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "Abstract", "text": "Recently, we reported on the efficacy and safety of a combination of topical dexamethasone 0.1% and ciprofloxacin 0.3% in children with AOMT. 15 Otorrhea resolved more rapidly with the combination preparation than with ciprofloxacin alone and produced significantly greater clinical responses early after completion of a 7-day course of treatment. 15 The present study was designed to evaluate further the efficacy and the safety of the topical ciprofloxacin/ dexamethasone combination by comparing it with the related fluoroquinolone ofloxacin administered alone in children with AOMT. Topical ofloxacin was chosen as the comparator for this study because of its reported efficacy and safety in ear infections, including AOMT, 16 by guest on October 3, 2017 http://pediatrics.aappublications.org/ Downloaded from methasone 0.1% otic suspension with ofloxacin 0.3% otic solution in children with AOMT conducted at 39 centers in the United States and Canada. The primary objectives were to 1) demonstrate that ciprofloxacin/dexamethasone is at least as effective as ofloxacin for clinical and microbiologic response at the test of cure (TOC) visit and 2) evaluate the safety and efficacy of ciprofloxacin/ dexamethasone otic suspension in pediatric patients with AOMT. The study protocol was approved by independent ethics committees/institutional review boards at each investigative site and conducted in accordance with the ethical principles contained in the Declaration of Helsinki. Written informed consent was obtained from the parents or legal guardians of all patients before enrollment.", "cite_spans": [{"start": 142, "end": 144, "text": "15", "ref_id": "BIBREF14"}, {"start": 348, "end": 350, "text": "15", "ref_id": "BIBREF14"}, {"start": 728, "end": 730, "text": "16", "ref_id": "BIBREF15"}], "ref_spans": []}, {"section": "Abstract", "text": "A total of 599 children who were aged 6 months to 12 years and had patent tympanostomy tubes and a clinical diagnosis of uncomplicated AOM with otorrhea (drainage visible to the parent or guardian) of \u05453 weeks' duration in 1 or both ears were enrolled into the study. Patients were randomized to receive either 1) topical ciprofloxacin/dexamethasone otic suspension (Ciprodex; Alcon Research, Ltd, Fort Worth, TX) 4 drops twice daily for 7 days or 2) topical ofloxacin otic solution (Floxin; Daiichi Pharmaceutical Corp, Montvale, NJ) 5 drops twice daily for 10 days. Because of the physical distinction and difference in administration schedules between the 2 treatments, the study was not double blinded, but it was observer masked such that those conducting the clinical observations were unaware of the treatment assignments.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Patients who were not eligible for enrollment included those in whom otorrhea had been present for \u03fe3 weeks and those with acute or malignant otitis externa. Key differences between AOM patients who had otorrhea and were enrolled in the study compared with patients who had acute otitis externa and were excluded from the trial included the absence or presence of pain on palpation of the pinna and the degree of edema or erythema present in the external ear canal. Additional exclusions were known or suspected fungal or mycobacterial ear infections, a history of or active viral infection of the tympanic membrane, mastoiditis, or infections requiring systemic antibacterial therapy. Patients were also excluded when there was a requirement for otologic surgery (except that confined to the tympanic membrane) in the previous year or when they presented with or had a history of diabetes, immunosuppressive disorders, acute or chronic renal disease, active hepatitis, chronic nasal obstruction and/or persistent rhinorrhea, complicating structural abnormalities, known or suspected quinolone hypersensitivity, and, in girls, menarche. Patients were not permitted to receive topical (otic or ophthalmic) corticosteroids or antibiotics concurrently or within the preceding 3 days, systemic corticosteroids within the preceding 7 days, inhaled corticosteroids at doses \u0546800 g/d, topical antibiotics for skin infections within the preceding 7 days, topical otic analgesics/anesthetics or antiseptic washes, or nonsteroidal anti-inflammatory drugs, with the exception of oral acetaminophen for relief of pain.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Eligible patients were evaluated at 4 scheduled visits: baseline (day 1), on therapy (3 \u03e9 2 days), end of therapy (11 \u03e9 2 days), and TOC (18 \u03e9 3 days). At the baseline visit, a complete clinical assessment was performed. The ear canal first was cleaned of all fluid and debris via suction, and then a culture specimen was obtained from the lumen of the tube under direct microscopic vision, paying particular attention to avoid contamination by contact with the surface of the external auditory canal. Ear cultures were taken in all patients at baseline and were repeated only in patients who were discontinued from the study as a result of treatment failure or adverse events. A specimen was obtained from the lumen of the tympanostomy tube from any patient when the physician declared a \"clinical failure,\" regardless of the visit day. The parents or guardians were instructed in the use of patient diaries and the need for avoiding significant water immersion of the ear(s). At subsequent visits, clinical assessments were repeated to assess responses, patient diaries were reviewed, and adverse events were recorded. Audiologic evaluations, including speech reception threshold, were conducted by certified audiologists in children aged 4 to 12 years at the baseline and TOC visits.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Three primary efficacy variables were selected for evaluation at the test of cure (TOC) visit. 1) Clinical response to therapy (patients who were rated as cured/resolved by the investigator) based on a 4-point scale (0, cured/resolved; 1, improved; 2, not changed; 3, worsened compared with the baseline visit). An overall clinical response of cured/resolved was defined as the absence of otorrhea at the TOC visit. Improved was defined as a significant improvement in clinical signs or symptoms compared with the baseline (day 1) visit. 2) Microbiologic response (success or failure) in patients with positive pretherapy cultures. In the event of a clinical failure (and the taking of an additional ear specimen for culture), there were several possible microbiologic outcomes: a) \"microbiologic failure\" as a result of the persistence of pretherapy pathogen(s), b) \"microbiologic failure\" as a result of superinfection (if a new pathogen was recovered during therapy), and c) \"microbiologic failure\" as a result of reinfection (if a new pathogen was recovered after the end of therapy). 3) Treatment failure rate based on the number of patients who were discontinued from the study because they did not respond to assigned therapy. Secondary efficacy variables included time to cessation of otorrhea as recorded twice daily in the patient's diary (0, absent; 1, present) and as assessed by the physician at each study visit (0, absent; 1, present); physicians' assessment of clinical response on a 4-point scale (0, cured/resolved; 1, improved; 2, no change; 3, worsened) by visit; and otic discharge volume (0, absent; 1, scant; 2, moderate; 3, severe) at each visit. Scant discharge was defined as a little fluid (serous, mucoid, or mucopurulent) accumulating in the anterior sulcus but the tube was still clearly visible in its entirety. Moderate discharge was defined as the anterior sulcus being full and the fluid comes to or nearly to the edge of the tympanostomy tube. Part of the tympanostomy tube may be covered with fluid. Copious discharge was defined as not being able to see the tube until fluid was aspirated from the ear canal. Fluid often recurs during the course of the examination, even after it has been suctioned.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "The safety evaluation was conducted on all patients who were randomized into the trial and received at least 1 dose of study drug. The safety analysis was based on the extent of exposure to the study drug, adverse events, and audiometry examination. The occurrence of adverse effects was assessed at each study visit and via questioning of parents or guardians during daily telephone calls relating to completion of the patient diaries. All adverse events were recorded in the patients' case report forms. Patients who experienced adverse events that, in the opinion of the investigator, presented a significant risk to their safety or well-being were withdrawn from the study. Data from the exit audiometry examinations were evaluated to determine whether any clinically significant decrease in hearing had occurred.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "The primary statistical objective was to demonstrate that ciprofloxacin/dexamethasone was at least as effective (noninferior) as ofloxacin treatment in clinical and microbiologic response at the TOC visit. Two-sided 95% confidence intervals for the difference in proportions between the 2 treatment groups were constructed. Noninferiority was demonstrated for both variables, and the confidence interval constructed around these differences did not include 0. This result enabled statistical testing for superiority, using 2 tests of independence. For analysis of secondary variables, the number and proportion of patients per response in each treatment group was presented and assessed using LSMEANS (Mixed Model Analysis of Variance) or the 2 test as appropriate. The log-rank test (Kaplan-Meier survival analysis) was conducted to compare median time to cessation of otorrhea between the 2 treatments.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "A total of 599 patients (297 in the ciprofloxacin/dexamethasone group and 302 in the ofloxacin group) were randomized to treatment and assessable for the intention-to-treat (ITT) analysis. Of these, 424 (208 in the ciprofloxacin/dexamethasone group and 216 in the ofloxacin group) were included in the modified ITT analyses in that they had received treatment, had met inclusion/excluhttp://www.pediatrics.org/cgi/content/full/113/1/e40 e41 by guest on October 3, 2017 http://pediatrics.aappublications.org/ Downloaded from sion criteria at baseline, and had a positive culture for bacteria on day 1. The modified per protocol data set composed a total of 357 patients (182 in the ciprofloxacin/dexamethasone group and 175 in the ofloxacin group) who received drug treatment, met inclusion/exclusion criteria at baseline, were culture positive, and presented at all scheduled study visits.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "", "text": "T he most common surgery performed in children for treatment of recurrent otitis media with effusion is the insertion of a tympanostomy tube into the eardrum. 1 However, otorrhea is a common complication after their insertion. The vast majority (90%-95%) of cases of acute otitis media with otorrhea through tympanostomy tubes (AOMT) occur in children aged 1 to 12 years, and typically 2 to 6 episodes of AOMT are experienced. 2, 3 Topical ciprofloxacin is an effective and safe therapy for AOMT 4, 5 and chronic suppurative otitis media (CSOM). 6 -8 Bacteria commonly isolated from patients with AOMT include Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus, and Pseudomonas aeruginosa. 3 Because of the inflammatory response induced by these microorganisms, topical corticosteroids have often been given empirically together with topical antibiotics in an effort to reduce the sequelae. Although several studies demonstrated the efficacy and safety of antibiotic-corticosteroid combinations in the treatment or prophylaxis of AOMT, 9 -14 definitive evidence of the benefit of adding a topical corticosteroid has not been shown in randomized, controlled trials.", "cite_spans": [{"start": 159, "end": 160, "text": "1", "ref_id": "BIBREF0"}, {"start": 427, "end": 429, "text": "2,", "ref_id": "BIBREF1"}, {"start": 430, "end": 431, "text": "3", "ref_id": "BIBREF2"}, {"start": 496, "end": 498, "text": "4,", "ref_id": "BIBREF3"}, {"start": 499, "end": 500, "text": "5", "ref_id": "BIBREF4"}, {"start": 734, "end": 735, "text": "3", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "", "text": "Recently, we reported on the efficacy and safety of a combination of topical dexamethasone 0.1% and ciprofloxacin 0.3% in children with AOMT. 15 Otorrhea resolved more rapidly with the combination preparation than with ciprofloxacin alone and produced significantly greater clinical responses early after completion of a 7-day course of treatment. 15 The present study was designed to evaluate further the efficacy and the safety of the topical ciprofloxacin/ dexamethasone combination by comparing it with the related fluoroquinolone ofloxacin administered alone in children with AOMT. Topical ofloxacin was chosen as the comparator for this study because of its reported efficacy and safety in ear infections, including AOMT, 16, 17 CSOM, 18 and acute otitis externa. 19 ", "cite_spans": [{"start": 142, "end": 144, "text": "15", "ref_id": "BIBREF14"}, {"start": 348, "end": 350, "text": "15", "ref_id": "BIBREF14"}, {"start": 728, "end": 731, "text": "16,", "ref_id": "BIBREF15"}, {"start": 732, "end": 734, "text": "17", "ref_id": "BIBREF16"}, {"start": 741, "end": 743, "text": "18", "ref_id": "BIBREF17"}, {"start": 770, "end": 772, "text": "19", "ref_id": "BIBREF18"}], "ref_spans": []}, {"section": "METHODS", "text": "This study was a randomized, prospective, observer-masked, parallel-group clinical trial comparing ciprofloxacin 0.3%/dexa-methasone 0.1% otic suspension with ofloxacin 0.3% otic solution in children with AOMT conducted at 39 centers in the United States and Canada. The primary objectives were to 1) demonstrate that ciprofloxacin/dexamethasone is at least as effective as ofloxacin for clinical and microbiologic response at the test of cure (TOC) visit and 2) evaluate the safety and efficacy of ciprofloxacin/ dexamethasone otic suspension in pediatric patients with AOMT. The study protocol was approved by independent ethics committees/institutional review boards at each investigative site and conducted in accordance with the ethical principles contained in the Declaration of Helsinki. Written informed consent was obtained from the parents or legal guardians of all patients before enrollment.", "cite_spans": [], "ref_spans": []}, {"section": "Patients and Medication", "text": "A total of 599 children who were aged 6 months to 12 years and had patent tympanostomy tubes and a clinical diagnosis of uncomplicated AOM with otorrhea (drainage visible to the parent or guardian) of \u05453 weeks' duration in 1 or both ears were enrolled into the study. Patients were randomized to receive either 1) topical ciprofloxacin/dexamethasone otic suspension (Ciprodex; Alcon Research, Ltd, Fort Worth, TX) 4 drops twice daily for 7 days or 2) topical ofloxacin otic solution (Floxin; Daiichi Pharmaceutical Corp, Montvale, NJ) 5 drops twice daily for 10 days. Because of the physical distinction and difference in administration schedules between the 2 treatments, the study was not double blinded, but it was observer masked such that those conducting the clinical observations were unaware of the treatment assignments.", "cite_spans": [], "ref_spans": []}, {"section": "Patients and Medication", "text": "Patients who were not eligible for enrollment included those in whom otorrhea had been present for \u03fe3 weeks and those with acute or malignant otitis externa. Key differences between AOM patients who had otorrhea and were enrolled in the study compared with patients who had acute otitis externa and were excluded from the trial included the absence or presence of pain on palpation of the pinna and the degree of edema or erythema present in the external ear canal. Additional exclusions were known or suspected fungal or mycobacterial ear infections, a history of or active viral infection of the tympanic membrane, mastoiditis, or infections requiring systemic antibacterial therapy. Patients were also excluded when there was a requirement for otologic surgery (except that confined to the tympanic membrane) in the previous year or when they presented with or had a history of diabetes, immunosuppressive disorders, acute or chronic renal disease, active hepatitis, chronic nasal obstruction and/or persistent rhinorrhea, complicating structural abnormalities, known or suspected quinolone hypersensitivity, and, in girls, menarche. Patients were not permitted to receive topical (otic or ophthalmic) corticosteroids or antibiotics concurrently or within the preceding 3 days, systemic corticosteroids within the preceding 7 days, inhaled corticosteroids at doses \u0546800 g/d, topical antibiotics for skin infections within the preceding 7 days, topical otic analgesics/anesthetics or antiseptic washes, or nonsteroidal anti-inflammatory drugs, with the exception of oral acetaminophen for relief of pain.", "cite_spans": [], "ref_spans": []}, {"section": "Patients and Medication", "text": "Eligible patients were evaluated at 4 scheduled visits: baseline (day 1), on therapy (3 \u03e9 2 days), end of therapy (11 \u03e9 2 days), and TOC (18 \u03e9 3 days). At the baseline visit, a complete clinical assessment was performed. The ear canal first was cleaned of all fluid and debris via suction, and then a culture specimen was obtained from the lumen of the tube under direct microscopic vision, paying particular attention to avoid contamination by contact with the surface of the external auditory canal. Ear cultures were taken in all patients at baseline and were repeated only in patients who were discontinued from the study as a result of treatment failure or adverse events. A specimen was obtained from the lumen of the tympanostomy tube from any patient when the physician declared a \"clinical failure,\" regardless of the visit day. The parents or guardians were instructed in the use of patient diaries and the need for avoiding significant water immersion of the ear(s). At subsequent visits, clinical assessments were repeated to assess responses, patient diaries were reviewed, and adverse events were recorded. Audiologic evaluations, including speech reception threshold, were conducted by certified audiologists in children aged 4 to 12 years at the baseline and TOC visits.", "cite_spans": [], "ref_spans": []}, {"section": "Efficacy Assessment", "text": "Three primary efficacy variables were selected for evaluation at the test of cure (TOC) visit. 1) Clinical response to therapy (patients who were rated as cured/resolved by the investigator) based on a 4-point scale (0, cured/resolved; 1, improved; 2, not changed; 3, worsened compared with the baseline visit). An overall clinical response of cured/resolved was defined as the absence of otorrhea at the TOC visit. Improved was defined as a significant improvement in clinical signs or symptoms compared with the baseline (day 1) visit. 2) Microbiologic response (success or failure) in patients with positive pretherapy cultures. In the event of a clinical failure (and the taking of an additional ear specimen for culture), there were several possible microbiologic outcomes: a) \"microbiologic failure\" as a result of the persistence of pretherapy pathogen(s), b) \"microbiologic failure\" as a result of superinfection (if a new pathogen was recovered during therapy), and c) \"microbiologic failure\" as a result of reinfection (if a new pathogen was recovered after the end of therapy). 3) Treatment failure rate based on the number of patients who were discontinued from the study because they did not respond to assigned therapy. Secondary efficacy variables included time to cessation of otorrhea as recorded twice daily in the patient's diary (0, absent; 1, present) and as assessed by the physician at each study visit (0, absent; 1, present); physicians' assessment of clinical response on a 4-point scale (0, cured/resolved; 1, improved; 2, no change; 3, worsened) by visit; and otic discharge volume (0, absent; 1, scant; 2, moderate; 3, severe) at each visit. Scant discharge was defined as a little fluid (serous, mucoid, or mucopurulent) accumulating in the anterior sulcus but the tube was still clearly visible in its entirety. Moderate discharge was defined as the anterior sulcus being full and the fluid comes to or nearly to the edge of the tympanostomy tube. Part of the tympanostomy tube may be covered with fluid. Copious discharge was defined as not being able to see the tube until fluid was aspirated from the ear canal. Fluid often recurs during the course of the examination, even after it has been suctioned.", "cite_spans": [], "ref_spans": []}, {"section": "Safety Assessment", "text": "The safety evaluation was conducted on all patients who were randomized into the trial and received at least 1 dose of study drug. The safety analysis was based on the extent of exposure to the study drug, adverse events, and audiometry examination. The occurrence of adverse effects was assessed at each study visit and via questioning of parents or guardians during daily telephone calls relating to completion of the patient diaries. All adverse events were recorded in the patients' case report forms. Patients who experienced adverse events that, in the opinion of the investigator, presented a significant risk to their safety or well-being were withdrawn from the study. Data from the exit audiometry examinations were evaluated to determine whether any clinically significant decrease in hearing had occurred.", "cite_spans": [], "ref_spans": []}, {"section": "Statistical Analysis", "text": "The primary statistical objective was to demonstrate that ciprofloxacin/dexamethasone was at least as effective (noninferior) as ofloxacin treatment in clinical and microbiologic response at the TOC visit. Two-sided 95% confidence intervals for the difference in proportions between the 2 treatment groups were constructed. Noninferiority was demonstrated for both variables, and the confidence interval constructed around these differences did not include 0. This result enabled statistical testing for superiority, using 2 tests of independence. For analysis of secondary variables, the number and proportion of patients per response in each treatment group was presented and assessed using LSMEANS (Mixed Model Analysis of Variance) or the 2 test as appropriate. The log-rank test (Kaplan-Meier survival analysis) was conducted to compare median time to cessation of otorrhea between the 2 treatments.", "cite_spans": [], "ref_spans": []}, {"section": "Data Sets Analyzed", "text": "A total of 599 patients (297 in the ciprofloxacin/dexamethasone group and 302 in the ofloxacin group) were randomized to treatment and assessable for the intention-to-treat (ITT) analysis. Of these, 424 (208 in the ciprofloxacin/dexamethasone group and 216 in the ofloxacin group) were included in the modified ITT analyses in that they had received treatment, had met inclusion/exclu-sion criteria at baseline, and had a positive culture for bacteria on day 1. The modified per protocol data set composed a total of 357 patients (182 in the ciprofloxacin/dexamethasone group and 175 in the ofloxacin group) who received drug treatment, met inclusion/exclusion criteria at baseline, were culture positive, and presented at all scheduled study visits.", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Demographics", "text": "Study demographics for all 599 patients enrolled are summarized in Table 1 . The mean age of all patients in the ITT data set was 2.45 years (standard deviation: 2.37 years), with a range from 6 months to 12 years. No statistically significant differences were identified between the 2 groups with respect to age, ethnicity, affected ear(s), or discharge volume. There was a difference in baseline sex, with more boys than girls randomized in both treatment groups. This imbalance was exaggerated in the ofloxacin group (67% compared with 58%; P \u03ed .0291). However, this sex difference did not affect the outcomes of the study and is likely a spurious result that arose because of the many baseline tests that were performed. The treatment group difference in the distribution of boys and girls randomized was not seen in any of the other data sets that were analyzed for this study.", "cite_spans": [], "ref_spans": [{"start": 67, "end": 74, "text": "Table 1", "ref_id": "TABREF0"}]}, {"section": "Clinical Efficacy", "text": "Ciprofloxacin/dexamethasone treatment (90%) was superior to ofloxacin treatment (78%) for the primary efficacy variable of clinical cure at the TOC visit (P \u03ed .0025; Table 2 ). There were significantly fewer treatment failures in patients who were treated with ciprofloxacin/dexamethasone (4%) compared with ofloxacin (14%; P \u03ed .0017). There is a significant difference in favor of ciprofloxacin/dexamethasone (4 days) compared with ofloxacin (6 days) in the median time to cessation of otorrhea, indicating earlier resolution of AOMT in patients who were treated with the antibiotic/steroid combination compared with the single agent fluoroquinolone ( Table 2 , Fig  1) . This difference (2 days) in favor of ciprofloxacin/ dexamethasone over ofloxacin is considered to be clinically meaningful because it represents a 33% improvement in clinical response and was obtained using considerably less drug (56 drops compared with 100 drops) for a shorter time (7 days compared with 10 days). The finding is confirmed by data obtained in the physicians' assessment of clinical response at each visit, which showed significantly greater cure rates with ciprofloxacin/dexamethasone at days 3 (P \u03fd .0001), 11 (P \u03fd .0001), and 18 (P \u03ed .0023; Table 2 ). Similar findings are also evident for the proportion of patients in whom otorrhea and otic discharge were absent at each visit (Table 2) .", "cite_spans": [], "ref_spans": [{"start": 663, "end": 670, "text": "Fig  1)", "ref_id": "FIGREF0"}]}, {"section": "Microbiologic Efficacy", "text": "Pretherapy pathogens that were present at the baseline examination are listed in Table 3 . The eradication rates of pretherapy organisms after treatment with ciprofloxacin/dexamethasone or ofloxacin are summarized in Table 4 for bacterial species with 5 or more reported cases. These data show that substantially similar rates for microbiologic success by species are obtained for either treatment. However, we note there are significantly fewer treatment failures reported for ciprofloxacin/dexamethasone compared with ofloxacin therapy. In terms of overall response, treatment with ciprofloxacin/dexamethasone was superior to ofloxacin for microbiologic eradication at the TOC visit (92% and 82%, respectively; P \u03ed .0061; Table 2 ). Therefore, microbiologic success favors ciprofloxacin over ofloxacin in treating AOMT infections in pediatric patients.", "cite_spans": [], "ref_spans": [{"start": 81, "end": 88, "text": "Table 3", "ref_id": "TABREF1"}]}, {"section": "Adverse Events", "text": "The safety of ciprofloxacin/dexamethasone and ofloxacin was evaluated in 599 pediatric patients who had AOMT and were randomized to treatment and received study drug. Overall, the adverse-event profiles of ciprofloxacin/dexamethasone and ofloxacin are similar. Ciprofloxacin/dexamethasone or ofloxacin administered twice daily in the affected ears is safe and well tolerated in pediatric patients with AOMT. No serious treatment-related adverse events were reported during the study. Fewer patient discontinuations as a result of adverse events were noted in the ciprofloxacin/dexamethasone group (32 patients) compared with ofloxacin (46 patients).", "cite_spans": [], "ref_spans": []}, {"section": "Adverse Events", "text": "Adverse events in the overall safety population all were nonserious with the exception of 3 reports unrelated to treatment (abdominal pain, pneumonia, and cellulitis). In general, adverse events were generally mild to moderate, usually resolved with or without treatment, and generally did not interrupt patient continuation in the study. Similar types of related otic and nonotic adverse events were noted in pediatric patients who were treated in both treatment groups (Table 5) . No clinically relevant or statistically significant differences in mean change of speech recognition threshold from baseline or decrease in hearing from baseline were observed after treatment with either ciprofloxacin/dexamethasone or ofloxacin, based on bone and air conduction audiometry.", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "Both ciprofloxacin and ofloxacin, when used alone as topical otic preparations, are effective for the treat- ment of AOMT in children, with no apparent risk of ototoxicity with either agent. 4, 5, 16, 17 The present study shows that the addition of the corticosteroid dexamethasone to the fluoroquinolone ciprofloxacin achieves superior rates of clinical cure and microbiologic success, results in fewer treatment failures, and provides earlier resolution of AOMT compared with treatment with the single-agent fluoroquinolone ofloxacin. In this regard, the findings confirm our earlier clinical report of ciprofloxacin/dexamethasone versus ciprofloxacin 15 and in experimental animal studies showing that antibiotic/dexamethasone combinations are more effective than antibiotic therapy alone in resolving otorrhea in a primate model of CSOM 14 and in reducing and preventing persistent middle ear mucosal changes in rats with experimental AOM. 20 In the current AOMT study in children aged \u05466 months to 12 years, we show that a 7-day course of ciprofloxacin/dexamethasone (4 drops twice daily, 56 total drops) with less total drug administered is superior to a 10-day course of ofloxacin (5 drops twice daily, 100 total drops) for clinical cure, microbial eradication, and treatment failures. Physicians' assessment of clinical response at each visit showed significantly greater cure rates with ciprofloxacin/ dexamethasone at days 3, 11, and 18 (Table 2 ) compared with the single agent ofloxacin. In addition, ciprofloxacin/dexamethasone treatment results in a clinically significant earlier resolution of AOMT of 2 days. This finding is especially relevant because it provides a substantial advantage to the parent or caregiver of the AOMT patient by allowing an earlier return to normal activities, child care, or school. Economic benefit can be expected from caregivers' being able to return to work earlier.", "cite_spans": [{"start": 191, "end": 193, "text": "4,", "ref_id": "BIBREF3"}, {"start": 194, "end": 196, "text": "5,", "ref_id": "BIBREF4"}, {"start": 197, "end": 200, "text": "16,", "ref_id": "BIBREF15"}, {"start": 201, "end": 203, "text": "17", "ref_id": "BIBREF16"}, {"start": 654, "end": 656, "text": "15", "ref_id": "BIBREF14"}, {"start": 841, "end": 843, "text": "14", "ref_id": "BIBREF13"}, {"start": 944, "end": 946, "text": "20", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "DISCUSSION", "text": "The data presented in the current study demon- strate that ciprofloxacin/dexamethasone is clinically and microbiologically superior to ofloxacin. A review of the published clinical study of the efficacy of ofloxacin in AOMT patients tends to corroborate this conclusion. In a prospective, randomized, controlled trial comparing topical otic ofloxacin with oral amoxicillin/clavulanate potassium, no difference was noted between the 2 treatments for overall clinical cure or improvement by visit. 16 Clinical cure rate at the TOC visit was 89% for both treatments. Overall clinical/microbiologic eradication was also not significantly different, 77% for ofloxacin and 67% for amoxicillin/clavulanate. 16 Our study results for ofloxacin demonstrated similar outcomes for clinical cure (78%) and microbiologic eradication (82%) compared with 90% and 92%, respectively, for ciprofloxacin/dexamethasone treatment.", "cite_spans": [{"start": 496, "end": 498, "text": "16", "ref_id": "BIBREF15"}, {"start": 700, "end": 702, "text": "16", "ref_id": "BIBREF15"}], "ref_spans": []}, {"section": "CONCLUSIONS", "text": "Topical ciprofloxacin/dexamethasone treatment is superior to topical ofloxacin in clinical cure and microbiologic eradication, results in fewer treatment failures, provides earlier resolution of AOMT, and gives a significantly better overall therapeutic response. Topical administration of the antibiotic/corticosteroid combination represents a significant clinical advantage over single-agent antibiotic therapy and can be expected to result in important medical and economic benefits. * One patient receiving ciprofloxacin/dexamethasone and 1 patient receiving ofloxacin discontinued from the study as a result of a therapy-related event. \u2020 Precipitate ear was described as study drug residue.", "cite_spans": [], "ref_spans": []}, {"section": "CONCLUSIONS", "text": "http://www.pediatrics.org/cgi/content/full/113/1/e40 e45", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Care of the child with tympanostomy tubes", "authors": [{"first": "G", "middle": [], "last": "Isaacson", "suffix": ""}, {"first": "R", "middle": ["M"], "last": "Rosenfeld", "suffix": ""}], "year": 1996, "venue": "Pediatr Clin North Am", "link": "29636225"}, "BIBREF1": {"title": "Acute otorrhea: bacteriology of a common complication of tympanostomy tubes", "authors": [{"first": "E", "middle": ["M"], "last": "Mandel", "suffix": ""}, {"first": "M", "middle": ["L"], "last": "Casselbrant", "suffix": ""}, {"first": "M", "middle": [], "last": "Kurs-Lasky", "suffix": ""}], "year": 1994, "venue": "Ann Otol Rhinol Laryngol", "link": "43238295"}, "BIBREF2": {"title": "Otitis Media in Infants and Children", "authors": [{"first": "C", "middle": ["D"], "last": "Bluestone", "suffix": ""}, {"first": "J", "middle": ["O"], "last": "Klein", "suffix": ""}, {"first": "", "middle": [], "last": "Microbiology", "suffix": ""}], "year": 2001, "venue": "", "link": "12310894"}, "BIBREF3": {"title": "Topical ciprofloxacin for otorrhea after tympanostomy tube placement", "authors": [{"first": "R", "middle": ["W"], "last": "Force", "suffix": ""}, {"first": "M", "middle": ["C"], "last": "Hart", "suffix": ""}, {"first": "S", "middle": ["A"], "last": "Plummer", "suffix": ""}], "year": 1995, "venue": "Arch Otolaryngol Head Neck Surg", "link": "37114578"}, "BIBREF4": {"title": "The effect of topical ciprofloxacin on postoperative otorrhea after tympanostomy tube insertion", "authors": [{"first": "T", "middle": ["E"], "last": "Zipfel", "suffix": ""}, {"first": "W", "middle": ["E"], "last": "Wood", "suffix": ""}, {"first": "D", "middle": ["F"], "last": "Street", "suffix": ""}], "year": 1999, "venue": "Am J Otol", "link": null}, "BIBREF5": {"title": "Multicentre study comparing the efficacy and tolerance of topical ciprofloxacin (0.3%) versus topical gentamicin (0.3%) in the treatment of simple, non-cholesteatomatous chronic otitis media in the suppurative phase", "authors": [{"first": "J", "middle": [], "last": "Lorente", "suffix": ""}, {"first": "F", "middle": [], "last": "Sabater", "suffix": ""}, {"first": "M", "middle": [], "last": "Maristany", "suffix": ""}], "year": 1995, "venue": "An Otorrinolaringol Ibero Am", "link": "37548888"}, "BIBREF6": {"title": "Treatment of chronic ear disease: topical ciprofloxacin vs topical gentamicin", "authors": [{"first": "A", "middle": [], "last": "Tutkun", "suffix": ""}, {"first": "A", "middle": [], "last": "Ozagar", "suffix": ""}, {"first": "A", "middle": [], "last": "Koc", "suffix": ""}], "year": 1995, "venue": "Arch Otolaryngol Head Neck Surg", "link": "25493038"}, "BIBREF7": {"title": "Chronic otitis media treated topically with ciprofloxacin or tobramycin", "authors": [{"first": "M", "middle": [], "last": "Fradis", "suffix": ""}, {"first": "A", "middle": [], "last": "Brodsky", "suffix": ""}, {"first": "J", "middle": [], "last": "Ben-David", "suffix": ""}], "year": 1997, "venue": "Arch Otolaryngol Head Neck Surg", "link": "7919564"}, "BIBREF8": {"title": "Local treatment of purulent chronic otitis media with ciprofloxacin", "authors": [{"first": "L", "middle": [], "last": "Podoshin", "suffix": ""}, {"first": "A", "middle": [], "last": "Brodzki", "suffix": ""}, {"first": "M", "middle": [], "last": "Fradis", "suffix": ""}], "year": 1998, "venue": "Harefuah", "link": "39497645"}, "BIBREF9": {"title": "Safety of ototopical antibiotics. Laryngoscope", "authors": [{"first": "D", "middle": ["B"], "last": "Welling", "suffix": ""}, {"first": "L", "middle": ["A"], "last": "Forrest", "suffix": ""}, {"first": "F", "middle": [], "last": "Goll", "suffix": ""}], "year": 1995, "venue": "", "link": null}, "BIBREF10": {"title": "Prophylactic antibiotic drops alter tympanostomy tube placement", "authors": [{"first": "T", "middle": ["O"], "last": "Hester", "suffix": ""}, {"first": "R", "middle": ["O"], "last": "Jones", "suffix": ""}, {"first": "S", "middle": ["M"], "last": "Archer", "suffix": ""}, {"first": "R", "middle": ["C"], "last": "Haydon", "suffix": ""}], "year": 1995, "venue": "Arch Otolaryngol Head Neck Surg", "link": null}, "BIBREF11": {"title": "Safety of topical ear drops containing ototoxic antibiotics", "authors": [{"first": "Y", "middle": [], "last": "Rakover", "suffix": ""}, {"first": "K", "middle": [], "last": "Keywan", "suffix": ""}, {"first": "G", "middle": [], "last": "Rosen", "suffix": ""}], "year": 1997, "venue": "J Otolaryngol", "link": null}, "BIBREF12": {"title": "Early postoperative otorrhea after tympanostomy tube placement: a comparison of topical ophthalmic and otic drops", "authors": [{"first": "D", "middle": ["R"], "last": "Charnock", "suffix": ""}], "year": 1997, "venue": "Ear Nose Throat J", "link": "28371958"}, "BIBREF13": {"title": "Treatment of chronic suppurative otitis media with topical tobramycin and dexamethasone", "authors": [{"first": "C", "middle": ["M"], "last": "Alper", "suffix": ""}, {"first": "J", "middle": ["E"], "last": "Dohar", "suffix": ""}, {"first": "M", "middle": [], "last": "Gulhan", "suffix": ""}], "year": 2000, "venue": "Arch Otolaryngol Head Neck Surg", "link": "23115810"}, "BIBREF14": {"title": "Topical ciprofloxacin/ dexamethasone is superior to ciprofloxacin alone in pediatric patients with acute otitis media with tympanostomy tubes (AOMT). Laryngoscope", "authors": [{"first": "P", "middle": ["S"], "last": "Roland", "suffix": ""}, {"first": "J", "middle": ["B"], "last": "Anon", "suffix": ""}, {"first": "P", "middle": ["J"], "last": "Conroy", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF15": {"title": "Topical ofloxacin versus systemic amoxicillin/clavulanate in purulent otorrhea in children with tympanostomy tubes", "authors": [{"first": "E", "middle": ["L"], "last": "Goldblatt", "suffix": ""}, {"first": "J", "middle": [], "last": "Dohar", "suffix": ""}, {"first": "R", "middle": ["J"], "last": "Nozza", "suffix": ""}], "year": 1998, "venue": "Int J Pediatr Otorhinolaryngol", "link": "4150301"}, "BIBREF16": {"title": "Topical ofloxacin treatment of otorrhea in children with tympanostomy tubes", "authors": [{"first": "J", "middle": ["E"], "last": "Dohar", "suffix": ""}, {"first": "E", "middle": ["T"], "last": "Garner", "suffix": ""}, {"first": "R", "middle": ["W"], "last": "Nielsen", "suffix": ""}], "year": 1999, "venue": "Arch Otolaryngol Head Neck Surg", "link": "9292545"}, "BIBREF17": {"title": "Clinical trial of ototopical ofloxacin for treatment of chronic suppurative otitis media", "authors": [{"first": "A", "middle": ["S"], "last": "Agro", "suffix": ""}, {"first": "E", "middle": ["T"], "last": "Garner", "suffix": ""}, {"first": "J", "middle": ["W"], "last": "Wright", "suffix": ""}, {"first": "", "middle": [], "last": "Iii", "suffix": ""}], "year": 1998, "venue": "Clin Ther", "link": "31383842"}, "BIBREF18": {"title": "Ofloxacin otic solution for treatment of otitis externa in children and adults", "authors": [{"first": "R", "middle": ["N"], "last": "Jones", "suffix": ""}, {"first": "J", "middle": [], "last": "Milazzo", "suffix": ""}, {"first": "M", "middle": [], "last": "Seidlin", "suffix": ""}], "year": 1997, "venue": "Arch Otolaryngol Head Neck Surg", "link": "42754898"}, "BIBREF19": {"title": "Effects of antibiotics and steroid on middle ear mucosa in rats with experimental acute otitis media", "authors": [{"first": "S", "middle": [], "last": "Park", "suffix": ""}, {"first": "S", "middle": ["W"], "last": "Yeo", "suffix": ""}], "year": 2001, "venue": "Acta Otolaryngol", "link": "21762684"}, "BIBREF22": {"title": "Otic Solution in the Treatment of Children With Acute Otitis Media With Topical Ciprofloxacin/Dexamethasone Otic Suspension Is Superior to Ofloxacin Services Updated Information &", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF25": {"title": "Otic Solution in the Treatment of Children With Acute Otitis Media With Topical Ciprofloxacin/Dexamethasone Otic Suspension Is Superior to Ofloxacin", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF26": {"title": "The online version of this article, along with updated information and services", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF27": {"title": "Copyright \u00a9 2004 by the American Academy of Pediatrics. All rights reserved", "authors": [], "year": "", "venue": "", "link": null}}, "ref_entries": {"FIGREF0": {"text": "Fig 1. Kaplan-Meier survival plot of days to cessation of otorrhea (modified ITT data set) for ciprofloxacin/dexamethasone compared with ofloxacin treatment in AOMT patients.", "type": "figure"}, "TABREF0": {"text": "", "type": "table"}, "TABREF1": {"text": "", "type": "table"}, "TABREF2": {"text": "Continued", "type": "table"}, "TABREF3": {"text": "Microbiologic Response Rates by Pathogen of MPP Subjects at TOC VisitTherapy-Related Adverse Events: ITT Group", "type": "table"}}}
{"paper_id": "8331913", "_pdf_hash": "4e69d0263ad81c5f4e9276b62dd210898f05bd0e", "abstract": [{"section": "Abstract", "text": "The cycloserine, cefoxitin, fructose agar medium (CCF agar) devised by George et al' and the modification of it where egg yolk is replaced by horse blood (Oxoid CCF agar), have been widely and successfully used for the isolation of Clostridium diffiwile from faecal specimens.'-4 For epidemiological and environmental work where only small numbers of organisms may be present, it is likely that a more sensitive method of culture is required. Hafiz et al used a broth containing p-cresol in studying vaginal carriage of C diffcile5 whilst Wilson et a16 have reported that the incorporation of sodium taurocholate in CCF agar (in place of egg yolk) enhances the recovery of spore forms of C difficile from solid media. We describe the use of cycloserine cefoxitin fructose broth containing 0 1 % sodium taurocholate (CCFT broth) for the isolation of C diffjile from vaginal and faecal specimens.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "women attending the Department of Genital Medicine (DGM). Groups IVa and IVb were mothers attending the matemity unit. Predelivery high vaginal swabs were taken by the midwife at onset of labour. Post delivery vaginal swabs were taken just prior to discharge. Group V were the babies delivered to mothers in group IV.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Culture method Swabs were inoculated onto solid media and then discarded. When enrichment cultures were performed (see Table) , a duplicate swab was broken off into the CCFT broth.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Cultures were incubated in an anaerobic cabinet (10% CO2) for 7 days. Plates were examined for typical C difficile colonies after 48 h and seven days. Suspect colonies were subcultured to blood agar for \"purity\" prior to further tests.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "ENRICHMENT CCFT broths were subcultured to blood agar after 48 h and seven days. Suspect colonies on blood agar after 48 h were streaked out for purity and treated as for the direct plate subcultures. Isolates were identified as C difficile by their typical colonial and Gram stain morphology, distinctive odour and pattem of volatile fatty acid production as detected by gas liquid chromatography.7 ", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Material and methods", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "MEDIA", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Five groups of subjects were studied independently (Table) . Groups I-III were unselected consecutive Accepted for publication 23 August 1983 Results and discussion", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "The results are summarised in the Table. Only on, C difficile isolation was made from 132 high vaginal swabs examined using CCF agar in groups I and II. No positive isolates were obtained using the RCA medium containing p-cresol (group II). However the use of CCFT broth greatly increased the isolation rates from vaginal swabs. In groups III and IVa the isolation rates from broth were 11% and 18% respectively compared with 1-2% and 0% from CCF agar alone. These differences in isolation rates are significant (p < 0-01). In group IVb (post-delivery mothers) CCFT broth was again superior to CCF agar but the total numbers are small and not statistically significant. However, when the overall isolation rates from vaginal specimens are examined for groups II, III and IV combined, the rate of isolation from CCFT 22/177 (12%) is significantly greater than that from CCF agar 3/177 (p < 0.001). 98 group.bmj.com on January 27, 2018 -Published by", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "", "text": "have reported that the incorporation of sodium taurocholate in CCF agar (in place of egg yolk) enhances the recovery of spore forms of C difficile from solid media. We describe the use of cycloserine cefoxitin fructose broth containing 0 1 % sodium taurocholate (CCFT broth) for the isolation of C diffjile from vaginal and faecal specimens.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "women attending the Department of Genital Medicine (DGM). Groups IVa and IVb were mothers attending the matemity unit. Predelivery high vaginal swabs were taken by the midwife at onset of labour. Post delivery vaginal swabs were taken just prior to discharge. Group V were the babies delivered to mothers in group IV.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Culture method Swabs were inoculated onto solid media and then discarded. When enrichment cultures were performed (see Table) , a duplicate swab was broken off into the CCFT broth.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Cultures were incubated in an anaerobic cabinet (10% CO2) for 7 days. Plates were examined for typical C difficile colonies after 48 h and seven days. Suspect colonies were subcultured to blood agar for \"purity\" prior to further tests. ", "cite_spans": [], "ref_spans": []}, {"section": "PATIENTS", "text": "Five groups of subjects were studied independently (Table) . Groups I-III were unselected consecutive Accepted for publication 23 August 1983 Results and discussion", "cite_spans": [], "ref_spans": []}, {"section": "High vaginal swabs", "text": "The results are summarised in the Table. Only on, C difficile isolation was made from 132 high vaginal swabs examined using CCF agar in groups I and II. No positive isolates were obtained using the RCA medium containing p-cresol (group II). However the use of CCFT broth greatly increased the isolation rates from vaginal swabs. In groups III and IVa the isolation rates from broth were 11% and 18% respectively compared with 1-2% and 0% from CCF agar alone. These differences in isolation rates are significant (p < 0-01). In group IVb (post-delivery mothers) CCFT broth was again superior to CCF agar but the total numbers are small and not statistically significant. However, when the overall isolation rates from vaginal specimens are examined for groups II, III and IV combined, the rate of isolation from CCFT 22/177 (12%) is significantly greater than that from CCF agar 3/177 (p < 0.001).", "cite_spans": [], "ref_spans": []}, {"section": "High vaginal swabs", "text": "Isolation rates of C difficile in five groups of subjects In contrast to the results obtained with vaginal swabs, the isolation rate obtained using CCFT broth was not significantly different to that obtained using CCF agar. This may be explained by the relatively high counts of C difficile organisms present in many faecal specimens and by the occasional failure of CCFT broth to yield C difficile when overgrowth of \"coliform\" organisms had taken place in the broth. In conclusion we suggest that a liquid culture medium, such as that described here, is a useful addition to conventional agar culture when only small numbers of C diffirile organisms are likely to be present.", "cite_spans": [], "ref_spans": []}, {"section": "High vaginal swabs", "text": "Rapid demonstration of nucleic acids using \"oxidised\" gallocyanin and chromic potassium sulphate: methods and applications OAN HUSAIN, KC WAiTS Department of Cytopathology, Charing Cross Hospital, London W6 Studies of metallic salt lakes of the oxazine dyes gallamin blue, celestine blue and gallocyanin led to the introduction of techniques for selective staining of Nissl and nuclear substance in nerve cells' and specific nuclear stains2-4 and to the theory of galAccepted for publication 21 September 1983 locyanin chromalum staining and its application for quantitative estimation of basophilia.5", "cite_spans": [], "ref_spans": []}, {"section": "High vaginal swabs", "text": "The gallocyanin chromalum technique of Einarson' was reviewed by us for use with the Quantimet image analysing computer6 and has now been adopted as a nuclear stain for the automated interactive cervical cancer screening system CERVIFIP where detection by integrated optical density is utilised, but its use in routine service conditions is limited by the fact that the staining technique requires incubation at 42\u00b0C for 16 h.7", "cite_spans": [], "ref_spans": []}, {"section": "High vaginal swabs", "text": "We have therefore conducted experiments to reduce the staining time required to a minimum but still retain its degree of stoichiometry and stain density. Our results have also shown that the rapid staining technique is useful for staining cells other than those exfoliated from the cervix, namely ", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Selective and differential medium for isolation of C difficik", "authors": [{"first": "L", "middle": ["W"], "last": "George", "suffix": ""}, {"first": "", "middle": [], "last": "Sutter", "suffix": ""}, {"first": "", "middle": [], "last": "Lv", "suffix": ""}, {"first": "D", "middle": [], "last": "Citron", "suffix": ""}, {"first": "S", "middle": ["M"], "last": "Finegold", "suffix": ""}], "year": 1979, "venue": "J Clin Microbiol", "link": null}, "BIBREF1": {"title": "Clostridium difficile in relation to enteric bacterial pathogens", "authors": [{"first": "E", "middle": [], "last": "Enevold Falsen", "suffix": ""}, {"first": "Bertil", "middle": [], "last": "Kaijger", "suffix": ""}, {"first": "B", "middle": [], "last": "", "suffix": ""}, {"first": "Lars", "middle": [], "last": "Nehls", "suffix": ""}, {"first": "L", "middle": [], "last": "", "suffix": ""}, {"first": "Borje", "middle": [], "last": "Nygren", "suffix": ""}, {"first": "B", "middle": [], "last": "Svedhem", "suffix": ""}, {"first": "A", "middle": [], "last": "", "suffix": ""}], "year": 1980, "venue": "J Clin Microbiol", "link": "22554851"}, "BIBREF2": {"title": "Recovery of Clostridium diffxile from children", "authors": [{"first": "E", "middle": [], "last": "", "suffix": ""}, {"first": "Helin", "middle": ["I"], "last": "Mardh", "suffix": ""}, {"first": "P-A", "middle": [], "last": "", "suffix": ""}], "year": 1981, "venue": "Scand J Infect Dis", "link": null}, "BIBREF3": {"title": "Clostridium difficile and cytotoxin in routine faecal specimens", "authors": [{"first": "Chattopadhyay", "middle": ["B"], "last": "Jq", "suffix": ""}, {"first": "J", "middle": [], "last": "Honeycombe", "suffix": ""}, {"first": "S", "middle": [], "last": "Tabaqchali", "suffix": ""}], "year": 1982, "venue": "J Clin Pathol", "link": "16683115"}, "BIBREF4": {"title": "C diffaile in the urogenital tract of males and females", "authors": [{"first": "S", "middle": [], "last": "Mcentegart", "suffix": ""}, {"first": "M", "middle": ["G"], "last": "Morton", "suffix": ""}, {"first": "R", "middle": ["S"], "last": "Waitkim", "suffix": ""}, {"first": "S", "middle": ["A"], "last": "", "suffix": ""}], "year": 1975, "venue": "Lancet", "link": null}, "BIBREF5": {"title": "Use of sodium taurocholate to enhance spore recovery in a medium for Clostridium difjkile", "authors": [{"first": "Kennedy", "middle": ["Mj"], "last": "Kh", "suffix": ""}, {"first": "F", "middle": ["R"], "last": "Fekety", "suffix": ""}], "year": 1982, "venue": "J Clin Microbiol", "link": null}, "BIBREF6": {"title": "Anaerobic laboratory manual 4th ed", "authors": [{"first": "L", "middle": ["V"], "last": "&apos;holdemann", "suffix": ""}, {"first": "E", "middle": ["P"], "last": "Cato", "suffix": ""}, {"first": "Wec", "middle": [], "last": "Moore", "suffix": ""}], "year": 1977, "venue": "", "link": null}, "BIBREF7": {"title": "St. Bartholomew's Hospital", "authors": [], "year": "", "venue": "", "link": null}}, "ref_entries": {"FIGREF0": {"text": "http://jcp.bmj.com/content/37/1/98.citation Updated information and services can be found at: These include: service Email alerting online article. article. Sign up in the box at the top right corner of the Receive free email alerts when new articles cite this Notes http://group.bmj.com/group/rights-licensing/permissions To request permissions go to: http://journals.bmj.com/cgi/reprintform To order reprints go to: http://group.bmj.com/subscribe/ To subscribe to BMJ go to:", "type": "figure"}, "TABREF0": {"text": "ENRICHMENT CCFT broths were subcultured to blood agar after 48 h and seven days. Suspect colonies on blood agar after 48 h were streaked out for purity and treated as for the direct plate subcultures. Isolates were identified as C difficile by their typical colonial and Gram stain morphology, distinctive odour and pat- tem of volatile fatty acid production as detected by gas liquid chromatography.7Enrichment broth The broth was made up in our laboratory to the same formula as the commercial CCF medium (Oxoid), but omitting the agar and including 1 g/l of sodium taurocholate.", "type": "table"}}}
{"paper_id": "8331927", "_pdf_hash": "2747f893aabc04f7cb61d7b4f841d5757c53a16b", "abstract": [{"section": "Abstract", "text": "mTOR is the target of the immunosuppressive drug rapamycin and the central component of a nutrientand hormone-sensitive signaling pathway that regulates cell growth and proliferation. We now appreciate that this pathway becomes deregulated in many human cancers and has an important role in the control of metabolism and aging. We have identified two distinct mTOR-containing proteins complexes, one of which regulates growth through S6K and another that regulates cell survival through Akt. These complexes, mTORC1 and mTORC2, define both rapamycin-sensitive and insensitive branches of the mTOR pathway. I will discuss new results from our lab on the regulation and functions of the mTORC1 and mTORC2 pathways.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "", "text": "mTOR is the target of the immunosuppressive drug rapamycin and the central component of a nutrientand hormone-sensitive signaling pathway that regulates cell growth and proliferation. We now appreciate that this pathway becomes deregulated in many human cancers and has an important role in the control of metabolism and aging. We have identified two distinct mTOR-containing proteins complexes, one of which regulates growth through S6K and another that regulates cell survival through Akt. These complexes, mTORC1 and mTORC2, define both rapamycin-sensitive and insensitive branches of the mTOR pathway. I will discuss new results from our lab on the regulation and functions of the mTORC1 and mTORC2 pathways. ", "cite_spans": [], "ref_spans": []}], "bib_entries": {}, "ref_entries": {"FIGREF0": {"text": "this article as: Sabatini: Regulation of growth and metabolism. Cancer & Metabolism 2014 2(Suppl 1):O20. Submit your next manuscript to BioMed Central and take full advantage of: \u2022 Convenient online submission \u2022 Thorough peer review \u2022 No space constraints or color figure charges \u2022 Immediate publication on acceptance \u2022 Inclusion in PubMed, CAS, Scopus and Google Scholar \u2022 Research which is freely available for redistribution Submit your manuscript at www.biomedcentral.com/submit Whitehead Institute for Biomedical Research; Howard Hughes Medical Institute and Department of Biology, MIT; Broad Institute of Harvard and MIT; The David H Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA, USA", "type": "figure"}}}
{"paper_id": "8332005", "_pdf_hash": "daadccd6ae051e08f340089c97a8fdda8ba6cc24", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "A Survey on Sensor Network", "authors": [{"first": "I", "middle": ["F"], "last": "Akyildiz", "suffix": ""}, {"first": "W", "middle": [], "last": "Su", "suffix": ""}, {"first": "Y", "middle": [], "last": "Sankarasubramaniam", "suffix": ""}, {"first": "E", "middle": [], "last": "Cayircl", "suffix": ""}], "year": 2002, "venue": "IEEE Communication Magazine", "link": null}, "BIBREF1": {"title": "Spatiotemporal Multicast in Sensor Network", "authors": [{"first": "Q", "middle": [], "last": "Hang", "suffix": ""}, {"first": "C", "middle": [], "last": "Lu", "suffix": ""}, {"first": "G", "middle": ["C"], "last": "Roman", "suffix": ""}], "year": 2003, "venue": "Proceedings of the ACM Conference on Embedded Networked sensor systems (Sensys)", "link": "7611602"}, "BIBREF2": {"title": "Design and Analysis of Spatiotemporal Multicast Protocols for Wireless Sensor Networks", "authors": [{"first": "Q", "middle": [], "last": "Hang", "suffix": ""}, {"first": "C", "middle": [], "last": "Lu", "suffix": ""}, {"first": "G", "middle": ["C"], "last": "Roman", "suffix": ""}], "year": 2004, "venue": "Telecommunication Systems, Special Issue on Wireless Sensor Networks", "link": null}, "BIBREF3": {"title": "Reliable Mobicast via Faceaware Routing", "authors": [{"first": "Q", "middle": [], "last": "Hang", "suffix": ""}, {"first": "C", "middle": [], "last": "Lu", "suffix": ""}, {"first": "G.-C", "middle": [], "last": "Roman", "suffix": ""}], "year": 2004, "venue": "Proceeding of the IEEE International Conference on Computer Communications (INFOCM)", "link": null}, "BIBREF4": {"title": "VE-Mobicast: A VariantEgg-Based Mobicast Routing Protocol for Sensornets", "authors": [{"first": "Yuh-Shyan", "middle": [], "last": "Chen", "suffix": ""}, {"first": "Shin-Yi", "middle": [], "last": "Ann", "suffix": ""}], "year": 2006, "venue": "", "link": "60691644"}, "BIBREF5": {"title": "HVE-Mobicast:A Hierarchical-Variant-Egg-Based Mobi-cast Routing Protocol for Sensornets", "authors": [{"first": "Yuh-Shyan", "middle": [], "last": "Chen", "suffix": ""}, {"first": "Shin-Yi", "middle": [], "last": "Ann", "suffix": ""}], "year": 2006, "venue": "Proceedings of IEEE Wireless Communications and Networking Conference (IEEE WCNC 2006)", "link": null}, "BIBREF6": {"title": "Habit Monitoring: Application Driver for Wireless Communications Technology", "authors": [{"first": "A", "middle": [], "last": "Cerpa", "suffix": ""}, {"first": "J", "middle": [], "last": "Elson", "suffix": ""}, {"first": "D", "middle": [], "last": "Estrin", "suffix": ""}, {"first": "L", "middle": [], "last": "Girod", "suffix": ""}, {"first": "M", "middle": [], "last": "Hamilton", "suffix": ""}], "year": 2001, "venue": "ACM SIGCOMN Workshop on Data communications in Latin America and the Caribbean", "link": "61859242"}, "BIBREF7": {"title": "Detection, Classification and Tracking of Targets in Distributed Sensor Networks", "authors": [{"first": "D", "middle": [], "last": "Li", "suffix": ""}, {"first": "K", "middle": [], "last": "Wong", "suffix": ""}, {"first": "Y", "middle": [], "last": "Hu", "suffix": ""}, {"first": "A", "middle": [], "last": "Sayeed", "suffix": ""}], "year": 2002, "venue": "IEEE Signal processing magazine", "link": "15804507"}, "BIBREF9": {"title": "Relative Neighborhood Graphs and Their Relatives", "authors": [{"first": "J", "middle": ["W"], "last": "Jaromczyk", "suffix": ""}, {"first": "G", "middle": ["T"], "last": "Toussaint", "suffix": ""}], "year": 1995, "venue": "Proceedings of IEEE", "link": "9819258"}, "BIBREF10": {"title": "GPSR: Greedy Perimeter Stateless Routing for Wireless Network", "authors": [{"first": "B", "middle": [], "last": "Karp", "suffix": ""}, {"first": "H", "middle": ["T"], "last": "Kung", "suffix": ""}], "year": 2000, "venue": "Proceeding of the 6th ACM/IEEE International Conference on Mobile Computing and networking (mobicom2000)", "link": "632158"}, "BIBREF11": {"title": "Geometric Ad-Hoc Routing: Of Theory and Practice", "authors": [{"first": "F", "middle": [], "last": "Kuhn", "suffix": ""}, {"first": "R", "middle": [], "last": "Wattenhofer", "suffix": ""}, {"first": "Y", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "A", "middle": [], "last": "Zollinger", "suffix": ""}], "year": 2003, "venue": "Proceedings of 22nd ACM Int. Symposium on the Priciples of Distributed computing (PODC)", "link": "11713469"}}, "ref_entries": {}}
{"paper_id": "8332093", "_pdf_hash": "0e5b9077df5cf6fa0725d9e0c878b5dd022e4628", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Prevalence of impaired glucose tolerance and diabetes in women with polycystic ovary syndrome", "authors": [{"first": "D", "middle": ["A"], "last": "Ehrmann", "suffix": ""}, {"first": "R", "middle": ["B"], "last": "Barnes", "suffix": ""}, {"first": "R", "middle": ["L"], "last": "Rosenfield", "suffix": ""}], "year": 1999, "venue": "Diabetes Care", "link": "25388868"}, "BIBREF1": {"title": "A prospective study of the prevalence of the polycystic ovary syndrome in unselected Caucasian women from Spain", "authors": [{"first": "M", "middle": [], "last": "Asuncion", "suffix": ""}, {"first": "R", "middle": ["M"], "last": "Calvo", "suffix": ""}, {"first": "San", "middle": [], "last": "Millan", "suffix": ""}, {"first": "J", "middle": ["L"], "last": "", "suffix": ""}], "year": 2000, "venue": "J Clin Endocrinol Metab", "link": null}, "BIBREF2": {"title": "The prevalence and features of the polycystic ovary syndrome in an unselected population", "authors": [{"first": "R", "middle": [], "last": "Azziz", "suffix": ""}, {"first": "K", "middle": ["S"], "last": "Woods", "suffix": ""}, {"first": "R", "middle": [], "last": "Reyna", "suffix": ""}], "year": 2004, "venue": "J Clin Endocrinol Metab", "link": "17665624"}, "BIBREF3": {"title": "A survey of the polycystic ovary syndrome in the Greek island of Lesbos: hormonal and metabolic profile", "authors": [{"first": "E", "middle": [], "last": "Diamanti-Kandarakis", "suffix": ""}, {"first": "C", "middle": ["R"], "last": "Kouli", "suffix": ""}, {"first": "A", "middle": ["T"], "last": "Bergiele", "suffix": ""}], "year": 1999, "venue": "J Clin Endocrinol Metab", "link": "21405534"}, "BIBREF4": {"title": "Diagnosis, epidemiology, and genetics of the polycystic ovary syndrome", "authors": [{"first": "M", "middle": ["O"], "last": "Goodarzi", "suffix": ""}, {"first": "R", "middle": [], "last": "Azziz", "suffix": ""}], "year": 2006, "venue": "Best Pract Res Clin Endocrinol Metab", "link": "35517017"}, "BIBREF5": {"title": "PCOS according to the Rotterdam consensus criteria: change in prevalence among WHO-II anovulation and association with metabolic factors", "authors": [{"first": "F", "middle": ["J"], "last": "Broekmans", "suffix": ""}, {"first": "E", "middle": ["A"], "last": "Knauff", "suffix": ""}, {"first": "O", "middle": [], "last": "Valkenburg", "suffix": ""}], "year": 2006, "venue": "BJOG", "link": "26998404"}, "BIBREF6": {"title": "Polycystic ovaries and infertility: our experience", "authors": [{"first": "L", "middle": [], "last": "Rajashekar", "suffix": ""}, {"first": "D", "middle": [], "last": "Krishna", "suffix": ""}, {"first": "M", "middle": [], "last": "Patil", "suffix": ""}], "year": 2008, "venue": "J Hum Reprod Sci", "link": "10887005"}, "BIBREF7": {"title": "A controlled-study comparing patients with and without polycystic ovaries undergoing invitro fertilization", "authors": [{"first": "M", "middle": ["J"], "last": "Macdougall", "suffix": ""}, {"first": "S", "middle": ["L"], "last": "Tan", "suffix": ""}, {"first": "A", "middle": [], "last": "Balen", "suffix": ""}, {"first": "H", "middle": ["S"], "last": "Jacobs", "suffix": ""}], "year": 1993, "venue": "Hum Reprod", "link": "37123606"}, "BIBREF8": {"title": "Miscarriage rates following invitro fertilization are increased in women with polycystic ovaries and reduced by pituitary desensitization with buserelin", "authors": [{"first": "A", "middle": ["H"], "last": "Balen", "suffix": ""}, {"first": "S", "middle": ["L"], "last": "Tan", "suffix": ""}, {"first": "J", "middle": [], "last": "Macdougall", "suffix": ""}, {"first": "H", "middle": ["S"], "last": "Jacobs", "suffix": ""}], "year": 1993, "venue": "Hum Reprod", "link": "12094811"}, "BIBREF9": {"title": "Polycystic ovarian syndrome and the risk of spontaneous abortion following assisted reproductive technology treatment", "authors": [{"first": "J", "middle": ["X"], "last": "Wang", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Davies", "suffix": ""}, {"first": "R", "middle": ["J"], "last": "Norman", "suffix": ""}], "year": 2001, "venue": "Hum Reprod", "link": "31626227"}, "BIBREF10": {"title": "Early pregnancy loss following assisted reproductive technology treatment", "authors": [{"first": "E", "middle": [], "last": "Winter", "suffix": ""}, {"first": "J", "middle": [], "last": "Wang", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Davies", "suffix": ""}, {"first": "R", "middle": ["J"], "last": "Norman", "suffix": ""}], "year": 2002, "venue": "Hum Reprod", "link": "33405850"}, "BIBREF11": {"title": "Effects of norethindrone on gonadotropin and ovarian-steroid secretion when used for cycle programming during invitro fertilization", "authors": [{"first": "R", "middle": ["E"], "last": "Anderson", "suffix": ""}, {"first": "A", "middle": ["L"], "last": "Stein", "suffix": ""}, {"first": "R", "middle": ["J"], "last": "Paulson", "suffix": ""}], "year": 1990, "venue": "Fertil Steril", "link": "30622821"}, "BIBREF12": {"title": "Dual suppression with oral contraceptives and gonadotrophin releasing-hormone agonists improves in-vitro fertilization outcome in high responder patients", "authors": [{"first": "M", "middle": ["A"], "last": "Damario", "suffix": ""}, {"first": "L", "middle": [], "last": "Barmat", "suffix": ""}, {"first": "H", "middle": ["C"], "last": "Liu", "suffix": ""}], "year": 1997, "venue": "Hum Reprod", "link": "1821756"}, "BIBREF13": {"title": "Pretreatment with oral contraceptives in infertile anovulatory patients with polycystic ovary syndrome who receive gonadotropins for controlled ovarian stimulation", "authors": [{"first": "S", "middle": [], "last": "Palomba", "suffix": ""}, {"first": "A", "middle": [], "last": "Falbo", "suffix": ""}, {"first": "F", "middle": [], "last": "Orio", "suffix": ""}], "year": 2008, "venue": "Fertil Steril", "link": "12038543"}, "BIBREF14": {"title": "First intention IVF protocol for polycystic ovaries: does oral contraceptive pill pretreatment influence COH outcome?", "authors": [{"first": "C", "middle": [], "last": "Decanter", "suffix": ""}, {"first": "G", "middle": [], "last": "Robin", "suffix": ""}, {"first": "P", "middle": [], "last": "Thomas", "suffix": ""}], "year": 2013, "venue": "Reprod Biol Endocrinol", "link": "14002006"}, "BIBREF15": {"title": "Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS)", "authors": [{"first": "Ea-Spcwg", "middle": [], "last": "Rotterdam", "suffix": ""}], "year": 2004, "venue": "Hum Reprod", "link": "40264627"}, "BIBREF16": {"title": "High maternal serum estradiol environment in the first trimester is associated with the increased risk of small-for-gestational-age birth", "authors": [{"first": "X", "middle": ["L"], "last": "Hu", "suffix": ""}, {"first": "C", "middle": [], "last": "Feng", "suffix": ""}, {"first": "X", "middle": ["H"], "last": "Lin", "suffix": ""}], "year": 2014, "venue": "J Clin Endocrinol Metab", "link": "8128465"}, "BIBREF17": {"title": "Polycystic ovary syndrome", "authors": [{"first": "R", "middle": ["J"], "last": "Norman", "suffix": ""}, {"first": "D", "middle": [], "last": "Dewailly", "suffix": ""}, {"first": "R", "middle": ["S"], "last": "Legro", "suffix": ""}, {"first": "T", "middle": ["E"], "last": "Hickey", "suffix": ""}], "year": 2007, "venue": "Lancet", "link": "20834096"}, "BIBREF18": {"title": "Alterations in stress responses of the hypothalamic-pituitary-adrenal axis in small for gestational age infants", "authors": [{"first": "E", "middle": ["A"], "last": "Osterholm", "suffix": ""}, {"first": "C", "middle": ["E"], "last": "Hostinar", "suffix": ""}, {"first": "M", "middle": ["R"], "last": "Gunnar", "suffix": ""}], "year": 2012, "venue": "Psychoneuroendocrinology", "link": "25098969"}, "BIBREF19": {"title": "Weight status in the first 6 months of life and obesity at 3 years of age", "authors": [{"first": "E", "middle": ["M"], "last": "Taveras", "suffix": ""}, {"first": "S", "middle": ["L"], "last": "Rifas-Shiman", "suffix": ""}, {"first": "M", "middle": ["B"], "last": "Belfort", "suffix": ""}], "year": 2009, "venue": "Pediatrics", "link": "782949"}, "BIBREF20": {"title": "Pituitary and ovarian function in women receiving hormonal contraception", "authors": [{"first": "B", "middle": ["L"], "last": "Cohen", "suffix": ""}, {"first": "M", "middle": [], "last": "Katz", "suffix": ""}], "year": 1979, "venue": "Contraception", "link": "24219247"}, "BIBREF21": {"title": "Synchronization of endogenous and exogenous FSH stimuli in controlled ovarian hyperstimulation (COH)", "authors": [{"first": "D", "middle": [], "last": "De Ziegler", "suffix": ""}, {"first": "A", "middle": ["S"], "last": "Jaaskelainen", "suffix": ""}, {"first": "P", "middle": ["A"], "last": "Brioschi", "suffix": ""}], "year": 1998, "venue": "Hum Reprod", "link": "2464349"}, "BIBREF22": {"title": "The impact of metformin, oral contraceptives, and lifestyle modification on polycystic ovary syndrome in obese adolescent women in two randomized, placebocontrolled clinical trials", "authors": [{"first": "K", "middle": [], "last": "Hoeger", "suffix": ""}, {"first": "K", "middle": [], "last": "Davidson", "suffix": ""}, {"first": "L", "middle": [], "last": "Kochman", "suffix": ""}], "year": 2008, "venue": "J Clin Endocrinol Metab", "link": "6439871"}, "BIBREF23": {"title": "Initial and cyclic recruitment of ovarian follicles 1", "authors": [{"first": "E", "middle": ["A"], "last": "Mcgee", "suffix": ""}, {"first": "Ajw", "middle": [], "last": "Hsueh", "suffix": ""}], "year": 2000, "venue": "Endocr Rev", "link": "16324211"}, "BIBREF24": {"title": "Dynamics of follicular growth in the human: a model from preliminary results", "authors": [{"first": "A", "middle": [], "last": "Gougeon", "suffix": ""}], "year": 1986, "venue": "Hum Reprod", "link": "9547105"}}, "ref_entries": {}}
{"paper_id": "8332224", "_pdf_hash": "4bf633853510b1e7d8c3729087f908da30c02749", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Small cell carcinoma of the esophagus. The Me morial Hospital expe rie nce 1970 to", "authors": [{"first": "L", "middle": ["N"], "last": "Nichols", "suffix": ""}, {"first": "", "middle": [], "last": "Ke Lsen Dp", "suffix": ""}], "year": 1987, "venue": "Cancer", "link": null}, "BIBREF1": {"title": "Small ce ll carcinoma of the esophagus", "authors": [{"first": "Syk", "middle": [], "last": "Law", "suffix": ""}, {"first": "M", "middle": [], "last": "Fok", "suffix": ""}, {"first": "K", "middle": ["Y"], "last": "Lam", "suffix": ""}, {"first": "S", "middle": ["L"], "last": "Loke", "suffix": ""}, {"first": "L", "middle": ["T"], "last": "Ma", "suffix": ""}, {"first": "J", "middle": [], "last": "Wong", "suffix": ""}], "year": 1994, "venue": "Cancer", "link": null}, "BIBREF2": {"title": "Small ce ll carcinoma of the e sophagus. The Massachuse tts Gene ral Hospital e xperie nce", "authors": [{"first": "M", "middle": [], "last": "Huncharek", "suffix": ""}, {"first": "J", "middle": [], "last": "Muscat", "suffix": ""}], "year": 1978, "venue": "Chest", "link": null}, "BIBREF3": {"title": "Primary small-ce ll cance r of the e sophagus", "authors": [{"first": "S", "middle": ["R"], "last": "Craig", "suffix": ""}, {"first": "F", "middle": ["A"], "last": "Carey", "suffix": ""}, {"first": "W", "middle": ["S"], "last": "Walker", "suffix": ""}, {"first": "Ewj", "middle": [], "last": "Cameron", "suffix": ""}], "year": 1995, "venue": "J Thorac Cardiovasc Surg", "link": null}, "BIBREF4": {"title": "E sophageal carcinoma. The unusual variants", "authors": [{"first": "", "middle": [], "last": "Lie Be Rman", "suffix": ""}, {"first": "", "middle": [], "last": "Md", "suffix": ""}, {"first": "D", "middle": [], "last": "Franceschi", "suffix": ""}, {"first": "B", "middle": [], "last": "Marsan", "suffix": ""}, {"first": "M", "middle": [], "last": "Burt", "suffix": ""}], "year": 1994, "venue": "J Thorac Cardiovasc Surg", "link": null}, "BIBREF5": {"title": "Extrapulmonary oat ce ll carcinoma", "authors": [{"first": "N", "middle": ["B"], "last": "Ibrahim", "suffix": ""}, {"first": "J", "middle": ["C"], "last": "Briggs", "suffix": ""}, {"first": "C", "middle": ["M"], "last": "Corbishley", "suffix": ""}], "year": 1984, "venue": "Cance r", "link": null}, "BIBREF6": {"title": "Small cell carcinoma of the esophagus: Evide nce of a uni\u00ae ed histogenesis", "authors": [{"first": "K", "middle": ["J"], "last": "Ho", "suffix": ""}, {"first": "G", "middle": ["A"], "last": "He Rre Ra", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Jones", "suffix": ""}], "year": 1984, "venue": "Hum Pathol", "link": null}, "BIBREF7": {"title": "Oat ce ll carcinoma of the e sophagus with multiple differentiation", "authors": [{"first": "K", "middle": [], "last": "Sasajima", "suffix": ""}, {"first": "N", "middle": [], "last": "Hayasi", "suffix": ""}, {"first": "K", "middle": [], "last": "Yamashita", "suffix": ""}, {"first": "M", "middle": [], "last": "Onda", "suffix": ""}, {"first": "K", "middle": [], "last": "Takubo", "suffix": ""}], "year": 1988, "venue": "J Clin Gastroente rol", "link": null}, "BIBREF8": {"title": "Ye sner R: Carcinomas of the lung with neuroe ndocrine differentiation", "authors": [{"first": "D", "middle": [], "last": "Carte R", "suffix": ""}], "year": 1985, "venue": "Semin Diagn Pathol", "link": null}, "BIBREF9": {"title": "Differe ntial diagnostic patte rns of lung neuroendocrine tumors. A clinicopathological and immunohistochemical study of 122 cases", "authors": [{"first": "M", "middle": [], "last": "Bonato", "suffix": ""}, {"first": "M", "middle": [], "last": "Cerati", "suffix": ""}, {"first": "A", "middle": [], "last": "Pagani", "suffix": ""}, {"first": "M", "middle": [], "last": "Papotti", "suffix": ""}, {"first": "F", "middle": [], "last": "Bosi", "suffix": ""}, {"first": "G", "middle": [], "last": "Bussolati", "suffix": ""}, {"first": "C", "middle": [], "last": "Capella", "suffix": ""}], "year": 1992, "venue": "Virchows Arch A", "link": null}, "BIBREF10": {"title": "Primary small cell carcinoma of the esophagus with ectopic gastrin production. Re port of a case and revie w of the literature", "authors": [{"first": "T", "middle": [], "last": "Nishimaki", "suffix": ""}, {"first": "T", "middle": [], "last": "Susuzki", "suffix": ""}, {"first": "T", "middle": [], "last": "Fukuda", "suffix": ""}, {"first": "K", "middle": [], "last": "Aizawa", "suffix": ""}, {"first": "O", "middle": [], "last": "Tanaka", "suffix": ""}, {"first": "T", "middle": [], "last": "Muto", "suffix": ""}], "year": 1993, "venue": "Dig Dis Sci", "link": null}, "BIBREF11": {"title": "Small cell undifferentiated carcinoma of the esophagus. Case re port with hormonal studies", "authors": [{"first": "F", "middle": ["E"], "last": "Johnson", "suffix": ""}, {"first": "M", "middle": ["C"], "last": "Clawson", "suffix": ""}, {"first": "M", "middle": [], "last": "Bashiti", "suffix": ""}, {"first": "A", "middle": ["B"], "last": "Silverbe Rg", "suffix": ""}, {"first": "G", "middle": ["O"], "last": "Broun", "suffix": ""}], "year": 1984, "venue": "Cancer", "link": "37150915"}, "BIBREF12": {"title": "A cytologic study on small ce ll carcinoma of the esophagus", "authors": [{"first": "T", "middle": [], "last": "Horai", "suffix": ""}, {"first": "A", "middle": [], "last": "Kobayashi", "suffix": ""}, {"first": "R", "middle": [], "last": "Tate Ishi", "suffix": ""}, {"first": "A", "middle": [], "last": "Wada", "suffix": ""}, {"first": "H", "middle": [], "last": "Taniguchi", "suffix": ""}, {"first": "K", "middle": [], "last": "Taniguchi", "suffix": ""}, {"first": "M", "middle": [], "last": "Sano", "suffix": ""}, {"first": "H", "middle": [], "last": "Tamura", "suffix": ""}], "year": 1978, "venue": "Cancer", "link": null}, "BIBREF13": {"title": "Wate ry diarrhea\u00b1 hypokalemia\u00b1 achlorhydria syndrome and carcinoma of the esophagus", "authors": [{"first": "Kjr", "middle": [], "last": "Watoson", "suffix": ""}, {"first": "A", "middle": [], "last": "Shulkes", "suffix": ""}, {"first": "R", "middle": ["A"], "last": "Smallwood", "suffix": ""}, {"first": "M", "middle": ["C"], "last": "Douglas", "suffix": ""}, {"first": "R", "middle": [], "last": "Hurley", "suffix": ""}, {"first": "R", "middle": [], "last": "Kalnins", "suffix": ""}, {"first": "L", "middle": [], "last": "Moran", "suffix": ""}], "year": 1985, "venue": "Gastroenterology", "link": null}, "BIBREF14": {"title": "World He alth Organization: The World He alth Organization histological typing of lung tumors, 2", "authors": [], "year": 1982, "venue": "Am J Clin Pathol", "link": null}, "BIBREF15": {"title": "Improve d avidin\u00b1 biotin\u00b1 peroxidase comple x (ABC) staining. Histoche m", "authors": [{"first": "G", "middle": [], "last": "Cattoretti", "suffix": ""}, {"first": "E", "middle": [], "last": "Berti", "suffix": ""}, {"first": "R", "middle": [], "last": "Schiro", "suffix": ""}], "year": 1988, "venue": "J", "link": null}, "BIBREF16": {"title": "We instein WM: E ndocrine cells", "authors": [{"first": "K", "middle": ["J"], "last": "Le Win", "suffix": ""}, {"first": "R", "middle": ["H"], "last": "Riddell", "suffix": ""}], "year": 1992, "venue": "Gastrointestinal Pathology and Its Clinical Implications", "link": null}, "BIBREF17": {"title": "Parathyroid hormone-related protein puri\u00ae ed from a human lung cancer ce ll line", "authors": [{"first": "Mose", "middle": [], "last": "Ley", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Kubota", "suffix": ""}, {"first": "M", "middle": [], "last": "Difenbach-Jagger", "suffix": ""}, {"first": "H", "middle": [], "last": "", "suffix": ""}, {"first": "Wette", "middle": [], "last": "Re H, Ke Mp", "suffix": ""}, {"first": "", "middle": [], "last": "Be", "suffix": ""}, {"first": "L", "middle": ["J"], "last": "Suva", "suffix": ""}, {"first": "C", "middle": ["P"], "last": "Rodda", "suffix": ""}, {"first": "P", "middle": ["R"], "last": "Ebeling", "suffix": ""}, {"first": "P", "middle": ["J"], "last": "Hudson", "suffix": ""}, {"first": "J", "middle": ["D"], "last": "Zajac", "suffix": ""}, {"first": "T", "middle": ["J"], "last": "Martin", "suffix": ""}], "year": 1987, "venue": "Proc Natl Acad Sci", "link": null}, "BIBREF18": {"title": "Immunological identi\u00ae cation and distribution of parathyroid hormone-like protein polypeptides in normal and malignant tissues", "authors": [{"first": "S", "middle": [], "last": "Kramer", "suffix": ""}, {"first": "F", "middle": ["H"], "last": "Reynolds", "suffix": ""}, {"first": "M", "middle": [], "last": "Castillo", "suffix": ""}, {"first": "D", "middle": ["M"], "last": "Thorikay", "suffix": ""}, {"first": "M", "middle": [], "last": "Sorvillo", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "", "suffix": ""}], "year": 1991, "venue": "Endocrinology", "link": "9213951"}, "BIBREF19": {"title": "Parathyroid hormone-re late d protein of malignancy: Immunohistochemical and bioche mical studies in normocalcaemic and hype rcalcaemic patients with cance r", "authors": [{"first": "S", "middle": ["H"], "last": "Ralston", "suffix": ""}, {"first": "J", "middle": [], "last": "Danks", "suffix": ""}, {"first": "J", "middle": [], "last": "Hayman", "suffix": ""}, {"first": "W", "middle": ["D"], "last": "Fraser", "suffix": ""}, {"first": "C", "middle": ["S"], "last": "Stewart", "suffix": ""}, {"first": "T", "middle": [], "last": "Martin", "suffix": ""}], "year": 1991, "venue": "J Clin Pathol", "link": null}, "BIBREF20": {"title": "A parathyroid hormone -relate d protein implicated in malignant hype rcalce mia: Cloning and e xpression", "authors": [{"first": "L", "middle": ["J"], "last": "Suva", "suffix": ""}, {"first": "G", "middle": ["A"], "last": "Winslow", "suffix": ""}, {"first": "Reh", "middle": [], "last": "Wettenhall", "suffix": ""}, {"first": "R", "middle": ["G"], "last": "Hammonds", "suffix": ""}, {"first": "Mose", "middle": [], "last": "Ley", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "", "suffix": ""}, {"first": "Die", "middle": [], "last": "Fe Nbach-Jagge R, Rodda", "suffix": ""}, {"first": "C", "middle": ["P"], "last": "Ke", "suffix": ""}, {"first": "", "middle": [], "last": "Be", "suffix": ""}, {"first": "H", "middle": [], "last": "Rodrigue Z", "suffix": ""}, {"first": "E", "middle": ["Y"], "last": "Chen", "suffix": ""}, {"first": "P", "middle": ["J"], "last": "Hudson", "suffix": ""}, {"first": "T", "middle": ["J"], "last": "Martin", "suffix": ""}, {"first": "W", "middle": ["I"], "last": "Wood", "suffix": ""}], "year": 1987, "venue": "Science", "link": null}, "BIBREF21": {"title": "Hypercalcem ia in patie nts with e sophageal carcinoma. The pathophysiologic role of parathyroid hormone -relate d protein", "authors": [{"first": "Y", "middle": [], "last": "Tachimori", "suffix": ""}, {"first": "H", "middle": [], "last": "Watanabe", "suffix": ""}, {"first": "H", "middle": [], "last": "Kato", "suffix": ""}, {"first": "H", "middle": [], "last": "Yamaguchi", "suffix": ""}, {"first": "K", "middle": [], "last": "Nagasaki", "suffix": ""}, {"first": "S", "middle": [], "last": "Honda", "suffix": ""}, {"first": "M", "middle": [], "last": "Itabashi", "suffix": ""}, {"first": "K", "middle": [], "last": "Yamaguchi", "suffix": ""}], "year": 1991, "venue": "Cancer", "link": null}, "BIBREF22": {"title": "Granulocytosis associated with tumor ce ll production of colony-stimulating activity", "authors": [{"first": "W", "middle": [], "last": "Hocking", "suffix": ""}, {"first": "J", "middle": [], "last": "Goodman", "suffix": ""}, {"first": "D", "middle": [], "last": "Golde", "suffix": ""}], "year": 1983, "venue": "Blood", "link": "208197886"}, "BIBREF23": {"title": "Le ukocytosis and lung ce ll cance r. A frequent association", "authors": [{"first": "J", "middle": ["L"], "last": "Ascensao", "suffix": ""}, {"first": "M", "middle": ["M"], "last": "Oken", "suffix": ""}, {"first": "S", "middle": ["L"], "last": "Ewing", "suffix": ""}, {"first": "R", "middle": ["J"], "last": "Goldbe Rg", "suffix": ""}, {"first": "M", "middle": ["E"], "last": "Kaplan", "suffix": ""}], "year": 1987, "venue": "Cancer", "link": null}, "BIBREF24": {"title": "Serum granulocyte colony-stimulating factor leve ls in healthy voluntee rs and patie nts with various disorders as estimated by e nzyme immunoassay", "authors": [{"first": "K", "middle": [], "last": "Watari", "suffix": ""}, {"first": "S", "middle": [], "last": "Asano", "suffix": ""}, {"first": "N", "middle": [], "last": "Shirafuji", "suffix": ""}, {"first": "H", "middle": [], "last": "Kodo", "suffix": ""}, {"first": "K", "middle": [], "last": "Ozawa", "suffix": ""}, {"first": "F", "middle": [], "last": "Takaku", "suffix": ""}, {"first": "S", "middle": [], "last": "Kamachi", "suffix": ""}], "year": 1989, "venue": "Blood", "link": null}, "BIBREF25": {"title": "Urinary bladde r carcinoma producing granulocyte colony stimulating factor (G-CSF): A re port with immunohistochemistry", "authors": [{"first": "T", "middle": [], "last": "Ito", "suffix": ""}, {"first": "K", "middle": [], "last": "Shimamura", "suffix": ""}, {"first": "K", "middle": [], "last": "Shoji", "suffix": ""}, {"first": "A", "middle": [], "last": "Akatsuka", "suffix": ""}, {"first": "Y", "middle": [], "last": "Kiryu", "suffix": ""}, {"first": "N", "middle": [], "last": "Tamaoki", "suffix": ""}, {"first": "Y", "middle": [], "last": "Osamura", "suffix": ""}], "year": 1993, "venue": "Virchows Arch A", "link": null}, "BIBREF26": {"title": "Production of bone -resorbing activity and colony-stimulating activity in vivo and in vitro by a squamous ce ll carcinoma associated with hype rcalce mia and leukocytosis", "authors": [{"first": "K", "middle": [], "last": "Sato", "suffix": ""}, {"first": "H", "middle": [], "last": "Mimura", "suffix": ""}, {"first": "D", "middle": ["C"], "last": "Han", "suffix": ""}, {"first": "T", "middle": [], "last": "Kakiuchi", "suffix": ""}, {"first": "Y", "middle": [], "last": "Ue Yama", "suffix": ""}, {"first": "H", "middle": [], "last": "Ohkawa", "suffix": ""}, {"first": "T", "middle": [], "last": "Okabe", "suffix": ""}, {"first": "Y", "middle": [], "last": "Kondo", "suffix": ""}, {"first": "N", "middle": [], "last": "Ohsawa", "suffix": ""}, {"first": "T", "middle": [], "last": "Tsushima", "suffix": ""}, {"first": "K", "middle": [], "last": "Shizume", "suffix": ""}], "year": 1986, "venue": "J Clin Invest", "link": null}, "BIBREF27": {"title": "Me chanisms of tumor-induced neutrophilia: constitutive production of colony-stimulating factors and their synergistic actions", "authors": [{"first": "M", "middle": ["Y"], "last": "Le E", "suffix": ""}, {"first": "K", "middle": [], "last": "Kaushansky", "suffix": ""}, {"first": "S", "middle": ["A"], "last": "Judkins", "suffix": ""}, {"first": "J", "middle": ["L"], "last": "Lottsfeldt", "suffix": ""}, {"first": "A", "middle": [], "last": "Waheed", "suffix": ""}, {"first": "R", "middle": ["K"], "last": "Shadduck", "suffix": ""}], "year": 1989, "venue": "Blood", "link": null}, "BIBREF28": {"title": "Physiology of the e xocrine pancreas", "authors": [{"first": "T", "middle": ["E"], "last": "Solomon", "suffix": ""}], "year": 1995, "venue": "", "link": null}, "BIBREF29": {"title": "A nove l proteinase, glucagon-de grading e nzyme, secre ted by a human pancreatic cance r ce ll line, HPC-YO", "authors": [{"first": "N", "middle": [], "last": "Yamaguchi", "suffix": ""}, {"first": "K", "middle": [], "last": "Koyama", "suffix": ""}, {"first": "Y", "middle": [], "last": "Yamamura", "suffix": ""}, {"first": "A", "middle": [], "last": "Okui", "suffix": ""}, {"first": "E", "middle": [], "last": "Konishi", "suffix": ""}, {"first": "T", "middle": [], "last": "Katayama", "suffix": ""}, {"first": "N", "middle": [], "last": "Katsuragi", "suffix": ""}, {"first": "T", "middle": [], "last": "Kurihara", "suffix": ""}, {"first": "H", "middle": [], "last": "Nakazato", "suffix": ""}, {"first": "J", "middle": [], "last": "Imanishi", "suffix": ""}], "year": 1995, "venue": "J Bioche m", "link": null}, "BIBREF30": {"title": "Long-term survival associated with me tastatic small ce ll carcinoma of the esophagus treate d by che mothe rapy, autologus bone marrow transplantation, and adjuvant radiation therapy", "authors": [{"first": "M", "middle": [], "last": "Mccullen", "suffix": ""}, {"first": "", "middle": [], "last": "Sk", "suffix": ""}, {"first": "P", "middle": ["J"], "last": "Winwood", "suffix": ""}, {"first": "C", "middle": ["A"], "last": "Loehry", "suffix": ""}, {"first": "D", "middle": ["M"], "last": "Parham", "suffix": ""}, {"first": "T", "middle": [], "last": "Hamblin", "suffix": ""}], "year": 1994, "venue": "Cancer", "link": null}}, "ref_entries": {}}
{"paper_id": "8332695", "_pdf_hash": "eb0937bafefd160070f993882851c5348fa848ee", "abstract": [], "body_text": [{"section": "", "text": "VOL. XXXII NO. 10 THE JOURNAL OF ANTIBIOTICS", "cite_spans": [], "ref_spans": []}, {"section": "LOW HEART AND SKIN TOXICITY OF A TETRAHYDROPYRANYL DERIVATIVE OF ADRIAMYCIN (THP-ADM) AS OBSERVED BY ELECTRON AND LIGHT MICROSCOPY", "text": "Sir: Cardiotoxicity and alopecia caused by anthracyclines were examined in an experimental model in which golden hamsters were treated three times a week with i.p. doses equivalent to 3/4 of the optimally oncostatic dosages against murine L1210 leukemia, where they were given at days 1, 5 and 9 after tumor cell inoculation. Each drug was administered to 21 hamsters, and every week 3 animals from each group and 3 control animals were sacrificed. Relevant tissues were quickly removed and immediately processed for examination.", "cite_spans": [], "ref_spans": []}, {"section": "LOW HEART AND SKIN TOXICITY OF A TETRAHYDROPYRANYL DERIVATIVE OF ADRIAMYCIN (THP-ADM) AS OBSERVED BY ELECTRON AND LIGHT MICROSCOPY", "text": "In preceding publications1,2) it was shown, by electron microscopy (EM), that AD32 is less myocardiotoxic than adriamycin (ADM), detorubicin (DTR), daunorubicin (DNR), 4'-epiadriamycin (eADM), adriamycin hydrochloride (ADMh) and rubidazon (RBZ); and that aclacinomycin (ACM) is less cardiotoxic than AD32. By light microscopic (LM) studies of skin, it was also observed that ACM and AD32 preserved the normal histological structures of skin, without causing alopecia, as contrasted with the 6 other anthracyclines which caused marked atrophy of all epidermic layers and loss of hair (alopecia)1,2).", "cite_spans": [], "ref_spans": []}, {"section": "LOW HEART AND SKIN TOXICITY OF A TETRAHYDROPYRANYL DERIVATIVE OF ADRIAMYCIN (THP-ADM) AS OBSERVED BY ELECTRON AND LIGHT MICROSCOPY", "text": "The most recent anthracycline studied by these techniques is THP-ADM, a new Japanese drug3), at a dosage of 4 mg/kg i.p. This communication, briefly reports our findings concerning the EM alterations of the myocardium, the LM lesions of the skin and the mortality of this drug as compared with those of the 8 preceding anthracyclines studied.", "cite_spans": [], "ref_spans": []}, {"section": "LOW HEART AND SKIN TOXICITY OF A TETRAHYDROPYRANYL DERIVATIVE OF ADRIAMYCIN (THP-ADM) AS OBSERVED BY ELECTRON AND LIGHT MICROSCOPY", "text": "Mortality was very high for the animals receiving the first 6 drugs (ADM, DTR, DNR, eADM, ADMh and RBZ), and all animals died before the end of the 4th week of treatment. By contrast, the mortality was very low for animals receiving the other three drugs (ACM, AD32, and THP-ADM). Only one out of 21 ACM and AD32 treated hamsters died during the 4 weeks of treatment, and there were no deaths in the group of THP-ADM treated animals at the end of the 4th week of treatment. As with ACM and AD32 treated animals, all THP-ADM treated hamsters preserved their good general status, without loss of weight and without digestive trouble. All animals treated with the other six anthracyclines (ADM, etc.) showed 30% to 40% weight losses and severe digestive troubles with severe diarrhoea.", "cite_spans": [], "ref_spans": []}, {"section": "LOW HEART AND SKIN TOXICITY OF A TETRAHYDROPYRANYL DERIVATIVE OF ADRIAMYCIN (THP-ADM) AS OBSERVED BY ELECTRON AND LIGHT MICROSCOPY", "text": "At the end of the first and second weeks of treatment, EM examination of the myocardium of both the THP-ADM and the ACM treated hamsters showed very rare and mild lesions. Some myocytes had swelling of the mitochondriae, clearing of their matrices, and lysis of the crests. Generally, mitochondriae, myofilaments and intercalated discs were as well preserved as those in the controls. The myocardium of all animals treated with ADM, DTR, DNR, eADM, ADMh and RBZ showed very severe alterations by EM, viz., swelling of mitochondriae with lysis of their crests, dilation of sarcoplasmic reticulum, separation and lysis of myofilaments with disruption of z-band registry, separation of fascia adherens of intercalated discs, vacuolization of the cytoplasma and formation of myelinic figures. At the end of the first and second weeks of AD32 treatment, lesions in these animals were less marked than those seen in the animals treated with the preceding 6 antibiotics but changes were apparent in the mitochondriae, the myofilaments and intercalated discs.", "cite_spans": [], "ref_spans": []}, {"section": "LOW HEART AND SKIN TOXICITY OF A TETRAHYDROPYRANYL DERIVATIVE OF ADRIAMYCIN (THP-ADM) AS OBSERVED BY ELECTRON AND LIGHT MICROSCOPY", "text": "At the end of the 4th week of treatment, all surviving THP-ADM treated hamsters had very mild and rare EM alterations of their myocardium, with moderate lesions of the mitochondriae, myofilaments and intercalated discs.", "cite_spans": [], "ref_spans": []}, {"section": "LOW HEART AND SKIN TOXICITY OF A TETRAHYDROPYRANYL DERIVATIVE OF ADRIAMYCIN (THP-ADM) AS OBSERVED BY ELECTRON AND LIGHT MICROSCOPY", "text": "Two months after THP-ADM treatment had been terminated, an EM study of the myocardium of sacrificed animals revealed that there was recovery in the myocardial alterations, as was also observed with ACM and AD32 treated hamsters1,2). The myofibrils and mitochondriae were generally as well preserved as those in the controls.", "cite_spans": [], "ref_spans": []}, {"section": "LOW HEART AND SKIN TOXICITY OF A TETRAHYDROPYRANYL DERIVATIVE OF ADRIAMYCIN (THP-ADM) AS OBSERVED BY ELECTRON AND LIGHT MICROSCOPY", "text": "LM studies of the skins of the THP-ADM treated animals showed normal histologic structures of the epidermic layers and hair (without alopecia) as in ACM and AD32 treated animals, even after 4 weeks of treatment. Histopathologic studies of the skins of the animals treated with the six other groups of antibiotics (ADM, etc.) showed degenerative lesions with very marked atrophy of epidermic layers and loss of hair (alopecia). ", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Electron microscopic studies of the heart and light microscopic studies of the skin after treatment of golden hamsters with adriamycin, detorubicin, AD32 and aclacinomycin", "authors": [{"first": "D", "middle": ["; V"], "last": "Dantchev", "suffix": ""}, {"first": "M", "middle": [], "last": "Slioussartchouk", "suffix": ""}, {"first": "M", "middle": [], "last": "Paintrand", "suffix": ""}, {"first": "C", "middle": [], "last": "Hayat", "suffix": ""}, {"first": "", "middle": [], "last": "Bourut &amp; G", "suffix": ""}, {"first": "", "middle": [], "last": "Mathe", "suffix": ""}], "year": 1979, "venue": "Cancer Treat. Rep", "link": "23536766"}, "BIBREF1": {"title": "Ultrastructural study of the cardiotoxicity and light microscopic findings of the skin after treatment of golden hamsters with 8 different anthracyclines. Recent Results in Cancer Research", "authors": [{"first": "D", "middle": ["; V"], "last": "Dantchev", "suffix": ""}, {"first": "M", "middle": [], "last": "Slioussartchouk", "suffix": ""}, {"first": "C", "middle": [], "last": "Pain-Trand", "suffix": ""}, {"first": "M", "middle": [], "last": "Bourut", "suffix": ""}, {"first": "", "middle": [], "last": "Hayat &amp; G", "suffix": ""}, {"first": "", "middle": [], "last": "Maths", "suffix": ""}], "year": 1979, "venue": "", "link": null}, "BIBREF2": {"title": "Tetrahydropyranyl derivatives of daunomycin and adriamycin", "authors": [{"first": "H", "middle": ["; Y"], "last": "Umezawa", "suffix": ""}, {"first": "M", "middle": [], "last": "Takahashi", "suffix": ""}, {"first": "H", "middle": [], "last": "Kinoshita", "suffix": ""}, {"first": "T", "middle": [], "last": "Naganawa", "suffix": ""}, {"first": "M", "middle": [], "last": "Masuda", "suffix": ""}, {"first": "K", "middle": [], "last": "Ishizuka", "suffix": ""}, {"first": "", "middle": [], "last": "Tatsuta &amp; T", "suffix": ""}, {"first": "", "middle": [], "last": "Takeuchi", "suffix": ""}], "year": 1979, "venue": "J. Antibiotics", "link": "37183721"}}, "ref_entries": {}}
{"paper_id": "8332850", "_pdf_hash": "d9f313854b9feaf04e1d91cf9f2dfbfff06e4a07", "abstract": [], "body_text": [{"section": "", "text": ": Characterization of the molecular markers surrounding RTN4IP1 in the four families.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "(A) Physical map of the chromosome 6 region flanking RTN4IP1. Distances between RTN4IP1 and the markers are indicated above the line. (B) For each marker, the sequence of the forward and reverse primers is provided, together with the minimal and maximal sizes of the amplified fragment, and their position on chromosome 6. (C) Size in nucleotides of the markers in affected persons, parents and wild-type alleles in family I, II and III on the left and family IV on the right. Colocalization of RTN4IP1 with mitochondria in (A) and with the endoplasmic reticulum in (B). NIH3T3 cells transfected by a plasmid expressing RTN4IP1-EYFP fusion protein, were fixed using 4% PFA for 20 min at room temperature and rinsed twice with PBS, then permeabilized using a blocking solution containing 0.1% Triton X-100, 5% donkey serum in PBS. Primary antibodies were in (A) mouse antibodies to ATP synthase (Millipore, MAB3494, dilution 1:1000) and in (B) rabbit polyclonal antibodies to GRP78 (Abcam, ab21685, dilution 1:500), incubated overnight at 4\u00b0C and visualized using Alexa594-labeled secondary antibodies at a dilution of 1:1000 (Jackson ImmunoResearch). After 2 hours incubation, cells were rinsed twice with PBS for 10 min and incubated with a Hoechst 33242 solution at 1\u00b5g/ml for 5 min. Finally, cells were rinsed once for 10 min and coverslips were mounted using fluorescence Mounting Medium (Dako, S3023). Images were captured with an AxioImager microscope (Zeiss). (C) Mitochondria were isolated from control fibroblasts as described (Wittig, I., Braun, H.P., Sch\u00e4gger, H. (2006) . Blue Native PAGE. Nat. Protoc. 1, 418-428.), and resuspended in mitochondrial buffer (mannitol 210mM, sucrose 70mM, EDTA 1mM and HEPES 10mM pH 7.5) containing (+) or not (-) proteinase K (50\u00b5g/ml), without (lanes 1 and 2) or with increasing concentrations of digitonin (lanes 3 to 8: 0.5, 1, 2, 3, 4 and 5 mg/ml) or with 2% Triton X-100 (lane 9, Trit.). After 30 minutes on ice, proteolysis was ended by adding 5mM PMSF and Laemli sample buffer, and heating at 95\u00b0C for 15 minutes. Samples (100\u00b5g of mitochondrial proteins) were analyzed by Western blotting using monoclonal mouse anti-RTN4IP1 (Abcam, dilution 1:1000), anti-BCL-2 (outer membrane, BD Biosciences, dilution 1:1000), polyclonal rabbit anti-OPA1 (inter membrane space, Abcam, dilution 1:300) and anti-MCU (inner membrane, Abcam, dilution 1:1000) antibodies. The direct proteolysis of RTN4IP1 as that of BCL2, in absence of digitonin treatment suggests that RTN4IP1 is located on the outer membrane, while OPA1 from the inter membrane space, is protected from low concentrations of digitonin, and MCU from the inner membrane is protect from the highest concentrations of digitonin. ", "cite_spans": [], "ref_spans": []}], "bib_entries": {}, "ref_entries": {"FIGREF0": {"text": "Figure S2: Subcellular localization of RTN4IP1.", "type": "figure"}, "FIGREF1": {"text": "Figure S3: UV light sensitivity of RTN4IP1 mutated fibroblasts.", "type": "figure"}, "TABREF0": {"text": "Clinical features of persons with optic neuropathy and RTN4IP1 mutations*best corrected visual acuity measured in decimal values with Snellen chart; nd: not done; LE: left eye; RE: right eye; retard: retardation; y: years", "type": "table"}}}
{"paper_id": "8332928", "_pdf_hash": "cb995fd48cd566747b5856da1def3e51d3b2cb8f", "abstract": [], "body_text": [], "bib_entries": {"BIBREF3": {"title": "Lipid Metabolism in the Normoxic and Ischaemic Heart", "authors": [{"first": "J", "middle": ["F"], "last": "Koster", "suffix": ""}, {"first": "P", "middle": [], "last": "Biemond", "suffix": ""}, {"first": "H", "middle": [], "last": "Stare", "suffix": ""}], "year": 1986, "venue": "", "link": "9805094"}, "BIBREF5": {"title": "Oxygen Radicals in Cerebral Ischemia, Cerebrovascular Diseases", "authors": [{"first": "H", "middle": ["A"], "last": "Kontos", "suffix": ""}], "year": 1989, "venue": "", "link": null}, "BIBREF17": {"title": "New Trends in Clinical Neuropharmacology", "authors": [{"first": "S", "middle": [], "last": "Stolc", "suffix": ""}, {"first": "L", "middle": [], "last": "Horakova", "suffix": ""}], "year": 1988, "venue": "", "link": null}, "BIBREF18": {"title": "Ischemia-reperfusion injury: Role of oxygen-derived free radicals", "authors": [{"first": "R", "middle": ["J"], "last": "Korthuis", "suffix": ""}, {"first": "D", "middle": ["N"], "last": "Granger", "suffix": ""}], "year": 1986, "venue": "Physiology of Oxygen Radicals", "link": "20653979"}}, "ref_entries": {}}
{"paper_id": "8332999", "_pdf_hash": "cc167efc58b3a8d9601a5175e16ba007eb7fc1f2", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Functional nanoscale electronic devices assembled using silicon nanowire building blocks", "authors": [{"first": "Y", "middle": [], "last": "Cui", "suffix": ""}, {"first": "C", "middle": ["M"], "last": "Lieber", "suffix": ""}], "year": 2001, "venue": "Science", "link": "1496968"}, "BIBREF1": {"title": "Mechanical Properties of Nanosprings", "authors": [{"first": "F", "middle": [], "last": "Alexandre", "suffix": ""}, {"first": "Douglas", "middle": ["S"], "last": "Da Fonseca", "suffix": ""}, {"first": "", "middle": [], "last": "Galvao", "suffix": ""}], "year": 2004, "venue": "Phys. Rev. Lett", "link": null}, "BIBREF2": {"title": "Electromagnetic wave absorption property of carbon microcoils in 12-110 GHz region", "authors": [{"first": "S", "middle": [], "last": "Motojima", "suffix": ""}, {"first": "Y", "middle": [], "last": "Noda", "suffix": ""}, {"first": "S", "middle": [], "last": "Hoshiya", "suffix": ""}, {"first": "Y", "middle": [], "last": "Hishikawa", "suffix": ""}], "year": 2003, "venue": "J. Appl. Phys", "link": "119588070"}, "BIBREF3": {"title": "Spontaneous Polarization-Induced Nanohelixes, Nanosprings, and Nanorings of Piezoelectric Nanobelts", "authors": [{"first": "X", "middle": ["Y"], "last": "Kong", "suffix": ""}, {"first": "Z", "middle": ["L"], "last": "Wang", "suffix": ""}], "year": 2003, "venue": "Nano. Lett", "link": "34119691"}, "BIBREF4": {"title": "The texture of catalytically grown coil-shaped carbon nanotubules", "authors": [{"first": "X", "middle": ["B"], "last": "Zhang", "suffix": ""}, {"first": "X", "middle": ["F"], "last": "Zhang", "suffix": ""}, {"first": "D", "middle": [], "last": "Bernaerts", "suffix": ""}, {"first": "G", "middle": ["T"], "last": "Vantendeloo", "suffix": ""}, {"first": "S", "middle": [], "last": "Amelinckx", "suffix": ""}, {"first": "J", "middle": [], "last": "Vanlanduyt", "suffix": ""}, {"first": "V", "middle": [], "last": "Ivanov", "suffix": ""}, {"first": "J", "middle": ["B"], "last": "Nagy", "suffix": ""}, {"first": "P", "middle": [], "last": "Lambin", "suffix": ""}, {"first": "A", "middle": ["A"], "last": "Lucas", "suffix": ""}], "year": 1994, "venue": "Europhys. Lett", "link": "123627789"}, "BIBREF5": {"title": "Three-Dimensional Nanosprings for Electromechanical Sensors", "authors": [{"first": "D", "middle": ["J"], "last": "Bell", "suffix": ""}, {"first": "Y", "middle": [], "last": "Sun", "suffix": ""}, {"first": "L", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "L", "middle": ["X"], "last": "Dong", "suffix": ""}, {"first": "B", "middle": ["J"], "last": "Nelson", "suffix": ""}, {"first": "D", "middle": [], "last": "Grutzmacher", "suffix": ""}], "year": 2005, "venue": "Digest Tech. Papers the 13 th International Conference on Solid-State Sensors and Actuators (Transducers'05)", "link": "110205932"}, "BIBREF6": {"title": "Three-Dimensional Nanostructure Fabrication by Focused-Ion-Beam Chemical Vapor Deposition", "authors": [{"first": "Shinji", "middle": [], "last": "Matsui", "suffix": ""}], "year": 2003, "venue": "Digest Tech. Papers the 12 th International Conference on Solid-State Sensors and Actuators (Transducers'03)", "link": "10989406"}, "BIBREF7": {"title": "Nano-Net Fabrication on the Glass Capillary by Focused-Ion-Beam Chemical-Vapor-Deposition", "authors": [{"first": "Reo", "middle": [], "last": "Kometani", "suffix": ""}, {"first": "Takayuki", "middle": [], "last": "Hoshino", "suffix": ""}, {"first": "Kazuhiro", "middle": [], "last": "Kanda", "suffix": ""}, {"first": "Yuichi", "middle": [], "last": "Haruyama", "suffix": ""}, {"first": "Takashi", "middle": [], "last": "Kaito", "suffix": ""}, {"first": "Jun-Ichi", "middle": [], "last": "Fujita", "suffix": ""}, {"first": "Masahiko", "middle": [], "last": "Ishida", "suffix": ""}, {"first": "Yukinori", "middle": [], "last": "Ochiai", "suffix": ""}, {"first": "Shinji", "middle": [], "last": "Matsui", "suffix": ""}], "year": 2005, "venue": "Digest Tech. Papers the 13 th International Conference on Solid-State Sensors and Actuators (Transducers'05)", "link": "23781315"}, "BIBREF8": {"title": "Surface damage formation during ion-beam thinning of samples for transmission electron microscopy", "authors": [{"first": "J", "middle": [], "last": "Mccaffrey", "suffix": ""}, {"first": "M", "middle": [], "last": "Phaneufc", "suffix": ""}, {"first": "L", "middle": [], "last": "Madsen", "suffix": ""}], "year": 2001, "venue": "Ultramicroscopy", "link": "33428652"}, "BIBREF9": {"title": "FIB-induced damage in silicon", "authors": [{"first": "S", "middle": [], "last": "Rubanov", "suffix": ""}, {"first": "P", "middle": ["R"], "last": "Munroe", "suffix": ""}], "year": 2004, "venue": "J. Microscopy", "link": "20939008"}, "BIBREF10": {"title": "3D assembly using the FIB stress-introducing process: (1) initial 2D pattern", "authors": [], "year": "", "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "8333443", "_pdf_hash": "c1ef40be7d4004be2355653ba77627d88f78dab0", "abstract": [{"section": "Abstract", "text": "We present a simple and eficient protocol for mutual exclusion in synchronous, message-passing distributed systems subject to failures. ", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "In this paper we describe a very simple, distributed mutual exclusion protocol by which a process can gain the right to execute for a fixed time interval A without interference from other processes. Our protocol is directly inspired by backoff protocols for multiple access channels; the collision detection protocol of Ethernet is the most well-known example. In Ethernet, a process wishing to send on an (apparently) empty channel simply does so. If it detects that its send collided with another process', it \"backs off\" for a random delay and tries again later. Here we use similar principles to derive a mutual exclusion algorithm for synchronous message-passing systems that is deterministically safe and that ensures entry to the \"critical section'.' with probability one.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "The performance of our protocol can generally be characterized in terms of amortized system response time [ 5 ] .", "cite_spans": [], "ref_spans": []}, {"section": "Michael K. Reiter Secure Systems Research Department", "text": "Bell Labs, Lucent Technologies 600 Mountain Ave., Murray Hill, NJ 07974 USA reiter @ research.bel1-labs.com", "cite_spans": [], "ref_spans": []}, {"section": "Michael K. Reiter Secure Systems Research Department", "text": "The amortized system response time is the mean delay that each o f t processes incurs before entering the critical section, assuming that all t (and no others) start contending at the same time. We prove an upper bound on the expected amortized system response time of O ( A t ) , thereby showing that our protocol is adaptive in that the amortized system response time is independent of the maximum number of processes that might contend. In addition, in the case of no contention, the delay a process incurs before entering the critical section is merely one round-trip message delay on the network, and thus is independent of A.", "cite_spans": [], "ref_spans": []}, {"section": "Michael K. Reiter Secure Systems Research Department", "text": "Fault tolerance is a feature of our protocol. We present our protocol in a system model with distinct clients and servers, motivated by the system in which we have implemented it, described later. Clients, which contend for mutual exclusion, may crash without affecting the protocol. In particular, since a client is granted exclusion for a fixed time period A-and there is no designated \"unlock\" operation that a client must perform-a client's failure after it succeeds in gaining exclusion does not preclude other clients from subsequently gaining exclusion after the A time period expires. Moreover, our protocol masks the arbitrary (Byzantine) failure of a threshold number of servers.", "cite_spans": [], "ref_spans": []}, {"section": "Michael K. Reiter Secure Systems Research Department", "text": "We use this mutual exclusion protocol to develop a protocol by which operations on a replicated object can be serially ordered. Despite the fact that this ordering protocol is deterministically safe even in an asynchronous systemand our mutual exclusion protocol is not-the mutual exclusion protocol is key to ensuring that operations are ordered and complete (with probability one) once the system stabilizes. Our ordering protocol orders arbitrarily many operations on the object as soon as a single contender gains access to the critical section.", "cite_spans": [], "ref_spans": []}, {"section": "Michael K. Reiter Secure Systems Research Department", "text": "Aside from always-safe operation ordering, we have found our mutual exclusion protocol useful for other tasks within the system that motivated it, called Fleet [ 161. Fleet supports highly available, shared data for clients using an infrastructure of servers that may suffer arbitrary (Byzantine) failures. In order to detect the presence of faulty servers, statistical fault detection algorithms mine for evidence of faulty servers in the responses they return [I] . Since detection is most accurate when data is accessed sequentially, Fleet attempts to serialize data accesses, and we employ the mutual exclusion protocol described here for this purpose. Our mutual exclusion protocol has the useful property that it remains probabilistically live even during periods of instability (asynchrony) in the system.' So, while fault detection may suffer during periods of instabiliity, the nonblocking properties of the Fleet data access protocols are never compromised.", "cite_spans": [], "ref_spans": []}, {"section": "Michael K. Reiter Secure Systems Research Department", "text": "The rest of this paper is structured as follows. We review related work in Section 2 and more precisely state our system model in Section 3. In Section 4 we describe our mutual exclusion protocol, and we outline certain optimizations to it in Section 5. We then develop our ordering protocol based upon it in Section 6. A proof of correctness for our ordering protocol can be found in Section 7.", "cite_spans": [], "ref_spans": []}, {"section": "Related work", "text": "In Singhal's taxonomy [21], the mutual exclusion protocol we present is a \"Maekawa-type\" protocol, following [12] . In this class of protocols, a process pi requests permission to enter the critical section from a set Qi of processes, such that Qi f l Qj # 8 for all i, j . Each process in a request set Qi grants exclusive access to the critical section until it is exited, and pi is allowed to enter the critical section only if all processes in Qi grant pi access. Due to the intersection property of request sets and exclusive locking at each process in a request set, only one process can be in the critical section at any time. Also due to these properties, however, Maekawa-type algorithms are generally prone to deadlock and consequently require extra messages to 'detect and recover from deadlocks. Deadlock-free Maekawa-type protocols, such as [ 10,201, have been proposed by strengthening the constraints on request sets so that for all i , j , eitherpi E Qj o r p j E Qi [21]. However, in our context, this strengthening is not possible because the clients requesting mutual exclusion are distinct from the servers that comprise the request sets. Clients cannot be added to reque., qt sets because they are transient and because the population of clients that might contend is not known a priori. The protocol that we present here works with Maekawa's original (weaker) intersection property Qi n Q j # 8 in the fault model addressed in [12]. At the same time, our protocol is not prone to deadlock.", "cite_spans": [], "ref_spans": []}, {"section": "Related work", "text": "'Formally, probabilistic liveness during periods of instability holds only if the scheduling adversary is nonadaptive. That is, for any execution, the scheduler chooses the distribution from which message delays will be drawn before the protocol execution begins; it cannot change this distribution in response to events in the execution. We omit further discussion of this issue here, except to note that in practice, this is an assumption we are willing to adopt for Fleet.", "cite_spans": [], "ref_spans": []}, {"section": "12", "text": "As discussed in Section I , we evaluate our protocol based on the amortized system response time that it achieves. This measure was introduced in the context of shared-memory mutual exclusion algorithms [ 5 ] , where there are examples boasting amortized system response times of O ( t ) or even O(1) (e.g., [3, 51). An alternative to using our protocol is to employ one of these algorithms, using a distributed protocol to emulate each shared variable it uses (e.g., [ 151). While the resulting algorithm would have superior amortized system response time (asymptotically), the performance in practice would be far worse than our prolocol in the main case we care about-i.e., contentionfree performance-due to the overheads of the variable emulation protocols. This also holds for backoff-style mutual exclusion algorithms explored for the shared-memory setting (e.g., [ 2 ] , which assumes even stronger objects than shared variables).", "cite_spans": [], "ref_spans": []}, {"section": "12", "text": "The manner in which we build upon our mutual exclusion protocol to order operations on data objects in an asynchronous system is similar to work of Fetzer and Cristian on consensus in the tinied asynchronous model [6], and the works of Lamport on Paxos [ 1 11 and of Keidar and Dolev on extended3-phase commit (E3PC) [8] . These works compose a (not necessarily safe) mutual exclusion protocol with a commit protocol to derive solutions to problems equivalent to our ordering problem. Paxos and E3PC, while building on mutual exclusion protocols, do not propose mutual exclusion implementations of their own. Fetzer and Cristian employ a mutual exclusion protocol that rotates the preference for access to the critical section among the possible contenders in sequence, but enables the next preferred contender to be bypassed without delay if that contender is unavailable. As such, its mutual exclusion primitive is also adaptive in the sense above. In order to achieve this, however, the: protocol relies on clock synchronization among the participating servers. Clock synchronization is not required by our protocol. More generally, however, our work contributes relative to all the above by providing a new and efficient mutual exclusion primitive, and by admitting arbitrary (Byzantine) server failures in our ordering protocol.", "cite_spans": [], "ref_spans": []}, {"section": "System model", "text": "Our system model divides the set of processes into clients and servers. We assume a fixed, known set I / of n servers and an arbitrary, finite, but unknown number of clients. The protocol of a process is described in terms of event handlers that are triggered by the arrival of events such as the receipt of a message, the tick of a local clock, or input from a calling application. Once triggered, we assume that Ihe event handler runs to completion without delay.", "cite_spans": [], "ref_spans": []}, {"section": "System model", "text": "Processes that obey their protocol specifications and receive (and handle) infinitely many events in an infinite run are called correct, Other processes are calledfuully. Up to a threshold b of servers may fail, and may do so arbitrarily (Byzantine failures); i.e., the event handlers of a faulty server may not conform to their specifications. While any number of clients may fail, clients are assumed to fail only by crashing, i.e., simply by no longer receiving events. This restriction of client failures to crashes may seem unrealistic when servers are presumed to fail arbitrarily. However, typically little can be done to protect an application from Byzantine clients, as such clients can always corrupt an object's data by submitting requests with incorrect content. One way of dealing with this in practice is to allow the creator of an object to prohibit untrusted clients from modifying objects using access control mechanisms that remain in force at correct servers provided that b or fewer servers fail (even arbitrarily). Thus, our assumption of client crashes in practice reduces to an assumption about the clients trusted to modify that object by its creator.", "cite_spans": [], "ref_spans": []}, {"section": "System model", "text": "We assume that the local clock of each correct process ticks at the same rate as real time, so that a process can accurately measure the passage of a chosen, real-time timeout period. Since the timeout periods involved in our protocols would be very short in practice, this is a reasonable assumption. We do not assume that clocks at processes are synchronized.", "cite_spans": [], "ref_spans": []}, {"section": "System model", "text": "Processes communicate by message passing. We assume that communication channels provide at-most-once message transmission: if pl and p2 are correct, then p2 receives any message m from pl at most once, and then only if pl sent m to pa. (Obviously, we further assume that p l never sends the same message twice to p 2 , which it can implement by, e.g., including a unique sequence number in the message.) There is a globally known constant 6. We say that a run is stable ut real time T if for each correct client, there exists a quorum of correct servers such that any message sent at time T' 2 T between that client and a server in that quorum arrives by time T' + 6. The definition of quorum that we use will be given in Section 4. A run is synchronous if it is stable at the time the run begins. Though processes communicate by message passing, we present our protocols in terms of remote operation invocations on servers, for simplicity of presentation. In synchronous runs, we also neglect the processing time of such remote invokations and assume that they complete instantaneously. We will return to explicit message passing events when necessary to prove correctness.", "cite_spans": [], "ref_spans": []}, {"section": "Mutual exclusion", "text": "In this section we present our mutual exclusion protocol by which clients can contend for the opportunity to run for A time units without interference by other clients. More precisely, there is an operation contend that a client can invoke. When the invocation returns at the client, the client then has A time units in which to execute in isolation. After A time units pass, however, another client's contend operation may return, As discussed in Section 1, in addition to requiring mutual exclusion, we will also be concerned with the system response time.", "cite_spans": [], "ref_spans": []}, {"section": "Mutual exclusion", "text": "The idea of the protocol is for clients to access servers simply to find out whether other clients are simultaneously contending. In order to provide mutual exclusion, every pair of clients must access 2b + 1 correct servers in common. If a client detects that another client is contending, it backs off for a random delay, chosen from a distribution that adapts to the number of contending clients. Intuitively, clients thus delay an amount of time proportional to the number of simultaneously contending clients, while eventually, when they sufficiently space their contentions, each succeeds. More precisely, the protocol is probabilistically live in a synchronous system, i.e., with probability 1 some client's contend operation returns.", "cite_spans": [], "ref_spans": []}, {"section": "Mutual exclusion", "text": "The requirement that any two clients access at least 2b+ 1 common correct servers can be satisfied if each client queries the servers according to a special variant of masking quorum systems [ In this figure, ' ' 11' ' denotes concurrent invocation of statements, and \" d t~ S\" denotes the selection of an element of set S uniformly at random and assignment of that element to d. At a high level, the protocol executes as follows.", "cite_spans": [], "ref_spans": []}, {"section": "Mutual exclusion", "text": "When presented with a request from a client, the server re- where s is a \"retry value\" that records the number of times the client has previously queried servers in this contend operation. That is, clients employ an exponential backoff strategy: the expected duration of a client's delay is proportional to twice its delay during its last retry.", "cite_spans": [], "ref_spans": []}, {"section": "Mutual exclusion", "text": "The correctness of this protocol is proved easily in the following lemma: As discussed previously, t h e m e a s u r e o f quality on which w e focus for our mutual exclusion protocol is amortized system response time. T h e following l e m m a implies that the expected amortized s y s t e m response t i m e i s O(At). In t h e mutual exclusion protocol as presented in Figure 1 a n d analyzed in Lemma 2, client backoff w a s exponential a s a function of t h e n u m b e r o f retries in its contend operation.", "cite_spans": [], "ref_spans": []}, {"section": "Mutual exclusion", "text": "Even though exponential backoff yields O(At) amortized system response time, analysis of backoff strategies in the context of multiple access channels shows that it performs less well in other measures than various polynomial backoff strategies (e.g ., [ 7 ] ) . While this analysis does not apply to our case directly, we expect that similar properties hold in our setting, and thus in practice it may be preferable to experiment with other backoff strategies.", "cite_spans": [], "ref_spans": []}, {"section": "Improvements and optimizations for the mutual exclusion protocol", "text": "In this section we sketch several possible improvements and optimizations to the mutual exclusion protocol. The implementation of the proposed ideas and the assessment of their practical implications are the subject of our ongoing work.", "cite_spans": [], "ref_spans": []}, {"section": "Improvements and optimizations for the mutual exclusion protocol", "text": "Avoiding backoff by breaking symmetry If the application is such that one client c repeatedly contends with little delay between contentions, then we can improve c's response time if c does not back off between consecutive try attempts. The backoff protocol will adequately space the other client's retries, and c's asymmetric strategy will enable it to gain mutual exclusion quickly.", "cite_spans": [], "ref_spans": []}, {"section": "Enqueing client requests", "text": "In this optimization, each server maintains an internal data structure, called delayed reply fist, where it records IDS of the clients whose try requests arrive while the server is locked. As soon as the server's status becomes FREE, it goes through the records in the delayed reply list and sends FREE to the client with the lowest ID and LOCKED to everyone else. This optimization may allow the lowest ranking contending client a smooth entry to the critical section, without backoff.", "cite_spans": [], "ref_spans": []}, {"section": "Making mutex safe", "text": "It is possible to make the protocol safe even during instability periods if clients disregard those replies to their try() requests that arrive after 26 time units. However, in practice, this optimization can negatively affect the throughput of the applications whose implementation does not require the underlying mutex to be safe (e.g., the operation ordering presented in Section 6).", "cite_spans": [], "ref_spans": []}, {"section": "Making mutex safe", "text": "Parameterized contend In order to allow for better adaptation to changing system conditions and to application needs, it is possible to make A a parameter of the contend operation (and, consequently, of the try request) instead of being a system-wide constant. Both safety and the expected delay become parameterized by the actual A's employed.", "cite_spans": [], "ref_spans": []}, {"section": "Operation ordering", "text": "As discussed in Section 1, one of the main applications for the mutual exclusion protocol of Section 4 is a protocol for serializing operations on replicas of an object in a distributed system. In order to perform an operation o on the replicated object, a client application submits the operation for execution. The properties that our ordering protocol satisfies are the following:", "cite_spans": [], "ref_spans": []}, {"section": "Operation ordering", "text": "Order There is a well-defined sequence in which submitted operations are applied, and the result of each operation that returns is consistent with that sequence.", "cite_spans": [], "ref_spans": []}, {"section": "Operation ordering", "text": "Liveness If a run is eventually stable, then every operation submitted by a correct client is performed with probability one, and if performed, its result is returned to the client.", "cite_spans": [], "ref_spans": []}, {"section": "Operation ordering", "text": "Due to the Order and Liveness properties, our protocol emulates state machine replication [ 191. Among others, our implementation supports the following distinct features: First, the ordering responsibilities are delegated to the clients, which are not Byzantine by assumption. This way, we need not employ digital signatures or signaturelike cryptographic constructions, thus improving the performance and scalability of the protocol. Second, our protocol makes progress by updating only quorums of replicas, which helps to achieve better load balancing and enhances scalability. Third, our protocol supports nondeterministic operations, since each operation is applied at a client and the resulting object state is then copied back to servers.", "cite_spans": [], "ref_spans": []}, {"section": "Operation ordering", "text": "Some modern protocols for implementing state machine replication in Byzantine environments (e.g., [ 17, 9, 41) assume a less restricted failure model by allowing arbitrary client failures. In these solutions, clients do not actively participate in the protocol, but serve merely as users that inject new operations into the server universe and collect responses. While this approach prevents Byzantine clients from interfering with the ordering protocol, it does not prevent attacks in which faulty clients corrupt object's data by submitting operations with arbitrary parameter values. Thus, in practice, the added value of providing protection against Byzantine client failures in terms of the system security guarantees is outweighed by the performance and scalability gain resulting from delegating ordering responsibilities to the clients.", "cite_spans": [], "ref_spans": []}, {"section": "Operation ordering", "text": "The detailed client and server programs are shown in Figure 2 and Figure 3 respectively. The client program for submit(o) consists of two threads executed concurrently. The first thread, described in lines 2.3-7, simply submits the operation o to the servers for execution and awaits responses. The second thread, lines 2.8-32, invokes operations to create a new state and commits states in a serial order; we call this the ordering thread. I f f and g are: functions, then f1g denotes a function such that (flg)(o) == g ( o ) if g(o) # I and f ( o ) otherwise; see line 3.24. The following subsections contain details about operations, states, and ranks that are essential to understanding the ordering thread.", "cite_spans": [], "ref_spans": [{"start": 66, "end": 74, "text": "Figure 3", "ref_id": "FIGREF2"}]}, {"section": "Operations and states", "text": "Our protocol works by applying an operation to ii state to produce a new state and a return result. A client submits an operation o to be performed by invoking submit(o). For simplicity of presentation, we assume that the same operation is never submitted by two distinct clients or twice by the same client. In practice, enforcing such uniqueness of operations can be implemented by each client labeling each of its operations with the client's identifier and a sequence number.", "cite_spans": [], "ref_spans": []}, {"section": "Operations and states", "text": "A state, denoted by (T (possibly with subscripts and/or superscripts), is an abstract data type that has the following interfaces:", "cite_spans": [], "ref_spans": []}, {"section": "Operations and states", "text": "a.version is an integer-valued field. It denotes the \"version'' of the state. This field can be set by the protocol manipulating the state. A state's interfaces are assumed to satisfy the following properties. First, a.reflects(o) = t r u e iff doOp(o) vias invoked on some previous state. In practice, this can be implemented by recording within the state the highest operation sequence number already performed for each client. Second, if (T is the result of applying operations (via do0p) to a prior instance (T' such that d.reflects(o) = false, g.reflects(o) = true, and cT.version = d.version + -1, then a.response(o) is defined and returns the result for operation o. Note that by this assumption, a.response(o) can be eliminated (\"garbage collected\") when o.version is incremented. In this way, the size of (T can be limited.", "cite_spans": [], "ref_spans": []}, {"section": "Operations and states", "text": "Aside from the instance of garbage collection just mentioned, we do not further elaborate on garbage collection here. The primary data structures that grow in our protocol as presented in Figures 2 and 3 are (i) the record of which client operations have been performed (to compute u.reflects(o)) and (ii) a response function maintained at each server that records the response for each client operation (see lines 3.34,24). In practice, eliminating unnecessary data from these structures can be achieved, for example, by propagating information among servers in the background (e.g., using the techniques of [ 131) to convey when information about a given operation can be purged from the system. Other optimizations are possible, e.g., that trade off passing complete states versus update suffixes.", "cite_spans": [], "ref_spans": [{"start": 188, "end": 203, "text": "Figures 2 and 3", "ref_id": "FIGREF2"}]}, {"section": "Rank", "text": "Each client executes the ordering thread of our protocol with an associated integer called its rank. We assume that no (WO clients ever adopt the same rank, which can be ensured, e.g., if each client's rank is formed with its identifier in the low-order bits. When invoking an operation on a server U in our protocol, a client always sends its current rank: as an argument to the invocation; this rank is denoted by r in u.get(r), u.propose(a, T ) and u.commit(a, r ) invocations. A server responds to only the highest-ranked client that has contacted it. In particular, if a server U is contacted by a client with a lower rank than another client to which it has already responded, then it throws a RankException that notifies the client of the higher rank under which another client contacted it. In order to get U to respond to it, the client will have to abort its current protocol execution, adjust its rank, and try again (starting at line 2.8).", "cite_spans": [], "ref_spans": []}, {"section": "Rank", "text": "The precise criteria that dictate when a client aborts its protocol run to adjust its rank are important to the liveness of our protocol. On the one hand, if a client aborts its protocol run based upon receiving a single RankException. then the client risks being aborted by a faulty server who in fact was not contacted by a higher ranking client. On the other hand, if the client requires b + 1 RankExceptions in order to abort, then the client may not abort even though b correct servers have been contacted by a higher-ranking client and thus will refuse to return responses to this client.", "cite_spans": [], "ref_spans": []}, {"section": "Rank", "text": "Our solution to this issue therefore mandates that the quorum system Q we employ satisfy the following property: For every B1, B2 s U with lBll = (Bzl = b, there exists Q E Q such that Q n (B1 U Bz) = 0. This restriction enables the client to complete its protocol run using quorums provided up to b correct servers respond with RankException. Consequently, whereas original masking quorum systems existed as long as n > 4b [ 141, this stronger constraint limits their existence to systems in which n > 6b (see Corollary 4.4 in [ 141). When a client is forced to adjust its rank due to receiving b + 1 RankExceptions, it does so by choosing a value larger than the maximum of all ranks reported by those RankExceptions.", "cite_spans": [], "ref_spans": []}, {"section": "Rank", "text": "We note that an alternative approach would be for clients to digitally sign (e.g., [IS] ) their ranks using a key available only to clients allowed to access the object (or a subset of them designated to execute the ordering protocol). When a scrver throws a RankException to a client, it passes the highest rank under which any client has contacted it, includ-1) submit (0):", "cite_spans": [], "ref_spans": []}, {"section": "Rank", "text": "2) waiting t true; contend(); ] until (pending = 0); a'.version t a'.version + 1;", "cite_spans": [], "ref_spans": []}, {"section": "Figure 2. Client side of ordering protocol", "text": "ing the digital signature on that rank from that client. The client receiving the RankException can verify the validity of the rank by verifying the digital signature on it. In this implementation, a client can abort its protocol run based on a single RankException with which the client receives a validly signed rank, since a faulty server cannot forge signatures. This approach imposes overheads in terms of key management and computation, and we therefore opt against it. In particular, digital signatures tend to be relatively intensive to compute and verify. While for a small number r of clients, digital signatures can be emulated using message authentication codes, this approach does not scale well.", "cite_spans": [], "ref_spans": []}, {"section": "Protocol overview", "text": "At a high level, the ordering thread of the protocol at a client works by first contending for mutual exclusion,, using the protocol of Section 4 (line 2.9). Once this contend returns, the protocol executes similarly to a 3-phase c:ommit protocol. It first invokes get on each server U in some quorum Qg\" to obtain the states last committed to U (0:) and last proposed to U ((TE\"); the rank proposer, of the: client who proposed a : \" ; and the current set pending, of pending operations submitted to U . The client then computes the following values: a' is set to be the state with the highest version number that has been committed to some correct server ((i.e., at least b + 1 servers) in Qget (lines 2.14-15). 0 upc is set to be the state proposed to some correct server (Le., at least b + l servers) in Qg\" by the h:ighestranking set of proposers (lines 2.16,33-43) .", "cite_spans": [], "ref_spans": []}, {"section": "Protocol overview", "text": "completed is set to be the highest version number of all states that the responses from the servers iin Qget reveal to be committed at a full quorum. In part.icular, if b + 1 servers report proposed states atC with version numbers larger than U , then a state with version v must be committed at a full quorum (line 2.17).", "cite_spans": [], "ref_spans": []}, {"section": "Protocol overview", "text": "'The client chooses which state (T to propose and commit to quorums based on these values. If oc has a version number larger than completed, then it will propose and com-. mit a' to ensure that c f gets committed to a full quorum (line 2.19). Its second choice will be to propose and commit the proposed state upc if its version number is larger than completed (line 2.21). Otherwise, it creates a new state by applying operations to a' (lines 2.23-24,44-5 1), and proposes and commits that state.", "cite_spans": [], "ref_spans": []}, {"section": "Protocol overview", "text": "The protocol ensures that each newly proposed object state (T' is derived from the state CT that has been most recently committed by applying operations in the pending sets of correct servers to (T (line 2.24). This is guaranteed as follows. If 0 has been committed to a full quorum, then (T' = U at each correct server in that quorum. This implies that any client that succeeds in invoking get at a full quorum evaluates (T' to (T, and applies any pending operations to it. If, on the other hand, (T has not been committed at a full quorum, then it is possible for clients to evaluate ac to a prior state. However, since U must be proposed to a full quorum before it is committed, any client that invokes get on a full quorum evaluates nPC to 0. The client will therefore complete the commitment of a (bypassing (T' since completed 2 aC.version) and then continue by applying new operations to a to derive a'.", "cite_spans": [], "ref_spans": []}, {"section": "Protocol overview", "text": "Kank is used to break ties between clients that attempt to propose different states simultaneously. Suppose that p and q each invoke get on a quorum of servers and obtain cc := a as above. ", "cite_spans": [], "ref_spans": []}, {"section": "Correctness proof of the ordering protocol", "text": "In this section we prove that Order and Liveness are satisfied by our protocol. Let M denote a finite set of methods that for any object state U , a rank r and an operation o, consists of get(.), propose(a, r ) , commit(a, r ) and submit(o).", "cite_spans": [], "ref_spans": []}, {"section": "Correctness proof of the ordering protocol", "text": "We assume that any method p E M can be invoked at a server u at most once throughout the execution. In practice such a requirement can be easily enforced using unique method identifiers composed of client identifier and the sequence number. Let p.rnnk be the rank with which method p is invoked. We consider the following system events: For a client p , let p.send(u, p ) be the client event that sends the method invocation p E M to server U, and let p.ret(u.p, p ) , be the client event triggered by the reply of the server U with return value p to a previously sent method p.", "cite_spans": [], "ref_spans": []}, {"section": "Correctness proof of the ordering protocol", "text": "A server event is a computation performed upon receiving g e t , propose, commit, or submit invocations from a client. The event that occurs at a server U as a result of the invocation of a p E M is denoted u.p. The code executed by a correct server upon reception of such an invocation is the code of the corresponding server method (see Figure 3) . This code executes to completion (return) atomically, with the exception of submit ; submit executes atomically until the sleep command, and its return constitutes a separate event. A faulty server can perform arbitrary computation steps upon reception of client invocations.", "cite_spans": [], "ref_spans": [{"start": 339, "end": 348, "text": "Figure 3)", "ref_id": "FIGREF2"}]}, {"section": "Correctness proof of the ordering protocol", "text": "We model the system execution as a countable set H of events partially ordered by -+ relation induced by the natural order of the method invocations and returns. We define the causal cone of an event e in H , denoted ccone(e, H ) , to be the subset of H such that Ve' E H , e' E ccone(e, H ) iff e' -+ e.", "cite_spans": [], "ref_spans": []}, {"section": "Correctness proof of the ordering protocol", "text": "If a client p invokes method p on every server U E S C U in H , then we will unite all p.send (u,p) ", "cite_spans": [], "ref_spans": []}, {"section": "H", "text": "For the following lemma, we introduce the following definition. For any p.propose(a,r), we define its closest complete propose to be p'.propose(a', r') such that p.propose(u,r); and (iii) there does not exist a comp\".propose(u\", r \" ) -+ p.propose(a, r ) . Note that any p.propose(a, r ) , other than the propose of a' at system initialization, has a closest complete propose, and that its closest complete propose is unique by Corollary 3.", "cite_spans": [], "ref_spans": []}, {"section": "H", "text": "(i) p'.propose(u', r') is complete; (ii) p'.propose(u', r') + H plete p\".propose (a\", r\") (a2, r g ) ) . That is, we suppose the result holds for any q'.propsse(a', T ' ) E ccone(q.propose(a2, T Z ) ) , and we prove the result for q.propose(a2, T Z ) . Let p.propose(C, T ) be the first complete propose invocation in the causal chain leading to p.propose(a1, T I ) such that 5.version = u1.version. By the induction hypothesis for 4.2, C = a l .", "cite_spans": [], "ref_spans": []}, {"section": "H", "text": "According to the protocol, the value of a2 is computed based on the values of ( 0 ; ; ar, proposeru, pending,) returned by each server U in some quorum ~g~~(~z ) in response to g.get(r2) invocation. Furthemore, if U is correct, then the value of each a:, a,P' and proposer,, is determined by some (not necessarily complete) propose invocation p'.propose(a', T ' ) E ccone(q.get(r2)). By applying results of Lemma 3, Corollary 3 and the induction hypothesis, we conclude the following: If T' 3 f , then the closest complete propose ofp'.propose(a', T ' ) is eitherp.propose (5, F ) or the one that causally follows p.propose(6, T ) . Therefore, either U' = (TI, or U' is a state that extends U I with some previously submitted operations. Otherwise, if T' < F , then the closest complete propose of p'.propose(u', T ' ) causally precedes p.propose (5, F ) and therefore, a'.version 5 5.version.", "cite_spans": [], "ref_spans": []}, {"section": "H", "text": "Once we know the possible values of U : , u u p C and proposer, as returned by q.get(rz), and given that any two quorums intersect by at least 2b + 1 servers, we derive that the value of U 2 computed in lines 2.14-24 satisfies the lemma results.0 Theorem 1 (Order) There is a well-deJinfid sequelwe in which submitted operations are applied and the result of each operation that returns is consistent with that sequence. Theorem 2 (Liveness) If a run is eventually stable, then every operation submitted by a correct client is petjhrmed with probability one, and $performed, its result is rerurned to the client.", "cite_spans": [], "ref_spans": []}, {"section": "H", "text": "Proof :(Sketch) Once the system is stable, eventually some (correct client q returns from its invocation of contend with probability m e . This client executes for sufficiently long (if A is chosen adequately) in isolation of other clients. It either commits an existing state a to a full quorum or else extends U with operations in pending and proposes and commits the new state U' at a full quorum.0", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Fault detection for Byzantine quorum systems", "authors": [{"first": "L", "middle": [], "last": "Alvisi", "suffix": ""}, {"first": "D", "middle": [], "last": "Malkhi", "suffix": ""}, {"first": "E", "middle": [], "last": "Pierce", "suffix": ""}, {"first": "M", "middle": [], "last": "Reiter", "suffix": ""}], "year": 1999, "venue": "Proceedings ($the 7th IFIP Internutiunul Working Conference on Dependable Computing fi,r (Criticul Applications", "link": "17286571"}, "BIBREF1": {"title": "The performance of spin-lock alternatives for sharedmemory multiprocessors", "authors": [{"first": "T", "middle": ["E"], "last": "Anderson", "suffix": ""}], "year": 1990, "venue": "IEEE Trunsuctions on furullel und Distributed Systems I( l)", "link": null}, "BIBREF2": {"title": "Fast timing-based algorithms. Distributed Computing lO(l):l-lO", "authors": [{"first": "R", "middle": [], "last": "Alur", "suffix": ""}, {"first": "G", "middle": [], "last": "Taubenefeld", "suffix": ""}], "year": 1996, "venue": "", "link": null}, "BIBREF3": {"title": "Practical Byzantine fault tolerance", "authors": [{"first": "M", "middle": [], "last": "Castro", "suffix": ""}, {"first": "B", "middle": [], "last": "Liskov", "suffix": ""}], "year": 1999, "venue": "P mreedings of the 3rd Syniposium on Operating Sjstems Design und Implementmion", "link": "47369760"}, "BIBREF4": {"title": "Adaptive solutions to the mutual exclusion problem", "authors": [{"first": "M", "middle": [], "last": "Choy", "suffix": ""}, {"first": "A", "middle": [], "last": "Singh", "suffix": ""}], "year": 1994, "venue": "", "link": "153665"}, "BIBREF5": {"title": "On the possibility of consensus in asynchronous systems", "authors": [{"first": "C", "middle": [], "last": "Fetzer", "suffix": ""}, {"first": "F", "middle": [], "last": "Cristian", "suffix": ""}], "year": 1995, "venue": "Proceedings qf the 1995 fucifc Rim Internutionul Symposium on Fhlr-To/erunt Systems", "link": null}, "BIBREF6": {"title": "Analysis of backoff protocols for multiple access channels", "authors": [{"first": "J", "middle": [], "last": "Hastad", "suffix": ""}, {"first": "T", "middle": [], "last": "Leighton", "suffix": ""}, {"first": "B", "middle": [], "last": "Rogoff", "suffix": ""}], "year": "", "venue": "SIAM Journul i$ Coniputing", "link": "8532665"}, "BIBREF7": {"title": "Increasing the resilience of distributed and replicated database systems", "authors": [{"first": "I", "middle": [], "last": "Keidar", "suffix": ""}, {"first": "D", "middle": [], "last": "Dolev", "suffix": ""}], "year": 1998, "venue": "Journul of Cumputer cmd S y w m Sciences", "link": "11028834"}, "BIBREF8": {"title": "The SecureRing protocols for securing group communication", "authors": [{"first": "K", "middle": [], "last": "Kihlstrom", "suffix": ""}, {"first": "L", "middle": ["E"], "last": "Moser", "suffix": ""}, {"first": "P", "middle": ["M"], "last": "Melliar-Smith", "suffix": ""}], "year": 1998, "venue": "Proceedings of the 3lst IEEE Huwuii Inrernutionul Cunference on System Sciences", "link": "6536806"}, "BIBREF9": {"title": "Time, clocks, and the ordering of events in distributed systems", "authors": [{"first": "L", "middle": [], "last": "Lamport", "suffix": ""}], "year": 1978, "venue": "Cr,mmunicurions of the ACM", "link": "207766375"}, "BIBREF10": {"title": "The Part-time parliament", "authors": [{"first": "L", "middle": [], "last": "Lamport", "suffix": ""}], "year": 1998, "venue": "ACM Trunsucrions on Computer Systems", "link": "215404458"}, "BIBREF11": {"title": "A fi algorithm for mutual exclusion in decentralized systems", "authors": [{"first": "M", "middle": [], "last": "Maekawa", "suffix": ""}], "year": 1985, "venue": "ACM Trunsuctions on Computer Systems", "link": null}, "BIBREF12": {"title": "On diffusing updates in a Byzantine environment", "authors": [{"first": "D", "middle": [], "last": "Malkhi", "suffix": ""}, {"first": "Y", "middle": [], "last": "Mansour", "suffix": ""}, {"first": "M", "middle": ["K"], "last": "Reiter", "suffix": ""}], "year": 1999, "venue": "Proceedings ufthe 18th IEEE Synposium on Reliuble Distributed Systems", "link": "6984534"}, "BIBREF13": {"title": "Byzantine quorum systems", "authors": [{"first": "D", "middle": [], "last": "Malkhi", "suffix": ""}, {"first": "M", "middle": [], "last": "Reiter", "suffix": ""}], "year": 1998, "venue": "Distributed Contputing", "link": "812968"}, "BIBREF14": {"title": "Secure and scalable replication in Phalanx", "authors": [{"first": "D", "middle": [], "last": "", "suffix": ""}, {"first": "M", "middle": ["K"], "last": "Reiter", "suffix": ""}], "year": 1998, "venue": "Proceedings uf' the 17th IEEE Symposium on Reliuble Distributed Systems", "link": "5865792"}, "BIBREF15": {"title": "An architecture for survivable coordination in large-scale systems", "authors": [{"first": "D", "middle": [], "last": "", "suffix": ""}, {"first": "M", "middle": ["K"], "last": "Reiter", "suffix": ""}], "year": 2000, "venue": "IEEE Trunsuctions on fhowkdge und Datu Engineering", "link": null}, "BIBREF16": {"title": "The Rampart toolkit for building high-integrity services", "authors": [{"first": "M", "middle": ["I&lt;"], "last": "Reiter", "suffix": ""}], "year": 1995, "venue": "Theory und Practice in Distributed Systems (Lecture Notes in Computer Science 938)", "link": "2794478"}, "BIBREF17": {"title": "A method for obtaining digital signatures and public-key cryptosystems", "authors": [{"first": "R", "middle": ["L"], "last": "Rivest", "suffix": ""}, {"first": "A", "middle": [], "last": "Shamir", "suffix": ""}, {"first": "L", "middle": [], "last": "Adleman", "suffix": ""}], "year": 1978, "venue": "Communications of the ACM", "link": "30798417"}, "BIBREF18": {"title": "Implementing fault-tolerant services using the state machine approach: A tutorial", "authors": [{"first": "E", "middle": ["B"], "last": "Schneider", "suffix": ""}], "year": 1990, "venue": "ACM Computing Surveys", "link": "678818"}, "BIBREF19": {"title": "A class of deadlock-free Maekawa-type mutual exclusion algorithms for distributed systems", "authors": [{"first": "M", "middle": [], "last": "Singhd", "suffix": ""}], "year": "", "venue": "Distributed Computing", "link": null}, "BIBREF20": {"title": "A taxonomy of distributed mutual exclusion", "authors": [{"first": "M", "middle": [], "last": "Singhal", "suffix": ""}], "year": 1993, "venue": "Journul qf furullel und Distributed Computing", "link": "43754502"}}, "ref_entries": {"FIGREF0": {"text": "141. The specific variant we need is a system & & 2u such that (i) for any quorums Q1, Q 2 E &: I Q l n Q 2 1 2 3 b + l , a n d ( i i ) f o r e v e r y B C U w i t h I B [ = b , there exists Q E &! such that Q n B = 0. Property (i) en- sures that if each client queries a quorum of servers, then any two clients' queries intersect in at least 2b + 1 correct servers. Property (ii) ensures that some quorum is always available. These quorum systems are a special variants of the request sets used in Maekawa's protocol [ 121 (see Sec- tion 2) to address up to b arbitrary server failures. Using a straightforward adaptation of Corollary 4.4 in [ 141, we find that our requirement of quorums implies n > 5b. The protocol, then, is extremely simple; see Figure 1.", "type": "figure"}, "FIGREF1": {"text": "a.doOp(o) applies the operation o to the state ( J , per- forming any modifications on (T in place. cT.response(o), if defined, is the return result for oper- ation 0. a.reflects(o) indicates whether a.doOp(o) was previ- ously executed.", "type": "figure"}, "FIGREF2": {"text": "Figure 3. Server side of ordering protocol", "type": "figure"}, "TABREF0": {"text": "turns FREE if it last returned FREE over A + 26 time ago; otherwise it returns LOCKED. To contend, a client collects FREE or LOCKED responses from a quorum and succeeds if at most b responses are LOCKED. If more than b responses are LOCKED, then it delays for some random duration in the interval [(A + 46) . . .2'(A + 46)] before trying again,", "type": "table"}, "TABREF1": {"text": "if(clock() -IastGranted > A + 26)Qi +-{ U } U Q i ; I until (3Q E C 2 : Q & QI); if ( / { U : status,, = locked}/ 5 b)d t R [ ( A + 4 6 ) . . .2'(:A + 46)];Figure 1. Mutual exclusion protocol Lemma 1 Ifthe system is synchronous, and a client's con- tend operation returns at real time T , then no other (client's contend returns in the interval [T, T + A]. Proof: Suppose that at client c, a contend returns at tim'e T . By assumption, this implies that c invoked try on servers no earlier than T -26. Consider any other client c' whose contend returns in the interval [T, T + A]. Again, our assumption implie:; that c' invoked try on servers no earlier than T -26. Then all correct servers in the quorum Q that c queried, except at most h, responded to c in the time frame [T -26, T ] with the response FREE. Simi- larly, all correct servers in the quorum Q' that c' queried responded to c' in the time frame [T -26, T + A] with FREE. Since Q and Q' intersect in at least 2b + 1 correct servers, at least one such correct server must have responded FREE to both c and c'. Since any correct server retums FREE to only one client in any .h + 26 time period, this is a contradiction.0", "type": "table"}, "TABREF2": {"text": "the system is synchronous, t clients contend, and none of these clients fails, then all client's conte,nd op- erations return in expected O ( A t ) time. Proof: (Sketch.) Let T denote a time by which all t clients are contending, and let Rk = 2\"(A + 46). At time T + Rk, every client ci whose contend operation has not returned has a retry value si that satisfies si 2 k , since the s'th retry of a client is made within at most 2\"(A + 46) time units after the previous try.t k 5 t denote the number of number of clients whose clontend operations have not returned by time T + Rk, and denote them c1, . . . , c t k . For each such client's first attempt afterT+Rk. to fail, the time at which it attempts must follow some other client's by at most A + 46. This happens with probability at most ( t k -l ) / Z k . Let -U : , 1 5 z 5 t k , be an indicator random variable such that = 0 if et's first attempt after time T + R k succeeds; X: = I otherwise. By the analysis above, P[X: = 1 1 5 ( t k -l ) / Z k . Let .gk = X:; X k is the number of clients whose attempt following time T + Rk fails. By linearity of expectation, Since E[agk] 2 x P [ X k 2 x], it follows that for any constant c > 1,It follows that the expected k by which all clients succeed is. O(logt), meaning that the expected time by which all clients' contend operations return is at most", "type": "table"}, "TABREF3": {"text": "max{v : I{u : aEc.version > w}I 2 b + 1)); if (ac # I A ac.version > completed) else if (apc # I A #.version > completed)", "type": "table"}, "TABREF6": {"text": "events into a single event called the client invocation of a method p, de- noted p . p . We will write p . p -+ u . p for some U E U iff y.send(u, p ) E p . p . We also define the server invocation of a method p to be simply the event u.p that occurs in H . A server invocation u.p is called complete in H , if u.pdoes not result in RankException. A client invocation p . p is called complete in H if there exists a quorum Q such that for each correct server U E Q, u.p is complete. We assume that each history begins with the complete propose and commit invocations with the initial object state a' and the rank 0 as the arguments. We first set out to prove the Order property of the pro- tocol. We start with proving simple facts that correlate the causal order of propose events with their ranks: Lemma 3 Let p.propose(al, T I ) be complete in H and q.propose(a2,rz)If r1 < 7-2, then p.propose(a1 , T I ) 4 q.propose(a2, Q). Otherwise, q.get(r2) -+ p.propose(a1 , TI).Proof : The result is straightforward from the protocol and the definition of the causal order. 0and q.propose(aa7r2) are complete in H , then they are ordered by the + relation.", "type": "table"}, "TABREF7": {"text": "such that p'.propose(a', r') + HLemma 4 Consider any q.propose(a2,~2>, I f p.propose(al. r l ) is its closest complete propose then all the following results are true: ( I ) u2 .version = 01 .version or u2 .version = u1 .version+ 1; ( 2 ) ifa2.version = a1 .version, then a1 = (T.; (3) (f u2 .version = 01 .version + 1, then there exists a com- plete p'.commit(al , r') in ccone(q.propose(u2, Q)), and u2 is rhe result of applying operations in { o : ff..reflects(o) A lal.reflects(o)} to a1 in some sequential orde,: Proof :(Sketch) We prove the result by induction on ccone(q.propose", "type": "table"}, "TABREF8": {"text": "Proof :(Sketch) By Lemma 4 for each committed state LT, a is derived by applying a block of pending operations (line 2.2:4) to a previously committed state a' such that u' .version = o.version - 1 and for no state a\" # a', cr\".version = u'.version. Since the operations within each such pending block are applied in a serial order (lines 2.44-51), there is a well-defined sequence in which operations are applied.0", "type": "table"}}}
{"paper_id": "8333561", "_pdf_hash": "7737926227492eb5838e3b55c00f988fbdfe0a47", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Activiti 5.15 User Guide", "authors": [{"first": "", "middle": [], "last": "Activiti", "suffix": ""}], "year": 2013, "venue": "", "link": null}, "BIBREF1": {"title": "An extension of business process model and notation for security risk management", "authors": [{"first": "O", "middle": [], "last": "Altuhhova", "suffix": ""}, {"first": "R", "middle": [], "last": "Matulevicius", "suffix": ""}, {"first": "N", "middle": [], "last": "Ahmed", "suffix": ""}], "year": 2013, "venue": "", "link": null}, "BIBREF2": {"title": "Apache Rampart-Axis2 Security Model", "authors": [], "year": 2009, "venue": "", "link": null}, "BIBREF3": {"title": "Apache Orchestration Director Engine (ODE)", "authors": [], "year": 2008, "venue": "Apache Software Foundation", "link": null}, "BIBREF4": {"title": "Delivering value, security, and speed with BPM in the Cloud", "authors": [{"first": "", "middle": [], "last": "Appian", "suffix": ""}], "year": 2014, "venue": "", "link": null}, "BIBREF5": {"title": "Security for Web services and service-oriented architectures", "authors": [{"first": "E", "middle": [], "last": "Bertino", "suffix": ""}], "year": 2010, "venue": "", "link": "23943146"}, "BIBREF6": {"title": "Security and privacy-enhancing multicloud architectures", "authors": [{"first": "J", "middle": [], "last": "Bohli", "suffix": ""}], "year": 2013, "venue": "IEEE Trans Dependable Secur Comput", "link": null}, "BIBREF7": {"title": "Integrating security aspects into business process models", "authors": [{"first": "A", "middle": ["D"], "last": "Brucker", "suffix": ""}], "year": 2013, "venue": "Inf Technol", "link": "199666946"}, "BIBREF8": {"title": "An aspect-oriented framework for specification and enforcement of non-functional concerns in WS-BPEL", "authors": [{"first": "A", "middle": [], "last": "Charfi", "suffix": ""}, {"first": "B", "middle": [], "last": "Schmeling", "suffix": ""}, {"first": "M", "middle": [], "last": "Mezini", "suffix": ""}], "year": 2012, "venue": "Int J Web Grid Serv", "link": "207429209"}, "BIBREF9": {"title": "Eclipse Foundation", "authors": [], "year": 2008, "venue": "", "link": null}, "BIBREF10": {"title": "Eucalyptus open-source Cloud computing infrastructure-an overview", "authors": [], "year": 2009, "venue": "Eucalyptus Systems", "link": null}, "BIBREF11": {"title": "Aspect oriented approach to building secure service composition", "authors": [{"first": "G", "middle": [], "last": "Fan", "suffix": ""}], "year": 2010, "venue": "Proceedings of the 17th Asia Pacific software engineering conference (APSEC)", "link": "17134626"}, "BIBREF12": {"title": "Bridging the Gap between BPMN and WS-BPEL: M2M transformations in practice", "authors": [{"first": "P", "middle": [], "last": "Giner", "suffix": ""}, {"first": "V", "middle": [], "last": "Torres", "suffix": ""}, {"first": "V", "middle": [], "last": "Pelechano", "suffix": ""}], "year": 2007, "venue": "", "link": "15365045"}, "BIBREF13": {"title": "Trust mechanisms for cloud computing", "authors": [{"first": "J", "middle": [], "last": "Huang", "suffix": ""}, {"first": "D", "middle": ["M"], "last": "Nicol", "suffix": ""}], "year": 2013, "venue": "J Cloud Comput", "link": "5974343"}, "BIBREF14": {"title": "IBM (2012) IBM Business Process Manager on Cloud", "authors": [], "year": 2014, "venue": "", "link": null}, "BIBREF15": {"title": "Security architecture for open system interconnection for CCITT applications. Recommendation X.800", "authors": [{"first": "", "middle": [], "last": "Itu-T", "suffix": ""}], "year": 1991, "venue": "", "link": null}, "BIBREF16": {"title": "Recommendation Z.150 (02/03): User Requirements Notation (URN)-Language definition", "authors": [{"first": "", "middle": [], "last": "Itu-T", "suffix": ""}], "year": 2008, "venue": "", "link": null}, "BIBREF17": {"title": "JBoss jBPM User Guide v", "authors": [], "year": 2014, "venue": "Jboss Community", "link": null}, "BIBREF18": {"title": "An experimental study on the design and modeling of security concepts in business processes", "authors": [{"first": "M", "middle": [], "last": "Leitner", "suffix": ""}], "year": 2013, "venue": "Proceedings of the 6th IFIP WG 8.1 working conference on the practice of enterprise modeling. LNBIP", "link": null}, "BIBREF19": {"title": "The Service Security Lab: a model-driven platform to compose and explore service security in the Cloud", "authors": [{"first": "M", "middle": [], "last": "Menzel", "suffix": ""}], "year": 2010, "venue": "Proceedings of the IEEE international world congress of services", "link": "3241874"}, "BIBREF20": {"title": "A pattern-driven generation of security policies for service-oriented architectures", "authors": [{"first": "M", "middle": [], "last": "Menzel", "suffix": ""}, {"first": "R", "middle": [], "last": "Warschofsky", "suffix": ""}, {"first": "C", "middle": [], "last": "Meinel", "suffix": ""}], "year": 2010, "venue": "Proceddings of the IEEE international conference on Web services (ICWS 2010)", "link": "17625776"}, "BIBREF21": {"title": "The NIST definition of Cloud computing. Recommendations of the National Institute of Standards and Technology", "authors": [{"first": "P", "middle": [], "last": "Mell", "suffix": ""}, {"first": "T", "middle": [], "last": "Grance", "suffix": ""}], "year": 2011, "venue": "Special Publication", "link": null}, "BIBREF23": {"title": "Business process model and notation v 2", "authors": [{"first": "", "middle": [], "last": "Omg", "suffix": ""}], "year": 2011, "venue": "", "link": null}, "BIBREF24": {"title": "From business process models to process-oriented software systems", "authors": [{"first": "C", "middle": [], "last": "Ouyang", "suffix": ""}], "year": 2009, "venue": "ACM Trans Softw Eng Methodol", "link": "1058065"}, "BIBREF25": {"title": "Security requirements engineering for secure business processes", "authors": [{"first": "E", "middle": [], "last": "Paja", "suffix": ""}], "year": 2012, "venue": "Lect Notes Bus Inf Process", "link": "15415090"}, "BIBREF26": {"title": "Service oriented architectures: approaches, technologies and research issues", "authors": [{"first": "M", "middle": [], "last": "Papazoglou", "suffix": ""}, {"first": "W", "middle": [], "last": "Heuvel", "suffix": ""}], "year": 2007, "venue": "VLDB J", "link": "16695713"}, "BIBREF27": {"title": "Secure business process model specification through a UML 2.0 activity diagram profile", "authors": [{"first": "A", "middle": [], "last": "Rodriguez", "suffix": ""}, {"first": "E", "middle": [], "last": "Fernndez-Medina", "suffix": ""}, {"first": "J", "middle": [], "last": "Trujillo", "suffix": ""}, {"first": "M", "middle": [], "last": "Piattini", "suffix": ""}], "year": 2011, "venue": "Decis Support Syst", "link": "11053617"}, "BIBREF28": {"title": "An approach for reasoning and refining non-functional requirements", "authors": [{"first": "N", "middle": ["S"], "last": "Rosa", "suffix": ""}, {"first": "Grr", "middle": [], "last": "Justo", "suffix": ""}, {"first": "Prf", "middle": [], "last": "Cunha", "suffix": ""}], "year": 2004, "venue": "J Braz Comput Soc", "link": null}, "BIBREF29": {"title": "Enforcement of security requirements for a business model", "authors": [{"first": "N", "middle": ["S"], "last": "Rosa", "suffix": ""}], "year": 2014, "venue": "US Patent", "link": null}, "BIBREF30": {"title": "Composing non-functional concerns in composite Web services", "authors": [{"first": "B", "middle": [], "last": "Schmeling", "suffix": ""}], "year": 2011, "venue": "2011 IEEE international conference on Web services", "link": "14735825"}, "BIBREF31": {"title": "WSMO use case modeling and testing", "authors": [{"first": "M", "middle": [], "last": "Stollberg", "suffix": ""}], "year": 2004, "venue": "", "link": null}, "BIBREF32": {"title": "A threat analysis methodology for security evaluation and enhancement planning", "authors": [{"first": "A", "middle": [], "last": "Stango", "suffix": ""}, {"first": "N", "middle": ["R"], "last": "Prasad", "suffix": ""}, {"first": "D", "middle": ["M"], "last": "Kyriazanos", "suffix": ""}], "year": 2009, "venue": "Third international conference on emerging security information, systems and technologies", "link": "14514299"}, "BIBREF33": {"title": "Modeling security requirements in service based business processes", "authors": [{"first": "S", "middle": ["H"], "last": "Turki", "suffix": ""}], "year": 2012, "venue": "Lect Notes Bus Inf Process", "link": "7934304"}, "BIBREF34": {"title": "A security pattern-driven approach toward the automation of risk treatment in business processes", "authors": [{"first": "A", "middle": ["J"], "last": "Varela-Vaca", "suffix": ""}], "year": 2013, "venue": "Adv Intell Syst Comput", "link": "39703863"}, "BIBREF35": {"title": "Model-driven business process security requirement specification", "authors": [{"first": "C", "middle": [], "last": "Wolter", "suffix": ""}], "year": 2009, "venue": "J Syst Archit", "link": "40561723"}, "BIBREF36": {"title": "International conference on service oriented computing workshops (ICSOC Workshops)", "authors": [{"first": "I", "middle": [], "last": "Yahia", "suffix": ""}, {"first": "S", "middle": ["H"], "last": "Turki", "suffix": ""}, {"first": "A", "middle": [], "last": "Charfi", "suffix": ""}, {"first": "S", "middle": [], "last": "Kallel", "suffix": ""}, {"first": "R", "middle": [], "last": "Bouaziz", "suffix": ""}], "year": 2013, "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "8333821", "_pdf_hash": "ae30830293308bc439d55a66bf2a5999f028f8aa", "abstract": [{"section": "Abstract", "text": "Background: Case reports and case series studies suggest a positive association between intussusception and celiac disease (CD). Methods: We contacted Sweden's 28 pathology departments and obtained data on 29,096 patients with biopsy-verified CD (equal to Marsh stage 3) through biopsy reports. Patients with CD were matched for age, sex, calendar period and county of residence with up to five reference individuals from the general population (n = 144,522). Cases of intussusception were identified from nationwide inpatient, hospital-based outpatient and day-surgery data from the Swedish Patient Register. Odds ratios (ORs) for future CD in patients with intussusception were estimated using conditional logistic regression. Results: 34 (0.12%) individuals with CD had a diagnosis of intussusception vs. 143 (0.10%) reference individuals, suggesting that intussusception was not a risk factor for later CD (OR = 1.17; 95% confidence interval (CI) = 0.82-1.67). The OR for CD in patients with at least two records of intussusception was 0.40 (95% CI = 0.06-2.99). In contrast, a post-hoc analysis showed that CD was associated with a statistically significantly increased risk of intussusception after CD diagnosis (hazard ratio = 1.95; 95% CI = 1.01-3.77); however, this analysis was based on only 12 cases with both CD and intussusception. Conclusion: We found no association between intussusception and future CD; and a mostly modest increased risk of intussusception after a diagnosis of CD.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Background", "text": "Intussusception is a condition in which a segment of intestine invaginates into another section of intestine. Signs and symptoms of intussusception include acute pain, nausea, lethargy, vomiting and sometimes bleeding from the rectum (\"red currant jelly\") [1] . Although intussusception generally remits spontaneously, in a number of cases either contrast enema or surgery is needed to treat the disorder [2] . The causes of intussusception include infections and vaccination with rotavirus vaccine, but organic disorders such as malignancy tend to predominate in adults.", "cite_spans": [{"start": 256, "end": 259, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 405, "end": 408, "text": "[2]", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Background", "text": "Celiac disease (CD) is a chronic inflammatory small intestinal disorder that occurs in about 1-2% of the general population [3, 4] . Undiagnosed CD is characterized by small bowel inflammation [5] and will sometimes cause small bowel wall edema [6] , intestinal lymph node swelling [7] and dysmotility [7] but also ulcers and strictures [8] . It has therefore been suggested that untreated CD may be linked to intussusception; a number of casereports and case series substantiate this hypothesishesis [9] [10] [11] [12] [13] [14] . In a recent paper from a tertiary institution in the US [14] , 3/252 (1.2%) of children with newly diagnosed CD had a history of intussusception compared with 0.07% of the child population attending this center.", "cite_spans": [{"start": 124, "end": 127, "text": "[3,", "ref_id": "BIBREF2"}, {"start": 128, "end": 130, "text": "4]", "ref_id": "BIBREF3"}, {"start": 193, "end": 196, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 245, "end": 248, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 282, "end": 285, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 302, "end": 305, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 337, "end": 340, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 501, "end": 504, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 505, "end": 509, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 510, "end": 514, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 515, "end": 519, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 520, "end": 524, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 525, "end": 529, "text": "[14]", "ref_id": "BIBREF13"}, {"start": 588, "end": 592, "text": "[14]", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "Background", "text": "This suggests intussusception may be associated with CD, however, due to small numbers or lack of controls, none of these studies have estimated relative risks or odds ratios (ORs) [9] [10] [11] [12] [13] [14] .", "cite_spans": [{"start": 181, "end": 184, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 185, "end": 189, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 190, "end": 194, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 195, "end": 199, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 200, "end": 204, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 205, "end": 209, "text": "[14]", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "Background", "text": "The main objective of this study was therefore to examine the association between intussusception and later biopsy-verified CD in a large nationwide populationbased case-control study. In a post-hoc analysis we examined the risk of intussusception in patients who already had a diagnosis of CD.", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "We identified patients with intussusception through the Swedish Patient Register [15] (data on inpatient care, hospital-based outpatient care and day-care surgery). Intussusception data were linked to data on CD obtained from biopsy reports at Sweden's 28 pathology registers [16] . Linkages were performed using the Swedish personal identity number (PIN) [17] .", "cite_spans": [{"start": 81, "end": 85, "text": "[15]", "ref_id": "BIBREF14"}, {"start": 276, "end": 280, "text": "[16]", "ref_id": "BIBREF15"}, {"start": 356, "end": 360, "text": "[17]", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "Intussusception", "text": "Cases with intussusception were identified from the Swedish Patient Register [15] by reference to relevant International Classification of Disease (ICD) codes ICD-7: 570.0; ICD-8: 560.0; ICD-9: 560A; and ICD-10: K56.1. In subanalyses we restricted intussusception to cases with surgery or to those who had radiological intervention (code TJG30 or 4780) for intussusception. In a separate analysis we examined the risk of CD in patients with at least two recorded health care contacts that were due to intussusception.", "cite_spans": [{"start": 77, "end": 81, "text": "[15]", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "Intussusception", "text": "The Swedish Patient Register started in 1964 and since 1987 the register has nationwide coverage. Day-surgery data were added from 1997 and hospital-based outpatient data since 2001 [15] .", "cite_spans": [{"start": 182, "end": 186, "text": "[15]", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "Celiac disease", "text": "In 2006-2008 we collected small intestinal biopsy report data from all pathology departments (n = 28) in Sweden. The biopsies were performed between 1969 and 2008. IT personnel carried out computerized searches for arrival date of biopsies, PIN [17] , morphology and topography (duodenum and jejunum). CD was defined as having a biopsy with villous atrophy (VA, equals Marsh stage 3) [18] according to the Swedish SnoMed classification. We did not require patients to have a positive antibodies against tissue transglutaminase (TTG), endomysium (EMA), or gliadin for a CD diagnosis, but in a random subset of patients with VA and available data on CD serology about 88% were positive for either of these antibodies at the time of biopsy [16] . An earlier validation of 114 patients with VA found that 108 (95%) had CD [16] . Approximately 79% of individuals with CD had gastrointestinal symptoms before biopsy and 35% had anemia.", "cite_spans": [{"start": 245, "end": 249, "text": "[17]", "ref_id": "BIBREF16"}, {"start": 384, "end": 388, "text": "[18]", "ref_id": "BIBREF17"}, {"start": 737, "end": 741, "text": "[16]", "ref_id": "BIBREF15"}, {"start": 818, "end": 822, "text": "[16]", "ref_id": "BIBREF15"}], "ref_spans": []}, {"section": "Controls", "text": "Each individual undergoing biopsy was matched with up to five controls for age, sex, calendar period and county of residence. Controls were identified from the Total Population Register by the Swedish government agency, Statistics Sweden and had no previous duodenal/jejunal biopsy.", "cite_spans": [], "ref_spans": []}, {"section": "Controls", "text": "We then excluded individuals whose biopsy may have originated from the ileum, CD individuals lacking a serial number from Statistics Sweden or having no matched controls since all analyses were carried out per stratum. The remaining individuals were identical to those in our study on mortality in CD [19] . Thus, the final sample on which this study is based was 29,096 individuals with CD and 144,522 matched controls.", "cite_spans": [{"start": 301, "end": 305, "text": "[19]", "ref_id": "BIBREF18"}], "ref_spans": []}, {"section": "Statistics", "text": "We used conditional logistic regression to estimate ORs for CD and earlier intussusception. The conditional approach entails that each individual with CD is only compared with his or her controls within the same stratum. We also present percentages of CD patients and controls with a previous diagnosis of intussusception.", "cite_spans": [], "ref_spans": []}, {"section": "Statistics", "text": "In pre-defined subanalyses we examined intussusception and CD in relation to sex, age (0-19, 20-39, 40-59 and \u226560 years at age of diagnosis) and calendar period (1989, 1990-1999 and 2000-) at CD diagnosis.", "cite_spans": [], "ref_spans": []}, {"section": "Statistics", "text": "In another pre-defined subanalysis we examined the association between intussusception and CD in children aged <2 years (CD: n = 4,589). We did so for two reasons. First, in Sweden, CD is often diagnosed in this age group [20] , and second, as opposed to adults in which intussusception may be caused by cancers [11] , underlying cancers are unusual in childhood when most intussusception is idiopathic. We therefore hypothesized that the association with CD would be strongest with idiopathic intussusception in infancy and childhood. For consistency, we also examined the risk of intussusception in individuals diagnosed with CD \u22652 years of age (CD: n = 24,507). In a post-hoc analysis we excluded all intussusception occurring before the age of 2 years (not equal to the previous analysis in which we examined risk of CD after the age of 2 years but included intussusceptions occurring before age 2) and calculated OR for future CD.", "cite_spans": [{"start": 222, "end": 226, "text": "[20]", "ref_id": "BIBREF19"}, {"start": 312, "end": 316, "text": "[11]", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "Statistics", "text": "We also examined the risk of future CD in patients with at least 2 health care contacts for intussusception (repeated intussusceptions) of which at least one intussusception had to occur before CD diagnosis. Having at least 2 records of intussusception will increase the likelihood that the patient really had intussusception.", "cite_spans": [], "ref_spans": []}, {"section": "Statistics", "text": "Cancer is sometimes the underlying cause of intussusception [11] and CD has been linked to both lymphoproliferative [21] and gastrointestinal cancer [22] (at least about the time of CD diagnosis [23] ). To rule out that a positive association between CD and intussusception would be due to cancer we performed a separate analysis in which we excluded all individuals (CD patients and controls) who ever had a diagnosis of cancer according to the Swedish Cancer Registry (CD: n = 25,869). The Swedish Cancer Registry began in 1958. About 99% of all cancers are morphologically verified [24] and almost 100% of all cancers are reported to this register each year [24] .", "cite_spans": [{"start": 60, "end": 64, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 116, "end": 120, "text": "[21]", "ref_id": "BIBREF21"}, {"start": 149, "end": 153, "text": "[22]", "ref_id": "BIBREF22"}, {"start": 195, "end": 199, "text": "[23]", "ref_id": "BIBREF23"}, {"start": 585, "end": 589, "text": "[24]", "ref_id": "BIBREF24"}, {"start": 661, "end": 665, "text": "[24]", "ref_id": "BIBREF24"}], "ref_spans": []}, {"section": "Post-hoc analysis: CD and risk of future intussusception", "text": "In a post-hoc analysis we examined the risk of future intussusception in patients with CD. This analysis was done to explore whether the null relationship that we found between intussusception and later CD was independent of temporal sequence. In the prospective analysis we used a cohort study design. Individuals with CD were compared with matched reference individuals and followed from biopsy (or matching date) until first event of intussusception, emigration, death or end of followup (Dec 31, 2009), whichever occurred first. We used Cox regression models to calculate hazard ratios (HRs) for the risk of future intussusception in CD. All analyses were internally stratified, i.e. one individual with CD was only compared with his or her matched reference individuals (within a stratum) before a summary estimate for the whole CD population was calculated. This approach eliminates the influence of matching variables, such as sex, age, county of residence and calendar year at CD diagnosis. The prospective cohort analysis was based on 29,060 individuals with no earlier record of intussusception and 144,304 matched reference individuals. SPSS version 20.0 (SPSS Inc, Chicago, IL, USA) was used for all analyses. Statistical significance was defined as 95% confidence intervals (CIs) for risk estimates (ORs and HRs) not including 1.0.", "cite_spans": [], "ref_spans": []}, {"section": "Ethics", "text": "The study was approved by the regional ethical review board in Stockholm, Sweden. Since none of the participants was contacted and individual information was \"anonymized\" before the analyses, informed consent was not required by the board.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "The median age at CD diagnosis was 30 years (range 0-95) ( Table 1) . Most patients with CD were diagnosed after 1990 since this study was based on computerized biopsy reports and computerized registers were usually introduced in this decade. Data on the sub-cohort of children diagnosed with CD <2 years of age are presented in Additional file 1. Slightly more than 6 of 10 study participants (all ages) were women.", "cite_spans": [], "ref_spans": [{"start": 59, "end": 67, "text": "Table 1)", "ref_id": "TABREF0"}]}, {"section": "Intussusception and risk of CD", "text": "Of 29,096 individuals with CD, 34 (0.12%) had a diagnosis of intussusception vs. 143/144,522 of the controls (0.10%). Hence, we found no association between intussusception and later CD (OR = 1.17; 95% CI = 0.82-1.67). The OR for having a diagnosis of CD was 1.31 (95% CI = 0.64-2.68) within 1 year after intussusception, 0.56 (95% CI = 0.17-1.78) 1-< 5 years after intussusception and 1.31 (95% CI = 0.84-2.05) \u22655 years after intussusception.", "cite_spans": [], "ref_spans": []}, {"section": "Intussusception and risk of CD", "text": "The risk of future CD was similar in females (OR = 0.97; 95% CI = 0.57-1.66) and males (OR = 1.40; 95% CI = 0.86-2.28) ( Table 2) , and there were no significant differences in ORs according to age at CD diagnosis or calendar year (Table 2) . Adjustment for education and country of birth (Nordic vs. Non-Nordic) did not affect our ORs (data not shown).", "cite_spans": [], "ref_spans": [{"start": 121, "end": 129, "text": "Table 2)", "ref_id": "TABREF1"}, {"start": 231, "end": 240, "text": "(Table 2)", "ref_id": "TABREF1"}]}, {"section": "Subanalyses", "text": "When we restricted our dataset to children <2 years of age (at diagnosis of CD or at date of matching), 6 individuals with CD had a previous intussusception vs. 32 controls. Intussusception was no risk factor for CD in this subset of young children (OR = 0.94; 95% CI = 0.42-2.14) ( Table 3) . Table 3 shows additional data. Similarly, intussusception was no risk factor for having a diagnosis of CD after 2 years of age (OR = 1.24; 95% CI = 0.83-1.86). However, we did find a statistically significant association (OR = 2.11; 95% CI = 1.26-3.53) in a post-hoc analysis that only examined intussusceptions occurring after the age of 2 years and risk of future CD.", "cite_spans": [], "ref_spans": [{"start": 283, "end": 291, "text": "Table 3)", "ref_id": "TABREF2"}, {"start": 294, "end": 301, "text": "Table 3", "ref_id": "TABREF2"}]}, {"section": "Subanalyses", "text": "Restricting our exposure to intussusception with either radiological intervention or surgery, the OR for future CD was 1.27 (95% CI = 0.60-2.69).", "cite_spans": [], "ref_spans": []}, {"section": "Subanalyses", "text": "One patient with CD vs. 13 controls had \u22652 records of intussusception (out of which at least one intussusception occurred before CD diagnosis and study entry). This outcome corresponded to a non-significant OR of 0.40 for future CD (95% CI = 0.06-2.99). In eleven of the fourteen (1 + 13) patients with \u22652 records of intussusception, did the two records correspond to the same intussusception (e.g. follow-up visit shortly after first diagnosis). All three patients with \u226530 days between the two intussusceptions (our definition of different episodes), were controls.", "cite_spans": [], "ref_spans": []}, {"section": "Subanalyses", "text": "Excluding study participants who had a diagnosis of cancer at some stage in life, the OR for future CD in patients with intussusception was 1.10 (95% CI = 0.76-1.59) (31/25,869 CD patients vs. 140/130,041 controls had an earlier diagnosis of intussusception).", "cite_spans": [], "ref_spans": []}, {"section": "Celiac disease and risk of future intussusception", "text": "Using a prospective cohort approach, a post-hoc analysis found that 12 of 29,060 individuals with CD had a diagnosis of intussusception after CD onset (expected n = 6), corresponding to a hazard ratio and relative risk of 1.95 (95% CI = 1.01-3.77, p = 0.046).", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "To our knowledge this is the first case-control study examining intussusception and risk of future CD. It found no association between intussusception and CD (overall OR = 1.17). In a post-hoc analysis intended to confirm the null relationship between prior intussusception and CD before diagnosis we instead found that patients with diagnosed CD were at an almost twofold increased risk of later intussusception.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "Most literature on CD and intussusception has been limited to case reports or case series [9] [10] [11] [12] [13] 25] . Germann et al. suggest that intussusception in CD has a mild clinical course [25] . Intussusception may take place in the duodenum or jejunum but may occur in other parts of the intestine. In our study we were unable to differentiate between intussusceptions in the small intestine and the colon. If intussusception is associated with CD, it is most likely associated with small intestinal intussusception and thus the inclusion of colonic intussusception may have diluted a positive relationship. Still, the overall OR for future CD was very close to 1.0, and if there had been a significant association between previous intussusception and CD, this would have appeared in our data. Reilly et al. reported that 1.2% of their celiac children had experienced a known intussusception [14] but since the authors do not present any statistical comparison with the general population this may or may not represent an increase. Our study differs from that of Reilly et al. [14] by different source populations (nationwide approach vs. tertiary institution), and larger number of celiac patients (29,096 vs. 254) .", "cite_spans": [{"start": 90, "end": 93, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 94, "end": 98, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 99, "end": 103, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 104, "end": 108, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 109, "end": 113, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 114, "end": 117, "text": "25]", "ref_id": "BIBREF25"}, {"start": 197, "end": 201, "text": "[25]", "ref_id": "BIBREF25"}, {"start": 902, "end": 906, "text": "[14]", "ref_id": "BIBREF13"}, {"start": 1087, "end": 1091, "text": "[14]", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "Discussion", "text": "In a recent paper we studied the role of surgery in adult intussusception [11] . In that case series 8/196 (4%) patients with intussusception had CD [11] . In a paper looking at the risk of intussusception in patients with a diagnosis of CD 14/880 (1.6%) developed intussusception during follow-up [13] . In both these series, with strong associations between CD and intussusception, participants were recruited from single tertiary centers, making it is possible that this procedure selected cases with more severe CD and intussusception [11, 13] , or that these patients were at higher risk of undergoing investigation or contacting health care for a number of disorders. We have previously shown that the relative risk of another disorder in CD (tuberculosis) is twice as high in CD patients identified through hospital records [26] as in patients identified through biopsy reports [27] . Further, the risk of mortality in CD seems higher in patients with a hospital record of CD [28] than in patients diagnosed through biopsy reports [19] . More than 96% of pediatricians and gastroenterologists in Sweden perform a biopsy in at least 90% of patients with suspected CD before diagnosis [29] . Other strengths of our paper include the high specificity of VA for CD. When two independent reviewers manually scrutinized more than 1500 biopsy reports, very few individuals had other comorbidities than CD (0.3% of patients with VA had inflammatory bowel disease and 0.2% had Helicobacter pylori). The nationwide ascertainment of CD yielded a large number of CD cases, which contributed to high statistical power. We were therefore able to stratify for age, sex and calendar period at CD diagnosis.", "cite_spans": [{"start": 74, "end": 78, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 149, "end": 153, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 298, "end": 302, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 539, "end": 543, "text": "[11,", "ref_id": "BIBREF10"}, {"start": 544, "end": 547, "text": "13]", "ref_id": "BIBREF12"}, {"start": 831, "end": 835, "text": "[26]", "ref_id": "BIBREF26"}, {"start": 885, "end": 889, "text": "[27]", "ref_id": "BIBREF27"}, {"start": 983, "end": 987, "text": "[28]", "ref_id": "BIBREF28"}, {"start": 1038, "end": 1042, "text": "[19]", "ref_id": "BIBREF18"}, {"start": 1190, "end": 1194, "text": "[29]", "ref_id": "BIBREF29"}], "ref_spans": []}, {"section": "Discussion", "text": "Restricting our analyses to intussusception with radiological intervention and surgery did not affect the OR (1.27). Only after we restricted our analyses to individuals with intussusception after the age of 2 years, did we find a positive association between intussusception and future CD. We urge caution when interpreting these data since they made up a post-hoc finding and could be due to chance. Still, these data may reflect a true association between inflammation from undiagnosed CD in older children and adults and secondary intussusception.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "This study has some limitations. We used a case-control design to examine the association between previous intussusception and future CD. This design means that we did not screen individuals with intussusception for serological markers. Still, if any, patients with intussusception would have been more likely to undergo investigation for CD and this would have driven up the OR for CD. The lack of serological data can therefore not explain our null findings for later CD risk.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "We did not have access to radiological data such as computed tomography and thus could not confirm the intussusception diagnosis. However, in several analyses we increased the specificity of intussusception through various restrictions of the dataset and this had only marginal effects on the ORs. Nor did we screen CD patients for intussusception with MRI, CT or ultrasound [7] . Thus, we have no information on the association between CD and intussusception that did not require health care.", "cite_spans": [{"start": 375, "end": 378, "text": "[7]", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "Discussion", "text": "We know of no earlier incidence study of intussusception in Sweden but a study from nearby Germany found an incidence of 60/100,000 person-years in children <1 year of age [30] . When we examined control children who were born in 1987 or later (when the Swedish Patient Registry was complete) in our dataset, there were 37 intussusceptions in the first year of life corresponding to an incidence of 83/100,000 (37/44,759 person-years). This incidence suggests that the low OR of our study is unlikely to be due to underreporting of intussusceptions.", "cite_spans": [{"start": 172, "end": 176, "text": "[30]", "ref_id": "BIBREF30"}], "ref_spans": []}, {"section": "Discussion", "text": "Finally, despite the large number of patients, we cannot rule out a weak association between intussusception and later CD since the upper 95% CI reached 1.67.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "Early versions of Rotavirus immunizations have been linked to intussusception [31] , and we lacked immunization data. However a recent study from Sweden [32] found no association between childhood immunizations and CD, and rotavirus immunizations have not yet been included in the general childhood immunization program in Sweden. Hence, biased immunization coverage in CD children is unlikely to explain our results.", "cite_spans": [{"start": 78, "end": 82, "text": "[31]", "ref_id": "BIBREF31"}, {"start": 153, "end": 157, "text": "[32]", "ref_id": "BIBREF32"}], "ref_spans": []}, {"section": "Conclusion", "text": "In conclusion, this study found no association between intussusception and CD before CD diagnosis (undiagnosed CD), but did find a twofold increased risk of intussusception after CD diagnosis. However, because only 12/29,060 (0.04%) individuals with CD developed intussusception during follow-up, intussusception is probably a rare complication in CD. This study does not support CD screening in patients with intussusception.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusion", "text": "JFL. Wrote the first draft of the paper: JFL. Contributed to the writing of the paper: AN, JAM, OO. Contributed to the study design and interpretation of the data analyses: JFL, AN, JAM, OO. Approved the final version of the manuscript: JFL, AN, JAM, OO. Responsible for data integrity: JFL. Obtained funding: JFL. Guarantor: JFL had full access to all the data in the study and takes responsibility for the integrity of the data. JFL takes responsibility for the accuracy of the data analyses. All authors read and approved the final manuscript.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Prospective surveillance study of the management of intussusception in UK and Irish infants", "authors": [{"first": "L", "middle": [], "last": "Samad", "suffix": ""}, {"first": "S", "middle": [], "last": "Marven", "suffix": ""}, {"first": "El", "middle": [], "last": "Bashir", "suffix": ""}, {"first": "H", "middle": [], "last": "Sutcliffe", "suffix": ""}, {"first": "A", "middle": ["G"], "last": "Cameron", "suffix": ""}, {"first": "J", "middle": ["C"], "last": "Lynn", "suffix": ""}, {"first": "R", "middle": [], "last": "Taylor", "suffix": ""}, {"first": "B", "middle": [], "last": "", "suffix": ""}], "year": 2012, "venue": "Br J Surg", "link": "21387479"}, "BIBREF1": {"title": "Intussusception: an anatomical perspective with review of the literature", "authors": [{"first": "M", "middle": [], "last": "Loukas", "suffix": ""}, {"first": "M", "middle": [], "last": "Pellerin", "suffix": ""}, {"first": "Z", "middle": [], "last": "Kimball", "suffix": ""}, {"first": "La", "middle": [], "last": "De", "suffix": ""}, {"first": "J", "middle": [], "last": "Garza-Jordan", "suffix": ""}, {"first": "R", "middle": ["S"], "last": "Tubbs", "suffix": ""}, {"first": "R", "middle": [], "last": "Jordan", "suffix": ""}], "year": 2011, "venue": "Clin Anat", "link": "19185791"}, "BIBREF2": {"title": "The prevalence of celiac disease in average-risk and at-risk Western European populations: a systematic review", "authors": [{"first": "C", "middle": [], "last": "Dube", "suffix": ""}, {"first": "A", "middle": [], "last": "Rostom", "suffix": ""}, {"first": "R", "middle": [], "last": "Sy", "suffix": ""}, {"first": "A", "middle": [], "last": "Cranney", "suffix": ""}, {"first": "N", "middle": [], "last": "Saloojee", "suffix": ""}, {"first": "C", "middle": [], "last": "Garritty", "suffix": ""}, {"first": "M", "middle": [], "last": "Sampson", "suffix": ""}, {"first": "L", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "F", "middle": [], "last": "Yazdi", "suffix": ""}, {"first": "V", "middle": [], "last": "Mamaladze", "suffix": ""}], "year": 2005, "venue": "Gastroenterology", "link": "37919555"}, "BIBREF3": {"title": "Agreus L: Detection of Celiac Disease and Lymphocytic Enteropathy by Parallel Serology and Histopathology in a PopulationBased Study", "authors": [{"first": "M", "middle": ["M"], "last": "Walker", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Murray", "suffix": ""}, {"first": "J", "middle": [], "last": "Ronkainen", "suffix": ""}, {"first": "P", "middle": [], "last": "Aro", "suffix": ""}, {"first": "T", "middle": [], "last": "Storskrubb", "suffix": ""}, {"first": "D", "middle": [], "last": "&apos;amato", "suffix": ""}, {"first": "M", "middle": [], "last": "Lahr", "suffix": ""}, {"first": "B", "middle": [], "last": "Talley", "suffix": ""}, {"first": "N", "middle": ["J"], "last": "", "suffix": ""}], "year": 2010, "venue": "Gastroenterology", "link": null}, "BIBREF4": {"title": "An update in the diagnosis of coeliac disease", "authors": [{"first": "Mm:", "middle": [], "last": "Walker", "suffix": ""}, {"first": "", "middle": [], "last": "Murray", "suffix": ""}], "year": 2010, "venue": "Histopathology: JA", "link": "5196629"}, "BIBREF5": {"title": "Adult celiac disease: what is the role of MRI?", "authors": [{"first": "E", "middle": [], "last": "Tomei", "suffix": ""}, {"first": "R", "middle": ["C"], "last": "Semelka", "suffix": ""}, {"first": "L", "middle": [], "last": "Braga", "suffix": ""}, {"first": "A", "middle": [], "last": "Laghi", "suffix": ""}, {"first": "P", "middle": [], "last": "Paolantonio", "suffix": ""}, {"first": "M", "middle": [], "last": "Marini", "suffix": ""}, {"first": "R", "middle": [], "last": "Passariello", "suffix": ""}, {"first": "Di", "middle": [], "last": "Tola", "suffix": ""}, {"first": "M", "middle": [], "last": "Sabbatella", "suffix": ""}, {"first": "L", "middle": [], "last": "Picarelli", "suffix": ""}, {"first": "A", "middle": [], "last": "", "suffix": ""}], "year": 2006, "venue": "J Magn Reson Imaging", "link": "31761910"}, "BIBREF6": {"title": "Small bowel ultrasound in patients with celiac disease. Retrospective study", "authors": [{"first": "D", "middle": [], "last": "Bartusek", "suffix": ""}, {"first": "V", "middle": [], "last": "Valek", "suffix": ""}, {"first": "J", "middle": [], "last": "Husty", "suffix": ""}, {"first": "J", "middle": [], "last": "Uteseny", "suffix": ""}], "year": 2007, "venue": "Eur J Radiol", "link": "21817583"}, "BIBREF7": {"title": "Postbulbar duodenal ulceration and stenosis associated with celiac disease", "authors": [{"first": "G", "middle": ["D"], "last": "Schweiger", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Murray", "suffix": ""}], "year": 1998, "venue": "Abdom Imaging", "link": "30428680"}, "BIBREF8": {"title": "Small bowel intussusception in celiac disease: revisiting a classic association", "authors": [{"first": "D", "middle": ["S"], "last": "Fishman", "suffix": ""}, {"first": "B", "middle": ["P"], "last": "Chumpitazi", "suffix": ""}, {"first": "P", "middle": ["D"], "last": "Ngo", "suffix": ""}, {"first": "H", "middle": ["B"], "last": "Kim", "suffix": ""}, {"first": "J", "middle": ["R"], "last": "Lightdale", "suffix": ""}], "year": 2010, "venue": "J Pediatr Gastroenterol Nutr", "link": "11702602"}, "BIBREF9": {"title": "Small bowel intussusception in celiac disease", "authors": [{"first": "N", "middle": [], "last": "Mushtaq", "suffix": ""}, {"first": "Marven", "middle": ["S"], "last": "Walker", "suffix": ""}, {"first": "J", "middle": [], "last": "Puntis", "suffix": ""}, {"first": "J", "middle": ["W"], "last": "Rudolf", "suffix": ""}, {"first": "M", "middle": [], "last": "Stringer", "suffix": ""}, {"first": "M", "middle": ["D"], "last": "", "suffix": ""}], "year": 1999, "venue": "J Pediatr Surg", "link": "44250510"}, "BIBREF10": {"title": "Adult intussusception in the last 25 years of modern imaging: is surgery still indicated?", "authors": [{"first": "E", "middle": ["O"], "last": "Onkendi", "suffix": ""}, {"first": "T", "middle": ["E"], "last": "Grotz", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Murray", "suffix": ""}, {"first": "J", "middle": ["H"], "last": "Donohue", "suffix": ""}], "year": 2011, "venue": "J Gastrointest Surg", "link": "24333685"}, "BIBREF11": {"title": "Transient small bowel intussusception in adult coeliac disease", "authors": [{"first": "M", "middle": ["D"], "last": "Cohen", "suffix": ""}, {"first": "D", "middle": ["J"], "last": "Lintott", "suffix": ""}], "year": 1978, "venue": "Clin Radiol", "link": "22890284"}, "BIBREF12": {"title": "Association of intussusception and celiac disease in adults", "authors": [{"first": "T", "middle": ["A"], "last": "Gonda", "suffix": ""}, {"first": "S", "middle": ["U"], "last": "Khan", "suffix": ""}, {"first": "J", "middle": [], "last": "Cheng", "suffix": ""}, {"first": "S", "middle": ["K"], "last": "Lewis", "suffix": ""}, {"first": "M", "middle": [], "last": "Rubin", "suffix": ""}, {"first": "P", "middle": ["H"], "last": "Green", "suffix": ""}], "year": 2010, "venue": "Dig Dis Sci", "link": "499208"}, "BIBREF13": {"title": "Should intussusception in children prompt screening for celiac disease?", "authors": [{"first": "N", "middle": ["R"], "last": "Reilly", "suffix": ""}, {"first": "K", "middle": ["M"], "last": "Aguilar", "suffix": ""}, {"first": "P", "middle": ["H"], "last": "Green", "suffix": ""}], "year": 2013, "venue": "J Pediatr Gastroenterol Nutr", "link": "21073789"}, "BIBREF14": {"title": "Otterblad Olausson P: External review and validation of the Swedish national inpatient register", "authors": [{"first": "J", "middle": ["F"], "last": "Ludvigsson", "suffix": ""}, {"first": "E", "middle": [], "last": "Andersson", "suffix": ""}, {"first": "A", "middle": [], "last": "Ekbom", "suffix": ""}, {"first": "M", "middle": [], "last": "Feychting", "suffix": ""}, {"first": "J", "middle": ["L"], "last": "Kim", "suffix": ""}, {"first": "C", "middle": [], "last": "Reuterwall", "suffix": ""}, {"first": "M", "middle": [], "last": "Heurgren", "suffix": ""}], "year": 2011, "venue": "BMC Public Health", "link": null}, "BIBREF15": {"title": "Validation study of villous atrophy and small intestinal inflammation in Swedish biopsy registers", "authors": [{"first": "J", "middle": ["F"], "last": "Ludvigsson", "suffix": ""}, {"first": "L", "middle": [], "last": "Brandt", "suffix": ""}, {"first": "S", "middle": ["M"], "last": "Montgomery", "suffix": ""}, {"first": "F", "middle": [], "last": "Granath", "suffix": ""}, {"first": "A", "middle": [], "last": "Ekbom", "suffix": ""}], "year": 2009, "venue": "BMC Gastroenterol", "link": "15345062"}, "BIBREF16": {"title": "The Swedish personal identity number: possibilities and pitfalls in healthcare and medical research", "authors": [{"first": "J", "middle": ["F"], "last": "Ludvigsson", "suffix": ""}, {"first": "P", "middle": [], "last": "Otterblad-Olausson", "suffix": ""}, {"first": "B", "middle": ["U"], "last": "Pettersson", "suffix": ""}, {"first": "A", "middle": [], "last": "Ekbom", "suffix": ""}], "year": 2009, "venue": "Eur J Epidemiol", "link": "18818811"}, "BIBREF17": {"title": "Gluten, major histocompatibility complex, and the small intestine. A molecular and immunobiologic approach to the spectrum of gluten sensitivity ('celiac sprue')", "authors": [{"first": "M", "middle": ["N"], "last": "Marsh", "suffix": ""}], "year": 1992, "venue": "Gastroenterology", "link": "43373809"}, "BIBREF18": {"title": "Smallintestinal histopathology and mortality risk in celiac disease", "authors": [{"first": "J", "middle": ["F"], "last": "Ludvigsson", "suffix": ""}, {"first": "S", "middle": ["M"], "last": "Montgomery", "suffix": ""}, {"first": "A", "middle": [], "last": "Ekbom", "suffix": ""}, {"first": "L", "middle": [], "last": "Brandt", "suffix": ""}, {"first": "F", "middle": [], "last": "Granath", "suffix": ""}], "year": 2009, "venue": "JAMA", "link": null}, "BIBREF19": {"title": "Epidemic of coeliac disease in Swedish children", "authors": [{"first": "A", "middle": [], "last": "Ivarsson", "suffix": ""}, {"first": "L", "middle": ["A"], "last": "Persson", "suffix": ""}, {"first": "L", "middle": [], "last": "Nystrom", "suffix": ""}, {"first": "H", "middle": [], "last": "Ascher", "suffix": ""}, {"first": "B", "middle": [], "last": "Cavell", "suffix": ""}, {"first": "L", "middle": [], "last": "Danielsson", "suffix": ""}, {"first": "A", "middle": [], "last": "Dannaeus", "suffix": ""}, {"first": "T", "middle": [], "last": "Lindberg", "suffix": ""}, {"first": "B", "middle": [], "last": "Lindquist", "suffix": ""}, {"first": "L", "middle": [], "last": "Stenhammar", "suffix": ""}, {"first": "O", "middle": [], "last": "Hernell", "suffix": ""}], "year": "", "venue": "", "link": "23865409"}, "BIBREF21": {"title": "Risk of Lymphoproliferative Malignancy in Relation to Small Intestinal Histopathology Among Patients With Celiac Disease", "authors": [{"first": "P", "middle": [], "last": "Elfstrom", "suffix": ""}, {"first": "F", "middle": [], "last": "Granath", "suffix": ""}, {"first": "Ekstrom", "middle": [], "last": "Smedby", "suffix": ""}, {"first": "K", "middle": [], "last": "Montgomery", "suffix": ""}, {"first": "S", "middle": ["M"], "last": "Askling", "suffix": ""}, {"first": "J", "middle": [], "last": "Ekbom", "suffix": ""}, {"first": "A", "middle": [], "last": "Ludvigsson", "suffix": ""}, {"first": "J", "middle": ["F"], "last": "", "suffix": ""}], "year": 2011, "venue": "J Natl Cancer Inst", "link": "11379672"}, "BIBREF22": {"title": "Risk of malignancy in patients with celiac disease", "authors": [{"first": "P", "middle": ["H"], "last": "Green", "suffix": ""}, {"first": "A", "middle": ["T"], "last": "Fleischauer", "suffix": ""}, {"first": "G", "middle": [], "last": "Bhagat", "suffix": ""}, {"first": "R", "middle": [], "last": "Goyal", "suffix": ""}, {"first": "B", "middle": [], "last": "Jabri", "suffix": ""}, {"first": "A", "middle": ["I"], "last": "Neugut", "suffix": ""}], "year": 2003, "venue": "Am J Med", "link": "80482"}, "BIBREF23": {"title": "Low Risk of Gastrointestinal Cancer Among Patients With Celiac Disease, Inflammation, or Latent Celiac Disease", "authors": [{"first": "P", "middle": [], "last": "Elfstrom", "suffix": ""}, {"first": "F", "middle": [], "last": "Granath", "suffix": ""}, {"first": "W:", "middle": [], "last": "Ye", "suffix": ""}, {"first": "", "middle": [], "last": "Ludvigsson", "suffix": ""}], "year": 2011, "venue": "Clin Gastroenterol Hepatol: JF", "link": "33328721"}, "BIBREF24": {"title": "Socialstyrelsen: Cancer incidence in Sweden", "authors": [], "year": 2005, "venue": "Book Cancer incidence in", "link": null}, "BIBREF25": {"title": "Celiac disease: an uncommon cause of recurrent intussusception", "authors": [{"first": "R", "middle": [], "last": "Germann", "suffix": ""}, {"first": "M", "middle": [], "last": "Kuch", "suffix": ""}, {"first": "K", "middle": [], "last": "Prinz", "suffix": ""}, {"first": "A", "middle": [], "last": "Ebbing", "suffix": ""}, {"first": "F", "middle": [], "last": "Schindera", "suffix": ""}], "year": 1997, "venue": "J Pediatr Gastroenterol Nutr", "link": "33517805"}, "BIBREF26": {"title": "Coeliac disease and risk of tuberculosis: a population based cohort study", "authors": [{"first": "J", "middle": ["F"], "last": "Ludvigsson", "suffix": ""}, {"first": "J", "middle": [], "last": "Wahlstrom", "suffix": ""}, {"first": "J", "middle": [], "last": "Grunewald", "suffix": ""}, {"first": "A", "middle": [], "last": "Ekbom", "suffix": ""}, {"first": "S", "middle": ["M"], "last": "Montgomery", "suffix": ""}], "year": 2007, "venue": "Thorax", "link": "20552791"}, "BIBREF27": {"title": "Risk of tuberculosis in a large sample of patients with coeliac diseasea nationwide cohort study", "authors": [{"first": "J", "middle": ["F"], "last": "Ludvigsson", "suffix": ""}, {"first": "D", "middle": ["S"], "last": "Sanders", "suffix": ""}, {"first": "M", "middle": [], "last": "Maeurer", "suffix": ""}, {"first": "J", "middle": [], "last": "Jonsson", "suffix": ""}, {"first": "J", "middle": [], "last": "Grunewald", "suffix": ""}, {"first": "J", "middle": [], "last": "Wahlstrom", "suffix": ""}], "year": 2011, "venue": "Aliment Pharmacol Ther", "link": "19635031"}, "BIBREF28": {"title": "Causes of death in patients with celiac disease in a population-based Swedish cohort", "authors": [{"first": "U", "middle": [], "last": "Peters", "suffix": ""}, {"first": "J", "middle": [], "last": "Askling", "suffix": ""}, {"first": "G", "middle": [], "last": "Gridley", "suffix": ""}, {"first": "A", "middle": [], "last": "Ekbom", "suffix": ""}, {"first": "M", "middle": [], "last": "Linet", "suffix": ""}], "year": 2003, "venue": "Arch Intern Med", "link": "36442681"}, "BIBREF29": {"title": "Symptoms and signs in individuals with serology positive for celiac disease but normal mucosa", "authors": [{"first": "J", "middle": ["F"], "last": "Ludvigsson", "suffix": ""}, {"first": "L", "middle": [], "last": "Brandt", "suffix": ""}, {"first": "S", "middle": ["M"], "last": "Montgomery", "suffix": ""}], "year": 2009, "venue": "BMC Gastroenterol", "link": "8412001"}, "BIBREF30": {"title": "Intussusception: incidence and treatment-insights from the nationwide German surveillance", "authors": [{"first": "A", "middle": ["C"], "last": "Jenke", "suffix": ""}, {"first": "R", "middle": [], "last": "Klaassen-Mielke", "suffix": ""}, {"first": "M", "middle": [], "last": "Zilbauer", "suffix": ""}, {"first": "U", "middle": [], "last": "Heininger", "suffix": ""}, {"first": "H", "middle": [], "last": "Trampisch", "suffix": ""}, {"first": "S", "middle": [], "last": "Wirth", "suffix": ""}], "year": 2011, "venue": "J Pediatr Gastroenterol Nutr", "link": "205853956"}, "BIBREF31": {"title": "MMWR Morb Mortal Wkly RepIntussusception among recipients of rotavirus vaccine--United States", "authors": [], "year": 1998, "venue": "", "link": null}, "BIBREF32": {"title": "Ivarsson A: Early vaccinations are not risk factors for celiac disease", "authors": [{"first": "A", "middle": [], "last": "Myleus", "suffix": ""}, {"first": "H", "middle": [], "last": "Stenlund", "suffix": ""}, {"first": "O", "middle": [], "last": "Hernell", "suffix": ""}, {"first": "L", "middle": [], "last": "Gothefors", "suffix": ""}, {"first": "M", "middle": ["L"], "last": "Hammarstrom", "suffix": ""}, {"first": "L", "middle": ["A"], "last": "Persson", "suffix": ""}], "year": 2012, "venue": "Pediatrics", "link": null}, "BIBREF33": {"title": "A large nationwide population-based case-control study of the association between intussusception and later celiac disease", "authors": [{"first": "", "middle": [], "last": "Ludvigsson", "suffix": ""}], "year": 2013, "venue": "BMC Gastroenterology", "link": "8333821"}}, "ref_entries": {"TABREF0": {"text": "Characteristics of study participants", "type": "table"}, "TABREF1": {"text": "Intussusception and risk of later celiac disease", "type": "table"}, "TABREF2": {"text": "", "type": "table"}}}
{"paper_id": "8334260", "_pdf_hash": "c73897d3e7e90bf7a1d1414a1edc69ca17b062b6", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Developmental Origins of Variation in Human Hand Preference", "authors": [{"first": "R", "middle": ["A"], "last": "Yeo", "suffix": ""}, {"first": "S", "middle": ["W"], "last": "Gangestad", "suffix": ""}], "year": 1993, "venue": "Genetica", "link": "84023868"}, "BIBREF1": {"title": "Does Cerebral Hemispheres Develop?, Language Development and Neurological Theory", "authors": [{"first": "M", "middle": [], "last": "Kinsbourne", "suffix": ""}, {"first": "M", "middle": [], "last": "Hiscock", "suffix": ""}], "year": 1977, "venue": "", "link": null}, "BIBREF2": {"title": "Development of Handedness, Handedness and Developmental Disorders", "authors": [{"first": "D", "middle": ["V M"], "last": "Bishop", "suffix": ""}], "year": 1990, "venue": "", "link": null}, "BIBREF3": {"title": "Origins of Handedness in Human Infants", "authors": [{"first": "G", "middle": ["E"], "last": "Butterworth", "suffix": ""}, {"first": "B", "middle": [], "last": "Hopkins", "suffix": ""}], "year": 1993, "venue": "Develop. Med. and Child Neurology", "link": "28522085"}, "BIBREF4": {"title": "Biomekhanika i fiziologiya dvizhenii (Biomechanics and Physiology of Movements), Moscow-Voronezh: Institut prakticheskoi psikhologii", "authors": [{"first": "N", "middle": ["A"], "last": "Bernstein", "suffix": ""}], "year": 1997, "venue": "", "link": null}, "BIBREF5": {"title": "Biological Foundations of Language", "authors": [{"first": "E", "middle": ["H"], "last": "Lennenberg", "suffix": ""}], "year": 1980, "venue": "", "link": null}, "BIBREF6": {"title": "Developmental Time Course in Human Infants and Infant Monkeys, and the Neural Bases of Inhibitory Control in Reaching, The Development and Neural Bases of Higher Cognitive Functions", "authors": [{"first": "A", "middle": [], "last": "Diamond", "suffix": ""}], "year": 1990, "venue": "Ann. of the New York Acad. Sci", "link": null}, "BIBREF7": {"title": "Toward Understanding Commonalities in the Development of Object Search, Detour Navigation, Categorization, and Speech Perception, Human Behavior and the Developing Brain", "authors": [{"first": "A", "middle": [], "last": "Diamond", "suffix": ""}, {"first": "J", "middle": ["F"], "last": "Werker", "suffix": ""}, {"first": "C", "middle": [], "last": "Lalonde", "suffix": ""}], "year": 1994, "venue": "", "link": null}, "BIBREF8": {"title": "Bayley Scales of Infant Development", "authors": [{"first": "N", "middle": [], "last": "Bayley", "suffix": ""}], "year": 1969, "venue": "", "link": "57955042"}, "BIBREF9": {"title": "Annotation: Laterality and Cerebral Dominance", "authors": [{"first": "M", "middle": [], "last": "Annet", "suffix": ""}], "year": 1991, "venue": "Childhood Psychol. and Psychiatry", "link": null}, "BIBREF10": {"title": "Definition and Measurement of Handedness", "authors": [{"first": "D", "middle": ["V M"], "last": "Bishop", "suffix": ""}], "year": 1990, "venue": "Handedness and Developmental Disorders", "link": null}, "BIBREF11": {"title": "Laterality of Function in the Infant: Historical and Contemporary Trends in Theory and Research, Manual Specialization and the Developing Brain", "authors": [{"first": "L", "middle": ["J"], "last": "Harris", "suffix": ""}], "year": 1982, "venue": "", "link": null}, "BIBREF12": {"title": "Notes on the Development of a Child", "authors": [{"first": "M", "middle": ["W"], "last": "Shinn", "suffix": ""}], "year": 1984, "venue": "", "link": "143785527"}, "BIBREF13": {"title": "First Served: About the Development of Hemispheric Specialization in Face Recognition during Infancy", "authors": [{"first": "S", "middle": [], "last": "De Shonen", "suffix": ""}, {"first": "E", "middle": [], "last": "Mathivet", "suffix": ""}, {"first": "", "middle": [], "last": "First Come", "suffix": ""}], "year": 1989, "venue": "Cahiers de Psychologie Cognitive European Bulletin of Cognitive Psychology", "link": null}, "BIBREF14": {"title": "Emotional Expression in Infancy", "authors": [{"first": "R", "middle": ["N"], "last": "Emde", "suffix": ""}, {"first": "T", "middle": ["Y"], "last": "Gaensbower", "suffix": ""}, {"first": "R", "middle": ["J"], "last": "Harmon", "suffix": ""}], "year": 1976, "venue": "A Biobehavioral Study", "link": null}, "BIBREF15": {"title": "Neurobiological Bases of Behavioral Development in the First Year", "authors": [{"first": "N", "middle": [], "last": "Hershkowitz", "suffix": ""}, {"first": "J", "middle": [], "last": "Kagan", "suffix": ""}, {"first": "K", "middle": [], "last": "Zilles", "suffix": ""}], "year": 1997, "venue": "Neuropediatrics", "link": null}, "BIBREF16": {"title": "Handedness and Developmental Disorders", "authors": [{"first": "E", "middle": [], "last": "Bates", "suffix": ""}], "year": 1990, "venue": "", "link": null}, "BIBREF17": {"title": "Origin of Fetal Handedness", "authors": [{"first": "P", "middle": ["G"], "last": "Hepper", "suffix": ""}, {"first": "S", "middle": [], "last": "Shahidullah", "suffix": ""}, {"first": "R", "middle": [], "last": "White", "suffix": ""}], "year": 1990, "venue": "Nature", "link": null}, "BIBREF18": {"title": "Lateralization of Sensory and Motor Functions in Human Neonates", "authors": [{"first": "G", "middle": [], "last": "Cioni", "suffix": ""}, {"first": "G", "middle": [], "last": "Pellegrinetti", "suffix": ""}], "year": 1982, "venue": "Percept. and Motor Skills", "link": "27308412"}, "BIBREF19": {"title": "The Development of Handedness", "authors": [{"first": "A", "middle": [], "last": "Gesell", "suffix": ""}, {"first": "L", "middle": ["B"], "last": "Ames", "suffix": ""}], "year": 1974, "venue": "J. Genetic Psychol", "link": "7478921"}, "BIBREF20": {"title": "Visually Elicited Reaching in Neonates", "authors": [{"first": "N", "middle": [], "last": "Rader", "suffix": ""}, {"first": "J", "middle": ["D"], "last": "Stern", "suffix": ""}], "year": 1982, "venue": "Child Devel", "link": "44795871"}, "BIBREF21": {"title": "Developing Emotions and Cortical Networks, Developmental Behavioral Neuroscience, Gunnar", "authors": [{"first": "D", "middle": [], "last": "Tucker", "suffix": ""}], "year": 1992, "venue": "Lowrence Erlbaum Ass", "link": null}}, "ref_entries": {}}
{"paper_id": "8334431", "_pdf_hash": "ed404b9baf46394c69776b2786991e3341d758ec", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "The Temperley-Lieb algebra at roots of unity", "authors": [{"first": "F", "middle": [], "last": "Goodman", "suffix": ""}, {"first": "H", "middle": [], "last": "Wenzl", "suffix": ""}], "year": 1993, "venue": "Pacific J. Math", "link": "59331153"}, "BIBREF1": {"title": "Diagram algebras, Hecke algebras and decomposition numbers at roots of unity", "authors": [{"first": "J", "middle": [], "last": "Graham", "suffix": ""}, {"first": "G", "middle": [], "last": "Lehrer", "suffix": ""}], "year": 2003, "venue": "Ann. Sci.\u00c9cole Norm. Sup", "link": "123189295"}, "BIBREF2": {"title": "The two-step nilpotent representations of the extended affine Hecke algebra of type A", "authors": [{"first": "J", "middle": [], "last": "Graham", "suffix": ""}, {"first": "G", "middle": [], "last": "Lehrer", "suffix": ""}], "year": 2002, "venue": "Compositio Math", "link": "127122042"}}, "ref_entries": {}}
{"paper_id": "8335017", "_pdf_hash": "f8eda46b7277b5a72293f8c645bee3803c2321e2", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Office of the Secretary of Defense, FY2009-2034 Unmanned Systems Integrated Roadmap", "authors": [], "year": 2009, "venue": "", "link": null}, "BIBREF1": {"title": "Cooperative Control: Models, Applications, and Algorithms", "authors": [{"first": "S", "middle": [], "last": "Butenko", "suffix": ""}, {"first": "R", "middle": [], "last": "Murphey", "suffix": ""}, {"first": "P", "middle": ["M"], "last": "Pardalos", "suffix": ""}], "year": 2003, "venue": "", "link": "109876436"}, "BIBREF2": {"title": "UAV Cooperative Decision and Control: Challenges and Practical Approaches", "authors": [{"first": "T", "middle": [], "last": "Shima", "suffix": ""}, {"first": "S", "middle": [], "last": "Rasmussen", "suffix": ""}], "year": 2009, "venue": "", "link": "208651423"}, "BIBREF3": {"title": "Genetic Algorithm Task Allocation in UAV Cooperative Control", "authors": [{"first": "G", "middle": [], "last": "Chen", "suffix": ""}, {"first": "J", "middle": [], "last": "", "suffix": ""}, {"first": "Jose", "middle": ["B"], "last": "Cruz", "suffix": ""}], "year": 2003, "venue": "AIAA Guidance, Navigation, and Control Conference and Exhibit", "link": null}, "BIBREF4": {"title": "Ground Target Detection Using Cooperative Unmanned Aerial Systems", "authors": [{"first": "G", "middle": [], "last": "York", "suffix": ""}, {"first": "D", "middle": ["J"], "last": "Pack", "suffix": ""}], "year": "", "venue": "J Intell Robot Syst", "link": "35229580"}, "BIBREF5": {"title": "Coordinated searching and target identification using teams of autonomous agents", "authors": [{"first": "Christopher", "middle": [], "last": "Lum", "suffix": ""}], "year": 2009, "venue": "Aeronautics & Astronautics, Eng", "link": "109686644"}, "BIBREF6": {"title": "Cooperative search strategies of multi-UAVs for random targets", "authors": [{"first": "", "middle": [], "last": "Xuan Yong-Bo", "suffix": ""}, {"first": "", "middle": [], "last": "Chang-Qiang", "suffix": ""}, {"first": "", "middle": [], "last": "Wu Wen-Chao", "suffix": ""}], "year": 2013, "venue": "Control and Decision", "link": null}, "BIBREF7": {"title": "Extended search map approach for multiple UAVs wide area target searching", "authors": [{"first": "", "middle": [], "last": "Peng Hui", "suffix": ""}, {"first": "", "middle": [], "last": "Su Fei", "suffix": ""}, {"first": "", "middle": [], "last": "Shen Lin Cheng", "suffix": ""}], "year": 2010, "venue": "Systems Engineering and Electronics", "link": "63187021"}, "BIBREF8": {"title": "Coverage search strategies for moving targets using multiple unmanned aerial vehicles teams", "authors": [{"first": "", "middle": [], "last": "Xuan Yong-Bo", "suffix": ""}, {"first": "", "middle": [], "last": "Chang-Qiang", "suffix": ""}, {"first": "", "middle": [], "last": "Wu Wen-Chao", "suffix": ""}], "year": 2013, "venue": "Systems Engineering and Electronics", "link": "63421340"}, "BIBREF9": {"title": "Decentralized Cooperative Search by Networked Multi-UAVs in Uncertain Environment", "authors": [{"first": "Y", "middle": [], "last": "Yang", "suffix": ""}, {"first": "M", "middle": [], "last": "Polycarpou", "suffix": ""}, {"first": "A", "middle": [], "last": "Minai", "suffix": ""}], "year": 2004, "venue": "Proceedings of the 2004 American Control Conference", "link": null}, "BIBREF10": {"title": "Cooperative control for multiple autonomous UAV's seaching for targets", "authors": [{"first": "M", "middle": [], "last": "Flint", "suffix": ""}, {"first": "M", "middle": [], "last": "Polycarpou", "suffix": ""}, {"first": "E", "middle": [], "last": "Fernandez", "suffix": ""}], "year": 2002, "venue": "Proceedings of the 41th IEEE Conference on Decision and Control", "link": "55773996"}, "BIBREF11": {"title": "Cooperative Search by Uninhabited Air Vehicles in Dynamic Environment", "authors": [{"first": "Yanli", "middle": [], "last": "Yang", "suffix": ""}], "year": 2005, "venue": "", "link": "130709104"}, "BIBREF12": {"title": "Cooperative Graph-Based Model Predictive Search", "authors": [{"first": "J", "middle": ["R"], "last": "Riehl", "suffix": ""}, {"first": "G", "middle": ["E"], "last": "Collins", "suffix": ""}, {"first": "J", "middle": ["P"], "last": "Hespanha", "suffix": ""}], "year": 2007, "venue": "Proceedings of the 46th IEEE Conference on Decision and Control", "link": "18779909"}}, "ref_entries": {}}
{"paper_id": "8335253", "_pdf_hash": "60bc4c93a0b8ff0a7f30721eb2893d2aafc307c9", "abstract": [], "body_text": [{"section": "Introduction", "text": "The PHERMEX facility consists of a 50-MHz standing-wave linear accelerator. Electrons with up to 550-keV kinetic energy are injected into the accelerating column by a hot-cathode electron gun. The present lO0-mm-diam cathode has been in operation since 1963.1 The gun has performed extremely well since that time, and to date there have been no substantial design changes. Early gun experiments involved measurement of current, voltage, and beam distribution; however, no emittance measurements had been made. As part of the PHERMEX upgrade program, it was felt that this gun design could be extended to higher perveance. Early experiments indicated that it was necessary to maintain beam quality to transport the beam through the three PHERMEX accelerator cavities.", "cite_spans": [], "ref_spans": []}, {"section": "Experimental Results", "text": "Details of the electron-gun design, materials, and engineering are described extensively in Ref. 1 . Here we discuss only the anode-cathode (A-K) geometry as it relates to our experiments. Figure 1 is Figure 3b is the signal measured by this monitor.", "cite_spans": [{"start": 97, "end": 98, "text": "1", "ref_id": "BIBREF0"}], "ref_spans": [{"start": 201, "end": 210, "text": "Figure 3b", "ref_id": "FIGREF1"}]}, {"section": "Experimental Results", "text": "The hot cathode is pulsed with a negative voltage and electrons are driven through the anode aperture. The resulting cylindrical electron beam strikes a 1.5-mm-thick, 102-mm-diam disk. The disk contains a cylindrically symmetric hole pattern with slots for determining the beam diameter. Figure 4 is a diagram of this disk. Approximately 98% of the beam is intercepted by the disk. The collected electron current on the disk goes to ground through twenty 10-Q, 2-W carbon resistors in parallel. This resistance was measured to be 0.510 Q. The voltage across the resistor ring was monitored and a sample trace is shown in Fig. 3c . This was used for the time-resolved current measurement.", "cite_spans": [], "ref_spans": [{"start": 288, "end": 296, "text": "Figure 4", "ref_id": "FIGREF2"}, {"start": 621, "end": 628, "text": "Fig. 3c", "ref_id": "FIGREF1"}]}, {"section": "Experimental Results", "text": "The beamlets, which are transmitted through the aluminum mask, drift 102 mm and impinge on an aluminized glass surface. Light is generated by the electron-aluminum oxide interaction and is transmitted through the glass. Three experiments involving minor design changes in the A-K geometry will be discussed in detail. These include: (1) standard gun A-K geometry (Fig. 1 Table I . A sample r vs a plot from which the emittance is determined is shown in Fig. 8 .", "cite_spans": [], "ref_spans": [{"start": 371, "end": 378, "text": "Table I", "ref_id": "TABREF2"}]}, {"section": "Experimental Arrangements", "text": "The electron-gun perveance depends only on the A-K geometry. Therefore, the internal consistency of the perveance calculation for a single experiment is a measure of the relative accuracy of the technique used to determine the voltage and current. The average value of the perveance for each experiment is summarized in Table II . It should be noted, however, that the absolute measure of the perveance probably contains systematic errors. Here we desire only internal consistency for intercomparison. A measure of the internal constancy is presented by the statistical error quoted in Table II. Clearly, the addition of the return-current cone (Exp. 2) did not change the perveance. However, displacement of the anode 5.1 mm toward the cathode (Exp.", "cite_spans": [], "ref_spans": [{"start": 320, "end": 328, "text": "Table II", "ref_id": "TABREF2"}, {"start": 586, "end": 595, "text": "Table II.", "ref_id": "TABREF2"}]}, {"section": "Experimental Arrangements", "text": "U. S. Government work not protected by U. S. copyright.", "cite_spans": [], "ref_spans": []}, {"section": "Experimental Arrangements", "text": "3) did increase the perveance by 15%. A substantial improvement in emittance was realized simply by the addition of the return-current cone. Apparently the presence of a transverse gap just beyond the anode of the standard gun configuration induces a significant amount of transverse momentum in the beam through lack of local image currents flowing near the beam axis in the region just beyond the anode. Displacement of the anode toward the cathode (Exp. 3) increases the beam area at emittance mask substantially (30%). However, the presence of the return-current shield decreases the emittance and makes it comparable to that of standard gun configuration at the same voltage.", "cite_spans": [], "ref_spans": []}, {"section": "Theoretical Results", "text": "The time-dependent, two-dimensional Particle-inCell (PIC) simulation code CCUBE has been used to study beam dynamics in the A-K gap. Although the code has been successfully used on a variety of intense beam problems, initial studies were directed at code validation for the existing standard gun geometry. Such numerical tools include all self-consistent fields but at the expense of limited resolution and enhanced highfrequency noise. Since perveance is determined by the geometry for space-charge-limited flow, this parameter was felt to provide a fair test of resolution. Perveance of the calculated beams was found to agree with experiment to within 10-20%. Though the values were consistently lower than experimental ones, scaling was consistent. Numerical values for voltage of 450 kV are given in Table II . Further, inclusion of a conducting shield beyond the anode aperture seemed to reduce the transverse energy of the transported beam. Future calculations will quantify the emittance. Finally, a trial variation on the standard gun geometry has resulted in an increase of calculated perveance from 0.8 pperv to 1.8 pperv at 1.022 MV.", "cite_spans": [], "ref_spans": [{"start": 805, "end": 813, "text": "Table II", "ref_id": "TABREF2"}]}, {"section": "Conclusions", "text": "Experimental measurements and theoretical calculations have been performed and compared for the PHERMEX standard electron gun. Slight changes in the gun configuration have produced significant changes in beam intensity and quality. It is hoped that the present gun configuration can be extended to even higher perveances (without significant loss of beam quality) through a joint theoretical and experimental effort. ", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "PHERMEX: A Pulsed High-Energy Radiographic Machine Emitting X-Rays", "authors": [{"first": "D", "middle": [], "last": "Venable", "suffix": ""}], "year": 1967, "venue": "Los Alamos National Laboratory report LA", "link": "116631525"}}, "ref_entries": {"FIGREF0": {"text": "Photographs are taken of the beam- *Work performed under the auspices of the U.S. Department of Energy. let distribution. A typical photograph is shown in Fig. 5.", "type": "figure"}, "FIGREF1": {"text": "Fig. 3 Measurements of the gun (a) voltage, (b) current to the gun, and (c) transmitted current (all 100 ns/div)", "type": "figure"}, "FIGREF2": {"text": "Fig. 4 Emittance-mask charge collector", "type": "figure"}, "TABREF0": {"text": "a drawing of the PHERMEX standard 100-rn gun A-K geometry. 0 A type-B dispenser cathode operated at 1100 C was selected as the best possible cathode for PHERMEX ap- plication. It has a long lifetime and is not extremely susceptible to poisoning. All of the experiments dis- cussed in this paper have used this type cathode. Figure 2 is a schematic diagram of the experimen- tal arrangement. The voltage is supplied across the A-K gap by a 600-kV Femcor pulser. The pulser is a Marx generator with coaxial-cable capacitor elements. The internal impedance of the pulser is 280 Q and is matched by placing a load resistor in parallel with the electron gun. The pulser voltage is monitored by meas- uring the voltage across a low resistance (0.1 Q) in series with the load resistor. Figure 3a shows a typ- ical voltage trace measured across the current-viewing resistor (CVR). Current to the gun is measured using a Pearson Model 410 current monitor. The monitor signal is con- verted to light by a light-emitting current diode. The light is transmitted through an optical fiber to a light-to-voltage converter, and the signal is monitored by an oscilloscope. At present, this monitor has a bandwidth of 10-to-50 MHz. Development of a faster monitor is in progress.", "type": "table"}, "TABREF1": {"text": "solid line); (2) standard gun with return-current cone (Fig. 1 solid line plus copper return-current cone noted by the dashed line); and (3) same as (2) with the A-K gap, d, decreased by 5.1 mm.Figures 3a and 3c are typical current-viewing resistor and emittance-mask/charge-collector voltage traces, respectively. The CVR gives a measure of the voltage on the gun because all elements shown in Fig. 2 schematic are in parallel. The charge collector yields a proportional measurement of the beam current extract- ed from the cathode. The current and voltage are meas- ured at the 150-ns width of the pulse. Results of these measurements for all three experiments are shown in Columns 2 and 3 of Table I. The gun perveance, g, is calculated from the formula I = gV / and is shown in Column 4. The beam emittance is determined from the beamlets distribution shown in Fig. 5. The negatives of the", "type": "table"}, "TABREF2": {"text": "UNNORMALIZED EMITTANCE*. . Cero. Z. ho1.0l iWp of dIWO RL . LOOd t-.tO V/L. vo o fiO eo- LV . ugm to Holtto 00n,r, 2. Kulke, B. and Kihara, R., \"Emittance Measurement on Field Emitter Diodes, Proceedings of 2nd Interna- tional Pulse Power Conference, 209 (1979).", "type": "table"}}}
{"paper_id": "8335267", "_pdf_hash": "4b1e62db248bd3000a83cb51ed36db89a515ca2b", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Biometric Authentication", "authors": [{"first": "Alfred", "middle": ["C"], "last": "Weaver", "suffix": ""}], "year": 2006, "venue": "", "link": null}, "BIBREF1": {"title": "FINGERPRINT MATCHING", "authors": [{"first": "K", "middle": [], "last": "Anil", "suffix": ""}, {"first": "", "middle": [], "last": "Jain", "suffix": ""}], "year": 2010, "venue": "", "link": null}, "BIBREF2": {"title": "On the Influence of Fingerprint Area in Partial Fingerprint Recognition", "authors": [{"first": "Fanglin", "middle": [], "last": "Chen", "suffix": ""}, {"first": "Jie", "middle": [], "last": "Zhou", "suffix": ""}], "year": 2012, "venue": "CCBR 2012", "link": "14029743"}, "BIBREF3": {"title": "High resolution partialfmgerprint alignment using pore-valleydescriptors", "authors": [{"first": "Qijun", "middle": [], "last": "Zhao", "suffix": ""}, {"first": "", "middle": [], "last": "Davidzhang", "suffix": ""}, {"first": "Nanluo", "middle": [], "last": "Leizhang", "suffix": ""}], "year": 2009, "venue": "", "link": null}, "BIBREF4": {"title": "Aminutia-based partial fingerprint recognition system", "authors": [{"first": "", "middle": [], "last": "Tsai-Yang Jea", "suffix": ""}, {"first": "", "middle": [], "last": "Venu Govindaraju", "suffix": ""}], "year": 2005, "venue": "", "link": null}, "BIBREF5": {"title": "Partial fmgerprint matching based on SIFf Features", "authors": [{"first": "", "middle": ["S"], "last": "Ms", "suffix": ""}, {"first": "", "middle": [], "last": "Malathi", "suffix": ""}], "year": 2010, "venue": "IJCSE", "link": null}, "BIBREF6": {"title": "Fuzzy Logic Method for Partial Fingerpint", "authors": [{"first": "Radu", "middle": [], "last": "Miron", "suffix": ""}, {"first": "Tiberiu", "middle": [], "last": "Letia", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF7": {"title": "Fingerprint Recognition Algorithms for Paltial and Full Fingerprints", "authors": [{"first": "S", "middle": [], "last": "Mil&apos;shtein", "suffix": ""}, {"first": "A", "middle": [], "last": "Pillai", "suffix": ""}, {"first": "A", "middle": [], "last": "Shendye", "suffix": ""}, {"first": "C", "middle": [], "last": "Liessner", "suffix": ""}, {"first": "M", "middle": [], "last": "Baier", "suffix": ""}], "year": 2008, "venue": "Advanced Electronic Technology Center, ECE Dept", "link": null}, "BIBREF8": {"title": "DOTS AND INCIPIENTS: EXTENDED FEATURES FOR PARTIAL FINGERPRINT MATCHING", "authors": [{"first": "Yi", "middle": [], "last": "Chen", "suffix": ""}, {"first": "K", "middle": [], "last": "Anil", "suffix": ""}, {"first": "", "middle": [], "last": "Jain", "suffix": ""}], "year": 2007, "venue": "IEEE", "link": "14894885"}, "BIBREF9": {"title": "An efficient method for partial fingerprint recognition based on Local Binary Pattern", "authors": [{"first": "S", "middle": [], "last": "Malathi", "suffix": ""}, {"first": ".", "middle": ["C"], "last": "Dr", "suffix": ""}, {"first": "", "middle": [], "last": "Meena", "suffix": ""}], "year": "", "venue": "IEEE", "link": null}, "BIBREF10": {"title": "Partial Fingerprint Matching using Projection based Weak Descriptor", "authors": [{"first": "Manasa", "middle": [], "last": "Nadipally", "suffix": ""}, {"first": "*", "middle": [], "last": "", "suffix": ""}, {"first": "A", "middle": [], "last": "Govardhan", "suffix": ""}, {"first": "Ch", "middle": [], "last": "Satyanarayana", "suffix": ""}], "year": 2013, "venue": "", "link": "14442632"}, "BIBREF11": {"title": "Latent Fingerprint Matcbing:Fusion of Rolled and Plain Fingerprints", "authors": [{"first": "Jianjiang", "middle": [], "last": "Feng", "suffix": ""}, {"first": "Soweon", "middle": [], "last": "Yoon", "suffix": ""}, {"first": "", "middle": [], "last": "Jain", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF12": {"title": "Technical Document About FAR, FRR and EER Version 1.0, SYRIS Technology Corp", "authors": [], "year": 2004, "venue": "", "link": null}, "BIBREF13": {"title": "Multibiometric Identification System Based On Score Level Fusion", "authors": [{"first": "P", "middle": ["D"], "last": "Garje", "suffix": ""}, {"first": "Prof", "middle": ["S S"], "last": "", "suffix": ""}], "year": 2012, "venue": "10SR Journal of Electronics and COImnunication Engineering", "link": "15664899"}}, "ref_entries": {}}
{"paper_id": "8335837", "_pdf_hash": "463160164f4c203ae1fde4324448e412f948266e", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "How were new medicines discovered?", "authors": [{"first": "D", "middle": ["C"], "last": "Swinney", "suffix": ""}, {"first": "J", "middle": [], "last": "Anthony", "suffix": ""}], "year": 2011, "venue": "Nature Reviews Drug Discovery", "link": "19171881"}, "BIBREF2": {"title": "Automated Image-Based Phenotypic Screening for HighThroughput Drug Discovery", "authors": [{"first": "", "middle": [], "last": "Caffrey", "suffix": ""}], "year": 2009, "venue": "IEEE Symposium on Computer-Based Medical Systems", "link": "9441338"}, "BIBREF3": {"title": "Quantification and clustering of phenotypic screening data using time-series analysis for chemotherapy of schistosomiasis", "authors": [{"first": "H", "middle": [], "last": "Lee", "suffix": ""}], "year": 2012, "venue": "BMC Genomics", "link": "7086195"}, "BIBREF4": {"title": "Whole Organism High-Content Screening by Label-Free, Image-Based Bayesian Classification for Parasitic Diseases", "authors": [{"first": "R", "middle": ["A"], "last": "Paveley", "suffix": ""}], "year": 2012, "venue": "PLoS Negl Trop Dis", "link": "14757094"}, "BIBREF5": {"title": "WormAssay: A Novel Computer Application for WholePlate Screening of Macroscopic Parasites", "authors": [{"first": "C", "middle": [], "last": "Marcellino", "suffix": ""}, {"first": "J", "middle": [], "last": "Gut", "suffix": ""}, {"first": "K", "middle": ["C"], "last": "Lim", "suffix": ""}, {"first": "R", "middle": [], "last": "Singh", "suffix": ""}, {"first": "J", "middle": [], "last": "Mckerrow", "suffix": ""}, {"first": "J", "middle": [], "last": "Sakanari", "suffix": ""}], "year": 2012, "venue": "PLoS Neglected Tropical Diseases", "link": null}, "BIBREF6": {"title": "A quantitative analysis and performance study for similarity-search methods in highdimensional spaces", "authors": [{"first": "R", "middle": [], "last": "Weber", "suffix": ""}, {"first": "H", "middle": ["J"], "last": "Schek", "suffix": ""}, {"first": "S", "middle": [], "last": "Blott", "suffix": ""}], "year": 1998, "venue": "Proc. Inter. Conf. on Very Large Data Bases", "link": "8109758"}, "BIBREF7": {"title": "Segmenting the Etiological Agent of Schistosomiasis for High-Content Screening", "authors": [{"first": "D", "middle": [], "last": "Asarnow", "suffix": ""}, {"first": "R", "middle": [], "last": "Singh", "suffix": ""}], "year": 2013, "venue": "IEEE Transactions on Medical Imaging", "link": "18789548"}, "BIBREF8": {"title": "Fast algorithms for projected clustering", "authors": [{"first": "C", "middle": ["C"], "last": "Aggarwal", "suffix": ""}, {"first": "J", "middle": ["L"], "last": "Wolf", "suffix": ""}, {"first": "P", "middle": ["S"], "last": "Yu", "suffix": ""}, {"first": "C", "middle": [], "last": "Procopiuc", "suffix": ""}, {"first": "J", "middle": ["S"], "last": "Park", "suffix": ""}], "year": 1999, "venue": "Proc. ACM Inter. Conf. on Manage. of Data", "link": "16144421"}}, "ref_entries": {}}
{"paper_id": "8335938", "_pdf_hash": "467ed40212d67630af9e7ddaf4aeca90d6285c3b", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Registre, genre and style", "authors": [{"first": "D", "middle": [], "last": "Biber", "suffix": ""}, {"first": "S", "middle": [], "last": "Conrad", "suffix": ""}], "year": 2009, "venue": "", "link": null}, "BIBREF1": {"title": "Open borders? immigration in open source projects", "authors": [{"first": "C", "middle": [], "last": "Bird", "suffix": ""}, {"first": "A", "middle": [], "last": "Devanbu", "suffix": ""}, {"first": "P", "middle": [], "last": "Swaminathan", "suffix": ""}, {"first": "G", "middle": [], "last": "Hsu", "suffix": ""}], "year": 2007, "venue": "MSR '07. Proceedings of the Fourth International Workshop on Mining Software Repositories", "link": "636686"}, "BIBREF2": {"title": "Cathedrals. Bazaars and the town council", "authors": [{"first": "A", "middle": [], "last": "Cox", "suffix": ""}], "year": 1998, "venue": "", "link": null}, "BIBREF3": {"title": "Hierarchy and centralization in free and open source software team communications. Knowledge", "authors": [{"first": "K", "middle": [], "last": "Crowston", "suffix": ""}, {"first": "J", "middle": [], "last": "Howison", "suffix": ""}], "year": 2006, "venue": "Technology & Policy", "link": null}, "BIBREF4": {"title": "A structuration perspective on leadership in free/libre open source software teams", "authors": [{"first": "K", "middle": [], "last": "Crowston", "suffix": ""}, {"first": "R", "middle": [], "last": "Heckman", "suffix": ""}, {"first": "H", "middle": [], "last": "Annabi", "suffix": ""}, {"first": "C", "middle": [], "last": "Masango", "suffix": ""}], "year": 2005, "venue": "Proceedings of the first international conference on open source systems", "link": "14204450"}, "BIBREF5": {"title": "Channelling Firefox developers: Mom and dad aren't happy yet", "authors": [{"first": "M", "middle": [], "last": "Den Besten", "suffix": ""}, {"first": "H", "middle": [], "last": "Masmoudi", "suffix": ""}, {"first": "J.-M", "middle": [], "last": "Dalle", "suffix": ""}], "year": 2008, "venue": "Open Source Systems", "link": "14101155"}, "BIBREF6": {"title": "Analyzing and Relating Bug Report Data for Feature Tracking", "authors": [{"first": "M", "middle": [], "last": "Fischer", "suffix": ""}, {"first": "M", "middle": [], "last": "Pinzger", "suffix": ""}, {"first": "H", "middle": [], "last": "Gall", "suffix": ""}], "year": 2003, "venue": "", "link": "13214951"}, "BIBREF7": {"title": "Case Study", "authors": [{"first": "B", "middle": [], "last": "Flyvbjerg", "suffix": ""}], "year": 2011, "venue": "The Sage Handbook of Qualitative Research", "link": null}, "BIBREF8": {"title": "Managing rights", "authors": [{"first": "R", "middle": [], "last": "Ghosh", "suffix": ""}], "year": 2006, "venue": "free/libre/open source software", "link": null}, "BIBREF9": {"title": "Distributed Collective Practices and Free/Open-Source Software Problem", "authors": [{"first": "L", "middle": [], "last": "Gasser", "suffix": ""}, {"first": "R", "middle": [], "last": "Gabriel", "suffix": ""}], "year": 2003, "venue": "Management: Perspectives and Methods. Conference on Cooperation, Innovation & Technologie (CITE'03)", "link": null}, "BIBREF10": {"title": "The Constitution of Society", "authors": [{"first": "A", "middle": [], "last": "Giddens", "suffix": ""}], "year": 1984, "venue": "", "link": null}, "BIBREF11": {"title": "The geography of coordination: Deling with distance in R&D work", "authors": [{"first": "R", "middle": ["E"], "last": "Grinter", "suffix": ""}, {"first": "J", "middle": ["D"], "last": "Herbsleb", "suffix": ""}, {"first": "D", "middle": ["W"], "last": "Perry", "suffix": ""}], "year": 2006, "venue": "Proceedings of SIGGROUP Conference on Supporting Group Work", "link": "2320177"}, "BIBREF12": {"title": "Factors leading to integration failures in global feature-oriented development: an empirical analysis", "authors": [{"first": "J", "middle": ["D"], "last": "Herbsleb", "suffix": ""}, {"first": "M", "middle": [], "last": "Cataldo", "suffix": ""}], "year": 2011, "venue": "Proceedings, International Conference on Software Engineering", "link": "10647633"}, "BIBREF13": {"title": "A Linguistic Analysis of How People Describe Software Problems in Bug Reports", "authors": [{"first": "A", "middle": ["J"], "last": "Ko", "suffix": ""}, {"first": "B", "middle": ["A"], "last": "Myers", "suffix": ""}, {"first": "D", "middle": ["H"], "last": "Chau", "suffix": ""}], "year": 2006, "venue": "Visual Languages and Human-Centric Computing", "link": null}, "BIBREF14": {"title": "The core and the periphery in distributed and self-organizing innovation systems", "authors": [{"first": "K", "middle": ["R"], "last": "Lakhani", "suffix": ""}], "year": 2006, "venue": "Thesis (Ph. D.) from Sloan School of Management. Cambridge", "link": "106678381"}, "BIBREF15": {"title": "Outils de statistique textuelle. Manuel d'utilisation", "authors": [{"first": "C", "middle": [], "last": "Lamalle", "suffix": ""}, {"first": "W", "middle": [], "last": "Martinez", "suffix": ""}, {"first": "S", "middle": [], "last": "Fleury", "suffix": ""}, {"first": "A", "middle": [], "last": "Salem", "suffix": ""}], "year": 2002, "venue": "", "link": null}, "BIBREF16": {"title": "Exploring textual data. Dordrecht", "authors": [{"first": "L", "middle": [], "last": "Lebart", "suffix": ""}, {"first": "A", "middle": [], "last": "Salem", "suffix": ""}, {"first": "L", "middle": [], "last": "Berry", "suffix": ""}], "year": 1998, "venue": "", "link": null}, "BIBREF17": {"title": "Can Development Work Describe Itself", "authors": [{"first": "W", "middle": [], "last": "Maalej", "suffix": ""}, {"first": "H", "middle": ["J"], "last": "Happel", "suffix": ""}], "year": 2012, "venue": "Proceedings of the 7th IEEE Conference on Mining Software Repositories", "link": "7227935"}, "BIBREF18": {"title": "Toward an interdisciplinary theory of coordination", "authors": [{"first": "T", "middle": ["W"], "last": "Malone", "suffix": ""}], "year": 1991, "venue": "CCS 120", "link": null}, "BIBREF19": {"title": "The governance of free/open source software projects: monolithic, multidimensional, or configurational", "authors": [{"first": "M", "middle": ["L"], "last": "Markus", "suffix": ""}], "year": 2007, "venue": "Journal of Management and Governance", "link": null}, "BIBREF20": {"title": "La r\u00e9solution distribu\u00e9e dans les communaut\u00e9s Open Source : propri\u00e9t\u00e9s organisationnelles et modes de coordination", "authors": [{"first": "H", "middle": [], "last": "Masmoudi", "suffix": ""}], "year": 2011, "venue": "", "link": null}, "BIBREF21": {"title": "Two case studies of open source software development: Apache and mozilla", "authors": [{"first": "A", "middle": [], "last": "Mockus", "suffix": ""}, {"first": "R", "middle": ["T"], "last": "Fielding", "suffix": ""}, {"first": "J", "middle": ["D"], "last": "Herbsleb", "suffix": ""}], "year": 2002, "venue": "ACM Transactions on Software Engineering and Methodology", "link": "1938015"}, "BIBREF22": {"title": "The emergence of governance in an open source community", "authors": [{"first": "S", "middle": [], "last": "O&apos;mahony", "suffix": ""}, {"first": "F", "middle": [], "last": "Ferraro", "suffix": ""}], "year": 2007, "venue": "Academy of Management Journal", "link": null}, "BIBREF23": {"title": "Usability Discussions in Open Source Development", "authors": [{"first": "D", "middle": ["M"], "last": "Nichols", "suffix": ""}, {"first": "M", "middle": ["B"], "last": "Twidale", "suffix": ""}], "year": 2005, "venue": "HICSS", "link": null}, "BIBREF24": {"title": "The Duality of Technology: Rethinking the Concept of Technology in Organizations", "authors": [{"first": "W", "middle": ["J"], "last": "Orlikowski", "suffix": ""}], "year": 1992, "venue": "Organization Science", "link": "145653991"}, "BIBREF25": {"title": "How do developers blog?: an exploratory study", "authors": [{"first": "D", "middle": [], "last": "Pagano", "suffix": ""}, {"first": "", "middle": [], "last": "Maalej", "suffix": ""}], "year": 2011, "venue": "Proceedings of the 8th Working Conference on Mining Software Repositories (MSR '11)", "link": "5780088"}, "BIBREF26": {"title": "The cathedral and the bazaar", "authors": [{"first": "E", "middle": ["S"], "last": "Raymond", "suffix": ""}], "year": 1998, "venue": "First Monday", "link": "908300"}, "BIBREF27": {"title": "Experiences in automating the analysis of linguistic interactions for the study of distributed collectives", "authors": [{"first": "G", "middle": [], "last": "Ripoche", "suffix": ""}, {"first": "J", "middle": ["P"], "last": "Sansonnet", "suffix": ""}], "year": 2006, "venue": "Computer Supported Cooperative Work", "link": "11780445"}, "BIBREF28": {"title": "Research methods for business students", "authors": [{"first": "M", "middle": [], "last": "Saunders", "suffix": ""}, {"first": "A", "middle": [], "last": "Thornhill", "suffix": ""}], "year": 2005, "venue": "", "link": null}, "BIBREF29": {"title": "Case Study Research: Design and Methods. Fourth Edition", "authors": [{"first": "R", "middle": ["K"], "last": "Yin", "suffix": ""}], "year": 2009, "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "8336388", "_pdf_hash": "f93986180d0455e274756bc9cc28d156d4ee63a7", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "A novel membrane sodium current induced by injection of cyclic nucleotides into gastropod neurones", "authors": [{"first": "J", "middle": ["A"], "last": "Connor", "suffix": ""}, {"first": "P", "middle": [], "last": "Hockberger", "suffix": ""}], "year": 1984, "venue": "J. Physiol", "link": "44848106"}, "BIBREF1": {"title": "Intracellular calcium accumulation during depolarization in a molluscan neuron", "authors": [{"first": "A", "middle": ["L F"], "last": "Gorman", "suffix": ""}, {"first": "M", "middle": ["V"], "last": "Thomas", "suffix": ""}], "year": 1980, "venue": "J. Physiol", "link": "6237985"}, "BIBREF2": {"title": "Peptide factor extracted from molluscan ganglia that modulates bursting pacemaker activity", "authors": [{"first": "M", "middle": ["S"], "last": "Ifshin", "suffix": ""}, {"first": "H", "middle": [], "last": "Gainer", "suffix": ""}, {"first": "J", "middle": ["L"], "last": "Barker", "suffix": ""}], "year": 1975, "venue": "Nature", "link": null}, "BIBREF3": {"title": "Investigations of the ionic mechanisms of bursting activity in Helix pomatia neurons", "authors": [{"first": "N", "middle": ["I"], "last": "Kononenko", "suffix": ""}], "year": 1978, "venue": "Neurophysiology (Kiev)", "link": "21234415"}, "BIBREF4": {"title": "Modulation of the endogenous electrical activity of the bursting neuron in the snail Helix pomatia. I. The generator of the slow rhythms", "authors": [{"first": "N", "middle": ["I"], "last": "Kononenko", "suffix": ""}], "year": 1979, "venue": "Neuroscience", "link": "6617968"}, "BIBREF5": {"title": "Modulation of the endogenous electrical activity of the bursting neuron in the snail Helix pomatia. II. The membrane characteristics related to modulation of the endogenous activity of the neuron", "authors": [{"first": "N", "middle": ["I"], "last": "Kononenko", "suffix": ""}], "year": 1979, "venue": "Neuroscience", "link": "6542226"}, "BIBREF6": {"title": "Modulation of the endogenous electrical activity of the bursting neuron in the snail Helix pomatia. III. A factor modulating the endogenous electrical activity of the bursting neuron", "authors": [{"first": "N", "middle": ["I"], "last": "Kononenko", "suffix": ""}], "year": 1979, "venue": "Neuroscience", "link": "40336751"}, "BIBREF7": {"title": "The axosomatic contacts on the bursting neuron of the snail Helix pomatia. I. Ultrastructural features of the axosomatic contacts", "authors": [{"first": "L", "middle": ["M"], "last": "Koval", "suffix": ""}, {"first": "N", "middle": ["I"], "last": "Kononenko", "suffix": ""}, {"first": "G", "middle": ["G"], "last": "Skibo", "suffix": ""}], "year": 1984, "venue": "Cell. Mol. Neurobiol", "link": "20405522"}, "BIBREF8": {"title": "Blocking action of cadmium ions on calcium inward current in nerve-cell membrane", "authors": [{"first": "O", "middle": ["A"], "last": "Krishtal", "suffix": ""}], "year": 1976, "venue": "Dokl. Akad. Nauk SSSR", "link": "88580696"}, "BIBREF9": {"title": "Two identified interneurons modulate the firing pattern of pacemaker bursting cells in Helix", "authors": [{"first": "T", "middle": [], "last": "Pin", "suffix": ""}, {"first": "M", "middle": [], "last": "Gola", "suffix": ""}], "year": 1983, "venue": "Neurosci, Lett", "link": "42613622"}, "BIBREF10": {"title": "The Genealogy of Neurons", "authors": [{"first": "D", "middle": ["A"], "last": "Sakharov", "suffix": ""}], "year": 1974, "venue": "", "link": null}, "BIBREF11": {"title": "Requirements for bursting pacemaker potential activity in molluscan neurones", "authors": [{"first": "T", "middle": ["G"], "last": "Smith", "suffix": ""}, {"first": "", "middle": [], "last": "Jr", "suffix": ""}, {"first": "J", "middle": ["L"], "last": "Barker", "suffix": ""}, {"first": "H", "middle": [], "last": "Gainer", "suffix": ""}], "year": 1975, "venue": "Nature", "link": null}, "BIBREF12": {"title": "Ultrastructure and histochemistry of neurosecretory cells and neurohaemal areas in the pond snail Lymnaea stagnalis (L)", "authors": [{"first": "Wendelaar", "middle": [], "last": "Bonga", "suffix": ""}, {"first": "S", "middle": ["E"], "last": "", "suffix": ""}], "year": 1970, "venue": "Z. Zellforsch", "link": "2545736"}, "BIBREF13": {"title": "Furosemide blockage of the chloride conductance induced in mollusc neurons by acetylcholine or 7-aminobutyric acid", "authors": [{"first": "E", "middle": ["V"], "last": "Zeimal", "suffix": ""}, {"first": "A", "middle": ["N"], "last": "Kachman", "suffix": ""}], "year": 1983, "venue": "Neirofiziologiya (Kiev)", "link": null}}, "ref_entries": {}}
{"paper_id": "8336483", "_pdf_hash": "bf8d36a5f4b9e4d4221c12e1fbb3a453d2a731f0", "abstract": [{"section": "Abstract", "text": "SUMMARY: NATO war medical doctrine was applied in the war in Croatia, Bosnia and Herzegovina. However, due to rather specific martial and organizational circumstances, the doctrine had to be modified. sometimes substantially. A medical team from the war hospital in Livno, Bosnia and Herzegovina decribes their work with respect to the four-echelon NATO doctrine. The team covered a relatively large and active battlefield, and treated 597 patients with 314 major surgical interventions. Due to the lack of surgeons and medical personnel in general, the second echelon concentrated on fast transportation, and the third echelon fulfilled the function of the fourth echelon, completing the surgical treatment except for 12 patients with head and spine injuries.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "The way, time and circumstances in which Bosnia and Herzegovina was recognized as an independent and sovereign state on the one hand, and a highly delicate political situation and ethnic relations on the other, make the war in Bosnia and Herzegovina a highly specific one. In the spring of 1992 Croats and Muslims had neither regular army forces nor organized logistics and rear echelon, thus they were vulnerable to the strong and wellorganized Yugoslav Federal Army (YFA) and many Serbian paramilitary formations. The parliament, government and presidium of the newly formed state of Bosnia and Herzegovina, consisting of Croats, Serbs and Muslims were dissolved and the legislative, executive and judiciary power ceased to exist. The national economy and production were destroyed within a short time. After a few months, about 50% of the territory was controlled by the YFA and Serbian paramilitary forces.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "", "text": "The way, time and circumstances in which Bosnia and Herzegovina was recognized as an independent and sovereign state on the one hand, and a highly delicate political situation and ethnic relations on the other, make the war in Bosnia and Herzegovina a highly specific one. In the spring of 1992 Croats and Muslims had neither regular army forces nor organized logistics and rear echelon, thus they were vulnerable to the strong and wellorganized Yugoslav Federal Army (YFA) and many Serbian paramilitary formations. The parliament, government and presidium of the newly formed state of Bosnia and Herzegovina, consisting of Croats, Serbs and Muslims were dissolved and the legislative, executive and judiciary power ceased to exist. The national economy and production were destroyed within a short time. After a few months, about 50% of the territory was controlled by the YFA and Serbian paramilitary forces.", "cite_spans": [], "ref_spans": []}, {"section": "Public Health Service in Bosnia and Herzegovina during the First Year of the War", "text": "General disintegration of Bosnia and Herzegovina also affected the public health service. In the part controlled by the Cioats and Muslims each medical facility operated independently and managed to remain in function only owing to the enthusiastic efforts of its medical personnel and abundant donations given by numerous individuals and organizations from all parts of the world. Despite such chaos, the public health service system had to be organized in order to provide health care to the population, but also to treat growing numbers of war casualties, both soldiers and civilians. In addition to the lack of organized regular army forces, Croats and Muslims did not have organized military medical care. Therefore, the already existing civilian medical institutions took over the organization of all types of military medical services, including the system of the emergency war surgical care.", "cite_spans": [], "ref_spans": []}, {"section": "Organization and Operation of War Surgical Care in Bosnia and Herzegovina", "text": "The NATO Handbook of Emergency War Surgery (1) served as a basis for the formation and further development of war surgical care system in Bosnia and Herzegovina. However, specific circumstances dictated certain modifications of the NATO schemes. Of course, departures from the basic principles of surgical, resuscitation and anaesthetic management could not be made, but some changes in the staged management of the wounded were necessary. Bearing in mind the autonomous operation of each medical institution, the evacuation of the wounded was organised and performed to the best of the abilities of each medical institution and depending upon the war circumstances. It has to be pointed out that within the borders of Bosnia and Herzegovina there was no rear, and consequently no fourth echelon. Owing to the fact that Croatia has and is still, accepting all the wounded from Bosnia and Herzegovina, it has been possible to have the war casualties treated securely in rear medical facilities in Croatia.", "cite_spans": [], "ref_spans": []}, {"section": "Organization and Operation of War Surgical Care in Bosnia and Herzegovina", "text": "We want to present our modification of the third echelon, using the example of the Sturba war hospital near the town of Livno in the southwest part of Bosnia and Herzegovina, fully controlled by Croats and Muslims.", "cite_spans": [], "ref_spans": []}, {"section": "Phased Approach to Management of War Casualties in the Livno Battlefield", "text": "The NATO medical doctrine of echelonment recommends that the surgical care at the level of the third echelon should not comprise complete surgical management but only initial surgical effort to save life and limb, prevent infection and render the casualty transportable to a rear medical facility (l ). We think that this recommendation has been based upon the assumption that in the long and change-prone evacuation chain casualties are cared for by an undefined number of surgeons of various nationalities.", "cite_spans": [], "ref_spans": []}, {"section": "Phased Approach to Management of War Casualties in the Livno Battlefield", "text": "Our opinion is that such a concept of treatment at the level of the third echelon has been designed for powerful and well-organized multinational armies whose possible war operations would be waged in large areas, perhaps in foreign territory, supported with excellent logistics and always secure rear in the home countries.", "cite_spans": [], "ref_spans": []}, {"section": "Phased Approach to Management of War Casualties in the Livno Battlefield", "text": "A well-equipped war hospital was located at Sturba, 5 km away from the town of Livno (2) . When planning the organization of war surgical service system we decided that the evacuation chain of the casualties from the Livno battlefield should end at this hospital, which was at the level of the third echelon of medical care. Contrary to the NATO war doctrine, complete surgical care was given to casualties at this hospital in terms of definitive treatment of acute trauma. In case of severely wounded persons, especially those with life-threatening injuries, surgery, resuscitation and anaesthesia were done simultaneously because we adhered to the principle that surgical intervention was an integral part of resuscitation and that resuscitation without simultaneous complete surgical care would prove unsuccessful. Intensive care was continued during the postoperative course until stabilization of vital functions and the general condition, as well as elimination of early complications. After this, patients were transported to a fourth echelon medical facility, i.e. various hospitals in Croatia, mostly in Split and Zagreb (2) .", "cite_spans": [{"start": 85, "end": 88, "text": "(2)", "ref_id": "BIBREF1"}, {"start": 1130, "end": 1133, "text": "(2)", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Phased Approach to Management of War Casualties in the Livno Battlefield", "text": "Being close to the first front lines and having wellorganized road evacuation, casualties were transported to Sturba shortly after wounding, and those most seriously wounded were operated on within 1 -1.5 hours post injury. It was more than once that we were made aware of the importance of time in salvation of life and limb, as well as prevention of infection. The same conviction was shared by surgical and anaesthesiological teams assigned to auxiliary war hospitals in Croatia (3) (4) (5) (6) . In contrast to this, the reports from the Afghanistan war (7) speak of high rates of various complications, even fatal outcomes, due to delays in delivering adequate surgical care. Therefore, the proverb \"Time is money\" could be paraphrased as \"Time is life\".", "cite_spans": [{"start": 482, "end": 485, "text": "(3)", "ref_id": "BIBREF2"}, {"start": 486, "end": 489, "text": "(4)", "ref_id": "BIBREF3"}, {"start": 490, "end": 493, "text": "(5)", "ref_id": "BIBREF4"}, {"start": 494, "end": 497, "text": "(6)", "ref_id": "BIBREF5"}, {"start": 558, "end": 561, "text": "(7)", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "Phased Approach to Management of War Casualties in the Livno Battlefield", "text": "Following the mentioned principles, we treated a total of 597 patients at the Sturba war hospital and performed 1,014 minor surgical procedures (treatment of large nonpenetrating wounds with extensive soft tissue destruction, including injuries of muscles, tendons, small bones of the hand and foot) and 314 various major and complex surgical procedures (2) . Wound debridement was performed in accordance with the NATO handbook instructions and findings of Fackler (8) and Ryan (9), based upon ballistic studies. When having doubts about sparing or radical excision, we chose a radical one.", "cite_spans": [{"start": 354, "end": 357, "text": "(2)", "ref_id": "BIBREF1"}, {"start": 466, "end": 469, "text": "(8)", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "Phased Approach to Management of War Casualties in the Livno Battlefield", "text": "We believe that this method of work decreased the intraoperative and postoperative mortality rates to zero. Medicamentous therapy also played a significant role and cases of anaerobic or severe aerobic infections or sepsis were not recorded (2) .", "cite_spans": [{"start": 241, "end": 244, "text": "(2)", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Phased Approach to Management of War Casualties in the Livno Battlefield", "text": "The exception were casualties with isolated severe craniocerebral injuries. Following initial surgical care and resuscitation they were immediately transferred to Split. This city in Croatia was the fourth echelon and our rear, as well as the last resort for all the war casualties from the central and southwest parts of Bosnia and the west part of Herzegovina.", "cite_spans": [], "ref_spans": []}, {"section": "Phased Approach to Management of War Casualties in the Livno Battlefield", "text": "Our work at the Sturba war hospital was put to an end 16 months ago. Treatment, including secondary reconstructive surgery and rehabilitation, were completed in almost all of the patients. Due to the spread of war in Bosnia: and Herzegovina, we were not able to summon all patients for a detailed follow-up examination. Some of them presented for the control check-up, and for rather a large number of them we have data available from our fellow-physicians who finished their treatment or were in the process of bringing it to an end. In these two groups of followed-up patients quite good end results were obtained. Some of the patients were lost completely for the follow-up. We learned that some went back to their combat units and were injured or killed during the last year.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "We were forced to adapt the NATO war doctrine of echelonment in accordance with special circumstances of the war waged against Croatia, Bosnia and Herzegovina. The NATO organizational scheme was suitable for the treatment of war casualties in Bosnia and Herzegovina, and we strongly recommend it as a basic model which can be further developed in accordance with local conditions and potentials in a defence war.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "In addition to the recommended organization at the level of the third echelon of medical care, special attention should be paid to the second echelon (1, 2) . It is an important link in the chain of evacuation and our opinion was that it should be staffed by young physicians trained during graduate and postgraduate studies in the treatment of medical-surgical emergencies. There are not enough surgeons and anaethesiologists in Bosnia and Herzegovina that can be appointed to the third echelon, let alone the s~cond. Therefore, it is not possible to form mobile surgical teams, except in special cases such as aid given to the encircled hospitals in Sarajevo, Nova Bila, Zepce, etc (10) .", "cite_spans": [{"start": 150, "end": 153, "text": "(1,", "ref_id": "BIBREF0"}, {"start": 154, "end": 156, "text": "2)", "ref_id": "BIBREF1"}, {"start": 684, "end": 688, "text": "(10)", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "Conclusions", "text": "The destiny of war casualties, except for those having fatal injuries, depends upon the quality and promptness of first aid and complete surgical treatment and resuscitation. If the first two echelons fulfill their tasks properly and the wounded are treated in terms of complete surgical group.bmj.com on October 11, 2017 -Published by http://jramc.bmj.com/ Downloaded from treatment and resuscitation within the shortest possible period, preferably within one to two hours, they are given the best chance for quoad vitam et quoad sanationem.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Emergency war surgery. Second United States revision of the Emergency War Surgery NATO Handbook, United States Department of Defence. Washington, D.e.: United States Government Printing Office", "authors": [], "year": 1988, "venue": "General considerations of forward surgery", "link": null}, "BIBREF1": {"title": "Organization and work of the war hospital in Sturba near the town of Livno", "authors": [{"first": "Atias-Nikolov V", "middle": [], "last": "Saric V", "suffix": ""}, {"first": "", "middle": [], "last": "Kovac T", "suffix": ""}], "year": 1994, "venue": "Milit Med", "link": null}, "BIBREF2": {"title": "War hospital in Velika Gorica: The first seventy days", "authors": [{"first": "Gopcevic A", "middle": [], "last": "Stanch: V", "suffix": ""}, {"first": "", "middle": [], "last": "Heitzler-Nikolic V", "suffix": ""}], "year": 1992, "venue": "Croatian Med", "link": null}, "BIBREF3": {"title": "Organization and functioning of the Sisters of Mercy University Hospital in the war against Croatia", "authors": [{"first": "", "middle": [], "last": "Petrac D", "suffix": ""}, {"first": "", "middle": [], "last": "Georgijevic A", "suffix": ""}, {"first": "", "middle": [], "last": "Kusic Z", "suffix": ""}], "year": 1992, "venue": "Croatian Med", "link": null}, "BIBREF4": {"title": "Mobile Surgical Teams in Croatian Special Forces Units (1990-1991)", "authors": [{"first": "", "middle": [], "last": "Husar J", "suffix": ""}], "year": 1993, "venue": "Croatian Med", "link": null}, "BIBREF5": {"title": "Battlefield experience of a Mobile Surgical Team: anaesthesiological approach", "authors": [{"first": "", "middle": [], "last": "Peric M", "suffix": ""}, {"first": "", "middle": [], "last": "Hamel D", "suffix": ""}, {"first": "", "middle": [], "last": "Kelecic M", "suffix": ""}], "year": 1992, "venue": "Croatian Med", "link": null}, "BIBREF6": {"title": "Trauma in the Aghan guerrilla war: Effects of lack of access to care", "authors": [{"first": "", "middle": [], "last": "Bhatnagar M K", "suffix": ""}, {"first": "", "middle": [], "last": "Smith G S", "suffix": ""}], "year": 1989, "venue": "Surgery", "link": null}, "BIBREF7": {"title": "A Review of common misconceptions", "authors": [{"first": "", "middle": [], "last": "Fackler M L. Wound", "suffix": ""}, {"first": "", "middle": [], "last": "Ballistics", "suffix": ""}], "year": 1988, "venue": "lAMA", "link": null}, "BIBREF8": {"title": "Field surgery on a future conventional battlefield: Strategy and wound management", "authors": [{"first": "Cooper G J", "middle": [], "last": "Ryan J M", "suffix": ""}, {"first": "", "middle": [], "last": "Haywood I R", "suffix": ""}], "year": "", "venue": "Ann R Coli Surg", "link": "10937059"}, "BIBREF9": {"title": "White road for Nova Bila and Silver Bosnia: A Chronology of the humanitarian convoy", "authors": [{"first": "", "middle": [], "last": "Marusic A", "suffix": ""}, {"first": "", "middle": [], "last": "Marusic M", "suffix": ""}, {"first": "", "middle": [], "last": "Lang S", "suffix": ""}], "year": 1994, "venue": "Croatian Med", "link": null}}, "ref_entries": {}}
{"paper_id": "8336604", "_pdf_hash": "4d38a3907ddeda61b36326248fe33e2baf4512bf", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Asynchronous design methodologies: An overview", "authors": [{"first": "S", "middle": [], "last": "Hauck", "suffix": ""}], "year": 1995, "venue": "Proceedings of the IEEE", "link": "18207326"}, "BIBREF1": {"title": "What is the cost of delay insensitivity?", "authors": [{"first": "H", "middle": [], "last": "Saito", "suffix": ""}, {"first": "A", "middle": [], "last": "Kondratyev", "suffix": ""}, {"first": "J", "middle": [], "last": "Cortadella", "suffix": ""}, {"first": "L", "middle": [], "last": "Lavagno", "suffix": ""}, {"first": "A", "middle": [], "last": "Yakovlev", "suffix": ""}], "year": 1999, "venue": "", "link": "2469197"}, "BIBREF3": {"title": "Early Output Logic using Anti-tokens", "authors": [{"first": "C", "middle": [], "last": "Brej", "suffix": ""}], "year": 2003, "venue": "Twelfth International Workshop on Logic and Synhtesis, IWLS 2003", "link": "48357808"}, "BIBREF4": {"title": "Checking delay-insensitivity: 104 gates and beyond", "authors": [{"first": "A", "middle": [], "last": "Kondratyev", "suffix": ""}, {"first": "L", "middle": [], "last": "Neukom", "suffix": ""}, {"first": "O", "middle": [], "last": "Roig", "suffix": ""}, {"first": "A", "middle": [], "last": "Taubin", "suffix": ""}, {"first": "K", "middle": [], "last": "Fant", "suffix": ""}], "year": 2002, "venue": "Proc. of Eighth International Symposium on Asynchronous Circuits and Systems", "link": "203663077"}, "BIBREF5": {"title": "Stubborn Sets for Reduced State Space Generation", "authors": [{"first": "A", "middle": [], "last": "Valmari", "suffix": ""}], "year": 1990, "venue": "Advances in Petri Nets", "link": "17870925"}, "BIBREF6": {"title": "Model checking and abstraction", "authors": [{"first": "E", "middle": ["M"], "last": "Clarke", "suffix": ""}, {"first": "O", "middle": [], "last": "Grumberg", "suffix": ""}, {"first": "D", "middle": ["E"], "last": "Long", "suffix": ""}], "year": 1992, "venue": "Proc. of the 9th Annual ACM Symp. on Principles of Programming Languages", "link": "4553749"}, "BIBREF7": {"title": "Partial-Order Methods for the Verification of Concurrent Systems --An Approach to the State-Explosion Problem", "authors": [{"first": "P", "middle": [], "last": "Godefroid", "suffix": ""}], "year": 1996, "venue": "Lecture Notes in Computer Science", "link": "18149427"}, "BIBREF8": {"title": "Petrify: A tool for manipulating concurrent specifications and synthesis of asynchronous controllers", "authors": [{"first": "J", "middle": [], "last": "Cortadella", "suffix": ""}, {"first": "M", "middle": [], "last": "Kishinevsky", "suffix": ""}, {"first": "A", "middle": [], "last": "Kondratyev", "suffix": ""}, {"first": "L", "middle": [], "last": "Lavagno", "suffix": ""}, {"first": "A", "middle": [], "last": "Yakovlev", "suffix": ""}], "year": 1997, "venue": "IEICE Trans. Information Syst", "link": "6223968"}, "BIBREF9": {"title": "Synthesis of asynchronous control circuits with automatically generated relative timing assumptions", "authors": [{"first": "J", "middle": [], "last": "Cortadella", "suffix": ""}, {"first": "M", "middle": [], "last": "Kishinevsky", "suffix": ""}, {"first": "S", "middle": ["M"], "last": "Burns", "suffix": ""}, {"first": "K", "middle": [], "last": "Stevens", "suffix": ""}], "year": 1999, "venue": "IEEE/ACM Int. Conf. on", "link": "952005"}, "BIBREF10": {"title": "Very Large Scale Integration (VLSI) Systems", "authors": [{"first": "K", "middle": [], "last": "Stevens", "suffix": ""}, {"first": "R", "middle": [], "last": "Ginosar", "suffix": ""}, {"first": "S", "middle": [], "last": "Rotem", "suffix": ""}], "year": 2003, "venue": "IEEE Trans. on", "link": null}, "BIBREF11": {"title": "Lazy transition systems: application to timing optimization of asynchronous circuits", "authors": [{"first": "J", "middle": [], "last": "Cortadella", "suffix": ""}, {"first": "M", "middle": [], "last": "Kishinevsky", "suffix": ""}, {"first": "A", "middle": [], "last": "Kondratyev", "suffix": ""}, {"first": "L", "middle": [], "last": "Lavagno", "suffix": ""}, {"first": "A", "middle": [], "last": "Taubin", "suffix": ""}, {"first": "A", "middle": [], "last": "Yakovlev", "suffix": ""}], "year": 1998, "venue": "Digest of Technical Papers", "link": "12302564"}, "BIBREF12": {"title": "IEEE/ACM International Conference on", "authors": [], "year": 1998, "venue": "", "link": null}, "BIBREF13": {"title": "Lazy transition systems and asynchronous circuit synthesis with relative timing assumptions", "authors": [{"first": "J", "middle": [], "last": "Cortadella", "suffix": ""}, {"first": "M", "middle": [], "last": "Kishinevsky", "suffix": ""}, {"first": "S", "middle": ["M"], "last": "Burns", "suffix": ""}, {"first": "A", "middle": [], "last": "Kondratyev", "suffix": ""}, {"first": "L", "middle": [], "last": "Lavagno", "suffix": ""}, {"first": "K", "middle": [], "last": "Stevens", "suffix": ""}, {"first": "A", "middle": [], "last": "Taubin", "suffix": ""}, {"first": "A", "middle": [], "last": "Yakovlev", "suffix": ""}], "year": 2002, "venue": "IEEE Trans. on", "link": "15185670"}, "BIBREF14": {"title": "Verification of timed circuits with symbolic delays", "authors": [{"first": "R", "middle": [], "last": "Clariso", "suffix": ""}, {"first": "J", "middle": [], "last": "Cortadella", "suffix": ""}], "year": 2004, "venue": "Design Automation Conference", "link": "62719855"}, "BIBREF15": {"title": "Verification of concurrent systems with parametric delays using octahedral", "authors": [{"first": "R", "middle": [], "last": "Clariso", "suffix": ""}, {"first": "J", "middle": [], "last": "Cortadella", "suffix": ""}], "year": 2005, "venue": "Application of Concurrency to System Design, 2005. ACSD 2005. Fifth Int. Conf. on", "link": "2127356"}, "BIBREF16": {"title": "Asynchronous design using commercial HDL synthesis tools", "authors": [{"first": "M", "middle": [], "last": "Ligthart", "suffix": ""}, {"first": "K", "middle": [], "last": "Fant", "suffix": ""}, {"first": "R", "middle": [], "last": "Smith", "suffix": ""}, {"first": "A", "middle": [], "last": "Taubin", "suffix": ""}, {"first": "A", "middle": [], "last": "Kondratyev", "suffix": ""}], "year": 2000, "venue": "Proc. Int. Symposium on Advanced Research in Asynchronous Circuits and Systems", "link": "40413163"}, "BIBREF17": {"title": "Design of asynchronous circuits using synchronous CAD tools", "authors": [{"first": "A", "middle": [], "last": "Kondratyev", "suffix": ""}, {"first": "K", "middle": [], "last": "Lwin", "suffix": ""}], "year": 2002, "venue": "IEEE Design & Test of Computers", "link": "12821066"}, "BIBREF19": {"title": "Cost-aware synthesis of asynchronous circuits based on partial acknowledgement", "authors": [{"first": "D", "middle": [], "last": "Sokolov", "suffix": ""}, {"first": "A", "middle": [], "last": "Yakovlev", "suffix": ""}], "year": 2006, "venue": "Computer-Aided Design, ICCAD '06", "link": "52140481"}, "BIBREF20": {"title": "Optimization of Robust Asynchronous Circuits by Local Input Completeness Relaxation", "authors": [{"first": "C", "middle": [], "last": "Jeong", "suffix": ""}, {"first": "S", "middle": ["M"], "last": "Nowick", "suffix": ""}], "year": 2007, "venue": "Design Automation Conference", "link": "14219703"}, "BIBREF21": {"title": "NULL Convention LogicTM: A complete and consistent logic for asynchronous digital circuit synthesis", "authors": [{"first": "K", "middle": ["M"], "last": "Fant", "suffix": ""}, {"first": "S", "middle": ["A"], "last": "Brandt", "suffix": ""}], "year": 1996, "venue": "Proc. of Int. Conf. on Applications Specific Systems, Architectures and Processors (ASAP'96)", "link": "27464576"}, "BIBREF22": {"title": "CMOS Circuit Design of Threshold Gates with Hysteresis", "authors": [{"first": "G", "middle": ["E"], "last": "Sobelman", "suffix": ""}, {"first": "K", "middle": ["M"], "last": "Fant", "suffix": ""}], "year": 1998, "venue": "Proc. of IEEE Int. Conf. on Circuits and Systems'98", "link": "62541553"}, "BIBREF23": {"title": "Introduction to VLSI Systems", "authors": [{"first": "C", "middle": ["L"], "last": "Seitz", "suffix": ""}], "year": 1980, "venue": "", "link": null}, "BIBREF24": {"title": "Micropipelines", "authors": [{"first": "I", "middle": ["E"], "last": "Sutherland", "suffix": ""}], "year": 1989, "venue": "Turing Award Lecture Communications of the ACM", "link": null}, "BIBREF25": {"title": "Completion-Completeness for NULL Convention digital circuits utilizing the bitwise completion strategy", "authors": [{"first": "S", "middle": ["C"], "last": "Smith", "suffix": ""}], "year": 2003, "venue": "The 2003 Int. Conf. on VLSI", "link": "41269191"}, "BIBREF26": {"title": "Asynchronous Design Of Systolic Array Architectures In CMOS", "authors": [{"first": "A", "middle": ["N"], "last": "Ismailoglu", "suffix": ""}], "year": 2008, "venue": "", "link": null}, "BIBREF27": {"title": "Performance comparison of asynchronous adders", "authors": [{"first": "M", "middle": ["A"], "last": "Franklin", "suffix": ""}, {"first": "T", "middle": [], "last": "Pan", "suffix": ""}], "year": 1994, "venue": "Proc. of Int. Symposium on Advanced Research in Asynchronous Circuits and Systems", "link": "36528014"}, "BIBREF28": {"title": "NULL Convention LogicTM", "authors": [{"first": "K", "middle": ["M"], "last": "Fant", "suffix": ""}, {"first": "S", "middle": ["A"], "last": "Brandt", "suffix": ""}], "year": 1997, "venue": "", "link": "63710658"}, "BIBREF29": {"title": "Optimization of NULL Convention Self-Timed Circuits", "authors": [{"first": "S", "middle": ["C"], "last": "Smith", "suffix": ""}, {"first": "R", "middle": ["F"], "last": "Demara", "suffix": ""}, {"first": "J", "middle": ["S"], "last": "Yuan", "suffix": ""}, {"first": "D", "middle": [], "last": "Ferguson", "suffix": ""}, {"first": "D", "middle": [], "last": "Lamb", "suffix": ""}], "year": 2004, "venue": "Integration, The VLSI Journal", "link": "9539630"}, "BIBREF30": {"title": "Application of Bit-level Pipelining to Delay Insensitive Null Convention Adders", "authors": [{"first": "A", "middle": ["N"], "last": "Ismailoglu", "suffix": ""}, {"first": "M", "middle": [], "last": "A\u015fkar", "suffix": ""}], "year": 2007, "venue": "Proc. of IEEE Int. Symposium on Circuits and Systems (ISCAS'2007)", "link": "27451916"}, "BIBREF31": {"title": "Early Output Logic and Anti-tokens", "authors": [{"first": "C", "middle": [], "last": "Brej", "suffix": ""}], "year": 2005, "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "8336834", "_pdf_hash": "d08ea4ea8706ce96882bd0afc191615f4a7e6b8a", "abstract": [], "body_text": [], "bib_entries": {"BIBREF1": {"title": "Measuring synchronisation and scheduling overheads in OpenMP", "authors": [{"first": "Mark", "middle": [], "last": "Bull", "suffix": ""}], "year": 1999, "venue": "Proceedings of First European Workshop on OpenMP", "link": "18396931"}, "BIBREF2": {"title": "A proposal for error handling in OpenMP", "authors": [{"first": "Alejandro", "middle": [], "last": "Duran", "suffix": ""}, {"first": "Roger", "middle": [], "last": "Ferrer", "suffix": ""}, {"first": "Juanjos\u00e9", "middle": [], "last": "Costa", "suffix": ""}, {"first": "Marc", "middle": [], "last": "Gonz\u00e0lez", "suffix": ""}, {"first": "Xavier", "middle": [], "last": "Martorell", "suffix": ""}, {"first": "Eduard", "middle": [], "last": "Ayguad\u00e9", "suffix": ""}, {"first": "Jes\u00fas", "middle": [], "last": "Labarta", "suffix": ""}], "year": 2007, "venue": "International Journal of Parallel Programming", "link": "1575997"}, "BIBREF3": {"title": "OpenMP 3.0 feature: Error detection capability", "authors": [{"first": "", "middle": [], "last": "Kang Su Gatlin", "suffix": ""}], "year": 2005, "venue": "", "link": null}, "BIBREF4": {"title": "Parallelizing a real-time steering simulation for computer games with OpenMP", "authors": [{"first": "Bjoern", "middle": [], "last": "Knafla", "suffix": ""}, {"first": "Claudia", "middle": [], "last": "Leopold", "suffix": ""}], "year": 2008, "venue": "Parallel Computing: Architectures, Algorithms, and Applications", "link": "6623479"}, "BIBREF5": {"title": "Web service call parallelization using OpenMP. In A Practical Programming Model for the Multi-Core Era", "authors": [{"first": "S\u00e9bastien", "middle": [], "last": "Salva", "suffix": ""}, {"first": "Cl\u00e9ment", "middle": [], "last": "Delamare", "suffix": ""}, {"first": "C\u00e9dric", "middle": [], "last": "Bastoul", "suffix": ""}], "year": 2008, "venue": "Lecture Notes in Computer Science", "link": null}, "BIBREF6": {"title": "Pyjama: OpenMP-like implementation for java, with gui extensions", "authors": [{"first": "Nasser", "middle": [], "last": "Vikas", "suffix": ""}, {"first": "Oliver", "middle": [], "last": "Giacaman", "suffix": ""}, {"first": "", "middle": [], "last": "Sinnen", "suffix": ""}], "year": 2013, "venue": "Proceedings of the 2013 International Workshop on Programming Models and Applications for Multicores and Manycores, PMAM '13", "link": "7566574"}, "BIBREF7": {"title": "Using OpenMP under Android", "authors": [{"first": "Travis", "middle": [], "last": "Vikas", "suffix": ""}, {"first": "Nasser", "middle": [], "last": "Scott", "suffix": ""}, {"first": "Oliver", "middle": [], "last": "Giacaman", "suffix": ""}, {"first": "", "middle": [], "last": "Sinnen", "suffix": ""}], "year": 2013, "venue": "OpenMP in the Era of Low Power Devices and Accelerators", "link": "34490882"}, "BIBREF8": {"title": "Towards an error model for OpenMP", "authors": [{"first": "Michael", "middle": [], "last": "Wong", "suffix": ""}, {"first": "Michael", "middle": [], "last": "Klemm", "suffix": ""}, {"first": "Alejandro", "middle": [], "last": "Duran", "suffix": ""}, {"first": "Tim", "middle": [], "last": "Mattson", "suffix": ""}, {"first": "Grant", "middle": [], "last": "Haab", "suffix": ""}, {"first": "", "middle": [], "last": "Bronisr", "suffix": ""}, {"first": "Andrey", "middle": [], "last": "De Supinski", "suffix": ""}, {"first": "", "middle": [], "last": "Churbanov", "suffix": ""}], "year": 2010, "venue": "Beyond Loop Level Parallelism in OpenMP: Accelerators, Tasking and More", "link": "34905815"}}, "ref_entries": {}}
{"paper_id": "8337224", "_pdf_hash": "ebc35a365429bcd23363736f87019c5a168b82d4", "abstract": [{"section": "Abstract", "text": "Background: In this study, we further investigated the association of two biomarkers, CCL18 and A1AT, with bladder cancer (BCa) and evaluated the influence of potentially confounding factors in an experimental model.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Background", "text": "Non-invasive urine tests for the early detection or postsurgical surveillance of bladder cancer (BCa) are highly desirable for both the patient and the healthcare system. Currently, voided urinary cytology (VUC) is the most widely used non-invasive urine test, with reported specificities ranging from 85-100% and sensitivities ranging from 13-75% [1, 2] . Two single-protein biomarker urinebased assays, bladder tumor antigen (BTA) test and nuclear matrix protein-22 (NMP-22) test, have been developed and FDA approved for use in this context. However, these assays have significant limitations. The BTA tests (BTA stat\u2122 and BTA TRAK\u2122 (Polymedco Inc. Cortlandt Manor, NY, USA) have diagnostic sensitivities ranging from 29-83% and specificities ranging from 56-86% [3, 4] . In addition, we and others have demonstrated in an experimental model that hematuria adversely affects the accuracy of the BTA assay [5, 6] . The NMP-22 tests (NMP22\u00ae Bladder Cancer ELISA Test Kit and the NMP22\u00ae BladderChek\u00ae point-of-care test, Alere Scarborough, Inc. Waltham, MA) have diagnostic sensitivities ranging from 47-100% and specificities ranging from 55-98% [7, 8] . Atsu et al. and others have recently demonstrated in an experimental model that NMP-22 assays measure the cellularity or amount of cell turnover that may be introduced into the urine by a variety of conditions, including hematuria, infection and instrumentation [9, 10] . Thus, the search for more accurate urine-based biomarkers continues.", "cite_spans": [{"start": 348, "end": 351, "text": "[1,", "ref_id": "BIBREF0"}, {"start": 352, "end": 354, "text": "2]", "ref_id": "BIBREF1"}, {"start": 766, "end": 769, "text": "[3,", "ref_id": "BIBREF2"}, {"start": 770, "end": 772, "text": "4]", "ref_id": "BIBREF3"}, {"start": 908, "end": 911, "text": "[5,", "ref_id": "BIBREF4"}, {"start": 912, "end": 914, "text": "6]", "ref_id": "BIBREF5"}, {"start": 1146, "end": 1149, "text": "[7,", "ref_id": "BIBREF6"}, {"start": 1150, "end": 1152, "text": "8]", "ref_id": "BIBREF7"}, {"start": 1417, "end": 1420, "text": "[9,", "ref_id": "BIBREF8"}, {"start": 1421, "end": 1424, "text": "10]", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "Background", "text": "Through genomic and proteomic profiling of urine components, we have previously identified a panel of biomarkers that can outperform current urine-based biomarkers for the non-invasive detection of BCa [11] [12] [13] [14] . In a case-controlled validation study, the urinary concentrations of our panel of 14 biomarkers (IL-8, MMP-9, MMP-10, SDC1, CCL18, PAI-1, CD44, VEGF, ANG, CA9, A1AT, SPP1, PTX3, and APOE) were measured by enzyme-linked immunosorbent assay (ELISA) in voided urines from 127 patients (64 tumor bearing subjects) [15] [16] [17] [18] . Of these 14 biomarkers, two biomarkers (CCL18 and A1AT) had high correlation coefficients (Spearman correlation coefficient >0.76) with urinary blood content and therefore, rather than measuring a valid tumor antigen the biomarker may be merely a surrogate for hematuria. Subsequently, these two biomarkers have been excluded from ongoing multiplex studies [19] until we can clarify the source of these protein biomarkers. Herein, we report the urinary concentrations of CCL18 and A1AT in an independent larger case-control study, and illustrate in an experimental model the influence of cellular proteins and whole blood on the performance of these potential urine-based biomarkers.", "cite_spans": [{"start": 202, "end": 206, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 207, "end": 211, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 212, "end": 216, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 217, "end": 221, "text": "[14]", "ref_id": "BIBREF13"}, {"start": 534, "end": 538, "text": "[15]", "ref_id": "BIBREF14"}, {"start": 539, "end": 543, "text": "[16]", "ref_id": "BIBREF15"}, {"start": 544, "end": 548, "text": "[17]", "ref_id": "BIBREF16"}, {"start": 549, "end": 553, "text": "[18]", "ref_id": "BIBREF17"}, {"start": 913, "end": 917, "text": "[19]", "ref_id": "BIBREF18"}], "ref_spans": []}, {"section": "Methods", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Ethics statement", "text": "Under Institutional Review Board approval by the committees at MD Anderson Cancer Center Orlando and Hospital Clinic of Barcelona, written informed consent was obtained prior to collection and storage of biological specimens (voided urine samples and blood) in genitourinary biorepositories. Furthermore under Institutional Review Board approval by the committee at MD Anderson Cancer Center Orlando with a waiver of written informed consent, archived bladder tissues from the Department of Pathology at Orlando Health was identified for immunohistochemical analysis. The above review boards monitored study recruitment and study compliance.", "cite_spans": [], "ref_spans": []}, {"section": "Patients and data collection", "text": "For the urinary ELISA validation study, 308 nonconsecutive subjects (102 with BCa) from MD Anderson Cancer Center Orlando and Hospital Cl\u00ednic of Barcelona were available for analysis. The control cohort consisted of 206 individuals (47 with voiding symptoms, 44 with urolithiasis, 9 with gross hematuria, 14 with urinary tract infection and 92 without any diagnosed condition). Patients with a history of renal dysfunction were excluded. The cohort of 308 subjects served as our phase II (validation study) according to the International Consensus Panel on Bladder Tumor Markers and findings were reported according to the STARD criteria [20] . For the experimental model, three healthy volunteers (2 males, 1 female, mean age 36 years) provided urine and blood samples. For the immunohistochemical study, formalin-fixed paraffin embedded blocks containing 165 bladder tumor tissue specimens and 8 benign tissue specimens were retrieved from the Orlando Health Department of Pathology.", "cite_spans": [{"start": 638, "end": 642, "text": "[20]", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "Specimen processing", "text": "Fifty milliliters of voided urine from each subject was assigned a unique identifying number before delivery to the laboratory for processing. Each urine sample was centrifuged at 1000 \u00d7 g 4\u00b0C for 10 min. The supernatant was decanted and aliquoted, and the urinary pellet was snap frozen. Both the supernatant and pellet were stored at -80\u00b0C prior to analysis. Urine supernatant protein concentration was determined using Pierce 660-nm Protein Assay Kit (Thermo Fisher Scientific Inc., Waltham, MA, USA). Patients with significant proteinuria were excluded.", "cite_spans": [], "ref_spans": []}, {"section": "Specimen processing", "text": "Enzyme-linked immunosorbent assays for urinary CCL18 and A1AT", "cite_spans": [], "ref_spans": []}, {"section": "Specimen processing", "text": "The levels of human CCL18 (Cat # ab100620, Abcam, Cambridge, MA) and human A1AT (Cat# ab108799, Abcam) in urine samples were monitored using ELISA. The assays were conducted according to the manufacturer's instructions. Laboratory personnel were blinded to final diagnosis. Calibration curves were prepared using purified standards for each protein assessed. Curve fitting was accomplished by either linear or four-parameter logistic regression following manufacturer's instructions. Urinary creatinine levels were monitored with a commercial ELISA assay (Cat# KGE005 R&D Systems Inc., Minneapolis, MN, USA) as previously described [21] .", "cite_spans": [{"start": 632, "end": 636, "text": "[21]", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "Cell lines and culture", "text": "Human bladder cancer cell lines T24 (ATCC, Manassas, VA) and UM-UC-14 (a generous gift from Dr. H. Bart Grossman, The University of Texas M.D. Anderson Cancer Center, Houston, TX) [22] were available for analysis. The benign human bladder cell line, UROtsa, was a generous gift from Dr. Donald Sens at the University of North Dakota School Of Medicine (Grand Forks, ND) [23] . T24 and UM-UC-14 cell lines were maintained in RPMI 1640 media. UROtsa cells were maintained in McCoy's 5A medium (Life Technologies, Inc., Gaithersburg, MD). All media were supplemented with 10% fetal bovine serum, 100 units/ml of penicillin and 100 \u03bcg/ml of streptomycin. All cells were incubated at 37\u00b0C in a humidified atmosphere of 5% CO 2 .", "cite_spans": [{"start": 180, "end": 184, "text": "[22]", "ref_id": "BIBREF21"}, {"start": 370, "end": 374, "text": "[23]", "ref_id": "BIBREF22"}], "ref_spans": []}, {"section": "Experimental model", "text": "The experimental model was essentially as previously published [6, 10] . Figure 1 illustrates the experimental model components and dilutions. Briefly, 10 milliliters of whole blood in heparinized tube and 200 ml of freshly voided urine samples in sterile containers were obtained from three healthy controls. The urine samples from the three healthy subjects were pooled, mixed and distributed into 10 ml aliquots in 15 6 cells from each cell line were lysed with RIPA buffer (Pierce, Rockford, IL) and total protein concentration measured. The total protein extracted from 1\u00d710 6 cells of UROtsa, T24 and UM-UC-14 were 431 \u03bcg, 471 \u03bcg, 280 \u03bcg and 420 \u03bcg, respectively, with a mean total protein extract of 400 \u03bcg. In the spiking experiments, 4 \u03bcg, 40 \u03bcg and 400 \u03bcg of cellular proteins from either UROtsa or the pooled BCa cell lines were used, corresponding t\u00f5 1\u00d710 4 cells (low concentration),~1\u00d710 5 cells (medium concentration) and~1\u00d710 6 cells (high concentration).", "cite_spans": [{"start": 63, "end": 66, "text": "[6,", "ref_id": "BIBREF5"}, {"start": 67, "end": 70, "text": "10]", "ref_id": "BIBREF9"}, {"start": 418, "end": 420, "text": "15", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "Experimental model", "text": "UROtsa lysates and pooled cancer cell lysates were added to pooled urine samples in triplicate. To monitor the influence of hematuria, pooled whole blood from three healthy subjects was added in triplicate to 10 ml of pooled urine samples in the following amounts; 1 \u03bcl, 1/ 10000 final dilution; 5 \u03bcl, 1/2000 final dilution; 20 \u03bcl, 1/ 500 final dilution; 50 \u03bcl, 1/200 final dilution and zero control. The number of red blood cells (RBC) in each urine sample was determined by microscopic examination before and after adding whole blood. Standard urinalysis was performed with MULTISTIX PRO Reagent Strips (Bayer HealthCare, Elkhart, IN).", "cite_spans": [], "ref_spans": []}, {"section": "Immunohistochemistry", "text": "A total of 173 paraffin blocks were verified histologically by H&E staining. For immunochemical staining, blocks were cut in 5 \u03bcm sections and placed on a Superfrost Plus Miscroslide. Sections were deparaffinized, followed by antigen retrieval using citric acid buffer (pH 6.0, 95\u00b0C for 20 min). The slides were treated with 1% hydrogen peroxide in methanol to block endogenous peroxidase activity. After 20 min blocking in 1% bovine serum albumin (BSA), the slides were incubated overnight at 4\u00b0C with anti-human CCL18 antibody (MAB394; mouse monoclonal, dilution 1/500 in 1% BSA) from R&D Systems Inc., or anti-human A1AT antibody (NBP1-90309; rabbit polyclonal, dilution 1/2500 in 1% BSA) from Novus Biologicals Inc. (Littleton, CO). Next, the slides were incubated with 2 \u03bcg/mL of biotinylated anti-mouse or anti-rabbit IgG secondary antibody (Vector Laboratories, Burlingame, CA) for 30 min at room temperature. Subsequently, the sections were stained using Standard Ultra-Sensitive ABC Peroxidase Staining kit (Pierce/Thermo Fisher Scientific, San Jose, CA) and 3, 3'-diaminobenzidine (DAB; Vector Laboratories), counterstained by hematoxylin, dehydrated, and mounted with a cover slide. Human liver, known to stain strongly for CCL18 and A1AT, was used as a positive control, and negative controls were performed by omitting the primary antibodies. Using light microscopy, two investigators (MM and AL) interpreted immunostaining results blinded to specimen and patient data. A third investigator (CJR) reviewed discrepancies and rendered a final score. The location of immunoreactivity (e.g., nuclear, cytoplasm, cell membrane, and stroma) was noted. CCL18 immunostaining was positive only in inflammatory cells in the stroma. Three randomly chosen high power fields (1 HPF = 0.237 mm 2 ) were analyzed for CCL18-positive cells in the stromal area and averaged in each case. A1AT immunostaining was positive only in the cytoplasm of epithelial cells. Immunostaining intensity was reported as weak, moderate or strong.", "cite_spans": [], "ref_spans": []}, {"section": "Data analysis", "text": "The Wilcoxon rank sum test was used on ELISA data to determine the association between urinary CCL18, Figure 1 Schematic of the experimental model. Low concentration (1\u00d710 4 ), medium concentration (1\u00d710 5 ) and high concentrations (1\u00d710 6 ) of intact UROtsa benign human bladder cells, or a mixture of human bladder cancer lines, T24 and UM-UC-14 were added to 10 ml of pooled urine from three healthy controls. Low protein concentration of cellular lysate (4 \u03bcg), medium concentration (40 \u03bcg) and high concentrations (400 \u03bcg) of UROtsa benign human bladder cells, or from a mixture of human bladder cancer lines, T24 and UM-UC-14 were added to 10 ml of pooled urine from three healthy controls. Whole blood (1, 5, 20 and 50 \u03bcl) was also added to 10 ml of pooled urine from healthy controls.", "cite_spans": [{"start": 238, "end": 239, "text": "6", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Data analysis", "text": "A1AT and BCa status. Nonparametric receiver operating characteristic (ROC) curves were plotted and the ability of the biomarker to predict the presence of BCa was estimated by calculating the area under the ROC curves (AUROC). The sensitivity and specificity of the biomarker at the optimal cutoff value was defined by calculating the Youden index [24] . Comparison of immunohistochemical distribution data was performed using Chi square test. Spearman rank correlation coefficients were used to examine the correlation between urinary CCL18 and A1AT concentrations and urinary hemoglobin concentration. The association between CCL18 and A1AT levels and BCa was tested using the Mann Whitney test. Statistical significance in this study was set at p < 0.05 and all reported p values were 2-sided. All analyses were performed using PRISM software version 5.00 (San Diego, CA). Table 1 depicts demographics and clinical characteristics of the study cohorts. Ninety percent of the BCa subjects sampled were Caucasian (median age 69 years) with 60% noted to have non-muscle invasive bladder cancer (NMIBC) and 37% with low-grade disease. In the cancer cohort, urinary cytology achieved a diagnostic sensitivity of 39%. Median urinary protein concentrations of CCL18 (52.84 pg/ml vs. 11.13 pg/ml, p < 0.0001) and A1AT (606.4 ng/ml vs. 120 ng/ml, p < 0.0001) were significantly elevated in BCa subjects compared to controls. Furthermore, median urinary CCL18 was significantly elevated in muscle invasive bladder cancer (MIBC) compared to NMIBC (90.65 pg/ml vs. 44.72 pg/ml, p = 0.044), and approached significance (Figure 2a ) in high-grade compared to low-grade disease (79.57 pg/ml vs. 38.10 pg/ml, p = 0.073). Similarly, median urinary A1AT was significantly elevated in MIBC compared to NMIBC (978.1 ng/ml vs. 414.5 ng/ml, p = 0.0042) and approached significance (Figure 2b ) in high-grade compared to low-grade (917.8 ng/ml vs. 414.5 ng/ml, p = 0.073). The ability of the tested biomarkers to predict the presence of BCa was analyzed using nonparametric ROC analyses, according to National Cancer Institute guidelines [25] . Based on the AUROC, we determined Youden index cutoff values to maximize the sum of sensitivity and specificity. Urinary CCL18 had an area under the curve of 0.768 (95% CI: 0.713-0.824) (Figure 3) , achieved a sensitivity of 70.4%, specificity of 67.7%, positive predictive value of 53.1% and a negative predictive value of 81.5%. Urinary A1AT had an area under the curve of 0.775 (95% CI: 0.721-0.829) (Figure 3) , achieved a sensitivity of 70.6%, specificity of 71.8%, positive predictive value of 55.4% and negative predictive value of 83.2%.", "cite_spans": [{"start": 348, "end": 352, "text": "[24]", "ref_id": "BIBREF23"}, {"start": 2118, "end": 2122, "text": "[25]", "ref_id": "BIBREF24"}], "ref_spans": [{"start": 876, "end": 883, "text": "Table 1", "ref_id": "TABREF1"}, {"start": 1609, "end": 1619, "text": "(Figure 2a", "ref_id": "FIGREF0"}, {"start": 1862, "end": 1872, "text": "(Figure 2b", "ref_id": "FIGREF0"}]}, {"section": "Results", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "CCL18 and A1AT in voided urine samples", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Experimental model", "text": "Urine and blood samples were obtained from three healthy volunteer controls for analysis in the experimental model. There was no evidence of gross hematuria, urinary tract infection or any biochemical abnormalities in any volunteer urine samples. Both urinary dipstick and urinary microscopy were negative for hematuria, however, urinary hemoglobin measured by ELISA assay revealed trace amounts in all samples (3.63 \u00b1 0.59 ng/ ml). In these healthy controls, the mean urinary CCL18 level was 5.96 \u00b1 7.73 pg/ml, and the mean urinary A1AT level was 1170 \u00b1 71.94 ng/ml (Table 2) . Urine samples were pooled, and whole cells or cell lysates of the cancer cell line pool and UROtsa cells were added to the urine sample (as depicted in Figure 1 ) and re-analyzed for CCL18 and A1AT using ELISA. The addition of a high concentration (400 \u03bcg) of protein lysate from UROtsa cells, or medium to high concentration (40 \u03bcg to 400 \u03bcg) of protein lysate from pooled cancerous cells resulted in a significant increase in test sample CCL18 (Additional file 1). Furthermore, the addition of whole blood (50 \u03bcL) resulted in a significant increase in CCL18 (p < 0.05) ( Figure 4) . As for A1AT, the addition of high concentration of whole blood (50 \u03bcL) resulted in a significant increase in test sample A1AT levels (p < 0.05) (Figure 4) .", "cite_spans": [], "ref_spans": [{"start": 567, "end": 576, "text": "(Table 2)", "ref_id": "TABREF2"}]}, {"section": "Experimental model", "text": "With the addition of only 1 \u03bcl of whole blood to 10 mL of test urines (1/10,000 dilution), the mean urinary hemoglobin level was 174.28 \u00b1 15.69 ng/ml, and microscopy revealed a median 1 RBC/hpf. This level would be termed 'Negative' or 'Trace' in clinical tests such as the Multistix Pro dipstick test (negative blood is <100ng/ml). At this level, CCL18 and A1AT concentrations were unaffected at 7.06 \u00b1 7.78 ng/ml and 1227.31 \u00b1 1.22 ng/ml, respectively. With the addition of 50 \u03bcl of whole blood to 10 mL of urine, all urines had visibly gross hematuria, the mean urinary hemoglobin level was 7,898.05 \u00b1 184.67 ng/ ml and median of 17 RBC/hpf was noted. At this level, CCL18 concentration was raised to 31.90 \u00b1 43.19 ng/ml (~4.5 fold increase), but the A1AT concentration was similar to controls at 1,273.16 \u00b1 5.53 ng/ml ( Table 2) . As the concentration of whole blood added to the urine samples increased, the mean urinary hemoglobin level, the extent of hematuria assessed by microscopy, and the mean urinary concentrations of CCL18 and A1AT increased accordingly (Table 2 ). There were high correlation coefficients between hemoglobin and CCL18 (Spearman correlation coefficient = 0.90) and hemoglobin and A1AT (Spearman correlation coefficient = 1.00).", "cite_spans": [], "ref_spans": [{"start": 824, "end": 832, "text": "Table 2)", "ref_id": "TABREF2"}, {"start": 1068, "end": 1076, "text": "(Table 2", "ref_id": "TABREF2"}]}, {"section": "Immunohistochemical analysis of bladder tumors", "text": "The study cohort consisted of 8 subjects without cancer and 165 non-consecutive subjects with BCa (37 subjects with low-grade BCa and 128 subjects with high-grade BCa, 45 subjects with NMIBC and 120 MIBC). Immunohistochemical staining patterns for CCL18 and A1AT were assessed in both malignant and normal bladder tissue. No epithelial staining was evident for CCL18, however, inflammatory cells in the stromal were positive.", "cite_spans": [], "ref_spans": []}, {"section": "Immunohistochemical analysis of bladder tumors", "text": "The number of CCL18-positive inflammatory cells per high power field was not increased in bladder tumors compared to controls (1.0 \u00b1 1.2 vs. 4.5 \u00b1 6.9, p = 0.57). In addition, an increase in CCL18-positive inflammatory cells was not associated with higher grade or higher stage disease (Figure 5a ). Immunostaining for A1AT revealed a predominantly epithelial and cytoplasmic localization. Intensity of staining ranged from weak and focal to strong and diffuse. No difference in staining intensity was seen between benign and cancer (p = 0.99). Staining intensity increased with an increase in tumor grade (p = 0.05), however, staining pattern was not significantly associated with tumor stage (p = 0.79) (Figure 5b ).", "cite_spans": [], "ref_spans": []}, {"section": "Discussion and conclusions", "text": "We have previously identified CCL18 and A1AT as potential biomarkers for the detection of BCa in voided urine samples [15, 18] . CCL18 is a member of the serumbased cytokine family of secreted proteins involved in immunoregulatory and inflammatory processes. CCL18 is thought to promote the invasiveness of cancer cells by triggering integrin clustering and enhancing their adherence to the extracellular matrix, and a receptor (PITPNM3) for this cytokine has been recently identified [26] . CCL18 has been identified in gynecological tumors Figure 3 Diagnostic performance of urinary CCL18 and A1AT. Receiver operator characteristic (ROC) curves were calculated from the analysis of urine samples obtained from a cohort of 308 subjects (102 with confirmed bladder cancer) for CCL18 and A1AT. AUROC, area under the ROC curve. but not urologic tumors [27, 28] . A1AT, also known as SERPINA1, is a member of a family of serine proteases inhibitors. Specifically A1AT irreversibly inhibits trypsin, chymotrypsin and plasminogen activator. Serpins are known to have diverse but critical roles in the cell, including regulation of homeostasis, cellular survival and blood clotting [29] . Within the oncology literature, reports describe genetic aberrations in cancers, elevated levels in the sera of cancer patients, and survival disadvantage in tumors expressing A1AT [30, 31] .", "cite_spans": [{"start": 118, "end": 122, "text": "[15,", "ref_id": "BIBREF14"}, {"start": 123, "end": 126, "text": "18]", "ref_id": "BIBREF17"}, {"start": 485, "end": 489, "text": "[26]", "ref_id": "BIBREF25"}, {"start": 850, "end": 854, "text": "[27,", "ref_id": "BIBREF26"}, {"start": 855, "end": 858, "text": "28]", "ref_id": "BIBREF27"}, {"start": 1176, "end": 1180, "text": "[29]", "ref_id": "BIBREF28"}, {"start": 1364, "end": 1368, "text": "[30,", "ref_id": "BIBREF29"}, {"start": 1369, "end": 1372, "text": "31]", "ref_id": "BIBREF30"}], "ref_spans": []}, {"section": "Discussion and conclusions", "text": "In our early studies, we noted that these biomarkers had a relatively high correlation (Spearman correlation coefficient > 0.76) with urinary hemoglobin. Given the confounding effects of hematuria that we and others have described for the urine-based BCa detection assays BTA and NMP-22 [6, 10] , we set out to more methodically analyze the association of CCL18 and A1AT with BCa by analyzing cohorts of urine and tissue samples. In this study, ELISA analysis of urine samples from a cohort of 308 subjects confirmed our previous findings [19] that both CCL18 and A1AT are significantly elevated in the urines of subjects with BCa.", "cite_spans": [{"start": 287, "end": 290, "text": "[6,", "ref_id": "BIBREF5"}, {"start": 291, "end": 294, "text": "10]", "ref_id": "BIBREF9"}, {"start": 539, "end": 543, "text": "[19]", "ref_id": "BIBREF18"}], "ref_spans": []}, {"section": "Discussion and conclusions", "text": "To investigate the potential influence of hematuria and other factors on the performance of these biomarkers we employed an experimental model. Although the model does not mimic the actual physiological situation exactly, it does enable the identification of potential sources of specific analytes and to what extent incursion of blood components into the urine may influence the data. We previously used a similar model approach to demonstrate that BTA urine tests primarily detect a serum-based protein [6] , and that NMP-22 urine tests monitor cellular turnover, rather a specific bladder tumor antigen [10] .", "cite_spans": [{"start": 505, "end": 508, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 606, "end": 610, "text": "[10]", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "Discussion and conclusions", "text": "Analyses from the model and the ELISA assays revealed different characteristics for CCL18 and A1AT with respect to them being potentially reliable BCa diagnostic biomarkers. For CCL18, the first observation is that three healthy control samples had very low urinary CCL18 levels (5.96 pg/ml). The median level of CCL18 in the non-cancer samples from the 308 subject cohort was also very low (23.4 pg/ml). A low baseline level is an advantage that can enable a clear distinction between healthy and disease state for a given assay. Conversely, if the differential between urine and blood is large, then a small amount of hematuria may have a significant impact. In the spiking experiment, we observed that 50 \u03bcl of blood in 10 ml of urine, a level that would be termed 'gross hematuria' in clinical tests, raised the CCL18 level in healthy controls to 31.9 pg/ml, an increase of~5.3 fold. In the 308 subject cohort, the median level of CCL18 was 10-fold higher in BCa subjects (230.5 pg/ml vs. 23.4 pg/ml). The addition of benign and tumor cell lysates to the urine sample is designed to indicate whether the release of ubiquitous cellular factors may be the source of the biomarker. Increased cellular turnover is to be expected in a malignant condition, and so such factors, for example NMP22, may increase even though they are not actually cancer-specific biomarkers. Due to the low levels of CCL18 in the healthy urine samples, the addition of cell lysates from benign and tumor cells did significantly impact the CCL18 levels. Finally, immunohistochemical analysis of bladder tumor tissues revealed that CCL18 was present only in the inflammatory cells located in the stroma. No difference in the number of the immunoreactive cells was observed in benign versus cancerous tissue, or among the various grades or stages of bladder cancer. Together, these findings suggest that CCL18 monitoring is unlikely to be a reliable biomarker for the non-invasive detection of BCa.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion and conclusions", "text": "The analysis of the A1AT biomarker revealed opposite characteristics for the most part. ELISA data and the experimental model confirmed that A1AT is present at high levels in healthy and non-cancer subject urine samples. The median level in the 308 subject cohort was 120 ng/ml in non-cancer cases, rising 5.5-fold to 606.4 ng/ml in subjects with confirmed BCa. The median level in the three healthy volunteer samples was intermediate (1,170 ng/ml). Lower levels in the non-cancer subjects from the ELISA data is most likely due to degradation with freezing and storage in these samples compared to the fresh urines obtained from the volunteers. The high baseline level of A1AT in healthy urine samples may not be ideal for diagnostic evaluation, but the impact of hematuria on A1AT assays would be expected to be less pronounced. Accordingly, gross hematuria in the Figure 4 Analysis of CCL18 and A1AT biomarker performance in an experimental model. Using the experimental model depicted in Figure 1 , urinary levels of CCL18 and A1AT were analyzed by ELISA. The addition of whole blood resulted in an increase in CCL18 as well as an increase in A1AT. Error bars indicate standard deviations. *, significance (p < 0.05) compared to pooled urines from healthy subjects.^, significance (p < 0.05) compared to corresponding lower concentration.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion and conclusions", "text": "experimental model (50 \u03bcl of blood into 10 ml of urine) raised A1AT to 1,273 ng/ml, an increase of only 9%. Compare this to the >400% rise in CCL18 in the same experimental model conditions. The addition of benign or cancer cell lysates in the experimental model had no impact on the A1AT levels. Previous preliminary research has linked the presence of urinary A1AT as a biomarker for renal dysfunction [32] . However we took precautions in our study to minimize renal dysfunction as a confounder by excluding subjects with a history of renal dysfunction as well as exclude subjects with grossly elevated urinary protein levels. Recently, researchers have reported that impaired renal function (i.e., reduced glomerular filtration rate) may adversely affect urinary Figure 5 Assessment of CCL18 and A1AT in bladder tissue. a) Representative immunostaining of benign bladder for CCL18 (top-left), lowgrade non-muscle invasive bladder cancer for CCL18 (top-middle), and high-grade muscle invasive bladder cancer for CCL18 (top-right). Red arrows indicate CCL18-positive cells in the stroma. CCL18 staining was present only in inflammatory cells associated with the stroma. Lower panels are boxplots of CCL18 immunohistochemical staining intensity of benign bladder vs. bladder cancer, low-grade vs. high-grade, non-muscle invasive bladder cancer (NMIBC) vs. muscle invasive bladder cancer (MIBC). Error bars indicate standard deviations. Wilcoxon rank sum test was used to assess significance. b) Representative immunostaining of benign bladder for A1AT (top-left), low-grade non-muscle invasive BCa for A1AT (top-middle), and high-grade muscle invasive BCa for A1AT (top-right). A1AT staining was present in the cytoplasm and stroma. A1AT staining varied from weak and focal to strong and diffuse. Lower panel shows column bar graphs of A1AT immunohistochemical staining intensity of benign bladder vs. bladder cancer, low-grade vs. high-grade, NMIBC vs. MIBC.", "cite_spans": [{"start": 404, "end": 408, "text": "[32]", "ref_id": "BIBREF31"}], "ref_spans": []}, {"section": "Discussion and conclusions", "text": "biomarkers performance [33, 34] . This is an excellent point and should be taken into consideration in future studies. However, we must stress that we confirmed these A1AT ELISA results by performing immunohistochemistry and thus demonstrated that A1AT is present within urothelial cells. We reported A1AT reactivity was epithelial in normal bladder tissue, and strongly positive in all tumor cells, specifically high-grade cells. Although A1AT IHC may not be particularly useful in differential histological evaluations, it does suggest that the source of the increased A1AT observed in BCa samples is most likely bladder tumor cells. The release into the urine may be via secretion or the turnover of tumor cells at the urine interface. Thus, even though normal urinary levels of A1AT are relatively high, measurement of this biomarker in the context of cancer detection may be worthwhile. The good separation between non-cancer and BCa urinary levels and the limited influence by secondary sources suggest that valid diagnostic cutoff thresholds may be possible for urinary A1AT monitoring.", "cite_spans": [{"start": 23, "end": 27, "text": "[33,", "ref_id": "BIBREF32"}, {"start": 28, "end": 31, "text": "34]", "ref_id": "BIBREF33"}], "ref_spans": []}, {"section": "Discussion and conclusions", "text": "When novel urinary biomarkers are proposed, the investigation of reliability in the face of potentially confounding effects is warranted, especially those introduced into the urine through bleeding, a common presenting factor in bladder tumor-bearing patients. Further studies into the utility of A1AT as a biomarker for the non-invasive detection of BCa are currently underway.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Urine cytology of transitional cell neoplasms", "authors": [{"first": "C", "middle": ["C"], "last": "Rife", "suffix": ""}, {"first": "G", "middle": ["M"], "last": "Farrow", "suffix": ""}, {"first": "D", "middle": ["C"], "last": "Utz", "suffix": ""}], "year": 1979, "venue": "Urol Clin North Am", "link": "38125982"}, "BIBREF1": {"title": "Cytology, flow cytometry, image analysis, and interphase cytogenetics by fluorescence in situ hybridization in the diagnosis of transitional cell carcinoma in bladder washes: a comparative study", "authors": [{"first": "R", "middle": ["S"], "last": "Cajulis", "suffix": ""}, {"first": "G", "middle": ["K"], "last": "Haines", "suffix": ""}, {"first": "D", "middle": [], "last": "Frias-Hidvegi", "suffix": ""}, {"first": "K", "middle": [], "last": "Mcvary", "suffix": ""}, {"first": "J", "middle": ["W"], "last": "Bacus", "suffix": ""}], "year": 1995, "venue": "Diagn Cytopathol", "link": "19290097"}, "BIBREF2": {"title": "Quantitative detection of human complement factor H-related protein in transitional cell carcinoma of the urinary bladder", "authors": [{"first": "R", "middle": [], "last": "Heicappell", "suffix": ""}, {"first": "I", "middle": ["C"], "last": "Wettig", "suffix": ""}, {"first": "M", "middle": [], "last": "Schostak", "suffix": ""}], "year": 1999, "venue": "Eur Urol", "link": "46872099"}, "BIBREF3": {"title": "Complement factor H or a related protein is a marker for transitional cell cancer of the bladder", "authors": [{"first": "R", "middle": [], "last": "Kinders", "suffix": ""}, {"first": "T", "middle": [], "last": "Jones", "suffix": ""}, {"first": "R", "middle": [], "last": "Root", "suffix": ""}], "year": 1998, "venue": "Clin Cancer Res", "link": "14405601"}, "BIBREF4": {"title": "The BTA stat test is nonspecific for hematuria: an experimental hematuria model", "authors": [{"first": "O", "middle": [], "last": "Oge", "suffix": ""}, {"first": "D", "middle": [], "last": "Kozaci", "suffix": ""}, {"first": "H", "middle": [], "last": "Gemalmaz", "suffix": ""}], "year": 2002, "venue": "J Urol", "link": "24624674"}, "BIBREF5": {"title": "Urinary BTA: indicator of bladder cancer or of hematuria", "authors": [{"first": "M", "middle": [], "last": "Miyake", "suffix": ""}, {"first": "S", "middle": [], "last": "Goodison", "suffix": ""}, {"first": "W", "middle": [], "last": "Rizwani", "suffix": ""}, {"first": "S", "middle": [], "last": "Ross", "suffix": ""}, {"first": "Bart", "middle": [], "last": "Grossman", "suffix": ""}, {"first": "H", "middle": [], "last": "Rosser", "suffix": ""}, {"first": "C", "middle": ["J"], "last": "", "suffix": ""}], "year": "", "venue": "World J Urol", "link": "9970841"}, "BIBREF6": {"title": "Detection of bladder cancer using a point-of-care proteomic assay", "authors": [{"first": "H", "middle": ["B"], "last": "Grossman", "suffix": ""}, {"first": "E", "middle": [], "last": "Messing", "suffix": ""}, {"first": "M", "middle": [], "last": "Soloway", "suffix": ""}, {"first": "K", "middle": [], "last": "Tomera", "suffix": ""}, {"first": "G", "middle": [], "last": "Katz", "suffix": ""}, {"first": "Y", "middle": [], "last": "Berger", "suffix": ""}, {"first": "Y", "middle": [], "last": "Shen", "suffix": ""}], "year": 2005, "venue": "JAMA", "link": "14931460"}, "BIBREF7": {"title": "Comparison of the nuclear matrix protein 22 with voided urine cytology and BTA stat test in the diagnosis of transitional cell carcinoma of the bladder", "authors": [{"first": "S", "middle": [], "last": "S\u00f6zen", "suffix": ""}, {"first": "H", "middle": [], "last": "Biri", "suffix": ""}, {"first": "Z", "middle": [], "last": "Sinik", "suffix": ""}, {"first": "B", "middle": [], "last": "K\u00fcpeli", "suffix": ""}, {"first": "T", "middle": [], "last": "Alkibay", "suffix": ""}, {"first": "I", "middle": [], "last": "Bozkirli", "suffix": ""}], "year": 1999, "venue": "Eur Urol", "link": null}, "BIBREF8": {"title": "False-positive results of the NMP22 test due to hematuria", "authors": [{"first": "N", "middle": [], "last": "Ats\u00fc", "suffix": ""}, {"first": "S", "middle": [], "last": "Ekici", "suffix": ""}, {"first": "O", "middle": ["O"], "last": "Oge", "suffix": ""}, {"first": "A", "middle": [], "last": "Ergen", "suffix": ""}, {"first": "G", "middle": [], "last": "Has\u00e7elik", "suffix": ""}, {"first": "H", "middle": [], "last": "Ozen", "suffix": ""}], "year": 2002, "venue": "J Urol", "link": "43046013"}, "BIBREF9": {"title": "Influencing factors on the NMP-22 urine assay: an experimental model", "authors": [{"first": "M", "middle": [], "last": "Miyake", "suffix": ""}, {"first": "S", "middle": [], "last": "Goodison", "suffix": ""}, {"first": "E", "middle": ["G"], "last": "Giacoia", "suffix": ""}, {"first": "W", "middle": [], "last": "Rizwani", "suffix": ""}, {"first": "S", "middle": [], "last": "Ross", "suffix": ""}, {"first": "C", "middle": ["J"], "last": "Rosser", "suffix": ""}], "year": 2012, "venue": "BMC Urol", "link": "11401592"}, "BIBREF10": {"title": "Bladder cancerassociated gene expression signatures identified by profiling of exfoliated urothelia", "authors": [{"first": "C", "middle": ["J"], "last": "Rosser", "suffix": ""}, {"first": "L", "middle": [], "last": "Liu", "suffix": ""}, {"first": "Y", "middle": [], "last": "Sun", "suffix": ""}, {"first": "P", "middle": [], "last": "Villicana", "suffix": ""}, {"first": "M", "middle": [], "last": "Mccullers", "suffix": ""}], "year": 2009, "venue": "Cancer Epidemiol Biomarkers Prev", "link": "10272001"}, "BIBREF11": {"title": "Molecular Biomarker Signature for the Non-Invasive Detection of Bladder Cancer", "authors": [{"first": "V", "middle": [], "last": "Uriquidi", "suffix": ""}, {"first": "S", "middle": [], "last": "Goodison", "suffix": ""}, {"first": "Y", "middle": [], "last": "Cai", "suffix": ""}, {"first": "Y", "middle": [], "last": "Sun", "suffix": ""}, {"first": "C", "middle": ["J"], "last": "Rosser", "suffix": ""}], "year": 2012, "venue": "CEBP", "link": "74843594"}, "BIBREF12": {"title": "Bladder cancer associated glycoprotein signatures revealed by urinary proteomic profiling", "authors": [{"first": "P", "middle": [], "last": "Kreunin", "suffix": ""}, {"first": "J", "middle": [], "last": "Zhao", "suffix": ""}, {"first": "C", "middle": [], "last": "Rosser", "suffix": ""}, {"first": "V", "middle": [], "last": "Urquidi", "suffix": ""}, {"first": "D", "middle": ["M"], "last": "Lubman", "suffix": ""}, {"first": "S", "middle": [], "last": "Goodison", "suffix": ""}], "year": 2007, "venue": "J Proteome Res", "link": "34128161"}, "BIBREF13": {"title": "Urinary glycoprotein biomarker discovery for bladder cancer detection using LC-MS/MS and label-free quantification", "authors": [{"first": "N", "middle": [], "last": "Yang", "suffix": ""}, {"first": "S", "middle": [], "last": "Feng", "suffix": ""}, {"first": "K", "middle": [], "last": "Shedden", "suffix": ""}, {"first": "X", "middle": [], "last": "Xie", "suffix": ""}, {"first": "Y", "middle": [], "last": "Liu", "suffix": ""}], "year": 2011, "venue": "Clin Cancer Res", "link": "2061411"}, "BIBREF14": {"title": "CCL18 In a multiplex urinebased assay for the detection of bladder cancer", "authors": [{"first": "V", "middle": [], "last": "Urquidi", "suffix": ""}, {"first": "J", "middle": [], "last": "Kim", "suffix": ""}, {"first": "M", "middle": [], "last": "Chang", "suffix": ""}, {"first": "Y", "middle": [], "last": "Dai", "suffix": ""}, {"first": "C", "middle": ["J"], "last": "Rosser", "suffix": ""}], "year": 2012, "venue": "PLoS One", "link": "2517496"}, "BIBREF15": {"title": "VEGF, CA9 and angiogenin as a urinary biomarker for bladder cancer detection", "authors": [{"first": "V", "middle": [], "last": "Urquidi", "suffix": ""}, {"first": "S", "middle": [], "last": "Goodison", "suffix": ""}, {"first": "J", "middle": [], "last": "Kim", "suffix": ""}, {"first": "M", "middle": [], "last": "Chang", "suffix": ""}, {"first": "Y", "middle": [], "last": "Dai", "suffix": ""}], "year": 2012, "venue": "Urology", "link": null}, "BIBREF16": {"title": "L-8 as a urinary biomarker for the detection of bladder cancer", "authors": [{"first": "V", "middle": [], "last": "Urquidi", "suffix": ""}, {"first": "M", "middle": [], "last": "Chang", "suffix": ""}, {"first": "Y", "middle": [], "last": "Dai", "suffix": ""}, {"first": "J", "middle": [], "last": "Kim", "suffix": ""}, {"first": "E", "middle": ["D"], "last": "Wolfson", "suffix": ""}], "year": 2012, "venue": "BMC Urol", "link": "9912494"}, "BIBREF17": {"title": "Diagnostic potential of urinary alpha 1-antitrypsin and apolipoprotein E in the detection of bladder cancer", "authors": [{"first": "V", "middle": [], "last": "Urquidi", "suffix": ""}, {"first": "S", "middle": [], "last": "Goodison", "suffix": ""}, {"first": "Ross", "middle": [], "last": "Chang", "suffix": ""}, {"first": "M", "middle": [], "last": "Dai", "suffix": ""}, {"first": "Y", "middle": [], "last": "", "suffix": ""}], "year": 2012, "venue": "J Urol", "link": "3374057"}, "BIBREF18": {"title": "A multi-analyte assay for the non-invasive detection of bladder cancer", "authors": [{"first": "S", "middle": [], "last": "Goodison", "suffix": ""}, {"first": "M", "middle": [], "last": "Chang", "suffix": ""}, {"first": "Y", "middle": [], "last": "Dai", "suffix": ""}, {"first": "V", "middle": [], "last": "Urquidi", "suffix": ""}, {"first": "C", "middle": ["J"], "last": "Rosser", "suffix": ""}], "year": 2012, "venue": "PLoS One", "link": "991711"}, "BIBREF19": {"title": "Towards complete and accurate reporting of studies of diagnostic accuracy: the STARD initiative", "authors": [{"first": "P", "middle": ["M"], "last": "Bossuyt", "suffix": ""}, {"first": "J", "middle": ["B"], "last": "Reitsma", "suffix": ""}, {"first": "D", "middle": ["E"], "last": "Bruns", "suffix": ""}, {"first": "C", "middle": ["A"], "last": "Gatsonis", "suffix": ""}, {"first": "P", "middle": ["P"], "last": "Glasziou", "suffix": ""}], "year": 2004, "venue": "Fam Pract", "link": "78440415"}, "BIBREF20": {"title": "Discovery of urinary biomarkers", "authors": [{"first": "T", "middle": [], "last": "Pisitkun", "suffix": ""}, {"first": "R", "middle": [], "last": "Johnstone", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Knepper", "suffix": ""}], "year": 2006, "venue": "Mol Cell Proteomics", "link": "13775258"}, "BIBREF21": {"title": "An improved intravesical model using human bladder cancer cell lines to optimize gene and other therapies", "authors": [{"first": "T", "middle": [], "last": "Watanabe", "suffix": ""}, {"first": "N", "middle": [], "last": "Shinohara", "suffix": ""}, {"first": "A", "middle": [], "last": "Sazawa", "suffix": ""}, {"first": "T", "middle": [], "last": "Harabayashi", "suffix": ""}, {"first": "Y", "middle": [], "last": "Ogiso", "suffix": ""}, {"first": "T", "middle": [], "last": "Koyanagi", "suffix": ""}, {"first": "M", "middle": [], "last": "Takiguchi", "suffix": ""}, {"first": "A", "middle": [], "last": "Hashimoto", "suffix": ""}, {"first": "N", "middle": [], "last": "Kuzumaki", "suffix": ""}, {"first": "M", "middle": [], "last": "Yamashita", "suffix": ""}, {"first": "M", "middle": [], "last": "Tanaka", "suffix": ""}, {"first": "H", "middle": ["B"], "last": "Grossman", "suffix": ""}, {"first": "W", "middle": ["F"], "last": "Benedict", "suffix": ""}], "year": 2000, "venue": "Cancer Gene Ther", "link": "28521375"}, "BIBREF22": {"title": "The immortalized UROtsa cell line as a potential cell culture model of human urothelium", "authors": [{"first": "M", "middle": ["R"], "last": "Rossi", "suffix": ""}, {"first": "J", "middle": ["R"], "last": "Masters", "suffix": ""}, {"first": "S", "middle": [], "last": "Park", "suffix": ""}, {"first": "J", "middle": ["H"], "last": "Todd", "suffix": ""}, {"first": "S", "middle": ["H"], "last": "Garrett", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Sens", "suffix": ""}, {"first": "S", "middle": [], "last": "Somji", "suffix": ""}, {"first": "J", "middle": [], "last": "Nath", "suffix": ""}, {"first": "D", "middle": ["A"], "last": "Sens", "suffix": ""}], "year": 2001, "venue": "Environ Health Perspect", "link": "9273861"}, "BIBREF23": {"title": "Estimation of the Youden Index and its associated cutoff point", "authors": [{"first": "R", "middle": [], "last": "Fluss", "suffix": ""}, {"first": "D", "middle": [], "last": "Faraggi", "suffix": ""}, {"first": "B", "middle": [], "last": "Reiser", "suffix": ""}], "year": 2005, "venue": "Biom J", "link": "17106528"}, "BIBREF24": {"title": "Pivotal evaluation of the accuracy of a biomarker used for classification or prediction: standards for study design", "authors": [{"first": "M", "middle": ["S"], "last": "Pepe", "suffix": ""}, {"first": "Z", "middle": [], "last": "Feng", "suffix": ""}, {"first": "H", "middle": [], "last": "Janes", "suffix": ""}, {"first": "P", "middle": ["M"], "last": "Bossuyt", "suffix": ""}, {"first": "J", "middle": ["D"], "last": "Potter", "suffix": ""}], "year": 2008, "venue": "J Natl Cancer Inst", "link": null}, "BIBREF25": {"title": "CCL18 From tumorassociated macrophages promotes breast cancer metastasis via PITPNM3", "authors": [{"first": "J", "middle": [], "last": "Chen", "suffix": ""}, {"first": "Y", "middle": [], "last": "Yao", "suffix": ""}, {"first": "C", "middle": [], "last": "Gong", "suffix": ""}, {"first": "F", "middle": [], "last": "Yu", "suffix": ""}, {"first": "S", "middle": [], "last": "Su", "suffix": ""}, {"first": "B", "middle": [], "last": "Liu", "suffix": ""}], "year": 2011, "venue": "Cancer Cell", "link": "16554978"}, "BIBREF26": {"title": "Clinical utility of circulating matrix metalloproteinase-7 (MMP-7), CC chemokine ligand 18 (CCL18) and CC chemokine ligand 11 (CCL11) as markers for diagnosis of epithelial ovarian cancer", "authors": [{"first": "S", "middle": ["F"], "last": "Zohny", "suffix": ""}, {"first": "S", "middle": ["T"], "last": "Fayed", "suffix": ""}], "year": 2010, "venue": "Med Oncol", "link": "22298113"}, "BIBREF27": {"title": "Evaluation of proteomics-identified CCL18 and CXCL1 as circulating tumor markers for differential diagnosis between ovarian carcinomas and benign pelvic masses", "authors": [{"first": "Q", "middle": [], "last": "Wang", "suffix": ""}, {"first": "D", "middle": [], "last": "Li", "suffix": ""}, {"first": "W", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "B", "middle": [], "last": "Tang", "suffix": ""}, {"first": "Q", "middle": ["Q"], "last": "Li", "suffix": ""}, {"first": "L", "middle": [], "last": "Li", "suffix": ""}], "year": 2011, "venue": "Int: J Biol Markers", "link": null}, "BIBREF28": {"title": "Protease inhibitor SERPINA1 expression in epithelial ovarian cancer", "authors": [{"first": "K", "middle": [], "last": "Normandin", "suffix": ""}, {"first": "B", "middle": [], "last": "Peant", "suffix": ""}, {"first": "Le", "middle": [], "last": "Page", "suffix": ""}, {"first": "C", "middle": [], "last": "", "suffix": ""}], "year": 2010, "venue": "Clin Exp Metastasis", "link": "20274949"}, "BIBREF29": {"title": "Alpha-1-antitrypsin deficiency and smoking as risk factors for mismatch repair deficient colorectal cancer: a study from the colon cancer family registry", "authors": [{"first": "N", "middle": ["M"], "last": "Lindor", "suffix": ""}, {"first": "P", "middle": [], "last": "Yang", "suffix": ""}, {"first": "I", "middle": [], "last": "Evans", "suffix": ""}], "year": 2010, "venue": "Mol Genet Metab", "link": "37391598"}, "BIBREF30": {"title": "Proteomics-based identification of alpha1-antitrypsin and haptoglobin precursors as novel serum markers in infiltrating ductal breast carcinomas", "authors": [{"first": "B", "middle": [], "last": "Hamrita", "suffix": ""}, {"first": "K", "middle": [], "last": "Chahed", "suffix": ""}, {"first": "M", "middle": [], "last": "Trimeche", "suffix": ""}], "year": 2009, "venue": "Clin Chim Acta", "link": "9487080"}, "BIBREF31": {"title": "Uromodulin and \u03b1(1)-antitrypsin urinary peptide analysis to differentiate glomerular kidney diseases", "authors": [{"first": "M", "middle": [], "last": "Navarro-Mu\u00f1oz", "suffix": ""}, {"first": "M", "middle": [], "last": "Ibernon", "suffix": ""}, {"first": "J", "middle": [], "last": "Bonet", "suffix": ""}, {"first": "V", "middle": [], "last": "P\u00e9rez", "suffix": ""}, {"first": "M", "middle": ["C"], "last": "Pastor", "suffix": ""}, {"first": "B", "middle": [], "last": "Bay\u00e9s", "suffix": ""}, {"first": "J", "middle": [], "last": "Casadovela", "suffix": ""}, {"first": "M", "middle": [], "last": "Navarro", "suffix": ""}, {"first": "Ara", "middle": ["J"], "last": "Espinal", "suffix": ""}, {"first": "A", "middle": [], "last": "Fluvi\u00e0", "suffix": ""}, {"first": "L", "middle": [], "last": "Serra", "suffix": ""}, {"first": "A", "middle": [], "last": "L\u00f3pez", "suffix": ""}, {"first": "D", "middle": [], "last": "Romero", "suffix": ""}, {"first": "R", "middle": [], "last": "", "suffix": ""}], "year": "", "venue": "Kidney Blood Press Res", "link": "719018"}, "BIBREF32": {"title": "The clinical usefulness of nuclear matrix protein-22 in patients with end-stage renal disease and microscopic hematuria", "authors": [{"first": "B", "middle": [], "last": "Trojan", "suffix": ""}, {"first": "A", "middle": [], "last": "Tang", "suffix": ""}, {"first": "J", "middle": [], "last": "Chandrapal", "suffix": ""}, {"first": "S", "middle": [], "last": "Filleur", "suffix": ""}, {"first": "T", "middle": [], "last": "Nelius", "suffix": ""}], "year": 2013, "venue": "Ren Fail", "link": "25806180"}, "BIBREF33": {"title": "Influence of renal excretory function on the performance of urine based markers to detect bladder cancer", "authors": [{"first": "T", "middle": [], "last": "Todenh\u00f6fer", "suffix": ""}, {"first": "J", "middle": [], "last": "Hennenlotter", "suffix": ""}, {"first": "M", "middle": [], "last": "Witstruk", "suffix": ""}, {"first": "G", "middle": [], "last": "Gakis", "suffix": ""}, {"first": "S", "middle": [], "last": "Aufderklamm", "suffix": ""}, {"first": "U", "middle": [], "last": "Kuehs", "suffix": ""}, {"first": "A", "middle": [], "last": "Stenzl", "suffix": ""}, {"first": "C", "middle": [], "last": "Schwentner", "suffix": ""}], "year": "", "venue": "J Urol", "link": "21223527"}, "BIBREF34": {"title": "Submit your next manuscript to BioMed Central and take full advantage of: \u2022 Convenient online submission \u2022 Thorough peer review \u2022 No space constraints or color figure charges \u2022 Immediate publication on acceptance \u2022 Inclusion in PubMed, CAS, Scopus and Google Scholar \u2022 Research which is freely available for redistribution", "authors": [{"first": "", "middle": [], "last": "Miyake", "suffix": ""}], "year": 2013, "venue": "BMC Urology", "link": null}}, "ref_entries": {"FIGREF0": {"text": "Figure 2 Urinary biomarker levels. a) Comparison of urine concentrations of CCL-18 between the cancer and non-cancer groups (left panel), low-grade and high-grade (middle panel) and non-muscle invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC). b) Comparison of urine concentrations of A1AT between the same groups. Median levels are depicted by horizontal lines within boxes, standard deviations are depicted by bars. Significance (p < 0.05) was assessed by the Wilcoxon rank sum test.", "type": "figure"}, "TABREF1": {"text": "Demographic and clinicopathologic characteristics of 308 subjects comprising ELISA study cohort and 173 subjects comprising IHC study cohort", "type": "table"}, "TABREF2": {"text": "Results of CCL18 and A1AT in experimental hematuria model", "type": "table"}}}
{"paper_id": "8337318", "_pdf_hash": "d8b94fc85c06f0b4208cd936a9ad907aea3e9231", "abstract": [{"section": "Abstract", "text": "Dysferlin and Caveolin-3 are plasma membrane proteins associated with muscular dystrophy. Patients with mutations in the CAV3 gene show dysferlin mislocalization in muscle cells. By utilizing caveolin-null cells, expression of caveolin mutants, and different mutants of dysferlin, we have dissected the site of action of caveolin with respect to dysferlin trafficking pathways. We now show that Caveolin-1 or -3 can facilitate exit of a dysferlin mutant that accumulates in the Golgi complex of Cav1 \u060a/\u060a cells. In contrast, wild type dysferlin reaches the plasma membrane but is rapidly endocytosed in Cav1 \u060a/\u060a cells. We demonstrate that the primary effect of caveolin is to cause surface retention of dysferlin. Caveolin-1 or Caveolin-3, but not specific caveolin mutants, inhibit endocytosis of dysferlin through a clathrin-independent pathway colocalizing with internalized glycosylphosphatidylinositol-anchored proteins. Our results provide new insights into the role of this endocytic pathway in surface remodeling of specific surface components. In addition, they highlight a novel mechanism of action of caveolins relevant to the pathogenic mechanisms underlying caveolin-associated disease.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Dysferlin and Caveolin-3 (muscle-specific caveolin, Cav3) are sarcolemmal proteins whose role in muscle has gained clinical attention because mutations in their genes are associated with a number of muscle pathologies. Patients with mutations in the dysferlin (DYSF) gene develop disorders such as limb girdle muscular dystrophy type 2B, miyoshi myopathy, and distal myopathy (1-5). Whereas disruption in the Caveolin-3 (CAV3) gene has been linked to limb girdle muscular dystrophy 1C, Rippling muscle diseases, hyperCKemia, and distal myopathy among other myopathies (6 -15). Dysferlin and Cav3 have been co-purified from muscle cells (16, 17) and shown to localize to adjacent membrane domains at the surface in mature muscle fibers (18). Moreover, dysferlin is depleted from the plasma membrane (PM) 2 when Cav3 is mutated (8, 9, 14, 17, 19) . We have recently demonstrated a role for caveolin in dysferlin localization at the PM (18). However, the interplay of dysferlin and caveolin membrane trafficking dynamics remains to be examined.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Dysferlin belongs to the ferlin family of proteins comprising otoferlin, myoferlin, and fer1L3 (20 -22). The DYSF gene encodes a 230-kDa skeletal muscle membrane protein (2, 5, 23) with homology to the Caenorhabditis elegans sperm-vesicle fusion factor, fer-1 (2). Because of this dysferlin has been suggested to play a role in vesicle fusion in skeletal muscle (2, 24). Moreover, in the absence of dysferlin muscle cells show defective resealing of membrane disruptions (25). Dysferlin has a single transmembrane domain at the C terminus and a long N-terminal cytoplasmic region containing six C2 domains. C2 domains are a common feature of the synaptotagmin family of proteins implicated in vesicular traffic and membrane fusion events through calcium-dependent interactions with phospholipids and proteins (26 -29). Interestingly, dysferlin and synaptotagmins share structural similarities (20, 24) further implicating dysferlin in membrane trafficking processes.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "In mammalian cells, the CAV gene family consists of three isoforms: , which are crucial structural components of caveolar membranes (\u03f365 nm, uncoated flask-shaped PM pits). Caveolins are 21-24-kDa integral membrane proteins, Caveolin-1 (Cav1) and -2 (Cav2) are mainly co-expressed in non-muscle cells, whereas Cav3 is largely expressed in skeletal and cardiac muscle but is also found in some smooth muscle (36, 37) . Caveolins are cholesterol-and fatty acid-binding proteins, and are thought to play a role in vesicular traffic and signal transduction events (38 -42). The protein structure of caveolins is characterized by a hairpin loop topology with a hydrophobic region immersed in the lipid bilayer (the intramembrane domain), and both N and C terminus regions facing the cytoplasm (43-45). Additionally, the conserved juxtamembrane region, the caveolin scaffolding", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "", "text": "Dysferlin and Caveolin-3 (muscle-specific caveolin, Cav3) are sarcolemmal proteins whose role in muscle has gained clinical attention because mutations in their genes are associated with a number of muscle pathologies. Patients with mutations in the dysferlin (DYSF) gene develop disorders such as limb girdle muscular dystrophy type 2B, miyoshi myopathy, and distal myopathy (1) (2) (3) (4) (5) . Whereas disruption in the Caveolin-3 (CAV3) gene has been linked to limb girdle muscular dystrophy 1C, Rippling muscle diseases, hyperCKemia, and distal myopathy among other myopathies (6 -15) . Dysferlin and Cav3 have been co-purified from muscle cells (16, 17) and shown to localize to adjacent membrane domains at the surface in mature muscle fibers (18) . Moreover, dysferlin is depleted from the plasma membrane (PM) 2 when Cav3 is mutated (8, 9, 14, 17, 19) . We have recently demonstrated a role for caveolin in dysferlin localization at the PM (18) . However, the interplay of dysferlin and caveolin membrane trafficking dynamics remains to be examined.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Dysferlin belongs to the ferlin family of proteins comprising otoferlin, myoferlin, and fer1L3 (20 -22) . The DYSF gene encodes a 230-kDa skeletal muscle membrane protein (2, 5, 23) with homology to the Caenorhabditis elegans sperm-vesicle fusion factor, fer-1 (2) . Because of this dysferlin has been suggested to play a role in vesicle fusion in skeletal muscle (2, 24) . Moreover, in the absence of dysferlin muscle cells show defective resealing of membrane disruptions (25) . Dysferlin has a single transmembrane domain at the C terminus and a long N-terminal cytoplasmic region containing six C2 domains. C2 domains are a common feature of the synaptotagmin family of proteins implicated in vesicular traffic and membrane fusion events through calcium-dependent interactions with phospholipids and proteins (26 -29) . Interestingly, dysferlin and synaptotagmins share structural similarities (20, 24) further implicating dysferlin in membrane trafficking processes.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "In mammalian cells, the CAV gene family consists of three isoforms: Caveolin-1, -2, and -3 (30 -35) , which are crucial structural components of caveolar membranes (\u03f365 nm, uncoated flask-shaped PM pits). Caveolins are 21-24-kDa integral membrane proteins, Caveolin-1 (Cav1) and -2 (Cav2) are mainly co-expressed in non-muscle cells, whereas Cav3 is largely expressed in skeletal and cardiac muscle but is also found in some smooth muscle (36, 37) . Caveolins are cholesterol-and fatty acid-binding proteins, and are thought to play a role in vesicular traffic and signal transduction events (38 -42) . The protein structure of caveolins is characterized by a hairpin loop topology with a hydrophobic region immersed in the lipid bilayer (the intramembrane domain), and both N and C terminus regions facing the cytoplasm (43) (44) (45) . Additionally, the conserved juxtamembrane region, the caveolin scaffolding * This work was supported by grants from the National Health and Medical domain (CSD), has been shown to bind in vitro to a consensus sequence (XXXXXXX, aromatic residues, X any amino acid) (46) present in various proteins. Dysferlin has several putative CSD binding motifs (17) .", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "We have recently described the subcellular distribution of dysferlin with respect to Cav3 and showed that dysferlin association with the PM is impaired in the absence of caveolin, or in the presence of dystrophy-associated mutant forms of Cav3 (18) . Although Cav3 and dysferlin copurify (16, 17) , the precise interacting domains and roles in their trafficking dynamics are poorly understood. We show here that in the absence of caveolin, dysferlin reaches the PM but is rapidly endocytosed through a caveolin-, clathrin-, and dynamin-independent pathway. Wild type caveolin, but not mutant forms of caveolin associated with muscle disease, specifically inhibit dysferlin endocytosis causing its retention at the cell surface.", "cite_spans": [], "ref_spans": []}, {"section": "EXPERIMENTAL PROCEDURES", "text": "DNA Constructs, Reagents, and Antibodies-Cell culture reagents were obtained from Invitrogen. The antibodies used were: mouse anti-LBPA, mouse anti-LAMP-1 (Southern Biotech), mouse anti-GM130 (BD Biosciences), rabbit antibody made against the conserved region of Cav3 (47), rabbit anti-HA (Dr. T. Nilsson, Gothenburg University, Gothenburg, Sweden), rabbit anti-GFP (48), mouse anti-myc 9B11 (Cell Signaling Technology), and anti-protein-disulfide isomerase. Secondary antibodies conjugated to Alexa Fluor 488, 350, 546, 647, and CTB conjugated to Alexa Fluor 555 and Tf-Alexa Fluor 647 (Molecular Probes), CY3-conjugated anti-mouse antibody (Jackson Immunoresearch), and HRP-conjugated secondary antibodies (Zymed Laboratories) were used. SuperSignal substrate was obtained from Pierce Chemical Company. All other chemicals and reagents were obtained from Sigma.", "cite_spans": [], "ref_spans": []}, {"section": "EXPERIMENTAL PROCEDURES", "text": "GFP-dysferlin cDNA was used as a template to generate different truncation mutants by restriction digestion at unique enzymatic sites (49) (see Fig. 1 ), GFP\u232c-C2 (GFP-TM), GFP\u232c-1 (GFP3\u0408GFP-2), GFP\u232c-2 (GFP-Tth), GFP\u232c-3 (GFP-Xho), and GFP-\u232c-TM. Expression of the complete fusion proteins was confirmed in multiple cell lines. Cav3G55S-HA, Cav3C71W-HA, and Flotillin-HA were made as described (50, 51) . The glycosylphosphatidylinositol (GPI)-GFP, Cav1\u232c81-100-HA, and transferrin receptor constructs were gifts from C. Zurzolo (Institut Pasteur, France), D. Brown (State University of New York), S. L. Schmid (Scripps Research Institute), and V. Gerke (Center for Molecular Biology of Inflammation, ZMBE), respectively. Dynamin inhibitor, dynasore, was a kind gift from T. Kirchhausen (Harvard Medical School).", "cite_spans": [], "ref_spans": [{"start": 144, "end": 150, "text": "Fig. 1", "ref_id": "FIGREF0"}]}, {"section": "EXPERIMENTAL PROCEDURES", "text": "Cell Culture and Transfection-We utilized immortalized mouse embryonic fibroblasts (MEF) cell lines derived from Cav1 WT or knock-out mice as in previous studies (18, 52, 53) . Cells were grown on glass coverslips and cDNAs were transiently expressed utilizing Lipofectamine 2000 (Invitrogen) according to the manufacturer's directions.", "cite_spans": [], "ref_spans": []}, {"section": "EXPERIMENTAL PROCEDURES", "text": "Immunofluorescence and Microscopy-Immunolabeling of MEFs were carried out as described previously (18) . Confocal images were acquired with an inverted Zeiss LSM 510 META microscope system (Axiovert 200M, Carl Zeiss MicroImaging) under a Plan apochromatic \u03eb63 1.4 NA oil immersion objective. Images were processed and merged using Adobe Photoshop 9.0 software. Identical imaging and processing parameters were used for all figures.", "cite_spans": [], "ref_spans": []}, {"section": "EXPERIMENTAL PROCEDURES", "text": "Surface Labeling and Single Cell Fluorescence QuantificationSurface labeling and quantification of the fluorescence intensity of dysferlin pool at the PM was performed as described previously (18) . The average pixel intensity for PM and IC/Golgi pools were measured using Adobe Photoshop 9.0 software. Experiments were repeated three times.", "cite_spans": [], "ref_spans": []}, {"section": "EXPERIMENTAL PROCEDURES", "text": "Quantifications shown in Figs. 1D, 2C, 3B, and 7B are representative of 3 individual experiments and were performed once on 250 -350 cells and twice on a total of 30 cells for each construct. Subcellular phenotypes were determined based on colabeling with relevant IC markers. Results are presented as percentage of cells showing a common phenotype.", "cite_spans": [], "ref_spans": []}, {"section": "EXPERIMENTAL PROCEDURES", "text": "Myc, Tfn, CTB, and GPI Uptake Assays-Uptake assays were performed as described previously (54) . In brief, 20 mg/ml monoclonal anti-myc antibody, 1 mg/ml CTxB-Alexa Fluor 555, or 5 mg/ml Tfn Alexa Fluor 647 was bound to cells on ice for 30 min in CO 2 -independent medium. Cells were washed with ice-cold CO 2 -independent medium to remove unbound reagent prior to uptake in growth media (10% fetal bovine serum, 2 mM L-glutamine/Dulbecco's modified Eagle's medium) at 37\u00b0C, for the times indicated. Cells were placed on ice-cold CO 2 -independent medium and washed 2 times for 30 s in 0.5 M glycine (pH 2.2). The cells were fixed in 2% paraformaldehyde and processed for immunofluorescence. For inhibition of dynamin-dependent uptake, cells were preincubated in either 80 mM dynasore/growth media or 0.4% Me 2 SO/growth media for 30 min at 37\u00b0C, followed by Tfn and anti-myc uptake in the presence or absence of dynasore.", "cite_spans": [], "ref_spans": []}, {"section": "Ultrastructural Analysis of Dysferlin Endocytosis in WT Cav1 and Cav1", "text": "\u03ea/\u03ea MEFs-WT Cav1 or Cav1 \u03ea/\u03ea MEFs were transfected with GFPDysf. After overnight incubation, to allow expression of the constructs, the cells were incubated with mouse anti-myc antibodies at 4\u00b0C for 20 min, washed, and further incubated with anti-mouse HRP at 4\u00b0C for 20 min. The cells were warmed to 37\u00b0C for 2 min to allow uptake and then incubated in DAB, with or without ascorbic acid (AA), fixed, and processed for resin embedding, exactly as described previously (54) . Due to the low transfection efficiency, GFP-expressing cells were identified by light microscopy before processing. They were marked to allow subsequent location for sectioning. Quantitation of PM coverage of the HRP reaction product was by intersection counting. The number of intersections of a square lattice grid with unlabeled and DAB-covered areas of the PM in random areas of transfected WT Cav1 or Cav1 \u03ea/\u03ea MEFs was measured on digital images to gain an estimate of PM coverage by the HRP reaction.", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Subcellular Distribution of Dysferlin Truncation Mutants in WT Cav1 and Cav1", "text": "\u03ea/\u03ea MEF Cells-To better understand the functional link between dysferlin and Cav3 we examined the subcellular distribution of truncation mutants of dysferlin and analyzed their trafficking dependence on caveolin. We used WT Cav1 and Cav1 \u03ea/\u03ea MEFs as a model system. Cav1 \u03ea/\u03ea cells have no detectable caveolae as they lack Cav1 (as well as the muscle-specific isoform Cav3). This represents a powerful model system to analyze dysferlin trafficking with respect to caveolin as caveolin reexpression rescues the dysferlin trafficking defects (18) .", "cite_spans": [], "ref_spans": []}, {"section": "Subcellular Distribution of Dysferlin Truncation Mutants in WT Cav1 and Cav1", "text": "Truncated versions of dysferlin with an N-terminal GFP tag were generated (see summary in Fig. 1) . Expression of these mutants in baby hamster kidney cells showed single bands of the predicted molecular weight for each of the truncation mutants (Fig. 1B) . We compared the subcellular distribution of the mutant proteins to the WT protein by heterologous expression of truncation mutant forms of dysferlin in WT Cav1 or Cav1", "cite_spans": [], "ref_spans": [{"start": 90, "end": 97, "text": "Fig. 1)", "ref_id": "FIGREF0"}, {"start": 246, "end": 255, "text": "(Fig. 1B)", "ref_id": "FIGREF0"}]}, {"section": "Subcellular Distribution of Dysferlin Truncation Mutants in WT Cav1 and Cav1", "text": "MEFs (refer to summary table in Fig.  1 ). Full-length dysferlin efficiently reaches the PM in WT Cav1 MEFs (Fig. 1C) , consistent with previous results (18) . In contrast, dysferlin localized to intracellular structures but not to the Golgi complex in Cav1 \u03ea/\u03ea cells (Fig. 1C ). GFP\u232c-2, which lacks the three first C2 domains, was found to mainly localize to the endoplasmic reticulum as judged by a large overlap with the endoplasmic reticulum marker, protein-disulfide isomerase (Fig. 1,  C-E) . Truncated versions of dysferlin lacking the TM domain, GFP\u232c-3 and GFP\u232c-TM, were however, mainly cytosolic (Fig. 1, C MEFs. GFP\u232c-1 efficiently exited the Golgi apparatus and reached the PM (Fig.  2) . Quantitation showed that in \u03f366% of Cav1 \u03ea/\u03ea MEFs expressing Cav1-HA or Cav3-HA, GFP\u232c-1 was localized to the PM and to intracellular puncta (Fig. 2B) . GFP\u232c-C2, a mutant lacking all six C2 domains was predominantly targeted to the PM in both WT Cav1 (not shown) and Cav1 \u03ea/\u03ea MEFs (Figs. 1, C-E, and 3, A and B). Quantitation of Cav1 \u03ea/\u03ea MEFs expressing GFP\u232c-C2 showed that in \u03f397% of the cells, GFP\u232c-C2 localized to the PM.", "cite_spans": [], "ref_spans": [{"start": 32, "end": 39, "text": "Fig.  1", "ref_id": "FIGREF0"}, {"start": 108, "end": 117, "text": "(Fig. 1C)", "ref_id": "FIGREF0"}, {"start": 268, "end": 276, "text": "(Fig. 1C", "ref_id": "FIGREF0"}, {"start": 482, "end": 496, "text": "(Fig. 1,  C-E)", "ref_id": "FIGREF0"}, {"start": 605, "end": 615, "text": "(Fig. 1, C", "ref_id": "FIGREF0"}, {"start": 687, "end": 696, "text": "(Fig.  2)", "ref_id": "FIGREF1"}, {"start": 839, "end": 848, "text": "(Fig. 2B)", "ref_id": "FIGREF1"}]}, {"section": "Subcellular Distribution of Dysferlin Truncation Mutants in WT Cav1 and Cav1", "text": "Taken together these results show that GFP\u232c-1, which lacks the first four C2 domains, predominantly accumulates in the Golgi complex in the absence of caveolin. This suggests that caveolin is required for GFP\u232c-1 transport from the Golgi complex to the PM. In contrast, a mutant lacking all six C2 domains is not retained in the Golgi complex in the presence or absence of caveolin. The loss of all six C2 domains renders mutated dysferlin independent of caveolin for surface delivery.", "cite_spans": [], "ref_spans": []}, {"section": "Subcellular Distribution of Dysferlin Truncation Mutants in WT Cav1 and Cav1", "text": "The fact that GFP\u232c-C2 efficiently reached the PM in Cav1 \u03ea/\u03ea MEFs ( Fig. 3) showed that this truncated protein was not dependent on caveolin for surface targeting. We investigated whether a Golgi-localized dystrophy mutant of Cav3 (Cav3P104L-HA), which causes retention of full-length dysferlin in the Golgi complex (18) would affect the traffic of GFP\u232c-C2 to the PM. Cells co-expressing epitope-tagged Cav3P104L (Cav3P104L-HA) and GFP\u232c-C2 showed a dramatic accumulation in the Golgi complex (66% of the cells) compared with cells expressing mutated dysferlin alone (4% of the cells) (Fig. 3) . Thus GFP\u232c-C2, which does not require caveolin for Golgi exit and PM targeting, is blocked in trafficking from the Golgi by the P104L caveolin mutant.", "cite_spans": [], "ref_spans": [{"start": 68, "end": 75, "text": "Fig. 3)", "ref_id": "FIGREF4"}, {"start": 584, "end": 592, "text": "(Fig. 3)", "ref_id": "FIGREF4"}]}, {"section": "Characterization of Dysferlin Trafficking in Cells Lacking Caveolin-", "text": "In the absence of caveolin dysferlin accumulates in an intracellular compartment of unknown nature. The identification of these structures should provide insights into the role of caveolins in dysferlin trafficking. We first examined whether dysferlin was targeted for degradation in Cav1 \u03ea/\u03ea cells. However, dysferlin failed to co-localize significantly with markers of the late endocytic pathway such as LBPA and LAMP1 (supplemental Fig.  S1A ). Despite the low surface labeling in the Cav1 \u03ea/\u03ea MEFs, we speculated that dysferlin is able to reach the PM but then is efficiently endocytosed in the absence of caveolin. If this was the case, antibodies to the lumenal myc epitope should be readily internalized by Cav1 \u03ea/\u03ea cells expressing GFPDysf but not by WT Cav1 cells. WT Cav1 and Cav1 \u03ea/\u03ea MEFs were transfected with a dysferlin cDNA containing an N-terminal GFP tag and a C-terminal (lumenal/extracellular) myc tag (GFPDysf). After 4 h post-transfection, antibodies against the dysferlin ectoplasmic myc tag were added to the culture medium and antibodies were allowed to internalize overnight. The cells were then fixed, permeabilized, and labeled with secondary antibodies. A striking accumulation ", "cite_spans": [], "ref_spans": [{"start": 435, "end": 444, "text": "Fig.  S1A", "ref_id": "FIGREF0"}]}, {"section": "of myc antibodies was observed in the Cav1", "text": "\u03ea/\u03ea MEFs (Fig. 4A ), very little was internalized in WT Cav1 and no uptake was observed in neighboring non-transfected cells (see Fig. 4A ) indicating that the antibodies were taken up specifically after binding to the exposed lumenal myc epitope and not by fluid phase uptake. Consistent with this, the internalized antibodies colocalized with GFPDysf. Identical results were obtained when experiments were performed using Fab fragments against the myc epitope (supplemental Fig. S1B ). Cav1 \u03ea/\u03ea MEFs expressing GFP-dysf showed higher uptake of Fab fragments compared with WT Cav1 cells (supplemental Fig. S1B ). There was no colocalization of Fab fragments and transferrin in WT Cav1 or Cav1 \u03ea/\u03ea cells at any of the time points examined (data not shown).", "cite_spans": [], "ref_spans": [{"start": 9, "end": 17, "text": "(Fig. 4A", "ref_id": "FIGREF5"}, {"start": 130, "end": 137, "text": "Fig. 4A", "ref_id": "FIGREF5"}, {"start": 476, "end": 484, "text": "Fig. S1B", "ref_id": "FIGREF0"}, {"start": 602, "end": 610, "text": "Fig. S1B", "ref_id": "FIGREF0"}]}, {"section": "of myc antibodies was observed in the Cav1", "text": "To investigate this in more detail, myc antibodies were bound to the surface of GFPDysf expressing Cav1 \u03ea/\u03ea or WT Cav1 cells at 4\u00b0C and warmed for 30 min at 37\u00b0C to allow internalization of the antibodies. Surface antibodies were removed by an acid wash. Interestingly, in WT Cav1 or Cav1 \u03ea/\u03ea MEFs, significant GFPDysf internalization was observed after 30 min. Despite the low level of PM dysferlin, Cav1 \u03ea/\u03ea MEFs contained many more vesicles positive for both GFP and myc ( , IC/PM ratio \u03ed 1.07 \u03ee 0.12) (Fig. 4C) . Furthermore, and consistent with our previous work (18), we predicted that re-expression of Cav1-HA in Cav1 \u03ea/\u03ea MEFs would inhibit dysferlin internalization (Fig. 4D) . Cav1 \u03ea/\u03ea MEFs co-expressing GFPDysf and Cav1-HA showed a distribution of dysferlin similar to that seen in WT Cav1 MEFs (refer to supplemental 4D) . Thus these results demonstrate that the major effect of caveolin is to retain dysferlin at the PM and inhibit its internalization. These results demonstrate that dysferlin is not absolutely dependent on caveolin to reach the PM but is efficiently retained at the PM in the presence of caveolin. Taken together, these results show a hitherto unexpected dynamic cycling of dysferlin in Cav1 \u03ea/\u03ea cells. Dysferlin Is Internalized Through a Clathrin-independent Endocytic Pathway-We next examined the pathway by which dysferlin is internalized in Cav1 \u03ea/\u03ea MEFs using transferrin to label the clathrin pathway and cholera toxin binding subunit (CTB) or GPI-anchored proteins (AP) as markers of other pathways. Myc antibodies taken up by expressed GFP-dysferlin for various times did not colocalize significantly with transferrin (Fig. 5A) . However, significant colocalization of internalized myc antibodies and CTB was evident after 2, 10, and 40 min of internalization (Fig. 5A) . No significant difference in the internalization rate of transferrin or CTB was seen between WT Cav1 or Cav1 \u03ea/\u03ea MEFs (supplemental Fig. S2B ). GPI-AP are internalized via a clathrin-and dynamin-independent endocytic pathway (54 -56) . To test if dysferlin was trafficking from the PM via this pathway we co-internalized antibodies against the extracellular tags (mouse anti-myc for dysferlin and rabbit anti-GFP for GPI-GFP). Cav1 \u03ea/\u03ea MEFs co-expressing GFPDysf and GPI-GFP were labeled on ice with anti-myc and anti-GFP antibodies, warmed to 37\u00b0C for 2, 10, and 40 min, and then acid-washed. Internalized antibodies were detected with anti-mouse Alexa Fluor 546 and anti-rabbit Alexa Fluor 647 antibodies after permeabilization. At all time points endocytic vesicles containing myc and GFP antibodies were readily detectable (Fig. 5A) , demonstrating that internalized dysferlin was targeted to a GPI-AP enriched compartment. We further investigated if dysferlin vesicular traffic followed a dynamin-dependent route using the dynamin inhibitor, Dynasore (57, 58) . Whereas transferrin uptake was blocked, dysferlin endocytosis was unaffected by incubation with Dynasore (Fig. 5B) . We conclude that the major endocytic pathway involved in dysferlin endocytosis in Cav1 \u03ea/\u03ea cells is dynamin-independent.", "cite_spans": [], "ref_spans": [{"start": 505, "end": 514, "text": "(Fig. 4C)", "ref_id": "FIGREF5"}, {"start": 674, "end": 683, "text": "(Fig. 4D)", "ref_id": "FIGREF5"}, {"start": 829, "end": 832, "text": "4D)", "ref_id": "FIGREF5"}, {"start": 1658, "end": 1667, "text": "(Fig. 5A)", "ref_id": "FIGREF6"}, {"start": 1800, "end": 1809, "text": "(Fig. 5A)", "ref_id": "FIGREF6"}, {"start": 1944, "end": 1952, "text": "Fig. S2B", "ref_id": "FIGREF1"}, {"start": 2639, "end": 2648, "text": "(Fig. 5A)", "ref_id": "FIGREF6"}, {"start": 2984, "end": 2993, "text": "(Fig. 5B)", "ref_id": "FIGREF6"}]}, {"section": "of myc antibodies was observed in the Cav1", "text": "Ultrastructural Analysis of Dysferlin Trafficking-To gain further insights into dysferlin endocytosis, Cav1 \u03ea/\u03ea or WT Cav1 MEFs were transfected with GFP-dysf, then incubated with anti-myc antibodies followed by an anti-mouse HRP-labeled antibody at 4\u00b0C. The cells were then warmed for 2 min at 37\u00b0C, and the DAB reaction visualized in the presence or absence of AA to identify internal structures, as in previous studies (54) . The cells were then fixed and processed for correlative light and electron microscopy, identifying GFP-dysfexpressing cells by light microscopy and then sectioning the plastic embedded cells for EM. Consistent with the light microscopy, WT cells showed a uniform, almost continuous, layer of HRP reaction product over the entire cell surface (WT Cav1 \u03ea AA; Fig. 6, A and B) and little internal staining. No preferential staining of caveolae was observed, consistent with our previous immunoelectromicrograph studies (18) . In contrast, Cav1 \u03ea/\u03ea MEFs showed very patchy sparse labeling over the cell surface (KO \u03ea AA; Fig. 6 , C and D) but with some tubular profiles apparently enriched in reaction product (Fig. 6, E and G) . Quantitation of the surface coverage of the HRP reaction product in WT Cav1 versus Cav1 \u03ea/\u03ea cells showed a far higher surface coverage in the WT Cav1 cells (see Fig. 6 , A and C) consistent with the low level of surface labeling in Cav1 \u03ea/\u03ea cells as observed by light microscopy. Endocytic structures were clearly observed in the Cav1 \u03ea/\u03ea cells treated with AA (KO \u03e9 AA, Fig. 6, H and I) . The ring-shaped morphology and size of the labeled elements are consistent with \u03ea/\u03ea cells (*, untransfected cell; **, cell expressing low levels of dysferlin) but in WT Cav1 cells there is very little internalization. B, in WT Cav1 MEFs dysferlin is mainly localized at the PM although some internalized myc can be seen after 30 min (see inset). In contrast after 30 min of myc antibody internalization, dysferlin shows a highly dynamic endocytic traffic in Cav1 \u03ea/\u03ea cells; inset, extensive overlay between GFPDysf and internalized myc. C, time course of myc antibodies uptake in WT or Cav1 \u03ea/\u03ea MEFs expressing GFPDysf. The mean fluorescence intensity of dysferlin associated with the PM (myc surface labeling) and internalized myc (2, 10, and 40 min chase at 37\u00b0C) was measured and expressed as IC/PM ratio. D, dysferlin internalization is rescued to WT levels by expression of epitope-tagged Cav1 in Cav1 \u03ea/\u03ea MEFs. WT Cav1 and Cav1 \u03ea/\u03ea MEFs were transfected with GFPDysf or co-transfected with GFPDysf and Cav1-HA and anti-myc antibodies were internalized for 20 min at 37\u00b0C. The mean fluorescence intensity of internalized dysferlin (myc labeling) was quantified. Error bars are S.E. of three experiments (n \u03ed 30). Bars, 10 m.", "cite_spans": [], "ref_spans": [{"start": 786, "end": 802, "text": "Fig. 6, A and B)", "ref_id": "FIGREF8"}, {"start": 1046, "end": 1052, "text": "Fig. 6", "ref_id": "FIGREF8"}, {"start": 1135, "end": 1152, "text": "(Fig. 6, E and G)", "ref_id": "FIGREF8"}, {"start": 1316, "end": 1322, "text": "Fig. 6", "ref_id": "FIGREF8"}, {"start": 1526, "end": 1542, "text": "Fig. 6, H and I)", "ref_id": "FIGREF8"}]}, {"section": "structures labeled by CTB HRP in WT and Cav1", "text": "\u03ea/\u03ea MEFs in the previous studies (54) . These studies show that dysferlin is retained over the entire cell surface in the presence of caveolin but is rapidly internalized in its absence.", "cite_spans": [], "ref_spans": []}, {"section": "Dysferlin Trafficking Is Not Rescued by Caveolin Scaffolding Domain Mutants in Cav1", "text": "\u03ea/\u03ea MEF Cells-To gain further insights into the functional interaction between dysferlin and caveolin and the relevance of these observations to muscle disease, we examined the effect of caveolin mutants on dysferlin endocytosis as compared with wild type caveolin. We made use of HAtagged CSD point mutants, Cav3G55S (Cav3G55S-HA) and Cav3C71W (Cav3C71W-HA) (50, 59) , which have been linked to muscular dystrophy (11, 13) and the CSD deletion mutant, Cav1\u232c81-100 (Cav1\u232c-81-100-HA) (60) . Quantitation of surface versus intracellular dysferlin was performed using antibodies to the lumenal myc tag as in previous studies (18) . Cav3G55S-HA or Cav3C71W-HA expressed in Cav1 \u03ea/\u03ea MEFs localized predominantly at the surface in a similar fashion to the wild type protein (Fig. 7) , whereas Cav1\u232c81-100-HA mainly targeted to the Golgi complex as judged by colocalization with the Golgi marker, GM130 (Fig. 7) . GFP-dysf was largely localized to intracellular puncta in Cav1 \u03ea/\u03ea cells (PM/IC ratio 0.67 \u03ee 0.07) but PM association was restored by re-expression of either Cav1-HA (PM/IC ratio 1.99 \u03ee 0.96) or Cav3-HA (PM/IC ratio 2.3 \u03ee 0.55) (18) (Fig. 8, A and  B) . In contrast, expression of Cav1\u232c81-100-HA (PM/IC ratio 0.61 \u03ee 0.10), Cav3G55S-HA (PM/IC ratio 0.65 \u03ee 0.15), or Cav3C71W-HA (PM/IC ratio 1.16 \u03ee 0.57) did not affect dysferlin traffic to the PM and dysferlin remained enriched in intracellular vesicles of Cav1 \u03ea/\u03ea MEFs (Fig. 8B) . The lack of an inhibitory effect of these mutants on dysferlin endocytosis is also shown by the uptake of myc antibodies when these mutants are expressed together with GFP-dysf, as compared with the WT Cav3 protein (Fig. 8C) . The above results suggest that this conserved domain of caveolin is required for inhibition of dysferlin endocytosis and its retention at the PM.", "cite_spans": [], "ref_spans": [{"start": 768, "end": 776, "text": "(Fig. 7)", "ref_id": "FIGREF9"}, {"start": 896, "end": 904, "text": "(Fig. 7)", "ref_id": "FIGREF9"}]}, {"section": "Dysferlin Trafficking Is Not Rescued by Caveolin Scaffolding Domain Mutants in Cav1", "text": "Dominant acting mutants of Cav3 cause a reduction in surface Cav3, retention of Cav3 in the Golgi complex, and increased degradation (61, 62) . We have previously shown that these mutants cause an accumulation of dysferlin in the Golgi complex. We investigated whether this was a result of a block of dysferlin exit from the Golgi rather than a consequence of redistribution due to dysferlin instability at the PM in the \u03ea/\u03ea cells were transfected with GFP-dysf or co-transfected with GFP-dysf and TFR or GPI-GFP. Anti-myc antibodies were co-internalized with fluorophore-conjugated Tfn or CTB or anti-GFP antibodies for various times at 37\u00b0C. Dysferlin is internalized mainly via a non-clathrin pathway. No significant colocalization is seen between internalized myc antibodies and Tfn. Dysferlin follows CTB and GPI in their endocytic traffic. Extensive co-internalization is visualized with anti-myc (GFP-dysf) and CTB and GFP (GPI-GFP) after 2, 10, and 40 min uptake. B, dynamin inhibitor, Dynasore, does not block dysferlin endocytic traffic. absence of caveolin. No myc antibody uptake was evident in the perinuclear region or intracellular vesicles (Fig. 9A) suggesting that dysferlin exit from the Golgi complex was blocked by the dystrophy-associated mutant caveolin and that these mutants have a dominant inhibitory role on Golgi exit. This effect of caveolin-dystrophy mutants on dysferlin exit from the Golgi complex is specific and not a result of their Golgi localization. Expression of a CSD deletion mutant, Cav1\u232c81-100, which is also Golgi localized does not restrain dysferlin from exiting the Golgi (Fig. 9B) . Taken together, these results show two distinct effects of caveolin mutants on trafficking of dysferlin.", "cite_spans": [], "ref_spans": [{"start": 1156, "end": 1165, "text": "(Fig. 9A)", "ref_id": "FIGREF10"}, {"start": 1618, "end": 1627, "text": "(Fig. 9B)", "ref_id": "FIGREF10"}]}, {"section": "DISCUSSION", "text": "In this work we have provided novel insights into dysferlin trafficking dynamics with respect to caveolin. Through the use of cells lacking caveolin, by expression of caveolin mutants, and by using different mutants of dysferlin, we have now identified the precise steps in dysferlin trafficking that are regulated by caveolin. We show directly that caveolins can facilitate exit of dysferlin mutants from the Golgi complex. In addition, dominant-acting caveolin mutants inhibit Golgi exit of mutant or wild type dysferlin. However, most unexpectedly, we now show that the primary effect of caveolin is to inhibit dysferlin endocytosis, implicating an endocytic mechanism in caveolin-associated muscle pathology.", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "Caveolin Modulation of Dysferlin Exit from the Golgi Complex-In cells devoid of caveolin dysferlin accumulates in intracellular vesicular structures, which we now show are endocytic in nature. No accumulation was observed in the Golgi complex and we demonstrated that despite the lack of surface labeling, dysferlin is rapidly transiting the cell surface in these cells, as shown by uptake of extracellular antibodies to a lumenal tag. These results suggest that dysferlin does not absolutely depend on caveolin for Golgi exit. Recent studies have suggested that novel exocytic carriers, containing defined quanta of caveolin, leave the Golgi complex and fuse directly with the PM (63). These carriers, termed exocytic caveolar carriers (64) , form a novel exocytic pathway distinct from classical exocytic carriers (see scheme in Fig. 10) ; these carriers would presumably be absent in cells lacking caveolin. Our data provide new insights into these pathways. Full-length dysferlin can clearly utilize a non-caveolar carrier pathway to reach the PM, as shown in Cav1 \u03ea/\u03ea cells. Similarly, a dysferlin mutant lacking all six C2 domains (\u232c-C2) can also efficiently reach the PM, both in the absence or presence of caveolin again showing use of a non-caveolar carrier. However, in stark contrast to these two constructs, a protein of intermediate length, which lacks four C2 domains, shows an absolute dependence on caveolin for exit from the Golgi complex ( Fig. 2 and scheme in Fig. 10 ). Whereas this is an artificially generated construct, these results clearly demonstrate a role for caveolin in Golgi exit, as suggested previously for a number of proteins including the angiotensin receptor (59), insulin receptor (65) , and the stretch-activated channel, TRPC1 (66) . The structural features that make these proteins dependent on caveolin for Golgi exit \u03ea/\u03ea MEFs were transfected with GFPDysf and then after 14 h were incubated sequentially with antibodies to the lumenal myc tag and then HRP-labeled secondary (anti-mouse) antibodies at 4\u00b0C. The cells were then warmed to 37\u00b0C for 2 min to allow endocytosis to occur. The DAB reaction was performed on the living cells at 4\u00b0C in the presence (\u03e9AA) or absence (\u03eaAA) of ascorbic acid as indicated. After fixation the transfected cells were identified under the light microscope by their GFP fluorescence and were marked to allow subsequent identification after embedding in resin. The marked areas were sectioned and viewed unstained. In the absence of AA, allowing visualization of both surface and intracellular pools of HRP, WT Cav1 cells showed HRP reaction product over the entire cell surface (A and B) . In striking contrast, all transfected Cav1 \u03ea/\u03ea cells showed sparse patchy surface labeling (C and D; arrowheads) consistent with greatly reduced retention of dysferlin at the plasma membrane. Quantitation of surface coverage by intersection counting (see \"Experimental Procedures\") showed that 10.3% of the PM of Cav1 \u03ea/\u03ea cells was covered in HRP reaction product and 89.0% of the PM of WT cells. Neighboring untransfected cells showed no trace of HRP labeling (results not shown) demonstrating the specificity of the antibody labeling. Potential clathrin-independent early endocytic carriers (arrowheads) were frequently observed in the Cav1 \u03ea/\u03ea cells (E-G). In the presence of ascorbic acid to quench extracellular HRP, internal ring-shaped endocytic elements were clearly demonstrated in the Cav1", "cite_spans": [], "ref_spans": [{"start": 831, "end": 839, "text": "Fig. 10)", "ref_id": "FIGREF0"}, {"start": 1458, "end": 1464, "text": "Fig. 2", "ref_id": "FIGREF1"}, {"start": 1479, "end": 1486, "text": "Fig. 10", "ref_id": "FIGREF0"}]}, {"section": "DISCUSSION", "text": "are as yet, unclear. In the case of dysferlin, it appears that the shorter construct is absolutely dependent on the caveolar pathway, whereas the additional cytoplasmic region of the fulllength protein allows the protein to use multiple pathways. This might involve interaction of the terminal C2 domains with cellular machinery involved in trafficking via these caveolin-independent pathways. One candidate protein is Ahnak, which interacts with the C2A domain of dysferlin (67) . Ahnak is a marker of a distinct exocytic vesicle, the enlargeosome (68, 69) . Consistent with a role for dysferlin in membrane repair (24) , enlargeosomes are proposed to be the source of membrane during PM resealing (68) . Although enlargeosomes do not associate with caveolin-enriched detergent-resistant membranes (69) it remains to be examined whether dysferlin exits the Golgi via enlargeosomes. As C2 domains have also been implicated in phospholipid binding it is also possible that interaction with the distinct domains of the Golgi membrane allow segregation of dysferlin away from the caveolar domain.", "cite_spans": [], "ref_spans": []}, {"section": "Dystrophy Mutants of Caveolin Disrupt Golgi Exit of Both Full-length Dysferlin and Dysferlin Truncation Mutants-We", "text": "have previously demonstrated that dystrophy-associated mutants of caveolin (Cav3P104L and Cav3R26Q) cause dysferlin accumulation within the Golgi complex (18) . We find no evidence for dysferlin transport to the cell surface under these conditions suggesting that the caveolin mutants cause a complete block in Golgi exit. Interestingly, this was true for all the tested membraneassociated dysferlin constructs, including \u232c-C2, which lacks most of the cytoplasmic domain and traffics to the PM in a caveolinindependent manner. This raises the possibility that mutant caveolin might perturb dysferlin trafficking at an earlier stage in the Golgi complex, before divergence of the two pathways. Consistent with this, Golgi caveolin mutants accumulate throughout the Golgi complex including the cis Golgi (18, 47) . The specificity of this effect is shown by the fact that a Golgi-localized form of caveolin lacking amino acids 81-100 does not prevent dysferlin from exiting the Golgi. This suggests that a direct interaction between dysferlin and caveolin, at least, at the Golgi level may be taking place. If so, this narrows down the interacting domain of dysferlin to the TM domain and nearby cytoplasmic region, which contains four potential CSD binding motifs. However, these findings do not rule out perturbation of lipid domains of the Golgi complex, which may be influenced by expression of a form of caveolin with mutations in this potential lipid-binding domain (45) . If so, these effects are restricted to specific cargo proteins as the transit of other proteins, such as GPI-anchored proteins, through the Golgi complex is unaffected by the expression of the mutant caveolin proteins (18) .", "cite_spans": [], "ref_spans": []}, {"section": "Dystrophy Mutants of Caveolin Disrupt Golgi Exit of Both Full-length Dysferlin and Dysferlin Truncation Mutants-We", "text": "Caveolins Inhibit Dysferlin Endocytosis-We show here for the first time that caveolins inhibit endocytosis of dysferlin. In cells lacking Cav1 and Cav3, dysferlin is rapidly cleared from the PM resulting in a low level of PM dysferlin in contrast to a large intracellular pool at steady state. Our results show a much higher endocytic rate for dysferlin in Cav1 \u03ea/\u03ea cells as antibodies to a lumenal tag accumulate far more rapidly in Cav1 \u03ea/\u03ea cells than in cells expressing Cav1 or Cav3 despite the higher level of surface dysferlin in these cells (see Figs. 4 and 8) (18) . Expression of Cav1 or Cav3, but not specific caveolin mutants, inhibits dysferlin endocytosis resulting in its retention at the cell surface and a high level of PM dysferlin. Dysferlin endocytosis in Cav1 \u03ea/\u03ea cells is via a dynamin (and caveolin-)-independent pathway. Colocalization with GPI-anchored proteins and CTB, but not transferrin, at early stages of endocytosis strongly implicates the CLIC/GEEC clathrin-independent pathway (54, 56) in dysferlin endocytosis. This is supported by ultrastructural analysis of the endocytic pathway showing dysferlin in tubular/ring-shaped early endosomal elements. These results suggest a novel role of this pathway in regulating dysferlin surface expression and, a role for caveolin in inhibiting the clathrin-independent endocytosis of specific markers.", "cite_spans": [], "ref_spans": [{"start": 553, "end": 567, "text": "Figs. 4 and 8)", "ref_id": "FIGREF5"}]}, {"section": "Dystrophy Mutants of Caveolin Disrupt Golgi Exit of Both Full-length Dysferlin and Dysferlin Truncation Mutants-We", "text": "The inhibitory effect of caveolins on dysferlin endocytosis presents an interesting conundrum. We believe that a direct inhibitory effect of caveolin by binding dysferlin to immobile caveolar domains is unlikely; both electron microscopy and light microscopy show that dysferlin does not colocalize significantly with caveolin, even at the level of light microscopy, and both immuno-EM on frozen sections (18) and EM surface labeling experiments (this study) confirmed that dysferlin was not concentrated within caveolae. Thus, the inhibition by caveolin appears to be indirect. Yet our results suggest that the effect of caveolin on dysferlin endocytosis is specific; whereas acute Cav1 expression has been shown to inhibit clathrin-independent endocytosis of CTB (54, 70) and SV40 is efficiently internalized by cells devoid of caveolae (71) CTB and SV40 internalization was quantitatively identical in WT Cav1 and Cav1 \u03ea/\u03ea MEFs as used here. Furthermore, no effect on GPI-AP internalization could be detected in Cav1 \u03ea/\u03ea cells. This argues against a general negative inhibitory role of caveolins on clathrin-independent endocytosis, but suggests that caveolins specifically inhibit dysferlin entry into this pathway. We could also show that the increased uptake of dysferlin in Cav1 \u03ea/\u03ea cells was not due to increased endocytosis caused by dysferlin expression (results not shown). Caveolae have been suggested to be negative regulators of clathrin-independent endocytosis (70, 72) but other work identifies caveolae as endocytic vehicles (73) (74) (75) . A new concept described here is that caveolin is regulating the non-caveolar endocytosis of dysferlin as we have FIGURE 8 . Dysferlin retention at the PM is dependent on an intact CSD. Expression of CSD point mutants does not rescue dysferlin traffic to the PM in Cav1 \u03ea/\u03ea MEF cells. Cav1 \u03ea/\u03ea cells were transfected with GFPDysf or co-transfected with GFPDysf and HA-tagged Cav3, Cav3G55S, Cav3C71W, Cav1\u232c81-100, and Cav3P104L and labeled with rabbit anti-HA and mouse anti-myc antibodies. Surface labeling of dysferlin and quantification of PM and intracellular pools of dysferlin were performed as described under \"Experimental Procedures.\" A, in cells lacking caveolin dysferlin is mainly targeted to intracellular puncta throughout the cytoplasm. Whereas expression of epitope-tagged Cav3 rescues dysferlin traffic to the PM, expression of CSD mutants (i.e. Cav3G55S) does not rescue dysferlin traffic to the PM. B, the mean fluorescence intensity of dysferlin associated with the PM (myc labeling) and intracellular structures (GFP labeling) was measured and expressed as the PM/IC ratio. Error bars are S.E. of three experiments (n \u03ed 30); **, p \u03fd 0.001. C, Cav1", "cite_spans": [], "ref_spans": []}, {"section": "Dystrophy Mutants of Caveolin Disrupt Golgi Exit of Both Full-length Dysferlin and Dysferlin Truncation Mutants-We", "text": "\u03ea/\u03ea cells co-expressing GFPDysf and HA-tagged, Cav3C71W, Cav3G55S, or Cav3 were allowed to uptake anti-myc antibodies for 10 min at 37\u00b0C. Expression of Cav3C71W or Cav3G55S, but not WT Cav3 protein, have no effect on dysferlin endocytosis as demonstrated by the internalization of anti-myc antibodies. Bars, 10 m.", "cite_spans": [], "ref_spans": []}, {"section": "Dystrophy Mutants of Caveolin Disrupt Golgi Exit of Both Full-length Dysferlin and Dysferlin Truncation Mutants-We", "text": "clearly demonstrated that dysferlin is not concentrated in caveolae.", "cite_spans": [], "ref_spans": []}, {"section": "Dystrophy Mutants of Caveolin Disrupt Golgi Exit of Both Full-length Dysferlin and Dysferlin Truncation Mutants-We", "text": "A model for the inhibitory effect of caveolin on endocytosis must take into account the intriguing finding that two Cav3 single point mutants, which occur naturally in the human population, did not inhibit dysferlin endocytosis in complete contrast to the wild type protein. This implicates the scaffolding domain of caveolin in its inhibitory activity. The two inhibitory mutants were initially reported as dystrophy mutants (11) but subsequently have been shown to occur as polymorphisms in the population (76, 77) . Yet two previous studies have shown specific effects of these mutant proteins in cultured cells (50, 59) . Further studies should elucidate the underlying mechanisms involved in the inhibitory activity of the wild type protein in comparison to these single point mutants and whether these mutations can contribute to disease under certain conditions.", "cite_spans": [], "ref_spans": []}, {"section": "Dystrophy Mutants of Caveolin Disrupt Golgi Exit of Both Full-length Dysferlin and Dysferlin Truncation Mutants-We", "text": "In conclusion, these studies have elucidated distinct roles of caveolin in regulating dysferlin trafficking pathways, both in positively regulating exocytosis and negatively regulating endocytosis via a clathrin-independent pathway for which dysferlin acts as a new marker. An interesting possibility is that this inhibitory activity of caveolin on endocytosis is regulated in vivo, allowing modulation of the surface levels of dysferlin and membrane remodeling. Whether caveolin acts in a similar fashion on other surface proteins will require further investigation. The involvement of endocytosis in muscle disease may be a more general phenomenon. Another sarcolemmal protein, \u2423-sarcoglycan, which is linked to a subset of muscle disease limb girdle muscular dystrophy 2D (78, 79) , is translocated from the cell surface to endosomes upon perturbation of its PM stability (80) . \u2423-Sarcoglycan stability at the PM relies on a proper assembly of the sarcoglycan complex (80) . Thus dysferlin and \u2423-sarcoglycan represent examples of sarcolemmal proteins where endocytic mechanisms play a central role in maintaining the integrity of the PM.", "cite_spans": [], "ref_spans": []}, {"section": "Dystrophy Mutants of Caveolin Disrupt Golgi Exit of Both Full-length Dysferlin and Dysferlin Truncation Mutants-We", "text": "These results provide new insights into the functions of caveolins and the mechanisms underlying caveolin-related diseases. In addition, they provide fundamental insights into the regulation of exocytic and endocytic trafficking pathways of membrane proteins in mammalian cells and the importance of this poorly characterized clathrin-independent endocytic pathway in surface remodeling of specific PM components. \u03ea/\u03ea cells were co-transfected with GFPDysf and HA-tagged Cav3P104L or Cav1\u232c81-100 and labeled with rabbit anti-HA (A and B) and mouse anti-GM130 (B) antibodies. Anti-myc antibody was internalized overnight (B). A, expression of Cav3P04L-HA blocks dysferlin exit from the Golgi apparatus. No significant Golgi pool of internalized myc antibodies is seen after overnight incubation at 37\u00b0C. B, expression of Golgilocalized epitope-tagged Cav1\u232c81-100 mutant does not affect GFP-dysf exit from the Golgi apparatus. Cav1\u232c81-100, but not GFPDysf, is retained in the Golgi complex as demonstrated by colocalization with the Golgi marker, GM130. Bars, 10 m. \u03ea/\u03ea cells dysferlin must use an alternative pathway(s). However, a truncation mutant lacking part of the cytoplasmic domain (\u232c-1) is completely dependent on caveolin for Golgi exit as it cannot enter the non-caveolar pathway. A more severe mutant (\u232c-C2) traffics to the PM in a caveolin-independent manner as it lacks information for incorporation into caveolar carriers. Retention of dysferlin at the PM is dependent on caveolin/caveolae due to inhibition of dysferlin endocytosis by caveolin. A truncation of dysferlin lacking all six C2 domains, \u232c-C2, is not internalized suggesting a role for the cytoplasmic domain in endocytosis.", "cite_spans": [], "ref_spans": []}], "bib_entries": {}, "ref_entries": {"FIGREF0": {"text": "FIGURE 1. Subcellular distribution of dysferlin truncation mutants in Cav1 \u060a/\u060a cells. A, schematic representations of full-length and truncation mutants of GFPDysf. B, baby hamster kidney cells were transfected with either GFP or different GFPDysf constructs. Total cell lysates were separated in a 5.5% SDS gel, electrotransferred, and immunoblotted using anti-GFP antibody. Truncated GFP-tagged mutants appear as single polypeptides of predicted sizes. C, full-length dysferlin, GFPDysf, is mainly targeted to the PM or to intracellular vesicles in WT Cav1 or Cav1 \u03ea/\u03ea MEFs, respectively. GFP\u232c-C2 is mainly targeted to the PM and to fine punctate structures. GFP\u232c-1 predominantly accumulates in the Golgi as demonstrated by colocalization with the Golgi marker, GM130. GFP\u232c-2 is mostly concentrated in endoplasmic reticulum shown by the extensive overlay with protein-disulfide isomerase, an endoplasmic reticulum marker, whereas GFP\u232c-3 and GFP\u232c-TM are predominantly cytosolic. D, predominant subcellular phenotypes were scored based on colabeling with relevant intracellular markers. Results are presented as percentage of cells showing a prevalent phenotype, and are representative of three individual experiments (n \u03ed 30 -350/for each construct). E, summary table of dysferlin constructs and subcellular localizations. Bar, 10 m.", "type": "figure"}, "FIGREF1": {"text": "FIGURE 2. Cav1 and Cav3 redistribute GFP\u232c-1 from the Golgi to the plasma membrane in Cav1 \u060a/\u060a cells. MEF cells were transfected with GFPDysf or GFP\u232c-1 or co-transfected with GFP\u232c-1 and epitope-tagged Cav3-HA, and colabeled with anti-HA or anti-Cav and anti-GM130 antibodies. A, in Cav1 \u03ea/\u03ea cells dysferlin is mainly localized to punctate structures throughout the cytoplasm, whereas GFP\u232c-1 mutant accumulates in the Golgi complex as demonstrated by colocalization with the Golgi marker, GM130. Interestingly, expression of epitope-tagged Cav3 redistributes GFP\u232c-1 to the PM. Similarly in WT Cav1 MEFs endogenous caveolin is sufficient for GFP\u232c-1 Golgi exit and PM targeting. B, phenotype quantification. Cav1 \u03ea/\u03ea or WT Cav1 cells expressing GFP\u232c-1 or co-expressing GFP\u232c-1 and Cav1-HA or Cav3-HA were subject to phenotype scoring. Predominant subcellular phenotypes were scored based on colabeling with relevant intracellular markers. Results are presented as percentage of cells showing a prevalent phenotype, and are representative of three individual experiments (n \u03ed 30 -350/for each construct). Bar, 10 m.", "type": "figure"}, "FIGREF2": {"text": "Fig. 4B) suggesting a much higher endocytic rate. This was confirmed by quantitation of the intracellular", "type": "figure"}, "FIGREF3": {"text": "Fig. S2A); the ability of dysferlin to reside at the PM membrane has been rescued by expression of Cav-1 (Fig. 4D and supplemental Fig. S2A). This was further confirmed by quantifying the amount of internal- ized myc antibodies in WT Cav1 and Cav1 \u03ea/\u03ea MEFs expressing GFPDysf (WT Cav1, 9.06 \u03ee 0.67; Cav1 \u03ea/\u03ea , 24.04 \u03ee 1.89) or Cav1 \u03ea/\u03ea cells co-expressing GFP-dysf and Cav1-HA (9.33 \u03ee 0.56) (refer to \"Experimental Procedures\") (Fig.", "type": "figure"}, "FIGREF4": {"text": "FIGURE 3. Dystrophy-associated mutant of Cav3 retains GFP\u232c-C2 in the Golgi complex. Cav1 \u03ea/\u03ea cells were transfected with GFP\u232c-C2 or co-transfected with GFP\u232c-C2 or GFPDysf and HA-tagged Cav3P104L, and colabeled with anti-HA and anti-GM130 antibodies. A, GFP\u232c-C2 is targeted to the PM and punctate structures throughout the cytoplasm. As seen with full-length dysferlin (18), expression of epitope-tagged Cav3P104L-HA causes a dramatic redistribution of GFP\u232c-C2 to the Golgi complex as judged by triple labeling with anti-GM130 antibody. B, phenotype quantification. Cav1 \u03ea/\u03ea cells expressing GFP\u232c-C2 or co-expressing GFP\u232c-C2 and Cav3P104L-HA or GFPDysf and Cav3P104L-HA were subject to phenotype scoring. Predominant subcellular phenotypes were scored based on colabeling with relevant intracellular markers. Results are presented as percentage of cells showing a prevalent phenotype and are representative of three individual experiments (n \u03ed 30 -350/for each construct). Bar, 10 m.", "type": "figure"}, "FIGREF5": {"text": "FIGURE 4. Dysferlin cycles between an intracellular compartment and the plasma membrane. WT Cav1 and Cav1 \u03ea/\u03ea MEFs were transfected with GFPDysf and allowed to internalized anti-myc antibodies overnight or for 30 min at 37\u00b0C. A, in both WT and Cav1 \u03ea/\u03ea cells dysferlin is cycling between the PM and an intracellular endocytic compartment. Inset shows extensive colocalization between GFPDysf and internalized myc antibodies in Cav1 \u03ea/\u03ea cells (*, untransfected cell; **, cell expressing low levels of dysferlin) but in WT Cav1 cells there is very little internalization. B, in WT Cav1 MEFs dysferlin is mainly localized at the PM although some internalized myc can be seen after 30 min (see inset). In contrast after 30 min of myc antibody internalization, dysferlin shows a highly dynamic endocytic traffic in Cav1 \u03ea/\u03ea cells; inset, extensive overlay between GFPDysf and internalized myc. C, time course of myc antibodies uptake in WT or Cav1 \u03ea/\u03ea MEFs expressing GFPDysf. The mean fluorescence intensity of dysferlin associated with the PM (myc surface labeling) and internalized myc (2, 10, and 40 min chase at 37\u00b0C) was measured and expressed as IC/PM ratio. D, dysferlin internalization is rescued to WT levels by expression of epitope-tagged Cav1 in Cav1 \u03ea/\u03ea MEFs. WT Cav1 and Cav1 \u03ea/\u03ea MEFs were transfected with GFPDysf or co-transfected with GFPDysf and Cav1-HA and anti-myc antibodies were internalized for 20 min at 37\u00b0C. The mean fluorescence intensity of internalized dysferlin (myc labeling) was quantified. Error bars are S.E. of three experiments (n \u03ed 30). Bars, 10 m.", "type": "figure"}, "FIGREF6": {"text": "FIGURE 5. Dysferlin co-internalizes with the early endocytic markers CTB and GPI-AP in a dynaminindependent manner. A, Cav1 \u03ea/\u03ea cells were transfected with GFP-dysf or co-transfected with GFP-dysf and TFR or GPI-GFP. Anti-myc antibodies were co-internalized with fluorophore-conjugated Tfn or CTB or anti-GFP antibodies for various times at 37\u00b0C. Dysferlin is internalized mainly via a non-clathrin pathway. No significant colocalization is seen between internalized myc antibodies and Tfn. Dysferlin follows CTB and GPI in their endocytic traffic. Extensive co-internalization is visualized with anti-myc (GFP-dysf) and CTB and GFP (GPI-GFP) after 2, 10, and 40 min uptake. B, dynamin inhibitor, Dynasore, does not block dysferlin endocytic traffic. Cav1 \u03ea/\u03ea MEFs were transfected with GFPDysf and incubated in 80 mM Dynasore, 0.4% Me 2 SO, Dulbecco's modified Eagle's medium or 0.4% Me 2 SO, Dulbecco's modified Eagle's medium alone. Anti-myc antibody or Tfn were internalized for 20 min at 37\u00b0C. Inhibition of dynamin does not block the internalization of anti-myc antibodies by dysferlin, whereas Tfn internalization was blocked. Bars, 10 m (A); 20 m (B).", "type": "figure"}, "FIGREF7": {"text": "FIGURE 5. Dysferlin co-internalizes with the early endocytic markers CTB and GPI-AP in a dynaminindependent manner. A, Cav1 \u03ea/\u03ea cells were transfected with GFP-dysf or co-transfected with GFP-dysf and TFR or GPI-GFP. Anti-myc antibodies were co-internalized with fluorophore-conjugated Tfn or CTB or anti-GFP antibodies for various times at 37\u00b0C. Dysferlin is internalized mainly via a non-clathrin pathway. No significant colocalization is seen between internalized myc antibodies and Tfn. Dysferlin follows CTB and GPI in their endocytic traffic. Extensive co-internalization is visualized with anti-myc (GFP-dysf) and CTB and GFP (GPI-GFP) after 2, 10, and 40 min uptake. B, dynamin inhibitor, Dynasore, does not block dysferlin endocytic traffic. Cav1 \u03ea/\u03ea MEFs were transfected with GFPDysf and incubated in 80 mM Dynasore, 0.4% Me 2 SO, Dulbecco's modified Eagle's medium or 0.4% Me 2 SO, Dulbecco's modified Eagle's medium alone. Anti-myc antibody or Tfn were internalized for 20 min at 37\u00b0C. Inhibition of dynamin does not block the internalization of anti-myc antibodies by dysferlin, whereas Tfn internalization was blocked. Bars, 10 m (A); 20 m (B).", "type": "figure"}, "FIGREF8": {"text": "FIGURE 6. Ultrastructural characterization of dysferlin endocytosis in Cav1 \u060a/\u060a and WT Cav1 MEFs. WT Cav1 or Cav1 \u03ea/\u03ea MEFs were transfected with GFPDysf and then after 14 h were incubated sequentially with antibodies to the lumenal myc tag and then HRP-labeled secondary (anti-mouse) antibodies at 4\u00b0C. The cells were then warmed to 37\u00b0C for 2 min to allow endocytosis to occur. The DAB reaction was performed on the living cells at 4\u00b0C in the presence (\u03e9AA) or absence (\u03eaAA) of ascorbic acid as indicated. After fixation the transfected cells were identified under the light microscope by their GFP fluorescence and were marked to allow subsequent identification after embedding in resin. The marked areas were sectioned and viewed unstained. In the absence of AA, allowing visualization of both surface and intracellular pools of HRP, WT Cav1 cells showed HRP reaction product over the entire cell surface (A and B). In striking contrast, all transfected Cav1 \u03ea/\u03ea cells showed sparse patchy surface labeling (C and D; arrowheads) consistent with greatly reduced retention of dysferlin at the plasma membrane. Quantitation of surface coverage by intersection counting (see \"Experimental Procedures\") showed that 10.3% of the PM of Cav1 \u03ea/\u03ea cells was covered in HRP reaction product and 89.0% of the PM of WT cells. Neighboring untransfected cells showed no trace of HRP labeling (results not shown) demonstrating the specificity of the antibody labeling. Potential clathrin-independent early endocytic carriers (arrowheads) were frequently observed in the Cav1 \u03ea/\u03ea cells (E-G). In the presence of ascorbic acid to quench extracellular HRP, internal ring-shaped endocytic elements were clearly demonstrated in the Cav1", "type": "figure"}, "FIGREF9": {"text": "FIGURE 7. Subcellular distribution of caveolin scaffolding domain mutants. Cav1 \u03ea/\u03ea cells were transfected with HA-tagged Cav3, Cav3G55S, Cav3C71W, Cav1\u232c81-100, and Cav3P104L, and colabeled with anti-HA and anti-GM130 antibodies. A, similarly to the wild type Cav3, the CSD mutants Cav3G55S and Cav3C71W CSD are targeted to the PM. In contrast, deletion of the CSD, Cav1\u232c81-100, results in accumulation in the Golgi complex similarly to the dystrophy mutant Cav3P104L, demonstrated by the extensive overlap with the Golgi marker, GM130. B, CSD mutant predominant phenotypes were scored based on colabeling with relevant intracellular markers. Results are presented as percentage of cells showing a prevalent subcellular localization, and are representative of three individual experiments (n \u03ed 30 -250/for each construct). Bar, 10 m.", "type": "figure"}, "FIGREF10": {"text": "FIGURE 9. Dystrophy mutant of Cav3 has a dominant inhibitory effect on dysferlin exit from the Golgi. Cav1 \u03ea/\u03ea cells were co-transfected with GFPDysf and HA-tagged Cav3P104L or Cav1\u232c81-100 and labeled with rabbit anti-HA (A and B) and mouse anti-GM130 (B) antibodies. Anti-myc antibody was internalized overnight (B). A, expression of Cav3P04L-HA blocks dysferlin exit from the Golgi apparatus. No significant Golgi pool of internalized myc antibodies is seen after overnight incubation at 37\u00b0C. B, expression of Golgilocalized epitope-tagged Cav1\u232c81-100 mutant does not affect GFP-dysf exit from the Golgi apparatus. Cav1\u232c81-100, but not GFPDysf, is retained in the Golgi complex as demonstrated by colocalization with the Golgi marker, GM130. Bars, 10 m.", "type": "figure"}, "FIGREF11": {"text": "FIGURE 10. Model for regulation of caveolin trafficking by caveolin. In WT Cav1 cells full-length dysferlin exit from the Golgi complex may take place via caveolar and noncaveolar exocytic carriers. In Cav1 \u03ea/\u03ea cells dysferlin must use an alternative pathway(s). However, a truncation mutant lacking part of the cytoplasmic domain (\u232c-1) is completely dependent on caveolin for Golgi exit as it cannot enter the non-caveolar pathway. A more severe mutant (\u232c-C2) traffics to the PM in a caveolin-independent manner as it lacks information for incorporation into caveolar carriers. Retention of dysferlin at the PM is dependent on caveolin/caveolae due to inhibition of dysferlin endocytosis by caveolin. A truncation of dysferlin lacking all six C2 domains, \u232c-C2, is not internalized suggesting a role for the cytoplasmic domain in endocytosis.", "type": "figure"}}}
{"paper_id": "8337861", "_pdf_hash": "ab6feb41aea1dc48b268afc4683e399d5246e3b6", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "A standardized approach to relay coordination", "authors": [{"first": "A", "middle": ["H"], "last": "Knable", "suffix": ""}], "year": 1969, "venue": "presented at the IEEE Winter Power Meeting", "link": null}, "BIBREF1": {"title": "An application of linear graph theory for coordination of directional overcurrent relays", "authors": [{"first": "M", "middle": ["H"], "last": "Dwaraknath", "suffix": ""}, {"first": "L", "middle": [], "last": "Nowita", "suffix": ""}], "year": 1980, "venue": "Proc. SIAM Conf. Electr. Power Problems-The Mathematical Challenge", "link": null}, "BIBREF2": {"title": "Computer aided transmission protection system design, Part I: Algorithm", "authors": [{"first": "M", "middle": ["J"], "last": "Damborg", "suffix": ""}, {"first": "R", "middle": [], "last": "Ramaswami", "suffix": ""}, {"first": "S", "middle": ["S"], "last": "Venkata", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Postforoosh", "suffix": ""}], "year": 1984, "venue": "IEEE Trans. Power App. Syst", "link": null}, "BIBREF3": {"title": "An application of function dependencies to the topological analysis of protection schemes", "authors": [{"first": "L", "middle": [], "last": "Jenkins", "suffix": ""}, {"first": "H", "middle": [], "last": "Khicha", "suffix": ""}, {"first": "S", "middle": [], "last": "Shivakumar", "suffix": ""}, {"first": "P", "middle": [], "last": "Dash", "suffix": ""}], "year": 1992, "venue": "IEEE Trans. Power Del", "link": null}, "BIBREF4": {"title": "Optimal coordination of directional overcurrent relays in interconnected power systems", "authors": [{"first": "A", "middle": ["J"], "last": "Urdaneta", "suffix": ""}, {"first": "R", "middle": [], "last": "Nadira", "suffix": ""}, {"first": "L", "middle": ["G P"], "last": "Jim\u00e9nez", "suffix": ""}], "year": 1988, "venue": "IEEE Trans. Power Del", "link": "110765391"}, "BIBREF5": {"title": "A method for adaptive coordination of overcurrent relays in an interconnected power system", "authors": [{"first": "N", "middle": [], "last": "Laway", "suffix": ""}, {"first": "H", "middle": ["O"], "last": "Gupta", "suffix": ""}], "year": 1993, "venue": "Proc. 5th Int. Conf. Develop. Power Syst. Protection", "link": "61055323"}, "BIBREF6": {"title": "An on-line relay coordination algorithm for adaptive protection using linear programming technique", "authors": [{"first": "B", "middle": [], "last": "Chattopadhyay", "suffix": ""}, {"first": "M", "middle": ["S"], "last": "Sachdev", "suffix": ""}, {"first": "T", "middle": ["S"], "last": "Sidhu", "suffix": ""}], "year": 1996, "venue": "IEEE Trans. Power Del", "link": "110967039"}, "BIBREF7": {"title": "Time coordination method for power system protection by evolutionary algorithm", "authors": [{"first": "C", "middle": ["W"], "last": "So", "suffix": ""}, {"first": "K", "middle": ["K"], "last": "Li", "suffix": ""}], "year": 2000, "venue": "IEEE Trans. Ind. Appl", "link": "195863556"}, "BIBREF8": {"title": "Effect of distributed generation and protective device coordination in distribution system", "authors": [{"first": "A", "middle": [], "last": "Girgis", "suffix": ""}, {"first": "S", "middle": [], "last": "Grahma", "suffix": ""}], "year": 2001, "venue": "Proc. LESCOPE", "link": null}, "BIBREF9": {"title": "Autonomous Systems and Intelligent Agents in Power System Control and Operation", "authors": [{"first": "C", "middle": [], "last": "Rehtanz", "suffix": ""}], "year": 2003, "venue": "", "link": "64766549"}, "BIBREF10": {"title": "Multiagent Systems: A Modern Approach to Distributed Artificial Intelligence", "authors": [{"first": "G", "middle": [], "last": "Weiss", "suffix": ""}, {"first": "Ed", "middle": [], "last": "", "suffix": ""}], "year": 1999, "venue": "", "link": "60675985"}, "BIBREF11": {"title": "Java Agent DEvelopment Framework", "authors": [{"first": "", "middle": [], "last": "Telecom Italia", "suffix": ""}], "year": 2007, "venue": "", "link": null}, "BIBREF12": {"title": "Since 2007, she has been a Research Assistant Professor in the Lane Department of Computer Science and Electrical Engineering, West Virginia University, Morgantown. Her research interests include power system protection and control, distributed generation", "authors": [{"first": "Hui", "middle": [], "last": "Wan", "suffix": ""}], "year": 2007, "venue": "2002, and the Ph.D. degree in electrical engineering from The Hong Kong Polytechnic University", "link": null}}, "ref_entries": {}}
{"paper_id": "8337987", "_pdf_hash": "5491bf29549f631e3c0e3589104ac8fa4a59b3ea", "abstract": [{"section": "Abstract", "text": "Objective: To perform whole-brain morphometry in patients with frontal lobe epilepsy and evaluate the utility of group-level patterns for individualized diagnosis and prognosis.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Methods: We compared MRI-based cortical thickness and folding complexity between 2 frontal lobe epilepsy cohorts with histologically verified focal cortical dysplasia (FCD) (13 type I; 28 type II) and 41 closely matched controls. Pattern learning algorithms evaluated the utility of group-level findings to predict histologic FCD subtype, the side of the seizure focus, and postsurgical seizure outcome in single individuals. Focal cortical dysplasia (FCD) is a frequent epileptogenic developmental malformation in children and adults undergoing epilepsy surgery.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "1 While FCD type II combining cytological anomalies with varying degrees of dyslamination 2 is generally associated with obvious morphology and signal changes on MRI, 3 the imaging signature of FCD type I, characterized by subtle cortical thinning and dyslamination, 2 remains elusive. Because of the crucial role of MRI in defining the surgical target, imaging studies in FCD have been primarily dedicated to lesion detection in single patients. 4 Whole-brain cohortspecific structural brain anomalies remain largely unknown. 5 In other epilepsy syndromes, group-based designs have provided new insights by unveiling clinically relevant characteristics and helped in formulating hypotheses about disease mechanisms. 6, 7 In this study, we aimed to compare whole-brain morphology between frontal lobe epilepsy cohorts with histologically verified FCD type I and II. Our approach was motivated by case reports indicating that FCD type II may present with histologic 8 and MRI anomalies 9,10 in remote cortices resembling those found in the primary lesion and that type I may be associated with subtle multilobar hypoplasia on MRI.", "cite_spans": [{"start": 447, "end": 448, "text": "4", "ref_id": "BIBREF6"}, {"start": 527, "end": 528, "text": "5", "ref_id": "BIBREF7"}, {"start": 717, "end": 719, "text": "6,", "ref_id": "BIBREF8"}, {"start": 720, "end": 721, "text": "7", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "Abstract", "text": "We hypothesized widespread, yet diverging patterns of anomalies, with cortical thinning in FCD type I and thickening in type II. Our MRI phenotyping combined group-and *These authors have contributed equally to this work.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "From the Neuroimaging", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "", "text": "Focal cortical dysplasia (FCD) is a frequent epileptogenic developmental malformation in children and adults undergoing epilepsy surgery. 1 While FCD type II combining cytological anomalies with varying degrees of dyslamination 2 is generally associated with obvious morphology and signal changes on MRI, 3 the imaging signature of FCD type I, characterized by subtle cortical thinning and dyslamination, 2 remains elusive. Because of the crucial role of MRI in defining the surgical target, imaging studies in FCD have been primarily dedicated to lesion detection in single patients. 4 Whole-brain cohortspecific structural brain anomalies remain largely unknown. 5 In other epilepsy syndromes, group-based designs have provided new insights by unveiling clinically relevant characteristics and helped in formulating hypotheses about disease mechanisms. 6, 7 In this study, we aimed to compare whole-brain morphology between frontal lobe epilepsy cohorts with histologically verified FCD type I and II. Our approach was motivated by case reports indicating that FCD type II may present with histologic 8 and MRI anomalies 9, 10 in remote cortices resembling those found in the primary lesion and that type I may be associated with subtle multilobar hypoplasia on MRI. 11 We hypothesized widespread, yet diverging patterns of anomalies, with cortical thinning in FCD type I and thickening in type II. Our MRI phenotyping combined group-and individual-level analysis of cortical thickness and folding complexity, 2 established in vivo markers of brain morphology and development. We evaluated the clinical utility of group-level patterns to classify the histopathologic FCD subtype, lateralize the seizure focus, and to predict postsurgical seizure outcome in individual patients using machine learning.", "cite_spans": [{"start": 305, "end": 306, "text": "3", "ref_id": "BIBREF5"}, {"start": 585, "end": 586, "text": "4", "ref_id": "BIBREF6"}, {"start": 665, "end": 666, "text": "5", "ref_id": "BIBREF7"}, {"start": 855, "end": 857, "text": "6,", "ref_id": "BIBREF8"}, {"start": 858, "end": 859, "text": "7", "ref_id": "BIBREF9"}, {"start": 1103, "end": 1104, "text": "8", "ref_id": "BIBREF10"}, {"start": 1123, "end": 1125, "text": "9,", "ref_id": "BIBREF11"}, {"start": 1126, "end": 1128, "text": "10", "ref_id": "BIBREF12"}, {"start": 1269, "end": 1271, "text": "11", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "", "text": "METHODS Participants. From a database of patients hospitalized for presurgical workup of drug-resistant extratemporal epilepsy at the Montreal Neurological Institute (MNI) and Hospital who underwent video-EEG telemetry and were examined on a single scanner with an identical imaging protocol 12 (n 5 73), we selected those with frontal lobe epilepsy and histologically verified FCD (type I, n 5 13; type II, n 5 28).", "cite_spans": [{"start": 292, "end": 294, "text": "12", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "", "text": "In patients with FCD type II, the lesion was seen either on conventional MRI (n 5 18) or became visible through texture analysis 13 (n 5 10). In the latter group, surgery was preceded by invasive monitoring using stereotactic implanted depth electrodes (stereoelectroencephalography [SEEG]), with positioning of the leads guided by the putative lesion seen on texture maps; in all, SEEG demonstrated a very active interictal activity and focal changes at seizure onset in the electrodes targeting the lesion. Mean postoperative follow-up time was 4.9 6 3 years; 18 patients became seizure-free (Engel Class I), 14 6 had rare disabling seizures (Engel II), and 4 with lesions encroaching eloquent areas had worthwhile improvement (Engel III) as lesionectomy was incomplete. In patients with FCD type I, both preoperative visual MRI and image processing were unremarkable; surgery in these patients was preceded by SEEG. Implantations were guided by findings derived from video-EEG telemetry with scalp electrodes in all, with additional help from FDG-PET ([ 18 F]-fluorodeoxyglucose-PET) (n 5 9) and SPECT (n 5 7) data, and resulted in focal corticectomies in the supplementary motor area in 5 patients, prefrontal cortex in 4, lower central in 3, and orbitofrontal in one. Mean postoperative follow-up was 3.9 6 2 years; 3 patients became seizure-free (Engel I), 3 had rare disabling seizures (Engel II), 5 a worthwhile improvement (Engel III) , and 2 no improvement (Engel IV).", "cite_spans": [{"start": 129, "end": 131, "text": "13", "ref_id": "BIBREF15"}, {"start": 611, "end": 613, "text": "14", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "", "text": "Patient cohorts did not differ in age, disease duration, sex distribution, seizure focus lateralization, and number of generalized seizures (p . 0.15). The control group consisted of 41 age-and sex-matched healthy individuals. Demographic, clinical, and electrophysiologic data are presented in the table.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Standard protocol approvals, registrations, and patient consents. The ethics committee of the MNI approved the study and written informed consent was obtained from all participants.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "MRI acquisition and image preparation. Images were acquired on a 1.5T Gyroscan (Philips, Eindhoven, the Netherlands) using a 3-dimensional T1 fast field echo sequence (repetition time 5 18 milliseconds; echo time 5 10 milliseconds; flip angle 5 30\u00b0; matrix 5 256 3 256; field of view 5 256 3 256 mm 2 ; slice thickness 5 1 mm) providing isotropic voxel dimensions of 1 3 1 3 1 mm. MRI preprocessing included correction for intensity nonuniformity, intensity standardization, linear registration to the MNI152 template, and classification into white matter (WM), gray matter (GM), and CSF. 15 The Constrained Laplacian Anatomic Segmentation using Proximity (CLASP) algorithm 16 generated a model of the inner (WM-GM) and outer (GM-CSF) surfaces with 40k surface points (or vertices) for each hemisphere. Surfaces were aligned to a hemisphere-symmetric surface template to improve interindividual correspondence. 17 The accuracy of surface extractions was verified in all individuals before further analysis.", "cite_spans": [{"start": 589, "end": 591, "text": "15", "ref_id": "BIBREF17"}, {"start": 911, "end": 913, "text": "17", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "", "text": "Surface-based morphometry. We generated cortical thickness and curvature maps using a previously reported methodology. 18, 19 Cortical thickness was measured as the distance between corresponding vertices of inner and outer surfaces. To measure curvature, we generated a surface model running at middistance between the inner and outer surfaces. We subsequently applied a barycentric smoothing with 3 iterations to reduce highfrequency noise in vertex positions. 20 Absolute mean curvature was calculated at each vertex to quantify changes in frequency and depth of sulcal and gyral folds, expressing local gyrification complexity. Structural metrics were blurred with a surfacebased kernel of full width at half maximum 5 20 mm that preserves cortical topology. 15 Analysis. Statistical analysis was performed using SurfStat for MATLAB. 21 Patients were analyzed relative to the epileptogenic hemisphere; the symmetric template used for surface registration ensured an unbiased analysis when sorting hemispheres into ipsilateral/contralateral to the focus. Furthermore, we normalized thickness and curvature at each vertex using a z-transformation with respect to the corresponding distribution in controls; in other words, each patient's right/left feature was expressed as z score with respect to right/left values in controls.", "cite_spans": [{"start": 119, "end": 122, "text": "18,", "ref_id": "BIBREF20"}, {"start": 123, "end": 125, "text": "19", "ref_id": "BIBREF21"}, {"start": 463, "end": 465, "text": "20", "ref_id": "BIBREF22"}, {"start": 763, "end": 765, "text": "15", "ref_id": "BIBREF17"}, {"start": 838, "end": 840, "text": "21", "ref_id": "BIBREF23"}], "ref_spans": []}, {"section": "", "text": "Mapping structural changes relative to controls. We assessed differences in cortical thickness and folding complexity between each patient group (i.e., FCD type I and type II) and controls using 2-tailed Student t tests at each vertex. Because curvature might be affected by variations of cortical thickness, we statistically adjusted this metric at every vertex by the corresponding thickness measure. 22 In FCD type II, to eliminate potential effect of the lesion on group comparisons, we performed an additional analysis in which lesion labels obtained through expert manual segmentation (D.S.) were projected onto cortical surfaces and blurred with a 20-mm kernel, excluding cortical measures that fell within the blurred labels.", "cite_spans": [{"start": 403, "end": 405, "text": "22", "ref_id": "BIBREF24"}], "ref_spans": []}, {"section": "", "text": "For individual analysis, we calculated proportions of patients with thickness/curvature measures beyond 62 SD from the mean of controls across the cortical surface. 23 In FCD type II, lesional labels were excluded. A leave-one-out approach calculated unbiased prevalences in controls.", "cite_spans": [{"start": 165, "end": 167, "text": "23", "ref_id": "BIBREF25"}], "ref_spans": []}, {"section": "", "text": "Direct contrast between patient groups. Cortical thickness and curvature were directly compared between groups using vertex-wise 2-sample t tests. Abbreviations: FCD 5 focal cortical dysplasia; GTCS 5 generalized tonic-clonic seizures.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Age, age at seizure onset, and duration of epilepsy are presented as mean 6 SD.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Group differences in postsurgical outcome. We subdivided patients into seizure-free (Engel Class I) and non-seizure-free (Classes II-IV) and compared cortical markers between outcome classes.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Automatic classification of individual patients. We evaluated the yield of group-level findings to predict FCD subtypes, lateralize the seizure focus, and determine postsurgical outcome using a machine-learning approach with leave-one-out validation. Each hemisphere was subdivided into 500 equally sized parcels. 24 The search space was confined to regions displaying group-level differences (FCD type I vs type II for subtype prediction, FCDs vs healthy controls for focus lateralization, and seizure-free vs non-seizure-free for outcome prediction). Each parcel falling into a significant cluster was mirrored to both left and right hemispheres, as one cannot assume to know focus-laterality in a new patient. We extracted mean thickness and curvature z scores from these parcels and fed them to a support vector machine (SVM) classifier that evaluated prediction performance based on single pairs of parcels. To optimize classification sensitivity, borrowing the concept of searchlight-based multivoxel pattern analysis, 10 we evaluated combinations of single pairs of parcels (preselected from those achieving .80% accuracy) using a separate SVM. The optimal number of parcel pairs was empirically set to 3.", "cite_spans": [{"start": 314, "end": 316, "text": "24", "ref_id": "BIBREF26"}, {"start": 1025, "end": 1027, "text": "10", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "", "text": "Correction for multiple comparisons and assessment of classification accuracy. Group results were corrected using random field theory for nonisotropic images at a cluster level. 25 We used the function SurfStatP.m, with a search space constrained to the neocortical mantle in both hemispheres. This controlled the family-wise error (FWE) probability to p , 0.05. In all machinelearning experiments, we used permutation tests to confirm whether the achieved accuracy exceeded chance level (Bonferronicorrected p , 0.05). ipsilateral 26 and idiopathic generalized epilepsy, 27 is thought to reflect combined effects of neuronal disconnection and seizure-related damage. Sustained seizure activity may lead to cell loss in both seizure-generating regions and areas of spread, 28 particularly through upregulation of glutamate. 29 While this scenario may explain cortical thinning in our patients with type I FCD, it is seemingly at odds with findings in those with type II lesions, who showed increased thickness in several cortices. This paradox was further amplified when stratifying patients according to disease duration: close to the onset, patients with type I FCD displayed diffuse bilateral cortical atrophy, while those with type II lesions presented with marked and fairly extensive cortical thickening, even when controlling for age and after excluding the lesion label.", "cite_spans": [{"start": 178, "end": 180, "text": "25", "ref_id": "BIBREF27"}, {"start": 532, "end": 534, "text": "26", "ref_id": "BIBREF28"}, {"start": 572, "end": 574, "text": "27", "ref_id": "BIBREF29"}, {"start": 773, "end": 775, "text": "28", "ref_id": "BIBREF30"}, {"start": 824, "end": 826, "text": "29", "ref_id": "BIBREF31"}], "ref_spans": []}, {"section": "RESULTS", "text": "Diverging morphometric patterns, particularly at early disease stages, may point to distinct mechanisms and timing underlying the anomalous cortical development in these cohorts. Typical brain growth entails Figure 3 Morphologic markers of postsurgical seizure outcome", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS", "text": "Cortical thickness comparison between seizure-free (Engel Class I) and non-seizure-free patients (Classes II-IV). See figure  1 for details on statistical procedures. Given the small number of seizure-free patients (n 5 3) in type I, findings were crossvalidated using nonparametric permutation tests, both for group comparison and family-wise error correction. FCD 5 focal cortical dysplasia.", "cite_spans": [], "ref_spans": [{"start": 118, "end": 127, "text": "figure  1", "ref_id": "FIGREF0"}]}, {"section": "RESULTS", "text": "a series of complex and overlapping steps, including synaptogenesis with elaboration of dendrites, which continue into early childhood. 30 In this context, pruning, a self-regulatory process starting in late gestation (which eliminates redundant axons, dendrites, and synapses, as well as neurons) has a pivotal role in shaping cortical network organization until late adolescence, sparing only the most efficient connectivity configurations. 31 Of note, in FCD type II, aberrant synaptogenesis of dysmorphic neurons and failure of oligodendroglial differentiation result in erroneous axonal processes and hypomyelination. 32 In light of our observations, one may postulate that the primary lesion and mutually connected cortices show delayed pruning that manifest as gray matter excess. Moreover, according to models of structural covariance and maturational coupling of brain networks, regions belonging to the same network show correlated growth due to exchange of trophic factors and common molecular signaling pathways. 33 Conceivably, developing cortices sharing links with the lesion may be influenced in similar ways. A post hoc analysis indeed supported a selective thickening of contralateral neocortices homotopic to the primary FCD type II in patients with short disease duration (p , 0.05 relative to controls), while thickness of nonhomotopic contralateral vertices was not increased.", "cite_spans": [{"start": 136, "end": 138, "text": "30", "ref_id": "BIBREF32"}, {"start": 443, "end": 445, "text": "31", "ref_id": "BIBREF33"}, {"start": 623, "end": 625, "text": "32", "ref_id": "BIBREF34"}, {"start": 1025, "end": 1027, "text": "33", "ref_id": "BIBREF35"}], "ref_spans": []}, {"section": "RESULTS", "text": "Diffuse cortical thinning in FCD type I warrants several considerations. First, in light of the recent histopathologic findings showing a tendency for reduced cortical thickness in FCD type I, 32 primary frontal cortical thinning observed in our patients may reflect, in part, the primary lesion. This hypothesis is justified by our inclusion criteria, as we restricted the Figure 4 Machine-learning framework applied to FCD subtype prediction (A) Feature generation. Each hemisphere was subdivided into 500 equally sized parcels. The search space was confined to significant clusters of group-level differences (i.e., FCD type I vs type II). After mirroring each parcel to both left and right hemispheres, we generated a feature vector by extracting mean thickness and curvature z scores. (B) Single-parcel classification. Features obtained in panel A were fed to a support vector machine classifier, which evaluated subtype prediction performance at each pair of parcels. (C) Multiparcel classification. To optimize sensitivity, among parcels achieving .80% accuracy in panel B (color-coded in green), combinations of k pairs of parcels (optimal k empirically set at 3) were fed to a separate classifier. Multidimensional scaling allows reducing dimensionality to 2 dimensions while preserving interfeature distances. Misclassified cases are highlighted with an x. Steps A through C are performed in a leave-one-out framework that allows determining prediction accuracy for previously unseen cases. FCD 5 focal cortical dysplasia.", "cite_spans": [{"start": 193, "end": 195, "text": "32", "ref_id": "BIBREF34"}], "ref_spans": []}, {"section": "RESULTS", "text": "assessment to patients with frontal lobe epilepsy only. Second, in young children with psychomotor handicap, this malformation may span across several lobes. 34 Further support for the widespread nature of morphologic anomalies and the associated epileptogenic zone may come from the unfavorable surgical outcome after focal resections in our patients, in line with reported series of patients with nonlesional frontal lobe epilepsy. 1, 35 While pathogenic mechanisms underlying FCD type I remain largely uncertain, it is enticing to hypothesize that cortical architecture in this condition may relate to abnormal tangential migration. Contrary to excitatory projection neurons obeying the laws of gliophilic radial migration, the vast majority of GABAergic inhibitory interneurons arrive in the cortex via a tangential migratory corridor. 36 Of note, in this migration mode, neurons move parallel to the brain surface and their final positioning often transgresses regional boundaries. 37 Reduced arrival and abnormal maturation of inhibitory interneurons into the cortical plate may alter the balance between excitatory and inhibitory signaling, resulting in aberrant network hyperexcitability and widespread subtle morphologic defects. This hypothesis is supported by metabolic imaging studies showing diffuse abnormalities of g-aminobutyric acid type A receptors. 38 Alterations of folding patterns are often used to typify malformations of cortical development, ranging from reduction in lissencephaly spectrum disorders caused by defective early neuronal proliferation to increased folding frequency in polymicrogyrias related to abnormal postmigrational development. 39 Considering this continuum, decreased sulcal-gyral complexity in FCD type II reinforces the notion of a defect occurring during the initial stages of corticogenesis; conversely, increased complexity in FCD type I suggests a postmigrational anomaly. 39 Evidence-based clinical practice parameters foster novel combinations of quantitative neuroimaging with pattern learning techniques to objectively extract critical features and high-dimensional data relationships. 40 Our findings emphasize that group-level phenotypes may guide fully automated and accurate diagnostic procedures in single patients. While seizure focus lateralization may optimize the performance of automated lesion-detection algorithms, especially for previously overlooked lesions, noninvasive preoperative prediction of FCD subtype and outcome may have implications for surgical planning and optimized patient counseling.", "cite_spans": [{"start": 158, "end": 160, "text": "34", "ref_id": "BIBREF36"}, {"start": 437, "end": 439, "text": "35", "ref_id": "BIBREF37"}, {"start": 840, "end": 842, "text": "36", "ref_id": "BIBREF38"}, {"start": 987, "end": 989, "text": "37", "ref_id": "BIBREF39"}, {"start": 1368, "end": 1370, "text": "38", "ref_id": "BIBREF40"}, {"start": 1674, "end": 1676, "text": "39", "ref_id": "BIBREF41"}, {"start": 1926, "end": 1928, "text": "39", "ref_id": "BIBREF41"}, {"start": 2143, "end": 2145, "text": "40", "ref_id": "BIBREF42"}], "ref_spans": []}, {"section": "AUTHOR CONTRIBUTIONS", "text": "Seok-Jun Hong: drafting manuscript for content, including medical writing, study concept and design, statistical analysis and interpretation of data. Boris C. Bernhardt: drafting manuscript for content, including medical writing, study concept and design, interpretation of data. Dewi S. Schrader: expert lesion segmentation. Neda Bernasconi: revising manuscript for content, including medical writing, study concept and design, interpretation of data, study supervision, obtaining funding. Andrea Bernasconi: revising manuscript for content, including medical writing, study concept and design, interpretation of data, acquisition of data, study supervision, obtaining funding. ", "cite_spans": [], "ref_spans": []}, {"section": "STUDY FUNDING", "text": "", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Assessment and surgical outcomes for mild type I and severe type II cortical dysplasia: a critical review and the UCLA experience", "authors": [{"first": "J", "middle": ["T"], "last": "Lerner", "suffix": ""}, {"first": "N", "middle": [], "last": "Salamon", "suffix": ""}, {"first": "J", "middle": ["S"], "last": "Hauptman", "suffix": ""}], "year": 2009, "venue": "Epilepsia", "link": "414591"}, "BIBREF1": {"title": "The clinicopathologic spectrum of focal cortical dysplasias: a consensus classification proposed by an ad hoc Task Force of the ILAE Diagnostic Methods Commission", "authors": [{"first": "I", "middle": [], "last": "Blumcke", "suffix": ""}, {"first": "M", "middle": [], "last": "Thom", "suffix": ""}, {"first": "E", "middle": [], "last": "Aronica", "suffix": ""}], "year": 2011, "venue": "Epilepsia", "link": "7915115"}, "BIBREF2": {"title": "Diagnostic methods and treatment options for focal cortical dysplasia", "authors": [{"first": "R", "middle": [], "last": "Guerrini", "suffix": ""}, {"first": "M", "middle": [], "last": "Duchowny", "suffix": ""}, {"first": "P", "middle": [], "last": "Jayakar", "suffix": ""}], "year": 2015, "venue": "Epilepsia", "link": "30176291"}, "BIBREF3": {"title": "Whole-brain MRI phenotyping in dysplasia-related frontal lobe epilepsy", "authors": [{"first": "S", "middle": ["J"], "last": "Hong", "suffix": ""}, {"first": "B", "middle": ["C"], "last": "Bernhardt", "suffix": ""}, {"first": "D", "middle": ["S"], "last": "Schrader", "suffix": ""}, {"first": "N", "middle": [], "last": "Bernasconi", "suffix": ""}, {"first": "A", "middle": [], "last": "Bernasconi", "suffix": ""}], "year": 2016, "venue": "Neurology", "link": "8337987"}, "BIBREF4": {"title": "Disclosure: R.E. Hogan has received institutional support of clinical trials from Upsher-Smith and Eisai Pharmaceuticals and has served as a consultant for Upsher-Smith Pharmaceuticals", "authors": [{"first": "R", "middle": ["Edward"], "last": "Hogan", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF5": {"title": "Focal cortical dysplasia type II: biological features and clinical perspectives", "authors": [{"first": "S", "middle": ["M"], "last": "Sisodiya", "suffix": ""}, {"first": "S", "middle": [], "last": "Fauser", "suffix": ""}, {"first": "J", "middle": ["H"], "last": "Cross", "suffix": ""}, {"first": "M", "middle": [], "last": "Thom", "suffix": ""}], "year": 2009, "venue": "Lancet Neurol", "link": "1061044"}, "BIBREF6": {"title": "Automated detection of cortical dysplasia type II in MRI-negative epilepsy", "authors": [{"first": "S", "middle": ["J"], "last": "Hong", "suffix": ""}, {"first": "H", "middle": [], "last": "Kim", "suffix": ""}, {"first": "D", "middle": [], "last": "Schrader", "suffix": ""}, {"first": "N", "middle": [], "last": "Bernasconi", "suffix": ""}, {"first": "B", "middle": ["C"], "last": "Bernhardt", "suffix": ""}, {"first": "A", "middle": [], "last": "Bernasconi", "suffix": ""}], "year": 2014, "venue": "Neurology", "link": "207107122"}, "BIBREF7": {"title": "White matter abnormalities in patients with focal cortical dysplasia revealed by diffusion tensor imaging analysis in a voxelwise approach", "authors": [{"first": "C", "middle": [], "last": "Fonseca Vde", "suffix": ""}, {"first": "C", "middle": ["L"], "last": "Yasuda", "suffix": ""}, {"first": "G", "middle": ["G"], "last": "Tedeschi", "suffix": ""}, {"first": "L", "middle": ["E"], "last": "Betting", "suffix": ""}, {"first": "F", "middle": [], "last": "Cendes", "suffix": ""}], "year": 2012, "venue": "Front Neurol", "link": "14025869"}, "BIBREF8": {"title": "Voxel-based morphometry of temporal lobe epilepsy: an introduction and review of the literature", "authors": [{"first": "S", "middle": ["S"], "last": "Keller", "suffix": ""}, {"first": "N", "middle": [], "last": "Roberts", "suffix": ""}], "year": 2008, "venue": "Epilepsia", "link": "30913109"}, "BIBREF9": {"title": "Imaging structural and functional brain networks in temporal lobe epilepsy", "authors": [{"first": "B", "middle": ["C"], "last": "Bernhardt", "suffix": ""}, {"first": "S", "middle": [], "last": "Hong", "suffix": ""}, {"first": "A", "middle": [], "last": "Bernasconi", "suffix": ""}, {"first": "N", "middle": [], "last": "Bernasconi", "suffix": ""}], "year": 2013, "venue": "Front Hum Neurosci", "link": "6889919"}, "BIBREF10": {"title": "Multi-focal occurrence of cortical dysplasia in epilepsy patients", "authors": [{"first": "S", "middle": [], "last": "Fauser", "suffix": ""}, {"first": "S", "middle": ["M"], "last": "Sisodiya", "suffix": ""}, {"first": "L", "middle": [], "last": "Martinian", "suffix": ""}], "year": 2009, "venue": "Brain", "link": "14138987"}, "BIBREF11": {"title": "Voxel-based morphometry reveals excess gray matter concentration in patients with focal cortical dysplasia", "authors": [{"first": "L", "middle": [], "last": "Bonilha", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Montenegro", "suffix": ""}, {"first": "C", "middle": [], "last": "Rorden", "suffix": ""}], "year": 2006, "venue": "Epilepsia", "link": "25203602"}, "BIBREF12": {"title": "Informationbased functional brain mapping", "authors": [{"first": "N", "middle": [], "last": "Kriegeskorte", "suffix": ""}, {"first": "R", "middle": [], "last": "Goebel", "suffix": ""}, {"first": "P", "middle": [], "last": "Bandettini", "suffix": ""}], "year": 2006, "venue": "Proc Natl Acad Sci", "link": null}, "BIBREF13": {"title": "Different features of histopathological subtypes of pediatric focal cortical dysplasia", "authors": [{"first": "P", "middle": [], "last": "Krsek", "suffix": ""}, {"first": "B", "middle": [], "last": "Maton", "suffix": ""}, {"first": "B", "middle": [], "last": "Korman", "suffix": ""}], "year": 2008, "venue": "Ann Neurol", "link": "20687733"}, "BIBREF14": {"title": "Small focal cortical dysplasia lesions are located at the bottom of a deep sulcus", "authors": [{"first": "P", "middle": [], "last": "Besson", "suffix": ""}, {"first": "F", "middle": [], "last": "Andermann", "suffix": ""}, {"first": "F", "middle": [], "last": "Dubeau", "suffix": ""}, {"first": "A", "middle": [], "last": "Bernasconi", "suffix": ""}], "year": 2008, "venue": "Brain", "link": "15605083"}, "BIBREF15": {"title": "Texture analysis and morphological processing of magnetic resonance imaging assist detection of focal cortical dysplasia in extratemporal partial epilepsy", "authors": [{"first": "A", "middle": [], "last": "Bernasconi", "suffix": ""}, {"first": "S", "middle": ["B"], "last": "Antel", "suffix": ""}, {"first": "D", "middle": ["L"], "last": "Collins", "suffix": ""}], "year": 2001, "venue": "Ann Neurol", "link": "22939712"}, "BIBREF16": {"title": "Outcome with respect to epileptic seizures", "authors": [{"first": "J", "middle": [], "last": "Engel", "suffix": ""}, {"first": "Van", "middle": [], "last": "Ness", "suffix": ""}, {"first": "P", "middle": ["C"], "last": "Rasmussen", "suffix": ""}, {"first": "T", "middle": [], "last": "Ojemann", "suffix": ""}, {"first": "L", "middle": ["M"], "last": "", "suffix": ""}], "year": 1993, "venue": "", "link": "56548465"}, "BIBREF17": {"title": "Longitudinal and crosssectional analysis of atrophy in pharmacoresistant temporal lobe epilepsy", "authors": [{"first": "B", "middle": ["C"], "last": "Bernhardt", "suffix": ""}, {"first": "K", "middle": ["J"], "last": "Worsley", "suffix": ""}, {"first": "H", "middle": [], "last": "Kim", "suffix": ""}, {"first": "A", "middle": ["C"], "last": "Evans", "suffix": ""}, {"first": "A", "middle": [], "last": "Bernasconi", "suffix": ""}, {"first": "N", "middle": [], "last": "Bernasconi", "suffix": ""}], "year": 2009, "venue": "Neurology", "link": null}, "BIBREF18": {"title": "Automated 3-D extraction and evaluation of the inner and outer cortical surfaces using a Laplacian map and partial volume effect classification", "authors": [{"first": "J", "middle": ["S"], "last": "Kim", "suffix": ""}, {"first": "V", "middle": [], "last": "Singh", "suffix": ""}, {"first": "J", "middle": ["K"], "last": "Lee", "suffix": ""}], "year": 2005, "venue": "Neuroimage", "link": "5392946"}, "BIBREF19": {"title": "An unbiased iterative group registration template for cortical surface analysis", "authors": [{"first": "O", "middle": [], "last": "Lyttelton", "suffix": ""}, {"first": "M", "middle": [], "last": "Boucher", "suffix": ""}, {"first": "S", "middle": [], "last": "Robbins", "suffix": ""}, {"first": "A", "middle": [], "last": "Evans", "suffix": ""}], "year": 2007, "venue": "Neuroimage", "link": "207165774"}, "BIBREF20": {"title": "Increased temporolimbic cortical folding complexity in temporal lobe epilepsy", "authors": [{"first": "N", "middle": ["L"], "last": "Voets", "suffix": ""}, {"first": "B", "middle": ["C"], "last": "Bernhardt", "suffix": ""}, {"first": "H", "middle": [], "last": "Kim", "suffix": ""}, {"first": "U", "middle": [], "last": "Yoon", "suffix": ""}, {"first": "N", "middle": [], "last": "Bernasconi", "suffix": ""}], "year": 2011, "venue": "Neurology", "link": null}, "BIBREF21": {"title": "Cortical thickness analysis in temporal lobe epilepsy: reproducibility and relation to outcome", "authors": [{"first": "B", "middle": ["C"], "last": "Bernhardt", "suffix": ""}, {"first": "N", "middle": [], "last": "Bernasconi", "suffix": ""}, {"first": "L", "middle": [], "last": "Concha", "suffix": ""}, {"first": "A", "middle": [], "last": "Bernasconi", "suffix": ""}], "year": 2010, "venue": "Neurology", "link": "31509203"}, "BIBREF22": {"title": "Brain size and cortical structure in the adult human brain", "authors": [{"first": "K", "middle": [], "last": "Im", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Lee", "suffix": ""}, {"first": "O", "middle": [], "last": "Lyttelton", "suffix": ""}, {"first": "S", "middle": ["H"], "last": "Kim", "suffix": ""}, {"first": "A", "middle": ["C"], "last": "Evans", "suffix": ""}, {"first": "S", "middle": ["I"], "last": "Kim", "suffix": ""}], "year": 2008, "venue": "Cereb Cortex", "link": "9111352"}, "BIBREF23": {"title": "SurfStat: a Matlab toolbox for the statistical analysis of univariate and multivariate surface and volumetric data using linear mixed effects models and random field theory", "authors": [{"first": "K", "middle": [], "last": "Worsley", "suffix": ""}, {"first": "J", "middle": [], "last": "Taylor", "suffix": ""}, {"first": "F", "middle": [], "last": "Carbonell", "suffix": ""}], "year": 2009, "venue": "Neuroimage", "link": "54308392"}, "BIBREF24": {"title": "Mapping human cortical areas in vivo based on myelin content as revealed by T1-and T2-weighted MRI", "authors": [{"first": "M", "middle": ["F"], "last": "Glasser", "suffix": ""}, {"first": "D", "middle": ["C"], "last": "Van Essen", "suffix": ""}], "year": 2011, "venue": "J Neurosci", "link": "8379593"}, "BIBREF25": {"title": "Mapping limbic network organization in temporal lobe epilepsy using morphometric correlations: insights on the relation between mesiotemporal connectivity and cortical atrophy", "authors": [{"first": "B", "middle": ["C"], "last": "Bernhardt", "suffix": ""}, {"first": "K", "middle": ["J"], "last": "Worsley", "suffix": ""}, {"first": "P", "middle": [], "last": "Besson", "suffix": ""}], "year": 2008, "venue": "Neuroimage", "link": "19855598"}, "BIBREF26": {"title": "Mapping the human connectome at multiple scales with diffusion spectrum MRI", "authors": [{"first": "L", "middle": [], "last": "Cammoun", "suffix": ""}, {"first": "X", "middle": [], "last": "Gigandet", "suffix": ""}, {"first": "D", "middle": [], "last": "Meskaldji", "suffix": ""}], "year": 2012, "venue": "J Neurosci Methods", "link": "17453828"}, "BIBREF27": {"title": "Detecting changes in nonisotropic images", "authors": [{"first": "K", "middle": [], "last": "Worsley", "suffix": ""}, {"first": "M", "middle": [], "last": "Andermann", "suffix": ""}, {"first": "T", "middle": [], "last": "Koulis", "suffix": ""}, {"first": "D", "middle": [], "last": "Macdonald", "suffix": ""}, {"first": "A", "middle": [], "last": "Evans", "suffix": ""}], "year": 1999, "venue": "Hum Brain Mapp", "link": "16175353"}, "BIBREF28": {"title": "Gray matter atrophy associated with duration of temporal lobe epilepsy", "authors": [{"first": "L", "middle": [], "last": "Bonilha", "suffix": ""}, {"first": "C", "middle": [], "last": "Rorden", "suffix": ""}, {"first": "S", "middle": [], "last": "Appenzeller", "suffix": ""}, {"first": "A", "middle": ["C"], "last": "Coan", "suffix": ""}, {"first": "F", "middle": [], "last": "Cendes", "suffix": ""}, {"first": "L", "middle": ["M"], "last": "Li", "suffix": ""}], "year": 2006, "venue": "Neuroimage", "link": "22786652"}, "BIBREF29": {"title": "Thalamo-cortical network pathology in idiopathic generalized epilepsy: insights from MRI-based morphometric correlation analysis", "authors": [{"first": "B", "middle": ["C"], "last": "Bernhardt", "suffix": ""}, {"first": "D", "middle": ["A"], "last": "Rozen", "suffix": ""}, {"first": "K", "middle": ["J"], "last": "Worsley", "suffix": ""}, {"first": "A", "middle": ["C"], "last": "Evans", "suffix": ""}, {"first": "N", "middle": [], "last": "Bernasconi", "suffix": ""}, {"first": "A", "middle": [], "last": "Bernasconi", "suffix": ""}], "year": 2009, "venue": "Neuroimage", "link": "24227715"}, "BIBREF30": {"title": "From molecules to networks: cortical/subcortical interactions in the pathophysiology of idiopathic generalized epilepsy", "authors": [{"first": "H", "middle": [], "last": "Blumenfeld", "suffix": ""}], "year": 2003, "venue": "Epilepsia", "link": "33775614"}, "BIBREF31": {"title": "Regulators of synaptic transmission: roles in the pathogenesis and treatment of epilepsy", "authors": [{"first": "P", "middle": ["M"], "last": "Casillas-Espinosa", "suffix": ""}, {"first": "K", "middle": ["L"], "last": "Powell", "suffix": ""}, {"first": "O", "middle": [], "last": "&apos;brien", "suffix": ""}, {"first": "T", "middle": ["J"], "last": "", "suffix": ""}], "year": 2012, "venue": "Epilepsia", "link": "27930716"}, "BIBREF32": {"title": "Normal development of brain circuits", "authors": [{"first": "G", "middle": ["Z"], "last": "Tau", "suffix": ""}, {"first": "B", "middle": ["S"], "last": "Peterson", "suffix": ""}], "year": 2010, "venue": "Neuropsychopharmacology", "link": "205459188"}, "BIBREF33": {"title": "Patterns of coordinated anatomical change in human cortical development: a longitudinal neuroimaging study of maturational coupling", "authors": [{"first": "A", "middle": [], "last": "Raznahan", "suffix": ""}, {"first": "J", "middle": ["P"], "last": "Lerch", "suffix": ""}, {"first": "N", "middle": [], "last": "Lee", "suffix": ""}], "year": 2011, "venue": "Neuron", "link": "8589609"}, "BIBREF34": {"title": "Neuropathologic measurements in focal cortical dysplasias: validation of the ILAE 2011 classification system and diagnostic implications for MRI", "authors": [{"first": "A", "middle": [], "last": "Muhlebner", "suffix": ""}, {"first": "R", "middle": [], "last": "Coras", "suffix": ""}, {"first": "K", "middle": [], "last": "Kobow", "suffix": ""}], "year": 2012, "venue": "Acta Neuropathol", "link": "24823674"}, "BIBREF35": {"title": "Which is the best multiclass SVM method? An empirical study", "authors": [{"first": "K", "middle": ["B"], "last": "Duan", "suffix": ""}, {"first": "S", "middle": ["S"], "last": "Keerthi", "suffix": ""}], "year": 2005, "venue": "Multiple Classifier Systems. Berlin", "link": "5292272"}, "BIBREF36": {"title": "Incomplete resection of focal cortical dysplasia is the main predictor of poor postsurgical outcome", "authors": [{"first": "P", "middle": [], "last": "Krsek", "suffix": ""}, {"first": "B", "middle": [], "last": "Maton", "suffix": ""}, {"first": "P", "middle": [], "last": "Jayakar", "suffix": ""}], "year": 2009, "venue": "Neurology", "link": "207103510"}, "BIBREF37": {"title": "Clinical, EEG, and quantitative MRI differences in pediatric frontal and temporal lobe epilepsy", "authors": [{"first": "J", "middle": ["A"], "last": "Lawson", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Cook", "suffix": ""}, {"first": "S", "middle": [], "last": "Vogrin", "suffix": ""}], "year": 2002, "venue": "Neurology", "link": "2086839"}, "BIBREF38": {"title": "Cell migration in the forebrain", "authors": [{"first": "O", "middle": [], "last": "Marin", "suffix": ""}, {"first": "J", "middle": ["L"], "last": "Rubenstein", "suffix": ""}], "year": 2003, "venue": "Annu Rev Neurosci", "link": "9090351"}, "BIBREF39": {"title": "Modes of neuronal migration in the developing cerebral cortex", "authors": [{"first": "B", "middle": [], "last": "Nadarajah", "suffix": ""}, {"first": "J", "middle": ["G"], "last": "Parnavelas", "suffix": ""}], "year": 2002, "venue": "Nat Rev Neurosci", "link": "38910547"}, "BIBREF40": {"title": "PET: central benzodiazepine neuroreceptor mapping in localization-related epilepsies", "authors": [{"first": "J", "middle": ["S"], "last": "Duncan", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Koepp", "suffix": ""}], "year": 2000, "venue": "Adv Neurol", "link": "39413848"}, "BIBREF41": {"title": "A developmental and genetic classification for malformations of cortical development: update 2012", "authors": [{"first": "A", "middle": ["J"], "last": "Barkovich", "suffix": ""}, {"first": "R", "middle": [], "last": "Guerrini", "suffix": ""}, {"first": "R", "middle": ["I"], "last": "Kuzniecky", "suffix": ""}, {"first": "G", "middle": ["D"], "last": "Jackson", "suffix": ""}, {"first": "W", "middle": ["B"], "last": "Dobyns", "suffix": ""}], "year": 2012, "venue": "Brain", "link": "16468744"}, "BIBREF42": {"title": "Magnetic resonance imaging pattern learning in temporal lobe epilepsy: classification and prognostics", "authors": [{"first": "B", "middle": ["C"], "last": "Bernhardt", "suffix": ""}, {"first": "S", "middle": ["J"], "last": "Hong", "suffix": ""}, {"first": "A", "middle": [], "last": "Bernasconi", "suffix": ""}, {"first": "N", "middle": [], "last": "Bernasconi", "suffix": ""}], "year": 2015, "venue": "Ann Neurol", "link": "2613171"}}, "ref_entries": {"FIGREF0": {"text": "Figure 1 Group-level alterations in cortical thickness (A) and folding complexity (B) in patients with FCD", "type": "figure"}, "FIGREF1": {"text": "Figure 2 Duration-stratified analysis of cortical thickness", "type": "figure"}, "FIGREF2": {"text": "This work was supported by the Canadian Institutes of Health Research (CIHR, MOP-57840 and 123520). S.-J.H. received a Desjardins fellow- ship. B.C.B. was funded by CIHR and a JTC fellowship of the Montreal Neurological Institute.", "type": "figure"}, "TABREF1": {"text": "Group analysis. Cortical thickness. Compared with controls, FCD type I showed bilateral multilobar cortical thinning, with ipsilateral lateral frontal and mesial precentral changes (FWE-corrected p value, p FWE , 0.0001; Cohen d 5 0.78; 95% confidence interval [CI] 5 21.53 to 20.40) (figure 1). Atrophy was also present in ipsilateral insular, supramarginal, and temporal cortices (p FWE", "type": "table"}, "TABREF2": {"text": "and cingulate atrophy in type I (p FWE , 0.005; Cohen d 5 0.82; 95% CI 5 21.66 to 20.34). Cortical folding complexity. Compared with controls, while FCD type I showed increased curvature in", "type": "table"}, "TABREF3": {"text": "fuse and bilateral cortical thinning, with a somewhat more marked and extended distribution in ipsilateral frontal cortices in those with long disease duration. In type II, however, patients with short duration showed bilateral symmetric thickening in frontal, central, and temporal areas (p FWE , 0.04), while those with long duration presented with pericentral and temporo- occipital thinning (p FWE , 0.04). Results in type II remained unchanged after excluding lesional vertices. In a separate analysis, linearly modeling vertex-wise duration effects revealed progressive cortical thinning in ipsilateral middle frontal and contralateral", "type": "table"}}}
{"paper_id": "8338400", "_pdf_hash": "1dc5d3ed3245fdf512bcbeae3a9bbe8767c272af", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "The power of processor consistency", "authors": [{"first": "Rida", "middle": ["A"], "last": "Abj + 93] Mustaque Ahamad", "suffix": ""}, {"first": "Ranjit", "middle": [], "last": "Bazzi", "suffix": ""}, {"first": "Prince", "middle": [], "last": "John", "suffix": ""}, {"first": "Gil", "middle": [], "last": "Kohli", "suffix": ""}, {"first": "", "middle": [], "last": "Neiger", "suffix": ""}], "year": 1993, "venue": "", "link": null}, "BIBREF1": {"title": "Midway: Shared memory parallel programming with entry consistency for distributed memory multiprocessors", "authors": [{"first": "N", "middle": [], "last": "Brian", "suffix": ""}, {"first": "Matthew", "middle": ["J"], "last": "Bershad", "suffix": ""}, {"first": "", "middle": [], "last": "Zekauskas", "suffix": ""}], "year": 1991, "venue": "", "link": "135915"}, "BIBREF2": {"title": "The midway distributed shared memory system", "authors": [{"first": "Brian", "middle": ["N"], "last": "Bershad", "suffix": ""}, {"first": "Matthew", "middle": ["J"], "last": "Zekauskas", "suffix": ""}, {"first": "W", "middle": ["A"], "last": "Sawdon", "suffix": ""}], "year": 1993, "venue": "Proceedings of the IEEE COMPCOM Conference", "link": "62595539"}, "BIBREF3": {"title": "The Messenger Paradigm and its Impact on Distributed Systems", "authors": [{"first": "Giovanna", "middle": [], "last": "Di Marzo", "suffix": ""}, {"first": "Murhimanya", "middle": [], "last": "Muhugusa", "suffix": ""}, {"first": "Christian", "middle": ["F"], "last": "Tschudin", "suffix": ""}, {"first": "", "middle": [], "last": "Harms", "suffix": ""}], "year": 1995, "venue": "ICC'95 workshop on Intelligent Computer Communication", "link": null}, "BIBREF4": {"title": "Memory access bu ering in multiprocessors", "authors": [{"first": "Michel", "middle": [], "last": "Dubois", "suffix": ""}, {"first": "Christoph", "middle": [], "last": "Scheurich", "suffix": ""}, {"first": "Fay", "middle": [], "last": "", "suffix": ""}, {"first": "A", "middle": [], "last": "Briggs", "suffix": ""}], "year": 1986, "venue": "Proceedings of the 13th Annual International Symposium on Computer Architecture", "link": null}, "BIBREF5": {"title": "Synchronization, coherence, and event ordering in multiprocessors", "authors": [{"first": "Michel", "middle": [], "last": "Dubois", "suffix": ""}, {"first": "Christoph", "middle": [], "last": "Scheurich", "suffix": ""}, {"first": "Fay", "middle": [], "last": "", "suffix": ""}, {"first": "A", "middle": [], "last": "Briggs", "suffix": ""}], "year": 1988, "venue": "IEEE Computer", "link": "1749330"}, "BIBREF6": {"title": "Memory consistency and event ordering in scalable shared-memory multiprocessors", "authors": [{"first": "", "middle": [], "last": "Gll + 90] Kourosh", "suffix": ""}, {"first": "Daniel", "middle": [], "last": "Gharachorloo", "suffix": ""}, {"first": "James", "middle": [], "last": "Lenoski", "suffix": ""}, {"first": "Phillip", "middle": [], "last": "Laudon", "suffix": ""}, {"first": "Anoop", "middle": [], "last": "Gibbons", "suffix": ""}, {"first": "John", "middle": [], "last": "Gupta", "suffix": ""}, {"first": "", "middle": [], "last": "Hennessy", "suffix": ""}], "year": 1990, "venue": "Proceedings of the 17th Annual International Symposium on Computer Architecture", "link": "47089892"}, "BIBREF7": {"title": "Cache Consistency and Sequential Consistency", "authors": [{"first": "J", "middle": ["R"], "last": "Goodman", "suffix": ""}], "year": 1989, "venue": "", "link": null}, "BIBREF8": {"title": "Improving Release-Consistent Shared Virtual Memory using Automatic Update", "authors": [{"first": "Liviu", "middle": [], "last": "Iftode", "suffix": ""}, {"first": "Cezary", "middle": [], "last": "Dubnicki", "suffix": ""}, {"first": "Edward", "middle": ["W"], "last": "Felten", "suffix": ""}, {"first": "Kai", "middle": [], "last": "Li", "suffix": ""}], "year": 1996, "venue": "Proceedings of the 2nd International Symposium on High-Performance Computer Architecture", "link": "9001144"}, "BIBREF9": {"title": "Lazy Release Consistency", "authors": [{"first": "Peter", "middle": [], "last": "Keleher", "suffix": ""}, {"first": "Alan", "middle": ["L"], "last": "Cox", "suffix": ""}, {"first": "Willy", "middle": [], "last": "Zwaenepoel", "suffix": ""}], "year": 1992, "venue": "Proceedings of the 19th Annual International Symposium on Computer Architecture", "link": null}, "BIBREF10": {"title": "Lazy Release Consistency for Distributed Shared Memory", "authors": [{"first": "Peter", "middle": [], "last": "Keleher", "suffix": ""}], "year": 1995, "venue": "", "link": "60890187"}, "BIBREF11": {"title": "A characterization of scalable shared memories", "authors": [{"first": "Prince", "middle": [], "last": "Kohli", "suffix": ""}, {"first": "Gil", "middle": [], "last": "Neiger", "suffix": ""}, {"first": "Mustaque", "middle": [], "last": "Ahamad", "suffix": ""}], "year": 1993, "venue": "", "link": "5797793"}, "BIBREF12": {"title": "How to make a multiprocessor computer that correctly executes multiprocess programs", "authors": [{"first": "Leslie", "middle": [], "last": "Lamport", "suffix": ""}], "year": 1979, "venue": "IEEE Transactions on Computers, C", "link": "215404438"}, "BIBREF13": {"title": "Pram: A scalable shared memory", "authors": [{"first": "J", "middle": [], "last": "Richard", "suffix": ""}, {"first": "Jonathan", "middle": ["S"], "last": "Lipton", "suffix": ""}, {"first": "", "middle": [], "last": "Sandberg", "suffix": ""}], "year": 1988, "venue": "", "link": "59765068"}, "BIBREF14": {"title": "Axioms for memory access in asynchronous hardware systems", "authors": [{"first": "Jayadev", "middle": [], "last": "Misra", "suffix": ""}], "year": "", "venue": "142{153, 1986. Memory Model", "link": "47131957"}, "BIBREF15": {"title": "Memory consistency models", "authors": [{"first": "David", "middle": [], "last": "Mosberger", "suffix": ""}], "year": 1993, "venue": "", "link": "14614641"}, "BIBREF16": {"title": "Sequential Consistency in Distributed Systems: Theory and Implementatio", "authors": [{"first": "M", "middle": [], "last": "Mizuno", "suffix": ""}, {"first": "M", "middle": [], "last": "Raynal", "suffix": ""}, {"first": "J", "middle": ["Z"], "last": "Zhou", "suffix": ""}], "year": 1995, "venue": "", "link": "60761293"}, "BIBREF17": {"title": "Distributed Operating Systems", "authors": [{"first": "Andrew", "middle": ["S"], "last": "Tanenbaum", "suffix": ""}], "year": 1995, "venue": "", "link": "5378019"}, "BIBREF18": {"title": "Messenger-based Operating Systems", "authors": [{"first": "F", "middle": [], "last": "Christian", "suffix": ""}, {"first": "Giovanna", "middle": ["Di"], "last": "Tschudin", "suffix": ""}, {"first": "Murhimanya", "middle": [], "last": "Marzo", "suffix": ""}, {"first": "", "middle": [], "last": "Muhugusa", "suffix": ""}, {"first": "", "middle": [], "last": "Harms", "suffix": ""}], "year": 1994, "venue": "", "link": "14458681"}, "BIBREF19": {"title": "On the Structuring of Computer Communications", "authors": [{"first": "Christian", "middle": ["F"], "last": "Tschudin", "suffix": ""}], "year": 1993, "venue": "", "link": null}, "BIBREF20": {"title": "An Introduction to the M0 Messenger Language", "authors": [{"first": "Christian", "middle": ["F"], "last": "Tschudin", "suffix": ""}], "year": 1994, "venue": "", "link": "59624058"}}, "ref_entries": {}}
{"paper_id": "8338411", "_pdf_hash": "2487d4e968244c19ab57d4e85d05eac3ddaaf8fd", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Two strategies for learning a route in a driving simulator", "authors": [{"first": "V", "middle": [], "last": "Aginsky", "suffix": ""}, {"first": "C", "middle": [], "last": "Harris", "suffix": ""}, {"first": "R", "middle": [], "last": "Rensink", "suffix": ""}, {"first": "J", "middle": [], "last": "Beusmans", "suffix": ""}], "year": 1997, "venue": "Journal of Environmental Psychology", "link": null}, "BIBREF1": {"title": "Mental representation and processing of geographic knowledge -A computational approach", "authors": [{"first": "T", "middle": [], "last": "Barkowsky", "suffix": ""}], "year": 2002, "venue": "", "link": "39088951"}, "BIBREF2": {"title": "Computational modeling of reasoning with mental images: basic requirements", "authors": [{"first": "S", "middle": [], "last": "Bertel", "suffix": ""}, {"first": "T", "middle": [], "last": "Barkowsky", "suffix": ""}, {"first": "D", "middle": [], "last": "Engel", "suffix": ""}, {"first": "C", "middle": [], "last": "Freksa", "suffix": ""}], "year": 2006, "venue": "Proceedings of ICCM", "link": null}, "BIBREF3": {"title": "Switching between environmental representations in memory", "authors": [{"first": "J", "middle": ["R"], "last": "Brockmole", "suffix": ""}, {"first": "R", "middle": ["F"], "last": "Wang", "suffix": ""}], "year": 2002, "venue": "Cognition", "link": "329648"}, "BIBREF4": {"title": "Selecting a reference frame", "authors": [{"first": "L", "middle": ["A"], "last": "Carlson", "suffix": ""}], "year": 1999, "venue": "Spatial Cognition and Computation", "link": "39896681"}, "BIBREF5": {"title": "An Architecture for Problem Solving with Diagrams", "authors": [{"first": "B", "middle": [], "last": "Chandrasekaran", "suffix": ""}, {"first": "U", "middle": [], "last": "Kurup", "suffix": ""}, {"first": "B", "middle": [], "last": "Banerjee", "suffix": ""}, {"first": "J", "middle": ["R"], "last": "Josephson", "suffix": ""}, {"first": "R", "middle": [], "last": "Winkler", "suffix": ""}], "year": 2004, "venue": "Proceedings of Diagrams", "link": "14410317"}, "BIBREF6": {"title": "Iconic indexing by 2-D string", "authors": [{"first": "S", "middle": ["K"], "last": "Chang", "suffix": ""}, {"first": "Q", "middle": ["Y"], "last": "Shi", "suffix": ""}, {"first": "C", "middle": ["W"], "last": "Yan", "suffix": ""}], "year": 1987, "venue": "IEEE Transactions on Pattern Analysis and Machine Intelligence", "link": "12115567"}, "BIBREF7": {"title": "Different mental imagery abilities result in different regional cerebral blood flow activation patterns during cognitive tests", "authors": [{"first": "V", "middle": [], "last": "Charlot", "suffix": ""}, {"first": "N", "middle": [], "last": "Tzourio", "suffix": ""}, {"first": "M", "middle": [], "last": "Zilbovicius", "suffix": ""}, {"first": "B", "middle": [], "last": "Mazoyer", "suffix": ""}, {"first": "M", "middle": [], "last": "Denis", "suffix": ""}], "year": 1992, "venue": "Neuropsychologia", "link": "25784296"}, "BIBREF8": {"title": "RCC: a calculus for region based qualitative spatial reasoning", "authors": [{"first": "A", "middle": ["G"], "last": "Cohn", "suffix": ""}, {"first": "B", "middle": [], "last": "Bennett", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Gooday", "suffix": ""}, {"first": "N", "middle": [], "last": "Gotts", "suffix": ""}], "year": 1997, "venue": "GeoInformatica", "link": "115231684"}, "BIBREF9": {"title": "Retrieval time from semantic memory", "authors": [{"first": "A", "middle": ["M"], "last": "Collins", "suffix": ""}, {"first": "M", "middle": ["R"], "last": "Quillian", "suffix": ""}], "year": 1969, "venue": "Journal ofVerbal Learning and Verbal Behavior", "link": "60922154"}, "BIBREF11": {"title": "Object-array structure, frames of reference, and retrieval of spatial knowledge", "authors": [{"first": "R", "middle": ["D"], "last": "Easton", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Sholl", "suffix": ""}], "year": 1995, "venue": "Journal of Experimental Psychology: Learning, Memory, and Cognition", "link": "8435581"}, "BIBREF12": {"title": "Deriving the composition of binary topological relations", "authors": [{"first": "M", "middle": ["J"], "last": "Egenhofer", "suffix": ""}], "year": 1994, "venue": "Journal of Visual Languages and Computing", "link": "622982"}, "BIBREF13": {"title": "Qualitative spatial reasoning: Cardinal directions as an example. International Journal of Geographical Information Systems", "authors": [{"first": "A", "middle": [], "last": "Frank", "suffix": ""}], "year": 1995, "venue": "", "link": null}, "BIBREF14": {"title": "Problem-solving with diagrammatic representations", "authors": [{"first": "B", "middle": [], "last": "Funt", "suffix": ""}], "year": 1980, "venue": "Artificial Intelligence", "link": "20019039"}, "BIBREF15": {"title": "Working memory and strategies in syllogistic reasoning tasks", "authors": [{"first": "K", "middle": ["J"], "last": "Gilhooly", "suffix": ""}, {"first": "R", "middle": ["H"], "last": "Logie", "suffix": ""}, {"first": "N", "middle": ["E"], "last": "Wetherick", "suffix": ""}, {"first": "V", "middle": [], "last": "Wynn", "suffix": ""}], "year": 1993, "venue": "Mem Cognit", "link": "44614216"}, "BIBREF16": {"title": "Computational imagery", "authors": [{"first": "J", "middle": [], "last": "Glasgow", "suffix": ""}, {"first": "D", "middle": [], "last": "Papadias", "suffix": ""}], "year": 1992, "venue": "Cognitive Science", "link": "8520008"}, "BIBREF17": {"title": "Reasoning About Relations. Psychological Review", "authors": [{"first": "G", "middle": ["P"], "last": "Goodwin", "suffix": ""}, {"first": "P", "middle": ["N"], "last": "Johnson-Laird", "suffix": ""}], "year": 2005, "venue": "", "link": null}, "BIBREF18": {"title": "Dissociation of object and spatial visual processing pathways in human extrastriate cortex", "authors": [{"first": "J", "middle": ["V"], "last": "Haxby", "suffix": ""}, {"first": "C", "middle": ["L"], "last": "Grady", "suffix": ""}, {"first": "B", "middle": [], "last": "Horwitz", "suffix": ""}, {"first": "L", "middle": ["G"], "last": "Ungerleider", "suffix": ""}, {"first": "M", "middle": [], "last": "Mishkin", "suffix": ""}, {"first": "R", "middle": ["E"], "last": "Carson", "suffix": ""}, {"first": "P", "middle": [], "last": "Herscovitch", "suffix": ""}, {"first": "M", "middle": ["B"], "last": "Schapiro", "suffix": ""}, {"first": "S", "middle": ["I"], "last": "Rapoport", "suffix": ""}], "year": 1991, "venue": "Proceedings of the National Academy of Sciences", "link": "39556099"}, "BIBREF19": {"title": "Types of visual-spatial representations and mathematical problem solving", "authors": [{"first": "M", "middle": [], "last": "Hegarty", "suffix": ""}, {"first": "M", "middle": [], "last": "Kozhevnikov", "suffix": ""}], "year": 1999, "venue": "Journal of Educational Psychology", "link": "9455734"}, "BIBREF20": {"title": "Evidence of hierarchies in cognitive maps", "authors": [{"first": "S", "middle": ["C"], "last": "Hirtle", "suffix": ""}, {"first": "J", "middle": [], "last": "Jonides", "suffix": ""}], "year": 1985, "venue": "Memory & Cognition", "link": "32411729"}, "BIBREF21": {"title": "Visual imagery facilitates visual perception: Psychophysical evidence", "authors": [{"first": "A", "middle": [], "last": "Ishai", "suffix": ""}, {"first": "D", "middle": [], "last": "Sagi", "suffix": ""}], "year": 1997, "venue": "Journal of Cognitive Neuroscience", "link": "207597732"}, "BIBREF22": {"title": "Hybrid representation of spatial descriptions. International workshop Spatial and Visual Components in Mental Reasoning about Large-Scale Spaces", "authors": [{"first": "G", "middle": [], "last": "Jahn", "suffix": ""}], "year": 2003, "venue": "", "link": null}, "BIBREF23": {"title": "Mental models", "authors": [{"first": "P", "middle": ["N"], "last": "Johnson-Laird", "suffix": ""}], "year": 1983, "venue": "", "link": null}, "BIBREF24": {"title": "Object-oriented representation of depictions on the basis of cell matrices", "authors": [{"first": "M", "middle": [], "last": "Khenkhar", "suffix": ""}], "year": 1991, "venue": "Text understanding in LILOG", "link": "40963990"}, "BIBREF25": {"title": "Double dissociations in visual and spatial short-term memory", "authors": [{"first": "K", "middle": ["C"], "last": "Klauer", "suffix": ""}, {"first": "Z", "middle": [], "last": "Zhao", "suffix": ""}], "year": 2004, "venue": "Journal of Experimental Psychology: General", "link": "7224613"}, "BIBREF26": {"title": "Visual imagery can impede reasoning", "authors": [{"first": "M", "middle": [], "last": "Knauff", "suffix": ""}, {"first": "P", "middle": ["N"], "last": "Johnson-Laird", "suffix": ""}], "year": 2002, "venue": "Memory & Cognition", "link": "7330724"}, "BIBREF27": {"title": "Image and Mind", "authors": [{"first": "S", "middle": ["M"], "last": "Kosslyn", "suffix": ""}], "year": 1980, "venue": "", "link": "122391431"}, "BIBREF28": {"title": "Image and brain -The resolution of the imagery debate", "authors": [{"first": "S", "middle": ["M"], "last": "Kosslyn", "suffix": ""}], "year": 1994, "venue": "", "link": "31936897"}, "BIBREF29": {"title": "Roles of imagery in perception: Or, there is no such thing as immaculate perception", "authors": [{"first": "S", "middle": ["M"], "last": "Kosslyn", "suffix": ""}, {"first": "A", "middle": ["L"], "last": "Sussman", "suffix": ""}], "year": 1995, "venue": "The cognitive neurosciences", "link": "141212750"}, "BIBREF30": {"title": "When is early visual cortex activated during visual mental imagery?", "authors": [{"first": "S", "middle": ["M"], "last": "Kosslyn", "suffix": ""}, {"first": "W", "middle": ["L"], "last": "Thompson", "suffix": ""}], "year": 2003, "venue": "Psychological Bulletin", "link": "31734929"}, "BIBREF31": {"title": "Revisiting the visualizer-verbalizer dimension: Evidence for two types of visualizers", "authors": [{"first": "M", "middle": [], "last": "Kozhevnikov", "suffix": ""}, {"first": "M", "middle": [], "last": "Hegarty", "suffix": ""}, {"first": "R", "middle": ["E"], "last": "Mayer", "suffix": ""}], "year": 2002, "venue": "Cognition & Instruction", "link": "999405"}, "BIBREF32": {"title": "Spatial versus object visualizers: A new characterization of visual cognitive style. Memory & Cognition", "authors": [{"first": "M", "middle": [], "last": "Kozhevnikov", "suffix": ""}, {"first": "S", "middle": [], "last": "Kosslyn", "suffix": ""}, {"first": "J", "middle": [], "last": "Shepard", "suffix": ""}], "year": "", "venue": "", "link": "11705318"}, "BIBREF33": {"title": "Structural information theory and visual form", "authors": [{"first": "E", "middle": [], "last": "Leeuwenberg", "suffix": ""}], "year": 2004, "venue": "Psychophysics beyond sensation", "link": "142940820"}, "BIBREF34": {"title": "Two visual systems in mental imagery: Dissociation of \"what\" and \"where\" in imagery disorders due to bilateral posterior cerebral lesions", "authors": [{"first": "D", "middle": ["N"], "last": "Levine", "suffix": ""}, {"first": "J", "middle": [], "last": "Warach", "suffix": ""}, {"first": "M", "middle": [], "last": "Farah", "suffix": ""}], "year": 1985, "venue": "Neurology", "link": "144543553"}, "BIBREF35": {"title": "Revised Minnesota Paper Form Board Test (Series AA)", "authors": [{"first": "A", "middle": [], "last": "Likert", "suffix": ""}, {"first": "W", "middle": ["H"], "last": "Quasha", "suffix": ""}], "year": 1941, "venue": "", "link": null}, "BIBREF36": {"title": "Mental representations of spatial judgments", "authors": [{"first": "T", "middle": ["P"], "last": "Mcnamara", "suffix": ""}], "year": 1986, "venue": "Cognitive Psychology", "link": null}, "BIBREF37": {"title": "A positron emission tomography study of visual and mental spatial exploration", "authors": [{"first": "E", "middle": [], "last": "Mellet", "suffix": ""}, {"first": "N", "middle": [], "last": "Tzourio", "suffix": ""}, {"first": "M", "middle": [], "last": "Denis", "suffix": ""}, {"first": "B", "middle": [], "last": "Mazoyer", "suffix": ""}], "year": 1995, "venue": "Journal of Cognitive Neuroscience", "link": "15713502"}, "BIBREF38": {"title": "Qualitative spatial reasoning about relative position: The tradeoff between strong formal properties and successful reasoning about route graphs", "authors": [{"first": "R", "middle": [], "last": "Moratz", "suffix": ""}, {"first": "B", "middle": [], "last": "Nebel", "suffix": ""}, {"first": "C", "middle": [], "last": "Freksa", "suffix": ""}], "year": 2003, "venue": "Spatial Cognition III", "link": "36424806"}, "BIBREF39": {"title": "A Computational Model for Spatial Reasoning with Mental Models", "authors": [{"first": "M", "middle": [], "last": "Ragni", "suffix": ""}, {"first": "M", "middle": [], "last": "Knauff", "suffix": ""}, {"first": "B", "middle": [], "last": "Nebel", "suffix": ""}], "year": 2005, "venue": "Proceedings of the 27th Annual Cognitive Science Conference", "link": null}, "BIBREF40": {"title": "Access to knowledge of spatial structure at novel points of observation", "authors": [{"first": "J", "middle": ["J"], "last": "Rieser", "suffix": ""}], "year": 1989, "venue": "Journal of Experimental Psychology: Learning, Memory, and Cognition", "link": "8944897"}, "BIBREF41": {"title": "Mental model construction in spatial reasoning: A comparison of two computational theories", "authors": [{"first": "C", "middle": [], "last": "Schlieder", "suffix": ""}, {"first": "B", "middle": [], "last": "Berendt", "suffix": ""}], "year": 1998, "venue": "Mind modelling: A cognitive science approach to reasoning, learning and discovery", "link": null}, "BIBREF42": {"title": "Integrated Spatial Reasoning in Geographic Information Systems: Combining Topology and Direction", "authors": [{"first": "J", "middle": [], "last": "Sharma", "suffix": ""}], "year": 1996, "venue": "", "link": null}, "BIBREF43": {"title": "Why we need many knowledge representation formalisms", "authors": [{"first": "A", "middle": [], "last": "Sloman", "suffix": ""}], "year": 1984, "venue": "Proceedings BCS Expert Systems Conf", "link": null}, "BIBREF44": {"title": "A cognitive theory of graphical and linguistic reasoning: logic and implementation", "authors": [{"first": "K", "middle": [], "last": "Stenning", "suffix": ""}, {"first": "J", "middle": [], "last": "Oberlander", "suffix": ""}], "year": 1995, "venue": "Cognitive Science", "link": "74221"}, "BIBREF45": {"title": "Two cortical visual systems", "authors": [{"first": "L", "middle": ["G"], "last": "Ungerleider", "suffix": ""}, {"first": "M", "middle": [], "last": "Mishkin", "suffix": ""}], "year": 1982, "venue": "Analysis of visual behavior", "link": "142774685"}, "BIBREF46": {"title": "Mental Rotations, a group test of three-dimensional spatial visualization. Perception and Motor Skills", "authors": [{"first": "S", "middle": ["G"], "last": "Vandenberg", "suffix": ""}, {"first": "A", "middle": ["R"], "last": "Kuse", "suffix": ""}], "year": 1978, "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "8338898", "_pdf_hash": "30ad71b51234d3ec12c0ce7d3c7294ad2f24f5eb", "abstract": [], "body_text": [], "bib_entries": {"BIBREF1": {"title": "A min-max cut algorithm for graph partitioning and data clustering", "authors": [{"first": "C", "middle": [], "last": "Ding", "suffix": ""}, {"first": "X", "middle": [], "last": "He", "suffix": ""}, {"first": "H", "middle": [], "last": "Zha", "suffix": ""}, {"first": "M", "middle": [], "last": "Gu", "suffix": ""}, {"first": "H", "middle": [], "last": "Simon", "suffix": ""}], "year": 2001, "venue": "Proc. of 1st IEEE Int'l Conf. Data Mining", "link": "18520895"}, "BIBREF2": {"title": "On the use of windows for harmonic analysis with the discrete Fourier transform", "authors": [{"first": "F", "middle": ["J"], "last": "Harris", "suffix": ""}], "year": 1978, "venue": "Proceedings of the IEEE", "link": "426548"}, "BIBREF3": {"title": "Spatial-frequency analysis in the perception of perspective depth", "authors": [{"first": "K", "middle": [], "last": "Kakai", "suffix": ""}, {"first": "L", "middle": ["H"], "last": "Finkel", "suffix": ""}], "year": 1997, "venue": "Network: Comput. Neural Syst", "link": "122269006"}, "BIBREF4": {"title": "Indoor vs outdoor classification of consumer photographs using low-level and semantic features", "authors": [{"first": "J", "middle": [], "last": "Luo", "suffix": ""}, {"first": "A", "middle": [], "last": "Savakis", "suffix": ""}], "year": 2001, "venue": "2001 Int Conf on Image Processing", "link": "14489330"}, "BIBREF5": {"title": "Automatic content extraction of filled form images based on clustering component block projection vectors", "authors": [{"first": "H", "middle": ["C"], "last": "Peng", "suffix": ""}, {"first": "X", "middle": [], "last": "He", "suffix": ""}, {"first": "F", "middle": [], "last": "Long", "suffix": ""}], "year": 2004, "venue": "IS&T/SPIE 16th Annual Symp. on Electronic Imaging, Conf. on Document Recognition and Retrieval XI", "link": "43064353"}, "BIBREF6": {"title": "Partitioning sparse matrices with eigenvectors of graph", "authors": [{"first": "A", "middle": [], "last": "Pothen", "suffix": ""}, {"first": "H", "middle": ["D"], "last": "Simon", "suffix": ""}, {"first": "K", "middle": ["P"], "last": "Liou", "suffix": ""}], "year": 1990, "venue": "SIAM Journal of Matrix Anal. Appl", "link": "8978853"}, "BIBREF7": {"title": "From blobs to boundary edges: evidence for time and spatial scale dependent scene recognition", "authors": [{"first": "P", "middle": ["G"], "last": "Schyns", "suffix": ""}, {"first": "A", "middle": [], "last": "Oliva", "suffix": ""}], "year": 1994, "venue": "Psychol. Sci", "link": "145641722"}, "BIBREF8": {"title": "Normalized cuts and image segmentation", "authors": [{"first": "J", "middle": [], "last": "Shi", "suffix": ""}, {"first": "Malik", "middle": [], "last": "", "suffix": ""}, {"first": "J", "middle": [], "last": "", "suffix": ""}], "year": 2000, "venue": "IEEE Trans. PAMI", "link": "177653"}, "BIBREF9": {"title": "Statistics of natural image categories", "authors": [{"first": "A", "middle": [], "last": "Torralba", "suffix": ""}, {"first": "A", "middle": [], "last": "Oliva", "suffix": ""}], "year": 2003, "venue": "Network: Comput. Neural Syst", "link": null}, "BIBREF10": {"title": "Image classification for content-based indexing", "authors": [{"first": "A", "middle": [], "last": "Vailaya", "suffix": ""}, {"first": "M", "middle": ["A F"], "last": "Figueiredo", "suffix": ""}, {"first": "A", "middle": ["K"], "last": "Jain", "suffix": ""}, {"first": "H", "middle": ["J"], "last": "Zhang", "suffix": ""}], "year": 2001, "venue": "IEEE Trans. on Image Processing", "link": "9140319"}, "BIBREF11": {"title": "Modelling the power spectra of natural images: statistics and information", "authors": [{"first": "A", "middle": [], "last": "Van Der Schaaf", "suffix": ""}, {"first": "J", "middle": ["H"], "last": "Van Hateren", "suffix": ""}], "year": 1996, "venue": "Vision Research", "link": "18823051"}, "BIBREF12": {"title": "Information Retrieval (2nd Ed.), (www.dcs.gla.ac.uk/Keith/Preface.html) Butterworths", "authors": [{"first": "K", "middle": [], "last": "Van Rijsbergen", "suffix": ""}], "year": 1979, "venue": "", "link": null}, "BIBREF13": {"title": "Clustering gene expression data using a graph-theoretic approach: an application of minimum spanning tree", "authors": [{"first": "Y", "middle": [], "last": "Xu", "suffix": ""}, {"first": "V", "middle": [], "last": "Olman", "suffix": ""}, {"first": "D", "middle": [], "last": "Xu", "suffix": ""}], "year": 2002, "venue": "Bioinformatics", "link": "2766366"}, "BIBREF14": {"title": "A scheme for visual feature based image indexing", "authors": [{"first": "H", "middle": ["J"], "last": "Zhang", "suffix": ""}, {"first": "D", "middle": [], "last": "Zhong", "suffix": ""}], "year": 1995, "venue": "Proc. SPIE Conf. on Storage and Retrieval for Image and Video Databases", "link": "64571006"}}, "ref_entries": {}}
{"paper_id": "8338948", "_pdf_hash": "3560796053266d7eb436166516243d580540ea5a", "abstract": [{"section": "Abstract", "text": "Using a fast silicon strip detector, a multi-frame acquisition scheme was implemented to perform energy-dispersive X-ray magnetic circular dichroism at the iron K-edge in pulsed high magnetic fields. The acquisition scheme makes use of the entire field pulse. The quality of the signal obtained from samples of ferrimagnetic erbium iron garnet allows for quantitative evaluation of the signal amplitude. Below the compensation point, two successive field-induced phase transitions and the reversal of the net magnetization of the iron sublattices in the intermediate phase were observed.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "The development of X-ray magnetic circular dichroism (XMCD) in pulsed magnetic fields (PMF) (Mathon et al., 2007) has significantly increased the field range accessible for XMCD studies from the limits of current superconducting magnets to fields of 30 T and beyond. The elemental and orbital selectivity of XMCD make it an important tool for studying the microscopic physics of magnetism and magnetic phase transitions at high fields. Recent examples of scientific applications include the study of magnetic-field-induced valence transitions (Matsuda et al., 2009 ) and magneto-structural effects (Sikora et al., 2009) .", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "Two different acquisition schemes are currently used to perform XMCD studies in PMF: in energy-scanning XMCD a series of field pulses is performed at each energy, using fast photodiodes and amplifiers capable of following the magnetic field pulse to detect the signal. This provides excellent consistency of the magnetic field dependence, while the energy spectra are constructed point by point. In energy-dispersive (ED) XMCD a focusing polychromator is used to introduce a correlation between the propagation direction and the photon energy. Using a position-sensitive detector the XMCD spectra are acquired simultaneously, resulting in excellent quality and resolution of the energy spectra. Up to now, however, ED-XMCD in PMF has been limited to the acquisition of one detector frame around peak field.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "The present paper describes a multi-frame acquisition scheme for ED-XMCD. A series of spectra is acquired during the field pulse, thus combining the high quality of the energy spectra usually obtained in ED-XMCD with the consistency of the field dependence achieved in energy-scanning XMCD. The method was used to detect the weak XMCD signal at the Fe K-edge in ferrimagnetic erbium iron garnet (ErIG; Er 3 Fe 5 O 12 ). The quality of the spectra and of the field dependence of the XMCD amplitude allow for a quantitative evaluation of the Fe K-edge signal amplitude for the study of the Fe sublattice magnetization.", "cite_spans": [], "ref_spans": []}, {"section": "Experimental set-up", "text": "The experiments were performed at the energy-dispersive X-ray absorption spectroscopy beamline ID24 (Pascarelli et al., 2006) at the European Synchrotron Radiation Facility. Fig. 1(a) shows the beamline layout.", "cite_spans": [], "ref_spans": [{"start": 174, "end": 183, "text": "Fig. 1(a)", "ref_id": "FIGREF0"}]}, {"section": "Experimental set-up", "text": "The beam from an undulator source is focused vertically onto the detector by a first mirror (VFM), which also acts as a filter to reject higher harmonics and to reduce the heat load on the optics further downstream. A second mirror (HFM) focuses the beam horizontally, creating the divergence necessary to illuminate the polychromator and to obtain the desired spectral bandwidth. An ideally elliptically bent Si (111) polychromator crystal (PC) then refocuses the beam horizontally on the sample while introducing a correlation between the propagation direction and the photon energy. Finally, a position-sensitive detector (PSD) makes use of the energy-direction correlation to simultaneously acquire the energy dependence of the transmitted intensity. In order to generate light of circular polarization for the XMCD measurements over a large bandwidth a diamond (111) quarter-wave plate (QWP) is used in a quasi non-dispersive setting with the polychromator (Pizzini et al., 1998) . The miniature pulsed magnet system (M) consists of a liquidnitrogen-cooled coil reaching fields of 30 T and an independent He sample cryostat of the flow type covering sample temperatures from 5 K to 250 K. The coil is wound from Cu:Ag wire in two concentric parts with a gap for internal cooling in order to increase the pulse repetition rate. The magnet is energized through a bipolar thyristor-switched capacitive storage pulsed power supply, commercially available from Metis (http://www.metis.be/). A detailed description of the miniature pulsed magnet system is found by van der Linden et al. (2008) .", "cite_spans": [], "ref_spans": []}, {"section": "Experimental set-up", "text": "For the PSD we used the 'Quantum Detectors Ultra System' Si-strip detector, developed by the STFC (Science and Technology Facilities Council, http://www.stfc.ac.uk/) and commercially available through Quantum Detectors (http:// www.quantumdetectors.com/). The detector consists of a 300 mm-thick back-illuminated Si sensor with a linear array of 512 strips of pitch 50 mm and a usable strip length of 1.7 mm. The absorption at the Fe K-edge at 7.112 keV is about 99.8%. The detector strips are wire bonded directly to four X2CHIP readout application-specific integrated circuits. The X2CHIP contains 128 integrating amplifiers, each with four storage capacitors. The amplifier voltages are sampled at the beginning and end of the integration period on pairs of capacitors, and the voltages are then multiplexed onto the analogue outputs. Multiplexing is controlled by shift-registers and is configured as four separate 32-channel blocks. During the read-out cycle the amplifier voltages are stored on different capacitors so that readout and integration periods can be overlapped. The back-end data electronics removes common mode noise artifacts by taking a difference measurement between the X2CHIP outputs for the voltage sampled at the beginning and end of integration. This difference is then digitized by 16-bit 1 MHz analog-to-digital converters (ADCs). The output data from the ADCs are fed into a fieldprogrammable gate array which handles formatting of the data and transfer to a host by a 1 Gbit Ethernet connection. Our version of the detector is software limited (for compatibility with existing beamline systems) to recording a sequence of a maximum of 1500 frames. The detector can be set with exposure times ranging from 2 ms to 65 ms, has a fixed readout time of 50 ms per frame and a maximum repetition rate of 20 kHz. For integration with other beamline hardware the detector integration/readout is operated in an external trigger configuration with a trigger latency of 40 ns and a trigger jitter of AE 5 ns. However, the system can also be placed into a selftriggered mode. After completion of each sequence the data are transferred to a device server where they are recovered by the beamline control software.", "cite_spans": [], "ref_spans": []}, {"section": "Experimental set-up", "text": "Samples were small single crystals of ErIG oriented by Laue backscattering and mechanically polished with the surfaces perpendicular to the crystallographic (100) direction to a thickness of about 28 mm, resulting in an absorption step of 2.0 at the Fe K-edge. The samples were sandwiched between two 250 mm-thick Si plates with holes of diameter 500 mm, resulting in a free-standing sample in the area illuminated by the beam.", "cite_spans": [], "ref_spans": []}, {"section": "Experimental set-up", "text": "3. Multi-frame acquisition Fig. 1(b) shows the electronics used to control the experiment and the trigger chain for the detector.", "cite_spans": [], "ref_spans": [{"start": 27, "end": 36, "text": "Fig. 1(b)", "ref_id": "FIGREF0"}]}, {"section": "Experimental set-up", "text": "The charging and triggering of the power supply (Metis) are carried out via the beamline control software, as detailed by Mathon et al. (2007) . The signal from the pick-up coil is recorded by an internally developed fast data acquisition card (MUSST), and serves to obtain the temporal profile of the field pulse through integration of the pick-up voltage (Fig. 1a) , as well as to generate a trigger for the delay and frame generators to synchronize the PSD to the field pulse. The trigger signal is passed through a delay generator (Stanford DG535) and then starts a pulse train generated by a Berkeley Nucleonics Corporation BNC 555 pulse generator to trigger the detector for the desired number of frames.", "cite_spans": [], "ref_spans": [{"start": 357, "end": 366, "text": "(Fig. 1a)", "ref_id": "FIGREF0"}]}, {"section": "Experimental set-up", "text": "In the present experiment the XMCD signal was acquired at fixed left-or right-circular polarization while flipping the magnetic field. Each single acquisition results in an (n \u00c2 m) array of intensities, where n and m are the frame and pixel indices, respectively. A typical XMCD acquisition requires about 50 to 350 pairs of positive and negative magnetic field pulses. In order to obtain the XMCD spectra from the arrays of raw data, the series of vectors corresponding to each frame index was then processed using the scheme outlined by Mathon et al. (2004) , which eliminates the need to record (the energy dependence of) the incident intensity.", "cite_spans": [], "ref_spans": []}, {"section": "Experimental set-up", "text": "For cases in which the maximum detector frame rate of 20 kHz is too slow to precisely follow the field dependence of the XMCD signal, such as for example for the study of phase Metis: thyristor-switched capacitive storage pulsed power supply; minicoil: miniature pulsed magnet system; MUSST: fast data acquisition card; delay: Stanford DG535 delay generator; pulse-train: Berkeley Nucleonics Corporation BNC 555 pulse generator; PSD: Quantum Detectors 'Ultra' Si strip detector; spec: beamline control software.", "cite_spans": [], "ref_spans": []}, {"section": "Experimental set-up", "text": "transitions, two (x) acquisition series with pulse trains shifted by half (1/x) of the period can be acquired separately and then interleaved to increase the number of points in a field dependence. Here, two pulse trains with a period of 60 ms and an exposure time of 30 ms were interleaved (Fig. 2b) , resulting in the acquisition windows shown in Fig. 2(a) as red and green boxes. The period and exposure time were chosen as a compromise between the statistics per frame and the desired resolution. Fig. 3(a) shows the normalized absorption in ErIG at 65 K taken at the beamline ID24 (points) along with an ambient temperature spectrum from a powder sample recorded at beamline BM29 (line) that was used to calibrate the energy scale of the PSD. Fig. 3(b) shows the XMCD spectra obtained in two series of 350 pairs of positive and negative field pulses for each set of acquisitions. The whole energy range is affected by a floor of spatial noise, whereas the difference in the noise level below and above the absorption edge is mainly due to photon count statistics. The flux after the sample was estimated to be 4 \u00c2 10 8 and 5 \u00c2 10 7 photons stripe \u00c01 s \u00c01 for energies below and above the edge, respectively (note that the profile of the incident flux is not flat over the energy spectrum). Fig. 3 (c) once more shows the corresponding acquisition windows for reference. In the present experiment the miniature coil was operated with a repetition rate of approximately 2 pulses min \u00c01 and the entire data set was acquired in just under 12 h.", "cite_spans": [], "ref_spans": [{"start": 291, "end": 300, "text": "(Fig. 2b)", "ref_id": "FIGREF3"}, {"start": 349, "end": 358, "text": "Fig. 2(a)", "ref_id": "FIGREF3"}, {"start": 501, "end": 510, "text": "Fig. 3(a)", "ref_id": "FIGREF5"}, {"start": 748, "end": 757, "text": "Fig. 3(b)", "ref_id": "FIGREF5"}, {"start": 1295, "end": 1301, "text": "Fig. 3", "ref_id": "FIGREF5"}]}, {"section": "Results", "text": "The experiments were carried out on samples of ErIG which crystallizes in the cubic garnet structure. The cations are located at the centers of oxygen polyhedra with different symmetries. Per formula unit, two Fe occupy sites of octahedral and three Fe occupy sites of tetrahedral symmetry, whereas three Er are in a dodecahedral environment. Each site further occurs in different orientations within the unit cell. The cations interact magnetically via an antiferromagnetic exchange over the oxygen anions, where the relative strength of the interaction is determined mainly by the bond angles and distances. The antiferromagnetic interaction between the tetrahedral and octahedral Fe sites is strongest and remains unaffected up to high temperatures and very high applied fields. The interactions between the Fe sites and the Er sites are, however, much weaker and the fields available in the present experiment are comparable with the corresponding molecular field. In this context the system can thus be approximately described as a two-sublattice ferrimagnet (Clark & Callen, 1968) temperature T comp . Below T comp the system undergoes two successive phase transitions as a function of the applied field (Nakao et al., 1986) . Below H l the Er sublattice is aligned with the field while the net Fe moment is opposite; between H l and H u the Er and Fe moments form a canted phase in which the net Fe magnetization undergoes a continuous reversal while the Er spins are canted away from the applied field; and above H u both sublattices become aligned with the external field.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "In the present experiments the beam and the magnetic field were parallel to the crystallographic (100) direction. The sample was cooled below the compensation point (T comp ' 79 K) at a temperature of 65 K. The XMCD signal visible in Fig. 3 coincides with the pre-peak which is attributed to the sites of tetrahedral symmetry (Kawamura et al., 1997; Maruyama & Kawamura, 2004) . For the interpretation we here make the simplifying assumption that the pre-edge signal is directly related to the tetrahedral Fe sites and thus to the net magnetization of Fe sublattices. At the main edge there is barely any XMCD signal visible with the available resolution. In the raw spectra in Fig. 3 a decrease, disappearance, reversal of sign and subsequent increase of the magnitude of the XMCD signal as a function of field are clearly observable. In order to plot the field dependence of the XMCD signal its amplitude was evaluated as the difference between the averages over the strips 174-176 and 178-180 in the raw spectra, which correspond to the minima and maxima centered at 7112.9 eV and 7114.2 eV, respectively. Fig. 4(a) shows the evolution of this amplitude during the magnetic field pulse, and Fig. 4(b) shows the resulting field dependence.", "cite_spans": [], "ref_spans": [{"start": 234, "end": 240, "text": "Fig. 3", "ref_id": "FIGREF5"}, {"start": 678, "end": 684, "text": "Fig. 3", "ref_id": "FIGREF5"}]}, {"section": "Results", "text": "Below $ 8.4 T the amplitude barely evolves with the field; at $ 8.4 T the amplitude starts to decrease, crosses zero and continues to decrease until it saturates around $ 25.5 T at a magnitude slightly lower than the low field value, and opposite in sign. The data clearly reflect the expected behavior for the Fe sublattice magnetization and the transition fields are in agreement with the phase diagram published by Nakao et al. (1986) . A more detailed description and interpretation of the scientific results will be given elsewhere (Strohm et al., 2011) .", "cite_spans": [], "ref_spans": []}, {"section": "Conclusion and outlook", "text": "We have implemented a multi-frame acquisition scheme to perform ED-XMCD in pulsed high magnetic fields. This detection scheme allows the entire field pulse to be followed and thus combines the high quality of the energy spectra obtained in the dispersive geometry with a good consistency of the field dependence. The multi-frame detection significantly increases the overall efficiency of energy-dispersive experiments in pulsed magnetic fields. At the moment the speed of the available detector system is limited to 20 kHz. It was shown that higher temporal resolution can nevertheless be obtained by interleaving several acquisition series when required. The multi-frame acquisition scheme was used to perform Fe K-edge XMCD in samples of ErIG. Up to now, most, if not all, XMCD experiments in pulsed fields have been performed at L-edges, where the signal is typically of the order of several percent. The possibility to quantitatively exploit the small Fe K-edge signal significantly enlarges the number of accessible subjects. In the future we expect to use other Kedges in the energy range compatible with ID24 and the Ultra System, in particular the K-edges of Mn, Co, Ni and Cu. For the L-edges in the accessible energy range we may hope to be able to detect even small induced moments. We have studied the field dependence of the Fe K-edge XMCD signal in ErIG, below the compensation point. The pre-peak signal, associated with the Fe sites of tetrahedral symmetry, allows two successive phase transitions to be identified and the reversal of the net magnetization of the Fe sublattices in the intermediate canted phase to be observed.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF6": {"title": "Multi-frame acquisition scheme 227", "authors": [{"first": "Cornelius", "middle": [], "last": "Strohm", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF7": {"title": "Figure 4", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF8": {"title": "XMCD at the Fe K-edge in Er 3 Fe 5 O 12 at 65 K. (a) Evolution of the XMCD amplitude (points) during the field pulse (dashed line). (b) Field dependence of the XMCD amplitude. Red and green color denote data taken in acquisition sequences with delays of 0 ms and 30 ms", "authors": [], "year": "", "venue": "", "link": null}}, "ref_entries": {"FIGREF0": {"text": "Figure 1", "type": "figure"}, "FIGREF1": {"text": "layout (not to scale). ESRF: storage ring; US: undulator source; VFM: vertical focusing mirror; HFM: horizontal focusing mirror; PC: polychromator; QWP: quarter-wave plate; M: minicoil magnet system; PSD: position-sensitive detector. (b) Electronics and triggering.", "type": "figure"}, "FIGREF2": {"text": "between the net Fe and the Er moments. At high temperatures the Fe net magnetization dominates, and aligns with an applied field. With decreasing temperature the magnitude of the Er magnetization increases and both the Fe and Er sublattices reverse orientation with respect to the applied (low) field at the compensation research papers 226 Cornelius Strohm et al. Multi-frame acquisition scheme J. Synchrotron Rad. (2011). 18, 224-228", "type": "figure"}, "FIGREF3": {"text": "Figure 2", "type": "figure"}, "FIGREF4": {"text": "a) Line: typical magnetic field pulse; boxes: acquisition windows. (b) Trigger sequences (schematic) for the acquisition windows shown in (a). The two traces were offset for clarity. Red boxes and line: delay 0 ms; green boxes and line: delay 30 ms. The period of both trigger sequences is 60 ms. The combination of acquisition series with trigger sequences shifted by half a period allows the limitation of the maximum frame rate of the detector system to be overcome.", "type": "figure"}, "FIGREF5": {"text": "Figure 3 XMCD at the Fe K-edge in Er 3 Fe 5 O 12 at 65 K. (a) Normalized absorption. Points: data taken at ID24; line: reference spectrum for energy calibration recorded at BM29. (b) XMCD spectra. The spectra are offset by 0.005 for clarity. (c) Field pulse and acquisition windows corresponding to the spectra in (b). Red boxes and lines: delay 0 ms; green boxes and lines: delay 30 ms.", "type": "figure"}}}
{"paper_id": "8339153", "_pdf_hash": "1c542761da496b30ed22f337b419378edcf534c1", "abstract": [{"section": "Abstract", "text": "In this paper, we propose a novel way to include unsupervised feature selection methods in probabilistic taxonomy learning models. We leverage on the computation of logistic regression to exploit unsupervised feature selection of singular value decomposition (SVD). Experiments show that this way of using SVD for feature selection positively affects performances.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Taxonomies and, in general, networks of words connected with transitive relations are extremely important knowledge repositories for a variety of applications in natural language processing (NLP) and knowledge representation (KR). In NLP, taxonomies such as WordNet [17] are widely used in intermediate tasks such as word sense disambiguation (e.g. [1] ) and selectional preference induction (e.g., [25] ) as well as in final applications such as question answering (e.g., [4] ) and textual entailment recognition (e.g. [5] ). In KR, taxonomies as well as other word networks are the bulk of domain ontologies.", "cite_spans": [{"start": 266, "end": 270, "text": "[17]", "ref_id": "BIBREF16"}, {"start": 349, "end": 352, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 399, "end": 403, "text": "[25]", "ref_id": "BIBREF24"}, {"start": 473, "end": 476, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 520, "end": 523, "text": "[5]", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "Introduction", "text": "To be effectively used in NLP and KR applications, taxonomies and knowledge repositories have to be large or, at least, adapted to specific domains. Yet, even huge knowledge repositories such as WordNet [17] are extremely poor when used in specific domains such as the medical domain (see [29] ). Automatically creating, adapting, or extending existing knowledge repositories using domain texts is, then, a very important and active area. A large variety of methods have been proposed: ontology learning methods [16, 3, 19] in KR as well as knowledge harvesting methods in NLP such as [13, 21] . These learning methods use variants of the distributional hypothesis [12] or exploit some induced lexical-syntactic patterns (originally used in [26] ). The task is generally seen as a classification (e.g., [22, 27] ) or a clustering (e.g., [3] ) problem. This allows the use of machine learning models.", "cite_spans": [{"start": 203, "end": 207, "text": "[17]", "ref_id": "BIBREF16"}, {"start": 289, "end": 293, "text": "[29]", "ref_id": "BIBREF28"}, {"start": 512, "end": 516, "text": "[16,", "ref_id": "BIBREF15"}, {"start": 517, "end": 519, "text": "3,", "ref_id": "BIBREF2"}, {"start": 520, "end": 523, "text": "19]", "ref_id": "BIBREF18"}, {"start": 585, "end": 589, "text": "[13,", "ref_id": "BIBREF12"}, {"start": 590, "end": 593, "text": "21]", "ref_id": "BIBREF20"}, {"start": 665, "end": 669, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 741, "end": 745, "text": "[26]", "ref_id": "BIBREF25"}, {"start": 803, "end": 807, "text": "[22,", "ref_id": "BIBREF21"}, {"start": 808, "end": 811, "text": "27]", "ref_id": "BIBREF26"}, {"start": 837, "end": 840, "text": "[3]", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "Introduction", "text": "Yet, as any other machine learning problem, knowledge harvesting and ontology learning models exploit the above hypothesis to build feature spaces where instances, i.e., words as in [22] or word pairs as in [27] , are represented. These feature spaces are used to determine whether or not new word pairs coming from the text collection have to be included in existing knowledge repositories. Decision models are learnt * DISP University Rome \"Tor Vergata\" using existing knowledge repositories and then applied to new words or word pairs. Generally, these models use as features all the possible and relevant generalized contexts where words or word pairs can appear. For example, possible features in the word pair classification problem are \"is a\" and \"as well as\". Given the nature of the problem, these feature spaces can then be huge as they include all potential relevant features for a particular relation among words. Relevant features are not known in advance. Yet, large feature spaces can have negative effects on machine learning models such as increasing the computational load and introducing redundant or noisy features. Feature selection is the solution (see [11] ).", "cite_spans": [{"start": 182, "end": 186, "text": "[22]", "ref_id": "BIBREF21"}, {"start": 207, "end": 211, "text": "[27]", "ref_id": "BIBREF26"}, {"start": 1175, "end": 1179, "text": "[11]", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "Introduction", "text": "In this paper, we want to study how to improve performances of taxonomy learning methods by using feature selection. We focus on the probabilistic taxonomy learning model introduced by [27] as it uses existing taxonomies exploiting the transitivity of the isa relation. Leveraging on the particular model, we propose a novel way of using singular value decomposition (SVD) as unsupervised model for feature selection. In a nutshell, given the probabilistic model for taxonomy learning, we use SVD as a way to compute the pseudoinverse matrix needed in logistic regression. We will analyze if our method for using unsupervised feature selection positively affect performances.", "cite_spans": [{"start": 185, "end": 189, "text": "[27]", "ref_id": "BIBREF26"}], "ref_spans": []}, {"section": "Introduction", "text": "Before staring, in Sec. 2 we will shortly review methods for taxonomy learning and for feature selection. We motivate our choice of working within the probabilistic setting. In Sec. 3, as SVD is the core of our method, we will then introduce SVD as unsupervised feature selection model. In Sec. 4 we then describe how we introduced SVD as natural feature selector in the probabilistic taxonomy learning model introduced by [27] . To describe how we use SVD as natural feature selector, we will shortly review the logistic regression used to compute the taxonomy learning model. We will describe our experiments in Sec. 5. Finally, in Sec. 6, we will draw some conclusions and describe our future work.", "cite_spans": [{"start": 423, "end": 427, "text": "[27]", "ref_id": "BIBREF26"}], "ref_spans": []}, {"section": "Related work", "text": "Extracting knowledge bases from texts is one of the major goal of NLP and KR. These methods can give an important boost to knowledge-based systems. In this section we want to shortly analyze some of these methods in order to motivate our choice to work within an existing probabilistic model for learning taxonomies. We also review the more traditional models for super-vised and unsupervised feature selection.", "cite_spans": [], "ref_spans": []}, {"section": "Related work", "text": "The models for automatically extracting structured knowledge, such as taxonomies, from texts use variants of the distributional hypothesis [12] exploit some induced lexical-syntactic patterns (originally used in [26] ).", "cite_spans": [{"start": 139, "end": 143, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 212, "end": 216, "text": "[26]", "ref_id": "BIBREF25"}], "ref_spans": []}, {"section": "Related work", "text": "The distributional hypothesis is widely used in many approaches for taxonomy induction from texts. For example, it is used in [3] for populating lattices, i.e. graphs of a particular class, of formal concepts.", "cite_spans": [{"start": 126, "end": 129, "text": "[3]", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "Related work", "text": "Lexical syntactic patterns are also a source of relevant information for deciding whether or not a particular relation holds between two words. This approach has been widely used for detecting hypernymy relations such as in [13, 18] , for other ontological relations such as in [21] , or for more generic relations such as in [24, 28] . These learning models generally use the hypothesis that two words are related according to a particular relation if these often appear in specific text fragments.", "cite_spans": [{"start": 224, "end": 228, "text": "[13,", "ref_id": "BIBREF12"}, {"start": 229, "end": 232, "text": "18]", "ref_id": "BIBREF17"}, {"start": 278, "end": 282, "text": "[21]", "ref_id": "BIBREF20"}, {"start": 326, "end": 330, "text": "[24,", "ref_id": "BIBREF23"}, {"start": 331, "end": 334, "text": "28]", "ref_id": "BIBREF27"}], "ref_spans": []}, {"section": "Related work", "text": "Despite the wide range of models for taxonomy learning, only very few exploit the structure of existing taxonomies. The task is seen as building taxonomies from scratch. In [3] , for example, lattices and the related taxonomies are the target. Yet, existing taxonomies may be used to drive the process of building new taxonomies. In [19] , WordNet [17] and WordNet glosses are used to drive the construction of domain specific ontologies. In [22] , taxonomies are augmented exploiting their structure. Inserting a new word in the network is seen as a classification problem. The target classes are the nodes of the existing hierarchy. The distributional description of the word as well as the existing taxonomy structure is used to make the decision. This model is purely distributional. In [27] , a probabilistic model exploiting existing taxonomies is introduced. This model is purely based on lexicalsyntactical patterns. Also in this case, the insertion of a new word in the hierarchy is seen as a binary classification problem. Yet, the classification decision is taken over a pair of words, i.e., a word and its possible generalization. The probabilistic classifier should decide if this pair belongs or not to the taxonomy.", "cite_spans": [{"start": 173, "end": 176, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 333, "end": 337, "text": "[19]", "ref_id": "BIBREF18"}, {"start": 348, "end": 352, "text": "[17]", "ref_id": "BIBREF16"}, {"start": 442, "end": 446, "text": "[22]", "ref_id": "BIBREF21"}, {"start": 791, "end": 795, "text": "[27]", "ref_id": "BIBREF26"}], "ref_spans": []}, {"section": "Related work", "text": "The probabilistic taxonomy learning models has at least two advantages with respect to the other models. The first advantage is that it coherently uses existing taxonomies in the expansion phase. Both existing and new information is modeled in the same probabilistic way. The second advantage is that classification problem is binary, i.e., a word pair belongs or not to the taxonomy. This allows to build a unique binary classifier. This is not the case for models such as the one of [22] , where we need a multi-class classifier or a set of binary classifiers. For these two reasons, we are using the probabilistic taxonomy learning setting for our study.", "cite_spans": [{"start": 485, "end": 489, "text": "[22]", "ref_id": "BIBREF21"}], "ref_spans": []}, {"section": "Related work", "text": "Yet, in applications involving texts such as taxonomy learning, machine learning models are exposed to huge feature spaces. This has not always positive effects. A first important problem is that huge feature spaces require large computational and storage resources for applying machine learning models. A second problem is that more features not always result in better accuracies of learnt classification models. Many features can be noise. Feature selection, i.e., the reduction of the feature space offered to machine learners, is seen as a solution (see [11] ).", "cite_spans": [{"start": 559, "end": 563, "text": "[11]", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "Related work", "text": "There is a wide range of feature selection models that can be classified in two main families: supervised and unsupervised. Supervised models directly exploit the class of the instances for determining if a feature is relevant or not. The idea is to select features that are highly correlated with final target classes. Information theoretic ranking criteria such as mutual information and information gain are often used (see [8] ). Unsupervised models are instead used when the information on classes of instances is not available at the training time or it is inapplicable such as in information retrieval. Straightforward and simple models for unsupervised feature selection can be derived from information retrieval weighting schemes, e.g., term frequency times inverse document frequency (tf * idf ). In this case, relevant features are respectively those appearing more often or those more selective, i.e., appearing in fewer instances.", "cite_spans": [{"start": 427, "end": 430, "text": "[8]", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "Related work", "text": "Feature selection models are also widely used in taxonomy learning. For example, attribute selection for building lattices of concepts in [3] is done applying specific thresholds on specific information measures on the attributes extracted from corpora. This models uses conditional probabilities, point-wise mutual information, and a selectional-preference-like measure as the one introduced in [25] .", "cite_spans": [{"start": 138, "end": 141, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 396, "end": 400, "text": "[25]", "ref_id": "BIBREF24"}], "ref_spans": []}, {"section": "Unsupervised Feature Selection with SVD", "text": "A very important way of unsupervised feature selection is the application of the SVD. As this is the bulk of our methodology we will review how SVD can be used for this purpose. SVD has been largely used in information retrieval for reducing the dimension of the document vector space [7] . SVD, originally, is a decomposition of a rectangular matrix. Given a generic rectangular n \u00d7 m matrix A, its singular value decomposition is A = U \u03a3V T where U is a matrix n \u00d7 r, V T is a r \u00d7 m and \u03a3 is a diagonal matrix r \u00d7 r. The diagonal elements of the \u03a3 are the singular values such as \u03b4 1 \u2265 \u03b4 2 \u2265 ... \u2265 \u03b4 r > 0 where r is the rank of the matrix A. For the decomposition, SVD exploits the linear combination of rows and columns of A.", "cite_spans": [{"start": 285, "end": 288, "text": "[7]", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "Unsupervised Feature Selection with SVD", "text": "There are different ways of using SVD as unsupervised feature reduction. An interesting way is to exploit its approximated computations, i.e. :", "cite_spans": [], "ref_spans": []}, {"section": "Unsupervised Feature Selection with SVD", "text": "where k is smaller than the rank r. The computation algorithm [10] allows to stop at a given k different from the real rank r. The property of the singular values, i.e., \u03b4 1 \u2265 \u03b4 2 \u2265 ... \u2265 \u03b4 r > 0, guarantees that the first k are bigger than the discarded ones. There is a direct relation between the informativeness of the i-th new dimension and the singular value \u03b4 i . High singular values correspond to dimensions of the new space where examples have more variability whereas low singular values determine dimensions where examples have a smaller variability (see [15] ). These latter dimensions can be then hardly used as efficient features in learning. The possibility of computing approximated versions of matrices gives a powerful method for feature selection and filtering as we can decide in advance how many features or, better, linear combination of original features we want to use.", "cite_spans": [{"start": 62, "end": 66, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 567, "end": 571, "text": "[15]", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "Probabilistic Taxonomy Learning and SVD", "text": "In this section we will firstly introduce the probabilistic model (Sec. 4.1) and, then, we will describe how SVD is used as feature selector in the logistic regression that estimates the probabilities of the model (Sec. 4.2). To describe this part we need to go in depth into the definition of the logistic regression and some ways of computing it.", "cite_spans": [], "ref_spans": []}, {"section": "Probabilistic model", "text": "In the probabilistic formulation [27] , the task of learning taxonomies from a corpus is seen as a maximum likelihood problem. The taxonomy is seen as a set T of assertions R over pairs R i,j . If R i,j is in T , i is a concept and j is one of its generalization (i.e., the direct or the indirect generalization). For example, R dog,animal \u2208 T describes that dog is an animal according to the taxonomy T .", "cite_spans": [{"start": 33, "end": 37, "text": "[27]", "ref_id": "BIBREF26"}], "ref_spans": []}, {"section": "Probabilistic model", "text": "The main probabilities are then: (1) the prior probability P (R i,j \u2208 T ) of an assertion R i,j to belong to the taxonomy T and (2) the posterior probability P (R i,j \u2208 T | \u2212 \u2192 e i,j ) of an assertion R i,j to belong to the taxonomy T given a set of evidences \u2212 \u2192 e i,j derived from the corpus. These evidences are derived from the contexts where the pair (i, j) is found in the corpus. The vector \u2212 \u2192 e i,j is a feature vector associated with a pair (i, j). For example, a feature may describe how many times i and j are seen in patterns like \"i as j\" or \"i is a j\". These among many other features are indicators of an is-a relation between i and j (see [13] ). Given a set of evidences E over all the relevant word pairs, the probabilistic taxonomy learning task is defined as the problem of finding a taxonomy T that maximizes the probability of having the evidences E, i.e.:", "cite_spans": [{"start": 656, "end": 660, "text": "[13]", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "Probabilistic model", "text": "In [27] , this maximization problem is solved with a local search. What is maximized at each step is the ratio between the likelihood P (E|T ) and the likelihood P (E|T ) where T = T \u222a N and N are the relations added at each step. This ratio is called multiplicative change \u2206(N ) and is defined as follows \u2206(N ) = P (E|T )/P (E|T ). The main innovation of the model in [27] is the possibility of adding at each step the best relation N = {R i,j } as well as R i,j with all the relations induced from R i,j , i.e., N = {R i,j } \u222a I(R i,j ) where I(R i,j ) are the relations induced using the existing taxonomy and R i,j . Given the taxonomy T and the relation R i,j , the", "cite_spans": [{"start": 3, "end": 7, "text": "[27]", "ref_id": "BIBREF26"}, {"start": 369, "end": 373, "text": "[27]", "ref_id": "BIBREF26"}], "ref_spans": []}, {"section": "Probabilistic model", "text": "We will experiment with our feature selection methodology in two different models:", "cite_spans": [], "ref_spans": []}, {"section": "Probabilistic model", "text": "flat: at each iteration step, a single relation is added, i.e. R i,j = arg max Ri,j \u2206(R i,j ) inductive: at each iteration step, a set of relations is added, i.e. I( R i,j ) where R i,j = arg max Ri,j \u2206(I(R i,j )).", "cite_spans": [], "ref_spans": []}, {"section": "Probabilistic model", "text": "The last important fact is that it is possible to demonstrate that", "cite_spans": [], "ref_spans": []}, {"section": "Probabilistic model", "text": "where k is a constant (see [27] ) that will be neglected in the maximization process. This last equation gives the possibility of using the logistic regression as it is. In the next sections we will see how SVD and the related feature selection can be used to compute the odds.", "cite_spans": [{"start": 27, "end": 31, "text": "[27]", "ref_id": "BIBREF26"}], "ref_spans": []}, {"section": "Exploiting SVD in Logistic Regression", "text": "We here show that the odds(R i,j ) in eq. 2 can be computed with logistic regression (Sec. 4.2.1). We then describe how we can compute logistic regression using a particular pseudo-inverse matrix (Sec. 4.2.2). Finally, we show that approximated pseudo-inverse matrices can be computed using SVD (Sec. 4.2.3).", "cite_spans": [], "ref_spans": []}, {"section": "Logistic Regression", "text": "Logistic Regression [6] is a particular type of statistical model for relating responses Y to linear combinations of predictor variables X. It is a specific kind of Generalized Linear Model (see [20] ) where its function is the logit function and the dependent variable Y is a binary or dichotomic variable which has a Bernoulli distribution. The dependent variable Y takes value 0 or 1. The probability that Y has value 1 is function of the regressors x = (1, x 1 , ..., x k ).", "cite_spans": [{"start": 20, "end": 23, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 195, "end": 199, "text": "[20]", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "Logistic Regression", "text": "The probabilistic taxonomy learner model introduced in the previous section falls in the category of probabilistic models where the logistic regression can be applied as R i,j \u2208 T is the binary dependent variable and \u2212 \u2192 e i,j is the vector of its regressors. In the rest of the section we will see how the odds, i.e., the multiplicative change, can be computed. We start from formally describing the Logistic Regression Model. Given the two stochastic variables Y and X, we can define as p the probability of Y to be 1 given that X=x, i.e.p = P (Y = 1|X = x) The distribution of the variable Y is a Bernoulli distribution. Given the definition of the logit(p) as logit(p) = ln ", "cite_spans": [], "ref_spans": []}, {"section": "Logistic Regression", "text": "where \u03b2 0 , \u03b2 1 , ..., \u03b2 k are called regression coefficients of the variables x 1 , ..., x k respectively. It is obviously trivial to determine the odds(R i,j ) related to the multiplicative change of the probabilistic taxonomy model. The odds, the ratio between the positive and the negative event, can be determined as follows:", "cite_spans": [], "ref_spans": []}, {"section": "Estimating Coefficients with Pseudoinverse", "text": "The remaining problem is how to estimate the regression coefficients. This estimation is done using the maximal likelihood estimation to prepare a set of linear equations using the above logit definition and, then, solving a linear problem. This will give us the possibility of introducing the necessity of determining a pseudo-inverse matrix where we will use the singular value decomposition and its natural possibility of performing feature selection. Once we have the regression coefficients, we have the possibility of estimating a probability P (R i,j \u2208 T | \u2212 \u2192 e i,j ) given any configuration of the values of the regressors \u2212 \u2192 e i,j , i.e., the observed values of the features. Let assume we have a multiset O of observations extracted from Y \u00d7 E where Y \u2208 {0, 1} and we know that some of them are positive observations (i.e., Y = 1) and some of them are negative observations (i.e., Y = 0). For each pair, the relative configuration \u2212 \u2192 e l \u2208 E appears at least once in O and can be determined using the maximal likelihood estimation P (Y = 1| \u2212 \u2192 e l ). Then, from the equation of the logit (Eq. 3), we have a linear equation system, i.e.:", "cite_spans": [], "ref_spans": []}, {"section": "Estimating Coefficients with Pseudoinverse", "text": "where Q is a matrix that includes a constant column of 1, necessary for the \u03b2 0 of the linear combination of the values of the regression. Moreover it includes the set of evidences, i.e. Q = (1, \u2212 \u2192 e 1 ... \u2212 \u2192 e m ).", "cite_spans": [], "ref_spans": []}, {"section": "Estimating Coefficients with Pseudoinverse", "text": "The set of equations in Eq. 5 are a particular case multiple linear regression [2] . As Q is a rectangular and singular matrix, the system (Eq.5) has no solution. This problem can be solved by the Moore-Penrose pseudoinverse Q + [23] . Then, we determine the re-", "cite_spans": [{"start": 79, "end": 82, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 229, "end": 233, "text": "[23]", "ref_id": "BIBREF22"}], "ref_spans": []}, {"section": "Computing Pseudoinverse with SVD", "text": "We finally reached the point where it is possible to explain our idea that is naturally using singular value decomposition (SVD) as feature selection in a probabilistic taxonomy learner. In previous sections we described how the probabilities of the taxonomy learner can be estimated using logistic regressions and we concluded that a way to determine the regression coefficients \u03b2 is computing the Moore-Penrose pseudoinverse Q + . It is possible to compute the MoorePenrose pseudoinverse using the SVD in the following way [23] . Given an SVD decomposition of the matrix Q = U \u03a3V T the pseudo-inverse matrix is:", "cite_spans": [{"start": 525, "end": 529, "text": "[23]", "ref_id": "BIBREF22"}], "ref_spans": []}, {"section": "Computing Pseudoinverse with SVD", "text": "The diagonal matrix \u03a3 + is a matrix r \u00d7 r obtained calculating the reciprocals of the singular value of \u03a3.", "cite_spans": [], "ref_spans": []}, {"section": "Computing Pseudoinverse with SVD", "text": "We have now our opportunity of using SVD as natural feature selector as we can compute different approximations of the pseudo-inverse matrix. The algorithm for computing SVD is iterative (Sec. 3). The firstly derived dimensions are those with higher singular value. We can then decide how many dimensions we want to use. The first k dimensions are more informative than the k + 1. We can consider different k in order to obtain different SVD as approximations of the original matrix (Eq. 1). We can define different approximations of the inverse matrix Q + as Q + k , i.e.:", "cite_spans": [], "ref_spans": []}, {"section": "Experimental Evaluation", "text": "In this section, we want to empirically explore whether our use of SVD feature selection positively affects performances of the probabilistic taxonomy learner. The best way of determining how a taxonomy learner is performing is to see if it can replicate an existing \"taxonomy\". We will experiment with the attempt of replicating a portion of WordNet [17] . In the experiments, we will address two issues: determining to what extent SVD feature selection affect performances of the taxonomy learner and determining if, for the probabilistic taxonomy learner, SVD is better than other simpler models for supervised and unsupervised feature selection. We will explore the effects on both the flat and the inductive probabilistic taxonomy learner.", "cite_spans": [{"start": 351, "end": 355, "text": "[17]", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "Experimental Evaluation", "text": "In the rest of the section we will describe: the experimental set-up (Sec. 5.1) and the results of the experiments in term of performance (Sec. 5.2).", "cite_spans": [], "ref_spans": []}, {"section": "Experimental Set-up", "text": "To completely define the experiments we need to describe some issues: how we defined the taxonomy to replicate, which corpus we have used to extract evidences for pairs of words, which feature space we used, and, finally, the feature selection models we compared against. As target taxonomy we selected a portion of WordNet 2 [17] . Namely, we started from the 44 concrete nouns divided in 3 classes: animal, artifact, and vegetable. For each word w, we selected the synset s w that is compliant with the class it belongs to. We then obtained a set S of synsets. We then expanded the set to S adding the siblings (i.e., the coordinate terms) for each synset in S. The set S contains 265 coordinate terms plus the 44 original concrete nouns. For each element in S we collected its hypernyms, obtaining the set H. We then removed from the set H the 4 topmosts: entity, unit, object, and whole. The set H contains 77 hypernyms. For the purpose of the experiments we both derived from the previous sets a taxonomy T and produced a set of negative examples T . The two sets have been obtained as follows. The taxonomy T is the portion of WordNet implied by O = H \u222a S , i.e. T contains all the (s, h) \u2208 O \u00d7 O that are in WordNet and T contains all the (s, h) \u2208 O \u00d7 O that are not in WordNet. We have 5108 positive pairs in T and 52892 negative pairs in T . 2 We used the version 3.0", "cite_spans": [{"start": 326, "end": 330, "text": "[17]", "ref_id": "BIBREF16"}, {"start": 1351, "end": 1352, "text": "2", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Experimental Set-up", "text": "We then produced two experimental settings: a natural and an artificial one. In the natural setting we used only positive pairs in the training set. This is the natural situation when augmenting existing taxonomies. Only positive word pairs can be derived from existing taxonomies. Yet, negative pairs cannot. In the artificial setting we used both positive and negative examples.", "cite_spans": [], "ref_spans": []}, {"section": "Experimental Set-up", "text": "To obtain the training and the testing sets, we randomly divided the set T \u222a T in two parts T tr and T ts , respectively, of 70% and 30% of the original T \u222a T .", "cite_spans": [], "ref_spans": []}, {"section": "Experimental Set-up", "text": "As corpus we used ukWaC [9] . This is a web extracted corpus of about 2700000 web pages containing more than 2 billion words. The corpus contains documents of different topics such as web, computers, education, public sphere, etc.. It has been largely demonstrated that the web documents are good models for natural language [14] .", "cite_spans": [{"start": 24, "end": 27, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 325, "end": 329, "text": "[14]", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "Experimental Set-up", "text": "As the focus of the paper is the analysis of the effect of the SVD feature selection, we used as feature spaces both n-grams and bag-of-words. Out of the T \u222a T , we selected only those pairs that appeared at a distance of at most 3 tokens. Using this 3 tokens, we generated two spaces: (1) bag-of-word and (2) the bigram space that contains bigrams and monograms. For the purpose of this experiment, we used a reduced stop list as classical stop words as punctuation, parenthesis, the verb to be are very relevant in the context of features for learning a taxonomy.", "cite_spans": [], "ref_spans": []}, {"section": "Experimental Set-up", "text": "Finally, we want define the feature selection models we compared against. As unsupervised feature selection models we used the term frequency times the inverse document frequency (tf*idf ). Instances \u2212 \u2192 e have the role of the documents. As supervised feature selection models we used the mutual information (mi). For all the feature selection models, we selected the first k features. Finally, we used a manual feature selection model based on the Heart's patterns [13] . In this model that we call manual, we used as features only the classical Hearst's patterns.", "cite_spans": [{"start": 466, "end": 470, "text": "[13]", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "Results", "text": "In the first set of experiments we want to focus on the issue whether or not performances of the proba-bilistic taxonomy learner is positively affected by the proposed feature selection model based on the singular value decomposition. We then determined the performance with respect to different values of k. This latter represents the number of surviving dimensions where the pseudo-inverse is computed. The features of this experiment are unigrams derived from a 3-sizedwindow. Punctuation has been considered. Figures 1 plots the accuracy of the probabilistic learner with respect to the size of the feature set, i.e. the number k of single values considered for computing the pseudoinverse matrix. To determine if the effect of the feature selection is preserved during the iteration of the local search algorithm, we report curves at different sizes of the set of added pairs. Curves are reported for both the flat model and the inductive model. The flat algorithm adds one pair at each iteration. Then, we reported curves for 40 and 80 added pairs. The curves show that accuracy doesn't increase after a dimension of k=400. For the inductive model we report the accuracies for around 40, 80, 130 added pairs. The optimal dimension of the feature space seems to be around 500 as after that value performances decrease or stay stable. SVD feature selection has then a positive effect for both the flat and the inductive probabilistic taxonomy learners. This has beneficial effects both on the performances and on the computation time.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "In the second set of experiments we want to determine whether or not SVD feature selection for the probabilistic taxonomy learner behaves better than other feature selection models. We then fixed k to 600 both for the SVD selection model and for the other feature selection models. In this experiments, the original feature space is the bigram space. Figure 2 shows results. Curves report accuracies of the different models after n added pairs. In the natural setting, we compared our model against the tf * idf and the manual feature selection. Our SVD model outperforms both models of feature selection. The same happened against mutual information (M I) in the artificial setting. Our SVD way of selecting features seems to be very effective.", "cite_spans": [], "ref_spans": [{"start": 351, "end": 359, "text": "Figure 2", "ref_id": "FIGREF2"}]}, {"section": "Conclusions and Future Work", "text": "We presented a model to naturally introduce SVD feature selection in a probabilistic taxonomy learner. The method is effective as allows the designing of better probabilistic taxonomy learners. We still need to explore whether or not the positive effect of SVD feature selection is preserved in more complex feature spaces such as syntactic feature spaces as those used in [27] .", "cite_spans": [{"start": 373, "end": 377, "text": "[27]", "ref_id": "BIBREF26"}], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Word sense disambiguation using conceptual density", "authors": [{"first": "E", "middle": [], "last": "Agirre", "suffix": ""}, {"first": "G", "middle": [], "last": "Rigau", "suffix": ""}], "year": 1996, "venue": "Proc. of the 16th COLING", "link": "6012701"}, "BIBREF1": {"title": "Variance estimation of linear regression coefficients in complex sampling situation", "authors": [{"first": "D", "middle": [], "last": "Caron", "suffix": ""}, {"first": "W", "middle": [], "last": "Hospital", "suffix": ""}, {"first": "P", "middle": ["N"], "last": "Corey", "suffix": ""}], "year": 1988, "venue": "Sampling Error: Methodology, Software and Application", "link": "6825182"}, "BIBREF2": {"title": "Learning concept hierarchies from text corpora using formal concept analysis", "authors": [{"first": "P", "middle": [], "last": "Cimiano", "suffix": ""}, {"first": "A", "middle": [], "last": "Hotho", "suffix": ""}, {"first": "S", "middle": [], "last": "Staab", "suffix": ""}], "year": 2005, "venue": "JAIR", "link": "6168648"}, "BIBREF3": {"title": "Using and extending wordnet to support question-answering", "authors": [{"first": "P", "middle": [], "last": "Clark", "suffix": ""}, {"first": "C", "middle": [], "last": "Fellbaum", "suffix": ""}, {"first": "J", "middle": [], "last": "Hobbs", "suffix": ""}], "year": 2008, "venue": "Proc. 4th GWC", "link": "14641829"}, "BIBREF4": {"title": "Measuring the semantic similarity of texts", "authors": [{"first": "C", "middle": [], "last": "Corley", "suffix": ""}, {"first": "R", "middle": [], "last": "Mihalcea", "suffix": ""}], "year": 2005, "venue": "Proc. of the ACL Workshop on Empirical Modeling of Semantic Equivalence and Entailment", "link": "4948322"}, "BIBREF5": {"title": "The regression analysis of binary sequences", "authors": [{"first": "D", "middle": ["R"], "last": "Cox", "suffix": ""}], "year": 1958, "venue": "JRSS,B", "link": "202590023"}, "BIBREF6": {"title": "Indexing by latent semantic analysis", "authors": [{"first": "S", "middle": [], "last": "Deerwester", "suffix": ""}, {"first": "S", "middle": ["T"], "last": "Dumais", "suffix": ""}, {"first": "G", "middle": ["W"], "last": "Furnas", "suffix": ""}, {"first": "T", "middle": ["K"], "last": "", "suffix": ""}, {"first": "R", "middle": [], "last": "Harshman", "suffix": ""}], "year": 1990, "venue": "Journal of the American Society for Information Science", "link": "61894598"}, "BIBREF7": {"title": "A divisive information-theoretic feature clustering algorithm for text classification", "authors": [{"first": "I", "middle": ["S"], "last": "Dhillon", "suffix": ""}, {"first": "S", "middle": [], "last": "Mallela", "suffix": ""}, {"first": "I", "middle": [], "last": "Guyon", "suffix": ""}, {"first": "A", "middle": [], "last": "Elisseeff", "suffix": ""}], "year": 2003, "venue": "Journal of Machine Learning Research", "link": "7827065"}, "BIBREF8": {"title": "Introducing and evaluating ukwac, a very large web-derived corpus of english", "authors": [{"first": "A", "middle": [], "last": "Ferraresi", "suffix": ""}, {"first": "E", "middle": [], "last": "Zanchetta", "suffix": ""}, {"first": "M", "middle": [], "last": "Baroni", "suffix": ""}, {"first": "S", "middle": [], "last": "Bernardini", "suffix": ""}], "year": 2008, "venue": "Proc. of the WAC4 Workshop at LREC", "link": "4847295"}, "BIBREF9": {"title": "Calculating the singular values and pseudo-inverse of a matrix", "authors": [{"first": "G", "middle": [], "last": "Golub", "suffix": ""}, {"first": "W", "middle": [], "last": "Kahan", "suffix": ""}], "year": 1965, "venue": "J Soc Ind Appl Math B Num Anal", "link": "18407786"}, "BIBREF10": {"title": "An introduction to variable and feature selection", "authors": [{"first": "I", "middle": [], "last": "Guyon", "suffix": ""}, {"first": "A", "middle": [], "last": "Elisseeff", "suffix": ""}], "year": 2003, "venue": "JMLR", "link": "379259"}, "BIBREF11": {"title": "Distributional structure", "authors": [{"first": "Z", "middle": [], "last": "Harris", "suffix": ""}], "year": 1964, "venue": "The Philosophy of Linguistics", "link": null}, "BIBREF12": {"title": "Automatic acquisition of hyponyms from large text corpora", "authors": [{"first": "M", "middle": ["A"], "last": "Hearst", "suffix": ""}], "year": 1992, "venue": "Proc. of the 15th CoLing", "link": "15763200"}, "BIBREF13": {"title": "The web as a baseline: Evaluating the performance of unsupervised web-based models for a range of nlp tasks", "authors": [{"first": "M", "middle": [], "last": "Lapata", "suffix": ""}, {"first": "F", "middle": [], "last": "Keller", "suffix": ""}], "year": 2004, "venue": "Proc. of the HLT-NAACL", "link": "9426034"}, "BIBREF14": {"title": "Web Data Mining: Exploring Hyperlinks, Contents, and Usage Data. Data-Centric Systems and Applications", "authors": [{"first": "B", "middle": [], "last": "Liu", "suffix": ""}], "year": 2007, "venue": "", "link": "22596877"}, "BIBREF15": {"title": "Ontology Learning for the Semantic Web", "authors": [{"first": "A", "middle": [], "last": "Medche", "suffix": ""}], "year": 2002, "venue": "Engineering and Computer Science. Kluwer International", "link": null}, "BIBREF16": {"title": "WordNet: A lexical database for English", "authors": [{"first": "G", "middle": ["A"], "last": "Miller", "suffix": ""}], "year": 1995, "venue": "Communications of the ACM", "link": "207846993"}, "BIBREF17": {"title": "Extraction de liens s\u00e9mantiques entre termes\u00e0 partir de corpus de textes techniques", "authors": [{"first": "E", "middle": [], "last": "Morin", "suffix": ""}], "year": 1999, "venue": "Facult\u00e9 des Sciences et de Techniques", "link": null}, "BIBREF18": {"title": "Learning domain ontologies from document warehouses and dedicated web sites", "authors": [{"first": "R", "middle": [], "last": "Navigli", "suffix": ""}, {"first": "P", "middle": [], "last": "Velardi", "suffix": ""}], "year": 2004, "venue": "Comput. Linguist", "link": "2453822"}, "BIBREF19": {"title": "Generalized linear models", "authors": [{"first": "J", "middle": ["A"], "last": "Nelder", "suffix": ""}, {"first": "R", "middle": ["W M"], "last": "Wedderburn", "suffix": ""}], "year": 1972, "venue": "JRSS,A", "link": "126123958"}, "BIBREF20": {"title": "Espresso: Leveraging generic patterns for automatically harvesting semantic relations", "authors": [{"first": "P", "middle": [], "last": "Pantel", "suffix": ""}, {"first": "M", "middle": [], "last": "Pennacchiotti", "suffix": ""}], "year": 2006, "venue": "Proc. of the 21st COLING and 44th Annual Meeting of the ACL", "link": "7463996"}, "BIBREF21": {"title": "Taxonomy learning: factoring the structure of a taxonomy into a semantic classification decision", "authors": [{"first": "V", "middle": [], "last": "Pekar", "suffix": ""}, {"first": "S", "middle": [], "last": "Staab", "suffix": ""}], "year": 2002, "venue": "Proc. of the 19th COLING", "link": "6517211"}, "BIBREF22": {"title": "A generalized inverse for matrices", "authors": [{"first": "R", "middle": [], "last": "Penrose", "suffix": ""}], "year": 1955, "venue": "Proc. Cambridge Philosophical Society", "link": "120106233"}, "BIBREF23": {"title": "Learning surface text patterns for a question answering system", "authors": [{"first": "D", "middle": [], "last": "Ravichandran", "suffix": ""}, {"first": "E", "middle": [], "last": "Hovy", "suffix": ""}], "year": 2002, "venue": "Proceedings of the 40th ACL Meeting", "link": "226541"}, "BIBREF24": {"title": "Selection and Information: A Class-Based Approach to Lexical Relationships", "authors": [{"first": "P", "middle": [], "last": "Resnik", "suffix": ""}], "year": 1993, "venue": "", "link": "116972934"}, "BIBREF25": {"title": "Computer-detectable semantic structures", "authors": [{"first": "H", "middle": ["R"], "last": "Robison", "suffix": ""}], "year": 1970, "venue": "Storage and Retrieval", "link": "28068242"}, "BIBREF26": {"title": "Semantic taxonomy induction from heterogenous evidence", "authors": [{"first": "R", "middle": [], "last": "Snow", "suffix": ""}, {"first": "D", "middle": [], "last": "Jurafsky", "suffix": ""}, {"first": "A", "middle": ["Y"], "last": "Ng", "suffix": ""}], "year": 2006, "venue": "ACL", "link": "14680675"}, "BIBREF27": {"title": "Scaling web-based acquisition of entailment relations", "authors": [{"first": "I", "middle": [], "last": "Szpektor", "suffix": ""}, {"first": "H", "middle": [], "last": "Tanev", "suffix": ""}, {"first": "I", "middle": [], "last": "Dagan", "suffix": ""}, {"first": "B", "middle": [], "last": "Coppola", "suffix": ""}], "year": 2004, "venue": "Proc. of the EMNLP", "link": "15455102"}, "BIBREF28": {"title": "Adapting wordnet to the medical domain using lexicosyntactic patterns in the ohsumed corpus", "authors": [{"first": "A", "middle": [], "last": "Toumouth", "suffix": ""}, {"first": "A", "middle": [], "last": "Lehireche", "suffix": ""}, {"first": "D", "middle": [], "last": "Widdows", "suffix": ""}, {"first": "M", "middle": [], "last": "Malki", "suffix": ""}], "year": 2006, "venue": "Proc. of the AICCSA", "link": "16025650"}}, "ref_entries": {"FIGREF1": {"text": "Fig. 1: Accuracy over different cuts with SVD of the feature space", "type": "figure"}, "FIGREF2": {"text": "Fig. 2: Comparison of different feature selection models", "type": "figure"}}}
{"paper_id": "8339451", "_pdf_hash": "ab3cbe6095bfe7543cfedb0489bbd7223509d721", "abstract": [{"section": "Abstract", "text": "Abstract The small heat shock protein aB-crystallin is a molecular chaperone that is induced by stress and protects cells by inhibiting protein aggregation and apoptosis. To identify novel transcriptional regulators of the aB-crystallin gene, we examined the aB-crystallin promoter for conserved transcription factor DNA-binding elements and identified a putative response element for the p53 tumor suppressor protein. Ectopic expression of wild-type p53 induced aBcrystallin mRNA and protein with delayed kinetics compared to p21. Additionally, the induction of aB-crystallin by genotoxic stress was inhibited by siRNAs targeting p53. Although the p53-dependent transactivation of an aB-crystallin promoter luciferase reporter required the putative p53RE, chromatin immunoprecipitation failed to detect p53 binding to the aB-crystallin promoter. These results suggested an indirect mechanism of transactivation involving p53 family members p63 or p73. DNp73 was dramatically induced by p53 in a TAp73-dependent manner, and silencing p73 suppressed the transcriptional activation of aB-crystallin by p53. Moreover, ectopic expression of DNp73a (but not other p73 isoforms) increased aB-crystallin mRNA levels in the absence of p53. Collectively, our results link the molecular chaperone aB-crystallin to the cellular genotoxic stress response via a novel mechanism of transcriptional regulation by p53 and p73.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "", "text": "Introduction aB-crystallin/HspB5 is a widely expressed member of the small heat shock protein (sHSP) family, which also includes Hsp27/HspB1 and HspB2/MKBP, defined by the presence of a conserved a-crystallin domain [1] . aB-crystallin promotes cell survival following its induction by cellular stressors, such as heat and reactive oxygen species (ROS), by inhibiting the aggregation of denatured or misfolded proteins and by increasing intracellular glutathione levels [2] [3] [4] [5] . More recently, aB-crystallin has been shown to inhibit apoptosis by suppressing caspase-3 activation and by sequestering pro-apoptotic effectors, such as Bax and Bcl-X s , in the cytoplasm, thereby conferring additional cytoprotection against cellular stress [6] [7] [8] [9] . HSF-1, lens epithelial derived growth factor (LEDGF)/p75 and the glucocorticoid receptor have been demonstrated to regulate the induction of aB-crystallin in response to hyperthermia, ROS and glucocorticoids [10] [11] [12] .", "cite_spans": [{"start": 216, "end": 219, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 470, "end": 473, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 474, "end": 477, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 478, "end": 481, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 482, "end": 485, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 747, "end": 750, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 751, "end": 754, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 755, "end": 758, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 759, "end": 762, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 973, "end": 977, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 978, "end": 982, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 983, "end": 987, "text": "[12]", "ref_id": "BIBREF11"}], "ref_spans": []}, {"section": "", "text": "We postulated that additional transcriptional regulators of the mammalian stress response might regulate aB-crystallin gene expression. Here, we report that the aB-crystallin gene is regulated by a novel mechanism involving multiple p53 family members. The p53 protein is a critical mediator of the cellular response to genotoxic stress and plays a fundamental role in tumor suppression, as evidenced by the Electronic supplementary material The online version of this article (doi:10.1007/s10549-009-0542-7) contains supplementary material, which is available to authorized users. frequent inactivation of the p53 pathway in a broad spectrum of tumors [13] . Classically, p53 inhibits tumor initiation by transcriptionally coordinating several cellular programs that prevent propagation of damaged genomes: cell cycle arrest, DNA repair, senescence and apoptosis. p53 biology has been dramatically revised with the discovery of additional p53 family members, p63 and p73. TAp63 and TAp73 have been shown to transactivate many p53 target genes [14] [15] [16] . Moreover, p63 and p73 are required for p53-dependent apoptosis and/or cell cycle arrest in some systems, and p73 can mediate these responses in the absence of p53 [17] [18] [19] . Through an alternative promoter, the p63 and p73 genes also express DN isoforms that lack the N-terminal transactivation domain. DNp63 and DNp73 act in a dominant negative fashion on p53 activity by competing for p53RE binding and on TAp63 and TAp73 activity through the formation of inactive heterotetramers [20, 21] . In light of their ability to inhibit p53, DN isoforms likely play an important role in tumor biology. Indeed, DNp73 expression enhances Ras-mediated transformation, counters p53-mediated apoptosis in development, and is expressed in several clinically aggressive tumor types [22] [23] [24] [25] [26] [27] . In addition to this antagonistic function, DNp63 and DNp73 appear to independently transactivate genes and induce cell cycle arrest or apoptosis [28] [29] [30] [31] . Alternative 3 0 splicing generates 3 p63 (a, b, c) and 8 p73 (a, b, c, f, d, h, g, g1) Cterminal isoforms [32, 33] . Additionally, p53 family members transcriptionally regulate each other to form overlapping positive and negative feedback loops [20, 34, 35] . The complexity of the p53 family transcriptional regulation network and its role in cancer are topics of intense investigation and have yet to be fully resolved.", "cite_spans": [{"start": 653, "end": 657, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 1044, "end": 1048, "text": "[14]", "ref_id": "BIBREF13"}, {"start": 1049, "end": 1053, "text": "[15]", "ref_id": "BIBREF14"}, {"start": 1054, "end": 1058, "text": "[16]", "ref_id": "BIBREF15"}, {"start": 1224, "end": 1228, "text": "[17]", "ref_id": "BIBREF16"}, {"start": 1229, "end": 1233, "text": "[18]", "ref_id": "BIBREF17"}, {"start": 1234, "end": 1238, "text": "[19]", "ref_id": "BIBREF18"}, {"start": 1550, "end": 1554, "text": "[20,", "ref_id": "BIBREF19"}, {"start": 1555, "end": 1558, "text": "21]", "ref_id": "BIBREF20"}, {"start": 1836, "end": 1840, "text": "[22]", "ref_id": "BIBREF21"}, {"start": 1841, "end": 1845, "text": "[23]", "ref_id": "BIBREF22"}, {"start": 1846, "end": 1850, "text": "[24]", "ref_id": "BIBREF23"}, {"start": 1851, "end": 1855, "text": "[25]", "ref_id": "BIBREF24"}, {"start": 1856, "end": 1860, "text": "[26]", "ref_id": "BIBREF25"}, {"start": 1861, "end": 1865, "text": "[27]", "ref_id": "BIBREF26"}, {"start": 2013, "end": 2017, "text": "[28]", "ref_id": "BIBREF27"}, {"start": 2018, "end": 2022, "text": "[29]", "ref_id": "BIBREF28"}, {"start": 2023, "end": 2027, "text": "[30]", "ref_id": "BIBREF29"}, {"start": 2028, "end": 2032, "text": "[31]", "ref_id": "BIBREF30"}, {"start": 2141, "end": 2145, "text": "[32,", "ref_id": "BIBREF31"}, {"start": 2146, "end": 2149, "text": "33]", "ref_id": "BIBREF32"}, {"start": 2280, "end": 2284, "text": "[20,", "ref_id": "BIBREF19"}, {"start": 2285, "end": 2288, "text": "34,", "ref_id": "BIBREF33"}, {"start": 2289, "end": 2292, "text": "35]", "ref_id": "BIBREF34"}], "ref_spans": []}, {"section": "", "text": "In this manuscript, we demonstrate that genotoxic stress induces aB-crystallin by a p53-dependent mechanism. Intriguingly, p53 activates aB-crystallin gene expression by an indirect mechanism that results in delayed induction of aB-crystallin compared to p21. Instead, p53 robustly induces DNp73, which in turn activates aB-crystallin gene expression. Taken together, our findings point to a novel link between aB-crystallin and genotoxic stress that is regulated by the cooperative actions of multiple p53 family members.", "cite_spans": [], "ref_spans": []}, {"section": "Materials and methods", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Cell culture", "text": "EJ-p53 cells (kind gift of Sam W. Lee, Harvard Medical School) were grown in DMEM (Invitrogen) supplemented with 10% FBS (Hyclone), 300 lg/ml G418 (Mediatech), 100 lg/ml hygromycin B (Mediatech), and 1% penicillin/ streptomycin/L-glutamine (Invitrogen). Tetracycline (1 lg/ml, Sigma-Aldrich) was added fresh to the media for every 3-4 days to maintain repression of p53 [36] . MCF-10A cells (ATCC) were grown in DMEM/F-12 (1:1 mixture, Invitrogen) supplemented with 5% horse serum (Invitrogen), 0.5 lg/ml hydrocortisone (Sigma-Aldrich), 100 ng/ml cholera toxin (Sigma-Aldrich), 10 lg/ml insulin (SigmaAldrich), 20 ng/ml EGF (Sigma-Aldrich), and 1% penicillin/streptomycin/L-glutamine. Phoenix cells (ATCC) were grown in DMEM supplemented with 10% FBS (Invitrogen) and 1% penicillin/streptomycin/L-glutamine. Doxorubicin (Sigma-Aldrich) was dissolved in DMSO.", "cite_spans": [{"start": 370, "end": 374, "text": "[36]", "ref_id": "BIBREF35"}], "ref_spans": []}, {"section": "Retrovirus production and infection", "text": "Retrovirus was produced in Phoenix cells and used to infect MCF-10A cells as previously described [37, 38] . Briefly, 2.5 9 10", "cite_spans": [{"start": 98, "end": 102, "text": "[37,", "ref_id": "BIBREF36"}, {"start": 103, "end": 106, "text": "38]", "ref_id": "BIBREF37"}], "ref_spans": []}, {"section": "Retrovirus production and infection", "text": "6 Phoenix cells were transfected with 5.45 lg pLXSN retroviral expression plasmid and 0.55 lg pMD2-VSV-G (a kind gift of Ronald DePinho, Harvard Medical School) using 50 ll 2.5 M CaCl 2 and 500 ll 29 HBS, pH 7.10 with 25 lM chloroquine (Sigma-Aldrich) in the media. Retrovirus production was carried out at 32\u00b0C, and EGF was added to 20 ng/ml in addition to polybrene after 0.45 lm-filtering. Retroviral supernatant was used to infect 300,000 MCF-10A cells in 6 cm dishes for 3-5 h, then fresh media was added.", "cite_spans": [], "ref_spans": []}, {"section": "Retrovirus production and infection", "text": "Site-directed mutagenesis Point mutations were made using the QuikChange Site Directed Mutagenesis kit (Stratagene) according to the manufacturer's protocol with the primers listed in Supplementary Table 1 . The coding sequence of wild-type p53 (GenBank NM_000546) in the pLXSN retroviral expression vector was mutated to R175H and R273H. The aBcrystallin/HspB2 promoter sequence in the pGL3 luciferase reporter vector was mutated at the 5 0 and 3 0 p53RE halfsites (the sequences of the putative wild-type and mutated p53 REs are shown in Fig. 2a Protein lysates were separated by size using SDS-PAGE and transferred to a PVDF membrane (Immobilon P, Millipore) using a semi-dry transfer apparatus. The membranes were blocked for 1 h at RT in TBS with 0.05% Tween-20 and 5% non-fat milk, incubated overnight at 4\u00b0C with the primary antibodies listed in Supplementary Table 2 , and then incubated with anti-mouse HRP-conjugated secondary antibody (Southern Biotech) for 1 h at RT. Proteins were detected by enhanced chemiluminescence (ECL) assay.", "cite_spans": [], "ref_spans": []}, {"section": "Retrovirus production and infection", "text": "RNA isolation, cDNA synthesis, and real-time PCR RNA was isolated with the RNeasy Plus Mini Kit (QIA-GEN). cDNA was made from 0.5 lg total RNA with the ReactionReady First Strand Synthesis Kit (SABiosciences) according to the manufacturer's protocol. cDNA was used as template for real-time PCR with 0.4 lM each primer using the RT 2 SYBR Green/ROX PCR Master Mix (SABiosciences). Commercially available primer sets listed in Supplementary Table 3 (RT  2 qPCR Primer Set for Human genes, SABiosciences) were used to amplify the following genes: CDKN1A (p21), CRYAB (aB-crystallin), GAPDH, HSPB1 (Hsp27), HSPB2 and TP53. Primer sequences obtained from the literature (Supplementary Table 4 ) were used to amplify TAp63, DNp63, TAp73, and DNp73 [39] .", "cite_spans": [{"start": 743, "end": 747, "text": "[39]", "ref_id": "BIBREF38"}], "ref_spans": []}, {"section": "Retrovirus production and infection", "text": "Reactions were carried out in triplicate in 384-Well Clear Optical Reaction Plates (Applied Biosystems) using a 7900HT Fast Real-Time PCR Machine (Applied Biosystems) with the following thermal cycling profile: 50\u00b0C 2 min, 95\u00b0C 10 min, 409 (95\u00b0C 15 s, 60\u00b0C 1 min with fluorescence detection). SDS 2.3 software (Applied Biosystems) generated cycle threshold (C t ) values that were converted to L values by the standard curve method followed by internal normalization to the GAPDH L value.", "cite_spans": [], "ref_spans": []}, {"section": "Retrovirus production and infection", "text": "Each fold-induction value reported is the mean of 3-6 independent experiments. siRNA oligo duplex transfection MCF-10A cells (878,000 cells in 6 cm dishes) were transfected with 100 nM ON-TARGETplus siRNA oligo duplexes targeting TP53 (Dharmacon, J-003329-14 and J-003329-15) or Non-Targeting siRNA Control #2 (Dharmacon, D-001810-02) with Oligofectamine transfection reagent (Invitrogen) according to the manufacturer's protocol. EJ-p53 cells (100,000 cells per well in 6-well plates) were transfected with 5 pmol siRNA oligo duplexes using 7.5 ll Lipofectamine RNAiMAX (Invitrogen) according to the manufacturer's protocol. Targeting sequences for TAp73, DNp73, and panp73 isoforms (Supplementary Table 5 ) were obtained from the literature [35, 40] .", "cite_spans": [{"start": 743, "end": 747, "text": "[35,", "ref_id": "BIBREF34"}, {"start": 748, "end": 751, "text": "40]", "ref_id": "BIBREF39"}], "ref_spans": []}, {"section": "EJ-p53 transient transfection", "text": "EJ-p53 cells (630,000 cells in 6 cm dishes) were transfected with 2.21 lg pcDNA3 expression plasmid DNA using Lipofectamine 2000.", "cite_spans": [], "ref_spans": []}, {"section": "Chromatin immunoprecipitation", "text": "Chromatin immunoprecipitation was performed according to the EZChIP kit (Upstate) protocol. Briefly, EJ-p53 cells were plated at 4.5 9 10 6 cells per 15 cm dish. The cells were then lysed at a final concentration of 2.5 9 10 7 cells/ml. Chromatin immunoprecipitation (ChIP) lysates were sonicated on ice with 15 cycles of 10 s ON/20 s OFF using a microtip probe with a sonicator (Fisher Sonic Dismembrator). For each IP, 5 lg antibody was added to *1 9 10 7 cells of pre-cleared input lysate. The DO-1 p53 mouse monoclonal antibody was used for p53 ChIP, and normal mouse IgG (Santa Cruz Biotechnologies) was used as a negative control. The DNA was eluted into 50 ll Elution Buffer with the PCR Purification kit (QIAGEN). One ll DNA was assayed by real-time PCR as described earlier. The primer sequences used are listed in Supplementary Table 6 . Dilutions of the 2% input DNA were used to generate a standard curve.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "The human aB-crystallin gene is juxtaposed head-to-head with the related sHSP, HspB2 on chromosome 11q22.3-q23.1. The two genes share an 1,111 base pair intergenic promoter that is transcribed in an orientation-dependent fashion to allow for differential gene regulation [41, 42] . In searching the aB-crystallin/HspB2 promoter for DNAbinding elements that might be utilized by stress-induced transcription factors, we found a sequence at -199/-169 (relative to the aB-crystallin transcription start site) that closely matches the consensus sequence for a p53 response element (p53RE) (Fig. 1a) [43, 44] . This putative p53RE is highly conserved across mammals and features two p53RE half-sites separated by 11 base pairs that match the consensus sequence at 17/20 bases, including the required cytosines and guanines at positions 4 and 7 in each halfsite, respectively. The presence of this putative p53RE in the shared aB-crystallin/HspB2 promoter suggests that aBcrystallin or HspB2 might be transcriptionally regulated by p53. Half-site Half-site Fig. 1 The shared aB-crystallin and HspB2 promoter contains a putative p53 response element (p53RE), and p53 induces aB-crystallin expression. a Schematic representation of the shared intergenic aB-crystallin and HspB2 promoter. The sequence -199/-169 relative to the aB-crystallin transcriptional start site is shown compared to the p53RE consensus sequence. Vertical lines indicate the base pairs in the human sequence half-sites that match the consensus sequence, and bases conserved among human, mouse, and rat are highlighted in gray. R, purine; Y, pyrimidine; W, A or T. b and c EJ-p53 cells were grown in the presence or absence of tetracycline, and mRNA and protein were collected at the indicated times. b p53 (triangles), p21 (inverted triangles), aB-crystallin (squares), and Hsp27 (diamonds) mRNA levels were measured by real-time RT-PCR and are shown as fold induction relative to the level before induction. Statistical significance was determined by two-way ANOVA with a Bonferroni post-test and is noted for the fold-induction value compared to the initial value. * P \\ 0.05, ** P \\ 0.01, *** P \\ 0.001. c p53, p21, aB-crystallin, and tubulin protein levels were assayed by immunoblotting. d MCF-10A cells were infected with wild-type p53 or empty pLXSN retrovirus, and protein was collected at the indicated times. p53, p21, aB-crystallin, and tubulin levels were determined by immunoblotting. e MCF-10A cells were mock infected or infected with empty vector, N-FLAG-tagged wildtype p53, untagged wild-type p53, R175H p53, or R273H p53 pLXSN retrovirus. Forty-eight hours later, p53, aB-crystallin, and actin protein levels were assayed by immunoblotting. f MCF-10A cells were transfected with siRNAs targeting p53 (sip53-14 or sip53-15) or luciferase (NS). Sixteen hours later, the cells were treated with 500 nM doxorubicin or DMSO vehicle. Forty-eight hours later, p53, p21, aB-crystallin, HspB2, and tubulin expressions were determined by immunoblotting. Positive control lysates (C) were used for immunoblotting", "cite_spans": [{"start": 271, "end": 275, "text": "[41,", "ref_id": "BIBREF40"}, {"start": 276, "end": 279, "text": "42]", "ref_id": "BIBREF41"}, {"start": 595, "end": 599, "text": "[43,", "ref_id": "BIBREF42"}, {"start": 600, "end": 603, "text": "44]", "ref_id": "BIBREF44"}], "ref_spans": []}, {"section": "Results", "text": "To determine whether aB-crystallin or HspB2 is induced by p53, we utilized an inducible p53 expression system (EJ-p53 cells) in which wild-type p53 expression is induced by tetracycline removal in p53-null human EJ bladder carcinoma cells [36] . Upon removal of tetracycline from the media, p53 and p21 mRNA levels increased rapidly within 12 h (Fig. 1b) . Moreover, aB-crystallin mRNA levels were dramatically increased, although the induction of aB-crystallin mRNA, which was first apparent 24 h after tetracycline removal, was delayed compared to that of p53 or p21. Importantly, mRNA levels of the related sHSP Hsp27 were unchanged (Fig. 1b) , and HspB2 mRNA levels were at the lower limit of detection or undetectable at all time points examined (data not shown). These results indicate that the aB-crystallin gene is specifically and robustly induced by p53. Immunoblotting of whole cell lysates collected in parallel confirmed rapid p53-dependent induction of p21 protein levels within 12 h and delayed induction of aB-crystallin protein levels within 48 h (Fig. 1c) . Similar results were obtained when wild-type p53 was expressed by retroviral transduction in immortalized human MCF-10A breast epithelial cells (Fig. 1d) , indicating that the observed induction of aB-crystallin protein by p53 is not cell type specific. In contrast, retroviral delivery of p53 DNA-binding mutants (R175H and R273H) into MCF-10A cells did not induce aB-crystallin protein (Fig. 1e) , thereby confirming that the induction of aB-crystallin by p53 is mediated by a transcriptional mechanism. To determine whether genotoxic stress induces aB-crystallin by a p53-dependent mechanism, we transfected MCF-10A cells with two different p53 siRNAs (sip53-14 and sip53-15) or control non-silencing siRNA (NS) targeting luciferase and then treated the cells with the topoisomerase II inhibitor doxorubicin (Fig. 1f) . Fortyeight hours later, p53, p21, and aB-crystallin protein levels were greatly increased in NS-transfected MCF-10A cells treated with doxorubicin (lane 9) compared to NS-transfected cells treated with DMSO vehicle (lane 6). In contrast, siRNAs targeting p53 (sip53-14 and to a lesser extent sip53-15) partly inhibited p53 induction and dramatically suppressed p21 and aB-crystallin induction by doxorubicin (lanes 10 and 11 vs. lane 9). Collectively, these data indicate that p53 is required for aB-crystallin induction in response to genotoxic stress.", "cite_spans": [{"start": 239, "end": 243, "text": "[36]", "ref_id": "BIBREF35"}], "ref_spans": []}, {"section": "Results", "text": "We next investigated whether the putative p53RE in the aB-crystallin promoter is transactivated by p53. To this end, EJ-p53 cells were transiently transfected with luciferase reporters containing the full-length aB-crystallin promoter (-1,081/?30) or progressive 5 0 truncations that contained (-289/?30) or lacked (-171/?30) the putative p53RE (Fig. 2a) . In addition, the conserved cytosine and guanine residues in both half-sites of the putative p53RE were mutated in the full-length and -289/?30 truncated promoter constructs; mutation of these sites in p53REs abrogates p53 binding [43, 44] . When p53 was induced in the EJ-p53 cells by tetracycline removal, the fulllength and -289/?30 aB-crystallin promoter reporters mediated 10.5-and 7-fold increased luciferase activities, respectively, compared to the promoter-less pGL3-Basic luciferase vector. Mutation of the putative p53RE in the full-length and -289/?30 promoter constructs attenuated p53 transactivation of these reporters. Similarly, deletion of the putative p53RE in the -171/?30 aBcrystallin promoter reporter completely abrogated p53 activation of the promoter. These data demonstrate that p53 activates the aB-crystallin promoter through the putative p53RE.", "cite_spans": [{"start": 587, "end": 591, "text": "[43,", "ref_id": "BIBREF42"}, {"start": 592, "end": 595, "text": "44]", "ref_id": "BIBREF44"}], "ref_spans": []}, {"section": "Results", "text": "In order to determine whether p53 binds to the putative p53RE in vivo, chromatin immunoprecipitation (ChIP) assays were performed. ChIP with anti-p53 antibodies enriched for p21 5 0 p53RE genomic DNA as expected (Fig. 2b) , confirming that the ChIP assay worked. In contrast, no enrichment of aB-crystallin promoter genomic DNA was seen. While it is formally possible that p53 may be binding to the aB-crystallin promoter in a manner not detectable by ChIP, these data strongly suggest that p53 does not directly bind to the putative p53RE in the aBcrystallin promoter. Together with the delayed kinetics of aB-crystallin induction by p53 compared to p21 (Fig. 1b,  c) , these results suggest an indirect mechanism of transactivation whereby p53 induces the expression of other target genes, such as p63 or p73, which also bind to p53REs to regulate gene expression.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "In order to investigate the potential role of the p53 family network in aB-crystallin transactivation, we first determined p63 and p73 mRNA levels following wild-type p53 induction in EJ-p53 cells. TAp63 mRNA levels were initially low and unaffected by p53 induction, while DNp63 mRNA levels were undetectable at all time points (data not shown). TAp73 mRNA levels showed a modest transient increase at 6 h with and without p53 induction (Fig. 3a) . In contrast, DNp73 mRNA levels increased dramatically upon p53 expression (Fig. 3b) , consistent with previous reports showing that DNp73 is a p53 target gene [20, 45, 46] . The observed induction of DNp73 suggests that DNp73 may serve as an intermediary factor between p53 expression and aB-crystallin transactivation. To test this hypothesis, we examined the requirement for p73 in the p53-dependent induction of aB-crystallin. Pan p73, TAp73, and DNp73 siRNAs inhibited p53 induction of aB-crystallin mRNA levels, indicating that both TAp73 and DNp73 are required for p53-dependent transactivation of aB-crystallin (Fig. 3c) . Intriguingly, the TAp73 siRNA suppressed DNp73 mRNA induction by p53, suggesting that TAp73 is required for p53-mediated DNp73 transactivation. Importantly, the p73 siRNAs had modest or no effect on p53, p21, and Mdm2 mRNA levels following p53 induction, indicating that p73 RNAi does not globally disrupt p53-mediated transcription (Fig. 3d) . Collectively, these results implicate one or more p73 isoforms in the observed p53-dependent transactivation of aB-crystallin.", "cite_spans": [{"start": 609, "end": 613, "text": "[20,", "ref_id": "BIBREF19"}, {"start": 614, "end": 617, "text": "45,", "ref_id": "BIBREF45"}, {"start": 618, "end": 621, "text": "46]", "ref_id": "BIBREF46"}], "ref_spans": []}, {"section": "Results", "text": "In order to specifically determine which p73 isoform(s) transactivate aB-crystallin, EJ-p53 cells were transiently transfected with N-terminal HA-tagged TAp73a, TAp73b, DNp73a, DNp73b, and untagged DNp73b-13 expression constructs. DNp73b-13 lacks the N-terminal 13 amino acids unique to DNp73 that are required for transactivation by DNp73b [30] . Immunoblotting confirmed that the p73 isoforms are expressed 24 and 48 h after transfection (Fig. 4a) . Although ectopic expression of most of the p73 isoforms had little effect on aB-crystallin mRNA levels, DNp73a increased aB-crystallin mRNA 11-and 17-fold at 24 and 48 h, respectively (Fig. 4b) . Taken together, these data strongly support a model whereby p53 transactivates DNp73a which, in turn, induces aB-crystallin expression.", "cite_spans": [{"start": 341, "end": 345, "text": "[30]", "ref_id": "BIBREF29"}], "ref_spans": [{"start": 440, "end": 449, "text": "(Fig. 4a)", "ref_id": "FIGREF4"}, {"start": 636, "end": 645, "text": "(Fig. 4b)", "ref_id": "FIGREF4"}]}, {"section": "Discussion", "text": "We have demonstrated for the first time that the molecular chaperone aB-crystallin is induced by a novel collaborative relationship among p53 and multiple p73 isoforms. Specifically, p53 leads to the robust transactivation of DNp73, which subsequently induces aB-crystallin gene expression by a p53-independent mechanism. Although DNp73a is a well-established dominant negative inhibitor of p53 and TAp73 [20, 45, 47] , it has also been implicated in p53-dependent and p53-independent transcriptional regulation of a variety of target genes, including EGR1 and BTG2 [29, 31] . As is the case with aB-crystallin, the mechanisms by which DNp73a transactivates these genes is unclear but may involve a direct interaction (e.g., as a transcriptional co-activator) or indirect mechanism (e.g., by repressing a negative transcriptional regulator or activating a positive regulator of the target gene). Interestingly, ectopic expression of DNp73a has been reported to induce HSF-1 expression, thereby providing a potential indirect mechanism for aB-crystallin transactivation by DNp73a [48] . Our Fig. 2 The putative p53RE mediates p53-dependent activation of the aB-crystallin promoter without binding p53. a The top line schematically depicts the shared aB-crystallin/HspB2 promoter. The transcriptional start sites of aB-crystallin and HspB2 are indicated by bent arrows; open-ended boxes depict coding sequences. Below, the portion of the promoter upstream of the firefly luciferase-coding sequence in each of the pGL3 reporter constructs is displayed. The indicated point mutations in the putative p53RE in the aB-crystallin promoter (highlighted in gray) were introduced to abrogate wild-type p53 protein binding. EJ-p53 cells transfected with 100 ng of wildtype, truncated, or p53RE-mutated aB-crystallin promoter luciferase reporter, and 100 pg of a Renilla luciferase reporter was induced to express p53 for 24 h. Firefly luciferase activity was normalized to Renilla luciferase activity and is indicated relative to promoter-less pGL3-Basic sample activity. For wild-type p53RE samples, statistical significance (two-way ANOVA with Bonferroni post-test) is noted for the difference compared to the promoter-less pGL3-Basic construct (labeled '0'). For the mutated p53RE samples, statistical significance is noted for differences compared to wild-type p53RE. *** P \\ 0.001. b EJ-p53 cells after 24 h with or without p53 induction were assayed by p53 ChIP for binding of p53 to the aB-crystallin promoter. ChIP-isolated DNA was assayed by realtime RT-PCR with primers flanking the putative p53REs in the aB-crystallin or p21 promoters. The fraction of input chromatin (%INPUT) immunoprecipitated was calculated by the standard curve method. Statistical significance (two-way ANOVA with Bonferroni post-test) is noted for %INPUT differences between p53 and IgG ChIP under each condition. * P \\ 0.05 \u03b1B-crystallin HspB2 00 observation that silencing TAp73 inhibits the induction of DNp73 by p53 adds another layer of complexity. These results suggest that TAp73 cooperates with p53 to transactivate DNp73 in this system, a plausible scenario given that TAp73 itself has been demonstrated to transactivate DNp73 [49] . Collectively, our data point to an intricate and tightly coordinated cooperation between p53, TAp73 and DNp73 in the transcriptional regulation of aB-crystallin in response to genotoxic stress.", "cite_spans": [{"start": 405, "end": 409, "text": "[20,", "ref_id": "BIBREF19"}, {"start": 410, "end": 413, "text": "45,", "ref_id": "BIBREF45"}, {"start": 414, "end": 417, "text": "47]", "ref_id": "BIBREF47"}, {"start": 566, "end": 570, "text": "[29,", "ref_id": "BIBREF28"}, {"start": 571, "end": 574, "text": "31]", "ref_id": "BIBREF30"}, {"start": 1079, "end": 1083, "text": "[48]", "ref_id": "BIBREF48"}, {"start": 3210, "end": 3214, "text": "[49]", "ref_id": "BIBREF49"}], "ref_spans": []}, {"section": "Discussion", "text": "The induction of aB-crystallin, an anti-apoptotic and anti-oxidant protein [4, [6] [7] [8] [9] , by genotoxic stress may also serve a homeostatic function to suppress apoptosis and reduce ROS levels in the setting of DNA damage. Indeed, recent studies indicate that p53 induces the expression of several pro-survival and anti-oxidant genes, including COX-2, the sestrins, TIGAR, glutathione peroxidase 1, aldehyde dehydrogenase 4 family member A1, and receptor tyrosine kinase DDR1 [50] [51] [52] [53] [54] [55] . Induction of anti-oxidant genes by p53 inhibits tumor initiation by reducing ROS levels, which can cause oxidative DNA damage and promote genomic instability [56] . Transactivation of aBcrystallin downstream of p53 represents a potentially novel mechanism of countering pro-apoptotic and pro-oxidant signaling initiated by genotoxic stress, a hypothesis we will explore in future studies. Intriguingly, aB-crystallin was also recently reported to bind p53 and sequester it in the cytoplasm, suggesting an additional mechanism by which aB-crystallin may inhibit p53 signaling [57] .", "cite_spans": [{"start": 75, "end": 78, "text": "[4,", "ref_id": "BIBREF3"}, {"start": 79, "end": 82, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 83, "end": 86, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 87, "end": 90, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 91, "end": 94, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 482, "end": 486, "text": "[50]", "ref_id": "BIBREF50"}, {"start": 487, "end": 491, "text": "[51]", "ref_id": "BIBREF51"}, {"start": 492, "end": 496, "text": "[52]", "ref_id": "BIBREF52"}, {"start": 497, "end": 501, "text": "[53]", "ref_id": "BIBREF53"}, {"start": 502, "end": 506, "text": "[54]", "ref_id": "BIBREF54"}, {"start": 507, "end": 511, "text": "[55]", "ref_id": "BIBREF55"}, {"start": 672, "end": 676, "text": "[56]", "ref_id": "BIBREF56"}, {"start": 1089, "end": 1093, "text": "[57]", "ref_id": "BIBREF57"}], "ref_spans": []}, {"section": "Discussion", "text": "Our results also provide potentially new insights into the mechanisms of deregulated expression of aB-crystallin in cancer. The cytoprotective function of aB-crystallin has been exploited by diverse cancers, which constitutively express aB-crystallin to overcome apoptosis. For instance, aB-crystallin is aberrantly expressed in apoptosis-resistant triple negative (estrogen receptor, progesterone receptor, and HER2/ErbB2-negative) breast tumors and glioblastoma multiforme and contributes to their aggressive tumor biology [8, 37, 58] . Furthermore, expression of aB-crystallin correlates with poor survival in several malignancies, including breast cancer, head and neck cancer, and hepatocellular carcinoma [37, [59] [60] [61] . Although p53 is frequently inactivated in cancer, DNp73 is commonly expressed in a wide range of clinically aggressive human tumors and is associated with poor outcomes [24] [25] [26] [27] . Given the novel link between DNp73 and aB-crystallin we have demonstrated, it will be important in future studies to determine whether DNp73 and aB-crystallin are coexpressed in human tumors and whether they cooperate in tumor initiation and/or progression. ", "cite_spans": [{"start": 525, "end": 528, "text": "[8,", "ref_id": "BIBREF7"}, {"start": 529, "end": 532, "text": "37,", "ref_id": "BIBREF36"}, {"start": 533, "end": 536, "text": "58]", "ref_id": "BIBREF58"}, {"start": 711, "end": 715, "text": "[37,", "ref_id": "BIBREF36"}, {"start": 716, "end": 720, "text": "[59]", "ref_id": "BIBREF59"}, {"start": 721, "end": 725, "text": "[60]", "ref_id": "BIBREF60"}, {"start": 726, "end": 730, "text": "[61]", "ref_id": "BIBREF61"}, {"start": 902, "end": 906, "text": "[24]", "ref_id": "BIBREF23"}, {"start": 907, "end": 911, "text": "[25]", "ref_id": "BIBREF24"}, {"start": 912, "end": 916, "text": "[26]", "ref_id": "BIBREF25"}, {"start": 917, "end": 921, "text": "[27]", "ref_id": "BIBREF26"}], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Small heat-shock proteins and their potential role in human disease", "authors": [{"first": "P", "middle": ["J"], "last": "Clark", "suffix": ""}, {"first": "J", "middle": ["I"], "last": "Muchowski", "suffix": ""}], "year": 2000, "venue": "Curr Opin Struct Biol", "link": "29753795"}, "BIBREF1": {"title": "1992) a-crystallin can function as a molecular chaperone", "authors": [{"first": "J", "middle": [], "last": "Horwitz", "suffix": ""}], "year": "", "venue": "Proc Natl Acad Sci", "link": null}, "BIBREF2": {"title": "LEDGF binding to stress response element increases aB-crystallin expression in astrocytes with oxidative stress", "authors": [{"first": "J", "middle": ["H"], "last": "Shin", "suffix": ""}, {"first": "C", "middle": ["S"], "last": "Piao", "suffix": ""}, {"first": "C", "middle": ["M"], "last": "Lim", "suffix": ""}, {"first": "J", "middle": ["K"], "last": "Lee", "suffix": ""}], "year": 2008, "venue": "Neurosci Lett", "link": "12677417"}, "BIBREF3": {"title": "Human hsp27, Drosophila hsp27 and human aB-crystallin expressionmediated increase in glutathione is essential for the protective activity of these proteins against TNFa-induced cell death", "authors": [{"first": "P", "middle": [], "last": "Mehlen", "suffix": ""}, {"first": "C", "middle": [], "last": "Kretz-Remy", "suffix": ""}, {"first": "X", "middle": [], "last": "Preville", "suffix": ""}, {"first": "A", "middle": ["P"], "last": "Arrigo", "suffix": ""}], "year": 1996, "venue": "EMBO J", "link": "37853056"}, "BIBREF4": {"title": "Some like it hot: the structure and function of small heat-shock proteins", "authors": [{"first": "M", "middle": [], "last": "Haslbeck", "suffix": ""}, {"first": "T", "middle": [], "last": "Franzmann", "suffix": ""}, {"first": "D", "middle": [], "last": "Weinfurtner", "suffix": ""}, {"first": "J", "middle": [], "last": "Buchner", "suffix": ""}], "year": 2005, "venue": "Nat Struct Mol Biol", "link": "31850847"}, "BIBREF5": {"title": "The small heat shock protein aB-crystallin negatively regulates cytochrome c-and caspase-8-dependent activation of caspase-3 by inhibiting its autoproteolytic maturation", "authors": [{"first": "M", "middle": ["C"], "last": "Kamradt", "suffix": ""}, {"first": "F", "middle": [], "last": "Chen", "suffix": ""}, {"first": "V", "middle": ["L"], "last": "Cryns", "suffix": ""}], "year": 2001, "venue": "J Biol Chem", "link": "13163245"}, "BIBREF6": {"title": "The small heat shock protein aB-crystallin is a novel inhibitor of TRAIL-induced apoptosis that suppresses the activation of caspase-3", "authors": [{"first": "M", "middle": ["C"], "last": "Kamradt", "suffix": ""}, {"first": "M", "middle": [], "last": "Lu", "suffix": ""}, {"first": "M", "middle": ["E"], "last": "Werner", "suffix": ""}], "year": 2005, "venue": "J Biol Chem", "link": "29003415"}, "BIBREF7": {"title": "Bcl2L12-mediated inhibition of effector caspase-3 and caspase-7 via distinct mechanisms in glioblastoma", "authors": [{"first": "A", "middle": ["H"], "last": "Stegh", "suffix": ""}, {"first": "S", "middle": [], "last": "Kesari", "suffix": ""}, {"first": "J", "middle": ["E"], "last": "Mahoney", "suffix": ""}], "year": 2008, "venue": "Proc Natl Acad Sci", "link": "12599129"}, "BIBREF8": {"title": "Human aA-and aBcrystallins bind to Bax and Bcl-X s to sequester their translocation during staurosporine-induced apoptosis", "authors": [{"first": "Y", "middle": ["W"], "last": "Mao", "suffix": ""}, {"first": "J", "middle": ["P"], "last": "Liu", "suffix": ""}, {"first": "H", "middle": [], "last": "Xiang", "suffix": ""}, {"first": "D", "middle": ["W"], "last": "Li", "suffix": ""}], "year": 2004, "venue": "Cell Death Differ", "link": null}, "BIBREF9": {"title": "Transcription regulation of aB-crystallin in astrocytes: analysis of HSF and AP1 activation by different types of physiological stress", "authors": [{"first": "M", "middle": ["W"], "last": "Head", "suffix": ""}, {"first": "L", "middle": [], "last": "Hurwitz", "suffix": ""}, {"first": "J", "middle": ["E"], "last": "Goldman", "suffix": ""}], "year": 1996, "venue": "J Cell Sci", "link": "33262187"}, "BIBREF10": {"title": "LEDGF binds to heat shock and stress-related element to activate the expression of stress-related genes", "authors": [{"first": "D", "middle": ["P"], "last": "Singh", "suffix": ""}, {"first": "N", "middle": [], "last": "Fatma", "suffix": ""}, {"first": "A", "middle": [], "last": "Kimura", "suffix": ""}, {"first": "L", "middle": ["T"], "last": "Chylack", "suffix": ""}, {"first": "T", "middle": [], "last": "Shinohara", "suffix": ""}], "year": 2001, "venue": "Biochem Biophys Res Commun", "link": "39465087"}, "BIBREF11": {"title": "Regulation of the mouse aB-crystallin and MKBP/HspB2 promoter activities by shared and gene specific intergenic elements: the importance of context dependency", "authors": [{"first": "S", "middle": ["K"], "last": "Swamynathan", "suffix": ""}, {"first": "J", "middle": [], "last": "Piatigorsky", "suffix": ""}], "year": 2007, "venue": "Int J Dev Biol", "link": "10441596"}, "BIBREF12": {"title": ") p53 in health and disease", "authors": [{"first": "K", "middle": ["H"], "last": "Vousden", "suffix": ""}, {"first": "D", "middle": ["P"], "last": "Lane", "suffix": ""}], "year": 2007, "venue": "Nat Rev Mol Cell Biol", "link": null}, "BIBREF13": {"title": "Identification of direct p73 target genes combining DNA microarray and chromatin immunoprecipitation analyses", "authors": [{"first": "G", "middle": [], "last": "Fontemaggi", "suffix": ""}, {"first": "I", "middle": [], "last": "Kela", "suffix": ""}, {"first": "N", "middle": [], "last": "Amariglio", "suffix": ""}], "year": 2002, "venue": "J Biol Chem", "link": "6973078"}, "BIBREF14": {"title": "Induces apoptosis via PUMA transactivation and Bax mitochondrial translocation", "authors": [{"first": "G", "middle": [], "last": "Melino", "suffix": ""}, {"first": "F", "middle": [], "last": "Bernassola", "suffix": ""}, {"first": "M", "middle": [], "last": "Ranalli", "suffix": ""}], "year": 2004, "venue": "J Biol Chem", "link": "22468709"}, "BIBREF15": {"title": "Differential recognition of response elements determines target gene specificity for p53 and p63", "authors": [{"first": "M", "middle": [], "last": "Osada", "suffix": ""}, {"first": "H", "middle": ["L"], "last": "Park", "suffix": ""}, {"first": "Y", "middle": [], "last": "Nagakawa", "suffix": ""}], "year": 2005, "venue": "Mol Cell Biol", "link": "45392010"}, "BIBREF16": {"title": ") p63 and p73 are required for p53-dependent apoptosis in response to DNA damage", "authors": [{"first": "E", "middle": ["R"], "last": "Flores", "suffix": ""}, {"first": "K", "middle": ["Y"], "last": "Tsai", "suffix": ""}, {"first": "D", "middle": [], "last": "Crowley", "suffix": ""}, {"first": "S", "middle": [], "last": "Sengupta", "suffix": ""}, {"first": "A", "middle": [], "last": "Yang", "suffix": ""}, {"first": "F", "middle": [], "last": "Mckeon", "suffix": ""}, {"first": "T", "middle": [], "last": "Jacks", "suffix": ""}], "year": 2002, "venue": "Nature", "link": "4408567"}, "BIBREF17": {"title": "P73 functionally replaces p53 in adriamycin-treated, p53-deficient breast cancer cells", "authors": [{"first": "M", "middle": [], "last": "Vayssade", "suffix": ""}, {"first": "H", "middle": [], "last": "Haddada", "suffix": ""}, {"first": "L", "middle": [], "last": "Faridoni-Laurens", "suffix": ""}, {"first": "S", "middle": [], "last": "Tourpin", "suffix": ""}, {"first": "A", "middle": [], "last": "Valent", "suffix": ""}, {"first": "J", "middle": [], "last": "Benard", "suffix": ""}, {"first": "J", "middle": ["C"], "last": "Ahomadegbe", "suffix": ""}], "year": 2005, "venue": "Int J Cancer", "link": "25145133"}, "BIBREF18": {"title": "poses a barrier to malignant transformation by limiting anchorageindependent growth", "authors": [{"first": "M", "middle": [], "last": "Beitzinger", "suffix": ""}, {"first": "L", "middle": [], "last": "Hofmann", "suffix": ""}, {"first": "C", "middle": [], "last": "Oswald", "suffix": ""}], "year": 2008, "venue": "EMBO J", "link": null}, "BIBREF19": {"title": "Human DNp73 regulates a dominant negative feedback loop for TAp73 and p53", "authors": [{"first": "T", "middle": ["J"], "last": "Grob", "suffix": ""}, {"first": "U", "middle": [], "last": "Novak", "suffix": ""}, {"first": "C", "middle": [], "last": "Maisse", "suffix": ""}], "year": 2001, "venue": "Cell Death Differ", "link": "841882"}, "BIBREF20": {"title": "Transactivationdeficient DTA-p73 inhibits p53 by direct competition for DNA binding: implications for tumorigenesis", "authors": [{"first": "T", "middle": [], "last": "Stiewe", "suffix": ""}, {"first": "C", "middle": ["C"], "last": "Theseling", "suffix": ""}, {"first": "B", "middle": ["M"], "last": "Putzer", "suffix": ""}], "year": 2002, "venue": "J Biol Chem", "link": null}, "BIBREF21": {"title": "DNp73 facilitates cell immortalization and cooperates with oncogenic Ras in cellular transformation in vivo", "authors": [{"first": "O", "middle": [], "last": "Petrenko", "suffix": ""}, {"first": "A", "middle": [], "last": "Zaika", "suffix": ""}, {"first": "U", "middle": ["M"], "last": "Moll", "suffix": ""}], "year": 2003, "venue": "Mol Cell Biol", "link": "17787671"}, "BIBREF22": {"title": "An anti-apoptotic role for the p53 family member, p73, during developmental neuron death", "authors": [{"first": "C", "middle": ["D"], "last": "Pozniak", "suffix": ""}, {"first": "S", "middle": [], "last": "Radinovic", "suffix": ""}, {"first": "A", "middle": [], "last": "Yang", "suffix": ""}, {"first": "F", "middle": [], "last": "Mckeon", "suffix": ""}, {"first": "D", "middle": ["R"], "last": "Kaplan", "suffix": ""}, {"first": "F", "middle": ["D"], "last": "Miller", "suffix": ""}], "year": 2000, "venue": "Science", "link": "39810284"}, "BIBREF23": {"title": "Expression of DNp73 is a molecular marker for adverse outcome in neuroblastoma patients", "authors": [{"first": "I", "middle": [], "last": "Casciano", "suffix": ""}, {"first": "K", "middle": [], "last": "Mazzocco", "suffix": ""}, {"first": "L", "middle": [], "last": "Boni", "suffix": ""}], "year": 2002, "venue": "Cell Death Differ", "link": "22145663"}, "BIBREF24": {"title": "Clinical relevance of dominant-negative p73 isoforms for responsiveness to chemotherapy and survival in ovarian cancer: evidence for a crucial p53-p73 cross-talk in vivo", "authors": [{"first": "N", "middle": [], "last": "Concin", "suffix": ""}, {"first": "G", "middle": [], "last": "Hofstetter", "suffix": ""}, {"first": "A", "middle": [], "last": "Berger", "suffix": ""}], "year": 2005, "venue": "Clin Cancer Res", "link": "13184994"}, "BIBREF25": {"title": "Expression of DNp73 predicts poor prognosis in lung cancer", "authors": [{"first": "H", "middle": [], "last": "Uramoto", "suffix": ""}, {"first": "K", "middle": [], "last": "Sugio", "suffix": ""}, {"first": "T", "middle": [], "last": "Oyama", "suffix": ""}, {"first": "S", "middle": [], "last": "Nakata", "suffix": ""}, {"first": "K", "middle": [], "last": "Ono", "suffix": ""}, {"first": "M", "middle": [], "last": "Morita", "suffix": ""}, {"first": "K", "middle": [], "last": "Funa", "suffix": ""}, {"first": "K", "middle": [], "last": "Yasumoto", "suffix": ""}], "year": 2004, "venue": "Clin Cancer Res", "link": null}, "BIBREF26": {"title": "DTAp73 upregulation correlates with poor prognosis in human tumors: putative in vivo network involving p73 isoforms, p53, and E2F-1", "authors": [{"first": "G", "middle": [], "last": "Dominguez", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Garcia", "suffix": ""}, {"first": "C", "middle": [], "last": "Pena", "suffix": ""}], "year": 2006, "venue": "J Clin Oncol", "link": "43210451"}, "BIBREF27": {"title": ") p63a and DNp63alpha can induce cell cycle arrest and apoptosis and differentially regulate p53 target genes", "authors": [{"first": "M", "middle": [], "last": "Dohn", "suffix": ""}, {"first": "S", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "X", "middle": [], "last": "Chen", "suffix": ""}], "year": 2001, "venue": "Oncogene", "link": null}, "BIBREF28": {"title": "DNp73 can modulate the expression of various genes in a p53-independent fashion", "authors": [{"first": "N", "middle": ["N"], "last": "Kartasheva", "suffix": ""}, {"first": "C", "middle": [], "last": "Lenz-Bauer", "suffix": ""}, {"first": "O", "middle": [], "last": "Hartmann", "suffix": ""}, {"first": "H", "middle": [], "last": "Schafer", "suffix": ""}, {"first": "M", "middle": [], "last": "Eilers", "suffix": ""}, {"first": "M", "middle": [], "last": "Dobbelstein", "suffix": ""}], "year": 2003, "venue": "Oncogene", "link": "10450903"}, "BIBREF29": {"title": "DNp73b is active in transactivation and growth suppression", "authors": [{"first": "G", "middle": [], "last": "Liu", "suffix": ""}, {"first": "S", "middle": [], "last": "Nozell", "suffix": ""}, {"first": "H", "middle": [], "last": "Xiao", "suffix": ""}, {"first": "X", "middle": [], "last": "Chen", "suffix": ""}], "year": 2004, "venue": "Mol Cell Biol", "link": null}, "BIBREF30": {"title": "The neurogene BTG2TIS21/PC3 is transactivated by DNp73a via p53 specifically in neuroblastoma cells", "authors": [{"first": "D", "middle": [], "last": "Goldschneider", "suffix": ""}, {"first": "K", "middle": [], "last": "Million", "suffix": ""}, {"first": "A", "middle": [], "last": "Meiller", "suffix": ""}, {"first": "H", "middle": [], "last": "Haddada", "suffix": ""}, {"first": "A", "middle": [], "last": "Puisieux", "suffix": ""}, {"first": "J", "middle": [], "last": "Benard", "suffix": ""}, {"first": "E", "middle": [], "last": "May", "suffix": ""}, {"first": "S", "middle": [], "last": "Douc-Rasy", "suffix": ""}], "year": 2005, "venue": "J Cell Sci", "link": null}, "BIBREF31": {"title": "Functional regulation of p73 and p63: development and cancer", "authors": [{"first": "G", "middle": [], "last": "Melino", "suffix": ""}, {"first": "X", "middle": [], "last": "Lu", "suffix": ""}, {"first": "M", "middle": [], "last": "Gasco", "suffix": ""}, {"first": "T", "middle": [], "last": "Crook", "suffix": ""}, {"first": "R", "middle": ["A"], "last": "Knight", "suffix": ""}], "year": 2003, "venue": "Trends Biochem Sci", "link": "22675604"}, "BIBREF32": {"title": "Lack of p73 expression in mature B-ALL and identification of three new splicing variants restricted to pre B and C-ALL indicate a role of p73 in B cell ALL differentiation", "authors": [{"first": "P", "middle": [], "last": "Scaruffi", "suffix": ""}, {"first": "I", "middle": [], "last": "Casciano", "suffix": ""}, {"first": "L", "middle": [], "last": "Masiero", "suffix": ""}, {"first": "G", "middle": [], "last": "Basso", "suffix": ""}, {"first": "M", "middle": [], "last": "Romani", "suffix": ""}, {"first": "G", "middle": ["P"], "last": "Tonini", "suffix": ""}], "year": 2000, "venue": "Leukemia", "link": "19277663"}, "BIBREF33": {"title": "A network of p73, p53 and Egr1 is required for efficient apoptosis in tumor cells", "authors": [{"first": "J", "middle": [], "last": "Yu", "suffix": ""}, {"first": "V", "middle": [], "last": "Baron", "suffix": ""}, {"first": "D", "middle": [], "last": "Mercola", "suffix": ""}, {"first": "T", "middle": [], "last": "Mustelin", "suffix": ""}, {"first": "E", "middle": ["D"], "last": "Adamson", "suffix": ""}], "year": 2007, "venue": "Cell Death Differ", "link": "43258863"}, "BIBREF34": {"title": "Crosstalks in the p53 family: DNp63 is an anti-apoptotic target for DNp73a and p53 gain-of-function mutants", "authors": [{"first": "M", "middle": [], "last": "Lanza", "suffix": ""}, {"first": "B", "middle": [], "last": "Marinari", "suffix": ""}, {"first": "M", "middle": [], "last": "Papoutsaki", "suffix": ""}, {"first": "M", "middle": ["L"], "last": "Giustizieri", "suffix": ""}, {"first": "D", "middle": [], "last": "&apos;alessandra", "suffix": ""}, {"first": "Y", "middle": [], "last": "Chimenti", "suffix": ""}, {"first": "S", "middle": [], "last": "Guerrini", "suffix": ""}, {"first": "L", "middle": [], "last": "Costanzo", "suffix": ""}, {"first": "A", "middle": [], "last": "", "suffix": ""}], "year": 2006, "venue": "Cell Cycle", "link": null}, "BIBREF35": {"title": "Wild-type p53 triggers a rapid senescence program in human tumor cells lacking functional p53", "authors": [{"first": "M", "middle": ["M"], "last": "Sugrue", "suffix": ""}, {"first": "D", "middle": ["Y"], "last": "Shin", "suffix": ""}, {"first": "S", "middle": ["W"], "last": "Lee", "suffix": ""}, {"first": "S", "middle": ["A"], "last": "Aaronson", "suffix": ""}], "year": 1997, "venue": "Proc Natl Acad Sci", "link": "9436986"}, "BIBREF36": {"title": "aB-crystallin is a novel oncoprotein that predicts poor clinical outcome in breast cancer", "authors": [{"first": "J", "middle": ["V"], "last": "Moyano", "suffix": ""}, {"first": "J", "middle": ["R"], "last": "Evans", "suffix": ""}, {"first": "F", "middle": [], "last": "Chen", "suffix": ""}], "year": 2006, "venue": "J Clin Invest", "link": null}, "BIBREF37": {"title": "Production of high-titer helper-free retroviruses by transient transfection", "authors": [{"first": "W", "middle": ["S"], "last": "Pear", "suffix": ""}, {"first": "G", "middle": ["P"], "last": "Nolan", "suffix": ""}, {"first": "M", "middle": ["L"], "last": "Scott", "suffix": ""}, {"first": "D", "middle": [], "last": "Baltimore", "suffix": ""}], "year": 1993, "venue": "Proc Natl Acad Sci", "link": "10287752"}, "BIBREF38": {"title": "The p63/p73 network mediates chemosensitivity to cisplatin in a biologically defined subset of primary breast cancers", "authors": [{"first": "C", "middle": ["O"], "last": "Leong", "suffix": ""}, {"first": "N", "middle": [], "last": "Vidnovic", "suffix": ""}, {"first": "M", "middle": ["P"], "last": "Deyoung", "suffix": ""}, {"first": "D", "middle": [], "last": "Sgroi", "suffix": ""}, {"first": "L", "middle": ["W"], "last": "Ellisen", "suffix": ""}], "year": 2007, "venue": "J Clin Invest", "link": "4866969"}, "BIBREF39": {"title": "Ellisen LW (2006) p63 mediates survival in squamous cell carcinoma by suppression of p73-dependent apoptosis", "authors": [{"first": "J", "middle": ["W"], "last": "Rocco", "suffix": ""}, {"first": "C", "middle": ["O"], "last": "Leong", "suffix": ""}, {"first": "N", "middle": [], "last": "Kuperwasser", "suffix": ""}, {"first": "M", "middle": ["P"], "last": "Deyoung", "suffix": ""}], "year": "", "venue": "Cancer Cell", "link": null}, "BIBREF40": {"title": "Sequence and functional conservation of the intergenic region between the head-to-head genes encoding the small heat shock proteins aBcrystallin and HspB2 in the mammalian lineage", "authors": [{"first": "L", "middle": [], "last": "Doerwald", "suffix": ""}, {"first": "T", "middle": [], "last": "Van Rheede", "suffix": ""}, {"first": "R", "middle": ["P"], "last": "Dirks", "suffix": ""}], "year": 2004, "venue": "J Mol Evol", "link": "25042441"}, "BIBREF41": {"title": "Orientation-dependent influence of an intergenic enhancer on the promoter activity of the divergently transcribed mouse Shsp/aB-crystallin and Mkbp/ HspB2 genes", "authors": [{"first": "S", "middle": ["K"], "last": "Swamynathan", "suffix": ""}, {"first": "J", "middle": [], "last": "Piatigorsky", "suffix": ""}], "year": 2002, "venue": "J Biol Chem", "link": null}, "BIBREF42": {"title": "Definition of a consensus binding site for p53", "authors": [{"first": "W", "middle": ["S"], "last": "El-Deiry", "suffix": ""}, {"first": "S", "middle": ["E"], "last": "Kern", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Pietenpol", "suffix": ""}, {"first": "K", "middle": ["W"], "last": "Kinzler", "suffix": ""}, {"first": "B", "middle": [], "last": "Vogelstein", "suffix": ""}], "year": 1992, "venue": "Nat Genet", "link": null}, "BIBREF44": {"title": "A transcriptionally active DNA-binding site for human p53 protein complexes", "authors": [{"first": "W", "middle": ["D"], "last": "Funk", "suffix": ""}, {"first": "D", "middle": ["T"], "last": "Pak", "suffix": ""}, {"first": "R", "middle": ["H"], "last": "Karas", "suffix": ""}, {"first": "W", "middle": ["E"], "last": "Wright", "suffix": ""}, {"first": "J", "middle": ["W"], "last": "Shay", "suffix": ""}], "year": 1992, "venue": "Mol Cell Biol", "link": "36025422"}, "BIBREF45": {"title": "induces the expression of its antagonist p73 DN, establishing an autoregulatory feedback loop", "authors": [{"first": "N", "middle": ["N"], "last": "Kartasheva", "suffix": ""}, {"first": "A", "middle": [], "last": "Contente", "suffix": ""}, {"first": "C", "middle": [], "last": "Lenz-Stoppler", "suffix": ""}, {"first": "J", "middle": [], "last": "Roth", "suffix": ""}, {"first": "M", "middle": [], "last": "Dobbelstein", "suffix": ""}], "year": 2002, "venue": "Oncogene", "link": null}, "BIBREF46": {"title": "DN-p73 is activated after DNA damage in a p53-dependent manner to regulate p53-induced cell cycle arrest", "authors": [{"first": "S", "middle": [], "last": "Vossio", "suffix": ""}, {"first": "E", "middle": [], "last": "Palescandolo", "suffix": ""}, {"first": "N", "middle": [], "last": "Pediconi", "suffix": ""}, {"first": "F", "middle": [], "last": "Moretti", "suffix": ""}, {"first": "C", "middle": [], "last": "Balsano", "suffix": ""}, {"first": "M", "middle": [], "last": "Levrero", "suffix": ""}, {"first": "A", "middle": [], "last": "Costanzo", "suffix": ""}], "year": 2002, "venue": "Oncogene", "link": "22362916"}, "BIBREF47": {"title": "DNp73, a dominant-negative inhibitor of wild-type p53 and TAp73, is up-regulated in human tumors", "authors": [{"first": "A", "middle": ["I"], "last": "Zaika", "suffix": ""}, {"first": "N", "middle": [], "last": "Slade", "suffix": ""}, {"first": "S", "middle": ["H"], "last": "Erster", "suffix": ""}, {"first": "C", "middle": [], "last": "Sansome", "suffix": ""}, {"first": "T", "middle": ["W"], "last": "Joseph", "suffix": ""}, {"first": "M", "middle": [], "last": "Pearl", "suffix": ""}, {"first": "E", "middle": [], "last": "Chalas", "suffix": ""}, {"first": "U", "middle": ["M"], "last": "Moll", "suffix": ""}], "year": 2002, "venue": "J Exp Med", "link": "9278179"}, "BIBREF48": {"title": "Regulation of HSF1-responsive gene expression by N-terminal truncated form of p73a", "authors": [{"first": "Y", "middle": [], "last": "Tanaka", "suffix": ""}, {"first": "M", "middle": [], "last": "Kameoka", "suffix": ""}, {"first": "A", "middle": [], "last": "Itaya", "suffix": ""}, {"first": "K", "middle": [], "last": "Ota", "suffix": ""}, {"first": "K", "middle": [], "last": "Yoshihara", "suffix": ""}], "year": 2004, "venue": "Biochem Biophys Res Commun", "link": "808045"}, "BIBREF49": {"title": "Autoinhibitory regulation of p73 by DNp73 to modulate cell survival and death through a p73-specific target element within the DNp73 promoter", "authors": [{"first": "T", "middle": [], "last": "Nakagawa", "suffix": ""}, {"first": "M", "middle": [], "last": "Takahashi", "suffix": ""}, {"first": "T", "middle": [], "last": "Ozaki", "suffix": ""}, {"first": "Watanabe", "middle": [], "last": "Ki", "suffix": ""}, {"first": "K", "middle": [], "last": "Todo", "suffix": ""}, {"first": "S", "middle": [], "last": "Mizuguchi", "suffix": ""}, {"first": "H", "middle": [], "last": "Hayakawa", "suffix": ""}, {"first": "T", "middle": [], "last": "Nakagawara", "suffix": ""}, {"first": "A", "middle": [], "last": "", "suffix": ""}], "year": 2002, "venue": "Mol Cell Biol", "link": "23073092"}, "BIBREF50": {"title": "P53-mediated induction of Cox-2 counteracts p53-or genotoxic stress-induced apoptosis", "authors": [{"first": "J", "middle": ["A"], "last": "Han", "suffix": ""}, {"first": "J", "middle": ["I"], "last": "Kim", "suffix": ""}, {"first": "P", "middle": ["P"], "last": "Ongusaha", "suffix": ""}, {"first": "D", "middle": ["H"], "last": "Hwang", "suffix": ""}, {"first": "L", "middle": ["R"], "last": "Ballou", "suffix": ""}, {"first": "A", "middle": [], "last": "Mahale", "suffix": ""}, {"first": "S", "middle": ["A"], "last": "Aaronson", "suffix": ""}, {"first": "S", "middle": ["W"], "last": "Lee", "suffix": ""}], "year": 2002, "venue": "EMBO J", "link": "28183919"}, "BIBREF51": {"title": "Regeneration of peroxiredoxins by p53-regulated sestrins, homologs of bacterial AhpD", "authors": [{"first": "A", "middle": ["V"], "last": "Budanov", "suffix": ""}, {"first": "A", "middle": ["A"], "last": "Sablina", "suffix": ""}, {"first": "E", "middle": [], "last": "Feinstein", "suffix": ""}, {"first": "E", "middle": ["V"], "last": "Koonin", "suffix": ""}, {"first": "P", "middle": ["M"], "last": "Chumakov", "suffix": ""}], "year": 2004, "venue": "Science", "link": "27871118"}, "BIBREF52": {"title": "TIGAR, a p53-inducible regulator of glycolysis and apoptosis", "authors": [{"first": "K", "middle": [], "last": "Bensaad", "suffix": ""}, {"first": "A", "middle": [], "last": "Tsuruta", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Selak", "suffix": ""}, {"first": "M", "middle": ["N"], "last": "Vidal", "suffix": ""}, {"first": "K", "middle": [], "last": "Nakano", "suffix": ""}, {"first": "R", "middle": [], "last": "Bartrons", "suffix": ""}, {"first": "E", "middle": [], "last": "Gottlieb", "suffix": ""}, {"first": "K", "middle": ["H"], "last": "Vousden", "suffix": ""}], "year": 2006, "venue": "Cell", "link": "15006256"}, "BIBREF53": {"title": "Transcriptional activation of the human glutathione peroxidase promoter by p53", "authors": [{"first": "M", "middle": [], "last": "Tan", "suffix": ""}, {"first": "S", "middle": [], "last": "Li", "suffix": ""}, {"first": "M", "middle": [], "last": "Swaroop", "suffix": ""}, {"first": "K", "middle": [], "last": "Guan", "suffix": ""}, {"first": "L", "middle": ["W"], "last": "Oberley", "suffix": ""}, {"first": "Y", "middle": [], "last": "Sun", "suffix": ""}], "year": 1999, "venue": "J Biol Chem", "link": "19537056"}, "BIBREF54": {"title": "Identification of ALDH4 as a p53-inducible gene and its protective role in cellular stresses", "authors": [{"first": "K", "middle": ["A"], "last": "Yoon", "suffix": ""}, {"first": "Y", "middle": [], "last": "Nakamura", "suffix": ""}, {"first": "H", "middle": [], "last": "Arakawa", "suffix": ""}], "year": 2004, "venue": "J Hum Genet", "link": "9485646"}, "BIBREF55": {"title": "induction and activation of DDR1 kinase counteract p53-mediated apoptosis and influence p53 regulation through a positive feedback loop", "authors": [{"first": "P", "middle": ["P"], "last": "Ongusaha", "suffix": ""}, {"first": "J", "middle": ["I"], "last": "Kim", "suffix": ""}, {"first": "L", "middle": [], "last": "Fang", "suffix": ""}, {"first": "T", "middle": ["W"], "last": "Wong", "suffix": ""}, {"first": "G", "middle": ["D"], "last": "Yancopoulos", "suffix": ""}, {"first": "S", "middle": ["A"], "last": "Aaronson", "suffix": ""}, {"first": "S", "middle": ["W"], "last": "Lee", "suffix": ""}], "year": 2003, "venue": "EMBO J", "link": "22348052"}, "BIBREF56": {"title": "The antioxidant function of the p53 tumor suppressor", "authors": [{"first": "A", "middle": ["A"], "last": "Sablina", "suffix": ""}, {"first": "A", "middle": ["V"], "last": "Budanov", "suffix": ""}, {"first": "G", "middle": ["V"], "last": "Ilyinskaya", "suffix": ""}, {"first": "L", "middle": ["S"], "last": "Agapova", "suffix": ""}, {"first": "J", "middle": ["E"], "last": "Kravchenko", "suffix": ""}, {"first": "P", "middle": ["M"], "last": "Chumakov", "suffix": ""}], "year": 2005, "venue": "Nat Med", "link": "5343103"}, "BIBREF57": {"title": "Small heat shock protein aBcrystallin binds to p53 to sequester its translocation to mitochondria during hydrogen peroxide-induced apoptosis", "authors": [{"first": "S", "middle": [], "last": "Liu", "suffix": ""}, {"first": "J", "middle": [], "last": "Li", "suffix": ""}, {"first": "Y", "middle": [], "last": "Tao", "suffix": ""}, {"first": "X", "middle": [], "last": "Xiao", "suffix": ""}], "year": 2007, "venue": "Biochem Biophys Res Commun", "link": "3147359"}, "BIBREF58": {"title": "aB-crystallin is a novel predictor of resistance to neoadjuvant chemotherapy in breast cancer", "authors": [{"first": "O", "middle": [], "last": "Ivanov", "suffix": ""}, {"first": "F", "middle": [], "last": "Chen", "suffix": ""}, {"first": "E", "middle": ["L"], "last": "Wiley", "suffix": ""}], "year": 2008, "venue": "Breast Cancer Res Treat", "link": "23993478"}, "BIBREF59": {"title": "aB-crystallin as a marker of lymph node involvement in breast carcinoma", "authors": [{"first": "D", "middle": [], "last": "Chelouche-Lev", "suffix": ""}, {"first": "H", "middle": ["M"], "last": "Kluger", "suffix": ""}, {"first": "A", "middle": ["J"], "last": "Berger", "suffix": ""}, {"first": "D", "middle": ["L"], "last": "Rimm", "suffix": ""}, {"first": "J", "middle": ["E"], "last": "Price", "suffix": ""}], "year": 2004, "venue": "Cancer", "link": "25071987"}, "BIBREF60": {"title": "aB-crystallin, a new independent marker for poor prognosis in head and neck cancer", "authors": [{"first": "D", "middle": [], "last": "Chin", "suffix": ""}, {"first": "G", "middle": ["M"], "last": "Boyle", "suffix": ""}, {"first": "R", "middle": ["M"], "last": "Williams", "suffix": ""}], "year": 2005, "venue": "Laryngoscope", "link": "11310417"}, "BIBREF61": {"title": "Expression and prognostic significance of the aB-crystallin gene in human hepatocellular carcinoma", "authors": [{"first": "Q", "middle": [], "last": "Tang", "suffix": ""}, {"first": "Y", "middle": ["F"], "last": "Liu", "suffix": ""}, {"first": "X", "middle": ["J"], "last": "Zhu", "suffix": ""}, {"first": "Y", "middle": ["H"], "last": "Li", "suffix": ""}, {"first": "J", "middle": [], "last": "Zhu", "suffix": ""}, {"first": "J", "middle": ["P"], "last": "Zhang", "suffix": ""}, {"first": "Z", "middle": ["Q"], "last": "Feng", "suffix": ""}, {"first": "X", "middle": ["H"], "last": "Guan", "suffix": ""}], "year": 2009, "venue": "Hum Pathol", "link": "24775087"}}, "ref_entries": {"FIGREF3": {"text": "Fig. 3 p73 is required for aB-crystallin induction by p53. a and b EJp53 cells were grown with (filled boxes) or without p53 induction (open boxes), and RNA was collected at the indicated times. TAp73 a and DNp73 b mRNA levels were assayed by real-time RT-PCR, and the mRNA levels are shown normalized to the initial (0 h) level. Statistical significance (two-way ANOVA with Bonferroni post-test) is noted at each time point compared to the 0 h mRNA level. c and d EJ-p53 cells transfected with control non-silencing (NS) siRNA targeting luciferase or siRNAs targeting all p73 isoforms (siPANp73), DNp73 (siDNp73) [35], or TAp73 [40] were re-transfected 24 h later", "type": "figure"}, "FIGREF4": {"text": "Fig. 4 Ectopic expression of DNp73a induces aB-crystallin mRNA. EJ-p53 cells were transfected with empty vector, HA-TAp73a, HATAp73b, HA-DNp73a, HA-DNp73b, or untagged DNp73b-13 (13 amino acid N-terminal truncation) pcDNA3 plasmids. RNA and protein were collected at 0, 24, and 48 h post-transfection. a p73 protein levels were assayed by immunoblotting. b aB-crystallin mRNA levels 24 h", "type": "figure"}, "TABREF0": {"text": "). Mutations were confirmed by direct sequencing.Glo injection, respectively, in a Clarity Lumines- cence Microplate Reader (BioTek). Firefly luciferase activity was normalized to Renilla activity.", "type": "table"}}}
{"paper_id": "8339612", "_pdf_hash": "c1e2915004dc78d895f9cb7f4d1430981d30f7ea", "abstract": [{"section": "Abstract", "text": "Construction workers are exposed to considerable hazards carrying a health risk, e.g., dusts, fumes, noise and manual handling, yet there is often poor occupational health service provision particularly for subcontracted labourers. This paper presents seven case studies from large, engineering construction organizations, concerning current practice in occupational health management. The results supported the fact that data and records regarding health-related absence were limited and inconsistent, and that little existed in terms of medicals and health surveillance, particularly in the case of subcontracted workers. The main difficulties envisaged were reported to be the sizeable costs involved; the temporary and mobile work force; demonstrating cost-benefits to top management and a lack of interest amongst workers, perhaps exacerbated by the threat of lost livelihood. Managers also admitted limited health expertise and knowledge of the wider role health professionals could play in health management. Training and further research in this area are indicated.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "INTRODUCTION", "text": "One and a half million people work in the UK construction industry and it is known that its workers are among the highest risk occupational groups for lower respiratory disease, pneumoconiosis, skin disease, musculoskeletal disorders of the back and for trauma and poisoning. 1 ", "cite_spans": [], "ref_spans": []}, {"section": "\"", "text": "2 In addition, the construction industry has poor occupational health service provision in the UK despite its workers being exposed to many harmful substances (e.g., dusts, fumes, gases, toxic chemicals), biological hazards {e.g., acute and chronic infections, parasites) and physical hazards (e.g., noise, heat, cold, vibration, inflammable materials, compressed air). 3 Construction work is usually subcontracted by large, international organizations, to contractors who may then subcontract to smaller labour-only suppliers. Findings from previous research by the authors 45 con-easily solvable) problem of safety. Some of the reasons for this include: health is a complex issue; long term strategies are required; benefits are not immediate and are consequently difficult to demonstrate; exposure to hazards with different health risks can be multiple and vary in nature and level; it has a low profile; the 'macho culture' inherent in the workforce; the mobile and temporary workforce and a lack of health expertise within the industry. 6 Indeed, in a survey of 63 line and senior managers in the construction industry, it was found that there was a clear perception of the manager's role in injury prevention, but less clarity of their role in the prevention of ill-health. 7 Also, the urgent need for effective health management is diminished by the fact that generally there is no statutory requirement for health standards to be reached (with obvious exceptions, e.g., radiation, asbestos and lead).", "cite_spans": [{"start": 370, "end": 371, "text": "3", "ref_id": "BIBREF2"}, {"start": 1042, "end": 1043, "text": "6", "ref_id": "BIBREF5"}, {"start": 1280, "end": 1281, "text": "7", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "\"", "text": "The financial burden of many occupational illnesses/disabilities is largely borne by individual victims and the general public, i.e., taxation pays for the costs of the actual health treatment and any allowances (temporary or permanent). For example, drawing on data from two large surveys, the costs of work-related illness in 1990 to society, victims and employers were \u00a34.53-4.72 billion, \u00a32.72 billion and \u00a30.61-0.74 billion respectively. 8 However, over recent years there has been a large increase in the direct costs to employers of work-related ill-health. For example, employees made three times more claims against their employers in 1993 than in 1988 across all industry. 8 Reasons for this include early diagnosis of conditions, better causal identification, employee awareness of legal rights and increased trade union support in pursuing claims against employers.", "cite_spans": [{"start": 443, "end": 444, "text": "8", "ref_id": "BIBREF7"}, {"start": 683, "end": 684, "text": "8", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "\"", "text": "Health surveillance involves the identification of the early signs of work-related ill-health through systems which include keeping health records and conducting health checks. Surveillance data are used to determine the need for occupational safety and health action and to plan, implement and evaluate interventions and programmes. 9 It is widely acknowledged that in the construction industry, adequate health surveillance is not available and that early signs of work-related health problems are not identified.", "cite_spans": [{"start": 334, "end": 335, "text": "9", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "\"", "text": "There is an urgent need to address the extent, causes and management of the problem of occupational illhealth in the construction industry and to improve the health culture. This investigation develops the research reported previously. 5 The aim is to establish the extent of existing health and welfare provision, health surveillance activities and health information collected and establish its use and role in developing prevention strategies.", "cite_spans": [{"start": 236, "end": 237, "text": "5", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "RESEARCH METHOD Case studies", "text": "Case studies were used to explore how companies were addressing health issues on seven UK sites. One experienced researcher conducted all of the interviews between November 1996 and March 1997. Wider surveys have been undertaken, 7 but few investigations have attempted to study health management in detail.", "cite_spans": [{"start": 230, "end": 231, "text": "7", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "RESEARCH METHOD Case studies", "text": "As with the previous investigation, 5 the research involved the engineering construction sector, i.e., the construction activities of the process, power and energy industries, where health management is likely to be most rigorous. In addition, focus on the engineering construction sector (and choice of sites) was due to availability of access through the European Construction Institute (ECI), with the justification that the performance of these large, high profile organizations is likely to represent current best practice in the UK. ECI is a pan-European and pan-construction organization comprising clients, designers, contractors and trade associations. Although job titles varied between companies, interviewees were generally corporate health and safety advisors, site health and safety advisors, nurses and line managers on site at the time of the visit and employed by either the client or major contractor. In all cases the major contractor was the organization with overall responsibility for construction activities, but the specific contractual arrangements differed in each project.", "cite_spans": [{"start": 36, "end": 37, "text": "5", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "Interview schedule", "text": "The interviews were semi-structured in nature, guided by carefully prepared questions and issues to be explored to reflect the basic research question, but where neither the wording nor the exact order of questions, were pre-determined. The majority of the questions were 'open-ended' for flexibility and depth of information. The interviews were also exploratory, allowing discussion around health issues to evolve. Consequently some of the interview dialogue reflected the views of experienced individuals rather than those of a particular company. A summary of the central questions and issues explored during the interviews is shown in Table 1 . Copies of any relevant material such as health questionnaires, checklists, policies, etc. were gathered, site walkabouts were conducted and relevant meetings were attended to enrich information obtained from the interviews. The interviews took place over 1-2 days and were recorded on audiotape, transcribed by the researcher and then erased, assuring anonymity and confidentiality. Several techniques were used to ensure truth-value or credibility of the work. 10 Triangulation supports credibility by using multiple data sources to provide insights about the same events. For example, when considering the construction sites' health and welfare facilities, planning/proposal documents were examined and the reactions of workers, health staff and safety managers to these facilities were noted. Observation (on site) also provided further confirmation. In addition, member checking allowed the interviewees to respond to interpretations from the interview, for example, by verifying conclusions from earlier work, challenging interview summaries, providing written comments on the contents of resulting reports and by discussing the results during ECI task force meetings.", "cite_spans": [{"start": 1112, "end": 1114, "text": "10", "ref_id": "BIBREF9"}], "ref_spans": [{"start": 640, "end": 647, "text": "Table 1", "ref_id": "TABREF0"}]}, {"section": "Interview schedule", "text": "Due to the diversity of sites, project size, project stage, etc., the results are presented in the form of case studies from which points are drawn out for discussion. The details regarding project cost, manhours, etc. are not included to protect the identity of the companies. The term 'green-field site' is used when there has been no previous construction, no demolition and the building work is not within an existing facility. The sample sites indicate the range of construction activities in the UK engineering construction sector at the time of the study.", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS", "text": "The case studies represent current practice and expert judgements of the interviewees on a range of health issues in the construction industry. This 'snapshot' account reflects the position of large, high profile organizations, which it was judged by the research team are more likely to be proactive in terms of health management. The study must be placed in this context. The range of case study sites is shown in Table 2 and general health and welfare provision on these sites is summarized in Table 3 . A fully equipped clinic set up by the main contractor with a full-time RGN.", "cite_spans": [], "ref_spans": [{"start": 416, "end": 423, "text": "Table 2", "ref_id": "TABREF1"}, {"start": 497, "end": 504, "text": "Table 3", "ref_id": "TABREF2"}]}, {"section": "RESULTS", "text": "In line with and above regulations (WCs, sinks, canteen, drying rooms).", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS", "text": "In line with and above regulations (WCs, sinks, canteen, drying rooms).", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS", "text": "In line with and above regulations (WCs, sinks and drying rooms).", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS", "text": "Mobile facilities (WCs and sinks) -mobile drying rooms and showers were difficult to arrange.", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS", "text": "Excellent welfare facilities including hand wash areas, eye wash areas, showers, canteen and industrial chaplain. Contract workers had their own building with canteen, offices and car park.", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS", "text": "In line with and above regulations (WCs, sinks and drying rooms).", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS", "text": "In line with and above regulations (WCs, sinks, lockers, and canteen), however no showers or drying rooms.", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS", "text": "* This facility was not available for use by contract staff except for more serious accident injuries. N.B. All sites had first aid facilities, trained first aiders (in line with and above regulations) and emergency accident/health procedures.", "cite_spans": [], "ref_spans": []}, {"section": "Data collection and collation", "text": "Considering health data, all of the sites routinely collected first aid, over-3-day lost time injury data and RIDDOR reportable accidents and illnesses. Only one client and one of the major contractors were starting to collect health-related absence data on their subcontracted workers. Both of these organizations felt that there was not yet 100% reporting of occupational health-related lost time and that the system relied on the honesty and efficiency of individual contractors. These data were forwarded to a central location for collation, analysis of sickness absence trends and subsequent reports. The other four major contractors only collected this information if the individual employee visited the nurse (where available). A client representative interviewed indicated that currently there were no clear systems or frameworks in place to monitor health in either their own employees or their contractors. This research investigated the health surveillance procedures on the case study sites and within case study organizations. In some cases operatives or company staff had medicals or health checks on other projects or when working for other organizations, usually to fulfil the statutory requirements for specific workers, e.g., radiation workers. However, for the majority of subcontracted workers there appears to be no consistent approach to health management, emphasizing the need for an industry-wide standard.", "cite_spans": [], "ref_spans": []}, {"section": "Data collection and collation", "text": "Case study 1 (400-1,400 employees). The interviews took place during the final year of a four-year greenfield construction site for the building of a PowerStation where the client was closely involved on site. Interviewees were a client line manager, the site health and safety manager and a Registered General Nurse (RGN) with 5 years experience in occupational health. The latter two were both employed by the main contractor.", "cite_spans": [], "ref_spans": []}, {"section": "Data collection and collation", "text": "The full time RGN and retained occupational health physician were available to all site employees. All site employees completed a health assessment questionnaire at the start of their employment and any health concerns admitted were followed up. Pre-employment medicals and health surveillance were not undertaken for site employees. The site nurse suspected that the majority of subcontracted workers concealed information regarding their health to avoid questions raised about their fitness for work, despite confidentiality being assured. It was considered that her role was more reactive than proactive, i.e., workers visited her in the clinic for treatments. She did not attend health and safety meetings or accompany health and safety professionals on site walkabouts, although she felt that her role could be more proactive, e.g., she could advise on manual handling, sun protection, health risk assessment and check the welfare facilities (toilets, wash areas).", "cite_spans": [], "ref_spans": []}, {"section": "Data collection and collation", "text": "This site nurse thought that generally workers did not have an interest in health, e.g., protecting their skin from irritants, but that given time, encouragement and confidentiality workers would discuss their concerns. In support of this, it had been noticed that visits to the first aid facility by site managers, workers, etc. had increased and there was less stigma attached to them.", "cite_spans": [], "ref_spans": []}, {"section": "Data collection and collation", "text": "Regarding the management of health, difficulties were expressed as being the high cost to the industry, overall monitoring and maintaining confidentiality.", "cite_spans": [], "ref_spans": []}, {"section": "Data collection and collation", "text": "Finally, when asked for ideas concerning how the health of subcontractors could be managed, a form of 'swipe-card' system that workers carried, containing details of medicals, surveillance, work history, etc. was suggested.", "cite_spans": [], "ref_spans": []}, {"section": "Data collection and collation", "text": "Case study 2 (maximum of 600 employees). The interviews were carried out during the final year of a three-year green-field construction site of two sewage treatment plants. The client was not closely involved on these sites. Interviewees were the two site safety officers (with responsibility for health) employed by the main contractor.", "cite_spans": [], "ref_spans": []}, {"section": "Data collection and collation", "text": "No occupational health nurse was appointed to these sites, although the health and safety managers felt that, in retrospect, this was an omission. These projects involved work on contaminated land and airborne bacteria had been identified as a health risk. From the interviewees' perspective it was suspected that in some instances workers were abusing 'the seriousness' that was placed on this bacteria to take time off from work and they considered that a nurse may have been able to contribute to the validation of these claims. Preemployment questionnaires, medicals or health surveillance were not undertaken for site employees.", "cite_spans": [], "ref_spans": []}, {"section": "Data collection and collation", "text": "The lifestyle of the 'travelling workers' living away from home, which involved alcohol consumption, late nights, poor food and accommodation lead one of the managers to conclude that generally construction workers did not take care of their health and that attitudes were not changing. However it is of interest that on this particular site with the risk of airborne bacteria, workers were very diligent at washing their hands, wearing protective clothing, dressing all cuts, etc.", "cite_spans": [], "ref_spans": []}, {"section": "Data collection and collation", "text": "The high cost inherent in health management was the main concern of the safety officers, although evidence for this was anecdotal. Construction is a competitive industry and there was a fear that the UK could fall behind countries that do not have such 'restrictive' practices. In addition, the client would ultimately pay and as clients are generally the service industries, this cost would be passed on to the end user. There was also a belief that it was unrealistic (as well as too expensive) for the industry to be managing the general health and well-being of this transient work force: individuals needed to take responsibility for their own health.", "cite_spans": [], "ref_spans": []}, {"section": "Data collection and collation", "text": "Concerning the future management of the health of their contractors, the idea of establishing a central, computerized system was thought to be a possible solution. Subscribing companies would pay a registration and an annual fee for the central management of the health of the construction work force. This could take the form of a 'passport' type system where medicals, surveillance, check-ups, health training, etc. were routinely co-ordinated. As all companies were ultimately using the same pool of labour, the current employer of an individual worker would pay the costs of any medicals due during that employment.", "cite_spans": [], "ref_spans": []}, {"section": "Data collection and collation", "text": "Case study 3 (50-60 employees) . The interviews took place halfway though a two-year, new process building construction project on the existing factory site where the client was in close contact. Interviewees were all employed by the main contractor and comprised a corporate health and safety advisor, the site manager and the site safety advisor (with responsibility for health).", "cite_spans": [], "ref_spans": []}, {"section": "Data collection and collation", "text": "The client-run medical centre employed a full-time RGN and an occupational health physician one day a week for their own employees. However, this facility was only available to contractors for more serious accident injuries, which the trained first aiders on the construction site were unable to handle. Contractors were not encouraged to use the centre for other health reasons, medicals or health surveillance as this was not included in the project costs and would therefore be an additional expense for the client. Pre-employment questionnaires, medicals or health surveillance were not undertaken for workers on this construction site.", "cite_spans": [], "ref_spans": []}, {"section": "Data collection and collation", "text": "Once again the attitude of. workers to their health was felt to be poor, i.e., not interested in sun protection, skin care, good lifting practice, etc. It was thought unlikely that workers would take the initiative to arrange their own medical assessments/health surveillance with occupational health professionals. Although in one manager's experience, older, fit workers would be likely to have a medical, as it would be in their interest to prove their fitness for work.", "cite_spans": [], "ref_spans": []}, {"section": "Data collection and collation", "text": "It was expressed that any health management system would be difficult to implement due to the suspicion that it would create regarding possible job loss: prospective employees may conceal information about their health in order to secure employment.", "cite_spans": [], "ref_spans": []}, {"section": "Data collection and collation", "text": "Once again the creation of a 'passport' system was cited as the way forward for the future management of health. For example, extending the 'Safety Passport Scheme' managed by the Engineering Construction Industry Training Board (ECITB) on behalf of clients, to all workers and to include health as well as safety training information.", "cite_spans": [], "ref_spans": []}, {"section": "Case study 4 (150-300 employees).", "text": "The interviews took place during the early preparation and administration stage of a 12-month green-field site-laying 27 km of gas pipeline with the client on site. The individual pipes were 18 x 1.5 metres and weighed 14 tonnes. The site safety manager (with responsibility for health) was interviewed.", "cite_spans": [], "ref_spans": []}, {"section": "Case study 4 (150-300 employees).", "text": "There was no plan to employ an occupational health nurse or to install a treatment room at the site base. As the work on this site was distributed along the pipeline, and continually changing location, efforts were being made to ensure trained first aiders and medical kits were available to each team of workers. Pre-employment questionnaires, medicals or health surveillance would not be undertaken for workers on this site.", "cite_spans": [], "ref_spans": []}, {"section": "Case study 4 (150-300 employees).", "text": "This manager felt that the specialist group of 'high risk' workers involved in pipe-laying took a greater interest in their health, than those in general engineering construction, with regard to wearing sun protection, clothing, ear protection and gloves. However, it was considered unlikely that workers would organize medicals or health monitoring for themselves.", "cite_spans": [], "ref_spans": []}, {"section": "Case study 4 (150-300 employees).", "text": "Once again there was a fear that the management of health in the transient work force would be difficult and expensive, such that the UK may lose its competitive edge with companies/countries not requiring or achieving such high standards in health management.", "cite_spans": [], "ref_spans": []}, {"section": "Case study 4 (150-300 employees).", "text": "It was established that these pipelayers were mostly a stable work force, as the same team moved from site to site for employment. Consequently the management of health in this group of workers and similar groups (e.g., tunnellers) was perceived to be less complicated.", "cite_spans": [], "ref_spans": []}, {"section": "Case study 5: (600 employees plus 100-150 contract, staff).", "text": "The interviews took place in an existing PowerStation. It was a client operation with contractor involvement in routine maintenance, breakdown maintenance and outage work (every 18 months, whereby the plant was shut down for a more thorough service). A corporate health and safety advisor, the occupational health nurse (Diploma in Occupational Health) and a site health and safety officer (all employed by the client) were interviewed.", "cite_spans": [], "ref_spans": []}, {"section": "Case study 5: (600 employees plus 100-150 contract, staff).", "text": "This client ran a fully equipped medical centre for their own employees with a full-time occupational health nurse, a temporary RGN when required and a physiotherapist 1.5 days/week. A local GP and the company Chief Medical Officer also visited monthly. However, once again this facility was not available for any contract staff except in the case of a serious accident or acute illness. Contractors requiring medicals, etc. had to visit local GPs. Pre-employment questionnaires, medicals and health surveillance were undertaken for client employees and for certain categories of risk workers, e.g., radiation workers and heat-stress workers. The view was put forward that health professionals addressed very different issues to site safety officers, therefore the occupational health nurse's attendance and contribution to the Health and Safety Committee meetings was valued.", "cite_spans": [], "ref_spans": []}, {"section": "Case study 5: (600 employees plus 100-150 contract, staff).", "text": "It was considered that workers on this and similar sites with possible exposure to radiation took an interest in taking care of their health.", "cite_spans": [], "ref_spans": []}, {"section": "Case study 5: (600 employees plus 100-150 contract, staff).", "text": "Problems regarding the health management of contracted workers were perceived to be the costs involved, quantification and the need to persuade top management to build for the future with up-front investment. The increased modular nature of the work would also result in more contractors and less control over the work force. It was felt that health should be costed into a project but that these costs would be high as medicals and surveillance are time consuming and cannot be rushed.", "cite_spans": [], "ref_spans": []}, {"section": "Case study 5: (600 employees plus 100-150 contract, staff).", "text": "A way forward for the management of health was once again thought to be a 'swipe-card' system similar to that already used by this company for radiation dose reviews.", "cite_spans": [], "ref_spans": []}, {"section": "Case study 5: (600 employees plus 100-150 contract, staff).", "text": "Case study 6 (6, 000 contract employees at the time of the  interview) . The interviews took place in the final year of a nine-year tunnelling project with close client involvement. In addition to the above, the project also employed 1,000 personnel on the project management team. The client safety and quality manager (with responsibility for health) on this project was interviewed.", "cite_spans": [], "ref_spans": []}, {"section": "Case study 5: (600 employees plus 100-150 contract, staff).", "text": "This client ran its own fully equipped medical facility for employees with doctors and nursing staff. Contractors were responsible for their own provision of health care on site but the client health and safety advisor suspected a wide variation in standard of care, i.e., medical facilities, health surveillance offered. The client did not insist on contractors' compliance with pre-set standards/procedures of health management (with the exception of statuary requirements). It was also highlighted that their own medical staff were probably not familiar with dealing with the occupational health problems specific to construction activities, as they mainly dealt with office workers. Equally, it was felt that construction management professionals generally do not have a good appreciation of occupational health hazards and therefore were unable to appreciate the benefits of 'expensive' experts, i.e., doctors and nurses. For example construction managers may feel that they do not need the medical profession to be involved in risk assessments, manual handling training, hearing tests, etc.", "cite_spans": [], "ref_spans": []}, {"section": "Case study 5: (600 employees plus 100-150 contract, staff).", "text": "Once again the work environment was regarded anecdotally to be a 'macho' culture, but also that gradually workers were becoming more aware of the need to take care of their health, e.g., by wearing gloves. Health education was thought to originate from increased general public awareness rather than from any management activities. It was considered that employers do have a role in prevention of occupational ill-health but it was admitted that currently management awareness/interest was poor.", "cite_spans": [], "ref_spans": []}, {"section": "Case study 5: (600 employees plus 100-150 contract, staff).", "text": "Several issues were raised regarding the problem of health management. Firstly, it was difficult as a client to enforce high standards for health provision on contractors, when the benefits were not immediate and with the need to cut costs in the industry. Also, as a client it would be necessary to balance the desirable outcomes with what the whole industry could actually deliver. There was also fear that regular medicals may take away livelihoods (e.g., workers with dermatitis, deafness or back pain) and that eventually there would be no one to do the job. Finally, problems in persuading designers to consider health issues in construction D. E. Gyi el al.: OH management in the engineering construction industry 269 design when safety was still high on the agenda were anticipated.", "cite_spans": [], "ref_spans": []}, {"section": "Case study 5: (600 employees plus 100-150 contract, staff).", "text": "It was pointed out that the framework for health management was already in place (from the legislation) and therefore the way forward was considered to be a slow 'war of attrition' in a similar way to the management of safety, i.e., continual communication to workers and their managers, emphasizing the importance of occupational health. As a client they were only just beginning to take the initiative and consider health, e.g., by focusing their site Safety Management Award Scheme on health. In addition, they were examining the effectiveness of their management of health in their own employees, introducing medicals at the start and end of employment, and were generally raising health awareness. This approach would eventually provide them with the skills to enable them to review how well contractors were managing the health of their employees. The difficulties this could bring were appreciated but they felt that ultimately contractors would be expected to manage their subcontractors' health and that the client's role would be to advise and set standards. A concern was however expressed that with better records companies could be opening themselves up for litigation and that this may be seen by some as a disincentive to take a more proactive role in health surveillance.", "cite_spans": [], "ref_spans": []}, {"section": "Case study 7 (maximum of 550 employees).", "text": "The interviews took place approximately halfway into a 21-month green-field construction site involving the extension of an existing PowerStation. A corporate health and safety manager, the site safety manager (with responsibility for health) and the RGN (all employed by the main contractor) were interviewed.", "cite_spans": [], "ref_spans": []}, {"section": "Case study 7 (maximum of 550 employees).", "text": "The clinic employed a full-time RGN that all site employees could visit whether the health problem was work-related or not. Once again her role was more reactive than proactive. As a female in a mainly male environment and unused to construction activities, she admitted that she did not feel comfortable walking around the site unaccompanied. Once again preemployment questionnaires, medicals or health surveillance were not undertaken for workers on this site.", "cite_spans": [], "ref_spans": []}, {"section": "Case study 7 (maximum of 550 employees).", "text": "Workers were reported to exhibit variable attitudes and behaviours with regard to health, which was felt to be due to individual personalities rather than age, race, etc., although awareness of specific risks was thought to be improving, e.g., wearing gloves to protect the skin. With regard to medicals, it was indicated that workers who were 'fit' would co-operate, however, workers with any health problems would not, because of fear of job loss.", "cite_spans": [], "ref_spans": []}, {"section": "Case study 7 (maximum of 550 employees).", "text": "Cost was once again raised as the main concern regarding health management of this 'maze' of contractors with its mobile work force. Margins were already considered tight in the industry and there was a fear that the requirement of pricing health into contracts could reduce the competitive edge. It was admitted that it was unlikely that health management would be industry lead and that more specific legislation would be required, which clients/major contractors in turn would need to enforce.", "cite_spans": [], "ref_spans": []}, {"section": "Case study 7 (maximum of 550 employees).", "text": "A possibility for the future management of health was suggested involving the clients and major contractors sharing 'core contractors' to form a nucleus of steady workers. Costs would then be shared to maintain these workers with regard to medicals and surveillance. It was expressed that the industry needs to be seen to care about individuals and to be doing something for their benefit.", "cite_spans": [], "ref_spans": []}, {"section": "Alcohol and substance abuse", "text": "As a possible health issue, companies were asked the extent of screening for alcohol and substance abuse. Whilst all the organizations had policies to cover alcohol and substance abuse, none conducted postaccident, random or pre-hire screening on their construction sites. Although these interviewees were unaware of the extent of the problem, they were uncomfortable about enforcing any formal surveillance system (with breathalysers/blood tests) due to concern over breaching civil rights. However, should alcohol be discovered on site or an employee be suspected of consuming alcohol or drugs, they would immediately be removed from site and disciplinary procedures would commence. This fact is specifically addressed during the induction of workers. Individual alcohol and drug intake (with its wider effects) were only discussed as part of medicals, and as previously reported, the large group of subcontracted workers were not covered by this.", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "This paper considers seven case studies of the interviewees' perceptions of the existing situation with regard to health management. In so far as they represent the views of the UK engineering construction industry, the implications are striking. Data/records collected regarding absence and health in subcontracted workers were limited and inconsistent, with little systematic analysis. The majority of companies only examined the data if a problem had occurred. Since data and records are an important part of any health management system, it is not surprising that prevention strategies (health assessments, medicals and health surveillance) had not been developed for workers at risk.", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "Pre-employment questionnaires, medicals and health surveillance were not widespread among these organizations for either their own staff or any contracted workers. In a postal survey of 5,000 employers from across all industry, it was found that only 31% of companies who had identified at least one serious hazard at work were performing pre-employment medicals and 29% were carrying out health surveil-lance.\" It is suspected that figures for the construction industry would be even lower.", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "As identified in other work 7 these case studies also found a clear perception of construction managements' role in safety and the prevention of injury, but less clarity regarding the prevention of ill-health. Nevertheless, managers did have concerns about the health of their work force and were aware of the health risks in construction activities. The familiar and practical issues of resourcing occupational health management in the competitive construction environment; the numbers of temporary workers; the multi-contracted and mobile work force and a lack of interest by workers, possibly fuelled by the fear of job loss, were all raised as barriers to solutions. However, despite the often quoted 'mobility' and 'high turnover' of subcontracted labour, the work force mostly consists of the same group of core workers, who have been in the industry for years, rotating between contractors and projects. 12 It was argued by respondents that there needs to be a balance between what is desirable and what the industry (including the smaller contractors) can realistically begin to deliver.", "cite_spans": [{"start": 911, "end": 913, "text": "12", "ref_id": "BIBREF11"}], "ref_spans": []}, {"section": "DISCUSSION", "text": "The practice of employing an occupational health nurse specifically for construction site workers was not consistent. Two of the construction sites had a dedicated RGN for use by all employees including contracted workers, but although experienced in occupational health, these nurses did not have formal qualifications in occupational health. Three of the sites had a client-run Medical Centre which could only be used by contracted workers in emergencies and the other two sites had no health professionals, only trained first aiders. Although site size is a factor, one health and safety advisor cited that a general lack of understanding of health hazards and the failure to recognize the potential of the occupational health nurse in health and safety on a construction site, could be reasons for this. Interestingly, research\" has found that a doctor or nurse performed only 26% of 'inspections for readily detectable conditions'. Also, although 53% of 'enquiries about symptoms, inspection and examination' involved doctors or nurses, 38% of these were attributed to doctors and only 14% to nurses. It seems that many organizations (not just construction) have a limited perception of the extended role of the occupational health nurse in health and safety. In turn, occupational health professionals must promote the contribution they can make to health management. 13 Unfortunately, findings from this and our previous research have indicated that the construction industry is unlikely to begin to address health management specifically, without outside influence. However, the need to redress the balance between health and safety was recognized by these interviewees. Generally smaller companies do not have highly developed management systems, therefore it is the role of large organizations to provide support and take the lead in implementing health management systems. It should be remembered that over 50% of site workers are self-employed, 14 although this may change with recent legislation imposing stricter rules on self-employment and PAYE. 15 Cost-benefit analysis of health management is difficult to conduct but studies often indicate that medical examinations, health surveillance, etc. are expensive.", "cite_spans": [{"start": 1374, "end": 1376, "text": "13", "ref_id": "BIBREF12"}, {"start": 1957, "end": 1959, "text": "14", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "816", "text": "The essential issues for employers are the actual costs of investing in health and safety, and the benefits likely to be achieved in the short, medium and long term. 16 However, benefits such as higher productivity, improved morale, fewer compensation claims, greater control of hazards and confidence from insurers, will always be difficult to quantify in the short, medium and even long term. As highlighted by one health and safety manager, convincing top management of the benefits of an occupational health service will continue to be difficult. Nevertheless, large financial savings were demonstrated as a result of reductions in the average duration of sickness absence, by ensuring early referral of employees with longer term sickness absence to the occupational health departments. 17 Risk assessment determines the degree of risk employees face from exposure to hazards at work and can help establish what is necessary to control the risk and to protect health. These participating organizations were already undertaking risk assessments for certain health hazards, encouraged considerably by the need to comply with recent legislation, e.g., COSHH. Broadening risk assessment to identify specific short and long term health hazards (as well as safety) could be the way forward for the industry, driving targeted and effective health management. It must also be remembered that workers have a key part to play in the management of their own health, facilitated by the provision of education and training as part of the health management system. Alcohol and drug use was generally perceived to be difficult areas to enforce control and to judge the extent of the problem in the UK. Added to this, was a hesitance by the majority of the interviewees to formalize any monitoring systems, e.g., breathalysers and screening. The psychosocial issues surrounding alcohol and drug abuse in site workers were not generally addressed.", "cite_spans": [{"start": 166, "end": 168, "text": "16", "ref_id": "BIBREF15"}, {"start": 792, "end": 794, "text": "17", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "816", "text": "Finally, all the interviewees advocated the development of central management of the health (and safety) of the large, mobile work force of subcontracted workers where costs could be shared by the industry. Health and safety 'passports'/'swipe-cards' were popular suggestions as part of the management of this. Obviously, open debate and research are necessary prerequisites to these future possibilities.", "cite_spans": [], "ref_spans": []}, {"section": "816", "text": "The limitations of drawing conclusions from qualitative interview data are well-documented. However, it is believed that this exploratory study has provided some insight into the issues regarding occupational health management in the engineering construction industry reflecting the views of experienced individuals within the industry. It has also highlighted the need for a larger, more systematic and analytical study in this area, for example auditing health record keeping, health surveillance practices, expenditure on the site occupational health service, attendance at health and safety meetings, training in health hazards and conducting fitness for work assessments. CONCLUSIONS 1. Data and records regarding health-related absence were limited and inconsistent on the case study sites, particularly for subcontracted workers. It is suspected that die situation across the broader construction industry is likely to be worse.", "cite_spans": [], "ref_spans": []}, {"section": "816", "text": "2. These case studies illustrate that little exists in terms of pre-employment questionnaires, medicals, health assessments and health surveillance, once again particularly for subcontracted workers.", "cite_spans": [], "ref_spans": []}, {"section": "816", "text": "3. The main difficulties envisaged in occupational health management were the potential large costs involved; the sizeable, temporary and mobile work force; demonstrating cost-benefits to top management; and the lack of interest among workers, perhaps due to possible loss of livelihood.", "cite_spans": [], "ref_spans": []}, {"section": "816", "text": "4. The case studies confirmed limited health expertise among managers coupled with a lack of understanding of the potential role of health professionals in construction organizations, e.g., health surveillance, health and safety committees, specific health training, fitness for work and sickness absence management.", "cite_spans": [], "ref_spans": []}, {"section": "816", "text": "5. A lack of health professionals (with formal occupational health qualifications) on site was confirmed.", "cite_spans": [], "ref_spans": []}, {"section": "816", "text": "6. Research in the area of health management of construction workers is urgently needed to provide guidance to the industry.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF1": {"title": "Health and Safety Commission (HSC) Health and Safety Statistics 1995/96", "authors": [], "year": 1996, "venue": "", "link": null}, "BIBREF2": {"title": "Safety and health in the construction industry", "authors": [{"first": "D", "middle": [], "last": "Snashall", "suffix": ""}], "year": 1990, "venue": "Br MedJ", "link": "27198825"}, "BIBREF3": {"title": "A methodology to investigate the causes of accidents in the construction industry", "authors": [{"first": "D", "middle": ["E"], "last": "Gyi", "suffix": ""}, {"first": "Agf", "middle": [], "last": "Gibb", "suffix": ""}, {"first": "R", "middle": [], "last": "Haslam", "suffix": ""}], "year": 1996, "venue": "Proceedings of the ARCOM 12th Annual Conference", "link": null}, "BIBREF4": {"title": "The quality of accident and health data in the construction industry: Interviews with senior managers. Construction Management and Economics", "authors": [{"first": "D", "middle": ["E"], "last": "Gyi", "suffix": ""}, {"first": "Agf", "middle": [], "last": "Gibb", "suffix": ""}, {"first": "R", "middle": [], "last": "Haslam", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF5": {"title": "A mortality study of workers in die British construction industry 1975-1987", "authors": [{"first": "W", "middle": [], "last": "Dong", "suffix": ""}], "year": 1992, "venue": "", "link": null}, "BIBREF6": {"title": "The perceptions of line and senior managers in relation to occupational health issues", "authors": [{"first": "L", "middle": [], "last": "Falconer", "suffix": ""}, {"first": "H", "middle": [], "last": "Hoel", "suffix": ""}], "year": 1996, "venue": "OccupMed", "link": "17383074"}, "BIBREF7": {"title": "The Costs to the British Economy of Wbrk Accidents and Vifork-related 111 Health", "authors": [{"first": "N", "middle": ["V"], "last": "Davies", "suffix": ""}, {"first": "P", "middle": [], "last": "Teasdale", "suffix": ""}], "year": 1995, "venue": "", "link": null}, "BIBREF8": {"title": "V\\hrk-related Musculoskeletal Disorders (WMSD s): A Reference Book for Prevention", "authors": [{"first": "I", "middle": [], "last": "Kuorinka", "suffix": ""}, {"first": "L", "middle": [], "last": "Forcier", "suffix": ""}], "year": 1995, "venue": "", "link": null}, "BIBREF9": {"title": "Doing Naturalistic Enquiry. A Guide to Methods", "authors": [{"first": "D", "middle": ["A"], "last": "Erlandson", "suffix": ""}, {"first": "E", "middle": ["L"], "last": "Harris", "suffix": ""}, {"first": "B", "middle": ["L"], "last": "Skipper", "suffix": ""}, {"first": "S", "middle": ["D"], "last": "Allen", "suffix": ""}], "year": 1993, "venue": "", "link": null}, "BIBREF10": {"title": "Health surveillance in Great Britain", "authors": [{"first": "S", "middle": [], "last": "Honey", "suffix": ""}, {"first": "J", "middle": [], "last": "Hillage", "suffix": ""}, {"first": "A", "middle": [], "last": "Patch", "suffix": ""}, {"first": "S", "middle": [], "last": "Morris", "suffix": ""}], "year": 1996, "venue": "", "link": "150575216"}, "BIBREF11": {"title": "Total integration of the safety professional into the project management team", "authors": [{"first": "P", "middle": [], "last": "Brown", "suffix": ""}], "year": 1996, "venue": "Proceedings of the First International Conference of CIB Vhrking Commission W99", "link": null}, "BIBREF12": {"title": "How I help managers understand and value an occupational health department", "authors": [{"first": "S", "middle": [], "last": "Jones", "suffix": ""}], "year": 1997, "venue": "Occup Med", "link": "28281247"}, "BIBREF13": {"title": "Health and Safety at Work. COSHH: So far so good", "authors": [], "year": 1991, "venue": "Health and Safety at \\Abrk", "link": null}, "BIBREF15": {"title": "What do accidents cost? Health and Safety at", "authors": [{"first": "M", "middle": [], "last": "Everley", "suffix": ""}], "year": 1995, "venue": "Wbrk", "link": null}, "BIBREF16": {"title": "Effects of changing the pattern of sickness absence referrals in a local authority", "authors": [{"first": "R", "middle": ["M"], "last": "Malcolm", "suffix": ""}, {"first": "J", "middle": [], "last": "Harrison", "suffix": ""}, {"first": "H", "middle": [], "last": "Forster", "suffix": ""}], "year": 1993, "venue": "Occup Med", "link": "13461163"}}, "ref_entries": {"TABREF0": {"text": "A summary of the central questions and issues explored during the interview dialogueFacilities (hand washing, toilets, clothing storage, treatment room, etc.)? Number of health professionals (doctor, nurse, and physiotherapist)? Trained first aiders? Pre-employment? Includes subcontractors? Health questionnaires? Sickness absence (not accident related)? Fitness tests? Hearing tests? Central collation? Analysis of trends? Insurance claims?", "type": "table"}, "TABREF1": {"text": "Description of the case study sites", "type": "table"}, "TABREF2": {"text": "A summary of health and welfare provision on the case study sites", "type": "table"}}}
{"paper_id": "8339666", "_pdf_hash": "3eca61b4333bbe0bb6764b8151b20109519825ee", "abstract": [{"section": "Abstract", "text": "Study Design. Prospective randomized trial.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Objective. To examine the effect of the tumor necrosis factor alpha (TNF-a) inhibitor, etanercept, on radicular pain by its epidural administration onto spinal nerves in patients with lumbar spinal stenosis.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Summary of Background Data. TNF-a is thought to play a crucial role in the radicular pain caused by lumbar disc herniation and spinal stenosis. Intravenous infusion of infliximab for sciatica has been examined in 2 studies; however, the results were equivocal.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Methods. Eighty patients with low back and radicular leg pain were investigated. We diagnosed the patients by physical examination, and X-ray and magnetic resonance imaging. In 40 patients we epidural administered 2.0 mL of lidocaine and 10 mg of etanercept onto the affected spinal nerve, and 2.0 mL of lidocaine and 3.3 mg of dexamethasone was used in 40 patients. Low back pain, leg pain, and leg numbness were evaluated using a visual analogue scale (VAS) and Oswestry Disability Index (ODI) score before and for 1 month after epidural administration.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Results. Low back pain, leg pain, and leg numbness in the two groups were not significantly different before epidural administration. Epidural administration of etanercept was more effective than dexamethasone for leg pain (3 days, 1, 2, and 4 weeks: P < 0.05), low back pain (3 days, 1 and 2 weeks: P < 0.05), and leg numbness (3 days, 1 and 2 weeks: P < 0.05). No adverse event was observed in either group.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Our results indicate that epidural administration of a TNF-a inhibitor onto the spinal nerve produced pain relief, but no adverse event. TNF-a inhibitors may be useful tools for ", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Epidural administration of the TNF-a inhibitor, etanercept, onto spinal nerves in patients with lumbar spinal stenosis was more effective than similar application of dexamethasone for leg pain, low back pain, and leg numbness caused by spinal stenosis.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "l We examined the effect of the TNF-a inhibitor, etanercept, on radicular pain by its epidural administration onto spinal nerves in patients with lumbar spinal stenosis, compared with application of dexamethasone.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "l Epidural administration of etanercept was more effective than dexamethasone for leg pain, low back pain, and leg numbness.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "l We did not observe any adverse event in either the etanercept or dexamethasone group.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "l Epidural administration of a TNF-a inhibitor onto spinal nerves produced significant relief of pain caused by spinal stenosis.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "", "text": "lack of normal sensitivity. 6, 7 It has been shown that compression of the spinal nerve roots may induce neurophysiologic dysfunction, degeneration, and reduced blood flow in nerve roots in both animal models and humans. 6, 7 Recently, cytokines such as interleukins 1, 6 (IL-1, IL-6), and tumor necrosis factor-alpha (TNF-a) have been strongly linked to radicular pain. 2, 7, 8 It has also been reported that IL-1, IL-6, and TNF-a are activated in dorsal root ganglia and Schwann cells in the spinal nerve roots following lumbar spinal stenosis, and that their expression is closely related to pain, motor nerve dysfunction and degeneration. 3, 7 In animal models, the TNF-a inhibitors, infliximab (intravenous injection) and etanercept (subcutaneous injection), have prevented a nucleus pulposus-induced reduction of nerve conduction velocity and also seemed to limit nerve fiber injury, intracapillary thrombus formation, and intraneural edema. 9 In the clinic, inhibition of TNF-a has become a common modality for treating rheumatoid disease. It has been reported that a single intravenous infusion of infliximab was effective in treating sciatic pain caused by lumbar disc herniation. 10 On the other hand, intravenous infusion of infliximab was compared to a placebo by a Finnish group that conducted the first randomized controlled trial of this inhibitor. The results were disappointing. 11, 12 Cohen et al. have reported a preclinical safety study of transforaminal epidural etanercept for the treatment of sciatica caused by disc herniation in 24 patients. They found effectiveness was dependent on the dose of etanercept (4 groups). 13 In the clinical arm of the study, significant improvements in leg and back pain were collectively noted for the etanercept-treated patients one The purpose of the current study was to examine the effect on radicular pain of epidural administration of the TNF-a inhibitor, etanercept, onto spinal nerves in patients with lumbar spinal stenosis. We compared application of the TNF-a inhibitor, etanercept, with application of dexamethasone for the treatment of pain.", "cite_spans": [{"start": 28, "end": 30, "text": "6,", "ref_id": "BIBREF5"}, {"start": 31, "end": 32, "text": "7", "ref_id": "BIBREF6"}, {"start": 221, "end": 223, "text": "6,", "ref_id": "BIBREF5"}, {"start": 224, "end": 225, "text": "7", "ref_id": "BIBREF6"}, {"start": 371, "end": 373, "text": "2,", "ref_id": "BIBREF1"}, {"start": 374, "end": 376, "text": "7,", "ref_id": "BIBREF6"}, {"start": 377, "end": 378, "text": "8", "ref_id": "BIBREF7"}, {"start": 643, "end": 645, "text": "3,", "ref_id": "BIBREF2"}, {"start": 646, "end": 647, "text": "7", "ref_id": "BIBREF6"}, {"start": 948, "end": 949, "text": "9", "ref_id": "BIBREF8"}, {"start": 1190, "end": 1192, "text": "10", "ref_id": "BIBREF9"}, {"start": 1396, "end": 1399, "text": "11,", "ref_id": "BIBREF10"}, {"start": 1400, "end": 1402, "text": "12", "ref_id": "BIBREF11"}, {"start": 1644, "end": 1646, "text": "13", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "Methods", "text": "The ethics committee of our institution approved the protocol for the human procedures used in this study and informed written consent was obtained from each subject.", "cite_spans": [], "ref_spans": []}, {"section": "Patients", "text": "Patients had low back and leg pain, continuing for at least 1 month. Patients who had previously undergone spinal surgery were excluded from the study. We also excluded patients with spinal tumor, infection, or trauma. Patients were diagnosed with lumbar spinal stenosis on X-ray and magnetic resonance imaging (MRI) and by physical examination. Diagnosis by X-ray was spondylosis and spondylolisthesis (more than 3 mm of anterior slip in a normal position). The degree of spinal stenosis varied from slight to severe. MRI showed central stenosis, stenosis of the lateral recess, and foraminal stenosis. We measured degree of stenosis in case of stenosis of the lateral recess and central stenosis and classified it as: >0% to \u226430%, slight stenosis; >30% to \u226470%, moderate stenosis; >70% to \u2264100%, severe stenosis. Most patients diagnosed as having stenosis of the lateral recess fell into the category of slight stenosis in the current study. Details are shown in Table 1 infiltration was performed to confirm the finding. Patients were allowed nonsteroidal anti-inflammatory drugs (NSAIDs) to control low back pain and leg pain.", "cite_spans": [], "ref_spans": [{"start": 965, "end": 972, "text": "Table 1", "ref_id": "TABREF0"}]}, {"section": "Epidural administration", "text": "The patients were divided randomly into 2 groups. The patients were randomized according to the minimization method for injection using etanercept or injection using dexamethasone. 14 We employed sex and age as stratification factors. ", "cite_spans": [{"start": 181, "end": 183, "text": "14", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "Pain scores", "text": "We evaluated the change in low back and leg pain before and after epidural administration. To evaluate pain, the visual analogue scale (VAS) score (0, no pain; 10, worst pain) was recorded before and 30 minutes, 3 days, 1 week, 2 weeks, and 4 weeks after epidural administration.", "cite_spans": [], "ref_spans": []}, {"section": "Pain scores", "text": "Oswestry Disability Index (ODI) scores were recorded before and 4 weeks after epidural administration.", "cite_spans": [], "ref_spans": []}, {"section": "A C C E P T E D", "text": "Copyright \u00a9 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.", "cite_spans": [], "ref_spans": []}, {"section": "Subjective Outcomes", "text": "At 4 weeks after injection, patients were asked to choose one of the following responses regarding their satisfaction with the treatment: (1) treatment met my expectations; (2) I did not improve as much as I had hoped, but I would undergo the same treatment for the same outcome;", "cite_spans": [], "ref_spans": []}, {"section": "Subjective Outcomes", "text": "(3) treatment helped, but I would not undergo the same treatment for the same outcome; or (4) I am the same as or worse than I was before the treatment.", "cite_spans": [], "ref_spans": []}, {"section": "Complications", "text": "Deep or superficial infection including respiratory infection in both groups was evaluated. Spinal nerve injury (motor palsy or sensory disturbance) or other complications in both groups were also evaluated.", "cite_spans": [], "ref_spans": []}, {"section": "Statistical Analysis", "text": "Data were compared using a Kruskal-Wallis test to compare pain scales between the two groups, a one-way ANOVA with post hoc comparisons for age, symptom duration, and follow-up; and Fisher's test was used for dichotomous/categorical variables. P < 0.05 was considered statistically significant.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "Demographic characteristics of patients in both the etanercept and dexamethasone groups are shown in Table 1 . There was no significant difference in VAS score (leg pain, low back pain, leg numbness) and ODI score between the 2 groups (P > 0.05). There was no significant difference in the number of the patients who used NSAIDs between the 2 groups (P > 0.05). Affected spinal nerves were mainly in L5 spinal nerves in both groups.", "cite_spans": [], "ref_spans": [{"start": 101, "end": 108, "text": "Table 1", "ref_id": "TABREF0"}]}, {"section": "Results", "text": "In both groups, treatment was significantly effective in attenuating leg pain, leg numbness, and low back pain 30 min after injection (P < 0.05) (Figures 1, 2, and 3 ). For leg pain in both groups, treatment was significantly effective in attenuating the pain during the 4 weeks of testing (P < 0.05) (Figure 1 ). VAS scores of leg pain in the etanercept group were significantly lower than those in the dexamethasone group at 3 days, and 1, 2, and 4 weeks (P < 0.05) (Figure 1 ).", "cite_spans": [], "ref_spans": [{"start": 145, "end": 165, "text": "(Figures 1, 2, and 3", "ref_id": "FIGREF2"}, {"start": 301, "end": 310, "text": "(Figure 1", "ref_id": "FIGREF9"}, {"start": 468, "end": 477, "text": "(Figure 1", "ref_id": "FIGREF9"}]}, {"section": "Results", "text": "For leg numbness, treatment was significantly effective in attenuating the pain during the 4 weeks in both groups (P < 0.05) ( Figure 2 ). VAS scores of leg numbness in the etanercept group were significantly lower than those in the dexamethasone group at 3 days, and 1, and 2 weeks (P < 0.05) (Figure 2 ).", "cite_spans": [], "ref_spans": [{"start": 127, "end": 135, "text": "Figure 2", "ref_id": "FIGREF2"}, {"start": 294, "end": 303, "text": "(Figure 2", "ref_id": "FIGREF2"}]}, {"section": "Results", "text": "Both epidural administrations were effective for low back pain (VAS) in both group during the 4 weeks (P<0.05) (Figure 3 ). VAS scores of low back pain in the etanercept group were significantly lower than those in the dexamethasone group at 3 days, and 1, and 2 weeks (P < 0.05) (Figure 3 ).", "cite_spans": [], "ref_spans": [{"start": 111, "end": 120, "text": "(Figure 3", "ref_id": "FIGREF11"}, {"start": 280, "end": 289, "text": "(Figure 3", "ref_id": "FIGREF11"}]}, {"section": "Results", "text": "There was no significant difference in ODI scores before epidural administration between the groups (P > 0.05). The average ODI score decreased at 4 weeks, and there was significant improvement in both groups compared with before epidural administration (P < 0.05) ( Table 1 and 3). However, there was no significant difference in ODI score between the etanercept and dexamethasone groups at 4 weeks (P > 0.05) ( Table 3 ).", "cite_spans": [], "ref_spans": [{"start": 267, "end": 274, "text": "Table 1", "ref_id": "TABREF0"}, {"start": 413, "end": 420, "text": "Table 3", "ref_id": "TABREF2"}]}, {"section": "Results", "text": "Details of subjective outcomes 4 weeks after injection are presented in Table 4 . Subjective outcomes for most patients in both groups were good or fair; however, 6 patients in the etanercept group and 11 patients in the dexamethasone group reported an unexpected or poor outcome. Table 5 shows complications, from injection through 4 weeks of follow-up. There was no respiratory infection, deep, or superficial infection in either group. There was no spinal nerve injury or other complications in either group.", "cite_spans": [], "ref_spans": [{"start": 72, "end": 79, "text": "Table 4", "ref_id": "TABREF3"}, {"start": 281, "end": 288, "text": "Table 5", "ref_id": "TABREF4"}]}, {"section": "Complications", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "In the current study, results indicate that single epidural administration of a TNF-a inhibitor onto the spinal nerve produced significantly more pain relief than application of dexamethasone, and produced no adverse event. TNF-a may mediate the radicular pain caused by spinal stenosis in humans.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "It has also been reported that TNF-a is activated in dorsal root ganglia and Schwann cells in the spinal nerve roots following lumbar spinal stenosis, and is closely related to pain. 3, 7 In human studies, the concentration of TNF-a has been found to be high in synovium in facet joints in lumbar spinal stenosis patients compared with lumbar disc herniation patients, thus suggesting that TNF-a in degenerated facet joints may be related to the cause of pain in degenerative lumbar disorders. 15 Recently, two types of TNF-a inhibitors, infliximab and etanercept, have been used to treat radicular leg pain in animal and human studies. Intraperitoneal injection of infliximab prevents nucleus pulposus-induced histologic changes in the rat DRG. 16 Treatment with infliximab significantly reduced pain-related behavior in rats. 4 Etanercept prevented nerve degeneration. 9 It has recently been reported that intravenous injection of infliximab is clinically effective in treating sciatic pain caused by lumbar disc herniation. 10 On the other hand, the effect of intravenous injection of infliximab was examined in a randomized controlled trial, and found not to be effective. 11, 12 These studies in animal models and in humans are controversial, and the effect of direct application of TNF-a inhibitor onto damaged nerves including those found in spinal stenosis has not been fully explored.", "cite_spans": [{"start": 183, "end": 185, "text": "3,", "ref_id": "BIBREF2"}, {"start": 186, "end": 187, "text": "7", "ref_id": "BIBREF6"}, {"start": 494, "end": 496, "text": "15", "ref_id": "BIBREF14"}, {"start": 746, "end": 748, "text": "16", "ref_id": "BIBREF15"}, {"start": 828, "end": 829, "text": "4", "ref_id": "BIBREF3"}, {"start": 871, "end": 872, "text": "9", "ref_id": "BIBREF8"}, {"start": 1027, "end": 1029, "text": "10", "ref_id": "BIBREF9"}, {"start": 1177, "end": 1180, "text": "11,", "ref_id": "BIBREF10"}, {"start": 1181, "end": 1183, "text": "12", "ref_id": "BIBREF11"}], "ref_spans": []}, {"section": "Discussion", "text": "Several authors have reported that the effects of direct application of a TNF-a inhibitor onto spinal nerves affected disc herniation in animals and humans. Norimoto et al. have reported that nucleus pulposus application onto crushed sciatic nerves produced mechanical allodynia;", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "however, epidural administration of a TNF-a inhibitor (etanercept) onto the sciatic nerve did not suppress pain-related behavior. 17 Cohen et al. have reported a study in which 24 patients with subacute lumbosacral radiculopathy caused by disc herniation were randomly assigned to receive two transforaminal epidural injections of 2, 4, or 6 mg of etanercept, and significant improvements in leg and back pain were noted for the etanercept-treated patients, but not for the saline-treated control group, at one month after treatment. No adverse event was reported. 13 In the current study, we showed that epidural administration of a TNF-a inhibitor onto spinal nerves relieved pain caused by spinal stenosis. We concluded that TNF-a may play a crucial role in pain caused by both lumbar disc herniation and spinal stenosis. VAS scores of low back pain in the etanercept group were significantly lower than those in the dexamethasone group during a 2-week follow-up. However, there was no significant difference in ODI scores between the etanercept and dexamethasone groups at 4 weeks. In this regard, single application of 10 mg of etanercept had a relatively short term effect for low back pain.", "cite_spans": [{"start": 130, "end": 132, "text": "17", "ref_id": "BIBREF16"}, {"start": 565, "end": 567, "text": "13", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "Discussion", "text": "In the current study, we compared lidocaine+etanercept with lidocaine+dexamethasone. The efficacy of steroids for nerve root injection has been reported. Fifty-five patients who were deemed to be surgical candidates were treated and randomized to receive either a selective nerve root injection of betamethasone 6 mg with bupivacaine or a selective nerve root injection of bupivacaine alone. This study showed that 67% of patients in the group receiving both local anesthetic and steroid avoided the need for surgical intervention, compared with 28% in the group receiving local anesthetic alone. 18 A systematic review of therapeutic lumbar transforaminal epidural steroid therapy has shown that the indicated evidence for transforaminal lumbar epidural steroid injections is both short-and long-term pain relief compared with local anesthetic alone. 19 In the current study, we showed that application of etanercept produced significantly more pain relief than application of dexamethasone alone. We did not examine a lidocaine only group; however, etanercept is probably more effective for pain than application of lidocaine alone by analogy with the previous studies.", "cite_spans": [{"start": 597, "end": 599, "text": "18", "ref_id": "BIBREF17"}, {"start": 852, "end": 854, "text": "19", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "Discussion", "text": "It is not clear whether systemic or direct administration of the inhibitor is the most effective route. In previous reports, intravenous injection of infliximab was effective or ineffective in treating sciatic pain caused by lumbar disc herniation 10, 11, 12 TNF-a is mainly expressed around or in the disc tissue, where blood supply is generally considered to be insufficient. Therefore we believe that the supply of TNF-a inhibitors is insufficient in case of systemic administration. It is also known that TNF-a inhibitors can have adverse effects when administered in high doses systemically. 18 It is not known if these effects occur after direct administration to nerve; 2) I did not improve as much as I had hoped, but I would undergo the same treatment for the same outcome 12 12 3) Treatment helped, but I would not undergo the same treatment for the same outcome ", "cite_spans": [{"start": 248, "end": 251, "text": "10,", "ref_id": "BIBREF9"}, {"start": 252, "end": 255, "text": "11,", "ref_id": "BIBREF10"}, {"start": 256, "end": 258, "text": "12", "ref_id": "BIBREF11"}, {"start": 597, "end": 599, "text": "18", "ref_id": "BIBREF17"}], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Autologous nucleus pulposus induces neurophysiologic and histologic changes in porcine cauda equina nerve roots", "authors": [{"first": "K", "middle": [], "last": "Olmarker", "suffix": ""}, {"first": "B", "middle": [], "last": "Rydevik", "suffix": ""}, {"first": "C", "middle": [], "last": "Nordborg", "suffix": ""}], "year": 1993, "venue": "Spine", "link": "40866629"}, "BIBREF1": {"title": "Tumor necrosis factor alpha and nucleus-pulposus-induced nerve root injury", "authors": [{"first": "K", "middle": [], "last": "Olmarker", "suffix": ""}, {"first": "K", "middle": [], "last": "Larsson", "suffix": ""}], "year": 1998, "venue": "Spine", "link": "6935365"}, "BIBREF2": {"title": "Hyperalgesic actions of cytokines on peripheral nerves", "authors": [{"first": "R", "middle": ["R"], "last": "Myers", "suffix": ""}, {"first": "R", "middle": [], "last": "Wagner", "suffix": ""}, {"first": "L", "middle": ["S"], "last": "Sorkin", "suffix": ""}], "year": 1999, "venue": "Cytokines and Pain", "link": "68147682"}, "BIBREF3": {"title": "Changes in spontaneous behavior in rats exposed to experimental disc herniation are blocked by selective TNF-alpha inhibition", "authors": [{"first": "K", "middle": [], "last": "Olmarker", "suffix": ""}, {"first": "M", "middle": [], "last": "Nutu", "suffix": ""}, {"first": "R", "middle": [], "last": "St\u00f8rkson", "suffix": ""}], "year": 2003, "venue": "Spine", "link": "36425958"}, "BIBREF4": {"title": "Infliximab attenuates immunoreactivity of brain-derived neurotrophic factor in a rat model of herniated nucleus pulposus", "authors": [{"first": "A", "middle": [], "last": "Onda", "suffix": ""}, {"first": "Y", "middle": [], "last": "Murata", "suffix": ""}, {"first": "B", "middle": [], "last": "Rydevik", "suffix": ""}], "year": 2004, "venue": "Spine", "link": "1002023"}, "BIBREF5": {"title": "A model for acute, chronic, and delayed graded compression of the dog cauda equina: presentation of the gross, microscopic, and vascular anatomy of the dog cauda equina and accuracy in pressure transmission of the compression model", "authors": [{"first": "S", "middle": [], "last": "Konno", "suffix": ""}, {"first": "S", "middle": [], "last": "Yabuki", "suffix": ""}, {"first": "K", "middle": [], "last": "Sato", "suffix": ""}], "year": 1995, "venue": "Spine", "link": "32698902"}, "BIBREF6": {"title": "Experimental spinal stenosis: relationship between degree of cauda equina compression, neuropathology, and pain", "authors": [{"first": "M", "middle": [], "last": "Sekiguchi", "suffix": ""}, {"first": "S", "middle": [], "last": "Kikuchi", "suffix": ""}, {"first": "R", "middle": ["R"], "last": "Myers", "suffix": ""}], "year": 2004, "venue": "Spine", "link": "41308365"}, "BIBREF7": {"title": "Glial phosphorylated p38 MAP kinase mediates pain in a rat model of lumbar disc herniation and induces motor dysfunction in a rat model of lumbar spinal canal stenosis", "authors": [{"first": "T", "middle": [], "last": "Ito", "suffix": ""}, {"first": "S", "middle": [], "last": "Ohtori", "suffix": ""}, {"first": "G", "middle": [], "last": "Inoue", "suffix": ""}], "year": 2007, "venue": "Spine", "link": "37317881"}, "BIBREF8": {"title": "Selective inhibition of tumor necrosis factor-alpha prevents nucleus pulposus-induced thrombus formation, intraneural edema, and reduction of nerve conduction velocity: possible implications for future pharmacologic treatment strategies of sciatica", "authors": [{"first": "K", "middle": [], "last": "Olmarker", "suffix": ""}, {"first": "B", "middle": [], "last": "Rydevik", "suffix": ""}], "year": 2001, "venue": "Spine", "link": "30488308"}, "BIBREF9": {"title": "Efficacy of infliximab for disc herniation-induced sciatica: one-year follow-up", "authors": [{"first": "T", "middle": [], "last": "Korhonen", "suffix": ""}, {"first": "J", "middle": [], "last": "Karppinen", "suffix": ""}, {"first": "A", "middle": [], "last": "Malmivaara", "suffix": ""}], "year": 2004, "venue": "Spine", "link": "10866356"}, "BIBREF10": {"title": "The treatment of disc herniation-induced sciatica with infliximab: results of a randomized, controlled, 3-month follow-up study", "authors": [{"first": "T", "middle": [], "last": "Korhonen", "suffix": ""}, {"first": "J", "middle": [], "last": "Karppinen", "suffix": ""}, {"first": "L", "middle": [], "last": "Paimela", "suffix": ""}], "year": 2005, "venue": "Spine", "link": null}, "BIBREF11": {"title": "The treatment of disc-herniation-induced sciatica with infliximab: one-year follow-up results of FIRST II, a randomized controlled trial", "authors": [{"first": "T", "middle": [], "last": "Korhonen", "suffix": ""}, {"first": "J", "middle": [], "last": "Karppinen", "suffix": ""}, {"first": "L", "middle": [], "last": "Paimela", "suffix": ""}], "year": 2006, "venue": "Spine", "link": "43278611"}, "BIBREF12": {"title": "Randomized, double-blind, placebo-controlled, dose-response, and preclinical safety study of transforaminal epidural etanercept for the treatment of sciatica", "authors": [{"first": "S", "middle": ["P"], "last": "Cohen", "suffix": ""}, {"first": "N", "middle": [], "last": "Bogduk", "suffix": ""}, {"first": "A", "middle": [], "last": "Dragovich", "suffix": ""}], "year": 2009, "venue": "Anesthesiology", "link": "20812089"}, "BIBREF13": {"title": "Sequential treatment assignment with balancing for prognostic factors in the controlled clinical trial", "authors": [{"first": "S", "middle": ["J"], "last": "Pocock", "suffix": ""}, {"first": "R", "middle": [], "last": "Simon", "suffix": ""}], "year": 1975, "venue": "Biometrics", "link": "12364101"}, "BIBREF14": {"title": "Inflammatory cytokines released from the facet joint tissue in degenerative lumbar spinal disorders", "authors": [{"first": "A", "middle": [], "last": "Igarashi", "suffix": ""}, {"first": "S", "middle": [], "last": "Kikuchi", "suffix": ""}, {"first": "S", "middle": [], "last": "Konno", "suffix": ""}], "year": 2004, "venue": "Spine", "link": "46717050"}, "BIBREF15": {"title": "Selective inhibition of tumor necrosis factor-alpha prevents nucleus pulposus-induced histologic changes in the dorsal root ganglion", "authors": [{"first": "Y", "middle": [], "last": "Murata", "suffix": ""}, {"first": "A", "middle": [], "last": "Onda", "suffix": ""}, {"first": "B", "middle": [], "last": "Rydevik", "suffix": ""}], "year": 2004, "venue": "Spine", "link": "42491970"}, "BIBREF16": {"title": "Direct application of the TNF-alpha inhibitor, etanercept, does not affect CGRP expression and phenotypic change of DRG neurons following application of nucleus pulposus onto injured sciatic nerves in rats", "authors": [{"first": "M", "middle": [], "last": "Norimoto", "suffix": ""}, {"first": "S", "middle": [], "last": "Ohtori", "suffix": ""}, {"first": "M", "middle": [], "last": "Yamashita", "suffix": ""}], "year": 2008, "venue": "Spine", "link": "33656939"}, "BIBREF17": {"title": "Clinical use of anti-TNF-alpha biological agents-a guide for GPs", "authors": [{"first": "J", "middle": [], "last": "Chang", "suffix": ""}, {"first": "L", "middle": [], "last": "Girgis", "suffix": ""}], "year": "", "venue": "", "link": "2448384"}, "BIBREF19": {"title": "The effect of nerve root injections on the need for operative treatment of lumbar radicular pain", "authors": [{"first": "K", "middle": ["D"], "last": "Riew", "suffix": ""}, {"first": "Y", "middle": [], "last": "Yin", "suffix": ""}, {"first": "L", "middle": [], "last": "Gilula", "suffix": ""}], "year": 2000, "venue": "J Bone Joint Surg Am", "link": null}, "BIBREF20": {"title": "Systematic review of therapeutic lumbar transforaminal epidural steroid injections", "authors": [{"first": "R", "middle": ["M"], "last": "Buenaventura", "suffix": ""}, {"first": "S", "middle": [], "last": "Datta", "suffix": ""}, {"first": "S", "middle": [], "last": "Abdi", "suffix": ""}], "year": 2009, "venue": "Pain Physician", "link": "5241473"}}, "ref_entries": {"FIGREF0": {"text": "Copyright \u00a9 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.", "type": "figure"}, "FIGREF1": {"text": "Copyright \u00a9 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.", "type": "figure"}, "FIGREF2": {"text": "Patients who showed monoradiculopathy were evaluated. Patients who showed cauda equine syndrome, or polyradiculopathies were excluded from the current study. If a single affected spinal nerve was found using imaging and physical examination, spinal A C C E P T E D Copyright \u00a9 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.", "type": "figure"}, "FIGREF3": {"text": "Patients received a single epidural administration (2.0 mL of lidocaine and 10 mg of etanercept, etanercept group; n = 40) or a single epidural administration (2.0 mL of lidocaine and 3.3 mg of dexamethasone, dexamethasone group; n = 40). Both groups received 1.5 mL of 1% lidocaine solution into the skin. Then a 22-gauge spinal-nerve-block needle was advanced obliquely to the corresponding spinal nerve under fluoroscopic control and 0.5 mL of the contrast medium Iotorolan (Schering AG, Berlin, Germany) was injected to confirm the position of the spinal nerve. Subsequently unilateral epidural administration of lidocaine and the agent (2.0 mL of lidocaine and 10 mg of etanercept, or 2.0 mL of lidocaine and 3.3 mg of dexamethasone) was performed.", "type": "figure"}, "FIGREF4": {"text": "Copyright \u00a9 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.", "type": "figure"}, "FIGREF5": {"text": "Copyright \u00a9 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.", "type": "figure"}, "FIGREF6": {"text": "Copyright \u00a9 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.", "type": "figure"}, "FIGREF7": {"text": "Copyright \u00a9 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.", "type": "figure"}, "FIGREF8": {"text": "however, both Cohen's study and the current study demonstrated the safety of direct application of the TNF-a inhibitor, etanercept, onto spinal nerves. Limitations of the current study include its small size and prospective nature, and a short follow-up period of only 4 weeks. Second, as mentioned above, we did not examine a lidocaine only group; the only dose of etanercept used was 10 mg. Third, there are no evidence or dose A C C E P T E D Copyright \u00a9 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. comparison studies that suggest that 10 mg of etanercept is equivalent to 3.3 mg of dexamethasone, and most patients also used NSAIDs. Fourth, we did not show any difference in pain based on ODI, because etanercept had a short-term effect for low back pain. Further study using different doses, multiple applications, or different tools for evaluation are required to clarify these points. In summary, based on VAS scale scores, epidural administration of the TNF-a inhibitor, etanercept, onto spinal nerves, reduced low back pain, leg pain, and leg numbness caused by spinal stenosis. We did not observe any adverse event in the etanercept administration group. TNF-a inhibitors may therefore be useful tools for the treatment of radicular pain caused by spinal stenosis.Copyright \u00a9 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.", "type": "figure"}, "FIGREF9": {"text": "Figure 1.", "type": "figure"}, "FIGREF10": {"text": "Figure 2", "type": "figure"}, "FIGREF11": {"text": "Figure 3", "type": "figure"}, "FIGREF12": {"text": "Copyright \u00a9 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.", "type": "figure"}, "FIGREF13": {"text": "Copyright \u00a9 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.", "type": "figure"}, "FIGREF14": {"text": "Copyright \u00a9 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.", "type": "figure"}, "TABREF0": {"text": "Demographic Characteristics", "type": "table"}, "TABREF1": {"text": "-ray and MR-imaging evaluation, and affected spinal nerve", "type": "table"}, "TABREF2": {"text": "Pain score 4 weeks after epidural administration", "type": "table"}, "TABREF3": {"text": "Subjective Outcomes (Number of patients)", "type": "table"}, "TABREF4": {"text": "", "type": "table"}}}
{"paper_id": "8339730", "_pdf_hash": "e996d41758d0fa2a8ea0fbd3778ea5a9cf4dbc85", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Are Agile Methods Good for Design? Interactions", "authors": [{"first": "J", "middle": [], "last": "Armitage", "suffix": ""}], "year": 2004, "venue": "", "link": null}, "BIBREF1": {"title": "Firm Resources and Sustained Competitive Advantage", "authors": [{"first": "Jay", "middle": [], "last": "Barney", "suffix": ""}], "year": 1991, "venue": "Journal of Management", "link": "199331872"}, "BIBREF2": {"title": "An Agile CustomerCentered Method: Rapid Contextual Design", "authors": [{"first": "H", "middle": [], "last": "Beyer", "suffix": ""}, {"first": "K", "middle": [], "last": "Holtzblatt", "suffix": ""}, {"first": "L", "middle": [], "last": "Baker", "suffix": ""}], "year": 2004, "venue": "Proc of CP/AU", "link": null}, "BIBREF3": {"title": "Towards a Model for Bridging Agile Development and User-Centered Design. Human-Centered Software EngineeringIntegrating Usability in the Software Development Lifecycle", "authors": [{"first": "S", "middle": [], "last": "Blomkvist", "suffix": ""}], "year": 2005, "venue": "HumanComputer Interaction Series", "link": null}, "BIBREF4": {"title": "The bid switch: Rewriting the World, from Edison to Google", "authors": [{"first": "N", "middle": [], "last": "Carr", "suffix": ""}], "year": 2009, "venue": "", "link": null}, "BIBREF5": {"title": "Towards a Framework for Integrating Agile Development and User-Centered Design. Extreme Programming and Agile Processes in Software Engineering", "authors": [{"first": "S", "middle": [], "last": "Chamberlain", "suffix": ""}, {"first": "H", "middle": [], "last": "Sharp", "suffix": ""}, {"first": "N", "middle": [], "last": "Maiden", "suffix": ""}], "year": 2006, "venue": "Lecture Notes in Computer Science", "link": null}, "BIBREF6": {"title": "Towards Extreme(ly) Usable Software: Exploring Tensions Between Usability and Agile Software Development. AGILE 2007", "authors": [{"first": "Chong", "middle": [], "last": "Lee", "suffix": ""}, {"first": "J", "middle": [], "last": "Mccrickard", "suffix": ""}, {"first": "D", "middle": ["S"], "last": "", "suffix": ""}], "year": 2007, "venue": "", "link": "17653725"}, "BIBREF7": {"title": "Strategy under uncertainty", "authors": [{"first": "H", "middle": [], "last": "Courtney", "suffix": ""}, {"first": "J", "middle": [], "last": "Kirkland", "suffix": ""}, {"first": "P", "middle": [], "last": "Viguerie", "suffix": ""}], "year": 1997, "venue": "Harvard Business Review", "link": "54560711"}, "BIBREF8": {"title": "The Impact of Agile on User-centered Design: Two Surveys Tell the Story", "authors": [{"first": "D", "middle": [], "last": "Dayton", "suffix": ""}, {"first": "C", "middle": [], "last": "Barnum", "suffix": ""}], "year": 2009, "venue": "Technical Communication", "link": null}, "BIBREF9": {"title": "The Research Act. A Theoretical Introduction to Sociological Methods", "authors": [{"first": "N", "middle": [], "last": "Denzin", "suffix": ""}], "year": 1970, "venue": "", "link": "141840815"}, "BIBREF11": {"title": "Cloud Computing: Distributed Internet Computing for IT and Scientific Research", "authors": [{"first": "M", "middle": ["D"], "last": "Dikaiakos", "suffix": ""}, {"first": "D", "middle": [], "last": "Katsaros", "suffix": ""}, {"first": "P", "middle": [], "last": "Mehra", "suffix": ""}, {"first": "G", "middle": [], "last": "Pallis", "suffix": ""}, {"first": "A", "middle": [], "last": "Vakali", "suffix": ""}], "year": 2009, "venue": "Internet Computing", "link": "8930046"}, "BIBREF12": {"title": "Empirical studies of agile software development: A systematic review. Information and Software Technology", "authors": [{"first": "T", "middle": [], "last": "Dyb\u00e5", "suffix": ""}, {"first": "T", "middle": [], "last": "Dings\u00f8yr", "suffix": ""}], "year": 2008, "venue": "", "link": null}, "BIBREF13": {"title": "Up-Front Interaction Design in Agile Development", "authors": [{"first": "J", "middle": [], "last": "Ferreira", "suffix": ""}, {"first": "J", "middle": [], "last": "Noble", "suffix": ""}, {"first": "R", "middle": [], "last": "Biddle", "suffix": ""}], "year": 2007, "venue": "Agile Processes in Software Engineering and Extreme Programming", "link": "41255615"}, "BIBREF14": {"title": "The Thing and I: Understanding the Relationship Between User and Product", "authors": [{"first": "M", "middle": [], "last": "Hassenzahl", "suffix": ""}], "year": 2003, "venue": "Funology: From Usability to Enjoyment", "link": "52072573"}, "BIBREF15": {"title": "User Experience -A Research Agenda", "authors": [{"first": "M", "middle": [], "last": "Hassenzahl", "suffix": ""}, {"first": "N", "middle": [], "last": "Tractinsky", "suffix": ""}], "year": 2006, "venue": "Behaviour & Information Technology", "link": null}, "BIBREF16": {"title": "Technology for All the Right Reasons", "authors": [{"first": "M", "middle": [], "last": "Hassenzahl", "suffix": ""}], "year": 2010, "venue": "", "link": null}, "BIBREF17": {"title": "Integration of Extreme Programming and User-Centered Design: Lessons Learned", "authors": [{"first": "Z", "middle": [], "last": "Hussain", "suffix": ""}, {"first": "H", "middle": [], "last": "Milchrahm", "suffix": ""}, {"first": "S", "middle": [], "last": "Shahzad", "suffix": ""}, {"first": "W", "middle": [], "last": "Slany", "suffix": ""}, {"first": "M", "middle": [], "last": "Tscheligi", "suffix": ""}, {"first": "P", "middle": [], "last": "Wolkerstorfer", "suffix": ""}], "year": 2009, "venue": "LNBIP", "link": "29030796"}, "BIBREF18": {"title": "Current State of Agile User-Centered Design: A Survey. HCI and Usability for eInclusion", "authors": [{"first": "Z", "middle": [], "last": "Hussain", "suffix": ""}, {"first": "W", "middle": [], "last": "Slany", "suffix": ""}, {"first": "A", "middle": [], "last": "Holzinger", "suffix": ""}], "year": 2009, "venue": "Lecture Notes in Computer Science", "link": null}, "BIBREF19": {"title": "Usability Assessment of an Extreme Programming Project: Close Co-operation with the Customer Does Not Equal to Good Usability", "authors": [{"first": "T", "middle": [], "last": "Jokela", "suffix": ""}, {"first": "P", "middle": [], "last": "Abrahamsson", "suffix": ""}], "year": 2004, "venue": "PROFES 2004", "link": "41726812"}, "BIBREF20": {"title": "Finding a Place for Discount Usability Engineering in Agile Development: Throwing Down the Gauntlet", "authors": [{"first": "D", "middle": [], "last": "Kane", "suffix": ""}], "year": 2003, "venue": "Proceedings of the Agile Development Conference", "link": "215688"}, "BIBREF21": {"title": "Content analysis: an introduction to its methodology", "authors": [{"first": "K", "middle": [], "last": "Krippendorff", "suffix": ""}], "year": 2003, "venue": "", "link": "62392461"}, "BIBREF22": {"title": "Agile Transformation Study at Nokia -One Year After", "authors": [{"first": "M", "middle": [], "last": "Laanti", "suffix": ""}], "year": 2010, "venue": "Proceedings of LESS 2010", "link": "33794551"}, "BIBREF23": {"title": "Understanding, scoping and defining user experience: a survey approach", "authors": [{"first": "Lai-Chong", "middle": [], "last": "Law", "suffix": ""}, {"first": "E", "middle": [], "last": "Roto", "suffix": ""}, {"first": "V", "middle": [], "last": "Hassenzahl", "suffix": ""}, {"first": "M", "middle": [], "last": "Vermeeren", "suffix": ""}, {"first": "A", "middle": [], "last": "Kort", "suffix": ""}, {"first": "J", "middle": [], "last": "", "suffix": ""}], "year": 2009, "venue": "Proceedings of the 27th International Conference on Human Factors in Computing Systems (CHI '09)", "link": "10465690"}, "BIBREF24": {"title": "A Lean and Scalable Information Model for the Agile Enterprise", "authors": [{"first": "D", "middle": [], "last": "Leffingwell", "suffix": ""}, {"first": "J.-M", "middle": [], "last": "Aalto", "suffix": ""}], "year": 2009, "venue": "", "link": null}, "BIBREF25": {"title": "Empirical analysis on the satisfaction of IT employees comparing XP practices with other software development methodologies", "authors": [{"first": "K", "middle": [], "last": "Mannaro", "suffix": ""}, {"first": "M", "middle": [], "last": "Melis", "suffix": ""}, {"first": "M", "middle": [], "last": "Marchesi", "suffix": ""}], "year": 2004, "venue": "Proc of Extreme Programming and Agile Processes in Software Engineering", "link": "12090640"}, "BIBREF27": {"title": "Agile HumanCentered Software Engineering", "authors": [{"first": "T", "middle": [], "last": "Memmel", "suffix": ""}, {"first": "F", "middle": [], "last": "Gundelsweiler", "suffix": ""}, {"first": "H", "middle": [], "last": "Reiterer", "suffix": ""}], "year": 2007, "venue": "Proc of the 21 st British HCI Group Annual Conference on People and Computer", "link": null}, "BIBREF28": {"title": "Lean software development: two case studies", "authors": [{"first": "P", "middle": [], "last": "Middleton", "suffix": ""}], "year": 2001, "venue": "Software Quality Journal", "link": "24727130"}, "BIBREF29": {"title": "The Core Competence of the Corporation", "authors": [{"first": "C", "middle": ["K"], "last": "Prahalad", "suffix": ""}, {"first": "G", "middle": [], "last": "Hamel", "suffix": ""}], "year": 1990, "venue": "Harvard Business Review", "link": "166730461"}, "BIBREF30": {"title": "The New Age of Innovation: Driving Co-created Value through Global Networks", "authors": [{"first": "C", "middle": ["K"], "last": "Prahalad", "suffix": ""}, {"first": "M", "middle": ["S"], "last": "Krishnan", "suffix": ""}], "year": 2008, "venue": "", "link": "167915176"}, "BIBREF31": {"title": "Guidelines for conducting and reporting case study research in software engineering", "authors": [{"first": "P", "middle": [], "last": "Runeson", "suffix": ""}, {"first": "M", "middle": [], "last": "H\u00f6st", "suffix": ""}], "year": 2009, "venue": "", "link": "207144526"}, "BIBREF32": {"title": "Integrating Usability Engineering and Agile Software Development: A Literature Review. International Conference on Computer Design and Applications", "authors": [{"first": "O", "middle": [], "last": "Sohaib", "suffix": ""}, {"first": "K", "middle": [], "last": "Khan", "suffix": ""}], "year": 2010, "venue": "", "link": null}, "BIBREF33": {"title": "Introducing agile process in a software maintenance and evolution organization", "authors": [{"first": "H", "middle": [], "last": "Svensson", "suffix": ""}, {"first": "M", "middle": [], "last": "H\u00f6st", "suffix": ""}], "year": 2005, "venue": "Proceedings of the 9 th European Conference on Software Maintenance and Reengineering (CSMR)", "link": "14348005"}, "BIBREF34": {"title": "Adapting Usability Investigations for Agile UserCentered Design", "authors": [{"first": "D", "middle": [], "last": "Sy", "suffix": ""}], "year": 2007, "venue": "", "link": "1023557"}, "BIBREF35": {"title": "Dynamic capabilities and strategic management", "authors": [{"first": "D", "middle": ["J"], "last": "Teece", "suffix": ""}, {"first": "G", "middle": [], "last": "Pisano", "suffix": ""}, {"first": "A", "middle": [], "last": "Shuen", "suffix": ""}], "year": 1997, "venue": "Strategic Management Journal", "link": "132035501"}, "BIBREF36": {"title": "Explicating dynamic capabilities: the nature and microfoundations of (sustainable) enterprise performance", "authors": [{"first": "D", "middle": ["J"], "last": "Teece", "suffix": ""}], "year": 2007, "venue": "Strategic Management Journal", "link": "9284642"}, "BIBREF37": {"title": "Comparison of student experiences with plan-driven and agile methodologies", "authors": [{"first": "C", "middle": [], "last": "Wellington", "suffix": ""}, {"first": "T", "middle": [], "last": "Briggs", "suffix": ""}, {"first": "C", "middle": [], "last": "Girard", "suffix": ""}], "year": 2005, "venue": "Proceedings of IEEE Frontiers in Education Conference", "link": "9062628"}, "BIBREF38": {"title": "Lean Thinking: Banish Waste and Create Wealth in Your Corporation", "authors": [{"first": "J", "middle": ["P"], "last": "Womack", "suffix": ""}, {"first": "D", "middle": ["T"], "last": "Jones", "suffix": ""}], "year": 2003, "venue": "", "link": "144090707"}, "BIBREF39": {"title": "User experience evaluation methods: current state and development needs", "authors": [{"first": "A", "middle": [], "last": "Vermeeren", "suffix": ""}, {"first": "", "middle": [], "last": "Lai-Chong", "suffix": ""}, {"first": "E", "middle": [], "last": "Law", "suffix": ""}, {"first": "V", "middle": [], "last": "Roto", "suffix": ""}, {"first": "M", "middle": [], "last": "Obrist", "suffix": ""}, {"first": "J", "middle": [], "last": "Hoonhout", "suffix": ""}, {"first": "K", "middle": [], "last": "V\u00e4\u00e4n\u00e4nen-Vainio-Mattila", "suffix": ""}], "year": 2010, "venue": "Proceedings of the 6th Nordic Conference on Human-Computer Interaction: Extending Boundaries", "link": null}, "BIBREF40": {"title": "A Survey of User-Centered Design Practice", "authors": [{"first": "K", "middle": [], "last": "Vredenburg", "suffix": ""}, {"first": "J-Y", "middle": [], "last": "Mao", "suffix": ""}, {"first": "P", "middle": [], "last": "Smith", "suffix": ""}, {"first": "Carey", "middle": [], "last": "", "suffix": ""}, {"first": "T", "middle": [], "last": "", "suffix": ""}], "year": 2002, "venue": "Proceedings of CHI 2002", "link": "5766633"}}, "ref_entries": {}}
{"paper_id": "8339923", "_pdf_hash": "35746dd2354e2cd203d6f17f419a855e35449849", "abstract": [], "body_text": [], "bib_entries": {"BIBREF1": {"title": "Workshops on Extreme Scale Design Automation (ESDA) Challenges and Opportunities for 2025 and Beyond", "authors": [{"first": "I", "middle": [], "last": "Bahar", "suffix": ""}, {"first": "A", "middle": ["K"], "last": "Jones", "suffix": ""}, {"first": "S", "middle": [], "last": "Katkoori", "suffix": ""}, {"first": "", "middle": [], "last": "Etc", "suffix": ""}], "year": 2014, "venue": "CCC Workshop Report", "link": "17767436"}, "BIBREF2": {"title": "A Study of Floorplanning Challenges and Analysis of macro placement approaches in Physical Aware Synthesis", "authors": [{"first": "G", "middle": [], "last": "Shivani", "suffix": ""}, {"first": "", "middle": [], "last": "Kr", "suffix": ""}, {"first": "", "middle": [], "last": "Neeraj", "suffix": ""}], "year": 2016, "venue": "International Journal of Hybrid Information Technology", "link": null}, "BIBREF3": {"title": "VLSI physical design: from graph partitioning to timing closure", "authors": [{"first": "A", "middle": [], "last": "Kahng", "suffix": ""}, {"first": "J", "middle": [], "last": "Lienig", "suffix": ""}, {"first": "I", "middle": [], "last": "Markov", "suffix": ""}, {"first": "", "middle": [], "last": "Hu", "suffix": ""}], "year": 2011, "venue": "", "link": "116084071"}, "BIBREF4": {"title": "Proceedings of Problems of Development of Advanced Micro-and Nanoelectronic Systems -2016 / under editorship of the A.L. Stempkovsky", "authors": [{"first": "A", "middle": [], "last": "Harutyunyan", "suffix": ""}], "year": 2016, "venue": "", "link": null}, "BIBREF5": {"title": "Theory of Heat and Mass Transfer", "authors": [{"first": "G", "middle": ["N"], "last": "Dulnev", "suffix": ""}], "year": "", "venue": "", "link": "92058885"}, "BIBREF6": {"title": "Thermal effects and junction temperature evaluation of Power MOSFETs // DocID028570 Rev 1", "authors": [{"first": "M", "middle": [], "last": "Melito", "suffix": ""}, {"first": "A", "middle": [], "last": "Gaito", "suffix": ""}, {"first": "G", "middle": [], "last": "Sorrentino", "suffix": ""}], "year": 2015, "venue": "", "link": null}, "BIBREF7": {"title": "Thermal Analysis of Semiconductor Systems // International Journal of Innovative Research in Technology", "authors": [{"first": "S", "middle": [], "last": "Sharma", "suffix": ""}, {"first": "M", "middle": [], "last": "Kumar", "suffix": ""}, {"first": "R", "middle": [], "last": "Chaudhary", "suffix": ""}], "year": 2014, "venue": "", "link": null}, "BIBREF8": {"title": "TemperatureAware Placement for SOCs", "authors": [{"first": "B", "middle": [], "last": "Tsai", "suffix": ""}, {"first": "Ch", "middle": [], "last": "Chen", "suffix": ""}, {"first": "G", "middle": [], "last": "Chen", "suffix": ""}], "year": 2006, "venue": "", "link": null}, "BIBREF9": {"title": "Electro thermal simulation of the thermal field of integrated circuits when elements placement", "authors": [{"first": "A", "middle": [], "last": "Harutyunyan", "suffix": ""}], "year": 2011, "venue": "Thematic Issue \"Electronics and Nanotechnology\" No1. Kiev", "link": null}}, "ref_entries": {}}
{"paper_id": "45910368", "_pdf_hash": "516cc0dc29c082bac4ab23ff8d527da0eda95d75", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Production of electric power by mixing fresh and salt water in hydroelectric pile", "authors": [{"first": "R", "middle": ["E"], "last": "Pattle", "suffix": ""}], "year": 1954, "venue": "Nature", "link": null}, "BIBREF1": {"title": "Osmotic power plants", "authors": [{"first": "S", "middle": [], "last": "Loeb", "suffix": ""}, {"first": "R", "middle": ["S"], "last": "Norman", "suffix": ""}], "year": 1975, "venue": "Science", "link": "30939629"}, "BIBREF2": {"title": "Membrane-based processes for sustainable power generation using water", "authors": [{"first": "B", "middle": ["E"], "last": "Logan", "suffix": ""}, {"first": "M", "middle": [], "last": "Elimelech", "suffix": ""}], "year": 2012, "venue": "Nature", "link": "4404568"}, "BIBREF3": {"title": "Osmotic power potential in remote regions of Quebec", "authors": [{"first": "J", "middle": [], "last": "Maisonneuve", "suffix": ""}, {"first": "P", "middle": [], "last": "Pillay", "suffix": ""}, {"first": "C", "middle": ["B"], "last": "Laflamme", "suffix": ""}], "year": 2015, "venue": "Renewable Energy", "link": "109204911"}, "BIBREF4": {"title": "RO-PRO desalination: An integrated low-energy approach to seawater desalination", "authors": [{"first": "J", "middle": ["L"], "last": "Prante", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Ruskowitz", "suffix": ""}, {"first": "A", "middle": ["E"], "last": "Childress", "suffix": ""}, {"first": "A", "middle": [], "last": "Achilli", "suffix": ""}], "year": 2014, "venue": "Applied Energy", "link": "17657184"}, "BIBREF5": {"title": "Thermodynamic and energy efficiency analysis of power generation from natural salinity gradients by pressure retarded osmosis", "authors": [{"first": "N", "middle": ["Y"], "last": "Yip", "suffix": ""}, {"first": "M", "middle": [], "last": "Elimelech", "suffix": ""}], "year": 2012, "venue": "Environmental Science and Technology", "link": "206955094"}, "BIBREF6": {"title": "Maximum power point tracking (MPPT) of a scale-up pressure retarded osmosis (PRO) osmotic power plant", "authors": [{"first": "W", "middle": [], "last": "He", "suffix": ""}, {"first": "Y", "middle": [], "last": "Wang", "suffix": ""}, {"first": "M", "middle": ["H"], "last": "Shaheed", "suffix": ""}], "year": 2015, "venue": "Applied Energy", "link": "111263279"}, "BIBREF7": {"title": "Modeling pressure-retarded osmotic power in commercial length membranes", "authors": [{"first": "M", "middle": ["F"], "last": "Naguib", "suffix": ""}, {"first": "J", "middle": [], "last": "Maisonneuve", "suffix": ""}, {"first": "C", "middle": ["B"], "last": "Laflamme", "suffix": ""}, {"first": "P", "middle": [], "last": "Pillay", "suffix": ""}], "year": 2015, "venue": "Renewable Energy", "link": "95126713"}, "BIBREF8": {"title": "Pressure-retarded osmotic power model considering non-ideal effects", "authors": [{"first": "J", "middle": [], "last": "Maisonneuve", "suffix": ""}, {"first": "P", "middle": [], "last": "Pillay", "suffix": ""}, {"first": "C", "middle": ["B"], "last": "Laflamme", "suffix": ""}], "year": 2015, "venue": "Renewable Energy", "link": null}, "BIBREF9": {"title": "Experimental investigation of pressure retarded osmosis for renewable energy conversion: Towards increased net power", "authors": [{"first": "J", "middle": [], "last": "Maisonneuve", "suffix": ""}, {"first": "C", "middle": ["B"], "last": "Laflamme", "suffix": ""}, {"first": "P", "middle": [], "last": "Pillay", "suffix": ""}], "year": 2016, "venue": "Applied Energy", "link": "100806059"}, "BIBREF10": {"title": "Introduction to PRO for energy conversion applications including an electric equivalent circuit", "authors": [{"first": "J", "middle": [], "last": "Maisonneuve", "suffix": ""}, {"first": "P", "middle": [], "last": "Pillay", "suffix": ""}], "year": 2016, "venue": "IET Renewable Power Generation", "link": "114694628"}, "BIBREF11": {"title": "Visualizing concentration polarization -a new method for in-situ measurement in RO/NF", "authors": [{"first": "O", "middle": [], "last": "Jung", "suffix": ""}, {"first": "F", "middle": [], "last": "Saravia", "suffix": ""}, {"first": "M", "middle": [], "last": "Wagner", "suffix": ""}, {"first": "S", "middle": [], "last": "Heibler", "suffix": ""}, {"first": "H", "middle": [], "last": "Horn", "suffix": ""}], "year": 2017, "venue": "International Congress on Membrane and Membrane Processes", "link": null}}, "ref_entries": {}}
{"paper_id": "45910444", "_pdf_hash": "5623bf183d2186512d0dd59c21975f0f74526702", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Single chip RF front-end MMIC solutions for future low cost, miniature size, WLAN transceiver module applications", "authors": [{"first": "C", "middle": [], "last": "Yuen", "suffix": ""}, {"first": "K", "middle": [], "last": "Laursen", "suffix": ""}, {"first": "M", "middle": [], "last": "Adams", "suffix": ""}, {"first": "D", "middle": [], "last": "Chu", "suffix": ""}, {"first": "H", "middle": [], "last": "Nguyen", "suffix": ""}], "year": "", "venue": "APMC 2005", "link": "32769484"}, "BIBREF1": {"title": "A miniature low current fully integrated front end module for WLAN 802.11b/g applications", "authors": [{"first": "R", "middle": [], "last": "Vaidya", "suffix": ""}, {"first": "D", "middle": [], "last": "Gupta", "suffix": ""}, {"first": "M", "middle": [], "last": "Bhakuni", "suffix": ""}, {"first": "R", "middle": [], "last": "Prince", "suffix": ""}], "year": "", "venue": "IEEE CSIC 2007", "link": "15301320"}, "BIBREF2": {"title": "A compact 802.11 a/b/g/n WLAN front-end module using passives embedded in a flipchip BGA organic package substrate", "authors": [{"first": "T", "middle": [], "last": "Kamgaing", "suffix": ""}, {"first": "E", "middle": ["D"], "last": "Venn", "suffix": ""}, {"first": "K", "middle": [], "last": "Radhakrishnan", "suffix": ""}], "year": "", "venue": "", "link": "33413018"}, "BIBREF3": {"title": "A complete antenna-to-CMOS 4x6mm front end module for dual band 802.11abg WLAN,\" in IEEE IMS", "authors": [{"first": "H", "middle": [], "last": "Morkner", "suffix": ""}, {"first": "M", "middle": [], "last": "Vice", "suffix": ""}, {"first": "M", "middle": [], "last": "Karakucuk", "suffix": ""}, {"first": "W", "middle": [], "last": "Abey", "suffix": ""}, {"first": "L", "middle": [], "last": "Nguyen", "suffix": ""}, {"first": "J", "middle": [], "last": "Kessler", "suffix": ""}, {"first": "G", "middle": [], "last": "Carr", "suffix": ""}], "year": 2007, "venue": "", "link": null}, "BIBREF4": {"title": "Highly-integrated dual-band front-end module for WLAN and WiMAX applications based on LTCC technology", "authors": [{"first": "A", "middle": [], "last": "Yatsenko", "suffix": ""}, {"first": "J", "middle": [], "last": "Heyen", "suffix": ""}, {"first": "S", "middle": [], "last": "Sakhnenko", "suffix": ""}, {"first": "B", "middle": [], "last": "Vorotnikov", "suffix": ""}, {"first": "P", "middle": [], "last": "Heide", "suffix": ""}], "year": 2008, "venue": "IEEE IMS", "link": "36379382"}, "BIBREF5": {"title": "InGaPPlus TM A major advance in GaAs HBT Technology", "authors": [{"first": "A", "middle": [], "last": "Gupta", "suffix": ""}, {"first": "B", "middle": [], "last": "Peatman", "suffix": ""}, {"first": "M", "middle": [], "last": "Shokrani", "suffix": ""}, {"first": "W", "middle": [], "last": "Krystek", "suffix": ""}, {"first": "T", "middle": [], "last": "", "suffix": ""}], "year": "", "venue": "IEEE CSIS 2006", "link": null}}, "ref_entries": {}}
{"paper_id": "45911643", "_pdf_hash": "046e392c2c34e1d384442cd9e325aae156ab03e0", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Wavelet-Based Signal Processing Method for Detecting Ice Accretion on Wind Turbines", "authors": [{"first": "S", "middle": ["A R"], "last": "Saleh; R. Ahshan; C", "suffix": ""}, {"first": "", "middle": [], "last": "Moloney", "suffix": ""}], "year": 2012, "venue": "IEEE Trans. on Sustainable Energy", "link": "20740044"}, "BIBREF1": {"title": "Flicker emission of wind turbines during continuous operation", "authors": [{"first": "A", "middle": [], "last": "Larsson", "suffix": ""}], "year": 2002, "venue": "IEEE Trans. Energy Conversion", "link": null}, "BIBREF3": {"title": "Flicker study on variable speed wind turbines with doubly fed induction generators", "authors": [{"first": "F", "middle": [], "last": "Blaabjerg", "suffix": ""}], "year": 2005, "venue": "IEEE Trans. Energy Conversion", "link": "29275406"}, "BIBREF4": {"title": "Propagation of Flicker in Electric Power Networks Due to Wind Energy Conversions Systems", "authors": [{"first": "C", "middle": [], "last": "Vilar", "suffix": ""}, {"first": "H", "middle": [], "last": "Amaris", "suffix": ""}, {"first": "J", "middle": [], "last": "Usaola", "suffix": ""}], "year": 2002, "venue": "IEEE Trans. Power Engineering", "link": "110377864"}, "BIBREF5": {"title": "Validation of the Standard Method for Assessing Flicker From Wind Turbines", "authors": [{"first": "B", "middle": [], "last": "Barahona", "suffix": ""}, {"first": "P", "middle": [], "last": "S\u00f8rensen", "suffix": ""}, {"first": "L", "middle": [], "last": "Christensen", "suffix": ""}, {"first": "T", "middle": [], "last": "S\u00f8rensen", "suffix": ""}, {"first": "H", "middle": ["K"], "last": "Nielsen", "suffix": ""}, {"first": "X", "middle": ["G"], "last": "Lars\u00e9n", "suffix": ""}], "year": 2011, "venue": "IEEE Trans. Energy Conversion", "link": null}, "BIBREF6": {"title": "Power Quality: Problems and Mitigation Techniques", "authors": [{"first": "Bhim", "middle": [], "last": "Singh", "suffix": ""}, {"first": "Ambrish", "middle": [], "last": "Chandra", "suffix": ""}, {"first": "Kamal", "middle": [], "last": "Al-Haddad", "suffix": ""}], "year": 2015, "venue": "", "link": "130399368"}, "BIBREF7": {"title": "Power system quality assessment", "authors": [{"first": "J", "middle": [], "last": "Arrillaga", "suffix": ""}, {"first": "N", "middle": ["R"], "last": "Watson", "suffix": ""}, {"first": "S", "middle": [], "last": "Chen", "suffix": ""}], "year": 2000, "venue": "", "link": "60010328"}, "BIBREF8": {"title": "Power Quality Indices in Liberalized Markets", "authors": [{"first": "Guido", "middle": [], "last": "Pierluigicaramia", "suffix": ""}, {"first": "Paola", "middle": [], "last": "Carpinelli", "suffix": ""}, {"first": "", "middle": [], "last": "Verde", "suffix": ""}], "year": 2009, "venue": "", "link": "56396410"}, "BIBREF9": {"title": "Power Quality", "authors": [{"first": "Zia", "middle": [], "last": "Ul-Haquesyed", "suffix": ""}], "year": 2005, "venue": "", "link": null}, "BIBREF13": {"title": "Wind turbine blade profile thickness effects on atmospheric ice accretion", "authors": [{"first": "Muhammad", "middle": ["S"], "last": "Virk", "suffix": ""}], "year": 2016, "venue": "IEEE International Conf. on Power and Renewable Energy (ICPRE)", "link": "24000644"}, "BIBREF14": {"title": "Pooja Kulhari", "authors": [{"first": ".", "middle": ["S"], "last": "Datta", "suffix": ""}, {"first": "", "middle": [], "last": "Chavan", "suffix": ""}], "year": "", "venue": "Nehal Kadaganchi", "link": null}, "BIBREF15": {"title": "Prediction of power yield from wind turbines for hilly sites", "authors": [{"first": "P", "middle": ["B"], "last": "Karandikar; Puneet Singh; Rajesh", "suffix": ""}, {"first": "", "middle": [], "last": "Giri", "suffix": ""}], "year": 2015, "venue": "IEEE 2nd International Future Energy Electronics Conf. (IFEEC)", "link": "38958925"}, "BIBREF16": {"title": "A model-based robust icing detection and estimation scheme for windturbines", "authors": [{"first": "M", "middle": ["L"], "last": "Corradini", "suffix": ""}, {"first": "; A", "middle": [], "last": "Cristofaro", "suffix": ""}, {"first": ";", "middle": ["S"], "last": "Pettinari", "suffix": ""}], "year": 2016, "venue": "", "link": "19816998"}, "BIBREF20": {"title": "A robust observer for detection and estimation of icing in wind turbines", "authors": [{"first": "G", "middle": [], "last": "Orlando", "suffix": ""}], "year": 2016, "venue": "IECON 2016 -42nd Annual Conf. of the IEEE Industrial Electronics Society", "link": "3503844"}, "BIBREF21": {"title": "Assessment of Flicker Due to Vertical Wind Shear in a Wind Turbine Mounted on a Hill with Linear Approach", "authors": [{"first": "", "middle": ["S"], "last": "Datta", "suffix": ""}, {"first": "", "middle": ["B"], "last": "Chavan; P", "suffix": ""}, {"first": "", "middle": [], "last": "Karandikar", "suffix": ""}], "year": 2014, "venue": "4th International Conference on Artificial Intelligence with Applications in Engineering and Technology", "link": "19015860"}, "BIBREF24": {"title": "Computational closed-loop controller design for active deicing of wind turbines using distributed resistive heaters and temperature sensors", "authors": [{"first": "Robert", "middle": ["R"], "last": "Mcleod", "suffix": ""}], "year": 2016, "venue": "American Control Conf. (ACC)", "link": "25790950"}, "BIBREF25": {"title": "Linear Model of Flicker Due to Vertical Wind Shear for a Turbine Mounted on a Green Building", "authors": [{"first": "", "middle": ["S"], "last": "Datta", "suffix": ""}, {"first": "", "middle": ["B"], "last": "Chavan; P", "suffix": ""}, {"first": "", "middle": [], "last": "Karandikar", "suffix": ""}], "year": 2014, "venue": "4th International Conference on Artificial Intelligence with Applications in Engineering and Technology", "link": "10866917"}, "BIBREF26": {"title": "Outdoor Ice Accretion Estimation of Wind Turbine Blades Using Computer Vision", "authors": [{"first": "Moulay", "middle": [], "last": "Akhloufi", "suffix": ""}, {"first": "; Nassim", "middle": [], "last": "Benmesbah", "suffix": ""}], "year": 2014, "venue": "", "link": "574738"}, "BIBREF30": {"title": "Assessment of flicker owing to turbulence in a wind turbine placed on a hill using wind tunnel", "authors": [{"first": "Abhay Kumar Pande; Santhosh", "middle": [], "last": "Kumar", "suffix": ""}], "year": 2014, "venue": "International Conference on Circuits, Power and Computing Technologies", "link": "15837864"}, "BIBREF33": {"title": "Direct ice sensing and localized closedloop heating for active de-icing of wind turbine blades", "authors": [{"first": "Eric", "middle": ["D"], "last": "Moore; Robert", "suffix": ""}, {"first": "R", "middle": [], "last": "Mcleod", "suffix": ""}], "year": "", "venue": "", "link": "22548695"}, "BIBREF36": {"title": "Grey-model based ice prediction sensor system on wind turbine system", "authors": [{"first": "Chris", "middle": [], "last": "Papachristou", "suffix": ""}], "year": 2012, "venue": "2012 IEEE National Aerospace and Electronics Conf. (NAECON)", "link": "20050154"}, "BIBREF39": {"title": "Computation of flicker as a result of turbulence in a wind turbine sited on a green building using wind tunnel", "authors": [{"first": "Abhay Kumar Pande; Santhosh", "middle": [], "last": "Kumar", "suffix": ""}], "year": 2014, "venue": "International Conf. on Circuits, Power and Computing Technologies", "link": "7765492"}, "BIBREF41": {"title": "A Status of Study on Icing of Wind Turbine Blades", "authors": [{"first": "Xiaohu", "middle": [], "last": "Deng", "suffix": ""}], "year": 2011, "venue": "Second International Conf. on Digital Manufacturing & Automation", "link": null}, "BIBREF42": {"title": "Development and testing of wavelet packet transform-based detector for ice accretion on wind turbines", "authors": [{"first": "S", "middle": ["A R"], "last": "Saleh; C", "suffix": ""}, {"first": "", "middle": [], "last": "Moloney", "suffix": ""}], "year": 2011, "venue": "Digital Signal Processing and Signal Processing Education Meeting", "link": null}, "BIBREF46": {"title": "Empirical model of flicker due to vertical wind shear instigated by civilization in a seashore wind turbine using wind tunnel", "authors": [{"first": "P", "middle": ["B D"], "last": "Karandikar; S", "suffix": ""}, {"first": "", "middle": [], "last": "Bhide", "suffix": ""}], "year": 2014, "venue": "2nd International Conf. on Devices, Circuits and Systems (ICDCS)", "link": "12692833"}, "BIBREF47": {"title": "Fang Feng", "authors": [{"first": "Yan", "middle": [], "last": "Li", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF49": {"title": "Wind tunnel tests on ice accretions on the surface of a static straight blade for the vertical axis wind turbine", "authors": [{"first": "Shengmao", "middle": [], "last": "Li", "suffix": ""}], "year": 2010, "venue": "2nd International Conf. on Mechanical and Electronics Engineering", "link": "24792213"}, "BIBREF53": {"title": "Modeling of flicker due to vertical wind shear initiated by vegetation in a riverside wind turbine using wind tunnel", "authors": [{"first": "P", "middle": ["B D"], "last": "Karandikar; S", "suffix": ""}, {"first": "", "middle": [], "last": "Bhide", "suffix": ""}], "year": 2014, "venue": "2nd International Conference on Devices, Circuits and Systems (ICDCS)", "link": "42619502"}, "BIBREF56": {"title": "Research on fault mechanism of icing of wind turbine blades", "authors": [{"first": "Shaohua", "middle": [], "last": "Li", "suffix": ""}], "year": 2009, "venue": "", "link": "30426829"}, "BIBREF60": {"title": "Computation of flicker due to vertical wind shear in a wind turbine sited on a hill using wind tunnel", "authors": [{"first": "S", "middle": ["S B"], "last": "Deo; P", "suffix": ""}, {"first": "", "middle": [], "last": "Karandikar", "suffix": ""}], "year": 2014, "venue": "IEEE 8th International Power Engineering and Optimization Conference (PEOCO2014)", "link": "43529696"}, "BIBREF62": {"title": "Computer simulation on the icing accretions on a static straight blade used for the vertical axis wind turbine", "authors": [{"first": "Shengmao", "middle": [], "last": "Li", "suffix": ""}], "year": "", "venue": "2010 International Conf. on Computer Design and Applications, Year: 2010", "link": "14284834"}, "BIBREF66": {"title": "Modeling of flicker in wind turbine on a green building due to vertical wind shear", "authors": [{"first": "S", "middle": ["S B"], "last": "Deo; P", "suffix": ""}, {"first": "", "middle": [], "last": "Karandikar", "suffix": ""}], "year": "", "venue": "", "link": "29189455"}}, "ref_entries": {}}
{"paper_id": "45911744", "_pdf_hash": "6ebc8fbf6219e75bf3cf10fe3cd3b9455fdc2a3c", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "The future of lamellar keratoplasty", "authors": [{"first": "G", "middle": ["R"], "last": "Melles", "suffix": ""}, {"first": "L", "middle": [], "last": "Remeijer", "suffix": ""}, {"first": "A", "middle": ["J"], "last": "Geerards", "suffix": ""}, {"first": "W", "middle": ["H"], "last": "Beekhuis", "suffix": ""}], "year": 1999, "venue": "Curr Opin Ophthalmol", "link": "12175804"}, "BIBREF1": {"title": "Comparison of deep lamellar keratoplasty and penetrating keratoplasty in patients with keratoconus", "authors": [{"first": "S", "middle": ["L"], "last": "Watson", "suffix": ""}, {"first": "A", "middle": [], "last": "Ramsay", "suffix": ""}, {"first": "J", "middle": ["K"], "last": "Dart", "suffix": ""}, {"first": "C", "middle": [], "last": "Bunce", "suffix": ""}, {"first": "E", "middle": [], "last": "Craig", "suffix": ""}], "year": 2004, "venue": "Ophthalmology", "link": "10402424"}, "BIBREF2": {"title": "Deep Lamellar Keratoplasty dissection of host tissue with intrastromal air injection", "authors": [{"first": "E", "middle": ["A"], "last": "Archila", "suffix": ""}], "year": 1984, "venue": "Cornea", "link": "23333681"}, "BIBREF3": {"title": "Deep lamellar keratoplasty with complete removal of pathological stroma for vision improvement", "authors": [{"first": "J", "middle": [], "last": "Sugita", "suffix": ""}, {"first": "J", "middle": [], "last": "Kondo", "suffix": ""}], "year": 1997, "venue": "Br J Ophtalmol", "link": "6548835"}, "BIBREF4": {"title": "Intralamellar dissection techniques in lamellar keratoplasty", "authors": [{"first": "A", "middle": [], "last": "Panda", "suffix": ""}, {"first": "R", "middle": [], "last": "Singh", "suffix": ""}], "year": 2000, "venue": "Cornea", "link": "20577377"}, "BIBREF5": {"title": "A technique to visualize corneal incision and lamellar dissection deph during surgery", "authors": [{"first": "G", "middle": ["R"], "last": "Melles", "suffix": ""}, {"first": "F", "middle": [], "last": "Lander", "suffix": ""}, {"first": "F", "middle": ["J"], "last": "Rietveld", "suffix": ""}], "year": 1999, "venue": "Cornea", "link": "21139789"}, "BIBREF6": {"title": "Big-bubble technique to bare Descemet's membrane in anterior lamellar keratoplasty", "authors": [{"first": "M", "middle": [], "last": "Anwar", "suffix": ""}, {"first": "D", "middle": [], "last": "Klaus", "suffix": ""}, {"first": "M", "middle": [], "last": "Teichmann", "suffix": ""}], "year": 2002, "venue": "Journal of Cataract and Refract Surg", "link": "41951758"}, "BIBREF7": {"title": "Anterior lamellar surgeries: Ferrara technique", "authors": [{"first": "L", "middle": [], "last": "Fabiani", "suffix": ""}], "year": 2006, "venue": "International Scientific meeting of the Italian Society of Stem Cells and Ocular Surfaces (SICSSO )", "link": null}, "BIBREF8": {"title": "Corneal Lamellar Dissection by using Suture Threads in Porcine Eyes", "authors": [{"first": "G", "middle": [], "last": "Rocha", "suffix": ""}, {"first": "J", "middle": [], "last": "Dur\u00e1n", "suffix": ""}], "year": 2007, "venue": "Cornea", "link": "3048283"}, "BIBREF9": {"title": "Deep anterior Lamellar keratoplasty performed with the femtosecond laser zig-zag incision for the treatment of stromal corneal pathology and ecstatic disease", "authors": [{"first": "M", "middle": [], "last": "Farid", "suffix": ""}, {"first": "R", "middle": [], "last": "Steinert", "suffix": ""}], "year": 2009, "venue": "Journal of Cataract and Refract Surg", "link": "2952589"}, "BIBREF10": {"title": "Microkeratome -Assisted lamellar keratoplasty for the surgical treatment of keratoconus", "authors": [{"first": "M", "middle": [], "last": "Busin", "suffix": ""}, {"first": "L", "middle": [], "last": "Zambiachi", "suffix": ""}, {"first": "C", "middle": [], "last": "Robert", "suffix": ""}], "year": 2005, "venue": "Ophthalmology", "link": "25979054"}, "BIBREF11": {"title": "Wound Healing in rabbit corneas after photorefractive keratectomy and laser in situ keratomileusis", "authors": [{"first": "T", "middle": [], "last": "Miyamoto", "suffix": ""}, {"first": "S", "middle": [], "last": "Saika", "suffix": ""}, {"first": "A", "middle": [], "last": "Yamanaka", "suffix": ""}, {"first": "Y", "middle": [], "last": "Kawashima", "suffix": ""}, {"first": "Y", "middle": [], "last": "Suzuki", "suffix": ""}], "year": 2003, "venue": "Journal of Cataract and Refract Surg", "link": "40729865"}, "BIBREF12": {"title": "Induction of controlled Wound Healing with PMMA segments in the deep stroma in corneas of hens", "authors": [{"first": "J", "middle": [], "last": "Merayo-Lloves", "suffix": ""}, {"first": "T", "middle": [], "last": "Blanco-Mezquita", "suffix": ""}, {"first": "L", "middle": [], "last": "Ibares-Frias", "suffix": ""}], "year": 2010, "venue": "Eur J Ophthalmol", "link": "5812504"}, "BIBREF13": {"title": "Wound healing following refractive surgery in hens", "authors": [{"first": "M", "middle": ["C"], "last": "Martinez-Garcia", "suffix": ""}, {"first": "J", "middle": [], "last": "Merayo-Lloves", "suffix": ""}, {"first": "T", "middle": [], "last": "Blanco-Mezquita", "suffix": ""}, {"first": "S", "middle": [], "last": "Mar-Sardana", "suffix": ""}], "year": 2006, "venue": "Exp Eye Res", "link": "5576831"}, "BIBREF14": {"title": "Ibares-Fr\u00edas L. Clinical and pathological effects of different acrylic intracorneal ring segments in corneal additive surgery", "authors": [{"first": "P", "middle": [], "last": "P\u00e9rez-Merino", "suffix": ""}, {"first": "F", "middle": [], "last": "Parra", "suffix": ""}], "year": 2010, "venue": "Acta Biomaterialia", "link": null}}, "ref_entries": {}}
{"paper_id": "45911968", "_pdf_hash": "276e450175b0c518b2a14d2c232705e605afb879", "abstract": [{"section": "Abstract", "text": "The combination of carbon dioxide (CO 2 ) emissions mitigation and geoengineering options of solar radiation management (SRM) such as placing sunshades in space and stratospheric aerosol injection is discussed quantitatively using an extended version of the DICE-2007, an integrated assessment model for climate policy analysis. Though SRM measures can contribute considerably to the cost-effectiveness of climate change mitigation, they might cause harmful side effects, such as rapid air temperature increases, if the SRM implementation were to be discontinued for any reason. The author suggests a guideline for the use of SRM: namely, that unexpected SRM termination at any time would not exceed the constraints on the rate of global warming recommended by the German Advisory Council on Global Change. The paper describes a method to incorporate this guideline in the DICE-2007 model, and shows the result of the extended model, which recommends an 80% reduction of global industrial CO 2 emissions below the 2005 level by the end of the 21st century while implementing a complementary SRM option to mitigate climate change.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "INTRODUCTION", "text": "Technological measures to mitigate climatic change include greenhouse gas (GHG) emission reductions and climate geoengineering options. Among these measures, solar radiation management (SRM) technologies such as placing sunshades in space and injecting sulfur aerosol into the stratosphere have been evaluated as having relatively large potential to contribute to the mitigation of climate change (The Royal Society, 2009 ).", "cite_spans": [], "ref_spans": []}, {"section": "INTRODUCTION", "text": "However, while earlier studies dealing with strategies of climate change mitigation have focused on deriving optimal dynamic paths of the GHG emissions, especially carbon dioxide (CO 2 ), few have additionally considered the timing and scale of implementing SRM options. Though a pioneering study by Wigley (2006) shows plausible trajectories of the combination of CO 2 emissions reduction and SRM by stratospheric aerosol injection in the future, it lacks deep discussion of economics and risk management.", "cite_spans": [{"start": 300, "end": 313, "text": "Wigley (2006)", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "INTRODUCTION", "text": "The present study aims at drawing desirable scenarios based on those combined points of view by using an integrated assessment model of climate and economy. For discussing the combination of CO 2 emissions reduction and SRM, the study pays special attention to the so-called \"termination problem,\" i.e., the risk of adverse effects to climatic condition accompanied with a rapid global warming if the use of the SRM option is terminated for any reason after its implementation.", "cite_spans": [], "ref_spans": []}, {"section": "INCORPORATING SRM OPTIONS IN A CLIMATE-ECONOMY MODEL", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Modification of the DICE-2007 Integrated Assessment Model", "text": "The 2007 version of the DICE model known as an integrated assessment model of climate change, DICE-2007 (Nordhaus, 2008 , is modified to deal explicitly with SRM options. The DICE model is available for public use through its developer's Web page and has served as the basis of most other economic models of climate change. The model is a nonlinear programming model that integrates a neoclassical macroeconomic growth model with the following three models: an emissions model that computes the amount of CO 2 emissions caused by economic production and the cost of mitigating the emissions, a climate model that simulates the flow and stock of CO 2 in the air and ocean and their impact on the changes in global mean atmospheric temperature, and a damage model that estimates the damage cost caused by a given rise in air temperature. The objective function is the total discounted sum of a representative individual's instantaneous utility stream. It is a one-region model that covers the entire world and derives the optimal dynamic paths of macro investment and CO 2 reduction rate. The total period of time is divided into 60 time periods, the first of which comprises the ten years centered on 2005.", "cite_spans": [{"start": 104, "end": 119, "text": "(Nordhaus, 2008", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "Modification of the DICE-2007 Integrated Assessment Model", "text": "Since radiative forcing that determines the greenhouse effect is controllable only by atmospheric CO 2 concentration in the DICE model, this study modifies the model to include SRM options as a factor controlling radiative forcing, as applied earlier in Kosugi (2010) . The two most important points of the modification are described as follows.", "cite_spans": [{"start": 254, "end": 267, "text": "Kosugi (2010)", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Modification of the DICE-2007 Integrated Assessment Model", "text": "(i) Either placing sunshades in space or injecting aerosols into stratosphere is considered to be applicable. The balance of flow and stock of the sunshading materials is modeled; the service life of the materials, i.e., the period in which the materials stay in the area effective for SRM, is taken into account When we define the variables ) (t S and ) (t G as the mass stock of sun-shading materials accumulated in space or the stratosphere (Mt) and the mass flow of the materials lifted into space or the stratosphere (Mt/yr.), respectively, at time period t , and the parameter S \u03b4 as the depreciation rate of the sunshading materials accumulated in space or the stratosphere (yr.", "cite_spans": [], "ref_spans": []}, {"section": "Modification of the DICE-2007 Integrated Assessment Model", "text": "-1 ), the balance of flow and stock of sunshades in space is modeled as:", "cite_spans": [], "ref_spans": []}, {"section": "Modification of the DICE-2007 Integrated Assessment Model", "text": "noticing that a time period consists of ten years in the DICE model. Given the short staying period of injected aerosol in the stratosphere of a few years at the longest, the model for it is as follows:", "cite_spans": [], "ref_spans": []}, {"section": "Modification of the DICE-2007 Integrated Assessment Model", "text": "(1')", "cite_spans": [], "ref_spans": []}, {"section": "Modification of the DICE-2007 Integrated Assessment Model", "text": "(ii) The decrease in radiative forcing by implementing an option is assumed to be proportional to the up-mass stock of the sun-shading material. Letting ) (t F and ) (t F EX be total radiative forcing and its exogenous part due to non-CO 2 GHGs (W/m 2 relative to 1900) and ) (t M AT the mass of carbon in the atmosphere (GtC), this is modeled as:", "cite_spans": [], "ref_spans": []}, {"section": "Modification of the DICE-2007 Integrated Assessment Model", "text": "where \u03b7 and m denote the parameters connecting radiative forcing with temperature (\u00b0C/W/m 2 ) and the sunshade mass-effectiveness coefficient, i.e., the mass of the stock of sun-shading materials required to offset the increase in radiative forcing due to a doubling of the atmospheric CO 2 concentration (Mt/2\u00d7CO 2 ), respectively.", "cite_spans": [], "ref_spans": []}, {"section": "Modification of the DICE-2007 Integrated Assessment Model", "text": "By using the calculated radiative forcing, the air temperature is estimated through the following simple climate model as in the original DICE model: (4) where variables ) (t T AT and ) (t T LO represent the global mean surface temperature and the temperature of the ocean depths (\u00b0C relative to 1900), respectively. Other modifications include: (iii) the cost of installing the sun-shading materials is subtracted from consumption; (iv) CO 2 emissions induced by installing the sun-shading materials are taken into account; (v) constraints to avoid an air temperature drop are imposed; the global mean air temperature is kept at no less than its 1900 value in the whole period and the rate of temperature decrease doesn't exceed 0.2 \u00b0C per decade; and (vi) the CO 2 mitigating trend is assumed to be continued; the rate of CO 2 mitigation is constrained not to decline with an elapse of time.", "cite_spans": [], "ref_spans": []}, {"section": "Assumptions", "text": "Among the variety of parameters in the model, the parameters used in the original DICE model were set to be the same as the reference values applied in the DICE-2007. Table 1 (a) shows a major set of extractions from those parameter settings.", "cite_spans": [], "ref_spans": []}, {"section": "Assumptions", "text": "The parameters introduced to incorporate SRM options in the model are set based on a survey of literature data (Hertzfeld, et al., 2005; Lenton and Vaughan, 2009; McClellan et al., 2010; Pearson, et al., 2006) as shown in Table 1 (b). Figure 1 shows the trajectory of the global mean air temperature calculated by using the modified DICE model described above. The figures hereafter show the results up to 2125 out of the whole time period calculated in the model. As seen from Figure 1 , the optimal path of SRM deployment follows the maximum allowable implementation starting from 2045 or 2015 if the space-sunshade installation or the stratospheric aerosol injection is applicable, respectively. This result implies that depending largely on an SRM option can be a more cost-effective measure for mitigating climatic change than facilitating CO 2 emissions reduction. In this case, as shown in Figure 2 (see \"w/o temp. limit\" in the figure) the global industrial CO 2 emission is allowed to rise steadily.", "cite_spans": [{"start": 111, "end": 136, "text": "(Hertzfeld, et al., 2005;", "ref_id": "BIBREF4"}, {"start": 137, "end": 162, "text": "Lenton and Vaughan, 2009;", "ref_id": "BIBREF6"}, {"start": 163, "end": 186, "text": "McClellan et al., 2010;", "ref_id": "BIBREF7"}, {"start": 187, "end": 209, "text": "Pearson, et al., 2006)", "ref_id": "BIBREF10"}], "ref_spans": [{"start": 222, "end": 229, "text": "Table 1", "ref_id": "TABREF0"}, {"start": 235, "end": 243, "text": "Figure 1", "ref_id": "FIGREF0"}, {"start": 478, "end": 486, "text": "Figure 1", "ref_id": "FIGREF0"}, {"start": 897, "end": 905, "text": "Figure 2", "ref_id": "FIGREF1"}]}, {"section": "Initial Results: An Outrageous Influence of SRM on Air Temperature", "text": "However, in the case of such a large dependency on SRM for mitigating climate change, we would be faced with the problem described below should the implementation of SRM be terminated. Space, w/o temp. limit Stratosph., w/o temp. limit Space, w/ temp. limit Stratosph., w/ temp. limit The broken lines in Figure 1 indicate the temperature increases after SRM termination at the respective time periods. More specifically, it shows the calculated global mean air temperature rise hypothesizing that the values of all the variables, e.g., CO 2 emissions, are the same as those calculated earlier through the model while no new sun-shading materials are placed into space or the stratosphere after each of the time periods. The abrupt rise in air temperature after the SRM termination is called the \"termination problem,\" which has been described as one of the most serious risks concerning the use of SRM (Brovkin, et al., 2009 ).", "cite_spans": [{"start": 903, "end": 925, "text": "(Brovkin, et al., 2009", "ref_id": "BIBREF1"}], "ref_spans": [{"start": 305, "end": 313, "text": "Figure 1", "ref_id": "FIGREF0"}]}, {"section": "EXTENDING THE MODEL TO MANAGE THE RISK OF SRM TERMINATION", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Proposal of a Guideline for the Use of SRM", "text": "For the safer use of SRM options, we need to avoid the risk of abrupt warming, which would occur in a situation where SRM implementation is terminated. The causes of termination could include unsuccessful continuous multilateral political negotiations regarding SRM or the unexpected revelation of a major adverse side effect of the SRM. Although such an occurrence is itself unforeseeable, the extent of the adverse effect brought about by the SRM termination can be estimated, and it is possible to control the use of SRM to keep the damage from unforeseen discontinuation at a certain allowable level.", "cite_spans": [], "ref_spans": []}, {"section": "Proposal of a Guideline for the Use of SRM", "text": "Given the climate control recommendation by WBGU (2003) to constrain the rise in global average air temperature below 2 \u00b0C and the per-decade rate of temperature rise within 0.2 \u00b0C, a guideline for SRM use is derived such that the above condition holds even if SRM is terminated at any time.", "cite_spans": [], "ref_spans": []}, {"section": "Extension of the Model for Managing the Risk of the SRM Termination Problem", "text": "The above guideline can be implemented in the model by introducing the following formulae. Let ) , ( t t S \u2032 be the group of variables representing the virtual dynamic path of the mass stock of sun-shading materials accumulated in space or the stratosphere (Mt) assuming an SRM termination at time t\u2032 . For t t \u2032 < , clearly", "cite_spans": [], "ref_spans": []}, {"section": "Extension of the Model for Managing the Risk of the SRM Termination Problem", "text": "while for T t t < \u2264 \u2032 , setting the value of ) (t G to null in Eqs. (1) ", "cite_spans": [], "ref_spans": []}, {"section": "Extension of the Model for Managing the Risk of the SRM Termination Problem", "text": "while for", "cite_spans": [], "ref_spans": []}, {"section": "Extension of the Model for Managing the Risk of the SRM Termination Problem", "text": ", consistently with Eqs. (3) and (4), ", "cite_spans": [], "ref_spans": []}, {"section": "Extension of the Model for Managing the Risk of the SRM Termination Problem", "text": "These two constraints should be applied for all t and t\u2032 ; however, incorporating Eq. (10) for 3 < t makes the model infeasible, i.e., the rise in global mean air temperature in the next decade will inevitably be above 0.2 \u00b0C. We therefore apply Eq. (10) for 3 \u2265 t . The total numbers of variables and constraints become 13 and 20 times, respectively, as many as those of the model before the extension. The computation time to find the utility maximizing solution is 41 seconds for the extended model when space-sunshades are assumed to be available as an SRM option, which is 27 seconds longer than the preextension when the model is solved by GAMS/ CONOPT3 (Brooke et al., 1992; Drud, 1994) with a PC based on the Intel(R) Core(TM) 2 Duo CPU P9300, 2.26GHz with 1.93 GB RAM.", "cite_spans": [{"start": 660, "end": 681, "text": "(Brooke et al., 1992;", "ref_id": "BIBREF0"}, {"start": 682, "end": 693, "text": "Drud, 1994)", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "Results", "text": "The global mean air temperature calculated through the extended model is shown as the solid line in Figure 3 . Compared with Figure 1 , this figure suggests a moderate use of SRM, especially in the case of stratospheric aerosol injection, to lower the air temperature when we adopt the guideline introduced above. As in Figure 1 , the broken lines in Figure 3 indicate the trajectory of the temperature after an unexpected SRM termination at the respective time periods; we can confirm that, when the use of SRM is moderated to reflect the guideline of limiting the temperature rise that would occur by SRM termination, abrupt warming by SRM use termination is avoided. Figure 2 includes the optimal paths of the industrial CO 2 emissions when the constraint on the limit of temperature rise in case of SRM termination is adopted (see \"w/ temp. limit\") together with those without the limit of temperature rise explained in Section 2.3. The results imply that reducing CO 2 emissions is expected to play a more important role in mitigating climate change when we adopt the guideline of limiting temperature rise. Specifically, the amount of industrial CO 2 emissions should be kept at around the present level in the former half of this century and is expected to be reduced rapidly afterward, reaching only 20% of the 2005 levels by 2085. Figure 4 shows the calculated atmospheric CO 2 concentration, which steadily increases in this century and reaches 700 ppmv a century hence if the guideline of limiting the temperature rise in case of SRM termination is not adopted. With the limit of temperature rise in such a case, on the other hand, the increase in CO 2 concentration is expected to be mitigated to peak at 490 ppmv by 2075; afterward the concentration decreases to below 450 ppmv after 2125.", "cite_spans": [], "ref_spans": [{"start": 100, "end": 108, "text": "Figure 3", "ref_id": "FIGREF2"}, {"start": 125, "end": 133, "text": "Figure 1", "ref_id": "FIGREF0"}, {"start": 320, "end": 328, "text": "Figure 1", "ref_id": "FIGREF0"}, {"start": 351, "end": 359, "text": "Figure 3", "ref_id": "FIGREF2"}, {"start": 670, "end": 678, "text": "Figure 2", "ref_id": "FIGREF1"}, {"start": 1340, "end": 1348, "text": "Figure 4", "ref_id": "FIGREF3"}]}, {"section": "Results", "text": "To observe the desirable combination of CO 2 emissions reduction and SRM for contributing to mitigating climate change derived under the guideline of limiting temperature rise in case of SRM termination, the decrease in radiative forcing by use of each measure to mitigate climate change, i.e., the difference from the radiative forcing compared to the case where no climate mitigation policy is implemented, is illustrated in Figure 5 assuming that stratospheric aerosol injection is usable as an SRM option.", "cite_spans": [], "ref_spans": [{"start": 427, "end": 435, "text": "Figure 5", "ref_id": "FIGREF4"}]}, {"section": "Results", "text": "CO 2 emissions reduction contributes more to lessening radiative forcing than SRM throughout the time periods addressed by the model, and the Space, w/o temp. limit Stratosph., w/o temp. limit Space, w/ temp. limit Stratosph., w/ temp. limit contribution of emissions reduction becomes much greater as time passes. Though we omit a figure corresponding to the case of using space-based sunshades instead of stratospheric aerosol injection, a similar tendency is observed for this case. ", "cite_spans": [], "ref_spans": []}, {"section": "CONCLUDING REMARKS", "text": "SRM geoengineering is expected to be a lower-cost option of climate control compared to CO 2 emissions reduction, and may considerably contribute to the cost-effectiveness of global climatic change mitigation. However, this option is accompanied by the risk of rapid global warming if the implementation of SRM is unexpectedly terminated for any reason. As a guideline for the use of SRM to avoid the risk, this study suggests that the adverse effect should be controlled within an acceptable range in case of unexpected SRM termination at any time after its implementation. We incorporated the guideline into the integrated climate-economy model DICE by extending the model and quantitatively showed the contributions of CO 2 emissions reduction and SRM recommended to prevent global warming.", "cite_spans": [], "ref_spans": []}, {"section": "CONCLUDING REMARKS", "text": "The extension of the model brings increases in the numbers of variables and constraint equations, resulting in a longer computation time to solve the model. The model is still solved within a minute using a PC because it incorporates a very simplified climate module; if we further extend the model to deal with geographic distribution of climate change, the computation time is estimated to increase, which may impose a barrier to practical evaluation.", "cite_spans": [], "ref_spans": []}, {"section": "CONCLUDING REMARKS", "text": "Finally, it should be emphasized that there are some risks with the use of SRM other than those considered in the present modeling study. The quantitative results obtained from this study should be interpreted as the economic potential of SRM use assuming that such risks are low. If we needed to regard these risks as considerably high, more restrained use of SRM would be recommended.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "GAMS: A User's Guide, release 2.25", "authors": [{"first": "A", "middle": [], "last": "Brooke", "suffix": ""}, {"first": "D", "middle": [], "last": "Kendrick", "suffix": ""}, {"first": "A", "middle": [], "last": "Meeraus", "suffix": ""}], "year": 1992, "venue": "", "link": "154203886"}, "BIBREF1": {"title": "Geoengineering climate by stratospheric sulfur injections", "authors": [{"first": "V", "middle": [], "last": "Brovkin", "suffix": ""}, {"first": "V", "middle": [], "last": "Petoukhov", "suffix": ""}, {"first": "M", "middle": [], "last": "Claussen", "suffix": ""}, {"first": "E", "middle": [], "last": "Bauer", "suffix": ""}, {"first": "D", "middle": [], "last": "Archer", "suffix": ""}, {"first": "C", "middle": [], "last": "Jaeger", "suffix": ""}], "year": 2009, "venue": "Climatic Change", "link": null}, "BIBREF2": {"title": "CONOPT: A large-scale GRG code", "authors": [{"first": "A", "middle": ["S"], "last": "Drud", "suffix": ""}], "year": 1994, "venue": "ORSA Journal on Computing", "link": "207225645"}, "BIBREF3": {"title": "Climate Protection Strategies for the 21st Century: Kyoto and Beyond", "authors": [], "year": 2003, "venue": "", "link": "127000869"}, "BIBREF4": {"title": "Launch Vehicles: An Economic Perspective", "authors": [{"first": "H", "middle": ["R"], "last": "Hertzfeld", "suffix": ""}, {"first": "R", "middle": ["A"], "last": "Williamson", "suffix": ""}, {"first": "N", "middle": [], "last": "Peter", "suffix": ""}], "year": 2005, "venue": "", "link": null}, "BIBREF5": {"title": "Role of sunshades in space as a climate control option", "authors": [{"first": "T", "middle": [], "last": "Kosugi", "suffix": ""}], "year": 2010, "venue": "Acta Astronautica", "link": "109520703"}, "BIBREF6": {"title": "The radiative forcing potential of different climate geoengineering options", "authors": [{"first": "T", "middle": [], "last": "Lenton", "suffix": ""}, {"first": "N", "middle": ["E"], "last": "Vaughan", "suffix": ""}], "year": 2009, "venue": "Atmospheric Chemistry and Physics", "link": null}, "BIBREF7": {"title": "Geoengineering Cost Analysis: Final Report", "authors": [{"first": "J", "middle": [], "last": "Mcclellan", "suffix": ""}, {"first": "J", "middle": [], "last": "Sisco", "suffix": ""}, {"first": "B", "middle": [], "last": "Suarez", "suffix": ""}, {"first": "G", "middle": [], "last": "Keogh", "suffix": ""}], "year": 2010, "venue": "", "link": null}, "BIBREF8": {"title": "Aurora Flight Sciences Corporation", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF9": {"title": "A Question of Balance: Weighing the Options on Global Warming Policies", "authors": [{"first": "W", "middle": ["D"], "last": "Nordhaus", "suffix": ""}], "year": 2008, "venue": "", "link": null}, "BIBREF10": {"title": "Earth rings for planetary environment control", "authors": [{"first": "J", "middle": [], "last": "Pearson", "suffix": ""}, {"first": "J", "middle": [], "last": "Oldson", "suffix": ""}, {"first": "E", "middle": [], "last": "Levin", "suffix": ""}], "year": 2006, "venue": "Acta Astronautica", "link": "110271831"}, "BIBREF11": {"title": "Geoengineering the Climate: Science, Governance and Uncertainty", "authors": [], "year": 2009, "venue": "", "link": "128602961"}, "BIBREF12": {"title": "A combined mitigation/ geoengineering approach to climate stabilization", "authors": [{"first": "T", "middle": ["M L"], "last": "Wigley", "suffix": ""}], "year": 2006, "venue": "Science", "link": "40846810"}}, "ref_entries": {"FIGREF0": {"text": "Figure 1: Global mean air temperature without limiting temperature rise after SRM termination, \u00b0C relative to 1900. The solid line represents the optimal solution while the broken lines indicate the temperature increases after termination at the respective time periods.", "type": "figure"}, "FIGREF1": {"text": "Figure 2: Industrial CO 2 emissions, GtC/yr.", "type": "figure"}, "FIGREF2": {"text": "Figure 3: Global mean air temperature with limiting temperature rise after SRM termination, \u00b0C relative to 1900. The solid line represents the optimal solution while the broken lines indicate the temperature increases after termination at the respective time periods.", "type": "figure"}, "FIGREF3": {"text": "Figure 4: Atmospheric CO 2 concentration, ppmv.", "type": "figure"}, "FIGREF4": {"text": "Figure 5: Contribution of CO 2 emissions reduction and SRM to the mitigation of radiative forcing, W/m 2 relative to 1900, in the case of stratospheric aerosol injection.", "type": "figure"}, "TABREF0": {"text": "Major parameter settings. (a) Reference values in DICE-2007 modelRise in global mean air temperature relative to 1900. *2 Assumed to decline by 2%/yr. from the initial value of 6000 US$/kg in 2005.", "type": "table"}}}
{"paper_id": "45912310", "_pdf_hash": "761c6194b997c606b962ca529b905bf07296d671", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Mechanics of a constrained chair-rise", "authors": [{"first": "P", "middle": ["O"], "last": "Riley", "suffix": ""}, {"first": "M", "middle": ["L"], "last": "Schneckman", "suffix": ""}, {"first": "R", "middle": ["W"], "last": "Mamm", "suffix": ""}, {"first": "R", "middle": ["W"], "last": "Hodge", "suffix": ""}, {"first": "W", "middle": ["A"], "last": "Hodge", "suffix": ""}], "year": 1991, "venue": "J Biomech", "link": "8034963"}, "BIBREF1": {"title": "Rising from chair after total knee arthroplasty", "authors": [{"first": "F", "middle": ["C"], "last": "Su", "suffix": ""}, {"first": "K", "middle": ["A"], "last": "Lai", "suffix": ""}, {"first": "W", "middle": ["H"], "last": "Hong", "suffix": ""}], "year": 1998, "venue": "Clin Biochem", "link": "24013039"}, "BIBREF2": {"title": "Biomechanical analysis of sit-to-stand transfer in healthy and paraplegic subjects", "authors": [{"first": "F", "middle": [], "last": "Bahrami", "suffix": ""}, {"first": "R", "middle": [], "last": "Reiner", "suffix": ""}, {"first": "P", "middle": [], "last": "Jabedar-Maralani", "suffix": ""}, {"first": "G", "middle": [], "last": "Schmidt", "suffix": ""}], "year": 2000, "venue": "Clin Biomech", "link": null}, "BIBREF3": {"title": "Effect of bench height on sit-to-stand in children without diabilities and children with cerebral palsy", "authors": [{"first": "G", "middle": [], "last": "Hennington", "suffix": ""}, {"first": "J", "middle": [], "last": "Johnson", "suffix": ""}, {"first": "J", "middle": [], "last": "Penrose", "suffix": ""}, {"first": "K", "middle": [], "last": "Barr", "suffix": ""}, {"first": "M", "middle": ["L"], "last": "Mcmulkin", "suffix": ""}, {"first": "D", "middle": ["W"], "last": "Vander Linden", "suffix": ""}], "year": 2004, "venue": "Arch Phys Med Rehabil", "link": "23547648"}, "BIBREF4": {"title": "Anklefoot orthoses for preambulatory children with spastic diplegia", "authors": [{"first": "H", "middle": [], "last": "Wilson", "suffix": ""}, {"first": "N", "middle": [], "last": "Harideri", "suffix": ""}, {"first": "K", "middle": [], "last": "Song", "suffix": ""}, {"first": "D", "middle": [], "last": "Telford", "suffix": ""}], "year": 1977, "venue": "J Pediatr Orthop", "link": null}, "BIBREF5": {"title": "The characteristics of sit-to-stand transfer in young children with spastic cerebral palsy based on kinematic and kinetic data", "authors": [{"first": "E", "middle": ["S"], "last": "Park", "suffix": ""}, {"first": "C", "middle": ["I"], "last": "Park", "suffix": ""}, {"first": "H", "middle": ["J"], "last": "Lee", "suffix": ""}, {"first": "D", "middle": ["Y"], "last": "Kim", "suffix": ""}, {"first": "D", "middle": ["S"], "last": "Lee", "suffix": ""}, {"first": "S", "middle": ["R"], "last": "Cho", "suffix": ""}], "year": 2003, "venue": "Gait Posture", "link": "11435253"}, "BIBREF6": {"title": "Leg muscle activation patterns of sit-to-stand movement in stroke patients", "authors": [{"first": "P", "middle": ["T"], "last": "Cheng", "suffix": ""}, {"first": "C", "middle": ["L"], "last": "Chen", "suffix": ""}, {"first": "C", "middle": ["M"], "last": "Wang", "suffix": ""}, {"first": "W", "middle": ["H"], "last": "Hong", "suffix": ""}], "year": 2004, "venue": "Am J Phys Med Rehabil", "link": "17984754"}, "BIBREF7": {"title": "Botulinum toxin in the management of the lower limb in cerebral palsy", "authors": [{"first": "A", "middle": ["P"], "last": "Cosgrove", "suffix": ""}, {"first": "I", "middle": ["S"], "last": "Corry", "suffix": ""}, {"first": "H", "middle": ["K"], "last": "Graham", "suffix": ""}], "year": 1993, "venue": "Dev Med Child Neurol", "link": "35056579"}, "BIBREF8": {"title": "Management of spasticity in cerebral palsy with botulinum toxin A: preliminary investigation", "authors": [{"first": "L", "middle": ["A"], "last": "Koman", "suffix": ""}, {"first": "J", "middle": ["F"], "last": "Mooney", "suffix": ""}, {"first": "B", "middle": ["P"], "last": "Smith", "suffix": ""}, {"first": "A", "middle": [], "last": "Goodman", "suffix": ""}, {"first": "T", "middle": [], "last": "Mulvaney", "suffix": ""}], "year": 1993, "venue": "J Pediatr Orthop", "link": null}, "BIBREF9": {"title": "Further evaluation of botulinum toxin (Botox) in the management of cerebral palsy", "authors": [{"first": "L", "middle": ["A"], "last": "Koman", "suffix": ""}, {"first": "J", "middle": ["F"], "last": "Mooney", "suffix": ""}, {"first": "T", "middle": [], "last": "Mulvaney", "suffix": ""}, {"first": "S", "middle": [], "last": "Roberts", "suffix": ""}, {"first": "B", "middle": ["P"], "last": "Smith", "suffix": ""}], "year": 1993, "venue": "Dev Med Child Neurol", "link": null}, "BIBREF10": {"title": "Management of spasticity in cerebral palsy with botulinum A toxin: report of a preliminary, randomized, double blind trial", "authors": [{"first": "L", "middle": ["A"], "last": "Koman", "suffix": ""}, {"first": "J", "middle": ["F"], "last": "Mooney", "suffix": ""}, {"first": "", "middle": [], "last": "Iii", "suffix": ""}, {"first": "B", "middle": ["P"], "last": "Smith", "suffix": ""}, {"first": "A", "middle": [], "last": "Goodman", "suffix": ""}, {"first": "T", "middle": [], "last": "Mulvaney", "suffix": ""}], "year": 1994, "venue": "J Pediatr Orthop", "link": "115509"}, "BIBREF11": {"title": "Injection of botulinum A toxin into the gastrocnemius muscle of patients with cerebral palsy; a 3-dimensional motion analysis study", "authors": [{"first": "D", "middle": ["H"], "last": "Sutherland", "suffix": ""}, {"first": "K", "middle": ["R"], "last": "Kaufman", "suffix": ""}, {"first": "M", "middle": ["P"], "last": "Wyatt", "suffix": ""}, {"first": "H", "middle": ["G"], "last": "Chambers", "suffix": ""}], "year": 1996, "venue": "Gait Posture", "link": "72585786"}, "BIBREF12": {"title": "Musculoskeletal modeling in determining the effect of botulinum toxin on the hamstring of patients with crouch gait", "authors": [{"first": "N", "middle": ["S"], "last": "Thompson", "suffix": ""}, {"first": "I", "middle": ["S"], "last": "Cosgrove", "suffix": ""}, {"first": "H", "middle": ["K"], "last": "Graham", "suffix": ""}], "year": 1998, "venue": "Dev Med Child Neurol", "link": "24127428"}, "BIBREF13": {"title": "Randomized double blind placebo controlled trial of the effect of botulinum toxin on walking in cerebral palsy", "authors": [{"first": "T", "middle": [], "last": "Ubhi", "suffix": ""}, {"first": "B", "middle": ["B"], "last": "Bhakta", "suffix": ""}, {"first": "H", "middle": ["L"], "last": "Ives", "suffix": ""}, {"first": "V", "middle": [], "last": "Allgar", "suffix": ""}, {"first": "S", "middle": ["H"], "last": "Roussounits", "suffix": ""}], "year": 2000, "venue": "Arch Dis Child", "link": null}, "BIBREF14": {"title": "Interrater reliability of a modified Ashworth scale of muscle spasticity", "authors": [{"first": "R", "middle": ["W"], "last": "Bohannon", "suffix": ""}, {"first": "M", "middle": ["B"], "last": "Smith", "suffix": ""}], "year": 1987, "venue": "Phys Ther", "link": "14637733"}, "BIBREF15": {"title": "Comparison of balance responses and motor patterns during sit-to-stand task with functional mobility in stroke patients", "authors": [{"first": "M", "middle": ["Y"], "last": "Lee", "suffix": ""}, {"first": "M", "middle": ["K"], "last": "Wong", "suffix": ""}, {"first": "F", "middle": ["T"], "last": "Tang", "suffix": ""}, {"first": "P", "middle": ["T"], "last": "Cheng", "suffix": ""}, {"first": "P", "middle": ["S"], "last": "Lin", "suffix": ""}], "year": 1997, "venue": "Am J Phys Med Rehabil", "link": "23852789"}, "BIBREF16": {"title": "Postural control during sit-to-stand and gait in stroke patients", "authors": [{"first": "W", "middle": ["S"], "last": "Chou", "suffix": ""}, {"first": "Amk", "middle": [], "last": "Wong", "suffix": ""}, {"first": "C", "middle": ["P"], "last": "Leong", "suffix": ""}, {"first": "W", "middle": ["S"], "last": "Hong", "suffix": ""}, {"first": "F", "middle": ["T"], "last": "Tang", "suffix": ""}, {"first": "T", "middle": ["H"], "last": "Lin", "suffix": ""}], "year": 2003, "venue": "Am J Phys Med Rehabil", "link": "41945481"}, "BIBREF17": {"title": "Lower limb muscle activity in ambulatory children with cerebral palsy before and after the treatment with botulinum toxin A", "authors": [{"first": "S", "middle": [], "last": "Hesse", "suffix": ""}, {"first": "B", "middle": [], "last": "Brandl-Hesse", "suffix": ""}, {"first": "U", "middle": [], "last": "Seidel", "suffix": ""}, {"first": "B", "middle": [], "last": "Doll", "suffix": ""}, {"first": "M", "middle": [], "last": "Gregoric", "suffix": ""}], "year": 2000, "venue": "Restor Neurol Neurosci", "link": "22810454"}, "BIBREF18": {"title": "Ankle muscle activity before and after botulinum toxin therapy for lower limb extensor spasticity in chronic hemiparetic patients", "authors": [{"first": "S", "middle": [], "last": "Hesse", "suffix": ""}, {"first": "K", "middle": [], "last": "Kranjnik", "suffix": ""}, {"first": "D", "middle": [], "last": "Luecke", "suffix": ""}, {"first": "M", "middle": ["T"], "last": "Jahnke", "suffix": ""}, {"first": "M", "middle": [], "last": "Gregoric", "suffix": ""}, {"first": "K", "middle": ["H"], "last": "Mauritz", "suffix": ""}], "year": 1996, "venue": "Stroke", "link": "74029201"}, "BIBREF19": {"title": "Biomechanics of transfer from sitting to the standing position in some neuromuscular diseases", "authors": [{"first": "P", "middle": ["B"], "last": "Butler", "suffix": ""}, {"first": "A", "middle": ["V"], "last": "Nene", "suffix": ""}, {"first": "R", "middle": ["E"], "last": "Major", "suffix": ""}], "year": 1991, "venue": "Physiotherapy", "link": "71711038"}, "BIBREF20": {"title": "Biomechanical analysis of rising from a chair", "authors": [{"first": "A", "middle": ["B"], "last": "Schultz", "suffix": ""}, {"first": "N", "middle": ["B"], "last": "Alexander", "suffix": ""}, {"first": "Ashton", "middle": ["-"], "last": "Miller", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "", "suffix": ""}], "year": 1992, "venue": "J Biomech", "link": null}, "BIBREF21": {"title": "Two strategies of transferring from sit-to-stand; the activation of monoarticular and biarticular muscles", "authors": [{"first": "Cam", "middle": [], "last": "Doorenbosch", "suffix": ""}, {"first": "J", "middle": [], "last": "Harlaar", "suffix": ""}, {"first": "M", "middle": ["E"], "last": "Roebroeck", "suffix": ""}, {"first": "G", "middle": ["J"], "last": "Lankhorst", "suffix": ""}], "year": 1994, "venue": "J Biomech", "link": "32563431"}, "BIBREF22": {"title": "Speed variation and resultant joint torques during sit-to-stand", "authors": [{"first": "Y", "middle": ["C"], "last": "Pai", "suffix": ""}, {"first": "M", "middle": ["W"], "last": "Rogers", "suffix": ""}], "year": 1991, "venue": "Arch Phys Med Rehabil", "link": "40452462"}, "BIBREF23": {"title": "The speed of sit-tostand can be modulated in Parkinson's disease", "authors": [{"first": "M", "middle": ["K"], "last": "Mark", "suffix": ""}, {"first": "C", "middle": ["W"], "last": "Hui-Chan", "suffix": ""}], "year": 2005, "venue": "Clin Neurophysiol", "link": null}}, "ref_entries": {}}
{"paper_id": "45912650", "_pdf_hash": "5b7b3b35b18df0685ae14c6200dac3f860980886", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "45912720", "_pdf_hash": "eaac4e121fa760d1eb0cb08c408fff1b1c7ce56a", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Biosynthesis and transport of lysosoraal enzymes", "authors": [{"first": "A", "middle": [], "last": "Hasilik", "suffix": ""}, {"first": "R", "middle": [], "last": "Pohlmann", "suffix": ""}, {"first": "F", "middle": [], "last": "Steckel", "suffix": ""}, {"first": "V", "middle": [], "last": "Gieselmann", "suffix": ""}, {"first": "K", "middle": [], "last": "Figura", "suffix": ""}, {"first": "R", "middle": [], "last": "Olsen", "suffix": ""}, {"first": "A", "middle": [], "last": "Waheed", "suffix": ""}], "year": 1983, "venue": "", "link": null}, "BIBREF2": {"title": "Ultrastructural localization of mannose &phosphate receptors in rat liver", "authors": [{"first": "Geuze", "middle": ["H J"], "last": "", "suffix": ""}, {"first": "J", "middle": ["W"], "last": "Slot", "suffix": ""}, {"first": "G", "middle": [], "last": "", "suffix": ""}, {"first": "J", "middle": ["A M"], "last": "Strous", "suffix": ""}, {"first": "A", "middle": [], "last": "Hasilik", "suffix": ""}, {"first": "K", "middle": [], "last": "Figura", "suffix": ""}], "year": 1983, "venue": "Z Cell Biol", "link": null}, "BIBREF3": {"title": "The mannose 6-0hosphate receptor for lysosornal enzymes is concentrated in cis Golgi cisternae", "authors": [{"first": "W", "middle": ["J"], "last": "Brown", "suffix": ""}, {"first": "M", "middle": ["G"], "last": "Farquhar", "suffix": ""}], "year": 1983, "venue": "Celt", "link": null}, "BIBREF4": {"title": "Functions of coated vesicles during protein absorption in the rat vas deferens", "authors": [{"first": "D", "middle": [], "last": "Friend", "suffix": ""}, {"first": "S", "middle": [], "last": "", "suffix": ""}, {"first": "M", "middle": [], "last": "", "suffix": ""}, {"first": "G", "middle": [], "last": "Farqubar", "suffix": ""}], "year": 1967, "venue": "J. CellBiol", "link": "9008382"}, "BIBREF5": {"title": "Morphology study of the internalization of a lysosornal enzyme by the mannose 6-phosphate receptor in cultured hamster ovary cells", "authors": [{"first": "M", "middle": ["C"], "last": "Willingham", "suffix": ""}, {"first": "J", "middle": ["H"], "last": "Pastan", "suffix": ""}, {"first": "G", "middle": ["G"], "last": "Sahagian", "suffix": ""}, {"first": "G", "middle": ["W"], "last": "Jourdian", "suffix": ""}, {"first": "E", "middle": ["F"], "last": "Neufeld", "suffix": ""}], "year": 1981, "venue": "Proe Nail Acad Sci. USA", "link": null}, "BIBREF6": {"title": "Coated vesicles from rat liver and calf brain contain lysosomal enzymes bound to rnannose 6-phospbate receptors", "authors": [{"first": "C", "middle": ["H"], "last": "Campbell", "suffix": ""}, {"first": "L", "middle": ["H"], "last": "Rome", "suffix": ""}], "year": 1983, "venue": "L Biol. Chem", "link": null}, "BIBREF7": {"title": "Molecular forms of cathepsin D in coated vesicle preparations", "authors": [{"first": "S", "middle": [], "last": "T/Irnmers", "suffix": ""}, {"first": "M", "middle": [], "last": "Ziihlsdorf", "suffix": ""}, {"first": "H", "middle": [], "last": "Robenek", "suffix": ""}, {"first": "A", "middle": [], "last": "Hasilik", "suffix": ""}, {"first": "K", "middle": [], "last": "Figura", "suffix": ""}], "year": 1983, "venue": "Hoppe Seyler's Z. Physiol Chem", "link": "31755142"}, "BIBREF8": {"title": "Coated vesicles from rat liver and calf brain contain cryptic mannose 6-phosphate receptors", "authors": [{"first": "C", "middle": ["H"], "last": "Campbell", "suffix": ""}, {"first": "R", "middle": ["E"], "last": "Fine", "suffix": ""}, {"first": "J", "middle": [], "last": "Squicciarini", "suffix": ""}, {"first": "L", "middle": ["H"], "last": "Rome", "suffix": ""}], "year": 1983, "venue": "Z BioL Chem", "link": "8144214"}, "BIBREF9": {"title": "Coated vesicle isolation by imrnunoadsorption on Staphylococcus aureus cells", "authors": [{"first": "B", "middle": ["M F"], "last": "Pearse", "suffix": ""}, {"first": "M", "middle": [], "last": "", "suffix": ""}, {"first": "S", "middle": [], "last": "Bretscher", "suffix": ""}, {"first": "E", "middle": [], "last": "I981 ; Merisko", "suffix": ""}, {"first": "M", "middle": [], "last": "", "suffix": ""}, {"first": "G", "middle": ["M"], "last": "Farquhar", "suffix": ""}, {"first": "G", "middle": ["E"], "last": "Palade", "suffix": ""}], "year": 1982, "venue": "Annu. Rev. Biochem", "link": null}, "BIBREF10": {"title": "Cleavage of structural proteins during assembly of the head of bacteriophage T4", "authors": [{"first": "V", "middle": [], "last": "Gieselrnann", "suffix": ""}, {"first": "R", "middle": [], "last": "Pohlmann", "suffix": ""}, {"first": "A", "middle": [], "last": "Hasilik", "suffix": ""}, {"first": "K", "middle": [], "last": "", "suffix": ""}, {"first": "Yon", "middle": [], "last": "Figura", "suffix": ""}], "year": 1970, "venue": "Nature (Lond.)", "link": null}, "BIBREF11": {"title": "Coated vesicles from human placenta carry ferritin, transferrin and immunoglobulin G", "authors": [{"first": "B", "middle": ["M F"], "last": "Pearse", "suffix": ""}], "year": 1982, "venue": "Proc. Natl. Acad Sci. USA", "link": "26390841"}, "BIBREF12": {"title": "Clathrin and coated vesicle proteins. Immunological characterization", "authors": [{"first": "J", "middle": ["H"], "last": "Keen", "suffix": ""}, {"first": "M", "middle": ["C"], "last": "Willingham", "suffix": ""}, {"first": "J", "middle": [], "last": "", "suffix": ""}, {"first": "Pastan", "middle": [], "last": "", "suffix": ""}], "year": 1981, "venue": "L Biol. Chem", "link": "20298772"}, "BIBREF13": {"title": "Juvenile and adult metachrornatic leucodystrophy: partial restoration of arylsulfatase A (cerebroside sulfata.~) activity by inhibitors of thiol proteinases", "authors": [{"first": "K", "middle": [], "last": "Yon Figura", "suffix": ""}, {"first": "F", "middle": [], "last": "Steckel", "suffix": ""}, {"first": "A", "middle": [], "last": "Hasilik", "suffix": ""}], "year": 1983, "venue": "Proc. NatL Acad. SoL USA", "link": null}, "BIBREF14": {"title": "Mannose 6-phospbate-specific receptor is a transmembrane protein with a C-terminal extension oriented towards the cytosol", "authors": [{"first": "K", "middle": [], "last": "Von Figura", "suffix": ""}, {"first": "A", "middle": [], "last": "V. Gieselmann", "suffix": ""}, {"first": "", "middle": [], "last": "Hasilik", "suffix": ""}], "year": 1985, "venue": "Biochem. J", "link": "2252799"}, "BIBREF15": {"title": "Quantitative film detection of 3H and 14C in polyacrylarnide gels by fluorography", "authors": [{"first": "R", "middle": ["A"], "last": "Laskey", "suffix": ""}, {"first": "A", "middle": [], "last": "", "suffix": ""}, {"first": "D", "middle": [], "last": "Mills", "suffix": ""}], "year": 1975, "venue": "Eur .Z Biochem", "link": null}, "BIBREF16": {"title": "Molecular forms of $-hexosarninidase and cathepsin D in serum and urine of healthy subjects and patients with elevated activity of lysosornal enzymes", "authors": [{"first": "M", "middle": [], "last": "Zijhlsdorf", "suffix": ""}, {"first": "A", "middle": [], "last": "Hasilik", "suffix": ""}, {"first": "K", "middle": [], "last": "Figura", "suffix": ""}], "year": 1983, "venue": "Biochem. J", "link": null}, "BIBREF17": {"title": "Intracellular sorting during endocylosis, Comparative immunoelectron microscopy of multiple receptors in rat liver", "authors": [{"first": "H", "middle": ["J"], "last": "Geuze", "suffix": ""}, {"first": "J", "middle": ["W"], "last": "Slot", "suffix": ""}, {"first": "G", "middle": ["J A M"], "last": "Strous", "suffix": ""}, {"first": "K", "middle": [], "last": "Peppard", "suffix": ""}, {"first": "A", "middle": [], "last": "Figura", "suffix": ""}, {"first": "Hasilik", "middle": [], "last": "", "suffix": ""}, {"first": "A", "middle": ["L"], "last": "Schwartz", "suffix": ""}], "year": 1984, "venue": "Cell", "link": "31538463"}, "BIBREF18": {"title": "Accumulation of coated vesicles bearing rnannose 6-phosphate receptors for lysosomal enzymes in the Golgi ~,ion of l-cell fibroblasts", "authors": [{"first": "W", "middle": ["J"], "last": "Brown", "suffix": ""}, {"first": "M", "middle": ["G"], "last": "Farquhar", "suffix": ""}], "year": 1984, "venue": "Proc Nat/. Acad Sci. USA", "link": null}, "BIBREF19": {"title": "Biosynthesis and turnover of the rnannose 6-phosphate receptor in cultured Chinese hamster ovary cells", "authors": [{"first": "V", "middle": [], "last": "Gieselrnann", "suffix": ""}, {"first": "A", "middle": [], "last": "Hasilik", "suffix": ""}, {"first": "K", "middle": [], "last": "Figura ; Sahagian", "suffix": ""}, {"first": "G", "middle": ["G"], "last": "", "suffix": ""}, {"first": "E", "middle": ["F"], "last": "Neufeld ; Yon Figura", "suffix": ""}, {"first": "K", "middle": [], "last": "V. Gieselmaon", "suffix": ""}, {"first": "A", "middle": [], "last": "Hasilik", "suffix": ""}], "year": 1983, "venue": "EMBO (Eur. Mol. Biochem. Organ.) J", "link": "37062177"}, "BIBREF20": {"title": "Redistribution ofrnannose 6-phosphate receptors induced by tunicamycin and chloroquine", "authors": [{"first": "W", "middle": ["J"], "last": "Brown", "suffix": ""}, {"first": "E", "middle": [], "last": "Coostantinescu", "suffix": ""}, {"first": "M", "middle": ["G"], "last": "Farquhar", "suffix": ""}], "year": 1984, "venue": "Z Cell BioL", "link": null}}, "ref_entries": {}}
{"paper_id": "45914585", "_pdf_hash": "1d5319d78681fce3adf10d4848616e486d3cc856", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Neglected rupture of the Achilles tendon. Treatment by V-Y tendinous flap", "authors": [{"first": "E", "middle": [], "last": "Abraham", "suffix": ""}, {"first": "A", "middle": ["M"], "last": "Pankovich", "suffix": ""}], "year": 1975, "venue": "J Bone Joint Surg Am", "link": "40248338"}, "BIBREF1": {"title": "Repair of defects in the tendo achillis", "authors": [{"first": "D", "middle": ["M"], "last": "Bosworth", "suffix": ""}], "year": 1956, "venue": "J Bone Joint Surg Am", "link": "31329848"}, "BIBREF2": {"title": "Late versus early repair of Achilles tendon rupture. Clinical and biomechanical evaluation", "authors": [{"first": "E", "middle": ["M"], "last": "Boyden", "suffix": ""}, {"first": "H", "middle": ["B"], "last": "Kitaoka", "suffix": ""}, {"first": "T", "middle": ["D"], "last": "Cahalan", "suffix": ""}, {"first": "K", "middle": ["N"], "last": "An", "suffix": ""}], "year": 1995, "venue": "Clin Orthop Relat Res", "link": "12231332"}, "BIBREF3": {"title": "Rupture of the calcaneal tendon. The early and late management", "authors": [{"first": "D", "middle": ["G"], "last": "Carden", "suffix": ""}, {"first": "J", "middle": [], "last": "Noble", "suffix": ""}, {"first": "J", "middle": [], "last": "Chalmers", "suffix": ""}, {"first": "P", "middle": [], "last": "Lunn", "suffix": ""}, {"first": "J", "middle": [], "last": "Ellis", "suffix": ""}], "year": 1987, "venue": "J Bone Joint Surg Br", "link": "16289682"}, "BIBREF4": {"title": "Rupture of the Achilles tendon: analysis of 57 cases", "authors": [{"first": "I", "middle": [], "last": "Christensen", "suffix": ""}], "year": 1953, "venue": "Acta Chir Scand", "link": null}, "BIBREF5": {"title": "The flexor hallucis longus tendon transfer for chronic tendo-Achilles ruptures revisited", "authors": [{"first": "R", "middle": ["B"], "last": "Dalal", "suffix": ""}, {"first": "M", "middle": [], "last": "Zenios", "suffix": ""}], "year": 2003, "venue": "Ann R Coll Surg Engl", "link": "19572908"}, "BIBREF6": {"title": "Neglected rupture of the Achilles tendon", "authors": [{"first": "S", "middle": [], "last": "Gabel", "suffix": ""}, {"first": "A", "middle": [], "last": "Manoli", "suffix": ""}, {"first": "", "middle": [], "last": "Ii", "suffix": ""}], "year": 1994, "venue": "Foot Ankle Int", "link": "413901"}, "BIBREF7": {"title": "Results of surgical repair of spontaneous rupture of the Achilles tendon", "authors": [{"first": "H", "middle": ["S"], "last": "Gillespie", "suffix": ""}, {"first": "E", "middle": ["A"], "last": "George", "suffix": ""}], "year": 1969, "venue": "J Trauma", "link": "27210886"}, "BIBREF8": {"title": "Trauma to the heel cord", "authors": [{"first": "S", "middle": ["T"], "last": "Hansen", "suffix": ""}], "year": 1991, "venue": "Disorders of the Foot and Ankle", "link": null}, "BIBREF9": {"title": "A review of ruptures of the Achilles tendon", "authors": [{"first": "S", "middle": ["J"], "last": "Hattrup", "suffix": ""}, {"first": "K", "middle": ["A"], "last": "Johnson", "suffix": ""}], "year": 1985, "venue": "Foot Ankle", "link": "8012210"}, "BIBREF10": {"title": "Muscle Testing: Techniques of Manual Examination", "authors": [{"first": "H", "middle": ["J"], "last": "Hislop", "suffix": ""}, {"first": "Montgomery", "middle": ["J"], "last": "Daniels", "suffix": ""}, {"first": "Worthingham", "middle": [], "last": "", "suffix": ""}], "year": 2002, "venue": "", "link": "72889549"}, "BIBREF11": {"title": "Ruptures of the tendo achillis. An objective assessment of surgical and non-surgical treatment", "authors": [{"first": "A", "middle": ["E"], "last": "Inglis", "suffix": ""}, {"first": "W", "middle": ["N"], "last": "Scott", "suffix": ""}, {"first": "T", "middle": ["P"], "last": "Sculco", "suffix": ""}, {"first": "A", "middle": ["H"], "last": "Patterson", "suffix": ""}], "year": 1976, "venue": "J Bone Joint Surg Am", "link": "28898399"}, "BIBREF12": {"title": "Chronic rupture of tendo Achillis. Long-term results of operative management using polyester tape", "authors": [{"first": "A", "middle": ["G"], "last": "Jennings", "suffix": ""}, {"first": "G", "middle": ["K"], "last": "Sefton", "suffix": ""}], "year": 2002, "venue": "J Bone Joint Surg Br", "link": "44286477"}, "BIBREF13": {"title": "Semitendinosus tendon augmentation for a large defect after Achilles tendon rupture: two case reports", "authors": [{"first": "J", "middle": ["H"], "last": "Ji", "suffix": ""}, {"first": "W", "middle": ["Y"], "last": "Kim", "suffix": ""}, {"first": "Y", "middle": ["Y"], "last": "Kim", "suffix": ""}, {"first": "Y", "middle": ["S"], "last": "Lee", "suffix": ""}, {"first": "J", "middle": ["S"], "last": "Yoon", "suffix": ""}], "year": 2007, "venue": "Foot Ankle Int", "link": "46565488"}, "BIBREF14": {"title": "Management of chronic ruptures of the Achilles tendon", "authors": [{"first": "N", "middle": [], "last": "Maffulli", "suffix": ""}, {"first": "A", "middle": [], "last": "Ajis", "suffix": ""}], "year": 2008, "venue": "J Bone Joint Surg Am", "link": "1095103"}, "BIBREF15": {"title": "Ipsilateral free semitendinosus tendon graft transfer for reconstruction of chronic tears of the Achilles tendon", "authors": [{"first": "N", "middle": [], "last": "Maffulli", "suffix": ""}, {"first": "U", "middle": ["G"], "last": "Longo", "suffix": ""}, {"first": "N", "middle": [], "last": "Gougoulias", "suffix": ""}, {"first": "V", "middle": [], "last": "Denaro", "suffix": ""}], "year": 2008, "venue": "BMC Musculoskelet Disord", "link": "9659319"}, "BIBREF16": {"title": "Chronic rupture of the Achilles tendon: a new technique of repair", "authors": [{"first": "R", "middle": ["A"], "last": "Mann", "suffix": ""}, {"first": "G", "middle": ["B"], "last": "Holmes", "suffix": ""}, {"first": "K", "middle": ["S"], "last": "Seale", "suffix": ""}, {"first": "D", "middle": ["N"], "last": "Collins", "suffix": ""}], "year": 1991, "venue": "J Bone Joint Surg Am", "link": "29401788"}, "BIBREF17": {"title": "A classification of Achilles tendon disease", "authors": [{"first": "G", "middle": [], "last": "Puddu", "suffix": ""}, {"first": "E", "middle": [], "last": "Ippolito", "suffix": ""}, {"first": "F", "middle": [], "last": "Postacchini", "suffix": ""}], "year": 1976, "venue": "Am J Sports Med", "link": "9432640"}, "BIBREF18": {"title": "Traumatic rupture of the Achilles Tendon. Reconstruction by transplant and graft using the lateral peroneus brevis", "authors": [{"first": "P\u00e9rez", "middle": [], "last": "Teuffer", "suffix": ""}, {"first": "A", "middle": [], "last": "", "suffix": ""}], "year": 1974, "venue": "Orthop Clin North Am", "link": "77879758"}, "BIBREF19": {"title": "Treatment of chronic Achilles tendon disorders with flexor hallucis longus tendon transfer/augmentation", "authors": [{"first": "D", "middle": ["K"], "last": "Wilcox", "suffix": ""}, {"first": "D", "middle": ["R"], "last": "Bohay", "suffix": ""}, {"first": "J", "middle": ["G"], "last": "Anderson", "suffix": ""}], "year": 2000, "venue": "Foot Ankle Int", "link": "24880127"}}, "ref_entries": {}}
{"paper_id": "45914828", "_pdf_hash": "0d936c444c3b0f79b1d4729c57f70497fecee484", "abstract": [], "body_text": [{"section": "Introduction", "text": "Club drugs have been a growing concern in the United States since the 1980s. Although a number of psychoactive agents have been referred to as \"club drugs,\" the most common substances encompassed by the term are: ecstasy (3,4-methylenedioxymethamphetamine or MDMA), GHB (gamma-hydroxybutyrate), ketamine, LSD (lysergic acid diethylamide), methamphetamines, PCP (phencyclidine), and Rohypnol R (flunitrazepam). Currently available data suggest that ecstasy use in the United States is most common (Arria et al., 2002; . Recently, national surveillance data have suggested that ecstasy use is declining among adolescents . However, these observations arise from studies conducted among predominantly white populations. With the exception of the national surveillance studies (e.g., Monitoring the Future Study, National Household Survey on Drug Abuse), most domestic studies have been conducted among rave or circuit party attendees (Arria et al., 2002; Colfax et al., 2001; Mansergh et al., 2001; Mattison et al., 2001) , and men who have sex with men 1400 Ompad et al. Mansergh et al., 2001; Mattison et al., 2001; Klitzman, Pope, and Hudson, 2000) , most of whom are white.", "cite_spans": [{"start": 496, "end": 516, "text": "(Arria et al., 2002;", "ref_id": "BIBREF0"}, {"start": 931, "end": 951, "text": "(Arria et al., 2002;", "ref_id": "BIBREF0"}, {"start": 952, "end": 972, "text": "Colfax et al., 2001;", "ref_id": "BIBREF4"}, {"start": 973, "end": 995, "text": "Mansergh et al., 2001;", "ref_id": "BIBREF14"}, {"start": 996, "end": 1018, "text": "Mattison et al., 2001)", "ref_id": "BIBREF15"}, {"start": 1069, "end": 1091, "text": "Mansergh et al., 2001;", "ref_id": "BIBREF14"}, {"start": 1092, "end": 1114, "text": "Mattison et al., 2001;", "ref_id": "BIBREF15"}, {"start": 1115, "end": 1148, "text": "Klitzman, Pope, and Hudson, 2000)", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "Introduction", "text": "There is emerging evidence that the club drug economy may be changing. Recent reports have documented the movement of club drugs from clubs and raves to the streets. The National Institute on Drug Abuse's Community Epidemiology Working Group has reported that ecstasy was moving from the clubs to the street in several cities, including Baltimore and New York (Community Epidemiology Work Group, 2001) . In light of these changes in drug use availability and the paucity of data available among minorities, we investigated the use of ecstasy among minority substance users in New York City (N.Y.C.). To investigate whether or not to conduct major efforts to estimate ecstasy use in minority communities, we chose to start with a survey of use within an ongoing project that involves recruitment of injectors as well as noninjectors of heroin or cocaine within two minority communities. This sampling was not considered representative of the respective communities but was meant to provide an indication of the presence of ecstasy that may then warrant closer attention.", "cite_spans": [], "ref_spans": []}, {"section": "Method", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Research Sample", "text": "Between October 2002 and September 2003, we interviewed substance users participating in three ongoing observational studies in N.Y.C. Eligibility for the parent studies included age, \u226515 years old and recent (past 2 months) use of heroin, crack, or cocaine more than monthly. Recruitment involved targeted sampling with street outreach techniques, and data collection was conducted at two stationary storefronts in Central Harlem (Manhattan) and the South Bronx and a recreational vehicle that parked in Brooklyn, the Lower East Side of Manhattan, and Queens, all in N.Y.C. Recruitment methods used in these studies have been described in more detail elsewhere (Diaz et al., 2001a; Diaz et al., 2001b) . This study was approved by the Institutional Review Board at the New York Academy of Medicine.", "cite_spans": [{"start": 662, "end": 682, "text": "(Diaz et al., 2001a;", "ref_id": "BIBREF6"}, {"start": 683, "end": 702, "text": "Diaz et al., 2001b)", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "Data Collection", "text": "After providing informed consent, participants completed an interviewer-administered questionnaire that elicited information on demographic characteristics and drug use (i.e., type, frequency, duration). A supplemental questionnaire was added to ongoing studies to elicit detailed information on club drug use. Participants were reimbursed $20 for participation in the study.", "cite_spans": [], "ref_spans": []}, {"section": "Statistical Analysis", "text": "Bivariate analyses were conducted to assess the relation between demographic and club drug use variables by race using chi-square statistics for categorical variables and ANOVA for continuous variables. Covariates that were significantly associated with use of ecstasy in bivariate analyses (p < 0.2) were entered into a multivariate logistic model. Variables were retained in the final model if they were significant at the p = 0.10 level. Potential interactions were examined, including race and country of birth and race and injection drug use. All analyses were conducted using Intercooled STATA 7 (Stata Corp., College Station, Texas).", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "Between October 2002 and September 2003, we recruited 715 substance users. Among these, 546 (76.4%) were male and 169 (23.6%) were female. Hispanics were the 85 (11.9) 61 (13.7) 15 (7.7) 9 (12.2) 0.098 ecstasy use predominant racial group (62.4%), followed by blacks (27.3%) and whites (10.3%). The median age at enrollment was 32 (range 17-64). Half (49.0%) were currently homeless. One-third (34.5%) had been born outside the United States, and 11.9% had lived in New York City for less than a year. The proportion of the substance users that injected drugs was 58.3%. Overall, 25.6% reported using ecstasy in their lifetime and 11.9% had used it in the last 6 months.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "We assessed racial differences in demographic characteristics and ecstasy use (Table 1) . Hispanics were significantly more likely than blacks and whites to be male (81.4% vs. 71.8% and 58.1%, respectively) and to have lived in New York City for less than a year (16.4% vs. 2.6% and 9.5%, respectively) and less likely to have been born in the U.S. (52.1% vs. 90.7% and 83.6%, p < 0.001). Blacks tended to be older; whites were more likely to have a high school diploma (or equivalent) and less likely to have dropped out of school. In terms of substance use, whites were more likely than Hispanics and blacks to have a lifetime history of both ecstasy use (44.6% vs. 26.7% and 15.9%, respectively) and crack use (93.2% vs. 84.3% and 89.2%, respectively) as well as to have a history of injection drug use (85.1% vs. 64.7% and 33.3%, respectively). Compared to blacks, whites and Hispanics were more likely to have used ecstasy in the last 6 months, although this association was not significant (p = 0.098). Among the 85 people who had used ecstasy in the last 6 months, 47 (55.3%) had used once a month or less, 13 (15.3%) had used 2 to 3 days a month, 11 (12.9%) had used about once per week or 2 to 3 days per week, two (2.4%) had used 4 to 6 days per week, and one (1.2%) had used everyday. We next constructed a multivariate logistic regression model to examine correlates of lifetime ecstasy use (Table 2) . Ecstasy users were more likely to be 25 years old or younger [Adjusted Odds Ratio (AOR) = 4.26, 95% Confidence Interval (CI): 2.87, 6.33], born in the U.S. (AOR = 1.65, 95% CI: 1.08, 2.54), and currently homeless (AOR = 1.56, 95% CI: 1.08, 2.27). We observed a significant interaction between injection drug use and race where, compared to black noninjectors, Hispanic noninjectors and white injectors were significantly more likely to have a history of lifetime ecstasy use (AOR = 2.07, 95% CI: 1.16, 3.67 and AOR = 3.08, 95% CI: 1.53, 6.18, respectively), while black injectors were significantly less likely (AOR = 0.24, 95% CI: 0.07, 0.82). The Pearson \u03c7 2 goodness-of-fit test for the estimated model indicated that we could not reject the model (p = 0.1457).", "cite_spans": [], "ref_spans": [{"start": 78, "end": 87, "text": "(Table 1)", "ref_id": "TABREF0"}, {"start": 1403, "end": 1412, "text": "(Table 2)", "ref_id": "TABREF1"}]}, {"section": "Results", "text": "Finally, we constructed a multivariate logistic regression model to examine correlates of recent ecstasy use (Table 3) . Compared to blacks, Hispanics were significantly more likely to have used ecstasy in the last 6 months (AOR = 2.13, 95% CI: 1.11, 4.09). Ecstasy users were more likely to be under 25 years old (AOR = 4.66, 95% CI: 2.87, 7.55), currently homeless (AOR = 1.60, 95% CI: 0.98, 2.61), but less likely to be an injection drug user (AOR = 0.39, 95% CI: 0.34, 0.66). We did not observe any significant interactions. The Pearson \u03c7 2 goodness-of-fit test for the estimated model indicated good model fit (p = 0.7620).", "cite_spans": [], "ref_spans": [{"start": 109, "end": 118, "text": "(Table 3)", "ref_id": "TABREF2"}]}, {"section": "Discussion", "text": "To date, evidence of club drug use among minority populations, and ecstasy use in particular, is sparse. What little evidence there is suggests that, in broader population contexts, Asians were more likely and blacks were less likely than whites to have used ecstasy in the past year (Boyd, McCaben, and d'Arcy, 2003) . Data from the Monitoring the Future (MTF) Study found that ecstasy users in the general population are overwhelmingly white, where between 89 and 91% of 12-month ecstasy users were white . While at least 30% of these samples are non-white, they represent students attending high school or college (Boyd, McCaben, and d'Arcy, 2003) . In our study, whites reported a higher prevalence of lifetime ecstasy use (44.6%). However, lifetime history of ecstasy use was common among street-recruited Hispanic and black users of heroin, cocaine, and crack in New York City (26.7% and 15.9%, respectively). Caution is needed in interpreting data from this study, as our sample included persons selected for using other illicit drugs. This data then should not be construed as generalizing to minority communities in general. What the data suggest instead is that street-based ecstasy use is present at least in some measure within a subset of illicit drug users from predominantly minority communities. Much of the current knowledge of the epidemiology of ecstasy use relies on surveillance studies like the MTF Study, which samples public and private school students in the United States . In our sample, only 46.1% had finished high school (or equivalent), and 77.0% had dropped out of school at least once. Whether minority ecstasy users are more likely to drop out of school is unclear, and needs further examination. It is likely that persons like the participants in our studies are overlooked by surveillance systems such as the MTF, suggesting that current U.S. estimates of prevalence of club drug use, particularly among minorities, are low.", "cite_spans": [{"start": 284, "end": 317, "text": "(Boyd, McCaben, and d'Arcy, 2003)", "ref_id": "BIBREF1"}, {"start": 617, "end": 650, "text": "(Boyd, McCaben, and d'Arcy, 2003)", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Discussion", "text": "Congruent with previous studies Strote, Lee, and Wechsler, 2002) , we observed that ecstasy users were young. We observed a significant interaction between injection drug use and race where Hispanic noninjectors and white injectors were significantly more likely, and black injectors were significantly less likely, to have a history of lifetime ecstasy use. We also found that being U.S.-born was an independent correlate of lifetime ecstasy use, but did not observe an interaction between race and country of birth. Previous studies have reported that individuals born in the U.S., and Hispanics in particular (Brindis et al., 1995) , have higher rates of drug use as compared non-U.S. born immigrants (Johnson, VanGeest, and Cho, 2002) . Further investigation of this finding will be necessary to understand the social environment and context of ecstasy use among U.S. minorities.", "cite_spans": [{"start": 32, "end": 64, "text": "Strote, Lee, and Wechsler, 2002)", "ref_id": "BIBREF16"}, {"start": 612, "end": 634, "text": "(Brindis et al., 1995)", "ref_id": "BIBREF2"}, {"start": 704, "end": 738, "text": "(Johnson, VanGeest, and Cho, 2002)", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "Discussion", "text": "We also found that current homelessness was associated with lifetime ecstasy use. This relationship has not been reported previously. A possible explanation for this relationship could be that homeless people are more mobile through the city or the country, and therefore have access to different drug markets. Such data are not available in this dataset, but would be an area for additional research. Qualitative data would also further our understanding of this finding.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "While the sample studied here is not representative of all minorities or all minority drug users, it does provide evidence for ecstasy use among young black and Hispanic heroin, crack, and cocaine users that is higher than the previously reported prevalences of ecstasy use among minorities. Anecdotal reports suggest that MDMA is being sold on the streets of Harlem and the South Bronx, areas that are predominantly Hispanic and black. The changing venues of club drug use and the evolving club drug trade are beginning to be documented (Community Epidemiology Work Group, 2001 ). Our findings provide further evidence for availability of club drugs outside their tradition venues.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "The burden of \"substance abuse\" is already high among minority communities in the United States (Galea et al., 2003; Buka, 2002; Harlow, 1990) , and the precarious health status of these communities could be further compromised by another \"epidemic\" of drug use. Our findings highlight the need for further investigation of ecstasy use in minority populations, to determine the extent of use and to understand the posited risk factors and their dimensions, the necessary conditions for them to operate or not, as well as correlates of use among minorities.", "cite_spans": [{"start": 96, "end": 116, "text": "(Galea et al., 2003;", "ref_id": "BIBREF8"}, {"start": 117, "end": 128, "text": "Buka, 2002;", "ref_id": "BIBREF3"}, {"start": 129, "end": 142, "text": "Harlow, 1990)", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "Acknowledgments", "text": "This study was partly funded by grants DA13146 and DA12801 from the National Institute on Drug Abuse.", "cite_spans": [], "ref_spans": []}, {"section": "R\u00c9SUM\u00c9", "text": "Des donn\u00e9es recueillies semblent indiquer que l'usage de l'Ecstasy dans les\u00c9tats-Unis est pr\u00e9dominante parmi les adolescents et les jeunes adult\u00e9s. Pour\u00e9tudier l'usage de l'Ecstasy\u00e0 New York City nous avons ajout\u00e9 des questions aux oeuvres en cours pour recruter des comsommateurs de l'h\u00e9ro\u00efne et de la coca\u00efne. Parmi les 715 participants, 58,3% etaient consommateurs d'injections de drogues (IDUs). L'\u00e2ge m\u00e9diane\u00e9tait de de 32 ans (de 17\u00e0 64), 76,4%\u00e9taient m\u00e2les, 49.0%\u00e9taient sans abri, 62.4%\u00e9taient Hispaniques et 27.3%\u00e9taient Noirs. 34.5% n'\u00e9taient pas n\u00e9s dans les\u00c9tats Unis.", "cite_spans": [], "ref_spans": []}, {"section": "R\u00c9SUM\u00c9", "text": "En g\u00e9n\u00e9ral, 23.4% ont consomm\u00e9 de l'Ecstasy une fois ou l'autre et 11.9% l'ont consomm\u00e9e pendant les derniers six mois. Dans l'analyse de r\u00e9gression logistique multivari\u00e9e, la corr\u00e9lation de l'usage de l'Ecstasy de toute une vie y compris les jeunes,\u00e9tant n\u00e9 dans les\u00c9tats Unis, et les sans abri courants. Nous avons observ\u00e9 une interaction consid\u00e9rable entre la consommation de la drogue inject\u00e9e et la race o\u00f9, compar\u00e9s aux non-IDUs Noirs, non-IDUs Hispaniques et IDUs Blancs avaient consid\u00e9rablement une histoire de consommation de drogue pendant toute la vie plus probable tandis que les IDUs Noirs en\u00e9taient consid\u00e9rablement moins problables. Ces conclusions sont limit\u00e9s aux personnes qui consomment d'autres drogues mais elles indiquent qu'une investigation plus ample de la consommation de l'Ecstasy dans la population minoritaire est justifi\u00e9e.", "cite_spans": [], "ref_spans": []}, {"section": "RESUMEN", "text": "Los datos observados nos sugieren que el uso de la droga\u00c9xtasis en los EE. UU. ocurre predominantemente entre los adolescentes blancos y los adultos j\u00f3venes. Para investigar el uso de Extasis entre los usuarios de drogas en la ciudad de Nueva York, a\u00f1adimos preguntas a las formuladas en nuestros esfuerzos actuales para reclutar usuarios de hero\u00edna y de coca\u00edna para un estudio. De los 715 participantes reclutados, 58.3% eran usuarios de drogas por inyecci\u00f3n. La mediana de edad era de 32 a\u00f1os, en un grupo que abarcaba desde los 17 a los 64 a\u00f1os; 76.4% eran varones; 49% eran desamparados; 62.4% eran hispanos, y 27.3% eran negros. 34.5% nacieron fuera de los EE. UU. En conjunto, 23.4% de ellos hab\u00edan consumido Extasis en alg\u00fan momento de sus vidas, y 11.9% la hab\u00edan usado en los\u00faltimos 6 meses.", "cite_spans": [], "ref_spans": []}, {"section": "RESUMEN", "text": "En regresi\u00f3n log\u00edstica multivariada, los correlatos de uso del Extasis incluyeron una menor edad del usuario, el haber nacido en los EE.UU., y el encontrarse actualmente sin hogar. Observamos una interacci\u00f3n significativa entre el uso de drogas inyectadas y la raza: comparados con los negros no usuarios de drogas inyectadas, los hispanos no usuarios de drogas inyectadas y los blancos usuarios se mostraban significativamente m\u00e1s tendientes al consumo de\u00c9xtasis a lo largo de su vida, en tanto que los negros usuarios de drogas inyectadas aparec\u00edan como significativamente menos tendientes a ello.", "cite_spans": [], "ref_spans": []}, {"section": "RESUMEN", "text": "Estas conclusiones se limitan a personas que consumen otras drogas, pero sugieren que est\u00e1 justificado el realizar investigaciones adicionales sobre el uso de Extasis entre grupos demogr\u00e1ficos minoritarios. He has extensive experience in the design, conduct, and analysis of infectious disease and substance abuse epidemiological studies. He is the Editor-in-Chief of the Journal of Urban Health and has been appointed to the National Advisory Council on Drug Abuse within the Department of Health and Human Services. Dr. Vlahov has received funding from the NIH and the CDC to conduct epidemiologic intervention studies of HIV prevention in Harlem and the South Bronx involving young, adult recent consent injection drug users and noninjection drug users.", "cite_spans": [], "ref_spans": []}, {"section": "THE AUTHORS", "text": "", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "The pediatric forum: Ecstasy use among club rave attendees", "authors": [{"first": "A", "middle": ["M"], "last": "Arria", "suffix": ""}, {"first": "G", "middle": ["S"], "last": "Yacoubian", "suffix": ""}, {"first": "", "middle": [], "last": "Jr", "suffix": ""}, {"first": "E", "middle": [], "last": "Fost", "suffix": ""}, {"first": "E", "middle": ["D"], "last": "Wish", "suffix": ""}], "year": 2002, "venue": "Arch. Pediatr. Adolesc. Med", "link": "36762109"}, "BIBREF1": {"title": "Ecstasy use among college undergraduates: Gender, race and sexual identity", "authors": [{"first": "C", "middle": ["J"], "last": "Boyd", "suffix": ""}, {"first": "S", "middle": ["E"], "last": "Mccaben", "suffix": ""}, {"first": "H", "middle": [], "last": "Arcy", "suffix": ""}], "year": 2003, "venue": "J. Subst. Abuse. Treat", "link": "34500300"}, "BIBREF2": {"title": "The associations between immigrant status and risk-behavior patterns in Latino adolescents", "authors": [{"first": "C", "middle": [], "last": "Brindis", "suffix": ""}, {"first": "A", "middle": ["L"], "last": "Wolfe", "suffix": ""}, {"first": "V", "middle": [], "last": "Mccarter", "suffix": ""}, {"first": "S", "middle": [], "last": "Ball", "suffix": ""}, {"first": "S", "middle": [], "last": "Starbuck-Morales", "suffix": ""}], "year": 1995, "venue": "J. Adolesc. Health", "link": "26006871"}, "BIBREF3": {"title": "Disparities in health status and substance use: Ethnicity and socioeconomic factors", "authors": [{"first": "S", "middle": ["L"], "last": "Buka", "suffix": ""}], "year": 2002, "venue": "Public Health Rep", "link": "41735338"}, "BIBREF4": {"title": "Drug use and sexual risk behavior among gay and bisexual men who attend circuit parties: A venue-based comparison", "authors": [{"first": "G", "middle": ["N"], "last": "Colfax", "suffix": ""}, {"first": "G", "middle": [], "last": "Mansergh", "suffix": ""}, {"first": "R", "middle": [], "last": "Guzman", "suffix": ""}, {"first": "E", "middle": [], "last": "Vittinghoff", "suffix": ""}, {"first": "G", "middle": [], "last": "Marks", "suffix": ""}, {"first": "M", "middle": [], "last": "Rader", "suffix": ""}], "year": 2001, "venue": "J. Acquir. Immune. Defic. Syndr", "link": "25681550"}, "BIBREF5": {"title": "Epidemiologic trends in drug abuse", "authors": [], "year": 2001, "venue": "Proceedings from the Community Epidemiology Work Group", "link": null}, "BIBREF6": {"title": "Factors associated with prevalent hepatitis C: Differences among young adult injection drug users in lower and upper Manhattan", "authors": [{"first": "T", "middle": [], "last": "Diaz", "suffix": ""}, {"first": "D", "middle": [], "last": "Des Jarlais", "suffix": ""}, {"first": "D", "middle": [], "last": "Vlahov", "suffix": ""}, {"first": "T", "middle": ["E"], "last": "Perlis", "suffix": ""}, {"first": "V", "middle": [], "last": "Edwards", "suffix": ""}, {"first": "S", "middle": ["R"], "last": "Friedman", "suffix": ""}], "year": 2001, "venue": "Am. J. Public. Health", "link": null}, "BIBREF7": {"title": "Sexual orientation and HIV infection prevalence among young Latino injection drug users in Harlem", "authors": [{"first": "T", "middle": [], "last": "Diaz", "suffix": ""}, {"first": "D", "middle": [], "last": "Vlahov", "suffix": ""}, {"first": "B", "middle": [], "last": "Greenberg", "suffix": ""}, {"first": "Y", "middle": [], "last": "Cuevas", "suffix": ""}, {"first": "R", "middle": [], "last": "Garfein", "suffix": ""}], "year": 2001, "venue": "J. Womens. Health Gend. Based Med", "link": "37516801"}, "BIBREF8": {"title": "Racial/ethnic disparities in overdose mortality trends", "authors": [{"first": "S", "middle": [], "last": "Galea", "suffix": ""}, {"first": "J", "middle": [], "last": "Ahern", "suffix": ""}, {"first": "K", "middle": [], "last": "Tardiff", "suffix": ""}, {"first": "A", "middle": ["C"], "last": "Leon", "suffix": ""}, {"first": "P", "middle": ["O"], "last": "Coffin", "suffix": ""}, {"first": "K", "middle": [], "last": "Derr", "suffix": ""}], "year": 1990, "venue": "J. Urban. Health", "link": null}, "BIBREF9": {"title": "Patterns of rates of mortality from narcotics and cocaine overdose in Texas", "authors": [{"first": "K", "middle": ["C"], "last": "Harlow", "suffix": ""}], "year": 1976, "venue": "Public Health Rep", "link": "28931617"}, "BIBREF10": {"title": "Migration and substance use: Evidence from the U.S. National Health Interview Survey", "authors": [{"first": "T", "middle": ["P"], "last": "Johnson", "suffix": ""}, {"first": "J", "middle": ["B"], "last": "Vangeest", "suffix": ""}, {"first": "Y", "middle": ["I"], "last": "Cho", "suffix": ""}], "year": 2002, "venue": "Subst. Use Misuse", "link": "43630352"}, "BIBREF11": {"title": "Monitoring the Future National Survey Results on Drug Use", "authors": [{"first": "L", "middle": ["D"], "last": "Johnston", "suffix": ""}, {"first": "P", "middle": ["M"], "last": "O&apos;malley", "suffix": ""}, {"first": "J", "middle": ["G"], "last": "Bachman", "suffix": ""}], "year": 1975, "venue": "Secondary School Students", "link": "6338551"}, "BIBREF12": {"title": "Ecstasy use among American teens drops for the first time in recent years, and overall drug and alcohol use also decline in the year after 9/11", "authors": [{"first": "L", "middle": ["D"], "last": "Johnston", "suffix": ""}, {"first": "P", "middle": ["M"], "last": "O&apos;malley", "suffix": ""}, {"first": "J", "middle": ["G"], "last": "Bachman", "suffix": ""}], "year": 2002, "venue": "University of Michigan News and Information Services", "link": null}, "BIBREF13": {"title": "MDMA (\"ecstasy\") abuse and high-risk sexual behaviors among 169 gay and bisexual men", "authors": [{"first": "R", "middle": ["L"], "last": "Klitzman", "suffix": ""}, {"first": "H", "middle": ["G"], "last": "Pope", "suffix": ""}, {"first": "", "middle": [], "last": "Jr", "suffix": ""}, {"first": "J", "middle": ["I"], "last": "Hudson", "suffix": ""}], "year": 2000, "venue": "Am. J. Psychiatry", "link": "39551692"}, "BIBREF14": {"title": "The Circuit Party Men's Health Survey: Findings and implications for gay and bisexual men", "authors": [{"first": "G", "middle": [], "last": "Mansergh", "suffix": ""}, {"first": "G", "middle": ["N"], "last": "Colfax", "suffix": ""}, {"first": "G", "middle": [], "last": "Marks", "suffix": ""}, {"first": "M", "middle": [], "last": "Rader", "suffix": ""}, {"first": "R", "middle": [], "last": "Guzman", "suffix": ""}, {"first": "S", "middle": [], "last": "Buchbinder", "suffix": ""}], "year": 2001, "venue": "Am. J. Public. Health", "link": "733160"}, "BIBREF15": {"title": "Circuit party attendance, club drug use, and unsafe sex in gay men", "authors": [{"first": "A", "middle": ["M"], "last": "Mattison", "suffix": ""}, {"first": "M", "middle": ["W"], "last": "Ross", "suffix": ""}, {"first": "T", "middle": [], "last": "Wolfson", "suffix": ""}, {"first": "D", "middle": [], "last": "Franklin", "suffix": ""}], "year": 2001, "venue": "J. Subst. Abuse", "link": "21313968"}, "BIBREF16": {"title": "Increasing MDMA use among college students: Results of a national survey", "authors": [{"first": "J", "middle": [], "last": "Strote", "suffix": ""}, {"first": "J", "middle": ["E"], "last": "Lee", "suffix": ""}, {"first": "H", "middle": [], "last": "Wechsler", "suffix": ""}], "year": 2002, "venue": "J. Adolesc. Health", "link": "1101445"}, "BIBREF17": {"title": "Assessing the temporal relationship between race and ecstasy use among high school seniors", "authors": [{"first": "G", "middle": ["S"], "last": "Yacoubian", "suffix": ""}, {"first": "", "middle": [], "last": "Jr", "suffix": ""}], "year": 2002, "venue": "J. Drug. Educ", "link": "27361790"}}, "ref_entries": {"TABREF0": {"text": "Selected demographic characteristics and ecstasy use among 715 substance users in", "type": "table"}, "TABREF1": {"text": "Multivariate logistic regression model for correlates of lifetime ecstasy use among 642 Hispanic and black substance users in New York City, October 2002-March 2003", "type": "table"}, "TABREF2": {"text": "Multivariate logistic regression model for correlates of recent a ec- stasy use among 642 Hispanic and black substance users in New", "type": "table"}, "TABREF3": {"text": "Danielle C. Ompad, Ph.D., is an Investigator at the Cen- ter for Urban Epidemiologic Studies at the New York Academy of Medicine. Dr. Ompad completed her M.H.S. and Ph.D. in infectious disease epidemiology at the Johns Hopkins University School of Public Health. Dr. Ompad has extensive experience in design, conduct, and analy- sis of community-based cross-sectional and prospective studies focusing on illicit substance use and risky sexual behavior. Currently, Dr. Ompad's work involves assessing adolescent and young adult risk for HIV, HCV, and other blood-borne pathogens. Sandro Galea, M.D., M.P.H., Dr.PH., is a Medical Epi- demiologist and Associate Director at the Center for Ur- ban Epidemiologic Studies at the New York Academy of Medicine. He did his graduate training at the Harvard Uni- versity School of Public Health, the Columbia University Mailman School of Public Health, and at the University of Toronto Medical School, Canada. Dr. Galea is primarily in- terested in the social and economic determinants of health and risk behavior in urban settings. His work includes basic epidemiologic research, theoretic development, and the ap- plication of innovative methods to epidemiologic problems. Dr. Galea is an elected member of the American College of Epidemiology and a fellow of the Royal Institute of Public Health. He is board certified in Family Medicine and Emergency Medicine. He has worked as a clinician in remote rural communities in Northern Canada and in Mudug Region, Somalia. He is a licensed physician in Ontario, Canada and New York State. Crystal M. Fuller, Ph.D., is an Investigator in the Cen- ter for Urban Epidemiologic Studies at The New York Academy of Medicine. Dr. Fuller completed her M.P.H. in epidemiology at Tulane University School of Public Health, and earned her Ph.D. in infectious disease epi- demiology at the Johns Hopkins University School of Pub- lic Health. Dr. Fuller is an infectious disease epidemiolo- gist and an Assistant Professor at Columbia University's Mailman School of Public Health. Dr. Fuller has exten- sive experience in design, conduct, and analysis of cross- section and follow-up studies focusing on HIV, STDs, and hepatitis infections among urban populations, using a community-based approach.Edwards is the Field Director for the Center for Urban Epidemiologic Studies (CUES) at The New York Academy of Medicine. He has held this position for the past 4 years. Mr. Edwards has more than 14 years of experience working in the substance use/HIV-AIDS field. Mr. Edwards began his work at CUES directing the field activities of the Collaborative Injection Drug Users Study II (CIDUS II), and is the Director of Field Operations for several observational and intervention studies currently in the field. David Vlahov, Ph.D., is Director for the Center for Urban Epidemiologic Studies at The New York Academy of Medicine, Professor of Clinical Epidemiology at the Mailman School of Public Health at Columbia University, and Adjunct Professor in Epidemiology at the Johns Hop- kins School of Public Health. He is also Adjunct Professor in Psychiatry at New York University Medical School, Adjunct Professor at Cornell Weill Medical School, and Visiting Professor at the Albert Einstein College of Medicine at Yeshiva University. Dr. Vlahov completed his B.S.N. and M.S. in Nursing at the University of Maryland and a Ph.D. in epidemiology at Johns Hopkins School of Public Health.", "type": "table"}}}
{"paper_id": "45916674", "_pdf_hash": "0947236a1712637c71f39140e2801f27366e214d", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Blood components contribute to rise in gerbil brain levels of leukotriene-like immunoreactivity after ischemia and reperfusion", "authors": [{"first": "K", "middle": [], "last": "Saito", "suffix": ""}, {"first": "L", "middle": [], "last": "Levine", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Moskowitz", "suffix": ""}], "year": 1988, "venue": "Stroke", "link": "11693373"}, "BIBREF1": {"title": "A role for PAF-acether (plateletactivating factor) in platelet-dependent vascular diseases?", "authors": [{"first": "J", "middle": [], "last": "Benveniste", "suffix": ""}, {"first": "M", "middle": [], "last": "Chignard", "suffix": ""}], "year": 1985, "venue": "Circulation", "link": "7661392"}, "BIBREF2": {"title": "The effect of l-0-alkyl-2-acetyl-sn-glycero-3-phosphocholine (PAF-acether) on the arterial wall", "authors": [{"first": "R", "middle": ["H"], "last": "Bourgain", "suffix": ""}, {"first": "L", "middle": [], "last": "Maes", "suffix": ""}, {"first": "P", "middle": [], "last": "Braquet", "suffix": ""}, {"first": "R", "middle": [], "last": "Andries", "suffix": ""}, {"first": "L", "middle": [], "last": "Touqui", "suffix": ""}, {"first": "M", "middle": [], "last": "Braquet", "suffix": ""}], "year": 1985, "venue": "Prostaglandins", "link": null}, "BIBREF3": {"title": "Activity of platelet-activating factor (PAF) acetylhydrolase in plasma from patients with ischemic cerebrovascular disease", "authors": [{"first": "K", "middle": [], "last": "Satoh", "suffix": ""}, {"first": "T", "middle": [], "last": "Imaizumi", "suffix": ""}, {"first": "Y", "middle": [], "last": "Kawamura", "suffix": ""}, {"first": "H", "middle": [], "last": "Yoshida", "suffix": ""}, {"first": "S", "middle": [], "last": "Takamatsu", "suffix": ""}, {"first": "S", "middle": [], "last": "Mizono", "suffix": ""}], "year": 1988, "venue": "Prostaglandins", "link": "41060396"}, "BIBREF4": {"title": "Neuroregulatory and neuropathological actions of the ether-phospholipid platelet-activating factor", "authors": [{"first": "E", "middle": [], "last": "Kornecki", "suffix": ""}, {"first": "Y", "middle": ["H"], "last": "Ehrlich", "suffix": ""}], "year": 1988, "venue": "Science", "link": "38883614"}, "BIBREF5": {"title": "Platelet activating factor: A potent constrictor of cerebral arterioles in newborn pigs", "authors": [{"first": "W", "middle": ["M"], "last": "Armstead", "suffix": ""}, {"first": "M", "middle": [], "last": "Pourcyrous", "suffix": ""}, {"first": "R", "middle": [], "last": "Mirro", "suffix": ""}, {"first": "C", "middle": ["W"], "last": "Leffler", "suffix": ""}, {"first": "D", "middle": ["W"], "last": "Busija", "suffix": ""}], "year": 1988, "venue": "Circ Res", "link": "1914795"}, "BIBREF6": {"title": "Platelet-activating factor-induced hypotension alters cerebral blood flow and metabolism in rats (abstract)", "authors": [{"first": "P", "middle": ["M"], "last": "Kochanek", "suffix": ""}, {"first": "E", "middle": ["M"], "last": "Nemoto", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Melick", "suffix": ""}, {"first": "R", "middle": ["W"], "last": "Evans", "suffix": ""}, {"first": "D", "middle": ["F"], "last": "Burke", "suffix": ""}], "year": 1988, "venue": "Stroke", "link": null}, "BIBREF7": {"title": "Presence of specific binding sites for platelet-activating factor (PAF) in brain", "authors": [{"first": "M", "middle": ["T"], "last": "Domingo", "suffix": ""}, {"first": "B", "middle": [], "last": "Spinnewyn", "suffix": ""}, {"first": "P", "middle": ["E"], "last": "Chabrier", "suffix": ""}, {"first": "P", "middle": [], "last": "Braquet", "suffix": ""}], "year": 1988, "venue": "Biochem Biophys Res Commun", "link": "6460548"}, "BIBREF8": {"title": "Platelet activating factor receptor blockade enhances recovery after multifocal brain ischemia", "authors": [{"first": "P", "middle": ["M"], "last": "Kochanek", "suffix": ""}, {"first": "A", "middle": ["J"], "last": "Dutka", "suffix": ""}, {"first": "K", "middle": ["K"], "last": "Kumaroo", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Hallenbeck", "suffix": ""}], "year": 1987, "venue": "Life Sci", "link": "27585654"}, "BIBREF9": {"title": "Baseline and activated platelet cytoplasmic ionized calcium in acute ischemic stroke: Effect of aspirin", "authors": [{"first": "R", "middle": [], "last": "Joseph", "suffix": ""}, {"first": "Kma", "middle": [], "last": "Welch", "suffix": ""}, {"first": "S", "middle": [], "last": "Grunfeld", "suffix": ""}, {"first": "S", "middle": ["B"], "last": "Oster", "suffix": ""}, {"first": "D", "middle": [], "last": "&apos;andrea", "suffix": ""}, {"first": "G", "middle": [], "last": "", "suffix": ""}], "year": 1988, "venue": "Stroke", "link": "1735390"}, "BIBREF10": {"title": "Pulsed Doppler assessment of innominate artery obstructive diseases", "authors": [{"first": "W", "middle": [], "last": "Rautenberg", "suffix": ""}, {"first": "M", "middle": [], "last": "Hennerici", "suffix": ""}], "year": 1988, "venue": "Stroke", "link": "39337326"}}, "ref_entries": {}}
{"paper_id": "45916789", "_pdf_hash": "ff8b5f3463442d37448538d8ec97b2863255ba78", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "45916991", "_pdf_hash": "985ecbe5f1c6ffbe98b7f34165a37036fd963f1a", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "142A. and references therein", "authors": [{"first": "N", "middle": [], "last": "Winograd", "suffix": ""}], "year": 2005, "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "45917474", "_pdf_hash": "74374a6eb0240d216b4f6fde60bf5e69830dd244", "abstract": [], "body_text": [], "bib_entries": {"BIBREF1": {"title": "A Theory of Exit in Oligopoly", "authors": [{"first": "D", "middle": [], "last": "Fudenberg", "suffix": ""}, {"first": "J", "middle": [], "last": "T1role", "suffix": ""}], "year": 1983, "venue": "", "link": null}, "BIBREF2": {"title": "Animal Behavior 24, 159", "authors": [{"first": "P", "middle": [], "last": "Hammerstetn", "suffix": ""}, {"first": "G", "middle": ["A"], "last": "Parker", "suffix": ""}, {"first": "J", "middle": [";"], "last": "Smith", "suffix": ""}, {"first": "", "middle": [], "last": "Maynard", "suffix": ""}, {"first": "J", "middle": [], "last": "Smith", "suffix": ""}, {"first": "G", "middle": ["A"], "last": "Parker", "suffix": ""}], "year": "", "venue": "Game Theoretic Models of Bargaining", "link": null}, "BIBREF4": {"title": "Games of Timing with Incomplete Information", "authors": [{"first": "C", "middle": ["A"], "last": "Wilson", "suffix": ""}], "year": 1983, "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "45918463", "_pdf_hash": "5d9e17e81bf3a36ff4eebf7ac20a69b3b5bdba7d", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "91041031", "_pdf_hash": "2cc8b1e5c54c1576f9d61c3459586db3dd6a11c3", "abstract": [{"section": "Abstract", "text": "Abstract] RNA-dependent RNA polymerase (RdRp) is essential for the replication of viral RNA for RNA viruses. It synthesizes the complementary strand of viral genomic RNA, which is used subsequently as a template to generate more copies of viral genome. This assay measures activity of the hepatitis E virus (HEV) RdRp. In contrast to protocols available to assay the RdRp activity of many other viruses, this assay utilizes DIG-11-UTP as a nonradioactive alternative to 32 P-UTP, thereby increasing the convenience of performing the assay.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "", "text": "2. 48 h post transfection, wash the cells with 1x PBS and resuspend each dish in 800 \u03bcl IP buffer.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "3. Generate a homogenous suspension by repeated pipetting and vortexing, and incubate overnight (16 h) on ice at 4 \u00b0C (cold room or fridge). 4 . Next day, clarify the lysate by centrifugation at 13,000 x g, 4 \u00b0C, 10 min and collect the supernatant into a fresh 1.6 ml RNase free microcentrifuge tube. 6. Check an aliquot of the purified protein by Western blotting using octa-probe antibody and silver staining, as mentioned below.", "cite_spans": [{"start": 141, "end": 142, "text": "4", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "", "text": "7. Resolve the proteins by 10% SDS-PAGE and transfer onto a PVDF (Polyvinylidene fluoride) membrane.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "8. Block the membrane using 5% skimmed milk in 1x PBS for 45 min at room temperature, incubate overnight (16 h) with 1:1,000 octa-probe primary antibody diluted using 5% skimmed milk in 1x PBST at 4 \u00b0C, wash 3 x in PBST, incubate with 1:5,000 anti-rabbit IgG HRPO secondary antibody diluted using 5% skimmed milk in 1x PBST at room temperature, followed www.bio-protocol.org/e2199 4 . Run one additional sample containing RNA template with RdRp and digest it with RNase A (add 1 \u03bcl of 10 mg/ml RNase A to the tube, incubate at 37 \u00b0C for 10 min).", "cite_spans": [{"start": 381, "end": 382, "text": "4", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "", "text": "5. Add 50 \u00b5l 2x proteinase K buffer and 1 \u00b5l proteinase K (50 mg/ml stock solution in water) and incubate for 10 min at 37 \u00b0C.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "6. Add 1 \u00b5l glycogen (10 mg/ml stock solution in water) and 1 ml of ice-cold absolute ethanol to the samples; incubate at -80 \u00b0C for 45 min.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "7. Centrifuge the samples at 14,000 x g, 15 min, 4 \u00b0C.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "8. Wash the pellet with 1 ml 75% ethanol and resuspend in 10 \u00b5l nuclease free water. ", "cite_spans": [], "ref_spans": []}, {"section": "temperature.", "text": "Note: Be careful not to allow the membrane to dry at any point from this step onwards.", "cite_spans": [], "ref_spans": []}, {"section": "temperature.", "text": "17. Incubate in 10 ml of anti-DIG antibody solution (1:10,000 in 1x blocking solution) for 30 min at room temperature. Antibody comes in the DIG Northern Starter Kit.", "cite_spans": [], "ref_spans": []}, {"section": "temperature.", "text": "18. Equilibrate in 100 ml detection buffer for 5 min at room temperature.", "cite_spans": [], "ref_spans": []}, {"section": "temperature.", "text": "19. Place the membrane on a development folder and apply CDP star (part of DIG Northern Starter Kit) and incubate for 5 min in the dark at room temperature.", "cite_spans": [], "ref_spans": []}, {"section": "Note: Remove all air bubbles.", "text": "20. Acquire chemiluminescent images using a gel documentation system or using an X ray film.", "cite_spans": [], "ref_spans": []}, {"section": "Data analysis", "text": "While setting up the RdRp assay, appropriate controls should be included in order to interpret the data and rule out non-specific signal. Must have negative controls such as omission of nucleotides from the reaction mixture and inclusion of RNase A in the reaction mixture. No bands should be obtained in both the cases. A titration experiment using increasing quantities of RdRp protein in the assay should also be performed to rule out non-specific signals. Assay using an unrelated protein instead of RdRp will also rule out the possible non-specific signal. A sample assay with all controls has been illustrated in Figure 1 . The effect of other factors or compounds on RdRp activity may be evaluated by adding them to the reaction mixture. In our experience, template itself does not give www.bio-protocol.org/e2199 any false signal, as the assay is dependent on detection of DIG, which is incorporated into the RNA only as DIG-UTP. Free DIG-UTP is removed from the reaction during migration of the sample in agarose gel. Moreover, the labeled RNA migrates at ~800 base pairs size whereas template RNA size is 380 base pairs. Monitoring the size of the band also allows one to be confident of the output of the assay. 3. 2x proteinase K buffer 300 mM NaCl", "cite_spans": [], "ref_spans": [{"start": 619, "end": 627, "text": "Figure 1", "ref_id": "FIGREF5"}]}], "bib_entries": {"BIBREF0": {"title": "Incubate the positively charged nylon membrane in DEPC-treated water until it is completely wet from beneath", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF1": {"title": "Place the gel in inverted position. Make a notch on left side of the gel", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF2": {"title": "Incubate the membrane in 20 ml of 1x blocking solution (see Recipes) for 30 min at room www.bio-protocol", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF3": {"title": "Iss 07", "authors": [], "year": 2017, "venue": "", "link": null}, "BIBREF4": {"title": "The Authors", "authors": [{"first": "\u00a9", "middle": [], "last": "Copyright", "suffix": ""}], "year": 2017, "venue": "", "link": null}, "BIBREF5": {"title": "Dilute the 10x blocking solution available in the DIG Northern Starter Kit with maleic acid buffer to 1x Note: Prepare fresh", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF6": {"title": "3% Tween 20", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF7": {"title": "Identification and properties of the RNAdependent RNA polymerase of hepatitis C virus", "authors": [{"first": "S", "middle": ["E"], "last": "Behrens", "suffix": ""}, {"first": "L", "middle": [], "last": "Tomei", "suffix": ""}, {"first": "R", "middle": [], "last": "De Francesco", "suffix": ""}], "year": 1996, "venue": "EMBO J", "link": "45898538"}, "BIBREF8": {"title": "Efficient initiation of HCV RNA replication in cell culture", "authors": [{"first": "K", "middle": ["J"], "last": "Blight", "suffix": ""}, {"first": "A", "middle": ["A"], "last": "Kolykhalov", "suffix": ""}, {"first": "C", "middle": ["M"], "last": "Rice", "suffix": ""}], "year": 2000, "venue": "Science", "link": "34484231"}, "BIBREF10": {"title": "Iss 07", "authors": [], "year": 2017, "venue": "", "link": null}, "BIBREF11": {"title": "The Authors; exclusive licensee Bio-protocol LLC", "authors": [{"first": "\u00a9", "middle": [], "last": "Copyright", "suffix": ""}], "year": 2017, "venue": "", "link": null}, "BIBREF12": {"title": "In vitro replication of hepatitis E virus (HEV) genomes and of an HEV replicon expressing green fluorescent protein", "authors": [], "year": "", "venue": "J Virol", "link": "6034274"}, "BIBREF13": {"title": "Endoplasmic reticulum stress induced synthesis of a novel viral factor mediates efficient replication of genotype-1 hepatitis E virus", "authors": [{"first": "V", "middle": ["P"], "last": "Nair", "suffix": ""}, {"first": "S", "middle": [], "last": "Anang", "suffix": ""}, {"first": "C", "middle": [], "last": "Subramani", "suffix": ""}, {"first": "A", "middle": [], "last": "Madhvi", "suffix": ""}, {"first": "K", "middle": [], "last": "Bakshi", "suffix": ""}, {"first": "A", "middle": [], "last": "Srivastava", "suffix": ""}, {"first": "", "middle": [], "last": "Shalimar", "suffix": ""}, {"first": "B", "middle": [], "last": "Nayak", "suffix": ""}, {"first": "R", "middle": ["K"], "last": "Ct", "suffix": ""}, {"first": "M", "middle": [], "last": "Surjit", "suffix": ""}], "year": 2016, "venue": "PLoS Pathog", "link": "215064118"}}, "ref_entries": {"FIGREF0": {"text": "ORF2-flag RP; digested with BglII and ligated into pUNO vector digested with NheI [blunted] and BamHI); Nair et al. [2016]) 9. Huh7 (human hepatoma cells, obtained from Dr. C. M. Rice; Blight et al. [2000]) 10. pSKHEV2 RdRp template (pSK HRt) plasmid (Genbank No. AF444002.1, Emerson et al.,Phosphate-buffered saline (PBS) (Bio Basic, catalog number: PD0100) 15. Flag M2 agarose resin (Sigma-Aldrich, catalog number: A2220) 16. Flag peptide (Sigma-Aldrich, catalog number: F4799) 17. Octa-probe antibody (Santa Cruz Biotechnology, catalog number: sc-807) 18. Skimmed milk powder (Sigma-Aldrich, catalog number: 70166) Note: This product has been discontinued. 19. Anti-rabbit IgG Horseradish peroxidase(HRPO) (Santa Cruz Biotechnology, catalog number: sc- 2004) 20. Clarity Western ECL blotting substrate (Bio-Rad Laboratories, catalog number: 1705061)", "type": "figure"}, "FIGREF1": {"text": "Magnesium chloride (MgCl2) (Sigma-Aldrich, catalog number: M8266) 58. DL-dithiothreitol (DTT) (Sigma-Aldrich, catalog number: D0632) 59. Potassium chloride (KCl) (Sigma-Aldrich, catalog number: P9333) 60. SDS 61. MOPS (Sigma-Aldrich, catalog number: M5162) 62. Sodium acetate (Sigma-Aldrich, catalog number: S2889) 63. Maleic acid (Sigma-Aldrich, catalog number: M0375) 64. Tween 20 (Sigma-Aldrich, catalog number: P9416) 65. Tri-sodium citrate dihydrate (Himedia, catalog number: RM1415) 66. IP (Immunoprecipitation) buffer (UV cross linker (UVP, model: CL-1000) Procedure A. Preparation of flag-affinity purified proteins 1. Transfect 3 \u03bcg each of pUNO RdRp-flag and pUNO ORF2-flag plasmids into ten 60 mm plates (each plasmid transfected into 10 plates, not cotransfected), containing Huh7 human hepatoma cells, using Lipofectamine 2000 in 1:1 ratio, following manufacturer's instructions. Incubate cells at 37 \u00b0C in 5% CO2 incubator. 24 h post-transfection, replace media with 2 ml DMEM supplemented with 10% fetal bovine serum.", "type": "figure"}, "FIGREF2": {"text": "Pool lysates of all ten plates and add 100 \u03bcl of flag agarose beads, incubate on rocker at 4 \u00b0C for 4 h, wash 3 x in 1 ml IP buffer each by centrifuging at 800 x g, 1 min, at 4 \u00b0C. Add 200 \u03bcl flag peptide (0.2 mg/ml in PBS) and incubate on a rocker for 15 min at 4 \u00b0C. Centrifuge at 800 x g, 1 min, at 4 \u00b0C and collect the supernatant, which contains the eluted protein.", "type": "figure"}, "FIGREF3": {"text": "Linearize 10 \u00b5g pSK HRt plasmid using 50 U BglII (R0144L, NEB, buffer 3.1) in 50 \u00b5l reaction mix (5 \u00b5l 10x buffer, 20 \u00b5l DNA, 2.5 \u00b5l enzyme and 22.5 \u00b5l water). Purify the linearized DNA using PCR purification kit. Use 1 \u00b5g linearized DNA for in vitro transcription using mMessage mMachine T7 Kit, following manufacturer's instruction, to generate a 340 nucleotide long capped RNA, which is to be used as template in RdRp assay to monitor antisense strand synthesis. 3. Verify the size and integrity of the RNA by formaldehyde agarose gel electrophoresis. 4. Quantify the RNA by spectrophotometry and store in single use aliquots in RNase free microcentrifuge tubes at -80 \u00b0C. C. RdRp assay 1. Assemble the reaction as described below in RNase free tubes.", "type": "figure"}, "FIGREF4": {"text": "Resolve the samples by 1.5% formaldehyde agarose gel electrophoresis in a chemical fume hood. D. Formaldehyde agarose gel electrophoresis of RNA samples 1. For 100 ml, add 0.75 g agarose in 72 ml DEPC-treated water in a conical flask and boil. When the solution has cooled to 55 \u00b0C, add 18 ml of 37% formaldehyde and 10 ml 10x MOPS. Cast the gel in gel running apparatus and allow to solidify. Note: Do not add formaldehyde and MOPS to very hot agarose solution. Perform the entire procedure in a chemical fume hood.", "type": "figure"}, "FIGREF5": {"text": "Figure 1. Assay of HEV RNA-dependent RNA polymerase activity. NTPs: nucleotide triphosphates.", "type": "figure"}, "TABREF0": {"text": "Silver stain kit (Thermo Fisher Scientific, Thermo Scientific TM , catalog number: 24612) 22. Bradford assay reagent (Bio-Rad Laboratories, catalog number: 5000002) 23. StuI, NheI and Tth111I restriction enzymes 24. BglII (New England Biolabs, catalog number: R0144L) 25. PCR purification kit (Agilent Technologies, catalog number: 400771) 26. mMessage mMachine T7 kit (Thermo Fisher Scientific, Ambion56. Protease inhibitor cocktail (Roche Diagnostics, catalog number: 04693132001)", "type": "table"}, "TABREF1": {"text": "StuI, NheI and Tth111I restriction enzymes, followed by gel extraction of ~3.5 kb band. This fragment was treated with DNA polymerase I klenow fragment to generate blunt end, followed by self-ligation. Resulting plasmid is named as pSK HRt. Plasmid is available on request. This plasmid has been described in our earlier publication (Nair et al., 2016).", "type": "table"}, "TABREF4": {"text": "Copyright \u00a9 2017 The Authors; exclusive licensee Bio-protocol LLC.", "type": "table"}}}
{"paper_id": "91042122", "_pdf_hash": "9004ed0febf337e8ad6680608c0dd61d323f7f2d", "abstract": [{"section": "Abstract", "text": "In this work, we investigated the anti-cancer effect of torulene, a carotenoid from Sporidiobolus pararoseus, on androgen-sensitive/insensitive prostate cancer cells lines and found that torulene induced apoptosis at moderate cytotoxic concentrations in both cell lines. It was further demonstrated that the apoptosis induced by torulene was due to the modulation of Bcl-2 family members, resulting in decrease of mitochondria membrane potential and increase of the intracellular calcium concentration. Furthermore, its growth-inhibitory effects on LNCaP cells also showed a relationship with the down-regulation of AR and PSA expression. Therefore, the results indicated that a mitochondria-mediated pathway and the expression of AR might play essential roles in the apoptosis process induced by torulene in prostate cancer cells.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Prostate cancer (PCa) is the second most abundant male cancer in the world and accounts for 33% of all male cancer incidences and 10% of male cancer mortality in the United States.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "1,2 Constitutive activation of the androgen receptor (AR) by high levels of androgens is presumed to be responsible for the development and progression of PCa. Hence, the \ue103rst choice among treatment options is surgical castration or chemo/radiotherapy, which is based on hormonal regulation through AR. [3] [4] [5] Although the disease initially regresses in response to androgen ablation, it eventually relapses to become castration resistant. With the consideration of the high failure rates and predictable ineffectiveness of the treatment, novel targets are urgently required depending on the presence or absence of functional AR status. [6] [7] [8] Apoptosis is a naturally occurring process of programmed cell death. Many plant-origin chemotherapy drugs can promote apoptosis of cancer cells, and some signal pathways are involved in the process.", "cite_spans": [{"start": 303, "end": 306, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 307, "end": 310, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 311, "end": 314, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 642, "end": 645, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 646, "end": 649, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 650, "end": 653, "text": "[8]", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "Introduction", "text": "9,10 Among them, mitochondrial pathway is the best known one. Bcl-2 family proteins play important regulatory roles in mitochondrial pathway: Bax is a pro-apoptotic protein that can permeabilizes the mitochondrial outer membrane and lead to the loss of mitochondrial integrity and cell death, whereas Bcl-2 promotes the maintenance of mitochondrial integrity and prevents apoptotic cell death. 11 Thus, novel alternatives that target both Bcl-2 family proteins and AR are attracting increasing interest.", "cite_spans": [{"start": 394, "end": 396, "text": "11", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "Introduction", "text": "Due to the de\ue103ciency and side effects of current therapies for prostate cancer, more and more patients turn to dietary supplements, including vitamins, herbal preparations and phytochemicals to control the risk of PCa. 6 Torulene, one of the most principal carotenoid in Sporidiobolus pararoseus, has 13 conjugated double bonds, and the differences of structure between it and lycopene are subtle. However, it has not been well-studied with respect to its bioactivity and nutritional function.", "cite_spans": [{"start": 219, "end": 220, "text": "6", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "12", "text": "The present study was carried out to evaluate the anti-cancer effect of torulene on androgen-sensitive human prostate cancer LNCaP cells and androgen-insensitive human prostate cancer PC-3 cells, as well as its relevant molecular mechanisms.", "cite_spans": [], "ref_spans": []}, {"section": "Materials and methods", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Cell culture and chemicals", "text": "S. pararoseus (JD-2 CCTCC M 2010326) was obtained and characterized by our lab. Human prostate cancer cell lines LNCaP and PC-3 were obtained from Cell Bank of Chinese Academy of Sciences (Shanghai, China). The cells were cultured in RPMI-1640 medium supplemented with 10% fetal bovine serum (FBS, Gibco, Carlsbad, CA, USA), 100 IU mL \u00c01 penicillin, and 100 mg mL \u00c01 streptomycin in a humidi\ue103ed atmosphere of 95% air and 5% CO 2 at 37 C.", "cite_spans": [], "ref_spans": []}, {"section": "Cell culture and chemicals", "text": "Torulene was isolated from the extracts of Sporidiobolus pararoseus and then puri\ue103ed according to the previous method. 13 The purity was above 96% as determined by High Performance Liquid Chromatography with UV detection at 450 nm. The carotenoid was stored at \u00c080 C, and 10 mmol stock solutions were freshly prepared with tetrahydrofuran (THF, Sigma) just before use. The \ue103nal concentration of THF for all experiments and treatments (including the controls in which no drug was added) was maintained at the level less than 0.1%. The concentration of THF less than 0.1% maintaining for 72 h was non-cytotoxic.", "cite_spans": [{"start": 119, "end": 121, "text": "13", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "Cell culture and chemicals", "text": "14 Antibodies against Bcl-2 (#2876), Bax (#2272), AR(#3202), PSA(#2475) and b-actin (#4967) were purchased from Cell Signaling Technology (CST, Danvers, MA, USA).", "cite_spans": [], "ref_spans": []}, {"section": "Cell culture and chemicals", "text": "were purchased from Beyotime Institute of Biotechnology (Haimen, China). Other reagents were all obtained from Sinopharm Chemical Reagent Co., Ltd (Shanghai, China).", "cite_spans": [], "ref_spans": []}, {"section": "Cell viability assay", "text": "The inhibitory effects of torulene on the cancer cells were estimated via WST-1 assay. Cells were cultured in 96-well plates and exposed to different concentrations of torulene for 24 h. Then the plates were incubated with WST-1 reagent for 3 h at 37 C, and the inhibitory effects of the carotenoid on the cancer cells were measured by determining the absorbance at 450 nm. centrifugation and cells were washed twice with JC-1 staining buffer and analyzed using \ue104ow cytometry. The intracellular Ca 2+ level in LNCaP and PC-3 cells was measured using the \ue104uorescence Ca 2+ indicator Fluo-3 AM. The cell culture and carotenoid-exposure is in the same way above. A\ue09der 24 h treatment, the cells were collected, rinsed twice with PBS, and stained with Fluo-3 AM in darkness at room temperature for 30 min. A\ue09der staining, the cells were washed twice with PBS and incubated for another 10 min at 37 C before \ue104uorescence-intensity detection. 18 ", "cite_spans": [{"start": 934, "end": 936, "text": "18", "ref_id": "BIBREF17"}], "ref_spans": []}, {"section": "RNA extraction and quantitative real-time polymerase chain reaction (PCR)", "text": "Total RNA was extracted from LNCaP and PC-3 cells of each sample using 1 mL of Trizol Reagent (Invitrogen, USA). Equal amounts of isolated RNA were reversely transcribed into cDNA using Revert Aid TM M-Mu LV Reverse Transcriptase (Thermo Scienti\ue103c, Rockford, USA) according to the manufacturer's instructions. 19 Real-time PCR was carried out on cDNA according to the SYBR Green method with an ABI 7900 Fast Real-Time PCR System (Applied Biosystems, Carlsbad, USA). The primers (Table  1) were synthesized by Generay Biotechnology (Shanghai, China). Quantitative real-time PCR was performed by initial incubation at 95 C for 10 min and subsequent 40 cycles of a two-step PCR:", "cite_spans": [{"start": 310, "end": 312, "text": "19", "ref_id": "BIBREF18"}], "ref_spans": [{"start": 478, "end": 488, "text": "(Table  1)", "ref_id": "TABREF1"}]}, {"section": "RNA extraction and quantitative real-time polymerase chain reaction (PCR)", "text": "annealing at 95 C for 3 s and \ue103nally extension at 60 C for 30 s.", "cite_spans": [], "ref_spans": []}, {"section": "RNA extraction and quantitative real-time polymerase chain reaction (PCR)", "text": "The threshold cycle (C t ) values of each sample were analyzed according to the 2 \u00c0\u0394\u0394Ct data analysis method a\ue09der normalizing to b-actin. 20 ", "cite_spans": [{"start": 138, "end": 140, "text": "20", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "Western blot", "text": "To evaluate the expression levels of various intracellular proteins related to apoptosis, LNCaP and PC-3 cells were treated with different concentrations of torulene (0, 10, 20 and 30 mmol L \u00c01 ) for 24 h. Then total proteins from different groups were extracted with cell lysis buffer containing phenylmethanesulfonyl \ue104uoride (PMSF). Lysates were centrifuged at 13 200 rpm for 15 min at 4 C and protein concentrations were determined with an enhanced BCA Protein Assay Kit (Beyotime, China). Equal amounts of protein from each sample were loaded on 4-15% sodium dodecyl sulfate (SDS)-polyacrylamide gel and then transferred to a polyvinylidene di\ue104uoride (PVDF) membrane. A\ue09der blocking the nonspeci\ue103c blinding with nonfat milk, the membranes were incubated overnight at 4 C with rabbit polyclonal antibody against Bcl-2, Bax, AR, PSA and b-actin (1 : 1000). A\ue09der washing for several times and conjugation with secondary antibodies, the membranes were incubated in the incubation solution added with enhanced chemiluminescence reagent (ECL Plus, Solarbio, Beijing, China) and then exposed to Chemiluminescence imaging analysis system (Protein Simple, California, USA).", "cite_spans": [], "ref_spans": []}, {"section": "16,19", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Statistical analysis", "text": "All assays were performed at least in triplicate independent experiments. Values were expressed as means AE standard deviations (SD). Experimental data were analyzed by one-way analysis of variance (ANOVA) with Statistical Package for Social Science (SPSS) version 21.0. p < 0.05 was considered to be statistically signi\ue103cant.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Effects of torulene on the viability of LNCaP and PC-3 cells", "text": "Torulene treatment led to a dose-dependent decrease in cell viability of LNCaP and PC-3 cells, as indicated by the WST-1 assays, and PC-3 cells appeared to be slightly more sensitive than LNCaP to the treatment (Fig. 1) . At 40 mmol L \u00c01 concentration, torulene decreased cell viability approx. 50% on androgen-insensitive PC-3 cells, while the cell viability of androgen-sensitive LNCaP cells decrease approx. 15% vs. untreated control group. ", "cite_spans": [], "ref_spans": [{"start": 211, "end": 219, "text": "(Fig. 1)", "ref_id": "FIGREF5"}]}, {"section": "Morphological changes caused by torulene", "text": "In the optical images ( Fig. 2A) , the control cells were in the elongated spindle shape and the number of control cells gradually increased. However, a\ue09der the treatment with torulene for 12 h, the cells began to shrink and became round and then the number of cells decreased a\ue09der 24 h. A\ue09der 48 h treatment, cell arrangement was loose and cells were not adhered well and \ue103nally most of cells were \ue104oated in the medium.", "cite_spans": [], "ref_spans": [{"start": 24, "end": 32, "text": "Fig. 2A)", "ref_id": "FIGREF7"}]}, {"section": "15", "text": "The viable cells were bright blue, while the apoptotic cells were red as distinguished by Hoechst 33342/PI staining (Fig. 2B) . A\ue09der the exposures to 30 mmol L \u00c01 torulene, the number of red cells gradually increased while there were few red cells in control group. As shown in Fig. 3 , an obvious difference in apoptosis rate among different groups was observed a\ue09der the treatment of ", "cite_spans": [], "ref_spans": [{"start": 116, "end": 125, "text": "(Fig. 2B)", "ref_id": "FIGREF7"}, {"start": 278, "end": 284, "text": "Fig. 3", "ref_id": "FIGREF8"}]}, {"section": "16", "text": "Calcium is a vital intracellular second messenger and involved in many different cell functions. 21 A sustained increase in intracellular Ca 2+ content was found in the all treatment groups when compared to the control groups (Fig. 4B) . 18 The result indicated that torulene had a stronger effect on the induction of apoptosis in LNCaP cells than PC-3 cells.", "cite_spans": [{"start": 97, "end": 99, "text": "21", "ref_id": "BIBREF20"}, {"start": 238, "end": 240, "text": "18", "ref_id": "BIBREF17"}], "ref_spans": [{"start": 226, "end": 235, "text": "(Fig. 4B)", "ref_id": "FIGREF9"}]}, {"section": "Torulene decreased the expression of Bcl-2 and increased the expression of Bax", "text": "Bcl-2 and Bax are two key in\ue104uencing factors of cells' susceptibility to apoptosis. 22 As shown in Fig. 5 , quantitative PCR and western blot analysis revealed a signi\ue103cant decrease in Bcl-2 expression in both cells, whereas a signi\ue103cant increase in the expression of Bax was observed, indicating that the Bcl-2/Bax ratio decreased signi\ue103cantly. What's more, the mRNA expression of Bcl-2 was decreased from 1.00 in control group to 0.94-and 0.59-fold, whereas the expression of Bax increased from 1.00 in control group to 2.29-and 3.08-fold a\ue09der 24 h treatment with 30 mmol L \u00c01 torulene in LNCaP and PC-3 cells (Fig. 5A) , respectively.", "cite_spans": [{"start": 84, "end": 86, "text": "22", "ref_id": "BIBREF21"}], "ref_spans": [{"start": 99, "end": 105, "text": "Fig. 5", "ref_id": "FIGREF10"}, {"start": 612, "end": 621, "text": "(Fig. 5A)", "ref_id": "FIGREF10"}]}, {"section": "10,16", "text": "3.6 Torulene increase the expression of AR and PSA Downregulation of AR inhibits the proliferation of LNCaP cells. 22 To investigate whether the induction of apoptosis by torulene was due to the downregulation of AR, cells were subjected to western blot and quantitative PCR analysis. As shown in Fig. 6 , torulene signi\ue103cantly decreased AR and PSA protein and mRNA expression in a dose-dependent manner in LNCaP cells. Torulene treatment at 30 mmol L \u00c01 for 24 h downregulated AR by 29%, whereas PSA was down-regulated by 28% compared with the control, respectively.", "cite_spans": [{"start": 115, "end": 117, "text": "22", "ref_id": "BIBREF21"}], "ref_spans": [{"start": 297, "end": 303, "text": "Fig. 6", "ref_id": "FIGREF11"}]}, {"section": "Discussion", "text": "Prostatic adenocarcinoma is the most frequently diagnosed malignancy and the second cause of cancer deaths amongst men, and it development process can be divided into two distinct operationally divisible androgen-sensitive and androgen-insensitive stages. 23 Thus, exploration of new chemicals for treatment of androgen-sensitive and androgeninsensitive prostate cancer is necessary. In the present study, LNCaP and PC-3 cells have been used to study the effects of torulene on the androgen-sensitive and androgen-insensitive human prostate cancer cells.", "cite_spans": [{"start": 256, "end": 258, "text": "23", "ref_id": "BIBREF22"}], "ref_spans": []}, {"section": "23", "text": "Torulene is one of the most principal carotenoids in Sporidiobolus pararoseus and the differences of structure between torulene and lycopene are subtle. Galano et al. reported that torulene owns better free-radical scavenging activity than bcarotene towards the OOH radical 24 and exerted more efficient electron-transfer reactions than lycopene, which has been recognized as one of the most reactive carotenoids towards free radicals. 25, 26 However, the effect of torulene on human prostate carcinoma was still unknown. In the present study, we con\ue103rmed that torulene inhibited growth and induced apoptosis in androgen-sensitive LNCaP and androgeninsensitive PC-3 prostate cancer cells. When the exposure concentration increased, the cellular viability decreased in both groups. Moreover, according to WST-1 assay, PC-3 cells were more sensitive against torulene treatment compared to LNCaP cells. 18, 27 Cell morphology plays vital roles in diverse cellular processes, including cell growth, motility, proliferation, and division. 21 To investigate the mechanism induced by the carotenoids, the changes in cell morphology were also observed and the observation results were consistent with that of viability analysis.", "cite_spans": [{"start": 274, "end": 276, "text": "24", "ref_id": "BIBREF23"}, {"start": 436, "end": 439, "text": "25,", "ref_id": "BIBREF24"}, {"start": 440, "end": 442, "text": "26", "ref_id": "BIBREF25"}, {"start": 900, "end": 903, "text": "18,", "ref_id": "BIBREF17"}, {"start": 904, "end": 906, "text": "27", "ref_id": "BIBREF26"}, {"start": 1034, "end": 1036, "text": "21", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "23", "text": "In the explorations of cell death mechanism, \ue104ow cytometric analysis of annexin V-FITC/PI-labeled cells, MMP and intracellular Ca 2+ levels had been carried out. 27, 28 The decrease in MMP is the earliest intracellular event before the apoptosis caused by the mitochondria-mediated death pathway, so the decline of MMP is considered as a symbolic event of early cellular apoptosis. 16 In this assay, both groups showed a significant (p < 0.05) decrease in MMP when treated with carotenoids compared to the control group. This result demonstrated the early damage was happened to MMP, which may further activate the intrinsic pathway of apoptosis.", "cite_spans": [{"start": 162, "end": 165, "text": "27,", "ref_id": "BIBREF26"}, {"start": 166, "end": 168, "text": "28", "ref_id": "BIBREF28"}, {"start": 382, "end": 384, "text": "16", "ref_id": "BIBREF15"}], "ref_spans": []}, {"section": "23", "text": "Moreover, intracellular Ca 2+ is an important intracellular secondary messenger, which regulates lots of cellular processes including cell growth, proliferation, and signal transduction. The abnormal rise of cytosol Ca 2+ is considered to be responsible for a series of disturbances in cells. Disturbance of Ca 2+ balance will trigger diverse abnormal cellular processes, even apoptosis or necrosis. 21 In our experiments, a\ue09der the treatment with torulene, there was a rapid rise of cytosol Ca 2+ level, which might be caused by the Ca 2+ release from endoplasmic reticulum and mitochondria in the apoptotic process. These results indicate that carotenoids may interfere with the cellular maintenance functions of LNCaP and PC-3 cells and lead to apoptosis. A similar result was obtained by Hua Jin et al. 21 in the hepatocellular carcinoma cell line (HepG2), suggesting that the induced alteration of cellular maintenance might be partly responsible for apoptosis.", "cite_spans": [{"start": 400, "end": 402, "text": "21", "ref_id": "BIBREF20"}, {"start": 806, "end": 808, "text": "21", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "23", "text": "Pro-apoptotic protein Bax and anti-apoptotic protein Bcl-2 also play signi\ue103cant roles in mediating the cell apoptosis.", "cite_spans": [], "ref_spans": []}, {"section": "23", "text": "11 In mitochondrial pathway, the release of cytochrome c is regulated by Bcl-2 family proteins, which is inhibited by anti-apoptotic members of the Bcl-2 family of protein and stimulated by proapoptotic members, such as Bax. In this paper, the expression of anti-apoptotic Bcl-2 protein was inhibited, whereas the expression of pro-apoptotic Bax protein was enhanced steadily with the increase of the carotenoids' concentrations. 16 The changes of the protein expression levels of Bcl-2 and Bax were almost parallel to that of their mRNA expression according to the analysis results of quantitative real-time PCR and western blot. The ratio of Bcl-2/Bax plays an important role in cell apoptosis or survival. In our study, torulene treatment caused the decrease of the ratio of Bcl-2/Bax in both LNCaP and PC-3 cells. The result was much more effective toward androgeninsensitive PC-3 cells, which can explain the susceptivity difference to torulene in PCa cells with different androgen sensitivity. To sum up, these results con\ue103rmed that torulene induced the prostate cancer cells apoptosis by inhibiting Bcl-2 and activating Bax, which suggested that the intrinsic pathway might be activated directly.", "cite_spans": [{"start": 430, "end": 432, "text": "16", "ref_id": "BIBREF15"}], "ref_spans": []}, {"section": "23", "text": "11 That is to say, the apoptosis of LNCaP and PC-3 cells treated with torulene was induced by activating the mitochondrial pathway.", "cite_spans": [], "ref_spans": []}, {"section": "23", "text": "AR is expressed in almost all prostate cancers, and its expression plays an important role in the development and progression of prostate cancer. Therefore, downregulation of AR, which inhibits PCa cell proliferation, is currently used as an effective strategy to treat prostate cancer. 8 PSA, a key AR target gene, is a common biomarker for PCa screening and one of the most important indicators of treatment efficacy. In this paper, we investigated whether AR and PSA are molecular targets of torulene on androgen-sensitive LNCaP cells. Our results showed that torulene down-regulated the protein and mRNA expression of AR and PSA in a dose-sensitive manner in LNCaP cells. These \ue103ndings suggested that torulene may exert its anti-proliferative effects through both activating the mitochondrial pathway and inhibiting the expression of AR and PSA in androgen-sensitive PCa cells.", "cite_spans": [{"start": 287, "end": 288, "text": "8", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "23", "text": "Although androgen-sensitive PCa cells appeared to be less sensitive than androgen-insensitive ones to the treatment according to WST-1 assay (Fig. 1) , torulene induced more apoptosis in LNCaP cells as analyzed by annexin V and PI double staining (Fig. 3) . WST-1 assay was usually used to evaluate the proliferation of the cells rather than to distinguish the apoptosis cells to the normal ones.", "cite_spans": [], "ref_spans": [{"start": 141, "end": 149, "text": "(Fig. 1)", "ref_id": "FIGREF5"}, {"start": 247, "end": 255, "text": "(Fig. 3)", "ref_id": "FIGREF8"}]}, {"section": "23", "text": "10 Thus, we presume that the mechanism related to the inhibitory effect of torulene on androgen-sensitive LNCaP cells and androgen-insensitive PC-3 cells was different, other pathway was involved in besides mitochondria mediated apoptosis.", "cite_spans": [], "ref_spans": []}, {"section": "23", "text": "In summary, our data indicated that the inhibition of torulene on proliferation of LNCaP and PC-3 cells was associated with the inducement of apoptosis, which partly resulted from the loss of MMP and the accumulation of intracellular Ca", "cite_spans": [], "ref_spans": []}, {"section": "2+", "text": ". Over expressions of Bax and the decreased expression of Bcl-2 induced by torulene also contributed to the programmed cell death of prostate cancer cells. Furthermore, the apoptotic effect of torulene on LNCaP cells had relationship with the down-regulation of the expression of AR and PSA as well. These results provide a potential molecular mechanism for torulene-induced apoptosis on LNCaP and PC-3 prostate cancer cells and suggest that torulene may process a health bene\ue103t for humans prostate. However, further studies on other signaling pathways and deep molecular mechanisms still require investigation.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Lycopene and apo-12 cells", "authors": [{"first": "N", "middle": ["A"], "last": "Ford", "suffix": ""}, {"first": "A", "middle": ["C"], "last": "Elsen", "suffix": ""}, {"first": "K", "middle": [], "last": "Zuniga", "suffix": ""}, {"first": "B", "middle": ["L"], "last": "Lindshield", "suffix": ""}, {"first": "J", "middle": ["W"], "last": "Erdman", "suffix": ""}], "year": 2011, "venue": "Nutr. Cancer", "link": null}, "BIBREF1": {"title": "Lycopene Inhibits the Growth of Human Androgen-Independent Prostate Cancer Cells In Vitro and in BALB/c Nude Mice", "authors": [{"first": "L", "middle": [], "last": "Tang", "suffix": ""}, {"first": "T", "middle": [], "last": "Jin", "suffix": ""}, {"first": "X", "middle": [], "last": "Zeng", "suffix": ""}, {"first": "J.-S", "middle": [], "last": "Wang", "suffix": ""}], "year": 2005, "venue": "J. Nutr", "link": "4496647"}, "BIBREF2": {"title": "Autophagy is differentially induced in prostate cancer LNCaP, DU145 and PC-3 cells via distinct splicing pro\ue103les of ATG5", "authors": [{"first": "Y", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "D", "middle": [], "last": "Ouyang", "suffix": ""}, {"first": "L", "middle": [], "last": "Xu", "suffix": ""}, {"first": "X", "middle": [], "last": "He", "suffix": ""}, {"first": "L", "middle": [], "last": "Zeng", "suffix": ""}, {"first": "J", "middle": [], "last": "Cai", "suffix": ""}, {"first": "S", "middle": [], "last": "Ren", "suffix": ""}], "year": 2013, "venue": "Autophagy", "link": "17018880"}, "BIBREF3": {"title": "Feno\ue103brate down-regulates the expressions of androgen receptor (AR) and AR target genes and induces oxidative stress in the prostate cancer cell line LNCaP", "authors": [{"first": "H", "middle": [], "last": "Zhao", "suffix": ""}, {"first": "C", "middle": [], "last": "Zhu", "suffix": ""}, {"first": "C", "middle": [], "last": "Qin", "suffix": ""}, {"first": "T", "middle": [], "last": "Tao", "suffix": ""}, {"first": "J", "middle": [], "last": "Li", "suffix": ""}, {"first": "G", "middle": [], "last": "Cheng", "suffix": ""}, {"first": "P", "middle": [], "last": "Li", "suffix": ""}, {"first": "Q", "middle": [], "last": "Cao", "suffix": ""}, {"first": "X", "middle": [], "last": "Meng", "suffix": ""}, {"first": "X", "middle": [], "last": "Ju", "suffix": ""}, {"first": "P", "middle": [], "last": "Shao", "suffix": ""}, {"first": "L", "middle": [], "last": "Hua", "suffix": ""}, {"first": "M", "middle": [], "last": "Gu", "suffix": ""}, {"first": "C", "middle": [], "last": "Yin", "suffix": ""}], "year": 2013, "venue": "Biochem. Biophys. Res. Commun", "link": "26232609"}, "BIBREF4": {"title": "Lycopene Enhances Docetaxel's Effect in Castration-Resistant Prostate Cancer Associated with Insulin-like Growth Factor I Receptor Levels", "authors": [{"first": "Y", "middle": [], "last": "Tang", "suffix": ""}, {"first": "B", "middle": [], "last": "Parmakhtiar", "suffix": ""}, {"first": "A", "middle": ["R"], "last": "Simoneau", "suffix": ""}, {"first": "J", "middle": [], "last": "Xie", "suffix": ""}, {"first": "J", "middle": [], "last": "Fruehau", "suffix": ""}, {"first": "M", "middle": [], "last": "Lilly", "suffix": ""}, {"first": "X", "middle": [], "last": "Zi", "suffix": ""}], "year": 2011, "venue": "Neoplasia", "link": "32283816"}, "BIBREF5": {"title": "Role of androgen receptor in progression of LNCaP prostate cancer cells from G1 to S phase", "authors": [{"first": "S", "middle": [], "last": "Murthy", "suffix": ""}, {"first": "M", "middle": [], "last": "Wu", "suffix": ""}, {"first": "V", "middle": ["U"], "last": "Bai", "suffix": ""}, {"first": "Z", "middle": [], "last": "Hou", "suffix": ""}, {"first": "M", "middle": [], "last": "Menon", "suffix": ""}, {"first": "E", "middle": ["R"], "last": "Barrack", "suffix": ""}, {"first": "G", "middle": [], "last": "Sahn-Ho Kim", "suffix": ""}, {"first": "P.-V", "middle": [], "last": "Reddy", "suffix": ""}], "year": 2013, "venue": "PLoS One", "link": "5448410"}, "BIBREF6": {"title": "Lycopene differentially induces quiescence and apoptosis in androgen-responsive and -independent prostate cancer cell lines", "authors": [{"first": "N", "middle": ["I"], "last": "Ivanov", "suffix": ""}, {"first": "S", "middle": ["P"], "last": "Cowell", "suffix": ""}, {"first": "P", "middle": [], "last": "Brown", "suffix": ""}, {"first": "P", "middle": ["S"], "last": "Rennie", "suffix": ""}, {"first": "E", "middle": ["S"], "last": "Guns", "suffix": ""}, {"first": "M", "middle": ["E"], "last": "Cox", "suffix": ""}], "year": 2007, "venue": "Clin. Nutr", "link": "1734913"}, "BIBREF7": {"title": "The suppression of prostate LNCaP cancer cells growth by selenium nanoparticles through Akt/Mdm2/AR controlled apoptosis", "authors": [{"first": "L", "middle": [], "last": "Kong", "suffix": ""}, {"first": "Q", "middle": [], "last": "Yuan", "suffix": ""}, {"first": "H", "middle": [], "last": "Zhu", "suffix": ""}, {"first": "Y", "middle": [], "last": "Li", "suffix": ""}, {"first": "Q", "middle": [], "last": "Guo", "suffix": ""}, {"first": "Q", "middle": [], "last": "Wang", "suffix": ""}, {"first": "X", "middle": [], "last": "Bi", "suffix": ""}, {"first": "X", "middle": [], "last": "Gao", "suffix": ""}], "year": 2011, "venue": "Biomaterials", "link": "12717610"}, "BIBREF8": {"title": "A new anticancer compound, oblongifolin C, inhibits tumor growth and promotes apoptosis in HeLa cells through Bax activation", "authors": [{"first": "C", "middle": [], "last": "Feng", "suffix": ""}, {"first": "L", "middle": [], "last": "Zhou", "suffix": ""}, {"first": "T", "middle": [], "last": "Yu", "suffix": ""}, {"first": "G", "middle": [], "last": "Xu", "suffix": ""}, {"first": "H", "middle": [], "last": "Tian", "suffix": ""}, {"first": "J", "middle": [], "last": "Xu", "suffix": ""}, {"first": "H", "middle": [], "last": "Xu", "suffix": ""}, {"first": "K", "middle": [], "last": "Luo", "suffix": ""}], "year": 2012, "venue": "Int. J. Cancer", "link": "19674875"}, "BIBREF9": {"title": "Chamaejasmine arrests cell cycle, induces apoptosis and inhibits nuclear NFkappaB translocation in the human breast cancer cell line MDA-MB-231", "authors": [{"first": "T", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "H", "middle": [], "last": "Yu", "suffix": ""}, {"first": "G", "middle": [], "last": "Dong", "suffix": ""}, {"first": "L", "middle": [], "last": "Cai", "suffix": ""}, {"first": "Y", "middle": [], "last": "Bai", "suffix": ""}], "year": 2013, "venue": "Molecules", "link": "2240075"}, "BIBREF10": {"title": "Steroids from Commiphora mukul display antiproliferative effect against human prostate cancer PC3 cells via induction of apoptosis", "authors": [{"first": "T", "middle": [], "last": "Shen", "suffix": ""}, {"first": "L", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "Y", "middle": [], "last": "Wang", "suffix": ""}, {"first": "P", "middle": [], "last": "Fan", "suffix": ""}, {"first": "X", "middle": [], "last": "Wang", "suffix": ""}, {"first": "Z", "middle": [], "last": "Lin", "suffix": ""}, {"first": "H", "middle": [], "last": "Lou", "suffix": ""}], "year": 2012, "venue": "Bioorg. Med. Chem. Lett", "link": "25541117"}, "BIBREF11": {"title": "Synthesis of carotenoids by Rhodotorula rubra GED8 co-cultured with yogurt starter cultures in whey ultra\ue103ltrate", "authors": [{"first": "E", "middle": ["D"], "last": "Simova", "suffix": ""}, {"first": "G", "middle": ["I"], "last": "Frengova", "suffix": ""}, {"first": "D", "middle": ["M"], "last": "Beshkova", "suffix": ""}], "year": 2004, "venue": "J. Ind. Microbiol. Biotechnol", "link": "25797026"}, "BIBREF12": {"title": "Tentative Identi\ue103cation of Torulene Cis/trans Geometrical Isomers isolated from Sporidiobolus pararoseus by HighPerformance Liquid Chromatography-Diode Array Detection-Mass Spectrometry and Preparation by Column Chromatography", "authors": [{"first": "Q", "middle": [], "last": "Shi", "suffix": ""}, {"first": "H", "middle": [], "last": "Wang", "suffix": ""}, {"first": "C", "middle": [], "last": "Du", "suffix": ""}, {"first": "W", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "H", "middle": [], "last": "Qian", "suffix": ""}], "year": 2013, "venue": "Anal. Sci", "link": "37805178"}, "BIBREF13": {"title": "Antiproliferative and apoptosis-inducing activity of curcumin against human gallbladder adenocarcinoma cells", "authors": [{"first": "M", "middle": [], "last": "Ono", "suffix": ""}, {"first": "T", "middle": [], "last": "Higuchi", "suffix": ""}, {"first": "M", "middle": [], "last": "Takeshima", "suffix": ""}, {"first": "C", "middle": [], "last": "Chen", "suffix": ""}, {"first": "S", "middle": [], "last": "Nakano", "suffix": ""}], "year": 2013, "venue": "Anticancer Res", "link": "33393184"}, "BIBREF14": {"title": "Different effects of histone deacetylase inhibitors nicotinamide and trichostatin A (TSA) in C17.2 neural stem cells", "authors": [{"first": "H", "middle": [], "last": "Wang", "suffix": ""}, {"first": "T", "middle": [], "last": "Wen", "suffix": ""}, {"first": "H", "middle": [], "last": "Cheng", "suffix": ""}, {"first": "K", "middle": [], "last": "Wang", "suffix": ""}], "year": 2012, "venue": "J. Neural Transm", "link": null}, "BIBREF15": {"title": "Role of mitochondrial pathway in compression-induced apoptosis of nucleus pulposus cells", "authors": [{"first": "F", "middle": [], "last": "Ding", "suffix": ""}, {"first": "Q", "middle": [], "last": "Wu", "suffix": ""}, {"first": "Z", "middle": [], "last": "Shao", "suffix": ""}, {"first": "F", "middle": [], "last": "Gao", "suffix": ""}, {"first": "S", "middle": [], "last": "Yang", "suffix": ""}, {"first": "L", "middle": [], "last": "Xiong", "suffix": ""}], "year": 2012, "venue": "Apoptosis", "link": "18138007"}, "BIBREF16": {"title": "Lanthanum citrate induces anoikis of Hela cells", "authors": [{"first": "X", "middle": [], "last": "Su", "suffix": ""}, {"first": "X", "middle": [], "last": "Zheng", "suffix": ""}, {"first": "J", "middle": [], "last": "Ni", "suffix": ""}], "year": 2009, "venue": "Cancer Lett", "link": "26694912"}, "BIBREF17": {"title": "Toxic cytological alteration and mitochondrial dysfunction in PC12 cells induced by 1-octyl-3-methylimidazolium chloride", "authors": [{"first": "X", "middle": [], "last": "Li", "suffix": ""}, {"first": "C", "middle": [], "last": "Jing", "suffix": ""}, {"first": "X", "middle": [], "last": "Zang", "suffix": ""}, {"first": "S", "middle": [], "last": "Yang", "suffix": ""}, {"first": "J", "middle": [], "last": "Wang", "suffix": ""}], "year": 2012, "venue": "Toxicol. In Vitro", "link": "29772222"}, "BIBREF18": {"title": "Adenovirusmediated transfer of tris-shRNAs induced apoptosis of nasopharyngeal carcinoma cell in vitro and in vivo", "authors": [{"first": "J", "middle": [], "last": "Han", "suffix": ""}, {"first": "Z", "middle": [], "last": "Tao", "suffix": ""}, {"first": "S", "middle": [], "last": "Chen", "suffix": ""}, {"first": "Y", "middle": [], "last": "Kong", "suffix": ""}, {"first": "B", "middle": [], "last": "Xiao", "suffix": ""}], "year": 2011, "venue": "Cancer Lett", "link": "10476375"}, "BIBREF19": {"title": "Anti-cancer effects of dioscin on three kinds of human lung cancer cell lines through inducing DNA damage and activating mitochondrial signal pathway", "authors": [{"first": "Y", "middle": [], "last": "Wei", "suffix": ""}, {"first": "Y", "middle": [], "last": "Xu", "suffix": ""}, {"first": "X", "middle": [], "last": "Han", "suffix": ""}, {"first": "Y", "middle": [], "last": "Qi", "suffix": ""}, {"first": "L", "middle": [], "last": "Xu", "suffix": ""}, {"first": "Y", "middle": [], "last": "Xu", "suffix": ""}, {"first": "L", "middle": [], "last": "Yin", "suffix": ""}, {"first": "H", "middle": [], "last": "Sun", "suffix": ""}, {"first": "K", "middle": [], "last": "Liu", "suffix": ""}, {"first": "J", "middle": [], "last": "Peng", "suffix": ""}], "year": 2013, "venue": "Food Chem. Toxicol", "link": "32282419"}, "BIBREF20": {"title": "Photothermal effects of folate", "authors": [{"first": "H", "middle": [], "last": "Jin", "suffix": ""}, {"first": "P", "middle": [], "last": "Yang", "suffix": ""}, {"first": "J", "middle": [], "last": "Cai", "suffix": ""}, {"first": "J", "middle": [], "last": "Wang", "suffix": ""}, {"first": "M", "middle": [], "last": "Liu", "suffix": ""}], "year": 2012, "venue": "Appl. Microbiol. Biotechnol", "link": null}, "BIBREF21": {"title": "Involvement of GPR12 in the regulation of cell proliferation and survival", "authors": [{"first": "X", "middle": [], "last": "Lu", "suffix": ""}, {"first": "S", "middle": [], "last": "Dong", "suffix": ""}, {"first": "N", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "Y", "middle": [], "last": "Hu", "suffix": ""}, {"first": "B", "middle": [], "last": "Meng", "suffix": ""}], "year": 2012, "venue": "Mol. Cell. Biochem", "link": "417264"}, "BIBREF22": {"title": "Induction of apoptosis and inhibition of PI3K/Akt pathway in PC-3 and LNCaP prostate cancer cells by ethanolic neem leaf extract", "authors": [{"first": "D", "middle": ["N"], "last": "Gunadharini", "suffix": ""}, {"first": "P", "middle": [], "last": "Elumalai", "suffix": ""}, {"first": "R", "middle": [], "last": "Arunkumar", "suffix": ""}, {"first": "K", "middle": [], "last": "Senthilkumar", "suffix": ""}, {"first": "J", "middle": [], "last": "Arunakaran", "suffix": ""}], "year": 2011, "venue": "J. Ethnopharmacol", "link": "8830842"}, "BIBREF23": {"title": "Canolol: a promising chemical agent against oxidative stress", "authors": [{"first": "A", "middle": [], "last": "Galano", "suffix": ""}, {"first": "M", "middle": [], "last": "Francisco-Marquez", "suffix": ""}, {"first": "J", "middle": ["R"], "last": "Alvarez-Idaboy", "suffix": ""}], "year": 2011, "venue": "J. Phys. Chem. B", "link": "33683450"}, "BIBREF24": {"title": "Transient Lens Spectroscopy of Ultrafast Internal Conversion Processes in Citranaxanthin", "authors": [{"first": "T", "middle": [], "last": "Lenzer", "suffix": ""}, {"first": "K", "middle": [], "last": "Oum", "suffix": ""}, {"first": "J", "middle": [], "last": "Seehusen", "suffix": ""}, {"first": "M", "middle": ["T"], "last": "Seidel", "suffix": ""}], "year": 2006, "venue": "J. Phys. Chem. A", "link": "42422508"}, "BIBREF25": {"title": "In\ue104uence of Silicon Defects on the Adsorption of Thiophene-like Compounds on Polycyclic Aromatic Hydrocarbons: A Theoretical Study Using Thiophene + Coronene as the Simplest Model", "authors": [{"first": "A", "middle": [], "last": "Galano", "suffix": ""}], "year": 2007, "venue": "J. Phys. Chem. A", "link": "42473170"}, "BIBREF26": {"title": "CDK Inhibitors Induce Mitochondria-mediated Apoptosis Through the Activation of Polyamine Catabolic Pathway in LNCaP", "authors": [{"first": "E", "middle": ["D"], "last": "Arisan", "suffix": ""}, {"first": "P", "middle": [], "last": "Obakan", "suffix": ""}, {"first": "A", "middle": [], "last": "Coker-G\u00fcrkan", "suffix": ""}, {"first": "A", "middle": [], "last": "Calcabrini", "suffix": ""}, {"first": "E", "middle": [], "last": "Agostinelli", "suffix": ""}, {"first": "N", "middle": ["P"], "last": "", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF28": {"title": "Fluoxetine-induced Apoptosis in Hepatocellular Carcinoma Cells", "authors": [{"first": "A", "middle": [], "last": "Mun", "suffix": ""}, {"first": "S", "middle": [], "last": "Lee", "suffix": ""}, {"first": "G", "middle": [], "last": "Kim", "suffix": ""}, {"first": "H", "middle": [], "last": "Kang", "suffix": ""}, {"first": "J", "middle": [], "last": "Kim", "suffix": ""}, {"first": "S", "middle": [], "last": "Kim", "suffix": ""}], "year": 2013, "venue": "Anticancer Res", "link": "38799918"}}, "ref_entries": {"FIGREF1": {"text": "Mitochondrial membrane potential (MMP) assessment by JC-1 staining A\ue09der treatment with the same process above, the mitochondrial membrane potential (MMP) of LNCaP and PC-3 cells was determined by JC-1 staining. Cells were \ue103rstly collected and resuspended in fresh medium. A\ue09der the addition of 0.5 mL of JC-1 working solution, the cells were incubated in the dark at 37 C for 20 min. The staining solution was removed by", "type": "figure"}, "FIGREF2": {"text": "Article. Published on 12 January 2017. Downloaded on 10/25/2019 5:23:59 PM. This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence.", "type": "figure"}, "FIGREF4": {"text": "Torulene induced apoptotic cell death in LNCaP and PC- 3 cells", "type": "figure"}, "FIGREF5": {"text": "Fig. 1 Inhibitory effects of torulene on LNCaP and PC-3 cells. Cells were treated with the carotenoid at different concentrations for 24 h, and the inhibition was detected by WST-1 assay. Data are expressed as mean AE SD, n \u00bc 5.", "type": "figure"}, "FIGREF6": {"text": "Disruption of MMP and increase of intracellular Ca 2+ in cells treated with torulene The results in Fig. 4A showed that treatment with torulene reduced the MMP in both cell lines. As monitored by JC-1 staining, in the cells treated with 30 mmol L \u00c01 torulene, the MMP was decreased by 12.57% in LNCaP cells and 9.04% in PC- 3 cells compared with the control group.", "type": "figure"}, "FIGREF7": {"text": "Fig. 2 (A) Cell morphology alteration of LNCaP and PC-3 cells following torulene exposure. The cells were planted in 6-well plates were treated with torulene (30 mmol L \u00c01 ) exposure for 12 h, 24 h and 48 h, and then observed through an optical microscope (200\u00c2 , final magnification). (B) Estimation of apoptosis using Hoechst 33342/PI staining on LNCaP and PC-3 cells. Torulene (30 mmol L \u00c01 ) was added to cancer cells for 24 h and 48 h following which cells were washed and stained with Hoechst 33342 (blue fluorescence) and PI (red fluorescence), and examined with a Laser Scanning Confocal Microscope. Figures are representative of three independent experiments.", "type": "figure"}, "FIGREF8": {"text": "Fig. 3 Flow Cytometry analysis of apoptotic LNCaP and PC-3 cells using annexin V-PI staining. 2.5 \u00c2 10 5 cells were seeded into a 6-well plate and treated with or without torulene (10, 20 and 30 mmol L \u00c01 ) for 24 h. Annexin V-PI staining was proceeded to determine apoptotic cell populations. Fluorescence signals from annexin V-FITC and from PI are reported on x-axis and y-axis, respectively. Numbers shown in the lower right quadrant represent the percentage of viable (lower left), necrotic (upper left), early apoptotic (lower right), and late apoptotic (upper right) cells, n \u00bc 3.", "type": "figure"}, "FIGREF9": {"text": "Fig. 4 (A) The mitochondrial membrane potential changes in LNCaP and PC-3 cells. (B) Changes in intracellular Ca 2+ level of LNCaP and PC-3 cells. Cells were treated with or without torulene (10, 20, 30, and 40 mmol L \u00c01 ) for 24 h and the results were assayed by flow cytometry. Data are expressed as mean AE SD, n \u00bc 3. p < 0.05 compared with control group.", "type": "figure"}, "FIGREF10": {"text": "Fig. 5 (A) The mRNA expression of Bcl-2 and Bax and the ratio of Bcl-2/Bax in LNCaP and PC-3 cells. b-Actin was used as the control. Cancer cells were treated with or without torulene (10, 20 and 30 mmol L \u00c01 ) for 24 h (p < 0.05). (B) The effect of torulene on Bcl-2 protein expression was determined in LNCaP and PC-3 cells by western blot. Following 24 h-torulene treatment, total proteins were isolated and separated in 12% SDS gel, blotted in PVDF membrane and applied with Bcl-2 and Bax antibodies. b-Actin was used as a loading control.", "type": "figure"}, "FIGREF11": {"text": "Fig. 6 (A) The mRNA expression of AR and PSA in LNCaP cells. b-Actin was used as the control. Cancer cells were treated with or without torulene (10, 20 and 30 mmol L \u00c01 ) for 24 h (p < 0.05). (B) The protein expression of AR and PSA in LNCaP cells. The effect of torulene on AR and PSA protein expression was determined in LNCaP cells by western blot. Following 24 h-torulene treatment, total proteins were isolated and separated in 12% SDS gel, blotted in PVDF membrane and applied with AR and PSA antibodies. b-Actin was used as a loading control.", "type": "figure"}, "TABREF1": {"text": "The sequences of primers used for quantitative real-time PCR", "type": "table"}}}
{"paper_id": "91043930", "_pdf_hash": "34ce11b8315734c937fafc50c631aa94249891e5", "abstract": [{"section": "Abstract", "text": "Evolutionary conditions may favor development of parasitism in practice. Orobanche spp. (broomrape) is holoparasitic flowering plant at the root of a large number of crops that greatly reduce the yield in dry, warm, temperate and semi-arid regions. The problem of pathogenic organisms is focused primarily on fungi, nematodes, bacteria and viruses. These organisms certainly cause economically significant damages on plants, and the fact that parasitic flowering plants are economically significant pathogens can be surprising. Roots of parasitic plants develop primarily on annual plants on which parasitic seedlings form haustoria and thus gain a functional root system. In order to create connection between the host and the parasite, some kind of stimulus is needed. The substance for stimulation of connecting the host and the parasite is highly unstable, so the distance between the parasite seed and the root of the host plays a vital role in creating a contact. Cuscuta campestris Yuncker -field dodder has always been known as a plant without root and chlorophyll, i.e. parasitic plant that is completely dependent upon the host. It is generally accepted that water and inorganic nutrients are absorbed through the xylem between the host and the parasite, and organic compounds are transported through the phloem of the host, so that the parasite adapts it by phloem connections. This view has been accepted by almost all reference works and textbooks. The research has proved the existence of chlorophyll A and B in very small quantities in Cuscuta campestris in relation 2.5:1.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "The first association problem of pathogenic organisms is directed to fungi, nematodes, bacteria and viruses. These organisms certainly lead to economically significant damages of plants, and the fact that parasitic flowering plants are also economically significant pathogens can be surprising. Parasitic plants are angiosperms (flowering plants) that are directly linked to other plants by haustoria. Haustoria are root modifications that form morphological and physiological bonds between the parasite and the host. Parasitic plants (originating from Greek word para -beside and zitos -guard oneself) are organisms that cause parasitic plant diseases. These are predominantly heterotrophic organisms, because they feed by ready to eat food that they take from either living cells or dead organic matter. Only a limited number of autotrophic organisms adapted to parasitic way of life. Between parasites and saprophytes (sapro -rot, phyton -plant), there is a great number of transitional forms, and among them there are no clear boundaries. Some authors use this name to mark any agent of plant diseases, either of parasitic or non-parasitic nature. Therefore, it would be a broader concept in relation to parasite which is of biotic nature. However, phytopathologists often use the term pathogen, mainly for parasitic organisms. If the symptoms of disease are created on the host, then it is pathogen, as well as parasite. Until now, great number of parasitic organisms was identified on plants. For example, so far in North America there are about 8.000 parasitic fungi, 300 bacteria, 500 viruses, 75 species of organisms that look like mycoplasma and about 3.000 described parasitic flowering plants. Parasitic weed species, known as broomrape -Orobanche cumana Wallr. is one of limiting factors in sunflower production, as well as in other world countries. Genetic resistance in combination with herbicides is the best manner for control of this weed species (Eizenberg et al., 2006; Rubiales et al., 2009; Fernandez -Martinez et al., 2010) . Even beside possible control, there is significant increase of infected areas. This parasitic weed originates from Russia, and nowadays is widely spread in Eurasia, including Black Sea region (Antonova et al., 2009) . In Serbia, presence of broomrape has also been confirmed (Ma\u0161irevi\u0107 and Medi\u0107-Pap, 2009 ), as well as on the territory of Romania (Pricop et al., 2011 ), Turkey (Demirci and Kaya, 2009 ), Spain (Fernandez-Martinez et al., 2009 ), Israel (Eizenberg et al., 2003 , and it has recently been also discovered in Africa (Amri et al., 2012) . Certainly that intensive exchange of sunflower seeds between countries in the world, as well as small broomrape seed enable fast spread of this weed species. High genetic resistance of commercial sunflower hybrids to this weed species in Argentina could be potential answer to high distribution of this weed species (Cantamutto et al., 2012) . Parasitic flowering plants, such as species of the genus Cuscuta L. (dod-der) and Orobanche L. (broomrape), quantitatively do not have significant number in relation to total weedy vegetation of Serbia that numbers 1,009 species (Koji\u0107 and Vrbni\u010danin, 1998 ). Cuscuta genus includes over 100 species, distributed in moderate and warmer regions of the world. In vegetation Serbia, represented are only 10 species of this genus (Koji\u0107 and Vrbni\u010danin, 2000) .", "cite_spans": [{"start": 1965, "end": 1989, "text": "(Eizenberg et al., 2006;", "ref_id": "BIBREF6"}, {"start": 1990, "end": 2012, "text": "Rubiales et al., 2009;", "ref_id": "BIBREF19"}, {"start": 2013, "end": 2046, "text": "Fernandez -Martinez et al., 2010)", "ref_id": "BIBREF9"}, {"start": 2241, "end": 2264, "text": "(Antonova et al., 2009)", "ref_id": "BIBREF1"}, {"start": 2324, "end": 2354, "text": "(Ma\u0161irevi\u0107 and Medi\u0107-Pap, 2009", "ref_id": "BIBREF15"}, {"start": 2397, "end": 2417, "text": "(Pricop et al., 2011", "ref_id": "BIBREF17"}, {"start": 2581, "end": 2600, "text": "(Amri et al., 2012)", "ref_id": "BIBREF0"}, {"start": 2919, "end": 2944, "text": "(Cantamutto et al., 2012)", "ref_id": "BIBREF2"}, {"start": 3176, "end": 3203, "text": "(Koji\u0107 and Vrbni\u010danin, 1998", "ref_id": "BIBREF11"}], "ref_spans": []}, {"section": "Species of parasitic plants", "text": "Unlike ordinary weeds, parasitic plants are heterogeneous plant organisms that are not able to synthetize sufficient nutrients need for their development, due to which they lodge to other, host plant out of which they extract nutrients through structures called haustoria that anatomically connect binding channels of two plants (Konstantinovi\u0107, 1999) .", "cite_spans": [{"start": 329, "end": 351, "text": "(Konstantinovi\u0107, 1999)", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "Species of parasitic plants", "text": "There are two basic types of parasitic plants that can be distinguished: parasites of stem and parasites of root. Stem parasites occurred in several families, and pathogens are some mistletoe and field dodder (Cassitha and Cuscuta). Stem parasites are more frequent and are found in different taxonomic groups. Some of economically important stem pathogens belong to the family of flowering plants, Orobanchaceae. Holoparasite and hemiparasite species differ according to the degree of dependence of parasites on the host plant. Hemiparasites can be obligatory and facultative parasites. Optional (facultative or semi-) parasitic weeds contain chlorophyll and can survive without host. Facultative parasites or necrotrophs held mostly on dead organic matter (saprophytic phase), and only a part of development cycle they spend on plants (parasitic phase). From the other hand, complete (obligatory or parasitic) weeds, demand host for survival. Obligatory parasites can develop only on alive tissues of the host plant. Hemiparazites contain chlorophyll during their growth, thus being photosyntetically active, and uptake water by binding with the host by haustoria. Holoparazites lack chlorophyll i.e. they are photosyntetically inactive and therefore they must rely on the host xylem and phloem content. All holoparasites are obligatory parasites. Although these definitions imply absolute and partial categorization, some parasitic plants are intermediators between hemi-and holoparasitic plants, e.g. Cuscuta (dodder).", "cite_spans": [], "ref_spans": []}, {"section": "Species of parasitic plants", "text": "Morphological characteristics. On some stem parasites such as Cassitha (mistletoe) and Cuscuta (dodder), vegetative part consists exclusively from stem and rudimentary leaves. Opposite to this, numerous photosynthetic hemiparasites of root will not be accepted as parasites because they are green with completely formed leaves. As the level of parasitic dependence grows (evolution from hemiparasites to holoparasites), great changes occurred in morphology of parasitic plants. The best example of evolutionary phase from hemi-to holoparasites can be seen between different representatives of the family of flowering plants (Orobanchaceae).", "cite_spans": [], "ref_spans": []}, {"section": "Orobanchaceae (flowering plants)", "text": "This family includes the greatest number of genus (90) and species (about 1800) of all families of parasitic flowering plants. In Serbia there are 26 different broomrape species, 56 varieties and 226 forms that make total of 308 taxa (Ma\u0161irevi\u0107 and Medi\u0107-Pap, 2009 ). In the past hemiparasitic members of this family have been classified as a part of Scrophulariaceae family, while holoparasitic members have been included in Orobanchaceae family. The most recent molecular phylogenetic studies that have included both hemi-and holoparasites show that Orobanchaceae are monophyletic -i.e. they originate from a common ancestor, and that evolutionary line is offspring of non-parasitic Scrophulariaceae. In further text, two economically most important genus, Striga and Orobanche are described separately, with similarities and differences of their life cycles.", "cite_spans": [{"start": 234, "end": 264, "text": "(Ma\u0161irevi\u0107 and Medi\u0107-Pap, 2009", "ref_id": "BIBREF15"}], "ref_spans": []}, {"section": "Orobanchaceae (flowering plants)", "text": "Orobanche L. The genus Orobanche contains about 150 species of holoparasites that attack the root of the host. These plants are known for their English names ''broomrape'', because it was thought to grow as tubers (\"rapum\") from broom (the common name for legumes Cytisus). This genus reaches its greatest diversity in Mediterranean climate and north Asia. The majority of economically significant pathogenic species are of ancient origin. Molecular proves suggest that Orobanche is not monophyletic, so that other generic terms can eventually be applied. The main families of host for parasitic Orobanche are legumes, nightshades (eggplant, tomato, tobacco, potato, but not paprika), then squires (carrot, parsley, celery), brassicas (cabbage, cauliflower) and composites (lettuce, sunflower). Control is difficult due to seed dormancy in the soil (more than five decades), tiny seeds (smaller than width of the human hair), fertility (thousands of seeds per plant), as well as due to underground phases (seed germination) under soil and lives as parasite host before it emerges and becomes evident. Populations that naturally occur in red clover (Trifolium pratense) and carrot (Daucus carota subsp. Gummifer), show different host specificities, indicating possibilities of fast adaptation. There are numerous studies on hosts that attack Orobanche species. It has been shown that O. ramosa L. can parasitize plants in 11 different dicotyledonous families, in fact, on several different hosts than any other flowering plants. Related species of O. aegiptiaca cause especially heavy damages of melon in Central Asia, where flowering plants not only reduce yield, but also encourage production of toxins within melons that become commercially unusable. For example, there are no reports of parasitism in soybean by any flowering plant, although O. crenata Forsk. is soybean parasite in a pot. However, pot assays are valuable, for potential hosts can be identified on the bases of specificity of domestic parasite strains that can be identified. In general, Orobanche is the parasite of colder climates, and germination temperature is between 10 to 20 \u00b0C, alternately with temperatures of 5 \u00b0C. This can explain why O. ramosa represents a problem in the river Nile valley in Sudan only in winter, and the fact why O. cernua Loefl. attacks tobacco in India, and it does not represent a problem in sunflower (Helianthus annuus) grown in the same region during summer. Orobanche noticeably weaken roots of its host. The longest dormancy of Orobanche seed in the soil was documented in Bulgaria in 1956 due to severe Orobanche infection, in tobacco fields of Tobacco Research Institute near Plovdiv, was planted a vineyard. In 1991 vineyards were removed and tobacco was sown again. Great number of O. ramosa occurred probably out of seed that were dispersed during previous tobacco cropping in 1956. O. ramosa imported in California makes a problem on tomato. Despite efforts to eradicate it, the parasite keeps surviving. It is highly probable that parasite seed was imported by the crop, by either infected plant or contaminated tomato seed. More recent of tomato in Chile should be used as a warning that O. ramosa infection can be expected wherever there is a convenient host.", "cite_spans": [], "ref_spans": []}, {"section": "Orobanchaceae (flowering plants)", "text": "Orobanche cernua is widely distributed in East Europe and Middle East, with heavy invasions in South India and sporadical occurrences in North Africa, China and East Europe. Its primary hosts are crops from Solanaceae family and sunflower. Sunflower is the most important oil plant in some parts of East Europe, and O. cernua is a major constraint for production, especially in Bulgaria in which sunflower oil is a national brend. Infected plants are stunted and have smaller heads and lower oil quality. Between 1947 and 1950, Orobanche created a problem that in Bulgaria became so serious that it threatened further sunflower existence. Tobacco can be seriously damaged by O. cernua; however, tobacco was not attacked in Bulgaria, even in regions near heavily infected sunflower fields. In India in which tobacco is heavily damaged, situation is inverted and sunflower was not attacked. It has been proved that O. cernua devel-ops on hosts from family Solanaceae and that it will not attack sunflower. Russian breeders studied O. cernua development for many years. Their data should be studied and proved by new genetic methods (PCR). Given the size of the area under sunflower, more awareness on this pathogen is needed. Yet another of the species from Orobanche genus is O. crenata. Main hosts of this species are ordinary beans, lentils, forage legumes, carrot, parsley, celery and etc.", "cite_spans": [], "ref_spans": []}, {"section": "Orobanchaceae (flowering plants)", "text": "The other two genus of Orobanchaceae family, Aeginetia and Christisonia, can be considered smaller problem on monocotyledonous plants. In agro-ecological region of Serbia, broomrape on sunflower in greater or lesser extent occurs almost annually and can cause significant damages. One of the most efficient and the most economical ways of control of these parasitic flowering plants is certainly sowing of resistant hybrids. For studies on hybrid resistance to broomrape it is very important to have broomrape seed of good rate of emergence. Trifender is biological product based Trichoderma asperellum. Broomrape rate of emergence is the lowest on medium with trifender; thus, the effect of this biological product for seed germination should be studied in more detail (Ma\u0161irevi\u0107 et al., 2011) .", "cite_spans": [{"start": 770, "end": 794, "text": "(Ma\u0161irevi\u0107 et al., 2011)", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "Orobanchaceae (flowering plants)", "text": "Orobanche cumana Wallr., as well as other parasitic plants from the family Orobanchaceae, demand presence of chemical compounds from the environment as stimulus for germination. In the study of Plakhine et al. (2009) showed that seed germination of O. cumana. is improved due to influence of synthetic nijmegen-1 strigolactone applied directly to dry seed. Studies directed toward development of PCR methods for detection of seed abundance of two parasitic plants Phelipanche ramosa and Orobanche cumana, as well as related species are used during harvest of rapeseed and sunflower. The method is based upon design of the starting probing. The method is based on the design of initial probing that is set for each parasitic plant with determination of transcribed space sequences for quantitative PCR determination. Together with the proposed DNA protocol, this diagnostic method allows a faster, high-throughput and accurate assessment of contaminated rapeseed, without complex purification steps and identification under a binocular microscope. TaqMan assay is highly specific, since it is not possible to detect plant impurities that are present in a given crops seed. The results of this test can be presented via the number of parasite seeds per kilogram of crops seed, which can contribute to improved sales of crops seed (Rodriguez et al., 2010) . It is known that a new specific bioassays lead to the discovery of new classes of biologically active compounds (Yoneyama, 2010) .", "cite_spans": [{"start": 194, "end": 216, "text": "Plakhine et al. (2009)", "ref_id": "BIBREF17"}, {"start": 1328, "end": 1352, "text": "(Rodriguez et al., 2010)", "ref_id": "BIBREF18"}, {"start": 1467, "end": 1483, "text": "(Yoneyama, 2010)", "ref_id": "BIBREF24"}], "ref_spans": []}, {"section": "Cuscuta L.", "text": "Cuscuta species, commonly known as dodder is among the best known parasitic plants, and is one of the most invasive weeds in the world. Species of Cuscuta, known as field dodder is among the best known parasitic plants, and it is one of the most invasive weeds in the world (Lowe et al., 2001) . Field dodders have wide spectrum of hosts, although they favour less monocotyledonous species. Genus Cuscuta contains three sub-genuses. Members of subgenus monogina are robust vines that attack and destroy fruit trees, while the species in subgenus Cuscuta represents a problem for hosts of the herbaceous plants, as well as subgenus Grammica. Infected plants weaken; vegetative luxuriance is reduced, as well as their fertility (Koskela et al., 2001; Fathoulla and Duhoky, 2008) . In moderate climate, field dodder is maybe the most important parasitic weed of legumes. C. campestris in alfalfa (Medicago sativa) is of special importance. Alfalfa and field dodder seed are alike by size, and by alfalfa sowing the parasites spreads with the host. The most efficient control measure is sowing of pure seed. Due to bumpy surface of field dodder seed, it retains, and cylindrical seed of alfalfa passes. Genus Cuscuta belongs to the family Convolvulaceae, although some authors think that it belongs to the other family (Cuscutaceae). Many species that are hardly recognizable and are able to parasite numerous shrubby and woody species belong to this genus. Although the results of the mitochondrial genome analysis confirmed a link between the family Convolvulaceae (McNeal & DePamphilis, 2000) , some studies also show that Cuscuta phylogenetically belongs to the family Convolvulaceae (Stefanovic et al., 2002; . Stefanovic & Olmstead, 2004) .", "cite_spans": [{"start": 274, "end": 293, "text": "(Lowe et al., 2001)", "ref_id": "BIBREF13"}, {"start": 726, "end": 748, "text": "(Koskela et al., 2001;", "ref_id": "BIBREF13"}, {"start": 749, "end": 776, "text": "Fathoulla and Duhoky, 2008)", "ref_id": "BIBREF7"}, {"start": 1563, "end": 1591, "text": "(McNeal & DePamphilis, 2000)", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "Cuscuta L.", "text": "The most widespread species in our country is Cuscuta campestris, that is considered holoparasitic for it does not have pigments for photosynthesis. Performed assays showed that it contains chlorophyll (a or b), during its whole vital cycle, although in much smaller quantities than other green plants. Presence of this pigment varies depending on plant development stage and reaches maximum during flowering. In it are present chloroplasts that function during whole plant life cycles that are able to perform photosynthesis by chlorophyll, although to a lesser extent, which forces it into heterophyl nutrition. Cuscuta campestris is extremely difficult to control, due to its well coated seeds, as well as its natural joining in host-parasite association. Making part of ''seed bank'', Cuscuta seed in the soil maintains rate of emergence for long time, and it can survive at least 10 years in the field and up to 50 years in dry warehouses, depending upon the species (Dawson et al., 1984) . Chickpeas are very susceptible to C. campestris. However, there are several efficient selective products that are used in control of this parasite in chickpeas crops. After studies of several genotypes of Israeli varieties that are resistant to C. campestris, genotypes ICCV 95333 and Hazera 4 showed high resistance in more than 80% of the studied chickpeas (Goldwasser et al., 2012) .", "cite_spans": [{"start": 972, "end": 993, "text": "(Dawson et al., 1984)", "ref_id": "BIBREF3"}, {"start": 1355, "end": 1380, "text": "(Goldwasser et al., 2012)", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Cuscuta L.", "text": "Seeds of C. campestris are different in size and usually germinate in the following year, creating radicle rich in nutrients and a stem. Radicle first penetrates slowly into the soil, but later it degenerates and decays so that the plant loses all connection with land. The stem is able to grow up to a month until it meets the host plant on which it fastens. It is in the form of a thread, with varying looks, yellow-whitish in colour, with no leaves and it is able to hold onto the host plant due to hooks, or papillae. The flowers are white, small and produce many seeds. The most frequent host plants of Cuscuta campestris are medicinal plants from family Fabaceae, as well as sugar beet crop. Control of this parasite is performed primarily by preventive measures, in order to inhibit seed germination. If the parasitic plant has already spread, herbicide application that acts on cell division is efficient. Field dodder is certainly great problem in cultivation of cranberry and other fruit trees shrubs (Sandler, 2010) . With the aim of field dodder control, treatment is made in alfalfa 1-3 trifoliate leaf stage, or after first cutting with some of the following herbicides: imazethapyr, clethodim, propyzamid, diquat and fluazifop-p-butyl (Konstantinovi\u0107 et al., 2004) . Use of Cuscuta species in control of invasive weed species is a new approach that is being developed in China in last years (Yu et al., 2011; Shen et al., 2011) .", "cite_spans": [{"start": 1011, "end": 1026, "text": "(Sandler, 2010)", "ref_id": "BIBREF20"}, {"start": 1250, "end": 1279, "text": "(Konstantinovi\u0107 et al., 2004)", "ref_id": "BIBREF12"}, {"start": 1406, "end": 1423, "text": "(Yu et al., 2011;", "ref_id": "BIBREF25"}, {"start": 1424, "end": 1442, "text": "Shen et al., 2011)", "ref_id": "BIBREF21"}], "ref_spans": []}, {"section": "Conclusions", "text": "Even though 270 genera and 4400 species of flowering parasites are parasites, only about 25 genera have negative impact to cultivated plants and thus are considered pathogenic. Among them, two genera are the most harmful -Orobanche (broomrape) and Cuscuta (field dodder). Parasitic flowering plants are particularly harmful on legumes and crops belonging to family Solanaceae, primarily genus Orobanche. It produces thousands of tiny seeds that survive in the soil ''seed bank'' that makes control very difficult. However, as an integral part of every ecosystem that is compatible with its hosts, control is the only way for control of this parasite. Knowledge of the complex biology of parasitic flowering plants requires simultaneous studies of the host and parasitic flowering plant.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Detection of the parasitic plant, Orobanche cumana on sunflower (Helianthus annuus L.) in Tunisia", "authors": [{"first": "M", "middle": [], "last": "Amri", "suffix": ""}, {"first": "Z", "middle": [], "last": "Abbes", "suffix": ""}, {"first": "S", "middle": [], "last": "Ben", "suffix": ""}, {"first": "M", "middle": [], "last": "Youssef", "suffix": ""}, {"first": "H", "middle": [], "last": "Bouhadida", "suffix": ""}, {"first": "", "middle": [], "last": "Ben", "suffix": ""}, {"first": "M", "middle": [], "last": "Salah", "suffix": ""}, {"first": "", "middle": [], "last": "Khar-Rat", "suffix": ""}], "year": 2012, "venue": "Afr. J. Biotech", "link": null}, "BIBREF1": {"title": "Virulence of sunflower broomrape (Orobanche cumana Wallr.) in some regions of Northern Caucasus", "authors": [{"first": "T", "middle": ["S"], "last": "Antonova", "suffix": ""}, {"first": "N", "middle": ["M"], "last": "Araslanova", "suffix": ""}, {"first": "S", "middle": ["Z"], "last": "Guchetl", "suffix": ""}, {"first": "T", "middle": ["A"], "last": "Tchelustnikova", "suffix": ""}, {"first": "S", "middle": ["A"], "last": "Ramazanova", "suffix": ""}, {"first": "E", "middle": ["N"], "last": "Trembak", "suffix": ""}], "year": 2009, "venue": "Helia", "link": null}, "BIBREF2": {"title": "Comparative study of abiotic environmental factors in broomrape (Orobanche cumana Wallr.) infested and non-infested sunflower areas of Serbia and Argentina", "authors": [{"first": "M", "middle": [], "last": "Cantamutto", "suffix": ""}, {"first": "D", "middle": [], "last": "Miladinovic", "suffix": ""}, {"first": "J", "middle": [], "last": "Vasin", "suffix": ""}, {"first": "B", "middle": [], "last": "Dedic", "suffix": ""}, {"first": "D", "middle": [], "last": "Alvarez", "suffix": ""}, {"first": "F", "middle": [], "last": "Quiroz", "suffix": ""}, {"first": "M", "middle": [], "last": "Poverene", "suffix": ""}], "year": 2012, "venue": "Proceed. 18th International Sunflower Conference", "link": null}, "BIBREF3": {"title": "A vegetative character that separates species of Cuscuta. Pages 184-187 in", "authors": [{"first": "J", "middle": ["H"], "last": "Dawson", "suffix": ""}], "year": 1984, "venue": "Proc. 3rd Intern. Symp. on Parasitic Weeds", "link": null}, "BIBREF4": {"title": "Status of Orobanche cernua Loefl. and weeds in sunflower production in Turkey", "authors": [{"first": "M", "middle": ["&amp; Y"], "last": "Demirci", "suffix": ""}, {"first": "", "middle": [], "last": "Kaya", "suffix": ""}], "year": 2009, "venue": "Helia", "link": null}, "BIBREF5": {"title": "Resistance to broomrape (Orobanche spp.) in sunflower (Helianthus annuus L.) is temperature dependent", "authors": [{"first": "Y", "middle": [], "last": "Goldwasser", "suffix": ""}, {"first": "H", "middle": [], "last": "Miryamchik", "suffix": ""}, {"first": "M", "middle": [], "last": "Sibony", "suffix": ""}, {"first": "B", "middle": [], "last": "Rubin ; X Eizenberg", "suffix": ""}, {"first": "H", "middle": [], "last": "", "suffix": ""}, {"first": "D", "middle": [], "last": "Plakhine", "suffix": ""}, {"first": "J", "middle": [], "last": "Hershenhorn", "suffix": ""}, {"first": "Y", "middle": [], "last": "Kleifeld", "suffix": ""}, {"first": "B", "middle": [], "last": "Rubin", "suffix": ""}], "year": 2003, "venue": "Weed Research", "link": "34853587"}, "BIBREF6": {"title": "Imazamox application timing for small broomrape (Orobanche minor) control in red clover", "authors": [{"first": "H", "middle": [], "last": "Eizenberg", "suffix": ""}, {"first": "J", "middle": ["B"], "last": "Colquhoun", "suffix": ""}, {"first": "C", "middle": ["A"], "last": "Mallory-Smith", "suffix": ""}], "year": 2006, "venue": "Weed Sci", "link": "85883210"}, "BIBREF7": {"title": "Biological and anatomical study of different Cuscuta species. Kurdistan 1 st Conference on", "authors": [{"first": "C", "middle": ["N M M S"], "last": "Fathoulla", "suffix": ""}, {"first": "", "middle": [], "last": "Duhoky", "suffix": ""}], "year": 2008, "venue": "Biological Sciences. J. Dohuk Univ", "link": null}, "BIBREF8": {"title": "Current research strategies for sunflower broomrape control in Spain. Helia", "authors": [{"first": "J", "middle": ["M"], "last": "Fernandez-Martinez", "suffix": ""}, {"first": "J", "middle": [], "last": "Dominguez", "suffix": ""}, {"first": "B", "middle": [], "last": "Perez-Vich", "suffix": ""}, {"first": "L", "middle": [], "last": "Velasco", "suffix": ""}], "year": 2009, "venue": "", "link": null}, "BIBREF9": {"title": "Update on breeding for resistance to sunflower broomrape", "authors": [{"first": "J", "middle": ["M"], "last": "Fernandez-Martinez", "suffix": ""}, {"first": "J", "middle": [], "last": "Dominguez", "suffix": ""}, {"first": "B", "middle": [], "last": "Perez-Vich", "suffix": ""}, {"first": "L", "middle": [], "last": "Velasco", "suffix": ""}], "year": 2010, "venue": "Helia", "link": null}, "BIBREF10": {"title": "2000: Parazitski korovi -osnovne karakteristike, taksonomija, diverzitet i rasprostranjenje. I deo: Vilina kosica (Cuscuta L.). Acta biologica Iugoslavica, series G: Acta herbologica", "authors": [{"first": "M", "middle": [], "last": "Koji\u0107", "suffix": ""}, {"first": "&amp;", "middle": ["S"], "last": "Vrbni\u010danin", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF11": {"title": "Agrestal, ruderal, grass and aquatic weeds in Serbia. Acta biologica Iugoslavica, series G: Acta herbologica", "authors": [{"first": "M", "middle": [], "last": "Koji\u0107", "suffix": ""}, {"first": "&amp;", "middle": ["S"], "last": "Vrbni\u010danin", "suffix": ""}], "year": 1998, "venue": "", "link": null}, "BIBREF12": {"title": "Zna\u010daj vi\u0161egodi\u0161njih korova i parazitnh cvetnica u usevu lucerke i mogu\u0107nosti suzbijanja", "authors": [{"first": "B", "middle": [], "last": "Konstantinovi\u0107", "suffix": ""}, {"first": "", "middle": [], "last": "Srbija", "suffix": ""}, {"first": "B", "middle": [], "last": "Konstantinovi\u0107", "suffix": ""}, {"first": "M", "middle": [], "last": "Meseld\u017eija", "suffix": ""}, {"first": "B", "middle": ["O"], "last": "Konstantinovi\u0107", "suffix": ""}], "year": 1999, "venue": "Poznavanje i suzbijanje korova. Poljoprivredni fakultet", "link": null}, "BIBREF13": {"title": "Interaction of a host plant and its holoparasite: effects of previous selection by the parasite", "authors": [{"first": "T", "middle": [], "last": "Koskela", "suffix": ""}, {"first": "V", "middle": [], "last": "Salonen", "suffix": ""}, {"first": "P", "middle": [], "last": "Mutikainen ; X Lowe", "suffix": ""}, {"first": "S", "middle": [], "last": "", "suffix": ""}, {"first": "M", "middle": [], "last": "Browne", "suffix": ""}, {"first": "S", "middle": [], "last": "Boudjelas", "suffix": ""}, {"first": "M", "middle": [], "last": "Depoorter", "suffix": ""}], "year": 2001, "venue": "A Selection from the Global Invasive Species Database", "link": "83159778"}, "BIBREF14": {"title": "Germination of broomrape seed on differnt nutritive media. 11th World Congress on Parasitic Plants", "authors": [{"first": "S", "middle": [], "last": "Ma\u0161irevi\u0107", "suffix": ""}, {"first": "S", "middle": [], "last": "Medi\u0107-Pap", "suffix": ""}, {"first": "B", "middle": [], "last": "Konstantinovi\u0107", "suffix": ""}, {"first": "A", "middle": [], "last": "Terzi\u0107", "suffix": ""}], "year": 2011, "venue": "", "link": null}, "BIBREF15": {"title": "Status of broomrape in Serbia from the occurence up to now-days", "authors": [{"first": "S", "middle": ["&amp; S"], "last": "Ma\u0161irevi\u0107", "suffix": ""}, {"first": "", "middle": [], "last": "Medi\u0107-Pap", "suffix": ""}], "year": 2009, "venue": "Helia", "link": null}, "BIBREF16": {"title": "Origin and molecular systematics of the parasitic plant genus Cuscuta (dodder)", "authors": [{"first": "J", "middle": ["R C W"], "last": "Mcneal", "suffix": ""}, {"first": "", "middle": [], "last": "Depamphilis", "suffix": ""}], "year": 2000, "venue": "", "link": null}, "BIBREF17": {"title": "Review: Is seed conditioning essential for Orobanche germination? Pest Management Science", "authors": [{"first": "D", "middle": [], "last": "Plakhine", "suffix": ""}, {"first": "H", "middle": [], "last": "Ziadna", "suffix": ""}, {"first": "D", "middle": ["M"], "last": "Joel ; Press", "suffix": ""}, {"first": "J", "middle": ["D"], "last": "Mc", "suffix": ""}, {"first": "S", "middle": ["M"], "last": "Pricop", "suffix": ""}, {"first": "S", "middle": [], "last": "Cristea", "suffix": ""}, {"first": "E", "middle": [], "last": "Petcu", "suffix": ""}], "year": 2009, "venue": "Results on the virulence of the Orobanche cumana Wallr. Populations in Dobrogea", "link": null}, "BIBREF18": {"title": "The influence of flowering plant isolation on seed production and seed quality in Orobanche cumana", "authors": [{"first": "M", "middle": ["J"], "last": "Rodriguez-Ojeda", "suffix": ""}, {"first": "B", "middle": [], "last": "Perez-Vich", "suffix": ""}, {"first": "L", "middle": ["C"], "last": "Alonso", "suffix": ""}, {"first": "J", "middle": [], "last": "Fernandez-Esco-Bar", "suffix": ""}], "year": 2010, "venue": "Weed Research", "link": "82055589"}, "BIBREF19": {"title": "Parasitic plant management in sustainable agriculture", "authors": [{"first": "D", "middle": [], "last": "Rubiales", "suffix": ""}, {"first": "J", "middle": [], "last": "Verkleij", "suffix": ""}, {"first": "M", "middle": [], "last": "Vurro", "suffix": ""}, {"first": "A", "middle": ["J"], "last": "Murdoch", "suffix": ""}, {"first": "D", "middle": ["M"], "last": "Joel", "suffix": ""}], "year": 2009, "venue": "Weed Res", "link": "84706379"}, "BIBREF20": {"title": "Managing Cuscuta gronovii (Swamp Dodder) in Cranberry Requires an Integrated Approach. Cranberry Station", "authors": [{"first": "A", "middle": [], "last": "Sandler Hilary", "suffix": ""}], "year": 2010, "venue": "P.O. Box", "link": "84139285"}, "BIBREF21": {"title": "Do higher resource capture ability and utilization efficiency facilitate the successful invasion of native plants?", "authors": [{"first": "X", "middle": ["Y"], "last": "Shen", "suffix": ""}, {"first": "S", "middle": ["L"], "last": "Peng", "suffix": ""}, {"first": "B", "middle": ["M"], "last": "Chen", "suffix": ""}, {"first": "J", "middle": ["X"], "last": "Pang", "suffix": ""}, {"first": "L", "middle": ["Y"], "last": "Chen", "suffix": ""}], "year": 2011, "venue": "Biological Invasions", "link": "36069107"}, "BIBREF22": {"title": "Monophyly of the Convolvulaceae and circumscription of their major lineages based on DNA sequences of multiple chloroplast loci", "authors": [{"first": "S", "middle": [], "last": "Stefanovi\u0107", "suffix": ""}, {"first": "L", "middle": [], "last": "Krueger", "suffix": ""}, {"first": "R", "middle": ["G"], "last": "Olmstead", "suffix": ""}], "year": 2002, "venue": "Am. J. Bot", "link": "12624970"}, "BIBREF23": {"title": "Testing the phylogenetic position of a parasitic plant (Cuscuta, Convolvulaceae, Asteridae): Bayesian inference and the parametric bootstrap on data drawn from three genomes", "authors": [{"first": "S", "middle": ["R G"], "last": "Stefanovi\u0107", "suffix": ""}, {"first": "", "middle": [], "last": "Olmstead", "suffix": ""}], "year": 2004, "venue": "Syst. Biol", "link": null}, "BIBREF24": {"title": "Studies on the host recognition mechanism of root parasitic plants", "authors": [{"first": "K", "middle": [], "last": "Yoneyama", "suffix": ""}], "year": 2010, "venue": "Journal of Pesticide Science", "link": "84765898"}, "BIBREF25": {"title": "Cuscuta australis restrain three exotic invasive plants and benefits native species", "authors": [{"first": "H", "middle": [], "last": "Yu", "suffix": ""}, {"first": "J", "middle": [], "last": "Liu", "suffix": ""}, {"first": "W", "middle": ["M"], "last": "He", "suffix": ""}, {"first": "S", "middle": ["L"], "last": "Miao", "suffix": ""}, {"first": "M", "middle": [], "last": "Dong", "suffix": ""}], "year": 2011, "venue": "Biological Invasions", "link": "1402894"}}, "ref_entries": {}}
{"paper_id": "91045479", "_pdf_hash": "5b9486ca01eac681c847adaceb521d2f80083859", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "91046838", "_pdf_hash": "1b440a45a58caa465e6e52acb1e9fe6b4c02e344", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Contribution No. 2016-009 the Hawaii Biological Survey", "authors": [], "year": "", "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "91048341", "_pdf_hash": "97bfa79c6322b28ad6f70a3afd5430e4cbfcbd33", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Nonvoiding activity of the guinea pig bladder", "authors": [{"first": "B", "middle": ["T"], "last": "Biallosterski", "suffix": ""}, {"first": "G", "middle": ["A"], "last": "Van Koeveringe", "suffix": ""}, {"first": "P", "middle": ["E"], "last": "Van Kerrebroeck", "suffix": ""}, {"first": "J", "middle": ["I"], "last": "Gillespie", "suffix": ""}, {"first": "S", "middle": ["G"], "last": "De Wachter", "suffix": ""}], "year": 2011, "venue": "J Urol", "link": "32626232"}, "BIBREF1": {"title": "Autonomous activity in the isolated guinea pig bladder", "authors": [{"first": "M", "middle": ["J"], "last": "Drake", "suffix": ""}, {"first": "I", "middle": ["J"], "last": "Harvey", "suffix": ""}, {"first": "J", "middle": ["I"], "last": "Gillespie", "suffix": ""}], "year": 2003, "venue": "Exp Physiol", "link": "31988101"}, "BIBREF2": {"title": "Disclosures Funding: FP7 Marie Curie Actions Trust programe Clinical Trial: No Subjects: ANIMAL Species: rat Ethics Committee: Animals were humanely killed according to local regulations", "authors": [], "year": "", "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "41510104", "_pdf_hash": "9c1d8c4d32c511f1e823d89649c60451b5ea5bf2", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "41510685", "_pdf_hash": "c4b712c044933fd84cdf22437badd2554c05e3bc", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Bayes or bootstrap? A simulation study comparing the performance of Bayesian Markov chain Monte Carlo sampling and bootstrapping in assessing phylogenetic confidence", "authors": [{"first": "M", "middle": ["E"], "last": "Alfaro", "suffix": ""}, {"first": "S", "middle": [], "last": "Zoller", "suffix": ""}, {"first": "F", "middle": [], "last": "Lutzoni", "suffix": ""}], "year": 2003, "venue": "Mol. Biol. Evol", "link": "8399221"}, "BIBREF1": {"title": "Reproductive isolation among sympatric cryptic species in marine diatoms", "authors": [{"first": "A", "middle": [], "last": "Amato", "suffix": ""}, {"first": "W", "middle": ["H"], "last": "Kooistra", "suffix": ""}, {"first": "J", "middle": ["H"], "last": "Levialdi Ghiron", "suffix": ""}, {"first": "D", "middle": ["G"], "last": "Mann", "suffix": ""}, {"first": "T", "middle": [], "last": "Pr\u00f6schold", "suffix": ""}, {"first": "M", "middle": [], "last": "Montresor", "suffix": ""}], "year": 2007, "venue": "Protist", "link": "20599205"}, "BIBREF2": {"title": "Mitochondrial markers reveal deep population subdivision in the European protected spider Macrothele calpeiana (Walckenaer, 1805) (Araneae, Hexathelidae)", "authors": [{"first": "M", "middle": ["A"], "last": "Arnedo", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Ferr\u00e1ndez", "suffix": ""}], "year": 2007, "venue": "Conserv. Genet", "link": "40545152"}, "BIBREF3": {"title": "Principles of genealogical concordance in species concepts and biological taxonomy", "authors": [{"first": "J", "middle": ["C"], "last": "Avise", "suffix": ""}, {"first": "R", "middle": ["M"], "last": "Ball", "suffix": ""}], "year": 1990, "venue": "Oxford Surv. Evol. Biol", "link": "83179200"}, "BIBREF4": {"title": "Utility of the nuclear proteincoding gene, elongation factor-1 gamma (EF-1c) for spider systematics, emphasizing family level relationships of tarantulas and their kin (Aranaea: Mygalomorphae)", "authors": [{"first": "N", "middle": ["A"], "last": "Ayoub", "suffix": ""}, {"first": "J", "middle": ["E"], "last": "Garb", "suffix": ""}, {"first": "M", "middle": [], "last": "Hedin", "suffix": ""}, {"first": "C", "middle": ["Y"], "last": "Hayashi", "suffix": ""}], "year": 2007, "venue": "Mol. Phylogenet. Evol", "link": null}, "BIBREF5": {"title": "The challenge of species delimitation at the extremes: diversification without morphological change in Philippine sun skinks", "authors": [{"first": "A", "middle": ["J"], "last": "Barley", "suffix": ""}, {"first": "J", "middle": [], "last": "White", "suffix": ""}, {"first": "A", "middle": ["C"], "last": "Diesmos", "suffix": ""}, {"first": "R", "middle": ["M"], "last": "Brown", "suffix": ""}], "year": 2013, "venue": "Evolution", "link": "17018015"}, "BIBREF6": {"title": "The Biosystematics of the Spider Genus Brachythele Ausserer (Araneidae: Dipluridae). PhD Dissertation", "authors": [{"first": "M", "middle": ["M"], "last": "Bentzien", "suffix": ""}], "year": 1976, "venue": "", "link": null}, "BIBREF7": {"title": "An integrative method for delimiting cohesion species: finding the population-species interface in a group of Californian trapdoor spiders with extreme genetic divergence and geographic structuring", "authors": [{"first": "J", "middle": ["E"], "last": "Bond", "suffix": ""}, {"first": "A", "middle": ["K"], "last": "Stockman", "suffix": ""}], "year": 2008, "venue": "Syst. Biol", "link": "205728993"}, "BIBREF8": {"title": "Combining genetic and geospatial analyses to infer population extinction in mygalomorph spiders endemic to the Los Angeles region", "authors": [{"first": "J", "middle": ["E"], "last": "Bond", "suffix": ""}, {"first": "D", "middle": ["A"], "last": "Beamer", "suffix": ""}, {"first": "T", "middle": [], "last": "Lamb", "suffix": ""}, {"first": "M", "middle": [], "last": "Hedin", "suffix": ""}], "year": 2006, "venue": "Anim. Conserv", "link": "33888672"}, "BIBREF9": {"title": "A reconsideration of the classification of the spider infraorder Mygalomorphae based on three nuclear genes and morphology (Arachnida: Araneae)", "authors": [{"first": "J", "middle": ["E"], "last": "Bond", "suffix": ""}, {"first": "B", "middle": ["E"], "last": "Hendrixson", "suffix": ""}, {"first": "C", "middle": ["A"], "last": "Hamilton", "suffix": ""}, {"first": "M", "middle": [], "last": "Hedin", "suffix": ""}], "year": 2012, "venue": "PLoS One", "link": "15954281"}, "BIBREF10": {"title": "Phylogenomics resolves a spider backbone phylogeny and rejects a prevailing paradigm for orb web evolution", "authors": [{"first": "J", "middle": ["E"], "last": "Bond", "suffix": ""}, {"first": "N", "middle": ["L"], "last": "Garrison", "suffix": ""}, {"first": "C", "middle": ["A"], "last": "Hamilton", "suffix": ""}, {"first": "R", "middle": ["L"], "last": "Godwin", "suffix": ""}, {"first": "M", "middle": [], "last": "Hedin", "suffix": ""}, {"first": "I", "middle": [], "last": "Agnarsson", "suffix": ""}], "year": 2014, "venue": "Curr. Biol", "link": "18009264"}, "BIBREF11": {"title": "Barcoding of mygalomorph spiders (Araneae: Mygalomorphae) in the Pilbara bioregion of Western Australia reveals a highly diverse biota", "authors": [{"first": "M", "middle": ["A"], "last": "Castalanelli", "suffix": ""}, {"first": "R", "middle": [], "last": "Teale", "suffix": ""}, {"first": "M", "middle": ["G"], "last": "Rix", "suffix": ""}, {"first": "W", "middle": ["J"], "last": "Kennington", "suffix": ""}, {"first": "M", "middle": ["S"], "last": "Harvey", "suffix": ""}], "year": 2014, "venue": "Invertebr. Syst", "link": "83870814"}, "BIBREF12": {"title": "Selection of conserved blocks from multiple alignments for their use in phylogenetic analysis", "authors": [{"first": "J", "middle": [], "last": "Castresana", "suffix": ""}], "year": 2000, "venue": "Mol. Phylogenet. Evol", "link": "6306476"}, "BIBREF13": {"title": "New tarantulas from the southwestern states", "authors": [{"first": "R", "middle": ["V"], "last": "Chamberlin", "suffix": ""}, {"first": "W", "middle": [], "last": "Ivie", "suffix": ""}], "year": 1939, "venue": "Bull. Univ. Utah", "link": null}, "BIBREF14": {"title": "Deep phylogeographic structuring of populations of the trapdoor spider Moggridgea tingle (Migidae) from southwestern Australia: evidence for long-term refugia within refugia", "authors": [{"first": "S", "middle": ["J"], "last": "Cooper", "suffix": ""}, {"first": "M", "middle": ["S"], "last": "Harvey", "suffix": ""}, {"first": "K", "middle": ["M"], "last": "Saint", "suffix": ""}, {"first": "B", "middle": ["Y"], "last": "Main", "suffix": ""}], "year": 2011, "venue": "Mol. Ecol", "link": "28573356"}, "BIBREF15": {"title": "Iberesia, a new genus of trapdoor spiders (Araneae, Nemesiidae) from Portugal and Spain", "authors": [{"first": "A", "middle": [], "last": "Decae", "suffix": ""}, {"first": "P", "middle": [], "last": "Cardoso", "suffix": ""}], "year": 2005, "venue": "Rev. Ib\u00e9rica Aracnol", "link": "55538672"}, "BIBREF16": {"title": "Species diversity in the supposedly monotypic genus Amblyocarenum Simon, 1892, with the description of a new species from Sardinia", "authors": [{"first": "A", "middle": [], "last": "Decae", "suffix": ""}, {"first": "M", "middle": [], "last": "Colombo", "suffix": ""}, {"first": "B", "middle": [], "last": "Manunza", "suffix": ""}], "year": 2014, "venue": "", "link": null}, "BIBREF18": {"title": "Integrative taxonomy and species delimitation in harvestmen: A revision of the western North American genus Sclerobunus (Opiliones: Laniatores: Travunioidea)", "authors": [{"first": "S", "middle": [], "last": "Derkarabetian", "suffix": ""}, {"first": "M", "middle": [], "last": "Hedin", "suffix": ""}], "year": 2014, "venue": "PLoS One", "link": null}, "BIBREF19": {"title": "Nuclear DNA recapitulates the cryptic mitochondrial lineages of Lumbricus rubellus and suggests the existence of cryptic species in an ecotoxological soil sentinel", "authors": [{"first": "R", "middle": ["K"], "last": "Donnelly", "suffix": ""}, {"first": "G", "middle": ["L"], "last": "Harper", "suffix": ""}, {"first": "A", "middle": ["J"], "last": "Morgan", "suffix": ""}, {"first": "P", "middle": [], "last": "Orozco-Terwengel", "suffix": ""}, {"first": "G", "middle": ["A"], "last": "Pinto-Juma", "suffix": ""}, {"first": "M", "middle": ["W"], "last": "Bruford", "suffix": ""}], "year": 2013, "venue": "Biol. J. Linn. Soc", "link": "83493046"}, "BIBREF20": {"title": "A revision of the South American spiders of the family Nemesiidae (Araneae, Mygalomorphae). Part I: species from Peru", "authors": [{"first": "P", "middle": ["A"], "last": "Goloboff", "suffix": ""}], "year": 1995, "venue": "Bull. Am. Mus. Nat. Hist", "link": null}, "BIBREF21": {"title": "Miocene extensional tectonics explain ancient patterns of diversification among turretbuilding tarantulas (Aphonopelma mojave group) in the Mojave and Sonoran deserts", "authors": [{"first": "M", "middle": ["R"], "last": "Graham", "suffix": ""}, {"first": "B", "middle": ["E"], "last": "Hendrixson", "suffix": ""}, {"first": "C", "middle": ["A"], "last": "Hamilton", "suffix": ""}, {"first": "J", "middle": ["E"], "last": "Bond", "suffix": ""}], "year": 2015, "venue": "J. Biogeogr", "link": null}, "BIBREF22": {"title": "Species delimitation using Bayes factors: simulations and application to the Sceloporus scalaris species group (Squamata: Phrynosomatidae)", "authors": [{"first": "J", "middle": ["A"], "last": "Grummer", "suffix": ""}, {"first": "R", "middle": ["W"], "last": "Bryson", "suffix": ""}, {"first": "T", "middle": ["W"], "last": "Reeder", "suffix": ""}], "year": 2014, "venue": "Syst. Biol", "link": "8959946"}, "BIBREF23": {"title": "Species delimitation and phylogeography of Aphonopelma hentzi (Araneae, Mygalomorphae, Theraphosidae): cryptic diversity in North American tarantulas", "authors": [{"first": "C", "middle": ["A"], "last": "Hamilton", "suffix": ""}, {"first": "D", "middle": ["R"], "last": "Formanowicz", "suffix": ""}, {"first": "J", "middle": ["E"], "last": "Bond", "suffix": ""}], "year": 2011, "venue": "PLoS One", "link": "3885082"}, "BIBREF24": {"title": "An evaluation of sampling effects on multiple DNA barcoding methods leads to an integrative approach for delimiting species: a case study of the North American tarantula genus Aphonopelma (Araneae, Mygalomorphae, Theraphosidae)", "authors": [{"first": "C", "middle": ["A"], "last": "Hamilton", "suffix": ""}, {"first": "B", "middle": ["E"], "last": "Hendrixson", "suffix": ""}, {"first": "M", "middle": ["S"], "last": "Brewer", "suffix": ""}, {"first": "J", "middle": ["E"], "last": "Bond", "suffix": ""}], "year": 2014, "venue": "Mol. Phylogenet. Evol", "link": "19178780"}, "BIBREF25": {"title": "Phylogenetic and coalescent strategies of species delimitation in snubnose darters (Percidae: Etheostoma)", "authors": [{"first": "R", "middle": ["C"], "last": "Harrington", "suffix": ""}, {"first": "T", "middle": ["J"], "last": "Near", "suffix": ""}], "year": 2012, "venue": "Syst. Biol", "link": "17334889"}, "BIBREF26": {"title": "Protecting the innocent: studying short-range endemic taxa enhances conservation outcomes", "authors": [{"first": "M", "middle": ["S"], "last": "Harvey", "suffix": ""}, {"first": "M", "middle": ["G"], "last": "Rix", "suffix": ""}, {"first": "V", "middle": ["W"], "last": "Framenau", "suffix": ""}, {"first": "Z", "middle": ["R"], "last": "Hamilton", "suffix": ""}, {"first": "M", "middle": ["S"], "last": "Johnson", "suffix": ""}, {"first": "R", "middle": ["J"], "last": "Teale", "suffix": ""}, {"first": "G", "middle": [], "last": "Humphreys", "suffix": ""}, {"first": "W", "middle": ["F"], "last": "Humphreys", "suffix": ""}], "year": 2011, "venue": "Invertebr. Syst", "link": "86800914"}, "BIBREF27": {"title": "Biological identifications through DNA barcodes", "authors": [{"first": "P", "middle": [], "last": "Hebert", "suffix": ""}, {"first": "A", "middle": [], "last": "Cywinska", "suffix": ""}, {"first": "S", "middle": [], "last": "Ball", "suffix": ""}, {"first": "J", "middle": [], "last": "Dewaard", "suffix": ""}], "year": 2003, "venue": "Philos. Trans. R. Soc. Lond. B", "link": "1606831"}, "BIBREF28": {"title": "Barcoding animal life: cytochrome c oxidase subunit 1 divergences among closely related species", "authors": [{"first": "P", "middle": [], "last": "Hebert", "suffix": ""}, {"first": "S", "middle": [], "last": "Ratnasingham", "suffix": ""}, {"first": "J", "middle": ["R"], "last": "De Waard", "suffix": ""}], "year": 2003, "venue": "Philos. Trans. R. Soc. B", "link": "6517747"}, "BIBREF29": {"title": "High-stakes species delimitation in eyeless cave spiders (Cicurina, Dictynidae, Araneae) from central Texas", "authors": [{"first": "M", "middle": [], "last": "Hedin", "suffix": ""}], "year": 2015, "venue": "Mol. Ecol", "link": "1065314"}, "BIBREF30": {"title": "Molecular phylogenetics of the spider infraorder Mygalomorphae using nuclear rRNA genes (18S and 28S): conflict and agreement with the current system of classification", "authors": [{"first": "M", "middle": [], "last": "Hedin", "suffix": ""}, {"first": "J", "middle": ["E"], "last": "Bond", "suffix": ""}], "year": 2006, "venue": "Mol. Phylogenet. Evol", "link": "41298505"}, "BIBREF31": {"title": "A new trapdoor spider species from the southern Coast Ranges of California (Mygalomorphae, Antrodiaetidae, Aliatypus coylei, nov sp), including consideration of mitochondrial phylogeographic structuring", "authors": [{"first": "M", "middle": [], "last": "Hedin", "suffix": ""}, {"first": "D", "middle": [], "last": "Carlson", "suffix": ""}], "year": 2011, "venue": "Zootaxa", "link": "55808264"}, "BIBREF32": {"title": "Crossing the uncrossable: novel trans-valley biogeographic patterns revealed in the genetic history of low dispersal mygalomorph spiders (Antrodiaetidae, Antrodiaetus) from California", "authors": [{"first": "M", "middle": [], "last": "Hedin", "suffix": ""}, {"first": "J", "middle": [], "last": "Starrett", "suffix": ""}, {"first": "C", "middle": [], "last": "Hayashi", "suffix": ""}], "year": 2013, "venue": "Mol. Ecol", "link": "206179479"}, "BIBREF33": {"title": "Sky island diversification meets the multispecies coalescent: divergence in the spruce-fir moss spider (Microhexura montivaga) on the highest peaks of southern Appalachia", "authors": [{"first": "M", "middle": [], "last": "Hedin", "suffix": ""}, {"first": "D", "middle": [], "last": "Carlson", "suffix": ""}, {"first": "F", "middle": [], "last": "Coyle", "suffix": ""}], "year": "", "venue": "Mol. Ecol", "link": null}, "BIBREF34": {"title": "An exploration of species boundaries in turret-building tarantulas of the Mojave Desert (Araneae, Mygalomorphae, Theraphosidae, Aphonopelma)", "authors": [{"first": "B", "middle": ["E"], "last": "Hendrixson", "suffix": ""}, {"first": "B", "middle": ["M"], "last": "Derussy", "suffix": ""}, {"first": "C", "middle": ["A"], "last": "Hamilton", "suffix": ""}, {"first": "J", "middle": ["E"], "last": "Bond", "suffix": ""}], "year": 2013, "venue": "Mol. Phylogenet. Evol", "link": "13393946"}, "BIBREF35": {"title": "Detecting cryptic species in phylogeographic studies: Speciation in the California Slender Salamander, Batrachoseps attenuatus", "authors": [{"first": "R", "middle": [], "last": "Highton", "suffix": ""}], "year": 2014, "venue": "Mol. Phylogenet. Evol", "link": "12572492"}, "BIBREF36": {"title": "An empirical test of bootstrapping as a method for assessing confidence in phylogenetic analysis", "authors": [{"first": "D", "middle": ["M"], "last": "Hillis", "suffix": ""}, {"first": "J", "middle": ["J"], "last": "Bull", "suffix": ""}], "year": 1993, "venue": "Syst. Biol", "link": "17210196"}, "BIBREF37": {"title": "Phylogeographic breaks without geographic barriers to gene flow", "authors": [{"first": "D", "middle": ["E"], "last": "Irwin", "suffix": ""}], "year": 2002, "venue": "Evolution", "link": "9505549"}, "BIBREF38": {"title": "Evolutionary conservation and versatility of a new set of primers for amplifying the ribosomal internal transcribed spacer regions in insects and other invertebrates", "authors": [{"first": "Y", "middle": ["J"], "last": "Ji", "suffix": ""}, {"first": "D", "middle": ["X"], "last": "Zhang", "suffix": ""}, {"first": "L", "middle": ["J"], "last": "He", "suffix": ""}], "year": 2003, "venue": "Mol. Ecol. Notes", "link": "39305093"}, "BIBREF39": {"title": "DISSECT: an assignment-free Bayesian discovery method for species delimitation under the multispecies coalescent", "authors": [{"first": "G", "middle": [], "last": "Jones", "suffix": ""}, {"first": "Z", "middle": [], "last": "Aydin", "suffix": ""}, {"first": "B", "middle": [], "last": "Oxelman", "suffix": ""}], "year": 2015, "venue": "Bioinformatics", "link": "196679638"}, "BIBREF40": {"title": "MAFFT version 5: improvement in accuracy of multiple sequence alignment", "authors": [{"first": "K", "middle": [], "last": "Katoh", "suffix": ""}, {"first": "K.-I", "middle": [], "last": "Kuma", "suffix": ""}, {"first": "H", "middle": [], "last": "Toh", "suffix": ""}, {"first": "T", "middle": [], "last": "Miyata", "suffix": ""}], "year": 2005, "venue": "Nucleic Acids Res", "link": "7611279"}, "BIBREF41": {"title": "Extreme mitochondrial population subdivision in southern Appalachian paleoendemic spiders (Araneae: Hypochilidae: Hypochilus), with implications for species delimitation", "authors": [{"first": "R", "middle": [], "last": "Keith", "suffix": ""}, {"first": "M", "middle": [], "last": "Hedin", "suffix": ""}], "year": 2012, "venue": "J. Arachnol", "link": "85889680"}, "BIBREF42": {"title": "Phylogeographic breaks in low-dispersal species: the emergence of concordance across gene trees", "authors": [{"first": "C", "middle": ["H"], "last": "Kuo", "suffix": ""}, {"first": "J", "middle": ["C"], "last": "Avise", "suffix": ""}], "year": 2005, "venue": "Genetica", "link": "19155540"}, "BIBREF43": {"title": "Complex patterns of speciation in cosmopolitan ''rock posy'' lichensDiscovering and delimiting cryptic fungal species in the lichen-forming Rhizoplaca melanophthalma species-complex (Lecanoraceae, Ascomycota)", "authors": [{"first": "S", "middle": ["D"], "last": "Leavitt", "suffix": ""}, {"first": "J", "middle": ["D"], "last": "Fankhauser", "suffix": ""}, {"first": "D", "middle": ["H"], "last": "Leavitt", "suffix": ""}, {"first": "L", "middle": ["D"], "last": "Porter", "suffix": ""}, {"first": "L", "middle": ["A"], "last": "Johnson", "suffix": ""}, {"first": "L", "middle": ["L"], "last": "St Clair", "suffix": ""}], "year": 2011, "venue": "Mol. Phylogenet. Evol", "link": "3184871"}, "BIBREF44": {"title": "Gene trees in species trees", "authors": [{"first": "W", "middle": ["P"], "last": "Maddison", "suffix": ""}], "year": 1997, "venue": "Syst. Biol", "link": "19940411"}, "BIBREF45": {"title": "Extreme population subdivision throughout a continuous range: phylogeography of Batrachoseps attenuatus (Caudata: Plethodontidae) in western North America", "authors": [{"first": "I", "middle": [], "last": "Mart\u00ednez-Solano", "suffix": ""}, {"first": "E", "middle": ["L"], "last": "Jockusch", "suffix": ""}, {"first": "D", "middle": ["B"], "last": "Wake", "suffix": ""}], "year": 2007, "venue": "Mol. Ecol", "link": "3195594"}, "BIBREF46": {"title": "Parallel evolution of truncated transfer RNA genes in arachnid mitochondrial genomes", "authors": [{"first": "S", "middle": ["E"], "last": "Masta", "suffix": ""}, {"first": "J", "middle": ["L"], "last": "Boore", "suffix": ""}], "year": 2008, "venue": "Mol. Phylogenet. Evol", "link": "10403187"}, "BIBREF47": {"title": "Systematics and the Origin of Species", "authors": [{"first": "E", "middle": [], "last": "Mayr", "suffix": ""}], "year": 1942, "venue": "", "link": "83566302"}, "BIBREF48": {"title": "Mitochondrial introgression and incomplete lineage sorting through space and time: phylogenetics of crotaphytid lizards", "authors": [{"first": "J", "middle": ["A"], "last": "Mcguire", "suffix": ""}, {"first": "C", "middle": ["W"], "last": "Linkem", "suffix": ""}, {"first": "M", "middle": ["S"], "last": "Koo", "suffix": ""}, {"first": "D", "middle": ["W"], "last": "Hutchison", "suffix": ""}, {"first": "A", "middle": ["K"], "last": "Lappin", "suffix": ""}, {"first": "D", "middle": ["I"], "last": "Orange", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Lemos-Espinal", "suffix": ""}, {"first": "B", "middle": ["R"], "last": "Riddle", "suffix": ""}, {"first": "J", "middle": ["R"], "last": "Jaeger", "suffix": ""}], "year": 2007, "venue": "Evolution", "link": "11135712"}, "BIBREF50": {"title": "Comparative phylogeography and the identification of genetically divergent areas for conservation", "authors": [{"first": "C", "middle": [], "last": "Moritz", "suffix": ""}, {"first": "D", "middle": ["P"], "last": "Faith", "suffix": ""}], "year": 1998, "venue": "Mol. Ecol", "link": "84623663"}, "BIBREF51": {"title": "Molecular evidence for ecological speciation in tropical habitats", "authors": [{"first": "R", "middle": [], "last": "Ogden", "suffix": ""}, {"first": "R", "middle": ["S"], "last": "Thorpe", "suffix": ""}], "year": 2002, "venue": "Proc. Natl. Acad. Sci", "link": "14636302"}, "BIBREF52": {"title": "From Gondwana to Europe: inferring the origins of Mediterranean Macrothele spiders (Araneae: Hexathelidae) and the limits of the family Hexathelidae", "authors": [{"first": "V", "middle": [], "last": "Opatova", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Arnedo", "suffix": ""}], "year": 2014, "venue": "Invertebr. Syst", "link": "86553675"}, "BIBREF53": {"title": "Spiders on a hot volcanic roof: colonisation pathways and phylogeography of the Canary Islands endemic trap-door spider Titanidiops canariensis (Araneae, Idiopidae)", "authors": [{"first": "V", "middle": [], "last": "Opatova", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Arnedo", "suffix": ""}], "year": 2014, "venue": "PLoS One", "link": "7399389"}, "BIBREF54": {"title": "Ancient origins of the Mediterranean trap-door spiders of the family Ctenizidae (Araneae, Mygalomorphae)", "authors": [{"first": "V", "middle": [], "last": "Opatova", "suffix": ""}, {"first": "J", "middle": ["E"], "last": "Bond", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Arnedo", "suffix": ""}], "year": 2013, "venue": "Mol. Phylogenet. Evol", "link": "24781627"}, "BIBREF55": {"title": "Species are hypotheses: avoid connectivity assessments based on pillars of sand", "authors": [{"first": "E", "middle": [], "last": "Pante", "suffix": ""}, {"first": "N", "middle": [], "last": "Puillandre", "suffix": ""}, {"first": "A", "middle": [], "last": "Viricel", "suffix": ""}, {"first": "S", "middle": [], "last": "Arnaud-Haond", "suffix": ""}, {"first": "D", "middle": [], "last": "Aurelle", "suffix": ""}, {"first": "M", "middle": [], "last": "Castelin", "suffix": ""}, {"first": "A", "middle": [], "last": "Chenuil", "suffix": ""}, {"first": "C", "middle": [], "last": "Destombe", "suffix": ""}, {"first": "D", "middle": [], "last": "Forcioli", "suffix": ""}, {"first": "M", "middle": [], "last": "Valero", "suffix": ""}, {"first": "F", "middle": [], "last": "Viard", "suffix": ""}, {"first": "S", "middle": [], "last": "Samadi", "suffix": ""}], "year": 2015, "venue": "Mol. Ecol", "link": "3561776"}, "BIBREF56": {"title": "Sequence-based species delimitation for the DNA taxonomy of undescribed insects", "authors": [{"first": "J", "middle": [], "last": "Pons", "suffix": ""}, {"first": "T", "middle": ["G"], "last": "Barraclough", "suffix": ""}, {"first": "J", "middle": [], "last": "Gomez-Zurita", "suffix": ""}, {"first": "A", "middle": [], "last": "Cardoso", "suffix": ""}, {"first": "D", "middle": ["P"], "last": "Duran", "suffix": ""}, {"first": "S", "middle": [], "last": "Hazell", "suffix": ""}, {"first": "S", "middle": [], "last": "Kamoun", "suffix": ""}, {"first": "W", "middle": ["D"], "last": "Sumlin", "suffix": ""}, {"first": "A", "middle": ["P"], "last": "Vogler", "suffix": ""}], "year": 2006, "venue": "Syst. Biol", "link": "29334259"}, "BIBREF57": {"title": "JModelTest: phylogenetic model averaging", "authors": [{"first": "D", "middle": [], "last": "Posada", "suffix": ""}], "year": 2008, "venue": "Mol. Biol. Evol", "link": "16866739"}, "BIBREF58": {"title": "ABGD, Automatic Barcode Gap Discovery for primary species delimitation", "authors": [{"first": "N", "middle": [], "last": "Puillandre", "suffix": ""}, {"first": "A", "middle": [], "last": "Lambert", "suffix": ""}, {"first": "S", "middle": [], "last": "Brouillet", "suffix": ""}, {"first": "G", "middle": [], "last": "Achaz", "suffix": ""}], "year": 2012, "venue": "Mol. Ecol", "link": "135371"}, "BIBREF59": {"title": "The spider infraorder Mygalomorphae (Araneae): cladistics and systematics", "authors": [{"first": "A", "middle": [], "last": "Rambaut", "suffix": ""}, {"first": "A", "middle": ["J"], "last": "Drummond", "suffix": ""}, {"first": "", "middle": ["J"], "last": "; R", "suffix": ""}], "year": 1985, "venue": "Bull. Am. Mus. Nat. Hist", "link": "82520536"}, "BIBREF60": {"title": "A new mygalomorph spider genus from Mexico (Nemesiinae, Nemesiidae, Arachnida)", "authors": [{"first": "R", "middle": ["J"], "last": "Raven", "suffix": ""}], "year": 1987, "venue": "J. Arachnol", "link": "85867307"}, "BIBREF61": {"title": "Arthropods and multispecies habitat conservation plans: are we missing something?", "authors": [{"first": "R", "middle": ["A"], "last": "Redak", "suffix": ""}], "year": 2000, "venue": "Environ. Manage", "link": "2671435"}, "BIBREF62": {"title": "Multilocus species delimitation in a complex of morphologically conserved trapdoor spiders (Mygalomorphae, Antrodiaetidae, Aliatypus)", "authors": [{"first": "J", "middle": ["D"], "last": "Satler", "suffix": ""}, {"first": "B", "middle": ["C"], "last": "Carstens", "suffix": ""}, {"first": "M", "middle": [], "last": "Hedin", "suffix": ""}], "year": 2013, "venue": "Syst. Biol", "link": "3222428"}, "BIBREF63": {"title": "High genetic diversity in the hydroid Plumularia setacea: a multitude of cryptic species or extensive population subdivision?", "authors": [{"first": "P", "middle": [], "last": "Schuchert", "suffix": ""}], "year": 2014, "venue": "Mol. Phylogenet. Evol", "link": "2719015"}, "BIBREF64": {"title": "Introduction. Extent, processes and evolutionary impact of interspecific hybridization in animals", "authors": [{"first": "K", "middle": [], "last": "Schwenk", "suffix": ""}, {"first": "N", "middle": [], "last": "Brede", "suffix": ""}, {"first": "B", "middle": [], "last": "Streit", "suffix": ""}], "year": 2008, "venue": "Philos. Trans. R. Soc. B", "link": "11915756"}, "BIBREF65": {"title": "Etudes arachnologiques. 23e M\u00e9moire. XXXVIII. Descriptions d'esp\u00e8ces et de genres nouveaux de la famille des Aviculariidae", "authors": [{"first": "E", "middle": [], "last": "Simon", "suffix": ""}], "year": "", "venue": "Ann. Soc. Entomol. France", "link": null}, "BIBREF66": {"title": "A rapid bootstrap algorithm for the RAxML web-servers", "authors": [{"first": "A", "middle": [], "last": "Stamatakis", "suffix": ""}, {"first": "P", "middle": [], "last": "Hoover", "suffix": ""}, {"first": "J", "middle": [], "last": "Rougemont", "suffix": ""}], "year": 2008, "venue": "Syst. Biol", "link": null}, "BIBREF67": {"title": "Multilocus genealogies reveal multiple cryptic species and biogeographic complexity in the California turret spider Antrodiaetus riversi (Mygalomorphae, Antrodieatidae)", "authors": [{"first": "J", "middle": [], "last": "Starrett", "suffix": ""}, {"first": "H", "middle": [], "last": "Hedin", "suffix": ""}], "year": 2007, "venue": "Mol. Ecol", "link": "20761006"}, "BIBREF68": {"title": "Hemocyanin gene family evolution in spiders (Araneae), with implications for phylogenetic relationships and divergence times in the infraorder Mygalomorphae", "authors": [{"first": "J", "middle": [], "last": "Starrett", "suffix": ""}, {"first": "M", "middle": [], "last": "Hedin", "suffix": ""}, {"first": "N", "middle": [], "last": "Ayoub", "suffix": ""}, {"first": "C", "middle": ["Y"], "last": "Hayashi", "suffix": ""}], "year": 2013, "venue": "Gene", "link": "45651828"}, "BIBREF69": {"title": "Delimiting cohesion species: extreme population structuring and the role of ecological interchangeability", "authors": [{"first": "A", "middle": ["K"], "last": "Stockman", "suffix": ""}, {"first": "J", "middle": ["E"], "last": "Bond", "suffix": ""}], "year": 2007, "venue": "Mol. Ecol", "link": "44513975"}, "BIBREF70": {"title": "Genome-enabled development of DNA markers for ecology, evolution and conservation", "authors": [{"first": "R", "middle": ["C"], "last": "Thomson", "suffix": ""}, {"first": "I", "middle": ["J"], "last": "Wang", "suffix": ""}, {"first": "J", "middle": ["R"], "last": "Johnson", "suffix": ""}], "year": 2010, "venue": "Mol. Ecol", "link": "30504901"}, "BIBREF71": {"title": "Nemesiidae", "authors": [{"first": "D", "middle": [], "last": "Ubick", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Ledford", "suffix": ""}], "year": 2005, "venue": "Spiders of North America: An Identification Manual", "link": null}, "BIBREF72": {"title": "Spiders of North America: An Identification Manual", "authors": [{"first": "D", "middle": [], "last": "Ubick", "suffix": ""}, {"first": "P", "middle": [], "last": "Paquin", "suffix": ""}, {"first": "P", "middle": ["E"], "last": "Cushing", "suffix": ""}], "year": 2005, "venue": "", "link": "84079292"}, "BIBREF73": {"title": "Testing the species limits of the tarantulas (Araneae: Theraphosidae) endemic to California's Southern Coast Ranges", "authors": [{"first": "J", "middle": ["S"], "last": "Wilson", "suffix": ""}, {"first": "C", "middle": ["F"], "last": "Gunnell", "suffix": ""}, {"first": "D", "middle": ["B"], "last": "Wahl", "suffix": ""}, {"first": "J", "middle": ["P"], "last": "Pitts", "suffix": ""}], "year": 2013, "venue": "USA. Insect Conserv. Divers", "link": "85727866"}, "BIBREF74": {"title": "World Spider Catalog. Natural History Museum Bern", "authors": [], "year": 2015, "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "41512309", "_pdf_hash": "34c2bc527bfcee6284578fa5f645a305e4f413d4", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Textbook of the Autoimmune Diseases", "authors": [{"first": "G", "middle": ["L"], "last": "Robert", "suffix": ""}], "year": 2000, "venue": "", "link": "72737782"}, "BIBREF1": {"title": "Lupus pleuritis: clinical features and pleural fluid characteristics with special reference to pleural fluid antinuclear antibodies", "authors": [{"first": "J", "middle": ["T"], "last": "Good", "suffix": ""}, {"first": "T", "middle": ["E"], "last": "King", "suffix": ""}, {"first": "V", "middle": ["B"], "last": "Antony", "suffix": ""}], "year": 1983, "venue": "Chest", "link": "43604720"}, "BIBREF2": {"title": "Immune complexes and other laboratory features of pleural effusions", "authors": [{"first": "J", "middle": ["T"], "last": "Halla", "suffix": ""}, {"first": "R", "middle": ["E"], "last": "Schronbenloher", "suffix": ""}, {"first": "J", "middle": ["E"], "last": "Volanakis", "suffix": ""}], "year": 1980, "venue": "Ann Intern Med", "link": "26082879"}, "BIBREF3": {"title": "Lupus erythematosus cells in pleural effusions: diagnostic of systemic lupus erythematosus?", "authors": [{"first": "T", "middle": ["Y"], "last": "Chao", "suffix": ""}, {"first": "S", "middle": ["H"], "last": "Huang", "suffix": ""}, {"first": "C", "middle": ["C"], "last": "Chu", "suffix": ""}], "year": 1997, "venue": "Acta Cytol", "link": "31657682"}, "BIBREF4": {"title": "vivo LE phenomenon in pleural fluid. Arthritis Rheum", "authors": [{"first": "M", "middle": ["R"], "last": "Pandya", "suffix": ""}, {"first": "B", "middle": [], "last": "Agus", "suffix": ""}, {"first": "R", "middle": ["F"], "last": "Grady", "suffix": ""}], "year": 1976, "venue": "", "link": null}, "BIBREF5": {"title": "Diagnostic significance of antinuclear antibodies in pleural effusion", "authors": [{"first": "M", "middle": [], "last": "Leechawengwong", "suffix": ""}, {"first": "H", "middle": [], "last": "Berger", "suffix": ""}, {"first": "M", "middle": [], "last": "Sukumaran", "suffix": ""}], "year": 1979, "venue": "Mt Sinai J Med", "link": "45645331"}, "BIBREF6": {"title": "Antinuclear antibodies in pleural fluid", "authors": [{"first": "V", "middle": [], "last": "Khare", "suffix": ""}, {"first": "B", "middle": [], "last": "Baethge", "suffix": ""}, {"first": "S", "middle": [], "last": "Lang", "suffix": ""}], "year": 1994, "venue": "Chest", "link": "43495588"}, "BIBREF8": {"title": "This article reviews the significance of pleural fluid and pericardial fluid ANA titres in 156 patients with various diseases. The clinical usefulness of ANA staining patterns and fluid to serum ANA ratios was also evaluated", "authors": [{"first": "D", "middle": ["Y"], "last": "Wang", "suffix": ""}, {"first": "P", "middle": ["C"], "last": "Yang", "suffix": ""}, {"first": "W", "middle": ["L"], "last": "Yu", "suffix": ""}], "year": 2000, "venue": "Eur Respir J", "link": null}, "BIBREF10": {"title": "This book provides a practical", "authors": [{"first": "R", "middle": ["W"], "last": "Light", "suffix": ""}], "year": 2001, "venue": "Pleural diseases. 4th Edn", "link": null}, "BIBREF11": {"title": "Acute pulmonary complications in systemic lupus erythematosus. Immunofluorescence and light microscopic study", "authors": [{"first": "L", "middle": ["P"], "last": "Pertschuk", "suffix": ""}, {"first": "L", "middle": ["F"], "last": "Moccia", "suffix": ""}, {"first": "Y", "middle": [], "last": "Rosen", "suffix": ""}], "year": 1977, "venue": "Am J Clin Pathol", "link": "25437928"}, "BIBREF12": {"title": "The role of immune complexes in pathogenesis of pleural effusions", "authors": [{"first": "B", "middle": ["S"], "last": "Andrews", "suffix": ""}, {"first": "N", "middle": ["S"], "last": "Arora", "suffix": ""}, {"first": "M", "middle": ["F"], "last": "Shadforth", "suffix": ""}], "year": 1981, "venue": "Am Rev Respir Dis", "link": "42107160"}, "BIBREF13": {"title": "Antibody deposition in the pleura: a finding in drug-induced lupus", "authors": [{"first": "A", "middle": ["J"], "last": "Chandrasekhar", "suffix": ""}, {"first": "J", "middle": [], "last": "Robinson", "suffix": ""}, {"first": "L", "middle": [], "last": "Barr", "suffix": ""}], "year": 1978, "venue": "J Allergy Clin Immunol", "link": "42475407"}, "BIBREF14": {"title": "Pleural fluid complement in systemic lupus erythematosus and rheumatoid arthritis", "authors": [{"first": "G", "middle": ["G"], "last": "Hunder", "suffix": ""}, {"first": "F", "middle": ["C"], "last": "Mcduffie", "suffix": ""}, {"first": "Ngg", "middle": [], "last": "Hepper", "suffix": ""}], "year": 1972, "venue": "Ann Intern Med", "link": "30071007"}, "BIBREF15": {"title": "Treatment of chronic pleural effusion with intravenous immunoglobnlin and cyclosporin", "authors": [{"first": "Y", "middle": [], "last": "Sherer", "suffix": ""}, {"first": "P", "middle": [], "last": "Langevitz", "suffix": ""}, {"first": "Y", "middle": [], "last": "Levy", "suffix": ""}], "year": 1999, "venue": "", "link": null}, "BIBREF16": {"title": "Intravenous immunoglobulin therapy in a patient with lupus serositis and nephritis", "authors": [{"first": "M", "middle": [], "last": "Meissner", "suffix": ""}, {"first": "Y", "middle": [], "last": "Sherer", "suffix": ""}, {"first": "Y", "middle": [], "last": "Levy", "suffix": ""}], "year": 2000, "venue": "Rheumatol Int", "link": "41271007"}, "BIBREF17": {"title": "A study of 20 SLE patient with inmunoglobulin-clinical and serologic response", "authors": [{"first": "Y", "middle": [], "last": "Levy", "suffix": ""}, {"first": "Y", "middle": [], "last": "Sherer", "suffix": ""}, {"first": "A", "middle": [], "last": "Ahmed", "suffix": ""}], "year": 1999, "venue": "Lupus", "link": null}, "BIBREF18": {"title": "Successful use of tetracycline pleurodesis to treat massive pleural effusion secondary to systemic lupus erythmatosus", "authors": [{"first": "K", "middle": ["M"], "last": "Mcknight", "suffix": ""}, {"first": "N", "middle": ["E"], "last": "Adair", "suffix": ""}, {"first": "C", "middle": ["A"], "last": "Agudelo", "suffix": ""}], "year": 1991, "venue": "Arthritis Rheum", "link": "10985938"}, "BIBREF19": {"title": "Successful talc slurry pleurodesis in patients with nonmalignant pleural effusion", "authors": [{"first": "M", "middle": [], "last": "Glazer", "suffix": ""}, {"first": "N", "middle": [], "last": "Berkman", "suffix": ""}, {"first": "J", "middle": ["S"], "last": "Lafair", "suffix": ""}], "year": 2000, "venue": "Chest", "link": "19585174"}}, "ref_entries": {}}
{"paper_id": "41512378", "_pdf_hash": "c6240be20aab648473ae8066429c6669c185203b", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "On the electrical characteristics of complementary metamaterial resonators", "authors": [{"first": "J", "middle": [], "last": "Bonache", "suffix": ""}, {"first": "M", "middle": [], "last": "Gil", "suffix": ""}, {"first": "I", "middle": [], "last": "Gil", "suffix": ""}, {"first": "J", "middle": [], "last": "Garcia-Garcia", "suffix": ""}, {"first": "F", "middle": [], "last": "Martin", "suffix": ""}], "year": 2006, "venue": "IEEE Microwave and Wireless Components Letters", "link": "26282801"}}, "ref_entries": {}}
{"paper_id": "41512902", "_pdf_hash": "2de5d8c172e6431ab69ab97d6cd609ef0c372866", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "41513262", "_pdf_hash": "1843f52dad38e8ae63870e40b2c7fbd8e7927ba7", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Ku-Band Low-Profi le Rx-only and Tx-Rx Antennas for Mobile Satellite Communications", "authors": [{"first": "S", "middle": [], "last": "Vaccaro", "suffix": ""}, {"first": "F", "middle": [], "last": "Tiezzi", "suffix": ""}, {"first": "M", "middle": [], "last": "Fajardo R\u00faa", "suffix": ""}, {"first": "C", "middle": [], "last": "Dom\u00ednguez Grano De Oro", "suffix": ""}], "year": 2010, "venue": "2010 IEEE International Symposium on Phased Array Systems and Technology", "link": "24906868"}, "BIBREF1": {"title": "Low Cost Ku-band Electronic Steerable Array Antenna for Mobile Satellite Communications", "authors": [{"first": "S", "middle": [], "last": "Vaccaro", "suffix": ""}, {"first": "D", "middle": [], "last": "Del R\u00edo", "suffix": ""}, {"first": "J", "middle": [], "last": "Padilla", "suffix": ""}, {"first": "R", "middle": [], "last": "Baggen", "suffix": ""}], "year": 2011, "venue": "European Conference on Antennas and Propagation (EuCAP)", "link": "22306701"}, "BIBREF2": {"title": "Design Review of a Compact and Low Cost Elementary Radiating Cell for Satellite Broadcasting Automotive Receiving Arrays", "authors": [{"first": "R", "middle": [], "last": "Torres S\u00e1nchez", "suffix": ""}, {"first": "J", "middle": ["R"], "last": "Mosig", "suffix": ""}, {"first": "S", "middle": [], "last": "Vaccaro", "suffix": ""}, {"first": "D", "middle": [], "last": "Llorens Del R\u00edo", "suffix": ""}], "year": 2011, "venue": "33rd ESA Antenna Workshop on Challenges for Space Antenna Systems", "link": "112210473"}, "BIBREF3": {"title": "Low Cost Phased Array for Mobile Ku-Band Satel lite Terminal", "authors": [{"first": "S", "middle": [], "last": "Vaccaro", "suffix": ""}, {"first": "D", "middle": [], "last": "Del R\u00edo", "suffix": ""}, {"first": "R", "middle": ["Torres"], "last": "S\u00e1nchez", "suffix": ""}, {"first": "L", "middle": [], "last": "Baggen", "suffix": ""}], "year": 2010, "venue": "European Conference on Antennas and Propa gation", "link": "1238396"}, "BIBREF4": {"title": "A Low Cost Switched Beam Array Antenna for L-band Land Mobile Satellite Communications in Australia", "authors": [{"first": "N", "middle": ["C"], "last": "Karmakar", "suffix": ""}, {"first": "M", "middle": ["E"], "last": "Bialkowski", "suffix": ""}], "year": 1997, "venue": "IEEE International Symposium on Antennas and Propagation", "link": "24743163"}, "BIBREF5": {"title": "Power Synthesis of Reconfi gurable Conformal Arrays with Phase-Only Control", "authors": [{"first": "O", "middle": ["M"], "last": "Bucci", "suffix": ""}, {"first": "G", "middle": [], "last": "D&apos;elia", "suffix": ""}], "year": 1998, "venue": "IEE Proceedings on Microwaves, Antennas and Propagation", "link": "123416814"}, "BIBREF6": {"title": "Switched-Beam Tx-Only Ku-Band Termi nal Antenna for Mobile Satellite Applications", "authors": [{"first": "F", "middle": [], "last": "Bongard", "suffix": ""}, {"first": "D", "middle": [], "last": "Llorens Del R\u00edo", "suffix": ""}, {"first": "Carolina", "middle": [], "last": "Vigano", "suffix": ""}, {"first": "Stefano", "middle": [], "last": "Vaccaro", "suffix": ""}], "year": 2011, "venue": "33rd ESA Antenna Workshop on Challenges for Space Antenna Sys tems", "link": null}, "BIBREF7": {"title": "Array Grating Lobes Due to Periodic Phase, Amplitude and Time Delay Quantization", "authors": [{"first": "R", "middle": ["J"], "last": "Mailloux", "suffix": ""}], "year": 1984, "venue": "IEEE Transactions on Antennas and Propagation", "link": "85536503"}, "BIBREF8": {"title": "Spatial Density Tapered Sunfl ower Antenna Array", "authors": [{"first": "M", "middle": ["C"], "last": "Vigano", "suffix": ""}, {"first": "G", "middle": [], "last": "Toso", "suffix": ""}, {"first": "G", "middle": [], "last": "Caille", "suffix": ""}, {"first": "C", "middle": [], "last": "Mangenot", "suffix": ""}, {"first": "I", "middle": ["E"], "last": "Lager", "suffix": ""}], "year": 2009, "venue": "European Conference on Antennas and Propagation (EuCAP)", "link": null}, "BIBREF9": {"title": "The Application of a Biquadratic Programming Method to Phase-Only Optimization of Antenna Arrays", "authors": [{"first": "K", "middle": [], "last": "Hirasawa", "suffix": ""}], "year": 1988, "venue": "IEEE Transactions on Antennas and Propagation", "link": "123328224"}}, "ref_entries": {}}
{"paper_id": "41513494", "_pdf_hash": "d23ed03e749c71f523defcdc4158e19376847c60", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Sub-wavelength array with embedded chirped delay lines based on time reversal technique", "authors": [{"first": "S", "middle": [], "last": "Ding", "suffix": ""}, {"first": "B", "middle": ["Z"], "last": "Wang", "suffix": ""}, {"first": "G", "middle": ["D"], "last": "Ge", "suffix": ""}, {"first": "D", "middle": ["S"], "last": "Zhao", "suffix": ""}], "year": 2013, "venue": "IEEE Trans. Antennas Propag", "link": "21868977"}, "BIBREF1": {"title": "High spatial resolution imaging for structural health monitoring based on virtual time reversal", "authors": [{"first": "J", "middle": [], "last": "Cai", "suffix": ""}], "year": 2011, "venue": "Smart Mater. Struct", "link": "108649420"}, "BIBREF2": {"title": "Beamspace time-reversal microwave imaging for breast cancer detection", "authors": [{"first": "M", "middle": ["D"], "last": "Hossain", "suffix": ""}, {"first": "A", "middle": ["S"], "last": "Mohan", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Abedin", "suffix": ""}], "year": 2013, "venue": "IEEE Antennas Wireless Propag. Lett", "link": "44025112"}, "BIBREF3": {"title": "Ultrasound time-reversal MUSIC imaging with diffraction and attenuation compensation", "authors": [{"first": "Y", "middle": [], "last": "Labyed", "suffix": ""}, {"first": "L", "middle": ["J"], "last": "Huang", "suffix": ""}], "year": 2012, "venue": "IEEE Trans. Ultrason., Ferroelectr., Freq. Control", "link": "25655552"}, "BIBREF4": {"title": "Transmitting-mode time reversal imaging using MUSIC algorithm for surveillance in wireless sensor network", "authors": [{"first": "X", "middle": ["F"], "last": "Liu", "suffix": ""}, {"first": "B", "middle": ["Z"], "last": "Wang", "suffix": ""}, {"first": "J", "middle": ["L"], "last": "Li", "suffix": ""}], "year": 2012, "venue": "IEEE Trans. Antennas Propag", "link": "22997392"}, "BIBREF5": {"title": "Comparison of the imaging resolutions of time reversal and back-projection algorithms in EM inverse scattering", "authors": [{"first": "P", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "X", "middle": ["J"], "last": "Zhang", "suffix": ""}, {"first": "G", "middle": ["Y"], "last": "Fang", "suffix": ""}], "year": 2013, "venue": "IEEE Geosci. Remote Sens. Lett", "link": "35495365"}, "BIBREF6": {"title": "Subwavelength target detection using ultrawideband time-reversal techniques with a multilayered dielectric slab", "authors": [{"first": "T", "middle": ["H"], "last": "Liao", "suffix": ""}, {"first": "P", "middle": ["C"], "last": "Hsieh", "suffix": ""}, {"first": "F", "middle": ["C"], "last": "Chen", "suffix": ""}], "year": 2009, "venue": "IEEE Antennas Wireless Propag. Lett", "link": "28397960"}, "BIBREF7": {"title": "A relationship between time-reversal imaging and maximum likelihood scattering estimation", "authors": [{"first": "G", "middle": [], "last": "Shi", "suffix": ""}, {"first": "A", "middle": [], "last": "Nehorai", "suffix": ""}], "year": 2007, "venue": "IEEE Trans. Signal Process", "link": "61173465"}, "BIBREF8": {"title": "Symmetry-based imaging condition in time reversed acoustics", "authors": [{"first": "T", "middle": ["J"], "last": "Ulrich", "suffix": ""}, {"first": "M", "middle": [], "last": "Griffa", "suffix": ""}, {"first": "B", "middle": ["E"], "last": "Anderson", "suffix": ""}], "year": 2008, "venue": "J. Appl. Phys", "link": "18250370"}}, "ref_entries": {}}
{"paper_id": "41514098", "_pdf_hash": "42241b71ab531199c9cc2923a796e9c85f01e526", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "On the origin of the histone 209 fold", "authors": [{"first": "V", "middle": [], "last": "Alva", "suffix": ""}, {"first": "M", "middle": [], "last": "Ammelburg", "suffix": ""}, {"first": "J", "middle": [], "last": "S\u00f6ding", "suffix": ""}, {"first": "A", "middle": ["N"], "last": "Lupas", "suffix": ""}], "year": 2007, "venue": "BMC Struct. Biol", "link": null}, "BIBREF1": {"title": "The histone fold: a ubiquitous architectural 211 motif utilized in DNA compaction and protein dimerization", "authors": [{"first": "G", "middle": [], "last": "Arents", "suffix": ""}, {"first": "E", "middle": ["N"], "last": "Moudrianakis", "suffix": ""}], "year": 1995, "venue": "Proc. Natl. Acad. Sci. USA", "link": "27485172"}, "BIBREF2": {"title": "Both DNA and histone fold 214 sequences contribute to archaeal nucleosome stability", "authors": [{"first": "K", "middle": ["A"], "last": "Bailey", "suffix": ""}, {"first": "F", "middle": [], "last": "Marc", "suffix": ""}, {"first": "K", "middle": [], "last": "Sandman", "suffix": ""}, {"first": "J", "middle": ["N"], "last": "Reeve", "suffix": ""}], "year": 2002, "venue": "J. Biol. Chem", "link": "23395985"}, "BIBREF3": {"title": "Phylogenetic analysis of fungal centromere H3 216 proteins", "authors": [{"first": "R", "middle": ["E"], "last": "Baker", "suffix": ""}, {"first": "K", "middle": [], "last": "Rogers", "suffix": ""}], "year": 2006, "venue": "Genetics", "link": null}, "BIBREF4": {"title": "A rapid and sensitive method for the quantitation of microgram 218 quantities of protein utilizing the principle of protein-dye binding", "authors": [{"first": "M", "middle": ["M"], "last": "Bradford", "suffix": ""}], "year": 1976, "venue": "Anal. Biochem", "link": null}, "BIBREF5": {"title": "Adaptive evolution of the histone fold domain in 221 centrometric histones", "authors": [{"first": "J", "middle": ["L"], "last": "Cooper", "suffix": ""}, {"first": "S", "middle": [], "last": "Henikoff", "suffix": ""}], "year": 2004, "venue": "Mol. Biol. Evol", "link": null}, "BIBREF8": {"title": "Nanoarchaeum equitans and Ignicoccus hospitalis: new 243 insights into a unique, intimate association of two archaea", "authors": [{"first": "H", "middle": [], "last": "Rachel", "suffix": ""}, {"first": "", "middle": [], "last": "Huber", "suffix": ""}], "year": 2008, "venue": "J. Bacteriol", "link": "5157775"}, "BIBREF9": {"title": "Translating the histone code", "authors": [{"first": "T", "middle": [], "last": "Jenuwein", "suffix": ""}, {"first": "C", "middle": ["D"], "last": "Allis", "suffix": ""}], "year": 2001, "venue": "Science", "link": "1883924"}, "BIBREF10": {"title": "MJ1647 encodes a 247 very thermostable archaeal histone with a C-terminal extension in the hyperthermophile with GA were separated by SDS-PAGE and stained using Commassie brilliant blue", "authors": [{"first": "W-T", "middle": [], "last": "Li", "suffix": ""}, {"first": "K", "middle": [], "last": "Sandman", "suffix": ""}, {"first": "S", "middle": ["L"], "last": "Pereira", "suffix": ""}, {"first": "J", "middle": ["N"], "last": "Reeve", "suffix": ""}], "year": 2000, "venue": "", "link": null}, "BIBREF11": {"title": "Control lanes contained untreated pUC18 DNA (-) and DNA size standards (S, 250 to 343 3000 bp; s, 50 to 1000 bp)", "authors": [], "year": "", "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "41514267", "_pdf_hash": "c4226cc8c1a235c87e2fbe39273544af1f17d82c", "abstract": [{"section": "Abstract", "text": "Many researchers require a high resolution trigger to synchronize their data gathering electronics with the arrival of a synchrotron radiation pulse at their target. At the Advanced Light Source (ALS), this requirement was initially satisfied in a case by case manner by running Heliax cables from the Accelerator Timing System[ 11 to the various experiment locations. This approach was less than ideal due to poor risetimes, cost and difficulty of running Heliax cables, and the inconvenience of fixed timing. A new system has been installed at ALS that provides the researcher with a high quality, adjustable delay fiducial trigger, and a low level sample of the Accelerator RF (499.66 Mhz). The Ring Orbit Clock (1.523 Mhz) is distributed from the Accelerator Timing System to the various experiment locations using inexpensive twisted pair cable, where it is processed by a Phase Locked Loop Multiplier and High Speed Logic to integrate out noise/jitter and to produce the desired signals. Local drivers provide the researcher with sharp edged robust triggers.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "INTRODUCTION", "text": "High resolution timing signals degrade as they are transported from their source to the timing user. Both high frequency losses and dispersion effects take their toll in the sharpness and accuracy of the product. These effects can be minimized by using higher grade transmission lines, but these lines are both expensive and awkward to handle. Noise, resulting in apparent jitter, is added by ground loop and inductive mechanism to further degrade the signal. Since ALS houses about 6000 square meters of experimental floor, a means of wide distribution, without excessive cost, was needed.", "cite_spans": [], "ref_spans": []}, {"section": "CONCEPT", "text": "Since ALS timing is strictly periodic, a solution that employs a low resolution fiducial that is processed in the user-end equipment to improve its quality is acceptable.", "cite_spans": [], "ref_spans": []}, {"section": "CONCEPT", "text": "' mpfahmie@lbl.gov Clearly, a signal can be distributed at much lower cost if significant degradation can be tolerated, this is the basis of my solution.", "cite_spans": [], "ref_spans": []}, {"section": "CONCEPT", "text": "Instead of distributing the accelerator RF signal (499.66 MHz), I use its 328\" subharmonic, the Storage Ring Orbit Clock (SROC), at 1.523 MHz. This moderately low frequency can easily be distributed over inexpensive twisted pair cable and general purpose fiber optic links.", "cite_spans": [], "ref_spans": []}, {"section": "CONCEPT", "text": "This signal, along with any phase and amplitude noise that it may have acquired in the course of distribution, is used as a reference signal to a Phase Locked Loop[2,3] (PLL) frequency multiplier that reproduces the desired 499.66 Mhz clock. If the PLL loop filter bandwidth is sufficiently narrow, then the noise integrates out and the quality of the output is primarily dependent on the quality of the PLL Voltage Controlled Oscillator (VCO).", "cite_spans": [], "ref_spans": []}, {"section": "DESIGN CONSIDERATIONS", "text": "Since low jitter is a primary goal, some effort was put into selection of the VCO. Oscillator jitter is a strong function of the loaded Q of the oscillator resonator [4] , so an oscillator employing a high Q resonator was desirable. Since Quartz resonators typically possess Q's a thousand times those typical of LC oscillators, several crystal controlled VCO's (VCXO) were evaluated. A small module from Raltron Inc.", "cite_spans": [], "ref_spans": []}, {"section": "DESIGN CONSIDERATIONS", "text": "[5] was chosen for its low jitter and comparatively low cost.", "cite_spans": [], "ref_spans": []}, {"section": "DESIGN CONSIDERATIONS", "text": "Although long term stability is controlled by the reference signal, temperature variations in an early prototype produced large phase offsets. These offsets were traced to the temperature sensitivity of the threshold voltage in the digital logic and its effect on the relatively slow risetime of the reference signal, later versions utilize the fully differential features of the ECL logic family to eliminate this phase error.", "cite_spans": [], "ref_spans": []}, {"section": "DESIGN CONSIDERATIONS", "text": "The loop bandwidth is set at 10 Hz in order to use as much of the short term stability of the VCXO as possible. Such narrow bandwidths can make it difficult to achieve initial phase lock if a simple phase comparator is used. This manufacturer has solved a deadband problem that existed in phaselfrequency comparators of other designs. An additional feature of the Analog Devices device is its fully differential input and output structure. This allows us to use differential techniques throughout the phase detecto; and loop amplifier to minimize baseline errors in the analog circuitry.", "cite_spans": [], "ref_spans": []}, {"section": "FEATURES", "text": "The User Timing Chassis provides two output signals; the accelerator RF frequency (499.66 Mhz.) and a user configurable trigger. The user can select 1,2,4, or 8 evenly spaced triggers per storage ring revolution, and he may position these triggers anywhere in the accelerator period in precision steps of one beam bucket.", "cite_spans": [], "ref_spans": []}, {"section": "FEATURES", "text": "The trigger is simultaneously available in Tn, Differential ECL, and NIM. The NIM output features 500 picosecond riselfall time. All output drivers are designed to drive 50 ohm loads, but are also series terminated to minimize reflections when driving a mismatched load.", "cite_spans": [], "ref_spans": []}, {"section": "FEATURES", "text": "Distribution of the reference signal to the various User Timing Chassis around the accelerator is simplified since the only signal that is distributed is a relatively low frequency (1.523 MHz.). The PLL effectively cleanses it of any noise it may have acquired in transit and inexpensive twisted pair wiring is all that is necessary.", "cite_spans": [], "ref_spans": []}, {"section": "PERFORMANCE", "text": "The output of the User Timing Chassis has been compared with a highly filtered signal from the ALS Master Oscillator to evaluate the phase jitter of the regenerated RF signal. The reference signal was routed across the accelerator through cable trays and used a combination of fiber optic and RS-422 twisted pair transmission. A Tektronics CSA-803 Communications analyzer was used to create a jitter histogram. The analyzer's statistical functions indicate that the RMS jitter measured -16 picoseconds.", "cite_spans": [], "ref_spans": []}, {"section": "ACKNOWLEDGMENTS", "text": "The author would like to acknowledge the assistance of Allen Geyer, Moises Balagot, and Ronald Gervasoni of LBNL in the construction, debug, and deployment of this system. ", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Design of the Advanced Light Source Timing System", "authors": [{"first": "M", "middle": [], "last": "Fahmie", "suffix": ""}], "year": "", "venue": "Proceedings of the 1993 IEEE PaRicle Accelerator Conference", "link": "54851326"}, "BIBREF1": {"title": "Phased Locked Laap Design Anicles", "authors": [{"first": "Motomla", "middle": [], "last": "Inc", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF2": {"title": "Servo Techniques in Oscillaton and Measurement Systems", "authors": [{"first": "F", "middle": ["S"], "last": "Walls", "suffix": ""}, {"first": "", "middle": [], "last": "Stein", "suffix": ""}], "year": "", "venue": "", "link": null}}, "ref_entries": {"FIGREF0": {"text": "A fairly new dual mode comparator is now available from 0-7803-5573-3/99/$10.00@ 1999 IEEE..-. . . . . . . . . . . . . . . _. . .", "type": "figure"}, "FIGREF1": {"text": "Figure 1 Analog Devices (AD9901) that begins the lock sequence in the frequency comparator mode and automatically becomes a phase comparator after frequency lock has occurred. This manufacturer has solved a deadband problem that existed in phaselfrequency comparators of other designs. An additional feature of the Analog Devices device is its fully differential input and output structure. This allows us to use differential techniques throughout the phase detecto; and loop amplifier to minimize baseline errors in the analog circuitry.", "type": "figure"}, "FIGREF2": {"text": "Figure 2 -Block Diagram", "type": "figure"}}}
{"paper_id": "41514438", "_pdf_hash": "99ce7e1009b2ae88b07ff9cb53db1295c9dbf850", "abstract": [], "body_text": [], "bib_entries": {"BIBREF24": {"title": "Stably transfected EL-4 cells (5 \u00d7 10 5 cells) were mixed with 100 ng (blue line) or 500 ng (red line) of rIL-33 for 1 h. Binding of rIL-33 was detected with biotinylated anti-T7-tag antibody and RPE-conjugated streptavidin. The gray-filled histogram shows unstained cells. B and C, The data of clone numbers 1-1-A-3 (EV/EL-4 cells", "authors": [], "year": "", "venue": "Binding analysis of rIL-33 to EL-4 cells", "link": null}, "BIBREF25": {"title": "Analysis of interaction between ST2-V5 and rIL-33, or rIL-1\u03b2. ST2-V5 (500 ng) was mixed with rIL-33 or rIL-1\u03b2 (2 \u00b5g) in RIPA buffer. The protein complexes were immunoprecipitated with anti-T7-tag antibody-conjugated agarose (IP: \u03b1T7). The proteins were eluted with 0.1 M citric acid (pH 2.2) and neutralized with 2 M Tris (pH 10.4), followed by western blotting with anti-V5 (\u03b1V5) and anti-T7-tag (\u03b1T7) antibodies. Input was analyzed by western blotting with anti-His antibody (\u03b1His) using 1/20 volumes of reaction mixture. Single and double asterisks indicate heavy and light chains of immunogloblin, respectively. A and B, Protein size is indicated in kDa at the left. C, Effect of ST2-V5 on binding activity of rIL-33 or rIL-1\u03b2. Stably transfected EL-4 cells (5 \u00d7 10 5 cells) were either left untreated or treated with ST2-V5 (1 \u00b5g) for 1 h, then rIL-33 or rIL-1\u03b2 (100 ng) was admixed for 1 h. Binding of rIL-33 or rIL-1\u03b2 was detected with biotinylated anti-T7-tag antibody and RPE-conjugated streptavidin. Upper panel, Binding of rIL-33 to ST2L/EL-4 cells (clone, 1-2-G-12). Lower panel, Binding of rIL-1\u03b2 to IL-1RI/EL-4 cells (clone, 3-2-A-8). Blue-and orange-lined histograms represent cells untreated or treated with ST2-V5, respectively. The gray-filled histogram shows", "authors": [], "year": "", "venue": "Analysis of purified recombinant soluble ST2. Purified ST2-V5 and ST2-FLAG (100 ng) were left untreated or treated with PNGase F. Proteins were separated on SDS-10% polyacrylamide gel, followed by silver staining. Glycosylated and deglycosylated proteins are indicated by black and gray arrowheads, respectively. PNGase F is indicated by a white arrowhead. B", "link": null}, "BIBREF26": {"title": "ST2-V5 for 1 h alone (-/ ST2)", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF27": {"title": "rIL-33 for 1 h alone", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF28": {"title": "rIL-33 for 1 h prior to ST2-V5 for another 1 h (IL-33 / ST2)", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF29": {"title": "ST2-V5 and rIL-33 at the same time for 1 h (ST2 + IL-33)", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF30": {"title": "ST2-V5 for 1 h prior to rIL-33 for another 1 h (ST2 / IL-33)", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF31": {"title": "Cytoplasmic extracts were separated on SDS-12.5% polyacrylamide gels, followed by western blotting with anti-I\u03baB\u03b1 and anti-GAPDH antibodies. B, Supershift assay using anti-NF-\u03baB antibodies. Nuclear extracts were kept on ice for 1 h without antibody (lanes 2 and 7) or with a series of anti-NF-\u03baB antibodies (lanes 3 -6 and 8 -11), and then the 32 P-labeled oligonucleotide probe was admixed. The mixture was kept at 30 \u02daC for 30 min, then subjected to EMSA. C, Suppression of DNA-binding activity of NF-\u03baB by the addition of ST2-V5. Stably transfected EL-4 cells were either left untreated or treated with ST2-V5 (10 ng and 100 ng) for 3 h, and then left unstimulated or stimulated with rIL-33 or rIL-1\u03b2 for 30 min. After stimulation, cytoplasmic and nuclear extracts were prepared. a, DNA-binding activity of NF-\u03baB was analyzed by EMSA. b, Degradation of I\u03baB\u03b1 was analyzed by western blotting. Lane 1 of A-a, B, and C-a contained the 32 P-labeled oligonucleotide probe alone. The DNA/NF-\u03baB and supershifted complexes are indicated by white, gray (supershifted by \u03b1p50), and black (supershifted by \u03b1p65) arrowheads, respectively. D, Transcriptional activity of rIL-33-or rIL-1\u03b2-induced NF-\u03baB", "authors": [], "year": "", "venue": "Suppression of IL-33-induced NF-\u03baB activation by soluble ST2. A, Analysis of intracellular responses in the IL-33 and IL-1\u03b2 signalings. Stably transfected EL-4 cells (2 \u00d7 10 7 cells) were either left unstimulated or stimulated with rIL-33 or rIL-1\u03b2", "link": null}, "BIBREF32": {"title": "ng/ml) for 24 h. The cells were harvested and subjected to luciferase assay. Firefly luciferase activity was normalized with renilla luciferase activity, and the luciferase activity of the untreated and unstimulated cells was given a reference value of 1. Data are shown as means \u00b1 SEM from four independent experiments (**p < 0.01, IL-33 alone versus ST2 plus IL-33)", "authors": [], "year": "", "venue": "then either left unstimulated or stimulated with rIL-33 or rIL-1\u03b2", "link": null}, "BIBREF33": {"title": "Level of soluble ST2 in sera after aeroallergen challenge. Mice were sensitized with saline and challenged with OVA (SAL/OVA), sensitized and challenged with OVA (OVA/OVA), sensitized and challenged with saline (SAL/SAL), or sensitized with OVA and challenged with saline (OVA/SAL). Sera were obtained at 24 h after the last aeroallergen challenge. Concentration of soluble ST2 was measured by sandwich ELISA", "authors": [], "year": "", "venue": "Expression of soluble ST2 and ST2L in a murine model of asthma. A", "link": null}, "BIBREF34": {"title": "Expression analysis of ST2L in splenocytes. Splenocytes were prepared from SAL/OVA and OVA/OVA mice at 24 h after the last OVA challenge", "authors": [{"first": "Ova", "middle": [], "last": "**p &lt; ;", "suffix": ""}, {"first": "Sal", "middle": ["/"], "last": "Ova", "suffix": ""}, {"first": "Sal", "middle": [")"], "last": "Sal", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF35": {"title": "\u00d7 10 6 cells) were stained with FITC-conjugated anti-mouse T1/ST2 antibody (solid line), and then analyzed by flow cytometry. The thin-lined histogram shows unstained cells. Percentages of ST2L-positive splenocytes are shown as means \u00b1 SEM (n = 8 mice", "authors": [{"first": "", "middle": [], "last": "Splenocytes", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF36": {"title": "RT-PCR analysis of expression of ST2, ST2L, and IL-33 mRNAs in tissues of asthmatic mice. DNase Itreated total RNAs were prepared from tissues of untreated mice (control; C) and OVA/OVA mice at the indicated time shown above each lane (3 -48 h) after the last OVA challenge, and then were subjected to RT-PCR analysis. Beta-actin was detected as an internal control. PCR products were separated on 2% agarose gels. The data show one of three independent experiments. B, Kinetic analysis of expression of ST2, ST2L, and IL-33 mRNAs. Densitometric analysis was performed using the public domain NIH image program. Expression of ST2, ST2L, and IL-33 mRNAs was normalized with that of \u03b2-actin mRNA, and expression of control mice was given a reference value of 1", "authors": [], "year": "", "venue": "Expression of ST2, ST2L, and IL-33 mRNAs after the last OVA challenge. A", "link": null}, "BIBREF37": {"title": "Suppression of Th2 cytokine production from IL-33-stimulated splenocytes of asthmatic mice. A, Binding analysis of rIL-33 to splenocytes by flow cytometry. Splenocytes were prepared from SAL/OVA and OVA/OVA mice at 24 h after the last OVA challenge", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF38": {"title": "RPE-conjugated streptavidin, and FITC-conjugated antimouse T1/ST2 antibody. Percentages of IL-33-bound ST2L-positive splenocytes are shown as means \u00b1 SEM (n = 8 mice in SAL/OVA, n = 9 mice in OVA/OVA; *p < 0.05, OVA/OVA versus SAL/OVA). B, Schematic diagram for stimulation of splenocytes. Splenocytes were prepared from SAL/OVA and OVA/OVA mice at 24 h after the last OVA challenge. Stimulation of splenocytes was performed as described in \"Experimental Procedures", "authors": [{"first": "", "middle": [], "last": "Splenocytes", "suffix": ""}], "year": "", "venue": "\u00d7 10 6 cells) were mixed with rIL-33 (1 \u00b5g) for 1 h. The splenocytes were stained with biotinylated anti-T7-tag antibody", "link": null}, "BIBREF39": {"title": "IL-33 alone versus ST2 plus IL-33 in splenocytes of OVA/OVA mice, ND = not detected for below detectable limits)", "authors": [{"first": "", "middle": [], "last": "**p &lt; 0", "suffix": ""}], "year": "", "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "41515024", "_pdf_hash": "a46a6747feadbfcbf5a1c96aa8ab58d96b04c6d2", "abstract": [], "body_text": [{"section": "388", "text": "Sexual Abuse: A Journal of Research and Treatment 22(4) assessment of these women remains as problematic as the assessment of male sexual offenders was 20 years ago. Reliable estimates of the recidivism base rates of female sexual offenders would be a valuable aid to applied decision makers. Providing these estimates is the primary goal of this study.", "cite_spans": [], "ref_spans": []}, {"section": "Prevalence of Sexual Offending by Women", "text": "The prevalence rate of female sexual offending is difficult to ascertain. Some authors believe that sexual offending by females is relatively common but that its extent is unknown because of the lack of reporting or because these women tend to be diverted from the criminal justice system (Vandiver & Walker, 2002) . Others suggest that sexual offending by women is likely to be underidentified because of societal and cultural stereotypes of female sexual behavior, including professional biases (Denov, 2003 (Denov, , 2004 Giguere & Bumby, 2007) .", "cite_spans": [{"start": 289, "end": 314, "text": "(Vandiver & Walker, 2002)", "ref_id": "BIBREF46"}, {"start": 497, "end": 509, "text": "(Denov, 2003", "ref_id": "BIBREF10"}, {"start": 510, "end": 524, "text": "(Denov, , 2004", "ref_id": "BIBREF11"}, {"start": 525, "end": 547, "text": "Giguere & Bumby, 2007)", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "Prevalence of Sexual Offending by Women", "text": "In efforts to provide more systematic information about the prevalence of female sexual offenders, in comparison with male sexual offenders, Cortoni and Hanson (2005; Cortoni, Hanson, & Coache, 2009 ) estimated the proportion of sexual offenders who are women from two general sources of information. The first source of information was official police or court reports that detailed the gender of the offender. The second source of information was victimization surveys. For both sources, information was available for Australia, Canada, New Zealand, the United Kingdom, and the United States. Results from the updated 2009 review were consistent with the earlier 2005 findings. Based on official records, the proportion of all sexual offenders who were female ranged from 0.6% in New Zealand to 8.7% for nonrape sexual offenders in the United States. When these numbers were averaged across all countries in the study, women constituted 4.6% of all sexual offenders. Based on victimization studies, the proportion of sexual offenders who were female ranged from 3.1% for New Zealand to 7.0% for Australia, an average of 4.8%.", "cite_spans": [{"start": 141, "end": 166, "text": "Cortoni and Hanson (2005;", "ref_id": "BIBREF8"}, {"start": 167, "end": 198, "text": "Cortoni, Hanson, & Coache, 2009", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "Prevalence of Sexual Offending by Women", "text": "In summary, available data indicate that women constitute approximately 5% of all sexual offenders. To place this number in a more concrete societal context, it is useful to estimate their proportion in real terms. To establish an overall international figure of the prevalence of child sexual abuse, Pereda, Guilera, Forns, and G\u00f3mez-Benito (2009) conducted a meta-analysis of its prevalence in 22 countries. Their results showed that nearly 8% of men and 20% of women had been sexually victimized prior to age 18. If 4% to 5% of all these victims were sexually abused by women, this would mean that 1.4% of all child victims were sexually abused by women. These findings indicate that sexual offending by women is significant enough to warrant systematic attention.", "cite_spans": [{"start": 301, "end": 348, "text": "Pereda, Guilera, Forns, and G\u00f3mez-Benito (2009)", "ref_id": "BIBREF38"}], "ref_spans": []}, {"section": "Prevalence of Sexual Offending by Women", "text": "It is important to note, however, that despite the increased recent attention paid to sexual offending by women, we cannot say that sexual offending by women is actually a growing phenomenon. For example, in Canada, between 1994 and 2003 , the yearly rate of women accused of sexual assault has consistently been between 1% and 2% of all accused of sexual offences (Statistics Canada, 2007) . Instead, sexual offending by women appears to have been a long underrecognized issue, which is finally coming to the forefront in the field. The increased attention to female sexual offenders motivates the need for empirical evidence to inform the assessment, treatment, and management of these women.", "cite_spans": [{"start": 233, "end": 237, "text": "2003", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "The Importance of Base Rates", "text": "The evaluation of risk of recidivism requires knowledge of static and dynamic risk factors that have been empirically linked to sexual offending. Much is known about risk factors among male sexual offenders (e.g., Hanson & Morton-Bourgon, 2005) , but very little is known about the factors linked to sexual offending among women (Hedderman, 2004; Kemshall, 2004) . To establish this knowledge, systematic information about the recidivism rates of the population is required.", "cite_spans": [{"start": 214, "end": 244, "text": "Hanson & Morton-Bourgon, 2005)", "ref_id": "BIBREF20"}, {"start": 329, "end": 346, "text": "(Hedderman, 2004;", "ref_id": "BIBREF23"}, {"start": 347, "end": 362, "text": "Kemshall, 2004)", "ref_id": "BIBREF31"}], "ref_spans": []}, {"section": "The Importance of Base Rates", "text": "Base rates are the proportion of the population that exhibits the phenomenon of interest. Understanding the base rates of recidivism is fundamental to the evaluation of risk of future offending (Hanson & Bussi\u00e8re, 1998; Quinsey, Lalumi\u00e8re, Rice, & Harris, 1995) . Recidivism rates vary according to factors such as jurisdictions, types of crimes being measured, length of time of follow-up, and how they were measured. Among male sexual offenders, research has shown that recidivism rates, with a follow-up period of 5 years, are 13.5% for new sexual offenses, 25.5% for violent (including sexual) offenses, and 36% for any type of recidivism (Hanson & MortonBourgon, 2004) .", "cite_spans": [{"start": 194, "end": 219, "text": "(Hanson & Bussi\u00e8re, 1998;", "ref_id": "BIBREF17"}, {"start": 220, "end": 261, "text": "Quinsey, Lalumi\u00e8re, Rice, & Harris, 1995)", "ref_id": "BIBREF41"}], "ref_spans": []}, {"section": "The Importance of Base Rates", "text": "After years of neglect, research into the recidivism rates of female sexual offenders has started to receive attention. Cortoni and Hanson's (2005) review found that the recidivism rates of female sexual offenders are generally low. The number of female offenders included in that review, however, was small (total of 380); a number of large sample studies have appeared since that review was complete. Also, Cortoni and Hanson (2005) did not provide a meta-analytic summary of recidivism rates, such that it was impossible to know whether the variability across studies was significant. Consequently, the current study provides an updated, meta-analytic review of the empirical literature concerning the recidivism rates of female sexual offenders.", "cite_spans": [{"start": 120, "end": 147, "text": "Cortoni and Hanson's (2005)", "ref_id": "BIBREF8"}, {"start": 409, "end": 434, "text": "Cortoni and Hanson (2005)", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "Method", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Selection of Studies", "text": "Studies included conference presentations, government reports, official recidivism data drawn from websites or through direct communication with government agencies, and reports of unpublished studies obtained directly from the researchers. Recidivism studies were included if they identified the gender of the offenders and provided a follow-up period. As necessary, clarifications of the data were obtained by directly contacting the authors of the studies included in this review. For example, to ensure accurate coding of recidivism rates of the Sandler and Freeman (2009) (4) offenses or not. There were times, however, that such verifications were impossible. In these circumstances, only clearly identifiable recidivism rates were included in the study. As a result, not all types of recidivism were present in every study.", "cite_spans": [{"start": 550, "end": 576, "text": "Sandler and Freeman (2009)", "ref_id": "BIBREF43"}], "ref_spans": []}, {"section": "Selection of Studies", "text": "For this review, recidivism was defined as being arrested, charged, convicted, or incarcerated for a new offense. Sexual recidivism included a new charge, conviction, or reincarceration for a sexual offence. Violent recidivism was defined as a new violent charge, conviction, or incarceration for a new violent offense (including sexual offences). Any recidivism was defined as any new charge, conviction, or incarceration. Consequently, the categories of recidivism are cumulative rather than mutually exclusive.", "cite_spans": [], "ref_spans": []}, {"section": "Selection of Studies", "text": "The search yielded two published studies (Broadhurst & Loh, 2003; Sandler & Freeman, 2009) , two government reports (Hanson, Harris, Scott, & Helmus, 2007; Minnesota Department of Corrections, 2007) , four conference presentations (Peterson, Colebank, & Motta, 2001; Vandiver, 2007; Wijkman, Zoutewelle-Terovan, & Bijleveld, 2009; Williams & Nicholaichuk, 2001) , and two official sources of recidivism data (Holley & Ensley, 2003, Florida State, United States; Home Office, 1998 -2003 . Table 1 provides a summary of these studies; additional comments about these studies are provided below.", "cite_spans": [{"start": 66, "end": 90, "text": "Sandler & Freeman, 2009)", "ref_id": "BIBREF43"}, {"start": 116, "end": 155, "text": "(Hanson, Harris, Scott, & Helmus, 2007;", "ref_id": "BIBREF18"}, {"start": 231, "end": 266, "text": "(Peterson, Colebank, & Motta, 2001;", "ref_id": "BIBREF39"}, {"start": 283, "end": 330, "text": "Wijkman, Zoutewelle-Terovan, & Bijleveld, 2009;", "ref_id": "BIBREF48"}, {"start": 331, "end": 361, "text": "Williams & Nicholaichuk, 2001)", "ref_id": "BIBREF49"}, {"start": 480, "end": 485, "text": "-2003", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "Selection of Studies", "text": "Broadhurst and Loh (2003) 11.5 (7) 32.8 (20) Nicholaichuk (2001) Note: \"-\", no information available. ", "cite_spans": [], "ref_spans": []}, {"section": "Aggregation of Findings", "text": "The basic effect size indicator was p, the proportion of recidivists (i.e., the number of recidivists divided by n, the sample size). Although raw proportions are easily interpreted, they have certain limitations as effect size indicators for meta-analysis. Using the standard formula, the variance of p is estimated as p(1 -p)/n (Fleiss, Levin, & Paik, 2003) . This variance is small in two quite different circumstances: (a) when the same size is very large and (b) when sample size is so small that there are no recidivists. This formula also assumes that the variance decreases as the proportions approach zero, which has the effect of giving the most weight to studies with the smallest recidivism rates.", "cite_spans": [{"start": 330, "end": 359, "text": "(Fleiss, Levin, & Paik, 2003)", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "Aggregation of Findings", "text": "Given the problems with analyzing raw proportions from different studies, variance stabilization transformations are recommended (Cohen, 1988; Eisenhart, 1947; Fleiss et al., 2003) . The most common variance stabilization transformation for proportions is the arcsine transformation, which we will denote by \u0102, defined as \u0102 = 2 arcsin\u221aP, with a variance of 1/n. In other words, the variance of \u0102 depends only on the sample size and not on the size of the proportion. Consequently, analyses were conducted using both the raw proportions and the transformed proportions. All results were reported as proportions, however, because \u0102 in its original units (radians) is not easily interpreted.", "cite_spans": [{"start": 129, "end": 142, "text": "(Cohen, 1988;", "ref_id": "BIBREF5"}, {"start": 143, "end": 159, "text": "Eisenhart, 1947;", "ref_id": "BIBREF12"}, {"start": 160, "end": 180, "text": "Fleiss et al., 2003)", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "Aggregation of Findings", "text": "To analyze studies in which there were no recidivists for certain categories (Broadhurst & Loh, 2003; Hanson et al., 2007; Peterson et al., 2001) , the recidivism rate (p) was estimated as 1/4n (i.e., Bartlett's adjustment, see Eisenhart, 1947; Cohen, 1988) .", "cite_spans": [{"start": 102, "end": 122, "text": "Hanson et al., 2007;", "ref_id": "BIBREF18"}, {"start": 123, "end": 145, "text": "Peterson et al., 2001)", "ref_id": "BIBREF39"}, {"start": 228, "end": 244, "text": "Eisenhart, 1947;", "ref_id": "BIBREF12"}, {"start": 245, "end": 257, "text": "Cohen, 1988)", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Aggregation of Findings", "text": "The magnitude and consistency of recidivism rates across studies were calculated using both fixed-effect and random-effects models (Hedges & Vevea, 1998) . Each approach asks slightly different questions and neither approach has won universal acceptance (Whitehead, 2002) . On a conceptual level, the conclusions of the fixedeffect analyses are restricted to the particular set of studies included in the meta-analysis. In contrast, the random-effects model aims for conclusions that apply to the population of studies of which the current sample of studies is a part. In practical terms, the randomeffects model includes an additional between-study error term representing the unexplained variation across studies (a constant). Compared with the fixed-effect model, the random-effects model has higher variance estimates (wider confidence intervals), and the differences in sample size across the studies is given less importance. Consequently, the random-effects model gives relatively more weight to small studies than does the fixed-effect model (approximating unweighted averages).", "cite_spans": [{"start": 131, "end": 153, "text": "(Hedges & Vevea, 1998)", "ref_id": "BIBREF26"}, {"start": 254, "end": 271, "text": "(Whitehead, 2002)", "ref_id": "BIBREF51"}], "ref_spans": []}, {"section": "Aggregation of Findings", "text": "When the assumptions are violated, the fixed-effect model is too liberal and the random-effects model is too conservative (Overton, 1998) . The results of the randomeffects and fixed-effect models converge as the amount of between-study variability decreases. When the variation between studies is less than would be expected by chance (Q < degrees of freedom, using Cochran's Q statistic; Hedges & Olkin, 1985) , both approaches yield identical results. To test the generalizability of fixed effects across studies, the Q statistic was used:", "cite_spans": [{"start": 122, "end": 137, "text": "(Overton, 1998)", "ref_id": "BIBREF37"}, {"start": 390, "end": 411, "text": "Hedges & Olkin, 1985)", "ref_id": "BIBREF25"}], "ref_spans": []}, {"section": "Aggregation of Findings", "text": "where p i is the observed proportion in each of k studies and p. is the weighted average. The Q statistic is distributed as a c 2 with k -1 degrees of freedom (k is the number of studies). A significant Q statistic indicates that there is more variability across studies than would be expected by chance. In such cases, further examinations of the data were conducted to establish whether an outlier could be identified. An individual finding was considered to be an outlier if (a) it was an extreme value (highest or lowest), (b) the Q statistic was significant, and (c) the single finding accounted for more than 50% of the value of the Q statistic. When an outlier was detected, the results are reported with and without the exceptional case.", "cite_spans": [], "ref_spans": []}, {"section": "Aggregation of Findings", "text": "Fixed-effect estimates of recidivism rates were calculated using the formula and procedures presented in Hedges (1994) . Random-effects estimates were calculated using Formulae 10, 12, and 14 from Hedges and Vevea (1998) . Hand calculations or SPSS syntax was used for all analyses. Both fixed-effect and random-effects models were estimated for both the raw proportions (p) and the transformed proportions (\u0102).", "cite_spans": [{"start": 105, "end": 118, "text": "Hedges (1994)", "ref_id": "BIBREF24"}, {"start": 197, "end": 220, "text": "Hedges and Vevea (1998)", "ref_id": "BIBREF26"}], "ref_spans": []}, {"section": "Results", "text": "A total of 2,490 offenders with an average follow-up time of 6.5 years were included in this review. Sexual, violent, and any recidivism were examined separately in the analyses. Table 2 presents the weighted averages of recidivism rates across studies. Table 3 and Figure 1 show the results of the meta-analysis of both raw and transformed proportions. ", "cite_spans": [], "ref_spans": [{"start": 179, "end": 186, "text": "Table 2", "ref_id": "TABREF3"}, {"start": 254, "end": 261, "text": "Table 3", "ref_id": "TABREF2"}, {"start": 266, "end": 274, "text": "Figure 1", "ref_id": "FIGREF0"}]}, {"section": "Sexual Recidivism Estimates", "text": "For sexual recidivism, the observed recidivism rates ranged from 0% to 10.8%, with a median value of 1.5%. In the nine studies reporting sexual recidivism rates involving 2,416 female sexual offenders, there were 77 sexual recidivists (3.19%). Fixed-effect analyses of the raw proportions and the transformed proportions produced estimates of 1.24% and 2.43%, respectively. Random-effects analyses produced estimates of 2.43% and 2.33%. The analyses showed a greater variability of recidivism among studies than would be expected by chance, and Vandiver (2007) was identified as an outlier. Once Vandiver was removed, the variability between studies was no more than would be expected by chance (Q < df; see Table 3 ). Without Vandiver, fixed-effect and random-effects estimates were the same: 1.00% for the raw proportions and 1.28% for the transformed proportions.", "cite_spans": [], "ref_spans": [{"start": 708, "end": 715, "text": "Table 3", "ref_id": "TABREF2"}]}, {"section": "Violent Recidivism Estimates", "text": "For violent recidivism, of the seven studies involving 2,260 female sexual offenders, there were 146 violent recidivists (6.46%). The observed violent recidivism rates ranged from 1.2% to 16.6%, with a median value of 9.3%. Fixed-effect analyses of the raw proportions and the transformed proportions produced estimates of 4.41% and 5.81%, respectively. Random-effects analyses produced estimates of 7.57% and 7.43%. There was greater variability in the violent recidivism rates across studies than would be expected by chance, and Vandiver (2007) was again identified as the outlier. When the fixed-effect analyses were repeated without the Vandiver study, variability among studies dropped considerably but remained significant (Q = 12.00 and 13.33, respectively, df = 4, p < .05; see Table 3 ). Without Vandiver, the fixed-effect analyses of the raw proportions and the transformed proportions were 3.65% and 4.08%, respectively. Random-effects estimates were 4.64% and 5.54%, respectively.", "cite_spans": [], "ref_spans": [{"start": 787, "end": 794, "text": "Table 3", "ref_id": "TABREF2"}]}, {"section": "Any Recidivism Estimates", "text": "For any recidivism, of the eight studies involving 2,406 female sexual offenders, there were 590 recidivists (24.42%). The observed rate for recidivism ranged from 11.1% to", "cite_spans": [], "ref_spans": []}, {"section": "396", "text": "Sexual Abuse: A Journal of Research and Treatment 22(4) 45.0%, with a median value of 23.5%. Fixed-effect analyses of the raw proportions and the transformed proportions produced estimates of 22.35% and 23.89%, respectively. Random-effects analyses produced estimates of 23.82% and 23.30%. There was greater variability across studies than would be expected by chance, with Vandiver (2007) being the sole outlier. When the fixed effects analysis was repeated without the Vandiver study, variability among studies dropped considerably but remained significant, Q = 18.61 (raw proportions)] and 18.12 (transformed proportions), df = 6, p < .01; see Table 3 . Without Vandiver, the fixed-effect analyses of the raw proportions and the transformed proportions were 18.96% and 19.40%, respectively. Random-effects estimates were 19.79% and 20.17%, respectively.", "cite_spans": [], "ref_spans": [{"start": 647, "end": 654, "text": "Table 3", "ref_id": "TABREF2"}]}, {"section": "Discussion", "text": "This meta-analytic review found that the recidivism rates of female sexual offenders were much lower for all types of crime than the comparable rates for male sexual offenders. Specifically, the women had extremely low rates of sexual recidivism (between 1% and 3%), regardless of the studies included or the method of analysis. Violent (including sexual) recidivism rates were higher but still low: Depending on whether fixed or random effects were examined, violent recidivism rates ranged from 4% to 8%. In contrast, rates for any type of recidivism were higher, ranging from 19% to 24%. These results provide clear evidence that female sexual offenders, once they have been detected and sanctioned by the criminal justice system, tend not to reengage in sexually offending behavior. Most female sexual offenders are not convicted of any new crimes, and of those who are, they are 10 times more likely to be reconvicted for a nonsexual crime than a sexual crime (\u224820% vs. \u22482%).", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "The low recidivism rates of the female sexual offenders are consistent with previous findings showing that, compared with men, women are less likely to be involved with any type of crime (Barker, 2009; Blanchette & Brown, 2006; Kong & AuCoin, 2008; Langan & Levin, 2002) . Depending on the jurisdictions, women constitute approximately 17% to 23% of all adult offenders, although they constitute only about 10% of all violent offenders and 5% of all sexual offenders (Blanchette & Brown, 2006; Cortoni et al., 2009) . Similarly, women also have lower recidivism rates than males. For offenders released from the Correctional Service of Canada during the 1990s, the 2-year reconviction rate for male offenders ranged between 41% and 44%, compared with rates of 23% to 30% for the female offenders (Bonta, Rugge, & Dauvergne, 2003) . The rate of violent recidivism for the women was half that observed for the men in the Correctional Service of Canada samples (6.7% vs. 13.2%). In the United States, 39.9% of the women had been reconvicted for a new offense versus 47.6% of the men in a 3-year follow-up of 272,111 offenders, including 23,674 women (Langan & Levin, 2002 ).", "cite_spans": [{"start": 187, "end": 201, "text": "(Barker, 2009;", "ref_id": "BIBREF1"}, {"start": 202, "end": 227, "text": "Blanchette & Brown, 2006;", "ref_id": "BIBREF2"}, {"start": 228, "end": 248, "text": "Kong & AuCoin, 2008;", "ref_id": "BIBREF32"}, {"start": 249, "end": 270, "text": "Langan & Levin, 2002)", "ref_id": "BIBREF33"}, {"start": 467, "end": 493, "text": "(Blanchette & Brown, 2006;", "ref_id": "BIBREF2"}, {"start": 494, "end": 515, "text": "Cortoni et al., 2009)", "ref_id": "BIBREF9"}, {"start": 796, "end": 829, "text": "(Bonta, Rugge, & Dauvergne, 2003)", "ref_id": "BIBREF3"}, {"start": 1147, "end": 1168, "text": "(Langan & Levin, 2002", "ref_id": "BIBREF33"}], "ref_spans": []}, {"section": "Discussion", "text": "Women's involvement in crime is generally low. The reasons for this are unclearbut the fact is well established (e.g., Blanchette & Brown, 2006) , and it is particularly true of female sexual offenders (Giguere & Bumby, 2007) . Despite low numbers, women are increasingly coming to the attention of the criminal justice system for sexual offenses, thereby increasing the need for appropriate assessment practices. The accumulating evidence suggests that females have particular vulnerabilities that are linked to their sexually offending behavior. Specifically, social and psychological alienation, along with extensive histories of victimization, are particularly common among female sexual offenders (Comack & Brickey, 2007; Gannon, Rose, & Ward, 2008; Johansson-Love & Fremouw, 2006; Pollock, Mullings, & Crouch, 2002; Sommers & Baskin, 1993; Wijkman & Bijleveld, 2008) . For these women, it is likely that their offending is related to early experiences of severe physical and sexual abuse in combination with biological (e.g., genetic factors; Quinsey, Skilling, Lalumi\u00e8re, & Craig, 2004) and social learning variables (e.g., socialization ; Campbell, Muncer, & Bibel, 2001 ). The precise etiological mechanisms mediating the relationship between victimization and subsequent offending are unknown, as of yet.", "cite_spans": [{"start": 119, "end": 144, "text": "Blanchette & Brown, 2006)", "ref_id": "BIBREF2"}, {"start": 202, "end": 225, "text": "(Giguere & Bumby, 2007)", "ref_id": "BIBREF16"}, {"start": 702, "end": 726, "text": "(Comack & Brickey, 2007;", "ref_id": "BIBREF6"}, {"start": 727, "end": 754, "text": "Gannon, Rose, & Ward, 2008;", "ref_id": "BIBREF15"}, {"start": 755, "end": 786, "text": "Johansson-Love & Fremouw, 2006;", "ref_id": "BIBREF30"}, {"start": 787, "end": 821, "text": "Pollock, Mullings, & Crouch, 2002;", "ref_id": "BIBREF40"}, {"start": 822, "end": 845, "text": "Sommers & Baskin, 1993;", "ref_id": "BIBREF44"}, {"start": 846, "end": 872, "text": "Wijkman & Bijleveld, 2008)", "ref_id": "BIBREF47"}, {"start": 1049, "end": 1093, "text": "Quinsey, Skilling, Lalumi\u00e8re, & Craig, 2004)", "ref_id": "BIBREF42"}, {"start": 1147, "end": 1178, "text": "Campbell, Muncer, & Bibel, 2001", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "Discussion", "text": "In the overall collection of studies included in this meta-analysis, there was greater variability than would be expected by chance. Much of this variability could be explained by the high recidivism rates observed by Vandiver (2007) . Vandiver's (2007) study was the only one in which the sexual recidivism rates were virtually identical for the male and female sexual offenders (11.4% vs. 10.8%, respectively). Vandiver (2007) counted as sexual recidivism any offense that led to the registration of the woman as a sexual offender, as defined by the State of Texas. This definition not only included the sexual offences typical of males, such as child molestation, but also included other types of offences, such as compelling prostitution, kidnapping, and Court or Board ordered registration (D. Vandiver, personal communication, October 14, 2008) . The inclusion of prostitution-related offenses likely inflated the rate of sexual recidivism among the female sexual offenders as this type of offences was only present for the women in the study. Consistent definitions facilitate cumulative knowledge. In the male sexual offender literature, there have been sustained efforts to adopt consistent definitions of what constitutes a sexual crime (e.g., Hanson & Morton-Bourgon, 2004; Harris, Phenix, Hanson, & Thornton, 2003; Quinsey et al., 1995) . In the current study, both the Vandiver (2007) and the Sandler and Freeman (2009) data sets included females who were actually only convicted of prostitutionrelated offenses. In contrast, males with only prostitution-related offenses are typically not viewed as sexual offenders. Future research on female sexual offenders would do well to consider standardizing the definitions of sexual offending by women. In particular, researchers should separate prostitution-related offences committed by females from sexual offences involving sexual acts directed toward victims unable or unwilling to consent (i.e., the sexual offences typical of contemporary samples of male sexual offenders).", "cite_spans": [{"start": 1254, "end": 1284, "text": "Hanson & Morton-Bourgon, 2004;", "ref_id": "BIBREF19"}, {"start": 1285, "end": 1326, "text": "Harris, Phenix, Hanson, & Thornton, 2003;", "ref_id": "BIBREF22"}, {"start": 1327, "end": 1348, "text": "Quinsey et al., 1995)", "ref_id": "BIBREF41"}, {"start": 1406, "end": 1432, "text": "Sandler and Freeman (2009)", "ref_id": "BIBREF43"}], "ref_spans": []}, {"section": "Discussion", "text": "This study demonstrated the value of meta-analysis in summarizing the recidivism rates across studies. Although it is possible to create averages by simply dividing the aggregated total of recidivists by the aggregated total sample size, meta-analysis provides estimates of the stability of the results. Evaluators and policy makers can have the most confidence in results that are consistent across studies. When there is 398 Sexual Abuse: A Journal of Research and Treatment 22(4) meaningful variation across studies, meta-analysis can identify statistical outliers and moderator variables. Furthermore, meta-analysis will have an essential role in the identification of recidivism risk factors for female sexual offenders. Given the low recidivism rates, very large samples are needed to identify factors that distinguish the recidivists from the nonrecidivists, samples that can most easily be obtained by accumulating female sexual offenders from different settings.", "cite_spans": [], "ref_spans": []}, {"section": "Implications for Applied Risk Assessment", "text": "The low base rates of sexual recidivism among female sexual offenders means that risk assessment tools for male sexual offenders will overestimate the recidivism risk of female sexual offenders. Consequently, they should not be used in applied decision making. Given that general (i.e., nonsexual) recidivism is much more common among female sexual offenders than sexual recidivism, evaluators should consider the use of tools validated to assess risk of general and violent (nonsexual) recidivism among these women (e.g., Level of Service Inventory-Revised; Andrews & Bonta, 1995) . Even the use of general risk assessment tools, however, requires an understanding of the general research on risk factors and recidivism among female offenders (e.g., Blanchette & Brown, 2006; Folsom & Atkinson, 2007; Holtfreter & Cupp, 2007; Manchak, Skeem, Douglas, & Siranosian, 2009) .", "cite_spans": [{"start": 751, "end": 776, "text": "Blanchette & Brown, 2006;", "ref_id": "BIBREF2"}, {"start": 777, "end": 801, "text": "Folsom & Atkinson, 2007;", "ref_id": "BIBREF14"}, {"start": 802, "end": 826, "text": "Holtfreter & Cupp, 2007;", "ref_id": "BIBREF28"}, {"start": 827, "end": 871, "text": "Manchak, Skeem, Douglas, & Siranosian, 2009)", "ref_id": "BIBREF35"}], "ref_spans": []}, {"section": "Implications for Applied Risk Assessment", "text": "If the evaluation question specifically concerns the risk for sexual recidivism (e.g., Sexual Violent Predator laws in the United States), then the risk factors must be so blatant that they overcome the presumption of low risk for sexual recidivism implied by the observed base rates. The risk factors for sexual recidivism among females are unknown but could plausibly include the same three general factors generally identified for males (i.e., sexual deviancy, antisociality, intimacy deficits). Research to date, however, indicates that the ways in which these factors manifest themselves in female sexual offenders are different from the typical patterns found in male sexual offenders (see Cortoni, in press , for a review). In addition, the extent to which these factors actually play a role in sexual recidivism among women remains an open question.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "The psychology of criminal conduct", "authors": [{"first": "D", "middle": ["A"], "last": "Andrews", "suffix": ""}, {"first": "J", "middle": [], "last": "Bonta", "suffix": ""}], "year": 2006, "venue": "", "link": "143961121"}, "BIBREF1": {"title": "Women and the criminal justice system: A Canadian perspective", "authors": [{"first": "J", "middle": [], "last": "Barker", "suffix": ""}], "year": 2009, "venue": "", "link": null}, "BIBREF2": {"title": "The assessment and treatment of women offenders: An integrated perspective", "authors": [{"first": "K", "middle": [], "last": "Blanchette", "suffix": ""}, {"first": "S", "middle": ["L"], "last": "Brown", "suffix": ""}], "year": 2006, "venue": "", "link": null}, "BIBREF3": {"title": "The reconviction rate of federal offenders (User Report No. 2003-03)", "authors": [{"first": "J", "middle": [], "last": "Bonta", "suffix": ""}, {"first": "T", "middle": [], "last": "Rugge", "suffix": ""}, {"first": "M", "middle": ["; R"], "last": "Dauvergne", "suffix": ""}, {"first": "N", "middle": [], "last": "Loh", "suffix": ""}], "year": 2003, "venue": "Criminal Behaviour and Mental Health", "link": null}, "BIBREF4": {"title": "Women and crime: An evolutionary approach", "authors": [{"first": "A", "middle": [], "last": "Campbell", "suffix": ""}, {"first": "S", "middle": [], "last": "Muncer", "suffix": ""}, {"first": "D", "middle": [], "last": "Bibel", "suffix": ""}], "year": 2001, "venue": "Aggression and Violent Behavior", "link": "143637194"}, "BIBREF5": {"title": "Statistical power analysis for the behavioural sciences", "authors": [{"first": "J", "middle": [], "last": "Cohen", "suffix": ""}], "year": 1988, "venue": "", "link": null}, "BIBREF6": {"title": "Constituting the violence of criminalized women", "authors": [{"first": "E", "middle": [], "last": "Comack", "suffix": ""}, {"first": "S", "middle": [], "last": "Brickey", "suffix": ""}], "year": 2007, "venue": "Canadian Journal of Criminology and Criminal Justice", "link": "144792809"}, "BIBREF7": {"title": "Female sexual offenders: Theory, assessment, and treatment", "authors": [{"first": "F", "middle": [], "last": "Cortoni", "suffix": ""}], "year": "", "venue": "", "link": "144675481"}, "BIBREF8": {"title": "A review of the recidivism rates of adult female sexual offenders (Research Rep. No. R-169)", "authors": [{"first": "F", "middle": [], "last": "Cortoni", "suffix": ""}, {"first": "R", "middle": ["K"], "last": "Hanson", "suffix": ""}], "year": 2005, "venue": "", "link": null}, "BIBREF9": {"title": "Les d\u00e9linquantes sexuelles: Pr\u00e9valence et r\u00e9cidive [Female sexual offenders: Prevalence and recidivism", "authors": [{"first": "F", "middle": [], "last": "Cortoni", "suffix": ""}, {"first": "R", "middle": ["K"], "last": "Hanson", "suffix": ""}, {"first": "M", "middle": ["E"], "last": "Coache", "suffix": ""}], "year": 2009, "venue": "Revue internationale de criminologie et de police technique et scientifique, LXII", "link": null}, "BIBREF10": {"title": "The myth of innocence: sexual scripts and the recognition of child sexual abuse by female perpetrators", "authors": [{"first": "M", "middle": ["S"], "last": "Denov", "suffix": ""}], "year": 2003, "venue": "Journal of Sex Research", "link": "41459407"}, "BIBREF11": {"title": "Perspectives on female sex offending", "authors": [{"first": "M", "middle": ["S"], "last": "Denov", "suffix": ""}], "year": 2004, "venue": "", "link": null}, "BIBREF12": {"title": "Selected techniques of statistical analysis for scientific and industrial research and production and management engineering", "authors": [{"first": "C", "middle": [], "last": "Eisenhart", "suffix": ""}], "year": 1947, "venue": "", "link": "110626349"}, "BIBREF13": {"title": "Statistical methods for rates and proportions", "authors": [{"first": "J", "middle": ["L"], "last": "Fleiss", "suffix": ""}, {"first": "B", "middle": [], "last": "Levin", "suffix": ""}, {"first": "M", "middle": ["C"], "last": "Paik", "suffix": ""}], "year": 2003, "venue": "", "link": null}, "BIBREF14": {"title": "The generalizability of the LSI-R and the CAT to the prediction of recidivism in female offenders", "authors": [{"first": "J", "middle": [], "last": "Folsom", "suffix": ""}, {"first": "J", "middle": ["L"], "last": "Atkinson", "suffix": ""}], "year": 2007, "venue": "Criminal Justice and Behavior", "link": "145329023"}, "BIBREF15": {"title": "A descriptive model of the offense process for female sexual offenders", "authors": [{"first": "T", "middle": ["A"], "last": "Gannon", "suffix": ""}, {"first": "M", "middle": ["R"], "last": "Rose", "suffix": ""}, {"first": "T", "middle": [], "last": "Ward", "suffix": ""}], "year": 2008, "venue": "Sexual Abuse: A Journal of Research and Treatment", "link": "271465"}, "BIBREF16": {"title": "Female sex offenders", "authors": [{"first": "R", "middle": [], "last": "Giguere", "suffix": ""}, {"first": "K", "middle": [], "last": "Bumby", "suffix": ""}], "year": 2007, "venue": "", "link": null}, "BIBREF17": {"title": "Predicting relapse: A meta-analysis of sexual offender recidivism", "authors": [{"first": "R", "middle": ["K"], "last": "Hanson", "suffix": ""}, {"first": "M", "middle": ["T"], "last": "Bussi\u00e8re", "suffix": ""}], "year": 1998, "venue": "Journal of Consulting and Clinical Psychology", "link": null}, "BIBREF18": {"title": "Assessing the risk of sexual offenders on community supervision: The Dynamic Supervision Project (User Rep. No. 2007-05)", "authors": [{"first": "R", "middle": ["K"], "last": "Hanson", "suffix": ""}, {"first": "A", "middle": ["J R"], "last": "Harris", "suffix": ""}, {"first": "T", "middle": ["L"], "last": "Scott", "suffix": ""}, {"first": "L", "middle": [], "last": "Helmus", "suffix": ""}], "year": 2007, "venue": "", "link": null}, "BIBREF19": {"title": "Predictors of sexual recidivism: An updated meta-analysis (User Rep. No. 2004-02)", "authors": [{"first": "R", "middle": ["K"], "last": "Hanson", "suffix": ""}, {"first": "K", "middle": ["E"], "last": "Morton-Bourgon", "suffix": ""}], "year": 2004, "venue": "", "link": null}, "BIBREF20": {"title": "The characteristics of persistent sexual offenders: A meta-analysis of recidivism studies", "authors": [{"first": "R", "middle": ["K"], "last": "Hanson", "suffix": ""}, {"first": "K", "middle": ["E"], "last": "Morton-Bourgon", "suffix": ""}], "year": 2005, "venue": "Journal of Consulting and Clinical Psychology", "link": "14984239"}, "BIBREF21": {"title": "The Dynamic Supervision Project: Improving the community supervision of sex offenders", "authors": [{"first": "A", "middle": ["J R"], "last": "Harris", "suffix": ""}, {"first": "R", "middle": ["K"], "last": "Hanson", "suffix": ""}], "year": 2003, "venue": "Corrections Today", "link": null}, "BIBREF22": {"title": "STATIC-99 coding rules revised-2003", "authors": [{"first": "A", "middle": ["J R"], "last": "Harris", "suffix": ""}, {"first": "A", "middle": [], "last": "Phenix", "suffix": ""}, {"first": "R", "middle": ["K"], "last": "Hanson", "suffix": ""}, {"first": "D", "middle": [], "last": "Thornton", "suffix": ""}], "year": 2003, "venue": "", "link": null}, "BIBREF23": {"title": "The \"criminogenic\" needs of women offenders", "authors": [{"first": "C", "middle": [], "last": "Hedderman", "suffix": ""}], "year": 2004, "venue": "Women who offend", "link": null}, "BIBREF24": {"title": "Fixed effect models", "authors": [{"first": "L", "middle": ["V"], "last": "Hedges", "suffix": ""}], "year": 1994, "venue": "The handbook of research synthesis", "link": "119009428"}, "BIBREF25": {"title": "Statistical methods for meta-analysis", "authors": [{"first": "L", "middle": ["V"], "last": "Hedges", "suffix": ""}, {"first": "I", "middle": [], "last": "Olkin", "suffix": ""}], "year": 1985, "venue": "", "link": null}, "BIBREF26": {"title": "Fixed-and random-effects models in meta-analysis", "authors": [{"first": "L", "middle": ["V"], "last": "Hedges", "suffix": ""}, {"first": "J", "middle": ["L"], "last": "Vevea", "suffix": ""}], "year": 1998, "venue": "Psychological Methods", "link": "119814256"}, "BIBREF27": {"title": "Recidivism report: Inmates released from Florida prisons", "authors": [{"first": "G", "middle": [], "last": "Holley", "suffix": ""}, {"first": "D", "middle": [], "last": "Ensley", "suffix": ""}], "year": 1995, "venue": "", "link": null}, "BIBREF28": {"title": "Gender and risk assessment: The empirical status of the LSI-R for women", "authors": [{"first": "K", "middle": [], "last": "Holtfreter", "suffix": ""}, {"first": "R", "middle": [], "last": "Cupp", "suffix": ""}], "year": 2007, "venue": "Journal of Contemporary Criminal Justice", "link": "144245646"}, "BIBREF29": {"title": "Prison statistics England and Wales (yearly reports: 1997 to", "authors": [{"first": "", "middle": [], "last": "*home Office", "suffix": ""}], "year": 1998, "venue": "", "link": null}, "BIBREF30": {"title": "A critique of the female sexual perpetrator research", "authors": [{"first": "J", "middle": [], "last": "Johansson-Love", "suffix": ""}, {"first": "W", "middle": [], "last": "Fremouw", "suffix": ""}], "year": 2006, "venue": "Aggression and Violent Behavior", "link": "144507072"}, "BIBREF31": {"title": "Risk, dangerousness and female offenders", "authors": [{"first": "H", "middle": [], "last": "Kemshall", "suffix": ""}], "year": 2004, "venue": "Women who offend", "link": null}, "BIBREF32": {"title": "Female offenders in Canada (No. 85-002-XIE)", "authors": [{"first": "R", "middle": [], "last": "Kong", "suffix": ""}, {"first": "K", "middle": [], "last": "Aucoin", "suffix": ""}], "year": 2008, "venue": "", "link": null}, "BIBREF33": {"title": "Recidivism of prisoners released in 1994", "authors": [{"first": "P", "middle": ["A"], "last": "Langan", "suffix": ""}, {"first": "D", "middle": ["J"], "last": "Levin", "suffix": ""}], "year": 2002, "venue": "", "link": "144872078"}, "BIBREF34": {"title": "Bureau of Justice Statistics, US Department of Justice", "authors": [{"first": "D", "middle": ["C"], "last": "Washington", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF35": {"title": "Does gender moderate the predictive utility of the Level of Service Inventory-Revised (LSI-R) for serious violent offenders?", "authors": [{"first": "M", "middle": ["A"], "last": "Manchak", "suffix": ""}, {"first": "J", "middle": ["L"], "last": "Skeem", "suffix": ""}, {"first": "K", "middle": ["S"], "last": "Douglas", "suffix": ""}, {"first": "M", "middle": [], "last": "Siranosian", "suffix": ""}], "year": 2009, "venue": "Criminal Justice and Behavior", "link": "144196091"}, "BIBREF36": {"title": "Sex offender recidivism in Minnesota", "authors": [], "year": 2007, "venue": "", "link": null}, "BIBREF37": {"title": "A comparison of fixed-effects and mixed (random-effects) models for meta-analysis tests of moderator variable effects", "authors": [{"first": "R", "middle": ["C"], "last": "Overton", "suffix": ""}], "year": 1998, "venue": "Psychological Methods", "link": "118794532"}, "BIBREF38": {"title": "The prevalence of child sexual abuse in community and student samples: A meta-analysis", "authors": [{"first": "N", "middle": [], "last": "Pereda", "suffix": ""}, {"first": "G", "middle": [], "last": "Guilera", "suffix": ""}, {"first": "M", "middle": [], "last": "Forns", "suffix": ""}, {"first": "J", "middle": [], "last": "G\u00f3mez-Benito", "suffix": ""}], "year": 2009, "venue": "Clinical Psychology Review", "link": "8928060"}, "BIBREF39": {"title": "Female sexual offender recidivism. Paper presented at the 20th Annual Research and Treatment Conference of the Association for the Treatment of Sexual Abusers", "authors": [{"first": "K", "middle": ["D"], "last": "Peterson", "suffix": ""}, {"first": "K", "middle": ["D"], "last": "Colebank", "suffix": ""}, {"first": "L", "middle": ["L"], "last": "Motta", "suffix": ""}], "year": 2001, "venue": "", "link": null}, "BIBREF40": {"title": "Drugs and criminality: Results from the Texas women inmates study. Women and Criminal Justice", "authors": [{"first": "J", "middle": ["M"], "last": "Pollock", "suffix": ""}, {"first": "J", "middle": [], "last": "Mullings", "suffix": ""}, {"first": "B", "middle": [], "last": "Crouch", "suffix": ""}], "year": 2002, "venue": "", "link": null}, "BIBREF41": {"title": "Assessing dangerousness: Violence by sexual offenders, batterers, and child abusers", "authors": [{"first": "V", "middle": ["L"], "last": "Quinsey", "suffix": ""}, {"first": "M", "middle": ["L"], "last": "Lalumi\u00e8re", "suffix": ""}, {"first": "M", "middle": ["E"], "last": "Rice", "suffix": ""}, {"first": "G", "middle": ["T"], "last": "Harris", "suffix": ""}], "year": 1995, "venue": "", "link": "143150754"}, "BIBREF42": {"title": "Juvenile delinquency: Understanding the origins of individual differences", "authors": [{"first": "V", "middle": ["L"], "last": "Quinsey", "suffix": ""}, {"first": "T", "middle": ["A"], "last": "Skilling", "suffix": ""}, {"first": "M", "middle": ["L"], "last": "Lalumi\u00e8re", "suffix": ""}, {"first": "W", "middle": ["M"], "last": "Craig", "suffix": ""}], "year": 2004, "venue": "", "link": "141987189"}, "BIBREF43": {"title": "Female sex offender recidivism: A large-scale empirical analysis", "authors": [{"first": "J", "middle": ["C"], "last": "Sandler", "suffix": ""}, {"first": "N", "middle": ["J"], "last": "Freeman", "suffix": ""}], "year": 2009, "venue": "Sexual Abuse: A Journal of Research and Treatment", "link": "19389092"}, "BIBREF44": {"title": "The situational context of violent female offending", "authors": [{"first": "I", "middle": [], "last": "Sommers", "suffix": ""}, {"first": "D", "middle": ["R"], "last": "Baskin", "suffix": ""}], "year": 1993, "venue": "", "link": "145129227"}, "BIBREF45": {"title": "Adult criminal court survey, number of cases by sex of accused, annual (CANSIM Table 252-0023)", "authors": [], "year": 2007, "venue": "Feature Panel on Sex Offenders", "link": null}, "BIBREF46": {"title": "Female sex offenders: An overview and analysis of 40 cases", "authors": [{"first": "D", "middle": ["M"], "last": "Vandiver", "suffix": ""}, {"first": "J", "middle": ["T"], "last": "Walker", "suffix": ""}], "year": 2002, "venue": "Criminal Justice Review", "link": "145395733"}, "BIBREF47": {"title": "Female sex offenders: Recidivism and criminal careers", "authors": [{"first": "M", "middle": [], "last": "Wijkman", "suffix": ""}, {"first": "C", "middle": [], "last": "Bijleveld", "suffix": ""}], "year": 2008, "venue": "European Society of Criminology", "link": null}, "BIBREF48": {"title": "Vrouwelijke zedendelinquenten", "authors": [{"first": "M", "middle": [], "last": "*wijkman", "suffix": ""}, {"first": "M", "middle": [], "last": "Zoutewelle-Terovan", "suffix": ""}, {"first": "C", "middle": [], "last": "Bijleveld", "suffix": ""}], "year": 2009, "venue": "Paper presented at the Annual Meeting of the Netherlands Society of Criminology", "link": null}, "BIBREF49": {"title": "Assessing static risk factors in adult female sex offenders under federal jurisdiction in Canada", "authors": [{"first": "S", "middle": ["M"], "last": "Williams", "suffix": ""}, {"first": "R", "middle": [], "last": "Nicholaichuk", "suffix": ""}], "year": 2001, "venue": "", "link": null}, "BIBREF50": {"title": "Annual Research and Treatment Conference of the Association for the Treatment of Sexual Abusers", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF51": {"title": "Meta-analysis of controlled clinical trials", "authors": [{"first": "A", "middle": [], "last": "Whitehead", "suffix": ""}], "year": 2002, "venue": "", "link": null}}, "ref_entries": {"FIGREF0": {"text": "examined the probability of rearrest for sexual offend- ers in the state of Western Australia between 1984 and 1994. Recidivism for the female sexual offenders was reported in Footnote 1 (p. 134). Hanson et al.'s (2007; Harris & Hanson, 2003) Dynamic Supervision Project was a prospective study designed to test the validity of a system of risk assessment for sex- ual offenders on community supervision (probation or parole). Assessments were con- ducted between 2001 and 2004, with recidivism information provided on an ongoing basis by the officers supervising the cases (up to March 2007). The full study exam- ined 997 sexual offenders from Canada and two U.S. states, of which 6 were female (1 from New Brunswick, 2 from Iowa, and 3 from Newfoundland). In 2003, Holley and Ensley produced a government recidivism report on inmates released from Florida prisons between 1995 and 2001. Home Office Reports to the U.K. Parliament: The Home Office provides informa- tion on the reconviction rates of offenders released from prisons in England and Wales. The data used in this review cover the period from 1994 to 1999. The Minnesota Department of Corrections published a report in 2007 on the recidi- vism rates of sexual offenders released from a Minnesota Correctional Facility between 1990 and 2002. The women in Peterson et al. (2001) had been or continued to be in treatment for their sexually offending behavior. Recidivism was coded from official Kentucky Court records. Sandler and Freeman (2009) examined the recidivism patterns and risk factors of registered sexual offenders in the State of New York. The study included by far the largest sample ever reported in a recidivism study of female sexual offenders (N = 1,466). Recidivism was coded from computerized criminal history files in New York State between January 1, 1986, and December 31, 2006.Summary", "type": "figure"}, "FIGREF1": {"text": "Figure 1. Percentages and confidence intervals of aggregated estimates of recidivism: Random and fixed effects", "type": "figure"}, "TABREF1": {"text": "Vandiver (2007) conducted a follow-up of the 2001 cohort of registered sexual offenders in Texas. Recidivism was coded from criminal records and included any registerable sexual offense in the State of Texas. These offenses include compelling prostitution, offenses related to possession or distribution of child pornography, kid- napping, and board/court ordered registration (Donna Vandiver, personal communica- tion, October 14, 2008). Wijkman et al. (2009) conducted a latent class analysis to investigate specialization versus generalization in the patterns of criminal behavior of 132 female sexual offend- ers. Data were coded from complete official criminal convictions records of the women from 12 years to August 2008 (Catrien Bijleveld, personal communication, February 3, 2009). Williams and Nicholaichuk (2001) conducted a follow-up of 72 female sexual offenders who received federal sentences (2 years or more) in Canada between 1972 and 1998. Because of deportation or continued incarceration, recidivism data could be obtained only for 61 of the cases. Recidivism was coded from Royal Canadian Mounted Police records, a national database that contains all charges and convictions on every offender in Canada.", "type": "table"}, "TABREF2": {"text": "Random and Fixed Effects Estimates of Recidivism", "type": "table"}, "TABREF3": {"text": "Weighted Average Recidivism Rates of Female Sexual Offenders", "type": "table"}}}
{"paper_id": "41515844", "_pdf_hash": "c02a70d2768e3a31ca095f8eb45a04c27d494059", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Chemical transformations of 7,9-disubstituted purines and related heterocycles. Selective reduction of imines and immonium salts", "authors": [{"first": "S", "middle": ["M"], "last": "Hecht", "suffix": ""}, {"first": "B", "middle": ["L"], "last": "Adams", "suffix": ""}, {"first": "J", "middle": ["W"], "last": "Kozarich", "suffix": ""}], "year": 1976, "venue": "The Journal of Organic Chemistry", "link": "45387129"}, "BIBREF1": {"title": "Marcus Theory of a Parallel Effect on \u03b1 for Hydride Transfer Reaction between NAD+ Analogues", "authors": [{"first": "I.-S", "middle": ["H"], "last": "Lee", "suffix": ""}, {"first": "E", "middle": ["H"], "last": "Jeoung", "suffix": ""}, {"first": "M", "middle": ["M"], "last": "Kreevoy", "suffix": ""}], "year": 1997, "venue": "Journal of the American Chemical Society", "link": "98446871"}, "BIBREF4": {"title": "Single Scan and Cyclic Methods Applied to Reversible, Irreversible, and Kinetic Systems", "authors": [{"first": "R", "middle": ["S"], "last": "Nicholson", "suffix": ""}, {"first": "I", "middle": [], "last": "Shain", "suffix": ""}], "year": 1964, "venue": "Analytical Chemistry", "link": null}, "BIBREF6": {"title": "Rate-determining general-base catalysis in an obligate 1e-oxidation of a dihydropyridine", "authors": [{"first": "A", "middle": [], "last": "Sinha", "suffix": ""}, {"first": "T", "middle": ["C"], "last": "Bruice", "suffix": ""}], "year": 1984, "venue": "Journal of the American Chemical Society", "link": "96355579"}, "BIBREF7": {"title": "A Thermodynamic and Kinetic Study of Hydride Transfer of a Caffeine Derivative", "authors": [{"first": "X", "middle": [], "last": "Han", "suffix": ""}, {"first": "W", "middle": [], "last": "Hao", "suffix": ""}, {"first": "X.-Q", "middle": [], "last": "Zhu", "suffix": ""}, {"first": "V", "middle": ["D"], "last": "Parker", "suffix": ""}], "year": 2012, "venue": "The Journal of Organic Chemistry", "link": "41515844"}, "BIBREF8": {"title": "Hydrogen Atom, Proton, and Electron Transfer Driving Forces of Various Five-Membered Heterocyclic Organic Hydrides and Their Reaction Intermediates in Acetonitrile", "authors": [{"first": "X.-Q", "middle": [], "last": "Zhu", "suffix": ""}, {"first": "M.-T", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "A", "middle": [], "last": "Yu", "suffix": ""}, {"first": "C.-H", "middle": [], "last": "Wang", "suffix": ""}, {"first": "J.-P", "middle": [], "last": "Cheng", "suffix": ""}, {"first": "", "middle": [], "last": "Hydride", "suffix": ""}], "year": 2008, "venue": "Journal of the American Chemical Society", "link": "11397903"}, "BIBREF9": {"title": "Formal transfers of hydride from carbon-hydrogen bonds. Attempted generation of molecular hydrogen by intramolecular reduction of protons bound by 2,3-dihydro-1,3-dimethyl-2-(8-quinolinyl)-1H-benzimidazole", "authors": [{"first": "B", "middle": [], "last": "Bachand", "suffix": ""}, {"first": "S", "middle": ["M"], "last": "Ramos", "suffix": ""}, {"first": "J", "middle": ["D"], "last": "Wuest", "suffix": ""}], "year": 1987, "venue": "The Journal of Organic Chemistry", "link": "94994609"}, "BIBREF10": {"title": "Hydride Transfer versus Hydrogen Radical Transfer in Thymidylate Synthase", "authors": [{"first": "B", "middle": [], "last": "Hong", "suffix": ""}, {"first": "M", "middle": [], "last": "Haddad", "suffix": ""}, {"first": "F", "middle": [], "last": "Maley", "suffix": ""}, {"first": "J", "middle": ["H"], "last": "Jensen", "suffix": ""}, {"first": "A", "middle": [], "last": "Kohen", "suffix": ""}], "year": 2006, "venue": "Journal of the American Chemical Society", "link": null}, "BIBREF11": {"title": "Mechanistic Borderline between One-Step Hydrogen Transfer and Sequential Transfers of Electron and Proton in Reactions of NADH Analogues with Triplet Excited States of Tetrazines and Ru(bpy)32+*", "authors": [{"first": "J", "middle": [], "last": "Yuasa", "suffix": ""}, {"first": "S", "middle": [], "last": "Fukuzumi", "suffix": ""}], "year": 2006, "venue": "Journal of the American Chemical Society", "link": "24009403"}}, "ref_entries": {}}
{"paper_id": "41517017", "_pdf_hash": "48c60552bf92f6a9e31fcfa0b6d11b9b9dab0624", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Strong Democracy: Participatory Politics for a New Age", "authors": [{"first": "Benjamin", "middle": ["R"], "last": "Barber", "suffix": ""}], "year": 1984, "venue": "", "link": "156172250"}, "BIBREF1": {"title": "Strong Democracy: Participatory Politics for a New Age", "authors": [{"first": "Benjamin", "middle": ["R"], "last": "Barber", "suffix": ""}], "year": 2003, "venue": "", "link": "156172250"}, "BIBREF2": {"title": "Bush Officials Lift Development Ban on Millions of Acres", "authors": [{"first": "Seth", "middle": [], "last": "Borenstein", "suffix": ""}], "year": 2005, "venue": "Philadelphia Inquirer", "link": null}, "BIBREF3": {"title": "Online Rulemaking and Other Tools for Strengthening Our Civic Infrastructure", "authors": [{"first": "Barbara", "middle": ["H"], "last": "Brandon", "suffix": ""}, {"first": "Robert", "middle": ["D"], "last": "Carlitz", "suffix": ""}], "year": 2002, "venue": "Admin. L. Rev", "link": null}, "BIBREF4": {"title": "The Internet and Citizen Participation in Rulemaking", "authors": [{"first": "Cary", "middle": [], "last": "Coglianese", "suffix": ""}], "year": 2005, "venue": "Info. Soc", "link": "153229332"}, "BIBREF5": {"title": "E-Rulemaking: Information Technology and the Regulatory Process", "authors": [{"first": "Cary", "middle": [], "last": "Coglianese", "suffix": ""}], "year": 2004, "venue": "Admin. L. Rev", "link": null}, "BIBREF6": {"title": "Shifting Sands: The Limits of Science in Setting Risk Standards", "authors": [{"first": "Cary", "middle": [], "last": "Coglianese", "suffix": ""}, {"first": "Gary", "middle": [], "last": "Marchant", "suffix": ""}], "year": 2004, "venue": "Univ. Penn. L. Rev", "link": "152314854"}, "BIBREF7": {"title": "Seeking Truth for Power: Informational Strategy and Regulatory Policy Making. Minn", "authors": [{"first": "Cary", "middle": [], "last": "Coglianese", "suffix": ""}, {"first": "Richard", "middle": [], "last": "Zeckhauser", "suffix": ""}, {"first": "Edward", "middle": [], "last": "Parson", "suffix": ""}], "year": 2004, "venue": "L. Rev", "link": "38813002"}, "BIBREF8": {"title": "Administrative Law", "authors": [{"first": "Cary", "middle": [], "last": "Coglianese", "suffix": ""}], "year": 2001, "venue": "International Encyclopedia of Social and Behavioral Sciences", "link": null}, "BIBREF9": {"title": "Litigating Within Relationships: Disputes and Disturbance in the Regulatory Process", "authors": [{"first": "Cary", "middle": [], "last": "Coglianese", "suffix": ""}], "year": 1996, "venue": "Law and Society Review", "link": "143862992"}, "BIBREF10": {"title": "Rethinking Regulatory Democracy", "authors": [{"first": "Mariano-Florentino", "middle": [], "last": "Cu\u00e9llar", "suffix": ""}], "year": 2005, "venue": "Admin. L. Rev", "link": "55019175"}, "BIBREF11": {"title": "On Democracy", "authors": [{"first": "Robert", "middle": ["A"], "last": "Dahl", "suffix": ""}], "year": 1998, "venue": "", "link": null}, "BIBREF12": {"title": "Democracy and Its Critics", "authors": [{"first": "Robert", "middle": ["A"], "last": "Dahl", "suffix": ""}], "year": 1989, "venue": "", "link": "157570686"}, "BIBREF13": {"title": "Who Governs? Democracy and Power in an American City", "authors": [{"first": "Robert", "middle": ["A"], "last": "Dahl", "suffix": ""}], "year": 1961, "venue": "", "link": "158558549"}, "BIBREF14": {"title": "Memorandum on Redundant Information Systems Relating to Online Rulemaking Initiative", "authors": [{"first": "Mitchell", "middle": ["E"], "last": "Daniels", "suffix": ""}], "year": 2002, "venue": "", "link": null}, "BIBREF15": {"title": "E-Rulemaking: Bringing Data to Theory. Duke L", "authors": [{"first": "De", "middle": [], "last": "Figueiredo", "suffix": ""}, {"first": "M", "middle": [], "last": "John", "suffix": ""}], "year": 2006, "venue": "J", "link": null}, "BIBREF16": {"title": "Delegating Powers : A Transaction Cost Politics Approach to Policy Making under Separate Powers", "authors": [{"first": "David", "middle": [], "last": "Epstein", "suffix": ""}, {"first": "Sharyn O&apos;", "middle": [], "last": "Halloran", "suffix": ""}], "year": 1999, "venue": "", "link": "151069920"}, "BIBREF17": {"title": "Crisis and Legitimacy: The Administrative Process and American Government", "authors": [{"first": "James", "middle": ["O"], "last": "Freedman", "suffix": ""}], "year": 1978, "venue": "", "link": "153145793"}, "BIBREF18": {"title": "Electronic Rulemaking: Efforts to Facilitate Public Participation Can Be Improved", "authors": [], "year": 2003, "venue": "", "link": null}, "BIBREF19": {"title": "The Internet Changes Everything: Revolutionizing Public Participation and Access to Government Information through the Internet", "authors": [{"first": "Stephen", "middle": [], "last": "Johnson", "suffix": ""}], "year": 1998, "venue": "Admin. L. Rev", "link": null}, "BIBREF20": {"title": "Presidential Administration", "authors": [{"first": "Elena", "middle": [], "last": "Kagan", "suffix": ""}], "year": 2001, "venue": "Harv. L. Rev", "link": null}, "BIBREF21": {"title": "Rulemaking: How Government Agencies Write Law and Make Policy", "authors": [{"first": "Cornelius", "middle": [], "last": "Kerwin", "suffix": ""}], "year": 2003, "venue": "", "link": "152385657"}, "BIBREF22": {"title": "Information and Legislative Organization", "authors": [{"first": "Keith", "middle": [], "last": "Krehbiel", "suffix": ""}], "year": 1991, "venue": "", "link": "153573119"}, "BIBREF23": {"title": "Regulatory Review: Presidential Control through Selective Communication and Institutionalized Conflict", "authors": [{"first": "David", "middle": [], "last": "Lazer", "suffix": ""}], "year": 2001, "venue": "", "link": "155402491"}, "BIBREF24": {"title": "Mobilizing Public Opinion: Black Insurgency and Racial Attitudes in the Civil Rights Era", "authors": [{"first": "Taeku", "middle": [], "last": "Lee", "suffix": ""}], "year": 2002, "venue": "", "link": "153382184"}, "BIBREF25": {"title": "The End of Liberalism: Ideology, Policy, and the Crisis of Public Authority", "authors": [{"first": "Theodore", "middle": ["J"], "last": "Lowi", "suffix": ""}], "year": 1969, "venue": "", "link": null}, "BIBREF26": {"title": "Congressional Oversight Overlooked: Police Patrols Versus Fire Alarms", "authors": [{"first": "Matthew", "middle": [], "last": "Mccubbins", "suffix": ""}, {"first": "Thomas", "middle": [], "last": "Schwartz", "suffix": ""}], "year": 1984, "venue": "Amer. J. Pol. Sci", "link": "107754284"}, "BIBREF27": {"title": "Administrative Regulation and Democracy. Baldy Center for Law and Social Policy Working Paper No", "authors": [{"first": "Errol", "middle": [], "last": "Meidinger", "suffix": ""}], "year": 1992, "venue": "", "link": null}, "BIBREF28": {"title": "EPA Chief Information Officer Statement before the House Committee on Government Reform", "authors": [{"first": "Kimberly", "middle": [], "last": "Nelson", "suffix": ""}], "year": 2004, "venue": "", "link": null}, "BIBREF29": {"title": "The Electronic Revolution in Rulemaking", "authors": [{"first": "Beth", "middle": [], "last": "Noveck", "suffix": ""}], "year": 2004, "venue": "Emory L. J", "link": "117212244"}, "BIBREF30": {"title": "Report to Congress on the Costs and Benefits of Regulations and Unfunded Mandates on State, Local and Tribal Entities", "authors": [{"first": "", "middle": [], "last": "Omb", "suffix": ""}], "year": 2001, "venue": "", "link": null}, "BIBREF31": {"title": "The Vanishing Voter: Public Involvement in an Age of Uncertainty", "authors": [{"first": "Thomas", "middle": ["E"], "last": "Patterson", "suffix": ""}], "year": 2002, "venue": "", "link": "154154582"}, "BIBREF32": {"title": "Retooling Collaboration: A Vision for Environmental Change Research", "authors": [{"first": "William", "middle": [], "last": "Pike", "suffix": ""}, {"first": "Brent", "middle": [], "last": "Yarnal", "suffix": ""}, {"first": "Alan", "middle": ["M"], "last": "Maceachren", "suffix": ""}, {"first": "Mark", "middle": [], "last": "Gahegan", "suffix": ""}, {"first": "Chaoqing", "middle": [], "last": "Yu", "suffix": ""}], "year": 2005, "venue": "Envt", "link": "128446243"}, "BIBREF33": {"title": "The Semi-Sovereign People", "authors": [{"first": "E", "middle": ["E"], "last": "Schattschneider", "suffix": ""}], "year": 1960, "venue": "", "link": "154539530"}, "BIBREF34": {"title": "To Submit a Form or Not to Submit a Form, That is the (Real) Question': Deliberation and Mass Participation in U.S. Regulatory Rulemaking, paper presented at the annual meeting of the Western Political Science Association", "authors": [{"first": "David", "middle": [], "last": "Schlosberg", "suffix": ""}, {"first": "Stephen", "middle": [], "last": "Zavestocki", "suffix": ""}, {"first": "Stuart", "middle": [], "last": "Shulman", "suffix": ""}], "year": 2005, "venue": "", "link": null}, "BIBREF35": {"title": "Power Without Responsibility: How Congress Abuses the People Through Delegation", "authors": [{"first": "David", "middle": [], "last": "Schoenbrod", "suffix": ""}], "year": 1993, "venue": "", "link": "153562286"}, "BIBREF36": {"title": "The Psychology of Accountability and Political Review of Agency Rules. Duke L", "authors": [{"first": "Mark", "middle": [], "last": "Seidenfeld", "suffix": ""}], "year": 2001, "venue": "J", "link": "142618161"}, "BIBREF37": {"title": "Turning GOLD into EPG: Lessons from Low-Tech Democratic Experimentalism for Electronic Rulemaking and Other Ventures in Cyberdemocracy. I/S", "authors": [{"first": "Peter", "middle": ["M"], "last": "Shane", "suffix": ""}], "year": 2005, "venue": "J. L. and Pol", "link": "152712941"}, "BIBREF38": {"title": "Pragmatic Administrative Law", "authors": [{"first": "Sidney", "middle": [], "last": "Shapiro", "suffix": ""}], "year": 2005, "venue": "Issues in L. Scholarship", "link": null}, "BIBREF39": {"title": "An Experiment in Digital Government at the United States National Organics Program", "authors": [{"first": "Stuart", "middle": ["W"], "last": "Shulman", "suffix": ""}], "year": 2003, "venue": "Agri. and Hum. Val", "link": null}, "BIBREF40": {"title": "The Effects of Internet Use on Political Participation: Evidence from an Agency Online Discussion Forum", "authors": [{"first": "J", "middle": [], "last": "Stanley", "suffix": ""}, {"first": "Christopher", "middle": [], "last": "Woody", "suffix": ""}, {"first": "", "middle": [], "last": "Weare", "suffix": ""}], "year": 2004, "venue": "Admin. and Soc", "link": null}, "BIBREF41": {"title": "Beyond Delegation Doctrine", "authors": [{"first": "Richard", "middle": ["B"], "last": "Stewart", "suffix": ""}], "year": 1987, "venue": "Amer. Univ. L. Rev", "link": null}, "BIBREF42": {"title": "The Reformation of American Administrative Law", "authors": [{"first": "Richard", "middle": ["B"], "last": "Stewart", "suffix": ""}], "year": 1975, "venue": "Harv. L. Rev", "link": null}, "BIBREF43": {"title": "Why Societies Need Dissent", "authors": [{"first": "Cass", "middle": ["R"], "last": "Sunstein", "suffix": ""}], "year": 2003, "venue": "", "link": "152389621"}}, "ref_entries": {}}
{"paper_id": "41517496", "_pdf_hash": "ad60b6d777ab5dda8a67dc4bdf974abec69d258a", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Statistik Kriminal", "authors": [{"first": "Statistik", "middle": [], "last": "Badan Pusat", "suffix": ""}], "year": 2014, "venue": "Katalog BPS", "link": null}, "BIBREF1": {"title": "Pelaku di Bawah Umur Kasus Pemerkosaan di Bengkulu Wajib Direhabilitasi", "authors": [{"first": "", "middle": [], "last": "Metrotvnews", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF3": {"title": "Pooling in Image Representation: the Visual Codeword Point of View. Computer Vision and Image Understanding (CVIU)", "authors": [{"first": "Sandra", "middle": [], "last": "Avila", "suffix": ""}, {"first": "Nicolas", "middle": [], "last": "Thome", "suffix": ""}, {"first": "Matthieu", "middle": [], "last": "Cord", "suffix": ""}, {"first": "Eduardo", "middle": [], "last": "Valle", "suffix": ""}], "year": 2013, "venue": "", "link": null}, "BIBREF4": {"title": "Adult Content Detection in Videos with Convolutional and Recurrent Neural Networks", "authors": [{"first": "Jonatas", "middle": [], "last": "Wehrmann", "suffix": ""}, {"first": "Gabriel", "middle": ["S"], "last": "Simes", "suffix": ""}, {"first": "Rodrigo", "middle": ["C"], "last": "Barros", "suffix": ""}, {"first": "Victor", "middle": ["F"], "last": "Cavalcante", "suffix": ""}], "year": 2017, "venue": "Neurocomputing", "link": "1126751"}, "BIBREF5": {"title": "A bag-of-features approach based on hue-SIFT descriptor for nude detection", "authors": [{"first": "A", "middle": [], "last": "Lopes", "suffix": ""}, {"first": "S", "middle": [], "last": "Avila", "suffix": ""}, {"first": "A", "middle": [], "last": "Peixoto", "suffix": ""}, {"first": "R", "middle": [], "last": "Oliveira", "suffix": ""}, {"first": "A", "middle": [], "last": "Jo", "suffix": ""}], "year": 2009, "venue": "European Signal Processing Conference", "link": "13315896"}, "BIBREF6": {"title": "The mask-SIFT cascading classifier for pornography detection", "authors": [{"first": "C", "middle": [], "last": "Steel", "suffix": ""}], "year": 2012, "venue": "IEEE World Congress on Internet Security (WorldCIS)", "link": "15075591"}, "BIBREF7": {"title": "Bag-of-visual-words models for adult image classification and filtering", "authors": [{"first": "T", "middle": [], "last": "Deselaers", "suffix": ""}, {"first": "L", "middle": [], "last": "Pimenidis", "suffix": ""}, {"first": "H", "middle": [], "last": "Ney", "suffix": ""}], "year": 2008, "venue": "IEEE International Conference on Pattern Recognition (ICPR)", "link": "5876009"}, "BIBREF8": {"title": "Automatic detection of child pornography using color visual words", "authors": [{"first": "A", "middle": [], "last": "Ulges", "suffix": ""}, {"first": "A", "middle": [], "last": "Stahl", "suffix": ""}], "year": 2011, "venue": "IEEE International Conference on Multimedia and Expo (ICME)", "link": "33173871"}, "BIBREF9": {"title": "An approach of bag-of-words based on visual attention model for pornographic images recognition in compressed domain", "authors": [{"first": "J", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "L", "middle": [], "last": "Sui", "suffix": ""}, {"first": "L", "middle": [], "last": "Zhuo", "suffix": ""}, {"first": "Z", "middle": [], "last": "Li", "suffix": ""}, {"first": "Y", "middle": [], "last": "Yang", "suffix": ""}], "year": 2013, "venue": "Neurocomputing", "link": "207104310"}, "BIBREF10": {"title": "BOSSA: Extended bow formalism for image classification", "authors": [{"first": "S", "middle": [], "last": "Avila", "suffix": ""}, {"first": "N", "middle": [], "last": "Thome", "suffix": ""}, {"first": "M", "middle": [], "last": "Cord", "suffix": ""}, {"first": "E", "middle": [], "last": "Valle", "suffix": ""}, {"first": "A", "middle": [], "last": "De A", "suffix": ""}, {"first": "", "middle": [], "last": "Arajo", "suffix": ""}], "year": 2011, "venue": "18th IEEE International Conference on Image Processing", "link": "63641044"}, "BIBREF11": {"title": "Pornography Classification: The Hidden Clues in Video Space-Time", "authors": [{"first": "D", "middle": [], "last": "Moreira", "suffix": ""}, {"first": "S", "middle": [], "last": "Avila", "suffix": ""}, {"first": "M", "middle": [], "last": "Perez", "suffix": ""}, {"first": "D", "middle": [], "last": "Moraes", "suffix": ""}, {"first": "V", "middle": [], "last": "Testoni", "suffix": ""}, {"first": "E", "middle": [], "last": "Valle", "suffix": ""}, {"first": "S", "middle": [], "last": "Goldenstein", "suffix": ""}, {"first": "A", "middle": [], "last": "Rocha", "suffix": ""}], "year": 2016, "venue": "Forensic Science International", "link": "3467167"}, "BIBREF12": {"title": "Deep Residual Learning for Image Recognition", "authors": [{"first": "K", "middle": [], "last": "He", "suffix": ""}, {"first": "X", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "S", "middle": [], "last": "Ren", "suffix": ""}, {"first": "J", "middle": [], "last": "Sun", "suffix": ""}], "year": 2015, "venue": "", "link": "206594692"}, "BIBREF13": {"title": "Very deep convolutional networks for large-scale image recognition", "authors": [{"first": "K", "middle": [], "last": "Simonyan", "suffix": ""}, {"first": "A", "middle": [], "last": "Zisserman", "suffix": ""}], "year": 2014, "venue": "http:arxiv.orgabs pp", "link": "14124313"}, "BIBREF14": {"title": "ImageNet Large Scale Visual Recognition Challenge", "authors": [{"first": "O", "middle": [], "last": "Russakovsky", "suffix": ""}, {"first": "J", "middle": [], "last": "Deng", "suffix": ""}, {"first": "S", "middle": [], "last": "Hao", "suffix": ""}, {"first": "J", "middle": [], "last": "Krause", "suffix": ""}, {"first": "S", "middle": [], "last": "Satheesh", "suffix": ""}, {"first": "S", "middle": [], "last": "Ma", "suffix": ""}, {"first": "Z", "middle": [], "last": "Huang", "suffix": ""}, {"first": "A", "middle": [], "last": "Karpathy", "suffix": ""}, {"first": "A", "middle": [], "last": "Khosla", "suffix": ""}, {"first": "M", "middle": [], "last": "Bernstein", "suffix": ""}, {"first": "A", "middle": ["C"], "last": "Berg", "suffix": ""}, {"first": "L", "middle": [], "last": "Fei-Fei", "suffix": ""}], "year": 2015, "venue": "International Journal of Computer Vision (IJCV)", "link": "2930547"}, "BIBREF15": {"title": "Adam: A Method for Stochastic Optimization", "authors": [{"first": "Diederik", "middle": [], "last": "Kingma", "suffix": ""}, {"first": "Jimmy", "middle": [], "last": "Ba", "suffix": ""}], "year": 2014, "venue": "", "link": "6628106"}, "BIBREF16": {"title": "Keras", "authors": [{"first": "Fran\u00e7ois", "middle": [], "last": "Chollet", "suffix": ""}, {"first": "", "middle": [], "last": "Others", "suffix": ""}], "year": 2015, "venue": "", "link": null}, "BIBREF17": {"title": "TensorFlow: Large-scale machine learning on heterogeneous systems", "authors": [{"first": "A", "middle": [], "last": "Martn", "suffix": ""}], "year": 2015, "venue": "Software available from tensorflow.org", "link": null}}, "ref_entries": {}}
{"paper_id": "41518354", "_pdf_hash": "dbd1baa81981868761bc1865538f092a10d08b13", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Modelling the fast fluorescence rise of photosynthesis", "authors": [{"first": "E", "middle": [], "last": "Baake", "suffix": ""}, {"first": "J", "middle": ["P"], "last": "Schl\u00f6der", "suffix": ""}], "year": 1992, "venue": "Bull. Math. Biol", "link": "50674049"}, "BIBREF1": {"title": "Evidence for a respiratory chain in the chloroplast", "authors": [{"first": "P", "middle": [], "last": "Bennoun", "suffix": ""}], "year": 1982, "venue": "Proc. Natl. Acad. Sci", "link": "22487030"}, "BIBREF2": {"title": "Alternative photosystem I-driven electron transport routes: mechanisms and functions", "authors": [{"first": "N", "middle": [], "last": "Bukhov", "suffix": ""}, {"first": "R", "middle": [], "last": "Carpentier", "suffix": ""}], "year": 2004, "venue": "Photosynth. Res", "link": "5812496"}, "BIBREF3": {"title": "Light modulation of chloroplast membrane-bound ferredoxin-NADP+ oxidoreductase", "authors": [{"first": "N", "middle": [], "last": "Carrillo", "suffix": ""}, {"first": "H", "middle": ["A"], "last": "Lucero", "suffix": ""}, {"first": "R", "middle": ["H"], "last": "Vallejos", "suffix": ""}], "year": 1981, "venue": "J. Biol. Chem", "link": "30486955"}, "BIBREF4": {"title": "Consequences of the structure of the cytochrome b 6 f complex for its charge transfer pathways", "authors": [{"first": "W", "middle": ["A"], "last": "Cramer", "suffix": ""}, {"first": "H", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "A", "middle": ["R"], "last": "Crofts", "suffix": ""}, {"first": "C", "middle": ["A"], "last": "Wraight", "suffix": ""}], "year": 1983, "venue": "Biochim. Biophys. Acta", "link": null}, "BIBREF5": {"title": "Molecular mechanism and quantitative models of variable photosystem II fluorescence", "authors": [{"first": "H", "middle": [], "last": "Dau", "suffix": ""}], "year": 1994, "venue": "Photochem. Photobiol", "link": "96837423"}, "BIBREF6": {"title": "Effect of light-induced changes in thylakoid voltage on chlorophyll fluorescence of Aegopodium podagraria leaves", "authors": [{"first": "H", "middle": [], "last": "Dau", "suffix": ""}, {"first": "R", "middle": [], "last": "Windecker", "suffix": ""}, {"first": "U.-P", "middle": [], "last": "Hansen", "suffix": ""}], "year": 1991, "venue": "Biochim. Biophys. Acta", "link": "95788253"}, "BIBREF7": {"title": "Mechanism of the two photochemical reactions in algae as studied by means of fluorescence", "authors": [{"first": "L", "middle": ["N M"], "last": "Duysens", "suffix": ""}, {"first": "H", "middle": ["E"], "last": "Sweers", "suffix": ""}], "year": 1963, "venue": "Studies on Microalgae and Photosynthetic Bacteria", "link": null}, "BIBREF8": {"title": "Nonphotochemical reduction of the plastoquinone pool in sunflower leaves originates from chlororespiration", "authors": [{"first": "T", "middle": ["S"], "last": "Feild", "suffix": ""}, {"first": "L", "middle": [], "last": "Nedbal", "suffix": ""}, {"first": "D", "middle": ["R"], "last": "Ort", "suffix": ""}, {"first": "C", "middle": [], "last": "Giersch", "suffix": ""}], "year": 1995, "venue": "Curr. Opin. Plant Biol", "link": "28257934"}, "BIBREF9": {"title": "The polyphasic rice of the chlorophyll a fluorescence (O-K-J-I-P) in heat-stressed leaves", "authors": [{"first": "B", "middle": [], "last": "Guiss\u00e9", "suffix": ""}, {"first": "A", "middle": [], "last": "Srivastava", "suffix": ""}, {"first": "R", "middle": ["J"], "last": "Strasser", "suffix": ""}], "year": 1995, "venue": "Arch. Sci", "link": null}, "BIBREF10": {"title": "The use of light-induced absorbance changes at 820 nm to monitor the oxidation state of P-700 in leaves", "authors": [{"first": "J", "middle": [], "last": "Harbinson", "suffix": ""}, {"first": "F", "middle": ["I"], "last": "Woodward", "suffix": ""}], "year": 1987, "venue": "Plant Cell Environ", "link": "85006351"}, "BIBREF11": {"title": "Fluorescence induction of Photosystem II membranes shows the steps till reduction and protonation of the quinone pool", "authors": [{"first": "P", "middle": [], "last": "Heredia", "suffix": ""}, {"first": "J", "middle": [], "last": "De Las Rivas", "suffix": ""}], "year": 2003, "venue": "J. Plant Physiol", "link": "25203161"}, "BIBREF12": {"title": "Decreased content of leaf ferredoxin changes electron distribution and limits photosynthesis in transgenic potato plants", "authors": [{"first": "S", "middle": [], "last": "Holtgrefe", "suffix": ""}, {"first": "K", "middle": ["P"], "last": "Bader", "suffix": ""}, {"first": "P", "middle": [], "last": "Horton", "suffix": ""}, {"first": "R", "middle": [], "last": "Scheibe", "suffix": ""}, {"first": "A", "middle": [], "last": "Von Schaewen", "suffix": ""}, {"first": "J", "middle": ["E"], "last": "Backhausen", "suffix": ""}], "year": 2003, "venue": "Plant Physiol", "link": "13645424"}, "BIBREF13": {"title": "Spectral characterization of chlorophyll fluorescence in barley leaves during linear heating", "authors": [{"first": "P", "middle": [], "last": "Il\u00edk", "suffix": ""}, {"first": "R", "middle": [], "last": "Kou\u0159il", "suffix": ""}, {"first": "J", "middle": [], "last": "Fiala", "suffix": ""}, {"first": "J", "middle": [], "last": "Nau\u0161", "suffix": ""}, {"first": "F", "middle": [], "last": "V\u00e1cha", "suffix": ""}], "year": 2000, "venue": "J. Photochem. Photobiol", "link": null}, "BIBREF14": {"title": "A dip in the chlorophyll fluorescence induction at 0.2 -2 s in Trebouxia-possessing lichens reflects a fast reoxidation of photosystem I. A comparison with higher plants", "authors": [{"first": "P", "middle": [], "last": "Il\u00edk", "suffix": ""}, {"first": "G", "middle": [], "last": "Schansker", "suffix": ""}, {"first": "E", "middle": [], "last": "Kotabov\u00e1", "suffix": ""}, {"first": "P", "middle": [], "last": "V\u00e1czi", "suffix": ""}, {"first": "R", "middle": ["J"], "last": "Strasser", "suffix": ""}, {"first": "M", "middle": [], "last": "Bart\u00e1k", "suffix": ""}], "year": 2006, "venue": "Biochim. Biophys. Acta", "link": "22744650"}, "BIBREF15": {"title": "Evidence for intermediate S-states as initial phase in the process of oxygen-evolving complex oxidation", "authors": [{"first": "J", "middle": [], "last": "Jablonsky", "suffix": ""}, {"first": "D", "middle": [], "last": "Lazar", "suffix": ""}], "year": 2008, "venue": "Biophys. J", "link": "207118931"}, "BIBREF16": {"title": "Impact of dimeric organization of enzyme on its function: the case of photosynthetic water splitting", "authors": [{"first": "J", "middle": [], "last": "Jablonsky", "suffix": ""}, {"first": "P", "middle": [], "last": "Susila", "suffix": ""}, {"first": "D", "middle": [], "last": "Lazar", "suffix": ""}], "year": 2008, "venue": "Bioinformatics", "link": null}, "BIBREF17": {"title": "Cyclic electron transport in C 3 plants: fact or artefact?", "authors": [{"first": "G", "middle": ["N"], "last": "Johnson", "suffix": ""}], "year": 2005, "venue": "J. Exp. Bot", "link": "16233386"}, "BIBREF18": {"title": "\u00c9tude cin\u00e9tique de la r\u00e9action photochimique lib\u00e9rant l' oxyg\u00e8ne au cours de la photosynth\u00e8se", "authors": [{"first": "A", "middle": [], "last": "Joliot", "suffix": ""}, {"first": "P", "middle": [], "last": "Joliot", "suffix": ""}], "year": 1964, "venue": "C. R. Acad. Sci", "link": null}, "BIBREF19": {"title": "Mechanism of electron transfer in the cytochrome b/f complex of algae: Evidence for a semiquinone cycle", "authors": [{"first": "P", "middle": [], "last": "Joliot", "suffix": ""}, {"first": "A", "middle": [], "last": "Joliot", "suffix": ""}, {"first": "P", "middle": [], "last": "Joliot", "suffix": ""}, {"first": "A", "middle": [], "last": "Joliot", "suffix": ""}], "year": 1994, "venue": "Proc. Natl. Acad. Sci", "link": "21638596"}, "BIBREF20": {"title": "Kinetic analyses of the OJIP chlorophyll fluorescence rise in thylakoid membranes", "authors": [{"first": "D", "middle": [], "last": "Joly", "suffix": ""}, {"first": "C", "middle": [], "last": "Bigras", "suffix": ""}, {"first": "J", "middle": [], "last": "Harnois", "suffix": ""}, {"first": "S", "middle": [], "last": "Govindachary", "suffix": ""}, {"first": "R", "middle": [], "last": "Carpentier", "suffix": ""}], "year": 2005, "venue": "Photosynth. Res", "link": "37885375"}, "BIBREF21": {"title": "Plastocyanin redox kinetics in spinach chloroplasts: evidence for disequilibrium in the high potential chain", "authors": [{"first": "H", "middle": [], "last": "Kirchhoff", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Sch\u00f6ttler", "suffix": ""}, {"first": "J", "middle": [], "last": "Maurer", "suffix": ""}, {"first": "E", "middle": [], "last": "Weis", "suffix": ""}], "year": "", "venue": "", "link": "31077987"}, "BIBREF22": {"title": "-dimethylurea-treated barley leaves at room and high temperatures", "authors": [], "year": 1999, "venue": "Eur. Biophys. J", "link": null}, "BIBREF23": {"title": "Photosynthesis in silico: Understanding Complexity from Molecules to Ecosystems", "authors": [{"first": "D", "middle": [], "last": "Laz\u00e1r", "suffix": ""}, {"first": "G", "middle": [], "last": "Schansker", "suffix": ""}], "year": 2009, "venue": "", "link": "89198747"}, "BIBREF24": {"title": "A kinetic model of primary photosynthetic processes. Description of the fast phase of chlorophyll fluorescence induction under different light intensities", "authors": [{"first": "G", "middle": ["V"], "last": "Lebedeva", "suffix": ""}, {"first": "N", "middle": ["E"], "last": "Belyaeva", "suffix": ""}, {"first": "O", "middle": ["V"], "last": "Demin", "suffix": ""}, {"first": "G", "middle": ["Y"], "last": "Riznichenko", "suffix": ""}, {"first": "A", "middle": ["B"], "last": "Rubin", "suffix": ""}], "year": 2002, "venue": "Biofizika", "link": "54634935"}, "BIBREF25": {"title": "On the interpretation of absorption-spectra of leaves. 2. The nonabsorbed ray of the sieve effect and the mean optical pathlength in the remainder of the leaf", "authors": [{"first": "J", "middle": ["H"], "last": "Mcclendon", "suffix": ""}, {"first": "L", "middle": [], "last": "Fukshansky", "suffix": ""}], "year": 1990, "venue": "Photochem. Photobiol", "link": null}, "BIBREF26": {"title": "GEPASI -a software package for modelling the dynamics, steady states and control of biochemical and other systems", "authors": [{"first": "P", "middle": [], "last": "Mendes", "suffix": ""}], "year": 1993, "venue": "Comput. Appl. Biosci", "link": "23362644"}, "BIBREF27": {"title": "Reductive titration of photosystem I and differential extinction coefficient of P700 + at 810-950 nm in leaves", "authors": [{"first": "V", "middle": [], "last": "Oja", "suffix": ""}, {"first": "I", "middle": [], "last": "Bichele", "suffix": ""}, {"first": "K", "middle": [], "last": "H\u00fcve", "suffix": ""}, {"first": "B", "middle": [], "last": "Rasulov", "suffix": ""}, {"first": "A", "middle": [], "last": "Laisk", "suffix": ""}], "year": "", "venue": "", "link": "20860454"}, "BIBREF29": {"title": "Chlorophyll fluorescence transients of Photosystem II membrane particles as a tool for studying photosynthetic oxygen evolution", "authors": [{"first": "P", "middle": [], "last": "Posp\u00ed\u0161il", "suffix": ""}, {"first": "H", "middle": [], "last": "Dau", "suffix": ""}], "year": 2000, "venue": "Photosynth. Res", "link": "5651778"}, "BIBREF30": {"title": "Valinomycin sensitivity proves that lightinduced thylakoid voltages result in millisecond phase of chlorophyll fluorescence transients", "authors": [{"first": "P", "middle": [], "last": "Posp\u00ed\u0161il", "suffix": ""}, {"first": "H", "middle": [], "last": "Dau", "suffix": ""}], "year": 2002, "venue": "Biochim. Biophys. Acta", "link": "25939559"}, "BIBREF31": {"title": "Experimental and mathematical approaches to modeling plant metabolic network", "authors": [{"first": "R", "middle": [], "last": "Rios-Estepa", "suffix": ""}, {"first": "B", "middle": ["M"], "last": "Lange", "suffix": ""}], "year": 2007, "venue": "Phytochemistry", "link": "5887338"}, "BIBREF32": {"title": "Modeling of the primary processes in a photosynthetic membrane", "authors": [{"first": "A", "middle": ["B"], "last": "Rubin", "suffix": ""}, {"first": "G", "middle": [], "last": "Riznichenko", "suffix": ""}], "year": 2009, "venue": "Photosynthesis in silico: Understanding Complexity from Molecules to Ecosystems", "link": "92175447"}, "BIBREF33": {"title": "Modelling of the electron transfer reactions in Photosystem I by electron tunnelling theory: The phylloquinones bound to the PsaA and the PsaB reaction centre subunits of PS I are almost isoenergetic to the iron-sulfur cluster F X", "authors": [{"first": "S", "middle": [], "last": "Santabarbara", "suffix": ""}, {"first": "P", "middle": [], "last": "Heathcote", "suffix": ""}, {"first": "M", "middle": ["C V"], "last": "Evans", "suffix": ""}], "year": 2005, "venue": "Biochim. Biophys. Acta", "link": "11831092"}, "BIBREF34": {"title": "Fluorescence induction and activity of ferredoxin-NADP + reductase in Bryopsis chloroplasts", "authors": [{"first": "K", "middle": [], "last": "Satoh", "suffix": ""}], "year": "", "venue": "", "link": "85408954"}, "BIBREF36": {"title": "Characterization of the 820-nm transmission signal paralleling the chlorophyll a fluorescence rise (OJIP) in pea leaves", "authors": [{"first": "G", "middle": [], "last": "Schansker", "suffix": ""}, {"first": "A", "middle": [], "last": "Srivastava", "suffix": ""}, {"first": "", "middle": [], "last": "Govindjee", "suffix": ""}, {"first": "R", "middle": ["J"], "last": "Strasser", "suffix": ""}], "year": 2003, "venue": "Funct. Plant Biol", "link": "16830108"}, "BIBREF37": {"title": "Methylviologen and dibromorhymoquinone treatments of pea leaves reveal the role of photosystem I in the Chl a fluorescence rise OJIP", "authors": [{"first": "G", "middle": [], "last": "Schansker", "suffix": ""}, {"first": "S", "middle": ["Z"], "last": "T\u00f3th", "suffix": ""}, {"first": "R", "middle": ["J"], "last": "Strasser", "suffix": ""}], "year": 2005, "venue": "Biochim. Biophys. Acta", "link": "45525687"}, "BIBREF38": {"title": "O 2 -dependent electron flow, membrane energization and the mechanism of nonphotochemical quenching of chlorophyll fluorescence", "authors": [{"first": "U", "middle": [], "last": "Schreiber", "suffix": ""}, {"first": "C", "middle": [], "last": "Neubauer", "suffix": ""}], "year": 1990, "venue": "Photosynth. Res", "link": "25864481"}, "BIBREF39": {"title": "Chlorophyll a fluorescence induction in higher plants: Modelling and numerical simulation", "authors": [{"first": "A", "middle": [], "last": "Stirbet", "suffix": ""}, {"first": "", "middle": [], "last": "Govindjee", "suffix": ""}, {"first": "B", "middle": ["J"], "last": "Strasser", "suffix": ""}, {"first": "R", "middle": ["J"], "last": "Strasser", "suffix": ""}], "year": 1998, "venue": "J. Theor. Biol", "link": "17849928"}, "BIBREF40": {"title": "Donor side capacity of Photosystem II probed by chlorophyll a fluorescence transients", "authors": [{"first": "B", "middle": ["J"], "last": "Strasser", "suffix": ""}], "year": 1997, "venue": "Photosynth. Res", "link": "43250319"}, "BIBREF41": {"title": "Govindjee: Polyphasic chlorophyll a fluorescence transient in plants and cyanobacteria", "authors": [{"first": "R", "middle": ["J"], "last": "Strasser", "suffix": ""}, {"first": "A", "middle": [], "last": "Srivastava", "suffix": ""}], "year": 1995, "venue": "Photochem. Photobiol", "link": null}, "BIBREF42": {"title": "Estimation of the energetic connectivity of PS II centres in plants using the fluorescence rise O-J-I-P -Fitting of experimental data to three different PS II models", "authors": [{"first": "R", "middle": ["J"], "last": "Strasser", "suffix": ""}, {"first": "A", "middle": ["D"], "last": "Stirbet", "suffix": ""}], "year": 2001, "venue": "Math. Comput. Simulat", "link": null}, "BIBREF43": {"title": "The gradient of exciting radiation within a sample affects relative heights of steps in the fast chlorophyll a fluorescence rise", "authors": [{"first": "P", "middle": [], "last": "Su\u0161ila", "suffix": ""}, {"first": "D", "middle": [], "last": "Laz\u00e1r", "suffix": ""}, {"first": "P", "middle": [], "last": "Il\u00edk", "suffix": ""}, {"first": "P", "middle": [], "last": "Tomek", "suffix": ""}, {"first": "J", "middle": [], "last": "Nau\u0161", "suffix": ""}], "year": 2004, "venue": "Photosynthetica", "link": "20671337"}, "BIBREF44": {"title": "On the intermediate steps between the O and P steps in chlorophyll alpha fluorescence rise measured at different intensities of exciting light", "authors": [{"first": "P", "middle": [], "last": "Tomek", "suffix": ""}, {"first": "D", "middle": [], "last": "Laz\u00e1r", "suffix": ""}, {"first": "P", "middle": [], "last": "Il\u00edk", "suffix": ""}, {"first": "J", "middle": [], "last": "Nau\u0161", "suffix": ""}], "year": 2001, "venue": "Aust. J. Plant Physiol", "link": null}, "BIBREF45": {"title": "In intact leaves, the maximum fluorescence level (F M ) is independent of the redox state of the plastoquinone pool: A DCMU-inhibition study", "authors": [{"first": "S", "middle": ["Z"], "last": "T\u00f3th", "suffix": ""}, {"first": "G", "middle": [], "last": "Schansker", "suffix": ""}, {"first": "R", "middle": ["J"], "last": "Strasser", "suffix": ""}], "year": "", "venue": "", "link": "20490021"}, "BIBREF46": {"title": "Vitality and stress adaptation of the symbionts of coral reef and temperature foraminifers probed in hospite by the fluorescence kinetics OJIP", "authors": [{"first": "M", "middle": [], "last": "Tsimilli-Michael", "suffix": ""}, {"first": "M", "middle": [], "last": "P\u00eacheux", "suffix": ""}, {"first": "R", "middle": ["J"], "last": "Strasser", "suffix": ""}, {"first": "J", "middle": ["J"], "last": "Van Thor", "suffix": ""}, {"first": "T", "middle": ["H"], "last": "Geerlings", "suffix": ""}, {"first": "H", "middle": ["C P"], "last": "Matthijs", "suffix": ""}, {"first": "K", "middle": ["J"], "last": "Hellingwerf", "suffix": ""}], "year": 1998, "venue": "Biochim. Biophys. Acta", "link": null}, "BIBREF47": {"title": "Quenching of the system II chlorophyll fluorescence by the plastoquinone pool", "authors": [{"first": "C", "middle": [], "last": "Vernotte", "suffix": ""}, {"first": "A.-L", "middle": [], "last": "Etienne", "suffix": ""}, {"first": "J.-M", "middle": [], "last": "Briantais", "suffix": ""}], "year": 1979, "venue": "Biochim. Biophys. Acta", "link": "20235700"}, "BIBREF48": {"title": "Modeling of chlorophyll a fluorescence kinetics in plant cells: derivation of a descriptive algorithm", "authors": [{"first": "W", "middle": ["J"], "last": "Vredenberg", "suffix": ""}, {"first": "W", "middle": ["J"], "last": "Vredenberg", "suffix": ""}, {"first": "A", "middle": ["A"], "last": "Bulychev", "suffix": ""}, {"first": "W", "middle": [], "last": "Vredenberg", "suffix": ""}, {"first": "O", "middle": [], "last": "Pr\u00e1\u0161il", "suffix": ""}], "year": 2000, "venue": "A three-state model for energy trapping and chlorophyll fluorescence in photosystem II incorporating radical pair recombination", "link": "98223840"}, "BIBREF49": {"title": "Chlorophyll a fluorescence induction kinetics in leaves predicted from a model describing each discrete step of excitation energy and electron transfer associated with Photosystem II", "authors": [{"first": "X.-G", "middle": [], "last": "Zhu", "suffix": ""}, {"first": "", "middle": [], "last": "Govindjee", "suffix": ""}, {"first": "N", "middle": ["R"], "last": "Baker", "suffix": ""}, {"first": "E", "middle": [], "last": "Desturler", "suffix": ""}, {"first": "D", "middle": ["R"], "last": "Ort", "suffix": ""}, {"first": "S", "middle": ["P"], "last": "Long", "suffix": ""}], "year": 2005, "venue": "Planta", "link": "9698923"}}, "ref_entries": {}}
{"paper_id": "41518378", "_pdf_hash": "3885463cd580cc60ff69602121c872e89e74e6c2", "abstract": [], "body_text": [], "bib_entries": {"BIBREF1": {"title": "Materials processing: Two-photon fabrication", "authors": [{"first": "M", "middle": [], "last": "Farsari", "suffix": ""}, {"first": "B", "middle": ["N"], "last": "Chichkov", "suffix": ""}], "year": 2009, "venue": "Nature Photonics", "link": null}, "BIBREF2": {"title": "Morphology and size dependence of silver microstructures in fatty salts-assisted multiphoton photoreduction microfabrication", "authors": [{"first": "Y", "middle": ["Y"], "last": "Cao", "suffix": ""}, {"first": "X", "middle": ["Z"], "last": "Dong", "suffix": ""}, {"first": "N", "middle": [], "last": "Takeyasu", "suffix": ""}, {"first": "T", "middle": [], "last": "Tanaka", "suffix": ""}, {"first": "Z", "middle": ["S"], "last": "Zhao", "suffix": ""}, {"first": "X", "middle": ["M"], "last": "Duan", "suffix": ""}, {"first": "S", "middle": [], "last": "Kawata", "suffix": ""}], "year": 2009, "venue": "Appl. Phys. A-Mater. Sci. Process", "link": "93610644"}, "BIBREF3": {"title": "3D Metallic Nanostructure Fabrication by Surfactant-Assisted Multiphoton-Induced Reduction", "authors": [{"first": "Y", "middle": ["Y"], "last": "Cao", "suffix": ""}, {"first": "N", "middle": [], "last": "Takeyasu", "suffix": ""}, {"first": "T", "middle": [], "last": "Tanaka", "suffix": ""}, {"first": "X", "middle": ["M"], "last": "Duan", "suffix": ""}, {"first": "S", "middle": [], "last": "Kawata", "suffix": ""}], "year": 2009, "venue": "Small", "link": "11477058"}, "BIBREF4": {"title": "Gold Helix Photonic Metamaterial as Broadband Circular Polarizer", "authors": [{"first": "J", "middle": ["K"], "last": "Gansel", "suffix": ""}, {"first": "M", "middle": [], "last": "Thiel", "suffix": ""}, {"first": "M", "middle": ["S"], "last": "Rill", "suffix": ""}, {"first": "M", "middle": [], "last": "Decker", "suffix": ""}, {"first": "K", "middle": [], "last": "Bade", "suffix": ""}, {"first": "V", "middle": [], "last": "Saile", "suffix": ""}, {"first": "G", "middle": [], "last": "Von Freymann", "suffix": ""}, {"first": "S", "middle": [], "last": "Linden", "suffix": ""}, {"first": "M", "middle": [], "last": "Wegener", "suffix": ""}], "year": 2009, "venue": "Science", "link": "9948158"}, "BIBREF5": {"title": "Gold helix photonic metamaterials: A numerical parameter study", "authors": [{"first": "J", "middle": ["K"], "last": "Gansel", "suffix": ""}, {"first": "M", "middle": [], "last": "Wegener", "suffix": ""}, {"first": "S", "middle": [], "last": "Burger", "suffix": ""}, {"first": "S", "middle": [], "last": "Linden", "suffix": ""}], "year": 2010, "venue": "Opt. Express", "link": "24814201"}, "BIBREF6": {"title": "Two-photon polymerization of metal ions doped acrylate monomers and oligomers for three-dimensional structure fabrication", "authors": [{"first": "X", "middle": ["M"], "last": "Duan", "suffix": ""}, {"first": "H", "middle": ["B"], "last": "Sun", "suffix": ""}, {"first": "K", "middle": [], "last": "Kaneko", "suffix": ""}, {"first": "S", "middle": [], "last": "Kawata", "suffix": ""}], "year": 2004, "venue": "Thin Solid Films", "link": "97086311"}, "BIBREF7": {"title": "Metal-nanoshelled three-dimensional photonic lattices", "authors": [{"first": "K", "middle": [], "last": "Kaneko", "suffix": ""}, {"first": "K", "middle": [], "last": "Yamamoto", "suffix": ""}, {"first": "S", "middle": [], "last": "Kawata", "suffix": ""}, {"first": "H", "middle": [], "last": "Xia", "suffix": ""}, {"first": "J", "middle": ["F"], "last": "Song", "suffix": ""}, {"first": "H", "middle": ["B"], "last": "Sun", "suffix": ""}], "year": 1999, "venue": "Optics Letters", "link": "36004411"}, "BIBREF8": {"title": "Two-and three-dimensional micro/nanostructure patterning of CdS-polymer nanocomposites with a laser interference technique and in situ synthesis", "authors": [{"first": "Z", "middle": ["B"], "last": "Sun", "suffix": ""}, {"first": "X", "middle": ["Z"], "last": "Dong", "suffix": ""}, {"first": "W", "middle": ["Q"], "last": "Chen", "suffix": ""}, {"first": "S", "middle": [], "last": "Shoji", "suffix": ""}, {"first": "X", "middle": ["M"], "last": "Duan", "suffix": ""}, {"first": "S", "middle": [], "last": "Kawata", "suffix": ""}], "year": 2008, "venue": "Nanotechnology", "link": "13105844"}, "BIBREF9": {"title": "Electroless Plating: Fundamentals and Applications", "authors": [{"first": "G", "middle": ["O"], "last": "Mallory", "suffix": ""}, {"first": "J", "middle": ["B"], "last": "Hajdu", "suffix": ""}, {"first": "Eds", "middle": [], "last": "", "suffix": ""}], "year": 1990, "venue": "", "link": "137244406"}, "BIBREF10": {"title": "New strategy for preparing thin gold films on modified glass surfaces by electroless deposition", "authors": [{"first": "S", "middle": [], "last": "Hrapovic", "suffix": ""}, {"first": "Y", "middle": ["L"], "last": "Liu", "suffix": ""}, {"first": "G", "middle": [], "last": "Enright", "suffix": ""}, {"first": "F", "middle": [], "last": "Bensebaa", "suffix": ""}, {"first": "J", "middle": ["H T"], "last": "Luong", "suffix": ""}], "year": 2003, "venue": "Langmuir", "link": "98334708"}, "BIBREF11": {"title": "Fabrication and Characterization of Three-Dimensional Silver-Coated Polymeric Microstructures", "authors": [{"first": "Y.-S", "middle": [], "last": "Chen", "suffix": ""}, {"first": "A", "middle": [], "last": "Tal", "suffix": ""}, {"first": "D", "middle": ["B"], "last": "Torrance", "suffix": ""}, {"first": "S", "middle": ["M"], "last": "Kuebler", "suffix": ""}], "year": 2006, "venue": "Adv. Funct. Mater", "link": "95983564"}, "BIBREF12": {"title": "Fabrication of 3D metal/polymer microstructures by site-selective metal coating", "authors": [{"first": "N", "middle": [], "last": "Takeyasu", "suffix": ""}, {"first": "T", "middle": [], "last": "Tanaka", "suffix": ""}, {"first": "S", "middle": [], "last": "Kawata", "suffix": ""}], "year": 2008, "venue": "Appl. Phys. A-Mater. Sci. Process", "link": "94286323"}, "BIBREF13": {"title": "Three-dimensional photonic crystal structures achieved with two-photon-absorption photopolymerization of resin", "authors": [{"first": "H.-B", "middle": [], "last": "Sun", "suffix": ""}, {"first": "S", "middle": [], "last": "Matsuo", "suffix": ""}, {"first": "Misawa", "middle": [], "last": "", "suffix": ""}], "year": 1999, "venue": "Appl. Phys. Lett", "link": "122876038"}, "BIBREF14": {"title": "Complex micromachines produced and driven by light", "authors": [{"first": "P", "middle": [], "last": "Galajda", "suffix": ""}, {"first": "Ormosa", "middle": [], "last": "", "suffix": ""}], "year": 2001, "venue": "Appl. Phys. Lett", "link": "120182171"}, "BIBREF15": {"title": "Laser-fabricated dielectric optical components for surface plasmon polaritons", "authors": [{"first": "C", "middle": [], "last": "Reinhardt", "suffix": ""}, {"first": "S", "middle": [], "last": "Passinger", "suffix": ""}, {"first": "B", "middle": ["N"], "last": "Chichkov", "suffix": ""}, {"first": "C", "middle": [], "last": "Marquart", "suffix": ""}, {"first": "I", "middle": ["P"], "last": "Radko", "suffix": ""}, {"first": "", "middle": [], "last": "Bozhevolnyi", "suffix": ""}], "year": 2006, "venue": "Opt.Lett", "link": "31795452"}, "BIBREF16": {"title": "Three-Dimensional Biodegradable Structures Fabricated by Two-Photon Polymerization", "authors": [{"first": "R", "middle": ["J"], "last": "Narayan", "suffix": ""}, {"first": "C", "middle": ["M"], "last": "Jin", "suffix": ""}, {"first": "A", "middle": [], "last": "Doraiswamy", "suffix": ""}, {"first": "I", "middle": ["N"], "last": "Mihailescu", "suffix": ""}, {"first": "M", "middle": [], "last": "Jelinek", "suffix": ""}, {"first": "A", "middle": [], "last": "Ovsianikov", "suffix": ""}, {"first": "B", "middle": [], "last": "Chichkov", "suffix": ""}, {"first": "", "middle": [], "last": "Chrisey", "suffix": ""}], "year": 2005, "venue": "Adv.Eng.Mater", "link": "26826965"}, "BIBREF17": {"title": "Construction of three-dimensional biomolecule structures employing femtosecond lasers", "authors": [{"first": "T", "middle": ["S"], "last": "Drakakis", "suffix": ""}, {"first": "G", "middle": [], "last": "Papadakis", "suffix": ""}, {"first": "K", "middle": [], "last": "Sambani", "suffix": ""}, {"first": "G", "middle": [], "last": "Filippidis", "suffix": ""}, {"first": "S", "middle": [], "last": "Georgiou", "suffix": ""}, {"first": "E", "middle": [], "last": "Gizeli", "suffix": ""}, {"first": "C", "middle": [], "last": "Fotakis", "suffix": ""}, {"first": "M", "middle": [], "last": "Farsari", "suffix": ""}], "year": 2006, "venue": "Applied Physics Letters", "link": "121177816"}, "BIBREF18": {"title": "65 nm feature sizes using visible wavelength 3D multiphoton lithography", "authors": [{"first": "W", "middle": [], "last": "Haske", "suffix": ""}, {"first": "V W", "middle": [], "last": "Chen", "suffix": ""}, {"first": "J M", "middle": [], "last": "Hales", "suffix": ""}, {"first": "W T", "middle": [], "last": "Dong", "suffix": ""}, {"first": "S", "middle": [], "last": "Barlow", "suffix": ""}, {"first": "S", "middle": [], "last": "Marder", "suffix": ""}, {"first": "J W", "middle": [], "last": "Perry", "suffix": ""}], "year": 2007, "venue": "Opt. Expres", "link": "9529749"}, "BIBREF19": {"title": "Multiphoton polymerization of hybrid materials", "authors": [{"first": "M", "middle": [], "last": "Farsari", "suffix": ""}, {"first": "M", "middle": [], "last": "Vamvakaki", "suffix": ""}, {"first": "B", "middle": [], "last": "Chichkov", "suffix": ""}], "year": 2010, "venue": "J. Opt", "link": "121335889"}}, "ref_entries": {}}
{"paper_id": "41518549", "_pdf_hash": "7af12fc19bfe74919a7a24f05f8cb51f89a6619c", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "An Analysis of Convective Losses From Cavity Solar Central Receiver", "authors": [{"first": "A", "middle": ["M"], "last": "Clausing", "suffix": ""}], "year": 1981, "venue": "Sol. Energy", "link": "120420829"}, "BIBREF1": {"title": "Convection Losses From Cavity Solar Receivers-Comparisons Between Analytical Predictions and Experimental Results", "authors": [{"first": "A", "middle": ["M"], "last": "Clausing", "suffix": ""}], "year": 1983, "venue": "Journal of Solar Energy Engineering", "link": "111164099"}, "BIBREF2": {"title": "Economic Mass Producible Mirror Panels for Solar Concentrators", "authors": [{"first": "G", "middle": [], "last": "Johnston", "suffix": ""}, {"first": "G", "middle": [], "last": "Burgess", "suffix": ""}, {"first": "K", "middle": [], "last": "Lovegrove", "suffix": ""}, {"first": "Luzzi", "middle": ["A"], "last": "", "suffix": ""}], "year": 2001, "venue": "Proceedings of ISES World Congress", "link": "38905185"}, "BIBREF3": {"title": "Thermal performance of concentrator/cavity receiver systems", "authors": [{"first": "J", "middle": ["A"], "last": "Harris", "suffix": ""}, {"first": "T", "middle": ["G"], "last": "Lenz", "suffix": ""}], "year": 1985, "venue": "Solar energy", "link": null}, "BIBREF4": {"title": "Heat transfer", "authors": [{"first": "J", "middle": ["P"], "last": "Holman", "suffix": ""}], "year": 1997, "venue": "", "link": null}, "BIBREF5": {"title": "Convection heat loss sensitivity in open cavity solar receivers", "authors": [{"first": "A", "middle": ["A"], "last": "Koenig", "suffix": ""}, {"first": "M", "middle": [], "last": "Marvin", "suffix": ""}], "year": 1981, "venue": "DOE contract", "link": null}, "BIBREF6": {"title": "Convective Heat Loss from Upward and Downward-Facing Cavity Solar Receivers: Measurements and Calculations", "authors": [{"first": "U", "middle": [], "last": "Leibfried", "suffix": ""}, {"first": "J", "middle": [], "last": "Ortjohann", "suffix": ""}], "year": 1995, "venue": "J. Sol. Eng", "link": "110021988"}, "BIBREF7": {"title": "Developing Ammonia Based Thermochemical Energy Storage for Dish Power Plants -Smelly Experiments, Good Technology", "authors": [{"first": "K", "middle": [], "last": "Lovegrove", "suffix": ""}, {"first": "A", "middle": [], "last": "Luzzi", "suffix": ""}, {"first": "I", "middle": [], "last": "Soldiani", "suffix": ""}, {"first": "H", "middle": [], "last": "Kreetz", "suffix": ""}], "year": 2001, "venue": "Proceedings of ISES World Congress", "link": null}, "BIBREF8": {"title": "Numerical Investigation of Natural Convection Loss in Cavity Type Solar Receivers", "authors": [{"first": "S", "middle": [], "last": "Paitoonsurikarn", "suffix": ""}, {"first": "K", "middle": [], "last": "Lovegrove", "suffix": ""}], "year": 2000, "venue": "Proceedings of Solar", "link": "19365317"}, "BIBREF9": {"title": "Cavity Receiver Heat Loss Measurements, presented at ISES World Congress", "authors": [{"first": "W", "middle": ["B"], "last": "Stine", "suffix": ""}, {"first": "C", "middle": ["G"], "last": "Mcdonald", "suffix": ""}], "year": 1989, "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "41518687", "_pdf_hash": "0ae73ca07e1d48bf315397dcab34549f19cf4b8b", "abstract": [], "body_text": [{"section": "", "text": "Sirs, Increased serum prolactin (PRL) levels have been demonstrated in several autoimmune diseases including polymyositis (PM) and systemic sclerosis (SSc) [1] [2] [3] . PRL is produced by the lactotrophs of the pituitary gland, but the immune cells can produce PRL as well, and PRL acts as a cytokine with role in B, T, and dendritic cell maturation [1] . Czuwara-Ladykowska et al.", "cite_spans": [{"start": 156, "end": 159, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 351, "end": 354, "text": "[1]", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "", "text": "[4] demonstrated higher PRL mRNA synthesis in lymphocytes from patients suVering from SSc than in healthy individuals. Multiple promoters regulate PRL gene transcription. Unlike the pituitary production controlled by the pituitary promoter under the inXuence of transcriptional factor Pit-1, the extrapituitary (including that by immune cells) PRL secretion is regulated by the Pit-1 independent alternative promoter located 5840 bp distal to the start of the PRL transcriptional site [5] . This extrapituitary promoter contains functional single nucleotide polymorphism (SNP) \u00a11149 G/T (rs1341239) in the GATA sequence; G allele leads to higher PRL mRNA in lymphocytes synthesis [6] . GG genotype has been associated with systemic lupus erythematosus (SLE) [6, 7] , while TT genotype was identiWed as protective for non-Hodgkin and follicular lymphoma, and rheumatoid arthritis development [8, 9] .", "cite_spans": [{"start": 895, "end": 897, "text": "9]", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "", "text": "In this study, we looked for distribution of allele and genotype of the \u00a11149 G/T SNP of the extrapituitary PRL promoter in 75 patients with SSc (average age 61.4), in 47 subjects with PM (average age 57.8), in 68 patients with dermatomyositis (DM) (average age 58.3), and in 123 healthy Czech individuals (blood donors and medical students, average age 39.7). SSc and PM/DM patients met classiWcation criteria for these illnesses [10, 11] . PCR-RFLP methodology was used for \u00a11149G/T SNP detection [7] . BrieXy, we ampliWed 137 bp region of the PRL extrapituitary promoter and for restriction used ApoI endonuclease. We determined the following genotypes: the homozygote TT characterized by 120 + 17 bp, the homozygote GG by 85 + 35 + 17 bp, and the heterozygote GT by 120 + 85 + 35 + 17 bp DNA fragments. Results were evaluated by 2 test with Bonferroni correction. Control group was in Hardy-Weinberg equilibrium.", "cite_spans": [{"start": 431, "end": 435, "text": "[10,", "ref_id": "BIBREF2"}, {"start": 436, "end": 439, "text": "11]", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "", "text": "The genotype and allele distribution did not show any signiWcant diVerences in groups of PM, DM, and SSc patients compared to healthy individuals (Table 1) , and we detected neither gender distribution diVerences (data not shown) nor correlation with speciWc clinical or serological manifestation of these diseases (lung Wbrosis, type of scleroderma, antiScl-70 and antiJo-1 positivity) (Table 1) . However, we found a signiWcant inverse association between TT genotype in SSc patients with disease onset after 45 years compared to individuals with SSc and diseases onset prior to 45 years (2/47 = 4.1 vs. 6/18 = 25%, respectively; P corrected = 0.02; OR = 0.13; CI (95%): 0.02-0.69).", "cite_spans": [], "ref_spans": [{"start": 146, "end": 155, "text": "(Table 1)", "ref_id": "TABREF0"}, {"start": 387, "end": 396, "text": "(Table 1)", "ref_id": "TABREF0"}]}, {"section": "", "text": "Thus, genotype \u00a11149 TT of the extrapituitary PRL promoter SNP (via reduced PRL promoter activity and consequently lower PRL levels in lymphocytes) seems to be associated with decreased risk to SSc development in older age. With regards to the age of onset, no diferences in allele or genotype frequences in patients with polymyositis and dermatomyositis were found. We can assume that this polymorphism might be somewhat speciWc for SSc and therefore warrants further investigation into PRL genetics and its levels during the disease course. ", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Novel biomarkers in autoimmune diseases-prolactin, ferritin, vitamin D, and TPA levels in autoimmune diseases", "authors": [{"first": "H", "middle": [], "last": "Orbach", "suffix": ""}, {"first": "G", "middle": [], "last": "Zandman-Goddard", "suffix": ""}, {"first": "H", "middle": [], "last": "Amital", "suffix": ""}], "year": 2007, "venue": "Ann NY Acad Sci", "link": "31770656"}, "BIBREF1": {"title": "The PRL \u00a11149 G/T polymorphism and rheumatoid arthritis susceptibility", "authors": [{"first": "Y", "middle": ["C"], "last": "Lee", "suffix": ""}, {"first": "S", "middle": [], "last": "Raychaudhuri", "suffix": ""}, {"first": "J", "middle": [], "last": "Cui", "suffix": ""}], "year": 2009, "venue": "Arthritis Rheum", "link": "20965724"}, "BIBREF2": {"title": "Subcommittee for Scleroderma Criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee (1980) Preliminary criteria for the classiWcation of systemic sclerosis (scleroderma)", "authors": [], "year": "", "venue": "Arthritis Rheum", "link": null}, "BIBREF3": {"title": "Polymyositis and dermatomyositis (Wrst of two parts)", "authors": [{"first": "A", "middle": [], "last": "Bohan", "suffix": ""}, {"first": "J", "middle": ["B"], "last": "Peter", "suffix": ""}], "year": 1975, "venue": "N Engl J Med", "link": null}}, "ref_entries": {"FIGREF0": {"text": "La Montagna G, Meli R, Criscuolo T et al (2004) Bioactivity of prolactin in systemic sclerosis. Clin Exp Rheumatol 22:145-150 3. Mirone L, Barini A, Barini A (2006) Androgen and prolactin (Prl) levels in systemic sclerosis (SSc) relationship to disease Severiny. Ann NY Acad Sci 1069:257-262 4. Czuwara-Ladykowska J, Sicinska J, Olsewska M et al (2006) Prolactin synthesis by lymphocytes from patiens with systemic sclerosis. Biomed Pharmacother 60:152-155 5. Gellersen B, Kempf R, Telgmann R et al (1994) Nonpituitary human prolactin gene transcription is independent of Pit-1 and diVerentially controlled in lymphocytes and in endometrial stro- ma. Mol Endocrinol 8:356-373 6. Stevens A, Ray DW, Worthington J et al (2001) Polymorphisms of the human prolactin gene-implications for production of lym- phocyte prolactin and systemic lupus erythematosus. Lupus 10:676-683 7. Fojtikova M, Cerna M, Cejkova P et al (2007) Extrapituitary pro- lactin promoter polymorphism in Czech patients with systemic lupus erythematosus and rheumatoid arthritis. Ann Rheum Dis 66:706-707 8. Skibola CF, Bracci PM, Paynter RA et al (2005) Polymorphisms and haplotypes in the cytochrome P450 17A1, prolactin, and cate- chol-O-methyltransferase genes and non-Hodgkin lymphoma risk. Cancer Epidemiol Biomarkers Prev 14:2391-2401", "type": "figure"}, "TABREF0": {"text": "P2 P value was determined by the \u00b2 test comparing positive/negative feature and comparing each feature and controls, Pc P value corrected for multiple comparisons (3 detected genotypes, 2 alleles), ns not signiWcant, ANA Antinuclear antibodies, Jo-1 antibodies against histidyl-tRNA synthethase, Scl-70 antibodies against DNA topoisomerase I, lSSc limited cutaneous SSc, dSSc diVuse cutaneus SSc, CPM cancer associated Polymyositis, CDM cancer-associated Der-PRL extrapituitary promoter \u00a11149 G/T SNP", "type": "table"}}}
{"paper_id": "41519200", "_pdf_hash": "94ef5202d66b0ddafad8e77eda4759a006481c8d", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Profile of bacterial isolates and antimicrobial susceptibility: Multi-centre study using a one-day cut-off", "authors": [{"first": "R", "middle": [], "last": "Alonso", "suffix": ""}, {"first": "A", "middle": [], "last": "Fernandez-Aranquiz", "suffix": ""}, {"first": "K", "middle": [], "last": "Colorn", "suffix": ""}, {"first": "A", "middle": [], "last": "Herreras", "suffix": ""}, {"first": "R", "middle": [], "last": "Cistema", "suffix": ""}], "year": 2000, "venue": "Revista Espnola de Quimioterapia", "link": null}, "BIBREF1": {"title": "Reference method for dilution antimicrobial susceptibility tests for bacteria that grow aerobically. Approved standard M7-A6", "authors": [], "year": 2003, "venue": "", "link": null}, "BIBREF2": {"title": "Plant products as antimicrobial agents", "authors": [{"first": "M", "middle": ["M"], "last": "Cowan", "suffix": ""}], "year": 1999, "venue": "Clinical Microbiology Revision", "link": "12801438"}, "BIBREF3": {"title": "Extraction and evaluation of antibacterial activity from selected flowering plants", "authors": [{"first": "A", "middle": [], "last": "Erlina", "suffix": ""}, {"first": "A", "middle": ["R"], "last": "Raha", "suffix": ""}, {"first": "J", "middle": [], "last": "Parveen", "suffix": ""}], "year": 2012, "venue": "American Medical Journal", "link": "83775127"}, "BIBREF4": {"title": "Novel use of panduratin derivatives or extracts of Kempferia pandurata comprising the same", "authors": [{"first": "E", "middle": ["J"], "last": "Choi", "suffix": ""}, {"first": "S", "middle": ["H"], "last": "Gwon", "suffix": ""}, {"first": "Y", "middle": ["S"], "last": "Han", "suffix": ""}, {"first": "J", "middle": ["K"], "last": "Hwang", "suffix": ""}, {"first": "D", "middle": ["U"], "last": "Kim", "suffix": ""}, {"first": "Y", "middle": ["Y"], "last": "Kwon", "suffix": ""}, {"first": "H", "middle": ["I"], "last": "Oh", "suffix": ""}, {"first": "J", "middle": ["S"], "last": "Shim", "suffix": ""}], "year": 2012, "venue": "", "link": null}, "BIBREF5": {"title": "Antibiotic resistance of Enterobacteriaceae genera and Salmonella spp., Salmonella enterica ser. Typhimurium and Enteritidis isolated from milk, cheese and other dairy products from conventional farm in Slovakia", "authors": [{"first": "L", "middle": [], "last": "Hleba", "suffix": ""}, {"first": "M", "middle": [], "last": "Ka\u010d\u00e1niov\u00e1", "suffix": ""}, {"first": "J", "middle": [], "last": "Pochop", "suffix": ""}, {"first": "J", "middle": [], "last": "Lejkov\u00e1", "suffix": ""}, {"first": "", "middle": [], "last": "\u010cubo\u0148", "suffix": ""}, {"first": "J", "middle": [], "last": "Kunov\u00e1", "suffix": ""}], "year": 2011, "venue": "Biotechnology and Food Sciences", "link": "82484054"}, "BIBREF6": {"title": "Screening of some Indian medicinal plants for their antimicrobials properties", "authors": [{"first": "A", "middle": [], "last": "Iqbal", "suffix": ""}, {"first": "M", "middle": [], "last": "Zafar", "suffix": ""}, {"first": "M", "middle": [], "last": "Faiz", "suffix": ""}], "year": 1998, "venue": "Journal of Ethnopharmacology", "link": "40714610"}, "BIBREF7": {"title": "Antimicrobial activity of plant extracts against Salmonella Typhimurium, Escherichia coli O157:H7 and Listeria monocytogenes on fresh lettuce", "authors": [{"first": "S", "middle": ["Y"], "last": "Kim", "suffix": ""}, {"first": "D", "middle": ["H"], "last": "Kang", "suffix": ""}, {"first": "J", "middle": ["K"], "last": "Kim", "suffix": ""}, {"first": "Y", "middle": ["G"], "last": "Ha", "suffix": ""}, {"first": "J", "middle": ["Y"], "last": "Hwang", "suffix": ""}, {"first": "T", "middle": ["W"], "last": "Kim", "suffix": ""}, {"first": "S", "middle": ["H"], "last": "Lee", "suffix": ""}], "year": 2011, "venue": "Journal of Food Science", "link": "27551989"}, "BIBREF8": {"title": "Record IR, McIntosh GH. Anticancer properties of panduratin A isolated from Boesenbergia pandurata (Zingiberaceae)", "authors": [{"first": "C", "middle": [], "last": "Kirana", "suffix": ""}, {"first": "G", "middle": ["P"], "last": "Jones", "suffix": ""}], "year": 2007, "venue": "Journal of Natural Medicine", "link": null}, "BIBREF9": {"title": "Medicinal plants and plant extracts: A review of their importation into", "authors": [{"first": "A", "middle": [], "last": "Lewington", "suffix": ""}], "year": 1993, "venue": "Traffic International", "link": null}, "BIBREF10": {"title": "Antimicrobial susceptibility on solid media", "authors": [{"first": "V", "middle": [], "last": "Lorian", "suffix": ""}], "year": 2005, "venue": "Antibiotic in Laboratory Medicine", "link": null}, "BIBREF11": {"title": "Risk of Escherichia coli O157:H7 transmission linked to the consumption of raw milk", "authors": [{"first": "Y", "middle": ["L"], "last": "Lye", "suffix": ""}, {"first": "L", "middle": [], "last": "Afsah-Hejri", "suffix": ""}, {"first": "W", "middle": ["S"], "last": "Chang", "suffix": ""}, {"first": "Y", "middle": ["Y"], "last": "Loo", "suffix": ""}, {"first": "S", "middle": [], "last": "Puspanadan", "suffix": ""}, {"first": "C", "middle": ["H"], "last": "Kuan", "suffix": ""}, {"first": "S", "middle": ["G"], "last": "Goh", "suffix": ""}, {"first": "N", "middle": [], "last": "Shahril", "suffix": ""}, {"first": "Y", "middle": [], "last": "Rukayadi", "suffix": ""}, {"first": "A", "middle": [], "last": "Khatib", "suffix": ""}, {"first": "Y", "middle": ["H T"], "last": "John", "suffix": ""}, {"first": "M", "middle": [], "last": "Nishibuchi", "suffix": ""}, {"first": "Y", "middle": [], "last": "Nakaguchi", "suffix": ""}, {"first": "R", "middle": [], "last": "Son", "suffix": ""}], "year": 2013, "venue": "International Food Research Journal", "link": "34819593"}, "BIBREF12": {"title": "Antimicrobial activity of some important medicinal plant against plant and human pathogens", "authors": [{"first": "B", "middle": [], "last": "Mahesh", "suffix": ""}, {"first": "S", "middle": [], "last": "Satish", "suffix": ""}], "year": 2008, "venue": "World Journal of Agriculture Sciences", "link": null}, "BIBREF13": {"title": "An improved direct plate method for the enumeration of stressed Escherichia coli O157:H7 from food", "authors": [{"first": "J", "middle": ["H"], "last": "Mccarthy", "suffix": ""}], "year": 1998, "venue": "Journal of Food Microbiology", "link": "42904346"}, "BIBREF14": {"title": "In vitro antibacterial activity of tigecycline against resistant Gram-negative bacilli and enterococci by time-kill assay", "authors": [{"first": "G", "middle": ["A"], "last": "Pankey", "suffix": ""}, {"first": "D", "middle": ["S"], "last": "Ashcraft", "suffix": ""}], "year": 2009, "venue": "Diagnosis Microbiology of Infectious Disease", "link": "177927"}, "BIBREF15": {"title": "Frequency of antimicrobial resistance of E. coli isolates from dairy farms in Trinidad by source and presence of virulence markers", "authors": [{"first": "R", "middle": [], "last": "Roopnarine", "suffix": ""}, {"first": "D", "middle": [], "last": "Ammons", "suffix": ""}, {"first": "A", "middle": ["A"], "last": "Adesiyun", "suffix": ""}], "year": 2009, "venue": "Veterinary Archive", "link": "17029768"}, "BIBREF16": {"title": "Screening of Thai medicinal plants for anticandidal activity", "authors": [{"first": "Y", "middle": [], "last": "Rukayadi", "suffix": ""}, {"first": "J", "middle": ["S"], "last": "Shim", "suffix": ""}, {"first": "J", "middle": ["K"], "last": "Hwang", "suffix": ""}], "year": 2008, "venue": "Journal Compilation Mycoses", "link": "27403287"}, "BIBREF17": {"title": "In vitro activities of panduratin against clinical Staphylococcus strains", "authors": [{"first": "Y", "middle": [], "last": "Rukayadi", "suffix": ""}, {"first": "K", "middle": ["H"], "last": "Lee", "suffix": ""}, {"first": "S", "middle": ["H"], "last": "Han", "suffix": ""}, {"first": "D", "middle": ["G"], "last": "Yong", "suffix": ""}, {"first": "J", "middle": ["K"], "last": "Hwang", "suffix": ""}], "year": 2009, "venue": "Antimicrobial agents and Chemotherapy", "link": "8822809"}, "BIBREF18": {"title": "In vitro antibacterial activity of panduratin A against Enterococci clinical isolates", "authors": [{"first": "Y", "middle": [], "last": "Rukayadi", "suffix": ""}, {"first": "S", "middle": ["H"], "last": "Han", "suffix": ""}, {"first": "D", "middle": ["G"], "last": "Yong", "suffix": ""}, {"first": "J", "middle": ["K"], "last": "Hwang", "suffix": ""}], "year": 2010, "venue": "Biology Pharmaceutical Bulletin", "link": "33452575"}, "BIBREF19": {"title": "Skin and soft tissue infections in Latin American Medical Centres: Four year assessment of pathogenic frequency and antimicrobial susceptibility patterns", "authors": [{"first": "H", "middle": ["S"], "last": "Sader", "suffix": ""}, {"first": "R", "middle": ["N"], "last": "Jones", "suffix": ""}, {"first": "J", "middle": ["B"], "last": "Sibu", "suffix": ""}], "year": 2002, "venue": "Diagnostic Microbiology of Infectious Diseases", "link": null}, "BIBREF20": {"title": "Antibacterial activity of natural spices on multiple drug resistant Escherichia coli isolated from drinking water", "authors": [{"first": "R", "middle": [], "last": "Shahedur", "suffix": ""}, {"first": "K", "middle": ["P"], "last": "Anowar", "suffix": ""}, {"first": "I", "middle": [], "last": "Rezuanul", "suffix": ""}, {"first": "H", "middle": ["K"], "last": "Mahboob", "suffix": ""}], "year": 2011, "venue": "Bangladesh. Annals of Clinical Microbiology and Antimicrobials", "link": null}, "BIBREF21": {"title": "Evalution of polymerase chain reaction-based system for detection of Salmonella Enteritidis, Escherichia coli O157:H7, Listeria spp., and Listeria monocytogenes on fresh fruits and vegetables", "authors": [{"first": "A", "middle": ["E H"], "last": "Shearer", "suffix": ""}, {"first": "C", "middle": ["M"], "last": "Strapp", "suffix": ""}, {"first": "R", "middle": ["D"], "last": "Joerger", "suffix": ""}], "year": 2001, "venue": "Journal of Food Protection", "link": "22424875"}, "BIBREF22": {"title": "Activity of panduratin A Isolated from Kaempferia pandurata Roxb. against multi-species oral biofilm in vitro", "authors": [{"first": "Rukayadi", "middle": ["Y"], "last": "Yanti", "suffix": ""}, {"first": "K", "middle": ["H"], "last": "Lee", "suffix": ""}, {"first": "J", "middle": ["K"], "last": "Hwang", "suffix": ""}], "year": 2009, "venue": "Journal of Oral Science", "link": "12469007"}}, "ref_entries": {}}
{"paper_id": "10700033", "_pdf_hash": "74d5aa3aaa276223220266ae2ba2cbc2d6cd0a60", "abstract": [{"section": "Abstract", "text": "Background. A number of parameters reflecting the effects of idiopathic dilated cardiomyopathy (IDC) on the structure and function of myosin from the human myocardium were analyzed.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Methods and Results. The content of the regulatory light chain, LC2, was reduced in myopathic heart myosin in contrast to the controls in which it was present in stoichiometric amounts relative to the essential light chain, LC1. In IDC hearts, the absence or significant reduction in amount of LC2 was related to the presence of an active protease, which was isolated and purified about 130-fold. The protease", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "", "text": "Cardiac myosin contains one mole each of essential light chain (LC1) and regulatory light chain (LC2) on each of the two myosin heads.78 These light chains are also subject to transitions from one isotype to another by external factors.9'0 One of the light chains, the phosphorylatable LC2, appears to be sensitive to the presence of proteolytic enzymes under certain conditions. For example, slow degradation of skeletal muscle myosin LC2 occurred over a period of storage.\" More significantly, LC2 is greatly reduced or absent in freshly prepared cardiac myosin from myopathic hamsters. '2 ", "cite_spans": [], "ref_spans": []}, {"section": "See p 1945", "text": "Frequent attempts have been made to evaluate myosin from cardiac tissue in humans suffering from a variety of heart diseases to comprehend the molecular basis of the pathophysiology of this disorder. The findings have been inconsistent. A possible explanation for conflicting reports based on human heart experiments may be the diversity or complexity of the cardiomyopathy being investigated. Idiopathic dilated (or congestive) cardio-myopathy (IDC) is the result of a variety of insults13 and is by definition a disease of unknown etiology14 as opposed to hypertrophic cardiomyopathy, which may in some cases be associated with a genetic defect in myosin heavy chain. 15 Regardless of the inciting cause, the natural history of the disease is not well-defined because the presenting symptoms are those of heart failure, basically the end stage of the condition. 16 '7 Histologically, the picture reveals diffuse fibrosis and in some cases, small focal scars. 18 The progression of the disease from onset of symptoms to terminal heart failure is quite variable, and in some cases occurs within months and in others takes years, with the same final appearance of the heart. As a result, patients with IDC usually are diagnosed when symptoms of heart failure occur and other causes of heart failure are eliminated; thus, the disease tends to appear well past the initial insult.16'17 Furthermore, recent reports have shown a decrease in the myofibrillar content of myocytes from patients with IDC.1920 On the basis of the above considerations, we undertook an examination of the contractile proteins in hearts excised at transplant time, which provided fresh tissue for analysis of the contractile apparatus. In this communication, we report that the LC1-to-LC2 ratio, which is normally 1 in cardiac myosin, is reduced to 1/0.1 to 1/0.69 in patients with IDC. Furthermore, we have identified a neutral protease present at a threefold to fivefold higher activity in IDC samples over control hearts. This particular neutral protease had a high degree of substrate specificity for human heart myosin LC2, unlike that found in the hamster cardiomyopathy model,12 which cleaved LC2 equally extensively in rabbit skeletal or cardiac myosin. The modified, LC2-deficient myosin has been shown to possess a lower Vm for the actin-activated MgATPase, and synthetic thick filaments prepared from it tended to be shorter by 50% or more when compared with control myosin filaments. Methods", "cite_spans": [{"start": 670, "end": 672, "text": "15", "ref_id": "BIBREF14"}, {"start": 864, "end": 866, "text": "16", "ref_id": "BIBREF15"}, {"start": 961, "end": 963, "text": "18", "ref_id": "BIBREF17"}], "ref_spans": []}, {"section": "Description of Cardiomyopathy and Treatment of Human Cardiac Tissue", "text": "In all, 17 hearts were obtained at the time of transplant (see Table 1 ). All patients except No. 29 were in New York Heart Association class III or IV heart failure and receiving appropriate medications. Case 29 had intractable ventricular tachycardia, and case K had Eisenmenger's complex with severe pulmonary hypertension for which a heart-lung transplant had been performed. Upon excision, the hearts were placed in Krebs-Henseleit solution buffered with 10 mM HEPES to pH 7.4 at 4-5\u00b0C. The epicardial arteries, veins, and when present, bypass grafts were removed for other studies. The remainder of the left and right ventricles were diced into 1-1.5-cm3 sections, the epicardial fat was dissected away, and the cubes were placed in a buffer consisting of 50% glycerol, 0.03 M KCl, 0.01 M K2HPO4, 5 mM MgCl2, and 1 mM dithiothreitol (DTT) (pH 6.5). At this time, tissue for scanning and transmission electron microscopy and light microscopy was prepared for diagnosis.21 '22 The samples were stored at 4\u00b0C for 24 hours and were then placed in fresh 50% glycerol buffer, quick-frozen in dry ice. At the time of dissection, obvious scars and areas of grossly visible diffuse fibrosis were avoided. All of the hearts available were hypertrophied to varying degrees. The hearts diagnosed as IDC were the experimental group, and all others were considered controls. In some cases, a single heart did not supply enough tissue and had to be combined with others. This is indicated in Table 1 . Twenty to 40 arterial rings were obtained from each heart and subjected to a variety of functional tests.23 '24 All rings were embedded in paraffin, and the amounts of intimal thickening, atherosclerosis, and medial thickness were evaluated using a Bioquant system. Regions of atherosclerosis when present were noted. The IDC patients had either no or minimal atherosclerosis, i.e., no plaque region involving more than 20% of the lumen. Of the atherosclerotic patients, all had at least 90-100% occlusive old plaques corresponding to the region or regions of infarction.", "cite_spans": [], "ref_spans": [{"start": 63, "end": 70, "text": "Table 1", "ref_id": "TABREF1"}, {"start": 1483, "end": 1490, "text": "Table 1", "ref_id": "TABREF1"}]}, {"section": "Preparation of Human Cardiac Myofibrils and Myosin", "text": "Human cardiac tissue was washed several times with 0.03 M KCl, 0.01 M potassium phosphate (pH 7.0), 1 mM DTT, 1 mM EDTA, and was then ground. Myofibrils were prepared from ground tissue according to the method of Solaro et al, 25 and myosin was extracted by the procedure described before.26 Phenylmethylsulfonyl fluoride (PMSF, 0.1 mM) and N-p-tosyl-lysine chloromethyl ketone (TLCK, 0.015 mM) were included in buffers used for myofibrillar protein preparations from control tissues. Myosin was further purified by chromatography on a DE52 column equilibrated in 0.02 M sodium pyrophosphate27 to remove actin and tropomyosin. Myosin subfragment 1 (S1) was prepared by a-chymotryptic digestion,27 and rabbit skeletal muscle actin was prepared from acetone-dried muscle residue by the A TPase Assays Steady-state rates of ATP hydrolysis were measured by the colorimetric determination of phosphate37 at the indicated actin concentrations using the method of initial rates. The dependence of rate on actin concentration was fitted using a computer program that uses a nonlinear least-squares simplex method.", "cite_spans": [{"start": 227, "end": 229, "text": "25", "ref_id": "BIBREF24"}], "ref_spans": []}, {"section": "Kinetics ofATP Binding", "text": "The kinetics of ATP binding to myosin and Si were measured in 0.6 M NaCI, 20 mM imidazole (pH 7.0), and 2 mM MgCl2 at 15\u00b0C from the increase in tryptophan fluorescence observed upon mixing protein with ATP in a stopped-flow fluorometer.37 The excitation wavelength was 295 nm, and emission wavelength was 320-380 nm. Data were collected with a Nicolet III oscilloscope and then transferred to a Zenith 148 personal computer for analysis and long-term storage.", "cite_spans": [], "ref_spans": []}, {"section": "Kinetics ofATP Binding", "text": "Observed rate constants, k0b,, were obtained by fitting the equation I(t)=oe-kobs+C by the method of moments, where I is the observed fluorescence intensity, and I0 is the amplitude of fluorescence change. 38 ", "cite_spans": [{"start": 206, "end": 208, "text": "38", "ref_id": "BIBREF37"}], "ref_spans": []}, {"section": "Light-Scattering Measurements", "text": "The rate and extent of myosin aggregation caused by self-association into filamentous polymers was measured by injecting 0.2 ml of 2.0-mg/ml stock myosin in 0.6 M KCI, 20 mM imidazole (pH 7.0), 0.5 mM DTT, and 5 mM MgCl2 with a spring-loaded Hamilton syringe into a rapidly stirring solution of 1.6 ml of 0.1 M KCI in the same buffer. Aggregation was quantified with a Spex fluorolog spectrofluorometer using the amount of 340-nm light scattered at 900.", "cite_spans": [], "ref_spans": []}, {"section": "Isolation of a Neutral Protease From Myopathic Human Hearts", "text": "The procedure used to isolate the crude protease from myopathic heart tissue was similar to that used to isolate it from hamster hearts.1239 After eluting the protein from a Sephacryl S-200 column equilibrated in 0.4 M KCl, 0.05 M potassium phosphate (pH 7.0), 2 mM EDTA, and 1 mM DTT, the fractions containing proteolytic activity were pooled and sometimes used as such to digest human and canine cardiac myosin. The crude preparation was further purified using the following steps: It was first dialyzed against 0.05 M sodium acetate, pH 5.5, 1 mM DTT, and 1 mM EDTA, at which point a noticeable amount of protein precipitated. After spinning, both the supernatant and precipitate were assayed for activity. All the activity remained in the supernatant, which was applied to a CM52 column in the sodium acetate/EDTA buffer. After washing with the starting buffer, the retarded proteins were eluted with a linear NaCl gradient in the same buffer. The eluted active fractions were pooled and further purified on a heparin-Sepharose-Cl affinity column (bed volphate (pH 7.0), 2 mM EDTA, and 1 mM DTT. Heparin-Sepharose-Cl has been shown to be useful in the purification of a large number of proteins and in particular enzymes either by binding impurities or by binding the specific protein desired, releasing individual proteins at characteristic ionic strength.40,41 The column was washed with this buffer, and the retarded proteins were eluted with stepwise application of 0.1, 0.3, 0.6, 1.0, and 2.0 M NaCI in starting buffer. The active fractions were not retained by the column. Although several contaminating proteins were separated, the final preparation was still not pure, and a number of protein bands were still visible on SDS gels stained with silver. However, the purity of the protease at this stage was sufficient to demonstrate its presence in the myopathic heart and its specificity for LC2 in human cardiac myosin.", "cite_spans": [], "ref_spans": []}, {"section": "Protease Assays", "text": "Fractions from the chromatographic columns during purification were monitored for protease activity using 3H-casein as substrate. Relative specific activities were expressed as cpm/OD280. Assays were done at 40\u00b0C, and liberated 3H was counted after stopping the reaction with TCA.12 To test the activity of the protease on LC2, it was incubated overnight with canine and control human heart and rabbit skeletal myosins in 0.45 M KCI, 0.01 M imidazole (pH 7.0), 2 mM EDTA, and 1 mM DPI as described before.2642 The following day, the mixture was dialyzed against a low-ionic strength buffer containing PMSF to precipitate the digested myosin. Both the supernatant and the precipitate were run on SDS-PAGE to monitor the extent of digestion. Table 1 summarizes the characteristics of the control and IDC cases used in this study. The major difference between the structures of myosins isolated from control and myopathic heart tissue was in the content of LC2 present as revealed by quantitative SDS-PAGE ( Figure  1) . Because of the limited amount of material available, cardiac tissue from cases 9, 10, and 11 (see Table 1 ) were combined for the preparation of control myosin. The relative molar ratio of LC1 to LC2 in this preparation was 1:1.0 ( Figure 1A and Table 1 ), i.e., a full complement of both light chains was present in myosin. The content of LC2 in myopathic myosin, on the other hand, was reduced appreciably ( Figure 1B) . The relative molar ratio of LC1 to LC2 in the myosin preparation of case 22 was 1:0.2, i.e., LC2 was reduced to 20% of LC1. In almost all of the control myosin preparations from cases 11, 24, and 77, the LC1/LC2 ratio remained nearly constant (1:1.0, 1:1.2, 1:0.9, and 1:0.9, respectively; Table 1 ). In case 24, the ratio was 1:1.2 in myofibrils and remained essentially the same at 1:0.9 when myosin was purified from the same sample. However, the LC1/LC2 ratio in all of the IDC cases not only varied but was always less than 1. In case 48, the ratio was less than 1:0.1 ( Figure  1D ) when compared with control myosin ( Figure 1C ).", "cite_spans": [], "ref_spans": [{"start": 740, "end": 747, "text": "Table 1", "ref_id": "TABREF1"}, {"start": 1116, "end": 1123, "text": "Table 1", "ref_id": "TABREF1"}, {"start": 1264, "end": 1271, "text": "Table 1", "ref_id": "TABREF1"}, {"start": 1731, "end": 1738, "text": "Table 1", "ref_id": "TABREF1"}]}, {"section": "Results", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Light Chain Profile of Normal and Myopathic Human Cardiac Myosin", "text": "When Western blots were semiquantified in one case (case 22), it was found that the LC2 level in myopathic myosin was reduced to background level, whereas control levels of LC2 remained positive and comparable to LCI levels.", "cite_spans": [], "ref_spans": []}, {"section": "Light Chain Profile of Normal and Myopathic Human Cardiac Myosin", "text": "Kinetics ofA TP Binding to Normal and Myopathic", "cite_spans": [], "ref_spans": []}, {"section": "Light Chain Profile of Normal and Myopathic Human Cardiac Myosin", "text": "Human Heart Myosins The fluorescence increase observed upon mixing human cardiac myosin with ATP in a stopped-flow fluorometer were fitted to a single rate constant, k,b,. The dependence of k0,, on the rate of ATP binding to normal and myopathic human cardiac myosin on ATP concentration is shown in Figure 2A . There is no These same parameters were calculated using Si from both myosins ( Figure 2B ). Figure 4 . The initial rate of increase in turbidity was very fast and apparently similar in all of the myosins tested. However, the extent of turbidity (maximum absorbance at 340 nm, 1.0 OD unit) in normal ( Figure 4A ) or myopathic myosin recombined with LC2 ( Figure 4C ) was about double that of the myopathic myosin (maximum absorbance at 340 nm, 0.6 OD unit, Figure 4B ). Because intensity of turbidity is directly related to size of the scattering particles (i.e., the bigger the particle, the larger the turbidity), similar results should be obtained by actually observing the filaments formed. This was confirmed by electron microscopic analysis of synthetic thick filaments formed by each type of myosin ( Figure 5 ). Comparison of various filaments stained with uranyl acetate indicates that synthetic thick filaments from normal ( Figure 5A ) human cardiac myosin were 0.7-2.0 ,um in length, with a clear bare zone and crossbridges on either side of the central bare zone. The positively contrasted control filaments ( Figure 5B) tend to appear relatively thinner, but again, the crossbridges seem to project almost at right angles to the filament shaft. Myopathic filaments, on the other hand, were generally shorter, about 0.35-0.5 ,um long ( Figure 5C ), with a relatively stubby appearance caused by the clustering of crossbridges at opposite sides of the bare zone instead of the more tapered tips seen in normal myosin filaments. Myopathic filaments after LC2 reassociation were essentially 0.5-1.8 ,um long ( Figure 5D ), i.e., as long as the controls, and also normal in shape with pointed tips rather than the more knobby, blunt tips seen in myopathic filaments.", "cite_spans": [], "ref_spans": [{"start": 1120, "end": 1128, "text": "Figure 5", "ref_id": "FIGREF1"}, {"start": 1247, "end": 1256, "text": "Figure 5A", "ref_id": "FIGREF1"}, {"start": 1661, "end": 1670, "text": "Figure 5C", "ref_id": "FIGREF1"}, {"start": 1932, "end": 1941, "text": "Figure 5D", "ref_id": "FIGREF1"}]}, {"section": "Light Chain Profile of Normal and Myopathic Human Cardiac Myosin", "text": "The changes in filament size appeared to be regulated by the composition of the myosin head; thus, to determine whether the tail of myosin had any influence on assembly, the ability of myosin rod to form ordered aggregates was monitored using a comparative approach involving rod preparations from both control and myopathic heart myosin. For this, we chose conditions favoring generation of three-dimensional quasicrystalline assemblies found in gizzard myosin,36which produced highly ordered aggregates. Figure 6 shows the results of electron microscopy of epoxy-embedded paracrystals formed from rod preparations of both control and myopathic myosin sectioned in various planes. When these new paracrystalline forms were sectioned through the planes indicated in Figure 6B , neither the control ( Figures 6A and 6C ) nor the myopathic ( Figures 6D and 6E ) rod paracrystals revealed any difference in structure or in their packing order. In Figure 6C , the section through plane A-A reveals an axial repeat of about 14 nm. The same periodicity is found in sections through the B-B plane of the myopathic rod paracrystal shown in Figures 6D and 6E . In Figure 6D , small arrows indicate the microperiod of 14 nm, and the large arrow indicates the wider spacing at 21-24 nm, the main structural feature of the paracrys- tals that appears to be a fiber formed of many rod elements.", "cite_spans": [], "ref_spans": [{"start": 506, "end": 514, "text": "Figure 6", "ref_id": "FIGREF3"}, {"start": 766, "end": 775, "text": "Figure 6B", "ref_id": "FIGREF3"}, {"start": 800, "end": 817, "text": "Figures 6A and 6C", "ref_id": "FIGREF3"}, {"start": 840, "end": 857, "text": "Figures 6D and 6E", "ref_id": "FIGREF3"}, {"start": 944, "end": 953, "text": "Figure 6C", "ref_id": "FIGREF3"}, {"start": 1132, "end": 1149, "text": "Figures 6D and 6E", "ref_id": "FIGREF3"}, {"start": 1155, "end": 1164, "text": "Figure 6D", "ref_id": "FIGREF3"}]}, {"section": "Susceptibility of Myosin Heavy Chain to Trypsin", "text": "The kinetic results of ATP binding and hydrolysis and the differences among the calculated values of Vm and Km, suggested the existence of subtle differences in the structure of myosin heavy chain other than the absence of LC2 alone in myopathic myosin. One way to monitor subtle differences was to use limited tryptic digestion31 and measure the kinetic rates of proteolysis of Si heavy chain from control and myopathic myosin. The end result of limited tryptic digestion is the generation of three structural domains with Mrs of 25-50-20 kDa, as indicated in the gel pictures of trypsin-cleaved Si from normal ( Figure 7A ) and myopathic ( Figure 7B ) myosins. Although the gel pictures do not reveal a striking difference in the susceptibilities of normal and myopathic Si to trypsin, when they were traced, the myopathic Si heavy chain revealed somewhat greater resistance to tryptic cleavage. The rate of disappearance of Si heavy chain obtained from densitometer traces of gels seen in Figure 7 was calculated from graphs of the areas of Si heavy chain remaining at each time interval (Figure 8 ). The rate constants of heavy chain hydrolysis computed from the slopes of the plots were 0.10 min' and 0.08 min1 for control and myopathic Si, respectively, suggesting some variability either within the structures or the conformation of Si heavy chains.", "cite_spans": [], "ref_spans": []}, {"section": "Isolation of a Neutral Protease From Myopathic Human Hearts", "text": "It seemed very likely that the lack of LC2 in purified myopathic myosin could be a result of endogenous proteolysis. Consequently, an attempt was made to isolate and purify the responsible protease. The crude protease was obtained after chromatographing the muscle extract (from case 21, for example; Table 1 ) on a Sephacryl S-200 column. The elution profile is shown in Figure 9A . The eluted fractions across the protein peak were assayed for activity, most of which was associated with fractions 29-31. These fractions were pooled, concentrated, clarified by centrifugation, and dialyzed against 0.45 M KCI, 0.01 M imidazole (pH 7.0), 2 mM EDTA, and 1 mM DTT. To determine whether such a protease was present in control heart tissues, the extract from control heart tissues (from cases 29 and 30, Table  1 ) was subjected to a similar purification step. Figure 9B shows the elution profile. There was some proteolytic ", "cite_spans": [], "ref_spans": [{"start": 301, "end": 308, "text": "Table 1", "ref_id": "TABREF1"}, {"start": 372, "end": 381, "text": "Figure 9A", "ref_id": "FIGREF5"}, {"start": 801, "end": 809, "text": "Table  1", "ref_id": "TABREF1"}, {"start": 858, "end": 867, "text": "Figure 9B", "ref_id": "FIGREF5"}]}, {"section": "1728", "text": "Circulation Vol 85, No 5 May 1992 activity in fractions 30 and 31; however, the activity associated with these fractions was not only one fourth that shown in Figure 9A (from the IDC case), but it also did not digest LC2 in control myosin. The protease was also isolated from two other samples, cases 28 and 31, which had threefold and fivefold higher activity than that present in control tissues from case 44, case K, and the combined cases 29 and 30 ( Table 1 ).", "cite_spans": [], "ref_spans": [{"start": 159, "end": 168, "text": "Figure 9A", "ref_id": "FIGREF5"}, {"start": 455, "end": 462, "text": "Table 1", "ref_id": "TABREF1"}]}, {"section": "1728", "text": "The crude protease from myopathic heart was then used to establish its specificity for LC2 by incubating it with control human and canine heart myosin as well as rabbit skeletal muscle myosin (at a protease-to-myosin weight ratio of 1 to 30) in 0.45 M KCl, 0.01 M imidazole (pH 7.0), 2 mM EDTA, and 1 mM DYT. The digested myosins were monitored by SDS-PAGE (Figure 10 ). The striking result was that the protease was more specific for human heart myosin than with the others: LC2 visible in control heart myosin ( Figure 1OA ) was almost totally digested (Figure lOB) . In the case of canine heart myosin ( Figure 101 ), there was a substantial amount of LC2 present after digestion ( Figure 1OJ ). The same was true for LC2 or the DTNB light chain ( Figure 1OC ) in rabbit skeletal muscle myosin: Its level appeared to decrease ( Figure IOD) but did not totally disappear. Under similar conditions, the protease from hamster hearts or skeletal muscle totally digested LC2 from both canine heart and rabbit skeletal muscle myosin.122642 In none of the samples shown in Figure 10 was there any evidence of an appreciable degree of heavy chain cleavage, as was the case with the hamster protease.", "cite_spans": [], "ref_spans": []}, {"section": "1728", "text": "To evaluate further the possibility of the protease presence in controls, tissues from two separate non-IDC cases (44 and K) were used for protease preparation. Fractions with proteolytic activity were incubated with human heart myosin to determine whether LC2 would be cleaved. The extent of LC2 cleavage was monitored by blotting the gels onto nitrocellulose paper and revealing LC2 transfer by anti-LC2 antibody. LC2 was prominently revealed in control myosin ( Figure 1OE) ; however, when myosin was incubated with protease fractions eluted early from the column from the extract of case 44, there was very little digestion of LC2 ( Figure  1OF ). The extent of digestion increased with a later fraction from the same preparation (Figure lOG) . The degree of degradation of LC2 was somewhat less when using fractions with protease activity from case K (Figure IOH) .", "cite_spans": [], "ref_spans": []}, {"section": "Further Purification of Protease", "text": "The steps required to partially purify the protease included the following steps: the crude preparation (from case 28) was dialyzed against 0.05 M NaOAc (pH 5.5), 2 mM EDTA, and 1 mM DTT,39 which resulted in the precipitation of some of the proteins present. Both the supernatant and the precipitated material were assayed for activity. The activity remained in the supernatant, which was applied to a MonoS (HR 10/10) FPLC column equilibrated in the same buffer. The bound proteins were eluted with a linear NaCl gradient (0-0.5 M in the starting buffer), and fractions were monitored at 235 nm to optimize detection. Proteolytic activity was confined to fractions 32-35 eluted between 0.2 and 0.29 M NaCI. These fractions were pooled, dialyzed against 0.05 M potassium phosphate (pH 7.0), 2 mM EDTA, and 1 mM DTT, and applied to a heparin-Sepharose-Cl affinity column; the protein was eluted with stepwise NaCI gradient, and active protease fractions were eluted unretarded. At this point, there was about 130-fold purification with respect to the crude preparation. Fractions with protease activity were pooled and dialyzed against 0.02 M Tris-HCI (pH 8.0), 2 mM EDTA, and 1 mM DTT and chromatographed on a MonoQ (HR 5/5) FPLC column. Two major protein peaks were eluted, but neither demonstrated proteolytic activity, suggesting that the protease was either denatured or extremely diluted such that no activity could be measured.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "The question of linking a number of pathological states to an altered function or dysfunction of the Ac 95-* All of the cases of IDC studied here exhibited cardiac hypertrophy, and all were in severe heart failure ( Table  1 ). The only human control tissue available in a state permitting valid examination of myosin were hearts excised at transplant and thus, all abnormal. However, these are considered useful controls because all were clearly hypertrophied and all were in severe heart failure. All patients were receiving a variety of medications for heart failure, although the usual regimen for the atherosclerotic patients did vary from those with Figures 1B and ID) . In one instance (case 31), the LC1/LC2 ratio was determined from the traces of myofibrils run on SDS gels, i.e., at the earliest stage of preparation; this same material was subsequently used for protease preparation. The reduced level of LC2 found in this IDC case confirms the conclusion that the reduction in LC2 content correlates with the substantial presence of active protease. Also, this result argues against proteolysis of LC2 occurring during later stages of the protein preparation during which proteolysis might conceivably be facilitated. Thus, the modification in the structure of myopathic myosin provided impetus to analyze its functional properties, namely, its ability to bind and hydrolyze ATP, its affinity for actin, and its self-assembly into ordered aggregates or thick filaments.", "cite_spans": [], "ref_spans": [{"start": 216, "end": 224, "text": "Table  1", "ref_id": "TABREF1"}]}, {"section": "Discussion", "text": "Several of these properties were influenced by cardiomyopathy: The rate of ATP binding (Figure 2 ), steadystate ATP hydrolysis (Figure 3) , and affinity for actin were all diminished.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "Some assembly properties were also destabilized: There was no difference between the ability of control and myopathic myosin rod to form the paracrystalline structure shown in Figure 6 . Synthetic thick filaments from myopathic myosin, on the other hand, despite having the same outward morphology (i.e., bipolar structures with a bare zone, myosin heads projecting outward from the filament surface on either side of the bare zone), were consistently and significantly shorter than those from control myosin, terminating in a knobby structural feature. The absence of LC2 in myopathic myosin thus appeared to lead to the formation of shorter, stunted filaments, because when myopathic myosin was recombined with LC2, the filament lengths were comparable to those of normal filaments ( Figure  5 ), as reported earlier46 and subsequently confirmed.35", "cite_spans": [], "ref_spans": [{"start": 176, "end": 184, "text": "Figure 6", "ref_id": "FIGREF3"}, {"start": 786, "end": 795, "text": "Figure  5", "ref_id": "FIGREF1"}]}, {"section": "Discussion", "text": "These changes were confirmed by light-scattering measurements in which turbidity is a direct function of particle size. Thus, two independent methods generated fundamentally identical results. Myopathic myosin is thus judged to be defective in the globular SI head, There have been a number of studies of the genetic composition of patients with IDC implicating the immune system.50.51 There would appear to be an excess of specific human leukocyte antigen molecules in the population with the disease, although there is not complete agreement as to which specific haplotypes are involved. The presence of specific haplotypes occurs in one third to one half of the cases and in a small percentage of control subjects. Besides involvement of the cellular component of the immune system, humoral antibodies to a variety of myocyte intracellular antigens are demonstrable in patients with IDC.5253 Studies involving the immune system are generally retrospective, and the incidence of a prior insult, especially viral myocarditis, is unknown but assumed to be high. However, the immune system is thought to be involved in one third to one half of the cases of IDC.51,52,54 If it is accepted that a specific insult occurring in a properly prepared host (i.e., the correct haplotype) results in a higher probability of IDC than in an individual with a dissimilar HLA makeup, it then follows that there could be other underlying host conditions predisposing development of IDC after an insult. The underlying condition may involve the cardiac myocyte and be sufficiently benign as to be unnoticeable until an initiating cause occurs, as with the HLA subtypes prone to develop IDC.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "In the cases described here, the absence of LC2 was due to the presence of a protease that was either synthesized de novo during cardiomyopathy or present in reduced amount or in an inactive state until it was activated. The latter possibility seems to be more likely in humans, because its presence was detectable at low levels in the preparation shown in Figure 9B from the combined tissues of control cases 29 and 30 and from control cases 44 and K (Table 1 ). There are other proteases present in the heart or skeletal muscle tissues,55 but some of these lack a clear specificity and/or are involved in regulating normal protein turnover in these tissues. The protease described here is unique in that it is even more specific for human LC2 than that isolated from hamsters. It does not attack the myosin heavy chain at all, as shown in Figure 1B , or else heavychain cleavage is negligible. Furthermore, it did not hydrolyze LC2 as readily in canine heart or rabbit skeletal myosin ( Figure 10 ).", "cite_spans": [], "ref_spans": [{"start": 357, "end": 366, "text": "Figure 9B", "ref_id": "FIGREF5"}, {"start": 452, "end": 460, "text": "(Table 1", "ref_id": "TABREF1"}]}, {"section": "Discussion", "text": "What emerges, therefore, is a comprehensive picture of a possible molecular mechanism of interdependent changes (as indicated by the parameters evaluated in this study and summarized in a simplified manner in Table 2 ) upon onset of cardiomyopathy: Probably the activation of the protease or its de novo synthesis is the critical step. Regardless of the mechanism of activation and/or synthesis of the protease, once active, it hydrolyzes LC2. Eventually, the rate of LC2 breakdown surpasses that of its synthesis, resulting in myosin with substoichiometric amounts of LC2 that subsequently form shorter filaments in in vitro preparations and have altered ATPase activity. If a similar reduction in size were to occur in the sarcomere, it would most likely lead to a generalized destabilization within the lattice geometry of the sarcomere, eventually leading to a collapse of contractile function and distinct morphological changes as reported. 20 The results discussed here would allow the inference of such a sequence of changes to explain the molecular basis of cardiomyopathy at the level of the major contractile protein, myosin, identifying it directly as being the critical target upon which the degenerative effects of the protease are impacted.", "cite_spans": [{"start": 946, "end": 948, "text": "20", "ref_id": "BIBREF19"}], "ref_spans": [{"start": 209, "end": 216, "text": "Table 2", "ref_id": "TABREF7"}]}], "bib_entries": {"BIBREF0": {"title": "Electrophoretic analysis of multiple forms of rat cardiac myosin: Effect of hypohysectomy and thyroxine replacement", "authors": [{"first": "Jfy", "middle": [], "last": "Hoh", "suffix": ""}, {"first": "P", "middle": ["A"], "last": "Mcgrath", "suffix": ""}, {"first": "P", "middle": ["T"], "last": "Hale", "suffix": ""}], "year": 1978, "venue": "J Mol Cell Cardiol", "link": "33762923"}, "BIBREF1": {"title": "Nadal-Ginard B: Cardiac a-and 3-myosin heavy chain genes are organized in tandem", "authors": [{"first": "V", "middle": [], "last": "Mahdavi", "suffix": ""}, {"first": "A", "middle": ["P"], "last": "Chambers", "suffix": ""}], "year": 1984, "venue": "Proc Natl Acad Sci", "link": null}, "BIBREF2": {"title": "Expression of the cardiac ventricular a-and ,B-myosin heavy chain genes is developmentally and hormonally regulated", "authors": [{"first": "A", "middle": ["M"], "last": "Lompre", "suffix": ""}, {"first": "B", "middle": [], "last": "Nadal-Ginard", "suffix": ""}, {"first": "V", "middle": [], "last": "Mahdavi", "suffix": ""}], "year": 1984, "venue": "J Biol Chem", "link": null}, "BIBREF3": {"title": "Myosin isoenzymes in normal and hypertrophied human ventricular myocardium", "authors": [{"first": "J", "middle": ["J"], "last": "Mercadier", "suffix": ""}, {"first": "P", "middle": [], "last": "Bouveret", "suffix": ""}, {"first": "L", "middle": [], "last": "Gorza", "suffix": ""}, {"first": "S", "middle": [], "last": "Schiaffino", "suffix": ""}, {"first": "W", "middle": ["A"], "last": "Clark", "suffix": ""}, {"first": "Zak", "middle": ["R"], "last": "Swynghedauw", "suffix": ""}, {"first": "B", "middle": [], "last": "Schwartz", "suffix": ""}, {"first": "K", "middle": [], "last": "", "suffix": ""}], "year": 1983, "venue": "Circ Res", "link": "16002559"}, "BIBREF4": {"title": "Chronic swimming reverses cardiac dysfunction and myosin abnormalities in rats with established hypertension", "authors": [{"first": "T", "middle": ["F"], "last": "Schaible", "suffix": ""}, {"first": "A", "middle": [], "last": "Malhotra", "suffix": ""}, {"first": "G", "middle": ["J"], "last": "Ciambrone", "suffix": ""}, {"first": "J", "middle": [], "last": "Scheuer", "suffix": ""}], "year": 1986, "venue": "JAppl Physiol", "link": null}, "BIBREF5": {"title": "Hormonal regulation of myosin heavy chain and a-actin gene expression in cultured fetal rat heart myocytes", "authors": [{"first": "T", "middle": ["A"], "last": "Gustafson", "suffix": ""}, {"first": "J", "middle": ["J"], "last": "Bahl", "suffix": ""}, {"first": "B", "middle": ["E"], "last": "Markham", "suffix": ""}, {"first": "W", "middle": ["R"], "last": "Roeske", "suffix": ""}, {"first": "E", "middle": [], "last": "Morkin", "suffix": ""}], "year": 1987, "venue": "J Biol Chem", "link": "36509488"}, "BIBREF6": {"title": "Light chains from fast and slow muscle myosins", "authors": [{"first": "S", "middle": [], "last": "Lowey", "suffix": ""}, {"first": "D", "middle": [], "last": "Risby", "suffix": ""}], "year": 1971, "venue": "Nature", "link": null}, "BIBREF7": {"title": "Light chains of myosins from white, red and cardiac muscles", "authors": [{"first": "S", "middle": [], "last": "Sarkar", "suffix": ""}, {"first": "F", "middle": ["A"], "last": "Sreter", "suffix": ""}, {"first": "J", "middle": [], "last": "Gergely", "suffix": ""}], "year": 1971, "venue": "Proc NatlAcad Sci USA", "link": "12079258"}, "BIBREF8": {"title": "Transitions in human atrial and ventricular myosin light-chain isoenzymes in response to cardiac-pressure-overloadinduced hypertrophy", "authors": [{"first": "P", "middle": [], "last": "Cummins", "suffix": ""}], "year": 1982, "venue": "Biochem J", "link": "9305318"}, "BIBREF9": {"title": "Myosin isoenzymes in human hypertrophic hearts: Shift in atrial myosin heavy chains and in ventricular myosin light chains", "authors": [{"first": "M", "middle": ["C"], "last": "Schaub", "suffix": ""}, {"first": "C", "middle": ["R"], "last": "Tuchschmid", "suffix": ""}, {"first": "T", "middle": [], "last": "Srihari", "suffix": ""}, {"first": "H", "middle": ["O"], "last": "Hirzel", "suffix": ""}], "year": 1984, "venue": "Eur Heart J", "link": "1378668"}, "BIBREF10": {"title": "Effect of ageing of myosin on its ability to form synthetic filaments and on proteolysis of the LC2 light chain", "authors": [{"first": "I", "middle": [], "last": "Pinset-Harstrom", "suffix": ""}, {"first": "R", "middle": ["G"], "last": "Whalen", "suffix": ""}], "year": 1979, "venue": "J Mol Biol", "link": "27152923"}, "BIBREF11": {"title": "Partial characterization of a protease from cardiac myofibrils of dystrophic hamsters", "authors": [{"first": "A", "middle": [], "last": "Bhan", "suffix": ""}, {"first": "A", "middle": [], "last": "Malhotra", "suffix": ""}, {"first": "V", "middle": ["B"], "last": "Hatcher", "suffix": ""}], "year": 1978, "venue": "Protein Turnover and Lysosome Function", "link": "81431183"}, "BIBREF12": {"title": "The challenge of cardiomyopathy", "authors": [{"first": "W", "middle": ["H"], "last": "Abelman", "suffix": ""}, {"first": "B", "middle": ["H"], "last": "Lorell", "suffix": ""}], "year": 1989, "venue": "JAm Coil Cardiol", "link": null}, "BIBREF13": {"title": "Idiopathic dilated cardiomyopathy: An immunologic, genetic, or infectious disease, or all of the above?", "authors": [{"first": "J", "middle": ["R"], "last": "Bender", "suffix": ""}], "year": 1991, "venue": "Circulation", "link": "35132424"}, "BIBREF14": {"title": "A molecular basis for familial hypertrophic cardiomyopathy: A -3-cardiac myosin heavy chain gene missense mutation", "authors": [{"first": "Aat", "middle": [], "last": "Geisterfer-Lowrance", "suffix": ""}, {"first": "Kass", "middle": ["S"], "last": "Tanigawa", "suffix": ""}, {"first": "G", "middle": [], "last": "Vosberg", "suffix": ""}, {"first": "H-P", "middle": [], "last": "Mckenna", "suffix": ""}, {"first": "W", "middle": [], "last": "Seidman", "suffix": ""}, {"first": "C", "middle": ["E"], "last": "Seidman", "suffix": ""}, {"first": "J", "middle": ["G"], "last": "", "suffix": ""}], "year": 1990, "venue": "Cell", "link": "45182243"}, "BIBREF15": {"title": "Cardiomyopathy and myocarditis, in Cheng TO", "authors": [{"first": "J", "middle": ["F"], "last": "Goodwin", "suffix": ""}], "year": 1986, "venue": "", "link": null}, "BIBREF16": {"title": "Cardiomyopathies, in Silver MD", "authors": [{"first": "M", "middle": ["M"], "last": "Silver", "suffix": ""}, {"first": "M", "middle": ["D"], "last": "Silver", "suffix": ""}], "year": 1983, "venue": "", "link": null}, "BIBREF17": {"title": "Diagnosis and natural history of congested (dilated) cardiomyopathies", "authors": [{"first": "C", "middle": ["M"], "last": "Oakley", "suffix": ""}], "year": 1978, "venue": "Postgrad Med J", "link": "39580806"}, "BIBREF18": {"title": "Predictive value of immunofluorescence and electron microscopic evaluation of endomyocardial biopsies in the diagnosis and prognosis of myocarditis and idiopathic dilated cardiomyopathy", "authors": [{"first": "E", "middle": ["H"], "last": "Hammond", "suffix": ""}, {"first": "R", "middle": ["L"], "last": "Menlove", "suffix": ""}, {"first": "J", "middle": ["L"], "last": "Anderson", "suffix": ""}], "year": 1987, "venue": "Am Heart J", "link": "9092687"}, "BIBREF19": {"title": "Impairment of the myocardial ultrastructure and changes of the cytoskeleton in dilated cardiomyopathy", "authors": [{"first": "J", "middle": [], "last": "Schaper", "suffix": ""}, {"first": "R", "middle": [], "last": "Froede", "suffix": ""}, {"first": "M", "middle": ["D"], "last": "St Hein", "suffix": ""}, {"first": "A", "middle": [], "last": "Buck", "suffix": ""}, {"first": "H", "middle": [], "last": "Hashizume", "suffix": ""}, {"first": "B", "middle": [], "last": "Speiser", "suffix": ""}, {"first": "A", "middle": [], "last": "Briedl", "suffix": ""}, {"first": "N", "middle": [], "last": "Bleese", "suffix": ""}], "year": 1991, "venue": "Circulation", "link": null}, "BIBREF20": {"title": "The collagen network of the heart", "authors": [{"first": "J", "middle": ["B"], "last": "Caulfield", "suffix": ""}, {"first": "T", "middle": ["K"], "last": "Borg", "suffix": ""}], "year": 1979, "venue": "Lab Invest", "link": "24637157"}, "BIBREF21": {"title": "The osmotic effect of glutaraldehyde during fixation: A transmission electron microscopy, scanning electron microscopy and cytochemical study", "authors": [{"first": "B", "middle": ["I"], "last": "Arborgh", "suffix": ""}, {"first": "P", "middle": [], "last": "Bell", "suffix": ""}, {"first": "V", "middle": [], "last": "Brunk", "suffix": ""}, {"first": "V", "middle": ["P"], "last": "Collins", "suffix": ""}], "year": 1976, "venue": "J Ultrastruct Res", "link": "42798792"}, "BIBREF22": {"title": "Endothelium-dependent responses in long-term human coronary artery bypass grafts", "authors": [{"first": "D", "middle": ["D"], "last": "Ku", "suffix": ""}, {"first": "J", "middle": ["B"], "last": "Caulfield", "suffix": ""}, {"first": "J", "middle": ["K"], "last": "Kirklin", "suffix": ""}], "year": 1991, "venue": "Circulation", "link": "39601451"}, "BIBREF23": {"title": "Endothelium-dependent responses in human coronary blood vessels", "authors": [{"first": "D", "middle": ["D"], "last": "Ku", "suffix": ""}, {"first": "J", "middle": ["B"], "last": "Caulfield", "suffix": ""}, {"first": "J", "middle": ["K"], "last": "Kirklin", "suffix": ""}], "year": 1992, "venue": "Endothelium Regulation of Vascular Tone", "link": null}, "BIBREF24": {"title": "The purification of cardiac myofibrils with triton X-100", "authors": [{"first": "R", "middle": ["J"], "last": "Solaro", "suffix": ""}, {"first": "D", "middle": ["C"], "last": "Pang", "suffix": ""}, {"first": "F", "middle": ["N"], "last": "Briggs", "suffix": ""}], "year": 1971, "venue": "Biochim Biophys Acta", "link": "27683761"}, "BIBREF25": {"title": "Reversible dissociation of dog cardiac myosin regulatory light chain 2 and its influence on ATP hydrolysis", "authors": [{"first": "S", "middle": ["S"], "last": "Margossian", "suffix": ""}], "year": 1985, "venue": "J Biol Chem", "link": "23517778"}, "BIBREF26": {"title": "Preparation of myosin and its subfragments from rabbit skeletal muscle", "authors": [{"first": "S", "middle": ["S"], "last": "Margossian", "suffix": ""}, {"first": "S", "middle": [], "last": "Lowey", "suffix": ""}], "year": 1982, "venue": "Methods Enzymol", "link": "34658980"}, "BIBREF27": {"title": "The regulation of rabbit skeletal muscle contraction", "authors": [{"first": "J", "middle": ["A"], "last": "Spudich", "suffix": ""}, {"first": "S", "middle": [], "last": "Watt", "suffix": ""}], "year": 1971, "venue": "J Biol Chem", "link": "94140745"}, "BIBREF28": {"title": "Cleavage of structural proteins during assembly of the head of bacteriophage T4", "authors": [{"first": "U", "middle": ["K"], "last": "Laemmli", "suffix": ""}], "year": 1970, "venue": "Nature", "link": null}, "BIBREF29": {"title": "Electrophoretic transfer of proteins from acrylamide gels to nitrocellulose sheets: Procedure and some applications", "authors": [{"first": "M", "middle": [], "last": "Towbin", "suffix": ""}, {"first": "Y", "middle": [], "last": "Staehlin", "suffix": ""}, {"first": "J", "middle": [], "last": "Gordon", "suffix": ""}], "year": 1979, "venue": "Proc Natl Acad Sci", "link": null}, "BIBREF30": {"title": "Tryptic cleavage and substructure of bovine cardiac myosin subfragment 1", "authors": [{"first": "D", "middle": [], "last": "Applegate", "suffix": ""}, {"first": "A", "middle": [], "last": "Azarcon", "suffix": ""}, {"first": "E", "middle": [], "last": "Reisler", "suffix": ""}], "year": 1984, "venue": "Biochemistry", "link": "8802006"}, "BIBREF31": {"title": "Thrombospondin is expressed in traumatized skeletal muscle: Indication for a role in the repair process", "authors": [{"first": "S", "middle": ["C"], "last": "Watkins", "suffix": ""}, {"first": "G", "middle": ["W"], "last": "Lynch", "suffix": ""}, {"first": "L", "middle": [], "last": "Kane", "suffix": ""}, {"first": "H", "middle": ["S"], "last": "Slayter", "suffix": ""}], "year": 1990, "venue": "Cell Tissue Res", "link": null}, "BIBREF32": {"title": "Thrombin-independent activation of platelet factor XIII by endogenous platelet acid proteases", "authors": [{"first": "G", "middle": ["W"], "last": "Lynch", "suffix": ""}, {"first": "S", "middle": ["L"], "last": "Pfueller", "suffix": ""}], "year": 1988, "venue": "Thromb Haemost", "link": "19768408"}, "BIBREF33": {"title": "Use of radioimmunoassay to quantify thrombospondin", "authors": [{"first": "S", "middle": ["D"], "last": "Saglio", "suffix": ""}, {"first": "H", "middle": ["S"], "last": "Slayter", "suffix": ""}], "year": 1982, "venue": "Blood", "link": "208313146"}, "BIBREF34": {"title": "LC2 involvement in the assembling of skeletal myosin filaments", "authors": [{"first": "P", "middle": [], "last": "Chowrashi", "suffix": ""}, {"first": "S", "middle": [], "last": "Pemrick", "suffix": ""}, {"first": "F", "middle": ["A"], "last": "Pepe", "suffix": ""}], "year": 1989, "venue": "Biochim Biophys Acta", "link": null}, "BIBREF35": {"title": "Formation of new, quasicrystalline ordered aggregates by turkey gizzard myosin", "authors": [{"first": "S", "middle": ["S"], "last": "Margossian", "suffix": ""}, {"first": "J", "middle": ["R"], "last": "Sellers", "suffix": ""}, {"first": "S", "middle": ["C"], "last": "Watkins", "suffix": ""}, {"first": "H", "middle": ["S"], "last": "Slayter", "suffix": ""}], "year": 1989, "venue": "I Muscle Res Cell Motil", "link": null}, "BIBREF36": {"title": "White HD: Special instrumentation and techniques for kinetic studies of contractile proteins", "authors": [], "year": 1982, "venue": "Methods Enzymol", "link": null}, "BIBREF37": {"title": "Analysis of exponential curves by a method of moments with special attention to sedimentation equilibrium and fluorescence decay", "authors": [{"first": "R", "middle": ["D"], "last": "Dyson", "suffix": ""}, {"first": "I", "middle": [], "last": "Isenberg", "suffix": ""}], "year": 1973, "venue": "Biochemistry", "link": "38902982"}, "BIBREF38": {"title": "Studies of a myosin-cleaving protease from dystrophic hamster heart", "authors": [{"first": "T", "middle": [], "last": "Kuo", "suffix": ""}, {"first": "A", "middle": [], "last": "Bhan", "suffix": ""}], "year": 1980, "venue": "Biochem Biophys Res Commun", "link": "6518233"}, "BIBREF39": {"title": "Purification of enzymes by heparin-Sepharose affinity chromatography", "authors": [{"first": "A", "middle": ["A"], "last": "Farooqui", "suffix": ""}], "year": 1980, "venue": "I Chromatogr", "link": "28826451"}, "BIBREF40": {"title": "Secretion of thrombospondin from human blood platelets", "authors": [{"first": "H", "middle": ["S"], "last": "Slayter", "suffix": ""}], "year": 1989, "venue": "Methods Enzymol", "link": "11688384"}, "BIBREF41": {"title": "Role of the regulatory light chains in skeletal muscle actomyosin ATPase and in minifilament formation", "authors": [{"first": "S", "middle": ["S"], "last": "Margossian", "suffix": ""}, {"first": "A", "middle": [], "last": "Bhan", "suffix": ""}, {"first": "H", "middle": ["S"], "last": "Slayter", "suffix": ""}], "year": 1983, "venue": "J Biol Chem", "link": "25754497"}, "BIBREF42": {"title": "Bovine cardiac myosin subfragment-1: Transient kinetics of ATP hydrolysis", "authors": [{"first": "S", "middle": ["J"], "last": "Smith", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Cusanovich", "suffix": ""}], "year": 1985, "venue": "J Biol Chem", "link": "8178578"}, "BIBREF43": {"title": "Kinetics of the interaction between actin, ADP and cardiac myosin Si", "authors": [{"first": "R", "middle": ["F"], "last": "Siemankowski", "suffix": ""}, {"first": "H", "middle": ["D"], "last": "White", "suffix": ""}], "year": 1984, "venue": "J Biol Chem", "link": "29904285"}, "BIBREF44": {"title": "Biochemical kinetics of porcine cardiac subfragment-1: II. Pre-steady-state studies of the initial phosphate burst", "authors": [{"first": "L", "middle": ["A"], "last": "Stein", "suffix": ""}, {"first": "M", "middle": ["P"], "last": "White", "suffix": ""}, {"first": "D", "middle": ["T"], "last": "Annis", "suffix": ""}], "year": 1989, "venue": "Circ Res", "link": "452556"}, "BIBREF45": {"title": "Control of filament length by regulatory light chain in skeletal and cardiac myosins", "authors": [{"first": "S", "middle": ["S"], "last": "Margossian", "suffix": ""}, {"first": "T", "middle": ["W"], "last": "Huiatt", "suffix": ""}, {"first": "H", "middle": ["S"], "last": "Slayter", "suffix": ""}], "year": 1987, "venue": "J Biol Chem", "link": null}, "BIBREF46": {"title": "Cummins P: Cardiac myosin light and heavy chain isotypes in tetralogy of Fallot", "authors": [{"first": "L", "middle": ["M"], "last": "Auckland", "suffix": ""}, {"first": "S", "middle": ["J"], "last": "Lambert", "suffix": ""}], "year": 1986, "venue": "Cardiovasc Res", "link": null}, "BIBREF47": {"title": "Structural and enzymatic comparison of human cardiac muscle myosins isolated from adults, and patients with hypertrophic cardiomyopathy", "authors": [{"first": "J", "middle": ["J"], "last": "Schier", "suffix": ""}, {"first": "R", "middle": ["S"], "last": "Adelstein", "suffix": ""}], "year": 1982, "venue": "J Clin Invest", "link": "8527134"}, "BIBREF48": {"title": "Pathway for the communication between the ATPase and actin sites in myosin", "authors": [{"first": "E", "middle": [], "last": "Audemard", "suffix": ""}, {"first": "R", "middle": [], "last": "Bertrand", "suffix": ""}, {"first": "A", "middle": [], "last": "Bonet", "suffix": ""}, {"first": "P", "middle": [], "last": "Chaussepied", "suffix": ""}, {"first": "D", "middle": [], "last": "Mornet", "suffix": ""}], "year": 1988, "venue": "J Muscle Res Cell Motil", "link": "1380543"}, "BIBREF49": {"title": "Associations of HLA-A, B, DR antigens with primary disease in cardiac allograft recipients", "authors": [{"first": "T", "middle": ["R"], "last": "Zerbe", "suffix": ""}, {"first": "C", "middle": [], "last": "Kaufmann", "suffix": ""}, {"first": "Y", "middle": [], "last": "Colson", "suffix": ""}, {"first": "R", "middle": [], "last": "Duquesnoy", "suffix": ""}], "year": 1988, "venue": "Am J Cardiol", "link": "19922332"}, "BIBREF50": {"title": "Deficient natural killer cell activity in patients with idiopathic dilated cardiomyopathy", "authors": [{"first": "J", "middle": ["L"], "last": "Anderson", "suffix": ""}, {"first": "J", "middle": ["F"], "last": "Carlquist", "suffix": ""}, {"first": "E", "middle": ["H"], "last": "Hammond", "suffix": ""}], "year": 1982, "venue": "Lancet", "link": "21874280"}, "BIBREF51": {"title": "HLA Class II (DR and DQ) antigen associations in idiopathic dilated cardiomyopathy: Validation study and meta-analysis of published HLA association studies", "authors": [{"first": "J", "middle": ["F"], "last": "Carlquist", "suffix": ""}, {"first": "R", "middle": ["L"], "last": "Menlove", "suffix": ""}, {"first": "M", "middle": ["B"], "last": "Murray", "suffix": ""}, {"first": "J", "middle": ["B"], "last": "O&apos;connell", "suffix": ""}, {"first": "J", "middle": ["L"], "last": "Anderson", "suffix": ""}], "year": 1991, "venue": "Circulation", "link": "16243511"}, "BIBREF52": {"title": "Novel organ-specific circulating cardiac autoantibodies in dilated cardiomyopathy", "authors": [{"first": "A", "middle": ["L"], "last": "Caforio", "suffix": ""}, {"first": "E", "middle": [], "last": "Bonifacio", "suffix": ""}, {"first": "J", "middle": ["T"], "last": "Stewart", "suffix": ""}, {"first": "D", "middle": [], "last": "Neglia", "suffix": ""}, {"first": "", "middle": [], "last": "Paroi 0", "suffix": ""}, {"first": "G", "middle": ["F"], "last": "Bottazzo", "suffix": ""}, {"first": "W", "middle": ["J"], "last": "Mckenna", "suffix": ""}], "year": 1990, "venue": "JAm Coll Cardiol", "link": "24209551"}, "BIBREF53": {"title": "Anti-beta-receptor antibodies in human dilated cardiomyopathy and correlation with HLA-DR antigens", "authors": [{"first": "C", "middle": ["J"], "last": "Limas", "suffix": ""}, {"first": "C", "middle": [], "last": "Limas", "suffix": ""}, {"first": "S", "middle": ["H"], "last": "Kubo", "suffix": ""}, {"first": "M", "middle": ["T"], "last": "Olivari", "suffix": ""}], "year": 1990, "venue": "Am J Cardiol", "link": "23937256"}, "BIBREF54": {"title": "Historical background and current status of the Ca2'-dependent proteinase system", "authors": [{"first": "D", "middle": ["E"], "last": "Goll", "suffix": ""}, {"first": "W", "middle": ["C"], "last": "Kleese", "suffix": ""}, {"first": "A", "middle": [], "last": "Okitani", "suffix": ""}, {"first": "T", "middle": [], "last": "Kumamoto", "suffix": ""}, {"first": "J", "middle": [], "last": "Cong", "suffix": ""}, {"first": "H-P", "middle": [], "last": "Kapprell", "suffix": ""}], "year": 1990, "venue": "Intracellular Calcium-Dependent Proteolysis", "link": null}}, "ref_entries": {"FIGREF0": {"text": "FIGURE 2. Graphs show kinetics ofATP binding to normal (filled squares) and myopathic (open squares) human cardiac", "type": "figure"}, "FIGREF1": {"text": "FIGURE 5. Facingpage: photomicrographs ofsynthetic thick filaments stained with uranyl acetate. Magnification of all fields: x32,000; insets show individual filaments at a magnification x64,000. Panel A: Field of normal human heart control myosin filaments negatively contrasted and micrographed underfocus to show phase contrast effects. Panel B: Field ofnormalfilaments in positive stain. Note thatfilaments are thinner in positive contrast. Panel C: Myopathic myosin thick filaments showing nodular ends and generally relatively shorter lengths. Panel D: Myopathic filaments after recombination with light chain 2 showing generally more normal appearance and longer lengths after reconstitution.", "type": "figure"}, "FIGREF2": {"text": ".................", "type": "figure"}, "FIGREF3": {"text": "FIGURE 6. Facing page: photomicrographs and diagram of human cardiac myosin rod microcrystal formed by dialysis against 0.2 MKCl, 2 mM Tris-HCG, and 1 mMDTT (pH 8.0) embedded in plastic and thin-sectioned, showing various cross sections through microcrystals. Magnification of all micrographs, X 115,OO. Panel A: Control human cardiac myosin rod microcrystal sectioned through plane C-C as shown in panel B: diagram showingplacement ofmicrocrystal elements and planes of sectioning used for micrographs in panels A, C, D, and E. Panel C: Control myosin rod microcrystal sectioned in plane A-A. Panel D: Human myopathic myosin rod microcrystal sectioned in plane B-B. Small arrows show 14-nm axial period. Large arrows indicate individual microcrystal filaments with a 21-24-nm period. Panel E: Human myopathic rod microcrystal sectioned as in panel D along the B-B plane.", "type": "figure"}, "FIGREF4": {"text": "FIGURE 7. SDS-PAGE gelsofnormal(panelA).and", "type": "figure"}, "FIGREF5": {"text": "FIGURE 9. Graphs show chromatographic profile ofthe neutralprotease from myopathic (panel A) and normal (panel B) heart tissue on a Sephacryl S-200 column (2.5 xllO cm) equilibrated in 0.4 MKCl, 0.05 Mpotassium phosphate (pH 6.9), 1 mMDTT, and 2 mM EDTA. Solid lines, optical densities at 280 nm; dashed lines, radioactivity counts corresponding to proteolytic activity. Note high activity in fractions from myopathic hearts in comparison with normal hearts in which radioactivity offractions was slightly above background.", "type": "figure"}, "TABREF0": {"text": "method of Spudich and Watt.28 SDS-Polyacrylamide and Agarose Gel Electrophoresis and Western Blotting Sodium dodecylsulfate-polyacrylamide gel electro- phoresis (SDS-PAGE) was carried out as described by Laemmli,29 using a 4% stacking gel. Samples were treated with Laemmli's sample buffer containing 0.062 M Tris-HCl (pH 6.8), 2% SDS, 10% glycerol, 8 M urea, 0.001% bromphenol blue, with or without 5% DTT (reduced), or 10 mM iodoacetamide (nonreduced). Samples were incubated for 10 minutes at 96\u00b0C. Either 7% and 10% or 4-18% acrylamide gradient slab gels were used. To calculate the relative molar ratios of LC1 to LC2, the gels were scanned by a two-dimensional scanning densitometer with a laser light source (Biomed Instruments, Fullerton, Calif.). The nitrocellulose (Schleicher and Schuell, Keene, N.H.) used for elec- troblotting30 was incubated and autoradiographed as described below. Molecular weights were calibrated by using prestained molecular weight standards (BRL, Bethesda, Md.) and included fibrinogen, thyroglobulin, and ferritin. Control and myopathic myosin Sls at 2 mg/ml were subjected to limited tryptic digestion as described.31 Aliquots were removed at regular intervals, digestion was stopped with soybean trypsin inhibitor (twice the amount of trypsin by weight), and samples were treated liquid nitrogen, and stored at -70'C until shipment on", "type": "table"}, "TABREF1": {"text": "Diagnoses and Analyses of the Available HeartsLC, light chain; M, male; F, female; HF, heart failure; VT, ventricular tachycardia; EC, Eisenmonger's complex; AS, severe atherosclerosis; H, healed and I, infarct; ant, anterior; CABG, coronary artery bypass graft; PMVP, prior mitral valve prosthesis; PH, pulmonary hypertension; CHL, congenital heart lesion; IDC, idiopathic dilated cardiomyopathy; ND, not determined, preparation used for another purpose. All cases had one or more 90-100% old occlusive plaques. None of these cases had plaques of 20% occlusion or greater.OD280, with which IDC samples were compared. for SDS-PAGE. Equivalent amounts (micrograms) of samples were run on 12% slab gels and the amount of Si heavy chain remaining was determined by scanning the gels with a computerized, soft laser scanning, two- dimensional densitometer as described above. Gels were traced for quantitative analysis by computerized true integration of the area times density of each band. The calculated area densities were then plotted as log% of control against time (minutes) and the kinetic rate constants of heavy chain hydrolysis were determined from the slopes.jugate of goat anti-rabbit antibody. Rabbit polyclonal anti-LC2 antibody was not affinity purified because of the unavailability of pure antigen. Instead, it was ad- sorbed by adding pure LC1 for use in blotting experi- ments only. In some cases, the autoradiogram was superimposed on the blot, and the required regions were thus specifically excised, counted, and compared. Polyclonal rabbit IgG directed against LC1 or LC2 was prepared according to a modified procedure.34", "type": "table"}, "TABREF2": {"text": ", i.e., the myosin contained less than 10% of the normal LC2 complement. In cases 49 and 36, the ratio was 1: 0.6 and 1: 0.69, respectively. In one IDC sample (case 31), the tissue was used to ume, 3.5 ml) equilibrated in 0.05 M potassium phos-FIGURE 1. SDS-PAGE and Western blots ofhuman cardiac myosin. Lanes A and B are Coomassie-stained SDS gels of myosin isolated from control and myopathic heart tissue, respectively, showing significantly reduced levels of light chain 2 (LC2) in myopathic cardiac myosin. Lanes C and D show respective Western blots using anti-LC2 antibody to reveal the relative quantitative presence of LC2. Reduction is demon- strated in lane D for the myopathic sample relative to the control cardiac myosin in lane C.obtain the protease. but when the myofibrils from this particular tissue were analyzed for LC1/LC2 ratio, it was calculated to be 1:0.3 (Table 1). The reduced level of LC2 in myopathic myosin was further confirmed by Western blots. Autoradiograms of normal and myo- pathic heart myosins blotted with anti-LC2 antibodies paralleled the results obtained by SDS-PAGE. The intensity of the LC2 band revealed by the autoradio- gram was barely detectable in myopathic myosin (", "type": "table"}, "TABREF3": {"text": "2. Graphs show kinetics ofATP binding to normal (filled squares) and myopathic (open squares) human cardiac myosin (panel A) and Si (panel B). Experimental condi- tions: 0.5 mg/ml myosin, 0.6 M or 0.1 M KCI, 20 mM imidazole, 2 mMMgC12, pH 7.0, 15\u00b0C. The kOb, were obtained by fitting the data to a single exponential equation. The solid line drawn through the data is the best fit of the data to the hyperbolic equation kosb = kmJ,; / (1 + Kapp /[A TP]) for the val- ues kmax=58 sec-and Ka =415 gM. Corresponding values for normal S] were 43.2 sec`' and 7.5 ,uM and for dilated cardiomyopathy S] were 18.8 sec`and 3.7 ,uM. significant difference in the rate of binding between the data observed for the normal and myopathic myosins. The combined sets of data were fitted by the values kmax=58\u00b18 sec 1and Kapp=415\u00b1130 ,M. The maximum rate was similar to the value measured by Smith and Cusanovich43 for ATP binding to bovine cardiac Si under similar conditions.", "type": "table"}, "TABREF4": {"text": "The rate of binding (kmas) of ATP to normal Si was 43.2 sec`with a Ka,pp of Margossian et al Myosin Structure and Activity in Dilated Cardiomyopathy 1725FIGURE 3. Graphs show dependence of the rate of steady- stateATPhydrolysis ofnormal (filled squares) and myopathic (open squares) human heart myosin (panel A) and Si (panel B) upon actin concentration. Experimental conditions: 0.2the indicated concentration of actin. Lines drawn through the data represent best fits of the data to the equation V= V,,j (1 +Km/[actinJ). For normal myosin Si, V,,, =0.69 sec-',and K,pp=7.5 ,uM; for myopathic myosin, V,,=0.29 sec-', and Kapp=63 ,uM. Vm and K,pp formyosin: control, 0.08 sec-, 1.4 guM; myopathic, 0.06 sec-1, 2.3 ,uM. 7.5 ,uM, and for myopathic Si, the rate was calculated to be 18.8 sec-1, and the Kapp was 3.7 ,uM. Steady-State ATP Hydrolysis by Normal and Myopathic Myosins The dependence of the steady-state rate of ATP hydrolysis on [actin] is shown in Figure 3. The data are fitted reasonably well by a hyperbolic equation. The", "type": "table"}, "TABREF6": {"text": "mM EDTA. Solid lines, optical densities at 280 nm; dashed lines, radioactivity counts corresponding to proteolytic activity. Note high activity in fractions from myopathic hearts in comparison with normal hearts in which radioactivity offractions was slightly above background.FIGURE 10. Coomassie-stained SDS-PAGE and autoradiograms of Western blots of a number of myosins before and after treatment with human myopathic heartprotease and an extractfrom normal heart tissue having some proteolytic activity. Lanes A-Dand H totally hydrolyzed LC2, whereas protease from the IDC heart tissue shown in lane B did. IDC, as one would expect. Cases 28 and 31 both had left ventricular assist devices. None of the patients with atherosclerotic heart disease had received a left ventric- ular assist device. Though no strictly normal hearts were available, our findings are clearly not induced by either hypertrophy or heart failure. The major structural change immediately noticeable in IDC tissues analyzed (cases 22, 31, 36, 48, and 49; Table 1) was the absence or appreciable reduction of LC2 content in myosin purified from these tissues (see", "type": "table"}, "TABREF7": {"text": "Comparison of Protease Level, Structure, and Activity of Myosin in Control and Human Hearts With IdiopathicLC, light chain; EM, electron microscopy; AS, severe atherosclerosis; IDC, idiopathic dilated cardiomyopathy. *Characteristic paracrystals produced with either control or IDC myosin rod. suggesting either that the presence of LC2 causes myofilaments to form normally, resulting from a specific interaction involving LC2 with other LC2s, or else that LC2 has a stabilizing effect on the globular head of myosin, which is in turn able to stabilize filament structure. That there was some change within myosin Si was further supported by the observation of a 20% reduction in the rate of heavy chain cleavage of cardi- omyopathic Si during limited tryptic digestion (Figure 8). Given the relatively small difference in the cleavage rates, this may reflect a conformational change rather than an amino acid substitution within the primary structure at the 25-70 kd or the 50-20 kd linker region where tryptic attack occurs.49 A crucial point is that the decrease in turbidity (Figure 4) and in filament length and the reduction in the steady-state rate of ATP hydrolysis were reversible upon recombination with LC2, as reported before.26,4246", "type": "table"}}}
{"paper_id": "10700169", "_pdf_hash": "3dc32ec35256a364a53602439dc5e321bbec1f01", "abstract": [{"section": "Abstract", "text": "The purpose of this paper is to estimate the Certain Coefficient for generalized Starlike functions with reference to symmetric points described on the open unit disk for which R k \u03bb ,\u03b4 (\u03c6 ) of normalized analytic functions f (z) that lies in a region with reference to 1 and symmetric with reference to the real axis.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Let A symbolize the class of all analytic function f (z) as concerns to f (z) = z + \u221e \u2211 n=2 a n z n (1.1) that are analytic in U = {z \u2208 C : |z| < 1} and agree the conditions f (0) = 0, f (0) = 1. Also S the subclass of A consisting of all functions that are univalent in U. For f (z) and g(z) analytic in U, f (z) is said to subordinate to g(z) when there exist a schwarz function \u03c9(z), analytic in U amidst \u03c9(0) = 0 and |\u03c9(z)| < 1 (z \u2208 U), satisfying f (z) = g(\u03c9(z)) (z \u2208 U). This subordination is symbolized as f \u227a g or f (z) \u227a g(z) (z \u2208 U).", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "More precisely,, when g(z) is univalent in U, then the subordination be correspondent to f (0) = g(0) and f (U) \u2282 g(U).", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "Assume \u03c6 (z) an analytic function in U with \u03c6 (0) = 1, \u03c6 (0) > 0 and Re{\u03c6 (z)} > 0, z \u2208 U that map U onto a starlike region with referrence to 1 and symmetric amidst the real axis. We signify S * (\u03c6 ) and C(\u03c6 ), respectively, the subclasses of A , that accomplish the relations of subordination:", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "The above functions were put forward and studied by Ma and Minda [9] . Specifically, while", "cite_spans": [{"start": 65, "end": 68, "text": "[9]", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "Introduction", "text": "these functions diminish respectively to the established classes S * (\u03b1), (0 \u2264 \u03b1 < 1) of \u03b1 in U and C(\u03b1), (0 \u2264 \u03b1 < 1) \u03b1 in U. Ma and Minda [9] , the Fekete-Szeg\u00f6 inequality for f (z) in C(\u03c6 ) was acknowledged in relating the classes S * (\u03c6 ) and C(\u03c6 ) of Alexander result.", "cite_spans": [{"start": 139, "end": 142, "text": "[9]", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "Introduction", "text": "To recollect the Fekete-Szeg\u00f6 problems in consideration to starlike, convex including numerous subclasses in A , the readers are advised to refer the work carried out by Srivatsava et al [20] . Moreover, the primary outcome be oblidged to Fekete and szeg\u00f6 [2] ", "cite_spans": [{"start": 187, "end": 191, "text": "[20]", "ref_id": "BIBREF19"}, {"start": 256, "end": 259, "text": "[2]", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Introduction", "text": "In this paper, we attain the Fekete-szeg\u00f6 inequality considering the function f \u2208 A in the class R k \u03bb ,\u03b4 (\u03c6 ) characterized as follows", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "while \u03bb = 1 and \u03b4 = 0 s\u0203l\u0203gean differential operator is obtained. when k = 0 or \u03bb = 0 leads to Ruscheweyh operator, also \u03b4 = 0 leads to Al-oboudi differential operator with order", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "2. An univalent starlike function \u03c6 (z) with referrence to 1 that maps U onto the right half plane that is symmetric with referrence to the real axis \u03c6 (0) = 1 and", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "In order to establish our important results, we require the subsequent lemma.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "while v < 0 or v > 1, the equality satisfies iff p 1 (z) = 1 + z 1 \u2212 z or one of its rotations. When 0 < v < 1, the equality satisfies iff p 1 (z) = 1 + z 2 1 \u2212 z 2 or one of its rotation. When v = 0, the equality satisfies iff", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "or one of its rotations. When v = 1, the equality satisfies iff p 1 is the reciprocal of one of the functions where the equality satisfies if v = 0. Moreover, the upper bound is sharp, the same can be improvised as follows, if 0 < v < 1:", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "The following result is more important forour enquiry.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": ". is a function with positive real part in U, then", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "The conclusion is sharp for p 1 (z) given by", "cite_spans": [], "ref_spans": []}, {"section": "Fekete-szeg\u00f6 Problem for the Function of the class", "text": "Using Lemma 1.2, Fekete-szeg\u00f6 Problem for the class R k \u03bb ,\u03b4 (\u03c6 ) can be proved.", "cite_spans": [], "ref_spans": []}, {"section": "Fekete-szeg\u00f6 Problem for the Function of the class", "text": "where", "cite_spans": [], "ref_spans": []}, {"section": "Fekete-szeg\u00f6 Problem for the Function of the class", "text": ".", "cite_spans": [], "ref_spans": []}, {"section": "Fekete-szeg\u00f6 Problem for the Function of the class", "text": "Where", "cite_spans": [], "ref_spans": []}, {"section": "Fekete-szeg\u00f6 Problem for the Function of the class", "text": "The result is sharp.", "cite_spans": [], "ref_spans": []}, {"section": "Fekete-szeg\u00f6 Problem for the Function of the class", "text": "Proof. When f \u2208 R k \u03bb ,\u03b4 (\u03c6 ), there shall exist a Schwarz function w(z), analytic in U with w(0) = 0 and | w(z) |< 1 in U satisfying", "cite_spans": [], "ref_spans": []}, {"section": "Fekete-szeg\u00f6 Problem for the Function of the class", "text": "A function p 1 (z) is defined as", "cite_spans": [], "ref_spans": []}, {"section": "Fekete-szeg\u00f6 Problem for the Function of the class", "text": "since w(z) is a Schwarz function, it is known that Re{p 1 (z)} > 0 and p 1 (0) = 0. A function p(z) is defined by", "cite_spans": [], "ref_spans": []}, {"section": "Fekete-szeg\u00f6 Problem for the Function of the class", "text": "From (2.1), we obtain", "cite_spans": [], "ref_spans": []}, {"section": "Fekete-szeg\u00f6 Problem for the Function of the class", "text": "and", "cite_spans": [], "ref_spans": []}, {"section": "Fekete-szeg\u00f6 Problem for the Function of the class", "text": "while equating the coefficients of z and z 2 , we infer", "cite_spans": [], "ref_spans": []}, {"section": "Fekete-szeg\u00f6 Problem for the Function of the class", "text": "From (2.2) and (2.4), we get", "cite_spans": [], "ref_spans": []}, {"section": "Fekete-szeg\u00f6 Problem for the Function of the class", "text": "Therefore we have", "cite_spans": [], "ref_spans": []}, {"section": "Fekete-szeg\u00f6 Problem for the Function of the class", "text": "If \u00b5 \u2264 \u03c3 1 , using Lemmas 1.1 and 1.2, the following is obtained.", "cite_spans": [], "ref_spans": []}, {"section": "Fekete-szeg\u00f6 Problem for the Function of the class", "text": "which is the first part of Theorem 1.1. Similarly, if \u00b5 \u2265 \u03c3 2 , using Lemmas 1.1 and 1.2, we get", "cite_spans": [], "ref_spans": []}, {"section": "Fekete-szeg\u00f6 Problem for the Function of the class", "text": "when \u03c3 1 \u2264 \u00b5 \u2264 \u03c3 2 , we see that", "cite_spans": [], "ref_spans": []}, {"section": "Fekete-szeg\u00f6 Problem for the Function of the class", "text": "Finally,we see that", "cite_spans": [], "ref_spans": []}, {"section": "Fekete-szeg\u00f6 Problem for the Function of the class", "text": "In order to express that the bounds are sharp, the function k", "cite_spans": [], "ref_spans": []}, {"section": "Fekete-szeg\u00f6 Problem for the Function of the class", "text": "and the function F \u03b3 and", "cite_spans": [], "ref_spans": []}, {"section": "Fekete-szeg\u00f6 Problem for the Function of the class", "text": "Clearly the functions k \u03c6 n , F \u03b3 and G \u03b3 \u2208 R k \u03bb ,\u03b4 (\u03c6 ). It can also be denoted as K \u03c6 = K \u03c6 2 . If \u00b5 < \u03c3 1 or \u00b5 > \u03c3 2 , then the equality in Theorem 2.1 satisfies iff f is K \u03c6 or one of its rotations. If \u03c3 1 < \u00b5 < \u03c3 2 , then the equality satisfies iff f is K \u03c6 3 or one of its rotations. When \u00b5 = \u03c3 1 , the equality satisfies iff f is F \u03b3 or one of its rotations. When \u00b5 = \u03c3 2 , the equality satisfies iff f is G \u03b3 or one of its rotations.", "cite_spans": [], "ref_spans": []}, {"section": "Fekete-szeg\u00f6 Problem for the Function of the class", "text": "Using Lemma 1.2,the following theorem can easily be obtained. ", "cite_spans": [], "ref_spans": []}, {"section": "Fekete-szeg\u00f6 Problem for the Function of the class", "text": "The result is Sharp. Remark 2.4. In its distinctive case when \u03bb = 1, \u03b4 = 0 and k = 0, a known result of Ma and Minda [9] was arrived.", "cite_spans": [{"start": 117, "end": 120, "text": "[9]", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "Fekete-szeg\u00f6 Problem for the Function of the class", "text": "Remark 2.5. In its distinctive case, when \u03bb = 1, \u03b4 = 0 and k = 0,s = 1, t = \u22121, a known result due to T.N Shanmugam et al [17] was arrived.", "cite_spans": [{"start": 122, "end": 126, "text": "[17]", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "Applications to Analytic Function Defined by Fractional Calculus", "text": "The dependece of fractional calculus has earned appreciable demand upon early decades. Two of the current contributions on this area of deeprooted investigations include comprehensive treatises on the theory and applications of fractional differential equations by Podlubny [13] and Kilbas et al. [5] We first introduce the class M \u03b4 \u03b1,\u03b2 ,\u03bb (\u03c6 ), that is defined using Hadamard product and a certain operator Owa-Srivatsava operator (see for details, [18] and [8] ; see also [11] , [12] and [21] ) in fractional calculus.", "cite_spans": [{"start": 274, "end": 278, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 297, "end": 300, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 451, "end": 455, "text": "[18]", "ref_id": "BIBREF17"}, {"start": 460, "end": 463, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 475, "end": 479, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 482, "end": 486, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 491, "end": 495, "text": "[21]", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "Applications to Analytic Function Defined by Fractional Calculus", "text": "Suppose also that", "cite_spans": [], "ref_spans": []}, {"section": "Applications to Analytic Function Defined by Fractional Calculus", "text": "where the coefficients B n are real with B 1 > 0, B 2 > 0, and B n > 0 (n \u2208 N\\{1, 2}).", "cite_spans": [], "ref_spans": []}, {"section": "Applications to Analytic Function Defined by Fractional Calculus", "text": "If f (z) given by (1.1) belongs to the class M g \u03b1,\u03b2 ,\u03bb (\u03c6 ), then", "cite_spans": [], "ref_spans": []}, {"section": "Applications to Analytic Function Defined by Fractional Calculus", "text": "where, for convenience, Theorem 3.5 coincides with the following result due to Srivatsava et al. [19] for which \u2126 \u03bb f (z) is a parabolic starlike function ( [3] and [16] ). Theorem 3.5 would coincide with the result obtained earlier by Ma and Minda [10] ", "cite_spans": [{"start": 97, "end": 101, "text": "[19]", "ref_id": "BIBREF18"}, {"start": 157, "end": 160, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 165, "end": 169, "text": "[16]", "ref_id": "BIBREF15"}, {"start": 249, "end": 253, "text": "[10]", "ref_id": "BIBREF9"}], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Differential Sandwich theorem with generalized derivative operator", "authors": [{"first": "M", "middle": [], "last": "Darus", "suffix": ""}, {"first": "K", "middle": [], "last": "Al-Shaqsi", "suffix": ""}], "year": 2008, "venue": "Proc.World Acad. Sci. Eng. Tech", "link": null}, "BIBREF1": {"title": "Eine Bermerkung ber ungerade schlichte Funktionen", "authors": [{"first": "M", "middle": [], "last": "Fekete", "suffix": ""}, {"first": "G", "middle": [], "last": "Szeg\u00f6", "suffix": ""}], "year": 1933, "venue": "J.Lond.Math.Soc", "link": null}, "BIBREF2": {"title": "Uniformly Convex Functions", "authors": [{"first": "A", "middle": ["W"], "last": "Goodman", "suffix": ""}], "year": 1991, "venue": "Ann. Polon. Math", "link": null}, "BIBREF3": {"title": "A Coefficient inequality for certain classes of analytic functions", "authors": [{"first": "F", "middle": ["R"], "last": "Keogh", "suffix": ""}, {"first": "E", "middle": ["P"], "last": "Merkes", "suffix": ""}], "year": 1969, "venue": "Proc.Amer.Math.Soc", "link": "115621074"}, "BIBREF4": {"title": "Theory and Applications of Fractional Differential Equations", "authors": [{"first": "A", "middle": ["A"], "last": "Kilbas", "suffix": ""}, {"first": "H", "middle": ["M"], "last": "Srivatsava", "suffix": ""}, {"first": "J", "middle": ["J"], "last": "Trujillo", "suffix": ""}], "year": 2006, "venue": "", "link": null}, "BIBREF5": {"title": "On the Fekete-szeg\u00f6 problem for Close-toconvex functions II", "authors": [{"first": "W", "middle": [], "last": "Koepf", "suffix": ""}], "year": 1987, "venue": "Arch.Math", "link": null}, "BIBREF6": {"title": "On the Fekete-szeg\u00f6 problem for Close-toconvex functions II", "authors": [{"first": "W", "middle": [], "last": "Koepf", "suffix": ""}], "year": 1987, "venue": "Proc.Amer.Math.Soc", "link": null}, "BIBREF7": {"title": "An Application of the Fractional Derivative", "authors": [{"first": "S", "middle": [], "last": "Owa", "suffix": ""}], "year": 1984, "venue": "Math. Japan", "link": null}, "BIBREF8": {"title": "A Unified treatment of some special classes of univalent functions", "authors": [{"first": "W", "middle": [], "last": "Ma", "suffix": ""}, {"first": "D", "middle": [], "last": "Minda", "suffix": ""}], "year": "", "venue": "Proc. Conf. on Complex Analysis", "link": "116431363"}, "BIBREF9": {"title": "Uniformly Convex Functions", "authors": [{"first": "W", "middle": [], "last": "Ma", "suffix": ""}, {"first": "D", "middle": [], "last": "Minda", "suffix": ""}], "year": 1993, "venue": "Ann. Polon. Math", "link": "117969405"}, "BIBREF10": {"title": "On the Distortion Theorems, I", "authors": [{"first": "S", "middle": [], "last": "Owa", "suffix": ""}], "year": 1978, "venue": "Kyungpook Math.J", "link": null}, "BIBREF11": {"title": "Univalent and Starlike Generalized Hypergeometric Functions", "authors": [{"first": "S", "middle": [], "last": "Owa", "suffix": ""}, {"first": "H", "middle": ["M"], "last": "Srivatsava", "suffix": ""}], "year": 1987, "venue": "Canad. J.Math", "link": "119716731"}, "BIBREF12": {"title": "Fractional Differential Equations:An Introduction to Fractional Derivatives, Fractional Differential Equations, Methods of their solutions and some of their Applications, Mathematics in Science and Engineering", "authors": [{"first": "I", "middle": [], "last": "Podlubny", "suffix": ""}], "year": 1999, "venue": "", "link": null}, "BIBREF13": {"title": "Coefficient inequalities for certain subclasses of analytic functions and their applications involving the Owa-Srivatsava operator of fractional calculus", "authors": [{"first": "C", "middle": [], "last": "Ramachandran", "suffix": ""}, {"first": "S", "middle": [], "last": "Sivasubramanian", "suffix": ""}, {"first": "H", "middle": ["M"], "last": "Srivatsava", "suffix": ""}, {"first": "A", "middle": [], "last": "Swaminathan", "suffix": ""}], "year": 2009, "venue": "J.Math. Inequal. Appl", "link": "123976066"}, "BIBREF14": {"title": "Certain Subclasses of Starlike and Convex functions of complex order", "authors": [{"first": "Metin", "middle": [], "last": "V Ravichandran", "suffix": ""}, {"first": "Yasar", "middle": [], "last": "Bolcal", "suffix": ""}, {"first": "A", "middle": [], "last": "Polotoglu", "suffix": ""}, {"first": "", "middle": [], "last": "Sen", "suffix": ""}], "year": 2005, "venue": "Hacettepe J. Math. and Stat", "link": "55120100"}, "BIBREF15": {"title": "Uniformly Convex Functions and a corresponding class of starlike Functions", "authors": [{"first": "F", "middle": [], "last": "Ronning", "suffix": ""}], "year": 1993, "venue": "Proc. Amer. Math. Soc", "link": "204013078"}, "BIBREF16": {"title": "Fekete-szeg\u00f6Problem for Subclass of Starlike Functions With Respect to Symmetric Points", "authors": [{"first": "T", "middle": ["N"], "last": "Shanmugam", "suffix": ""}, {"first": "C", "middle": [], "last": "Ramachandran", "suffix": ""}, {"first": "V", "middle": [], "last": "Ravichandran", "suffix": ""}], "year": 2006, "venue": "Bull. Korean Math. Soc", "link": null}, "BIBREF17": {"title": "Some families of fractional derivative and other linear operators associated with analytic, univalent and multivalent functions", "authors": [{"first": "H", "middle": ["M"], "last": "Srivatsava", "suffix": ""}], "year": 2000, "venue": "Analysis and its applications", "link": null}, "BIBREF18": {"title": "Applications of Fractional Calculus to Parabolic Starlike and Uniformly Convex Functions", "authors": [{"first": "H", "middle": ["M"], "last": "Srivatsava", "suffix": ""}, {"first": "A", "middle": ["K"], "last": "Mishra", "suffix": ""}], "year": 2000, "venue": "Comput. Math Appl", "link": null}, "BIBREF19": {"title": "the Feketeszeg\u00f6 problem for a subclass of Close-to-convex functions", "authors": [{"first": "H", "middle": ["M"], "last": "Srivatsava", "suffix": ""}, {"first": "A", "middle": ["K"], "last": "Mishra", "suffix": ""}, {"first": "M", "middle": ["K"], "last": "Das", "suffix": ""}], "year": 2001, "venue": "Complex Variables Theory Appl", "link": null}, "BIBREF20": {"title": "Univalent Functions, Fractional Calculus and their Applications", "authors": [{"first": "H", "middle": ["M"], "last": "Srivatsava", "suffix": ""}, {"first": "S", "middle": [], "last": "Owa", "suffix": ""}], "year": 1989, "venue": "", "link": "117950175"}}, "ref_entries": {"FIGREF0": {"text": "Let \u03c6 (z) = 1 + B 1 z + B 2 z 2 + \u00b7 \u00b7 \u00b7 , where B n are real with B 1 > 0 and B 2 \u2265 0. If f (z) given by (1.1) belongs to", "type": "figure"}, "FIGREF1": {"text": "The coefficient bounds for | a 2 | and | a 3 | are special cases of those claimed by Theorem 2.1", "type": "figure"}, "FIGREF2": {"text": "1)(s + t \u2212 2)(1 + \u03bb ) 2k 2(\u03b4 + 2)(1 + 2\u03bb ) k [(s 2 + st + t 2 )1)(s + t \u2212 2)(1 + \u03bb ) 2k 2(\u03b4 + 2)(1 + 2\u03bb ) k [(s 2 + st + t 2 ) \u2212 3]", "type": "figure"}, "FIGREF3": {"text": "\u039b and \u03b7 are defined as in Theorem 2.1, respectively.", "type": "figure"}, "FIGREF4": {"text": "In its special case, when \u03bb = 0, \u03b2 = 1 \u03b1 = 0,", "type": "figure"}, "FIGREF5": {"text": "When \u03bb = 0, \u03b2 = 1 \u03b1 = 0, \u03b4 = 1,", "type": "figure"}}}
{"paper_id": "10700179", "_pdf_hash": "027acda09e8463f30492fb1a8621d7da1ab30d2b", "abstract": [{"section": "Abstract", "text": "Background: The nucleolus is a multi-domain enriched with proteins involved in ribosome biogenesis, cell cycle and apoptosis control, viral replication and differentiation of stem cells. Several authors have suggested a role for the nucleolus also in malignant transformation. We have recently demonstrated that under specific circumstances the transcriptional factor EGR1 is shuttled to the nucleolus where it functions as a negative regulator of RNA polymerase I. Since this activity is hampered in ARF \u2212/\u2212 cells, and ARF transcription is regulated by EGR1 while the turnover of ARF protein is under the control of B23, we speculated that some sort of cooperation between EGR1 and B23 might also exist.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Background", "text": "During tumorigenesis, cancer cells increase the production of ribosomes to support the higher rate of protein synthesis associated with cancer growth. This is supported by the increase in rRNA synthesis transcribed in the nucleolus by RNA polymerase I, and correlates with adverse prognosis [1] [2] [3] . To contrast this mechanism, the products of Rb and p53, two important tumour suppressor genes, negatively interfere with the RNA polymerase I and the assembly of the transcriptional machinery on the rDNA promoter [4, 5] . p53 activation is under direct control of the negative regulator MDM2, which in turn is inactivated by ARF. This explains why ARF is pivotal for triggering the cell-cycle arrest and the apoptotic programme after oncogenic cues [6] . The stability of ARF is significantly increased in cells that overexpress exogenous B23 (known also as nucleophosmin, numatrim, and NOR38). B23 associates with ARF within the nucleolus, delaying its turnover. As a consequence, the inhibition of B23 by shRNA has destabilizing effects over ARF [7] . ARF mutants unable to bind B23 are unstable and functionally impaired [8] . In mouse embryonic fibroblasts (MEFs) lacking both B23 and p53, ARF is mainly found outside the nucleolus and with a shortened half-life, conferring the cells with higher proliferation rates [9] . B23 is an abundant, multifunctional protein present at high amount in the granular region of nucleoli [10] . It is involved in the regulation of ribosome biogenesis, and the control of genome stability and survival in response to a variety of stress stimuli [11] [12] [13] . In fact, B23 \u2212/\u2212 fibroblasts become aneuploid and have increased levels of P53 in a stable form [7] . Conversely, B23 has been shown to induce senescence in normal primary fibroblasts [14] and its overexpression in tumors lacking p53 is known to promote proliferation [15] . The transcription factor EGR1 (early growth response protein 1) is involved in the transcriptional regulation of responses to a wide number of proliferative, differentiation and stress stimuli [16, 17] . In particular, EGR1 regulates the expression of key genes, including p53, TGFB, CDKN1A/p21 and PTEN, involved in the growth and division of cancer cells, [18] [19] [20] . Egr-1 +/\u2212 and Egr-1 \u2212/\u2212 MEFs bypass senescence and grow as typically immortalized cells. Besides to cover the role as \"gatekeeper\" of p53-dependent growth regulatory mechanisms [18] , EGR1 has been suggested to play a role as tumour suppressor in several tumor types [21] [22] [23] . We have recently demonstrated that EGR1 behaves as a negative regulator of RNA polymerase I [24] . EGR1 localizes to the nucleolus and the more it is expressed the less is the 47S pre-rRNA synthesized. ARF is required for the nucleolar localization of EGR1. Indeed, in cells ARF \u2212/\u2212 such as the NIH-3 T3 Egr1 does not keep the nucleolar localization and the ability to suppress the synthesis of the 47S ribosomal precursor [24] . In view of the functional interaction of ARF with B23, and the fact that EGR1 regulates the transcription of ARF [25] we have hypothesized that EGR1 might extend its control also on B23 expression. Here, we show that EGR1 promotes its stability and the transcription of B23 gene.", "cite_spans": [{"start": 291, "end": 294, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 295, "end": 298, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 299, "end": 302, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 518, "end": 521, "text": "[4,", "ref_id": "BIBREF3"}, {"start": 522, "end": 524, "text": "5]", "ref_id": "BIBREF4"}, {"start": 754, "end": 757, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 1053, "end": 1056, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 1129, "end": 1132, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 1326, "end": 1329, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 1434, "end": 1438, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 1590, "end": 1594, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 1595, "end": 1599, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 1600, "end": 1604, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 1703, "end": 1706, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 1791, "end": 1795, "text": "[14]", "ref_id": "BIBREF13"}, {"start": 1875, "end": 1879, "text": "[15]", "ref_id": "BIBREF14"}, {"start": 2075, "end": 2079, "text": "[16,", "ref_id": "BIBREF15"}, {"start": 2080, "end": 2083, "text": "17]", "ref_id": "BIBREF16"}, {"start": 2240, "end": 2244, "text": "[18]", "ref_id": "BIBREF17"}, {"start": 2245, "end": 2249, "text": "[19]", "ref_id": "BIBREF18"}, {"start": 2250, "end": 2254, "text": "[20]", "ref_id": "BIBREF19"}, {"start": 2434, "end": 2438, "text": "[18]", "ref_id": "BIBREF17"}, {"start": 2524, "end": 2528, "text": "[21]", "ref_id": "BIBREF20"}, {"start": 2529, "end": 2533, "text": "[22]", "ref_id": "BIBREF21"}, {"start": 2534, "end": 2538, "text": "[23]", "ref_id": "BIBREF22"}, {"start": 2633, "end": 2637, "text": "[24]", "ref_id": "BIBREF23"}, {"start": 2964, "end": 2968, "text": "[24]", "ref_id": "BIBREF23"}, {"start": 3084, "end": 3088, "text": "[25]", "ref_id": "BIBREF24"}], "ref_spans": []}, {"section": "Results", "text": "The expression of nucleolar B23 correlates with the levels of EGR1", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "To verify our hypothesis we first monitored the effects on the expression of B23 in HeLa cells by either increasing or reducing the levels of EGR1. After transient transfection of the pEGFP-EGR1 expression vector, showed a six-fold increase of B23 mRNA in low serum conditions (Fig. 1a) . No changes were observed under culture conditions with 10 % FBS. Accordingly, lowering the EGR1 mRNA levels with siRNA specific to EGR1 sequence, we observed a significant reduction of B23 mRNA levels compared to cells treated with non-specific (scrambled) siRNA ( Fig. 1d upper panel) . Here again, the inhibitory effect on B23 mRNA synthesis was observed only in cells cultured in low serum conditions, and not in presence of 10 % FBS. Similar changes were observed with the B23 protein synthesis under the same experimental conditions. In summary, in condition of serum deprivation the B23 mRNA and protein levels increased after EGR1 overexpression and decreased after EGR1 silencing.", "cite_spans": [], "ref_spans": [{"start": 277, "end": 286, "text": "(Fig. 1a)", "ref_id": "FIGREF0"}, {"start": 554, "end": 574, "text": "Fig. 1d upper panel)", "ref_id": "FIGREF0"}]}, {"section": "Results", "text": "To verify that the above results in HeLa cells are not dependent upon the specific cellular context, we replicated the experiments with a primary culture of human lung tumor and a glioblastoma derived established cell line, U87MG and 293 T (Additional file 1: Figure S1 ). In all these cultures the B23 mRNA and protein underwent variations in their levels similar to those observed in HeLa under the same experimental conditions. We conclude that the levels of B23 expression are strongly influenced by EGR1 under lower FBS concentration, a known stress inducing condition.", "cite_spans": [], "ref_spans": [{"start": 260, "end": 269, "text": "Figure S1", "ref_id": "FIGREF0"}]}, {"section": "Results", "text": "To investigate whether EGR1 can influence the expression of B23 under different stress conditions, we sought to examine their response to actinomycin D, a genotoxic agent known to inhibit the RNA Polymerase I and II activity and to induce DNA damage [26] . The levels of EGR1 and B23 mRNA and protein showed a step-wise increase when cells were treated with increasing concentrations (0.04, 0.5, and 1 \u03bcg/ml) of actinomycin D (Fig. 2a-b -e-f-g). Also the expression of p300, a specific EGR1 target gene, increases, whereas the synthesis of 47S and 45S is strongly inhibited, as shown in Fig. 2c-d . Pre-treatment with EGR1 silencing siRNA abolished the response of B23 and p300 genes and restored the production of 47S rRNA ( Fig. 2c-d) . Finally, we asked the question of whether the B23 protein would translocate to the nucleoplasm in response to Pol I-induced transcription repression, as suggested by Yao Z. et al. [27] . We confirm that in our experimental conditions actinomycin D causes the translocation of B23 to the nucleoplasm (Additional file 2: Figure S2 ).", "cite_spans": [{"start": 250, "end": 254, "text": "[26]", "ref_id": "BIBREF25"}, {"start": 919, "end": 923, "text": "[27]", "ref_id": "BIBREF26"}], "ref_spans": [{"start": 426, "end": 436, "text": "(Fig. 2a-b", "ref_id": "FIGREF1"}, {"start": 587, "end": 596, "text": "Fig. 2c-d", "ref_id": "FIGREF1"}, {"start": 726, "end": 736, "text": "Fig. 2c-d)", "ref_id": "FIGREF1"}, {"start": 1058, "end": 1067, "text": "Figure S2", "ref_id": "FIGREF1"}]}, {"section": "EGR1 binds to B23 promoter", "text": "Since the levels of B23 expression vary in response to EGR1, we hypothesized that as a transcriptional regulator it might control the B23 expression by interacting with the promoter. To verify this hypothesis, we first searched the B23 promoter (NCBI, Accession: NG_016018) for the presence of canonical sequences that were recognized and bound by-EGR1.", "cite_spans": [], "ref_spans": []}, {"section": "EGR1 binds to B23 promoter", "text": "By-bioinformatics-approach (http://bip.weizmann.ac.il/ index.html) one of such elements was found at \u2212172 bp to the TATA box (Fig. 3a) . To establish the function of the putative EGR1 binding site, we cloned a partial sequence of the B23 promoter (4328 to 5240 bp) from HeLa DNA and inserted into a luciferase reporter gene to assay the responsiveness to the activity of EGR1. As above, EGR1 was exogenously expressed following transient transfection of the pEGFP-EGR1 expression vector. All experiments were carried out in HeLa cells cultured in low serum conditions (0.2 % FBS). The B23 minimal promoter carrying the sequence of the EGR1 binding site found in HeLa was successfully transactivated by the exogenously expressed EGR1, providing high levels of luciferase activity (Fig. 3b) . No luciferase activity was detected when the B23 minimal promoter was deleted of the sequence or carried a mutated version of the EGR1 binding site and tested in the same conditions as above ( Fig. 3a-b) .", "cite_spans": [], "ref_spans": []}, {"section": "EGR1 binds to B23 promoter", "text": "In vitro DNA binding assays were performed to establish whether EGR1 specifically associated with the minimal B23 promoter. We incubated DNA fragments of the promoter sequence with anti-EGR1 antibody in presence of extracts of HeLa cells either transfected with full length EGR1 or EGFP [24] . Cells were cultured either in low serum conditions or at 10 % FBS. An abundant (about twenty-fold) enrichment of promoter sequences was obtained by RT-qPCR ( Fig. 3c-d ) and PCR (Additional file 3: Figure S3 ) only with extracts of cells transfected with EGR1 and cultured in low serum. No statistically significant differences were detected in 10 % FBS. Furthermore, when the PCR was performed with oligonucleotides specific for a region located upstream the minimal B23 promoter no amplification products were obtained (data not shown).", "cite_spans": [{"start": 287, "end": 291, "text": "[24]", "ref_id": "BIBREF23"}], "ref_spans": []}, {"section": "B23 expression is downregulated in the brain of Egr1 \u2212/\u2212 mice", "text": "In order to gain further evidence about the role of EGR1 as a regulator of B23 expression, we compared the levels of B23 mRNA and protein from brain of Egr1 \u2212/\u2212 with Egr1 +/+ mice. Since EGR1 is present at high levels in mouse and human brain [28] but not, the levels of B23 expression should likely be different in the brain of wild-type compared to Egr1 \u2212/\u2212 mice, in case B23 were regulated by EGR1. A significant reduction of B23 mRNA and protein was detected in the brain of Egr1 \u2212/\u2212 mice (Fig. 4) . B23 increases the EGR1 steady-state level of expression B23 plays an important role in cell growth by regulating the function of proteins such as ARF and p53 [29] . This is accomplished by delaying the turnover of these proteins, thus contributing to the activation of suppressor activities aimed to the control of cell cycle. In the case of ARF, a physical interaction with B23 has been demonstrated which protected ARF from proteasomal degradation [29] . We asked the question of whether a similar interaction might exist also between EGR1 and B23. If B23 stabilizes EGR1, then a fall in the B23 synthesis would likely translate into a change in the detectable levels of EGR1, due to a loss of stability. To test this hypothesis, we treated the HeLa cells with 30nM B23 specific siRNA, and monitored the expression of both genes EGR1 and B23. We show that following a decrease of B23 mRNA and protein, the levels of EGR1 mRNA remained unchanged (Fig. 5c) . However, the levels of EGR1 protein detected by immunoblotting were significantly lower (Fig. 5a-b) . We also confirm that under the same experimental conditions the level of 47S pre-rRNA increased whereas the level of p300 diminished, both significantly ( Fig. 5d-e) . To investigate whether the lower levels of EGR1 protein following B23 silencing were the result of a proteasome-dependent degradation, we tested in HeLa cells the effect of the proteasome inhibitor MG-132 (at the concentration of 10 \u03bcM) on the stability of EGR1 during B23 silencing after 16, 20, and 24 h. Only after 16 h from the treatment the levels of EGR1 did actually increase (Fig. 5f-g ). These experiments clearly suggest the partial involvement of proteasome machinery on EGR1 turnover, and that, EGR1 stability and accumulation within the nucleolus is likely regulated by B23.", "cite_spans": [{"start": 243, "end": 247, "text": "[28]", "ref_id": "BIBREF27"}, {"start": 662, "end": 666, "text": "[29]", "ref_id": "BIBREF28"}, {"start": 954, "end": 958, "text": "[29]", "ref_id": "BIBREF28"}], "ref_spans": [{"start": 493, "end": 501, "text": "(Fig. 4)", "ref_id": "FIGREF2"}, {"start": 1451, "end": 1460, "text": "(Fig. 5c)", "ref_id": "FIGREF3"}, {"start": 1551, "end": 1562, "text": "(Fig. 5a-b)", "ref_id": "FIGREF3"}, {"start": 1720, "end": 1730, "text": "Fig. 5d-e)", "ref_id": "FIGREF3"}, {"start": 2116, "end": 2126, "text": "(Fig. 5f-g", "ref_id": "FIGREF3"}]}, {"section": "Discussion", "text": "B23 (also known as NPM1, nucleophosmin, nucleoplasmin, NO38, and numatrin) is the best studied member of the NPM family of chaperones, a highly conserved protein found in humans, rodents, chicken and fish. Human B23 is mapped to chromosome 5q35 and is made up of 12 exons. B23, first isolated from Xenopus laevis oocyte extracts [30] is a histone storage protein affecting many intracellular processes such as: i) the rate of ribosome synthesis by binding to pre-ribosomal complexes; ii) DNA duplication and transcriptional regulation; iii) nucleo-cytoplasmic shuttling and assistance to small basic proteins such as REV, REX, TAT and p120 for transport to the nucleolus [31] [32] [33] [34] . Within the nucleolus, In a recent publication, we have shown that the transcriptional factor EGR1 also localizes to the nucleolus and acts as negative regulator of RNA polymerase I activity, similarly to p53 [24] . Both B23 and EGR1 are activated and expressed under at least two different stress stimuli, i.e., after UV exposure and H 2 O 2 treatment [35, 36] . We do not know whether the two genes are independently. To investigate this hypothesis, we conducted a series of experiments where HeLa cells grown in serum deprived conditions and treated either to express high levels of exogenous EGR1 or to silence the expression of the endogenous EGR1 gene, were examined for changes in the localization and the expression of B23 mRNA and protein, and in the regulation of 47S and 45S pre-rRNA synthesis. The above results show that both pre-rRNAs (47S and ", "cite_spans": [{"start": 329, "end": 333, "text": "[30]", "ref_id": "BIBREF29"}, {"start": 671, "end": 675, "text": "[31]", "ref_id": "BIBREF30"}, {"start": 676, "end": 680, "text": "[32]", "ref_id": "BIBREF31"}, {"start": 681, "end": 685, "text": "[33]", "ref_id": "BIBREF32"}, {"start": 686, "end": 690, "text": "[34]", "ref_id": "BIBREF33"}, {"start": 901, "end": 905, "text": "[24]", "ref_id": "BIBREF23"}, {"start": 1045, "end": 1049, "text": "[35,", "ref_id": "BIBREF34"}, {"start": 1050, "end": 1053, "text": "36]", "ref_id": "BIBREF35"}], "ref_spans": []}, {"section": "45S", "text": ") have a rise in their levels when EGR1 is silenced. Though very preliminar this observation leading us to hypothesize that the regulation of 47S could be not an abortive transcription. However, further investigations will help us to clarify this point. Here we show that in HeLa cells the levels of B23 mRNA and protein increase after EGR1 overexpression, and decrease after EGR1 silencing. We know that this correlation is not cell specific. In fact, very similar results were obtained also with established glioma cell line and a primary culture of lung adenocarcinoma. In addition, the same effect can be assumed in vivo for the brain of B23 by comparing the expression levels of B23 in the brain of EGR1 \u2212/\u2212 with that from EGR1 +/+ mice. An investigation of the human and mouse B23 promoter nucleotide sequence allowed the recognition of a potential EGR1 binding site, which proved to be effective in a reporter gene transactivation assay. The association of EGR1 to the B23 promoter was further demonstrated by chromatin immunoprecipitation (ChIP). It has been shown that following DNA damage B23 binds to chromatin [37] and to other proteins as well, such as GADD45 [38] , the retinoblastoma protein pRB [39] , PARP1 and PARP2 [40] . They are all intimately linked to the maintenance of DNA structure, replication or repair. Following treatment with actinomycin D, nucleolar B23 protein undergoes a rapid translocation to the nucleoplasm [41] . Here we confirm these data and find that the levels of both EGR1 and B23 increase with different concentrations of the drug. However, if cells are treated under conditions inhibiting the expression of EGR1, then the levels of B23 remain constant. One of the mechanism of actinomycin D is inhibit the transcription by intercalating with DNA, in particular at the GC-rich RNA Polymerase I genes. In our experiments EGR1 seem to facilitate the action of genotoxic drug. We have already demonstrate in a previous paper that EGR1 bind UBF protein and the formation of this proteins complex could help the action of Actinomycin D on the inhibition of RNA Polymerase I gene. This is only one of the possible scenario further experiments will help to clarify the role of EGR1 under actinomycin action. These data further suggest a direct role for EGR1 in regulating the expression of B23, and that the correlation between EGR1 and B23 is maintained under several conditions of cellular stress. Several studies have demonstrated the involvement of B23 in the p53 tumor suppressor pathway. Colombo et al. found that B23 when overexpressed promotes cellular senescence in fibroblasts and regulates the stability of p53 through direct interaction [14] . Further, in response to nucleolar stress, B23 does promote the stabilization of ARF protein [25] . In view of the multiple interactions that link B23 to the above molecules and likely to EGR1, we finally studied the effects of B23 over EGR1. Indeed, by inhibiting the expression of B23 we observed a reduction of EGR1 protein levels but not of EGR1 mRNA. Since MG-132, a proteosomal inhibitor, can reduce this effect we speculate that B23 might have a role for keeping adequate levels of the intracellular concentration of EGR1 following stress conditions.", "cite_spans": [{"start": 1122, "end": 1126, "text": "[37]", "ref_id": "BIBREF36"}, {"start": 1173, "end": 1177, "text": "[38]", "ref_id": "BIBREF37"}, {"start": 1211, "end": 1215, "text": "[39]", "ref_id": "BIBREF38"}, {"start": 1234, "end": 1238, "text": "[40]", "ref_id": "BIBREF39"}, {"start": 1445, "end": 1449, "text": "[41]", "ref_id": "BIBREF40"}, {"start": 2687, "end": 2691, "text": "[14]", "ref_id": "BIBREF13"}, {"start": 2786, "end": 2790, "text": "[25]", "ref_id": "BIBREF24"}], "ref_spans": []}, {"section": "Conclusion", "text": "In summary, these findings provide the evidence that B23 is regulated by EGR1 under stress conditions, and highlights EGR1 as an important link of the ARF-B23-rRNA nucleolar network [42] , regulating ribosome biogenesis and promoting growth arrest.", "cite_spans": [{"start": 182, "end": 186, "text": "[42]", "ref_id": "BIBREF41"}], "ref_spans": []}, {"section": "Methods", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Cell lines, primary tumour cell and mice", "text": "The cell lines, uterine cervix cancer HeLa (ATCC CCL2), human embryonic kidney 293 T (ATCC CRL-1573) and glioma U87MG (ATCC HTB-14) were grown in DMEM supplemented with 1 % nonessential amino acids, 1 % Lglutamine, 100 IU/ml penicillin, 100 IU/ml streptomycin and FBS (Sigma-Aldrich St. Louis, Mo, USA) 10 % or 0.2 % (serum starvation) at 37\u00b0C in 5 % CO 2 humidified atmosphere in air. The cell lines used were obtained from the American Type Culture Collection, Rockville MD, USA. The primary lung tumour cells were grown in DMEM-F12 [43] . The research protocol was approved by ethic committee of S. Andrea Hospital, University of Roma Sapienza. The study was conducted using C57BL/6 wild-type and Egr1 deficient mice (Egr-1\u2212/\u2212) [44] . Animals were housed four per cage. All the experiments were performed in accordance with the EU Directive 2010/63/ EU for animal experiments and approved by ethic committee of Department of Medico-Surgical Sciences and Biotechnologies, University of Roma Sapienza.", "cite_spans": [{"start": 535, "end": 539, "text": "[43]", "ref_id": "BIBREF42"}, {"start": 731, "end": 735, "text": "[44]", "ref_id": "BIBREF43"}], "ref_spans": []}, {"section": "RT-qPCR", "text": "RNA extraction was performed after EGR1 silencing, B23 silencing and EGR1 overexpression into HeLa cells. For silencing, EGR1 and B23 pre-designed siRNA (Invitrogen, Grand Island, NY USA, 4390822) or scrambled sequence RNA oligonucleotide (Negative Control siRNA 4390846) were transiently transfected at 20, 30 nM or 60 nM using High-Perfect Transfecting Agent (as indicated in the figures) (Qiagen, Valencia, CA) following the Qiagen protocol. The treatment with actinomycin D (Sigma) was performed for 1 h at 37\u00b0C at the three concentrations indicated in Fig. 2 . The treatment with the proteasome inhibitor MG-132 (Sigma) was performed at 37\u00b0C for 16, 20 and 24 h during B23 silencing. For EGR1 overexpression pGFP-EGR1 expression vector [24] was transfected using lipofectamin (Invitrogen, Grand Island, NY USA). To analyse the levels of B23 in vivo, total RNA was extracted from female mice of wild type and Egr1 \u2212/\u2212 mice. Total RNA extraction and cDNA preparation were accomplished using RNeasy (Qiagen, Valencia, CA) and Superscript III RT (Invitrogen, Grand Island, NY USA) according to the manufacturer's recommendations. For the silencing and overexpression experiments we used the protocols described previously [24] . Quantitative RT-PCR was performed using Fast SYBR Green Master mix and the StepOnePlus real-time PCR system (both from Applied Biosystems). Each experiment was performed in triplicate. Experiments were independently repeated three times. Gene expression levels were quantified from realtime PCR data by the comparative threshold cycle (CT) method using 18S as an internal control gene. ", "cite_spans": [{"start": 741, "end": 745, "text": "[24]", "ref_id": "BIBREF23"}, {"start": 1223, "end": 1227, "text": "[24]", "ref_id": "BIBREF23"}], "ref_spans": [{"start": 557, "end": 563, "text": "Fig. 2", "ref_id": "FIGREF1"}]}, {"section": "Immunoblotting", "text": "Immunoblotting analysis was performed using whole extracts (40 \u03bcg) from HeLa cells after silencing and overexpression of EGR1 [23] , or B23 silencing. Total extract (40 \u03bcg) were prepared from subconfluent cultures by resuspending cells in RIPA-Buffer (20 mM Hepes, pH 6.8, 5 mM KCl, 5 mM MgCl 2 , 0.5 % NP-40, 0.1 % sodium. Furthermore whole extracts (80 \u03bcg) were obtained from brain of nine of wild type and Egr1 \u2212/\u2212 female mice of three months using RIPA buffer (20 mM Hepes pH 6.8, 5 mM KCl, 5 mM MgCl 2 , 0,5 % NP-40, 0,1 % sodium deoxycholate, protease inhibitor (Sigma), 0.1 mM phenylmethylsulfonyl fluoride) using a Dounce homogenizer. After incubation for 30 min at 0\u00b0C the lysate was centrifuged at 10000 rpm \u00d7 15 min 4\u00b0C. The samples were loaded on SDS-PAGE gel at 8 % or 10 % of acrylamide (Sigma 29:1) and blotted on PVDF (Biorad) using a semidry apparatus (Biorad). After blocking in 5 % dry milk the membrane was incubated with the appropriate antibody. The primary antibodies used are: rabbit polyclonal anti-EGR1 (sc-101, Santa Cruz Biotechnology), mouse monoclonal antibody anti-B23 (ab10530, Abcam), rabbit polyclonal antibody anti-GAPDH (2118, Cell Signaling Technology Biotechnology) and monoclonal antibody anti-actin (sc-47778, Santa Cruz). The secondary antibodies used for western blot are anti-mouse and anti-rabbit (GE Healthcare Bio-Sciences, Piscataway, NJ, USA). After ECL assay (GE Healthcare) the membrane was incubated with film specific for protein detection (Kodak).", "cite_spans": [{"start": 126, "end": 130, "text": "[23]", "ref_id": "BIBREF22"}], "ref_spans": []}, {"section": "Luciferase and \u03b2-galactosidase activity assay", "text": "Cloning of the B23 minimal promoter To amplify the proximal B23 promoter region, genomic DNA from HeLa cells was used as template. The primers used are: FW 5'-GGGGGTACCGCTTTCTTTCAGGAGGAAT-3' REV 5'-CCGCTCGAGGGCACGCACTTAGGTAG-3'. To verify the specificity of the PCR amplification, the fragment obtained was excised from agarose gel and isolated using DNA gel extraction kit (Millipore). The PCR product (region 4328 bp to 5240 bp of B23, NPM1, numatrin sequence; Accession: NG_016018) was KpnI/XhoI digested and cloned into the pGL3 basic luciferase vector (Promega). The correct sequence was checked by direct sequence (Applied Biosystem). Site-specific mutations in the EGR1-binding sites within the B23 promoter were made with the QuickChangeII Site-Directed Mutagenesis Kit (Stratagene, La Jolla, CA). Briefly, primer sequences used to generate point mutations are: FW 5'-GGAAGGAGGCTT AAAGGAGGTAGAAAGGAGTG-3 REV 5'-CACTCCTT TCTACCTCCTTTAAGCCTCCTTCC-3'. PCR reaction conditions were: 95\u00b0C for 1 min followed by 18 cycles at 95\u00b0C for 50 s, 60\u00b0C for 50 s, 68\u00b0C for 5 min, then 68\u00b0C for 7 min. Following the PCR reaction, the mix was digested by incubating with Dpn I for 1 h at 37\u00b0C. Clones of mutated plasmids were replicated in bacteria and screened for the correct mutation by DNA sequencing (Applied Biosystem). Luciferase assay. HeLa cells were seeded into 6-well plates and transfected with 0.3 \u03bcg transactivator plasmid pEgr1-GFP, 0.3 \u03bcg pB23-Luc or 0.3 \u03bcg pB23-mut-Luc, plus 0.5 \u03bcg of \u03b2-galactosidase vector. At 24 h post-transfection, the levels of luciferase activity were measured sequentially from a single sample using the Luciferase reporter assay system (Promega) with a luminometer (TD-20/20 Turner Design). Measurement of luciferase enzyme activity was assayed on whole-cell extract performed using 20 \u03bcl of lysate cleared and 100 \u03bcl of Luciferase assay Reagent. The luciferase values were normalized to \u03b2-galactosidase activity and protein content. The experiments of luciferase assay were repeated three times in triplicate.", "cite_spans": [], "ref_spans": []}, {"section": "Chromatin immunoprecipitation (ChIP)", "text": "HeLa cells were transfected with full length EGR1 expression vector pEGFEGR1 or pEGFP empty vector using lipofectamine 2000, fixed 48 h after transfection with 1 % formaldehyde for 15 min at room temperature and the reaction stopped by addition of 125 mM glycine for 5 min. The other steps of the ChIP experiments were", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "RNA polymerase I and III growth control and cancer", "authors": [{"first": "R", "middle": ["J"], "last": "Withe", "suffix": ""}], "year": 2005, "venue": "Nat Rev Mol Cell Biol", "link": null}, "BIBREF1": {"title": "The RNA polymerase I transcription machinery: an emerging target for the treatment of cancer", "authors": [{"first": "D", "middle": [], "last": "Drygin", "suffix": ""}, {"first": "W", "middle": ["G"], "last": "Rice", "suffix": ""}, {"first": "I", "middle": [], "last": "Grummt", "suffix": ""}], "year": 2010, "venue": "Annu Rev Pharmacol Toxicol", "link": "34773755"}, "BIBREF2": {"title": "Nascent pre-rRNA overexpression correlates with an adverse prognosis in alveolar rhabdomyosarcoma", "authors": [{"first": "D", "middle": [], "last": "Williamson", "suffix": ""}, {"first": "Y", "middle": ["J"], "last": "Lu", "suffix": ""}, {"first": "C", "middle": [], "last": "Fang", "suffix": ""}, {"first": "K", "middle": [], "last": "Pritchard-Jones", "suffix": ""}, {"first": "J", "middle": [], "last": "Shipley", "suffix": ""}], "year": 2006, "venue": "Genes Chromosomes Cancer", "link": "39711313"}, "BIBREF3": {"title": "Overlapping functions of the pRB family in the regulation of rRNA synthesis", "authors": [{"first": "S", "middle": [], "last": "Ciarmatori", "suffix": ""}, {"first": "P", "middle": ["H"], "last": "Scott", "suffix": ""}, {"first": "J", "middle": ["E"], "last": "Sutcliffe", "suffix": ""}, {"first": "A", "middle": [], "last": "Mclees", "suffix": ""}, {"first": "H", "middle": ["M"], "last": "Alzuherri", "suffix": ""}], "year": 2001, "venue": "Mol Cell Biol", "link": "17391143"}, "BIBREF4": {"title": "Repression of RNA polymerase I transcription by the tumor suppressor p53", "authors": [{"first": "W", "middle": [], "last": "Zhai", "suffix": ""}, {"first": "L", "middle": [], "last": "Comai", "suffix": ""}], "year": 2000, "venue": "Mol Cell Biol", "link": "36535169"}, "BIBREF5": {"title": "Functional and physical interactions of the ARF tumor suppressor with p53 and Mdm2", "authors": [{"first": "T", "middle": [], "last": "Kamijo", "suffix": ""}, {"first": "J", "middle": ["D"], "last": "Weber", "suffix": ""}, {"first": "G", "middle": [], "last": "Zambetti", "suffix": ""}, {"first": "F", "middle": [], "last": "Zindy", "suffix": ""}, {"first": "M", "middle": ["F"], "last": "Roussel", "suffix": ""}, {"first": "C", "middle": ["J"], "last": "Sherr", "suffix": ""}], "year": 1998, "venue": "Proc Natl Acad Sci", "link": "28903070"}, "BIBREF6": {"title": "Nucleophosmin regulates the stability and transcriptional activity of p53", "authors": [{"first": "E", "middle": [], "last": "Colombo", "suffix": ""}], "year": 2002, "venue": "Nat Cell Biol", "link": "24923289"}, "BIBREF7": {"title": "Physical and functional interactions of the Arf tumor suppressor protein with nucleophosmin/B23", "authors": [{"first": "D", "middle": [], "last": "Bertwistle", "suffix": ""}, {"first": "M", "middle": [], "last": "Sugimoto", "suffix": ""}, {"first": "C", "middle": ["J"], "last": "Sherr", "suffix": ""}], "year": 2004, "venue": "Mol Cell Biol", "link": "24907611"}, "BIBREF8": {"title": "Nucleophosmin is required for DNA integrity and p19Arf protein stability", "authors": [{"first": "E", "middle": [], "last": "Colombo", "suffix": ""}, {"first": "P", "middle": [], "last": "Bonetti", "suffix": ""}, {"first": "Lazzerini", "middle": [], "last": "Denchi", "suffix": ""}, {"first": "E", "middle": [], "last": "Martinelli", "suffix": ""}, {"first": "P", "middle": [], "last": "Zamponi", "suffix": ""}, {"first": "R", "middle": [], "last": "Marine", "suffix": ""}, {"first": "J", "middle": ["C"], "last": "", "suffix": ""}], "year": 2005, "venue": "Mol Cell Biol", "link": "26381440"}, "BIBREF9": {"title": "N-terminal polyubiquitination and degradation of the Arf tumor suppressor", "authors": [{"first": "M", "middle": ["L"], "last": "Kuo", "suffix": ""}, {"first": "W", "middle": [], "last": "Den Besten", "suffix": ""}, {"first": "D", "middle": [], "last": "Bertwistle", "suffix": ""}, {"first": "M", "middle": ["F"], "last": "Roussel", "suffix": ""}, {"first": "C", "middle": ["J"], "last": "Sherr", "suffix": ""}], "year": 2004, "venue": "Genes Dev", "link": "41056551"}, "BIBREF10": {"title": "Identification of nucleophosmin/B23 a nucleolar acidic protein, as a histone chaperone", "authors": [{"first": "M", "middle": [], "last": "Okuwaki", "suffix": ""}, {"first": "A", "middle": [], "last": "Iwamatsu", "suffix": ""}, {"first": "M", "middle": [], "last": "Tsujimoto", "suffix": ""}, {"first": "K", "middle": [], "last": "Nagata", "suffix": ""}], "year": 2001, "venue": "FEBS Lett", "link": null}, "BIBREF11": {"title": "Temporal and spatial control of nucleophosmin by the RanCrm1 complex in centrosome duplication", "authors": [{"first": "W", "middle": [], "last": "Wang", "suffix": ""}, {"first": "A", "middle": [], "last": "Budhu", "suffix": ""}, {"first": "M", "middle": [], "last": "Forgues", "suffix": ""}, {"first": "X", "middle": ["W"], "last": "Wang", "suffix": ""}], "year": 2005, "venue": "Nat Cell Biol", "link": "29462406"}, "BIBREF12": {"title": "Nucleophosmin and its complex network: a possible therapeutic target in haematological diseases", "authors": [{"first": "E", "middle": [], "last": "Colombo", "suffix": ""}, {"first": "M", "middle": [], "last": "Alcalay", "suffix": ""}, {"first": "P", "middle": ["G"], "last": "Pelicci", "suffix": ""}], "year": 2011, "venue": "Oncogene", "link": "3194463"}, "BIBREF13": {"title": "Nucleophosmin regulates the stability and transcriptional activity of p53", "authors": [{"first": "E", "middle": [], "last": "Colombo", "suffix": ""}], "year": 2002, "venue": "Nature Cell Biol Nat Cell Biol", "link": "24923289"}, "BIBREF14": {"title": "Tumor suppressor ARF degrades B23, a nucleolar protein involved in ribosome biogenesis and cell proliferation", "authors": [{"first": "K", "middle": [], "last": "Itahana", "suffix": ""}], "year": 2003, "venue": "Mol Cel", "link": "37923791"}, "BIBREF15": {"title": "The transcriptional factor EGR-1 suppresses transformation of human fibrosarcoma HT1080 cells by coordinated induction of transforming growth factor beta1, fibronectin, and plasminogen activator inhibitor-1", "authors": [{"first": "C", "middle": [], "last": "Liu", "suffix": ""}, {"first": "J", "middle": [], "last": "Yao", "suffix": ""}, {"first": "I", "middle": [], "last": "De Belle", "suffix": ""}, {"first": "R", "middle": ["P"], "last": "Huang", "suffix": ""}, {"first": "E", "middle": [], "last": "Adamson", "suffix": ""}, {"first": "D", "middle": [], "last": "Mercola", "suffix": ""}], "year": 1999, "venue": "J Biol Chem", "link": "20601788"}, "BIBREF16": {"title": "The transcriptional factor Egr1 is a direct regulator of multiple tumor suppressors including TGFbeta1, PTEN, p53 and fibronectin", "authors": [{"first": "V", "middle": [], "last": "Baron", "suffix": ""}, {"first": "E", "middle": ["D"], "last": "Adamson", "suffix": ""}, {"first": "A", "middle": [], "last": "Calogero", "suffix": ""}, {"first": "G", "middle": [], "last": "Ragona", "suffix": ""}, {"first": "D", "middle": [], "last": "Mercola", "suffix": ""}], "year": 2006, "venue": "Cancer Gene Ther", "link": null}, "BIBREF17": {"title": "Early growth response I acts as a tumor suppressor in vivo and in vitro via regulation of p53", "authors": [{"first": "A", "middle": [], "last": "Krones-Herzig", "suffix": ""}, {"first": "S", "middle": [], "last": "Mittal", "suffix": ""}, {"first": "Yule", "middle": ["K"], "last": "Liang", "suffix": ""}, {"first": "H", "middle": [], "last": "English", "suffix": ""}, {"first": "C", "middle": [], "last": "Urcis", "suffix": ""}, {"first": "R", "middle": [], "last": "", "suffix": ""}], "year": 2005, "venue": "Cancer Res", "link": null}, "BIBREF18": {"title": "The Egr-1 transcription factor directly activates PTEN during irradiation-induced signalling", "authors": [{"first": "T", "middle": [], "last": "Virolle", "suffix": ""}, {"first": "E", "middle": ["D"], "last": "Adamson", "suffix": ""}, {"first": "V", "middle": [], "last": "Baron", "suffix": ""}, {"first": "D", "middle": [], "last": "Birle", "suffix": ""}, {"first": "D", "middle": [], "last": "Mercola", "suffix": ""}, {"first": "T", "middle": [], "last": "Mustelin", "suffix": ""}], "year": 2001, "venue": "Nat Cell Biol", "link": "8473518"}, "BIBREF19": {"title": "p53 and Egr1 additively suppress transformed growth in HT1080 cells but Egr1 counteracts p53-dependent apoptosis", "authors": [{"first": "I", "middle": [], "last": "De Belle", "suffix": ""}, {"first": "R", "middle": ["P"], "last": "Huang", "suffix": ""}, {"first": "Y", "middle": [], "last": "Fan", "suffix": ""}, {"first": "C", "middle": [], "last": "Liu", "suffix": ""}, {"first": "D", "middle": [], "last": "Mercola", "suffix": ""}, {"first": "E", "middle": ["D"], "last": "Adamson", "suffix": ""}], "year": 1999, "venue": "Oncogene", "link": "9625072"}, "BIBREF20": {"title": "Descreased Egr-1 expression in human, mouse and rat mammary cells and tissues correlates with tumor formation", "authors": [{"first": "R", "middle": ["P"], "last": "Huang", "suffix": ""}, {"first": "Y", "middle": [], "last": "Fan", "suffix": ""}, {"first": "I", "middle": [], "last": "De Belle", "suffix": ""}, {"first": "C", "middle": [], "last": "Niemeyer", "suffix": ""}, {"first": "M", "middle": ["M"], "last": "Gottardis", "suffix": ""}, {"first": "D", "middle": [], "last": "Mercola", "suffix": ""}], "year": 1997, "venue": "Int J Cancer", "link": "27209786"}, "BIBREF21": {"title": "The transcription factor EGR1 suppresses transformation of human fibrosarcoma HT1080 cells by coordinated induction of transforming growth factor-beta1, fibronectin, and plasminogen activator inhibitor-1", "authors": [{"first": "C", "middle": [], "last": "Liu", "suffix": ""}, {"first": "J", "middle": [], "last": "Yao", "suffix": ""}, {"first": "I", "middle": [], "last": "De Belle", "suffix": ""}, {"first": "R", "middle": ["P"], "last": "Huang", "suffix": ""}, {"first": "E", "middle": [], "last": "Adamson", "suffix": ""}], "year": 1999, "venue": "J Biol Chem", "link": "20601788"}, "BIBREF22": {"title": "Inhibition of cell growth by EGR-1 in human primary cultures from malignant glioma", "authors": [{"first": "A", "middle": [], "last": "Calogero", "suffix": ""}, {"first": "V", "middle": [], "last": "Lombardi", "suffix": ""}, {"first": "De", "middle": [], "last": "Gregorio", "suffix": ""}, {"first": "G", "middle": [], "last": "Porcellini", "suffix": ""}, {"first": "A", "middle": [], "last": "Ucci", "suffix": ""}, {"first": "S", "middle": [], "last": "Arcella", "suffix": ""}, {"first": "A", "middle": [], "last": "", "suffix": ""}], "year": 2004, "venue": "Cancer Cell Int", "link": "469732"}, "BIBREF23": {"title": "The transcriptional factor EGR1 localizes to the nucleolus and is linked to suppression of ribosomal precursor synthesis", "authors": [{"first": "D", "middle": [], "last": "Ponti", "suffix": ""}, {"first": "G", "middle": ["C"], "last": "Bellenchi", "suffix": ""}, {"first": "R", "middle": [], "last": "Puca", "suffix": ""}, {"first": "D", "middle": [], "last": "Bastianelli", "suffix": ""}, {"first": "M", "middle": [], "last": "Maroder", "suffix": ""}, {"first": "G", "middle": [], "last": "Ragona", "suffix": ""}], "year": 2014, "venue": "PloS One", "link": "11446281"}, "BIBREF24": {"title": "PTEN regulation by Akt-EGR1-ARF-PTEN axis", "authors": [{"first": "J", "middle": [], "last": "Yu", "suffix": ""}, {"first": "S", "middle": ["S"], "last": "Zhang", "suffix": ""}, {"first": "K", "middle": [], "last": "Saito", "suffix": ""}, {"first": "S", "middle": [], "last": "Williams", "suffix": ""}, {"first": "Y", "middle": [], "last": "Arimura", "suffix": ""}], "year": 2009, "venue": "EMBO J", "link": "22348610"}, "BIBREF25": {"title": "In vivo release of mitotic silencing of ribosomal gene transcription does not give rise to precursor ribosomal RNA processing", "authors": [{"first": "V", "middle": [], "last": "Sirri", "suffix": ""}, {"first": "P", "middle": [], "last": "Roussel", "suffix": ""}, {"first": "D", "middle": [], "last": "Hernandez-Verdun", "suffix": ""}], "year": 2000, "venue": "J Cell Biol", "link": "11093618"}, "BIBREF26": {"title": "B23 acts as a nucleolar stress sensor and promotes cell survival through its dynamic interaction with hnRNPU and hnRNPA1", "authors": [{"first": "Z", "middle": [], "last": "Yao", "suffix": ""}, {"first": "S", "middle": [], "last": "Duan", "suffix": ""}, {"first": "D", "middle": [], "last": "Hou", "suffix": ""}, {"first": "W", "middle": [], "last": "Wang", "suffix": ""}, {"first": "G", "middle": [], "last": "Wang", "suffix": ""}, {"first": "Y", "middle": [], "last": "Liu", "suffix": ""}], "year": 2010, "venue": "Oncogene", "link": "23154280"}, "BIBREF27": {"title": "Basal EGR1 (zif268, NGFI-A, Krox-24) expression in developing striatal patches: role of dopamine and glutamate", "authors": [{"first": "A", "middle": [], "last": "Snyder-Keller", "suffix": ""}, {"first": "R", "middle": [], "last": "Chandra", "suffix": ""}, {"first": "Y", "middle": [], "last": "Lin", "suffix": ""}, {"first": "E", "middle": ["S"], "last": "Mitchell", "suffix": ""}], "year": 2002, "venue": "Brain Res", "link": "40905135"}, "BIBREF28": {"title": "B23 and ARF Friends or Foes?", "authors": [{"first": "M", "middle": ["S"], "last": "Lindstrom", "suffix": ""}, {"first": "Y", "middle": [], "last": "Zhang", "suffix": ""}], "year": 2006, "venue": "Cell Biochem Biophys", "link": null}, "BIBREF29": {"title": "Nucleophosmin cDNA sequence reveals polyglutamic acid tracts and a cluster of sequences homologous to putative nuclear localization signals", "authors": [{"first": "C", "middle": [], "last": "Dingwall", "suffix": ""}, {"first": "S", "middle": ["M"], "last": "Dilworth", "suffix": ""}, {"first": "S", "middle": ["J"], "last": "Black", "suffix": ""}, {"first": "S", "middle": ["E"], "last": "Kearsey", "suffix": ""}, {"first": "L", "middle": ["S"], "last": "Cox", "suffix": ""}, {"first": "R", "middle": ["A"], "last": "Laskey", "suffix": ""}], "year": 1987, "venue": "EMBO J", "link": "43128533"}, "BIBREF30": {"title": "NPM/B23: a multifunctional chaperone in ribosome biogenesis and chromatin remodelling", "authors": [{"first": "M", "middle": ["S"], "last": "Lindstrom", "suffix": ""}], "year": 2011, "venue": "Biochem Res Int", "link": null}, "BIBREF31": {"title": "Specific complex of human immunodeficiency virus type 1 rev and nucleolar B23 proteins: dissociation by the Rev response element", "authors": [{"first": "C", "middle": [], "last": "Fankhauser", "suffix": ""}, {"first": "E", "middle": [], "last": "Izaurralde", "suffix": ""}, {"first": "Y", "middle": [], "last": "Adachi", "suffix": ""}, {"first": "P", "middle": [], "last": "Wingfield", "suffix": ""}, {"first": "U", "middle": ["K"], "last": "Laemmli", "suffix": ""}], "year": 1991, "venue": "Mol Cell Biol", "link": "22042833"}, "BIBREF32": {"title": "Protein B23 is an important human factor for the nucleolar localization of the Human Immunodeficiency virus protein Tat", "authors": [{"first": "Y", "middle": ["P"], "last": "Li", "suffix": ""}], "year": 1997, "venue": "J Virol", "link": "7422983"}, "BIBREF33": {"title": "Identification of the nuclear and nucleolar localization signals of the protein p120: interaction with translocation protein B23", "authors": [{"first": "B", "middle": ["C"], "last": "Valdez", "suffix": ""}, {"first": "L", "middle": [], "last": "Perlaky", "suffix": ""}, {"first": "D", "middle": [], "last": "Henning", "suffix": ""}, {"first": "Pkc", "middle": [], "last": "Saijo", "suffix": ""}, {"first": "H", "middle": [], "last": "Busch", "suffix": ""}], "year": 1994, "venue": "J Biol Chem", "link": "28774899"}, "BIBREF34": {"title": "UV stimulation of nucleophosmin/B23 expression is an immediate-early gene response induced by damaged DNA", "authors": [{"first": "M", "middle": ["H"], "last": "Wu", "suffix": ""}, {"first": "B", "middle": ["Y"], "last": "Yung", "suffix": ""}], "year": 2002, "venue": "J Biol Chem", "link": "20825693"}, "BIBREF35": {"title": "A proteomic approach to identify early molecular targets of oxidative stress in human epithelial lens cells", "authors": [{"first": "I", "middle": [], "last": "Paron", "suffix": ""}, {"first": "D", "middle": [], "last": "&apos;elia", "suffix": ""}, {"first": "A", "middle": [], "last": "", "suffix": ""}, {"first": "D", "middle": [], "last": "&apos;ambrosio", "suffix": ""}, {"first": "C", "middle": [], "last": "Scaloni", "suffix": ""}, {"first": "A", "middle": [], "last": "", "suffix": ""}, {"first": "D", "middle": [], "last": "&apos;aurizio", "suffix": ""}, {"first": "F", "middle": [], "last": "Prescott", "suffix": ""}, {"first": "A", "middle": [], "last": "", "suffix": ""}], "year": 2004, "venue": "Biochem J", "link": null}, "BIBREF36": {"title": "A proteomics approach for the identification of nucleophosmin and heterogeneous nuclear ribonuclearprotein C1/C2 as chromatin-binding proteins in response to DNA double-strand breaks", "authors": [{"first": "S", "middle": ["Y"], "last": "Lee", "suffix": ""}, {"first": "J", "middle": ["H"], "last": "Park", "suffix": ""}, {"first": "S", "middle": [], "last": "Kim", "suffix": ""}, {"first": "E", "middle": ["J"], "last": "Park", "suffix": ""}, {"first": "Y", "middle": [], "last": "Yun", "suffix": ""}, {"first": "J", "middle": [], "last": "Kwon", "suffix": ""}], "year": 2005, "venue": "Biochem J", "link": null}, "BIBREF37": {"title": "B23 regulates GADD45a nuclear translocation and contributes to GADD45a-induced cell cycle G2-M arrest", "authors": [{"first": "H", "middle": [], "last": "Gao", "suffix": ""}, {"first": "Jin", "middle": ["S"], "last": "Song", "suffix": ""}, {"first": "Y", "middle": [], "last": "Fu", "suffix": ""}, {"first": "M", "middle": [], "last": "Wang", "suffix": ""}, {"first": "M", "middle": [], "last": "Liu", "suffix": ""}, {"first": "Z", "middle": [], "last": "", "suffix": ""}], "year": 2005, "venue": "J Biol Chem", "link": "23982900"}, "BIBREF38": {"title": "Nucleolar protein B23.1 binds to retinoblastoma protein and synergistically stimulates DNA polymerase \u03b1 activity", "authors": [{"first": "M", "middle": [], "last": "Takemura", "suffix": ""}, {"first": "K", "middle": [], "last": "Sato", "suffix": ""}, {"first": "M", "middle": [], "last": "Nishio", "suffix": ""}, {"first": "T", "middle": [], "last": "Akiyama", "suffix": ""}, {"first": "H", "middle": [], "last": "Umekawa", "suffix": ""}, {"first": "S", "middle": [], "last": "Yoshida", "suffix": ""}], "year": 1999, "venue": "J Biochem", "link": "21940954"}, "BIBREF39": {"title": "PARP1 and PARP2 interact with nucleophosmin/B23 and accumulate in transcriptionally active nucleoli", "authors": [{"first": "V", "middle": ["S"], "last": "Meder", "suffix": ""}, {"first": "M", "middle": [], "last": "Boeglin", "suffix": ""}, {"first": "G", "middle": [], "last": "De Murcia", "suffix": ""}, {"first": "V", "middle": [], "last": "Schreiber", "suffix": ""}], "year": 2005, "venue": "J Cell Sci", "link": null}, "BIBREF40": {"title": "Effects of actinomycin D analogs on nucleolar phosphoprotein B23 (37,000 daltons/pI 5.1)", "authors": [{"first": "B", "middle": ["Y"], "last": "Yung", "suffix": ""}, {"first": "R", "middle": ["K"], "last": "Busch", "suffix": ""}, {"first": "H", "middle": [], "last": "Busch", "suffix": ""}, {"first": "A", "middle": ["B"], "last": "Mauger", "suffix": ""}, {"first": "P", "middle": ["K"], "last": "Chan", "suffix": ""}], "year": 1985, "venue": "Biochem Pharmacol", "link": "46392822"}, "BIBREF41": {"title": "Nucleophosmin (B23) targets ARF to nucleoli and inhibits its function", "authors": [{"first": "C", "middle": [], "last": "Korgaonkar", "suffix": ""}, {"first": "J", "middle": [], "last": "Hagen", "suffix": ""}, {"first": "V", "middle": [], "last": "Tompkins", "suffix": ""}, {"first": "A", "middle": ["A"], "last": "Frazier", "suffix": ""}, {"first": "C", "middle": [], "last": "Allamargot", "suffix": ""}, {"first": "F", "middle": ["W"], "last": "Quelle", "suffix": ""}], "year": 2005, "venue": "Mol Cell Biol", "link": "20544812"}, "BIBREF42": {"title": "Axitinib affects cell viability and migration of primary fetal lung adenocarcinoma culture", "authors": [{"first": "C", "middle": [], "last": "Menna", "suffix": ""}, {"first": "De", "middle": [], "last": "Falco", "suffix": ""}, {"first": "E", "middle": [], "last": "Pacini", "suffix": ""}, {"first": "L", "middle": [], "last": "Scafetta", "suffix": ""}, {"first": "G", "middle": [], "last": "Ruggieri", "suffix": ""}, {"first": "P", "middle": [], "last": "Puca", "suffix": ""}, {"first": "R", "middle": [], "last": "", "suffix": ""}], "year": 2014, "venue": "Cancer Invest", "link": null}, "BIBREF43": {"title": "Submit your next manuscript to BioMed Central and take full advantage of: \u2022 Convenient online submission \u2022 Thorough peer review \u2022 No space constraints or color figure charges \u2022 Immediate publication on acceptance \u2022 Inclusion in PubMed, CAS, Scopus and Google Scholar \u2022 Research which is freely available for redistribution", "authors": [{"first": "L", "middle": [], "last": "Pacini", "suffix": ""}, {"first": "S", "middle": [], "last": "Suffredini", "suffix": ""}, {"first": "D", "middle": [], "last": "Ponti", "suffix": ""}, {"first": "R", "middle": [], "last": "Coppini", "suffix": ""}, {"first": "G", "middle": [], "last": "Frati", "suffix": ""}, {"first": "G", "middle": [], "last": "Ragona", "suffix": ""}], "year": 2013, "venue": "Can J Physiol Pharmacol", "link": null}}, "ref_entries": {"FIGREF0": {"text": "Fig. 1 B23 levels are directly correlated to EGR1 under serum deprivation. EGR1 and B23 expression in HeLa cells transfected with a GFP fused full length EGR1 (named EGR1-GFP) or incubated with siRNA specific for EGR1 (named siRNA EGR1). A control empty vector for GFP (named GFP) or a scrambled sequence of the siRNA EGR1 (named siRNA SCRAMBLED) were used for comparison, respectively. Experiments were carried out in medium with either 0.2 % or 10 % FCS. Relative levels of B23 and EGR1 mRNA were quantitated by RT-qPCR in cells transfected with EGR1-GFP or control GFP (Panel a), and in cells incubated with siRNA EGR1 or control siRNA scrambled (Panel d). Protein signal ratios of EGR1 and B23 to GAPDH were quantitated by densitometry in cells transfected with EGR1-GFP or control GFP (Panel c), and in cells incubated with siRNA EGR1 or control siRNA scrambled (Panel f), limitedly to serum deprived conditions. Immunoblot of EGR1 and B23 proteins from a representative experiment (Panel b and e). Data are the mean +/\u2212 s.e. of three independent experiments. Comparisons were performed by t-test. Significant results are highlighted with asterisks (*p < 0.05; **p < 0.01; ***p < 0.001)", "type": "figure"}, "FIGREF1": {"text": "Fig. 2 Actinomycin D induces EGR1 and B23. Relative mRNA levels of EGR1, B23, 47S,45S pre-rRNA and p300 (the last two are known gene targets of EGR1) expressed in HeLa cells treated with Actinomycin D for 1 h at 37\u00b0C (Panel a to d). The smaller inserts in the panels compare the effect of siRNA EGR1 plus Actinomycin D to that of Actinomycin D alone. Quantitative evaluation of EGR1 and B23 proteins under the effect of Actinomycin D, together with a representative immunoblot, are shown in Panel e to g. Data are the mean +/\u2212 s.e. of three independent experiments. Comparisons were performed by one way ANOVA. Significant results are highlighted with asterisks (*p < 0.05; **p < 0.01; ***p < 0.001)", "type": "figure"}, "FIGREF2": {"text": "Fig. 4 B23 is downregulated in EGR1 \u2212/\u2212 mouse brain. a B23 mRNA and b-c protein levels in EGR1 +/+ and EGR1 \u2212/\u2212 mice. Whole brain extracts (80 \u03bcg) were obtained from nine wt and EGR1 \u2212/\u2212 female three month old mice. The EGR1 protein was quantified as relative to that of GAPDH taken as control. Comparisons were performed by t-test. Significant results are highlighted with asterisks (**p < 0.001)", "type": "figure"}, "FIGREF3": {"text": "Fig. 5 EGR1 protein level is linked to B23. Analysis of EGR1 after B23 siRNA in HeLa cells grown at 0.2 % FBS. a Immunoblotting of EGR1 and B23 in whole extracts of HeLa cells after B23 siRNA. EGR1 protein significantly decreases following endogenous B23 silencing at 30 nM. b-c-d-e Real time PCR analysis of B23, EGR1, p300 mRNA and 47S pre-rRNA under B23 silencing. The level of expression of EGR1 remained unchanged (c). As expected p300 mRNA decrease (d) while the 47S rRNA levels increase levels (e). f-g Immunoblotting of EGR1 under MG-132 treatment after B23 siRNA for 16, 20 and 24 h. The level of EGR1 protein is restored during B23 silencing after treatment with proteosome inhibitor at 10 \u03bcM for 16 h at 37\u00b0C. Comparison tests were performed by one way ANOVA and significant results are highlighted with asterisks (*p < 0.05; **p < 0.01; ***p < 0.001)", "type": "figure"}, "FIGREF4": {"text": "The follow- ing gene-specific primers were used: B23: FW 5'-A GAAAAAGCGCCAGTGAAGA-3' , REV 5'-TGGTGTT GATGATTGGTTTTGA-3' (for human gene), FW 5'- GGGGGTACCGCTTTCTTTCAGGAGG-3' , REV 5'-CC GCTCGAGGGCACGCACTTAGGTA-3' (form mouse gene); EGR1: FW 5'-AGCCCTACGAGCACCTGAC-3' and REV 5'-GGTTTGGCTGGGGTAACTG-3'; 47S: FW 5'-TGTCAGGCGTTCTCGTCTC-3' and REV 5'-GAGAG CACGACGTCACCAC-3'. 18S: FW 5'-GCAATTATTCC CCATGAACG-3' and REV 5'-GGGACTTAATCAACG CAAGC-3'; GAPDH: FW 5'-AGCCACATCGCTCAGA CAC-3' REV 5'-GCCCAATACGACCAAATCC-3'; p300: FW 5'-GGTCAAGCTCCAGTGTCTCAA-3' REV: 5'-GGG ACTTAATCAACGCAAGC-3'. Each experiment of trans- fection, immunoblotting and qPCR were repeated three times in triplicate.", "type": "figure"}}}
{"paper_id": "10700182", "_pdf_hash": "29b0e21ead43faa0cca7901cc5341e88c853c2b7", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Characteristics of problem gambling in a Canadian context: A preliminary study using a DSM-IV-based questionnaire", "authors": [{"first": "C", "middle": ["M"], "last": "Beaudoin", "suffix": ""}, {"first": "B", "middle": ["J"], "last": "Cox", "suffix": ""}], "year": 1999, "venue": "Canadian Journal of Psychiatry", "link": "21366393"}, "BIBREF1": {"title": "Ambiguities in survey questionnaire items", "authors": [{"first": "A", "middle": [], "last": "Blaszczynski", "suffix": ""}, {"first": "V", "middle": [], "last": "Dumlao", "suffix": ""}, {"first": "M", "middle": [], "last": "Lange", "suffix": ""}], "year": 1997, "venue": "Journal of Gambling Studies", "link": null}, "BIBREF2": {"title": "Gambling History Questionnaire", "authors": [{"first": "R", "middle": ["B"], "last": "Breen", "suffix": ""}], "year": 2000, "venue": "", "link": null}, "BIBREF3": {"title": "Rapid Onset of Pathological Gambling in Machine Gambling Compared to Other Forms", "authors": [{"first": "R", "middle": ["B"], "last": "Breen", "suffix": ""}], "year": 2000, "venue": "11th International Conference on Gambling and Risk Taking, sponsored by the University of Nevada, Reno-the Institute for the Study of Gambling and Commercial Gaming", "link": null}, "BIBREF4": {"title": "Harm Reduction in Machine Gambling: How the Stimulus Situation Affects Impulsive Responding-Suggestions for Impulse-Control Re-Training", "authors": [{"first": "R", "middle": ["B"], "last": "Breen", "suffix": ""}], "year": 2000, "venue": "Paper presentation: 11th International Conference on Gambling and Risk Taking, sponsored by the University of Nevada, Reno-the Institute for the Study of Gambling and Commercial Gaming", "link": null}, "BIBREF5": {"title": "Casino backers set to up the ante", "authors": [], "year": 2000, "venue": "Christiansen Capital Advisors", "link": null}, "BIBREF6": {"title": "Sex differences in the treatment needs and outcomes of problem gamblers", "authors": [{"first": "B", "middle": ["R"], "last": "Crisp", "suffix": ""}, {"first": "S", "middle": ["A"], "last": "Thomas", "suffix": ""}, {"first": "A", "middle": ["C"], "last": "Jackson", "suffix": ""}, {"first": "N", "middle": [], "last": "Thomason", "suffix": ""}, {"first": "S", "middle": [], "last": "Smith", "suffix": ""}, {"first": "J", "middle": [], "last": "Borrell", "suffix": ""}, {"first": "W", "middle": [], "last": "Ho", "suffix": ""}, {"first": "T", "middle": ["A"], "last": "Holt", "suffix": ""}], "year": 2000, "venue": "Research on Social Work Practice", "link": "141592792"}, "BIBREF7": {"title": "Internal and external determinants of persistent gambling: Problems in generalizing from one form to another", "authors": [{"first": "M", "middle": [], "last": "Dickerson", "suffix": ""}], "year": 1993, "venue": "Gambling behavior and problem gambling. Reno: Institute For the Study of Gambling and Commercial Gaming", "link": null}, "BIBREF8": {"title": "Pathological gambling: A comparison of gambling at German-style slot machines and \"classical\" gambling", "authors": [{"first": "T", "middle": [], "last": "Fabian", "suffix": ""}], "year": 1995, "venue": "Journal of Gambling Studies", "link": "2397143"}, "BIBREF9": {"title": "The Structured Clinical Interview for DSM-IV Axis I disorders", "authors": [{"first": "M", "middle": ["B"], "last": "First", "suffix": ""}, {"first": "R", "middle": ["L"], "last": "Spitzer", "suffix": ""}, {"first": "M", "middle": [], "last": "Gibbon", "suffix": ""}, {"first": "J", "middle": ["B W"], "last": "Williams", "suffix": ""}], "year": 1995, "venue": "", "link": null}, "BIBREF10": {"title": "Current trends in slot machine gambling: Research and policy issues", "authors": [{"first": "S", "middle": [], "last": "Fisher", "suffix": ""}, {"first": "M", "middle": [], "last": "Griffiths", "suffix": ""}], "year": 1995, "venue": "Journal of Gambling Studies", "link": "6046824"}, "BIBREF11": {"title": "The chase: Career of the compulsive gambler", "authors": [{"first": "H", "middle": ["R"], "last": "Lesieur", "suffix": ""}], "year": 1984, "venue": "", "link": "147688180"}, "BIBREF12": {"title": "The South Oaks Gambling Screen (SOGS): A new instrument for the identification of pathological gamblers", "authors": [{"first": "H", "middle": ["R"], "last": "Lesieur", "suffix": ""}, {"first": "S", "middle": [], "last": "Blume", "suffix": ""}], "year": 1987, "venue": "American Journal of Psychiatry", "link": "6242602"}, "BIBREF13": {"title": "A feminist critique of problem gambling research", "authors": [{"first": "M", "middle": ["E"], "last": "Mark", "suffix": ""}, {"first": "H", "middle": ["R"], "last": "Lesieur", "suffix": ""}], "year": 1992, "venue": "British Journal of Addiction", "link": "23316483"}, "BIBREF14": {"title": "Video lottery gambling: Effects on pathological gamblers seeking treatment in South Dakota", "authors": [{"first": "T", "middle": [], "last": "Morgan", "suffix": ""}, {"first": "L", "middle": [], "last": "Kofoed", "suffix": ""}, {"first": "J", "middle": [], "last": "Buchkoski", "suffix": ""}, {"first": "R", "middle": ["D"], "last": "Carr", "suffix": ""}], "year": 1996, "venue": "Journal of Gambling Studies", "link": "23033384"}, "BIBREF15": {"title": "The psychology of the near miss", "authors": [{"first": "R", "middle": [], "last": "Reid", "suffix": ""}], "year": 1986, "venue": "Journal of Gambling Studies", "link": null}, "BIBREF16": {"title": "Gender differences in gambling", "authors": [{"first": "H", "middle": [], "last": "Tavares", "suffix": ""}, {"first": "M", "middle": ["L"], "last": "Zilberman", "suffix": ""}, {"first": "F", "middle": ["J"], "last": "Beites", "suffix": ""}, {"first": "V", "middle": [], "last": "Gentil", "suffix": ""}], "year": 2001, "venue": "Journal of Gambling Studies", "link": null}}, "ref_entries": {}}
{"paper_id": "10700198", "_pdf_hash": "ea5cdee2e3b616064ee80abb3c5b45937ed135d9", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Accepted for Knowledge, Rationality & Action. Presented at Logic, Game Theory and Social Choice 6", "authors": [{"first": "T", "middle": [], "last": "\u00c5gotnes", "suffix": ""}, {"first": "H", "middle": [], "last": "Van Ditmarsch", "suffix": ""}], "year": 2009, "venue": "", "link": null}, "BIBREF1": {"title": "Mastermind strategy", "authors": [{"first": "M", "middle": ["M"], "last": "Flood", "suffix": ""}], "year": 1985, "venue": "Journal of Recreational Mathematics", "link": null}, "BIBREF2": {"title": "Handbook of Logic and Language", "authors": [{"first": "J", "middle": [], "last": "Groenendijk", "suffix": ""}, {"first": "M", "middle": [], "last": "Stokhof", "suffix": ""}, {"first": "", "middle": [], "last": "Questions", "suffix": ""}], "year": 1997, "venue": "", "link": null}, "BIBREF3": {"title": "Games with Incomplete Information Played by 'Bayesian' Players, Parts I, II, and III", "authors": [{"first": "J", "middle": ["C"], "last": "Harsanyi", "suffix": ""}], "year": 1967, "venue": "Management Science", "link": null}, "BIBREF4": {"title": "Agents that know how to play", "authors": [{"first": "W", "middle": [], "last": "Jamroga", "suffix": ""}, {"first": "W", "middle": [], "last": "Van Der Hoek", "suffix": ""}], "year": 2004, "venue": "Fundamenta Informaticae", "link": null}, "BIBREF5": {"title": "The Logic of Reliable Inquiry", "authors": [{"first": "K", "middle": [], "last": "Kelly", "suffix": ""}], "year": 1996, "venue": "", "link": null}, "BIBREF6": {"title": "Yet another mastermind strategy", "authors": [{"first": "B", "middle": ["P"], "last": "Kooi", "suffix": ""}], "year": 2005, "venue": "ICGA Journal", "link": null}, "BIBREF7": {"title": "Knowledge, belief and time", "authors": [{"first": "S", "middle": [], "last": "Kraus", "suffix": ""}, {"first": "D", "middle": [], "last": "Lehmann", "suffix": ""}], "year": 1988, "venue": "Theoretical Computer Science", "link": "13139237"}, "BIBREF8": {"title": "A Course in Game Theory", "authors": [{"first": "M", "middle": ["J"], "last": "Osborne", "suffix": ""}, {"first": "A", "middle": [], "last": "Rubinstein", "suffix": ""}], "year": 1994, "venue": "", "link": null}, "BIBREF9": {"title": "Rough Sets: Theoretical Aspects of Reasoning about Data", "authors": [{"first": "Z", "middle": [], "last": "Pawlak", "suffix": ""}], "year": 1992, "venue": "", "link": "61529991"}, "BIBREF10": {"title": "Logics of public communications", "authors": [{"first": "J", "middle": ["A"], "last": "Plaza", "suffix": ""}], "year": 1989, "venue": "Proceedings of the 4th International Symposium on Methodologies for Intelligent Systems: Poster Session Program", "link": "41619205"}, "BIBREF11": {"title": "One is a lonely number': on the logic of communication", "authors": [{"first": "J", "middle": [], "last": "Van Benthem", "suffix": ""}], "year": 2006, "venue": "Logic Colloquium '02. Association for Symbolic Logic", "link": "90572247"}, "BIBREF12": {"title": "Dynamic logic of preference upgrade", "authors": [{"first": "J", "middle": [], "last": "Van Benthem", "suffix": ""}, {"first": "F", "middle": [], "last": "Liu", "suffix": ""}], "year": 2007, "venue": "Journal of Applied Non-Classical Logics", "link": "537068"}, "BIBREF13": {"title": "Toward a dynamic logic of questions", "authors": [{"first": "J", "middle": [], "last": "Van Benthem", "suffix": ""}, {"first": "S", "middle": [], "last": "Minica", "suffix": ""}], "year": 2009, "venue": "Logic, Rationality, and Interaction. Proceedings of LORI 2009", "link": "18840221"}, "BIBREF14": {"title": "The description of game actions in Cluedo", "authors": [{"first": "H", "middle": [], "last": "Van Ditmarsch", "suffix": ""}], "year": 2002, "venue": "Game Theory and Applications", "link": null}, "BIBREF15": {"title": "Some game theory of Pit", "authors": [{"first": "H", "middle": [], "last": "Van Ditmarsch", "suffix": ""}], "year": 2004, "venue": "Proceedings of PRICAI 2004 (Eighth Pacific Rim International Conference on Artificial Intelligence)", "link": null}, "BIBREF16": {"title": "The secret of my success", "authors": [{"first": "H", "middle": [], "last": "Van Ditmarsch", "suffix": ""}, {"first": "B", "middle": ["P"], "last": "Kooi", "suffix": ""}], "year": 2006, "venue": "Synthese", "link": null}, "BIBREF17": {"title": "The interpretation of formulae in a pointed Kripke structure is defined as follows (the other clauses are defined in usual truth-functional way): M, s |= K i \u03d5 iff for every t such that s \u223c i t", "authors": [{"first": "R", "middle": [], "last": "Van Rooij", "suffix": ""}, {"first": "; M", "middle": [], "last": "", "suffix": ""}, {"first": "M", "middle": [], "last": "", "suffix": ""}, {"first": "S", "middle": [], "last": "|=", "suffix": ""}], "year": 2003, "venue": "iff M, s |= \u03d5 implies that M |\u03d5, s |= \u03c8", "link": null}, "BIBREF18": {"title": "n} is the finite set of players; for each i \u2208 N , A i is the set of strategies (or actions) available to i. A = \u00d7 j\u2208N A j is the set of strategy profiles; and for each i \u2208 N , u i : A \u2192 R is the payoff function for i, mapping each strategy profile to a number. Notation (a 1 , . . . , a n )strategy profile is a (pure strategy) Nash equilibrium if every strategy is the best response of that agent to the strategies of the other agents, i.e., if the agent can not do any better by choosing a different strategy given that the strategies of the other agents are fixed. Formally, a profile (a 1", "authors": [{"first": "G = N", "middle": [], "last": "{a I : I \u2208 N }", "suffix": ""}, {"first": ".", "middle": [], "last": "{u I : I \u2208 N } Where: N = {1", "suffix": ""}], "year": "", "venue": "Strategic Game A strategic game is a triple", "link": null}}, "ref_entries": {}}
{"paper_id": "10700331", "_pdf_hash": "c4c8a65a81ddfeb50b0d30b8717452254beeecdf", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Role of the retinal pigment epithelium in macular disease", "authors": [{"first": "M", "middle": ["J"], "last": "Hogan", "suffix": ""}], "year": 1972, "venue": "Trans. Am. Acad. Ophthalmol. Otol", "link": null}, "BIBREF1": {"title": "Renaissance of the retinal pigment epithelium", "authors": [{"first": "W", "middle": ["H"], "last": "Spencer", "suffix": ""}], "year": 1972, "venue": "Arch. Ophthalmol", "link": "40000763"}, "BIBREF2": {"title": "The phagolysosomal system of the pigment epithelium. A key to retinal disease", "authors": [{"first": "L", "middle": [], "last": "Feeney", "suffix": ""}], "year": 1973, "venue": "INVEST. OPHTHALMOL", "link": "44910070"}, "BIBREF3": {"title": "Morphological and biochemical study of whole and fractionated retinal pigment epithelium", "authors": [{"first": "L", "middle": [], "last": "Feeney", "suffix": ""}, {"first": "E", "middle": ["R"], "last": "Berman", "suffix": ""}], "year": 1972, "venue": "J. Cell Biol", "link": null}, "BIBREF4": {"title": "C : The acid mucopolysaccharides of cattle retina", "authors": [{"first": "E", "middle": ["R"], "last": "Berman", "suffix": ""}, {"first": "", "middle": [], "last": "Bach", "suffix": ""}], "year": 1968, "venue": "Biochem. J", "link": "11588134"}, "BIBREF5": {"title": "A biochemical and radioautographic analysis of protein secretion by thyroid lobes incubated in vitro", "authors": [{"first": "L", "middle": [], "last": "Feeney", "suffix": ""}, {"first": "S", "middle": ["L"], "last": "Wissig", "suffix": ""}], "year": 1972, "venue": "J. Cell Biol", "link": "7074860"}, "BIBREF6": {"title": "A simple method for the purification of total lipids from animal tissues", "authors": [{"first": "J", "middle": [], "last": "Folch", "suffix": ""}, {"first": "M", "middle": [], "last": "Lees", "suffix": ""}, {"first": "Sloane-Stanley", "middle": [], "last": "", "suffix": ""}, {"first": "G", "middle": ["H"], "last": "", "suffix": ""}], "year": 1957, "venue": "J. Biol. Chem", "link": null}, "BIBREF8": {"title": "Protein measurement with the Folin phenol reagent", "authors": [{"first": "O", "middle": ["H"], "last": "Lowry", "suffix": ""}, {"first": "N", "middle": ["J"], "last": "Rosenbrough", "suffix": ""}, {"first": "A", "middle": ["L"], "last": "Farr", "suffix": ""}], "year": 1951, "venue": "J. Biol. Chem", "link": "677129"}, "BIBREF9": {"title": "A study of the conditions and mechanism of the diphenylamine reaction for the colorimetric estimation of deoxyribonucleic acid", "authors": [{"first": "K", "middle": [], "last": "Burton", "suffix": ""}], "year": 1956, "venue": "Biochem. J", "link": null}, "BIBREF10": {"title": "Phosphorus assay in column chromatography", "authors": [{"first": "G", "middle": ["R"], "last": "Bartlett", "suffix": ""}], "year": 1959, "venue": "J. Biol. Chem", "link": "34897997"}, "BIBREF11": {"title": "Cytophotometry of nucleic acids", "authors": [{"first": "A", "middle": ["D"], "last": "Deitch", "suffix": ""}], "year": 1966, "venue": "Introduction to Quantitative Cytochemistry", "link": null}, "BIBREF12": {"title": "Deoxyribonucleic acid cytophotometry of stained human leukocytes. II. The mechanical scanner of CYDAC, the theory of scanning photometry, and the magnitude of residual errors", "authors": [{"first": "B", "middle": ["H"], "last": "Mayall", "suffix": ""}, {"first": "M", "middle": ["L"], "last": "Mendelson", "suffix": ""}], "year": 1970, "venue": "J. Histochem. Cytochem", "link": "36326866"}, "BIBREF13": {"title": "Application of fluorometry to the determination of vitamin A", "authors": [{"first": "B", "middle": ["J"], "last": "Drujan", "suffix": ""}, {"first": "R", "middle": [], "last": "Castillon", "suffix": ""}, {"first": "E", "middle": [], "last": "Guerrero", "suffix": ""}], "year": 1968, "venue": "Anal. Biochem", "link": null}, "BIBREF14": {"title": "Preparation of fatty acid methyl esters and dimethylacytals from lipids with boron fluoridemethanol", "authors": [{"first": "W", "middle": ["R"], "last": "Morrison", "suffix": ""}, {"first": "L", "middle": ["M"], "last": "Smith", "suffix": ""}], "year": 1964, "venue": "J. Lipid Res", "link": null}, "BIBREF15": {"title": "Biology Data Book", "authors": [{"first": "P", "middle": ["L"], "last": "Airman", "suffix": ""}, {"first": "D", "middle": ["S"], "last": "Dittmer", "suffix": ""}], "year": 1972, "venue": "Federation of American Societies for Experimental Biology", "link": "83652339"}, "BIBREF16": {"title": "Biochemical aspects of the visual process. VI. The lipid composition of native and hexane-extracted cattle rod outer segments", "authors": [{"first": "J", "middle": ["M P M"], "last": "Borggreven", "suffix": ""}, {"first": "F", "middle": ["M J"], "last": "Daemen", "suffix": ""}, {"first": "S", "middle": ["L"], "last": "Bonting", "suffix": ""}], "year": 1970, "venue": "Biochim. Biophys. Acta", "link": "9773480"}, "BIBREF17": {"title": "Lipid composition of bovine retinal outer segment fragments", "authors": [{"first": "N", "middle": ["C"], "last": "Nielsen", "suffix": ""}, {"first": "S", "middle": [], "last": "Fleischer", "suffix": ""}, {"first": "D", "middle": ["G"], "last": "Mcconnell", "suffix": ""}], "year": 1970, "venue": "Biochim. Biophys. Acta", "link": "7954403"}, "BIBREF18": {"title": "Lipids of ocular tissues. VII. Positional distribution of the fatty acids in the phospholipids of bovine retina rod outer segments", "authors": [{"first": "R", "middle": ["E"], "last": "Anderson", "suffix": ""}, {"first": "L", "middle": [], "last": "Sperling", "suffix": ""}], "year": 1971, "venue": "Arch. Biochem. Biophys", "link": "8597264"}, "BIBREF19": {"title": "C : Fatty acid composition and level of diacylglycerols and phosphoglycerides in brain and retina", "authors": [{"first": "M", "middle": ["I"], "last": "Aveldano", "suffix": ""}, {"first": "N", "middle": [], "last": "Bazan", "suffix": ""}], "year": 1973, "venue": "Biochim. Biophys. Acta", "link": "36159411"}, "BIBREF20": {"title": "The enzymatic esterification of vitamin A", "authors": [{"first": "N", "middle": ["I"], "last": "Krinsky", "suffix": ""}], "year": 1958, "venue": "J. Biol. Chem", "link": "5646203"}, "BIBREF21": {"title": "Metabolism of the retina. IV. The composition of vitamin A ester synthesized by the retina", "authors": [{"first": "S", "middle": [], "last": "Futterman", "suffix": ""}, {"first": "J", "middle": ["S"], "last": "Andrews", "suffix": ""}], "year": 1964, "venue": "J. Biol. Chem", "link": null}, "BIBREF22": {"title": "The composition of liver vitamin A ester and the synthesis of vitamin A ester by liver mircosomes", "authors": [{"first": "S", "middle": [], "last": "Futterman", "suffix": ""}, {"first": "J", "middle": ["S"], "last": "Andrews", "suffix": ""}], "year": 1964, "venue": "J. Biol. Chem", "link": null}, "BIBREF23": {"title": "The Vitamins", "authors": [{"first": "O", "middle": ["A"], "last": "Roels", "suffix": ""}, {"first": "W", "middle": ["H"], "last": "Sebrell", "suffix": ""}, {"first": "R", "middle": ["S"], "last": "Harris", "suffix": ""}], "year": 1967, "venue": "", "link": null}, "BIBREF24": {"title": "The metabolism of the retinal pigment cell epithelium", "authors": [{"first": "V", "middle": ["C"], "last": "Glocklin", "suffix": ""}, {"first": "A", "middle": ["M"], "last": "Potts", "suffix": ""}], "year": 1962, "venue": "INVEST. OPHTHALMOL", "link": null}, "BIBREF25": {"title": "Microsomal electron transfer system of bovine retinal pigment epithelium", "authors": [{"first": "H", "middle": [], "last": "Shichi", "suffix": ""}], "year": 1969, "venue": "Exp. Res", "link": "45765320"}, "BIBREF26": {"title": "Acid hydrolases of the retinal pigment epithelium", "authors": [{"first": "E", "middle": ["R"], "last": "Berman", "suffix": ""}], "year": 1971, "venue": "INVEST. OPHTHALMOL", "link": "27848660"}, "BIBREF27": {"title": "The effect of retinol on the lysosomal enzymes of bovine retina and pigment epithelium", "authors": [{"first": "R", "middle": [], "last": "Vento", "suffix": ""}, {"first": "F", "middle": [], "last": "Cacioppo", "suffix": ""}], "year": 1973, "venue": "Exp. Eye Res", "link": "30996683"}, "BIBREF28": {"title": "The interphotoreceptor space. I. Postnatal ontogeny in mice and rats", "authors": [{"first": "L", "middle": [], "last": "Feeney", "suffix": ""}], "year": 1973, "venue": "Dev. Biol", "link": "38687298"}, "BIBREF29": {"title": "Lipids of ocular tissues. II. The phospholipids of mature bovine and rabbit whole retina", "authors": [{"first": "R", "middle": ["E"], "last": "Anderson", "suffix": ""}, {"first": "L", "middle": ["S"], "last": "Feldman", "suffix": ""}, {"first": "G", "middle": ["L"], "last": "Feldman", "suffix": ""}], "year": 1970, "venue": "Biochim. Biophys. Acta", "link": "31175404"}, "BIBREF30": {"title": "Studies on human ocular pigment, In: The Structure of the Eye", "authors": [{"first": "L", "middle": [], "last": "Feeney", "suffix": ""}, {"first": "J", "middle": [], "last": "Grieshaber", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Hogan", "suffix": ""}], "year": 1965, "venue": "", "link": null}, "BIBREF31": {"title": "The morphogenesis and biochemical characteristics of ceroid isolated from cases of neuronal ceroidlipofuscinosis", "authors": [{"first": "A", "middle": ["N"], "last": "Siakotos", "suffix": ""}, {"first": "H", "middle": ["H"], "last": "Goebel", "suffix": ""}, {"first": "V", "middle": [], "last": "Patel", "suffix": ""}], "year": 1972, "venue": "Sphingolipids, Sphingolipidoses, and Allied Disorders", "link": "83068463"}, "BIBREF32": {"title": "Membrane fatty acids associated with the electrical response in visual excitation", "authors": [{"first": "R", "middle": ["M"], "last": "Benolken", "suffix": ""}, {"first": "R", "middle": ["E"], "last": "Anderson", "suffix": ""}, {"first": "T", "middle": ["G"], "last": "Wheeler", "suffix": ""}], "year": 1973, "venue": "Science", "link": "19358295"}, "BIBREF33": {"title": "Lipid composition of synaptic plasma membranes isolated from rat brain by zonal centrifugation", "authors": [{"first": "C", "middle": [], "last": "Cotman", "suffix": ""}, {"first": "M", "middle": ["L"], "last": "Blank", "suffix": ""}, {"first": "A", "middle": [], "last": "Moehl", "suffix": ""}], "year": 1969, "venue": "Biochemistry", "link": "26437734"}, "BIBREF34": {"title": "Participation of the retinal pigment epithelium in the rod outer segment renewal process", "authors": [{"first": "R", "middle": ["W"], "last": "Young", "suffix": ""}, {"first": "Bok", "middle": [], "last": "", "suffix": ""}, {"first": "D", "middle": [], "last": "", "suffix": ""}], "year": 1969, "venue": "J. Cell Biol", "link": null}, "BIBREF35": {"title": "Autoradiographic localization of ( 3 H) retinol and derivatives in rat retina", "authors": [{"first": "B", "middle": ["S"], "last": "Sherman", "suffix": ""}], "year": 1970, "venue": "Exp. Eye Res", "link": "31597571"}, "BIBREF36": {"title": "Tissue culture of human retinal pigment epithelium", "authors": [{"first": "J", "middle": [], "last": "Mannagh", "suffix": ""}, {"first": "D", "middle": ["V"], "last": "Arya", "suffix": ""}, {"first": "A", "middle": ["R"], "last": "Irvine", "suffix": ""}, {"first": "", "middle": [], "last": "Jr", "suffix": ""}], "year": 1973, "venue": "INVEST. OPHTHALMOL", "link": "34883452"}}, "ref_entries": {}}
{"paper_id": "10700455", "_pdf_hash": "b20f83f693e2c86e2bad83c9a48d018d3805b3a5", "abstract": [{"section": "Abstract", "text": "Abstract Cocaine use is highly prevalent and a major public health problem. While some studies have reported frequent comorbidity problems among cocaine users, few studies have included evaluation of gambling problems. This study aimed to estimate the prevalence of gambling problems and compare those who were at-risk gamblers with nonproblem gamblers in terms of mental health problems, substance use problems, and some risk factors (i.e. family antecedents, erroneous perceptions and coping strategies) among individuals who smoke or inject cocaine. A total of 424 smoked or injected cocaine users recruited through community-based programs in Montreal (Quebec) completed the questionnaire, including the Canadian Pathological Gambling Index, the Composite International Diagnostic Interview, the CAGE, and the Severity Dependence Scale. Of the sample, 18.4 % were considered at-risk gamblers, of whom 7.8 % had problems gambling and 10.6 % were moderate-risk gamblers. The at-risk group was more likely to have experienced a recent phobic disorder and alcohol problems than the non-problem group. A multivariate analysis showed that, compared to those who were non-problem gamblers, the at-risk ones were more likely to have lost a large sum of money when they first started gambling, believed that their luck would turn, and gambled in reaction to painful life ", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "", "text": "Abstract Cocaine use is highly prevalent and a major public health problem. While some studies have reported frequent comorbidity problems among cocaine users, few studies have included evaluation of gambling problems. This study aimed to estimate the prevalence of gambling problems and compare those who were at-risk gamblers with nonproblem gamblers in terms of mental health problems, substance use problems, and some risk factors (i.e. family antecedents, erroneous perceptions and coping strategies) among individuals who smoke or inject cocaine. A total of 424 smoked or injected cocaine users recruited through community-based programs in Montreal (Quebec) completed the questionnaire, including the Canadian Pathological Gambling Index, the Composite International Diagnostic Interview, the CAGE, and the Severity Dependence Scale. Of the sample, 18.4 % were considered at-risk gamblers, of whom 7.8 % had problems gambling and 10.6 % were moderate-risk gamblers. The at-risk group was more likely to have experienced a recent phobic disorder and alcohol problems than the non-problem group. A multivariate analysis showed that, compared to those who were non-problem gamblers, the at-risk ones were more likely to have lost a large sum of money when they first started gambling, believed that their luck would turn, and gambled in reaction to painful life", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "In 2011, 17 million people worldwide had used cocaine in the last year. A large proportion of these users lived in North America, a continent where the demand for cocaine is highest (UNODC World Drug Report 2014). In Canada, cocaine use affects approximately 1.1 % of individuals above the age of 14 years old (CADUMS 2012) . Cocaine misuse contributes to the development of several psychosocial and health consequences (L\u00e9vesque et al. 2014; Riezzo et al. 2012; Smith et al. 2014 ) including social dysfunction, unemployment, mental health problems, HIV and hepatitis C viral infections (Cunha et al. 2010a, b; Hser et al. 2004; Karila et al. 2009 ). It is therefore important to better characterize cocaine users in order to develop effective interventions to reduce the health burden related to problematic cocaine use (McRae et al. 2007) .", "cite_spans": [{"start": 420, "end": 442, "text": "(L\u00e9vesque et al. 2014;", "ref_id": "BIBREF46"}, {"start": 443, "end": 462, "text": "Riezzo et al. 2012;", "ref_id": "BIBREF59"}, {"start": 463, "end": 480, "text": "Smith et al. 2014", "ref_id": "BIBREF68"}, {"start": 612, "end": 629, "text": "Hser et al. 2004;", "ref_id": "BIBREF35"}, {"start": 630, "end": 648, "text": "Karila et al. 2009", "ref_id": "BIBREF40"}, {"start": 822, "end": 841, "text": "(McRae et al. 2007)", "ref_id": "BIBREF51"}], "ref_spans": []}, {"section": "Introduction", "text": "Mental health problems are a major concern among individuals addicted to cocaine (Kandel et al. 2001; Vergara-Moragues et al. 2012) . In fact, between 35 and 65 % of cocaine dependent users are diagnosed with a, or multiple, mental health issue(s) during their lifetime (Falck et al. 2002; Herrero et al. 2008; Vergara-Moragues et al. 2012) . When compared with those who do not have psychiatric comorbidity, cocaine dependent users who have dual diagnoses are more likely to abandon their treatment and report less improvement (Gonzalez-Saiz et al. 2009; King et al. 2014) . While comorbidity between cocaine dependence and mood disorders (Conner et al. 2008; Vergara-Moragues et al. 2012) , alcohol dependence (Ford et al. 2009 ), post traumatic stress disorder (PTSD) (Saunders et al. 2015) , attention deficit hyperactivity disorder (ADHD) (Daigre et al. 2013) , psychotic disorders (Vergara-Moragues et al. 2012 ) and some personality disorders (Ford et al. 2009 ) have been previously documented, few studies have focused on problem gambling (PG) within these populations.", "cite_spans": [{"start": 81, "end": 101, "text": "(Kandel et al. 2001;", "ref_id": "BIBREF39"}, {"start": 102, "end": 131, "text": "Vergara-Moragues et al. 2012)", "ref_id": "BIBREF80"}, {"start": 270, "end": 289, "text": "(Falck et al. 2002;", "ref_id": "BIBREF20"}, {"start": 290, "end": 310, "text": "Herrero et al. 2008;", "ref_id": "BIBREF32"}, {"start": 311, "end": 340, "text": "Vergara-Moragues et al. 2012)", "ref_id": "BIBREF80"}, {"start": 528, "end": 555, "text": "(Gonzalez-Saiz et al. 2009;", "ref_id": "BIBREF27"}, {"start": 640, "end": 660, "text": "(Conner et al. 2008;", "ref_id": "BIBREF8"}, {"start": 661, "end": 690, "text": "Vergara-Moragues et al. 2012)", "ref_id": "BIBREF80"}, {"start": 712, "end": 729, "text": "(Ford et al. 2009", "ref_id": "BIBREF24"}, {"start": 771, "end": 793, "text": "(Saunders et al. 2015)", "ref_id": "BIBREF63"}, {"start": 844, "end": 864, "text": "(Daigre et al. 2013)", "ref_id": "BIBREF16"}, {"start": 887, "end": 916, "text": "(Vergara-Moragues et al. 2012", "ref_id": "BIBREF80"}, {"start": 950, "end": 967, "text": "(Ford et al. 2009", "ref_id": "BIBREF24"}], "ref_spans": []}, {"section": "Introduction", "text": "Problem gambling has been linked to a variety of harmful mental and physical health consequences, as well as a wide variety of problems such as high criminality and homelessness (Blaszczynski and Silove 1996; Shaffer et al. 2004; Stein et al. 2012; Turner et al. 2009 ). These consequences make PG an important public health problem, especially for more vulnerable populations (Gainsbury et al. 2014; Korn and Shaffer 1999; Papineau 2010; Shaffer and Hall 2001) such as individuals with a history of problematic substance use. Indeed, within this vulnerable population, PG is 8 to 24 times the prevalence reported for the general population (Cowlishaw et al. 2014; Cowlishaw and Hakes 2015; Cunningham-Williams et al. 2000; Fernandez-Montalvo et al. 2012; Mathias et al. 2009; Toneatto and Brennan 2002) . The few studies that have focused on cocaine users, all of which were carried out in drug treatment centers, have found prevalence rates of problem gambling among cocaine dependent users ranging from 8 to 15 % (Hall et al. 2000; Steinberg et al. 1992; Toneatto and Brennan 2002) .", "cite_spans": [{"start": 178, "end": 208, "text": "(Blaszczynski and Silove 1996;", "ref_id": "BIBREF7"}, {"start": 209, "end": 229, "text": "Shaffer et al. 2004;", "ref_id": "BIBREF66"}, {"start": 230, "end": 248, "text": "Stein et al. 2012;", "ref_id": "BIBREF70"}, {"start": 249, "end": 267, "text": "Turner et al. 2009", "ref_id": "BIBREF78"}, {"start": 377, "end": 400, "text": "(Gainsbury et al. 2014;", "ref_id": "BIBREF25"}, {"start": 401, "end": 423, "text": "Korn and Shaffer 1999;", "ref_id": "BIBREF44"}, {"start": 424, "end": 438, "text": "Papineau 2010;", "ref_id": "BIBREF54"}, {"start": 439, "end": 461, "text": "Shaffer and Hall 2001)", "ref_id": "BIBREF65"}, {"start": 641, "end": 664, "text": "(Cowlishaw et al. 2014;", "ref_id": "BIBREF10"}, {"start": 665, "end": 690, "text": "Cowlishaw and Hakes 2015;", "ref_id": "BIBREF9"}, {"start": 691, "end": 723, "text": "Cunningham-Williams et al. 2000;", "ref_id": "BIBREF14"}, {"start": 724, "end": 755, "text": "Fernandez-Montalvo et al. 2012;", "ref_id": "BIBREF22"}, {"start": 756, "end": 776, "text": "Mathias et al. 2009;", "ref_id": "BIBREF49"}, {"start": 777, "end": 803, "text": "Toneatto and Brennan 2002)", "ref_id": "BIBREF75"}, {"start": 1016, "end": 1034, "text": "(Hall et al. 2000;", "ref_id": "BIBREF30"}, {"start": 1035, "end": 1057, "text": "Steinberg et al. 1992;", "ref_id": "BIBREF71"}, {"start": 1058, "end": 1084, "text": "Toneatto and Brennan 2002)", "ref_id": "BIBREF75"}], "ref_spans": []}, {"section": "Introduction", "text": "This comorbidity between PG and substance dependence has significant repercussions on mental health and living conditions (Cunningham-Williams et al. 2000; Mathias et al. 2009 ). In fact, gamblers who also have another form of dependence (e.g. alcohol or drugs) present a more severe clinical picture when entering treatment and report more mental health problems when compared with those who have one dependence problem (Arseneault et al. 2001; Cunningham-Williams et al. 2000; Feigelman et al. 1998; FernandezMontalvo et al. 2012; Hall et al. 2000; Liu et al. 2009; Mathias et al. 2009; Petry 2007) . Treatment studies concerning cocaine users have found those with gambling problems to be more likely unemployed, to have had a higher prevalence of antisocial personality disorders and more frequent issues with the justice system (Hall et al. 2000; Toneatto and Brennan 2002) . However, these results do not provide much needed information concerning those active cocaine users neither contributed to understand which risk factors are associated with gambling problems.", "cite_spans": [{"start": 122, "end": 155, "text": "(Cunningham-Williams et al. 2000;", "ref_id": "BIBREF14"}, {"start": 156, "end": 175, "text": "Mathias et al. 2009", "ref_id": "BIBREF49"}, {"start": 421, "end": 445, "text": "(Arseneault et al. 2001;", "ref_id": "BIBREF3"}, {"start": 446, "end": 478, "text": "Cunningham-Williams et al. 2000;", "ref_id": "BIBREF14"}, {"start": 479, "end": 501, "text": "Feigelman et al. 1998;", "ref_id": "BIBREF21"}, {"start": 533, "end": 550, "text": "Hall et al. 2000;", "ref_id": "BIBREF30"}, {"start": 551, "end": 567, "text": "Liu et al. 2009;", "ref_id": "BIBREF47"}, {"start": 568, "end": 588, "text": "Mathias et al. 2009;", "ref_id": "BIBREF49"}, {"start": 589, "end": 600, "text": "Petry 2007)", "ref_id": "BIBREF57"}, {"start": 833, "end": 851, "text": "(Hall et al. 2000;", "ref_id": "BIBREF30"}, {"start": 852, "end": 878, "text": "Toneatto and Brennan 2002)", "ref_id": "BIBREF75"}], "ref_spans": []}, {"section": "Introduction", "text": "In an effort to improve our understanding of problem gambling and comorbid mental disorders in a population rarely studied, this exploratory study aims to investigate gambling behaviours, characteristics (socio-demographic) of problem gamblers, and some risk factors (family addiction antecedents, first gambling experience, erroneous perceptions and avoidant coping strategies) in a community-based sample of cocaine users.", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "A prospective cohort study of mental health disorders, HIV and hepatitis C virus (HCV) infections among street-based cocaine users called the COSMO project was carried out in Montr\u00e9al, Canada (L\u00e9vesque et al. 2014) . Analyses were run using data pertaining to gambling behaviors and risk factors (family addiction antecedents, first gambling experience, erroneous perceptions and avoidant coping strategies) collected during one visit over the course of the study. All participants gave explicit consented to take part in the study and ethics approval for the study was provided by the 'Comit\u00e9 d'\u00e9thique de la recherche en sant\u00e9 chez l'humain du Centre hospitalier universitaire de Sherbrooke'.", "cite_spans": [{"start": 192, "end": 214, "text": "(L\u00e9vesque et al. 2014)", "ref_id": "BIBREF46"}], "ref_spans": []}, {"section": "Participants and Procedure", "text": "To take part in the cohort study, participants must have used cocaine in the last month, either by smoking crack or by injection. Other eligibility criteria included being at least 14 years old, English-or French-speaking, the ability to provide informed consent and complete an interviewer-administered questionnaire, and having plans to stay in the Montr\u00e9al area in the following year. Recruitment took place between June 2011 and May 2014. Participants were recruited in community-based programs located in downtown Montr\u00e9al (Qu\u00e9bec) including: day programs for the homeless, various shelters, and needle exchange programs. Recruitment was carried out by study interviewers who visited collaborating community-based programs on a weekly basis except for the smallest ones for which visits were scheduled monthly. Cocaine users willing to participate in the study were invited to the research office located close to the recruitment sites. Participation included baseline and follow-up appointments every three months for 18 months. At each visit, participants were asked to sign a consent form, provide contact information, and complete an interviewer-administered questionnaire. Participants received financial compensation of CAD 30 $ at the end of each interview.", "cite_spans": [], "ref_spans": []}, {"section": "Materials", "text": "Interviews took approximately 90 and 120 min to complete and covered various themes related to the objectives of the cohort study. To avoid unduly prolonging visits, some questions were completed during only one visit during the study period. For example, questions assessing diagnoses of mental health disorders were completed only at baseline while questions on gambling problems and risk factors were asked two visits later at time 3. All other questions were asked at each visit. Variables typically associated with problematic gambling examined including: socio-demographic characteristics, gambling activities, gambling problems, drug and alcohol consumption, and various risk factors (i.e. family history of addiction, first gambling experience, erroneous perceptions and avoidant coping strategies) (Ferris and Wynne 2001; Welte et al. 2004 ).", "cite_spans": [{"start": 807, "end": 830, "text": "(Ferris and Wynne 2001;", "ref_id": "BIBREF23"}, {"start": 831, "end": 848, "text": "Welte et al. 2004", "ref_id": "BIBREF81"}], "ref_spans": []}, {"section": "Sociodemographic Characteristics", "text": "These variables included age, gender, ethnicity (born in Canada vs. outside of Canada), level of education (less than high school vs. higher level), homelessness (defined as having lived or slept at least once in a shelter or in any place not intended for housing in the past 3 months), having an unstable income (defined as having a marginal or criminal source of income in the past 3 months).", "cite_spans": [], "ref_spans": []}, {"section": "Gambling Activity and Problems", "text": "Participation, in the last 12 months, to eighteen types of gambling activities was examined (Ferris and Wynne 2001) . Severity of gambling problems was evaluated using the 9-item Problem Gambling Severity Index (PGSI), a quantitative sub-section of the Canadian Problem Gambling Index (CPGI) (Ferris and Wynne 2001) . The PGSI consists of 9 items with answers reported on a 4-point Likert scale ('Never'; 'Sometimes'; 'Most of the time'; 'Almost always'). The PGSI demonstrates strong internal validity and reliability, as well as satisfactory temporal reliability (Currie et al. 2013) . The instrument was used to create four categories of players: no risk (score of 0); low risk (score of 1-2); moderate risk (score of 3-7); and problem gambler (score of 8-27).", "cite_spans": [{"start": 92, "end": 115, "text": "(Ferris and Wynne 2001)", "ref_id": "BIBREF23"}, {"start": 292, "end": 315, "text": "(Ferris and Wynne 2001)", "ref_id": "BIBREF23"}, {"start": 565, "end": 585, "text": "(Currie et al. 2013)", "ref_id": "BIBREF15"}], "ref_spans": []}, {"section": "Risk Factors", "text": "When designing the CPGI, authors Ferris and Wynne (2001) found a number of variables pertaining to respondents' predispositions and environment that, although peripheral to the core construct of problem gambling, were associated with the development and severity of gambling problems. These variables include: (1) first gambling experience (i.e. 'Do you remember a big win when you first started gambling?'; 'Do you remember a big loss when you first started gambling?'); (2) family addiction antecedents (i.e. 'Has anyone in your family ever had a gambling problem?'; 'Has anyone in your family ever had an alcohol or drug problem?'); (3) erroneous perception (i.e. Chance: 'After losing many times in a row, you are more likely to win'; Strategy: 'You could win more if you used a certain system or strategy'); (4) the use of psychoactive substances while gambling (i.e. 'In the 12 last months, have you used alcohol or drugs while gambling?'; 'In the last 12 months, have you gambled while drunk, or high?'); (5) avoidant coping strategies (i.e. 'In the last 12 months, if something painful happened in your life, did you have the urge to gamble?'; 'In the last 12 months, if something painful happened in your life, did you have the urge to have a drink?'; 'In the last 12 months, if something painful happened in your life did you have the urge to use drugs or medication?').", "cite_spans": [{"start": 33, "end": 56, "text": "Ferris and Wynne (2001)", "ref_id": "BIBREF23"}], "ref_spans": []}, {"section": "Problematic Substance Use", "text": "Problematic alcohol consumption was assessed using the CAGE questionnaire (Mayfield et al. 1974 ), a quick yet sensitive and specific instrument for screening alcohol use disorder (Bernadt et al. 1982) . Two positive responses on this instrument indicate a high probability of problematic alcohol consumption. Severity of cocaine dependence was estimated using the severity of dependence scale (SDS) (Gossop et al. 1995) . The SDS is a five-item tool measuring the intensity of dependence to a drug over the past 3 months. The score ranges between 0 and 15. Cocaine dependence was determined by a SDS score of 4 or higher (Gonzalez-Saiz et al. 2009 ).", "cite_spans": [{"start": 74, "end": 95, "text": "(Mayfield et al. 1974", "ref_id": "BIBREF50"}, {"start": 180, "end": 201, "text": "(Bernadt et al. 1982)", "ref_id": "BIBREF6"}, {"start": 400, "end": 420, "text": "(Gossop et al. 1995)", "ref_id": "BIBREF28"}, {"start": 622, "end": 648, "text": "(Gonzalez-Saiz et al. 2009", "ref_id": "BIBREF27"}], "ref_spans": []}, {"section": "Mental Health Disorders", "text": "Questions regarding past year diagnosis of one or multiple primary mental disorders were taken using two instruments. Psychotic (delusional disorder, brief psychotic disorder and schizophrenic disorder) and affective disorders (major depression, bipolar disorders and dysthymia) were assessed using the World Mental Health Composite International Diagnostic Interview (CIDI) version 2.1 (Kessler and Ustun 2004) . Anxiety disorders (panic disorders, phobic disorder, generalized anxiety disorder) were assessed using the CIDIS developed by Kovess et al. (2001) . Both instruments used are well-validated tools that can be administered by lay interviewers to produce psychiatric diagnoses according to the fourth version of the Diagnostic and Statistical Manual of Mental Health Disorders published by the American Psychiatric Association (2010).", "cite_spans": [{"start": 387, "end": 411, "text": "(Kessler and Ustun 2004)", "ref_id": "BIBREF42"}, {"start": 540, "end": 560, "text": "Kovess et al. (2001)", "ref_id": "BIBREF45"}], "ref_spans": []}, {"section": "Analyses", "text": "Analyses were conducted using data from 424 participants who completed the questionnaire on gambling behaviours and risk factors, representing 70 % of the 605 participants participating in the COSMO project. Respondents had sociodemographic characteristics similar to the total sample of COSMO. Descriptive statistics were employed to characterize the study population, including means or medians with corresponding standard deviation or interquartile ranges (IQR) for continuous variables, and frequency distributions for categorical variables. Based on individual PGSI score, the sample was divided into two categories: at-risk gamblers group (moderate risk and problem gamblers) and non-problem gamblers group (non gamblers and low risk gambling). Pearson's Chi square test and when appropriate Fischer's exact test were used to compare gambling activities between the two groups.", "cite_spans": [], "ref_spans": []}, {"section": "Analyses", "text": "To identify independent correlates of at-risk gambling behaviours, co-variables pertaining to socio-demographics, diagnoses of mental health disorders and risk factors were examined using logistic regression analyses. Covariables with a p value B.05 in univariate analyses were considered in the multivariate linear regression model. The standard method of entry (the enter method) was used, i.e. all independent variables were entered into the equation at the same time. This method is an appropriate analysis when dealing with a small set of predictors and when the researcher does not know which independent variables will create the best prediction equation (Tabachnick and Fidell 2001 ", "cite_spans": [{"start": 662, "end": 689, "text": "(Tabachnick and Fidell 2001", "ref_id": "BIBREF72"}], "ref_spans": []}, {"section": "Results", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Population Characteristics", "text": "Of the 424 participants, 92.9 % reported smoking crack and 59.6 % reported injecting crack/cocaine. The majority were men (87.2 %) and the mean age was 40.46 years old (SD = 10.70). Most participants reported at least one episode of homelessness in the last three months (65.3 %), were born in Canada (94.8 %), had more than higher level of education (52.1 %) and reported an unstable source of income (70.5 %).", "cite_spans": [], "ref_spans": []}, {"section": "Gambling Activities and Gambling Problems", "text": "Gambling was common among participants, with 240 individuals (56.6 %) reporting participation in at least one gambling activity in the previous 12 months. According to overall PGSI scores, 162 out of 424 participants (38.2 %) were non-problem gamblers including 135 (31.8 %) who were no risk and 27 (6.4 %) low-risk gamblers, while 78 (18.4 %) were at-risk gamblers including 45 (10.6 %) moderate gamblers and 33 (7.8 %) problem gamblers.", "cite_spans": [], "ref_spans": []}, {"section": "Gambling Activities and Gambling Problems", "text": "The at-risk (n = 78) and non-problem groups (n = 346) were similar with respect to age (mean age: 42 years old and 41 years old respectively, p = .970), recent episode of homelessness (62.8 and 59.9 %, p = .641), ethnicity (93.6 and 95.1, p = .590), level of education (less than high school, 46.5 and 53.8, p = .244), and reporting an unstable source of income (70.8 and 69.2, p = .782). However, the at-risk group had a slightly greater proportion of male participants than the non-problem group (94.9 and 85.8 %, p = .03).", "cite_spans": [], "ref_spans": []}, {"section": "Gambling Activities and Gambling Problems", "text": "The three most frequently reported gambling activities were buying lottery tickets (34.2 %), buying instant win or scratch tickets (31.6 %), and playing video lottery terminals (VLTs) in bars (26.0 %) ( Table 1) . No matter the activity, at-risk gamblers were more likely to play than non-problem gamblers. For the at-risk group, the three most frequent gambling activities were playing VLTs in bars (71.8 %), buying lottery ticket (62.8 %), buying instant win or scratch tickets (59.0 %) and the three most gambling activities in which they spent money were slot machines in a casino (M = 476.4), VLTs in bars (M = 267.8), and poker in a casino (M = 265.0).", "cite_spans": [], "ref_spans": []}, {"section": "Mental Health Disorders and Problematic Substance Use", "text": "Results of univariate analyses only yielded significant differences for phobic disorders and alcohol problems (CAGE score) (Table 2) . Specifically, the at-risk group was more likely to have experienced recent phobic disorder and to have a CAGE score equal to or higher than 2. ", "cite_spans": [], "ref_spans": []}, {"section": "Risk Factors for Gambling Problems", "text": "Univariate analyses of the risk factors showed statistically significant difference for seven of twelves risk factors (Table 3) . Specifically, at-risk individuals, when compared to nonproblem gamblers, were more likely to have won a large sum of money when they first started gambling, to have lost a large sum of money when they first started gambling, to have consumed alcohol or drugs while gambling, to have gambled under the influence of such substances, to have gambled in reaction to a painful life event, to have consumed alcohol in reaction to a painful life event and to have an erroneous perception of chance.", "cite_spans": [], "ref_spans": [{"start": 118, "end": 127, "text": "(Table 3)", "ref_id": "TABREF2"}]}, {"section": "Multivariate Model: Independent Predictors of At-Risk Gambling Behaviours", "text": "Multiple linear regression analyses showed that at-risk group, when compared to nonproblem gamblers, were more likely to have lost a large sum when first gambling (OR 6.13; 95 % CI 2.73-13.78), more likely to have gambled in reaction to painful life events (OR 22.79; ) and more likely to think that they have a better chance winning after losing repeatedly (OR 3.10; 95 % CI 1.22-7.91) (Table 4) . However, recent phobic disorder, gender, having won a large sum when fist started gambling, having used alcohol or drugs while gambling, having the urge to have a drink in reaction to a painful event and alcohol problem and were not associated to the at-risk group. ", "cite_spans": [], "ref_spans": [{"start": 387, "end": 396, "text": "(Table 4)", "ref_id": "TABREF3"}]}, {"section": "Discussion", "text": "This is the first study to report on gambling behaviors, mental health problems and risk factors in a sample of community-based crack-cocaine injectors and/or smokers. More than half (57 %) of these heavy cocaine users had taken part in gambling activities in the previous year. While the majority reported no or few gambling problems, a significant proportion (10.6 % moderate risk and 7.8 % problem gamblers) reported problems associated with their gambling. Findings are similar to those observed among people addicted to cocaine who are in treatment (Hall et al. 2000; Toneatto and Brennan 2002) and those reported by consumers of alcohol or other drugs in treatment (Barnes et al. 2015) . Also, results align with previous studies of active consumers of substances such as the homeless (Nower et al. 2014; Shaffer et al. 2002; Sharman et al. 2015) . The present study findings highlight the vulnerability of community-based cocaine users attending homeless and harm reduction programs to gambling problems. Considering nearly one in five cocaine users in this sample suffered from the harmful consequences of gambling activities, it is crucial that the resources they are offered address problems associated with these types of activities (Nower et al. 2014) . Research by Holdsworth and Tiyce (2013) has previously emphasized the secretive nature of problems gambling, stemming perhaps from feelings of shame and from associated stigma, which underscores the importance of engaging in proactive efforts to detect them. Among at-risk gamblers, the most frequently reported gambling activities were VLTs, buying lottery tickets, and buying scratch tickets. Results corroborate previous findings of studies with other vulnerable populations, among whom the problem gamblers reported a preference for VLTs (Antonetti and Horn 2001; Rogers et al. 2005; Shaffer et al. 2002; Talbot 2004) . It has been shown that, due to their structural characteristics (Parke and Griffiths 2006; Harrigan 2008) and their availability (Holtgraves 2009 ), VLTs are often associated to the development of gambling problems (Cox et al. 2005; El-Guebaly et al. 2006) . In addition, it is likely that, for these populations, VLTs and buying lottery and scratch tickets are associated with precarious living conditions and lack of resources . In such a scenario, gambling is used as a subsistence strategy to gain money and improve one's living conditions (Holdsworth and Tiyce 2013; Shaffer et al. 2002) .", "cite_spans": [{"start": 554, "end": 572, "text": "(Hall et al. 2000;", "ref_id": "BIBREF30"}, {"start": 573, "end": 599, "text": "Toneatto and Brennan 2002)", "ref_id": "BIBREF75"}, {"start": 671, "end": 691, "text": "(Barnes et al. 2015)", "ref_id": "BIBREF5"}, {"start": 791, "end": 810, "text": "(Nower et al. 2014;", "ref_id": "BIBREF52"}, {"start": 811, "end": 831, "text": "Shaffer et al. 2002;", "ref_id": "BIBREF64"}, {"start": 832, "end": 852, "text": "Sharman et al. 2015)", "ref_id": "BIBREF67"}, {"start": 1244, "end": 1263, "text": "(Nower et al. 2014)", "ref_id": "BIBREF52"}, {"start": 1278, "end": 1305, "text": "Holdsworth and Tiyce (2013)", "ref_id": "BIBREF33"}, {"start": 1808, "end": 1833, "text": "(Antonetti and Horn 2001;", "ref_id": "BIBREF2"}, {"start": 1834, "end": 1853, "text": "Rogers et al. 2005;", "ref_id": "BIBREF61"}, {"start": 1854, "end": 1874, "text": "Shaffer et al. 2002;", "ref_id": "BIBREF64"}, {"start": 1875, "end": 1887, "text": "Talbot 2004)", "ref_id": "BIBREF73"}, {"start": 1954, "end": 1980, "text": "(Parke and Griffiths 2006;", "ref_id": "BIBREF55"}, {"start": 1981, "end": 1995, "text": "Harrigan 2008)", "ref_id": "BIBREF31"}, {"start": 2019, "end": 2035, "text": "(Holtgraves 2009", "ref_id": "BIBREF34"}, {"start": 2105, "end": 2122, "text": "(Cox et al. 2005;", "ref_id": "BIBREF11"}, {"start": 2123, "end": 2146, "text": "El-Guebaly et al. 2006)", "ref_id": "BIBREF19"}, {"start": 2434, "end": 2461, "text": "(Holdsworth and Tiyce 2013;", "ref_id": "BIBREF33"}, {"start": 2462, "end": 2482, "text": "Shaffer et al. 2002)", "ref_id": "BIBREF64"}], "ref_spans": []}, {"section": "Discussion", "text": "Problematic substance use as measured by the SDS for cocaine and the CAGE for alcohol was highly prevalent among study participants, and at-risk gamblers were twice as likely as the non-problem gamblers to have a possible alcohol problem. These concurring addictive disorders point to the complexity of mental health problems among heavy cocaine users which translate clinically into an intricate constellation of needs spanning several other areas of wellbeing such as physical health, and housing (Holdsworth and Tiyce 2013) . According to Holdsworth and Tiyce (2013) , these compounded needs have an amplifying and accumulating outcome that, over time, generates new problems and barriers to the resolution of addictive problems. More research is needed, particularly using longitudinal study design, to better understand the overlapping origins of these problems as well as better intervention approaches. Although different studies of clinical samples (Fernandez-Montalvo et al. 2012; Mathias et al. 2009; Petry 2005) and in the general population (El-Guebaly et al. 2006; Lorains et al. 2011 for a review) have highlighted higher prevalence of anxiety disorders and depression among problem gamblers, these findings were only partially supported by the present study. In fact, with the exception of phobic disorders, the at-risk group did not differ from non-problem gamblers. A higher prevalence of phobic disorder has also been observed in other at-risk populations such as intravenous drug users (Roy et al. 2015) . Furthermore, the fact that more than half gamblers presented an anxiety disorder in the past 12 months, suggests that there may be the underlying mechanism linking anxiety disorders and PG (Desai and Potenza 2008; Kessler et al. 2008; Petry et al. 2005) . Impulsivity and difficulty making decisions could also be integral to the mechanisms of these two issues (Gonzales-Ortega et al. 2013; Ochoa et al. 2013) . This high comorbidity with mental health problems underlines the necessity of thoroughly assessing the full range of mental health problems whenever someone is seeking help for recovery (Lorains et al. 2011) .", "cite_spans": [{"start": 499, "end": 526, "text": "(Holdsworth and Tiyce 2013)", "ref_id": "BIBREF33"}, {"start": 542, "end": 569, "text": "Holdsworth and Tiyce (2013)", "ref_id": "BIBREF33"}, {"start": 957, "end": 989, "text": "(Fernandez-Montalvo et al. 2012;", "ref_id": "BIBREF22"}, {"start": 990, "end": 1010, "text": "Mathias et al. 2009;", "ref_id": "BIBREF49"}, {"start": 1011, "end": 1022, "text": "Petry 2005)", "ref_id": "BIBREF56"}, {"start": 1053, "end": 1077, "text": "(El-Guebaly et al. 2006;", "ref_id": "BIBREF19"}, {"start": 1078, "end": 1097, "text": "Lorains et al. 2011", "ref_id": "BIBREF48"}, {"start": 1505, "end": 1522, "text": "(Roy et al. 2015)", "ref_id": "BIBREF62"}, {"start": 1714, "end": 1738, "text": "(Desai and Potenza 2008;", "ref_id": "BIBREF17"}, {"start": 1739, "end": 1759, "text": "Kessler et al. 2008;", "ref_id": "BIBREF41"}, {"start": 1760, "end": 1778, "text": "Petry et al. 2005)", "ref_id": "BIBREF58"}, {"start": 1886, "end": 1915, "text": "(Gonzales-Ortega et al. 2013;", "ref_id": "BIBREF26"}, {"start": 1916, "end": 1934, "text": "Ochoa et al. 2013)", "ref_id": "BIBREF53"}, {"start": 2123, "end": 2144, "text": "(Lorains et al. 2011)", "ref_id": "BIBREF48"}], "ref_spans": []}, {"section": "Discussion", "text": "In regard to risk factors associated with gambling problems, remembering a large win from when an individual began gambling has been previously associated with the development gambling problems in different studies (Turner et al. 2006 (Turner et al. , 2008 . Still, few studies have underlined the importance of remembering a large loss in one's first gambling experience even though it is likely that such a distressing event, in a population already struggling with financial problems, could rapidly precipitate chasing behavior. Thus, the financial difficulties associated with substance consumption and gambling losses could add to overall stress, potentiating the anxiety disorders and the gambling problems concurrently. Furthermore, as observed in previous studies (Joukhador et al. 2003; Xian et al. 2014) , erroneous beliefs pertaining to chance also contributed here to the identification of gambling problems. However, a more extensive evaluation of erroneous beliefs using a validated measurement instrument like the Gamblers's Beliefs Questionnaire (Steenbergh et al. 2002) would help to better understand the importance of this risk factor in the development of gambling problems within this vulnerable group.", "cite_spans": [{"start": 215, "end": 234, "text": "(Turner et al. 2006", "ref_id": "BIBREF77"}, {"start": 235, "end": 256, "text": "(Turner et al. , 2008", "ref_id": "BIBREF76"}, {"start": 772, "end": 795, "text": "(Joukhador et al. 2003;", "ref_id": "BIBREF37"}, {"start": 796, "end": 813, "text": "Xian et al. 2014)", "ref_id": "BIBREF83"}, {"start": 1062, "end": 1086, "text": "(Steenbergh et al. 2002)", "ref_id": "BIBREF69"}], "ref_spans": []}, {"section": "Discussion", "text": "Finally, one interesting finding in this study pertains to the variables (mental health, risk factors, socio-demographic) strongly associated with the at-risk group. In fact, the final model indicated that most of the factors that were found to be associated with at-risk group gamblers are emotional components linked to anxiety or to its management. More specifically, having lost a large sum when an individual had first started gambling, having the urge to gamble in reaction to a painful event and having erroneous beliefs about chance are all determinants of the at-risk group. This finding is consistent with Jacobs' General Theory of Addictions (Jacobs 1986) and suggests that problematic gamblers use gambling as a maladaptive coping strategy (Gupta and Derevensky 1998) . It is therefore possible, for cocaine users, that gambling is used as a way to escape from negative emotional state or distract oneself from distressing thoughts or distressing living conditions (Baker et al. 2004; Kaiser et al. 2012; Koob 2013; Rockloff et al. 2011; Thomas et al. 2009; Wood and Griffiths 2007) .", "cite_spans": [{"start": 653, "end": 666, "text": "(Jacobs 1986)", "ref_id": "BIBREF36"}, {"start": 752, "end": 779, "text": "(Gupta and Derevensky 1998)", "ref_id": "BIBREF29"}, {"start": 977, "end": 996, "text": "(Baker et al. 2004;", "ref_id": "BIBREF4"}, {"start": 997, "end": 1016, "text": "Kaiser et al. 2012;", "ref_id": "BIBREF38"}, {"start": 1017, "end": 1027, "text": "Koob 2013;", "ref_id": "BIBREF43"}, {"start": 1028, "end": 1049, "text": "Rockloff et al. 2011;", "ref_id": "BIBREF60"}, {"start": 1050, "end": 1069, "text": "Thomas et al. 2009;", "ref_id": "BIBREF74"}, {"start": 1070, "end": 1094, "text": "Wood and Griffiths 2007)", "ref_id": "BIBREF82"}], "ref_spans": []}, {"section": "Limitation", "text": "This study has several limitations to be considered including the self-recruitment process, which may have affected the representativeness of the sample. Generalizability of our findings to other populations might be difficult since the study sample was composed of regular cocaine users who either smoked or injected cocaine. They were recruited mainly in community-based programs located in downtown Montr\u00e9al (i.e. homeless day programs, shelters, and needle exchange programs). Study participants might thus not be representative of all regular cocaine users such as those who do not access these services and those who do not smoke or inject cocaine. Also, data collection by interview-administered questionnaires may have led to the minimization of certain stigmatized behaviors. Recall bias may have occurred because of the broad period of time covered by the questions. Finally, the cross-sectional design could not ascertain causality. A longitudinal follow-up of this cohort will help to better understand the gambling trajectories of cocaine users.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusion", "text": "Despite these limitations, these results underline the presence of a significant proportion of smoked or injected cocaine users exhibiting gambling problems alongside other mental health problems, particularly anxiety problems. These results suggest that gambling may be a strategy to cope with difficult life situations and underline the importance of considering the full range of mental health problems when developing prevention or treatment interventions targeting cocaine users. A initial approach to be considered could be asking community workers to integrate questions on gambling activities as a way to show openness to discuss this topic. Furthermore, cocaine users need integrated plans of intervention to address gambling, drug, alcohol and mental health problems at the same time. In order to do that, it is important that homeless and harm reduction resources have suitable and up to date knowledge of the gambling services offered in their area. Finally, future longitudinal studies need to be conducted in order to better understand the relationship between gambling behaviours of cocaine users and the development other at-risk behaviours like injection of substance. They should also expand research to explore the temporal development between substance use disorders, gambling and mental health problems.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusion", "text": "institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Agence de la sant\u00e9 publique du Canada-Previous statistics from the Canadian alcohol and drug use monitoring survey (CADUMS) Highlight report", "authors": [], "year": 2011, "venue": "", "link": null}, "BIBREF1": {"title": "Diagnostic and statistical manual of mental disorders", "authors": [], "year": 2010, "venue": "American Psychiatric Association", "link": null}, "BIBREF2": {"title": "Gambling the home away: A study of the impact of gambling on homelessness", "authors": [{"first": "E", "middle": [], "last": "Antonetti", "suffix": ""}, {"first": "M", "middle": [], "last": "Horn", "suffix": ""}], "year": 2001, "venue": "Research report Commissioned by Hanover Welfare Services", "link": null}, "BIBREF3": {"title": "Jeu de hasard et consommation de substances psychotropes: Pr\u00e9valence, coexistence et cons\u00e9quences", "authors": [{"first": "L", "middle": [], "last": "Arseneault", "suffix": ""}, {"first": "R", "middle": [], "last": "Ladouceur", "suffix": ""}, {"first": "F", "middle": [], "last": "Vitaro", "suffix": ""}], "year": 2001, "venue": "Canadian Psychology/Psychologie Canadienne", "link": null}, "BIBREF4": {"title": "Addiction motivation reformulated: an affective processing model of negative reinforcement", "authors": [{"first": "T", "middle": ["B"], "last": "Baker", "suffix": ""}, {"first": "M", "middle": ["E"], "last": "Piper", "suffix": ""}, {"first": "D", "middle": ["E"], "last": "Mccarthy", "suffix": ""}, {"first": "M", "middle": ["R"], "last": "Majeskie", "suffix": ""}, {"first": "M", "middle": ["C"], "last": "Fiore", "suffix": ""}], "year": 2004, "venue": "Psychological Review", "link": "15808727"}, "BIBREF5": {"title": "Gambling and substance use: Cooccurence among adults in a recent general population study in the United States", "authors": [{"first": "G", "middle": ["M"], "last": "Barnes", "suffix": ""}, {"first": "J", "middle": ["W"], "last": "Welte", "suffix": ""}, {"first": "M.-C", "middle": ["O"], "last": "Tidwell", "suffix": ""}, {"first": "J", "middle": ["H"], "last": "Hoffman", "suffix": ""}], "year": 2015, "venue": "International Gambling Studies", "link": "23490936"}, "BIBREF6": {"title": "Comparison of questionnaire and laboratory tests in the detection of excessive drinking and alcoholism", "authors": [{"first": "M", "middle": ["W"], "last": "Bernadt", "suffix": ""}, {"first": "J", "middle": [], "last": "Mumford", "suffix": ""}, {"first": "C", "middle": [], "last": "Taylor", "suffix": ""}, {"first": "B", "middle": [], "last": "Smith", "suffix": ""}, {"first": "R", "middle": ["M"], "last": "Murray", "suffix": ""}], "year": 1982, "venue": "Lancet", "link": "42263163"}, "BIBREF7": {"title": "Pathological gambling: Forensic issues", "authors": [{"first": "A", "middle": [], "last": "Blaszczynski", "suffix": ""}, {"first": "D", "middle": [], "last": "Silove", "suffix": ""}], "year": 1996, "venue": "Australian and New Zealand Journal of Psychiatry", "link": "24510331"}, "BIBREF8": {"title": "Meta-analysis of depression and substance use and impairment among cocaine users. Drug and Alcohol Dependence", "authors": [{"first": "K", "middle": ["R"], "last": "Conner", "suffix": ""}, {"first": "M", "middle": [], "last": "Pinquart", "suffix": ""}, {"first": "A", "middle": ["P"], "last": "Holbrook", "suffix": ""}], "year": 2008, "venue": "", "link": null}, "BIBREF9": {"title": "Pathological and problem gambling in substance use treatment: Results from the national epidemiologic survey on alcohol and related conditions (nesarc)", "authors": [{"first": "S", "middle": [], "last": "Cowlishaw", "suffix": ""}, {"first": "J", "middle": ["K"], "last": "Hakes", "suffix": ""}], "year": 2015, "venue": "The American Journal on Addictions", "link": "25000804"}, "BIBREF10": {"title": "Pathological and problem gambling in substance use treatment: A systematic review and meta-analysis", "authors": [{"first": "S", "middle": [], "last": "Cowlishaw", "suffix": ""}, {"first": "S", "middle": [], "last": "Merkouris", "suffix": ""}, {"first": "A", "middle": [], "last": "Chapman", "suffix": ""}, {"first": "H", "middle": [], "last": "Radermacher", "suffix": ""}], "year": 2014, "venue": "Journal of Substance Abuse Treatment", "link": "206488971"}, "BIBREF11": {"title": "A national survey of gambling problems in Canada", "authors": [{"first": "B", "middle": ["J"], "last": "Cox", "suffix": ""}, {"first": "N", "middle": [], "last": "Yu", "suffix": ""}, {"first": "T", "middle": ["O"], "last": "Afifi", "suffix": ""}, {"first": "R", "middle": [], "last": "Ladouceur", "suffix": ""}], "year": 2005, "venue": "The Canadian Journal of Psychiatry", "link": "15347676"}, "BIBREF12": {"title": "Decision-making deficits linked to reallife social dysfonction in crack cocaine dependent individuals", "authors": [{"first": "P", "middle": ["J"], "last": "Cunha", "suffix": ""}, {"first": "A", "middle": [], "last": "Bechara", "suffix": ""}, {"first": "A", "middle": ["G"], "last": "De Andrade", "suffix": ""}, {"first": "S", "middle": [], "last": "Nicastri", "suffix": ""}], "year": 2010, "venue": "The american Journal on Addictions", "link": null}, "BIBREF13": {"title": "The frontal assessment battery (FAB) reveals neurocognitive dysfunction in substance-dependent individuals in distinct executive domains: Abstract reasoning, motor programming, and cognitive flexibility", "authors": [{"first": "P", "middle": ["J"], "last": "Cunha", "suffix": ""}, {"first": "S", "middle": [], "last": "Nicastri", "suffix": ""}, {"first": "A", "middle": ["G"], "last": "De Andrade", "suffix": ""}, {"first": "K", "middle": ["I"], "last": "Bolla", "suffix": ""}], "year": 2010, "venue": "Addictive Behaviors", "link": "14940202"}, "BIBREF14": {"title": "Problem gambling and comorbid psychiatric and substance use disorders among drug users recruited from drug treatment and community settings", "authors": [{"first": "R", "middle": ["M"], "last": "Cunningham-Williams", "suffix": ""}, {"first": "L", "middle": ["B"], "last": "Cottler", "suffix": ""}, {"first": "W", "middle": ["M"], "last": "Compton", "suffix": ""}, {"first": "E", "middle": ["L"], "last": "Spitznagel", "suffix": ""}, {"first": "A", "middle": [], "last": "Ben-Abdallah", "suffix": ""}], "year": 2000, "venue": "Journal of Gambling Studies", "link": "28228355"}, "BIBREF15": {"title": "Validity of the Problem Gambling Severity Index interpretive categories", "authors": [{"first": "S", "middle": ["R"], "last": "Currie", "suffix": ""}, {"first": "D", "middle": ["C"], "last": "Hodgins", "suffix": ""}, {"first": "D", "middle": ["M"], "last": "Casey", "suffix": ""}], "year": 2013, "venue": "Journal of Gambling Studies", "link": "24323199"}, "BIBREF16": {"title": "Attention deficit hyperactivity disorder in cocaine-dependent adults: A psychiatric comorbidity analysis", "authors": [{"first": "C", "middle": [], "last": "Daigre", "suffix": ""}, {"first": "C", "middle": [], "last": "Roncero", "suffix": ""}, {"first": "L", "middle": [], "last": "Grau-L\u00f3pez", "suffix": ""}, {"first": "N", "middle": [], "last": "Mart\u00ednez-Luna", "suffix": ""}, {"first": "G", "middle": [], "last": "Prat", "suffix": ""}, {"first": "S", "middle": [], "last": "Valero", "suffix": ""}, {"first": "M", "middle": [], "last": "Casas", "suffix": ""}], "year": 2013, "venue": "The American Journal on Addictions", "link": "28501024"}, "BIBREF17": {"title": "Gender differences in the associations between past-year gambling problems ans psychiatric disorders", "authors": [{"first": "R", "middle": ["A"], "last": "Desai", "suffix": ""}, {"first": "M", "middle": ["N"], "last": "Potenza", "suffix": ""}], "year": 2008, "venue": "Social Psychiatry and Psychoatric Epidemiology", "link": "143720499"}, "BIBREF18": {"title": "Correlates of at-risk gambling behaviors of homeless youth", "authors": [{"first": "M", "middle": [], "last": "Dufour", "suffix": ""}, {"first": "E", "middle": [], "last": "Roy", "suffix": ""}, {"first": "J.-F", "middle": [], "last": "Boivin", "suffix": ""}, {"first": "J.-F", "middle": [], "last": "Boudreau", "suffix": ""}, {"first": "M", "middle": [], "last": "Robert", "suffix": ""}], "year": 2014, "venue": "Addiction Research and Therapy", "link": "147670683"}, "BIBREF19": {"title": "Epidemiological associations between gambling behavior, substance use and mood and anxiety disorders", "authors": [{"first": "N", "middle": [], "last": "El-Guebaly", "suffix": ""}, {"first": "S", "middle": ["B"], "last": "Patten", "suffix": ""}, {"first": "S", "middle": [], "last": "Currie", "suffix": ""}, {"first": "J", "middle": ["V"], "last": "Williams", "suffix": ""}, {"first": "C", "middle": ["A"], "last": "Beck", "suffix": ""}, {"first": "C", "middle": ["J"], "last": "Maxwell", "suffix": ""}, {"first": "J", "middle": ["L"], "last": "Wang", "suffix": ""}], "year": 2006, "venue": "Journal of Gambling Studies", "link": "32746691"}, "BIBREF20": {"title": "The prevalence and correlates of depressive symptomatology among a community sample of crack-cocaine smokers", "authors": [{"first": "R", "middle": ["S"], "last": "Falck", "suffix": ""}, {"first": "J", "middle": [], "last": "Wang", "suffix": ""}, {"first": "R", "middle": ["G"], "last": "Carlson", "suffix": ""}, {"first": "M", "middle": [], "last": "Eddy", "suffix": ""}, {"first": "H", "middle": ["A"], "last": "Siegal", "suffix": ""}], "year": 2002, "venue": "Journal of Psychoactive Drugs", "link": "24443327"}, "BIBREF21": {"title": "Problem gamblers, problem substance users, and dual-problem individuals: an epidemiological study", "authors": [{"first": "W", "middle": [], "last": "Feigelman", "suffix": ""}, {"first": "L", "middle": ["S"], "last": "Wallisch", "suffix": ""}, {"first": "H", "middle": ["R"], "last": "Lesieur", "suffix": ""}], "year": 1998, "venue": "American Journal of Public Health", "link": "20958773"}, "BIBREF22": {"title": "Prevalence of pathological gambling in treatment-seeking addicted patients: An exploratory study with the South Oaks Gambling Screen", "authors": [{"first": "J", "middle": [], "last": "Fernandez-Montalvo", "suffix": ""}, {"first": "J", "middle": ["J"], "last": "Lopez-Goni", "suffix": ""}, {"first": "A", "middle": [], "last": "Arteaga", "suffix": ""}], "year": 2012, "venue": "Anales de Psicolog\u00eda", "link": "51859129"}, "BIBREF23": {"title": "The Canadian problem gambling index", "authors": [{"first": "J", "middle": [], "last": "Ferris", "suffix": ""}, {"first": "H", "middle": [], "last": "Wynne", "suffix": ""}], "year": 2001, "venue": "", "link": null}, "BIBREF24": {"title": "Association of psychiatric and substance use disorder comorbidity with cocaine dependence severity and treatment utilization in cocaine-dependemt individuals", "authors": [{"first": "J", "middle": ["D"], "last": "Ford", "suffix": ""}, {"first": "J", "middle": [], "last": "Gelernter", "suffix": ""}, {"first": "J", "middle": ["S"], "last": "Devoe", "suffix": ""}, {"first": "W", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "R", "middle": ["D"], "last": "Weiss", "suffix": ""}, {"first": "K", "middle": [], "last": "Brady", "suffix": ""}], "year": 2009, "venue": "Drug and Alcohol Dependence", "link": null}, "BIBREF25": {"title": "The prevalence and determinants of problem gambling in Australia: Assessing the impact of interactive gambling and new technologies", "authors": [{"first": "S", "middle": ["M"], "last": "Gainsbury", "suffix": ""}, {"first": "A", "middle": [], "last": "Russell", "suffix": ""}, {"first": "N", "middle": [], "last": "Hing", "suffix": ""}, {"first": "R", "middle": [], "last": "Wood", "suffix": ""}, {"first": "D", "middle": ["I"], "last": "Lubman", "suffix": ""}, {"first": "A", "middle": [], "last": "Blaszczynski", "suffix": ""}], "year": 2014, "venue": "Psychology of Addictive Behavior", "link": "28669270"}, "BIBREF26": {"title": "Predictors of pathological gambling severity taking gender differences into account", "authors": [{"first": "I", "middle": [], "last": "Gonzales-Ortega", "suffix": ""}, {"first": "E", "middle": [], "last": "Echeburua", "suffix": ""}, {"first": "P", "middle": [], "last": "Corral", "suffix": ""}, {"first": "R", "middle": [], "last": "Polo-Lopez", "suffix": ""}, {"first": "S", "middle": [], "last": "Alberich", "suffix": ""}], "year": 2013, "venue": "European Addiction Research", "link": "7402489"}, "BIBREF27": {"title": "Severity of dependence scale as a diagnostic tool for heroin and cocaine dependence", "authors": [{"first": "F", "middle": [], "last": "Gonzalez-Saiz", "suffix": ""}, {"first": "A", "middle": [], "last": "Domingo-Salvany", "suffix": ""}, {"first": "G", "middle": [], "last": "Barrio", "suffix": ""}, {"first": "A", "middle": [], "last": "S\u00e1nchez-Niub\u00f3", "suffix": ""}, {"first": "M", "middle": ["T"], "last": "Brugal", "suffix": ""}, {"first": "L", "middle": [], "last": "De La Fuente", "suffix": ""}, {"first": "J", "middle": [], "last": "Alonso", "suffix": ""}], "year": 2009, "venue": "European Addiction Research", "link": "29289066"}, "BIBREF28": {"title": "The Severity of Dependence Scale (SDS): Psychometric properties of the SDS in English and Australian samples of heroin, cocaine and amphetamine users", "authors": [{"first": "M", "middle": [], "last": "Gossop", "suffix": ""}, {"first": "S", "middle": [], "last": "Darke", "suffix": ""}, {"first": "P", "middle": [], "last": "Griffiths", "suffix": ""}, {"first": "J", "middle": [], "last": "Hando", "suffix": ""}, {"first": "B", "middle": [], "last": "Powis", "suffix": ""}, {"first": "W", "middle": [], "last": "Hall", "suffix": ""}, {"first": "J", "middle": [], "last": "Strang", "suffix": ""}], "year": 1995, "venue": "Addiction", "link": "7059087"}, "BIBREF29": {"title": "Adolescent gambling behavior: A prevalence study and examinations of the correlates with problem gambling", "authors": [{"first": "R", "middle": [], "last": "Gupta", "suffix": ""}, {"first": "J", "middle": ["L"], "last": "Derevensky", "suffix": ""}], "year": 1998, "venue": "Journal of Gambling Studies", "link": null}, "BIBREF30": {"title": "Pathological gambling among cocaine-dependent outpatients", "authors": [{"first": "G", "middle": ["W"], "last": "Hall", "suffix": ""}, {"first": "N", "middle": ["J"], "last": "Carriero", "suffix": ""}, {"first": "R", "middle": ["Y"], "last": "Takushi", "suffix": ""}, {"first": "I", "middle": ["D"], "last": "Montoya", "suffix": ""}, {"first": "K", "middle": ["L"], "last": "Preston", "suffix": ""}, {"first": "D", "middle": ["A"], "last": "Gorelick", "suffix": ""}], "year": 2000, "venue": "American Journal of Psychiatry", "link": "207557503"}, "BIBREF31": {"title": "Slot machine structural characteristics: Creating near misses using high award symbol ratios", "authors": [{"first": "K", "middle": ["A"], "last": "Harrigan", "suffix": ""}], "year": 2008, "venue": "International Journal of Mental Health and Addiction", "link": "22598293"}, "BIBREF32": {"title": "Psychiatric comorbidity in young cocaine users: Induced versus independent disorders", "authors": [{"first": "M", "middle": ["J"], "last": "Herrero", "suffix": ""}, {"first": "A", "middle": [], "last": "Domingo-Salvany", "suffix": ""}, {"first": "M", "middle": [], "last": "Torrens", "suffix": ""}, {"first": "M", "middle": ["T"], "last": "Brugal", "suffix": ""}], "year": 2008, "venue": "Addiction", "link": "27020396"}, "BIBREF33": {"title": "Untangling the complex needs of people experiencing gambling problems and homelessness", "authors": [{"first": "L", "middle": [], "last": "Holdsworth", "suffix": ""}, {"first": "M", "middle": [], "last": "Tiyce", "suffix": ""}], "year": 2013, "venue": "International Journal of Mental Health and Addiction", "link": "33333138"}, "BIBREF34": {"title": "Gambling, gambling activities, and problem gambling", "authors": [{"first": "T", "middle": [], "last": "Holtgraves", "suffix": ""}], "year": 2009, "venue": "Psychology of Addictive Behaviors", "link": "34106854"}, "BIBREF35": {"title": "Health conditions among aging narcotics addicts: Medical examination results", "authors": [{"first": "Y", "middle": [], "last": "Hser", "suffix": ""}, {"first": "L", "middle": [], "last": "Gelberg", "suffix": ""}, {"first": "V", "middle": [], "last": "Hoffman", "suffix": ""}, {"first": "C", "middle": ["E"], "last": "Grella", "suffix": ""}, {"first": "W", "middle": [], "last": "Mccarthy", "suffix": ""}, {"first": "M", "middle": ["D"], "last": "Anglin", "suffix": ""}], "year": 2004, "venue": "Journal of Behavioral Medicine", "link": "34141706"}, "BIBREF36": {"title": "A general theory of addictions. A new theoritical model", "authors": [{"first": "D", "middle": ["F"], "last": "Jacobs", "suffix": ""}], "year": 1986, "venue": "Journal of Gambling Behavior", "link": null}, "BIBREF37": {"title": "Differences in cognitive distortions between problem and social gamblers", "authors": [{"first": "J", "middle": [], "last": "Joukhador", "suffix": ""}, {"first": "F", "middle": [], "last": "Maccallum", "suffix": ""}, {"first": "A", "middle": [], "last": "Blaszczynski", "suffix": ""}], "year": 2003, "venue": "Psychological Reports", "link": "9282543"}, "BIBREF38": {"title": "Negative urgency, distress tolerance, and substance abuse among college students", "authors": [{"first": "A", "middle": ["J"], "last": "Kaiser", "suffix": ""}, {"first": "R", "middle": [], "last": "Milich", "suffix": ""}, {"first": "D", "middle": ["R"], "last": "Lynam", "suffix": ""}, {"first": "R", "middle": ["J"], "last": "Charnigo", "suffix": ""}], "year": 2012, "venue": "Addictive Behaviors", "link": "997353"}, "BIBREF39": {"title": "Comorbidity between patterns of substance use dependence and psychiatric syndromes", "authors": [{"first": "D", "middle": ["B"], "last": "Kandel", "suffix": ""}, {"first": "F", "middle": [], "last": "Huang", "suffix": ""}, {"first": "M", "middle": [], "last": "Davies", "suffix": ""}], "year": 2001, "venue": "Drug and Alcohol Dependence", "link": "25915020"}, "BIBREF40": {"title": "Complications of cocaine addiction", "authors": [{"first": "L", "middle": [], "last": "Karila", "suffix": ""}, {"first": "W", "middle": [], "last": "Lowenstein", "suffix": ""}, {"first": "S", "middle": [], "last": "Coscas", "suffix": ""}, {"first": "A", "middle": [], "last": "Benyamina", "suffix": ""}, {"first": "M", "middle": [], "last": "Reynaud", "suffix": ""}], "year": 2009, "venue": "La Revue Du Praticien", "link": null}, "BIBREF41": {"title": "DSM-IV pathological gambling in the National Co-morbidity Survey Replication", "authors": [{"first": "R", "middle": ["C"], "last": "Kessler", "suffix": ""}, {"first": "I", "middle": [], "last": "Hwang", "suffix": ""}, {"first": "R", "middle": [], "last": "Labrie", "suffix": ""}, {"first": "M", "middle": [], "last": "Petukhova", "suffix": ""}, {"first": "N", "middle": ["A"], "last": "Sampson", "suffix": ""}, {"first": "K", "middle": ["C"], "last": "Winters", "suffix": ""}, {"first": "H", "middle": ["J"], "last": "Shaffer", "suffix": ""}], "year": 2008, "venue": "Psychological Medicine", "link": "4658406"}, "BIBREF42": {"title": "The World Mental Health (WMH) Survey Initiative version of the World Health Organization (WHO) Composite International Diagnostic Interview (CIDI). The International", "authors": [{"first": "R", "middle": ["C"], "last": "Kessler", "suffix": ""}, {"first": "T", "middle": ["B. ; V L"], "last": "Ustun", "suffix": ""}, {"first": "R", "middle": ["K"], "last": "Brooner", "suffix": ""}, {"first": "J", "middle": [], "last": "Peirce", "suffix": ""}, {"first": "K", "middle": [], "last": "Kolodner", "suffix": ""}, {"first": "M", "middle": [], "last": "Kidorf", "suffix": ""}], "year": 2004, "venue": "Journal of Methods in Psychiatric Research", "link": "11556216"}, "BIBREF43": {"title": "Negative reinforcement in drug addiction: The darkness within", "authors": [{"first": "G", "middle": ["F"], "last": "Koob", "suffix": ""}], "year": 2013, "venue": "Current Opinion in Neurobiology", "link": "206951546"}, "BIBREF44": {"title": "Gambling and the health of the public: Adopting a public health perspective", "authors": [{"first": "D", "middle": ["A"], "last": "Korn", "suffix": ""}, {"first": "H", "middle": ["J"], "last": "Shaffer", "suffix": ""}], "year": 1999, "venue": "Journal of Gambling Studies", "link": "31375166"}, "BIBREF45": {"title": "Two validation studies of the CIDIS: A simplified version of the Composite International Diagnostic Interview", "authors": [{"first": "V", "middle": [], "last": "Kovess", "suffix": ""}, {"first": "L", "middle": [], "last": "Fournier", "suffix": ""}, {"first": "A", "middle": ["D"], "last": "Lesage", "suffix": ""}, {"first": "F", "middle": ["A"], "last": "Lebigre", "suffix": ""}, {"first": "A", "middle": [], "last": "Caria", "suffix": ""}], "year": 2001, "venue": "Psychiatric Networks", "link": null}, "BIBREF46": {"title": "Psychological distress increases needle sharing among cocaine users : results from the COSMO study", "authors": [{"first": "A", "middle": [], "last": "L\u00e9vesque", "suffix": ""}, {"first": "D", "middle": [], "last": "Jutras-Aswad", "suffix": ""}, {"first": "K", "middle": [], "last": "Bertrand", "suffix": ""}, {"first": "F", "middle": [], "last": "Chanut", "suffix": ""}, {"first": "M", "middle": [], "last": "Dufour", "suffix": ""}, {"first": "F", "middle": [], "last": "Lesp\u00e9rance", "suffix": ""}], "year": 2014, "venue": "Journal of Addiction Research and Therapy", "link": "74375142"}, "BIBREF47": {"title": "The relationship between recreational gambling and substance abuse/dependence: Data from a nationally representative sample", "authors": [{"first": "T", "middle": [], "last": "Liu", "suffix": ""}, {"first": "P", "middle": ["K"], "last": "Maciejewski", "suffix": ""}, {"first": "M", "middle": ["N"], "last": "Potenza", "suffix": ""}], "year": 2009, "venue": "Drug and Alcohol Dependence", "link": "8042686"}, "BIBREF48": {"title": "Prevalence of comorbid disorders in problem and pathological gambling: Systematic review and meta-analysis of population surveys", "authors": [{"first": "F", "middle": ["K"], "last": "Lorains", "suffix": ""}, {"first": "S", "middle": [], "last": "Cowlishaw", "suffix": ""}, {"first": "S", "middle": ["A"], "last": "Thomas", "suffix": ""}], "year": 2011, "venue": "Addiction", "link": "195688817"}, "BIBREF49": {"title": "Differences in addiction severity between social and probable pathological gamblers among substance abusers in treatment in Rio de Janeiro", "authors": [{"first": "A", "middle": ["C R"], "last": "Mathias", "suffix": ""}, {"first": "R", "middle": ["W"], "last": "Vargens", "suffix": ""}, {"first": "F", "middle": ["H"], "last": "Kessler", "suffix": ""}, {"first": "M", "middle": ["S"], "last": "Cruz", "suffix": ""}], "year": 2009, "venue": "International Journal of Mental Health and Addiction", "link": "25157465"}, "BIBREF50": {"title": "The CAGE questionnaire: Validation of a new alcoholism screening instrument", "authors": [{"first": "D", "middle": [], "last": "Mayfield", "suffix": ""}, {"first": "G", "middle": [], "last": "Mcleod", "suffix": ""}, {"first": "P", "middle": [], "last": "Hall", "suffix": ""}], "year": 1974, "venue": "American Journal of Psychiatry", "link": "11240495"}, "BIBREF51": {"title": "Characteristics of cocaine-and marijuana-dependent subjects presenting for medication treatment trials", "authors": [{"first": "A", "middle": ["L"], "last": "Mcrae", "suffix": ""}, {"first": "S", "middle": ["L"], "last": "Hedden", "suffix": ""}, {"first": "R", "middle": ["J"], "last": "Malcolm", "suffix": ""}, {"first": "R", "middle": ["E"], "last": "Carter", "suffix": ""}, {"first": "K", "middle": ["T"], "last": "Brady", "suffix": ""}], "year": 2007, "venue": "Addictive Behaviors", "link": "37511392"}, "BIBREF52": {"title": "Problem gambling and homelessness: Results from an epidemiologic study", "authors": [{"first": "L", "middle": [], "last": "Nower", "suffix": ""}, {"first": "K", "middle": ["M"], "last": "Eyrich-Garg", "suffix": ""}, {"first": "D", "middle": ["E"], "last": "Pollio", "suffix": ""}, {"first": "C", "middle": ["S"], "last": "North", "suffix": ""}], "year": 2014, "venue": "Journal of Gambling Studies", "link": "21627511"}, "BIBREF53": {"title": "Decision-making deficits in pathological gambling: The role of executive functions, explicit knowledge and impulsivity in relation to decisions made under ambiguity and risk", "authors": [{"first": "C", "middle": [], "last": "Ochoa", "suffix": ""}, {"first": "E", "middle": ["M"], "last": "Alvarez-Moya", "suffix": ""}, {"first": "E", "middle": [], "last": "Penelo", "suffix": ""}, {"first": "M", "middle": ["N"], "last": "Aymami", "suffix": ""}, {"first": "M", "middle": [], "last": "G\u00f3mez-Pe\u00f1a", "suffix": ""}, {"first": "F", "middle": [], "last": "Fern\u00e1ndez-Aranda", "suffix": ""}], "year": 2013, "venue": "The American Journal on Addiction", "link": "40886441"}, "BIBREF54": {"title": "Enjeux de sant\u00e9 publique reli\u00e9s \u00e0 l'\u00e9tatisation des jeux d'argent sur Internet", "authors": [{"first": "E", "middle": [], "last": "Papineau", "suffix": ""}], "year": 2010, "venue": "", "link": null}, "BIBREF55": {"title": "The psychology of the fruit machine: The role of structural characteristics (revisited)", "authors": [{"first": "J", "middle": [], "last": "Parke", "suffix": ""}, {"first": "M", "middle": [], "last": "Griffiths", "suffix": ""}], "year": 2006, "venue": "International Journal of Mental Health and Addiction", "link": "19183320"}, "BIBREF56": {"title": "Comorbidity of disorderd gambling and other psychiatric disorders", "authors": [{"first": "N", "middle": ["M"], "last": "Petry", "suffix": ""}], "year": 2005, "venue": "Pathological gambling: Etiology, comorbidity, and treatment", "link": null}, "BIBREF57": {"title": "Gambling and substance use disorders: current status and future directions", "authors": [{"first": "N", "middle": ["M"], "last": "Petry", "suffix": ""}], "year": 2007, "venue": "The American Journal on Addictions", "link": "3010817"}, "BIBREF58": {"title": "Co-morbidity of DSM-IV pathological gambling and other psychiatric disorders: Results from the National Epidemiologic Survey on Alcohol and Related Conditions", "authors": [{"first": "N", "middle": ["M"], "last": "Petry", "suffix": ""}, {"first": "F", "middle": ["S"], "last": "Stinson", "suffix": ""}, {"first": "B", "middle": ["F"], "last": "Grant", "suffix": ""}], "year": 2005, "venue": "Journal of Clinical Psychiatry", "link": "45503044"}, "BIBREF59": {"title": "Side effects of cocaine abuse: Multiorgan toxicity and pathological consequences", "authors": [{"first": "I", "middle": [], "last": "Riezzo", "suffix": ""}, {"first": "C", "middle": [], "last": "Fiore", "suffix": ""}, {"first": "D", "middle": [], "last": "De Carlo", "suffix": ""}, {"first": "N", "middle": [], "last": "Pascale", "suffix": ""}, {"first": "M", "middle": [], "last": "Neri", "suffix": ""}, {"first": "E", "middle": [], "last": "Turillazzi", "suffix": ""}, {"first": "V", "middle": [], "last": "Fineschi", "suffix": ""}], "year": 2012, "venue": "Current Medicinal Chemistry", "link": null}, "BIBREF60": {"title": "Gambling on electronic gaming machines is an escape from negative self reflection", "authors": [{"first": "M", "middle": ["J"], "last": "Rockloff", "suffix": ""}, {"first": "N", "middle": [], "last": "Greer", "suffix": ""}, {"first": "C", "middle": [], "last": "Fay", "suffix": ""}, {"first": "L", "middle": ["G"], "last": "Evans", "suffix": ""}], "year": 2011, "venue": "Journal of Gambling Studies", "link": "39784001"}, "BIBREF61": {"title": "Safe as houses: An exploration of the link between gambling and homelessness. Adelaide: South Australian Government Department for Families and Communities", "authors": [{"first": "N", "middle": [], "last": "Rogers", "suffix": ""}, {"first": "E", "middle": [], "last": "Button", "suffix": ""}, {"first": "A", "middle": [], "last": "Hume", "suffix": ""}], "year": 2005, "venue": "", "link": null}, "BIBREF62": {"title": "Anxiety, mood disorders and injection risk behaviors among cocaine users: Results from the COSMO study", "authors": [{"first": "E", "middle": [], "last": "Roy", "suffix": ""}, {"first": "D", "middle": [], "last": "Justras-Aswad", "suffix": ""}, {"first": "K", "middle": [], "last": "Bertrand", "suffix": ""}, {"first": "M", "middle": [], "last": "Dufour", "suffix": ""}, {"first": "M", "middle": [], "last": "Perreault", "suffix": ""}, {"first": "E", "middle": [], "last": "Laverdiere", "suffix": ""}], "year": 2015, "venue": "The American Journal on Addictions", "link": "36409930"}, "BIBREF63": {"title": "Prevalence of posttraumatic stress disorder symptoms among addiction treatment patients with cocaine use disorders", "authors": [{"first": "E", "middle": ["C"], "last": "Saunders", "suffix": ""}, {"first": "C", "middle": [], "last": "Lambert-Harris", "suffix": ""}, {"first": "M", "middle": ["P"], "last": "Mcgovern", "suffix": ""}, {"first": "A", "middle": [], "last": "Meier", "suffix": ""}, {"first": "H", "middle": [], "last": "Xie", "suffix": ""}], "year": 2015, "venue": "Journal of Psychoactive Drugs", "link": "23447533"}, "BIBREF64": {"title": "Gambling disorders among homeless persons with substance use disorders seeking treatment at a community center", "authors": [{"first": "H", "middle": ["J"], "last": "Shaffer", "suffix": ""}, {"first": "C", "middle": ["R"], "last": "Freed", "suffix": ""}, {"first": "D", "middle": [], "last": "Healea", "suffix": ""}], "year": 2002, "venue": "Psychiatric Services", "link": "23253076"}, "BIBREF65": {"title": "Updating and refining prevalence estimates of disordered gambling behaviour in the United States and Canada", "authors": [{"first": "H", "middle": ["J"], "last": "Shaffer", "suffix": ""}, {"first": "M", "middle": ["N"], "last": "Hall", "suffix": ""}], "year": 2001, "venue": "", "link": "17048883"}, "BIBREF66": {"title": "Toward a syndrome model of addiction: Multiple expressions, common etiology", "authors": [{"first": "H", "middle": ["J"], "last": "Shaffer", "suffix": ""}, {"first": "D", "middle": ["A"], "last": "Laplante", "suffix": ""}, {"first": "R", "middle": ["A"], "last": "Labrie", "suffix": ""}, {"first": "R", "middle": ["C"], "last": "Kidman", "suffix": ""}, {"first": "A", "middle": ["N"], "last": "Donato", "suffix": ""}, {"first": "M", "middle": ["V"], "last": "Stanton", "suffix": ""}], "year": 2004, "venue": "Harvard Review of Psychiatry", "link": "17591918"}, "BIBREF67": {"title": "Rates of problematic gambling in a British homeless sample: a preliminary study", "authors": [{"first": "S", "middle": [], "last": "Sharman", "suffix": ""}, {"first": "J", "middle": [], "last": "Dreyer", "suffix": ""}, {"first": "M", "middle": [], "last": "Aitken", "suffix": ""}, {"first": "L", "middle": [], "last": "Clark", "suffix": ""}, {"first": "H", "middle": [], "last": "Bowden-Jones", "suffix": ""}], "year": 2015, "venue": "Journal of Gambling Studies", "link": "26705231"}, "BIBREF68": {"title": "Deficits in behavioural inhibition in substance abuse and addiction. A meta-analysis", "authors": [{"first": "J", "middle": ["L"], "last": "Smith", "suffix": ""}, {"first": "R", "middle": ["P"], "last": "Mattick", "suffix": ""}, {"first": "S", "middle": ["D"], "last": "Jamadar", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Iredale", "suffix": ""}], "year": 2014, "venue": "Drug and Alcohol Dependence", "link": null}, "BIBREF69": {"title": "Development and validation of the Gamblers' Beliefs Questionnaire", "authors": [{"first": "T", "middle": ["A"], "last": "Steenbergh", "suffix": ""}, {"first": "A", "middle": ["W"], "last": "Meyers", "suffix": ""}, {"first": "R", "middle": ["K"], "last": "May", "suffix": ""}, {"first": "J", "middle": ["P"], "last": "Whelan", "suffix": ""}], "year": 2002, "venue": "Psychology of Addictive Behaviors", "link": "15605130"}, "BIBREF70": {"title": "Addiction syndrome and homelessness", "authors": [{"first": "J", "middle": ["A"], "last": "Stein", "suffix": ""}, {"first": "C", "middle": ["E"], "last": "Grella", "suffix": ""}, {"first": "B", "middle": ["T"], "last": "Conner", "suffix": ""}, {"first": "L", "middle": [], "last": "Gelberg", "suffix": ""}], "year": 2012, "venue": "Recovery, prevention, and other issues", "link": "148412259"}, "BIBREF71": {"title": "Cocaine abuse and pathological gambling", "authors": [{"first": "M", "middle": ["A"], "last": "Steinberg", "suffix": ""}, {"first": "T", "middle": ["A"], "last": "Kosten", "suffix": ""}, {"first": "B", "middle": ["J"], "last": "Rounsaville", "suffix": ""}], "year": 1992, "venue": "The American Journal on Addictions", "link": "73314621"}, "BIBREF72": {"title": "Using multivariate statistics", "authors": [{"first": "B", "middle": ["G"], "last": "Tabachnick", "suffix": ""}, {"first": "L", "middle": ["S"], "last": "Fidell", "suffix": ""}], "year": 2001, "venue": "", "link": "118426685"}, "BIBREF73": {"title": "Gambling and Homelessness. A case management resource", "authors": [{"first": "C", "middle": [], "last": "Talbot", "suffix": ""}], "year": 2004, "venue": "", "link": null}, "BIBREF74": {"title": "A theoretical model of EGM problem gambling: More than a cognitive escape", "authors": [{"first": "A", "middle": ["C"], "last": "Thomas", "suffix": ""}, {"first": "G", "middle": ["B"], "last": "Sullivan", "suffix": ""}, {"first": "F", "middle": ["C L"], "last": "Allen", "suffix": ""}], "year": 2009, "venue": "International Journal of Mental Health and Addiction", "link": "29534842"}, "BIBREF75": {"title": "Pathological gambling in treatment-seeking substance abusers", "authors": [{"first": "T", "middle": [], "last": "Toneatto", "suffix": ""}, {"first": "J", "middle": [], "last": "Brennan", "suffix": ""}], "year": 2002, "venue": "Addictive Behaviors", "link": "4907507"}, "BIBREF76": {"title": "Pathways to pathological gambling: Component analysis of variables related to pathological gambling", "authors": [{"first": "N", "middle": ["E"], "last": "Turner", "suffix": ""}, {"first": "U", "middle": [], "last": "Jain", "suffix": ""}, {"first": "W", "middle": [], "last": "Spence", "suffix": ""}, {"first": "M", "middle": [], "last": "Zangeneh", "suffix": ""}], "year": 2008, "venue": "International Gambling Studies", "link": "144537553"}, "BIBREF77": {"title": "The experience of gambling and its role in problem gambling", "authors": [{"first": "N", "middle": [], "last": "Turner", "suffix": ""}, {"first": "N", "middle": [], "last": "Littman-Sharp", "suffix": ""}, {"first": "M", "middle": [], "last": "Zangeneh", "suffix": ""}], "year": 2006, "venue": "International Gambling Studies", "link": null}, "BIBREF78": {"title": "The relationship of problem gambling to criminal behavior in a sample of Canadian male federal offenders", "authors": [{"first": "N", "middle": ["E"], "last": "Turner", "suffix": ""}, {"first": "D", "middle": ["L"], "last": "Preston", "suffix": ""}, {"first": "C", "middle": [], "last": "Saunders", "suffix": ""}, {"first": "S", "middle": [], "last": "Mcavoy", "suffix": ""}, {"first": "U", "middle": [], "last": "Jain", "suffix": ""}], "year": 2009, "venue": "Journal of Gambling Studies", "link": "630009"}, "BIBREF80": {"title": "Psychiatric comorbidity in cocaine users treated in therapeutic community: Substance-induced versus independent disorders", "authors": [{"first": "E", "middle": [], "last": "Vergara-Moragues", "suffix": ""}, {"first": "F", "middle": [], "last": "Gonz\u00e1lez-Saiz", "suffix": ""}, {"first": "O", "middle": ["M"], "last": "Lozano", "suffix": ""}, {"first": "P", "middle": ["B"], "last": "Espinosa", "suffix": ""}, {"first": "F", "middle": ["F"], "last": "Calder\u00f3n", "suffix": ""}, {"first": "I", "middle": [], "last": "Bilbao-Acebos", "suffix": ""}, {"first": "A", "middle": ["V"], "last": "Garc\u00eda", "suffix": ""}], "year": 2012, "venue": "Psychiatry Research", "link": "1110825"}, "BIBREF81": {"title": "Risk factors for pathological gambling", "authors": [{"first": "J", "middle": ["W"], "last": "Welte", "suffix": ""}, {"first": "G", "middle": ["M"], "last": "Barnes", "suffix": ""}, {"first": "W", "middle": ["F"], "last": "Wieczorek", "suffix": ""}, {"first": "M.-C", "middle": ["O"], "last": "Tidwell", "suffix": ""}, {"first": "J", "middle": ["C"], "last": "Parker", "suffix": ""}], "year": 2004, "venue": "Addictive Behaviors", "link": "21856166"}, "BIBREF82": {"title": "A qualitative investigation of problem gambling as an escape-based coping strategy", "authors": [{"first": "R", "middle": ["T"], "last": "Wood", "suffix": ""}, {"first": "M", "middle": ["D"], "last": "Griffiths", "suffix": ""}], "year": 2007, "venue": "Psychology and Psychotherapy: Theory, Research and Practice", "link": "25041941"}, "BIBREF83": {"title": "Environmental factors selectively impact co-occurrence of problem/pathological gambling with specific drug-use disorders in male twins", "authors": [{"first": "H", "middle": [], "last": "Xian", "suffix": ""}, {"first": "J", "middle": ["L"], "last": "Giddens", "suffix": ""}, {"first": "J", "middle": ["F"], "last": "Scherrer", "suffix": ""}, {"first": "S", "middle": ["A"], "last": "Eisen", "suffix": ""}, {"first": "M", "middle": ["N"], "last": "Potenza", "suffix": ""}], "year": 2014, "venue": "Addiction", "link": "36954114"}}, "ref_entries": {"TABREF0": {"text": "). The final model included significant variables at a level alpha B.05. Statistical analyses were performed using IBM SPSS Statistics for Windows, version 19.0 (Armonk, NY: IBM Corp) and SAS version 9.3 (SAS Institute, Cary NC).", "type": "table"}, "TABREF1": {"text": "Participation to gambling activities in the past 12 months among all gamblers, at-risk and non- problem gamblers* p \\ .05; ** p \\ .01; *** p .001Recent mental health disorders for gambling problems among at-risk and non-problem gamblers", "type": "table"}, "TABREF2": {"text": "Risk factors for gambling problems among at-risk and non-problem gamblers", "type": "table"}, "TABREF3": {"text": "Multivariate model: Independent correlates of at-risk group", "type": "table"}}}
{"paper_id": "10700749", "_pdf_hash": "06df60a7caafa1634fa47599d7ac70d878cb2006", "abstract": [{"section": "Abstract", "text": "A 25-year-old construction worker presented to the emergency department (ED) after the accidental fall of a metal bar on his neck. In the field, he was appropriately managed with a cervical collar for possible spine injury. On arrival at the ED, he was fully conscious with severe neck pain, hypotensive 80/50 mmHg and bradycardiac 48 beats/min. Physical examination revealed a flaccid paralysis and sensory loss in all four extremities. A chest X-ray study was unremarkable (Fig. 1, panel a) . Two hours later, after examination revealed absent air entry over the right lung base, a repeat X-ray study showed an elevated right hemidiaphragm and an ipsilateral mediastinal shift ( Fig. 1 panel b ). Computed tomography (CT scan) of the neck showed a comminuted, posteriorly displaced fracture of the third cervical vertebrae (Fig. 1,  panel c and d ). In view of the established quadriplegia and neurogenic shock, this X-ray finding is suggestive of unilateral diaphragmatic paralysis. The delayed onset of diaphragmatic paralysis probably coincides with the evolving post-traumatic spinal cord edema. A few hours later, he developed respiratory distress with evident abdominal wall retraction during inspiration and protrusion during expiration in addition to hypoxia, hypercapnia and respiratory acidosis on blood gas analysis. The trachea was intubated and mechanical ventilation was started. This worsening respiratory status was concerning for the progression into bilateral diaphragmatic paralysis. Throughout the ICU course, his neurological status failed to improve requiring continued mechanical ventilation and subsequent tracheostomy. He was transferred to a subacute rehabilitation facility for further care.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "The diagnosis of diaphragmatic paralysis is suggested clinically by the presence of abdominal wall retraction during inspiration and protrusion during expiration. Whereas unilateral diaphragmatic paralysis is usually well tolerated in the absence of underlying lung pathology, bilateral paralysis requires long-term ventilatory support. In contrast to bilateral diaphragmatic paralysis, a chest X-ray study is more specific for diagnosing a unilateral paralysis. Fluoroscopy confirms the diagnosis when paradoxical inspiratory elevation of the paralyzed hemidiaphragm is evident.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "", "text": "A 25-year-old construction worker presented to the emergency department (ED) after the accidental fall of a metal bar on his neck. In the field, he was appropriately managed with a cervical collar for possible spine injury. On arrival at the ED, he was fully conscious with severe neck pain, hypotensive 80/50 mmHg and bradycardiac 48 beats/min. Physical examination revealed a flaccid paralysis and sensory loss in all four extremities. A chest X-ray study was unremarkable (Fig. 1, panel a) . Two hours later, after examination revealed absent air entry over the right lung base, a repeat X-ray study showed an elevated right hemidiaphragm and an ipsilateral mediastinal shift ( Fig. 1 panel b ). Computed tomography (CT scan) of the neck showed a comminuted, posteriorly displaced fracture of the third cervical vertebrae (Fig. 1 , panel c and d). In view of the established quadriplegia and neurogenic shock, this X-ray finding is suggestive of unilateral diaphragmatic paralysis. The delayed onset of diaphragmatic paralysis probably coincides with the evolving post-traumatic spinal cord edema. A few hours later, he developed respiratory distress with evident abdominal wall retraction during inspiration and protrusion during expiration in addition to hypoxia, hypercapnia and respiratory acidosis on blood gas analysis. The trachea was intubated and mechanical ventilation was started. This worsening respiratory status was concerning for the progression into bilateral diaphragmatic paralysis. Throughout the ICU course, his neurological status failed to improve requiring continued mechanical ventilation and subsequent tracheostomy. He was transferred to a subacute rehabilitation facility for further care.", "cite_spans": [], "ref_spans": [{"start": 475, "end": 492, "text": "(Fig. 1, panel a)", "ref_id": "FIGREF0"}, {"start": 681, "end": 695, "text": "Fig. 1 panel b", "ref_id": "FIGREF0"}, {"start": 825, "end": 832, "text": "(Fig. 1", "ref_id": "FIGREF0"}]}, {"section": "", "text": "The diagnosis of diaphragmatic paralysis is suggested clinically by the presence of abdominal wall retraction during inspiration and protrusion during expiration. Whereas unilateral diaphragmatic paralysis is usually well tolerated in the absence of underlying lung pathology, bilateral paralysis requires long-term ventilatory support. In contrast to bilateral diaphragmatic paralysis, a chest X-ray study is more specific for diagnosing a unilateral paralysis. Fluoroscopy confirms the diagnosis when paradoxical inspiratory elevation of the paralyzed hemidiaphragm is evident. ", "cite_spans": [], "ref_spans": []}], "bib_entries": {}, "ref_entries": {"FIGREF0": {"text": "Fig. 1 a Normal chest X-ray. b chest X-ray performed 2 h later revealing significant elevation of the right hemidiaphragm up to the right infrahilar region with ipsilateral cardiomediastinal shift. CT scan of the neck in the sagittal (c) and axial (d) plane showing an acute", "type": "figure"}}}
{"paper_id": "10700949", "_pdf_hash": "2f06864a5bd51562d50eddcaba2a877639583d38", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "10701360", "_pdf_hash": "291b049ffc5ee41644732a66adfa23e512e292da", "abstract": [{"section": "Abstract", "text": "Independent Component Analysis (ICA) is the problem of learning a square matrix A, given samples of X = AS, where S is a random vector with independent coordinates. Most existing algorithms are provably efficient only when each Si has finite and moderately valued fourth moment. However, there are practical applications where this assumption need not be true, such as speech and finance. Algorithms have been proposed for heavy-tailed ICA, but they are not practical, using random walks and the full power of the ellipsoid algorithm multiple times. The main contributions of this paper are:", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "(1) A practical algorithm for heavy-tailed ICA that we call HTICA. We provide theoretical guarantees and show that it outperforms other algorithms in some heavy-tailed regimes, both on real and synthetic data. Like the current state-of-the-art, the new algorithm is based on the centroid body (a first moment analogue of the covariance matrix). Unlike the state-of-the-art, our algorithm is practically efficient. To achieve this, we use explicit analytic representations of the centroid body, which bypasses the use of the ellipsoid method and random walks.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "(2) We study how heavy tails affect different ICA algorithms, including HTICA. Somewhat surprisingly, we show that some algorithms that use the covariance matrix or higher moments can successfully solve a range of ICA instances with infinite second moment. We study this theoretically and experimentally, with both synthetic and real-world heavy-tailed data.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Independent component analysis (ICA) is a computational and statistical technique with applications in areas ranging from signal processing to machine learning and more. Formally, if S is an n-dimensional random vector with independent coordinates and A \u2208 R n\u00d7n is invertible, then the ICA problem is to estimate A given access to i.i.d. samples of the mixed signals X = AS. We say that X is generated by an ICA model X = AS. The recovery of A (the mixing matrix ) is possible only up to scaling and permutation of the columns. Moreover, for the recovery to be possible, the distributions of the random variables S i must not be Gaussian (except possibly one of them). Since its inception in the eighties (see [CJ10] for historical remarks), ICA has been thoroughly studied and a vast literature exists (e.g. [HKO01, CJ10] ). The theory is well-developed and practical algorithms-e.g., FastICA [Hyv99] , JADE [CS93] -are now available along with implementations, e.g. [CAS + ]. However, to our knowledge, rigorous complexity analyses of these assume that the fourth moment of each component is finite: E(S 4 i ) < \u221e. If at least one of the independent components does not satisfy this assumption we will say that the input is in the heavy-tailed regime. Many ICA algorithms first preprocess the data to convert the given ICA model into another one where the mixing matrix A has orthogonal columns; this step is often called whitening. We will instead call it orthogonalization, as this describes more precisely the desired outcome. Traditional whitening is a second order method that may not make sense in the heavy-tailed regime. In this regime, it is not clear how the existing algorithms would perform, because they depend on empirical estimation of various statistics of the data such as the covariance matrix or the fourth cumulant tensor, which diverge in general for heavy-tailed data. For example, for the covariance matrix in the mean-0 case this is done by taking the empirical average (1/N )", "cite_spans": [{"start": 710, "end": 716, "text": "[CJ10]", "ref_id": "BIBREF9"}, {"start": 809, "end": 816, "text": "[HKO01,", "ref_id": "BIBREF14"}, {"start": 817, "end": 822, "text": "CJ10]", "ref_id": "BIBREF9"}, {"start": 894, "end": 901, "text": "[Hyv99]", "ref_id": "BIBREF15"}, {"start": 909, "end": 915, "text": "[CS93]", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "Introduction", "text": "where the {x(i)} are i.i.d. samples of X. ICA in the heavy-tailed regime is of considerable interest, directly (e.g., [Kid01b, Kid01a, SYM01, CB04, CB05, SAML + 05, WKZ09, JEK01, CS07, BC99]) and indirectly (e.g., [BG10, GTG09, WOH02] ) and has applications in speech and finance. We also mention an informal connection with robust statistics: Algorithms solving heavy-tailed ICA might work by focusing on samples in a small (but high probability) region to get reliable statistics about the data and avoid the instability of the tail. Thus, if the data has outliers, the outliers are less likely to affect such an algorithm.", "cite_spans": [{"start": 214, "end": 220, "text": "[BG10,", "ref_id": "BIBREF3"}, {"start": 221, "end": 227, "text": "GTG09,", "ref_id": "BIBREF13"}, {"start": 228, "end": 234, "text": "WOH02]", "ref_id": "BIBREF24"}], "ref_spans": []}, {"section": "Introduction", "text": "Recent theoretical work [AGNR15] proposed a polynomial time algorithm for ICA that works in the regime where each component S i has finite (1 + \u03b3)-moment for \u03b3 > 0. This algorithm follows the two phases of several ICA algorithms: (i) Orthogonalize the independent components. The purpose of this step is to apply an affine transformation to the samples from X so that the resulting samples correspond to an ICA model where the unknown matrix A has orthogonal columns. (ii) Learn the matrix with orthogonal columns. Each of these two phases required new techniques: (1) Orthogonalization via uniform distribution in the centroid body. The input is assumed to be samples from an ICA model X = AS where each S i is symmetrically distributed (w.l.o.g, see Sec. 2) and has at least (1 + \u03b3)-moments. The goal is to construct an orthogonalization matrix B so that BA has orthogonal columns. In [AGNR15] , the inverse of the square root of the covariance matrix of the uniform distribution in the centroid body is one such matrix. (2) Gaussian damping. The previous step allows one to assume that the mixing matrix A is orthogonal. The modified second step is: If X has density \u03c1 X (t) for t \u2208 R n , then the algorithm constructs another ICA model X R = AS R where X R has pdf proportional to \u03c1 X (t) exp(\u2212 t 2 2 /R 2 ), where R > 0 is a parameter chosen by the algorithm. This explains the term Gaussian damping. This achieves two goals: (1) All moments of X R and S R are finite. (2) The product structure of is retained. This follows from two facts: A has orthogonal columns, and the Gaussian has independent components in any orthonormal basis. Because of these properties, the model can be solved by traditional ICA algorithms.", "cite_spans": [{"start": 24, "end": 32, "text": "[AGNR15]", "ref_id": "BIBREF1"}, {"start": 887, "end": 895, "text": "[AGNR15]", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Introduction", "text": "The algorithm in [AGNR15] is theoretically efficient but impractical. Their orthogonalization uses the ellipsoid algorithm for linear programming, which is not practical. It is not clear how to replace their use of the ellipsoid algorithm by practical linear programming tools, as their algorithm only has oracle access to a sort of dual and not an explicit linear program. Moreover, their orthogonalization technique uses samples uniformly distributed in the centroid body, generated by a random walk. This is computationally efficient in theory but, to the best of our knowledge, only efficient in practice for moderately low dimension.", "cite_spans": [{"start": 17, "end": 25, "text": "[AGNR15]", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Introduction", "text": "Our contributions. Our contributions are experimental and theoretical. We provide a new and practical ICA algorithm, HTICA, building upon the previous theoretical work in [AGNR15] . HTICA works as follows: (1) Compute an orthogonalization matrix B. (2) Pre-multiply samples by B to get an orthogonal model. (3) Damp the data, run an existing ICA algorithm. For step (1), we propose two theoretically sound and practically efficient ways below, orthogonalization via centroid body scaling and orthogonalization via covariance. Our algorithm is simpler and more efficient, but needs a more technical justification than the method in [AGNR15] . We demonstrate the effectiveness of HTICA on both synthetic and real-world data.", "cite_spans": [{"start": 171, "end": 179, "text": "[AGNR15]", "ref_id": "BIBREF1"}, {"start": 631, "end": 639, "text": "[AGNR15]", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Introduction", "text": "Orthogonalization via centroid body scaling. We propose a more practical orthogonalization matrix than the one from [AGNR15] (orthogonalization via the uniform distribution in the centroid body, mentioned before). First, consider the centroid body of random vector X, denoted \u0393X (this is really a function of the distribution of X; formal definition in Sec. 2). For intuition, it is helpful to think of the centroid body as an ellipsoid whose axes are aligned with the independent components of X. The centroid body is in general not an ellipsoid, but it has certain symmetries aligned with the independent components. Let random vector Y be a scaling of X along every ray so that points at infinity are mapped to the boundary of \u0393X, the origin is mapped to itself and the scaling interpolates smoothly. One such scaling is obtained in the following way: It is helpful to consider how far a point is in its ray with respect to the boundary of \u0393X. This is given by the Minkoswki functional of \u0393X, denoted p : R n \u2192 R, which maps the boundary of \u0393X to 1 and interpolates linearly along every ray. We can then achieve the desired scaling by first mapping a given point to the boundary point on its ray (the mapping x \u2192 x/p(x)) and then using the function tanh, which maps [0, \u221e) to [0, 1] with tanh(0) = 0 and lim x\u2192\u221e tanh(x) = 1 to determine the final scale along the ray, namely, tanh p(x). More formally, our scaling is the following: Let Y be tanh p(X) p(X) X. We show in Sec. 4.1 that B = Cov(Y ) \u22121/2 is an orthogonalization matrix when Cov(Y ) is invertible. In order to make this practical, one needs a practical estimator of the Minkowski functional of \u0393X from a sample of X. In Sec. 4.1 and 5, we describe such an algorithm and provide a theoretical justification, including finite sample estimates. The proposed algorithm is much simpler and practical than the one described in [AGNR15] . In particular, it avoids the use of the ellipsoid algorithm by the use of a closed-form linear programming representation of the centroid body (Prop. 10, Lemma 11) and new approximation guarantees between the empirical (sample estimate) and true centroid body of a heavy-tailed distribution. In Sec. 4.1, we discuss our practical implementation and show results where orthogonalization via centroid body scaling produces results with smaller error. Orthogonalization via covariance. Previously, (e.g., in [CB04] ), the empirical covariance matrix was used for whitening in the heavy-tailed regime and, surprisingly, worked well in some situations. Unfortunately, the understanding of this was quite limited . We give a theoretical explanation for this phenomenon in a fairly general heavy-tailed regime: Covariance-based orthogonalization works well when each component S i has finite (1 + \u03b3)-moment, where \u03b3 > 0. We also study this algorithm in experimental settings. As we will see, while orthogonalization via covariance improves over previous algorithms, in general orthogonalization via centroid body has better performance because it has better numerical stability; but there are some situations where orthogonalization via covariance matrix is better.", "cite_spans": [{"start": 116, "end": 124, "text": "[AGNR15]", "ref_id": "BIBREF1"}, {"start": 1886, "end": 1894, "text": "[AGNR15]", "ref_id": "BIBREF1"}, {"start": 2402, "end": 2408, "text": "[CB04]", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "Introduction", "text": "Empirical Study. We perform experiments on both synthetic and real data to see the effect of heavy-tails on ICA.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "In the synthetic data setting, we generate samples from a fixed heavy-tailed distribution and study how well the algorithm can recover a random mixing matrix (Sec. 3).", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "To study the algorithm with real data, we use recordings of human speech provided by [Don09] . This involves a room with different arrangements of microphones, and six humans speaking independently. The speakers are recorded individually, so we can artificially mix them and have access to a ground truth. We study the statistical properties of the data, observing that it does indeed behave as if the underlying processes are heavy-tailed. The performance of our algorithm shows improvement over using FastICA on its own.", "cite_spans": [], "ref_spans": []}, {"section": "Preliminaries", "text": "Heavy-tailed distributions arise in a wide range of applications (e.g., [Nol15] ). They are characterized by the slow decay of their tails. Examples of heavy-tailed distributions include the Pareto and log-normal distributions.", "cite_spans": [{"start": 72, "end": 79, "text": "[Nol15]", "ref_id": "BIBREF21"}], "ref_spans": []}, {"section": "Preliminaries", "text": "We denote the pdf of random variable Z by \u03c1 Z . We will assume that our distributions are symmetric, that is \u03c1(x) = \u03c1(\u2212x) for x \u2208 R. As observed in [AGNR15] , this is without loss of generality for our purposes. This follows from the fact that if X = AS is an ICA model, and if we let X = AS be an i.i.d. copy of the same model, then X \u2212 X = A(S \u2212 S ) is an ICA model with components of S \u2212 S having symmetric pdfs. One further needs to check that if the components of S are away from Gaussians then the same holds for S \u2212 S ; see [AGNR15] . We formulate our algorithms for the symmetric case; the general case immediately reduces to the symmetric case.", "cite_spans": [{"start": 148, "end": 156, "text": "[AGNR15]", "ref_id": "BIBREF1"}, {"start": 531, "end": 539, "text": "[AGNR15]", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Preliminaries", "text": "For K \u2286 R n , K denotes the set of points that are at distance at most from K. The set K \u2212 is all points for which an -ball around them is still contained in K. The n-dimensional p ball is denoted as B n p . An important related family of distributions is that of stable distributions (e.g., [Nol15] ). In general, the density of a stable distribution has no closed form, but is fully defined by four real-valued parameters. Some stable distributions do admit a closed form, such as the Cauchy and Gaussian distributions. For us the most important parameter is \u03b1 \u2208 (0, 2], known as the stability parameter; we will think of the other three parameters as being fixed to constants.", "cite_spans": [{"start": 292, "end": 299, "text": "[Nol15]", "ref_id": "BIBREF21"}], "ref_spans": []}, {"section": "Preliminaries", "text": "We use the notation poly(\u00b7) to indicate a function which is asymptotically upper bounded by a polynomial expression of the given variables.", "cite_spans": [], "ref_spans": []}, {"section": "Preliminaries", "text": "If \u03b1 = 2, the distribution is Gaussian (the only non-heavy-tailed stable distribution), and if \u03b1 = 1, it is the Cauchy distribution.", "cite_spans": [], "ref_spans": []}, {"section": "Preliminaries", "text": "Definition 1 (Centroid body). Let X \u2208 R n be a random vector with finite first moment, that is, for all u \u2208 R n we have E(| u, X |) < \u221e. The centroid body of X is the compact convex set, denoted \u0393X, whose support function is h \u0393X (u) = E(| u, X |). For a probability measure P, we define \u0393P, the centroid body of P, as the centroid body of any random vector distributed according to P.", "cite_spans": [], "ref_spans": []}, {"section": "Preliminaries", "text": "Note that for the centroid body to be well-defined, the mean of the data must be finite. This excludes, for instance, the Cauchy distribution from consideration in the present work.", "cite_spans": [], "ref_spans": []}, {"section": "HTICA and experiments", "text": "In this section, we show experimentally that heavy-tailed data poses a significant challenge for current ICA algorithms, and compare them with HTICA in different settings. We observe some clear situations where heavy-tails seriously affect the standard ICA algorithms, and that these problems are frequently avoided by using the heavy-tailed ICA framework. In some cases, HTICA does not help much, but maintains the same performance of plain FastICA.", "cite_spans": [], "ref_spans": []}, {"section": "HTICA and experiments", "text": "To generate the synthetic data, we create a simple heavy-tailed density function f \u03b7 (x) proportional to (|x| + 1.5) \u2212\u03b7 , which is symmetric, and for \u03b7 > 1, f \u03b7 is the density of a distribution which has finite k < \u03b7 \u2212 1 moment. The signal S is generated with each S i independently distributed from f \u03b7i . The mixing matrix A \u2208 R n\u00d7n is generated with each coordinate i.i.d. N (0, 1), columns normalized to unit length. To compare the quality of recovery, the columns of the estimated mixing matrix,\u00c3 are permuted to align with the closest matching column of A, via the Hungarian algorithm. We use the Frobenius norm to measure the error, but all experiments were also performed using the well-known Amari index [ACY + 96]; the results have similar behavior and are not presented here.", "cite_spans": [], "ref_spans": []}, {"section": "Heavy-tailed ICA when A is orthogonal: Gaussian damping and experiments", "text": "Focusing on the third step above, where the mixing matrix already has orthogonal columns, ICA algorithms already suffer dramatically from the presence of heavy-tailed data. As proposed in [AGNR15] , Gaussian damping is a preprocessing technique that converts data from an ICA model X = AS, where A is unitary (columns are orthogonal with unit l 2 -norm) to data from a related ICA model X R = AS R , where R > 0 is a parameter to be chosen. The independent components of S R have finite moments of all orders and so the existing algorithms can estimate A.", "cite_spans": [{"start": 188, "end": 196, "text": "[AGNR15]", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Heavy-tailed ICA when A is orthogonal: Gaussian damping and experiments", "text": "Using samples of X, we construct the damped random variable X R , with pdf \u03c1 X R (x) \u221d \u03c1 X (x) exp(\u2212 x 2 /R 2 ). To normalize the right hand side, we can estimate", "cite_spans": [], "ref_spans": []}, {"section": "Heavy-tailed ICA when A is orthogonal: Gaussian damping and experiments", "text": "If x is a realization of X R , then s = A \u22121 x is a realization of the random variable S R and we have that S R has pdf \u03c1 S R (s) = \u03c1 X R (x). To generate samples from this distribution, we use rejection sampling on samples from \u03c1 X . When performing the damping, we binary search over R so that about 25% of the samples are rejected. For more details about the technical requirements for choosing R, see [AGNR15] . Figure 1 shows that, when A is already a perfectly orthogonal matrix, but where S may have heavy-tailed coordinates, several standard ICA algorithms perform better after damping the data. In fact, without damping, some do not appear to converge to a correct solution. We compare ICA with and without damping in this case: (1) FastICA using the fourth cumulant (\"FastICA -pow3\"), (2) FastICA using log cosh (\"FastICAtanh\"), (3) JADE, and (4) Second Order Joint Diagonalization as in, e.g., [Car89] . The Frobenius error of the recovered mixing matrix with the 'pow3' and 'tanh' contrast functions, on 10-dimensional data, averaged over ten trials. The mixing matrix A is random with unit norm columns, not orthogonal. In the left and middle figures, the distribution has \u03b7 = (6, . . . , 6, 2.1, 2.1) while in the right figure, \u03b7 = (2.1, . . . , 2.1) (see Section 3.2 for a discussion).", "cite_spans": [{"start": 405, "end": 413, "text": "[AGNR15]", "ref_id": "BIBREF1"}, {"start": 905, "end": 912, "text": "[Car89]", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Experiments on synthetic heavy-tailed data", "text": "We now present the results of HTICA using different orthogonalization techniques: (1) Orthogonalization via covariance (Section 4.2 (2) Orthogonalization via the centroid body (Section 4.1) (3) the ground truth, directly inverting the mixing matrix (oracle), and (4) No orthogonalization, and also no damping (for comparison with plain FastICA) (identity). The \"mixed\" regime in the left and middle of Figure 2 (where some signals are not heavy-tailed) demonstrates a very dramatic contrast between different orthogonalization methods, even when only two heavy-tailed signals are present.", "cite_spans": [], "ref_spans": [{"start": 402, "end": 410, "text": "Figure 2", "ref_id": "FIGREF1"}]}, {"section": "Experiments on synthetic heavy-tailed data", "text": "In the experiment with different methods of orthogonalization it was observed that when all exponents are the same or very close, orthogonalization via covariance performs better than orthogonalization via centroid and the true mixing matrix as seen in Figure 2 . A partial explanation is that, given the results in Figure 1 , we know that equal exponents favor FastICA without damping and orthogonalization (identity in Figure 2 ). The line showing the performance with no orthogonalization and no damping (\"identity\") behaves somewhat erratically, most likely due the presence of the heavy-tailed samples. Additionally, damping and the choice of parameter R is sensitive to scaling. A scaled-up distribution will be somewhat hurt because fewer samples The data was sampled with parameter \u03b7 = (6, 6, 6, 6, 6, 6, 6, 6, 2.1, 2.1).", "cite_spans": [], "ref_spans": [{"start": 253, "end": 261, "text": "Figure 2", "ref_id": "FIGREF1"}, {"start": 421, "end": 429, "text": "Figure 2", "ref_id": "FIGREF1"}]}, {"section": "Experiments on synthetic heavy-tailed data", "text": "will survive damping.", "cite_spans": [], "ref_spans": []}, {"section": "ICA on speech data", "text": "While the above study on synthetic data provides interesting situations where heavy-tails can cause problems for ICA, we provide some results here which use real-world data, specifically human speech. To study the performance of HTICA on voice data, we first examine whether the data is heavy-tailed. The motivation to use speech data comes from observations by the signal processing community (e.g. [Kid00] ) that speech data can be modeled by \u03b1-stable distributions. For an \u03b1-stable distribution, with \u03b1 \u2208 (0, 2), only the moments of order less than \u03b1 will be finite. We present here some results on a data set of human speech according to the standard cocktail party model, from [Don09] . The physical setup of the experiments (the human speakers and microphones) is shown in Figure 3 . To estimate whether the data is heavy-tailed, as in [Kid00], we estimate parameter \u03b1 of a best-fit \u03b1-stable distribution. This estimate is in Figure 4 for one of the data sets collected. We can see that the estimated \u03b1 is clearly in the heavy-tailed regime for some signals.", "cite_spans": [{"start": 400, "end": 407, "text": "[Kid00]", "ref_id": "BIBREF17"}], "ref_spans": [{"start": 779, "end": 787, "text": "Figure 3", "ref_id": "FIGREF2"}, {"start": 932, "end": 940, "text": "Figure 4", "ref_id": "FIGREF3"}]}, {"section": "ICA on speech data", "text": "Using data from [Don09] , we perform the same experiment as in Section 3.2: generate a random mixing matrix with unit length columns, mix the data, and try to recover the mixing matrix. Although the mixing is synthetic, the setting makes the resulting mixed signals same as real. Specifically, the experiment was conducted in a room with chairs, carpet, plasterboard walls, and windows on one side. There was natural noise including vents, computers, florescent lights, and traffic noise through the windows. Figure 4 demonstrates that HTICA (orthogonalizing with centroid body scaling, Section 4.1) applied to speech data yields some noticeable improvement in the recovery of the mixing matrix, primarily in that it is less susceptible to data that causes FastICA to have large error \"spikes.\" Moreover, in many cases, running only FastICA on the mixed data failed to even recover all of the speech signals, while HTICA succeeded. In these cases, we had to re-start FastICA until it recovered all the signals.", "cite_spans": [], "ref_spans": [{"start": 509, "end": 517, "text": "Figure 4", "ref_id": "FIGREF3"}]}, {"section": "ICA on speech data", "text": "4 New approach to orthogonalization and a new analysis of empirical covariance", "cite_spans": [], "ref_spans": []}, {"section": "ICA on speech data", "text": "As noted above, the technique in [AGNR15] , while being provably efficient and correct, suffers from practical implementation issues. Here we discuss two alternatives: orthogonalization by centroid body scaling and orthogonalization by using the empirical covariance. The former, orthogonalization via centroid body scaling, uses the samples already present in the algorithm rather than relying on a random walk to draw samples which are approximately uniform in the algorithm's approximation of the centroid body (as is done in [AGNR15] ). This removes the dependence on random walks and the ellipsoid algorithm; instead, we use samples that are distributed according to the original heavy-tailed distribution but non-linearly scaled to lie inside the centroid body. We prove in Lemma 3 that the covariance of this subset of samples is enough to orthogonalize the mixing matrix A. Secondly, we prove that one can, in fact, \"forget\" that the data is heavy tailed and orthogonalize by using the empirical covariance of the data, even though it diverges, and that this is enough to orthogonalize the mixing matrix A. However, as observed in experimental results, in general this has a downside compared to orthogonalization via centroid body in that it could cause numerical instability during the \"second\" phase of ICA as the data obtained is less well-conditioned. This is illustrated directly in the table in Figure 4 containing the singular value and condition number of the mixing matrix BA in the approximately orthogonal ICA model.", "cite_spans": [{"start": 33, "end": 41, "text": "[AGNR15]", "ref_id": "BIBREF1"}, {"start": 529, "end": 537, "text": "[AGNR15]", "ref_id": "BIBREF1"}], "ref_spans": [{"start": 1410, "end": 1418, "text": "Figure 4", "ref_id": "FIGREF3"}]}, {"section": "Orthogonalization via centroid body scaling", "text": "In [AGNR15] , another orthogonalization procedure, namely orthogonalization via the uniform distribution in the centroid body is theoretically proven to work. Their procedure does not suffer from the numerical instabilities and composes well with the second phase of ICA algorithms. An impractical aspect of that procedure is that it needs samples from the uniform distribution in the centroid body. We described orthogonalization via centroid body in Section 1, except for the estimation of p(x), the Minkowski functional of the centroid body. The complete procedure is stated in Subroutine 1.", "cite_spans": [{"start": 3, "end": 11, "text": "[AGNR15]", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Orthogonalization via centroid body scaling", "text": "We now explain how to estimate the Minkowski functional. The Minkowski functional was informally described in Section 1. The Minkowski functional of \u0393X is formally defined by p(x) := inf{t > 0 : x \u2208 t\u0393X}. Our estimation of p(x) is based on an explicit linear program (LP) (10) that gives the Minkowski functional of the centroid body of a finite sample of X exactly and then arguing that a sample estimate is close to the actual value for \u0393X. For clarity of exposition, we only analyze formally a special case of LP (10) that decides membership in the centroid body of a finite sample of X (LP (9)) and approximate membership in \u0393X. This analysis is in Section 5. Accuracy guarantees for the approximation of the Minkowski functional follow from this analysis.", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 2 ([AGNR15]", "text": "). Let U be a family of n-dimensional product distributions. Let\u016a be the closure of U under invertible linear transformations. Let Q(P) be an n-dimensional distribution defined as a function of P \u2208\u016a . Assume that U and Q satisfy:", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 2 ([AGNR15]", "text": "1. For all P \u2208 U , Q(P) is absolutely symmetric.", "cite_spans": [], "ref_spans": []}, {"section": "Q is linear equivariant (that is, for any invertible linear transformation T we have Q(T P) = T Q(P)).", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Subroutine 1 Orthogonalization via centroid body scaling", "text": "of ICA model X = AS so each S i is symmetric with (1 + \u03b3) moments. Output: Matrix B approximate orthogonalizer of A 1: for i = 1 : N do,", "cite_spans": [], "ref_spans": []}, {"section": "2:", "text": "Let \u03bb * be the optimal value of (10) with q = X (i) .", "cite_spans": [], "ref_spans": []}, {"section": "2:", "text": "3. For any P \u2208\u016a , Cov(Q(P)) is positive definite.", "cite_spans": [], "ref_spans": []}, {"section": "2:", "text": "Then for any symmetric ICA model X = AS with P S \u2208 U we have Cov(Q(P X )) \u22121/2 is an orthogonalizer of X.", "cite_spans": [], "ref_spans": []}, {"section": "2:", "text": "Lemma 3. Let X be a random vector drawn from an ICA model X = AS such that for all i we have", "cite_spans": [], "ref_spans": []}, {"section": "2:", "text": "Proof. We will be applying Lemma 2. Let U denote the set of absolutely symmetric product distributions P W over R n such that E|W i | = 1 for all i. For P V \u2208\u016a , let Q(P V ) be equal to the distribution obtained by scaling", "cite_spans": [], "ref_spans": []}, {"section": "2:", "text": "For all P W \u2208 U , W i is symmetric and E|W i | = 1 which implies that \u03b1W , that is, Q(P W ) is absolutely symmetric. Let P V \u2208\u016a . Then Q(P V ) is equal to the distribution of \u03b1V . For any invertible linear transformation T and measurable set M, we have", "cite_spans": [], "ref_spans": []}, {"section": "2:", "text": ". Thus Q is linear equivariant. Let P \u2208\u016a . Then there exist A and P W \u2208 U such that P = AP W . We get", "cite_spans": [], "ref_spans": []}, {"section": "2:", "text": ") is a diagonal matrix with elements E(\u03b1 2 W 2 i ) which are non-zero because we assume E|W i | = 1. This implies that Cov(Q(P)) is positive definite and thus by Lemma 2, Cov(Y ) \u22121/2 is an orthogonalizer of X.", "cite_spans": [], "ref_spans": []}, {"section": "Orthogonalization via covariance", "text": "Here we show the somewhat surprising fact that orthogonalization of heavy-tailed signals is sometimes possible by using the \"standard\" approach: inverting the empirical covariance matrix. The advantage here, is that it is computationally very simple, specifically that having heavy-tailed data incurs very little computational penalty on the process of orthogonalization alone. It's standard to use covariance matrix for whitening when the second moments of all independent components exist [HKO01] : Given samples from the ICA model X = AS, we compute the empirical covariance matrix\u03a3 which tends to the true covariance matrix as we take more samples and set B =\u03a3 \u22121/2 . Then one can show that BA is a rotation matrix, and thus by pre-multiplying the data by B we obtain an ICA model Y = BX = (BA)S, where the mixing matrix BA is a rotation matrix, and this model is then amenable to various algorithms. In the heavy-tailed regime where the second moment does not exist for some of the components, there is no true covariance matrix and the empirical covariance diverges as we take more samples. However, for any fixed number of samples one can still compute the empirical covariance matrix. In previous work (e.g., [CB04] ), the empirical covariance matrix was used for whitening in the heavy-tailed regime with good empirical performance; [CB04] also provided some theoretical analysis to explain this surprising performance. However, their work (both experimental and theoretical) was limited to some very special cases (e.g., only one of the components is heavy-tailed, or there are only two components both with stable distributions without finite second moment).", "cite_spans": [{"start": 491, "end": 498, "text": "[HKO01]", "ref_id": "BIBREF14"}, {"start": 1217, "end": 1223, "text": "[CB04]", "ref_id": "BIBREF7"}, {"start": 1342, "end": 1348, "text": "[CB04]", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "Orthogonalization via covariance", "text": "We will show that the above procedure (namely pre-multiplying the data by B :=\u03a3 \u22121/2 ) \"works\" under considerably more general conditions, namely if (1 + \u03b3)-moment exists for \u03b3 > 0 for each independent component S i . By \"works\" we mean that instead of whitening the data (that is BA is rotation matrix) it does something slightly weaker but still just as good for the purpose of applying ICA algorithms in the next phase. It orthogonalizes the data, that is now BA is close to a matrix whose columns are orthogonal. In other words, (BA)", "cite_spans": [], "ref_spans": []}, {"section": "Orthogonalization via covariance", "text": "T (BA) is close to a diagonal matrix (in a sense made precise in Theorem 5). Let X be a real-valued symmetric random variable such that E(|X| 1+\u03b3 ) \u2264 M for some M > 1 and 0 < \u03b3 < 1. The following lemma from [AGNR15] says that the empirical average of the absolute value of X converges to the expectation of |X|. The proof, which we omit, follows an argument similar to the proof of the Chebyshev's inequality. Let\u1ebc N [|X|] be the empirical average obtained from N independent samples X (1) , . . . , X (N ) , i.e., (", "cite_spans": [{"start": 207, "end": 215, "text": "[AGNR15]", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Orthogonalization via covariance", "text": "Lemma 4. Let \u2208 (0, 1). With the notation above, for N \u2265", "cite_spans": [], "ref_spans": []}, {"section": "Orthogonalization via covariance", "text": "Theorem 5 (Orthogonalization via covariance matrix). Let X be given by ICA model X = AS. Assume that there exist t, p, M > 0 and \u03b3 \u2208 (0, 1) such that for all i we have", "cite_spans": [], "ref_spans": []}, {"section": "Orthogonalization via covariance", "text": "} for all i with probability 1 \u2212 \u03b4 when N \u2265 poly(n, M, 1/p, 1/t, 1/ , 1/\u03b4).", "cite_spans": [], "ref_spans": []}, {"section": "Orthogonalization via covariance", "text": "Proof idea. For i = j we have E(S i S j ) = 0 (due to our symmetry assumption on S) and E(", "cite_spans": [], "ref_spans": []}, {"section": "Orthogonalization via covariance", "text": ". Now by our assumption that (1 + \u03b3)-moments exist, Lemma 4 is applicable and implies that empirical average\u1ebcS i tends to the true average ES i as we increase the number of samples. The true average is 0 because of our assumption of symmetry (alternatively, we could just assume that the X i and hence S i have been centered). The diagonal entries of L are bounded away from 0: This is clear when the second moment is finite, and follows easily by hypothesis (c) when it is not. Finally, one shows that if in L the diagonal entries highly dominate the off-diagonal entries, then the same is true of", "cite_spans": [], "ref_spans": []}, {"section": "Orthogonalization via covariance", "text": "and so by Lemma 4, for i = j,", "cite_spans": [], "ref_spans": []}, {"section": "Orthogonalization via covariance", "text": "when N \u2265 ( \u03b3 . Next, we aim to bound D 2 which can be done by writing", "cite_spans": [], "ref_spans": []}, {"section": "Orthogonalization via covariance", "text": "where", "cite_spans": [], "ref_spans": []}, {"section": "Orthogonalization via covariance", "text": ". Consider the random variable 1(s", "cite_spans": [], "ref_spans": []}, {"section": "Orthogonalization via covariance", "text": "\u2265 N p and use a Chernoff bound to see", "cite_spans": [], "ref_spans": []}, {"section": "Orthogonalization via covariance", "text": "and when k\u2208[N ] 1(s", "cite_spans": [], "ref_spans": []}, {"section": "Orthogonalization via covariance", "text": "Then with probability at least 1 \u2212 n exp(\u2212N p/8),", "cite_spans": [], "ref_spans": []}, {"section": "Orthogonalization via covariance", "text": "all entries of D \u22121 are at least t 2 p/2. Using this, if N \u2265 N 1 := (8/p) ln(3n/\u03b4) then D 2 \u2264 2/pt 2 with probability at least 1 \u2212 \u03b4/3.", "cite_spans": [], "ref_spans": []}, {"section": "Orthogonalization via covariance", "text": "Similarly, suppose that D 2 \u2264 2/pt 2 and choose 1 = min{", "cite_spans": [], "ref_spans": []}, {"section": "Orthogonalization via covariance", "text": "pt 2 } and", "cite_spans": [], "ref_spans": []}, {"section": "Orthogonalization via covariance", "text": "2 \u2264 t 4 p 2 /8 with probability at least 1 \u2212 \u03b4/3. Invoking (7), when N \u2265 max{N 1 , N 2 }, we have", "cite_spans": [], "ref_spans": []}, {"section": "Orthogonalization via covariance", "text": "with probability at least 1 \u2212 2\u03b4/3. Finally, we upper bound 1/d i for a fixed i by using Markov's inequality:", "cite_spans": [], "ref_spans": []}, {"section": "Orthogonalization via covariance", "text": "so that 1/d i \u2264 N 4 for all i with probability at least 1 \u2212 \u03b4/3 when N \u2265 N 3 := n/3\u03b4. Therefore, when", "cite_spans": [], "ref_spans": []}, {"section": "Orthogonalization via covariance", "text": "for all i with overall probability at least 1 \u2212 \u03b4.", "cite_spans": [], "ref_spans": []}, {"section": "Orthogonalization via covariance", "text": "We used the following technical result.", "cite_spans": [], "ref_spans": []}, {"section": "Orthogonalization via covariance", "text": "Lemma 6. Let \u00b7 be a matrix norm such that AB \u2264 A B . Let matrices C, E \u2208 R n\u00d7n be such that C \u22121 E 2 \u2264 1, and letC = C + E. Then", "cite_spans": [], "ref_spans": []}, {"section": "Orthogonalization via covariance", "text": "This implies that if", "cite_spans": [], "ref_spans": []}, {"section": "Orthogonalization via covariance", "text": "2 ), then", "cite_spans": [], "ref_spans": []}, {"section": "Orthogonalization via covariance", "text": "In Theorem 5, the diagonal entries are lower bounded, which avoids some degeneracy, but they could still grow quite large because of the heavy tails. This is a real drawback of orthogonalization via covariance. HTICA, using the more sophisticated orthogonalization via centroid body scaling does not have this problem. We can see this in the right table of Figure 4 , where the condition number of \"centroid\" is much smaller than the condition number of \"covariance.\"", "cite_spans": [], "ref_spans": [{"start": 357, "end": 365, "text": "Figure 4", "ref_id": "FIGREF3"}]}, {"section": "Orthogonalization via covariance", "text": "5 Membership oracle for the centroid body, without polarity", "cite_spans": [], "ref_spans": []}, {"section": "Orthogonalization via covariance", "text": "We will see now how to implement an -weak membership oracle for \u0393X directly, without using polarity. We start with an informal description of the algorithm and its correctness.", "cite_spans": [], "ref_spans": []}, {"section": "Orthogonalization via covariance", "text": "The algorithm implementing the oracle (Subroutine 2) is the following: Let q \u2208 R n be a query point. Let X 1 , . . . , X N be a sample of random vector X. Given the sample, let Y be uniformly distributed in {X 1 , . . . , X N }. Output YES if q \u2208 \u0393Y , else output NO.", "cite_spans": [], "ref_spans": []}, {"section": "Orthogonalization via covariance", "text": "Idea of the correctness of the algorithm: If q is not in (\u0393X) , then there is a hyperplane separating q from (\u0393X) . Let {x : a T x = b} be the hyperplane, satisfying a = 1, a T q > b and a T x \u2264 b for every x \u2208 (\u0393X) . Thus, we have h (\u0393X) (a) \u2264 b and h \u0393X (a) \u2264 b \u2212 . We have", "cite_spans": [], "ref_spans": []}, {"section": "Orthogonalization via covariance", "text": "when N is large enough with probability at least 1 \u2212 \u03b4 over the sample X 1 , . . . , X N . In particular, h \u0393Y (a) \u2264 b, which implies q / \u2208 \u0393Y and the algorithm outputs NO, with probability at least 1 \u2212 \u03b4.", "cite_spans": [], "ref_spans": []}, {"section": "Orthogonalization via covariance", "text": "If q is in (\u0393X) \u2212 , let y = q + q \u2208 \u0393X. We will prove the following claim: Informal claim (Lemma 13): For p \u2208 \u0393X, for large enough N and with probability at least 1 \u2212 \u03b4 there is z \u2208 \u0393Y so that z \u2212 p \u2264 /10.", "cite_spans": [], "ref_spans": []}, {"section": "Orthogonalization via covariance", "text": "This claim applied to p = y to get z, convexity of \u0393Y and the fact that \u0393Y contains B \u03c3 min (A)B n 2 (Lemma 9) imply that q \u2208 conv(B \u222a {z}) \u2286 \u0393Y and the algorithm outputs YES. We will prove the claim now. Let p \u2208 \u0393X. By the dual characterization of the centroid body (Proposition 10), there exists a function \u03bb :", "cite_spans": [], "ref_spans": []}, {"section": "Orthogonalization via covariance", "text": "By Lemma 4 and a union bound over every coordinate we get P( p \u2212 z \u2265 ) \u2264 \u03b4 for N large enough.", "cite_spans": [], "ref_spans": []}, {"section": "Formal Argument", "text": "Lemma 7 ([AGNR15]). Let S = (S 1 , . . . , S n ) \u2208 R n be an absolutely symmetrically distributed random vector such that E(", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 8 ([AGNR15]", "text": "). Let X be a random vector on R n . Let A : R n \u2192 R n be an invertible linear transformation. Then \u0393(AX) = A(\u0393X).", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 8 ([AGNR15]", "text": "Lemma 9. Let S = (S 1 , . . . , S n ) \u2208 R n be an absolutely symmetrically distributed random vector such that", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 8 ([AGNR15]", "text": "Proof. From Lemma 7 we know \u00b1e i \u2208 \u0393S. It is enough to apply Lemma 13 to \u00b1e i with = / \u221a n and \u03b4 = \u03b4 /(2n). This gives, for any", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 8 ([AGNR15]", "text": "Proposition 10 (Dual characterization of centroid body). Let X be a n-dimensional random vector with finite first moment, that is, for all u \u2208 R n we have E(| u, X |) < \u221e. Then", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 8 ([AGNR15]", "text": "Proof. Let K denote the rhs of the conclusion.We will show that K is a non-empty, closed convex set and show that h K = h \u0393X , which implies (8).", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 8 ([AGNR15]", "text": "By definition, K is a non-empty bounded convex set. To see that it is closed, let (y k ) k be a sequence in K such that y k \u2192 y \u2208 R n . Let \u03bb k be the function associated to y k \u2208 K according to the definition of K. Let P X be the distribution of X. We have \u03bb k L \u221e (P X ) \u2264 1 and, passing to a subsequence k j ,", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 8 ([AGNR15]", "text": "Thus, we have y = lim j y kj = lim j E((\u03bb kj (X)X) = E(\u03bb(X)X) and K is closed.", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 8 ([AGNR15]", "text": "To conclude, we compute h K and see that it is the same as the definition of h \u0393X . In the following equations \u03bb ranges over functions such that \u03bb : R n \u2192 R is Borel-measurable and \u22121 \u2264 \u03bb \u2264 1.", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 8 ([AGNR15]", "text": "and setting \u03bb * (x) = sgn x, \u03b8 ,", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 8 ([AGNR15]", "text": "Lemma 11 (LP). Let X be a random vector uniformly distributed in {x", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 8 ([AGNR15]", "text": "2. Point q \u2208 \u0393X iff there is a solution \u03bb \u2208 R N to the following linear feasibility problem:", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 8 ([AGNR15]", "text": "3. Let \u03bb * be the optimal value of (always feasible) linear program", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 8 ([AGNR15]", "text": "with \u03bb * = \u221e if the linear program is unbounded. Then the Minkowski functional of \u0393X at q is 1/\u03bb * .", "cite_spans": [], "ref_spans": []}, {"section": "Proof.", "text": "1. This is proven in [McM71] . It is also a special case of Proposition 10. We include an argument here for completeness.", "cite_spans": [{"start": 21, "end": 28, "text": "[McM71]", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "Proof.", "text": ". We compute h K to see it is the same as h \u0393X in the definition of \u0393X (Definition 1). As K and \u0393X are non-empty compact convex sets, this implies K = \u0393X. We have", "cite_spans": [], "ref_spans": []}, {"section": "Proof.", "text": "2. This follows immediately from part 1.", "cite_spans": [], "ref_spans": []}, {"section": "Proof.", "text": "3. This follows from part 1 and the definition of Minkowski functional.", "cite_spans": [], "ref_spans": []}, {"section": "Subroutine 2 Weak Membership Oracle for \u0393X", "text": "Input: Query point q \u2208 R n , samples from symmetric ICA model X = AS, bounds s M \u2265 \u03c3 max (A), s m \u2264 \u03c3 min (A), closeness parameter , failure probability \u03b4. Output: ( , \u03b4)-weak membership decision for q \u2208 \u0393X.", "cite_spans": [], "ref_spans": []}, {"section": "Subroutine 2 Weak Membership Oracle for \u0393X", "text": "1:", "cite_spans": [], "ref_spans": []}, {"section": "Subroutine 2 Weak Membership Oracle for \u0393X", "text": "Check the feasibility of linear program (9). If feasible, output YES, otherwise output NO.", "cite_spans": [], "ref_spans": []}, {"section": "Subroutine 2 Weak Membership Oracle for \u0393X", "text": "Proposition 12 (Correctness of Subroutine 2). Let X = AS be given by an ICA model such that for all i we have E(|S i | 1+\u03b3 ) \u2264 M < \u221e, S i is symmetrically distributed and normalized so that E|S i | = 1. Then, given a query point q \u2208 R n , > 0, \u03b4 > 0, s M \u2265 \u03c3 max (A), and s m \u2264 \u03c3 min (A), Subroutine 2 is an -weak membership oracle for q and \u0393X with probability 1 \u2212 \u03b4 using time and sample complexity poly(n, M, 1/s m , s M , 1/ , 1/\u03b4).", "cite_spans": [], "ref_spans": []}, {"section": "Subroutine 2 Weak Membership Oracle for \u0393X", "text": "Proof. Let Y be uniformly random in (", "cite_spans": [], "ref_spans": []}, {"section": "Subroutine 2 Weak Membership Oracle for \u0393X", "text": ". There are two cases corresponding to the guarantees of the oracle:", "cite_spans": [], "ref_spans": []}, {"section": "Subroutine 2 Weak Membership Oracle for \u0393X", "text": "\u2022 Case q / \u2208 (\u0393X) . Then there is a hyperplane separating q from (\u0393X) . Let {x \u2208 R n : a T x = b} be the separating hyperplane, parameterized so that a \u2208 R n , b \u2208 R, a = 1, a T q > b and a T x \u2264 b for every x \u2208 (\u0393X) . ", "cite_spans": [], "ref_spans": []}, {"section": "Subroutine 2 Weak Membership Oracle for \u0393X", "text": "we have", "cite_spans": [], "ref_spans": []}, {"section": "Subroutine 2 Weak Membership Oracle for \u0393X", "text": "In particular, with probability at least 1 \u2212 \u03b4 we have h \u0393Y (a) \u2264 b, which implies q / \u2208 \u0393Y and, by Lemma 11, Subroutine 2 outputs NO.", "cite_spans": [], "ref_spans": []}, {"section": "Subroutine 2 Weak Membership Oracle for \u0393X", "text": "\u2022 Case q \u2208 (\u0393X) \u2212 . Let y = q + q = q(1 + q ). Let \u03b1 = 1 + q . Then y \u2208 \u0393X. Invoke Lemma 13 for i.i.d. sample (x (i) ) N i=1 of X with p = y and equal to some 1 > 0 to be fixed later to conclude y \u2208 (\u0393Y ) 1 . That is, there exist z \u2208 \u0393Y such that z \u2212 y \u2264 1 .", "cite_spans": [], "ref_spans": []}, {"section": "Subroutine 2 Weak Membership Oracle for \u0393X", "text": "Let w = z/\u03b1. Given (12) and the relationships y = \u03b1q and z = \u03b1w, we have w \u2212 q \u2264 z \u2212 y \u2264 1 . To conclude, remember that q \u2208 (\u0393X) \u2212 . Therefore q + \u2264 \u221a n\u03c3 max (A) (from Lemma 7 and equivariance of the centroid body, Lemma 8). This implies", "cite_spans": [], "ref_spans": []}, {"section": "Subroutine 2 Weak Membership Oracle for \u0393X", "text": "The claim follows.", "cite_spans": [], "ref_spans": []}, {"section": "Subroutine 2 Weak Membership Oracle for \u0393X", "text": "Lemma 13. Let X be a n-dimensional random vector such that for all coordinates i we have E(|X i | 1+\u03b3 ) \u2264 M < \u221e. Let p \u2208 \u0393X. Let (X Proof. By Proposition 10, there exists a measurable function \u03bb : R n \u2192 R, \u22121 \u2264 \u03bb \u2264 1 such that p = E(X\u03bb(X)). Let", "cite_spans": [], "ref_spans": []}, {"section": "Subroutine 2 Weak Membership Oracle for \u0393X", "text": "By Proposition 10, z \u2208 \u0393Y . We have E X (i) (X (i) \u03bb(X (i) )) = p and, for every coordinate j,", "cite_spans": [], "ref_spans": []}, {"section": "Subroutine 2 Weak Membership Oracle for \u0393X", "text": "By Lemma 4 and for any fixed coordinate j we have, over the choice of (X (i) )", "cite_spans": [], "ref_spans": []}, {"section": "Subroutine 2 Weak Membership Oracle for \u0393X", "text": "whenever N \u2265 (8M \u221a n/ ) 1 2 + 1 \u03b3 . A union bound over n choices of j gives: ", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "A new learning algorithm for blind signal separation", "authors": [{"first": "Andrzej", "middle": [], "last": "Amari", "suffix": ""}, {"first": "", "middle": [], "last": "Cichocki", "suffix": ""}, {"first": "H", "middle": [], "last": "Howard", "suffix": ""}, {"first": "", "middle": [], "last": "Yang", "suffix": ""}], "year": 1996, "venue": "Advances in neural information processing systems", "link": null}, "BIBREF1": {"title": "Heavy-tailed independent component analysis", "authors": [{"first": "Joseph", "middle": [], "last": "Anderson", "suffix": ""}, {"first": "Navin", "middle": [], "last": "Goyal", "suffix": ""}, {"first": "Anupama", "middle": [], "last": "Nandi", "suffix": ""}, {"first": "Luis", "middle": [], "last": "Rademacher", "suffix": ""}], "year": 2015, "venue": "56th Annual IEEE Symposium on Foundations of Computer Science (FOCS 2015)", "link": "13228472"}, "BIBREF2": {"title": "Approximate likelihood for noisy mixtures", "authors": [{"first": "Olivier", "middle": [], "last": "Bermond", "suffix": ""}, {"first": "Jean-Fran\u00e7ois", "middle": [], "last": "Cardoso", "suffix": ""}], "year": 1999, "venue": "Proc. ICA", "link": "16897849"}, "BIBREF3": {"title": "Inference with multivariate heavy-tails in linear models", "authors": [{"first": "Danny", "middle": [], "last": "Bickson", "suffix": ""}, {"first": "Carlos", "middle": [], "last": "Guestrin", "suffix": ""}], "year": 2010, "venue": "Advances in Neural Information Processing Systems", "link": "13361482"}, "BIBREF4": {"title": "Functional analysis, Sobolev spaces and partial differential equations", "authors": [{"first": "Haim", "middle": [], "last": "Brezis", "suffix": ""}], "year": 2011, "venue": "", "link": "117299718"}, "BIBREF5": {"title": "Source separation using higher order moments", "authors": [{"first": "J", "middle": ["F"], "last": "Cardoso", "suffix": ""}], "year": 1989, "venue": "International Conference on Acoustics, Speech, and Signal Processing", "link": "17064088"}, "BIBREF7": {"title": "Robustness of prewhitening against heavy-tailed sources", "authors": [{"first": "Aiyou", "middle": [], "last": "Chen", "suffix": ""}, {"first": "Peter", "middle": ["J"], "last": "Bickel", "suffix": ""}], "year": 2004, "venue": "Independent Component Analysis and Blind Signal Separation, Fifth International Conference", "link": "36169037"}, "BIBREF8": {"title": "Consistent independent component analysis and prewhitening. Signal Processing", "authors": [{"first": "Aiyou", "middle": [], "last": "Chen", "suffix": ""}, {"first": "J", "middle": [], "last": "Peter", "suffix": ""}, {"first": "", "middle": [], "last": "Bickel", "suffix": ""}], "year": 2005, "venue": "IEEE Transactions on", "link": null}, "BIBREF9": {"title": "Handbook of Blind Source Separation", "authors": [], "year": 2010, "venue": "", "link": null}, "BIBREF10": {"title": "Blind beamforming for non-gaussian signals", "authors": [{"first": "J.-F", "middle": [], "last": "Cardoso", "suffix": ""}, {"first": "A", "middle": [], "last": "Souloumiac", "suffix": ""}], "year": 1993, "venue": "Radar and Signal Processing", "link": "18332005"}, "BIBREF11": {"title": "On portfolio selection under extreme risk measure: The heavy-tailed ica model", "authors": [{"first": "Stephan", "middle": [], "last": "Clemencon", "suffix": ""}, {"first": "Skander", "middle": [], "last": "Slim", "suffix": ""}], "year": 2007, "venue": "International Journal of Theoretical and Applied Finance", "link": "154161287"}, "BIBREF13": {"title": "The infinite factorial hidden markov model", "authors": [{"first": "V", "middle": [], "last": "Jurgen", "suffix": ""}, {"first": "Yee", "middle": ["W"], "last": "Gael", "suffix": ""}, {"first": "Zoubin", "middle": [], "last": "Teh", "suffix": ""}, {"first": "", "middle": [], "last": "Ghahramani", "suffix": ""}], "year": 2009, "venue": "Advances in Neural Information Processing Systems", "link": "7829560"}, "BIBREF14": {"title": "Independent Component Analysis", "authors": [{"first": "Aapo", "middle": [], "last": "Hyvarinen", "suffix": ""}, {"first": "Juha", "middle": [], "last": "Karhunen", "suffix": ""}, {"first": "Erkki", "middle": [], "last": "Oja", "suffix": ""}], "year": 2001, "venue": "", "link": "198120196"}, "BIBREF15": {"title": "Fast and robust fixed-point algorithms for independent component analysis", "authors": [{"first": "A", "middle": [], "last": "Hyvarinen", "suffix": ""}], "year": 1999, "venue": "IEEE Transactions on", "link": "16135158"}, "BIBREF16": {"title": "Novel characteristic function based criteria for ica", "authors": [{"first": "A", "middle": [], "last": "Kankainen", "suffix": ""}, {"first": "J", "middle": [], "last": "Eriksson", "suffix": ""}, {"first": "V", "middle": [], "last": "Koivunen", "suffix": ""}], "year": 2001, "venue": "Proceedings ICA", "link": "12008403"}, "BIBREF17": {"title": "Alpha-stable distributions in signal processing of audio signals", "authors": [{"first": "Preben", "middle": [], "last": "Kidmose", "suffix": ""}], "year": 2000, "venue": "41st Conference on Simulation and Modelling", "link": "17366616"}, "BIBREF18": {"title": "Blind Separation of Heavy Tail Signals", "authors": [{"first": "Preben", "middle": [], "last": "Kidmose", "suffix": ""}], "year": 2001, "venue": "", "link": "125866098"}, "BIBREF19": {"title": "Independent component analysis using the spectral measure for alpha-stable distributions", "authors": [{"first": "Preben", "middle": [], "last": "Kidmose", "suffix": ""}], "year": 2001, "venue": "Proceedings of IEEE-EURASIP Workshop on Nonlinear Signal and Image Processing", "link": null}, "BIBREF20": {"title": "On zonotopes", "authors": [{"first": "P", "middle": [], "last": "Mcmullen", "suffix": ""}], "year": 1971, "venue": "Trans. Amer. Math. Soc", "link": null}, "BIBREF21": {"title": "Blind source separation of noisy mixtures using a semi-parametric approach with application to heavy-tailed signals", "authors": [{"first": "J", "middle": ["P"], "last": "Nolan", "suffix": ""}, {"first": "; M", "middle": [], "last": "Sahmoudi", "suffix": ""}, {"first": "K", "middle": [], "last": "Abed-Meraim", "suffix": ""}, {"first": "M", "middle": [], "last": "Lavielle", "suffix": ""}, {"first": "E", "middle": [], "last": "Kuhn", "suffix": ""}, {"first": "Ph", "middle": [], "last": "Ciblat", "suffix": ""}], "year": 2005, "venue": "Proc. of EUSIPCO 2005", "link": "2489542"}, "BIBREF22": {"title": "Super-efficiency in blind signal separation of symmetric heavy-tailed sources", "authors": [{"first": "Yoav", "middle": [], "last": "Shereshevski", "suffix": ""}, {"first": "Arie", "middle": [], "last": "Yeredor", "suffix": ""}, {"first": "Hagit", "middle": [], "last": "Messer", "suffix": ""}], "year": 2001, "venue": "Proceedings of the 11th IEEE Signal Processing Workshop on", "link": "38050911"}, "BIBREF23": {"title": "Ica by maximizing non-stability", "authors": [{"first": "Baijie", "middle": [], "last": "Wang", "suffix": ""}, {"first": "E", "middle": [], "last": "Ercan", "suffix": ""}, {"first": "Junying", "middle": [], "last": "Kuruoglu", "suffix": ""}, {"first": "", "middle": [], "last": "Zhang", "suffix": ""}], "year": 2009, "venue": "Independent Component Analysis and Signal Separation", "link": "206738664"}, "BIBREF24": {"title": "Learning sparse topographic representations with products of student-t distributions", "authors": [{"first": "Max", "middle": [], "last": "Welling", "suffix": ""}, {"first": "Simon", "middle": [], "last": "Osindero", "suffix": ""}, {"first": "Geoffrey", "middle": ["E"], "last": "Hinton", "suffix": ""}], "year": 2002, "venue": "Advances in neural information processing systems", "link": "7406434"}}, "ref_entries": {"FIGREF1": {"text": "Figure 2: The Frobenius error of the recovered mixing matrix with the 'pow3' and 'tanh' contrast functions, on 10-dimensional data, averaged over ten trials. The mixing matrix A is random with unit norm columns, not orthogonal. In the left and middle figures, the distribution has \u03b7 = (6, . . . , 6, 2.1, 2.1) while in the right figure, \u03b7 = (2.1, . . . , 2.1) (see Section 3.2 for a discussion).", "type": "figure"}, "FIGREF2": {"text": "Figure 3: Microphone (blue circles) and human speaker (red \"x\") layouts for the \"ceilreg\" and \"perimeterreg\" voice separation data sets.", "type": "figure"}, "FIGREF3": {"text": "Figure 4: (Left): Error of estimated mixing matrix on the \"perimeterreg\" data, averaged over ten trials. HTICA is more robust than FastICA. (Middle): Stability parameter \u03b1 estimates of each component in the \"perimeterreg\" data. Values below 2 are in the heavy-tailed regime. (Right): Smallest singular value and condition number of the orthogonalization matrix BA computed via the centroid body and the covariance. The data was sampled with parameter \u03b7 = (6, 6, 6, 6, 6, 6, 6, 6, 2.1, 2.1).", "type": "figure"}, "FIGREF5": {"text": "In this case h (\u0393X) (a) \u2264 b and h \u0393X (a) \u2264 b \u2212 . At the same time, h \u0393Y (a) = E(|a T Y |)We want to apply Lemma 4 to a T X to get that h \u0393Y (a) = (1/N ) N i=1 |a T x (i) | is within of h \u0393X (a) = E(|a T X|). For this we need a bound on the (1 + \u03b3)-moment of a T X. We use the bound from [AGNR15, Equation (10)]: E(|a T X| 1+\u03b3 )", "type": "figure"}, "FIGREF6": {"text": "in \u0393Y . The choice 1 = r \u2265 and (13) imply q \u2208 \u0393Y and Subroutine 2 outputs YES whenever", "type": "figure"}, "FIGREF7": {"text": "an i.i.d. sample of X. Let Y be uniformly random in (Xthen, with probability at least 1 \u2212 \u03b4, p \u2208 (\u0393Y ) .", "type": "figure"}, "FIGREF8": {"text": ". The claim follows.", "type": "figure"}, "TABREF0": {"text": "Damped vs. Raw Performance -10 DimensionsLeft, middle): The error of ICA with and without damping (solid lines and dashed lines, resp.), with unitary mixing matrix. The error is averaged over ten trials, in 3 and 10 dimensions where \u03b7 = (6, 6, 2.1) and \u03b7 = (6, . . . , 6, 2.1, 2.1), resp. (Right): The difference between the errors of FastICA with and without damping in 2 dimensions, averaged over 40 trials. For a single cell, the parameters are given by the coordinates, \u03b7 = (i, j). Red indicates that FastICA without damping does better than FastICA with damping, white indicates that the error difference is 0 and the blue indicates that FastICA with damping performs better than without damping. Black indicates that FastICA without damping failed (did not return two independent components).", "type": "table"}}}
{"paper_id": "10701397", "_pdf_hash": "e76e55dca7a4c115d44f6b20cc8439ad9f500e14", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "10701615", "_pdf_hash": "20ed71d709b07d58e93c0acb9b5a95ae50939038", "abstract": [{"section": "Abstract", "text": "In an ideal world, inclusive products and services would be the standard and not the exception. This paper presents a systematic approach to an overlap between Visual Communication Design, Printed Colour and Inclusive Design, for older people, with the aim to develop of a set of research-based ageing and ergonomics-centred communication design guidelines and recommendations for printed material (analogical displays). The approach included an initial extensive literature review in the area of colour, older people and ergonomics issues and vision common diseases, communication design. The second phase was the implementation of an experiment to measure the different colour experiences of the participants in two sample groups (one in UK and another one in Portugal), using printed material, to find out the colours one should use in analogical communication material, being aware of the colour contrast importance (foreground versus background) and the difficulties experienced by older people to read and understand lettering, signs. As main contribution of this research project, we developed a set of guidelines and recommendations based on the reviewed literature and the sample groups' findings, trying to demonstrate the importance of these guidelines when conceiving a new communicational design project in a way this project will achieve vision comfort and understandability, especially for older people, in an inclusive design perspective.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "This paper summarises the content and output of a 18 months scoping research study concerned with colour and visual communication in analogical support for older people. The output from this project is the initial stage of colour guidance and recommendations for older people, community care professionals and designers. Throughout the project the research team consulted an advisory panel whose members represented a wide range of disciplines, among which colourists, communicational designers and older people associations.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "To work in Visual Communication one needs to have knowledge of different techniques and how to manipulate them. However, there is a gap in knowledge of Colour and Inclusive Design. Most of the studies that have been implemented until now focus on the use of colour and text in digital displays, not in analogical supports.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "The research object of this study is the overlap between Visual Communication Design, Printed Colour and Inclusivity, for older people.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "The main objective is to introduce colour as a variable of great importance in Visual Communication, in an Inclusive Design perspective, having as a target older people.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "Other objectives of this research project are: x to measure the different colour experiences of the participants (having two sample groups: x one in UK and another one in Portugal); x to find out the colours one should use in printed communication material, being aware of the colour contrast importance (object versus background) and the difficulties experienced by older people, of understanding the communicated object (lettering, signs), using printed material; x to identify important key points and draw recommendations for designers' policy when using colour, in a way of improving visual communica-tion design quality, infusing an inclusive design perspective. An inevitable outcome of the ageing population is an increase in the difficulty of reading and understanding visual printed messages (analogical support) due to the lack of information about colour, mainly for communicational designers, in an inclusive design perspective. Until now, little research has been carried out on how colours in form and background relationship affect older people. If text does not have sufficient contrast compared to its background, people will have problems.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "This study is aimed at addressing this lack of evidence-based data. As well as a literature search, the project has involved two sample groups of older people between 65 and 87, in Marple (Great Manchester, UK) and in Cascais (Lisbon District, Portugal).", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "The purpose of the sample groups was to test and validate information gathered during the literature review and to generate other findings for future development and well as to identify research needs.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "A range of results has been obtained from this study and these results are summarised in this work.", "cite_spans": [], "ref_spans": []}, {"section": "Context", "text": "In an ideal world, inclusive products and services would be standard and not the exception.", "cite_spans": [], "ref_spans": []}, {"section": "Context", "text": "Collaboration between users, designers and producers from the very beginning of the project until its completion, would be the key for success. However, in the real world it isn't like this. Designers complain about the lack of tools and information necessary to deliver inclusive products and services for their clients. What is available, they say, is in a language that they can't understand and in shapes difficult to implement. The producers point out constrictions of time and cost, besides the lack of appropriate information at enterprise management level for inclusive design. They can be aware of the demographic reality in what concerns older people all around the world, about the pension crises and the potential market, but they have difficulties in visualising precisely in what way inclusivity can be applied to their actual or future range of products or services, or even its relevance for the product innovation. Meanwhile, \"critical\" users who could supply the creative stimulus that designers need are still out of the process.", "cite_spans": [], "ref_spans": []}, {"section": "Context", "text": "To work in the Graphic Design and Visual Communication area one needs to have knowledge of different techniques and how to manipulate them. Despite the knowledge in this professional circle, there is a gap in knowledge of Colour and Inclusive Design. The interpretation of visual information, as well as semiotics is closer to meaning interpretation, is consequently highly subjective and projective. Gibson [8] affirms that visual perception is \"richer and more open to personal interpretation\".", "cite_spans": [{"start": 408, "end": 411, "text": "[8]", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "Context", "text": "The visual and non-verbal systems operate relatively without a \"tutor\" in our society, at least in comparison with language. Visual communication is a primary system, which is located at the same expression level as is verbal language. In terms of human development, the visual system of signs occurs earlier than language itself. In terms of complexity, one can find visual interpretation more complex than verbal interpretation, because of the absence of a conventional sign system and the formalization of a training protocol. Visual communication could also be considered primary because the observer has to learn how to control better, and independently, the visual interpretative function.", "cite_spans": [], "ref_spans": []}, {"section": "Context", "text": "Finally, visual communication is neither derivative nor peripheral to verbal language, and consequently the designation of visual communication as secondary, tertiary or of a \"superstructure\" built in verbal language is not right. In Paivio notion [23] [24] , a more appropriated model would be built of a dual codification, saying that visual and verbal information are codified and uncodified by perceptive and cognitive separated systems. A system is considered visual/pictorial and manipulates simultaneously the elements of imagination; the other one is linguistic and propositional and operates in sequence.", "cite_spans": [{"start": 248, "end": 252, "text": "[23]", "ref_id": "BIBREF22"}, {"start": 253, "end": 257, "text": "[24]", "ref_id": "BIBREF23"}], "ref_spans": []}, {"section": "Context", "text": "Messaris [20] explains that the two systems are structural and functionally distinct. Although being independent, the two systems are also interdependent in a way that a certain visual concept may be converted in a verbal etiquette and vice versa. A new interpretation to explain the interaction between the two systems is the metaphor of processing interactively in parallel. Redefining the notion of a \"primary\" system, and including visual communication as well as the verbal one, we can achieve a more complete analysis of the complexity of communication.", "cite_spans": [{"start": 9, "end": 13, "text": "[20]", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "Detailed description", "text": "The Project overlaps different areas and knowledge, among which: x Colour contrasts and colour measurement; x Light sources (natural and artificial);", "cite_spans": [], "ref_spans": []}, {"section": "Detailed description", "text": "x The evaluation of the proprieties of the light sources and the influence of the surfaces; x The evaluation of the colour aspects inside visual communication area; x Legibility and the obstacles to reading; x Older people and visual limitations.", "cite_spans": [], "ref_spans": []}, {"section": "Detailed description", "text": "To accomplish this, a literature review considered relevant for the study was undertaken.", "cite_spans": [], "ref_spans": []}, {"section": "Detailed description", "text": "The work with experts in the area of Colour, Visual Communication, Inclusive Design and Older People, as well as with the users and the associations of people with impairments, was also fundamental for the study developed. Also the direct field work with the users (sample groups), was a factor of great importance for the present study.", "cite_spans": [], "ref_spans": []}, {"section": "Detailed description", "text": "A qualitative method was chosen in order to allow a detailed exploration and the handling of complex and diverse information. A structured questionnaire was designed and used with the two sample groups of older people (65 -87 years). The obtained data was used to identify and describe the issues raised and to consider replication, linkages and differences.", "cite_spans": [], "ref_spans": []}, {"section": "Detailed description", "text": "This study doesn't intend to provide numerical data. To measure the different colour experiences of the participants, we used only printed material.", "cite_spans": [], "ref_spans": []}, {"section": "Older people and visual impairment", "text": "As the population is growing and ageing, the proportion of older people is expected to increase. One of the effects that growing older has on vision is that, on average, less light falls on the retina, and there is less tolerance to glare. Statistics from the Department of Health in UK [4] clearly show that a large percentage of people both blind and partially sighted people are 75 and over. Information from the RNIB [25] suggests that the most common eye pathologies are: macular degeneration, cataract, glaucoma, retinitis pigmentosa and diabetic retinopathy. Loss in the fovea affects visual acuity and colour perception and general loss of vision across the whole visual field. Fristr\u00f6m and Lundh [11] arrived to the conclusion that peripheral colour contrast sensitivity was affected by cataract, even when only moderately developed. This finding is of importance and should be considered when the method is used to study other eye diseases e.g. glaucoma. Central colour contrast sensitivity was also affected by cataract.", "cite_spans": [{"start": 287, "end": 290, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 421, "end": 425, "text": "[25]", "ref_id": "BIBREF24"}, {"start": 705, "end": 709, "text": "[11]", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "Older people and visual impairment", "text": "Maintenance and Refurbishment Programme used these resulting effects to propose three categories: central, peripheral and general visual field loss [2] . Macular degeneration, one of the most common causes of visual impairment, makes close up tasks such as reading more difficult. This can, in some cases, be helped by the use of optical aids.", "cite_spans": [{"start": 148, "end": 151, "text": "[2]", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Older people and visual impairment", "text": "Impairment of peripheral vision can result in 'tunnel vision', which can make it difficult to spot potential hazards. Retinitis pigmentosa, macular degeneration and cataracts can result in problems or discomfort with glare and bright lights or backgrounds.", "cite_spans": [], "ref_spans": []}, {"section": "Older people and visual impairment", "text": "Vision is one of the primary senses and serious or complete loss of sight also has a major impact on a person's ability to communicate effectively and function independently [13] . Lakowski and Drance [16] found that a large number of patients with ocular hypertension (OH) showed acquired colour vision losses. These losses were particularly in the bluegreen part of the spectrum, the called tritan defects [14] . They seemed to precede nerve fibre bundle defects in the visual field [5] . The loss of chromatic sensitivity in the short wavelength part of the spectrum in glaucoma was confirmed by others. Short wavelength automated perimetry (SWAP) has been shown to detect glaucoma damage earlier than conventional white-on-white perimetry and also to be more sensitive to progression of visual field loss, and to progression of glaucomatous disc cupping [10] . Other eye diseases, such as low-grade type 2 diabetic retinopathy [9] and moderate cataract [11] have been shown to affect peripheral colour contrast. Central colour contrast sensitivity is affected by macular degeneration, even with early age-related maculopathy [8] . In the UK, loss of sight most frequently happens later in life and as part of the ageing process. Recent figures [6] suggest that more than 12% of people over 75 have some sight loss. Visual acuity is reduced by 10% for 60-69 year olds, 30% for 70-79 year olds and 35% in the over-80s. In the UK, 65,000 people are diagnosed with low vision each year [21] .", "cite_spans": [{"start": 174, "end": 178, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 201, "end": 205, "text": "[16]", "ref_id": "BIBREF15"}, {"start": 408, "end": 412, "text": "[14]", "ref_id": "BIBREF13"}, {"start": 485, "end": 488, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 858, "end": 862, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 931, "end": 934, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 957, "end": 961, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 1129, "end": 1132, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 1248, "end": 1251, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 1486, "end": 1490, "text": "[21]", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "Older people and visual impairment", "text": "With age, changes to the eye increase sensitivity to glare, difficulty of adapting to changing light levels, and make contrast and colour harder to discern. A good colour use for visual communication, as well as helping to improve visual performance, it may also increase general well-being and health. The effect of sight ageing is partially attributed to the yellowing of the retina, lens and vitreous humor yellow with age causing colours such as violet, blue and green to be filtered out, reducing the contrast sensitivity of the eye [14] and increasing the requirement for light in older subjects [3] . The effect of age on measurement legibility is further compounded by a reduced ability of the iris to dilate, under all light conditions.", "cite_spans": [{"start": 538, "end": 542, "text": "[14]", "ref_id": "BIBREF13"}, {"start": 602, "end": 605, "text": "[3]", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "Human striate cortex and colour contrast processing", "text": "According to Weiskrantz et al [27] , colour appearance is not simply determined by the composition of reflected light. Colour appearance is more closely related to a constant property of a surface, its spectral reflectance. The relative reflectances of adjacent surfaces at any specific wavelength of light determine the relative intensities of light reflected from them at that wavelength, regardless of the spectral composition of the light illuminating them. Ratios of cone signals are approximately invariant under changes of illumination [7] . If the reflectance properties of one surface are known, then the properties of all other surfaces seen under the same illuminant can be inferred on the basis of these cone ratios or colour contrasts (this is the essence of Land's \"retinex\" colour constancy algorithm) [17] .", "cite_spans": [{"start": 30, "end": 34, "text": "[27]", "ref_id": "BIBREF26"}], "ref_spans": []}, {"section": "Human striate cortex and colour contrast processing", "text": "Questions about the role striate cortex, the first visual area of the higher mammalian brain, plays in colour perception have been reignited recently [13] . These cells in striate cortex are excited by light of one distribution of wavelengths and inhibited by light of another distribution falling in one small region of space. Adjacent or surrounding regions show the opposite pattern of responses. The cells therefore respond optimally to borders with a specific chromatic contrast that fall across the centre and surround regions of their spatial receptive fields. These findings suggest colour-specific processing starts earlier in the visual system than previously thought. The earliest mechanisms of colour constancy, our ability to recognize objects' colours regardless of the colour of light illuminating them, might occur in striate cortex. If so, people without striate cortex, like some older people, will lose colour contrast processing. They should behave as if objects change colour as the light illuminating them changes, their apparent colour depending on the wavelengths of light they reflect, rather than the properties of their surface material [27] . The influence of contrast in reading is important not only because text of a wide range of contrasts is encountered in the environment but also because many ocular conditions lower the effective contrast of the reading stimulus. Most studies of the role of contrast in reading, however, have treated only the luminance dimension. In general, reading is found to be fastest when the luminance difference between text and background is maximal. For example, using high-contrast edges, Legge and Rubin [18] demonstrated that for observers with normal vision the luminance contrast and the background luminance (or the text luminance when the background was dark) determine reading rate regardless of the colour of the text [15] . Tinker and Paterson [26] found the legibility of coloured inks on differently coloured papers to depend primarily on the luminance difference between the text and the background, but the range of conditions that they could examine was limited by the nature of their stimulus medium. Lippert [19] reported that legibility of briefly presented digits depended on the colour difference between the digits and the background. While Lippert systematically varied luminance and chromatic differences between text and background, he used a range of character sizes that was near the acuity limit of the chromaticcontrast-sensitivity function. Many eye conditions that result in low vision also result in colour vision deficiencies. While the most common congenital colour defects produce little in the way of performance limitations in and of themselves, the additional loss of sensory information that arises from a colour defect for an already compromised visual system could have greater consequences. Conversely, the residual colour discrimination that some people with low vision show could provide a viable avenue along which information could be presented to enhance performance on certain tasks dependent upon visual input. This line of reasoning suggested that a useful approach would be: a) to evaluate what residual colour discrimination low vision people display and b) to evaluate what influence the introduction of chromatic contrast might have on specific tasks for normal and low vision people [1] . With knowledge of the colour contrasts that an individual discriminates best, the degree to which colour cues influence performance on specific tasks can be evaluated.", "cite_spans": [{"start": 150, "end": 154, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 1164, "end": 1168, "text": "[27]", "ref_id": "BIBREF26"}, {"start": 1670, "end": 1674, "text": "[18]", "ref_id": "BIBREF17"}, {"start": 1891, "end": 1895, "text": "[15]", "ref_id": "BIBREF14"}, {"start": 1918, "end": 1922, "text": "[26]", "ref_id": "BIBREF25"}, {"start": 2189, "end": 2193, "text": "[19]", "ref_id": "BIBREF18"}, {"start": 3401, "end": 3404, "text": "[1]", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "Human striate cortex and colour contrast processing", "text": "A major goal of our colour contrast work is the dissemination of simple, comprehensible guidelines for choosing colours that work effectively for all, including those with the acquired colour deficiencies that almost always accompany low vision, and those with congenital colour deficiencies.", "cite_spans": [], "ref_spans": []}, {"section": "Methodology", "text": "After a literature review of the relevant material we were able to produce the State of the Art, from which emerged this hypothesis for our study:", "cite_spans": [], "ref_spans": []}, {"section": "Methodology", "text": "To", "cite_spans": [], "ref_spans": []}, {"section": "produce a more inclusive design project when designing visual communication analogical products, designers must be aware of the issues related with F.M. da Silva / A Visual Communication Design Project with Older People 4749", "text": "colour and text legibility, due to the reading problems experienced by many users, like older people. For the second stage of this research project, we decided to develop an experiment (active research) using two sample groups of older people with the same gender composition and general characteristics. The process involved development of tools to work with the groups, especially printed colour material always relating front and background colours. The search was carried out in several occasions (rounds), using the same material in similar lighting conditions and the same distances. During the experiment sessions, the sample groups of older people who took part in this study had the light up, on average, 900 lux (illuminance), as recommended by O'Neill [22] in a study conducted by a Research Group for Inclusive Environments at the University of Reading, in terms of having a \"Good\" colour rendering. The examples were very simple and designed to be readily understood. They were written in plain English for the UK sample group and in Portuguese for the Portuguese group. For this reason no technical terms were required when participants were asked to read the different words and sentences. The words and sentences acted as forms, using different colour schemes, in form/background relationship. Participants in the sample groups were volunteers recruited by the research team, among their acquaintances. In total, 8 people volunteered to take part in the UK sample group: 5 female persons and three men, with ages comprised between 65 and 85, all in sight normal conditions for people in this range of age, only with aged vision, but with no specific sight diseases.", "cite_spans": [{"start": 763, "end": 767, "text": "[22]", "ref_id": "BIBREF21"}], "ref_spans": []}, {"section": "produce a more inclusive design project when designing visual communication analogical products, designers must be aware of the issues related with F.M. da Silva / A Visual Communication Design Project with Older People 4749", "text": "In the Portuguese sample group 8 people took part in it: also 5 female persons and three men, with ages comprised between 65 and 87, all with the same sight characteristics as the UK group. Several messages, in different colour contrasts (see example in Figure 1 ) were printed on A4 format cards for a total of 24. This is the reference formula for graphic designers, in terms of text legibility. The lettering size was chosen having in mind that the group members would be placed at a two meters distance from the cards.", "cite_spans": [], "ref_spans": []}, {"section": "produce a more inclusive design project when designing visual communication analogical products, designers must be aware of the issues related with F.M. da Silva / A Visual Communication Design Project with Older People 4749", "text": "For the colour production, we used the Pantone Matching System (PMS) Colours. The colours used in this research are colours that the researcher found more appropriated for the research aim and the target group. For this experiment, the inside level of light was measured by an A.W. Sperry light meter. Two sample groups of subjects (with ages 65-87) were tested to measure the legibility of 24 cards. Information for each group included the gender, age, requirement for eye wear. The results for colour blindness were recorded as \"normal\" for all group members. To be selected for each of the sample groups, the members could have any eye disease, only older vision.", "cite_spans": [], "ref_spans": []}, {"section": "produce a more inclusive design project when designing visual communication analogical products, designers must be aware of the issues related with F.M. da Silva / A Visual Communication Design Project with Older People 4749", "text": "After informed consent had been obtained, and the subjects' visual acuity and ability to perceive colour had been tested, each one was seated in front of a researcher holding the A4 cards, with a 2 meters distance between them, and asked to look to each card (see fig 2) . They were told to read the text written in each card, where object (text) and background had different colour combinations. There were also cards with different types of lettering and spacing, but using always the same letter dimensions. We also wanted to test the level of legibility and the eventual experi-enced difficulty, as well as the level of eye comfort and colour contrast. After the implementation of the experiment with the two sample groups of older people, we could achieve findings, which were confronted with the drawn hypothesis. We were able to verify that not only we had proved the hypothesis but also we had amplified the initial knowledge with a contribution for the study area.", "cite_spans": [], "ref_spans": [{"start": 264, "end": 270, "text": "fig 2)", "ref_id": "FIGREF1"}]}, {"section": "Research findings", "text": "With the sample groups, the research team verified some conclusions from the literature review and found some solutions for an inclusive approach in visual communication design, using colour in analogical material, for older people. The different rounds of tests allowed the research team to identify the main problems with colour use for visual communication for older people. During the experiment developed with both sample groups there were immediately negative comments about some colour combinations. Examples are: \"Have trouble with reds,\" \"Reds are hard,\" \"Black on red is terrible,\" \"Yellow on red is not a good combination,\" \"I hate reading on red paper,\" \"Yellow on red is very hard to read \".", "cite_spans": [], "ref_spans": []}, {"section": "Research findings", "text": "After the experiment with the UK sample group we have achieved the following results: x All the participants had a good legibility when the contrast between background and object (word or sentence) was clear, such is the case of the background in white, light grey or yellow and the object in dark blue or black; or the background in dark grey, dark blue, red or black, and the object in white or yellow; x Three of the participants had experienced difficulties with the orange over the yellow; x The green on pink was really difficult for 6 of the participants; x None could read black on dark grey, or yellow on white; x Five of the participants had difficulties of legibility with green on red, or light blue on red; x White on light grey was very difficult to read for 6 participants; x Five participants experienced difficulties with light blue on black; x Three had difficulties with light grey on light blue, or red on dark blue; x Two had difficulties when reading red on light blue;", "cite_spans": [], "ref_spans": []}, {"section": "Research findings", "text": "x Four participants had problems when reading purple over light blue; x None could read orange on dark yellow.", "cite_spans": [], "ref_spans": []}, {"section": "Research findings", "text": "The experiment also included other aspects besides colour contrast, concerning the type of lettering; the use of uppercase letters and upper and lower case letters; the space between letters; the line spacing; and the type of paper, with glare and non-glare coverings.", "cite_spans": [], "ref_spans": []}, {"section": "Research findings", "text": "When working with the Portuguese sample group, we have achieved the following results: x All the participants had a good legibility when the contrast between background and object was clear, such is the case of the background in white, light grey or yellow and the object in dark blue or black; or white or yellow on dark grey, dark blue, red or black; x Four of the participants had experienced difficulties with the orange over the yellow; x The green on pink was really difficult for 7 of the participants; x None could read black on dark grey, or yellow on white; x Five of the participants had difficulties of legibility with green on red, or light blue on red; x White on light grey was very difficult to read for 5 participants; x Four participants experienced difficulties with light blue on black; x Four had difficulties with light grey on light blue; x There were no difficulties when reading red on light blue; x Six participants had problems when reading purple over light blue; x None could read orange on dark yellow; x Three had difficulties when reading red on dark blue.", "cite_spans": [], "ref_spans": []}, {"section": "Research findings", "text": "Comparing the results of the two sample groups: x All the participants had a good legibility when the contrast between background and object (word or sentence) was clear, such is the case of the background in white, light grey or yellow and the object in dark blue or black; or the background in dark grey, dark blue, red or black, and the object in white or yellow; x Seven in sixteen of the participants had experienced difficulties with the orange on yellow; x The green on pink was really difficult for 13 out of 16 of the participants; x None could read black on dark grey, or yellow on white;", "cite_spans": [], "ref_spans": []}, {"section": "Research findings", "text": "x Ten in sixteen had difficulties of legibility with green on red, or light blue on red; x White on light grey was very difficult to read for 11/16 participants; x Nine in sixteen participants experienced difficulties with light blue on black; x Seven in sixteen had difficulties with light grey on light blue; x Ten in sixteen participants had problems when reading purple over light blue; x None could read orange on dark yellow; x Six in sixteen had difficulties when reading red on dark blue. In what concerns the other aspects of the reading problems, all the participants in both groups (100%) had the same opinion, as follow: x Type of lettering: they all had difficulties with complicated, decorative or cursive fonts; x Standard serif or sans-serif fonts, with familiar, easily recognizable characters are best; x The use of uppercase letters and upper and lower case letters: They were much more comfortable with the use of upper and lower case letters; x The space between letters: they couldn't read the words or sentences which had no space between letters; x Line spacing: they all experienced difficulties if there were no line spacing; x Leading, or spacing between lines of text, should be at least 25 to 30 percent of the point size; x Type of paper: much more difficult to read if the paper has a glare covering (reflecting surface). In general terms, the only important difference between the two tables is that the Portuguese sample group had no difficulties when reading red on light blue whilst some of the participants in the UK sample group had some reading difficulties with this contrast.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusion", "text": "After the literature review implemented during the research and the experiment with the two sample groups, we achieved the following conclusions:", "cite_spans": [], "ref_spans": []}, {"section": "Conclusion", "text": "x After further analysis, the contrast combinations were separated into two groups: most legible and least legible; x There is a good legibility when the contrast between background and object (word or sentence) is clear, such as: o the background in white, light grey or yellow and the object in dark blue or black;", "cite_spans": [], "ref_spans": []}, {"section": "Conclusion", "text": "o the background in dark grey, dark blue, red or black, and the object in white or yellow; x Green on pink or white on light grey are really difficult to read; x Black on dark grey, orange on dark yellow or yellow on white are not effective; x Green on red, red on dark blue, red on light blue or light blue on red are difficult to read; x There are legibility difficulties with light blue on black, purple over light blue or orange on yellow; x Light grey on light blue is not effective; x Decorative or cursive fonts are difficult to read; x Standard serif or sans-serif fonts, are best for the legibility; x The use of uppercase letters is not very comfortable; x The use of upper and lower case letters is very comfortable; x The words or sentences which had no space between letters aren't effective; x There are difficulties if there is no line spacing; x Leading, or spacing between lines of text, less than 25 to 30 percent of the point size are not effective; x Paper with a glare covering (reflecting surface) is not good for the legibility.", "cite_spans": [], "ref_spans": []}, {"section": "Design Guidelines", "text": "This study represents a scoping project to investigate colour and visual communication problems for older people, using analogical supports, and it provides useful context and background information, which confirms that there has been relatively little work on colour and analogical communication design and even less focusing on the needs of older people that naturally have aged vision.", "cite_spans": [], "ref_spans": []}, {"section": "Design Guidelines", "text": "After the research project conclusions, it is possible to design some guidelines for an inclusive visual communication project for graphic printed material: x An objective measurement of legibility is a useful tool for the designer who wants assurance that his design will be easy to read; x When one creates visuals that are intended to be read, it is important to have enough contrast between the background and the text; x The human eye requires contrasts for visibility and legibility; x The more an object contrasts with its surrounds, the more visible it becomes;", "cite_spans": [], "ref_spans": []}, {"section": "Design Guidelines", "text": "x When the colour value is too close between text and background colours, it can create legibility problems; x Too much contrast or the use of complementary colours take the idea of contrast too far: colours will appear to \"vibrate\" and will create legibility problems; x Colours that are close in value tend to blur together, and their borders \"melt.\"; x Black on red should be avoided when designing printed material; x Black text on a dark blue background or black type on a red background are hard to read; x On a blue background yellow jumps out at the reader; x Yellow text on a red background is difficult to read, possibly because of the poor contrast provided by this combination; x Black text on a white background is the most legible contrast combination for all age groups; x Patterned backgrounds or an image in the background of text reduces its legibility; x The most common forms of colour blindness are associated with the inability to discriminate red and green wavelengths, so it's not effective to use red on green; x Bright colours can produce glare, which might distract the user and cause the eyes to become tired; x Paper with a reflecting surface is not good for the legibility.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Effective color contrast and low vision", "authors": [{"first": "A", "middle": [], "last": "Arditi", "suffix": ""}, {"first": "K", "middle": [], "last": "Knoblauch", "suffix": ""}], "year": 1996, "venue": "", "link": null}, "BIBREF1": {"title": "The effect of subject age on legibility", "authors": [{"first": "L", "middle": [], "last": "Bix", "suffix": ""}], "year": 1998, "venue": "", "link": null}, "BIBREF2": {"title": "Colour, Contrast & Perception -Design Guidance for Internal Built Environments", "authors": [{"first": "K", "middle": [], "last": "Bright", "suffix": ""}, {"first": "G", "middle": [], "last": "Cook", "suffix": ""}, {"first": "J", "middle": [], "last": "Harris", "suffix": ""}], "year": 1997, "venue": "", "link": "108167547"}, "BIBREF3": {"title": "Registered Blind and Partially Sighted People Year Ending 31March", "authors": [], "year": 2000, "venue": "", "link": null}, "BIBREF4": {"title": "Acquired colour vision changes in glaucoma", "authors": [{"first": "S", "middle": ["M"], "last": "Drance", "suffix": ""}, {"first": "R", "middle": [], "last": "Lakowski", "suffix": ""}, {"first": "M", "middle": [], "last": "Schulzer", "suffix": ""}, {"first": "G", "middle": ["R"], "last": "Douglas", "suffix": ""}], "year": 1981, "venue": "Arch Ophthalmol", "link": null}, "BIBREF5": {"title": "Prevalence of visual impairment in people aged 75 years and older in Britain: results of the MRC Trial of Assessment and Management of Older People in the Community", "authors": [{"first": "J", "middle": ["R"], "last": "Evans", "suffix": ""}, {"first": "A", "middle": ["E"], "last": "Fletcher", "suffix": ""}, {"first": "R", "middle": ["P L"], "last": "Wormald", "suffix": ""}], "year": 2002, "venue": "British Journal of Ophthalmology", "link": "10394340"}, "BIBREF7": {"title": "Colour contrast sensitivity in patients with soft drusen, an early stage of ARM", "authors": [{"first": "C", "middle": [], "last": "Frennesson", "suffix": ""}, {"first": "U", "middle": ["L"], "last": "Nilsson", "suffix": ""}, {"first": "S", "middle": ["E G"], "last": "Nilsson", "suffix": ""}], "year": 1995, "venue": "Doc Ophthalmol", "link": "21411521"}, "BIBREF8": {"title": "Peripheral and central colour contrast sensitivity in diabetes", "authors": [{"first": "B", "middle": [], "last": "Fristr\u00f6m", "suffix": ""}], "year": 1998, "venue": "Acta Ophthalmol Scand", "link": "3221350"}, "BIBREF9": {"title": "Colour contrast sensitivity in ocular hypertension. A five-year prospective study", "authors": [{"first": "B", "middle": [], "last": "Fristr\u00f6m", "suffix": ""}], "year": 2002, "venue": "Acta Ophthalmologica Scandinavica", "link": "8001043"}, "BIBREF10": {"title": "Colour contrast sensitivity in cataract and pseudophakia", "authors": [{"first": "B", "middle": [], "last": "Fristr\u00f6m", "suffix": ""}, {"first": "B", "middle": ["L"], "last": "Lundh", "suffix": ""}], "year": 2000, "venue": "Acta Ophthalmologica Scandinavica", "link": "21205135"}, "BIBREF11": {"title": "The Information Available in Pictures\". Leonardo. 4 (Winter)", "authors": [{"first": "J", "middle": ["J"], "last": "Gibson", "suffix": ""}, {"first": "E", "middle": ["N"], "last": "Johnson", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Hawken", "suffix": ""}, {"first": "R", "middle": [], "last": "Shapley", "suffix": ""}], "year": 1971, "venue": "", "link": null}, "BIBREF12": {"title": "Dementia and serious sight loss", "authors": [{"first": "R", "middle": [], "last": "Jones", "suffix": ""}, {"first": "R", "middle": [], "last": "Trigg", "suffix": ""}], "year": 2007, "venue": "", "link": "133205005"}, "BIBREF13": {"title": "Visual impairment in the elderly and its impact on their daily lives", "authors": [{"first": "M", "middle": [], "last": "Kelly", "suffix": ""}], "year": 1993, "venue": "", "link": null}, "BIBREF14": {"title": "Effects of chromatic and luminance contrast on reading", "authors": [{"first": "K", "middle": [], "last": "Knoblauch", "suffix": ""}], "year": 1991, "venue": "J. Opt. Soc. Am. A", "link": null}, "BIBREF15": {"title": "Acquired dyschromatopsias: the earliest functional losses in glaucoma", "authors": [{"first": "R", "middle": [], "last": "Lakowski", "suffix": ""}, {"first": "S", "middle": ["M"], "last": "Drance", "suffix": ""}], "year": 1979, "venue": "Doc Ophthalmol Proc Ser", "link": "59007948"}, "BIBREF17": {"title": "Psychophysics of reading\". I. Normal vision", "authors": [{"first": "G", "middle": ["E"], "last": "Legge", "suffix": ""}, {"first": "D", "middle": ["G"], "last": "Pelli", "suffix": ""}, {"first": "G", "middle": ["S"], "last": "Rubin", "suffix": ""}, {"first": "M", "middle": ["M"], "last": "Schleske", "suffix": ""}], "year": 1985, "venue": "Vision Research", "link": "16462008"}, "BIBREF18": {"title": "Color difference prediction of legibility performance for CRT raster imagery", "authors": [{"first": "T", "middle": ["M"], "last": "Lippert", "suffix": ""}], "year": 1986, "venue": "", "link": "196197040"}, "BIBREF19": {"title": "Visual Literacy: Image, Mind, & Reality", "authors": [{"first": "P", "middle": [], "last": "Messaris", "suffix": ""}], "year": 1994, "venue": "", "link": "194040070"}, "BIBREF20": {"title": "Visual impairments and problems with perception", "authors": [{"first": "C", "middle": [], "last": "Morris", "suffix": ""}], "year": 1999, "venue": "Journal of Dementia and Care", "link": null}, "BIBREF21": {"title": "Lighting the homes of people with sight loss", "authors": [{"first": "L", "middle": [], "last": "O&apos;neill", "suffix": ""}], "year": 2003, "venue": "", "link": null}, "BIBREF22": {"title": "Imagery and Verbal Processes", "authors": [{"first": "A", "middle": [], "last": "Pavio", "suffix": ""}], "year": 1971, "venue": "", "link": null}, "BIBREF23": {"title": "Mental Representations: A Dual Coding Approach", "authors": [{"first": "A", "middle": [], "last": "Pavio", "suffix": ""}], "year": 1986, "venue": "", "link": "141738880"}, "BIBREF24": {"title": "Fact sheet 3 -\"Older people, visual impairment and accidents", "authors": [], "year": 2001, "venue": "", "link": null}, "BIBREF25": {"title": "Studies of typographical factors influencing speed of reading\". VII", "authors": [{"first": "M", "middle": ["A"], "last": "Tinker", "suffix": ""}, {"first": "D", "middle": ["G"], "last": "Paterson", "suffix": ""}], "year": 1931, "venue": "Journal of Applied Psychology", "link": "143280227"}, "BIBREF26": {"title": "Color contrast processing in human striate cortex", "authors": [{"first": "L", "middle": [], "last": "Weiskrantz", "suffix": ""}], "year": 2007, "venue": "", "link": "19291797"}}, "ref_entries": {"FIGREF0": {"text": "Fig1. -Example of card used during the experiment", "type": "figure"}, "FIGREF1": {"text": "Fig. 2 -Experiment session with one of the members of the target group in UK", "type": "figure"}}}
{"paper_id": "10701804", "_pdf_hash": "4cad2711621f6b0da4d12fcbb5a971a553a94246", "abstract": [{"section": "Abstract", "text": "We study finite state transduction of automatic and morphic sequences. Dekking [4] proved that morphic sequences are closed under transduction and in particular morphic images. We present a simple proof of this fact, and use the construction in the proof to show that non-erasing transductions preserve a condition called \u03b1-substitutivity. Roughly, a sequence is \u03b1-substitutive if the sequence can be obtained as the limit of iterating a substitution with dominant eigenvalue \u03b1. Our results culminate in the following fact: for multiplicatively independent real numbers \u03b1 and \u03b2, if v is a \u03b1-substitutive sequence and w is an \u03b2-substitutive sequence, then v and w have no common non-erasing transducts except for the ultimately periodic sequences. We rely on Cobham's theorem for substitutions, a recent result of Durand [5] .", "cite_spans": [{"start": 79, "end": 82, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 820, "end": 823, "text": "[5]", "ref_id": "BIBREF4"}], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Infinite sequences of symbols are of paramount importance in a wide range of fields, ranging from formal languages to pure mathematics and physics. A landmark was the discovery in 1912 by Axel Thue, founding father of formal language theory, of the famous sequence 0110 1001 1001 0110 1001 0110 \u00b7 \u00b7 \u00b7 .Thue was interested in infinite words which avoid certain patterns, like squares ww or cubes www, when w is a non-empty word. Indeed, the sequence shown above, called the Thue-Morse sequence, is cube-free. It is perhaps the most natural cube-free infinite word. A common way to transform infinite sequences is by using finite state transducers. These transducers are deterministic finite automata with input letters and output words for each transition; an example is shown in Figure 1 . Usually we omit the words \"finite state\" and refer to transducers. A transducer maps infinite sequences to infinite sequences by reading the input sequence letter by letter. Each of these transitions produces an output word, and the sequence formed by concatenating each of these output words in the order they were produced is the output sequence. In particular, since this transducer runs for infinite time to read its entire input, this model of transduction does not have final states. A transducer is called k-uniform if each step produces k-letter words. For example, Mealy machines are 1-uniform transducers. A transducer is non-erasing if each step produces a non-empty word; this condition is prominent in this paper.", "cite_spans": [], "ref_spans": [{"start": 779, "end": 787, "text": "Figure 1", "ref_id": "FIGREF0"}]}, {"section": "Introduction", "text": "Although transducers are a natural machine model, hardly anything is known about their capabilities of transforming infinite sequences. To state the issues more clearly, let us write x y if there is a transducer taking y to x. This transducibility gives rise to a partial order of stream degrees [6] that is analogous to, but more fine-grained than, recursiontheoretic orderings such as Turing reducibility \u2264 T and many-one reducibility \u2264 m . We find it surprising that so little is known about . As of now, the structure of this order is vastly unexplored territory with many open questions. To answer these questions, we need a better understanding of transducers.", "cite_spans": [{"start": 296, "end": 299, "text": "[6]", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Introduction", "text": "The main things that are known at this point concern two particularly well-known sets of streams, namely the morphic and automatic sequences. Morphic sequences are obtained as the limit of iterating a morphism on a starting word (and perhaps applying a coding to the limit word). Automatic sequences have a number of independent characterizations (see [1] ); we shall not repeat these here. There are two seminal closure results concerning the transduction of morphic and automatic sequences:", "cite_spans": [{"start": 352, "end": 355, "text": "[1]", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "Introduction", "text": "(1) The class of morphic sequences is closed under transduction (Dekking [4] ).", "cite_spans": [{"start": 73, "end": 76, "text": "[4]", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "Introduction", "text": "(2) For all k, the class of k-automatic sequences is closed under uniform transduction (Cobham [3] ).", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "The restriction in (2) to uniform transducers is shown by the following example.", "cite_spans": [{"start": 19, "end": 22, "text": "(2)", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Example 1.", "text": "Let w \u2208 { 0, 1 } \u03c9 be defined by w(n) = 1 if n is a power of 2 and w(n) = 0 otherwise. This sequence is 2-automatic. Let h be the morphism 0 \u2192 0 and 1 \u2192 01. Taking the image of w under h, that is h(w), yields a sequence that is no longer automatic (but still morphic). Here is a sketch that h(w) is not 2-automatic. Note that the i th digit in h(w) is 1 iff i = 2 n + n for some n. Suppose that M is a finite-state machine with the property that reading in each number i in binary yields the i th digit of h(w). Let N be large enough so that the binary representation of 2 N + N has a run of zeroes longer than the number of states in N. Then by pumping, N must accept a number which is not of the form 2 n + n.", "cite_spans": [], "ref_spans": []}, {"section": "Example 1.", "text": "In this paper, we do not attack the central problems concerning the stream degrees. Instead, we are interested in a closure result for non-erasing transductions. Our interest comes from the following easy observation: This motivates the question: how powerful is non-erasing transduction?", "cite_spans": [], "ref_spans": []}, {"section": "Our contribution", "text": "The main result of this paper is stated in terms of the notion of \u03b1-substitutivity. This condition is defined in Definition 8 below, and the definition uses the eigenvalues of matrices naturally associated with morphisms on finite alphabets. Indeed, the core of our work is a collection of results on eigenvalues of these matrices. We prove that the set of \u03b1-substitutive words is closed under non-erasing finite state transduction. We follow Allouche and Shallit [1] in obtaining transducts of a given morphic sequence w by annotating an iteration morphism, and then taking a morphic image of the annotated limit sequence. For the first part of this transformation, we show that a morphism and its annotation have the same eigenvalues with non-negative eigenvectors. For the second part, we revisit the proof given in Allouche and Shallit [1] of Dekking's theorem that morphic images of morphic sequences are morphic. We simplify the construction in the proof to make it amenable for an analysis of the eigenvalues of the resulting morphism.", "cite_spans": [{"start": 464, "end": 467, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 840, "end": 843, "text": "[1]", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "Related work", "text": "Durand [5] proved that if w is an \u03b1-substitutive sequence and h is a non-erasing morphism, then h(w) is \u03b1 k -substitutive for some k \u2208 N. We strengthen this result in two directions. First, we show that k may be taken to be 1; hence h(w) is \u03b1 k -substitutive for every k \u2208 N. Second, we show that Durand's result also holds for non-erasing transductions.", "cite_spans": [{"start": 7, "end": 10, "text": "[5]", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "Preliminaries", "text": "We recall some of the main concepts that we use in the paper. For a thorough introduction to morphic sequences, automatic sequences and finite state transducers, we refer to [1, 8] .", "cite_spans": [{"start": 174, "end": 177, "text": "[1,", "ref_id": "BIBREF0"}, {"start": 178, "end": 180, "text": "8]", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "Preliminaries", "text": "We are concerned with infinite sequences \u03a3 \u03c9 over a finite alphabet \u03a3. We write \u03a3 * for the set of finite words, \u03a3 + for the finite, non-empty words, \u03a3 \u03c9 for the infinite words, and \u03a3 \u221e = \u03a3 * \u222a \u03a3 \u03c9 for all finite or infinite words over \u03a3.", "cite_spans": [], "ref_spans": []}, {"section": "Morphic sequences and automatic sequences Definition 2.", "text": "A morphism is a map h : \u03a3 \u2192 \u0393 * . This map extends by concatenation to h : \u03a3 * \u2192 \u0393 * , and we do not distinguish the two notationally. Notice also that", "cite_spans": [], "ref_spans": []}, {"section": "Morphic sequences and automatic sequences Definition 2.", "text": "An erased letter (with respect to h) is some a \u2208 \u03a3 such that h(a) = \u03b5. A morphism h : \u03a3 * \u2192 \u0393 * is called erasing if has an erased letter. A morphism is k-uniform (for k \u2208 N) if |h(a)| = k for all a \u2208 \u03a3. A coding is a 1-uniform morphism c : \u03a3 \u2192 \u0393.", "cite_spans": [], "ref_spans": []}, {"section": "Morphic sequences and automatic sequences Definition 2.", "text": "A morphic sequence is obtained by iterating a morphism, and applying a coding to the limit word.", "cite_spans": [], "ref_spans": []}, {"section": "Definition 3. Let s \u2208 \u03a3", "text": "+ be a word, h : \u03a3 \u2192 \u03a3 * a morphism, and c : \u03a3 \u2192 \u0393 a coding. If the limit h \u03c9 (s) = lim n\u2192\u221e h n (s) exists and is infinite, then h \u03c9 (s) is a pure morphic sequence, and c(h \u03c9 (s)) a morphic sequence.", "cite_spans": [], "ref_spans": []}, {"section": "Definition 3. Let s \u2208 \u03a3", "text": "If h(x 1 ) = x 1 z for some z \u2208 \u03a3 + , then we say that h is prolongable on x 1 . In this case,", "cite_spans": [], "ref_spans": []}, {"section": "Definition 3. Let s \u2208 \u03a3", "text": "is a pure morphic sequence. If additionally, the morphism h is k-uniform, then c(h", "cite_spans": [], "ref_spans": []}, {"section": "Definition 3. Let s \u2208 \u03a3", "text": "Example 4. A well-known example of a purely morphic word is the Thue-Morse sequence. This sequence can be obtained as the limit of iterating the morphism 0 \u2192 01, 1 \u2192 10 on the starting word 0. The first iterations are 0 \u2192 01 \u2192 0110 \u2192 01101001 \u2192 0110100110010110 \u2192 \u00b7 \u00b7 \u00b7 , and they converge, in the limit, to the Thue-Morse sequence. As the morphism h is 2-uniform, the sequence is also 2-automatic.", "cite_spans": [], "ref_spans": []}, {"section": "Example 5.", "text": "An example of a purely morphic word which is not automatic is provided by the Fibonacci substitution a \u2192 ab, b \u2192 a. Starting with a, the fixed point is abaababaabaababaababaabaababaabaababaaba \u00b7 \u00b7 \u00b7 .", "cite_spans": [], "ref_spans": []}, {"section": "Cobham's Theorem for morphic words", "text": "Definition 6. For a \u2208 \u03a3 and w \u2208 \u03a3 * we write |w| a for the number of occurrences of a in w. Let h be a morphism over \u03a3. The incidence matrix of h is the matrix M h = (m i, j ) i\u2208\u03a3, j\u2208\u03a3 where m i, j = |h( j)| i is the number of occurrences of the letter i in the word h( j).", "cite_spans": [], "ref_spans": []}, {"section": "Cobham's Theorem for morphic words", "text": "Theorem 7 (Perron-Frobenius). Every non-negative square matrix M has a real eigenvalue \u03b1 \u2265 0 that is greater than or equal to the absolute value of any other eigenvalue of M and the corresponding eigenvector is non-negative. We refer to \u03b1 as the dominating eigenvalue of M.", "cite_spans": [], "ref_spans": []}, {"section": "Definition 8.", "text": "The dominating eigenvalue of a morphism h is the dominating eigenvalue of M h . An infinite sequence w \u2208 \u03a3 \u03c9 over a finite alphabet \u03a3 is said to be \u03b1-substitutive (\u03b1 \u2208 R)", "cite_spans": [], "ref_spans": []}, {"section": "Definition 8.", "text": "if there exist a morphism h : \u03a3 \u2192 \u03a3 * with dominating eigenvalue \u03b1, a coding c : \u03a3 \u2192 \u03a3 and a letter a \u2208 \u03a3 such that (i) w = c(h \u03c9 (a)), and (ii) every letter of \u03a3 occurs in h \u03c9 (a).", "cite_spans": [], "ref_spans": []}, {"section": "Definition 8.", "text": "Remark. Let us remark on the importance of the condition (ii) in Definition 8. Without this condition every \u03b1-substitutive sequence w \u2208 \u03a3 \u03c9 would also be \u03b2-substitutive for every \u03b2 > \u03b1 that is the dominating eigenvalue of a non-negative integer matrix.", "cite_spans": [], "ref_spans": []}, {"section": "Definition 8.", "text": "This can be seen as follows. Let h : \u03a3 \u2192 \u03a3 * be a morphism with dominating eigenvalue \u03b1. Let a \u2208 \u03a3 such that w = h \u03c9 (a) exists, is infinite and contains all letters from \u03a3. Then w is \u03b1-substitutive. Now let \u03b2 > \u03b1 be the dominating eigenvalue of a non-negative integer matrix. Then there exists an alphabet \u0393 (disjoint from \u03a3, \u0393 \u222a \u03a3 = \u2205) and a morphism g : \u0393 \u2192 \u0393 * with dominating eigenvalue \u03b2.", "cite_spans": [], "ref_spans": []}, {"section": "Definition 8.", "text": "\u03c9 (a) = w and the dominating eigenvalue of z is \u03b2.", "cite_spans": [], "ref_spans": []}, {"section": "Definition 8.", "text": "Two complex numbers x, y are called multiplicatively independent if for all k, \u2208 Z it holds that x k = y implies k = = 0. We shall use the following version of Cobham's theorem due to Durand [5] . Theorem 9. Let \u03b1 and \u03b2 be multiplicatively independent Perron numbers. If a sequence w is both \u03b1-substitutive and \u03b2-substitutive, then w is eventually periodic.", "cite_spans": [{"start": 191, "end": 194, "text": "[5]", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "Transducers", "text": "Example 11. The transducer (\u03a3, \u2206, Q, q 0 , \u03b4, \u03bb) shown in Figure 1 can be defined as follows: \u03a3 = \u2206 = { 0, 1 }, Q = { q 0 , q 1 , q 2 } with q 0 the initial state, and the transition function \u03b4 and output function \u03bb are given by:", "cite_spans": [], "ref_spans": [{"start": 58, "end": 66, "text": "Figure 1", "ref_id": "FIGREF0"}]}, {"section": "Transducers", "text": "We use transducers to transform infinite words. The transducer reads the input word letter by letter, and the transformation result is the concatenation of the output words encountered along the edges.", "cite_spans": [], "ref_spans": []}, {"section": "Transducers", "text": "Definition 12. Let M = (\u03a3, \u2206, Q, q 0 , \u03b4, \u03bb) be a transducer. We extend the state transition function \u03b4 from letters \u03a3 to finite words \u03a3 * as follows: \u03b4(q, \u03b5) = q and \u03b4(q, aw) = \u03b4(\u03b4(q, a), w) for q \u2208 Q, a \u2208 \u03a3, w \u2208 \u03a3 * . The output function \u03bb is extended to the set of all words \u03a3 \u221e = \u03a3 \u03c9 \u222a \u03a3 * by the following definition: \u03bb(q, \u03b5) = \u03b5 and \u03bb(q, aw) = \u03bb(q, a) \u03bb(\u03b4(q, a), w) for q \u2208 Q, a \u2208 \u03a3, w \u2208 \u03a3 \u221e . We introduce \u03b4(w) and \u03bb(w) as shorthand for \u03b4(q 0 , w) and \u03bb(q 0 , w), respectively. Moreover, we define M(w) = \u03bb(w), the output of M on w \u2208 \u03a3 \u03c9 . In this way, we think of M as a function from (finite or infinite) words on its input alphabet to infinite words on its output alphabet", "cite_spans": [], "ref_spans": []}, {"section": "Transducers", "text": "\u03c9 and y \u2208 \u2206 \u03c9 , we write y x if for some transducer M, we have M(x) = y.", "cite_spans": [], "ref_spans": []}, {"section": "Transducers", "text": "Notice that every morphism is computable by a transducer (with one state). In particular, every coding is computable by a transducer.", "cite_spans": [], "ref_spans": []}, {"section": "Transducers", "text": "Definition 13. Let M = (\u03a3, \u2206, Q, q 0 , \u03b4, \u03bb) and N = (\u03a3 , \u2206 , Q , q 0 , \u03b4 , \u03bb ) be transducers, and assume that \u03a3 = \u2206. We define the composition N \u2022 M to be the transducer", "cite_spans": [], "ref_spans": []}, {"section": "Transducers", "text": "Here \u03b4 and \u03bb are the extensions of the transition and output functions of N to \u03a3 * , respectively. Proposition 14. Concerning the composition relation on transducers and on finite and infinite words:", "cite_spans": [], "ref_spans": []}, {"section": "Closure of Morphic Sequences under Morphic Images", "text": "Definition 15. Let h : \u03a3 * \u2192 \u03a3 * be morphisms, and let \u0393 \u2286 \u03a3 be a set of letters. We call a letter a \u2208 \u03a3 (i) dead if h n (a) \u2208 \u0393 * for all n \u2265 0, (ii) near dead if a \u0393, and for all n > 0, h n (a) consists of dead letters,", "cite_spans": [], "ref_spans": []}, {"section": "Closure of Morphic Sequences under Morphic Images", "text": "with respect to h and \u0393. We say that the morphism h respects \u0393 if every letter a \u2208 \u03a3 is either dead, near dead, resilient, or resurrecting. (Note that all of these definitions are with respect to some fixed h and \u0393.)", "cite_spans": [], "ref_spans": []}, {"section": "Closure of Morphic Sequences under Morphic Images", "text": "Lemma 16. Let g : \u03a3 * \u2192 \u03a3 * be a morphism, and let \u0393 \u2286 \u03a3. Then g r respects \u0393 for some natural number r > 0.", "cite_spans": [], "ref_spans": []}, {"section": "Closure of Morphic Sequences under Morphic Images", "text": "Proof. See Lemma 7.7.3 in Allouche and Shallit [1] .", "cite_spans": [{"start": 47, "end": 50, "text": "[1]", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "Closure of Morphic Sequences under Morphic Images", "text": "Definition 17. For a set of letters \u0393 \u2286 \u03a3 and a word w \u2208 \u03a3 \u221e , we write \u03b3 \u0393 (w) for the word obtained from w by erasing all occurrences of letters in \u0393.", "cite_spans": [], "ref_spans": []}, {"section": "Closure of Morphic Sequences under Morphic Images", "text": "Definition 18. Let g : \u03a3 * \u2192 \u03a3 * be a morphism, and \u0393 \u2286 \u03a3 a set of letters. We construct an alphabet \u2206, a morphism \u03be : \u2206 * \u2192 \u2206 * and a coding \u03c1 : \u2206 \u2192 \u03a3 as follows. We refer to \u2206, \u03be, \u03c1 as the morphic system associated with the erasure of \u0393 from g \u03c9 .", "cite_spans": [], "ref_spans": []}, {"section": "Closure of Morphic Sequences under Morphic Images", "text": "Let r \u2208 N >0 be minimal such that g r respects \u0393 (r exists by Lemma 16). Let D be the set of dead letters with respect to g r and \u0393. For x \u2208 \u03a3 * we use brackets [x] to denote a new letter. For words w \u2208 {g r (a) | a \u2208 \u03a3}, whenever \u03b3 D (w) = w 0 a 1 w 1 a 2 w 2 \u00b7 \u00b7 \u00b7 a k\u22121 w k\u22121 a k w k with a 1 , . . . , a k \u0393 and w 0 , . . . , w k \u2208 \u0393 * , we define", "cite_spans": [], "ref_spans": []}, {"section": "Closure of Morphic Sequences under Morphic Images", "text": "Here it is to be understood that", "cite_spans": [], "ref_spans": []}, {"section": "Closure of Morphic Sequences under Morphic Images", "text": "Let the alphabet \u2206 consist of all letters [a] and all bracketed letters [w] occurring in words blocks(g r (a)) for a \u2208 \u03a3. We define the morphism \u03be : \u2206 \u2192 \u2206 * and the coding \u03c1 : \u2206 \u2192 \u03a3 by", "cite_spans": [], "ref_spans": []}, {"section": "Closure of Morphic Sequences under Morphic Images", "text": "Remark. The requirement that g r respects \u0393 in Definition 18 guarantees for every a \u2208 \u03a3 that either g r (a) consists of dead letters only or g r (a) contains at least one near dead or resilient letter. In both cases, blocks(g r (a)) is well-defined. As a consequence \u03be([w]) is well-defined for every [w] \u2208 \u2206.", "cite_spans": [], "ref_spans": []}, {"section": "Closure of Morphic Sequences under Morphic Images", "text": "Example 19. We let \u03a3 = { a, b, c } and define a morphism g : \u03a3 \u2192 \u03a3 * by a \u2192 ab, b \u2192 ac and c \u2192 a. The word g \u03c9 (a) = abacabaabacababacabaabacabacabaabacababa \u00b7 \u00b7 \u00b7 is known as the tribonacci word.", "cite_spans": [], "ref_spans": []}, {"section": "Closure of Morphic Sequences under Morphic Images", "text": "Let \u0393 = { a }, that is, we delete the letter a. The morphism g does not respect \u0393 since g(c) = a \u2208 \u0393 * but g 2 (c) = ab \u0393 * . However, g 2 respects \u0393: g 2 (a) = abac, g 2 (b) = aba and g 2 (c) = ab. The letter a is resurrecting and b, c are resilient with respect to g 2 and \u0393. ", "cite_spans": [], "ref_spans": []}, {"section": "Closure of Morphic Sequences under Morphic Images", "text": "Then an application of the coding \u03c1 yields \u03c1(", "cite_spans": [], "ref_spans": []}, {"section": "Closure of Morphic Sequences under Morphic Images", "text": "Example 20. We let \u03a3 = { a,", "cite_spans": [], "ref_spans": []}, {"section": "Closure of Morphic Sequences under Morphic Images", "text": "where", "cite_spans": [], "ref_spans": []}, {"section": "Closure of Morphic Sequences under Morphic Images", "text": "Proposition 21. Let g : \u03a3 * \u2192 \u03a3 * be a morphism, a \u2208 \u03a3 such that g \u03c9 (a) \u2208 \u03a3 \u03c9 , and \u0393 \u2286 \u03a3 a set of letters. Let \u2206, \u03be and \u03c1 be the morphic system associated to the erasure of \u0393 from g \u03c9 in Definition 18. Then", "cite_spans": [], "ref_spans": []}, {"section": "Closure of Morphic Sequences under Morphic Images", "text": "We prove by induction on n that for all words w \u2208 \u2206 * , and for all n \u2208 N, cat(\u03be n (w)) = g nr (cat(w)). The base case is immediate. For the induction step, assume that we have n \u2208 N such that for all words w \u2208 \u2206 * , cat(\u03be", "cite_spans": [], "ref_spans": []}, {"section": "Closure of Morphic Sequences under Morphic Images", "text": "By the induction hypothesis, cat(\u03be n+1 (w)) = g nr (cat(\u03be(w))) = g nr (g r (cat(w))) = g (n+1)r (cat(w)). To complete the proof, note that by definition \u03c1([w a u]) = \u03b3 \u0393 (w a u) and thus \u03c1(w) = \u03b3 \u0393 (cat(w)) for every w \u2208 \u2206 * . Hence, for all n \u2265 1,", "cite_spans": [], "ref_spans": []}, {"section": "Closure of Morphic Sequences under Morphic Images", "text": "Definition 22. Let g, h : \u03a3 * \u2192 \u03a3 * be morphisms such that h is non-erasing. We construct an alphabet \u2206, a morphism \u03be : \u2206 * \u2192 \u2206 * and a coding \u03c1 : \u2206 \u2192 \u03a3 as follows. We refer to \u2206, \u03be, \u03c1 as the morphic system associated with the morphic image of g \u03c9 under h.", "cite_spans": [], "ref_spans": []}, {"section": "Closure of Morphic Sequences under Morphic Images", "text": "For nonempty words w = a 1 a 2 \u00b7 \u00b7 \u00b7 a k \u2208 \u03a3 * we define head(w) = a 1 and tail(w) = a 2 \u00b7 \u00b7 \u00b7 a k . We also define img(w)", "cite_spans": [], "ref_spans": []}, {"section": "Closure of Morphic Sequences under Morphic Images", "text": "We define the morphism \u03be : \u2206 * \u2192 \u2206 * and the coding \u03c1 : \u2206 \u2192 \u03a3 by", "cite_spans": [], "ref_spans": []}, {"section": "Closure of Morphic Sequences under Morphic Images", "text": "Notice here the \u03c1([a]) and u i , defined using head() and tail(), are well-defined since h is non-erasing and hence h(a i ) will be nonempty.", "cite_spans": [], "ref_spans": []}, {"section": "Example 23.", "text": "Here is an example illustrating Definition 22. Let g be the substitution from the Fibonacci word, g(a) = ab and g(b) = a. Further, let h be defined so that h(a) = bb and h(b) = a. As in Definition 22, let \u03be and \u03c1 be defined by", "cite_spans": [], "ref_spans": []}, {"section": "Example 23.", "text": "The point here is that applying \u03c1 to the limit word \u03be \u03c9 ([a]) is the same as h(g \u03c9 (a)):", "cite_spans": [], "ref_spans": []}, {"section": "Example 23.", "text": "Proposition 24. Let g, h : \u03a3 * \u2192 \u03a3 * be morphisms such that h is non-erasing, and a \u2208 \u03a3 such that g \u03c9 (a) \u2208 \u03a3 \u03c9 . Let \u2206, \u03be and \u03c1 be as in Definition 18. Then", "cite_spans": [], "ref_spans": []}, {"section": "Example 23.", "text": "Proof. We define z : \u2206 \u2192 \u03a3 * by z(a) = \u03b5 and z([a]) = a for all a \u2208 \u03a3. By induction on n > 0 we show", "cite_spans": [], "ref_spans": []}, {"section": "Example 23.", "text": "We start with the base case. Note that \u03c1(\u03be([a])) = h(g(a)) = h(g(z([a]))) and \u03c1(\u03be(a)) = \u03b5 = h(g(z(a))) for all a \u2208 \u03a3, and thus \u03c1(\u03be(w)) = h(g(z(w))) for all w \u2208 \u2206 * . Moreover, we have z(\u03be([a])) = g(a) = g(z([a])) and z(\u03be(a)) = \u03b5 = g(z(a)) for all a \u2208 \u03a3, and hence z(\u03be(w)) = g(z(w)) for all w \u2208 \u2206 * .", "cite_spans": [], "ref_spans": []}, {"section": "Example 23.", "text": "Let us consider the induction step. By the base case and induction hypothesis", "cite_spans": [], "ref_spans": []}, {"section": "Example 23.", "text": "Thus \u03c1(\u03be n ([a])) = h(g n (a)) for all n \u2208 N, and taking limits yields", "cite_spans": [], "ref_spans": []}, {"section": "Example 23.", "text": "Every morphic image of a word can be obtained by erasing letters, followed by the application of a non-erasing morphism. As a consequence we obtain:", "cite_spans": [], "ref_spans": []}, {"section": "Example 23.", "text": "Corollary 25. The morphic image of a pure morphic word is morphic or finite.", "cite_spans": [], "ref_spans": []}, {"section": "Proof. Let w \u2208 \u03a3", "text": "\u03c9 be a word and h : \u03a3 \u2192 \u03a3 * a morphism. Let \u0393 = { a | h(a) = \u03b5 } be the set of letters erased by h, and \u2206 = \u03a3 \\ \u0393. Then h(w) = g(\u03b3 \u0393 (w)) where g is the non-erasing morphism obtained by restricting h to \u2206. Hence for purely morphic w, the result follows from Propositions 21 and 24.", "cite_spans": [], "ref_spans": []}, {"section": "Proof. Let w \u2208 \u03a3", "text": "Theorem 26 (Cobham [2] , Pansiot [7] ). The morphic image of a morphic word is morphic.", "cite_spans": [{"start": 33, "end": 36, "text": "[7]", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "Proof. Let w \u2208 \u03a3", "text": "Proof. Follows from Corollary 25 since the coding can be absorbed into the morphic image.", "cite_spans": [], "ref_spans": []}, {"section": "Eigenvalue analysis", "text": "The following lemma states that if a square matrix N is an extension of a square matrix M, and all added columns contain only zeros, then M and N have the same non-zero eigenvalues.", "cite_spans": [], "ref_spans": []}, {"section": "Eigenvalue analysis", "text": "Lemma 27. Let \u03a3, \u2206 be disjoint, finite alphabets. Let M = (m i, j ) i, j\u2208\u03a3 and N = (n i, j ) i,j\u2208\u03a3\u222a\u2206 be matrices such that (i) n i, j = m i, j for all i, j \u2208 \u03a3 and (ii) n i, j = 0 for all i \u2208 \u03a3 \u222a \u2206, j \u2208 \u2206. Then M and N have the same non-zero eigenvalues.", "cite_spans": [], "ref_spans": []}, {"section": "Eigenvalue analysis", "text": "Proof. N is a block lower triangular matrix with M and 0 as the matrices on the diagonal. Hence the eigenvalues of N are the combined eigenvalues of M and 0. Therefore M and N have the same non-zero eigenvalues.", "cite_spans": [], "ref_spans": []}, {"section": "Eigenvalue analysis", "text": "We now show that morphic images with respect to non-erasing morphisms preserve \u03b1-substitutivity. This strengthens a result obtained in [5] where it has been shown that the non-erasing morphic image of an \u03b1-substitutive sequence is \u03b1 k -substitutive for some k \u2208 N. We show that one can always take k = 1. Note that every \u03b1-substitutive sequence is also \u03b1 k -substitutive for all k \u2208 N, k > 0.", "cite_spans": [{"start": 135, "end": 138, "text": "[5]", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "Eigenvalue analysis", "text": "Theorem 28. Let \u03a3 be a finite alphabet, w \u2208 \u03a3 \u03c9 be an \u03b1-substitutive sequence and h : \u03a3 \u2192 \u03a3 * a non-erasing morphism. Then the morphic image of w under h, that is h(w), is \u03b1-substitutive.", "cite_spans": [], "ref_spans": []}, {"section": "Eigenvalue analysis", "text": "Proof. Let \u03a3 = { a 1 , . . . , a k } be a finite alphabet, w \u2208 \u03a3 \u03c9 be an \u03b1-substitutive sequence and h : \u03a3 \u2192 \u03a3 * a non-erasing morphism. As the sequence w is \u03b1-substitutive, there exist a morphism g : \u03a3 \u2192 \u03a3 * with dominant eigenvalue \u03b1, a coding c : \u03a3 \u2192 \u03a3 and a letter a \u2208 \u03a3 such that w = c(g \u03c9 (a)) and all letters from \u03a3 occur in g \u03c9 (a). Then h(w) = h(c(g \u03c9 (a))) = (h\u2022c)(g \u03c9 (a))), and h \u2022 c is a non-erasing morphism. Without loss of generality, by absorbing c into h, we may assume that c is the identity. From h and g, we obtain an alphabet \u2206, a morphism \u03be, and a coding \u03c1 as in Example 29. Let F be the Fibonacci word (generated by the morphism a \u2192 ab and b \u2192 a) and let T be the Thue-Morse sequence. We show that there exist no non-erasing morphisms g, h such that g(F) = h(T) and this image is not ultimately periodic. Let g and h be non-erasing morphisms. The Fibonacci word is \u03d5-substitutive where \u03d5 = (1 + \u221a 5)/2 is the golden ratio, and the Thue-Morse sequence is 2-substitutive. By Theorem 28, g(F) is \u03d5-substitutive and h(T) is 2-substitutive. Note that \u03d5 and 2 are multiplicatively independent: using induction on k \u2208 N >0 it follows that every \u03d5 k is of the form a + b \u221a 5 for rational numbers a, b > 0. It follows by Theorem 9 that g(F) = h(T) implies that this word is ultimately periodic.", "cite_spans": [], "ref_spans": []}, {"section": "Eigenvalue analysis", "text": "Remark. The restriction to non-erasing morphisms in Theorem 28 is important since every morphic sequence can be obtained by erasure of letters from a 2-substitutive sequence.", "cite_spans": [], "ref_spans": []}, {"section": "Eigenvalue analysis", "text": "Nevertheless, we can use the above theorem to reason about morphic images with respect to erasing morphisms as follows. Let w \u2208 \u03a3 \u03c9 , and g : \u03a3 \u2192 \u03a3 * a morphism. Let \u0393 be the letters erased by g, and let h be the restriction of g to \u03a3 \\ \u0393. Then h is non-erasing and g(w) = h(\u03b3 \u0393 (w)). Hence, if \u03b3 \u0393 (w) is \u03b1-substitutive, then so is g(w) by Theorem 28. As a consequence, it suffices to determine \u03b1-substitutivity of all sequences \u03b3 \u0393 (w) with \u0393 \u2286 \u03a3 (using Definition 18 and Proposition 21).", "cite_spans": [], "ref_spans": []}, {"section": "Closure of Morphic Sequences under Transduction", "text": "In this section, we give a proof of the following theorem due to Dekking [4] .", "cite_spans": [{"start": 73, "end": 76, "text": "[4]", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "Closure of Morphic Sequences under Transduction", "text": "Theorem 30 (Transducts of morphic sequences are morphic). If M = (\u03a3, \u2206, Q, q 0 , \u03b4, \u03bb) is a transducer with input alphabet \u03a3 and x \u2208 \u03a3 \u03c9 is a morphic sequence, then M(x) is morphic or finite.", "cite_spans": [], "ref_spans": []}, {"section": "Closure of Morphic Sequences under Transduction", "text": "This proof will proceed by annotating entries in the original sequence x with information about what state the transducer is in upon reaching that entry. This allows us to construct a new morphism which produces the transduced sequence M(x) as output. After proving this theorem, we will show that this process of annotation preserves \u03b1-substitutivity. Example 31. To illustrate several points in this section, we will consider the Fibonacci morphism (h(a) = ab, h(b) = a) and the transducer which doubles every other letter, shown in Figure 2. ", "cite_spans": [], "ref_spans": [{"start": 535, "end": 544, "text": "Figure 2.", "ref_id": "FIGREF3"}]}, {"section": "Transducts of morphic sequences are morphic", "text": "We show in Lemma 40 that transducts of morphic sequences are morphic. In order to prove this, we also need several lemmas about transducers which are of independent interest. The approach here is adapted from a result in Allouche and Shallit [1] ; it is attributed in that book to Dekking. We repeat it here partly for the convenience of the reader, but mostly because there are some details of the proof which are used in the analysis of the substitutivity property.", "cite_spans": [{"start": 242, "end": 245, "text": "[1]", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "Transducts of morphic sequences are morphic", "text": "Definition 32 (\u03c4 w , \u039e(w)). Given a transducer M = (\u03a3, \u2206, Q, q 0 , \u03b4, \u03bb) and a word w \u2208 \u03a3 * , we define \u03c4 w \u2208 Q Q to be \u03c4 w (q) = \u03b4(q, w).", "cite_spans": [], "ref_spans": []}, {"section": "Transducts of morphic sequences are morphic", "text": "Example 33. Recall the transducer M from Figure 2 . Let id : Q \u2192 Q be the identity, and let \u03bd : Q \u2192 Q be the transposition \u03bd(s) = t and \u03bd(t) = s. For this transducer, \u03c4 w = id if |w| is even and \u03c4 w = \u03bd if |w| is odd. We have \u039e(a) = (\u03c4 a , \u03c4 ab , \u03c4 aba , \u03c4 abaab , \u03c4 abaababa , . . .). In this notation,", "cite_spans": [], "ref_spans": [{"start": 41, "end": 49, "text": "Figure 2", "ref_id": "FIGREF3"}]}, {"section": "Transducts of morphic sequences are morphic", "text": "Next, we show that { \u039e(w) : w \u2208 \u03a3 * } is finite.", "cite_spans": [], "ref_spans": []}, {"section": "Transducts of morphic sequences are morphic", "text": "Lemma 34. For any transducer M and any morphism h : \u03a3 \u2192 \u03a3Lemma 39. For all \u03c3 \u2208 \u03a3, all w \u2208 \u03a3 * and all natural numbers n, if h", "cite_spans": [], "ref_spans": []}, {"section": "Transducts of morphic sequences are morphic", "text": "In particular, for 1 \u2264 i \u2264 , the first component of the i th term in h n (\u03c3, \u0398(w)) is s i .", "cite_spans": [], "ref_spans": []}, {"section": "Transducts of morphic sequences are morphic", "text": "Proof. By induction on n. For n = 0, the claim is trivial. Assume that it holds for n. Let h n (\u03c3) = s 1 s 2 \u00b7 \u00b7 \u00b7 s , and for 1", "cite_spans": [], "ref_spans": []}, {"section": "Transducts of morphic sequences are morphic", "text": "Concatenating the sequences h(s i , \u0398((h n w)s 1 \u00b7 \u00b7 \u00b7 s i\u22121 )) for i = 1, . . . , completes our induction step. ", "cite_spans": [], "ref_spans": []}, {"section": "Transducts of morphic sequences are morphic", "text": "This sequence z is morphic in the alphabet \u03a3 \u00d7 Q.", "cite_spans": [], "ref_spans": []}, {"section": "Transducts of morphic sequences are morphic", "text": "Proof. For (i), write h(x 1 ) as x 1 x 2 \u00b7 \u00b7 \u00b7 x . Using the fact that h i ( ) = for all i, we see that", "cite_spans": [], "ref_spans": []}, {"section": "Transducts of morphic sequences are morphic", "text": "This verifies the prolongability. For (ii): if \u0398(w) = \u0398(u), then \u03c4 w and \u03c4 u are the first component of \u0398(w) and are thus equal.", "cite_spans": [], "ref_spans": []}, {"section": "Transducts of morphic sequences are morphic", "text": "We turn to (iii). Taking w = in Lemma 39 shows that h", "cite_spans": [], "ref_spans": []}, {"section": "Transducts of morphic sequences are morphic", "text": "The image of this sequence under the coding c is", "cite_spans": [], "ref_spans": []}, {"section": "Transducts of morphic sequences are morphic", "text": "In view of the \u03c4 functions' definition (Def. 32), we obtain z in (2) . By definition, z is morphic.", "cite_spans": [{"start": 65, "end": 68, "text": "(2)", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Transducts of morphic sequences are morphic", "text": "Therefore, row k of N times v is", "cite_spans": [], "ref_spans": []}, {"section": "Transducts of morphic sequences are morphic", "text": "v b m a,b = \u03b1v a , since v is an eigenvector of M. Finally we note that the kth entry of v is v a by its definition. Hence multiplying v by N multiplies the kth entry of v by \u03b1 for all k.", "cite_spans": [], "ref_spans": []}, {"section": "Transducts of morphic sequences are morphic", "text": "We have shown that v is a column eigenvector of N with eigenvalue \u03b1, so the (column) eigenvalues of M are all present in N. However, since a matrix and its transpose have the same eigenvalues, the (column) qualification on the eigenvalues is unnecessary.", "cite_spans": [], "ref_spans": []}, {"section": "Transducts of morphic sequences are morphic", "text": "If h is an annotation of h, then we have", "cite_spans": [], "ref_spans": []}, {"section": "Transducts of morphic sequences are morphic", "text": "Lemma 44. Let h, h be morphisms such that h :", "cite_spans": [], "ref_spans": []}, {"section": "Transducts of morphic sequences are morphic", "text": "Then every eigenvalue of h with a non-negative eigenvector is also an eigenvalue for h.", "cite_spans": [], "ref_spans": []}, {"section": "Transducts of morphic sequences are morphic", "text": "Proof. Let M = (m i, j ) i, j\u2208\u03a3 be the incidence matrix of h and N = (n i, j ) i, j\u2208\u03a3\u00d7A be the incidence matrix of h. Let r be an eigenvalue of N with corresponding eigenvector v = (v (b, a) ) (b, a)\u2208\u03a3\u00d7A , that is, Nv = rv and v 0. We define a vector w = (w b ) b\u2208\u03a3 as follows:", "cite_spans": [], "ref_spans": []}, {"section": "Transducts of morphic sequences are morphic", "text": "Hence Mw = rw. If w 0 it follows that r is an eigenvalue of M. Note that if v is non-negative, then w 0. This proves the claim.", "cite_spans": [], "ref_spans": []}, {"section": "Corollary 45. Let h, h be morphisms such that h : (\u03a3", "text": "* is an annotation of h : \u03a3 \u2192 \u03a3 * . Then the dominant eigenvalue for h coincides with the dominant eigenvalue for h.", "cite_spans": [], "ref_spans": []}, {"section": "Corollary 45. Let h, h be morphisms such that h : (\u03a3", "text": "Proof. By Lemma 43 every eigenvalue of h is an eigenvalue of h. Thus the dominant eigenvalue of h is greater or equal to that of h. By Theorem 7, the dominant eigenvalue of a non-negative matrix is a real number \u03b1 > 1 and its corresponding eigenvector is nonnegative. By Lemma 43, every eigenvalue of h with a non-negative eigenvector is also an eigenvalue of h. Thus the dominant eigenvalue of h is also greater or equal to that of h.", "cite_spans": [], "ref_spans": []}, {"section": "Corollary 45. Let h, h be morphisms such that h : (\u03a3", "text": "Hence the dominant eigenvalues of h and h must be equal.", "cite_spans": [], "ref_spans": []}, {"section": "Corollary 45. Let h, h be morphisms such that h : (\u03a3", "text": "Theorem 46. Let \u03b1 and \u03b2 be multiplicatively independent real numbers. If v is a \u03b1-substitutive sequence and w is an \u03b2-substitutive sequence, then v and w have no common non-erasing transducts except for the ultimately periodic sequences.", "cite_spans": [], "ref_spans": []}, {"section": "Corollary 45. Let h, h be morphisms such that h : (\u03a3", "text": "Proof. Let h v and h w be morphisms whose fixed points are v and w, respectively. By the proof of Theorem 30, x is a morphic image of an annotation h v of h v , and also of an annotation h w of h w . The morphisms must be non-erasing, by the assumption in this theorem. By Corollary 45 and Theorem 28, x is both \u03b1-and \u03b2-substitutive. By Durand's Theorem 9, x is eventually periodic.", "cite_spans": [], "ref_spans": []}, {"section": "Example", "text": "We conclude the section with an example of Theorem 30 and the lemmas in this section.", "cite_spans": [], "ref_spans": []}, {"section": "Example", "text": "Example 47. We saw the Fibonacci sequence in Example 5:", "cite_spans": [], "ref_spans": []}, {"section": "Example", "text": "We conclude our series of examples pertaining to this sequence and the transducer M which doubles every other letter (see Example 31 and Figure 2) . We want to exhibit h, following the recipe of Lemma 40. First, some examples of how h works: It turns out that only a few elements from this A end up appearing in the expressions for h(\u03c3, \u0398(w)): It is convenient to abbreviate some of the elements of \u03a3 \u00d7 A: Let us use x as an element of {a, b}, and also write (x, \u0398( )) as x 0 , (x, \u0398(a)) as x 1 , (x, \u0398(b)) as x 2 and (x, \u0398(ab)) as x 3 . It turns out that we do not need to exhibit h in full because only eight points are reachable from a 0 . We may take h to be", "cite_spans": [], "ref_spans": [{"start": 137, "end": 146, "text": "Figure 2)", "ref_id": "FIGREF3"}]}, {"section": "Example", "text": "The fixpoint of this morphism starting with a 0 starts as Recall that \u03bb : \u03a3 \u00d7 Q \u2192 \u2206 * = \u03a3 * in our transducer doubles whatever letter it sees while in state s and copies whatever letter it sees while in state t. That is, \u03bb(x s ) = xx, and \u03bb(x t ) = x. Thus when we apply the morphism \u03bb to the sequence z, we get \u03bb(z) = aa b aa a bb a bb a aa b aa a bb a bb a aa b aa b aa a bb a aa b aa b \u00b7 \u00b7 \u00b7 As we saw in the proof of Theorem 30, this sequence aabaaabbabbaaabaaabbabbaaabaabaaabbaaabaab \u00b7 \u00b7 \u00b7 is exactly M(x).", "cite_spans": [], "ref_spans": []}, {"section": "Conclusion", "text": "We have re-proven some of the central results in the area of morphic sequences, the closure of the morphic sequences under morphic images and transduction. However, the main results in this paper come from the eigenvalue analyses which followed our proofs in Sections 3 and 4. These are some of the only results known to us which enable one to prove negative results on the transducibility relation . One such result is in Theorem 46; this is perhaps the culmination of this paper.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusion", "text": "The next step in this line of work is to weaken the hypothesis in some of results that the transducers be non-erasing. Although our results can be used to reason about erasing morphisms, see Remark 3, this does not help us with erasing transducers since annotating a morphism can yield an unbounded large alphabet. As a consequence, to reason about erasing transducers, we need to understand better what form of annotated morphisms arise from transducers, and how these interact with the erasure of letters (Proposition 21).", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Automatic Sequences: Theory, Applications, Generalizations", "authors": [{"first": "J.-P", "middle": [], "last": "Allouche", "suffix": ""}, {"first": "J", "middle": [], "last": "Shallit", "suffix": ""}], "year": 2003, "venue": "", "link": "39101087"}, "BIBREF1": {"title": "On the Hartmanis-Stearns problem for a class of tag machines", "authors": [{"first": "A", "middle": [], "last": "Cobham", "suffix": ""}], "year": 1968, "venue": "IEEE Conference Record of 1968 Ninth Annual Symposium on Switching and Automata Theory", "link": "3270596"}, "BIBREF2": {"title": "Uniform tag sequences", "authors": [{"first": "A", "middle": [], "last": "Cobham", "suffix": ""}], "year": 1972, "venue": "Math. Systems Theory", "link": "28356747"}, "BIBREF3": {"title": "Iteration of maps by an automaton", "authors": [{"first": "F", "middle": ["M"], "last": "Dekking", "suffix": ""}], "year": 1994, "venue": "Discrete Math", "link": "9434002"}, "BIBREF4": {"title": "Cobham's theorem for substitutions", "authors": [{"first": "F", "middle": [], "last": "Durand", "suffix": ""}], "year": 2011, "venue": "Journal of the European Mathematical Society", "link": "12939082"}, "BIBREF5": {"title": "Proceedings of the Leiden Numeration Conference", "authors": [{"first": "J", "middle": [], "last": "Endrullis", "suffix": ""}, {"first": "D", "middle": [], "last": "Hendriks", "suffix": ""}, {"first": "J", "middle": ["W"], "last": "Klop", "suffix": ""}], "year": 2010, "venue": "", "link": null}, "BIBREF6": {"title": "Hi\u00e9rarchie et fermeture de certaines classes de tag-syst\u00e8mes", "authors": [{"first": "Jean-Jacques", "middle": [], "last": "Pansiot", "suffix": ""}], "year": 1983, "venue": "Acta Inform", "link": null}, "BIBREF7": {"title": "Elements of Automata Theory", "authors": [{"first": "Jacques", "middle": [], "last": "Sakarovitch", "suffix": ""}], "year": 2009, "venue": "", "link": "7858949"}, "BIBREF8": {"title": "Eigenvalues and Transduction of Morphic Sequences", "authors": [{"first": "D", "middle": [], "last": "Sprunger", "suffix": ""}, {"first": "W", "middle": [], "last": "Tune", "suffix": ""}, {"first": "J", "middle": [], "last": "Endrullis", "suffix": ""}, {"first": "L", "middle": ["S"], "last": "Moss", "suffix": ""}], "year": 2014, "venue": "Proc. Conf. on Developments in Language Theory (DLT 2014)", "link": "38218622"}}, "ref_entries": {"FIGREF0": {"text": "Figure 1 A transducer computing the difference (exclusive or) of consecutive bits.", "type": "figure"}, "FIGREF1": {"text": "For every morphic sequence w \u2208 \u03a3 \u03c9 there is a 2-automatic sequence w \u2208 (\u03a3 \u222a { a }) \u03c9 such that w is obtained from w by erasing all occurrences of a. (See Allouche and Shallit [1, Theorem 7.7.1])", "type": "figure"}, "FIGREF2": {"text": "Definition 22. Then by Proposition 24, we have \u03c1(\u03be \u03c9 ([a])) = h(g \u03c9 (a)). As a consequence, it suffices to show that \u03c1(\u03be \u03c9 ([a])) is \u03b1-substitutive. Let M = (M i,j ) i, j\u2208\u03a3 and N = (N i, j ) i,j\u2208\u2206 be the incidence matrices of g and \u03be, respectively. By Definition 22 we have for all a, b \u2208 \u03a3: |\u03be([a])| [b] = |g(a)| b and |\u03be(a)| b = |\u03be(a)| [b] = 0. Hence we obtain N [b],[a] = M b,a , N b,a = 0 and N [b],a = 0 for all a, b \u2208 \u03a3. After changing the names (swapping a with [a]) in N, we obtain from Lemma 27 that N and M have the same non-zero eigenvalues, and thus the same dominant eigenvalue.", "type": "figure"}, "FIGREF3": {"text": "Figure 2 A transducer that doubles every other letter.", "type": "figure"}, "FIGREF4": {"text": "Let M = (\u03a3, \u2206, Q, q 0 , \u03b4, \u03bb) be a transducer, let h be a morphism prolongable on the letter x 1 , and write h \u03c9 (x 1 ) as x = x 1 x 2 x 3 \u00b7 \u00b7 \u00b7 x n \u00b7 \u00b7 \u00b7 . Let \u0398 be from Definition 35. Using this, let A be from Lemma 37(i), and h from Definition 38. Then (i) h is prolongable on (x 1 , \u0398( )). (ii) Let c : \u03a3 \u00d7 A \u2192 \u03a3 \u00d7 Q be the coding c(\u03c3, \u0398(w)) = (\u03c3, \u03c4 w (q 0 )). Then c is well-defined. (iii) The image under c of h", "type": "figure"}, "FIGREF5": {"text": "(b, \u0398(a)) \u2192 (a, \u0398(ab)) (a, \u0398( )) \u2192 (a, \u0398( ))(b, \u0398(a)) (b, \u0398(ab)) \u2192 (a, \u0398(aba)) = (a, \u0398(b)) (a, \u0398(a)) \u2192 (a, \u0398(ab))(b, \u0398(aba)) = (a, \u0398(ab))(b, \u0398(b))", "type": "figure"}, "FIGREF6": {"text": "= a 0 b 1 a 2 a 3 b 2 a 1 b 0 a 3 a 2 b 3 a 0 a 1 b 0 a 3 b 2 a 1 a 0 b 1 a 2 b 3 a 0 a 1 b 0 a 3 a 2 b 3 a 0 b 1 \u00b7 \u00b7 \u00b7 Turning to the coding c, recall that the set Q of states of M is {s, t}. Let us abbreviate the elements of \u03a3 \u00d7 Q the same way we did with \u03a3 \u00d7 A. It is not hard to check that c(\u03c3 0 ) = \u03c3 s , c(\u03c3 1 ) = \u03c3 t , c(\u03c3 2 ) = \u03c3 s , and c(\u03c3 3 ) = \u03c3 t . Then the state-annotated sequence z from Lemma 40 is z = c(y)", "type": "figure"}, "TABREF0": {"text": ", and \u03c1([a]) = a. The starting letter for iterating \u03be is [a] (since the tribonacci word starts with a). The first iterations of \u03be are:", "type": "table"}}}
{"paper_id": "10701996", "_pdf_hash": "d7ea2e58793e9c29a7fcc31f4bfe6ed9598b4f21", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Human immunodeficiency virus (HIV)-negative plasmablastic lymphoma: a single institutional experience and literature review", "authors": [{"first": "J", "middle": ["J"], "last": "Liu", "suffix": ""}, {"first": "L", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "E", "middle": [], "last": "Ayala", "suffix": ""}], "year": 2011, "venue": "Leukemia Res", "link": "21510842"}, "BIBREF1": {"title": "Clinical and pathological differences between HIV-positive and HIV-negative patients with plasmablastic lymphoma", "authors": [{"first": "J", "middle": ["J"], "last": "Castillo", "suffix": ""}, {"first": "E", "middle": ["S"], "last": "Winer", "suffix": ""}, {"first": "D", "middle": [], "last": "Stachurski", "suffix": ""}], "year": 2010, "venue": "Leuk Lymphoma", "link": null}, "BIBREF2": {"title": "HIV-associated plasmablastic lymphoma: lessons learned from 112 published cases", "authors": [{"first": "J", "middle": [], "last": "Castillo", "suffix": ""}, {"first": "L", "middle": [], "last": "Pantanowitz", "suffix": ""}, {"first": "B", "middle": ["J"], "last": "Dezube", "suffix": ""}], "year": 2008, "venue": "Am J Hematol", "link": "32041913"}, "BIBREF3": {"title": "National Comprehensive Cancer Network [website]. NCCN Guidelines Version 3.2011: AIDS-related B-cell lymphoma", "authors": [], "year": "", "venue": "AIDS", "link": null}, "BIBREF4": {"title": "Prognostic factors in chemotherapytreated patients with HIV-associated Plasmablastic lymphoma", "authors": [{"first": "J", "middle": ["J"], "last": "Castillo", "suffix": ""}, {"first": "E", "middle": ["S"], "last": "Winer", "suffix": ""}, {"first": "D", "middle": [], "last": "Stachurski", "suffix": ""}], "year": 2010, "venue": "Oncologist", "link": "12907965"}, "BIBREF5": {"title": "Differential efficacy of bortezomib plus chemotherapy within molecular subtypes of diffuse large B-cell lymphoma", "authors": [{"first": "K", "middle": [], "last": "Dunleavy", "suffix": ""}, {"first": "S", "middle": [], "last": "Pittaluga", "suffix": ""}, {"first": "M", "middle": ["S"], "last": "Czuczman", "suffix": ""}], "year": 2009, "venue": "Blood", "link": "14840840"}, "BIBREF6": {"title": "Randomized phase III U.S./Canadian intergroup trial (SWOG S9704) comparing CHOP {+/\u2212} R for eight cycles to CHOP {+/\u2212} R for six cycles followed by autotransplant for patients with high-intermediate (H-Int) or high IPI grade diffuse aggressive non-Hodgkin lymphoma (NHL)", "authors": [{"first": "P", "middle": ["J"], "last": "Stiff", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Unger", "suffix": ""}, {"first": "J", "middle": [], "last": "Cook", "suffix": ""}], "year": 2011, "venue": "ASCO Meet Abstr", "link": "23362879"}}, "ref_entries": {}}
{"paper_id": "10702155", "_pdf_hash": "bf6e95f7fe295aed6138190d963fad1d9951ded9", "abstract": [], "body_text": [], "bib_entries": {"BIBREF2": {"title": "Res. Symp. Proc", "authors": [{"first": "M", "middle": ["L"], "last": "Lee", "suffix": ""}], "year": 2001, "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "10702237", "_pdf_hash": "41bebc306bbf05932607b26b7ba8be20e52b7f6c", "abstract": [{"section": "Abstract", "text": "In this paper we present an algorithm for computing 3F2, 2F2, 1F2 and 0F2 hypergeometric solutions for third order linear ODEs. This work generalizes previous work for computing p Fq solutions for 2nd order linear ODEs and for performing rational function decomposition in the framework of classical invariant theory. The algorithm being presented can thus compute solutions for the classes of hypergeometric equations constructed from the 3F2, 2F2, 1F2 and 0F2 standard equations using transformations of the form x \u2192 F (x), y \u2192 P (x)y, where F (x) is rational in x and P (x) is arbitrary. A computer algebra implementation of this work is present in Maple 12.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Given a third order linear ODE y \u2032\u2032\u2032 + c 2 y \u2032\u2032 + c 1 y \u2032 + c 0 y = 0", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "where y \u2261 y(x) is the dependent variable and the c j \u2261 c j (x) are any functions of x such that the quantities", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "are rational functions of x, the problem under consideration is that of systematically computing solutions for (1) even when no Liouvillian solutions exist 2 . Recalling, Liouvillian solutions can be computed systematically [1] and implementations of the related algorithm exist in various computer algebra systems. The linear ODEs involved in mathematical physics formulations, however, frequently admit only non-Liouvillian special function solutions, and for this case the existing algorithms cover a rather restricted portion of the problem.", "cite_spans": [{"start": 224, "end": 227, "text": "[1]", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "Introduction", "text": "The special functions associated with linear ODEs frequently happen to be particular cases of some generalized hypergeometric p F q functions [2] . One natural approach is thus to directly search for p F q solutions instead of special function solutions of one or another kind, and this is the approach discussed here. Related computer algebra routines were implemented in 2007 and are now at the root of the Maple (release 12) ability for solving non-trivial 3rd order linear ODE problems.", "cite_spans": [{"start": 142, "end": 145, "text": "[2]", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Introduction", "text": "The approach used consists of resolving an equivalence problem between a given equation of the form (1) and the four standard p F q differential equations associated to third order linear ODEs, that is, the 3 ", "cite_spans": [{"start": 207, "end": 208, "text": "3", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "Introduction", "text": "where {\u03b1, \u03b2, \u03b3, \u03b4, \u03b7} represent arbitrary expressions constant with respect to x. The equivalence classes are constructed by applying to these equations the general transformation", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "where P (x) is arbitrary, with the only restriction that F (x) is rational in x, resulting in rather general ODE families. When a solution of this kind exists, apart from providing the values of F (x) and P (x) that resolve the problem, the algorithm systematically returns the values of the (five, four, three or two) p F q parameters entering each of the three independent solutions. It is important to note that the idea of seeking hypergeometric function solutions for linear ODEs or using an equivalence approach for that purpose is not new, although in most cases the approaches presented only handle second order linear equations [4, 5, 6, 7, 8] . An exception to that situation is the algorithm [9] implemented in Maple 9 for computing p F q solutions for third and higher order linear ODEs, and a similar one implemented in Mathematica. The transformations defining the classes of equivalence that those implementations can handle, however, are restricted to x \u2192 ax b , y \u2192 P (x)y, with a and b constants, not having the generality of (4) with rational F (x) used here.", "cite_spans": [{"start": 637, "end": 640, "text": "[4,", "ref_id": "BIBREF3"}, {"start": 641, "end": 643, "text": "5,", "ref_id": "BIBREF4"}, {"start": 644, "end": 646, "text": "6,", "ref_id": "BIBREF5"}, {"start": 647, "end": 649, "text": "7,", "ref_id": "BIBREF6"}, {"start": 650, "end": 652, "text": "8]", "ref_id": "BIBREF7"}, {"start": 703, "end": 706, "text": "[9]", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "Introduction", "text": "Apart from expanding the solving capabilities regarding third order linear ODEs, the approach being presented generalizes previous work in that:", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "1. The ideas presented in [8] and in [10] useful for decomposing two sets of invariants into each other were elaborated further and coded into a user level Maple 12 command for resolving equivalence problems in the framework of classical invariant theory.", "cite_spans": [{"start": 26, "end": 29, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 37, "end": 41, "text": "[10]", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "Introduction", "text": "2. The classification ideas presented in [8] for second order linear equations were extended for third order.", "cite_spans": [{"start": 41, "end": 44, "text": "[8]", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "Introduction", "text": "3. When the p F q parameters are such that less than three independent p F q solutions exist, instead of introducing integrals [9] , or developing the solution around a different point, alternative forms of MeijerG functions are used to express the missing independent solutions.", "cite_spans": [{"start": 127, "end": 130, "text": "[9]", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "Introduction", "text": "The combination of 1. and 2. resulted in the new ability to solve the p F q ODE classes generated by transformations as general as (4) with F (x) rational. Item 3. is not new 4 , though we are not aware of literature with a clear presentation of the related problem and solution. Altogether, these ideas resulted in a new algorithm and related Maple routines for systematically computing three independent solutions for a large set of third order linear equations that we didn't know how to solve before.", "cite_spans": [], "ref_spans": []}, {"section": "Computing hypergeometric solutions", "text": "To compute p F q solutions to (1) the idea is to formulate an equivalence approach to the underlying hypergeometric differential equations, that is, to determine whether a given linear ODE can be obtained from one 3 The problem of equivalence under transformations {x \u2192 F (x), y \u2192 P (x) y + Q(x)} for linear ODEs can always be mapped into one with Q(x) = 0, see [13] .", "cite_spans": [{"start": 214, "end": 215, "text": "3", "ref_id": "BIBREF2"}, {"start": 362, "end": 366, "text": "[13]", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "Computing hypergeometric solutions", "text": "4 Mathematica 6 also uses MeijerG functions as described in item 3.", "cite_spans": [], "ref_spans": []}, {"section": "Computing hypergeometric solutions", "text": "of the p F q ODEs (3) by means of a transformation of a certain type. If so, the solution to the given ODE is obtained by applying the same transformation to the solution of the corresponding p F q equation. The approach also requires determining the values of the hypergeometric parameters {\u03b1, \u03b2, \u03b3, \u03b4, \u03b7} for which the equivalence exists, and it is clear that the bottleneck in this approach is the generality of the class of transformations to be considered. For instance, one can verify that for linear transformations of the form (4) with arbitrary F (x), in the case of second order linear ODEs, the problem is too general in that the determination of F (x) requires solving the given ODE itself [11] , making the approach of no practical use. This has to do with the fact that in the second order case, any linear ODE can be obtained from any other one through a transformation of the form (4). The situation for third order equations is different: the transformation (4) is not enough to map any equation into any other one, so that its determination when the equivalence exists is in principle possible [12] . By restricting the form of F (x) entering (4) to be rational in x the problem becomes tractable by using a two step strategy:", "cite_spans": [{"start": 702, "end": 706, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 1112, "end": 1116, "text": "[12]", "ref_id": "BIBREF11"}], "ref_spans": []}, {"section": "Computing hypergeometric solutions", "text": "1. Compute a rational transformation 5 R(x) mapping the normal form of the given equation into one having invariants with minimal degrees (defined in sec. 3).", "cite_spans": [], "ref_spans": []}, {"section": "2.", "text": "Resolve an equivalence problem between this equation with minimal degrees and the standard p F q equations (3) under transformations of the form discussed in [8] , that is", "cite_spans": [{"start": 158, "end": 161, "text": "[8]", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "2.", "text": "with P (x) arbitrary and {a, b, c, d, k} constants with respect to x. In doing so, determine also the parameters {\u03b1, \u03b2, \u03b3, \u03b4, \u03b7} of the p F q or MeijerG functions entering the three independent solutions.", "cite_spans": [], "ref_spans": []}, {"section": "2.", "text": "The key observation in this \"two steps\" approach is that a transformation of the form (4) with rational F (x) mapping into the p F q equations (3) can always be expressed as the composition of two transformations, each one related to each of the two steps above (see sec. 3), because (3) have invariants with minimal degrees. The advantage of splitting the problem in this way is that the determination of R(x) is systematic (this is essentially a tricky gcd problem) and that, when the problem is solvable, the determination of the (up to five) p F q parameters in step two, as well as of the values of {a, b, c, d, k} entering (5) is also systematic, even when the problem is nonlinear in many variables.", "cite_spans": [], "ref_spans": []}, {"section": "Equivalence under", "text": "This type of equivalence is discussed in [8] and generalized here for third order ODEs. Recalling the main points, these transformations, which do not form a group in the strict sense, can be obtained by sequentially composing three different transformations, each of which does constitute a group. The sequence starts with linear fractional -also called M\u00f6bius -transformations", "cite_spans": [{"start": 41, "end": 44, "text": "[8]", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "Equivalence under", "text": "is followed by power transformations", "cite_spans": [], "ref_spans": []}, {"section": "Equivalence under", "text": "and ends with linear homogeneous transformations of the dependent variable", "cite_spans": [], "ref_spans": []}, {"section": "Equivalence under transformations of the dependent variable y \u2192 P (x)y", "text": "Transformations of the form (8) can easily be factored out of the problem: if two equations of the form (1) can be obtained from each other by means of (8), the transformation relating them is computable directly from these coefficients. For that purpose first rewrite both equations in normal form using", "cite_spans": [], "ref_spans": []}, {"section": "Equivalence under transformations of the dependent variable y \u2192 P (x)y", "text": "and the transformation relating the two hypothetical ODEs -say with coefficients c j andc k , when it exists, is given by y \u2192 y e (c2(x)\u2212c2(x))/3 dx .", "cite_spans": [], "ref_spans": []}, {"section": "Equivalence under M\u00f6bius transformations, singularities and classification", "text": "M\u00f6bius transformations preserve the structure of the singularities of (1). For example, all of the 0 F 2 , 1 F 2 and 2 F 2 hypergeometric equations in (3) have one regular singularity at the origin and one irregular singularity at infinity, and after transforming them using the M\u00f6bius transformations (6), they continue having one regular singularity and one irregular singularity, now respectively located at 6 \u2212b/a and \u2212d/c. In the case of the 3 F 2 differential equation (the first listed in (3)), under (6) the three regular singularities move from {0, 1,", "cite_spans": [], "ref_spans": []}, {"section": "Equivalence under M\u00f6bius transformations, singularities and classification", "text": "So from the singularities of an ODE, not only one can tell with respect to which of the four differential equations (3) could the equivalence under (6) be resolved, but also one can extract the values of the parameters {a, b, c, d} entering the transformation (6).", "cite_spans": [], "ref_spans": []}, {"section": "Equivalence under M\u00f6bius transformations, singularities and classification", "text": "More generally, through M\u00f6bius transformations one can formulate a classification of singularities of the linear ODEs \"equivalent\" to the third order p F q equations (3) in the same way it is done in [8] for second order p F q equations. For each p F q family obtained from (3) using (6), this classification is based on:", "cite_spans": [{"start": 200, "end": 203, "text": "[8]", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "Equivalence under M\u00f6bius transformations, singularities and classification", "text": "\u2022 the degrees of the numerators and denominators of the invariants (2);", "cite_spans": [], "ref_spans": []}, {"section": "Equivalence under M\u00f6bius transformations, singularities and classification", "text": "\u2022 the presence of roots with multiplicity in the denominators;", "cite_spans": [], "ref_spans": []}, {"section": "Equivalence under M\u00f6bius transformations, singularities and classification", "text": "\u2022 the possible cancellation of factors between the numerator and denominator of each invariant.", "cite_spans": [], "ref_spans": []}, {"section": "Equivalence under M\u00f6bius transformations, singularities and classification", "text": "With this classification in hands, from the knowledge of the degrees with respect to x of the numerator and denominator of the invariants (2) of a given third order linear ODE, the computational routines determine, without further computations, whether or not the equation could be obtained from the 3 F 2 , 2 F 2 , 1 F 2 or 0 F 2 equations (3) using (6). (1), the new invariants\u0128 j can be expressed in terms of the invariants (2) of (1) b\u1ef9", "cite_spans": [], "ref_spans": []}, {"section": "Transformations x \u2192 F (x) and equivalence under", "text": "where S(x) is the Schwarzian [14]", "cite_spans": [], "ref_spans": []}, {"section": "Transformations x \u2192 F (x) and equivalence under", "text": "The form of S(F \u2032 ) is particularly simple when F (x) is a M\u00f6bius transformation, in which case S(F \u2032 ) = 0. Regarding power transformations F (x) = x k , the first thing to note is that, unlike M\u00f6bius transformations, they do not preserve the structure of singularities; the Schwarzian (11) is:", "cite_spans": [], "ref_spans": []}, {"section": "Transformations x \u2192 F (x) and equivalence under", "text": "6 When either a or c are equal to zero, the corresponding singularity is located at \u221e From (10) and (12) for instance, the transformation rule for I 1 (x) becomes", "cite_spans": [], "ref_spans": []}, {"section": "Transformations x \u2192 F (x) and equivalence under", "text": "Generalizing to third order the suggestion presented in [8] we define here two shifted invariants", "cite_spans": [{"start": 56, "end": 59, "text": "[8]", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "Transformations x \u2192 F (x) and equivalence under", "text": "Rewriting (10) in terms of the J n (x), their transformation rule under x \u2192 x k is given b\u1ef9", "cite_spans": [], "ref_spans": []}, {"section": "Transformations x \u2192 F (x) and equivalence under", "text": "The equivalence of two linear ODEs A and B under x \u2192 x k can then be formulated as follows: Given the shifted invariantsJ n,A (x) andJ n,B (x), computed using their definition (14) in terms of\u0128 n (x) defined in (2), compute k A and k B entering (15) such that the degrees of J n,A (x) and J n,B (x) are minimal. This approach is systematic: from the knowledge of x \u2192 x kA and x \u2192 x kB , respectively leading to J n,A and J n,B with minimized degrees, equations A and B are related through power transformations only when J n,A = J n,B and, if so, the mapping relating A and B is just x \u2192 x kA\u2212kB . Finally, the computation of k simultaneously minimizing the degrees of the two J n (x) in (15) is performed as explained in section 3 of [8] .", "cite_spans": [{"start": 176, "end": 180, "text": "(14)", "ref_id": "BIBREF13"}, {"start": 245, "end": 249, "text": "(15)", "ref_id": "BIBREF14"}, {"start": 735, "end": 738, "text": "[8]", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "Mapping into equations having invariants with minimal degrees", "text": "The algorithm presented in the previous section solves well defined families of p F q 3rd order equations for which no solving algorithm was available before. However, the restriction in the form of F (x) entering (4) to the composition of M\u00f6bius with power transformations is unsatisfactory: for linear equations of order higher than two, (4) does not map any linear equation into any other one of the same order and so the problem is already restricted 7 One possible extension of the algorithm is thus to consider the general transformations (4) restricting F (x) to be a rational function of x. For that purpose, instead of working with invariants I j under y \u2192 P (x) y we introduce absolute invariants L i under {x \u2192 F (x), y \u2192 P (x) y}:", "cite_spans": [{"start": 455, "end": 456, "text": "7", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "Mapping into equations having invariants with minimal degrees", "text": "where r = I 1 \u2032 \u2212 2I 0 is a relative invariant of weight 3. These formulas can be inverted using as intermediate", "cite_spans": [], "ref_spans": []}, {"section": "Mapping into equations having invariants with minimal degrees", "text": "\u2032 , and t = L 1 /s 3 :", "cite_spans": [], "ref_spans": []}, {"section": "Mapping into equations having invariants with minimal degrees", "text": "Under (F (x) ). Because the relation between the L i and I j is invertible, we can find a canonical form for the ODE by simply putting the invariants into a minimal form with respect to rational transformations x \u2192 F (x): that is, the maximum degree d i of the denominator and numerator of each of the invariants L i (x) should be made as small as possible, given the freedom to choose F (x) (arbitrary subject to the condition that the L i should remain rational). We can thus formulate the equivalence problem under rational transformations as a rational function decomposition problem:", "cite_spans": [], "ref_spans": []}, {"section": "Mapping into equations having invariants with minimal degrees", "text": "Can two sequences of invariants be \"functionally decomposed\" into one and the same sequence: the one with \"minimal degrees\"? If so, how?", "cite_spans": [], "ref_spans": []}, {"section": "Mapping into equations having invariants with minimal degrees", "text": "The idea is not new, and our development of an algorithm for performing rational function decomposition started as part of the work in [15] as a constructive method of obtaining minimally rational representative equations (MRREs) for equivalence classes of ODEs for y(x) under arbitrary transformations of the independent variable x. The goal was to perform the decomposition by means of only univariate GCD computations and to implement the libraries at user level in a computer algebra system, so that they could be used to resolve equivalence between differential equations in general.", "cite_spans": [{"start": 135, "end": 139, "text": "[15]", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "Mapping into equations having invariants with minimal degrees", "text": "MRREs have the following useful properties:", "cite_spans": [], "ref_spans": []}, {"section": "Mapping into equations having invariants with minimal degrees", "text": "1. Any other rational member equation of the equivalence class can be obtained from the MRRE by means of a rational transformation.", "cite_spans": [], "ref_spans": []}, {"section": "Mapping into equations having invariants with minimal degrees", "text": "2. The invariants -rational functions of the coefficients of the ODE and its derivatives -of MRREs are of minimal degree.", "cite_spans": [], "ref_spans": []}, {"section": "Mapping into equations having invariants with minimal degrees", "text": "Property 1 allows a restrictive search -ie. just searching for rational functions -for the equivalence function. Property 2 means that the computations are more efficient.", "cite_spans": [], "ref_spans": []}, {"section": "Mapping into equations having invariants with minimal degrees", "text": "In fact, due to the following remark, to achieve MRREs it is enough to find the invariants of minimal degree satisfying Property 2. While simple formulas such as (2) are well known for the invariants in terms of the coefficients of the ODE, the reverse is also true if we consider the ODE in a normal form with respect to all dependent variable transformations. In other words, the coefficients c i of the normal form of the equation (1) can be written as functions of the invariants I j .", "cite_spans": [], "ref_spans": []}, {"section": "Mapping into equations having invariants with minimal degrees", "text": "The algorithm developed for [15] actually determines a rational function decomposition, ie. solves the following problem:", "cite_spans": [{"start": 28, "end": 32, "text": "[15]", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "Mapping into equations having invariants with minimal degrees", "text": "Given two \"invariants\", rational functions", "cite_spans": [], "ref_spans": []}, {"section": "and such that the rational degree of F is maximized (and therefore the degrees of the equivalent invariants G i are minimized). Note that these functions are determined only modulo a M\u00f6bius transformation x \u2192 (ax + b)/(cx + d), that doesn't change the degree of F .", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Algorithm", "text": ".n, and F (x) = p(x)/q(x), satisfying the maximal degree property mentioned above, with N i relatively prime to D i and p relatvely prime to q. Construct polynomials", "cite_spans": [], "ref_spans": []}, {"section": "Algorithm", "text": "and let P (x, t) be the GCD of these Q i (x, t). Consequently", "cite_spans": [], "ref_spans": []}, {"section": "Algorithm", "text": "In particular, the coefficient P i (x) of each power of t in P (x, t) is a linear combination of p(x) and q(x) and hence the quotientF (x) of any two relatively prime coefficients is fractional linear in F (x). In fact we can assume equality, owing to the freedom afforded by the definition of F (x) up to a M\u00f6bius transformation. The function G i (F ) can then be determined by eliminating x from L i (x) usingF (x) = F . The slowest step of this algorithm is the computation of the multivariate GCD between the Q i (x, t) that determines the function P (x, t). It is possible however to compute the equivalence function F (x) without computing that multivariate GCD, using a small number of univariate GCD computations instead. This is accomplished by substituting values for t before computing the GCD defining P . Showing that this approach works and the details of the implementation require some explanation.", "cite_spans": [], "ref_spans": []}, {"section": "Algorithm", "text": "Notice that, because the P i (x) in (19) are linear combinations of p(x) and q(x), we could obtain some of these linear combinations by substituting numerical values for t into the function P (x, t). Moreover, in general, this substitution could occur before computing P (x, t), by substituting t = t j instead into the Q i (x, t), and proceeding with univariate GCDs of the Q i (x, t j ).", "cite_spans": [], "ref_spans": []}, {"section": "Algorithm", "text": "For example, suppose the x-solutions of P (x, t) = 0 are x = X j (t), j = 1..m, ie. P (x, t) = \u2212P m (t) j x \u2212 X j (t). If t 0 is some number, then each x = X j (t 0 ) is a solution of both Q 1 (x, t 0 ) = 0 and Q 2 (x, t 0 ) = 0. For most values of t 0 (all but a finite set in fact) these will be the only such common solutions, and therefore the GCD Q(x) of Q 1 (x, t 0 ) and Q 2 (x, t 0 ) is in fact P (x, t 0 ), which, as mentioned above, is some linear combination of p(x) and q(x).", "cite_spans": [], "ref_spans": []}, {"section": "Algorithm", "text": "We still need to take care of the situation where Q(x) could be the product of P (x, t 0 ) with some other nonconstant polynomial. In particular, in this case the candidate for Q(x) would have degree greater than what it should be 8 . Repeating this process with another t-value would give a second, in general different, such linear combination, with F being the resulting quotient. The rest of the algorithm entails choosing a valid set of t-values, and this is accomplished by iterating until the appropriate conditions have been satisfied. These conditions are checked in the following order:", "cite_spans": [], "ref_spans": []}, {"section": "Algorithm", "text": "1. Two candidates for P (x, t 0 ), P (x, t 1 ) must be relatively prime.", "cite_spans": [], "ref_spans": []}, {"section": "Algorithm", "text": "2. The degree of F must divide the degrees of each L i , i = 1..n.", "cite_spans": [], "ref_spans": []}, {"section": "Algorithm", "text": "3. The candidate equivalence function F must actually satisfy the given formula", "cite_spans": [], "ref_spans": []}, {"section": "Algorithm", "text": "This can be checked by attempting to reduce the expressions L i to obtain G i as explained above.", "cite_spans": [], "ref_spans": []}, {"section": "Algorithm", "text": "If the candidate for Q(x) has degree greater than what it should be, condition 3 would fail, on account of the minimality property 2 listed at the beginning of this section. Satisfying these conditions therefore sufficiently determines a pair of correct t-values.", "cite_spans": [], "ref_spans": []}, {"section": "Algorithm", "text": "After an initial implementation we noticed that one of the algorithms for rational function decomposition existing in the literature [10, 16, 17] happens to use a similar approach to that described above, namely substitution of t-values to change the two-variable GCD computation into a 1-variable computation. However, the only description of this algorithm we found is [10] , and contains not enough details to determine if their implementation uses similar efficiency optimizations as those described above. We also were unable to contact the authors to obtain a copy of their implementation FRAC for comparison purposes.", "cite_spans": [{"start": 133, "end": 137, "text": "[10,", "ref_id": "BIBREF9"}, {"start": 138, "end": 141, "text": "16,", "ref_id": "BIBREF15"}, {"start": 142, "end": 145, "text": "17]", "ref_id": "BIBREF16"}, {"start": 371, "end": 375, "text": "[10]", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "Algorithm", "text": "The algorithm described in this section has been implemented in Maple 12 as the core engine of a new command, rational equivalent, in the DEtools package. In turn, rational equivalent is used in this new p F q approach being presented as described in the following Summary.", "cite_spans": [], "ref_spans": []}, {"section": "Summary of the p F q approach for third order linear ODEs", "text": "The idea consists of assuming that the given linear ODE is one of p F q equations (3) transformed using (4) for some F (x) rational in x and P (x) arbitrary and for some values of the pFq parameters. Resolving the equivalence is about determining the F (x), P (x) and the values of the p F q parameters {\u03b1, \u03b2, \u03b3, \u03b4, \u03b7} such that the equivalence exists.", "cite_spans": [], "ref_spans": []}, {"section": "Summary of the p F q approach for third order linear ODEs", "text": "An itemized description of the algorithm to resolve the equivalence proposed in the introduction and discussed by parts in the previous sections is as follows.", "cite_spans": [], "ref_spans": []}, {"section": "Summary of the p F q approach for third order linear ODEs", "text": "1. Rewrite the given equation (1) we want to solve, in normal form", "cite_spans": [], "ref_spans": []}, {"section": "Summary of the p F q approach for third order linear ODEs", "text": "where the invariants\u0128 n (x) are constructed using the formulas (2).", "cite_spans": [], "ref_spans": []}, {"section": "Summary of the p F q approach for third order linear ODEs", "text": "2. Verify whether an equivalence of the form x \u2192 (a x k + b)/(c x k + d), y \u2192 P (x) y can be resolved; for this purpose: (a) ComputeJ n (x), the shifted invariants (14) , and use transformations x \u2192 x k to reduce to the integer minimal values the powers entering the numerator and denominator; i.e., compute k and J n (x) in (15).", "cite_spans": [{"start": 164, "end": 168, "text": "(14)", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "Summary of the p F q approach for third order linear ODEs", "text": "(b) Determine the singularities of the J n (x) and use the classification of singularities mentioned in section 2 to tell whether an equivalence under M\u00f6bius transformations to any of the 3 F 2 , 2 F 2 , (3) is possible. (c) When the equivalence is possible, from the singularities of the two J n (x) compute the parameters {a, b, c, d} entering the M\u00f6bius transformation (6) as well as the hypergeometric parameters {\u03b1, \u03b2, \u03b3, \u03b4, \u03b7} entering the p F q equation (3) such that the equivalence exists.", "cite_spans": [], "ref_spans": []}, {"section": "Summary of the p F q approach for third order linear ODEs", "text": "(d) Compose the three transformations to obtain one of the form", "cite_spans": [], "ref_spans": []}, {"section": "Summary of the p F q approach for third order linear ODEs", "text": "mapping the p F q equation involved into the ODE being solved.", "cite_spans": [], "ref_spans": []}, {"section": "Summary of the p F q approach for third order linear ODEs", "text": "3. When the previous step failed, perform step 1 in the itemization of section 1, that is, compute the absolute invariants L i (16) and compute a rational transformation R(x) mapping the given linear equation into one with absolute invariants with minimal degrees.", "cite_spans": [], "ref_spans": []}, {"section": "Summary of the p F q approach for third order linear ODEs", "text": "(a) When the previous step results in R(x) not of M\u00f6bius form, re-enter step (2) to resolve the remaining M\u00f6bius transformation and determining the values of the p F q parameters.", "cite_spans": [], "ref_spans": []}, {"section": "Summary of the p F q approach for third order linear ODEs", "text": "4. When either of the steps (2) or (3) were successful, compose all the transformations used and apply the composition to the known solution of the p F q equation to which the equivalence was resolved, obtaining the solution to the given ODE.", "cite_spans": [], "ref_spans": []}, {"section": "Special cases and MeijerG functions", "text": "Giving a look at the series expansion of any of the 3 F 2 , 2 F 2 , 1 F 2 or 0 F 2 functions one can see that there are some different situations that require special attention at the time of constructing the three independent solutions to (1). Consider for instance the standard 0 F 2 equation and its three independent solutions,", "cite_spans": [], "ref_spans": []}, {"section": "Special cases and MeijerG functions", "text": "where the C i are arbitrary constants. Expanding in series the first 0 F 2 function entering this solution we get", "cite_spans": [], "ref_spans": []}, {"section": "Special cases and MeijerG functions", "text": "This series does not exist when \u03b1 or \u03b2 are zero or negative integers, and the same happens when the p F q parameters entering any of the other two independent solutions is a non-positive integer. By inspection, however, one of the three p F q functions entering the solution in (21) always exists, because there are no \u03b1 and \u03b2 such that the three 0 F 2 functions simultaneously contain non-positive integer parameters. Consider now the second independent solution, x 1\u2212\u03b2 0 F 2 ( ; 2 \u2212 \u03b2, 1 + \u03b1 \u2212 \u03b2; x): when \u03b2 = 1 it becomes equal to the first one and so we have only two independent p F q solutions. In the same way, when \u03b1 = 1 the first and third solutions entering (21) are the same and when \u03b1 = \u03b2 the second and third solutions are the same. And when the two conditions hold, that is \u03b1 = \u03b2 = 1, actually the three solutions are the same. Notwithstanding, in these cases too one of the three 0 F 2 solutions always exists.", "cite_spans": [], "ref_spans": []}, {"section": "Special cases and MeijerG functions", "text": "The same two type of special cases exist for the 1 F 2 , 2 F 2 and 3 F 2 function solutions and the problem at hand consists of having a way to represent the three independent solutions to (1) without introducing integrals or iterating reductions of order 9 . For this purpose, we use a set of 3 MeijerG functions for each of the four p F q families that can be used to replace the missing p F q solutions in these special cases. The key observation is that at these special values of the last two parameters of the p F q functions the MeijerG replacements exist, satisfy the same differential equation and are independent of the available p F q function solutions. A table with these 3 x 4 = 12 MeijerG function replacements is as follows: ", "cite_spans": [{"start": 256, "end": 257, "text": "9", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "Special cases and MeijerG functions", "text": "This equation has two regular singularities at {0, \u221e} and two irregular singularities at {\u22121, 1}. Following the steps mentioned in the Summary, we rewrite the equation in normal form and, in step 2.(a), compute the value of k leading to an equation with minimal degrees entering J n (x) in (15) . The value of k found is k = 2 so the equation from which (23) is derived changing x \u2192 x 2 is", "cite_spans": [{"start": 290, "end": 294, "text": "(15)", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "Special cases and MeijerG functions", "text": "and has invariants with minimal degrees with respect to power transformations. In step 2.(b), analyzing the structure of singularities of (24) we find one regular singularity at the origin and one irregular at \u221e. Using the classification discussed in section 3.2 based on the degrees with respect to x of the numerators and denominators of the invariants of (24) ", "cite_spans": [], "ref_spans": []}, {"section": "Special cases and MeijerG functions", "text": "Composing M above with the power transformation used to obtain (24) and using the values above for \u03b1 and \u03b2, in step 4 we obtain the solution of (23) Consider the following equation, with no symbolic parameters and only integer powers", "cite_spans": [], "ref_spans": []}, {"section": "Special cases and MeijerG functions", "text": "Following steps 1 and 2 in the Summary, the routines confirm that there is no possible equivalence under", "cite_spans": [], "ref_spans": []}, {"section": "Special cases and MeijerG functions", "text": "y, so in step 3 they search for a rational transformation minimizing the degrees of the invariants (16), finding", "cite_spans": [], "ref_spans": []}, {"section": "Special cases and MeijerG functions", "text": "Therefore (27) can be obtained by changing variables x \u2192 R(x) in", "cite_spans": [], "ref_spans": []}, {"section": "Special cases and MeijerG functions", "text": "This equation 10 has invariants with minimal degrees and has one regular singularity at 1 and one irregular at the origin. According to the classification in terms of singularites (29) admits an equivalence under M\u00f6bius transformations to the p F q equations ( 1 F 2 case) and hence is solved in the iteration mentioned in the summary. When constructing the p F q solutions to (29), however, the routines find that the 1 F 2 parameters in the second list are both equal to 1, so only one 1 F 2 solution is available, and hence two of the MeijerG alternative solutions presented in the table (5) ", "cite_spans": [], "ref_spans": []}, {"section": "Special cases and MeijerG functions", "text": "Note that the first p F q function is a 0 F 1 . This is due to the automatic cancellation of identical parameters in both lists of a 1 F 2 function; this 0 F 1 can also be expressed in terms of Bessel functions.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "In this work we presented an algorithm for third order linear ODEs, which computes three independent solutions even when they are not Liouvillian or when the hypergeometric parameters involved are such that only two or one p F q solution around the orign exists. This algorithm solves complete ODE families we didn't know how to solve before. The strategy used is that of resolving an equivalence problem to the 3 F 2 , 2 F 2 , 1 F 2 and 0 F 2 equations, and in doing so, two important generalizations of the algorithm presented in [8] were developed. First, the classification according to singularities and the use of power composed with M\u00f6bius transformations, presented in [8] for 2nd order equations, was generalized for third order ones. Second, the idea of resolving the equivalence mapping into an equation with invariants with \"minimal degrees under power transformations\" was generalized by determining a transformation mapping into an equation having invariants with \"minimal degrees under general rational transformations\". This permits resolving a much larger class of p F q equations, defined by changing variables in (3) using {x \u2192 R(x), y \u2192 P (x) y} where R(x) is a rational function.", "cite_spans": [{"start": 532, "end": 535, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 677, "end": 680, "text": "[8]", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "Conclusions", "text": "Routines implementing this algorithm were integrated into the Maple system in 2007. To the best of our knowledge there are no equivalent routines or similar algorithms implemented in any of the Axiom, Maple, Mathematica, MuPAD or Reduce computer algebra systems (CAS). These CAS frequently fail whenever the linear ODE solution admits no Liouvillian form, but for restricted success (simple forms of F (x) entering (4)) by previous Maple and Mathematica existing routines.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "Since at the core of the algorithm there is the concept of singularities, two natural extensions of this work consist of applying the same ideas to compute solutions for linear ODEs of arbitrary order, where the equivalence can be solved exactly [12] , and for second order equations under rational transformations, perhaps generalizing the work by M.Bronstein [7] with regards to 1 F 1 solutions. Related work is in progress.", "cite_spans": [{"start": 246, "end": 250, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 361, "end": 364, "text": "[7]", "ref_id": "BIBREF6"}], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Liouvillian solutions of linear differential equations of order three and higher", "authors": [{"first": "M", "middle": [], "last": "Van Hoeij", "suffix": ""}, {"first": "J", "middle": ["F"], "last": "Ragot", "suffix": ""}, {"first": "F", "middle": [], "last": "Ulmer", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Weil", "suffix": ""}], "year": 1999, "venue": "J. Symb. Comp", "link": "6411972"}, "BIBREF1": {"title": "Hypergeometric Functions and Their Applications", "authors": [{"first": "J", "middle": ["B"], "last": "Seaborn", "suffix": ""}], "year": 1991, "venue": "Text in Applied Mathematics", "link": "117097056"}, "BIBREF2": {"title": "Handbook of mathematical functions", "authors": [{"first": "M", "middle": [], "last": "Abramowitz", "suffix": ""}, {"first": "I", "middle": ["A"], "last": "Stegun", "suffix": ""}], "year": 1964, "venue": "", "link": "117843805"}, "BIBREF3": {"title": "Equivalence of Differential Operators", "authors": [{"first": "N", "middle": [], "last": "Kamran", "suffix": ""}, {"first": "P", "middle": ["J"], "last": "Olver", "suffix": ""}], "year": 1989, "venue": "SIAM J. Math. Anal", "link": "523471"}, "BIBREF4": {"title": "Finding All Hypergeometric Solutions of Linear Differential Equations", "authors": [{"first": "M", "middle": [], "last": "Petkovsek", "suffix": ""}, {"first": "B", "middle": [], "last": "Salvy", "suffix": ""}], "year": 1993, "venue": "Proceedings of ISSAC '93", "link": "16347937"}, "BIBREF5": {"title": "An extensible differential equation solver for computer algebra", "authors": [{"first": "B", "middle": [], "last": "Willis", "suffix": ""}], "year": 2001, "venue": "SIGSAM", "link": null}, "BIBREF6": {"title": "Solutions of linear ordinary differential equations in terms of special functions", "authors": [{"first": "M", "middle": [], "last": "Bronstein", "suffix": ""}, {"first": "S", "middle": [], "last": "Lafaille", "suffix": ""}], "year": 2002, "venue": "Proceedings of ISSAC'02", "link": "6229086"}, "BIBREF7": {"title": "Non-Liouvillian solutions for second order linear ODEs", "authors": [{"first": "L", "middle": [], "last": "Chan", "suffix": ""}, {"first": "E", "middle": ["S"], "last": "Cheb-Terrab", "suffix": ""}], "year": 2004, "venue": "Proceedings of ISSAC'04", "link": "6347047"}, "BIBREF8": {"title": "Recognizing MeijerG ODEs for higher order", "authors": [{"first": "G", "middle": [], "last": "Labahn", "suffix": ""}], "year": 2001, "venue": "", "link": null}, "BIBREF9": {"title": "FRAC: A Maple package for computing in the rational function field K(x)", "authors": [{"first": "C", "middle": [], "last": "Alonso", "suffix": ""}, {"first": "J", "middle": [], "last": "Gutierriez", "suffix": ""}, {"first": "T", "middle": [], "last": "Recio", "suffix": ""}], "year": 1994, "venue": "Proceedings of the Maple Summer Workshop and Symposium", "link": "59885102"}, "BIBREF10": {"title": "Equivalence methods for second order linear differential equations", "authors": [{"first": "K", "middle": [], "last": "B\u00fclow", "suffix": ""}], "year": 2000, "venue": "", "link": null}, "BIBREF11": {"title": "ODE trends in computer algebra: four linear and nonlinear challenges", "authors": [{"first": "E", "middle": ["S"], "last": "Cheb-Terrab", "suffix": ""}], "year": 2002, "venue": "proceedings of the Maple Summer Workshop", "link": "15079206"}, "BIBREF12": {"title": "Ordinary Differential Equations", "authors": [{"first": "E", "middle": ["L"], "last": "Ince", "suffix": ""}], "year": 1956, "venue": "", "link": "125571791"}, "BIBREF13": {"title": "Concise Encyclopedia of Mathematics", "authors": [{"first": "E", "middle": ["W"], "last": "Weisstein", "suffix": ""}], "year": 1999, "venue": "", "link": "118555429"}, "BIBREF14": {"title": "Functional decomposition of parameterized invariants", "authors": [{"first": "E", "middle": ["S"], "last": "Cheb-Terrab", "suffix": ""}, {"first": "A", "middle": ["D"], "last": "Roche", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF15": {"title": "A Rational Function Decomposition Algorithm by Near-separated Polynomials", "authors": [{"first": "C", "middle": [], "last": "Alonso", "suffix": ""}, {"first": "J", "middle": [], "last": "Gutierriez", "suffix": ""}, {"first": "T", "middle": [], "last": "Recio", "suffix": ""}], "year": 1995, "venue": "Journal of Symbolic Computation", "link": "35972061"}, "BIBREF16": {"title": "Cadecom: Computer Algebra software for functional DECOMposition", "authors": [{"first": "J", "middle": [], "last": "Gutierrez", "suffix": ""}, {"first": "R", "middle": [], "last": "Rubio", "suffix": ""}], "year": 2000, "venue": "Computer Algebra in Scientific Computing CASC'00", "link": "59869034"}}, "ref_entries": {"FIGREF2": {"text": "Meijerg functions and equivalence under rational transformations for the 1 F 2 class", "type": "figure"}, "TABREF0": {"text": "MeijerG alternative solutions to the p F q equations", "type": "table"}, "TABREF1": {"text": "as well as the factors entering these denominators the equation is identified as equivalent to the 0 F 2 class under M\u00f6bius transformations (6). So we proceed with step 2.(c), constructing the M\u00f6bius transformation and computing the values of the hypergeometric parameters {\u00b5, \u03bd} entering the 0 F 2 equation in (3) such that the equivalence under M\u00f6bius exists, obtaining:", "type": "table"}}}
{"paper_id": "10702430", "_pdf_hash": "569f83f731b9ce30daa63409c6a3d07370e9194c", "abstract": [{"section": "Abstract", "text": "Background: It is often desirable to separate effects of different regulators on gene expression, or to identify effects of the same regulator across several systems. Here, we focus on the rat brain following stroke or seizures, and demonstrate how the two tasks can be approached simultaneously.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Background", "text": "Stroke and seizures-induced neurodegeneration share a number of biological processes, including increased neuronal activity, neuronal plasticity, inflammation, and apoptosis [1, 2] . Separation of effects of these processes on gene expression, identification of participating transcription factors, and comparison of transcriptional regulation between the two pathological conditions remain a challenging task. Global gene expression following stroke and seizures were compared before at a single time-point [3] , but no comparison of time-series gene profiling datasets from the two conditions was reported to date.", "cite_spans": [{"start": 174, "end": 177, "text": "[1,", "ref_id": "BIBREF0"}, {"start": 178, "end": 180, "text": "2]", "ref_id": "BIBREF1"}, {"start": 508, "end": 511, "text": "[3]", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "Background", "text": "Alter et al. first introduced a concept that orthogonal components (eigensystems) resulting from the singular value decomposition (SVD) of time-series gene expression dataset [4, 5] may help to separate concurrent effects of different processes and regulators on gene expression. These authors proposed that an eigen array may reflect a genome-wide input from a particular regulator, with the corresponding eigen gene reflecting this regulator's activity across the samples (arrays). For an illustration of the SVD nomenclature, when applied to gene expression -see Additional file 1.", "cite_spans": [{"start": 175, "end": 178, "text": "[4,", "ref_id": "BIBREF3"}, {"start": 179, "end": 181, "text": "5]", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "Background", "text": "A number of recent studies concentrated on usefulness of eigengenes [6] [7] [8] [9] [10] , whereas the properties and interpretation of eigenarrays remained relatively less explored. We previously suggested that conservation of eigenarrays between related biological systems may identify eigensystems of biological origin [11] . In the same work, utilizing a comparative SVD approach we identified an eigensystem conserved between hippocampal development and differentiation of hippocampal neurons in vitro. Analysis of cis-regulation of that eigensystem revealed that it reflected exit of neural precursors from the cell cycle and beginning of neuronal differentiation, regulated by transcription factors E2f1 and Nr2f1 [12] .", "cite_spans": [{"start": 68, "end": 71, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 72, "end": 75, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 76, "end": 79, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 80, "end": 83, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 84, "end": 88, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 322, "end": 326, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 721, "end": 725, "text": "[12]", "ref_id": "BIBREF11"}], "ref_spans": []}, {"section": "Background", "text": "Bayesian Networks (BN) learning approach is a wellestablished method of modelling gene regulation and interactions between gene regulatory motifs, starting from gene expression data [13] or gene expression and genomic sequence data [14] [15] [16] [17] [18] [19] [20] . The use of linear regression in analysis of gene cis-regulation is grounded in the linear response model of gene regulation [21, 22] .", "cite_spans": [{"start": 182, "end": 186, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 232, "end": 236, "text": "[14]", "ref_id": "BIBREF13"}, {"start": 237, "end": 241, "text": "[15]", "ref_id": "BIBREF14"}, {"start": 242, "end": 246, "text": "[16]", "ref_id": "BIBREF15"}, {"start": 247, "end": 251, "text": "[17]", "ref_id": "BIBREF16"}, {"start": 252, "end": 256, "text": "[18]", "ref_id": "BIBREF17"}, {"start": 257, "end": 261, "text": "[19]", "ref_id": "BIBREF18"}, {"start": 262, "end": 266, "text": "[20]", "ref_id": "BIBREF19"}, {"start": 393, "end": 397, "text": "[21,", "ref_id": "BIBREF20"}, {"start": 398, "end": 401, "text": "22]", "ref_id": "BIBREF21"}], "ref_spans": []}, {"section": "Background", "text": "Here, we report a time-series dataset from gene expression profiling in the rat MCAO model of stroke, and compare these data to the published time-series dataset from the kainate-induced seizures model [23] . By comparative SVD approach, followed by Bayesian network analysis of cis-regulation, we identified two conserved eigensystems separating the effects of different well-defined biological processes on gene expression and regulated by distinct sets of transcription factor binding sites. The results obtained on either dataset were validated on the other.", "cite_spans": [{"start": 202, "end": 206, "text": "[23]", "ref_id": "BIBREF22"}], "ref_spans": []}, {"section": "Results", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Experimental data and analysis setup", "text": "We compared two time-series gene expression datasets from experimental rat models of stroke and epilepsy, which were the transient middle-cerebral artery occlusion (MCAO) and the kainate-induced seizures, respectively. The MCAO dataset was generated in our laboratory and probed gene expression in the cortex of the ischemic hemisphere at four time-points (6, 12, 24, 48 h ) following a 90 minutes occlusion of the right middle-cerebral artery in adult anesthetized rats, and included sham-operated animals as controls. The kainate dataset, published by Koh and co-workers [23] probed gene expression in the hippocampus of adult rats at five time-points (1, 6, 24, 72, 240 h) following the injection of kainate -a neurotransmitter analogue inducing seizures, which can last for several hours, followed by a seizure-free latent period.", "cite_spans": [{"start": 573, "end": 577, "text": "[23]", "ref_id": "BIBREF22"}], "ref_spans": []}, {"section": "Experimental data and analysis setup", "text": "As immobilization of a conscious animal and injection alters gene expression in the brain, this dataset included a control time-series following the injection of saline.", "cite_spans": [], "ref_spans": []}, {"section": "Experimental data and analysis setup", "text": "The overall design of our study is illustrated in Figure  1 . We transform each dataset (MCAO, kainate) separately by SVD ( Figure 1A ) and identify eigenarrays conserved between the two systems ( Figure 1B ). This is followed by analysis of biological function using Gene Ontology (GO), and gene cis-regulation using Bayesian networks (BN) and our TRAM database of putative regulatory regions and motifs. These analyses are performed separately for either dataset and then the results for the corresponding eigensystems are compared (GO terms) or statistically cross-validated (BN results) on the other dataset. The cross-validation between the stroke and seizures data is not contradictory with the goal of gaining information by comparison of the two, because the two experimental models can be assumed -on biological grounds -to share some, but not all, regulatory mechanisms. Note that features specific for one model can be identified, as for each model we separately account for the multiplicity of testing. The eigenarrays resulting from the SVD of either dataset were compared by correlation analysis performed for the genes common between the two datasets. (C) For the emerging conserved eigensystems 2 and 3, separately for all the genes in either dataset, we studied their functional Gene Ontology (GO) associations and employed Bayesian Networks (BN) to study their cis-regulation. The results obtained on one dataset were then compared (GO) or statistically tested (BN) on the other.", "cite_spans": [], "ref_spans": [{"start": 50, "end": 59, "text": "Figure  1", "ref_id": "FIGREF0"}, {"start": 124, "end": 133, "text": "Figure 1A", "ref_id": "FIGREF0"}, {"start": 197, "end": 206, "text": "Figure 1B", "ref_id": "FIGREF0"}]}, {"section": "Distinct eigengenes following stroke and seizures", "text": "The global temporal changes in gene expression following MCAO in the stroke model are dominated by the top three eigensystems (Figure 2A ). The eigengene of the first eigensystem in the MCAO dataset (M1, \"M\" to indicate MCAO) is constant in time (data not shown) in the log-expression space and thus represents the average level of expression across all the conditions. The second eigengene (M2) represents an increased expression, as compared to control value, at 12-48 h following MCAO, with a peak at 12 h ( Figure 2B ). The third eigengene (M3) represents a complex pattern with an increase in gene expression at 12 h followed by down-regulation of expression at 24 h and further drop at 48 h ( Figure 2C ). Notably, the three top eigengenes indicate no changes in gene expression at 6 h after MCAO, which is in agreement with our earlier PCR results showing no changes in mRNA levels of a smaller number of genes [24] .", "cite_spans": [{"start": 918, "end": 922, "text": "[24]", "ref_id": "BIBREF23"}], "ref_spans": [{"start": 126, "end": 136, "text": "(Figure 2A", "ref_id": "FIGREF1"}, {"start": 511, "end": 520, "text": "Figure 2B", "ref_id": "FIGREF1"}, {"start": 699, "end": 708, "text": "Figure 2C", "ref_id": "FIGREF1"}]}, {"section": "Distinct eigengenes following stroke and seizures", "text": "The global temporal pattern of gene expression following kainate-induced seizures in adult rats is dominated by the top three eigensystems ( Figure 2D ), of which the first again represents the magnitude (data not shown). The second eigengene (A2), represents an increased expression following the injection of kainate; starting at 1 h, largest at 6 and 24 h, returning to the baseline level at 72 and 240 h; and no change at any time-point after the injection of saline ( Figure 2E ). The third eigengene (A3) represents an increased expression at 1 and 6 h after the injection of kainite; followed by strong decrease in expression at 24 h, continuing, but less pronounced, also at the 72 and 240 h ( Figure 2F ).", "cite_spans": [], "ref_spans": [{"start": 141, "end": 150, "text": "Figure 2D", "ref_id": "FIGREF1"}, {"start": 473, "end": 482, "text": "Figure 2E", "ref_id": "FIGREF1"}, {"start": 702, "end": 711, "text": "Figure 2F", "ref_id": "FIGREF1"}]}, {"section": "Distinct eigengenes following stroke and seizures", "text": "Despite their overall similarity, the corresponding eigengenes are distinct between the two experimental models. In particular, eigengenes M2 and M3 show no change in expression at 6 h following the MCAO, in contrast to eigengenes A2 and A3, showing an increase at 6 h following the injection of kainate.", "cite_spans": [], "ref_spans": []}, {"section": "Conserved eigenarrays following stroke and seizures", "text": "The kainate datasets comprised of expression profiles for 2786 genes (distinct Ensembl gene_stable_id) that significantly changed expression and the stroke dataset consisted of 2392 such genes, with 737 genes common between the two datasets. The correlation analysis revealed that the top three eigenarrays (compared for the common genes) were highly correlated ( Figure  2G ). The correlations between the respective first, second, and third eigenarrays were 0.87, 0.84, and 0.63, respectively. Note that the correspondence between the three conserved eigenarrays was one-to-one. Given the length (737) of the correlated vectors, these correlations are highly significant (p-values: 10 -229 , 10 -197 , 10 -83 , respectively, assuming independence of genes). This indicates that the top three eigenarrays are highly conserved between the two datasets. Figure 2H -I shows directly genes' loadings of the respective second (H) or third (I) eigensystem in the two datasets, sorted on their average loading in both datasets. This sorting of the genes aids visualization of the eigenarrays conservation, but is not in any way a reason for it, as the correlations shown in Figure 2G were computed before the sorting (and would not be affected by it, anyway). The tangent-like shape of the plots reflects the bell shape of the distributions of genes' loadings of eigensystems 2 and 3.", "cite_spans": [], "ref_spans": [{"start": 364, "end": 374, "text": "Figure  2G", "ref_id": "FIGREF1"}, {"start": 853, "end": 862, "text": "Figure 2H", "ref_id": "FIGREF1"}, {"start": 1168, "end": 1177, "text": "Figure 2G", "ref_id": "FIGREF1"}]}, {"section": "Conserved eigenarrays following stroke and seizures", "text": "Further, we focus on eigensystems 2 and 3 characterized by conservation of their eigenarrays occurring despite differences between the corresponding eigengenes ( Figure 2B vs. E, C vs. F). This suggests that the two eigensystems reflect regulatory inputs operating in both systems, but with different kinetics and relative strengths.", "cite_spans": [], "ref_spans": [{"start": 162, "end": 171, "text": "Figure 2B", "ref_id": "FIGREF1"}]}, {"section": "Separation of effects of biological processes on gene expression", "text": "A universal reason underlying co-regulation of genes is participation of their products in a common biological process. To assess if the contribution of the eigensystems 2 and 3 to the gene expression profiles is associated with biological functions, we analyzed the Gene Ontology \"biological process\" annotations of all genes in either dataset, ranked on the loadings of the respective eigensystems 2-3.", "cite_spans": [], "ref_spans": []}, {"section": "Separation of effects of biological processes on gene expression", "text": "In both experimental models, the positive loading of the second eigensystem was significantly associated with overlapping GO terms describing the inflammatory response to the brain injury ( Figure 3A, B) . Additionally, in the MCAO system the positive loading of eigensystem M2 was also significantly associated with GO terms describing programmed cell death (apoptosis).", "cite_spans": [], "ref_spans": []}, {"section": "Separation of effects of biological processes on gene expression", "text": "In the kainate system, the positive loading of eigensystem A3 was highly significantly associated with several overlapping GO terms describing neuronal activity, such as: synaptic transmission, transmission of the nerve impulse ( Figure 3C ). No such association was detected for third eigensystem (M3) from the SVD on the MCAO dataset, following its initial filtering (ANOVA p-value < 0.05). However, when the GO analysis was repeated for the third eigenarray in the SVD result on the MCAO dataset filtered at ANOVA p-value < 0.5 and thus containing more genes, there was a clear association between the loadings of the third eigensystem and GO terms describing neuronal activity ( Figure 3D ). Loosening of the p-value threshold was possible, because the top three eigensystems were extremely robust to the change of the p-value threshold, with eigenarrays correlations > 0.999 between vectors of length 2786 for the change of the threshold from 0.05 to 0.5 (data not shown). Comparison of the singular values ( Figure 2A vs. 2D) indicates that the relative contribution of the conserved third eigensystem (reflecting neuronal activity) was higher in the kainate system, while the relative contribution of the conserved second eigensystem (reflecting inflammation and/or apoptosis) was higher in the stroke.", "cite_spans": [], "ref_spans": [{"start": 1014, "end": 1023, "text": "Figure 2A", "ref_id": "FIGREF1"}]}, {"section": "Bayesian networks analysis of cis-regulation of the conserved eigensystems", "text": "Conservation of eigenarrays suggests that they reflect regulatory mechanisms, possibly operating at the level of transcription regulation. To identify such mechanisms, we employed Bayesian networks, previously successfully applied to modelling transcriptional regulation [14, 15, [17] [18] [19] [20] . We follow the above approaches in general, but several essentials are specific to our methodology:", "cite_spans": [{"start": 271, "end": 275, "text": "[14,", "ref_id": "BIBREF13"}, {"start": 276, "end": 279, "text": "15,", "ref_id": "BIBREF14"}, {"start": 280, "end": 284, "text": "[17]", "ref_id": "BIBREF16"}, {"start": 285, "end": 289, "text": "[18]", "ref_id": "BIBREF17"}, {"start": 290, "end": 294, "text": "[19]", "ref_id": "BIBREF18"}, {"start": 295, "end": 299, "text": "[20]", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "Bayesian networks analysis of cis-regulation of the conserved eigensystems", "text": "\u2022 Regulation of gene expression is analysed separately for each conserved eigensystem. In the subspace of a given eigensystem gene expression is binarized into up-and down-regulation, according to the sign of its loading. (Figure 4B , D).", "cite_spans": [], "ref_spans": []}, {"section": "Bayesian networks analysis of cis-regulation of the conserved eigensystems", "text": "\u2022 Our combinatorial model of cis-regulation takes into account fragmentation of metazoan cis-regulatory regions into multiple conserved non-coding sequences (CNSs) [25, 26] , and distinguishes between co-occurrence of several TF-binding motifs in the Figure 3 Functional Gene Ontology annotations associated with the conserved eigensystems (A-D) Association of loadings of the conserved eigensystems with the functional annotations from the GO \"biological process\" ontology were analyzed by Wilcoxon sign rank test using RankGOstat [55] . Twenty GO terms most associated with a given eigensystem, and their association FDR q-values are shown as bar plots. For the plots the q-values were log10-transformed and multiplied by +1 or -1, to reflect association with the positive or negative loadings of a particular eigensystem. GO terms with overlapping meanings (identified by human inspection) are indicated by the same colour of the bars, with red marking terms related to \"synaptic transmission\", blue marking terms similar to \"inflammatory response\", and black marking terms describing cell death/apoptosis.", "cite_spans": [{"start": 164, "end": 168, "text": "[25,", "ref_id": "BIBREF24"}, {"start": 169, "end": 172, "text": "26]", "ref_id": "BIBREF25"}, {"start": 532, "end": 536, "text": "[55]", "ref_id": "BIBREF55"}], "ref_spans": []}, {"section": "Bayesian networks analysis of cis-regulation of the conserved eigensystems", "text": "same CNS and their co-occurrence in the same gene ( Figure 4A , C). Following previous work [27, 28] , we term every possible subset of the motifs present in the same CNS a composite motif.", "cite_spans": [{"start": 92, "end": 96, "text": "[27,", "ref_id": "BIBREF26"}, {"start": 97, "end": 100, "text": "28]", "ref_id": "BIBREF27"}], "ref_spans": []}, {"section": "Bayesian networks analysis of cis-regulation of the conserved eigensystems", "text": "\u2022 Regulatory mechanism is predicted by learning Bayesian networks with an exact algorithm. Computations are performed by double application of the BNFinder program [29] . The first run selects the most promising composite motifs (possibly single motifs), while the second run selects the sets of such composite motifs that best predict the sign of the loading the chosen eigensystem ( Figure 4E , F).", "cite_spans": [{"start": 164, "end": 168, "text": "[29]", "ref_id": "BIBREF28"}], "ref_spans": []}, {"section": "Bayesian networks analysis of cis-regulation of the conserved eigensystems", "text": "Four BN analyses were performed, separately for each conserved eigensystem in either experimental model (M2, A2, M3, A3). BN scores were directly converted to q-values -the false discovery rate [30] analogue of p-values, by comparing each feature's score on the Figure 4 Bayesian network model of fragmented cis-regulatory regions (A, C) Sequence preprocessing consists of extracting instances of composite motifs i.e. sets of (up to three motifs) in the same conserved non-coding sequence (CNS), from the flanks of transcription start sites of all human-rat orthologous genes. (B, D) Expression data preprocessing consists of SVD, followed by discretization of expression into up-and down-regulation in the subspace of a particular conserved eigensystem -based on the sign of its loading. (C, D) Composite motifs and expression data are combined in one dataset, in which the data records correspond to genes. (E) This dataset becomes an input for our Bayesian networks (BN) learning algorithm, which identifies sets of composite motifs most associated with the sign of loadings of a given eigensystem. (F) The final output consists of a ranking of such sets, with conditional probability distributions representing their impact on a given eigensystem. BN learning was performed independently for each of the eigensystems: A2, A3, M2, M3; on the data for all the genes in the respective dataset. Eigensystem A3 is shown as an example.", "cite_spans": [{"start": 194, "end": 198, "text": "[30]", "ref_id": "BIBREF29"}], "ref_spans": []}, {"section": "Bayesian networks analysis of cis-regulation of the conserved eigensystems", "text": "original data to the distribution of scores from 1000 BN analyses on permuted data -each following an independent random permutation and assignment of expression values to the genes' putative cis-regulatory regions. The conservation of the two eigensystems between the stroke allowed for selection of best features on one dataset (we choose up to ten features with training q-values < 0.05) and then testing them on the other -containing the data for largely different genes. The training and testing were performed for the conserved second ( Figure 5A , B) and third eigensystem ( Figure 5C , D) in both directions. During the test we used the same q-values as during the training, i.e. they were corrected for all the hypotheses ever looked at on the test dataset. We note that this is a very stringent correction, as only up to 20 hypotheses Figure 5 BN analysis of cis-regulation for the conserved eigensystems. The four tables (A-D) present the results of BN analysis of cisregulation for the conserved second and third eigensystems from either dataset, followed by testing of highest-ranking features on the corresponding eigensystem from the other dataset. In each panel, the column Feature lists up to 10 nonempty sets of composite motifs with highest BN score and q-value < 0.05 on the indicated training dataset. Note that single motifs are included in the set of composite motifs. BN score of a composite motif set is the ratio of its posterior probability to the posterior probability of the empty set. The corresponding q-value derives from the permutational test. The shaded columns give the values of BN score and the corresponding q-value for the same feature computed on the other (test) dataset. Red color marks the cells with the test q-values < 0.05 for the features that also had training q-value < 0.05 and the descriptions of such features are given in bold. The q-values take into account the multiplicity of testing for each dataset separately, so it is possible to identify the features significant for one dataset only. (E, F) The conditional probability tables for the pairs of motifs: {AP1F, SATB} (E) and {EGRF, LHXF} (F).", "cite_spans": [], "ref_spans": []}, {"section": "Bayesian networks analysis of cis-regulation of the conserved eigensystems", "text": "were considered for each eigensystem during the test stage (up to ten for either direction of the comparison).", "cite_spans": [], "ref_spans": []}, {"section": "Bayesian networks analysis of cis-regulation of the conserved eigensystems", "text": "Antagonistic effects of motifs binding AP1 and SATB on gene expression following the stroke BN search identified just one feature, namely the motif AP1F -a family of binding sites for the transcription factor AP1 (Additional file 2) as the feature significantly (q-value < 0.05) associated with the positive sign of eigensystem A2 in the kainate model ( Figure 5A , columns: \"Training: Kainate\"). Notably, this feature was significantly associated with the corresponding eigensystem M2, when tested on the dataset from the MCAO model ( Figure 5A , column Test: MCAO). The choice of the MCAO data as the training dataset resulted in identification of 7 significant features, of which the second was again AP1F, and only this feature was significant also in the cross-system test on the kainate dataset ( Figure 5B , columns \"Test: kainate\"). All remaining features identified as significant (q-value < 0.05) on the training datasets included AP1F as one motif, and two of them were pairs of AP1F with another motif in the same gene. Of the features significant in the MCAO system, particularly interesting is the pair {AP1F, SATB} -a set of two motifs co-occurring in the same gene, which have antagonistic effects on expression in the subspace of eigensystem M2. The presence of motif AP1F in the absence of SATB in the same gene was associated with the positive sign of M2 loading, while the presence of SATB in the absence of AP1F was associated with the negative M2 loading ( Figure 5E ).", "cite_spans": [], "ref_spans": []}, {"section": "Bayesian networks analysis of cis-regulation of the conserved eigensystems", "text": "Identification of known and new regulators/targets for the eigensystem reflecting synaptic activity BN search identified a number of features as highly significantly (q-value < 0.001) associated with the sign of M3 loading during the training on the kainate dataset. The ten highest-ranking features, ranked on their BN score were tested on the MCAO dataset ( Figure 5C ). Of the top ten features significant on the kainate dataset, four were also significant on the MCAO dataset. All of these features, marked in bold in Figure 5C , were pairs of motifs co-occurring in the same gene. All these pairs contained LHXF as one motif, with EGRF, AHRR, ZF5F or ZBPF as the other motif. The highest-ranking featurethe pair EGRF and LHXF in the same gene, but neither motif of its own, was 79% specific for the positive sign of eigensystem 3 ( Figure 5F ). When the training was performed on the MCAO dataset, several features significantly (q-value < 0.001) associated with the sign of M3 were identified ( Figure 5D ). Importantly, out of the top ten features identified on the stroke dataset, nine were also significantly associated with the same sign of M3 on the kainate dataset. The features significant in the cross-system test were either single motifs (AP1R, PARF, CREB, AHRR) or pairs of motifs in the same gene. All these pairs contained AP1R as one motif, with PARF, AHRR, ZF5F, EGRF, E4FF as the other motif. Three motifs, namely EGRF, ZF5F, AHRR were common between the top ten features identified during training on the kainate and the MCAO datasets.", "cite_spans": [], "ref_spans": []}, {"section": "Effects of multiplicity of motifs and CNSs on gene logexpression", "text": "We wanted to check if a model taking into account motif multiplicity would allow a more precise prediction of the value of expression. Therefore, we applied a linear regression analysis to the motifs identified by BN analysis as significant in both systems, and additionally the motif SATB significant in the MCAO system only. For the reasons detailed in the Materials and methods, we always performed a weighted linear regression, with the average loadings in groups of genes with the same motif count as the response variable, and the weights set to the numbers of genes in each group, as suggested by Faraway [31] .", "cite_spans": [{"start": 612, "end": 616, "text": "[31]", "ref_id": "BIBREF30"}], "ref_spans": []}, {"section": "Effects of multiplicity of motifs and CNSs on gene logexpression", "text": "The regression analyses were performed separately for the MCAO and the kainate datasets. The linear regression confirmed that the AP1F and SATB motifs had antagonistic effects on expression in the subspace of eigensystem M2 (Figure 6A-C) . The count of motif SATB per gene had a clear linear (R 2 = 0.91) and highly significant (p = 1.6 \u00d7 10 -5 ) effect on the group-average expression in the subspace of eigensystem M2 ( Figure  6A ). In agreement with the earlier BN result, the count SATB had no effect on loading of eigensystem A2 (data not shown). The inhibitory effect of SATB on gene expression in the MCAO system was specific for eigensystem M2, with no inhibition of expression in the subspace of any other eigensystem (data not shown).", "cite_spans": [], "ref_spans": [{"start": 224, "end": 237, "text": "(Figure 6A-C)", "ref_id": "FIGREF3"}, {"start": 422, "end": 432, "text": "Figure  6A", "ref_id": "FIGREF3"}]}, {"section": "Effects of multiplicity of motifs and CNSs on gene logexpression", "text": "The count of motif AP1F had a significant, positive and possibly linear effect on the average expression in a subspace of the second eigensystem, both in the MCAO (p = 0.0019, R 2 = 0.64) and in the kainate dataset ( Figure 6B , p = 0.00059, R 2 = 0.71). Remarkably, when the effect of AP1F count on M2 loading was analyzed separately for the genes with and without motif SATB, the effect became more apparent for the genes without motif SATB ( Figure 6C , p = 0.00044, R 2 = 0.76), while the effect was nullified for the genes with the motif SATB ( Figure 6D) .", "cite_spans": [], "ref_spans": [{"start": 217, "end": 226, "text": "Figure 6B", "ref_id": "FIGREF3"}, {"start": 445, "end": 454, "text": "Figure 6C", "ref_id": "FIGREF3"}, {"start": 550, "end": 560, "text": "Figure 6D)", "ref_id": "FIGREF3"}]}, {"section": "Effects of multiplicity of motifs and CNSs on gene logexpression", "text": "The linear regression revealed that the count of motif CREB had a highly significant and approximately linear effect on the average expression in a subspace of the third eigensystem in the kainate ( Figure 7A eigensystem, in particular in the MCAO model, where it had no effect on the loadings of the eigensystem M2 (data not shown).", "cite_spans": [], "ref_spans": [{"start": 199, "end": 208, "text": "Figure 7A", "ref_id": "FIGREF4"}]}, {"section": "Effects of multiplicity of motifs and CNSs on gene logexpression", "text": "The effects of motif multiplicity on gene expression prompted us to investigate by the linear regression if a related variable -the count of conserved non-coding sequences (CNSs) per gene had an effect on gene expression. That we found was true in both experimental models (Figure 7E, F) . Similarly to the effect of CREB count, the effect of CNS count was highly specific for the third eigensystem (data not shown). However, when the effect of CNS count was analyzed in a bivariate linear regression model, together with that of CREB, the effect of the CNS was completely (MCAO) or nearly completely (kainate) dependent on the CNSs' content of Creb-binding motifs ( Figure 7E, F) .", "cite_spans": [], "ref_spans": [{"start": 273, "end": 287, "text": "(Figure 7E, F)", "ref_id": "FIGREF4"}, {"start": 667, "end": 680, "text": "Figure 7E, F)", "ref_id": "FIGREF4"}]}, {"section": "Discussion", "text": "Here, we demonstrated that eigensystems conserved between stroke and seizures separate effects of inflammation/apoptosis and synaptic activity on gene expression. The contribution of the eigensystem 3 reflecting synaptic activity was relatively greater (compared to eigensystem 2) in the seizures model, in agreement with higher electrical activity of neurons. Remarkably, our analysis of cis-regulation revealed that the these two functionally well-interpretable eigensystems were regulated by distinct sets of transcription factors, with AP1 and SATB regulating the eigensystem reflecting inflammation/apoptosis, and numerous TFs including Creb and Egr regulating the eigensystem reflecting neuronal synaptic activity.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "Activation of transcription factor AP1 following the kainate-induced seizures and cerebral ischemia is well established [32, 33] . In particular, Timp1 was shown to be the target of AP1 following kainate-induced seizures [34] . The mRNA profiles of Timp1 in both systems ( Figure 6E, F) are highly similar to the profiles of the respective second eigengenes, which is compatible with our identification of AP1 as the key regulator of this eigensystem. It is well established that activation of Mapk8-Jun/AP1 signalling pathway has a predominantly pro-apoptotic effect in neurons [35] , however, only few Mapk8-AP1 targets genes have been identified. Therefore, demonstrating the importance of the number of AP1-binding motifs per gene and the simultaneous absence of SATB motif for gene activation contributes to identification of AP1 target genes.", "cite_spans": [{"start": 120, "end": 124, "text": "[32,", "ref_id": "BIBREF31"}, {"start": 125, "end": 128, "text": "33]", "ref_id": "BIBREF32"}, {"start": 221, "end": 225, "text": "[34]", "ref_id": "BIBREF33"}, {"start": 579, "end": 583, "text": "[35]", "ref_id": "BIBREF34"}], "ref_spans": [{"start": 273, "end": 286, "text": "Figure 6E, F)", "ref_id": "FIGREF3"}]}, {"section": "Discussion", "text": "We report novel and exciting finding that presence of the motif binding Satb1 prevents -in a motif number dependent manner -transcriptional activation in the stroke system. Satb1, which is the best characterized MAR-binding protein, has recently emerged as a key factor integrating higher-order chromatin architecture and gene regulation -reviewed in [36] . Depending on cell type and locus, its effect on chromatin looping may either activate transcription, as described for Th2 interleukin gene cluster [37] , or inhibit transcription, as for the MHC class 1 locus [38] and tentatively for our eigensystem M2. A hypothetical mechanism, in which genes in longer chromatin loops, or at the peaks of the loops, are more accessible to binding or activation by AP1, is depicted in Figure 6G . Proteolytic degradation of Satb1 occurs during early phases of apoptosis [39] [40] [41] . In the current work, the effect of SATB motif on expression was limited to the MCAO eigensystem 2 associated with the apoptosis.", "cite_spans": [{"start": 351, "end": 355, "text": "[36]", "ref_id": "BIBREF35"}, {"start": 505, "end": 509, "text": "[37]", "ref_id": "BIBREF36"}, {"start": 567, "end": 571, "text": "[38]", "ref_id": "BIBREF38"}, {"start": 863, "end": 867, "text": "[39]", "ref_id": "BIBREF39"}, {"start": 868, "end": 872, "text": "[40]", "ref_id": "BIBREF40"}, {"start": 873, "end": 877, "text": "[41]", "ref_id": "BIBREF41"}], "ref_spans": [{"start": 778, "end": 787, "text": "Figure 6G", "ref_id": "FIGREF3"}]}, {"section": "Discussion", "text": "Our analysis of cis-regulation of conserved eigensystem 3 -reflecting neuronal (synaptic) activity correctly predicted the known role of Creb/Atf/E4f1 and Egr as key regulators of neuronal activity regulated genes, important for neuronal plasticity and memory -for review, see [42, 43] . CREB motif binds transcription factors of the Creb family [43] [44] [45] , while E4FF motif binds transcription factors from the Atf family. EGRF binds transcription factors of the Egr family [46, 47] . PARF binds PAR/bZIP family of TFs (Dbp, Hlf, Tef, and Vbp1). The motifs binding Creb, Atf and Vbp1 are similar (Additional file 2) and these transcription factors have been shown to bind to overlapping sites [48] . A loss of the PAR/bZIP transcription factors results in seizures [49] . Using classical experimental methods, about a hundred Creb target genes have been identified, of which about half encodes neuronspecific proteins -reviewed by Lonze & Ginty [44] . A genome-wide chromatin immunoprecipitation study by Impey et al. identified Creb binding genes in the neuron-like differentiating rat pheochromocytoma PC12 cells [50] . When this set of genes was analyzed in our datasets, we found a clear association between Crebbinding to the gene and the positive loading of the third eigensystem ( Figure 7D) . Thus, the experimental data of Impey and co-authors support our in silico results, demonstrating an importance of the presence of CREB motif for gene up-regulation in the subspace of eigensystem reflecting neuronal activity.", "cite_spans": [{"start": 277, "end": 281, "text": "[42,", "ref_id": "BIBREF42"}, {"start": 282, "end": 285, "text": "43]", "ref_id": "BIBREF43"}, {"start": 346, "end": 350, "text": "[43]", "ref_id": "BIBREF43"}, {"start": 351, "end": 355, "text": "[44]", "ref_id": "BIBREF44"}, {"start": 356, "end": 360, "text": "[45]", "ref_id": "BIBREF45"}, {"start": 480, "end": 484, "text": "[46,", "ref_id": "BIBREF46"}, {"start": 485, "end": 488, "text": "47]", "ref_id": "BIBREF47"}, {"start": 699, "end": 703, "text": "[48]", "ref_id": "BIBREF48"}, {"start": 771, "end": 775, "text": "[49]", "ref_id": "BIBREF49"}, {"start": 951, "end": 955, "text": "[44]", "ref_id": "BIBREF44"}, {"start": 1121, "end": 1125, "text": "[50]", "ref_id": "BIBREF50"}], "ref_spans": [{"start": 1294, "end": 1304, "text": "Figure 7D)", "ref_id": "FIGREF4"}]}, {"section": "Discussion", "text": "Much experimental evidence supports an important role of Egr transcription factors in brain function. Transcription factors from the Egr family are induced in the rat hippocampus following kainate-induced seizures with kinetics closely resembling eigengene A3 (data not shown) and regulate expression of Arc [51] , a gene important for neuronal plasticity and memory formation [52] . Transcriptional activation of Egrs was also demonstrated following brain ischemia -reviewed in [47] . In addition to Creb and Egr, our BN analysis identified several novel tentative transcriptional regulators of the eigensystem reflecting synaptic activity ( Figure 5 and Additional file 2).", "cite_spans": [{"start": 308, "end": 312, "text": "[51]", "ref_id": "BIBREF51"}, {"start": 377, "end": 381, "text": "[52]", "ref_id": "BIBREF52"}, {"start": 479, "end": 483, "text": "[47]", "ref_id": "BIBREF47"}], "ref_spans": []}, {"section": "Discussion", "text": "We demonstrate linear effects of the counts of the motifs SATB and CREB on log-expression in subspaces of the respective regulated eigensystems following the MCAO. These findings are in agreement with the predictions of the linear response model of gene regulation [21] . Moreover -because this model is valid only for TFs operating within the same cell -the observed agreement is revealing of the underlying biology ( Figure 7F) . First, it suggests that Satb and Creb operate within the same cells, namely neurons. This prediction is in agreement with our previous experimental data that majority of the cells undergoing apoptosis in the MCAO system are neurons [24] . Second, our results suggest that neuronal apoptosis is triggered by inflammation occurring in other cell types, namely microglia and astrocytes. This could explain why effects of inflammation and apoptosis are reflected by the same eigensystem, uncorrelated to the one reflecting effects of synaptic transmission.", "cite_spans": [{"start": 265, "end": 269, "text": "[21]", "ref_id": "BIBREF20"}, {"start": 664, "end": 668, "text": "[24]", "ref_id": "BIBREF23"}], "ref_spans": [{"start": 419, "end": 429, "text": "Figure 7F)", "ref_id": "FIGREF4"}]}, {"section": "Discussion", "text": "The observed linear effect of CNSs' count per gene on log-transformed gene expression, depending on their content of CREB, is very interesting in the context of high specificity of this effect (data not shown) for the conserved eigensystem reflecting neuronal synaptic activity. Lee et al. [53] reported relatively greater cumulative length of CNSs in the upstream regions of genes involved in development, cell communication, neural functions and signaling processes, and suggested that this may reflect their greater regulatory complexity. We suggest, as another possibility, that neuronal genes need more CNSs (putative enhancers) to accommodate CREB motifs needed for responsiveness to rapidly changing synaptic activity.", "cite_spans": [{"start": 290, "end": 294, "text": "[53]", "ref_id": "BIBREF53"}], "ref_spans": []}, {"section": "Discussion", "text": "Our results, demonstrating conservation of eigenarrays of temporal log-expression profiles, between hippocampus following seizures and cortex following the stroke, corroborate and extend recent findings of Oldham et al. [54] . These authors applied SVD to clusters ('modules' in their terminology) of expression profiles identified separately for several brain regions, and demonstrated conservation of 'module membership' between the corresponding clusters from different regions. As the 'module membership' is closely related to the first eigenarray of each cluster, their findings imply conservation of the first eigenarrays between the corresponding clusters. Our results demonstrate conservation of eigenarrays that occurs genome-wide for three eigensystems, two of which reflect distinct well-defined biological processes and are regulated via different sets of transcription factor binding sites.", "cite_spans": [{"start": 220, "end": 224, "text": "[54]", "ref_id": "BIBREF54"}], "ref_spans": []}, {"section": "Conclusions", "text": "Eigensystems conserved between stroke and seizures separate effects of different biological processes on gene expression, exerted via distinct sets of transcription factor binding motifs. Motif recognized by the nuclear matrix attachment region-binding protein Satb1 blocks AP1-driven transcriptional activation. The effects of motifs binding Creb and Satb1 on gene expression conform to the assumptions of the linear response model of gene regulation.", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "Gene expression profiling in the MCAO system Animals and surgical procedures", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "The experimental protocol was approved by the Local Animal Care and Use Committee and conforms to the national guidelines for the care and use of animals in research. 3-months old male Wistar rats weighing 270-320 g were used.", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "The MCAO (a middle cerebral artery occlusion) surgeries were performed under general halothane anaesthesia. Transient MCAO was induced with the intraluminal filament method (3-0 nylon monofilament suture) as described before [24] . A filament was withdrawn after 90 min. of MCAO to allow reperfusion, the incision was closed and anaesthesia discontinued. Sham-operated animals were subjected to the similar surgery with exception of MCA occlusion.", "cite_spans": [{"start": 225, "end": 229, "text": "[24]", "ref_id": "BIBREF23"}], "ref_spans": []}, {"section": "RNA isolation and microarray hybridization", "text": "At various times after reperfusion, sham-operated and MCAO subjected rats were anesthetized with an overdose of pentobarbital and decapitated. Brains were rapidly removed, bisected at the midline and dorsolateral fragments of cerebral cortex containing MCA territory was dissected from the ipsilateral to occlusion (right) and contralateral (left) hemisphere. Total RNA was extracted from the samples using a phenol-guanidine thiocyanatebased method (TRI REAGENT, Sigma, Germany) and cleaned using RNeasy Total RNA kit (Qiagen, Germany) according to the manufacturer's recommendations followed by DNAse treatment. The amount and quality of the RNA was determined by spectrophotometry and capillary electrophoresis. The microarray hybridizations were conducted in the microarray facility of the Institute of Oncology, Maria Sklodowska-Curie Memorial Cancer Center, Gliwice Branch, Gliwice, Poland. Each time-point (6, 12, 24, 48 h ) and sham-operated (sh) group consisted three animals per group; RNAs from each individual were separately labelled and analyzed by microarray hybridization, for a total of 15 microarray hybridizations. The experiment was loaded to ArrayExpress (accession E-MEXP-2222).", "cite_spans": [], "ref_spans": []}, {"section": "Source of the kainate gene expression data", "text": "The published dataset of Wilson et al. [23] from expression profiling in the hippocampus of adult rats with Affymetrix RG-U34A chip was downloaded from the NIH Neuroscience Microarray Consortium http://arrayconsortium.tgen.org/, projects: Koh-7K08NS002068-05-3, Koh-2K08NS002068-04. These datasets probed gene expression in the hippocampus of adult (P30) and young (P15) rats at 5 time-points (1, 6, 24, 72, 240 h) following the intraperitoneal injection of kainate (treatment) or saline (control). Only animals with nearly continuous seizures for more than half an hour were included in that study. Age-specific doses of kainate (3 mg/kg at P15, and 10 mg/kg at P30) were used that had been determined previously to result in < 25% mortality while inducing seizures in >60% of the animals. At the time of RNA isolation the animal could be seizing or during the latent period. Each condition was probed by three microarray hybridizations. The kainate data from both projects were pre-processed together, and the MAS5 detection calls for both ages were used together for the P/A/M filtering described below. Subsequently, the Mas5 signal data only from the adult rats (10 conditions) were used in the current work.", "cite_spans": [{"start": 39, "end": 43, "text": "[23]", "ref_id": "BIBREF22"}], "ref_spans": []}, {"section": "Pre-processing and annotation of the expression data", "text": "The CEL files from the MCAO experiment and separately the CEL files from the kainate experiment (from the young and adult rats together) were pre-processed with the MAS 5.0 algorithm as implemented in the affy R Bioconductor package (Irizarry et al. 2002) . Only the profiles of the probesets detected (MAS 5 call: Present or Marginal) in all hybridizations for at least one condition in a given experiment were used. The profiles from either experiment identified by probe set identifiers were mapped to the Ensembl 39 gene_stable_ids. Separately for either dataset, we computed a single average MAS5 signal profile for each gene_stable_id, resulting in gene expression matrices: (11012 \u00d7 15) for the MCAO system, and (3908 \u00d7 30) for the Adult rats from the kainate system. These data matrices were log2 transformed and analyzed separately by ANOVA. For further analysis from either dataset we selected the genes with the respective ANOVA p-value < 0.05. The average log2 expression profiles of these genes over the three biological replicates were computed, resulting in matrices: M (2786 \u00d7 5) for the MCAO system, and A (2392 \u00d7 10) for the kainate system.", "cite_spans": [], "ref_spans": []}, {"section": "Comparative SVD analysis", "text": "The SVD analysis and the comparison of eigenarrays between two datasets were performed essentially as previously described [11] . Briefly, SVD was performed separately on matrices M, A, resulting in matrices u M (2786 \u00d7 5), m genes common between these two datasets. This resulted in matrices u MA and u AM . We calculated the Pearson correlation coefficient r between each pair of columns of u MA and u AM . The two-sided p-values corresponding to these correlations were obtained from the Student t distribution, with the t statistics calculated with the formula t = r[d /(1-r", "cite_spans": [{"start": 123, "end": 127, "text": "[11]", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "Comparative SVD analysis", "text": "2 )] 1/2 , where d is the number of the degrees of freedom.", "cite_spans": [], "ref_spans": []}, {"section": "Gene Ontology annotation", "text": "GO terms associated with loadings of conserved eigensystems were identified, separately for either dataset, using RankGOstat [55] , available at http://gostat.wehi. edu.au/. The lists of gene symbols (Ensembl display_id), together with loadings of a particular eigensystem for a given (ANOVA-filtered) dataset were used as the input files. Default options (Wilcoxon Signed Rank test, Benjamini False Discovery Rate correction for multiple testing) were used, with the RGD database chosen as the source of GO annotations and the analysis was restricted to the \"biological process\" ontology. The result files were saved, parsed and converted to graphics using local scripts.", "cite_spans": [{"start": 125, "end": 129, "text": "[55]", "ref_id": "BIBREF55"}], "ref_spans": []}, {"section": "Transcription regulatory regions and motifs (TRAM) database Putative regulatory regions", "text": "We used conserved non-coding sequences (CNSs) between human and rat as putative regulatory regions. For each human-rat orthologous gene pair (ortholog_one2one and apparent_ortholog_one2one) in Ensembl release 39, a flank of 20 kilobase (kb) of the genomic sequence from -10 kb to + 10 kb from the transcription start site were aligned using the AVID global alignment algorithm [25] . Sequence windows at least 100 base-pairs (bp) long with \u2265 75% identity were selected as putative regulatory regions. This resulted in the identification of 49425 CNSs for 9099 orthologous gene pairs in the human and rat genomes. A large proportion of similarly identified human-rodent CNSs was shown experimentally to function as enhancers [26] . The input genomic sequence and annotation data, and the results of this analysis were stored in a relational database named TRAM (Transcription regulatory Regions And Motifs), built on the open MySQL platform. The average length of the CNSs was 190 +/-SD 136 bp.", "cite_spans": [{"start": 377, "end": 381, "text": "[25]", "ref_id": "BIBREF24"}, {"start": 724, "end": 728, "text": "[26]", "ref_id": "BIBREF25"}], "ref_spans": []}, {"section": "Motifs and composite motifs", "text": "Instances of transcription factor binding motifs were predicted for all the vertebrate nucleotide distribution matrices of the Matrix Family Library version 6.2 using the program MatInspector [56] (Genomatix). Default thresholds, optimized for each motif as described in [57] were used. Search was performed for all CNSs in the TRAM database, separately for the human and the rat sequence, resulting in identification of 1679998 vertebrate motif instances in the human and 1601216 in the rat. The motif library contained 464 vertebrate nucleotide distribution matrices grouped into 151 matrix families [57] . Motifs identified with matrices from the same family were treated as the same nonredundant (n-r) motif identified by the family name. An instance of a n-r motif X in a given CNS is defined as conserved, if both the human and the rat sequence of this CNS contain at least one instance of X (not necessarily in the same AVID-aligned position). According to this definition, TRAM contains 1061884 instances of conserved n-r motifs. Only the conserved n-r motifs, referred to as \"motifs\" in the main text, were used in further analysis.", "cite_spans": [{"start": 192, "end": 196, "text": "[56]", "ref_id": "BIBREF56"}, {"start": 271, "end": 275, "text": "[57]", "ref_id": "BIBREF57"}, {"start": 602, "end": 606, "text": "[57]", "ref_id": "BIBREF57"}], "ref_spans": []}, {"section": "Motifs and composite motifs", "text": "A composite motif X_Y_... is defined to have an instance in a CNS if this CNS contains at least one instance of each of the conserved n-r motifs X, Y, ... . Note that every single motif is also a composite motif.", "cite_spans": [], "ref_spans": []}, {"section": "Bayesian networks analysis", "text": "In our model of transcription regulation the set of Bayesian network vertices is split into two subsets: cisregulatory features (composite motifs) and expression patterns (sign of the loading of a particular eigensystem). Furthermore, all the edges lead from cis-regulatory features to a particular expression pattern. In order to identify these relationships, we learn Bayesian networks from a dataset joining cis-regulatory and expression data for each gene. The input dataset joins presence or absence of every composite motif with the sign of loading of a single conserved eigensystem ( Figure 4C, D) .", "cite_spans": [], "ref_spans": []}, {"section": "Bayesian networks analysis", "text": "In Step 1 of our procedure (not illustrated) over 100 promising composite motifs (built of up to three motifs) associated with the sign of the chosen eigensystem are identified. Only these selected composite motifs are then used as the input for the Step 2 ( Figure 4E ) identifying the best sets of composite motifs and their conditional probability distributions ( Figure 4F ). Each set of composite motifs has a q-value derived from 1000 random permutations of gene labels. For each permutation we created a new cis-regulatory dataset (with gene labels permuted accordingly) and learned the optimal composite motif set. Both steps of a learning procedure were performed with the BNFinder software [29] -a Python package for learning Bayesian networks from data. BNFinder implements the polynomial time learning algorithm dedicated to dynamic Bayesian networks, as well as to static ones with constraints forcing the network acyclicity [58] , as is the case here.", "cite_spans": [{"start": 700, "end": 704, "text": "[29]", "ref_id": "BIBREF28"}, {"start": 938, "end": 942, "text": "[58]", "ref_id": "BIBREF58"}], "ref_spans": []}, {"section": "Bayesian networks analysis", "text": "We used the Bayesian-Dirichlet equivalence (BDe) [59, 60] criterion with priors on the conditional probability distributions according to [59] . A prior on the network structures is proportional to the product of penalty parameters over all the edges in the graph of the refined model. Furthermore, penalty parameters increase with composite motif size. This choice results in a preference for sparse graphs, and thus protects our procedure from overfitting. BN score of a composite motif set was computed as the ratio of its posterior probability to the posterior probability of the empty set. To permit the cross-system validation of BN scores, the sets of composite motifs selected during Step 1 for the corresponding eigensystems (e.g. A2-M2) from either dataset were combined to form their union, which was then used during Step 2.", "cite_spans": [{"start": 49, "end": 53, "text": "[59,", "ref_id": "BIBREF59"}, {"start": 54, "end": 57, "text": "60]", "ref_id": "BIBREF60"}, {"start": 138, "end": 142, "text": "[59]", "ref_id": "BIBREF59"}], "ref_spans": []}, {"section": "Regression analysis", "text": "The motif count per gene was defined as the number of instances of conserved non-redundant motifs in the rat sequences of all the CNSs assigned to this gene. Only the genes with at least one CNS were used in the univariate regression analysis when the count of a particular motif was used as the regressor variable. When the CNS count, or CNS count and the motif count, were used as the regressor variable(s), the genes with zero CNS count were also included during the analysis", "cite_spans": [], "ref_spans": []}, {"section": "Regression analysis", "text": "The single gene loadings of eigensystems 2, 3 were not normally distributed, which precludes statistical interpretation of the results of the regression with singlegene loadings used as the response variable. Therefore, in linear regression analysis, we decided to use the average loadings of a particular eigensystem in groups of genes with the same motif count as the response variable. In the regression analysis on the average values we confirmed the approximate normality of the residua (Additional file 3). Since the average values for different motif counts were computed from different numbers of observations, generally decreasing with the motif count, which was accompanied by changing variance of the loadings, we employed the Goldfeld-Quandt (GQ) test to detect the existence and magnitude of heteroskedasticity. Results of this test indicate that (i) for MCAO data heretoscedastic errors were detected (p < 0.05) in all the regression models. Therefore, we used weighted least squares approach, with weights set to the number of genes in each group [31] , which is the well-known solution to the heteroskedasticity problem. The regression analysis was performed in Mathematica 7, and the GQ tests were performed in R.", "cite_spans": [{"start": 1062, "end": 1066, "text": "[31]", "ref_id": "BIBREF30"}], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Pathobiology of ischaemic stroke: an integrated view", "authors": [{"first": "U", "middle": [], "last": "Dirnagl", "suffix": ""}, {"first": "C", "middle": [], "last": "Iadecola", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Moskowitz", "suffix": ""}], "year": 1999, "venue": "Trends in neurosciences", "link": "41984070"}, "BIBREF1": {"title": "Kainic acid-mediated excitotoxicity as a model for neurodegeneration", "authors": [{"first": "Q", "middle": [], "last": "Wang", "suffix": ""}, {"first": "S", "middle": [], "last": "Yu", "suffix": ""}, {"first": "A", "middle": [], "last": "Simonyi", "suffix": ""}, {"first": "G", "middle": ["Y"], "last": "Sun", "suffix": ""}, {"first": "A", "middle": ["Y"], "last": "Sun", "suffix": ""}], "year": 2005, "venue": "Molecular neurobiology", "link": "21440899"}, "BIBREF2": {"title": "Genomic responses of the brain to ischemic stroke, intracerebral haemorrhage, kainate seizures, hypoglycemia, and hypoxia. The European journal of neuroscience", "authors": [{"first": "Y", "middle": [], "last": "Tang", "suffix": ""}, {"first": "A", "middle": [], "last": "Lu", "suffix": ""}, {"first": "B", "middle": ["J"], "last": "Aronow", "suffix": ""}, {"first": "K", "middle": ["R"], "last": "Wagner", "suffix": ""}, {"first": "F", "middle": ["R"], "last": "Sharp", "suffix": ""}], "year": 2002, "venue": "", "link": null}, "BIBREF3": {"title": "Singular value decomposition for genomewide expression data processing and modeling", "authors": [{"first": "O", "middle": [], "last": "Alter", "suffix": ""}, {"first": "P", "middle": ["O"], "last": "Brown", "suffix": ""}, {"first": "D", "middle": [], "last": "Botstein", "suffix": ""}], "year": 2000, "venue": "Proceedings of the National Academy of Sciences of the United States of America", "link": "14290622"}, "BIBREF4": {"title": "Fundamental patterns underlying gene expression profiles: simplicity from complexity", "authors": [{"first": "N", "middle": ["S"], "last": "Holter", "suffix": ""}, {"first": "M", "middle": [], "last": "Mitra", "suffix": ""}, {"first": "A", "middle": [], "last": "Maritan", "suffix": ""}, {"first": "M", "middle": [], "last": "Cieplak", "suffix": ""}, {"first": "J", "middle": ["R"], "last": "Banavar", "suffix": ""}, {"first": "N", "middle": ["V"], "last": "Fedoroff", "suffix": ""}], "year": 2000, "venue": "Proceedings of the National Academy of Sciences of the United States of America", "link": "1739070"}, "BIBREF5": {"title": "Eigengene networks for studying the relationships between co-expression modules", "authors": [{"first": "P", "middle": [], "last": "Langfelder", "suffix": ""}, {"first": "S", "middle": [], "last": "Horvath", "suffix": ""}], "year": 2007, "venue": "BMC systems biology", "link": "1796870"}, "BIBREF6": {"title": "Alter O: A tensor higher-order singular value decomposition for integrative analysis of DNA microarray data from different studies", "authors": [{"first": "L", "middle": [], "last": "Omberg", "suffix": ""}, {"first": "G", "middle": ["H"], "last": "Golub", "suffix": ""}], "year": 2007, "venue": "Proceedings of the National Academy of Sciences of the United States of America", "link": null}, "BIBREF7": {"title": "Eigengene-based linear discriminant model for tumor classification using gene expression microarray data", "authors": [{"first": "R", "middle": [], "last": "Shen", "suffix": ""}, {"first": "D", "middle": [], "last": "Ghosh", "suffix": ""}, {"first": "A", "middle": [], "last": "Chinnaiyan", "suffix": ""}, {"first": "Z", "middle": [], "last": "Meng", "suffix": ""}], "year": 2006, "venue": "Bioinformatics", "link": "3257574"}, "BIBREF8": {"title": "Geometric interpretation of gene coexpression network analysis", "authors": [{"first": "S", "middle": [], "last": "Horvath", "suffix": ""}, {"first": "J", "middle": [], "last": "Dong", "suffix": ""}], "year": 2008, "venue": "PLoS computational biology", "link": null}, "BIBREF9": {"title": "Singular value decomposition-based regression identifies activation of endogenous signaling pathways in vivo", "authors": [{"first": "Z", "middle": [], "last": "Liu", "suffix": ""}, {"first": "M", "middle": [], "last": "Wang", "suffix": ""}, {"first": "J", "middle": ["V"], "last": "Alvarez", "suffix": ""}, {"first": "M", "middle": ["E"], "last": "Bonney", "suffix": ""}, {"first": "C", "middle": ["C"], "last": "Chen", "suffix": ""}, {"first": "D&apos;", "middle": [], "last": "Cruz", "suffix": ""}, {"first": "C", "middle": [], "last": "Pan", "suffix": ""}, {"first": "T", "middle": ["C"], "last": "Tadesse", "suffix": ""}, {"first": "M", "middle": ["G"], "last": "Chodosh", "suffix": ""}, {"first": "L", "middle": ["A"], "last": "", "suffix": ""}], "year": 2008, "venue": "Genome biology", "link": "2322469"}, "BIBREF10": {"title": "Identification of conserved modes of expression profiles during hippocampal development and neuronal differentiation in vitro", "authors": [{"first": "M", "middle": [], "last": "Dabrowski", "suffix": ""}, {"first": "A", "middle": [], "last": "Adach", "suffix": ""}, {"first": "S", "middle": [], "last": "Aerts", "suffix": ""}, {"first": "Y", "middle": [], "last": "Moreau", "suffix": ""}, {"first": "B", "middle": [], "last": "Kaminska", "suffix": ""}], "year": 2006, "venue": "Journal of neurochemistry", "link": "39660516"}, "BIBREF11": {"title": "Prediction of a key role of motifs binding E2F and NR2F in down-regulation of numerous genes during the development of the mouse hippocampus", "authors": [{"first": "M", "middle": [], "last": "Dabrowski", "suffix": ""}, {"first": "S", "middle": [], "last": "Aerts", "suffix": ""}, {"first": "B", "middle": [], "last": "Kaminska", "suffix": ""}], "year": 2006, "venue": "BMC bioinformatics", "link": "15894049"}, "BIBREF12": {"title": "Using Bayesian networks to analyze expression data", "authors": [{"first": "N", "middle": [], "last": "Friedman", "suffix": ""}, {"first": "M", "middle": [], "last": "Linial", "suffix": ""}, {"first": "I", "middle": [], "last": "Nachman", "suffix": ""}, {"first": "Pe", "middle": [], "last": "", "suffix": ""}], "year": 2000, "venue": "J Comput Biol", "link": "53303729"}, "BIBREF13": {"title": "Predicting gene expression from sequence", "authors": [{"first": "M", "middle": ["A"], "last": "Beer", "suffix": ""}, {"first": "S", "middle": [], "last": "Tavazoie", "suffix": ""}], "year": 2004, "venue": "Cell", "link": null}, "BIBREF14": {"title": "Predicting gene expression from sequence: a reexamination", "authors": [{"first": "Y", "middle": [], "last": "Yuan", "suffix": ""}, {"first": "L", "middle": [], "last": "Guo", "suffix": ""}, {"first": "L", "middle": [], "last": "Shen", "suffix": ""}, {"first": "J", "middle": ["S"], "last": "Liu", "suffix": ""}], "year": 2007, "venue": "PLoS computational biology", "link": "2711821"}, "BIBREF15": {"title": "Bayesian Orthogonal Least Squares (BOLS) algorithm for reverse engineering of gene regulatory networks", "authors": [{"first": "C", "middle": ["S"], "last": "Kim", "suffix": ""}], "year": 2007, "venue": "BMC bioinformatics", "link": "7946056"}, "BIBREF16": {"title": "Integrative bioinformatics analysis of transcriptional regulatory programs in breast cancer cells", "authors": [{"first": "A", "middle": [], "last": "Niida", "suffix": ""}, {"first": "A", "middle": ["D"], "last": "Smith", "suffix": ""}, {"first": "S", "middle": [], "last": "Imoto", "suffix": ""}, {"first": "S", "middle": [], "last": "Tsutsumi", "suffix": ""}, {"first": "H", "middle": [], "last": "Aburatani", "suffix": ""}, {"first": "M", "middle": ["Q"], "last": "Zhang", "suffix": ""}, {"first": "T", "middle": [], "last": "Akiyama", "suffix": ""}], "year": 2008, "venue": "BMC bioinformatics", "link": "7287"}, "BIBREF17": {"title": "Prediction of tissue-specific cis-regulatory modules using Bayesian networks and regression trees", "authors": [{"first": "X", "middle": [], "last": "Chen", "suffix": ""}, {"first": "M", "middle": [], "last": "Blanchette", "suffix": ""}], "year": 2007, "venue": "BMC bioinformatics", "link": "7391650"}, "BIBREF18": {"title": "GBNet: deciphering regulatory rules in the coregulated genes using a Gibbs sampler enhanced Bayesian network approach", "authors": [{"first": "L", "middle": [], "last": "Shen", "suffix": ""}, {"first": "J", "middle": [], "last": "Liu", "suffix": ""}, {"first": "W", "middle": [], "last": "Wang", "suffix": ""}], "year": 2008, "venue": "BMC bioinformatics", "link": "7641777"}, "BIBREF19": {"title": "Genome-wide discovery of transcriptional modules from DNA sequence and gene expression", "authors": [{"first": "E", "middle": [], "last": "Segal", "suffix": ""}, {"first": "R", "middle": [], "last": "Yelensky", "suffix": ""}, {"first": "D", "middle": [], "last": "Koller", "suffix": ""}], "year": 2003, "venue": "Bioinformatics", "link": "1451988"}, "BIBREF20": {"title": "Predictive modeling of genome-wide mRNA expression: from modules to molecules. Annual review of biophysics and biomolecular structure", "authors": [{"first": "H", "middle": ["J"], "last": "Bussemaker", "suffix": ""}, {"first": "B", "middle": ["C"], "last": "Foat", "suffix": ""}, {"first": "L", "middle": ["D"], "last": "Ward", "suffix": ""}], "year": 2007, "venue": "", "link": null}, "BIBREF21": {"title": "Regulatory element detection using correlation with expression", "authors": [{"first": "H", "middle": ["J"], "last": "Bussemaker", "suffix": ""}, {"first": "H", "middle": [], "last": "Li", "suffix": ""}, {"first": "E", "middle": ["D"], "last": "Siggia", "suffix": ""}], "year": 2001, "venue": "Nature genetics", "link": "1757992"}, "BIBREF22": {"title": "Microarray analysis of postictal transcriptional regulation of neuropeptides", "authors": [{"first": "D", "middle": ["N"], "last": "Wilson", "suffix": ""}, {"first": "H", "middle": [], "last": "Chung", "suffix": ""}, {"first": "R", "middle": ["C"], "last": "Elliott", "suffix": ""}, {"first": "E", "middle": [], "last": "Bremer", "suffix": ""}, {"first": "D", "middle": [], "last": "George", "suffix": ""}, {"first": "S", "middle": [], "last": "Koh", "suffix": ""}], "year": 2005, "venue": "J Mol Neurosci", "link": "28896672"}, "BIBREF23": {"title": "A novel mechanism of FK506-mediated neuroprotection: downregulation of cytokine expression in glial cells", "authors": [{"first": "M", "middle": [], "last": "Zawadzka", "suffix": ""}, {"first": "B", "middle": [], "last": "Kaminska", "suffix": ""}], "year": 2005, "venue": "Glia", "link": "38897028"}, "BIBREF24": {"title": "A VID: A global alignment program", "authors": [{"first": "N", "middle": [], "last": "Bray", "suffix": ""}, {"first": "I", "middle": [], "last": "Dubchak", "suffix": ""}, {"first": "L", "middle": [], "last": "Pachter", "suffix": ""}], "year": 2003, "venue": "Genome research", "link": null}, "BIBREF25": {"title": "In vivo enhancer analysis of human conserved non-coding sequences", "authors": [{"first": "L", "middle": ["A"], "last": "Pennacchio", "suffix": ""}, {"first": "N", "middle": [], "last": "Ahituv", "suffix": ""}, {"first": "A", "middle": ["M"], "last": "Moses", "suffix": ""}, {"first": "S", "middle": [], "last": "Prabhakar", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Nobrega", "suffix": ""}, {"first": "M", "middle": [], "last": "Shoukry", "suffix": ""}, {"first": "S", "middle": [], "last": "Minovitsky", "suffix": ""}, {"first": "I", "middle": [], "last": "Dubchak", "suffix": ""}, {"first": "A", "middle": [], "last": "Holt", "suffix": ""}, {"first": "K", "middle": ["D"], "last": "Lewis", "suffix": ""}], "year": 2006, "venue": "Nature", "link": "4307332"}, "BIBREF26": {"title": "TRANSCompel: a database on composite regulatory elements in eukaryotic genes", "authors": [{"first": "O", "middle": ["V"], "last": "Kel-Margoulis", "suffix": ""}, {"first": "A", "middle": ["E"], "last": "Kel", "suffix": ""}, {"first": "I", "middle": [], "last": "Reuter", "suffix": ""}, {"first": "I", "middle": ["V"], "last": "Deineko", "suffix": ""}, {"first": "E", "middle": [], "last": "Wingender", "suffix": ""}], "year": 2002, "venue": "Nucleic acids research", "link": "205226302"}, "BIBREF27": {"title": "Compo: composite motif discovery using discrete models", "authors": [{"first": "G", "middle": ["K"], "last": "Sandve", "suffix": ""}, {"first": "O", "middle": [], "last": "Abul", "suffix": ""}, {"first": "F", "middle": [], "last": "Drablos", "suffix": ""}], "year": 2008, "venue": "BMC bioinformatics", "link": "5124230"}, "BIBREF28": {"title": "BNFinder: exact and efficient method for learning Bayesian networks", "authors": [{"first": "B", "middle": [], "last": "Wilczynski", "suffix": ""}, {"first": "N", "middle": [], "last": "Dojer", "suffix": ""}], "year": 2009, "venue": "Bioinformatics", "link": "9920920"}, "BIBREF29": {"title": "Controlling the false discovery rate: a practical and powerful approach to multiple testing", "authors": [{"first": "Y", "middle": [], "last": "Benjamini", "suffix": ""}, {"first": "Y", "middle": [], "last": "Hochberg", "suffix": ""}], "year": 1995, "venue": "J Roy Statist Soc Ser B", "link": "45174121"}, "BIBREF30": {"title": "Linear Models with R", "authors": [{"first": "J", "middle": ["J"], "last": "Faraway", "suffix": ""}], "year": 2005, "venue": "", "link": "118508179"}, "BIBREF31": {"title": "Seizures-evoked activation of transcription factors", "authors": [{"first": "B", "middle": [], "last": "Kaminska", "suffix": ""}, {"first": "K", "middle": [], "last": "Lukasiuk", "suffix": ""}, {"first": "L", "middle": [], "last": "Kaczmarek", "suffix": ""}], "year": 1994, "venue": "Acta neurobiologiae experimentalis", "link": "25576043"}, "BIBREF32": {"title": "AP1 transcriptional factor activation and its relation to apoptosis of hippocampal CA1 pyramidal neurons after transient ischemia in gerbils", "authors": [{"first": "K", "middle": [], "last": "Domanska-Janik", "suffix": ""}, {"first": "P", "middle": [], "last": "Bong", "suffix": ""}, {"first": "A", "middle": [], "last": "Bronisz-Kowalczyk", "suffix": ""}, {"first": "H", "middle": [], "last": "Zajac", "suffix": ""}, {"first": "B", "middle": [], "last": "Zablocka", "suffix": ""}], "year": 1999, "venue": "Journal of neuroscience research", "link": "22288954"}, "BIBREF33": {"title": "Neuronal excitation-driven and AP-1-dependent activation of tissue inhibitor of metalloproteinases-1 gene expression in rodent hippocampus", "authors": [{"first": "J", "middle": [], "last": "Jaworski", "suffix": ""}, {"first": "I", "middle": ["W"], "last": "Biedermann", "suffix": ""}, {"first": "J", "middle": [], "last": "Lapinska", "suffix": ""}, {"first": "A", "middle": [], "last": "Szklarczyk", "suffix": ""}, {"first": "I", "middle": [], "last": "Figiel", "suffix": ""}, {"first": "D", "middle": [], "last": "Konopka", "suffix": ""}, {"first": "D", "middle": [], "last": "Nowicka", "suffix": ""}, {"first": "R", "middle": ["K"], "last": "Filipkowski", "suffix": ""}, {"first": "M", "middle": [], "last": "Hetman", "suffix": ""}, {"first": "A", "middle": [], "last": "Kowalczyk", "suffix": ""}, {"first": "L", "middle": [], "last": "Kaczmarek", "suffix": ""}], "year": 1999, "venue": "The Journal of biological chemistry", "link": "25596586"}, "BIBREF34": {"title": "JNK signaling in apoptosis", "authors": [{"first": "D", "middle": ["N"], "last": "Dhanasekaran", "suffix": ""}, {"first": "E", "middle": ["P"], "last": "Reddy", "suffix": ""}], "year": 2008, "venue": "Oncogene", "link": "22480427"}, "BIBREF35": {"title": "The third dimension of gene regulation: organization of dynamic chromatin loopscape by SATB1. Current opinion in genetics & development", "authors": [{"first": "S", "middle": [], "last": "Galande", "suffix": ""}, {"first": "P", "middle": ["K"], "last": "Purbey", "suffix": ""}, {"first": "D", "middle": [], "last": "Notani", "suffix": ""}, {"first": "P", "middle": ["P"], "last": "Kumar", "suffix": ""}], "year": 2007, "venue": "", "link": null}, "BIBREF36": {"title": "Transcription in the loop", "authors": [{"first": "A", "middle": [], "last": "Gondor", "suffix": ""}, {"first": "R", "middle": [], "last": "Ohlsson", "suffix": ""}], "year": 2006, "venue": "Nature genetics", "link": "735277"}, "BIBREF38": {"title": "Functional interaction between PML and SATB1 regulates chromatinloop architecture and transcription of the MHC class I locus", "authors": [{"first": "P", "middle": ["P"], "last": "Kumar", "suffix": ""}, {"first": "O", "middle": [], "last": "Bischof", "suffix": ""}, {"first": "P", "middle": ["K"], "last": "Purbey", "suffix": ""}, {"first": "D", "middle": [], "last": "Notani", "suffix": ""}, {"first": "H", "middle": [], "last": "Urlaub", "suffix": ""}, {"first": "A", "middle": [], "last": "Dejean", "suffix": ""}, {"first": "S", "middle": [], "last": "Galande", "suffix": ""}], "year": 2007, "venue": "Nature cell biology", "link": null}, "BIBREF39": {"title": "SATB1 cleavage by caspase 6 disrupts PDZ domain-mediated dimerization, causing detachment from chromatin early in T-cell apoptosis", "authors": [{"first": "S", "middle": [], "last": "Galande", "suffix": ""}, {"first": "L", "middle": ["A"], "last": "Dickinson", "suffix": ""}, {"first": "I", "middle": ["S"], "last": "Mian", "suffix": ""}, {"first": "M", "middle": [], "last": "Sikorska", "suffix": ""}, {"first": "T", "middle": [], "last": "Kohwi-Shigematsu", "suffix": ""}], "year": 2001, "venue": "Molecular and cellular biology", "link": "21508785"}, "BIBREF40": {"title": "The behavior of SATB1, a MAR-binding protein, in response to apoptosis stimulation", "authors": [{"first": "Y", "middle": [], "last": "Sun", "suffix": ""}, {"first": "T", "middle": [], "last": "Wang", "suffix": ""}, {"first": "Y", "middle": [], "last": "Su", "suffix": ""}, {"first": "Y", "middle": [], "last": "Yin", "suffix": ""}, {"first": "S", "middle": [], "last": "Xu", "suffix": ""}, {"first": "C", "middle": [], "last": "Ma", "suffix": ""}, {"first": "X", "middle": [], "last": "Han", "suffix": ""}], "year": 2006, "venue": "Cell biology international", "link": "26706596"}, "BIBREF41": {"title": "Durrin LK: SUMO conjugation to the matrix attachment region-binding protein, special AT-rich sequence-binding protein-1 (SATB1), targets SATB1 to promyelocytic nuclear bodies where it undergoes caspase cleavage", "authors": [{"first": "J", "middle": ["A"], "last": "Tan", "suffix": ""}, {"first": "Y", "middle": [], "last": "Sun", "suffix": ""}, {"first": "J", "middle": [], "last": "Song", "suffix": ""}, {"first": "Y", "middle": [], "last": "Chen", "suffix": ""}, {"first": "T", "middle": ["G"], "last": "Krontiris", "suffix": ""}], "year": 2008, "venue": "The Journal of biological chemistry", "link": "27497320"}, "BIBREF42": {"title": "Transcription factors in long-term memory and synaptic plasticity", "authors": [{"first": "C", "middle": ["M"], "last": "Alberini", "suffix": ""}], "year": 2009, "venue": "Physiological reviews", "link": null}, "BIBREF43": {"title": "Molecular and cellular mechanisms of memory allocation in neuronetworks", "authors": [{"first": "J", "middle": [], "last": "Won", "suffix": ""}, {"first": "A", "middle": ["J"], "last": "Silva", "suffix": ""}], "year": 2008, "venue": "Neurobiology of learning and memory", "link": "5037022"}, "BIBREF44": {"title": "Function and regulation of CREB family transcription factors in the nervous system", "authors": [{"first": "B", "middle": ["E"], "last": "Lonze", "suffix": ""}, {"first": "D", "middle": ["D"], "last": "Ginty", "suffix": ""}], "year": 2002, "venue": "Neuron", "link": "14028417"}, "BIBREF45": {"title": "CREB and cAMP response element-mediated gene expression in the ischemic brain", "authors": [{"first": "K", "middle": [], "last": "Kitagawa", "suffix": ""}], "year": 2007, "venue": "The FEBS journal", "link": "29917569"}, "BIBREF46": {"title": "Distinct functions of egr gene family members in cognitive processes", "authors": [{"first": "R", "middle": [], "last": "Poirier", "suffix": ""}, {"first": "H", "middle": [], "last": "Cheval", "suffix": ""}, {"first": "C", "middle": [], "last": "Mailhes", "suffix": ""}, {"first": "S", "middle": [], "last": "Garel", "suffix": ""}, {"first": "P", "middle": [], "last": "Charnay", "suffix": ""}, {"first": "S", "middle": [], "last": "Davis", "suffix": ""}, {"first": "S", "middle": [], "last": "Laroche", "suffix": ""}], "year": 2008, "venue": "Frontiers in neuroscience", "link": "17707344"}, "BIBREF47": {"title": "Inducible and constitutive transcription factors in the mammalian nervous system: control of gene expression by Jun, Fos and Krox, and CREB/ATF proteins", "authors": [{"first": "T", "middle": [], "last": "Herdegen", "suffix": ""}, {"first": "J", "middle": ["D"], "last": "Leah", "suffix": ""}], "year": 1998, "venue": "Brain research", "link": "11848651"}, "BIBREF48": {"title": "DNA-binding specificity of the PAR basic leucine zipper protein VBP partially overlaps those of the C/EBP and CREB/ATF families and is influenced by domains that flank the core basic region", "authors": [{"first": "N", "middle": ["B"], "last": "Haas", "suffix": ""}, {"first": "C", "middle": ["A"], "last": "Cantwell", "suffix": ""}, {"first": "P", "middle": ["F"], "last": "Johnson", "suffix": ""}, {"first": "J", "middle": ["B"], "last": "Burch", "suffix": ""}], "year": 1995, "venue": "Molecular and cellular biology", "link": "15751814"}, "BIBREF49": {"title": "The loss of circadian PAR bZip transcription factors results in epilepsy", "authors": [{"first": "F", "middle": [], "last": "Gachon", "suffix": ""}, {"first": "P", "middle": [], "last": "Fonjallaz", "suffix": ""}, {"first": "F", "middle": [], "last": "Damiola", "suffix": ""}, {"first": "P", "middle": [], "last": "Gos", "suffix": ""}, {"first": "T", "middle": [], "last": "Kodama", "suffix": ""}, {"first": "J", "middle": [], "last": "Zakany", "suffix": ""}, {"first": "D", "middle": [], "last": "Duboule", "suffix": ""}, {"first": "B", "middle": [], "last": "Petit", "suffix": ""}, {"first": "M", "middle": [], "last": "Tafti", "suffix": ""}, {"first": "U", "middle": [], "last": "Schibler", "suffix": ""}], "year": 2004, "venue": "Genes & development", "link": null}, "BIBREF50": {"title": "Defining the CREB regulon: a genome-wide analysis of transcription factor regulatory regions", "authors": [{"first": "S", "middle": [], "last": "Impey", "suffix": ""}, {"first": "S", "middle": ["R"], "last": "Mccorkle", "suffix": ""}, {"first": "H", "middle": [], "last": "Cha-Molstad", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Dwyer", "suffix": ""}, {"first": "G", "middle": ["S"], "last": "Yochum", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Boss", "suffix": ""}, {"first": "S", "middle": [], "last": "Mcweeney", "suffix": ""}, {"first": "J", "middle": ["J"], "last": "Dunn", "suffix": ""}, {"first": "G", "middle": [], "last": "Mandel", "suffix": ""}, {"first": "R", "middle": ["H"], "last": "Goodman", "suffix": ""}], "year": 2004, "venue": "Cell", "link": "6438776"}, "BIBREF51": {"title": "The neuroplasticityassociated arc gene is a direct transcriptional target of early growth response (Egr) transcription factors", "authors": [{"first": "L", "middle": [], "last": "Li", "suffix": ""}, {"first": "J", "middle": [], "last": "Carter", "suffix": ""}, {"first": "X", "middle": [], "last": "Gao", "suffix": ""}, {"first": "J", "middle": [], "last": "Whitehead", "suffix": ""}, {"first": "W", "middle": ["G"], "last": "Tourtellotte", "suffix": ""}], "year": 2005, "venue": "Molecular and cellular biology", "link": null}, "BIBREF52": {"title": "Arc/Arg3.1: linking gene expression to synaptic plasticity and memory", "authors": [{"first": "A", "middle": ["V"], "last": "Tzingounis", "suffix": ""}, {"first": "R", "middle": ["A"], "last": "Nicoll", "suffix": ""}], "year": 2006, "venue": "Neuron", "link": "8125886"}, "BIBREF53": {"title": "Genes involved in complex adaptive processes tend to have highly conserved upstream regions in mammalian genomes", "authors": [{"first": "S", "middle": [], "last": "Lee", "suffix": ""}, {"first": "I", "middle": [], "last": "Kohane", "suffix": ""}, {"first": "S", "middle": [], "last": "Kasif", "suffix": ""}], "year": 2005, "venue": "BMC genomics", "link": "1941148"}, "BIBREF54": {"title": "Functional organization of the transcriptome in human brain", "authors": [{"first": "M", "middle": ["C"], "last": "Oldham", "suffix": ""}, {"first": "G", "middle": [], "last": "Konopka", "suffix": ""}, {"first": "K", "middle": [], "last": "Iwamoto", "suffix": ""}, {"first": "P", "middle": [], "last": "Langfelder", "suffix": ""}, {"first": "T", "middle": [], "last": "Kato", "suffix": ""}, {"first": "S", "middle": [], "last": "Horvath", "suffix": ""}, {"first": "D", "middle": ["H"], "last": "Geschwind", "suffix": ""}], "year": 2008, "venue": "Nature neuroscience", "link": "10809183"}, "BIBREF55": {"title": "GOstat: find statistically overrepresented Gene Ontologies within a group of genes", "authors": [{"first": "T", "middle": [], "last": "Beissbarth", "suffix": ""}, {"first": "T", "middle": ["P"], "last": "Speed", "suffix": ""}], "year": 2004, "venue": "Bioinformatics", "link": "34702038"}, "BIBREF56": {"title": "MatInspector and beyond: promoter analysis based on transcription factor binding sites", "authors": [{"first": "K", "middle": [], "last": "Cartharius", "suffix": ""}, {"first": "K", "middle": [], "last": "Frech", "suffix": ""}, {"first": "K", "middle": [], "last": "Grote", "suffix": ""}, {"first": "B", "middle": [], "last": "Klocke", "suffix": ""}, {"first": "M", "middle": [], "last": "Haltmeier", "suffix": ""}, {"first": "A", "middle": [], "last": "Klingenhoff", "suffix": ""}, {"first": "M", "middle": [], "last": "Frisch", "suffix": ""}, {"first": "M", "middle": [], "last": "Bayerlein", "suffix": ""}, {"first": "T", "middle": [], "last": "Werner", "suffix": ""}], "year": 2005, "venue": "Bioinformatics", "link": null}, "BIBREF57": {"title": "Transcription regulatory region analysis using signal detection and fuzzy clustering", "authors": [{"first": "L", "middle": [], "last": "Pickert", "suffix": ""}, {"first": "I", "middle": [], "last": "Reuter", "suffix": ""}, {"first": "F", "middle": [], "last": "Klawonn", "suffix": ""}, {"first": "E", "middle": [], "last": "Wingender", "suffix": ""}], "year": 1998, "venue": "Bioinformatics", "link": "32346117"}, "BIBREF58": {"title": "Learning Bayesian Networks Does Not Have to Be NP-Hard", "authors": [{"first": "N", "middle": [], "last": "Dojer", "suffix": ""}], "year": 2006, "venue": "Proceedings of Mathematical Foundations of Computer Science", "link": "32246838"}, "BIBREF59": {"title": "A Bayesian method for the induction of probabilistic networks from data", "authors": [{"first": "G", "middle": ["F"], "last": "Cooper", "suffix": ""}, {"first": "E", "middle": [], "last": "Herskovits", "suffix": ""}], "year": 1992, "venue": "Machine Learning", "link": "57701457"}, "BIBREF60": {"title": "Learning Bayesian networks: The combination of knowledge and statistical data", "authors": [{"first": "D", "middle": [], "last": "Heckerman", "suffix": ""}, {"first": "D", "middle": [], "last": "Geiger", "suffix": ""}, {"first": "D", "middle": ["M"], "last": "Chickering", "suffix": ""}], "year": 1995, "venue": "Machine Learning", "link": "53928084"}, "BIBREF61": {"title": "Comparative analysis of cisregulation following stroke and seizures in subspaces of conserved eigensystems", "authors": [{"first": "", "middle": [], "last": "Dabrowski", "suffix": ""}], "year": 2010, "venue": "BMC Systems Biology", "link": null}}, "ref_entries": {"FIGREF0": {"text": "Figure 1 Design of the study (A) The datasets from gene profiling of rat brain following stroke in the MCAO model and kainateinduced seizures were each separately transformed by SVD. (B) The eigenarrays resulting from the SVD of either dataset were compared by correlation analysis performed for the genes common between the two datasets. (C) For the emerging conserved eigensystems 2 and 3, separately for all the genes in either dataset, we studied their functional Gene Ontology (GO) associations and employed Bayesian Networks (BN) to study their cis-regulation. The results obtained on one dataset were then compared (GO) or statistically tested (BN) on the other.", "type": "figure"}, "FIGREF1": {"text": "Figure 2 Comparative SVD analysis of gene expression following ischemia and seizures. The MCAO and kainate dataset were each separately transformed by SVD and the results were compared. (A, D) The singular values plotted as bars. The large singular values for the respective first eigensystems reflecting the magnitude (constant in time) are omitted for clarity. (B-C, E-F) The two most important non-constant eigengenes in the MCAO system (M2, M3) and in the kainate system (A2, A3). Red squares indicate loadings on the conditions of treatment, blue -control. The eigengenes A2 and A3, which are vectors of length 10, have been folded in (E-F), to match the loadings onto the same timepoints following the injection of kainate and saline. (G) Correlations between eigenarrays from either system for the 737 common genes. (H-I) Loadings of the respective second (H) and third (I) eigensystems, in the MCAO (blue) and kainate (violet) model, to the expression profiles of the 737 common genes. The genes were sorted on each gene's average loading of M2 and A2 (H) or of M3 and A3 (I).", "type": "figure"}, "FIGREF2": {"text": "0.68) and in the MCAO system (Figure 7C p = 4.1 \u00d7 10 -6 , R 2 = 0.58). The effect of CREB sites number on gene expression was specific for the third", "type": "figure"}, "FIGREF3": {"text": "Figure 6 Effects of motifs binding AP1 and Satb1 on gene expression in the subspace of conserved eigensystem 2. The effects of motif count per gene on the loadings of the indicated eigensystem were analyzed by weighted linear regression. The response variable was the average loadings of a given eigensystem in groups of genes with the same count of the motif used as the regressor variable, with the weights equal to the numbers of genes per group. The average loadings for each motif count are indicated as blue dots, with their standard deviations shown as error bars, and the group gene count plotted next to each fitted data point. (A) The effect of SATB count on the loadings of eigensystem M2. (B) The effect of AP1F count on the loadings of eigensystem A2. (C) The effect of AP1F count on the loadings of eigensystem M2 analyzed for the genes without SATB motif. (D) The effect of AP1F count on the loadings of eigensystem M2 analyzed for the genes with SATB motif. (E-F) The log-expression profiles of Timp1 in the MCAO and kainate system. (G) A hypothetical mechanism, by which binding to the nuclear matrix via Satb1 makes a gene less accessible for binding or activation by AP1.", "type": "figure"}, "FIGREF4": {"text": "Figure 7 Effects of CREB motif count on gene expression in the subspace of the conserved eigensystem 3 (A, B) The effects of CREB motif count per gene on the average loadings of the eigensystem A3 or M3 analyzed by weighted linear regression, as described in the legend to Figure 6. (C, D) Effect of CREB count and direct and indirect (via CREB count) effect of CNS count per gene on the average loadings of eigensystems A3 or M3 analyzed by weighted linear regression, either univariate (edges 1, 2, 3) or bivariate (edges 4, 5), in groups of genes with the same numbers of CNSs, CREB motifs, or both. The results are represented as path analysis graphs, with each edge marked by the values of the respective linear regression directional coefficient \u03b1 and its corresponding t-test p-value. In the univariate regression of CREB count on CNS count (edge 3) the data for all the genes with at least one CNS in the TRAM database were used. (E) The single gene A3 loadings and CREB counts for all the genes with CNS(s) in the kainate dataset (grey dots) compared to the values the Creb-binding genes in PC12 cells identified by genome-wide ChIP analysis by Impey et al. [50] (blue dots). (F) Uncorrelated, additive effects of the motifs SATB and CREB on gene logexpression provide an insight into the biology of the MCAO system.", "type": "figure"}}}
{"paper_id": "10702436", "_pdf_hash": "86bb660d8bffc3b5a1c85c10e47d6543291811e8", "abstract": [{"section": "Abstract", "text": "Developing B cells undergo dramatic changes in their responses to chemoattractant cytokines (chemokines) and in expression of chemokine receptors. Bone marrow pre-pro-B cells (AA4.1 \u03e9 /natural killer 1.1 \u03ea Fraction A cells) and cells capable of generating pro-B colonies in the presence of interleukin 7 and flt3 ligand migrate to thymus-expressed chemokine (TECK), a response lost in later stages of B cell development. B cell-attracting chemokine 1 (BCA-1) responses correlate with CXC chemokine receptor (CXCR)5 expression, are first displayed by a pro-B cell subset, are lost in pre-B cells, and then are regained just before and after egress from the marrow. All peripheral B cell subsets, including follicular and germinal center as well as marginal zone and peritoneal B1 B cells, respond to BCA-1, implying that responsiveness to this follicular chemokine is not sufficient to predict follicle localization. Responses to the CC chemokine receptor (CCR)7 ligands secondary lymphoid tissue chemoattractant (SLC) and macrophage inflammatory protein (MIP)-3 \u2424 , implicated in homing to lymphoid tissues, are upregulated before B cell exit from the marrow, but increase further in the periphery and are shared by all peripheral B cells. In contrast, responsiveness to MIP-3 \u2423 and expression of CCR6 are acquired only after emigration to the periphery and during maturation into the recirculating B cell pool. Chemotaxis to stromal cell-derived factor 1 \u2423 is observed at all stages of B cell differentiation. Thus, unique patterns of chemokine responses may help define developing B cell populations and direct their maturation in the marrow and migration to the periphery.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "B cells provide a two-pronged defense against invading pathogens. B cells internalize specific antigens via their surface Ig (sIg) 1 receptors, process the antigen into peptides, and present the peptides to T cells in the context of the B cells' class II MHC. In this manner, they act as sentinels and survey the body for the presence of nonself-antigens. If nonself-antigens are detected, B cells undergo a complex developmental program to generate large quantities of high-affinity neutralizing antibodies that help in clearing the pathogen from the host. To encounter antigen and to obtain help in generating a potent humoral response, the fulfillment of these two complex tasks requires that B cells migrate into specific areas at specific times during their development. Although the physical site(s) of B cell precursor development and differentiation in the bone marrow (BM) remain poorly defined, mature peripheral B cell subsets occupy characteristic microenvironments or domains. The major B cell microenvironment in all secondary lymphoid tissues is the primary follicle. The follicle contains recirculating naive B cells that sample secondary lymphoid organs such as the spleen, LNs, and Peyer's patches (PPs) for the presence of nonself-antigens and contribute to T celldependent humoral responses (1) . In the spleen, an additional B cell population occupies the marginal zone (MZ) that surrounds the white pulp and are positioned near the efficient antigen-trapping marginal sinus macrophages. MZ B cells are thought to sample blood-borne T cell-independent antigens that flow through the marginal sinus (2-4). They turn over more slowly than follicular B cells and recirculate poorly to other lymphoid organs (4, 5) , but are translocated rapidly into the splenic white pulp in response to endotoxin stimulation (6) . During active immune responses, the follicle or follicular mantle surrounds another distinct B cell microenvironment, the germinal center (GC). GCs are sites of antigen-driven proliferation, affinity maturation, and memory B cell generation (7, 8) . Finally, serosal surface cavities are populated by B1 or CD5 \u03e9 B cells, which may represent an alternative B cell development pathway. They are the primary source of natural antibodies and contribute to auto-antibody production in autoimmune diseases (9, 10) . The unique and distinctive microenvironmental location of each of these well-defined B cell populations requires that they display differential homing properties.", "cite_spans": [{"start": 131, "end": 132, "text": "1", "ref_id": "BIBREF0"}, {"start": 1311, "end": 1314, "text": "(1)", "ref_id": "BIBREF0"}, {"start": 1725, "end": 1728, "text": "(4,", "ref_id": "BIBREF3"}, {"start": 1729, "end": 1731, "text": "5)", "ref_id": "BIBREF4"}, {"start": 1828, "end": 1831, "text": "(6)", "ref_id": "BIBREF5"}, {"start": 2075, "end": 2078, "text": "(7,", "ref_id": "BIBREF6"}, {"start": 2079, "end": 2081, "text": "8)", "ref_id": "BIBREF7"}, {"start": 2335, "end": 2338, "text": "(9,", "ref_id": "BIBREF8"}, {"start": 2339, "end": 2342, "text": "10)", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "Introduction", "text": "Chemotactic signals are thought to play important roles in leukocyte navigation by regulating migration from the blood into tissues, as well as subsequent microenvironmental localization within those tissues. The list of characterized leukocyte chemoattractants has grown rapidly with the identification of the chemoattractant cytokine (chemokine) superfamily (11) . Chemokines send directional signals to leukocytes by binding to seven transmembrane receptors that are coupled to pertussis toxin-inhibitable G \u2423 i G protein heterotrimers. Most leukocytes express multiple chemokine and other chemoattractant receptors in overlapping patterns as a function of their development and activation state. Cells expressing multiple receptors can navigate in a step-by-step fashion through spatial arrays of overlapping chemokine and chemoattractant gradients (12) . Thus, the migration and microenvironmental targeting of leukocytes are thought to be determined as a function (in part) of the set of chemokines to which they can respond: their chemokine response profile or \"fingerprint.\"", "cite_spans": [{"start": 360, "end": 364, "text": "(11)", "ref_id": "BIBREF10"}, {"start": 853, "end": 857, "text": "(12)", "ref_id": "BIBREF11"}], "ref_spans": []}, {"section": "Introduction", "text": "Several chemokines attract primary B cells or B cell lines and have been hypothesized to play a role in the homing and microenvironmental localization of B cell subsets at different stages of antigen-independent and -dependent B cell differentiation (13) (14) (15) (16) (17) (18) (19) (20) . To explore the signals that guide B cells, we identified chemokines to which developing and mature B cells respond and assessed how those responses change as the B cells develop and populate various locales throughout the body. Our results reveal dramatic developmental switches in chemotactic response profiles during B cell development and suggest that altered chemotactic responses may play a major role in determining the migration patterns of developing B cells emigrating to the periphery after differentiation in the BM. Conversely, the major peripheral mature B cell subsets (follicular, MZ, GC, and B1 B cells) display surprisingly similar responses to the known secondary lymphoid and follicular chemokines, suggesting that microenvironmental localization in the periphery involves additional uncharacterized elements.", "cite_spans": [{"start": 250, "end": 254, "text": "(13)", "ref_id": "BIBREF12"}, {"start": 255, "end": 259, "text": "(14)", "ref_id": "BIBREF13"}, {"start": 260, "end": 264, "text": "(15)", "ref_id": "BIBREF14"}, {"start": 265, "end": 269, "text": "(16)", "ref_id": "BIBREF15"}, {"start": 270, "end": 274, "text": "(17)", "ref_id": "BIBREF16"}, {"start": 275, "end": 279, "text": "(18)", "ref_id": "BIBREF17"}, {"start": 280, "end": 284, "text": "(19)", "ref_id": "BIBREF18"}, {"start": 285, "end": 289, "text": "(20)", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "Materials and Methods", "text": "Mice. Male and female C57BL/6 mice were housed and bred at the Veterans Affairs Palo Alto Health Care Systems mouse facility under specific pathogen-free conditions.", "cite_spans": [], "ref_spans": []}, {"section": "Materials and Methods", "text": "Flow Cytometric and Chemokine Reagents. The following antibodies were used (specificities and modifications in parentheses), all from PharMingen: RA3-6B2 (allophycocyanin [APC]-conjugated rat anti-mouse CD45R/B220); 145-2C11 (biotin-conjugated Armenian hamster anti-mouse CD3 \u2440 ); AF6-78 (PE-conjugated rat anti-mouse IgM b ); 53-7.3 (PE-conjugated anti-mouse CD5); 1D3 (PE-conjugated rat anti-mouse CD19); B3B4 (PEconjugated rat anti-mouse CD23); M1/69 (PE-conjugated rat anti-mouse CD24 [heat-stable antigen, HSA]); 11-26c.2a (FITCconjugated rat anti-mouse IgD); II/41 (FITC-conjugated rat anti-mouse IgM); 145-2C11 (FITC-conjugated Armenian hamster anti-mouse CD3 \u2440 ); 7G6 (FITC-conjugated rat anti-mouse CD21); M1/69 (FITC-conjugated rat anti-mouse CD24 [HSA]); S7 (FITC-conjugated rat anti-mouse CD43); and PK136 (FITCconjugated rat anti-mouse NK1.1). Purified rabbit anti-mouse CXC chemokine receptor (CXCR)5 was obtained from Dr. Jason Cyster (University of California at San Francisco, San Francisco, CA), and biotin-conjugated goat anti-rabbit IgG was purchased from PharMingen. Rat anti-mouse CXCR3 (5B4) and CC chemokine receptor (CCR)6 (1C12) mAb supernatants were obtained from LeukoSite, and biotin-conjugated mouse anti-rat IgG H \u03e9 L was purchased from Jackson Immunoresearch Laboratories. Peridinine chlorophyll protein (PerCP)-conjugated streptavidin (SAv; Becton Dickinson) was used to visualize biotinylated anti-mouse CD3 \u2440 , anti-mouse CXCR3, anti-mouse CXCR5, and anti-mouse CCR6. FITC-conjugated peanut agglutinin (PNA; EY Laboratories) was used to visualize GC cells. Technical grade rat IgG was purchased from Sigma Chemical Co.", "cite_spans": [], "ref_spans": []}, {"section": "Materials and Methods", "text": "The following chemokines were purchased from PeproTech: recombinant mouse eotaxin, human I-309, mouse JE (monocyte chemoattractant protein [MCP]-1), mouse KC (Gro-\u2423 ), human macrophage inflammatory protein (MIP)-3 \u2423 (liver and activation-regulated chemokine [LARC]), mouse regulated on activation, normal T cell expressed and secreted (RANTES), and human thymus and activation-regulated chemokine (TARC). The following chemokines were purchased from R&D Systems: recombinant human B cell-attracting chemokine 1 (BCA-1), recombinant mouse B lymphocyte chemoattractant (BLC), mouse monokine induced by IFN-\u2425 (MIG), mouse MIP-1 \u2424 , rat MIP-3 \u2423 (LARC), mouse MIP-3 \u2424 (EBV-induced molecule 1 ligand chemokine [ELC]), mouse secondary lymphoid tissue chemoattractant (SLC, 6Ckine), and mouse thymus-expressed chemokine (TECK). Human stromal cell-derived factor (SDF)-1 \u2423 was either provided by Gryphon or purchased from PeproTech.", "cite_spans": [], "ref_spans": []}, {"section": "Materials and Methods", "text": "Lymphocyte Isolation. 6-10-wk-old mice of both sexes were killed by cervical dislocation. Peripheral LNs (subiliac, proper axillary, accessory axillary, and cervical), mesenteric LNs, PPs, and spleen were harvested, minced with scissors in RPMI/10% bovine calf serum (BCS), and pressed through a wire mesh screen with a rubber syringe plunger. Peritoneal cavity cells were harvested by injecting 10 ml of RPMI/10% BCS into the peritoneal cavity using a 27-gauge needle, agitating the cavity periodically for 5 min, and removing the lymphocyte-rich solution with a 19-gauge needle. BM cells were harvested by dissecting the femur and tibia, removing all muscle from the bone, cutting the ends off the bones, flushing with 3 ml of RPMI/10% BCS through both ends of the bone, and passing the disrupted marrow though a wire mesh screen. Splenocytes and BM cells were depleted of erythrocytes by lysis in ACK buffer (5 min at room temperature). The lymphocytes were allowed to incubate in RPMI/10% BCS for 1 h at 37 \u040a C in a CO 2 incubator in T-75 flasks to remove tissue culture flask adherent cells and to allow time for resensitization of potentially desensitized chemokine responses.", "cite_spans": [], "ref_spans": []}, {"section": "Materials and Methods", "text": "Chemotaxis Assay and Quantitation. Chemotaxis assays were performed in 5-m pore transwell inserts as described by Campbell et al. (21) , with the following modifications. Chemokines were used at the following concentrations: 500 nM BCA-1, 1 nM JE, 100 nM MCP-3, 100 nM MIG, 10 nM MIP-1 \u2423 , 3 nM MIP-1 \u2424 , 100 nM MIP-3 \u2423 , 100 nM MIP-3 \u2424 , 100 nM RANTES, 50 nM SDF-1 \u2423 , 100 nM SLC, and 300 nM TECK. The chemotaxis assay proceeded for 2 h, a known number of counting beads were added to each chemotaxis well after Transwell insert removal, and the contents of the chemotaxis well were transferred to a polypropylene pointed bottom tube. The beads and cells were centrifuged at 200 g for 10 min, excess medium was removed, and the cells were resuspended in 25 l of cold Staining Buffer (PBS/1 mM MgCl 2 /1 mM CaCl 2 /0.1% NaN 3 /2% Fraction V BSA) containing 30 g of rat IgG (Sigma Chemical Co.). The cells were incubated on ice for 15 min and 25 l of the appropriate antibody cocktail was added. The cells were further incubated on ice for 30 min, washed with 3 ml of Staining Buffer, centrifuged, and incubated with 50 l of Staining Buffer containing 2.5 l Sav-PerCP for 30 min. The cells were either washed, centrifuged, and analyzed by flow cytometry (non-PNA-stained cells), or incubated with 50 l of PNA-FITC for 4-6 min, stopped by addition of 3 ml of PBS/2% formaldehyde or Staining Buffer, centrifuged, and analyzed by flow cytometry (for some PP B cell staining).", "cite_spans": [{"start": 130, "end": 134, "text": "(21)", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "Materials and Methods", "text": "Chemokine Receptor Staining. The indicated lymphoid organs were disrupted and lymphocytes were isolated as described. The cells were incubated for 1 h at 37 \u040a C to remove tissue culture plate-adherent cells. 5 \u03eb 10 5 lymphocytes were stained with either purified rabbit anti-mouse CXCR5 polyclonal antibody at 1:25 dilution or purified rabbit anti-R-ras (0.5 g) as a negative control in 25 l of Staining Buffer (22) . Cells were washed and stained with biotin-conjugated goat anti-rabbit IgG. Cells were washed, blocked with 30 g rat IgG, and incubated with the appropriate cocktail of conjugated antibodies (and SAv-PerCP) to visualize the relevant B cell populations. 10 6 lymphocytes were stained with supernatants from either rat anti-mouse CXCR3 mAb, rat anti-mouse CCR6 mAb, or irrelevant control supernatants (HECA-452, MK2.7). Cells were washed and stained with biotin-conjugated mouse anti-rat IgG H \u03e9 L. Cells were washed, blocked with 30 g rat IgG, and incubated with the appropriate cocktail of conjugated antibodies (and SAv-PerCP) to visualize the relevant B cell populations.", "cite_spans": [{"start": 411, "end": 415, "text": "(22)", "ref_id": "BIBREF21"}], "ref_spans": []}, {"section": "Materials and Methods", "text": "During chemokine receptor staining of the splenic Transition 1 population, anti-mouse CD3 \u2440 -FITC, was included with B220-APC, CD23-PE, and CD21-FITC to prevent B220 \u03e9 T cells (which do not have CD23 or CD21) from contaminating the Transition 1 population (B220 \u03e9 CD23 \u03ea CD21 \u03ea /lo ). During chemokine receptor staining of PP GC B cells, B220 \u03e9 T cells were excluded from analysis by staining with B220-APC, CD19-PE, and PNA-FITC because B cells but not B220 \u03e9 T cells express CD19.", "cite_spans": [], "ref_spans": []}, {"section": "Materials and Methods", "text": "Pro-B CFU Assay. Unfractioned BM cells were isolated and allowed to migrate to chemokines as described. Responding cells from two chemotaxis wells (input 2E6 BM cells per Transwell insert) were harvested, pelleted by centrifugation, and resuspended in 75 l of RPMI/10% BCS. 1.35 ml of Methocult M3630 containing 10 ng/ml recombinant human IL-7 (StemCell Technologies Inc.) was aliquoted into 12 \u03eb 75 mm polypropylene tubes, and 75 l of recombinant murine flt3 ligand (Flt3-L; R&D Systems) was added to give a final concentration of 50 ng/ ml Flt3-L (based on the methods of Hunte et al. [23] and Veiby et al. [24] ). Responding cells were added to the Methocult mixture, vortexed for 5 s, and aliquoted to 35 \u03eb 10 mm tissue culture polystyrene dishes using a 20-gauge needle. Multiple plates were placed in a 150 \u03eb 15 mm plate containing an uncovered 35 \u03eb 10 mm plate filled with water to prevent dehydration. The plates were incubated in a 37 \u040a C incubator for 12-17 d. Colonies were identified and counted using a dissecting microscope. Colonies were harvested by removing them with a pipette and stained with B220-APC, HSA-biotin/SAv-PerCP, CD19-PE, and Mac-1-FITC to confirm the pro-B colony identification. The TECKresponding pro-B CFUs only became apparent in the second week of the assay, and they were tightly compact colonies compared with a few very spread and disorganized B220 \u03ea colonies that were found in all assays (including the Basal Medium control plates). Many pro-B CFU colonies had a multilobed shape or were a collection of three to six small colonies very close together. In all cases, these were counted as a single colony because the relatively few number of colonies per plate did not suggest that these colonies arose from multiple pro-B CFUs that happen to settle out close together.", "cite_spans": [{"start": 587, "end": 591, "text": "[23]", "ref_id": "BIBREF22"}, {"start": 609, "end": 613, "text": "[24]", "ref_id": "BIBREF23"}], "ref_spans": []}, {"section": "Results", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Developmental Shifts in Chemokine Response", "text": "Profiles during B Cell Development in the BM. B cells develop in the BM through sequential developmental stages, from stem cells to multipotent progenitors to pre-pro-B cells, to pro-B cells, to pre-B cells, and finally to immature B cells. After commitment to the B cell lineage, these stages have been associated with particular surface phenotypic markers according to Hardy et al. and Li et al. (25, 26) . To explore the developmental control of the chemotaxis response profiles during B cell development, we assessed the chemotactic responses of cells at each of these antigenically defined stages (Fig. 1 A) . A panel of chemokines was selected that bound all of the currently described CC and CXC receptors (Table I). Naive splenic \u2426 \u03e9 follicular B cells ( \u03ed sIgM heavy chain, and \u2426 \u03ed sIgD heavy chain), the most abundant mature peripheral B cell population, were evaluated in parallel for comparison. Chemokines were titered from 0.1-100 nM (TECK was tested up to 1 M and BCA-1 was tested up to 2.5 M), and results shown here reflect responses to the concentrations that gave the optimal migration of BM and peripheral B cells (concentrations used are given in the legend of Table I ). No significant difference was observed in the dose-response curves to any chemokine by any B cell subset analyzed in this paper (differences in the magnitude of response will be presented below).", "cite_spans": [{"start": 403, "end": 406, "text": "26)", "ref_id": "BIBREF25"}], "ref_spans": [{"start": 602, "end": 612, "text": "(Fig. 1 A)", "ref_id": "FIGREF0"}]}, {"section": "Developmental Shifts in Chemokine Response", "text": "None of the BM B cell populations nor the splenic \u2426 \u03e9 B cells responded to eotaxin, TARC, I-309, or KC; migration to these chemokines at all concentrations tested was indistinguishable from background migration (data not shown). Non-B cell populations present in the BM and periphery responded to KC and TARC, confirming these chemokines' activity in our assay. MIP-3 \u2423 , a well-characterized peripheral lymphocyte-active chemokine also failed to attract B lineage cells in the BM (but see next section). All populations responded fairly equally to SDF-1 \u2423 , confirming their competence to migrate under our experimental conditions (Fig. 1 C) .", "cite_spans": [], "ref_spans": [{"start": 632, "end": 642, "text": "(Fig. 1 C)", "ref_id": "FIGREF0"}]}, {"section": "Developmental Shifts in Chemokine Response", "text": "Interestingly, cells of pre-pro-B cell phenotype (B220 lo HSA \u03ea /lo AA4.1 \u03e9 NK1.1 \u03ea ; a subpopulation within the original Fraction A population of Hardy et al. [25] that combines the A1 and A2 fractions [26] ) displayed substantial migration to RANTES, JE (mouse MCP-1), MIG, and TECK, chemokines associated with monocyte and/or activated T cell responses in the periphery. As illustrated in Fig. 1 B, these cells responded well, but the response to these chemokines was lost rapidly during progression to the pro-B cell stage. B cell migration to these chemokines was not observed in any more developed BM B cell or peripheral B cell population tested (follicular \u2426 \u03e9 B cells to the right of the dotted line are shown as an example of a peripheral B cell population). In preliminary experiments, MIP-1 \u2423 , MIP-1 \u2424 , and MCP-3 stimulated migration of Fraction A BM B cells (data not shown). As these chemokines are known to bind the same receptors as RANTES Unfractioned BM cells were prepared and added to inserts that were placed in wells containing the following chemokines: 100 nM RANTES, 1 nM JE, 100 nM MIG, or 300 nM TECK. Responding cells were harvested and stained with either B220-APC, unlabeled AA4.1/mouse anti-rat IgG-biotin/SAv-PerCP, HSA-PE, and NK1.1-FITC or AA4.1-APC, HSA-biotin/SAv-PerCP, B220-PE, NK1.1-FITC to identify the AA4.1 \u03e9 NK1.1 \u03ea Fraction A population or with combinations of B220-APC, IgM b -PE, HSA-PE, and CD43-FITC to identify the later stages during B cell development. The data are the mean \u03ee SEM from two to eight experiments. (C) Responses to peripheral lymphoid chemokines appear late during BM B cell development. Same procedure as above except the following chemokines were used: 100 nM MIP-3\u2423, 100 nM SLC, 100 nM MIP-3\u2424, 50 nM SDF-1\u2423, and 500 nM BCA-1. The data are the mean \u03ee SEM from 3-15 experiments. All symbols have error bars even though in some instances (i.e., Basal migration and pro-B/BCA-1 migration) the error bars are smaller than the symbol.", "cite_spans": [{"start": 160, "end": 164, "text": "[25]", "ref_id": "BIBREF24"}, {"start": 203, "end": 207, "text": "[26]", "ref_id": "BIBREF25"}], "ref_spans": [{"start": 392, "end": 398, "text": "Fig. 1", "ref_id": "FIGREF0"}]}, {"section": "Table I. Chemokines Used and Their Known Receptors", "text": "Chemokine Receptor", "cite_spans": [], "ref_spans": []}, {"section": "Table I. Chemokines Used and Their Known Receptors", "text": "The chemokines were used at the following concentrations: 100 nM MIP-1\u2423, 100 nM MCP-3, 1 nM JE, 100 nm Eotaxin, 100 nM TARC, 100 nM RANTES, 3 nM MIP-1\u2424, 100 nM MIP-3\u2423, 100 nM MIP-3\u2424, 100 nM SLC, 100 nM I-309, 300 nM TECK, 100 nM KC, 100 nM MIG, 50 nM SDF-1\u2423, or 500 nM BCA-1. *Mouse SLC, but not human SLC, binds to CXCR3 (reference 64).", "cite_spans": [], "ref_spans": []}, {"section": "Table I. Chemokines Used and Their Known Receptors", "text": "and JE (Table I) , they were not used in subsequent experiments.", "cite_spans": [], "ref_spans": []}, {"section": "Table I. Chemokines Used and Their Known Receptors", "text": "To confirm that the Fraction A1/A2 responses to these chemokines included B lineage cells, BM cells were allowed migrate to each of these chemokines and the responding cells were placed into subsequent assays that facilitated growth of B lineage progenitors into colonies of pro-B cells or pro-B CFUs by incubation with IL-7 and Flt3-L in methylcellulose (23, 24) . BM cells capable of generating pro-B CFUs responded to TECK (Fig. 2) , whereas RANTES and JE were much weaker at attracting pro-B CFUs and no response over control was seen to MIG. The TECK-responding cells required both IL-7 and Flt3-L to generate colonies, as they yielded much fewer colonies in the CFU assay with only IL-7 (data not shown). Therefore, very early B lineage progenitors can respond to TECK and this response is lost as B cells enter into the pro-B compartment.", "cite_spans": [{"start": 355, "end": 359, "text": "(23,", "ref_id": "BIBREF22"}, {"start": 360, "end": 363, "text": "24)", "ref_id": "BIBREF23"}], "ref_spans": [{"start": 426, "end": 434, "text": "(Fig. 2)", "ref_id": "FIGREF2"}]}, {"section": "Table I. Chemokines Used and Their Known Receptors", "text": "The loss of response to TECK during B cell development occurred at the same stage as a gain of responsiveness to chemokines associated with homing in secondary lymphoid organs: SLC, MIP-3\u2424, and BCA-1 (16) . BCA-1 (BLC), a chemokine implicated in B cell entry into the follicles of PPs and spleen (but interestingly, not most PLNs [27] ) is of particular interest in the context of B cell behavior and microenvironmental homing. It is known to attract the majority of B cells in the periphery, as well as a small subset of CD4 \u03e9 T cells. We found that there is a consistent but small response in the pro-B cell compartment (P \u03fd 0.02 by Mann-Whitney rank sum test) that is lost with progression to the pre-B cell stage. Regained BCA-1 responsiveness in the immature B cell compartment is consistently observed, but the magnitude was variable from experiment to experiment. Mature peripheral \u2426 \u03e9 B cells responded strongly to BCA-1.", "cite_spans": [{"start": 200, "end": 204, "text": "(16)", "ref_id": "BIBREF15"}, {"start": 330, "end": 334, "text": "[27]", "ref_id": "BIBREF26"}], "ref_spans": []}, {"section": "Table I. Chemokines Used and Their Known Receptors", "text": "The differential migration of gated B220 \u03e9 BM subpopulations to chemokines is illustrated in Fig. 3 . Responding B lineage cells (bold lines) are stained for various markers and compared with the B lineage cells in the initial input population (light line) after migration to SLC (Fig. 3, left) and BCA-1 (Fig. 3, right) . BM B cells that respond to SLC and to BCA-1 are enriched for IgM expression, but they are not identical populations. SLC-responding BM B cells contain both IgM \u03ea and IgM \u03e9 cells, with an enrichment in IgM \u03e9 cells (Fig. 3 A) . Conversely, only IgM \u03e9 cells are found after chemotaxis to BCA-1 (Fig. 3 B) , consistent with later acquisition of BCA-1 responsiveness. As a control, we showed that incubation with various chemokines did not change the surface level expression of any of the markers used in this study (data not shown).", "cite_spans": [], "ref_spans": [{"start": 93, "end": 99, "text": "Fig. 3", "ref_id": "FIGREF3"}, {"start": 280, "end": 294, "text": "(Fig. 3, left)", "ref_id": "FIGREF3"}, {"start": 305, "end": 320, "text": "(Fig. 3, right)", "ref_id": "FIGREF3"}, {"start": 536, "end": 546, "text": "(Fig. 3 A)", "ref_id": "FIGREF3"}, {"start": 614, "end": 624, "text": "(Fig. 3 B)", "ref_id": "FIGREF3"}]}, {"section": "Table I. Chemokines Used and Their Known Receptors", "text": "Receptor expression for one of the Fraction A1/A2 chemokines, MIG, was investigated in order to study the unexpected chemotactic responses by these cells in more detail. The only known receptor for MIG is CXCR3 (11), and we used an anti-mouse CXCR3 mAb in combination with the staining cocktails described above to visualize CXCR3 expression at the different stages of B cell development in Fig. 4 A. Fraction A1/A2 cells (Fig. 4 A, first column) displayed very low to no staining with anti-CXCR3 mAb, whereas the AA4.1 \u03ea Fraction A subpopulation displayed fairly uniform CXCR3 staining (data not shown). No B lineage cells at later stages of development in the BM or in the periphery (Fig. 4 A, last column) expressed CXCR3, consistent with their failure to migrate to MIG (Fig. 1 B) . Flow cytometry plots illustrate the selectivity of chemokine responses by antigenically defined B cell subsets. Unfractioned BM cells were prepared and added to inserts that were placed in wells containing either 100 nM SLC (left) or 500 nM BCA-1 (right). Initial input (light line) and responding (bold line) cells were harvested and stained with different combinations of B220-APC, IgM b -PE, and CD43-FITC. All panels were gated on B220 \u03e9 cells. The presented histograms were obtained by overlaying individual histograms from three to four experiments, adding them together using CELLQuest\u2122 software (Becton Dickinson) to obtain an average representative histogram, and normalizing them to the peak cell number. CTX, chemotaxis.", "cite_spans": [], "ref_spans": [{"start": 391, "end": 397, "text": "Fig. 4", "ref_id": "FIGREF5"}, {"start": 422, "end": 429, "text": "(Fig. 4", "ref_id": "FIGREF5"}, {"start": 685, "end": 692, "text": "(Fig. 4", "ref_id": "FIGREF5"}, {"start": 774, "end": 784, "text": "(Fig. 1 B)", "ref_id": "FIGREF0"}]}, {"section": "Table I. Chemokines Used and Their Known Receptors", "text": "As the biphasic response pattern of BM B cells to BCA-1 was unique among the peripherally important chemokines tested, we further explored this chemokine-chemokine receptor interaction by determining the expression pattern of the only known receptor for BCA-1, CXCR5 (14, 15) . No detectable expression of CXCR5 above background was observed in the Fraction A1/A2 or pre-B cell population (Fig. 4 B, first and third column). CXCR5 expression was detectable on a subset of the pro-B cell population (Fig. 4 B, second column) , although the magnitude of the shift was variable. The immature B cell population displayed CXCR5 (Fig. 4 B, fourth column) but the frequency of expression was again variable, consistent with their variable responses to BCA-1. In contrast, splenic \u2426 \u03e9 follicular B cells were uniformly and strongly CXCR5 \u03e9 (Fig. 4 B, (Fig. 5 B) . Moreover, the responses of putative blood-borne peripheral B cells passing through the BM at the time of harvest (Fraction F in the classification scheme of Hardy et al. [25] , B220 hi CD43 \u03ea sIgM \u03e9 ) were indistinguishable from those of splenic follicular \u2426 \u03e9 B cells (data not shown).", "cite_spans": [{"start": 267, "end": 271, "text": "(14,", "ref_id": "BIBREF13"}, {"start": 272, "end": 275, "text": "15)", "ref_id": "BIBREF14"}, {"start": 1026, "end": 1030, "text": "[25]", "ref_id": "BIBREF24"}], "ref_spans": [{"start": 389, "end": 396, "text": "(Fig. 4", "ref_id": "FIGREF5"}, {"start": 498, "end": 523, "text": "(Fig. 4 B, second column)", "ref_id": "FIGREF5"}, {"start": 623, "end": 648, "text": "(Fig. 4 B, fourth column)", "ref_id": "FIGREF5"}, {"start": 832, "end": 842, "text": "(Fig. 4 B,", "ref_id": "FIGREF5"}, {"start": 843, "end": 853, "text": "(Fig. 5 B)", "ref_id": "FIGREF6"}]}, {"section": "Table I. Chemokines Used and Their Known Receptors", "text": "CXCR5 expression increases, paralleling BCA-1 responsiveness, as B cells exit the BM and progress through the transitional stages into recirculating \u2426 \u03e9 follicular B cells. Few immature BM B cells expressed significant levels of CXCR5 (Fig. 5 D, first column) , but a majority of Transition 1 recent emigrants expressed CXCR5 (Fig. 5 D,  second column) , and expression became more uniform and more intense on Transition 2 and \u2426 \u03e9 follicular B cells ( Fig. 5 D, third and fourth columns) . CCR6 shows a different temporal pattern of acquisition compared with CXCR5. CCR6 is undetectable on any BM B cell population (Fig. 4 C, first four columns) including immature BM B cells and the Transition 1 B cells to which they give rise (Fig. 5 C, first and second columns, respectively) . In contrast, all Transition 2 and recirculating \u2426 \u03e9 follicular B cells display uniform CCR6 expression (Fig. 5 C, (Fig. 6 A) . In stimulated lymphoid tissues, such as PPs, B cells in GCs are identified as B220 \u03e9 cells that have higher level expression of terminal galactosyl residues that are recognized by the plant lectin peanut agglutinin (PNA hi ) compared with the surrounding B220 \u03e9 PNA lo follicular mantle subset (Fig. 6 B [32-34] ). In addition, GC B cells are \u2426 \u03ea compared with the follicular mantle \u2426 \u03e9 B cells. In the experiments described here, we analyzed the migration properties of cells in each of these regions individually.", "cite_spans": [], "ref_spans": [{"start": 235, "end": 259, "text": "(Fig. 5 D, first column)", "ref_id": "FIGREF6"}, {"start": 326, "end": 352, "text": "(Fig. 5 D,  second column)", "ref_id": "FIGREF6"}, {"start": 452, "end": 487, "text": "Fig. 5 D, third and fourth columns)", "ref_id": "FIGREF6"}, {"start": 615, "end": 645, "text": "(Fig. 4 C, first four columns)", "ref_id": "FIGREF5"}, {"start": 729, "end": 779, "text": "(Fig. 5 C, first and second columns, respectively)", "ref_id": "FIGREF6"}, {"start": 885, "end": 895, "text": "(Fig. 5 C,", "ref_id": "FIGREF6"}, {"start": 896, "end": 906, "text": "(Fig. 6 A)", "ref_id": "FIGREF7"}, {"start": 1203, "end": 1220, "text": "(Fig. 6 B [32-34]", "ref_id": "FIGREF2"}]}, {"section": "Table I. Chemokines Used and Their Known Receptors", "text": "Splenic follicular (B220 hi CD21 int CD23 int ) and MZ (B220 \u03e9 CD21 hi CD23 lo/\u03ea) B cells migrate with similar efficiency to SLC, SDF-1\u2423, and BCA-1 (Fig. 7 B) . In contrast to IgM \u03e9 immature BM B cells and Transition 1 B cells (Fig. 5 A) , follicular B cells also migrate significantly to MIP-3\u2423 (Fig. 7 A) . MZ splenocytes also respond to MIP-3\u2423, but substantially less efficiently (Fig. 7 A) . Follicular B cells are also found in peripheral LNs, mesenteric LNs, and PPs (also called follicular mantle B cells if GCs are present); however, MZ B cells are far less numerous in these organs compared with spleen (35) . As expected, LN (data not shown) and PP (Fig. 7, E and F) follicular B cell subsets displayed very similar chemotactic fingerprints to those of their splenic counterparts. The only difference observed was that the MIP-3\u2423 responses of splenic follicular B cells were less pronounced in the corresponding PP (Fig. 7 E) and LN (data not shown but similar to PP) populations. Chemotaxis profiles of CD3\u2440 \u03e9 B220 \u03ea T cells found in the corresponding organs are shown for comparison.", "cite_spans": [{"start": 612, "end": 616, "text": "(35)", "ref_id": "BIBREF34"}], "ref_spans": [{"start": 148, "end": 158, "text": "(Fig. 7 B)", "ref_id": "FIGREF8"}, {"start": 227, "end": 237, "text": "(Fig. 5 A)", "ref_id": "FIGREF6"}, {"start": 296, "end": 306, "text": "(Fig. 7 A)", "ref_id": "FIGREF8"}, {"start": 383, "end": 393, "text": "(Fig. 7 A)", "ref_id": "FIGREF8"}, {"start": 659, "end": 676, "text": "(Fig. 7, E and F)", "ref_id": "FIGREF8"}, {"start": 925, "end": 935, "text": "(Fig. 7 E)", "ref_id": "FIGREF8"}]}, {"section": "Table I. Chemokines Used and Their Known Receptors", "text": "The expression of CCR6 and CXCR5 correlates with the functional responses to MIP-3\u2423 and BCA-1 by splenic B cells. In Fig. 7 C (second column) , staining for CCR6 \u03e9 reveals a sharp, uniform peak of expression on CD21 int CD23 int follicular B cells, whereas CD21 hi CD23 \u03ea/lo MZ B cells display broader and dimmer CCR6 expression levels ( Fig. 7 C, first column) . Fig. 7 D shows a sharp, uniform were prepared and stained with B220-APC, CD3\u2440-biotin/SAv-PerCP, CD23-PE, and CD21-FITC for spleen or B220-APC, CD3\u2440-biotin/ SAv-PerCP, and PNA-FITC for PPs. The data shown have been gated on the B220 \u03e9 CD3\u2440 \u03ea population. peak of CXCR5 expression on both CD21 int CD23 int follicular (second column) and CD21 hi CD23 \u03ea/lo MZ (first column) B cells. The levels of CCR6 and CXCR5 on peripheral LN and PP Region 1 B cells are identical to the levels observed on splenic follicular B cells (data not shown). Similar CXCR5 expression by follicular and MZ B cells has been observed by Cyster et al. (22) . No detectable CXCR3 expression was observed on splenic or PP B cells (data not shown).", "cite_spans": [{"start": 988, "end": 992, "text": "(22)", "ref_id": "BIBREF21"}], "ref_spans": [{"start": 117, "end": 141, "text": "Fig. 7 C (second column)", "ref_id": "FIGREF8"}, {"start": 338, "end": 361, "text": "Fig. 7 C, first column)", "ref_id": "FIGREF8"}, {"start": 364, "end": 370, "text": "Fig. 7", "ref_id": "FIGREF8"}]}, {"section": "Table I. Chemokines Used and Their Known Receptors", "text": "We studied GC B cells in PPs, secondary lymphoid organs of the gut wall, which are chronically stimulated by their constant exposure to food-borne antigens and the intestinal microflora. PP GC B cells (B220 \u03e9 PNA hi ) responded to SLC, SDF-1\u2423, and BCA-1 as well as the unactivated follicular mantle B cell population (B220 \u03e9 PNA lo ), with a slight reduction in the SDF-1\u2423 response (Fig. 7 F) . Interestingly, GC B cells in the PPs of C57BL/6 mice (the principle strain studied here) displayed somewhat enhanced chemotaxis to MIP-3\u2423 (Fig. 7 E) . In contrast, GC B cells in the PPs of Balb/c mice displayed significantly reduced MIP-3\u2423 responses compared with their follicular mantle counterparts (data not shown). In spite of their relatively efficient migration to MIP-3\u2423, many C57BL/6 GC B cells lacked CCR6 expression (Fig. 7 C, fourth column), with only a small number displaying high levels comparable to PP follicular B cells (Fig. 7 C, third column). PP GC B cells displayed uniform levels of CXCR5 expression (Fig. 7 D , fourth column) that were similar in magnitude to splenic follicular (Fig. 7 D, second column) and PP follicular mantle (Fig. 7 D, third column CD5 \u03e9 Ly-1 \u03e9 B cells are part of the preimmune repertoire and may arise via an alternative developmental pathway. They are self-renewing (1) and are associated with autoimmune diseases and B cell leukemias and lymphomas (10) . Peritoneal B1 B cells are B220 lo and most are CD5 \u03e9 and CD43 \u03e9 (1). The conventional B cells (termed B2) in the peritoneal cavity have higher levels of B220 and are CD5 \u03ea and CD43 \u03ea . Both types of B cells from the peritoneal cavity had zero to very low basal migration compared with any of the other B cell populations we tested (Fig. 8, A and  B) . Both B1 and B2 B cells responded to SLC, SDF-1\u2423, and BCA-1 equally well, though to a lesser degree than splenic B cells (compare Fig. 8 B with Fig. 7 B) , and their response to MIP-3\u2423 was reduced compared with splenic B cells (compare Fig. 8 A with Fig. 7 A) . CCR6 expression was demonstrated on both B1 and B2 cells, although background staining of B1 B cells was relatively high (Fig. 8 C) . Both B cell populations expressed high levels of the BCA-1 receptor CXCR5 (Fig. 8 D) . Cyster et al. has also demonstrated CXCR5 expression on peritoneal cavity B1 B cells (22) .", "cite_spans": [{"start": 1392, "end": 1396, "text": "(10)", "ref_id": "BIBREF9"}, {"start": 2318, "end": 2322, "text": "(22)", "ref_id": "BIBREF21"}], "ref_spans": [{"start": 382, "end": 392, "text": "(Fig. 7 F)", "ref_id": "FIGREF8"}, {"start": 533, "end": 543, "text": "(Fig. 7 E)", "ref_id": "FIGREF8"}, {"start": 821, "end": 828, "text": "(Fig. 7", "ref_id": "FIGREF8"}, {"start": 932, "end": 939, "text": "(Fig. 7", "ref_id": "FIGREF8"}, {"start": 1017, "end": 1026, "text": "(Fig. 7 D", "ref_id": "FIGREF8"}, {"start": 1097, "end": 1122, "text": "(Fig. 7 D, second column)", "ref_id": "FIGREF8"}, {"start": 1148, "end": 1171, "text": "(Fig. 7 D, third column", "ref_id": "FIGREF8"}, {"start": 1730, "end": 1748, "text": "(Fig. 8, A and  B)", "ref_id": "FIGREF9"}, {"start": 1880, "end": 1903, "text": "Fig. 8 B with Fig. 7 B)", "ref_id": "FIGREF8"}, {"start": 1986, "end": 2009, "text": "Fig. 8 A with Fig. 7 A)", "ref_id": "FIGREF8"}, {"start": 2133, "end": 2143, "text": "(Fig. 8 C)", "ref_id": "FIGREF9"}, {"start": 2220, "end": 2230, "text": "(Fig. 8 D)", "ref_id": "FIGREF9"}]}, {"section": "Discussion", "text": "A central tenet of current models of leukocyte trafficking is that coordinated regulation of adhesive and migratory responses controls cellular positioning or homing in vivo (36) . In turn, this homing determines the leukocyte's cellular and microenvironmental interactions, and therefore its fate and function. For example, developmental switches in homing receptor and vascular addressin expression have been implicated in the maturation of peripheral lymphoid tissue during the perinatal period (37) and in developmental and antigen-induced transitions in T cells (38, 39) . We show here that developing B lineage cells undergo dramatic alterations in their chemotactic responses to different chemokines, alterations that may help define particular stages of B cell maturation and may regulate their cellular and microenvironmental interactions, development, and/ or function. We will discuss our findings in relation to (a) the major changes that occur during B lineage development, including the unique expression of a TECK response during an early B lineage stage and a dramatic switch to peripheral secondary lymphoid organ-expressed chemokine responses associated with B cell export from the marrow compartment, and (b) the patterns of chemokine responses displayed by B cells occupying different microenvironmental niches in the periphery.", "cite_spans": [{"start": 174, "end": 178, "text": "(36)", "ref_id": "BIBREF35"}, {"start": 567, "end": 571, "text": "(38,", "ref_id": "BIBREF37"}, {"start": 572, "end": 575, "text": "39)", "ref_id": "BIBREF38"}], "ref_spans": []}, {"section": "Discussion", "text": "We first addressed the chemokine responses of B cells at their earliest committed stage of development in the adult BM. B cell genesis derives from dividing hematopoietic stem cells (HSCs) that differentiate into progenitor cells, which in turn give rise to various hematopoietic lineages. The first identifiable BM cells committed to the B lineage are Fraction A1/A2 (AA4.1 \u03e9 NK1.1 \u03ea cells within Fraction A [25, 26, 40] ); these cells still have their Ig genes in the germline state but display the B lineage marker B220. Surprisingly, we found that a significant fraction of AA4.1 \u03e9 NK1.1 \u03ea Fraction A cells, unlike B lineage cells at later stages of development, migrate in response to RANTES, JE (mouse MCP-1), MIG, and TECK. These chemokines attract monocytes (RANTES and JE) and subsets of T cells (RANTES, JE, MIG, TECK) in the periphery, but have no activity on mature B cells.", "cite_spans": [{"start": 409, "end": 413, "text": "[25,", "ref_id": "BIBREF24"}, {"start": 414, "end": 417, "text": "26,", "ref_id": "BIBREF25"}, {"start": 418, "end": 421, "text": "40]", "ref_id": "BIBREF39"}], "ref_spans": []}, {"section": "Discussion", "text": "Limiting dilution analysis of B220 \u03ea HSA \u03ea AA4.1 \u03e9 CD4 \u03e9 multipotent progenitors demonstrated that a large number of colonies derived from single cells gave rise to progeny colonies containing both B cells and macrophages, suggesting a close developmental relationship between monocytes and B cells (40) . These data, and the observation of bipo- tential precursors of B cells and macrophages in the fetal liver (41), may explain the low level responses of AA4.1 \u03e9 NK1.1 \u03ea Fraction A cells to seemingly monocytic chemokines if both cell types arose from a common precursor. Interestingly, a recent report has shown that CXCR3 is expressed on leukemic B cells from all patients with chronic lymphocytic leukemia and is found on a subset of other B cell leukemias and lymphomas (42) . In other studies, we have found that the JE/MCP-1 response in Fraction A cells is absent in CCR2-deficient mice, further confirming the association of functional responses with specific chemokine receptor expression (Bowman, E., unpublished results). However, the lack of significant response by RANTES-, JE-, and MIG-responding cells in secondary pro-B CFU assays (Fig. 2) lessens the emphasis we can place on these chemokine responses in the scheme of B cell development. Other non-B lineage cells within the Fraction A gate including AA4.1 \u03ea NK1.1 \u03e9 immature NK precursors (26, 43) migrate very efficiently to these chemokines, and the responses seen in the AA4.1 \u03e9 NK1.1 \u03ea population may be due to contaminating non-B lineage cells that fall within the flow cytometry gates we have set. AA4.1 \u03e9 Fraction A cells do not express consistently detectable levels of CXCR3 (Fig. 4 A) even though they consistently migrated to MIG (Fig. 1 B) . Either this population expresses another undescribed MIG receptor or they may express levels of CXCR3 that, while functional, are much lower than those on CXCR3 \u03e9 AA4.1 \u03ea Fraction A cells, levels beneath our detection limits. Preliminary studies suggest that earlier HSCs, like later stage B lineage cells shown here, are also unresponsive to these chemokines (data not shown).", "cite_spans": [{"start": 299, "end": 303, "text": "(40)", "ref_id": "BIBREF39"}, {"start": 776, "end": 780, "text": "(42)", "ref_id": "BIBREF41"}, {"start": 1359, "end": 1363, "text": "(26,", "ref_id": "BIBREF25"}, {"start": 1364, "end": 1367, "text": "43)", "ref_id": "BIBREF42"}], "ref_spans": [{"start": 1148, "end": 1156, "text": "(Fig. 2)", "ref_id": "FIGREF2"}, {"start": 1654, "end": 1664, "text": "(Fig. 4 A)", "ref_id": "FIGREF5"}, {"start": 1711, "end": 1721, "text": "(Fig. 1 B)", "ref_id": "FIGREF0"}]}, {"section": "Discussion", "text": "TECK was the only chemokine that could effectively migrate BM cells that would give rise to pro-B CFUs in the presence of IL-7 and Flt3-L (Fig. 2) , but not IL-7 alone (data not shown). IL-7 alone stimulates the proliferation of late pro-B cells and early pre-B cells, but early pro-B cells, pre-B cells, and immature B cells are unresponsive (23) . Flt3-L can not stimulate the proliferation of any B lineage population alone, but Flt3-L synergizes with IL-7 to increase the growth of Lineage \u03ea /Sca-1 \u03e9 BM cells (a heterogeneous population of cells containing B cell progenitors before they express B220 [24] ) and the B cell progenitors among the B220 lo CD43 \u03e9 HSA \u03ea/lo Fraction A population (23) . These data combined suggests that TECK selectively attracts very early B220 \u03e9 B lineage progenitors (23) and/or B220 \u03ea BM cells with potential to develop into B220 \u03e9 B cells (24) , as these cell types require both IL-7 and Flt3-L for growth into pro-B colonies.", "cite_spans": [{"start": 343, "end": 347, "text": "(23)", "ref_id": "BIBREF22"}, {"start": 606, "end": 610, "text": "[24]", "ref_id": "BIBREF23"}, {"start": 696, "end": 700, "text": "(23)", "ref_id": "BIBREF22"}, {"start": 803, "end": 807, "text": "(23)", "ref_id": "BIBREF22"}, {"start": 877, "end": 881, "text": "(24)", "ref_id": "BIBREF23"}], "ref_spans": [{"start": 138, "end": 146, "text": "(Fig. 2)", "ref_id": "FIGREF2"}]}, {"section": "Discussion", "text": "It is attractive to postulate that responsiveness to TECK (and potentially RANTES and JE) by B lineage progenitors may help target them into supportive specialized niches appropriate to their developmental stage, and that downregulation of this (these) response with subsequent maturation would then allow their progression to different marrow microenvironments. However, B lineage progenitors may respond to these chemokines not only as chemotactic agents, but also as growth promoting and/or arresting cytokines. Several chemokines have been demonstrated to have potent effects on the growth of BM progenitors (especially myeloid progenitors) (44-48) and a feedback system has been hypothesized whereby chemokines produced in the periphery control the further production of different leukocyte lineages. Therefore, B lineage progenitor responses to these chemokines may play a role in the total B cell output by the BM by regulating the total number of B lineage cells that are allowed to develop.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "As Interestingly, B lineage cells at all stages of development migrate with similar efficiency to SDF-1\u2423, at least when assayed at the optimal chemotactic concentrations used here. This finding of uniform SDF-1\u2423 responsiveness is similar to that of Kim et al. (49) . However, it contrasts with the results by D'Apuzzo et al. (50) ; these authors report that early B lineage cells from mouse BM migrate much better to SDF-1\u2423 than do more developed B cells, and postulated that SDF-1\u2423 selectively attracts and confines early B cell precursors within the BM. The basis for this difference is unclear. Our results and those of Kim et al. also raise the possibility that apparent effects of SDF-1\u2423 and CXCR4 on B cell retention in the BM may reflect secondary or indirect effects, rather than a direct SDF-1\u2423-mediated retention mechanism. One scenario would be that stromal-produced SDF-1\u2423 stimulates hematopoietic non-B cells in the BM to produce the factor required to retain B cells in BM until their development is complete, at which time the B cells would lose responsiveness to this factor and exit the BM. Reconstitution of lethally irradiated mice with CXCR4 \u03ea\u0580\u03ea fetal liver cells (as performed by Ma et al. [51] ) would leave both the hypothetical non-B cell and B lineage cells incapable of responding to stromal-produced SDF-1\u2423. In this indirect manner, B lineage cells would not be retained in the BM, but this would be due to the lack of action of SDF-1\u2423 on the non-B cell, which then prevent expression of the pro-retention factor, instead of a direct SDF-1\u2423-B cell interaction. Also unclear is the significance of the increased SDF-1\u2423 responsiveness in B cells after exit to the periphery, since CXCR4 \u03ea/\u03ea lymphocytes migrate to secondary lymphoid organs and repopulate their niches efficiently (51) .", "cite_spans": [{"start": 325, "end": 329, "text": "(50)", "ref_id": "BIBREF49"}, {"start": 1211, "end": 1215, "text": "[51]", "ref_id": "BIBREF50"}, {"start": 1805, "end": 1809, "text": "(51)", "ref_id": "BIBREF50"}], "ref_spans": []}, {"section": "Discussion", "text": "Though sIgM \u03e9 immature BM B cells respond to SLC, MIP-3\u2424, SDF-1\u2423, and BCA-1, the magnitude of the responses by B cells increases substantially after their migration to the spleen (i.e., as transitioning recent emigrants). These heightened responses are further increased after progression of the splenic Transition 1 B cells into Transition 2 B cells. No further increase in responsiveness to these chemokines is seen as Transition 2 B cells convert into the naive, recirculating \u2426 \u03e9 B cells. In the case of BCA-1 responses, the increased chemotaxis is associated with an increase in both the frequency and intensity of CXCR5 expression (Fig. 5, B and D) .", "cite_spans": [], "ref_spans": [{"start": 637, "end": 654, "text": "(Fig. 5, B and D)", "ref_id": "FIGREF6"}]}, {"section": "Discussion", "text": "BCA-1 is preferentially expressed by dendritic cells in B cell follicles (14) . Along with its receptor, CXCR5, it has been postulated to control B cell entry into the follicular environment (14, 15, 52) . Consistent with studies of CXCR5 expression on human B cells by Forster et al. (52) , we observed that peripheral B cells migrate better to BCA-1 than immature BM B cells, supporting an important role for these molecules in peripheral B cell function. Moreover, we have found that (a) immature BM B cells respond relatively poorly to BCA-1; (b) there is an increased BCA-1 response in splenic transitioning populations; (c) the recirculating pool of splenic B cells possesses the most robust response to BCA-1 measured; and (d) CXCR5 expression and responsiveness to BCA-1 characterize all the major peripheral B cell subsets, including MZ B cells and B1 B cells-cells that are not associated with the follicular microenvironment. Together, these results indicate that CXCR5 expression and BCA-1 responsiveness are not, in and of themselves, sufficient to confer follicular localization to B cells. It is important to consider this conclusion in light of studies that demonstrated that CXCR5-deficient B cells display selective follicular localization defects in PPs and spleen (but not in most peripheral LNs, where follicular homing was normal [52] ).Taken together with our finding of CXCR5 expression and BCA-1 responsiveness by B cells that are normally excluded from the follicular compartment, these data suggest that follicular localization may be under complex (combinatorial) control as a function of tissue site (and other factors), so that a contribution of CXCR5 is essential in PPs and spleen, but is accessory or redundant in most normal LNs. BCA-1 may have other important functions in peripheral B cell biology as well.", "cite_spans": [{"start": 73, "end": 77, "text": "(14)", "ref_id": "BIBREF13"}, {"start": 191, "end": 195, "text": "(14,", "ref_id": "BIBREF13"}, {"start": 196, "end": 199, "text": "15,", "ref_id": "BIBREF14"}, {"start": 200, "end": 203, "text": "52)", "ref_id": "BIBREF51"}, {"start": 285, "end": 289, "text": "(52)", "ref_id": "BIBREF51"}, {"start": 1352, "end": 1356, "text": "[52]", "ref_id": "BIBREF51"}], "ref_spans": []}, {"section": "Discussion", "text": "The increasing responsiveness to SLC and MIP-3\u2424 during B cell maturation in and after emigration from the BM is of particular interest because these chemokines signal through a common receptor, CCR7, and have been implicated in directing peripheral lymphocyte homing. SLC but not MIP-3\u2424 can also signal through CXCR3 (53) , but this receptor is not expressed by peripheral B cells. SLC is made and displayed by high endothelial venule (HEV) cells (54, 55) , can trigger rapid shear-resistant integrin-dependent arrest of rolling lymphocytes (16, 56) , and has been implicated in the recognition and arrest of circulating lymphocytes on HEVs in PPs and LNs (55, 57) . SLC and MIP-3\u2424 are also expressed by stromal dendritic cells in T cell zones of all secondary lymphoid organs (54) . Although recent in situ studies show that B cells do not require SLC or MIP-3\u2424 signaling to arrest on HEVs in vivo (55) , the ability of all B cell subsets to respond to these chemokines may nevertheless permit or facilitate their entry into lymphoid organs from the blood, perhaps at the level of diapedesis as evidenced by the poor homing of CCR7 \u03ea\u0580\u03ea B cells into LNs and PPs compared with wild-type B cells (58) . Interestingly, SLC is also expressed by lymphatic endothelium and has been implicated in lymphatic entry of activated dendritic cells. It may play a similar role for lymphatic recruitment of activated or memory lymphocytes in extralymphoid tissues. Thus, the upregulation of MIP-3\u2424 and SLC responses in association with B cell export to the periphery may facilitate mature B cell migration and circulation through secondary lymphoid organs at multiple levels.", "cite_spans": [{"start": 317, "end": 321, "text": "(53)", "ref_id": "BIBREF52"}, {"start": 447, "end": 451, "text": "(54,", "ref_id": "BIBREF53"}, {"start": 452, "end": 455, "text": "55)", "ref_id": "BIBREF54"}, {"start": 541, "end": 545, "text": "(16,", "ref_id": "BIBREF15"}, {"start": 546, "end": 549, "text": "56)", "ref_id": "BIBREF55"}, {"start": 656, "end": 660, "text": "(55,", "ref_id": "BIBREF54"}, {"start": 661, "end": 664, "text": "57)", "ref_id": "BIBREF56"}, {"start": 777, "end": 781, "text": "(54)", "ref_id": "BIBREF53"}, {"start": 899, "end": 903, "text": "(55)", "ref_id": "BIBREF54"}, {"start": 1194, "end": 1198, "text": "(58)", "ref_id": "BIBREF57"}], "ref_spans": []}, {"section": "Discussion", "text": "Importantly, all mature peripheral B cell populations, including follicular and MZ B cells as well as GC and B1 B cells, respond equally well to SLC and MIP-3\u2424, as they do to SDF-1\u2423 and BCA-1. Therefore, although these chemokine responses may be critical to B cell trafficking in the periphery, they appear unlikely to be responsible for the specialized homing properties that target B cell subsets to distinct microenvironments.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "B cell responses to MIP-3\u2423 were unique, in that detectable chemotaxis to MIP-3\u2423 was limited to a subset of peripheral mature B cells. No migration to MIP-3\u2423 and no CCR6 expression were observed in any BM B cell population, including the most developed sIgM \u03e9 immature BM B cell. Recently emigrated Transition 1 splenic B cells also lacked CCR6 and did not respond to MIP-3\u2423, but Transition 2 B cells and splenic follicular \u2426 \u03e9 B cells are uniformly CCR6 \u03e9 and migrate consistently (albeit at lower efficiency than the other peripheral chemokines tested). Although only a subset of PP GC B cells display CCR6, GC B cells respond well to MIP-3\u2423, suggesting that the CCR6 \u03e9 GC B cells have an enhanced migratory response to this chemokine.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "Our finding of significant MIP-3\u2423 responses in these mature B cell population conflicts with the conclusions by Liao et al. (59) , who were unable to generate a calcium flux with MIP-3\u2423 in human B cells in spite of low level uniform expression of CCR6, as revealed by mAb staining. They proposed that B cells are unresponsive to MIP-3\u2423. However, our chemotaxis data and parallel studies with human lymphocytes (Campbell, J.J., unpublished data) clearly demonstrate that B cells migrate to MIP-3\u2423. Moreover, in recent studies, Tanaka et al. confirm our findings that PP B cells migrate to MIP-3\u2423 and report an efficiency of MIP-3\u2423-induced chemotaxis similar to that observed here (20) .", "cite_spans": [{"start": 124, "end": 128, "text": "(59)", "ref_id": "BIBREF58"}, {"start": 679, "end": 683, "text": "(20)", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "Discussion", "text": "MIP-3\u2423 is primarily expressed by epithelial cells, especially during inflammation or on epithelium associated with lymphoepithelial organs such as PPs. For example, in Northern blot analysis it is reportedly absent or only weakly expressed in resting spleen and LNs, but it is detectable in inflamed tonsils, intestine, and appendices (lymphoid tissues intimately associated with epithelial surfaces [20, [60] [61] [62] ). In situ hybridization studies reveal high level expression by antigen-recruiting epithelium in the lymphoepithelial tonsils and PPs (20, 61) . MIP-3\u2423 expression by such epithelium has been postulated to help recruit antigen-presenting dendritic cells, and it may also help define sites of B cell recruitment to epithelial-associated lymphoid organs, including PPs and also bronchus-associated lymphoid tissue. Such a concept might provide teleological explanation for the association of MIP-3\u2423 responses and CCR6 expression with follicle-homing B cell populations.", "cite_spans": [{"start": 400, "end": 404, "text": "[20,", "ref_id": "BIBREF19"}, {"start": 405, "end": 409, "text": "[60]", "ref_id": "BIBREF59"}, {"start": 410, "end": 414, "text": "[61]", "ref_id": "BIBREF60"}, {"start": 415, "end": 419, "text": "[62]", "ref_id": "BIBREF61"}, {"start": 555, "end": 559, "text": "(20,", "ref_id": "BIBREF19"}, {"start": 560, "end": 563, "text": "61)", "ref_id": "BIBREF60"}], "ref_spans": []}, {"section": "Discussion", "text": "There are only minor differences in the chemotactic responses between resting follicular mantle and antigen-reactive GC B cells to the chemokines studied here. This contrasts with the results of Bleul et al. (63) , who showed that human tonsillar GC (CD38 \u03e9 ) B cells were unable to respond to SDF-1\u2423 even though they express the SDF-1\u2423 receptor CXCR4. We have extended their studies and examined the chemokine responsiveness of human tonsil B cells to MIP-3\u2423, SLC, and BCA-1 in addition to SDF-1\u2423. In each case, human tonsil GC B cells failed to respond to any of the chemokines tested, whereas tonsillar non-GC CD38 \u03ea B cells responded robustly (Campbell, J.J., unpublished observation). This discrepancy in functional responses may be due to a species difference between mice and humans, or alternatively may reflect differences in GCs from different lymphoid organs. In this context, it is relevant that we observed consistent significant strain-dependent differences in the GC B cell responses to MIP-3\u2423, suggesting genetic variability in GC responses.", "cite_spans": [{"start": 208, "end": 212, "text": "(63)", "ref_id": "BIBREF62"}], "ref_spans": []}, {"section": "Discussion", "text": "Receptor expression alone has not proven an adequate parameter to predict a cell's chemotactic potential. Forster et al. reported that human tonsil GC CD38 \u03e9 B cells express CXCR5 on their surface (52) and Bleul et al. reported that human tonsil CD38 \u03e9 B cells express CXCR4 (63) even though these cells were unresponsive to the chemokines BCA-1 and SDF-1\u2423 (see above paragraph). We conclude that the functional measurement of chemotaxis is the only way to determine the chemotactic response profile for any given cell population. By assessing the correlation between function and surface expression of known receptors (as presented here for CCR6, CXCR3, and CXCR5), a secondary question can be investigated: Which receptors mediate the distinctive chemotactic fingerprints of cells? However, potential involvement of unidentified receptors (as yet) must always be kept in mind.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "Both B1 and B2 B cells from the mouse peritoneal cavity respond to SLC, SDF-1\u2423, and BCA-1 with equal efficiency (albeit not as well as splenic follicular B cells). However, unlike splenic B cells, there was no response of B1 B cells and very little response of B2 B cells to MIP-3\u2423 even though both cell types expressed CCR6. It was surprising that B1 B cells, which are not found in great quantities in secondary lymphoid organs, can nevertheless respond to the follicle-associated chemokine BCA-1 and the HEVassociated chemokine SLC. If B1 B cells do arise through a unique developmental program (9, 10) , that program still enables them to respond to all the same chemokines (except MIP-3\u2423) to which more conventional B cells respond. As it seems unlikely that these lymphoid organ chemokines play a role in recruiting cells into the peritoneal or other serosal cavities, they may function in allowing B1 B cells to migrate or circulate through lymphoid tissues themselves.", "cite_spans": [{"start": 598, "end": 601, "text": "(9,", "ref_id": "BIBREF8"}, {"start": 602, "end": 605, "text": "10)", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "Discussion", "text": "In conclusion, we have uncovered a dynamic regulation of the chemotactic responses of B cells as they progress through development (Fig. 9 ). Responses to secondary lymphoid chemokines increase progressively during B cell differentiation in the BM and are upregulated even further in cells that have progressed into fully mature recirculating peripheral B cells. The remarkable similarity in chemotactic responses to the peripheral chemokines by different mature peripheral B cell subsets (follicular, MZ, GC, and B1 B cells) was unexpected in light of their unique patterns of microenvironmental homing. The only exception was the response to MIP-3\u2423, which was mainly detected in follicleassociated \u2426 \u03e9 and GC B cells. We conclude that these chemokines and their receptors likely act in combination with other chemoattractants, signaling, and adhesion molecules to control the microenvironmental homing and the localization of distinct B cell subsets in the periphery. In contrast to the similar chemotactic fingerprints of microenvironmentally defined peripheral B cell populations, developing BM B cells display striking, stage-specific chemokine response profiles. The dramatic switches in chemokine responses in maturing B cells suggest that chemoattractant responsiveness may play an important role in B cell development.", "cite_spans": [], "ref_spans": [{"start": 131, "end": 138, "text": "(Fig. 9", "ref_id": "FIGREF11"}]}], "bib_entries": {"BIBREF0": {"title": "Self-tolerance checkpoints in B lymphocyte development", "authors": [{"first": "C", "middle": ["C"], "last": "Goodnow", "suffix": ""}, {"first": "J", "middle": ["G"], "last": "Cyster", "suffix": ""}, {"first": "S", "middle": ["B"], "last": "Hartley", "suffix": ""}, {"first": "S", "middle": ["E"], "last": "Bell", "suffix": ""}, {"first": "M", "middle": ["P"], "last": "Cooke", "suffix": ""}, {"first": "J", "middle": ["I"], "last": "Healy", "suffix": ""}, {"first": "S", "middle": [], "last": "Akkaraju", "suffix": ""}, {"first": "J", "middle": ["C"], "last": "Rathmell", "suffix": ""}, {"first": "S", "middle": ["L"], "last": "Pogue", "suffix": ""}, {"first": "K", "middle": ["P"], "last": "Shokat", "suffix": ""}], "year": 1995, "venue": "Adv. Immunol", "link": "28067747"}, "BIBREF1": {"title": "Tolerogenic or immunogenic activity of hapten-conjugated polysaccharides correlated with cellular localization", "authors": [{"first": "J", "middle": ["H"], "last": "Humphrey", "suffix": ""}], "year": 1981, "venue": "Eur. J. Immunol", "link": "39370851"}, "BIBREF2": {"title": "Differences in the recruitment of virgin B cells into antibody responses to thymus-dependent and thymus-independent type-2 antigens", "authors": [{"first": "P", "middle": ["J"], "last": "Lane", "suffix": ""}, {"first": "D", "middle": [], "last": "Gray", "suffix": ""}, {"first": "S", "middle": [], "last": "Oldfield", "suffix": ""}, {"first": "I", "middle": ["C"], "last": "Maclennan", "suffix": ""}], "year": 1986, "venue": "Eur. J. Immunol", "link": "38110405"}, "BIBREF3": {"title": "Marginal zone B cells exhibit unique activation, proliferative and immunoglobulin secretory responses", "authors": [{"first": "A", "middle": ["M"], "last": "Oliver", "suffix": ""}, {"first": "F", "middle": [], "last": "Martin", "suffix": ""}, {"first": "G", "middle": ["L"], "last": "Gartland", "suffix": ""}, {"first": "R", "middle": ["H"], "last": "Carter", "suffix": ""}, {"first": "J", "middle": ["F"], "last": "Kearney", "suffix": ""}], "year": 1997, "venue": "Eur. J. Immunol", "link": "7409203"}, "BIBREF4": {"title": "Memory B cells in T cell-dependent antibody responses colonize the splenic marginal zones", "authors": [{"first": "Y", "middle": ["J"], "last": "Liu", "suffix": ""}, {"first": "S", "middle": [], "last": "Oldfield", "suffix": ""}, {"first": "I", "middle": ["C"], "last": "Maclennan", "suffix": ""}], "year": 1988, "venue": "Eur. J. Immunol", "link": "46025312"}, "BIBREF5": {"title": "In vivo effects of LPS on B lymphocyte subpopulations. Migration of marginal zone-lymphocytes and IgD-blast formation in the mouse spleen", "authors": [{"first": "P", "middle": ["H"], "last": "Groeneveld", "suffix": ""}, {"first": "T", "middle": [], "last": "Erich", "suffix": ""}, {"first": "G", "middle": [], "last": "Kraal", "suffix": ""}], "year": 1985, "venue": "Immunobiology", "link": "24790221"}, "BIBREF6": {"title": "Life and death in germinal centers (redux). Immunity", "authors": [{"first": "G", "middle": [], "last": "Kelsoe", "suffix": ""}], "year": 1996, "venue": "", "link": null}, "BIBREF7": {"title": "The cellular origins of memory B cells", "authors": [{"first": "N", "middle": ["R"], "last": "Klinman", "suffix": ""}], "year": 1997, "venue": "Semin. Immunol", "link": "24569297"}, "BIBREF8": {"title": "B-cell development and differentiation", "authors": [{"first": "M", "middle": ["A"], "last": "Duchosal", "suffix": ""}], "year": 1997, "venue": "Semin. Hematol", "link": "10630779"}, "BIBREF9": {"title": "B cell development in mice", "authors": [{"first": "J", "middle": ["F"], "last": "Kearney", "suffix": ""}, {"first": "W", "middle": ["J"], "last": "Won", "suffix": ""}, {"first": "C", "middle": [], "last": "Benedict", "suffix": ""}, {"first": "C", "middle": [], "last": "Moratz", "suffix": ""}, {"first": "P", "middle": [], "last": "Zimmer", "suffix": ""}, {"first": "A", "middle": [], "last": "Oliver", "suffix": ""}, {"first": "F", "middle": [], "last": "Martin", "suffix": ""}, {"first": "F", "middle": [], "last": "Shu", "suffix": ""}], "year": 1997, "venue": "Int. Rev. Immunol", "link": "40764821"}, "BIBREF10": {"title": "Recent advances in chemokines and chemokine receptors", "authors": [{"first": "A", "middle": [], "last": "Zlotnik", "suffix": ""}, {"first": "J", "middle": [], "last": "Morales", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Hedrick", "suffix": ""}], "year": 1999, "venue": "Crit. Rev. Immunol", "link": "29173493"}, "BIBREF11": {"title": "Multistep navigation and the combinatorial control of leukocyte chemotaxis", "authors": [{"first": "E", "middle": ["F"], "last": "Foxman", "suffix": ""}, {"first": "J", "middle": ["J"], "last": "Campbell", "suffix": ""}, {"first": "E", "middle": ["C"], "last": "Butcher", "suffix": ""}], "year": 1997, "venue": "J. Cell Biol", "link": "12428898"}, "BIBREF12": {"title": "Isolation and characterization of Exodus-2, a novel C-C chemokine with a unique 37-amino acid carboxyl-terminal extension", "authors": [{"first": "R", "middle": [], "last": "Hromas", "suffix": ""}, {"first": "C", "middle": ["H"], "last": "Kim", "suffix": ""}, {"first": "M", "middle": [], "last": "Klemsz", "suffix": ""}, {"first": "M", "middle": [], "last": "Krathwohl", "suffix": ""}, {"first": "K", "middle": [], "last": "Fife", "suffix": ""}, {"first": "S", "middle": [], "last": "Cooper", "suffix": ""}, {"first": "C", "middle": [], "last": "Schnizlein-Bick", "suffix": ""}, {"first": "H", "middle": ["E"], "last": "Broxmeyer", "suffix": ""}], "year": 1997, "venue": "J. Immunol", "link": "33971251"}, "BIBREF13": {"title": "A B-cell-homing chemokine made in lymphoid follicles activates Burkitt's lymphoma receptor-1", "authors": [{"first": "M", "middle": ["D"], "last": "Gunn", "suffix": ""}, {"first": "V", "middle": ["N"], "last": "Ngo", "suffix": ""}, {"first": "K", "middle": ["M"], "last": "Ansel", "suffix": ""}, {"first": "E", "middle": ["H"], "last": "Ekland", "suffix": ""}, {"first": "J", "middle": ["G"], "last": "Cyster", "suffix": ""}, {"first": "L", "middle": ["T"], "last": "Williams", "suffix": ""}], "year": 1998, "venue": "Nature", "link": "4373691"}, "BIBREF14": {"title": "B cell-attracting chemokine 1, a human CXC chemokine expressed in lymphoid tissues, selectively attracts B lymphocytes via BLR1/CXCR5", "authors": [{"first": "D", "middle": ["F"], "last": "Legler", "suffix": ""}, {"first": "M", "middle": [], "last": "Loetscher", "suffix": ""}, {"first": "R", "middle": ["S"], "last": "Roos", "suffix": ""}, {"first": "I", "middle": [], "last": "Clark-Lewis", "suffix": ""}, {"first": "M", "middle": [], "last": "Baggiolini", "suffix": ""}, {"first": "B", "middle": [], "last": "Moser", "suffix": ""}], "year": 1998, "venue": "J. Exp. Med", "link": "11035175"}, "BIBREF15": {"title": "6-C-kine (SLC), a lymphocyte adhesion-triggering chemokine expressed by high endothelium, is an agonists for the MIP-3beta receptor CCR7", "authors": [{"first": "J", "middle": ["J"], "last": "Campbell", "suffix": ""}, {"first": "E", "middle": ["P"], "last": "Bowman", "suffix": ""}, {"first": "K", "middle": [], "last": "Murphy", "suffix": ""}, {"first": "K", "middle": ["R"], "last": "Youngman", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Siani", "suffix": ""}, {"first": "D", "middle": ["A"], "last": "Thompson", "suffix": ""}, {"first": "L", "middle": [], "last": "Wu", "suffix": ""}, {"first": "A", "middle": [], "last": "Zlotnik", "suffix": ""}, {"first": "E", "middle": ["C"], "last": "Butcher", "suffix": ""}], "year": 1998, "venue": "J. Cell Biol", "link": null}, "BIBREF16": {"title": "Epstein-Barr virus-induced molecule 1 ligand chemokine is expressed by dendritic cells in lymphoid tissues and strongly attracts naive T cells and activated B cells", "authors": [{"first": "V", "middle": ["N"], "last": "Ngo", "suffix": ""}, {"first": "H", "middle": ["L"], "last": "Tang", "suffix": ""}, {"first": "J", "middle": ["G"], "last": "Cyster", "suffix": ""}], "year": 1998, "venue": "J. Exp. Med", "link": null}, "BIBREF17": {"title": "CK beta-11/macrophage inflammatory protein-3 beta/EBI1-ligand chemokine is an efficacious chemoattractant for T and B cells", "authors": [{"first": "C", "middle": ["H"], "last": "Kim", "suffix": ""}, {"first": "L", "middle": ["M"], "last": "Pelus", "suffix": ""}, {"first": "J", "middle": ["R"], "last": "White", "suffix": ""}, {"first": "E", "middle": [], "last": "Applebaum", "suffix": ""}, {"first": "K", "middle": [], "last": "Johanson", "suffix": ""}, {"first": "H", "middle": ["E"], "last": "Broxmeyer", "suffix": ""}], "year": 1998, "venue": "J. Immunol", "link": "42095864"}, "BIBREF18": {"title": "A lymphocyte-specific CC chemokine, secondary lymphoid tissue chemokine (SLC), is a highly efficient chemoattractant for B cells and activated T cells", "authors": [{"first": "M", "middle": [], "last": "Nagira", "suffix": ""}, {"first": "T", "middle": [], "last": "Imai", "suffix": ""}, {"first": "R", "middle": [], "last": "Yoshida", "suffix": ""}, {"first": "S", "middle": [], "last": "Takagi", "suffix": ""}, {"first": "M", "middle": [], "last": "Iwasaki", "suffix": ""}, {"first": "M", "middle": [], "last": "Baba", "suffix": ""}, {"first": "Y", "middle": [], "last": "Tabira", "suffix": ""}, {"first": "J", "middle": [], "last": "Akagi", "suffix": ""}, {"first": "H", "middle": [], "last": "Nomiyama", "suffix": ""}, {"first": "O", "middle": [], "last": "Yoshie", "suffix": ""}], "year": 1998, "venue": "Eur. J. Immunol", "link": "21657498"}, "BIBREF19": {"title": "Selective expression of liver and activation-regulated chemokine (LARC) in intestinal epithelium in mice and humans", "authors": [{"first": "Y", "middle": [], "last": "Tanaka", "suffix": ""}, {"first": "T", "middle": [], "last": "Imai", "suffix": ""}, {"first": "M", "middle": [], "last": "Baba", "suffix": ""}, {"first": "I", "middle": [], "last": "Ishikawa", "suffix": ""}, {"first": "M", "middle": [], "last": "Uehira", "suffix": ""}, {"first": "H", "middle": [], "last": "Nomiyama", "suffix": ""}, {"first": "O", "middle": [], "last": "Yoshie", "suffix": ""}], "year": 1999, "venue": "Eur. J. Immunol", "link": "13797528"}, "BIBREF20": {"title": "Biology of chemokine and classical chemoattractant receptors: differential requirements for adhesion-triggering versus chemotactic responses in lymphoid cells", "authors": [{"first": "J", "middle": ["J"], "last": "Campbell", "suffix": ""}, {"first": "S", "middle": [], "last": "Qin", "suffix": ""}, {"first": "K", "middle": ["B"], "last": "Bacon", "suffix": ""}, {"first": "C", "middle": ["R"], "last": "Mackay", "suffix": ""}, {"first": "E", "middle": ["C"], "last": "Butcher", "suffix": ""}], "year": 1996, "venue": "J. Cell Biol", "link": "2962436"}, "BIBREF21": {"title": "Chemokines and B-cell homing to follicles", "authors": [{"first": "J", "middle": [], "last": "Cyster", "suffix": ""}, {"first": "V", "middle": ["N"], "last": "Ngo", "suffix": ""}, {"first": "E", "middle": ["H"], "last": "Ekland", "suffix": ""}, {"first": "M", "middle": ["D"], "last": "Gunn", "suffix": ""}, {"first": "J", "middle": ["D"], "last": "Sedgwick", "suffix": ""}, {"first": "K", "middle": ["M"], "last": "", "suffix": ""}], "year": 1999, "venue": "Curr. Top. Microbiol. Immunol", "link": "34620845"}, "BIBREF22": {"title": "Rennick. 1996. flk2/flt3 ligand is a potent cofactor for the growth of primitive B cell progenitors", "authors": [{"first": "B", "middle": ["E"], "last": "Hunte", "suffix": ""}, {"first": "S", "middle": [], "last": "Hudak", "suffix": ""}, {"first": "D", "middle": [], "last": "Campbell", "suffix": ""}, {"first": "Y", "middle": [], "last": "Xu", "suffix": ""}, {"first": "D", "middle": [], "last": "", "suffix": ""}], "year": "", "venue": "J. Immunol", "link": null}, "BIBREF23": {"title": "Combined signaling through interleukin-7 receptors and flt3 but not c-kit potently and selectively promotes B-cell commitment and differentiation from uncommitted murine bone marrow progenitor cells", "authors": [{"first": "O", "middle": ["P"], "last": "Veiby", "suffix": ""}, {"first": "S", "middle": ["D"], "last": "Lyman", "suffix": ""}, {"first": "S", "middle": ["E"], "last": "Jacobsen", "suffix": ""}], "year": 1996, "venue": "Blood", "link": "10222758"}, "BIBREF24": {"title": "Resolution and characterization of pro-B and pre-pro-B cell stages in normal mouse bone marrow", "authors": [{"first": "R", "middle": ["R"], "last": "Hardy", "suffix": ""}, {"first": "C", "middle": ["E"], "last": "Carmack", "suffix": ""}, {"first": "S", "middle": ["A"], "last": "Shinton", "suffix": ""}, {"first": "J", "middle": ["D"], "last": "Kemp", "suffix": ""}, {"first": "K", "middle": [], "last": "Hayakawa", "suffix": ""}], "year": 1991, "venue": "J. Exp. Med", "link": "7064726"}, "BIBREF25": {"title": "Identification of the earliest B lineage stage in mouse Chemokine Responses during B Cell Development bone marrow", "authors": [{"first": "Y", "middle": ["S"], "last": "Li", "suffix": ""}, {"first": "R", "middle": [], "last": "Wasserman", "suffix": ""}, {"first": "K", "middle": [], "last": "Hayakawa", "suffix": ""}, {"first": "R", "middle": ["R"], "last": "Hardy", "suffix": ""}], "year": 1996, "venue": "Immunity", "link": null}, "BIBREF26": {"title": "A putative chemokine receptor, BLR1, directs B cell migration to defined lymphoid organs and specific anatomic compartments of the spleen", "authors": [{"first": "R", "middle": [], "last": "Forster", "suffix": ""}, {"first": "A", "middle": ["E"], "last": "Mattis", "suffix": ""}, {"first": "E", "middle": [], "last": "Kremmer", "suffix": ""}, {"first": "E", "middle": [], "last": "Wolf", "suffix": ""}, {"first": "G", "middle": [], "last": "Brem", "suffix": ""}, {"first": "M", "middle": [], "last": "Lipp", "suffix": ""}], "year": 1996, "venue": "Cell", "link": "17558174"}, "BIBREF27": {"title": "Regulation of expression of chemokine receptor BLR1/CXCR5 during B cell maturation", "authors": [{"first": "V", "middle": [], "last": "Pevzner", "suffix": ""}, {"first": "R", "middle": [], "last": "Wolf", "suffix": ""}, {"first": "R", "middle": [], "last": "Burgstahler", "suffix": ""}, {"first": "M", "middle": [], "last": "Forster", "suffix": ""}, {"first": "", "middle": [], "last": "Lipp", "suffix": ""}], "year": 1999, "venue": "Curr. Top. Microbiol. Immunol", "link": "20873046"}, "BIBREF28": {"title": "Peripheral B cell maturation. I. Immature peripheral B cells in adults are heat-stable antigen hi and exhibit unique signaling characteristics", "authors": [{"first": "D", "middle": ["M"], "last": "Allman", "suffix": ""}, {"first": "S", "middle": ["E"], "last": "Ferguson", "suffix": ""}, {"first": "M", "middle": ["P"], "last": "Cancro", "suffix": ""}], "year": 1992, "venue": "J. Immunol", "link": "38398038"}, "BIBREF29": {"title": "B cell development in the spleen takes place in discrete steps and is determined by the quality of B cell receptor-derived signals", "authors": [{"first": "F", "middle": [], "last": "Loder", "suffix": ""}, {"first": "B", "middle": [], "last": "Mutschler", "suffix": ""}, {"first": "R", "middle": ["J"], "last": "Ray", "suffix": ""}, {"first": "C", "middle": ["J"], "last": "Paige", "suffix": ""}, {"first": "P", "middle": [], "last": "Sideras", "suffix": ""}, {"first": "R", "middle": [], "last": "Torres", "suffix": ""}, {"first": "M", "middle": ["C"], "last": "Lamers", "suffix": ""}, {"first": "R", "middle": [], "last": "Carsetti", "suffix": ""}], "year": 1999, "venue": "J. Exp. Med", "link": "18363942"}, "BIBREF30": {"title": "The rat B cell system: the anatomical localization of flow cytometry-defined B cell subpopulations", "authors": [{"first": "F", "middle": ["G"], "last": "Kroese", "suffix": ""}, {"first": "E", "middle": ["C"], "last": "Butcher", "suffix": ""}, {"first": "P", "middle": ["A"], "last": "Lalor", "suffix": ""}, {"first": "A", "middle": ["M"], "last": "Stall", "suffix": ""}, {"first": "L", "middle": ["A"], "last": "Herzenberg", "suffix": ""}], "year": 1990, "venue": "Eur. J. Immunol", "link": "32741883"}, "BIBREF31": {"title": "Peanut lectin binding properties of germinal centres of mouse lymphoid tissue", "authors": [{"first": "M", "middle": ["L"], "last": "Rose", "suffix": ""}, {"first": "M", "middle": ["S"], "last": "Birbeck", "suffix": ""}, {"first": "V", "middle": ["J"], "last": "Wallis", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Forrester", "suffix": ""}, {"first": "A", "middle": ["J"], "last": "Davies", "suffix": ""}], "year": 1980, "venue": "Nature", "link": null}, "BIBREF32": {"title": "Surface phenotype of Peyer's patch germinal center cells: implications for the role of germinal centers in B cell differentiation", "authors": [{"first": "E", "middle": ["C"], "last": "Butcher", "suffix": ""}, {"first": "R", "middle": ["V"], "last": "Rouse", "suffix": ""}, {"first": "R", "middle": ["L"], "last": "Coffman", "suffix": ""}, {"first": "C", "middle": ["N"], "last": "Nottenburg", "suffix": ""}, {"first": "R", "middle": ["R"], "last": "Hardy", "suffix": ""}, {"first": "I", "middle": ["L"], "last": "Weissman", "suffix": ""}], "year": 1982, "venue": "J. Immunol", "link": "28928681"}, "BIBREF33": {"title": "Germinal centre B cells: antigen specificity and changes in heavy chain class expression", "authors": [{"first": "G", "middle": [], "last": "Kraal", "suffix": ""}, {"first": "I", "middle": ["L"], "last": "Weissman", "suffix": ""}, {"first": "E", "middle": ["C"], "last": "Butcher", "suffix": ""}], "year": 1982, "venue": "Nature", "link": "34311271"}, "BIBREF34": {"title": "Herzenberg. 1982. B-cell subpopulations identified by two-colour fluorescence analysis", "authors": [{"first": "R", "middle": ["R"], "last": "Hardy", "suffix": ""}, {"first": "K", "middle": [], "last": "Hayakawa", "suffix": ""}, {"first": "J", "middle": [], "last": "Haaijman", "suffix": ""}, {"first": "L", "middle": ["A"], "last": "", "suffix": ""}], "year": "", "venue": "Nature", "link": null}, "BIBREF35": {"title": "Lymphocyte homing and homeostasis", "authors": [{"first": "E", "middle": ["C"], "last": "Butcher", "suffix": ""}, {"first": "L", "middle": ["J"], "last": "Picker", "suffix": ""}], "year": 1996, "venue": "Science", "link": "6956957"}, "BIBREF36": {"title": "A developmental switch in lymphocyte homing receptor and endothelial vascular addressin expression regulates lymphocyte homing and permits CD4\u03e9 CD3\u03ea cells to colonize lymph nodes", "authors": [{"first": "R", "middle": ["E"], "last": "Mebius", "suffix": ""}, {"first": "P", "middle": ["R"], "last": "Streeter", "suffix": ""}, {"first": "S", "middle": [], "last": "Michie", "suffix": ""}, {"first": "E", "middle": ["C"], "last": "Butcher", "suffix": ""}, {"first": "I", "middle": ["L"], "last": "Weissman", "suffix": ""}], "year": 1996, "venue": "Proc. Natl. Acad. Sci. USA", "link": "21299391"}, "BIBREF37": {"title": "Developmental switches in the immune system", "authors": [{"first": "I", "middle": ["L"], "last": "Weissman", "suffix": ""}], "year": 1994, "venue": "Cell", "link": "44315239"}, "BIBREF38": {"title": "Lymphocyte trafficking and regional immunity", "authors": [{"first": "E", "middle": ["C"], "last": "Butcher", "suffix": ""}, {"first": "M", "middle": [], "last": "Williams", "suffix": ""}, {"first": "K", "middle": [], "last": "Youngman", "suffix": ""}, {"first": "L", "middle": [], "last": "Rott", "suffix": ""}, {"first": "M", "middle": [], "last": "Briskin", "suffix": ""}], "year": 1999, "venue": "Adv. Immunol", "link": "26814300"}, "BIBREF39": {"title": "Commitment to the B lymphoid lineage occurs before DH-JH recombination", "authors": [{"first": "D", "middle": [], "last": "Allman", "suffix": ""}, {"first": "J", "middle": [], "last": "Li", "suffix": ""}, {"first": "R", "middle": ["R"], "last": "Hardy", "suffix": ""}], "year": 1999, "venue": "J. Exp. Med", "link": "16690347"}, "BIBREF40": {"title": "Bipotential precursors of B cells and macrophages in murine fetal liver", "authors": [{"first": "A", "middle": [], "last": "Cumano", "suffix": ""}, {"first": "C", "middle": ["J"], "last": "Paige", "suffix": ""}, {"first": "N", "middle": ["N"], "last": "Iscove", "suffix": ""}, {"first": "G", "middle": [], "last": "Brady", "suffix": ""}], "year": 1992, "venue": "Nature", "link": null}, "BIBREF41": {"title": "The chemokine receptor CXCR3 is expressed on malignant B cells and mediates chemotaxis", "authors": [{"first": "L", "middle": [], "last": "Trentin", "suffix": ""}, {"first": "C", "middle": [], "last": "Agostini", "suffix": ""}, {"first": "M", "middle": [], "last": "Facco", "suffix": ""}, {"first": "F", "middle": [], "last": "Piazza", "suffix": ""}, {"first": "A", "middle": [], "last": "Perin", "suffix": ""}, {"first": "M", "middle": [], "last": "Siviero", "suffix": ""}, {"first": "C", "middle": [], "last": "Gurrieri", "suffix": ""}, {"first": "S", "middle": [], "last": "Galvan", "suffix": ""}, {"first": "F", "middle": [], "last": "Adami", "suffix": ""}, {"first": "R", "middle": [], "last": "Zambello", "suffix": ""}, {"first": "G", "middle": [], "last": "Semenzato", "suffix": ""}], "year": 1999, "venue": "J. Clin. Invest", "link": "1257903"}, "BIBREF42": {"title": "A subpopulation of B220 \u03e9 cells in murine bone marrow does not express CD19 and contains natural killer cell progenitors", "authors": [{"first": "A", "middle": [], "last": "Rolink", "suffix": ""}, {"first": "E", "middle": [], "last": "Boekel", "suffix": ""}, {"first": "F", "middle": [], "last": "Melchers", "suffix": ""}, {"first": "D", "middle": ["T"], "last": "Fearon", "suffix": ""}, {"first": "I", "middle": [], "last": "Krop", "suffix": ""}, {"first": "J", "middle": [], "last": "Andersson", "suffix": ""}], "year": 1996, "venue": "J. Exp. Med", "link": null}, "BIBREF43": {"title": "A novel chemokine, macrophage inflammatory protein-related protein-2, inhibits colony formation of bone marrow myeloid progenitors", "authors": [{"first": "B", "middle": ["S"], "last": "Youn", "suffix": ""}, {"first": "I", "middle": ["K"], "last": "Jang", "suffix": ""}, {"first": "H", "middle": ["E"], "last": "Broxmeyer", "suffix": ""}, {"first": "S", "middle": [], "last": "Cooper", "suffix": ""}, {"first": "N", "middle": ["A"], "last": "Jenkins", "suffix": ""}, {"first": "D", "middle": ["J"], "last": "Gilbert", "suffix": ""}, {"first": "N", "middle": ["G"], "last": "Copeland", "suffix": ""}, {"first": "T", "middle": ["A"], "last": "Elick", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Fraser", "suffix": ""}, {"first": "Jr", "middle": [], "last": "", "suffix": ""}, {"first": "B", "middle": ["S"], "last": "Kwon", "suffix": ""}], "year": 1995, "venue": "J. Immunol", "link": "45372325"}, "BIBREF44": {"title": "Involvement of interleukin (IL)-8 receptor in negative regulation of myeloid progenitor cells in vivo: evidence from mice lacking the murine IL-8 receptor homologue", "authors": [{"first": "H", "middle": ["E"], "last": "Broxmeyer", "suffix": ""}, {"first": "S", "middle": [], "last": "Cooper", "suffix": ""}, {"first": "G", "middle": [], "last": "Cacalano", "suffix": ""}, {"first": "N", "middle": ["L"], "last": "Hague", "suffix": ""}, {"first": "E", "middle": [], "last": "Bailish", "suffix": ""}, {"first": "M", "middle": ["W"], "last": "Moore", "suffix": ""}], "year": 1996, "venue": "J. Exp. Med", "link": "7590942"}, "BIBREF45": {"title": "Molecular and functional characterization of two novel human C-C chemokines as inhibitors of two distinct classes of myeloid progenitors", "authors": [{"first": "V", "middle": ["P"], "last": "Patel", "suffix": ""}, {"first": "B", "middle": ["L"], "last": "Kreider", "suffix": ""}, {"first": "Y", "middle": [], "last": "Li", "suffix": ""}, {"first": "H", "middle": [], "last": "Li", "suffix": ""}, {"first": "K", "middle": [], "last": "Leung", "suffix": ""}, {"first": "T", "middle": [], "last": "Salcedo", "suffix": ""}, {"first": "B", "middle": [], "last": "Nardelli", "suffix": ""}, {"first": "V", "middle": [], "last": "Pippalla", "suffix": ""}, {"first": "S", "middle": [], "last": "Gentz", "suffix": ""}, {"first": "R", "middle": [], "last": "Thotakura", "suffix": ""}], "year": 1997, "venue": "J. Exp. Med", "link": "12958452"}, "BIBREF46": {"title": "Characterization of CKbeta8 and CKbeta8-1: two alternatively spliced forms of human beta-chemokine, chemoattractants for neutrophils, monocytes, and lymphocytes, and potent agonists at CC chemokine receptor 1", "authors": [{"first": "B", "middle": ["S"], "last": "Youn", "suffix": ""}, {"first": "S", "middle": ["M"], "last": "Zhang", "suffix": ""}, {"first": "H", "middle": ["E"], "last": "Broxmeyer", "suffix": ""}, {"first": "S", "middle": [], "last": "Cooper", "suffix": ""}, {"first": "K", "middle": [], "last": "Antol", "suffix": ""}, {"first": "M", "middle": [], "last": "Fraser", "suffix": ""}, {"first": "Jr", "middle": [], "last": "", "suffix": ""}, {"first": "B", "middle": ["S"], "last": "Kwon", "suffix": ""}], "year": 1998, "venue": "Blood", "link": "22064905"}, "BIBREF47": {"title": "Eotaxin modulates myelopoiesis and mast cell development from embryonic hematopoietic progenitors", "authors": [{"first": "E", "middle": ["J"], "last": "Quackenbush", "suffix": ""}, {"first": "B", "middle": ["K"], "last": "Wershil", "suffix": ""}, {"first": "V", "middle": [], "last": "Aguirre", "suffix": ""}, {"first": "J", "middle": ["C"], "last": "Gutierrez-Ramos", "suffix": ""}], "year": 1998, "venue": "Blood", "link": "12341024"}, "BIBREF48": {"title": "CCR7 ligands, SLC/ 6Ckine/Exodus2/TCA4 and CKbeta-11/MIP-3beta/ELC, are chemoattractants for CD56 \u03e9 CD16 \u03ea NK cells and late stage lymphoid progenitors", "authors": [{"first": "C", "middle": ["H"], "last": "Kim", "suffix": ""}, {"first": "L", "middle": ["M"], "last": "Pelus", "suffix": ""}, {"first": "E", "middle": [], "last": "Appelbaum", "suffix": ""}, {"first": "K", "middle": [], "last": "Johanson", "suffix": ""}, {"first": "N", "middle": [], "last": "Anzai", "suffix": ""}, {"first": "H", "middle": ["E"], "last": "Broxmeyer", "suffix": ""}], "year": 1999, "venue": "Cell. Immunol", "link": "11965691"}, "BIBREF49": {"title": "The chemokine SDF-1, stromal cell-derived factor 1, attracts early stage B cell precursors via the chemokine receptor CXCR4", "authors": [{"first": "M", "middle": [], "last": "D&apos;apuzzo", "suffix": ""}, {"first": "A", "middle": [], "last": "Rolink", "suffix": ""}, {"first": "M", "middle": [], "last": "Loetscher", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Hoxie", "suffix": ""}, {"first": "I", "middle": [], "last": "Clark-Lewis", "suffix": ""}, {"first": "F", "middle": [], "last": "Melchers", "suffix": ""}, {"first": "M", "middle": [], "last": "Baggiolini", "suffix": ""}, {"first": "B", "middle": [], "last": "Moser", "suffix": ""}], "year": 1997, "venue": "Eur. J. Immunol", "link": "6019500"}, "BIBREF50": {"title": "The chemokine receptor CXCR4 is required for the retention of B lineage and granulocytic precursors within the bone marrow microenvironment", "authors": [{"first": "Q", "middle": [], "last": "Ma", "suffix": ""}, {"first": "D", "middle": [], "last": "Jones", "suffix": ""}, {"first": "T", "middle": ["A"], "last": "Springer", "suffix": ""}], "year": 1999, "venue": "Immunity", "link": "22745293"}, "BIBREF51": {"title": "Expression of the G-protein-coupled receptor BLR1 defines mature, recirculating B cells and a subset of T-helper memory cells", "authors": [{"first": "R", "middle": [], "last": "Forster", "suffix": ""}, {"first": "T", "middle": [], "last": "Emrich", "suffix": ""}, {"first": "E", "middle": [], "last": "Kremmer", "suffix": ""}, {"first": "M", "middle": [], "last": "Lipp", "suffix": ""}], "year": 1994, "venue": "Blood", "link": "30837383"}, "BIBREF52": {"title": "The CC chemokine 6Ckine binds the CXC chemokine receptor CXCR3", "authors": [{"first": "H", "middle": [], "last": "Soto", "suffix": ""}, {"first": "W", "middle": [], "last": "Wang", "suffix": ""}, {"first": "R", "middle": ["M"], "last": "Strieter", "suffix": ""}, {"first": "N", "middle": ["G"], "last": "Copeland", "suffix": ""}, {"first": "D", "middle": ["J"], "last": "Gilbert", "suffix": ""}, {"first": "N", "middle": ["A"], "last": "Jenkins", "suffix": ""}, {"first": "J", "middle": [], "last": "Hedrick", "suffix": ""}, {"first": "A", "middle": [], "last": "Zlotnik", "suffix": ""}], "year": 1998, "venue": "Proc. Natl. Acad. Sci. USA", "link": "38310026"}, "BIBREF53": {"title": "A chemokine expressed in lymphoid high endothelial venules promotes the adhesion and chemotaxis of naive T lymphocytes", "authors": [{"first": "M", "middle": ["D"], "last": "Gunn", "suffix": ""}, {"first": "K", "middle": [], "last": "Tangemann", "suffix": ""}, {"first": "C", "middle": [], "last": "Tam", "suffix": ""}, {"first": "J", "middle": ["G"], "last": "Cyster", "suffix": ""}, {"first": "S", "middle": ["D"], "last": "Rosen", "suffix": ""}, {"first": "L", "middle": ["T"], "last": "Williams", "suffix": ""}], "year": 1998, "venue": "Proc. Natl. Acad. Sci. USA", "link": "19943728"}, "BIBREF54": {"title": "The role of chemokines in the microenvironmental control of T versus B cell arrest in Peyer's patch high endothelial venules", "authors": [{"first": "R", "middle": ["A"], "last": "Warnock", "suffix": ""}, {"first": "J", "middle": ["J"], "last": "Campbell", "suffix": ""}, {"first": "M", "middle": ["E"], "last": "Dorf", "suffix": ""}, {"first": "L", "middle": ["M"], "last": "Mcevoy", "suffix": ""}, {"first": "E", "middle": ["C"], "last": "Butcher", "suffix": ""}], "year": 2000, "venue": "J. Exp. Med", "link": "6968772"}, "BIBREF55": {"title": "Secondary lymphoid-tissue chemokine (SLC) stimulates integrin alpha 4 beta 7-mediated adhesion of lymphocytes to mucosal addressin cell adhesion molecule-1 (MAd-CAM-1) under flow", "authors": [{"first": "R", "middle": ["K"], "last": "Pachynski", "suffix": ""}, {"first": "S", "middle": ["W"], "last": "Wu", "suffix": ""}, {"first": "M", "middle": ["D"], "last": "Gunn", "suffix": ""}, {"first": "D", "middle": ["J"], "last": "Erle", "suffix": ""}], "year": 1998, "venue": "J. Immunol", "link": "36537253"}, "BIBREF56": {"title": "The CC chemokine thymus-derived chemotactic agent 4 (TCA-4, secondary lymphoid tissue chemokine, 6Ckine, exodus-2) triggers lymphocyte function-associated antigen 1-mediated arrest of rolling T lymphocytes in peripheral lymph node high endothelial venules", "authors": [{"first": "J", "middle": ["V"], "last": "Stein", "suffix": ""}, {"first": "A", "middle": [], "last": "Rot", "suffix": ""}, {"first": "Y", "middle": [], "last": "Luo", "suffix": ""}, {"first": "M", "middle": [], "last": "Narasimhaswamy", "suffix": ""}, {"first": "H", "middle": [], "last": "Nakano", "suffix": ""}, {"first": "M", "middle": ["D"], "last": "Gunn", "suffix": ""}, {"first": "A", "middle": [], "last": "Matsuzawa", "suffix": ""}, {"first": "E", "middle": ["J"], "last": "Quackenbush", "suffix": ""}, {"first": "M", "middle": ["E"], "last": "Dorf", "suffix": ""}, {"first": "U", "middle": ["H"], "last": "Von Andrian", "suffix": ""}], "year": 2000, "venue": "J. Exp. Med", "link": "555411"}, "BIBREF57": {"title": "CCR7 coordinates the primary immune response by establishing functional microenvironments in secondary lymphoid organs", "authors": [{"first": "R", "middle": [], "last": "Forster", "suffix": ""}, {"first": "A", "middle": [], "last": "Schubel", "suffix": ""}, {"first": "D", "middle": [], "last": "Breitfeld", "suffix": ""}, {"first": "E", "middle": [], "last": "Kremmer", "suffix": ""}, {"first": "I", "middle": [], "last": "Renner-Muller", "suffix": ""}, {"first": "E", "middle": [], "last": "Wolf", "suffix": ""}, {"first": "M", "middle": [], "last": "Lipp", "suffix": ""}], "year": 1999, "venue": "Cell", "link": "9857352"}, "BIBREF58": {"title": "CC-chemokine receptor 6 is expressed on diverse memory subsets of T cells and determines responsiveness to macrophage inflammatory protein 3 alpha", "authors": [{"first": "F", "middle": [], "last": "Liao", "suffix": ""}, {"first": "R", "middle": ["L"], "last": "Rabin", "suffix": ""}, {"first": "C", "middle": ["S"], "last": "Smith", "suffix": ""}, {"first": "G", "middle": [], "last": "Sharma", "suffix": ""}, {"first": "T", "middle": ["B"], "last": "Nutman", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Farber", "suffix": ""}], "year": 1999, "venue": "J. Immunol", "link": "8951449"}, "BIBREF59": {"title": "Identification through bioinformatics of two new macrophage proinflammatory human chemokines: MIP-3alpha and MIP-3beta", "authors": [{"first": "D", "middle": ["L"], "last": "Rossi", "suffix": ""}, {"first": "A", "middle": ["P"], "last": "Vicari", "suffix": ""}, {"first": "K", "middle": [], "last": "Franz-Bacon", "suffix": ""}, {"first": "T", "middle": ["K"], "last": "Mcclanahan", "suffix": ""}, {"first": "A", "middle": [], "last": "Zlotnik", "suffix": ""}], "year": 1997, "venue": "J. Immunol", "link": "39291729"}, "BIBREF60": {"title": "Selective recruitment of immature and mature dendritic cells by distinct chemokines expressed in different anatomic sites", "authors": [{"first": "M", "middle": ["C"], "last": "Dieu", "suffix": ""}, {"first": "B", "middle": [], "last": "Vanbervliet", "suffix": ""}, {"first": "A", "middle": [], "last": "Vicari", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Bridon", "suffix": ""}, {"first": "E", "middle": [], "last": "Oldham", "suffix": ""}, {"first": "S", "middle": [], "last": "Ait-Yahia", "suffix": ""}, {"first": "F", "middle": [], "last": "Briere", "suffix": ""}, {"first": "A", "middle": [], "last": "Zlotnik", "suffix": ""}, {"first": "S", "middle": [], "last": "Lebecque", "suffix": ""}, {"first": "C", "middle": [], "last": "Caux", "suffix": ""}], "year": 1998, "venue": "J. Exp. Med", "link": "237987"}, "BIBREF61": {"title": "Molecular cloning, functional characterization and mRNA expression analysis of the murine chemokine receptor CCR6 and its specific ligand MIP-3alpha", "authors": [{"first": "R", "middle": [], "last": "Varona", "suffix": ""}, {"first": "A", "middle": [], "last": "Zaballos", "suffix": ""}, {"first": "J", "middle": [], "last": "Gutierrez", "suffix": ""}, {"first": "P", "middle": [], "last": "Martin", "suffix": ""}, {"first": "F", "middle": [], "last": "Roncal", "suffix": ""}, {"first": "J", "middle": ["P"], "last": "Albar", "suffix": ""}, {"first": "C", "middle": [], "last": "Ardavin", "suffix": ""}, {"first": "G", "middle": [], "last": "Marquez", "suffix": ""}], "year": 1998, "venue": "FEBS Lett", "link": "38714241"}, "BIBREF62": {"title": "B lymphocyte chemotaxis regulated in association with microanatomic localization, differentiation state, and B cell receptor engagement", "authors": [{"first": "C", "middle": ["C"], "last": "Bleul", "suffix": ""}, {"first": "J", "middle": ["L"], "last": "Schultze", "suffix": ""}, {"first": "T", "middle": ["A"], "last": "Springer", "suffix": ""}], "year": 1998, "venue": "J. Exp. Med", "link": "17102936"}, "BIBREF63": {"title": "Cutting edge: species specificity of the CC chemokine 6Ckine signaling through the CXC chemokine receptor CXCR3: human 6Ckine is not a ligand for the human or mouse CXCR3 receptors", "authors": [{"first": "C", "middle": ["H"], "last": "Jenh", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Cox", "suffix": ""}, {"first": "H", "middle": [], "last": "Kaminski", "suffix": ""}, {"first": "M", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "H", "middle": [], "last": "Byrnes", "suffix": ""}, {"first": "J", "middle": [], "last": "Fine", "suffix": ""}, {"first": "D", "middle": [], "last": "Lundell", "suffix": ""}, {"first": "C", "middle": ["C"], "last": "Chou", "suffix": ""}, {"first": "S", "middle": ["K"], "last": "Narula", "suffix": ""}, {"first": "P", "middle": ["J"], "last": "Zavodny", "suffix": ""}], "year": 1999, "venue": "J. Immunol", "link": "23946439"}}, "ref_entries": {"FIGREF0": {"text": "Figure 1. The chemotactic fingerprint of B cells undergoes a dramatic shift during development in the BM. (A) List of antigenically defined stages in B cell development, according to Hardy et al. and Li et al. (references 25, 26). (B) AA4.1 \u03e9 NK1.1 \u03ea Fraction A cells respond to RANTES, JE, MIG, and TECK. Unfractioned BM cells were prepared and added to inserts that were placed in wells containing the following chemokines: 100 nM RANTES, 1 nM JE, 100 nM MIG, or 300 nM TECK. Responding cells were harvested and stained with either B220-APC, unlabeled AA4.1/mouse anti-rat IgG-biotin/SAv-PerCP, HSA-PE, and NK1.1-FITC or AA4.1-APC, HSA-biotin/SAv-PerCP, B220-PE, NK1.1-FITC to identify the AA4.1 \u03e9 NK1.1 \u03ea Fraction A population or with combinations of B220-APC, IgM b -PE, HSA-PE, and CD43-FITC to identify the later stages during B cell development. The data are the mean \u03ee SEM from two to eight experiments. (C) Responses to peripheral lymphoid chemokines appear late during BM B cell development. Same procedure as above except the following chemokines were used: 100 nM MIP-3\u2423, 100 nM SLC, 100 nM MIP-3\u2424, 50 nM SDF-1\u2423, and 500 nM BCA-1. The data are the mean \u03ee SEM from 3-15 experiments. All symbols have error bars even though in some instances (i.e., Basal migration and pro-B/BCA-1 migration) the error bars are smaller than the symbol.", "type": "figure"}, "FIGREF1": {"text": "Fig. 1 C demonstrates that Fraction A1/A2 cells responded rela- tively poorly to SLC and MIP-3\u2424, chemokines implicated in lymphocyte homing into peripheral lymphoid organs. However, the responses increased dramatically in the fur- ther differentiated BM B cell populations and in peripheral \u2426 \u03e9 follicular B cells. Similar responses of pre-B and im- mature B cells to MIP-3\u2424 have been reported by Ngo et al. (17).", "type": "figure"}, "FIGREF2": {"text": "Figure 2. Early B cells respond to TECK. Unfractioned BM cells were prepared and added to inserts that were placed in wells containing the following chemokines: 100 nM RANTES, 1 nM JE, 100 nM MIG, or 300 nM TECK. Responding cells were harvested and placed in methylcellulose containing IL-7 and Flt3-L. The number of colonies was scored on days 12-17 by isolating colonies and staining with B220-APC, HSA-biotin/SAv-PerCP, CD19-PE, and Mac-1-FITC to verify its pro-B CFU classification. The data are the mean \u03ee SEM from three individual experiments.", "type": "figure"}, "FIGREF3": {"text": "Figure 3. Flow cytometry plots illustrate the selectivity of chemokine responses by antigenically defined B cell subsets. Unfractioned BM cells were prepared and added to inserts that were placed in wells containing either 100 nM SLC (left) or 500 nM BCA-1 (right). Initial input (light line) and responding (bold line) cells were harvested and stained with different combinations of B220-APC, IgM b -PE, and CD43-FITC. All panels were gated on B220 \u03e9 cells. The presented histograms were obtained by overlaying individual histograms from three to four experiments, adding them together using CELLQuest\u2122 software (Becton Dickinson) to obtain an average representative histogram, and normalizing them to the peak cell number. CTX, chemotaxis.", "type": "figure"}, "FIGREF4": {"text": "last column). No staining above controls was ob- served in any of the BM B cell populations (including pro-B cells) harvested from CXCR5 knockout mice (data not shown). Similar CXCR5 expression patterns for pre-B cell and immature B cell populations have been reported by Pevzner et al. (28) and Cyster et al. (22). Taken together, these data demonstrate a shift in chemo- tactic responses during B cell maturation in the BM, char- acterized by the loss of responsiveness to TECK and an ini- tial increase in responsiveness to the peripheral B cell chemokines SLC, MIP-3\u2424, and BCA-1 in the later stages of BM B cell development (the immature BM B cell). How- ever, neither the chemotactic responses nor the CXCR5 ex- pression levels by immature B cells approached the high lev- els displayed by naive splenic \u2426 \u03e9 B cells, suggesting that further alterations in chemokine responses occur during de- velopmental transition to mature peripheral B cells. Major Shift to Peripheral Chemokine Responsiveness Associ- ated with B Cell Emigration to Peripheral Lymphoid Tissues. The large numbers of relatively short lived B cells that have recently emigrated from the adult BM, and which are transitioning into follicular B cells, can be found in the spleen (4, 29, 30). Transition 1 B cells are B220 \u03e9 , sIgM hi , sIgD \u03ea , CD21 lo/\u03ea , and CD23 \u03ea ; Transition 2 B cells are B220 \u03e9 , sIgM hi , sIgD hi , CD21 hi , CD23 int ; whereas, fully ma- ture recirculating naive splenic B cells are B220 hi , sIgM lo , sIgD hi , CD21 int , CD23 int , and HSA lo (1, 4, 29, 30). We asked whether the chemotactic responses of splenic transi- tional B cells were different from those of either immature BM B cells (B220 lo CD43 \u03ea sIgM \u03e9 ) or mature naive splenic \u2426 \u03e9 follicular B cells (B220 hi sIgM lo sIgD hi ). Fig. 5 A illustrates that, like the sIgM \u03e9 but immature BM B cells that gave rise to them, Transition 1 recent BM emigrants (B220 \u03e9 CD21 lo/\u03ea CD23 \u03ea ) to the spleen do not respond to MIP-3\u2423. However, B cells that have progressed to Transition 2 B cells (B220 \u03e9 sIgM hi sIgD hi ), or that have become members of the naive, recirculating pool of follic- ular \u2426 \u03e9 B cells, show a greatly increased responsiveness to MIP-3\u2423. Responses to SLC, MIP-3\u2424, SDF-1\u2423, and BCA-1 exhibited by immature BM B cells were increased in the Transition 1 population and increased further in both the Transition 2 and the naive, splenic \u2426 \u03e9 B cells", "type": "figure"}, "FIGREF5": {"text": "Figure 4. Chemokine receptor expression by B cells at different stages of development in the BM. Control staining (dashed line) and antichemokine receptor staining (bold line) for CXCR3 (A), CXCR5 (B), and CCR6 (C) are shown for the indicated BM populations identified by their surface expression of antigens listed in Fig. 1 A except for Fraction A1/A2, which were identified for chemokine receptor staining purposes using AA4.1-APC, B220-PE, and HSA-FITC. Fraction (Fxn) A1/ A2 cells were identified as B220 \u03e9 HSA \u03ea/lo AA4.1 \u03e9 .NK1.1 \u03e9 AA4.1 \u03ea immature NK precursors are excluded by these gates. The data are representative of two experiments.", "type": "figure"}, "FIGREF6": {"text": "Figure 5. Continued maturation of B cell chemotactic responses after exit from the BM. Unfractioned BM cells or splenic lymphocytes were prepared and added to inserts that were placed in wells containing 100 nM MIP-3\u2423 (A) or 100 nM SLC, 100 nM MIP-3\u2424, 50 nM SDF-1\u2423, or 500 nM BCA-1 (B). Responding cells were harvested and stained with combinations of B220-APC, CD3\u2440-biotin/SAv-PerCP, IgM b -PE, CD23-PE, IgD-FITC, and CD21-FITC to identify different cell populations. The data are the mean \u03ee SEM from two to six experiments. (C) Control mAb staining (dashed line) and anti-CCR6 staining (bold line) are shown for the indicated BM and splenic populations. The data are representative of two experiments. (D) Control Ab staining (dashed line) and anti-CXCR5 staining (bold line) are shown for the indicated BM and splenic populations. The data are representative of two experiments. All symbols have error bars even though in some instances (i.e., Basal migration) the error bars are smaller than the symbol.", "type": "figure"}, "FIGREF7": {"text": "Figure 6. Flow cytometric separation of anatomically distinct B cell subsets. Unfractioned splenic lymphocytes (A) and PP lymphocytes (B) were prepared and stained with B220-APC, CD3\u2440-biotin/SAv-PerCP, CD23-PE, and CD21-FITC for spleen or B220-APC, CD3\u2440-biotin/ SAv-PerCP, and PNA-FITC for PPs. The data shown have been gated on the B220 \u03e9 CD3\u2440 \u03ea population.", "type": "figure"}, "FIGREF8": {"text": "Figure 7. Chemotactic responses of follicular, MZ, and GC B cells. (A and B) Unfractioned splenic lymphocytes were added to inserts that were placed in wells containing 100 nM MIP-3\u2423 (A), or 100 nM SLC, 50 nM SDF-1\u2423, or 500 nM BCA-1 (B). Responding cells were harvested, stained with the mAbs, and gated on the follicular and MZ regions shown in Fig. 6 A. The data are the mean \u03ee SEM from three to eight experiments. (C) Control mAb staining (dashed line) and anti-CCR6 staining (bold line) are shown for the splenic CD21 hi CD23 \u03ea/lo MZ (first column), CD21 int CD23 int splenic follicular B cells (second column), B220 \u03e9 PNA lo PP follicular mantle (third column), and B220 \u03e9 PNA hi PP GC B cells (fourth column). The data are representative of two experiments. (D) Control Ab staining (dashed line) and anti-CXCR5 staining (bold line) are shown for the indicated splenic and PP populations described in C. The data are representative of two experiments. (E and F) Unfractioned PP lymphocytes were prepared and added to inserts that were placed in wells containing 100 nM MIP-3\u2423 (E) or 100 nM SLC, 50 nM SDF-1\u2423, or 500 nM BCA-1 (F). Responding cells were harvested, stained with the mAbs, and gated on the follicular mantle and GC regions shown in Fig. 6 B. The data are the mean \u03ee SEM from two to four experiments.", "type": "figure"}, "FIGREF9": {"text": "Figure 8. B1 (CD5 \u03e9 ) B cells respond to lymphoid tissue chemokines but not significantly to MIP-3\u2423. (A and B) Unfractioned peritoneal cavity lymphocytes were prepared and added to inserts that were placed in wells containing 100 nM MIP-3\u2423 (A) or 100 nM SLC, 50 nM SDF-1\u2423, or 500 nM BCA-1 (B). Responding cells were harvested and stained with B220-APC, CD3\u2440-biotin/SAv-PerCP, CD5-PE, and CD43-FITC. The data are the mean \u03ee SEM from two to four experiments. (C) Control mAb staining (dashed line) and anti-CCR6 staining (bold line) are shown for the indicated peritoneal cavity populations. The data are representative of two experiments. (D) Control Ab staining (dashed line) and anti-CXCR5 staining (bold line) are shown for the indicated peritoneal cavity populations. The data are representative of two experiments.", "type": "figure"}, "FIGREF10": {"text": "B cells progress through their developmental pro- gram, there is a dramatic switch in their chemotactic pro- files. AA4.1 \u03e9 NK1.1 \u03ea Fraction A cells convert into pro-B cells (Fraction B and C) with increasing D-J H but not V-D- J H rearrangement (25). Concomitant with Ig gene recom- bination, these cells lose their response to TECK and ac- quire responsiveness to BCA-1. Pro-B cells progress into pre-B cells (Fraction D) with increasing V-D-J H and V-J rearrangement (25). These cells lose the BCA-1 response present in pro-B cells, but still possess the same small re- sponse to the CCR7 ligands exhibited by both AA4.1 \u03e9 NK1.1 \u03ea Fraction A cells and pro-B cells. Pre-B cells differ- entiate into immature B cells (Fraction E) with fully rear- ranged Ig-encoded DNA, completing the BM stage of B cell development (25). These sIgM \u03e9 immature B cells mi- grate better to the CCR7 ligands SLC and MIP-3\u2424 than their pre-B cell precursors, and reacquire responsiveness to BCA-1. CXCR5 expression mirrors BCA-1 responsive- ness, with a minor proportion of pro-B cells and immature B cells expressing detectable levels of the receptor and mi- grating to BCA-1. Thus, developing B cells undergo a va- riety of developmental alterations, from the on/off re- sponse to TECK (and potentially RANTES, JE, and MIG), the on/off/on again response to BCA-1, and the progres- sive increases in responses to the secondary lymphoid hom- ing-associated chemokines, SLC and MIP-3\u2424. Similar conclusions concerning CCR7 ligands have been made in the human system by Kim et al. (49), who demonstrated that the CCR7 ligands SLC and MIP-3\u2424 induce the mi- gration of late stage B cell progenitors (pre-B II, immature, and mature B cells), but not early pro/pre-B I cells.", "type": "figure"}, "FIGREF11": {"text": "Figure 9. Schematic depiction of the acquisition and loss of chemokine responsiveness as B cells develop in the BM and migrate to the periphery.", "type": "figure"}, "TABREF0": {"text": "third and fourth columns, respectively). Chemotaxis Profiles of B Cells Occupying Distinct Microenvi- ronmental Niches within Lymphoid Tissues: Follicular, Splenic MZ, and GC Cells. B cells occupying distinct anatomical sites in lymphoid tissue can be distinguished by their anti- genic phenotypes (31). Follicular B cells are B220 hi CD21 int CD23 int and are sIgD hi and sIgM lo (\u2426 \u03e9 ). In com- parison, splenic MZ B cells are B220 \u03e9 CD21 hi CD23 lo/\u03ea and have low to zero IgD but high levels of IgM on their surface", "type": "table"}, "TABREF1": {"text": ") B cells. Similar chemotaxis and receptor expression data were ob- tained when \u2426 \u03ea staining was used to discriminate PP fol- licular mantle and GC B cells (data not shown). Chemotaxis Profiles of Extrafollicular Peritoneal Cavity B Cells. A unique type of B cell is found primarily in the peritoneal and pleural cavities of the mouse. B1 or", "type": "table"}}}
{"paper_id": "10703029", "_pdf_hash": "642dfeec1c395f11382dcaa7ad2f39bb75781227", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Results of pancreaticoduodenectomy for lymphoplasmacytic sclerosing pancreatitis", "authors": [{"first": "J", "middle": ["M"], "last": "Hardacre", "suffix": ""}, {"first": "C", "middle": ["A"], "last": "Iacobuzio-Donahue", "suffix": ""}, {"first": "T", "middle": ["A"], "last": "Sohn", "suffix": ""}], "year": 2003, "venue": "Ann Surg", "link": "20615331"}, "BIBREF1": {"title": "Pancreaticoduodenectomy (Whipple resections) in patients without malignancy: Are they all 'chronic pancreatitis'?", "authors": [{"first": "S", "middle": ["C"], "last": "Abraham", "suffix": ""}, {"first": "R", "middle": ["E"], "last": "Wilentz", "suffix": ""}, {"first": "C", "middle": ["J"], "last": "Yeo", "suffix": ""}], "year": 2003, "venue": "Am J Surg Pathol", "link": "5620245"}, "BIBREF4": {"title": "Chronic inflammatory sclerosis of the pancreas-an autonomous pancreatic disease?", "authors": [{"first": "H", "middle": [], "last": "Sarles", "suffix": ""}, {"first": "J", "middle": ["C"], "last": "Sarles", "suffix": ""}, {"first": "R", "middle": [], "last": "Muratore", "suffix": ""}], "year": 1961, "venue": "Am J Dig Dis", "link": "37306006"}, "BIBREF5": {"title": "Chronic pancreatitis caused by an autoimmune abnormality. Proposal of the concept of autoimmune pancreatitis", "authors": [{"first": "K", "middle": [], "last": "Yoshida", "suffix": ""}, {"first": "F", "middle": [], "last": "Toki", "suffix": ""}, {"first": "T", "middle": [], "last": "Takeuchi", "suffix": ""}], "year": 1995, "venue": "Dig Dis Sci", "link": null}, "BIBREF6": {"title": "Autoimmune pancreatitis as a new clinical entity. Three cases of autoimmune pancreatitis with effective steroid therapy", "authors": [{"first": "T", "middle": [], "last": "Ito", "suffix": ""}, {"first": "I", "middle": [], "last": "Nakano", "suffix": ""}, {"first": "S", "middle": [], "last": "Koyanagi", "suffix": ""}], "year": 1997, "venue": "Dig Dis Sci", "link": "24273522"}, "BIBREF7": {"title": "Corticosteroid-responsive diabetes mellitus associated with autoimmune pancreatitis", "authors": [{"first": "S", "middle": [], "last": "Tanaka", "suffix": ""}, {"first": "T", "middle": [], "last": "Kobayashi", "suffix": ""}, {"first": "K", "middle": [], "last": "Nakanishi", "suffix": ""}], "year": 2000, "venue": "Lancet", "link": "31908313"}, "BIBREF8": {"title": "Clinical analysis of autoimmune-related pancreatitis", "authors": [{"first": "K", "middle": [], "last": "Uchida", "suffix": ""}, {"first": "K", "middle": [], "last": "Okazaki", "suffix": ""}, {"first": "Y", "middle": [], "last": "Konishi", "suffix": ""}], "year": 2000, "venue": "Am J Gastroenterol", "link": "11380640"}, "BIBREF9": {"title": "Autoimmune-related pancreatitis", "authors": [{"first": "K", "middle": [], "last": "Okazaki", "suffix": ""}], "year": 2001, "venue": "Curr Treat Options Gastroenterol", "link": "10515114"}, "BIBREF10": {"title": "Autoimmune related pancreatitis", "authors": [{"first": "K", "middle": [], "last": "Okazaki", "suffix": ""}, {"first": "T", "middle": [], "last": "Chiba", "suffix": ""}], "year": 2002, "venue": "Gut", "link": "10515114"}, "BIBREF11": {"title": "Bile duct involvement in a case of autoimmune pancreatitis successfully treated with an oral steroid", "authors": [{"first": "T", "middle": [], "last": "Kuroiwa", "suffix": ""}, {"first": "T", "middle": [], "last": "Suda", "suffix": ""}, {"first": "T", "middle": [], "last": "Takahashi", "suffix": ""}], "year": 2002, "venue": "Dig Dis Sci", "link": "9268157"}, "BIBREF12": {"title": "Primary sclerosing cholangitis associated with autoimmune pancreatitis", "authors": [{"first": "T", "middle": [], "last": "Ichimura", "suffix": ""}, {"first": "S", "middle": [], "last": "Kondo", "suffix": ""}, {"first": "Y", "middle": [], "last": "Ambo", "suffix": ""}], "year": 2002, "venue": "Hepatogastroenterology", "link": "25898655"}, "BIBREF13": {"title": "Autoimmune pancreatitis and multiple bile duct strictures treated effectively with steroid", "authors": [{"first": "E", "middle": [], "last": "Kojima", "suffix": ""}, {"first": "K", "middle": [], "last": "Kimura", "suffix": ""}, {"first": "Y", "middle": [], "last": "Noda", "suffix": ""}], "year": 2003, "venue": "J Gastroenterol", "link": "499671"}, "BIBREF14": {"title": "Autoimmune pancreatitis with effective steroid therapy", "authors": [{"first": "S", "middle": ["P"], "last": "Hong", "suffix": ""}, {"first": "S", "middle": ["W"], "last": "Park", "suffix": ""}, {"first": "J", "middle": ["P"], "last": "Chung", "suffix": ""}], "year": 2003, "venue": "Yonsei Med J", "link": "7312684"}, "BIBREF15": {"title": "Lymphoplasmacytic sclerosing pancreatitis: Inflammatory mimic of pancreatic carcinoma", "authors": [{"first": "S", "middle": ["M"], "last": "Weber", "suffix": ""}, {"first": "O", "middle": [], "last": "Cubukcu-Dimopulo", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Palesty", "suffix": ""}], "year": 2003, "venue": "J GASTROINTEST SURG", "link": "26727279"}, "BIBREF16": {"title": "Idiopathic tumefactive chronic pancreatitis: Clinical profile, histology, and natural history after resection", "authors": [{"first": "D", "middle": [], "last": "Yadav", "suffix": ""}, {"first": "K", "middle": [], "last": "Notahara", "suffix": ""}, {"first": "T", "middle": [], "last": "Smyrk", "suffix": ""}], "year": 2003, "venue": "Clin Gastroenterol Hepatol", "link": "2074905"}, "BIBREF17": {"title": "High serum IgG 4 concentrations in patients with sclerosing pancreatitis", "authors": [{"first": "H", "middle": [], "last": "Hamano", "suffix": ""}, {"first": "S", "middle": [], "last": "Kawa", "suffix": ""}, {"first": "A", "middle": [], "last": "Horiuchi", "suffix": ""}], "year": 2001, "venue": "N Engl J Med", "link": "31370680"}, "BIBREF18": {"title": "Clinical study of chronic pancreatitis with focal irregular narrowing of the main pancreatic duct and mass formation: Comparison with chronic pancreatitis showing diffuse irregular narrowing of the main pancreatic duct", "authors": [{"first": "T", "middle": [], "last": "Wakabayashi", "suffix": ""}, {"first": "Y", "middle": [], "last": "Kawaura", "suffix": ""}, {"first": "Y", "middle": [], "last": "Satomura", "suffix": ""}], "year": 2002, "venue": "Pancreas", "link": "41110771"}, "BIBREF19": {"title": "Non-alcoholic duct destructive chronic pancreatitis", "authors": [{"first": "N", "middle": [], "last": "Ectors", "suffix": ""}, {"first": "B", "middle": [], "last": "Maillet", "suffix": ""}, {"first": "R", "middle": [], "last": "Aerts", "suffix": ""}], "year": 1997, "venue": "Gut", "link": "16904895"}, "BIBREF20": {"title": "Non-alcoholic duct destructive chronic pancreatitis\" or \"primary chronic pancreatitis", "authors": [{"first": "L", "middle": [], "last": "Frulloni", "suffix": ""}, {"first": "P", "middle": [], "last": "Bovo", "suffix": ""}, {"first": "Di", "middle": [], "last": "Francesco", "suffix": ""}, {"first": "V", "middle": [], "last": "", "suffix": ""}], "year": 1999, "venue": "Gut", "link": "29336877"}, "BIBREF21": {"title": "Autoimmune chronic pancreatitis: A plea for simplification and consistency", "authors": [{"first": "E", "middle": ["P"], "last": "Dimagno", "suffix": ""}], "year": 2003, "venue": "Clin Gastroenterol Hepatol", "link": "11531740"}, "BIBREF22": {"title": "Autoimmune pancreatitis associated with primary sclerosing cholangitis: MR imaging findings", "authors": [{"first": "I", "middle": [], "last": "Eerens", "suffix": ""}, {"first": "D", "middle": [], "last": "Vanbeckevoort", "suffix": ""}, {"first": "W", "middle": [], "last": "Vansteenbergen", "suffix": ""}, {"first": "L", "middle": [], "last": "Van Hoe", "suffix": ""}], "year": 2001, "venue": "Eur Radiol", "link": "24631161"}, "BIBREF23": {"title": "Atypical primary sclerosing cholangitis cases associated with unusual pancreatitis", "authors": [{"first": "T", "middle": [], "last": "Nakazawa", "suffix": ""}, {"first": "H", "middle": [], "last": "Ohara", "suffix": ""}, {"first": "T", "middle": [], "last": "Yamada", "suffix": ""}], "year": 2001, "venue": "Hepatogastroenterology", "link": "25879195"}, "BIBREF24": {"title": "Sclerosing cholangitis, chronic pancreatitis, and Sjogren's syndrome: A syndrome complex", "authors": [{"first": "P", "middle": ["P"], "last": "Montefusco", "suffix": ""}, {"first": "A", "middle": ["C"], "last": "Geiss", "suffix": ""}, {"first": "R", "middle": ["L"], "last": "Bronzo", "suffix": ""}], "year": 1984, "venue": "Am J Surg", "link": "1335494"}, "BIBREF25": {"title": "Specific cellular immune responses to pancreatic antigen in chronic pancreatitis and Sjogren's syndrome", "authors": [{"first": "I", "middle": [], "last": "Nishimori", "suffix": ""}, {"first": "K", "middle": [], "last": "Okazaki", "suffix": ""}, {"first": "Y", "middle": [], "last": "Yamamoto", "suffix": ""}], "year": 1993, "venue": "J Clin Immunol", "link": "25694682"}, "BIBREF26": {"title": "Identification of autoantibodies to a pancreatic antigen in patients with idiopathic chronic pancreatitis and Sjogren's syndrome", "authors": [{"first": "I", "middle": [], "last": "Nishimori", "suffix": ""}, {"first": "Y", "middle": [], "last": "Yamamoto", "suffix": ""}, {"first": "K", "middle": [], "last": "Okazaki", "suffix": ""}], "year": 1994, "venue": "Pancreas", "link": "10267759"}, "BIBREF27": {"title": "Multiple pancreatic masses associated with autoimmunity", "authors": [{"first": "M", "middle": [], "last": "Ohana", "suffix": ""}, {"first": "K", "middle": [], "last": "Okazaki", "suffix": ""}, {"first": "K", "middle": [], "last": "Hajiro", "suffix": ""}], "year": 1998, "venue": "Am J Gastroenterol", "link": "140103688"}, "BIBREF28": {"title": "Evidence of primary beta-cell destruction by T-cells and beta-cell differentiation from pancreatic ductal cells in diabetes associated with active autoimmune chronic pancreatitis", "authors": [{"first": "S", "middle": [], "last": "Tanaka", "suffix": ""}, {"first": "T", "middle": [], "last": "Kobayashi", "suffix": ""}, {"first": "K", "middle": [], "last": "Nakanishi", "suffix": ""}], "year": 2001, "venue": "Diabetes Care", "link": "7485625"}, "BIBREF29": {"title": "Corticosteroid-responsive diabetes mellitus associated with autoimmune pancreatitis: Pathological examinations of the endocrine and exocrine pancreas", "authors": [{"first": "S", "middle": [], "last": "Tanaka", "suffix": ""}, {"first": "T", "middle": [], "last": "Kobayashi", "suffix": ""}, {"first": "K", "middle": [], "last": "Nakanishi", "suffix": ""}], "year": 2002, "venue": "Ann N Y Acad Sci", "link": "19577595"}, "BIBREF31": {"title": "IgG 4 -associated idiopathic tubulointerstitial nephritis complicating autoimmune pancreatitis", "authors": [{"first": "S", "middle": [], "last": "Takeda", "suffix": ""}, {"first": "J", "middle": [], "last": "Haratake", "suffix": ""}, {"first": "T", "middle": [], "last": "Kasai", "suffix": ""}], "year": 2004, "venue": "Nephrol Dial Transplant", "link": "14626633"}, "BIBREF32": {"title": "Acute tubulointerstitial nephritis associated with autoimmune-related pancreatitis", "authors": [{"first": "Y", "middle": [], "last": "Uchiyama-Tanaka", "suffix": ""}, {"first": "Y", "middle": [], "last": "Mori", "suffix": ""}, {"first": "T", "middle": [], "last": "Kimura", "suffix": ""}], "year": 2004, "venue": "Am J Kidney Dis", "link": "41017356"}, "BIBREF33": {"title": "Controversies in Clinical Pancreatology: Autoimmune pancreatitis: Does it exist?", "authors": [{"first": "R", "middle": ["K"], "last": "Pearson", "suffix": ""}, {"first": "D", "middle": ["S"], "last": "Longnecker", "suffix": ""}, {"first": "S", "middle": ["T"], "last": "Chari", "suffix": ""}], "year": 2003, "venue": "Pancreas", "link": "35017600"}, "BIBREF34": {"title": "Clinical relevance of autoimmune-related pancreatitis", "authors": [{"first": "K", "middle": [], "last": "Okazaki", "suffix": ""}], "year": 2002, "venue": "Best Pract Res Clin Gastroenterol", "link": "23076663"}, "BIBREF35": {"title": "Is chronic pancreatitis a primary disease of the pancreatic ducts? A new pathogenetic hypothesis", "authors": [{"first": "G", "middle": [], "last": "Cavallini", "suffix": ""}], "year": 1993, "venue": "Ital J Gastroenterol", "link": "30243151"}, "BIBREF36": {"title": "HLA DRB10405-DQB10401 haplotype is associated with autoimmune pancreatitis in the Japanese population", "authors": [{"first": "S", "middle": [], "last": "Kawa", "suffix": ""}, {"first": "M", "middle": [], "last": "Ota", "suffix": ""}, {"first": "K", "middle": [], "last": "Yoshizawa", "suffix": ""}], "year": 2002, "venue": "Gastroenterology", "link": "5938985"}, "BIBREF37": {"title": "Serum antibodies to carbonic anhydrase I and II in patients with idiopathic chronic pancreatitis and Sjogren's syndrome", "authors": [{"first": "J", "middle": [], "last": "Kino-Ohsaki", "suffix": ""}, {"first": "I", "middle": [], "last": "Nishimori", "suffix": ""}, {"first": "M", "middle": [], "last": "Morita", "suffix": ""}], "year": 1996, "venue": "Gastroenterology", "link": "24429655"}, "BIBREF38": {"title": "Distribution of the carbonic anhydrase isoenzymes I, II, and VI in the human alimentary tract", "authors": [{"first": "S", "middle": [], "last": "Parkkila", "suffix": ""}, {"first": "A", "middle": ["K"], "last": "Parkkila", "suffix": ""}, {"first": "T", "middle": [], "last": "Juvonen", "suffix": ""}], "year": 1994, "venue": "Gut", "link": "26193683"}, "BIBREF39": {"title": "Autoimmune-related pancreatitis is associated with autoantibodies and a Th1/Th2-type cellular immune response", "authors": [{"first": "K", "middle": [], "last": "Okazaki", "suffix": ""}, {"first": "K", "middle": [], "last": "Uchida", "suffix": ""}, {"first": "M", "middle": [], "last": "Ohana", "suffix": ""}], "year": 2000, "venue": "Gastroenterology", "link": "23517110"}, "BIBREF40": {"title": "Autoimmune pancreatitis is increasing in Japan", "authors": [{"first": "K", "middle": [], "last": "Okazaki", "suffix": ""}], "year": 2003, "venue": "Gastroenterology", "link": "30671399"}, "BIBREF41": {"title": "Autoimmune pancreatitis: Radiologic findings in three histologically proven cases", "authors": [{"first": "N", "middle": [], "last": "Furukawa", "suffix": ""}, {"first": "T", "middle": [], "last": "Muranaka", "suffix": ""}, {"first": "K", "middle": [], "last": "Yasumori", "suffix": ""}], "year": 1998, "venue": "J Comput Assist Tomogr", "link": "7013830"}, "BIBREF42": {"title": "Autoimmune pancreatitis: Possibilities of CT characterization", "authors": [{"first": "C", "middle": [], "last": "Procacci", "suffix": ""}, {"first": "G", "middle": [], "last": "Carbognin", "suffix": ""}, {"first": "C", "middle": [], "last": "Biasiutti", "suffix": ""}], "year": 2001, "venue": "Pancreatology", "link": "10146175"}, "BIBREF43": {"title": "Autoimmune pancreatitis: CT and MR characteristics", "authors": [{"first": "H", "middle": [], "last": "Irie", "suffix": ""}, {"first": "H", "middle": [], "last": "Honda", "suffix": ""}, {"first": "S", "middle": [], "last": "Baba", "suffix": ""}], "year": 1998, "venue": "AJR Am J Roentgenol", "link": "38349573"}, "BIBREF44": {"title": "Current status of imaging in pancreatic diseases", "authors": [{"first": "M", "middle": ["K"], "last": "Kalra", "suffix": ""}, {"first": "M", "middle": ["M"], "last": "Maher", "suffix": ""}, {"first": "D", "middle": ["V"], "last": "Sahani", "suffix": ""}], "year": 2002, "venue": "J Comput Assist Tomogr", "link": "38594209"}, "BIBREF45": {"title": "ERCP features in 27 patients with autoimmune pancreatitis", "authors": [{"first": "A", "middle": [], "last": "Horiuchi", "suffix": ""}, {"first": "S", "middle": [], "last": "Kawa", "suffix": ""}, {"first": "H", "middle": [], "last": "Hamano", "suffix": ""}], "year": 2002, "venue": "Gastrointest Endosc", "link": "10671242"}, "BIBREF46": {"title": "Endoscopic ultrasound in pancreatic tumor diagnosis", "authors": [{"first": "T", "middle": [], "last": "Rosch", "suffix": ""}, {"first": "R", "middle": [], "last": "Lorenz", "suffix": ""}, {"first": "C", "middle": [], "last": "Braig", "suffix": ""}], "year": 1991, "venue": "Gastrointest Endosc", "link": "37346683"}, "BIBREF47": {"title": "Ursodeoxycholic acid as an alternative therapy for autoimmune pancreatitis", "authors": [{"first": "K", "middle": [], "last": "Okazaki", "suffix": ""}], "year": 2002, "venue": "Intern Med", "link": "34478991"}}, "ref_entries": {}}
{"paper_id": "10703071", "_pdf_hash": "a81e554eef7190a9f79052c22441b110133d5303", "abstract": [{"section": "Abstract", "text": "(1) In order to study the relationship between the energy metabolism via TCA cycle and amino acid metabolism as well as protein synthesis , C14-labelled substrates were used for tracer experiment .", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "(2) Considerable C14O2 formation was noted from carbohydrates such as acetate-1-C14, pyruvate-1-C14, and pyruvate-3-C14 , while a smaller amount of C14O2 was produced from amino acids such as glycine-1-C14, alanine-1-C14, and glutamic acid-1-C14. Since glutamine-C14(U) was a universal type, a direct comparison with other labelled substrates was not possible, but a considerable amount of C14O2 production was noted.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "(3) The transfer from acetate-1-C14 to glutamic acid, from pyruvate-3-C14 to alanine and glutamic acid suggests the presence of the process of formation of glutamic acid from TCA cycle in the myocardium.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "(4) Comparison between pyruvate-1-C14 and pyruvate-3-C14 revealed more transference of -3-C14 to amino acid.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "(5) The carbon chains of glycine, alanine, and glutamic acid were transferred into other amino acids in the myocardium. Glutamine was also changed into many amino acids, and the transfer to glutamic acid was especially pronounced.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "(6) The increase in C14O2 production from carbohydrate and glutamine through digitalis administration might suggest the facilitation of the utilization of these substrates by digitalis.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "(7) Administration of ammonia inhibited oxidation of pyruvate-3-C 14.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Additional Indexing Words : C14-acetate C14-pyruvate C14-glutamic acid C14-alanine C14-glycine C14-glutamine Effect of digitalis Effect of ammonia Intermediary metabolism of myocardium.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "HE role of amino acids as the components of protein is well known. For the myocardium to perform the incessant contractile movement, amino acids may have an important significance as the components of proteins such From the", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "", "text": "The effect of digitalis and ammonia on such intermediary metabolism was, therefore, also studied.", "cite_spans": [], "ref_spans": []}, {"section": "METHODS", "text": "1. Preparation of the isolated heart In a guinea pig, approximately 250Gm. of body weight, the tip of the reservoir chamber described below was inserted into the lumen of the left auricle and fixed, under artificial respiration, according to the method described by Clarke.4) The aorta and the pulmonary artery were then ligated, and the heart was separated from the surrounding tissue.", "cite_spans": [], "ref_spans": []}, {"section": "Experimental apparatus", "text": "The experimental apparatus is shown in Fig.1 tion into the myocardial protein was also noted in cases after addition of ammonia (Table III, IV) . addition of digitalis. In the free amino acid fractions in the myocardium, radioactivity was noted in glutamic acid, N3 fraction, and alanine. In addition of ammonia, transition to glutamic acid and N3 fraction was rather pronounced. In the free amino acid fractions in plasma of the perfused blood, radioactivity was noted in the glutamic acid and alanine. No definite tendency was noted in the incorporation into myocardial protein (Table VII, VIII) . 4 . Experiment of glutamic acid-1-C14 administration C14O2 production averaged 384 CPM/gww upon perfusion for 15 min. 6. Experiment with administration of glycine-1-C14 C14O2 production was 91 CPM/gww in the case of perfusion for 35 min. and 332 CPM/gww in the case of perfusion for 60 min. The radioactivity of the myocardial non-protein components was 632 x 103 CPM after 35 min. and 1,300 X 103 CPM after 60 min., indicating an increase of uptake in the myocardium in the course of time. In the myocardial free amino acid fractions, radioactivity was noted in aspartic acid and glutamic acid. In the plasma of the perfused blood, radioactivity was noted in aspartic acid and N1 fraction. The incorporation into the myocardial protein was 114 CPM after 35 min. and increased to 465 CPM after 60 min. (Table XIII , XIV).", "cite_spans": [], "ref_spans": [{"start": 128, "end": 143, "text": "(Table III, IV)", "ref_id": "TABREF2"}, {"start": 580, "end": 597, "text": "(Table VII, VIII)", "ref_id": "TABREF2"}, {"start": 1402, "end": 1413, "text": "(Table XIII", "ref_id": "TABREF2"}]}, {"section": "Experimental apparatus", "text": "7. Experiment with glutamine-C14 (U) administration C14O2 production averaged 1,356 CPM/gww after 1 min. perfusion, 1,648 CPM/gww after 3 min., 1,630 CPM/gww after 8 min. and 1,656 CPM/gww after 30 min. These results suggest a rather early combustion of glutamine.", "cite_spans": [], "ref_spans": []}, {"section": "Experimental apparatus", "text": "In Fig. 3 . Radioactivity of respiratory 0140,.", "cite_spans": [], "ref_spans": []}, {"section": "Experimental apparatus", "text": "(", "cite_spans": [], "ref_spans": []}, {"section": "Experimental apparatus", "text": "Pyruvate-3-C14 (3A) Pyruvate-3-C74+Ammonia (3D) Pyruvate-3-C14+Digitalis (4)", "cite_spans": [], "ref_spans": []}, {"section": "Experimental apparatus", "text": "Glutamic acid-l-C14 (5) Alanine-l-C74 (6) Glycine-l-C14 (7) Glutamine-C14(U) (7D) Glutamine-C14(U)+Digitalis (Isotopes value; 5 \u00b5c.) course of time, no radioactivity was noted at all in the group of digitalis administration (Table XV, XVI) . Fig.3, 4 and 5 illustrate the summary of the results described above. Jap. Heart J. July, 1968 Concerning the C14O2 production from C14-glutamic acid , Clark4) estimated the rate of 0.5% in the guinea pig heart . Doell and Felts11) observed that the glutamic acid administered into the perfused rabbit heart disappeared rapidly and 48% of the administered radioactivity was removed from the perfused fluid and 22% was oxidized into C14O2 after 1 hour . The amount of production of C14O2 from C14-glutamic acid in the author's experiment was lower than from acetate-1-C14 and pyruvate-1-C14, but indicating the utilization of glutamic acid as the energy source to some extent. As to the incorporation of glutamic acid into protein, Nyhan and Busch11) injected L-glutamic acid-C14(U) into rats and observed the incorporation of isotope into various organs, tode monstrate less than 5% of the administered isotope in cardiac muscle protein.", "cite_spans": [], "ref_spans": [{"start": 224, "end": 239, "text": "(Table XV, XVI)", "ref_id": "TABREF7"}]}, {"section": "Experimental apparatus", "text": "In the author's results the incorporation into protein was hardly noted. Concerning the relationship between glutamic acid and other amino acids, Awapara31) observed the formation of equivalent aspartic acid following glutamic acid administration in the rat myocardial homogenate. In the heart-lung preparation of guinea pig, Matsubara13) found radioactivity in aspartic acid, alanine, N3 and B2 fractions besides added glutamic acid after the administration of C14-glutamic acid (generally labelled). In the author's results, aspartic acid and N3 fraction showed radioactivity besides added glutamic acid in the perfused blood plasma and myocardium. Considering together with the high GOT and GPT activities in the myocardium, the transamination reaction appears to play an important role in the amino acid metabolism of the myocardium, and glutamic acid is probably changed into various amino acids in the myocardium. Since alanine is simply deaminized to change into pyruvate, it is supposed to play the role of the bridge between protein and carbohydrate. Lusk et al. 32) and Green & Goldberger33) reported on the effect of alanine on carbohydrate metabolism. In the experiment using the heart-lung preparation of dogs, Taguchi4) observed that the decreases in the concentrations of pyruvate, lactate, and fatty acid in the perfusing blood were less following alanine administration than following glutamic acid administration, and suggested the liability of alanine to be used as energy source. Clarke1) calculated, in the guinea pig heart, the rate of C14O2, formation from alanine-1-C14 as 3.6%, which was greater than that from glutamic acid. This would also indicate the liability of alanine to be used fuel. According to the authors results, C14O2 production was smaller than from glutamic acid. However, the demonstration of radioactivity in the ninhydrin negative fraction, which was supposed to represent pyruvate, in the perfusing blood might also indicate the transition of alanine to carbohydrate.", "cite_spans": [], "ref_spans": []}, {"section": "Experimental apparatus", "text": "Lorber and Olsen34) administered C13-carboxyl labelled glycine into the ", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF1": {"title": "Studies on myocardial ammonia metabolism", "authors": [{"first": "T", "middle": [], "last": "Kato", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF2": {"title": "Symposium on coronary insufficiency . The 17th General Assembly of the Japan Medical Congress", "authors": [{"first": "N", "middle": [], "last": "Yamazaki", "suffix": ""}], "year": 1967, "venue": "", "link": null}, "BIBREF5": {"title": "The application technique of isotope to medicine", "authors": [{"first": "H", "middle": [], "last": "Yamashita", "suffix": ""}], "year": 1965, "venue": "", "link": null}, "BIBREF10": {"title": "Isotopic equilibration between the citric acid cycle and glutamic acid", "authors": [{"first": "H", "middle": [], "last": "Busch", "suffix": ""}, {"first": "H", "middle": ["A"], "last": "Baltrush", "suffix": ""}], "year": 1955, "venue": "", "link": null}}, "ref_entries": {"TABREF2": {"text": "", "type": "table"}, "TABREF3": {"text": "min., indicating increase of pyruvate combustion in the course Table VI. Incorporation of Pyruvate-1-C14 into Non-protein Component", "type": "table"}, "TABREF4": {"text": "MYOCARDIAL METABOLISM OF PROTEIN AND AMINO ACIDS 379", "type": "table"}, "TABREF5": {"text": "Metabolism of DL-Alanine-1-C14", "type": "table"}, "TABREF6": {"text": "noted even in the ninhydrin negative fraction. Incorporation into the myo- cardial protein was slight (Table XI, XII).", "type": "table"}, "TABREF7": {"text": "Continued", "type": "table"}}}
{"paper_id": "10703504", "_pdf_hash": "00faeff99319f0dc331deee0fe225fe675a09ef5", "abstract": [{"section": "Abstract", "text": "Background: Autosomal dominant spinocerebellar ataxia type 1 is an adult onset progressive disorder with well characterized neurodegeneration in the cerebellum and brainstem. Beyond brain atrophy, few data exist concerning retinal and optic nerve involvement.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Spinocerebellar ataxia type 1 (SCA1) is an autosomaldominantly inherited, late-onset neurodegenerative disease primarily affecting the cerebellar cortex and brainstem. Affected patients suffer from disturbed motor coordination, slurred speech, dysphagia, spasticity, extrapyramidal movements such as dystonia or chorea, cerebellar oculomotor disturbances and ophthalmoparesis, saccade slowing and -at late disease stage -cognitive impairment [1] . A gain-of-function toxicity of the ataxin 1 protein was identified as the main causative agent in SCA1: In the ATXN1 gene on chromosome 6p23 a CAG-repeat expansion of variable length reaching between 39 and 83 repeats encodes for a prolonged polyglutamine chain in ataxin1 protein [2] . The physiologic function of ataxin1 is barely understood [3] . Subsequent nuclear and cytosolic protein aggregation in cerebellar Purkinje cells and brainstem neurons finally leads to cell death. Patients with longer CAG repeat tend to have an earlier disease onset and a faster progression than patients with short repeat expansions, causing great variations in disease severity even within families [1] .", "cite_spans": [{"start": 442, "end": 445, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 729, "end": 732, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 792, "end": 795, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 1136, "end": 1139, "text": "[1]", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "Introduction", "text": "Historically the classification of spinocerebellar ataxias has been directed by additional extracerebellar sign presence (autosomal dominant ataxia type I, ADCA I) or absence (ADCAIII), with cerebellar ataxia plus retinal degeneration being termed ADCA II [4] . Since genetic testing became available, at least 30 spinocerebellar ataxia subtypes have been identified with different gene localisation. SCA1 belongs to ADCA I group without known retinal involvement, whereas in SCA7 (ADCA II) degeneration of macula or retina is well established [5] [6] . In SCA1 patients, however, some groups found ophthalmologic pathology besides well described cerebellar oculomotor abnormalities: Visual acuity reduction with color vision failure and visual field contraction are reported. Some case collections suggest an increase of these symptoms with disease duration [7] [8], but do not find prominent changes at disease onset [8] . Electroretinogram (ERG) is reported to show mild attenuation of oscillatory potentials and corneal endothelial cell density was reported decreased [8] . The reduced visual acuity in SCA1 has been attributed to optic atrophy, which was first described by fundus examination [8] . Optic nerve involvement was also suggested by a significant percentage of VEP abnormalities in SCA1 patients [9] [10] . However in these studies 40-50% of SCA1 patients did not show VEP alteration and earlier neuro-pathologic work could not establish retinal or optic nerve pathology in SCA1 [11] . In summary, descriptions on retinal and optic nerve changes in SCA1 are controversial and no data exists on retinal pathology using high resolution OCT so far.", "cite_spans": [{"start": 256, "end": 259, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 544, "end": 547, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 548, "end": 551, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 859, "end": 862, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 919, "end": 922, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 1072, "end": 1075, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 1198, "end": 1201, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 1313, "end": 1316, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 1317, "end": 1321, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 1496, "end": 1500, "text": "[11]", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "Introduction", "text": "Optical coherence tomography (OCT) is a modern non-invasive method for high-resolution retinal investigations. The recently developed spectral domain technique allows spatial resolution down to 3 mm when measuring retinal nerve fiber layer thickness (RNFLT), which has previously only been possible with histopathology and ranges far above MRI resolution [12] . OCT has become a powerful tool in ophthalmologic diagnostics of diseases affecting retinal tissue e.g. glaucoma [12] or multiple sclerosis [13] [14] . Since it allows unique morphologic characterization of neuronal cells belonging to the CNS, the method is currently explored for diagnosis and monitoring of disease progression in a variety of neurodegenerative disorders as a surrogate parameter for cerebral and/or optic nerve axonal loss [15] [16] [17] .", "cite_spans": [{"start": 355, "end": 359, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 474, "end": 478, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 501, "end": 505, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 506, "end": 510, "text": "[14]", "ref_id": "BIBREF13"}, {"start": 803, "end": 807, "text": "[15]", "ref_id": "BIBREF14"}, {"start": 813, "end": 817, "text": "[17]", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "Introduction", "text": "Due to its simple application even in severely handicapped individuals the method is well suited for examination of ataxia patients. It has so far been applied in SCA7, where a significant reduction in RNFLT in all quadrants sparing the temporal one is consistently found [6] [5] . To the best of our knowledge in other forms of SCA no systematic study of retinal involvement using OCT has been performed so far.", "cite_spans": [{"start": 272, "end": 275, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 276, "end": 279, "text": "[5]", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "Introduction", "text": "Against this background, we set out to examine individuals with genetically proven SCA1 compared to age-and-gender matched healthy controls with OCT and VEP for retinal and optic nerve involvement.", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Ethics statement", "text": "The study was approved by the institutional ethics committee and all participants gave informed written consent.", "cite_spans": [], "ref_spans": []}, {"section": "Objectives", "text": "To evaluate retinal changes in SCA1 patients compared to age and gender matched healthy controls.", "cite_spans": [], "ref_spans": []}, {"section": "Participants", "text": "Patients were recruited from the ataxia outpatient clinic of the Charit\u00e9 university hospital in Berlin from December 2009 to January 2011. Inclusion criteria were a genetically diagnosed SCA1 and age ranging from 18 to 75 years. Healthy controls were matched by gender and age with a tolerance of 63 years. Participants with known pre-existing ophthalmological diseases were excluded.", "cite_spans": [], "ref_spans": []}, {"section": "Participants", "text": "If available, patients provided data of the number of CAG repeats in the ATXN1 gene, which were genetically ascertained by external laboratories. The disease duration was defined as the time (in years) since the first symptom appeared. Visual Acuity (VA) was assessed using Snellen Charts and refractive error (REF) was estimated using the Heidelberg Spectralis integrated confocal scanning laser ophthalmoscope (SLO).", "cite_spans": [], "ref_spans": []}, {"section": "Clinical examination", "text": "The SARA score was used for assessment and rating of patients' ataxia [18] . Briefly, the test assesses the following functions: gait, stance, sitting, speech disturbance, finger chase, nose-finger test, fast alternating hand movements and heel-shin slide. A summary score of these functional items gives the final SARA score, with a range from 0 (no ataxia) to 40 (most severe ataxia).", "cite_spans": [{"start": 70, "end": 74, "text": "[18]", "ref_id": "BIBREF17"}], "ref_spans": []}, {"section": "Optical Coherence Tomography", "text": "A spectral domain OCT device (Heidelberg Spectralis SD-OCT, Heidelberg Engineering, Germany, Spectralis software version 5.2.4.0, Eye Explorer Software 1.6.2.0) was used to measure the RNFLT and the total macular volume (TMV). For RNFLT, three 3.4 mm circular scans were acquired using the standard protocol and the scan with the highest quality value was chosen (in case of equal quality, an arbitrary scan was taken). The thickness between the inner limiting membrane and the retinal nerve fiber layer was calculated by the device software's segmentation algorithm. As parameters we used the average RNFLT of the full circle scan (G) and the partition of the circle in the following sectors: nasal-superior (NS), nasal (N), nasal-inferior (NI), temporal-inferior (TI), temporal (T) and temporal-superior (TS). The partition is visualized in figure 1C .", "cite_spans": [], "ref_spans": [{"start": 843, "end": 852, "text": "figure 1C", "ref_id": "FIGREF0"}]}, {"section": "Optical Coherence Tomography", "text": "For the analysis of further retinal tissue layers, the program OCTseg [19] was used for automatic layer segmentation. Each segmentation result was manually corrected in a blinded fashion and the exported segmentation lines were used to calculate the thicknesses of the following layers: ganglion cell layer (GCL) and inner plexiform layer (IPL), inner nuclear layer (INL) and outer plexiform layer (OPL), outer nuclear layer (ONL) and photoreceptor layer (PRL) and the retinal pigment epithelium (RPE) (figure 2A). The RNFL segmentation of OCTseg confirmed the previous results.", "cite_spans": [{"start": 70, "end": 74, "text": "[19]", "ref_id": "BIBREF18"}], "ref_spans": []}, {"section": "Optical Coherence Tomography", "text": "The TMV was appointed by a custom protocol which generated 61 slices (B-scans) focusing the fovea centralis with a scanning angle of 30u625u and a resolution of 768 A-scans per B-scan. Some patients were not able to focus the fixation point during examination due to strong eye and head movement. TMV was calculated by estimating the distance between the inner limiting membrane and the Bruch-membrane in a cylinder with 6mm in diameter using the device software's segmentation algorithm.", "cite_spans": [], "ref_spans": []}, {"section": "Optical Coherence Tomography", "text": "All measurements were performed by one of three experienced operators. The computationally generated segmentation lines were reviewed by the operators and manually corrected in cases of errors.", "cite_spans": [], "ref_spans": []}, {"section": "Visually Evoked Potentials", "text": "VEPs were recorded from Oz electrode against a Cz reference electrode following checkerboard stimulation. Between 40 and 80 recordings were averaged twice until clear peaks became visible. The latencies of the P100 peaks were used for analysis. Responses of P100 above 119 ms were defined as abnormal.", "cite_spans": [], "ref_spans": []}, {"section": "Statistical methods", "text": "A Mann-Whitney U-test was used to identify statistical differences of age between the study cohorts. Spearman's Rho tests were used for cross-correlation analysis of the clinical parameters (SARA score, disease duration and number of repeats) within the SCA1 cohort.", "cite_spans": [], "ref_spans": []}, {"section": "Statistical methods", "text": "Statistical differences between SCA1 patients and the group of healthy controls were calculated using General Estimation Equation (GEE) models to account for within-subject inter-eye dependencies. The multiple tests of all sectors from all retinal layers were adjusted using Bonferroni-Holm Correction. Correlation analysis of a clinical parameter (SARA score, disease duration and visual acuity) to the OCT data (RNFLT and macular volumes) were equally performed with GEE. In all GEEs, OCT measurements were included as the dependent variable.", "cite_spans": [], "ref_spans": []}, {"section": "Statistical methods", "text": "All statistical analyses and graphical representations were performed with R (R version 2.12.1) including the packages geepack for calculating GEE, psych, Hmisc for basic statistics and plotrix and gplots for graphic generation. All results from R were validated using SPSS 18 (SPSS, Chicago, IL, USA). Graphical presentations were prepared using Adobe Illustrator CS5 (Adobe Systems, Munich, Germany).", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Cohort Description", "text": "In this study, we included nine patients with a genetically diagnosed SCA1 and compared them to a gender-and agematched cohort of nine healthy controls. Demographic parameters of the investigated cohorts and the clinical results of the SARA score, VEP, visual acuity, refractive error and the number of repeats in the polyglutamine trace of the ATXN1 alleles are summarized in table 1. Due to the small sample size and the pilot character of this study, an additional overview with single patient profiles is given in table 2. The difference in age between the groups was not significant (Mann-Whitney U test, p = 0.93).", "cite_spans": [], "ref_spans": []}, {"section": "Cohort Description", "text": "SARA scores for SCA1 patients ranged from 5 to 28 with a median of 15 and the mean disease duration was 13.1 years, ranging from 3 to 30 years. A general tendency towards higher SARA scores for longer disease duration was visible (figure 3A) but did not reach a significant level for the correlation (Spearman's Rho = 0.64, p = 0.061). Seven SCA1 patients provided trinucleotide repeat numbers of the glutamine encoding part of the diseased ATXN1 allele (mean = 48.1, SD = 2.9) and, in addition, six of the patients could provide the repeat numbers of the unaffected allele (mean = 30.7, SD = 1.8).", "cite_spans": [], "ref_spans": []}, {"section": "Cohort Description", "text": "Refractive error of patients (mean = 20.68D, SD = 1.33D, Range = 22.90 -1.84D) and healthy controls (mean = 0.19D, SD = 1.50D, Range = 21.67 -3.95D) did not differ significantly (GEE: p = 0.20). One patient and the corresponding healthy control had to be excluded due to high refractive error.", "cite_spans": [], "ref_spans": []}, {"section": "Cohort Description", "text": "The visual acuity of SCA1 patients (mean = 0.54, SD = 0.32) was significantly reduced (GEE: p = 0.003) compared to healthy controls (0.86, SD = 0.17).", "cite_spans": [], "ref_spans": []}, {"section": "Optical coherence tomography", "text": "All study subjects (n = 18) underwent an OCT examination for both eyes (36 eyes). For RNFLT, two eyes from SCA1 patients were excluded from further analysis: one right eye due to bad image quality and one left eye due to blindness (post operation of eye tumor). RNFLT was separated as depicted in figure 1C . The total average RNFLT (G) of SCA1 patients was significantly reduced compared to healthy controls (84.0612.7 mm vs. 97.267.7 mm, GEE: p = 0.004). RNFL thinning was predominant and significant in temporal sectors (TS: p = 0.005, T: p,0.001, TI: p,0.001) and was not found in nasal sectors (NS: p = 0.480, N: figure 1A) . The most pronounced thinning was found in the temporal-inferior and temporal sectors. When comparing the complete RNFLT profile of both study cohorts (figure 1B), the regional degeneration of the temporal retinal nerve fiber layer became apparent.", "cite_spans": [], "ref_spans": [{"start": 297, "end": 306, "text": "figure 1C", "ref_id": "FIGREF0"}, {"start": 618, "end": 628, "text": "figure 1A)", "ref_id": "FIGREF0"}]}, {"section": "Optical coherence tomography", "text": "The Spectralis device provided a normative database that was used to compare the individual results of the RNFLT sectors to a large cohort of healthy controls. RNFL thickness below 5% of the normative database controls was colored in yellow, while sectors in red indicated values in the 1%-percentile. The normal range of RNFLT values was defined as the 95%-percentile and was colored in green ( figure 1C gives an example). Two patients did not have any sectors below the 5%-border while the rest exhibited at least one sector below the normal range. Three patients showed RNFLT values below 1% of the normative database for one or more sectors. Table 3 summarized the occurrence of classifications for the different sectors. In contrast, only a single sector of one healthy control was in the 5%-percentile.", "cite_spans": [], "ref_spans": [{"start": 396, "end": 405, "text": "figure 1C", "ref_id": "FIGREF0"}]}, {"section": "Optical coherence tomography", "text": "The mean thickness profiles of the additional retinal layers for both study cohorts are shown in figure 2B . None of the additional layers revealed apparent differences between the groups. When averaging all layer profiles in sectors (data not shown), only the thickness of the NS sector of the ganglion cell and inner plexiform layer showed a reduction in SCA1 patients (GEE: p = 0.001).", "cite_spans": [], "ref_spans": [{"start": 97, "end": 106, "text": "figure 2B", "ref_id": "FIGREF1"}]}, {"section": "Optical coherence tomography", "text": "Some patients with a distinct nystagmus or uncontrolled head movements were not able to complete the more demanding macular volume scans. Therefore, only 11 eyes of the SCA1 cohort could be analyzed. One TMV measurement of a healthy control had to be excluded due to an erroneous scan. Thus, only the related subjects from the matched group of healthy controls were considered for the cohort comparison. SCA1 patients showed a not significant reduction of the TMV (SCA1: mean = 8. ", "cite_spans": [], "ref_spans": []}, {"section": "VEP", "text": "For 11 eyes from 6 SCA1 patients VEPs could be acquired in sufficient quality and compared to VEPs of the corresponding healthy controls. None of the participants showed a pathologic increase in latency of the P100 peak and no significant difference between the cohorts was detected (SCA1: mean = 102.9 ms (SD = 5.6 ms) vs. HC: mean = 102.4 ms (SD = 3.3 ms), GEE: p = 0.69).", "cite_spans": [], "ref_spans": []}, {"section": "VEP", "text": "Correlation of RNFLT with disease duration,SARA score and visual acuity Next, OCT findings were correlated with disease duration and disease severity measured by SARA score. When comparing RNFLT (G) with SARA score and disease duration, GEEs for both were not significant (SARA: p = 0.073, duration: p = 0.098). Scatter plots of RNFLT with SARA score and disease duration are given in figures 3B and 3C, respectively, proposing a possible trend for a correlation of RNFLT with SARA score. Figure 3D show the correlation of the visual acuity with RNFLT (G) for SCA1 patients (red) and healthy controls (blue) with no significant correlations between the combined cohorts (GEE: p = 0.46).", "cite_spans": [], "ref_spans": [{"start": 489, "end": 498, "text": "Figure 3D", "ref_id": "FIGREF3"}]}, {"section": "Discussion", "text": "This is the first study investigating retinal involvement in SCA1 patients using optical coherence tomography. We found a pattern of temporal atrophy of the retinal nerve fiber layer in most patients. Layer segmentation analysis confirmed temporal RNFLT reduction whereas no significant differences were seen in average of ganglion cell layer, inner and outer plexiform layer, photoreceptor layer and pigment epithelium. In sector analysis of layers only the NS sector of the ganglion cell and inner plexiform layer showed a reduction in SCA1 patients. Two patients (table 2, cases 6 and 8) displayed no significant RNFLT changes. The patient with longest disease duration (30 years; table 2, case no. 2) and highest SARA score (28) showed additional severe macular atrophy. However, in this patient RNFLT reduction was very prominent, indicating that in late stage disease nerve fiber atrophy could lead to ganglion cell degeneration and consecutively to macular volume reduction. Although a reduction of retinal nerve fiber layer thickness was not present in each individual SCA1 patient, a correlation trend of RNFLT with disease duration and severity was seen. In contrast to OCT, VEP P100 latencies were not able to detect changes in our patients. However, since VEP amplitudes correlate better with axonal loss but were not analyzable in our small sample size due to high inter-and intrasubject variability, we might have missed a significant difference, which might be shown in a larger cohort. Strengths of the study are the prospective design, the matched control group and the use of spectral domain OCT with layer segmentation analysis. The used OCT device provides an eye tracking function that registers OCT scans to a fundus image and thereby reduces the effects of eye movement during scans. This function makes the application of OCT examination and especially of 3D volume scans possible for patients with severe head ataxia or eye movement abnormalities. However, in several patients this correction was not sufficient, leading to missing scans in the demanding macular volume scans. Another weakness of the study is the low sample size which is owed to the rarity of the disease and the severe disability of many patients. Most likely this contributed to not significant changes to macular volumes and correlations to SARA score or disease duration.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "Interestingly, the consistent pattern of selective temporal RNFLT reduction in our study prompts the question of pathophysiologic relevance. One explanation could be that RNFLT analysis enables early detection of incipient optic atrophy in SCA1 since a temporal emphasis of RNFLT reduction is found in a variety of diseases associated with optic nerve atrophy. These conditions comprise post neuritic optic atrophy in multiple sclerosis [16] [20], hereditary optic atrophies such as dominant optic atrophy (DOA) and Leber's hereditary optic neuropathy (LHON) and toxic optic atrophies. However VEP did not detect optic atrophy in our study with all the drawbacks discussed above. But also previous studies using VEP did not find optic nerve involvement to such an extent as our results would suggest [9] [10] .", "cite_spans": [{"start": 437, "end": 441, "text": "[16]", "ref_id": "BIBREF15"}, {"start": 800, "end": 803, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 804, "end": 808, "text": "[10]", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "Discussion", "text": "Selective temporal RNFLT involvement could be explained pathophysiologically by a differential vulnerability of retinal axons to mutated ataxin1.The temporal quadrant of the retinal nerve fiber layer is built primarily by parvo-cellular axons from the papillo-macular bundle. These fibers consist of smaller, thinly myelinated axons with rapid firing rates which serve the visual functions of high resolution visual acuity, color vision and high spatial frequency of contrast sensitivity. On the other hand, magno-cellular ganglion cell axons and photoreceptors which are both distributed evenly throughout the retina seem relatively unaffected from damage. Magno-cellular ganglion cells have thicker axons with lower firing rate and serve low-spatialfrequency contrast sensitivity and motion stereopsis.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "Other diseases with primary involvement of parvocellular axons comprise the so called non-syndromic mitochondrial optic neuropathies such as Leber's hereditary optic neuropathy (LHON) and OPA1 related dominant optic nerve atrophy (DOA) and toxic and nutritional optic neuropathies such as tobacco-alcohol amblyopia or ethambutol-induced optic neuropathy [21] .", "cite_spans": [{"start": 354, "end": 358, "text": "[21]", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "Discussion", "text": "As common etiologic pathway of such disparate diseases the disruption of mechanisms participating in the correction of oxidative stress with primary insult to mitochondria is discussed [21] [22] . Due to their small volume and fast firing response, parvo-cellular axons may be more susceptible to energy depletion by defective oxidative phosphorylation resulting from vitamin depletion or mutations affecting mitochondrial function.", "cite_spans": [{"start": 185, "end": 189, "text": "[21]", "ref_id": "BIBREF20"}, {"start": 190, "end": 194, "text": "[22]", "ref_id": "BIBREF21"}], "ref_spans": []}, {"section": "Discussion", "text": "In SCA1, nuclear and cytosolic protein aggregates are associated with neurodegeneration of cerebellar Purkinje neurons. Although many protein interaction partners of ataxin1 have been RNFLT results were obtained from 9 SCA1 and compared to 9 age/sex matched healthy controls (HC). 2 eyes of SCA1 patients had to be excluded, one left eye due to blindness and one right eye because of errors in the OCT image. In total, 11 eyes of SCA1 patients fulfilled quality criteria for the TMV scan and were compared to the corresponding eyes of the matching healthy controls. doi:10.1371/journal.pone.0023024.t004", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "identified and its impact on transcriptional dysregulation has been stated, the clear pathophysiologic processes leading to cell death remain to be elucidated [3] . Few hints point towards impeded antioxidant mechanisms such as reduced Cu/ZnSOD dismutase activity with subsequent accumulation of reactive oxygen species in the disease process [23] . Hypothetically the patchy pattern of temporal RNFLT reduction seen in our patients could be caused by localised breakdown of oxidative defense mechanisms.", "cite_spans": [{"start": 159, "end": 162, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 343, "end": 347, "text": "[23]", "ref_id": "BIBREF22"}], "ref_spans": []}, {"section": "Discussion", "text": "In terms of retinal damage other previously examined ataxia disorders such as Friedreich's ataxia and neuropathy ataxia retinitis pigmentosa (NARP) belonging to the group of syndromic mitochondriopathies present with more general retinal thinning [24] [25] . One explanation could be the disruption of complex I, II and III as compared to only complex I in the non-syndromic mitochondrial neuropathies [22] . However, the role of respiratory chain complexes in SCA1 is not clear yet.", "cite_spans": [{"start": 247, "end": 251, "text": "[24]", "ref_id": "BIBREF23"}, {"start": 252, "end": 256, "text": "[25]", "ref_id": "BIBREF24"}, {"start": 402, "end": 406, "text": "[22]", "ref_id": "BIBREF21"}], "ref_spans": []}, {"section": "Discussion", "text": "In SCA7, along with a peripheral RNFLT reduction even a sparing of the temporal sector has been observed in RNFLT measurements resembling the pattern in other retinal dystrophies such as retinitis pigmentosa [26] . Key to understanding the complementary findings could be the diverse function of ataxin 1 and ataxin7. In SCA7 a pronounced retinal cone-rod dystrophy associated with visual loss is a characteristic feature especially in early disease stages. Additionally in late stage disease a maculopathy can evolve ('bull's eye' maculopathy) [27] . In transgenic mice it has been shown that ataxin 7 can suppress a cone-rod homebox protein transactivation in retinal photoreceptor cells thus controlling expression level of several photoreceptorspecific genes such as rhodopsin [28] . The relative sparing of the temporal sector has been discussed as possible result of the relative sparing of the inner macula around the central fovea associated with normal ganglion cell layer thickness of the peripapillary temporal quadrant in earlier disease stage [6] .", "cite_spans": [{"start": 208, "end": 212, "text": "[26]", "ref_id": "BIBREF25"}, {"start": 545, "end": 549, "text": "[27]", "ref_id": "BIBREF26"}, {"start": 781, "end": 785, "text": "[28]", "ref_id": "BIBREF27"}, {"start": 1056, "end": 1059, "text": "[6]", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Discussion", "text": "These distinct patterns raise the question whether OCT may serve a purpose in differential diagnosis in ataxia disorders, a topic yet to be addressed by examination of larger patient cohorts composed of different ataxia disorders in direct comparison. Additionally larger studies should allow more precise layer segmentation analysis. A longitudinal study design could also serve to evaluate potential use of RNFLT as non invasive disease progression marker.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Autosomal dominant cerebellar ataxias: clinical features, genetics, and pathogenesis", "authors": [{"first": "L", "middle": [], "last": "Sch\u00f6ls", "suffix": ""}, {"first": "P", "middle": [], "last": "Bauer", "suffix": ""}, {"first": "T", "middle": [], "last": "Schmidt", "suffix": ""}, {"first": "T", "middle": [], "last": "Schulte", "suffix": ""}, {"first": "O", "middle": [], "last": "Riess", "suffix": ""}], "year": 2004, "venue": "Lancet Neurol", "link": "23982743"}, "BIBREF1": {"title": "Identification and characterization of the gene causing type 1 spinocerebellar ataxia", "authors": [{"first": "S", "middle": [], "last": "Banfi", "suffix": ""}, {"first": "A", "middle": [], "last": "Servadio", "suffix": ""}, {"first": "M", "middle": ["Y"], "last": "Chung", "suffix": ""}, {"first": "T", "middle": ["J"], "last": "Kwiatkowski", "suffix": ""}, {"first": "A", "middle": ["E"], "last": "Mccall", "suffix": ""}], "year": 1994, "venue": "Nat. Genet", "link": "32479936"}, "BIBREF2": {"title": "Molecular pathogenesis of spinocerebellar ataxia type 1 disease", "authors": [{"first": "S", "middle": [], "last": "Kang", "suffix": ""}, {"first": "S", "middle": [], "last": "Hong", "suffix": ""}], "year": 2009, "venue": "Mol. Cells", "link": "207047842"}, "BIBREF3": {"title": "The clinical features and classification of the late onset autosomal dominant cerebellar ataxias. A study of 11 families, including descendants of the 'the Drew family of Walworth", "authors": [{"first": "A", "middle": ["E"], "last": "Harding", "suffix": ""}], "year": 1982, "venue": "Brain", "link": "31855523"}, "BIBREF4": {"title": "Neuroophthalmologic features of spinocerebellar ataxia type 7", "authors": [{"first": "R", "middle": ["C"], "last": "Miller", "suffix": ""}, {"first": "A", "middle": [], "last": "Tewari", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Miller", "suffix": ""}, {"first": "J", "middle": [], "last": "Garbern", "suffix": ""}, {"first": "G", "middle": ["P"], "last": "Van Stavern", "suffix": ""}], "year": 2009, "venue": "J Neuroophthalmol", "link": "43154258"}, "BIBREF5": {"title": "Ophthalmic features of spinocerebellar ataxia type 7", "authors": [{"first": "R", "middle": ["K"], "last": "Manrique", "suffix": ""}, {"first": "S", "middle": [], "last": "Noval", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Aguilar-Amat", "suffix": ""}, {"first": "J", "middle": [], "last": "Arpa", "suffix": ""}, {"first": "I", "middle": [], "last": "Rosa", "suffix": ""}], "year": 2009, "venue": "J Neuroophthalmol", "link": "20647853"}, "BIBREF6": {"title": "Ophthalmological findings in patients with spinocerebellar ataxia type 1 are not correlated with neurological anticipation", "authors": [{"first": "T", "middle": [], "last": "Abe", "suffix": ""}, {"first": "K", "middle": [], "last": "Abe", "suffix": ""}, {"first": "T", "middle": [], "last": "Tsuda", "suffix": ""}, {"first": "Y", "middle": [], "last": "Itoyama", "suffix": ""}, {"first": "M", "middle": [], "last": "Tamai", "suffix": ""}], "year": 2001, "venue": "Graefes Arch. Clin. Exp. Ophthalmol", "link": "39978062"}, "BIBREF7": {"title": "Ocular changes in patients with spinocerebellar degeneration and repeated trinucleotide expansion of spinocerebellar ataxia type 1 gene", "authors": [{"first": "T", "middle": [], "last": "Abe", "suffix": ""}, {"first": "K", "middle": [], "last": "Abe", "suffix": ""}, {"first": "M", "middle": [], "last": "Aoki", "suffix": ""}, {"first": "Y", "middle": [], "last": "Itoyama", "suffix": ""}, {"first": "M", "middle": [], "last": "Tamai", "suffix": ""}], "year": 1997, "venue": "Arch. Ophthalmol", "link": "24397133"}, "BIBREF8": {"title": "Autosomal dominant cerebellar ataxia type I. Nerve conduction and evoked potential studies in families with SCA1, SCA2 and SCA3", "authors": [{"first": "M", "middle": [], "last": "Abele", "suffix": ""}, {"first": "K", "middle": [], "last": "B\u00fcrk", "suffix": ""}, {"first": "F", "middle": [], "last": "Andres", "suffix": ""}, {"first": "H", "middle": [], "last": "Topka", "suffix": ""}, {"first": "F", "middle": [], "last": "Laccone", "suffix": ""}], "year": 1997, "venue": "Brain", "link": null}, "BIBREF9": {"title": "Autosomal dominant cerebellar ataxia type I: multimodal electrophysiological study and comparison between SCA1 and SCA2 patients", "authors": [{"first": "A", "middle": [], "last": "Perretti", "suffix": ""}, {"first": "L", "middle": [], "last": "Santoro", "suffix": ""}, {"first": "B", "middle": [], "last": "Lanzillo", "suffix": ""}, {"first": "A", "middle": [], "last": "Filla", "suffix": ""}, {"first": "G", "middle": [], "last": "De Michele", "suffix": ""}], "year": 1996, "venue": "J. Neurol. Sci", "link": "41003593"}, "BIBREF10": {"title": "Structural and immunocytochemical features of olivopontocerebellar atrophy caused by the spinocerebellar ataxia type 1 (SCA-1) mutation define a unique phenotype", "authors": [{"first": "Y", "middle": [], "last": "Robitaille", "suffix": ""}, {"first": "L", "middle": [], "last": "Schut", "suffix": ""}, {"first": "S", "middle": ["J"], "last": "Kish", "suffix": ""}], "year": 1995, "venue": "Acta Neuropathol", "link": "24645776"}, "BIBREF11": {"title": "Recent developments in optical coherence tomography for imaging the retina", "authors": [{"first": "Mej", "middle": [], "last": "Van Velthoven", "suffix": ""}, {"first": "D", "middle": ["J"], "last": "Faber", "suffix": ""}, {"first": "F", "middle": ["D"], "last": "Verbraak", "suffix": ""}, {"first": "T", "middle": ["G"], "last": "Van Leeuwen", "suffix": ""}, {"first": "M", "middle": ["D"], "last": "De Smet", "suffix": ""}], "year": 2007, "venue": "Prog Retin Eye Res", "link": null}, "BIBREF12": {"title": "Optical coherence tomography in multiple sclerosis: a systematic review and metaanalysis", "authors": [{"first": "A", "middle": [], "last": "Petzold", "suffix": ""}, {"first": "J", "middle": ["F"], "last": "De Boer", "suffix": ""}, {"first": "S", "middle": [], "last": "Schippling", "suffix": ""}, {"first": "P", "middle": [], "last": "Vermersch", "suffix": ""}, {"first": "R", "middle": [], "last": "Kardon", "suffix": ""}], "year": 2010, "venue": "Lancet Neurol", "link": null}, "BIBREF13": {"title": "Primary retinal pathology in multiple sclerosis as detected by optical coherence tomography", "authors": [{"first": "S", "middle": [], "last": "Saidha", "suffix": ""}, {"first": "S", "middle": ["B"], "last": "Syc", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Ibrahim", "suffix": ""}, {"first": "C", "middle": [], "last": "Eckstein", "suffix": ""}, {"first": "C", "middle": ["V"], "last": "Warner", "suffix": ""}], "year": 2011, "venue": "Brain", "link": "8985715"}, "BIBREF14": {"title": "Morphologic changes and functional retinal impairment in patients with Parkinson disease without visual loss", "authors": [{"first": "M", "middle": ["M"], "last": "Moschos", "suffix": ""}, {"first": "G", "middle": [], "last": "Tagaris", "suffix": ""}, {"first": "I", "middle": [], "last": "Markopoulos", "suffix": ""}, {"first": "I", "middle": [], "last": "Margetis", "suffix": ""}, {"first": "S", "middle": [], "last": "Tsapakis", "suffix": ""}], "year": 2011, "venue": "Eur J Ophthalmol", "link": "20625499"}, "BIBREF15": {"title": "Retinal nerve fiber layer structure abnormalities in early Alzheimer's disease: evidence in optical coherence tomography", "authors": [{"first": "Y", "middle": [], "last": "Lu", "suffix": ""}, {"first": "Z", "middle": [], "last": "Li", "suffix": ""}, {"first": "X", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "B", "middle": [], "last": "Ming", "suffix": ""}, {"first": "J", "middle": [], "last": "Jia", "suffix": ""}], "year": 2010, "venue": "Neurosci. Lett", "link": "32642536"}, "BIBREF16": {"title": "Patterns of retinal nerve fiber layer loss in multiple sclerosis patients with or without optic neuritis and glaucoma patients", "authors": [{"first": "M", "middle": [], "last": "Bock", "suffix": ""}, {"first": "A", "middle": ["U"], "last": "Brandt", "suffix": ""}, {"first": "J", "middle": [], "last": "D\u00f6rr", "suffix": ""}, {"first": "H", "middle": [], "last": "Kraft", "suffix": ""}, {"first": "N", "middle": [], "last": "Weinges-Evers", "suffix": ""}], "year": 2010, "venue": "Clin Neurol Neurosurg", "link": "22935128"}, "BIBREF17": {"title": "Scale for the assessment and rating of ataxia: development of a new clinical scale", "authors": [{"first": "T", "middle": [], "last": "Schmitz-H\u00fcbsch", "suffix": ""}, {"first": "S", "middle": ["T"], "last": "Du Montcel", "suffix": ""}, {"first": "L", "middle": [], "last": "Baliko", "suffix": ""}, {"first": "J", "middle": [], "last": "Berciano", "suffix": ""}, {"first": "S", "middle": [], "last": "Boesch", "suffix": ""}], "year": 2006, "venue": "Neurology", "link": "24069559"}, "BIBREF18": {"title": "Retinal Nerve Fiber Layer Segmentation on FD-OCT Scans of Normal Subjects and Glaucoma Patients", "authors": [{"first": "M", "middle": ["A"], "last": "Mayer", "suffix": ""}, {"first": "J", "middle": [], "last": "Hornegger", "suffix": ""}, {"first": "C", "middle": ["Y"], "last": "Mardin", "suffix": ""}, {"first": "R", "middle": ["P"], "last": "Tornow", "suffix": ""}], "year": "", "venue": "Biomed Opt Express", "link": "18528041"}, "BIBREF19": {"title": "Correlation between functional and structural assessments of the optic nerve and retina in multiple sclerosis patients", "authors": [{"first": "C", "middle": [], "last": "Almarcegui", "suffix": ""}, {"first": "I", "middle": [], "last": "Dolz", "suffix": ""}, {"first": "V", "middle": [], "last": "Pueyo", "suffix": ""}, {"first": "E", "middle": [], "last": "Garcia", "suffix": ""}, {"first": "F", "middle": [], "last": "Fernandez", "suffix": ""}], "year": 2010, "venue": "Neurophysiologie Clinique/Clinical Neurophysiology", "link": "36952823"}, "BIBREF20": {"title": "Optic nerve degeneration and mitochondrial dysfunction: genetic and acquired optic neuropathies", "authors": [{"first": "V", "middle": [], "last": "Carelli", "suffix": ""}, {"first": "F", "middle": ["N"], "last": "Ross-Cisneros", "suffix": ""}, {"first": "A", "middle": ["A"], "last": "Sadun", "suffix": ""}], "year": 2002, "venue": "Neurochem. Int", "link": "22161913"}, "BIBREF21": {"title": "Mitochondrial dysfunction as a cause of optic neuropathies", "authors": [{"first": "V", "middle": [], "last": "Carelli", "suffix": ""}, {"first": "F", "middle": ["N"], "last": "Ross-Cisneros", "suffix": ""}, {"first": "A", "middle": ["A"], "last": "Sadun", "suffix": ""}], "year": 2004, "venue": "Prog Retin Eye Res", "link": "15862778"}, "BIBREF22": {"title": "Polyglutamine-expanded ataxin-1 recruits Cu/Zn-superoxide dismutase into the nucleus of HeLa cells", "authors": [{"first": "S", "middle": [], "last": "Kim", "suffix": ""}, {"first": "T", "middle": [], "last": "Kim", "suffix": ""}, {"first": "I", "middle": ["Y"], "last": "Kim", "suffix": ""}, {"first": "S", "middle": [], "last": "Hong", "suffix": ""}, {"first": "H", "middle": [], "last": "Rhim", "suffix": ""}], "year": 2003, "venue": "Biochem. Biophys. Res. Commun", "link": "31287963"}, "BIBREF23": {"title": "Visual system involvement in patients with Friedreich's ataxia", "authors": [{"first": "F", "middle": [], "last": "Fortuna", "suffix": ""}, {"first": "P", "middle": [], "last": "Barboni", "suffix": ""}, {"first": "R", "middle": [], "last": "Liguori", "suffix": ""}, {"first": "M", "middle": ["L"], "last": "Valentino", "suffix": ""}, {"first": "G", "middle": [], "last": "Savini", "suffix": ""}], "year": 2009, "venue": "Brain", "link": "16060850"}, "BIBREF24": {"title": "Heterogeneous patterns of tissue injury in NARP syndrome", "authors": [{"first": "J", "middle": ["M"], "last": "Gelfand", "suffix": ""}, {"first": "J", "middle": ["L"], "last": "Duncan", "suffix": ""}, {"first": "C", "middle": ["A"], "last": "Racine", "suffix": ""}, {"first": "L", "middle": ["A"], "last": "Gillum", "suffix": ""}, {"first": "C", "middle": ["T"], "last": "Chin", "suffix": ""}], "year": 2010, "venue": "J Neurol", "link": "5212899"}, "BIBREF25": {"title": "Retinal nerve fiber layer defects in RP patients", "authors": [{"first": "S", "middle": [], "last": "Walia", "suffix": ""}, {"first": "G", "middle": ["A"], "last": "Fishman", "suffix": ""}, {"first": "D", "middle": ["P"], "last": "Edward", "suffix": ""}, {"first": "M", "middle": [], "last": "Lindeman", "suffix": ""}], "year": 2007, "venue": "Invest. Ophthalmol. Vis. Sci", "link": "27381585"}, "BIBREF26": {"title": "Ocular findings in spinocerebellar ataxia 7", "authors": [{"first": "M", "middle": ["E"], "last": "Mclaughlin", "suffix": ""}, {"first": "T", "middle": ["P"], "last": "Dryja", "suffix": ""}], "year": 2002, "venue": "Arch. Ophthalmol", "link": "19197825"}, "BIBREF27": {"title": "Polyglutamine-Expanded Ataxin-7 Antagonizes CRX Function and Induces Cone-Rod Dystrophy in a Mouse Model of SCA7", "authors": [{"first": "La", "middle": [], "last": "Spada", "suffix": ""}, {"first": "A", "middle": ["R"], "last": "Fu", "suffix": ""}, {"first": "Y", "middle": [], "last": "Sopher", "suffix": ""}, {"first": "B", "middle": ["L"], "last": "Libby", "suffix": ""}, {"first": "R", "middle": ["T"], "last": "Wang", "suffix": ""}, {"first": "X", "middle": [], "last": "", "suffix": ""}], "year": 2001, "venue": "Neuron", "link": "51784415"}}, "ref_entries": {"FIGREF0": {"text": "Figure 1. Differences of RNFLT between SCA1 and HC. (A) Average RNFLT (in mm) of the total ring scan (G) and in the different sectors (nasal-superior (NS), nasal (N), nasal-inferior (NI), temporal-inferior (TI), temporal (T) and temporal-superior (TS)). Error bars indicate standard deviation. Significance levels (*** for p,0.001, ** for p,0.01 and * for p,0.05) were calculated by GEE. (B) Mean RNFLT profile of both study groups in mm. (C) Both eyes (OD = right, OS = left) of a sample patient (upper line) with typical RNFLT sectors in comparison with matched healthy control (bottom line). The colors of the sectors are related to the comparison with the Spectralis normative database. Green indicates thickness values within the 95%-percentile of the database, while sectors in yellow were thinner than the 5%-percentile of the normative database and sectors in red were within the lowest 1%. doi:10.1371/journal.pone.0023024.g001", "type": "figure"}, "FIGREF1": {"text": "Figure 2. Segmentation of retinal layers. (A) Sample ring scan with additional layer segmentation. Layers from top: Nerve fiber layer (NFL), ganglion cell layer (GCL), inner plexiform layer (IPL), inner nuclear layer (INL), outer plexiform layer (OPL), outer nuclear layer (ONL), photoreceptor layer (PRL) and retinal pigment epithelium (RPE). (B) Comparison of the mean thickness of the additional retinal layers between healthy controls (in blue) and SCA1 patients (in red). doi:10.1371/journal.pone.0023024.g002", "type": "figure"}, "FIGREF3": {"text": "Figure 3. Correlation of clinical parameters with RNFLT. (A) Dependency of disease duration to SARA score. RNFLT with respect to SARA score (B), disease duration (C) and visual acuity (D) for SCA1 patients (red) and healthy controls (blue). doi:10.1371/journal.pone.0023024.g003", "type": "figure"}, "FIGREF4": {"text": "Comparison of RNFLT results to the Spectralis normative Database.Temporal (T) [mm] N eyes classified ,5% 2 0 N eyes classified ,1% 1 0 RNFLT Temporal-Superior (TS) [mm] N eyes classified ,5% 4 0 N eyes classified ,1% 2 0 doi:10.1371/journal.pone.0023024.t003", "type": "figure"}, "TABREF0": {"text": "Demographic information and clinical of the patient cohort (SCA1) and the matched healthy controls group (HC).Results for the VEP examination were available for 6 SCA1 patients and of 5 of the matching healthy controls. For 1 SCA1 patients repeat length of the diseased allele were missing and 2 patients lack values for the healthy allele and 1 patient had no examination of the visual acuity. doi:10.1371/journal.pone.0023024.t001", "type": "table"}, "TABREF1": {"text": "Single case reports of SCA1 patients.", "type": "table"}, "TABREF2": {"text": "OCT examination results.", "type": "table"}}}
{"paper_id": "10703598", "_pdf_hash": "c82bd89005fd66dc5a1bf400ae161060e7759289", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Pattern Recognition with Fuzzy Objective Function Algorithms", "authors": [{"first": "J", "middle": ["C"], "last": "Bezdek", "suffix": ""}], "year": 1981, "venue": "", "link": "30806637"}, "BIBREF1": {"title": "Determining the feature relevance for nonclassically described objects and a new algorithm to compute typical fuzzy testors", "authors": [{"first": "M", "middle": [], "last": "Lazo-Cort\u00e9s", "suffix": ""}, {"first": "J", "middle": [], "last": "Ruiz-Shulcloper", "suffix": ""}], "year": 1995, "venue": "Pattern Recognition Letters", "link": "9968165"}, "BIBREF2": {"title": "A global solution for the use of testors in Pattern Recognition problems, Memorias del III Taller Iberoamericano de Reconocimiento de Patrones", "authors": [{"first": "E", "middle": [], "last": "Alba-Cabrera", "suffix": ""}, {"first": "M", "middle": [], "last": "Lazo-Cort\u00e9s", "suffix": ""}], "year": 1997, "venue": "", "link": null}, "BIBREF3": {"title": "Fuzzy semantic clustering", "authors": [{"first": "J", "middle": [], "last": "Fco", "suffix": ""}, {"first": "J", "middle": [], "last": "Mart\u00ednez-Trinidad", "suffix": ""}, {"first": "", "middle": [], "last": "Ruiz-Shulcloper", "suffix": ""}], "year": 1996, "venue": "Proceedings of the Fourth European Congress on Intelligent Techniques and Soft Computing", "link": null}, "BIBREF4": {"title": "On the construction of similarity measure that does not fulfill the redundant symmetric property", "authors": [{"first": "E", "middle": ["D"], "last": "Moskalienskii", "suffix": ""}], "year": 1984, "venue": "Computational Methods of Geology", "link": null}, "BIBREF5": {"title": "On classification similarity functions between objects described in Boolean variables", "authors": [{"first": "E", "middle": ["D"], "last": "Moskalienskii", "suffix": ""}, {"first": "Y", "middle": ["B"], "last": "Chinaiev", "suffix": ""}], "year": 1984, "venue": "Computational Methods of Geology", "link": null}, "BIBREF6": {"title": "A new model of f uzzy clustering algorithms", "authors": [{"first": "J", "middle": [], "last": "Ruiz-Shulcloper", "suffix": ""}, {"first": "J", "middle": ["J"], "last": "Montellano-Ballesteros", "suffix": ""}], "year": 1995, "venue": "Proceedings of the Third European Congress on Fuzzy and Intelligent Technologies and Soft Computing", "link": null}, "BIBREF7": {"title": "A new approach to fuzzy clustering", "authors": [{"first": "J", "middle": [], "last": "Ruiz-Shulcloper", "suffix": ""}, {"first": "J", "middle": ["J"], "last": "Montellano-Ballesteros", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF8": {"title": "A new approach to clustering", "authors": [{"first": "E", "middle": [], "last": "Ruspini", "suffix": ""}], "year": 1969, "venue": "", "link": "16158382"}, "BIBREF9": {"title": "Multidimensional scaling in Minkowski space", "authors": [{"first": "Y", "middle": [], "last": "Sato", "suffix": ""}], "year": 1992, "venue": "Hokkaido Behavioral Science Report, Series M", "link": null}, "BIBREF10": {"title": "Extended fuzzy clustering models for asymmetric similarity", "authors": [{"first": "M", "middle": [], "last": "Sato", "suffix": ""}, {"first": "Y", "middle": [], "last": "Sato", "suffix": ""}], "year": 1995, "venue": "Fuzzy Logic and Soft Computing. (Advances in Fuzzy Systems-Applications and Theory", "link": "123220448"}, "BIBREF11": {"title": "Features of similarity", "authors": [{"first": "P", "middle": [], "last": "Tversky", "suffix": ""}], "year": 1977, "venue": "Psychological Review", "link": "9173202"}, "BIBREF12": {"title": "Integer-valued problems of transforming the training tables in k-valued code in pattern recognition problems", "authors": [{"first": "V", "middle": [], "last": "Valev", "suffix": ""}, {"first": "Y", "middle": ["I"], "last": "Zhuravliov", "suffix": ""}], "year": 1991, "venue": "Pattern Recognition", "link": "37376606"}}, "ref_entries": {}}
{"paper_id": "10703903", "_pdf_hash": "95b96ff38f9db6838160d77f4fb0ff46438c8531", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Conversational impliciture. Mind & Language", "authors": [{"first": "K", "middle": [], "last": "Bach", "suffix": ""}], "year": 1994, "venue": "", "link": null}, "BIBREF1": {"title": "Knowledge in and out of context", "authors": [{"first": "K", "middle": [], "last": "Bach", "suffix": ""}], "year": 2010, "venue": "Topics in contemporary philosophy", "link": "147997638"}, "BIBREF2": {"title": "WAMs: Why worry? Philosophical Papers", "authors": [{"first": "P", "middle": [], "last": "Baumann", "suffix": ""}], "year": 2011, "venue": "", "link": null}, "BIBREF3": {"title": "Knowledge and implicatures", "authors": [{"first": "M", "middle": [], "last": "Blome-Tillmann", "suffix": ""}], "year": 2013, "venue": "Synthese", "link": "26904684"}, "BIBREF4": {"title": "The myth of knowledge", "authors": [{"first": "L", "middle": [], "last": "Bonjour", "suffix": ""}], "year": 2010, "venue": "Philosophical Perspectives", "link": "171053920"}, "BIBREF5": {"title": "Contextualism defended", "authors": [{"first": "S", "middle": [], "last": "Cohen", "suffix": ""}], "year": 2005, "venue": "Contemporary debates in epistemology. Contemporary debates in philosophy", "link": null}, "BIBREF6": {"title": "Contextualism contested", "authors": [{"first": "E", "middle": [], "last": "Conee", "suffix": ""}], "year": 2005, "venue": "Contemporary debates in epistemology. Contemporary debates in philosophy", "link": null}, "BIBREF7": {"title": "Contextualism contested some more", "authors": [{"first": "E", "middle": [], "last": "Conee", "suffix": ""}], "year": 2005, "venue": "Contemporary debates in epistemology. Contemporary debates in philosophy", "link": null}, "BIBREF8": {"title": "Are knowledge claims indexical?", "authors": [{"first": "W", "middle": ["A"], "last": "Davis", "suffix": ""}], "year": 2004, "venue": "Erkenntnis", "link": "189871908"}, "BIBREF9": {"title": "Knowledge claims and context: Loose use", "authors": [{"first": "W", "middle": ["A"], "last": "Davis", "suffix": ""}], "year": 2007, "venue": "Philosophical Studies", "link": "170657869"}, "BIBREF10": {"title": "The case for contextualism: Knowledge, skepticism, and context", "authors": [{"first": "W", "middle": ["A"], "last": "Davis", "suffix": ""}], "year": 2010, "venue": "", "link": null}, "BIBREF11": {"title": "Knowledge claims and context: Belief", "authors": [{"first": "W", "middle": ["A"], "last": "Davis", "suffix": ""}], "year": 2015, "venue": "Philosophical Studies", "link": "170192869"}, "BIBREF12": {"title": "The case for contextualism: Knowledge, skepticism, and context", "authors": [{"first": "K", "middle": [], "last": "Derose", "suffix": ""}], "year": 2009, "venue": "", "link": "171014455"}, "BIBREF13": {"title": "Replies to Nagel, Ludlow, and Fantl and McGrath", "authors": [{"first": "K", "middle": [], "last": "Derose", "suffix": ""}], "year": 2012, "venue": "Philosophy and Phenomenological Research", "link": "170772534"}, "BIBREF14": {"title": "Knowledge, conservatism, and pragmatics", "authors": [{"first": "P", "middle": [], "last": "Dimmock", "suffix": ""}, {"first": "T", "middle": [], "last": "Huvenes", "suffix": ""}], "year": 2014, "venue": "Synthese", "link": "9698321"}, "BIBREF15": {"title": "Epistemic invariantism and contextualist intuitions", "authors": [{"first": "A", "middle": [], "last": "Dinges", "suffix": ""}], "year": 2015, "venue": "Episteme, FirstView", "link": "145459577"}, "BIBREF16": {"title": "Innocent implicatures", "authors": [{"first": "A", "middle": [], "last": "Dinges", "suffix": ""}], "year": 2015, "venue": "Journal of Pragmatics", "link": null}, "BIBREF17": {"title": "A pragmatic dissolution of Harman's paradox", "authors": [{"first": "I", "middle": [], "last": "Douven", "suffix": ""}], "year": 2007, "venue": "Philosophy and Phenomenological Research", "link": "144127629"}, "BIBREF18": {"title": "Knowledge in an uncertain world", "authors": [{"first": "J", "middle": [], "last": "Fantl", "suffix": ""}, {"first": "M", "middle": [], "last": "Mcgrath", "suffix": ""}], "year": 2009, "venue": "", "link": "142725669"}, "BIBREF19": {"title": "On the cognitive basis of knowledge ascriptions", "authors": [{"first": "M", "middle": [], "last": "Gerken", "suffix": ""}], "year": 2012, "venue": "Knowledge ascriptions", "link": null}, "BIBREF20": {"title": "Studies in the way of words", "authors": [{"first": "P", "middle": [], "last": "Grice", "suffix": ""}], "year": 1989, "venue": "", "link": null}, "BIBREF21": {"title": "Experimenting on contextualism", "authors": [{"first": "N", "middle": [], "last": "Hansen", "suffix": ""}, {"first": "E", "middle": [], "last": "Chemla", "suffix": ""}], "year": 2013, "venue": "Mind & Language", "link": "145579075"}, "BIBREF22": {"title": "Knowledge and lotteries", "authors": [{"first": "J", "middle": [], "last": "Hawthorne", "suffix": ""}], "year": 2004, "venue": "", "link": "171955723"}, "BIBREF23": {"title": "The assessment sensitivity of knowledge attributions", "authors": [{"first": "J", "middle": [], "last": "Macfarlane", "suffix": ""}], "year": 2005, "venue": "Oxford studies in epistemology. Oxford studies in epistemology", "link": null}, "BIBREF24": {"title": "The Routledge companion to epistemology", "authors": [{"first": "J", "middle": [], "last": "Macfarlane", "suffix": ""}], "year": 2011, "venue": "", "link": null}, "BIBREF25": {"title": "Implicature", "authors": [{"first": "J", "middle": [], "last": "Meibauer", "suffix": ""}], "year": 2009, "venue": "Concise encyclopedia of pragmatics", "link": null}, "BIBREF26": {"title": "Skepticism, contextualism, and discrimination", "authors": [{"first": "J", "middle": [], "last": "Schaffer", "suffix": ""}], "year": 2004, "venue": "Philosophy and Phenomenological Research", "link": "15245598"}, "BIBREF27": {"title": "How to defeat opposition to Moore", "authors": [{"first": "E", "middle": [], "last": "Sosa", "suffix": ""}], "year": 1999, "venue": "Philosophical Perspectives", "link": "170606488"}, "BIBREF28": {"title": "A defense of skepticism", "authors": [{"first": "P", "middle": [], "last": "Unger", "suffix": ""}], "year": 1971, "venue": "The Philosophical Review", "link": null}}, "ref_entries": {}}
{"paper_id": "10703959", "_pdf_hash": "a019268a857bbd524e9db87dff58afb7bd246f6d", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Proposal for Territorial distribution of the EU 2020 political renewable energy goal", "authors": [{"first": "A", "middle": [], "last": "Tolon-Becerra", "suffix": ""}, {"first": "X", "middle": [], "last": "Lastra-Bravo", "suffix": ""}, {"first": "", "middle": [], "last": "Bienvenido-Barcena", "suffix": ""}], "year": 2011, "venue": "Renewable Energy", "link": "154726395"}, "BIBREF1": {"title": "Design of a cost-efficient solar energy based electrical power generation system for a remote Island-Pulau Perhentian Besar in Malaysia", "authors": [{"first": "M", "middle": [], "last": "Aghaei", "suffix": ""}, {"first": "M", "middle": [], "last": "Thayoob", "suffix": ""}, {"first": "Y", "middle": [], "last": "Hanum", "suffix": ""}, {"first": "M", "middle": [], "last": "Imamzai", "suffix": ""}, {"first": "P", "middle": [], "last": "Piyous", "suffix": ""}, {"first": "N", "middle": [], "last": "Amin", "suffix": ""}], "year": 2013, "venue": "Power Engineering and Optimization Conference (PEOCO)", "link": null}, "BIBREF2": {"title": "A review on the role of materials science in solar cells", "authors": [{"first": "N", "middle": [], "last": "Asim", "suffix": ""}, {"first": "K", "middle": [], "last": "Sopian", "suffix": ""}, {"first": "S", "middle": [], "last": "Ahmadi", "suffix": ""}, {"first": "K", "middle": [], "last": "Saeedfar", "suffix": ""}, {"first": "M", "middle": [], "last": "Alghoul", "suffix": ""}, {"first": "O", "middle": [], "last": "Saadatian", "suffix": ""}, {"first": "S", "middle": ["H"], "last": "Zaidi", "suffix": ""}], "year": 2012, "venue": "Renewable and Sustainable Energy Reviews", "link": "110237082"}, "BIBREF3": {"title": "Numerical Analysis of CdZnTe/CIGS Tandem Thin Film Solar Cells by Analysis of Microelectronic and Photonic Structures Simulator (AMPS-1D)", "authors": [{"first": "M", "middle": [], "last": "Aghaei", "suffix": ""}], "year": 2013, "venue": "", "link": null}, "BIBREF4": {"title": "Team of EMPA's Laboratory", "authors": [{"first": "N", "middle": [], "last": "Ayodhya", "suffix": ""}, {"first": "", "middle": [], "last": "Tiwari", "suffix": ""}], "year": 2014, "venue": "", "link": null}, "BIBREF5": {"title": "Solar Cells: Operating Principles, Technology, and System Applications", "authors": [{"first": "M", "middle": ["A"], "last": "Green", "suffix": ""}], "year": 1982, "venue": "", "link": "53458999"}, "BIBREF6": {"title": "Numerical modeling and analysis of CdS/Cd1-XZnXTe solar cells as a function of CdZnTe doping, lifetime and thickness", "authors": [{"first": "M", "middle": [], "last": "Imamzai", "suffix": ""}, {"first": "M", "middle": [], "last": "Aghaei", "suffix": ""}, {"first": "N", "middle": [], "last": "Amin", "suffix": ""}], "year": 2013, "venue": "IEEE 4th International Conference on Malaysia", "link": "30204021"}, "BIBREF7": {"title": "Strategies to increase CdTe solar-cell voltage", "authors": [{"first": "J", "middle": [], "last": "Sites", "suffix": ""}, {"first": "J", "middle": [], "last": "Pan", "suffix": ""}], "year": 2007, "venue": "Thin Solid Films", "link": "135892566"}, "BIBREF8": {"title": "Analytical model for the photocurrent of solar cells based on graded band-gap CdZnTe thin films", "authors": [{"first": "", "middle": [], "last": "Morales-Acevedo", "suffix": ""}], "year": 2011, "venue": "Solar Energy Materials and Solar Cells", "link": "196803033"}, "BIBREF9": {"title": "Prospects of novel front and back contacts for high efficiency cadmium telluride thin film solar cells from numerical analysis", "authors": [{"first": "M", "middle": [], "last": "Matin", "suffix": ""}, {"first": "M", "middle": [], "last": "Aliyu", "suffix": ""}, {"first": "A", "middle": ["H"], "last": "Quadery", "suffix": ""}, {"first": "N", "middle": [], "last": "Amin", "suffix": ""}], "year": 2010, "venue": "Solar Energy Materials and Solar Cells", "link": "94432476"}}, "ref_entries": {}}
{"paper_id": "10704448", "_pdf_hash": "e9477d9ef22a24d90b8bbec7343cdea6811285d3", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Microstructure and food product engineering", "authors": [{"first": "J", "middle": ["M"], "last": "Aguilera", "suffix": ""}], "year": 2000, "venue": "Food Technol", "link": "92454724"}, "BIBREF1": {"title": "Why food microstructure?", "authors": [{"first": "J", "middle": ["M"], "last": "Aguilera", "suffix": ""}], "year": 2005, "venue": "J Food Eng", "link": "97959002"}, "BIBREF2": {"title": "Product/process integration in food manufacture: engineering sustained health", "authors": [{"first": "I", "middle": [], "last": "Nortan", "suffix": ""}, {"first": "P", "middle": [], "last": "Fryer", "suffix": ""}, {"first": "S", "middle": [], "last": "Moore", "suffix": ""}], "year": 2006, "venue": "AICHE J", "link": null}, "BIBREF3": {"title": "The nomenclature, structure, and properties of food lipids", "authors": [{"first": "D", "middle": ["S"], "last": "Nichols", "suffix": ""}, {"first": "K", "middle": [], "last": "Sanderson", "suffix": ""}], "year": 2002, "venue": "Chemical and Functional Properties of Food Lipids", "link": "86078556"}, "BIBREF4": {"title": "Self-assembly of polar food lipids", "authors": [{"first": "M", "middle": ["E"], "last": "Leser", "suffix": ""}, {"first": "L", "middle": [], "last": "Sagalowicz", "suffix": ""}, {"first": "M", "middle": [], "last": "Michel", "suffix": ""}, {"first": "H", "middle": ["J"], "last": "Watzke", "suffix": ""}], "year": 2006, "venue": "Adv Colloid Interface Sci", "link": "190228"}, "BIBREF5": {"title": "Lipid chemistry and biochemistry", "authors": [{"first": "P", "middle": ["M"], "last": "Richards", "suffix": ""}], "year": 2006, "venue": "Technology and Engineering", "link": "89108000"}, "BIBREF6": {"title": "Introduction to food colloids", "authors": [{"first": "E", "middle": [], "last": "Dickinson", "suffix": ""}], "year": 1992, "venue": "", "link": null}, "BIBREF7": {"title": "Colloids in foods", "authors": [{"first": "E", "middle": [], "last": "Dickinson", "suffix": ""}, {"first": "G", "middle": [], "last": "Stainby", "suffix": ""}], "year": 1982, "venue": "London: Applied Science", "link": "134004312"}, "BIBREF8": {"title": "Food emulsions: principles, practice and techniques", "authors": [{"first": "D", "middle": ["J"], "last": "Mcclements", "suffix": ""}], "year": 2005, "venue": "", "link": "97866099"}, "BIBREF9": {"title": "Food emulsions", "authors": [{"first": "S", "middle": ["E"], "last": "Friberg", "suffix": ""}, {"first": "K", "middle": [], "last": "Larsson", "suffix": ""}, {"first": "J", "middle": [], "last": "Sjoblom", "suffix": ""}], "year": 2004, "venue": "", "link": null}, "BIBREF10": {"title": "Food emulsions: their structures and properties", "authors": [{"first": "D", "middle": ["G"], "last": "Dalgleish", "suffix": ""}], "year": 2004, "venue": "Food Emulsions", "link": "135816608"}, "BIBREF11": {"title": "Conformations and structures of milk proteins adsorbed to oilwater interfaces", "authors": [{"first": "D", "middle": ["G"], "last": "Dalgleish", "suffix": ""}], "year": 1996, "venue": "Food Res Int", "link": "84041067"}, "BIBREF12": {"title": "The conformation of proteins on solid/water interfaces -caseins and phosvitin on polystyrene latices", "authors": [{"first": "D", "middle": ["G"], "last": "Dalgleish", "suffix": ""}], "year": 1990, "venue": "Coll Surf", "link": "96665212"}, "BIBREF13": {"title": "Preliminary studies of b-lactoglobulin adsorbed on polystyrene latex", "authors": [{"first": "A", "middle": ["R"], "last": "Mackie", "suffix": ""}, {"first": "J", "middle": [], "last": "Mingins", "suffix": ""}, {"first": "R", "middle": [], "last": "Dann", "suffix": ""}], "year": 1993, "venue": "Food Colloids and Polymers: Stability and Mechanical Properties", "link": "138337188"}, "BIBREF14": {"title": "Dimensions and possible structures of milk proteins at oil-water interfaces", "authors": [{"first": "D", "middle": ["G"], "last": "Dalgleish", "suffix": ""}, {"first": "J", "middle": [], "last": "Leaver", "suffix": ""}], "year": 1993, "venue": "Food Colloids and Polymers: Stability and Mechanical Properties", "link": "99369387"}, "BIBREF15": {"title": "Structures and properties of adsorbed layers in emulsions containing milk proteins", "authors": [{"first": "D", "middle": ["G"], "last": "Dalgleish", "suffix": ""}], "year": 1995, "venue": "Foods Macromolecules and Colloids", "link": "94771784"}, "BIBREF16": {"title": "Advances in food colloids. London: Blackie Academic and Professional", "authors": [{"first": "E", "middle": [], "last": "Dickinson", "suffix": ""}, {"first": "D", "middle": ["J"], "last": "Mcclements", "suffix": ""}], "year": 1995, "venue": "", "link": null}, "BIBREF17": {"title": "The conformation of a-lactalbumin as a function of pH, heat treatment and adsorption at hydrophobic surfaces studied by FTIR", "authors": [{"first": "Y", "middle": [], "last": "Fang", "suffix": ""}, {"first": "D", "middle": ["G"], "last": "Dalgleish", "suffix": ""}], "year": 1998, "venue": "Food Hydrocoll", "link": "95258691"}, "BIBREF18": {"title": "Proteins at interfaces and in emulsions: stability, rheology and interactions", "authors": [{"first": "E", "middle": [], "last": "Dickinson", "suffix": ""}], "year": 1998, "venue": "J Chem Soc Faraday Trans", "link": "97403595"}, "BIBREF19": {"title": "Time-dependent polymerization of b-lactoglobulin through disulphide bonds at the oil-water interface in emulsions", "authors": [{"first": "E", "middle": [], "last": "Dickinson", "suffix": ""}, {"first": "Y", "middle": [], "last": "Matsumura", "suffix": ""}], "year": 1991, "venue": "Int J Biol Macromol", "link": "21286248"}, "BIBREF20": {"title": "Disulfide bond formation affects stability of whey protein isolate emulsions", "authors": [{"first": "D", "middle": ["J"], "last": "Mcclements", "suffix": ""}, {"first": "F", "middle": ["J"], "last": "Monahan", "suffix": ""}, {"first": "J", "middle": ["E"], "last": "Kinsella", "suffix": ""}], "year": 1993, "venue": "J Food Sci", "link": "84175062"}, "BIBREF21": {"title": "Time-dependent competitive adsorption of milk proteins and surfactants in oil-in-water emulsions", "authors": [{"first": "J", "middle": [], "last": "Chen", "suffix": ""}, {"first": "E", "middle": [], "last": "Dickinson", "suffix": ""}], "year": 1998, "venue": "J Sci Food Agri", "link": "84103242"}, "BIBREF22": {"title": "Competitive adsorption between sodium caseinate and oil-soluble and water-soluble surfactants in oil-in-water emulsions", "authors": [{"first": "S", "middle": ["E"], "last": "Euston", "suffix": ""}, {"first": "H", "middle": [], "last": "Singh", "suffix": ""}, {"first": "P", "middle": ["A"], "last": "Munro", "suffix": ""}, {"first": "D", "middle": ["G"], "last": "Dalgleish", "suffix": ""}], "year": 1995, "venue": "J Food Sci", "link": "84220387"}, "BIBREF23": {"title": "Oil-in-water emulsions stabilized by sodium caseinate or whey protein isolate as influenced by glycerol monostearate", "authors": [{"first": "S", "middle": ["E"], "last": "Euston", "suffix": ""}, {"first": "H", "middle": [], "last": "Singh", "suffix": ""}, {"first": "P", "middle": ["A"], "last": "Munro", "suffix": ""}, {"first": "D", "middle": ["G"], "last": "Dalgleish", "suffix": ""}], "year": 1996, "venue": "J Food Sci", "link": "84462916"}, "BIBREF24": {"title": "Surface properties of oil-in-water emulsion droplets containing casein and Tween 60", "authors": [{"first": "D", "middle": ["G"], "last": "Dalgleish", "suffix": ""}, {"first": "M", "middle": [], "last": "Srinivasan", "suffix": ""}, {"first": "H", "middle": [], "last": "Singh", "suffix": ""}], "year": 1995, "venue": "J Agri Food Chem", "link": "83800809"}, "BIBREF25": {"title": "Casein adsorption on the surfaces of oil-in-water emulsions modified by lecithin", "authors": [{"first": "Y", "middle": [], "last": "Fang", "suffix": ""}, {"first": "D", "middle": ["G"], "last": "Dalgleish", "suffix": ""}], "year": 1993, "venue": "Coll Surf B", "link": "97411065"}, "BIBREF26": {"title": "Competitive adsorption of lecithin and b-casein in oil-in-water emulsions", "authors": [{"first": "J", "middle": [], "last": "Courthaudon", "suffix": ""}, {"first": "E", "middle": [], "last": "Dickinson", "suffix": ""}], "year": 1991, "venue": "J Agri Food Chem", "link": null}, "BIBREF27": {"title": "Intestinal fat digestion, absorption, and transport -a review", "authors": [{"first": "H", "middle": ["I"], "last": "Friedman", "suffix": ""}, {"first": "B", "middle": [], "last": "Nylund", "suffix": ""}], "year": 1980, "venue": "Am J Clin Nutr", "link": "4440088"}, "BIBREF28": {"title": "Lipid digestion and absorption", "authors": [{"first": "M", "middle": ["C"], "last": "Carey", "suffix": ""}], "year": 1983, "venue": "Ann Rev Physiol", "link": "10191234"}, "BIBREF29": {"title": "Assessment of antral grinding of model solid meals with echo-planar imaging", "authors": [{"first": "Luca", "middle": [], "last": "Marciani", "suffix": ""}, {"first": "I", "middle": [], "last": "Gowland", "suffix": ""}, {"first": "P", "middle": ["A"], "last": "Fillery-Travis", "suffix": ""}, {"first": "A", "middle": [], "last": "Manoj", "suffix": ""}, {"first": "P", "middle": [], "last": "Wright", "suffix": ""}, {"first": "J", "middle": [], "last": "Smith", "suffix": ""}, {"first": "A", "middle": [], "last": "", "suffix": ""}], "year": 2001, "venue": "Am J Physiol Gastrointest Liver Physiol", "link": null}, "BIBREF30": {"title": "The role of polysaccharides in the gastric processing of food", "authors": [{"first": "A", "middle": [], "last": "Fillery-Travis", "suffix": ""}, {"first": "I", "middle": [], "last": "Marciani", "suffix": ""}, {"first": "P", "middle": ["A"], "last": "Garland", "suffix": ""}, {"first": "R", "middle": ["C"], "last": "Spiller", "suffix": ""}], "year": 2002, "venue": "Gums and Stabilisers for the Food Industry", "link": null}, "BIBREF31": {"title": "Enhancement of intragastric acid stability of a fat emulsion meal delays gastric emptying and increases cholecystokinin release and gallbladder contraction", "authors": [{"first": "L", "middle": [], "last": "Marciani", "suffix": ""}, {"first": "M", "middle": [], "last": "Wickham", "suffix": ""}, {"first": "G", "middle": [], "last": "Singh", "suffix": ""}, {"first": "D", "middle": [], "last": "Bush", "suffix": ""}, {"first": "B", "middle": [], "last": "Pick", "suffix": ""}, {"first": "E", "middle": [], "last": "Cox", "suffix": ""}], "year": 2007, "venue": "Am J Physiol Gastrointest Liver Physiol", "link": "16040740"}, "BIBREF32": {"title": "On the extent of hydrolysis of triglyceride ester bonds in the lumen of the human small intestine during digestion", "authors": [{"first": "B", "middle": [], "last": "Borgstrom", "suffix": ""}, {"first": "N", "middle": [], "last": "Tryding", "suffix": ""}, {"first": "G", "middle": [], "last": "Westoo", "suffix": ""}], "year": 1957, "venue": "Acta Physiol Scand", "link": "32111512"}, "BIBREF33": {"title": "Emulsification of fat in the intestine of the rat and its relationship to absorption", "authors": [{"first": "A", "middle": ["C"], "last": "Frazer", "suffix": ""}, {"first": "J", "middle": ["H"], "last": "Schulmann", "suffix": ""}, {"first": "H", "middle": ["C"], "last": "Stewart", "suffix": ""}], "year": 1944, "venue": "J Physiol", "link": "9362654"}, "BIBREF34": {"title": "Does the pancreas really produce much more lipase than required for fat digestion?", "authors": [{"first": "F", "middle": [], "last": "Carriere", "suffix": ""}, {"first": "P", "middle": [], "last": "Grandval", "suffix": ""}, {"first": "P", "middle": ["C"], "last": "Gregory", "suffix": ""}, {"first": "C", "middle": [], "last": "Renou", "suffix": ""}, {"first": "F", "middle": [], "last": "Henniges", "suffix": ""}, {"first": "S", "middle": [], "last": "Sander-Struckmeier", "suffix": ""}], "year": 2005, "venue": "J Pancreas", "link": "5587321"}, "BIBREF35": {"title": "The complete digestion of human milk triacylglycerol in vitro requires gastric lipase, pancreatic colipase-dependent lipase and bile salt-stimulated lipase", "authors": [{"first": "S", "middle": [], "last": "Bernback", "suffix": ""}, {"first": "L", "middle": [], "last": "Blackberg", "suffix": ""}, {"first": "O", "middle": [], "last": "Hernell", "suffix": ""}], "year": 1990, "venue": "J Clin Invest", "link": "23875547"}, "BIBREF36": {"title": "Lipases in milk", "authors": [{"first": "T", "middle": [], "last": "Olivecrona", "suffix": ""}, {"first": "S", "middle": [], "last": "Vilaro", "suffix": ""}, {"first": "G", "middle": [], "last": "Olivecrona", "suffix": ""}], "year": 2003, "venue": "Advanced Dairy Chemistry -1, Proteins", "link": "81644883"}, "BIBREF37": {"title": "Nutritional aspects of milk proteins", "authors": [{"first": "L", "middle": [], "last": "Hambraeus", "suffix": ""}], "year": 1993, "venue": "Proteins. Amsterdam", "link": "178098180"}, "BIBREF38": {"title": "The fate of dietary fat in the body", "authors": [{"first": "A", "middle": ["C"], "last": "Frazer", "suffix": ""}], "year": 1962, "venue": "Chem Ind", "link": null}, "BIBREF39": {"title": "Intestinal absorption of fats", "authors": [{"first": "J", "middle": ["R"], "last": "Senior", "suffix": ""}], "year": 1964, "venue": "J Lipid Res", "link": "12246715"}, "BIBREF40": {"title": "Emulsion stability", "authors": [{"first": "E", "middle": [], "last": "Dickinson", "suffix": ""}, {"first": "G", "middle": [], "last": "Stainsby", "suffix": ""}], "year": 1988, "venue": "Advances in Food Emulsions and Foams", "link": null}, "BIBREF41": {"title": "Milk protein functionality in food colloids", "authors": [{"first": "H", "middle": [], "last": "Singh", "suffix": ""}], "year": 2005, "venue": "editor. Food Colloids: Interactions Microstructure and Processing", "link": null}, "BIBREF42": {"title": "Food emulsions: principles, practice and techniques", "authors": [{"first": "D", "middle": ["J"], "last": "Mcclements", "suffix": ""}], "year": 1999, "venue": "", "link": "97866099"}, "BIBREF43": {"title": "Structure and biosynthesis of human salivary mucins", "authors": [{"first": "A", "middle": [], "last": "Zalewska", "suffix": ""}, {"first": "K", "middle": [], "last": "Zwierz", "suffix": ""}, {"first": "K", "middle": [], "last": "Z\u00f3lkowski", "suffix": ""}, {"first": "A", "middle": [], "last": "Gindzienski", "suffix": ""}], "year": 2000, "venue": "Acta Biochim Pol", "link": null}, "BIBREF44": {"title": "A review of saliva: normal composition, flow, and function", "authors": [{"first": "S", "middle": ["P"], "last": "Humphrey", "suffix": ""}, {"first": "R", "middle": ["T"], "last": "Williamson", "suffix": ""}], "year": 2001, "venue": "J Prosthet Dent", "link": "33564938"}, "BIBREF45": {"title": "Emulsion flocculation induced by saliva and mucin", "authors": [{"first": "M", "middle": ["H"], "last": "Vingerhoeds", "suffix": ""}, {"first": "Tbj", "middle": [], "last": "Blijdenstein", "suffix": ""}, {"first": "F", "middle": ["D"], "last": "Zoet", "suffix": ""}, {"first": "G", "middle": ["A"], "last": "Van Aken", "suffix": ""}], "year": 2005, "venue": "Food Hydrocoll", "link": "83870381"}, "BIBREF46": {"title": "Colloidal behaviour of food emulsions under oral conditions", "authors": [{"first": "G", "middle": ["A"], "last": "Van Aken", "suffix": ""}, {"first": "M", "middle": ["H"], "last": "Vingerhoeds", "suffix": ""}, {"first": "Eha", "middle": [], "last": "De Hoog", "suffix": ""}], "year": 2005, "venue": "editor. Food Colloids: Interactions, Microstructure and Processing", "link": "137696688"}, "BIBREF47": {"title": "Complex formation in mixtures of lysozyme-stabilized emulsions and human saliva", "authors": [{"first": "E", "middle": [], "last": "Silletti", "suffix": ""}, {"first": "M", "middle": ["H"], "last": "Vingerhoeds", "suffix": ""}, {"first": "W", "middle": [], "last": "Norde", "suffix": ""}, {"first": "G", "middle": ["A"], "last": "Van Aken", "suffix": ""}], "year": 2007, "venue": "J Coll Interface Sci", "link": "25516407"}, "BIBREF48": {"title": "Colloidal stability and interactions of milk-proteinstabilized emulsions in an artificial saliva", "authors": [{"first": "A", "middle": [], "last": "Sarkar", "suffix": ""}, {"first": "K", "middle": [], "last": "Goh", "suffix": ""}, {"first": "H", "middle": [], "last": "Singh", "suffix": ""}], "year": "", "venue": "", "link": "96538193"}, "BIBREF49": {"title": "The specificity of proanthocyanidin-protein interactions", "authors": [{"first": "A", "middle": ["E"], "last": "Hagerman", "suffix": ""}, {"first": "L", "middle": ["G"], "last": "Butler", "suffix": ""}], "year": 1981, "venue": "J Biol Chem", "link": "24182515"}, "BIBREF50": {"title": "Application of oral tissue in tribological measurements in an emulsion perception context", "authors": [{"first": "D", "middle": ["M"], "last": "Dresselhuis", "suffix": ""}, {"first": "Eha", "middle": [], "last": "De Hoog", "suffix": ""}, {"first": "Cohen", "middle": [], "last": "Stuart", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Van Aken", "suffix": ""}, {"first": "G", "middle": ["A"], "last": "", "suffix": ""}], "year": 2008, "venue": "Food Hydrocoll", "link": "96909996"}, "BIBREF52": {"title": "Digestion and absorption of 2 fat emulsions with different droplet sizes in the human digestive tract", "authors": [{"first": "M", "middle": [], "last": "Armand", "suffix": ""}, {"first": "B", "middle": [], "last": "Pasquier", "suffix": ""}, {"first": "M", "middle": [], "last": "Andre", "suffix": ""}, {"first": "P", "middle": [], "last": "Borel", "suffix": ""}, {"first": "M", "middle": [], "last": "Senft", "suffix": ""}, {"first": "J", "middle": [], "last": "Peyrot", "suffix": ""}], "year": 1999, "venue": "Am J Clin Nutr", "link": "4467753"}, "BIBREF53": {"title": "Behaviour of an oil-in-water emulsion stabilized by beta lactoglobulin in an in vitro gastric model. Food Hydrocoll, in press", "authors": [{"first": "A", "middle": [], "last": "Sarkar", "suffix": ""}, {"first": "K", "middle": [], "last": "Goh", "suffix": ""}, {"first": "R", "middle": ["P"], "last": "Singh", "suffix": ""}, {"first": "H", "middle": [], "last": "Singh", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF54": {"title": "Characterization of the human upper gastrointestinal contents under conditions simulating bioavailability/bioequivalence studies", "authors": [{"first": "L", "middle": [], "last": "Kalantzi", "suffix": ""}, {"first": "K", "middle": [], "last": "Goumas", "suffix": ""}, {"first": "V", "middle": [], "last": "Kalioras", "suffix": ""}, {"first": "B", "middle": [], "last": "Abrahamsson", "suffix": ""}, {"first": "J", "middle": ["B"], "last": "Dressman", "suffix": ""}, {"first": "C", "middle": [], "last": "Reppas", "suffix": ""}], "year": 2006, "venue": "Pharm Res", "link": "2564956"}, "BIBREF55": {"title": "Inhibition of pancreatic lipase by ovalbumin and beta-lactoglobulin-a at the air-water-interface", "authors": [{"first": "M", "middle": ["G"], "last": "Ivanova", "suffix": ""}, {"first": "I", "middle": [], "last": "Panaiotov", "suffix": ""}, {"first": "A", "middle": ["G"], "last": "Bois", "suffix": ""}, {"first": "Y", "middle": [], "last": "Gargouri", "suffix": ""}, {"first": "R", "middle": [], "last": "Verger", "suffix": ""}], "year": 1990, "venue": "J Coll Interface Sci", "link": "96987412"}, "BIBREF56": {"title": "Modification of a phospholipid stabilized emulsion interface by bile salt: effect on pancreatic lipase activity", "authors": [{"first": "M", "middle": [], "last": "Wickham", "suffix": ""}, {"first": "M", "middle": [], "last": "Garrood", "suffix": ""}, {"first": "J", "middle": [], "last": "Leney", "suffix": ""}, {"first": "Pdg", "middle": [], "last": "Wilson", "suffix": ""}, {"first": "A", "middle": [], "last": "Fillery-Travis", "suffix": ""}], "year": 1998, "venue": "J Lipid Res", "link": "22180421"}, "BIBREF57": {"title": "Physico-chemical properties of lipids: new strategies to manage fatty acid bioavailability", "authors": [{"first": "G", "middle": [], "last": "Fave", "suffix": ""}, {"first": "T", "middle": ["C"], "last": "Coste", "suffix": ""}, {"first": "Armand", "middle": ["M"], "last": "", "suffix": ""}], "year": 2004, "venue": "Cell Mol Biol", "link": null}, "BIBREF58": {"title": "Influence of droplet characteristics on the formation of oil-in-water emulsions stabilized by surfactant-chitosan layers", "authors": [{"first": "S", "middle": [], "last": "Mun", "suffix": ""}, {"first": "E", "middle": ["A"], "last": "Decker", "suffix": ""}, {"first": "D", "middle": ["J"], "last": "Mcclements", "suffix": ""}], "year": 2007, "venue": "Food Res Int", "link": "21566814"}, "BIBREF59": {"title": "Effect of human milk or formula on gastric function and fat digestion in the premature infant", "authors": [{"first": "M", "middle": [], "last": "Armand", "suffix": ""}, {"first": "M", "middle": [], "last": "Hamosh", "suffix": ""}, {"first": "N", "middle": ["R"], "last": "Mehta", "suffix": ""}, {"first": "P", "middle": ["A"], "last": "Angelus", "suffix": ""}, {"first": "J", "middle": ["R"], "last": "Philpott", "suffix": ""}, {"first": "T", "middle": ["R"], "last": "Henderson", "suffix": ""}], "year": 1996, "venue": "Pediatr Res", "link": "12860945"}, "BIBREF60": {"title": "Studies on the detergent inhibition of pancreatic lipase activity", "authors": [{"first": "Y", "middle": [], "last": "Gargouri", "suffix": ""}, {"first": "R", "middle": [], "last": "Julien", "suffix": ""}, {"first": "A", "middle": ["G"], "last": "Bois", "suffix": ""}, {"first": "R", "middle": [], "last": "Verger", "suffix": ""}, {"first": "L", "middle": [], "last": "Sarda", "suffix": ""}], "year": 1983, "venue": "J Lipid Res", "link": "2015097"}, "BIBREF61": {"title": "Physiology of Gastro-intestinal Tract", "authors": [{"first": "J", "middle": ["S"], "last": "Patton", "suffix": ""}], "year": 1981, "venue": "", "link": null}, "BIBREF62": {"title": "Secretion and contribution to lipolysis of gastric and pancreatic lipases during a test meal in humans", "authors": [{"first": "F", "middle": [], "last": "Carriere", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Barrowman", "suffix": ""}, {"first": "R", "middle": [], "last": "Verger", "suffix": ""}, {"first": "R", "middle": [], "last": "Laugier", "suffix": ""}], "year": 1993, "venue": "Gastroenterology", "link": "43562996"}, "BIBREF63": {"title": "Effects of droplet size, triacylglycerol composition, and calcium on the hydrolysis of complex emulsions by pancreatic lipase -an invitro study", "authors": [{"first": "M", "middle": [], "last": "Armand", "suffix": ""}, {"first": "P", "middle": [], "last": "Borel", "suffix": ""}, {"first": "P", "middle": [], "last": "Ythier", "suffix": ""}, {"first": "G", "middle": [], "last": "Dutot", "suffix": ""}, {"first": "C", "middle": [], "last": "Melin", "suffix": ""}, {"first": "M", "middle": [], "last": "Senft", "suffix": ""}], "year": 1992, "venue": "J Nutr Biochem", "link": "85094264"}, "BIBREF64": {"title": "Digestion and absorption of tube-feeding emulsions with different droplet sizes and compositions in the rat", "authors": [{"first": "P", "middle": [], "last": "Borel", "suffix": ""}, {"first": "Armand", "middle": ["M"], "last": "Pasquier", "suffix": ""}, {"first": "B", "middle": [], "last": "Senft", "suffix": ""}, {"first": "M", "middle": [], "last": "Dutot", "suffix": ""}, {"first": "G", "middle": [], "last": "Melin", "suffix": ""}, {"first": "C", "middle": [], "last": "", "suffix": ""}], "year": 1994, "venue": "J Parenter Enter Nutr", "link": "25593661"}, "BIBREF65": {"title": "Effect of pH on the in vitro interactions between bile acids and pectin", "authors": [{"first": "G", "middle": [], "last": "Dongowski", "suffix": ""}], "year": 1997, "venue": "Z Lebensm Unters Forsch A", "link": "85037188"}, "BIBREF66": {"title": "Binding of taurocholate by pectin in the presence of calcium ions", "authors": [{"first": "M", "middle": [], "last": "Koseki", "suffix": ""}, {"first": "N", "middle": [], "last": "Kitabatake", "suffix": ""}, {"first": "E", "middle": [], "last": "Doi", "suffix": ""}, {"first": "T", "middle": [], "last": "Yasuno", "suffix": ""}, {"first": "S", "middle": [], "last": "Ogino", "suffix": ""}, {"first": "M", "middle": [], "last": "Kazama", "suffix": ""}], "year": 1987, "venue": "J Food Sci", "link": "86823319"}, "BIBREF67": {"title": "Influence of environmental conditions on the stability of oil in water emulsions containing droplets stabilized by lecithin-chitosan membranes", "authors": [{"first": "S", "middle": [], "last": "Ogawa", "suffix": ""}, {"first": "E", "middle": ["A"], "last": "Decker", "suffix": ""}, {"first": "D", "middle": ["J"], "last": "Mcclements", "suffix": ""}], "year": 2003, "venue": "J Agri Food Chem", "link": "39740081"}, "BIBREF68": {"title": "Drug delivery systems based on porous chitosan/polyacrylic acid microspheres", "authors": [{"first": "C", "middle": [], "last": "Peniche", "suffix": ""}, {"first": "P", "middle": [], "last": "Fernandez", "suffix": ""}, {"first": "A", "middle": [], "last": "Gallardo", "suffix": ""}, {"first": "A", "middle": [], "last": "Lopez-Bravo", "suffix": ""}, {"first": "San", "middle": [], "last": "Roman", "suffix": ""}, {"first": "J", "middle": [], "last": "", "suffix": ""}], "year": 2003, "venue": "Macromol Biosci", "link": "84925632"}, "BIBREF69": {"title": "Preliminary study of the influence of dietary fiber on the properties of oil-in-water emulsions passing through an in vitro human digestion model", "authors": [{"first": "M", "middle": [], "last": "Beysseriat", "suffix": ""}, {"first": "E", "middle": ["A"], "last": "Decker", "suffix": ""}, {"first": "D", "middle": ["J"], "last": "Mcclements", "suffix": ""}], "year": 2006, "venue": "Food Hydrocoll", "link": "98360549"}, "BIBREF70": {"title": "Effects of modification of encapsulant materials on the susceptibility of fish oil microcapsules to lipolysis", "authors": [{"first": "C", "middle": [], "last": "Chung", "suffix": ""}, {"first": "L", "middle": [], "last": "Sanguansri", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Augustin", "suffix": ""}], "year": 2008, "venue": "Food Biophys", "link": "93628212"}, "BIBREF71": {"title": "Influence of lipid physical state on the in vitro digestibility of emulsified lipids", "authors": [{"first": "L", "middle": [], "last": "Bonnaire", "suffix": ""}, {"first": "S", "middle": [], "last": "Sandra", "suffix": ""}, {"first": "T", "middle": [], "last": "Helgason", "suffix": ""}, {"first": "E", "middle": ["A"], "last": "Decker", "suffix": ""}, {"first": "J", "middle": [], "last": "Weiss", "suffix": ""}, {"first": "D", "middle": ["J"], "last": "Mcclements", "suffix": ""}], "year": 2008, "venue": "J Agric Food Chem", "link": "5479098"}, "BIBREF72": {"title": "Magnetic resonance imaging of the behaviour of oil-in-water emulsions in the gastric lumen of man", "authors": [{"first": "L", "middle": [], "last": "Marciani", "suffix": ""}, {"first": "M", "middle": [], "last": "Wickham", "suffix": ""}, {"first": "D", "middle": [], "last": "Bush", "suffix": ""}, {"first": "R", "middle": [], "last": "Faulks", "suffix": ""}, {"first": "J", "middle": [], "last": "Wright", "suffix": ""}, {"first": "A", "middle": [], "last": "Fillery-Travis", "suffix": ""}], "year": 2006, "venue": "Br J Nutr", "link": "24432924"}, "BIBREF73": {"title": "Enhancement of intragastric acid stability of a fat emulsion meal delays gastric emptying and increases cholecystokinin release and gall bladder contraction", "authors": [{"first": "L", "middle": [], "last": "Marciani", "suffix": ""}, {"first": "M", "middle": [], "last": "Wickham", "suffix": ""}, {"first": "G", "middle": [], "last": "Singh", "suffix": ""}, {"first": "D", "middle": [], "last": "Bush", "suffix": ""}, {"first": "B", "middle": [], "last": "Pick", "suffix": ""}, {"first": "E", "middle": [], "last": "Cox", "suffix": ""}], "year": 2007, "venue": "Am J Gastrointest Liver Physiol", "link": "16040740"}}, "ref_entries": {}}
{"paper_id": "10704481", "_pdf_hash": "58f6df4194bd4fab4bef5dc612d3c4640955e05f", "abstract": [{"section": "Abstract", "text": "SUMMARY", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Commonly in Australia and New Zealand, initial ", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": ") and the availability of a scenario-based simulation module (\u03b2=0.22, 95% confidence interval 0.17 to 0.27, R 2 =0.38, P <0.001). Participants generally found they had learned a great deal from the program and that the course material was of an appropriate level.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "The BASIC course was found to be a positive learning experience for health care practitioners inexperienced in the management of the critically ill.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "", "text": "Regional centres and countries where health services are limited commonly need to provide care to critically ill patients in the absence of formal intensive care facilities and trained staff. In Australia and New Zealand, geographical isolation forces remote hospitals to be responsible for the care of a critically unwell patient for a significant period of time. It is therefore important that the staff, frequently inexperienced junior doctors, can sustain the patient until inter-hospital transfer occurs. In order to meet this need and the needs of junior doctors starting intensive care training, the Basic Assessment and Support in Intensive Care (BASIC) course was developed by a group of intensive care specialists in Australia, New Zealand, Hong Kong and the United Kingdom. The majority of members of the international steering committee are Fellows of the Australian and New Zealand College of Intensive Care Medicine.", "cite_spans": [], "ref_spans": []}, {"section": "COURSE DESCRIPTION", "text": "The aim of the program is to improve the standard of care delivered by non-intensive care specialist staff to the critically ill. BASIC is not an intensive care training program for specialist intensive care practice or a surrogate for an advanced training program in intensive care. Rather, it is aimed at junior medical staff who may be rotating through acute care specialties or starting intensive care training. It also aims to assist senior nursing staff, career medical officers, paramedical staff and consultants from non-critical care disciplines who require additional skills and knowledge in the management of the intensive care patient.", "cite_spans": [], "ref_spans": []}, {"section": "COURSE DESCRIPTION", "text": "The first course was conducted in Hong Kong in 2004 and subsequent courses were run in Hawke's Bay, New Zealand and Brisbane, Queensland since 2005. BASIC courses have since been established in Bahrain, Cambodia, the Peoples Republic of China, Fiji, India, Indonesia, Israel, Korea, Kuwait, Malaysia, Qatar, Saudi Arabia, South Africa, Syria, United Arab Emirates and the United Kingdom. In addition, a military version of BASIC has been run for the Australian Defence Force targeting medical, nursing and paramedical staff. The international steering committee oversees curriculum development, audit and research. There are no licence fees for use of course material and all courses are run on a notfor-profit basis. Tutors are not paid for their participation but travel expenses can be met where required. Ongoing development has been partially funded by unrestricted educational grants from Dr\u00e4ger Medical and Maquet. There was no company involvement in the development of the course content or teaching resources.", "cite_spans": [], "ref_spans": []}, {"section": "COURSE DESCRIPTION", "text": "Each tutor is required to attend an entire BASIC course and to complete an instructor program whereby the philosophy behind BASIC is described, along with specific instruction in the principles of lecturing and small group teaching. In addition, the instructor program uses senior tutors experienced in BASIC to critique a concise version of lectures and skills stations which will be taught in a subsequent course by new tutors. Each tutor is provided with the participant evaluation of the course, including the specific assessment of their particular teaching sessions as well as the performance of all sessions. Specific participant comments are also made available, as well as participant performance in the pre-and post-course examination. Each course's program director has been approved by the BASIC Steering Committee. The course program director is responsible for ensuring that tutors have completed training and for the maintenance of the educational standards of the teaching faculty and keeping the program to time. A minimum faculty of six is required to run the course.", "cite_spans": [], "ref_spans": []}, {"section": "COURSE DESCRIPTION", "text": "BASIC is a course conducted with the intention that in a relatively short time period, candidates are trained to identify the need for and provide initial support to the critically ill patient. The course has a particular emphasis on cardiorespiratory pathophysiology, mechanical ventilation, renal failure, neurological emergencies, severe sepsis, trauma and patient transport. Important concepts in nutrition, deep vein thrombosis and stress ulcer prophylaxis are also considered providing a knowledge base with respect to daily intensive care routines. Clinical reasoning and problem-solving skills in relation to interpretation of arterial blood gases and electrolytes are also developed. Advanced life support skills including cardiopulmonary resuscitation and defibrillation, airway support, intubation, vascular access and patient transport are reviewed in dedicated skill stations with special emphasis placed on mechanical ventilation.", "cite_spans": [], "ref_spans": []}, {"section": "COURSE DESCRIPTION", "text": "Multiple teaching methods are employed. Precourse self-directed learning is essential, being facilitated by the provision of written and electronic resources at least four weeks prior to the course commencement. The breadth of the required learning was illustrated by performance on the pre-course web-based multiple choice examination. Access to pre-course examination was made available when course materials were delivered. The workshop, run over two to three days, consists of short lectures (20 to 30 minutes), practical skill stations (30 to 40 minutes), low fidelity simulations as well as small group interactive scenario-based sessions. Course lectures use a single tutor while the maximal number of course participants per tutor in the skill stations is six. The course teaching material does not rely on high fidelity simulation and therefore can be conducted in most hospitals with standard educational facilities. The participants have a summative assessment by a multiple choice exam which is case scenario based and emphasises clinical decision making. Participants evaluate the course using an objective survey tool.", "cite_spans": [], "ref_spans": []}, {"section": "COURSE DESCRIPTION", "text": "The purpose of this paper is to evaluate the success of the BASIC course in improving specific assessable knowledge and satisfaction of participant expectations in Australia and New Zealand.", "cite_spans": [], "ref_spans": []}, {"section": "MATERIALS AND METHODS", "text": "The BASIC courses from Brisbane, Queensland and Hawke's Bay, New Zealand were assessed to define the early Australasian experience from 2005 until mid 2009. Both courses use local faculty comprising specialist intensivists, specialist emergency physicians, anaesthetists or senior registrars in intensive care. In order to maintain diversity, interstate national and international instructors are often invited.", "cite_spans": [], "ref_spans": []}, {"section": "MATERIALS AND METHODS", "text": "Since November 2006 the Brisbane BASIC course has included five integrated advanced simulation scenarios. Consequently the contact period was extended to three days.", "cite_spans": [], "ref_spans": []}, {"section": "MATERIALS AND METHODS", "text": "From implementation of the BASIC course in Australia and New Zealand, a database of participant performance was collated. This database was used to analyse the participants' demographics and the results of pre-and post-course examinations. The data collected from participant feedback was not collected similarly. As such, only the Brisbane data is presented.", "cite_spans": [], "ref_spans": []}, {"section": "MATERIALS AND METHODS", "text": "A pre-course online 'open book' formative assessment of 41 multiple choice questions and a post-course \"closed-book\" summative assessment of 30 multiple choice exam questions were used to assess clinical skills developed though the course. The pre-course examination comprised factual questions with simple clinical scenarios while the final examination only used acute clinical scenarios which emphasised clinical decision making and investigation interpretation. The exams were developed and reviewed by the steering committee of BASIC with referencing back to course materials. Exams were also reviewed by local program directors for applicability in each country with minor changes made for local drug availability and resources.", "cite_spans": [], "ref_spans": []}, {"section": "MATERIALS AND METHODS", "text": "The post-course exam results were analysed comparing the Brisbane and Hawke's Bay programs. Demographic data, course program and pre-course exam performance were assessed for their ability to predict final exam mark.", "cite_spans": [], "ref_spans": []}, {"section": "MATERIALS AND METHODS", "text": "Participant feedback was acquired through a survey at the completion of the course using structured responses from five-point Likert scales for each component of the course as well as the overall conduct of the course. Unstructured free comments were also elicited.", "cite_spans": [], "ref_spans": []}, {"section": "MATERIALS AND METHODS", "text": "Data was analysed using paired t-tests and KruskalWallis for continuous data. Categorical data was assessed using chi-squared or Fisher's exact test where analysis assumptions were met. The final exam score was analysed using forward multiple regression modelling with the model assessed for normal distribution, linearity and homoscedasticity.", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS", "text": "Since Tables 2 and 3 . The pre-course open book examination result averaged 79% (95% confidence interval [CI] 78 to 80) and the post-course closed book exam was 64% (95% CI 63 to 65). A score of less than 50% was made by 16 participants (2.3%) on the pre-course examination and 127 (16%) on the post course examination. One hundred and sixteen participants failed to submit the precourse test and were excluded from the pre-course failure rate analysis.", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS", "text": "Univariate and multivariate regression analysis were used to establish the predictors of post-course examination results (Table 4 ). The pre-course test result and the opportunity to perform advanced simulations positively predicted examination performance. Nursing staff examination results were lower than other participants. The model predicted 38% of the variance in post-course results and the assumptions of normality, homoscedasticity and linearity were met. However, there were few important differences between the final exam performance between participants in Brisbane and Hawke's Bay. The structured component assessment was made using a five-point Likert scale representing satisfaction, greatest at 5, and dissatisfaction, at worst, scoring 1 (Figures 1 and 2) . Both lectures and skill stations performed well in terms of participant satisfaction (Figures 1 and 2 General comments about the course conduct and content was assessed on a Likert scale with agreement with a given statement being least at 1 and greatest at 5 (Figure 3) . Candidate consensus opinion is in support of the course in its current format with respect to both content and conduct (Figure 3) . Importantly, all participants believed the course to be beneficial and that the general level of the program was correct. There was candidate ambivalence with regard to the amount of course material and the balance between practical and didactic sessions. The themes and general responses in the Hawke's Bay cohort were similar. Free comments were reviewed and important themes extracted. Of 205 written comments received, gratitude for the course quality was expressed (53%) but there was disappointment at the limited time for the acquisition of \"such critical skills and knowledge\" (40%). Requests for separate targeted lectures for nurses (5 from 15 nurses attending) were infrequent, but highlight a real or perceived learning style difference. This request for separation was reversed in the simulation environment, where nurses consistently wanted to be integrated into realistic emergency response teams or teams derived from the same originating hospital.", "cite_spans": [], "ref_spans": [{"start": 121, "end": 129, "text": "(Table 4", "ref_id": "TABREF3"}, {"start": 757, "end": 774, "text": "(Figures 1 and 2)", "ref_id": "FIGREF0"}, {"start": 862, "end": 878, "text": "(Figures 1 and 2", "ref_id": "FIGREF0"}, {"start": 1037, "end": 1047, "text": "(Figure 3)", "ref_id": "FIGREF2"}, {"start": 1169, "end": 1179, "text": "(Figure 3)", "ref_id": "FIGREF2"}]}, {"section": "DISCUSSION", "text": "Critical care skills are not broadly available to a geographically disseminated population 1 . As such, local health practitioners may be required to provide initial support for such patients until transfer can be organised to a definitive care facility. In addition, new medical graduates are increasingly recognised as needing critical care skills upon graduation 2 . Consequently there has been an increase in the number of courses available to meet this need. This paper describes the outcomes of the BASIC course in Brisbane and Hawke's Bay. The program was designed to provide training to clinicians who infrequently needed to provide care to the critically ill. BASIC met this aim with 58% of participants attending from regional or rural areas. The course was generally well received with participants believing it should continue to be available. The end of course exam score was not improved compared to the pre-course exam. The failure rate was also higher in the end of course exam. However, the preand post-course examinations are not comparable. The pre-course exam tests individual pieces of knowledge in an open-book format designed to stimulate the participant to go to the manual and find the answer, raise awareness of deficiencies and in the process encourage reading of the pre-course material. The post-course exam is a summative assessment, designed to test correct application of knowledge and concepts taught. The pre-course exam predicts post-course exam results. This may reflect better preparation or motivation. Locally, we have had a similar experience with the results of the Society for Critical Care Medicine course. Here the difference between the pre-and post-exam in 271 participants completing 13 courses was only 3%, with 49% of participants worsening their scores and the proportion with less than 50% increasing from 1% to 3% (Ross Freebairn unpublished data). Performance on the final paper does vary internationally; Africa (n=24, mean 65% range 27 to 87%), East Asia (n=1494, mean 58% range 3 to 97%), Europe (n=291, mean 65% range 27 to 90%), Oceania (n=1481, mean 64% range 23 to 100%) and West Asia (n=276, mean 52% range 20 to 90%.", "cite_spans": [{"start": 91, "end": 92, "text": "1", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "P=0.001 [Charles Gomersall unpublished data]).", "text": "Importantly, the majority of the participants felt they had learned a great deal from the course. The pitch of the content and the amount of material was judged to be appropriate. Participants believed the amount of didactic teaching was appropriate despite 14 lectures in the program. The increase in the course duration to three days reduced the feedback of that insufficient time had been provided for training.", "cite_spans": [], "ref_spans": []}, {"section": "P=0.001 [Charles Gomersall unpublished data]).", "text": "The BASIC course was not designed to achieve clinical competency as an intensive care specialist or in crisis resource management. Rather, its aim is to provide an opportunity for specific learning in the principles of critical care management for those practitioners new to the area or required to provide this type of support infrequently. The assessment of understanding of the material was achieved using a multiple choice examination. Such a format was used to provide an efficient standardised approach for assessment across many countries, where both teaching and assessment resources are often limited. The questions are scenario-based and emphasise common clinical decisions that need to be regularly made in the early management of the clinically ill. Skill stations represent an initial phase of learning in a safe environment with many opportunities for revision and reinforcement.", "cite_spans": [], "ref_spans": []}, {"section": "P=0.001 [Charles Gomersall unpublished data]).", "text": "Our analysis reveals the performance of participants in the BASIC course. Ideally, longer term assessment of knowledge retention would be useful. While such assessments are planned for future study, resuscitation courses predominantly targeting basic and advanced life support generally find significant skill deterioration within six months unless some form of refresher program is available [4] [5] [6] [7] [8] . This is especially so for practitioners where such need for resuscitation skills are not part of their routine clinical practice 9 . Importantly, the skills taught in BASIC are more complex and wide-ranging compared to a conventional advanced cardiac life support or cardiopulmonary resuscitation course. Knowledge of the BASIC course performance is critical in facilitating program improvement such that the quality of clinical decisions in diagnosis and treatment is enhanced following course attendance.", "cite_spans": [{"start": 393, "end": 396, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 397, "end": 400, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 401, "end": 404, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 405, "end": 408, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 409, "end": 412, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 544, "end": 545, "text": "9", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "P=0.001 [Charles Gomersall unpublished data]).", "text": "BASIC is still evolving as a program. The clinical scenarios of the present pre-and post-course examinations were written by experienced tertiary educators with long experience of intensive care trainees from many disciplines and levels. BASIC courses continue to be assessed for the optimal teaching and assessment tools suitable for a short course and the inexperienced trainee or practitioner. A difficult question is where to set the passing grade or indeed whether such courses can truly grade competence 10 . Choosing a passing grade is a policy decision which must withstand stakeholder scrutiny. Such scores generally are based upon either qualified expert opinion of the level of knowledge and skill necessary to be demonstrated by participants as well as the skill composition of the passing cohort based upon a particular passing grade. As such there can be no perfectly selected passing score and the setting of the standard will always be controversial 11 . For the BASIC multiple choice written examination, a large body of data is now available to review the performance of questions for their ability to assess objective knowledge as well as decision making for paper-based clinical scenarios. This is the subject of further study along with the longer term utility of the program for skills maintenance.", "cite_spans": [{"start": 510, "end": 512, "text": "10", "ref_id": "BIBREF9"}, {"start": 966, "end": 968, "text": "11", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "P=0.001 [Charles Gomersall unpublished data]).", "text": "It is important to consider whether an assessment is to be formative with the aim to drive further learning or summative for the accomplishment of a minimal skill set. Short courses always have the problem of ensuring any degree of competence, especially where the range of skills is broad. Time is generally insufficient for the repeated practice required to acquire the appropriate skills. The final examination scores are not dissimilar to those commonly achieved in generic clinical examinations, a target passing score is relatively easy to arbitrarily set. An example may be an 80% overall passing score and 100% performance on key marker questions perhaps with a formal weighting of the remaining questions based upon a grading of the essential need for the knowledge or decision making. As such the questions are developed to ensure this occurs for the average participant. Such passing score standards must be acceptable and defensible while ensuring that the passing score reflects acceptable levels of knowledge, skill and ability. The latter is very difficult to accomplish in a short two-to three-day course especially where the precourse preparation by the trainees can be exceedingly variable and there are differing expectations of the proportion of time for student-driven as opposed to tutor-driven teaching. The importance of preparation for the course by participants is manifest by the association between completion to the pre-course assessment, and improved performance in the final examination. This allows for greater targeted study to the level of understanding required and to focus the participants on areas requiring greater attention and explanation during the course. Information on the expected time to adequately complete the course materials and perhaps advertising of a 'passing' score prior to the course may be a useful learning driver. Simulation perhaps allows the opportunity to contextualise the knowledge.", "cite_spans": [], "ref_spans": []}, {"section": "P=0.001 [Charles Gomersall unpublished data]).", "text": "BASIC courses utilise adult learning techniques and varied teaching formats to encourage candidate participation 12 , while reinforcement of factual content with practical application in skills stations encourages effective learning 13 . The assimilation of new information is more complex, but still achievable when the participants are from diverse clinical backgrounds 9 . Despite the unanimous support for the lectures, the feedback was significantly varied between courses in those topics traditionally known to be conceptually difficult such as arterial blood gas analysis, or unexciting, like electrolyte disturbances. In these areas attention to delivery format is important to ensure a successful program.", "cite_spans": [{"start": 113, "end": 115, "text": "12", "ref_id": "BIBREF11"}, {"start": 233, "end": 235, "text": "13", "ref_id": "BIBREF12"}, {"start": 372, "end": 373, "text": "9", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "P=0.001 [Charles Gomersall unpublished data]).", "text": "Cohorting of occupational groups for small group teaching may be advantageous given the differences in final examination results 14 . Such cohorting allows use of preferred teaching styles of particular craft groups. For small group skill stations such cohorting is commonly practised in BASIC. However, mixing groups, particularly in team clinical practice sessions such as cardiopulmonary resuscitation and clinical simulations, allows participants to practice together with improvement of teamwork skills within a multidisciplinary intensive care unit team 15 . Such a complex curriculum and diverse participant background requires tutors to be trained in the principles of small group teaching and lecturing and have an understanding of how the overall course is integrated. Ongoing supervision and feedback of teaching performance has been shown to improve the quality of teaching 16 and BASIC employs this strategy. An opportunity for simulation training can improve proficiency to allow participants to perform or assist in the conduct of critical care interventions appropriate to their occupational craft group 17 . The incorporation of simulation-based training in the Brisbane BASIC course correlated with improved final test outcomes. However, the reason for this is not entirely clear. Perhaps the availability of high fidelity simulation resulted in the self-selection of those participants who were more highly committed to success on the course. It is also possible that the stress of simulation training which includes realistic scenarios with peer-review based assessment is a stronger motivator for exam performance. Alternatively this form of assessment may influence the instructors such that they are more focused on the necessary outcomes, as compared with more traditional instructional modalities.", "cite_spans": [{"start": 129, "end": 131, "text": "14", "ref_id": "BIBREF13"}, {"start": 560, "end": 562, "text": "15", "ref_id": "BIBREF14"}, {"start": 886, "end": 888, "text": "16", "ref_id": "BIBREF15"}, {"start": 1120, "end": 1122, "text": "17", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "CONCLUSION", "text": "The BASIC course aims to provide an approach to the management of the critically ill by enhancing core knowledge, improving team work and inspiring confidence and enthusiasm in intensive care medicine. This review of the BASIC course as taught in Australia and New Zealand documents our experience of a course found to be a positive learning experience for participants in managing critical care patients.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "General competencies are intrinsic to emergency medicine training: a multicenter study", "authors": [{"first": "E", "middle": ["J"], "last": "Reisdorff", "suffix": ""}, {"first": "O", "middle": ["W"], "last": "Hayes", "suffix": ""}, {"first": "B", "middle": [], "last": "Reynolds", "suffix": ""}, {"first": "K", "middle": ["C"], "last": "Wilkinson", "suffix": ""}, {"first": "D", "middle": ["T"], "last": "Overton", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Wagner", "suffix": ""}], "year": 2003, "venue": "Acad Emerg Med", "link": "19268996"}, "BIBREF1": {"title": "Simulation-based training to improve acute care skills in medical undergraduates", "authors": [{"first": "J", "middle": [], "last": "Weller", "suffix": ""}, {"first": "B", "middle": [], "last": "Robinson", "suffix": ""}, {"first": "P", "middle": [], "last": "Larsen", "suffix": ""}, {"first": "C", "middle": [], "last": "Caldwell", "suffix": ""}], "year": 2004, "venue": "N Z Med J", "link": "3938269"}, "BIBREF2": {"title": "Teaching acute care: a course for undergraduates", "authors": [{"first": "P", "middle": ["C"], "last": "Gruber", "suffix": ""}, {"first": "C", "middle": ["D"], "last": "Gomersall", "suffix": ""}, {"first": "G", "middle": ["M"], "last": "Joynt", "suffix": ""}, {"first": "F", "middle": ["M"], "last": "Shields", "suffix": ""}, {"first": "Chu", "middle": [], "last": "Mci", "suffix": ""}, {"first": "J", "middle": ["L"], "last": "Derrick", "suffix": ""}], "year": 2007, "venue": "Resuscitation", "link": "46386626"}, "BIBREF3": {"title": "How frequently should basic cardiopulmonary resuscitation training be repeated to maintain adequate skills?", "authors": [{"first": "H", "middle": ["J"], "last": "Berden", "suffix": ""}, {"first": "F", "middle": ["F"], "last": "Willems", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Hendrick", "suffix": ""}, {"first": "N", "middle": ["H"], "last": "Pijls", "suffix": ""}, {"first": "J", "middle": ["T"], "last": "Knape", "suffix": ""}], "year": 1993, "venue": "BMJ", "link": "33658114"}, "BIBREF4": {"title": "Nurses' knowledge and skill retention following cardiopulmonary resuscitation training: a review of the literature", "authors": [{"first": "R", "middle": [], "last": "Hamilton", "suffix": ""}], "year": 2005, "venue": "J Adv Nurs", "link": "2188332"}, "BIBREF5": {"title": "Performance of aeromedical crewmembers: training or experience?", "authors": [{"first": "B", "middle": ["H"], "last": "Harris", "suffix": ""}], "year": 1986, "venue": "Am J Emerg Med", "link": "26350220"}, "BIBREF6": {"title": "Cardiopulmonary resuscitation skills of preregistration house officers: five years on", "authors": [{"first": "F", "middle": [], "last": "Morris", "suffix": ""}, {"first": "S", "middle": ["G"], "last": "Tordoff", "suffix": ""}, {"first": "D", "middle": [], "last": "Wallis", "suffix": ""}, {"first": "D", "middle": ["V"], "last": "Skinner", "suffix": ""}], "year": 1991, "venue": "BMJ", "link": "37774561"}, "BIBREF7": {"title": "A behavioral system for assessing and training cardiopulmonary resuscitation skills among emergency medical technicians", "authors": [{"first": "J", "middle": ["E"], "last": "Seaman", "suffix": ""}, {"first": "B", "middle": ["F"], "last": "Greene", "suffix": ""}, {"first": "M", "middle": [], "last": "Watson-Perczel", "suffix": ""}], "year": 1986, "venue": "J Appl Behav Anal", "link": "2675006"}, "BIBREF8": {"title": "Review of effective advanced cardiac life support training using experiential learning", "authors": [{"first": "T", "middle": [], "last": "Kidd", "suffix": ""}, {"first": "S", "middle": [], "last": "Kendall", "suffix": ""}], "year": 2007, "venue": "J Clin Nurs", "link": "22611685"}, "BIBREF9": {"title": "Passing standards scores: a manual for setting standards for performance on educational and occupational tests", "authors": [{"first": "S", "middle": ["A"], "last": "Livingston", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Zeiky", "suffix": ""}], "year": 1982, "venue": "Princeton: Education Testing Service", "link": null}, "BIBREF10": {"title": "Standards and criteria", "authors": [{"first": "G", "middle": ["V"], "last": "Glass", "suffix": ""}], "year": 1978, "venue": "J Educ Measurement", "link": "56780548"}, "BIBREF11": {"title": "Education techniques for lifelong learning: principles of adult learning", "authors": [{"first": "J", "middle": [], "last": "Collins", "suffix": ""}], "year": 2004, "venue": "Radiographics", "link": null}, "BIBREF12": {"title": "Effects of basic clinical skills training on objective structured clinical examination performance", "authors": [{"first": "J", "middle": [], "last": "Junger", "suffix": ""}, {"first": "S", "middle": [], "last": "Schafer", "suffix": ""}, {"first": "C", "middle": [], "last": "Roth", "suffix": ""}, {"first": "D", "middle": [], "last": "Schellberg", "suffix": ""}, {"first": "Bdm", "middle": [], "last": "Friedman", "suffix": ""}, {"first": "C", "middle": [], "last": "Nikendei", "suffix": ""}], "year": 2005, "venue": "Med Educ", "link": "40740930"}, "BIBREF13": {"title": "Learning together: clinical skills teaching for medical and nursing students", "authors": [{"first": "K", "middle": [], "last": "Tucker", "suffix": ""}, {"first": "A", "middle": [], "last": "Wakefield", "suffix": ""}, {"first": "C", "middle": [], "last": "Boggis", "suffix": ""}, {"first": "M", "middle": [], "last": "Lawson", "suffix": ""}, {"first": "T", "middle": [], "last": "Roberts", "suffix": ""}, {"first": "J", "middle": [], "last": "Gooch", "suffix": ""}], "year": 2003, "venue": "Med Educ", "link": "12023903"}, "BIBREF14": {"title": "Not just another multi-professional course! Part 1. Rationale for a transformative curriculum", "authors": [{"first": "M", "middle": [], "last": "Duncan", "suffix": ""}, {"first": "M", "middle": [], "last": "Alperstein", "suffix": ""}, {"first": "P", "middle": [], "last": "Mayers", "suffix": ""}, {"first": "L", "middle": [], "last": "Olckers", "suffix": ""}, {"first": "T", "middle": [], "last": "Gibbs", "suffix": ""}], "year": 2006, "venue": "Med Teach", "link": "21559547"}, "BIBREF15": {"title": "Can brief workshops improve clinical instruction?", "authors": [{"first": "N", "middle": [], "last": "Notzer", "suffix": ""}, {"first": "R", "middle": [], "last": "Abramovitz", "suffix": ""}], "year": 2008, "venue": "Med Educ", "link": "6403040"}, "BIBREF16": {"title": "Does simulation improve patient safety? Self-efficacy, competence, operational performance, and patient safety", "authors": [{"first": "A", "middle": [], "last": "Nishisaki", "suffix": ""}, {"first": "R", "middle": [], "last": "Keren", "suffix": ""}, {"first": "V", "middle": [], "last": "Nadkarni", "suffix": ""}], "year": 2007, "venue": "Anesthesiol Clin", "link": "6531612"}}, "ref_entries": {"FIGREF0": {"text": "figurE 1: Participant assessment of lectures in the Basic Assessment and Support in Intensive Care course.", "type": "figure"}, "FIGREF1": {"text": "figurE 2: Participant assessment of skill stations in the Basic Assessment and Support in Intensive Care course.", "type": "figure"}, "FIGREF2": {"text": "figurE 3: Participant overall assessment of the Basic Assessment and Support in Intensive Care course.", "type": "figure"}, "FIGREF3": {"text": "These include; Acute Life-threatening Events- Recognition and Treatment, Care of the Critically Ill Surgical Patient, DR WHO: a workshop for house officer preparation, Fundamental Critical Care Support, Advanced Life Support, Immediate Life Support, Advanced Trauma Life Support and Early Management of Severe Trauma 3 . Unlike the others, BASIC courses are founded upon the principles of Australian and New Zealand intensive care practice, emphasising recognition of critical illness, implementation of organ support and the early involvement of senior staff.", "type": "figure"}, "TABREF0": {"text": "implementation, some 796 participants have attended between 2005 and 2009; 338 (42%) in Brisbane and 458 (58%) in Hawke's Bay. In Brisbane the course candidates were mostly doctors (86.7%), with nurses and paramedics representing the remaining 12.1% and 1.2% respectively. This contrasts with New Zealand, where nurses (47.2%) and doctors (51.8%) are evenly represented (P <0.001, Table 1). Participants from regional or rural hospitals comprised 58% of the Brisbane participants and 75% in Hawke's Bay. Formal assessment of participants via the pre- course 'open book' and post-course multiple choice question (MCQ) examination (closed book) are presented in", "type": "table"}, "TABREF1": {"text": "Demographics of participants completing the course* Five Hawke's Bay participants did not have their training stream recorded (n=453). NR=not recorded.Participant performance on the pre-course multiple choice question paper*", "type": "table"}, "TABREF2": {"text": "). There were significantly different participant scores for individual course tutors for the lectures on cardio- pulmonary resuscitation (P=0.03) and patient transport (P=0.004) as well as the skill stations on components of a ventilator (Mechanical Ventilation 1, P=0.02), applications of mechanical ventilation to obstructive and restrictive disease (Mechanical", "type": "table"}, "TABREF3": {"text": "Regression modelling for post-course score", "type": "table"}}}
{"paper_id": "10704872", "_pdf_hash": "cd56909790692064f4392c03ae752e0fe17e978a", "abstract": [], "body_text": [{"section": "Optical Unification", "text": "An enduring issue in string theory has been the discrepancy between the SU(3) C \u00d7 SU(2) L \u00d7 U (1) 17 [2] . Three types of solutions have been proposed to resolve this factor of 20 disagreement [3] . One proposal is a grand unified theory between \u039b U and \u039b H . Here the MSSM couplings merge at \u039b U and then run together within a GUT to \u039b H . However, with the exception of flipped SU(5) [4] (or partial GUTs such as the Pati-Salam SU(4) C \u00d7 SU(2) L \u00d7 SU(2) R [5] ) string GUT models based on level-one Ka\u010d-Moody algebras encounter a difficulty: they lack the required adjoint higgs (and higher representations). Alternately, strong coupling effects of M-theory can lower \u039b H down to \u039b U [6] . Conversely, intermediate scale exotics could shift the MSSM unification scale upward to the string scale [7] .", "cite_spans": [{"start": 193, "end": 196, "text": "[3]", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "Optical Unification", "text": "The near ubiquitous appearance of MSSM-charged exotics in heterotic string models adds weight to the third proposal.", "cite_spans": [], "ref_spans": []}, {"section": "Optical Unification", "text": "* If MSSM exotics exist with intermediate scale masses of order \u039b I , then the actual [321] running couplings are altered above \u039b I . It is then, perhaps, phenomenologically puzzling that the illusion of MSSM unification should still be maintained when the intermediate scale MSSM exotics are ignored [11] . Maintaining this illusion likely requires very fine tuning of \u039b I for a generic exotic particle set and \u039b H . Slight shifting of \u039b I would, with high probability, destroy appearances. Thus, in some sense, the apparent MSSM unification below the string scale might be viewed as accidental [12, 11] .", "cite_spans": [{"start": 301, "end": 305, "text": "[11]", "ref_id": "BIBREF33"}, {"start": 601, "end": 604, "text": "11]", "ref_id": "BIBREF33"}], "ref_spans": []}, {"section": "Optical Unification", "text": "A mechanism whereby the appearance of a \u039b U is not accidental would be very appealing. Just such a mechanism, entitled \"optical unification,\" has recently been discussed by Joel Giedt [11] . Optical unification results in \u039b U not disappearing under shifts of \u039b I . Instead, \u039b U likewise shifts in value. This effect is parallel to a virtual image always appearing between a diverging lens and a real object, independent of the position of the lens or real object. Hence, Giedt's choice of appellation for this mechanism.", "cite_spans": [{"start": 184, "end": 188, "text": "[11]", "ref_id": "BIBREF33"}], "ref_spans": []}, {"section": "Optical Unification", "text": "Successful optical unification requires three things [11] . First, the effective level of the hypercharge generator must be the standard", "cite_spans": [{"start": 53, "end": 57, "text": "[11]", "ref_id": "BIBREF33"}], "ref_spans": []}, {"section": "Optical Unification", "text": "( 1.1) pair, respectively The models of [19] , [20] , and Table 5 model of [21] each contain 3 pairs. The [322] left-right symmetric models 1, 2, and 3 of [22] contain one, four, and two pairs, while the model of [23] contains three pairs. Thus, the models of [16] , [17] , and [18] , along with models 1 and 3 of [22] , contain too few SU(3) exotics to generate optical unification. The basis vectors of the [18] , [19] , and [20] models are the same. The variations among the corresponding models are solely a function of some differing GSO phase choices. Noting this, we have investigated further variations in GSO phase choices for these basis vectors.", "cite_spans": [], "ref_spans": []}, {"section": "Optical Unification", "text": "\u2021 Our investigation has resulted in five additional models, denoted FCREU1 through FCREU5, which respectively contain four pairs, three pairs, two pairs, no pairs, and, again, no pairs of exotic triplets/anti-triplets. The gauge groups and MSSM-charged exotic particle content of these models appear in Table A1 . The corresponding GSO phase variations from those of [18] are listed in Table A2 .", "cite_spans": [], "ref_spans": []}, {"section": "Optical Unification", "text": "Of the [321] models with three or more exotic 3/3 pairs, we focus on model FCREU1 with its 4 exotic pairs. (In Table A3 we list the complete set of states of this model and their charges.) Each of the other models presents difficulties: The model of [20] contains too few exotic doublets (only three rather than four) to satisfy (1.3) . The model FCREU2 with three exotic triplet/anti-triplet pairs contains nine exotic SU(2) L doublets, but six of these doublets are coupled in pairs via a custodial SU(2) C . Further, with regard to MSSM exotics, model FCREU1 is an enhanced version of the model in [19] . Any optical solution involving exactly three triplet/antitriplet pairs from model FCREU1 is also a solution for the model of [19] (and vice versa). The left-right symmetric models of [22] and [23] with three or more exotic 3/3 pairs will be discussed in a separate paper.", "cite_spans": [], "ref_spans": [{"start": 111, "end": 119, "text": "Table A3", "ref_id": "TABREF2"}]}, {"section": "Optical Unification", "text": "The MSSM-charged exotics of model FCREU1 are four SU(3) C 3/3 pairs, three SU(2) L doublet pairs, and seven pairs of MSSM exotic non-Abelian singlets carrying Q Y = \u00b1 . None of the exotic SU(2) L non-higgs doublets carry hypercharge. For successful optical unification, when all four 3/3 exotic pairs receive intermediate scale masses, all three pairs of exotic non-higgs doublets must also. Further, the total contribution to \u03b4b Y from all 3/3 pairs is 2 1 6 , while (1.2) requires a total \u03b4b Y = 2 2 3 . Since the exotic non-higgs doublets have no hypercharge, the remainder of 2 must be provided by exactly two exotic singlets, each contributing 1 4 to \u03b4b Y . The six remaining pairs of exotic singlets must acquire FayetIliopoulos (FI) scale masses.", "cite_spans": [], "ref_spans": []}, {"section": "Optical Unification", "text": "If one exotic 3/3 pair receives near string scale mass, leaving only three exotic 3/3 pairs to receive intermediate scale masses, the total triplet/anti-triplet contribution \u2021 Because of the symmetries within the basis vectors generating these models, differing GSO phase choices can yield identical models. The complete set of models produced from the distinct GSO phase choices for the basis vectors of [18] will be discussed elsewhere.", "cite_spans": [], "ref_spans": []}, {"section": "Optical Unification", "text": "to \u03b4b Y can be 2, 1 3 4 , or 1 1 2 , depending on whether zero, one, or two intermediate scale (anti-)triplets carry Q Y = \u00b1 1 6 , respectively. Even the lowest of these choices provides too large of a contribution to \u03b4b Y , since for three exotic 3/3 pairs (1.2) and (1.3) require \u03b4b Y = 1. Hence, optical unification cannot be achieved for this model when only three 3/3 pairs acquire intermediate scale masses. This also implies optical unification is not possible for the model of [19] . The Table 5 model of [21] is another with three exotic 3/3 pairs, of which each has Q Y = \u00b1 1 3 . Thus, the Table 5 model is similarly prohibited from optical unification.", "cite_spans": [], "ref_spans": []}, {"section": "Optical Unification", "text": "Optical lensing might be possible in other models containing exactly three hypercharged exotic 3/3 pairs, if these pairs were of the Q Y = \u00b1 1 6 class. Then their total contribution to \u03b4b Y would be 1 2 . The remaining contribution of 1 2 for the required total \u03b4b Y = 1 could be provided by two singlets, each with", "cite_spans": [], "ref_spans": []}, {"section": "Optical Unification", "text": "originates in a sector for which the fermions generating the SU(3) C symmetry have antiperiodic boundary conditions, while a 3 or3 with Q Y = \u00b1 1 6 originates in a sector for which these fermions have periodic boundary conditions. Whether or not a model can have exactly three exotic 3/3 pairs with", "cite_spans": [], "ref_spans": []}, {"section": "Optical Unification", "text": "is under investigation [24] .", "cite_spans": [], "ref_spans": []}, {"section": "Optical Unification", "text": "In addition to containing the set of four 3/3 pairs, three non-higgs-like doublet pairs, and one pair of singlets, which satisfies the optical unification constraints (1.1) singlets and the three extra higgs-like doublets. For successful optical unification these additional MSSM exotics must receive near string scale masses, while the optical unifying set does not.", "cite_spans": [], "ref_spans": []}, {"section": "Optical Unification", "text": "Like the other NAHE-based standard-like models, the model of [18] , and its variations in [19, 20, 21] and herein, contain an anomalous U(1) [25] .", "cite_spans": [{"start": 141, "end": 145, "text": "[25]", "ref_id": "BIBREF52"}], "ref_spans": []}, {"section": "Optical Unification", "text": "\u00a7 The anomalous Abelian symmetry is broken by the Green-Schwarz-Dine-Seiberg-Witten mechanism [26] , which generates a contribution, \u03be, to the anomalous FI D-term in the process. A flat direction of vacuum expectation values (VEVs) of scalars is then non-perturbatively chosen to cancel the FI \u03be-term, restoring supersymmetry and stabilizing the vacuum. The FI VEV scale is typically \u223c 1 10 of the string scale. Superpotential interaction of the flat direction VEVs with superfields can generate (near) FI scale masses for various states. Thus, ideally it may be possible for the six additional pairs of exotic singlets and three pairs of extra higgs-like doublets to receive FI scale masses from the flat direction VEVs, while the optical unification exotics remain massless at the FI scale.", "cite_spans": [], "ref_spans": []}, {"section": "Optical Unification", "text": "Singlet and non-singlet flat directions of the MSHSM were constructed in [8, 9, 10 ] that give FI scale masses to exactly three out of four pairs of higgs-like doublets. For these flat directions, the physical higgs doublets h andh are formed from a linear combination of three or more h i andh i , respectively, while three orthogonal linear combinations of h i and ofh i receive FI scale mass. Similar flat directions may accomplish this for model FCREU1 also. Such flat directions must also generate \u00a7 A few semi-realistic non-anomalous NAHE-based models have been constructed, such as the first two left-right symmetric models in [22] , but these have enhanced observable sector symmetries.", "cite_spans": [], "ref_spans": []}, {"section": "Optical Unification", "text": "FI scale masses for exactly six of the seven pairs of exotic Q Y -carrying singlets. Interestingly, as Table A3 indicates, the pair of singlets denoted A 1 /\u0100 1 does not follow the charge pattern of the other six. This is the singlet pair most likely to remain massless at the FI scale. To be consistent with optical unification, a flat direction must, of course, keep the four pairs of exotic MSSM triplets and the three pairs of exotic non-higgs-like doublets FI scale massless, as we have discussed. Studies of model FCREU1 perturbative flat directions and of their implications regarding masses are underway [24] . The methods of this investigation are parallel to those followed in the flat direction studies of the MSHSM [8, 9, 10] , flipped SU(5) [27, 28] , and of other standard-like and semi-GUT models [22, 23, 29, 30] located in the parameter space of NAHE-based models.", "cite_spans": [{"start": 825, "end": 828, "text": "30]", "ref_id": "BIBREF62"}], "ref_spans": [{"start": 103, "end": 111, "text": "Table A3", "ref_id": "TABREF2"}]}, {"section": "Optical Unification", "text": "Assuming that the required exotic triplets, doublets, and non-Abelian singlets remain massless at the FI scale, an intermediate mass scale must be generated for them, perhaps through ninth or higher order mass terms resulting from flat direction VEVs or hidden sector condensation. Mass terms for specific flat directions will be studied in [24] . Alternately, for a generic SU(N c ) gauge group containing N f flavors of matter states in vector-like pairings H iHi , i = 1, . . . N f , the gauge coupling g i , though weak at the string scale M str , becomes strong for N f < 3N c at a condensation scale defined by 1) where the \u03b2-function is given by,", "cite_spans": [], "ref_spans": []}, {"section": "Optical Unification", "text": "2)", "cite_spans": [], "ref_spans": []}, {"section": "Optical Unification", "text": "The N f flavors counted are only those that ultimately receive masses m \u226a \u039b. The hidden sector matter states of model FCREU1 are four 5/5 pairs of SU(5) H and four 3/3 pairs of SU (3) H . Any number of these states from none to all might become FI scale massive under a flat direction. Thus, \u03b2 5 could be anywhere from -15 to -11, corresponding to a SU(5) condensate scale range of 1 \u00d7 10 14 GeV to 2 \u00d7 10 15 GeV. Similarly, \u03b2 3 could be anywhere from -9 to -5, corresponding to a SU(3) condensate scale range of 1 \u00d7 10 9 GeV to 2 \u00d7 10 13 GeV. Thus, when generated by hidden sector condensation, the intermediate mass scale for the MSSM exotics could be anywhere from 10 9 GeV to 10 15 GeV.", "cite_spans": [], "ref_spans": []}, {"section": "Concluding Comments", "text": "In this letter we have discussed the possibility of achieving optical unification within a [321] heterotic string. Optical unification, recently suggested by J. Giedt [11] , would explain the apparent MSSM unification scale near 2.5 \u00d7 10", "cite_spans": [{"start": 167, "end": 171, "text": "[11]", "ref_id": "BIBREF33"}], "ref_spans": []}, {"section": "Concluding Comments", "text": "16 GeV as a \"virtual image effect\" of an actual unification of couplings at the string scale, \u223c 5\u00d710 17 GeV. An intriguing aspect of optical unification is that the apparent MSSM We presented herein a model possessing the potential for optical unification. This model is of free fermionic construction in the NAHE class. Its basis vectors first appeared in [18, 19, 20] . The differences between this model and those in [18, 19, 20] result from a few changes in GSO phases. These changes produce a set of MSSM exotic states with properties strongly suggesting that optical unification may be possible within some regions of the parameter space of NAHE-based weakly coupled heterotic strings. Further research will reveal if this is indeed so [24] . Variations on [321] NAHE-Based Models.", "cite_spans": [], "ref_spans": []}, {"section": "Acknowledgments", "text": "Table A1: Gauge Groups and MSSM Exotics Fields of Models. The second column gives the gauge group for each model. The third column entry specifies the MSSMcharged exotic matter content. An exotic's representation under SU(3) C \u00d7 SU(2) L is specified by the two numbers in brackets. Hypercharge is given by the first subscript and anomalous U(1) charge is given for non-Abelian singlets by a second subscript.", "cite_spans": [], "ref_spans": []}, {"section": "GSO Phases Variations", "text": "Model Name GSO Phase Variations FCREU1 C Table A2 : New Models and Their GSO Phase Variations. Only the GSO phases differing from those of [18] are given.", "cite_spans": [], "ref_spans": []}, {"section": "13", "text": "Model FCREU1 Fields ", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF7": {"title": "For a summary of the various proposed solutions see for example", "authors": [{"first": "K", "middle": ["R"], "last": "Dienes", "suffix": ""}, {"first": "A", "middle": ["E"], "last": "Faraggi", "suffix": ""}], "year": 1995, "venue": "Phys. Rev. Lett", "link": null}, "BIBREF13": {"title": "Flipped SU(5): A Grand Unified Superstring Theory (GUST) Prototype", "authors": [{"first": "J", "middle": [], "last": "Lopez", "suffix": ""}, {"first": "D", "middle": ["V"], "last": "Nanopoulos", "suffix": ""}], "year": "", "venue": "", "link": "14650726"}, "BIBREF16": {"title": "Nonperturbative Flipped SU(5) vacua in heterotic M Theory", "authors": [{"first": "A", "middle": ["E"], "last": "Faraggi", "suffix": ""}, {"first": "R", "middle": [], "last": "Garavuso", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Isidro", "suffix": ""}], "year": "", "venue": "", "link": "14317382"}, "BIBREF26": {"title": "M-Fluences on String Model Building", "authors": [{"first": "G", "middle": ["B"], "last": "Cleaver", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF31": {"title": "Phenomenological Survey of a Minimal Superstring Standard Model", "authors": [{"first": "G", "middle": ["B"], "last": "Cleaver", "suffix": ""}], "year": "", "venue": "", "link": "17521700"}, "BIBREF33": {"title": "Optical Unification", "authors": [{"first": "J", "middle": [], "last": "Giedt", "suffix": ""}], "year": "", "venue": "", "link": "8362051"}, "BIBREF35": {"title": "Heterotic Orbifolds", "authors": [{"first": "J", "middle": [], "last": "Giedt", "suffix": ""}], "year": "", "venue": "", "link": "119452572"}, "BIBREF52": {"title": "Superstring Construction", "authors": [{"first": "A", "middle": [], "last": "Schellekens", "suffix": ""}], "year": 1989, "venue": "", "link": null}, "BIBREF62": {"title": "Geometric Interpretation of Non-Abelian D-and F -Flat Direction Constraints", "authors": [{"first": "G", "middle": ["B"], "last": "Cleaver", "suffix": ""}, {"first": "D", "middle": ["V"], "last": "Nanopoulos", "suffix": ""}, {"first": "J", "middle": [], "last": "Perkins", "suffix": ""}, {"first": "J", "middle": ["W"], "last": "Walker", "suffix": ""}], "year": "", "venue": "", "link": null}}, "ref_entries": {"FIGREF0": {"text": "addition to three pairs of linear combinations of the MSSM higgs-like doublets, h i=1 to 4 andh i=1 to 4 . The extra higgs-like doublets are generally present in NAHE-based [321] models. Three of the SU(3) C exotic pairs carry Q Y", "type": "figure"}, "FIGREF2": {"text": "- (1.3), model FCREU1 possesses the other six pairs of Q Y = \u00b1 1 2", "type": "figure"}, "FIGREF3": {"text": "This letter is a product of the 2002 NSF High School Summer Science Research (HSSSR) and Research Experiences for Undergraduates (REU) programs sponsored by the Center for Astrophysics, Space Physics, and Engineering Research (CASPER) at Baylor University. Research funding for Viren Desai was provided by the HSSSR program; Research funding for Heather Hanson, David Robbins, and Scot Shields was provided by the REU program. G.C. thanks Alon Faraggi and Dimitri Nanopoulos for numerous helpful discussions regarding NAHE-based models and thanks Joel Giedt for helpful discussions regarding optical unification.", "type": "figure"}, "FIGREF5": {"text": "", "type": "figure"}, "TABREF0": {"text": "Y ([321]) gauge coupling unification scale \u039b U for the Min- imal Supersymmetric Standard Model (MSSM) with intermediate scale desert and the string scale \u039b H for the weakly coupled heterotic string. When couplings are run upward from their values near M Z o , a MSSM unification scale \u039b U \u223c 2.5 \u00d7 10 16 GeV [1] is predicted for an intermediate scale desert. In contrast, the weakly coupled heterotic string scale is around \u039b H \u223c 5 \u00d7 10", "type": "table"}, "TABREF1": {"text": "unification is not accidental. Rather, in this case, like the guaranteed appearance of a virtual image between a diverging lens and a real object, a MSSM unification scale will always appear between the intermediate mass scale of the MSSM exotics and the string unification scale, when coupling strengths are run upward from their measured values at low energy scales, under the assumption of an intermediate scale desert. As movement of the diverging lens or of the real object simply alters the position of the virtual image, so too movement of the intermediate mass scale or of the string scale simply alters the location of the predicted MSSM unification scale.", "type": "table"}, "TABREF2": {"text": "Model FCREU1 Fields and Their Charges. 14", "type": "table"}, "TABREF3": {"text": ": Model FCREU1 Fields and Their Charges. 15Table A3 continued: Model FCREU1 Fields and Their Charges.", "type": "table"}}}
{"paper_id": "10705295", "_pdf_hash": "4e5eb0e580d45bd5d771696c0f4d2ccb39ad9720", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Systematic determination of genetic network architecture", "authors": [{"first": "S", "middle": [], "last": "Tavazoie", "suffix": ""}, {"first": "J", "middle": [], "last": "Hughes", "suffix": ""}, {"first": "M", "middle": [], "last": "Campbell", "suffix": ""}, {"first": "R", "middle": [], "last": "Cho", "suffix": ""}, {"first": "G", "middle": [], "last": "Church", "suffix": ""}], "year": 1999, "venue": "Nature Genetics", "link": "14688842"}, "BIBREF1": {"title": "Temporal Boolean Network Models of Genetic Networks and Their Inference from Gene Expression Time Series", "authors": [{"first": "A", "middle": [], "last": "Silvescu", "suffix": ""}, {"first": "V", "middle": [], "last": "Honavar", "suffix": ""}], "year": 2001, "venue": "Complex Systems", "link": "18458627"}, "BIBREF2": {"title": "Integrative Analysis of Cell Cycle Control in Budding Yeast", "authors": [{"first": "K", "middle": [], "last": "Chen", "suffix": ""}, {"first": "L", "middle": [], "last": "Calzone", "suffix": ""}, {"first": "A", "middle": [], "last": "Csikasz-Nagy", "suffix": ""}, {"first": "F", "middle": [], "last": "Cross", "suffix": ""}, {"first": "B", "middle": [], "last": "Novak", "suffix": ""}, {"first": "J", "middle": [], "last": "Tyson", "suffix": ""}], "year": 2004, "venue": "Molecular Biology of the Cell", "link": null}, "BIBREF3": {"title": "Hybrid Petri net representation of gene regulatory network", "authors": [{"first": "H", "middle": [], "last": "Matsuno", "suffix": ""}, {"first": "A", "middle": [], "last": "Doi", "suffix": ""}, {"first": "M", "middle": [], "last": "Nagasaki", "suffix": ""}, {"first": "S", "middle": [], "last": "Miyano", "suffix": ""}], "year": 2000, "venue": "Pacic Symposium on Biocomputing", "link": "11716588"}, "BIBREF4": {"title": "Gene perturbation and intervention in probabilistic Boolean networks", "authors": [{"first": "I", "middle": [], "last": "Shmulevich", "suffix": ""}, {"first": "E", "middle": [], "last": "Dougherty", "suffix": ""}, {"first": "W", "middle": [], "last": "Zhang", "suffix": ""}], "year": 2002, "venue": "Bioinformatics", "link": "10614809"}, "BIBREF5": {"title": "A gene-coexpression network for global discovery of conserved genetic modules", "authors": [{"first": "J", "middle": ["M"], "last": "Stuart", "suffix": ""}, {"first": "E", "middle": [], "last": "Segal", "suffix": ""}, {"first": "D", "middle": [], "last": "Koller", "suffix": ""}, {"first": "S", "middle": ["K"], "last": "Kim", "suffix": ""}], "year": 2003, "venue": "Science", "link": "3131371"}, "BIBREF6": {"title": "Estimating genomic coexpression networks using rstorder conditional independence", "authors": [{"first": "P", "middle": ["M"], "last": "Magwene", "suffix": ""}, {"first": "J", "middle": [], "last": "Kim", "suffix": ""}], "year": 2004, "venue": "Genome Biol", "link": null}, "BIBREF7": {"title": "Reverse engineering of regulatory networks in human B cells", "authors": [{"first": "K", "middle": [], "last": "Basso", "suffix": ""}, {"first": "A", "middle": [], "last": "Margolin", "suffix": ""}, {"first": "G", "middle": [], "last": "Stolovitzky", "suffix": ""}, {"first": "U", "middle": [], "last": "Klein", "suffix": ""}, {"first": "R", "middle": [], "last": "Dalla-Favera", "suffix": ""}, {"first": "A", "middle": [], "last": "Califano", "suffix": ""}], "year": 2005, "venue": "Nature Genetics", "link": "2289426"}, "BIBREF8": {"title": "Using bayesian networks to analyze expression data", "authors": [{"first": "N", "middle": [], "last": "Friedman", "suffix": ""}], "year": 2001, "venue": "Journal of Computational Biology", "link": "53303729"}, "BIBREF9": {"title": "Learning with continuous classes", "authors": [{"first": "J", "middle": [], "last": "Quinlan", "suffix": ""}], "year": 1992, "venue": "Procedings Australian Joint Conference on Articial Intelligence", "link": "1056674"}, "BIBREF10": {"title": "Data Mining: Practical Machine Learning Tools and Techniques with Java Implementations", "authors": [{"first": "I", "middle": [], "last": "Witten", "suffix": ""}, {"first": "E", "middle": [], "last": "Frank", "suffix": ""}], "year": 2000, "venue": "", "link": "61973115"}, "BIBREF11": {"title": "Linear regression in regression tree leaves", "authors": [{"first": "A", "middle": [], "last": "Karalic", "suffix": ""}], "year": 1992, "venue": "Proceedings of the ISSEK92", "link": "14680306"}, "BIBREF12": {"title": "Functional models for regression tree leaves", "authors": [{"first": "L", "middle": [], "last": "Torgo", "suffix": ""}], "year": 1997, "venue": "Proceedings of the Fourteenth International Conference on Machine Learning", "link": "9213164"}, "BIBREF13": {"title": "Partial linear trees", "authors": [{"first": "L", "middle": [], "last": "Torgo", "suffix": ""}], "year": 2000, "venue": "Proceedings of the 17th International Conference on Machine Learning", "link": "12261705"}, "BIBREF14": {"title": "Interactive Tree-Structured Regression Via Principal Hessian Directions", "authors": [{"first": "K", "middle": [], "last": "Li", "suffix": ""}, {"first": "H", "middle": [], "last": "Lue", "suffix": ""}, {"first": "C", "middle": [], "last": "Chen", "suffix": ""}], "year": 2000, "venue": "Journal of the American Statistical Association", "link": "119481329"}, "BIBREF15": {"title": "Probabilistic discovery of overlapping cell processes and their regulation", "authors": [{"first": "A", "middle": [], "last": "Battle", "suffix": ""}, {"first": "E", "middle": [], "last": "Segal", "suffix": ""}, {"first": "D", "middle": [], "last": "Koller", "suffix": ""}], "year": 2004, "venue": "Eight Annual International Conference on Research in Computational Molecular Biology (RECOMB)", "link": null}, "BIBREF16": {"title": "Module networks: identifying regulatory modules and their condition-specic regulators from gene expression data", "authors": [{"first": "E", "middle": [], "last": "Segal", "suffix": ""}, {"first": "M", "middle": [], "last": "Shapira", "suffix": ""}, {"first": "A", "middle": [], "last": "Regev", "suffix": ""}, {"first": "D", "middle": [], "last": "Pe&apos;er", "suffix": ""}, {"first": "D", "middle": [], "last": "Botstein", "suffix": ""}, {"first": "D", "middle": [], "last": "Koller", "suffix": ""}], "year": 2003, "venue": "Nature Genetics", "link": "6146032"}, "BIBREF17": {"title": "Functional Discovery via a Compendium of Expression Proles", "authors": [{"first": "T", "middle": [], "last": "Hughes", "suffix": ""}, {"first": "M", "middle": [], "last": "Marton", "suffix": ""}, {"first": "A", "middle": [], "last": "Jones", "suffix": ""}, {"first": "C", "middle": [], "last": "Roberts", "suffix": ""}, {"first": "R", "middle": [], "last": "Stoughton", "suffix": ""}, {"first": "C", "middle": [], "last": "Armour", "suffix": ""}, {"first": "H", "middle": [], "last": "Bennett", "suffix": ""}, {"first": "E", "middle": [], "last": "Coey", "suffix": ""}, {"first": "H", "middle": [], "last": "Dai", "suffix": ""}, {"first": "Y", "middle": [], "last": "He", "suffix": ""}], "year": 2002, "venue": "Cell", "link": null}, "BIBREF18": {"title": "Comprehensive Identication of Cell Cycleregulated Genes of the Yeast Saccharomyces cerevisiae by Microarray Hybridization", "authors": [{"first": "G", "middle": [], "last": "Fink", "suffix": ""}, {"first": "P", "middle": [], "last": "Spellman", "suffix": ""}, {"first": "G", "middle": [], "last": "Sherlock", "suffix": ""}, {"first": "M", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "V", "middle": [], "last": "Iyer", "suffix": ""}, {"first": "K", "middle": [], "last": "Anders", "suffix": ""}, {"first": "M", "middle": [], "last": "Eisen", "suffix": ""}, {"first": "P", "middle": [], "last": "Brown", "suffix": ""}, {"first": "D", "middle": [], "last": "Botstein", "suffix": ""}, {"first": "B", "middle": [], "last": "Futcher", "suffix": ""}], "year": 1998, "venue": "Molecular Biology of the Cell", "link": "5839507"}, "BIBREF19": {"title": "Discovering statistically signicant biclusters in gene expression data", "authors": [{"first": "J", "middle": [], "last": "Pe\u00f1a", "suffix": ""}, {"first": "J", "middle": [], "last": "Bjorkegren", "suffix": ""}, {"first": "J", "middle": [], "last": "Tegner", "suffix": ""}], "year": 2005, "venue": "", "link": "2552378"}, "BIBREF20": {"title": "Siderophore uptake and use by the yeast Saccharomyces cerevisiae", "authors": [{"first": "E", "middle": [], "last": "Lesuisse", "suffix": ""}, {"first": "P", "middle": [], "last": "Blaiseau", "suffix": ""}, {"first": "A", "middle": [], "last": "Dancis", "suffix": ""}, {"first": "J", "middle": [], "last": "Camadro", "suffix": ""}], "year": 2001, "venue": "", "link": "25563758"}, "BIBREF21": {"title": "Aracne:an algorithm for the reconstruction of gene regulatory networks in a mammalian cellular context", "authors": [{"first": "A", "middle": [], "last": "Margolin", "suffix": ""}, {"first": "I", "middle": [], "last": "Nemenman", "suffix": ""}, {"first": "K", "middle": [], "last": "Basso", "suffix": ""}, {"first": "C", "middle": [], "last": "Wiggins", "suffix": ""}, {"first": "G", "middle": [], "last": "Stolovitzky", "suffix": ""}, {"first": "R", "middle": [], "last": "Dalla Favera", "suffix": ""}, {"first": "A", "middle": [], "last": "Califano", "suffix": ""}], "year": 2006, "venue": "BMC Bioinformatics", "link": "7060566"}, "BIBREF22": {"title": "Inferring Subnetworks from Perturbed Expression Proles", "authors": [{"first": "D", "middle": [], "last": "Peer", "suffix": ""}, {"first": "A", "middle": [], "last": "Regev", "suffix": ""}, {"first": "G", "middle": [], "last": "Elidan", "suffix": ""}, {"first": "N", "middle": [], "last": "Friedman", "suffix": ""}], "year": 2002, "venue": "Bioinformatics", "link": null}}, "ref_entries": {}}
{"paper_id": "10705398", "_pdf_hash": "4a06fb4e50983f1878afa896d774dfd58caa3360", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "U:Prvi jugoslavenski kongres o o\u010duvanju \u010disto\u0107e vazduha. Jedinstvena jugoslovenska strategija o\u010duvanja \u010disto\u0107e vazduha. Zbornik referata. Knjiga I. Zenica, BiH", "authors": [{"first": "A", "middle": [], "last": "Buza", "suffix": ""}], "year": 1989, "venue": "Stanje zaga\u0111enosti zraka u op\u0161tini Kakanj", "link": null}, "BIBREF1": {"title": "Italian MISA Group.Meta-analysis of the Italian studies on short-term effects of air pollution", "authors": [{"first": "A", "middle": [], "last": "Biggeri", "suffix": ""}, {"first": "P", "middle": [], "last": "Bellini", "suffix": ""}, {"first": "B", "middle": [], "last": "Terracini", "suffix": ""}], "year": 2001, "venue": "Epidemiol Prev", "link": null}, "BIBREF2": {"title": "Short-term assotiations between outdoor air pollution and visits to accident and emergency departments in London for respiratory complaints", "authors": [{"first": "R", "middle": ["W"], "last": "Atikson", "suffix": ""}, {"first": "H", "middle": ["R"], "last": "Anderson", "suffix": ""}, {"first": "D", "middle": ["P"], "last": "Starchan", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Bland", "suffix": ""}, {"first": "S", "middle": ["A"], "last": "Bremnere", "suffix": ""}, {"first": "A", "middle": [], "last": "Ponce De Leon", "suffix": ""}], "year": 1999, "venue": "Eur Respir J", "link": "11864094"}, "BIBREF3": {"title": "Ambient air pollution and cardiovascular emergency department visits", "authors": [{"first": "K", "middle": ["B"], "last": "Metzger", "suffix": ""}, {"first": "P", "middle": ["E"], "last": "Tolbert", "suffix": ""}, {"first": "M", "middle": [], "last": "Klein", "suffix": ""}, {"first": "J", "middle": ["L"], "last": "Peel", "suffix": ""}, {"first": "W", "middle": ["D"], "last": "Flanders", "suffix": ""}, {"first": "K", "middle": [], "last": "Todd", "suffix": ""}], "year": 2004, "venue": "Epidemiology", "link": "1469654"}, "BIBREF4": {"title": "Air pollution and hospital admissions for respiratory conditions in", "authors": [{"first": "D", "middle": [], "last": "Fusco", "suffix": ""}, {"first": "F", "middle": [], "last": "Forastiere", "suffix": ""}, {"first": "P", "middle": [], "last": "Michelozzi", "suffix": ""}, {"first": "T", "middle": [], "last": "Spadea", "suffix": ""}, {"first": "B", "middle": [], "last": "Ostro", "suffix": ""}, {"first": "M", "middle": [], "last": "Arca", "suffix": ""}], "year": 2001, "venue": "", "link": null}, "BIBREF5": {"title": "Meta-analysis of the Italian studies on short-term effects of air pollution-MISA", "authors": [{"first": "A", "middle": [], "last": "Biggeri", "suffix": ""}, {"first": "P", "middle": [], "last": "Bellini", "suffix": ""}, {"first": "B", "middle": [], "last": "Terracini", "suffix": ""}], "year": 1996, "venue": "Epidemiol Prev", "link": "35611444"}, "BIBREF6": {"title": "Temporal relationship between air pollution and hospital admissions for asthmatic children in Hong Kong", "authors": [{"first": "G", "middle": ["W"], "last": "Wong", "suffix": ""}, {"first": "F", "middle": ["W"], "last": "Ko", "suffix": ""}, {"first": "T", "middle": ["S"], "last": "Lau", "suffix": ""}, {"first": "S", "middle": ["T"], "last": "Li", "suffix": ""}, {"first": "D", "middle": [], "last": "Hui", "suffix": ""}, {"first": "S", "middle": ["W"], "last": "Pang", "suffix": ""}], "year": 2001, "venue": "Clin Exp Allergy", "link": "21309481"}, "BIBREF7": {"title": "Air pollution and health effects: A study of medical visits among children in", "authors": [{"first": "B", "middle": ["D"], "last": "Ostro", "suffix": ""}, {"first": "G", "middle": ["S"], "last": "Eskeland", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Sanchez", "suffix": ""}, {"first": "T", "middle": [], "last": "Fevzioglu", "suffix": ""}], "year": 1999, "venue": "Environ Health Perspect", "link": null}, "BIBREF8": {"title": "Effect of air pollution on pediatric respiratory emergency room visits and hospital admissions", "authors": [{"first": "S", "middle": ["C"], "last": "Farhat", "suffix": ""}, {"first": "R", "middle": ["L"], "last": "Paulo", "suffix": ""}, {"first": "T", "middle": ["M"], "last": "Shimoda", "suffix": ""}, {"first": "G", "middle": ["M"], "last": "Conceicao", "suffix": ""}, {"first": "C", "middle": ["A"], "last": "Lin", "suffix": ""}, {"first": "A", "middle": ["L"], "last": "Braga", "suffix": ""}], "year": 2005, "venue": "Braz J Med Biol Res", "link": "22932643"}, "BIBREF9": {"title": "Acute effects of particulate air pollution on respiratory admissions: result from APHEA 2 project. Air Pollution and health: a European Approach", "authors": [{"first": "R", "middle": ["W"], "last": "Atkinson", "suffix": ""}, {"first": "H", "middle": ["R"], "last": "Anderson", "suffix": ""}, {"first": "J", "middle": [], "last": "Sunyer", "suffix": ""}, {"first": "J", "middle": [], "last": "Ayres", "suffix": ""}, {"first": "M", "middle": [], "last": "Baccini", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Vonk", "suffix": ""}], "year": 2001, "venue": "Am J Respir Crit Care Med", "link": "36164409"}, "BIBREF10": {"title": "Effects of atmospheric sulphur diocside and particulate matter concentracions on emergency room admissions due asthma in Ankara", "authors": [{"first": "B", "middle": ["M"], "last": "Berktas", "suffix": ""}, {"first": "A", "middle": [], "last": "Bircan", "suffix": ""}], "year": 2003, "venue": "Tuberk Toraks", "link": null}, "BIBREF11": {"title": "Particulate air pollution and hospital emergency room visits for asthma in Seattle", "authors": [{"first": "J", "middle": [], "last": "Schwartz", "suffix": ""}, {"first": "D", "middle": [], "last": "Slater", "suffix": ""}, {"first": "T", "middle": ["V"], "last": "Larson", "suffix": ""}, {"first": "W", "middle": ["E"], "last": "Pierson", "suffix": ""}, {"first": "J", "middle": ["Q"], "last": "Koenig", "suffix": ""}], "year": 1993, "venue": "Am Rev Respir", "link": "25247131"}, "BIBREF12": {"title": "Short-term effects of ambient nitrogen oxides on number of emergency asthma cases in", "authors": [{"first": "A", "middle": [], "last": "Jazbec", "suffix": ""}, {"first": "D", "middle": [], "last": "Simic", "suffix": ""}, {"first": "J", "middle": [], "last": "Hrsac", "suffix": ""}, {"first": "T", "middle": [], "last": "Peros-Golubcic", "suffix": ""}, {"first": "D", "middle": [], "last": "Kujundzic", "suffix": ""}, {"first": "K", "middle": [], "last": "Sega", "suffix": ""}], "year": 1999, "venue": "Arh Hig Rada Toksikol", "link": null}, "BIBREF13": {"title": "The role of air pollution in asthma and other pediatric morbidities", "authors": [{"first": "L", "middle": [], "last": "Trasande", "suffix": ""}, {"first": "G", "middle": ["D"], "last": "Thurston", "suffix": ""}], "year": 2005, "venue": "J Allergy Clin Immunol", "link": "13309712"}}, "ref_entries": {}}
{"paper_id": "10705612", "_pdf_hash": "2316abf836d730bc149f6e0d69ccd7792e2e7c73", "abstract": [], "body_text": [], "bib_entries": {"BIBREF1": {"title": "Empirical analysis of predictive algorithms for collaborative filtering", "authors": [{"first": "J", "middle": ["S"], "last": "Breese", "suffix": ""}, {"first": "D", "middle": [], "last": "Heckerman", "suffix": ""}, {"first": "C", "middle": ["M"], "last": "Kadie", "suffix": ""}], "year": 1998, "venue": "Proceedings of the 14th Conference on Uncertainty in Artificial Intelligence", "link": "2885948"}, "BIBREF2": {"title": "Mining skewed and sparse transaction data for personalized shopping recommendation", "authors": [{"first": "C.-N", "middle": [], "last": "Hsu", "suffix": ""}, {"first": "H.-H", "middle": [], "last": "Chung", "suffix": ""}, {"first": "H.-S", "middle": [], "last": "Huang", "suffix": ""}], "year": 2004, "venue": "Machine Learning", "link": "6321276"}, "BIBREF3": {"title": "Amazon.com recommendations: item-to-item collaborative filtering", "authors": [{"first": "G", "middle": [], "last": "Linden", "suffix": ""}, {"first": "B", "middle": [], "last": "Smith", "suffix": ""}, {"first": "J", "middle": [], "last": "York", "suffix": ""}], "year": 2003, "venue": "Internet Computing", "link": null}, "BIBREF4": {"title": "Item-based collaborative filtering recommendation algorithms", "authors": [{"first": "B", "middle": [], "last": "Sarwar", "suffix": ""}, {"first": "G", "middle": [], "last": "Karypis", "suffix": ""}, {"first": "J", "middle": [], "last": "Konstan", "suffix": ""}, {"first": "J", "middle": [], "last": "Reidl", "suffix": ""}], "year": 2001, "venue": "Proceedings of the 10th international conference on World Wide Web, WWW '01", "link": null}, "BIBREF5": {"title": "Measuring playlist diversity for recommendation systems", "authors": [{"first": "M", "middle": [], "last": "Slaney", "suffix": ""}, {"first": "W", "middle": [], "last": "White", "suffix": ""}], "year": 2006, "venue": "Proceedings of the ACM Workshop on Audio and Music Computing for Multimedia", "link": "16980217"}, "BIBREF6": {"title": "A survey of collaborative filtering techniques", "authors": [{"first": "X", "middle": [], "last": "Su", "suffix": ""}, {"first": "T", "middle": [], "last": "Khoshgoftaar", "suffix": ""}], "year": 2009, "venue": "Advances in Artificial Intelligence", "link": null}}, "ref_entries": {}}
{"paper_id": "10705817", "_pdf_hash": "f8a78c5eb0cf1a9ae5383b1267e76b366692d9b3", "abstract": [{"section": "Abstract", "text": "This paper presents a new approach to sensor placement based on diagnosability criteria. It is based on the study of structural matrices. Properties of structural matrices regarding detectability, discriminability and diagnosability are established in order to be used by sensor placement methods. The proposed approach manages any number of constraints modelled by linear or nonlinear equations and it does not require the design of analytical redundancy relations. Assuming that a constraint models a component and that the cost of the measurement of each variable is defined, a method determining sensor placements satisfying diagnosability specifications, where all the diagnosable, discriminable and detectable constraint sets are specified, is proposed. An application example dealing with a dynamical linear system is presented.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "In the scientific literature, many approaches to fault diagnosis have been proposed since 1980. The FDI approach, which focuses on fault detection in dynamical systems, was summarized in (Blanke, Kinnaert, Lunze and Staroswiecki, 2006) . Related papers in this journal deal with the design of redundancy relations (Shumsky, 2007) as well as with the use of fuzzy logic (Dalton, Klotzek and Frank, 1999; Koscielny, Syfert and Bartys, 1999; Lopez-Toribio, Patton and Uppal, 1999) and neural networks (Korbicz, Patan and Obuchowicz, 1999; Witczak, 2006) . The DX approach focuses on diagnosis reasoning. It is summarized in (Hamscher, Console and De Kleer, 1992) . Recently, a bridge approach between FDI and DX was proposed (Cordier, Dague, L\u00e9vy, Dumas, Montmain, Staroswiecki and Trav\u00e9-Massuy\u00e8s, 2000; Nyberg and Krysander, 2003; Ploix, Touaf and Flaus, 2003) . Thus, tools for solving diagnosis problems are now well established. However, designing an efficient diagnosis system does not start after the system design but it has to be done during the system design. Indeed, the performance of a diagnostic system highly depends on the number and location of actuators and sensors. Therefore, designing a system that has to be diagnosed requires not only relevant fault diagnosis procedures, but also efficient sensor placement algorithms. Madron and Veverka (1992) proposed a sensor placement method which deals with a linear system. This method makes use of the Gauss-Jordan elimination to find a minimum set of variables to be measured. This ensures the observability of variables while simultaneously minimizing the cost of sensors. In this approach, the observable variables include the measurable variables plus the unmeasured but deductible variables. Another method of sensor placement was proposed in (Maquin, Luong and Ragot, 1997) . This method aims at guaranteeing the detectability and isolability of sensor failures. It is based on the concept of the redundancy degree in variables and on the structural analysis of the system model. The sensor placement problem can be solved by an analysis of a cycle matrix or by using the technique of mixed linear programming. Commault, Dion and Yacoub Agha (2006) proposed an alternative method of sensor placement where a new set of separators (irreducible input separators), which generates sets of system variables in which additional sensors must be implemented to solve the considered problem, is defined.", "cite_spans": [{"start": 187, "end": 235, "text": "(Blanke, Kinnaert, Lunze and Staroswiecki, 2006)", "ref_id": "BIBREF1"}, {"start": 314, "end": 329, "text": "(Shumsky, 2007)", "ref_id": "BIBREF24"}, {"start": 369, "end": 402, "text": "(Dalton, Klotzek and Frank, 1999;", "ref_id": "BIBREF7"}, {"start": 403, "end": 438, "text": "Koscielny, Syfert and Bartys, 1999;", "ref_id": "BIBREF13"}, {"start": 439, "end": 477, "text": "Lopez-Toribio, Patton and Uppal, 1999)", "ref_id": "BIBREF15"}, {"start": 498, "end": 535, "text": "(Korbicz, Patan and Obuchowicz, 1999;", "ref_id": "BIBREF12"}, {"start": 536, "end": 550, "text": "Witczak, 2006)", "ref_id": "BIBREF28"}, {"start": 621, "end": 659, "text": "(Hamscher, Console and De Kleer, 1992)", "ref_id": "BIBREF11"}, {"start": 722, "end": 800, "text": "(Cordier, Dague, L\u00e9vy, Dumas, Montmain, Staroswiecki and Trav\u00e9-Massuy\u00e8s, 2000;", "ref_id": "BIBREF6"}, {"start": 801, "end": 828, "text": "Nyberg and Krysander, 2003;", "ref_id": "BIBREF18"}, {"start": 829, "end": 858, "text": "Ploix, Touaf and Flaus, 2003)", "ref_id": "BIBREF21"}, {"start": 1339, "end": 1364, "text": "Madron and Veverka (1992)", "ref_id": "BIBREF16"}, {"start": 1809, "end": 1840, "text": "(Maquin, Luong and Ragot, 1997)", "ref_id": "BIBREF17"}, {"start": 2178, "end": 2215, "text": "Commault, Dion and Yacoub Agha (2006)", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "Introduction", "text": "However, all these methods are not suitable for the design of systems that include a diagnosis system because, in this context, the goal of sensor placement should be to make it possible to monitor hazardous components. The sensor placement algorithm should compute solutions that satisfy detectability and diagnosability properties where detectability is the possibility of detecting a fault on a component and diagnosability is the possibility of isolating a fault on a component without ambiguities with any other faulty components. Few methods have focused on this problem.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "Trav\u00e9-Massuy\u00e8s, Escobet and Milne (2001) proposed a method based on consecutive additions of sensors, which takes into account diagnosability criteria. The principle of this method is to analyze the physical model of a system from a structural point of view. This structural approach is based on Analytical Redundancy Relations (ARRs) (Blanke et al., 2006) . However, this method requires an a priori design of all the ARRs for a given set of sensors. Recently, Frisk and Krysander (2007) proposed an efficient method based on a Dulmage-Mendelsohn decomposition (Dulmage and Mendelsohn, 1959; Pothen and Chin-Ju, 1990 ). Nevertheless, this method only applies to just-determined sets of constraints while most practical systems are under-determined when sensors are not taken into account and over-determined afterwards.", "cite_spans": [{"start": 16, "end": 40, "text": "Escobet and Milne (2001)", "ref_id": "BIBREF27"}, {"start": 335, "end": 356, "text": "(Blanke et al., 2006)", "ref_id": "BIBREF1"}, {"start": 462, "end": 488, "text": "Frisk and Krysander (2007)", "ref_id": "BIBREF10"}, {"start": 562, "end": 592, "text": "(Dulmage and Mendelsohn, 1959;", "ref_id": "BIBREF9"}, {"start": 593, "end": 617, "text": "Pothen and Chin-Ju, 1990", "ref_id": "BIBREF22"}], "ref_spans": []}, {"section": "Introduction", "text": "This paper presents a new sensor placement algorithm that takes into account detectability and diagnosability specifications. It applies to systems for which only the structure is known. Thanks to this algorithm, sensor placements satisfying diagnosability objectives can be computed without designing all the ARRs, which is still an open problem. It applies to any system described structurally and does not assume just-determination. Section 2 details the main concepts that are useful to model systems for sensor placement. Then, Section 3 presents how the sensor placement problem is formulated. Section 4 introduces tools for analyzing structural matrices. These tools are then used in Section 5 to determine diagnosability properties directly from the analysis of structural matrices. Section 6 proposes basic algorithms for extracting blocks with useful properties from structural matrices, and Section 7 shows how to use these algorithms to compute sensor placements that satisfy diagnosability specifications. Finally, Section 8 presents an application to an electronic circuit.", "cite_spans": [], "ref_spans": []}, {"section": "System modelling for sensor placement", "text": "Let us introduce the concepts and the formalism used in the paper to formalize the sensor placement problem. Behavioural knowledge starts with phenomena. A phenomenon is a potentially observable element of information about the actual state of a system. It is modelled by an implicitly time-varying variable, which has to be distinguished from a parameter that is model-dependent. Generally speaking, even if a phenomenon is observable, it is not possible to merge it with data because in fault diagnosis data are only known provided that some actuators or sensors behave properly. Phenomena V (t) = {. . . , v i (t), . . . } are linked to a phenomenological space F(T, V ) = {V (t); t \u2208 T }, where T stands for a continuous or discrete time set. At any given time t in T , these phenomena belong to a domain dom(t, V ) = dom(V (t)) representing all the possible values that the phenomena may have. Consequently, when considering all t \u2208 T , {dom(V (t)); t \u2208 T } represents a tube in the timed phenomenological space F(T, V ).", "cite_spans": [], "ref_spans": []}, {"section": "System modelling for sensor placement", "text": "All the phenomena have thus to be considered as unknown because observable phenomena are not observations. Let us introduce the concept of a data flow to model actual data recorded on a system. A data flow models data provided by a source of information concerning a phenomenon. A data flow concerning a phenomenon v is denoted by val (t, v) with val(t, v) \u2208 dom(t, v) . It corresponds to a trajectory belonging to the tube {dom (t, v) ; t \u2208 T } (see Fig. 1 ). When information about v is coming from different sources, the different data flows can be denoted by val i (t, v) . Formally, a data flow provided by a component c can be linked to a phenomenon: ok(c) \u2192 \u2200t \u2208 T, val(t, v) = v, which means that if the component named c is in the mode ok, then the data val (t, v) correspond to the actual value of the phenomenon v at any time t \u2208 T . In fault diagnosis, a system is not supposed to remain in a given mode. Indeed, diagnostic analysis aims at retrieving the actual behavioral modes of the components of a system. At minimum, two modes are defined: the ok mode, which corresponds to the expected normal behavior, and the cf mode, which is the complementary fault mode: it refers to all the behaviours that do not fit to the expected normal behavior. Sometimes, specific fault modes may be modelled (de Kleer and Williams, 1992; Struss, 1992) . They are denoted by a specific label, e.g., the leak mode. Consider, e.g., a pipe where ok and leak are modelled. It yields M odes(pipe) = {ok, leak, cf }, where cf (pipe) refers to the behaviours that do not correspond to ok(pipe) or to leak(pipe).", "cite_spans": [{"start": 1307, "end": 1336, "text": "(de Kleer and Williams, 1992;", "ref_id": "BIBREF8"}, {"start": 1337, "end": 1350, "text": "Struss, 1992)", "ref_id": "BIBREF25"}], "ref_spans": [{"start": 451, "end": 457, "text": "Fig. 1", "ref_id": "FIGREF0"}]}, {"section": "System modelling for sensor placement", "text": "Except for the complementary fault mode, behavioural modes are modelled by cause-effect relationships between phenomena, which are represented by constraints. Each constraint refers to a set of mappings containing unknown variables and known data flows. Generally speaking, a mapping over dom(t, V ) is defined from one subspace dom(t, V 1 ) to another dom(t, V 2 ), where", "cite_spans": [], "ref_spans": []}, {"section": "System modelling for sensor placement", "text": "is a mapping representing a constraint k that models, for example, a component c 1 in mode mode 1 and a component c 2 in mode mode 2 , we have", "cite_spans": [], "ref_spans": []}, {"section": "System modelling for sensor placement", "text": "where the data flow val(V 3 ) is considered as being included in the mapping. But constraint is not strictly equivalent to mapping. A constraint corresponds to a set of equivalent mappings. Firstly, although mappings to multidimensional spaces could be used, they are difficult to manage. It is better to break them down into one-dimensional mappings. In the following, one-dimensional mappings modelling a constraint k are named realizations of k. Moreover, several realizations of a constraint may be equivalent. Let \u03ba i be a realization from V \\{v} to {v}. There may be equivalent realizations defined on V that also model the constraint. Therefore, the notion of constraint can be extended to represent all the equivalent realizations representing a given subset of dom(V ). In the following, a constraint k will be understood as a set of equivalent realizations. It is summarized by the set of variables occurring in the realizations: var(k). It is assumed that if k is a constraint, for all v \u2208 var(k), there is an equivalent realization \u03ba i : dom (t, var(k) ", "cite_spans": [], "ref_spans": []}, {"section": "System modelling for sensor placement", "text": "To summarize, a system \u03a3 is composed of a set of constraints K \u03a3 and a set of behavioural modes M odes(\u03a3) related to components in \u03a3. var(K \u03a3 ) is the set of variables, named port in (Chittaro and Ranon, 2004) , which models observable phenomena involved in \u03a3. Indeed, by extension, the set of variables appearing in a set of constraints K is denoted by var(K) = k\u2208K var(k). Each constraint \u03ba \u2208 K \u03a3 is linked to a mode m \u2208 M odes(\u03a3) by a first order relationship: m \u2192 \u03ba. For the sake of simplicity, in this paper, it is assumed that:", "cite_spans": [{"start": 183, "end": 209, "text": "(Chittaro and Ranon, 2004)", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "System modelling for sensor placement", "text": "\u2022 only ok modes are considered in the sensor placement,", "cite_spans": [], "ref_spans": []}, {"section": "System modelling for sensor placement", "text": "\u2022 each constraint \u03ba \u2208 K \u03a3 models one mode and, conversely, that a mode can be modelled by at most one constraint.", "cite_spans": [], "ref_spans": []}, {"section": "System modelling for sensor placement", "text": "The sensor placement problem then consists in defining the variables of var(\u03a3) that have to be measured to facilitate the detection and identification of ok modes from M odes (\u03a3) . These modes are denoted by M odes ok (\u03a3). From a mathematical point a view, it is a kind of combinatorial problem. The next section proposes a precise problem formulation.", "cite_spans": [], "ref_spans": []}, {"section": "Problem formulation", "text": "Let us present an intuitive formulation of the problem. Full definitions are given afterwards. The solving of a diagnostic problem is generally decomposed into two consecutive steps. The conflict or symptom generation, also called fault detection in the automatic control community, and the diagnostic analysis, also called fault isolation. The first step relies on consistency tests among minimal testable subsets of constraints 1 K \u2208 K \u03a3 that include data flows (often called OBS for observations). Let K be the set of minimal testable subsets of constraints. If K \u2208 K is a set of constraints leading to a test which is inconsistent, this means that, at least, one of the modes corresponding to the constraints of K is not actual. It is therefore important to trace the constraints belonging to a minimal testable subset K because this makes it possible to solve the second sub-problem: the diagnostic analysis, which provides global conclusions in terms of modes about the actual system states. The performance of a diagnostic system is highly dependent on the set K and, consequently, dependent on the set K \u03a3 , which highly depends on the dataflows, i.e., on the observations. Additional sensors lead to addtional constraints in K \u03a3 and, therefore, to new sets in K. K can be obtained from combinations of constraints from K \u03a3 using possible conflict generation (Pulido and Alonso, 2002) , a bipartite graph (Blanke et al., 2006) , the Dulmage-Mendelsohn decomposition (Krysander, Aslund and Nyberg, 2008) or elimination rules (Ploix, D\u00e9sinde and Touaf, 2005) . Basically, once K has been generated, it is possible to compute the performance of the diagnostic system in terms of detectability, discriminability or discernability, and diagnosability. Irrespective of whether or not the performance satisfies the requested performance requirements, the set K \u03a3 is modified and the process is conducted once again until the requested performance is reached. However, this process requires lots of computations because the generation of K is time consuming. Moreover, up to now, no one of these algorithms has been proved to be complete.", "cite_spans": [{"start": 1367, "end": 1392, "text": "(Pulido and Alonso, 2002)", "ref_id": "BIBREF23"}, {"start": 1413, "end": 1434, "text": "(Blanke et al., 2006)", "ref_id": "BIBREF1"}, {"start": 1474, "end": 1510, "text": "(Krysander, Aslund and Nyberg, 2008)", "ref_id": "BIBREF14"}, {"start": 1532, "end": 1564, "text": "(Ploix, D\u00e9sinde and Touaf, 2005)", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "Problem formulation", "text": "Another approach to sensor placement is proposed in this paper. It does not require the computation of K from K \u03a3 . It directly solves the following problem by studying the structure of \u03a3: Let K \u03a3 be a set of constraints modeling the ok modes of a system \u03a3. Let var(K \u03a3 ) be the variables appearing in K \u03a3 . The problem to be solved is as follows: What are the complementary constraints modelling sensors dedicated to variables from var(K \u03a3 ) that have to be added to satisfy requested diagnosability performance requirements?", "cite_spans": [], "ref_spans": []}, {"section": "Problem formulation", "text": "Let us precise the problem formulation by defining the concept of a testable subset or a subsystem (TSS) of constraints and its relationship with the concept of the ARR. Definition 1. Let K be a set of constraints and v a variable in var(K) characterized by its domain dom (v) . K is a solving constraint set for v if, using K, it is possible to instantiate v with a value set S such that S \u2282 dom (v) . A solving constraint set for v is minimal if there is no subset of K, which is also a solving constraint set for v. A minimal solving constraint set K for v is denoted by K v.", "cite_spans": [], "ref_spans": []}, {"section": "Problem formulation", "text": "Definition 2. Let K be a set of constraints. K is testable if and only if there is a partition", "cite_spans": [], "ref_spans": []}, {"section": "Problem formulation", "text": "If this property is satisfied, it is indeed possible to check if the value set S 1 deduced from K 1 is consistent with the value set S 2 deduced from K 2 :", "cite_spans": [], "ref_spans": []}, {"section": "Problem formulation", "text": "Adding any constraint to a testable set also leads to a testable set of constraints. Only minimal testable sets are interesting.", "cite_spans": [], "ref_spans": []}, {"section": "Problem formulation", "text": "Definition 3. A testable set of constraints is minimal if it is not possible to keep testability when removing a constraint.", "cite_spans": [], "ref_spans": []}, {"section": "Problem formulation", "text": "A global testable constraint that can be deduced from a TSS is called an analytical relation (ARR). Let", "cite_spans": [], "ref_spans": []}, {"section": "Problem formulation", "text": ". .} be the set of all the testable subsystems that can be deduced from K \u03a3 according to (Blanke et al., 2006; Ploix et al., 2005) . Because of the assumed one-to-one relationships between constraints and components, the notions of detectability and discriminability can be extended to constraints.", "cite_spans": [{"start": 89, "end": 110, "text": "(Blanke et al., 2006;", "ref_id": "BIBREF1"}, {"start": 111, "end": 130, "text": "Ploix et al., 2005)", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "Definition 4.", "text": "Let K be a set of TSSs coming from (Struss, Rehfus, Brignolo, Cascio, Console, Dague, Dubois, Dressler and Millet, 2002) (Struss et al., 2002) ", "cite_spans": [{"start": 35, "end": 120, "text": "(Struss, Rehfus, Brignolo, Cascio, Console, Dague, Dubois, Dressler and Millet, 2002)", "ref_id": "BIBREF26"}, {"start": 121, "end": 142, "text": "(Struss et al., 2002)", "ref_id": "BIBREF26"}], "ref_spans": []}, {"section": "Definition 4.", "text": "Obviously, nondetectability implies nondiscriminability. (Struss et al., 2002; Console, Picardi and Ribando, 2000) ", "cite_spans": [{"start": 57, "end": 78, "text": "(Struss et al., 2002;", "ref_id": "BIBREF26"}, {"start": 79, "end": 114, "text": "Console, Picardi and Ribando, 2000)", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Definition 4.", "text": "In order to formulate the sensor placement problem, the notion of a terminal constraint has to be introduced.", "cite_spans": [], "ref_spans": []}, {"section": "Definition 4.", "text": "Definition 7. A terminal constraint k is a constraint that satisfies card(var(k)) = 1, where var(k) is the set of variables appearing in the constraint k.", "cite_spans": [], "ref_spans": []}, {"section": "Definition 4.", "text": "A terminal constraint usually models a sensor or an actuator. It is thus a major concept in sensor placement. Note that if a candidate sensor measures not only one variable v but a combination of several variables", "cite_spans": [], "ref_spans": []}, {"section": "Definition 4.", "text": "where v * is a virtual measurable variable, has to be added into K \u03a3 . Then, the solving is similar to the standard problem.", "cite_spans": [], "ref_spans": []}, {"section": "Definition 4.", "text": "In fault diagnosis, sensor placement has to satisfy specifications dealing with detectability and diagnosability. Because a one-to-one relation between components and constraints is assumed, what is true for components is also true for constraints. In the following, only constraints will be considered: the analogy with components is implicit. In this paper, complete specifications are considered. Partial specifications can also be managed: they will be presented in a forthcoming paper. These complete specifications consist of a partition of the constraint set K \u03a3 into the following subsets:", "cite_spans": [], "ref_spans": []}, {"section": "Definition 4.", "text": "\u2022 the set of constraints K diag that must be diagnosable,", "cite_spans": [], "ref_spans": []}, {"section": "Definition 4.", "text": "\u2022 the set of subsets of constraints K nondis = {. . . , K i , . . .} for which each set K i must be nondiscriminable but detectable,", "cite_spans": [], "ref_spans": []}, {"section": "Definition 4.", "text": "\u2022 the set of constraints K nondet that must be nondetectable,", "cite_spans": [], "ref_spans": []}, {"section": "Definition 4.", "text": "Complete specifications K diag , K nondis and K nondet for sensor placement problems are meaningful if the following two properties are satisfied:", "cite_spans": [], "ref_spans": []}, {"section": "Definition 4.", "text": "1. Sets in specifications must not overlap one another to make sense. Constraint sets have to satisfy", "cite_spans": [], "ref_spans": []}, {"section": "Definition 4.", "text": "2. The union of all the components appearing in K diag , K nondis and K nondet has to correspond to K \u03a3 :", "cite_spans": [], "ref_spans": []}, {"section": "Definition 4.", "text": "If these properties are satisfied, the complete specifications are qualified as consistent in K \u03a3 . Satisfying the diagnosability specifications requires information delivered by sensors. Let K \u03a3 represent the system \u03a3 with additional sensors where K \u03a3 contains the constraints K \u03a3 of the system \u03a3 plus the additional terminal constraints modelling the additional sensors. Therefore, solving a sensor placement problem consists in determining additional terminal constraints in K \u03a3 that lead to the satisfaction of complete specifications.", "cite_spans": [], "ref_spans": []}, {"section": "Definition 4.", "text": "In the next sections, diagnosability properties of structural matrices are established and used for the design of a sensor placement satisfying diagnosability specifications.", "cite_spans": [], "ref_spans": []}, {"section": "Basic properties of structural matrices", "text": "Before pointing out diagnosability properties, some basic properties of structural matrices have to be established.", "cite_spans": [], "ref_spans": []}, {"section": "Basic properties of structural matrices", "text": ". .} can be represented by a structural matrix M \u03a3 , which is an incidence matrix representing the mapping", "cite_spans": [], "ref_spans": []}, {"section": "Basic properties of structural matrices", "text": "According to the definition, a TSS is a minimum set of constraints K such that there is at least one variable for which two different minimal solving sets can be found. A minimal solving set leading to a variable v corresponds to a value propagation (Apt, 2003) starting usually, but not necessarily, by terminal constraints and leading to v. Therefore, a TSS can also be seen as two distinct value propagations leading to a given variable. This point of view has been adopted as a theoretical tool to develop proofs.", "cite_spans": [{"start": 250, "end": 261, "text": "(Apt, 2003)", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "Basic properties of structural matrices", "text": "Let k 1 and k 2 be two constraints. The propagation of a variable v between k 1 and k 2 is possible only if v \u2208 var(k 1 ) \u2229 var(k 2 ). The variable v is qualified as propagable between k 1 and k 2 : v is a link between k 1 and k 2 . In the corresponding structural matrix, this link is represented by a thick line:", "cite_spans": [], "ref_spans": []}, {"section": "Basic properties of structural matrices", "text": "Consider now a system defined by", "cite_spans": [], "ref_spans": []}, {"section": "Basic properties of structural matrices", "text": "Terminal constraints k 4 and k 5 model sensors or actuators. Each terminal constraint contains known data. Figure 2 represents examples of propagations that lead to a TSS with a bipartite graph. But in a bipartite graph, links do not appear clearly: they correspond to alternate paths (or chains) with the pattern 'constraintvariable-constraint'. Links appear more clearly in structural matrices as lines linking two constraints. In the fol- lowing structural matrices, the variables surrounded by a circle represent the variables that can be instantiated twice. The relevance of links remains obvious in Example 2, where a propagation does not start by a terminal constraint. The paths corresponding to propagations of solving sets were drawn. Variable v 2 was instantiated twice.", "cite_spans": [], "ref_spans": [{"start": 107, "end": 115, "text": "Figure 2", "ref_id": "FIGREF1"}]}, {"section": "Basic properties of structural matrices", "text": "Once again, paths may be reduced to links (thick lines).", "cite_spans": [], "ref_spans": []}, {"section": "Basic properties of structural matrices", "text": "The following example points out another structural matrix with two propagations leading to variable v 3 :", "cite_spans": [], "ref_spans": []}, {"section": "Basic properties of structural matrices", "text": "The concept of linked constraints has to be formalized because discriminability depends on this concept. Before defining linked constraints, the concept of interconnected constraints has to be introduced. The constraints of a system \u03a3 may be modelled by a non-directed bipartite graph (K \u03a3 , var(K \u03a3 ), E \u03a3 ), where E \u03a3 is the set of edges. Each edge e = (k, v) reflects v \u2208 var(k).", "cite_spans": [], "ref_spans": []}, {"section": "Basic properties of structural matrices", "text": "with constraints at extremities (see, e.g., (Bollob\u00e1s, 1998) ", "cite_spans": [{"start": 44, "end": 60, "text": "(Bollob\u00e1s, 1998)", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "Basic properties of structural matrices", "text": "To point out the link with bipartite graph theory, if K is interconnected by V in K \u03a3 , V is necessarily a complete coupling for K with respect to variables. The notion of a linked set of constraints can now be introduced. ", "cite_spans": [], "ref_spans": []}, {"section": "Basic properties of structural matrices", "text": "The shape of a structural matrix dealing with linked constraints is drawn in Fig. 3 . The concept of linked constraints is strongly connected with discriminability.", "cite_spans": [], "ref_spans": [{"start": 77, "end": 83, "text": "Fig. 3", "ref_id": "FIGREF2"}]}, {"section": "Basic properties of structural matrices", "text": "Proof. Indeed, because variables in V only appear in the constraints belonging to K, the only way for propagating variables is to use the constraints in K and the variables in V . What is more, because there is a tree (K, V, E) \u2282 (K \u03a3 , var(K \u03a3 ), E \u03a3 ) with constraints at extremities, instantiating all the variables in V involves at least the achievement of the propagations defined by the tree.", "cite_spans": [], "ref_spans": []}, {"section": "Basic properties of structural matrices", "text": "Therefore, all the constraints are invariably found together in the TSS. In order to improve the clarity of these explanations, let us introduce the notion of stump variables.", "cite_spans": [], "ref_spans": []}, {"section": "Basic properties of structural matrices", "text": "Definition 10. A set of variables var(K) appearing in a set of constraints K but not in the other constraints of K \u03a3 (i.e., K \u03a3 \\K) are named stump variables in K \u03a3 with respect to K. They are denoted by var stump (K, K \u03a3 ).", "cite_spans": [], "ref_spans": []}, {"section": "Basic properties of structural matrices", "text": "For instance, the set of variables V that link a set of constraints K belong to the stump variables", "cite_spans": [], "ref_spans": []}, {"section": "Basic properties of structural matrices", "text": "A set of constraints cannot be used to generate a TSS if they are linked and if there are additional variables that cannot be propagated. These constraints are qualified as isolated. Detectability depends on this concept.", "cite_spans": [], "ref_spans": []}, {"section": "Basic properties of structural matrices", "text": "it is linked by V and if there is at least one variable in var(K)\\V that does not belong to other constraints of K \u03a3 (i.e., K \u03a3 \\K). If the set contains only one constraint, the link condition disappears.", "cite_spans": [], "ref_spans": []}, {"section": "Basic properties of structural matrices", "text": "The shape of a structural matrix dealing with isolated constraints is shown in Fig. 4 . The concept of isolated constraints is strongly linked with detectability.", "cite_spans": [], "ref_spans": [{"start": 79, "end": 85, "text": "Fig. 4", "ref_id": "FIGREF3"}]}, {"section": "Lemma 2. A set of constraints", "text": "Proof. The constraints K isolated in K \u03a3 by V will always come together in the TSS because, by definition, they are linked by V . Because of the fact that, in isolated constraints, there is at least one additional variable in var(K) which does not appear in other constraints (i.e., K \u03a3 \\K), it is not possible to instantiate this variable and, therefore, this set of constraints cannot be involved into a TSS: constraints K are thus non-detectable.", "cite_spans": [], "ref_spans": []}, {"section": "Diagnosability properties of structural matrices", "text": "This section aims at setting up a direct link from sets of constraints to detectability and diagnosability properties.", "cite_spans": [], "ref_spans": []}, {"section": "Diagnosability properties of structural matrices", "text": "Firstly, it is obvious that adding additional constraints connected to all the variables var(k) appearing in a constraint k ensures the diagnosability of k. Lemma 3 can be directly applied to all the constraints of a constraint set.", "cite_spans": [], "ref_spans": []}, {"section": "Corollary 1. If additional terminal constraints dealing with all the variables var(K) of a constraint set", "text": "In Lemma 2, a relationship between isolated constraints and the detectability property has been presented. The next lemma generalizes the previous results.", "cite_spans": [], "ref_spans": []}, {"section": "Corollary 1. If additional terminal constraints dealing with all the variables var(K) of a constraint set", "text": "Lemma 4. A sufficient condition for a subset of constraints K \u2282 K \u03a3 to be non-detectable is that there is a sequence", "cite_spans": [], "ref_spans": []}, {"section": "Corollary 1. If additional terminal constraints dealing with all the variables var(K) of a constraint set", "text": "Proof. The case of K 1 has been discussed in Lemma 2: because the constraints in K 1 are isolated in K \u03a3 , they are non-detectable and therefore cannot be included in the TSS. Then, the remaining candidate constraints for the TSS belong to K \u03a3 \\K 1 . Because K 2 is isolated in K \u03a3 \\K 1 , they are non-detectable. The reasoning can be extended to any K i . Consequently, the constraints in K = i K i are non-detectable. Figure 5 indicates the shape of a structural matrix of non-detectable constraints.", "cite_spans": [], "ref_spans": [{"start": 420, "end": 428, "text": "Figure 5", "ref_id": "FIGREF4"}]}, {"section": "Corollary 1. If additional terminal constraints dealing with all the variables var(K) of a constraint set", "text": "Consider, e.g., a system modelled by the following structural matrix:", "cite_spans": [], "ref_spans": []}, {"section": "Corollary 1. If additional terminal constraints dealing with all the variables var(K) of a constraint set", "text": "Assume that the set K = {k 1 , k 2 , k 3 } is required to be non-detectable. In this example, there exists a pair ({k 1 } , {k 2 , k 3 }) such that each element K i satisfies Lemma 4. If there are no additional terminal constraints containing v 1 , v 2 and v 3 , the subset K is necessarily nondetectable.", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 5. A sufficient condition for each set K i \u2282 K belonging to a set of m constraint sets", "text": "Proof. This lemma is a direct application of Lemma 1 to several sets of constraints.", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 5. A sufficient condition for each set K i \u2282 K belonging to a set of m constraint sets", "text": "Consider, for example, a system modelled by the following structural matrix:", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 5. A sufficient condition for each set K i \u2282 K belonging to a set of m constraint sets", "text": "} is a constraint subset that should be non-discriminable. Because the constraints k 1 , k 2 , k 3 and k 4 are linked by V = {v 1 , v 2 , v 3 }, Lemma 5 is satisfied. Therefore, k 1 , k 2 , k 3 and k 4 are nondiscriminable provided that no additional terminal constraints contain a variable of V .", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 5. A sufficient condition for each set K i \u2282 K belonging to a set of m constraint sets", "text": "The following theorem collects the results of Lemmas 3, 4 and 5. ", "cite_spans": [], "ref_spans": []}, {"section": "Each set", "text": "K i belonging to K nondis = {K 1 , . . . , K m } such that \u2200K i = K j , K i \u2229 K j = \u2205,", "cite_spans": [], "ref_spans": []}, {"section": "Additional terminal constraints are added on the variables", "text": "Proof. The proof relies on the resulting structure of the structural matrix, which directly stems from Corollary 5 as well as Lemmas 4 and 5. Note that Point 2 could also be stated for the whole set of constraints K \u03a3 . However, it is not useful to include non-detectable constraints, which will not appear in the resulting TSS: it would be less conservative. Because of Lemmas 4 and 5, the variables of var(K diag ) cannot contain variables appearing in the variables involved in (1) and (2), that is to say, in var stump (K nondet , K \u03a3 ) and in", "cite_spans": [], "ref_spans": []}, {"section": "Additional terminal constraints are added on the variables", "text": "Because the variables of V candidate can be instantiated with measured values, all the constraints of K diag are diagnosable following Corollary 5.", "cite_spans": [], "ref_spans": []}, {"section": "Additional terminal constraints are added on the variables", "text": "The point which has to be proved is that, in specifications, K nondis defines non-discriminable but detectable sets and not only non-discriminable sets as in Lemma 5: the detectability of sets in K nondis has to be proved. The variables var(K i ) of a constraint set K i \u2208 K nondis can be decomposed into two sets: V constraint set K i is necessarily detectable. Because this result holds for any K i \u2208 K nondis , it proves the theorem.", "cite_spans": [], "ref_spans": []}, {"section": "Additional terminal constraints are added on the variables", "text": "A block containing the set of isolated constraints subsets of K \u0394 in K \u03a3 and the isolating variables, considering only the varcostiables V \u0394 Require:", "cite_spans": [], "ref_spans": []}, {"section": "Additional terminal constraints are added on the variables", "text": "Satisfying the assumptions of Theorem 1 guarantees that the specifications are satisfied. However, because the theorem provides only a sufficient condition for diagnosability, the number of additional terminal constraints is not necessarily minimal. It has to be checked afterwards.", "cite_spans": [], "ref_spans": []}, {"section": "Additional terminal constraints are added on the variables", "text": "In the next section, an algorithm for extracting blocks from a structural matrix is presented. This algorithm is required by methods for sensor placement based on complete specifications.", "cite_spans": [], "ref_spans": []}, {"section": "Extracting blocks from a structural matrix", "text": "Before presenting an algorithm for extracting blocks from a structural matrix K \u03a3 , let us introduce some notation. Firstly, the notion of a block is formalized: a block is a couple defined by block = (K, V ) where block.cons = K and block.var = V stand respectively for a set of con- ", "cite_spans": [], "ref_spans": []}, {"section": "var).", "text": "A set of blocks is denoted by the symbol B. By extension, the block resulting from the merging of sets of blocks B is denoted by merge(B). Figure 7 represents the dependency scheme between the methods that are defined. The main algorithm is named findBlocks (Algorithm 1). It extracts the different blocks that appear in Theorem 1, considering only the variables V \u0394 .", "cite_spans": [], "ref_spans": []}, {"section": "var).", "text": "In order to describe the methods findIsolatedBlocks() and findLinkedBlocks(), the notions of Knode and buffer of Knodes are introduced. A Knode is a couple of constraint sets:", "cite_spans": [], "ref_spans": []}, {"section": "var).", "text": "A buffer is a special First-In First-Out buffer. The basic functionalities are buffer .push(Knode) and buffer .pop(). They respectively correspond to adding a Knode in the buffer and getting a Knode from the buffer.", "cite_spans": [], "ref_spans": []}, {"section": "var).", "text": "Using these notions, the algorithm findIsolatedBlocks() (Algorithm 2) extracts the set of isolated blocks from a set of constraints K \u0394 \u2286 K \u03a3 , considering only the variables V \u0394 . According to Lemma 4, the constraints belonging to the resulting blocks are not detectable.", "cite_spans": [], "ref_spans": []}, {"section": "var).", "text": "This algorithm depends on the findIsolatingVariables() method. It is given by Algorithm 3.", "cite_spans": [], "ref_spans": []}, {"section": "var).", "text": "The algorithm findLinkedBlocks() (Algorithm 4) extracts the set of linked constraints from a set K \u0394 \u2286 K \u03a3 , considering only the variables V \u0394 . The structure of this algorithm is very closed to that of Algorithm 2. Accord-", "cite_spans": [], "ref_spans": []}, {"section": "var).", "text": "A set of blocks, where each one corresponds to a linked but not isolated set of constraints, and its corresponding linking variables, considering only the variables V \u0394 Require:", "cite_spans": [], "ref_spans": []}, {"section": "var).", "text": "ing to Lemma 5, the constraints belonging to the resulting blocks are not discriminable. This algorithm depends on the findLinkingStumpVariables() method, which is given by Algorithm 5.", "cite_spans": [], "ref_spans": []}, {"section": "var).", "text": "Finally, according the Fig. 7 , the algorithms findIsolatingVariables() and findLinkedBlocks() depend on two methods findStumpVariables() (Algorithm 6) and isInter-", "cite_spans": [], "ref_spans": []}, {"section": "if", "text": "The top-level method findBlocks(K \u03a3 ) leads to the blocks depicted in Fig. 6 . These results are very useful to support the sensor placement. Indeed, constraints belonging to B diag .cons are already diagnosable. Therefore, finding a sensor placement satisfying the specifications requires that the specified In much the same way, the constraints merge(B nondis ).cons \u222a B diag .cons are already detectable. Therefore, finding a sensor placement satisfying the specifications requires that the specified K spec nondet should be included in merge(B nondet ).cons:", "cite_spans": [], "ref_spans": []}, {"section": "Method for sensor placement", "text": "A method for optimal sensor placements satisfying diagnosability specifications is proposed in this section. This method deals with complete specifications: K spec diag , K spec nondis and K spec nondet (see Section 4). There may be several sensor placements that satisfy diagnosability specifications. In order to select the most interesting one, a criterion based on the cost of the sensor placement is considered. Introduce the following notation: The cost of the measurement of a variable v is denoted cost (v) . By extension, the cost of the measurement of a set of variables V is defined as cost(V ) = v\u2208V cost (v) .", "cite_spans": [], "ref_spans": []}, {"section": "Method for sensor placement", "text": "Adding sensors amounts to adding terminal constraints (see Definition 7). Indeed, as mentioned in Section 3, a sensor measuring a variable v is modelled by the constraint val (t, v) = v, where val(t, v) is a datum coming from the sensor. Therefore, structurally speaking, a sensor measuring v is modelled by a terminal constraint k satisfying var(k) = {v}. The constraint k will be denoted by k sensor (v) . By extension, the terminal constraints modelling sensors measuring variables V are denoted by K sensor (V ). ", "cite_spans": [], "ref_spans": []}, {"section": "Method for sensor placement", "text": "The method to solve these complete specifications can be decomposed into two steps: the determination of candidate variables for sensor placements using Theorem 1, and the reduction of the candidate variables in order to find the minimal cost sensor placement that satisfies the complete diagnosability specifications using a branchand-bound algorithm. Figure 8 presents the dependency scheme of the method.", "cite_spans": [], "ref_spans": [{"start": 353, "end": 361, "text": "Figure 8", "ref_id": "FIGREF8"}]}, {"section": "Method for sensor placement", "text": "The findCandidates() (Algorithm 8) method is based on Theorem 1. It takes into account the specifications to determine a set of variables to be measured. If these variables are measured, the complete specifications will be satisfied. This algorithm depends on the findLinkingVariables() method, which is given by Algorithm 9. This algorithm uses the results issuing from Algorithm 5 to find a subset of variables linking a subset of constraints K \u0394 , considering only the variables V \u0394 .", "cite_spans": [], "ref_spans": []}, {"section": "Method for sensor placement", "text": "In this algorithm, the cost of variables is considered. This algorithm depends on the sortVariables() method, which sorts a list of variables according to measurement costs in descending order.", "cite_spans": [], "ref_spans": []}, {"section": "Method for sensor placement", "text": "A subset of the candidate variables may also lead to the satisfaction of the specifications. A branch-and-bound algorithm is used to select the most interesting candidate variables to be measured in order to find an optimal sensor placement. Before defining the optimisation algorithm, it is necessary to be able to check if the complete specifications are satisfied for a given subset of candidate variables.", "cite_spans": [], "ref_spans": []}, {"section": "Method for sensor placement", "text": "True is the sensor placement satisfies the specifications Require: The optimality criterion for a feasible sensor placement defined by V measured is given by cost(V measured ). The branch-and-bound search algorithm is implemented in the placeSensor() method (Algorithm 11) using a simple First-In First-Out buffer of nodes of variables.", "cite_spans": [], "ref_spans": []}, {"section": "Application", "text": "In this section, the special case of a dynamical system modelled by recurrent or differential equations is discussed. Then, an example is presented. ", "cite_spans": [], "ref_spans": []}, {"section": "Application", "text": "Dynamical systems. The sensor placement method relies on structural modelling. Therefore it should be suitable for most systems. Let us examine the special case of dynamical systems. Generally speaking, a model is said to be dynamic if either:", "cite_spans": [], "ref_spans": []}, {"section": "Application", "text": "\u2022 a variable appears several times in a system but at different time, stamps, or", "cite_spans": [], "ref_spans": []}, {"section": "Application", "text": "\u2022 a variable and some of its derivatives or summations (whatever the order is) appear in the system.", "cite_spans": [], "ref_spans": []}, {"section": "Application", "text": "The first case mainly concerns time-delays and discrete time recurrent systems. According to Section 3, each variable stands for a tube in a phenomenological space. Therefore, a time delay, modelled by y(t + \u0394) = x(t), is a constraint that establishes a link between two tubes: {dom(y(t + \u0394)); \u2200t} and {dom(x(t)); \u2200t}. Therefore, even if the two variables model the same phenomenon, in the structural model they cannot be merged. Consider now the following discrete-time recurrent model:", "cite_spans": [], "ref_spans": []}, {"section": "Application", "text": "k \u2208 N, where T e stands for the sampling period.", "cite_spans": [], "ref_spans": []}, {"section": "A method for sensor placement taking into account diagnosability criteria", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "509", "text": "The phenomenon modelled by x appears twice. Therefore, the constraint must be implicitly completed by a time delay between variables x((k + 1)T e ) and x(kT e ). Structurally speaking, these constraints are modelled by the following structures:", "cite_spans": [], "ref_spans": []}, {"section": "509", "text": "Moreover, if the tube corresponding to x((k + 1)T e ) appears only once in these constraints (which is usually the case in practice), constraints k 1 and k 2 can be merged:", "cite_spans": [], "ref_spans": []}, {"section": "509", "text": "The second case mainly concerns integration and differential equations. Consider, e.g., the following model: and var(k 2 ) = {x, dx dt, x 0 }. In the same way as timedelays, the constraints k 1 and k 2 can be merged to obtain the following structure: var(k 12 ) = {u, x} or, if the initial condition is considered, var(k 12 ) = {u, x, x 0 }. This result remains true for summations and derivatives of any order.", "cite_spans": [], "ref_spans": []}, {"section": "509", "text": "Consequently, these kinds of dynamical systems can be handled just like other systems.", "cite_spans": [], "ref_spans": []}, {"section": "509", "text": "8.2. Example. The method presented in this paper has been applied to a sensor placement for an electronic circuit (Fig. 9) . It is modelled by the following constraints:", "cite_spans": [], "ref_spans": [{"start": 114, "end": 122, "text": "(Fig. 9)", "ref_id": "FIGREF11"}]}, {"section": "509", "text": "with", "cite_spans": [], "ref_spans": []}, {"section": "509", "text": "The corresponding structural matrix is given by Table 1. Suppose that the costs of the measurements are", "cite_spans": [], "ref_spans": []}, {"section": "509", "text": "Consider the following complete specifications:", "cite_spans": [], "ref_spans": []}, {"section": "509", "text": "In order to check if the specifications K nondet are satisfiable, Algorithm 2 is used with K \u0394 = {k 1 , k 4 , k 10 }, K \u03a3 and V \u0394 = var(K \u03a3 ). Algorithm 2 computes the following sets of isolated constraints: {{k 10 , k 1 } , {k 4 }}. The specifications K nondet are consequently satisfiable. Algorithm 2 also provides the isolated variables", "cite_spans": [], "ref_spans": []}, {"section": "509", "text": "In order to check if the specifications K nondis are satisfiable, Algorithm 9 is used with two subsets,", "cite_spans": [], "ref_spans": []}, {"section": "509", "text": ". Algorithm 9 computes the linking variable subsets V 1 = {i 1 } and V 2 = {v 3 }.", "cite_spans": [], "ref_spans": []}, {"section": "509", "text": "In order to find the candidate variables to be measured to satisfy the specifications, Algorithm 8 is used. It yields terminal constraints that correspond to the measurements of variables", "cite_spans": [], "ref_spans": []}, {"section": "509", "text": "In order to find the cheapest sensor placement that satisfies the specifications, Algorithm 11 is used. It yields", "cite_spans": [], "ref_spans": []}, {"section": "509", "text": "In order to validate the result, the method proposed in (Ploix et al., 2005) has been used to design all the ARRs. It has led to the fault signature given by Table 2 . According to these results, the constraint sets that cannot be discriminated are {k 2 , k 6 } and {k 7 , k 8 }. The constraint set that cannot be detected is {k 1 , k 4 , k 10 } and the diagnosable constraints are {k 3 , k 5 , k 9 , k 11 , k 12 }. Applying the function \u03a6 : K \u03a3 \u2212\u2192 C \u03a3 , it is obvious that the components that cannot be discriminated are {c 2 , c 6 } and {c 7 , c 8 }, the components that cannot be detected are {c 1 , c 4 , c 10 }, and the diagnosable components are {c 3 , c 5 , c 9 , c 11 , c 12 }.", "cite_spans": [{"start": 56, "end": 76, "text": "(Ploix et al., 2005)", "ref_id": "BIBREF20"}], "ref_spans": [{"start": 158, "end": 165, "text": "Table 2", "ref_id": "TABREF8"}]}, {"section": "509", "text": "Suppose now that the specifications are given by K nondis = {{k 2 , k 3 } , {k 7 , k 8 }} ,", "cite_spans": [], "ref_spans": []}, {"section": "509", "text": "In order to check if the specifications K nondet are satisfiable, Algorithm 2 is used with K \u0394 = {k 1 , k 10 }, K \u03a3 and V \u0394 = var(K \u03a3 ). Algorithm 2 computes the following sets of isolated constraints: {{k 10 , k 1 }}. The specifications K nondet are consequently satisfiable. Algorithm 2 also provides the isolating variables V isolated = {i 4 , v 2 }.", "cite_spans": [], "ref_spans": []}, {"section": "509", "text": "In order to check if the specifications K nondis are satisfiable, Algorithm 9 is used with the two subsets K \u03941 = {k 2 , k 3 } and K \u03942 = {k 7 , k 8 }, considering V \u0394 = var(K \u03a3 \\ V isolated ). Because Algorithm 9 computes the linking variable subset V 1 = {\u2205} for the constraint subset K \u03941 = {k 2 , k 3 }, there is no solution that satisfies these specifications.", "cite_spans": [], "ref_spans": []}, {"section": "509", "text": "The results presented in this paper demonstrate that it is possible to design optimal sensor placements satisfying diagnosability criteria without designing the ARR a priori.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusion", "text": "A new approach to sensor placement has been proposed that makes it possible to satisfy diagnosability specifications. It is thus possible to specify the performances that a diagnostic system has to meet and then to compute where the sensors should be placed.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusion", "text": "The presented lemmas, theorems and algorithms are general and can be reused to develop other methods for sensor placement that deal with various kinds of specifications, e.g., a set of components that have to be at least detectable and another one of those that have to be diagnosable. The provided tools apply to any system including dynamical systems described by recurrent or differential equations because they are based on a structural approach: only the variables appearing in constraints are considered. However, the generality of the structural approach is paid by possible over-estimation depending on the nature of constraints: it is well known that it relies on the conditioning of constraints. But solutions taking into account the nature of constraints can only be specific.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusion", "text": "An algorithm for sensor placement managing complete specifications has been presented. It deals with elements that have to be diagnosable, discriminable and nondetectable. Thanks to the proposed algorithm, cost optimal sensor placement satisfying complete diagnosability specifications is possible without designing the ARR a priori. This is a very important feature since it is no longer necessary to design all the possible ARRs assuming all the variables are measured.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusion", "text": "This approach manages only specifications dealing with models of the normal behaviour. It does not take into account specific fault models such as a leak in a pipe. Therefore, if such models are considered, the sensor placement algorithm will lead to an over-estimation of the required sensors. Taking into account specific fault models may lead to a reduction of the required sensors. Nevertheless, fault models cannot be easily taken into account in sensor placement methods. It is still an open problem.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Principles of Constraint Programming", "authors": [{"first": "K", "middle": [], "last": "Apt", "suffix": ""}], "year": 2003, "venue": "", "link": "5616873"}, "BIBREF1": {"title": "Diagnosis and Fault-tolerant Control", "authors": [{"first": "M", "middle": [], "last": "Blanke", "suffix": ""}, {"first": "M", "middle": [], "last": "Kinnaert", "suffix": ""}, {"first": "J", "middle": [], "last": "Lunze", "suffix": ""}, {"first": "M", "middle": [], "last": "Staroswiecki", "suffix": ""}], "year": 2006, "venue": "", "link": "113315757"}, "BIBREF2": {"title": "Modern Graph Theory", "authors": [{"first": "B", "middle": [], "last": "Bollob\u00e1s", "suffix": ""}], "year": 1998, "venue": "", "link": "120529008"}, "BIBREF3": {"title": "Hierarchical model-based diagnosis based on structural abstraction", "authors": [{"first": "L", "middle": [], "last": "Chittaro", "suffix": ""}, {"first": "R", "middle": [], "last": "Ranon", "suffix": ""}], "year": 2004, "venue": "Artificial Intelligence", "link": "16223193"}, "BIBREF4": {"title": "Structural analysis for the sensor location problem in fault detection and isolation", "authors": [{"first": "C", "middle": [], "last": "Commault", "suffix": ""}, {"first": "J.-M", "middle": [], "last": "Dion", "suffix": ""}, {"first": "Yacoub", "middle": [], "last": "Agha", "suffix": ""}, {"first": "S", "middle": [], "last": "", "suffix": ""}], "year": 2006, "venue": "Proceedings of the IFAC Symposium SAFE-PROCESS'2006", "link": "205763623"}, "BIBREF5": {"title": "Diagnosis and diagnosability analysis using process algebra", "authors": [{"first": "L", "middle": [], "last": "Console", "suffix": ""}, {"first": "C", "middle": [], "last": "Picardi", "suffix": ""}, {"first": "M", "middle": [], "last": "Ribando", "suffix": ""}], "year": 2000, "venue": "Proceedings of the 11th International Workshop on Principles of Diagnosis DX'2000", "link": "116652868"}, "BIBREF6": {"title": "A comparative analysis of AI and control theory approaches to model-based diagnosis", "authors": [{"first": "M.-O", "middle": [], "last": "Cordier", "suffix": ""}, {"first": "P", "middle": [], "last": "Dague", "suffix": ""}, {"first": "F", "middle": [], "last": "L\u00e9vy", "suffix": ""}, {"first": "M", "middle": [], "last": "Dumas", "suffix": ""}, {"first": "J", "middle": [], "last": "Montmain", "suffix": ""}, {"first": "M", "middle": [], "last": "Staroswiecki", "suffix": ""}, {"first": "L", "middle": [], "last": "Trav\u00e9-Massuy\u00e8s", "suffix": ""}], "year": 2000, "venue": "Proceedings of the IFAC Symposium SAFEPROCESS", "link": null}, "BIBREF7": {"title": "Application of sensitivity theory to fuzzy logic based FDI", "authors": [{"first": "T", "middle": [], "last": "Dalton", "suffix": ""}, {"first": "P", "middle": [], "last": "Klotzek", "suffix": ""}, {"first": "P", "middle": [], "last": "Frank", "suffix": ""}], "year": 1999, "venue": "International Journal of Applied Mathematics and Computer Science", "link": "119083916"}, "BIBREF8": {"title": "Diagnosis with behavioral modes", "authors": [{"first": "J", "middle": [], "last": "De Kleer", "suffix": ""}, {"first": "B", "middle": ["C"], "last": "Williams", "suffix": ""}], "year": 1992, "venue": "Readings in Model-Based Diagnosis", "link": "8810032"}, "BIBREF9": {"title": "A structure theory of bi-partite graphs of finite exterior extension, Transactions of the", "authors": [{"first": "A", "middle": ["L"], "last": "Dulmage", "suffix": ""}, {"first": "N", "middle": ["S"], "last": "Mendelsohn", "suffix": ""}], "year": 1959, "venue": "Royal Society of Canada", "link": null}, "BIBREF10": {"title": "Sensor placement for maximum fault isolability", "authors": [{"first": "E", "middle": [], "last": "Frisk", "suffix": ""}, {"first": "M", "middle": [], "last": "Krysander", "suffix": ""}], "year": 2007, "venue": "Proceedings of the 18th International Workshop on Principles of Diagnosis (DX-07)", "link": "16564201"}, "BIBREF11": {"title": "Readings in Model-Based Diagnosis", "authors": [{"first": "W", "middle": [], "last": "Hamscher", "suffix": ""}, {"first": "L", "middle": [], "last": "Console", "suffix": ""}, {"first": "De", "middle": [], "last": "Kleer", "suffix": ""}, {"first": "J", "middle": [], "last": "", "suffix": ""}], "year": 1992, "venue": "", "link": "60494763"}, "BIBREF12": {"title": "Dynamic neural networks for process modelling in fault detection and isolation", "authors": [{"first": "J", "middle": [], "last": "Korbicz", "suffix": ""}, {"first": "K", "middle": [], "last": "Patan", "suffix": ""}, {"first": "A", "middle": [], "last": "Obuchowicz", "suffix": ""}], "year": 1999, "venue": "International Journal of Applied Mathematics and Computer Science", "link": "106966609"}, "BIBREF13": {"title": "Fuzzy logic faut diagnosis of industrial process actuators", "authors": [{"first": "J", "middle": [], "last": "Koscielny", "suffix": ""}, {"first": "M", "middle": [], "last": "Syfert", "suffix": ""}, {"first": "M", "middle": [], "last": "Bartys", "suffix": ""}], "year": 1999, "venue": "International Journal of Applied Mathematics and Computer Science", "link": null}, "BIBREF14": {"title": "An efficient algorithm for finding minimal overconstrained subsystems for model-based diagnosis", "authors": [{"first": "M", "middle": [], "last": "Krysander", "suffix": ""}, {"first": "J", "middle": [], "last": "Aslund", "suffix": ""}, {"first": "M", "middle": [], "last": "Nyberg", "suffix": ""}], "year": 2008, "venue": "IEEE Transactions on Systems, Man and Cybernetics", "link": "25004015"}, "BIBREF15": {"title": "Artificial intelligence approaches to fault diagnosis for dynamic systems", "authors": [{"first": "C", "middle": [], "last": "Lopez-Toribio", "suffix": ""}, {"first": "R", "middle": [], "last": "Patton", "suffix": ""}, {"first": "F", "middle": [], "last": "Uppal", "suffix": ""}], "year": 1999, "venue": "International Journal of Applied Mathematics and Computer Science", "link": "118370073"}, "BIBREF16": {"title": "Optimal selection of measuring points in complex plants by linear models", "authors": [{"first": "F", "middle": [], "last": "Madron", "suffix": ""}, {"first": "V", "middle": [], "last": "Veverka", "suffix": ""}], "year": 1992, "venue": "AIChE Journal", "link": "122665734"}, "BIBREF17": {"title": "Fault detection and isolation and sensor network design", "authors": [{"first": "D", "middle": [], "last": "Maquin", "suffix": ""}, {"first": "M", "middle": [], "last": "Luong", "suffix": ""}, {"first": "J", "middle": [], "last": "Ragot", "suffix": ""}], "year": 1997, "venue": "European Journal of Automation", "link": "108731398"}, "BIBREF18": {"title": "Combining AI, FDI, and statistical hypothesis-testing in a framework for diagnosis", "authors": [{"first": "M", "middle": [], "last": "Nyberg", "suffix": ""}, {"first": "M", "middle": [], "last": "Krysander", "suffix": ""}], "year": 2003, "venue": "Proceedings of the IFAC Symposium SAFEPROCESS'03", "link": "13962635"}, "BIBREF20": {"title": "Automatic design of detection tests in complex dynamic systems", "authors": [{"first": "S", "middle": [], "last": "Ploix", "suffix": ""}, {"first": "M", "middle": [], "last": "D\u00e9sinde", "suffix": ""}, {"first": "S", "middle": [], "last": "Touaf", "suffix": ""}], "year": 2005, "venue": "Proceedings of the 16th IFAC World Congress", "link": "9958593"}, "BIBREF21": {"title": "A logical framework for isolation in fault diagnosis", "authors": [{"first": "S", "middle": [], "last": "Ploix", "suffix": ""}, {"first": "S", "middle": [], "last": "Touaf", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Flaus", "suffix": ""}], "year": 2003, "venue": "Proceedings of the IFAC Symposium SAFEPROCESS'2003", "link": "195995952"}, "BIBREF22": {"title": "Computing the block triangular form of a sparse matrix", "authors": [{"first": "A", "middle": [], "last": "Pothen", "suffix": ""}, {"first": "F", "middle": [], "last": "Chin-Ju", "suffix": ""}], "year": 1990, "venue": "ACM Transactions on Mathematical Software", "link": "207643706"}, "BIBREF23": {"title": "Possible conflicts, arrs, and conflicts", "authors": [{"first": "B", "middle": [], "last": "Pulido", "suffix": ""}, {"first": "C", "middle": [], "last": "Alonso", "suffix": ""}], "year": 2002, "venue": "Proceedings of the 13th International Workshop on Principles of Diagnosis (DX02)", "link": null}, "BIBREF24": {"title": "Redundancy relations for fault diagnosis in nonlinear uncertain systems", "authors": [{"first": "A", "middle": [], "last": "Shumsky", "suffix": ""}], "year": 2007, "venue": "International Journal of Applied Mathematics and Computer Science", "link": "9157170"}, "BIBREF25": {"title": "What's in SD? Towards a theory of modeling for diagnosis", "authors": [{"first": "P", "middle": [], "last": "Struss", "suffix": ""}], "year": 1992, "venue": "Readings in model-based diagnosis", "link": "58734924"}, "BIBREF26": {"title": "Modelbased tools for the integration of design and diagnosis into a common process -A project report", "authors": [{"first": "P", "middle": [], "last": "Struss", "suffix": ""}, {"first": "B", "middle": [], "last": "Rehfus", "suffix": ""}, {"first": "R", "middle": [], "last": "Brignolo", "suffix": ""}, {"first": "F", "middle": [], "last": "Cascio", "suffix": ""}, {"first": "L", "middle": [], "last": "Console", "suffix": ""}, {"first": "P", "middle": [], "last": "Dague", "suffix": ""}, {"first": "P", "middle": [], "last": "Dubois", "suffix": ""}, {"first": "O", "middle": [], "last": "Dressler", "suffix": ""}, {"first": "D", "middle": [], "last": "Millet", "suffix": ""}], "year": 2002, "venue": "Proceedings of the International Workshop on Principles of Diagnosis DX'02", "link": null}, "BIBREF27": {"title": "Modelbased diagnosability and sensor placement application to a frame 6 gas turbine subsystem", "authors": [{"first": "L", "middle": [], "last": "Trav\u00e9-Massuy\u00e8s", "suffix": ""}, {"first": "T", "middle": [], "last": "Escobet", "suffix": ""}, {"first": "R", "middle": [], "last": "Milne", "suffix": ""}], "year": 2001, "venue": "Proceedings of the 12th International Workshop on Principles of Diagnosis", "link": "16991573"}, "BIBREF28": {"title": "Advances in model-based fault diagnosis with evolutionary algorithms and neural networks", "authors": [{"first": "M", "middle": [], "last": "Witczak", "suffix": ""}], "year": 2006, "venue": "International Journal of Applied Mathematics and Computer Science", "link": "6746892"}}, "ref_entries": {"FIGREF0": {"text": "Fig. 1. Tube modelling a variable and a related observation.", "type": "figure"}, "FIGREF1": {"text": "Fig. 2. Link between propagations and minimal testable subsets.", "type": "figure"}, "FIGREF2": {"text": "Fig. 3. Structural matrix of a constraint set K, which is linked by a set of variables V .", "type": "figure"}, "FIGREF3": {"text": "Fig. 4. Structural matrix of a constraint set, which is isolated by the set of variables V .", "type": "figure"}, "FIGREF4": {"text": "Fig. 5. Structural matrix of non-detectable constraints.", "type": "figure"}, "FIGREF5": {"text": "var linking (K i , K \u03a3 \\K nondet ) contains the link- ing variables and V + i contains the remaining variables V + i = var(K i )\\V \u2212 i . Lemmas 4 and 5 imply that the set V + i cannot contain variables in var stump (K nondet , K \u03a3 ) and in Kj \u2208K nondis ;Kj =Ki var linking (K j , K \u03a3 ). There- fore, V + i satisfies V + i \u2282 V candidate . Because of the third point of the theorem, all the vari- ables of V candidate are known: additional terminal con- straints are indeed added, and there is necessarily a TSS dealing with all the constraints in K i . It proves that the", "type": "figure"}, "FIGREF6": {"text": "FindBlocks(K \u03a3 , V \u0394 ): A triple of block sets (B nondet , B nondis , B diag ), considering only the variables", "type": "figure"}, "FIGREF7": {"text": "Fig. 6. Shape of a structural matrix satisfying Theorem 1.", "type": "figure"}, "FIGREF8": {"text": "Fig. 8. Dependency scheme of the sensor placement method for complete specifications.", "type": "figure"}, "FIGREF9": {"text": "): A set of variables to be measured to satisfied complete specifications, \u2205 if no solution Require: Specifications are consistent in", "type": "figure"}, "FIGREF10": {"text": "dx dt corresponds to a tube, which can be con- nected to x in adding the implicit constraint x = dx dt dt. The initial condition could also be taken into account by considering x = t f 0 dx dt dt + x 0 . In this case, the struc- tures of the constraints become var(k 1 ) = { dx dt, u}", "type": "figure"}, "FIGREF11": {"text": "Fig. 9. Scheme of an electronic circuit.", "type": "figure"}, "FIGREF13": {"text": "k 1 k 2 k 3 k 4 k 5 k 6 k 7 k 8 k 9 k 10 k 11 k 12 k 13", "type": "figure"}, "TABREF0": {"text": "- connected by V and iff the other constraints of K \u03a3 (i.e., K \u03a3 \\K) do not contain any variable of V . The variables of V are called linking variables for K. They are denoted by var linking", "type": "table"}, "TABREF2": {"text": "Let K \u03a3 be a set of constraints and K nondet , K nondis and K diag be the specifications of a sensor place- 504 A.A. Yassine et al. ment problem consistent in K \u03a3 . Sufficient conditions for the specifications to be fulfilled are as follows: 1. There exists a system (K 1 , . . . , K p ) of p sets of constraints making up a partition P(K nondet ) of K nondet such that each K i is isolated in K \u03a3 \\ j<i K j (K 1 is a limit case: it should be iso- lated in K \u03a3 ) as shown in Fig. 5.", "type": "table"}, "TABREF4": {"text": "straints and a set of variables. Two blocks can be merged:", "type": "table"}, "TABREF5": {"text": "return false else if B nondet .cons = K", "type": "table"}, "TABREF6": {"text": "spec diag ): a set of variables to be measured Require: Specifications are consistent in K \u03a3 Require: cost() is defined for each variable in", "type": "table"}, "TABREF7": {"text": "Structural matrix of the electronic circuit.", "type": "table"}, "TABREF8": {"text": "Analytical relations for the complete specifications.", "type": "table"}}}
{"paper_id": "10705876", "_pdf_hash": "cb2f64d3b9df923472755ee3aa090c274cf1ec75", "abstract": [], "body_text": [{"section": "", "text": ". By mimicking the human cell-surface glycosylation in the stomach they act as molecular decoys for the immune system and therefore contribute to the persistence of the infection [9, 10] . Another feature of some H. pylori strains is the presence of an additional chain of d-glycerod-manno-heptose (dd-Hep), which has been reported to connect the O-chain to the LPS core [11] . Also, some LPS strains have been shown to express elongated a-glucan chains linked to the core [8, 12, 13] . LPS a-glucans can be either found O-6-linked [8, 12] [13] . Proof have also been presented for the expression of a highly branched cell-surface a-mannan composed of terminal, O-2-, O-6-, and O-2,6-substituted mannose (Man) residues [14] .", "cite_spans": [{"start": 179, "end": 182, "text": "[9,", "ref_id": "BIBREF8"}, {"start": 183, "end": 186, "text": "10]", "ref_id": "BIBREF9"}, {"start": 371, "end": 375, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 473, "end": 476, "text": "[8,", "ref_id": "BIBREF7"}, {"start": 477, "end": 480, "text": "12,", "ref_id": "BIBREF11"}, {"start": 481, "end": 484, "text": "13]", "ref_id": "BIBREF12"}, {"start": 532, "end": 535, "text": "[8,", "ref_id": "BIBREF7"}, {"start": 536, "end": 539, "text": "12]", "ref_id": "BIBREF11"}, {"start": 540, "end": 544, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 719, "end": 723, "text": "[14]", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "", "text": "Cell-surface glycosylation is known to be involved in the control of various biologic and physiologic events such the modulation of protein conformational and functional properties [15, 16] , mediation of cell-cell adhesion and cell-host interaction [16, 17] , regulatory [16, 18] and immunologic [16, 19, 20] phenomena. Alteration of the cell-surface glycosylation patterns often occurs as a result of the adaptive responses to environmental changes comprising events such as the expression of capsular polysaccharides as well as excretion of polysaccharides to the surrounding media as exopolysaccharides [21] . These events are thought to confer extra protection against harsh environments and external aggressions. Production of exopolysaccharides is strongly correlated with the formation of biofilms responsible for the colonization of unfriendly environments and the promotion of bacterial life on community [22] .", "cite_spans": [{"start": 181, "end": 185, "text": "[15,", "ref_id": "BIBREF14"}, {"start": 186, "end": 189, "text": "16]", "ref_id": "BIBREF15"}, {"start": 250, "end": 254, "text": "[16,", "ref_id": "BIBREF15"}, {"start": 255, "end": 258, "text": "17]", "ref_id": "BIBREF16"}, {"start": 272, "end": 276, "text": "[16,", "ref_id": "BIBREF15"}, {"start": 277, "end": 280, "text": "18]", "ref_id": "BIBREF17"}, {"start": 297, "end": 301, "text": "[16,", "ref_id": "BIBREF15"}, {"start": 302, "end": 305, "text": "19,", "ref_id": "BIBREF18"}, {"start": 306, "end": 309, "text": "20]", "ref_id": "BIBREF19"}, {"start": 607, "end": 611, "text": "[21]", "ref_id": "BIBREF20"}, {"start": 915, "end": 919, "text": "[22]", "ref_id": "BIBREF21"}], "ref_spans": []}, {"section": "", "text": "In this work, we devote our attention to the identification and structural characterization of novel H. pylori cell-surface glycosides mainly produced as a result of environmental adaptation to growth in vitro solid and liquid media. Such insight can provide some enlightenment on the bacterial colonization strategies outside the human host, namely through the production of exopolysaccharides involved in the formation of biofilms or expression of capsular polysaccharides under very specific environmental conditions.", "cite_spans": [], "ref_spans": []}, {"section": "Materials and Methods", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Bacterial Cultures", "text": "Reference strain H. pylori NCTC 11637 was obtained from the National Collection of Type Cultures (London, UK), clinical isolate 968 was provided by the Centre of Biological Engineering of the University of Minho (Braga, Portugal), and clinical isolate 14255 was provided by IPATIMUP (Porto, Portugal).", "cite_spans": [], "ref_spans": []}, {"section": "Bacterial Growth in CBA", "text": "H. pylori cells were maintained as stock cultures in trypticase soy broth with 20% glycerol, recovered on prewarmed Gelose Columbia solid media supplemented with 5% horse blood (bioM\u00e9 rieux, France) and incubated at 37\u00b0C for 72 hours, on a microaerophilic atmosphere generated by a CampyGen gas pack (Oxoid, Basingstoke, UK). Cells were subcultivated after 48-hour incubation periods in the conditions described before. The resulting biomass was harvested to sterile and filtered (0.22 lm) distilled water.", "cite_spans": [], "ref_spans": []}, {"section": "Bacterial Growth in F12 Liquid Media", "text": "H. pylori reference strain NCTC 11637 and clinical isolate 968 were grown on Ham's F12 defined liquid media without the addition of enhancing growth factors. The medium was inoculated with cellular extracts obtained from Columbia blood agar (CBA) growth media. Cells were allowed to grow for 24 hours in a glass flask under microaerophilic atmosphere by gentile stirring at 37\u00b0C as described by Testerman et al. [6] .", "cite_spans": [{"start": 412, "end": 415, "text": "[6]", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Purity Assessment of Bacterial Growth", "text": "Purity assessment was assured by using a highly specific peptide nucleic acid probe in a fluorescence in situ hybridization procedure, according to the protocol described by Guimaraes et al. [23] . For every experiment, a negative control was performed simultaneously where all the steps described before were carried out but where no probe was added during the hybridization procedure. Microscopy visualization was performed using an Olympus BX51 (OLYMPUS Portugal SA, Porto, Portugal) epifluorescence microscope equipped with one filter sensitive to the Alexa fluor 594 signaling molecule attached to the PNA probe (excitation 530-550 nm; barrier 570 nm; emission LP 591 nm).", "cite_spans": [{"start": 191, "end": 195, "text": "[23]", "ref_id": "BIBREF22"}], "ref_spans": []}, {"section": "Extraction and Purification of Cell-Surface Glycans", "text": "Cell-surface glycans were isolated from cells using the hot phenol : water extraction according to Westphal and Jann [24] . The aqueous layer was dialyzed against distilled water using a 1000 Da cut-off membrane and lyophilized. The resulting material was fractioned by gel permeation \u2044 adsorption chromatography (GPC) on a polyacrylamide Bio-Gel P-6 (Bio-Rad Laboratories, Hercules, CA, USA) (0.6 m in length and 1.0 cm in diameter) column using distilled water as the eluting solvent at a constant flow rate of 0.33 mL \u2044 minute. The initial material (2.5 mg) was suspended in 400 lL of degassed distilled water and introduced in the column. Fractions of 2.8 mL were collected. The mass content in the fractions was estimated on evaporative light scattering detector SEDEX55 (SEDERE, Alfortville, France) and further assayed for total sugars with the phenol-H 2 SO 4 method [25] . Exclusion and total volume were calibrated with blue dextran and glucose, respectively.", "cite_spans": [{"start": 117, "end": 121, "text": "[24]", "ref_id": "BIBREF23"}, {"start": 875, "end": 879, "text": "[25]", "ref_id": "BIBREF24"}], "ref_spans": []}, {"section": "Sugars Composition and Linkage Analysis", "text": "Sugars composition analysis was performed by the alditol acetate method as described by Harris et al. [26] . The hydrolysis was done in 4 mol \u2044 L of trifluoroacetic acid (TFA) at 100\u00b0C for 3 hours, followed by reduction with NaBH 4 and subsequent acetylation with acetic anhydride in the presence of 1-methylimidazole. Alditol acetates derivatives were analyzed by gas chromatography-mass spectrometry (GC-MS), performed in an Agilent Technologies (Santa Clara, CA, USA) 6890N Network Gas Chromatograph connected to an Agilent 5973 Selective Mass Detector. The GC was equipped with a DB-1 capillary column (30 m in length, 0.32 mm in internal diameter, and 0.25 lm film thicknesses). The samples were injected in splitless mode (splitless time is 1.00 minute), with the injector and detector operating at 220 and 230\u00b0C, respectively, using the following temperature program: 100\u00b0C (1 minute) fi 150\u00b0C at 5\u00b0C \u2044 minute (8 minutes) fi 159\u00b0C at 0.5\u00b0C \u2044 minute (5 minutes) fi 250\u00b0C at 5\u00b0C \u2044 minute (2 minutes) fi 320\u00b0C at 2\u00b0C \u2044 minute (2 minutes). The carrier gas (He) had a flow of 1.7 mL \u2044 minute, with an average linear velocity of 47 cm \u2044 second, and a solvent delay of 9 minutes. The column head pressure was 5.34 psi. The mass spectrometer was operated in the electron impact mode at 70 eV, scanning the mass range m \u2044 z 40-500 and performing 3.18 scans per second.", "cite_spans": [{"start": 102, "end": 106, "text": "[26]", "ref_id": "BIBREF25"}], "ref_spans": []}, {"section": "Sugars Composition and Linkage Analysis", "text": "Linkage analysis was carried out by methylation with NaOH \u2044 Me 2 SO \u2044 CH 3 I, as described by Ref. [27] . The methylated polysaccharides were hydrolyzed with 2 mol \u2044 L of TFA at 121\u00b0C for 1 hour, reduced by NaBD 4 , and acetylated with acetic anhydride in the presence of 1-methylimidazole. The partially methylated alditol acetates were analyzed by GC-MS using the chromatographic conditions previously described, using the following temperature program: 45\u00b0C (5 minutes) fi 140\u00b0C at 10\u00b0C \u2044 minute (5 minutes) fi 170\u00b0C at 0.5\u00b0C \u2044 minute (1 minute) fi 280\u00b0C at 15\u00b0C \u2044 minute (5 minutes).", "cite_spans": [{"start": 99, "end": 103, "text": "[27]", "ref_id": "BIBREF26"}], "ref_spans": []}, {"section": "Iodine Test", "text": "A thin layer of fresh bacterial cells grown on solid medium was fixed on a cleaned sterile glass slide. Cells were then covered with Gram's iodine solution (0.33% (w \u2044 v) I 2 in 0.66% (w \u2044 v) KI aqueous solution; SigmaAldrich Qu\u00edmica S.A., Sintra, Portugal) and incubated for 1 minute at room temperature. After incubation, the cells were washed with water to remove the excess of staining agent and observed by light microscopy.", "cite_spans": [], "ref_spans": []}, {"section": "Enzymatic Assays", "text": "Digestion with a-amylase from human saliva (Type IX-A, lyophilized powder, 1000-3000 units \u2044 mg protein; Sigma Aldrich) was performed in 50 mmol \u2044 L phosphate buffer at pH 6.8 for 3 hours at 20\u00b0C. The enzyme was denatured by heating the solution for 15 minutes at 100\u00b0C and the precipitate material was removed by centrifugation.", "cite_spans": [], "ref_spans": []}, {"section": "Enzymatic Assays", "text": "The enzyme-treated material was separated on a polyacrilamide Bio-Gel P-4 column (0.6 m in length and 1.0 cm in diameter) using water as an eluent in the conditions previously mentioned for the separation on the Bio-Gel P6 column.", "cite_spans": [], "ref_spans": []}, {"section": "NMR Spectroscopy", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "1", "text": "H spectra were recorded on a Bruker (Bruker BioSpin GmbH, Rheinstetten, Germany) AMX 400 spectrometer at 295 K using standard Bruker software. Prior to performing the nuclear magnetic resonance (NMR) experiments, the samples were lyophilized thrice with D 2 O (99.9%). The HDO peak was used as the internal reference at d H of 4.76 ppm.", "cite_spans": [], "ref_spans": []}, {"section": "Mass Spectrometry", "text": "MS assays were performed in a linear ion trap (LIT) electrospray (ESI) spectrometer in positive mode. Samples were dissolved in 1 : 200 of water : methanol and introduced into the MS at 10 lL \u2044 min. Typical ESI conditions were as follows: nitrogen sheath gas 30 psi, spray voltage 5.5 kV, heated capillary temperature 350\u00b0C, capillary voltage 1 V, and tube lens voltage 40 V. CollisionInduced Dissociation-Mass Spectrometry (CID-MS/MS) experiments were performed on mass-selected precursor ions using standard isolation and excitation procedures (activation q value of 0.25, activation time of 30 ms). The spectra were collected in the positive mode and collision energy used was 32 (arbitrary units). Data acquisition was carried out with Xcalibur data system (Thermo Fisher Scientific Inc., Waltham, MA, USA).", "cite_spans": [], "ref_spans": []}, {"section": "Statistics", "text": "Statistical significance was determined using paired Student's t-tests (p = .05). Between-and within-sample variances were determined by one-way ANOVA and comparison between standard deviations performed using an F-test (p = .05). Correlation between samples was determined by linear regression method.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Carbohydrate Profile of Glycan-Rich Extracts from Helicobacter pylori Cells Grown in Solid Media", "text": "In this study, H. pylori reference strain NCTC 11637 and clinical isolates 968 and 14255 were evaluated in relation to their cell-surface glycan profile. The first step in the identification and structural characterization of cell-surface polysaccharides comprised the recovery of glycan-rich aqueous phase resulting from hot phenol : water extraction performed on intact bacterial cells. The overall sugars composition of such extracts is presented in Table 1 . The different strains present distinct sugars composition. NCTC 11637 contains a large amount of Rib, possibly a contamination from RNA, glucose (Glc), and galactose (Gal) whereas 968 presents also Gal and Glc but is richer in N-acetylglucosamine (GlcNAc) and d-glycero-d-manno-heptose (ddHep) and 14255 is richer in Gal and GlcNAc. Lower amounts of fucose (Fuc), arabinose (Ara), Man, and lglycero-d-manno-heptose (ld-Hep) have also been observed in all strains. The occurrence of Ara has never been reported to occur in H. pylori. The different sugar contents might reflect both strain-to-strain variability and biosynthetic microheterogeneity.", "cite_spans": [], "ref_spans": [{"start": 453, "end": 460, "text": "Table 1", "ref_id": "TABREF2"}]}, {"section": "Carbohydrate Profile of Glycan-Rich Extracts from Helicobacter pylori Cells Grown in Solid Media", "text": "To highlight the structural features of these polymers, the linkage profile held by the identified sugars was further evaluated by GC-MS of the permethylated alditol acetate derivatives released after hydrolysis of the original glycans.", "cite_spans": [], "ref_spans": []}, {"section": "Carbohydrate Profile of Glycan-Rich Extracts from Helicobacter pylori Cells Grown in Solid Media", "text": "Linkage analysis has revealed, in all CBA grown strains, a prevalence of O-3-linked Gal and O-4-linked GlcNAc residues in proportions of approximately 1 : 1. Based on previous knowledge on H. pylori cell-surface glycans [8] , these structures belong to N-acetyllactos- [8] . Low amounts (<5%) of other O-chain and corerelated residues have also been identified and assigned as shown in Table 2 .", "cite_spans": [{"start": 220, "end": 223, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 269, "end": 272, "text": "[8]", "ref_id": "BIBREF7"}], "ref_spans": [{"start": 386, "end": 393, "text": "Table 2", "ref_id": "TABREF3"}]}, {"section": "Carbohydrate Profile of Glycan-Rich Extracts from Helicobacter pylori Cells Grown in Solid Media", "text": "Man was observed in all extracts in percentages that span from 5 to 11% of total sugars (Table 1) . These residues are essentially found as terminal, O-2-, O-6-, and O-2,6-linked (Table 2) . Monteiro et al. [14] have shown the occurrence of a mannan containing these characteristic linkages when studying a H. pylori mutant strain. Methylation analysis shows that the Ara residues occur mainly as O-2-substituted even though trace amounts of terminal and O-5-linked residues could also be observed.", "cite_spans": [{"start": 207, "end": 211, "text": "[14]", "ref_id": "BIBREF13"}], "ref_spans": [{"start": 88, "end": 97, "text": "(Table 1)", "ref_id": "TABREF2"}, {"start": 179, "end": 188, "text": "(Table 2)", "ref_id": "TABREF3"}]}, {"section": "Carbohydrate Profile of Glycan-Rich Extracts from Helicobacter pylori Cells Grown in Solid Media", "text": "In addition to LPS sugars, Man and Ara, high amounts of O-4-linked Glc residues [fi4)-Glcp-(1fi] were also common to all extracts ( Table 2 ). The total amount of O-4-substituted Glc was found to vary from 5 to 26% of total sugars and its presence in glycan-rich water extracts is now being described for the first time for H. pylori. To confirm the presence of amylose-like glycans, H. pylori cells were treated with Lugol iodine solution. The bluestained cells shown in Fig. 1 demonstrate the presence of amylose, with (1fi4)-d-Glc in a configuration. Trace amounts of O-4,6-linked Glc residues were also identified in all samples, suggesting the existence of residual branching points in the glucan chain. Because the CBA culture medium contains starch, it is not possible to identify the origin of this material, if produced by the bacterium or uptaken from the medium.", "cite_spans": [], "ref_spans": [{"start": 132, "end": 139, "text": "Table 2", "ref_id": "TABREF3"}, {"start": 472, "end": 478, "text": "Fig. 1", "ref_id": "FIGREF3"}]}, {"section": "Carbohydrate Profile of Glycan-Rich Extracts from Helicobacter pylori Cells Grown on Liquid Media", "text": "To determine if H. pylori was capable of biosynthesizing amylose-like glycans, the reference strain NCTC 11637 and the clinical isolate 968 were grown in Ham's F12 defined liquid media, which is devoid of polysaccharides in its composition. Cellular growth was promoted in the absence of external growth enhancers such as FBS, BSA, or cyclodextrin further fulfilling the requirement for a glycan-depleted environment. As it can be observed from sugars (Table 1 ) and linkage (Table 2) analysis, growth in liquid medium resulted, in both strains, in an increase percentage of Man and sugars belonging to the LPS moiety (Glc, Gal, GlcNAc, and Hep). The two strains also retrieved positive for the presence of amylose in liquid medium thus demonstrating the capability of those strains to synthesize amylose-like glycans in a polysaccharide-depleted medium. To fully access the structural organization of the O-4-linked glucan, the water extracts from H. pylori reference strain NCTC 11637 was fractionated by sizeexclusion chromatography on a Bio-Gel P6 medium.", "cite_spans": [], "ref_spans": [{"start": 452, "end": 460, "text": "(Table 1", "ref_id": "TABREF2"}, {"start": 475, "end": 484, "text": "(Table 2)", "ref_id": "TABREF3"}]}, {"section": "Purification and Characterization of Helicobacter pylori Amylose-Like Glycans", "text": "Fractionation of the glycan-rich material in a Bio-Gel P6 resulted in the elution profile presented in Fig. 2 , from which six fractions were identified and labeled from A to F.", "cite_spans": [], "ref_spans": [{"start": 103, "end": 109, "text": "Fig. 2", "ref_id": "FIGREF4"}]}, {"section": "Purification and Characterization of Helicobacter pylori Amylose-Like Glycans", "text": "The high-molecular weight fractions (A-C) were composed mainly of Gal (31-36%), Man (24-30%), Glc (17-25%), and also contained Rib (7%). Lower amounts of GlcNAc (2-5%), Fuc (3%), dd-and ld-Hep (1-3%), and Ara (2%) have also been observed (Table 3 ). Linkage analysis allowed assigning the Fuc, Gal, GlcNAc, dd-and ld-Hep to the LPS moiety (Table 4 ) [8] . The Ara residues in fractions A-C were almost exclusively found O-2,3,5-linked (Table 4) , a very uncommon substitution pattern in nature, although reported to occur in some seeds [29] . Residual amounts of terminal, O-2-, and O-5-linked Ara residues were also identified. Their presence throughout all fractions points towards that variously linked Ara residues are structural motifs of H. pylori strains.", "cite_spans": [{"start": 350, "end": 353, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 536, "end": 540, "text": "[29]", "ref_id": "BIBREF28"}], "ref_spans": [{"start": 238, "end": 246, "text": "(Table 3", "ref_id": "TABREF4"}, {"start": 339, "end": 347, "text": "(Table 4", "ref_id": "TABREF6"}, {"start": 435, "end": 444, "text": "(Table 4)", "ref_id": "TABREF6"}]}, {"section": "Purification and Characterization of Helicobacter pylori Amylose-Like Glycans", "text": "The percentage of O-4-linked Glc residues increased from fractions A to F (Table 4) . Glc was found to be the second major component of fractions A-C, and predominantly identified as being O-4-linked (66-79% of the total Glc) The remaining Glc was either found in the O-3-linked form (7-14% of total Glc), assigned to the LPS, or O-6-linked form, assigned to dextran antenna in the LPS [12] . Terminal Glc was also present in percentages that span from 5% (fraction C) to 11% (fraction A) of total Glc and can either be found in the terminal ends of LPS core and dextran antenna as well as in the O-4-substituted glucan. Such structural diversity makes impossible the determination of the exact percentage of terminal Glc belonging to the glucan chain thus hindering the estimation of the molecular weight based on O-4-linked Glc \u2044 terminal Glc ratio. Linkage analysis on fractions A-C also showed residual amounts of O-4,6-disubstituted Glc (2%) thus reinforcing that, even though almost exclusively linear, the glucan might exhibit vestigial branching. In fraction D, the O-4-linked Glc was the most abundant linkage. Still, it contains significant amounts of Man and Gal (16 and 19% of total sugars, respectively) and, in lower percentages, Rib (9%), Fuc (5%), Ara (4%), GlcNAc (2%), dd-Hep (3%), and ld-Hep (4%). Fractions E and F were composed almost exclusively of O-4-linked Glc (83 and 78%, respectively). Assuming a linear structure, the (1fi4) \u2044 terminally linked Glc ratio allows inferring that the average length of these polymers can vary from 42 (7 kDa, fraction E) up to 28 residues (4 kDa, fraction F) Glc residues.", "cite_spans": [{"start": 386, "end": 390, "text": "[12]", "ref_id": "BIBREF11"}], "ref_spans": [{"start": 74, "end": 83, "text": "(Table 4)", "ref_id": "TABREF6"}]}, {"section": "Purification and Characterization of Helicobacter pylori Amylose-Like Glycans", "text": "The polyacrylamide Bio-Gel P6 is expected to separate molecules based on their molecular weight, from 6 kDa (void volume) to 1 kDa (inclusion volume). These conditions are valid when no interactions occur between the stationary phase and the eluted sample. In the present work, the eluent was water, which is known to not prevent molecular interactions. In that case, the sugar composition and linkage profile of the isolated fractions suggest that polyacrylamide Bio-Gel P6 separated the molecules based both on the molecular weight and their interactions with the gel medium. Linear molecules such as the described (1fi4)-glucan tend to be retained more in the column (fractions D-F) whereas the more branched and voluminous LPS carrying a lipid A moiety are found in earlier eluted fractions (A-C). In agreement with these observations, highly branched Man appear preferentially in fraction A (15% of O-2,6-disubstituted Man) whereas fraction B has only 2% of branched Man residues and no branching is found in fraction C. To confirm the anomeric configuration and other structural features of the H. pylori glucan, fraction E, which exhibits a higher percentage of Glc (79%) and contains only residual amounts of other sugars (>7%) was further used for NMR and ESI-MS analyses. The 1 H NMR spectra of fraction E retrieved a single anomeric resonance at 5.36 ppm thus demonstrating that Glc residues were in a configuration (Fig. 3A) . (Fig. 4A) . Even though the estimated chain length calculated from linkage analysis data was of 28 residues, some dispersion in the degree of polymerization is always expected, thus explaining the observation of molecules of lower molecular weight in the ESI-MS spectrum. Although the sugar composition of this fraction showed both Rib (8%) and Ara (6%) no evidences of a linkage between the Glc residues and a pentose was found.", "cite_spans": [], "ref_spans": [{"start": 1427, "end": 1436, "text": "(Fig. 3A)", "ref_id": "FIGREF6"}]}, {"section": "Purification and Characterization of Helicobacter pylori Amylose-Like Glycans", "text": "To observe the extent of the contiguous O-4-linked Glc chains, fraction E was digested with an (1fi4)-a-d-glucan glucanohydrolase (a-amylase). This enzyme is responsible for catalyzing the endo-hydrolysis of (1fi4)-a-d-glucosidic linkages in polysaccharides containing three or more (1fi4)-a-linked d-glucose units. The digested material was then purified on a Bio-Gel P4 resulting in an elution profile composed of two Terminal Glc residues can also be addressed to the (1fi4)-glucan or the (1fi6)-dextran antenna in the lipopolysaccharides (LPS). tr, vestigial amounts (>0.5%); CBA, Columbia blood agar. H NMR spectrum of the material recovered from the void volume showed the disappearance of the a-anomeric signal, demonstrating the effectiveness of the enzymatic treatment (Fig. 3B) . The nonretained material was composed exclusively of disaccharides resulting from the enzymatic hydrolysis of the oligomeric glucan as demonstrated by the ion at m \u2044 z 365 observed in the ESI-MS spectrum (Fig. 4B) .", "cite_spans": [], "ref_spans": [{"start": 778, "end": 787, "text": "(Fig. 3B)", "ref_id": "FIGREF6"}]}, {"section": "Bioaccumulation of Amylose under Subcultivation in Solid Medium", "text": "After having shown the expression of an amylose-like polysaccharide by H. pylori in both solid and liquid media, the impact of successive subcultivation on cell-surface glycans (LPS and amylose-type glycans) was evaluated. The reference strain NCTC 11637 and the clinical isolates 968 and 14255 were subcultivated in CBA. The impact of successive subcultivation on cell-surface glycans was determined by the analysis of the sugars carried out on the freeze-dried biomass of intact cells. The total LPS (Fig. 5A) , given by the amount of Fuc, Glc, Gal, GlcNAc, and Hep, LPS O-chain (Fig. 5C) , given by the amount of Fuc, Gal, and GlcNAc, were quantified independently based on the output from sugar analysis. The results are expressed in terms of concentration (w \u2044 w) for six passages in CBA comprising a total of 13 days in solid media. Betweenand within-sample variance was estimated by one-way ANOVA for each component (LPS, LPS O-chain, and amylose-type glycans) for the three strains during the subcultivation period. F-test (p = .05) performed on those estimates retrieved that between-measurements variance was more significant than random errors expressed by within-sample variance for all cases. For LPS (Fig. 5A) , an initial increase in the overall amount of the material was observed in all strains, possibly because of an initial adaptation of the bacteria when passing from a vegetative state in the glycerol inoculums to the solid media. However, this tendency is reversed after the third and the fourth passages after which the amount of total LPS expressed decreases. Figure 4 Electrospray-mass spectrometry spectra of (A) fraction E and (B) material recovered after digestion with a-amylase.", "cite_spans": [], "ref_spans": []}, {"section": "Bioaccumulation of Amylose under Subcultivation in Solid Medium", "text": "Variations in O-chain sugars, presented graphically in Fig. 6B , show the same tendency of the overall LPS. Amylose, in opposition to what has been observed for the LPS, is seen to increase continuously with the incubation time (Fig. 5C ). This effect was observed for all strains and demonstrates that H. pylori bioaccumulates amylose during the subcultivation period.", "cite_spans": [], "ref_spans": []}, {"section": "Bioaccumulation of Amylose under Subcultivation in Solid Medium", "text": "The plot of the total amount of LPS and LPS O-chain sugars versus the total amount of amylose throughout the incubation period (Fig. 6) suggests a correlation between the expression of LPS \u2044 LPS O-chains and amylose. However, this correlation could only be observed when the data from the first and second passages are not included. This seems to be most likely correlated with an initial adaptation period of the bacteria to solid medium upon recovery from a latent stage resulting from cryostorage.", "cite_spans": [], "ref_spans": []}, {"section": "Amylose Expression in F12 Liquid Media", "text": "The H. pylori reference strain NCTC 11637 and the clinical isolate 968 obtained after three passages in solid media (day 7) were further recovered to a F12 liquid media.", "cite_spans": [], "ref_spans": []}, {"section": "Amylose Expression in F12 Liquid Media", "text": "The glycan profile for each inoculum and F12 material are presented graphically in Fig. 7 . In both strains, a statistically significant (Student's t-test; p = .05) increase was observed in LPS content in the passage from solid to liquid media. This phenomenon was more pronounced in strain NCTC 11637 (48%) than in 968 (12%) and was caused almost exclusively by an increase in the concentration of O-chain sugars (62% for NCTC 11637 and 12% for 968). Conversely, the amount of amylose decreased significantly in the passage from solid to liquid media where only residual amounts were observed.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "In the present work, we describe that H. pylori is capable of producing an amylose-like a-(1fi4)-d-glucan and further bioaccumulates this polysaccharide under selective pressure induced by subcultivation in the agar medium. Gathered information also suggests that H. pylori cell surface is composed of a mixed population of glycans comprising LPS, mannose-rich glycosides as well as capsular \u2044 exopolysaccharide a-glucans. The now observed amylose belongs to the class of biomolecules generally referred to as ''bacterial glycogen'' and considered to be a source of readily available glucose [30] . However, unlike most bacteria that indeed produce 8-12% branching in the O-6 Glc residues in glycogen [30] , in H. pylori only vestigial branching was observed (<1%).", "cite_spans": [{"start": 592, "end": 596, "text": "[30]", "ref_id": "BIBREF29"}, {"start": 701, "end": 705, "text": "[30]", "ref_id": "BIBREF29"}], "ref_spans": []}, {"section": "Discussion", "text": "Glycogen-like metabolism in bacteria is strongly correlated with the mobilization of ADP-Glc mostly by intracellular synthetic and degradative enzymes belonging to clearly identified families of glycosyltransferases (GT) and of glycosidases \u2044 transglycosidases. In a study carried out by Henrissat et al. [31] , 55 currently sequenced bacterial genomes were screened for members of the most relevant families of GT (GT5, GT35, GH13, and GH15). The authors concluded that a significant proportion of those microorganisms, including H. pylori 26695 and J99 and Campylobacter jejuni NCTC 11168, lacked the necessary enzymatic machinery to metabolize glycogen-like molecules. Interestingly, all of them were parasitic, symbiotic, or fastidious thus suggesting that such genotype resulted from a trait associated with the parasitic behavior of the microorganisms. Our results now point in a different direction. Here, it is demonstrated that H. pylori, even though being recognized as extremely fastidious, indeed produces a-(1fi4)-d-glucans in vitro. This finding is in agreement with the recently reported capability of C. jejuni 81-176, a virulent model strain used in the study of mechanisms and pathogenesis of C. jejuni infection, of also producing a a-(1fi4) glucan [32] . Another example of a generally regarded as nonproducing glycogen Gramnegative bacteria is Neisseria meningitidis [31, 33] . Again, in this case, evidences of strains producing glycogenlike molecules have been presented, as demonstrated by the identification of a genetic loci encoding amylosucrase in N. meningitidis 93246, responsible for the production of amylose from sucrose [33] .", "cite_spans": [{"start": 305, "end": 309, "text": "[31]", "ref_id": "BIBREF30"}, {"start": 1268, "end": 1272, "text": "[32]", "ref_id": "BIBREF31"}, {"start": 1388, "end": 1392, "text": "[31,", "ref_id": "BIBREF30"}, {"start": 1393, "end": 1396, "text": "33]", "ref_id": "BIBREF32"}, {"start": 1654, "end": 1658, "text": "[33]", "ref_id": "BIBREF32"}], "ref_spans": []}, {"section": "Discussion", "text": "The events triggering the overexpression of a-(1fi4)-d-glucans have been correlated with the responses of the organism to environmental pressure or long-term survival strategies. The bioaccumulation phenomenon has been previously observed in microorganisms facing limiting growth conditions [34] as well as in grapevine plants as a nonspecific response to biotic and abiotic stresses [35] . This stress-related strategy based on the production of a-glucan seems to be common to microorganisms and plants. In bacteria, environmental pressure resulting from shortage of a nutrient such as nitrogen in the presence of excess of carbon has also been reported as responsible for the intracellular accumulation of this polysaccharide [31, 34, 36] . Some bacteria, however, accumulate them in the exponential growth phase [37] . In line with this observation, a recent report concerning the pathogenic Gram-negative bacteria Vibrio cholerae states that the capacity of this bacteria to store carbon as glycogen facilitates bacterial fitness when passing both from nutrient-rich human intestinal tract and nutrient-poor aquatic environments, facilitating the transmission to a new host [38] . Thus, it can be inferred that different organisms can trigger at some point of their life cycle the pathways leading to the expression of a-(1fi4)-d-glucans as a result of specific environmental pressure.", "cite_spans": [{"start": 291, "end": 295, "text": "[34]", "ref_id": "BIBREF33"}, {"start": 384, "end": 388, "text": "[35]", "ref_id": "BIBREF34"}, {"start": 728, "end": 732, "text": "[31,", "ref_id": "BIBREF30"}, {"start": 733, "end": 736, "text": "34,", "ref_id": "BIBREF33"}, {"start": 737, "end": 740, "text": "36]", "ref_id": "BIBREF35"}, {"start": 815, "end": 819, "text": "[37]", "ref_id": "BIBREF36"}, {"start": 1178, "end": 1182, "text": "[38]", "ref_id": "BIBREF37"}], "ref_spans": []}, {"section": "Discussion", "text": "In this work, aware of H. pylori high fastidiousness, we further devoted our attention to fully understanding the influence of environmental pressure resulting from subcultivation in solid agar medium and recovery to liquid medium in the bacterium cell-surface polysaccharides. The results suggest that H. pylori cells facing a lag stage resulting from subcultivation in agar medium bioaccumulate amylose-like polymers over time. The observation of the decrease of cell-surface LPS, namely the O-chain, during subcultivation in solid medium is in accordance with previous reports [8, 39, 40] . A more up-to-date work carried out by Nilson et al. [41] further reinforced that the absence of high-molecular weight O-chains was a common feature in two clinical isolates after a number of experimentally passages both in vitro and in mice models. However, this phenotype was not evident in fresh human clinical isolates, where all cells expressed high-molecular weight O-chains [41] . In contrast, when H. pylori was in an exponential growth phase resulting from cultivation in F12 liquid medium, the amount of expressed amylose-like polymers decreased considerably. This decrease was accompanied by an increase in the overall amount of LPS mainly because of an O-chain increment. The observed overexpression of O-chain material upon recovery to the liquid medium was in agreement with previous reports [8] . Anyway, F12 has been shown to be able to overcome some of the lower growth rates exhibited by the solid media [6] and to be ideal for the rapid isolation, cultivation, and identification of H. pylori from biopsy specimens [42] , suggesting its success in mimicking in vivo growth conditions. Furthermore, LPS with high-molecular weight O-chains can be considered a characteristic in vivo phenotype during colonization of the human gastric mucosa.", "cite_spans": [{"start": 580, "end": 583, "text": "[8,", "ref_id": "BIBREF7"}, {"start": 584, "end": 587, "text": "39,", "ref_id": "BIBREF38"}, {"start": 588, "end": 591, "text": "40]", "ref_id": "BIBREF39"}, {"start": 646, "end": 650, "text": "[41]", "ref_id": "BIBREF40"}, {"start": 974, "end": 978, "text": "[41]", "ref_id": "BIBREF40"}, {"start": 1399, "end": 1402, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 1515, "end": 1518, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 1627, "end": 1631, "text": "[42]", "ref_id": "BIBREF41"}], "ref_spans": []}, {"section": "Discussion", "text": "Facing these considerations, it can be stated that phenotypes resulting from F12 growth may resemble in vivo cell-surface patterns. Thus, in vivo cells are led to produce elongated O-chains bearing Lewis antigens that are recognized as a prerequisite in the modulation of host-cell interaction and evasion to immune response. Silencing of O-chain expression accompanied by bioaccumulation of amylose-like polymers in solid media suggests a redirection in metabolic efforts in response to the no-longer need for interaction with the host and a response to a new environment. Moreover, the expression of elongated O-chains might be considered a favorable phenotype among planktonic free-swimming bacteria like the ones encountered during F12 growth. Its substitution by amylose-like polymers upon cultivation in solid medium may be because of a swift toward life on community and formation of biofilm frameworks that render the bacteria protection in certain specific microenvironments.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "Based on these considerations, we are also led to think that H. pylori cell-surface polysaccharides undergo phase variation in response to different growth stages and environmental pressures. Even though at this stage the biologic role resulting from the decoration of H. pylori cell surface with a-glucans is still unclear, the expression of such structures in other bacteria reveals its key importance. Recent studies have highlighted that this class of polysaccharides do not restrict their function just to provide the microorganisms with resources to resist food depletion and long starvation periods. They have been shown to protect against phagocytosis [43] and modulate the host immune response [44, 45] . For example, inducing monocytes to differentiate into altered dendritic cells that fail to upregulate CD80 and to present lipid antigens to CD1-restricted T cells, and produce interleukin (IL)-10 but not IL-12 [45] . Thus, the expression \u2044 bioaccumulation of a-glucans can be thought to also contribute to the pathogenicity of the bacteria by aiding in the evasion \u2044 modulation of immune responses and conferring extra protection against external aggression and unfavorable environments.", "cite_spans": [{"start": 660, "end": 664, "text": "[43]", "ref_id": "BIBREF42"}, {"start": 703, "end": 707, "text": "[44,", "ref_id": "BIBREF43"}, {"start": 708, "end": 711, "text": "45]", "ref_id": "BIBREF44"}, {"start": 924, "end": 928, "text": "[45]", "ref_id": "BIBREF44"}], "ref_spans": []}, {"section": "Discussion", "text": "Facing all these considerations, further work is being conducted to clarify the biosynthetic pathways behind the expression of a-glucans by H. pylori, to clarify the impact of specific environmental factors in amylose bioaccumulation, and to understand its biologic role.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Impact of Helicobacter pylori on societyrole for a strategy of ''search and eradicate", "authors": [{"first": "D", "middle": [], "last": "Forman", "suffix": ""}, {"first": "D", "middle": ["Y"], "last": "Graham", "suffix": ""}], "year": 2004, "venue": "Aliment Pharmacol Ther", "link": "20489103"}, "BIBREF1": {"title": "Helicobacter and gastric malignancies", "authors": [{"first": "A", "middle": ["C"], "last": "Ferreira", "suffix": ""}, {"first": "H", "middle": [], "last": "Isomoto", "suffix": ""}, {"first": "M", "middle": [], "last": "Moriyama", "suffix": ""}, {"first": "T", "middle": [], "last": "Fujioka", "suffix": ""}, {"first": "J", "middle": ["C"], "last": "Machado", "suffix": ""}, {"first": "Y", "middle": [], "last": "Yamaoka", "suffix": ""}], "year": 2008, "venue": "Helicobacter", "link": "12243118"}, "BIBREF2": {"title": "Development of gastric cancer associated with Helicobacter pylori infection", "authors": [{"first": "T", "middle": [], "last": "Sugiyama", "suffix": ""}], "year": 2004, "venue": "Cancer Chemother Pharmacol", "link": "660069"}, "BIBREF3": {"title": "Determinants of Helicobacter pylori pathogenicity", "authors": [{"first": "A", "middle": [], "last": "Labigne", "suffix": ""}, {"first": "H", "middle": [], "last": "De Reuse", "suffix": ""}], "year": 1996, "venue": "Infect Agents Dis", "link": "1276468"}, "BIBREF4": {"title": "Growth of Helicobacter pylori in various liquid and plating media", "authors": [{"first": "T", "middle": ["H"], "last": "Stevenson", "suffix": ""}, {"first": "A", "middle": [], "last": "Castillo", "suffix": ""}, {"first": "L", "middle": ["M"], "last": "Lucia", "suffix": ""}, {"first": "G", "middle": ["R"], "last": "Acuff", "suffix": ""}], "year": 2000, "venue": "Lett Appl Microbiol", "link": "24668819"}, "BIBREF5": {"title": "Helicobacter pylori growth and urease detection in the chemical defined medium Ham's F-12 nutrient mixture", "authors": [{"first": "T", "middle": ["L"], "last": "Testerman", "suffix": ""}, {"first": "D", "middle": ["J"], "last": "Mcgee", "suffix": ""}, {"first": "Hlt", "middle": [], "last": "Mobley", "suffix": ""}], "year": 2001, "venue": "J Clin Microbiol", "link": "25572328"}, "BIBREF6": {"title": "Nutrient shock and incubation atmosphere influence the recovery of viable Helicobacter pylori from water", "authors": [{"first": "N", "middle": ["F"], "last": "Azevedo", "suffix": ""}, {"first": "A", "middle": ["P"], "last": "Pacheco", "suffix": ""}, {"first": "C", "middle": ["W"], "last": "Keevil", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Vieira", "suffix": ""}], "year": 2004, "venue": "Appl Environ Microbiol", "link": null}, "BIBREF7": {"title": "Helicobacter pylori: a wolf in sheep's clothing: the glycotype families of Helicobacter pylori lipopolysaccharides expressing histo-blood groups: structure, biosynthesis, and role in pathogenesis", "authors": [{"first": "M", "middle": ["A"], "last": "Monteiro", "suffix": ""}], "year": 2001, "venue": "Adv Carbohydr Chem Biochem", "link": "22913379"}, "BIBREF8": {"title": "Relevance of fucosylation and Lewis antigen expression in the bacterial gastroduodenal pathogen Helicobacter pylori", "authors": [{"first": "A", "middle": ["P"], "last": "Moran", "suffix": ""}], "year": 2008, "venue": "Carbohydr Res", "link": "40815587"}, "BIBREF9": {"title": "Roles of gastric mucin-type O-glycans in the pathogenesis of Helicobacter pylori infection", "authors": [{"first": "M", "middle": [], "last": "Kobayashi", "suffix": ""}, {"first": "H", "middle": [], "last": "Lee", "suffix": ""}, {"first": "J", "middle": [], "last": "Nakayama", "suffix": ""}, {"first": "M", "middle": [], "last": "Fukuda", "suffix": ""}], "year": 2009, "venue": "Glycobiology", "link": "15826635"}, "BIBREF10": {"title": "Helicobacter pylori from asymptomatic hosts expressing heptoglycan but lacking Lewis O-chains: Lewis blood-group O-chains may play a role in Helicobacter pylori induced pathology", "authors": [{"first": "M", "middle": ["A"], "last": "Monteiro", "suffix": ""}, {"first": "Fst", "middle": [], "last": "Michael", "suffix": ""}, {"first": "D", "middle": ["A"], "last": "Rasko", "suffix": ""}, {"first": "D", "middle": ["E"], "last": "Taylor", "suffix": ""}, {"first": "J", "middle": ["W"], "last": "Conlan", "suffix": ""}, {"first": "K", "middle": ["H"], "last": "Chan", "suffix": ""}, {"first": "S", "middle": ["M"], "last": "Logan", "suffix": ""}, {"first": "B", "middle": ["J"], "last": "Appelmelk", "suffix": ""}, {"first": "M", "middle": ["B"], "last": "Perry", "suffix": ""}], "year": 2001, "venue": "Biochem Cell Biol", "link": "29837925"}, "BIBREF11": {"title": "Occurrence of a nontypable Helicobacter pylori strain lacking Lewis blood group O antigens and dd-heptoglycan: evidence for the role of the core a-1,6-glucan chain in colonization", "authors": [{"first": "E", "middle": [], "last": "Altman", "suffix": ""}, {"first": "N", "middle": [], "last": "Smirnova", "suffix": ""}, {"first": "J", "middle": [], "last": "Li", "suffix": ""}, {"first": "Aubry", "middle": ["A"], "last": "Logan", "suffix": ""}, {"first": "S", "middle": ["M"], "last": "", "suffix": ""}], "year": 2003, "venue": "Glycobiology", "link": "19698235"}, "BIBREF12": {"title": "A novel Helicobacter pylori cell-surface polysaccharide", "authors": [{"first": "S", "middle": [], "last": "Britton", "suffix": ""}, {"first": "E", "middle": [], "last": "Papp-Szabo", "suffix": ""}, {"first": "J", "middle": [], "last": "Simala-Grant", "suffix": ""}, {"first": "L", "middle": [], "last": "Morrison", "suffix": ""}, {"first": "D", "middle": ["E"], "last": "Taylor", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Monteiro", "suffix": ""}], "year": 2005, "venue": "Carbohydr Res", "link": "20720454"}, "BIBREF13": {"title": "Polysaccharides of Helicobacter pylori", "authors": [{"first": "M", "middle": ["A"], "last": "Monteiro", "suffix": ""}, {"first": "J", "middle": [], "last": "Fulginiti", "suffix": ""}, {"first": "D", "middle": [], "last": "Dilts", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF14": {"title": "Protein glycosylation and its role in protein folding", "authors": [{"first": "A", "middle": ["J"], "last": "Parodi", "suffix": ""}], "year": 2000, "venue": "Annu Rev Biochem", "link": null}, "BIBREF15": {"title": "A genetic approach to mammalian glycan function", "authors": [{"first": "J", "middle": ["B"], "last": "Lowe", "suffix": ""}, {"first": "J", "middle": ["D"], "last": "Marth", "suffix": ""}], "year": 2003, "venue": "Annu Rev Biochem", "link": "13755327"}, "BIBREF16": {"title": "Adherence, anti-adherence, and oligosaccharides preventing pathogens from sticking to the host", "authors": [{"first": "K", "middle": ["D"], "last": "Shoaf-Sweeney", "suffix": ""}, {"first": "Rwa", "middle": [], "last": "Hutkins", "suffix": ""}], "year": 2009, "venue": "Adv Food Nutr Res", "link": "34757177"}, "BIBREF17": {"title": "Intracellular functions of N-linked glycans", "authors": [{"first": "A", "middle": [], "last": "Helenius", "suffix": ""}, {"first": "M", "middle": [], "last": "Aebi", "suffix": ""}], "year": 2001, "venue": "Science", "link": "7277949"}, "BIBREF18": {"title": "Innovative vaccine production technologies: the evolution and value of vaccine production technologies", "authors": [{"first": "K", "middle": [], "last": "Bae", "suffix": ""}, {"first": "J", "middle": [], "last": "Choi", "suffix": ""}, {"first": "Y", "middle": [], "last": "Jang", "suffix": ""}, {"first": "S", "middle": [], "last": "Ahn", "suffix": ""}, {"first": "B", "middle": [], "last": "Hur", "suffix": ""}], "year": 2009, "venue": "Arch Pharm Res", "link": "9066150"}, "BIBREF19": {"title": "M\u00fc ller I. Dendritic cells: functional aspects of glycosylation and lectins", "authors": [{"first": "A", "middle": [], "last": "Erbacher", "suffix": ""}, {"first": "F", "middle": [], "last": "Gieseke", "suffix": ""}, {"first": "R", "middle": [], "last": "Handgretinger", "suffix": ""}], "year": 2009, "venue": "Hum Immunol", "link": null}, "BIBREF20": {"title": "Critical pathways in microbial virulence", "authors": [{"first": "M", "middle": ["A"], "last": "Curtis", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Slaney", "suffix": ""}, {"first": "J", "middle": [], "last": "Aduse-Opoku", "suffix": ""}], "year": 2005, "venue": "J Clin Periodontol", "link": "46692426"}, "BIBREF21": {"title": "Biofilms -a microbial life perspective: a critical review", "authors": [{"first": "A", "middle": [], "last": "Jain", "suffix": ""}, {"first": "Y", "middle": [], "last": "Gupta", "suffix": ""}, {"first": "R", "middle": [], "last": "Agrawal", "suffix": ""}, {"first": "P", "middle": [], "last": "Khare", "suffix": ""}, {"first": "S", "middle": ["K"], "last": "Jain", "suffix": ""}], "year": 2007, "venue": "Crit Rev Ther Drug Carrier Syst", "link": "39062117"}, "BIBREF22": {"title": "Development and application of a novel peptide nucleic acid probe for the specific detection of Helicobacter pylori in gastric biopsy specimens", "authors": [{"first": "N", "middle": [], "last": "Guimar\u00e3 Es", "suffix": ""}, {"first": "N", "middle": ["F"], "last": "Azevedo", "suffix": ""}, {"first": "C", "middle": [], "last": "Figueiredo", "suffix": ""}, {"first": "C", "middle": ["W"], "last": "Keevil", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Vieira", "suffix": ""}], "year": 2007, "venue": "J Clin Microbiol", "link": null}, "BIBREF23": {"title": "Bacterial lipopolysaccharides: extraction with phenol-water and further applications of the procedure", "authors": [{"first": "O", "middle": [], "last": "Westphal", "suffix": ""}, {"first": "Jann", "middle": ["K"], "last": "", "suffix": ""}], "year": 1965, "venue": "Methods Carbohydr Chem", "link": "101523508"}, "BIBREF24": {"title": "Colorimetric method for the determination of sugars and related substances", "authors": [{"first": "M", "middle": [], "last": "Dubois", "suffix": ""}, {"first": "D", "middle": ["A"], "last": "Gilles", "suffix": ""}, {"first": "J", "middle": ["K"], "last": "Hamilton", "suffix": ""}, {"first": "P", "middle": ["A"], "last": "Rebers", "suffix": ""}, {"first": "F", "middle": [], "last": "Smith", "suffix": ""}], "year": 1956, "venue": "Anal Chem", "link": "38872824"}, "BIBREF25": {"title": "Gas-chromatographic determination of the monosaccharide composition of plant cell wall preparations", "authors": [{"first": "P", "middle": ["J"], "last": "Harris", "suffix": ""}, {"first": "A", "middle": ["B"], "last": "Blakeney", "suffix": ""}, {"first": "R", "middle": ["J"], "last": "Henry", "suffix": ""}, {"first": "B", "middle": ["A"], "last": "Stone", "suffix": ""}], "year": 1988, "venue": "J AOAC Int", "link": "81107101"}, "BIBREF26": {"title": "A simple and rapid method for the permethylation of carbohydrates", "authors": [{"first": "I", "middle": [], "last": "Ciucanu", "suffix": ""}, {"first": "F", "middle": [], "last": "Kerek", "suffix": ""}], "year": 1984, "venue": "Carbohydr Res", "link": "59463355"}, "BIBREF27": {"title": "Lipopolysaccharide of the Helicobacter pylori type strain NCTC 11637 (ATCC 43504): structure of the O antigen chain and core oligosaccharide regions", "authors": [{"first": "G", "middle": ["O"], "last": "Aspinall", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Monteiro", "suffix": ""}, {"first": "H", "middle": [], "last": "Pang", "suffix": ""}, {"first": "E", "middle": ["J"], "last": "Walsh", "suffix": ""}, {"first": "A", "middle": ["P"], "last": "Moran", "suffix": ""}], "year": 1996, "venue": "Biochemistry", "link": "23976587"}, "BIBREF28": {"title": "Purification, structure and immunobiological activity of an arabinan-rich pectic polysaccharide from the cell walls of Prunus dulcis seeds", "authors": [{"first": "F", "middle": [], "last": "Dourado", "suffix": ""}, {"first": "P", "middle": [], "last": "Madureira", "suffix": ""}, {"first": "V", "middle": [], "last": "Carvalho", "suffix": ""}, {"first": "R", "middle": [], "last": "Coelho", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Coimbra", "suffix": ""}, {"first": "M", "middle": [], "last": "Vilanova", "suffix": ""}, {"first": "M", "middle": [], "last": "Mota", "suffix": ""}, {"first": "F", "middle": ["M"], "last": "Gama", "suffix": ""}], "year": 2004, "venue": "Carbohydr Res", "link": "8266295"}, "BIBREF29": {"title": "From bacterial glycogen to starch: understanding the biogenesis of the plant starch granule", "authors": [{"first": "S", "middle": ["G"], "last": "Ball", "suffix": ""}, {"first": "M", "middle": ["K"], "last": "Morell", "suffix": ""}], "year": 2003, "venue": "Annu Rev Plant Biol", "link": "1634468"}, "BIBREF30": {"title": "Glycogen metabolism loss: a common marker of parasitic behaviour in bacteria?", "authors": [{"first": "B", "middle": [], "last": "Henrissat", "suffix": ""}, {"first": "E", "middle": [], "last": "Deleury", "suffix": ""}, {"first": "P", "middle": ["M"], "last": "Coutinho", "suffix": ""}], "year": 2002, "venue": "Trends Genet", "link": "89378948"}, "BIBREF31": {"title": "Cell-surface alpha-glucan in Campylobacter jejuni 81-176", "authors": [{"first": "E", "middle": [], "last": "Papp-Szab\u00f3", "suffix": ""}, {"first": "M", "middle": ["I"], "last": "Kanipes", "suffix": ""}, {"first": "P", "middle": [], "last": "Guerry", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Monteiro", "suffix": ""}], "year": 2005, "venue": "Carbohydr Res", "link": "28061915"}, "BIBREF32": {"title": "Nonencapsulated Neisseria meningitidis strain produces amylopectin from sucrose: altering the concept for differentiation between N. meningitidis and N. polysaccharea", "authors": [{"first": "P", "middle": [], "last": "Zhu", "suffix": ""}, {"first": "Rsw", "middle": [], "last": "Tsang", "suffix": ""}, {"first": "C", "middle": ["M"], "last": "Tsay", "suffix": ""}], "year": 2003, "venue": "J Clin Microbiol", "link": "20071076"}, "BIBREF33": {"title": "Regulation of glycogen synthesis", "authors": [{"first": "J", "middle": [], "last": "Preiss", "suffix": ""}], "year": 1996, "venue": "Escherichia coli and Salmonella -Cellular and Molecular Biology", "link": null}, "BIBREF34": {"title": "Effects of fungus inoculation and salt stress on physiology and biochemistry of in vitro grapevines: emphasis on sugar composition changes by FT-IR analyses", "authors": [{"first": "H", "middle": [], "last": "Oliveira", "suffix": ""}, {"first": "A", "middle": ["S"], "last": "Barros", "suffix": ""}, {"first": "I", "middle": [], "last": "Delgadillo", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Coimbra", "suffix": ""}, {"first": "C", "middle": [], "last": "Santos", "suffix": ""}], "year": 2009, "venue": "Environ Exp Bot", "link": "84127733"}, "BIBREF35": {"title": "Coordinate genetic regulation of glycogen catabolism and biosynthesis in Escherichia coli via the CsrA gene product", "authors": [{"first": "H", "middle": [], "last": "Yang", "suffix": ""}], "year": 1996, "venue": "J Bacteriol", "link": "30484867"}, "BIBREF36": {"title": "Physiology, biochemistry and genetics of bacterial glycogens synthesis", "authors": [{"first": "J", "middle": [], "last": "Preiss", "suffix": ""}, {"first": "T", "middle": [], "last": "Romeo", "suffix": ""}], "year": 1989, "venue": "Adv Microb Physiol", "link": "37226698"}, "BIBREF37": {"title": "Glycogen contributes to the environmental persistence and transmission of Vibrio cholerae", "authors": [{"first": "L", "middle": [], "last": "Bourassa", "suffix": ""}, {"first": "A", "middle": [], "last": "Camilli", "suffix": ""}], "year": 2009, "venue": "Mol Microbiol", "link": "24196134"}, "BIBREF38": {"title": "Compositional analysis of Helicobacter pylori rough-form lipopolysaccharides", "authors": [{"first": "A", "middle": ["P"], "last": "Moran", "suffix": ""}, {"first": "I", "middle": ["M"], "last": "Helander", "suffix": ""}, {"first": "T", "middle": ["U"], "last": "Kosunen", "suffix": ""}], "year": 1992, "venue": "J Bacteriol", "link": "25325936"}, "BIBREF39": {"title": "Influence of medium composition on the growth and antigen expression of Helicobacter pylori", "authors": [{"first": "E", "middle": ["J"], "last": "Walsh", "suffix": ""}, {"first": "A", "middle": ["P"], "last": "Moran", "suffix": ""}], "year": 1997, "venue": "J Appl Microbiol", "link": "11602428"}, "BIBREF40": {"title": "Lipopolysaccharide diversity evolving in Helicobacter pylori communities through genetic modifications in fucosyltransferases", "authors": [{"first": "C", "middle": [], "last": "Nilson", "suffix": ""}, {"first": "A", "middle": [], "last": "Skoglund", "suffix": ""}, {"first": "A", "middle": ["P"], "last": "Moran", "suffix": ""}, {"first": "H", "middle": [], "last": "Annuk", "suffix": ""}, {"first": "L", "middle": [], "last": "Engstrand", "suffix": ""}, {"first": "S", "middle": [], "last": "Normark", "suffix": ""}], "year": 2008, "venue": "PLoS ONE", "link": null}, "BIBREF41": {"title": "Liquid culture medium for the rapid cultivation of Helicobacter pylori from biopsy specimens", "authors": [{"first": "N", "middle": [], "last": "Sainsus", "suffix": ""}, {"first": "V", "middle": [], "last": "Cattori", "suffix": ""}, {"first": "C", "middle": [], "last": "Lepadatu", "suffix": ""}, {"first": "R", "middle": [], "last": "Hofmann-Lehmann", "suffix": ""}], "year": 2008, "venue": "Eur J Clin Microbiol Infect Dis", "link": "12213105"}, "BIBREF42": {"title": "The glycan-rich outer layer of the wall of Mycobacterium tuberculosis acts as an antiphagocity capsule limiting the association of the bacterium with macrophages", "authors": [{"first": "R", "middle": ["W"], "last": "Stokes", "suffix": ""}, {"first": "Norris-Jones", "middle": [], "last": "", "suffix": ""}, {"first": "R", "middle": [], "last": "Brooks", "suffix": ""}, {"first": "D", "middle": ["E"], "last": "Beveridge", "suffix": ""}, {"first": "T", "middle": ["J"], "last": "Doxsee", "suffix": ""}, {"first": "D", "middle": [], "last": "Thorson", "suffix": ""}, {"first": "L", "middle": ["M"], "last": "", "suffix": ""}], "year": 2004, "venue": "Infect Immun", "link": null}, "BIBREF43": {"title": "An a-glucan of Pseudallesscheria boydii is involved in fungal phagocytosis and Toll-like receptor activation", "authors": [{"first": "Vcb", "middle": [], "last": "Bittencourt", "suffix": ""}, {"first": "R", "middle": ["T"], "last": "Figueiredo", "suffix": ""}, {"first": "R", "middle": ["B"], "last": "Da Silva", "suffix": ""}, {"first": "D", "middle": ["S"], "last": "Mour\u00e3 O-Sa", "suffix": ""}, {"first": "P", "middle": ["L"], "last": "Fernandez", "suffix": ""}, {"first": "G", "middle": ["L"], "last": "Sassaki", "suffix": ""}], "year": 2006, "venue": "J Biol Chem", "link": "21300026"}, "BIBREF44": {"title": "Cell wall-associated alpha-glucan is instrumental for Mycobacterium tuberculosis to block CD1 molecule expression and disable the function of dendritic cells from infected monocyte", "authors": [{"first": "M", "middle": ["C"], "last": "Gagliardi", "suffix": ""}, {"first": "A", "middle": [], "last": "Lemassu", "suffix": ""}, {"first": "R", "middle": [], "last": "Teloni", "suffix": ""}, {"first": "S", "middle": [], "last": "Marriotti", "suffix": ""}, {"first": "V", "middle": [], "last": "Sargentini", "suffix": ""}, {"first": "M", "middle": [], "last": "Pardini", "suffix": ""}], "year": 2007, "venue": "Cell Microbiol", "link": "42398564"}}, "ref_entries": {"FIGREF0": {"text": "or, as recently observed for H. pylori serotype O:2, as an elongated O-chain composed of alternating O-2-and O-3-linked a-d-glucopyranose (a-d-Glcp) residues [fi2)- a-d-Glcp-(1fi3)-a-d-Glcp-(1fi] n", "type": "figure"}, "FIGREF2": {"text": "residues can also be addressed to the (1fi4)-glucan or the (1fi6)-dextran antenna in the lipopolysaccharides (LPS). tr, vestigial amounts (> 0.5%); CBA, Columbia blood agar.", "type": "figure"}, "FIGREF3": {"text": "Figure 1 Helicobacter pylori cells stained with iodine. Characteristic blue color is indicative of the presence of a-(1fi4)-D-Glc polysaccharides.", "type": "figure"}, "FIGREF4": {"text": "Figure 2 Helicobacter pylori NCTC 11637 glycan-rich extract elution profile on a Bio-Gel P6 column. Letters A-F correspond to isolated fractions.", "type": "figure"}, "FIGREF6": {"text": "Figure 3 1 H nuclear magnetic resonance anomeric region of fraction E (A) before and (B) after digestion with a-amylase.", "type": "figure"}, "FIGREF9": {"text": "Figure 5 Variation in (A) lipopolysaccharides (LPS), (B) LPS O-chains, and (C) amylose-like polymer content in Helicobacter pylori cells during subcultivation in Columbia blood agar.", "type": "figure"}, "TABREF2": {"text": "Relative sugar composition of glycan-rich water extracts of the Helicobacter pylori studied strains H. pylori strainsRib, ribose; Fuc, fucose; Ara, arabinose; Man, mannose; Glc, glucose; Gal, galactose; GlcNAc, N-acetylglucosamine; DD-Hep, D-glycero-D-manno- heptose; LD-Hep, L-glycero-D-manno-heptose; CBA, Columbia blood agar.", "type": "table"}, "TABREF3": {"text": "Sugar linkage profile of the sugars in glycan-rich extracts from the Helicobacter pylori studied strains", "type": "table"}, "TABREF4": {"text": "Sugar composition of Helicobacter pylori NCTC 11637 glycan-rich extract fractions collected from a Bio-Gel P6 column (A-F)", "type": "table"}, "TABREF6": {"text": "Linkage composition of Helicobacter pylori NCTC 11637 gly- can-rich extract fractions collected from a Bio-Gel P6 column (A-F)", "type": "table"}}}
{"paper_id": "10706360", "_pdf_hash": "b806b8892c3ce91ea93a444e5f8cb0538aab2504", "abstract": [{"section": "Abstract", "text": "Abstract-ZigBee is a popular communication standard for wireless sensor networks. It suggests a distributed address assignment mechanism (DAAM), which is easy to implement but may restrict the number of children of a router and the depth of the network. Since DAAM is too conservative, the utilization of the 16-bit address pool may become poor, causing the orphan problem. In this paper, we propose a distributed address assignment scheme by allowing a parent to borrow a subtree of address space from a neighbor to alleviate the orphan problem. When a new node tries to associate with a parent router which has no free address, this parent router will inquire its 2-hop neighbors for lending a subtree of free address space. We also propose a light-weight routing to support one-to-one routing in this environment.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "I. INTRODUCTION", "text": "Wireless sensor networks (WSNs) have attracted a lot of attention. Recently, research efforts have been dedicated to power management [9] , routing [6] , deployment and coverage [2] , and localization [1] . Nowadays, many WSN systems have adopted ZigBee [10] as their communication protocol. ZigBee adopts the physical (PHY) and the medium access control (MAC) layers defined by IEEE 802.15.4 [5] and extends to network, application, and security services. ZigBee supports three network topologies, star, tree, and mesh. Regardless of network topology, there is a coordinator responsible for initializing, maintaining, and controlling the network. Star networks can only cover small areas, but tree and mesh networks can cover larger fields by allowing multi-hop communications. The backbone of a tree/mesh network is formed by one coordinator and multiple routers. An end device must associate with the coordinator or a router. In a tree network, routing can be done in a stateless manner based on nodes' 16-bit short addresses.", "cite_spans": [{"start": 134, "end": 137, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 148, "end": 151, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 178, "end": 181, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 201, "end": 204, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 254, "end": 258, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 393, "end": 396, "text": "[5]", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "To form a ZigBee network, addressing is the first work to be done. ZigBee suggests a distributed address assignment mechanism (DAAM), which enforces some addressing rules. By this mechanism, the coordinator needs to decide three parameters: the maximum number of children of a router (C max ), the maximum number of child routers of a router (R max ), and the maximum network depth (L max ). While simple, the scheme may prohibit a node from accepting isolated child routers/devices. A node is an orphan node when it cannot associate with any parent router but there is still unused address space in the network. Some heuristics algorithms are proposed to reduce orphans [7] .", "cite_spans": [{"start": 671, "end": 674, "text": "[7]", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "Reference [3] proposes an address borrowing scheme. When a new node sends an association request to a router of a ZigBee network and this router does not have any free address, it will ask other neighboring routers to lend an unassigned address to serve the new node. Park et al. [8] propose a distributed borrowing addressing scheme (DBAS) by allowing a parent node to borrow a maximum unused address space to alleviate the orphan problem.", "cite_spans": [{"start": 10, "end": 13, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 280, "end": 283, "text": "[8]", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "The main goal of our work is to alleviate the orphan problem by a distributed address assignment scheme with address borrowing. We improve the borrowing scheme of [8] by allowing a parent router to borrow a flexible subtree of address space from a neighbor. We also define the detailed procedure for our address-borrowing scheme, which is compatible with the ZigBee standard. Our solution solves addressing and routing issues altogether. When a new node tries to associate with a parent router with no unassigned address, the new node will estimate the number of orphan nodes in its neighborhood and this parent router will ask its 2-hop neighbors to lend a suitable address space to serve the new node. Then this new node can use the ZigBee DAAM to serve its children. We also show that routing and maintaining the borrow and lend lists can be easily done. In ZigBee, address assignment is done in a distributed manner. To form a network, the coordinator determines C max , R max , and L max first. Note that the children of a router include both routers and end devices. So C max \u2265 R max and up to C max \u2212 R max children must be end devices. Addresses are assigned in a top-down manner. The coordinator takes 0 as its address and divides the remaining address space into R max + 1 blocks. The first R max blocks are to be assigned to its child routers and the last block has C max \u2212R max addresses, each to be assigned to one child end device. The similar process is adopted by each child router to partition its given address space in a recursive manner. From C max , R max , and", "cite_spans": [{"start": 163, "end": 166, "text": "[8]", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "which is the size of one address block to be assigned to a child router [10] :", "cite_spans": [{"start": 72, "end": 76, "text": "[10]", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "The value of d is 0 for the coordinator and is increased by one as we go down the tree.", "cite_spans": [], "ref_spans": []}, {"section": "III. THE PROPOSED ADDRESSING SCHEME", "text": "A. Basic Idea Fig. 1 (a) shows a ZigBee address assignment example. Router y cannot accept router x as its child because it already has the maximum R max = 3 child routers, making x an orphan node. The orphan problem [7] refers to the scenario where some nodes in Fig. 1 (a) cannot connect to the network even though there are free addresses in the network.", "cite_spans": [{"start": 217, "end": 220, "text": "[7]", "ref_id": "BIBREF6"}], "ref_spans": [{"start": 14, "end": 20, "text": "Fig. 1", "ref_id": "FIGREF0"}, {"start": 264, "end": 270, "text": "Fig. 1", "ref_id": "FIGREF0"}]}, {"section": "III. THE PROPOSED ADDRESSING SCHEME", "text": "We try to alleviate the orphan problem by allowing addressborrowing. We define a new Borrowing Information Base (BIB) attribute called MaxBorrowingNumber (B max ), which can be carried by any reserved field. B max is the maximum number of addresses that a router can borrow. A router can serve up to R max + B max child routers and up to C max \u2212 R max + B max child end devices. Here, these B max children can be routers or end devices. Fig. 1(b) shows an example where y has borrowed the address block rooted at 36 of depth 2 from router z. It also shows that the address block is assigned to router x. Then router x can assign them to its children.", "cite_spans": [], "ref_spans": [{"start": 437, "end": 446, "text": "Fig. 1(b)", "ref_id": "FIGREF0"}]}, {"section": "III. THE PROPOSED ADDRESSING SCHEME", "text": "Below, we propose a fully automated, distributed ZigBee address assignment scheme to facilitate such borrowing behaviors. Then we further show how to conduct address-based routing in the network.", "cite_spans": [], "ref_spans": []}, {"section": "B. Address-Borrowing Scheme (ABS) 1) Variables:", "text": "During the formation process, each node x maintains the following variables:", "cite_spans": [], "ref_spans": []}, {"section": "B. Address-Borrowing Scheme (ABS) 1) Variables:", "text": "\u2022 A x : the address of x in a ZigBee network.", "cite_spans": [], "ref_spans": []}, {"section": "B. Address-Borrowing Scheme (ABS) 1) Variables:", "text": "\u2022 R(x) and E(x): the child routers and the child end devices currently associating with x, respectively.", "cite_spans": [], "ref_spans": []}, {"section": "B. Address-Borrowing Scheme (ABS) 1) Variables:", "text": "\u2022 L r (x) and L e (x): the lend lists of child routers' addresses and child end devices' addresses, respectively, which x has lent out.", "cite_spans": [], "ref_spans": []}, {"section": "B. Address-Borrowing Scheme (ABS) 1) Variables:", "text": "\u2022 B r (x) and B e (x): the borrow lists of child router's addresses and child end device's addresses, respectively, which has borrowed.", "cite_spans": [], "ref_spans": []}, {"section": "B. Address-Borrowing Scheme (ABS) 1) Variables:", "text": "\u2022 p(x): the address of x's parent in a ZigBee network.", "cite_spans": [], "ref_spans": []}, {"section": "B. Address-Borrowing Scheme (ABS) 1) Variables:", "text": "\u2022 o(x): the estimated number of orphans in x's neighborhood.", "cite_spans": [], "ref_spans": []}, {"section": "B. Address-Borrowing Scheme (ABS) 1) Variables:", "text": "\u2022 d x : the depth of x in the ZigBee network. Note that there are two interpretations for the value of d x . Under the normal situation, d x is the actual depth value of x. However, d x is the \"depth\" of the address counting from its original location (not x's location). For example, the d z of z in Fig. 2 is 1 since originally address 107 is the child of address 0 (the coordinator t) even though its current physical depth in the ZigBee tree is 4. Similarly, the d y of y in Fig. 2 is 2 since it is the child of z, and its physical depth in the ZigBee tree is 5.", "cite_spans": [], "ref_spans": [{"start": 301, "end": 307, "text": "Fig. 2", "ref_id": "FIGREF1"}, {"start": 479, "end": 485, "text": "Fig. 2", "ref_id": "FIGREF1"}]}, {"section": "B. Address-Borrowing Scheme (ABS) 1) Variables:", "text": "\u2022 s x : the state of A x 's location. We allow an address block to lent out if it is not a borrowed address black. Note that a child address block of a \"borrowed\" address block is also considered a \"borrowed\" address block. That is, a borrowed address block connot be further lent out to other nodes, and so is its sub-blocks. We set s x = \"original\" if A x is not a borrowed address; otherwise, we set s x = ICC'14 -W7: Workshop on M2M Communications for Next Generation IoT \"borrowed\". For example, in Fig. 2 , s z = \"borrowed\" since A z = 107 is borrowed from the coordinator. Since A y is a child of A z , s y = \"borrowed\", too. On the other hand, A w is not a borrowed address, so s w = \"original\". 2) Associating Scheme: To start a new network, a coordinator t first sets the following parameters: C max , R max , L max , and B max . Then t assigns A t = 0, d t = 0, and s t = \"original\", and sets R(t), E(t), B r (t), B e (t), L r (t), and L e (t) as empty sets. The detailed associating scheme is presented below.", "cite_spans": [], "ref_spans": [{"start": 504, "end": 510, "text": "Fig. 2", "ref_id": "FIGREF1"}]}, {"section": "B. Address-Borrowing Scheme (ABS) 1) Variables:", "text": "(a) Router v receiving a MLME-ASSOCIATION-REQ request from a node u:", "cite_spans": [], "ref_spans": []}, {"section": "B. Address-Borrowing Scheme (ABS) 1) Variables:", "text": "is free, and assigns the address A u to u by replying a MLME-ASSOCIATION response with A v , d v and s v to u. ", "cite_spans": [], "ref_spans": []}, {"section": "ICC'14 -W7: Workshop on M2M Communications for Next Generation IoT", "text": "(ii) Otherwise, x ignores the request. (g) Router x receiving an ASK-ADD-Confirm with the lending address A y from router v: Router x updates L r (x) if this address would be assigned to a child router; otherwise, it updates L e (x). In the example of Fig. 1(b) , z lends address 36 to y, so its lend list L r (z) = {(36, y = 54)}. On the other hand, y should update its borrow list B r (y) = {(36, z = 1, 1)}. Fig. 3 shows the flow chart for an orphan node x to request a router node v to lend an address block to serve it. Next, we analyze the depth of the ZigBee tree after borrowing. Since we do not allow recursive borrowing and a node can only inquire its 2-hop neighbors for borrowing, the maximum depth of the ZigBee tree formed by ABS is L max + 2.", "cite_spans": [], "ref_spans": [{"start": 252, "end": 261, "text": "Fig. 1(b)", "ref_id": "FIGREF0"}]}, {"section": "ICC'14 -W7: Workshop on M2M Communications for Next Generation IoT", "text": "3) Disassociation Scheme: When a node wants to disassociate with its parent router, it should broadcast a MLME-DISASSOCIATION request to its parent and descendants to ensure that its address block can be re-used and its descendants can try to reassociate with other parents. The detailed disassociating scheme is presented below.", "cite_spans": [], "ref_spans": []}, {"section": "ICC'14 -W7: Workshop on M2M Communications for Next Generation IoT", "text": "\u2022 Node v receiving a MLME-DISASSOCIATION request from node u:", "cite_spans": [], "ref_spans": []}, {"section": "ICC'14 -W7: Workshop on M2M Communications for Next Generation IoT", "text": ", and B e (v). If this address is a borrowed one, then v sends a Return-ADD with the address A u to its original lender. This address A u then can be reused by other nodes. (b) If u is v's parent, then v sends a MLME-DISASSOCIATION request to its children. Since v is not an orphan, it should try to reassociate with the ZigBee network. (c) Otherwise, v ignores the request.", "cite_spans": [], "ref_spans": []}, {"section": "ICC'14 -W7: Workshop on M2M Communications for Next Generation IoT", "text": "\u2022 Router x receiving a Return-ADD with A u from node v: Then x removes A u from L r (x) and L e (x). Fig. 4 shows the flow chart of the above procedure. ", "cite_spans": [], "ref_spans": [{"start": 101, "end": 107, "text": "Fig. 4", "ref_id": "FIGREF4"}]}, {"section": "C. Routing Scheme with Address Borrowing", "text": "With the above address borrowing scheme, ZigBee can still support very simple address-based routing as follows. When router v receives a packet with a destination address A dest , it accepts the packet if A v = A dest . Otherwise, v forwards this packet as follows.", "cite_spans": [], "ref_spans": []}, {"section": "C. Routing Scheme with Address Borrowing", "text": "1) If dest is a child router or grandchild of v, then v forwards this packet to a router as follows.", "cite_spans": [], "ref_spans": []}, {"section": "C. Routing Scheme with Address Borrowing", "text": ". Then v forwards this packet to its child router A r if A r / \u2208 L r (v); otherwise, v forwards this packet to the borrower who borrows A r from v.", "cite_spans": [], "ref_spans": []}, {"section": "C. Routing Scheme with Address Borrowing", "text": "for some node x in B r (v), v forwards this packet to its child router x. 2) If dest is a child end device, then v forwards this packet to one of its child end device as follows.", "cite_spans": [], "ref_spans": []}, {"section": "C. Routing Scheme with Address Borrowing", "text": "; otherwise, v forwards this packet to the borrower who borrows A r from v. b) If A dest \u2208 B e (v), v forwards the packet to this child end device. 3) Otherwise, v forwards the packet to its parent p(v) if v is not the coordinator, and v ignores this packet if v is the coordinator. Fig. 5 is an example that a packet is transmitted from node 108 to node 45. This packet is transmitted to node 0 in accordance with the step 3) of the routing scheme first. Then node 0 forwards it to node 1 according to the step 1.a) of the routing scheme. Node 1 finds that address 45 should be one of its grandchildren, and this address is lent to node 54. According to the step 1.a), node 1 then forwards this packet to node 54 by looking address 45 up in the lend list of node 1. When node 54 receives the packet, it looks this address up in the borrow list and then forwards it to the child router 36 according to the step 1.b). Finally node 36 forwards this packet to node 45 in accordance with the step 1.a).", "cite_spans": [], "ref_spans": [{"start": 283, "end": 289, "text": "Fig. 5", "ref_id": "FIGREF5"}]}, {"section": "IV. SIMULATION RESULTS", "text": "To verify the benefit gained from our ABS, we evaluate the average number of orphans of our scheme as compared to other approaches. We assume the following simulation environment. The monitoring region is 500 \u00d7 500m 2 where 2000 routers are randomly deployed and the coordinator is set in the center. The communication range of each router is set to 50m.", "cite_spans": [], "ref_spans": []}, {"section": "IV. SIMULATION RESULTS", "text": "For comparison, we design three modifications of our ABS by relaxing the borrowing strategy in the step (e) of associating scheme. A parent router can ask for borrowing from its 1-hop neighbors (ABS-1), 2-hop neighbors (ABS-2), and 3-hop neighbors (ABS-3). We also set DBAS-1 and DBAS-2 as the strategies of asking its 1-hop, and 2-hop neighbors, respectively.", "cite_spans": [], "ref_spans": []}, {"section": "IV. SIMULATION RESULTS", "text": "We vary the maximum network depth (L max ) to see how this influences the average number of orphans. We set B max = 2. Fig. 6(a) shows the results. The average number of orphans is inversely proportional to the tree depth limit L max . Regardless of L max , our schemes always outperform other approaches. The average number of orphans by ABS-2 is fewer than that by ABS-1, since ABS-2 can serve further nodes. Fig. 6(b) shows the average number of orphans with different R max . Regardless of borrowing strategy, the higher R max = C max makes nodes join the network more easily, and thus fewer orphans.", "cite_spans": [], "ref_spans": [{"start": 119, "end": 128, "text": "Fig. 6(a)", "ref_id": "FIGREF6"}, {"start": 411, "end": 420, "text": "Fig. 6(b)", "ref_id": "FIGREF6"}]}, {"section": "IV. SIMULATION RESULTS", "text": "ABS always outperform DBAS, because it allows a parent router to borrow a flexible address space through counting orphans. On the contrary, DBAS always lets a parent router borrow a maximum address space, exhausting address quickly.", "cite_spans": [], "ref_spans": []}, {"section": "IV. SIMULATION RESULTS", "text": "Finally, we measure the impact of B max on the average number of orphans. B max affects the number of children that a router can serve in the ZigBee tree. In Fig. 7 , we observe that larger B max cause fewer orphans. ", "cite_spans": [], "ref_spans": [{"start": 158, "end": 164, "text": "Fig. 7", "ref_id": "FIGREF8"}]}, {"section": "V. CONCLUSIONS", "text": "To relieve the orphan problem in a ZigBee network, we have proposed the address-borrowing scheme (ABS) by allowing a node to borrow unused address spaces from neighbor nodes. We have shown that it effectively decreases the number of orphans in a ZigBee network when the network cannot expand due to the constraints of C max , R max , and/or L max . The unit of lending/borrowing is a subtree of address space under the original definition in ZigBee, thus reducing the cost of routing tables and the requirement of storage spaces in router nodes. We have also suggested a light-weight routing algorithm for ABS which follows the original ZigBee address-based routing strategy with a slight modification. In addition, the maximum depth of the ZigBee network is predictable. Simulation results also show that ABS can befit original ZigBee address assignment mechanism and thus effectively reduces orphans.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Simple Pedestrian Localization Algorithms Based on Distributed Wireless Sensor Networks", "authors": [{"first": "H.-S", "middle": [], "last": "Ahn", "suffix": ""}, {"first": "K", "middle": ["H"], "last": "Ko", "suffix": ""}], "year": 2009, "venue": "IEEE Trans. on Industrial Electronics", "link": "2377946"}, "BIBREF1": {"title": "Measuring and Guaranteeing Quality of Barrier-Coverage in Wireless Sensor Networks", "authors": [{"first": "A", "middle": [], "last": "Chen", "suffix": ""}, {"first": "T", "middle": ["H"], "last": "Lai", "suffix": ""}, {"first": "D", "middle": [], "last": "Xuan", "suffix": ""}], "year": 2008, "venue": "Proc. of ACM Int'l Symposium on Mobile Ad Hoc Networking and Computing (MobiHoc)", "link": "738774"}, "BIBREF2": {"title": "A Preemptive Distributed Address Assignment Mechanism Wireless Sensor Networks", "authors": [{"first": "M", "middle": [], "last": "Fang", "suffix": ""}, {"first": "J", "middle": [], "last": "Wan", "suffix": ""}, {"first": "X", "middle": [], "last": "Xu", "suffix": ""}], "year": 2008, "venue": "Proc. of WiCOM '08. 4th International Conference on Wireless Communications, Networking and Mobile Computing", "link": "15945942"}, "BIBREF3": {"title": "IEEE standard for information technology -telecommunications and information exchange between systems -local and metropolitan area networks specific requirements part 15.4: wireless medium access control (MAC) and physical layer (PHY) specifications for low-rate wireless personal area networks", "authors": [], "year": 2003, "venue": "", "link": null}, "BIBREF4": {"title": "IEEE standard for information technology -telecommunications and information exchange between systems -local and metropolitan area networks specific requirements part 15.4: wireless medium access control (MAC) and physical layer (PHY) specifications for low-rate wireless personal area networks (LR-WPANs)(revision of IEEE", "authors": [], "year": 2006, "venue": "", "link": null}, "BIBREF5": {"title": "An Algorithmic Approach to Geographic Routing in Ad Hoc and Sensor Networks", "authors": [{"first": "F", "middle": [], "last": "Kuhn", "suffix": ""}, {"first": "R", "middle": [], "last": "Wattenhofer", "suffix": ""}, {"first": "A", "middle": [], "last": "Zollinger", "suffix": ""}], "year": 2008, "venue": "IEEE/ACM Trans. on Networking", "link": "8661703"}, "BIBREF6": {"title": "The Orphan Problem in ZigBee Wireless Networks", "authors": [{"first": "M.-S", "middle": [], "last": "Pan", "suffix": ""}, {"first": "C.-H", "middle": [], "last": "Tsai", "suffix": ""}, {"first": "Y.-C", "middle": [], "last": "Tseng", "suffix": ""}], "year": 2009, "venue": "IEEE Trans. on Mobile Computing", "link": "14446625"}, "BIBREF7": {"title": "Distributed borrowing addressing scheme for ZigBee/IEEE 802.15.4 wireless sensor networks", "authors": [{"first": "S", "middle": [], "last": "Park", "suffix": ""}, {"first": "E", "middle": ["J"], "last": "Lee", "suffix": ""}, {"first": "J", "middle": ["H"], "last": "Ryu", "suffix": ""}, {"first": "S.-S", "middle": [], "last": "Joo", "suffix": ""}, {"first": "H", "middle": ["S"], "last": "Kim", "suffix": ""}], "year": 2009, "venue": "ETRI Journal", "link": "62136880"}, "BIBREF8": {"title": "Monitoring in Industrial Systems Using Wireless Sensor Network with Dynamic Power Management", "authors": [{"first": "F", "middle": [], "last": "Salvadori", "suffix": ""}, {"first": "M", "middle": [], "last": "De Campos", "suffix": ""}, {"first": "P", "middle": ["S"], "last": "Sausen", "suffix": ""}, {"first": "R", "middle": ["F"], "last": "De Camargo", "suffix": ""}, {"first": "C", "middle": [], "last": "Gehrke", "suffix": ""}, {"first": "C", "middle": [], "last": "Rech", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Spohn", "suffix": ""}, {"first": "A", "middle": ["C"], "last": "Oliveira", "suffix": ""}], "year": 2009, "venue": "IEEE Trans. on Instrumentation and Measurement", "link": "3591855"}, "BIBREF9": {"title": "ZigBee-2011 specification", "authors": [], "year": "", "venue": "ZigBee document 053474r19, 2011. ICC'14 -W7: Workshop on M2M Communications for Next Generation IoT", "link": null}}, "ref_entries": {"FIGREF0": {"text": "Fig. 1. An example of the ZigBee tree formed by (a) the original ZigBee DAAM and (b) our address-borrowing scheme.", "type": "figure"}, "FIGREF1": {"text": "Fig. 2. An example of depth in the ZigBee tree Z formed by ABS with Cmax = 4, Rmax = 3, Lmax = 4, and Bmax = 2.", "type": "figure"}, "FIGREF2": {"text": "is free, and assigns A u to u by replying a MLME-ASSOCIATION response with A v , d v and s v to u. Then v updates E(v) as E(v)\u222a {A u }. (iii) Otherwise, if |B r (v)| + |B e (v)| \u2264 B max and s v = \"original\", v notifies u its d v and asks u to issue a request Borrowing-REQ if u desires to connect to the network. (iv) If steps (i), (ii) and (iii) all fail, v ignores the request. (b) Node u receiving a MLME-ASSOCIATION response containing d v and s v from node v: Node u updates its network address A u , sets p(u) as A v , d u as d v + 1 and s u as s v , and joins as v's child. (c) Node u receiving a response from v containing d v referring u to issue a response of sending a request Borrowing-REQ: (i) If u is a FFD, then it sends an Orphan-Count-REQ with value d = min{L max \u2212(d v \u22122), L max \u22121} to its d-hop neighbors to compute o(u) by accumulat- ing Orphan-REPs. Then it sets o(u) as o(u)+1 and sends a Borrowing-REQ with the desired address space of o(u) to v. (ii) If u is a RFD, it sends a Borrowing-REQ with the desired address space of o(u) = 0 to v. (d) Node x receiving an Orphan-Count-REQ with a value d: If x is an orphan node and it is the first time that x receives this packet, then x sends a Orphan-REP to the source node first and x rebroadcasts an Orphan-Count- REQ to its neighbors with the value d + 1 if x is a FFD and d + 1 < L max . Otherwise, x ignores the request. (e) Router v receiving a Borrowing-REQ with the desired address space of o(u) from a node u: (i) Router v sends an ASK-ADD-REQ with the value h = 0 and the value o(u) to its ancestors and descendants which are in v's 2-hop neighbors. (ii) When router v receiving ASK-ADD-REPs with free address spaces, v selects one whose free address space f is the closest to o(u) and then updates B r (v) if u is a FFD (o(u) > 1). If u is a RFD (o(u) = 0), it selects the address whose depth is the smallest and updates B e (v). (iii) Then v sends this address or address space with its depth by replying a MLME-ASSOCIATION re- sponse with A v , d v and the value s v = \"borrowed\" to u and sends an ASK-ADD-Confirm with the borrowing address A y to the lender. (f) Router x receiving an ASK-ADDR-REQ with the value h and the value o(u): (i) If it is the first time that x receives this packet and s x = \"original\", then x checks its address space and rebroadcasts an ASK-ADDR-REQ to its neighbors with the value h + 1 if h + 1 < 2. (1) If o(u) > 1 and |R(v)| < R max \u2212|L r (v)|, then x finds an index l, 0 \u2264 l < R max , such that the address A y = A x + C skip (d x )\u00b7l + 1 is free, and replies an ASK-ADD-REP with d x , A y , and the value f = C skip (d x ) to the source node. (2) If o(u) = 0 and |E(x)| < C max \u2212 R max \u2212 |L e (x)|, then x finds an index l, 0 \u2264 l < C max \u2212 R max , such that the address A y = A x +R max \u00b7C skip (d x )+l+1 is free, and replies an ASK-ADD-REP with d x , A y , and the value f = 0 to the source node.", "type": "figure"}, "FIGREF3": {"text": "Fig. 3. The flow chart of borrowing address.", "type": "figure"}, "FIGREF4": {"text": "Fig. 4. The flow chart of disassociation and address returning.", "type": "figure"}, "FIGREF5": {"text": "Fig. 5. An example of the routing transmitted from node 108 to node 45 on the ZigBee tree formed by ABS.", "type": "figure"}, "FIGREF6": {"text": "Fig. 6. The average number of orphans with different Rmax.", "type": "figure"}, "FIGREF8": {"text": "Fig. 7. The average number of orphans with different Bmax.", "type": "figure"}, "TABREF0": {"text": "II. OVERVIEW OF IEEE 802.15.4 AND ZIGBEE STANDARDS IEEE 802.15.4 [4] specifies the physical and data link protocols for low-rate wireless personal area networks (LR- WPAN). IEEE 802.15.4 devices are classified as full function devices (FFDs) and reduced function devices (RFDs). IEEE 802.15.4 supports star and peer-to-peer topologies. In each personal area network (PAN), one device is designated as the coordinator, which is responsible for maintaining the network. A FFD has the capability of serving as a coordinator or associating with an existing coordinator/router and becoming a router. A RFD can only associate with a coordinator/router and cannot have children.", "type": "table"}}}
{"paper_id": "10706392", "_pdf_hash": "c8bac9a0373963922d00917f53b8da9a87073b07", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Estimation of the effective self-diffusion tensor from the NMR spin echo", "authors": [{"first": "P", "middle": ["J"], "last": "Basser", "suffix": ""}, {"first": "J", "middle": [], "last": "Mattiello", "suffix": ""}, {"first": "D", "middle": ["L"], "last": "Bihan", "suffix": ""}], "year": 1994, "venue": "J. Magn. Reson", "link": null}, "BIBREF1": {"title": "Diffusion tensor MR imaging of the human brain", "authors": [{"first": "C", "middle": [], "last": "Pierpaoli", "suffix": ""}, {"first": "P", "middle": [], "last": "Jezzard", "suffix": ""}, {"first": "P", "middle": ["J"], "last": "Basser", "suffix": ""}, {"first": "A", "middle": [], "last": "Barnett", "suffix": ""}, {"first": "G", "middle": ["D"], "last": "Chiro", "suffix": ""}], "year": 1996, "venue": "Radiology", "link": "12080234"}, "BIBREF2": {"title": "Diffusion tractography based group mapping of major white-matter pathways in the human brain", "authors": [{"first": "O", "middle": [], "last": "Ciccarelli", "suffix": ""}, {"first": "A", "middle": ["T"], "last": "Toosy", "suffix": ""}, {"first": "G", "middle": ["J"], "last": "Parker", "suffix": ""}, {"first": "C", "middle": ["A"], "last": "Wheeler-Kingshott", "suffix": ""}, {"first": "G", "middle": ["J"], "last": "Barker", "suffix": ""}, {"first": "D", "middle": ["H"], "last": "Miller", "suffix": ""}, {"first": "A", "middle": ["J"], "last": "Thompson", "suffix": ""}], "year": 2003, "venue": "NeuroImage", "link": "7700581"}, "BIBREF3": {"title": "White matter pathway asymmetry underlies functional laterlization", "authors": [{"first": "T", "middle": ["R"], "last": "Barrick", "suffix": ""}, {"first": "I", "middle": ["N"], "last": "Lawes", "suffix": ""}, {"first": "C", "middle": ["E"], "last": "Mackay", "suffix": ""}, {"first": "C", "middle": ["A"], "last": "Clark", "suffix": ""}], "year": 2007, "venue": "Cereb. Cortex", "link": "5973916"}, "BIBREF4": {"title": "White matter asymmetry in the human brain: A diffusion tensor MRI study", "authors": [{"first": "C", "middle": [], "last": "B\u00fcchel", "suffix": ""}, {"first": "T", "middle": [], "last": "Raedler", "suffix": ""}, {"first": "M", "middle": [], "last": "Sommer", "suffix": ""}, {"first": "M", "middle": [], "last": "Sach", "suffix": ""}, {"first": "C", "middle": [], "last": "Weiller", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Koch", "suffix": ""}], "year": 2004, "venue": "Cereb. Cortex", "link": "17223900"}, "BIBREF5": {"title": "Asymmetry of subinsular anisotropy by in vivo diffusion tensor imaging", "authors": [{"first": "Y", "middle": [], "last": "Cao", "suffix": ""}, {"first": "S", "middle": [], "last": "Whalen", "suffix": ""}, {"first": "J", "middle": [], "last": "Huang", "suffix": ""}, {"first": "K", "middle": ["L"], "last": "Berger", "suffix": ""}, {"first": "M", "middle": ["C"], "last": "Delano", "suffix": ""}], "year": 2003, "venue": "Human Brain Mapp", "link": "17021516"}, "BIBREF6": {"title": "Visualization and analysis of white matter structural asymmetry in diffusion tensor MRI", "authors": [{"first": "S", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "M", "middle": ["E"], "last": "Bastin", "suffix": ""}, {"first": "D", "middle": ["H"], "last": "Laidlaw", "suffix": ""}, {"first": "S", "middle": [], "last": "Sinha", "suffix": ""}, {"first": "P", "middle": ["A"], "last": "Armitage", "suffix": ""}, {"first": "T", "middle": ["S"], "last": "Deiboeck", "suffix": ""}], "year": 2004, "venue": "Magn. Reson. Med", "link": "8111184"}, "BIBREF7": {"title": "White and gray matter development in human fetal, newborn and pediatric brains", "authors": [{"first": "H", "middle": [], "last": "Huang", "suffix": ""}, {"first": "J", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "S", "middle": [], "last": "Wakana", "suffix": ""}, {"first": "W", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "T", "middle": [], "last": "Ren", "suffix": ""}, {"first": "L", "middle": ["J"], "last": "Richards", "suffix": ""}, {"first": "P", "middle": [], "last": "Yarowsky", "suffix": ""}, {"first": "P", "middle": [], "last": "Donohue", "suffix": ""}, {"first": "E", "middle": [], "last": "Graham", "suffix": ""}, {"first": "P", "middle": ["C"], "last": "Van Zijl", "suffix": ""}, {"first": "S", "middle": [], "last": "Mori", "suffix": ""}], "year": 2006, "venue": "NeuroImage", "link": "6583668"}, "BIBREF8": {"title": "White matter growth as a mechanism of cognitive development in children", "authors": [{"first": "D", "middle": ["J"], "last": "Mabbott", "suffix": ""}, {"first": "M", "middle": [], "last": "Noseworthy", "suffix": ""}, {"first": "E", "middle": [], "last": "Bouffet", "suffix": ""}, {"first": "S", "middle": [], "last": "Laughlin", "suffix": ""}, {"first": "C", "middle": [], "last": "Rockel", "suffix": ""}], "year": 2006, "venue": "NeuroImage", "link": "1471028"}, "BIBREF9": {"title": "Age-related alterations in white matter microstructure measured by diffusion tensor imaging", "authors": [{"first": "D", "middle": ["H"], "last": "Salat", "suffix": ""}, {"first": "D", "middle": ["S"], "last": "Tuch", "suffix": ""}, {"first": "D", "middle": ["N"], "last": "Greve", "suffix": ""}, {"first": "A", "middle": ["J W"], "last": "Van Der Kouwe", "suffix": ""}, {"first": "N", "middle": ["D"], "last": "Hevelone", "suffix": ""}, {"first": "A", "middle": ["K"], "last": "Zaleta", "suffix": ""}, {"first": "B", "middle": ["R"], "last": "Rosen", "suffix": ""}, {"first": "B", "middle": [], "last": "Fischl", "suffix": ""}, {"first": "S", "middle": [], "last": "Corkin", "suffix": ""}, {"first": "H", "middle": ["D"], "last": "Rosas", "suffix": ""}, {"first": "A", "middle": ["M"], "last": "Dale", "suffix": ""}], "year": 2005, "venue": "Neurobiol. Aging", "link": "16482628"}, "BIBREF10": {"title": "Age-related changes in prefrontal white matter measured by diffusion tensor imaging", "authors": [{"first": "D", "middle": ["H"], "last": "Salat", "suffix": ""}, {"first": "D", "middle": ["S"], "last": "Tuch", "suffix": ""}, {"first": "N", "middle": ["D"], "last": "Hevelone", "suffix": ""}, {"first": "B", "middle": [], "last": "Fischl", "suffix": ""}, {"first": "S", "middle": [], "last": "Corkin", "suffix": ""}, {"first": "H", "middle": ["D"], "last": "Rosas", "suffix": ""}, {"first": "A", "middle": ["M"], "last": "Dale", "suffix": ""}], "year": 2005, "venue": "Ann. NY Acad. Sci", "link": null}, "BIBREF11": {"title": "Applications of diffusion-weighted and diffusion tensor MRI to white matter diseases-A review", "authors": [{"first": "M", "middle": ["A"], "last": "Horsfield", "suffix": ""}, {"first": "D", "middle": ["K"], "last": "Jones", "suffix": ""}], "year": 2002, "venue": "NMR Biomed", "link": "40734758"}, "BIBREF12": {"title": "Diffusion magnetic resonance imaging in multiple sclerosis", "authors": [{"first": "M", "middle": ["A"], "last": "Horsfield", "suffix": ""}, {"first": "H", "middle": ["B"], "last": "Larsson", "suffix": ""}, {"first": "D", "middle": ["K"], "last": "Jones", "suffix": ""}, {"first": "A", "middle": [], "last": "Gass", "suffix": ""}], "year": 1998, "venue": "J. Neurol. Neurosurg. Psychiatry", "link": "21631540"}, "BIBREF13": {"title": "Diffusion MRI in multiple sclerosis", "authors": [{"first": "M", "middle": [], "last": "Rovaris", "suffix": ""}, {"first": "A", "middle": [], "last": "Gass", "suffix": ""}, {"first": "R", "middle": [], "last": "Bammer", "suffix": ""}, {"first": "S", "middle": ["J"], "last": "Hickman", "suffix": ""}, {"first": "O", "middle": [], "last": "Ciccarelli", "suffix": ""}, {"first": "D", "middle": ["H"], "last": "Miller", "suffix": ""}, {"first": "M", "middle": [], "last": "Filippi", "suffix": ""}], "year": 2005, "venue": "Neurology", "link": "16543384"}, "BIBREF14": {"title": "Diffusion tensor MRI assesses corticospinal tract damage in ALS", "authors": [{"first": "C", "middle": ["M"], "last": "Ellis", "suffix": ""}, {"first": "A", "middle": [], "last": "Simmons", "suffix": ""}, {"first": "D", "middle": ["K"], "last": "Jones", "suffix": ""}, {"first": "J", "middle": [], "last": "Bland", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Dawson", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Horsfield", "suffix": ""}], "year": 1999, "venue": "Neurology", "link": "20616818"}, "BIBREF15": {"title": "Diffusion tensor MRI of early upper motor neuron involvement in amyotrophic lateral sclerosis", "authors": [{"first": "M", "middle": [], "last": "Sach", "suffix": ""}, {"first": "G", "middle": [], "last": "Winkler", "suffix": ""}, {"first": "V", "middle": [], "last": "Glauche", "suffix": ""}, {"first": "J", "middle": [], "last": "Liepert", "suffix": ""}, {"first": "B", "middle": [], "last": "Heimbach", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Koch", "suffix": ""}, {"first": "C", "middle": [], "last": "B\u00fcchel", "suffix": ""}, {"first": "C", "middle": [], "last": "Weille", "suffix": ""}], "year": 2004, "venue": "Brain", "link": "16294906"}, "BIBREF16": {"title": "Diffusion tensor imaging in amyotrophic lateral sclerosis: Volumetric analysis of the cortiospinal tract", "authors": [{"first": "S", "middle": [], "last": "Wang", "suffix": ""}, {"first": "H", "middle": [], "last": "Poptani", "suffix": ""}, {"first": "M", "middle": [], "last": "Bilello", "suffix": ""}, {"first": "X", "middle": [], "last": "Wu", "suffix": ""}, {"first": "J", "middle": ["H"], "last": "Woo", "suffix": ""}, {"first": "L", "middle": ["B"], "last": "Elman", "suffix": ""}, {"first": "L", "middle": ["F"], "last": "Mccluskey", "suffix": ""}, {"first": "J", "middle": [], "last": "Krejza", "suffix": ""}, {"first": "E", "middle": ["R"], "last": "Melhem", "suffix": ""}], "year": 2006, "venue": "Amer. J. Neuroradiol", "link": null}, "BIBREF17": {"title": "Quantitative analysis of diffusion tensor imaging data in serial assessment of Krabbe disease", "authors": [{"first": "J", "middle": ["M"], "last": "Provenzale", "suffix": ""}, {"first": "M", "middle": [], "last": "Escolar", "suffix": ""}, {"first": "J", "middle": [], "last": "Kurtzberg", "suffix": ""}], "year": 2005, "venue": "Ann. NY Acad. Sci", "link": "7103301"}, "BIBREF18": {"title": "Diffusion tensor imaging and its application to neuropsychiatric disorders", "authors": [{"first": "M", "middle": [], "last": "Kubicki", "suffix": ""}, {"first": "C.-F", "middle": [], "last": "Westin", "suffix": ""}, {"first": "S", "middle": ["E"], "last": "Maier", "suffix": ""}, {"first": "H", "middle": [], "last": "Mamata", "suffix": ""}, {"first": "M", "middle": [], "last": "Frumin", "suffix": ""}, {"first": "H", "middle": [], "last": "Ersner-Hershfield", "suffix": ""}, {"first": "R", "middle": [], "last": "Kikinis", "suffix": ""}, {"first": "F", "middle": ["A"], "last": "Jolesz", "suffix": ""}, {"first": "R", "middle": [], "last": "Mccarley", "suffix": ""}, {"first": "M", "middle": ["E"], "last": "Shenton", "suffix": ""}], "year": 2002, "venue": "Harvard Rev. Psychiatry", "link": "11681492"}, "BIBREF19": {"title": "Diffusion tensor imaging in schizophrenia", "authors": [{"first": "M", "middle": ["S"], "last": "Buchsbaum", "suffix": ""}, {"first": "J", "middle": [], "last": "Friedman", "suffix": ""}, {"first": "B", "middle": ["R"], "last": "Buchsbaum", "suffix": ""}, {"first": "K.-W", "middle": [], "last": "Chu", "suffix": ""}, {"first": "E", "middle": ["A"], "last": "Hazlett", "suffix": ""}, {"first": "R", "middle": [], "last": "Newmark", "suffix": ""}, {"first": "J", "middle": ["S"], "last": "Schneiderman", "suffix": ""}, {"first": "Y", "middle": [], "last": "Torosjan", "suffix": ""}, {"first": "C", "middle": [], "last": "Tang", "suffix": ""}, {"first": "P", "middle": ["R"], "last": "Hot", "suffix": ""}, {"first": "D", "middle": [], "last": "Stewart", "suffix": ""}, {"first": "K", "middle": ["L"], "last": "Davis", "suffix": ""}, {"first": "J", "middle": [], "last": "Gorman", "suffix": ""}], "year": 2006, "venue": "Biological Psychiatry", "link": "13584409"}, "BIBREF20": {"title": "The application of DTI to investigate white matter abnormalities in schizophrenia", "authors": [{"first": "M", "middle": [], "last": "Kubicki", "suffix": ""}, {"first": "C.-F", "middle": [], "last": "Westin", "suffix": ""}, {"first": "R", "middle": ["W"], "last": "Mccarley", "suffix": ""}, {"first": "M", "middle": ["E"], "last": "Shenton", "suffix": ""}], "year": 2005, "venue": "Ann. NY Acad. Sci", "link": null}, "BIBREF21": {"title": "Brain anatomy in Turner syndrome: Evidence for impaired social and spatial-numerical networks", "authors": [{"first": "N", "middle": [], "last": "Molko", "suffix": ""}, {"first": "A", "middle": [], "last": "Cachia", "suffix": ""}, {"first": "D", "middle": [], "last": "Rivere", "suffix": ""}, {"first": "J", "middle": ["F"], "last": "Mangin", "suffix": ""}, {"first": "M", "middle": [], "last": "Bruandet", "suffix": ""}, {"first": "D", "middle": [], "last": "Lebihan", "suffix": ""}, {"first": "L", "middle": [], "last": "Cohen", "suffix": ""}, {"first": "S", "middle": [], "last": "Dehaene", "suffix": ""}], "year": 2004, "venue": "Cereb. Cortex", "link": "5999533"}, "BIBREF22": {"title": "Volumetric, connective and morphologic changes in the brains of children with chromosome 22q11.2 deletion syndrome: An integrative study", "authors": [{"first": "T", "middle": ["J"], "last": "Simon", "suffix": ""}, {"first": "L", "middle": [], "last": "Ding", "suffix": ""}, {"first": "J", "middle": ["P"], "last": "Bish", "suffix": ""}, {"first": "D", "middle": ["M"], "last": "Mcdonald-Mcginn", "suffix": ""}, {"first": "E", "middle": ["H"], "last": "Zackai", "suffix": ""}, {"first": "J", "middle": [], "last": "Gee", "suffix": ""}], "year": 2005, "venue": "NeuroImage", "link": "17093593"}, "BIBREF23": {"title": "The role of diffusion tensor imaging in the evaluation of ischemic brain injury-A review", "authors": [{"first": "C", "middle": ["H"], "last": "Sotak", "suffix": ""}], "year": 2002, "venue": "NMR Biomed", "link": "33386762"}, "BIBREF24": {"title": "Diffusion tensor imaging for the evaluation of white matter pathology in traumatic brain injury", "authors": [{"first": "D", "middle": ["J"], "last": "Tisserand", "suffix": ""}, {"first": "G", "middle": [], "last": "Stanisz", "suffix": ""}, {"first": "N", "middle": [], "last": "Lobaugh", "suffix": ""}, {"first": "E", "middle": [], "last": "Gibson", "suffix": ""}, {"first": "T", "middle": [], "last": "Li", "suffix": ""}, {"first": "S", "middle": ["E"], "last": "Black", "suffix": ""}, {"first": "B", "middle": [], "last": "Levine", "suffix": ""}], "year": 2006, "venue": "Brain Cogn", "link": null}, "BIBREF25": {"title": "Optic radiation changes after optic neuritis detected by tractography-based group mapping", "authors": [{"first": "O", "middle": [], "last": "Ciccarelli", "suffix": ""}, {"first": "A", "middle": ["T"], "last": "Toosy", "suffix": ""}, {"first": "S", "middle": ["J"], "last": "Hickman", "suffix": ""}, {"first": "G", "middle": ["J M"], "last": "Parker", "suffix": ""}, {"first": "C", "middle": ["A M"], "last": "Wheeler-Kingshott", "suffix": ""}, {"first": "D", "middle": ["H"], "last": "Miller", "suffix": ""}, {"first": "A", "middle": ["J"], "last": "Thompson", "suffix": ""}], "year": 2005, "venue": "Human Brain Mapp", "link": "20303089"}, "BIBREF26": {"title": "Diffusion tensor imaging in patients with epilepsy and malformations of cortical development", "authors": [{"first": "S", "middle": ["H"], "last": "Eriksson", "suffix": ""}, {"first": "F", "middle": ["J"], "last": "Rugg-Gunn", "suffix": ""}, {"first": "M", "middle": ["R"], "last": "Symms", "suffix": ""}, {"first": "G", "middle": ["J"], "last": "Barker", "suffix": ""}, {"first": "J", "middle": ["S"], "last": "Duncan", "suffix": ""}], "year": 2001, "venue": "Brain", "link": "8335110"}, "BIBREF27": {"title": "Amyotrophic lateral sclerosis: Diffusion tensor tractography and voxel-based analysis", "authors": [{"first": "O", "middle": [], "last": "Abe", "suffix": ""}, {"first": "H", "middle": [], "last": "Yamada", "suffix": ""}, {"first": "Y", "middle": [], "last": "Masutani", "suffix": ""}, {"first": "S", "middle": [], "last": "Aoki", "suffix": ""}, {"first": "A", "middle": [], "last": "Kunimatsu", "suffix": ""}, {"first": "H", "middle": [], "last": "Yamasue", "suffix": ""}, {"first": "R", "middle": [], "last": "Fukuda", "suffix": ""}, {"first": "K", "middle": [], "last": "Kasai", "suffix": ""}, {"first": "N", "middle": [], "last": "Hayashi", "suffix": ""}, {"first": "T", "middle": [], "last": "Masumoto", "suffix": ""}, {"first": "H", "middle": [], "last": "Mori", "suffix": ""}, {"first": "T", "middle": [], "last": "Soma", "suffix": ""}, {"first": "K", "middle": [], "last": "Ohtomo", "suffix": ""}], "year": 2004, "venue": "NMR Biomed", "link": "39883376"}, "BIBREF28": {"title": "Spatial registration and normalization of images", "authors": [{"first": "K", "middle": ["J"], "last": "Friston", "suffix": ""}, {"first": "J", "middle": [], "last": "Ashburner", "suffix": ""}, {"first": "C", "middle": ["D"], "last": "Frith", "suffix": ""}, {"first": "J.-B", "middle": [], "last": "Poline", "suffix": ""}, {"first": "J", "middle": ["D"], "last": "Heather", "suffix": ""}, {"first": "R", "middle": ["S J"], "last": "Frackowiak", "suffix": ""}], "year": 1995, "venue": "Human Brain Mapp", "link": "6596268"}, "BIBREF29": {"title": "Tract-based spatial statistics: Voxelwise analysis of multi-subject diffusion data", "authors": [{"first": "S", "middle": ["M"], "last": "Smith", "suffix": ""}, {"first": "M", "middle": [], "last": "Jenkinson", "suffix": ""}, {"first": "H", "middle": [], "last": "Johansen-Berg", "suffix": ""}, {"first": "D", "middle": [], "last": "Rueckert", "suffix": ""}, {"first": "T", "middle": ["E"], "last": "Nichols", "suffix": ""}, {"first": "C", "middle": ["E"], "last": "Mackay", "suffix": ""}, {"first": "K", "middle": ["E"], "last": "Watkins", "suffix": ""}, {"first": "O", "middle": [], "last": "Ciccarelli", "suffix": ""}, {"first": "M", "middle": ["Z"], "last": "Cader", "suffix": ""}, {"first": "P", "middle": ["M"], "last": "Matthews", "suffix": ""}, {"first": "T", "middle": ["E J"], "last": "Behrens", "suffix": ""}], "year": 2006, "venue": "NeuroImage", "link": null}, "BIBREF30": {"title": "White matter hemisphere asymmetries in healthy subjects and in schizophrenia: A diffusion tensor MRI study", "authors": [{"first": "H.-J", "middle": [], "last": "Park", "suffix": ""}, {"first": "C.-F", "middle": [], "last": "Westin", "suffix": ""}, {"first": "M", "middle": [], "last": "Kubicki", "suffix": ""}, {"first": "S", "middle": ["E"], "last": "Maier", "suffix": ""}, {"first": "M", "middle": [], "last": "Niznikiewicz", "suffix": ""}, {"first": "A", "middle": [], "last": "Baer", "suffix": ""}, {"first": "M", "middle": [], "last": "Frumin", "suffix": ""}, {"first": "R", "middle": [], "last": "Kikinis", "suffix": ""}, {"first": "F", "middle": ["A"], "last": "Jolesz", "suffix": ""}, {"first": "R", "middle": ["W"], "last": "Mccarley", "suffix": ""}, {"first": "M", "middle": ["E"], "last": "Shenton", "suffix": ""}], "year": 2004, "venue": "NeuroImage", "link": null}, "BIBREF31": {"title": "Making memories without trying: Medial temporal lobe activity associated with incidental memory formation during recognition", "authors": [{"first": "C", "middle": ["E L"], "last": "Stark", "suffix": ""}, {"first": "Y", "middle": [], "last": "Okado", "suffix": ""}], "year": 2003, "venue": "J. Neurosci", "link": "6980360"}, "BIBREF32": {"title": "Increasing the power of functional maps of the medial temporal lobe by using large deformation diffeomorphic metric mapping", "authors": [{"first": "M", "middle": ["I"], "last": "Miller", "suffix": ""}, {"first": "M", "middle": ["F"], "last": "Beg", "suffix": ""}, {"first": "C", "middle": [], "last": "Ceritoglu", "suffix": ""}, {"first": "C", "middle": [], "last": "Stark", "suffix": ""}], "year": 2005, "venue": "Proc. Nat. Acad. Sci. USA", "link": "12869164"}, "BIBREF33": {"title": "Hippocampus-specific fMRI group activation using the continuous medial representation", "authors": [{"first": "P", "middle": ["A"], "last": "Yushkevich", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Detre", "suffix": ""}, {"first": "D", "middle": [], "last": "Mechanic-Hamilton", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Fern\u00e1ndez-Seara", "suffix": ""}, {"first": "K", "middle": ["Z"], "last": "Tang", "suffix": ""}, {"first": "A", "middle": [], "last": "Hoang", "suffix": ""}, {"first": "M", "middle": [], "last": "Korczykowski", "suffix": ""}, {"first": "H", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "J", "middle": ["C"], "last": "Gee", "suffix": ""}], "year": 2007, "venue": "NeuroImage", "link": null}, "BIBREF34": {"title": "Diffusion-weighted MR imaging of anisotropic water diffusion in cat central nervous system", "authors": [{"first": "M", "middle": [], "last": "Moseley", "suffix": ""}, {"first": "Y", "middle": [], "last": "Cohen", "suffix": ""}, {"first": "M", "middle": [], "last": "Kucharaczyj", "suffix": ""}, {"first": "J", "middle": [], "last": "Mintorovitch", "suffix": ""}, {"first": "H", "middle": [], "last": "Asgari", "suffix": ""}, {"first": "M", "middle": [], "last": "Wendland", "suffix": ""}, {"first": "J", "middle": [], "last": "Tsuruda", "suffix": ""}, {"first": "D", "middle": [], "last": "Norman", "suffix": ""}], "year": 1990, "venue": "Radiology", "link": "11661193"}, "BIBREF35": {"title": "Toward a quantitative assessment of diffusion anisotropy", "authors": [{"first": "C", "middle": [], "last": "Pierpaoli", "suffix": ""}, {"first": "P", "middle": ["J"], "last": "Basser", "suffix": ""}], "year": 1996, "venue": "Magn. Reson. Med", "link": "3017290"}, "BIBREF36": {"title": "Fiber tracking: Principles and strategies-A technical review", "authors": [{"first": "S", "middle": [], "last": "Mori", "suffix": ""}, {"first": "P", "middle": ["C M"], "last": "Van Zijl", "suffix": ""}], "year": 2002, "venue": "NMR Biomed", "link": null}, "BIBREF37": {"title": "Diffusion tensor imaging and axonal tracking in the human brainstem", "authors": [{"first": "B", "middle": [], "last": "Stieltjes", "suffix": ""}, {"first": "W", "middle": ["E"], "last": "Kaufmann", "suffix": ""}, {"first": "P", "middle": ["C M"], "last": "Van Zijl", "suffix": ""}, {"first": "G", "middle": ["D"], "last": "Pearlson", "suffix": ""}, {"first": "S", "middle": [], "last": "Mori", "suffix": ""}], "year": 2001, "venue": "NeuroImage", "link": null}, "BIBREF38": {"title": "Imaging cortical association tracts in the human brain using diffusion-tensor-based axonal tracking", "authors": [{"first": "S", "middle": [], "last": "Mori", "suffix": ""}, {"first": "W", "middle": ["E"], "last": "Kaufmann", "suffix": ""}, {"first": "C", "middle": [], "last": "Davatzikos", "suffix": ""}, {"first": "B", "middle": [], "last": "Stieltjes", "suffix": ""}, {"first": "L", "middle": [], "last": "Amodei", "suffix": ""}, {"first": "K", "middle": [], "last": "Fredericksen", "suffix": ""}, {"first": "G", "middle": ["D"], "last": "Pearlson", "suffix": ""}, {"first": "M", "middle": [], "last": "Solaiiyappan", "suffix": ""}, {"first": "G", "middle": ["V"], "last": "Raymond", "suffix": ""}, {"first": "H", "middle": ["W"], "last": "Moser", "suffix": ""}, {"first": "P", "middle": ["C"], "last": "Van Zijl", "suffix": ""}], "year": 2002, "venue": "Magn. Reson. Med", "link": "17263019"}, "BIBREF39": {"title": "Fiber tract-based atlas of human white matter anatomy", "authors": [{"first": "S", "middle": [], "last": "Wakana", "suffix": ""}, {"first": "H", "middle": [], "last": "Jiang", "suffix": ""}, {"first": "L", "middle": ["M"], "last": "Nagae-Poetscher", "suffix": ""}, {"first": "P", "middle": ["C"], "last": "Van Zijl", "suffix": ""}, {"first": "S", "middle": [], "last": "Mori", "suffix": ""}], "year": 2004, "venue": "Radiology", "link": "87328169"}, "BIBREF40": {"title": "Diffusion-tensor image registration", "authors": [{"first": "J", "middle": ["C"], "last": "Gee", "suffix": ""}, {"first": "D", "middle": ["C"], "last": "Alexander", "suffix": ""}], "year": 2005, "venue": "Visualization and Image Processing of Tensor Fields", "link": "18894083"}, "BIBREF41": {"title": "Spatial transformations of diffusion tensor magnetic resonance images", "authors": [{"first": "D", "middle": ["C"], "last": "Alexander", "suffix": ""}, {"first": "C", "middle": [], "last": "Pierpaoli", "suffix": ""}, {"first": "P", "middle": ["J"], "last": "Basser", "suffix": ""}, {"first": "J", "middle": ["C"], "last": "Gee", "suffix": ""}], "year": 2001, "venue": "IEEE Trans. Med. Imag", "link": "6559551"}, "BIBREF42": {"title": "Deformable registration of DT-MRI data based on transformation invariant tensor characterisitics", "authors": [{"first": "A", "middle": [], "last": "Guimond", "suffix": ""}, {"first": "C", "middle": ["R G"], "last": "Guttmann", "suffix": ""}, {"first": "S", "middle": ["K"], "last": "Warfield", "suffix": ""}, {"first": "C.-F", "middle": [], "last": "Westin", "suffix": ""}], "year": 2002, "venue": "IEEE Int. Symp. Biomed. Imag.: Macro Nano", "link": "1726436"}, "BIBREF43": {"title": "Spatial normalization and averaging of diffusion tensor MRI data sets", "authors": [{"first": "D", "middle": ["K"], "last": "Jones", "suffix": ""}, {"first": "L", "middle": ["D"], "last": "Griffin", "suffix": ""}, {"first": "D", "middle": ["C"], "last": "Alexander", "suffix": ""}, {"first": "M", "middle": [], "last": "Catani", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Horsfield", "suffix": ""}, {"first": "R", "middle": [], "last": "Howard", "suffix": ""}, {"first": "S", "middle": ["C R"], "last": "Williams", "suffix": ""}], "year": 2002, "venue": "NeuroImage", "link": "195964670"}, "BIBREF44": {"title": "Elastic matching of diffusion tensor images", "authors": [{"first": "D", "middle": ["C"], "last": "Alexander", "suffix": ""}, {"first": "J", "middle": ["C"], "last": "Gee", "suffix": ""}], "year": 2000, "venue": "Comput. Vis. Image Understand", "link": "36933365"}, "BIBREF45": {"title": "Nonrigid registration of 3d tensor medical data", "authors": [{"first": "J", "middle": [], "last": "Ruiz-Alzola", "suffix": ""}, {"first": "C.-F", "middle": [], "last": "Westin", "suffix": ""}, {"first": "S", "middle": ["K"], "last": "Warfield", "suffix": ""}, {"first": "C", "middle": [], "last": "Alberola", "suffix": ""}, {"first": "S", "middle": [], "last": "Maier", "suffix": ""}, {"first": "R", "middle": [], "last": "Kikinis", "suffix": ""}], "year": 2002, "venue": "Med. Image Anal", "link": null}, "BIBREF46": {"title": "Spatial normalization of diffusion tensor MRI using multiple channels", "authors": [{"first": "H.-J", "middle": [], "last": "Park", "suffix": ""}, {"first": "M", "middle": [], "last": "Kubicki", "suffix": ""}, {"first": "M", "middle": ["E"], "last": "Shenton", "suffix": ""}, {"first": "A", "middle": [], "last": "Guimond", "suffix": ""}, {"first": "R", "middle": ["W"], "last": "Mccarley", "suffix": ""}, {"first": "S", "middle": ["E"], "last": "Maier", "suffix": ""}, {"first": "R", "middle": [], "last": "Kikinis", "suffix": ""}, {"first": "F", "middle": ["A"], "last": "Jolesz", "suffix": ""}, {"first": "C.-F", "middle": [], "last": "Westin", "suffix": ""}], "year": 1995, "venue": "NeuroImage", "link": "15800277"}, "BIBREF47": {"title": "Orientation matching for registration of diffusion tensor images", "authors": [{"first": "K", "middle": ["M"], "last": "Curran", "suffix": ""}, {"first": "D", "middle": ["C"], "last": "Alexander", "suffix": ""}], "year": 2003, "venue": "SPIE Med. Imag", "link": "63101701"}, "BIBREF48": {"title": "Orientation coherence optimisation in tensor image registration", "authors": [{"first": "K", "middle": ["M"], "last": "Curran", "suffix": ""}, {"first": "D", "middle": ["C"], "last": "Alexander", "suffix": ""}], "year": 2004, "venue": "Proc. Med. Image Understand. Anal", "link": null}, "BIBREF49": {"title": "Registration of diffusion tensor images", "authors": [{"first": "H", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "P", "middle": ["A"], "last": "Yushkevich", "suffix": ""}, {"first": "J", "middle": ["C"], "last": "Gee", "suffix": ""}], "year": 2004, "venue": "IEEE Comput. Soc. Conf. Comput. Vision Pattern Recognit", "link": "123045076"}, "BIBREF50": {"title": "Towards diffusion profile image registration", "authors": [{"first": "H", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "P", "middle": ["A"], "last": "Yushkevich", "suffix": ""}, {"first": "J", "middle": ["C"], "last": "Gee", "suffix": ""}], "year": 2004, "venue": "IEEE Int. Symp. Biomed. Imag.: Macro Nano", "link": "884235"}, "BIBREF51": {"title": "Large deformation diffeomorphic metric mapping of vector fields", "authors": [{"first": "Y", "middle": [], "last": "Cao", "suffix": ""}, {"first": "M", "middle": [], "last": "Miller", "suffix": ""}, {"first": "R", "middle": ["L"], "last": "Winslow", "suffix": ""}, {"first": "L", "middle": [], "last": "Younes", "suffix": ""}], "year": 2005, "venue": "IEEE Trans. Med. Imag", "link": "7046743"}, "BIBREF52": {"title": "Deformable registration of diffusion tensor MR images with explicit orientation optimization", "authors": [{"first": "H", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "P", "middle": ["A"], "last": "Yushkevich", "suffix": ""}, {"first": "D", "middle": ["C"], "last": "Alexander", "suffix": ""}, {"first": "J", "middle": ["C"], "last": "Gee", "suffix": ""}], "year": 2006, "venue": "Med. Image Anal.-Special Issue: 8th Int. Conf. Med. Imag. Comput. Asisted Intervention-MICCAI 2005", "link": "5780323"}, "BIBREF53": {"title": "Diffeomorphic matching of diffusion tensor images", "authors": [{"first": "Y", "middle": [], "last": "Cao", "suffix": ""}, {"first": "M", "middle": [], "last": "Miller", "suffix": ""}, {"first": "S", "middle": [], "last": "Mori", "suffix": ""}, {"first": "R", "middle": ["L"], "last": "Winslow", "suffix": ""}, {"first": "L", "middle": [], "last": "Younes", "suffix": ""}], "year": 2006, "venue": "Proc. CVPRW", "link": "14697785"}, "BIBREF54": {"title": "Quantitative diffusion tensor MRI fiber tractography of sensorimotor white matter development in premature infants", "authors": [{"first": "J", "middle": ["I"], "last": "Berman", "suffix": ""}, {"first": "P", "middle": [], "last": "Mukherjee", "suffix": ""}, {"first": "S", "middle": ["C"], "last": "Partridge", "suffix": ""}, {"first": "S", "middle": ["P"], "last": "Miller", "suffix": ""}, {"first": "D", "middle": ["M"], "last": "Ferriero", "suffix": ""}, {"first": "A", "middle": ["J"], "last": "Barkovich", "suffix": ""}, {"first": "D", "middle": ["B"], "last": "Vigneron", "suffix": ""}, {"first": "R", "middle": ["G"], "last": "Henry", "suffix": ""}], "year": 2005, "venue": "NeuroImage", "link": "284001"}, "BIBREF55": {"title": "DTI-based three-dimensional tractography detects differences in the pyramidal tracts of infants and children with congenital hemiparesis", "authors": [{"first": "O", "middle": ["A"], "last": "Glenn", "suffix": ""}, {"first": "R", "middle": ["G"], "last": "Henry", "suffix": ""}, {"first": "J", "middle": ["I"], "last": "Berman", "suffix": ""}, {"first": "P", "middle": ["C"], "last": "Chang", "suffix": ""}, {"first": "S", "middle": ["P"], "last": "Miller", "suffix": ""}, {"first": "D", "middle": ["B"], "last": "Vigneron", "suffix": ""}, {"first": "A", "middle": ["J"], "last": "Barkovich", "suffix": ""}], "year": 2003, "venue": "J. Magn. Reson. Imag", "link": "26080068"}, "BIBREF56": {"title": "Age effects on diffusion tensor magnetic resonance imaging tractography measures of frontal cortex connections in schizophrenia", "authors": [{"first": "D", "middle": ["K"], "last": "Jones", "suffix": ""}, {"first": "M", "middle": [], "last": "Catani", "suffix": ""}, {"first": "C", "middle": [], "last": "Pierpaoli", "suffix": ""}, {"first": "S", "middle": ["J C"], "last": "Reeves", "suffix": ""}, {"first": "S", "middle": ["S"], "last": "Shergill", "suffix": ""}, {"first": "M", "middle": ["O"], "last": "Sullivan", "suffix": ""}, {"first": "P", "middle": [], "last": "Golesworthy", "suffix": ""}, {"first": "P", "middle": [], "last": "Mcguire", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Horsfield", "suffix": ""}, {"first": "A", "middle": [], "last": "Simmons", "suffix": ""}, {"first": "S", "middle": ["C R"], "last": "Williams", "suffix": ""}, {"first": "R", "middle": ["J"], "last": "Howard", "suffix": ""}], "year": 2006, "venue": "Human Brain Mapp", "link": null}, "BIBREF57": {"title": "Tract-specific anisotropy measurements in diffusion tensor imaging", "authors": [{"first": "R", "middle": ["A"], "last": "Kanaan", "suffix": ""}, {"first": "S", "middle": ["S"], "last": "Shergill", "suffix": ""}, {"first": "G", "middle": ["J"], "last": "Barker", "suffix": ""}, {"first": "M", "middle": [], "last": "Catani", "suffix": ""}, {"first": "V", "middle": ["W"], "last": "Ng", "suffix": ""}, {"first": "R", "middle": [], "last": "Howard", "suffix": ""}, {"first": "P", "middle": ["K"], "last": "Mcguire", "suffix": ""}, {"first": "D", "middle": ["K"], "last": "Jones", "suffix": ""}], "year": 2006, "venue": "Psychiatry Res.: Neuroimag", "link": "32526046"}, "BIBREF58": {"title": "A method for obtaining tract-specfic diffusion tensor MRI measurements in the presence of disease: Application to patients with clinically isolated syndromes suggestive of multiple sclerosis", "authors": [{"first": "E", "middle": [], "last": "Pagani", "suffix": ""}, {"first": "M", "middle": [], "last": "Filippi", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Rocca", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Horsfield", "suffix": ""}], "year": 2005, "venue": "NeuroImage", "link": "22633066"}, "BIBREF59": {"title": "Fiber tract-oriented statistics for quantitative diffusion tensor MRI analysis", "authors": [{"first": "I", "middle": [], "last": "Corouge", "suffix": ""}, {"first": "P", "middle": ["T"], "last": "Fletcher", "suffix": ""}, {"first": "S", "middle": [], "last": "Joshi", "suffix": ""}, {"first": "S", "middle": [], "last": "Gouttard", "suffix": ""}, {"first": "G", "middle": [], "last": "Gerig", "suffix": ""}], "year": 2006, "venue": "Med. Image Anal", "link": "36871887"}, "BIBREF60": {"title": "PASTA: Pointwise assessment of streamline tractography attributes", "authors": [{"first": "D", "middle": ["K"], "last": "Jones", "suffix": ""}, {"first": "A", "middle": ["R"], "last": "Travis", "suffix": ""}, {"first": "G", "middle": [], "last": "Eden", "suffix": ""}, {"first": "C", "middle": [], "last": "Pierpaoli", "suffix": ""}, {"first": "P", "middle": ["J"], "last": "Basser", "suffix": ""}], "year": 2005, "venue": "Magn. Reson. Med", "link": "14771916"}, "BIBREF61": {"title": "Quantitative analysis along the pyramidal tract by length-normalized parametrization based on diffusion tensor tractography: Application to patients with relapsing neuromyelitis optica", "authors": [{"first": "F", "middle": [], "last": "Lin", "suffix": ""}, {"first": "C", "middle": [], "last": "Yu", "suffix": ""}, {"first": "T", "middle": [], "last": "Jiang", "suffix": ""}, {"first": "K", "middle": [], "last": "Li", "suffix": ""}, {"first": "X", "middle": [], "last": "Li", "suffix": ""}, {"first": "W", "middle": [], "last": "Qin", "suffix": ""}, {"first": "H", "middle": [], "last": "Sun", "suffix": ""}, {"first": "P", "middle": [], "last": "Chan", "suffix": ""}], "year": 2006, "venue": "NeuroImage", "link": "6040479"}, "BIBREF62": {"title": "Fiber-tracking does not accurately estiamte size of fiber bundle in pathological condition: Initial neurosurgical experience using neuronavigation and subcortical white matter stimulation", "authors": [{"first": "M", "middle": [], "last": "Kinoshita", "suffix": ""}, {"first": "K", "middle": [], "last": "Yamada", "suffix": ""}, {"first": "N", "middle": [], "last": "Hashimoto", "suffix": ""}, {"first": "A", "middle": [], "last": "Kato", "suffix": ""}, {"first": "S", "middle": [], "last": "Izumoto", "suffix": ""}, {"first": "T", "middle": [], "last": "Baba", "suffix": ""}, {"first": "M", "middle": [], "last": "Maruno", "suffix": ""}, {"first": "T", "middle": [], "last": "Nishimura", "suffix": ""}, {"first": "T", "middle": [], "last": "Yoshimine", "suffix": ""}], "year": 2005, "venue": "NeuroImage", "link": "19604751"}, "BIBREF63": {"title": "Distortion correction and robust tensor estimation for MR diffusiong imaging", "authors": [{"first": "J", "middle": ["F"], "last": "Mangin", "suffix": ""}, {"first": "C", "middle": [], "last": "Poupon", "suffix": ""}, {"first": "C", "middle": ["A"], "last": "Clark", "suffix": ""}, {"first": "D", "middle": ["L"], "last": "Bihan", "suffix": ""}, {"first": "I", "middle": [], "last": "Bloch", "suffix": ""}], "year": 2002, "venue": "Med. Image Anal", "link": "14515286"}, "BIBREF64": {"title": "Fast robust automated brain extraction", "authors": [{"first": "S", "middle": ["M"], "last": "Smith", "suffix": ""}], "year": 2002, "venue": "Human Brain Mapp", "link": null}, "BIBREF65": {"title": "Unbiased diffeomorphic atlas construction for computational anatomy", "authors": [{"first": "S", "middle": [], "last": "Joshi", "suffix": ""}, {"first": "B", "middle": [], "last": "Davis", "suffix": ""}, {"first": "M", "middle": [], "last": "Jomier", "suffix": ""}, {"first": "G", "middle": [], "last": "Gerig", "suffix": ""}], "year": 2004, "venue": "NeuroImage", "link": "2271742"}, "BIBREF66": {"title": "Voxel-based morphometry: The methods", "authors": [{"first": "J", "middle": [], "last": "Ashburner", "suffix": ""}, {"first": "K", "middle": ["J"], "last": "Friston", "suffix": ""}], "year": 2000, "venue": "NeuroImage", "link": "16777465"}, "BIBREF67": {"title": "Geodesic estimation for large deformation anatomical shape averaging and interpolation", "authors": [{"first": "B", "middle": ["B"], "last": "Avants", "suffix": ""}, {"first": "J", "middle": ["C"], "last": "Gee", "suffix": ""}], "year": 2004, "venue": "NeuroImage", "link": "38468630"}, "BIBREF68": {"title": "Nonparametric analysis of pet functional neuroimaging experiments: A primer", "authors": [{"first": "T", "middle": [], "last": "Nichols", "suffix": ""}, {"first": "A", "middle": ["P"], "last": "Holmes", "suffix": ""}], "year": 2001, "venue": "Human Brain Mapping", "link": "57823310"}, "BIBREF69": {"title": "Statistical parametric maps in functional imaging: A general linear approach", "authors": [{"first": "K", "middle": ["J"], "last": "Friston", "suffix": ""}, {"first": "A", "middle": ["P"], "last": "Holmes", "suffix": ""}], "year": 1995, "venue": "Human Brain Mapp", "link": "117574115"}, "BIBREF70": {"title": "Modeling brain deformations in Alzheimer disease by fluid registration of serial MR images", "authors": [{"first": "P", "middle": ["A"], "last": "Freeborough", "suffix": ""}, {"first": "N", "middle": ["C"], "last": "Fox", "suffix": ""}], "year": 1998, "venue": "J. Comput. Assisted. Tomogr", "link": "39706382"}, "BIBREF71": {"title": "Elastic matching: Continuum mechanical and probabilistic analysis", "authors": [{"first": "J", "middle": ["C"], "last": "Gee", "suffix": ""}, {"first": "R", "middle": ["K"], "last": "Bajcsy", "suffix": ""}], "year": 1999, "venue": "Brain Warping", "link": "15440763"}, "BIBREF72": {"title": "The effect of filter size on VBM analyses of DT-MRI data", "authors": [{"first": "D", "middle": ["K"], "last": "Jones", "suffix": ""}, {"first": "M", "middle": ["R"], "last": "Symms", "suffix": ""}, {"first": "M", "middle": [], "last": "Cercignani", "suffix": ""}, {"first": "R", "middle": ["J"], "last": "Howard", "suffix": ""}], "year": 2005, "venue": "NeuroImage", "link": "17157967"}}, "ref_entries": {}}
{"paper_id": "10706426", "_pdf_hash": "16df28ee0d164f52299f45eaf42648413115c806", "abstract": [{"section": "Abstract", "text": "Objective: The search for genetic vulnerability factors in cocaine dependence has focused on the role that neuroplasticity plays in addiction. However, like many other drugs, the ability of an individual to metabolize cocaine can also influence susceptibility to dependence. Butyrylcholinesterase (BChE) metabolizes cocaine, and genetic variants of the BChE gene (BCHE) alter its catalytic activity. Therefore, we hypothesize that cocaine users with polymorphisms in BCHE can show diverse addictive behaviors due to differences in effective plasma concentrations of cocaine. Those polymorphisms might also influence users to prefer one of the two main preparations (crack or powder cocaine), despite having equal access to both. The present work investigates polymorphisms in BCHE and if those genetic variants constitute risk factors for cocaine dependence and for crack cocaine use.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Methods: A total of 1,436 individuals (698 cocaine-dependent patients and 738 controls) were genotyped for three single nucleotide polymorphisms (SNPs) in BCHE: rs1803274, rs4263329, and rs4680662.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Results: For rs4263329, a nominal difference was found between cases and controls. For rs1803274 (the functional SNP), a statistically significant difference was found between patients who used crack cocaine exclusively and those who used only powder cocaine (P = 0.027; OR = 4.36; 95% CI = 1.18-16.04). Allele frequencies and genotypes related to other markers did not differ between cases and controls or between the two cocaine subgroups.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Conclusions: Our findings suggest that the AA genotype of rs1803274 is a risk factor for crack cocaine use, which is more addictive than powder cocaine use. Further studies are needed in order to confirm this preliminary result and clarify the role of BCHE and its variants in cocaine dependence.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Cocaine addiction is a complex behaviour that arises from the interactions between genetic and environmental risk factors. Twin studies indicate that the heritability of cocaine addiction is approximately 60% and fits a complex polygenic model [1] . Cocaine binds strongly to the dopamine transporter, and this blockade of dopamine reuptake is perhaps the key mechanism leading to cocaine addiction [2] . In fact, some studies have already reported genetic markers in dopaminergic brain systems associated with cocaine dependence [3] [4] [5] . However, many of those markers are also associated with other psychiatric disorders or substancerelated disorders other than cocaine-related disorders and therefore might not be specific markers for the cocaine dependency risk [6] [7] [8] . The results of twin studies indicate that the heritability of substance dependence can be general or drugspecific, suggesting that specific genetic markers increase susceptibility to dependence on distinct drugs [9, 10] . In one of the largest studies of cocaine dependence to date [3] various polymorphisms were found to be associated with the cocaine-dependent phenotype, as has also been demonstrated in animal studies involving markers related to the dopaminergic reward system and to other biochemical pathways [11, 12] .", "cite_spans": [{"start": 244, "end": 247, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 399, "end": 402, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 530, "end": 533, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 534, "end": 537, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 538, "end": 541, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 771, "end": 774, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 775, "end": 778, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 779, "end": 782, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 997, "end": 1000, "text": "[9,", "ref_id": "BIBREF8"}, {"start": 1001, "end": 1004, "text": "10]", "ref_id": "BIBREF9"}, {"start": 1067, "end": 1070, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 1301, "end": 1305, "text": "[11,", "ref_id": "BIBREF10"}, {"start": 1306, "end": 1309, "text": "12]", "ref_id": "BIBREF11"}], "ref_spans": []}, {"section": "Introduction", "text": "Although cocaine users use the drug in various forms, most can be distinguished by their preferred route of cocaine administration: inhalation (smoking crack cocaine); nasal (snorting powder cocaine); or injection (injecting a cocaine preparation) [13] . Those subgroups have been associated with specific characteristics of cocaine use: escalation of consumption; degree of abuse liability; propensity for dependence; and treatment response [14, 15] . It is argued that the reinforcing effect of smoked (crack) cocaine is greater than is that of snorted (powder) cocaine because, when the drug is smoked, the peak effect is achieved more quickly and concentrations of the drug in the central nervous system are higher for an equivalent amount of cocaine consumed [16] . Nevertheless, most cocaine-dependent patients have a preferred route of administration, despite having been exposed to both forms [13] . Therefore, the preferred route of administration can represent a distinct phenotype among cocaine users and should be taken into account when investigating individual genetic susceptibility to cocaine use and abuse.", "cite_spans": [{"start": 248, "end": 252, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 442, "end": 446, "text": "[14,", "ref_id": "BIBREF13"}, {"start": 447, "end": 450, "text": "15]", "ref_id": "BIBREF14"}, {"start": 764, "end": 768, "text": "[16]", "ref_id": "BIBREF15"}, {"start": 901, "end": 905, "text": "[13]", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "Introduction", "text": "One limitation of previous studies on genetic susceptibility to cocaine dependence, as well as to other complex disorders, is that known polymorphisms may explain only a small fraction of the heritability variance in cocaine dependence. Therefore, there is a need for studies investigating putative additional genetic markers associated with susceptibility to cocaine dependence, in particular those that might be specific to this disorder [17] .", "cite_spans": [{"start": 440, "end": 444, "text": "[17]", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "Introduction", "text": "Pharmacogenetic factors, especially genetic aspects that modulate the plasma concentration of cocaine, could play a role in cocaine susceptibility and have yet to be studied. Once absorbed, cocaine is rapidly transformed in two main metabolites, benzoylecgonine and ecgonine methyl ester, both of which are pharmacologically inactive [18] . The hydrolysis that leads to the formation of ecgonine methyl ester is catalyzed by butyrylcholinesterase (BChE), which is an enzyme involved in the metabolism of certain drugs (including cocaine and heroin), various local anesthetics, and short-acting muscle relaxants [19] . BChE is synthesized primarily in the liver and is distributed throughout the intestinal mucosa, in plasma, and in the white matter of the central nervous system [20] . The enzyme is encoded by the BChE gene (BCHE), which is located on chromosome 3q26 [21] . The BCHE genomic region spans approximately 70 kb, with four exons and three large introns [22] . Although more than 65 BCHE mutations have been identified, not all of them have been fully studied [23] . In general, these mutations produce enzymes with lower levels of catalytic activity than that of those produced by wild-type mutations [24] . BChE has also been tested as a novel therapeutic agent for cocaine dependence: a quadruple mutant hydrolase derived from human BChE suppressed cocaine toxicity and abolished drug-primed reinstatement in rats [25] . Our working hypothesis is that polymorphisms in BCHE lead to various enzyme profiles that allow different concentrations of cocaine to reach the reward system in the brain, thereby increasing or decreasing susceptibility to developing addictive behaviors.", "cite_spans": [{"start": 334, "end": 338, "text": "[18]", "ref_id": "BIBREF17"}, {"start": 611, "end": 615, "text": "[19]", "ref_id": "BIBREF18"}, {"start": 779, "end": 783, "text": "[20]", "ref_id": "BIBREF19"}, {"start": 869, "end": 873, "text": "[21]", "ref_id": "BIBREF20"}, {"start": 967, "end": 971, "text": "[22]", "ref_id": "BIBREF21"}, {"start": 1073, "end": 1077, "text": "[23]", "ref_id": "BIBREF22"}, {"start": 1215, "end": 1219, "text": "[24]", "ref_id": "BIBREF23"}, {"start": 1430, "end": 1434, "text": "[25]", "ref_id": "BIBREF24"}], "ref_spans": []}, {"section": "Introduction", "text": "The objective of this study is to identify genetic variations in BCHE as risk factors for dependence in patients whose primary drug of abuse is cocaine. We also investigate those genetic markers and the preferred route of cocaine administration for any existing correlation.", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "The patient sample consisted of 698 cocaine-dependent patients [mean age 26.867.2 years; 96% males (n = 669)], recruited and evaluated as inpatients and outpatients from seven drug dependence treatment clinics in S\u00e3o Paulo, Brazil. All of the patients met the criteria for cocaine dependence established in the tenth revision of the International Classification of Diseases. At enrollment, each patient was subjected to a screening interview, designed specifically for use in Brazil, that included questions related to sociodemographic variables and to drug use [26] .", "cite_spans": [{"start": 562, "end": 566, "text": "[26]", "ref_id": "BIBREF25"}], "ref_spans": []}, {"section": "Methods", "text": "We recruited 738 unrelated controls [mean age 31.369.8 years and 68% males (n = 501)] from the Funda\u00e7\u00e3o Pr\u00f3-Sangue, Hospital das Cl\u00ednicas, Universidade de S\u00e3o Paulo (Blood Donation Center at the University of S\u00e3o Paulo School of Medicine).", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "Exclusion criteria were: those with a history of drug abuse or recent use of illicit drugs, as were those with a history of psychiatric inpatient treatment or with a current psychiatric condition.", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "To conduct a comparative analysis according to the route of cocaine administration, we divided the patient sample into three subgroups: those who reported using only powder cocaine (typically by snorting); those who reported using only freebase cocaine hydrochloride (crack cocaine) which is smoked in small pipes and, those who reported using both routes of cocaine administration (dual users). A detailed description of the above subgroups can be found elsewhere [13] .", "cite_spans": [{"start": 465, "end": 469, "text": "[13]", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "Ethics Statement", "text": "The study was approved by the Comiss\u00e3o de \u00c9 tica para a An\u00e1lise de Projeto de Pesquisa (CAPPesq, Ethics Committee for the Analysis of Research Projects) of the University of S\u00e3o Paulo School of Medicine. All participants provided written informed consent.", "cite_spans": [], "ref_spans": []}, {"section": "Genotyping", "text": "All of the participants were genotyped for three single nucleotide polymorphisms (SNPs) in BCHE: rs1803274, rs4263329, and rs4680662. To that end, blood samples were collected in tubes containing ethylenediaminetetraacetic acid, and genomic DNA was extracted by standard methods.", "cite_spans": [], "ref_spans": []}, {"section": "Genotyping", "text": "The SNP rs1803274 was selected because it is a common variant, known as the K variant, that leads to a functional decrease in BChE activity [24] . The other two SNPs were selected on the basis of the linkage disequilibrium (LD) structure of the gene, allele frequency, and available Haplotype Map data (http://hapmap. ncbi.nlm.nih.gov/index.html.en). Genotyping was conducted by Prevention Genetics (Marshfield, Wisconsin, USA; http://www. preventiongenetics.com/). For all genotypes, the Hardy-Weinberg equilibrium was assessed using the Haploview software, version 4.2 [27] . To estimate the statistical power of the sample, we used the QUANTO program, version 1.2, assuming an odds ratio (OR) of 1.5, a disease prevalence of 0.03, a calculated average minor allele frequency of 0.27, and a significance level of 0.05 [28] .", "cite_spans": [{"start": 140, "end": 144, "text": "[24]", "ref_id": "BIBREF23"}, {"start": 571, "end": 575, "text": "[27]", "ref_id": "BIBREF26"}, {"start": 820, "end": 824, "text": "[28]", "ref_id": "BIBREF27"}], "ref_spans": []}, {"section": "Genotyping", "text": "We performed principal component analysis (PCA) to assess allele frequency differences between cases and controls due to ancestry differences and statistical analyses were performed using EIGENSTRAT [29, 30] . This software detects population structure inferring axes of genetic variation and outputs each individual's coordinates along axes of variation. The analysis was performed using a panel of 64 SNPs ancestry-informative markers (AIMs) and models were created with two to five principal components in order to detect the existence or absence of population structure; details of marker set are available on request. In our data set, we were not able to demonstrate a difference in population stratification between cases and controls therefore, no corrections using the PCA results were done in the association tests for the BCHE markers ( Figure 1) .", "cite_spans": [{"start": 199, "end": 203, "text": "[29,", "ref_id": "BIBREF28"}, {"start": 204, "end": 207, "text": "30]", "ref_id": "BIBREF29"}], "ref_spans": []}, {"section": "Genotyping", "text": "A general test of association (the two-degree-of-freedom test of genotypic association) was applied, and three individual contrasts, defined by a priori genetic models (additive, dominant, and recessive), were computed. In the dominant and recessive models, explanatory variables were binary. We employed logistic regression to adjust for age and sex. No statistical correction was made for multiple comparisons in the general test of association. The LD and the haplotype frequencies were estimated with the Haploview software, version 4.2. Haplotype blocks were identified using the solid spine of LD method in Haploview and correction for multiple testing was performed using permutation correction by the Haploview program [27] . Chi-square values, ORs, and 95% confidence intervals (95% CIs) were estimated using the Statistical Package for the Social Sciences, version 17.0 (SPSS Inc., Chicago, Illinois, USA).", "cite_spans": [{"start": 727, "end": 731, "text": "[27]", "ref_id": "BIBREF26"}], "ref_spans": []}, {"section": "Results", "text": "The socio-demographic and clinical characteristics of the participants are summarized in Table 1 . The patient and control groups differed significantly in terms of sex and age. Most of the patients used cannabis and were cigarette smokers. Roughly half of the patients ingested more than 50 units of alcohol per week and had been in prison at least once. In terms of the preferred route of cocaine administration, 23% of the participants reported using the nasal route (snorting powder cocaine) exclusively, 9% reported using the inhalation route (smoking crack cocaine) exclusively, and 68% reported using both routes concurrently (dual users). For cases and controls, none of the allele distributions deviated significantly from those expected on the basis of the HardyWeinberg equilibrium (Table 2) . When we adopted a recessive model of transmission, the GG genotype of rs4263329 was less common in cases than in controls [f(GG) = 1.2% vs. f(GG) = 2.6%; OR 2.3, 95% CI = 0.99-5.32]. After adjustment for age and sex, that association was no longer significant (P.0.1). As can be seen in Table 2 , genotypes of the two other markers did not differ between cases and controls, nor did the allele frequencies of the three markers. Measures of LD and haplotype blocks across BCHE did not produce any evidence for an association with disease (data not shown). Results of the general tests of association for the preferred route of cocaine administration can be seen in Table 3 . Of the three markers, only rs1803274 was associated with distinct genotypes among the subgroups of cocaine users. Among the a priori genetic models, the recessive model (genotype AA) best accounted for the significant difference between crack users and powder cocaine users (P = 0.027; OR = 4.36; 95% CI = 1.18-16.04), as well as for that observed between crack users and dual users (P = 0.001; OR = 5.83; 95% CI = 2.10-16.16). Those associations remained significant after adjustment for age and sex (data not shown).", "cite_spans": [], "ref_spans": [{"start": 89, "end": 96, "text": "Table 1", "ref_id": "TABREF0"}, {"start": 793, "end": 802, "text": "(Table 2)", "ref_id": "TABREF1"}, {"start": 1092, "end": 1099, "text": "Table 2", "ref_id": "TABREF1"}, {"start": 1469, "end": 1476, "text": "Table 3", "ref_id": "TABREF2"}]}, {"section": "Discussion", "text": "We evaluated the distribution of three SNPs in BCHE in a sample of cocaine-dependent patients and controls in Brazil. For the SNP rs4263329, there was a nominal association between patients and controls [GG genotype, P = 0.05, OR = 2.3; 95% CI = 0.99-5.32]. We also found a significant association between rs1803274 and crack cocaine (AA genotype) as the preferred route of administration (p,0,005). To our knowledge, this is the only report in the literature investigating BCHE variants and crack/ cocaine.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "We are aware that these results could be false positive ones, but in order to minimize the likelihood of it, we used the best available methodology and analysis. Firstly, the investigated sample is one of the largest samples of crack/cocaine patients reported in the Figure 1 . Population Structure Analysis. Graphic representation of the first two principal components for cases and controls genotyped with 64 AIMs, each point in this plot is an individual. The distribution of individuals in the axes is similar for both groups therefore the EIGENSTRAT software was not able to detect a difference in population stratification between cases and controls. doi:10.1371/journal.pone.0080505.g001 literature to study genetic susceptibility for cocaine dependence to date. We also adjusted for confounding factors (age and sex) to confirm that the association was not due to bias. Population stratification was tested with the EIGENSTRAT software and no differences were observed between cases and controls which could hinder the association results. In contrast with other studies investigating the association of genetic markers and cocaine dependence [31, 32] , subjects in the present study were stratified by .50 units/week, n (%) 247 ( their preferred route of drug administration. This may decrease the sample's clinical heterogeneity, which frequently reduces the power of genetic association studies. Another confounding factor in previous studies was a concomitant dependence on other drugs, mainly alcohol and heroin. In the present study, individuals with alcohol dependence were excluded, and heroin dependence is very rare in Brazil (less than 1% of our sample used heroin). This attempt to make the sample more homogeneous may strengthen the specificity of any genetic association found as related to the condition of cocaine use per se. From a statistical standpoint, our sample had a power of 88% of detecting true associations.", "cite_spans": [{"start": 1151, "end": 1155, "text": "[31,", "ref_id": "BIBREF30"}, {"start": 1156, "end": 1159, "text": "32]", "ref_id": "BIBREF31"}], "ref_spans": []}, {"section": "Discussion", "text": "One of the markers investigated in our study, rs1803274, was not associated with cocaine dependence but was associated with crack smoking as the preferred route of administration. Although the rs1803274 marker has previously been shown to be associated with behavioral and medical conditions [33, 34] , we found no studies investigating the role of rs1803274 in substance dependence or other substance-related psychiatric disorders to date. The fact that we found an association only when the sample was divided into subgroups is not unique. An association with a genetic marker in cocaine dependence was found when the sample was subdivided into those who had experienced psychotic symptoms during episodes of cocaine intoxication and those who had not [35] . Because cocaine dependent subjects constitute a heterogeneous group not only from a genetic standpoint but also from a clinical perspective, it is useful to study them in meaningful subgroups. Dual users have distinct clinical features that distinguish them from those who are exclusive users of crack or snorted cocaine [13] . In the present study, allele frequencies for rs1803274 were very similar to the values for the Haplotype Map population of Utah residents with ancestry from northern and western Europe (CEU population). We also found that the frequency of the AA genotype in our sample as a whole was greater than in the CEU population (3.3% compared to 1.7%). The other two markers investigated have been infrequently used in association studies. Twelve BCHE SNPs were tested in farmers exposed to organophosphates and rs4680663 was not found to be associated with cholinesterase activity [36] . We found no association studies using the SNP rs4263329 as a marker.", "cite_spans": [{"start": 292, "end": 296, "text": "[33,", "ref_id": "BIBREF32"}, {"start": 297, "end": 300, "text": "34]", "ref_id": "BIBREF33"}, {"start": 754, "end": 758, "text": "[35]", "ref_id": "BIBREF34"}, {"start": 1082, "end": 1086, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 1662, "end": 1666, "text": "[36]", "ref_id": "BIBREF35"}], "ref_spans": []}, {"section": "Discussion", "text": "Common variants have been associated with altered cholinesterase activity in samples drawn from the community [36] . The SNP rs1803274 is a common variant in BCHE, and the A allele leads to a point mutation at nucleotide 1615 that changes codon 539 from GCA (ala) to ACA (thr) [38] . In carriers of the A allele, serum BChE levels are reduced by 30%. Decreased BChE activity increase the amount of cocaine that reaches the reinforcing brain areas, thereby augmenting its propensity to lead to dependence. Most cocaine users in Brazil have equal access to crack and powder cocaine, and the AA genotype can, in part, explain the fact that some users prefer to use crack cocaine exclusively. It is likely that the enzymatic changes interact with other known predisposing factors for crack dependence and account for part of the genetic vulnerability to this route of administration.", "cite_spans": [{"start": 110, "end": 114, "text": "[36]", "ref_id": "BIBREF35"}, {"start": 277, "end": 281, "text": "[38]", "ref_id": "BIBREF37"}], "ref_spans": []}, {"section": "Discussion", "text": "Like any genetic association study, our study has limitations that must be addressed. First, although we found a nominal association between rs4263329 and cocaine dependence, that association lost its significance after being adjusted for sex and age. Nevertheless, that is an interesting finding that warrants further studies in comparable populations. Second, our sample size, although large for this particular line of research, could be considered small for a genetic association study looking for a susceptibility gene with a small magnitude effect. Third, although the marker reported here to be associated with exclusive crack cocaine use has been correlated with functional enzymatic alterations in other studies, we did not obtain any cholinesterase measures, which would have allowed us to make a functional correlation between carrying the marker and its function in patients and controls [23, 36] . By the same token, we had no objective parameters of cocaine use in cases and controls, such as toxicological measurements of cocaine in hair or urine. The subjective ratings reported by cocaine users are known to be unreliable markers of the true amount and frequency of illegal substance use, and that holds true for selfreported drug use by non-dependent subjects, such as our controls [37] . Although we consider it unlikely, it is possible that our controls underreported cocaine use and dependence, which would have decreased the strength of the association found in the present study. Finally, it is possible that the BCHE SNP that is associated with vulnerability to crack use is not the actual causative SNP; instead, other nearby SNPs in LD could be the alternative causation.", "cite_spans": [{"start": 900, "end": 904, "text": "[23,", "ref_id": "BIBREF22"}, {"start": 905, "end": 908, "text": "36]", "ref_id": "BIBREF35"}, {"start": 1300, "end": 1304, "text": "[37]", "ref_id": "BIBREF36"}], "ref_spans": []}, {"section": "Discussion", "text": "Although some investigators have identified genetic components of susceptibility to cocaine dependence, only a small portion of the heritability is explained by those findings [17] . So many of the genetic susceptibility makers or genetic mechanisms for crack/ cocaine dependence are still unknown. The identification of these new genetic markers will contribute to prevent and to treat drug abuse/dependent patients. In the present study, we evaluated three SNPs in BCHE, all of which are potentially involved in cocaine metabolism. Although we did not find an association between those markers and cocaine dependence per se, we observed an association between the known functional genotype (the K variant) and a preference for the inhalation (crack smoking) route of cocaine administration. Further studies involving a replication in other independent case-control samples and/or investigation involving a correlation between the function and the genetic variants and/or sequencing of this region would be very welcome to clarify the preliminary findings of the present report.", "cite_spans": [{"start": 176, "end": 180, "text": "[17]", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "Discussion", "text": "Author Contributions", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Illicit psychoactive substance use, heavy use, abuse, and dependence in a US population-based sample of male twins", "authors": [{"first": "K", "middle": ["S"], "last": "Kendler", "suffix": ""}, {"first": "L", "middle": ["M"], "last": "Karkowski", "suffix": ""}, {"first": "M", "middle": ["C"], "last": "Neale", "suffix": ""}, {"first": "C", "middle": ["A"], "last": "Prescott", "suffix": ""}], "year": 2000, "venue": "ArchGenPsychiatry", "link": "22442345"}, "BIBREF1": {"title": "Cocaine dependence: a disease of the brain's reward centers", "authors": [{"first": "C", "middle": ["A"], "last": "Dackis", "suffix": ""}, {"first": "C", "middle": ["P"], "last": "O&apos;brien", "suffix": ""}], "year": 2001, "venue": "JSubstAbuse Treat", "link": "25417466"}, "BIBREF2": {"title": "A dopamine transporter gene functional variant associated with cocaine abuse in a Brazilian sample", "authors": [{"first": "C", "middle": [], "last": "Guindalini", "suffix": ""}, {"first": "M", "middle": [], "last": "Howard", "suffix": ""}, {"first": "K", "middle": [], "last": "Haddley", "suffix": ""}, {"first": "R", "middle": [], "last": "Laranjeira", "suffix": ""}, {"first": "D", "middle": [], "last": "Collier", "suffix": ""}], "year": 2006, "venue": "ProcNatlAcadSciUSA", "link": "37624148"}, "BIBREF3": {"title": "Association study between the DAT1, DBH and DRD2 genes and cocaine dependence in a Spanish sample", "authors": [{"first": "N", "middle": [], "last": "Fernandez-Castillo", "suffix": ""}, {"first": "M", "middle": [], "last": "Ribases", "suffix": ""}, {"first": "C", "middle": [], "last": "Roncero", "suffix": ""}, {"first": "M", "middle": [], "last": "Casas", "suffix": ""}, {"first": "B", "middle": [], "last": "Gonzalvo", "suffix": ""}], "year": 2010, "venue": "PsychiatrGenet", "link": null}, "BIBREF4": {"title": "Association analysis between polymorphisms in the dopamine D2 receptor (DRD2) and dopamine transporter (DAT1) genes with cocaine dependence", "authors": [{"first": "F", "middle": ["W"], "last": "Lohoff", "suffix": ""}, {"first": "P", "middle": ["J"], "last": "Bloch", "suffix": ""}, {"first": "R", "middle": [], "last": "Hodge", "suffix": ""}, {"first": "A", "middle": ["H"], "last": "Nall", "suffix": ""}, {"first": "T", "middle": ["N"], "last": "Ferraro", "suffix": ""}], "year": 2010, "venue": "NeurosciLett", "link": "207130908"}, "BIBREF5": {"title": "Association between dopamine transporter genotypes and smoking cessation: a meta-analysis", "authors": [{"first": "J", "middle": ["A"], "last": "Stapleton", "suffix": ""}, {"first": "G", "middle": [], "last": "Sutherland", "suffix": ""}, {"first": "O", "middle": [], "last": "Gara", "suffix": ""}, {"first": "C", "middle": [], "last": "", "suffix": ""}], "year": 2007, "venue": "AddictBiol", "link": "33654916"}, "BIBREF6": {"title": "Association of the DRD2 gene Taq1A polymorphism and alcoholism: a meta-analysis of case-control studies and evidence of publication bias", "authors": [{"first": "M", "middle": ["R"], "last": "Munafo", "suffix": ""}, {"first": "I", "middle": ["J"], "last": "Matheson", "suffix": ""}, {"first": "J", "middle": [], "last": "Flint", "suffix": ""}], "year": 2007, "venue": "MolPsychiatry", "link": "41626358"}, "BIBREF7": {"title": "A common haplotype at the dopamine transporter gene 59 region is associated with attention-deficit/hyperactivity disorder", "authors": [{"first": "J", "middle": ["P"], "last": "Genro", "suffix": ""}, {"first": "G", "middle": ["V"], "last": "Polanczyk", "suffix": ""}, {"first": "C", "middle": [], "last": "Zeni", "suffix": ""}, {"first": "A", "middle": ["S"], "last": "Oliveira", "suffix": ""}, {"first": "T", "middle": [], "last": "Roman", "suffix": ""}], "year": 2008, "venue": "AmJMedGenetB NeuropsychiatrGenet", "link": "24767914"}, "BIBREF8": {"title": "Cooccurrence of abuse of different drugs in men: the role of drug-specific and shared vulnerabilities", "authors": [{"first": "M", "middle": ["T"], "last": "Tsuang", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Lyons", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Meyer", "suffix": ""}, {"first": "T", "middle": [], "last": "Doyle", "suffix": ""}, {"first": "S", "middle": ["A"], "last": "Eisen", "suffix": ""}], "year": 1998, "venue": "ArchGenPsychiatry", "link": "37898987"}, "BIBREF9": {"title": "Specificity of genetic and environmental risk factors for symptoms of cannabis, cocaine, alcohol, caffeine, and nicotine dependence", "authors": [{"first": "K", "middle": ["S"], "last": "Kendler", "suffix": ""}, {"first": "J", "middle": [], "last": "Myers", "suffix": ""}, {"first": "C", "middle": ["A"], "last": "Prescott", "suffix": ""}], "year": 2007, "venue": "ArchGenPsychiatry", "link": "10154809"}, "BIBREF10": {"title": "Loss of the Ca2+/calmodulin-dependent protein kinase type IV in dopaminoceptive neurons enhances behavioral effects of cocaine", "authors": [{"first": "A", "middle": [], "last": "Bilbao", "suffix": ""}, {"first": "J", "middle": ["R"], "last": "Parkitna", "suffix": ""}, {"first": "D", "middle": [], "last": "Engblom", "suffix": ""}, {"first": "S", "middle": [], "last": "Perreau-Lenz", "suffix": ""}, {"first": "C", "middle": [], "last": "Sanchis-Segura", "suffix": ""}], "year": 2008, "venue": "ProcNatlAcadSciUSA", "link": "24433022"}, "BIBREF11": {"title": "Cocaine effects on mouse incentive-learning and human addiction are linked to alpha2 subunit-containing GABAA receptors", "authors": [{"first": "C", "middle": ["I"], "last": "Dixon", "suffix": ""}, {"first": "H", "middle": ["V"], "last": "Morris", "suffix": ""}, {"first": "G", "middle": [], "last": "Breen", "suffix": ""}, {"first": "S", "middle": [], "last": "Desrivieres", "suffix": ""}, {"first": "S", "middle": [], "last": "Jugurnauth", "suffix": ""}], "year": 2010, "venue": "ProcNatlAcadSciUSA", "link": "9356562"}, "BIBREF12": {"title": "Concurrent crack and powder cocaine users from Sao Paulo: do they represent a different group", "authors": [{"first": "C", "middle": [], "last": "Guindalini", "suffix": ""}, {"first": "H", "middle": [], "last": "Vallada", "suffix": ""}, {"first": "G", "middle": [], "last": "Breen", "suffix": ""}, {"first": "R", "middle": [], "last": "Laranjeira", "suffix": ""}], "year": 2006, "venue": "BMCPublic Health", "link": "16932236"}, "BIBREF13": {"title": "Cocaine: patterns of use, route of administration, and severity of dependence", "authors": [{"first": "M", "middle": [], "last": "Gossop", "suffix": ""}, {"first": "P", "middle": [], "last": "Griffiths", "suffix": ""}, {"first": "B", "middle": [], "last": "Powis", "suffix": ""}, {"first": "J", "middle": [], "last": "Strang", "suffix": ""}], "year": 1994, "venue": "BrJPsychiatry", "link": "33567180"}, "BIBREF14": {"title": "Epidemiological estimates of risk in the process of becoming dependent upon cocaine: cocaine hydrochloride powder versus crack cocaine", "authors": [{"first": "C", "middle": ["Y"], "last": "Chen", "suffix": ""}, {"first": "J", "middle": ["C"], "last": "Anthony", "suffix": ""}], "year": 2004, "venue": "Psychopharmacology (Berl)", "link": "22363332"}, "BIBREF15": {"title": "Effects of route of administration on cocaine induced dopamine transporter blockade in the human brain", "authors": [{"first": "N", "middle": ["D"], "last": "Volkow", "suffix": ""}, {"first": "G", "middle": ["J"], "last": "Wang", "suffix": ""}, {"first": "M", "middle": ["W"], "last": "Fischman", "suffix": ""}, {"first": "R", "middle": [], "last": "Foltin", "suffix": ""}, {"first": "J", "middle": ["S"], "last": "Fowler", "suffix": ""}], "year": 2000, "venue": "Life Sci", "link": null}, "BIBREF16": {"title": "Genetic vulnerability and susceptibility to substance dependence", "authors": [{"first": "L", "middle": ["J"], "last": "Bierut", "suffix": ""}], "year": 2011, "venue": "Neuron", "link": "2890647"}, "BIBREF17": {"title": "Blood cocaine and metabolite concentrations, clinical findings, and outcome of patients presenting to an ED", "authors": [{"first": "K", "middle": [], "last": "Blaho", "suffix": ""}, {"first": "B", "middle": [], "last": "Logan", "suffix": ""}, {"first": "S", "middle": [], "last": "Winbery", "suffix": ""}, {"first": "L", "middle": [], "last": "Park", "suffix": ""}, {"first": "E", "middle": [], "last": "Schwilke", "suffix": ""}], "year": 2000, "venue": "AmJEmergMed", "link": "41460501"}, "BIBREF18": {"title": "Metabolism of cocaine and heroin is catalyzed by the same human liver carboxylesterases", "authors": [{"first": "L", "middle": ["M"], "last": "Kamendulis", "suffix": ""}, {"first": "M", "middle": ["R"], "last": "Brzezinski", "suffix": ""}, {"first": "E", "middle": ["V"], "last": "Pindel", "suffix": ""}, {"first": "W", "middle": ["F"], "last": "Bosron", "suffix": ""}, {"first": "R", "middle": ["A"], "last": "Dean", "suffix": ""}], "year": 1996, "venue": "JPharmacolExpTher", "link": "27179461"}, "BIBREF19": {"title": "Cholinesterase: phenotyping and genotyping", "authors": [{"first": "R", "middle": [], "last": "Goodall", "suffix": ""}], "year": 2004, "venue": "AnnClinBiochem", "link": "33566827"}, "BIBREF20": {"title": "The cloned butyrylcholinesterase (BCHE) gene maps to a single chromosome site, 3q26", "authors": [{"first": "P", "middle": ["W"], "last": "Allderdice", "suffix": ""}, {"first": "H", "middle": ["A"], "last": "Gardner", "suffix": ""}, {"first": "D", "middle": [], "last": "Galutira", "suffix": ""}, {"first": "O", "middle": [], "last": "Lockridge", "suffix": ""}, {"first": "B", "middle": ["N"], "last": "Ladu", "suffix": ""}], "year": 1991, "venue": "Genomics", "link": "16465765"}, "BIBREF21": {"title": "Structure of the gene for human butyrylcholinesterase. Evidence for a single copy", "authors": [{"first": "M", "middle": [], "last": "Arpagaus", "suffix": ""}, {"first": "M", "middle": [], "last": "Kott", "suffix": ""}, {"first": "K", "middle": ["P"], "last": "Vatsis", "suffix": ""}, {"first": "C", "middle": ["F"], "last": "Bartels", "suffix": ""}, {"first": "La", "middle": [], "last": "Du", "suffix": ""}, {"first": "B", "middle": ["N"], "last": "", "suffix": ""}], "year": 1990, "venue": "Biochemistry", "link": "35472142"}, "BIBREF22": {"title": "Five new naturally occurring mutations of the BCHE gene and frequencies of 12 butyrylcholinesterase alleles in a Brazilian population", "authors": [{"first": "L", "middle": ["R"], "last": "Mikami", "suffix": ""}, {"first": "S", "middle": [], "last": "Wieseler", "suffix": ""}, {"first": "R", "middle": ["L"], "last": "Souza", "suffix": ""}, {"first": "L", "middle": ["M"], "last": "Schopfer", "suffix": ""}, {"first": "F", "middle": [], "last": "Nachon", "suffix": ""}], "year": 2008, "venue": "PharmacogenetGenomics", "link": "7535285"}, "BIBREF23": {"title": "Identification of the structural mutation responsible for the dibucaine-resistant (atypical) variant form of human serum cholinesterase", "authors": [{"first": "M", "middle": ["C"], "last": "Mcguire", "suffix": ""}, {"first": "C", "middle": ["P"], "last": "Nogueira", "suffix": ""}, {"first": "C", "middle": ["F"], "last": "Bartels", "suffix": ""}, {"first": "H", "middle": [], "last": "Lightstone", "suffix": ""}, {"first": "A", "middle": [], "last": "Hajra", "suffix": ""}], "year": 1989, "venue": "ProcNatlAcadSciUSA", "link": "44598160"}, "BIBREF24": {"title": "A cocaine hydrolase engineered from human butyrylcholinesterase selectively blocks cocaine toxicity and reinstatement of drug seeking in rats", "authors": [{"first": "S", "middle": [], "last": "Brimijoin", "suffix": ""}, {"first": "Y", "middle": [], "last": "Gao", "suffix": ""}, {"first": "J", "middle": ["J"], "last": "Anker", "suffix": ""}, {"first": "L", "middle": ["A"], "last": "Gliddon", "suffix": ""}, {"first": "D", "middle": [], "last": "Lafleur", "suffix": ""}], "year": 2008, "venue": "Neuropsychopharmacology", "link": "41162806"}, "BIBREF25": {"title": "The development of a structured interview to evaluate cocaine use and risk behaviour", "authors": [{"first": "J", "middle": [], "last": "Dunn", "suffix": ""}, {"first": "R", "middle": [], "last": "Laranjeira", "suffix": ""}], "year": 2000, "venue": "Revista Brasileira de Psiquiatria", "link": null}, "BIBREF26": {"title": "Haploview: analysis and visualization of LD and haplotype maps", "authors": [{"first": "J", "middle": ["C"], "last": "Barrett", "suffix": ""}, {"first": "B", "middle": [], "last": "Fry", "suffix": ""}, {"first": "J", "middle": [], "last": "Maller", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Daly", "suffix": ""}], "year": 2005, "venue": "Bioinformatics", "link": "16747282"}, "BIBREF27": {"title": "QUANTO 1.1: A computer program for power and sample size calculations for genetic-epidemiology studies", "authors": [{"first": "W", "middle": ["J"], "last": "Gauderman", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Morrison", "suffix": ""}], "year": 2006, "venue": "", "link": "63689906"}, "BIBREF28": {"title": "Principal components analysis corrects for stratification in genome-wide association studies", "authors": [{"first": "A", "middle": ["L"], "last": "Price", "suffix": ""}, {"first": "N", "middle": ["J"], "last": "Patterson", "suffix": ""}, {"first": "R", "middle": ["M"], "last": "Plenge", "suffix": ""}, {"first": "M", "middle": ["E"], "last": "Weinblatt", "suffix": ""}, {"first": "N", "middle": ["A"], "last": "Shadick", "suffix": ""}], "year": 2006, "venue": "Nat Genet", "link": "8127858"}, "BIBREF29": {"title": "Population structure and eigenanalysis", "authors": [{"first": "N", "middle": [], "last": "Patterson", "suffix": ""}, {"first": "A", "middle": ["L"], "last": "Price", "suffix": ""}, {"first": "D", "middle": [], "last": "Reich", "suffix": ""}], "year": 2006, "venue": "PLoS Genet", "link": "9893119"}, "BIBREF30": {"title": "Polymorphisms TaqI A of the DRD2, BalI of the DRD3, exon III repeat of the DRD4, and 39 UTR VNTR of the DAT: association with childhood ADHD in male AfricanCaribbean cocaine dependents?", "authors": [{"first": "N", "middle": [], "last": "Ballon", "suffix": ""}, {"first": "S", "middle": [], "last": "Leroy", "suffix": ""}, {"first": "C", "middle": [], "last": "Roy", "suffix": ""}, {"first": "M", "middle": ["C"], "last": "Bourdel", "suffix": ""}, {"first": "J", "middle": ["P"], "last": "Olie", "suffix": ""}], "year": 2007, "venue": "AmJMedGenetB NeuropsychiatrGenet", "link": "44594856"}, "BIBREF31": {"title": "Genomewide linkage scan for cocaine dependence and related traits: significant linkages for a cocaine-related trait and cocaine-induced paranoia", "authors": [{"first": "J", "middle": [], "last": "Gelernter", "suffix": ""}, {"first": "C", "middle": [], "last": "Panhuysen", "suffix": ""}, {"first": "R", "middle": [], "last": "Weiss", "suffix": ""}, {"first": "K", "middle": [], "last": "Brady", "suffix": ""}, {"first": "V", "middle": [], "last": "Hesselbrock", "suffix": ""}], "year": 2005, "venue": "AmJMedGenetB NeuropsychiatrGenet", "link": "10833513"}, "BIBREF32": {"title": "Analysis of association between butyrylcholinesterase K variant and apolipoprotein E genotypes in Alzheimer's disease", "authors": [{"first": "A", "middle": ["V"], "last": "Raygani", "suffix": ""}, {"first": "M", "middle": [], "last": "Zahrai", "suffix": ""}, {"first": "A", "middle": [], "last": "Soltanzadeh", "suffix": ""}, {"first": "M", "middle": [], "last": "Doosti", "suffix": ""}, {"first": "E", "middle": [], "last": "Javadi", "suffix": ""}], "year": 2004, "venue": "NeurosciLett", "link": "23800921"}, "BIBREF33": {"title": "Butyrylcholinesterase K variant and the APOE-epsilon 4 allele work in synergy to increase the risk of coronary artery disease especially in diabetic patients", "authors": [{"first": "A", "middle": [], "last": "Vaisi-Raygani", "suffix": ""}, {"first": "Z", "middle": [], "last": "Rahimi", "suffix": ""}, {"first": "H", "middle": [], "last": "Tavilani", "suffix": ""}, {"first": "T", "middle": [], "last": "Pourmotabbed", "suffix": ""}], "year": 2010, "venue": "MolBiolRep", "link": "8970659"}, "BIBREF34": {"title": "Association of variants in MANEA with cocaine-related behaviors", "authors": [{"first": "L", "middle": ["A"], "last": "Farrer", "suffix": ""}, {"first": "H", "middle": ["R"], "last": "Kranzler", "suffix": ""}, {"first": "Y", "middle": [], "last": "Yu", "suffix": ""}, {"first": "R", "middle": ["D"], "last": "Weiss", "suffix": ""}, {"first": "K", "middle": ["T"], "last": "Brady", "suffix": ""}], "year": 2009, "venue": "ArchGenPsychiatry", "link": "35685935"}, "BIBREF35": {"title": "Evaluation of candidate genes for cholinesterase activity in farmworkers exposed to organophosphorus pesticides: association of single nucleotide polymorphisms in BCHE", "authors": [{"first": "T", "middle": ["D"], "last": "Howard", "suffix": ""}, {"first": "F", "middle": ["C"], "last": "Hsu", "suffix": ""}, {"first": "J", "middle": ["G"], "last": "Grzywacz", "suffix": ""}, {"first": "H", "middle": [], "last": "Chen", "suffix": ""}, {"first": "S", "middle": ["A"], "last": "Quandt", "suffix": ""}], "year": 2010, "venue": "EnvironHealth Perspect", "link": "2785030"}, "BIBREF36": {"title": "Validity of self-reported drug use in high risk populations: a meta-analytical review", "authors": [{"first": "S", "middle": [], "last": "Magura", "suffix": ""}, {"first": "S", "middle": ["Y"], "last": "Kang", "suffix": ""}], "year": 1996, "venue": "SubstUseMisuse", "link": "23294636"}, "BIBREF37": {"title": "DNA mutation associated with the human butyrylcholinesterase Kvariant and its linkage to the atypical variant mutation and other polymorphic sites", "authors": [{"first": "C", "middle": ["F"], "last": "Bartels", "suffix": ""}, {"first": "F", "middle": ["S"], "last": "Jensen", "suffix": ""}, {"first": "O", "middle": [], "last": "Lockridge", "suffix": ""}, {"first": "A", "middle": ["F"], "last": "Van Der Spek", "suffix": ""}, {"first": "H", "middle": ["M"], "last": "Rubinstein", "suffix": ""}], "year": 1992, "venue": "AmJHumGenet", "link": "45243298"}}, "ref_entries": {"FIGREF0": {"text": "standard deviation. doi:10.1371/journal.pone.0080505.t001", "type": "figure"}, "TABREF0": {"text": "Characteristics of cocaine-dependent patients and control subjects.", "type": "table"}, "TABREF1": {"text": "", "type": "table"}, "TABREF2": {"text": "", "type": "table"}}}
{"paper_id": "10706468", "_pdf_hash": "cf81d458b84d003483810cf52e5e833ae0ffd672", "abstract": [{"section": "Abstract", "text": "Hypersensitivity pneumonitis is a complex syndrome characterized by a combination of inflammation and fibrosis located in both the airways and the lung parenchyma. Both diagnosis and treatment are a real challenge for physicians. This review will focus on recent developments in this emerging field; furthermore, we will emphasize major gaps in the current knowledge, to stimulate further research in this field.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "The main diagnostic issue is not to miss the entity as the clinical presentation is extremely variable even as the nature of the causal antigen. This article provides an overview of current ways to uncover possible causes of hypersensitivity pneumonitis. A problem of another kind is treatment of this disorder. Crucial in treatment is antigen avoidance, often in combination with immunosuppressive agents. The treatment of acute forms is rather straightforward, but the biggest endeavour, however, is treatment of chronic forms of hypersensitivity pneumonitis, which not always respond to immunosuppressive agents. Therefore, new initiatives should be taken in order to help clinicians in making a proper diagnosis and develop more efficacious treatment especially for patients suffering from chronic hypersensitivity pneumonitis.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Diagnosis and treatment of hypersensitivity pneumonitis remain a real challenge; this article provides an overview of our current understanding and points out new opportunities for further research.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "INTRODUCTION", "text": "Hypersensitivity pneumonitis, also called extrinsic allergic alveolitis is characterized by a combination of inflammation and fibrosis located in both the airways and the lung parenchyma [1] . This field has majorly evolved in the past few years, but a better understanding of diagnosis and treatment is necessary. Epidemiological data are unreliable at present as many patients with hypersensitivity pneumonitis might be erroneously diagnosed with other (idiopathic) fibrotic diseases [2] . The clinical presentation might be extremely variable even as the nature of the causal antigen; therefore, the cause is often concealed. Furthermore, the diagnostic process is hampered by a lot of uncertainties such as the role of specific antibodies and lymphocyte stimulation test, the role of antigen challenge test and the role of bronchoalveolar lavage (BAL) in the diagnosis of hypersensitivity pneumonitis. Other fields that need further research are prognostic factors to guide clinical decision-making and large registries including both acute and chronic hypersensitivity pneumonitis.", "cite_spans": [{"start": 187, "end": 190, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 486, "end": 489, "text": "[2]", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "INTRODUCTION", "text": "A challenge of another kind is treatment of subacute and chronic forms. Next to antigen avoidance, pharmacological treatment still consists of immunosuppressive agents. This is a challenge as some chronic hypersensitivity pneumonitis patients suffer from a relentless progressive fibrosis [3, 4 & ]. Therefore, new initiatives should be taken in order to help clinicians in making a proper diagnosis and Unfortunately, there is no uniform definition for hypersensitivity pneumonitis; however, a few items are commonly applied in former definitions: presence of pulmonary disease and systemic manifestations (weight loss, fever). The cause is an antigen to which the patient is sensitized, but this is not enough to develop lung disease [5, 6] . A clear definition is needed both for daily clinical practice and to boost clinical trials, warranted to improve care and treatment of patients.", "cite_spans": [{"start": 289, "end": 292, "text": "[3,", "ref_id": "BIBREF2"}, {"start": 293, "end": 294, "text": "4", "ref_id": "BIBREF3"}, {"start": 736, "end": 739, "text": "[5,", "ref_id": "BIBREF5"}, {"start": 740, "end": 742, "text": "6]", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "INTRODUCTION", "text": "The clinical behaviour is conventionally classified into acute, subacute and chronic forms; however, there are no widely accepted criteria and it is not sure whether these represent clinical stages of the disease [7, 8] .", "cite_spans": [{"start": 213, "end": 216, "text": "[7,", "ref_id": "BIBREF7"}, {"start": 217, "end": 219, "text": "8]", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "Acute hypersensitivity pneumonitis", "text": "Acute hypersensitivity pneumonitis is a syndrome characterized by fever, chills and diffuse myopathy, which often occur a few hours after exposure. Simultaneously dyspnoea, cough and chest tightness occur, but might be less prominent. Clinical examination reveals bibasilar crackles. The symptoms usually decrease over the course of a few hours or at maximum days. Acute hypersensitivity pneumonitis is thought to result from a significant exposure that makes antigen detection and subsequent avoidance crucial [8] .", "cite_spans": [{"start": 511, "end": 514, "text": "[8]", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "Subacute hypersensitivity pneumonitis", "text": "Usually, subacute hypersensitivity pneumonitis is characterized by an insidious onset of cough and dyspnoea over a few months, which can be difficult to distinguish from another (idiopathic) interstitial lung disease or even an infection. Patients seem to have more pronounced systemic symptoms [8] . It is thought to result from a repeated (low-level) exposure to inhaled antigens.", "cite_spans": [{"start": 295, "end": 298, "text": "[8]", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "Chronic (progressive) hypersensitivity pneumonitis)", "text": "Chronic (progressive) hypersensitivity pneumonitis is assumed to be the result of continuous, low-level exposure to inhaled antigens [9] . Patients present with progressive dyspnoea, dry cough, fatigue and weight loss. This disease is often associated with progressive fibrosis, with a presentation and evolution that is difficult to distinguish from fibrotic nonspecific interstitial pneumonia (NSIP) or idiopathic pulmonary fibrosis (IPF) [10] .", "cite_spans": [{"start": 133, "end": 136, "text": "[9]", "ref_id": "BIBREF9"}, {"start": 441, "end": 445, "text": "[10]", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "Acute exacerbations of chronic hypersensitivity pneumonitis", "text": "Acute exacerbations are well recognized in IPF [11] , but have also been described in hypersensitivity pneumonitis [12] . They are characterized by fast progressive dyspnoea and the occurrence of new bilateral ground-glass opacities on high-resolution computed tomography (HRCT); exclusion of heart failure, infection or pulmonary embolism is mandatory [13] . Risk factors are low total lung capacity of diffusing capacity for carbon monoxide, a usual interstitial pneumonia (UIP)-like pattern on histology and increased neutrophils and decreased lymphocytes in BAL fluid [14] .", "cite_spans": [{"start": 47, "end": 51, "text": "[11]", "ref_id": "BIBREF11"}, {"start": 115, "end": 119, "text": "[12]", "ref_id": "BIBREF12"}, {"start": 353, "end": 357, "text": "[13]", "ref_id": "BIBREF13"}, {"start": 572, "end": 576, "text": "[14]", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "Acute exacerbations of chronic hypersensitivity pneumonitis", "text": "Categorization of hypersensitivity pneumonitis remains artificial; however, studies should be conducted aiming to determine disease behaviour and response to immunosuppressive agents in the individual patient.", "cite_spans": [], "ref_spans": []}, {"section": "EPIDEMIOLOGY", "text": "Epidemiologic data vary according to local practices, geography, season, population studied and host risk factors. A very recent trial reported the annual incidence in Denmark to be lower than one per 100 000 inhabitants [15 && ]. Similar numbers come from Great Britain with incidence rate 0.9 cases per 100 000 person-years [16] . Annual incidence of hypersensitivity pneumonitis in New Mexico was reported to be 30 per 100 000 inhabitants [17] . However, these numbers might not reflect all hypersensitivity pneumonitis cases and more probably hypersensitivity pneumonitis epidemiology data represent only the tip of the iceberg, due to substantial underdiagnosis. Despite diagnostic pitfalls, hypersensitivity pneumonitis was found third most frequent intestitial lung disease (ILD) after IPF and NSIP [15 Also the data on prevalence of hypersensitivity pneumonitis cover a wide range: in the USA, it was estimated to be 420-3000 per 100 000 inhabitants, France 4370 per 100 000 inhabitants and Finland 1400-1700 per 100 000 inhabitants [19] [20] [21] .", "cite_spans": [{"start": 326, "end": 330, "text": "[16]", "ref_id": "BIBREF17"}, {"start": 442, "end": 446, "text": "[17]", "ref_id": "BIBREF18"}, {"start": 806, "end": 809, "text": "[15", "ref_id": "BIBREF15"}, {"start": 1041, "end": 1045, "text": "[19]", "ref_id": "BIBREF20"}, {"start": 1046, "end": 1050, "text": "[20]", "ref_id": "BIBREF21"}, {"start": 1051, "end": 1055, "text": "[21]", "ref_id": "BIBREF22"}], "ref_spans": []}, {"section": "EPIDEMIOLOGY", "text": "Another way of looking at epidemiology is through specific data sorted per individual antigen. The incidence of hypersensitivity pneumonitis among pigeon breeders reaches 6-21% per year and among farmers 0.4-7% per year. But the burden of hypersensitivity pneumonitis might be even much more important as in one report hypersensitivity pneumonitis has been reported to develop in up to 52% exposed office workers (humidifier lung) and 37% lifeguards exposed to public swimming pools [19, 22] .", "cite_spans": [{"start": 483, "end": 487, "text": "[19,", "ref_id": "BIBREF20"}, {"start": 488, "end": 491, "text": "22]", "ref_id": "BIBREF23"}], "ref_spans": []}, {"section": "Pathogenesis", "text": "Pathogenesis of hypersensitivity pneumonitis is currently not fully understood, although the understanding of the different processes has massively increased in the past few years. Some aspects of the disease point to a certain systemic compound. For instance, only a small proportion of individuals exposed to hypersensitivity pneumonitis-associated antigens develop the disease, which raises the possibility that intrinsic factors of the host including genetic susceptibility may play a role [23,24,25 & ]. Other factors might be exposure to various environmental factors and subsequent changes in immune response in vitro and in early postnatal period. Examples are exposure to low doses of formaldehyde during pregnancy and perinatal antibiotics that may lead to alterations in susceptibility to Th2 or Th1/Th17-driven immune response [26 & ]. Furthermore, it has been shown that higher age may predispose to more pronounced fibrotic response [27] . An alternative explanation for the effect of aging might be the associated prolonged exposure to potentially harmful environmental agents or changes in the immune system associated with aging; this is currently not recognized.", "cite_spans": [{"start": 947, "end": 951, "text": "[27]", "ref_id": "BIBREF28"}], "ref_spans": []}, {"section": "Pathogenesis", "text": "The pathogenesis of hypersensitivity pneumonitis with marked inflammatory involvement (more acute forms) and hypersensitivity pneumonitis with dominant fibrotic response (more chronic forms) may also vary. Exposure to inhalation antigen may lead to a proinflammatory response by respiratory epithelial cells with further attraction of neutrophils (producing interferon g that is needed for Th1 immune response) and alveolar macrophages. Apoptosis of neutrophils leads to maturation of dendritic cells, which together with alveolar macrophages act as antigen-presenting cells. Release of interleukin-1, interleukin-12 and interleukin-18 enhances lymphocyte expansion and promotes Th1 differentiation. Profibrotic mechanisms have been less studied. Several mechanisms have been suggested: shift to Th2 cytokine milieu and role of interleukin-4 in fibroproliferation; exhausted antigen-specific T-cell lineage with functional impairment of antigen T-cell response may play an important role. Also bone marrow-derived circulating fibrocytes may participate in the pathogenesis of hypersensitivity pneumonitis by amplifying the inflammatory and fibrotic response [28 & ]. It is clear that the fibrotic response in hypersensitivity pneumonitis patients is different from IPF, as gene profile studies distinguished specific gene signatures in chronic hypersensitivity pneumonitis [29] and multiplex protein profiling in BAL suggested major differences between IPF and chronic hypersensitivity pneumonitis [30] .", "cite_spans": [{"start": 1373, "end": 1377, "text": "[29]", "ref_id": "BIBREF31"}, {"start": 1498, "end": 1502, "text": "[30]", "ref_id": "BIBREF32"}], "ref_spans": []}, {"section": "DIAGNOSIS", "text": "The diagnosis of hypersensitivity pneumonitis is based on a combination of antigen exposure and compatible clinical, laboratory radiologic and pathologic findings, but validated diagnostic criteria are lacking.", "cite_spans": [], "ref_spans": []}, {"section": "DIAGNOSIS", "text": "Crucial is a meticulous history-taking, which should be performed by a clinician highly experienced in identifying relevant antigens. The right diagnosis can only be made by integrating data from history (i.e. exposure), clinical examination, laboratory findings, imaging pulmonary function tests (PFTs), BAL and histopathology. A confident diagnosis can only be achieved in a multidisciplinary discussion [2] .", "cite_spans": [{"start": 406, "end": 409, "text": "[2]", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Antigen detection", "text": "Identification of causative antigen is crucial for diagnosis, preventive measures and prognosis of hypersensitivity pneumonitis; however, this represents a major challenge. Moreover, some cases primarily diagnosed as IPF or idiopathic NSIP might be revealed as undiagnosed hypersensitivity pneumonitis after multidisciplinary discussion [2] .", "cite_spans": [{"start": 337, "end": 340, "text": "[2]", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Antigen detection", "text": "All available tools should be used to detect the source of exposure. The first step is a highly detailed patient's history of exposure both at home and other situations. The investigating physician should have the necessary expertise in identifying all possible sources of sensitizing antigens, which is a challenge, as exposure is extremely specific and the amount of possible causes exponentially grows [31] . The second step is laboratory tests for confirmation of suspect antigen or as screening tool using precipitation reaction against causative antigens [32] and detection of specific immunoglobulin G (IgG) antibodies [33] . A third method is an exposure test that can be performed by exposure to the environment with potential source of antigen or by direct inhalation of the antigens or their mixtures (for instance, purified and diluted derivatives from the dusts or liquids from the workplace) [34 & ].", "cite_spans": [{"start": 405, "end": 409, "text": "[31]", "ref_id": "BIBREF33"}, {"start": 561, "end": 565, "text": "[32]", "ref_id": "BIBREF34"}, {"start": 626, "end": 630, "text": "[33]", "ref_id": "BIBREF35"}], "ref_spans": []}, {"section": "Antigen detection", "text": "There is a long list of potential antigens and there is only a limited number of antigens available for detection (Table 1 ). It would be helpful to have panels of antigens for screening, but the value of these panels should be investigated [35 36] . Moreover, we also miss reliable normal values of the specific IgGs [37] . It is also not known whether longitudinal monitoring of the specific IgGs has a meaning for evaluation of the disease activity or prognosis of the patient.", "cite_spans": [{"start": 245, "end": 248, "text": "36]", "ref_id": "BIBREF40"}, {"start": 318, "end": 322, "text": "[37]", "ref_id": "BIBREF41"}], "ref_spans": [{"start": 114, "end": 122, "text": "(Table 1", "ref_id": "TABREF0"}]}, {"section": "Imaging", "text": "Chest imaging is a crucial part of diagnostic process in hypersensitivity pneumonitis, as this should raise the suspicion of a possible hypersensitivity pneumonitis.", "cite_spans": [], "ref_spans": []}, {"section": "Imaging", "text": "Chest radiograph has almost always in sufficient resolution to recognize the typical changes of hypersensitivity pneumonitis [38] . Acute hypersensitivity pneumonitis can present with ill-defined nodules and areas of ground-glass opacification in both the lungs. In chronic hypersensitivity pneumonitis, reticulation and a honeycomb pattern can be detected.", "cite_spans": [{"start": 125, "end": 129, "text": "[38]", "ref_id": "BIBREF42"}], "ref_spans": []}, {"section": "Imaging", "text": "HRCT has substantially better resolution to distinguish and define the typical changes. Hypersensitivity pneumonitis presents as ground-glass opacification, centrilobular nodules, air trapping (mosaic pattern), fibrosis, emphysema and often a combination of patterns [39, 40] (Fig. 1) . For prognostic reasons, hypersensitivity pneumonitis can be subdivided into two radiological subtypes: fibrotic and nonfibrotic hypersensitivity pneumonitis. The presence and the extent of fibrosis on computed tomography are associated with increased mortality [41] . Moreover, the severity of traction bronchiectasis and extent of honeycombing are powerful predictors of mortality in chronic hypersensitivity pneumonitis. In the study of Walsh et al. [42] , scoring system for estimating prognosis of hypersensitivity pneumonitis was used. It comprised whole disease extent, ground-glass opacification, fine and coarse reticulation, honeycombing, emphysema and consolidation. The authors concluded that HRCT patterns, in particular, severity of traction bronchiectasis and extent of honeycombing, are superior to PFTs for predicting mortality in patients with hypersensitivity pneumonitis. Differentiation of NSIP and IPF is difficult; if lobular areas with decreased attenuation and vascularity, centrilobular nodules and absence of lower zone predominance are present, chronic hypersensitivity pneumonitis is more likely (Fig. 2 ) [43] .", "cite_spans": [{"start": 267, "end": 271, "text": "[39,", "ref_id": "BIBREF43"}, {"start": 272, "end": 275, "text": "40]", "ref_id": "BIBREF44"}, {"start": 548, "end": 552, "text": "[41]", "ref_id": "BIBREF45"}, {"start": 739, "end": 743, "text": "[42]", "ref_id": "BIBREF46"}, {"start": 1421, "end": 1425, "text": "[43]", "ref_id": "BIBREF47"}], "ref_spans": [{"start": 276, "end": 284, "text": "(Fig. 1)", "ref_id": "FIGREF0"}, {"start": 1411, "end": 1418, "text": "(Fig. 2", "ref_id": "FIGREF1"}]}, {"section": "Pulmonary function tests", "text": "In acute hypersensitivity pneumonitis, PFTs might be normal [44] ; however, PFT are often characterized by a restrictive pattern and a decreased diffusing capacity for carbon monoxide. In some patients with farmer's lung, an obstructive pattern might be present, resulting from emphysema. The role of PFTs is mainly to determine the severity of the functional impairment both at diagnosis and at follow-up [7] ; however, serial PFT data are sparse.", "cite_spans": [{"start": 60, "end": 64, "text": "[44]", "ref_id": "BIBREF48"}, {"start": 406, "end": 409, "text": "[7]", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "Bronchoalveolar lavage", "text": "However, BAL is not recommended routinely in the diagnosis of IPF, it is considered a highly sensitive method to evaluate lung inflammation in a patient suspected of having hypersensitivity pneumonitis [7] . In acute forms of hypersensitivity pneumonitis, an increase in both total cell count and percentage lymphocytes is usually found [7] . In chronic forms, BAL fluid lymphocyte count is lower or can even be normal. Lymphocyte count might also be influenced by age, smoking status and the use of corticosteroids [9, 45, 46] . A low T4/T8 ratio has been pathognomonic for hypersensitivity pneumonitis; however, this is not absolute [47, 48] . The main discussion is raised by the inflammatory pattern (elevated lymphocyte count) in BAL fluid becoming less prominent the more fibrotic the disease becomes [49 && ]. The cutoff for lymphocyte count also differs, but 30% is often used. However, in patients with hypersensitivity pneumonitis with a UIP pattern, lymphocyte count is lower than 30% [50, 51] . More than 80% of chronic hypersensitivity pneumonitis patients have at least 20% lymphocytes in BAL fluid [52, 53] . Also in the follow-up, BAL might be useful as persistent BAL fluid abnormalities may indicate that complete avoidance has not been achieved [1] .", "cite_spans": [{"start": 202, "end": 205, "text": "[7]", "ref_id": "BIBREF7"}, {"start": 337, "end": 340, "text": "[7]", "ref_id": "BIBREF7"}, {"start": 516, "end": 519, "text": "[9,", "ref_id": "BIBREF9"}, {"start": 520, "end": 523, "text": "45,", "ref_id": "BIBREF49"}, {"start": 524, "end": 527, "text": "46]", "ref_id": "BIBREF50"}, {"start": 635, "end": 639, "text": "[47,", "ref_id": "BIBREF51"}, {"start": 640, "end": 643, "text": "48]", "ref_id": "BIBREF52"}, {"start": 996, "end": 1000, "text": "[50,", "ref_id": "BIBREF54"}, {"start": 1001, "end": 1004, "text": "51]", "ref_id": "BIBREF55"}, {"start": 1113, "end": 1117, "text": "[52,", "ref_id": "BIBREF56"}, {"start": 1118, "end": 1121, "text": "53]", "ref_id": "BIBREF57"}, {"start": 1264, "end": 1267, "text": "[1]", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "Bronchoalveolar lavage", "text": "So it is clear that an elevated lymphocyte count in a patient with suspected UIP warrants thorough investigation to rule out chronic hypersensitivity pneumonitis. But a more comprehensive approach toward interpretation of BAL fluid is urgently necessary.", "cite_spans": [], "ref_spans": []}, {"section": "Histopathology", "text": "Histopathological evaluation is another crucial element in the multidisciplinary diagnosis. This is needed in case when antigen exposure is missing and/or when radiologic findings are not typical for hypersensitivity pneumonitis. Not all patients are able or willing to have a surgical biopsy, which leads to major diagnostic uncertainty. Recent developments show promising results for transbronchial cryobiopsy in the diagnosis of ILD [54] , although further confirmation of sensitivity and specificity is necessary. In the more acute form of the disease, the typical histopathologic changes comprise lymphocytic alveolitis with bronchiolocentric accentuation, non-necrotizing epitheloid cell granulomas, intraalveolar fibrosis and cellular bronchiolitis [55] . On the contrary, in chronic hypersensitivity pneumonitis, the morphologic features are not always specific to be diagnostic for hypersensitivity pneumonitis: UIP-like patterns can be observed, even as NSIP-like patterns with peribronchial distribution, mild alveolitis/bronchiolitis and limited granuloma formation [51] . In most cases, the histopathologic findings might suggest the diagnosis of chronic hypersensitivity pneumonitis, but as the differential with fibrotic NSIP and IPF should be thoroughly made, the definite diagnosis should be resulting from a multidisciplinary team discussion. UIP-like pattern exhibits the worst survival in chronic hypersensitivity pneumonitis patients [51, 56, 57] .", "cite_spans": [{"start": 436, "end": 440, "text": "[54]", "ref_id": "BIBREF58"}, {"start": 756, "end": 760, "text": "[55]", "ref_id": "BIBREF59"}, {"start": 1078, "end": 1082, "text": "[51]", "ref_id": "BIBREF55"}, {"start": 1455, "end": 1459, "text": "[51,", "ref_id": "BIBREF55"}, {"start": 1460, "end": 1463, "text": "56,", "ref_id": "BIBREF60"}, {"start": 1464, "end": 1467, "text": "57]", "ref_id": "BIBREF61"}], "ref_spans": []}, {"section": "Current diagnostic criteria", "text": "The diagnosis of hypersensitivity pneumonitis and more particular chronic hypersensitivity pneumonitis is difficult and as a result often missed. The diagnosis should be kept in mind when there is evidence of exposure to a relevant antigen. A relation between (start of) exposure and onset of symptoms is useful. In this regard, serum IgG/precipitins can be of help and in some instances challenge tests could be considered. In addition, BAL can provide more evidence for hypersensitivity pneumonitis. However, if the diagnosis is more difficult, surgical lung biopsy might be mandatory [58] . The use of lymphocytic transformation test should be considered in specific situations, for example if beryllium exposure is expected [59] . Specific inhalation testing has been described in a recent article suggesting that a positive test could be helpful in the diagnosis, whereas a negative test could not rule out hypersensitivity pneumonitis [60 && ]. In conclusion, an appropriate diagnosis of hypersensitivity pneumonitis is extremely complex, information of different levels should be integrated (clinical, radiologic, laboratory, histopathological data) and even then the diagnosis is often missed.", "cite_spans": [{"start": 587, "end": 591, "text": "[58]", "ref_id": "BIBREF62"}, {"start": 728, "end": 732, "text": "[59]", "ref_id": "BIBREF63"}], "ref_spans": []}, {"section": "Treatment", "text": "Sustained antigen exposure is associated with adverse outcome in many cases, so antigen avoidance is the main action, highlighting the importance of identifying hypersensitivity pneumonitis and uncovering the causal antigen in a certain patient. Another important issue is that the disease might relentlessly progress despite discontinuation of exposure. Next to prevention, the mainstay of pharmacological treatment is anti-inflammatory treatment (corticosteroids alone or in combination with immunosuppressive drugs), which might affect the disease course in few patients, especially in those with acute and subacute forms of the disease. However, it has become clear that more chronic forms do not always respond as well as expected.", "cite_spans": [], "ref_spans": []}, {"section": "Treatment", "text": "Prevention is important, not only for the patient but also for sensitized individuals exposed to the same antigens without signs of the disease yet, to avoid them developing hypersensitivity pneumonitis in future. Also changes in the industrial or agricultural process might be imposed (introduction of full face masks, regular measurements of air quality, . . .) or the patient is advised to avoid exposure by all means (change work post or even profession).", "cite_spans": [], "ref_spans": []}, {"section": "PHARMACOLOGICAL THERAPY", "text": "The mainstay of treatment in hypersensitivity pneumonitis is corticosteroids, based on a randomized, double-blind, placebo-controlled study in acute farmer's lung. The authors have shown that patients given prednisolone showed more rapid improvement in lung function and a significantly higher diffusing capacity at 1 month compared with the control group. However, there was no difference in the long-term outcome between the two groups [61] .", "cite_spans": [{"start": 438, "end": 442, "text": "[61]", "ref_id": "BIBREF66"}], "ref_spans": []}, {"section": "PHARMACOLOGICAL THERAPY", "text": "Interestingly, recurrence of acute farmer's lung was more common among corticosteroid-treated patients who had continuing antigen exposure, raising the possibility that corticosteroid treatment was also suppressing the counterregulatory aspects of the immune response in these patients.", "cite_spans": [], "ref_spans": []}, {"section": "PHARMACOLOGICAL THERAPY", "text": "Determination of dose and duration of systemic immunosuppressive drugs is still not really established. The empiric scheme that is suggested is 0.5 mg/kg/day of prednisolone for 4-6 weeks followed by a gradual reduction until maintenance dose of approximately 10 mg/day [62] . Some authors suggest for a (sub)acute form of hypersensitivity pneumonitis between 3 and 6 months of treatment duration to achieve disease remission [7] . Usually, it is thought that for chronic forms, corticosteroids should be continued for a longer time.", "cite_spans": [{"start": 270, "end": 274, "text": "[62]", "ref_id": "BIBREF67"}, {"start": 426, "end": 429, "text": "[7]", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "PHARMACOLOGICAL THERAPY", "text": "A pragmatic approach is used in several experienced centres. In case the extent of the pulmonary involvement is mild, the patient has almost no symptoms and a causal antigen has been identified, prevention is crucial and steroids could be avoided. This approach should be further evaluated in specific clinical trials.", "cite_spans": [], "ref_spans": []}, {"section": "PHARMACOLOGICAL THERAPY", "text": "The more inflammation is prominent, the better the effect of anti-inflammatory drugs can be anticipated; however, in more chronic forms, fibrosis might be the main driving mechanism. Therefore, the effect of anti-inflammatory treatment in these cases cannot be overestimated, as suggested by Fink et al. [63] and has been recently confirmed in an Asian population [9, 64] . This is supported by the findings of several articles that steroids seem not to alter the long-term course of the disease as shown in patients with farmer's lung [65, 66] . In order to find a solution for patients with relentless fibrotic forms of hypersensitivity pneumonitis, not responding to classical immunosuppression, we should urgently develop new clinical trials with antifibrotic agents that have shown efficacy in IPF. One of the key questions of the design of such trials is whether they will be performed with anti-inflammatory or antifibrotic agents or their combination [67 & ].", "cite_spans": [{"start": 304, "end": 308, "text": "[63]", "ref_id": "BIBREF68"}, {"start": 364, "end": 367, "text": "[9,", "ref_id": "BIBREF9"}, {"start": 368, "end": 371, "text": "64]", "ref_id": "BIBREF69"}, {"start": 536, "end": 540, "text": "[65,", "ref_id": "BIBREF70"}, {"start": 541, "end": 544, "text": "66]", "ref_id": "BIBREF71"}], "ref_spans": []}, {"section": "Prognosis", "text": "Data concerning mortality trends are scarce in the literature. In England and Wales from 1968 to 2008, 878 deaths due to hypersensitivity pneumonitis were reported and increased in time from a first period (1968) (1969) (1970) (1971) (1972) ) to a later period (2005) (2006) (2007) (2008) . Mortality was higher in men and with increasing age [68] . In the recent Danish cohort, 5-year survival in the hypersensitivity pneumonitis group was 93% [15 && ]. An interesting finding is that depending on the causative antigen, the prognosis seems to differ as there are some data suggesting that bird fancier's hypersensitivity pneumonitis might have a worse prognosis than farmer's lung. This might be because of the fact that patients with established fibrosis on HRCT and/or surgical lung biopsy have a poorer prognosis [50, 69, 70] .", "cite_spans": [{"start": 343, "end": 347, "text": "[68]", "ref_id": "BIBREF74"}, {"start": 818, "end": 822, "text": "[50,", "ref_id": "BIBREF54"}, {"start": 823, "end": 826, "text": "69,", "ref_id": "BIBREF75"}, {"start": 827, "end": 830, "text": "70]", "ref_id": "BIBREF76"}], "ref_spans": []}, {"section": "Prognosis", "text": "The prognoses of other varieties of hypersensitivity pneumonitis are less well described; this is another unexplored field with a high unmet need, even as the use of biomarkers that might be helpful in determining prognosis.", "cite_spans": [], "ref_spans": []}, {"section": "Prognosis", "text": "Another problem is that acute forms seem to be more easily diagnosed, which might lead to underreporting of more chronic cases that have a worse prognosis. This may lead to an overestimation of real life survival. A possible way to get more insight in this problem is the start of new registries to help us solve these questions.", "cite_spans": [], "ref_spans": []}, {"section": "CONCLUSION", "text": "In conclusion, we can state that hypersensitivity pneumonitis seems to be much more prevalent than initially thought as there is no clear definition and differential diagnosis is challenging in unexperienced hands. There is an urgent need for better definition, diagnostic criteria setting and validation (including panels of IgG) and closer collaboration with occupational physicists. Imaging is important and, if not specific, histopathology is of real help if possible. BAL cell analysis can be helpful when an integration is done in a multidisciplinary discussion. Further research is warranted to develop prognostic markers that can drive clinical decisionmaking even as worldwide registers to increase our knowledge on evolution of the different disease forms.", "cite_spans": [], "ref_spans": []}, {"section": "Perspective for the future", "text": "Although treatment is rather easy for acute forms, it is a real challenge for more fibrotic chronic forms. Here it is crucial to start new trials to find more efficacious ways of treating those patients.", "cite_spans": [], "ref_spans": []}, {"section": "Perspective for the future", "text": "However, the future for hypersensitivity pneumonitis patients might look brighter, as with the rapidly expanding programmes on genotyping, proteomics and biomarkers which are being put into position, the field will not be alike in 10 years from now. ", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Chronic hypersensitivity pneumonitis", "authors": [{"first": "U", "middle": [], "last": "Costabel", "suffix": ""}, {"first": "F", "middle": [], "last": "Bonella", "suffix": ""}, {"first": "J", "middle": [], "last": "Guzman", "suffix": ""}], "year": 2012, "venue": "Clin Chest Med", "link": "31065802"}, "BIBREF1": {"title": "Chronic hypersensitivity pneumonitis in patients diagnosed with idiopathic pulmonary fibrosis: a prospective casecohort study", "authors": [{"first": "F", "middle": [], "last": "Morell", "suffix": ""}, {"first": "A", "middle": [], "last": "Villar", "suffix": ""}, {"first": "M", "middle": ["\u00c1"], "last": "Montero", "suffix": ""}], "year": 2013, "venue": "Lancet Respir Med", "link": "20550727"}, "BIBREF2": {"title": "Rold\u00e1 n I. Immunopathology, diagnosis, and management of hypersensitivity pneumonitis", "authors": [{"first": "M", "middle": [], "last": "Selman", "suffix": ""}, {"first": "-", "middle": [], "last": "Buend\u00eda", "suffix": ""}], "year": 2012, "venue": "Semin Respir Crit Care Med", "link": null}, "BIBREF3": {"title": "A comparison of health-related quality of life in idiopathic pulmonary fibrosis and chronic hypersensitivity pneumonitis", "authors": [{"first": "M", "middle": [], "last": "&amp; Lubin", "suffix": ""}, {"first": "H", "middle": [], "last": "Chen", "suffix": ""}, {"first": "B", "middle": [], "last": "Elicker", "suffix": ""}], "year": 2014, "venue": "Chest", "link": null}, "BIBREF4": {"title": "This article is one of the sparse articles that describes quality of life not only in IPF but also in hypersensitivity pneumonitis", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF5": {"title": "Needs and opportunities for research in hypersensitivity pneumonitis", "authors": [{"first": "J", "middle": ["N"], "last": "Fink", "suffix": ""}, {"first": "H", "middle": ["G"], "last": "Ortega", "suffix": ""}, {"first": "H", "middle": ["Y"], "last": "Reynolds", "suffix": ""}], "year": 2005, "venue": "Am J Respir Crit Care Med", "link": "27874639"}, "BIBREF6": {"title": "Clinical diagnosis of hypersensitivity pneumonitis", "authors": [{"first": "Y", "middle": [], "last": "Lacasse", "suffix": ""}, {"first": "M", "middle": [], "last": "Selman", "suffix": ""}, {"first": "U", "middle": [], "last": "Costabel", "suffix": ""}], "year": 2003, "venue": "Am J Respir Crit Care Med", "link": "6285983"}, "BIBREF7": {"title": "Hypersensitivity pneumonitis: insights in diagnosis and pathobiology", "authors": [{"first": "M", "middle": [], "last": "Selman", "suffix": ""}, {"first": "A", "middle": [], "last": "Pardo", "suffix": ""}, {"first": "T", "middle": ["E"], "last": "King", "suffix": ""}], "year": 2012, "venue": "Am J Respir Crit Care Med", "link": "36000458"}, "BIBREF8": {"title": "Hypersensitivity pneumonitis", "authors": [{"first": "S", "middle": [], "last": "Oshimo", "suffix": ""}, {"first": "F", "middle": [], "last": "Bonella", "suffix": ""}, {"first": "J", "middle": [], "last": "Guzman", "suffix": ""}, {"first": "U", "middle": [], "last": "Costabel", "suffix": ""}], "year": 2012, "venue": "Immunol Allergy Clin N Am", "link": null}, "BIBREF9": {"title": "Clinical features of recurrent and insidious chronic bird fancier's lung", "authors": [{"first": "Y", "middle": [], "last": "Ohtani", "suffix": ""}, {"first": "S", "middle": [], "last": "Saiki", "suffix": ""}, {"first": "Y", "middle": [], "last": "Sumi", "suffix": ""}], "year": 2003, "venue": "Ann Allergy Athma Immunol", "link": "23249483"}, "BIBREF10": {"title": "Chronic hypersensitivity pneumonitis", "authors": [{"first": "A", "middle": [], "last": "Churg", "suffix": ""}, {"first": "N", "middle": ["L"], "last": "Muller", "suffix": ""}, {"first": "J", "middle": [], "last": "Flint", "suffix": ""}, {"first": "J", "middle": ["L"], "last": "Wright", "suffix": ""}], "year": 2006, "venue": "Am J surg pathol", "link": "20448523"}, "BIBREF11": {"title": "Acute exacerbation of idiopathic pulmonary fibrosis: a clinical review", "authors": [{"first": "F", "middle": [], "last": "Luppi", "suffix": ""}, {"first": "S", "middle": [], "last": "Cerri", "suffix": ""}, {"first": "S", "middle": [], "last": "Taddei", "suffix": ""}], "year": 2015, "venue": "Intern Emerg Med", "link": "29242073"}, "BIBREF12": {"title": "Acute exacerbations of interstitial lung diseases", "authors": [{"first": "I", "middle": ["C"], "last": "Papanikolaou", "suffix": ""}, {"first": "F", "middle": [], "last": "Drakopanagiotakis", "suffix": ""}, {"first": "V", "middle": ["S"], "last": "Polychronopoulos", "suffix": ""}], "year": 2010, "venue": "Curr Opin Pulm Med", "link": "23488657"}, "BIBREF13": {"title": "Acute exacerbations of fibrotic hypersensitivity pneumonitis: a case series", "authors": [{"first": "A", "middle": ["L"], "last": "Olson", "suffix": ""}, {"first": "T", "middle": ["J"], "last": "Huie", "suffix": ""}, {"first": "S", "middle": ["D"], "last": "Groshong", "suffix": ""}], "year": 2008, "venue": "Chest", "link": "5191537"}, "BIBREF14": {"title": "Clinical predictors and histologic appearance of acute exacerbations in chronic hypersensitivity pneumonitis", "authors": [{"first": "Y", "middle": [], "last": "Miyazaki", "suffix": ""}, {"first": "T", "middle": [], "last": "Tateishi", "suffix": ""}, {"first": "T", "middle": [], "last": "Akashi", "suffix": ""}], "year": 2008, "venue": "Chest", "link": "28672756"}, "BIBREF15": {"title": "A cohort study of interstitial lung diseases in central Denmark", "authors": [{"first": "C", "middle": [], "last": "&amp;&amp; Hyldgaard", "suffix": ""}, {"first": "O", "middle": [], "last": "Hilberg", "suffix": ""}, {"first": "A", "middle": [], "last": "Muller", "suffix": ""}, {"first": "E", "middle": [], "last": "Bendstrup", "suffix": ""}], "year": 2014, "venue": "Respir Med", "link": "25735898"}, "BIBREF16": {"title": "This article represents a high-quality registry, which provides us with real-life data with a diagnosis based on the current diagnostic criteria", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF17": {"title": "Extrinsic allergic alveolitis: incidence and mortality in the general population", "authors": [{"first": "M", "middle": [], "last": "Solaymani-Dodaran", "suffix": ""}, {"first": "J", "middle": [], "last": "West", "suffix": ""}, {"first": "C", "middle": [], "last": "Smith", "suffix": ""}, {"first": "R", "middle": [], "last": "Hubbard", "suffix": ""}], "year": 2007, "venue": "QJM", "link": "7646507"}, "BIBREF18": {"title": "The epidemiology of interstitial lung diseases", "authors": [{"first": "D", "middle": ["B"], "last": "Coultas", "suffix": ""}, {"first": "R", "middle": ["E"], "last": "Zumwalt", "suffix": ""}, {"first": "W", "middle": ["C"], "last": "Black", "suffix": ""}], "year": 1994, "venue": "Am J Respir Crit Care Med", "link": "6647848"}, "BIBREF19": {"title": "Diagnostic approach to interstitial pneumonias in a single centre: report on 88 cases", "authors": [{"first": "D", "middle": [], "last": "Theegarten", "suffix": ""}, {"first": "H", "middle": ["M"], "last": "Muller", "suffix": ""}, {"first": "F", "middle": [], "last": "Bonella", "suffix": ""}], "year": 2012, "venue": "Diagn Pathol", "link": "10257902"}, "BIBREF20": {"title": "Lifeguard lung': endemic granulomatous pneumonitis in an indoor swimming pool", "authors": [{"first": "C", "middle": ["S"], "last": "Rose", "suffix": ""}, {"first": "J", "middle": ["W"], "last": "Martyny", "suffix": ""}, {"first": "L", "middle": ["S"], "last": "Newman", "suffix": ""}], "year": 1998, "venue": "Am J Public Health", "link": "29851699"}, "BIBREF21": {"title": "The prevalence of farmer?s lung in an agricultural population", "authors": [{"first": "D", "middle": [], "last": "Madsen", "suffix": ""}, {"first": "L", "middle": ["E"], "last": "Klock", "suffix": ""}, {"first": "F", "middle": ["J"], "last": "Wenzel", "suffix": ""}], "year": 1976, "venue": "Am Rev Respir Dis", "link": "2333408"}, "BIBREF22": {"title": "Epidemiological study of farmer?s lung in five districts of the French Doubs province", "authors": [{"first": "A", "middle": [], "last": "Depierre", "suffix": ""}, {"first": "J", "middle": ["C"], "last": "Dalphin", "suffix": ""}, {"first": "D", "middle": [], "last": "Pernet", "suffix": ""}], "year": 1988, "venue": "Thorax", "link": "2518198"}, "BIBREF23": {"title": "Humifider lung: an outbreak in office workers", "authors": [{"first": "M", "middle": [], "last": "Ganier", "suffix": ""}, {"first": "P", "middle": [], "last": "Lieberman", "suffix": ""}, {"first": "J", "middle": [], "last": "Fink", "suffix": ""}, {"first": "D", "middle": ["G"], "last": "Lockwood", "suffix": ""}], "year": 1980, "venue": "Chest", "link": null}, "BIBREF24": {"title": "PSMB8 (LMP7) but not PSMB9 (LMP2) gene polymorphisms are associated to pigeon breeder?s hypersensitivity pneumonitis", "authors": [{"first": "A", "middle": [], "last": "Camarena", "suffix": ""}, {"first": "A", "middle": [], "last": "Aquino-Galvez", "suffix": ""}, {"first": "R", "middle": [], "last": "Falf\u00e1 N-Valencia", "suffix": ""}], "year": 2010, "venue": "Respir Med", "link": "25551980"}, "BIBREF25": {"title": "A familial history of pulmonary fibrosis in patients with chronic hypersensitivity pneumonitis", "authors": [{"first": "T", "middle": [], "last": "Okamoto", "suffix": ""}, {"first": "Y", "middle": [], "last": "Miyazaki", "suffix": ""}, {"first": "M", "middle": [], "last": "Tomita", "suffix": ""}], "year": 2013, "venue": "Respiration", "link": "24093506"}, "BIBREF26": {"title": "Perinatal antibiotic-induced shifts in gut microbiota have differential effect on inflammatory lung diseases", "authors": [{"first": "S", "middle": ["L"], "last": "Russell", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Gold", "suffix": ""}, {"first": "L", "middle": ["A"], "last": "Reynolds", "suffix": ""}], "year": 2015, "venue": "J Allergy Clin Immunol", "link": "22033713"}, "BIBREF27": {"title": "Not only genetic background but also environmental factors play an important role to determine whether or not an individual develops hypersensitivity pneumonitis", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF28": {"title": "Age influence on hypersensitivity pneumonitis induced in mice by exposure to Pantoea agglomerans", "authors": [{"first": "M", "middle": ["K"], "last": "Lemieszek", "suffix": ""}, {"first": "M", "middle": [], "last": "Chilosi", "suffix": ""}, {"first": "M", "middle": [], "last": "Golec", "suffix": ""}], "year": 2013, "venue": "Inhal Toxicol", "link": "207483855"}, "BIBREF29": {"title": "Fibrocytes contribute to inflammation and fibrosis in chronic hypersensitivity pneumonitis through paracrine effects", "authors": [{"first": "&amp;", "middle": [], "last": "Garcia-De-Alba", "suffix": ""}, {"first": "C", "middle": [], "last": "Buendia-Rold\u00e1 N I", "suffix": ""}, {"first": "A", "middle": [], "last": "Salgato", "suffix": ""}], "year": 2015, "venue": "Am J Respir Crit Care Med", "link": "207709238"}, "BIBREF30": {"title": "This article is an outstanding work unravelling crucial pathways leading to fibrosis in chronic hypersensitivity pneumonitis", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF31": {"title": "Gene expression profiles distinguish idiopathic pulmonary fibrosis from hypersensitivity pneumonitis", "authors": [{"first": "M", "middle": [], "last": "Selman", "suffix": ""}, {"first": "A", "middle": [], "last": "Pardo", "suffix": ""}, {"first": "L", "middle": [], "last": "Barrera", "suffix": ""}], "year": 2006, "venue": "Am J Respir Crit Care Med", "link": null}, "BIBREF32": {"title": "Multiplex protein profiling of bronchoalveolar lavage in idiopathic pulmonary fibrosis and hypersensitivity pneumonitis", "authors": [{"first": "S", "middle": [], "last": "Wilems", "suffix": ""}, {"first": "S", "middle": ["E"], "last": "Verleden", "suffix": ""}, {"first": "B", "middle": [], "last": "Vanaudenaerde", "suffix": ""}], "year": 2013, "venue": "Ann Thorac Med", "link": "8255658"}, "BIBREF33": {"title": "Newly recognized occupational and environmental causes of chronic terminal airways and parenchymal lung disease", "authors": [{"first": "M", "middle": [], "last": "Sauler", "suffix": ""}, {"first": "M", "middle": [], "last": "Gulati", "suffix": ""}], "year": 2012, "venue": "Clin Chest Med", "link": "25913734"}, "BIBREF34": {"title": "Use of co-immunoelectrodiffusion to detect presumed disease-associated precipitating antibodies, and timecourse value of specific isotypes in bird-breeder's disease", "authors": [{"first": "D", "middle": [], "last": "Toubas", "suffix": ""}, {"first": "Aubert", "middle": ["D"], "last": "Villena", "suffix": ""}, {"first": "I", "middle": [], "last": "", "suffix": ""}], "year": 2003, "venue": "J Immunol Methods", "link": "26172121"}, "BIBREF35": {"title": "Qualitative and quantitative evaluation of bird-specific IgG antibodies", "authors": [{"first": "A", "middle": ["L"], "last": "Lopata", "suffix": ""}, {"first": "M", "middle": [], "last": "Schinkel", "suffix": ""}, {"first": "P", "middle": ["C"], "last": "Potter", "suffix": ""}], "year": 2004, "venue": "Int Arch Allergy Immunol", "link": "22503649"}, "BIBREF36": {"title": "Detection of indoor and outdoor avian antigen in management of bird-related hypersensitivity pneumonitis", "authors": [{"first": "J", "middle": [], "last": "Kuramochi", "suffix": ""}, {"first": "N", "middle": [], "last": "Inase", "suffix": ""}, {"first": "K", "middle": [], "last": "Takayama", "suffix": ""}], "year": 2010, "venue": "Allergology International", "link": "73880740"}, "BIBREF37": {"title": "This article compares proteins in BAL in IPF and (chronic) hypersensitivity", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF38": {"title": "Immunoproteomics for serological diagnosis of hypersensitivity pneumonitis caused by environmental microorganisms", "authors": [{"first": "L", "middle": [], "last": "Millon", "suffix": ""}, {"first": "G", "middle": [], "last": "Reboux", "suffix": ""}, {"first": "C", "middle": [], "last": "Barrera", "suffix": ""}], "year": 2014, "venue": "Curr Protein Pept Sci", "link": "28417605"}, "BIBREF39": {"title": "An excellent article on serological diagnosis of hypersensitivity pneumonitis", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF40": {"title": "Immuno-reactive proteins from Mycobacterium immunogenum useful for serodiagnosis of metalworking fluid hypersensitivity pneumonitis", "authors": [{"first": "S", "middle": [], "last": "Roussel", "suffix": ""}, {"first": "B", "middle": [], "last": "Rognon", "suffix": ""}, {"first": "C", "middle": [], "last": "Barrera", "suffix": ""}], "year": 2011, "venue": "Int J Med Microbiol", "link": "34022637"}, "BIBREF41": {"title": "Hypersensitivity pneumonitis and metalworking fluids contaminated by mycobacteria", "authors": [{"first": "Tillie-Leblond I", "middle": [], "last": "Grenouillet", "suffix": ""}, {"first": "F", "middle": [], "last": "Reboux", "suffix": ""}, {"first": "G", "middle": [], "last": "", "suffix": ""}], "year": 2011, "venue": "Eur Respir J", "link": "348436"}, "BIBREF42": {"title": "Chest X-rays in hypersensitivitypneumonitis: a metaanalysis of secular trend", "authors": [{"first": "M", "middle": ["J"], "last": "Hodgson", "suffix": ""}, {"first": "D", "middle": ["K"], "last": "Parkinson", "suffix": ""}, {"first": "M", "middle": [], "last": "Karpf", "suffix": ""}], "year": 1989, "venue": "Am J Ind Med", "link": "37557172"}, "BIBREF43": {"title": "Clinical and radiologic manifestations of hypersensitivity pneumonitis", "authors": [{"first": "C", "middle": ["S"], "last": "Glazer", "suffix": ""}, {"first": "C", "middle": ["S"], "last": "Rose", "suffix": ""}, {"first": "D", "middle": ["A"], "last": "Lynch", "suffix": ""}], "year": 2002, "venue": "J Thorac Imaging", "link": "22597802"}, "BIBREF44": {"title": "Hypersesnsitivity pneumonitis: spectrum of high-resolution CT and pathologic findings", "authors": [{"first": "Cis", "middle": [], "last": "Siklva", "suffix": ""}, {"first": "A", "middle": [], "last": "Churg", "suffix": ""}, {"first": "N", "middle": ["L"], "last": "Muller", "suffix": ""}], "year": 2007, "venue": "Am J Roentgenol", "link": "9651941"}, "BIBREF45": {"title": "High-resolution CT findings of parenchymal fibrosis correlate with prognosis in hypersensitivity pneumonitis", "authors": [{"first": "V", "middle": [], "last": "Hanak", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Golbin", "suffix": ""}, {"first": "T", "middle": [], "last": "Hartman", "suffix": ""}, {"first": "J", "middle": ["H"], "last": "Ryu", "suffix": ""}], "year": 2008, "venue": "Chest", "link": "7949997"}, "BIBREF46": {"title": "Chronic hypersensitivity pneumonitis: high resolution computed tomography patterns and pulmonary function indices as prognostic determinants", "authors": [{"first": "S", "middle": ["L"], "last": "Walsh", "suffix": ""}, {"first": "N", "middle": [], "last": "Sverzellati", "suffix": ""}, {"first": "A", "middle": [], "last": "Devaraj", "suffix": ""}], "year": 2012, "venue": "Eur Radiol", "link": "12252328"}, "BIBREF47": {"title": "Chronic hypersensitivity pneumonitis: differentiation from idiopathic pulmonary fibrosis and nonspecific interstitial pneumonia by using thin-section CT", "authors": [{"first": "C", "middle": ["I"], "last": "Silva", "suffix": ""}, {"first": "N", "middle": ["L"], "last": "Muller", "suffix": ""}, {"first": "D", "middle": ["A"], "last": "Lynch", "suffix": ""}], "year": 2008, "venue": "Radiology", "link": "40941216"}, "BIBREF48": {"title": "Hypersensitivity pneumonitis: sensitivity of high-resolution CT in a population based study", "authors": [{"first": "D", "middle": ["A"], "last": "Lynch", "suffix": ""}, {"first": "C", "middle": ["S"], "last": "Rose", "suffix": ""}, {"first": "D", "middle": [], "last": "Way", "suffix": ""}, {"first": "T", "middle": ["E"], "last": "King", "suffix": ""}], "year": 1992, "venue": "Am J Rontgenol", "link": "33570233"}, "BIBREF49": {"title": "Morphologic diversity of chronic pigeon breeder's disease: clinical features and survival", "authors": [{"first": "M", "middle": [], "last": "Gaxiola", "suffix": ""}, {"first": "I", "middle": [], "last": "Buendia-Roldan", "suffix": ""}, {"first": "M", "middle": [], "last": "Mejia", "suffix": ""}], "year": 2011, "venue": "Respir Med", "link": "25369999"}, "BIBREF50": {"title": "Subacute and chronic bird breeder hypersensitivity pneumonitis: sequential evaluation with CT and correlation with lung function tests and bronchoalveolar lavage", "authors": [{"first": "M", "middle": [], "last": "Remy-Jardin", "suffix": ""}, {"first": "Remy", "middle": ["J"], "last": "Wallaert", "suffix": ""}, {"first": "B", "middle": [], "last": "M\u00fc Ller", "suffix": ""}, {"first": "N", "middle": ["L"], "last": "", "suffix": ""}], "year": 1993, "venue": "Radiology", "link": "19378189"}, "BIBREF51": {"title": "An official American Thoracic Society clinical practice guideline: the clinical utility of bronchoalveolar lavage cellular analysis in interstitial lung disease", "authors": [{"first": "K", "middle": ["C"], "last": "Meyer", "suffix": ""}, {"first": "G", "middle": [], "last": "Raghu", "suffix": ""}, {"first": "R", "middle": ["P"], "last": "Baughman", "suffix": ""}], "year": 2012, "venue": "Am J Respir Crit Care Med", "link": "45106771"}, "BIBREF52": {"title": "The clinical utility of bronchoalveolar lavage cellular analysis in interstitial lung disease", "authors": [{"first": "W", "middle": ["A"], "last": "Wuyts", "suffix": ""}, {"first": "C", "middle": [], "last": "Dooms", "suffix": ""}, {"first": "G", "middle": ["M"], "last": "Verleden", "suffix": ""}], "year": 2013, "venue": "Am J Respir Crit Care Med", "link": "42345706"}, "BIBREF53": {"title": "This outstanding article focuses on chronic hypersensitivity pneumonitis and provides useful tools for the physician confronted with a patient with suspected chronic hypersensitivity pneumonitis", "authors": [{"first": "C", "middle": ["S"], "last": "&amp;&amp; Glazer", "suffix": ""}], "year": 2015, "venue": "Curr Opin Pulm Med", "link": null}, "BIBREF54": {"title": "Chronic bird fancier's lung: histopathological and clinical correlation. An application of the 2002 ATS/ERS consensus classification of the idiopathic interstitial pneumonias", "authors": [{"first": "Y", "middle": [], "last": "Ohtani", "suffix": ""}, {"first": "S", "middle": [], "last": "Saiki", "suffix": ""}, {"first": "M", "middle": [], "last": "Kitaichi", "suffix": ""}], "year": 2005, "venue": "Thorax", "link": "26800239"}, "BIBREF55": {"title": "Histopathologic analysis of sixteen autopsy cases of chronic hypersensitivity pneumonitis and comparison with idiopathic pulmonary fibrosis/usual interstitial pneumonia", "authors": [{"first": "T", "middle": [], "last": "Akashi", "suffix": ""}, {"first": "T", "middle": [], "last": "Takemura", "suffix": ""}, {"first": "N", "middle": [], "last": "Ando", "suffix": ""}], "year": 2009, "venue": "Am J Clin Pathol", "link": "24235891"}, "BIBREF56": {"title": "Bird fancier's lung: a series of 86 patients", "authors": [{"first": "F", "middle": [], "last": "Morell", "suffix": ""}, {"first": "A", "middle": [], "last": "Roger", "suffix": ""}, {"first": "L", "middle": [], "last": "Reyes", "suffix": ""}], "year": 2008, "venue": "Medicine (Baltimore)", "link": "31550976"}, "BIBREF57": {"title": "Bronchoalveolar lavage in hypersensitivity pneumonitis: a series of 139 patients", "authors": [{"first": "D", "middle": ["M"], "last": "Caillaud", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Vergnon", "suffix": ""}, {"first": "A", "middle": [], "last": "Madroszyk", "suffix": ""}], "year": 2012, "venue": "Inflamm Allergy Drug Targets", "link": "43541428"}, "BIBREF58": {"title": "Transbronchial lung cryobiopsy in the diagnosis of fibrotic interstitial lung diseases", "authors": [{"first": "G", "middle": ["L"], "last": "Casoni", "suffix": ""}, {"first": "S", "middle": [], "last": "Tomassetti", "suffix": ""}, {"first": "A", "middle": [], "last": "Cavazza", "suffix": ""}], "year": 2014, "venue": "PLoS One", "link": "15849835"}, "BIBREF59": {"title": "Histologic diagnosis of extrinsic allergic alveolitis", "authors": [{"first": "A", "middle": [], "last": "Coleman", "suffix": ""}, {"first": "T", "middle": ["V"], "last": "Colby", "suffix": ""}], "year": 1988, "venue": "Am J Surg Pathol", "link": "26284490"}, "BIBREF60": {"title": "Usual interstitial pneumonia-pattern fibrosis in surgical lung biopsies. Clinical, radiological and histopathological clues to aetiology", "authors": [{"first": "M", "middle": [], "last": "Smith", "suffix": ""}, {"first": "M", "middle": [], "last": "Dalurzo", "suffix": ""}, {"first": "P", "middle": [], "last": "Panse", "suffix": ""}], "year": 2013, "venue": "J Clin Pathol", "link": "128577"}, "BIBREF61": {"title": "Distinct histopathology of acute onset or abrupt exacerbation of hypersensitivity pneumonitis", "authors": [{"first": "L", "middle": [], "last": "Hariri", "suffix": ""}, {"first": "M", "middle": [], "last": "Mino-Kenudson", "suffix": ""}, {"first": "B", "middle": [], "last": "Shea", "suffix": ""}], "year": 2012, "venue": "Hum Pathol", "link": "38465884"}, "BIBREF62": {"title": "The diagnosis of hypersensitivity pneumonitis", "authors": [{"first": "M", "middle": [], "last": "Schuyler", "suffix": ""}, {"first": "Y", "middle": [], "last": "Cormier", "suffix": ""}], "year": 1997, "venue": "Chest", "link": null}, "BIBREF63": {"title": "Diagnoses of chronic beryllium disease within cohorts of sarcoidosis patients", "authors": [{"first": "J", "middle": [], "last": "M\u00fc Ller-Quernheim", "suffix": ""}, {"first": "K", "middle": ["I"], "last": "Gaede", "suffix": ""}, {"first": "E", "middle": [], "last": "Fireman", "suffix": ""}, {"first": "G", "middle": [], "last": "Zissel", "suffix": ""}], "year": 2006, "venue": "ERJ", "link": "11500921"}, "BIBREF64": {"title": "Diagnostic yield of specific inhalation challenge in hypersensitivity pneumonitis", "authors": [{"first": "X", "middle": [], "last": "&amp;&amp; Mu\u00f1 Oz", "suffix": ""}, {"first": "M", "middle": [], "last": "S\u00e1 Nchez-Ortiz", "suffix": ""}, {"first": "F", "middle": [], "last": "Torres", "suffix": ""}], "year": 2014, "venue": "Eur Respir J", "link": "21082368"}, "BIBREF65": {"title": "This article advocates the use of specific inhalation challenge in hypersensitivity pneumonitis in a specific patient population", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF66": {"title": "Effect of corticosteroid treatment on the recovery of pulmonary function in farmer's lung", "authors": [{"first": "J", "middle": ["I"], "last": "Kokkarinen", "suffix": ""}, {"first": "H", "middle": ["O"], "last": "Tukjainen", "suffix": ""}, {"first": "E", "middle": ["O"], "last": "Terho", "suffix": ""}], "year": 1992, "venue": "Am Rev Respir Dis", "link": null}, "BIBREF67": {"title": "People's Medical Publishing House USA", "authors": [{"first": "M", "middle": [], "last": "Selman", "suffix": ""}, {"first": "", "middle": [], "last": "Hypersensitivity", "suffix": ""}], "year": 2011, "venue": "Interstitial lung disease", "link": null}, "BIBREF68": {"title": "Pigeon breeders disease. A clinical study of hypersensitivity pneumonitis", "authors": [{"first": "J", "middle": ["N"], "last": "Fink", "suffix": ""}, {"first": "A", "middle": ["J"], "last": "Sosman", "suffix": ""}, {"first": "J", "middle": ["J"], "last": "Barboriak", "suffix": ""}], "year": 1968, "venue": "Ann Intern Med", "link": "35843803"}, "BIBREF69": {"title": "A follow-up study of pulmonary function tests, bronchoalveolar lavage cells, and humoral and cellular immunity in bird fancier's lung", "authors": [{"first": "Y", "middle": [], "last": "Yoshizawa", "suffix": ""}, {"first": "S", "middle": [], "last": "Miyake", "suffix": ""}, {"first": "Y", "middle": [], "last": "Sumi", "suffix": ""}], "year": 1995, "venue": "J Allergy Clin Immunol", "link": "23924309"}, "BIBREF70": {"title": "Farmer's lung -a 5-year follow-up of eighty-six patients", "authors": [{"first": "S", "middle": [], "last": "M\u00f6 Nk\u00e4 Re", "suffix": ""}, {"first": "T", "middle": [], "last": "Haahtela", "suffix": ""}], "year": 1987, "venue": "Clin Allergy", "link": "24383512"}, "BIBREF71": {"title": "Mortality in Mexican patients with chronic pigeon breeder's lung compared with those with usual interstitial pneumonia", "authors": [{"first": "R", "middle": [], "last": "P\u00e9 Rez-Padilla", "suffix": ""}, {"first": "J", "middle": [], "last": "Salas", "suffix": ""}, {"first": "R", "middle": [], "last": "Chapela", "suffix": ""}], "year": 1993, "venue": "Am Rev Respir Dis", "link": "22842215"}, "BIBREF72": {"title": "Combination therapy: the future of management for idiopathic pulmonary fibrosis", "authors": [{"first": "W", "middle": ["A"], "last": "Wuyts", "suffix": ""}, {"first": "K", "middle": ["M"], "last": "Antoniou", "suffix": ""}, {"first": "K", "middle": [], "last": "Borensztajn", "suffix": ""}], "year": 2014, "venue": "Lancet Respir Med", "link": "20874422"}, "BIBREF73": {"title": "Next to a view on the future of IPF treatment, this article also comprises some considerations for other relentless fibrotic disorders", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF74": {"title": "Mortality trends in asbestosis, extrinsic allergic alveolitis and sarcoidosis in England and Wales", "authors": [{"first": "A", "middle": [], "last": "Hanley", "suffix": ""}, {"first": "R", "middle": ["B"], "last": "Hubbard", "suffix": ""}, {"first": "V", "middle": [], "last": "Navaratnam", "suffix": ""}], "year": 2011, "venue": "Respir Med", "link": "204997198"}, "BIBREF75": {"title": "The effect of pulmonary fibrosis on survival in patients with hypersensitivity pneumonitis", "authors": [{"first": "J", "middle": ["S"], "last": "Vourlekis", "suffix": ""}, {"first": "M", "middle": ["I"], "last": "Schwarz", "suffix": ""}, {"first": "R", "middle": ["M"], "last": "Cherniack", "suffix": ""}], "year": 2004, "venue": "Am J Med", "link": "26031493"}, "BIBREF76": {"title": "Chronic hypersensitivity pneumonitis: CT features comparison with pathologic evidence of fibrosis and survival", "authors": [{"first": "H", "middle": [], "last": "Sahin", "suffix": ""}, {"first": "K", "middle": ["K"], "last": "Brown", "suffix": ""}, {"first": "D", "middle": [], "last": "Curran-Everett", "suffix": ""}], "year": 2007, "venue": "Radiology", "link": "8535543"}}, "ref_entries": {"FIGREF0": {"text": "FIGURE 1. High-resolution computed tomography scan of a 38-year-old woman with acute hypersensitivity pneumonitis. The image shows extensive ground-glass opacities.", "type": "figure"}, "FIGREF1": {"text": "FIGURE 2. High-resolution computed tomography scan in a 72-year-old woman with chronic hypersensitivity pneumonitis with advanced fibrotic changes and traction bronchiectasis.", "type": "figure"}, "FIGREF2": {"text": "Valencia R, Camarena A, Pineda CL, et al. Genetic susceptibility to multicase hypersensitivity pneumonitis is associated with the TNF-238 GG genotype of the promoter region and HLA-DRB1\u00c304 bearing HLA haplo- types. Respir Med 2014; 108:211-217. This article investigated the link of HLA genes and occurrence of hypersensitivity pneumonitis. 26.", "type": "figure"}, "TABREF0": {"text": "Diagnostic criteria for extrinsic allergic alveolitisThis table depicts elements that should be taken into consideration before making a diagnosis of HP. Moreover, this table highlights the differences between subacute and more chronic forms of HP. BAL, bronchoalveolar lavage; DIP, desquamative interstitial pneumonia; GGOs, ground-glass opacities; HP, hypersensitivity pneumonitis; HRCT, high-resolution computed tomography; IgG, immunoglobulin G; NSIP, nonspecific interstitial pneumonia; OP, organizing pneumonia; UIP, usual interstitial pneumonia. Possible chronic EAA: negative history of exposure to inhaled antigens \u00fe BALF lymphocytosis \u00fe typical HRCT pattern/histology pattern (see the table). Probable chronic EAA: positive history of exposure to inhaled antigen \u00fe typical HRCT/histology pattern (see the table). Definite chronic EAA: positive history of exposure to inhaled antigen \u00fe BAL fluid lymphocytosis \u00fe typical HRCT/histology pattern (see the table). a The basic list of antigens usually used for specific antibodies detection comprises: moulds (Aspergillus spp., Penicilium spp.), thermophilic actinomycetes (Saccharomyces rectivirgula, Thermoactinomyces viridans), bacteria and mycobacteria (Pseudomonas spp., nontuberculous mycobacteria) and pigeon and parakeet droppings and feathers.", "type": "table"}}}
{"paper_id": "10706745", "_pdf_hash": "aa4c61fb8788db926e8f667a45cb81e436149315", "abstract": [{"section": "Abstract", "text": "Background: Niemann Pick C (NPC) disease is a neurovisceral lysosomal storage disorder due to mutations in NPC1 or NPC2 genes, characterized by the accumulation of endocytosed unesterified cholesterol, gangliosides and other lipids within the lysosomes/late endosomes. Even if the neurodegeneration is the main feature of the disease, the analysis of the molecular pathways linking the lipid accumulation and cellular damage in the brain has been challenging due to the limited availability of human neuronal models. Objective: The aim of this study was to develop a human neuronal model of NPC disease by inducing neuronal differentiation of multipotent adult stem cells (MASC) isolated from NPC patients.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Niemann Pick C [NPC-MIM 257220; MIM607625] disease is a neurodegenerative lysosomal storage disorder due to mutations in NPC1 or NPC2 genes, characterized by the accumulation of endocytosed unesterified cholesterol, gangliosides and other lipids within the lysosomes/late endosomes. Both proteins are involved in the intracellular trafficking of cholesterol and other lipids. Thus, the deficiency of either of them leads to the accumulation of the endocytosed unesterified cholesterol, gangliosides and other lipids within the lysosome/late endosome compartment [1] .", "cite_spans": [{"start": 562, "end": 565, "text": "[1]", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "Introduction", "text": "Clinically, NPC disease presents a highly variable phenotype ranging from fetal to adult age. Even though initial manifestations are typically systemic, including liver and spleen enlargement, the disease has been classified according to the age at onset of neurological symptoms in: severe infantile form (onset before 2 y of age), late infantile form (onset between 3-5 y of age), juvenile form (onset between 5 and 16 y) and adult form (onset at age>16 y) [1, 2] .", "cite_spans": [{"start": 459, "end": 462, "text": "[1,", "ref_id": "BIBREF0"}, {"start": 463, "end": 465, "text": "2]", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Introduction", "text": "Approximately 95% of NPC patients present mutations in NPC1 gene (MIM 607623; chr 18q11-q12) [3, 4] , which encodes a membrane glycoprotein of 1,278 amino acids containing 13 transmembrane domains and localized in late endosomes [5] . The other 5% of patients present mutations in NPC2 gene (MIM 601015; chr 14q24.3) [6] encoding a soluble 151 amino acid protein that is present in the lumen of lysosomes.", "cite_spans": [{"start": 93, "end": 96, "text": "[3,", "ref_id": "BIBREF2"}, {"start": 97, "end": 99, "text": "4]", "ref_id": "BIBREF3"}, {"start": 229, "end": 232, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 317, "end": 320, "text": "[6]", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Introduction", "text": "Despite the progress in characterizing the biochemical and genetic defects in NPC disease, the mechanisms underlying the pathophysiology of this disorder are not clear and the currently available therapeutic interventions are limited. In particular, the analysis of the molecular pathways linking the lipid accumulation and cellular damage in the brain has been challenging due to the limited availability of neuronal models.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "Two mouse models of NPC disease have been described and used to study NPC pathogenesis, the BALB\\c NPC [7] and the Npc1 (nmf164) mouse [8] . The naturally occurring BALB\\c NPC mouse recapitulates the main features of human pathology [7] . However, while this model presents a very severe phenotype, most NPC patients present with a less severe form of the disease. This issue is particularly relevant when this model is used to test new potential therapies since the very acute nature of the BALB\\c NPC mouse model may mask the potential benefits of therapies that could be useful in a clinical setting in patients. Recently, a new mouse model of NPC disease, Npc1 (nmf164) carrying a c.3163A>G mutation that results in an aspartate to glycine change at position 1005 (D1005G), has been generated. This mutant mouse displays a slower development of the NPC phenotype than the BALB\\c NPC mouse. Therefore, it may represent a good model for the late-onset, slower progressing forms of NPC disease [8] . However, it is worth noting that some characteristic features of NPC human neurons are not present in mice, suggesting important species differences between mice and human NPC neurons [9] [10] [11] .", "cite_spans": [{"start": 103, "end": 106, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 135, "end": 138, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 233, "end": 236, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 995, "end": 998, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 1185, "end": 1188, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 1189, "end": 1193, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 1194, "end": 1198, "text": "[11]", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "Introduction", "text": "Many studies have been performed in peripheral cells in culture. However, the obtained results might not be extrapolated to neuronal cells since the pattern of accumulated lipids is quite different between peripheral and central tissues [12] .", "cite_spans": [{"start": 237, "end": 241, "text": "[12]", "ref_id": "BIBREF11"}], "ref_spans": []}, {"section": "Introduction", "text": "Recent advances in human stem cell biology and the optimization of protocols for in vitro differentiation of stem cells into different cell lineages have opened new possibilities for generating disease cellular models.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "Pluripotent cells have the ability to form all the body's cell lineages, including germ cells and some extraembryonic cell types [13] . The analyisis of blastocyst chimerism and tetraploid aggregation followed by gestation are the most appropriate tests employed to assess mouse stem cell pluripotency [13] . Human stem cell pluripotency cannot be tested for their ability to generate fully functional germ cells in vivo without raising ethical concern. Consequently, a surrogate test for human stem cell pluripotency is teratoma formation upon administration to a receptive animal [13] . Interestingly, a number of reports have demonstrated that adult human tissues host widely multipotent cells. Although these latter are able to differentiate, both in vitro and in vivo [13, 14] , into mesodermal [15] , ectodermal [16] and endodermal [17] derivatives, even at a clonal level [18] , they do not form either teratomas in vivo or contribute to the germ cell lineages, thus not entirely fulfilling the criteria for pluripotency. This may be secondary to epigenetic differences between adult and embryonic stem cells [14] .", "cite_spans": [{"start": 129, "end": 133, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 302, "end": 306, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 582, "end": 586, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 773, "end": 777, "text": "[13,", "ref_id": "BIBREF12"}, {"start": 778, "end": 781, "text": "14]", "ref_id": "BIBREF13"}, {"start": 800, "end": 804, "text": "[15]", "ref_id": "BIBREF14"}, {"start": 818, "end": 822, "text": "[16]", "ref_id": "BIBREF15"}, {"start": 838, "end": 842, "text": "[17]", "ref_id": "BIBREF16"}, {"start": 879, "end": 883, "text": "[18]", "ref_id": "BIBREF17"}, {"start": 1116, "end": 1120, "text": "[14]", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "Introduction", "text": "Our group has described a highly reproducible method to isolate, from different adult human tissues (heart, liver and bone marrow), a population of multipotent stem cells (named Multipotent Adult Stem Cells or MASC), which express several pluripotent state specific transcription factors (i.e. OCT4, Nanog, Sox2, and Rex1), display high levels of telomerase activity and show all the characteristics of stem cells, such as clonogenicity and self renewal. Furthermore, they present a highly similar gene expression profile, irrespectively from the tissue of origin and they maintain the ability to differentiate along some derivatives of the 3 germ layers, including neuroectoderm [19] .", "cite_spans": [{"start": 680, "end": 684, "text": "[19]", "ref_id": "BIBREF18"}], "ref_spans": []}, {"section": "Introduction", "text": "The aim of this study was to develop a human neuronal model of NPC disease by inducing neuronal differentiation of stem cells isolated from skin biopsies or fibroblasts in culture obtained from NPC patients.", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Human samples", "text": "Specimens from 3 patients affected by NPC disease (two of them were siblings) and 3 normal controls have been used in this study. Samples from a patient affected by Sandhoff disease were used as positive control for ganglioside accumulation assays.", "cite_spans": [], "ref_spans": []}, {"section": "Human samples", "text": "All 3 NPC patients presented the classical biochemical phenotype characterized by massive lysosomal/ late endosomes accumulation of unesterified cholesterol in cultured fibroblasts. The diagnosis was confirmed by sequencing both NPC1 and NPC2 genes. All patients had mutations in the NPC1 gene. The two affected siblings presented the c.3182T>C (P.I1061T)/ c.3182T>C (p.I1061T) genotype, while the third unrelated NPC patient presented the c.2795+1G>C/ c.3493G>A (p.V1165M) genotype. This study was approved by the ethical committee of the University Hospital \"S. Maria della Misericordia\" and written consent was obtained from all subjects.", "cite_spans": [], "ref_spans": []}, {"section": "Stem cell selection and culture", "text": "Stem cell enriched cultures were obtained, both from skin biopsies and from already established skin fibroblast cultures at early passages (P1, P2, P3), adapting the methods previously described [19, 20] .", "cite_spans": [{"start": 195, "end": 199, "text": "[19,", "ref_id": "BIBREF18"}, {"start": 200, "end": 203, "text": "20]", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "Stem cell selection and culture", "text": "Briefly, skin biopsies were minced and digested with 0.04% of collagenase type I (Sigma-Aldrich) for 15 minutes at 37\u00b0C. Cell suspension was filtered through a 40 \u03bcm nylon membrane (Dako) and 4 \u00d7 10 4 cells/mm 2 were plated onto fibronectin coated dishes (10 \u03bcg/100 mm plate, from Sigma-Aldrich). In alternative, 2 \u00d7 10 6 cells directly isolated from human skin biopsies or 1 \u00d7 10 6 cells obtained from confluent primary skin fibroblast cultures, were seeded onto 100 mm plates coated with fibronectin and expanded at least for three passages in a selective media composed of 60% Dulbecco's Modified Eagle medium (DMEM)/40% MCDB-201 (Sigma-Aldrich) supplemented with 1 mg/ml Linoleic Acid-BSA (SigmaAldrich);10 -9 M dexamethasone (Sigma-Aldrich); 10 -4 M Ascorbic acid-2 phosphate (Sigma-Aldrich); 1X Insulintransferrin-sodium selenite (Sigma-Aldrich); 2% fetal bovine serum (FBS), (STEMCELL Technologies), 10 ng/ml human PDGF-BB (Peprotech EC); 10 ng/ml human EGF (Peprotech EC). Medium was replaced every 4 days and cells were split when they reached 70/80% confluence.", "cite_spans": [], "ref_spans": []}, {"section": "Single cell cloning", "text": "Stem cells, at the third passage in culture (P3), obtained from healthy donors (n = 600 cells) and NPC patients (n = 600 cells) were individually deposited directly into fibronectin-coated wells of 96-well plates (Falcon, BD-Biosciences, Italy) with an automated cell sorter (FACSAria, BD), and cultured in expansion medium supplemented with 10% FBS [19, 20] . To determine sorting efficiency and to verify if any well was seeded with more than one cell, we utilized the Vybrant CFDA SE (CFSE) as a cell tracker (Molecular Probes, Invitrogen). Wells were examined twice a week in order to determine the fraction of cells able to give rise to proliferating clones.", "cite_spans": [{"start": 350, "end": 354, "text": "[19,", "ref_id": "BIBREF18"}, {"start": 355, "end": 358, "text": "20]", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "Multilineage differentiation", "text": "Multilineage differentiation was evaluated as previously described [19, 20] .", "cite_spans": [{"start": 67, "end": 71, "text": "[19,", "ref_id": "BIBREF18"}, {"start": 72, "end": 75, "text": "20]", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "Multilineage differentiation", "text": "Muscle cell-and endothelial cell-differentiation was achieved plating 0.5 to 1 \u00d7 10 4 /cm 2 cells in expansion medium containing 5% FBS (Sigma-Aldrich), 10 ng/mL bFGF, 10 ng/mL VEGF, and 10 ng/mL IGF-1 (all from Peprotech EC), but not EGF. Cells were allowed to become confluent and cultured for up to 2 weeks with medium exchanges every 4 days.", "cite_spans": [], "ref_spans": []}, {"section": "Multilineage differentiation", "text": "Hepatocytic differentiation was induced growing cells for two weeks at high density (2 \u00d7 10 4 /cm 2 ) onto fibronectin coated coverslips in a medium containing 0.5% FBS, 10 ng/ml FGF-4 and 20 ng/ml HGF (both from Peprotech EC).", "cite_spans": [], "ref_spans": []}, {"section": "Multilineage differentiation", "text": "For neurogenic differentiation, stem cells obtained after 3 passages in selective medium, were seeded at a density of 8000 cells/cm 2 into 96 multiwell plates (BD Biosciences) or on coverslips. The differentiation protocol was adapted from a method previously described [19, 20] . Briefly, cells were plated in medium containing DMEM-HG with 10% FBS (called N1 medium). After 24 hours the DMEM-HG was replaced with fresh medium supplemented with 1% of B27 (Invitrogen), 10 ng/ml EGF (Peprotech) and 20 ng/ml bFGF (Peprotech) (called N2 medium) for 5 days. Thereafter, cells were incubated for 24/48 hours in DMEM supplemented with 5 \u03bcg/ml insulin, 200 \u03bcM of indomethacin and 0.5 mM IBMX (all from Sigma-Aldrich) without FBS (called N3 medium).", "cite_spans": [{"start": 270, "end": 274, "text": "[19,", "ref_id": "BIBREF18"}, {"start": 275, "end": 278, "text": "20]", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "Flow cytometry analysis", "text": "After at least 3 passages in selective medium, stem cells were detached and stained with the following primary conjugated antibodies: CD10, CD13, CD29, CD49a, CD49b, CD49d, CD90, CD73, CD44, CD45, HLA-DR, CD117, CD34, CD271 (BD Biosciences), CD105, CD66e, KDR (Serotech), CD133 (Miltenyi Biotec), CXCR4, (R&D), ABCG-2 (Chemicon International). The percentage of cells expressing all considered antigens was determined by flow cytometry analysis (CyAn, Beckman Coulter). Properly conjugated isotype matched antibodies were used as negative controls.", "cite_spans": [], "ref_spans": []}, {"section": "Filipin staining", "text": "Filipin staining was performed using the method described by Blanchette-Mackie et al. [21] . Briefly, cells grown on coverslips, were incubated in serum free medium for 24 hours and then treated for 24 hours with LDL enriched medium. Cells were rinsed with PBS and fixed with 3% paraformaldehyde. After washing them with PBS, the cells were incubated with 1.5 mg of glycine/ml PBS for 10 minutes, stained with filipin (0.05 mg/ml, in PBS 10% FCS) for 2 hours and examined using a Zeiss fluorescence microscope.", "cite_spans": [{"start": 86, "end": 90, "text": "[21]", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "Periodic acid Schiff staining (PAS)", "text": "PAS was employed to detect glycogen accumulation. Slides were oxidized in 1% periodic acid for 5 minutes, rinsed three times in distilled water and treated with Schiff's reagent for 25 minutes. After extensive washing, slides were stained with Mayer's hematoxylin for 10 minutes.", "cite_spans": [], "ref_spans": []}, {"section": "Immunofluorescence microscopy", "text": "Protein markers: Cells were grown on coverslips then fixed in 4% paraformaldehyde for 20 minutes at room temperature, permeabilized 10 minutes at room temperature with 0.1% Triton X-100 (Sigma-Aldrich) and stained overnight at 4\u00b0C to visualize stem cell markers: Oct4 (Abcam, Rabbit polyclonal, 1:150), Nanog (Abcam, Rabbit polyclonal, 1:200), Sox2 (Millipore, Mouse monoclonal, 1:200), Nestin (Millipore, 1:100); myocytes specific markers: smooth muscle actin (SMA) (Sigma, 1:50 mouse monoclonal) and \u03b1-sarcomeric actin (ASA) (Sigma, 1:100 mouse monoclonal); endothelial cell marker: CD31 (Dako, 1:50 mouse monoclonal); hepatic specific marker: cytokeratins 8, 18, and 19 (CK) (1:50 mouse monoclonal); or neural specific markers: tubulin beta 3 (COVANCE, 1:1000 mouse monoclonal), NeuN, (Millipore, 1:50 mouse monoclonal) and MAP2 (Millipore, 1:50 rabbit polyclonal). Secondary antibody staining was done with donkey antirabbit or donkey anti-mouse antibodies (Alexa-Fluor 555 or 488, Molecular Probes) at 1:600 dilutions. Images were obtained with a live cell imaging dedicated system consisting of a Leica DMI 6000B microscope connected to a Leica DFC350FX camera (Leica Microsystems); 10X (numerical aperture: 0.25), 40X oil immersion (numerical aperture: 1.25) and 63X oil immersion (numerical aperture: 1.40) objectives were employed.", "cite_spans": [], "ref_spans": []}, {"section": "Immunofluorescence microscopy", "text": "GM2 and GM3 analysis: The analysis of GM2 and GM3 gangliosides was performed as previously described [22] . Cells were grown on coverslips then fixed in 4% paraformaldehyde for 45 minutes at room temperature. Cells were then incubated at room temperature for 1 hour in blocking buffer [PBS with 10% normal donkey serum (NDS) and 0.02% saponin (Sigma-Aldrich)] and stained overnight at 4\u00b0C with mouse anti-GM2 (1:20 in blocking buffer) or mouse anti-GM3 (1:20 in blocking buffer). Cells were then incubated with a TRITC conjugated donkey anti-mouse IgM [1:80 in PBS with 2% NDS and 0.02% saponin (Sigma-Aldrich)]. For colocalization studies, a monoclonal anti-LIMP-1 (Novus Biologicals, Littleton, USA) was used as a primary antibody, and an Alexa fluorconjugated anti-mouse (Invitrogen, Carlsbad, CA, USA) as a secondary antibody.", "cite_spans": [{"start": 101, "end": 105, "text": "[22]", "ref_id": "BIBREF21"}], "ref_spans": []}, {"section": "Immunofluorescence microscopy", "text": "In all cases, nuclei were stained by DAPI (Vector Laboratories, Inc) and Vectashield (Vector) was used as mounting medium. Epifluorescence and phase contrast images were obtained with a live cell imaging dedicated system consisting of a Leica DMI 6000B microscope connected to a Leica DFC350FX camera (Leica Microsystems); 10X (numerical aperture: 0.25), 40X oil immersion (numerical aperture: 1.25) and 63X oil immersion (numerical aperture: 1.40) objectives were employed. Adobe Photoshop software was utilized to compose and overlay the images, and adjust contrast (Adobe, USA). The counts of positive cells were done manually, considering, where possible, 100 positive events per sample.", "cite_spans": [], "ref_spans": []}, {"section": "Real-time RT-PCR", "text": "Total RNA was extracted from both non-confluent cultures of undifferentiated and differentiated cells at P3 using the TRIzol Reagent (Invitrogen). After treatment with DNase I (Ambion), first strand cDNA synthesis was performed with 1 \u03bcg total RNA using random hexanucleotides and MMLV reverse transcriptase (Invitrogen). Primers were designed from available human sequences using the primer analysis software Primer3 (Additional file 1: Table S1 ). Quantitative RT-PCR was performed using Roche LightCycler 480 Real-Time PCR System and the LightCycler 480 SYBR Green I Master (Roche), following manufacturer's instructions. GAPDH was used as internal control for normalization. LightCycler 480 Basic software (Roche) utilized the second derivative maximum method to identify the crossing point (Cp).", "cite_spans": [], "ref_spans": [{"start": 438, "end": 446, "text": "Table S1", "ref_id": "TABREF0"}]}, {"section": "Evaluation of apoptosis", "text": "Apoptosis in differentiated cells at P3 was evaluated by staining of phosphatidylserine exposed on cell membranes with FITC labeled Annexin V, according to the manufacturer's instructions (Sigma-Aldrich) and analyzed by flow cytometry using a FACScan (Becton Dickinson, Franklin Lakes, NJ, USA).", "cite_spans": [], "ref_spans": []}, {"section": "Morphological analysis", "text": "Morphological analysis data were collected by using the BD Pathway bioimaging platform. Differentiated cells were first immunostained for the neural marker MAP-2, then images were acquired on a BD Pathway 855 using a 20X objective (0.75 NA) in the form of 2 \u00d7 2 montage. The images were then analyzed using BD's Neurite Outgrowth Algorithm that automatically measure parameters describing neurite outgrowth.", "cite_spans": [], "ref_spans": []}, {"section": "Statistical analysis", "text": "Statistical analysis was performed using Student's t test or one-way ANOVA test, followed by Bonferroni posttest. The analyses were carried out using the software Prism, version 4.0c, GraphPad Software, San Diego, CA, USA; JMP7, SAS Institute Inc., Cary, NC, USA.", "cite_spans": [], "ref_spans": []}, {"section": "Statistical analysis", "text": "p<0.05 was considered statistically significant.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Stem cell characterization", "text": "In order to isolate multipotent stem cells from NPC patient samples, we applied a protocol that was optimized for the growth of widely multipotent cells with mesenchymal features (named human multipotent adult stem cellshMASC) from several human tissues [19, 20] to both freshly obtained skin biopsies and previously established skin fibroblast cultures. If successful, this latter strategy would allow us to derive multipotent cells from already available bio-repositories of cell lines, obtained from patients suffering from rare diseases, such as NPC, for diagnostic purposes. When exposed to a selective culture medium enabling the growth of hMASC, proliferating cell lines could be obtained from all skin biopsies. On the contrary, only those fibroblast cultures that had not been extensively expanded in vitro (< 3 passages in vitro) were responsive to these stringent culture conditions. After 3 passages in the selective medium, the cells acquired a homogeneous morphology as shown in Figure 1A -D. No differences were observed neither between cells obtained from NPC patients and normal controls nor between cells obtained from biopsies or from already established skin fibroblast cultures.", "cite_spans": [{"start": 254, "end": 258, "text": "[19,", "ref_id": "BIBREF18"}, {"start": 259, "end": 262, "text": "20]", "ref_id": "BIBREF19"}], "ref_spans": [{"start": 993, "end": 1002, "text": "Figure 1A", "ref_id": "FIGREF0"}]}, {"section": "Stem cell characterization", "text": "In order to characterize the selected cells, their surface immunophenotype was analyzed. As shown in Figure 1E and Table 1 , cells obtained both from skin biopsies and fibroblast cell lines displayed an antigenic pattern characteristic of mesenchymal stem cells, very similar to the one observed in MASC isolated from heart, liver or bone marrow [19] . No major differences were observed between cells derived from NPC patients or normal controls.", "cite_spans": [{"start": 346, "end": 350, "text": "[19]", "ref_id": "BIBREF18"}], "ref_spans": [{"start": 101, "end": 110, "text": "Figure 1E", "ref_id": "FIGREF0"}, {"start": 115, "end": 122, "text": "Table 1", "ref_id": "TABREF0"}]}, {"section": "Stem cell characterization", "text": "Cultured cells were then evaluated for the expression of stem cell markers, such as the pluripotent state specific transcription factors Oct-4, Nanog and Sox-2 and the intermediate filament nestin. As shown in Figure 1F -K, the vast majority of cells (65 to 90%) expressed these markers and this expression was independent from the disease state. In fact, no significant differences were observed between NPC and normal cells or between cells isolated from both skin biopsies and early passages of fibroblast cell lines.", "cite_spans": [], "ref_spans": [{"start": 210, "end": 219, "text": "Figure 1F", "ref_id": "FIGREF0"}]}, {"section": "Stem cell characterization", "text": "In order to investigate whether the pathologic phenotype was retained in these cells, the intracellular accumulation of unesterified cholesterol was analyzed by filipin staining. A massive accumulation of cholesterol within the endosomal/lysosomal compartment was observed in cells isolated from either skin biopsies or fibroblast cultures of NPC patients (Figure 1L-N) .", "cite_spans": [], "ref_spans": [{"start": 356, "end": 369, "text": "(Figure 1L-N)", "ref_id": "FIGREF0"}]}, {"section": "Stem cell characterization", "text": "Therefore, in the light of these data, we decided to further characterize stem cells derived from already established skin fibroblast cultures and use them to develop a neuronal differentiation model.", "cite_spans": [], "ref_spans": []}, {"section": "Stem cell characterization", "text": "Cell cultures showed two of the major features of multipotent adult stem cells such as clonogenicity and wide differentiation capacity. Specifically, when sorted as single cells into the wells of 96-well Terasaki plates, skin-derived cells were able to form proliferating colonies within 2 weeks after seeding. It is worth noting that cells derived from NPC patients seem to be less clonogenic than cells derived from healthy controls. Even if the differences were not statistically significant, this result suggests that some stem cells features may be compromised in NPC disease. The cells were able to differentiate along derivatives of all the three germ layers (Figure 2 , Additional file 2: Figure S1 and Additional file 3: Figure S2 ). In this regard, cultured cells generated not only neurectodermic derivatives (see below) but mesodermal and endodermal ones as well. Specifically, cells derived from both healthy controls and NPC patients cultured in a medium added with IGF-1, bFGF and VEGF expressed the myocyte specific markers alpha-sarcomeric actin (ASA) and smooth muscle actin (SMA) and the endothelial cell marker CD31 (Additional file 2: Figure S1 ). Additionally, cells exposed to hepatocyte differentiation medium assumed a globular shape and became positive for cytokeratins 8, 18, and 19 (CK). Moreover, they acquired some hepatocitic functions such as the ability to store glycogen as demonstrated by the PAS staining (Additional file 3: Figure S2 ).", "cite_spans": [], "ref_spans": [{"start": 666, "end": 675, "text": "(Figure 2", "ref_id": "FIGREF1"}, {"start": 697, "end": 706, "text": "Figure S1", "ref_id": "FIGREF0"}, {"start": 730, "end": 739, "text": "Figure S2", "ref_id": "FIGREF1"}, {"start": 1156, "end": 1165, "text": "Figure S1", "ref_id": "FIGREF0"}, {"start": 1461, "end": 1470, "text": "Figure S2", "ref_id": "FIGREF1"}]}, {"section": "Stem cell characterization", "text": "Altogether these results indicate that cells obtained from fibroblast cultures of healthy controls and NPC patients exhibited almost an identical mesenchymal stem cell immunophenotype, expressed pluripotent state specific transcription factors, were clonogenic and multipotent; therefore, in analogy with our previous studies, we named them hSKIN-MASC.", "cite_spans": [], "ref_spans": []}, {"section": "Neural differentiation", "text": "Twenty-four hours after the induction of neural differentiation, hSKIN-MASC showed remarkable morphologic changes. As shown in Figure 2 (panels A-B) differentiated cells displayed an enlargement of the cellular bodies and the presence of long projections, closely resembling the morphology of neuronal cells. Importantly, the morphology of differentiated cells obtained from NPC patients and healthy donors was clearly distinct. In fact, with respect to healthy donors (Figure 2A ), differentiated cells obtained from NPC patients ( Figure 2B ) were larger and presented numerous projections similar to dendrites.", "cite_spans": [], "ref_spans": [{"start": 127, "end": 135, "text": "Figure 2", "ref_id": "FIGREF1"}, {"start": 469, "end": 479, "text": "(Figure 2A", "ref_id": "FIGREF1"}, {"start": 533, "end": 542, "text": "Figure 2B", "ref_id": "FIGREF1"}]}, {"section": "Neural differentiation", "text": "Upon differentiation, a large fraction of hSKIN-MASC became positive to markers of the neuronal lineage. In particular, they expressed NeuN ( Figure 2C-E) , a neuronal specific nuclear protein, and MAP2 ( Figure 2F-H) , a structural protein specifically present in neuronal cells. Interestingly, the percentage of cells expressing NeuN was significantly lower in cells derived from NPC patients than in cells derived from healthy donors. In addition, differentiated cells did not express markers associated with glial differentiation, such as glial fibrillary acidic protein (GFAP) and oligodendroglial protein 4 (O4) (data not shown). These data suggest that the differentiation protocol described here specifically favored the differentiation towards the neuronal lineage. It is worth noting that, after differentiation, the cells became negative for the pluripotent state specific transcription factors Oct-4, Nanog and Sox-2, while the expression of nestin was maintained throughout the differentiation process.", "cite_spans": [], "ref_spans": [{"start": 142, "end": 154, "text": "Figure 2C-E)", "ref_id": "FIGREF1"}, {"start": 205, "end": 217, "text": "Figure 2F-H)", "ref_id": "FIGREF1"}]}, {"section": "Neural differentiation", "text": "To further characterize the type of neuronal cells obtained, mRNA expression of specific markers of dopaminergic (tyrosine hydroxylase, TH and dopamine transporter, DAT), cholinergic (choline acetyltransferase, CHAT) and GABAergic (glutamic acid decarboxylase, GAD) neurons were analyzed by real time PCR. None of these markers were detected in undifferentiated cells. After differentiation, both cells derived from healthy donors and NPC patients expressed similar levels of CHAT mRNA (Additional file 4: Figure S3 ), while the levels of TH, DAT and GAD mRNA were undetectable.", "cite_spans": [], "ref_spans": [{"start": 506, "end": 515, "text": "Figure S3", "ref_id": "FIGREF2"}]}, {"section": "Neural differentiation", "text": "No differences in the levels of apoptosis have been detected between differentiated cells derived from healthy donors and NPC patients (Additional file 5: Figure S4 ).", "cite_spans": [], "ref_spans": [{"start": 155, "end": 164, "text": "Figure S4", "ref_id": "FIGREF3"}]}, {"section": "Neural differentiation", "text": "To determine whether neuronal cells obtained from NPC patients retained the characteristic NPC phenotype, intracellular accumulation of cholesterol and gangliosides was analyzed by filipin staining and immunofluorescence, respectively. As shown in Figure 3 , a massive accumulation of unesterified cholesterol was found in the bodies of differentiated cells obtained from NPC patients ( Figure 3B ). Furthermore, a percentage of these cells accumulated GM2 ganglioside as well ( Figure 3D) . Interestingly, the percentage of GM2 positive cells obtained applying the neuronal differentiation protocol to hSKIN-MASC from either NPC patients or a patient affected by Sandhoff disease was comparable ( Figure 3F ). GM2 accumulation was acquired during the differentiation process since this ganglioside could not be detected both in NPC fibroblasts (data not shown) and in undifferentiated hSKIN-MASC ( Figure 3C ). No accumulation of GM3 was detected both in normal and NPC cells (data not shown).", "cite_spans": [], "ref_spans": [{"start": 248, "end": 256, "text": "Figure 3", "ref_id": "FIGREF2"}, {"start": 387, "end": 396, "text": "Figure 3B", "ref_id": "FIGREF2"}, {"start": 479, "end": 489, "text": "Figure 3D)", "ref_id": "FIGREF2"}, {"start": 698, "end": 707, "text": "Figure 3F", "ref_id": "FIGREF2"}, {"start": 899, "end": 908, "text": "Figure 3C", "ref_id": "FIGREF2"}]}, {"section": "Morphologic analysis of neuronal cells", "text": "As mentioned above, NPC differentiated cells presented a morphology that was clearly different from normal cells. Therefore, in order to quantify the morphologic differences observed, we analyzed the neurite maximal and average length, neurite extremity, segment and root count and neurite node points, using the Neurite outgrowth image program on cells that stained positive for MAP-2. Statistically significant differences were found for all the analyzed parameters between normal and NPC neuronal cell. As shown in Figure 4 , NPC differentiated cells presented longer neurites and a greater number of neurite extremities, segments, roots and node points.", "cite_spans": [], "ref_spans": [{"start": 518, "end": 526, "text": "Figure 4", "ref_id": "FIGREF3"}]}, {"section": "Discussion", "text": "The remarkable advances in the ability to obtain stem cells from different tissues, including skin (reviewed in [13, 14] and [23] ), which are able to differentiate into several cell lineages, offer the possibility to generate cells with neuronal characteristics from easily accessible sources.", "cite_spans": [{"start": 112, "end": 116, "text": "[13,", "ref_id": "BIBREF12"}, {"start": 117, "end": 120, "text": "14]", "ref_id": "BIBREF13"}, {"start": 125, "end": 129, "text": "[23]", "ref_id": "BIBREF22"}], "ref_spans": []}, {"section": "Discussion", "text": "It is conceivable then to develop human cellular models for the study of neurodegenerative diseases harvesting cells from skin biopsies of affected patients and committing them to a neuronal fate, thus paving the way to the study of pathways involved in the development of neurological diseases at the cellular level. NPC is a genetic severe neurodegenerative disease characterized by the accumulation of cholesterol and other lipids within the late endosomes and lysosomes. Although the neuronal degeneration is the main feature in NPC patients, the molecular pathways linking the lipid accumulation and cellular damage in the central nervous system are largely unknown.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "Therefore, we developed a human neuronal model of NPC disease using a method based on the induction of neuronal differentiation of stem cells isolated from skin biopsies or primary cultures of fibroblasts obtained from NPC patients.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "Here, we demonstrated that it is possible to isolate clonogenic adult stem cells expressing mesenchymal and pluripotent state associated markers both from skin biopsies and fibroblast cultures. In analogy with the multipotent adult stem cells that we have previously isolated from several adult human tissues, these cells were widely multipotent, being able to differentiate into derivatives of the three germ layers [19, 20] . For these reasons we named them hSKIN-MASC. The fact that we could obtain multipotent stem cells only from early passages of fibroblasts suggests that immature progenitors may be retained in those cultures but are lost upon serial expansion in vitro.", "cite_spans": [{"start": 417, "end": 421, "text": "[19,", "ref_id": "BIBREF18"}, {"start": 422, "end": 425, "text": "20]", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "Discussion", "text": "In particular, cells differentiated to neuronal fate expressed markers of mature neurons (NeuN and MAP2) and displayed morphological features resembling neuronal cells. It is worth to highlight that nestin, a marker of the early ectoderm lineage, was expressed both in neural stem cells and in hSKIN-MASC. These data suggest that hSKIN-MASC may represent a population of cells that share some features with the ectoderm lineage. This observation also suggests a common origin between hSKIN-MASC and Skin-derived Precursors or SKP, a multipotent cell population isolated from human dermis that shows a differentiation potential towards both mesenchymal and neural lineages. SKP are believed to be of neural-crest origin [24] and are retained throughout adulthood, although they decrease with age [25] .", "cite_spans": [{"start": 719, "end": 723, "text": "[24]", "ref_id": "BIBREF23"}, {"start": 795, "end": 799, "text": "[25]", "ref_id": "BIBREF24"}], "ref_spans": []}, {"section": "Discussion", "text": "A preliminary characterization of the type of neuronal cells generated by this method, suggests that under the experimental conditions described, hSKIN-MASCs differentiated to cholinergic but not to dopaminergic or GABAergic neurons. and NPC patients (n = 3) skin fibroblast derived cultures, before (Undiff.) and after the exposure to neuron induction media (Diff.). At least 400 cells have been counted for each cell line. Data are presented as mean \u00b1 SD of 3 independent experiments one-way Anova test followed by Bonferroni post-test were utilized to compare means between groups. P values less than 0.05 were considered significant. P values less than 0.05 were considered significant. *, **, ***, p<0.05 vs. columns 1, 2, and 3, respectively. Differentiated cells obtained from NPC patients showed some characteristic features of NPC phenotype. They accumulate unesterified cholesterol and GM2 ganglioside. The accumulation of GM2 ganglioside observed in the differentiated cells but not in fibroblasts or undifferentiated hSKIN-MASC, is consistent with data previously reported in NPC patients and NPC mouse models [10, 12, [26] [27] [28] [29] . However, while these studies reported that NPC neuronal cells also accumulate relevant amounts of GM3 ganglioside, no significant accumulation of this ganglioside was found in our model. Since it has been described that the accumulation of GM2 in the brain precedes the accumulation of GM3 [10] , it is possible to hypothesize that the model developed here recapitulates the early stage of the disease.", "cite_spans": [{"start": 1122, "end": 1126, "text": "[10,", "ref_id": "BIBREF9"}, {"start": 1127, "end": 1130, "text": "12,", "ref_id": "BIBREF11"}, {"start": 1131, "end": 1135, "text": "[26]", "ref_id": "BIBREF25"}, {"start": 1136, "end": 1140, "text": "[27]", "ref_id": "BIBREF26"}, {"start": 1141, "end": 1145, "text": "[28]", "ref_id": "BIBREF27"}, {"start": 1146, "end": 1150, "text": "[29]", "ref_id": "BIBREF28"}, {"start": 1443, "end": 1447, "text": "[10]", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "Discussion", "text": "Furthermore, differentiated cells obtained from NPC patients displayed morphological features that are clearly different from those observed in cells obtained from healthy donors, such as the presence of longer neurites and a greater number of neurite extremities, segments, roots and node points. Interestingly, a distortion of the neuronal shape and an extensive growth of new ectopic neurites have been observed in cortical neurons obtained from human patients or animal models of NPC [29, 30] . In addition, although there is no clear loss of cholinergic neurons in NPC mice, it has been shown that in these animals cholinergic neurons display several morphological alterations [31] .", "cite_spans": [{"start": 488, "end": 492, "text": "[29,", "ref_id": "BIBREF28"}, {"start": 493, "end": 496, "text": "30]", "ref_id": "BIBREF29"}, {"start": 682, "end": 686, "text": "[31]", "ref_id": "BIBREF30"}], "ref_spans": []}, {"section": "Discussion", "text": "The identification of morphological alterations in differentiated NPC cells that seem to recapitulate what has , and compared to cells obtained in the same way but from a patient affected by Sandhoff disease, a specific GM2 gangliosidosis. No GM2 accumulation was detected in both healthy controls (CTRL, n = 3) and NPC (n = 3) undifferentiated cells, whereas a significant fraction of differentiated NPC (n = 3) and GM2 gangliosidosis derived cells showed accumulation of the glycosfingolipid. At least 400 cells have been counted for each cell line. Data are presented as mean \u00b1 SD of 3 independent experiments; one-way Anova test followed by Bonferroni post-test were utilized to compare means between groups. P values less than 0.05 were considered significant. *, **, ****, p<0.05 vs. columns 1, 2 and 4, respectively. The Sandhoff patient was omitted from the statistical analysis.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "been described in human cortical NPC neurons is certainly fascinating. However, we cannot exclude that this phenotype is secondary to an impaired/altered differentiation of MASC isolated from NPC patients. Indeed, the lower percentage of cells expressing NeuN obtained after differentiation of hSKIN-MASC isolated from NPC patients seems to support this hypothesis. Further studies are planned to dissect the molecular mechanisms involved in this phenomenon.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "Recently, two human cellular models of NPC disease have been developed by the specific silencing of NPC1 gene in the SH-SY5Y cells line [32] or in human embryonic stem cells [33] . Both models recapitulate the NPC biochemical phenotype. Although neuronal models obtained through the down-regulation of NPC1 expression in human cells may be useful to analyze some aspects of NPC pathogenesis, they are not suitable for the analysis of the impact of specific mutations on the pathologic phenotype or for testing mutation specific therapeutic strategies.", "cite_spans": [{"start": 136, "end": 140, "text": "[32]", "ref_id": "BIBREF31"}, {"start": 174, "end": 178, "text": "[33]", "ref_id": "BIBREF32"}], "ref_spans": []}, {"section": "Discussion", "text": "The model described here offers three main advantages with respect to the models cited above: 1-it was developed directly from patient's cells and therefore it would be useful to analyze the effect of specific NPC1 mutations within the context of the patient genetic/epigenetic background; 2-it was obtained through the differentiation of cells obtained from accessible sources, such as patients cultured fibroblasts, usually available in many laboratories for diagnostic purposes; 3-it did not involve the forced expression of transgenes in target cells, thus avoiding confounding results due to the reprogramming process.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusion", "text": "We have demonstrated that it is possible to isolate stem cells from skin biopsies or fibroblasts in culture and to commit them to a neuronal lineage. Differentiated cells obtained from NPC patients present the main features of NPC disease. Therefore, this model will be useful to study the molecular basis of NPC neurodegeneration and might represent a powerful tool to perform drug screening on cells obtained from NPC patients presenting different genotypes. In addition, the strategy described here may be applied to easily generate human neuronal models of other neurodegenerative diseases.", "cite_spans": [], "ref_spans": []}, {"section": "Additional files", "text": "Additional file 1: Table S1 . Sequences of oligonucleotides used for real-time PCR.", "cite_spans": [], "ref_spans": [{"start": 19, "end": 27, "text": "Table S1", "ref_id": "TABREF0"}]}, {"section": "Additional files", "text": "Additional file 2: Figure S1 . one-way Anova test followed by Bonferroni post-test were utilized to compare means between groups. P values less than 0.05 were considered significant. *, **, p<0.05 vs column 1 and 2, respectively. Additional file 4: Figure S3 . Relative expression of CHAT mRNA in cells derived from healthy donors and NPC patients. The relative abundance of CHAT mRNA were analyzed by real time PCR in cultures from healthy donors (CTRL, n = 3) and NPC patients (n = 3), before (Undiff.) and after neuronal differentiation (Diff.; 5 days in N2 medium + 48 h in N3 medium, see methods). Data were normalized by the expression of GAPDH and expressed as mean as mean \u00b1 SD of 3 independent experiments. Additional file 5: Figure S4 . Apoptosis in differentiated hSKIN-MASC derived from healthy donors and NPC patients. After induction of neural differentiation (5 days in N2 medium + 48 h in N3 medium, see methods) the levels of apoptosis were evaluated in cultures derived from healthy donors (CTRL, n = 3) and NPC patients (n = 3). Data are presented as mean \u00b1 SD of 3 independent experiments. ", "cite_spans": [], "ref_spans": [{"start": 19, "end": 28, "text": "Figure S1", "ref_id": "FIGREF0"}, {"start": 249, "end": 258, "text": "Figure S3", "ref_id": "FIGREF2"}, {"start": 735, "end": 744, "text": "Figure S4", "ref_id": "FIGREF3"}]}], "bib_entries": {"BIBREF0": {"title": "Pentchev: Niemann Pick disease type C: a lipid trafficking disorder. In The metabolic and molecular basis of inherited diseases", "authors": [{"first": "M", "middle": [], "last": "Patterson", "suffix": ""}, {"first": "M", "middle": ["T"], "last": "Vanier", "suffix": ""}, {"first": "K", "middle": [], "last": "Suzuki", "suffix": ""}, {"first": "E", "middle": ["D"], "last": "Morris", "suffix": ""}, {"first": "E", "middle": ["B"], "last": "Cartsea", "suffix": ""}, {"first": "E", "middle": ["J"], "last": "Neufeld", "suffix": ""}, {"first": "P", "middle": ["G"], "last": "Blanchette-Mackie", "suffix": ""}], "year": 2001, "venue": "", "link": null}, "BIBREF1": {"title": "Niemann-Pick disease type C", "authors": [{"first": "M", "middle": ["T"], "last": "Vanier", "suffix": ""}, {"first": "G", "middle": [], "last": "Millat", "suffix": ""}], "year": 2003, "venue": "Clin Genet", "link": "86711747"}, "BIBREF2": {"title": "Linkage of Niemann-Pick disease type C to human chromosome 18", "authors": [{"first": "E", "middle": ["D"], "last": "Carstea", "suffix": ""}, {"first": "M", "middle": ["H"], "last": "Polymeropoulos", "suffix": ""}, {"first": "C", "middle": ["C"], "last": "Parker", "suffix": ""}, {"first": "S", "middle": ["D"], "last": "Detera-Wadleigh", "suffix": ""}, {"first": "O", "middle": [], "last": "Neill", "suffix": ""}, {"first": "R", "middle": ["R"], "last": "Patterson", "suffix": ""}, {"first": "M", "middle": ["C"], "last": "Goldin", "suffix": ""}, {"first": "E", "middle": [], "last": "Xiao", "suffix": ""}, {"first": "H", "middle": [], "last": "Straub", "suffix": ""}, {"first": "R", "middle": ["E"], "last": "Vanier", "suffix": ""}, {"first": "M", "middle": ["T"], "last": "Roscoe", "suffix": ""}, {"first": "O", "middle": ["B"], "last": "Pentchev", "suffix": ""}, {"first": "P", "middle": ["G"], "last": "", "suffix": ""}], "year": 1993, "venue": "Proc Natl Acad Sci", "link": "23315846"}, "BIBREF3": {"title": "Genetic heterogeneity in Niemann-Pick C disease: a study using somatic cell hybridization and linkage analysis", "authors": [{"first": "M", "middle": ["T"], "last": "Vanier", "suffix": ""}, {"first": "S", "middle": [], "last": "Duthel", "suffix": ""}, {"first": "C", "middle": [], "last": "Rodriguez-Lafrasse", "suffix": ""}, {"first": "P", "middle": [], "last": "Pentchev", "suffix": ""}, {"first": "E", "middle": ["D"], "last": "Carstea", "suffix": ""}], "year": 1996, "venue": "Am J Hum Genet", "link": "29271268"}, "BIBREF4": {"title": "Topological analysis of Niemann-Pick C1 protein reveals that the membrane orientation of the putative sterol-sensing domain is identical to those of 3-hydroxy-3-methylglutaryl-CoA reductase and sterol regulatory element binding protein cleavage-activating protein", "authors": [{"first": "J", "middle": ["P"], "last": "Davies", "suffix": ""}, {"first": "Y", "middle": ["A"], "last": "Ioannou", "suffix": ""}], "year": 2000, "venue": "J Biol Chem", "link": "32330555"}, "BIBREF5": {"title": "Identification of HE1 as the second gene of Niemann-Pick C disease", "authors": [{"first": "S", "middle": [], "last": "Naureckiene", "suffix": ""}, {"first": "D", "middle": ["E"], "last": "Sleat", "suffix": ""}, {"first": "H", "middle": [], "last": "Lackland", "suffix": ""}, {"first": "A", "middle": [], "last": "Fensom", "suffix": ""}, {"first": "M", "middle": ["T"], "last": "Vanier", "suffix": ""}, {"first": "R", "middle": [], "last": "Wattiaux", "suffix": ""}, {"first": "M", "middle": [], "last": "Jadot", "suffix": ""}, {"first": "P", "middle": [], "last": "Lobel", "suffix": ""}], "year": 2000, "venue": "Science", "link": "22861888"}, "BIBREF6": {"title": "A genetic storage disorder in BALB/C mice with a metabolic block in esterification of exogenous cholesterol", "authors": [{"first": "A", "middle": ["D"], "last": "Boothe", "suffix": ""}, {"first": "H", "middle": ["S"], "last": "Kruth", "suffix": ""}, {"first": "H", "middle": [], "last": "Weintroub", "suffix": ""}, {"first": "J", "middle": [], "last": "Stivers", "suffix": ""}, {"first": "R", "middle": ["O"], "last": "Brady", "suffix": ""}], "year": 1984, "venue": "J Biol Chem", "link": "19683733"}, "BIBREF7": {"title": "RP: A novel mouse model of Niemann-Pick type C disease carrying a D1005G-Npc1 mutation comparable to commonly observed human mutations", "authors": [{"first": "R", "middle": ["A"], "last": "Maue", "suffix": ""}, {"first": "R", "middle": ["W"], "last": "Burgess", "suffix": ""}, {"first": "B", "middle": [], "last": "Wang", "suffix": ""}, {"first": "C", "middle": ["M"], "last": "Wooley", "suffix": ""}, {"first": "K", "middle": ["L"], "last": "Seburn", "suffix": ""}, {"first": "M", "middle": ["T"], "last": "Vanier", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Rogers", "suffix": ""}, {"first": "C", "middle": ["C"], "last": "Chang", "suffix": ""}, {"first": "T", "middle": ["Y"], "last": "Chang", "suffix": ""}, {"first": "B", "middle": ["T"], "last": "Harris", "suffix": ""}, {"first": "D", "middle": ["J"], "last": "Graber", "suffix": ""}, {"first": "C", "middle": ["A"], "last": "Penatti", "suffix": ""}, {"first": "D", "middle": ["M"], "last": "Porter", "suffix": ""}, {"first": "B", "middle": ["S"], "last": "Szwergold", "suffix": ""}, {"first": "L", "middle": ["P"], "last": "Henderson", "suffix": ""}, {"first": "J", "middle": ["W"], "last": "Totenhagen", "suffix": ""}, {"first": "T", "middle": ["P"], "last": "Trouard", "suffix": ""}], "year": 2012, "venue": "Hum Mol Genet", "link": "21990569"}, "BIBREF8": {"title": "Neurofibrillary tangles in Niemann-Pick disease type C. Brain", "authors": [{"first": "S", "middle": [], "last": "Love", "suffix": ""}, {"first": "L", "middle": ["R"], "last": "Bridges", "suffix": ""}, {"first": "C", "middle": ["P"], "last": "Case", "suffix": ""}], "year": 1995, "venue": "", "link": "31593301"}, "BIBREF9": {"title": "Consequences of NPC1 and NPC2 loss of function in mammalian neurons", "authors": [{"first": "S", "middle": ["U"], "last": "Walkley", "suffix": ""}, {"first": "K", "middle": [], "last": "Suzuki", "suffix": ""}], "year": 2004, "venue": "Biochim Biophys Acta", "link": "15790412"}, "BIBREF10": {"title": "Lipid dynamics in neurons", "authors": [{"first": "J", "middle": ["E"], "last": "Vance", "suffix": ""}, {"first": "B", "middle": [], "last": "Karten", "suffix": ""}, {"first": "H", "middle": [], "last": "Hayashi", "suffix": ""}], "year": 2006, "venue": "Biochem Soc Trans", "link": "16461723"}, "BIBREF11": {"title": "Critical role for glycosphingolipids in Niemann-Pick disease type C", "authors": [{"first": "M", "middle": [], "last": "Zervas", "suffix": ""}, {"first": "K", "middle": ["L"], "last": "Somers", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Thrall", "suffix": ""}, {"first": "S", "middle": ["U"], "last": "Walkley", "suffix": ""}], "year": 2001, "venue": "Curr Biol", "link": "15867108"}, "BIBREF12": {"title": "Pluripotency rush! Molecular cues for pluripotency, genetic reprogramming of adult stem cells, and widely multipotent adult cells", "authors": [{"first": "A", "middle": ["P"], "last": "Beltrami", "suffix": ""}, {"first": "D", "middle": [], "last": "Cesselli", "suffix": ""}, {"first": "C", "middle": ["A"], "last": "Beltrami", "suffix": ""}], "year": 2009, "venue": "Pharmacol Ther", "link": "42005106"}, "BIBREF13": {"title": "Pluripotent and multipotent stem cells in adult tissues", "authors": [{"first": "M", "middle": ["Z"], "last": "Ratajczak", "suffix": ""}, {"first": "E", "middle": [], "last": "Zuba-Surma", "suffix": ""}, {"first": "M", "middle": [], "last": "Kucia", "suffix": ""}, {"first": "A", "middle": [], "last": "Poniewierska", "suffix": ""}, {"first": "M", "middle": [], "last": "Suszynska", "suffix": ""}, {"first": "J", "middle": [], "last": "Ratajczak", "suffix": ""}], "year": 2012, "venue": "Adv Med Sci", "link": "34763725"}, "BIBREF14": {"title": "Comparative analysis of mesenchymal stem cells from bone marrow, umbilical cord blood, or adipose tissue", "authors": [{"first": "S", "middle": [], "last": "Kern", "suffix": ""}, {"first": "H", "middle": [], "last": "Eichler", "suffix": ""}, {"first": "J", "middle": [], "last": "Stoeve", "suffix": ""}, {"first": "H", "middle": [], "last": "Kl\u00fcter", "suffix": ""}, {"first": "K", "middle": [], "last": "Bieback", "suffix": ""}], "year": 2006, "venue": "Stem Cells", "link": "46125397"}, "BIBREF15": {"title": "Neuronal differentiation potential of human adiposederived mesenchymal stem cells", "authors": [{"first": "S", "middle": [], "last": "Anghileri", "suffix": ""}, {"first": "S", "middle": [], "last": "Marconi", "suffix": ""}, {"first": "A", "middle": [], "last": "Pignatelli", "suffix": ""}, {"first": "P", "middle": [], "last": "Cifelli", "suffix": ""}, {"first": "M", "middle": [], "last": "Gali\u00e9", "suffix": ""}, {"first": "A", "middle": [], "last": "Sbarbati", "suffix": ""}, {"first": "M", "middle": [], "last": "Krampera", "suffix": ""}, {"first": "O", "middle": [], "last": "Belluzzi", "suffix": ""}, {"first": "B", "middle": [], "last": "Bonetti", "suffix": ""}], "year": 2008, "venue": "Stem Cells Dev", "link": "42795019"}, "BIBREF16": {"title": "Differentiation of human adipose stromal cells into hepatic lineage in vitro and in vivo", "authors": [{"first": "M", "middle": ["J"], "last": "Seo", "suffix": ""}, {"first": "S", "middle": ["Y"], "last": "Suh", "suffix": ""}, {"first": "Y", "middle": ["C"], "last": "Bae", "suffix": ""}, {"first": "J", "middle": ["S"], "last": "Jung", "suffix": ""}], "year": 2005, "venue": "Biochem Biophys Res Commun", "link": "46236440"}, "BIBREF17": {"title": "In vitro clonal analysis of murine pluripotent stem cells isolated from skeletal muscle and adipose stromal cells", "authors": [{"first": "J", "middle": [], "last": "Case", "suffix": ""}, {"first": "T", "middle": ["L"], "last": "Horvath", "suffix": ""}, {"first": "C", "middle": ["B"], "last": "Ballas", "suffix": ""}, {"first": "K", "middle": ["L"], "last": "March", "suffix": ""}, {"first": "E", "middle": ["F"], "last": "Srour", "suffix": ""}], "year": 2008, "venue": "Exp Hematol", "link": "25746554"}, "BIBREF18": {"title": "Multipotent cells can be generated in vitro from several adult human organs (heart, liver and bone marrow)", "authors": [{"first": "A", "middle": ["P"], "last": "Beltrami", "suffix": ""}, {"first": "D", "middle": [], "last": "Cesselli", "suffix": ""}, {"first": "N", "middle": [], "last": "Bergamin", "suffix": ""}, {"first": "P", "middle": [], "last": "Marcon", "suffix": ""}, {"first": "S", "middle": [], "last": "Rigo", "suffix": ""}, {"first": "E", "middle": [], "last": "Puppato", "suffix": ""}, {"first": "D", "middle": [], "last": "&apos;aurizio", "suffix": ""}, {"first": "F", "middle": [], "last": "Verardo", "suffix": ""}, {"first": "R", "middle": [], "last": "Piazza", "suffix": ""}, {"first": "S", "middle": [], "last": "Pignatelli", "suffix": ""}, {"first": "A", "middle": [], "last": "Poz", "suffix": ""}, {"first": "A", "middle": [], "last": "Baccarani", "suffix": ""}, {"first": "U", "middle": [], "last": "Damiani", "suffix": ""}, {"first": "D", "middle": [], "last": "Fanin", "suffix": ""}, {"first": "R", "middle": [], "last": "Mariuzzi", "suffix": ""}, {"first": "L", "middle": [], "last": "Finato", "suffix": ""}, {"first": "N", "middle": [], "last": "Masolini", "suffix": ""}, {"first": "P", "middle": [], "last": "Burelli", "suffix": ""}, {"first": "S", "middle": [], "last": "Belluzzi", "suffix": ""}, {"first": "O", "middle": [], "last": "Schneider", "suffix": ""}, {"first": "C", "middle": [], "last": "Beltrami", "suffix": ""}, {"first": "C", "middle": ["A"], "last": "", "suffix": ""}], "year": 2007, "venue": "Blood", "link": "18498663"}, "BIBREF19": {"title": "Anversa P: Multipotent progenitor cells are present in human peripheral blood", "authors": [{"first": "D", "middle": [], "last": "Cesselli", "suffix": ""}, {"first": "A", "middle": ["P"], "last": "Beltrami", "suffix": ""}, {"first": "S", "middle": [], "last": "Rigo", "suffix": ""}, {"first": "N", "middle": [], "last": "Bergamin", "suffix": ""}, {"first": "D", "middle": [], "last": "&apos;aurizio", "suffix": ""}, {"first": "F", "middle": [], "last": "Verardo", "suffix": ""}, {"first": "R", "middle": [], "last": "Piazza", "suffix": ""}, {"first": "S", "middle": [], "last": "Klaric", "suffix": ""}, {"first": "E", "middle": [], "last": "Fanin", "suffix": ""}, {"first": "R", "middle": [], "last": "Toffoletto", "suffix": ""}, {"first": "B", "middle": [], "last": "Marzinotto", "suffix": ""}, {"first": "S", "middle": [], "last": "Mariuzzi", "suffix": ""}, {"first": "L", "middle": [], "last": "Finato", "suffix": ""}, {"first": "N", "middle": [], "last": "Pandolfi", "suffix": ""}, {"first": "M", "middle": [], "last": "Leri", "suffix": ""}, {"first": "A", "middle": [], "last": "Schneider", "suffix": ""}, {"first": "C", "middle": [], "last": "Beltrami", "suffix": ""}, {"first": "C", "middle": ["A"], "last": "", "suffix": ""}], "year": 2009, "venue": "Circ Res", "link": null}, "BIBREF20": {"title": "Type-C Niemann-Pick disease: low density lipoprotein uptake is associated with premature cholesterol accumulation in the Golgi complex and excessive cholesterol storage in lysosomes", "authors": [{"first": "E", "middle": ["J"], "last": "Blanchette-Mackie", "suffix": ""}, {"first": "N", "middle": ["K"], "last": "Dwyer", "suffix": ""}, {"first": "L", "middle": ["M"], "last": "Amende", "suffix": ""}, {"first": "H", "middle": ["S"], "last": "Kruth", "suffix": ""}, {"first": "J", "middle": ["D"], "last": "Butler", "suffix": ""}, {"first": "J", "middle": [], "last": "Sokol", "suffix": ""}, {"first": "M", "middle": ["E"], "last": "Comly", "suffix": ""}, {"first": "M", "middle": ["T"], "last": "Vanier", "suffix": ""}, {"first": "J", "middle": ["T"], "last": "August", "suffix": ""}, {"first": "R", "middle": ["O"], "last": "Brady", "suffix": ""}], "year": 1988, "venue": "Proc Natl Acad Sci U S A", "link": "30841857"}, "BIBREF21": {"title": "Endosomal/lysosomal processing of gangliosides affects neuronal cholesterol sequestration in Niemann-Pick disease type C", "authors": [{"first": "S", "middle": [], "last": "Zhou", "suffix": ""}, {"first": "C", "middle": [], "last": "Davidson", "suffix": ""}, {"first": "R", "middle": [], "last": "Mcglynn", "suffix": ""}, {"first": "G", "middle": [], "last": "Stephney", "suffix": ""}, {"first": "K", "middle": [], "last": "Dobrenis", "suffix": ""}, {"first": "M", "middle": ["T"], "last": "Vanier", "suffix": ""}, {"first": "S", "middle": ["U"], "last": "Walkley", "suffix": ""}], "year": 2011, "venue": "Am J Pathol", "link": "37002214"}, "BIBREF22": {"title": "Multipotent skin-derived precursors: from biology to clinical translation", "authors": [{"first": "D", "middle": ["P"], "last": "Hunt", "suffix": ""}, {"first": "C", "middle": [], "last": "Jahoda", "suffix": ""}, {"first": "S", "middle": [], "last": "Chandran", "suffix": ""}], "year": 2009, "venue": "Curr Opin Biotechnol", "link": "38826099"}, "BIBREF23": {"title": "A dermal niche for multipotent adult skinderived precursor cells", "authors": [{"first": "K", "middle": ["J"], "last": "Fernandes", "suffix": ""}, {"first": "I", "middle": ["A"], "last": "Mckenzie", "suffix": ""}, {"first": "P", "middle": [], "last": "Mill", "suffix": ""}, {"first": "K", "middle": ["M"], "last": "Smith", "suffix": ""}, {"first": "M", "middle": [], "last": "Akhavan", "suffix": ""}, {"first": "F", "middle": [], "last": "Barnab\u00e9-Heider", "suffix": ""}, {"first": "J", "middle": [], "last": "Biernaskie", "suffix": ""}, {"first": "A", "middle": [], "last": "Junek", "suffix": ""}, {"first": "N", "middle": ["R"], "last": "Kobayashi", "suffix": ""}, {"first": "J", "middle": ["G"], "last": "Toma", "suffix": ""}, {"first": "D", "middle": ["R"], "last": "Kaplan", "suffix": ""}, {"first": "P", "middle": ["A"], "last": "Labosky", "suffix": ""}, {"first": "V", "middle": [], "last": "Rafuse", "suffix": ""}, {"first": "C", "middle": ["C"], "last": "Hui", "suffix": ""}, {"first": "F", "middle": ["D"], "last": "Miller", "suffix": ""}], "year": 2004, "venue": "Nat Cell Biol", "link": "34420816"}, "BIBREF24": {"title": "Age-dependent depletion of human skin-derived progenitor cells", "authors": [{"first": "N", "middle": [], "last": "Gago", "suffix": ""}, {"first": "V", "middle": [], "last": "Perez-Lopez", "suffix": ""}, {"first": "J", "middle": ["P"], "last": "Sanz-Jaka", "suffix": ""}, {"first": "P", "middle": [], "last": "Cormenzana", "suffix": ""}, {"first": "I", "middle": [], "last": "Eizaguirre", "suffix": ""}, {"first": "A", "middle": [], "last": "Bernad", "suffix": ""}, {"first": "A", "middle": [], "last": "Izeta", "suffix": ""}], "year": 2009, "venue": "Stem Cells", "link": "206516820"}, "BIBREF25": {"title": "Niemann-Pick disease Type C: study on the nature of the cerebral storage process", "authors": [{"first": "M", "middle": [], "last": "Elleder", "suffix": ""}, {"first": "A", "middle": [], "last": "Jirasek", "suffix": ""}, {"first": "F", "middle": [], "last": "Smid", "suffix": ""}, {"first": "J", "middle": [], "last": "Ledvinova", "suffix": ""}, {"first": "Gtn", "middle": [], "last": "Besley", "suffix": ""}], "year": 1985, "venue": "Acta Neuropathol (Berl)", "link": "9584302"}, "BIBREF26": {"title": "Lipid changes in Niemann-Pick disease type C brain: personal experience and review of the literature", "authors": [{"first": "M", "middle": ["T"], "last": "Vanier", "suffix": ""}], "year": 1999, "venue": "Neurochem Res", "link": "38496878"}, "BIBREF27": {"title": "Genetic evidence for nonredundant functional cooperativity between NPC1 and NPC2 in lipid transport", "authors": [{"first": "D", "middle": ["E"], "last": "Sleat", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Wiseman", "suffix": ""}, {"first": "M", "middle": [], "last": "El-Banna", "suffix": ""}, {"first": "S", "middle": ["M"], "last": "Price", "suffix": ""}, {"first": "L", "middle": [], "last": "Verot", "suffix": ""}, {"first": "M", "middle": ["M"], "last": "Shen", "suffix": ""}, {"first": "G", "middle": ["S"], "last": "Tint", "suffix": ""}, {"first": "M", "middle": ["T"], "last": "Vanier", "suffix": ""}, {"first": "S", "middle": ["U"], "last": "Walkley", "suffix": ""}, {"first": "P", "middle": [], "last": "Lobel", "suffix": ""}], "year": 2004, "venue": "Proc Natl Acad Sci", "link": "13307883"}, "BIBREF28": {"title": "GABAergic neuroaxonal dystrophy and other cytopathological alterations in feline Niemann-Pick disease type C", "authors": [{"first": "P", "middle": ["A"], "last": "March", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Thrall", "suffix": ""}, {"first": "D", "middle": ["E"], "last": "Brown", "suffix": ""}, {"first": "T", "middle": ["W"], "last": "Mitchell", "suffix": ""}, {"first": "A", "middle": ["C"], "last": "Lowenthal", "suffix": ""}, {"first": "S", "middle": ["U"], "last": "Walkley", "suffix": ""}], "year": 1997, "venue": "Acta Neuropathol", "link": "34532487"}, "BIBREF29": {"title": "Neurons in Niemann-Pick disease type C accumulate gangliosides as well as unesterified cholesterol and undergo dendritic and axonal alterations", "authors": [{"first": "M", "middle": [], "last": "Zervas", "suffix": ""}, {"first": "K", "middle": [], "last": "Dobrenis", "suffix": ""}, {"first": "S", "middle": ["U"], "last": "Walkley", "suffix": ""}], "year": 2001, "venue": "J Neuropathol Exp Neurol", "link": "34594927"}, "BIBREF30": {"title": "Selectiveneurodegeneration, without neurofibrillary tangles, in a mouse model of Niemann-Pick C disease", "authors": [{"first": "D", "middle": ["C"], "last": "German", "suffix": ""}, {"first": "E", "middle": ["M"], "last": "Quintero", "suffix": ""}, {"first": "C", "middle": ["L"], "last": "Liang", "suffix": ""}, {"first": "B", "middle": [], "last": "Ng", "suffix": ""}, {"first": "S", "middle": [], "last": "Punia", "suffix": ""}, {"first": "C", "middle": [], "last": "Xie", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Dietschy", "suffix": ""}], "year": 2001, "venue": "J Comp Neurol", "link": "22122457"}, "BIBREF31": {"title": "Generation of a human neuronal stable cell model for Niemann-pick C disease by RNA interference", "authors": [{"first": "L", "middle": [], "last": "Rodr\u00edguez-Pascau", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Coll", "suffix": ""}, {"first": "J", "middle": [], "last": "Casas", "suffix": ""}, {"first": "L", "middle": [], "last": "Vilageliu", "suffix": ""}, {"first": "D", "middle": [], "last": "Grinberg", "suffix": ""}], "year": 2012, "venue": "JIMD Reports", "link": "21241931"}, "BIBREF32": {"title": "Disruption and therapeutic rescue of autophagy in a human neuronal model of Niemann Pick type C1", "authors": [{"first": "M", "middle": ["P"], "last": "Ordonez", "suffix": ""}, {"first": "E", "middle": ["A"], "last": "Roberts", "suffix": ""}, {"first": "C", "middle": [], "last": "Kidwell", "suffix": ""}, {"first": "S", "middle": [], "last": "Yuan", "suffix": ""}, {"first": "W", "middle": [], "last": "Plaisted", "suffix": ""}, {"first": "L", "middle": ["S"], "last": "Goldstein", "suffix": ""}], "year": 2012, "venue": "Hum Mol Genet", "link": "18001441"}, "BIBREF33": {"title": "Submit your next manuscript to BioMed Central and take full advantage of: \u2022 Convenient online submission \u2022 Thorough peer review \u2022 No space constraints or color figure charges \u2022 Immediate publication on acceptance \u2022 Inclusion in PubMed, CAS, Scopus and Google Scholar \u2022 Research which is freely available for redistribution", "authors": [{"first": "", "middle": [], "last": "Bergamin", "suffix": ""}], "year": 2013, "venue": "Orphanet Journal of Rare Diseases", "link": null}}, "ref_entries": {"FIGREF0": {"text": "Figure 1 Characterization of stem cell populations obtained from skin biopsies or already established skin fibroblast cultures. (A-D) Phase contrast images of hSKIN-MASC at the third passage in culture: A-B) hSKIN-MASC obtained from skin biopsies of a healthy donor (A) and a NPC patient (B). C-D) hSKIN-MASC obtained from already established skin fibroblasts from healthy donor (C) and NPC patient (D). (E) Surface immunophenotype: representative flow cytometry histograms of skin derived stem cell cultures. Plots show isotype control IgG-staining profile (green histograms) versus specific antibody staining (red histograms). (F-H) Pluripotent state specific transcription factor expression: representative fluorescence images of Oct-4 (green fluorescence; F), Nanog (green fluorescence; G) and Sox-2 expression (green fluorescence; H) localized in the nuclei of skin derived stem cell cultures. Nuclei are depicted by the blue fluorescence of DAPI staining (F-H). I) Quantification of the percentage of cells expressing Oct4 (white bars), Nanog (black bars) and Sox-2 (gray bars) in hSKIN-MASC obtained both from healthy donors (CTRL, n = 3) and NPC (n = 3) skin biopsies or healthy donors (CTRL, n = 3) and NPC (n = 3) skin fibroblast cultures. At least 400 cells have been counted for each cell line. Data are presented as mean \u00b1 SD of 3 independent experiments. (J-K) Nestin expression (red fluorescence) in hSKIN-MASC obtained from a healthy donor (J) and a NPC patient (K). (L-N) Unesterified cholesterol accumulation: images obtained after performing the filipin staining (blue fluorescence) in hSKIN-MASC derived from a healthy donor skin biopsy (L), a NPC patient skin biopsy (M) and a NPC skin fibroblast cell line (N), respectively.", "type": "figure"}, "FIGREF1": {"text": "Figure 2 Neural differentiation of hSKIN-MASC obtained from already established skin fibroblast cultures. (A-B) Phase contrast images of hSKIN-MASC after induced to differentiate toward a neuronal fate (5 days in N2 medium + 48 h in N3 medium, see methods) from a healthy donor (A) and a NPC patient (B). (C-H) Neuronal markers detection: differentiated cells (5 days in N2 medium + 48 h in N3 medium, see methods), obtained from a healthy donor (C, F) or a NPC patient (D, G), express the neuron specific markers NeuN (yellow fluorescence, C, D) and MAP2 (green fluorescence, F, G). Nuclei are depicted by the blue fluorescence of DAPI staining. Quantitative evaluation of the percentage of cells expressing NeuN (E) or MAP2 (H) in cultures from healthy donors (CTRL, n = 3) and NPC patients (n = 3) skin fibroblast derived cultures, before (Undiff.) and after the exposure to neuron induction media (Diff.). At least 400 cells have been counted for each cell line. Data are presented as mean \u00b1 SD of 3 independent experiments one-way Anova test followed by Bonferroni post-test were utilized to compare means between groups. P values less than 0.05 were considered significant. P values less than 0.05 were considered significant. *, **, ***, p<0.05 vs. columns 1, 2, and 3, respectively.", "type": "figure"}, "FIGREF2": {"text": "Figure 3 Pathologic accumulation of unesterified cholesterol and GM2 in differentiated hSKIN-MASC derived from NPC patients. (A -B) co-immunostaining for the lysosome marker Limp 1 (red fluorescence) and for unesterified cholesterol (blue fluorescence), revealed lysosomal accumulation of cholesterol after neuronal differentiation (5 days in N2 medium + 48 h in N3 medium, see methods) only in cultures derived from an NPC patient (B), but not in healthy donor derived cells (A). (C-F) Expression and relative quantification of the glycosphingolipid GM2 by immunofluorescence: co-immunostaining for the lysosome marker Limp 1 (green fluorescence) and for GM2 (red fluorescence), revealed accumulation of the ganglioside only in differentiated cultures derived from NPC (D) and Sandhoff (E) patients, but not in healthy donor derived cells (C). F) The percentage of GM2 expressing cells was assayed in undifferentiated cells and after exposure to the neural inductive media (5 days in N2 medium + 48 h in N3 medium, see methods), and compared to cells obtained in the same way but from a patient affected by Sandhoff disease, a specific GM2 gangliosidosis. No GM2 accumulation was detected in both healthy controls (CTRL, n = 3) and NPC (n = 3) undifferentiated cells, whereas a significant fraction of differentiated NPC (n = 3) and GM2 gangliosidosis derived cells showed accumulation of the glycosfingolipid. At least 400 cells have been counted for each cell line. Data are presented as mean \u00b1 SD of 3 independent experiments; one-way Anova test followed by Bonferroni post-test were utilized to compare means between groups. P values less than 0.05 were considered significant. *, **, ****, p<0.05 vs. columns 1, 2 and 4, respectively. The Sandhoff patient was omitted from the statistical analysis.", "type": "figure"}, "FIGREF3": {"text": "Figure 4 Morphometric analysis of differentiated cells obtained from hSKIN-MASC of healthy donors or NPC patients. (A-B): Phase contrast image showing the morphological differences between differentiated cells (5 days in N2 medium + 48 h in N3 medium, see methods) of a healthy donor (A) and a NPC patient (B). Specifically, NPC differentiated cells were characterized by distortion of neuron shape, ectopic neurites and meganeurite formation. (C): Quantitative analysis of neuronal morphological parameters linked to neurite outgrowth as evaluated by a specific Image analysis software on MAP-2 stained cells. Data are presented as mean \u00b1 SD of 3 independent experiments; \u00a7, p<0.01 vs healthy donors (CTRL).", "type": "figure"}, "FIGREF4": {"text": "Mesodermic differentiation of hSKIN-MASC obtained from already established skin fibroblast cultures (hSKIN-MASC). (A-B) Phase contrast images of healthy donor-(A) and NPC patient-(B) derived hSKIN-MASC after exposure to a medium added with IGF-1, bFGF and VEGF. (C-F) Myocyte marker detection: differentiated cells, obtained from healthy donor (C,E) or NPC patient (D,F), express the myocyte specific markers alpha- sarcomeric actin (ASA) (red fluorescence, C,D) and smooth muscle actin (SMA) (red fluorescence, E,F). (G-H) Endothelial cell marker detection: differentiated cells, obtained from healthy donor (G) or NPC patient (H) express CD31 (red fluorescence, G,H). Nuclei are depicted by the blue fluorescence of DAPI staining. (I) Quantitative evaluation of the percentage of cells expressing ASA (i), SMA(ii) and CD31(iii) in cultures from healthy donors (CTRL, n = 3) and NPC patients (n = 3), before (Undiff.) and after exposure to myocyte differentiation induction media (Diff.). At least 400 cells have been counted for each cell line. Data are presented as mean\u00b1SD; one-way Anova test followed by Bonferroni post-test was utilized to compare means between groups. *, **, ***, p<0.05 vs columns 1,2 and 3, respectively. Additional file 3: Figure S2. Hepatic differentiation of hSKIN-MASC obtained from already established skin fibroblast cultures. (A-B) Phase contrast images of healthy donor-(A) and NPC patient-(B) derived hSKIN- MASC after differentiation into hepatocytes. (C-F) Hepatic markers detection: differentiated cells, obtained from healthy donor (C,E) or NPC patient (D,F) express the hepatocytes specific markers cytokeratins 8-18-19 (red fluorescence, C,D) and stained positive for the Periodic Acid-Shiff (PAS) staining (pink stain, E,F). Nuclei are depicted by the blue fluorescence of DAPI staining (C, D) or by the blue-stain of hematoxylin (E, F). (G) Quantitative evaluation of the percentage of cells expressing CK in cultures from healthy donors (CTRL, n = 3) and NPC patients (n = 3), before (Undiff.) and after exposure to hepatocytes differentiation induction media (Diff.). At least 400 cells have been counted for each cell line. Data are presented as mean\u00b1SD;", "type": "figure"}, "FIGREF5": {"text": "Abbreviations NPC: Niemann Pick C; MASCs: Multipotent adult stem cells; FBS: Fetal bovine serum; DMEM: Dolbecco's Modified Eagle Medium; BSA: Albumin from bovine serum; PDGF: Platelet derived growth factor; EGF: Epidermal growth factor; bFGF: Basic fibroblast growth factor; VEGF: Vascular endothelial growth factor; IGF1: Insulin-like growth factor 1; HGF: Hepatocyte growth factor; NDS: Normal donkey serum; PAS: Periodic acid Schiff staining; CD31: Platelet endothelial cell adhesion molecule; SMA: Smooth muscle actin; ASA: \u03b1-sarcomeric actin; CK: Cytokeratins; MAP2: Microtubuleassociated protein 2; GFAP: Glial fibrillary acidic protein; O4: Oligodendroglial", "type": "figure"}, "TABREF0": {"text": "Surface immunophenotype of stem cells isolated from skin biopsies or culture fibroblasts", "type": "table"}}}
{"paper_id": "10706871", "_pdf_hash": "8ee52634353c2a028922c825948296941fef3c99", "abstract": [], "body_text": [{"section": "Introduction", "text": "Favorable results were reported from previous studies on childhood and adolescent B-cell non-Hodgkin lymphoma (B-NHL) and acute B-cell leukemia (B-AL) with 2 to 8 short intensive therapy courses depending on stage and tumor mass. [1] [2] [3] [4] [5] [6] [7] [8] The toxicity of these protocols was considerable, however. Therefore, the Non-Hodgkin Lymphoma-Berlin-Frankfurt-M\u00fcnster 95 (NHL-BFM95) study aimed at reducing treatment-related toxicity without jeopardizing treatment outcome. In our previous trials, increasing the dose of methotrexate (MTX) from 0.5 g/m 2 to 5 g/m 2 (administered over 24 hours) resulted in significant improvement of the probability of event-free survival (pEFS) for patients with B-AL as well as for patients with B-NHL stage III with higher tumor load. 4, 9 However, high-dose MTX particularly contributed to the toxicity of the treatment, namely orointestinal mucositis, which may increase the risk of sepsis and toxic death. 4 High-dose MTX combined with racemic tetrahydrofolic acid (leucovorin) is a key component of the majority of treatment regimens currently used for childhood and adolescent B-cell neoplasms. [1] [2] [3] [4] [5] [6] 8 However, dose and administration schedule of MTX varies considerably between therapy protocols. Dosages of MTX range from 0.5 g/m 2 to 8.0 g/m 2 ; duration of continuous intravenous infusion of MTX ranges from 1 hour to 24 hours, resulting in very different pharmacokinetic profiles. Furthermore, time of application of the first dose of leucovorin varies between 24 hours 6 and 42 hours 4 after the start of MTX infusion, which introduces potentially significant differences regarding the duration of MTX exposure of healthy and malignant cells.", "cite_spans": [{"start": 230, "end": 233, "text": "[1]", "ref_id": "BIBREF168"}, {"start": 234, "end": 237, "text": "[2]", "ref_id": "BIBREF169"}, {"start": 238, "end": 241, "text": "[3]", "ref_id": "BIBREF170"}, {"start": 242, "end": 245, "text": "[4]", "ref_id": "BIBREF171"}, {"start": 246, "end": 249, "text": "[5]", "ref_id": "BIBREF172"}, {"start": 250, "end": 253, "text": "[6]", "ref_id": "BIBREF173"}, {"start": 254, "end": 257, "text": "[7]", "ref_id": "BIBREF174"}, {"start": 258, "end": 261, "text": "[8]", "ref_id": "BIBREF175"}, {"start": 786, "end": 788, "text": "4,", "ref_id": "BIBREF171"}, {"start": 789, "end": 790, "text": "9", "ref_id": "BIBREF176"}, {"start": 960, "end": 961, "text": "4", "ref_id": "BIBREF171"}, {"start": 1151, "end": 1154, "text": "[1]", "ref_id": "BIBREF168"}, {"start": 1155, "end": 1158, "text": "[2]", "ref_id": "BIBREF169"}, {"start": 1159, "end": 1162, "text": "[3]", "ref_id": "BIBREF170"}, {"start": 1163, "end": 1166, "text": "[4]", "ref_id": "BIBREF171"}, {"start": 1167, "end": 1170, "text": "[5]", "ref_id": "BIBREF172"}, {"start": 1171, "end": 1174, "text": "[6]", "ref_id": "BIBREF173"}, {"start": 1175, "end": 1176, "text": "8", "ref_id": "BIBREF175"}, {"start": 1550, "end": 1551, "text": "6", "ref_id": "BIBREF173"}, {"start": 1565, "end": 1566, "text": "4", "ref_id": "BIBREF171"}], "ref_spans": []}, {"section": "Introduction", "text": "All mentioned parameters-dosage, administration schedule, drug exposure time-may influence efficacy and toxicity of MTX therapy. [10] [11] [12] [13] [14] Controlled clinical trials investigating the impact of these parameters on treatment efficacy and toxicity are still lacking. Therefore, in order to optimize the MTX therapy in the treatment of children and adolescents with B-cell neoplasms, we investigated 2 questions in study NHL-BFM95. First, we tested in a randomized trial whether the incidence of severe orointestinal mucositis can be reduced by shortening the duration of intravenous infusion of high-dose MTX from 24 hours to 4 hours without impairment of the probability of failure-free survival. Second, we tested whether for patients with unresected B-NHL of moderate tumor mass (lactate dehydrogenase [LDH] \u03fd 500 U/L), representing approximately 45% of B-NHL patients, the dose of MTX can be reduced to 1 g/m 2 without lowering the probability of EFS of 95% or higher that the patients achieved in our previous study NHL-BFM90, with therapy courses including MTX 5 g/m 2 . 4 Figure 1 . Treatment strategy. Patients were stratified into 4 risk groups: R1, R2, R3, and R4. The composition of therapy courses is given in Table 1 . V indicates cytoreductive prephase. IV indicates intravenously; h, hour; IT, intrathecally. *Doses were adjusted for children younger than 3 years. In courses A, B, AA, and BB, intrathecal therapy was administered 24 hours after beginning of MTX intravenous infusion.", "cite_spans": [{"start": 129, "end": 133, "text": "[10]", "ref_id": "BIBREF177"}, {"start": 134, "end": 138, "text": "[11]", "ref_id": "BIBREF178"}, {"start": 139, "end": 143, "text": "[12]", "ref_id": "BIBREF179"}, {"start": 144, "end": 148, "text": "[13]", "ref_id": "BIBREF180"}, {"start": 149, "end": 153, "text": "[14]", "ref_id": "BIBREF181"}], "ref_spans": [{"start": 1235, "end": 1242, "text": "Table 1", "ref_id": "TABREF0"}]}, {"section": "Introduction", "text": "\u2020Patients were randomized to receive MTX as continuous intravenous infusion either over 24 hours or over 4 hours. In the 24-hour arm, 10% of the MTX dose was given within 0.5 hours, 90% of dose intravenously over 23.5 hours. Racemic folinic acid (leucovorin) intravenously 15 mg/m 2 at hours 42, 48, and 54 after beginning of MTX. In courses AA and BB, the dose of leucovorin at hour 42 was 30 mg/m 2 intravenously. Adjustment of leucovorin dose in case of impaired MTX excretion as previously described. 4 \u2021For CNS-positive patients, chemotherapy was applied intraventricularly as described in \"Chemotherapy.\" \u00a7Courses AA and BB are the same as A and B, respectively, with the exceptions listed. \u00b6Subdivided in 3 doses. Maximum dose was 2 mg; vincristine was not given in patients of branch R1. **Doses are 12 hours apart. \u2020 \u2020Maximum dose was 5 mg.", "cite_spans": [{"start": 505, "end": 506, "text": "4", "ref_id": "BIBREF171"}], "ref_spans": []}, {"section": "Patients, materials, and methods", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Patients", "text": "Children and adolescents up to 18 years of age newly diagnosed with mature B-cell NHL or B-AL were eligible for trial NHL-BFM95. From April 1996 to March 2001, 566 patients were registered from 84 clinics in Austria, Germany, and Switzerland after informed consent according to the Declaration of Helsinki. Approval of the study was obtained from the ethical committee of the principal investigator (A.R.) and the participating investigators. Due to the following criteria, 61 patients were excluded: previous treatment (n \u03ed 4), no therapy (n \u03ed 3), NHL as a second malignancy (n \u03ed 4), severe immunodeficiency (n \u03ed 14, 4 failures), preexisting disease prohibiting protocol therapy (n \u03ed 1), AIDS-related NHL (n \u03ed 1, 1 failure), posttransplantation NHL (n \u03ed 11, 3 failures), treatment according to a different protocol due to decision of 2 participating clinics (n \u03ed 21, one failure), or erroneous diagnosis (n \u03ed 2). There were 505 patients eligible for the trial.", "cite_spans": [], "ref_spans": []}, {"section": "Diagnosis", "text": "NHL subtypes originally diagnosed according to the updated Kiel classification for non-Hodgkin lymphomas 15 were reclassified on the basis of the WHO Classification of Hematological Malignancies. 16 In 466 of 505 cases, the diagnosis was centrally reviewed by one of the reference laboratories.", "cite_spans": [{"start": 105, "end": 107, "text": "15", "ref_id": "BIBREF183"}, {"start": 196, "end": 198, "text": "16", "ref_id": "BIBREF184"}], "ref_spans": []}, {"section": "Staging", "text": "The St Jude staging system was used. 17 Staging included physical examination, peripheral blood and bone marrow (BM) aspiration smears, cerebrospinal fluid (CSF) analyses, ultrasonography, X-ray, computed tomography (CT) and/or magnetic resonance imaging (MRI), and skeletal scintigraphy. Initial central nervous system (CNS) disease was diagnosed if one of the following was present: lymphoma cells in the CSF, cerebral infiltrates on cranial CT or MRI, or cranial nerve palsy that was not caused by an extradural mass. The total serum LDH activity was measured as a parameter for the tumor mass.", "cite_spans": [{"start": 37, "end": 39, "text": "17", "ref_id": "BIBREF185"}], "ref_spans": []}, {"section": "Stratification of treatment intensity", "text": "Patients were stratified into 4 risk groups according to stage, resection status, pretherapeutic serum LDH, and presence of CNS disease ( Figure 1 ).", "cite_spans": [], "ref_spans": []}, {"section": "Chemotherapy", "text": "The treatment strategy is depicted in Figure 1 . The composition of therapy courses is given in Table 1 . Patients in risk groups R2, R3, and R4 received a 5-day cytoreductive prephase before the first course A (AA) was administered. By November 15, 1997, an amendment was introduced. All patients in R3 \u03e9 R4 had to receive urate oxidase 3 \u03eb 50 U/kg per day intravenously during the first days of cytoreductive chemotherapy. [18] [19] [20] Conditions for starting the second and subsequent courses were as follows: platelet levels higher than 50 \u03eb 10 9 /L and neutrophil counts higher than 0.5 \u03eb 10 9 /L after the nadir of postchemotherapeutic cytopenia. For patients of risk groups R3 and R4, granulocyte colony-stimulating factor 5 g/kg per day subcutaneously was recommended after the first 2 therapy courses. In CNS-positive patients, a device for intraventricular application of chemotherapy was implanted before the second course. MTX 3 mg and prednisolone 2.5 mg were administered intraventricularly on days 2, 3, 4, and 5, and cytarabine 30 mg was given on day 6 of courses AA and BB. In course CC, MTX 3 mg and prednisolone 2.5 mg were administered on days 3, 4, 5, and 6; cytarabine 30 mg was given on day 7. For patients in risk groups R3 \u03e9 R4 who had residual tumor after the fifth course of therapy, a second-look operation was performed. If viable lymphoma tissue was detected, megadose chemotherapy with autologous stem cell rescue (autologous stem cell transplantation [ASCT]) was performed as previously described. 4 If no viable lymphoma tissue was found, therapy was continued with the last course CC in risk group R4, while patients in risk group R3 did not receive any further therapy. For patients in risk group R2, no intervention was foreseen in case of a persistent tumor remnant during or after therapy.", "cite_spans": [{"start": 425, "end": 429, "text": "[18]", "ref_id": "BIBREF186"}, {"start": 430, "end": 434, "text": "[19]", "ref_id": "BIBREF188"}, {"start": 435, "end": 439, "text": "[20]", "ref_id": "BIBREF189"}, {"start": 1532, "end": 1533, "text": "4", "ref_id": "BIBREF171"}], "ref_spans": [{"start": 96, "end": 103, "text": "Table 1", "ref_id": "TABREF0"}]}, {"section": "Randomization of MTX infusion schedule", "text": "Patients were randomized to receive MTX as continuous intravenous infusion either over 24 hours (MTX-24h) or over 4 hours (MTX-4h). The dose of MTX was 1 g/m 2 in courses A and B, (risk groups R1 \u03e9 R2) and was 5 g/m 2 in courses AA and BB (risk groups R3 \u03e9 R4). Intrathecal therapy was given at hour 24 after the beginning of the MTX infusion in both randomized arms. The MTX serum concentration was measured at hours 24, 42, and 48 from the start of the MTX infusion. In both randomized arms, leucovorin 15 mg/m 2 was given intravenously at hours 42, 48, and 54 after the beginning of MTX. In courses AA and BB, the dose of leucovorin at hour 42 was 30 mg/m 2 intravenously. In case of impaired MTX excretion, intensified leucovorin rescue was carried out as previously described. 4 (10) 119 (24) 221 (44) 16 (3) 17 (3) 56 (11) 23 (5) Response criteria", "cite_spans": [], "ref_spans": []}, {"section": "Randomization of MTX infusion schedule", "text": "The response to the treatment was evaluated after each course of therapy. Follow-up studies were performed at 4-to 6-week intervals during the first 1.5 years. In patients with BM and/or CNS involvement, follow-up punctures of BM and/or CSF were performed only until the BM or the CNS, respectively, was cleared from blasts. Tumor failure was defined as a recurrence of lymphoma proven by biopsy, or regrowth of an incompletely resolved tumor, or persistence of BM blasts after the second course of therapy. Isolated BM relapse was based on 25% or more blasts in the BM. Isolated CNS relapse was based on the appearance of blasts in the CSF.", "cite_spans": [], "ref_spans": []}, {"section": "Study design and statistical analysis", "text": "Event-free survival (EFS) was calculated from the day of diagnosis to an event (tumor failure, death for any reason, second malignancy) or to the date of last follow-up contact. Failure-free survival (FFS) was calculated from the day of diagnosis to treatment failure (tumor failure, death due to therapy) or to the date of last follow-up contact, while patients who experienced second malignancy were censored at the time of that event.", "cite_spans": [], "ref_spans": []}, {"section": "Study design and statistical analysis", "text": "Analyses of EFS and FFS were performed using the Kaplan and Meier method with differences compared by the log-rank test. 21, 22 The 95% confidence interval (CI) for the Kaplan-Meier estimate of EFS and FFS was calculated using standard errors according to Greenwood. 23 In order to take into account prognostic factors when comparing FFS of patient subgroups, Cox regression analysis was used. 24 The statistical analysis was carried out using the SAS statistical program (SAS-PC, Version 6.12; SAS Institute, Cary, NC). Follow-up data were updated as of June 1, 2003 . Trial NHL-BFM95 was supervised by an external data safety and monitoring committee (DMC). The first aim of study NHL-BFM95 was to test whether the incidence of orointestinal mucositis grades III or IV can be reduced by shortening the duration of intravenous infusion of high-dose MTX from 24 hours to 4 hours, without impairment of the probability of FFS (pFFS). Patients were randomized to receive either MTX-24h or MTX-4h. Randomization was stratified by risk group. For safety reasons, the first question to be answered was: Is MTX-4h noninferior to MTX-24h? The end point of that analysis was the one-sided 95% CI for the difference of a one-year pFFS between the 2 arms. This test was planned as a per-protocol analysis; that is, only randomized patients who received therapy according to their randomized arm were analyzed. 25 Analysis was performed separately for branch R1, R2, and the combined branches R3 \u03e9 R4. MTX-4h was accepted to be noninferior to MTX-24h if the lower limit of the one-sided 95% CI for the difference of pFFS between randomized patients treated with MTX-4h and those treated with MTX-24h did not exceed \u03ea11% in risk group R2 and \u03ea17% in the combined risk groups R3 \u03e9 R4. The expected total number of randomized patients was 405 with a risk group distribution of 17%, 43%, 13%, and 27% for risk groups R1, R2, R3, and R4, respectively. With these expected numbers of patients for risk group R2, the power to prove noninferiority of MTX-4h was estimated to be 0.80 if the pFFS is 0.95 for the MTX-24h arm (type I error \u03ed 5%, n \u03ed 87 per arm). For the combined risk groups R3 \u03e9 R4, the test power was estimated to be 0.80 if the pFFS is 0.80 for the MTX-24h arm (type I error \u03ed 5%, n \u03ed 81 per arm). There was no planned test for risk group R1 because of the small number of patients and the extremely low number of expected events. 4 After the test for noninferiority, the second part of the study question was addressed: Is it possible to significantly reduce orointestinal toxicity by reducing the MTX infusion time from 24 hours to 4 hours? The end point of this analysis was the incidence of the maximum grade of mucositis per randomized arm. The analysis (Wilcoxon rank-sum test) was performed separately for risk group R1 (2 MTX-containing courses with MTX 1 g/m 2 ), risk group R2 (4 courses with MTX 1 g/m 2 ), and together for risk groups R3 \u03e9 R4 (4 MTXcontaining courses with MTX 5 g/m 2 ) with type I error equal to 5% for each test. For patients receiving courses including MTX 5 g/m 2 as intravenous infusion over 24 hours, an incidence of mucositis grade III or IV of 72% was expected based on observations in the preceding study NHL-BFM90. There were 2 interim analyses and a final analysis planned when 33%, 66%, and 100% of the expected total number of randomized patients would have a potential follow-up of at least one year. The overall alpha 0.05 was corrected according to O'Brien and Fleming for the first interim (P \u03ed .0005), the second interim (P \u03ed .014), and the final analysis (P \u03ed .045). 26 The second aim of study NHL-BFM95 was to investigate, against the historical control of study NHL-BFM90, whether for patients in risk group R2 the dose of MTX can be reduced from 5 g/m 2 in study NHL-BFM90 to 1 g/m 2 in study NHL-BFM95 without impairment of pEFS. The end point of that analysis was the one-sided 95% CI for the difference of a 3-year pEFS between patients in risk group R2 in studies NHL-BFM90 and NHL-BFM95. Treatment with MTX 1 g/m 2 was accepted to be noninferior to the therapy with MTX 5 g/m 2 if the lower limit of the one-sided 95% CI for the difference in pEFS of patients in risk group R2 in study NHL-BFM95 and study NHL-BFM90 did not exceed \u03ea7%. This test was planned as a per-protocol analysis; that is, only patients allocated to risk group R2 who received R2 therapy were included in that analysis. 25 ", "cite_spans": [{"start": 121, "end": 124, "text": "21,", "ref_id": "BIBREF190"}, {"start": 125, "end": 127, "text": "22", "ref_id": "BIBREF191"}, {"start": 394, "end": 396, "text": "24", "ref_id": "BIBREF193"}, {"start": 1400, "end": 1402, "text": "25", "ref_id": "BIBREF194"}, {"start": 2429, "end": 2430, "text": "4", "ref_id": "BIBREF171"}, {"start": 3613, "end": 3615, "text": "26", "ref_id": "BIBREF195"}, {"start": 4446, "end": 4448, "text": "25", "ref_id": "BIBREF194"}], "ref_spans": []}, {"section": "Results", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Patient characteristics", "text": "Of the 505 eligible patients, 119 were girls and 386 were boys. The median age was 9.3 years (range, 1.4-19.7 years) . The diagnoses of patients are given in Table 2 . Table 3 lists the distribution of For personal use only. on September 7, 2017 . by guest www.bloodjournal.org From patients according to risk groups and stages: 48, 233, 82, and 142 patients were assigned to risk group R1, R2, R3, and R4, respectively. Of the 40 patients with CNS disease, 27 had CSF blasts, 9 had an intraparenchymal mass, and 4 patients had a cranial nerve palsy only. Of the boys, 11 had testicular disease. The median pretreatment LDH was 371 U/L (range, 57-46 340 U/L).", "cite_spans": [], "ref_spans": [{"start": 158, "end": 165, "text": "Table 2", "ref_id": "TABREF1"}, {"start": 168, "end": 175, "text": "Table 3", "ref_id": "TABREF2"}]}, {"section": "Event-free survival", "text": "At a median follow-up of 3.3 years (range, 0.4-6.3 years), the 3-year pEFS was 89% \u03ee 1% (SE) for the total group (Figure 2) . The 3-year pEFS was 94% \u03ee 4%, 94% \u03ee 2%, 85% \u03ee 4%, and 81% \u03ee 3% for patients in risk groups R1, R2, R3, and R4, respectively ( Figure 3 ). pEFS according to stage is depicted in Figure 4 . There was no statistically significant difference between pEFS of patients with Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL). Patients with primary mediastinal large B-cell lymphoma had an inferior outcome, however (Table 2 ). Table 4 summarizes adverse events according to risk group and according to stage. One child in risk group R4 died early of tumor lysis syndrome. A total of 10 children died of sepsis (n \u03ed 6), invasive mycosis (n \u03ed 3), or meningitis (n \u03ed 1) after the first (n \u03ed 6), the third (n \u03ed 1), and the fourth (n \u03ed 3) course of therapy. There were 39 children who suffered from tumor failure. Local manifestations were the most frequent site of tumor failure followed by BM and new sites ( Table 2) . While on therapy, 11 patients suffered from tumor failure; 1 of them had persistent blasts after the second course of therapy. In 27 patients, tumor failure occurred after completion of chemotherapy within one year from diagnosis. There was one relapse 1.3 years after diagnosis. There were 3 patients who developed a second malignancy. There were 2 patients with BL who developed a second BL of different clonality 2.9 and 3.4 years after the first disease. One patient with DLBCL suffered a malignant melanoma. One BL patient suffered from a late recurrence 3.3 years after the first diagnosis. There was no material available for analysis regarding clonal identity or difference between the first and second malignant growths.", "cite_spans": [], "ref_spans": [{"start": 113, "end": 123, "text": "(Figure 2)", "ref_id": "FIGREF1"}, {"start": 252, "end": 260, "text": "Figure 3", "ref_id": "FIGREF2"}, {"start": 303, "end": 311, "text": "Figure 4", "ref_id": "FIGREF3"}, {"start": 548, "end": 556, "text": "(Table 2", "ref_id": "TABREF1"}, {"start": 560, "end": 567, "text": "Table 4", "ref_id": "TABREF3"}, {"start": 1039, "end": 1047, "text": "Table 2)", "ref_id": "TABREF1"}]}, {"section": "Events", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "CNS disease", "text": "The 3-year pEFS for the 40 CNS-positive patients was 69% \u03ee 7%. One patient died of infection (Table 4 ). Of the remaining 39 patients, 11 suffered from progression, 7 of them within the CNS.", "cite_spans": [], "ref_spans": [{"start": 93, "end": 101, "text": "(Table 4", "ref_id": "TABREF3"}]}, {"section": "Second-look surgery and autologous blood stem cell transplantation", "text": "Of the patients, 15 in risk group R3 and 16 in R4 received second-look surgery due to residual tumor after the fifth course. The histologic examination revealed viable residual tumor in only one patient of R4. This patient underwent ASCT and remained free of relapse (follow-up, 42 months). Another 4 patients (1 in R3, 3 in R4) underwent ASCT after completion of chemotherapy without undergoing second-look surgery. Although not foreseen in the protocol, 17 patients in risk group R2 underwent second-look surgery or biopsy after the fourth course of therapy due to a persistent tumor remnant. In 2 of these 17 cases, vital residual tumor was found. ASCT was performed in both patients, but one patient died of progressive disease thereafter.", "cite_spans": [], "ref_spans": []}, {"section": "Randomized trial of methotrexate as intravenous infusion over 4 hours versus 24 hours", "text": "Of the 505 patients, 364 were randomized to receive either MTX-4h (n \u03ed 180) or MTX-24h (n \u03ed 184) ( Table 5 ). Of the patients randomized to receive MTX-4h, 10 chose to receive MTX-24h. One patient randomized to receive MTX-24h chose to NA indicates not applicable. *Not randomized due to patients/guardians refusal or by physicians in charge. \u2020Because there was a trend for inferior results in the randomized arm MTX-4h, after the first and second interim analysis randomization was halted in blinded fashion for the time period until approval and recommendation of the external data safety and monitoring committee and the study committee regarding continuation or stopping of the trial. During this period, all requests for randomization of patients were answered with the allocation MTX-24 h.", "cite_spans": [], "ref_spans": [{"start": 99, "end": 106, "text": "Table 5", "ref_id": "TABREF5"}]}, {"section": "Randomized trial of methotrexate as intravenous infusion over 4 hours versus 24 hours", "text": "\u2021In risk groups R3 and R4, randomization was stopped after the second interim analysis. For personal use only. on September 7, 2017 . by guest www.bloodjournal.org From receive MTX-4h. In 63 cases (12%), patients/guardians did not give consent for randomization, preferring instead to choose the treatment arm. For the following reason, 20 patients were not randomized: In the first and second interim analysis, there was a trend toward inferior results in the randomized arm MTX-4h in risk groups R3 \u03e9 R4. Therefore, randomization was temporarily halted in a blinded fashion, pending approval and recommendation whether to stop or to continue the trial. In these periods, all requests of the participating clinics for randomization of patients were answered with the allocation MTX-24h.", "cite_spans": [], "ref_spans": []}, {"section": "Randomized trial of methotrexate as intravenous infusion over 4 hours versus 24 hours", "text": "In the second interim analysis in the combined risk groups R3 \u03e9 R4, the incidence of tumor failure was 5 times higher in the randomized arm MTX-4h than in the randomized arm MTX-24h, while in both arms 2 patients had died of toxicity. Because of this unexpected and alarming observation, in accordance with the DMC we changed from a test for noninferiority in pFFS to a log-rank test for difference. Because for a test of difference, an intent-to-treat analysis is the most conservative approach (not a per-protocol analysis), we also changed from the per-protocol analysis set of patients to an intent-to-treat set. 25 pFFS at one year was 91% \u03ee 4% for 56 patients with a minimal potential follow-up of one year and randomized to receive MTX-24h. In contrast, the one-year pFFS was 75% \u03ee 6% for 49 patients with a minimal potential follow-up of one year and randomized to receive MTX-4h (P \u03ed .03). Therefore, after consultation with the DMC, the randomization was stopped for patients in risk groups R3 \u03e9 R4 after the second interim analysis. The 57 patients thereafter enrolled in risk group R3 (n \u03ed 17) and risk group R4 (n \u03ed 40) and received MTX-24h. For patients in risk groups R1 and R2, however, randomization was continued until the end of the planned accrual period.", "cite_spans": [{"start": 617, "end": 619, "text": "25", "ref_id": "BIBREF194"}], "ref_spans": []}, {"section": "Randomized trial of methotrexate as intravenous infusion over 4 hours versus 24 hours", "text": "The final analysis was performed after a median follow-up of 3.3 years (range, 0.4-6.3 years). Table 6 shows the distribution of patient characteristics per randomized arm and according to risk group. The MTX serum concentrations at 24, 42, and 48 hours after the start of the MTX intravenous infusion were higher in patients receiving MTX-24h compared with those receiving MTX-4h (Table 7) . There was no statistically significant difference of intervals between 2 subsequent courses in either randomization group (Table 8) .", "cite_spans": [], "ref_spans": [{"start": 95, "end": 102, "text": "Table 6", "ref_id": "TABREF7"}, {"start": 381, "end": 390, "text": "(Table 7)", "ref_id": "TABREF8"}, {"start": 515, "end": 524, "text": "(Table 8)", "ref_id": "TABREF9"}]}, {"section": "Intent-to-treat analysis", "text": "Results of the intent-to-treat analysis are given in Table 9 and in Figure 5A -C. The one-year pFFS for patients randomized to receive MTX-4h versus MTX-24h was as follows: in the total group, 88% \u03ee 2% (n \u03ed 180) versus 95% \u03ee 2% (n \u03ed 184) *Indicates the number of hours over which the infusion was given. \u2020After the beginning of MTX intravenous infusion.", "cite_spans": [], "ref_spans": [{"start": 53, "end": 60, "text": "Table 9", "ref_id": "TABREF10"}, {"start": 68, "end": 77, "text": "Figure 5A", "ref_id": "FIGREF7"}]}, {"section": "Intent-to-treat analysis", "text": "(P \u03ed .015; Figure 5A ); in risk group R1, 95% \u03ee 5% (n \u03ed 21) versus 100% (n \u03ed 19) (P \u03ed 0.34); in risk group R2, 95% \u03ee 2% (n \u03ed 93) versus 96% \u03ee 2% (n \u03ed 96) (P \u03ed .71) (hazard ratio, 1.28; 95% CI, 0.34-4.78) ( Figure 5B) ; and in the combined risk groups R3 \u03e9 R4 77% \u03ee 5% (n \u03ed 66) versus 93% \u03ee 3% (n \u03ed 69) (P \u03ed .0077; hazard ratio, 3.58; 95% CI, 1.31-9.79) ( Figure 5C ). In univariate analysis of patients of the combined risk groups R3 \u03e9 R4, female sex (P \u03ed .03) and age older than 10 years (P \u03ed .01) were associated with inferior pFFS. In a Cox regression model with the covariables sex, age younger than 10 years versus 10 years or older, and risk group R3 versus R4, the hazard ratio of the randomized arm MTX-4h was 3.59 (95% CI, 1.30-9.93; P \u03ed .014; Table 10 ). This result is very close to the univariate analysis.", "cite_spans": [], "ref_spans": [{"start": 11, "end": 20, "text": "Figure 5A", "ref_id": "FIGREF7"}, {"start": 206, "end": 216, "text": "Figure 5B)", "ref_id": "FIGREF7"}, {"start": 355, "end": 364, "text": "Figure 5C", "ref_id": "FIGREF7"}, {"start": 753, "end": 761, "text": "Table 10", "ref_id": "TABREF0"}]}, {"section": "Per-protocol analysis to test for noninferiority of the randomized arm MTX-4h", "text": "Excluded from the per-protocol analysis were 11 patients who rejected the randomized arm but instead chose to receive the alternative MTX schedule (Table 5 ). In risk group R2 (MTX dose, 1 g/m 2 ), the one-year pFFS was 94% \u03ee 2% for 88 randomized patients who received MTX-4h compared with 96% \u03ee 2% for 95 randomized patients who received MTX-24h (hazard ratio, 1.34; 95% CI, 0.36-4.99). The lower limit of the one-sided 95.5% CI for the difference (pFFS MTX-4h \u03ea pFFS MTX-24h, alpha corrected for multiple testing) was \u03ea6.8%. This was above the predetermined loss of \u03ea11%, which was considered still to be acceptable.", "cite_spans": [], "ref_spans": [{"start": 147, "end": 155, "text": "(Table 5", "ref_id": "TABREF5"}]}, {"section": "Per-protocol analysis to test for noninferiority of the randomized arm MTX-4h", "text": "In the combined risk groups R3 \u03e9 R4 (MTX dose, 5 g/m 2 ), the one-year pFFS was 77% \u03ee 5% for 62 randomized patients who received MTX-4h (12 tumor failures) compared with 93% \u03ee 3% for 69 randomized patients who received MTX-24h (2 tumor failures). In both arms, 3 patients each died of toxicity. The hazard ratio was 3.56 (95% CI, 1.29-9.82). The lower limit of the one-sided 95% CI for the difference (pFFS MTX-4h \u03ea pFFS MTX-24h) was \u03ea25%, which was far lower than the predetermined level of \u03ea17%. This means that the possible loss in the efficacy is too high.", "cite_spans": [], "ref_spans": []}, {"section": "Toxicities with MTX-4h or MTX-24h", "text": "In all risk groups, the incidence of the maximum grade of mucositis was significantly lower in randomized patients who received MTX-4h compared with randomized patients who received MTX24h (Table 11 ). The frequencies of main toxicities grades III/IV per total number of courses administered are given as a descriptive analysis in Table 12 .", "cite_spans": [], "ref_spans": [{"start": 189, "end": 198, "text": "(Table 11", "ref_id": "TABREF0"}, {"start": 331, "end": 339, "text": "Table 12", "ref_id": "TABREF0"}]}, {"section": "Toxicities with MTX-4h or MTX-24h", "text": "Comparison of pEFS for patients in risk group R2 against the historical control group in study NHL-BFM90", "cite_spans": [], "ref_spans": []}, {"section": "Toxicities with MTX-4h or MTX-24h", "text": "The proportion of patients in risk group R2 was 40% in study NHL-BFM90 and 46% in study NHL-BFM95 (Table 13 ). In studies BFM90 and BFM95, 13 and 11 patients, respectively, received treatment differing from risk group R2. Thus, 154 and 222 R2 patients of studies NHL-BFM90 and NHL-BFM95, respectively, were evaluable for comparison. In study BFM90, the 3-year pEFS was 97% \u03ee 1% for the 154 patients of risk group R2 who received R2 therapy and was 95 \u03ee 2% for the 222 patients in study BFM95 ( Figure 6 ). The lower limit of the one-sided 95% CI for the difference in pEFS of risk group R2 in study NHL-BFM95 (MTX dose, 1 g/m 2 ) minus pEFS of risk group R2 in study NHL-BFM95 (MTX dose, 5 g/m 2 ) was \u03ea4.5%. The distribution of patient characteristics was comparable in studies NHL-BFM90 and NHL-BFM95 with one exception. In study NHL-BFM95, the percentage of BL patients was lower than in study NHL-BFM90, while the proportion of patients with DLBCL was higher. The 3-year pEFS for patients with BL or DLBCL was comparable in both studies, however (Table 13) . Tumor failure, no. (no. alive after rescue) 1 (1) 0 4 (2) 4 (0) 12 (2) 2 (0) 17 (5) Intent-to-treat analysis. Log-rank P \u03ed .34 for R1, .72 for R2, .0077 for R3 \u03e9 R4, and .015 for all.", "cite_spans": [], "ref_spans": [{"start": 98, "end": 107, "text": "(Table 13", "ref_id": "TABREF0"}, {"start": 494, "end": 502, "text": "Figure 6", "ref_id": "FIGREF8"}, {"start": 1050, "end": 1060, "text": "(Table 13)", "ref_id": "TABREF0"}]}, {"section": "Discussion", "text": "Favorable results have been reported from previous studies on childhood and adolescent B-cell neoplasms. [1] [2] [3] [4] [5] [6] [7] [8] The toxicity of these protocols was considerable, however. Therefore, study NHL-BFM95 aimed at reducing treatment-related toxicity without jeopardizing treatment outcome. The 3-year pEFS for the 505 eligible patients was 89% \u03ee 1% and thus comparable with the results of previous studies. [1] [2] [3] [4] [5] [6] [7] [8] The treatment proved equally efficacious for all subtypes of childhood and adolescent B-NHL, with the possible exception of primary mediastinal large B-cell lymphoma. Recent reports support the unique nature of this large cell lymphoma, which may need a specifically adapted treatment (eg, the high local failure rate [ Table 2 ] may ask for a role of local radiotherapy). 27 High-dose MTX is a key component of most protocols for childhood and adolescent B-cell neoplasms. However, the dose of MTX, the administration schedule, as well as the leucovorin rescue vary considerably between these protocols. All these parameters, especially the duration of the continuous intravenous infusion of MTX, may have a substantial influence on efficacy and toxicity. [10] [11] [12] [13] [14] In our previous trials, orointestinal toxicity appeared to be the most important therapy-associated toxicity, mainly attributable to high-dose MTX given as continuous intravenous infusion over 24 hours. 4 Therefore, the first aim of study NHL-BFM95 was to test in a randomized trial whether the incidence of orointestinal mucositis grade III/IV can be reduced by shortening the time of intravenous infusion of high-dose MTX from 24 hours to 4 hours, without impairment of the probability of FFS. Indeed, the present study showed an impressive reduction of severe orointestinal mucositis in patients having received MTX-4h compared with MTX-24h in all therapy branches.", "cite_spans": [{"start": 105, "end": 108, "text": "[1]", "ref_id": "BIBREF168"}, {"start": 109, "end": 112, "text": "[2]", "ref_id": "BIBREF169"}, {"start": 113, "end": 116, "text": "[3]", "ref_id": "BIBREF170"}, {"start": 117, "end": 120, "text": "[4]", "ref_id": "BIBREF171"}, {"start": 121, "end": 124, "text": "[5]", "ref_id": "BIBREF172"}, {"start": 125, "end": 128, "text": "[6]", "ref_id": "BIBREF173"}, {"start": 129, "end": 132, "text": "[7]", "ref_id": "BIBREF174"}, {"start": 133, "end": 136, "text": "[8]", "ref_id": "BIBREF175"}, {"start": 425, "end": 428, "text": "[1]", "ref_id": "BIBREF168"}, {"start": 429, "end": 432, "text": "[2]", "ref_id": "BIBREF169"}, {"start": 433, "end": 436, "text": "[3]", "ref_id": "BIBREF170"}, {"start": 437, "end": 440, "text": "[4]", "ref_id": "BIBREF171"}, {"start": 441, "end": 444, "text": "[5]", "ref_id": "BIBREF172"}, {"start": 445, "end": 448, "text": "[6]", "ref_id": "BIBREF173"}, {"start": 449, "end": 452, "text": "[7]", "ref_id": "BIBREF174"}, {"start": 453, "end": 456, "text": "[8]", "ref_id": "BIBREF175"}, {"start": 830, "end": 832, "text": "27", "ref_id": "BIBREF196"}, {"start": 1214, "end": 1218, "text": "[10]", "ref_id": "BIBREF177"}, {"start": 1219, "end": 1223, "text": "[11]", "ref_id": "BIBREF178"}, {"start": 1224, "end": 1228, "text": "[12]", "ref_id": "BIBREF179"}, {"start": 1229, "end": 1233, "text": "[13]", "ref_id": "BIBREF180"}, {"start": 1234, "end": 1238, "text": "[14]", "ref_id": "BIBREF181"}, {"start": 1442, "end": 1443, "text": "4", "ref_id": "BIBREF171"}], "ref_spans": [{"start": 777, "end": 784, "text": "Table 2", "ref_id": "TABREF1"}]}, {"section": "Discussion", "text": "However, in terms of efficacy, significant differences were observed regarding outcome and MTX infusion regimen in different risk groups. Regarding pFFS, the 4-hour infusion of high-dose MTX was noninferior to the 24-hour infusion for patients in risk groups R1 and R2 (55% of the total patient population). In risk groups R3 \u03e9 R4, however, pFFS was significantly worse for patients having received MTX as a 4-hour infusion. The second interim analysis of the trial showed a 5-fold excess of tumor failure if MTX was administered over 4 hours compared with a 24-hour infusion. As a consequence of this alarming finding, randomization was omitted for patients in risk groups R3 \u03e9 R4 after the second interim analysis. In the final analysis, pFFS of patients randomized to receive MTX 5 g/m 2 as infusion over 4 hours was significantly (P \u03ed .008) lower compared with patients randomized to receive MTX 5 g/m 2 as infusion over 24 hours. This difference in pFFS was not attributable to differences in patient characteristics between the 2 randomized arms. In a multivariate Cox regression analysis (including the covariables risk group, age, and sex), randomization in therapy arm MTX-4h was a significant risk factor for tumor failure. The leucovorin rescue as well as the application of all other chemotherapeutic agents were identical in both randomized arms. We conclude, therefore, that the difference in treatment efficacy between the 2 randomized arms for patients in risk groups R3 \u03e9 R4 can be attributed to the different schedule of intravenous MTX infusion. For personal use only. on September 7, 2017 . by guest www.bloodjournal.org From", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "The observed difference of the impact of MTX administration schedules on efficacy for patients in risk groups R3 \u03e9 R4 compared with those in risk groups R1 and R2 is intriguing. Patients in risk groups R3 \u03e9 R4 differ from those in risk groups R1 and R2 primarily with respect to the higher tumor mass, which, in turn, might be associated with a higher proportion of multiple resistant cells within the tumor cell population. 28 Because cytotoxicity of MTX is time dependent, 12 longer exposure times of these resistant cells during a 24-hour infusion of MTX might be associated with improved clearance of these cells and, thus, might explain the higher pFFS of patients with high tumor load and long MTX infusion. In fact, this observation may be interpreted as strong evidence for the efficacy of MTX as such in the treatment of B-cell neoplasms of childhood and adolescents. According to the Goldie Coldman postulation, 28 the lower tumor mass of the patients in risk groups R1 and R2 might be associated with a lower proportion of multiple resistant cells within the tumor cell population. Hence, these cells might be eradicated with a less efficacious schedule of MTX. On the other hand, the noninferiority of the short MTX infusion regimen compared with the long infusion regimen in terms of pFFS for patients in risk groups R1 and R2 may reflect that the impact of MTX on the overall therapeutic success may be of lesser importance in patients with lower tumor load compared with those with higher tumor masses.", "cite_spans": [{"start": 425, "end": 427, "text": "28", "ref_id": "BIBREF197"}, {"start": 922, "end": 924, "text": "28", "ref_id": "BIBREF197"}], "ref_spans": []}, {"section": "Discussion", "text": "Comparison of treatment outcome of patients in risk group R2 in the present trial NHL-BFM95 versus the previous study NHL-BFM90 supports the following hypothesis: pEFS for patients in risk group R2 did not differ between trials NHL-BFM90 and NHL-BFM95 despite a reduction of the dose of MTX to 1 g/m 2 in study NHL-BFM95 compared with 5 g/m 2 in the preceding trial NHL-BFM90. Furthermore, for this patient subgroup, intensification of chemotherapy in case of incomplete tumor regression after 2 therapy courses as performed in study NHL-BFM90 seems to be dispensable with the exception of single cases with very poor response to treatment. 4 Our data suggest that a favorable balance of efficacy and toxicity is possible for patients with B-NHL stage I, II, and III (LDH \u03fd 500 U/L) (55% of all cases of B-cell neoplasms of childhood and adolescence). They have a pFFS of 95% with only 2 (R1) or 4 (R2) 5-day courses of chemotherapy including MTX 1 g/m 2 as intravenous infusion over 4 hours. Mucositis grade III/IV was observed after only 6% of 374 courses, while infections grade III were observed after only 2% of 374 courses. However, further reduction of therapy in this patient subgroup may be crucial as long as no proven salvage regimen for relapsed patients is available. Surprisingly all 3 second malignancies occurred in risk groups R1 and R2 with less intense chemotherapy.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "For patients with advanced disease, however, FFS rates comparable with the excellent results in the French study LMB 89 6 were obtained only with the courses including MTX 5 g/m 2 as intravenous infusion over 24 hours. In study LMB 89, however, high-dose MTX was given as intravenous infusion over only 3 or 4 hours depending on treatment branch. Although almost the same drugs were used in the LMB and the BFM strategy, the weight of some drugs such as anthracyclines, etoposide, and alkylating agents differed considerably. This may have outweighed the effect of the short infusion time of MTX in the LMB regimen. This assumption is supported by the observation that the acute toxicity profiles of the COPADM courses used in study LMB 89, including MTX 3 g/m 2 and 8 g/m 2 as infusion over 3 and 4 hours, respectively, are similar to those of the courses AA and BB in study NHL-BFM95, including MTX 5 g/m 2 as infusion over 24 hours. 6 Interestingly, in study NHL-BFM95, the pFFS of patients in the combined risk groups R3 \u03e9 R4 who received MTX 5 g/m 2 as intravenous infusion over 24 hours was higher compared with the corresponding patients in study NHL-BFM90 (risk group R3 of study NHL-BFM90 was subdivided into risk groups R3 \u03e9 R4 by LDH \u03fd or \u03fe 1000 U/L in study NHL-BFM95). 4 In trial NHL-BFM95, all patients in risk groups R3 \u03e9 R4 received course CC including high-dose cytarabine and etoposide. High-dose cytarabine/ etoposide was described as effective even in relapsed B-NHL patients. 29 For comparison, in our preceding study NHL-BFM90 only 30% of the corresponding patients received course CC. Moreover, the dose of cytarabine and etoposide was increased in course CC of study NHL-BFM95.", "cite_spans": [{"start": 120, "end": 121, "text": "6", "ref_id": "BIBREF173"}, {"start": 936, "end": 937, "text": "6", "ref_id": "BIBREF173"}, {"start": 1282, "end": 1283, "text": "4", "ref_id": "BIBREF171"}, {"start": 1497, "end": 1499, "text": "29", "ref_id": "BIBREF198"}], "ref_spans": []}, {"section": "Discussion", "text": "To our knowledge, study NHL-BFM95 is the first randomized controlled trial describing the impact of different MTX administration regimens on patient outcome and toxicity in the therapy of NHL. The results and conclusions from this trial may help to further optimize treatment not only for children and adolescents with B-cell NHL/AL, but also for adults suffering from highly aggressive B-cell neoplasms. Furthermore, experience from this trial shows that changes in administration schedules of wellestablished drugs may have profound and unexpected impact on both efficacy and side effects of chemotherapy.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "BLOOD, 1 FEBRUARY 2005 \u2150 VOLUME 105, NUMBER 3 For personal use only. on September 7, 2017 . by guest www.bloodjournal.org From", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF168": {"title": "Improved survival for children with B-cell acute lymphoblastic leukemia and stage IV small noncleaved-cell lymphoma: a pediatric oncology group study", "authors": [{"first": "W", "middle": ["P"], "last": "Bowman", "suffix": ""}, {"first": "J", "middle": ["J"], "last": "Shuster", "suffix": ""}, {"first": "B", "middle": [], "last": "Cook", "suffix": ""}], "year": 1996, "venue": "J Clin Oncol", "link": "24713460"}, "BIBREF169": {"title": "Adults and children with small non-cleaved-cell lymphoma have a similar excellent outcome when treated with the same chemotherapy regimen", "authors": [{"first": "I", "middle": [], "last": "Magrath", "suffix": ""}, {"first": "M", "middle": [], "last": "Adde", "suffix": ""}, {"first": "A", "middle": [], "last": "Shad", "suffix": ""}], "year": 1996, "venue": "J Clin Oncol", "link": "2795687"}, "BIBREF170": {"title": "Fractionated cyclophosphamide and back to back high dose methotrexate and cytosine araginoside improves outcome in patients with stage III high grade small non-cleaved cell lymphomas (Snccl): a randomized trial of the Pediatric Oncology Group", "authors": [{"first": "M", "middle": ["L"], "last": "Brecher", "suffix": ""}, {"first": "M", "middle": ["R"], "last": "Schwenn", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Coppes", "suffix": ""}], "year": 1997, "venue": "Med Pediatr Oncol", "link": "7462054"}, "BIBREF171": {"title": "Improved treatment results in childhood B-cell neoplasms with tailored intensification of therapy: a report of the Berlin-Frankfurt-M\u00fc nster Group Trial NHL-BFM90", "authors": [{"first": "A", "middle": [], "last": "Reiter", "suffix": ""}, {"first": "M", "middle": [], "last": "Schrappe", "suffix": ""}, {"first": "M", "middle": [], "last": "Tiemann", "suffix": ""}], "year": 1999, "venue": "Blood", "link": "16278064"}, "BIBREF172": {"title": "Improved outcome in children with advanced stage B-cell non Hodgkin's lymphoma (B-NHL): results of the United Kingdom Children Cancer Study Group (UKCCSG) 9002 protocol", "authors": [{"first": "A", "middle": [], "last": "Atra", "suffix": ""}, {"first": "J", "middle": ["D"], "last": "Imeson", "suffix": ""}, {"first": "R", "middle": [], "last": "Hobson", "suffix": ""}], "year": 2000, "venue": "Br J Cancer", "link": "15479355"}, "BIBREF173": {"title": "The Societe Francasie d'Oncologie Pediatrique LMB89 protocol: highly effective multiagent chemotherapy tailored the tumor burden and initial response in 561 unselected children with B-cell lymphomas and L3 leukemia", "authors": [{"first": "C", "middle": [], "last": "Patte", "suffix": ""}, {"first": "A", "middle": [], "last": "Auperin", "suffix": ""}, {"first": "J", "middle": [], "last": "Michon", "suffix": ""}], "year": 2001, "venue": "Blood", "link": "22052439"}, "BIBREF174": {"title": "Long-term follow-up of short intensive multiagent chemotherapy without high-dose methotrexate ('Orange') in children with advanced non-lymphoblastic non-Hodgkin's lymphoma: a children's cancer group report", "authors": [{"first": "M", "middle": ["S"], "last": "Cairo", "suffix": ""}, {"first": "M", "middle": ["D"], "last": "Krailo", "suffix": ""}, {"first": "M", "middle": [], "last": "Morse", "suffix": ""}], "year": 2002, "venue": "Leukemia", "link": "626174"}, "BIBREF175": {"title": "Intensive, very short chemotherapy for advanced Burkitt's lymphoma in children", "authors": [{"first": "F", "middle": [], "last": "Spreafico", "suffix": ""}, {"first": "M", "middle": [], "last": "Massimino", "suffix": ""}, {"first": "R", "middle": [], "last": "Luksch", "suffix": ""}], "year": 2002, "venue": "J Clin Oncol", "link": "38824897"}, "BIBREF176": {"title": "Favorable outcome of B-cell acute lymphoblastic leukemia in childhood: a report of three consecutive studies of the BFM group", "authors": [{"first": "A", "middle": [], "last": "Reiter", "suffix": ""}, {"first": "M", "middle": [], "last": "Schrappe", "suffix": ""}, {"first": "W", "middle": ["D"], "last": "Ludwig", "suffix": ""}], "year": 1992, "venue": "Blood", "link": "40149057"}, "BIBREF177": {"title": "Membrane transport of methotrexate in human lymphoblastoid cells", "authors": [{"first": "R", "middle": ["D"], "last": "Warren", "suffix": ""}, {"first": "A", "middle": ["P"], "last": "Nichols", "suffix": ""}, {"first": "R", "middle": ["A"], "last": "Bender", "suffix": ""}], "year": 1978, "venue": "Cancer Res", "link": "9502943"}, "BIBREF178": {"title": "Alterations in kinetics of methotrexate transport during growth of L1210 murine leukemia cells in culture", "authors": [{"first": "P", "middle": ["L"], "last": "Chello", "suffix": ""}, {"first": "F", "middle": ["M"], "last": "Sirotnak", "suffix": ""}, {"first": "D", "middle": ["M"], "last": "Dorick", "suffix": ""}], "year": 1980, "venue": "Mol Pharmacol", "link": null}, "BIBREF179": {"title": "Methotrexate cytotoxicity for L5178Y/ASN-lymphoblasts relationship of dose and duration of exposure to tumor cell viability", "authors": [{"first": "D", "middle": ["A"], "last": "O&apos;keefe", "suffix": ""}, {"first": "R", "middle": ["L"], "last": "Capizzi", "suffix": ""}, {"first": "S", "middle": ["A"], "last": "Rudnick", "suffix": ""}], "year": 1982, "venue": "Cancer Res", "link": "6804068"}, "BIBREF180": {"title": "The effect of the rate of cell proliferation on the synthesis of methotrexate poly-gamma-glutamates in two human breast cancer cell lines", "authors": [{"first": "D", "middle": ["G"], "last": "Kennedy", "suffix": ""}, {"first": "H", "middle": ["W"], "last": "Van Den Berg", "suffix": ""}, {"first": "R", "middle": [], "last": "Clarke", "suffix": ""}], "year": 1985, "venue": "Biochem Pharmacol", "link": null}, "BIBREF181": {"title": "Randomized comparison of 36-hour intermediatedose versus 4-hour high-dose methotrexate infusions for remission induction in relapsed childhood acute lymphoblastic leukemia", "authors": [{"first": "C", "middle": [], "last": "Wolfrom", "suffix": ""}, {"first": "R", "middle": [], "last": "Hartmann", "suffix": ""}, {"first": "R", "middle": [], "last": "Fengler", "suffix": ""}], "year": "", "venue": "", "link": "43089964"}, "BIBREF183": {"title": "Updated Kiel classification for lymphomas", "authors": [{"first": "A", "middle": ["G"], "last": "Stansfeld", "suffix": ""}, {"first": "J", "middle": [], "last": "Diebold", "suffix": ""}, {"first": "H", "middle": [], "last": "Noel", "suffix": ""}], "year": 1988, "venue": "Lancet", "link": "8472235"}, "BIBREF184": {"title": "World Health Organization Classification of Tumours", "authors": [], "year": 2001, "venue": "Pathology & Genetics: Tumours of Haematopoietic and Lymphoid Tissues", "link": null}, "BIBREF185": {"title": "Classification, staging and end results of treatment in childhood non-Hodgkin's lymphoma: dissimilarities from lymphomas in adults", "authors": [{"first": "S", "middle": ["B"], "last": "Murphy", "suffix": ""}], "year": 1980, "venue": "Sem Oncol", "link": "56861624"}, "BIBREF186": {"title": "Use of uricozyme\u00ae and occurrence of metabolic problems during initial phase of the LMB 89 protocol", "authors": [{"first": "C", "middle": [], "last": "Sakiroglu", "suffix": ""}, {"first": "C", "middle": [], "last": "Patte", "suffix": ""}, {"first": "J", "middle": [], "last": "Michon", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF188": {"title": "Urate oxidase in prevention and treatment of hyperuricemia associated with lymphoid malignancies", "authors": [{"first": "C", "middle": ["H"], "last": "Pui", "suffix": ""}, {"first": "M", "middle": ["V"], "last": "Relling", "suffix": ""}, {"first": "F", "middle": [], "last": "Lascombes", "suffix": ""}], "year": 1997, "venue": "Leukemia", "link": "6740552"}, "BIBREF189": {"title": "Incidence of tumor lysis syndrome in children with advanced stage Burkitt's lymphoma/leukemia before and after introduction of prophylactic use of urate oxidase", "authors": [{"first": "W", "middle": [], "last": "W\u00f6 Ssmann", "suffix": ""}, {"first": "M", "middle": [], "last": "Schrappe", "suffix": ""}, {"first": "U", "middle": [], "last": "Meyer", "suffix": ""}, {"first": "M", "middle": [], "last": "Zimmermann", "suffix": ""}, {"first": "A", "middle": [], "last": "Reiter", "suffix": ""}], "year": 2003, "venue": "Ann Hematol", "link": "27279071"}, "BIBREF190": {"title": "Nonparametric estimation from incomplete observations", "authors": [{"first": "E", "middle": ["L"], "last": "Kaplan", "suffix": ""}, {"first": "P", "middle": [], "last": "Meier", "suffix": ""}], "year": 1958, "venue": "J Am Stat Assoc", "link": "18549513"}, "BIBREF191": {"title": "Evaluation of survival data and two new rank order statistics arising in its consideration", "authors": [{"first": "N", "middle": [], "last": "Mantel", "suffix": ""}], "year": 1966, "venue": "Cancer Chemother Rep", "link": "1176212"}, "BIBREF192": {"title": "United Kingdom: Her Majesty's Stationery Office", "authors": [{"first": "M", "middle": [], "last": "Greenwood", "suffix": ""}], "year": "", "venue": "In: Reports on Public Health and Statistical Subjects", "link": null}, "BIBREF193": {"title": "Regression models and life tables", "authors": [{"first": "D", "middle": ["R"], "last": "Cox", "suffix": ""}], "year": 1972, "venue": "J R Stat Soc", "link": "210698768"}, "BIBREF194": {"title": "ICH Expert Working Group & International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH Harmonised Tripartite Guideline: Statistical Principles for Clinical Trials E9", "authors": [], "year": 1998, "venue": "", "link": null}, "BIBREF195": {"title": "A multiple testing procedure for clinical trials", "authors": [{"first": "P", "middle": ["C"], "last": "O&apos;brien", "suffix": ""}, {"first": "T", "middle": ["R"], "last": "Fleming", "suffix": ""}], "year": 1979, "venue": "Biometrics", "link": "40193042"}, "BIBREF196": {"title": "Primary medistinal (thymic) large B-cell lymphoma with sclerosis in pediatric and adolescent patients: treatment and results from three therapeutic studies of the Berlin-Frankfurt-M\u00fc nster (BFM) group", "authors": [{"first": "K", "middle": [], "last": "Seidemann", "suffix": ""}, {"first": "M", "middle": [], "last": "Tiemann", "suffix": ""}, {"first": "I", "middle": [], "last": "Lauterbach", "suffix": ""}], "year": 2003, "venue": "J Clin Oncol", "link": null}, "BIBREF197": {"title": "The genetic origin of drug resistance in neoplasms: implications for systemic therapy", "authors": [{"first": "J", "middle": ["H"], "last": "Goldie", "suffix": ""}, {"first": "A", "middle": ["J"], "last": "Coldman", "suffix": ""}], "year": 1984, "venue": "Cancer Res", "link": "18119619"}, "BIBREF198": {"title": "Phase II study of cytarabine and etoposide in children with refractory or relapsed non-Hodgkin's lymphoma: a study of the French Society of Pediatric Oncology", "authors": [{"first": "J", "middle": ["C"], "last": "Gentet", "suffix": ""}, {"first": "C", "middle": [], "last": "Patte", "suffix": ""}, {"first": "E", "middle": [], "last": "Quintana", "suffix": ""}], "year": 1990, "venue": "J Clin Oncol", "link": "2309659"}}, "ref_entries": {"FIGREF1": {"text": "Figure 2. Kaplan-Meier estimate (P) of EFS at 3 years for the total group. SE indicates standard error.", "type": "figure"}, "FIGREF2": {"text": "Figure 3. Kaplan-Meier estimate (P) of EFS at 3 years according to risk groups R1, R2, R3, and R4. SE indicates standard error.", "type": "figure"}, "FIGREF3": {"text": "Figure 4. Kaplan-Meier estimate (P) of EFS at 3 years according to stage. SE indicates standard error.", "type": "figure"}, "FIGREF4": {"text": "Not possible to perform a successful molecular study on clonal differences between the first and the second malignant growths. \u2020Secondary NHL in 2 cases, malignant melanoma in 1 patient. \u2021After event-free follow-up duration of 0.4 to 5.4 years (median, 2.75 years). \u00a7Primary in parailiac nodes, combined local and bone marrow relapse 3 months after completion of front-line therapy. The patient is in complete second remission for 34 months following salvage therapy including megadose chemotherapy with autologous stem cell rescue.", "type": "figure"}, "FIGREF5": {"text": "serum concentration at hour 24, \u2020 M, median (range) 0.32 (0.1-75.9) 8.17 (0.1-107.0) 0.88 (0.1-31.0) 46.40 (0.3-344.9) MTX serum concentration at hour 42, \u2020 M, median (range) 0.09 (0-2.6) 0.18 (0-1.0) 0.18 (0-13.0) 0.43 (0-6.5) MTX serum concentration at hour 48, \u2020 M, median (range) 0.06 (0-1.2) 0.1 (0-0.7) 0.13 (0-4.9) 0.24 (0-5.0)", "type": "figure"}, "FIGREF7": {"text": "Figure 5. Kaplan-Meier estimate (P) of a one-year failure-free survival of patients randomized to receive MTX as intravenous infusion either over 4 hours or over 24 hours. Intent-to-treat analysis. (A) For the whole group; (B) for patients in risk group R2; and (C) for patients in combined risk groups R3 \u03e9 R4. SE indicates standard error.", "type": "figure"}, "FIGREF8": {"text": "Figure 6. Kaplan-Meier estimate (P) of EFS at 3 years for patients of risk group R2 in study NHL-BFM95 and in the preceding trial NHL-BFM90. SE indicates standard error.", "type": "figure"}, "TABREF0": {"text": "Therapy courses", "type": "table"}, "TABREF1": {"text": "Diagnosis, treatment results", "type": "table"}, "TABREF2": {"text": "Risk groups and stages", "type": "table"}, "TABREF3": {"text": "Adverse events according to risk groups and stages", "type": "table"}, "TABREF5": {"text": "Randomization Risk group, no.", "type": "table"}, "TABREF7": {"text": "Characteristics of randomized patients", "type": "table"}, "TABREF8": {"text": "Serum methotrexate concentrations of randomized patients", "type": "table"}, "TABREF9": {"text": "Number of days between beginning of 2 subsequent courses in randomized patients (MTX intravenous infusion as given)", "type": "table"}, "TABREF10": {"text": "Treatment results of randomized patients", "type": "table"}, "TABREF11": {"text": "Cox regression analysis for randomized patients of risk groups R3 \u0609 R4", "type": "table"}, "TABREF12": {"text": "Per protocol analysis as MTX given. Wilcoxon test P \u03ed .06 for R1, .0002 for R2, and .0027 for R3 \u03e9 R4. *Indicates the number of hours over which the infusion was given.", "type": "table"}, "TABREF13": {"text": "Percent courses with toxicity grade III/IV (NCI-CTC) of randomized patients (MTX IV infusion as given)NCI-CTC indicates National Cancer Institute-Common Toxicity Criteria. Hepatotoxicity grade III/IV was 0% for all courses. *Indicates the number of hours over which the infusion was given.", "type": "table"}, "TABREF14": {"text": "Characteristics and treatment results of patients of risk group R2 in studies NHL-BFM90 and NHL-BFM95 NHL-BFM90 patients NHL-BFM95 patientsEvents, no.DLBCL indicates diffuse large B-cell lymphoma; and PMLBL, primary mediastinal (thymic) large B-cell lymphoma.", "type": "table"}}}
{"paper_id": "10707050", "_pdf_hash": "1ffa157e65b0d29aff1ea8c7c0659babf45fa2cf", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "The discovery of diabetic nephropathy: from small 1. print to centre stage", "authors": [{"first": "J", "middle": ["S"], "last": "Cameron", "suffix": ""}], "year": 2006, "venue": "J Nephrol", "link": null}, "BIBREF2": {"title": "Diabetic nephropathy: diagnosis, prevention, and treatment", "authors": [{"first": "Zelmanovitz", "middle": ["T"], "last": "Ml", "suffix": ""}], "year": 2005, "venue": "Diabetes Care", "link": "79266954"}, "BIBREF3": {"title": "Diabetic nephropathy: a frontier for 3. personalized medicine", "authors": [{"first": "K", "middle": [], "last": "Susztak", "suffix": ""}, {"first": "E", "middle": ["P"], "last": "Bottinger", "suffix": ""}], "year": 2006, "venue": "J Am Soc Nephrol", "link": "38474744"}, "BIBREF4": {"title": "Glomerular and vas-4. cular \"insudative\" lesions of diabetic nephropathy: electron microscopic observations", "authors": [{"first": "L", "middle": [], "last": "Salinas-Madrigal", "suffix": ""}, {"first": "C", "middle": ["L"], "last": "Pirani", "suffix": ""}, {"first": "V", "middle": ["E"], "last": "Pollak", "suffix": ""}], "year": 1970, "venue": "Am J Pathol", "link": "42231917"}, "BIBREF5": {"title": "From hyperglycemia 5. to diabetic kidney disease: the role of metabolic, hemodynamic, intracellular factors and growth factors/cytokines", "authors": [{"first": "B", "middle": ["F"], "last": "Schrijvers", "suffix": ""}, {"first": "De", "middle": [], "last": "Vriese", "suffix": ""}, {"first": "A", "middle": ["S"], "last": "Flyvbjerg", "suffix": ""}, {"first": "A", "middle": [], "last": "", "suffix": ""}], "year": 2004, "venue": "Endocr Rev", "link": null}, "BIBREF6": {"title": "Biochemistry and molecular cell biology of dia-6. betic complications", "authors": [{"first": "M", "middle": [], "last": "Brownlee", "suffix": ""}], "year": 2001, "venue": "Nature", "link": null}, "BIBREF7": {"title": "Retinopathy and nephropathy in patients with type 1 diabetes 8. four years after a trial of intensive therapy. The Diabetes Control and Complications Trial/Epidemiology of Diabetes Intervention and Complications Research Group", "authors": [{"first": "J", "middle": [], "last": "Huang", "suffix": ""}, {"first": "Y", "middle": [], "last": "Kim", "suffix": ""}, {"first": "M", "middle": ["L"], "last": "Caramori", "suffix": ""}, {"first": "A", "middle": [], "last": "Fish", "suffix": ""}, {"first": "S", "middle": [], "last": "Rich", "suffix": ""}, {"first": "M", "middle": [], "last": "Miller", "suffix": ""}], "year": 2000, "venue": "N Engl J Med", "link": null}, "BIBREF8": {"title": "of diabetic kidney disease: Evidence for genetic susceptibility to diabetic nephropathy", "authors": [{"first": "E", "middle": ["R"], "last": "Seaquist", "suffix": ""}, {"first": "F", "middle": ["C"], "last": "Goetz", "suffix": ""}, {"first": "S", "middle": ["S"], "last": "Rich", "suffix": ""}, {"first": "J", "middle": [], "last": "Barbosa", "suffix": ""}, {"first": "A", "middle": ["S"], "last": "Krolewski", "suffix": ""}, {"first": "J", "middle": ["H"], "last": "Warram", "suffix": ""}, {"first": "A", "middle": ["R"], "last": "Christlieb", "suffix": ""}, {"first": "E", "middle": ["J"], "last": "Busick", "suffix": ""}, {"first": "C", "middle": ["R"], "last": "Kahn", "suffix": ""}, {"first": "K", "middle": [], "last": "Borch-Johnsen", "suffix": ""}, {"first": "K", "middle": [], "last": "Norgaard", "suffix": ""}, {"first": "E", "middle": [], "last": "Hommel", "suffix": ""}, {"first": "E", "middle": ["R"], "last": "Mathiesen", "suffix": ""}, {"first": "J", "middle": ["S"], "last": "Jensen", "suffix": ""}, {"first": "T", "middle": [], "last": "Deckert", "suffix": ""}], "year": 1985, "venue": "N Engl J Med", "link": null}, "BIBREF9": {"title": "Familial 12. factors determine the development of diabetic nephropathy in patients with IDDM", "authors": [{"first": "M", "middle": [], "last": "Quinn", "suffix": ""}, {"first": "M", "middle": ["C"], "last": "Angelico", "suffix": ""}, {"first": "J", "middle": ["H"], "last": "Warram", "suffix": ""}, {"first": "A", "middle": ["S"], "last": "Krolewski", "suffix": ""}], "year": 1996, "venue": "Diabetologia", "link": "11456149"}, "BIBREF11": {"title": "Ethnic disparities in diabetic complications in an insured population", "authors": [{"first": "", "middle": [], "last": "Jv", "suffix": ""}], "year": 2002, "venue": "JAMA", "link": "21308301"}, "BIBREF12": {"title": "Metabolic memory 14. and diabetic nephropathy: potential role for epigenetic mechanisms", "authors": [{"first": "S", "middle": [], "last": "Tonna", "suffix": ""}, {"first": "A", "middle": [], "last": "El-Osta", "suffix": ""}, {"first": "M", "middle": [], "last": "Cooper", "suffix": ""}, {"first": "C", "middle": [], "last": "Tikellis", "suffix": ""}], "year": 2010, "venue": "Nat Rev Nephrol", "link": "23349864"}, "BIBREF13": {"title": "Assessment of 115 candidate genes for diabetic nephropathy by transmission/disequilibrium test", "authors": [{"first": "K", "middle": ["G"], "last": "Ewens", "suffix": ""}, {"first": "R", "middle": ["A"], "last": "George", "suffix": ""}, {"first": "K", "middle": [], "last": "Sharma", "suffix": ""}, {"first": "F", "middle": ["N"], "last": "Ziyadeh", "suffix": ""}, {"first": "R", "middle": ["S"], "last": "Spielman", "suffix": ""}], "year": 2005, "venue": "Diabetes", "link": "5697538"}, "BIBREF14": {"title": "Gene for susceptibility to diabetic nephropathy in type 2 diabetes maps to 18q22.3-23", "authors": [{"first": "I", "middle": [], "last": "Vardarli", "suffix": ""}, {"first": "L", "middle": [], "last": "Baier", "suffix": ""}, {"first": "R", "middle": ["L"], "last": "Hanson", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Janssen", "suffix": ""}, {"first": "I", "middle": [], "last": "Akkoyun", "suffix": ""}, {"first": "", "middle": ["C"], "last": "Fisher 16", "suffix": ""}], "year": 2002, "venue": "Kidney Int", "link": "45446393"}, "BIBREF16": {"title": "A genome scan for diabetic nephropathy in African Americans", "authors": [{"first": "A", "middle": [], "last": "", "suffix": ""}, {"first": "Anderson", "middle": [], "last": "Pj", "suffix": ""}], "year": 2004, "venue": "Kidney Int", "link": "25191975"}, "BIBREF17": {"title": "Krowler WC. Sib-pair linkage analysis for susceptibility genes for microvascular complications among Pima Indians with type 2 diabetes. Pima Diabetes Genes Group", "authors": [{"first": "G", "middle": [], "last": "Imperatore", "suffix": ""}, {"first": "R", "middle": ["L"], "last": "Hanson", "suffix": ""}, {"first": "D", "middle": ["J"], "last": "Pettitt", "suffix": ""}, {"first": "S", "middle": [], "last": "Kobes", "suffix": ""}, {"first": "P", "middle": ["H"], "last": "Bennett", "suffix": ""}], "year": 1998, "venue": "Diabetes", "link": "23859931"}, "BIBREF18": {"title": "Jar-20. raya F. Gene and protein markers of diabetic nephropathy", "authors": [{"first": "C", "middle": [], "last": "Granier", "suffix": ""}, {"first": "K", "middle": [], "last": "Makni", "suffix": ""}, {"first": "L", "middle": [], "last": "Molina", "suffix": ""}, {"first": "B", "middle": [], "last": "Jardin-Watelet", "suffix": ""}, {"first": "H", "middle": [], "last": "Ayadi", "suffix": ""}], "year": 2008, "venue": "Nephrol Dial Transplant", "link": null}, "BIBREF19": {"title": "GATHER: A Systems Approach to Inter-21. preting Genomic Signatures", "authors": [{"first": "J", "middle": ["T"], "last": "Chang", "suffix": ""}, {"first": "J", "middle": ["R"], "last": "Nevins", "suffix": ""}], "year": 2006, "venue": "Bioinformatics", "link": null}, "BIBREF20": {"title": "Network biology: Understanding the 22. cell's functional organization", "authors": [{"first": "A", "middle": ["L"], "last": "Barabasi", "suffix": ""}, {"first": "Z", "middle": ["N"], "last": "Oltvai", "suffix": ""}], "year": 2004, "venue": "Nat Rev Genet", "link": "10950726"}, "BIBREF21": {"title": "Getting connected: analysis and 23. principles of biological networks", "authors": [{"first": "X", "middle": [], "last": "Zhu", "suffix": ""}, {"first": "M", "middle": [], "last": "Gerstein", "suffix": ""}, {"first": "M", "middle": [], "last": "Snyder", "suffix": ""}], "year": 2007, "venue": "Genes Development", "link": "51080"}}, "ref_entries": {}}
{"paper_id": "10707108", "_pdf_hash": "46b00213fe80eb59769d93bbe1fc0b82af3c36e2", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "How many steps/day are enough? Preliminary pedometer indices for public health", "authors": [{"first": "C", "middle": [], "last": "Tudor-Locke", "suffix": ""}, {"first": "D", "middle": ["R"], "last": "Bassett", "suffix": ""}], "year": 2004, "venue": "Sports Med", "link": "13212390"}, "BIBREF1": {"title": "Foot pressure measurement-History and development", "authors": [{"first": "R", "middle": ["J"], "last": "Abboud", "suffix": ""}, {"first": "D", "middle": ["I"], "last": "Rowley", "suffix": ""}], "year": "", "venue": "Surgery of Disorders of Foot and Ankle", "link": null}, "BIBREF3": {"title": "The plantar loading variations to uphill and downhill gradients during treadmill walking", "authors": [{"first": "J", "middle": [], "last": "Grampp", "suffix": ""}, {"first": "J", "middle": [], "last": "Willson", "suffix": ""}, {"first": "T", "middle": [], "last": "Kernozek", "suffix": ""}], "year": 2000, "venue": "Foot Ankle Int", "link": "30309458"}, "BIBREF4": {"title": "Foot structure and inshoe plantar pressure differences between males and females", "authors": [{"first": "E", "middle": ["J"], "last": "Higbie", "suffix": ""}, {"first": "B", "middle": ["S"], "last": "Contractor", "suffix": ""}, {"first": "L", "middle": ["L"], "last": "Tis", "suffix": ""}, {"first": "B", "middle": ["F"], "last": "Johnson", "suffix": ""}], "year": 1999, "venue": "Med Sci Sports Exerc", "link": "72227015"}, "BIBREF5": {"title": "The effect of increased weight on peak pressures: implications for obesity and diabetic foot pathology", "authors": [{"first": "S", "middle": ["A"], "last": "Vela", "suffix": ""}, {"first": "L", "middle": ["A"], "last": "Lavery", "suffix": ""}, {"first": "D", "middle": ["G"], "last": "Armstrong", "suffix": ""}, {"first": "A", "middle": ["A"], "last": "Anaim", "suffix": ""}], "year": 1998, "venue": "J Foot Ankle Surg", "link": "24265368"}, "BIBREF6": {"title": "Statistical methods for assessing agreement between two methods of clinical measurement", "authors": [{"first": "J", "middle": ["M"], "last": "Bland", "suffix": ""}, {"first": "D", "middle": ["G"], "last": "Altman", "suffix": ""}], "year": 1986, "venue": "Lancet", "link": "2844897"}, "BIBREF7": {"title": "Reliability of an in-shoe pressure measurement system during treadmill walking", "authors": [{"first": "T", "middle": ["W"], "last": "Kernozek", "suffix": ""}, {"first": "E", "middle": ["E"], "last": "Lamott", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Dancisak", "suffix": ""}], "year": 1996, "venue": "Foot Ankle Int", "link": "25555132"}, "BIBREF8": {"title": "Efficacy of plantar loading parameters during gait in terms of reliability, variability, effect of gender and relationship between contact area and plantar pressure", "authors": [{"first": "D", "middle": ["F"], "last": "Murphy", "suffix": ""}, {"first": "B", "middle": ["D"], "last": "Beynnon", "suffix": ""}, {"first": "J", "middle": ["D"], "last": "Michelson", "suffix": ""}, {"first": "P", "middle": ["M"], "last": "Vacek", "suffix": ""}], "year": 2005, "venue": "Foot Ankle Int", "link": "40694550"}, "BIBREF9": {"title": "Inshoe step-to-step pressure variations", "authors": [{"first": "F", "middle": [], "last": "Akhlaghi", "suffix": ""}, {"first": "J", "middle": [], "last": "Daw", "suffix": ""}, {"first": "M", "middle": [], "last": "Pepper", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Potter", "suffix": ""}], "year": 1994, "venue": "Foot", "link": null}}, "ref_entries": {}}
{"paper_id": "10707167", "_pdf_hash": "1352a8851f11ff15510542579e1fcb17ebb69d03", "abstract": [{"section": "Abstract", "text": "Recent research implicates the COMT Val 108/158 Met polymorphism in stress-sensitivity, via modulation of hypothalamic-pituitary-adrenal (HPA) function. In healthy samples, Methomozygosity has been associated with greater HPA activity (i.e., cortisol) and stress sensitivity, though findings are mixed among clinical samples. To date, there are no reports examining baseline or longitudinal changes in HPA activity as a function of COMT genotype in youth. This study examined the association of COMT with salivary cortisol across a one-year period in healthy and at-risk adolescents with DSM-IV-TR Axis II diagnoses. Results indicated higher cortisol levels for Met-homozygotes (compared to heterozygotes and Val homozygotes) at the one-year follow-up, and increased mean cortisol levels across a one-year period among Metcarriers, suggesting that COMT associates with differences in cortisol secretion during adolescence. Findings are discussed with respect to COMT genotype as a potential genetic indicator of psychiatric risk that modulates developmental changes in HPA activity.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Research is increasingly aimed at identifying genetic determinants of stress vulnerability as risk factors for mental disorders. It has been proposed that dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, a key system in the biological stress response, is a component of vulnerability for psychiatric disorders (Walker and Diforio, 1997) . Genetic factors account for approximately 50% of variability in cortisol secretion (Linkowski et al., 1993) , a measure of HPA activity. Thus, it appears that some genes, in concert with other genetic and environmental factors (van Os et al., 2003) , determine individual differences in HPA activity. Dopamine has also been implicated in the stress response (Laruelle, 2000) , and one of the genes responsible for dopamine metabolism, Catechol-O-Methyltransferase (COMT) is among the genes theorized to impact stress-sensitivity (Zubieta et al., 2003) . COMT Val 108/158 Met is a functional polymorphism (i.e., a single nucleotide involving an amino acid change from Valine (Val) to Methionine (Met) at codon 158) affecting enzyme activity. Val homozygosity is associated with 3-4 fold higher enzyme activity than Met homozygosity (Mannisto and Kaakkola, 1999; Lachman et al., 1996) , and because the alleles are codominant, heterozygotes are intermediate (M\u00e4nnisto and Kaakkola, 1999; Lachman et al., 1996) . Accordingly, Val/Val, Val/Met and Met/Met genotypes correspond, in theory, to highest, intermediary, and lowest dopamine degradation, respectively. Two mechanisms have been suggested for COMT allelic variants to alter HPA function (Oswald et al., 2004) . First, because low-activity COMT (Met variant) is associated with higher catecholinergic activity, it would be expected to be linked with greater hypothalamic corticotropin-releasing hormone (CRH) release. Second, more pronounced \u03bc-opioid receptor binding potential has been observed in response to stress in humans who are COMT Met/ Met homozygous (Zubieta et al., 2003) , suggesting that the low-activity form of COMT could alter HPA activity indirectly through influencing DA-mediated regulation of opioid neurotransmission.", "cite_spans": [{"start": 325, "end": 351, "text": "(Walker and Diforio, 1997)", "ref_id": "BIBREF21"}, {"start": 437, "end": 461, "text": "(Linkowski et al., 1993)", "ref_id": "BIBREF6"}, {"start": 581, "end": 602, "text": "(van Os et al., 2003)", "ref_id": "BIBREF17"}, {"start": 712, "end": 728, "text": "(Laruelle, 2000)", "ref_id": "BIBREF5"}, {"start": 883, "end": 905, "text": "(Zubieta et al., 2003)", "ref_id": "BIBREF23"}, {"start": 1185, "end": 1214, "text": "(Mannisto and Kaakkola, 1999;", "ref_id": "BIBREF8"}, {"start": 1215, "end": 1236, "text": "Lachman et al., 1996)", "ref_id": "BIBREF4"}, {"start": 1340, "end": 1361, "text": "Lachman et al., 1996)", "ref_id": "BIBREF4"}, {"start": 1595, "end": 1616, "text": "(Oswald et al., 2004)", "ref_id": "BIBREF10"}, {"start": 1968, "end": 1990, "text": "(Zubieta et al., 2003)", "ref_id": "BIBREF23"}], "ref_spans": []}, {"section": "Introduction", "text": "Several studies implicate COMT Val 108/158 Met in stress-sensitivity, including COMT modulation of HPA function. Among healthy individuals, greater stress-sensitivity among COMT Met homozygotes compared to Val-carriers is suggested by 1) higher plasma ACTH and cortisol response to psychosocial stress (Jabbi, 2007) , 2) greater cortisol response to naloxone, an opioid antagonist (Oswald et al., 2004) , 3) higher sensory and affective responses to pain, and more negative internal affective state, (Zubieta et al., 2003) , and increased limbic and prefrontal activation in response to unpleasant stimuli, with a greater propensity to negative mood (Smolka et al., 2004) .", "cite_spans": [{"start": 302, "end": 315, "text": "(Jabbi, 2007)", "ref_id": "BIBREF1"}, {"start": 381, "end": 402, "text": "(Oswald et al., 2004)", "ref_id": "BIBREF10"}, {"start": 500, "end": 522, "text": "(Zubieta et al., 2003)", "ref_id": "BIBREF23"}], "ref_spans": []}, {"section": "Introduction", "text": "Data from clinical populations are mixed. To date, we know of only one study examining COMT genotype and HPA activity in a clinical risk sample (N=25, Jabbi, 2007) , and the findings indicate that, among individuals at familial high-risk for depression, COMT genotype was not associated with cortisol response. However, a study of self-reported symptoms found that Met homozygote psychotic patients reported more negative affect and psychotic symptoms in response to daily stress compared to other genotypes (van Winkel et al., 2008) . In contrast, another study examining normal military inductees (19-24 years; N=2243) found Val-carriers (compared to Met homozygotes) to be more sensitive to army induction training stress as reflected by higher psychosis symptom ratings (Stefanis et al., 2007) .", "cite_spans": [{"start": 151, "end": 163, "text": "Jabbi, 2007)", "ref_id": "BIBREF1"}, {"start": 508, "end": 533, "text": "(van Winkel et al., 2008)", "ref_id": "BIBREF18"}, {"start": 774, "end": 797, "text": "(Stefanis et al., 2007)", "ref_id": "BIBREF15"}], "ref_spans": []}, {"section": "Introduction", "text": "Adolescence is a critical period for the onset of mental disorders, and it is also characterized by heightened stress sensitivity, including a marked increase in cortisol secretion (Walker, 2002) . Increased cortisol secretion during adolescence has been demonstrated in crosssectional (Kenny et al., 1966; Kiess et al 1995; Lupien et al., 2002) and longitudinal (Walker et al., 2001; Walker et al., 2002; Wajs-Kuto et al., 1999) studies, and has been implicated in the escalating risk of mental disorders during this period. Increases in cortisol levels occur with each year of age, beginning around 13 and may extend into the early twenties. To date, no studies have explored the modulating role of COMT on cortisol during adolescence.", "cite_spans": [{"start": 181, "end": 195, "text": "(Walker, 2002)", "ref_id": "BIBREF20"}, {"start": 286, "end": 306, "text": "(Kenny et al., 1966;", "ref_id": "BIBREF2"}, {"start": 307, "end": 324, "text": "Kiess et al 1995;", "ref_id": "BIBREF3"}, {"start": 325, "end": 345, "text": "Lupien et al., 2002)", "ref_id": "BIBREF7"}, {"start": 363, "end": 384, "text": "(Walker et al., 2001;", "ref_id": "BIBREF22"}, {"start": 385, "end": 405, "text": "Walker et al., 2002;", "ref_id": "BIBREF20"}, {"start": 406, "end": 429, "text": "Wajs-Kuto et al., 1999)", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "Introduction", "text": "The present study tested the hypothesis that COMT genotype would be associated with cortisol secretion in normal and at-risk adolescents: specifically, that COMT genotype would be linked in a dose-response manner, such that Met homozygotes would have the highest salivary cortisol levels, followed by heterozygotes, then Val homozygotes. In addition, the relation of COMT genotype with longitudinal changes in cortisol was examined.", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "The present sample is a subgroup of participants from the Emory University adolescent development project, a longitudinal study of youth at-risk for Axis I mental disorders. Data on COMT genotype and salivary cortisol (baseline and two follow-ups) were available for 63 adolescents, ages 12 to 18 years (mean=14.52, SD=1.87). Follow-up endocrine assessments were conducted at 7-10 months and one year later. (See Trotman et al. (2006) for a description of the sample.) Recruitment focused on adolescents with DSM-IV-TR schizotypal personality disorder (SPD) (n = 11 males and 6 females) and other Axis II syndromes (n=16 males and 13 females) linked with risk for developing Axis I disorders, especially psychosis; together, this constituted the high-risk group. Healthy adolescents (n=7 males and 10 females) did not meet criteria for any DSM-IV-TR disorder. No participant met criteria for an Axis I disorder at baseline. There were no diagnostic group differences in sex [\u03c7 2 (2)=1.926, p=0.382], age [F(2)=.148, p=0.862], or ethnicity [\u03c7 2 (6)=6.819, p=0.338]. Assent and written consent was obtained from all participants and a parent, in accordance with guidelines of the Emory University Institutional Review Board.", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "The Structured Interview of DSM-IV Personality Disorders (SIDP-IV; Pfohl et al., 1997) and the Structured Clinical Interview for Axis I DSM-IV Disorders (SCID-I/P; First et al., 1998) were administered. Diagnosticians demonstrated high inter-rater reliabilities (Kappa > 0.80).", "cite_spans": [{"start": 164, "end": 183, "text": "First et al., 1998)", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "Methods", "text": "A detailed description of methods for salivary collection and assay of cortisol can be found in Mittal et al. (2007) . The current analyses used the first three cortisol samples, which were collected in the morning before lunch. The measure of cortisol at baseline (upon the initial assessment) and each of the two follow-ups index an average of the individual's cortisol level over an approximate 1-2 hour period in the morning, when levels are at a relative peak in accord with the natural diurnal rhythm. Participants were instructed not to ingest products containing caffeine or engage in vigorous physical activity or exercise prior to sample collection.", "cite_spans": [{"start": 96, "end": 116, "text": "Mittal et al. (2007)", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "Methods", "text": "Participants provided saliva samples in the Oragene DNA Self-Collection kit (DNA Genotek Inc., Ottawa, Canada, Rylander-Rudqvist et al., 2006) . DNA was extracted from saliva by using the Qiagen M48 automated extraction system. COMT Val-Met (rs4680) genotypes were determined using the 5'-exonuclease (TaqMan\u00ae) method. The assay kits and genotyping reagents were ordered from Applied Biosystems (Foster City, CA). Genotyping was performed on an ABI 7900HT system, with samples arrayed in 384-well plates. For the total sample, genotype frequencies were Met/Met = 11, Val/Met = 30 and Val/Val = 22; there was no deviation from Hardy-Weinberg Equilibrium (chisq, 2 d.f. = .02, p = .88). There were no significant differences in distribution of allelic frequencies by diagnostic group [\u03c7 2 (4)=3.879, p=0.423] or racial/ethnic group [\u03c7 2 (6)=9.273, p=0.159].", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "Consistent with previous reports, the present sample showed a developmental increase in cortisol secretion, however, the magnitude of the increase varied by genotype. Mean cortisol by time and genotype is illustrated in Figure 1 Group differences in cortisol as a function of genotype were also examined using the average of the mean cortisol values across the 3 assessments (Baseline and Follow-ups 1 and 2). Accordingly, there were no significant differences across Met homozygotes (mean=. 5812, SD=.1547), Met heterozygotes (mean=.5505, SD=.2364), and Val homozygotes (mean=.5018, SD=.1647) [F(2)=.666, p>.10)].", "cite_spans": [], "ref_spans": [{"start": 220, "end": 228, "text": "Figure 1", "ref_id": "FIGREF1"}]}, {"section": "Results", "text": "Percentage change in cortisol levels at each of the follow-ups relative to baseline was also examined, as another method towards illustrating the pattern of longitudinal change in cortisol by gentoype. Percentage change values were calculated by dividing mean cortisol at each of the follow-ups by mean cortisol at baseline, respectively, and then multiplying by 100. Results indicated no significant genetic group differences ( Consistent with previous reports, Met/Met genotype was the least frequent, with only 3 such individuals in the healthy control group. Thus, for within-diagnostic group comparisons, Met heterozygotes (Val/Met) and homozygotes (Met/Met) were combined. Further, due to the small number of subjects when participants were divided by both genotype and diagnostic group, the psychiatric diagnostic groups were combined into one high-risk group for the initial comparison. This yielded 32 at-risk Met-carriers, 14 at-risk Val homozygotes, 9 healthy control Met-carriers, and 8 healthy control Val homozygotes.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "Within group comparisons revealed that, among healthy controls, Met-carriers showed significant increases in mean cortisol from baseline to Follow-up 1 [t(7)=-3.124, p=.017] and a trend at Follow-up 2 [t(6)=-2.297, p=.061]. Among Val/Val healthy controls, there were no significant increases.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "Among high-risk adolescents, Met-carriers showed a trend level increase in mean cortisol at Follow-up 2 compared to baseline [t (29) ", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "In summary, consistent with previous reports, this study revealed higher cortisol levels in COMT Met homozygotes compared to Val homozygotes and Met heterozygotes. However, the genotype-associated differences in cortisol were observed at Follow-up 2 only, not Baseline or Follow-up 1. The absence of a relation at Baseline and Follow-up 1, together with our finding of longitudinal increases in cortisol levels (that are stronger for Met homozygotes alone than all Met-carriers at Follow-up 2, and weaker for Met homozygotes alone than all Met-carriers at Follow-up 1), suggests the possibility that COMT Val/Met genotype modulates longitudinal changes in cortisol during adolescent maturation, a period marked by a variety of neurodevelopmental changes and increasing risk for the onset of mental disorder (Sowell et al., 2007; Walker, 2002) . We hypothesize that such an association reflects lower COMT activity in Met carriers, which in turn alters regulation of HPA function by dopamine, and possibly, norepinephrine. This study is unique in that it is the first to consider the modulating role of genetic factors, namely COMT, in regulating cortisol secretion specifically among youth at heightened risk for psychosis. Findings have implications for understanding the neurodevelopment of psychiatric disorders, particularly psychosis, and the advancement of novel treatment strategies and routes for prevention of mental disorders. One study limitation is the small sample size, which could result in false positives. Thus, replication of findings using a larger sample is warranted. Large-scale longitudinal studies examining the relation of genotype with neurohormonal development in adolescents may prove fruitful in elucidating heritable factors influencing the adolescent maturational process involved in the onset of Axis I disorders. Mean Salivary Cortisol Across a One-Year Period by COMT (rs4680) Genotype for the Total Sample", "cite_spans": [{"start": 807, "end": 828, "text": "(Sowell et al., 2007;", "ref_id": "BIBREF14"}, {"start": 829, "end": 842, "text": "Walker, 2002)", "ref_id": "BIBREF20"}], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Structured Clinical Interview for the DSM-IV Axis I Disorders, Patient Edition (SCID I)", "authors": [{"first": "M", "middle": ["B"], "last": "First", "suffix": ""}, {"first": "R", "middle": ["L"], "last": "Spitzer", "suffix": ""}, {"first": "M", "middle": [], "last": "Gibbon", "suffix": ""}, {"first": "B", "middle": ["W"], "last": "Williams", "suffix": ""}], "year": 1998, "venue": "", "link": null}, "BIBREF1": {"title": "Catechol-omethyltransferase polymorphism and susceptibility to major depressive disorder modulates psychological stress response", "authors": [{"first": "M", "middle": [], "last": "Jabbi", "suffix": ""}, {"first": "I", "middle": ["P"], "last": "Kema", "suffix": ""}, {"first": "G", "middle": [], "last": "Van Der Pompe", "suffix": ""}, {"first": "G", "middle": ["J"], "last": "Te Meerman", "suffix": ""}, {"first": "J", "middle": [], "last": "Ormel", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Den Boer", "suffix": ""}], "year": 2007, "venue": "Psychiatr Genet", "link": null}, "BIBREF2": {"title": "Cortisol production rate. II. Normal infants, children, and adults", "authors": [{"first": "F", "middle": ["M"], "last": "Kenny", "suffix": ""}, {"first": "C", "middle": [], "last": "Preeyasombat", "suffix": ""}, {"first": "C", "middle": ["J"], "last": "Migeon", "suffix": ""}], "year": 1966, "venue": "Pediatrics", "link": "23593280"}, "BIBREF3": {"title": "Salivary cortisol levels throughout childhood and adolescence: relation with age, pubertal stage, and weight", "authors": [{"first": "W", "middle": [], "last": "Kiess", "suffix": ""}, {"first": "A", "middle": [], "last": "Meidert", "suffix": ""}, {"first": "R", "middle": ["A"], "last": "Dressendorfer", "suffix": ""}, {"first": "K", "middle": [], "last": "Schriever", "suffix": ""}, {"first": "U", "middle": [], "last": "Kessler", "suffix": ""}, {"first": "A", "middle": [], "last": "Konig", "suffix": ""}, {"first": "H", "middle": ["P"], "last": "Schwarz", "suffix": ""}, {"first": "C", "middle": ["J"], "last": "Strasburger", "suffix": ""}], "year": 1995, "venue": "Pediatr Res", "link": "19495321"}, "BIBREF4": {"title": "Human catechol-Omethyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders", "authors": [{"first": "H", "middle": ["M"], "last": "Lachman", "suffix": ""}, {"first": "D", "middle": ["F"], "last": "Papolos", "suffix": ""}, {"first": "T", "middle": [], "last": "Saito", "suffix": ""}, {"first": "Y", "middle": ["M"], "last": "Yu", "suffix": ""}, {"first": "C", "middle": ["L"], "last": "Szumlanski", "suffix": ""}, {"first": "R", "middle": ["M"], "last": "Weinshilboum", "suffix": ""}], "year": 1996, "venue": "Pharmacogenetics", "link": "34685973"}, "BIBREF5": {"title": "The role of endogenous sensitization in the pathophysiology of schizophrenia: implications from recent brain imaging studies", "authors": [{"first": "M", "middle": [], "last": "Laruelle", "suffix": ""}], "year": 2000, "venue": "Brain Res Brain Res Rev", "link": "25926221"}, "BIBREF6": {"title": "Twin study of the 24-h cortisol profile: evidence for genetic control of the human circadian clock", "authors": [{"first": "P", "middle": [], "last": "Linkowski", "suffix": ""}, {"first": "A", "middle": [], "last": "Van Onderbergen", "suffix": ""}, {"first": "M", "middle": [], "last": "Kerkhofs", "suffix": ""}, {"first": "D", "middle": [], "last": "Bosson", "suffix": ""}, {"first": "J", "middle": [], "last": "Mendlewicz", "suffix": ""}, {"first": "E", "middle": [], "last": "Van Cauter", "suffix": ""}], "year": 1993, "venue": "Am J Physiol", "link": "22920536"}, "BIBREF7": {"title": "The modulatory effects of corticosteroids on cognition: Studies in young human populations", "authors": [{"first": "S", "middle": ["J"], "last": "Lupien", "suffix": ""}, {"first": "C", "middle": ["W"], "last": "Wilkinson", "suffix": ""}, {"first": "S", "middle": [], "last": "Briere", "suffix": ""}, {"first": "C", "middle": [], "last": "Menard", "suffix": ""}, {"first": "Ng", "middle": [], "last": "Ying Kin", "suffix": ""}, {"first": "N", "middle": ["M"], "last": "Nair", "suffix": ""}, {"first": "N", "middle": ["P"], "last": "", "suffix": ""}], "year": 2002, "venue": "Psychoneuroendocrinology", "link": "35926166"}, "BIBREF8": {"title": "Catechol-O-methyltransferase (COMT): biochemistry, molecular biology, pharmacology, and clinical efficacy of the new selective COMT inhibitors", "authors": [{"first": "P", "middle": ["T"], "last": "Mannisto", "suffix": ""}, {"first": "S", "middle": [], "last": "Kaakkola", "suffix": ""}], "year": 1999, "venue": "Pharmacol Rev", "link": "170858"}, "BIBREF9": {"title": "The relations among putative biorisk markers in schizotypal adolescents: Minor physical anomalies, movement abnormalities, and salivary cortisol", "authors": [{"first": "V", "middle": ["A"], "last": "Mittal", "suffix": ""}, {"first": "S", "middle": [], "last": "Dhruv", "suffix": ""}, {"first": "K", "middle": ["D"], "last": "Tessner", "suffix": ""}, {"first": "D", "middle": ["J"], "last": "Walder", "suffix": ""}, {"first": "E", "middle": ["F"], "last": "Walker", "suffix": ""}], "year": 2007, "venue": "Biol Psychiatry", "link": "22750130"}, "BIBREF10": {"title": "Catechol-O-methyltransferase polymorphism alters hypothalamic-pituitary-adrenal axis responses to naloxone: a preliminary report", "authors": [{"first": "L", "middle": ["M"], "last": "Oswald", "suffix": ""}, {"first": "M", "middle": [], "last": "Mccaul", "suffix": ""}, {"first": "L", "middle": [], "last": "Choi", "suffix": ""}, {"first": "X", "middle": [], "last": "Yang", "suffix": ""}, {"first": "G", "middle": ["S"], "last": "Wand", "suffix": ""}], "year": 2004, "venue": "Biol Psychiatry", "link": "30784188"}, "BIBREF11": {"title": "Structured Interview for DSM-IV Personality: SIDP-IV", "authors": [{"first": "B", "middle": [], "last": "Pfhol", "suffix": ""}, {"first": "N", "middle": [], "last": "Blum", "suffix": ""}, {"first": "M", "middle": [], "last": "Zimmerman", "suffix": ""}], "year": 1997, "venue": "", "link": "141278368"}, "BIBREF12": {"title": "Quality and quantity of saliva DNA obtained from the self-administrated oragene method--a pilot study on the cohort of Swedish men", "authors": [{"first": "T", "middle": [], "last": "Rylander-Rudqvist", "suffix": ""}, {"first": "N", "middle": [], "last": "Hakansson", "suffix": ""}, {"first": "G", "middle": [], "last": "Tybring", "suffix": ""}, {"first": "A", "middle": [], "last": "Wolk", "suffix": ""}], "year": 2006, "venue": "Cancer Epidemiol Biomarkers Prev", "link": "24494166"}, "BIBREF13": {"title": "Catechol-O-methyltransferase val158met genotype affects processing of emotional stimuli in the amygdala and prefrontal cortex", "authors": [{"first": "M", "middle": ["N"], "last": "Smolka", "suffix": ""}, {"first": "G", "middle": [], "last": "Schumann", "suffix": ""}, {"first": "J", "middle": [], "last": "Wrase", "suffix": ""}, {"first": "S", "middle": ["M"], "last": "Grusser", "suffix": ""}, {"first": "H", "middle": [], "last": "Flor", "suffix": ""}, {"first": "K", "middle": [], "last": "Mann", "suffix": ""}, {"first": "D", "middle": ["F"], "last": "Braus", "suffix": ""}, {"first": "D", "middle": [], "last": "Goldman", "suffix": ""}, {"first": "C", "middle": [], "last": "Buchel", "suffix": ""}, {"first": "A", "middle": [], "last": "Heinz", "suffix": ""}], "year": 2005, "venue": "J Neurosci", "link": "302707"}, "BIBREF14": {"title": "Adolescent psychopathology and the developing brain: Integrating brain and prevention science", "authors": [{"first": "E", "middle": ["R"], "last": "Sowell", "suffix": ""}, {"first": "P", "middle": ["M"], "last": "Thompson", "suffix": ""}, {"first": "A", "middle": ["W"], "last": "Toga", "suffix": ""}], "year": 2007, "venue": "", "link": "143191835"}, "BIBREF15": {"title": "COMT Val158Met moderation of stress-induced psychosis", "authors": [{"first": "N", "middle": ["C"], "last": "Stefanis", "suffix": ""}, {"first": "C", "middle": [], "last": "Henquet", "suffix": ""}, {"first": "D", "middle": [], "last": "Avramopoulos", "suffix": ""}, {"first": "N", "middle": [], "last": "Smyrnis", "suffix": ""}, {"first": "I", "middle": [], "last": "Evdokimidis", "suffix": ""}, {"first": "I", "middle": [], "last": "Myin-Germeys", "suffix": ""}, {"first": "C", "middle": ["N"], "last": "Stefanis", "suffix": ""}, {"first": "Van", "middle": [], "last": "Os", "suffix": ""}, {"first": "J", "middle": [], "last": "", "suffix": ""}], "year": 2007, "venue": "Psychol Med", "link": "39374640"}, "BIBREF16": {"title": "Cognitive function and symptoms in adolescents with schizotypal personality disorder", "authors": [{"first": "H", "middle": [], "last": "Trotman", "suffix": ""}, {"first": "A", "middle": [], "last": "Mcmillan", "suffix": ""}, {"first": "E", "middle": [], "last": "Walker", "suffix": ""}], "year": 2006, "venue": "Schizophr Bull", "link": "18003155"}, "BIBREF17": {"title": "Do urbanicity and familial liability coparticipate in causing psychosis?", "authors": [{"first": "J", "middle": [], "last": "Van Os", "suffix": ""}, {"first": "M", "middle": [], "last": "Hanssen", "suffix": ""}, {"first": "M", "middle": [], "last": "Bak", "suffix": ""}, {"first": "R", "middle": ["V"], "last": "Bijl", "suffix": ""}, {"first": "W", "middle": [], "last": "Vollebergh", "suffix": ""}], "year": 2003, "venue": "Am J Psychiatry", "link": "146618693"}, "BIBREF18": {"title": "Evidence that the COMT(Val158Met) polymorphism moderates sensitivity to stress in psychosis: an experience-sampling study", "authors": [{"first": "R", "middle": [], "last": "Van Winkel", "suffix": ""}, {"first": "C", "middle": [], "last": "Henquet", "suffix": ""}, {"first": "A", "middle": [], "last": "Rosa", "suffix": ""}, {"first": "S", "middle": [], "last": "Papiol", "suffix": ""}, {"first": "L", "middle": [], "last": "Fananas", "suffix": ""}, {"first": "De", "middle": [], "last": "Hert", "suffix": ""}, {"first": "M", "middle": [], "last": "Peuskens", "suffix": ""}, {"first": "J", "middle": [], "last": "Van Os", "suffix": ""}, {"first": "J", "middle": [], "last": "Myingermeys", "suffix": ""}, {"first": "I", "middle": [], "last": "", "suffix": ""}], "year": 2008, "venue": "Am J Med Genet Part B: Neuropsychiatr Genet", "link": "30159958"}, "BIBREF19": {"title": "Hormonal changes during the first year of oestrogen treatment in constitutionally tall girls", "authors": [{"first": "E", "middle": [], "last": "Wajs-Kuto", "suffix": ""}, {"first": "De", "middle": [], "last": "Beeck", "suffix": ""}, {"first": "L", "middle": ["O"], "last": "Rooman", "suffix": ""}, {"first": "R", "middle": ["P"], "last": "Caju", "suffix": ""}, {"first": "M", "middle": ["V"], "last": "", "suffix": ""}], "year": 1999, "venue": "Eur J Endocrinol", "link": "22043137"}, "BIBREF20": {"title": "Adolescent neurodevelopment and psychopathology", "authors": [{"first": "E", "middle": ["F"], "last": "Walker", "suffix": ""}], "year": 2002, "venue": "Curr Dir in Psychol Sci", "link": "145245375"}, "BIBREF21": {"title": "Schizophrenia: A neural diathesis-stress model", "authors": [{"first": "E", "middle": ["F"], "last": "Walker", "suffix": ""}, {"first": "D", "middle": [], "last": "Diforio", "suffix": ""}], "year": 1997, "venue": "Psychol Rev", "link": "21491692"}, "BIBREF22": {"title": "Developmental changes in cortisol secretion in normal and at-risk youth", "authors": [{"first": "E", "middle": ["F"], "last": "Walker", "suffix": ""}, {"first": "D", "middle": ["J"], "last": "Walder", "suffix": ""}, {"first": "F", "middle": [], "last": "Reynolds", "suffix": ""}], "year": 2001, "venue": "Dev Psychopathol", "link": "34554620"}, "BIBREF23": {"title": "COMT val158met genotype affects mu-opioid neurotransmitter responses to a pain stressor", "authors": [{"first": "J-K", "middle": [], "last": "Zubieta", "suffix": ""}, {"first": "M", "middle": ["M"], "last": "Heitzeg", "suffix": ""}, {"first": "Y", "middle": ["R"], "last": "Smith", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Bueller", "suffix": ""}, {"first": "K", "middle": [], "last": "Xu", "suffix": ""}, {"first": "Y", "middle": [], "last": "Xu", "suffix": ""}, {"first": "R", "middle": ["A"], "last": "Koeppe", "suffix": ""}, {"first": "C", "middle": ["S"], "last": "Stohler", "suffix": ""}, {"first": "D", "middle": [], "last": "Goldman", "suffix": ""}], "year": 2003, "venue": "Science", "link": "38705215"}}, "ref_entries": {"FIGREF0": {"text": "Met/Met, Met/Val, Val/Val) in percentage change in cortisol from Baseline to Follow-up 1 [F(2)=.882, p>.10)], or from Baseline to Follow-up 2 [F(2)=1.844, p>.10]. Analyses comparing Met-carriers to Val homozygotes revealed no significant genetic group differences in percentage change in cortisol from Baseline to Follow-up 1 [F(1)=1.725, p>.10], though there was a greater percentage change from Baseline to Follow-up 2 [F(1)=2.887, p<.10] among Met-carriers compared to Val homozygotes.", "type": "figure"}, "FIGREF1": {"text": "Figure 1.", "type": "figure"}, "TABREF0": {"text": ". In the Met/Met group, mean cortisol was increased significantly at Follow-up 1 [t(8)=-2.434, p=.041] and Follow-up 2 [t(10)=-3.310, p=.008], compared to Baseline, with no significant difference between Follow-ups 1 and 2 [t(8)=.840; p=.425]. Among Val/Met, mean cortisol was increased at Follow-up 1 compared to Baseline at the trend level [t(26)=-1.914, p=.067l), but the difference between Baseline and Follow-up 2 [t(25)=-1.394, p=.176] and between Follow-ups 1 and 2 [t(23)=.024, p=. 981] did not approach significance. Among Val/Val, there were no significant changes over time; Baseline vs. Follow-up 1 [t(19)=-.800, p=.434], Baseline vs. Follow-up 2 [t(21)=-.767, p=.452], and Follow-up 1 vs. 2 [t(19)=.122, p=.904]. In summary, Met/Met homozygotes demonstrated the greatest increase in mean cortisol level over time, with the most marked increase between Baseline and one year later (Follow-up 2). Given the small sample size, the aforementioned analyses were repeated after combining all Met-carriers into one group (that is, Met/Met and Val/Met). Accordingly, among Met-carriers, mean cortisol wasThere were no significant differences in cortisol levels as a function of genotype at Baseline. However, at Follow-up 1, there was a trend toward higher mean cortisol for Met/Met than Val/Val at the trend level [t(25)=1.504, p=.073]. At Follow-up 2, mean cortisol was significantly greater for Met/Met compared to Val/Val [t(31)=1.831, p=.039]. Comparisons by sample showed that cortisol sample #1 was significantly greater for Met/Met compared to Val/Met [t(34)=3.997, p=.000] and Val/Val [t(31)=2.064,p=.024], and at the trend level greater for Val/Met compared to Val/Val [t(45)=-1.437, p=.079]; cortisol #3 was greater for Met/Met [t(21)=1.567, p=.066] and Val/ Met [t(36)=1.528, p=.068] compared to Val/Val at the trend level.", "type": "table"}, "TABREF1": {"text": "=-1.920, p=.065]. Among Val/Val high-risk adolescents, there was a trend toward greater mean cortisol at Follow-up 1 compared to baseline [t(11)=-1.839, p=.093]. No other changes approached significance. Comparisons across genotypes within diagnostic groups revealed no significant differences in mean cortisol by genotype for the healthy controls, although analyses of the individual cortisol samples revealed that at Follow-up 1, cortisol 1 was greater for Met-carriers (mean=.8235; SD=.5260) than Val homozygotes (mean=.3979; SD=.3596) at the trend level [t(14)=1.889, p=.080]. No other results were significant for the healthy control group or the high-risk group, and this likely reflects the reduction in power due to the smaller number of subjects.", "type": "table"}}}
{"paper_id": "10707181", "_pdf_hash": "66bd8a0d1a346d564f9865bff7cd36ebc0b1944e", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Cyclic nucleotide phosphodiesterases", "authors": [{"first": "D", "middle": [], "last": "Essayan", "suffix": ""}], "year": 2001, "venue": "J Allergy Clin Immunol", "link": "21528985"}, "BIBREF1": {"title": "Cloning and chracterization of a novel human phosphodiesterase that hydrolyzes both cAMP and cGMP (PDE10A)", "authors": [{"first": "K", "middle": [], "last": "Fujishige", "suffix": ""}, {"first": "J", "middle": [], "last": "Kotera", "suffix": ""}, {"first": "H", "middle": [], "last": "Michibata", "suffix": ""}, {"first": "K", "middle": [], "last": "Yuasa", "suffix": ""}, {"first": "S", "middle": [], "last": "Takebayashi", "suffix": ""}, {"first": "K", "middle": [], "last": "Okumura", "suffix": ""}, {"first": "K", "middle": [], "last": "Omori", "suffix": ""}], "year": 1999, "venue": "J Biol Chem", "link": "10262238"}, "BIBREF2": {"title": "Neurobiology of dopamine in schizophrenia", "authors": [{"first": "O", "middle": [], "last": "Guillin", "suffix": ""}, {"first": "A", "middle": [], "last": "Abi-Dargham", "suffix": ""}, {"first": "M", "middle": [], "last": "Laruelle", "suffix": ""}], "year": 2007, "venue": "Int Rev Neurobiol", "link": "11201135"}, "BIBREF3": {"title": "Phosphdiesterase 10A inhibitor activity in preclinical models of the positive, cognitive, and negative symptoms of schizophrenia", "authors": [{"first": "S", "middle": ["M"], "last": "Grauer", "suffix": ""}, {"first": "V", "middle": ["L"], "last": "Pulito", "suffix": ""}, {"first": "R", "middle": ["L"], "last": "Navarra", "suffix": ""}, {"first": "M", "middle": ["P"], "last": "Kelly", "suffix": ""}, {"first": "C", "middle": [], "last": "Kelley", "suffix": ""}, {"first": "R", "middle": [], "last": "Graf", "suffix": ""}, {"first": "B", "middle": [], "last": "Langen", "suffix": ""}, {"first": "S", "middle": [], "last": "Logue", "suffix": ""}, {"first": "J", "middle": [], "last": "Brennan", "suffix": ""}, {"first": "L", "middle": [], "last": "Jiang", "suffix": ""}, {"first": "E", "middle": [], "last": "Charych", "suffix": ""}, {"first": "U", "middle": [], "last": "Egerland", "suffix": ""}, {"first": "F", "middle": [], "last": "Liu", "suffix": ""}, {"first": "K", "middle": ["L"], "last": "Marquis", "suffix": ""}, {"first": "M", "middle": [], "last": "Malamas", "suffix": ""}, {"first": "T", "middle": [], "last": "Hage", "suffix": ""}, {"first": "T", "middle": ["A"], "last": "Comery", "suffix": ""}, {"first": "N", "middle": ["J"], "last": "Brandon", "suffix": ""}], "year": 2009, "venue": "J Pharm Exp Ther", "link": "16083346"}, "BIBREF4": {"title": "Activation of postsynaptic striatal dopamine receptors; monitored by efflux of cAMP in vivo", "authors": [{"first": "P", "middle": [], "last": "Hutson", "suffix": ""}, {"first": "N", "middle": [], "last": "Suman-Chauhan", "suffix": ""}], "year": 1990, "venue": "Neuropharmacology", "link": "2769817"}, "BIBREF5": {"title": "Prevention of metamphetamine-induced behavioural sensitisation in rats by a cyclic AMP phosphodiesterase inhibitor, rolipram", "authors": [{"first": "M", "middle": [], "last": "Iyo", "suffix": ""}, {"first": "Y", "middle": [], "last": "Bi", "suffix": ""}, {"first": "K", "middle": [], "last": "Hashimoto", "suffix": ""}, {"first": "T", "middle": [], "last": "Inada", "suffix": ""}, {"first": "S", "middle": [], "last": "Fukui", "suffix": ""}], "year": 1996, "venue": "Eur J Pharmacol", "link": null}, "BIBREF6": {"title": "Half a century of antipsychotics and still a central role for dopamine D2 receptors", "authors": [{"first": "S", "middle": [], "last": "Kapur", "suffix": ""}, {"first": "D", "middle": [], "last": "Mamo", "suffix": ""}], "year": 2003, "venue": "Prog Neuropsychopharmacol Biol Psychiatry", "link": "19636741"}, "BIBREF7": {"title": "The potential therapeutic use of phosphodiesterase 10 inhibitors", "authors": [{"first": "J", "middle": [], "last": "Kehler", "suffix": ""}, {"first": "A", "middle": [], "last": "Ritz\u00e9n", "suffix": ""}, {"first": "D", "middle": ["R"], "last": "Greve", "suffix": ""}], "year": 2007, "venue": "Expert Opin Ther Pat", "link": "84512738"}, "BIBREF8": {"title": "Constitutive activation of G \u03b1 s within forebrain neurons causes deficits in sensorimotor gating because of PKA-dependent decreases in cAMP", "authors": [{"first": "M", "middle": ["P"], "last": "Kelly", "suffix": ""}, {"first": "C", "middle": [], "last": "Isiegas", "suffix": ""}, {"first": "Y", "middle": ["F"], "last": "Cheung", "suffix": ""}, {"first": "J", "middle": [], "last": "Tokarczyk", "suffix": ""}, {"first": "X", "middle": [], "last": "Yang", "suffix": ""}, {"first": "M", "middle": ["F"], "last": "Esposito", "suffix": ""}, {"first": "D", "middle": ["A"], "last": "Rapoport", "suffix": ""}, {"first": "S", "middle": ["A"], "last": "Fabian", "suffix": ""}, {"first": "S", "middle": ["J"], "last": "Siegel", "suffix": ""}, {"first": "G", "middle": [], "last": "Wand", "suffix": ""}, {"first": "M", "middle": ["D"], "last": "Houslay", "suffix": ""}, {"first": "S", "middle": ["J"], "last": "Kanes", "suffix": ""}, {"first": "T", "middle": [], "last": "Abel", "suffix": ""}], "year": 2007, "venue": "Neuropsychopharmacology", "link": "812497"}, "BIBREF9": {"title": "Regulation of cyclic GMP levels in the rat frontal cortex in vivo: effects of exogenous carbon monoxide and phosphodiesterase inhibition", "authors": [{"first": "K", "middle": [], "last": "Laitinen", "suffix": ""}, {"first": "K", "middle": [], "last": "Salovaara", "suffix": ""}, {"first": "S", "middle": [], "last": "Severgnini", "suffix": ""}, {"first": "J", "middle": [], "last": "Laitinen", "suffix": ""}], "year": 1997, "venue": "Brain Res", "link": "11606210"}, "BIBREF10": {"title": "Phosphodiesterase inhibitors: a novel mechanism for receptor-independent antipsychotic medications", "authors": [{"first": "C", "middle": [], "last": "Maxwell", "suffix": ""}, {"first": "S", "middle": [], "last": "Kanes", "suffix": ""}, {"first": "T", "middle": [], "last": "Abel", "suffix": ""}, {"first": "S", "middle": [], "last": "Siegel", "suffix": ""}], "year": 2004, "venue": "Neuroscience", "link": "19578277"}, "BIBREF11": {"title": "Phosphodiesterase 10A inhibitors: a novel approach to the treatment of the symptoms of schizophrenia", "authors": [{"first": "F", "middle": [], "last": "Menniti", "suffix": ""}, {"first": "T", "middle": [], "last": "Chappie", "suffix": ""}, {"first": "J", "middle": [], "last": "Humphrey", "suffix": ""}, {"first": "C", "middle": [], "last": "Schmidt", "suffix": ""}], "year": 2007, "venue": "Curr Opin Investig Drugs", "link": "20296501"}, "BIBREF12": {"title": "Signal transduction abnormalities in schizophrenia: the cAMP system", "authors": [{"first": "C", "middle": [], "last": "Muly", "suffix": ""}], "year": 2002, "venue": "Psychopharmacol Bull", "link": "33617091"}, "BIBREF13": {"title": "The Rat Brain in Stereotaxic Coordinates", "authors": [{"first": "G", "middle": [], "last": "Paxinos", "suffix": ""}, {"first": "C", "middle": [], "last": "Watson", "suffix": ""}], "year": 1997, "venue": "", "link": "86211914"}, "BIBREF14": {"title": "PDE10A inhibition reverses subchronic PCP-induced deficits in attantional set-shifting in rats", "authors": [{"first": "J", "middle": [], "last": "Rodefer", "suffix": ""}, {"first": "E", "middle": [], "last": "Murphy", "suffix": ""}, {"first": "M", "middle": [], "last": "Baxter", "suffix": ""}], "year": 2005, "venue": "Eur J Neurosci", "link": "23436299"}, "BIBREF15": {"title": "Role of adenylate cyclase in the modulation of the release of dopamine: a microdialysis study in the striatum of the rat", "authors": [{"first": "M", "middle": [], "last": "Santiago", "suffix": ""}, {"first": "B", "middle": [], "last": "Westerink", "suffix": ""}], "year": 1990, "venue": "J Neurochem", "link": "23997791"}, "BIBREF16": {"title": "Preclinical characterization of selective PDE10A inhibitors: A new therapeutic approach to the treatment of schizophrenia", "authors": [{"first": "C", "middle": ["J"], "last": "Schmidt", "suffix": ""}, {"first": "D", "middle": ["S"], "last": "Chapin", "suffix": ""}, {"first": "J", "middle": [], "last": "Cianfrogna", "suffix": ""}, {"first": "M", "middle": ["L"], "last": "Corman", "suffix": ""}, {"first": "M", "middle": [], "last": "Hajos", "suffix": ""}, {"first": "J", "middle": ["F"], "last": "Harms", "suffix": ""}, {"first": "W", "middle": ["E"], "last": "Hoffman", "suffix": ""}, {"first": "L", "middle": ["A"], "last": "Lebel", "suffix": ""}, {"first": "S", "middle": ["A"], "last": "Mccarthy", "suffix": ""}, {"first": "F", "middle": ["R"], "last": "Nelson", "suffix": ""}, {"first": "C", "middle": [], "last": "Proulx-Lafrance", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Majchrzak", "suffix": ""}, {"first": "A", "middle": ["D"], "last": "Ramirez", "suffix": ""}, {"first": "K", "middle": [], "last": "Schmidt", "suffix": ""}, {"first": "P", "middle": ["A"], "last": "Seymour", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Siuciak", "suffix": ""}, {"first": "R", "middle": ["D"], "last": "Williams", "suffix": ""}, {"first": "P", "middle": ["R"], "last": "Verhoest", "suffix": ""}, {"first": "F", "middle": ["S"], "last": "Menniti", "suffix": ""}], "year": 2008, "venue": "J Pharmacol Exp Ther", "link": "17938982"}, "BIBREF17": {"title": "Immunohistochemical localization of PDE10A in the rat brain", "authors": [{"first": "T", "middle": ["F"], "last": "Seeger", "suffix": ""}, {"first": "B", "middle": [], "last": "Bartlett", "suffix": ""}, {"first": "T", "middle": ["M"], "last": "Coskran", "suffix": ""}, {"first": "J", "middle": ["S"], "last": "Culp", "suffix": ""}, {"first": "L", "middle": ["C"], "last": "James", "suffix": ""}, {"first": "D", "middle": ["L"], "last": "Krull", "suffix": ""}, {"first": "J", "middle": [], "last": "Lanfear", "suffix": ""}, {"first": "A", "middle": ["M"], "last": "Ryan", "suffix": ""}, {"first": "C", "middle": ["J"], "last": "Schmidt", "suffix": ""}, {"first": "C", "middle": ["A"], "last": "Strick", "suffix": ""}, {"first": "A", "middle": ["H"], "last": "Varghese", "suffix": ""}, {"first": "R", "middle": ["D"], "last": "Williams", "suffix": ""}, {"first": "P", "middle": ["G"], "last": "Wylie", "suffix": ""}, {"first": "F", "middle": ["S"], "last": "Menniti", "suffix": ""}], "year": 2003, "venue": "Brain Res", "link": "20666352"}, "BIBREF18": {"title": "Inhibition of the striatum-enriched phosphodiesterase PDE10A: A novel approach to the treatment of Psychosis", "authors": [{"first": "J", "middle": ["A"], "last": "Siuciak", "suffix": ""}, {"first": "D", "middle": ["S"], "last": "Chapin", "suffix": ""}, {"first": "J", "middle": ["F"], "last": "Harms", "suffix": ""}, {"first": "L", "middle": ["A"], "last": "Lebel", "suffix": ""}, {"first": "S", "middle": ["A"], "last": "Mccarthy", "suffix": ""}, {"first": "L", "middle": [], "last": "Chambers", "suffix": ""}, {"first": "A", "middle": [], "last": "Shrikhande", "suffix": ""}, {"first": "S", "middle": [], "last": "Wong", "suffix": ""}, {"first": "F", "middle": ["S"], "last": "Menniti", "suffix": ""}, {"first": "C", "middle": ["J"], "last": "Schmidt", "suffix": ""}], "year": 2006, "venue": "Neuropharmacology", "link": "13447370"}, "BIBREF19": {"title": "Characteristic behavioural alterations in rats induced by rolipram and other selective adenosinecyclic 3',5'-monophosphate phosphodiesterase inhibitors", "authors": [{"first": "H", "middle": [], "last": "Wachtel", "suffix": ""}], "year": 1982, "venue": "Psychopharmacology", "link": "10122417"}, "BIBREF20": {"title": "Effects of forskolin on spontaneous behaviour, rectal temperature and brain cAMP levels of rats: interaction with rolipram", "authors": [{"first": "H", "middle": [], "last": "Wachtel", "suffix": ""}, {"first": "P", "middle": [], "last": "Loschmann", "suffix": ""}, {"first": "H", "middle": [], "last": "Schneider", "suffix": ""}, {"first": "K", "middle": [], "last": "Rettig", "suffix": ""}], "year": 1987, "venue": "Neurosci Lett", "link": "35989461"}, "BIBREF21": {"title": "The conditioned avoidance response test re-evaluated: is it a sensitive test for the detection of potentially atypical antipsychotics?", "authors": [{"first": "M", "middle": ["I"], "last": "Wadenberg", "suffix": ""}, {"first": "P", "middle": ["B"], "last": "Hicks", "suffix": ""}], "year": 1999, "venue": "Neurosci Biobehav Rev", "link": "28237220"}}, "ref_entries": {}}
{"paper_id": "10707190", "_pdf_hash": "1430edcb0775bdb2e86f1b54b6f7b7b139c590d9", "abstract": [{"section": "Abstract", "text": "ABSTRACT Two independently recognized in vitro polymer aggregation variables, electric field and pH, can be used in concert to produce suspended membranes from solutions of type I collagen monomers, without need of a supporting substrate. A collagen network film can form at the alkalineacidic pH interface created during the normal course of water electrolysis with parallel plate electrodes, and the anchoring location can be controlled by adjusting the bulk electrolyte pH. Electrosynthesized films remain intact upon drying and rehydration and function as ion separation membranes even in submillimeter channels. This approach could benefit lab-on-a-chip technologies for rational placement of membranes in microfluidic devices.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Films of collagen, the most abundant mammalian protein 1 , are sought for prosthetic coatings, as support matrices for cell growth, and for permeable membranes. 2 However, many in vitro collagen films are substrate supported 2-5 which limits their use as membranes. Our results demonstrate that two independently recognized in vitro polymer aggregation variables, electric field [6] [7] [8] [9] [10] and pH, 1, 11, 12 can be used in concert to form suspended collagen network films, without the presence of a supporting substrate. This approach could benefit lab-on-a-chip technologies 13 for rational placement of ion separation membranes in microfluidic devices.", "cite_spans": [], "ref_spans": []}, {"section": "1", "text": "Collagen's function in the body is intimately related to its structural transformations through aggregation. Conveniently, the hierarchical collagen structures observed from in vivo 14, 15 collagen aggregation can be replicated in vitro 11, 14 , without need of biological assistance from enzymes or growth factors. Collagen monomers can form oligomers that grow linearly and laterally and cross-link to create fibrils 15 . Alternate aggregation pathways produce different aggregate or fibril morphologies 1, 15, 16 .", "cite_spans": [], "ref_spans": []}, {"section": "1", "text": "Controlled collagen aggregation requires management of electrostatics, sterics, and hydrophobicity, all of which can be affected by pH 1, 14, 15 . Adding an electric field places further importance on electrostatics and charge.", "cite_spans": [], "ref_spans": []}, {"section": "1", "text": "Collagen's surface charge is pH-dependent due to amino acid protonation at acidic pH values and deprotonation at alkaline pH values 17 . Collagen, when net charged, migrates in an electric field like any charged polymer 7, 8 , but beyond that, collagen's behavior in an electric field has not been widely investigated 10, 17 , despite increasing use of electrochemical methods to create biopolymer and biocomposite coatings 2,18 . Collagen is electrochemically inactive over a wide range of applied potentials 19 . However, a sufficiently large applied voltage to its aqueous supporting electrolyte causes alkaline conditions near the cathode, due to the hydrogen evolution reaction (HER, with E 0 = -0.83 vs.", "cite_spans": [], "ref_spans": []}, {"section": "1", "text": "normal hydrogen electrode (NHE)), and acidic pH near the anode (oxygen evolution reaction, with E 0 = +1.71 vs. NHE), which can influence collagen migration and aggregation. Reduction of ambient dissolved oxygen also contributes to the pH change near the cathode. By exposing collagen monomers to the simultaneous pH gradient and electric field produced in an electrochemical cell, we have developed a method to control the spatial aggregation of collagen in the electrolyte, without need for a supporting substrate.", "cite_spans": [], "ref_spans": []}, {"section": "Experimental", "text": "Electrolytes, prepared using ultrapure water (Barnstead, 18.2 M\u2126), contained type I collagen monomers (final concentration 0.07 -0.30 mg/mL from 3 mg/mL Vitrogen stock solution, Inamed Biomaterials) and sufficient NaOH and HCl solutions (EMD chemicals, ACS reagent grade) to adjust the pH to the desired value (4) (5) (6) (7) (8) (9) (10) (11) . Stainless steel sheet electrodes provided an electric field of 5-10 V over 1.0-2.5 cm, yielding a current density of -0.7 to -1.2 mA/cm 2 . These voltages are large relative to the potentials required for the HER, oxygen evolution and oxygen reduction reactions. Macroscopic 2 films were formed in a glass electrochemical cell designed and built in-house (2.5 cm x 2.5 cm x 1 cm, 3.5 mL volume), while smaller films were prepared in glass (1.1 mm ID) or polyethylene (1.57 or 0.86 mm ID) capillaries, 1 cm long. We note that, while it is possible for peroxide to form at the cathode during the hydrogen and oxygen reduction processes, we do not observe any film degradation due to the presence of such strong oxidants over the time scales of our experiments (up to several hours).", "cite_spans": [], "ref_spans": []}, {"section": "Experimental", "text": "Optical microscopy investigations employed a Leica DM2500 with polarized light capability. Atomic force microscopy studies with an Asylum Research MFP-3D used silicon cantilevers (Au back coating, force constant ~ 0.3 N/m, Mikromasch). Raman scattering spectroscopy data were obtained with a Jobin Yvon Horiba LabRAM in the confocal configuration (532 nm excitation).", "cite_spans": [], "ref_spans": []}, {"section": "Experimental", "text": "Within minutes of exposing a pH-adjusted electrolyte of collagen monomers (0.3 mg/mL) to an electric field (3-20 V/cm), a collagen film -visible by eye -forms in the electrolyte, parallel to the anode and cathode, and with its edges anchored to the container walls, whether glass or polyethylene.", "cite_spans": [], "ref_spans": []}, {"section": "Experimental", "text": "Videos and representative current versus time data taken during the film formation process are available as Supporting Information.", "cite_spans": [], "ref_spans": []}, {"section": "Results and Discussion", "text": "Our electrosynthesis method for forming collagen films controls three essential stages of collagen aggregation: localization, organization, and association. The coexistence of the electric field and pH gradient enables a spatially localized region of high collagen concentration through a serendipitous combination of pH-dependent surface charge and the resulting electromobility it induces. When the electric field is first applied, collagen migrates away from the anode 10 to build up a critical mass of collagen near the middle of the cell. As the collagen migrates closer to the pH region that matches its isoelectric point, it approaches net neutral charge and is less affected by the electric field. These changes in surface charge distribution impact charge association and polymer alignment 6, 10 . ", "cite_spans": [], "ref_spans": []}, {"section": "Results and Discussion", "text": "wetted. They are robust enough to be handled with tweezers. Optical micrographs of a dried, partially folded film portray the sheet-like nature of the film (Fig. 1c) , and higher magnifications (Fig. 1d) highlight the complex microstructure of the collagen sheets. Atomic Force Microscopy (AFM) studies show that air-drying reduces film thickness from ~100 \u00b5m to 0.6\u00b10.2 \u00b5m. AFM images presented in the Supplemental Information show continuation of the mesh-like structure on the micrometer length scale. The aggregational heterogeneity evident in the Raman data suggests a time-dependent conversion from non-specific monomer aggregates to collagen fibrils during electrosynthesis. Early in film formation, it is possible to partially or wholly dissolve the film and reform it at a different location in the electrochemical cell simply by reversing the polarity of the applied electric field. However, films formed for longer times show incomplete or minimal dissolution upon field reversal, suggesting that more robust and massive fibrils 21 exist after prolonged exposure to electric field and pH gradients.", "cite_spans": [], "ref_spans": [{"start": 156, "end": 165, "text": "(Fig. 1c)", "ref_id": "FIGREF1"}, {"start": 194, "end": 203, "text": "(Fig. 1d)", "ref_id": "FIGREF1"}]}, {"section": "Results and Discussion", "text": "Despite the mixture of monomeric and fibrillar collagen, film formation and function is quite reliable when three key experimental parameters are controlled First, there exists a collagen concentration threshold below which no film-like aggregation occurs, dependent on the volume of electrolyte relative to the surface area of the desired collagen film. Surface area to volume ratios near 1 cm 2 : 1 mL, consistent with the conditions used to produce the films shown in Fig. 1 , required collagen concentrations of 0.10-0.30 mg/mL. Second, a sufficiently large electric field is essential for spatially controlled aggregation. Earlier studies that employed pH gradients in the absence of an electric field 12 show limited OH -diffusion away from the working electrode (< 50 mm) even after hours of HER. As a result, the optimal pH region for film formation is so close to the cathode surface that hydrogen bubbles from the HER physically disrupt film formation. Fig. 3 is a representative image that shows the reproducibility of film positioning. These anchored films can be reliably positioned in small channels where manually inserting membranes would be extremely difficult, as the sub-millimter capillaries shown in Figures 1 and 3 demonstrate. Thus, there is promise for using electrosynthesis to place collagen membranes in 6 microfluidic devices 13 with either parallel plate or more complicated electrode geometries. Fig. 4 shows that the functionality of such membranes could include maintaining pH gradients or other ion separation. The possibility of size selectivity for larger particles is also intriguing, and experiments (described in more detail in the Supporting Information) have shown that colloidal silica spheres (400-500 nm diameter) do not diffuse readily through these collagen membranes. Thus, suspended electrosynthesized collagen films offer exciting possibilities for lab-on-a-chip technologies. ", "cite_spans": [], "ref_spans": [{"start": 471, "end": 477, "text": "Fig. 1", "ref_id": "FIGREF1"}, {"start": 963, "end": 969, "text": "Fig. 3", "ref_id": "FIGREF4"}, {"start": 1221, "end": 1236, "text": "Figures 1 and 3", "ref_id": "FIGREF1"}, {"start": 1426, "end": 1432, "text": "Fig. 4", "ref_id": "FIGREF5"}]}], "bib_entries": {}, "ref_entries": {"FIGREF0": {"text": "Fig. 1a and Fig. 1b show electrosynthesized suspended collagen films, one with centimeter-scale dimensions (2.5 cm 2 ) prepared in an open cell and another with sub-millimeter dimensions (0.01 cm 2 )", "type": "figure"}, "FIGREF1": {"text": "Figure 1. Electrosynthesized collagen network films can be macroscopic and removable (a) or synthesized in smaller channels (b). The macroscopic film in (a) is shown during its later stages of growth, viewed edge-on with in situ polarized light microscopy. The edge-on view of the sub-millimeter film in (b) depicts the early stages of formation relative to the acidic and alkaline regions of the surrounding electrolyte. Air-dried collagen films, viewed with crossed polarizers, are sheet-like (c); higher magnifications (d) highlight their complex network structure.", "type": "figure"}, "FIGREF2": {"text": "Figure 2. Raman spectra indicate heterogeneous aggregation in the air-dried electrosynthesized collagen film (two regions, A and B) when compared with spectra for air-dried monomeric and fibrillar collagen. The C-N stretch (~1100 cm -1 , strongest intensity for fibrillar collagen), amide I (1630-1670 cm -1 ), and amide III (1240-1270 cm -1 ) regions are most sensitive to conformational changes.", "type": "figure"}, "FIGREF3": {"text": "report collagen aggregation but no evidence of film formation in the electrolyte. Other conditions 10 demonstrate electromigration of positively charged collagen away from an anode for smaller electric fields (< 1 V/cm), but show no film-bulk electrolyte pH influences the spatial location of film formation, offering interesting possibilities for membrane positioning in microfluidic channels. Measurements with pH microelectrodes and universal pH indicator show that the region where the film forms has pH ~6, regardless of the electrolyte's initial bulk pH. Extreme bulk pH values (< 4 or > 11) resulted in fragile or incomplete films, even at sufficiently high collagen concentrations. For example, acidic bulk electrolytes (pH = 2)", "type": "figure"}, "FIGREF4": {"text": "Figure 3. Collagen film positioning is quite reproducible. This representative image shows the films that", "type": "figure"}, "FIGREF5": {"text": "Figure 4. Representative pH versus time data shows that electrosynthesized collagen films can", "type": "figure"}}}
{"paper_id": "10707812", "_pdf_hash": "33bad51d7cbfac95441acf03b273f434652b49d7", "abstract": [{"section": "Abstract", "text": "Abstract. FCA has been successfully applied to software engineering tasks such as source code analysis and class hierarchy re-organization. Most notably, FCA puts mathematics behind the mechanism of abstracting from a set of concrete software artifacts. A key limitation of current FCA-based methods is the lack of support for relational information (e.g., associations between classes of a hierarchy): the focus is exclusively on artifact properties whereas inter-artifact relationships may encode crucial information. Consequently, feeding-in relations into the abstraction process may substantially improve its precision and thus open the access to qualitatively new generalizations. In this paper, we elaborate on ICG, an FCA-based methodology for extracting generic parts out of software models that are described as UML class diagrams. The components of ICG are located within the wider map of an FCA framework for relational data. A few experimental results drawn from an industrial project are also reflected on.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Current trends in object-oriented software construction, namely MDA (Model-Driven Architecture)-based approaches, promote designing high-level models that represent domain and application concepts (\"Platform Independent Models\"). These models, typically described in UML (Unified Modeling Language), are further on mapped to the target implementation platform (\"Platform Specific Models\"). Modeling has thus become a key activity within the software process whereas large efforts are currently spent in developing automated tools to assist it.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "Formal Concept Analysis (FCA) has already been successfully applied to the analysis [1] and restructuring [2] [3] [4] [5] [6] [7] of conceptual class models: it helps reach optimal hierarchical organization of the initial classes by discovering relevant new abstractions. However, providing far-reaching abstraction mechanisms requires the whole feature set of UML to be covered, inclusive those encoding relational information (e.g., UML associations), whereas such features clearly outgrow the scope of standard FCA.", "cite_spans": [{"start": 84, "end": 87, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 106, "end": 109, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 110, "end": 113, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 114, "end": 117, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 118, "end": 121, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 122, "end": 125, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 126, "end": 129, "text": "[7]", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "Introduction", "text": "Making FCA work on UML models is the global aim of our study. Here, we propose a new relationally-aware abstraction technique, ICG (Iterative Cross Generalization), which works on several mutually related formal contexts that jointly encode a UML class diagram. It performs simultaneous analysis tasks on the set of contexts where inter-context links are used to propagate knowledge about the abstractions from a context into its related contexts (and thus broaden the discovery horizon on those contexts).", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "The paper recalls the basics of FCA (Section 2) before providing a motivating example (Section 3). Our recent FCA-based framework for processing relational data is presented in Section 4. In Section 5 we specify ICG while emphasizing the role UML meta-model plays in data description within ICG. Experiments done in the framework of industrial projects are then reported (Section 6) with a discussion of benefits and difficulties in applying ICG.", "cite_spans": [], "ref_spans": []}, {"section": "FCA and class hierarchy restructuring", "text": "Formal concept analysis (FCA) [8] studies the way conceptual structures emerge out of observations. Basic FCA considers an incidence relation over a pair of sets (objects, further denoted by numbers) and (attributes, denoted by lower-case letters). Binary relations are introduced as formal contexts ! \" ! $ #", "cite_spans": [{"start": 30, "end": 33, "text": "[8]", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "FCA and class hierarchy restructuring", "text": ". An example of a context, Foo, is provided in Figure 1 is a complete lattice with joins and meets based on intersection of concept intents and extents, respectively. The lattice of the Foo context is drawn in Figure 1 on the right (as a Hasse diagram).", "cite_spans": [], "ref_spans": [{"start": 47, "end": 55, "text": "Figure 1", "ref_id": "FIGREF0"}, {"start": 210, "end": 218, "text": "Figure 1", "ref_id": "FIGREF0"}]}, {"section": "FCA and class hierarchy restructuring", "text": "Research on applications of FCA has yielded a set of meaningful substructures of the concept lattice. For instance, in object-oriented software engineering, the assignments of specifications/code to classes within a class hierarchy is easily modeled through a context, and applying FCA to a particular hierarchy may reveal crucial flaws in factorization [2] and therefore in maintainability. The dedicated substructure that specifies a maximally factorized class hierarchy of minimal size is called the Galois sub-hierarchy (GSH) of the corresponding context. Mathematically speaking, the GSH is made out of all the extremal concepts that contain an object/attribute in their extents/intents:", "cite_spans": [{"start": 354, "end": 357, "text": "[2]", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "FCA and class hierarchy restructuring", "text": ". Moreover, as practical applications of FCA may involve processing of non-binary data, many-valued contexts have been introduced in FCA. In a many-valued context 6 x V \" A t #", "cite_spans": [], "ref_spans": []}, {"section": "FCA and class hierarchy restructuring", "text": ", each object w is described by a set of attribute -value pairs S 7 9 G # , meaning that is a ternary relation that binds the objects from , the attributes from and the values from . The construction of a lattice on top of a many-valued context requires a pre-processing step, called scaling, which basically amounts to encoding each non-binary attribute by a set of binary ones.", "cite_spans": [], "ref_spans": []}, {"section": "FCA and class hierarchy restructuring", "text": "3 Improving UML models: a motivating example A highly simplified example introduces the problem domain. Consider the UML model in Figure 2 . A class Diary is associated to a class Date through the association orderedBy. Class Date has three attributes (or variables) day, month and year and two methods including isLeapYear() and a comparison method (Date). Another class Clock is linked to Time class via the association shows. Class Time is described by the three attributes hour, min and sec, and by a method To infer a more elaborate UML model, we apply an approach that may be summarized as follows. On the one hand, we process various sorts of UML entities such as attributes, methods and associations, as first-class formal objects and assign a formal context to each entity sort. Moreover, we use relational attributes to express links between entities and model them as inter-context binary relations.", "cite_spans": [], "ref_spans": [{"start": 130, "end": 138, "text": "Figure 2", "ref_id": "FIGREF1"}]}, {"section": "FCA and class hierarchy restructuring", "text": "On the other hand, we use a repeated scaling along the relational attributes to propagate the knowledge about possible generalizations between related contexts. Thus, the concept construction process amounts to alternating scaling and proper construction until stability in concept structures is reached.", "cite_spans": [], "ref_spans": []}, {"section": "FCA and class hierarchy restructuring", "text": "In Figure 4 , three many-valued formal contexts describe classes, associations and methods as first-level formal objects, respectively. Here, UML class attributes are not processed as objects for simplicity sake, but in the general case they are. Note that some formal attributes (e.g. originType) are relational ones while others are not (e.g. originMultiplicity or name). Figure 5 shows the main relational attributes of the example. The method lattice ( Figure 7 ) is now used as a scale for the formal attribute has owned by classes. Thus, if a class has a method \u00a9 in the initial many-valued context, then it owns all the formal attributes has:m in the scaled class context where m stands for a method concept whose extent contains the formal object representing \u00a9 . The resulting scaled class context and its lattice (with top and bottom dropped) are shown in Figure 8 . The lattice includes a new concept c1 which obviously represents comparable objects, hence it could be called Magnitude.", "cite_spans": [], "ref_spans": [{"start": 457, "end": 465, "text": "Figure 7", "ref_id": "FIGREF4"}, {"start": 866, "end": 874, "text": "Figure 8", "ref_id": "FIGREF5"}]}, {"section": "FCA and class hierarchy restructuring", "text": "Our knowledge about the concept structure on classes has thus grown and the new abstractions can be used as descriptors that could, whenever shared, induce potential abstractions on related contexts. For example, the method context could be fed with the knowledge about Magnitude thus prompting a re-consideration of its con- (1):Time). The resulting concept lattice remains isomorphic to that of Figure 7 , however its concepts are explicitly related to existing concepts on classes, e.g., the top concept intent is bound to c1 via typeOfParam(1):c1. The same procedure can be applied for scaling the association context, revealing that the two formal objects can be generalized by a new association which ends into the c1 concept. The scaling of isOrigin and isDestination from the class context, using the augmented association lattice, introduces a new generalization of Diary and Clock (representing devices which manipulate magnitudes). The resulting set of abstractions, re-interpreted in UML, is shown in Figure 9 . The associations orderedBy and shows are linked to the new association manipulate by the constraint subset which indicates a specialization relationship. Because of this constraint, their names are now prefixed by the symbol \"/\", used in UML for highlighting elements that derive from others.", "cite_spans": [], "ref_spans": [{"start": 397, "end": 405, "text": "Figure 7", "ref_id": "FIGREF4"}, {"start": 1013, "end": 1021, "text": "Figure 9", "ref_id": "FIGREF6"}]}, {"section": "FCA and class hierarchy restructuring", "text": "To sum up, we may claim that the apparent commonalties between the classes Time and Date have led to the constitution of common superclass, Magnitude. The discovery of this class has been propagated to both method and association contexts where new abstractions have been created to reflect the existence of Magnitude. In the following, we summarize the key elements of our relational FCA framework. A detailed description could be found in [10] . As in classical FCA, heterogeneous datasets, i.e., ones made out of several sorts of individuals, are introduced through a family of contexts, one per sort of formal objects. Here, a set of binary relations (or set-valued functions) is added to data description, which map objects from a context to sets of objects from another one.", "cite_spans": [{"start": 441, "end": 445, "text": "[10]", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "Definition 1 (Relational context family).", "text": "A relational context family . By bringing those attributes to the objects from , conceptual scaling allows new concepts to occur in which the members of the extent share abstractions of the initial values rather than values themselves. Clearly, the choice of scale attributes has a direct impact on the structure of the target concept lattice: different attribute sets may lead to different lattices.", "cite_spans": [], "ref_spans": []}, {"section": "Definition 1 (Relational context family).", "text": "The same principle may be applied to the processing of relations which are basically object-valued attributes: given a relation q { | } 1 P and w s | the set q e S w # could be replaced by a collection of binary attributes that characterize it. As the entire process is ultimately aimed at detecting commonalties in the abstractions that conceptually describe the target objects, the scaling binds scale attributes to existing concepts on the co-domain context rather than to formal attributes of this context (see the attributes typeOfParam(1):cX from Section 3). Moreover, as we argued in [10] , the most natural choice for the scale lattice of q is the lattice of the context c since it embeds the most precise knowledge about the meaningful abstractions on the set \"", "cite_spans": [{"start": 591, "end": 595, "text": "[10]", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "Definition 1 (Relational context family).", "text": ". However, in specific situations smaller structures, such as the GSH, may be more appropriate.", "cite_spans": [], "ref_spans": []}, {"section": "Definition 1 (Relational context family).", "text": "Consider an object ", "cite_spans": [], "ref_spans": []}, {"section": "Definition 1 (Relational context family).", "text": "(\"wide\"). The \"narrow\" scheme clearly fits lattice-shaped scales whereas the \"wide\" one suits also less extensive concept structures.", "cite_spans": [], "ref_spans": []}, {"section": "Definition 1 (Relational context family).", "text": "To sum up, the encoding by concepts rather than by formal attributes from the destination context eases the interpretation of the formal concepts discovered in the source context | . Moreover, such an encoding fits a step-wise discovery of the scale concepts as illustrated in Section 3: the formation of some new concepts within , one per context l , such that the concepts reflect both shared attributes and similarities in object relations, i.e., common concepts in the co-domain context. Obviously the relational scaling helps to reduce the lattice construction on relational data to the binary case so that the same algorithmic procedures could be applied. However, unlike conventional constructions, some RCF may require a step-wise construction process due to the mutual dependencies between contexts, as it was shown in the UML model analysis. Indeed, having aligned scales with actual concept hierarchies on the destination contexts, an apparent deadlock occurs whenever two contexts are connected both ways by a pair of relational attributes (or chains of such attributes). For instance, in Figure 5 , the class context is doubly connected to the method one by the initial attribute pair (typeOfParam(i), has).", "cite_spans": [], "ref_spans": []}, {"section": "Definition 1 (Relational context family).", "text": "To resolve the deadlocks resulting from circularity in the relational structure of a RCF, we apply a classical fixed-point computation mechanism that proceeds stepwise. Its grounding principle lies in the gradual incorporation of new knowledge gained through scaling: the computation starts with uniformly nominal scales for all relational attributes and at each subsequent step uses the previously discovered concept structures within the respective co-domain contexts as new and richer scales.", "cite_spans": [], "ref_spans": []}, {"section": "Definition 1 (Relational context family).", "text": "Technically speaking, the global lattice extraction process associated with a RCF alternates between relational scaling and lattice construction (see Algorithm 1) . At the initial step, relations are ignored (line 5), hence the lattices at this stage (line 6) are not impacted by the relational information and rather reflect common non-relational attributes. At the following step these lattices are used as new scales for a first-class relational scaling thus providing new possibilities for generalizations (lines 10-11). The scaling (line 10) / construction (line 11) steps go on until the global set of concepts stabilizes, i.e., for each context r . Stabilization of the process can be deduced from the fact that the formal objects do not change over the steps; the concept number of the lattice associated with ! \" A t #", "cite_spans": [], "ref_spans": []}, {"section": "Definition 1 (Relational context family).", "text": "is bounded by", "cite_spans": [], "ref_spans": []}, {"section": "Definition 1 (Relational context family).", "text": ", which gives a bound to the scaling of relational attributes.", "cite_spans": [], "ref_spans": []}, {"section": "Definition 1 (Relational context family).", "text": "Out:", "cite_spans": [], "ref_spans": []}, {"section": "Definition 1 (Relational context family).", "text": "\u00b2 array of lattices ) 3:", "cite_spans": [], "ref_spans": []}, {"section": "Definition 1 (Relational context family).", "text": "while not halt do 8:", "cite_spans": [], "ref_spans": []}, {"section": "Definition 1 (Relational context family).", "text": "Algorithm 1: Construction of the set of concept lattices corresponding to a RCF.", "cite_spans": [], "ref_spans": []}, {"section": "Definition 1 (Relational context family).", "text": "Once the lattices of all contexts are available, a post-processing step clarifies the links between concepts induced by relational scale attributes. In fact, many concept intents will present redundancies: a concept , only those corresponding to minimal Cl will be preserved. For instance, in Figure 8 , the attribute has:m3 is redundant in the intent of class concept c2 since c2 also owns has:m1, whereas m3 is a super-concept of m1 in the method lattice.", "cite_spans": [], "ref_spans": [{"start": 293, "end": 301, "text": "Figure 8", "ref_id": "FIGREF5"}]}, {"section": "Specifying the Iterative Cross Generalization Process", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "UML class diagrams (models) in more details", "text": "In class diagrams, classes are associated to structural features (attributes) and behavioral features (operations and methods). In Figure 10 (top) the main elements of attribute and method description are presented: visibility (+, -and #); attribute types e.g. String, Point or Color which can be classes; return type; parameter type list; multiplicity for many-valued attributes (like color), the multiplicity is a set of integer intervals restricting the value number (for color, multiplicity 1..* expresses the fact that color has one or more value); static status (underlined feature); derived status (introduced by /). Figure 10 (bottom) also illustrates the main aspects of UML associations. An association is composed of at least two association ends. When it has a name (for example place order), the name is followed by a triangle which establishes the direction for reading this name: a person places an order and not the other way round. An association end is typically characterized by: a type (the class involved in this end), for example Person and Order are the two end types of the association place order; a visibility; a multiplicity; a navigability (shown through an arrow next to the type end); a white or black diamond which indicates an aggregation or a composition. An association end is sometimes provided with a role name which gives more accurate semantics to objects when they are involved in the link, e.g.", "cite_spans": [], "ref_spans": [{"start": 131, "end": 140, "text": "Figure 10", "ref_id": "FIGREF0"}, {"start": 624, "end": 633, "text": "Figure 10", "ref_id": "FIGREF0"}]}, {"section": "UML class diagrams (models) in more details", "text": "for a person in association \u00a9 7 0 7 0 \u00ca G . When the association owns variables and methods it is considered as an association class, e.g. Access is an association class that supports the variable passwd. Using the UML meta-model to guide the context construction The definition of UML is established by the UML meta-model, that is a model that defines the language for models. The UML meta-model is described through a subset of UML, and is given with well-formedness rules in the formal language OCL (Object Constraint Language), as well as with semantics in natural language. Part of this meta-model [12] relevant to our problem, that considers the classes and their features, is shown in Figure 11 . The meta-class Class specializes Classifier, and as such, inherits from the possibility to own Features (Attribute or Method). An Attribute includes the meta-attributes initialValue, multiplicity, visibility, changeable; it has a type via the meta-association that links it to Classifier. A Method has the meta-attributes body, isQuery, visibility, and is composed of an ordered set of Parameters. An Association is composed of several AssociationEnds which have a type which is a classifier. AssociationEnds are described by a type (a classifier), and several meta-attributes including isNavigable, isOrdered, aggregation and multiplicity.", "cite_spans": [], "ref_spans": [{"start": 692, "end": 701, "text": "Figure 11", "ref_id": "FIGREF0"}]}, {"section": "UML class diagrams (models) in more details", "text": "As a meta-description of UML, the meta-model naturally contains the good abstractions for determining the right formal contexts: meta-classes are straightly interpreted as formal objects, while meta-attributes and ends of meta-associations are their formal attributes. Nevertheless, such an approach can lead to the manipulation of many tables of data, and to the use of descriptors that generate too numerous uninteresting concepts. Parameter for example is preferably included in the description of methods. Associations should be described by an ordered set of association ends, but if we consider only binary and directed associations, as often suggested in modeling [13] , we can avoid having a specific formal context for association end description. Conversely, if we want to inspect all possible generalizations of associations in the general case, a formal context describing association ends would be relevant. Notice that the algorithm may propose to factorize role names depending on the way the designer has named the associations: association names, role names or both. This corresponds to the formal attributes name, nameOrigin and nameDestination of the formal context on associations. The multiplicity on the side of the class @Authentication context is also properly factorized into a 1..* multiplicity. On the other hand, one may question the factorization of 0..1 and 1 multiplicities into * (it could have been factorized into 0..1) but this is an internal choice of the algorithm that could be fine-tuned.", "cite_spans": [{"start": 671, "end": 675, "text": "[13]", "ref_id": "BIBREF11"}], "ref_spans": []}, {"section": "Conclusion", "text": "We presented a new FCA-based technique (ICG) which processes several mutually related formal contexts and sketched its application to UML class diagram restructuring. Experiments on industrial-scale projects established the feasibility of our approach (execution time and semantic relevance of the results) and highlighted the crucial role of parameter tuning and appropriate user interface. A key track of improvement is the separation of formal attributes that guide the construction of new abstractions (e.g. names, types of attributes, association ends, etc.) from secondary ones that only help to increase the precision (e.g., multiplicity or navigability). Another current concern is the integration of a domain ontology into the ICG framework that should enable the comparison of symbolic names used by the designer. This is crucial for any automated reconstruction technique such as our, because terms are not uniformly used over UML diagrams, many synonymy, homonymy or polysemy situations occur. Although Objecteering offers an operational user interface for ICG there is a large space for improvement. First, designers that are FCA neophytes would benefit from an automated assistance in tool fine-tuning. Second, navigation and edition tools should help make the entire ICG process more interactive and thence more purposeful, e.g., by supporting run-time filtering of the discovered abstractions.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Understanding class hierarchies using concept analysis", "authors": [{"first": "G", "middle": [], "last": "Snelting", "suffix": ""}, {"first": "F", "middle": [], "last": "Tip", "suffix": ""}], "year": 2000, "venue": "ACM Transactions on Programming Languages and Systems", "link": "14152166"}, "BIBREF1": {"title": "Building and maintaining analysis-level class hierarchies using Galois lattices", "authors": [{"first": "R", "middle": [], "last": "Godin", "suffix": ""}, {"first": "H", "middle": [], "last": "Mili", "suffix": ""}], "year": 1993, "venue": "Proceedings of OOPSLA'93", "link": "5464621"}, "BIBREF2": {"title": "On Automatic Class Insertion with Overloading", "authors": [{"first": "H", "middle": [], "last": "Dicky", "suffix": ""}, {"first": "C", "middle": [], "last": "Dony", "suffix": ""}, {"first": "M", "middle": [], "last": "Huchard", "suffix": ""}, {"first": "T", "middle": [], "last": "Libourel", "suffix": ""}], "year": 1996, "venue": "Special issue of Sigplan Notice -Proceedings of ACM OOPSLA'96", "link": "10083647"}, "BIBREF3": {"title": "Design of Class Hierarchies Based on Concept (Galois) Lattices. Theory and Practice of Object Systems", "authors": [{"first": "R", "middle": [], "last": "Godin", "suffix": ""}, {"first": "H", "middle": [], "last": "Mili", "suffix": ""}, {"first": "G", "middle": [], "last": "Mineau", "suffix": ""}, {"first": "R", "middle": [], "last": "Missaoui", "suffix": ""}, {"first": "A", "middle": [], "last": "Arfi", "suffix": ""}, {"first": "T", "middle": [], "last": "Chau", "suffix": ""}], "year": 1998, "venue": "", "link": null}, "BIBREF4": {"title": "Computing Interfaces in Java", "authors": [{"first": "M", "middle": [], "last": "Huchard", "suffix": ""}, {"first": "H", "middle": [], "last": "Leblanc", "suffix": ""}], "year": 2000, "venue": "Proc. IEEE International conference on Automated Software Engineering (ASE'2000)", "link": "14899731"}, "BIBREF5": {"title": "iO2 -An Algorithmic Method for Building Inheritance Graphs in Object Database Design", "authors": [{"first": "A", "middle": [], "last": "Yahia", "suffix": ""}, {"first": "L", "middle": [], "last": "Lakhal", "suffix": ""}, {"first": "R", "middle": [], "last": "Cicchetti", "suffix": ""}, {"first": "J", "middle": [], "last": "Bordat", "suffix": ""}], "year": 1996, "venue": "Proceedings of the 15th International Conference on Conceptual Modeling ER'96", "link": "45717182"}, "BIBREF6": {"title": "Designing Class Hierarchies of Object Database Schemas", "authors": [{"first": "A", "middle": [], "last": "Yahia", "suffix": ""}, {"first": "L", "middle": [], "last": "Lakhal", "suffix": ""}, {"first": "J", "middle": [], "last": "Bordat", "suffix": ""}], "year": 1997, "venue": "13 i\u00e8mes journ\u00e9es Bases de Donn\u00e9es Avanc\u00e9es", "link": "34579130"}, "BIBREF7": {"title": "Formal Concept Analysis, Mathematical Foundations", "authors": [{"first": "B", "middle": [], "last": "Ganter", "suffix": ""}, {"first": "R", "middle": [], "last": "Wille", "suffix": ""}], "year": 1999, "venue": "", "link": "41383162"}, "BIBREF8": {"title": "Ordre et Classification: Alg\u00e8bre et Combinatoire", "authors": [{"first": "M", "middle": [], "last": "Barbut", "suffix": ""}, {"first": "B", "middle": [], "last": "Monjardet", "suffix": ""}], "year": 1970, "venue": "", "link": null}, "BIBREF9": {"title": "Extracting Formal Concepts out of Relational Data", "authors": [{"first": "P", "middle": [], "last": "Valtchev", "suffix": ""}, {"first": "M", "middle": ["H"], "last": "Rouane", "suffix": ""}, {"first": "M", "middle": [], "last": "Huchard", "suffix": ""}, {"first": "C", "middle": [], "last": "Roume", "suffix": ""}], "year": 2003, "venue": "Proceedings of the 4th Intl. Conference Journ\u00e9es de l'Informatique Messine (JIM'03): Knowledge Discovery and Discrete Mathematics", "link": "16537601"}, "BIBREF10": {"title": "Applications of combinatorics and graph theory to the biological and social sciences", "authors": [{"first": "B", "middle": [], "last": "Ganter", "suffix": ""}, {"first": "R", "middle": [], "last": "Wille", "suffix": ""}], "year": 1989, "venue": "", "link": null}, "BIBREF11": {"title": "Object Oriented Modeling and Design", "authors": [{"first": "J", "middle": [], "last": "Rumbaugh", "suffix": ""}, {"first": "M", "middle": [], "last": "Blaha", "suffix": ""}, {"first": "W", "middle": [], "last": "Premerlani", "suffix": ""}, {"first": "F", "middle": [], "last": "Eddy", "suffix": ""}, {"first": "W", "middle": [], "last": "Lorensen", "suffix": ""}], "year": 1991, "venue": "", "link": "29538562"}, "BIBREF12": {"title": "GALICIA: an open platform for lattices", "authors": [{"first": "P", "middle": [], "last": "Valtchev", "suffix": ""}, {"first": "D", "middle": [], "last": "Grosser", "suffix": ""}, {"first": "C", "middle": [], "last": "Roume", "suffix": ""}, {"first": "M", "middle": ["R"], "last": "Hacene", "suffix": ""}], "year": 2003, "venue": "Using Conceptual Structures: Contributions to 11th Intl. Conference on Conceptual Structures (ICCS'03)", "link": "16650318"}, "BIBREF13": {"title": "Validation sur de grands projets", "authors": [{"first": "M", "middle": [], "last": "Dao", "suffix": ""}], "year": 2003, "venue": "Projet MACAO (RNTL)", "link": null}}, "ref_entries": {"FIGREF0": {"text": "Fig. 1. A sample context and the Hasse diagram of its concept lattice", "type": "figure"}, "FIGREF1": {"text": "Fig. 2. Diary and clock", "type": "figure"}, "FIGREF2": {"text": "Fig. 3. Formal context for diary and clock", "type": "figure"}, "FIGREF3": {"text": "Fig. 4. Formal contexts for classes, methods and associations", "type": "figure"}, "FIGREF4": {"text": "Fig. 7. The first concept lattice on methods", "type": "figure"}, "FIGREF5": {"text": "Fig. 8. Scaling the class context (up), class concept lattice (down) without the top and the bottom", "type": "figure"}, "FIGREF6": {"text": "Fig. 9. Diary and clock after iterative cross generalization", "type": "figure"}, "FIGREF8": {"text": ", e.g., through refining of the descriptions of the context objects, results in the addition of new scale attributes in the encoding of |", "type": "figure"}, "FIGREF11": {"text": "Fig. 10. Classes and associations", "type": "figure"}, "FIGREF13": {"text": "Fig. 11. Extracts from the UML meta-model", "type": "figure"}, "FIGREF14": {"text": "Fig. 12. Factorization of an association", "type": "figure"}, "TABREF0": {"text": "satisfy the clo- sure properties. The underlying sub-families of closed sets are bijectively mapped to each other by", "type": "table"}, "TABREF1": {"text": "by a set of binary ones, called scale attributes. Scale attributes basically describe meaningful features of the values of the initial attribute, say , and therefore induce a lattice of concepts, called the scale lattice, on top of the value set", "type": "table"}}}
{"paper_id": "10707928", "_pdf_hash": "c9da127d0c4b04b97ad69682e0ace8ca1067f85b", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "First and second trimester antenatal screening for Down's syndrome: the results of the Serum, Urine and Ultrasound Screening Study (SURUSS)", "authors": [{"first": "N", "middle": ["J"], "last": "Wald", "suffix": ""}, {"first": "C", "middle": [], "last": "Rodeck", "suffix": ""}, {"first": "A", "middle": ["K"], "last": "Hackshaw", "suffix": ""}, {"first": "J", "middle": [], "last": "Walter", "suffix": ""}, {"first": "L", "middle": [], "last": "Chitty", "suffix": ""}, {"first": "A", "middle": ["M"], "last": "Mackinson", "suffix": ""}], "year": 2003, "venue": "J Med Screen", "link": "32047925"}, "BIBREF1": {"title": "Correct estimation of parameters for ultrasound nuchal translucency screening", "authors": [{"first": "K", "middle": ["H"], "last": "Nicolaides", "suffix": ""}, {"first": "Rjm", "middle": [], "last": "Snijders", "suffix": ""}, {"first": "H", "middle": ["S"], "last": "Cuckle", "suffix": ""}], "year": 1998, "venue": "Prenat Diagn", "link": "40410305"}, "BIBREF2": {"title": "A critical evaluation of sonar ''crown-rump length'' measurements", "authors": [{"first": "H", "middle": ["P"], "last": "Robinson", "suffix": ""}, {"first": "J", "middle": ["E"], "last": "Fleming", "suffix": ""}], "year": 1975, "venue": "Br J Obstet Gynaecol", "link": "31663686"}, "BIBREF3": {"title": "Improvements in antenatal screening for Down's syndrome", "authors": [{"first": "N", "middle": ["J"], "last": "Wald", "suffix": ""}, {"first": "J", "middle": ["P"], "last": "Bestwick", "suffix": ""}, {"first": "W", "middle": ["J"], "last": "Huttly", "suffix": ""}], "year": 2013, "venue": "J Med Screen", "link": "25422045"}, "BIBREF4": {"title": "Log-linear Log-quadratic Log-sigmoid", "authors": [], "year": "", "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "10708142", "_pdf_hash": "63d4ad6916766dbc7035b99e75cd875283720668", "abstract": [{"section": "Abstract", "text": "Leaf senescence is the orderly dismantling of older tissue that allows recycling of nutrients to developing portions of the plant and is accompanied by major changes in gene expression. Histone modifications correlate to levels of gene expression, and this study utilizes ChIP-seq to classify activating H3K4me3 and silencing H3K27me3 marks on a genomewide scale for soil-grown mature and naturally senescent Arabidopsis leaves. ChIPnorm was used to normalize data sets and identify genomic regions with significant differences in the two histone methylation patterns, and the differences were correlated to changes in gene expression. Genes that showed an increase in the H3K4me3 mark in older leaves were senescence up-regulated, while genes that showed a decrease in the H3K4me3 mark in the older leaves were senescence down-regulated. For the H3K27me3 modification, genes that lost the H3K27me3 mark in older tissue were senescence upregulated. Only a small number of genes gained the H3K27me3 mark, and these were senescence down-regulated. Approximately 50% of senescence up-regulated genes lacked the H3K4me3 mark in both mature and senescent leaf tissue. Two of these genes, SAG12 and At1g73220, display strong senescence up-regulation without the activating H3K4me3 histone modification. This study provides an initial epigenetic framework for the developmental transition into senescence.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Arabidopsis thaliana, similar to most crop plants, is a monocarpic species that undergoes whole plant senescence to maximize energy input into reproductive structures. Understanding the molecular mechanisms of nutrient recycling during leaf senescence is critical for the production of high yielding crops. Global gene expression has been characterized in senescent Arabidopsis tissue [1, 2, 3, 4] , and senescence up-regulated genes (SURGs) are enriched for autophagy, response to reactive oxygen species, chlorophyll and lipid catabolism as well as carbohydrate and nitrogen transport. Senescence downregulated genes (SDRGs) are enriched for cytoplasmic protein synthesis as well as chloroplast functions such as light harvesting, carbon fixation, and photorespiration. A leaf senescence database compiles senescence associated genes and orthologs from numerous plant species [5] . Transcription factors that play a role in these global changes in gene expression have been identified. Genetic and biochemical evidence support a role for WRKY53 (Locus:2128514) and NAC family members VNI2 (Locus:2179877) and AtNAP (Locus:2007166) as positive regulators of senescence [6, 7, 8, 9, 10] , and microarray analysis reveals over-representation for the AP2-EREBP, bZIP, C3H, CCAAT, NAC and WRKY transcription factor families as senescence progresses [1] .", "cite_spans": [{"start": 385, "end": 388, "text": "[1,", "ref_id": "BIBREF0"}, {"start": 389, "end": 391, "text": "2,", "ref_id": "BIBREF1"}, {"start": 392, "end": 394, "text": "3,", "ref_id": "BIBREF2"}, {"start": 395, "end": 397, "text": "4]", "ref_id": "BIBREF3"}, {"start": 878, "end": 881, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 1170, "end": 1173, "text": "[6,", "ref_id": "BIBREF5"}, {"start": 1174, "end": 1176, "text": "7,", "ref_id": "BIBREF6"}, {"start": 1177, "end": 1179, "text": "8,", "ref_id": "BIBREF7"}, {"start": 1180, "end": 1182, "text": "9,", "ref_id": "BIBREF8"}, {"start": 1183, "end": 1186, "text": "10]", "ref_id": "BIBREF9"}, {"start": 1346, "end": 1349, "text": "[1]", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "Introduction", "text": "Transcription factors can recruit histone modifying enzymes to specific promoter regions [11] and alterations in histone structure have been shown to be important for the vegetative to reproductive transition in Arabidopsis [12] . The floral repressor gene, FLC (Locus:2184118), is silenced during vernalization, a 40 day cold treatment, when activating H2BK143ub1, H3K4me3 and H3K36me3 histone marks are removed from FLC and replaced with silencing H3R3sme, H3K9me3 and H3K27me3 histone marks. FLC is reactivated in the globular stage of embryogenesis in a process that requires replacement of H2A with the H2AZ histone variant [13] . Endosperm development is regulated via genomic imprinting which utilizes histone modification and DNA methylation to silence maternal or paternal alleles [14] . In rice, expression of genes important for brassinosteroid synthesis and signaling are dependent on SDG725, an H3K36 methyltransferase [15] . In addition to development, histone modifications accompany changes in gene expression in response to deetiolation [16] and abiotic stresses including drought, cold, salt and hypoxia [17] .", "cite_spans": [{"start": 89, "end": 93, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 224, "end": 228, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 629, "end": 633, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 790, "end": 794, "text": "[14]", "ref_id": "BIBREF13"}, {"start": 932, "end": 936, "text": "[15]", "ref_id": "BIBREF14"}, {"start": 1054, "end": 1058, "text": "[16]", "ref_id": "BIBREF15"}, {"start": 1122, "end": 1126, "text": "[17]", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "Introduction", "text": "Dynamic chromatin modifications may also be important for the changes in gene expression associated with senescence. Decondensation of heterochromatin occurs in the early stages of Arabidopsis leaf senescence and overexpression of SUVH2 (Locus:2051083), an H3K9 methyltransferase which promotes the formation of ectopic heterochromatin, has pleiotropic phenotypic effects which include a delay in senescence [18] . Low-level overexpression of a chromatin-modifying AT-hook protein, ORE7/ESC (Locus:2037350), also resulted in delayed senescence [19] . In yeast, worms, flies and mammals, the sirtuin family of histone deacetylases function to prevent early senescence by deacetylation of H3K9 in a suite of promoters controlled by NF-kB [20] . Although the mechanism has not been reported, the Arabidopsis histone deacetylase mutant, hda6 (Locus:2162017), also has increased leaf longevity [21] .", "cite_spans": [{"start": 408, "end": 412, "text": "[18]", "ref_id": "BIBREF17"}, {"start": 544, "end": 548, "text": "[19]", "ref_id": "BIBREF18"}, {"start": 736, "end": 740, "text": "[20]", "ref_id": "BIBREF19"}, {"start": 889, "end": 893, "text": "[21]", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "Introduction", "text": "This work focuses on two histone modifications, H3K4me3 and H3K27me3. Trimethylation of H3K4 is catalyzed by the COMPASS-like protein complexes which form a scaffold for different SET-domain methyltransferases [22] . H3K4me3 marks have been evaluated on a genome-wide scale using chromatin immunoprecipitation (ChIP) followed by hybridization to highdensity genomic arrays [23] , and found to associate at and just downstream of the transcription start site (TSS) of expressed genes. This is similar to humans where H3K4me3 is associated with active genes near the TSS [24] . In Arabidopsis, the Pol IIassociating factor 1 complex (Paf1C) guides H3K4me3 marks to the 59-end of a subset of actively transcribed genes by linking elongating Pol II with histone methyltransferases after ubiquitination of H2B [25] , however this mechanism is not used for activation of all genes since H2BK143Ub1 precedes H3K4 trimethylation for some, but not all, Arabidopsis genes [26] .", "cite_spans": [{"start": 210, "end": 214, "text": "[22]", "ref_id": "BIBREF21"}, {"start": 373, "end": 377, "text": "[23]", "ref_id": "BIBREF22"}, {"start": 569, "end": 573, "text": "[24]", "ref_id": "BIBREF23"}, {"start": 805, "end": 809, "text": "[25]", "ref_id": "BIBREF24"}, {"start": 962, "end": 966, "text": "[26]", "ref_id": "BIBREF25"}], "ref_spans": []}, {"section": "Introduction", "text": "Trimethylation of H3K27 in plants, is catalyzed by the Polycomb-group protein complex 2 (PRC2) [27, 28] , and is found to be associated with highly tissue-specific genes when they are silenced. H3K27me3 is enriched within the body of the gene from 25% to 75% of gene length [29] . For some embryonic and stem cell regulator genes, H3K27me3 is recognized by a plant version of PRC1 which subsequently monoubiquitinates H2AK120 and aids in gene silencing [30] . The H3K27me3 histone modification plays an important role in controlling the size of the floral meristem [31] and in leaf development [32] .During vernalization, the COLDAIR noncoding intronic RNA, which is encoded by the first intron of FLC, targets PRC2 to the FLC locus to promote trimethylation of H3K27 and silencing of the floral repressor [33] .", "cite_spans": [{"start": 95, "end": 99, "text": "[27,", "ref_id": "BIBREF26"}, {"start": 100, "end": 103, "text": "28]", "ref_id": "BIBREF27"}, {"start": 274, "end": 278, "text": "[29]", "ref_id": "BIBREF28"}, {"start": 453, "end": 457, "text": "[30]", "ref_id": "BIBREF29"}, {"start": 565, "end": 569, "text": "[31]", "ref_id": "BIBREF30"}, {"start": 594, "end": 598, "text": "[32]", "ref_id": "BIBREF31"}, {"start": 806, "end": 810, "text": "[33]", "ref_id": "BIBREF32"}], "ref_spans": []}, {"section": "Introduction", "text": "In this study, genome-wide locations of H3K4me3 and H3K27me3 marks in mature and senescent Arabidopsis leaves were determined by ChIP-seq. Genomic regions that showed significant differences in these modifications were identified using ChIPnorm and correlated to changes in gene expression that accompany senescence. Gain or loss of the activating H3K4me3 mark correlated to up-or down-regulation during senescence and similar, but opposite, trends were observed for the silencing H3K27me3 mark. This loss in H3K4 trimethylation in older tissue was accompanied by an increase in expression of KDM5B-like genes encoding H3K4 demethylases. Surprisingly, two genes that were strongly up-regulated during senescence completely lacked the activating H3K4me3 mark.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "H3K4me3 and H3K27me3 marks in mature and senescent leaves", "text": "Arabidopsis plants, grown on soil in light chambers with continuous illumination, were used in this study. Mature leaves were harvested 23 days after germination (23 d) when plants had incipient bolts and large expanded green rosette leaves. Senescent leaves were obtained from 52 day-old (52 d) plants with elongated bolts in which about half of the siliques were brown and dry ( Figure 1 ). The rosettes of the older plants had yellow-green leaves near the soil, but only fully-expanded green leaves were harvested. No cauline leaves or newly developed rosette leaves were harvested.", "cite_spans": [], "ref_spans": [{"start": 381, "end": 389, "text": "Figure 1", "ref_id": "FIGREF0"}]}, {"section": "H3K4me3 and H3K27me3 marks in mature and senescent leaves", "text": "Chromatin immunoprecipitation was performed using antibodies that recognize H3K4me3, H3K27me3, and H3-general along with input samples. Approximately 20 million unique single end reads were obtained for H3-general and input samples and the H3K4me3_23d sample while approximately 13 million unique single end reads were obtained for the two H3K27me3 samples (_23d and _52d) and the H3K4me3_52d sample. For all subsequent analyses, the appropriate input sample was chosen as the control since input reads did not significantly differ from H3-gen reads ( Figure S1 ). Data are displayed on a mirror UCSC genome browser (http://genomes.mcdb.ucla.edu/) under Senescence ChIP-seq and tracks are displayed in the following order, from top to bottom: H3K4me3_23d, H3K4me3_52d, K4_diff, H3K27me3_23d, H3K27me3_52d, and K27_diff. Gray bars under sequence read tracks show regions with significant signal (p,1e-6) above the appropriate input background (see Genome Browser and Figure 2 ).", "cite_spans": [], "ref_spans": [{"start": 552, "end": 561, "text": "Figure S1", "ref_id": "FIGREF0"}, {"start": 966, "end": 974, "text": "Figure 2", "ref_id": "FIGREF1"}]}, {"section": "H3K4me3 and H3K27me3 marks in mature and senescent leaves", "text": "Validity of data was evaluated by observing gene tracks with expected histone methylation patterns. ACTIN2 (At3g18780, Locus:2093954 ) is highly expressed at both 23 d and 52 d, and strong H3K4me3 marks and no H3K27me3 marks were observed in leaf samples of both ages at this locus ( Figure 2A ). The FLC floral repressor (At5g10140) is not expressed in the fri (Locus:2127013) mutant Col-0 ecotype [34, 35] , and is known to be silenced, in part, by H3K27me3 marks [12] . In both mature and senescent leaf tissue, the FLC gene was heavily marked by H3K27me3 ( Figure 2B ). The H3K4me3 mark was absent except for a small peak that spans the first exon and the beginning of the first intron, and a second small peak that covers the last exon, and may be related to expression of the COOLAIR long non-coding RNA [36] .", "cite_spans": [{"start": 399, "end": 403, "text": "[34,", "ref_id": "BIBREF33"}, {"start": 404, "end": 407, "text": "35]", "ref_id": "BIBREF34"}, {"start": 466, "end": 470, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 810, "end": 814, "text": "[36]", "ref_id": "BIBREF35"}], "ref_spans": [{"start": 284, "end": 293, "text": "Figure 2A", "ref_id": "FIGREF1"}, {"start": 561, "end": 570, "text": "Figure 2B", "ref_id": "FIGREF1"}]}, {"section": "H3K4me3 and H3K27me3 marks in mature and senescent leaves", "text": "K4_diff and K27_diff tracks show regions with significant differences in levels of histone modification as determined by ChIPnorm [37] . Red bars indicate higher levels of histone methylation in the 23 d sample while green bars indicate higher levels of methylation in the 52 d sample in the Genome Browser. The ChIPnorm method was utilized to find differential regions between 23 d and 52 d H3K27me3 and H3K4me3 histone modification ChIP-seq data. ChIPnorm is a two-stage statistical approach to find differentially enriched regions of the genome given two ChIP-seq histone modification libraries. ChIPnorm removes the noise and the bias from two ChIP-seq libraries and normalizes the data to enable a direct comparison between the two libraries to identify differential regions. The first stage removes the regions which have stochastic background noise and local genomic bias, and in the second stage the two libraries are normalized using a quantile normalization procedure and then differential regions are identified. This approach outperformed other approaches in identifying differential regions without bias. Differential regions identified for the H3K4me3 mark were most abundant in the first kilobase (first five 200 bp bins) downstream of the TSS and were depleted in the same region upstream of the TSS ( Figure 3A) . Differential regions for the H3K27me3 mark were most abundant just downstream of the TSS, but did not show a marked depletion upstream of the TSS ( Figure 3B ). The location of the H3K4me3 differential regions generally matched the location of H3K4me3 modifications noted previously (20) while the location of H3K27me3 differential regions was further upstream than the previously noted peak of H3K27me3 marks (25% to 75% of gene length) (25) .", "cite_spans": [{"start": 130, "end": 134, "text": "[37]", "ref_id": "BIBREF36"}, {"start": 1614, "end": 1618, "text": "(20)", "ref_id": "BIBREF19"}, {"start": 1769, "end": 1773, "text": "(25)", "ref_id": "BIBREF24"}], "ref_spans": [{"start": 1318, "end": 1328, "text": "Figure 3A)", "ref_id": "FIGREF2"}, {"start": 1479, "end": 1488, "text": "Figure 3B", "ref_id": "FIGREF2"}]}, {"section": "H3K4me3 and H3K27me3 marks in SenescenceRegulated Genes", "text": "Senescence up-regulated genes (SURGs) and senescence downregulated genes (SDRGs) were identified from a published microarray analysis using naturally senescent leaf tissue that had lost approximately 25% of total chlorophyll, and was generally similar to the leaf tissue used in this study [4] with the exception that our plants were grown in continuous light at 24uC while the plants analyzed by microarray were grown under 16 hL:8 hD long-day conditions at 21uC during the day and 19uC at night. To confirm similarity between the two studies, 8 SURGs and 7 SDRGs were analyzed by real-time qPCR using RNA isolated from the same tissue used for ChIP-seq, and results are summarized in Table 1 . All 8 SURGs were found to be upregulated in our senescent leaves while 6 of 7 SDRGs were found to be down-regulated. These data indicate that our tissue is a fair representation of the published microarray results, and permit a larger scale analysis of gene expression and differential histone modifications ( Figure 4 ). A collection of 4090 genes, whose expression values were taken from a supplemental table published in [4] , were chosen for this expression analysis. These genes were divided into five groups with group A having the largest differential expression at 23 d (SDRGs), group C having approximately equal expression at 23 d and 52 d, and group E having the largest differential expression at 52 d (SURGs). Genes were categorized as having K4 at both developmental stages (K4-K4), at neither developmental stage (None-None) or only at 23 d (K4-None) or only at 52 d (None-K4). When histone methylation categories were graphed according to expression groups it could be seen that group A and B were enriched for K4-None while groups D and E were enriched for None-K4 ( Figure 4A ) demonstrating that H3K4me3 modifications play an activating role for SDRGs at 23 d and for SURGs at 52 d. The proportion of genes that were differentially marked was small, with most genes showing NoneNone (approximately 35% of 4090 genes) or K4-K4 (approximately 60% of 4090 genes). This is similar to observations made in mouse cells [37] . A similar analysis was done for the H3K27me3 modification, and group E genes were most highly enriched for K27-None demonstrating a repressive role for K27 at 23 d. Only a small number of genes showed the None-K27 pattern however these were concentrated in group E genes which do show reduced expression at 52 d ( Figure 4B ). For H3K27me3, the largest proportion of genes were unmodified (None-None, approximately 90% of 4090 genes), which is also similar to the analysis done for mouse [37] . SURGs (group E) that showed an increase in the H3K4me3 mark in older tissue were subject to GO analysis, and over-represented categories include response to stress and response to water deprivation. SURGs (group E) that showed a decrease in the H3K27me3 mark were over-represented in response to abiotic stress as well as response to water deprivation GO categories. Leaves undergoing senescence do experience oxidative stress and water loss. A small number of genes were shared among the response to water deprivation classification indicating that H3K4me3 increase was coupled to a decrease in H3K27me3 for a subset of genes. SDRGs (group A) that showed a decrease in the H3K4me3 mark were enriched for the response to auxin stimulus category, including four SAUR-like genes (At5g18030, At4g34760, At1g29460, At5g18060) and the AUX1 auxin influx transporter (At2g38120). These genes are recognized to be involved in rapid auxin response and cell elongation, and down-regulation during senescence is expected and appears to involve a decrease in the H3K4me3 mark.", "cite_spans": [{"start": 290, "end": 293, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 1120, "end": 1123, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 2128, "end": 2132, "text": "[37]", "ref_id": "BIBREF36"}, {"start": 2623, "end": 2627, "text": "[37]", "ref_id": "BIBREF36"}], "ref_spans": [{"start": 686, "end": 693, "text": "Table 1", "ref_id": "TABREF0"}, {"start": 1006, "end": 1014, "text": "Figure 4", "ref_id": "FIGREF3"}, {"start": 1780, "end": 1789, "text": "Figure 4A", "ref_id": "FIGREF3"}, {"start": 2449, "end": 2458, "text": "Figure 4B", "ref_id": "FIGREF3"}]}, {"section": "H3K4me3 and H3K27me3 marks in SenescenceRegulated Genes", "text": "ChIP-seq reads are shown for two SURGs in Figure 5 and two SDRGs in Figure 6 . At3g44300 is up-regulated 309-fold and At1g13340 is up-regulated 16-fold in older leaves ( Table 1) . The K4_diff track is visible and colored green for both genes since there is an increased level of the H3K4me3 mark in the 52 d sample. Lhcb2.3 is down-regulated 25-fold and At2g10940 is downregulated 14,000-fold in older leaves (Table 1) , and both have K4_diff tracks colored red since there is increased level of the H3K4me3 mark in the 23 d sample. Interestingly, the strongly down-regulated At2g10940 also shows a significant increase in the H3K27me3 mark in the 52 d tissue shown by the green bars in the K27_diff track.", "cite_spans": [], "ref_spans": [{"start": 42, "end": 50, "text": "Figure 5", "ref_id": "FIGREF4"}, {"start": 68, "end": 76, "text": "Figure 6", "ref_id": "FIGREF5"}, {"start": 170, "end": 178, "text": "Table 1)", "ref_id": "TABREF0"}, {"start": 410, "end": 419, "text": "(Table 1)", "ref_id": "TABREF0"}]}, {"section": "H3K4me3 and H3K27me3 marks in SenescenceRegulated Genes", "text": "A small number of genes showed bivalent H3K4me3 and H3K27me3 modifications at 23 d which became monovalent H3K4me3 or H3K27me3 modifications at 52 d. Genes retaining the activating H3K4me3 marks were in groups C, D and E, while genes retaining the H3K27me3 marks were only in groups A and B ( Figure 7) . These results provide additional support for an activating role for H3K4me3 and a silencing role for H3K27me3 as leaves age.", "cite_spans": [], "ref_spans": [{"start": 293, "end": 302, "text": "Figure 7)", "ref_id": "FIGREF6"}]}, {"section": "H3K4me3 and H3K27me3 marks in SenescenceRegulated Genes", "text": "H3K4me3 demethylation is catalyzed by KDM5B/JARID1B family members [38] , and there are 8 potential KDM5B-like genes in Arabidopsis [39, 40] . Expression of these eight genes was measured in 52 d and 23 d leaf tissue using real-time qPCR with ACT2 as the reference. One of the genes, At2g34880, had undetectable mRNA levels in both tissues. Six of the remaining 7 genes showed some degree of up-regulation in the senescent leaf tissue with At5g46910, At1g08620, At1g63490, At4g20400, At2g38950 and, At1g30810 all displaying a greater than 2-fold induction ( Figure 8) . One of these genes, At4g20400 has been shown to affect the timing of flowering [41, 42, 43] , but the five other KDM5B-like genes do not yet have ascribed functions (www.arabidopsis.org).", "cite_spans": [{"start": 67, "end": 71, "text": "[38]", "ref_id": "BIBREF37"}, {"start": 132, "end": 136, "text": "[39,", "ref_id": "BIBREF38"}, {"start": 137, "end": 140, "text": "40]", "ref_id": "BIBREF39"}, {"start": 649, "end": 653, "text": "[41,", "ref_id": "BIBREF40"}, {"start": 654, "end": 657, "text": "42,", "ref_id": "BIBREF41"}, {"start": 658, "end": 661, "text": "43]", "ref_id": "BIBREF42"}], "ref_spans": []}, {"section": "H3K4me3 and H3K27me3 marks in SenescenceRegulated Genes", "text": "One other study quantified H3K4me3 marks in senescent Arabidopsis leaf tissue at the WRKY53 locus (At4g23810, Locus:2128514), and found a small increase in this modification in senescent leaves [18] . Our genome-wide quantitative analysis also showed enriched H3K4me3 marks on the WRKY53 gene, however no quantitative difference in these marks was observed between the 23 d and 52 d samples ( Figure S2 ). No significant enrichment of H3K27me3 marks was observed for the WRKY53 gene. In our tissue, WRKY53 mRNA was only up-regulated by 1.7-fold at 52 d compared to 23 d. The largest increase in WRKY53 expression likely occurred prior to tissue harvest [44] , and this may explain the discrepancy with the previous study.", "cite_spans": [{"start": 194, "end": 198, "text": "[18]", "ref_id": "BIBREF17"}, {"start": 653, "end": 657, "text": "[44]", "ref_id": "BIBREF43"}], "ref_spans": [{"start": 393, "end": 402, "text": "Figure S2", "ref_id": "FIGREF1"}]}, {"section": "H3K4me3 and H3K27me3 marks in SenescenceRegulated Genes", "text": "Surprisingly, two genes that are strongly up-regulated during senescence did not show expected H3K4me3 histone modification patterns. SAG12 (At5g45890), which encodes a cysteine protease and is considered a molecular marker for senescence, was up-regulated 90,000-fold in the 52 d tissue (Table 1) , but this gene was devoid of H3K4me3 marks at both 23 d and 52 d. H3-general sequence reads showed that histones were present in the SAG12 promoter region (data not shown). In addition, H3K27me3 modifications were found in this region, but trimethylation levels were not significantly different between the two samples as shown by a lack of green or red bars in the K27_diff tracks. The adjacent gene, At5g45900, did contain H3K4me3 marks near its TSS indicating there is no general loss of this modification in this region of the genome, rather SAG12 specifically lacks H3K4me3 marks ( Figure 9A ). It is unlikely that increased mRNA stability is the cause of increased mRNA levels because the SAG12 promoter has been shown to activate reporter genes during senescence [45] . A second SURG, At1g73220, encodes a carbohydrate transporter, and mRNA levels were increased 113-fold at 52 d (Table 1 ). This gene also completely lacks the H3K4me3 mark despite high mRNA levels at 52 d ( Figure 9B ). At1g73220 does have similar levels of H3K27me3 marks in both mature and senescent leaves indicating that histones are present in this region. These two important exceptions show that the H3K4me3 mark is not required for high levels of gene expression in senescent leaf tissue.", "cite_spans": [{"start": 1069, "end": 1073, "text": "[45]", "ref_id": "BIBREF44"}], "ref_spans": [{"start": 288, "end": 297, "text": "(Table 1)", "ref_id": "TABREF0"}, {"start": 886, "end": 895, "text": "Figure 9A", "ref_id": "FIGREF7"}, {"start": 1186, "end": 1194, "text": "(Table 1", "ref_id": "TABREF0"}, {"start": 1282, "end": 1291, "text": "Figure 9B", "ref_id": "FIGREF7"}]}, {"section": "H3K4me3 and H3K27me3 marks in SenescenceRegulated Genes", "text": "A biological replicate was performed utilizing plants grown under similar conditions and harvested at 23 d and 53 d. Nuclei were isolated and ChIP was performed using antibodies from the same company, but different lot numbers. Immunoprecipitated DNA was analyzed by real-time qPCR, and results were similar to ChIP-seq findings (Figure 10 ). H3K4me3 modifications were associated with ACT2, but absent in FLC. At1g44300 (SURG, Figure 5A ) showed an increase in the H3K4me3 mark in older leaves while At2g10940 (SDRG, Figure 6B ) showed a decrease in the H3K4me3 mark in older leaves. The H3K4me3 modification was absent in SAG12 (SURG, Figure 10 ). The H3K27me3 antibody displayed reduced avidity, and only small amounts of the FLC genomic regions were immunoprecipitated. Increased H3K27me3 marks were observed at the At2g10940 gene at 52 d ( Figure 6B ), and this similar pattern was observed for the biological replicate ( Figure 10 ). ", "cite_spans": [], "ref_spans": [{"start": 329, "end": 339, "text": "(Figure 10", "ref_id": "FIGREF0"}, {"start": 428, "end": 437, "text": "Figure 5A", "ref_id": "FIGREF4"}, {"start": 518, "end": 527, "text": "Figure 6B", "ref_id": "FIGREF5"}, {"start": 637, "end": 646, "text": "Figure 10", "ref_id": "FIGREF0"}, {"start": 845, "end": 854, "text": "Figure 6B", "ref_id": "FIGREF5"}, {"start": 927, "end": 936, "text": "Figure 10", "ref_id": "FIGREF0"}]}, {"section": "Discussion", "text": "We report genome-wide patterns of histone H3 trimethylation at lysine 4 and lysine 27 in mature (23 d) and senescent (52 d) Arabidopsis leaves. Senescence is the orderly, final process of leaf development, and this study aimed to determine if there were any epigenetic changes that marked the chromatin of the senescent leaf and if these correlated to changes in gene expression. The H3K4me3 mark is predominantly associated with active genes while the H3K27me3 mark is predominantly associated with silenced, tissue-specific genes. Genome-wide analyses of both modifications have been reported for 10-14 day old seedlings grown in vitro on artificial medium that contained sucrose [16, 23, 29] , while the data presented in this work catalogue these histone methylations in chromatin from leaves harvested from plants grown on soil at two stages of development: mature, fullyexpanded leaves from plants with incipient bolts (23 d) and leaves harvested from plants undergoing natural senescence (52 d). Arabidopsis is a monocarpic plant in which whole-plant senescence follows seed production. Senescent leaves were harvested when approximately half of the siliques were brown, and therefore undergoing the process of whole-plant natural senescence. At this time, the oldest leaves of the rosette were yellow or brown, while the younger, but fully-expanded, leaves of the rosette were still green. These green fully-expanded leaves were harvested for the senescent sample and represent older leaves that will soon become yellow and go through cell death. Similar expression patterns for 15 of 16 genes shown to be upor down-regulated during senescence in previous studies [1, 4] , demonstrated that the 23 d leaf tissue was mature, while the 52 d sample was undergoing natural senescence and allowed a larger scale expression analysis from a separate study to be correlated with these ChIP-seq results.", "cite_spans": [{"start": 682, "end": 686, "text": "[16,", "ref_id": "BIBREF15"}, {"start": 687, "end": 690, "text": "23,", "ref_id": "BIBREF22"}, {"start": 691, "end": 694, "text": "29]", "ref_id": "BIBREF28"}, {"start": 1672, "end": 1675, "text": "[1,", "ref_id": "BIBREF0"}, {"start": 1676, "end": 1678, "text": "4]", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "Discussion", "text": "Correlation of changes in histone modifications to gene expression revealed that SURGs displayed increased H3K4me3 in the senescent tissue while SDRGs showed increased H3K4me3 modifications in the younger tissue. These changes in modification status were only observed in 9% of SURGs from group E and 6% of SDRGs from group A, which although a small fraction, is over 60 genes, and likely more since the analysis was performed with only 4090 genes. Only slight changes in the expression of ten ATX and ATXR genes which encode H3K4 methyltransferases [28] , were observed in older leaves [1] indicating that H3K4 trimethylation activity is not transcriptionally regulated. Group A SDRGs that showed a decreased H3K4me3 methylation were enriched in the response to auxin category. Enrichment of auxinresponse genes was also noted for the H3K27me3 mark in another study [32] indicating that histone modification may play an important role in the regulation of auxin responses.", "cite_spans": [{"start": 550, "end": 554, "text": "[28]", "ref_id": "BIBREF27"}, {"start": 587, "end": 590, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 867, "end": 871, "text": "[32]", "ref_id": "BIBREF31"}], "ref_spans": []}, {"section": "Discussion", "text": "For the 4090 genes analyzed by ChIPnorm, approximately 35% of the genes were classified as None-None with respect to H3K4me3 modifications at 23 d and 52 d, and this value was closer to 50% for group E SURGs. This large proportion of SURGs was expressed without significant levels of the activating H3K4me3 mark. Two striking examples are SAG12 and At1g73220, which were both highly expressed during senescence, yet completely lacked H3K4me3 marks. It is possible that other epigenetic marks, such as histone acetylation or cytosine methylation, may be changing as a leaf enters senescence, and these modifications will be evaluated at these two loci in future work. In addition, modifications at enhancers may affect gene expression, and this, too, can be evaluated [46] . H3K4me3-independent gene expression has not been widely reported, however one study demonstrated that the human Autoimmune Regulator (AIRE, NM_000383) protein can activate expression of target genes that lack H3K4me3 marks [47] , however induced expression levels were low, which differs from the highly expressed SAG12 mRNA. Thus, the observation of H3K4me3-independent high expression appears to be novel. The increased expression of SAG12 and At1g73220 could be mediated by the respective promoters in a histone-modification-independent manner. The presence of H3K27me3 marks was delayed compared to changes in gene expression for a dexamethasone-responsive FLC transgene [34] . In this study, addition of DEX increased DEX:: FLC gene expression within 6 h, yet a decrease in H3K27me3 was not observed for 12-24 h. These results show that changes in gene expression can precede changes in histone methylation, however H3K4me3 modifications were not measured in this study.", "cite_spans": [{"start": 767, "end": 771, "text": "[46]", "ref_id": "BIBREF45"}, {"start": 997, "end": 1001, "text": "[47]", "ref_id": "BIBREF46"}, {"start": 1449, "end": 1453, "text": "[34]", "ref_id": "BIBREF33"}], "ref_spans": []}, {"section": "Discussion", "text": "Six percent of SDRGs displayed a loss of the H3K4me3 mark. H3K4me3 demethylation is catalyzed by KDM5B JmJC-domain containing proteins [38] , and 8 putative KDM5B-like genes have been identified in Arabidopsis. One of these genes, At4g20400, displays H3K4me3 demethylase activity when recombinant protein is purified from E. coli [41, 43] . Other KDM5B-like genes play roles in flowering [42] , brassinosteroid signaling [48] and gametophyte development [49] . Seven of the 8 KDM5B-like genes were found to be up-regulated in the 52 d leaf tissue, and six of the genes were up-regulated over 2-fold. Expression of SDRGs is currently being evaluated in T-DNA insertion lines that disrupt senescence up-regulated KDM5B-like genes that do not affect the timing of flowering, and higher order mutants will be constructed based on results from single mutant studies.", "cite_spans": [{"start": 135, "end": 139, "text": "[38]", "ref_id": "BIBREF37"}, {"start": 330, "end": 334, "text": "[41,", "ref_id": "BIBREF40"}, {"start": 335, "end": 338, "text": "43]", "ref_id": "BIBREF42"}, {"start": 388, "end": 392, "text": "[42]", "ref_id": "BIBREF41"}, {"start": 421, "end": 425, "text": "[48]", "ref_id": "BIBREF47"}, {"start": 454, "end": 458, "text": "[49]", "ref_id": "BIBREF48"}], "ref_spans": []}, {"section": "Discussion", "text": "Differences in trimethylation of H3K27 were also evaluated by ChIPnorm and correlated to gene expression. A decrease in H3K27me3 marks at 52 d was observed for SURGs, but an increase in H3K27me3 at 52 d was only rarely observed for SDRGs. H3K27me3 marks can be removed by the REF6 demethylase [50] , which is expressed at both 23 and 52 d (data not shown). The H3K27me3 methylation status was NoneNone for approximately 90% of the genes in groups A through E indicating this histone methylation is one of many mechanisms that are utilized for the transition into leaf senescence. This study evaluated H3K4me3 and H3K27me3 histone marks in mature and senescent Arabidopsis leaf tissue using ChIP-seq and ChIPnorm and genome-wide results are displayed on a publicly available Genome Browser web site. Differentially modified regions were identified, and an activating role for H3K4me3 as well as a repressive role for H3K27me3, were revealed. Activating H3K4me3 marks were found to decrease in genes down-regulated during senescence and numerous KDM5B-like genes, encoding H3K4me3 demethylases, were found to have increased expression in senescent leaves. Surprisingly, two genes with high levels of expression in senescent leaf tissue lacked activating H3K4me3 marks. Although other histone modifications and DNA methylation need to be tested, these results show that high expression levels can be uncoupled from the H3K4me3 mark in senescent leaf tissue.", "cite_spans": [{"start": 293, "end": 297, "text": "[50]", "ref_id": "BIBREF49"}], "ref_spans": []}, {"section": "Materials and Methods", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Plant Growth Conditions", "text": "Arabidopsis thaliana ecotype Col-0 were grown on Sunshine Mix #1 soil under constant illumination (55 mmoles photons ) at 24uC in a Percival E36HO light chamber, and fertilized weekly, for the number of days indicated.", "cite_spans": [], "ref_spans": []}, {"section": "Preparation of Nuclei", "text": "Nuclei were isolated from leaf tissue using a modified version of a published protocol [51] . Well-watered plants were placed in the dark overnight to deplete starch reserves. Four g of leaf tissue was loosely packed into a 50 ml conical tube and 37 ml of crosslinking buffer (0.4 M sucrose, 10 mM Tris, pH 8.0, 1 mM EDTA, pH 8.0, 1% formaldehyde, 1 mM PMSF) was added to the tube which was covered with parafilm, pricked with a needle and placed in a vacuum chamber evacuated with the house vacuum line for 10 min. 2.5 ml of 2 M glycine was then added to the tube, and vacuum infiltration continued for 5 min. Leaves were rinsed 36 in cold, deionized water, and blotted dry on Kimwipes. Dried tissue was ground in liquid nitrogen for 2.5 min, and transferred to a 50 ml tube containing 25 ml of cold nuclei isolation buffer (0.25 M sucrose, 15 mM PIPES, pH 6.8, 5 mM MgCl 2 , 60 mM KCl, 15 mM NaCl, 1 mM CaCl 2 , 0.9% Triton X-100, 2 mg/ml pepstatin A, 2 mg/ml aprotinin) and vortexed for 10 sec every min for 15 min, returning sample to ice between vortex steps. The slurry was then filtered through four layers of autoclaved cheesecloth and the filtrate was centrifuged at 11,000 g for 20 min at 4uC. The supernatant was immediately poured off and the green/white pellet was gently resuspended in 2 ml cold nuclei lysis buffer (50 mM HEPES, pH 7.5, 150 mM NaCl, 1 mM EDTA, pH 8.0, 1% SDS, 0.1% Na deoxycholate, 1% Triton X-100, 1 mM PMSF, 1 mg/ml pepstatin A, 1 mg/ml aprotinin). Four ml of ChIP dilution buffer was added to the sample (150 mM NaCl, 16.7 mM Tris, pH 7.5, 3.3 mM EDTA, pH 8.0, 1% Triton X-100, 0.1% SDS, 0.5% Na deoxycholate, 1 mM PMSF, 1 mg/ml pepstatin A, 1 mg/ml aprotinin), and 300 ml aliquots were flash frozen in liquid N 2 , and stored at 280uC.", "cite_spans": [{"start": 87, "end": 91, "text": "[51]", "ref_id": "BIBREF50"}], "ref_spans": []}, {"section": "Chromatin Immunoprecipitation", "text": "Fifty ml of Dynabeads TM Protein G (Invitrogen, Inc) were washed 36 with 500 ml ChIP dilution buffer, and resuspended to 95 ml with ChIP dilution buffer plus 5 ml of antibody [H3K4me3 (Millipore 17-678), H3K27me3 (Millipore 07-449) H3-general (Millipore 17-10046)], and rotated at 4uC for 2 h. After a quick spin, Dyanbeads coupled to antibodies were washed once with 500 ml ChIP dilution buffer and then twice with 500 ml ChIP dilution buffer with 5 mg/ml BSA. After washes, Dynabeads coupled to antibodies were resuspended in 500 ml ChIP dilution buffer with 5 mg/ml BSA and rotated at 4uC for 2 h to saturate non-specific binding sites.", "cite_spans": [], "ref_spans": []}, {"section": "Chromatin Immunoprecipitation", "text": "Nuclei were thawed on ice and then transferred to 1.5 ml polymethyl pentene tubes (Diagenode, Inc) and sonicated in a Diagenode BioRupter at 4uC for 30 cycles of 30 sec sonication at the highest setting and 30 sec off. Sonicated nuclei were centrifuged at 14,000 rpm at 4uC for 10 min, and supernatant was transferred to a fresh tube containing 700 ml ChIP dilution buffer on ice. The 1 ml of sonicated nuclei were added to 50 ml of Dynabeads TM protein G that had been washed 36 with 500 ml ChIP dilution buffer, and rotated for 2 h at 4uC in order to preclear the nuclei for non-specific binding activity. Dynabeads coupled to antibody were pulled back, the supernatant was removed, and tubes with beads were placed on ice. Dynabeads from pre-cleared nuclei were pulled back, the precleared nuclei were transferred to the tubes with Dyanbeads coupled to antibody on ice (or an empty tube for the input sample), and tubes were rotated overnight at 4uC.", "cite_spans": [], "ref_spans": []}, {"section": "Chromatin Immunoprecipitation", "text": "Beads were washed 36(500 ml) with three sequential ChIP Wash Buffers (A, B, C). Each wash step was done for 4 min with rotation at RT. ChIP Wash Buffer A: 20 mM Tris, pH 8.1, 150 mM NaCl, 2 mM EDTA, 0.1% SDS, 1% Triton X-100; ChIP Wash Buffer B: 20 mM Tris, pH 8.1, 500 mM NaCl, 2 mM EDTA, 0.1% SDS, 1%Triton X-100; and ChIP Wash Buffer C: 10 mM Tris, pH 8.0, 250 mM LiCl, 1 mM EDTA, 1% Na-deoxycholate, 1% NP-40. Dynabeads were then washed twice in 1 ml 10 mM Tris, pH 7.5, 1 mM EDTA. Dynabeads were then eluted twice each with 100 ml of 100 mM Tris, pH 8.0, 18.75 mM EDTA, 1% SDS at 65uC for 15 min with vortexing every 2 min. Dynabeads were pelleted in a microcentrifuge and the eluants were combined. 200 mL of input sample was removed after overnight incubation without washes. 200 ml of 0.4 M NaCl diluted in TE was added along with 2 ml RNAse A (10 mg/ml), followed by 10 min at 37uC. Crosslinks were then reversed at 65uC for 5 h. Three ml of proteinase K (20 mg/ml) was added and incubated at 55uC for 1 h. DNA was then precipitated overnight using 8 mg glycogen carrier and 850 ml 100% ethanol, washed with 80% ethanol, and the dry pellet was resuspended in 30 ml H 2 O. DNA (2 ml) was quantified using the Quant-IT High Sensitivity Assay (Invitrogen, Inc).", "cite_spans": [], "ref_spans": []}, {"section": "Library Construction", "text": "End repair was performed on 5 ng of ChIP DNA using the End-IT kit from Epicentre Technologies with reactions running for 1 h at RT. DNA was then purified on a Mini-elute spin column (Qiagen) and eluted with 32 ml EB. Adenine overhang reactions were set up with 15 units of Klenow fragment (New England Biolabs) and 0.2 mM dATP and run for 30 min at 37uC. DNA was then purified on a mini-elute spin column and eluted with 18.8 ml of EB. Adaptors were obtained from the USC Epigenome center, and were diluted (1:40) and added to 26Rapid Buffer (Enzymatics) and this mixture was added to purified dAtailed DNA. 3,000 units of Enzymatics T4 DNA Ligase was then added, and ligation was done for 15 min at RT, and promptly These genes were classified into those that lost both modifications at 52 d (K4+K27-None, dark blue), those that retained the H3K27me3 mark at 52 d (K4+K27 -K27, light blue), those that retained the H3K4me3 mark at 23 d (K4+K27-K4, yellow) and those that retained the bivalent marks (K4+K27-K4+K27, brick red). Genes thus classified were then placed into the five groups shown in Figure 4 . Genes that retained the H3K27me3 mark were restricted to groups A and B while genes that retained the H3K4me3 mark were restricted to groups C-E. doi:10.1371/journal.pone.0033151.g007 Figure 8 . Expression of Arabidopsis KDM5B-like genes in senescent leaf tissue. KDM5B genes encode H3K4me3 demethylases, and eight KDM5B-like genes were identified in Arabidopsis. The same tissue used in the ChIP-seq analysis was analyzed for expression of the KDM5B-like genes using real-time qPCR. ACT2 was the reference gene and relative expression at 52 d compared to 23 d is shown. Two KDM5B-like genes affect flowering time [41, 42, 43] , and their published names as well as known target gene are shown. At2g34880 mRNA was undetectable in both RNA samples, and is not shown. doi:10.1371/journal.pone.0033151.g008 stopped by addition of 250 ml PB buffer (Qiagen) and purification on a mini-elute spin column. DNA was eluted twice, once with 20 ml of EB and then with 19.2 ml EB, and eluants were combined. PCR reactions were set up with 2 units of Platinum Pfx DNA Polymerase (Invitrogen) with 0.4 mM dNTPs, 2 mM MgSO 4 and 0.5 mM primers. Amplification conditions were 94uC for 2 min, 98uC for 30 sec followed by 18 cycles of 98uC for 10 sec, 65uC for 30 sec and 72uC for 30 sec followed by 72uC for 4 min. After PCR was complete, the sample was run on a 1.5% agarose TAE gel using loading buffer with no dye. Multiple samples were run on separate gels to prevent cross-contamination. DNA that was clearly separated from the adaptor dimer band was cut from the gel and purified using spin columns (Qiagen). Gel pieces were melted in QC buffer at 37uC to prevent loss of AT-rich fragments. DNA was eluted in 40 ml of EB and quantified as before. DNA was submitted to the USC Epigenome Center for clustering and singleend sequencing analysis on an Illumina HiSeq system. Adaptors and primers are standard Illumina sequences and are listed at http://epigenome.usc.edu/docs/making_libraries/DNA_Library_ Protocol_100428.pdf.", "cite_spans": [{"start": 1722, "end": 1726, "text": "[41,", "ref_id": "BIBREF40"}, {"start": 1727, "end": 1730, "text": "42,", "ref_id": "BIBREF41"}, {"start": 1731, "end": 1734, "text": "43]", "ref_id": "BIBREF42"}], "ref_spans": [{"start": 1097, "end": 1105, "text": "Figure 4", "ref_id": "FIGREF3"}]}, {"section": "Real-time qPCR", "text": "Total RNA was isolated with TRIzol TM reagent (Invitrogen, Inc), and 1 mg of total RNA was used for cDNA synthesis using random hexamer primers and M-MLV reverse transcriptase. The qPCR Design Tool available at Eurofins mwg/Operon was used for qPCR primer design, primers were tested for linearity with different amounts of cDNA, and all r-values for linearity were above 0.9 0.03 ng of ChIP DNA was used as a template for realtime qPCR amplification. Background was defined as the level of H3K4me3 at FLC and the level of H3K27me3 at ACT2. ABSOLUTE TM QPCR SYBR Green PCR mix (Thermo Scientific) was used in 12 mL reactions amplified in a Stratagene ", "cite_spans": [], "ref_spans": []}, {"section": "MX3000P", "text": "TM Real-Time PCR system with a 62uC annealing temperature. Real-time primers used in this study are listed in Table S1 along with TAIR Accession numbers.", "cite_spans": [], "ref_spans": [{"start": 110, "end": 118, "text": "Table S1", "ref_id": "TABREF0"}]}, {"section": "ChIP-seq Analysis", "text": "Reads were mapped to the TAIR7 genome using MAQ 0.7.1, and only reads that align to a unique position were retained for further analysis. Duplicate reads that map to the same location on the genome were counted once to reduce clonal amplification effects. The genome was tiled with 100 base windows, and each read was extended by 150 bases which adds one count to each window containing a portion of the read. The counts were estimated for the immunoprecipitate sample as well as the input sample, and the total counts of the input sample were normalized to equal those of the immunoprecipitate. The input sample was used to estimate the expected counts in a window, and if these were zero, they were set to the average value for all windows. Finally, the Poisson distribution was used to estimate the probability of observing the immunoprecipitate counts within a window given the expected counts in the input sample window. We considered all windows with p values less than 1e-6 to have significant peaks. By comparing the number of peaks in the comparison of two inputs, to those found by comparing an immunoprecipitated sample to input, we estimate that this threshold corresponds to a 2% false discovery rate.", "cite_spans": [], "ref_spans": []}, {"section": "ChIP-seq Analysis", "text": "For ChIPnorm, the fold change threshold t was set at 2.0, and the ChIP-seq data were binned at 200 bp. Figure 10 . Biological replicate to confirm ChIP-seq data. Plants were grown under similar growth chamber conditions for 23 d and 53 d and subject to ChIP followed by real-time qPCR with primers that were designed to amplify the peaks of histone modification observed with ChIP-seq. The ACT2 gene showed high enrichment for the H3K4me3 mark in both samples while the FLC gene showed some enrichment for the H3K27me3 mark in both samples. Differential H3K4me3 modifications were observed for the SURG At1g44300 and the SDRG At2g10940. In addition, the gain in H3K27me3 marks at 52 d was observed for At2g10940. The SAG12 gene lacked H3K4me3 marks. doi:10.1371/journal.pone.0033151.g010", "cite_spans": [], "ref_spans": [{"start": 103, "end": 112, "text": "Figure 10", "ref_id": "FIGREF0"}]}, {"section": "Supporting Information", "text": "", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "HIghresolution temporal profiling of transcripts during Arabidopsis leaf senescence reveals a distinct chronology of processes and regulation", "authors": [{"first": "E", "middle": [], "last": "Breeze", "suffix": ""}, {"first": "E", "middle": [], "last": "Harrison", "suffix": ""}, {"first": "S", "middle": [], "last": "Mchattie", "suffix": ""}, {"first": "L", "middle": [], "last": "Hughes", "suffix": ""}, {"first": "R", "middle": [], "last": "Hickman", "suffix": ""}], "year": 2011, "venue": "Plant Cell", "link": "23049957"}, "BIBREF1": {"title": "Comparative transcriptome analysis reveals significant differences in gene expression and signalling pathways between developmental and dark/ starvation-induced senescence in Arabidopsis", "authors": [{"first": "V", "middle": [], "last": "Buchanan-Wollaston", "suffix": ""}, {"first": "T", "middle": [], "last": "Page", "suffix": ""}, {"first": "E", "middle": [], "last": "Harrison", "suffix": ""}, {"first": "E", "middle": [], "last": "Breeze", "suffix": ""}, {"first": "P", "middle": [], "last": "Lim", "suffix": ""}], "year": 2005, "venue": "Plant Journal", "link": "36756341"}, "BIBREF2": {"title": "Transcriptome of Arabidopsis leaf senescence", "authors": [{"first": "Y", "middle": [], "last": "Guo", "suffix": ""}, {"first": "Z", "middle": [], "last": "Cai", "suffix": ""}, {"first": "S", "middle": [], "last": "Gan", "suffix": ""}], "year": 2004, "venue": "Plant, Cell and Environment", "link": "84945052"}, "BIBREF3": {"title": "Transcription analysis of Arabidopsis membrane transporters and hormone pathways during developmental and induced leaf senescence", "authors": [{"first": "E", "middle": [], "last": "Van Der Graaff", "suffix": ""}, {"first": "R", "middle": [], "last": "Schwacke", "suffix": ""}, {"first": "A", "middle": [], "last": "Schneider", "suffix": ""}, {"first": "M", "middle": [], "last": "Desimone", "suffix": ""}, {"first": "U-I", "middle": [], "last": "Flugge", "suffix": ""}], "year": 2006, "venue": "Plant Physiology", "link": "20723219"}, "BIBREF4": {"title": "LSD: a leaf senescence database", "authors": [{"first": "X", "middle": [], "last": "Liu", "suffix": ""}, {"first": "Z", "middle": [], "last": "Li", "suffix": ""}, {"first": "Z", "middle": [], "last": "Jiang", "suffix": ""}, {"first": "Y", "middle": [], "last": "Zhao", "suffix": ""}, {"first": "J", "middle": [], "last": "Peng", "suffix": ""}], "year": 2011, "venue": "Nucleic Acids Research", "link": "18804969"}, "BIBREF5": {"title": "Targets of the WRKY53 transcription factor and its role during leaf senescence in Arabidopsis", "authors": [{"first": "Y", "middle": [], "last": "Miao", "suffix": ""}, {"first": "T", "middle": [], "last": "Laun", "suffix": ""}, {"first": "P", "middle": [], "last": "Zimmermann", "suffix": ""}, {"first": "U", "middle": [], "last": "Zentgraf", "suffix": ""}], "year": 2004, "venue": "Plant Molecular Biology", "link": "30652063"}, "BIBREF6": {"title": "A HECT E3 ubiquitin ligase negatively regulates Arabidopsis leaf senescence through degradation of the transcription factor WRKY53", "authors": [{"first": "Y", "middle": [], "last": "Miao", "suffix": ""}, {"first": "U", "middle": [], "last": "Zentgraf", "suffix": ""}], "year": 2010, "venue": "Plant Journal", "link": "11530510"}, "BIBREF7": {"title": "The Arabidopsis NAC transcription factor VNI2 integrates abscisic acid signals into leaf senescence via the COR/RD genes", "authors": [{"first": "S-D", "middle": [], "last": "Yang", "suffix": ""}, {"first": "P", "middle": [], "last": "Seo", "suffix": ""}, {"first": "H-K", "middle": [], "last": "Yoon", "suffix": ""}, {"first": "C-M", "middle": [], "last": "Park", "suffix": ""}], "year": 2011, "venue": "Plant Cell", "link": "11654201"}, "BIBREF8": {"title": "An ABA-AtNAP Transcription Factor-SAG113 PP2C Regulatory Chain for Controlling Dehydration in Senescing Arabidopsis Leaves", "authors": [{"first": "K", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "S-S", "middle": [], "last": "Gan", "suffix": ""}], "year": 2011, "venue": "Plant Physiology", "link": null}, "BIBREF9": {"title": "AtNAP, a NAC family transcription factor, has an important role in leaf senescence", "authors": [{"first": "Y", "middle": [], "last": "Guo", "suffix": ""}, {"first": "S", "middle": [], "last": "Gan", "suffix": ""}], "year": 2006, "venue": "Plant Journal", "link": "40820747"}, "BIBREF10": {"title": "The chromatin signaling pathway: diverse mechanisms of recruitment of histone-modifying enzymes and varied biological outcomes", "authors": [{"first": "E", "middle": [], "last": "Smith", "suffix": ""}, {"first": "A", "middle": [], "last": "Shilatifard", "suffix": ""}], "year": 2010, "venue": "Molecular Cell", "link": "9493255"}, "BIBREF11": {"title": "Vernalization: Winter and the timing of flowering in plants", "authors": [{"first": "D-H", "middle": [], "last": "Kim", "suffix": ""}, {"first": "M", "middle": [], "last": "Doyle", "suffix": ""}, {"first": "S", "middle": [], "last": "Sung", "suffix": ""}, {"first": "R", "middle": [], "last": "Amasino", "suffix": ""}], "year": 2009, "venue": "Annual Review of Cell and Developmental Biology", "link": "10134324"}, "BIBREF12": {"title": "Resetting and regulation of FLOWERING LOCUS C expression during Arabidopsis reproductive development", "authors": [{"first": "J", "middle": [], "last": "Choi", "suffix": ""}, {"first": "Y", "middle": [], "last": "Hyun", "suffix": ""}, {"first": "M-J", "middle": [], "last": "Kang", "suffix": ""}, {"first": "H I", "middle": [], "last": "", "suffix": ""}, {"first": "J-Y Y", "middle": [], "last": "", "suffix": ""}], "year": 2009, "venue": "Plant Journal", "link": "22272147"}, "BIBREF13": {"title": "Polycomb group gene function in sexual and asexual seed development in angiosperms", "authors": [{"first": "J", "middle": [], "last": "Rodrigues", "suffix": ""}, {"first": "M", "middle": [], "last": "Luo", "suffix": ""}, {"first": "F", "middle": [], "last": "Berger", "suffix": ""}, {"first": "A", "middle": [], "last": "Koltunow", "suffix": ""}], "year": 2010, "venue": "Sexual Plant Reproduction", "link": "24543062"}, "BIBREF14": {"title": "H3K36 methylation is critical for brassinosteroid-regulated plant growth and development in rice", "authors": [{"first": "P", "middle": [], "last": "Sui", "suffix": ""}, {"first": "Jin", "middle": ["J"], "last": "Ye", "suffix": ""}, {"first": "S", "middle": [], "last": "Mu", "suffix": ""}, {"first": "C", "middle": [], "last": "Gao", "suffix": ""}, {"first": "J", "middle": [], "last": "", "suffix": ""}], "year": 2011, "venue": "Plant Journal", "link": "1408435"}, "BIBREF15": {"title": "Dynamic landscapes of four histone modifications during deetiolation in Arabidopsis", "authors": [{"first": "J-Bf", "middle": [], "last": "Charron", "suffix": ""}, {"first": "H", "middle": [], "last": "He", "suffix": ""}, {"first": "A", "middle": [], "last": "Elling", "suffix": ""}, {"first": "X", "middle": [], "last": "Deng", "suffix": ""}], "year": 2009, "venue": "Plant Cell", "link": null}, "BIBREF16": {"title": "Chromatin regulation functions in plant abiotic stress response", "authors": [{"first": "J-M", "middle": [], "last": "Kim", "suffix": ""}, {"first": "T", "middle": [], "last": "To", "suffix": ""}, {"first": "T", "middle": [], "last": "Nishioka", "suffix": ""}, {"first": "M", "middle": [], "last": "Seki", "suffix": ""}], "year": 2010, "venue": "Plant,Cell and Environment", "link": "38784513"}, "BIBREF17": {"title": "Epigenetic programmin via histone methylation at WRKY53 controls leaf senescence in Arabidopsis thaliana", "authors": [{"first": "N", "middle": [], "last": "Ay", "suffix": ""}, {"first": "K", "middle": [], "last": "Irmler", "suffix": ""}, {"first": "A", "middle": [], "last": "Fischer", "suffix": ""}, {"first": "R", "middle": [], "last": "Uhlemann", "suffix": ""}, {"first": "G", "middle": [], "last": "Reuter", "suffix": ""}], "year": 2009, "venue": "Plant Journal", "link": "89862824"}, "BIBREF18": {"title": "Overexpression of a chromatin architecture-controlling AT-hook protein extends leaf longevity and increases the post-harvest storage life of plants", "authors": [{"first": "P", "middle": [], "last": "Lim", "suffix": ""}, {"first": "Y", "middle": [], "last": "Kim", "suffix": ""}, {"first": "E", "middle": [], "last": "Breeze", "suffix": ""}, {"first": "J", "middle": [], "last": "Koo", "suffix": ""}, {"first": "H", "middle": [], "last": "Woo", "suffix": ""}], "year": 2007, "venue": "Plant Journal", "link": "19832224"}, "BIBREF19": {"title": "SIRT6 links histone H3 lysine 9 deacetylation to NF-kB-dependent gene expression and organismal life span", "authors": [{"first": "T", "middle": [], "last": "Kawahara", "suffix": ""}, {"first": "E", "middle": [], "last": "Michishita", "suffix": ""}, {"first": "A", "middle": [], "last": "Adler", "suffix": ""}, {"first": "M", "middle": [], "last": "Damian", "suffix": ""}, {"first": "E", "middle": [], "last": "Berber", "suffix": ""}], "year": 2009, "venue": "Cell", "link": "9873655"}, "BIBREF20": {"title": "HDA6 is required for jasmonate response, senescence and flowering in Arabidopsis", "authors": [{"first": "K", "middle": [], "last": "Wu", "suffix": ""}, {"first": "L", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "C", "middle": [], "last": "Zhou", "suffix": ""}, {"first": "C-W", "middle": [], "last": "Yu", "suffix": ""}, {"first": "V", "middle": [], "last": "Chaikam", "suffix": ""}], "year": 2008, "venue": "Journal of Experimental Botany", "link": "7008158"}, "BIBREF21": {"title": "Arabidopsis COMPASS-like complexes mediate histone H3 lysine-4 trimethylation to control floral transition and plant development", "authors": [{"first": "D", "middle": [], "last": "Jiang", "suffix": ""}, {"first": "N", "middle": [], "last": "Kong", "suffix": ""}, {"first": "X", "middle": [], "last": "Gu", "suffix": ""}, {"first": "Z", "middle": [], "last": "Li", "suffix": ""}, {"first": "Y", "middle": [], "last": "He", "suffix": ""}], "year": 2011, "venue": "PLoS Genetics", "link": "521865"}, "BIBREF22": {"title": "Genomewide analysis of mono-, di-and trimethylation of histone H3 lysine 4 in Arabidopsis thaliana", "authors": [{"first": "X", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "Y", "middle": [], "last": "Bernatavichute", "suffix": ""}, {"first": "S", "middle": [], "last": "Cokus", "suffix": ""}, {"first": "M", "middle": [], "last": "Pellegrini", "suffix": ""}, {"first": "S", "middle": [], "last": "Jacobsen", "suffix": ""}], "year": 2009, "venue": "Genome Biology", "link": "2738333"}, "BIBREF23": {"title": "Highresolution profiling of histone methylations in the human genome", "authors": [{"first": "A", "middle": [], "last": "Barski", "suffix": ""}, {"first": "S", "middle": [], "last": "Cuddapah", "suffix": ""}, {"first": "K", "middle": [], "last": "Cui", "suffix": ""}, {"first": "T-Y", "middle": [], "last": "Roh", "suffix": ""}, {"first": "D", "middle": [], "last": "Schones", "suffix": ""}], "year": 2007, "venue": "Cell", "link": "6326093"}, "BIBREF24": {"title": "Genic and global functions for Paf1C in chromatin modification and gene expression in Arabidopsis", "authors": [{"first": "S", "middle": [], "last": "Oh", "suffix": ""}, {"first": "S", "middle": [], "last": "Park", "suffix": ""}, {"first": "S", "middle": [], "last": "Van Nocker", "suffix": ""}], "year": 2008, "venue": "PLoS Genetics", "link": "6204539"}, "BIBREF25": {"title": "Repression of the floral transition via histone H2B monoubiquitination", "authors": [{"first": "X", "middle": [], "last": "Gu", "suffix": ""}, {"first": "D", "middle": [], "last": "Jiang", "suffix": ""}, {"first": "Y", "middle": [], "last": "Wang", "suffix": ""}, {"first": "A", "middle": [], "last": "Bachmair", "suffix": ""}, {"first": "Y", "middle": [], "last": "He", "suffix": ""}], "year": 2009, "venue": "Plant Journal", "link": "44367892"}, "BIBREF26": {"title": "From flour to flower: how Polycomb group proteins influence multiple aspects of plant development", "authors": [{"first": "T-F", "middle": [], "last": "Hsieh", "suffix": ""}, {"first": "Hakim", "middle": ["O"], "last": "Ohad", "suffix": ""}, {"first": "N", "middle": [], "last": "Fischer", "suffix": ""}, {"first": "R", "middle": [], "last": "", "suffix": ""}], "year": 2003, "venue": "Trends in Plant Science", "link": "32958715"}, "BIBREF27": {"title": "Polycomb group complexes mediate developmental transitions in plants", "authors": [{"first": "S", "middle": [], "last": "Holec", "suffix": ""}, {"first": "F", "middle": [], "last": "Berger", "suffix": ""}], "year": 2012, "venue": "Plant Physiology", "link": "206333923"}, "BIBREF28": {"title": "Whole-genome analysis of histone H3 lysine 27 trimethylation in Arabidopsis", "authors": [{"first": "X", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "O", "middle": [], "last": "Clarenz", "suffix": ""}, {"first": "S", "middle": [], "last": "Cokus", "suffix": ""}, {"first": "Y", "middle": [], "last": "Bernatavichute", "suffix": ""}, {"first": "M", "middle": [], "last": "Pellegrini", "suffix": ""}], "year": 2007, "venue": "PLoS Biology", "link": null}, "BIBREF29": {"title": "Keeping cell identity in Arabidopsis requires PRC1 RING-finger homologs that catalyze H2A monoubiquitination", "authors": [{"first": "F", "middle": [], "last": "Bratzel", "suffix": ""}, {"first": "G", "middle": [], "last": "Lopez-Torrejon", "suffix": ""}, {"first": "M", "middle": [], "last": "Koch", "suffix": ""}, {"first": "Del", "middle": [], "last": "Pozo", "suffix": ""}, {"first": "J", "middle": [], "last": "Calonje", "suffix": ""}, {"first": "M", "middle": [], "last": "", "suffix": ""}], "year": 2010, "venue": "Current Biology", "link": "6440072"}, "BIBREF30": {"title": "A timing mechanism for stem cell maintenance and differentiation in the Arabidopsis floral meristem", "authors": [{"first": "B", "middle": [], "last": "Sun", "suffix": ""}, {"first": "Y", "middle": [], "last": "Yxu", "suffix": ""}, {"first": "K-H", "middle": [], "last": "Ng", "suffix": ""}, {"first": "T", "middle": [], "last": "Ito", "suffix": ""}], "year": 2009, "venue": "Genes and Development", "link": "24813446"}, "BIBREF31": {"title": "Dynamic regulation of H3K27 trimethylation during Arabidopsis differentiation", "authors": [{"first": "M", "middle": [], "last": "Lafos", "suffix": ""}, {"first": "P", "middle": [], "last": "Kroll", "suffix": ""}, {"first": "M", "middle": [], "last": "Hohenstatt", "suffix": ""}, {"first": "F", "middle": [], "last": "Thorpe", "suffix": ""}, {"first": "O", "middle": [], "last": "Clarenz", "suffix": ""}], "year": 2011, "venue": "PLoS Genetics", "link": "9100329"}, "BIBREF32": {"title": "Vernalization-mediated epigenetic silencing by a long intronic noncoding RNA", "authors": [{"first": "J", "middle": [], "last": "Heo", "suffix": ""}, {"first": "S", "middle": [], "last": "Sung", "suffix": ""}], "year": 2011, "venue": "Science", "link": null}, "BIBREF33": {"title": "Transcriptiondependence of histone H3 lysine 27 trimethylation at the Arabidopsis polycomb target gene FLC", "authors": [{"first": "D", "middle": [], "last": "Buzas", "suffix": ""}, {"first": "M", "middle": [], "last": "Robertson", "suffix": ""}, {"first": "E", "middle": [], "last": "Finnegan", "suffix": ""}, {"first": "C", "middle": [], "last": "Helliwell", "suffix": ""}], "year": 2011, "venue": "Plant Journal", "link": "45947819"}, "BIBREF34": {"title": "The FRIGIDA complex activates transcription of FLC, a strong flowering repressor in Arabidopsis, by recruiting chromatin modification factors", "authors": [{"first": "K", "middle": [], "last": "Choi", "suffix": ""}, {"first": "J", "middle": [], "last": "Kim", "suffix": ""}, {"first": "H-J", "middle": [], "last": "Hwang", "suffix": ""}, {"first": "S", "middle": [], "last": "Kim", "suffix": ""}, {"first": "C", "middle": [], "last": "Park", "suffix": ""}], "year": 2011, "venue": "Plant Cell", "link": "42075872"}, "BIBREF35": {"title": "Cold-induced silencing by long antisense transcripts of an Arabidopsis Polycomb target", "authors": [{"first": "S", "middle": [], "last": "Swiezewski", "suffix": ""}, {"first": "F", "middle": [], "last": "Liu", "suffix": ""}, {"first": "A", "middle": [], "last": "Magusin", "suffix": ""}, {"first": "C", "middle": [], "last": "Dean", "suffix": ""}], "year": 2009, "venue": "Nature", "link": "4331051"}, "BIBREF36": {"title": "ChIPnorm: a statistical method for normalizing and identifying differential regions in histone modification ChIP-seq libraries", "authors": [{"first": "Ulhas", "middle": [], "last": "Nair", "suffix": ""}, {"first": "N", "middle": [], "last": "", "suffix": ""}, {"first": "Das", "middle": [], "last": "Sahu", "suffix": ""}, {"first": "A", "middle": [], "last": "Bucher", "suffix": ""}, {"first": "P", "middle": [], "last": "Moret", "suffix": ""}, {"first": "B", "middle": [], "last": "", "suffix": ""}], "year": 2012, "venue": "PlOS One", "link": "416101"}, "BIBREF37": {"title": "JARID1B is a histone H3 lysine 4 demethylase up-regulated in prostate cancer", "authors": [{"first": "Y", "middle": [], "last": "Xiang", "suffix": ""}, {"first": "Z", "middle": [], "last": "Zhu", "suffix": ""}, {"first": "G", "middle": [], "last": "Han", "suffix": ""}, {"first": "X", "middle": [], "last": "Ye", "suffix": ""}, {"first": "B", "middle": [], "last": "Xu", "suffix": ""}], "year": 2007, "venue": "Proceedings of the National Academy of Sciences", "link": "25551774"}, "BIBREF38": {"title": "Temporal and spatial expression patterns of nine Arabidopsis genes encoding Jumonji Cdomain proteins", "authors": [{"first": "E-H", "middle": [], "last": "Hong", "suffix": ""}, {"first": "Y-M", "middle": [], "last": "Jeong", "suffix": ""}, {"first": "J-Y", "middle": [], "last": "Ryu", "suffix": ""}, {"first": "R", "middle": [], "last": "Amasino", "suffix": ""}, {"first": "B", "middle": [], "last": "Noh", "suffix": ""}], "year": 2009, "venue": "Molecules and Cells", "link": "33582770"}, "BIBREF39": {"title": "Comparative analysis of JmjC domain-containing proteins reveals the potential histone demethylases in Arabidopsis and rice", "authors": [{"first": "F", "middle": [], "last": "Lu", "suffix": ""}, {"first": "G", "middle": [], "last": "Li", "suffix": ""}, {"first": "X", "middle": [], "last": "Cui", "suffix": ""}, {"first": "C", "middle": [], "last": "Liu", "suffix": ""}, {"first": "X-J", "middle": [], "last": "Wang", "suffix": ""}], "year": 2008, "venue": "Journal of Integrative Plant Biology", "link": "13868535"}, "BIBREF40": {"title": "Repression of FLOWERING LOCUS T chromatin by functionally redundant histone H3 lysine 4 demethylases in Arabidopsis", "authors": [{"first": "J-H", "middle": [], "last": "Jeong", "suffix": ""}, {"first": "H-R", "middle": [], "last": "Song", "suffix": ""}, {"first": "J-H", "middle": [], "last": "Ko", "suffix": ""}, {"first": "Y-M", "middle": [], "last": "Jeong", "suffix": ""}, {"first": "Y", "middle": ["E"], "last": "Kwon", "suffix": ""}], "year": 2009, "venue": "PLoS one", "link": "7229305"}, "BIBREF41": {"title": "Divergent roles of a pair of homologous Jumonji/zinc-finger-class transcription factor proteins in the regulation of Arabidopsis flowering time", "authors": [{"first": "B", "middle": [], "last": "Noh", "suffix": ""}, {"first": "S-H", "middle": [], "last": "Lee", "suffix": ""}, {"first": "H-J", "middle": [], "last": "Kim", "suffix": ""}, {"first": "Yi", "middle": ["G"], "last": "Shin", "suffix": ""}, {"first": "E-A", "middle": [], "last": "", "suffix": ""}], "year": 2004, "venue": "Plant Cell", "link": "31385902"}, "BIBREF42": {"title": "A plant-specific histone H3 lysine 4 demethylase represses the floral transition in Arabidopsis", "authors": [{"first": "W", "middle": [], "last": "Yang", "suffix": ""}, {"first": "D", "middle": [], "last": "Jiang", "suffix": ""}, {"first": "J", "middle": [], "last": "Jiang", "suffix": ""}, {"first": "Y", "middle": [], "last": "He", "suffix": ""}], "year": 2010, "venue": "Plant Journal", "link": null}, "BIBREF43": {"title": "Identification of a transcription factor specifically expressed at the onset of leaf senescence", "authors": [{"first": "K", "middle": [], "last": "Hinderhofer", "suffix": ""}, {"first": "U", "middle": [], "last": "Zentgraf", "suffix": ""}], "year": 2001, "venue": "Planta", "link": "24117081"}, "BIBREF44": {"title": "Identification of a promoter region responsible for the senescence-specific expression of SAG12", "authors": [{"first": "Y-S", "middle": [], "last": "Noh", "suffix": ""}, {"first": "R", "middle": [], "last": "Amasino", "suffix": ""}], "year": 1999, "venue": "Plant Molecular Biology", "link": "31316027"}, "BIBREF45": {"title": "A unique chromatin signature uncovers early developmental enhancers in humans", "authors": [{"first": "A", "middle": [], "last": "Rada-Iglesius", "suffix": ""}, {"first": "R", "middle": [], "last": "Bajpai", "suffix": ""}, {"first": "T", "middle": [], "last": "Swigut", "suffix": ""}, {"first": "S", "middle": [], "last": "Brugmann", "suffix": ""}, {"first": "R", "middle": [], "last": "Flynn", "suffix": ""}], "year": 2010, "venue": "Nature", "link": "205223441"}, "BIBREF46": {"title": "AIRE activated tissue specific genes have histone modifications associated with inactive chromatin", "authors": [{"first": "T", "middle": [], "last": "Org", "suffix": ""}, {"first": "A", "middle": [], "last": "Rebane", "suffix": ""}, {"first": "K", "middle": [], "last": "Kisand", "suffix": ""}, {"first": "M", "middle": [], "last": "Laan", "suffix": ""}, {"first": "U", "middle": [], "last": "Haljasorg", "suffix": ""}], "year": 2009, "venue": "Human Molecular Genetics", "link": null}, "BIBREF47": {"title": "Modulation of brassinosteroidregulated gene expression by jumonji domain-containing proteins ELF6 and REF6 in Arabidopsis", "authors": [{"first": "X", "middle": [], "last": "Yu", "suffix": ""}, {"first": "L", "middle": [], "last": "Li", "suffix": ""}, {"first": "L", "middle": [], "last": "Li", "suffix": ""}, {"first": "M", "middle": [], "last": "Guo", "suffix": ""}, {"first": "J", "middle": [], "last": "Chory", "suffix": ""}], "year": 2008, "venue": "Proceedings of the National Academy of Sciences", "link": "19299555"}, "BIBREF48": {"title": "Genetic and molecular identification of genes required for female gemetophyte development and function in Arabidopsis", "authors": [{"first": "G", "middle": [], "last": "Pagnussat", "suffix": ""}, {"first": "H-J", "middle": [], "last": "Yu", "suffix": ""}, {"first": "Q", "middle": [], "last": "Ngo", "suffix": ""}, {"first": "S", "middle": [], "last": "Rajani", "suffix": ""}, {"first": "S", "middle": [], "last": "Mayalagu", "suffix": ""}], "year": 2005, "venue": "Development", "link": null}, "BIBREF49": {"title": "Arabidopsis REF6 is a histone H3 lysine 27 demethylase", "authors": [{"first": "F", "middle": [], "last": "Lu", "suffix": ""}, {"first": "X", "middle": [], "last": "Cui", "suffix": ""}, {"first": "S", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "T", "middle": [], "last": "Jenuwein", "suffix": ""}, {"first": "X", "middle": [], "last": "Cao", "suffix": ""}], "year": 2011, "venue": "Nature Genetics", "link": "27425413"}, "BIBREF50": {"title": "An efficient chromatin immunoprecipitation (ChIP) protocol for studying histone modifications in plants", "authors": [{"first": "A", "middle": [], "last": "Saleh", "suffix": ""}, {"first": "R", "middle": [], "last": "Alvarez-Venegas", "suffix": ""}, {"first": "Z", "middle": [], "last": "Avramova", "suffix": ""}], "year": 2008, "venue": "Nature Protocols", "link": null}}, "ref_entries": {"FIGREF0": {"text": "Figure 1. Mature (23 d) and senescent (52 d) leaf tissue used for ChIP-seq and RNA isolation. Fully-expanded, green rosette leaves were harvested from mature and senescent plants similar to those shown above. doi:10.1371/journal.pone.0033151.g001", "type": "figure"}, "FIGREF1": {"text": "Figure 2. Expected patterns of H3K4me3 and H3K27me3 histone modifications on two representative genes. Genes with exons represented as green thick lines and introns shown as green thin lines are shown at the top of this Genome Browser image, and the green arrow shows the direction of transcription. The number of sequence reads for 23 d are shown in blue and for 52 d in brown. H3K4me3 (K4) is shown on the top two tracks, H3K27me3 (K27) on the next two tracks. Gray rectangles below tracks indicate regions with sequence reads significantly above relative input. A) ACT2 (At3g18780) shows significant enrichment above respective input samples for the H3K4me3 mark. This constitutive gene is associated with H3K4me3 marks, but lacks H3K27me3 marks. B) FLC (At5g10140) shows significant levels of silencing H3K27me3 marks, which is expected in the fri mutant Columbia ecotype that does not require vernalization for flowering. FLC has some H3K4me3 marks near the first and last exons. doi:10.1371/journal.pone.0033151.g002", "type": "figure"}, "FIGREF2": {"text": "Figure 3. Genic distributions of differential histone marks. Regions with significantly different levels of histone modification were identified by ChIPnorm and placed into 200 bp bins relative to the transcription start site (TSS). A) Differential regions for the H3K4me3 mark are most abundant in the five bins downstream of the TSS. B) Differential regions for the H3K27me3 mark are most abundant at the TSS and the first three bins downstream of the TSS. doi:10.1371/journal.pone.0033151.g003", "type": "figure"}, "FIGREF3": {"text": "Figure 4. Correlation between regions with differential histone modification and senescence regulated gene expression. 4090 genes were equally partitioned into five groups depending on differential expression in mature (23 d) vs. senescent (52 d) tissue. Group A genes have the highest differential expression at 23 d, group E genes have the highest differential expression at 52 d while group C genes have approximately equal expression at both time points. Genes that were identified as having different levels of histone modification (H3K4me3 in panel A, H3K27me3 in panel B) were then placed into the groups. Genes showing a decrease in the specific histone methylation at 52 d (K4-None or K27-None) are shown in blue while those that showed an increase in the specific histone methylation at 52 d (None-K4 or None-K27) are shown in brick red. doi:10.1371/journal.pone.0033151.g004", "type": "figure"}, "FIGREF4": {"text": "Figure 5. Genome Browser view of two genes that are up-regulated in senescent leaves and show differential histone modification. These GBrowse views are similar to Figure 2, but a new track, K4_diff (pink font) is now shown. The green bars indicate significantly higher histone methylations at 52 d. A) At4g44300 shows a 300-fold increase in mRNA at 52 d which is accompanied by increased H3K4me3 marks. B) At1g13340 shows a 16-fold increase in mRNA which is also accompanied by increased H3K4me3 marks. doi:10.1371/journal.pone.0033151.g005", "type": "figure"}, "FIGREF5": {"text": "Figure 6. Genome Browser view of two genes that are down-regulated in senescent leaves and show differential histone modification. These GBrowse views are similar to Figure 5, but a new track, K7_diff (pink font), is now shown. The red bars in the K4_diff track indicate significantly higher histone methylations at 23 d while the green bars in K7_diff indicate significantly higher histone methylations at 52 d. A) At3g27690 or Lhcb2.3, shows a 25-fold decrease at 52 d which is accompanied by a decrease in H3K4me3 marks. B) At2g10940 shows a 14,000-fold decrease at 52 d which is accompanied by a decrease in H3K4me3 marks and an increase in H3K27me3 marks. doi:10.1371/journal.pone.0033151.g006", "type": "figure"}, "FIGREF6": {"text": "Figure 7. Analysis of bivalently modified genes. Bivalent (H3K4me3 and H3K27me3) modifications were observed for a subset of genes at 23 d. These genes were classified into those that lost both modifications at 52 d (K4+K27-None, dark blue), those that retained the H3K27me3 mark at 52 d (K4+K27 -K27, light blue), those that retained the H3K4me3 mark at 23 d (K4+K27-K4, yellow) and those that retained the bivalent marks (K4+K27-K4+K27, brick red). Genes thus classified were then placed into the five groups shown in Figure 4. Genes that retained the H3K27me3 mark were restricted to groups A and B while genes that retained the H3K4me3 mark were restricted to groups C-E. doi:10.1371/journal.pone.0033151.g007", "type": "figure"}, "FIGREF7": {"text": "Figure 9. Two genes that are expressed at high levels in senescent tissue lack activating H3K4me3 marks. A) SAG12 (At5g45890) is upregulated 90,000-fold at 52 d, but is devoid of H3K4me 3 marks. B) At1g73220 is up-regulated 113-fold at 52 d and likewise shows no H3K4me3 marks. For both genes, H3K27me3 marks are present, but do not show a significant difference between 23 d and 52 d. doi:10.1371/journal.pone.0033151.g009", "type": "figure"}, "FIGREF8": {"text": "Figure S1 Comparison of sequence reads from H3 general and Input at 23 d. The genome wide comparison is", "type": "figure"}, "TABREF0": {"text": "Real-time qPCR measurement of senescence-up- regulated genes (SURGs) and senescence-down-regulated genes (SDRGs) mRNA levels in tissue used for ChIP-seq.Total RNA was harvested from the same leaves used in the ChIP-seq analysis, and real-time qPCR was performed using ACT2 as a reference. SURGs and SDRGs were identified from published microarray data [4]. Fold-induction at 52 d for SURGs and at 23 d for SDRGs is reported. Eight of 8 tested SURGs were up- regulated by at least 15-fold, while 6 of 7 tested SDRGs were down-regulated by at least 24-fold. doi:10.1371/journal.pone.0033151.t001", "type": "table"}, "TABREF1": {"text": "Primers used in real time qPCR analysis. An annealing temperature of 62uC was used for all primer pairs. (DOCX)", "type": "table"}}}
{"paper_id": "10708489", "_pdf_hash": "78a0d17acba5db59aa4d02667ddd5d1455f02ef3", "abstract": [{"section": "Abstract", "text": "We present a deterministic (1+o(1))-approximation O(n 1/2+o(1) + D 1+o(1) )-time algorithm for solving the single-source shortest paths problem on distributed weighted networks (the CONGEST model); here n is the number of nodes in the network and D is its (hop) diameter. This is the first non-trivial deterministic algorithm for this problem. It also improves (i) the running time of the randomized (1 + o (1) ", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "(1) )-time algorithm for approximating a network's weighted diameter which almost matches the lower bound by Holzer et al. [PODC 2012].", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "In achieving this result, we develop two techniques which might be of independent interest and useful in other settings: (i) a deterministic process that replaces the \"hitting set argument\" commonly used for shortest paths computation in var- * A full version of this paper is available at http://arxiv. ", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "+ D", "text": "1+o (1) )-time algorithm for solving the single-source shortest paths problem on distributed weighted networks (the CONGEST model); here n is the number of nodes in the network and D is its (hop) diameter. This is the first non-trivial deterministic algorithm for this problem. It also improves (i) the running time of the randomized (1 + o (1) In achieving this result, we develop two techniques which might be of independent interest and useful in other settings: (i) a deterministic process that replaces the \"hitting set argument\" commonly used for shortest paths computation in var- * A full version of this paper is available at http://arxiv.org/ abs/1504.07056 \u2020 This work was done in part while the author was visiting the Simons Institute for the Theory of Computing. The research leading to this work has received funding from the European ious settings, and (ii) a simple, deterministic, construction of an (n o (1) , o (1) )-hop set of size O(n 1+o (1) ). We combine these techniques with many distributed algorithmic techniques, some of which from problems that are not directly related to shortest paths, e.g. ruling sets [26] , source detection [39] , and partial distance estimation [38] . Our hop set construction also leads to single-source shortest paths algorithms in two other settings: (i) a (1 + o (1) every node to know how far it is from s. The unweighted version -the breadth-first search tree computation -is one of the most basic tools in distributed computing, and is well known to require \u0398(D) time (e.g. [44] ). In contrast, the only available solution for the weighted case is the distributed version of the Bellman-Ford algorithm [5, 23] , which requires O(n) time to compute an exact solution. In 2004, Elkin [16] raised the question whether distributed approximation algorithms can help improving this time complexity and showed that any \u03b1-approximation algorithm requires \u2126((n/\u03b1) 1/2 / log n + D) time [17] . Das Sarma et al. [12] (building on [45, 35] ) later strengthened this lower bound by showing that any poly(n)-approximation (randomized) algorithm requires \u2126(n 1/2 / log n + D) time. This lower bound was later shown to hold even for quantum algorithms [19] .", "cite_spans": [{"start": 923, "end": 926, "text": "(1)", "ref_id": "BIBREF0"}, {"start": 931, "end": 934, "text": "(1)", "ref_id": "BIBREF0"}, {"start": 961, "end": 964, "text": "(1)", "ref_id": "BIBREF0"}, {"start": 1136, "end": 1140, "text": "[26]", "ref_id": "BIBREF25"}, {"start": 1160, "end": 1164, "text": "[39]", "ref_id": "BIBREF38"}, {"start": 1199, "end": 1203, "text": "[38]", "ref_id": "BIBREF37"}, {"start": 1535, "end": 1539, "text": "[44]", "ref_id": "BIBREF43"}, {"start": 1663, "end": 1666, "text": "[5,", "ref_id": "BIBREF4"}, {"start": 1667, "end": 1670, "text": "23]", "ref_id": "BIBREF22"}, {"start": 1743, "end": 1747, "text": "[16]", "ref_id": "BIBREF15"}, {"start": 1938, "end": 1942, "text": "[17]", "ref_id": "BIBREF16"}, {"start": 1962, "end": 1966, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 1980, "end": 1984, "text": "[45,", "ref_id": "BIBREF44"}, {"start": 1985, "end": 1988, "text": "35]", "ref_id": "BIBREF34"}, {"start": 2197, "end": 2201, "text": "[19]", "ref_id": "BIBREF18"}], "ref_spans": []}, {"section": "+ D", "text": "Since running times of the form\u00d5(n 1/2 + D) 1 show up in many distributed algorithms (e.g. MST [36, 45] , connectivity [53, 46] , and minimum cut [43, 25] ) it is natural to ask whether the lower bound of [12] can be matched. The first answer to this question is a randomized O(", "cite_spans": [{"start": 44, "end": 45, "text": "1", "ref_id": "BIBREF0"}, {"start": 95, "end": 99, "text": "[36,", "ref_id": "BIBREF35"}, {"start": 100, "end": 103, "text": "45]", "ref_id": "BIBREF44"}, {"start": 119, "end": 123, "text": "[53,", "ref_id": "BIBREF52"}, {"start": 124, "end": 127, "text": "46]", "ref_id": "BIBREF45"}, {"start": 146, "end": 150, "text": "[43,", "ref_id": "BIBREF42"}, {"start": 151, "end": 154, "text": "25]", "ref_id": "BIBREF24"}, {"start": 205, "end": 209, "text": "[12]", "ref_id": "BIBREF11"}], "ref_spans": []}, {"section": "+ D", "text": "-time algorithm by Lenzen and Patt-Shamir [37] 2 . The running time of this algorithm is nearly tight if we are satisfied with a large approximation ratio. For a small approximation ratio, Nanongkai [42] presented a randomized ( ", "cite_spans": [{"start": 42, "end": 46, "text": "[37]", "ref_id": "BIBREF36"}, {"start": 199, "end": 203, "text": "[42]", "ref_id": "BIBREF41"}], "ref_spans": []}, {"section": "+ D", "text": "The running time of this algorithm is nearly tight when D is small, but can be close to\u0398(n 2/3 ) even when D = o(n 2/3 ). This created a rather unsatisfying situation: First, one has to sacrifice a large approximation factor in order to achieve the near-optimal running time, and to achieve a (1 + o(1)) approximation factor, one must pay an additional running time of D 1/4 which could be as far from the lower bound as n 1/8 when D is large. Because of this, the question whether we can close the gap between upper and lower bounds for the running time of (1 + o(1))-approximation algorithms was left as the main open problem in [42, Problem 7.1] . Secondly, and more importantly, both these algorithms are randomized. Given that designing deterministic algorithms is an important issue in distributed computing. This leaves an important open problem whether there is a deterministic algorithm that is faster than BellmanFord's algorithm, i.e. that runs in sublinear-time.", "cite_spans": [{"start": 631, "end": 635, "text": "[42,", "ref_id": "BIBREF41"}], "ref_spans": []}, {"section": "+ D", "text": "Our Results.", "cite_spans": [], "ref_spans": []}, {"section": "+ D", "text": "In this paper, we resolve the two issues above. We present a deterministic (1+o(1))-approximation O(n 1/2+o(1) +D 1+o(1) )-time algorithm for this problem (the o(1) term in the approximation ratio hides a 1/ polylog n factor and the o(1) term in the running time hides an O( log log n/ log n) factor). Our algorithm almost settles the status of this problem as its running time matches the lower bound of Das Sarma et al. up to an O(n o(1) ) factor. Since an \u03b1-approximate solution to SSSP gives a 2\u03b1-approximate value of the network's weighted diameter (cf. Section 2), our algorithm can (2 + o(1))-approximate the weighted diameter within the same running time. Previously, Holzer et al. [31] showed that for any > 0, a (2 \u2212 )-approximation algorithm for this problem requires\u03a9(n) time. Thus, the approximation ratio provided by our algorithm cannot be significantly improved without increasing the running time. The running time of our algorithm also cannot be significantly improved because of the lower bound of \u2126(n 1/2 / log n + D) [12] for approximate SSSP which holds for any poly(n)-approximation algorithm.", "cite_spans": [{"start": 690, "end": 694, "text": "[31]", "ref_id": "BIBREF30"}, {"start": 1038, "end": 1042, "text": "[12]", "ref_id": "BIBREF11"}], "ref_spans": []}, {"section": "+ D", "text": "Using the same techniques, we also obtain a deterministic (1 + o (1) (1))-approximation of the diameter requires\u03a9(n) time in the worst case [30] in the congested clique.", "cite_spans": [{"start": 140, "end": 144, "text": "[30]", "ref_id": "BIBREF29"}], "ref_spans": []}, {"section": "+ D", "text": "Our techniques also lead to a (non-distributed) streaming algorithm for (1 + o(1))-approximate SSSP where the edges are presented in an arbitrary-order stream, and an algorithm with limited space (preferably\u00d5(n log W ), when edge weights are in {1, 2, . . . W }) reads the stream in passes to determine the answer (see, e.g., [40] for a recent survey). It was known that\u00d5(n log W ) space and one pass are enough to compute an O(log n/ log log n)-spanner and therefore approximate all distances up to a factor of O(log n/ log log n) [22] (see also [21, 3, 20, 18] ). This almost matches a lower bound which holds even for the s-t-shortest path problem (stSP), where we just want to compute the distance between two specific nodes s and t [22] . On unweighted graphs one can compute (1 + , \u03b2)-spanners in \u03b2 passes and O(n 1+1/k ) space [20] , and get (1 + )-approximate SSSP in a total of O(\u03b2/ ) passes. In 2006, McGregor raised the question whether we can solve stSP better with a larger number of passes (see [1] ). Very recently Guruswami and Onak [27] showed that a p-pass algorithm on unweighted graphs requires\u03a9(n 1+\u2126(1/p) /O(p)) space. This does not rule out, for example, an O(log n)-pass\u00d5(n)-space algorithm. Our algorithm, which solves the more general SSSP problem, gets close to this: it takes O(n o(1) log W ) passes and O(n 1+o(1) log W ) space.", "cite_spans": [{"start": 326, "end": 330, "text": "[40]", "ref_id": "BIBREF39"}, {"start": 532, "end": 536, "text": "[22]", "ref_id": "BIBREF21"}, {"start": 547, "end": 551, "text": "[21,", "ref_id": "BIBREF20"}, {"start": 552, "end": 554, "text": "3,", "ref_id": "BIBREF2"}, {"start": 555, "end": 558, "text": "20,", "ref_id": "BIBREF19"}, {"start": 559, "end": 562, "text": "18]", "ref_id": "BIBREF17"}, {"start": 737, "end": 741, "text": "[22]", "ref_id": "BIBREF21"}, {"start": 834, "end": 838, "text": "[20]", "ref_id": "BIBREF19"}, {"start": 1009, "end": 1012, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 1049, "end": 1053, "text": "[27]", "ref_id": "BIBREF26"}], "ref_spans": []}, {"section": "Overview of Techniques.", "text": "Our crucial new technique is a deterministic process that can replace the following \"path hitting\" argument: For any c, if we pick\u0398(c) nodes uniformly at random as centers (typically c = n 1/2 ), then a shortest path containing n/c edges will contain a center with high probability. This allows us to create shortcuts between centers -where we replace each path of length n/c between centers by an edge of the same length -and focus on computing shortest paths between centers. This argument has been repetitively used to solve shortest paths problems in various settings (e.g. [54, 28, 15, 4, 48, 49, 13, 14, 41, 7, 37, 42] ). In the sequential model a set of centers of size\u0398(c) can be found deterministically with the greedy hitting set heuristic once the shortest paths containing n/c edges are known [55, 33] . We are not aware of any non-trivial deterministic process that can achieve the same effect in the distributed setting. The main challenge is that the greedy process is heavily sequential as the selection of the next node depends on all previous nodes, and is thus hard to implement efficiently in the distributed setting 4 . In this paper, we develop a new deterministic process to pick\u0398(c) centers. The key new idea is to carefully divide nodes into\u00d5(1) types. Roughly speaking, we associate each type t with a value wt and make sure that the following properties hold: (i) every path \u03c0 with \u2126(n/c) edges and weight \u0398(wt) contains a node of type t, and (ii) there is a set of O(n/c) centers of type t such that every node of type t has at least one center at distance o(wt). We define the set of centers to be the collection of centers of all types. The two properties together guarantee that every long path will be almost hit by a center: for every path \u03c0 containing at least n/c edges, there is a center whose distance to some node in \u03c0 is o(w(\u03c0)) where, w(\u03c0) is the total weight of \u03c0. This is already sufficient for us to focus on computing shortest paths only between centers as we would have done after picking centers using the path hitting argument. To the best of our knowledge, such a deterministically constructed set of centers that almost hits every long path was not known to exist before. The process itself is not constrained to the distributed setting and thus might be useful for derandomizing other algorithms that use the path hitting argument.", "cite_spans": [{"start": 578, "end": 582, "text": "[54,", "ref_id": "BIBREF53"}, {"start": 583, "end": 586, "text": "28,", "ref_id": "BIBREF27"}, {"start": 587, "end": 590, "text": "15,", "ref_id": "BIBREF14"}, {"start": 591, "end": 593, "text": "4,", "ref_id": "BIBREF3"}, {"start": 594, "end": 597, "text": "48,", "ref_id": "BIBREF47"}, {"start": 598, "end": 601, "text": "49,", "ref_id": "BIBREF48"}, {"start": 602, "end": 605, "text": "13,", "ref_id": "BIBREF12"}, {"start": 606, "end": 609, "text": "14,", "ref_id": "BIBREF13"}, {"start": 610, "end": 613, "text": "41,", "ref_id": "BIBREF40"}, {"start": 614, "end": 616, "text": "7,", "ref_id": "BIBREF6"}, {"start": 617, "end": 620, "text": "37,", "ref_id": "BIBREF36"}, {"start": 621, "end": 624, "text": "42]", "ref_id": "BIBREF41"}, {"start": 805, "end": 809, "text": "[55,", "ref_id": "BIBREF54"}, {"start": 810, "end": 813, "text": "33]", "ref_id": "BIBREF32"}, {"start": 1137, "end": 1138, "text": "4", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "Overview of Techniques.", "text": "To implement the above process in the distributed setting, we use the source detection algorithm of Lenzen and Peleg [39] to compute the type of each node. We then use the classic ruling set algorithm of Goldberg et al. [26] to compute the set of centers of each type that satisfies the second property above. (A technical note: we also need to compute a bounded-depth shortest-path tree from every center. In [42] , this was done using the random delay technique. We also derandomize this step by adapting the partial distance estimation algorithm of Lenzen and Patt-Shamir [38] .)", "cite_spans": [{"start": 117, "end": 121, "text": "[39]", "ref_id": "BIBREF38"}, {"start": 220, "end": 224, "text": "[26]", "ref_id": "BIBREF25"}, {"start": 410, "end": 414, "text": "[42]", "ref_id": "BIBREF41"}, {"start": 575, "end": 579, "text": "[38]", "ref_id": "BIBREF37"}], "ref_spans": []}, {"section": "Overview of Techniques.", "text": "Another tool, which is the key to the improved running time, is a new hop set construction. An (h, )-hop set of a graph G = (V, E) is a set F of weighted edges such that the distance between any pair of nodes in G can be (1 + )-approximated by their h-hop distance (given by a path containing at most h edges) on G = (V, E \u222aF ) (see Section 2 for details). The notion of hop set was defined by Cohen [10] in the context of parallel computing, although it has been used implicitly earlier, e.g. [54, 34] (see [10] for a detailed discussion). The previous SSSP algorithm [42] was able to construct an (n/k, 0)-hop set of size kn, for any integer k \u2265 1, as a subroutine (in [42] this was called shortest paths diameter reduction 5 ). In this paper, we show that this subroutine can be replaced by the construction of an ( (1) ). Our hop set construction is based on computing clusters which is the basic subroutine of Thorup and Zwick's distance oracles [51] and spanners [51, 52] . It builds on a line of work in dynamic graph algorithms. In [6] , Bernstein showed that clusters can be used to construct an (n o (1) , o(1))-hop set of size O(n 1+o (1) ). Later in [29] , we showed that the same kind of hop set can be constructed by using a structure similar to clusters while restricting the shortest-path trees involved to some small distance and use such a construction in the dynamic (more precisely, decremental) setting. The con-struction is, however, fairly complicated and heavily relies on randomization. In this paper, we build on the same idea, i.e., we construct a hop set using bounded-distance clusters. However, our construction is significantly simplified, to the point that we can treat the cluster computation as a black box. This makes it easy to apply on distributed networks and to derandomize. To this end, we derandomize the construction simply by invoking the deterministic clusters construction of Roditty, Thorup, and Zwick [47] and observe that it can be implemented efficiently on distributed networks 6 . We note that it might be possible to use Cohen's hop set construction instead. However, Cohen's construction heavily relies on randomness and derandomizing it seems significantly more difficult.", "cite_spans": [{"start": 400, "end": 404, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 494, "end": 498, "text": "[54,", "ref_id": "BIBREF53"}, {"start": 499, "end": 502, "text": "34]", "ref_id": "BIBREF33"}, {"start": 508, "end": 512, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 569, "end": 573, "text": "[42]", "ref_id": "BIBREF41"}, {"start": 671, "end": 675, "text": "[42]", "ref_id": "BIBREF41"}, {"start": 726, "end": 727, "text": "5", "ref_id": "BIBREF4"}, {"start": 951, "end": 955, "text": "[51]", "ref_id": "BIBREF50"}, {"start": 969, "end": 973, "text": "[51,", "ref_id": "BIBREF50"}, {"start": 974, "end": 977, "text": "52]", "ref_id": "BIBREF51"}, {"start": 1040, "end": 1043, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 1110, "end": 1113, "text": "(1)", "ref_id": "BIBREF0"}, {"start": 1146, "end": 1149, "text": "(1)", "ref_id": "BIBREF0"}, {"start": 1162, "end": 1166, "text": "[29]", "ref_id": "BIBREF28"}, {"start": 1948, "end": 1952, "text": "[47]", "ref_id": "BIBREF46"}, {"start": 2028, "end": 2029, "text": "6", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Organization.", "text": "We start by introducing notation and the main definition in Section 2. Then in Section 3 we explain the deterministic hop set construction in, which is based on a variation of Thorup and Zwick's clusters [51] In Section 4, we give our main result, namely the (", "cite_spans": [{"start": 204, "end": 208, "text": "[51]", "ref_id": "BIBREF50"}], "ref_spans": []}, {"section": "Organization.", "text": "In that section we explain the deterministic process for selecting centers mentioned above, as well as how to implement the hop set construction in the distributed setting.", "cite_spans": [], "ref_spans": []}, {"section": "PRELIMINARIES", "text": "In this paper we consider weighted undirected graphs. For a set of edges E, the weight of each edge (u, v) \u2208 E is given by a function w (u, v, E) .", "cite_spans": [], "ref_spans": []}, {"section": "PRELIMINARIES", "text": "Whenever we define a set of edges E as the union of two sets of edges E1 \u222a E2, we set the weight of every edge (u, v) \u2208 E to w(u, v, E) = min(w(u, v, E1), w(u, v, E2)). We denote the weight of a path \u03c0 in a graph G by w(\u03c0, G) and the number of edges of \u03c0 by |\u03c0|.", "cite_spans": [], "ref_spans": []}, {"section": "PRELIMINARIES", "text": "Given a graph G = (V, E) and a set of edges F \u2286 V 2 , we define G\u222aF as the graph that has V as its set of nodes and E\u222a F as its set of edges. The weight of each edge (u, v) is given by", "cite_spans": [], "ref_spans": []}, {"section": "PRELIMINARIES", "text": "We denote the distance between two nodes u and v, i.e., the weight of the shortest path between u and v, by d (u, v, G) . We define the distance between a node u and a set of nodes ", "cite_spans": [], "ref_spans": []}, {"section": "PRELIMINARIES", "text": "We denote the hop-distance between two nodes u and v, i.e., the distance between u and v when we treat G as an unweighted graph, by hop (u, v, G) . (u, v, G) . When G is clear from the context, we use D instead of D(G). We note that this is different from the weighted diameter, which is defined as WD(G) = max u,v\u2208V (G) d (u, v, G) . Throughout this paper we use \"diameter\" to refer to the hop diameter (as it is typically done in the literature).", "cite_spans": [], "ref_spans": []}, {"section": "PRELIMINARIES", "text": "Given any graph G = (V, E), any integer h, and \u2265 0, we say that a set of weighted edges F is an (h, )-hop set of G if", "cite_spans": [], "ref_spans": []}, {"section": "PRELIMINARIES", "text": "where H = (V, E \u222a F ). In this paper we are only interested in (n o (1) , o(1))-hop sets of size O(n 1+o(1) ). We refer to them simply as \"hop sets\" (without specifying parameters).", "cite_spans": [{"start": 68, "end": 71, "text": "(1)", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "PRELIMINARIES", "text": "In our algorithm we will repeatedly use the following established weight-rounding technique [9, 55, 6, 41, 7, 42 ] to scale down edge weights at the cost of approximation. ", "cite_spans": [{"start": 92, "end": 95, "text": "[9,", "ref_id": "BIBREF8"}, {"start": 96, "end": 99, "text": "55,", "ref_id": "BIBREF54"}, {"start": 100, "end": 102, "text": "6,", "ref_id": "BIBREF5"}, {"start": 103, "end": 106, "text": "41,", "ref_id": "BIBREF40"}, {"start": 107, "end": 109, "text": "7,", "ref_id": "BIBREF6"}, {"start": 110, "end": 112, "text": "42", "ref_id": "BIBREF41"}], "ref_spans": []}, {"section": "PRELIMINARIES", "text": "An important subroutine in our algorithm is a procedure for solving the source detection problem [39] in which we want to find the \u03c3 nearest \"sources\" in a set S for every node u, given that they are of distance at most \u03b3 from u. Ties are broken lexicographically. The following definition if from [38] ", "cite_spans": [{"start": 97, "end": 101, "text": "[39]", "ref_id": "BIBREF38"}, {"start": 298, "end": 302, "text": "[38]", "ref_id": "BIBREF37"}], "ref_spans": []}, {"section": "Definition 2.2 ((S, \u03b3, \u03c3)-detection). Consider a graph G, a set of \"sources\" S \u2286 V (G), and parameters \u03b3, \u03c3 \u2208 N. For any node u let L(u, S, \u03b3, \u03c3, G) denote the list resulting from ordering the set", "text": "{(d(u, v, G), v)|v \u2208 S \u2227 d(u, v, G) \u2264 \u03b3}((d(u, v, G), v) < (d(u, v , G), v ) \u21d0\u21d2 (d(u, v, G) < d(u, v , G))\u2228(d(u, v, G) = d(u, v , G)\u2227v < v ) ,", "cite_spans": [], "ref_spans": []}, {"section": "and restricting the resulting list to the first \u03c3 entries. The goal of the (S, \u03b3, \u03c3)-detection problem is to compute L(u, S, \u03b3, \u03c3, G) for every node u \u2208 V (G). In the distributed setting we assume that each node knows \u03b3, \u03c3, and whether it is in S or not and the goal is that every node u \u2208 V (G) knows its list L(u, S, \u03b3, \u03c3, G),", "text": "Lenzen and Peleg designed a source detection algorithm for unweighted networks [39] . One can also run the algorithm on weighted networks, following [38, proof of Theorem 3.3], by simulating each edge of some weight L with an unweighted path of length L. Note that nodes in the paths added in this way are never sources. We also use another source detection algorithm: Roditty, Thorup, and Zwick [47] also solve a variant of the source detection problem with \u03b3 = \u221e in their centralized algorithm for computing distances oracles and spanners deterministically. They reduce the source detection problem to a sequence of single-source shortest paths computations on graphs with some additional nodes and edges. Their algorithm can easily be generalized to arbitrary \u03b3. Theorem 2.4 (implicit in [47] The classic result of Goldberg et al. [26] shows that in the distributed setting, for any c \u2265 1, we can compute a (c, c\u03bb)-ruling set deterministically in O(c log n) rounds, where \u03bb is the number of bits used to represent each ID in the network. Since it was not explicitly stated that this algorithm works in the CONGEST model, we sketch an implementation of this algorithm in the full version of this paper (see [ ", "cite_spans": [{"start": 79, "end": 83, "text": "[39]", "ref_id": "BIBREF38"}, {"start": 396, "end": 400, "text": "[47]", "ref_id": "BIBREF46"}, {"start": 791, "end": 795, "text": "[47]", "ref_id": "BIBREF46"}, {"start": 834, "end": 838, "text": "[26]", "ref_id": "BIBREF25"}], "ref_spans": []}, {"section": "DETERMINISTIC HOP SET CONSTRUC-TION", "text": "In this section we present a deterministic algorithm for constructing an (n o (1) , o(1))-hop set.", "cite_spans": [{"start": 78, "end": 81, "text": "(1)", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "Deterministic Clusters", "text": "The basis of our hop set construction is a structure called cluster introduced by Thorup and Zwick [51] . Consider an integer p such that 2 \u2264 p \u2264 log n and a hierarchy A of sets of nodes (Ai) 0\u2264i\u2264p such that A0 = V , Ap = \u2205, and A0 \u2287 A1 \u2287 . . . \u2287 Ap. We say that a node v has priority i if v \u2208 Ai \\ Ai+1 (for 0 \u2264 i \u2264 p \u2212 1). For every node v \u2208 V we define the restricted cluster up to distance R as", "cite_spans": [], "ref_spans": []}, {"section": "Deterministic Clusters", "text": "where i is the priority of v. For every node v \u2208 V , every 0 \u2264 i \u2264 p \u2212 1, and every R \u2265 1, we define the restricted i-bunch up to distance R as", "cite_spans": [], "ref_spans": []}, {"section": "Deterministic Clusters", "text": "Clusters and bunches are dual concepts, i.e., u \u2208 C (v, A, R, G) if and only if v \u2208 0\u2264i\u2264p\u22121 Bi(u, A, R, G). In our hop set construction we will use sets of edges obtained from the clusters in the straightforward way: every node has an edge to each node in its cluster. Note that the size of such a set of edges (which in turn influences the size of our hop set) is at most v\u2208V |C (v, A, R, G)|, the size of all clusters, which is equal to", "cite_spans": [], "ref_spans": []}, {"section": "Deterministic Clusters", "text": "A second motivation for keeping cluster sizes small is that in the models of computation considered in this paper also the time needed for constructing all clusters will depend on both R and the size of the clusters. Given a hierarchy of sets A, the clusters can be computed as follows. First, for every 1 \u2264 i \u2264 p \u2212 1, compute the distance of every node to its closest node in Ai by constructing a shortest-path tree in a modification of the graph where all nodes of Ai are contracted to a single source node. Second, compute the cluster of every node v by constructing a shortest-path tree up to distance R from v under the following restriction: only let a node u to join the tree if d(u, v, G) < d(u, Ai+1, G) . This additionally computes the distances between v and every node in its cluster.", "cite_spans": [], "ref_spans": []}, {"section": "Deterministic Clusters", "text": "If randomization is allowed, bunches of small size can be obtained as follows [51] : If we set A0 = V and Ap = \u2205, and for each 0 \u2264 i \u2264 p \u2212 2 we obtain Ai+1 by picking each node from Ai with probability (ln n/n) 1/p , then the expected size of each i-bunch is at most n 1/p and thus the expected size of all bunches (and hence all clusters) is O(pn 1+1/p ). Roditty, Thorup and Zwick [47] also give a deterministic algorithm for setting A such that the resulting clusters will have the same asymptotic size. Following their algorithm we iteratively compute Ai's such that the restricted i-bunch of every node will have size q =\u00d5(n 1/p ). We set A0 = V and, given Ai, we construct Ai+1 as follows. Using a source detection algorithm, we first determine for each node v the set L(v, Ai, R, q, G), which among all nodes of Ai at distance at most R from v contains the q closest ones. We now find a set Ai+1 \u2286 Ai of size |Ai+1| \u2264 |Ai|/n 1/p such that, for every node v, L(v, Ai, R, q, G) contains at least one node of Ai+1. This restricts the size of each i-bunch to q. Finding such a set Ai+1 of minimum size is exactly the hitting set problem. By probabilistic arguments there exists a hitting set of size |Ai|/n 1/p . Once all sets L(v, Ai, R, q, G) are known, we can compute an approximation of the minimum hitting set using a greedy heuristic. The guarantees of our algorithm for computing clusters can be summarized as follows.", "cite_spans": [{"start": 78, "end": 82, "text": "[51]", "ref_id": "BIBREF50"}, {"start": 383, "end": 387, "text": "[47]", "ref_id": "BIBREF46"}], "ref_spans": []}, {"section": "Theorem 3.1. Given a weighted graph G and parameters p and R, there is a deterministic algorithm Clusters(G, p, R) that computes a hierarchy of sets", "text": "A = (Ai) 0\u2264i\u2264p , where V = A0 \u2286 A1 \u2286 \u00b7 \u00b7 \u00b7 \u2286 Ap = \u2205, such that v\u2208V |C (v, A, R, G)| = O(pn 1+1/p ).", "cite_spans": [], "ref_spans": []}, {"section": "It also computes, for every node v, the set C (v, A, R, G) and for each node w \u2208 C (v, A, R, G) the value of d(v, w, G).", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Hop Set from Clusters", "text": "We now explain how to construct the hop set. We omit many details, which can be found in the full version of the paper.", "cite_spans": [], "ref_spans": []}, {"section": "Hop Set from Clusters", "text": "Assume we are given a hierarchy of sets A and the corresponding clusters and consider the set of edges F containing for every node u edges to all nodes v in its cluster with weight equal to the distance from u to v. Using an analysis similar to [52] and [29] we can show that if the number of priorities p is small enough the following holds after adding the edges of F to the graph: for every \u2206 sufficiently smaller than the distance range R we can, for all pairs of nodes u and v find a path from u to v with O ((p + 1) d(u, v, G) /\u2206 ) edges that overestimates the distance from u to v by a multiplicative error of (1 + ) and an additive error of n o (1) .", "cite_spans": [{"start": 245, "end": 249, "text": "[52]", "ref_id": "BIBREF51"}, {"start": 254, "end": 258, "text": "[29]", "ref_id": "BIBREF28"}, {"start": 653, "end": 656, "text": "(1)", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "Lemma 3.2. Let F \u2286 V 2 be the set of edges computed by Procedure 1 for an integer-weighted graph G = (V, E)", "text": "and parameters \u2206 \u2265 1 and 0 < \u2264 1. Then F has siz\u1ebd O(pn 1+1/p ), where p = (log n)/(log (4/ )) , and in the graph H = G \u222a F , for every pair of nodes u and v, we have", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 3.2. Let F \u2286 V 2 be the set of edges computed by Procedure 1 for an integer-weighted graph G = (V, E)", "text": "Procedure 1: HopReductionAdditiveError(G, \u2206, ) Input: Graph G = (V, E) with non-negative integer edge weights, \u2206 \u2265 1, 0 < \u2264 1 Output: Hop-reducing set of edges F \u2286 V 2 as specified in Lemma 3.2", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 3.2. Let F \u2286 V 2 be the set of edges computed by Procedure 1 for an integer-weighted graph G = (V, E)", "text": "Consider a shortest path \u03c0 from u to v with h edges and weight R \u2265 \u2206. With the hop reduction of Procedure 1 we can compute a set of edges that reduces the number of hops from u to v to\u00d5(R/\u2206) (at the cost of approximating the distance). This is not yet sufficient for computing the desired hop set because R might be as large as nW . Instead we would like to reduce the number of hops to\u00d5(h/\u2206) as h can be at most n. We can achieve this by using the weight-rounding technique of Lemma 2.1: for every distance range of the form 2 j . . . 2 j+1 , we scale down the edge weights by a certain factor \u03c1j (depending on j, h, and ) and run Procedure 1 on this scaled-down version of G to obtain a set of edges Fj. The set j Fj will then provide a reduction to\u00d5(h/\u2206) hops. Additionally, if h is sufficiently larger than \u2206, then the additive error inherent in the hop reduction of Procedure 1 can be counted as an additional multiplicative error of . ", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 3.2. Let F \u2286 V 2 be the set of edges computed by Procedure 1 for an integer-weighted graph G = (V, E)", "text": "We now use the following iterative approach in which we repeatedly apply the hop reduction of Procedure 2 with \u2206 = n o (1) . We first compute a set of edges F1 that reduces the number of hops in G from h0 = n to h1 = h0/\u2206 = n/\u2206. We then add all these edges to G and consider the graph HopReduction(G, \u2206, h, , W ) Input: Weighted graph G = (V, E) with integer edge weights from 1 to W , \u2206 \u2265 1, 0 < \u2264 1 Output: Hop-reducing set of edges F \u2286 V 2 as specified in Lemma 3.3", "cite_spans": [{"start": 119, "end": 122, "text": "(1)", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "Lemma 3.2. Let F \u2286 V 2 be the set of edges computed by Procedure 1 for an integer-weighted graph G = (V, E)", "text": "We apply Procedure 2 again on H1 to compute a set of edges F2 that reduces the number of hops in H1 from h1 to h1/\u2206 = n/\u2206 2 . Now observe that the set of edges F1 \u222a F2 reduces the number of hops in G from n to n/\u2206 2 and in general, after i iterations, the number of hops is reduced to n/\u2206 i . This process stops when the number of hops reaches the bound h \u2265 n 1/p \u2206/(p + 2) of Lemma 3.3. We show that by repeating this process p = \u0398( log n/ log (1/ )) times we can compute a set F that reduces the number of hops to n/\u2206 p = n o (1) .", "cite_spans": [{"start": 528, "end": 531, "text": "(1)", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "Procedure 3: HopSet(G, , W )", "text": "Input: Weighted graph G = (V, E) with integer edge weights from 1 to", "cite_spans": [], "ref_spans": []}, {"section": "Procedure 3: HopSet(G, , W )", "text": "2 be the set of edges computed by Procedure 3 for a weighted graph G = (V, E) and a parameter 0 < \u2264 1. Then, for p = (log n)/(log (108", "cite_spans": [], "ref_spans": []}, {"section": "Procedure 3: HopSet(G, , W )", "text": "The main computational cost for constructing the hop set comes from computing the clusters in Procedure 1, which is used as a subroutine repeatedly. If 1/ \u2264 polylog n, then (1) and Procedure 3 will compute an (n o (1) , o(1))-hop set of size O(n 1+o(1) log W ); it will perform\u00d5(log W )", "cite_spans": [{"start": 173, "end": 176, "text": "(1)", "ref_id": "BIBREF0"}, {"start": 214, "end": 217, "text": "(1)", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "Procedure 3: HopSet(G, , W )", "text": "cluster computations each with p = \u0398( log n/ log (1/ )) priorities up to distance range O(n o(1) ) on a graphs of size O(m 1+o(1) log W ). The concrete time complexity depends on the model of computation we want to consider (see the implementation in Section 4.2). As for each cluster computation the priorities are set deterministically, our whole algorithm is deterministic.", "cite_spans": [], "ref_spans": []}, {"section": "DISTRIBUTED SSSP ALGORITHM ON NETWORKS WITH ARBITRARY TOPOL-OGY", "text": "Our algorithm consists of two parts, presented in two sections: In Section 4.1 we give a deterministic algorithm for constructing an overlay network such that it is sufficient to compute SSSP on this network. A randomized version of this result was given in [42] . In Section 4.2 we present a more efficient algorithm for computing SSSP on this overlay network using Procedures 1 to 3 from before. We finish the computation in the same way as in [42] .", "cite_spans": [{"start": 258, "end": 262, "text": "[42]", "ref_id": "BIBREF41"}, {"start": 446, "end": 450, "text": "[42]", "ref_id": "BIBREF41"}], "ref_spans": []}, {"section": "Computing an Overlay Network Deterministically", "text": "An overlay network (aka landmark or skeleton) [42, 50, 37] is a virtual network G of nodes and \"virtual edges\" that is built on top of an underlying real network G; i.e.,", "cite_spans": [{"start": 46, "end": 50, "text": "[42,", "ref_id": "BIBREF41"}, {"start": 51, "end": 54, "text": "50,", "ref_id": "BIBREF49"}, {"start": 55, "end": 58, "text": "37]", "ref_id": "BIBREF36"}], "ref_spans": []}, {"section": "Computing an Overlay Network Deterministically", "text": "such that the weight of an edge in G is an approximation of the distance of its endpoints in G. The nodes in V (G ) are called centers. Computing G means that after the computation every node in G knows whether it is a center and knows all virtual edges to its neighbors in G with their weights. We show in this subsection that there is a\u00d5(n 1/2 )-time algorithm that constructs an overlay network G of\u00d5(n 1/2 ) nodes such that a (1+o(1))-approximation to SSSP in G , can be converted to a (1 + o(1) )-approximation to SSSP in G, as stated formally below.", "cite_spans": [], "ref_spans": []}, {"section": "Computing an Overlay Network Deterministically", "text": "Theorem 4.1. Given any weighted undirected network G and source node s, there is an\u00d5(n 1/2 )-time deterministic distributed algorithm that computes an overlay network G and some additional information for every node with the following properties.", "cite_spans": [], "ref_spans": []}, {"section": "Computing an Overlay Network Deterministically", "text": "\u2022 Property 1: |V (G )| =\u00d5(n 1/2 ) and s \u2208 V (G ).", "cite_spans": [], "ref_spans": []}, {"section": "Computing an Overlay Network Deterministically", "text": "\u2022 Property 2: For every node u \u2208 V (G), as soon as", "cite_spans": [], "ref_spans": []}, {"section": "Computing an Overlay Network Deterministically", "text": "In Theorem 4.2 of the full version of [42] , the following randomized algorithm that achieves the result above was given 7 . In the first step of [42] , the algorithm selects each node to be a center with probability\u0398(1/n 1/2 ) and also makes s a center. By a standard \"hitting set\" argument (e.g. [54, 13] ), any shortest path containing n 1/2 edges will contain a center with high probability. Also, the number of centers is\u0398(n 1/2 ) with high probability. In the second step, the algorithm makes sure that every node v knows the\u0398(n 1/2 )-hop distances between v and all centers using a light-weight bounded-hop single-source shortest paths algorithm from all centers in parallel combined with the random delay technique to avoid congestion.", "cite_spans": [{"start": 38, "end": 42, "text": "[42]", "ref_id": "BIBREF41"}, {"start": 121, "end": 122, "text": "7", "ref_id": "BIBREF6"}, {"start": 146, "end": 150, "text": "[42]", "ref_id": "BIBREF41"}, {"start": 298, "end": 302, "text": "[54,", "ref_id": "BIBREF53"}, {"start": 303, "end": 306, "text": "13]", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "Computing an Overlay Network Deterministically", "text": "We derandomize the first step as follows: In Section 4.1.1 we assign to each node u a type t(u) such that every path \u03c0 containing n 1/2 edges contains a special node u with 2 t(u) =  O( w(\u03c0, G) ). This is comparable to the property obtained from the hitting set argument, which would be achieved if we made the special node of every path a center. However, this might create too many centers. Instead we select some nodes to be centers using the ruling set algorithm, as described in Section 4.1.2, which outputs a small set of centers and we can show that every special node u is at distance\u00d5 (2 t(u) ) to one of the centers. Thus, while we cannot guarantee that the path \u03c0 contains a center, we can guarantee that it contains a node that is not far from a center. To derandomize the second step, we use the recent algorithm of Lenzen and Patt-Shamir [38] for the Partial Distance Estimation (PDE) problem together with the above Procedures 1 to 3, as explained in Section 4.1.2. The parameters used by our algorithm in the following are = 1/ log", "cite_spans": [{"start": 852, "end": 856, "text": "[38]", "ref_id": "BIBREF37"}], "ref_spans": []}, {"section": "Computing an Overlay Network Deterministically", "text": ", and k = (1 + 2/ )k. Recall that \u03bb is the number of bits used to represent each ID in the network.", "cite_spans": [], "ref_spans": []}, {"section": "Types of Nodes", "text": "For any integer i, we let \u03c1i = Proof. Let l = |\u03c0|/h \u2265 1/ and let x and y denote the endpoints of \u03c0. Partition \u03c0 into the path \u03c0x consisting of the (l \u2212 1)h edges closest to x and the path \u03c0y consisting of the |\u03c0| \u2212 (l \u2212 1)h edges closest to y. Further partition \u03c0u into l \u2212 1 non-overlapping subpaths of exactly h edges, and expand the path \u03c0y by adding edges of \u03c0x to it until it has h edges. Thus, there are now l paths of exactly h edges each and total weight at most 2w(\u03c0, G). It follows that there exists a subpath \u03c0 of \u03c0 consisting of exactly h edges and weight at most 2w(\u03c0, G)/l \u2264 2 w(\u03c0, G). Let u and v be the two endpoints of \u03c0 and let i be the index such that", "cite_spans": [], "ref_spans": []}, {"section": "Types of Nodes", "text": "Computing Types of Nodes.", "cite_spans": [], "ref_spans": []}, {"section": "Types of Nodes", "text": "To compute t(u) for all nodes u, it is sufficient for every node u to know, for each i, whether |B(u, Gi, h )| \u2265 h. We do this by solving the (S, \u03b3, \u03c3)-detection problem on Gi with S = V (G), \u03b3 = h and \u03c3 = h, i.e., we compute the list L(u, S, \u03b3, \u03c3, G) for all nodes u, which contains the \u03c3 nodes from S that are closest to u, provided their distance is at most \u03b3. By Theorem 2. ", "cite_spans": [], "ref_spans": []}, {"section": "Selecting Centers via Ruling Sets and Computing Distances to Them", "text": "Having computed the types of the nodes, we compute ruling sets for the nodes of each type to select a small subset of nodes of each type as centers. Remember the two properties of an (\u03b1, \u03b2)-ruling set T of a base set U : (1) all nodes of T are at least distance \u03b1 apart and (2) each node in U \\ T has at least one \"ruling\" node of T in distance \u03b2. We use the algorithm of Theorem 2.6 to compute a (2h + 1, (2h + 1)\u03bb))-ruling set Ti for each graph Gi where the input set Ui consists of all nodes of type i. The number of rounds for this computation is O(h log n) =\u00d5(n 1/2 ). We define the set of centers as V = ( i Ti) \u222a {s}. Property (1) allows us to bound the number of centers and by property (2) the centers \"almost\" hit all paths with n 1/2 edges. We prove the following lemma in the full version of our paper. ", "cite_spans": [], "ref_spans": []}, {"section": "Selecting Centers via Ruling Sets and Computing Distances to Them", "text": "Next, we compute for every node u and every center v a valued(u, v) that is a (1 + o(1) The goal is that each node u knowsd(u, v) for all centers v. In particular we also computed(u, v) for all pairs of centers u and v. As in Section 4.1.1, we do this by solving the source detection problem on a graph with rounded weights. ", "cite_spans": [], "ref_spans": []}, {"section": "Selecting Centers via Ruling Sets and Computing Distances to Them", "text": "Equations (1) and (3) it then follows that", "cite_spans": [], "ref_spans": []}, {"section": "Selecting Centers via Ruling Sets and Computing Distances to Them", "text": "We define our final overlay network to be the graph G where the weight between any two centers u, v \u2208 V (G ) i\u015d d(u, v) (as computed in Section 4.1.2). Additionally, for every node u \u2208 V (G) we store the value ofd(u, v) to all centers v \u2208 V (G ). All steps for computing G above take\u00d5(n 1/2 / ) rounds and |V (G )| =\u00d5(n 1/2 ). It is thus left to prove Property 2 in Theorem 4.1. This is similar to the standard path-hitting argument (see the full version for details): The shortest path from node u to s can be partitioned into subpaths of at most n 1/2 hops with nodes u1, u2, . . . , ut hitting these paths (where t \u2264 n 1/2 and ut is nearest to u) such that each ui has a center vi nearby (by Lemma 4.3). The distance from vi to vi+1 (1 + o (1))-approximates the distance between ui and ui+1.", "cite_spans": [], "ref_spans": []}, {"section": "Computing a Hop Set on an Overlay Network", "text": "We now show how to simulate the hop set algorithm presented in Section 3 on an overlay network G , whose set of nodes V (G ) are the centers, to compute a hop set of G (not of G) and how to compute approximate shortest paths from s in G using the hop set. Throughout the algorithm we will work on overlay networks with the same nodes as G , but which might have different edge weights as, e.g., Procedure 2 calls Procedure 1 and Procedure 1 calls Clusters on overlay networks with modified edge weights. Thus, we will use G to refer to an overlay network on which the subroutines run.", "cite_spans": [], "ref_spans": []}, {"section": "Computing a Hop Set on an Overlay Network", "text": "Computing Bounded-Distance Single-Source Shortest Paths.", "cite_spans": [], "ref_spans": []}, {"section": "Computing a Hop Set on an Overlay Network", "text": "We will repeatedly use an algorithm for computing a shortest-paths tree up to distance R rooted at s on an overlay network G , where R = O(n o (1) ). At the end of the algorithm every center knows this tree. We do this in a breadth-first search manner, in R + 1 iterations. Like in Dijkstra's algorithm, every center keeps a tentative distance \u03b4(s, u) from s and a tentative parent in the shortest-paths tree, i. to all other centers a message (u, \u03b4(s, u), v) where v is the parent of u. Using this information, every center u will update (\"relax\") its tentative distance \u03b4(s, u) and its tentative parent.", "cite_spans": [{"start": 143, "end": 146, "text": "(1)", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "Computing a Hop Set on an Overlay Network", "text": "Clearly, after the L th iteration, centers that have distance L+1 from s will already know their correct distance. Thus, at the end of the last iteration every center knows the shortest- 9 More precisely, there is a designated center (e.g. the center with lowest ID) that aggregates and distributes the messages (via upcasting and downcasting on the breadth-first search tree of the network G), and tells other centers when the iteration starts and ends. Computing Priorities, Clusters, and Hop Sets.", "cite_spans": [{"start": 187, "end": 188, "text": "9", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "Computing a Hop Set on an Overlay Network", "text": "To compute the hop set of G we simulate the algorithm of Section 3 on the overlay network. We sketch the main idea here and refer to the full version of our paper for details. The main idea is that the main computational cost for computing the hop set comes from repeatedly calling its subroutine for computing bounded-distance clusters. We observe that computing these clusters on the overlay network basically needs the same analysis as the bounded-distance shortestpath trees discussed above. In particular, for computing the priorities of centers deterministically, we use the source detection algorithm of Theorem 2.4 as a subroutine, which reduces the problem to computing a series of bounded-depth shortest-path trees. Technically, this reduction would require us to add some nodes to the overlay network, which we can avoid by simulating the behaviour of the additional nodes by centers that are already present in the network. We can argue that a single cluster computation takes\u00d5(RD + N 1+o (1) ) rounds and thus the hop set can be computed deterministically in O(n o(1) D + n 1/2+o(1) ) rounds.", "cite_spans": [], "ref_spans": []}, {"section": "Computing a Hop Set on an Overlay Network", "text": "Final Steps. (1) ) rounds by the same method as in Lemma 4.6 in the full version of [42] . The details are given in the full version of our paper. ", "cite_spans": [{"start": 84, "end": 88, "text": "[42]", "ref_id": "BIBREF41"}], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "List of open problems in sublinear algorithms: Problem 14", "authors": [], "year": "", "venue": "", "link": "44547346"}, "BIBREF1": {"title": "Distributed Graph Coloring: Fundamentals and Recent Developments", "authors": [{"first": "L", "middle": [], "last": "Barenboim", "suffix": ""}, {"first": "M", "middle": [], "last": "Elkin", "suffix": ""}], "year": "", "venue": "Synthesis Lectures on Distributed Computing Theory", "link": "37859498"}, "BIBREF2": {"title": "Streaming algorithm for graph spanners-single pass and constant processing time per edge", "authors": [{"first": "S", "middle": [], "last": "Baswana", "suffix": ""}], "year": 2008, "venue": "Information Processing Letters", "link": "1884223"}, "BIBREF3": {"title": "Improved decremental algorithms for maintaining transitive closure and all-pairs shortest paths", "authors": [{"first": "S", "middle": [], "last": "Baswana", "suffix": ""}, {"first": "R", "middle": [], "last": "Hariharan", "suffix": ""}, {"first": "S", "middle": [], "last": "Sen", "suffix": ""}], "year": 2007, "venue": "Journal of Algorithms", "link": "29616158"}, "BIBREF4": {"title": "On a routing problem", "authors": [{"first": "R", "middle": [], "last": "Bellman", "suffix": ""}], "year": 1958, "venue": "Quarterly of Applied Mathematics", "link": "123639971"}, "BIBREF5": {"title": "Fully dynamic (2 + ) approximate all-pairs shortest paths with fast query and close to linear update time", "authors": [{"first": "A", "middle": [], "last": "Bernstein", "suffix": ""}], "year": 2009, "venue": "Symposium on Foundations of Computer Science (FOCS)", "link": null}, "BIBREF6": {"title": "Maintaining shortest paths under deletions in weighted directed graphs", "authors": [{"first": "A", "middle": [], "last": "Bernstein", "suffix": ""}], "year": 2013, "venue": "Symposium on Theory of Computing (STOC)", "link": "131408"}, "BIBREF7": {"title": "Algebraic methods in the congested clique", "authors": [{"first": "K", "middle": [], "last": "Censor-Hillel", "suffix": ""}, {"first": "P", "middle": [], "last": "Kaski", "suffix": ""}, {"first": "J", "middle": ["H"], "last": "Korhonen", "suffix": ""}, {"first": "C", "middle": [], "last": "Lenzen", "suffix": ""}, {"first": "A", "middle": [], "last": "Paz", "suffix": ""}, {"first": "J", "middle": [], "last": "Suomela", "suffix": ""}], "year": 2015, "venue": "Symposium on Principles of Distributed Computing (PODC)", "link": "13649853"}, "BIBREF8": {"title": "Fast algorithms for constructing t-spanners and paths with stretch t", "authors": [{"first": "E", "middle": [], "last": "Cohen", "suffix": ""}], "year": 1998, "venue": "SIAM Journal on Computing", "link": null}, "BIBREF9": {"title": "Polylog-time and near-linear work approximation scheme for undirected shortest paths", "authors": [{"first": "E", "middle": [], "last": "Cohen", "suffix": ""}], "year": 2000, "venue": "Journal of the ACM", "link": "52152025"}, "BIBREF10": {"title": "Efficient computation of distance sketches in distributed networks", "authors": [{"first": "A", "middle": [], "last": "Sarma", "suffix": ""}, {"first": "M", "middle": [], "last": "Dinitz", "suffix": ""}, {"first": "G", "middle": [], "last": "Pandurangan", "suffix": ""}], "year": 2012, "venue": "SPAA", "link": null}, "BIBREF11": {"title": "Distributed verification and hardness of distributed approximation", "authors": [{"first": "A", "middle": [], "last": "Sarma", "suffix": ""}, {"first": "S", "middle": [], "last": "Holzer", "suffix": ""}, {"first": "L", "middle": [], "last": "Kor", "suffix": ""}, {"first": "A", "middle": [], "last": "Korman", "suffix": ""}, {"first": "D", "middle": [], "last": "Nanongkai", "suffix": ""}, {"first": "G", "middle": [], "last": "Pandurangan", "suffix": ""}, {"first": "D", "middle": [], "last": "Peleg", "suffix": ""}, {"first": "R", "middle": [], "last": "Wattenhofer", "suffix": ""}], "year": 2012, "venue": "SIAM Journal on Computing", "link": "41760737"}, "BIBREF12": {"title": "Handbook on Data Structures and Applications, chapter 36: Dynamic Graphs", "authors": [{"first": "C", "middle": [], "last": "Demetrescu", "suffix": ""}, {"first": "I", "middle": [], "last": "Finocchi", "suffix": ""}, {"first": "G", "middle": [], "last": "Italiano", "suffix": ""}], "year": 2005, "venue": "", "link": null}, "BIBREF13": {"title": "Trading off space for passes in graph streaming problems", "authors": [{"first": "C", "middle": [], "last": "Demetrescu", "suffix": ""}, {"first": "I", "middle": [], "last": "Finocchi", "suffix": ""}, {"first": "A", "middle": [], "last": "Ribichini", "suffix": ""}], "year": 2009, "venue": "ACM Transactions on Algorithms", "link": "9483454"}, "BIBREF14": {"title": "Fully dynamic all pairs shortest paths with real edge weights", "authors": [{"first": "C", "middle": [], "last": "Demetrescu", "suffix": ""}, {"first": "G", "middle": ["F"], "last": "Italiano", "suffix": ""}], "year": 2006, "venue": "Journal of Computer and System Sciences", "link": "2900246"}, "BIBREF15": {"title": "Distributed approximation: a survey", "authors": [{"first": "M", "middle": [], "last": "Elkin", "suffix": ""}], "year": 2004, "venue": "SIGACT News", "link": "14896880"}, "BIBREF16": {"title": "An unconditional lower bound on the time-approximation trade-off for the distributed minimum spanning tree problem", "authors": [{"first": "M", "middle": [], "last": "Elkin", "suffix": ""}], "year": 2006, "venue": "SIAM Journal on Computing", "link": "7016758"}, "BIBREF17": {"title": "Streaming and fully dynamic centralized algorithms for constructing and maintaining sparse spanners", "authors": [{"first": "M", "middle": [], "last": "Elkin", "suffix": ""}], "year": 2011, "venue": "ACM Transactions on Algorithms", "link": "6783114"}, "BIBREF18": {"title": "Can quantum communication speed up distributed computation?", "authors": [{"first": "M", "middle": [], "last": "Elkin", "suffix": ""}, {"first": "H", "middle": [], "last": "Klauck", "suffix": ""}, {"first": "D", "middle": [], "last": "Nanongkai", "suffix": ""}, {"first": "G", "middle": [], "last": "Pandurangan", "suffix": ""}], "year": 2014, "venue": "Symposium on Principles of Distributed Computing (PODC)", "link": "14764654"}, "BIBREF19": {"title": "Efficient algorithms for constructing (1 + , \u03b2)-spanners in the distributed and streaming models", "authors": [{"first": "M", "middle": [], "last": "Elkin", "suffix": ""}, {"first": "J", "middle": [], "last": "Zhang", "suffix": ""}], "year": 2006, "venue": "Distributed Computing", "link": "40260738"}, "BIBREF20": {"title": "On graph problems in a semi-streaming model", "authors": [{"first": "J", "middle": [], "last": "Feigenbaum", "suffix": ""}, {"first": "S", "middle": [], "last": "Kannan", "suffix": ""}, {"first": "A", "middle": [], "last": "Mcgregor", "suffix": ""}, {"first": "S", "middle": [], "last": "Suri", "suffix": ""}, {"first": "J", "middle": [], "last": "Zhang", "suffix": ""}], "year": 2005, "venue": "Theoretical Computer Science", "link": "36339781"}, "BIBREF21": {"title": "Graph distances in the data-stream model", "authors": [{"first": "J", "middle": [], "last": "Feigenbaum", "suffix": ""}, {"first": "S", "middle": [], "last": "Kannan", "suffix": ""}, {"first": "A", "middle": [], "last": "Mcgregor", "suffix": ""}, {"first": "S", "middle": [], "last": "Suri", "suffix": ""}, {"first": "J", "middle": [], "last": "Zhang", "suffix": ""}], "year": 2008, "venue": "SIAM Journal on Computing", "link": "861166"}, "BIBREF22": {"title": "Network flow theory", "authors": [{"first": "L", "middle": ["R"], "last": "Ford", "suffix": ""}], "year": 1956, "venue": "", "link": "60085760"}, "BIBREF23": {"title": "A sublinear time distributed algorithm for minimum-weight spanning trees", "authors": [{"first": "J", "middle": ["A"], "last": "Garay", "suffix": ""}, {"first": "S", "middle": [], "last": "Kutten", "suffix": ""}, {"first": "D", "middle": [], "last": "Peleg", "suffix": ""}], "year": 1998, "venue": "SIAM Journal on Computing", "link": "206559765"}, "BIBREF24": {"title": "Distributed minimum cut approximation", "authors": [{"first": "M", "middle": [], "last": "Ghaffari", "suffix": ""}, {"first": "F", "middle": [], "last": "Kuhn", "suffix": ""}], "year": 2013, "venue": "Symposium on Distributed Computing (DISC)", "link": "270527"}, "BIBREF25": {"title": "Parallel symmetry-breaking in sparse graphs", "authors": [{"first": "A", "middle": ["V"], "last": "Goldberg", "suffix": ""}, {"first": "S", "middle": ["A"], "last": "Plotkin", "suffix": ""}, {"first": "G", "middle": ["E"], "last": "Shannon", "suffix": ""}], "year": 1988, "venue": "SIAM Journal on Discrete Mathematics", "link": "6264678"}, "BIBREF26": {"title": "Superlinear lower bounds for multipass graph processing", "authors": [{"first": "V", "middle": [], "last": "Guruswami", "suffix": ""}, {"first": "K", "middle": [], "last": "Onak", "suffix": ""}], "year": 2013, "venue": "Conference on Computational Complexity (CCC)", "link": "137620"}, "BIBREF27": {"title": "Fully dynamic biconnectivity and transitive closure", "authors": [{"first": "M", "middle": [], "last": "Henzinger", "suffix": ""}, {"first": "V", "middle": [], "last": "King", "suffix": ""}], "year": 1995, "venue": "Symposium on Foundations of Computer Science (FOCS)", "link": "206559885"}, "BIBREF28": {"title": "Decremental single-source shortest paths on undirected graphs in near-linear total update time", "authors": [{"first": "M", "middle": [], "last": "Henzinger", "suffix": ""}, {"first": "S", "middle": [], "last": "Krinninger", "suffix": ""}, {"first": "D", "middle": [], "last": "Nanongkai", "suffix": ""}], "year": 2014, "venue": "Symposium on Foundations of Computer Science (FOCS)", "link": "53878655"}, "BIBREF29": {"title": "Approximation of distances and shortest paths in the broadcast congest clique", "authors": [{"first": "S", "middle": [], "last": "Holzer", "suffix": ""}, {"first": "N", "middle": [], "last": "Pinsker", "suffix": ""}], "year": 2015, "venue": "International Conference on Principles of Distributed Systems (OPODIS)", "link": "11541"}, "BIBREF30": {"title": "Optimal distributed all pairs shortest paths and applications", "authors": [{"first": "S", "middle": [], "last": "Holzer", "suffix": ""}, {"first": "R", "middle": [], "last": "Wattenhofer", "suffix": ""}], "year": 2012, "venue": "Symposium on Principles of Distributed Computing (PODC)", "link": "15178383"}, "BIBREF31": {"title": "A fast distributed approximation algorithm for minimum spanning trees", "authors": [{"first": "M", "middle": [], "last": "Khan", "suffix": ""}, {"first": "G", "middle": [], "last": "Pandurangan", "suffix": ""}], "year": 2008, "venue": "Distributed Computing", "link": "34929405"}, "BIBREF32": {"title": "Fully dynamic algorithms for maintaining all-pairs shortest paths and transitive closure in digraphs", "authors": [{"first": "V", "middle": [], "last": "King", "suffix": ""}], "year": 1999, "venue": "Symposium on Foundations of Computer Science (FOCS)", "link": "2891724"}, "BIBREF33": {"title": "A parallel randomized approximation scheme for shortest paths", "authors": [{"first": "P", "middle": ["N"], "last": "Klein", "suffix": ""}, {"first": "S", "middle": [], "last": "Sairam", "suffix": ""}], "year": 1992, "venue": "Symposium on Theory of Computing (STOC)", "link": "15887176"}, "BIBREF34": {"title": "Tight bounds for distributed minimum-weight spanning tree verification. Theory of Computing Systems", "authors": [{"first": "L", "middle": [], "last": "Kor", "suffix": ""}, {"first": "A", "middle": [], "last": "Korman", "suffix": ""}, {"first": "D", "middle": [], "last": "Peleg", "suffix": ""}], "year": 2013, "venue": "", "link": null}, "BIBREF35": {"title": "Fast distributed construction of small k-dominating sets and applications", "authors": [{"first": "S", "middle": [], "last": "Kutten", "suffix": ""}, {"first": "D", "middle": [], "last": "Peleg", "suffix": ""}], "year": 1998, "venue": "Journal of Algorithms", "link": "10502211"}, "BIBREF36": {"title": "Fast routing table construction using small messages", "authors": [{"first": "C", "middle": [], "last": "Lenzen", "suffix": ""}, {"first": "B", "middle": [], "last": "Patt-Shamir", "suffix": ""}], "year": 2013, "venue": "Symposium on Theory of Computing (STOC)", "link": "42260085"}, "BIBREF37": {"title": "Fast partial distance estimation and applications", "authors": [{"first": "C", "middle": [], "last": "Lenzen", "suffix": ""}, {"first": "B", "middle": [], "last": "Patt-Shamir", "suffix": ""}], "year": 2015, "venue": "Symposium on Principles of Distributed Computing (PODC)", "link": "573235"}, "BIBREF38": {"title": "Efficient distributed source detection with limited bandwidth", "authors": [{"first": "C", "middle": [], "last": "Lenzen", "suffix": ""}, {"first": "D", "middle": [], "last": "Peleg", "suffix": ""}], "year": 2013, "venue": "Symposium on Principles of Distributed Computing (PODC)", "link": "2282176"}, "BIBREF39": {"title": "Graph stream algorithms: A survey", "authors": [{"first": "A", "middle": [], "last": "Mcgregor", "suffix": ""}], "year": 2014, "venue": "SIGMOD Record", "link": "2337679"}, "BIBREF40": {"title": "Faster approximation schemes for fractional multicommodity flow problems via dynamic graph algorithms", "authors": [{"first": "A", "middle": [], "last": "M\u0105dry", "suffix": ""}], "year": 2010, "venue": "Symposium on Theory of Computing (STOC)", "link": "7777761"}, "BIBREF41": {"title": "Distributed approximation algorithms for weighted shortest paths", "authors": [{"first": "D", "middle": [], "last": "Nanongkai", "suffix": ""}], "year": 2014, "venue": "Symposium on Theory of Computing (STOC)", "link": "13864239"}, "BIBREF42": {"title": "Almost-tight distributed minimum cut algorithms", "authors": [{"first": "D", "middle": [], "last": "Nanongkai", "suffix": ""}, {"first": "H", "middle": [], "last": "Su", "suffix": ""}], "year": 2014, "venue": "International Symposium on Distributed Computing (DISC)", "link": "14992250"}, "BIBREF43": {"title": "Distributed Computing: A Locality-sensitive Approach", "authors": [{"first": "D", "middle": [], "last": "Peleg", "suffix": ""}], "year": 2000, "venue": "Society for Industrial and Applied Mathematics", "link": "59719314"}, "BIBREF44": {"title": "A near-tight lower bound on the time complexity of distributed minimum-weight spanning tree construction", "authors": [{"first": "D", "middle": [], "last": "Peleg", "suffix": ""}, {"first": "V", "middle": [], "last": "Rubinovich", "suffix": ""}], "year": 2000, "venue": "SIAM Journal on Computing", "link": null}, "BIBREF45": {"title": "Fast computation of small cuts via cycle space sampling", "authors": [{"first": "D", "middle": [], "last": "Pritchard", "suffix": ""}, {"first": "R", "middle": [], "last": "Thurimella", "suffix": ""}], "year": 2011, "venue": "ACM Transactions on Algorithms", "link": "11387938"}, "BIBREF46": {"title": "Deterministic constructions of approximate distance oracles and spanners", "authors": [{"first": "L", "middle": [], "last": "Roditty", "suffix": ""}, {"first": "M", "middle": [], "last": "Thorup", "suffix": ""}, {"first": "U", "middle": [], "last": "Zwick", "suffix": ""}], "year": 2005, "venue": "International Colloquium on Automata, Languages and Programming (ICALP)", "link": "11301080"}, "BIBREF47": {"title": "On dynamic shortest paths problems", "authors": [{"first": "L", "middle": [], "last": "Roditty", "suffix": ""}, {"first": "U", "middle": [], "last": "Zwick", "suffix": ""}], "year": 2011, "venue": "Algorithmica", "link": "41530541"}, "BIBREF48": {"title": "Subquadratic algorithm for dynamic shortest distances", "authors": [{"first": "P", "middle": [], "last": "Sankowski", "suffix": ""}], "year": 2005, "venue": "International Computing and Combinatorics Conference (COCOON)", "link": "19686068"}, "BIBREF49": {"title": "Shortest-path queries in static networks", "authors": [{"first": "C", "middle": [], "last": "Sommer", "suffix": ""}], "year": 2014, "venue": "ACM Computing Surveys", "link": "1384190"}, "BIBREF50": {"title": "Approximate distance oracles", "authors": [{"first": "M", "middle": [], "last": "Thorup", "suffix": ""}, {"first": "U", "middle": [], "last": "Zwick", "suffix": ""}], "year": 2005, "venue": "Journal of the ACM", "link": "53245292"}, "BIBREF51": {"title": "Spanners and emulators with sublinear distance errors", "authors": [{"first": "M", "middle": [], "last": "Thorup", "suffix": ""}, {"first": "U", "middle": [], "last": "Zwick", "suffix": ""}], "year": 2006, "venue": "SODA", "link": "13056703"}, "BIBREF52": {"title": "Sub-linear distributed algorithms for sparse certificates and biconnected components", "authors": [{"first": "R", "middle": [], "last": "Thurimella", "suffix": ""}], "year": 1997, "venue": "Journal of Algorithms", "link": "10598069"}, "BIBREF53": {"title": "High-probability parallel transitive-closure algorithms", "authors": [{"first": "J", "middle": ["D"], "last": "Ullman", "suffix": ""}, {"first": "M", "middle": [], "last": "Yannakakis", "suffix": ""}], "year": 1991, "venue": "SIAM Journal on Computing", "link": "8666390"}, "BIBREF54": {"title": "All pairs shortest paths using bridging sets and rectangular matrix multiplication", "authors": [{"first": "U", "middle": [], "last": "Zwick", "suffix": ""}], "year": 2002, "venue": "Journal of the ACM", "link": "1065901"}}, "ref_entries": {"FIGREF0": {"text": "+ D)-time algorithm of Nanongkai [STOC 2014] by a factor of as large as n 1/8 , and (ii) the O( \u22121 log \u22121 )- approximation factor of Lenzen and Patt-Shamir's\u00d5(n 1/2+ + D)-time algorithm [STOC 2013] within the same running time. Our running time matches the known time lower bound of \u2126(n 1/2 / log n + D) [Das Sarma et al., STOC 2011] modulo some lower-order terms, thus essentially settling the status of this problem which was raised at least a decade ago [Elkin, SIGACT News 2004]. It also implies a (2 + o(1))- approximation O(n 1/2+o(1) + D 1+o(1) )-time algorithm for approximating a network's weighted diameter which almost matches the lower bound by Holzer et al. [PODC 2012].", "type": "figure"}, "FIGREF1": {"text": "Union's Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 317532 and from the European Re- search Council under the European Union's Seventh Frame- work Programme (FP7/2007-2013)/ERC Grant Agreement number 340506. This work was done in part while visiting the Simons Institute for Theory of Computing. \u2021 This work was done in part while the author was at the University of Vienna, Austria, and while visiting the Simons Institute for the Theory of Computing.", "type": "figure"}, "FIGREF2": {"text": ")-approximation O(n o(1) )- time algorithm on congested cliques, and (ii) a (1 + o(1))- approximation O(n o(1) log W )-pass O(n 1+o(1) log W )-space streaming algorithm, when edge weights are in {1, 2, . . . , W }. The first result answers an open problem in [Nanongkai, STOC 2014]. The second result partially answers an open problem raised by McGregor in 2006 [sublinear.info, Prob- lem 14].", "type": "figure"}, "FIGREF3": {"text": "For any positive integer h and any nodes u and v, we define the bounded- hop distance between u and v, denoted by d h (u, v, G), as the weight of the shortest among all u-v paths containing at most h edges. More precisely, let \u03a0 h (u, v) be the set of all paths between u and v such that each path \u03c0", "type": "figure"}, "FIGREF4": {"text": "Let h \u2265 1 and let G be a graph with integer edge weights from 1 to W . For every integer 0 \u2264 i \u2264 nW , set \u03c1i = 2 i h and let Gi be the graph with the same nodes and edges as G and weight w(u, v, Gi) = w(u,v,G) \u03c1 i for every edge (u, v). Then for all pairs of nodes u and v and every 0", "type": "figure"}, "FIGREF5": {"text": "Theorem 2.3 ([39]). In the CONGEST model there is an algorithm for solving the (S, \u03b3, \u03c3)-detection problem in min (\u03b3, D) + min (\u03c3, |S|) rounds on weighted networks.", "type": "figure"}, "FIGREF6": {"text": "Ruling Set). For a (possibly weighted) graph G, a subset U \u2286 V (G) of nodes, and a pair of positive integers \u03b1 and \u03b2, a set T \u2282 U is an (\u03b1, \u03b2)-ruling set for U in G if 1. for every pair of distinct nodes u, v \u2208 T , it holds that d(u, v, G) \u2265 \u03b1, and 2. for every node u \u2208 U \\ T , there exists a \"ruling\" node v \u2208 T , such that d(u, v, G) \u2264 \u03b2.", "type": "figure"}, "FIGREF7": {"text": "and [44, Chapter 22] for more detailed algorithm and analysis).", "type": "figure"}, "FIGREF8": {"text": "Theorem 2.6 (implicit in [26]). In the CONGEST model there is an algorithm that, for every c \u2265 1, computes a (c, c\u03bb)- ruling set in O(c log n) rounds, where \u03bb is the number of bits used to represent each ID in the network.", "type": "figure"}, "FIGREF9": {"text": "Let F \u2286 V 2 be the set of edges computed by Procedure 2 for a weighted graph G and parameters \u2206 \u2265 1, h \u2265 1, and 0 < \u2264 1. Then F has size\u00d5(pn 1+1/p log nW ), where p = (log n)/(log (54/ )) , and if h \u2265 n 1/p \u2206/(p+2), then in the graph H = G \u222a F we have, for every pair of nodes u and v,", "type": "figure"}, "FIGREF11": {"text": "Gi be the graph with the same nodes and edges as G and weight w(u, v, Gi) = w(u,v,G) \u03c1 i for every edge (u, v). Note that we have chosen h such that d(u, v, Gi) \u2264 h by Equation (2) of Lemma 2.1. For any node u, let the ball of u in Gi be B(u, Gi, h ) = {v \u2208 V (Gi) | d(u, v, Gi) \u2264 h }. Note that for any index i and nodes u and v, d(u, v, Gi+1) \u2264 d(u, v, Gi); thus, B(u, Gi, h ) \u2286 B(u, Gi+1, h ). Let the type t(u) of u be the smallest index i such that |B(u, Gi, h )| \u2265 h. We crucially exploit the following structural property. Lemma 4.2. For every path \u03c0 of G consisting of |\u03c0| = n 1/2 edges there is a node u on \u03c0 such that 2 t(u) \u2264 2 w(\u03c0, G).", "type": "figure"}, "FIGREF12": {"text": "3 this requires O(\u03b3 +\u03c3) = O(h+h ) = O(n 1/2 / ) rounds. For any node u, |L(u, V (G), h , h, G)| = h if and only if |B(u, Gi, h )| \u2265 h. Thus, after we solve the (S, \u03b3, \u03c3)-detection problem on all Gi, using\u00d5(n 1/2 / ) rounds, every node u can compute its type t(u).", "type": "figure"}, "FIGREF13": {"text": "Lemma 4.3. (1) The number of centers is |V | =\u00d5(n 1/2 / ). (2) For any path \u03c0 containing exactly n 1/2 edges, there is a node u in \u03c0 and a center v", "type": "figure"}, "FIGREF14": {"text": "Let\u011ci be the weighted graph such that w(u, v,\u011ci) = w(u,v,G) \u03d5 i for every edge (u, v) in G. We solve the (S, \u03b3, \u03c3)-detection problem on\u011ci for all 0 \u2264 i \u2264 log nW , with parameters S = V , \u03b3 = k , and \u03c3 = |V | (where |V | =\u00d5(n 1/2 / ) by Lemma 4.3). Using the algorithm of Theorem 2.3 this takes\u00d5(\u03b3 + \u03c3) =\u00d5(n 1/2 / ) rounds. At termination, every node u knows the distances up to k to all centers in all\u011ci; i.e., it knows d(u, v, k ,\u011ci) for all i and all centers v. For every node u and center v we set d(u, v) = mini{\u03d5i\u00b7d(u, v, k ,\u011ci)}. Every node u can comput\u00ea d(u, v) without any additional communication as soon as the source detection algorithm is finished. Now, observe that for the index i * such that 2 i *", "type": "figure"}, "FIGREF15": {"text": "e., a center v such that \u03b4(s, u) = \u03b4(s, v) + w(u, v, G ). Initially, \u03b4(s, s) = 0 and \u03b4(s, v) = \u221e for every center v = s. In the L th iteration, for L from 0 up to R, all centers in G whose tentative distance \u03b4(s, u) is exactly L broadcast 9", "type": "figure"}, "FIGREF16": {"text": "paths tree rooted at s up to distance R in G . To analyze the running time, note that over R rounds we broadcast N messages in total, and if mL messages are broadcast in the L th iteration, then this iteration takes O(mL + D) rounds. (We emphasize that the number of rounds depends on the diameter D of the original network, and not of G .) The total number of communication rounds used over all iterations is thus O(RD + L mL) = O(RD + N ).", "type": "figure"}, "FIGREF17": {"text": "Let H be the graph obtained by adding to G the edges of the (n o(1) , o(1))-hop set computed above. To (1 + o(1))- approximate d(s, v, G ) for every center v in G , it is sufficient to (1 + o(1))-approximate the h-hop distance d h (s, v, H), for some h = n o(1) . The latter task can be done in O(hD + |V (G )|) = O(n o(1) D+n 1/2+o", "type": "figure"}, "TABREF0": {"text": ")-approximation O(n o(1) )-time algorithm for the special case of congested clique, where the underlying network is fully-connected. This gives a positive answer to Problem 7.5 in [42]. Previous algorithms solved this problem", "type": "table"}, "TABREF1": {"text": "lexicographically in ascending order, i.e., where", "type": "table"}, "TABREF2": {"text": "). In the sequential model, the (S, \u03b3, \u03c3)-detection problem in directed graphs with posi- tive edge weights can be solved by performing \u03c3 single-source shortest paths computations up to distance \u03b3 on graphs with at most O(n) nodes and O(m) edges. Another subproblem arising in our algorithm is the com- putation of ruling sets The following definition was adapted from the recent survey of Barenboim and Elkin [2, Section 9.2].", "type": "table"}, "TABREF4": {"text": "Theorem 4.4. There is a deterministic distributed algo- rithm that, on any weighted undirected network, computes (1 + o(1))-approximate shortest paths between a given source node s and every other node in O(n 1/2+o(1) +D 1+o(1) ) rounds.", "type": "table"}}}
{"paper_id": "10708629", "_pdf_hash": "a6f1e092845bac7e83deda6eccd2624b49c8e0bb", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Status of Acroporid populations in Colombia. In: Bruckner AW (ed) Proceedings of the Caribbean Acropora workshop: potential application of US endangered species act as a conservation strategy NOAA", "authors": [{"first": "J", "middle": [], "last": "Garzo\u00b4n-Ferreira", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "D\u0131\u00b4az", "suffix": ""}], "year": 2002, "venue": "", "link": null}, "BIBREF1": {"title": "Proceedings of the Caribbean Acropora workshop: potential application of US endangered species act as a conservation strategy NOAA", "authors": [{"first": "W", "middle": ["C"], "last": "Jaap", "suffix": ""}], "year": 2002, "venue": "Acropora-a review of systematics, taxonomy, abundance, distribution, status, and trends: Florida 1881-2000. In: Bruckner AW", "link": null}}, "ref_entries": {}}
{"paper_id": "10708767", "_pdf_hash": "91ed17ca315610137139d4e044b07cca567a33d2", "abstract": [{"section": "Abstract", "text": "ABSTRACT", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "INTRODUCTION", "text": "Histone deacetylases (HDACs) mediate changes in nucleosome conformation and are important in the regulation of gene expression (1) . HDACs are involved in cell-cycle progression and differentiation, and their deregulation is associated with several cancers (2) . HDAC inhibitors, such as trichostatin A and suberoylanilide hydroxamic acid, have emerged recently as promising chemotherapeutic agents (1, 3) because they have antitumor effects. They can inhibit cell growth, induce terminal differentiation, and prevent the formation of tumors in mice models (1, 4, 5) . Suberoylanilide hydroxamic acid, in particular, has been shown to induce growth arrest, differentiation, and/or apoptosis in a variety of cell types (4 -7) and inhibit tumor growth in vivo (6, 8 -10) . Furthermore, because of its low toxicity, suberoylanilide hydroxamic acid is currently in clinical trials for the treatment of solid and hematologic tumors (5, 11, 12) .", "cite_spans": [{"start": 127, "end": 130, "text": "(1)", "ref_id": "BIBREF0"}, {"start": 257, "end": 260, "text": "(2)", "ref_id": "BIBREF1"}, {"start": 557, "end": 560, "text": "(1,", "ref_id": "BIBREF0"}, {"start": 561, "end": 563, "text": "4,", "ref_id": "BIBREF3"}, {"start": 564, "end": 566, "text": "5)", "ref_id": "BIBREF4"}, {"start": 927, "end": 930, "text": "(5,", "ref_id": "BIBREF4"}, {"start": 931, "end": 934, "text": "11,", "ref_id": "BIBREF10"}, {"start": 935, "end": 938, "text": "12)", "ref_id": "BIBREF11"}], "ref_spans": []}, {"section": "INTRODUCTION", "text": "Although suberoylanilide hydroxamic acid has been shown to cause cells to differentiate and undergo apoptosis, the mechanisms underlying these events are largely unknown. One previous study proposed that changes at the level of chromatin structure, induced by a HDAC inhibitor such as sodium butyrate (NaBT), leads to the expression of an unknown protein that facilitates the pathway by which mitochondria activate caspase-3 and trigger apoptotic death of cancer cells (13) . Another study has showed that butyrate induces 15-lipoxygenase-1 (14) . On the basis of these two studies, we hypothesized that 15-lipoxygenase-1 could be one such protein that activates the apoptotic pathway or commits the cells to apoptosis in the case of suberoylanilide hydroxamic acid. To assess whether suberoylanilide hydroxamic acid-induced growth inhibition, differentiation, and/or apoptosis involve 15-lipoxygenase-1, we examined whether suberoylanilide hydroxamic acid can induce 15-lipoxygenase-1 and whether suberoylanilide hydroxamic acid-induced apoptosis is dependent on 15-lipoxygenase-1 expression and function.", "cite_spans": [{"start": 469, "end": 473, "text": "(13)", "ref_id": "BIBREF12"}, {"start": 541, "end": 545, "text": "(14)", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "MATERIALS AND METHODS", "text": "Cell Culture. The human colorectal cell lines Caco-2, HCT-116, and SW-480 were obtained from the American Type Culture Collection and were grown at 37\u00b0C in a humidified 5% CO 2 /95% air atmosphere. The Caco-2 cells were grown in Eagle's minimal essential medium (1\u03eb; Life Technologies, Inc., Carlsbad, CA) with L-glutamine supplemented with 15% fetal bovine serum, 1 mmol/L sodium pyruvate (Life Technologies, Inc., and 1 mg/100 mL gentamicin (Life Technologies, Inc.). The HCT-116 and SW-480 cells were grown in RPMI media supplemented with 10% fetal bovine serum. Trypsin (Life Technologies, Inc.) was used to subculture cells.", "cite_spans": [], "ref_spans": []}, {"section": "MATERIALS AND METHODS", "text": "Treatment with HDAC Inhibitors. NaBT (Sigma, St. Louis, MO) was dissolved in PBS, and suberoylanilide hydroxamic acid was dissolved in DMSO. Cells were treated from 0 to 4 days and at the doses indicated. Treatment groups were compared with vehicle controls. Caffeic acid, a 15-lipoxygenase-1 inhibitor, was used at a concentration of 2.2 mol/L. The specificity of this concentration has been previously established for inhibiting 15-lipoxygenase-1 in colorectal cancer cells (15) . Nordihydroguaiaretic acid, a general lipoxygenase inhibitor, was used at a concentration of 10 mol/L. Cells were harvested at the various time points indicated.", "cite_spans": [{"start": 476, "end": 480, "text": "(15)", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "MATERIALS AND METHODS", "text": "Western Blot Analysis of 15-Lipoxygenase-1 Protein. In general, SDS-PAGE and Western blotting techniques were carried out as described previously (16) . Briefly, treated and control cells groups were washed twice with ice-cold PBS and lysed in protein lysis buffer containing protease and phosphatase inhibitors. Cells were sonicated three times for 5 seconds each at 50% power for a total protein preparation. Protein content was quantified by the Bradford method as described previously (16) . Aliquots of the protein preparation were heated to 70\u00b0C in protein sample buffer (Invitrogen, Carlsbad, CA) and separated by a 4 to 12% gradient gel (Invitrogen), according to the manufacturer's instructions. Proteins were transferred onto nitrocellulose membrane (Invitrogen). Blots were blocked with 10% nonfat dry milk in 20 mmol/L Tris-buffered saline (pH 7.4) containing 0.05% Tween 20 (TBS-T) and washed. The blots were then incubated in 1% milk in TBS-T with an appropriate primary antibody. Rabbit polyclonal antiserum to recombinant human 15-lipoxygenase-1 was a gift from Mary Mulkins and Elloit Sigal (Roche Bioscience, Palo Alto, CA) and was also generated by Lampire Biological Laboratories (Pipersville, PA). The 15-lipoxygenase-1 primary antibody was used at a dilution of 1:2000. Normal human tracheobronchial epithelial cells, as previously described (16) , were used as a positive control for the expression of 15-lipoxygenase-1. Actin antibody (Sigma) was used at a dilution of 1:2000. Actin was analyzed as a control for protein loading. After washing, blots were incubated with an appropriate horseradish peroxidaselinked secondary antibody (Amersham, Piscataway, NJ). After reaction with chemiluminescence reagents (Amersham enhanced chemiluminescence system), bands were detected by exposure to film (Amersham).", "cite_spans": [{"start": 146, "end": 150, "text": "(16)", "ref_id": "BIBREF15"}, {"start": 489, "end": 493, "text": "(16)", "ref_id": "BIBREF15"}, {"start": 1364, "end": 1368, "text": "(16)", "ref_id": "BIBREF15"}], "ref_spans": []}, {"section": "ELISA Measurement of 13-S-Hydroxyoctadecadienoic Acid Levels.", "text": "After treatment with suberoylanilide hydroxamic acid, cells were lysed in lysis buffer containing protease and phosphatase inhibitors. The protein concentration was determined by Bradford's method. 13-S-Hydroxyoctadecadienoic acid levels were determined with an ELISA kit (Assay Design, Ann Arbor, MI) according to the manufacturer's specifications. 13-S-Hydroxyoctadecadienoic acid concentrations were expressed as nanograms per microgram of crude protein.", "cite_spans": [], "ref_spans": []}, {"section": "ELISA Measurement of 13-S-Hydroxyoctadecadienoic Acid Levels.", "text": "Cellular Proliferation. Cells were grown in 100-mm plates and treated with compounds of interest or vehicle at indicated concentrations and for 0 to 96 hours. Cells were harvested and counted at the indicated time points. Growth curves were plotted with the number of attached cells at the time of harvesting. Cellular Differentiation. Cell differentiation was assessed by measuring the enzymatic activity of alkaline phosphates. Cell lysates were prepared after 0, 24, 48, 72, and 96 hours of incubation with suberoylanilide hydroxamic acid. Cells were lysed in lysis buffer containing protease and phosphatase inhibitors. The protein concentration was measured by Bradford's method. Alkaline phosphatase activity, a marker for differentiation, was used to assess differentiation. An alkaline phosphatase kit (Pointe Scientific, Inc., Lincoln Park, MI) was used according to the manufacturer's specifications.", "cite_spans": [], "ref_spans": []}, {"section": "ELISA Measurement of 13-S-Hydroxyoctadecadienoic Acid Levels.", "text": "DNA Fragmentation Assay. After treatment of interest, floating and attached cells were harvested at the indicated time points. Washed cell pellets were resuspended in cell lysis buffer [10 mmol/L Tris-HCl (pH7.4), 10 mmol/L EDTA (pH 8.0), 0.5% TritonX-100] and incubated for 10 minutes at 4\u00b0C. Cell lysates were centrifuged and then Rnase A (0.5 mg/mL) and proteinase K (0.5 mg/mL) were added and incubated for 2 hours at 37\u00b0C. DNA was extracted from an equal number of cells and then was precipitated by etomidate and run on a 2% agarose gel as described previously (15) . Agarose gels were stained with etomidate and DNA visualized by an UV transilluminater.", "cite_spans": [{"start": 567, "end": 571, "text": "(15)", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "ELISA Measurement of 13-S-Hydroxyoctadecadienoic Acid Levels.", "text": "Caspase 3 Assay. After treatment of interest, floating and attached cells were harvested at the indicated time points. Cells were counted and an equal number of cells were used for each sample with a Caspase 3 kit (BD Biosciences Clontech, Palo Alto, CA) according to the manufacturer's protocol.", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS", "text": "Suberoylanilide Hydroxamic Acid Effects on 15-Lipoxygenase-1 Expression in Colon Cancer Cells. Three different colorectal cancer cell lines, Caco-2, SW-480, and HCT-116, were found to express 15-lipoxygenase-1 after treatment with suberoylanilide hydroxamic acid (data not shown). We have selected the Caco-2 cell line for all subsequent experiments to study the effect of 15-lipoxygenase-1 on apoptosis because of its ability to undergo terminal differentiation. The induction of 15-lipoxygenase-1 by suberoylanilide hydroxamic acid was both dose and time dependent (Fig. 1) . Caco-2 cells were treated with varying concentration of suberoylanilide hydroxamic acid ranging from 0.1 to 10 mol/L for 24 hours. An increase in 15-lipoxygenase-1 was observed at concentrations as low as 1 mol/L but was strongly expressed at 2.5 mol/L and higher. The cells were also treated with 2.5 mol/L suberoylanilide hydroxamic acid for 0 to 96 hours, and 15-lipoxygenase-1 expression was determined (Fig. 1B) . 15-Lipoxygenase-1 was observed as early as 12 hours, and expression increased at 24 hours and remained at later time points.", "cite_spans": [], "ref_spans": [{"start": 567, "end": 575, "text": "(Fig. 1)", "ref_id": "FIGREF0"}, {"start": 985, "end": 994, "text": "(Fig. 1B)", "ref_id": "FIGREF0"}]}, {"section": "RESULTS", "text": "Suberoylanilide Hydroxamic Acid Effects on 13-S-Hydroxyoctadecadienoic Acid Formation. 13-S-Hydroxyoctadecadienoic acid is the primary metabolite of 15-lipoxygenase-1. To determine whether the suberoylanilide hydroxamic acid-induced expression of 15-lipoxygenase-1 also increased 13-S-hydroxyoctadecadienoic acid levels, 13-S-hydroxyoctadecadienoic acid was measured in treated and untreated cells. Treatment of Caco-2 cells with suberoylanilide hydroxamic acid for 24 hours increased endogenous 13-S-hydroxyoctadecadienoic acid levels by 2-fold compared with untreated control cells (Fig. 2) . Furthermore, the 13-S-hydroxyoctadecadienoic acid levels were reduced upon addition of 15-lipoxygenase-1 inhibitors caffeic acid (2.2 mol/L; ref. 15) or the more general lipoxygenase inhibitor nordihydroguaiaretic acid (10 mol/L).", "cite_spans": [{"start": 741, "end": 744, "text": "15)", "ref_id": "BIBREF14"}], "ref_spans": [{"start": 584, "end": 592, "text": "(Fig. 2)", "ref_id": "FIGREF1"}]}, {"section": "RESULTS", "text": "Effect of 15-Lipoxygenase-1 Inhibition on Cell Growth. Caco-2 cells were treated with suberoylanilide hydroxamic acid or suberoylanilide hydroxamic acid plus caffeic acid for 0 -96 h and cell growth examined. At 72 and 96 h, suberoylanilide hydroxamic acid reduced the cell count by 45% and 54% respectively compared with untreated control cells (Fig. 3) . Inhibiting 15-lipoxygenase-1 activity with caffeic acid (2.2 mol/L) attenuated the suberoylanilide hydroxamic acid-induced cell count reduction. Caffeic acid alone did not affect cell growth (data not shown). ", "cite_spans": [], "ref_spans": [{"start": 346, "end": 354, "text": "(Fig. 3)", "ref_id": "FIGREF2"}]}, {"section": "Effects of 15-Lipoxygenase-1 Inhibition on Suberoylanilide Hydroxamic Acid-induced Cellular Differentiation and Apoptosis.", "text": "To determine whether 15-lipoxygenase-1 is involved in suberoylanilide hydroxamic acid-induced differentiation, alkaline phosphatase activity, a marker for differentiation, was measured in Caco-2 cells treated with suberoylanilide hydroxamic acid or suberoylanilide hydroxamic acid plus caffeic acid for 0 to 96 hours. Treatment of the cells with suberoylanilide hydroxamic acid resulted in an increase in alkaline phosphatase activity over time compared with untreated control cells (Fig. 4A) . Inhibition of 15-lipoxygenase-1 activity with caffeic acid attenuated this effect.", "cite_spans": [], "ref_spans": [{"start": 483, "end": 492, "text": "(Fig. 4A)", "ref_id": "FIGREF3"}]}, {"section": "Effects of 15-Lipoxygenase-1 Inhibition on Suberoylanilide Hydroxamic Acid-induced Cellular Differentiation and Apoptosis.", "text": "To determine whether 15-lipoxygenase-1 also plays a role in suberoylanilide hydroxamic acid-induced apoptosis, DNA fragmentation assays were used to assess apoptosis in cells treated with suberoylanilide hydroxamic acid or suberoylanilide hydroxamic acid plus caffeic acid. At 72 hours, DNA laddering was observed for cells treated with suberoylanilide hydroxamic acid (Fig. 4B) . Inhibition of 15-lipoxygenase-1 with caffeic acid blocked the suberoylanilide hydroxamic acid-induced DNA laddering. No laddering was observed for untreated control cells or for cells treated with caffeic acid alone. Similar results were observed at 96 hours of treatment (data not shown). Suberoylanilide hydroxamic acid-induced apoptosis and its inhibition by caffeic acid were also confirmed by measuring caspase 3 activity. At 72 hours, caspase 3 activity of Caco-2 cells treated with suberoylanilide hydroxamic acid increased over 3.7-fold compared with untreated control cells (Fig. 4C) . Inhibition of 15-lipoxygenase-1 activity with caffeic acid attenuated the caspase 3 activity. Similar results were observed at 96 hours of treatment (data not shown).", "cite_spans": [], "ref_spans": [{"start": 369, "end": 378, "text": "(Fig. 4B)", "ref_id": "FIGREF3"}, {"start": 964, "end": 973, "text": "(Fig. 4C)", "ref_id": "FIGREF3"}]}, {"section": "DISCUSSION", "text": "The present study is the first to establish that HDAC inhibitorinduced apoptosis and 15-lipoxygenase-1 expression are linked mechanistically. We found that the HDAC inhibitor suberoylanilide hydroxamic acid induced 15-lipoxygenase-1 expression in a dose-and time-dependent manner and induced growth arrest and apoptosis. This is the first study to show a relationship between suberoylanilide hydroxamic acid and 15-lipoxygenase-1 expression. Inhibition of 15-lipoxygenase-1 with 2.2 mol/L caffeic acid, a concentration shown to be specific for 15-lipoxygenase-1 inhibition, resulted in the attenuation of the suberoylanilide hydroxamic acid-induced effects of growth inhibition, apoptosis, and, possibly, differentiation. The induction of 15-lipoxygenase-1 expression, which is suppressed in colon tumor cells, likely will play an important role in the potential clinical effects of suberoylanilide hydroxamic acid in colorectal cancer prevention and therapy.", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "Suberoylanilide hydroxamic acid is one of a number of chemically diverse agents, including the short chain fatty acid NaBT, that can inhibit HDAC activity. NaBT is an extensively studied low-potency HDAC inhibitor that has antitumor activity and can induce differentiation and apoptosis in various cancer cell lines. In human colorectal carcinoma Caco-2 cells, Kamitani et al. (14) found that NaBT induces the expression of 15-lipoxygenase-1 and differentiation and apoptosis. Although this study provided the first evidence that a HDAC inhibitor can upregulate 15-lipoxygenase-1 expression in human colorectal carcinoma cells, it did not establish a mechanistic link between 15-lipoxygenase-1 and HDAC inhibitor-induced differentiation and apoptosis. The authors did speculate that 15-lipoxygenase-1 induction may have been associated with differentiation and apoptosis after treatment with 5 mmol/L NaBT. Kamitani et al. (14) used the nonspecific lipoxygenase inhibitor nordihydroguaiaretic acid to assess the relationship of 15-lipoxygenase-1 with differentiation and apoptosis. Furthermore, nordihydroguaiaretic acid also can influence the redox state of cells. Because nordihydroguaiaretic acid can influence other lipoxygenases (besides 15-lipoxygenase-1) and the redox state, the authors concluded that the importance of 15-lipoxygenase-1 expression in the mechanism of NaBT-induced differentiation and apoptosis was not clear. Building on these findings, our presently reported results based on the specific inhibition of 15-lipoxygenase-1 show for the first time that HDAC inhibitor-induced apoptosis is mechanistically linked to 15-lipoxygenase-1. We also used the more clinically relevant HDAC inhibitor suberoylanilide hydroxamic acid at clinically achievable concentrations.", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "A broad spectrum of transformed cells are sensitive to suberoylanilide hydroxamic acid-induced growth inhibition in in vitro and in vivo studies (1) . Suberoylanilide hydroxamic acid is in phase I and II clinical trials for the treatment of various cancers and has shown anticancer activity at doses that are well tolerated by patients (11, 12) . These preclinical results and the clinical trials show that suberoylanilide hydroxamic acid targets transformed cells in preference to normal cells (9) .", "cite_spans": [{"start": 145, "end": 148, "text": "(1)", "ref_id": "BIBREF0"}, {"start": 336, "end": 340, "text": "(11,", "ref_id": "BIBREF10"}, {"start": 341, "end": 344, "text": "12)", "ref_id": "BIBREF11"}, {"start": 495, "end": 498, "text": "(9)", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "DISCUSSION", "text": "The inhibition of HDAC by suberoylanilide hydroxamic acid occurs through a direct interaction with the catalytic site of the enzyme as shown by X-ray crystallography studies (17) . Inhibition of HDAC activity results in the accumulation of acetylated histones H2a, H2b, H3, and H4. The result of HDAC inhibition is believed not to have a generalized effect on the genome but rather only effects the transcription of a small subset of the genome (18) . Evidence provided by DNA microarrays with malignant cell lines cultured with a HDAC inhibitor shows that there are a small (1 to 2%) number of genes of which the products are altered (7, 18, 19) . From this study and others (14) , it appears that 15-lipoxygenase-1 is among the few genes altered by HDACs in colorectal carcinoma cells.", "cite_spans": [{"start": 174, "end": 178, "text": "(17)", "ref_id": "BIBREF16"}, {"start": 445, "end": 449, "text": "(18)", "ref_id": "BIBREF17"}, {"start": 635, "end": 638, "text": "(7,", "ref_id": "BIBREF6"}, {"start": 639, "end": 642, "text": "18,", "ref_id": "BIBREF17"}, {"start": 643, "end": 646, "text": "19)", "ref_id": "BIBREF18"}, {"start": 676, "end": 680, "text": "(14)", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "DISCUSSION", "text": "We have investigated the effect of suberoylanilide hydroxamic acid on human colorectal cancer cell lines. We have shown that suberoylanilide hydroxamic acid can induce 15-lipoxygenase-1 expression in colorectal cancer cells and that inhibition of 15-lipoxygenase-1 can attenuate the effects of suberoylanilide hydroxamic acid in these cells. These findings indicate an important role for 15-lipoxygenase-1 in mediating suberoylanilide hydroxamic acid-induced and, more generally, HDAC inhibitor-induced growth inhibition, differentiation, and apoptosis in colorectal cancer cells. Furthermore, suberoylanilide hydroxamic acid can induce 15-lipoxygenase-1 at concentrations in the low micromolar range in comparison to NaBT, which has been reported to induce 15-lipoxygenase-1 with 5 mmol/L concentration range. Although appearing to have antitumor activity, NaBT has been hampered in its clinical development by a short half-life (5 minutes) and the inability to achieve a therapeutic level in plasma. The fact that suberoylanilide hydroxamic acid can induce 15-lipoxygenase-1 in the 1 to 2 mol/L concentration range is of clinical relevance and may also explain in part the success of suberoylanilide hydroxamic acid as a therapeutic agent in treatment of colon cancer.", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "The present study shows that the induction of 15-lipoxygenase-1 expression is involved mechanistically in suberoylanilide hydroxamic acid-induced growth arrest and apoptosis in colorectal cancer cells. Establishing this mechanistic link emphasizes the importance of future investigations of the mechanisms by which HDAC inhibitors such as suberoylanilide hydroxamic acid up-regulate 15-lipoxygenase-1. These mechanisms remain unknown and could occur at the transcriptional and/or posttranslational levels because 15-lipoxygenase-1 regulation occurs at both levels (20, 21) . Additional mechanistic studies of 15-lipoxygenase-1 regulation in colorectal cancer cells potentially will advance the development of effective agents for colorectal cancer prevention and therapy.", "cite_spans": [{"start": 564, "end": 568, "text": "(20,", "ref_id": "BIBREF19"}, {"start": 569, "end": 572, "text": "21)", "ref_id": "BIBREF20"}], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Histone deacetylases and cancer: causes and therapies", "authors": [{"first": "P", "middle": ["A"], "last": "Marks", "suffix": ""}, {"first": "R", "middle": ["A"], "last": "Rifkind", "suffix": ""}, {"first": "V", "middle": ["M"], "last": "Richon", "suffix": ""}, {"first": "R", "middle": [], "last": "Breslow", "suffix": ""}, {"first": "T", "middle": [], "last": "Miller", "suffix": ""}, {"first": "W", "middle": ["K"], "last": "Kelly", "suffix": ""}], "year": 2001, "venue": "Nat Rev Cancer", "link": "205023725"}, "BIBREF1": {"title": "Histone acetylases and deacetylases in cell proliferation", "authors": [{"first": "T", "middle": [], "last": "Kouzarides", "suffix": ""}], "year": 1999, "venue": "Curr Opin Genet Dev", "link": "22159789"}, "BIBREF2": {"title": "Histone deacetylase inhibitors: inducers of differentiation or apoptosis of transformed cells", "authors": [{"first": "P", "middle": ["A"], "last": "Marks", "suffix": ""}, {"first": "V", "middle": ["M"], "last": "Richon", "suffix": ""}, {"first": "R", "middle": ["A"], "last": "Rifkind", "suffix": ""}], "year": 2000, "venue": "J Natl Cancer Inst (Bethesda)", "link": "16960573"}, "BIBREF3": {"title": "Second generation hybrid polar compounds are potent inducers of transformed cell differentiation", "authors": [{"first": "Webb", "middle": ["Y"], "last": "Richonvm", "suffix": ""}, {"first": "R", "middle": [], "last": "Merger", "suffix": ""}], "year": 1996, "venue": "Proc Natl Acad Sci", "link": "7490997"}, "BIBREF4": {"title": "A class of hybrid polar inducers of transformed cell differentiation inhibits histone deacetylases", "authors": [{"first": "V", "middle": ["M"], "last": "Richon", "suffix": ""}, {"first": "S", "middle": [], "last": "Emiliani", "suffix": ""}, {"first": "E", "middle": [], "last": "Verdin", "suffix": ""}], "year": 1998, "venue": "Proc Natl Acad Sci", "link": "41040992"}, "BIBREF5": {"title": "Suberoylanilide hydroxamic acid, an inhibitor of histone deacetylase, suppresses the growth of prostate cancer cells in vitro and in vivo", "authors": [{"first": "L", "middle": ["M"], "last": "Butler", "suffix": ""}, {"first": "D", "middle": ["B"], "last": "Agus", "suffix": ""}, {"first": "H", "middle": ["I"], "last": "Scher", "suffix": ""}], "year": 2000, "venue": "Cancer Res", "link": "3075764"}, "BIBREF6": {"title": "The histone deacetylase inhibitor suberoylanilide hydroxamic acid induces differentiation of human breast cancer cells", "authors": [{"first": "P", "middle": ["N"], "last": "Munster", "suffix": ""}, {"first": "T", "middle": [], "last": "Troso-Sandoval", "suffix": ""}, {"first": "N", "middle": [], "last": "Rosen", "suffix": ""}, {"first": "R", "middle": [], "last": "Rifkind", "suffix": ""}, {"first": "P", "middle": ["A"], "last": "Marks", "suffix": ""}, {"first": "V", "middle": ["M"], "last": "Richon", "suffix": ""}], "year": 2001, "venue": "Cancer Res", "link": "10719953"}, "BIBREF7": {"title": "Inhibition of transformed cell growth and induction of cellular differentiation by pyroxamide, an inhibitor of histone deacetylase", "authors": [{"first": "L", "middle": ["M"], "last": "Butler", "suffix": ""}, {"first": "Y", "middle": [], "last": "Webb", "suffix": ""}, {"first": "D", "middle": ["B"], "last": "Agus", "suffix": ""}], "year": 2001, "venue": "Clin Cancer Res", "link": "18450045"}, "BIBREF8": {"title": "Anti-tumour activity in vitro and in vivo of selective differentiating agents containing hydroxamate", "authors": [{"first": "L", "middle": [], "last": "Qiu", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Kelso", "suffix": ""}, {"first": "C", "middle": [], "last": "Hansen", "suffix": ""}, {"first": "M", "middle": ["L"], "last": "West", "suffix": ""}, {"first": "D", "middle": ["P"], "last": "Fairlie", "suffix": ""}, {"first": "P", "middle": ["G"], "last": "Parsons", "suffix": ""}], "year": 1999, "venue": "Br J Cancer", "link": "18983926"}, "BIBREF9": {"title": "Histone deacetylase inhibitors induce remission in transgenic models of therapy-resistant acute promyelocytic leukemia", "authors": [{"first": "L", "middle": ["Z"], "last": "He", "suffix": ""}, {"first": "T", "middle": [], "last": "Tolentino", "suffix": ""}, {"first": "P", "middle": [], "last": "Grayson", "suffix": ""}], "year": 2001, "venue": "J Clin Investig", "link": "25934271"}, "BIBREF10": {"title": "Histone deacetylase inhibitors: from target to clinical trials", "authors": [{"first": "W", "middle": ["K"], "last": "Kelly", "suffix": ""}, {"first": "O", "middle": ["A"], "last": "O&apos;connor", "suffix": ""}, {"first": "P", "middle": ["A"], "last": "Marks", "suffix": ""}], "year": 2002, "venue": "Exp Opin Investig Drugs", "link": null}, "BIBREF11": {"title": "Phase I clinical trial of histone deacetylase inhibitor: suberoylanilide hydroxamic acid administered intravenously", "authors": [{"first": "W", "middle": ["K"], "last": "Kelly", "suffix": ""}, {"first": "V", "middle": ["M"], "last": "Richon", "suffix": ""}, {"first": "O&apos;", "middle": [], "last": "Connor", "suffix": ""}, {"first": "O", "middle": [], "last": "", "suffix": ""}], "year": 2003, "venue": "Clin Cancer Res", "link": "16892013"}, "BIBREF12": {"title": "Induction of caspase-3 protease activity and apoptosis by butyrate and trichostatin A (inhibitors of histone deacetylase): dependence on protein synthesis and synergy with a mitochondrial/cytochrome c-dependent pathway", "authors": [{"first": "V", "middle": [], "last": "Medina", "suffix": ""}, {"first": "B", "middle": [], "last": "Edmonds", "suffix": ""}, {"first": "G", "middle": ["P"], "last": "Young", "suffix": ""}, {"first": "R", "middle": [], "last": "James", "suffix": ""}, {"first": "S", "middle": [], "last": "Appleton", "suffix": ""}, {"first": "P", "middle": ["D"], "last": "Zalewski", "suffix": ""}], "year": 1997, "venue": "Cancer Res", "link": "25482301"}, "BIBREF13": {"title": "Expression of 15-lipoxygenase by human colorectal carcinoma Caco-2 cells during apoptosis and cell differentiation", "authors": [{"first": "H", "middle": [], "last": "Kamitani", "suffix": ""}, {"first": "M", "middle": [], "last": "Geller", "suffix": ""}, {"first": "T", "middle": [], "last": "Eling", "suffix": ""}], "year": 1998, "venue": "J Biol Chem", "link": "29115230"}, "BIBREF14": {"title": "15-LOX-1: a novel molecular target of nonsteroidal anti-inflammatory drug-induced apoptosis in colorectal cancer cells", "authors": [{"first": "I", "middle": [], "last": "Shureiqi", "suffix": ""}, {"first": "D", "middle": [], "last": "Chen", "suffix": ""}, {"first": "J", "middle": ["J"], "last": "Lee", "suffix": ""}], "year": 2000, "venue": "J Natl Cancer Inst (Bethesda)", "link": "33203674"}, "BIBREF15": {"title": "15-Lipoxygenase-1 metabolites down-regulate peroxisome proliferators-activated receptor gamma via the MAPK signaling pathway", "authors": [{"first": "L", "middle": ["C"], "last": "Hsi", "suffix": ""}, {"first": "L", "middle": ["C"], "last": "Wilson", "suffix": ""}, {"first": "T", "middle": ["E"], "last": "Eling", "suffix": ""}], "year": 2002, "venue": "J Biol Chem", "link": "32921004"}, "BIBREF16": {"title": "Structures of a histone deacetylase homologue bound to the TSA and SAHA inhibitors", "authors": [{"first": "M", "middle": ["S"], "last": "Finnin", "suffix": ""}, {"first": "J", "middle": ["R"], "last": "Donigian", "suffix": ""}, {"first": "A", "middle": [], "last": "Cohen", "suffix": ""}], "year": 1999, "venue": "Nature (Lond.)", "link": "4430326"}, "BIBREF17": {"title": "The expression of a small fraction of cellular genes is changed in response to histone hyperacetylation", "authors": [{"first": "C", "middle": [], "last": "Van Lint", "suffix": ""}, {"first": "S", "middle": [], "last": "Emiliani", "suffix": ""}, {"first": "E", "middle": [], "last": "Verdin", "suffix": ""}], "year": 1996, "venue": "Gene Expr", "link": "25860330"}, "BIBREF18": {"title": "Histone deacetylase inhibitor selectively induces p21WAF1 expression and gene-associated histone acetylation", "authors": [{"first": "V", "middle": ["M"], "last": "Richon", "suffix": ""}, {"first": "T", "middle": ["W"], "last": "Sandhoff", "suffix": ""}, {"first": "R", "middle": ["A"], "last": "Rifkind", "suffix": ""}, {"first": "P", "middle": ["A"], "last": "Marks", "suffix": ""}], "year": 2000, "venue": "Proc Natl Acad Sci", "link": "10490439"}, "BIBREF19": {"title": "A GATA binding site is involved in the regulation of 15-lipoxygense-1 expression in human colorectal carcinoma cell line Caco-2", "authors": [{"first": "H", "middle": [], "last": "Kamitani", "suffix": ""}, {"first": "H", "middle": [], "last": "Kameda", "suffix": ""}, {"first": "U", "middle": ["P"], "last": "Kelavkar", "suffix": ""}, {"first": "T", "middle": ["E"], "last": "Eling", "suffix": ""}], "year": 2000, "venue": "FEBS Lett", "link": "7693474"}, "BIBREF20": {"title": "GATA-6 transcriptional regulation of 15-lipoxygenase-1 during NSAID-induced apoptosis in colorectal cancer cells", "authors": [{"first": "I", "middle": [], "last": "Shureiqi", "suffix": ""}, {"first": "W", "middle": [], "last": "Jiang", "suffix": ""}, {"first": "S", "middle": ["M"], "last": "Fischer", "suffix": ""}], "year": 2002, "venue": "Cancer Res", "link": "15803646"}}, "ref_entries": {"FIGREF0": {"text": "Fig. 1. Suberoylanilide hydroxamic acid (SAHA) effects on 15-lipoxygenase-1 (15-LOX-1) expression in Caco-2 cells. Western blot analysis of cell lysates demonstrated dose-and time-dependent induction of 15-LOX-1 by SAHA. Actin is a control for the amount of protein loaded. Thirty micrograms of total protein were loaded per lane. The data shown represents one of three separate experiments with similar results. A. Western blot analysis of cell lysates shows dose-dependent expression of 15-LOX-1 after treatment with SAHA for 24 hours. Lane 1, 15-LOX-1 standard; Lanes 2-8, SAHA-treated cells at 0.1, 0.5, 1, 2.5, 5, 10, and 25 mol/L, respectively. B. Western blot analysis of cell lysates shows time-dependent expression of 15-LOX-1 after treatment with 2.5 mol/L SAHA. Lane 1, 15-LOX-1 standard; Lanes 2-9, SAHA-treated cells at 0, 3, 6, 12, 24, 48, 72, and 96 hours, respectively.", "type": "figure"}, "FIGREF1": {"text": "Fig. 2. Suberoylanilide hydroxamic acid (SAHA) effects on 13-S-hydroxyoctadecadienoic acid (13-S-HODE) formation. 13-S-HODE levels were increased by SAHA. Addition of caffeic acid (CAF) inhibited these SAHA effects on 13-S-HODE levels. Cells were treated with SAHA (2.5 mol/L), SAHA (2.5 mol/L) \u03e9 CAF (2.2 mol/L), SAHA (2.5 mol/L) \u03e9 nordihydroguaiaretic acid (NDGA) (10 mol/L), or vehicle treated (control) for 24 hours and harvested. 13-S-HODE was extracted and measured by enzyme-linked assay. The data shown represents one of two separate experiments with similar results. 13-S-HODE levels are expressed as nanograms per microgram of crude protein. Values are means and 95% confidence intervals of the means. SAHA versus SAHA \u03e9 CAF, P \u03ed 0.027; SAHA versus SAHA \u03e9 NDGA, P \u03ed 0.018. 8779", "type": "figure"}, "FIGREF2": {"text": "Fig. 3. 15-Lipoxygenase-1 inhibition attenuates suberoylanilide hydroxamic acid (SAHA)-induced effects on cell growth. SAHA reduced the growth of Caco-2 cells with the extent of growth inhibition dependent on time. Caffeic acid (CAF) attenuated this effect. Cells were treated with SAHA (2.5 mol/L), SAHA (2.5 mol/L) \u03e9 CAF (2.2 mol/L), or vehicle treated (control) for 0 to 96 hours and harvested. Proliferation rates are represented as the number of attached cells at the time of harvesting. The data shown represents one of two separate experiments with similar results. Values shown are the means and 95% confidence intervals of the means. At 72 hours: control versus SAHA, P \u03ed 0.019; SAHA versus SAHA \u03e9 CAF, P \u03ed 0.024. \u216a, Control; \u1b5b, SAHA; \u215c, SAHA \u03e9 CAF.", "type": "figure"}, "FIGREF3": {"text": "Fig. 4. 15-Lipoxygenase-1 inhibition attenuates suberoylanilide hydroxamic acid (SAHA)-induced effects on cellular differentiation and apoptosis. A. Alkaline phosphatase activity was used as an indicator of differentiation. SAHA increased cellular differentiation of Caco-2 cells. Caffeic acid (CAF) attenuated this effect. Cells were treated with SAHA (2.5 mol/L), SAHA (2.5 mol/L) \u03e9 CAF (2.2 mol/L), or vehicle treated (control) for 0 to 96 hours and harvested. Alkaline phosphatase activity was measured. The data shown represents one of two separate experiments with similar results. Values shown are the means and 95% confidence intervals of the means. At 72 hours: control versus SAHA, P \u03ed 0.005; SAHA versus SAHA \u03e9 CAF, P \u03ed 0.004. B. SAHA-induced apoptosis was blocked by inhibition of 15-lipoxygenase-1 in Caco-2 cells as measured by DNA laddering. Cells were treated with SAHA (2.5 mol/L), SAHA (2.5 mol/L) \u03e9 CAF (2.2 mol/L), or vehicle treated (control) for 72 hours and harvested. DNA fragmentation assay was done. The data shown represents one of three separate experiments with similar results. Lane 1, control cells; Lane 2, SAHA plus CAF-treated cells; Lane 3, SAHA-treated cells. C. SAHA-induced apoptosis was blocked by inhibition of 15-lipoxygenase-1 in Caco-2 cells as measured by caspase 3 activity. Cells were treated with SAHA (2.5 mol/L), SAHA (2.5 mol/L) \u03e9 CAF (2.2 mol/L), or vehicle treated (control) for 72 hours and harvested. Caspase 3 activity was measured and is reported in arbitrary units. The data shown represents one of two separate experiments with similar results. Values shown are the means and 95% confidence intervals of the means. At 72 hours: control versus SAHA, P \u03ed 0.006; SAHA versus SAHA \u03e9 CAF, P \u03ed 0.012.", "type": "figure"}}}
{"paper_id": "10709089", "_pdf_hash": "fca79405705e2382a92c18a8234003271c6b889c", "abstract": [{"section": "Abstract", "text": "A 24-year-old male nonalcoholic patient with acute pancreatitis presented to the hospital with severe abdominal pain, nausea, and vomiting. At the time of presentation, his serum amylase and lipase levels were elevated with normal liver and renal function. Duplex Doppler (\u25baFig. 1a) showed the presence of a large pseudoaneurysm with to and fro color flow and characteristic yin-yang pattern in the pancreatic head region. Multiphase contrastenhanced computed tomography (CT) of the abdomen (\u25baFig. 1b-d) demonstrated a pseudoaneurysm in the pancreatic head region, measuring 63 \u00c2 46 \u00c2 40 mm with a thin rim of peripheral thrombus. In addition, features of pancreatitis were noted as well as a large pseudocyst in the pancreatic tail causing displacement of the stomach anteriorly.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "As open surgery was not the best option in acute pancreatitis, transarterial embolization was considered. Digital subtraction angiography (\u25baFig. 2) of the common hepatic artery showed the presence of a large pseudoaneurysm in the pancreatic head region, at the origin of the gastroduodenal artery. Despite superselective angiography of the gastroduodenal artery and proper hepatic artery in different projection, the neck of the pseudoaneurysm could not be identified. Since we were not able to identify the neck and the feeding artery to the pseudoaneurysm, transarterial embolization was not considered and percutaneous embolization with thrombin injection was chosen. A spinal needle (22 G) was inserted into the aneurysmal sac through the anterior abdominal wall under ultrasound (US) guidance (\u25baFig. 3a) and 1,000 IU of reconstituted human thrombin (ReliStat, Reliance Life Science) was injected. US demonstrated thrombus formation within the aneurysmal sac and at the end of injection, there was complete obliteration of the sac with no color flow seen. A repeat angiogram (\u25baFig. 3b) through the common hepatic artery showed no filling of the aneurysm. No immediate complications were observed. Follow-up abdominal CT (\u25baFig. 4b, c) at 1 week and Doppler US (\u25baFig. 4a) examination at 4 weeks confirmed complete thrombosis of the pseudoaneurysm with preserved flow through celiac arterial branches.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "\u25ba pancreatic pseudoaneurysm \u25ba percutaneous thrombin injection \u25ba pseudoaneurysm embolization", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Pancreatic pseudoaneurysm is a rare but life-threatening complication secondary to pancreatitis, surgery, trauma, or infection. Early treatment is advocated due to high risk of rupture and bleeding. Surgical treatment has traditionally been the first line but is associated with high morbidity. Transarterial embolization or exclusion is the treatment of choice; however, in cases with failure of endovascular treatment, percutaneous thrombin injection can be used successfully. We present a case of a large pancreatic pseudoaneurysm managed successfully with percutaneous ultrasound-guided thrombin injection after failure of transarterial management.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Case Report", "text": "A 24-year-old male nonalcoholic patient with acute pancreatitis presented to the hospital with severe abdominal pain, nausea, and vomiting. At the time of presentation, his serum amylase and lipase levels were elevated with normal liver and renal function. Duplex Doppler (\u25baFig. 1a) showed the presence of a large pseudoaneurysm with to and fro color flow and characteristic yin-yang pattern in the pancreatic head region. Multiphase contrastenhanced computed tomography (CT) of the abdomen (\u25baFig. 1b-d) demonstrated a pseudoaneurysm in the pancreatic head region, measuring 63 \u00c2 46 \u00c2 40 mm with a thin rim of peripheral thrombus. In addition, features of pancreatitis were noted as well as a large pseudocyst in the pancreatic tail causing displacement of the stomach anteriorly.", "cite_spans": [], "ref_spans": []}, {"section": "Case Report", "text": "As open surgery was not the best option in acute pancreatitis, transarterial embolization was considered. Digital subtraction angiography (\u25baFig. 2) of the common hepatic artery showed the presence of a large pseudoaneurysm in the pancreatic head region, at the origin of the gastroduodenal artery. Despite superselective angiography of the gastroduodenal artery and proper hepatic artery in different projection, the neck of the pseudoaneurysm could not be identified. Since we were not able to identify the neck and the feeding artery to the pseudoaneurysm, transarterial embolization was not considered and percutaneous embolization with thrombin injection was chosen. A spinal needle (22 G) was inserted into the aneurysmal sac through the anterior abdominal wall under ultrasound (US) guidance (\u25baFig. 3a) and 1,000 IU of reconstituted human thrombin (ReliStat, Reliance Life Science) was injected. US demonstrated thrombus formation within the aneurysmal sac and at the end of injection, there was complete obliteration of the sac with no color flow seen. A repeat angiogram (\u25baFig. 3b) through the common hepatic artery showed no filling of the aneurysm. No immediate complications were observed. Follow-up abdominal CT (\u25baFig. 4b, c) at 1 week and Doppler US (\u25baFig. 4a) examination at 4 weeks confirmed complete thrombosis of the pseudoaneurysm with preserved flow through celiac arterial branches.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Pancreatic pseudoaneurysm is a rare but life-threatening complication secondary to pancreatitis, surgery, trauma, or infection. Early treatment is advocated due to high risk of rupture and bleeding. Surgical treatment has traditionally been the first line but is associated with high morbidity. Transarterial embolization or exclusion is the treatment of choice; however, in cases with failure of endovascular treatment, percutaneous thrombin injection can be used successfully. We present a case of a large pancreatic pseudoaneurysm managed successfully with percutaneous ultrasound-guided thrombin injection after failure of transarterial management.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "Pseudoaneurysms have been reported in almost all the visceral arteries but are most commonly seen in the splenic artery (46%), followed by the renal (22%), hepatic (16.2%), pancreaticoduodenal (1.3%), and gastroduodenal artery (1.5%).", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "1 Pancreatic pseudoaneurysm is a rare complication of pancreatitis with lethal outcome if ruptured. Other causes include surgery, trauma, and infection. In pancreatitis, the most commonly affected artery is the splenic artery followed by the gastroduodenal artery and the pancreaticoduodenal arcade.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "2 Mortality secondary to the pseudoaneurysm depends on duration of the pancreatitis and the vessels involved. If ruptured, mortality rates range from 15 to 50%.", "cite_spans": [], "ref_spans": []}, {"section": "3", "text": "CT angiography of the abdomen is the investigation of choice to assess the severity of pancreatitis, arterial source of the pseudoaneurysm, and associated complications such as the pseudopancreatic cyst. Treatment of pancreatic pseudoaneurysm is either surgical or endovascular. Surgery is traditionally the first-line treatment but is invasive, more challenging, associated with high morbidity and therefore indicated in hemodynamically unstable patients, failed/recurrent pseudoaneurysm after transarterial treatment, and in the presence of necrotizing pancreatitis.", "cite_spans": [], "ref_spans": []}, {"section": "3", "text": "Transarterial endovascular treatment includes embolization using coils, N-butyl cyano acrylate, gelfoam, stent graft, and vascular plug. Transarterial coil placement is preferred with a reported success rate of 92 to 97% and lower overall rate of serious complications. 4, 5 Coil embolization of the aneurysm can be performed if entry into the sac is possible and the neck of aneurysm is narrow. Coiling of the feeding artery is another option especially if the pseudoaneurysm is arising from the gastroduodenal artery. N-butyl cyanoacrylate and gelfoam can be used either alone or in association with coiling. In our case, the neck of the pseudoaneurysm could not identified despite obtaining angiography on different projections, hence aneurysmal coiling was not performed. Also, the feeding artery could not be identified. An alternative option to transarterial management of the pseudoaneurysm is the percutaneous embolization by thrombin injection under US or CT guidance.", "cite_spans": [{"start": 270, "end": 272, "text": "4,", "ref_id": "BIBREF3"}, {"start": 273, "end": 274, "text": "5", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "3", "text": "Thrombin injection is traditionally used for the treatment of an iatrogenic femoral artery pseudoaneurysm. In 1986, Cope and Zeit first reported the use of percutaneous thrombin injection for the treatment of aneurysms. 6 In recent years, it is also used for percutaneously accessible visceral artery pseudoaneurysm. 7 One report described the use of thrombin injection for treatment of a large pseudoaneurysm measuring 60 \u00c2 44 \u00c2 45 mm and arising from the superior mesenteric artery. 8 Thrombin is a clotting factor formed from prothrombin and allows polymerization of fibrinogen to form fibrin. Percutaneous injection of thrombin is safe if it is injected slowly according to the flow and size of the pseudoaneurysm. Nontarget embolization is one of the common complications associated with thrombin injection. The other potential complication associated with thrombin injection is anaphylaxis; however, with the use of human thrombin, the risk of anaphylaxis has markedly reduced. Furthermore, US-guided injection allows real-time visualization of the needle track and reduces the risk of accidental puncture of the bowel, vessels, and organs. The incidence of recurrent hemorrhage following embolization of pancreatic pseudoaneurysms has been reported to be as high as 30%; therefore, long-term follow-up is necessary in these patients.", "cite_spans": [{"start": 220, "end": 221, "text": "6", "ref_id": "BIBREF5"}, {"start": 317, "end": 318, "text": "7", "ref_id": "BIBREF6"}, {"start": 485, "end": 486, "text": "8", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "10", "text": "In conclusion, percutaneous US-guided thrombin injection could be the first-line treatment following failure of transarterial embolization or when cannulation or identification of the feeding arteries of the pseudoaneurysm is difficult. ", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Aneurysm of the visceral arteries", "authors": [{"first": "R", "middle": ["A"], "last": "Deterling", "suffix": ""}], "year": 1971, "venue": "J Cardiovasc Surg (Torino)", "link": "35837407"}, "BIBREF1": {"title": "Haemorrhagic complications of pancreatitis: presentation, diagnosis and management", "authors": [{"first": "B", "middle": ["J"], "last": "Ammori", "suffix": ""}, {"first": "M", "middle": [], "last": "Madan", "suffix": ""}, {"first": "D", "middle": ["J"], "last": "Alexander", "suffix": ""}], "year": 1998, "venue": "Ann R Coll Surg Engl", "link": "41834120"}, "BIBREF2": {"title": "Treatment of pancreatic pseudoaneurysm with percutaneous transabdominal thrombin injection", "authors": [{"first": "J", "middle": ["R"], "last": "Manazer", "suffix": ""}, {"first": "J", "middle": ["R"], "last": "Monzon", "suffix": ""}, {"first": "P", "middle": ["A"], "last": "Dietz", "suffix": ""}, {"first": "R", "middle": [], "last": "Moglia", "suffix": ""}, {"first": "M", "middle": [], "last": "Gold", "suffix": ""}], "year": 2003, "venue": "J Vasc Surg", "link": "9925070"}, "BIBREF3": {"title": "Endovascular treatment of visceral artery aneurysms", "authors": [{"first": "A", "middle": [], "last": "Gabelmann", "suffix": ""}, {"first": "J", "middle": [], "last": "G\u00f6rich", "suffix": ""}, {"first": "E", "middle": ["M"], "last": "Merkle", "suffix": ""}], "year": 2002, "venue": "J Endovasc Ther", "link": "24623756"}, "BIBREF4": {"title": "The endovascular management of visceral artery aneurysms and pseudoaneurysms", "authors": [{"first": "N", "middle": [], "last": "Tulsyan", "suffix": ""}, {"first": "V", "middle": ["S"], "last": "Kashyap", "suffix": ""}, {"first": "R", "middle": ["K"], "last": "Greenberg", "suffix": ""}], "year": 2007, "venue": "J Vasc Surg", "link": "12110230"}, "BIBREF5": {"title": "Coagulation of aneurysms by direct percutaneous thrombin injection", "authors": [{"first": "C", "middle": [], "last": "Cope", "suffix": ""}, {"first": "R", "middle": [], "last": "Zeit", "suffix": ""}], "year": 1986, "venue": "AJR Am J Roentgenol", "link": "26196112"}, "BIBREF6": {"title": "Expanded indications for ultrasound-guided thrombin injection of pseudoaneurysms", "authors": [{"first": "S", "middle": ["S"], "last": "Kang", "suffix": ""}, {"first": "N", "middle": [], "last": "Labropoulos", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Mansour", "suffix": ""}], "year": 2000, "venue": "J Vasc Surg", "link": "34402790"}, "BIBREF7": {"title": "Percutaneous thrombin embolization of a pancreatico-duodenal artery pseudoaneurysm after failing of the endovascular treatment", "authors": [{"first": "G", "middle": [], "last": "Barbiero", "suffix": ""}, {"first": "M", "middle": [], "last": "Battistel", "suffix": ""}, {"first": "A", "middle": [], "last": "Susac", "suffix": ""}, {"first": "D", "middle": [], "last": "Miotto", "suffix": ""}], "year": 2014, "venue": "World J Radiol", "link": "21833576"}, "BIBREF8": {"title": "Human thrombin injection for the percutaneous treatment of iatrogenic pseudoaneurysms", "authors": [{"first": "J", "middle": [], "last": "Elford", "suffix": ""}, {"first": "C", "middle": [], "last": "Burrell", "suffix": ""}, {"first": "S", "middle": [], "last": "Freeman", "suffix": ""}, {"first": "C", "middle": [], "last": "Roobottom", "suffix": ""}], "year": 2002, "venue": "Cardiovasc Intervent Radiol", "link": "1218583"}, "BIBREF9": {"title": "Aneurysms of the pancreaticoduodenal arteries: a change in management", "authors": [{"first": "D", "middle": ["P"], "last": "Coll", "suffix": ""}, {"first": "R", "middle": [], "last": "Ierardi", "suffix": ""}, {"first": "M", "middle": ["D"], "last": "Kerstein", "suffix": ""}, {"first": "S", "middle": [], "last": "Yost", "suffix": ""}, {"first": "A", "middle": [], "last": "Wilson", "suffix": ""}, {"first": "T", "middle": [], "last": "Matsumoto", "suffix": ""}], "year": 1998, "venue": "Ann Vasc Surg", "link": "24947702"}}, "ref_entries": {"FIGREF0": {"text": "Fig. 1 (a) Ultrasound with color Doppler showing large pseudoaneurysm with characteristic yin-yang color flow. CT angiography of abdomen in (b) axial and (c) coronal planes and (d) VRT images show large arterial phase enhancing pseudoaneurysm in the pancreatic head region. Also, presence of a large pseudopancreatic cyst in the pancreatic tail region causing displacement of the stomach anteriorly. CT, computed tomography; VRT, volume rendering technique.", "type": "figure"}, "FIGREF1": {"text": "Fig. 2 DSA image with catheter tip at the origin of the common hepatic artery shows filling of a large pseudoaneurysm with nonvisualization of a neck. DSA, digital subtraction angiography.", "type": "figure"}, "FIGREF3": {"text": "Fig. 3 (a) Ultrasound image at the time of percutaneous thrombin injection shows needle tip (small arrow) in the aneurysmal sac with surrounding hematoma (large arrow). (b) DSA image after completion of thrombin injection while the needle (white arrow) remained within the sac shows complete obliteration of the aneurysm sac. DSA, digital subtraction angiography.", "type": "figure"}, "FIGREF4": {"text": "Fig. 4 (a) Follow-up ultrasound and CT images in (b) axial and (c) coronal planes show complete obliteration of the pseudoaneurysm. CT, computed tomography.", "type": "figure"}}}
{"paper_id": "10709373", "_pdf_hash": "4f233cf10279891aa9ef0e2cff7fa34fd4e8055e", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "SOA Modeling Patterns for Service-Oriented Discovery and Analysis", "authors": [{"first": "Michael", "middle": [], "last": "Bell", "suffix": ""}], "year": 2010, "venue": "", "link": null}, "BIBREF1": {"title": "Service-Oriented Modeling: Service Analysis, Design, and Architecture", "authors": [{"first": "Michael", "middle": [], "last": "Bell", "suffix": ""}], "year": 2008, "venue": "", "link": "108102660"}, "BIBREF2": {"title": "The websites of international tourist hotels and tour wholesalers in Taiwan", "authors": [{"first": "C.-S", "middle": [], "last": "Wan", "suffix": ""}], "year": 2002, "venue": "Tourism Management", "link": null}, "BIBREF3": {"title": "Chinese Development Report of Ebusiness for Tourism", "authors": [], "year": 2011, "venue": "", "link": null}, "BIBREF4": {"title": "A strategic planning approach to Web site management", "authors": [{"first": "L", "middle": ["A"], "last": "Clyde", "suffix": ""}], "year": 2000, "venue": "The Electronic Library", "link": "39739132"}, "BIBREF5": {"title": "Alignment of Business Enterprise Architectures using fact-based ontologies", "authors": [{"first": "Dongwoo", "middle": [], "last": "Kang", "suffix": ""}, {"first": "Jeongsoo", "middle": [], "last": "Lee", "suffix": ""}, {"first": "Kwangsoo", "middle": [], "last": "Kim", "suffix": ""}], "year": 2010, "venue": "Expert Systems with Applications", "link": "33885651"}, "BIBREF6": {"title": "Tracking the Evolution of the Services Marketing Literature", "authors": [{"first": "Raymond", "middle": ["P"], "last": "Fisk", "suffix": ""}, {"first": "W", "middle": [], "last": "Stephen", "suffix": ""}, {"first": "Mary", "middle": ["Jo"], "last": "Brown", "suffix": ""}, {"first": "", "middle": [], "last": "Bitner", "suffix": ""}], "year": 1993, "venue": "Journal of Retailing", "link": "167765665"}, "BIBREF7": {"title": "Building Social Web Applications", "authors": [{"first": "Gavin", "middle": [], "last": "Bell", "suffix": ""}], "year": 2009, "venue": "", "link": "107938345"}, "BIBREF8": {"title": "Retailing and shopping on the Internet, Internet Research: Electronic Networking Applications and Policy", "authors": [{"first": "J", "middle": [], "last": "Rowley", "suffix": ""}], "year": 1996, "venue": "", "link": null}, "BIBREF9": {"title": "Seeking for Strategies to Deal With the Crises, Realizing the Scientific Development of Service Enterprises\", in the lecture of conference session included by Enterprises' Scientific Development Forum", "authors": [{"first": "Min", "middle": [], "last": "Fan", "suffix": ""}], "year": 2009, "venue": "", "link": null}, "BIBREF10": {"title": "Extended Web Assessment Method (EWAM) evaluation of electronic commerce applications from the customer's view point", "authors": [{"first": "P", "middle": [], "last": "Schubert", "suffix": ""}], "year": 2002, "venue": "International Journal of Electronic Commerce", "link": "29814850"}, "BIBREF11": {"title": "Breaking Free from Product Marketing", "authors": [{"first": "G", "middle": [], "last": "Shostack", "suffix": ""}, {"first": "", "middle": [], "last": "Lynn", "suffix": ""}], "year": 1977, "venue": "Journal of Marketing", "link": "167730483"}, "BIBREF12": {"title": "Transformation on the Internet: Results from the 2000 Study", "authors": [{"first": "Soumitra", "middle": [], "last": "Dutta", "suffix": ""}, {"first": "Beatrix", "middle": [], "last": "Biren", "suffix": ""}], "year": 2001, "venue": "", "link": null}, "BIBREF13": {"title": "An expanded and strategic view of discontinuous innovations: deploying a service-dominant logic", "authors": [{"first": "Stefan", "middle": [], "last": "Michel", "suffix": ""}, {"first": "Stephen", "middle": ["W"], "last": "Brown", "suffix": ""}, {"first": "Andrew", "middle": ["S"], "last": "Gallan", "suffix": ""}], "year": 2008, "venue": "Journal of the Academy of Marketing Science", "link": "14415041"}, "BIBREF14": {"title": "Customer Integration and Value Creation", "authors": [{"first": "L", "middle": [], "last": "Stephen", "suffix": ""}, {"first": "", "middle": [], "last": "Vargo", "suffix": ""}], "year": 2008, "venue": "Journal of Service Research", "link": null}, "BIBREF15": {"title": "Evolving to a New Dominant Logic for Marketing", "authors": [{"first": "L", "middle": [], "last": "Stephen", "suffix": ""}, {"first": "Robert", "middle": ["F"], "last": "Vargo", "suffix": ""}, {"first": "", "middle": [], "last": "Lusch", "suffix": ""}], "year": 2004, "venue": "Journal of Marketing", "link": "14130789"}, "BIBREF16": {"title": "E-business marketing-Marketing-led business", "authors": [{"first": "Steve", "middle": [], "last": "Whiteley", "suffix": ""}], "year": 2007, "venue": "", "link": null}, "BIBREF17": {"title": "Effect of store design on consumer purchases: van empirical study of on-line bookstores", "authors": [{"first": "T.-P", "middle": [], "last": "Liang", "suffix": ""}, {"first": "H", "middle": ["J"], "last": "Lai", "suffix": ""}], "year": 2002, "venue": "Information and Management", "link": "33290343"}, "BIBREF18": {"title": "Service-Oriented Architecture: Concepts, Technology and Design, Service Oriented Computing Series", "authors": [{"first": "Thomas", "middle": [], "last": "Erl", "suffix": ""}], "year": 2005, "venue": "", "link": null}, "BIBREF19": {"title": "Marketing Functions and Mercantile Organizations", "authors": [{"first": "Louis", "middle": ["D H"], "last": "Weld", "suffix": ""}], "year": 1917, "venue": "American Economic Review", "link": null}, "BIBREF20": {"title": "A strategic Website evaluation of online travel agencies", "authors": [{"first": "Wen-Chih", "middle": [], "last": "Chiou", "suffix": ""}, {"first": "Chin-Chao", "middle": [], "last": "Lin", "suffix": ""}, {"first": "Chyuan", "middle": [], "last": "Perng", "suffix": ""}], "year": 2011, "venue": "Tourism Management", "link": "153829423"}, "BIBREF21": {"title": "From policy implementation to business process management: Principles for creating flexibility and agility", "authors": [{"first": "Yiwei", "middle": [], "last": "Gong", "suffix": ""}, {"first": "Marijn", "middle": [], "last": "Janssen", "suffix": ""}], "year": 2012, "venue": "Government Information Quarterly", "link": "20587492"}}, "ref_entries": {}}
{"paper_id": "10709690", "_pdf_hash": "6aa2744801798f060fcd66901d55df2b3934a22d", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Hybrid feature extraction for facial emotion recognition", "authors": [{"first": "H", "middle": [], "last": "Ali", "suffix": ""}, {"first": "M", "middle": [], "last": "Hariharan", "suffix": ""}, {"first": "S", "middle": [], "last": "Yaacob", "suffix": ""}, {"first": "A", "middle": ["H"], "last": "Adom", "suffix": ""}], "year": 2014, "venue": "", "link": "41920352"}, "BIBREF2": {"title": "Robust real-time face tracker for use in cluttered environments", "authors": [{"first": "K", "middle": [], "last": "Anderson", "suffix": ""}, {"first": "P", "middle": ["W"], "last": "Mcowan", "suffix": ""}], "year": 2004, "venue": "Computer Vision and Image Understanding", "link": null}, "BIBREF3": {"title": "Eigenfaces vs. fisherfaces: recognition using class specific linear projection", "authors": [{"first": "P", "middle": ["N"], "last": "Belhumeur", "suffix": ""}, {"first": "J", "middle": ["P"], "last": "Hespanha", "suffix": ""}, {"first": "J", "middle": ["P"], "last": "", "suffix": ""}, {"first": "D", "middle": ["J"], "last": "Kriegman", "suffix": ""}, {"first": "D", "middle": ["J"], "last": "", "suffix": ""}], "year": 1997, "venue": "IEEE Transactions on Pattern Analysis and Machine Intelligence", "link": "30582"}, "BIBREF4": {"title": "Analyzing facial images using empirical mode decomposition for illumination artifact removal and improved face recognition", "authors": [{"first": "R", "middle": [], "last": "Bhagavatula", "suffix": ""}, {"first": "M", "middle": [], "last": "Savvides", "suffix": ""}], "year": 2007, "venue": "Proc. of IEEE ICASSP2007", "link": "18690533"}, "BIBREF5": {"title": "Emotion and sociable humanoid robots", "authors": [{"first": "C", "middle": [], "last": "Breazeal", "suffix": ""}], "year": 2003, "venue": "Int. J. Human-Computer Studies", "link": "14418847"}, "BIBREF6": {"title": "A new facial expression recognition method based on local gabor filter bank and PCA plus LDA", "authors": [{"first": "H", "middle": ["B"], "last": "Deng", "suffix": ""}, {"first": "L", "middle": ["W"], "last": "Jin", "suffix": ""}, {"first": "L", "middle": [], "last": "Zhen", "suffix": ""}, {"first": "J", "middle": ["C"], "last": "Huang", "suffix": ""}], "year": 2005, "venue": "International Journal of Information Technology", "link": "9054094"}, "BIBREF7": {"title": "Classifying facial actions", "authors": [{"first": "G", "middle": [], "last": "Donato", "suffix": ""}, {"first": "M", "middle": ["S"], "last": "Bartlett", "suffix": ""}, {"first": "J", "middle": ["C"], "last": "Hager", "suffix": ""}, {"first": "P", "middle": [], "last": "Ekman", "suffix": ""}, {"first": "T", "middle": ["J"], "last": "Sejnowski", "suffix": ""}], "year": 1999, "venue": "IEEE Trans. Pattern Anal. Mach. Intell", "link": "14465553"}, "BIBREF8": {"title": "Automatic facial expression analysis: A survey", "authors": [{"first": "B", "middle": [], "last": "Fasel", "suffix": ""}, {"first": "J", "middle": [], "last": "Luettin", "suffix": ""}], "year": 2003, "venue": "Pattern Recognition", "link": "62289168"}, "BIBREF9": {"title": "Facial expression recognition with local binary patterns and linear programming", "authors": [{"first": "X", "middle": ["Y"], "last": "Feng", "suffix": ""}, {"first": "A", "middle": [], "last": "Hadid", "suffix": ""}, {"first": "M", "middle": [], "last": "Pietik\u00a8ainen", "suffix": ""}], "year": 2005, "venue": "Pattern Recognition and Image Analysis", "link": null}, "BIBREF10": {"title": "A novel application of self-organizing network for facial expression recognition from radial encoded contours", "authors": [{"first": "W", "middle": ["F"], "last": "Gu", "suffix": ""}, {"first": "Y", "middle": ["V"], "last": "Venkatesh", "suffix": ""}, {"first": "C", "middle": [], "last": "Xiang", "suffix": ""}], "year": 2010, "venue": "", "link": "13192734"}, "BIBREF11": {"title": "Pain monitoring: A dynamic and context-sensitive system", "authors": [{"first": "Z", "middle": [], "last": "Hammal", "suffix": ""}, {"first": "M", "middle": [], "last": "Kunz", "suffix": ""}], "year": 2012, "venue": "Pattern Recognition", "link": "8714893"}, "BIBREF12": {"title": "Fusion of visible and infrared images using empirical mode decomposition to improve face recognition", "authors": [{"first": "H", "middle": [], "last": "Hariharan", "suffix": ""}, {"first": "A", "middle": [], "last": "Koschan", "suffix": ""}, {"first": "B", "middle": [], "last": "Abidi", "suffix": ""}, {"first": "A", "middle": [], "last": "Gribok", "suffix": ""}, {"first": "M", "middle": [], "last": "Abidi", "suffix": ""}], "year": 2006, "venue": "Proc. of IEEE international Conference on Image Processing ICIP", "link": "6525915"}, "BIBREF13": {"title": "The empirical mode decomposition and Hilbert spectrum for nonlinear and nonstationary time series analysis", "authors": [{"first": "N", "middle": ["E"], "last": "Huang", "suffix": ""}, {"first": "Z", "middle": [], "last": "Shen", "suffix": ""}, {"first": "S", "middle": [], "last": "Long", "suffix": ""}, {"first": "M", "middle": [], "last": "Wu", "suffix": ""}, {"first": "H", "middle": [], "last": "Shih", "suffix": ""}, {"first": "Q", "middle": [], "last": "Zheng", "suffix": ""}, {"first": "N", "middle": [], "last": "Yen", "suffix": ""}, {"first": "C", "middle": [], "last": "Tung", "suffix": ""}, {"first": "H", "middle": [], "last": "Liu", "suffix": ""}], "year": 1998, "venue": "Proc. R. Soc. London", "link": "1262186"}, "BIBREF14": {"title": "Comprehensive database for facial expression analysis", "authors": [{"first": "T", "middle": [], "last": "Kanade", "suffix": ""}, {"first": "J", "middle": [], "last": "Cohn", "suffix": ""}, {"first": "Y", "middle": [], "last": "Tian", "suffix": ""}], "year": 2000, "venue": "IEEE International Conference on Automatic Face and Gesture Recognition (FG)", "link": "16251989"}, "BIBREF15": {"title": "Waveletbased facial expression recognition using a bank of support vector machines", "authors": [{"first": "S", "middle": ["B"], "last": "Kazmi", "suffix": ""}, {"first": "", "middle": [], "last": "Qurat-Ul-Ain", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Jaffar", "suffix": ""}], "year": 2012, "venue": "Soft Computing", "link": "6591729"}, "BIBREF16": {"title": "Empirical mode decompsition on skeletonization pruning", "authors": [{"first": "S", "middle": [], "last": "Krinidis", "suffix": ""}, {"first": "M", "middle": [], "last": "Krinidis", "suffix": ""}], "year": 2013, "venue": "Image and Vision Computing", "link": null}, "BIBREF17": {"title": "Compression by image empirical mode decomposition", "authors": [{"first": "A", "middle": [], "last": "Linderhed", "suffix": ""}], "year": 2005, "venue": "IEEE International Conference on Image Processing", "link": "17471817"}, "BIBREF18": {"title": "Automatic facial expression recognition based on local binary patterns of local areas", "authors": [{"first": "W", "middle": ["F"], "last": "Liu", "suffix": ""}, {"first": "S", "middle": ["J"], "last": "Yi", "suffix": ""}, {"first": "Y", "middle": ["J"], "last": "Wang", "suffix": ""}], "year": 2009, "venue": "WASE International Conference on Information Engineering", "link": "13988078"}, "BIBREF19": {"title": "Facial expression based on fusion feature of PCA and LBP with SVM", "authors": [{"first": "Y", "middle": [], "last": "Luo", "suffix": ""}, {"first": "C-M", "middle": [], "last": "Wu", "suffix": ""}, {"first": "Y", "middle": [], "last": "Zhang", "suffix": ""}], "year": 2013, "venue": "Optik", "link": null}, "BIBREF20": {"title": "Automatic classification of single facial images", "authors": [{"first": "M", "middle": [], "last": "Lyons", "suffix": ""}, {"first": "Budynek", "middle": ["J"], "last": "Akamatsu", "suffix": ""}, {"first": "S", "middle": [], "last": "", "suffix": ""}], "year": 1999, "venue": "IEEE Trans. Pattern Anal. Mach. Intell", "link": null}, "BIBREF21": {"title": "PCA versus LDA", "authors": [{"first": "A", "middle": ["M"], "last": "Martinez", "suffix": ""}, {"first": "A", "middle": ["C"], "last": "Kak", "suffix": ""}], "year": 2001, "venue": "IEEE Transactions on Pattern Analysis and Machine Intelligence", "link": "5523504"}, "BIBREF22": {"title": "The effects of pose on facial expression recognition", "authors": [{"first": "S", "middle": [], "last": "Moore", "suffix": ""}, {"first": "R", "middle": [], "last": "Bowden", "suffix": ""}], "year": 2009, "venue": "Proceedings of the British Machine Conference", "link": null}, "BIBREF23": {"title": "Image analysis by bidimensional empirical mode decomposition", "authors": [{"first": "J", "middle": ["C"], "last": "Nunes", "suffix": ""}, {"first": "Y", "middle": [], "last": "Bouaoune", "suffix": ""}, {"first": "E", "middle": [], "last": "Delechelle", "suffix": ""}, {"first": "O", "middle": [], "last": "Niang", "suffix": ""}, {"first": "Bunel", "middle": [], "last": "Ph", "suffix": ""}], "year": 2003, "venue": "Image and Vision Computing", "link": "16006712"}, "BIBREF24": {"title": "Automatic analysis of facial expressions: The state of the art", "authors": [{"first": "M", "middle": [], "last": "Pantic", "suffix": ""}, {"first": "L", "middle": ["J M"], "last": "Rothkrantz", "suffix": ""}], "year": 2000, "venue": "IEEE Trans. Pattern Analysis and Machine Intelligence", "link": "11844016"}, "BIBREF25": {"title": "Empirical mode decomposition-based facial pose estimation inside video sequences", "authors": [{"first": "C", "middle": [], "last": "Qing", "suffix": ""}, {"first": "J", "middle": [], "last": "Jiang", "suffix": ""}, {"first": "Z", "middle": [], "last": "Yang", "suffix": ""}], "year": 2010, "venue": "Optical Engineering", "link": "14734609"}, "BIBREF26": {"title": "On empirical mode decomposition and its algorithms", "authors": [{"first": "G", "middle": [], "last": "Rilling", "suffix": ""}, {"first": "P", "middle": [], "last": "Flandrin", "suffix": ""}, {"first": "P", "middle": [], "last": "Goncalves", "suffix": ""}], "year": 2003, "venue": "Proc. of the IEEE-Eurasip Workshop on Nonlinear Signaland Image processing", "link": "16054541"}, "BIBREF27": {"title": "Facial expression recognition based on local binary patterns: a comprehensive study", "authors": [{"first": "C", "middle": [], "last": "Shan", "suffix": ""}, {"first": "S", "middle": [], "last": "Gong", "suffix": ""}, {"first": "P", "middle": ["W"], "last": "Mcowan", "suffix": ""}], "year": 2009, "venue": "Image and Vision Computing", "link": "589516"}, "BIBREF28": {"title": "Performance comparisons of facial expression recognition in JAFFE database", "authors": [{"first": "F", "middle": ["Y"], "last": "Shih", "suffix": ""}, {"first": "C", "middle": ["F"], "last": "Chuang", "suffix": ""}, {"first": "P", "middle": ["S P"], "last": "Wang", "suffix": ""}], "year": 2008, "venue": "International Journal of Pattern Recognition", "link": "16207169"}, "BIBREF29": {"title": "Why can LDA be performed in PCA transformed space", "authors": [{"first": "J", "middle": [], "last": "Yang", "suffix": ""}, {"first": "Yang J-Yu", "middle": [], "last": "", "suffix": ""}], "year": 2003, "venue": "Pattern Recognition", "link": "1581217"}, "BIBREF30": {"title": "Fusion of feature sets and classifiers for facial expression recognition", "authors": [{"first": "T", "middle": ["H H"], "last": "Zavaschi", "suffix": ""}, {"first": "", "middle": ["A S"], "last": "Britto", "suffix": ""}, {"first": "L", "middle": ["E S"], "last": "Oliveira", "suffix": ""}, {"first": "A", "middle": ["L"], "last": "Koerich", "suffix": ""}], "year": 2013, "venue": "Expert Systems with Applications", "link": "15568980"}, "BIBREF31": {"title": "Extraction of illumination-invariant features in face recognition by empirical mode decomposition", "authors": [{"first": "D", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "Y", "middle": ["Y"], "last": "Tang", "suffix": ""}], "year": 2009, "venue": "LNCS", "link": "37793592"}, "BIBREF32": {"title": "Facial expression recognition based on local binary patterns and kernel discriminant isomap. Sensors", "authors": [{"first": "X", "middle": [], "last": "Zhao", "suffix": ""}, {"first": "S", "middle": [], "last": "Zhang", "suffix": ""}], "year": 2011, "venue": "", "link": "7822509"}}, "ref_entries": {}}
{"paper_id": "188181726", "_pdf_hash": "5beece7503bbd819cbf0f4960d8c7b2a351499f6", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "olvle veiniz elgers whose xilrdil is usiE(liform veiniz elger of wximum vength", "authors": [{"first": "K", "middle": ["K"], "last": "Abdurasulov", "suffix": ""}, {"first": "J", "middle": ["Q"], "last": "Adashev", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Casas", "suffix": ""}, {"first": "B", "middle": ["A"], "last": "Omirov", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF1": {"title": "Balavoine h\u00a1 eformtions et rigidit\u00a1 e g\u00a1 eom\u00a1 etrique des lg eres de veinizF", "authors": [], "year": 1996, "venue": "Comm. Algebra", "link": null}, "BIBREF2": {"title": "On Levi's theorem for Leibniz algebras", "authors": [{"first": "D", "middle": [], "last": "Barnes", "suffix": ""}], "year": 2012, "venue": "Bull. Aust. Math. Soc", "link": "119130548"}, "BIBREF3": {"title": "Solvable Leibniz algebras with Heisenberg nilradical", "authors": [{"first": "L", "middle": [], "last": "Bosko-Dunbar", "suffix": ""}, {"first": "J", "middle": ["D"], "last": "Dunbar", "suffix": ""}, {"first": "J", "middle": ["T"], "last": "Hird", "suffix": ""}, {"first": "K", "middle": [], "last": "Stagg", "suffix": ""}], "year": 2015, "venue": "Commun. Algebra", "link": "119566369"}, "BIBREF4": {"title": "Quasi-liform Leibniz algebras of maximum length", "authors": [{"first": "L", "middle": ["M"], "last": "Camacho", "suffix": ""}, {"first": "E", "middle": ["M"], "last": "Ca\u00f1ete", "suffix": ""}, {"first": "J", "middle": ["R"], "last": "G\u00f3mez", "suffix": ""}, {"first": "B", "middle": ["A"], "last": "Omirov", "suffix": ""}], "year": 2011, "venue": "Sib. Math. J", "link": null}, "BIBREF5": {"title": "Solvable Leibniz algebras with liform nilradical", "authors": [{"first": "L", "middle": ["M"], "last": "Camacho", "suffix": ""}, {"first": "B", "middle": ["A"], "last": "Omirov", "suffix": ""}, {"first": "K", "middle": ["K"], "last": "Masutova", "suffix": ""}], "year": 2016, "venue": "Bull. Malays. Math. Sci. Soc", "link": null}, "BIBREF6": {"title": "Classication of solvable Leibniz algebras with null-liform nilradical", "authors": [{"first": "J", "middle": [], "last": "Casas", "suffix": ""}, {"first": "M", "middle": [], "last": "Ladra", "suffix": ""}, {"first": "B", "middle": ["A"], "last": "Omirov", "suffix": ""}, {"first": "I", "middle": [], "last": "Karimjanov", "suffix": ""}], "year": 2013, "venue": "Linear Mult. Alg. Appl", "link": null}, "BIBREF7": {"title": "Classication of solvable Leibniz algebras with naturally graded liform nilradical", "authors": [{"first": "J", "middle": [], "last": "Casas", "suffix": ""}, {"first": "M", "middle": [], "last": "Ladra", "suffix": ""}, {"first": "B", "middle": ["A"], "last": "Omirov", "suffix": ""}, {"first": "I", "middle": [], "last": "Karimjanov", "suffix": ""}], "year": 2013, "venue": "Linear Alg. Appl", "link": null}, "BIBREF8": {"title": "Solvable Leibniz algebras with triangular nilradicals", "authors": [{"first": "I", "middle": ["A"], "last": "Karimjanov", "suffix": ""}, {"first": "A", "middle": ["K"], "last": "Khudoyberdiyev", "suffix": ""}, {"first": "B", "middle": ["A"], "last": "Omirov", "suffix": ""}], "year": 2015, "venue": "Linear Alg. Appl", "link": "119178982"}, "BIBREF9": {"title": "Solvable Leibniz algebras with quasi-liform Lie algebras of maximum length nilradicals", "authors": [{"first": ".", "middle": ["A"], "last": "Kh", "suffix": ""}, {"first": "M", "middle": [], "last": "Khalkulova", "suffix": ""}, {"first": "B", "middle": ["A"], "last": "Ladra", "suffix": ""}, {"first": "A", "middle": ["M"], "last": "Omirov", "suffix": ""}, {"first": "", "middle": [], "last": "Sattorov", "suffix": ""}], "year": 2018, "venue": "", "link": "119117649"}, "BIBREF10": {"title": "On solvable Leibniz algebras whose nilradical is a direct sum of null-liform algebras", "authors": [{"first": "A", "middle": ["K"], "last": "Khudoyberdiyev", "suffix": ""}, {"first": "M", "middle": [], "last": "Ladra", "suffix": ""}, {"first": "B", "middle": ["A"], "last": "Omirov", "suffix": ""}], "year": 2014, "venue": "Linear. Mult. Alg", "link": "119531758"}, "BIBREF11": {"title": "Classication of solvable Leibniz algebras with naturally graded liform nilradical", "authors": [{"first": "M", "middle": [], "last": "Ladra", "suffix": ""}, {"first": "K", "middle": ["K"], "last": "Masutova", "suffix": ""}, {"first": "B", "middle": ["A"], "last": "Omirov", "suffix": ""}], "year": 2013, "venue": "Linear Alg. Appl", "link": null}, "BIBREF13": {"title": "Une version non commutative des alg\u00e9bres de Lie: les alg\u00e9bres de Leibniz", "authors": [{"first": "J.-L", "middle": [], "last": "Loday", "suffix": ""}], "year": 1993, "venue": "Enseign. Math", "link": null}, "BIBREF14": {"title": "Pirashvili niversl enveloping lgers of veiniz lgers nd @oAhomologyF", "authors": [{"first": "J.-L", "middle": [], "last": "Loday", "suffix": ""}, {"first": "T", "middle": [], "last": "", "suffix": ""}], "year": 1993, "venue": "Math. Ann", "link": null}}, "ref_entries": {}}
{"paper_id": "17430151", "_pdf_hash": "5020c8205807f134f1a789aa019b4532cb8d7633", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Automatic Text Categorization on Hierarchical Category Structure by using ICF(Inverted Category Frequency) Weighting KOREA INFORMATION SCIENCE SOCIETY", "authors": [{"first": "K", "middle": [], "last": "Cho", "suffix": ""}, {"first": "J", "middle": [], "last": "Kim", "suffix": ""}], "year": 1997, "venue": "", "link": null}, "BIBREF1": {"title": "Web-scale table census and classification", "authors": [{"first": "E", "middle": [], "last": "Crestan", "suffix": ""}, {"first": "P", "middle": [], "last": "Pantel", "suffix": ""}], "year": 2011, "venue": "Proceedings of the fourth ACM international conference on Web search and data mining", "link": "11989223"}, "BIBREF2": {"title": "Measuring nominal scale agreement among many raters", "authors": [{"first": "J", "middle": ["L"], "last": "Fleiss", "suffix": ""}], "year": 1971, "venue": "Psychological Bulletin", "link": "143544759"}, "BIBREF3": {"title": "The WEKA data mining software: an update", "authors": [{"first": "M", "middle": [], "last": "Hall", "suffix": ""}, {"first": "E", "middle": [], "last": "Frank", "suffix": ""}, {"first": "G", "middle": [], "last": "Holmes", "suffix": ""}, {"first": "B", "middle": [], "last": "Pfahringer", "suffix": ""}, {"first": "P", "middle": [], "last": "Reutemann", "suffix": ""}, {"first": "I", "middle": ["H"], "last": "Witten", "suffix": ""}], "year": 2009, "venue": "SIGKDD Explor. Newsl", "link": "13861754"}, "BIBREF5": {"title": "Functional-Based Table Category Identification in Digital Library", "authors": [{"first": "S", "middle": [], "last": "Kim", "suffix": ""}, {"first": "Y", "middle": [], "last": "Liu", "suffix": ""}], "year": 2011, "venue": "Proceedings of the 11th International Conference on Document Analysis and Recognition", "link": "5373335"}, "BIBREF6": {"title": "TableSeer: automatic table metadata extraction and searching in digital libraries", "authors": [{"first": "Y", "middle": [], "last": "Liu", "suffix": ""}, {"first": "K", "middle": [], "last": "Bai", "suffix": ""}, {"first": "P", "middle": [], "last": "Mitra", "suffix": ""}, {"first": "C", "middle": ["L"], "last": "Giles", "suffix": ""}], "year": 2007, "venue": "Proceedings of the 7th ACM/IEEE-CS joint conference on Digital libraries", "link": "2940120"}}, "ref_entries": {}}
{"paper_id": "17430770", "_pdf_hash": "90c80f960e061d0d5206b93a63d93760bff30f3f", "abstract": [{"section": "Abstract", "text": "The genome sequences of Neisseria meningitidis serogroup B strain MC58 and serogroup A strain Z2491 were systematically searched for open reading frames (ORFs) encoding autotransporters. Eight ORFs were identified, six of which were present in both genomes, whereas two were specific for MC58. Among the identified ORFs was the gene encoding the known autotransporter IgA1 protease. The deduced amino acid sequences of the other identified ORFs were homologous to known autotransporters and found to contain an N-terminal signal sequence and a C-terminal domain that could constitute a L-barrel in the outer membrane. The ORFs NMB1985 and NMB0992, encoding homologs of the Hap (for Haemophilus adhesion and penetration protein) and Hia (for Haemophilus influenzae adherence protein) autotransporters of H. influenzae, were cloned from serogroup B strain H44/76 and expressed in Escherichia coli. Western blots revealed that all sera of patients (n = 14) and healthy carriers (n = 3) tested contained antibodies against at least one of the recombinant proteins. These results indicate that both genes are widely distributed among N. meningitidis isolates and expressed during colonization and infection. \u00df", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Encapsulated Neisseria meningitidis is a major cause of septicaemia and meningitis world-wide [1] . Most diseasecausing isolates express one of the polysaccharide capsules of serogroups A, B, C, Y and W135. E\u00a1ective vaccines, at least for adults, have been developed based upon the capsular polysaccharides of serogroups A, C, Y and W135 [2] . However, the serogroup B capsule is poorly immunogenic, since it mimics a structure present on the surface of cells of host tissues. Moreover, capsular polysaccharides elicit immune responses with a poor memory, and such vaccines are only e\u00a1ective in children over 2 years of age, whereas the disease is a major problem in younger children. Outer membrane (OM) vesicles containing the major outer membrane proteins (OMPs) have been evaluated as an alternative vaccine [3, 4] . These major OMPs, however, are antigenically diverse and their expression is subject to phase variation. Therefore, these vesicle vaccines provided only limited protection [3, 5] .", "cite_spans": [{"start": 94, "end": 97, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 338, "end": 341, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 812, "end": 815, "text": "[3,", "ref_id": "BIBREF2"}, {"start": 816, "end": 818, "text": "4]", "ref_id": "BIBREF3"}, {"start": 993, "end": 996, "text": "[3,", "ref_id": "BIBREF2"}, {"start": 997, "end": 999, "text": "5]", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "Introduction", "text": "Vaccines may improve by the inclusion of minor OMPs, provided that these OMPs are expressed in su\u00a4cient quantities to elicit an immune response and that the resulting antibodies are cross-reactive to a broad range of strains. In addition, such a vaccine component should be expressed either during colonization of the epithelial layers of the upper respiratory tract or during infection of the blood and the meninges. The search for such additional components is greatly facilitated by the recent availability of the genome sequences of two N. meningitidis strains [6, 7] .", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "In this study, the genome sequences were searched for genes putatively encoding autotransporters. Autotransporters comprise a family of secreted proteins able to translocate themselves over the OM (hence their name) [8] . Their primary sequence harbors an N-terminal signal sequence directing transport over the inner membrane by the Sec system and a C-terminal domain of approximately 30 kDa presumably forming a L-barrel pore in the OM for translocation of the functional domain across the membrane. After translocation, the active domain is cell-surface exposed or secreted into the medium. Their surface exposure renders these types of proteins attractive candidates for application in a vaccine. Moreover, the majority of autotransporters studied to date were implicated in host^pathogen interactions [9] , and Pertactin, an autotransporter of Bordetella pertussis was included in an acellular vaccine currently in use [10] .", "cite_spans": [{"start": 216, "end": 219, "text": "[8]", "ref_id": "BIBREF8"}, {"start": 806, "end": 809, "text": "[9]", "ref_id": "BIBREF9"}, {"start": 924, "end": 928, "text": "[10]", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "Introduction", "text": "The \u00a2rst autotransporter described was the IgA1 protease of Neisseria gonorrhoeae [11] , homologs of which were also found to be ubiquitous in N. meningitidis isolates [12] . Until recently, information on other genes encoding autotransporters in Neisseria species was limited [13^15] . Here, we report the identi\u00a2cation of seven N. meningitidis genes, apart from iga encoding IgA1 protease, putatively encoding autotransporters. Two of them, homologous to autotransporters of Haemophilus in\u00a3uenzae, were cloned. We show that these proteins are expressed in vivo, since they are recognized by antibodies in sera from patients convalescent from meningitis and in sera from healthy carriers.", "cite_spans": [{"start": 82, "end": 86, "text": "[11]", "ref_id": "BIBREF11"}, {"start": 168, "end": 172, "text": "[12]", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "Materials and methods", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Bacterial strains, plasmids and growth conditions", "text": "N. meningitidis strain H44/76 (B:15:P1.7,16) was originally isolated from the cerebrospinal \u00a3uid of a meningitis patient in Norway and was shown to belong to the ET-5 group of strains associated with many cases of disease [16] . Cultures of the strain were started from frozen stocks and grown overnight in Tryptic soy broth. Escherichia coli strains used, DH5K, Top10F' (Invitrogen, Groningen, The Netherlands) and BL21(DE3) (Novagen, Madison, WI, USA), were grown on Luria broth (LB) supplemented with 100 Wg ml 31 ampicillin for plasmid maintenance and with 0.5% glucose for full repression of the lac promoter. Cloning and expression vectors used were pCRII-topo (Invitrogen), pET11a and pET16b (Novagen).", "cite_spans": [{"start": 222, "end": 226, "text": "[16]", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "Database searches", "text": "The genome sequences of N. meningitidis serogroup A strain Z2491 [6] and serogroup B strain MC58 [7] were searched for genes putatively encoding autotransporters by homology searching using the sequences of 28 autotransporters from 10 di\u00a1erent bacterial species (Table 1) . This list was based upon the sequences described by [16] and [10] , and, additionally, TibA [17] , PssA [18] and Vag8 [19] were included. Database searches were performed using the web sites of The Sanger Centre (http://www. sanger.ac.uk/projects/n_meningitidis/blast_server; this site was used extensively in the period prior to publication of the two genome sequences) and the NCBI Blast and the NCBI Blast of Finished and Un\u00a2nished Microbial Genomes web pages (via http://www.ncbi.nlm.nih.gov/ blast). The genomes were searched with the tBlastn program [20] , comparing the amino acid sequences of the autotransporters to the genomes translated into six reading frames. Default search matrices were used, but \u00a2lters for regions of low complexity were switched o\u00a1.", "cite_spans": [{"start": 326, "end": 330, "text": "[16]", "ref_id": "BIBREF16"}, {"start": 335, "end": 339, "text": "[10]", "ref_id": "BIBREF10"}, {"start": 366, "end": 370, "text": "[17]", "ref_id": "BIBREF17"}, {"start": 378, "end": 382, "text": "[18]", "ref_id": "BIBREF18"}, {"start": 392, "end": 396, "text": "[19]", "ref_id": "BIBREF19"}, {"start": 830, "end": 834, "text": "[20]", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "Database searches", "text": "Hits that showed more than 20% similarity over regions larger than 250 amino acid residues were further investigated. The complete ORFs corresponding to the homologous regions were retrieved and compared to sequences in the GenBank database to identify any homologous N. meningitidis sequences previously submitted. The selected Table 1 Autotransporter proteins used for screening of the genomes of N. meningitidis strains MC58 and Z2491", "cite_spans": [], "ref_spans": []}, {"section": "B. pertussis", "text": "The protein name is given with the GenBank accession numbers in brackets. In some cases the accession numbers refer to the DNA sequence. Also in those cases, searches were performed with the deduced amino acid sequence.", "cite_spans": [], "ref_spans": []}, {"section": "B. pertussis", "text": "ORFs were also searched for the presence of an N-terminal signal sequence, using the signalP program (http:// www.cbs.dtu.dk/services/signalp-2.0 ; [21] ). However, the N-terminal 100 instead of the recommended 70 amino acid residues were used, since autotransporters tend to have long signal sequences [9] . The C-terminal 350 amino acid residues were analyzed by hand for the presence of a domain that could form a L-barrel structure [8] . Finally, the last nine amino acid residues were compared to the signature sequence for the postulated last L-strand of the [9] , whereby the last three residues were described as the most important [22] . DNA and protein sequence analysis and handling were done using the ", "cite_spans": [{"start": 148, "end": 152, "text": "[21]", "ref_id": "BIBREF21"}, {"start": 303, "end": 306, "text": "[9]", "ref_id": "BIBREF9"}, {"start": 436, "end": 439, "text": "[8]", "ref_id": "BIBREF8"}, {"start": 565, "end": 568, "text": "[9]", "ref_id": "BIBREF9"}, {"start": 640, "end": 644, "text": "[22]", "ref_id": "BIBREF22"}], "ref_spans": []}, {"section": "Cloning of ORFs NMB0992 and NMB1985", "text": "Primers NMB0992Start (ggaattccatatgaacaaaatataccgcatcatttgga), NMB0992End (caagatcttaccactgataaccgacagatgcgga), NMB1985Start (catgccatggaaacaaccgacaaacggacaccga) and NMB1985End (gaagatcttaccagcggtacggtaatttgat) were designed to amplify the ORFs of NMB0992 and NMB1985 from the start codon up to and including the stop codon, without any up-or downstream sequences. They were based upon the Z2491 sequences (available at the time of primer selection), but all showed 100% identity to the comparable MC58 regions at the DNA level. Restriction sites (underlined) were included in the primers to facilitate cloning. In primer NMB0992Start, an NdeI site was included, whereas an NcoI site was included in primer NMB1985Start. In the latter case, this manipulation resulted in the substitution of the second amino acid of the ORF (E for K), which, however, was not expected to disrupt signal sequence function (not shown). In both cases, the primer located at the end of the gene included a BglII site.", "cite_spans": [], "ref_spans": []}, {"section": "Cloning of ORFs NMB0992 and NMB1985", "text": "PCR reactions were performed in a Biometra PCR machine, using Pwo DNA polymerase (Boehringer Mannheim, Germany) for NMB0992, and the High Fidelity Long Range PCR kit (Boehringer Mannheim) for NMB1985. Reactions were performed in the presence of 1% dimethylsulfoxide, according to the manufacturer's prescription, using genomic DNA of N. meningitidis strain H44/76 as the template. This DNA was puri\u00a2ed using the Qiagen Genomic DNA Midi preps (Qiagen, Hilden, Germany) according to manufacturer's prescription. PCR reactions typically included 30 cycles of ampli\u00a2cation, and the annealing temperature ranged from 55 to 62\u00b3C. After cycling, the reaction products were incubated for 30 min at 72\u00b3C in the presence of Taq DNA polymerase (MBI Fermentas, St. Leon-Roth, Germany) and fresh nucleotides to extend the products with adenine nucleotides to facilitate TA-cloning (Invitrogen). PCR fragments of the expected length were isolated from gel using the Qiaquick gel isolation kit (Qiagen) and cloned into pCRII-topo (Invitrogen), using the methods described by the manufacturer.", "cite_spans": [], "ref_spans": []}, {"section": "Cloning of ORFs NMB0992 and NMB1985", "text": "The ORF of NMB0992 was cut from the pCRII-topo vector by restriction with NdeI and BamHI, and cloned into expression vector pET11a restricted with the same enzymes, resulting in plasmid pPU100. The ORF was found to contain an extra BglII site within the coding region, requiring the use of the BamHI site located in the multiple cloning region of pCRII-topo. The ORF of NMB1985 was cut from the pCRII-topo clone by restriction with NcoI and BglII and cloned into expression vector pET16b restricted with NcoI and BamHI, resulting in plasmid pPU200. The plasmids pPU100 and pPU200 contained the ORF under the control of the T7 promoter [23] and were checked by restriction enzyme digestion and sequencing of the fusion sites using universal T7 primers hybridizing to regions up-and downstream of the insertion site.", "cite_spans": [{"start": 635, "end": 639, "text": "[23]", "ref_id": "BIBREF23"}], "ref_spans": []}, {"section": "Cloning of ORFs NMB0992 and NMB1985", "text": "The ORF of NMB1985 was completely sequenced using the pCRII-topo plasmid containing the PCR product as a template. Primers used were the universal M13 primers and a collection of 13 primers based upon the sequence of NMB1985 of MC58 and the resulting sequences completely covered the ORF on both strands of the DNA. All sequencing reactions were done with the BigDye sequencing kit (Perkin Elmer Applied Biosystems, Nieuwekerk a/d IJssel, The Netherlands) and on an ABI310 sequencer (Perkin Elmer).", "cite_spans": [], "ref_spans": []}, {"section": "Overproduction of proteins encoded by NMB0992 and", "text": "NMB1985 in E. coli E. coli strain BL21(DE3), containing an inducible T7 RNA polymerase gene (Novagen), was transformed with plasmids pET16b, pPU100 and pPU200. Fresh overnight cultures were diluted 1:100 in LB with 0.5% glucose and grown to an OD 600 of 0.6. Expression of the genes under the control of the T7 promoter was then induced by adding isopropyl-L-D-thiogalactopyranoside (IPTG) to a \u00a2nal concentration of 0.1 mM, after which incubation was prolonged for another 2 h.", "cite_spans": [], "ref_spans": []}, {"section": "Human sera and other antibodies", "text": "Sera of 10 patients convalescent of meningococcal disease, three healthy carriers of N. meningitidis, and three healthy non-carriers were obtained from the collection of the Department of Medical Microbiology, Academic Medical Centre, Amsterdam, The Netherlands. The infecting strains of the patients and the colonizing strains of the carriers have been serotyped. Four sera of convalescent patients and one non-carrier serum were obtained from the collection of the National Institute of Health and the Environment (RIVM), Bilthoven, The Netherlands. Antibodies against H. in\u00a3uenzae Hia (for H. in\u00a3uenzae adherence protein) and Hap (for Haemophilus adhesion and penetration protein) proteins were kindly donated by Dr. St. Geme (Washington University School of Medicine, St. Louis, MO, USA).", "cite_spans": [], "ref_spans": []}, {"section": "SDS^PAGE and Western blotting", "text": "Proteins were analyzed by SDS^PAGE with an 8% (w/v) polyacrylamide running gel and visualized by staining with Coomassie brilliant blue. Whole cell lysates of equal amounts of cells were loaded.", "cite_spans": [], "ref_spans": []}, {"section": "SDS^PAGE and Western blotting", "text": "To detect binding of antibodies to the overproduced proteins, Western blots were made containing proteins from isolated membrane fractions. To obtain the membrane fraction, cells were harvested by centrifugation at 7000Ug and resuspended in a bu\u00a1er of 50 mM Tris\u0124 Cl, pH 8.0, and 2 mM EDTA, and then disrupted in batches of 20 ml by sonication for 2U15 s in a Branson soni\u00a2er at full power while on ice and with 15 s in between steps. Lysates were cleared from unbroken cells and aggregates by two subsequent centrifugation steps at 1400Ug for 20 min. The membrane fractions (mostly OMs) were pelleted by 5 min centrifugation at 100 000Ug. The resulting pellets were dissolved in 5 mM Tris^HCl, pH 7.6. Samples of the fractions containing equal amounts of proteins, as derived from the OD 280 of the preparations, were separated by SDS^PAGE and blotted upon 0.45 Wm Protran \u00a2lters (Schleicher and Schuell, Dassel, Germany) using the Protean II minigel blotting system (Bio-Rad Laboratories, Veenendaal, The Netherlands) at 100 V for 1 h. Unspeci\u00a2c binding of antibodies to \u00a2lters was prevented by overnight incubation in phosphate-bu\u00a1ered saline (PBS), pH 7.0, supplemented with 0.5% Protifar (Nutricia, Zoetermeer, The Netherlands) and 0.1% Tween 20 (Merck and Co., NJ, USA). The sera were diluted 1:500 or 1:750 in the same bu\u00a1er and applied for 1 h to the blots. After extensive washing, the blots were incubated with goat anti-human IgG conjugated to horseradish peroxidase (Dako, Glostrup, Denmark) at a dilution of 1:5000 in the same bu\u00a1er. Binding of antibodies was visualized by chemiluminescence using the ECL kit (Pierce, Rockford, IL, USA).", "cite_spans": [], "ref_spans": []}, {"section": "SDS^PAGE and Western blotting", "text": "2.7. Protease-accessibility assay E. coli BL21(DE3) cells producing recombinant proteins were harvested by centrifugation at 7000Ug. Pellets were washed in PBS, pH 7.6, and resuspended in 10 mM Tris\u0124 Cl, pH 7.6, 10 mM MgCl 2 to an OD 600 of 1.0 and put on ice for 10 min. Next, 500-Wl samples of the cell suspensions were incubated with di\u00a1erent amounts of proteinase K or trypsin on ice for 20 min. Protease digestion was stopped by adding 10 Wl of a 100 mM phenylmethylsulfonyl \u00a3uo-ride solution in isopropanol, followed by an incubation on ice for 30 min. Cells were harvested by centrifugation and resuspended in 50 Wl of sample bu\u00a1er and proteins were separated by SDS^PAGE. To test whether the protease was active on the intra-cellular proteins, cells were resuspended in a bu\u00a1er containing 10 mM Tris^HCl, pH 7.6, 5 mM EDTA resulting in the disintegration of the OM.", "cite_spans": [], "ref_spans": []}, {"section": "SDS^PAGE and Western blotting", "text": "2.8. Immuno\u00a3uorescence microscopy E. coli BL21(DE3) cells producing recombinant proteins were harvested by centrifugation. Pellets were washed and resuspended in PBS to an OD 600 of 1.0. 300 Wl cell suspension was incubated for 30 min with 14-mm cover slips that had been coated for 30 min with poly-L-lysine (Sigma, St. Louis, MO, USA). Cover slips with bound cells were washed twice with PBS and \u00a2xed overnight with 2% formaldehyde in PBS at 4\u00b3C. Next, cover slips were washed twice with PBS and then incubated for 1 h at room temperature with PBS supplemented with 0.05% Tween 20 (Sigma) and 3% bovine serum albumin (BSA) (Sigma). Serum 780646 was diluted 1:250 in the same bu\u00a1er and then pre-incubated for 1 h with IPTG-induced E. coli cells containing pET16b, with the amount of cells being equivalent to a 1-ml culture with an OD 600 of 1.0. Cells were removed by centrifugation and the pre-adsorbed serum was incubated with the cover slips for 1 h at room temperature. The cover slips were washed thrice with PBS with 0.05% Tween 20 and subsequently incubated for 1 h with goat anti-human IgG antibodies to which the \u00a3uorogenic dye Alexa was coupled (Molecular Probes, Leiden, The Netherlands), diluted 1:300 in PBS with 0.05% Tween 20 and 3% BSA. After washing thrice with PBS with 0.05% Tween 20, cells were \u00a2xed again with 2% formaldehyde in PBS and washed, after which they were mounted on glass slides. The results were assessed using a \u00a3uorescence microscope. As a control, cover slips with cells were incubated with rabbit antibodies against L-lactamase at a dilution of 1:3000 in the same bu\u00a1er as used for the human serum. In these cases, the second antibody was Alexaconjugated goat anti-rabbit IgG antiserum. When applicable, the OMs of cells were permeabilized after the \u00a2rst \u00a2xation step by incubating the cover slips for 20 min in PBS with 0.5% Triton X-100 at room temperature, after which the cover slips were washed twice with PBS.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Identi\u00a2cation of ORFs putatively encoding autotransporters", "text": "The genome sequences of N. meningitidis serogroup A strain Z2491 and serogroup B strain MC58 were screened for the presence of ORFs putatively encoding proteins with homology to the amino acid sequences of 28 known autotransporters (Table 1) . Initial screening led to the identi\u00a2cation of 14 ORFs, showing homology to one or more autotransporters. Two of them, NMB0545 and NMB0711 and their serogroup A counterparts NMA0724 and NMA0916, were discarded because a signal sequence could not be identi\u00a2ed. One ORF, NMB1540/NMA1739, was discarded because it showed over 80% sequence identity to LbpA, a well-known integral OMP of N. meningitidis [24] . One ORF, NMA0688, which showed homology to the \u00a2lamentous hemagglutinin of B. pertussis was discarded since its C-terminal sequence did not match the C-terminal signature sequence of autotransporters. Moreover, an accessory protein involved in OM localization of \u00a2lamentous hemagglutinin has been described [25] , and a homolog of this protein was found adjacent to NMA0688. Interestingly, NMA0688 was only present in the serogroup A sequence. Finally, two ORFs, NMB0497 and NMB01779, only present in the serogroup B sequence and encoding proteins homologous to hemolysins, also had C-terminal sequences di\u00a1ering from the signature sequence and were subsequently discarded. The remaining eight ORFs (Table 2 ) complied with the criteria set: they encoded polypeptides homologous to known autotransporters, had an N-terminal signal sequence and a putative L-barrel domain containing the signature sequence of autotransporters at their C-terminus. The two genomes were also screened with the C-terminal signature sequence as a probe [9] , but this approach did not lead to the identi\u00a2cation of additional putative autotransporters.", "cite_spans": [{"start": 642, "end": 646, "text": "[24]", "ref_id": "BIBREF24"}, {"start": 956, "end": 960, "text": "[25]", "ref_id": "BIBREF25"}, {"start": 1680, "end": 1683, "text": "[9]", "ref_id": "BIBREF9"}], "ref_spans": [{"start": 1348, "end": 1356, "text": "(Table 2", "ref_id": "TABREF1"}]}, {"section": "Identi\u00a2cation of ORFs putatively encoding autotransporters", "text": "Six of the eight ORFs were identi\u00a2ed in both MC58 and Z2491, with homologies between the corresponding ORFs ranging from 85 to 98% sequence identity at the amino acid level ( Table 2 ). The highest identity was found between the ORFs encoding the IgA1 protease [12] . They both were 73% identical to the IgA1 protease of N. gonorrhoeae, the \u00a2rst autotransporter described in detail [11] .", "cite_spans": [{"start": 261, "end": 265, "text": "[12]", "ref_id": "BIBREF12"}, {"start": 382, "end": 386, "text": "[11]", "ref_id": "BIBREF11"}], "ref_spans": [{"start": 175, "end": 182, "text": "Table 2", "ref_id": "TABREF1"}]}, {"section": "Identi\u00a2cation of ORFs putatively encoding autotransporters", "text": "ORFs homologous to NMB1994 and NMB1998 were not identi\u00a2ed in the serogroup A sequence. However, these ORFs are not located in the three DNA regions speci\u00a2c for MC58 [7] .", "cite_spans": [], "ref_spans": []}, {"section": "Identi\u00a2cation of ORFs putatively encoding autotransporters", "text": "The presence of homologs of the identi\u00a2ed N. meningitidis ORFs in the un\u00a2nished N. gonorrhoeae genome sequence was examined using both the nucleotide and deduced amino acid sequences for screening. In addition to iga encoding IgA1 protease, homologs of NMB1525 (72% identity at the protein level) and NMB1985 (95% identity) were identi\u00a2ed. A nucleotide sequence homologous to NMB0312 was found, but the ORF was disrupted by premature stop codons. Similarly, a region homologous to NMB1969 was found, but the coding region appeared to be split up into two separate ORFs. No homologs were found of ORFs NMB0992, NMB1994 and NMB1998.", "cite_spans": [], "ref_spans": []}, {"section": "Cloning of ORFs NMB0992 and NMB1985 from vaccine strain H44/76", "text": "For the cloning of ORFs, serogroup B strain H44/76 was chosen since it has been used for vaccine development [3, 4] . The ORFs NMB0992 and NMB1985 were selected as \u00a2rst targets for cloning, since they encode proteins homologous to the Hia and Hap proteins of H. in\u00a3uenzae, respectively. Like N. meningitidis, H. in\u00a3uenzae colonizes the upper respiratory tract upon entry of the human body, and the Hia and the Hap proteins were both suggested to play a role in the colonization of epithelial cell layers [26, 27] . Furthermore, phase-variable expression of both ORFs seemed unlikely because of the complete absence (NMB0992) or limited number (NMB1985) of repeated nucleotide sequences [28] .", "cite_spans": [{"start": 109, "end": 112, "text": "[3,", "ref_id": "BIBREF2"}, {"start": 113, "end": 115, "text": "4]", "ref_id": "BIBREF3"}, {"start": 504, "end": 508, "text": "[26,", "ref_id": "BIBREF26"}, {"start": 509, "end": 512, "text": "27]", "ref_id": "BIBREF27"}, {"start": 686, "end": 690, "text": "[28]", "ref_id": "BIBREF28"}], "ref_spans": []}, {"section": "Cloning of ORFs NMB0992 and NMB1985 from vaccine strain H44/76", "text": "DNA fragments containing the ORFs were ampli\u00a2ed from genomic DNA of H44/76 by PCR and amplicons of expected lengths were puri\u00a2ed from the gel and cloned. Their identity was con\u00a2rmed by sequencing. The NMB1985 ORF was completely sequenced. It di\u00a1ered in only two nucleotides from NMB1985 of MC58. The \u00a2rst substitution, at position 4, resulted from the cloning procedure. The second substitution, at position 3229, resulted in a lysine residue at position 1077 of the amino acid sequence, where there is a glutamate in NMB1985 of MC58. NMB0992 of strain H44/76 was previously sequenced by others (accession number AF226374 [15] ). The deduced amino acid sequence of the ORF is 100% identical to that of MC58. The ORFs of NMB0992 and NMB1985 were cloned into expression vectors resulting in plasmids pPU100 and pPU200, respectively (see Section 2). Expression of the genes in E. coli BL21(DE3) led to the production of recombinant proteins (Fig. 1) . The precursor and mature forms of the Hia-homolog NMB0992 have calculated molecular masses (MWs) of 62.1 and 56.5 kDa, respectively, and a protein with an apparent molecular mass (M r ) corresponding to the precursor was produced (Fig. 1, lane 2) . Additional bands with a much higher M r also appeared on the gel (Fig. 1, lane 2) . These probably represented multimeric complexes of the protein. The precursor and processed forms of the Hap-homolog NMB1985 have calculated MWs of 160 kDa and 155 kDa, respectively, and a band with approximately this M r was observed on the gel (Fig. 1, lane 3) . Attempts to determine the N-terminal sequence of the major protein bands were unsuccessful, most probably because the N-termini were blocked. This suggested that in both cases, the majority of the proteins produced corresponded to the unprocessed precursor forms.", "cite_spans": [{"start": 622, "end": 626, "text": "[15]", "ref_id": "BIBREF15"}], "ref_spans": [{"start": 938, "end": 946, "text": "(Fig. 1)", "ref_id": "FIGREF0"}, {"start": 1179, "end": 1195, "text": "(Fig. 1, lane 2)", "ref_id": "FIGREF0"}, {"start": 1263, "end": 1279, "text": "(Fig. 1, lane 2)", "ref_id": "FIGREF0"}, {"start": 1528, "end": 1544, "text": "(Fig. 1, lane 3)", "ref_id": "FIGREF0"}]}, {"section": "Cloning of ORFs NMB0992 and NMB1985 from vaccine strain H44/76", "text": "The Hap protein of H. in\u00a3uenzae was reported to release its functional domain into the medium by autoproteolytic cleavage [27] . Such release was not observed for the Hia protein [29] . To investigate whether the neisserial homologs are proteolytically cleaved in E. coli, medium of E. coli cells expressing the proteins was concentrated by TCA precipitation and analyzed by SDS^PAGE. In neither case was a secreted product detected in the medium.", "cite_spans": [{"start": 122, "end": 126, "text": "[27]", "ref_id": "BIBREF27"}, {"start": 179, "end": 183, "text": "[29]", "ref_id": "BIBREF29"}], "ref_spans": []}, {"section": "Immunogenicity and in vivo expression of NMB0992 and NMB1985", "text": "To investigate whether the Hia-and Hap-homologs NMB0992 and NMB1985 are immunogenic in humans, a collection of sera was tested in Western blot experiments for the presence of antibodies recognizing the recombinant proteins (see Table 3 ). Twelve of a panel of 14 sera of convalescent patients tested recognized both NMB0992 and NMB1985 of strain H44/76, when produced in E. coli (see serum 790245 in Fig. 2A for an example) . Serum 790269 only recognized NMB1985 (Fig. 2B) , whereas serum 780287 only recognized NMB0992 (Fig. 2C) . Of two patients, serum taken at the day of hospital admittance and thus early in disease, could be tested as well. These sera showed a weaker reaction (Fig. 2, panels A and D) , as compared with the convalescent sera. Moreover, in the case of serum 790767, antibodies recognizing NMB1985 were only present at convalescence (Fig. 2D ). All sera of healthy carriers tested (n = 3) contained antibodies recognizing both proteins (Fig. 3A^C) , although the responses appeared lower than those of patient sera (Table 3) . Of one healthy carrier, two sera were available (Fig. 3C) , taken at 9-month interval, during which two di\u00a1erent N. meningitidis strains colonized this person ( Table 3 ). The sera contained antibodies to both NMB0992 and NMB1985, but the responses to NMB0992 decreased over time, whereas the response to NMB1985 was somewhat boosted, possibly as a result of the colonization by the second strain. Three of the four sera of non-carriers did not contain antibodies recognizing either protein (Fig.  3D^F) , whereas one recognized NMB1985 clearly and NMB0992 faintly (Fig. 3G) . Apparently, the person involved had been a carrier prior to the blood sampling. Taken together, the results demonstrate that the Hiaand Hap-homologs NMB0992 and NMB1985 were expressed by a wide range of N. meningitidis strains during infection and colonization and that these proteins are immunogenic in humans. ", "cite_spans": [], "ref_spans": [{"start": 228, "end": 235, "text": "Table 3", "ref_id": "TABREF2"}, {"start": 1037, "end": 1046, "text": "(Table 3)", "ref_id": "TABREF2"}, {"start": 1210, "end": 1217, "text": "Table 3", "ref_id": "TABREF2"}]}, {"section": "Cellular localization of the recombinant proteins in E. coli", "text": "To determine whether the proteins encoded by NMB0992 and NMB1985 were targeted to the OM of E. coli with the functional domains exposed on the bacterial cell surface, two approaches were followed. In the \u00a2rst approach, protease accessibility of the recombinant proteins in whole cells was assessed. Trypsin (Fig. 4A ) and proteinase K (Fig. 4B ) treatment of whole cells expressing the two recombinant proteins revealed that the higher molecular mass bands of NMB0992 were highly sensitive to these proteases, since the bands were digested at low protease concentrations, at which apparently no other bands were a\u00a1ected (Fig. 4A, lane 4 and Fig. 4B, lane 5) . This would suggest that the putative multimeric forms of NMB0992 were accessible for protease digestion at the cell surface. The monomeric bands of NMB0992 and NMB1985 appeared less protease sensitive, suggesting that these proteins are either not surface exposed, or are intrinsically resistant to proteases.", "cite_spans": [], "ref_spans": [{"start": 307, "end": 315, "text": "(Fig. 4A", "ref_id": "FIGREF1"}, {"start": 335, "end": 343, "text": "(Fig. 4B", "ref_id": "FIGREF1"}, {"start": 620, "end": 636, "text": "(Fig. 4A, lane 4", "ref_id": "FIGREF1"}, {"start": 641, "end": 657, "text": "Fig. 4B, lane 5)", "ref_id": "FIGREF1"}]}, {"section": "Cellular localization of the recombinant proteins in E. coli", "text": "In the second approach, serum 780646, which contained antibodies recognizing both NMB0992 and NMB1985, was used in immuno\u00a3uorescence microscopy. This serum was selected on the basis of its limited cross-reaction with E. coli bands in Western blot, and background binding to E. coli proteins was further diminished by pre-adsorption of the serum with E. coli cells containing pET16b. Next, it was incubated with E. coli cells producing either recombinant NMB0992 or NMB1985, or containing the empty vector. Control cells, containing the empty vector, were hardly stained by the serum (Fig. 5A) . The serum very clearly labelled cells expressing recombinant NMB1985, the Hap homolog (Fig. 5C) . Immunostaining of cells expressing the Hia homolog was less clear (Fig. 5B) , but staining was above the level of that of the controls. The integrity of the cells was tested by incubation with anti- serum against the periplasmic protein L-lactamase. This serum stained some of the cells expressing the recombinant proteins, but the level of labelling was lower than with the patient serum (Fig. 5D^F) . The L-lactamase antiserum could e\u00a1ectively stain cells when the OM was disrupted with Triton X-100 (results not shown). These results indicate that antigenic domains of the recombinant proteins were exposed on the cell surface.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "The class of autotransporter proteins might include interesting vaccine constituents since most of them appear to be involved in host^pathogen interactions [30] . A systematic search of the recently published genome sequences of two N. meningitidis strains revealed the presence of eight ORFs putatively encoding autotransporters in the genome of serogroup B strain MC58, six of which were also present in that of serogroup A strain Z2491. The di\u00a1erent repertoire of autotransporter-encoding genes in the two genomes suggests that additional autotransporters might be identi\u00a2ed when more disease isolates are screened. Such additional autotransporters might be less interesting for vaccine development because of lack of conservation. The genome of N. gonorrhoeae strain FA1090 contained only three intact homologs of the N. meningitidis autotransporters. Two disrupted homologs were identi\u00a2ed, which might be intact in other isolates.", "cite_spans": [{"start": 156, "end": 160, "text": "[30]", "ref_id": "BIBREF30"}], "ref_spans": []}, {"section": "Discussion", "text": "Some of the ORFs identi\u00a2ed have appeared in the literature or the GenBank database, apart from their presence in the sequenced genomes. The iga of N. meningitidis isolates have been studied extensively [12] . The nucleotide sequences of NMB0312 and NMB1525 have been identi\u00a2ed by the presence of sequence repeats [13] , indicative of phase-variable expression. A second, unpublished entry was found for NMB0312 (accession number AF118122) and during the preparation of this paper, NMB0312 (designated AutA) was reported to encode a CD4", "cite_spans": [{"start": 202, "end": 206, "text": "[12]", "ref_id": "BIBREF12"}, {"start": 313, "end": 317, "text": "[13]", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "Discussion", "text": "T-cell and B-cell stimulatory antigen [31] . The authors also identi\u00a2ed Fig. 3 . Western blots of membrane preparations of E. coli BL21(DE3) strains expressing recombinant proteins NMB0992 and NMB1985 from pPU100 and pPU200, respectively. Blots were incubated with the sera of healthy carriers (panels A^C), or non-carriers (panels D^F). Panel C shows two blots incubated with the sera of a carrier taken at a 9-month interval, as indicated. Bands corresponding to NMB0992 and NMB1985 are labelled with asterisks and dots, respectively. Fig. 2 . Western blots of membrane preparations of E. coli BL21(DE3) strains expressing recombinant proteins NMB0992 and NMB1985 from pPU100 and pPU200, respectively. Blots were incubated with the patient sera indicated underneath the panels, taken either at hospital admittance or at convalescence, as indicated. Bands corresponding to NMB0992 and NMB1985 are labelled with asterisks and dots, respectively. NMB1525 (designated AutB) as a homolog of NMB0312 and demonstrated that antibodies against this protein failed to react with N. meningitidis grown in vitro. NMB1969 and NMB1985 were very recently entered in the database (accession numbers AJ277537 and AJ242535) without published account. Finally, NMB0992 (designated NhhA [1] ) was identi\u00a2ed as a putative vaccine candidate based upon its homology to Hia of H. in\u00a3uenzae [14] and in a genome-wide screen for antigens [15] . No database entries were found for NMB1994 and NMB1998.", "cite_spans": [{"start": 38, "end": 42, "text": "[31]", "ref_id": "BIBREF31"}, {"start": 1269, "end": 1272, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 1368, "end": 1372, "text": "[14]", "ref_id": "BIBREF14"}, {"start": 1414, "end": 1418, "text": "[15]", "ref_id": "BIBREF15"}], "ref_spans": []}, {"section": "Discussion", "text": "In a \u00a2rst study of the vaccine potential of N. meningitidis autotransporters, we focused on two ORFs, NMB0992 and NMB1985, because they encode proteins that are very homologous to the Hia [26] and Hap [32] proteins of H. in\u00a3uenzae. Moreover, N. meningitidis and H. in\u00a3u-enzae both colonize the upper respiratory tract, and it was suggested that the proteins of H. in\u00a3uenzae might play a role in that process by functioning as adhesins [26, 27] .", "cite_spans": [{"start": 188, "end": 192, "text": "[26]", "ref_id": "BIBREF26"}, {"start": 201, "end": 205, "text": "[32]", "ref_id": "BIBREF32"}, {"start": 435, "end": 439, "text": "[26,", "ref_id": "BIBREF26"}, {"start": 440, "end": 443, "text": "27]", "ref_id": "BIBREF27"}], "ref_spans": []}, {"section": "Discussion", "text": "Expression of NMB0992 of serogroup B strain H44/76 in E. coli yielded a protein with an M r of 62 kDa, most probably representing the unprocessed full-length precursor protein, and two bands with M r s of over 200 kDa. These higher M r s bands might represent multimeric complexes, which appear to be surface-exposed, as suggested by the protease-accessibility experiments. Consistently, the immuno\u00a3uorescence experiments indicated that at least a proportion of the recombinant protein produced was cellsurface-exposed.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "The Hia homolog of strain MC58 was cloned in an independent study [14] , and antibodies raised against this protein recognized a band with an M r of over 200 kDa. Higher MW complexes were not observed when Hia of H. in\u00a3uenzae was expressed in either H. in\u00a3uenzae or E. coli [29] . The Hia protein and its neisserial homolog di\u00a1er considerably in size, being 1098 and 591 amino acid residues long, respectively. The C-terminal 318 residues of Hia \u00a2t with the model proposed for the autotransporter trans- locator domain [8] since they putatively constitute a Lbarrel of 14 amphipathic L-strands. In a sequence alignment, the translocator domain of NMB0992 appears to miss about 140 residues, which would result in the loss of about six to eight L-strands. The remaining number of L-strands would be too low for the formation of Lbarrel with a pore of su\u00a4cient size to allow for the translocation of a polypeptide chain. Possibly, multimer formation could result in the formation of a L-barrel with a larger pore size. Such a multimeric organization would represent a new type of molecular organization for the autotransporter L-barrel domain, and would be reminiscent of the multimeric L-barrel formed in the OM by the TolC protein [33] . Like many of the autotransporters [9] , the Hia protein of H. in\u00a3uenzae and its neisserial homologs were predicted to contain a long signal sequence of Fig. 5 . Immuno\u00a3uorescence microscopy of E. coli BL21(DE3) cells expressing recombinant proteins NMB0992 and NMB1985 from pPU100 and pPU200, respectively. Cells expressing recombinant proteins were incubated with patient serum 780646 or polyclonal rabbit serum recognizing periplasmic L-lactamase. Binding of antibodies was detected with anti-human or anti-rabbit IgG antibodies, respectively, both coupled to the \u00a3uorogenic dye Alexa. Cells were visualized by \u00a3uorescence microscopy. Panels A and D: background binding of serum to E. coli BL21(DE3) containing pET16b. Panels B and E: binding of serum to E. coli BL21(DE3) containing pPU100. Panel C and F: binding of serum to E. coli BL21(DE3) containing pPU200. approximately 50 amino acid residues. When compared to normal signal sequences, they seemed extended at the Nterminus with aromatic and hydrophobic residues near the N-terminus and a signature sequence IAVSELAR preceding the charged N-domain [9] .", "cite_spans": [{"start": 66, "end": 70, "text": "[14]", "ref_id": "BIBREF14"}, {"start": 274, "end": 278, "text": "[29]", "ref_id": "BIBREF29"}, {"start": 519, "end": 522, "text": "[8]", "ref_id": "BIBREF8"}, {"start": 1231, "end": 1235, "text": "[33]", "ref_id": "BIBREF33"}, {"start": 1272, "end": 1275, "text": "[9]", "ref_id": "BIBREF9"}, {"start": 2346, "end": 2349, "text": "[9]", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "Discussion", "text": "The putative signal sequence of the Hap homologs of the Neisseriae are predicted to be 42 amino acid residues long, which is markedly longer than the 25 residues of the H. in\u00a3uenzae Hap signal sequence [22] . These signal sequences, however, do not have the characteristics of the long signal sequences of autotransporters. The neisserial Hap-like proteins showed the highest homology with Hap of H. in\u00a3uenzae in the functional domain (65% similarity), with a serine protease consensus motif located at the same position in the protein sequence. The C-terminal domains are less homologous (57% similarity). Thus, the functional domains of the proteins might share a similar function, most probably in adhesion to host cells [27] , whereas the mode of translocation to the cell surface and the proteolytic cleavage of the proteins could be di\u00a1erent. For H. in\u00a3uenzae, Hap autoproteolytic processing was observed upon expression in E. coli [22] , which was not the case for NMB1985 of H44/76. This might indicate that autoproteolytic cleavage of the N. meningitidis protein does not occur. Alternatively, the majority of protein produced was not properly localized in E. coli and appeared in inclusion bodies. Nevertheless, immuno\u00a3uorescence microscopy suggested that at least a proportion of the protein produced was exposed at the cell surface. A possibly important difference between the neisserial Hap homologs is that the NMA0457 protein of serogroup A strain Z2491 contains an RGD motif, which is a binding site for host proteoglycans in \u00a2lamentous hemagglutinin of B. pertussis [34] . This motif is absent in the serogroup B Hap homologs and in the H. in\u00a3uenzae Hap.", "cite_spans": [{"start": 202, "end": 206, "text": "[22]", "ref_id": "BIBREF22"}, {"start": 724, "end": 728, "text": "[27]", "ref_id": "BIBREF27"}, {"start": 938, "end": 942, "text": "[22]", "ref_id": "BIBREF22"}, {"start": 1583, "end": 1587, "text": "[34]", "ref_id": "BIBREF34"}], "ref_spans": []}, {"section": "Discussion", "text": "Sera of convalescent patients, each infected by a di\u00a1er-ent N. meningitidis isolate, contained antibodies that recognized either NMB0992 or NMB1985, or, in most cases, both proteins. Apparently, during infection both proteins were expressed by most of the N. meningitidis isolates. Moreover, limited antigenic variation is suggested, since antibodies in most tested patient sera recognized the recombinant proteins cloned from strain H44/76. The presence of genes encoding Hap-homologs in clinical isolates had not been studied to date, but is clearly demonstrated here. The gene encoding the Hia-homolog of MC58 was cloned in two independent studies [14, 15] and both showed sequence variation of the Hia homologs in N. meningitidis. However, in both studies, antibodies raised against the recombinant protein appeared to be bactericidal and to recognize proteins from various strains. The data presented here add to this information the notion of expression during infection and the inter-strain cross-reactivity of human antibodies. In view of the reported sequence variation, this cross-reactivity may be somewhat surprising, but apparently the proteins share common epitopes that might be functionally important. Interestingly, we found no binding of antibodies raised against the C-terminal domains of the Hap and Hia proteins of H. in\u00a3uenzae to the recombinant N. meningitidis H44/76 proteins (results not shown).", "cite_spans": [{"start": 651, "end": 655, "text": "[14,", "ref_id": "BIBREF14"}, {"start": 656, "end": 659, "text": "15]", "ref_id": "BIBREF15"}], "ref_spans": []}, {"section": "Discussion", "text": "Included in our tests were sera from healthy carriers that contained antibodies against both recombinant proteins, suggesting that the proteins were also expressed during asymptomatic colonization of the upper respiratory tract.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "In conclusion, we have identi\u00a2ed the repertoire of autotransporters present in the genomes of MC58 and Z249. Further characterization of two of these genes, encoding homologs of the Hia and Hap proteins of H. in\u00a3uenzae, showed that these proteins were most likely present during infection and colonization. Therefore, these proteins are interesting candidates to be included in a vaccine against N. meningitidis.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Meningococcal disease: still with us", "authors": [{"first": "H", "middle": [], "last": "Peltola", "suffix": ""}], "year": 1983, "venue": "Rev. Infect. Dis", "link": "25253434"}, "BIBREF1": {"title": "Epidemiology and pathogenesis of Neisseria meningitidis", "authors": [{"first": "Y", "middle": ["L"], "last": "Tzeng", "suffix": ""}, {"first": "D", "middle": ["S"], "last": "Stephens", "suffix": ""}], "year": 2000, "venue": "Microbes Infect", "link": "21352465"}, "BIBREF2": {"title": "E\u00a1ect of outer membrane vesicle vaccine against group B meningococcal disease in Norway", "authors": [{"first": "G", "middle": [], "last": "Bjune", "suffix": ""}, {"first": "E", "middle": ["A"], "last": "H\u00f6iby", "suffix": ""}, {"first": "J", "middle": ["K"], "last": "Gronnesby", "suffix": ""}, {"first": "O", "middle": [], "last": "Arnesen", "suffix": ""}, {"first": "J", "middle": ["H"], "last": "Fredriksen", "suffix": ""}, {"first": "A", "middle": [], "last": "Halstensen", "suffix": ""}, {"first": "E", "middle": [], "last": "Holten", "suffix": ""}, {"first": "A", "middle": ["K"], "last": "Lindbak", "suffix": ""}, {"first": "H", "middle": [], "last": "N\u00f6kleby", "suffix": ""}, {"first": "E", "middle": [], "last": "Rosenqvist", "suffix": ""}], "year": 1991, "venue": "Lancet", "link": null}, "BIBREF3": {"title": "Immunogenicity and safety of a hexavalent meningococcal outermembrane-vesicle vaccine in children of 2-3 and 7-8 years of age", "authors": [{"first": "E", "middle": ["D"], "last": "De Kleijn", "suffix": ""}, {"first": "R", "middle": [], "last": "De Groot", "suffix": ""}, {"first": "J", "middle": [], "last": "Labadie", "suffix": ""}, {"first": "A", "middle": ["B"], "last": "Lafeber", "suffix": ""}, {"first": "G", "middle": [], "last": "Van Den Dobbelsteen", "suffix": ""}, {"first": "L", "middle": [], "last": "Van Alphen", "suffix": ""}, {"first": "H", "middle": [], "last": "Van Dijken", "suffix": ""}, {"first": "B", "middle": [], "last": "Kuipers", "suffix": ""}, {"first": "G", "middle": ["W"], "last": "Van Omme", "suffix": ""}, {"first": "M", "middle": [], "last": "Wala", "suffix": ""}, {"first": "R", "middle": [], "last": "Juttmann", "suffix": ""}, {"first": "H", "middle": ["C"], "last": "Ru \u00abmke", "suffix": ""}], "year": 2000, "venue": "Vaccine", "link": "39323509"}, "BIBREF4": {"title": "E\u00a1ect of sequence variation in meningococcal PorA outer membrane protein on the e\u00a1ectiveness of a hexavalent PorA outer membrane vesicle vaccine", "authors": [{"first": "S", "middle": ["L"], "last": "Martin", "suffix": ""}, {"first": "R", "middle": [], "last": "Borrow", "suffix": ""}, {"first": "P", "middle": [], "last": "Van Der Ley", "suffix": ""}, {"first": "M", "middle": [], "last": "Dawson", "suffix": ""}, {"first": "A", "middle": ["J"], "last": "Fox", "suffix": ""}, {"first": "K", "middle": ["A"], "last": "Cartwright", "suffix": ""}], "year": 2000, "venue": "Vaccine", "link": "34598931"}, "BIBREF6": {"title": "Complete DNA sequence of a serogroup A strain of Neisseria meningitidis Z2491", "authors": [{"first": "S", "middle": ["R"], "last": "Klee", "suffix": ""}, {"first": "G", "middle": [], "last": "Morelli", "suffix": ""}, {"first": "D", "middle": [], "last": "Basham", "suffix": ""}, {"first": "D", "middle": [], "last": "Brown", "suffix": ""}, {"first": "T", "middle": [], "last": "Chillingworth", "suffix": ""}, {"first": "R", "middle": ["M"], "last": "Davies", "suffix": ""}, {"first": "P", "middle": [], "last": "Davis", "suffix": ""}, {"first": "K", "middle": [], "last": "Devlin", "suffix": ""}, {"first": "T", "middle": [], "last": "Feltwell", "suffix": ""}, {"first": "N", "middle": [], "last": "Hamlin", "suffix": ""}, {"first": "S", "middle": [], "last": "Holroyd", "suffix": ""}, {"first": "K", "middle": [], "last": "Jagels", "suffix": ""}, {"first": "S", "middle": [], "last": "Leather", "suffix": ""}, {"first": "S", "middle": [], "last": "Moule", "suffix": ""}, {"first": "K", "middle": [], "last": "Mungall", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Quail", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Rajandream", "suffix": ""}, {"first": "K", "middle": ["M"], "last": "Rutherford", "suffix": ""}, {"first": "M", "middle": [], "last": "Simmonds", "suffix": ""}, {"first": "J", "middle": [], "last": "Skelton", "suffix": ""}, {"first": "S", "middle": [], "last": "Whitehead", "suffix": ""}, {"first": "B", "middle": ["G"], "last": "Spratt", "suffix": ""}, {"first": "B", "middle": ["G"], "last": "Barrell", "suffix": ""}], "year": 2000, "venue": "Nature", "link": "4430718"}, "BIBREF8": {"title": "A novel family of channelforming, autotransporting, bacterial virulence factors", "authors": [{"first": "B", "middle": ["J"], "last": "Loveless", "suffix": ""}, {"first": "M", "middle": ["H J"], "last": "Saier", "suffix": ""}], "year": 1997, "venue": "Mol. Membr. Biol", "link": "40556284"}, "BIBREF9": {"title": "The great escape: structure and function of the autotransporter proteins", "authors": [{"first": "I", "middle": ["R"], "last": "Henderson", "suffix": ""}, {"first": "F", "middle": [], "last": "Navarro-Garcia", "suffix": ""}, {"first": "J", "middle": ["P"], "last": "Nataro", "suffix": ""}], "year": 1998, "venue": "Trends Microbiol", "link": "44287043"}, "BIBREF10": {"title": "Antibody and cell-mediated immune responses to booster immunization with a new acellular pertussis vaccine in school children", "authors": [{"first": "M", "middle": ["N"], "last": "Tran", "suffix": ""}, {"first": "K", "middle": [], "last": "Edelman", "suffix": ""}, {"first": "Q", "middle": [], "last": "He", "suffix": ""}, {"first": "M", "middle": ["K"], "last": "Viljanen", "suffix": ""}, {"first": "H", "middle": [], "last": "Arvilommi", "suffix": ""}, {"first": "J", "middle": [], "last": "Mertsola", "suffix": ""}], "year": 1998, "venue": "Vaccine", "link": "41408210"}, "BIBREF11": {"title": "Gene structure and extracellular secretion of Neisseria gonorrhoeae IgA protease", "authors": [{"first": "J", "middle": [], "last": "Pohlner", "suffix": ""}, {"first": "R", "middle": [], "last": "Halter", "suffix": ""}, {"first": "K", "middle": [], "last": "Beyreuther", "suffix": ""}, {"first": "T", "middle": ["F"], "last": "Meyer", "suffix": ""}], "year": 1987, "venue": "Nature", "link": "25569"}, "BIBREF12": {"title": "Comparative characterization of the iga gene encoding IgA1 protease in Neisseria meningitidis, Neisseria gonorrhoeae and Haemophilus in\u00a3uenzae", "authors": [{"first": "H", "middle": [], "last": "Lomholt", "suffix": ""}, {"first": "K", "middle": [], "last": "Poulsen", "suffix": ""}, {"first": "M", "middle": [], "last": "Kilian", "suffix": ""}], "year": 1995, "venue": "Mol. Microbiol", "link": "34192660"}, "BIBREF13": {"title": "Tetranucleotide repeats identify novel virulence determinant homologues in Neisseria meningitidis", "authors": [{"first": "I", "middle": ["R"], "last": "Peak", "suffix": ""}, {"first": "M", "middle": ["P"], "last": "Jennings", "suffix": ""}, {"first": "D", "middle": ["W"], "last": "Hood", "suffix": ""}, {"first": "E", "middle": ["R"], "last": "Moxon", "suffix": ""}], "year": 1999, "venue": "Microb. Pathog", "link": "31863876"}, "BIBREF14": {"title": "Identi\u00a2cation and characterisation of a novel conserved outer membrane protein from Neisseria meningitidis", "authors": [{"first": "I", "middle": ["R"], "last": "Peak", "suffix": ""}, {"first": "Y", "middle": [], "last": "Srikhanta", "suffix": ""}, {"first": "", "middle": [], "last": "Dieckelmann", "suffix": ""}, {"first": "E", "middle": ["R"], "last": "Moxon", "suffix": ""}, {"first": "M", "middle": ["P"], "last": "Jennings", "suffix": ""}], "year": 2000, "venue": "FEMS Immunol. Med. Microbiol", "link": "38605357"}, "BIBREF15": {"title": "Identi\u00a2cation of vaccine candidates against serogroup B meningococcus by whole-genome sequencing", "authors": [{"first": "M", "middle": [], "last": "Pizza", "suffix": ""}, {"first": "V", "middle": [], "last": "Scarlato", "suffix": ""}, {"first": "V", "middle": [], "last": "Masignani", "suffix": ""}, {"first": "M", "middle": ["M"], "last": "Giuliani", "suffix": ""}, {"first": "B", "middle": [], "last": "Arico", "suffix": ""}, {"first": "M", "middle": [], "last": "Comanducci", "suffix": ""}, {"first": "G", "middle": ["T"], "last": "Jennings", "suffix": ""}, {"first": "L", "middle": [], "last": "Baldi", "suffix": ""}, {"first": "E", "middle": [], "last": "Bartolini", "suffix": ""}, {"first": "B", "middle": [], "last": "Capecchi", "suffix": ""}, {"first": "C", "middle": ["L"], "last": "Galeotti", "suffix": ""}, {"first": "E", "middle": [], "last": "Luzzi", "suffix": ""}, {"first": "R", "middle": [], "last": "Manetti", "suffix": ""}, {"first": "E", "middle": [], "last": "Marchetti", "suffix": ""}, {"first": "M", "middle": [], "last": "Mora", "suffix": ""}, {"first": "S", "middle": [], "last": "Nuti", "suffix": ""}, {"first": "G", "middle": [], "last": "Ratti", "suffix": ""}, {"first": "L", "middle": [], "last": "Santini", "suffix": ""}, {"first": "S", "middle": [], "last": "Savino", "suffix": ""}, {"first": "M", "middle": [], "last": "Scarselli", "suffix": ""}, {"first": "E", "middle": [], "last": "Storni", "suffix": ""}, {"first": "P", "middle": [], "last": "Zuo", "suffix": ""}, {"first": "M", "middle": [], "last": "Broeker", "suffix": ""}, {"first": "E", "middle": [], "last": "Hundt", "suffix": ""}, {"first": "B", "middle": [], "last": "Knapp", "suffix": ""}, {"first": "E", "middle": [], "last": "Blair", "suffix": ""}, {"first": "T", "middle": [], "last": "Mason", "suffix": ""}, {"first": "H", "middle": [], "last": "Tettelin", "suffix": ""}, {"first": "D", "middle": ["W"], "last": "Hood", "suffix": ""}, {"first": "A", "middle": ["C"], "last": "Je\u00a1ries", "suffix": ""}, {"first": "N", "middle": ["J"], "last": "Saunders", "suffix": ""}, {"first": "D", "middle": ["M"], "last": "Grano\u00a1", "suffix": ""}, {"first": "J", "middle": ["C"], "last": "Venter", "suffix": ""}, {"first": "E", "middle": ["R"], "last": "Moxon", "suffix": ""}, {"first": "G", "middle": [], "last": "Grandi", "suffix": ""}, {"first": "R", "middle": [], "last": "Rappuoli", "suffix": ""}], "year": 2000, "venue": "Science", "link": "43349049"}, "BIBREF16": {"title": "Clonal diversity of Neisseria meningitidis from a population of asymptomatic carriers", "authors": [{"first": "D", "middle": ["A"], "last": "Caugant", "suffix": ""}, {"first": "B", "middle": ["E"], "last": "Kristiansen", "suffix": ""}, {"first": "L", "middle": ["O"], "last": "Fr\u00f6holm", "suffix": ""}, {"first": "K", "middle": [], "last": "Bovre", "suffix": ""}, {"first": "R", "middle": ["K"], "last": "Selander", "suffix": ""}], "year": 1988, "venue": "Infect. Immun", "link": "5790000"}, "BIBREF17": {"title": "Identi\u00a2cation of a glycoprotein produced by enterotoxigenic Escherichia coli. Infect. Immun", "authors": [{"first": "C", "middle": [], "last": "Lindenthal", "suffix": ""}, {"first": "E", "middle": ["A"], "last": "Elsinghorst", "suffix": ""}], "year": 1999, "venue": "", "link": null}, "BIBREF18": {"title": "Characterization of an exported protease from Shiga toxin-producing Escherichia coli", "authors": [{"first": "S", "middle": [], "last": "Djafari", "suffix": ""}, {"first": "F", "middle": [], "last": "Ebel", "suffix": ""}, {"first": "C", "middle": [], "last": "Deibel", "suffix": ""}, {"first": "S", "middle": [], "last": "Kramer", "suffix": ""}, {"first": "M", "middle": [], "last": "Hudel", "suffix": ""}, {"first": "T", "middle": [], "last": "Chakraborty", "suffix": ""}], "year": 1997, "venue": "Mol. Microbiol", "link": "29864020"}, "BIBREF19": {"title": "Vag8, a Bordetella pertussis bvg-regulated protein", "authors": [{"first": "T", "middle": ["M"], "last": "Finn", "suffix": ""}, {"first": "D", "middle": ["F"], "last": "Amsbaugh", "suffix": ""}], "year": 1998, "venue": "Infect. Immun", "link": "29109325"}, "BIBREF20": {"title": "Gapped BLAST and PSI-BLAST : a new generation of protein database search programs", "authors": [{"first": "S", "middle": ["F"], "last": "Altschul", "suffix": ""}, {"first": "T", "middle": ["L"], "last": "Madden", "suffix": ""}, {"first": "A", "middle": ["A"], "last": "Scha \u00ab\u00a1er", "suffix": ""}, {"first": "J", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "Z", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "W", "middle": [], "last": "Miller", "suffix": ""}, {"first": "D", "middle": ["J"], "last": "Lipman", "suffix": ""}], "year": 1997, "venue": "Nucleic Acids Res", "link": null}, "BIBREF21": {"title": "A neural network method for identi\u00a2cation of prokaryotic and eukaryotic signal peptides and prediction of their cleavage sites", "authors": [{"first": "H", "middle": [], "last": "Nielsen", "suffix": ""}, {"first": "J", "middle": [], "last": "Engelbrecht", "suffix": ""}, {"first": "S", "middle": [], "last": "Brunak", "suffix": ""}, {"first": "G", "middle": [], "last": "Von Heijne", "suffix": ""}], "year": 1997, "venue": "Int. J. Neural Syst", "link": "6557809"}, "BIBREF22": {"title": "Structural determinants of processing and secretion of the Haemophilus in\u00a3uenzae Hap protein", "authors": [{"first": "D", "middle": ["R"], "last": "Hendrixson", "suffix": ""}, {"first": "M", "middle": ["L"], "last": "De La Morena", "suffix": ""}, {"first": "C", "middle": [], "last": "Stathopoulos", "suffix": ""}, {"first": "", "middle": [], "last": "St Geme", "suffix": ""}], "year": 1997, "venue": "Mol. Microbiol", "link": "24809427"}, "BIBREF23": {"title": "Use of T7 RNA polymerase to direct expression of cloned genes", "authors": [{"first": "F", "middle": ["W"], "last": "Studier", "suffix": ""}, {"first": "A", "middle": ["H"], "last": "Rosenberg", "suffix": ""}, {"first": "J", "middle": ["J"], "last": "Dunn", "suffix": ""}, {"first": "J", "middle": ["W"], "last": "Dubendor\u00a1", "suffix": ""}], "year": 1990, "venue": "Methods Enzymol", "link": "5177351"}, "BIBREF24": {"title": "Molecular characterization of the structural gene for the lactoferrin receptor of the meningococcal strain H44/ 76", "authors": [{"first": "A", "middle": [], "last": "Pettersson", "suffix": ""}, {"first": "V", "middle": [], "last": "Klarenbeek", "suffix": ""}, {"first": "J", "middle": [], "last": "Van Deurzen", "suffix": ""}, {"first": "J", "middle": ["T"], "last": "Poolman", "suffix": ""}, {"first": "J", "middle": [], "last": "Tommassen", "suffix": ""}], "year": 1994, "venue": "Microb. Pathog", "link": null}, "BIBREF25": {"title": "Mutational analysis of the Bordetella pertussis \u00a2m/fha gene cluster: identi\u00a2cation of a gene with sequence similarities to haemolysin accessory genes involved in export of FHA", "authors": [{"first": "R", "middle": ["J"], "last": "Willems", "suffix": ""}, {"first": "C", "middle": [], "last": "Geuijen", "suffix": ""}, {"first": "H", "middle": ["G"], "last": "Van Der Heide", "suffix": ""}, {"first": "G", "middle": [], "last": "Renauld", "suffix": ""}, {"first": "P", "middle": [], "last": "Bertin", "suffix": ""}, {"first": "W", "middle": ["M"], "last": "Van Den Akker", "suffix": ""}, {"first": "C", "middle": [], "last": "Locht", "suffix": ""}, {"first": "F", "middle": ["R"], "last": "Mooi", "suffix": ""}], "year": 1994, "venue": "Mol. Microbiol", "link": null}, "BIBREF26": {"title": "Identi\u00a2cation of a second family of high-molecular-weight adhesion proteins expressed by non-typable Haemophilus in\u00a3uenzae", "authors": [{"first": "S", "middle": ["J"], "last": "Barenkamp", "suffix": ""}, {"first": "Iii", "middle": [], "last": "St Geme", "suffix": ""}, {"first": "J", "middle": ["W"], "last": "", "suffix": ""}], "year": 1996, "venue": "Mol. Microbiol", "link": null}, "BIBREF27": {"title": "The Haemophilus in\u00a3uenzae Hap serine protease promotes adherence and microcolony formation, potentiated by a soluble host protein", "authors": [{"first": "D", "middle": ["R"], "last": "Hendrixson", "suffix": ""}, {"first": "Iii", "middle": [], "last": "St Geme", "suffix": ""}, {"first": "J", "middle": ["W"], "last": "", "suffix": ""}], "year": 1998, "venue": "Mol. Cell", "link": "13240389"}, "BIBREF28": {"title": "Repeat-associated phase variable genes in the complete genome sequence of Neisseria meningitidis strain MC58", "authors": [{"first": "N", "middle": ["J"], "last": "Saunders", "suffix": ""}, {"first": "A", "middle": ["C"], "last": "Je\u00a1ries", "suffix": ""}, {"first": "J", "middle": ["F"], "last": "Peden", "suffix": ""}, {"first": "D", "middle": ["W"], "last": "Hood", "suffix": ""}, {"first": "H", "middle": [], "last": "Tettelin", "suffix": ""}, {"first": "R", "middle": [], "last": "Rappuoli", "suffix": ""}, {"first": "E", "middle": ["R"], "last": "Moxon", "suffix": ""}], "year": 2000, "venue": "Mol. Microbiol", "link": "38204298"}, "BIBREF29": {"title": "The Haemophilus in\u00a3uenzae Hia adhesin is an autotransporter protein that remains uncleaved at the C terminus and fully cell associated", "authors": [{"first": "", "middle": [], "last": "St", "suffix": ""}, {"first": "J", "middle": ["W"], "last": "Geme", "suffix": ""}, {"first": "D", "middle": [], "last": "Cutter", "suffix": ""}], "year": 2000, "venue": "J. Bacteriol", "link": "7929227"}, "BIBREF30": {"title": "Virulence functions of autotransporter proteins", "authors": [{"first": "I", "middle": ["R"], "last": "Henderson", "suffix": ""}, {"first": "J", "middle": ["P"], "last": "Nataro", "suffix": ""}], "year": 2001, "venue": "Infect. Immun", "link": "5178330"}, "BIBREF31": {"title": "Auto-transporter A protein of Neisseria meningitidis: a potent CD4+ T-cell and B-cell stimulating antigen detected by expression cloning", "authors": [{"first": "K", "middle": [], "last": "Ait-Tahar", "suffix": ""}, {"first": "K", "middle": ["G"], "last": "Wooldridge", "suffix": ""}, {"first": "D", "middle": ["P"], "last": "Turner", "suffix": ""}, {"first": "M", "middle": [], "last": "Atta", "suffix": ""}, {"first": "I", "middle": [], "last": "Todd", "suffix": ""}, {"first": "D", "middle": ["A"], "last": "Ala&apos;aldeen", "suffix": ""}], "year": 2000, "venue": "Mol. Microbiol", "link": "31684605"}, "BIBREF32": {"title": "A Haemophilus in\u00a3uenzae IgA protease-like protein promotes intimate interaction with human epithelial cells", "authors": [{"first": "", "middle": [], "last": "St", "suffix": ""}, {"first": "J", "middle": ["W"], "last": "Geme", "suffix": ""}, {"first": "M", "middle": ["L"], "last": "De La Morena", "suffix": ""}, {"first": "S", "middle": [], "last": "Falkow", "suffix": ""}], "year": 1994, "venue": "Mol. Microbiol", "link": "30615746"}, "BIBREF33": {"title": "Crystal structure of the bacterial membrane protein TolC central to multidrug e\u00a5ux and protein export", "authors": [{"first": "V", "middle": [], "last": "Koronakis", "suffix": ""}, {"first": "A", "middle": [], "last": "Shar\u00a1", "suffix": ""}, {"first": "E", "middle": [], "last": "Koronakis", "suffix": ""}, {"first": "B", "middle": [], "last": "Luisi", "suffix": ""}, {"first": "C", "middle": [], "last": "Hughes", "suffix": ""}], "year": 2000, "venue": "Nature", "link": null}, "BIBREF34": {"title": "Recognition of a bacterial adhesion by an integrin : macrophage CR3 (KML2, CD11b/CD18) binds \u00a2la-mentous hemagglutinin of Bordetella pertussis", "authors": [{"first": "D", "middle": [], "last": "Relman", "suffix": ""}, {"first": "E", "middle": [], "last": "Tuomanen", "suffix": ""}, {"first": "S", "middle": [], "last": "Falkow", "suffix": ""}, {"first": "D", "middle": ["T"], "last": "Golenbock", "suffix": ""}, {"first": "K", "middle": [], "last": "Saukkonen", "suffix": ""}, {"first": "S", "middle": ["D"], "last": "Wright", "suffix": ""}], "year": 1990, "venue": "Cell", "link": null}}, "ref_entries": {"FIGREF0": {"text": "Fig. 1. Overproduction of recombinant neisserial autotransporter proteins NMB0992 and NMB1985 in E. coli. Whole cell lysates were analyzed by SDS^PAGE, followed by staining with Coomassie brilliant blue. Lane M: MW markers indicated in kDa; lane 1: BL21(DE3) containing vector pET16b ; lane 2: BL21(DE3) containing pPU100 encoding NMB0992; lane 3: BL21(DE3) containing pPU200 encoding NMB1985. Bands corresponding to NMB0992 and NMB1985 are labelled with asterisks and dot, respectively.", "type": "figure"}, "FIGREF1": {"text": "Fig. 4. Protease treatment of E. coli BL21(DE3) cells expressing recombinant proteins NMB0992 and NMB1985 from pPU100 and pPU200, respectively. Whole cells were treated with trypsin (panel A) or proteinase K (panel B). The amount of protease added is indicated in Wg ml 31 at the bottom of the lanes. Panel A: lane M: MW marker indicated in kDa; lanes 1,2: BL21(DE3) containing pET16b; lanes 3^5: BL21(DE3) containing pPU100; lanes 6^8: BL21(DE3) containing pPU200. Panel B: lane M: MW marker indicated in kDa; lanes 1^3: BL21(DE3) containing pET16b ; lanes 4^8: BL21(DE3) containing pPU100; lanes 9^13: BL21(DE3) containing pPU200. Bands corresponding to NMB0992 and NMB1985 are labelled with asterisks and dot, respectively. The bands corresponding to the major porin are labelled with diamonds.", "type": "figure"}, "TABREF1": {"text": "Identi\u00a2ed ORFs in the N. meningitidis genomes with homology to known autotransportersThe % identity and similarity given refers to the derived amino acid sequences of the ORFs.", "type": "table"}, "TABREF2": {"text": "Presence of antibodies against the recombinant proteins NMB0992 and NMB1985 in human sera", "type": "table"}}}
{"paper_id": "17430811", "_pdf_hash": "5f431f4bb3beb0d4597fbfd556ee29f7b245436f", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "A framework for the design for testability of communication protocols", "authors": [{"first": "S", "middle": ["T"], "last": "Vuong", "suffix": ""}, {"first": "A", "middle": ["A F"], "last": "Loureiro", "suffix": ""}, {"first": "S", "middle": ["T"], "last": "Chanson", "suffix": ""}], "year": 1993, "venue": "Proc. 6th International IFIP Workshop on Protocol Test Systems", "link": "37274858"}, "BIBREF1": {"title": "Design for testability -a survey", "authors": [{"first": "T", "middle": ["W"], "last": "Wiliams", "suffix": ""}, {"first": "K", "middle": ["P"], "last": "Parker", "suffix": ""}], "year": 1982, "venue": "IEEE Transactions on Computers, C", "link": "29395828"}, "BIBREF2": {"title": "Hardware testing and software metrics", "authors": [{"first": "D", "middle": [], "last": "Hoffman", "suffix": ""}], "year": 1989, "venue": "Proc. of Pacific Northwest Software Quality Conference", "link": null}, "BIBREF3": {"title": "Testability of software components", "authors": [{"first": "R", "middle": ["S"], "last": "Freedman", "suffix": ""}], "year": 1991, "venue": "IEEE Transaction on Software Engineering", "link": "3015591"}, "BIBREF4": {"title": "On evaluation of testability of protocol structures", "authors": [{"first": "A", "middle": [], "last": "Petrenko", "suffix": ""}, {"first": "R", "middle": [], "last": "Dssouli", "suffix": ""}, {"first": "H", "middle": [], "last": "Koenig", "suffix": ""}], "year": 1993, "venue": "Proc. 6 th International IFIP Workshop on Protocol Test Systems", "link": "5512270"}, "BIBREF5": {"title": "Test generation for VLSI circuits from testability profile distribution", "authors": [{"first": "H", "middle": [], "last": "Farhat", "suffix": ""}], "year": 2001, "venue": "Proc CAINE-2001: 14 th International Conference on Computer Applications in Industry and Engineering", "link": "43161533"}, "BIBREF6": {"title": "On Testability Analysis of Combinational Networks", "authors": [{"first": "F", "middle": [], "last": "Brglez", "suffix": ""}], "year": 1984, "venue": "Proc. Int. Symposium on Circuits and Systems (ISCAS)", "link": "59814316"}, "BIBREF7": {"title": "A Series of Impulse Functions as a Model for Random Detectability Profiles", "authors": [{"first": "H", "middle": [], "last": "Farhat", "suffix": ""}], "year": 1993, "venue": "Applied Mathematics Letters", "link": "122350749"}, "BIBREF8": {"title": "A New Metric for the Testability of Communication Protocols", "authors": [{"first": "A", "middle": [], "last": "Chung", "suffix": ""}, {"first": "T", "middle": [], "last": "Huang", "suffix": ""}], "year": 2002, "venue": "Proc. International Conference on Engineering, Information Technology, e-Business, and Applications (CSITeA'02)", "link": null}, "BIBREF9": {"title": "Specification of a", "authors": [], "year": 1983, "venue": "Transport Protocol for Computer Communications", "link": null}, "BIBREF10": {"title": "Further Study of a Metric for the Testability of Communication Protocols", "authors": [{"first": "A", "middle": [], "last": "Chung", "suffix": ""}, {"first": "T", "middle": [], "last": "Huang", "suffix": ""}], "year": 2003, "venue": "Proc. International Conference on Engineering, Information Technology, e-Business, and Applications (CSITeA'03)", "link": null}}, "ref_entries": {}}
{"paper_id": "17430819", "_pdf_hash": "43356c210b0bcc0743c4bd8a8364371b3cb5ec99", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Logistics in Manufacturing", "authors": [{"first": "C", "middle": [], "last": "Gopal", "suffix": ""}, {"first": "G", "middle": [], "last": "Cahill", "suffix": ""}], "year": 1992, "venue": "", "link": "166998294"}, "BIBREF1": {"title": "A computerized vendor rating system", "authors": [{"first": "A", "middle": [], "last": "Ghobadian", "suffix": ""}, {"first": "A", "middle": [], "last": "Stainer", "suffix": ""}, {"first": "T", "middle": [], "last": "Kiss", "suffix": ""}], "year": 1993, "venue": "Proceedings of the First International Symposium on Logistics, the University of Nottingham", "link": null}, "BIBREF2": {"title": "An analysis of vendor selection systems and decisions", "authors": [{"first": "G", "middle": ["W"], "last": "Dickson", "suffix": ""}], "year": 1966, "venue": "Journal of Purchasing", "link": null}, "BIBREF3": {"title": "Vendor selection criteria and methods", "authors": [{"first": "C", "middle": ["A"], "last": "Weber", "suffix": ""}, {"first": "J", "middle": ["R"], "last": "Current", "suffix": ""}, {"first": "W", "middle": ["C"], "last": "Benton", "suffix": ""}], "year": 1991, "venue": "European Journal of Operational Research", "link": "119897961"}, "BIBREF4": {"title": "Analytic network process and multi-period goal programming integration in purchasing decisions", "authors": [{"first": "E", "middle": ["A"], "last": "Demirtas", "suffix": ""}, {"first": "O", "middle": [], "last": "Ustun", "suffix": ""}], "year": "", "venue": "Computer & Industrial Engineering", "link": "12819305"}, "BIBREF5": {"title": "An approach to vendor performance evaluation", "authors": [{"first": "E", "middle": [], "last": "Timmerman", "suffix": ""}], "year": 1986, "venue": "Journal of Purchasing and Materials Management", "link": "47040754"}, "BIBREF6": {"title": "Source selection: a matrix approach", "authors": [{"first": "R", "middle": ["E"], "last": "Gregory", "suffix": ""}], "year": 1986, "venue": "Journal of Purchasing and Materials Management", "link": "168857712"}, "BIBREF7": {"title": "Allocation of order quantity among suppliers", "authors": [{"first": "A", "middle": ["C"], "last": "Pan", "suffix": ""}], "year": 1989, "venue": "Journal of Purchasing and Materials Management", "link": "168151931"}, "BIBREF8": {"title": "Theory and methodology: a multiobjective approach to vendor selection", "authors": [{"first": "C", "middle": ["A"], "last": "Weber", "suffix": ""}, {"first": "J", "middle": ["R"], "last": "Current", "suffix": ""}], "year": 1993, "venue": "European Journal of Operational Research", "link": null}, "BIBREF9": {"title": "Involving suppliers in new product development", "authors": [{"first": "R", "middle": ["B"], "last": "Handfield", "suffix": ""}, {"first": "", "middle": [], "last": "Gl", "suffix": ""}, {"first": "K", "middle": ["J"], "last": "Ragatz", "suffix": ""}, {"first": "R", "middle": ["M"], "last": "Petersen", "suffix": ""}, {"first": "", "middle": [], "last": "Monczka", "suffix": ""}], "year": 1999, "venue": "California Management Review", "link": "154361301"}, "BIBREF10": {"title": "An analytic approach to supplier selection", "authors": [{"first": "R", "middle": [], "last": "Narasimhan", "suffix": ""}], "year": 1983, "venue": "Journal of Purchasing and Materials Management", "link": null}, "BIBREF11": {"title": "The total cost of logistics in supplier selection, under conditions of multiple sourcing, multiple criteria and capacity constraint", "authors": [{"first": "S", "middle": ["H"], "last": "Ghodsypour", "suffix": ""}, {"first": "C", "middle": [], "last": "O&apos;brien", "suffix": ""}], "year": 2001, "venue": "International Journal of Production Economics", "link": "54876895"}, "BIBREF12": {"title": "A multi-objective model for purchasing of bulk raw materials of a large-scale integrated steel plant", "authors": [{"first": "Z", "middle": [], "last": "Gao", "suffix": ""}, {"first": "L", "middle": [], "last": "Tang", "suffix": ""}], "year": 2003, "venue": "International Journal of Production Economics", "link": "154939273"}, "BIBREF13": {"title": "An analytic approach to supplier selection", "authors": [{"first": "R", "middle": [], "last": "Narasimhan", "suffix": ""}], "year": 1983, "venue": "Journal of Purchasing and Materials Management", "link": null}, "BIBREF14": {"title": "A decision support system for supplier selection using an integrated analytic hierarchy process and linear programming", "authors": [{"first": "S", "middle": ["H"], "last": "Ghodsypour", "suffix": ""}, {"first": "C", "middle": [], "last": "O&apos;brien", "suffix": ""}], "year": 1998, "venue": "International Journal of Production Economics", "link": null}, "BIBREF15": {"title": "Non-cooperative negotiation strategies for vender selection", "authors": [{"first": "C", "middle": ["H"], "last": "Weber", "suffix": ""}, {"first": "J", "middle": ["R"], "last": "Current", "suffix": ""}, {"first": "A", "middle": [], "last": "Desai", "suffix": ""}], "year": 1998, "venue": "European Journal of Operational Research", "link": null}, "BIBREF16": {"title": "A search model with subjective judgments: Auditing of incorrect tax declarations", "authors": [{"first": "S", "middle": [], "last": "Iwasaki", "suffix": ""}, {"first": "K", "middle": [], "last": "Tone", "suffix": ""}], "year": 1998, "venue": "Omega-International Journal of Management Science", "link": "142499830"}, "BIBREF17": {"title": "Decision Making with Dependence and Feedback: the Analytic Network Process", "authors": [{"first": "T", "middle": ["L"], "last": "Saaty", "suffix": ""}], "year": 1996, "venue": "", "link": "168991974"}, "BIBREF18": {"title": "The Analytic Hierarchy Process", "authors": [{"first": "T", "middle": ["L"], "last": "Saaty", "suffix": ""}], "year": 1980, "venue": "", "link": "124731955"}, "BIBREF19": {"title": "Multiple-criteria decision-making using sectional supermatrix", "authors": [{"first": "N", "middle": [], "last": "Kameya", "suffix": ""}, {"first": "H", "middle": [], "last": "Miyagi", "suffix": ""}, {"first": "N", "middle": [], "last": "Taira", "suffix": ""}, {"first": "K", "middle": [], "last": "Yamashita", "suffix": ""}], "year": 2002, "venue": "The Proceedings of the International Technical Conference on Circuits/System, Computers and Communications", "link": "74109387"}, "BIBREF20": {"title": "Strategic analysis of logistics and supply chain management systems using the analytical network process", "authors": [{"first": "L", "middle": ["M"], "last": "Meade", "suffix": ""}], "year": 1998, "venue": "Transportation Research Part E-Logistics and Transportation Review", "link": null}, "BIBREF21": {"title": "Balanced Analytic Approach to Strategic Electronic Commerce Decisions: A Framework of the Evaluation Method, Information Technology Evaluation Methods and Management", "authors": [{"first": "M", "middle": [], "last": "Raisinghani", "suffix": ""}], "year": 2001, "venue": "", "link": null}, "BIBREF22": {"title": "The Analytic Hierarchy Process", "authors": [{"first": "T", "middle": ["L"], "last": "Saaty", "suffix": ""}], "year": 1990, "venue": "", "link": "124731955"}, "BIBREF23": {"title": "The theory and algorithm of ANP", "authors": [{"first": "L", "middle": ["F"], "last": "Wang", "suffix": ""}], "year": 2001, "venue": "System Engineering Theories and Practices", "link": null}, "BIBREF24": {"title": "Fundamentals of the analytic network process", "authors": [{"first": "L", "middle": ["T"], "last": "Saaty", "suffix": ""}], "year": 1999, "venue": "ISAHP Japan", "link": null}, "BIBREF25": {"title": "Analyzing organizational project alternatives for agile manufacturing process --an analytical network approach", "authors": [{"first": "L", "middle": ["M"], "last": "Meade", "suffix": ""}, {"first": "J", "middle": [], "last": "Sarkis", "suffix": ""}], "year": 1999, "venue": "International Journal of Production Research", "link": "110726287"}, "BIBREF26": {"title": "Evaluating digital video recorder systems using analytic hierarchy and analytic network process", "authors": [{"first": "C", "middle": ["W"], "last": "Chang", "suffix": ""}, {"first": "C", "middle": ["R"], "last": "Wu", "suffix": ""}, {"first": "C", "middle": ["T"], "last": "Lin", "suffix": ""}, {"first": "H", "middle": ["L"], "last": "Lin", "suffix": ""}], "year": "", "venue": "Information Sciences", "link": "969778"}, "BIBREF27": {"title": "Analytic network process in supplier selection: A case study in an electronic firm", "authors": [{"first": "C", "middle": [], "last": "Gencer", "suffix": ""}, {"first": "D", "middle": [], "last": "Gurpinar", "suffix": ""}], "year": "", "venue": "Applied Mathematical Modelling", "link": "109062449"}, "BIBREF28": {"title": "An application of the AHP in vendor selection of a telecommunications system", "authors": [{"first": "M", "middle": ["C Y"], "last": "Tam", "suffix": ""}, {"first": "V", "middle": ["M R"], "last": "Tummala", "suffix": ""}], "year": 2001, "venue": "", "link": "154489647"}, "BIBREF29": {"title": "Evaluating high-tech alternatives by using analytic network process with BOCR and multiactors", "authors": [{"first": "S", "middle": [], "last": "Erdogmus", "suffix": ""}, {"first": "M", "middle": [], "last": "Kapanoglu", "suffix": ""}, {"first": "E", "middle": [], "last": "Koc", "suffix": ""}], "year": 2005, "venue": "Evaluation and Program Planning", "link": "109860692"}, "BIBREF30": {"title": "The Analytic Network Process. Pittsburgh: RWS Publications", "authors": [{"first": "T", "middle": ["L"], "last": "Saaty", "suffix": ""}], "year": 2001, "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "17430945", "_pdf_hash": "f7f34e005f318d0813ec10627364e91842ca43df", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "A taxonomy of trace-based security properties for CCS", "authors": [{"first": "R", "middle": [], "last": "Focardi", "suffix": ""}, {"first": "R", "middle": [], "last": "Gomeri", "suffix": ""}], "year": 1994, "venue": "Proceedings of the Seventh Computer Security Foundations Workshop", "link": null}, "BIBREF1": {"title": "A general theory of (composition for trace sets closed under selective interleaving functions", "authors": [{"first": "J", "middle": [], "last": "Mclean", "suffix": ""}], "year": 1994, "venue": "Proceedings of the IEEE Symposium on Security und Privacy", "link": null}, "BIBREF2": {"title": "CSP and determinism in security modelling", "authors": [{"first": "A", "middle": ["W"], "last": "Roscoe", "suffix": ""}], "year": 1995, "venue": "Proceedings of the IEEE Symposium on Security und Privacy", "link": "946525"}}, "ref_entries": {}}
{"paper_id": "17430955", "_pdf_hash": "c8e8b789028c377ffb6ad24cc27ed2cc5e820b4f", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "On the Dispersion in Ag-SnO 2 based Contact Materials, Proc. 20th Int. Conf. on Electr. Contact Phenom", "authors": [{"first": "F", "middle": [], "last": "Heringhaus", "suffix": ""}, {"first": "P", "middle": [], "last": "Braumann", "suffix": ""}, {"first": "D", "middle": [], "last": "Ruhlicke", "suffix": ""}, {"first": "E", "middle": [], "last": "Susnik", "suffix": ""}, {"first": "R", "middle": [], "last": "Wolmer", "suffix": ""}], "year": 2000, "venue": "", "link": null}, "BIBREF2": {"title": "Comparison of properties of silver-metal oxide electrical contact materials", "authors": [{"first": "V", "middle": [], "last": "\u0106osovi\u0107", "suffix": ""}, {"first": "N", "middle": [], "last": "Talijan", "suffix": ""}, {"first": "D", "middle": [], "last": "\u017divkovi\u0107", "suffix": ""}, {"first": "D", "middle": [], "last": "Mini\u0107", "suffix": ""}, {"first": "\u017d", "middle": [], "last": "\u017divkovi\u0107", "suffix": ""}], "year": 2012, "venue": "J. Min. Metall. Sect. B-Metall", "link": "55927664"}, "BIBREF3": {"title": "Filter paper-templated preparation of ZnO thin films and examination of theirgas-sensing properties", "authors": [{"first": "B", "middle": [], "last": "Wang", "suffix": ""}, {"first": "N", "middle": [], "last": "Han", "suffix": ""}, {"first": "D", "middle": [], "last": "Meng", "suffix": ""}, {"first": "R", "middle": [], "last": "Yue", "suffix": ""}, {"first": "J", "middle": [], "last": "Yan", "suffix": ""}, {"first": "Y", "middle": [], "last": "Chen", "suffix": ""}], "year": 2011, "venue": "Particuology", "link": "98508012"}, "BIBREF4": {"title": "Completely \"Green\" Synthesis and Stabilization of Metal Nanoparticles", "authors": [{"first": "P", "middle": [], "last": "Raveendran", "suffix": ""}, {"first": "J", "middle": [], "last": "Fu", "suffix": ""}, {"first": "S", "middle": ["L"], "last": "Wallen", "suffix": ""}], "year": 2003, "venue": "J. Am. Chem. Soc", "link": "9563928"}, "BIBREF5": {"title": "Preparation and properties of nano-sized Ag and Ag 2 S particles in biopolymer matrix", "authors": [{"first": "D", "middle": ["K"], "last": "Bozanic", "suffix": ""}, {"first": "V", "middle": [], "last": "Djokovic", "suffix": ""}, {"first": "J", "middle": [], "last": "Blanusa", "suffix": ""}, {"first": "P", "middle": ["S"], "last": "Nair", "suffix": ""}, {"first": "M", "middle": ["K"], "last": "Georges", "suffix": ""}, {"first": "T", "middle": [], "last": "Radhakrishnan", "suffix": ""}], "year": 2007, "venue": "Eur. Phys. J. E", "link": null}}, "ref_entries": {}}
{"paper_id": "17431149", "_pdf_hash": "551694857e05b50361e724359016e8f92b7c17ba", "abstract": [{"section": "Abstract", "text": "Introduction: Composite mesh prostheses incorporate the properties of multiple materials for ventral hernia repair. This study evaluated a polypropylene/ePTFE composite mesh with a novel internal polydioxanone (PDO) absorbable ring.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "INTRODUCTION", "text": "Mesh prostheses are an essential component of successful ventral hernia repairs. Mesh is used to produce tensionfree repairs, where possible, and offers the best opportunity to restore abdominal wall integrity. Open repairs without mesh are associated with hernia recurrence in 24% to 54% of patients. [1] [2] [3] Mesh placement reduces hernia recurrences to 24% to 32% in open repairs 3, 4 and 5% to10% in laparoscopic repairs.", "cite_spans": [{"start": 302, "end": 305, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 306, "end": 309, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 310, "end": 313, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 386, "end": 388, "text": "3,", "ref_id": "BIBREF2"}, {"start": 389, "end": 390, "text": "4", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "INTRODUCTION", "text": "Mesh prostheses are composed of biologic materials from human and animal dermis (autoplastic) or synthetic materials (alloplastic). Synthetic mesh prostheses are further divided into 3 groups based on porosity. 5 Type I mesh is macroporous with pore sizes \u03fe10 microns, eg, polypropylene. Type II mesh is microporous with pore sizes \u03fd10 microns, eg, expanded polytetrafluoroethylene (ePTFE). Type III mesh is a composite structure with both microand macroporous components. Polypropylene material causes a local inflammatory response when in contact with host tissues. This combined with its large pore sizes allows for maximal in-growth of connective tissue and blood vessels from the abdominal wall into the mesh material, increasing the strength of ventral hernia repairs. Expanded PTFE is biologically inert and does not cause a host inflammatory response. The submicronic pore sizes of ePTFE mesh materials further impede in-growth of host tissues, thereby, limiting adhesion formation. 6 Composite mesh prostheses are manufactured to strategically position these materials on different surfaces to selectively promote and impede host tissue in-growth to produce a strong ventral hernia repair with minimal adhesions.", "cite_spans": [{"start": 211, "end": 212, "text": "5", "ref_id": "BIBREF4"}, {"start": 991, "end": 992, "text": "6", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "INTRODUCTION", "text": "Composite mesh prostheses are placed in the intraperitoneal position so that the parietal surface contacts the abdominal wall to promote tissue in-growth, and the visceral surface acts as a long-term barrier for the viscera. Clinical studies have shown that composite mesh materials are associated with short hospital stays, moderate complication rates, low infection rates, and low hernia recurrence rates. [7] [8] [9] The clinical success of composite mesh has led to several commercially available materials. The aim of this study was to evaluate a novel composite mesh with an absorbable polydioxanone (PDO) memory ring in a porcine model of open ventral hernia repair.", "cite_spans": [{"start": 408, "end": 411, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 412, "end": 415, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 416, "end": 419, "text": "[9]", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "METHODS", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Animals", "text": "Sixteen female Yorkshire pigs (35kg to 45kg) were implanted with composite mesh. Animals were randomized for explantation at 2, 4, 8, and 12 weeks. All animal protocols were approved by our medical center's Institutional Animal Care and Use Committee (IACUC) and conformed to Federal Care and Use of Laboratory Animals guidelines.", "cite_spans": [], "ref_spans": []}, {"section": "Mesh Prosthesis", "text": "Animals were implanted with Ventrio Hernia Patch (Bard Davol, Inc. Warwick, RI), an oval-shaped composite mesh (11cm x 14cm). This composite hernia patch combines 3 layers of mesh with an absorbable polydioxanone ring that aids in positioning (Figure 1) . The parietal surface consists of a double layer of polypropylene. A central opening between the polypropylene layers creates a positioning pocket for the placement of fixation devices. The visceral surface of the mesh is made of ePTFE. The most novel component is an absorbable PDO monofilament incorporated at the periphery of the mesh. This ring allows the flexible hernia patch to return to a flat position against the abdominal wall facilitating optimal positioning. Because this memory function is no longer necessary after the mesh is secured to the abdominal wall, the ring undergoes hydrolysis in vivo and is completely absorbed, decreasing the amount of foreign material in the abdomen.", "cite_spans": [], "ref_spans": [{"start": 243, "end": 253, "text": "(Figure 1)", "ref_id": "FIGREF0"}]}, {"section": "Surgical Procedures", "text": "Following overnight fasting, animals underwent anesthetic induction and endotracheal intubation for surgery. The surgical field was prepped with topical antimicrobial agents and draped to maintain sterility, and midline laparotomy incisions were made. The mesh was placed intraperitoneally and fixed at the periphery with absorbable fasteners at 1-cm intervals. Eight transfascial polydioxanone sutures were placed circumferentially. Each mesh was positioned at the midline, and the overlying fascia was closed primarily with polydioxanone suture in a running fashion. The skin edges were reapproximated with skin staples. A dry, sterile dressing and sulfadiazine cream were placed over the incision. Postoperatively, animals were placed in a recovery area and given appropriate analgesia. Animals had free access to food and water throughout the study duration.", "cite_spans": [], "ref_spans": []}, {"section": "Adhesion Scoring", "text": "Animals were euthanized at 2, 4, 8, and 12 weeks following mesh implantation (N\u03ed4 for each time period). Immediately following euthanasia, animals underwent laparoscopic evaluation of adhesions. An 11-mm trocar was inserted in the right lower quadrant, and pneumoperitoneum was established. A 10-mm, 30\u00b0laparoscope was used to directly visualize intraabdominal adhesions. Previously validated quantitative and qualitative scales were used to measure adhesions. The Modified Diamond Scale 10 was used to measure the proportion of mesh covered with adhesions (Table 1) , and a scale validated by Garrard and colleagues 11 was used to measure tenacity ( Table 2 ). ", "cite_spans": [], "ref_spans": [{"start": 557, "end": 566, "text": "(Table 1)", "ref_id": "TABREF0"}, {"start": 651, "end": 658, "text": "Table 2", "ref_id": "TABREF1"}]}, {"section": "Mesh Contraction", "text": "The length and width of each mesh prosthesis was measured at baseline and immediately following explantation. From these measurements, a percentage mesh contracture was calculated for the mesh length, mesh width, and mesh area for each explanted mesh (N\u03ed4 for each group). Percentage contracture was calculated by the following formula:", "cite_spans": [], "ref_spans": []}, {"section": "Mesh Contraction", "text": "baseline measurement \u03eb 100", "cite_spans": [], "ref_spans": []}, {"section": "Histological Evaluation of Cell Types", "text": "Immediately following euthanasia, mesh prostheses were explanted by excising each graft along with the overlying full-thickness abdominal wall. Portions of the mesh-abdominal wall complexes explanted from each animal were sectioned, fixed in formalin, and embedded in paraffin or plastic blocks. Replicate 4-m to 6-m sections were cut and stained with hematoxylin and eosin (H&E) and Masson's trichrome. Slides from each animal were divided into quadrants, and 3 fields from each quadrant were selected for cell counting. Twelve high-power fields (40X magnification) were evaluated for each animal, and group means were calculated for each time point (N\u03ed48 high power fields per group). Each field was independently scored for the presence of inflammatory cells, vascular structures, and fibroblasts by 2 observers who were blinded to specimen group assignments.", "cite_spans": [], "ref_spans": []}, {"section": "Tensiometric Evaluation of Mesh-Tissue Interface", "text": "Immediately following explantation, mesh-abdominal wall specimens were placed in normal saline. Skin and soft tissues were removed, leaving a thin, connective tissue lamina on the polypropylene surface of the mesh. Fixation constructs were removed. The degree of polypropylene mesh incorporation into the abdominal wall was assessed by measuring the force required to separate the connective tissue lamina from the underlying mesh (T-peel force). Specimens were cut into 2-cm x 7-cm strips, and T-peel forces were measured at a constant displacement of 20mm per minute. Explanted mesh was tested at 2 weeks (N\u03ed23), 4 weeks (N\u03ed20), 8 weeks (N\u03ed17), and 12 weeks (N\u03ed20) following implantation.", "cite_spans": [], "ref_spans": []}, {"section": "Evaluation of Internal PDO Ring", "text": "The mechanical properties of the absorbable PDO ring component of each mesh were evaluated in triplicates at baseline and 2, 4, 8, and 12 weeks (N\u03ed12 specimens for each group). These longitudinal measurements were used to quantify the amount of PDO ring degradation. The rings were dissected from the explanted mesh and maintained in normal saline before testing. Ultimate tensile strength was calculated from the peak load and initial diameter for each ring sample. Ring material from nonimplanted mesh was also tested for baseline values.", "cite_spans": [], "ref_spans": []}, {"section": "Data Analysis", "text": "Data are presented as mean values with standard deviations or proportions. Kruskal-Wallis tests were used for ordinal data, and ANOVA followed by Tukey post hoc tests were used for interval data. All tests were 2-tailed, and significance was considered P\u0545.05.", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Laparoscopic Inspection", "text": "There were no operative or postoperative complications. All animals survived to the designated endpoints by group (2, 4, 8, and 12 weeks) and were healthy throughout the study. Laparoscopic inspections showed that composite mesh prostheses were securely positioned and flat against the abdominal wall with no exposure of the parietal mesh surface. ", "cite_spans": [], "ref_spans": []}, {"section": "Adhesion Scoring", "text": "Quantitative and qualitative measurements of intraabdominal adhesions were performed using the Modified Diamond Scale and a tenacity scale, respectively. The overall mean Diamond score for all groups was 0.63\u03ee0.62 (N\u03ed16), and the overall mean tenacity score was 1.94\u03ee1.0 (N\u03ed16). Diamond and tenacity scores were not statistically different among groups (P\u03ed.38 and P\u03ed.51, respectively). All groups included animals with no adhesions: 2 week (25%), 4 week (75%), 8 week (50%), and 12 week (25%). Of the animals that developed adhesions, all measured \u03fd25%, and most were filmy omental attachments. See Tables 3 and 4 and Figure 2 for adhesion scores.", "cite_spans": [], "ref_spans": [{"start": 599, "end": 613, "text": "Tables 3 and 4", "ref_id": "TABREF3"}, {"start": 618, "end": 626, "text": "Figure 2", "ref_id": "FIGREF1"}]}, {"section": "Mesh Contraction", "text": "The width, length, and surface area of explanted mesh were compared with baseline measurements, and percentage of contraction for these dimensions was calculated for each time point. The percentage surface area contraction was 4% at 2 weeks, 19% at 4 weeks, 16% at 8 weeks, and 19% at 12 weeks. Mesh length contraction was slightly greater than width contraction at 2 weeks, and width contraction was greater than length contraction at 4, 8, and 12 weeks following implantation. See Figure 3 for mesh contraction results.", "cite_spans": [], "ref_spans": [{"start": 483, "end": 491, "text": "Figure 3", "ref_id": "FIGREF2"}]}, {"section": "Histological Evaluation of Cell Types", "text": "The tissue architecture was evaluated by light microscopy at 40X magnification. At 2 weeks, there was a preponderance of lymphocytes and other inflammatory cells with disorganized collagen fibers. By 12 weeks, there were fewer inflammatory cells, and the tissues had undergone marked remodeling with well-organized collagen fibers. ", "cite_spans": [], "ref_spans": []}, {"section": "Tenacity", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Tensiometric Evaluation Mesh-Tissue Interface", "text": "The force required (T-peel force) to separate host connective tissue lamina from the mesh was measured to assess the in-growth of host tissues into the mesh. T-peel force was highest at 2 weeks, 9.13\u03ee3 Newtons, and lowest at 8 weeks, 4.76\u03ee2 Newtons. There was no significant difference in T-peel forces among the groups (P\u03ed.29). See Figure 7 for T-peel force measurements.", "cite_spans": [], "ref_spans": [{"start": 333, "end": 341, "text": "Figure 7", "ref_id": "FIGREF6"}]}, {"section": "Evaluation of Internal PDO Ring", "text": "The absorbable ring component of the composite mesh underwent tensiometric testing to assess ring degradation. The ultimate tensile strength was calculated from the peak load and an initial ring diameter. The ultimate tensile strength at baseline was 367\u03ee5 Mpa and progressively decreased in each group following explantation: 275.2\u03ee49 Mpa at 2 weeks, 87\u03ee18 Mpa at 4 weeks, and 9.7\u03ee7 Mpa at 8 weeks (P\u03fd.001). The strain and modulus were measured and followed similar trends. All mechanical test samples at 12 weeks had degraded such that no mechanical tests could be successfully completed. The percentage of degradation of the PDO ring compared to baseline measurements was 25% at 2 weeks, 76.2% at 4 weeks, 97.4% at 8 weeks, and 100% at 12 weeks. See Figure 8 for measurements of the internal PDO ring.", "cite_spans": [], "ref_spans": [{"start": 753, "end": 761, "text": "Figure 8", "ref_id": "FIGREF7"}]}, {"section": "DISCUSSION", "text": "Our preclinical, observational study evaluated a new composite mesh for soft tissue reconstruction, the Ventrio Hernia Patch (Bard Davol, Inc. Warwick, RI). Adhesions were absent in some animals at each time point. Animals that developed adhesions were found to have thin, filmy omental attachments. Histological evaluation showed progressive host tissue in-growth into the mesh with increased vascular structures and fibroblasts at 8 weeks and 12 weeks compared to earlier time points. Two features were found to promote easy handling of the mesh and proper placement in the intraperitoneal space. The positioning pocket created by the polypropylene bi-layer facilitated appropriate mesh fixation with fasteners. The internal PDO ring enabled the mesh to maintain a flat orientation during placement. This PDO ring also underwent complete degradation by 12 weeks.", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "Ventral hernias are common complications following open laparotomies with a reported incidence ranging from 2% to 20%. 1, [12] [13] [14] [15] Mesh prostheses offer the lowest rate of hernia recurrence. There are many mesh products available for use during ventral hernia repairs; however, there is no consensus regarding the optimal graft because of the wide variability in patients as well as hernias. The ideal mesh material provides a strong repair with minimal adverse effects resulting from the foreign material within the abdomen. The use of composite mesh prostheses placed intraperitoneally seeks to accomplish aggressive host tissue response at the parietal surface to strengthen the repair while minimizing adhesions caused by contact on the visceral surface.", "cite_spans": [{"start": 119, "end": 121, "text": "1,", "ref_id": "BIBREF0"}, {"start": 122, "end": 126, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 127, "end": 131, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 132, "end": 136, "text": "[14]", "ref_id": "BIBREF13"}, {"start": 137, "end": 141, "text": "[15]", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "DISCUSSION", "text": "The composite mesh evaluated in this study incorporates 3 layers of mesh material with an absorbable ring to maximize strength for the hernia repair. Two layers of polypropylene material make up the parietal surface. The macroporosity of polypropylene is shown to promote in-growth of host tissue within the mesh, which adds to the longevity of strength for the hernia repair. 8, 9 This study evaluated this property mechanically by measuring the force required to separate host connective tissue from the mesh (T-peel force) and histologically by assessing cell types in the mesh following implantation. The T-peel force was highest at 2 weeks, indicating a strong initial mesh-abdominal association. The T-peel force was relatively weakest at 8 weeks but increased again by 12 weeks. The T-peel force at 2 weeks is likely a result of an early host inflammatory response. The relatively lower T-peel force at 8 weeks may be indicative of a window phase in which the acute inflammatory response has subsided and the process of remodeling has begun. This theory is supported by the progressive increase of vascular structures and well-organized fibroblasts at 12 weeks (Figures 5 and 6) . As the remodeling process continues (beyond 12 weeks), the T-peel force would likely exceed values observed at 2 weeks.", "cite_spans": [{"start": 377, "end": 379, "text": "8,", "ref_id": "BIBREF7"}, {"start": 380, "end": 381, "text": "9", "ref_id": "BIBREF8"}], "ref_spans": [{"start": 1168, "end": 1185, "text": "(Figures 5 and 6)", "ref_id": "FIGREF3"}]}, {"section": "DISCUSSION", "text": "The visceral surface of the composite mesh was made of ePTFE, a microporous material that inhibits tissue attachment and limits the formation of intraabdominal adhesions between viscera and the mesh surface. 8, 9 Results of this study show that many animals in each group formed no adhesions at all, including 75% at 4 weeks and 50% at 8 weeks. Of animals that formed adhesions, many of them were filmy omental adhesions that were easily broken with blunt dissection. Animal studies have reported Modified Diamond scores of 0.8 to 1.6 associated with ePTFE and polypropylene mesh materials. 16 The mean Modified Diamond score for the current study was lower at 0.63\u03ee0.62.", "cite_spans": [{"start": 208, "end": 210, "text": "8,", "ref_id": "BIBREF7"}, {"start": 211, "end": 212, "text": "9", "ref_id": "BIBREF8"}, {"start": 591, "end": 593, "text": "16", "ref_id": "BIBREF15"}], "ref_spans": []}, {"section": "DISCUSSION", "text": "The composite mesh evaluated in this study was most innovative in the components designed to ensure appropriate placement within the intraperitoneal cavity and adequate fixation of the mesh to the abdominal wall. The positioning pocket created by the polypropylene bi-layer helped to ensure adequate fixation at the mesh periphery. The absorbable PDO ring component ensured the mesh maintained a flat orientation against the abdominal wall during placement. The ring was also completely degraded by 12 weeks, leaving less foreign material in the abdomen and no risk for long-term complications caused by this component. These features are significant advances in composite mesh design and aid in adequate mesh placement and fixation, both of which are required for successful hernia repairs.", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "Contraction of mesh prostheses is well documented, and the cause is contraction of collagen and connective tissue as host tissues become incorporated in the woven mesh interface. Radiologic measurements have shown 20% mesh contraction 10 months after implantation in patients. 6 Gonzalez and colleagues 17 examined mesh contraction 3 months following implantation in a porcine model. Contraction of polyester mesh was between 5% and 24%, and contraction of polypropylene mesh was between 15% and 65%. Our data show a mean 19% mesh area contraction at 12 weeks. The structure of the composite hernia patch may be responsible for this relatively low contraction profile compared to that of other prostheses.", "cite_spans": [{"start": 277, "end": 278, "text": "6", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "CONCLUSION", "text": "Ventrio Hernia Patch incorporates 3 layers of mesh material with an absorbable PDO ring. Each layer performs a unique functional role to increase the strength of ventral hernia repairs while minimizing adhesion formation and mesh contraction. This study showed that the visceral ePTFE layer was associated with minimal adhesion formation. The parietal polypropylene layers contributed to aggressive in-growth of host tissues and provided a positioning pocket that aided in mesh fixation. The PDO ring aided in mesh placement and was completely absorbed by 12 weeks. This study provides sound evidence to support prospective clinical trials examining this composite mesh in clinical settings.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Recent trends in the management of incisional herniation", "authors": [{"first": "R", "middle": ["C"], "last": "Read", "suffix": ""}, {"first": "G", "middle": [], "last": "Yoder", "suffix": ""}], "year": 1989, "venue": "Arch Surg", "link": "19357918"}, "BIBREF1": {"title": "Factors affecting recurrence following incisional herniorrhaphy", "authors": [{"first": "T", "middle": [], "last": "Anthony", "suffix": ""}, {"first": "P", "middle": ["C"], "last": "Bergen", "suffix": ""}, {"first": "L", "middle": ["T"], "last": "Kim", "suffix": ""}], "year": 2000, "venue": "World J Surg", "link": "24639837"}, "BIBREF2": {"title": "A comparison of suture repair with mesh repair for incisional hernia", "authors": [{"first": "R", "middle": ["W"], "last": "Luijendijk", "suffix": ""}, {"first": "W", "middle": ["C"], "last": "Hop", "suffix": ""}, {"first": "M", "middle": ["P"], "last": "Van Den Tol", "suffix": ""}], "year": 2000, "venue": "N Engl J Med", "link": "6574300"}, "BIBREF3": {"title": "Long-term follow-up of a randomized controlled trial of suture versus mesh repair of incisional hernia", "authors": [{"first": "J", "middle": ["W"], "last": "Burger", "suffix": ""}, {"first": "R", "middle": ["W"], "last": "Luijendijk", "suffix": ""}, {"first": "W", "middle": ["C"], "last": "Hop", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Halm", "suffix": ""}, {"first": "E", "middle": ["G"], "last": "Verdaasdonk", "suffix": ""}, {"first": "J", "middle": [], "last": "Jeekel", "suffix": ""}], "year": 2004, "venue": "Ann Surg", "link": "6794331"}, "BIBREF4": {"title": "Classification of Biomaterials and Their Related Complications in Abdominal Wall Hernia Surgery", "authors": [{"first": "P", "middle": [], "last": "Amid", "suffix": ""}], "year": 1997, "venue": "Hernia", "link": "40586659"}, "BIBREF5": {"title": "The effect of porosity and biomaterial on the healing and long-term mechanical properties of vascular prostheses", "authors": [{"first": "R", "middle": ["A"], "last": "White", "suffix": ""}], "year": 1988, "venue": "ASAIO Trans", "link": null}, "BIBREF6": {"title": "Technique and outcomes of abdominal incisional hernia repair using a synthetic composite mesh: a report of 455 cases", "authors": [{"first": "D", "middle": ["A"], "last": "Iannitti", "suffix": ""}, {"first": "W", "middle": ["W"], "last": "Hope", "suffix": ""}, {"first": "H", "middle": ["J"], "last": "Norton", "suffix": ""}], "year": 2008, "venue": "J Am Coll Surg", "link": "25542315"}, "BIBREF7": {"title": "Composite mesh (polypropylene -e-PTFE) in the intraperitoneal position. A report of 30 cases", "authors": [{"first": "R", "middle": [], "last": "Bendavid", "suffix": ""}], "year": 1997, "venue": "Hernia", "link": null}, "BIBREF8": {"title": "Incisional herniorrhaphy with intraperitoneal composite mesh: a report of 95 cases", "authors": [{"first": "W", "middle": ["S"], "last": "Cobb", "suffix": ""}, {"first": "J", "middle": ["B"], "last": "Harris", "suffix": ""}, {"first": "J", "middle": ["S"], "last": "Lokey", "suffix": ""}, {"first": "E", "middle": ["S"], "last": "Mcgill", "suffix": ""}, {"first": "K", "middle": ["L"], "last": "Klove", "suffix": ""}], "year": 2003, "venue": "Am Surg", "link": "45067404"}, "BIBREF9": {"title": "The influence of differing pore sizes on the biocompatibility of two polypropylene meshes in the repair of abdominal defects. Experimental study in dogs. Hernia", "authors": [{"first": "F", "middle": ["H"], "last": "Greca", "suffix": ""}, {"first": "J", "middle": ["B"], "last": "De Paula", "suffix": ""}, {"first": "M", "middle": ["L"], "last": "Biondo-Simoes", "suffix": ""}], "year": 2001, "venue": "", "link": null}, "BIBREF10": {"title": "Adhesion formation is reduced after laparoscopic surgery. Surg Endosc", "authors": [{"first": "C", "middle": ["L"], "last": "Garrard", "suffix": ""}, {"first": "R", "middle": ["H"], "last": "Clements", "suffix": ""}, {"first": "L", "middle": [], "last": "Nanney", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Davidson", "suffix": ""}, {"first": "W", "middle": ["O"], "last": "Richards", "suffix": ""}], "year": 1999, "venue": "", "link": null}, "BIBREF11": {"title": "Burst abdomen and incisional hernia: a prospective study of 1129 major laparotomies", "authors": [{"first": "T", "middle": ["E"], "last": "Bucknall", "suffix": ""}, {"first": "P", "middle": ["J"], "last": "Cox", "suffix": ""}, {"first": "H", "middle": [], "last": "Ellis", "suffix": ""}], "year": 1982, "venue": "Br Med J (Clin Res Ed", "link": "2431315"}, "BIBREF12": {"title": "Incisional hernia: a 10 year prospective study of incidence and attitudes", "authors": [{"first": "M", "middle": [], "last": "Mudge", "suffix": ""}, {"first": "L", "middle": ["E"], "last": "Hughes", "suffix": ""}], "year": 1985, "venue": "Br J Surg", "link": "23697487"}, "BIBREF13": {"title": "Incidence of incisional hernia following emergency abdominal surgery", "authors": [{"first": "A", "middle": [], "last": "Mingoli", "suffix": ""}, {"first": "A", "middle": [], "last": "Puggioni", "suffix": ""}, {"first": "G", "middle": [], "last": "Sgarzini", "suffix": ""}], "year": 1999, "venue": "Ital J Gastroenterol Hepatol", "link": "10133167"}, "BIBREF14": {"title": "Incisional hernia after laparotomy: prospective randomized comparison between early-absorbable and late-absorbable suture materials", "authors": [{"first": "W", "middle": ["C"], "last": "Hsiao", "suffix": ""}, {"first": "K", "middle": ["C"], "last": "Young", "suffix": ""}, {"first": "S", "middle": ["T"], "last": "Wang", "suffix": ""}, {"first": "P", "middle": ["W"], "last": "Lin", "suffix": ""}], "year": 2000, "venue": "World J Surg", "link": "997791"}, "BIBREF15": {"title": "Assessment of adhesion formation to intra-abdominal polypropylene mesh and polytetrafluoroethylene mesh", "authors": [{"first": "B", "middle": ["D"], "last": "Matthews", "suffix": ""}, {"first": "B", "middle": ["L"], "last": "Pratt", "suffix": ""}, {"first": "H", "middle": ["S"], "last": "Pollinger", "suffix": ""}], "year": 2003, "venue": "J Surg Res", "link": "1219264"}, "BIBREF16": {"title": "Relationship between tissue ingrowth and mesh contraction", "authors": [{"first": "R", "middle": [], "last": "Gonzalez", "suffix": ""}, {"first": "K", "middle": [], "last": "Fugate", "suffix": ""}, {"first": "", "middle": [], "last": "Mcclusky D 3rd", "suffix": ""}], "year": 2005, "venue": "World j Surg", "link": "21470647"}, "BIBREF17": {"title": "Evaluation of Composite Mesh for Ventral Hernia Repair", "authors": [{"first": "J", "middle": ["F"], "last": "Byrd", "suffix": ""}], "year": 2011, "venue": "JSLS", "link": null}}, "ref_entries": {"FIGREF0": {"text": "Figure 1. Ventrio Hernia Patch. 1A: polypropylene surface with internalized, absorbable polydioxanone (PDO) ring (arrow), 1B: expanded polytetrafluoroethylene (ePTFE) surface.", "type": "figure"}, "FIGREF1": {"text": "Figure 2. Graph demonstrating mean adhesion scores over time.", "type": "figure"}, "FIGREF2": {"text": "Figure 3. Graph demonstrating the percent mesh contraction over time.", "type": "figure"}, "FIGREF3": {"text": "Figure 5. Histological preparation of explanted mesh at 2 weeks (20X magnification). 5A: H&E stain, 5B: Masson's trichrome stain. Note the prominence of inflammatory cells and disordered collagen fibers.", "type": "figure"}, "FIGREF4": {"text": "Figure 6. Histological preparation of explanted mesh at 12 weeks (20X magnification). 6A: H&E stain, 6B: Masson's trichrome stain. Note the decrease in inflammatory cells and the increased deposition of organized collagen fibers and vascular structures.", "type": "figure"}, "FIGREF5": {"text": "Figure 4. Graph demonstrating host cellular response to mesh over time.", "type": "figure"}, "FIGREF6": {"text": "Figure 7. Graph demonstrating the T-peel force of mesh-tissue interface over time.", "type": "figure"}, "FIGREF7": {"text": "Figure 8. Graph demonstrating the tensile strength of absorbable PDO ring over time.", "type": "figure"}, "TABREF0": {"text": "Modified Diamond Scale", "type": "table"}, "TABREF1": {"text": "Adhesion Tenacity Scale", "type": "table"}, "TABREF3": {"text": "Quantitative Adhesion Results", "type": "table"}, "TABREF4": {"text": "Qualitative Adhesion Results", "type": "table"}}}
{"paper_id": "17431394", "_pdf_hash": "affadd88eb1263e57016cbf609e7d9c25d960136", "abstract": [{"section": "Abstract", "text": "A female baby with an antenatal diagnosis of gastroschisis was transferred to our institution. The defect was large but the bowel was in good condition and a silo was placed. After successful reduction of the bowel the abdominal wall defect was too large to allow fascial or even skin closure. We utilised a Gore-tex patch with two prolene purse string sutures placed concentrically to enable the diameter of the patch to be sequentially reduced. This enabled gradual stretching of the tissues with a progressive reduction in the size of the defect. The patch was removed after 8 days and a delayed fascial closure was achieved.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "INTRODUCTION", "text": "The management of gastroschisis has evolved in recent times with many institutions utilising a delayed primary closure approach with the use of a silo. We present a case with a large defect where this technique could not be employed and describe an alternative approach.", "cite_spans": [], "ref_spans": []}, {"section": "CASE REPORT", "text": "A female baby was born at 35+1 week gestation by emergency caesarian section due to foetal distress. The diagnosis of gastroschisis was known antenatally. Her birth weight was 2.18 kg which placed her just above the 25th centile. She required minimal resuscitation and was transferred to our institution for further management.", "cite_spans": [], "ref_spans": []}, {"section": "CASE REPORT", "text": "At arrival, the stomach, small bowel, large bowel, ovaries and fallopian tubes were visible outside to the abdominal cavity. The bowel was matted, but well perfused with no visible atresia or perforation. The defect was to the right of the umbilicus and was large. There was significant abdomino-viscero size discrepancy and primary closure was deemed inappropriate. A size 5 \"medicina\" silo was placed over the bowel and after a period of 36 hours reduction of the bowel was commenced.", "cite_spans": [], "ref_spans": []}, {"section": "CASE REPORT", "text": "Reduction of the bowel was difficult and only on day 9 of life was the bowel reduced sufficiently for a plan for later definitive closure. This plan was expedited when turbid fluid was noted around the bowel in the silo, with cellulitis of the surrounding abdominal wall. The baby was pyrexial with an elevated C reactive protein of 122mg/L, cultures taken at the time subsequently grew Burkholderia Cepacia.", "cite_spans": [], "ref_spans": []}, {"section": "CASE REPORT", "text": "The baby was transferred to theatre for further assessment, the silo removed and the bowel washed with copious amounts of saline. The bowel appeared healthy, but there was still a significant abdomino-viscero size discrepancy. The diameter of the defect was now 5.5cm and fascial closure or even skin closure was not possible. The decision was made to patch the defect using a 1mm gortex patchwith two concentrically placed 3/0 prolene purse string su-tures to allow gradual closure of the defect. The patch was secured to the skin and fascia with 3.0 prolene horizontal mattress sutures to all layers of the abdominal wall with felt pledglets to protect the skin (Fig. 1) .", "cite_spans": [], "ref_spans": []}, {"section": "CASE REPORT", "text": "The baby returned to the neonatal intensive care unit paralysed and ventilated and was extubated after 48hours. The inner prolene purse string was tied on the fourth postoperative day reducing the defect by 1.5cm. This was well tolerated and the outer prolene suture was subsequently tied on the sixth postoperative day leaving a <3cm defect in the abdominal wall (Fig. 2) . Two days later, a fascial and skin closure was performed in theatre with removal of the gortex patch (Fig. 3) .", "cite_spans": [], "ref_spans": []}, {"section": "CASE REPORT", "text": "Enteral feeding was commenced on day 22; full enteral intake was achieved by day 62 of life. She was discharged on day 70 of life with a good cosmetic appearance of her neo-umbilicus (Fig. 4) . She has continued to do well requring no readmission and is thriving. ", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "The management of neonates born with gastroschisis has changed over the past few decades with a shift from primary fascial closure to staged closure with the use of a spring loaded preformed silo. These silos can be placed without anaesthetic at the cotside and delayed fascial closure performed when appropriate [1] . In selected cases, it is even possible to subsequently remove the silo and perform a sutureless closure at the bedside [2] .", "cite_spans": [{"start": 313, "end": 316, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 438, "end": 441, "text": "[2]", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "DISCUSSION", "text": "Although the spring loaded preformed silos have many advantages, but we believe that they can make the diameter of the defect larger There have been various methods reported to deal with closure of a large or complex gastroschisis. These include prosthetic materials such as sugisis [3] , gortex [4] , silastic silo [5] and autologous materials such as umbilical cord [6] , dura, musculo-cutaneous flaps and meshed skin grafts [7] reported.", "cite_spans": [{"start": 283, "end": 286, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 296, "end": 299, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 316, "end": 319, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 368, "end": 371, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 427, "end": 430, "text": "[7]", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "DISCUSSION", "text": "The synthetic agents have the disadvantage of infection causing significant morbidity and necessitating the removal of the patch in some cases. Surgisis has the reported advantage of causing tissue ingrowth and has the theoretical advantage of \"growth\" but reports have suggested a higher reoccurrence rate with its use. The autologous tissues although intuitively attractive can be problematic in small babies who have a paucity of available tissue.", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "Our neonate had a very large defect in comparison to the size of her abdomen and the presence of infection precluded the use of other techniques. Gortex was chosen as a temporaizing measure and the concentric purse string suture was devised to reduce the size of the defect for future closure. Sequentially tieing the two sutures at the bedside allowed us to progressively stretch the abdominal wall and close the defect. This progressive tension on the tissues acted like a form of tissue expansion, but in reverse. This technique was performed at the bedside and enabled us to eradicate the sepsis before returning to theatre for definitive closure. Without the use of this innovation, closure would have involved several operative procedures and anaesthetics.", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "In conclusion, our novel technique for closure of a large gastroschisis defect is easy to perform. It should be considered when the clinician is faced with a defect he cannot obtain skin or fascial closure once he has removed a silo.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Schuster SR A new method for staged repair of large omphaloceles", "authors": [], "year": 1967, "venue": "Surg Gynecol Obstet", "link": null}, "BIBREF1": {"title": "Minimal intervention management\" for gastroschisis", "authors": [{"first": "A", "middle": [], "last": "Bianchi", "suffix": ""}, {"first": "A", "middle": ["P"], "last": "Dickson", "suffix": ""}], "year": 1998, "venue": "J Pediatr Surg", "link": null}, "BIBREF2": {"title": "Evaluation of surgisis for patch repair of abdominal wall defects in children", "authors": [{"first": "A", "middle": [], "last": "Beres", "suffix": ""}, {"first": "E", "middle": [], "last": "Christison-Lagay", "suffix": ""}, {"first": "R", "middle": ["L"], "last": "Romao", "suffix": ""}, {"first": "J", "middle": ["C"], "last": "Langer", "suffix": ""}], "year": 2012, "venue": "J Pediatr Surg", "link": "206421104"}, "BIBREF3": {"title": "Large gastroschisis: Primary repair with gore-tex patch", "authors": [{"first": "G", "middle": [], "last": "Stringel", "suffix": ""}], "year": 1993, "venue": "J Pediatr Surg", "link": "35640795"}, "BIBREF4": {"title": "Gastroschisis Wringer Clamp: A safe, simplified method for delayed primary closure", "authors": [{"first": "R", "middle": [], "last": "Sawin", "suffix": ""}, {"first": "P", "middle": [], "last": "Glick", "suffix": ""}, {"first": "R", "middle": [], "last": "Schaller", "suffix": ""}, {"first": "E", "middle": [], "last": "Hatch", "suffix": ""}, {"first": "D", "middle": [], "last": "Hall", "suffix": ""}, {"first": "L", "middle": [], "last": "Hicks", "suffix": ""}], "year": 1992, "venue": "J Pediatr Surg", "link": "10437880"}, "BIBREF5": {"title": "Repair of gastroschisis using umbilical cord as a patch", "authors": [{"first": "S", "middle": ["M"], "last": "Zivkovic", "suffix": ""}], "year": 1991, "venue": "J Pediatr Surg", "link": "28512674"}, "BIBREF6": {"title": "Closure of gastroschisis by mesh skin grafts in problem cases", "authors": [{"first": "H", "middle": [], "last": "Anderi", "suffix": ""}, {"first": "G", "middle": [], "last": "Menardi", "suffix": ""}, {"first": "J", "middle": [], "last": "Hager", "suffix": ""}], "year": 1986, "venue": "J Pediatr Surg", "link": "22952414"}}, "ref_entries": {"FIGREF0": {"text": "Figure 1-4: 1-The purse string sutures have been placed with care not to include the underlying bowel and the patch has been tied in place with felt pledgets to minimize the trauma to the tissues. 2-Appearance after the tying of both prolene purse string sutures, patch 2.5 cm in diameter. 3-Appearance post fascial and skin closure. 4-Appearance 6 weeks post-surgery.", "type": "figure"}}}
{"paper_id": "17431411", "_pdf_hash": "874b2b6f5d33738eae64ebff3d79b27f96e9dbff", "abstract": [{"section": "Abstract", "text": ", and Michael Surko r r r r r r r r r r r r r r r r r r r r r r r r r r r r r r r r r r r r r r r r r r r r r r r r r r r r r r r r r r r r r r r r r r r r r r r r r r r r r r r r r r r r r A lthough positive youth development (PYD) is increasingly influential in the field of youth programming, core knowledge and competencies for youth workers continue to be defined. Youth serving agencies throughout the United States face serious obstacles in the creation of a stable and well-trained workforce, despite the presence of many talented and resourceful individuals who work with youth in the community. One strategy for organizational and staff development is through PYD-oriented, community-based partnerships designed to enhance youth worker knowledge and competence. Two different partnerships are described in this report. The first brought together experts in youth work, health, and trauma, and focused on improving youth worker response to psychologic trauma commonly experienced by urban youth. This partnership used an iterative reflective practice approach to describe best practices in youth work. The second partnership strategically taught evaluation skills to youth program consumers, AmeriCorps service members, and adult youth workers to advance youth-adult partnerships. These exemplars demonstrate that partnerships can drive systems for improving competencies in youth workers and the capacities of youth services.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "KEY WORDS: adolescent, capacity building, community-based, logic model, partnership, professional development, reflective practice, trauma, youth development, youth-focused Axiomatic to positive youth development (PYD) [1] [2] [3] [4] [5] are the beliefs that \"problem-free is not fully prepared\" for the future, 2(p20) and that effective prevention and remediation of problems require those who engage young people to provide opportunities for them to build personal and social assets that will prepare them for a healthy and productive adulthood. 6 As described by Bernat and Resnick, and others in this supplement, PYD offers opportunities for researchers and practitioners to better understand the contribution of social and institutional factors to both adolescent health promotion and vulnerability. 4 PYD also affirms that healthy development requires meaningful involvement of adolescents in their communities, and in the programs and institutions that serve them.", "cite_spans": [{"start": 219, "end": 222, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 223, "end": 226, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 227, "end": 230, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 231, "end": 234, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 235, "end": 238, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 549, "end": 550, "text": "6", "ref_id": "BIBREF5"}, {"start": 806, "end": 807, "text": "4", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "Abstract", "text": "7 However, community and consumer participation in traditionally bureaucratic medical institutions is not always welcomed, for both organization-cultural and practical reasons.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "8 Problemoriented public health funding and reimbursement for services tend to result in problem-focused approaches, with little incentive to adopt PYD practices.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "9 When PYD practices are adopted, they are sometimes misunderstood as an alternative to, rather than as an enhancement of, current models of public health or primary care.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "10 Thus, healthcare settings are not commonly considered as partners for youth serving agencies in PYD programming.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Youth serving agencies, themselves, may face obstacles in PYD programming because of the unmet need for a stable and well-trained workforce that has the knowledge and competence to address the myriad We gratefully thank the following people for their major contributions to the work described in this article: Janet Kelley, MSW, Lissette Resto-Brooks, MSW, and Elizabeth Goodman, MSW, of Partnership for Afterschool Education; Angela Diaz, MD, MPH, of the Mount Sinai Adolescent Health Center; Robert Eleteza of SafeHorizon; and Marie Louis and Paul Josephson of Community Counseling and Mediation. We also thank Claude Chemtob, PhD, of Mount Sinai School of Medicine for his intellectual contributions and trauma expertise.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Corresponding author: Ken Peake, DSW, Mount Sinai Adolescent Health Center, 320 East 94th Str, New York, NY 10128 (e-mail: ken.peake@mssm.edu).", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "", "text": "and productive adulthood. 6 As described by Bernat and Resnick, and others in this supplement, PYD offers opportunities for researchers and practitioners to better understand the contribution of social and institutional factors to both adolescent health promotion and vulnerability. 4 PYD also affirms that healthy development requires meaningful involvement of adolescents in their communities, and in the programs and institutions that serve them. 7 However, community and consumer participation in traditionally bureaucratic medical institutions is not always welcomed, for both organization-cultural and practical reasons. 8 Problemoriented public health funding and reimbursement for services tend to result in problem-focused approaches, with little incentive to adopt PYD practices. 9 When PYD practices are adopted, they are sometimes misunderstood as an alternative to, rather than as an enhancement of, current models of public health or primary care. 10 Thus, healthcare settings are not commonly considered as partners for youth serving agencies in PYD programming.", "cite_spans": [{"start": 26, "end": 27, "text": "6", "ref_id": "BIBREF5"}, {"start": 283, "end": 284, "text": "4", "ref_id": "BIBREF3"}, {"start": 450, "end": 451, "text": "7", "ref_id": "BIBREF6"}, {"start": 627, "end": 628, "text": "8", "ref_id": "BIBREF7"}, {"start": 790, "end": 791, "text": "9", "ref_id": "BIBREF8"}, {"start": 962, "end": 964, "text": "10", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "", "text": "Youth serving agencies, themselves, may face obstacles in PYD programming because of the unmet need for a stable and well-trained workforce that has the knowledge and competence to address the myriad We gratefully thank the following people for their major contributions to the work described in this article: Janet Kelley, MSW, Lissette Resto-Brooks, MSW, and Elizabeth Goodman, MSW, of Partnership for Afterschool Education; Angela Diaz, MD, MPH, of the Mount Sinai Adolescent Health Center; Robert Eleteza of SafeHorizon; and Marie Louis and Paul Josephson of Community Counseling and Mediation. We also thank Claude Chemtob, PhD, of Mount Sinai School of Medicine for his intellectual contributions and trauma expertise.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "challenges facing both urban and rural youth. [11] [12] [13] Staff shortages can lead to a focus on short-term, day-to-day operational problems, which in turn impede the development of far-sighted goals such as staff development. 11 As a result, many youth worker jobs are part-time, which often create unstable staffing structures that make it more difficult for programs to deliver on the PYD principle that youth benefit from long-term relationships with concerned adults. Thus, Noonan 11 has described working with youth in the United States as a developing, but still unrealized career track, in contrast to the UK, Irish, and Australian contexts in which youth work is a recognized and developing professional field.", "cite_spans": [{"start": 46, "end": 50, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 51, "end": 55, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 56, "end": 60, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 230, "end": 232, "text": "11", "ref_id": "BIBREF10"}, {"start": 489, "end": 491, "text": "11", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "", "text": "14, 15 The youth worker field in this country faces a number of problems, including inadequate funding, an \"elastic supply of low paid workers,\" and \"negative return\" on investment in advanced training (ie, the costs of continuing education exceed the salary benefits that can result). 11(p5) To become a recognized professional field, youth workers require (1) the identification of a core knowledge base, (2) a career \"matrix that links roles, qualifications and compensation,\" 11(p2) (3) a system of training, (4) a training approval system, and (5) a registry of practitioners.", "cite_spans": [{"start": 4, "end": 6, "text": "15", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "", "text": "Camino and Zeldin identify the creation of partnerships for capacity building as a key strategy for organizational and staff competency development.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "12 While the two efforts described in this article do not address all of the challenges posed by Noonan, 11 they serve, in the spirit of Camino and Zeldin's 12 recommendation, as practical exemplars of ways that core competencies can be defined and developed in youth service settings. This article presents two examples of partnerships involving a traditional adolescent health setting and other community organizations that were designed to enhance the capacity of community-based youth workers to engage in PYD. This increased capacity for PYD programming provides added value to community organizations in program marketing, participant recruitment and retention, staff recruitment and retention, as well as effectiveness studies. The first of these is not an example of PYD, per se, since youth involvement was not an essential element of its activities. Nonetheless, it is included in this supplement on PYD as a public health strategy because some organizations will find themselves needing this kind of capacity-building before attempting to institute full PYD programming.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "The Mount Sinai Adolescent Health Center (AHC) is the nation's largest comprehensive adolescent-specific health center, with more than 40,000 visits annually. The AHC provides primary care and mental health services to urban teens and conducts research, medical education training, and technical assistance, all intended to promote the health of adolescents. 4 A core component of AHC's mission is to influence adolescent health through the development of strategic partnerships within the youth serving and youth development communities. In New York City, where the capacity-building efforts were conducted, estimates of the number of children and youth involved in afterschool programs vary greatly, but may exceed a halfmillion. 16 A number of efforts to strengthen YD programs have been initiated through groups such as The After-School Corporation and the Fund for the City of New York's Youth Development Institute. Two community-based partnerships collaborated with the AHC.", "cite_spans": [{"start": 359, "end": 360, "text": "4", "ref_id": "BIBREF3"}, {"start": 732, "end": 734, "text": "16", "ref_id": "BIBREF15"}], "ref_spans": []}, {"section": "", "text": "\u2022 Partnership for After School Education Partnership for After School Education (PASE) was founded in January 1993, when 60 New York City youth agency leaders and funders were convened to address serious issues in the overall quality and consistency of critical youth services in the city. Services lacked mechanisms to share effective program practices, to explore issues of concern to practitioners, and to develop resources. As a peer-led network that now includes more than 1,200 participating youth-serving agencies, PASE was designed to develop a strong service-system for youth through professional development of the field and to involve young people in public policy development. Formed with the explicit aim of developing the professional field in YD work, PASE was the locus for, and initiator of, the Partners in Healing (PIH) program.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "\u2022", "cite_spans": [], "ref_spans": []}, {"section": "Partnership for Youth and Community Empowerment", "text": "Partnership for Youth and Community Empowerment (PYCE) is a partnership of three youth-serving organizations in the North Crown Heights section of Brooklyn, New York. The PYCE was a local community development partnership, while the AHC was the center for excellence that provided it with technical assistance, in the statewide Assets Coming Together for Youth initiative described by Riser and colleagues elsewhere in this supplement. 17 Thus, while PASE represented a vast network of more than 1,000 youth-serving agencies across New York City, the PYCE represented a much smaller group defined by a neighborhood. Each of these coalitions partnered with the AHC in ways that are illustrative for other public health entities interested in increasing the capacity of community-based groups, large or small, to engage in PYD programming.", "cite_spans": [{"start": 436, "end": 438, "text": "17", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "Partnership for Youth and Community Empowerment", "text": "\u2022 Methods", "cite_spans": [], "ref_spans": []}, {"section": "Partners in Healing", "text": "The goal of Partners in Healing (PIH) was to build capacity among front-line youth workers by improving their ability to help young people living in urban settings address traumatic life experiences. Without attempting to turn youth workers into mental health professionals, the PIH aimed to build on their existing strengths to engage trauma-affected young people and, where appropriate, to help them build bridges to professional mental health services. AHC's role was the creation of a youth worker guidebook, developed concurrently during a yearlong series of trainings for youth workers. The youth workers represented 31 community-based organizations, and the training was conducted by PASE and SafeHorizon, a leading nonprofit, victim assistance, advocacy, and violence prevention organization.", "cite_spans": [], "ref_spans": []}, {"section": "Partners in Healing", "text": "To create a guidebook that was both well-informed and useful, the AHC recognized the need to identify existing best practices in the fields of PYD and youth work, and mental health and adolescent psychologic trauma, which would require expertise in youth work, program development, administration, youth communications, professional development, and social work. Many expert practitioners are not accustomed to distilling heuristics from their accumulated \"practice wisdom\" and articulating practice principles. 18 Youth work training is generally hands-on, relying on having a supervisor directly involved in the service setting. While the PIH youth work experts actively train and supervise many youth workers every year, a significant challenge was to translate their practice wisdom into written principles and practical solutions. While one task was to tap their general expertise, a far more difficult task was to identify ways in which youth workers can respond appropriately to the common trauma-related issues of urban youth, without overstepping the limitations of their settings and roles.", "cite_spans": [{"start": 512, "end": 514, "text": "18", "ref_id": "BIBREF17"}], "ref_spans": []}, {"section": "Partners in Healing", "text": "To accomplish this, AHC engaged expert practitioners in the process of reflective inquiry. 19 This approach has been applied to understanding and iterating daily practice in human services, [20] [21] [22] [23] administration, 24 and knowledge development. 18, 25 It assumes that (1) theorizing, thinking, and action are not distinct activities separated in time, but occur concurrently, and (2) effective practitioners solve practical problems by drawing on experience through an analogical, nonlinear process. Thus, the AHC's work involved drawing on experts' abilities to reflect on specific practice problems and strategies and solutions that emerge everyday in youth work.", "cite_spans": [{"start": 91, "end": 93, "text": "19", "ref_id": "BIBREF18"}, {"start": 190, "end": 194, "text": "[20]", "ref_id": "BIBREF19"}, {"start": 195, "end": 199, "text": "[21]", "ref_id": "BIBREF20"}, {"start": 200, "end": 204, "text": "[22]", "ref_id": "BIBREF21"}, {"start": 205, "end": 209, "text": "[23]", "ref_id": "BIBREF22"}, {"start": 226, "end": 228, "text": "24", "ref_id": "BIBREF23"}, {"start": 256, "end": 259, "text": "18,", "ref_id": "BIBREF17"}, {"start": 260, "end": 262, "text": "25", "ref_id": "BIBREF24"}], "ref_spans": []}, {"section": "Partners in Healing", "text": "To scope out the project, a PIH planning group (PIHPG) was convened, composed of regional experts in the fields of youth work, training, social work education, mental health, and trauma. In addition to PASE staff and AHC staff and faculty, the PIHPG included the Director of Youth Communications and a psychologist from the Mount Sinai Medical Center, two social workers from SafeHorizon, a professor of social work from New York University, and a social worker from the Mental Health Association of New York City. Planning sessions with the PIHPG were used by the AHC to conduct a state of the field assessment related to trauma and training challenges encountered in youth service settings, a gaps analysis, and a needs assessment. The PIHPG remained involved in steering the PIH project, but its initial work was to develop two key elements of the guidebook.", "cite_spans": [], "ref_spans": []}, {"section": "Partners in Healing", "text": "An outline for the guidebook content and for the organization was generated from the state of the field assessment. Content covered eight key areas: (1) recognizing the effects of trauma, (2) recovery from trauma, (3) building resiliency, (4) helping kids feel safe, (5) using groups to build resiliency, (6) promoting healthy approaches to grief and loss, (7) supporting the youth worker, and (8) linking with mental health providers. The PIHPG then developed a unified approach to content presentation simultaneous to the AHC surveying relevant literature and tools, contemporary resources, published guides, and training materials that reflected practice wisdom and research. Workgroups were formed to review content developed by AHC. PASE's extensive network of experts in PYD-related technical assistance, training, youth programming, and communications facilitated recruitment of workgroup members; the AHC's expertise was in working with traumatized youth and other professionals who engage youth around high-risk issues, such as human immunodeficiency virus/acquired immunodeficiency syndrome.", "cite_spans": [], "ref_spans": []}, {"section": "Partners in Healing", "text": "The final and most complex stage of content development entailed obtaining detailed, real-life exemplars of best practices. To accomplish this, four focus groups were formed of workgroup participants and their extended networks. Each was composed of experienced youth work trainers and supervisors, program developers, and trauma service experts. The groups focused on two subject areas each: (1) defining trauma and its impact/PYD strategies for strengthening resilience; (2) making the service setting a safe space/group strategies for fostering recovery; (3) grief, loss, and endings/agency preparedness; and (4) supporting staff/linking with mental health services. Each focus group meeting was taped and transcribed, and in-depth, follow-up interviews were conducted to clarify and expand content. The groups focused on questions such as the following:", "cite_spans": [], "ref_spans": []}, {"section": "Partners in Healing", "text": "\u2022 How should youth workers be trained to recognize manifestations of trauma? ", "cite_spans": [], "ref_spans": []}, {"section": "Partnership for Youth and Community Empowerment", "text": "Another method to build capacity with youth workers to prepare for YD programming in their agencies is illustrated by the out-of-school programs developed by the PYCE in North Crown Heights, Brooklyn. In this approach, the learning environment creates informal skills-development opportunities for program consumers, young adults, and adult staff members, and internal capacity-building is supplemented by formal training and technical assistance delivered by external experts.", "cite_spans": [], "ref_spans": []}, {"section": "Internal capacity-building", "text": "AmeriCorps members aged 18 to 22 years partnered with full-time, adult youth workers from social service agencies to establish out-of-school programs. The AmeriCorps members committed to a year of part-time public service in exchange for training and a small stipend, and were responsible for planning, implementing, and staffing the programs. Offerings included entrepreneurial silk-screening, drama and debate, sports tournaments, mock court, and conducting a large community survey of more than 5,000 youth each summer. The programs were designed so that the program consumers, along with the AmeriCorps members who planned and ran the programs, gained experience that would be educational and relevant to workforce participation and later habits of civic engagement and service. In this model, the distinction between youth program consumers and adult youth workers was intentionally blurred; the AmeriCorps members were given a set of opportunities and support as a means of promoting their own positive development, and in turn provided opportunities and support for children and younger teens. Thus, they were both the recipients and providers of YD interventions. This duality allowed both internal and external capacity-building to be focused on the AmeriCorps members, as well as on the full-time adult youth workers. Although both AmeriCorps members and adult agency staff provided youth work services, for the sake of clarity we will use the terms \"program consumer,\" \"AmeriCorps member,\" and \"youth workers.\"", "cite_spans": [], "ref_spans": []}, {"section": "Internal capacity-building", "text": "Capacity with AmeriCorps members was built and maintained by their participation in a 60-hour orientation covering topics such as history of national service, recognizing and addressing child abuse, classroom management, team-building activities, play therapy techniques, and project and lesson planning. Each AmeriCorps member had to demonstrate mastery of the material before participating in the delivery of training. Youth workers also received targeted training intended for adult agency staff.", "cite_spans": [], "ref_spans": []}, {"section": "Internal capacity-building", "text": "Added to the formal internal capacity-building for youth workers described above were informal means of enhancing preparedness for YD work within programs. For example, some individuals had prior experience in the program as consumers and/or AmeriCorps members. The multiple levels of participation, as program consumer, AmeriCorps member, and/or youth worker, reflect an intentionally designed progression of involvement for young people who wished to stay active in the programs over time. Within a program that serves approximately 250 young people annually, 7 consumers became AmeriCorps members, 10 AmeriCorps members became youth workers, and 2 former AmeriCorps members became program directors over a 4-year period. Program experience gained by young people as consumers helped prepare them to assume roles as full-time agency staff. In addition, the youth workers expressed openness to learning from AmeriCorps members, both through written feedback on program activities and through adopting new practices developed by the AmeriCorps members.", "cite_spans": [], "ref_spans": []}, {"section": "External capacity-building", "text": "AmeriCorps members and youth workers both received training and technical assistance from the AHC through its Assets Coming Together for Youth Center for Excellence, described in greater detail in the article by Riser and colleagues elsewhere in this supplement. Training sessions by AHC staff included more general topics, as well as those that were tailored to the specific needs of one youth program. For example, one training session focused on fundamental concepts of public health and survey design. Health concepts included defining a population by one or more characteristics (eg, geographic, health behaviors), types of community health (eg, physical & mental health, civic responsibility, education, economic security, physical and social environment), and prevention strategies that can be used to reduce risk for negative health outcomes. Survey concepts addressed included fundamental principles of survey design and administration, as well as the types of survey questions used. AmeriCorps members then drafted surveys that focused on five public health topics and received technical assistance from AHC staff to refine and edit the surveys. Youth program consumers, with supervision from the AmeriCorps members, collected and analyzed the survey data and produced written reports, the results of which were presented to community leaders and at a city gang awareness conference. Youth workers reported that the training helped the AmeriCorps members develop broader concepts of community health and produce more rigorous (although still nonscientific) surveys.", "cite_spans": [], "ref_spans": []}, {"section": "External capacity-building", "text": "Other examples of external capacity building involved training sessions for both AmeriCorps members and youth workers to prepare them to evaluate the programs that they ran. Training began with the concepts of developmental assets and positive developmental settings, and then covered components of a logic model and of a consumer satisfaction survey. 26 In the first session, AmeriCorps members created logic models of the programs they ran. In the second session, they learned the principles of designing program participant surveys and created sample survey items that could assess consumer satisfaction and examine program elements identified in the logic models. AmeriCorps members demonstrated mastery of the concepts by drafting logic models of their programs, editing them with feedback from AHC staff, constructing a consumer satisfaction survey and key elements of their logic models (eg, are they reaching their target population, is the program space safe, clean, and attractive, do participants like the activities). Although this training was initially developed for the AmeriCorps members, youth workers requested it for themselves after they observed the AmeriCorps members produce and use logic models for their programs. Sometimes intimidating for adults with experience in program development, logic modeling was quickly grasped by AmeriCorps members who became fluent in using the framework. The program logic models guided the development of program participant surveys and the logic model terminology became a common language that was adopted by the adult staff.", "cite_spans": [{"start": 352, "end": 354, "text": "26", "ref_id": "BIBREF25"}], "ref_spans": []}, {"section": "External capacity-building", "text": "\u2022 Results/Discussion", "cite_spans": [], "ref_spans": []}, {"section": "Partnership for After-school Education and Partners in Healing program", "text": "Many mental health professionals who interact with young people are not aware of their adolescent clients' exposure to community violence, fail to ask about such exposure, 27 and fail to ask about the risk of exposure. 28, 29 Preliminary findings from the evaluation of PIH show that all of the 31 participating agencies reported that trauma is now part of their everyday focus. As a result, they are handling it more effectively and the youth they serve have improved access to mental health services. They reported an increased collaboration among youth workers to address the needs of traumatized youth, rather than removing them from program activities when they react with behavioral problems, as occurred previously. Overall, youth workers reported an increased acceptance of a role for mental health service providers and mental health discussions in the setting of a youth service program. In addition, PIH had significant unanticipated impacts, such as the establishment of, or improvement in, systems for tracking all youth across programs within each agency, including those with and without mental health needs. The PIH initiative demonstrates that a broad-based partnership can bring tremendous and widely varying expertise at the community level to improve the performance of individual youth workers, program directors, and programs. As a result of collaborating with the AHC, the PIH partners came to recognize that they and health and human service sectors with which they had rarely, if ever, interacted were now identifying common goals. With capacity building as the primary objective, the focus on adults in community settings was a logical point of intervention. Thus, although YD was not an immediate goal of this project, increasing the knowledge and competence of staff and administrators in youth serving agencies is a necessary first step in preparing organizations to be ready for YD programming. The absence of youth representation in program development, and of a data-collection process on the youth impact at the agency level, indicates areas for improvement in future efforts that will move toward the ideal goals of PY articulated by Schulman elsewhere in this supplement. However, enhancing organizational readiness is often the first step in preparing for YD programming.", "cite_spans": [{"start": 172, "end": 174, "text": "27", "ref_id": "BIBREF26"}, {"start": 219, "end": 222, "text": "28,", "ref_id": "BIBREF27"}, {"start": 223, "end": 225, "text": "29", "ref_id": "BIBREF28"}], "ref_spans": []}, {"section": "Partnership for After-school Education and Partners in Healing program", "text": "The PYCE initiative was characterized by the richness of the learning environment that emerged and the fact that youth program consumers, AmeriCorps members, and youth workers all learned from one another. A 2-month follow-up by AHC staff demonstrated that some of the practices developed in the training were being used. For example, the logic model had been adopted, which the adult staff would have been unlikely to embrace in the absence of the strongly favorable reaction from the AmeriCorps members. In addition, both AmeriCorps members and youth workers had adopted the language of the logic model and logic modeling had become the primary method for program development. Evaluation and participant feedback had been incorporated into everyday practice and was now the norm.", "cite_spans": [], "ref_spans": []}, {"section": "Partnership for After-school Education and Partners in Healing program", "text": "\u2022", "cite_spans": [], "ref_spans": []}, {"section": "Conclusion", "text": "Whereas the PIH initiative took a top-down approach with expert trainers working with adult staff only, the PYCE initiative employed a youth-adult partnership model characterized by youth and adults receiving training together and working collaboratively on program planning, program development, and program evaluation. While the latter example incorporated the PYD practice of involving young people directly in its implementation, the former initiative also has a significant implication for PYD. It demonstrated that PYD, which emphasizes a strengths-based approach in which youth are actively involved throughout program development, can benefit directly by having adults in youth service programs focus on the very real problems with which many youth struggle. While addressing social pathologies, the PIH initiative leveraged PYD principles by building on the capacity and strengths of youth workers and youth services. Although the two exemplars presented here are remarkably different in their scope and aims, together they demonstrate that partnerships can drive systems for improving competencies in youth workers and the capacities of youth services. Moreover, they each relied on the staff of an urban AHC, an entity often not considered as a partner in youth service sectors. These staff provided training and technical assistance to build capacity, demonstrating that healthcare service providers can have an important role in the public health practice of PYD.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Positive youth development, participation in community youth development programs and community contributions of fifth-grade adolescents: findings from the first wave of the 4-H study of positive youth development", "authors": [{"first": "R", "middle": ["M"], "last": "Lerner", "suffix": ""}, {"first": "J", "middle": ["V"], "last": "Lerner", "suffix": ""}, {"first": "J", "middle": ["B"], "last": "Alemerigi", "suffix": ""}], "year": 2005, "venue": "J Early Adolesc", "link": "16482192"}, "BIBREF1": {"title": "Unfinished business: further reflections on a decade of promoting youth development", "authors": [{"first": "K", "middle": [], "last": "Pittman", "suffix": ""}, {"first": "M", "middle": [], "last": "Irby", "suffix": ""}, {"first": "T", "middle": [], "last": "Ferber", "suffix": ""}], "year": 2000, "venue": "Youth Development: Issues, Challenges and Directions", "link": "150619887"}, "BIBREF2": {"title": "Balancing the equation: communities supporting youth, youth supporting communities", "authors": [{"first": "K", "middle": [], "last": "Pittman", "suffix": ""}], "year": 2000, "venue": "Community Youth Dev J", "link": null}, "BIBREF3": {"title": "Including at risk adolescents in their own health and mental healthcare: a youth development perspective", "authors": [{"first": "A", "middle": [], "last": "Diaz", "suffix": ""}, {"first": "K", "middle": [], "last": "Peake", "suffix": ""}, {"first": "M", "middle": [], "last": "Surko", "suffix": ""}, {"first": "K", "middle": [], "last": "Bhandarkar", "suffix": ""}], "year": 2004, "venue": "Soc Work Ment Health", "link": "71121159"}, "BIBREF4": {"title": "Theoretical frames for understanding and enhancing adolescent development. Paper presented at: the National Academy of Sciences", "authors": [{"first": "R", "middle": ["M"], "last": "Lerner", "suffix": ""}], "year": 2005, "venue": "", "link": null}, "BIBREF5": {"title": "Developmental Assets: A Synthesis of the Scientific Research on Adolescent Development. Minneapolis, Minn: Search Institute", "authors": [{"first": "P", "middle": ["C"], "last": "Scales", "suffix": ""}, {"first": "N", "middle": [], "last": "Leffert", "suffix": ""}], "year": 1999, "venue": "", "link": null}, "BIBREF6": {"title": "Community youth development: a framework for action", "authors": [{"first": "D", "middle": ["M"], "last": "Hughes", "suffix": ""}, {"first": "S", "middle": ["P"], "last": "Curnan", "suffix": ""}], "year": 2000, "venue": "Community Youth Dev J", "link": null}, "BIBREF7": {"title": "Community development and lay participation", "authors": [{"first": "K", "middle": [], "last": "Peake", "suffix": ""}, {"first": "B", "middle": [], "last": "Brenner", "suffix": ""}, {"first": "G", "middle": [], "last": "Rosenberg", "suffix": ""}], "year": 1998, "venue": "", "link": null}, "BIBREF8": {"title": "Positive youth development and adolescent health promotion: strengths, challenges & issues to consider. Paper presented at: the National Academy of Sciences", "authors": [{"first": "A", "middle": [], "last": "Diaz", "suffix": ""}], "year": 2005, "venue": "", "link": null}, "BIBREF9": {"title": "Prevention science and positive youth development: competitive or cooperative frameworks?", "authors": [{"first": "R", "middle": ["C"], "last": "Catalano", "suffix": ""}, {"first": "D", "middle": ["J"], "last": "Hawkins", "suffix": ""}, {"first": "M", "middle": ["L"], "last": "Berglund", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Pollard", "suffix": ""}, {"first": "M", "middle": ["W"], "last": "Arthur", "suffix": ""}], "year": 2002, "venue": "J Adolesc Health", "link": "5544850"}, "BIBREF10": {"title": "From contrast to concrete: issues in building a skilled and stable out-of-school time workforce. National Institute for Out-of-School-Time", "authors": [{"first": "A", "middle": [], "last": "Noonan", "suffix": ""}], "year": 2001, "venue": "", "link": null}, "BIBREF11": {"title": "Making the transition to community youth development: emerging roles and competencies for organizations and youth workers", "authors": [{"first": "L", "middle": [], "last": "Camino", "suffix": ""}, {"first": "S", "middle": [], "last": "Zeldin", "suffix": ""}], "year": 2002, "venue": "Community Youth Development Anthology", "link": null}, "BIBREF12": {"title": "Ready to roll: five cities share their experience with recruiting, orienting and first year training of after-school staff", "authors": [{"first": "W", "middle": ["B"], "last": "Surr", "suffix": ""}], "year": 2001, "venue": "After School Issues", "link": null}, "BIBREF13": {"title": "Youth research in Australia and New Zealand", "authors": [{"first": "J", "middle": [], "last": "Wyn", "suffix": ""}, {"first": "A", "middle": [], "last": "Harris", "suffix": ""}], "year": 2004, "venue": "Young J Youth Res", "link": "145786793"}, "BIBREF14": {"title": "Youth Health, Specialist Certificate in Health Promotion-Youth Work", "authors": [], "year": 2005, "venue": "", "link": null}, "BIBREF15": {"title": "Partnership for After School Education (PASE) Website. Available at", "authors": [], "year": 2005, "venue": "", "link": null}, "BIBREF16": {"title": "New York State's \"Assets Coming Together (ACT) for Youth\": A Statewide Approach Effects Community Change", "authors": [{"first": "M", "middle": ["H"], "last": "Riser", "suffix": ""}, {"first": "K", "middle": [], "last": "Mesler", "suffix": ""}, {"first": "T", "middle": ["C"], "last": "Tallon", "suffix": ""}, {"first": "G", "middle": ["S"], "last": "Birkhead", "suffix": ""}], "year": 2006, "venue": "J Public Health Manag Pract", "link": null}, "BIBREF17": {"title": "Theoretical and practical imperatives for reflective social work organizations in health and mental health: the place of practice-based research", "authors": [{"first": "K", "middle": [], "last": "Peake", "suffix": ""}, {"first": "I", "middle": [], "last": "Epstein", "suffix": ""}], "year": 2005, "venue": "Soc Work Ment Health", "link": "144329506"}, "BIBREF18": {"title": "The Reflective Practitioner: How Professionals Think in Action", "authors": [{"first": "D", "middle": [], "last": "Schon", "suffix": ""}], "year": 1983, "venue": "", "link": "145408602"}, "BIBREF19": {"title": "Promoting and maintaining a reflective professional staff in a hospital-based social work department", "authors": [{"first": "S", "middle": [], "last": "Blumenfield", "suffix": ""}, {"first": "I", "middle": [], "last": "Epstein", "suffix": ""}], "year": 2001, "venue": "Soc Work Health Care", "link": "45522658"}, "BIBREF20": {"title": "The Reflective Researcher: Social Workers' Theories of Practice Research", "authors": [{"first": "J", "middle": [], "last": "Fook", "suffix": ""}, {"first": "Ed", "middle": [], "last": "", "suffix": ""}], "year": 1996, "venue": "", "link": "140951726"}, "BIBREF21": {"title": "The development of practice wisdom through human problem solving processes", "authors": [{"first": "Y", "middle": ["S"], "last": "Deroos", "suffix": ""}], "year": 1990, "venue": "Soc Serv Rev", "link": "144822885"}, "BIBREF22": {"title": "Field education for reflective practice: a reconstructive proposal", "authors": [{"first": "H", "middle": [], "last": "Goldstein", "suffix": ""}], "year": 1993, "venue": "J Teach Soc Work", "link": null}, "BIBREF23": {"title": "Grounded theory meets the reflective practitioner: integrating qualitative and quantitative methods in administrative practice", "authors": [{"first": "S", "middle": [], "last": "Bernstein", "suffix": ""}, {"first": "I", "middle": [], "last": "Epstein", "suffix": ""}], "year": 1994, "venue": "Qualitative Research in Social Work", "link": null}, "BIBREF24": {"title": "Promoting reflective social work practice: research strategies and consulting principles", "authors": [{"first": "I", "middle": [], "last": "Epstein", "suffix": ""}], "year": 2001, "venue": "Practitioner-Researcher Partnerships: Building Knowledge From, in and for Practice", "link": null}, "BIBREF25": {"title": "Measuring Program Outcomes: A Practical Approach", "authors": [], "year": 1996, "venue": "", "link": "203293457"}, "BIBREF26": {"title": "Young clients' exposure to community violence: how much do their therapists know?", "authors": [{"first": "N", "middle": ["B"], "last": "Guterman", "suffix": ""}, {"first": "M", "middle": [], "last": "Cameron", "suffix": ""}], "year": 1999, "venue": "Am J Orthopsychiatry", "link": "39602028"}, "BIBREF27": {"title": "The Commonwealth Fund Survey of the Health of Adolescent Girls", "authors": [{"first": "C", "middle": [], "last": "Schoen", "suffix": ""}, {"first": "K", "middle": [], "last": "Davis", "suffix": ""}, {"first": "Scott", "middle": [], "last": "Collins", "suffix": ""}, {"first": "K", "middle": [], "last": "Greenberg", "suffix": ""}, {"first": "L", "middle": [], "last": "", "suffix": ""}, {"first": "Des", "middle": [], "last": "Roches", "suffix": ""}, {"first": "C", "middle": [], "last": "Abrams", "suffix": ""}, {"first": "M", "middle": [], "last": "", "suffix": ""}], "year": "", "venue": "", "link": "78103705"}, "BIBREF28": {"title": "Delivering quality care: adolescents' discussion of health risks with their providers", "authors": [{"first": "J", "middle": [], "last": "Klein", "suffix": ""}, {"first": "K", "middle": [], "last": "Wilson", "suffix": ""}], "year": 2002, "venue": "J Adolesc Health", "link": "30027347"}}, "ref_entries": {"TABREF0": {"text": "What are effective strategies for forming collabora- tions with mental health services? \u2022 How might an agency respond to youth after a trau- matic community event, such as a shooting? How do effective youth programs heal themselves after they have been affected by a traumatic event? \u2022 What would the job description of a trauma- competent youth worker look like?", "type": "table"}}}
{"paper_id": "17432145", "_pdf_hash": "852576b04d1385ffc7da399fd446d2929d725e24", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "C 3 NAV\u2122 Operating Manual", "authors": [{"first": "M", "middle": ["E"], "last": "Cannon", "suffix": ""}, {"first": "G", "middle": [], "last": "Lachapelle", "suffix": ""}, {"first": "W", "middle": [], "last": "Qui", "suffix": ""}], "year": 1995, "venue": "", "link": null}, "BIBREF1": {"title": "DGPS Kinematic Carrier Phase Signal Simulation Analysis for Precise Velocity and Position Determination", "authors": [{"first": "M", "middle": ["E"], "last": "Cannon", "suffix": ""}, {"first": "G", "middle": [], "last": "Lachapelle", "suffix": ""}, {"first": "M", "middle": [], "last": "Szarmes", "suffix": ""}, {"first": "J", "middle": [], "last": "Hebert", "suffix": ""}, {"first": "J", "middle": [], "last": "Keith", "suffix": ""}, {"first": "S", "middle": [], "last": "Jokerst", "suffix": ""}], "year": 1997, "venue": "Proceedings of the ION NTM", "link": "110278728"}, "BIBREF2": {"title": "NovAtel Communications Ltd. -What's New? Proceedings of KIS94", "authors": [{"first": "P", "middle": [], "last": "Fenton", "suffix": ""}, {"first": "B", "middle": [], "last": "Townsend", "suffix": ""}], "year": 1994, "venue": "", "link": null}, "BIBREF3": {"title": "High Accuracy GPS Velocity Using the Carrier Phase Observable", "authors": [{"first": "J", "middle": [], "last": "Hebert", "suffix": ""}], "year": 1997, "venue": "Proceedings of KIS97", "link": null}, "BIBREF4": {"title": "GPS Carrier Phase Signal Simulation Analysis for Aircraft Velocity Determination", "authors": [{"first": "G", "middle": [], "last": "Lachapelle", "suffix": ""}, {"first": "M", "middle": ["E"], "last": "Cannon", "suffix": ""}, {"first": "S", "middle": [], "last": "Ryan", "suffix": ""}, {"first": "J", "middle": [], "last": "Hebert", "suffix": ""}, {"first": "", "middle": [], "last": "Keith", "suffix": ""}], "year": 1997, "venue": "Proceedings of the ION 53rd Annual Meeting", "link": null}}, "ref_entries": {}}
{"paper_id": "17432301", "_pdf_hash": "1158c5bdbd5424e8f148bf04e55969b676ac3a01", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Humanoid robot hrp-4-humanoid robotics platform with lightweight and slim body", "authors": [{"first": "Kenji", "middle": [], "last": "Kaneko", "suffix": ""}, {"first": "Fumio", "middle": [], "last": "Kanehiro", "suffix": ""}, {"first": "Mitsuharu", "middle": [], "last": "Morisawa", "suffix": ""}, {"first": "Kazuhiko", "middle": [], "last": "Akachi", "suffix": ""}, {"first": "Gou", "middle": [], "last": "Miyamori", "suffix": ""}, {"first": "Atsushi", "middle": [], "last": "Hayashi", "suffix": ""}, {"first": "Noriyuki", "middle": [], "last": "Kanehira", "suffix": ""}], "year": 2011, "venue": "Intelligent Robots and Systems (IROS)", "link": "12182615"}, "BIBREF1": {"title": "IEEE/RSJ International Conference on", "authors": [], "year": 2011, "venue": "", "link": null}, "BIBREF2": {"title": "Honda humanoid robots development", "authors": [{"first": "Masato", "middle": [], "last": "Hirose", "suffix": ""}, {"first": "Kenichi", "middle": [], "last": "Ogawa", "suffix": ""}], "year": "", "venue": "Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences", "link": "2547994"}, "BIBREF3": {"title": "A study of function of foot's medial longitudinal arch using biped humanoid robot", "authors": [{"first": "Kenji", "middle": [], "last": "Hashimoto", "suffix": ""}, {"first": "Yuki", "middle": [], "last": "Takezaki", "suffix": ""}, {"first": "Kentaro", "middle": [], "last": "Hattori", "suffix": ""}, {"first": "Hideki", "middle": [], "last": "Kondo", "suffix": ""}, {"first": "Takamichi", "middle": [], "last": "Takashima", "suffix": ""}, {"first": "Hun-Ok", "middle": [], "last": "Lim", "suffix": ""}, {"first": "Atsuo", "middle": [], "last": "Takanishi", "suffix": ""}], "year": 2010, "venue": "Intelligent Robots and Systems (IROS), 2010 IEEE/RSJ International Conference on", "link": "10229074"}, "BIBREF4": {"title": "Humanlike ankle-foot complex for a biped robot", "authors": [{"first": "Kenichi", "middle": [], "last": "Narioka", "suffix": ""}, {"first": "Toshiyuki", "middle": [], "last": "Homma", "suffix": ""}, {"first": "Koh", "middle": [], "last": "Hosoda", "suffix": ""}], "year": 2012, "venue": "Humanoid Robots (Humanoids), 2012 12th IEEE-RAS International Conference on", "link": "8718113"}, "BIBREF5": {"title": "The body rolling with parallel mid-foot joint", "authors": [{"first": "", "middle": [], "last": "Fig", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF6": {"title": "The design of an anthropomorphic dexterous humanoid foot", "authors": [{"first": "Steve", "middle": [], "last": "Davis", "suffix": ""}, {"first": "Darwin", "middle": ["G"], "last": "Caldwell", "suffix": ""}], "year": 2010, "venue": "Intelligent Robots and Systems (IROS), 2010 IEEE/RSJ International Conference on", "link": "15481861"}, "BIBREF7": {"title": "Functional characteristics of the foot and plantar aponeurosis under tibiotalar loading", "authors": [{"first": "K", "middle": [], "last": "Shahan", "suffix": ""}, {"first": "", "middle": [], "last": "Sarrafian", "suffix": ""}], "year": 1987, "venue": "Foot and Ankle International", "link": null}, "BIBREF8": {"title": "The transverse tarsal joint and its control", "authors": [{"first": "Herbert", "middle": [], "last": "Elftman", "suffix": ""}], "year": 1960, "venue": "Clinical orthopaedics", "link": "36859356"}, "BIBREF9": {"title": "Six dof in vivo kinematics of the ankle joint complex: Application of a combined dual-orthogonal fluoroscopic and magnetic resonance imaging technique", "authors": [{"first": "Lu", "middle": [], "last": "Richard J De Asla", "suffix": ""}, {"first": "", "middle": [], "last": "Wan", "suffix": ""}, {"first": "E", "middle": [], "last": "Harry", "suffix": ""}, {"first": "Guoan", "middle": [], "last": "Rubash", "suffix": ""}, {"first": "", "middle": [], "last": "Li", "suffix": ""}], "year": 2006, "venue": "Journal of Orthopaedic Research", "link": "10423041"}, "BIBREF10": {"title": "Kinesiology of the musculoskeletal system: foundations for rehabilitation", "authors": [{"first": "A", "middle": [], "last": "Donald", "suffix": ""}, {"first": "", "middle": [], "last": "Neumann", "suffix": ""}], "year": 2013, "venue": "", "link": null}, "BIBREF11": {"title": "Movements of the subtalar and transverse tarsal joints", "authors": [{"first": "T", "middle": [], "last": "John", "suffix": ""}, {"first": "", "middle": [], "last": "Manter", "suffix": ""}], "year": 1941, "venue": "The Anatomical Record", "link": "83757146"}, "BIBREF12": {"title": "Roll motion control by stretch reflex in a continuously jumping musculoskeletal biped robot", "authors": [{"first": "Masahiro", "middle": [], "last": "Shimizu", "suffix": ""}, {"first": "Keiko", "middle": [], "last": "Suzuki", "suffix": ""}, {"first": "Kenichi", "middle": [], "last": "Narioka", "suffix": ""}, {"first": "Koh", "middle": [], "last": "Hosoda", "suffix": ""}], "year": 2012, "venue": "Intelligent Robots and Systems (IROS), 2012 IEEE/RSJ International Conference on", "link": "1697629"}, "BIBREF13": {"title": "Synergistic 3d limit cycle walking of an anthropomorphic biped robot. In Intelligent Robots and Systems", "authors": [{"first": "Koh", "middle": [], "last": "Hosoda", "suffix": ""}, {"first": "Kenichi", "middle": [], "last": "Narioka", "suffix": ""}], "year": 2007, "venue": "IEEE/RSJ International Conference on", "link": null}}, "ref_entries": {}}
{"paper_id": "17432350", "_pdf_hash": "d6d7c02dd776bcc4e5e184a3bf701b5104fff6c3", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Texture Segmentation Using Gaussian-Markov Random Fields and Neural Oscillator Networks", "authors": [{"first": "E", "middle": [], "last": "Cesmeli", "suffix": ""}, {"first": "D", "middle": ["L"], "last": "Wang", "suffix": ""}], "year": 2001, "venue": "IEEE Trans. NN", "link": "641980"}, "BIBREF1": {"title": "Weight Adaptation and Oscillatory Correlation for Image Segmentation", "authors": [{"first": "K", "middle": [], "last": "Chen", "suffix": ""}, {"first": "D", "middle": ["L"], "last": "Wang", "suffix": ""}, {"first": "X", "middle": [], "last": "Liu", "suffix": ""}], "year": 2000, "venue": "IEEE Trans. NN", "link": "2055059"}, "BIBREF2": {"title": "Coherent Oscillations: A mechanism of Feature Linking in the Visual Cortex?", "authors": [{"first": "R", "middle": [], "last": "Eckhorn", "suffix": ""}, {"first": "R", "middle": [], "last": "Bauer", "suffix": ""}, {"first": "W", "middle": [], "last": "Jordan", "suffix": ""}, {"first": "M", "middle": [], "last": "Brosch", "suffix": ""}, {"first": "W", "middle": [], "last": "Kruse", "suffix": ""}, {"first": "M", "middle": [], "last": "Munk", "suffix": ""}, {"first": "H", "middle": ["J"], "last": "Reitboek", "suffix": ""}], "year": 1988, "venue": "Biol. Cybern", "link": "206771651"}, "BIBREF3": {"title": "Spatial Properties of an EEG in the Olfactory Bulb and Olfactory Cortex. Electroenceph", "authors": [{"first": "W", "middle": ["J"], "last": "Freeman", "suffix": ""}], "year": 1978, "venue": "Clin. Neurophys", "link": null}, "BIBREF4": {"title": "A biologically motivated and analytically soluble model of collective oscillations in the cortex: I. Theory of weak locking", "authors": [{"first": "W", "middle": [], "last": "Gerstner", "suffix": ""}, {"first": "R", "middle": [], "last": "Ritz", "suffix": ""}, {"first": "L", "middle": ["J"], "last": "Van Hemmen", "suffix": ""}], "year": 1993, "venue": "Biol. Cyb", "link": null}, "BIBREF5": {"title": "Stimulus-speci c Neuronal in Orientation Columns of Cat Visual Cortex", "authors": [{"first": "C", "middle": ["M"], "last": "Gray", "suffix": ""}, {"first": "W", "middle": [], "last": "Singer", "suffix": ""}], "year": 1989, "venue": "Proc. Natl. Acad. Sci. USA", "link": null}, "BIBREF6": {"title": "The temporal correlation hypothesis is still alive and well", "authors": [{"first": "C", "middle": ["M"], "last": "Gray", "suffix": ""}], "year": 1999, "venue": "Neoron", "link": "59780502"}, "BIBREF7": {"title": "Eye, brain and vision", "authors": [{"first": "D", "middle": ["H"], "last": "Hubel", "suffix": ""}], "year": 1988, "venue": "Sci. American Lib. Division HPHLP", "link": "142566439"}, "BIBREF8": {"title": "Stimulus-dependent A s s e m bly Formation of Oscillatory Responses", "authors": [{"first": "K", "middle": [], "last": "", "suffix": ""}, {"first": "P", "middle": [], "last": "Schillen", "suffix": ""}, {"first": "T", "middle": ["B"], "last": "", "suffix": ""}], "year": 1991, "venue": "II. Desynchronization, Neur. Comp", "link": null}, "BIBREF9": {"title": "On the role of neural synchrony in primate visual cortex", "authors": [{"first": "A", "middle": ["K"], "last": "Kreiter", "suffix": ""}, {"first": "W", "middle": [], "last": "Singer", "suffix": ""}], "year": 1996, "venue": "Brain Theory", "link": "142129464"}, "BIBREF10": {"title": "Oscillatory networks with Hebbian matrix of connections", "authors": [{"first": "M", "middle": ["G"], "last": "Kuzmina", "suffix": ""}, {"first": "E", "middle": ["A"], "last": "Manykin", "suffix": ""}, {"first": "I", "middle": ["I"], "last": "Surina", "suffix": ""}], "year": 1995, "venue": "Proc. of IWANN'95", "link": "17165844"}, "BIBREF11": {"title": "Oscillatory networks of associative memory", "authors": [{"first": "M", "middle": ["G"], "last": "Kuzmina", "suffix": ""}, {"first": "E", "middle": ["A"], "last": "Manykin", "suffix": ""}, {"first": "I", "middle": ["I"], "last": "Surina", "suffix": ""}], "year": 1996, "venue": "Optical Memory and NN", "link": null}, "BIBREF12": {"title": "Exact solutions and modelling of associative memory in oscillatory networks", "authors": [{"first": "M", "middle": ["G"], "last": "Kuzmina", "suffix": ""}, {"first": "E", "middle": ["A"], "last": "Manykin", "suffix": ""}, {"first": "I", "middle": ["I"], "last": "Surina", "suffix": ""}], "year": 1997, "venue": "Proc. of SPIE", "link": "58815108"}, "BIBREF13": {"title": "Synchronization-Based Network Model for Contour Integration in Visual Processing", "authors": [{"first": "M", "middle": ["G"], "last": "Kuzmina", "suffix": ""}, {"first": "I", "middle": ["I"], "last": "Surina", "suffix": ""}], "year": 1999, "venue": "Proc. of AICS'99", "link": null}, "BIBREF14": {"title": "Spatially Distributed Oscillatory Networks Related to Modeling of the Brain Visual Cortex", "authors": [{"first": "M", "middle": ["G"], "last": "Kuzmina", "suffix": ""}, {"first": "E", "middle": ["A"], "last": "Manykin", "suffix": ""}, {"first": "I", "middle": ["I"], "last": "Surina", "suffix": ""}], "year": 2000, "venue": "Proc. of NOLTA'2000", "link": null}, "BIBREF15": {"title": "Tunable Oscillatory Network for Visual Image Segmentation", "authors": [{"first": "M", "middle": ["G"], "last": "Kuzmina", "suffix": ""}, {"first": "E", "middle": ["A"], "last": "Manykin", "suffix": ""}, {"first": "I", "middle": ["I"], "last": "Surina", "suffix": ""}], "year": 2001, "venue": "Proc. of ICANN'2001", "link": "10277238"}, "BIBREF16": {"title": "Modeling the Olfactory Bulb and Its Neural Oscillatory Processing", "authors": [{"first": "Z", "middle": [], "last": "Li", "suffix": ""}, {"first": "J", "middle": ["J"], "last": "Hop", "suffix": ""}], "year": 1989, "venue": "Biol. Cybern", "link": "7932310"}, "BIBREF17": {"title": "A Neural Model of Contour Integration in the Primary Visual Cortex", "authors": [{"first": "Z", "middle": [], "last": "Li", "suffix": ""}], "year": 1998, "venue": "Neur. Comp", "link": "13022636"}, "BIBREF18": {"title": "Visual Segmentation by Contextual In uences via Intra-Cortical Interactions in the Primary Visual Cortex", "authors": [{"first": "Z", "middle": [], "last": "Li", "suffix": ""}], "year": 1999, "venue": "Network", "link": "5735227"}, "BIBREF19": {"title": "Pre-attentive Segmentation in the Primary Visual Cortex", "authors": [{"first": "Z", "middle": [], "last": "Li", "suffix": ""}], "year": 2000, "venue": "Spatial Vision", "link": "15894154"}, "BIBREF20": {"title": "Computational Design and Nonlinear Dynamics of a Recurrent Network Model of the Primary Visual Cortex", "authors": [{"first": "Z", "middle": [], "last": "Li", "suffix": ""}], "year": 2001, "venue": "Neural Comp. 13/8", "link": "13898359"}, "BIBREF21": {"title": "The correlation theory of brain function, Max-Plank-Institut for", "authors": [{"first": "C", "middle": [], "last": "Von Der Malsburg", "suffix": ""}], "year": 1981, "venue": "Biophys. Chem., G ottingen", "link": null}, "BIBREF22": {"title": "Sensory segmentation with coupled neural oscillators", "authors": [{"first": "C", "middle": [], "last": "Von Der Malsburg", "suffix": ""}, {"first": "J", "middle": [], "last": "Buhmann", "suffix": ""}], "year": 1992, "venue": "Biol. Cyb", "link": "7479235"}, "BIBREF23": {"title": "Vision -A computational investigation into the human representation and processing of vision information", "authors": [{"first": "D", "middle": [], "last": "Marr", "suffix": ""}], "year": 1982, "venue": "", "link": "124937374"}, "BIBREF24": {"title": "A Model of Neuronal Oscillations in the Visual Cortex. 1 and 2", "authors": [{"first": "H", "middle": ["C"], "last": "Schuster", "suffix": ""}, {"first": "P", "middle": [], "last": "Wagner", "suffix": ""}], "year": 1990, "venue": "Biol. Cyb", "link": null}, "BIBREF25": {"title": "Cooperative Dynamics in Visual Processing", "authors": [{"first": "H", "middle": [], "last": "Sompolinsky", "suffix": ""}, {"first": "D", "middle": [], "last": "Golomb", "suffix": ""}, {"first": "D", "middle": [], "last": "Kleinfeld", "suffix": ""}], "year": 1991, "venue": "Phys. Rev. A", "link": "11985450"}, "BIBREF26": {"title": "Pattern Segmentation in Associative Memory", "authors": [{"first": "D", "middle": [], "last": "Wang", "suffix": ""}, {"first": "J", "middle": [], "last": "Buhman", "suffix": ""}, {"first": "C", "middle": [], "last": "Von Der Malsburg", "suffix": ""}], "year": 1990, "venue": "Neur. Comp", "link": "17122793"}, "BIBREF27": {"title": "Emergent S y n c hrony in Locally Coupled Neural Oscillators", "authors": [{"first": "D", "middle": ["L"], "last": "Wang", "suffix": ""}, {"first": "D", "middle": [], "last": "Terman", "suffix": ""}], "year": 1995, "venue": "IEEE Trans. NN", "link": null}, "BIBREF28": {"title": "Image Segmentation Based on Oscillatory Correlations", "authors": [{"first": "D", "middle": ["L"], "last": "Wang", "suffix": ""}, {"first": "D", "middle": [], "last": "Terman", "suffix": ""}], "year": 1997, "venue": "Neur. Comp", "link": "8221986"}, "BIBREF29": {"title": "Relaxation Oscillators and Networks", "authors": [{"first": "D", "middle": ["L"], "last": "Wang", "suffix": ""}], "year": 1999, "venue": "", "link": "16320360"}, "BIBREF30": {"title": "Bad design and good performance: strategies of the visual system for enhanced scene analysis", "authors": [{"first": "F", "middle": [], "last": "W Org Otter", "suffix": ""}], "year": 2001, "venue": "Proc. of ICANN'2001", "link": "35381706"}}, "ref_entries": {}}
{"paper_id": "17432654", "_pdf_hash": "1fb69dd8e38a369147b671b4f5c66d34def1749f", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Visualizing massive multi-graphs", "authors": [{"first": "J", "middle": [], "last": "Abello", "suffix": ""}, {"first": "J", "middle": [], "last": "Korn", "suffix": ""}], "year": 2000, "venue": "Proc. IEEE Symp. Information Visualization -InfoVis'00", "link": null}, "BIBREF5": {"title": "Drawing graphs with dot -dot User's manual Griffiths", "authors": [{"first": "W", "middle": ["C. ; E"], "last": "Gardiner", "suffix": ""}, {"first": "E", "middle": [], "last": "Koutsofios", "suffix": ""}, {"first": "G", "middle": [], "last": "North", "suffix": ""}], "year": 1995, "venue": "Prog. Energy Combust. Sci", "link": null}, "BIBREF7": {"title": "Proceedings of the 29th Annual ACM Symposium on Theory of Computing", "authors": [{"first": "P", "middle": [], "last": "Indyk", "suffix": ""}, {"first": "R", "middle": [], "last": "Motwami", "suffix": ""}, {"first": "P", "middle": [], "last": "Raghavan", "suffix": ""}, {"first": "S", "middle": [], "last": "Vempala", "suffix": ""}], "year": 1996, "venue": "", "link": null}, "BIBREF8": {"title": "Case study: Application of feature tracking to analysis of autoignition simulation data", "authors": [{"first": "D", "middle": ["E"], "last": "Knuth", "suffix": ""}, {"first": "W", "middle": ["S"], "last": "Addison-Wesley Koegler", "suffix": ""}], "year": 1997, "venue": "IEEE Visualization Conference", "link": "23797371"}, "BIBREF9": {"title": "SIGKDD'02", "authors": [{"first": "J", "middle": [], "last": "Lin", "suffix": ""}, {"first": "E", "middle": [], "last": "Keogh", "suffix": ""}, {"first": "S", "middle": [], "last": "Lonardi", "suffix": ""}, {"first": "P", "middle": [], "last": "Patel", "suffix": ""}], "year": 1997, "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "17432696", "_pdf_hash": "10ad963ca0dda7deda361460bab49bc8685d1142", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Video abstraction: a systematic review and classification", "authors": [{"first": "B", "middle": ["T"], "last": "Truong", "suffix": ""}, {"first": "Svetha", "middle": [], "last": "Venkatesh", "suffix": ""}], "year": 2007, "venue": "ACM Transactions on Multimedia Computing", "link": "207161932"}, "BIBREF1": {"title": "Techniques used and open challenges to the analysis, indexing and retrieval of digital video", "authors": [{"first": "A", "middle": ["F"], "last": "Smeaton", "suffix": ""}], "year": 2007, "venue": "Information Systems", "link": "18599724"}, "BIBREF2": {"title": "Highlight summarization in sports video based replay detection", "authors": [{"first": "Z", "middle": [], "last": "Zhao", "suffix": ""}, {"first": "S", "middle": ["Q"], "last": "Jiang", "suffix": ""}, {"first": "Q", "middle": ["M"], "last": "Huang", "suffix": ""}], "year": 2006, "venue": "IEEE International Conference on Multimedia and Expo (ICME2006)", "link": "7288679"}, "BIBREF3": {"title": "Replay detection based on semi-automatic logo template sequence extraction in sports video", "authors": [{"first": "Z", "middle": ["H"], "last": "Dang", "suffix": ""}, {"first": "J", "middle": [], "last": "Du", "suffix": ""}, {"first": "Q", "middle": ["M"], "last": "Huang", "suffix": ""}], "year": 2007, "venue": "Fourth International Conference on Image and Graphics (ICIG2007)", "link": "6343649"}, "BIBREF4": {"title": "Neural network based framework for goal event detection in soccer videos", "authors": [{"first": "K", "middle": [], "last": "Wickramaratna", "suffix": ""}, {"first": "M", "middle": [], "last": "Chen", "suffix": ""}, {"first": "S", "middle": ["C"], "last": "Chen", "suffix": ""}], "year": 2005, "venue": "Seventh IEEE International Symposium on Multimedia (ISM2005)", "link": "9693553"}, "BIBREF5": {"title": "Goal detection in soccer video using audio/visual keywords", "authors": [{"first": "Y", "middle": ["L"], "last": "Kang", "suffix": ""}, {"first": "J", "middle": ["H"], "last": "Lim", "suffix": ""}, {"first": "M", "middle": ["S"], "last": "Kankanhalli", "suffix": ""}], "year": 2004, "venue": "International Conference on Image Processing (ICIP2004)", "link": "12179848"}, "BIBREF6": {"title": "Affective video content representation and modeling", "authors": [{"first": "A", "middle": [], "last": "Hanjalic", "suffix": ""}, {"first": "L", "middle": ["Q"], "last": "Xu", "suffix": ""}], "year": 2005, "venue": "IEEE Transactions on Multimedia", "link": "6929070"}, "BIBREF7": {"title": "Adaptive extraction of highlights from a sport video based on excitement modeling", "authors": [{"first": "A", "middle": [], "last": "Hanjalic", "suffix": ""}], "year": 2005, "venue": "IEEE Transactions on Multimedia", "link": "14148400"}, "BIBREF8": {"title": "Enhanced shot change detection using motion features for soccer video analysis", "authors": [{"first": "Y", "middle": [], "last": "", "suffix": ""}, {"first": "Ch", "middle": [], "last": "Hu", "suffix": ""}, {"first": "B", "middle": [], "last": "Han", "suffix": ""}, {"first": "G", "middle": ["J"], "last": "Wang", "suffix": ""}], "year": "", "venue": "IEEE International Conference on Multimedia and Expo (ICME2007)", "link": "21923407"}, "BIBREF9": {"title": "Novel approach of shot boundary detection and static video abstract extraction for video flow", "authors": [{"first": "Q", "middle": ["K"], "last": "Bu", "suffix": ""}, {"first": "A", "middle": ["Q"], "last": "Hu", "suffix": ""}], "year": 2007, "venue": "Journal of Southeast University (Natural Science Edition)", "link": null}, "BIBREF10": {"title": "Content-based multimedia information retrieval: state of the art and challenges", "authors": [{"first": "M", "middle": ["S"], "last": "Lew", "suffix": ""}, {"first": "N", "middle": [], "last": "Sebe", "suffix": ""}, {"first": "C", "middle": [], "last": "Djeraba", "suffix": ""}], "year": 2006, "venue": "ACM Transactions on Multimedia Computing", "link": "387449"}, "BIBREF11": {"title": "Multimodal video indexing: a review of the state-of-the-art", "authors": [{"first": "C", "middle": ["G M"], "last": "Snoek", "suffix": ""}, {"first": "M", "middle": [], "last": "Worring", "suffix": ""}], "year": 2005, "venue": "Multimedia Tools and Applications", "link": "162180"}, "BIBREF12": {"title": "Relevance feedback methods in content based retrieval and video summarization", "authors": [{"first": "M", "middle": [], "last": "Haas", "suffix": ""}, {"first": "A", "middle": [], "last": "Oerlemans", "suffix": ""}, {"first": "M", "middle": ["S"], "last": "Lew", "suffix": ""}], "year": "", "venue": "IEEE International Conference on Multimedia and Expo (ICME2005)", "link": "16359240"}, "BIBREF13": {"title": "Relevance feedback: a power tool for interactive content based image retrieval", "authors": [{"first": "Y", "middle": [], "last": "Rui", "suffix": ""}, {"first": "T", "middle": ["S"], "last": "Huang", "suffix": ""}, {"first": "M", "middle": [], "last": "Ortega", "suffix": ""}], "year": 1998, "venue": "IEEE Transaction on Circuits and Systems for Video Technology", "link": "6288778"}, "BIBREF14": {"title": "Learning-based interactive video retrieval system", "authors": [{"first": "C", "middle": ["J"], "last": "Wu", "suffix": ""}, {"first": "H", "middle": ["C"], "last": "Zeng", "suffix": ""}, {"first": "S", "middle": ["H"], "last": "Huang", "suffix": ""}], "year": 2006, "venue": "IEEE International conference on Multimedia and Expo (ICME2006)", "link": "7772967"}, "BIBREF15": {"title": "Improved AdaBoost-based image retrieval with relevance feedback via paired feature learning", "authors": [{"first": "S", "middle": ["H"], "last": "Huang", "suffix": ""}, {"first": "Q", "middle": ["J"], "last": "Wu", "suffix": ""}, {"first": "S", "middle": ["H"], "last": "Lai", "suffix": ""}], "year": 2006, "venue": "Multimedia Systems", "link": "7519896"}, "BIBREF16": {"title": "Emotional image and musical information retrieval with interactive genetic algorithm", "authors": [{"first": "S", "middle": ["B"], "last": "Cho", "suffix": ""}], "year": 2004, "venue": "Proceedings of The IEEE", "link": "207882728"}, "BIBREF17": {"title": "Video scene retrieval with interactive genetic algorithm", "authors": [{"first": "H", "middle": ["W"], "last": "Yoo", "suffix": ""}, {"first": "S", "middle": ["B"], "last": "Cho", "suffix": ""}], "year": 2007, "venue": "Multimedia Tools and Applications", "link": "16916510"}, "BIBREF18": {"title": "Genetic algorithms and their applications", "authors": [{"first": "K", "middle": ["S"], "last": "Tang", "suffix": ""}, {"first": "K", "middle": ["F"], "last": "Man", "suffix": ""}, {"first": "S", "middle": [], "last": "Kwong", "suffix": ""}], "year": 1996, "venue": "IEEE Signal Processing Magazine", "link": "56893987"}, "BIBREF19": {"title": "Interactive evolutionary computation: Fusion of the capabilities of EC optimization and human evolution", "authors": [{"first": "H", "middle": [], "last": "Takagi", "suffix": ""}], "year": 2001, "venue": "Proceedings of the IEEE", "link": "16929436"}, "BIBREF20": {"title": "Application of interactive genetic algorithm to fashion designs", "authors": [{"first": "H", "middle": ["S"], "last": "Kim", "suffix": ""}, {"first": "S", "middle": ["B"], "last": "Cho", "suffix": ""}], "year": 2000, "venue": "Engineering Applications of Artificial Intelligence", "link": null}, "BIBREF21": {"title": "Music composition with interactive evolutionary computation", "authors": [{"first": "N", "middle": [], "last": "Tokui", "suffix": ""}, {"first": "H", "middle": [], "last": "Iba", "suffix": ""}], "year": 2000, "venue": "Proceedings of the 3rd International Conference on Generative Art", "link": "6899248"}, "BIBREF22": {"title": "Generating emotional voice and behavior expression by interactive evolutionary computation", "authors": [{"first": "T", "middle": [], "last": "Morita", "suffix": ""}, {"first": "H", "middle": [], "last": "Iba", "suffix": ""}, {"first": "M", "middle": [], "last": "Ishizuka", "suffix": ""}], "year": 2001, "venue": "Proceedings of the 62nd Annual Meeting of Japan Society for Information Processing", "link": null}, "BIBREF23": {"title": "Interactive virtual aquarium", "authors": [{"first": "T", "middle": [], "last": "Iwasaki", "suffix": ""}, {"first": "K", "middle": [], "last": "Kimura", "suffix": ""}, {"first": "Y", "middle": [], "last": "Todoroki", "suffix": ""}], "year": 2000, "venue": "Proceedings of the 5th Annual Conference of the Virtual Reality Society of Japan", "link": null}}, "ref_entries": {}}
{"paper_id": "17432700", "_pdf_hash": "ec2e5cc752693539c640347450882509e1d32653", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "PARO Pals; Japanese robot has brought out the best in elderly with Alzheimer's Disease", "authors": [{"first": "L", "middle": [], "last": "Barcousky", "suffix": ""}], "year": 2010, "venue": "", "link": null}, "BIBREF1": {"title": "Elderly give robotic pet the seal of approval while academics reserve judgement. The Australian", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF2": {"title": "Discovering a Soft Spot for Circuitry", "authors": [{"first": "A", "middle": [], "last": "Harmon", "suffix": ""}], "year": 2010, "venue": "A. 2010b. SMARTER THAN YOU THINK; Circuitry With a Feel for Humanity. The New York Times", "link": null}, "BIBREF3": {"title": "Cuddling with roboseal: therapy with a dash of creepy. The Globe and Mail (Canada)", "authors": [{"first": "L", "middle": [], "last": "Jutras", "suffix": ""}], "year": 2008, "venue": "", "link": null}, "BIBREF4": {"title": "Mechanical seal sparks debate over robots' role in eldercare", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF5": {"title": "McKnight's Long-Term Care News & Assisted Living. Meet the human face of robots", "authors": [], "year": 2011, "venue": "", "link": null}, "BIBREF6": {"title": "I, robot-manager. The Economist", "authors": [{"first": "J", "middle": [], "last": "Schumpeter", "suffix": ""}], "year": 2011, "venue": "", "link": null}, "BIBREF7": {"title": "Robots can already perform surgery and track your meds. Now, new models aim to provide therapy and support", "authors": [{"first": "A", "middle": [], "last": "Slomski", "suffix": ""}], "year": 2009, "venue": "The Washington Post", "link": null}, "BIBREF8": {"title": "It's Not a Stuffed Animal, It's a $6,000 Medical Device -Paro the Robo-Seal Aims to Comfort Elderly, but Is It Ethical", "authors": [{"first": "A", "middle": [], "last": "Tergensen", "suffix": ""}, {"first": "M", "middle": [], "last": "Inada", "suffix": ""}], "year": 2011, "venue": "The Wall Street Journal", "link": null}, "BIBREF9": {"title": "Alone Together: Why We Expect More From Technology and Less from Each Other", "authors": [{"first": "S", "middle": [], "last": "Turkle", "suffix": ""}], "year": 2011, "venue": "", "link": "64582678"}}, "ref_entries": {}}
{"paper_id": "17432774", "_pdf_hash": "51dbd53812936de05480a1a89a99970e6c0d532b", "abstract": [{"section": "Abstract", "text": "Abstract: ZnO nanoparticles were produced by flame spray pyrolysis (FSP) using zinc naphthenate as a precursor dissolved in toluene/acetonitrile (80/20 vol%). The particle properties were analyzed by XRD, BET, and HR-TEM. The sensing films were produced by mixing the particles into an organic paste composed of terpineol and ethyl cellulose as a vehicle binder and were fabricated by doctor-blade technique with various thicknesses (5, 10, 15 \u00b5m). The morphology of the sensing films was analyzed by SEM and EDS analyses. The gas sensing characteristics to ethanol (25-250 ppm) were evaluated as a function of film thickness at 400\u00b0C in dry air. The relationship between thickness and ethanol sensing characteristics of ZnO thick film on Al 2 O 3 substrate interdigitated with Au electrodes were investigated. The effects of film thickness, as well as the cracking phenomenon, though, many cracks were observed for thicker sensing films. Crack widths increased with increasing film thickness. The film thickness, cracking and ethanol concentration have significant effect on the sensing characteristics. The sensing characteristics with various thicknesses were compared, showing the tendency of the sensitivity to ethanol decreased with increasing film thickness and response time. The relationship between gas sensing properties and film thickness was discussed on the basis of diffusively and reactivity of the gases inside the oxide films. The thinnest sensing film (5 \u00b5m) showed the highest sensitivity and the fastest response time (within seconds).", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Zinc oxide (ZnO) is an n-type semiconductor of wurtzite structure, with a direct large-band gap of about 3.37 eV at room temperature [1, 2] . It is one of the most promising materials for sensors, especially for ethanol vapor [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] . However, the physical and sensing properties of semiconductor gas sensors are directly related to their preparation e.g. particle size, sensing film morphology, and film thickness as well as sensing film characteristics.", "cite_spans": [{"start": 133, "end": 136, "text": "[1,", "ref_id": "BIBREF0"}, {"start": 137, "end": 139, "text": "2]", "ref_id": "BIBREF1"}, {"start": 226, "end": 229, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 230, "end": 233, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 234, "end": 237, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 238, "end": 241, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 242, "end": 245, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 246, "end": 249, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 250, "end": 253, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 254, "end": 258, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 259, "end": 263, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 264, "end": 268, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 269, "end": 273, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 274, "end": 278, "text": "[14]", "ref_id": "BIBREF13"}, {"start": 279, "end": 283, "text": "[15]", "ref_id": "BIBREF14"}, {"start": 284, "end": 288, "text": "[16]", "ref_id": "BIBREF15"}, {"start": 289, "end": 293, "text": "[17]", "ref_id": "BIBREF16"}, {"start": 294, "end": 298, "text": "[18]", "ref_id": "BIBREF17"}, {"start": 299, "end": 303, "text": "[19]", "ref_id": "BIBREF18"}], "ref_spans": []}, {"section": "Introduction", "text": "Flame aerosol technology is employed widely for large-scale manufacture of carbon blacks and commodities such as fumed SiO 2 and TiO 2 and to a lesser extent, for specialty chemicals such as Al 2 O 3 and ZnO powders. Flame spray pyrolysis (FSP) is a promising technique for synthesis of high purity nano-sized materials with controlled size and crystallinity in one step [20, 21] . In general, a flame is used to force chemical reactions of precursor compounds, finally resulting in the information of clusters, which increase their size to a range of some nanometers by coagulation and sintering. Finally, the nanostructured powders are collected on a filter [22] . Reactant mixing, precursor mixing, additives, and electric fields also influence the particle size. Reactant mixing influences the flame temperature, flame height and the particle residence time. The more fuel is introduced the higher the flame is and due to that the residence time of particles in the flame is increased. As a consequence time for particle growth is enlarged and bigger particles are formed. External electric field reduces the average particle size in a narrow range up to a factor of two. Electric fields can be used in application as control devices [23] . Moreover, at low oxidant flow rates, the specific surface area increased with increasing oxidant flow rate as the spray flame length was reduced leading to shorter residence time allowing less time for particle growth. Using oxygen as oxidant the droplets burn much faster than with air, thus, product particles experience longer residence times at higher temperature [22, 24] . The effect of solution feed rate on particles specific surface area and crystalline size were investigated [25] . The solution feed rate increased the flame height, and therefore coalescence was enhanced, resulting in large primary particles [25] . Furthermore, the flame conditions can be used to control the morphology of particles. ZnO nanorods formation were produced by FSP, which was described basically by XRD lattice aspect ratio [26, 27] .", "cite_spans": [{"start": 123, "end": 124, "text": "2", "ref_id": "BIBREF1"}, {"start": 371, "end": 375, "text": "[20,", "ref_id": "BIBREF19"}, {"start": 376, "end": 379, "text": "21]", "ref_id": "BIBREF20"}, {"start": 660, "end": 664, "text": "[22]", "ref_id": "BIBREF21"}, {"start": 1238, "end": 1242, "text": "[23]", "ref_id": "BIBREF22"}, {"start": 1613, "end": 1617, "text": "[22,", "ref_id": "BIBREF21"}, {"start": 1618, "end": 1621, "text": "24]", "ref_id": "BIBREF23"}, {"start": 1731, "end": 1735, "text": "[25]", "ref_id": "BIBREF24"}, {"start": 1866, "end": 1870, "text": "[25]", "ref_id": "BIBREF24"}, {"start": 2062, "end": 2066, "text": "[26,", "ref_id": "BIBREF25"}, {"start": 2067, "end": 2070, "text": "27]", "ref_id": "BIBREF26"}], "ref_spans": []}, {"section": "Introduction", "text": "Several oxide materials commonly used as ethanol gas sensors including pure and metal-doped SnO 2 [28] [29] [30] [31] [32] [33] [34] [35] , In 2 O 3 [36, 37] , TiO 2 [35, [38] [39] [40] [41] [42] , ZrO 2 [35] , WO 3 [34, 42] , MoO 3 [42] , and Cu 2 O [43] . Many researchers reported that pure ZnO [3] [4] [5] [6] [7] [8] [9] and metal-doped ZnO [10] [11] [12] [13] [14] [15] [16] [17] [18] were widely used to detect the alcohol vapor. For examples, ZnO thin films were produced by spray pyrolysis [5] . Film layers of 20 \u00b5m in thickness showed sensitivity in terms of rather high ethanol concentration (1000-5000 ppm) at 150-350\u00b0C. At high operating temperature, they did not depend on the concentration of ethanol [5] . An ethanol sensor based on ZnO nanorods prepared by hydrothermal method [6] showed high sensitivity to ethanol concentration ranging from 10 to 2000 ppm at 330\u00b0C, with good response and recovery time. Furthermore, ZnO nanowire ethanol gas sensor showed high sensitivity and fast response to ethanol gas at concentration up to 200 ppm with operating temperature of 300\u00b0C [7] . In addition, pure ZnO nanorods and nano-needles produced by hybrid induction and laser heating (HILH) technique also showed capability to produce sensors with good sensitivity goes a maximum temperature around 400\u00b0C for a concentration of 100 ppm for volatile organic compounds (VOCs) including acetone, toluene, and ethanol. 4.58 at% In/ZnO showed highest sensitivity compared to pure ZnO [11] . ZnO films doped with 3 at% La showed enhancement of ethanol sensitivity of 350, shorter response and recovery time of about 60 s at an operating temperature of 300\u00b0C [14] . ZnO nanorods and nanowires doped with Pt also showed high sensitivity for 1000 ppm of ethanol at an operating temperature below 150\u00b0C, with short response and recovery time [15] . Therefore it is interesting to apply FSP for production of ZnO nanoparticles [24] [25] as used in gas sensor of ethanol vapor.", "cite_spans": [{"start": 98, "end": 102, "text": "[28]", "ref_id": "BIBREF27"}, {"start": 108, "end": 112, "text": "[30]", "ref_id": "BIBREF30"}, {"start": 113, "end": 117, "text": "[31]", "ref_id": "BIBREF31"}, {"start": 118, "end": 122, "text": "[32]", "ref_id": "BIBREF32"}, {"start": 123, "end": 127, "text": "[33]", "ref_id": "BIBREF33"}, {"start": 128, "end": 132, "text": "[34]", "ref_id": "BIBREF34"}, {"start": 133, "end": 137, "text": "[35]", "ref_id": "BIBREF35"}, {"start": 149, "end": 153, "text": "[36,", "ref_id": "BIBREF36"}, {"start": 154, "end": 157, "text": "37]", "ref_id": "BIBREF37"}, {"start": 166, "end": 170, "text": "[35,", "ref_id": "BIBREF35"}, {"start": 171, "end": 175, "text": "[38]", "ref_id": "BIBREF38"}, {"start": 176, "end": 180, "text": "[39]", "ref_id": "BIBREF39"}, {"start": 181, "end": 185, "text": "[40]", "ref_id": "BIBREF40"}, {"start": 186, "end": 190, "text": "[41]", "ref_id": "BIBREF41"}, {"start": 191, "end": 195, "text": "[42]", "ref_id": "BIBREF42"}, {"start": 204, "end": 208, "text": "[35]", "ref_id": "BIBREF35"}, {"start": 216, "end": 220, "text": "[34,", "ref_id": "BIBREF34"}, {"start": 221, "end": 224, "text": "42]", "ref_id": "BIBREF42"}, {"start": 233, "end": 237, "text": "[42]", "ref_id": "BIBREF42"}, {"start": 251, "end": 255, "text": "[43]", "ref_id": "BIBREF43"}, {"start": 298, "end": 301, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 302, "end": 305, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 306, "end": 309, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 310, "end": 313, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 314, "end": 317, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 318, "end": 321, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 322, "end": 325, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 346, "end": 350, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 351, "end": 355, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 356, "end": 360, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 361, "end": 365, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 366, "end": 370, "text": "[14]", "ref_id": "BIBREF13"}, {"start": 371, "end": 375, "text": "[15]", "ref_id": "BIBREF14"}, {"start": 376, "end": 380, "text": "[16]", "ref_id": "BIBREF15"}, {"start": 381, "end": 385, "text": "[17]", "ref_id": "BIBREF16"}, {"start": 386, "end": 390, "text": "[18]", "ref_id": "BIBREF17"}, {"start": 499, "end": 502, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 717, "end": 720, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 795, "end": 798, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 1093, "end": 1096, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 1489, "end": 1493, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 1662, "end": 1666, "text": "[14]", "ref_id": "BIBREF13"}, {"start": 1842, "end": 1846, "text": "[15]", "ref_id": "BIBREF14"}, {"start": 1926, "end": 1930, "text": "[24]", "ref_id": "BIBREF23"}, {"start": 1931, "end": 1935, "text": "[25]", "ref_id": "BIBREF24"}], "ref_spans": []}, {"section": "Introduction", "text": "The effect of film thickness, as well as the sensing temperature, on the sensor characteristics of sensing films was reported [44] [45] [46] [47] [48] [49] [50] [51] [52] [53] [54] . Many researchers mentioned a variety of techniques used to prepare the sensing films, i.e. plasma enhanced chemical vapor deposition (PECVD) [47] , spray pyrolysis [5, 47] , screen printing [50] , and doctor-blade [55, 56] . They have been shown that the sensor characteristics of sensing films are affected by the film structure, morphology, and film thickness, which are determined by the film preparation procedure. In addition, the sensing temperature and film thickness are important parameters that affect the gas sensing properties in terms of sensitivity, response, and recovery time. Especially, doctor-blade technique has several advantages in producing the sensing thick films suitable for the gas sensor including relatively homogeneous composition and easy control of film thickness. Therefore, it is very significant to investigate the most suitable thickness for the ethanol sensor based on flame-made ZnO nanoparticles.", "cite_spans": [{"start": 126, "end": 130, "text": "[44]", "ref_id": "BIBREF44"}, {"start": 131, "end": 135, "text": "[45]", "ref_id": "BIBREF45"}, {"start": 136, "end": 140, "text": "[46]", "ref_id": "BIBREF46"}, {"start": 141, "end": 145, "text": "[47]", "ref_id": "BIBREF47"}, {"start": 146, "end": 150, "text": "[48]", "ref_id": "BIBREF48"}, {"start": 151, "end": 155, "text": "[49]", "ref_id": "BIBREF49"}, {"start": 156, "end": 160, "text": "[50]", "ref_id": "BIBREF50"}, {"start": 161, "end": 165, "text": "[51]", "ref_id": "BIBREF51"}, {"start": 166, "end": 170, "text": "[52]", "ref_id": "BIBREF52"}, {"start": 171, "end": 175, "text": "[53]", "ref_id": "BIBREF53"}, {"start": 176, "end": 180, "text": "[54]", "ref_id": "BIBREF54"}, {"start": 324, "end": 328, "text": "[47]", "ref_id": "BIBREF47"}, {"start": 347, "end": 350, "text": "[5,", "ref_id": "BIBREF4"}, {"start": 351, "end": 354, "text": "47]", "ref_id": "BIBREF47"}, {"start": 373, "end": 377, "text": "[50]", "ref_id": "BIBREF50"}, {"start": 397, "end": 401, "text": "[55,", "ref_id": "BIBREF55"}, {"start": 402, "end": 405, "text": "56]", "ref_id": "BIBREF56"}], "ref_spans": []}, {"section": "Experimental", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Particle Synthesis", "text": "Zinc naphtenate (Strem, 10 wt% Zn) was used as zinc precursor. The precursor was dissolved in toluene (Riedel deHaen, 99.5%)/acetonitrile (Fluka, 99.5%) mixtures with ratio of 80/20 vol% to obtain a 0.5 mol/l precursor solution for the synthesis via FSP experiments. Fig. 1 shows the experimental set up of FSP. In a typical run, the precursor was fed into a FSP reactor by a syringe pump with a rate of 5 ml/min and dispersed of 5 l/min O 2 . This flame conditions will be depicted as 5/5 flame. The gas flow rates of methane and O 2 supporting flamelets were 1.13, and 2.40 l/min, respectively. The pressure drop at the capillary tip was kept constant at 1.5 bars by adjusting the orifice gap area at the nozzle. The liquid precursor mixture was rapidly dispersed by a gas stream and ignited by a premixed methane/oxygen flame. The flame height was 10 cm and showed a yellowish-orange flame appearance as shown in the inset. After evaporation and combustion of precursor droplets, particles are formed by nucleation, condensation, coagulation and coalescence. Finally, the nanoparticles were collected on a glass microfibre filters (Whatmann GF/A, 25.7 cm in diameter) with the aid of a vacuum pump. The flame made (5/5) ZnO as-prepared nanopowders were designated as P0. precursor mixture is rapidly dispersed by a gas stream and ignited by a premixed methane/oxygen flame.", "cite_spans": [], "ref_spans": [{"start": 267, "end": 273, "text": "Fig. 1", "ref_id": "FIGREF0"}]}, {"section": "Particle Characterization", "text": "The phase and crystallinity of flame-made nanopowders and sensor samples were also analyzed by XRD (Bruker D8 advance diffractometer, operated at 40 kV, 40 mA) using CuK\u03b1 radiation at 2\u03b8 = 20-80\u00b0 with a step size of 0.06\u00b0 and a scanning speed of 0.72\u00ba/minute. Using the fundamental parameter approach and Rietveld method [57] , the crystalline phase and the size of the particles were confirmed. The phase and the corresponding sizes were calculated using the software TOPAS-3. The specific surface areas of ZnO nanoparticles was determined with the 5-point nitrogen adsorption measurement applying the Bruneauer-Emmett-Teller (BET) method [58] at 77 K (Micromeritics Tristar 3000). All samples were degassed at 150\u00b0C for 1 h prior to analysis. The diameter of particles can be calculated by d BET = 6 / SSA BET * \u03c1 sample , where SSA BET is the specific surface area (m 2 /g) and \u03c1 samples is the density of ZnO (\u03c1 ZnO = 5.61 * 10 3 kg/m 3 ) [25] . The morphologies of nanoparticles of sample P0 were observed by the high-resolution transmission electron microscopy (HR-TEM) using the Tecanai 30F microscope (Philips; field emission cathode, operated at 300 kV). The HR-TEM bright-field images were obtained using a slow-scan CCD camera.", "cite_spans": [{"start": 321, "end": 325, "text": "[57]", "ref_id": "BIBREF57"}, {"start": 640, "end": 644, "text": "[58]", "ref_id": "BIBREF58"}, {"start": 943, "end": 947, "text": "[25]", "ref_id": "BIBREF24"}], "ref_spans": []}, {"section": "Preparation of Sensor", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Paste Preparation", "text": "An Al 2 O 3 substrates interdigitated with Au electrodes (Au/Al 2 O 3 ; 10 x 10 x 0.1 mm; Electronics Design Center, MicroFabrication Lab, Case Western Reserve University) were used as a sensor substrates as shown in Fig. 2(a) and designated as A0. The substrate layout ( Fig. 2(a) ) and the SEM micrographs of morphology were observed with different magnifications of Al 2 0 3 (dark view) substrate interdigitated with Au (bright view) electrodes were also observed using SEM analysis (Fig. 2(b-c) ). An appropriate quantity of 0.28 ml homogeneous mixed solution was prepared by stirring of ethyl cellulose (Fluka, 30-60 mPa.s) as the temporary binder and terpineol (Aldrich, 90%) as a solvent with a mixing ratio of 480 mg to 18 g. The viscous mixture was combined with 70 mg of samples P0 and mixed to form a paste for 30 min prior to doctor-blade. ", "cite_spans": [], "ref_spans": [{"start": 217, "end": 226, "text": "Fig. 2(a)", "ref_id": "FIGREF1"}, {"start": 272, "end": 281, "text": "Fig. 2(a)", "ref_id": "FIGREF1"}, {"start": 486, "end": 498, "text": "(Fig. 2(b-c)", "ref_id": "FIGREF1"}]}, {"section": "Doctor-bladed Thick Film Preparation", "text": "The resulting paste doctor-bladed on the Al 2 O 3 substrates interdigitated with Au electrodes were prepared [55, 56] . For the film thickness variance, all substrates were taped (Scotch Magic TM tape; Art.", "cite_spans": [{"start": 109, "end": 113, "text": "[55,", "ref_id": "BIBREF55"}, {"start": 114, "end": 117, "text": "56]", "ref_id": "BIBREF56"}], "ref_spans": []}, {"section": "Doctor-bladed Thick Film Preparation", "text": "Nr.11110300, Ethilux,Germany) upon the edges for 1, 2, 3 tapes which control the film thickness to be approximately 5, 10, 15 \u00b5m, respectively, prior to doctor-blade. We believe that the tape plays an important role in controlling the thick films layer by providing a template for film thickness formation", "cite_spans": [], "ref_spans": []}, {"section": "Doctor-bladed Thick Film Preparation", "text": "(1 tape can control thickness approximately 5 \u00b5m). The resulting substrates were heated in an oven at 400\u00b0C for 2h with a heating rate of 2\u00b0C/min for binder removal [59] and cooled down to 20\u00b0C with the heating rate of 5\u00b0C/min prior to sensing test. Finally, the gold bonding was fabricated using pure gold wires (Alfa Aesar, 0.2 mm (0.008in) dia, 99.9% (metal basis)) that were put through the tiny holes of gold electrodes by soldering. Figure 3 . Schematic of the sensing mechanism of semiconducting material doctor-bladed on Al 2 O 3 substrate interdigitated with Au electrodes with the analyte gas exposure", "cite_spans": [{"start": 165, "end": 169, "text": "[59]", "ref_id": "BIBREF59"}], "ref_spans": []}, {"section": "Characterization of Gas Sensing Characteristics", "text": "The sensor samples to be measure were placed in the center of quartz tube (3 cm diameter and 60 cm length). The tube was put in a tubular oven (Nabertherm Controller P320, Germany). Gold wires were soldered to the sensor Au electrodes externally connected with a digital multimeter (KEITHLEY model 2700 DMM, Germany) to record the sensor resistance. The sensors were tested for ethanol vapor at the operating temperature of 400\u00b0C. The sensors were certainly exposed to ethanol vapor at various concentrations ranging from 25-250 ppm. A total gas flow rate of 2 l/min was passed through the quartz tube and controlled by mass flow controllers (Bronkhorst HITEC, Germany). By monitoring the output voltage across the sensor, as the operating temperature increased up to 400\u00b0C, the resistances of the sensor in dry air and in test gas were alternately increased and decreased, which can be measured. The sensing mechanism of material was shown in Fig. 3 . The analyte ethanol gas adsorbs on the ZnO sensing layer and causes a change in resistance depending on the gas concentration. This is monitored by a digital multimeter connected to the sensor substrate with Au wires. The corresponding resistance and time showed the sensing characteristics in terms of sensitivity, response, and recovery time. The sensitivity, S is defined as the ratio R a /R g , where R a is the resistance in dry air, and R g is the resistance in test gas. The response time, T res is defined as the time required until 90 % of the response signal is reached. The recovery times, T rec denotes the time needed until 90 % of the original baseline signal is recovered. After annealing and sensing test of sensor fabricated using samples P0 with controlled a various film thicknesses of 5, 10, and 15 \u00b5m, they were designated as S1, S2, and S3, respectively. Finally, the film thickness sensing layers were analyzed by SEM and EDS analyses. 4 shows the XRD patterns of samples as-prepared (P0), Au/Al 2 O 3 substrate (A0), and sensors after annealing and sensing test at 400\u00b0C (S1, S2, and S3). The samples P0 were highly crystalline, and all peaks can be confirmed to be the hexagonal structure of ZnO (Inorganic Crystal Structure Database [ICSD] Coll. Code: 067454 [60] ), which also match well with the model by Abrahams et al. [61] . The diffraction peaks were slightly sharp for sensor samples S1, S2, and S3 as compared to sample P0, suggesting relatively larger particles. The diffraction patterns of Al 2 O 3 (modified structural parameters of ICSD Coll. Code: No. 085137 [62] ) (filled diamonds) and Au (modified structural parameters of ICSD Coll. CAS No. 7440-57-5 [63] ) (filled rectangular) from the substrates are also visible in the A0, S1, S2, and S3, especially, the sensors S1, S2, and S3 showed ZnO peaks (filled circles) which confirm the ZnO thick film sensing layer doctor-bladed on Au/Al 2 O 3 substrates, and also the Au (111) peak showed the strongest peak in terms of intensity. The average crystal sizes (d XRD ave.) were calculated by the fundamental parameter approach Rietveld method [57] based on the half-maximum widths of Sherrer's equation [64] using the TOPAS-3 software, which compared with the average BET-equivalent particle diameter (d BET ). The small particles sizes can be predicted from the diffraction broad peaks. The diffraction peaks were slightly sharp for sensor S1, S2, and S3 after sensing at 400\u00b0C as compared to sample P1 (P1, SSA=63. 5 (a, b) show bright-field TEM images of samples P0 were observed at the different magnifications. The corresponding diffraction patterns are shown in the insets. The diffraction patterns illustrating spot patterns of the hexagonal structure of ZnO, indicated that the ZnO nanoparticles are highly crystalline, which is in good agreement with the XRD data. The flame made ZnO nanoparticles can be observed as particles having the clear rod-like, hexagonal, and spheroidal shape. Fig. 5 (b) shows the morphologies of flame made (5/5) ZnO nanoparticle contains mainly spheroidal particles typically with diameters ranging from 10-20 nm with occasional hexagonal and rod-like particles. The crystalline sizes of ZnO hexagonal particles were in the range of 10-20 nm, and nanorod-like particles were in the range of 10-20 nm in width, 20-50 nm in length. The morphology can be clearly seen the ZnO nanorods particles as shown in Fig. 6 (b) . This is consistent with Tani et al. [25] and Height et al. [26, 27] .", "cite_spans": [{"start": 2238, "end": 2242, "text": "[60]", "ref_id": "BIBREF60"}, {"start": 2302, "end": 2306, "text": "[61]", "ref_id": "BIBREF61"}, {"start": 2551, "end": 2555, "text": "[62]", "ref_id": "BIBREF62"}, {"start": 2647, "end": 2651, "text": "[63]", "ref_id": "BIBREF63"}, {"start": 3085, "end": 3089, "text": "[57]", "ref_id": "BIBREF57"}, {"start": 3145, "end": 3149, "text": "[64]", "ref_id": "BIBREF64"}, {"start": 4433, "end": 4437, "text": "[25]", "ref_id": "BIBREF24"}, {"start": 4456, "end": 4460, "text": "[26,", "ref_id": "BIBREF25"}, {"start": 4461, "end": 4464, "text": "27]", "ref_id": "BIBREF26"}], "ref_spans": [{"start": 1912, "end": 1913, "text": "4", "ref_id": "FIGREF2"}, {"start": 3459, "end": 3467, "text": "5 (a, b)", "ref_id": "FIGREF4"}, {"start": 3938, "end": 3948, "text": "Fig. 5 (b)", "ref_id": "FIGREF4"}, {"start": 4384, "end": 4394, "text": "Fig. 6 (b)", "ref_id": "FIGREF5"}]}, {"section": "Results and Discussion", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Particles Properties", "text": "ZnO nanorods formation can be described by XRD lattice aspect ratio [26] based on the ZnO wurtzite hexagonal structure. ZnO wurtzite hexagonal structure consists of the alternating planes of Zn and O stacking and the corresponding nanorods morphology as also shown in Fig. 6 (a) and (b) . The (002) plane lies in parallel to the O and Zn planes, while the (100) plane lies in perpendicular to the (002) plane, intersecting alternating layers of Zn and O. The crystallite sizes calculated by (100) and (002) planes from XRD peak fitting were used to roughly calculate the XRD lattice aspect ratio, which essentially considered as a metrics of \"Length\" (L), and \"Diameter\" (D), respectively. The crystallite sizes ratio (L/D) can be designated as an aspect ratio. Fig. 7 (a) and (b) shows the sensitivity (S) and response time (T res ) versus the ethanol concentration ranging from 25-250 ppm plot for the sensors S1 (filled triangles), S2 (open rectangles), and S3 (filled triangles) with various film thicknesses during forward cycle towards reducing gas ethanol at sensing operating temperature of 400\u00b0C. The sensitivities of all sensors were found to increase rather linearly with increasing ethanol concentrations. As the film thickness increases from 5 to 15 \u00b5m, it can be clearly seen that at the thinnest sensing film (S1) can improve the sensor behaviors in terms of sensitivity and response times, which evidently shown better than S2, and S3. Better response should be expected for larger concentration of reducing gas adsorbed, because the reaction between the adsorbed reducing gas and oxygen species becomes more favorable. The sensor S1 has the best sensitivity (to 250 ppm, S=801). Further increase of the film thicknesses deteriorates the sensitivity (Fig. 7 (a) ) and response time (Fig. 7 (b) ). The sensor S1 showing the fastest response to ethanol vapor, whereas a thicker sensing films affected to the response of the sensors were slightly sluggish. For sensor S1, the response time, T res , was within a few seconds and rather constantly responded with increasing ethanol concentration (in the order of 5 s). The response time: T res was 10 and 5 s at 25 and 250 ppm, respectively. The trend of T rec was so long within minutes. Comparing with the same material references which reported by Liu et al. [3] , these sensors produced from flame-made ZnO nanoparticles have higher sensitivity and shorter response times than those made from ZnO single crystal flakes with different sizes and morphology of particles (to 300 ppm, S=14.3, T res =62 s). Also Zhu et al. [11] reported that ZnO nanorods and needle-shaped had a sensor response to 100 ppm of ethanol at 420\u00baC of 12. For the comparison with doping material, Zhu et al. [10] reported that the highest sensing behaviors to ethanol was at 370\u00baC of pure ZnO (to 100 ppm, S=15) and ZnO incorporated with 10 wt%TiO 2 (to 100 ppm, S=50, and to 200 ppm, S= 80) sensor. It can be clearly seen that high purity of flame made ZnO nanoparticles show very high sensitivity and also fast response time at the highest ethanol concentration. (T res ) were within a few seconds, and (c) change in resistance of sensor S1 under exposure to reducing gas ethanol during forward cycle.", "cite_spans": [{"start": 68, "end": 72, "text": "[26]", "ref_id": "BIBREF25"}, {"start": 2323, "end": 2326, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 2584, "end": 2588, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 2746, "end": 2750, "text": "[10]", "ref_id": "BIBREF9"}], "ref_spans": [{"start": 268, "end": 286, "text": "Fig. 6 (a) and (b)", "ref_id": "FIGREF5"}, {"start": 762, "end": 780, "text": "Fig. 7 (a) and (b)", "ref_id": "FIGREF7"}, {"start": 1766, "end": 1777, "text": "(Fig. 7 (a)", "ref_id": "FIGREF7"}, {"start": 1798, "end": 1809, "text": "(Fig. 7 (b)", "ref_id": "FIGREF7"}]}, {"section": "Gas Sensing Properties", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Film Thickness Sensing Layer", "text": "The cracking formation depended on film thickness sensing layer with rough controlling of sensor S1, S2, and S3. It was found that the film thicknesses increased with increasing crack widths. This is because of several cracking phenomena assumptions, such as the cracks between large grains formed as the small grains became closer and agglomerated at the heating temperature, and got shrinkage while undergoing the cooling process. Cracks increased with increasing film thickness because large grains or crack gaps caused the decreasing in the surface area, connectivity of films and deteriorating film properties of the electronic materials. Fig. 8 shows a speculation on how the morphology changes with increasing film thickness. Cracks showed up when the films shrank as a result of grain growth in the annealing process. It is suspected that the cracks do not penetrate through the film down to the bottom. Cracking formation can be formed with the difference in the thermal expansion coefficient mismatch between substrate, materials. Thicker sensing films caused these cracks, were related directly to tensile stress caused in the film thicker than the critical thickness. It has been found that a thicker film showed more cracks phenomena than thinner film. The cross-section, film thickness, and surface morphology of the sensing film layer (S1, S2, S3) after sensing test at 400\u00b0C were observed using SEM analysis with different magnifications as shown in Fig. 9 . The film thickness of sensing film was approximately 5, 10, and 15 \u00b5m as shown in Fig. 9 (a), (b), and (c), respectively, which benefited tremendously to ethanol gas sensing properties. The high density Al 2 O 3 substrate interdigitated with Au electrodes was also visible. After annealing process, a denser film layer was formed. ", "cite_spans": [], "ref_spans": [{"start": 644, "end": 650, "text": "Fig. 8", "ref_id": "FIGREF8"}, {"start": 1466, "end": 1472, "text": "Fig. 9", "ref_id": "FIGREF9"}, {"start": 1557, "end": 1563, "text": "Fig. 9", "ref_id": "FIGREF9"}]}, {"section": "Conclusions", "text": "The flame-made (5/5) ZnO nanoparticles used as the ethanol gas sensors were successfully produced by flame spray pyrolysis. The XRD patterns show that the particles correspond to hexagonal phase of ZnO, and also the corresponding Al 2 O 3 , Au, and ZnO peak were evidently seen from the flame made ZnO nanoparticles printed on Al 2 O 3 substrate interdigitated with Au electrodes after annealing and sensing test at 400\u00b0C used as an ethanol sensor. The d XRD average sizes calculated using conspicuous peaks based on XRD fitting of flame made ZnO as-prepared and after annealing and sensing test at 400\u00b0C were found to slightly change. The morphologies of ZnO nanoparticles was observed to be mainly spheroidal particles typically with diameters ranging from 10-20 nm with occasional hexagonal and rod-like particles. The crystalline sizes of ZnO hexagonal particles were found to be in the range of 10-20 nm, and nanorod-like particles were found to be ranging from 10-20 nm in width and 20-50 nm in length. ZnO thick sensing films were prepared by doctor-blade technique in film thickness ranging from 5 to 15 \u00b5m. The sensor characteristics to reducing ethanol gas showed remarkable dependence on the film thickness. The film thickness has effects on the sensor characteristics. The sensitivity and response time drastically increased and decreased with decreasing the film thicknesses. It can be observed the film thickness increased with increasing crack width which decrease the surface area and connectivity of films and deteriorate film properties of electronic materials. For the sensor test, the thinnest sensing film (5 \u00b5m) ZnO films showed tremendous sensing characteristics such as the highest sensitivity and the fastest response times (to 250 ppm, S=801, T res =", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Synthesis of nano-sized ZnO powders by thermal decomposition of zinc acetate using Broussonetia papyrifera (L.) Vent pulp as a dispersant", "authors": [{"first": "C", "middle": [], "last": "Liewhiran", "suffix": ""}, {"first": "S", "middle": [], "last": "Seraphin", "suffix": ""}, {"first": "S", "middle": [], "last": "Phanichphant", "suffix": ""}], "year": 2006, "venue": "Curr. Appl. Phys", "link": "96536437"}, "BIBREF1": {"title": "Optical and structural investigation of ZnO thin films prepared by chemical vapor deposition (CVD)", "authors": [{"first": "M", "middle": [], "last": "Purica", "suffix": ""}, {"first": "E", "middle": [], "last": "Budianu", "suffix": ""}, {"first": "E", "middle": [], "last": "Rusu", "suffix": ""}, {"first": "M", "middle": [], "last": "Danila", "suffix": ""}, {"first": "R", "middle": [], "last": "Gavrila", "suffix": ""}], "year": 2002, "venue": "Thin Solid Films", "link": "96768643"}, "BIBREF2": {"title": "Synthesis and gas sensing properties of ZnO single crystal flakes", "authors": [{"first": "Y", "middle": [], "last": "Liu", "suffix": ""}, {"first": "J", "middle": [], "last": "Dong", "suffix": ""}, {"first": "P", "middle": ["J"], "last": "Hesketh", "suffix": ""}, {"first": "M", "middle": [], "last": "Liu", "suffix": ""}], "year": 2005, "venue": "J. Mater. Chem", "link": "51912715"}, "BIBREF3": {"title": "Gas-sensing properties of thick film based on ZnO nano-tetrapods", "authors": [{"first": "C", "middle": [], "last": "Xiangfeng", "suffix": ""}, {"first": "J", "middle": [], "last": "Dongli", "suffix": ""}, {"first": "A", "middle": ["B"], "last": "Djuri\u0161ic", "suffix": ""}, {"first": "Y", "middle": ["H"], "last": "Leung", "suffix": ""}], "year": 2005, "venue": "Chem. Phys. Lett", "link": "94642261"}, "BIBREF4": {"title": "Sprayed ZnO thin films for ethanol sensor", "authors": [{"first": "P", "middle": ["P"], "last": "Sahay", "suffix": ""}, {"first": "S", "middle": [], "last": "Tewari", "suffix": ""}, {"first": "S", "middle": [], "last": "Jha", "suffix": ""}, {"first": "M", "middle": [], "last": "Shamsuddin", "suffix": ""}], "year": 2005, "venue": "J. Mater. Sci", "link": "98597550"}, "BIBREF5": {"title": "Gas sensing properties of ZnO nanorods prepared by hydrothermal method", "authors": [{"first": "J", "middle": [], "last": "Xu", "suffix": ""}, {"first": "Y", "middle": [], "last": "Chen", "suffix": ""}, {"first": "Y", "middle": [], "last": "Li", "suffix": ""}, {"first": "J", "middle": [], "last": "Shen", "suffix": ""}], "year": 2005, "venue": "J. Mater. Sci", "link": "100936275"}, "BIBREF6": {"title": "Fabrication and ethanol sensing characteristics of ZnO nanowire gas sensors", "authors": [{"first": "Q", "middle": [], "last": "Wan", "suffix": ""}, {"first": "Q", "middle": ["H"], "last": "Li", "suffix": ""}, {"first": "Y", "middle": ["J"], "last": "Chen", "suffix": ""}, {"first": "X", "middle": ["L"], "last": "He", "suffix": ""}, {"first": "J", "middle": ["P"], "last": "Li", "suffix": ""}, {"first": "C", "middle": ["L"], "last": "Lin", "suffix": ""}, {"first": "T", "middle": ["H"], "last": "Wang", "suffix": ""}], "year": 2004, "venue": "Appl. Phys. Lett", "link": "120445562"}, "BIBREF7": {"title": "Grain size control and gas sensing properties of ZnO gas sensor", "authors": [{"first": "J", "middle": [], "last": "Xu", "suffix": ""}, {"first": "Q", "middle": [], "last": "Pan", "suffix": ""}, {"first": "Y", "middle": [], "last": "Shun", "suffix": ""}, {"first": "Z", "middle": [], "last": "Tian", "suffix": ""}], "year": 2000, "venue": "Sens. Actuators B", "link": "95929675"}, "BIBREF8": {"title": "A novel method for improving the performance of ZnO gas sensors", "authors": [{"first": "H", "middle": [], "last": "Xu", "suffix": ""}, {"first": "X", "middle": [], "last": "Liu", "suffix": ""}, {"first": "D", "middle": [], "last": "Cui", "suffix": ""}, {"first": "M", "middle": [], "last": "Li", "suffix": ""}, {"first": "M", "middle": [], "last": "Jiang", "suffix": ""}], "year": 2006, "venue": "Sens. Actuators B", "link": "98169230"}, "BIBREF9": {"title": "Improvement in gas sensitivity of ZnO thick film to volatile organic compounds (VOCs) by adding TiO 2", "authors": [{"first": "B", "middle": ["L"], "last": "Zhu", "suffix": ""}, {"first": "C", "middle": ["S"], "last": "Xie", "suffix": ""}, {"first": "W", "middle": ["Y"], "last": "Wang", "suffix": ""}, {"first": "K", "middle": ["J"], "last": "Huang", "suffix": ""}, {"first": "J", "middle": ["H"], "last": "Hu", "suffix": ""}], "year": 2004, "venue": "Mater. Lett", "link": "189758458"}, "BIBREF10": {"title": "Synthesis and gas sensitivity of In-doped ZnO nanoparticles", "authors": [{"first": "B", "middle": ["L"], "last": "Zhu", "suffix": ""}, {"first": "D", "middle": ["W"], "last": "Zeng", "suffix": ""}, {"first": "J", "middle": [], "last": "Wu", "suffix": ""}, {"first": "W", "middle": ["L"], "last": "Song", "suffix": ""}, {"first": "C", "middle": ["S"], "last": "Xie", "suffix": ""}], "year": 2003, "venue": "J. Mater. Sci. -Mater. Electron", "link": "133721743"}, "BIBREF11": {"title": "Zinc oxide ceramic semi-conductor gas sensor for ethanol vapour", "authors": [{"first": "B", "middle": ["B"], "last": "Rao", "suffix": ""}], "year": 2000, "venue": "Mater. Chem. Phys", "link": "98092477"}, "BIBREF12": {"title": "Hydrothermal synthesis of highly crystalline ZnO nanoparticles: A competitive sensor for LPG and EtOH", "authors": [{"first": "B", "middle": [], "last": "Baruwati", "suffix": ""}, {"first": "D", "middle": ["K"], "last": "Kumar", "suffix": ""}, {"first": "S", "middle": ["V"], "last": "Manorama", "suffix": ""}], "year": 2006, "venue": "Sens. Actuators B", "link": "98076959"}, "BIBREF13": {"title": "Lanthanum doped SnO 2 and ZnO thin films sensitive to ethanol and humidity", "authors": [{"first": "I", "middle": [], "last": "Stambolova", "suffix": ""}, {"first": "K", "middle": [], "last": "Konstantinov", "suffix": ""}, {"first": "S", "middle": [], "last": "Vassilev", "suffix": ""}, {"first": "P", "middle": [], "last": "Peshev", "suffix": ""}, {"first": "Ts", "middle": [], "last": "Tsacheva", "suffix": ""}], "year": 2000, "venue": "Mater. Chem. Phys", "link": "97281713"}, "BIBREF14": {"title": "Hydrogen and ethanol sensors based on ZnO nanorods, nanowires and nanotubes", "authors": [{"first": "C", "middle": ["S"], "last": "Rout", "suffix": ""}, {"first": "S", "middle": ["H"], "last": "Krishna", "suffix": ""}, {"first": "S", "middle": ["R C"], "last": "Vivekchand", "suffix": ""}, {"first": "A", "middle": [], "last": "Govindaraj", "suffix": ""}, {"first": "C", "middle": ["N R"], "last": "Rao", "suffix": ""}], "year": 2005, "venue": "Chem. Phys. Lett", "link": "96031051"}, "BIBREF15": {"title": "Influence of Al, In, Cu, Fe and Sn dopants on the response of thin films ZnO gas sensor to ethanol vapour", "authors": [{"first": "F", "middle": ["D"], "last": "Paraguay", "suffix": ""}, {"first": "M", "middle": ["M"], "last": "Yoshida", "suffix": ""}, {"first": "J", "middle": [], "last": "Morales", "suffix": ""}, {"first": "J", "middle": [], "last": "Solis", "suffix": ""}, {"first": "W", "middle": ["L"], "last": "Estrada", "suffix": ""}], "year": 2000, "venue": "Thin Solid Films", "link": "93274871"}, "BIBREF16": {"title": "Gas-sensing characteristics of ZnO and copper-impregnated ZnO", "authors": [{"first": "A", "middle": ["R"], "last": "Raju", "suffix": ""}, {"first": "C", "middle": ["N R"], "last": "Rao", "suffix": ""}], "year": 1991, "venue": "Sens. Actuators B", "link": "98284352"}, "BIBREF17": {"title": "The preparation of ZnO based gas-sensing thin films by ink-jet printing method", "authors": [{"first": "W", "middle": [], "last": "Shen", "suffix": ""}, {"first": "Y", "middle": [], "last": "Zhao", "suffix": ""}, {"first": "C", "middle": [], "last": "Zhang", "suffix": ""}], "year": 2005, "venue": "Thin Solid Films", "link": "135528286"}, "BIBREF18": {"title": "Hydrothermal synthesis and gas sensing characters of ZnO nanorods", "authors": [{"first": "J", "middle": [], "last": "Xu", "suffix": ""}, {"first": "Y", "middle": [], "last": "Chen", "suffix": ""}, {"first": "D", "middle": [], "last": "Chen", "suffix": ""}, {"first": "J", "middle": [], "last": "Shen", "suffix": ""}], "year": 2006, "venue": "Sens. Actuators B", "link": null}, "BIBREF19": {"title": "Nanoparticle synthesis at high production rates by flame spray pyrolysis", "authors": [{"first": "R", "middle": [], "last": "Mueller", "suffix": ""}, {"first": "L", "middle": [], "last": "M\u00e4dler", "suffix": ""}, {"first": "S", "middle": ["E"], "last": "Pratsinis", "suffix": ""}], "year": 2003, "venue": "Chem. Eng. Sci", "link": "94118723"}, "BIBREF20": {"title": "Liquid-fed aerosol reactors for one-step synthesis of nano-structured particles", "authors": [{"first": "L", "middle": [], "last": "M\u00e4dler", "suffix": ""}], "year": 2004, "venue": "", "link": "137489424"}, "BIBREF21": {"title": "Controlled synthesis of nanostructured particles by flame spray pyrolysis", "authors": [{"first": "L", "middle": [], "last": "M\u00e4dler", "suffix": ""}, {"first": "H", "middle": ["K"], "last": "Kammler", "suffix": ""}, {"first": "R", "middle": [], "last": "Mueller", "suffix": ""}, {"first": "S", "middle": ["E"], "last": "Pratsinis", "suffix": ""}], "year": 2002, "venue": "J. Aeros. Sci", "link": "95064536"}, "BIBREF22": {"title": "Flame synthesis of nanoparticles", "authors": [{"first": "H", "middle": ["K"], "last": "Kammler", "suffix": ""}, {"first": "L", "middle": [], "last": "M\u00e4dler", "suffix": ""}, {"first": "S", "middle": ["E"], "last": "Pratsinis", "suffix": ""}], "year": 2001, "venue": "Chem. Eng. Tech", "link": "98251134"}, "BIBREF23": {"title": "Rapid synthesis of stable ZnO quantum dots", "authors": [{"first": "L", "middle": [], "last": "M\u00e4dler", "suffix": ""}, {"first": "W", "middle": ["J"], "last": "Stark", "suffix": ""}, {"first": "S", "middle": ["E"], "last": "Pratsinis", "suffix": ""}], "year": 2002, "venue": "J. Appl. Phys", "link": "120679100"}, "BIBREF24": {"title": "Homogeneous ZnO nanoparticles by flame spray pyrolysis", "authors": [{"first": "T", "middle": [], "last": "Tani", "suffix": ""}, {"first": "L", "middle": [], "last": "M\u00e4dler", "suffix": ""}, {"first": "S", "middle": ["E"], "last": "Pratsinis", "suffix": ""}], "year": 2002, "venue": "J. Nanopart. Res", "link": "92011833"}, "BIBREF25": {"title": "Nanorods of ZnO made by flame spray pyrolysis", "authors": [{"first": "M", "middle": ["J"], "last": "Height", "suffix": ""}, {"first": "L", "middle": [], "last": "M\u00e4dler", "suffix": ""}, {"first": "F", "middle": [], "last": "Krumeich", "suffix": ""}, {"first": "S", "middle": ["E"], "last": "Pratsinis", "suffix": ""}], "year": 2006, "venue": "Chem. Mater", "link": "96808884"}, "BIBREF26": {"title": "Ag-ZnO catalysts for UVphotodegradation of methylene blue", "authors": [{"first": "M", "middle": ["J"], "last": "Height", "suffix": ""}, {"first": "S", "middle": ["E"], "last": "Pratsinis", "suffix": ""}, {"first": "O", "middle": [], "last": "Mekasuwandumrong", "suffix": ""}, {"first": "P", "middle": [], "last": "Praserthdam", "suffix": ""}], "year": 2005, "venue": "Appl. Catal., B", "link": null}, "BIBREF27": {"title": "Flame spray synthesis of tin dioxide nanoparticles for gas sensing", "authors": [{"first": "T", "middle": [], "last": "Sahm", "suffix": ""}, {"first": "L", "middle": [], "last": "M\u00e4dler", "suffix": ""}, {"first": "A", "middle": [], "last": "Gurlo", "suffix": ""}, {"first": "N", "middle": [], "last": "Barsan", "suffix": ""}, {"first": "S", "middle": ["E"], "last": "Pratsinis", "suffix": ""}, {"first": "U", "middle": [], "last": "Weimar", "suffix": ""}], "year": 2004, "venue": "Sens. Actuators B", "link": "93573751"}, "BIBREF29": {"title": "Ethanol sensors based on Pt-doped tin oxide nanopowders synthesised by gel-combustion", "authors": [{"first": "P", "middle": [], "last": "Amato", "suffix": ""}, {"first": "I", "middle": [], "last": "Benedetti", "suffix": ""}, {"first": "B", "middle": ["D"], "last": "", "suffix": ""}], "year": 2006, "venue": "Sens. Actuators B", "link": "94298615"}, "BIBREF30": {"title": "One-step solid-state reaction synthesis and gas sensing property of tin oxide nanoparticles", "authors": [{"first": "F", "middle": [], "last": "Li", "suffix": ""}, {"first": "J", "middle": [], "last": "Xu", "suffix": ""}, {"first": "X", "middle": [], "last": "Yu", "suffix": ""}, {"first": "L", "middle": [], "last": "Chen", "suffix": ""}, {"first": "", "middle": ["J"], "last": "Zhu", "suffix": ""}, {"first": "Z", "middle": [], "last": "Yang", "suffix": ""}, {"first": "X", "middle": [], "last": "Xin", "suffix": ""}], "year": 2002, "venue": "Sens. Actuators B", "link": "95467395"}, "BIBREF31": {"title": "Tin oxide-based gas sensors prepared by the sol-gel process", "authors": [{"first": "R", "middle": [], "last": "Rella", "suffix": ""}, {"first": "A", "middle": [], "last": "Serra", "suffix": ""}, {"first": "P", "middle": [], "last": "Siciliano", "suffix": ""}, {"first": "L", "middle": [], "last": "Vasanelli", "suffix": ""}, {"first": "G", "middle": [], "last": "De", "suffix": ""}, {"first": "A", "middle": [], "last": "Licciulli", "suffix": ""}, {"first": "A", "middle": [], "last": "Quirini", "suffix": ""}], "year": 1997, "venue": "Sens. Actuators B", "link": "93515193"}, "BIBREF32": {"title": "Development of SnO 2 -based ethanol gas sensor", "authors": [{"first": "T", "middle": [], "last": "Maekawa", "suffix": ""}, {"first": "J", "middle": [], "last": "Tamaki", "suffix": ""}, {"first": "N", "middle": [], "last": "Miura", "suffix": ""}, {"first": "N", "middle": [], "last": "Yamazoe", "suffix": ""}], "year": 1992, "venue": "Sens. Actuators B", "link": null}, "BIBREF33": {"title": "Undoped and Pd-doped SnO 2 thin films for gas sensors", "authors": [{"first": "B", "middle": [], "last": "Gautheron", "suffix": ""}, {"first": "M", "middle": [], "last": "Labeau", "suffix": ""}, {"first": "G", "middle": [], "last": "Delabouglise", "suffix": ""}, {"first": "U", "middle": [], "last": "Schmatz", "suffix": ""}], "year": 1993, "venue": "Sens. Actuators B", "link": null}, "BIBREF34": {"title": "A route toward more selective and less humidity sensitive screen-printed SnO 2 and WO 3 gas sensitive layers", "authors": [{"first": "P", "middle": [], "last": "Ivanov", "suffix": ""}, {"first": "J", "middle": [], "last": "Hubalek", "suffix": ""}, {"first": "K", "middle": [], "last": "Pr\u00e1\u0161ek", "suffix": ""}, {"first": "X", "middle": [], "last": "Vilanova", "suffix": ""}, {"first": "E", "middle": [], "last": "Llobet", "suffix": ""}, {"first": "X", "middle": [], "last": "Correig", "suffix": ""}], "year": 2004, "venue": "Sens. Actuators B", "link": null}, "BIBREF35": {"title": "Ethanol sensors based on nano-sized \u03b1-Fe 2 O 3 with SnO 2 , ZrO 2 , TiO 2 solid solutions", "authors": [{"first": "O", "middle": ["K"], "last": "Tan", "suffix": ""}, {"first": "W", "middle": [], "last": "Cao", "suffix": ""}, {"first": "W", "middle": [], "last": "Zhu", "suffix": ""}, {"first": "J", "middle": ["W"], "last": "Chai", "suffix": ""}, {"first": "J", "middle": ["S"], "last": "Pan", "suffix": ""}], "year": 2003, "venue": "Sens. Actuators B", "link": null}, "BIBREF36": {"title": "Ethanol sensor based on indium oxide nanowires prepared by carbothermal reduction reaction", "authors": [{"first": "C", "middle": [], "last": "Xiangfeng", "suffix": ""}, {"first": "W", "middle": [], "last": "Caihong", "suffix": ""}, {"first": "J", "middle": [], "last": "Dongli", "suffix": ""}, {"first": "Z", "middle": [], "last": "Chenmou", "suffix": ""}], "year": 2004, "venue": "Chem. Phys. Lett", "link": "97467989"}, "BIBREF37": {"title": "Indium oxide thin film based ammonia gas and ethanol vapour sensor", "authors": [{"first": "K", "middle": ["K"], "last": "Makhija", "suffix": ""}, {"first": "A", "middle": [], "last": "Ray", "suffix": ""}, {"first": "R", "middle": ["M"], "last": "Patel", "suffix": ""}, {"first": "U", "middle": ["B"], "last": "Trivedi", "suffix": ""}, {"first": "H", "middle": ["N"], "last": "Kapse", "suffix": ""}], "year": 2005, "venue": "Bull. Mater. Sci", "link": "98249031"}, "BIBREF38": {"title": "Sensing of organic vapors by flamemade TiO 2 nanoparticles", "authors": [{"first": "A", "middle": [], "last": "Teleki", "suffix": ""}, {"first": "S", "middle": ["E"], "last": "Pratsinis", "suffix": ""}, {"first": "K", "middle": [], "last": "Kalyanasundaram", "suffix": ""}, {"first": "P", "middle": ["I"], "last": "Gouma", "suffix": ""}], "year": 2006, "venue": "Sens. Actuators B", "link": null}, "BIBREF39": {"title": "Titanium dioxide thin films prepared for alcohol microsensor applications", "authors": [{"first": "G", "middle": [], "last": "Sberveglieri", "suffix": ""}, {"first": "E", "middle": [], "last": "Comini", "suffix": ""}, {"first": "G", "middle": [], "last": "Faglia", "suffix": ""}, {"first": "M", "middle": ["Z"], "last": "Atashbar", "suffix": ""}, {"first": "W", "middle": [], "last": "Wlodarski", "suffix": ""}], "year": 2000, "venue": "Sens. Actuators B", "link": "94398451"}, "BIBREF40": {"title": "A rapidly-responding sensor for benzene, methanol and ethanol vapours based on films of titanium dioxide dispersed in a polymer operating at room temperature", "authors": [{"first": "M", "middle": [], "last": "Mabrook", "suffix": ""}, {"first": "P", "middle": [], "last": "Hawkins", "suffix": ""}], "year": 2001, "venue": "Sens. Actuators B", "link": "94196851"}, "BIBREF41": {"title": "Performances of La-TiO 2 nanoparticles as gas sensing material", "authors": [{"first": "A", "middle": ["M"], "last": "Ruiz", "suffix": ""}, {"first": "A", "middle": [], "last": "Cornet", "suffix": ""}, {"first": "J", "middle": ["R"], "last": "Morante", "suffix": ""}], "year": 2005, "venue": "Sens. Actuators B", "link": "95500919"}, "BIBREF42": {"title": "Comparison of single and binary oxide MoO 3 , TiO 2 and WO 3 sol-gel gas sensors", "authors": [{"first": "K", "middle": [], "last": "Galatsis", "suffix": ""}, {"first": "Y", "middle": ["X"], "last": "Li", "suffix": ""}, {"first": "W", "middle": [], "last": "Wlodarski", "suffix": ""}, {"first": "E", "middle": [], "last": "Comini", "suffix": ""}, {"first": "G", "middle": [], "last": "Sberveglieri", "suffix": ""}, {"first": "C", "middle": [], "last": "Cantalini", "suffix": ""}, {"first": "S", "middle": [], "last": "Santucci", "suffix": ""}, {"first": "M", "middle": [], "last": "Passacantando", "suffix": ""}], "year": 2002, "venue": "Sens. Actuators B", "link": null}, "BIBREF43": {"title": "Nearly monodisperse Cu 2 O and CuO nanospheres: Preparation and applications for sensitive gas sensors", "authors": [{"first": "J", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "J", "middle": [], "last": "Liu", "suffix": ""}, {"first": "Q", "middle": [], "last": "Peng", "suffix": ""}, {"first": "X", "middle": [], "last": "Wang", "suffix": ""}, {"first": "Y", "middle": [], "last": "Li", "suffix": ""}], "year": 2006, "venue": "Chem. Mater", "link": null}, "BIBREF44": {"title": "Effect of film thickness and curing temperature on the sensitivity of ZnO:Sb thick-film hydrogen sensor", "authors": [{"first": "N", "middle": ["J"], "last": "Dayan", "suffix": ""}, {"first": "R", "middle": ["N"], "last": "Karekar", "suffix": ""}, {"first": "R", "middle": ["C"], "last": "Aiyer", "suffix": ""}, {"first": "S", "middle": ["R"], "last": "Sainkar", "suffix": ""}], "year": 1997, "venue": "J. Mater. Sci. -Mater. Electron", "link": "134174715"}, "BIBREF45": {"title": "Influence of thickness on oxygen-sensing properties of TiO 2 thin films on Al 2 O 3", "authors": [{"first": "L", "middle": [], "last": "Zheng", "suffix": ""}, {"first": "T", "middle": [], "last": "Xu", "suffix": ""}, {"first": "G", "middle": [], "last": "Li", "suffix": ""}, {"first": "Q", "middle": [], "last": "Yin", "suffix": ""}], "year": 2002, "venue": "Jpn. J. Appl. Phys., Part", "link": null}, "BIBREF46": {"title": "Gas sensing characteristics of copper phthalocyanine films; effects of film thickness and sensing temperature", "authors": [{"first": "Y", "middle": ["L"], "last": "Lee", "suffix": ""}, {"first": "C", "middle": ["Y"], "last": "Sheu", "suffix": ""}, {"first": "R", "middle": ["H"], "last": "Hsiao", "suffix": ""}], "year": 2004, "venue": "Sens. Actuators B", "link": "94818386"}, "BIBREF47": {"title": "ZnO nanoparticulate thin film: preparation, characterization and gas-sensing property", "authors": [{"first": "X", "middle": ["L"], "last": "Cheng", "suffix": ""}, {"first": "H", "middle": [], "last": "Zhao", "suffix": ""}, {"first": "L", "middle": ["H"], "last": "Huo", "suffix": ""}, {"first": "S", "middle": [], "last": "Gao", "suffix": ""}, {"first": "J", "middle": ["G"], "last": "Zhao", "suffix": ""}], "year": 2004, "venue": "Sens. Actuators B", "link": "95275923"}, "BIBREF48": {"title": "Analysis of thickness dependence of the sensitivity in thin film resistive gas sensors", "authors": [{"first": "F", "middle": [], "last": "Hossein-Babari", "suffix": ""}, {"first": "M", "middle": [], "last": "Orvatinia", "suffix": ""}], "year": 2003, "venue": "Sens. Actuators B", "link": "97145352"}, "BIBREF49": {"title": "Electron theory of thin-film gas sensors", "authors": [{"first": "H", "middle": [], "last": "Geistlinger", "suffix": ""}], "year": 1993, "venue": "Sens. Actuators B", "link": "95094379"}, "BIBREF50": {"title": "Thick film ZnO based varistors prepared by screen printing", "authors": [{"first": "M", "middle": ["A R"], "last": "L\u00f3pez", "suffix": ""}, {"first": "M", "middle": [], "last": "Peiteado", "suffix": ""}, {"first": "J", "middle": ["F"], "last": "Fern\u00e1ndez", "suffix": ""}, {"first": "A", "middle": ["C"], "last": "Caballero", "suffix": ""}, {"first": "J", "middle": [], "last": "Holc", "suffix": ""}, {"first": "S", "middle": [], "last": "Drnovsek", "suffix": ""}, {"first": "D", "middle": [], "last": "Kuscer", "suffix": ""}, {"first": "S", "middle": [], "last": "Macek", "suffix": ""}, {"first": "M", "middle": [], "last": "Kosec", "suffix": ""}], "year": 2006, "venue": "J. Eur. Ceram. Soc", "link": "137549925"}, "BIBREF51": {"title": "The effects of thickness and operation temperature on ZnO:Al thin film CO gas sensor", "authors": [{"first": "J", "middle": ["F"], "last": "Chang", "suffix": ""}, {"first": "H", "middle": ["H"], "last": "Kuo", "suffix": ""}, {"first": "I", "middle": ["C"], "last": "Leu", "suffix": ""}, {"first": "M", "middle": ["H"], "last": "Hon", "suffix": ""}], "year": 2002, "venue": "Sens. Actuators B", "link": "95249583"}, "BIBREF52": {"title": "Thickness influence on surface morphology and ozone sensing properties of nanostructured ZnO transparent thin films grown by PLD", "authors": [{"first": "S", "middle": [], "last": "Christoulakis", "suffix": ""}, {"first": "M", "middle": [], "last": "Suchea", "suffix": ""}, {"first": "E", "middle": [], "last": "Koudoumas", "suffix": ""}, {"first": "M", "middle": [], "last": "Katharakis", "suffix": ""}, {"first": "N", "middle": [], "last": "Katsarakis", "suffix": ""}, {"first": "G", "middle": [], "last": "Kiriakidis", "suffix": ""}], "year": 2006, "venue": "Appl. Surf. Sci", "link": "55581793"}, "BIBREF53": {"title": "Gas sensing properties of tin oxide thin films fabricated from hydrothermally treated nanoparticles dependence of CO and H 2 response on film thickness", "authors": [{"first": "G", "middle": [], "last": "Sakai", "suffix": ""}, {"first": "N", "middle": ["S"], "last": "Baik", "suffix": ""}, {"first": "N", "middle": [], "last": "Miura", "suffix": ""}, {"first": "N", "middle": [], "last": "Yamazoe", "suffix": ""}], "year": 2001, "venue": "Sens. Actuators B", "link": null}, "BIBREF54": {"title": "Surface morphology and sensing property of NiO-WO 3 thin films prepared by thermal evaporation", "authors": [{"first": "D", "middle": ["M"], "last": "Na", "suffix": ""}, {"first": "L", "middle": [], "last": "Satyanarayana", "suffix": ""}, {"first": "G", "middle": ["P"], "last": "Choi", "suffix": ""}, {"first": "Y", "middle": ["J"], "last": "Shin", "suffix": ""}, {"first": "J", "middle": ["S"], "last": "Park", "suffix": ""}], "year": 2005, "venue": "Sensors", "link": "1696072"}, "BIBREF55": {"title": "Electrosprayed and selenized Cu/In metal particles films", "authors": [{"first": "M", "middle": [], "last": "Kaelin", "suffix": ""}, {"first": "H", "middle": [], "last": "Zogg", "suffix": ""}, {"first": "A", "middle": ["N"], "last": "Tiwari", "suffix": ""}, {"first": "O", "middle": [], "last": "Wilhelm", "suffix": ""}, {"first": "S", "middle": ["E"], "last": "Pratsinis", "suffix": ""}, {"first": "T", "middle": [], "last": "Meyer", "suffix": ""}, {"first": "A", "middle": [], "last": "Meyer", "suffix": ""}], "year": 2004, "venue": "Thin Solid Films", "link": null}, "BIBREF56": {"title": "Low cost processing of CIGS thin film solar cells", "authors": [{"first": "M", "middle": [], "last": "Kaelin", "suffix": ""}, {"first": "D", "middle": [], "last": "Rudmann", "suffix": ""}, {"first": "A", "middle": ["N"], "last": "Tiwari", "suffix": ""}], "year": 2004, "venue": "Sol. Energy", "link": "122300467"}, "BIBREF57": {"title": "Axial divergence in a conventional X-ray powder diffractometer. I. Theoretical foundations", "authors": [{"first": "R", "middle": ["W"], "last": "Cheary", "suffix": ""}, {"first": "A", "middle": ["A"], "last": "Coelho", "suffix": ""}], "year": 1998, "venue": "J. Appl. Crystallogr", "link": "12073578"}, "BIBREF58": {"title": "Adsorption of gases in multimolecular layers", "authors": [{"first": "S", "middle": [], "last": "Brunauer", "suffix": ""}, {"first": "P", "middle": [], "last": "Emmett", "suffix": ""}, {"first": "P", "middle": ["H"], "last": "Teller", "suffix": ""}], "year": 1938, "venue": "J. Am. Chem. Soc", "link": "53667309"}, "BIBREF59": {"title": "Burnout of the organic vehicle in an electrically conductive thick-film paste", "authors": [{"first": "Z", "middle": [], "last": "Liu", "suffix": ""}, {"first": "D", "middle": ["D L"], "last": "Chung", "suffix": ""}], "year": 2004, "venue": "J. Elec. Mater", "link": "94001136"}, "BIBREF60": {"title": "Parameters for the wurtzite structure of ZnS and ZnO using powder neutron diffraction", "authors": [{"first": "E", "middle": ["H"], "last": "Kisi", "suffix": ""}, {"first": "M", "middle": ["M"], "last": "Elcombe", "suffix": ""}], "year": 1989, "venue": "Acta Crystallogr., Sect. C: Cryst. Struct. Commun", "link": null}, "BIBREF61": {"title": "Remeasurement of the structure of hexagonal ZnO", "authors": [{"first": "S", "middle": ["C"], "last": "Abrahams", "suffix": ""}, {"first": "J", "middle": ["L"], "last": "Bernstein", "suffix": ""}], "year": 1969, "venue": "Acta Crystallogr., Sect. B: Struct. Sci", "link": "97546866"}, "BIBREF62": {"title": "Crystal structures and peculiar magnetic properties of alpha-and gamma-(Al 2 O 3 ) powders", "authors": [{"first": "R", "middle": ["S"], "last": "Liu", "suffix": ""}, {"first": "W", "middle": ["C"], "last": "Shi", "suffix": ""}, {"first": "Y", "middle": ["C"], "last": "Cheng", "suffix": ""}, {"first": "C", "middle": ["Y"], "last": "Huang", "suffix": ""}], "year": 1997, "venue": "Mod. Phys. Lett. B", "link": null}, "BIBREF63": {"title": "Standard X-ray diffraction powder patterns", "authors": [{"first": "H", "middle": ["E"], "last": "Swanson", "suffix": ""}, {"first": "E", "middle": [], "last": "Tatge", "suffix": ""}], "year": 1953, "venue": "National Bureau of Standards", "link": "95430289"}, "BIBREF64": {"title": "Structure of polycrystalline aggregates; Elements of X-ray diffraction", "authors": [{"first": "B", "middle": ["D"], "last": "Cullity", "suffix": ""}], "year": "", "venue": "", "link": null}}, "ref_entries": {"FIGREF0": {"text": "Figure 1. Schematic of the FSP experimental set up for the synthesis of ZnO nanoparticles. The liquid precursor mixture is rapidly dispersed by a gas stream and ignited by a premixed methane/oxygen flame.", "type": "figure"}, "FIGREF1": {"text": "Figure 2. Substrate layout (a) Top view and schematic, (b-c) SEM images were observed with different magnifications of Al 2 0 3 (dark view) substrate interdigitated with Au (bright view) electrodes.", "type": "figure"}, "FIGREF2": {"text": "Figure 4. XRD patterns of flame-made (5/5) ZnO as-prepared (P0), Al 2 O 3 substrate interdigitated with Au electrodes (A0), and samples P0 doctor-bladed on Au/Al 2 O 3 substrate with controlling a various film thicknesses of 5, 10, and 15 \u00b5m after annealing and sensing test at 400\u00baC (S1, S2, and S3) ((\u2022) ZnO; (\u25a0) Au; (\u2666) Al 2 O 3 ).", "type": "figure"}, "FIGREF3": {"text": "Fig. 4 shows the XRD patterns of samples as-prepared (P0), Au/Al 2 O 3 substrate (A0), and sensors after annealing and sensing test at 400\u00b0C (S1, S2, and S3). The samples P0 were highly crystalline, and all peaks can be confirmed to be the hexagonal structure of ZnO (Inorganic Crystal Structure Database [ICSD] Coll. Code: 067454 [60]), which also match well with the model by Abrahams et al. [61]. The diffraction peaks were slightly sharp for sensor samples S1, S2, and S3 as compared to sample P0, suggesting relatively larger particles. The diffraction patterns of Al 2 O 3 (modified structural parameters of ICSD Coll. Code: No. 085137 [62]) (filled diamonds) and Au (modified structural parameters of ICSD Coll. CAS No. 7440-57-5 [63]) (filled rectangular) from the substrates are also visible in the A0, S1, S2, and S3, especially, the sensors S1, S2, and S3 showed ZnO peaks (filled circles) which confirm the ZnO thick film sensing layer doctor-bladed on Au/Al 2 O 3 substrates, and also the Au (111) peak showed the strongest peak in terms of intensity. The average crystal sizes (d XRD ave.) were calculated by the fundamental parameter approach Rietveld method [57] based on the half-maximum widths of Sherrer's equation [64] using the TOPAS-3 software, which compared with the average BET-", "type": "figure"}, "FIGREF4": {"text": "Figure 5. TEM bright-fields image of highly crystalline flame-made (5/5) ZnO nanoparticles at: (a) low and (b) high magnifications. The morphologies can be observed (b) mainly spheroidal particles typically with occasional hexagonal and rod-like particles. Insets (a) show the corresponding diffraction patterns of the particles.", "type": "figure"}, "FIGREF5": {"text": "Figure 6. ZnO hexagonal-close-packed wurtzite structure shows the ZnO lattice along with the calculation of XRD lattice aspect ratio (L/D) using the (100) and (002) crystallite size measurement. The morphology can be clearly observed as particles having the clear (b) rod-like shape.", "type": "figure"}, "FIGREF6": {"text": "Fig. 5 (a, b) show bright-field TEM images of samples P0 were observed at the different magnifications. The corresponding diffraction patterns are shown in the insets. The diffraction patterns illustrating spot patterns of the hexagonal structure of ZnO, indicated that the ZnO nanoparticles are highly crystalline, which is in good agreement with the XRD data. The flame made ZnO nanoparticles can be observed as particles having the clear rod-like, hexagonal, and spheroidal shape. Fig. 5 (b) shows the morphologies of flame made (5/5) ZnO nanoparticle contains mainly spheroidal particles typically with diameters ranging from 10-20 nm with occasional hexagonal and rod-like particles. The crystalline sizes of ZnO hexagonal particles were in the range of 10-20 nm, and nanorod-like particles were in the range of 10-20 nm in width, 20-50 nm in length. The morphology can be clearly seen the ZnO nanorods particles as shown in Fig. 6 (b). This is consistent with Tani et al. [25] and Height et al. [26, 27]. ZnO nanorods formation can be described by XRD lattice aspect ratio [26] based on the ZnO wurtzite hexagonal structure. ZnO wurtzite hexagonal structure consists of the alternating planes of Zn and O stacking and the corresponding nanorods morphology as also shown in Fig. 6 (a) and (b). The (002) plane lies in parallel to the O and Zn planes, while the (100) plane lies in perpendicular to the (002) plane, intersecting alternating layers of Zn and O. The crystallite sizes calculated by (100) and (002) planes from XRD peak fitting were used to roughly calculate the XRD lattice aspect ratio, which essentially considered as a metrics of \"Length\" (L), and \"Diameter\" (D), respectively. The crystallite sizes ratio (L/D) can be designated as an aspect ratio.", "type": "figure"}, "FIGREF7": {"text": "Figure 7. (a) Sensitivity of S1, S2, and S3 (5, 10, and 15 \u00b5m) comparison dependence on ethanol concentration and various film thicknesses in dry air (O 2 /N 2 ) at 400\u00baC, (b) the response times (T res ) were within a few seconds, and (c) change in resistance of sensor S1 under exposure to reducing gas ethanol during forward cycle.", "type": "figure"}, "FIGREF8": {"text": "Figure 8. Model for the influence of film thickness on sensing film morphology", "type": "figure"}, "FIGREF9": {"text": "Figure 9. SEM micrographs of surface sensing morphology and cross-section of flame-made ZnO thick films. (a) 5 \u00b5m, (b) 10 \u00b5m, and (c) 15 \u00b5m thicknesses after annealing and sensing test at 400\u00baC in dry air at the different magnifications.", "type": "figure"}, "FIGREF10": {"text": "Fig. 10 (a) shows SEM images of sample S3. The image shows the selected regions of ZnO sensing layer (region 1) together with Au electrodes (region 2). Insets give the EDS elemental composition signal associated which each of regions as indicated. Region 1 and 2 emphasized clearly yield a signal corresponding to Zn, O, and Au. It can be clearly seen that the ZnO sensing layer doctor-bladed on the sensor substrate.", "type": "figure"}, "FIGREF11": {"text": "Figure 10. SEM micrographs of the selected areas showing the corresponding ZnO sensing layer (region 1) together with Au electrodes (region 2).EDS spectra for both regions emphasized clearly yield a signal corresponding to Zn, O, and Au were also shown in the inset.", "type": "figure"}}}
{"paper_id": "17433068", "_pdf_hash": "73bbb48757df2efbcac6852715181e88fcc3bc10", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Annotating digital documents", "authors": [{"first": "A", "middle": [], "last": "Brush", "suffix": ""}], "year": 2002, "venue": "CHI", "link": null}, "BIBREF1": {"title": "The Internet and Democratic Citizenship: Theory, Practice and Policy", "authors": [{"first": "S", "middle": [], "last": "Coleman", "suffix": ""}, {"first": "J", "middle": [], "last": "Blumler", "suffix": ""}], "year": 2008, "venue": "", "link": "150851209"}, "BIBREF2": {"title": "Using intelligent task routing and contribution review to help communities build artifacts of lasting value", "authors": [{"first": "D", "middle": [], "last": "Cosley", "suffix": ""}, {"first": "D", "middle": [], "last": "Frankowski", "suffix": ""}, {"first": "L", "middle": [], "last": "Terveen", "suffix": ""}, {"first": "J", "middle": [], "last": "Riedl", "suffix": ""}], "year": 2006, "venue": "CHI", "link": "2513972"}, "BIBREF3": {"title": "Recomposition: putting it all back together again", "authors": [{"first": "R", "middle": ["E"], "last": "Grinter", "suffix": ""}], "year": 1998, "venue": "CSCW '98", "link": "18978781"}, "BIBREF4": {"title": "Groupware and Social Dynamics", "authors": [{"first": "J", "middle": [], "last": "Grudin", "suffix": ""}], "year": 1994, "venue": "CACM", "link": "59743759"}, "BIBREF5": {"title": "Edit wear and read wear", "authors": [{"first": "W", "middle": ["C"], "last": "Hill", "suffix": ""}, {"first": "J", "middle": ["D"], "last": "Hollan", "suffix": ""}, {"first": "D", "middle": [], "last": "Wroblewski", "suffix": ""}, {"first": "T", "middle": [], "last": "Mccandless", "suffix": ""}], "year": 1992, "venue": "CHI", "link": "15416019"}, "BIBREF6": {"title": "Slash(dot) and burn: distributed moderation in a large online conversation space", "authors": [{"first": "C", "middle": [], "last": "Lampe", "suffix": ""}, {"first": "P", "middle": [], "last": "Resnick", "suffix": ""}], "year": 2004, "venue": "CHI", "link": "207548645"}, "BIBREF7": {"title": "Tools for Iterative Tasks on Mechanical Turk. Under Review. Accessible at", "authors": [{"first": "G", "middle": [], "last": "Little", "suffix": ""}, {"first": "L", "middle": ["B"], "last": "Chilton", "suffix": ""}, {"first": "R", "middle": [], "last": "Miller", "suffix": ""}, {"first": "M", "middle": [], "last": "Goldman", "suffix": ""}, {"first": "", "middle": [], "last": "Turkit", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF10": {"title": "Visualizing Argumentation: Software Tools for Collaborative and Educational Sense-Making", "authors": [{"first": "S", "middle": ["B"], "last": "Shum", "suffix": ""}], "year": 2003, "venue": "", "link": "16789132"}}, "ref_entries": {}}
{"paper_id": "17433069", "_pdf_hash": "61716543b79a3b03b0dfe9365e5bb2ad43cbc3f5", "abstract": [{"section": "Abstract", "text": "Abstract. -Theoretical studies suggest that the final earthquake (EQ) and neural-seizure dynamics should have many similar features and could be analyzed within similar mathematical frameworks. Herein, by monitoring the temporal evolution of the fractal spectral characteristics in EEG time series and pre-seismic electromagnetic (EM) time series we show that many similar distinctive symptoms (including common alterations in associated scaling parameters) emerge as epileptic seizures (ES) and EQs are approaching. These alterations reveal a gradual reduction of complexity as the catastrophic events approach. The transition from anti-persistent to persistent behaviour may indicate that the onset of a severe crisis is imminent. The observations find a unifying explanation within the school of the \"Intermittent Criticality\".", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Introduction. -Both EQ and ES involve interacting threshold elements. A large event, i.e. a seismic shock or an epileptic seizure, is the result of repeated nonlinear interactions among the respective sub-units, namely, opening cracks (that emit EM emission) or firing neurons. A common hallmark of these out-of-equilibrium phenomena is their extraordinary complexity. Complex systems self-organise their internal structure and their dynamics showing novel and surprising macroscopic properties including coherent large-scale collective behaviours. A basic reason for our interest in complexity is the striking similarity in behaviour close to irreversible phase transitions among systems that are otherwise quite different in nature [1] [2] [3] . Recent studies have demonstrated that a large variety of complex processes, including EQs [4, 5] , forest fires [6], heartbeats [7] , human coordination [8] , neuronal dynamics [9] [10] [11] , exhibits statistical similarities, most commonly the power law scaling behaviour of a particular observable. The strong analogies between the dynamics of the \"self-organizedcriticality\" (SOC) model for EQs and that of neurobiology have been realized by numerous of authors, e.g. [12] [13] [14] [15] . Interestingly, authors have suggested that EQ dynamics and neurodynamics should have many similar features and could be analyzed within similar mathematical frameworks [9] [10] [11] . Here, we attempt to verify this hypothesis.", "cite_spans": [{"start": 838, "end": 841, "text": "[4,", "ref_id": "BIBREF3"}, {"start": 842, "end": 844, "text": "5]", "ref_id": "BIBREF4"}], "ref_spans": []}], "body_text": [{"section": "", "text": "Introduction. -Both EQ and ES involve interacting threshold elements. A large event, i.e. a seismic shock or an epileptic seizure, is the result of repeated nonlinear interactions among the respective sub-units, namely, opening cracks (that emit EM emission) or firing neurons. A common hallmark of these out-of-equilibrium phenomena is their extraordinary complexity. Complex systems self-organise their internal structure and their dynamics showing novel and surprising macroscopic properties including coherent large-scale collective behaviours. A basic reason for our interest in complexity is the striking similarity in behaviour close to irreversible phase transitions among systems that are otherwise quite different in nature [1] [2] [3] . Recent studies have demonstrated that a large variety of complex processes, including EQs [4, 5] , forest fires [6] , heartbeats [7] , human coordination [8] , neuronal dynamics [9] [10] [11] , exhibits statistical similarities, most commonly the power law scaling behaviour of a particular observable. The strong analogies between the dynamics of the \"self-organizedcriticality\" (SOC) model for EQs and that of neurobiology have been realized by numerous of authors, e.g. [12] [13] [14] [15] . Interestingly, authors have suggested that EQ dynamics and neurodynamics should have many similar features and could be analyzed within similar mathematical frameworks [9] [10] [11] . Here, we attempt to verify this hypothesis. \u2020 Deceased.", "cite_spans": [{"start": 838, "end": 841, "text": "[4,", "ref_id": "BIBREF3"}, {"start": 842, "end": 844, "text": "5]", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "c EDP Sciences", "text": "Method of analysis. -A way to examine transient phenomena is to divide the measurements into time windows and analyze these windows. If this analysis yields different results for some precursory time intervals, then a transient behaviour can be extracted. On the other hand, complexity manifests itself in linkages between space and time, generally producing patterns on many scales and the emergence of fractal structure close to irreversible phase transitions. The emergence of a scale-free behaviour is generally named \"criticality\" [16] . Based on these concepts, recently, a fractal spectral statistical analysis under the criticalpoint hypothesis has been applied to EM signals emitted before EQs [17] [18] [19] . More precisely, the analysis shows that the pre-seismic EM time series are fractals, that is, have a power spectrum S(f ) of the form f \u2212\u03b2 . This reveals that the system shows interesting ordering phenomena as the opening cracks simultaneously change their behaviour to a common fractal pattern. Particularly, we focus on the way in which an individual unit's activity is dominated by its neighbours and these new properties appear. In this direction, dividing the series into sub-series, and studying how both the exponent \u03b2 and the correlation coefficient (that measures the goodness of the data which can be fitted by a power law) evolve as we go from one sub-series to another, we claim that characteristic footprints emerge as the global failure is approached, which could be used as diagnostic tools for Earth's crust failure. Herein, based on this new method, we concentrate on the question whether many similar distinguishing symptoms (including similar alterations in associated scaling parameters) emerge as epileptic seizures and EQs are approaching. For this purpose, we analyse both i) an electroencephalogram (EEG) including Sprague-Dawley rat epileptic seizure ( fig. 1a) and ii) a pre-seismic EM signal, which is associated with the Athens EQ (M = 5.9, 7 September 1999) [18] [19] [20] (fig. 1a ) .", "cite_spans": [], "ref_spans": [{"start": 1898, "end": 1906, "text": "fig. 1a)", "ref_id": "FIGREF2"}, {"start": 2022, "end": 2032, "text": "(fig. 1a )", "ref_id": "FIGREF2"}]}, {"section": "c EDP Sciences", "text": "We focus on the statistics of the fluctuations in the EEG (or pre-seismic time series) with respect to their amplitude, let us say A(t i ). If the time series A(t i ) is a temporal fractal, that series cannot have a characteristic frequency. The only possibility is then that the power spectrum S(f ) has a scaling form:", "cite_spans": [], "ref_spans": []}, {"section": "c EDP Sciences", "text": "where f is the frequency of the Fourier transform. In a log S(f )-log f representation, the power spectrum is a line with spectral slope \u03b2. The linear correlation coefficient, r, is a measure of the goodness of fit to the power law (1) . The nonstationary character of pre-seismic records requires the application of methods that can appropriately treat such nonstationarities. In practice, the condition of stationarity for nonstationary signals can be satisfied by dividing the signal into blocks of short, pseudo-stationary segments [21] . We divide the signals into successive segments of 1024 samples each, in order to study not only the presence of a power law S(f ) \u223c f \u2212\u03b2 but, mainly, the temporal evolution of the associated parameters \u03b2 and r. On the other hand, recent studies show that the wavelet transform can remove effects due to nonstationarities present in time series [22] . The wavelet transform has been found particularly useful for signal analysis because of its ability to localise in both time and frequency (see figs. 1f, f ). The \"global wavelet spectrum\" is used in order to provide an unbiased and consistent estimation of the true power spectrum of the time series. The continuous wavelet transform based on the Morlet wavelet makes the calculation. fig. 1b ) exhibits the temporal evolution of r. We observe a gradual increase of r values. At the tail of the precursory activity the fit to the power law is excellent: a region with r close to 1 is approached. The fact that the data follow the power law (1) implies that the pre-seizure (or pre-seismic activity) could be ascribed to a multi-time-scale cooperative activity of numerous activated firing neurons (or opening cracks) in which an individual unit's activity is dominated by its neighbours so that all units simultaneously alter their behaviour to a common pattern. The gradual increase of r-values with time suggests that the fractal character of the underlying processes and structures becomes clearer with time.", "cite_spans": [], "ref_spans": [{"start": 1280, "end": 1287, "text": "fig. 1b", "ref_id": "FIGREF2"}]}, {"section": "c EDP Sciences", "text": "Signatures indicating the approach to the global instability. -The \u03b2-exponent lies between 1 and 3 during the precursory epochs (red epochs in figs. 1a, a ) . This evidence implies that the associated time series follow the fractional Brownian motion (fBm) random field model [23, 24] , which is a generalization of the normal Brownian motion. The distribution of \u03b2-exponents is also shifted to higher values ( fig. 1c or c ) during the pre-ictal (or pre-seismic) period. This shift reveals several features of the underlying mechanism.", "cite_spans": [], "ref_spans": [{"start": 143, "end": 156, "text": "figs. 1a, a )", "ref_id": "FIGREF2"}, {"start": 411, "end": 425, "text": "fig. 1c or c )", "ref_id": "FIGREF2"}]}, {"section": "c EDP Sciences", "text": "As the \u03b2-exponent increases, the spatial correlation in the time series also increases. This behaviour indicates a gradual increase of the memory, and thus a gradual loss of complexity. In a geometrical sense, the \u03b2-exponent specifies the strength of the signal's irregularity as well. Indeed, the fractal dimension d is calculated from the relation d = (5\u2212\u03b2)/2 in the frame of the fBm model [24] , which, after considering the shift of the \u03b2-exponent to higher values, leads to a decrease of the fractal dimension as the epileptic (or seismic) crisis approaches. The decrease of d with time may reflect that the action of anisotropy inherent to the system leads to the appearance of preferred directions of elementary activities just before the main shock, thus the network of firing neurons (or opening cracks) becomes less ramified. Concerning the fracture, theoretical and experimental evidence strongly support the former hypothesis [18, 19] . On the other hand, the characteristic abnormalities associated with ESs include simplification of the dendrite tree [25] . This may justify a significant decrease of d just as the ES is approached. The above findings suggest that the ES (or EQ) onset may represent a gradual transition from a less orderly state to a more orderly state.", "cite_spans": [{"start": 1065, "end": 1069, "text": "[25]", "ref_id": "BIBREF24"}], "ref_spans": []}, {"section": "c EDP Sciences", "text": "The colour-type behaviour of the power spectrum density (\u03b2 > 0) means that the spectrum manifests more power at low frequencies than at high frequencies. The increase in the spectrum slope \u03b2 with time indicates the gradual enhancement of lower frequency fluctuations.", "cite_spans": [], "ref_spans": []}, {"section": "This behaviour may indicate that the activated neurons (or cracks) interact and coalesce to form larger fractal structures, i.e., the events are initiated at the lowest level of the hierarchy, with the smallest elements merging in turn to form larger and larger ones.", "text": "Is the evolution towards global instability unavoidable? -A question that scientists in these fields ought to address is as follows: Is the evolution towards global instability unavoidable after the appearance of distinguishing features in the time series? We focus on this question. The \u03b2-exponent is related to the Hurst exponent, H, by the formula", "cite_spans": [], "ref_spans": []}, {"section": "This behaviour may indicate that the activated neurons (or cracks) interact and coalesce to form larger fractal structures, i.e., the events are initiated at the lowest level of the hierarchy, with the smallest elements merging in turn to form larger and larger ones.", "text": "for the fBm model. The exponent H characterizes the persistence/anti-persistence properties of the signal [18] . The range 0 < H < 0.5 (1 < \u03b2 < 2) during the normal period (figs. 1c, c and figs. 1d, d ) indicates an anti-persistency, reflecting that increases in the value of a time series are likely to be followed by decreases and conversely. Physically, this implies a set of fluctuations tending to induce a stability to the system, namely a nonlinear feedback system that \"kicks\" the firing/opening rate away from extremes. The observed systematic increase of the H-exponent during the pre-epileptic (or pre-seismic) stage indicates that the fluctuations become less anti-correlated with time. This implies that the nonlinear negative feedback mechanism gradually loses its ability to \"kick\" the system away from extremes. Finally, the time series show persistent properties, 0.5 < H < 1 (2 < \u03b2 < 3), at the tail of the precursory phase ( figs. 1d, d ). This means that increases in the value of a time series are likely to be followed by further increases, namely the system has been starting to self-organize by a positive feedback process. The systems seem to acquire to a great degree the property of irreversibility. Thus, the launch of the persistence activity could give a significant hint of a considerable probability for a forthcoming significant epileptic (or seismic) event.", "cite_spans": [], "ref_spans": [{"start": 944, "end": 955, "text": "figs. 1d, d", "ref_id": "FIGREF2"}]}, {"section": "This behaviour may indicate that the activated neurons (or cracks) interact and coalesce to form larger fractal structures, i.e., the events are initiated at the lowest level of the hierarchy, with the smallest elements merging in turn to form larger and larger ones.", "text": "Figures 1e, e reveal an accelerating energy release as the main shock approaches. This shows that during this epoch the brain (or pre-focal area) is not only near the \"critical point\" in the sense of having power law correlations, but also in terms of exhibiting high susceptibility to perturbations. This finding further indicates the last stage of the shock preparation, when due to the high level of the clustering of firing neurons (or opening cracks) even a new small cluster, if it connects large clusters, may generate a significant event. The simultaneous appearance of persistent properties at the tail of the pre-ictal (or pre-seismic) activity further supports this consideration. Figures 1f, f also reveal that progressively new higher emission rates emerge, while the amplitudes in each emission rate increase too. This further indicates the approach to the global instability.", "cite_spans": [], "ref_spans": []}, {"section": "This behaviour may indicate that the activated neurons (or cracks) interact and coalesce to form larger fractal structures, i.e., the events are initiated at the lowest level of the hierarchy, with the smallest elements merging in turn to form larger and larger ones.", "text": "Common footprints distinguish the dynamics in brain and pre-focal area close to their instability. -To conclude, a unified method to assess the approach to the global instability in biological and geological systems has been applied. We monitor step-by-step the evolution of fractal characteristics of pre-epileptic and pre-seismic time series toward the \"critical point\" This reveals that the system exhibits high susceptibility even to small perturbations. The aforementioned footprints distinguish the dynamics in a complex system close to its final instability. The emergence of persistent properties, the increase of susceptibility of the system, the predominance of large events, the coherent fluctuations of all scales, may indicate that the generation of an extreme event becomes, indeed, unavoidable.", "cite_spans": [], "ref_spans": []}, {"section": "This behaviour may indicate that the activated neurons (or cracks) interact and coalesce to form larger fractal structures, i.e., the events are initiated at the lowest level of the hierarchy, with the smallest elements merging in turn to form larger and larger ones.", "text": "We note that all the aforementioned precursory symptoms are also hidden in the EM activity observed before the 13 May 1995 Kozani-Grevena (Greece) with M s = 6.6 [18, 19] . On the other hand, fig. 2 verifies that the appearance of fBm persistent behaviour with sufficient duration can be a candidate precursory symptom of an impending ES.", "cite_spans": [], "ref_spans": [{"start": 192, "end": 198, "text": "fig. 2", "ref_id": "FIGREF3"}]}, {"section": "This behaviour may indicate that the activated neurons (or cracks) interact and coalesce to form larger fractal structures, i.e., the events are initiated at the lowest level of the hierarchy, with the smallest elements merging in turn to form larger and larger ones.", "text": "A possible common scenario. -The experimental results might be indicating the following common scenario for epilepsy and EQ generation. In the first phase of the precursory stage, the brain (or the pre-focal area) is in a self-organized anti-persistent complexity, with a restricted and systematically fluctuating correlation length. During the pre-ictal (or preseismic) epoch, the long-range correlations gradually build up through local interactions until they extend throughout the entire system. The small events are the agents by which larger correlations are established. A population of small events will advance the correlation length by an amount depending on its magnitude and system's state, triggering catastrophic events only if the conditions are right. In the strong anti-persistent regime, with a restricted correlation length, a population of small events leads to a decaying activity, always dying out. In the strong persistent state, with long-range correlations, a population of events is just able to continue \"indefinitely\". This naturally explains why not every event can induce a shock. Consequently, the final shock is the end result of a process in which the pathological spiking neurons (or opening cracks) become persistently correlated over increasing long scale lengths. The scale over which the interacting units are correlated sets the size of the largest event that can be expected at that time. A large epileptic (or seismic) event destroys criticality on its associated network, creating a period of normal state after which the process repeats by rebuilding correlation lengths toward criticality and the next large event. Thus, a large shock may act as a sort of \"critical point\" dividing the epileptic (or seismic) cycle into a period of growing correlations before the great event and a relatively uncorrelated phase after.", "cite_spans": [], "ref_spans": []}, {"section": "This behaviour may indicate that the activated neurons (or cracks) interact and coalesce to form larger fractal structures, i.e., the events are initiated at the lowest level of the hierarchy, with the smallest elements merging in turn to form larger and larger ones.", "text": "Pure SOC models imply a system perpertually near global failure [4] , hence reducing the degree of predictability of individual events. The above-mentioned evolution may be characterized overall as \"Intermittent Criticality\" [26] [27] [28] [29] that predicts a time-dependent variation in the activity as the \"critical point\" is approached, implying, in contrast to SOC, a degree of predictability. As is mentioned, the analogies between the dynamics of the SOC model for EQs and that of neurobiology have been realized by numerous authors. The present study suggests that it is important to distinguish between SOC and \"Intermittent Criticality\" not only in the study of the seismic cycle but even in the study of the epileptic cycle.", "cite_spans": [{"start": 64, "end": 67, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 240, "end": 244, "text": "[29]", "ref_id": "BIBREF28"}], "ref_spans": []}, {"section": "This behaviour may indicate that the activated neurons (or cracks) interact and coalesce to form larger fractal structures, i.e., the events are initiated at the lowest level of the hierarchy, with the smallest elements merging in turn to form larger and larger ones.", "text": "A proper recognition and understanding of tuning parameters may lead to the development of improved algorithms having higher performance reliability. One of the main features of complex systems is the role that the topological disorder plays in such systems [30, 31] . The range of size scales characterizing heterogeneities of the thresholds may act as a tuning parameter of the underlying final EQ dynamics and neural-seizure dynamics.", "cite_spans": [], "ref_spans": []}, {"section": "This behaviour may indicate that the activated neurons (or cracks) interact and coalesce to form larger fractal structures, i.e., the events are initiated at the lowest level of the hierarchy, with the smallest elements merging in turn to form larger and larger ones.", "text": "Conclusions. -Understanding a complex phenomenon is usually achieved by relating it to less complex ones. Characteristically, Fukuda et al. [2] suggest that the understanding of the mechanism underlying the \"human-made\" Internet could help to understand the natural network that controls the heart. The hypothesis that the fracture in the disordered systems may provide another useful \"model-system\" to investigate the mechanism responsible for the dynamics of the nervous system that controls involuntarily the epilepsy generation cannot be excluded. In principle, it is difficult to prove associations between events separated in time, such as earthquakes and their EM precursors. The present state of research in this area requires a refined definition of a possible pre-seismic anomaly, and also the development of more objective methods of distinguishing seismogenic emissions from nonseismic EM events. EEG time series provide a window through which the dynamics of shock preparation can be investigated in the absence of noise. Consequently, the analysis of a pure pre-catastrophic time series may help in establishing a collection of criteria to indicate the approach to the shock. The existence of pre-seismic features is still in discussion, and the analogy between activated cracks and firing neurons is not totally accepted. However, the herein observed similarities further support the hypothesis that the detected EM anomaly could have originated during the preparation of the Athens EQ [17] [18] [19] [20] .", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF3": {"title": "How Nature Works", "authors": [{"first": "P", "middle": [], "last": "Bak", "suffix": ""}], "year": 1997, "venue": "", "link": "171176022"}, "BIBREF4": {"title": "Critical Phenomena in Natural Sciences", "authors": [{"first": "D", "middle": [], "last": "Sornette", "suffix": ""}], "year": 2000, "venue": "", "link": "153157069"}, "BIBREF24": {"title": "Chaos in the Brain", "authors": [{"first": "J", "middle": [], "last": "Sackellares", "suffix": ""}, {"first": "L", "middle": [], "last": "Iasemidis", "suffix": ""}, {"first": "D", "middle": [], "last": "Shiau", "suffix": ""}, {"first": "R", "middle": [], "last": "Gilmore", "suffix": ""}, {"first": "S", "middle": [], "last": "Roper", "suffix": ""}], "year": 2000, "venue": "", "link": null}, "BIBREF28": {"title": "Proc. Natl. Acad. Sci. USA", "authors": [{"first": "C", "middle": ["G"], "last": "Sammis", "suffix": ""}, {"first": "D", "middle": [], "last": "Sornette", "suffix": ""}], "year": 2002, "venue": "", "link": null}}, "ref_entries": {"FIGREF0": {"text": "Footprint of clustering in more compact fractal structures with time. -Figure 1b (or", "type": "figure"}, "FIGREF2": {"text": "Fig. 1 -(a) Rat EEG time series. The sampling rate was 200 Hz. Bicuculline i.p. injection was used to induce the rat epileptic seizures. The green, red and ochre epochs show the normal state, the pre-epileptic phase, and the stage of the epileptic seizure, respectively. (a ) EM anomalies recorded at magnetic loop antennas during the last days before the Athens EQ. The consecutive green, red and green epochs show the normal state, the pre-seismic phase, and the aftershock state (new normal state), respectively. The sampling rate was 1 Hz. (b)/(b ) Histograms of probability distribution of the correlation coefficient r calculated on 1024 measurements segments for the four consecutive time intervals marked in (a)/(a ). (c)/(c ) Histograms of probability distribution of the exponent \u03b2 calculated on 1024 measurements segments for the four consecutive time intervals marked in (a)/(a ). The insets show the percentage of segments with r > 0.97 and r > 0.85, respectively. (d)/(d ) Decomposition of time series into sub-sets, each characterized by a different local Hurst exponent H. The behaviour of the pre-ictal/pre-seismic signal becomes persistent in the tail of the precursory phase. (e)/(e ) depict the cumulative energy release, in arbitrary units, as a function of time. (f)/(f ) The wavelet power spectrum of the time series. The intensity scale on the top shows colours corresponding to the values of the square spectral amplitudes in arbitrary units.", "type": "figure"}, "FIGREF3": {"text": "Fig. 2 -The blue and red sectors demonstrate the percentage of segments exhibiting anti-persistent and persistent behaviour respectively. For this representation we use the segments that follow a power law spectrum S(f ) \u223c f \u2212\u03b2 with an excellent regression (r \u2265 0.98). This figure verifies that the appearance of fBm persistent behaviour with sufficient duration can be a candidate precursory symptom of an impending epileptic seizure.", "type": "figure"}, "FIGREF4": {"text": "in consecutive time windows. This analysis reveals: i) Emergence of long-range correlations, i.e., appearance of memory effects. This implies a multi-time-scale cooperative activity of numerous activated sub-units. ii) Increase of the spatial correlation in the time series with time. This in- dicates a gradual transition from a less orderly state to a more orderly state. iii) Decrease of the fractal dimension in the time series with time. This suggests the appearance of preferred direc- tions in elementary activities. iv) Gradual increase of number of time intervals with \"critical characteristic\". This signals that the \"quality\" of the underlying fractal structures increases. v) Gradual predominance of large events as the main shock is approached. This shows that the events are initiated at the lowest level of the hierarchy, with the smallest elements merging in turn to form larger and larger ones. vi) Decrease of the anti-persistent behaviour with time. It implies that the nonlinear negative feedback mechanism gradually loses its ability to \"kick\" the system away from extremes. This also may predict the launch of the persistent epoch. vii) Appearance of persistent properties in the \"tail\" of the precursors. This may inform that the system acquires to a great degree the property of irreversibility. viii) Significant divergence of the energy release with time.", "type": "figure"}}}
{"paper_id": "17433432", "_pdf_hash": "fcf25021c26ac3fbd8a53a4bf63219519b4927dd", "abstract": [{"section": "Abstract", "text": "Abstract-The underwater environment presents many challenges for robotic sensing including highly variable lighting and the presence of dynamic objects such as fish and suspended particulate matter. The dynamic six-degree-of-freedom nature of the environment presents further chalenges due to unpredictable external forces such as current and surge. Despite these chalenges the aquatic environment presents many real and practical applications for robotic systems. A common requirement of many of these tasks is the need to construct accurate 3D representations of specific environmental structures. In order to address these needs we have developed a stereo visioninertial sensing device that has been successfuly deployed to reconstruct complex 3D structures in both the aquatic and terrestrial domains. The sensor combines 3D information, obtained using stereo vision algorithms, with 3DOF inertial data to construct 3D models of the environment. The resulting model representation is then converted to a textured polygonal mesh for later processing. Semi-automatic tools have been developed to aid in the processing of these representations. Reconstruction and segmentation of coral and other underwater structures Fig. 1 . The AQUA robot shown with a diver for scale. The robot is powered obtained with the sensor are presented.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "by six fins which give it direct access to five degrees of freedom of motion.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "The robot can operate completely autonomously although it is shown here", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "", "text": "[5], [6] , [7] , [8] ). Terrestrial SLAM algorithms often assume within the AQUA robot. We combine range information exa predictable vehicle odometry model in order to assist tracted from stereo irnagery with 3DOF orientation from an in the probabilistic association of sensor information with inertial measurement unit (IMU) within a SLAM algorithm salient visual features. The underwater domain necessitates to accurately estimate dense 3D models of the environment solutions to the SLAM problem which are more dependent and the trajectory of the sensor. It is important to note that upon sensor information than is traditional in the terrestrial although the AQUASENSOR does not process the collected domain. This has prompted recent research in robotic vehicle data in realtime, the algorithms used to analyze the data are design, sensing, localization and mapping for underwater being developed with realtime performance in mind. vehicles (see [9] , [10] , [11] , [12] ).", "cite_spans": [{"start": 5, "end": 8, "text": "[6]", "ref_id": "BIBREF11"}, {"start": 11, "end": 14, "text": "[7]", "ref_id": "BIBREF12"}, {"start": 17, "end": 20, "text": "[8]", "ref_id": "BIBREF13"}, {"start": 949, "end": 952, "text": "[9]", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "", "text": "The AQUASENSOR is sealed within a custom underwater housing that permits operation of the device to a depth II. AQUA AND THE AQUASENSOR of 30 metres. The sensor is operated either via an IEEE One vehicle that requires robust and versatile sensing 802.1 Ig wireless link for surface operation, or via waterproof strategies to extract 3D models of the environment is the switches mounted on the exterior of the sensor. The wireless AQUA robot (see Figure 1 and [13] ). The AQUA robot is interface onboard the sensor provides status information a visually guided autonomous robot developed through a and sarnple imagery to offboard devices. LEDs mounted on collaboration between researchers at Dalhousie University, the exterior of the sensor provide status information to the McGill University, and York University. The vehicle is operator. The LEDs and waterproof switches are the only a hexapod capable of amphibious operation. On land, its communication possible with the device when submerged.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "legs provide foot-ground contact that propels the vehicle. Although designed primarily to be integrated within the Underwater these same legs act as flippers or fins to drive AQUA housing, the AQUASENSOR was also designed to the vehicle both along the surface of the water and at depths be deployed independently of the AQUA vehicle. Although of up to 30 metres. In order to meet the sensing needs of bulky when handled in the terrestrial domain, it is easily the AQUA robot a series of visual-inertial sensors [14] have operated by a single diver underwater (Figure 2(b) ). been constructed. The primary goal of these sensors is to III. OBTAINING LOCAL SURFACE MODELS collect high framerate multi-camera video imagery coupled Upon return to the surface, data from the AQUASENSOR with synchronized time-stamped inertial information. This is offloaded to higher performance computers and a larger data is later processed off-line to obtain 6DOF ego-motion disk array for processing. Recovering accurate depth from and 3D models of the environment. Although we describe stereo imagery is performed by leveraging the optimized the standalone sensor package here, the long-term goal is sum-of-squared differences algorithm implemented in the to incorporate the sensing hardware and algorithms into the Point Grey Triclops library'. This provides a dense set of 3D vehicle itself.", "cite_spans": [], "ref_spans": [{"start": 559, "end": 571, "text": "(Figure 2(b)", "ref_id": "FIGREF0"}]}, {"section": "", "text": "points per acquired image frame. To estimate the motion of", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "In order to permit the sensor package to be operated the camera, point sets from different times are combined into independently of the robot itself, an independent sensor a common reference frame. The change in the 6DOF position package known as AQUASENSOR (Figure 2 ) has been and orientation of the sensor between frames is estimated by developed. The hardware design goal for the AQUASEN-tracking interesting features temporally, using only features SOR is to provide a compact, fully-contained unit that is that correspond to estimated 3D locations in both framnes. (1) First, \"good\" features are extracted from the reference i=1 camera at time t using the Kanade-Lucas-Tomasi feature The rotation, R(.), and scale, s, are estimated using a linear tracking algorithm (see [15] , [16] ) and are tracked into least-squares approach (detailed in [18] ). After estimating the subsequent image at time t + 1. Using the disparity the rotation, the translation is estimated by transfomning the map previously extracted for both time steps, tracked points centroids into a common frame and subtracting. that do not have a corresponding disparity at both time t The final step is to refine the rotation and translation and t + 1 are eliminated. Surviving points are subsequently using a noninear Levenberg-Marquardt minimization [19] triangulated to determtne the metric 3D points associated over six parameters. For this stage we parameterize the with each disparity.", "cite_spans": [], "ref_spans": [{"start": 258, "end": 267, "text": "(Figure 2", "ref_id": "FIGREF0"}]}, {"section": "rotation as a Rodrigues vector [20] and estimate the rotation", "text": "In underwater scenes, many objects and points are visually and translation parameters by minimizing the transformation similar and thus many of the feature tracks will be incorrect. error Dynamic illumination effects, aquatic snow, and moving n objects (e.g. fish) increase the number of spurious points", "cite_spans": [], "ref_spans": []}, {"section": "rotation as a Rodrigues vector [20] and estimate the rotation", "text": "(2) that may be tracked from frame-to-frame. To overcome these problems, we employ robust statistical estimation techniques to label the feature tracks as belonging to either a static or In practice, we find that the minimization takes few iterations non-static world model. This is achieved by estimating a to minimize the error to acceptable levels and as such rotation and translation model under the assumption that the does not preclude realtime operation. This approach to pose scene is stationary. The resulting 3D temporal correspon-estimation differs from the traditional Bundle-Adjustment dences are associated with stable scene points for the basis approach [21] in the structure-from-motion literature in that of later processing.", "cite_spans": [], "ref_spans": []}, {"section": "rotation as a Rodrigues vector [20] and estimate the rotation", "text": "it does not refine the 3D locations of the features as well", "cite_spans": [], "ref_spans": []}, {"section": "rotation as a Rodrigues vector [20] and estimate the rotation", "text": "We represent the camera orientation using a quatemion as the trajectory. We chose not to refine the 3D structure to and compute the least-squares best-fit rotation and trans-limit the number of unknowns in our minimization and thus lation for the sequence in a two stage process. First, provide a solution to our system more quickly. ", "cite_spans": [], "ref_spans": []}, {"section": "B. IMU Integration C. Reconstruction Algorithm Egomotion estimation via visual motion introduces at least", "text": "The reconstruction algorithm is summarized below: two sources of error in the estimate of 6DOF pose. First, the 1) Perform stereo algorithm and extract 3D point cloud point-cloud registration computed from feature tracks can at time t never be perfect. As such, there is always a small residual 2) Track salient features from time t to t -1 error in the registration per frame which accumulates over 3) Prune 2D features to only the ones with a correspondtime. Second, the intrinsic camera parameters are not known ing 3D point perfectly and any error in these parameters introduces an 4) Estimate 3D vision-only pose change using RANSAC, error in each 3D point. In particular, the radial distortion CAM qb, Tt estimate of the lens is prone to error and as a result the 5) Compute IMUq6 and qt as above per-point error is non-uniform over the visual field. This 6) Refine qt, Tt using Levenberg-Marquardt minimization can introduce an artificial surface curvature in the 3D point for a few iterations (2-3) clouds which is subtle but noticeable when many frames are 7) Apply the pose to the point cloud and add the point registered. This effect can be seen in Figure 3(a) . Here, the cloud to the octree data structure registration error is small and the points line up very well 8) Extract the surface mesh using a constrained elastic creating a visually \"correct\" model when viewed closely, surface-net algorithm [22] or the Marching Cubes however after registering many frames it can be seen that algorithm [23] there is an introduced curvature to the recovered surface. D. Local surface models To help counteract this effect, we utilize the 3DOF IMU to provide more information about the orientation of the device.", "cite_spans": [{"start": 1510, "end": 1514, "text": "[23]", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "Experiments have been performed to both evaluate the", "text": "The IMU provides us with a quatemion representing absolute accuracy of the reconstruction system and to create 3D orientation in 3D space. We enforce the fact that the change models of real-world objects in the field. Results from in orientation as computed from the visual system must be field experiments near Holetown, Barbados show the reconconsistent with the change in the absolute orientation of struction of a coral bed and sections of a sunken barge the device. This is accomplished by transformning the IMU lying in the Folkstone Marine Reserve. Sample qualitative orientation change, reconstructions from underwater sequences are shown in Figure 4 . As in the 2D case, the problem of segmenting a 3D range of applications where the raw data must be segmented dataset can be expressed as a graph cut problem, with the cut into semantically important structures for later processing. dividing the foreground voxels from the background voxels.", "cite_spans": [], "ref_spans": [{"start": 650, "end": 658, "text": "Figure 4", "ref_id": "FIGREF1"}]}, {"section": "Experiments have been performed to both evaluate the", "text": "Consider the recovered surface model shown in Figure 4 . The 3D segmentation process begins by converting the input For some applications -such as investigating the cause of 3D polygon or point cloud representation into a discrete 3D the sinking -the surface that belongs to the wreck may be voxel grid. A graph is created, where a node in the graph of interest while for other applications -such as monitoring is used to represent each non-empty voxel. Adjacent nonecosystem health -the surface that belongs to the coral may empty voxels are considered to be connected nodes. A sink be more salient. For these and similar applications automatic node and a source node are added to the graph with edges and semi-automatic tools are required to segment the dataset to each voxel node. Weighting heuristics are applied to the into appropriate components. It is interesting to observe that voxel graph in a similar fashion to that performed on the this problem is not unique to the 3D environment. through the 3D voxel scene. An arbitrary number of voxels EDGE WEIGHT CALCULATIONS FOR VOXEL GRAPH. may be marked by the user and the view of the 3D scene can be translated and rotated to allow the user to mark voxels that may be hidden in some views. In addition to each voxel possessing a color value, a voxel has a state attribute. This being more likely to be marked as foreground, and similarly state attribute can be one of the following four values: empty, for background. colored, foreground, or background.", "cite_spans": [], "ref_spans": [{"start": 46, "end": 54, "text": "Figure 4", "ref_id": "FIGREF1"}]}, {"section": "Experiments have been performed to both evaluate the", "text": "A penalty term is assigned to adjacent nodes along the", "cite_spans": [], "ref_spans": []}, {"section": "Experiments have been performed to both evaluate the", "text": "The task of marking the voxels is simply an instance of segmentation boundary proportional to the difference tfl the common problem of 3D ray-picking. When a user wishes color The edge weight between these adjacent nodes thus to mark a voxel, the 2D window-coordinate of the mouse increases in proportion with the color similarity of the two position is converted into a 3D ray directed into the 3D voxel nodes, so that similar color nodes are less likely to be on grid. Each voxel intersected along the ray into the grid is different sides of the segmentation boundary. A small color tested. The first non-empty voxel encountered is tagged. difference between adjacent voxel nodes results in a large A graph is then constructed in which a node exists in the weight for their shared edge, and a large color difference graph for each non-empty voxel and edges are constructed results in a small weight.", "cite_spans": [], "ref_spans": []}, {"section": "Experiments have been performed to both evaluate the", "text": "between nodes that represent adjacent cells in the voxel Table I nodes that are connected to the source in the resulting cut are labelled as foreground nodes, and all nodes that are a) Create a graph node.", "cite_spans": [], "ref_spans": [{"start": 57, "end": 64, "text": "Table I", "ref_id": "TABREF2"}]}, {"section": "Experiments have been performed to both evaluate the", "text": "connected to the sink are labelled as background nodes. The b) Create an edge from this node to each node that dataset is now fully labelled and can be redisplayed using corresponds to an adjacent voxel. this semantic information. c) Create an edge from the source terminal node to Once the nodes in the graph have been marked the surface this node.", "cite_spans": [], "ref_spans": []}, {"section": "Experiments have been performed to both evaluate the", "text": "reconstruction can be performed. Points contained within d) Add an edge from this node to the sink terminal voxels with corresponding graph nodes marked as foreground node. are identified as foreground points. The remaining points If the node is tagged as foreground, then the edge from the are background points. A variation of the Marching Cubes source terminal is assigned a weight of oo. If the node is algorithm [23] is applied to the foreground points to generate tagged as background, then the edge from this node to the a 3D texture-mapped triangle mesh representation of the sink terminal is given a weight of oc.", "cite_spans": [{"start": 417, "end": 421, "text": "[23]", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "Experiments have been performed to both evaluate the", "text": "foreground object. Graph edge weights are established so that edges connecting similar voxels have a high weight, while edges B Example segmentation connecting dissimilar voxels have a low weight. Similar to Figure 6 shows the results of segmenting a coral growth the method used by [24] the colors in the foreground and from the 3D mesh recovered from a wreck in the Folkstone background seeds are clustered using the k-means method Marine Reserve, Barbados. The growth in the lower left [25] .", "cite_spans": [{"start": 283, "end": 287, "text": "[24]", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "Experiments have been performed to both evaluate the", "text": "hand view of Figure 6 (a) was segmented by having the For each node in the graph, the minimum distance from its user identify sample regions of the mesh as corresponding color to the foreground and background colors is computed. to either foreground or background (Figure 6(b) ). The 3D This information regarding the likelihood of a node being Lazy Snapping algorithm was then used to automatically foreground or background is represented as the weight be-identify regions as being foreground (here the coral growth) tween the node and the source and sink nodes. This has the or the background (everything else). Elements of the raw effect of making nodes with similar colors to the foreground point cloud that correspond to the foreground volume were then used to construct a textured mesh surface using the be used to overcome many of these difficulties. Results from Marching Cubes algorithm. The resulting segmented coral land-based experiments demonstrate the accuracy of our growth is shown in Figure 6(c)-(d ", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Marching cubes: A high resolution 3d surface construction algorithm", "authors": [{"first": "W", "middle": ["E"], "last": "Lorenson", "suffix": ""}, {"first": "H", "middle": ["E"], "last": "Cline", "suffix": ""}], "year": "", "venue": "Proceedings of the 14th Annual", "link": "58296097"}, "BIBREF1": {"title": "A visual language for robot control Conference on Computer Graphics and Interactive Techniques, 1987, and programming: a human-interface study", "authors": [{"first": "G", "middle": [], "last": "Dudek", "suffix": ""}, {"first": "J", "middle": [], "last": "Sattar", "suffix": ""}, {"first": "A", "middle": [], "last": "Xu", "suffix": ""}], "year": "", "venue": "IEEEICRA", "link": null}, "BIBREF2": {"title": "Lazy snapping", "authors": [{"first": "J", "middle": [], "last": "Li", "suffix": ""}, {"first": "C", "middle": [], "last": "Sun", "suffix": ""}, {"first": "H", "middle": [], "last": "Tang", "suffix": ""}, {"first": "", "middle": [], "last": "Shum", "suffix": ""}], "year": "", "venue": "", "link": "53235845"}, "BIBREF3": {"title": "smoothly degradable fiducial markers for use m human-robot interac", "authors": [{"first": "J", "middle": [], "last": "Sattar", "suffix": ""}, {"first": "E", "middle": [], "last": "Bourque", "suffix": ""}, {"first": "P", "middle": [], "last": "Giguere", "suffix": ""}, {"first": "G", "middle": [], "last": "Dudek", "suffix": ""}], "year": 2000, "venue": "Proc. Canadian Conference on Computer and", "link": null}, "BIBREF6": {"title": "Swanson, and of min-cut/max-flow algorithms for energy minimization in", "authors": [{"first": "R", "middle": ["B"], "last": "Aronson", "suffix": ""}, {"first": "P", "middle": ["J"], "last": "Edmunds", "suffix": ""}, {"first": "W", "middle": ["F"], "last": "Precht", "suffix": ""}, {"first": "D", "middle": ["W"], "last": "", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF7": {"title": "Large-scale, long-term monitoring of Carribean coral vision", "authors": [{"first": "D", "middle": ["R"], "last": "Levitan", "suffix": ""}], "year": 1994, "venue": "Energy Minimization Methods in Computer Vision reefs: simple, quick, inexpensive techniques", "link": null}, "BIBREF8": {"title": "Underwater 3D Floridian reef coral populations", "authors": [{"first": "J", "middle": ["W"], "last": "Porter", "suffix": ""}, {"first": ".", "middle": ["W"], "last": "Meier", "suffix": ""}, {"first": "; J", "middle": [], "last": "Saez", "suffix": ""}, {"first": "A", "middle": [], "last": "Hogue", "suffix": ""}, {"first": "F", "middle": [], "last": "Escolano", "suffix": ""}, {"first": "M", "middle": [], "last": "Jenkin", "suffix": ""}], "year": "", "venue": "IEEE International Confer-1992. ence on Robotics and Automation (ICRA)", "link": null}, "BIBREF9": {"title": "On the Representation and Estimation Press", "authors": [{"first": "R", "middle": [], "last": "Smith", "suffix": ""}, {"first": "P", "middle": [], "last": "Cheeseman", "suffix": ""}], "year": 2006, "venue": "", "link": null}, "BIBREF11": {"title": "Estimating uncertain spatial relationships in robotics", "authors": [{"first": "R", "middle": [], "last": "Smith", "suffix": ""}, {"first": "M", "middle": [], "last": "Self", "suffix": ""}, {"first": "P", "middle": [], "last": "Cheeseman", "suffix": ""}], "year": 1990, "venue": "", "link": "61822657"}, "BIBREF12": {"title": "Closed form solutions to the multiple platform simultaneous localisation and map building (SLAM) problem", "authors": [{"first": "E", "middle": [], "last": "Nettleton", "suffix": ""}, {"first": "P", "middle": [], "last": "Gibbens", "suffix": ""}, {"first": "H", "middle": [], "last": "Durrant-Whyte", "suffix": ""}], "year": 2000, "venue": "Sensor Fusion: Architectures, Algorithms,and Applications IV, B. Dasarathy", "link": "121662996"}, "BIBREF13": {"title": "FastSLAM 2.0: An Improved Particle Filtering Algorithm for Simultaneous Localization and Mapping that Provably Converges", "authors": [{"first": "M", "middle": [], "last": "Montemerlo", "suffix": ""}, {"first": "S", "middle": [], "last": "Thrun", "suffix": ""}, {"first": "D", "middle": [], "last": "Koller", "suffix": ""}, {"first": "B", "middle": [], "last": "Wegbreit", "suffix": ""}], "year": 2003, "venue": "Proceedings of the 18th International Joint Conference on Artificial Intelligence (IJCAI)", "link": "7310709"}, "BIBREF14": {"title": "Exactly Sparse DelayedState Filters", "authors": [{"first": "R", "middle": [], "last": "Eustice", "suffix": ""}, {"first": "H", "middle": [], "last": "Singh", "suffix": ""}, {"first": "J", "middle": [], "last": "Leonard", "suffix": ""}], "year": 2005, "venue": "IEEE International Conference on Robotics and Automation (ICRA)", "link": null}}, "ref_entries": {"FIGREF0": {"text": "Fig. 2. AQUASENSOR V3.0. (a) Front view with underwater housing, (b) shows the sensor in use scanning a sunken barge.", "type": "figure"}, "FIGREF1": {"text": "Fig. 4. Underwater Reconstruction. (a) shows the surface reconstruction in action. The bottom two panels show the raw left and right views obtained with the binocular sensor. The upper right panel shows the image flow vectors that are used to estimate ego-motion from the optical flow information. The upper left panel shows the currently reconstructed model. (b) Shows the the recovered surface model for extended motion of the sensor. The recovered egomotion of the sensor is overlayed along with the reference coordinate frame.", "type": "figure"}, "FIGREF2": {"text": "a) shows four panels. The lower two q6 = qmuq * qt (3) panels provide the raw stereo image pair obtained with the sensor. The upper right panel shows the optical flow vectors int the estimated camera frame, that are associated with temporally stable 3D points that will q = CAM q8CAMqt 1IMUq& (4) be used to obtain a vision-based estimate of ego-motion. The upper left panel shows the recovered model up to this frame and then performing the Levenberg-Marquardt minimization of the image sequence. Figure 4(b) shows a rendering of using this new pose as the initial guess. The effect of the recovered surface structure with recovered ego-motion utilizing this information can be seen in Figure 3(b) where overlaid. The rendering is obtained from a polygon mesh the curvature has been reduced in the resulting model. extracted from the recovered point cloud using the marching", "type": "figure"}, "FIGREF3": {"text": "shows the weight calculations for each type of grid. A single node may have up to 26 internal edges if its edge in the graph. Here dF = miril (i) - and dB = corresponding voxel is completely surrounded by non-empty minm 0(i)-Km|, where Kn' represents the mean colors of voxels. the foreground clusters, KB represents the mean colors of The voxel grid is converted into a graph as follows: the background colors, and C(i) represents the color value of a given voxel. Also g(() = and Cij =C(i)-C(j)12 1) Two nodes are created that are not associated with any [24] voxels -source (foreground) and sink (background) Using a standard min-cutlmax-flow algorithm [26] all nodes.", "type": "figure"}, "FIGREF4": {"text": "The 3D lazy snapping process. (a) shows the original point cloud. (b) shows the voxel representation of space with voxels labelled as either foreground or background by the user. Note that the vast majority of the voxels are not labelled and the actual segmentation is done by the lazy snapping algorithm. (c) and (d) show the segmented coral mound segmented using 3d lazy snapping from the lower left hand view of (a) and (b).", "type": "figure"}, "TABREF0": {"text": "the intrinsic calibration parameters for the cameras are not translation required to bring rt, into accordance with rt,. perfectly known any pose error caused by miscalibration will The centroid, to, rt, of each point cloud is computed and also accumulate causing the trajectory to diverge. To reduce subtracted from the points to obtain two new point sets,", "type": "table"}, "TABREF1": {"text": "tion of 2D datasets. Here we extend this technique to 3D Terrestrial evaluations have been performed with the sen-surface meshes. As in the 2D version of Lazy Snapping the sor in order to evaluate its ability to estimate ego-motion. user provides cues to the object to be segmented merely by To acquire ground truth 3D data, we constructed a scene identifying sample foreground and background elements of with known measurements and independently tracked the the image. The system then selects those surfaces it considers camera sensor with an IS-9OOTMmotion tracking system from to be part of the object and rejects those it considers to be Intersense2 (Figure 5). Preliminary analysis suggests that the part of the background. The user can then either augment average RMS error of the sensor trajectory over a distance the set of foreground and background structures and allow of 3 metres is approximately 2cm and an error of 0.5% for the system to recompute the selection or manually adjust any the reconstructed close range 3D data. polygons which have been mis-classified. Because most of the classification is performed automatically the demand on IV. SEGMENTING LOCAL MODELS the user is greatly reduced. Although the raw data obtained with the sensor is useful A. 3D lazy snapping for a number of applications including SLAM, there exist a", "type": "table"}, "TABREF2": {"text": "Popular pixels of an dataset in 2D lazy snapping. photo sharing websites such as Flickr3 allow users who share Starting with a 3D polygon mesh or point-cloud, a voxel their photos to add labels to areas in the pictures. This representation is constructed from the input representation.Let Pijk represent the set of points that intersect voxelThese are non-empty voxels tagged by the user as being either foreground or background. The user swipes a cursor", "type": "table"}, "TABREF3": {"text": "The lack of high bandwith communications underwater to reconstruct qualitatively correct 3D models of the aquatic requires that untethered underwater robot systems exhibit a environment. The entire reconstruction system operates at high level of autonomy. This autonomy requires effective 2.7 framnes per second and produces approximately 8 million sensing and reasoning. Traditional underwater sensing de-3D points per m-inute of data. vices have relied on active sensors (sonar in particular) to The ability to obtain 3D surface models of terrestrial and recover three-dimensional environmental structure. Advances aquatic structures is an enabling technology. The models can in stereo sensing and data fusion technologies demonstrates be used for specific applications and can also be used as the that passive stereo is a sufficiently robust technology to basis of simultaneous localization and mapping, a critical be applied in the aquatic domain as well. Although the ability in the development of fully autonomous systems. underwater domain presents unique challenges to traditional By combining binocular imagery with inertial sensors it is vision algorithms, robust noise-suppression mechanisms can possible to construct reasonably large local surface models, and when placed within a SLAM formalism it is possible to [10] R. Eustice, \"Large-Area Visually Augmented Navigation for Au- use the sensor to construct surface models of extended areas tonomous Underwater Vehicles,\" Ph.D. dissertation, MIT -Woods Hole Oceanographic Institute, June 2005. and maintain an ongoing estimate of the pose of the sensor [1H] o. Pizarro, g.Ill0. izaro,R. Eustice, and H. Singh, \"Large Area 3D Reconstructions in the process (see [27]). from Underwater Surveys,\" in MTS/IEEE OCEANS Conference and Once an environmental model has been constructed, var- Exhibition, November 2004, pp. 678-687, Kobe, Japan. [12] S. Williams and I. Mahon, \"Simultaneous Localisation and Mapping iOUS techniques can be applied to the model to segment on the Great Barrier Reef,\" in IEEE International Conference on salient features from the representation. The 3D lazy snap- Robotics and Automation (ICRA), April 26-May 1 2004. ping algorithm is an assisted alternative to manual feature [13] G. Dudek, P. Giguere, C. Prahacs, S. Saunderson, J. Sattar, L. Torres, segmentationwhich has shows promise in segmenting both M. Jenkin, A. German, A. Hogue, A. Ripsman, J. Zacher, E. Milios, segmentation which has shows promise in segmenting both H. Liu, P. Zhang, M. Buehler, and C. Georgiades, \"AQUA: An terrestrial and aquatic models. Amphibious Autonomous Robot,\" IEEE Computer, vol. 40, no. 1, pp. Future plans in the underwater domain include the con- 46-53, January 2007. struction of realistic modelsofalargescaleshipwreck [14] A. Hogue, A. German, J. Zacher, and M. Jenkin, \"Underwater 3D struction of realistic models of a large scale shipwreck Mapping: Experiences and Lessons Learned,\" in Third Canadian and larger coral structures. Of particular interest here is Conference on Computer and Robot Vision (CRV), June 7-9 2006. to compare the 3D models obtained using the sensor with [15] J. Shi and C. Tomasi, \"Good Features to Track,\" in IEEE Computer tocomparethemodels obtainedbymarinebiologis using tr sona . th Society Conference on Computer Vision and Pattern Recognition models obtained by marine biologists using traditional tech- (CVPR), Jun. 21-23 1994, pp. 593 -600. niques. We are also examining the use of the sensor and [16] B. Lucas and T. Kanade, \"An Iterative Image Registration Technique segmentation algorithm in a range of terrestrial applications. with an Application to Stereo Vision,\" in International Joint Confer- ence on Artificial Intelligence (IJCAI), 1981, pp. 67'679.sensing system described in this paper Is part of [I7] M. Fischler and R. Bolles, \"Random sample consensus: A paradigm the AQUA robot sensor package and can also be used as for model fitting with application to image analysis and automated a standalone single-diver-deployable sensor for coral reef cartography,\" Communications of the ACM, vol. 24, no. 6, pp. 381- analysi. Futur work icludes mbeddin the tehnology 385, 1981. analysis. Future work includes embedding the technlology [18] B. Horn, \"Closed-form solution of absolute orientaiton using unit within the robot housing and developing a more robust quatemions,\" AI Magazine, vol. A, no. 4, p. 629, April 1987. SLAM algorithm that incorporates large loop-closing to [19] W. Press, S. Teukolsky, W. Vetterling, and B. Flannery, Numerical further reduce the pose error over long distances. [20] Recipes in C. Cambridge University Press, 2002.", "type": "table"}}}
{"paper_id": "17433466", "_pdf_hash": "801e412335dd76187be3b5ba52d88deeea94c710", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Phytoremediation of toxic metals: using plants to clean up the environment", "authors": [{"first": "C", "middle": ["S"], "last": "Cobbett", "suffix": ""}, {"first": "P", "middle": ["B"], "last": "Goldsbrough", "suffix": ""}], "year": 2000, "venue": "", "link": "82084117"}, "BIBREF1": {"title": "Toxic metal accumulation, responses to exposure and mechanisms of tolerance in plants", "authors": [{"first": "S", "middle": [], "last": "Clemens", "suffix": ""}], "year": 2006, "venue": "Biochimie", "link": "9330355"}, "BIBREF2": {"title": "Role of hyperaccumulators in phytoextraction of metals from contaminated mining sites: a review", "authors": [{"first": "V", "middle": [], "last": "Sheoran", "suffix": ""}, {"first": "A", "middle": ["S"], "last": "Sheoran", "suffix": ""}, {"first": "P", "middle": [], "last": "Poonia", "suffix": ""}], "year": 2011, "venue": "Crit Rev Environ Sci Technol", "link": "108689339"}, "BIBREF3": {"title": "Cellular mechanisms for heavy metal detoxification and tolerance", "authors": [{"first": "J", "middle": ["L"], "last": "Hall", "suffix": ""}], "year": 2002, "venue": "J Exp Bot", "link": "12040503"}, "BIBREF4": {"title": "Phytochelatins and metallothioneins: roles in heavy metal detoxification and homeostasis", "authors": [{"first": "C", "middle": [], "last": "Cobbett", "suffix": ""}, {"first": "P", "middle": [], "last": "Goldsbrough", "suffix": ""}], "year": 2002, "venue": "Annu Rev Plant Biol", "link": "7172950"}, "BIBREF5": {"title": "Characterization of the Arabidopsis metallothionein gene family: tissue-specific expression and induction during senescence and in response to copper", "authors": [{"first": "W", "middle": ["J"], "last": "Guo", "suffix": ""}, {"first": "W", "middle": [], "last": "Bundithya", "suffix": ""}, {"first": "P", "middle": ["B"], "last": "Goldsbrough", "suffix": ""}], "year": 2003, "venue": "New Phytol", "link": "86415457"}, "BIBREF6": {"title": "Plant metallothionein domains: functional insight into physiological metal binding and protein folding", "authors": [{"first": "J", "middle": [], "last": "Dom\u00e8nech", "suffix": ""}, {"first": "G", "middle": [], "last": "Mir", "suffix": ""}, {"first": "G", "middle": [], "last": "Huguet", "suffix": ""}, {"first": "M", "middle": [], "last": "Capdevila", "suffix": ""}, {"first": "M", "middle": [], "last": "Molinas", "suffix": ""}], "year": 2006, "venue": "Biochimie", "link": "307429"}, "BIBREF7": {"title": "The Cd(II)-binding abilities of recombinant Quercus suber metallothionein, QsMT: bridging the gap between phytochelatins and metallothioneins", "authors": [{"first": "J", "middle": [], "last": "Domenech", "suffix": ""}, {"first": "R", "middle": [], "last": "Orihuela", "suffix": ""}, {"first": "G", "middle": [], "last": "Mir", "suffix": ""}, {"first": "M", "middle": [], "last": "Molinas", "suffix": ""}, {"first": "S", "middle": [], "last": "Atrian", "suffix": ""}], "year": 2007, "venue": "J Biol Inorg Chem", "link": null}, "BIBREF8": {"title": "Coordinated responses of phytochelatin synthase and metallothionein genes in black mangrove, Avicennia germinans, exposed to cadmium and copper", "authors": [{"first": "D", "middle": [], "last": "Gonzalez-Mendoza", "suffix": ""}, {"first": "A", "middle": ["Q"], "last": "Moreno", "suffix": ""}, {"first": "O", "middle": [], "last": "Zapata-Perez", "suffix": ""}], "year": 2007, "venue": "Aquat Toxicol", "link": "33664316"}, "BIBREF9": {"title": "Phytostabilization of nickel by the zinc and cadmium hyperaccumulator Solanum nigrum L. Are metallothioneins involved?", "authors": [{"first": "P", "middle": [], "last": "Ferraz", "suffix": ""}, {"first": "F", "middle": [], "last": "Fidalgo", "suffix": ""}, {"first": "A", "middle": [], "last": "Almeida", "suffix": ""}, {"first": "J", "middle": [], "last": "Teixeira", "suffix": ""}], "year": 2012, "venue": "Plant Physiol Biochem", "link": "44337616"}, "BIBREF10": {"title": "Zn-and Cu-thioneins: A functional classification for metallothioneins?", "authors": [{"first": "O", "middle": [], "last": "Palacios", "suffix": ""}, {"first": "S", "middle": [], "last": "Atrian", "suffix": ""}, {"first": "M", "middle": [], "last": "Capdevila", "suffix": ""}], "year": 2011, "venue": "J Biol Inorg Chem", "link": "26786966"}, "BIBREF11": {"title": "Research progress on metallothioneins: insights into structure, metal binding properties and molecular function by spectroscopic investigations", "authors": [{"first": "J", "middle": [], "last": "Domenech", "suffix": ""}, {"first": "A", "middle": [], "last": "Tinti", "suffix": ""}, {"first": "A", "middle": [], "last": "Torreggiani", "suffix": ""}], "year": 2007, "venue": "Nemeth TS", "link": "103347944"}, "BIBREF12": {"title": "Functional homologs of fungal metallothionein genes from Arabidopsis", "authors": [{"first": "J", "middle": [], "last": "Zhou", "suffix": ""}, {"first": "P", "middle": ["B"], "last": "Goldsbrough", "suffix": ""}], "year": 1994, "venue": "Plant Cell", "link": "22748915"}, "BIBREF13": {"title": "Plant metallothioneins", "authors": [{"first": "N", "middle": ["J"], "last": "Robinson", "suffix": ""}, {"first": "A", "middle": ["M"], "last": "Tommey", "suffix": ""}, {"first": "C", "middle": [], "last": "Kuske", "suffix": ""}, {"first": "P", "middle": ["J"], "last": "Jackson", "suffix": ""}], "year": 1993, "venue": "J Biochem", "link": "30398613"}, "BIBREF14": {"title": "Plant MTs-long neglected members of the metallothionein superfamily", "authors": [{"first": "E", "middle": [], "last": "Freisinger", "suffix": ""}], "year": 2008, "venue": "Dalton Trans", "link": "9043212"}, "BIBREF15": {"title": "Metallothionein in plants", "authors": [{"first": "E", "middle": [], "last": "Freisinger", "suffix": ""}], "year": 2009, "venue": "Met Ions Life Sci", "link": null}, "BIBREF16": {"title": "Structural features specific to plant metallothioneins", "authors": [{"first": "E", "middle": [], "last": "Freisinger", "suffix": ""}], "year": 2011, "venue": "J Biol Inorg Chem", "link": "24200835"}, "BIBREF17": {"title": "Structure, organization and expression of the metallothionein gene family in Arabidopsis", "authors": [{"first": "J", "middle": [], "last": "Zhou", "suffix": ""}, {"first": "P", "middle": ["B"], "last": "Goldsbrough", "suffix": ""}], "year": 1995, "venue": "Mol Gen Genet", "link": "6514117"}, "BIBREF18": {"title": "Molecular analyses of the metallothionein gene family in rice", "authors": [{"first": "G", "middle": [], "last": "Zhou", "suffix": ""}, {"first": "Y", "middle": [], "last": "Xu", "suffix": ""}, {"first": "J", "middle": [], "last": "Li", "suffix": ""}, {"first": "L", "middle": [], "last": "Yang", "suffix": ""}, {"first": "J", "middle": ["Y"], "last": "Liu", "suffix": ""}], "year": 2006, "venue": "Oryza sativa L.). J Biochem Mol Biol", "link": null}, "BIBREF19": {"title": "The isolation and characterization of type1 metallothionein (MT) cDNA from a heavy-metal-tolerant plant Festuca rubra cv", "authors": [{"first": "M", "middle": [], "last": "Ma", "suffix": ""}, {"first": "P", "middle": ["S"], "last": "Lau", "suffix": ""}, {"first": "Y", "middle": ["T"], "last": "Jia", "suffix": ""}, {"first": "W", "middle": ["K"], "last": "Tsang", "suffix": ""}, {"first": "Sks", "middle": [], "last": "Lam", "suffix": ""}], "year": 2003, "venue": "Merlin. Plant Sci", "link": "84355241"}, "BIBREF20": {"title": "OsMT1a, a type 1 metallothionein, plays the pivotal role in zinc homeostasis and drought tolerance in rice", "authors": [{"first": "Z", "middle": [], "last": "Yang", "suffix": ""}, {"first": "Y", "middle": ["R"], "last": "Wu", "suffix": ""}, {"first": "Y", "middle": [], "last": "Li", "suffix": ""}, {"first": "H", "middle": ["Q"], "last": "Ling", "suffix": ""}, {"first": "C", "middle": [], "last": "Chu", "suffix": ""}], "year": 2009, "venue": "Plant Mol Biol", "link": "21296497"}, "BIBREF21": {"title": "A plant type 2 MT from cork tissue responds to oxidative stress", "authors": [{"first": "G", "middle": [], "last": "Mir", "suffix": ""}, {"first": "J", "middle": [], "last": "Dom\u00e8nech", "suffix": ""}, {"first": "G", "middle": [], "last": "Huguet", "suffix": ""}, {"first": "W", "middle": ["J"], "last": "Guo", "suffix": ""}, {"first": "P", "middle": [], "last": "Goldsbrough", "suffix": ""}], "year": 2004, "venue": "J Exp Bot", "link": null}, "BIBREF22": {"title": "Expression of BjMT2, a metallothionein 2 from Brassica juncea, increases copper and cadmium tolerance in Escherichia coli and Arabidopsis thaliana, but inhibits root elongation in Arabidopsis thaliana seedlings", "authors": [{"first": "A", "middle": [], "last": "Zhigang", "suffix": ""}, {"first": "L", "middle": [], "last": "Cuijie", "suffix": ""}, {"first": "Z", "middle": [], "last": "Yuangang", "suffix": ""}, {"first": "D", "middle": [], "last": "Yejie", "suffix": ""}, {"first": "A", "middle": [], "last": "Wachter", "suffix": ""}], "year": 2006, "venue": "J Exp Bot", "link": "17186104"}, "BIBREF23": {"title": "Expression pattern of a type-2 metallothionein gene in a wild population of the psammophyte Silene nicaeensis", "authors": [{"first": "R", "middle": [], "last": "Cozza", "suffix": ""}, {"first": "L", "middle": [], "last": "Bruno", "suffix": ""}, {"first": "M", "middle": ["B"], "last": "Bitonti", "suffix": ""}], "year": 2012, "venue": "Protoplasma", "link": "12907582"}, "BIBREF24": {"title": "A novel metallothionein gene from a mangrove plant Kandelia candel", "authors": [{"first": "F", "middle": ["Q"], "last": "Zhang", "suffix": ""}, {"first": "Y", "middle": ["S"], "last": "Wang", "suffix": ""}, {"first": "C", "middle": ["C"], "last": "Sun", "suffix": ""}, {"first": "Z", "middle": ["P"], "last": "Lou", "suffix": ""}, {"first": "J", "middle": ["D"], "last": "Dong", "suffix": ""}], "year": 2012, "venue": "Ecotoxicology", "link": "207119651"}, "BIBREF25": {"title": "Plant metallothionein domains: functional insight into physiological metal binding and protein folding", "authors": [{"first": "J", "middle": [], "last": "Domenech", "suffix": ""}, {"first": "G", "middle": [], "last": "Mir", "suffix": ""}, {"first": "G", "middle": [], "last": "Huguet", "suffix": ""}, {"first": "M", "middle": [], "last": "Capdevila", "suffix": ""}, {"first": "M", "middle": [], "last": "Molinas", "suffix": ""}, {"first": "S", "middle": [], "last": "Atrian", "suffix": ""}], "year": 2005, "venue": "Biochimie", "link": "307429"}, "BIBREF26": {"title": "Structural study of the zinc and cadmium complexes of a type 2 plant (Quercus suber) metallothionein: insights by vibrational spectroscopy", "authors": [{"first": "J", "middle": [], "last": "Domenech", "suffix": ""}, {"first": "A", "middle": [], "last": "Tinti", "suffix": ""}, {"first": "M", "middle": [], "last": "Capdevila", "suffix": ""}, {"first": "S", "middle": [], "last": "Atrian", "suffix": ""}, {"first": "A", "middle": [], "last": "Torreggiani", "suffix": ""}], "year": 2007, "venue": "Biopolymers", "link": "34938762"}, "BIBREF27": {"title": "The plant metallothionein 2 from Cicer arietinum forms a single metal-thiolate cluster", "authors": [{"first": "X", "middle": [], "last": "Wan", "suffix": ""}, {"first": "E", "middle": [], "last": "Freisinger", "suffix": ""}], "year": 2009, "venue": "Metallomics", "link": "23987366"}, "BIBREF28": {"title": "Characterization of cDNA encoding metallothionein 3 from cotton (Gossypium hirsutum L.)", "authors": [{"first": "R", "middle": ["H"], "last": "Jordan", "suffix": ""}, {"first": "R", "middle": ["B"], "last": "Turley", "suffix": ""}, {"first": "S", "middle": ["L"], "last": "Defauw", "suffix": ""}, {"first": "M", "middle": [], "last": "Steele", "suffix": ""}], "year": 2005, "venue": "DNA Seq", "link": "23400868"}, "BIBREF29": {"title": "Spectroscopic characterization of a fruitspecific metallothionein: M. acuminata MT3", "authors": [{"first": "E", "middle": [], "last": "Freisinger", "suffix": ""}], "year": 2006, "venue": "Inorgan Chim Acta", "link": "84519936"}, "BIBREF30": {"title": "Expression of the seed-specific metallothionein mt4a in plant vegetative tissues increases Cu and Zn tolerance", "authors": [{"first": "", "middle": [], "last": "Rodr\u00edguez-Llorente", "suffix": ""}, {"first": "", "middle": [], "last": "Id", "suffix": ""}, {"first": "P", "middle": [], "last": "P\u00e9rez-Palacios", "suffix": ""}, {"first": "B", "middle": [], "last": "Doukkali", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Caviedes", "suffix": ""}, {"first": "E", "middle": [], "last": "Pajuelo", "suffix": ""}], "year": 2010, "venue": "Plant Sci", "link": null}, "BIBREF31": {"title": "Characteristic and expression analysis of a metallothionein gene, OsMT2b, downregulated by cytokinin suggests functions in root development and seed embryo germination of rice", "authors": [{"first": "J", "middle": [], "last": "Yuan", "suffix": ""}, {"first": "D", "middle": [], "last": "Chen", "suffix": ""}, {"first": "Y", "middle": [], "last": "Ren", "suffix": ""}, {"first": "X", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "J", "middle": [], "last": "Zhao", "suffix": ""}], "year": 2008, "venue": "J Plant Physiol", "link": "13399401"}, "BIBREF32": {"title": "Arabidopsis metallothioneins 2a and 3 enhance resistance to cadmium when expressed in Vicia faba guard cells", "authors": [{"first": "J", "middle": [], "last": "Lee", "suffix": ""}, {"first": "D", "middle": [], "last": "Shim", "suffix": ""}, {"first": "W", "middle": ["Y"], "last": "Song", "suffix": ""}, {"first": "I", "middle": [], "last": "Hwang", "suffix": ""}, {"first": "Y", "middle": [], "last": "Lee", "suffix": ""}], "year": 2004, "venue": "Plant Mol Biol", "link": "31965739"}, "BIBREF33": {"title": "Clustered metallothionein genes are co-regulated in rice and ectopic expression of OsMT1e-P confers multiple abiotic stress tolerance in tobacco via ROS scavenging", "authors": [{"first": "G", "middle": [], "last": "Kumar", "suffix": ""}, {"first": "H", "middle": ["R"], "last": "Kushwaha", "suffix": ""}, {"first": "V", "middle": ["P"], "last": "Sabharwal", "suffix": ""}], "year": 2012, "venue": "BMC Plant Biol", "link": "16389701"}, "BIBREF34": {"title": "Correlation of foliar MT2b expression with Cd and Zn concentrations in hybrid aspen (Populus tremula 9 tremloides) grown in contaminated soil", "authors": [{"first": "V", "middle": [], "last": "Hassinen", "suffix": ""}, {"first": "V", "middle": ["M"], "last": "Vallinkoski", "suffix": ""}, {"first": "S", "middle": [], "last": "Issakainen", "suffix": ""}, {"first": "A", "middle": [], "last": "Tervahauta", "suffix": ""}, {"first": "S", "middle": [], "last": "Karenlampi", "suffix": ""}, {"first": "K", "middle": [], "last": "Servomaa", "suffix": ""}], "year": 2009, "venue": "Environ Poll", "link": "32423313"}, "BIBREF35": {"title": "Metallothionein 2 and 3 contribute to the metal adapted phenotype but are not directly linked to Zn accumulation in the metal hyperaccumulator, Thlapsi caerulescens", "authors": [{"first": "V", "middle": ["H"], "last": "Hassinen", "suffix": ""}, {"first": "T", "middle": [], "last": "Tuomainen", "suffix": ""}, {"first": "S", "middle": [], "last": "Peraniemi", "suffix": ""}, {"first": "S", "middle": ["O"], "last": "Karenlampi", "suffix": ""}, {"first": "A", "middle": ["I"], "last": "Tervahauta", "suffix": ""}], "year": 2009, "venue": "J Exp Bot", "link": null}, "BIBREF36": {"title": "Plant metallothioneins-metal chelators with ROS scavenging activity?", "authors": [{"first": "V", "middle": ["H"], "last": "Hassinen", "suffix": ""}, {"first": "A", "middle": ["I"], "last": "Tervahauta", "suffix": ""}, {"first": "H", "middle": [], "last": "Schat", "suffix": ""}, {"first": "S", "middle": ["O"], "last": "Karenlampi", "suffix": ""}], "year": 2011, "venue": "Plant Biol", "link": "32908097"}, "BIBREF37": {"title": "Potent hydroxyl radical scavenging activity of drought-induced type-2 metallothionein in wild watermelon", "authors": [{"first": "K", "middle": [], "last": "Akashi", "suffix": ""}, {"first": "N", "middle": [], "last": "Nishimura", "suffix": ""}, {"first": "Y", "middle": [], "last": "Ishida", "suffix": ""}, {"first": "A", "middle": [], "last": "Yokota", "suffix": ""}], "year": 2004, "venue": "Biochem Biophys Res Commun", "link": "45325665"}, "BIBREF38": {"title": "Arabidopsis thaliana metallothionein, AtMT2a, mediates ROS balance during oxidative stress", "authors": [{"first": "W", "middle": [], "last": "Zhu", "suffix": ""}, {"first": "D", "middle": ["X"], "last": "Zhao", "suffix": ""}, {"first": "Q", "middle": [], "last": "Miao", "suffix": ""}, {"first": "T", "middle": ["T"], "last": "Xue", "suffix": ""}, {"first": "X", "middle": ["Z"], "last": "Li", "suffix": ""}, {"first": "C", "middle": [], "last": "Zheng", "suffix": ""}], "year": 2009, "venue": "J Plant Biol", "link": "34153761"}, "BIBREF39": {"title": "Tamarix hispida metallothionein-like ThMT3, a reactive oxygen species scavenger, increases tolerance against Cd2?, Zn2?, Cu2? and NaCl in transgenic yeast", "authors": [{"first": "J", "middle": [], "last": "Yang", "suffix": ""}, {"first": "Y", "middle": [], "last": "Wang", "suffix": ""}, {"first": "G", "middle": [], "last": "Liu", "suffix": ""}, {"first": "C", "middle": [], "last": "Yang", "suffix": ""}, {"first": "C", "middle": [], "last": "Li", "suffix": ""}], "year": 2011, "venue": "Mol Biol Rep", "link": "9822904"}, "BIBREF40": {"title": "Yeast functional screen to identify genetic determinants capable of conferring abiotic stress tolerance in Jatropha curcas", "authors": [{"first": "N", "middle": [], "last": "Eswaran", "suffix": ""}, {"first": "S", "middle": [], "last": "Parameswaran", "suffix": ""}, {"first": "B", "middle": [], "last": "Sathram", "suffix": ""}, {"first": "B", "middle": [], "last": "Anantharaman", "suffix": ""}, {"first": "Kkg", "middle": [], "last": "Raja", "suffix": ""}], "year": 2010, "venue": "BMC Biotechnol", "link": "17425934"}, "BIBREF41": {"title": "Bioaccumulation and phyto-translocation of arsenic, chromium and zinc by Jatropha curcas L.: impact of dairy sludge and bio fertilizer", "authors": [{"first": "S", "middle": ["K"], "last": "Yadav", "suffix": ""}, {"first": "A", "middle": ["A"], "last": "Juwarkar", "suffix": ""}, {"first": "K", "middle": ["G"], "last": "Phani", "suffix": ""}, {"first": "P", "middle": ["R"], "last": "Thawale", "suffix": ""}, {"first": "S", "middle": ["K"], "last": "Singh", "suffix": ""}], "year": 2009, "venue": "Bioresour Technol", "link": null}, "BIBREF42": {"title": "Effects of copper on growth, antioxidant enzymes and phenylalanine ammonia-lyase activities in Jatropha curcas L. seedling", "authors": [{"first": "S", "middle": [], "last": "Gao", "suffix": ""}, {"first": "R", "middle": [], "last": "Yan", "suffix": ""}, {"first": "M", "middle": [], "last": "Cao", "suffix": ""}, {"first": "W", "middle": [], "last": "Yang", "suffix": ""}, {"first": "S", "middle": [], "last": "Wang", "suffix": ""}, {"first": "F", "middle": [], "last": "Chen", "suffix": ""}], "year": 2008, "venue": "Plant Soil Environ", "link": null}, "BIBREF43": {"title": "Nickel toxicity induced antioxidant enzyme and phenylalanine ammonia-lyase activities in Jatropha curcas L. cotyledons", "authors": [{"first": "R", "middle": [], "last": "Yan", "suffix": ""}, {"first": "S", "middle": [], "last": "Gao", "suffix": ""}, {"first": "W", "middle": [], "last": "Yang", "suffix": ""}, {"first": "M", "middle": [], "last": "Cao", "suffix": ""}, {"first": "S", "middle": [], "last": "Wang", "suffix": ""}], "year": 2008, "venue": "Plant Soil Environ", "link": "53319538"}, "BIBREF44": {"title": "Jatropha curcas L. for phytoremediation of lead and cadmium polluted soil", "authors": [{"first": "S", "middle": [], "last": "Mangkoedihardjo", "suffix": ""}, {"first": "A", "middle": [], "last": "Surahmaida", "suffix": ""}], "year": 2008, "venue": "World Appl Sci J", "link": "16417667"}, "BIBREF45": {"title": "Phytoremediation of soil contaminated with used lubricating oil using Jatropha curcas", "authors": [{"first": "P", "middle": [], "last": "Agamutu", "suffix": ""}, {"first": "O", "middle": ["P"], "last": "Abioye", "suffix": ""}, {"first": "A", "middle": ["A"], "last": "Aziz", "suffix": ""}], "year": 2010, "venue": "J Hazard Mater", "link": "20929688"}, "BIBREF46": {"title": "CLUSTALW: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice", "authors": [{"first": "J", "middle": ["D"], "last": "Thompson", "suffix": ""}, {"first": "D", "middle": ["G"], "last": "Higgins", "suffix": ""}, {"first": "T", "middle": ["J"], "last": "Gibson", "suffix": ""}], "year": 1994, "venue": "Nucleic Acids Res", "link": "7260461"}, "BIBREF48": {"title": "Superoxide dismutase activity is essential for stationary phase survival in Sacchraromyces cerevisiae", "authors": [{"first": "V", "middle": ["D"], "last": "Longo", "suffix": ""}, {"first": "E", "middle": ["B"], "last": "Gralla", "suffix": ""}, {"first": "J", "middle": ["S"], "last": "Valentine", "suffix": ""}], "year": 1996, "venue": "J Biol Chem", "link": "82686881"}, "BIBREF49": {"title": "Analysis of relative gene expression data using real time quantitative PCR and the 2 -DDCT method", "authors": [{"first": "K", "middle": ["J"], "last": "Livak", "suffix": ""}, {"first": "T", "middle": ["D"], "last": "Schmittgen", "suffix": ""}], "year": 2001, "venue": "Methods", "link": null}, "BIBREF50": {"title": "YAP1 dependent activation of TRX2 is essential for the response of Saccharomyces cerevisiae to oxidative stress by hydroperoxides", "authors": [{"first": "S", "middle": [], "last": "Kuge", "suffix": ""}, {"first": "N", "middle": [], "last": "Jones", "suffix": ""}], "year": 1994, "venue": "EMBO J", "link": "11078250"}, "BIBREF51": {"title": "Function and auto regulation of yeast copperthionein", "authors": [{"first": "D", "middle": ["H"], "last": "Hamer", "suffix": ""}, {"first": "D", "middle": ["J"], "last": "Thiele", "suffix": ""}, {"first": "J", "middle": ["E"], "last": "Lemontt", "suffix": ""}], "year": 1985, "venue": "Science", "link": null}, "BIBREF52": {"title": "Heavy metal and abiotic stress inducible metallothionein isoforms from Prosopis juliflora (SW) D.C. show differences in binding to heavy metals in vitro", "authors": [{"first": "B", "middle": [], "last": "Usha", "suffix": ""}, {"first": "G", "middle": [], "last": "Venkataraman", "suffix": ""}, {"first": "A", "middle": [], "last": "Parida", "suffix": ""}], "year": 2009, "venue": "Mol Genet Genomics", "link": "36030493"}, "BIBREF53": {"title": "Characterization of a rice class II metallothionein gene: tissue expression patterns and induction in response to abiotic factors", "authors": [{"first": "G", "middle": ["K"], "last": "Zhou", "suffix": ""}, {"first": "Y", "middle": ["F"], "last": "Xu", "suffix": ""}, {"first": "J", "middle": ["Y"], "last": "Liu", "suffix": ""}], "year": 2005, "venue": "J Plant Physiol", "link": "25590619"}, "BIBREF54": {"title": "Metallothionein-like gene from Cicer microphyllumis regulated by multiple abiotic stresses", "authors": [{"first": "K", "middle": ["S"], "last": "Rupesh", "suffix": ""}, {"first": "A", "middle": [], "last": "Sivalingam", "suffix": ""}, {"first": "S", "middle": [], "last": "Shweta", "suffix": ""}, {"first": "Y", "middle": ["P"], "last": "Vikas", "suffix": ""}, {"first": "A", "middle": [], "last": "Zakwan", "suffix": ""}], "year": 2011, "venue": "Protoplasma", "link": "12801492"}, "BIBREF55": {"title": "Promoter structure and activity of type I rice metallothionein-like gene", "authors": [{"first": "H", "middle": ["M"], "last": "Hsieh", "suffix": ""}, {"first": "P", "middle": ["C"], "last": "Huang", "suffix": ""}], "year": 1998, "venue": "Mitochondrial DNA", "link": null}, "BIBREF56": {"title": "The b E -domain of wheat E c -1 metallothionein: a metal-binding domain with a distinctive structure", "authors": [{"first": "E", "middle": ["A"], "last": "Peroza", "suffix": ""}, {"first": "Schmucki", "middle": [], "last": "Guntert", "suffix": ""}, {"first": "P", "middle": [], "last": "Freisinger", "suffix": ""}, {"first": "E", "middle": [], "last": "Zerbe", "suffix": ""}, {"first": "O", "middle": [], "last": "", "suffix": ""}], "year": 2009, "venue": "J Mol Biol", "link": null}, "BIBREF57": {"title": "The two distinctive metal ion binding domains of the wheat metallothionein E c -1", "authors": [{"first": "E", "middle": ["A"], "last": "Peroza", "suffix": ""}, {"first": "A", "middle": ["A"], "last": "Kaabi", "suffix": ""}, {"first": "W", "middle": [], "last": "Meyer-Klaucke", "suffix": ""}, {"first": "G", "middle": [], "last": "Wellenreuther", "suffix": ""}, {"first": "E", "middle": [], "last": "Freisinger", "suffix": ""}], "year": 2009, "venue": "J Inorg Biochem", "link": "22662953"}, "BIBREF58": {"title": "Protein and metal cluster structure of the wheat metallothionein domain c-E c -1: the second part of the puzzle", "authors": [{"first": "J", "middle": [], "last": "Loebus", "suffix": ""}, {"first": "E", "middle": ["A"], "last": "Peroza", "suffix": ""}, {"first": "N", "middle": [], "last": "Bluthgen", "suffix": ""}], "year": 2011, "venue": "J Biol Inorg Chem", "link": null}, "BIBREF59": {"title": "Metallothionein 1 (CcMT1) of pigeonpea (Cajanus cajan L.) confers enhanced tolerance to copper and cadmium in Escherichia coli and Arabidopsis thaliana", "authors": [{"first": "K", "middle": [], "last": "Sekhar", "suffix": ""}, {"first": "B", "middle": [], "last": "Priyanka", "suffix": ""}, {"first": "V", "middle": ["D"], "last": "Reddy", "suffix": ""}, {"first": "K", "middle": ["V"], "last": "Rao", "suffix": ""}], "year": 2011, "venue": "Environ Exp Bot", "link": null}, "BIBREF60": {"title": "Cloning and transcript analysis of type 2 metallothionein gene (SbMT-2) from extreme halophyte Salicornia brachiata and its heterologous expression in E. coli", "authors": [{"first": "A", "middle": ["K"], "last": "Chaturvedi", "suffix": ""}, {"first": "A", "middle": [], "last": "Mishra", "suffix": ""}, {"first": "V", "middle": [], "last": "Tiwari", "suffix": ""}, {"first": "B", "middle": [], "last": "Jha", "suffix": ""}], "year": 2012, "venue": "Gene", "link": "25002690"}, "BIBREF61": {"title": "Examining the specific contributions of individual Arabidopsis metallothioneins to copper distribution and metal tolerance", "authors": [{"first": "G", "middle": ["J"], "last": "Guo", "suffix": ""}, {"first": "M", "middle": [], "last": "Meetam", "suffix": ""}, {"first": "P", "middle": ["B"], "last": "Goldsbrough", "suffix": ""}], "year": 2008, "venue": "Plant Physiol", "link": "8310142"}, "BIBREF62": {"title": "Cloning and characterization of type 2 metallothionein-like gene from a wetland plant Typha latifolia", "authors": [{"first": "Y", "middle": ["W"], "last": "Zhang", "suffix": ""}, {"first": "Nfy", "middle": [], "last": "Tan", "suffix": ""}, {"first": "Y", "middle": ["S"], "last": "Wong", "suffix": ""}], "year": 2004, "venue": "Plant Sci", "link": null}, "BIBREF63": {"title": "Enhanced copper tolerance in Silene vulgaris (Moench) Garcke populations from copper mines is associated with increased transcript levels of a 2b-type metallothionein gene", "authors": [{"first": "Nalm", "middle": [], "last": "Van Hoof", "suffix": ""}, {"first": "V", "middle": ["H"], "last": "Hassinen", "suffix": ""}, {"first": "Hwj", "middle": [], "last": "Hakvoort", "suffix": ""}, {"first": "K", "middle": ["F"], "last": "Ballintijn", "suffix": ""}, {"first": "H", "middle": [], "last": "Schat", "suffix": ""}], "year": 2001, "venue": "Plant Physiol", "link": "15029556"}, "BIBREF64": {"title": "A metallothionein-like gene htMT2 strongly expressed in internodes and nodes of Helianthus tuberosa and effect of metal ion treatment on its expression", "authors": [{"first": "T", "middle": [], "last": "Chang", "suffix": ""}, {"first": "X", "middle": [], "last": "Liu", "suffix": ""}, {"first": "H", "middle": [], "last": "Xu", "suffix": ""}, {"first": "K", "middle": [], "last": "Meng", "suffix": ""}, {"first": "S", "middle": [], "last": "Chen", "suffix": ""}], "year": 2004, "venue": "Planta", "link": "25523961"}, "BIBREF65": {"title": "Cloning and expression of multiple metallothioneins from hybrid poplar", "authors": [{"first": "A", "middle": [], "last": "Kohler", "suffix": ""}, {"first": "D", "middle": [], "last": "Blaudez", "suffix": ""}, {"first": "M", "middle": [], "last": "Chalot", "suffix": ""}, {"first": "F", "middle": [], "last": "Martin", "suffix": ""}], "year": 2004, "venue": "New Phytol", "link": "16321893"}, "BIBREF66": {"title": "Differential expression of two metallothionein encoding genes during heavy metal stress in the mangrove species, Avicennia marina (Forsk.) Vierh", "authors": [{"first": "B", "middle": [], "last": "Usha", "suffix": ""}, {"first": "S", "middle": ["R"], "last": "Prashanth", "suffix": ""}, {"first": "A", "middle": [], "last": "Parida", "suffix": ""}], "year": 2007, "venue": "Curr Sci", "link": "89297563"}, "BIBREF67": {"title": "Biogeochemistry of trace metals and diffuse pollution in mangrove ecosystems", "authors": [{"first": "L", "middle": ["D"], "last": "Lacerda", "suffix": ""}], "year": 1998, "venue": "International Society for Mangrove Ecosystems", "link": null}, "BIBREF68": {"title": "Potential of castor bean (Ricinus communis L.) for phytoremediation of mine tailings and oil production", "authors": [{"first": "A", "middle": ["R"], "last": "Olivares", "suffix": ""}, {"first": "R", "middle": [], "last": "Carillo-Gonzalez", "suffix": ""}, {"first": "Mca", "middle": [], "last": "Gonzalez-Chavez", "suffix": ""}, {"first": "Rms", "middle": [], "last": "Hernandez", "suffix": ""}], "year": 2013, "venue": "J Environ Manag", "link": "13190236"}, "BIBREF69": {"title": "Cellular distribution of copper, lead, and zinc in the grey mangrove, Avicennia maria (Forsk.) Vierh", "authors": [{"first": "G", "middle": ["R"], "last": "Mac Farlane", "suffix": ""}, {"first": "M", "middle": ["D"], "last": "Burchett", "suffix": ""}], "year": 2000, "venue": "Aquat Bot", "link": "83664753"}, "BIBREF70": {"title": "Cadmium and copper uptake and translocation in five willow (Salix L.) species", "authors": [{"first": "Y", "middle": ["A"], "last": "Kuzovkina", "suffix": ""}, {"first": "M", "middle": [], "last": "Knee", "suffix": ""}, {"first": "M", "middle": ["F"], "last": "Quigley", "suffix": ""}], "year": 2004, "venue": "Int J Phytoremediation", "link": "31577048"}, "BIBREF71": {"title": "Subcellular localization of cadmium in roots and leaves of Arabidopsis thaliana", "authors": [{"first": "F", "middle": ["V"], "last": "Belleghem", "suffix": ""}, {"first": "A", "middle": [], "last": "Cuypers", "suffix": ""}, {"first": "B", "middle": [], "last": "Semane", "suffix": ""}, {"first": "K", "middle": [], "last": "Smeets", "suffix": ""}, {"first": "J", "middle": [], "last": "Vangronsveld", "suffix": ""}], "year": 2007, "venue": "New Phytol", "link": "26902721"}, "BIBREF72": {"title": "Anatomical element localization by EDXS in Grevillea exul var. exul under nickel stress", "authors": [{"first": "J", "middle": [], "last": "Rabier", "suffix": ""}, {"first": "I", "middle": [], "last": "Laffont-Schwob", "suffix": ""}, {"first": "R", "middle": [], "last": "Notonier", "suffix": ""}, {"first": "B", "middle": [], "last": "Fogliani", "suffix": ""}, {"first": "S", "middle": [], "last": "Boura\u00efma-Madj\u00e8bi", "suffix": ""}], "year": 2008, "venue": "Environ Pollut", "link": "26265924"}, "BIBREF73": {"title": "Approaches for enhanced phytoextraction of heavy metals", "authors": [{"first": "A", "middle": [], "last": "Bhargava", "suffix": ""}, {"first": "F", "middle": ["F"], "last": "Carmona", "suffix": ""}, {"first": "M", "middle": [], "last": "Bhargava", "suffix": ""}, {"first": "S", "middle": [], "last": "Srivastava", "suffix": ""}], "year": 2012, "venue": "J Environ Manag", "link": "24987674"}, "BIBREF74": {"title": "Accumulation of cadmium in crop plants and its consequences to human health", "authors": [{"first": "G", "middle": ["J"], "last": "Wagner", "suffix": ""}], "year": 1993, "venue": "Adv Agron", "link": "80630069"}, "BIBREF75": {"title": "Jatropha curcas: a potential crop for phytoremediation of coal fly ash", "authors": [{"first": "S", "middle": [], "last": "Jamil", "suffix": ""}, {"first": "P", "middle": ["C"], "last": "Abhilash", "suffix": ""}, {"first": "N", "middle": [], "last": "Singh", "suffix": ""}, {"first": "P", "middle": ["N"], "last": "Sharma", "suffix": ""}], "year": 2009, "venue": "J Hazard Mater", "link": "12940920"}, "BIBREF76": {"title": "Advances in metallothionein studies in forest trees", "authors": [{"first": "D", "middle": [], "last": "Jia", "suffix": ""}, {"first": "Y", "middle": [], "last": "Jing-Li", "suffix": ""}, {"first": "L", "middle": [], "last": "Cheng-Hao", "suffix": ""}], "year": 2012, "venue": "Plant Omics J", "link": null}, "BIBREF77": {"title": "Long distance root-toshoot transport of phytochelatins and cadmium in plants", "authors": [{"first": "J", "middle": ["M"], "last": "Gong", "suffix": ""}, {"first": "D", "middle": ["A"], "last": "Lee", "suffix": ""}, {"first": "J", "middle": ["I"], "last": "Schroeder", "suffix": ""}], "year": 2003, "venue": "Proc Natl Acad Sci", "link": null}}, "ref_entries": {}}
{"paper_id": "17433573", "_pdf_hash": "9c7b6545f5ee1c3657ebb281ebae6321c0d416e2", "abstract": [{"section": "Abstract", "text": "[Purpose] The effect of screen size on smartphone functionality and usability for patients with stroke, considering both the non-dominant and dominant hand smartphone usage, was investigated in this study. [Subjects and Methods] Thirteen patients with stroke participated in this study-five pre-non-dominant hand users and eight pre-dominant hand users. The smartphone screen sizes used were 4.2, 4.5, and 5.6 inches. Usability was assessed in terms of discomfort experienced during dragging operations, which was self-reported using a four-point Likert scale. Functionality was assessed in terms of completion time and the frequency of errors in the task requiring users to quickly touch numbers 0 through 9 in order on the keypad.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "[Results] For all three screen sizes, a significant difference between the dominant and non-dominant hands was found in usability, completion time, and frequency of errors. For dominant hand users, differences in usability and completion time were found among the three screen sizes. Among the three screen sizes, no difference in the frequency of errors was found in either of the groups.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "[Conclusion] This study will be useful as basic research on usability and functionality with stroke patients using only pre-non-dominant or pre-dominant hand.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "INTRODUCTION", "text": "Cell phones are a necessity in modern society. Moreover, modern smartphones are subject to customization. Smartphones allow users to easily utilize information from websites. Through participation in social networking services, important relationships can be formed 1) . As smartphone functions become more varied and complex, the number of available screen sizes has increased. Studies on the functionality and usability of smartphones [1] [2] [3] and their effects on the body 4, 5) have been conducted to address these trends.", "cite_spans": [{"start": 266, "end": 268, "text": "1)", "ref_id": "BIBREF0"}, {"start": 437, "end": 440, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 441, "end": 444, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 445, "end": 448, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 479, "end": 481, "text": "4,", "ref_id": "BIBREF3"}, {"start": 482, "end": 484, "text": "5)", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "INTRODUCTION", "text": "Many people use only one hand to operate their smartphones 6) . Three scenarios that require users to operate smartphones with one-hand have been identified by Jeon 7) ; namely, when they are carrying baggage in one hand, when they are walking, and when they cannot use two hands owing to a physical disability.", "cite_spans": [{"start": 59, "end": 61, "text": "6)", "ref_id": "BIBREF5"}, {"start": 165, "end": 167, "text": "7)", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "INTRODUCTION", "text": "Most stroke patients are afflicted with hemiparalysis; as a result, regardless of whether it is pre-dominant hand or not, these patients must only use one hand. The functionality and usability of smartphones will be different for stroke patients than for non-disabled people. In some cases, stroke patients must change their dominant hand because the side of their predominant hand is paralyzed. The aim of this study was to investigate differences in functionality and usability among three smartphone screen sizes for stroke patients who are limited to the use of one hand, and to investigate the differences in terms of smartphone usage between the pre-dominant hand and non-dominant hand.", "cite_spans": [], "ref_spans": []}, {"section": "SUBJECTS AND METHODS", "text": "The patients included in this study were those who (1) had hemiplegia following a stroke, (2) were able to understand the task and express themselves, (3) had some experience in using a cell phone, and (4) provided consent to participate in the study. This research was approved by the Institutional Review Board of Inje University.", "cite_spans": [], "ref_spans": []}, {"section": "SUBJECTS AND METHODS", "text": "Patients excluded from the study included those suffering from tremors, involuntary movements, cognitive impairment, or visual problems. Thirteen patients with stroke participated in the study. All patients were right-hand dominant before the onset of stroke. Five participants suffered from right hemiplegia and eight suffered from left hemiplegia; thus, there were eight pre-dominant hand users and five pre-non-dominant hand users (Table 1) .", "cite_spans": [], "ref_spans": [{"start": 434, "end": 443, "text": "(Table 1)", "ref_id": "TABREF0"}]}, {"section": "SUBJECTS AND METHODS", "text": "Three smartphone screen sizes-4.2, 4.5, and 5.6 inch screens-were used in this study. In a previous study 8) , these were identified as the smartphone screen sizes most often used in Korea. The smartphones in this study are listed in Table  2 . For usability testing, the prototype containing the screen sections was printed on transparencies fitted to the sizes of the smartphone screen, which were subsequently attached to the smartphones. Participants performed dragging operations along the sections, using the simplest operation among the six common input interactions 8) . The participants assessed discomfort while performing two-way drags in the sections between numbers 1-3, 5-7, 9-11, 1-9, 2-10, 3-11, 1-11 and 3-9. Data coding for left-hand users was converted to be symmetric with that of right-hand users. The discomfort was measured using a four-point Likert scale: one point indicated that the operation was extremely comfortable, two points indicated that it was easy, three points indicated discomfort, and four points indicated extreme discomfort (Fig. 1) .", "cite_spans": [{"start": 106, "end": 108, "text": "8)", "ref_id": "BIBREF7"}, {"start": 574, "end": 576, "text": "8)", "ref_id": "BIBREF7"}], "ref_spans": [{"start": 1065, "end": 1073, "text": "(Fig. 1)", "ref_id": "FIGREF0"}]}, {"section": "SUBJECTS AND METHODS", "text": "For functionality, the participants quickly touched the numbers 0 through 9 in order on the keypad, and the assessor measured the completion time and number of errors. The participants performed this task three times. The average time and frequency of errors were analyzed. The tasks and the sizes of the smartphones were randomly ordered.", "cite_spans": [], "ref_spans": []}, {"section": "SUBJECTS AND METHODS", "text": "Data analysis was conducted using SPSS 20.0 statistical software. To test homogeneity between two groups, \u03c7 2 and Mann-Whitney tests were conducted. To compare functionality and usability among the three sizes of smartphone screens, a Kruskal-Wallis test was conducted. If significant differences were noted among the three sizes, a Mann-Whitney test was conducted to separately compare the two sizes. The significant values in the Kruskal-Wallis and Mann-Whitney tests were set to 0.05 and 0.016, respectively. To compare the functionality and usability between dominant hand and non-dominant hand operations, Mann-Whitney tests were conducted. The significant value was set to 0.05. ", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS", "text": "No significant differences were noted in the general characteristics of non-dominant and dominant hand users (Table 1 ). Usability differences among the three screen sizes were not found for non-dominant hand users; however, in dominant hand users, differences were found (p<0.016) among the three screen sizes for sections 3-11, 1-11, and 2-10. Usability differences between dominant and non-dominant hand users were found in three sections of the 5.6 inch screen, four sections of the 4.5 inch screen, and six sections on the 4.2 inch screen (p<0.05) ( Table 3) .", "cite_spans": [], "ref_spans": [{"start": 109, "end": 117, "text": "(Table 1", "ref_id": "TABREF0"}, {"start": 555, "end": 563, "text": "Table 3)", "ref_id": "TABREF2"}]}, {"section": "RESULTS", "text": "No differences in completion time were found among the three screen sizes in the non-dominant hand users; however, for dominant hand users, completion time differences were found between the operations performed on the 4.2 and 5.6inch screens and between the operations performed on the 4.5 and 5.6 inch screens (p<0.016). Among the three screen sizes, no differences in frequency errors were found in both dominant and non-dominant hand users (p>0.016). Completion time differences between non-dominant and dominant hand users were found for all screen sizes (p<0.05). Significant differences in frequency of errors between non-dominant and dominant hand users were found when 4.2 and 4.5 inch screens were used (p<0.05), but not when 5.6 inch screens were used (p>0.05) ( Table 4) .", "cite_spans": [], "ref_spans": [{"start": 774, "end": 782, "text": "Table 4)", "ref_id": "TABREF1"}]}, {"section": "DISCUSSION", "text": "When using a smartphone, users typically prefer using one-hand instead of both hands. The size of the smartphone is a key factor in determining whether users operate their smartphones with one hand or both hands 9) . Because of hemiparalysis, many stroke patients must use one hand to operate their smartphones. This study investigated smartphone usability and functionality for stroke patients and considered three sizes of smartphone screens and whether the patients used their predominant hand or not.", "cite_spans": [{"start": 212, "end": 214, "text": "9)", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "DISCUSSION", "text": "Analysis on usability among the three smartphones screen sizes for dominant hand users showed that stroke patients experienced significantly more discomfort in only three sections: 3-11, 1-11, and 2-10. These sections overlapped a portion of the screen that is difficult to tough 7) . Im 8) reported that users operating their smartphones with one hand were satisfied with all input modes when using a 3.5 inch screen, some input modes when using a 4.0, 4.5, or 5.0 inch screen, but dissatisfied with most input modes when using a 5.5 inch screen. However, the result of this study indicated that the smaller the smartphone screen, the larger the difference in usability between the dominant and non-dominant hand. It should be interpreted that the smaller the smartphone size, the more it required thumb sensitivity.", "cite_spans": [{"start": 280, "end": 282, "text": "7)", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "DISCUSSION", "text": "Regardless of the size of the smartphone, the completion time and usability between dominant and non-dominant hands were significantly different. It was considered that the pre-non-dominant hand user was not skillful at using a smartphone than the pre-dominant hand user. Both hands must be assessed because the performance of the dominant and non-dominant hands is different, as reported by Perry and Hourcade 10) . To the best of our knowledge, this is the first study to analyze smartphone functionality and usability for stroke patients while considering both the pre-dominant and pre-non-dominant hand. So, this study has a special meaning. When 4.2 and 4.5 inch screens were used, a significant difference in the frequency of errors was found between nondominant and dominant hand users, but not when 5.6 inch screens were used. This was considered because thumb movement This study has some limitations. It assessed functionality and usability while the smartphone was being held in the vertical position; horizontal position was not considered. Many variables such as flexibility of the thumb, smartphone grip patterns, and smartphone weight 6) , were not considered in this study. In the future, studies on smartphone functionality and usability of patients with stroke using only pre-non dominant hand need to be conducted. ", "cite_spans": [{"start": 1150, "end": 1152, "text": "6)", "ref_id": "BIBREF5"}], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Exploring iPhone usage: the influence of socioeconomic differences on smartphone adoption, usage and usability", "authors": [{"first": "A", "middle": [], "last": "Rahmati", "suffix": ""}, {"first": "C", "middle": [], "last": "Tossell", "suffix": ""}, {"first": "C", "middle": [], "last": "Shepard", "suffix": ""}], "year": 2012, "venue": "Smartphone", "link": "936414"}, "BIBREF1": {"title": "Studying smartphone usage: lessons from a four month field study", "authors": [{"first": "A", "middle": [], "last": "Rahmati", "suffix": ""}, {"first": "L", "middle": [], "last": "Zhong", "suffix": ""}], "year": 2013, "venue": "IEEE transactions on smartphone computing", "link": "15446983"}, "BIBREF2": {"title": "The effects of aesthetics of smartphones on usability", "authors": [{"first": "E", "middle": ["T"], "last": "Oh", "suffix": ""}, {"first": "M", "middle": ["Y"], "last": "Park", "suffix": ""}], "year": 2012, "venue": "Sci Emot Sensib", "link": null}, "BIBREF3": {"title": "Effect of smart phone use on dynamic postural balance", "authors": [{"first": "S", "middle": ["H"], "last": "Cho", "suffix": ""}, {"first": "M", "middle": ["H"], "last": "Choi", "suffix": ""}, {"first": "B", "middle": ["O"], "last": "Goo", "suffix": ""}], "year": 2014, "venue": "J Phys Ther Sci", "link": "5084944"}, "BIBREF4": {"title": "Effects of cervical flexion on the flexion-relaxation ratio during smartphone use", "authors": [{"first": "H", "middle": [], "last": "Shin", "suffix": ""}, {"first": "K", "middle": [], "last": "Kim", "suffix": ""}], "year": 2014, "venue": "J Phys Ther Sci", "link": "9531743"}, "BIBREF5": {"title": "Studies in one-handed smartphone design: Habit, desire and agility", "authors": [{"first": "A", "middle": ["K"], "last": "Karson", "suffix": ""}, {"first": "B", "middle": ["B"], "last": "Bederson", "suffix": ""}, {"first": "J", "middle": ["L"], "last": "Contreras-Vidal", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF6": {"title": "A study on smartphone UI design for one hand user", "authors": [{"first": "H", "middle": ["J"], "last": "Jeon", "suffix": ""}, {"first": "J", "middle": ["S"], "last": "Oh", "suffix": ""}, {"first": "H", "middle": ["C"], "last": "Youn", "suffix": ""}], "year": 2013, "venue": "Korea Contents", "link": null}, "BIBREF7": {"title": "Usability evaluation about the smartphone screen size change for one-handed", "authors": [{"first": "K", "middle": ["S"], "last": "Im", "suffix": ""}, {"first": "J", "middle": ["S"], "last": "Yoon", "suffix": ""}], "year": 2012, "venue": "J Korean Soc Des Forum", "link": "64956285"}, "BIBREF8": {"title": "Thumbspace: Generalized one-handed input for touch screen-based smartphone devices. Proceeding HCI international", "authors": [{"first": "A", "middle": ["K"], "last": "Karson", "suffix": ""}, {"first": "B", "middle": ["B"], "last": "Bederson", "suffix": ""}], "year": 2007, "venue": "", "link": null}, "BIBREF9": {"title": "Evaluating one handed thumb tapping on smartphone touchscreen devices", "authors": [{"first": "K", "middle": ["B"], "last": "Perry", "suffix": ""}, {"first": "J", "middle": ["P"], "last": "Hourcade", "suffix": ""}], "year": 2008, "venue": "Pro Graph Interf", "link": null}, "BIBREF10": {"title": "An ergonomics study of thumb movements on smartphone touch screen", "authors": [{"first": "J", "middle": [], "last": "Xiong", "suffix": ""}, {"first": "S", "middle": [], "last": "Muraki", "suffix": ""}], "year": 2014, "venue": "Ergonomics", "link": "32590122"}}, "ref_entries": {"FIGREF0": {"text": "Fig. 1. Prototype", "type": "figure"}, "TABREF0": {"text": "General characteristics of participants Group for pre-non-dominant hand (N=5)", "type": "table"}, "TABREF1": {"text": "The functionality according to the size of smartphoneSignificant difference at 0.016 between 4.2 and 4.5 inch b Significant difference at 0.016 between 4.5 and 5.6 inch c Significant difference at 0.016 between 4.2 and 5.6 inch *Significant difference at 0.05 between dominant hand use group and non-dominant hand use group", "type": "table"}, "TABREF2": {"text": "The usability according to the size of smartphone and comparison between dominant and non-dominant hand user groupSignificant difference at 0.016 between 4.2 and 4.5 inch b Significant difference at 0.016 between 4.5 and 5.6 inch c Significant difference at 0.016 between 4.2 and 5.6 inch *Significant difference at 0.05 between dominant hand use group and non-dominant hand use group", "type": "table"}}}
{"paper_id": "17433682", "_pdf_hash": "9d4b4ecf2c4ae6e269d46f7366f0f3a91fcf94a6", "abstract": [{"section": "Abstract", "text": ".", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Purpose. This study has researched the affect of different methodologies of harvesting and analysing the samples in determining the mediators emerging after the rat articular cartilage injury. Materials and Methods. One hundred and forty-four male wistar rats were divided into 2 groups. Synovial fluid samples were taken from all of the rats. We entered into the right knees of the rats in group I ( = 36) under anaesthesia and took cartilage tissue samples from their distal femur. Samples were taken as reference values for enzyme linked immunosorbent assay (ELISA) and histopathological evaluations. We entered into the right knees of the rats in group II ( = 108) and formed complete layer of cartilage injury in their medial femoral condyles. At the end of the 15th day, the rats were sacrificed after taking synovial fluid samples from their right knees creating defect in the rats in group II. The molecular markers in the synovial fluid and cartilage tissue samples which were taken from the experimental and control groups (MMP-9, MMP-13, TIMP-1, TNF-, and NO) were analysed by direct or indirect methodologies. SPSS 18.0 Package program was used in the statistical evaluation. Students t-test where the measurement variables between the experimental and control groups were compared was applied. Receiver Operating Characteristics (ROC) curves were used in the determination of the diagnostic sufficiency from the tissue. Results. No difference was found between TIMP-1 ( = 0.67) and MMP-9 ( = 0.28) levels in synovial fluid and cartilage tissue. From the molecular markers, when MMP-9, MMP-13, NO, TIMP-1, TNF-, the area under ROC curve, and P values were examined, MMP-13 ( < 0.0001, 95% CI: 0.70-0.85), NO ( < 0.0001, 95% CI: 0.72-0.86), and TNF-( < 0.0001, 95% CI: 0.91-0.98) results were found to be statistically significant. Inferences. The indirect ELISA protocol which we apply for the cartilage tissue as an alternative to synovial lavage fluid is a reliable method which can be used in the determination of articular cartilage injury markers.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "The molecular markers which emerge in the process after the articular cartilage injury are used in the monitoring of degenerative diseases, prognosis determination, monitoring of response to the treatment, and identification of the disease mechanism in molecular level [1, 2] . One important purpose of the measurement of molecular determinants is to examine the disease quantitatively in the early stages when the cartilage injury has not been radiologically determined yet.", "cite_spans": [{"start": 269, "end": 272, "text": "[1,", "ref_id": "BIBREF0"}, {"start": 273, "end": 275, "text": "2]", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Introduction", "text": "Chondrocytes have a directing role in the metabolism including the construction and destruction of matrix molecules in the lifetime [3, 4] . There are simultaneous changes in tissues in the articular cartilage injury, and there is a need for molecular markers related to each tissue for the comprehensive evaluation of these changes. However, there 2 Arthritis are no official study protocols for different tissues [5] . As there can be significant differences related to biological tissues, the way of sampling of the markers which are obtained from different tissues can influence the result should be predictable. Pharmaceutical researchers have published articles on the validity of the analytical method in the determination of the method applied [5] [6] [7] [8] [9] [10] .", "cite_spans": [{"start": 132, "end": 135, "text": "[3,", "ref_id": "BIBREF2"}, {"start": 136, "end": 138, "text": "4]", "ref_id": "BIBREF3"}, {"start": 415, "end": 418, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 752, "end": 755, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 756, "end": 759, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 760, "end": 763, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 764, "end": 767, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 768, "end": 771, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 772, "end": 776, "text": "[10]", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "Introduction", "text": "Molecular markers of the cartilage are molecules which can be in the structure of protein constituting collagen, proteoglycan, and extra cellular matrix (ECM) and they show increase and decrease in several cartilage pathologies and in the different stages of the same pathology [11] .", "cite_spans": [{"start": 278, "end": 282, "text": "[11]", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "Introduction", "text": "Depending on the severity of the ongoing inflammation, cartilage-based markers in several intensities go out of the cell and enter into the synovial fluid. Parts of the cartilage ECM macromolecules which are poured into the synovial fluid can pass to the systemic circulation [12] .", "cite_spans": [{"start": 276, "end": 280, "text": "[12]", "ref_id": "BIBREF11"}], "ref_spans": []}, {"section": "Introduction", "text": "This study aims to determine the biological markers, occurring in the articular cartilage injury, directly by cartilage tissue biopsies and in synovial fluid, and present the relationship between them.", "cite_spans": [], "ref_spans": []}, {"section": "Materials and Methods", "text": "This study was conducted after the decision of the meeting dated June 1, 2010, numbered 2010/04 and the permission of the Local Ethical Committee of Experimental Animals and the Use of Live Mammal of Namik Kemal University. Experimental analyses were repeated minimum 3 times. In order to minimize the differences in the technique, anaesthesia, injury formation, and analyses were performed by the same researchers.", "cite_spans": [], "ref_spans": []}, {"section": "Materials.", "text": "Male wistar rats were supplied from Istanbul University Experimental Medicine Research Institute. Ketamine HCl (Ketalar 500 mg) injectable 1 flacon Pfizer and xylazine (Rompun 2%) injectable solution, Parke-Davis, were used. Protein extraction solution (78510) and protease inhibitor cocktail (87785) Thermo Scientific Pierce Biotechnology, Rockford, IL & 1105, were supplied from the United States of America. NO kit was supplied from ELISA commercial kits, IL-TIMP-1 (BMS2018/BMS2018TEN) was supplied from Cayman Chemical, matrix metalloproteinase-9 (MMP-9) (BMS2016/2CE) and MMP-13 (BMS2022/BMS2022TEN) platinum were supplied from ELISA eBioscience, and TNF-(KRC3011) kit was supplied from Invitrogen. Mechanical disruption was provided with EpiSonic Multi-Functional Bioprocessor 1100. Mindray MR 96 A, Chinese brand device, was used as Enzyme L nked-Immuno-Sorbent Assay (ELISA) microplate reader. The tissues which are obtained from 144 wistar rats were studied double-blind by the same researchers.", "cite_spans": [], "ref_spans": []}, {"section": "Methods.", "text": "One hundred forty-four male wistar rats with an average weight of 300 grams were divided into 2 groups. Synovial fluid samples were taken from all of the rats. While taking synovial fluid, the knee joint was entered by the injector and the liquid which is given into the joint was withdrawn 45 seconds later and taken into the tubes containing EDTA. Synovial fluid aspirates with PBS in the rate of 75 L 1 : 3 were centrifuged at 24 \u2218 C in 3000 Revolutions Per Minute (rpm) for 15 minutes and cleared of cells and maintained at minus 40 \u2218 C to be evaluated with ELISA. All of the samples were taken at 05.00 in the morning.", "cite_spans": [], "ref_spans": []}, {"section": "Methods.", "text": "The rats in group I (control group, = 36) were applied arthrotomy under ketamine HCI and xylazine anaesthesia. Cartilage tissue samples were taken from distal femur medial condyles. These samples were taken as reference values for enzyme linked immunosorbent assay (ELISA) and histopathological evaluations. And then, these rats were sacrificed.", "cite_spans": [], "ref_spans": []}, {"section": "Methods.", "text": "The rats in group II ( = 108) were applied arthrotomy under ketamine HCl and xylazine anaesthesia, and a complete layer of cartilage injury was formed in their medial femoral condyles ( Figure 1 ) [13, 14] . From the right knees of the rats where injury was formed, synovial fluid samples were taken by the same technique on the 15th day. Then, arthrotomy was applied and cartilage tissue samples were taken from their distal medial condyles. These rats were sacrificed after this operation.", "cite_spans": [{"start": 197, "end": 201, "text": "[13,", "ref_id": "BIBREF12"}, {"start": 202, "end": 205, "text": "14]", "ref_id": "BIBREF13"}], "ref_spans": [{"start": 186, "end": 194, "text": "Figure 1", "ref_id": "FIGREF0"}]}, {"section": "Methods.", "text": "The synovial lavage fluid and cartilage tissue samples taken from the experimental and control groups were analysed by direct or indirect methodologies by MMP-9, MMP-13, NO, TIMP-1, TNF-, and commercial ELISA kits which are cartilage injury molecular markers in line with company bulletins.", "cite_spans": [], "ref_spans": []}, {"section": "Biochemical Analyses.", "text": "The samples were blindly studied. The synovial fluid tissue samples which were taken from the experimental and control groups were analysed by MMP-9, MMP-13, NO, TIMP-1, and TNF-values ELISA kits and in line with the company bulletins.", "cite_spans": [], "ref_spans": []}, {"section": "Biochemical Analyses.", "text": "Before conducting analyses in the cartilage tissue, the tissues were made compatible for kit study procedure. Porcelain mortar and pestle were subjected to 8% sodium hypochlorite solution. They were dried after having been washed with bidistillated water. They were wrapped with aluminium folios and kept in the drying oven at 134 \u2218 C for 1 hour. At the end of this time, they were kept at \u221220 \u2218 C for 30 minutes. The cartilage tissue samples which were broken up with and pulverized by a pestle in the presence of liquid nitrogen were taken into cryo tubes and coded (Figure 2 ). They were weighed at the rate of 1 : 20 (w/v) and transferred into eppendorf tubes by means of 15 no scalpel end. Primarily 400 L lysisbuffer was added on them. Then, a protease cocktail inhibitor ten times the ready volume (making 1x the last concentration) is added and vortexed for 1 minute, and centrifuging process was performed at +4 \u2218 C for 5 minutes in 10.000 (g) [15, 16] . The samples were kept at \u221280 \u2218 C for one night. For the mechanical disruption of the cartilage tissue; they were subjected to 2 times vibration and ultrasonic sound waves operation for 10 minutes under the same pressure at intervals of 20 minutes in sonicator by watering down with phosphate buffer saline (PBS; pH = 7, 4) in 1.5 mL microtubes (max 400 L of sample content). And then, in line with the company bulletins, the samples were placed in the wells. MMP-9, MMP-13, TIMP-1 and TNF-450 nm, NO was evaluated by reading at ELISA microplate reader at 540 nm wave length as a result of the calculation of the data which was obtained over the nitrate and nitrite values. Standards were studies as pairs.", "cite_spans": [{"start": 953, "end": 957, "text": "[15,", "ref_id": "BIBREF14"}, {"start": 958, "end": 961, "text": "16]", "ref_id": "BIBREF15"}], "ref_spans": [{"start": 568, "end": 577, "text": "(Figure 2", "ref_id": "FIGREF1"}]}, {"section": "Histopathological Analyses.", "text": "In order to prove the cartilage complete layer injury, the cartilage tissue samples which were taken from each of 6 rats from both groups were also evaluated histopathologically. The samples were buried in paraffin-embedded blocks after the routine tissue monitoring. Five-micron sections were put to hematoxylineosin staining and examined in the light microscope (\u00d7100). Histological sections were examined in terms of 8 parameters and scored and evaluated [17] .", "cite_spans": [{"start": 458, "end": 462, "text": "[17]", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "Statistical Analysis.", "text": "The data was evaluated by using SPSS 18.0 Package program. Descriptive statistics were calculated (mean, standard deviation) after performing data control. Students t-test, which is a test in the comparison of the quantitative data in the comparative analyses between the experimental and control groups, in which the measurement variables between two groups are compared, was applied. Partial correlation analysis was performed in order to explain the relationship between these mediators. Receiver Operating Characteristics (ROC) curves were used in the determination of diagnostic sufficiency from the tissue.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Histopathological Evaluation.", "text": "The formation of the cartilage complete layer injury was reported (Figure 3 ).", "cite_spans": [], "ref_spans": [{"start": 66, "end": 75, "text": "(Figure 3", "ref_id": "FIGREF2"}]}, {"section": "Statistical Evaluation.", "text": "All of the evaluations were evaluated in 95% confidence interval and bilaterally. Alpha meaningfulness level was determined as \u22640.05; according to the specific activity results in synovial lavage fluid and cartilage tissue of the mediators (MMP-9, MMP-13, NO, TIMP-1, and TNF-) emerging after complete layer articular cartilage injury.", "cite_spans": [], "ref_spans": []}, {"section": "Statistical Evaluation.", "text": "No meaningful difference was determined in statistical terms between the TIMP-1 ( = 0.67) and MMP-9 ( = 0.28) levels in synovial lavage fluid and cartilage tissue. A meaningful difference was found in statistical terms between the MMP-13 ( < 0.0001), TNF-( < 0.0001), and NO ( < 0.0001) levels (Table 1) .", "cite_spans": [], "ref_spans": [{"start": 294, "end": 303, "text": "(Table 1)", "ref_id": "TABREF0"}]}, {"section": "Statistical Evaluation.", "text": "It was determined that the measurements in intragroup and intergroup TIMP-1 and MMP-9 mediators were variable, and close measurements were obtained in NO, TIMP-1, and TNF-variables (Figure 4 ).", "cite_spans": [], "ref_spans": [{"start": 181, "end": 190, "text": "(Figure 4", "ref_id": "FIGREF3"}]}, {"section": "Statistical Evaluation.", "text": "In the partial correlation analysis performed, a negative linear meaningful relationship was found between TIMP-1 and MMP-13 ( < 0.0001, = \u22120.38); a positive meaningful relationship was found between TIMP-1 and TNF-( < 0.0001, = 0.33). A negative meaningful relationship was found between TIMP-1 and NO ( = 0.001, = \u22120.26). And a positive linear meaningful relationship was found between MMP-9 and TNF-( < 0.0001, = 0.34) and NO ( < 0.0001, = 0.46) ( Table 2) .", "cite_spans": [], "ref_spans": [{"start": 451, "end": 459, "text": "Table 2)", "ref_id": "TABREF1"}]}, {"section": "Statistical Evaluation.", "text": "When the area under ROC curve of TIMP-1, MMP-9, MMP-13, NO, and TNF-markers and P values were examined in the study groups, MMP-13 ( < 0.0001, 95% CI: 0.70-0.85), NO ( < 0.0001, 95% CI: 0.72-0.86), and TNF-( < 0.0001, 95% CI: 0.91-0.98), results were found to be statistically meaningful ( Figure 5 ).", "cite_spans": [], "ref_spans": [{"start": 290, "end": 298, "text": "Figure 5", "ref_id": "FIGREF4"}]}, {"section": "Discussion", "text": "Osteoartrit (OA) is a disease which emerges with the breakup of the balance between the construction and destruction of the cartilage in favour of destruction, results in the loss of the cartilage, and progresses slowly [18] . Recently, it has been shown that the MMPs whose levels in the joint at the time of injury increase play an important role in the destruction of the cartilage tissue [19] . One of the tissue inhibitors which enable the balancing of these enzymes which are destructive for the cartilage is identified as metalloproteinase [20] . Particularly, the metalloproteinase which increases in OA is produced by chondrocyte and synovial cells. Since the number of these cells is higher than that in the cartilage tissue, the main production source of MMP in the joint fluid is synovial tissue. It is shown that metalloproteinase and TIMP increased in the synovial fluid in OA and collagenase-TIMP-1 complex level generally stayed under the level which can be determined by immunoassay [21] . Lohmander et al. determined that metalloproteinase and TIMP levels stayed high for a long time in the knee joint after a traumatic injury [22] . In our study, it was seen that MMP-9 levels did not change even when different methodologies are used in synovial lavage fluid and cartilage tissue analyses in the samples which were examined after the formation of injury. Likewise, no change was determined in TIMP-1 levels ( Table 1) .", "cite_spans": [{"start": 220, "end": 224, "text": "[18]", "ref_id": "BIBREF17"}, {"start": 392, "end": 396, "text": "[19]", "ref_id": "BIBREF18"}, {"start": 547, "end": 551, "text": "[20]", "ref_id": "BIBREF19"}, {"start": 1000, "end": 1004, "text": "[21]", "ref_id": "BIBREF20"}], "ref_spans": [{"start": 1429, "end": 1437, "text": "Table 1)", "ref_id": "TABREF0"}]}, {"section": "Discussion", "text": "The role of proinflammatory was shown in the articular cartilage injury of TNF-which are among the cytokines other than those aforementioned molecules [23, 24] . Serum TNF-level is seen as a criterion of the synovial cell hyperactivity which becomes evident in the late stages of the cartilage injury [25] . It is known that TNF-in the joint with OA mainly originates from the cells in the cartilage tissue, and these cells perform more cytokine expression when compared to synovial cells [26] .", "cite_spans": [{"start": 151, "end": 155, "text": "[23,", "ref_id": "BIBREF23"}, {"start": 156, "end": 159, "text": "24]", "ref_id": "BIBREF24"}, {"start": 301, "end": 305, "text": "[25]", "ref_id": "BIBREF25"}, {"start": 489, "end": 493, "text": "[26]", "ref_id": "BIBREF26"}], "ref_spans": []}, {"section": "Discussion", "text": "In our study, statistically meaningful differences were determined in terms of TNF-and MMP-13 levels in the samples which were obtained from synovial lavage fluid and cartilage tissue (Table 1 ). In the subsequent partial correlation analysis, a negative meaningful relationship was found between TIMP-1 and MMP-13 ( < 0.0001, = \u22120.38), and a positive meaningful relationship was found between TIMP-1 and TNF-( < 0.0001, = 0.33). A positive linear meaningful relationship was found between MMP-9 and TNF-( < 0.0001, = 0.34) ( Table 2) . It was seen in ROC analysis that these two mediators can also be used in different methodologies in synovial lavage fluid and Arthritis 5 cartilage tissue. The molecular marker level results which are obtained from different areas in the literature and set forth with different methodologies are also in conformity with the data of our study [25] [26] [27] .", "cite_spans": [{"start": 879, "end": 883, "text": "[25]", "ref_id": "BIBREF25"}, {"start": 884, "end": 888, "text": "[26]", "ref_id": "BIBREF26"}, {"start": 889, "end": 893, "text": "[27]", "ref_id": "BIBREF27"}], "ref_spans": [{"start": 184, "end": 192, "text": "(Table 1", "ref_id": "TABREF0"}, {"start": 526, "end": 534, "text": "Table 2)", "ref_id": "TABREF1"}]}, {"section": "Discussion", "text": "In an experimental study, it was it shown that NO synthesis are stimulated by several cytokines such as TNF- [28] . Evidences regarding the fact that NO is a secondary fundamental mediator after TNF-in cartilage cells were set forth in the same study [28] . In our study, on the other hand, NO level was determined to be meaningfully high in the analysis results of the samples taken from synovial lavage fluid in conformity with the TNF-level in the experimental groups. A positive linear relationship was found between TNF-and NO ( < 0.0001, = 0.46). In the ROC analysis, the fact that these mediators which were taken from different places and examined can also be analysed over a different methodology cartilage tissue was confirmed.", "cite_spans": [{"start": 109, "end": 113, "text": "[28]", "ref_id": "BIBREF28"}, {"start": 251, "end": 255, "text": "[28]", "ref_id": "BIBREF28"}], "ref_spans": []}, {"section": "Arthritis", "text": "The affect of MMP enzymes on cartilage is inhibited by TIMP [29, 30] . NO is overexpressed at synovial tissue of injured cartilage by the stimulus of inducible nitric oxide synthase and TNF- [29] [30] [31] [32] . IL-1 and TNF-release is increased with the affect of degraded matrix molecules and so NO expression is also increased. It is reported that MMP-13 is discharged mostly via sinovial fluid [33] . We think that these data explain why TNF-, MMP-13, and NO were found more in synovial fluids in our results.", "cite_spans": [{"start": 60, "end": 64, "text": "[29,", "ref_id": "BIBREF29"}, {"start": 65, "end": 68, "text": "30]", "ref_id": "BIBREF30"}, {"start": 191, "end": 195, "text": "[29]", "ref_id": "BIBREF29"}, {"start": 196, "end": 200, "text": "[30]", "ref_id": "BIBREF30"}, {"start": 201, "end": 205, "text": "[31]", "ref_id": "BIBREF31"}, {"start": 206, "end": 210, "text": "[32]", "ref_id": "BIBREF32"}, {"start": 399, "end": 403, "text": "[33]", "ref_id": "BIBREF33"}], "ref_spans": []}, {"section": "Arthritis", "text": "We think the restriction of our study is that it cannot be crosschecked by a method other than ELISA method which is used in the analysis of the samples.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusion", "text": "When, among the molecular markers which are analyzed in the synovial lavage fluid, MMP-9, MMP-13, NO, TIMP-1 and TNF-, the area under the ROC curve and P values are evaluated, MMP-13 ( < 0.0001, 95% CI: 0.70-0.85), NO ( < 0.0001, 95% CI: 0.72-0.86), and TNF-( < 0.0001, 95% CI: 0.91-0.98) results are statistically significant. As a result, as it can be analyzed from the synovial lavage fluid of the molecular injury markers such as MMP-9, MMP-13, NO, TIMP-1, and TNF-which emerge in the articular cartilage injury, we can say that it can also be analyzed in a reliable manner by the indirect ELISA method described by us in the samples which are obtained from the cartilage tissue.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "TSG-6 protein, a negative regulator of inflammatory arthritis, forms a ternary complex with murine mast cell tryptases and heparin", "authors": [{"first": "G", "middle": [], "last": "Nagyeri", "suffix": ""}, {"first": "M", "middle": [], "last": "Radacs", "suffix": ""}, {"first": "S", "middle": [], "last": "Ghassemi-Nejad", "suffix": ""}], "year": 2011, "venue": "The Journal of Biological Chemistry", "link": "42235750"}, "BIBREF1": {"title": "Cytokine receptorlike factor 1 is highly expressed in damaged human knee osteoarthritic cartilage and involved in osteoarthritis downstream of TGF", "authors": [{"first": "K", "middle": [], "last": "Tsuritani", "suffix": ""}, {"first": "J", "middle": [], "last": "Takeda", "suffix": ""}, {"first": "J", "middle": [], "last": "Sakagami", "suffix": ""}], "year": 2010, "venue": "Calcified Tissue International", "link": "23107746"}, "BIBREF2": {"title": "Experimental morphological study of the effects of subchondral tunnelization and bone marrow stimulation on articular cartilage regeneration", "authors": [{"first": "T", "middle": ["A"], "last": "Stupina", "suffix": ""}, {"first": "V", "middle": ["D"], "last": "Makushin", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Stepanov", "suffix": ""}], "year": 2012, "venue": "Bulletin Experimental Biology and Medicine", "link": "8531707"}, "BIBREF3": {"title": "Operative treatment of chondral defects in the hip joint: a systematic review", "authors": [{"first": "M", "middle": ["A"], "last": "Jordan", "suffix": ""}, {"first": "G", "middle": ["S"], "last": "Van Thiel", "suffix": ""}, {"first": "J", "middle": [], "last": "Chahal", "suffix": ""}, {"first": "S", "middle": ["J"], "last": "Nho", "suffix": ""}], "year": 2012, "venue": "Current Reviews in Musculoskeletal Medicine", "link": "207397428"}, "BIBREF4": {"title": "An overview on analytical method validation", "authors": [{"first": "O", "middle": ["S"], "last": "Ertas", "suffix": ""}, {"first": "A", "middle": [], "last": "Kayali", "suffix": ""}], "year": 2005, "venue": "Journal of Faculty Pharmacy", "link": null}, "BIBREF5": {"title": "Selection of highperformance liquid chromatographic methods in pharmaceutical analysis. III. Method validation", "authors": [{"first": "G", "middle": [], "last": "Szepesi", "suffix": ""}, {"first": "M", "middle": [], "last": "Gazdag", "suffix": ""}, {"first": "K", "middle": [], "last": "Mihalyfi", "suffix": ""}], "year": 1989, "venue": "Journal of Chromatography A", "link": "35946347"}, "BIBREF6": {"title": "Some considerations on analytical methods validations, bioavailability, bioequivalence and pharmacokinetic studies", "authors": [{"first": "A", "middle": [], "last": "Kayal", "suffix": ""}, {"first": "O", "middle": [], "last": "Sogut", "suffix": ""}, {"first": "B", "middle": [], "last": "Tuncel", "suffix": ""}], "year": 1995, "venue": "European Journal of Drug Metabolism and Pharmacokinetics", "link": null}, "BIBREF7": {"title": "Development and validation of extraction methods for determination of zinc and arsenic speciation in soils using focused ultrasound: application to heavy metal study in mud and soils", "authors": [{"first": "A", "middle": [], "last": "Marin", "suffix": ""}, {"first": "A", "middle": [], "last": "L\u00f3pez-Gonz\u00e1lvez", "suffix": ""}, {"first": "C", "middle": [], "last": "Barbas", "suffix": ""}], "year": 2001, "venue": "Analytica Chimica Acta", "link": null}, "BIBREF8": {"title": "Validation of a highly sensitive ICP-MS method for the determination of platinum in biofluids: application to clinical pharmacokinetic studies with oxaliplatin", "authors": [{"first": "J", "middle": ["G"], "last": "Morrison", "suffix": ""}, {"first": "P", "middle": [], "last": "White", "suffix": ""}, {"first": "S", "middle": [], "last": "Mcdougall", "suffix": ""}], "year": 2000, "venue": "Journal of Pharmaceutical and Biomedical Analysis", "link": "23511852"}, "BIBREF9": {"title": "Prevalidation in pharmaceutical analysis, part 1, fundamentals and critical discussion", "authors": [{"first": "V", "middle": [], "last": "Grdinic", "suffix": ""}, {"first": "J", "middle": [], "last": "Vukovic", "suffix": ""}], "year": 2004, "venue": "Journal of Pharmaceutical and Biomedical Analysis", "link": "22111316"}, "BIBREF10": {"title": "Molecular basis and clinical use of biochemical markers of bone, cartilage, and synovium in joint diseases", "authors": [{"first": "P", "middle": [], "last": "Garnero", "suffix": ""}, {"first": "J", "middle": ["C"], "last": "Rousseau", "suffix": ""}, {"first": "P", "middle": ["D"], "last": "Delmas", "suffix": ""}], "year": 2000, "venue": "Arthritis & Rheumatism", "link": "46075742"}, "BIBREF11": {"title": "Lymphatic vessels in osteoarthritic human knees", "authors": [{"first": "D", "middle": ["A"], "last": "Walsh", "suffix": ""}, {"first": "P", "middle": [], "last": "Verghese", "suffix": ""}, {"first": "G", "middle": ["J"], "last": "Cook", "suffix": ""}], "year": 2012, "venue": "Osteoarthritis Cartilage", "link": "21113990"}, "BIBREF12": {"title": "Oxygen and reactive oxygen species in cartilage degradation: friends or foes?", "authors": [{"first": "Y", "middle": [], "last": "Henrotin", "suffix": ""}, {"first": "B", "middle": [], "last": "Kurz", "suffix": ""}, {"first": "T", "middle": [], "last": "Aigner", "suffix": ""}], "year": 2005, "venue": "Osteoarthritis and Cartilage", "link": "36353822"}, "BIBREF13": {"title": "Lipid peroxidation and antioxidant enzymes in synovial fluid of patients with primary and secondary osteoarthritis of the knee joint", "authors": [{"first": "A", "middle": [], "last": "Ostalowska", "suffix": ""}, {"first": "E", "middle": [], "last": "Birkner", "suffix": ""}, {"first": "M", "middle": [], "last": "Wiecha", "suffix": ""}], "year": 2006, "venue": "Osteoarthritis and Cartilage", "link": "45310886"}, "BIBREF14": {"title": "Anti-dsDNA antibodies and disease classification in antinuclear antibody positive patients: the role of analytical diversity", "authors": [{"first": "K", "middle": [], "last": "Haugbro", "suffix": ""}, {"first": "J", "middle": ["C"], "last": "Nossent", "suffix": ""}, {"first": "T", "middle": [], "last": "Winkler", "suffix": ""}, {"first": "Y", "middle": [], "last": "Figenschau", "suffix": ""}, {"first": "O", "middle": ["P"], "last": "Rekvig", "suffix": ""}], "year": 2004, "venue": "Annals of the Rheumatic Diseases", "link": "5321780"}, "BIBREF15": {"title": "A syndrome of joint laxity and impaired tendon integrity in lumican-and fibromodulin-deficient mice", "authors": [{"first": "K", "middle": ["J"], "last": "Jepsen", "suffix": ""}, {"first": "F", "middle": [], "last": "Wu", "suffix": ""}, {"first": "J", "middle": ["H"], "last": "Peragallo", "suffix": ""}], "year": 2002, "venue": "The Journal of Biological Chemistry", "link": "353982"}, "BIBREF16": {"title": "Effects of some nonsteroidal anti-inflammatory drugs on articular cartilage of rats in an experimental model of osteoarthritis", "authors": [{"first": "B", "middle": ["E"], "last": "Gencosmanoglu", "suffix": ""}, {"first": "M", "middle": [], "last": "Eryavuz", "suffix": ""}, {"first": "S", "middle": [], "last": "Dervisoglu", "suffix": ""}], "year": 2001, "venue": "Research in Experimental Medicine", "link": "11362376"}, "BIBREF17": {"title": "Pathology of osteoarthritis, \" in Arthritis and Allied Conditions", "authors": [{"first": "A", "middle": ["J"], "last": "Hough", "suffix": ""}], "year": 1997, "venue": "", "link": null}, "BIBREF18": {"title": "The structure of aggrecan fragments in human synovial fluid. Evidence for the involvement in osteoarthritis of a novel proteinase which cleaves the Glu 373-Ala 374 bond of the interglobular domain", "authors": [{"first": "J", "middle": ["D"], "last": "Sandy", "suffix": ""}, {"first": "C", "middle": ["R"], "last": "Flannery", "suffix": ""}, {"first": "P", "middle": ["J"], "last": "Neame", "suffix": ""}, {"first": "L", "middle": ["S"], "last": "Lohmander", "suffix": ""}], "year": 1992, "venue": "The Journal of Clinical Investigation", "link": "43324222"}, "BIBREF19": {"title": "Cartilage oligomeric matrix protein (COMP): a biomarker of arthritis", "authors": [{"first": "S", "middle": [], "last": "Tseng", "suffix": ""}, {"first": "A", "middle": ["H"], "last": "Reddi", "suffix": ""}, {"first": "P", "middle": ["E"], "last": "Di Cesare", "suffix": ""}], "year": 2009, "venue": "Biomarker Insights", "link": "24800117"}, "BIBREF20": {"title": "Metalloproteinases, tissue inhibitor, and proteoglycan fragments in knee synovial fluid in human osteoarthritis", "authors": [{"first": "L", "middle": ["S"], "last": "Lohmander", "suffix": ""}, {"first": "L", "middle": ["A"], "last": "Hoerrner", "suffix": ""}, {"first": "M", "middle": ["W"], "last": "Lark", "suffix": ""}], "year": 1993, "venue": "Arthritis & Rheumatism", "link": "7212745"}, "BIBREF22": {"title": "proteoglycan fragments in human knee joint fluid after injury to the cruciate ligament or meniscus", "authors": [], "year": 1994, "venue": "Journal of Orthopaedic Research", "link": null}, "BIBREF23": {"title": "Role of cytokines in rheumatoid arthritis", "authors": [{"first": "M", "middle": [], "last": "Feldmann", "suffix": ""}, {"first": "F", "middle": ["M"], "last": "Brennan", "suffix": ""}, {"first": "R", "middle": ["N"], "last": "Maini", "suffix": ""}], "year": 1996, "venue": "Annual Review of Immunology", "link": "24101167"}, "BIBREF24": {"title": "New cytokine targets in inflammatory rheumatic diseases", "authors": [{"first": "L", "middle": [], "last": "Connell", "suffix": ""}, {"first": "I", "middle": ["B"], "last": "Mcinnes", "suffix": ""}], "year": 2006, "venue": "Best Practice & Research", "link": "24017655"}, "BIBREF25": {"title": "Serum hyaluronic acid level as a predictor of disease progression in osteoarthritis of the knee", "authors": [{"first": "M", "middle": [], "last": "Sharif", "suffix": ""}, {"first": "E", "middle": [], "last": "George", "suffix": ""}, {"first": "L", "middle": [], "last": "Shepstone", "suffix": ""}], "year": 1995, "venue": "Arthritis & Rheumatism", "link": "36302307"}, "BIBREF26": {"title": "Enhanced and coordinated in vivo expression of inflammatory cytokines and nitric oxide synthase by chondrocytes from patients with osteoarthritis", "authors": [{"first": "C", "middle": [], "last": "Melchiorri", "suffix": ""}, {"first": "R", "middle": [], "last": "Meliconi", "suffix": ""}, {"first": "L", "middle": [], "last": "Frizziero", "suffix": ""}], "year": 1998, "venue": "Arthritis & Rheumatism", "link": "38543385"}, "BIBREF27": {"title": "Studies on certain cytoplasmic enzymes and specific estrogen receptors in human breast cancer and in nonmalignant diseases of the breast", "authors": [{"first": "R", "middle": [], "last": "Hilf", "suffix": ""}, {"first": "J", "middle": ["L"], "last": "Wittliff", "suffix": ""}, {"first": "W", "middle": ["D"], "last": "Rector", "suffix": ""}, {"first": "E", "middle": ["D"], "last": "Savlov", "suffix": ""}, {"first": "T", "middle": ["C"], "last": "Hall", "suffix": ""}, {"first": "R", "middle": ["A"], "last": "Orlando", "suffix": ""}], "year": 1973, "venue": "Cancer Research", "link": "35455994"}, "BIBREF28": {"title": "Reduced cartilage proteoglycan loss during zymosan-induced gonarthritis in NOS 2 -deficient mice and in anti-interleukin-1-treated wild-type mice with unabated joint inflammation", "authors": [{"first": "F", "middle": ["A"], "last": "Van De Loo", "suffix": ""}, {"first": "O", "middle": ["J"], "last": "Arntz", "suffix": ""}, {"first": "F", "middle": ["H"], "last": "Van Enckevort", "suffix": ""}, {"first": "P", "middle": ["L"], "last": "Van Lent", "suffix": ""}, {"first": "W", "middle": ["B"], "last": "Van Den", "suffix": ""}, {"first": "", "middle": [], "last": "Berg", "suffix": ""}], "year": 1998, "venue": "Arthritis & Rheumatism", "link": "23317467"}, "BIBREF29": {"title": "Integrins and cell signaling in chondrocytes", "authors": [{"first": "R", "middle": ["F"], "last": "Loeser", "suffix": ""}], "year": 2002, "venue": "Biorheology", "link": "13187123"}, "BIBREF30": {"title": "Etiopathogenesis of osteoarthritis", "authors": [{"first": "A", "middle": ["R"], "last": "Poole", "suffix": ""}, {"first": "F", "middle": [], "last": "Guilak", "suffix": ""}, {"first": "S", "middle": ["B"], "last": "Abramson", "suffix": ""}], "year": 2007, "venue": "", "link": null}, "BIBREF31": {"title": "The role of cytokines in cartilage matrix degeneration in osteoarthritis", "authors": [{"first": "S", "middle": ["R"], "last": "Goldring", "suffix": ""}, {"first": "M", "middle": ["B"], "last": "Goldring", "suffix": ""}], "year": 2004, "venue": "Clinical Orthopaedics and Related Research", "link": "27894903"}, "BIBREF32": {"title": "Osteoarthritis development in novel experimental mouse models induced by knee joint instability", "authors": [{"first": "S", "middle": [], "last": "Kamekura", "suffix": ""}, {"first": "K", "middle": [], "last": "Hoshi", "suffix": ""}, {"first": "T", "middle": [], "last": "Shimoaka", "suffix": ""}], "year": 2005, "venue": "Osteoarthritis and Cartilage", "link": "11334350"}, "BIBREF33": {"title": "Type II collagen degradation and its regulation in articular cartilage in osteoarthritis", "authors": [{"first": "A", "middle": ["R"], "last": "Poole", "suffix": ""}, {"first": "M", "middle": [], "last": "Kobayashi", "suffix": ""}, {"first": "T", "middle": [], "last": "Yasuda", "suffix": ""}], "year": 2002, "venue": "Annals of the Rheumatic Diseases", "link": "29747214"}}, "ref_entries": {"FIGREF0": {"text": "Figure 1: Macro view of the actualization of the cartilage complete layer injury.", "type": "figure"}, "FIGREF1": {"text": "Figure 2: Mechanical disruption of the tissue which is frozen in the presence of liquid nitrogen.", "type": "figure"}, "FIGREF2": {"text": "Figure 3: It is seen that complete layer of cartilage injury is histopathologically formed in the presence of H&E (\u00d7100). (a) Intact, (b) fibrillation, (c) fissure, and (d) osteophyte formation.", "type": "figure"}, "FIGREF3": {"text": "Figure 4: Distribution of the mediators in the synovial lavage fluid and cartilage tissue in all experimental groups (mean, 95% CI).", "type": "figure"}, "FIGREF4": {"text": "Figure 5: ROC analysis where the validities of the mediators in synovial lavage fluid and cartilage tissue is evaluated.", "type": "figure"}, "TABREF0": {"text": "", "type": "table"}, "TABREF1": {"text": "Partial Correlation analysis.", "type": "table"}}}
{"paper_id": "17433863", "_pdf_hash": "aedf18592963bf72034247d9934b8c39300f7fa2", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Digital Signal Processing using Barker Code for Application in Laser Range Finder", "authors": [{"first": "Prabhat", "middle": [], "last": "Sharma", "suffix": ""}, {"first": "G", "middle": ["S"], "last": "Visveswaran", "suffix": ""}, {"first": "S", "middle": ["P"], "last": "Gaba", "suffix": ""}], "year": 2012, "venue": "IACSIT Coimbatore Conferences IPCSIT", "link": "13132512"}, "BIBREF1": {"title": "The Diode Laser Range finder using the Cumulative Binary detection", "authors": [{"first": "Kyung-Mok", "middle": [], "last": "Kang", "suffix": ""}], "year": 2009, "venue": "", "link": null}, "BIBREF2": {"title": "Laser Range and Bearing finder for Autonomus Missions\" optical system", "authors": [{"first": "R", "middle": [], "last": "Stephen", "suffix": ""}, {"first": "", "middle": [], "last": "Rrande", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF3": {"title": "Digital Signal Processing Method and Implementation For Pulse Laser Rangefinder\" Proceeding of the Ninth International Conference on Electronic Measurement & Instruments, ICEMI", "authors": [{"first": "Jianke", "middle": [], "last": "Li", "suffix": ""}, {"first": "Baojun", "middle": [], "last": "Zhao", "suffix": ""}, {"first": "Linbo", "middle": [], "last": "Tang", "suffix": ""}, {"first": "Xiaoxia", "middle": [], "last": "Zhao", "suffix": ""}], "year": 2009, "venue": "", "link": null}, "BIBREF4": {"title": "Modified PN Codes for Laser Remote Sensing Measurements, NASA Goddard Space Flight Center", "authors": [{"first": "B", "middle": [], "last": "James", "suffix": ""}, {"first": "Xiaoli", "middle": [], "last": "Abshire", "suffix": ""}, {"first": "", "middle": [], "last": "Sun", "suffix": ""}], "year": 2009, "venue": "", "link": null}, "BIBREF5": {"title": "Application of Pseudorandom Code to Laser Detector", "authors": [{"first": "Wang", "middle": [], "last": "Wei", "suffix": ""}, {"first": "Guo", "middle": [], "last": "Yi-Song", "suffix": ""}, {"first": "L", "middle": ["I"], "last": "Wei", "suffix": ""}, {"first": "Wan", "middle": [], "last": "Jing-Sheng", "suffix": ""}], "year": "", "venue": "2008 International Conference on Computer and Electrical Engineering.other details. Check on google scholar", "link": "15804475"}, "BIBREF6": {"title": "System design of a pulsed laser rangefinder", "authors": [{"first": "H", "middle": ["N"], "last": "Burns", "suffix": ""}, {"first": "C", "middle": ["G"], "last": "Christodoulou", "suffix": ""}, {"first": "Glenn", "middle": ["D"], "last": "Boreman", "suffix": ""}], "year": 1991, "venue": "Optical Engineering", "link": null}, "BIBREF7": {"title": "Laser Safety, Eye safe laser systems and laser eye protection", "authors": [{"first": "Robert", "middle": [], "last": "Brun", "suffix": ""}], "year": 1990, "venue": "SPIE", "link": "107594912"}, "BIBREF8": {"title": "Laser Range Sensors", "authors": [{"first": "K", "middle": ["C"], "last": "Bahuguna", "suffix": ""}, {"first": "Prabhat", "middle": [], "last": "Sharma", "suffix": ""}, {"first": "N", "middle": ["S"], "last": "Vasan", "suffix": ""}, {"first": "S", "middle": ["P"], "last": "Gaba", "suffix": ""}], "year": 2007, "venue": "Defence Science Journal", "link": "109520813"}}, "ref_entries": {}}
{"paper_id": "17434525", "_pdf_hash": "21a43f0d4a926934611fad6a5ad980e27a0a931c", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "International Society for Optics and Photonics", "authors": [{"first": "Hoa", "middle": ["G"], "last": "Nguyen", "suffix": ""}], "year": 2004, "venue": "", "link": null}, "BIBREF1": {"title": "Toyota takes the i-Road", "authors": [{"first": "John", "middle": [], "last": "Kendall", "suffix": ""}], "year": 2013, "venue": "Automotive Engineering International", "link": null}, "BIBREF2": {"title": "Riding Honda's U3-X unicycle of the future", "authors": [{"first": "A", "middle": [], "last": "Corley", "suffix": ""}], "year": 2010, "venue": "IEEE Spectrum", "link": null}, "BIBREF3": {"title": "A novel method for tracking and counting pedestrians in real-time using a single camera", "authors": [{"first": "Osama", "middle": [], "last": "Masoud", "suffix": ""}, {"first": "Nikolaos", "middle": ["P"], "last": "Papanikolopoulos", "suffix": ""}], "year": 2001, "venue": "Vehicular Technology", "link": "2378249"}, "BIBREF4": {"title": "Multi-cue pedestrian detection and tracking from a moving vehicle", "authors": [{"first": "Dariu", "middle": ["M"], "last": "Gavrila", "suffix": ""}, {"first": "Stefan", "middle": [], "last": "Munder", "suffix": ""}], "year": 2007, "venue": "International journal of computer vision", "link": "59459"}, "BIBREF5": {"title": "Pedestrian tracking from a mobile robot using a laser range finder", "authors": [{"first": "Takehiro", "middle": [], "last": "Horiuchi", "suffix": ""}], "year": "", "venue": "IEEE International Conference", "link": "23884480"}}, "ref_entries": {}}
{"paper_id": "17434576", "_pdf_hash": "0cf2a35b7f8a911ac24653b82b9a45e50c267b28", "abstract": [], "body_text": [{"section": "Introduction", "text": "Calcium-dependent potassium (K Ca ) channels are known to form complexes with voltage-gated calcium (Ca 2+ ) sources. These interactions are important in linking the voltage-dependent and temporal properties of Ca 2+ influx to K Ca channel activation, allowing the K Ca channel to respond rapidly and effectively to Ca 2+ channel activity. Big conductance K Ca (KCa1.1) channels are both voltage-and Ca 2+ -dependent and were known to complex with high voltage-activated (HVA) Ca 2+ channels. [1] [2] [3] Recently, we showed that KCa1.1 channels also form a physical complex with low voltage-activated (LVA) Cav3 T-type Ca 2+ channels, as shown through coimmunoprecipitation. 4 Interaction with Cav3 Ca 2+ channels was shown to allow KCa1.1 channels to be activated at voltages as low as -70 mV, 30-40 mV lower than the activation threshold seen for KCa1.1-Cav2.1 complexes. 1 This lowvoltage KCa1.1 activity, which extended into the subthreshold region, was seen in both a heterologous expression system and neurons of the medial vestibular nucleus (MVN). 4 While determining the properties of the KCa1.1-Cav3. 2 ", "cite_spans": [{"start": 493, "end": 496, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 497, "end": 500, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 501, "end": 504, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 676, "end": 677, "text": "4", "ref_id": "BIBREF3"}, {"start": 875, "end": 876, "text": "1", "ref_id": "BIBREF0"}, {"start": 1057, "end": 1058, "text": "4", "ref_id": "BIBREF3"}, {"start": 1112, "end": 1113, "text": "2", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Methods", "text": "The KCa1.1-Cav complexes were modeled using systems of differential equations describing the activation and inactivation of the included ion channels, as well as diffusion of Ca 2+ from the Ca 2+ source. ), a n,n+1 is the surface area between the adjacent compartments, v i is the volume of the first compartment, \u03b4 n,n+1 is the distance between compartments, and the term in the brackets represents the concentration gradient. The radius of the smallest compartment was 20 nm and the radius of each consecutive compartment was increased by 20 nm. The KCa1.1 channel was placed in a compartment n and its activation calculated based on [Ca 2+ ] n , as described below. Therefore, the effect of Ca 2+ on KCa1.1 channels could be observed for distances of up to 200 nm from the Ca 2+ source by changing the compartment in which the KCa1.1 channel was located.", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "Large ", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "The distance between HVA Cav channels and KCa1.1 channels required to generate KCa1.1 activation and effects of Ca 2+ chelators has been solved analytically in previous studies. 5, 15 Here, we were interested in modeling the effects of varying the interchannel distance between either HVA (Cav2.2) or LVA (Cav3.2) Ca 2+ channels and KCa1.1 channels. In this way, we could determine how the properties of a Ca 2+ source affect the voltage-dependence and temporal properties of KCa1.1 channel activation. The Cav-mediated Ca 2+ source was modeled using 10 hemispherical compartments of increasing radii (20-200 nm; Fig. 1 ) and KCa1.1 channel activation was calculated based on [Ca 2+ ] i in a compartment. While this model did not include Ca 2+ buffers, it provides an estimation of the minimum distances and number of channels required to produce KCa1.1 activation. The parameters for Cav2.2 channels were drawn from the studies of references 8, 9, and 11, and Cav3.2 channels from experiments (data not shown) and reference 10, and KCa1.1 channels from references 6 and 7.", "cite_spans": [{"start": 178, "end": 180, "text": "5,", "ref_id": "BIBREF4"}, {"start": 181, "end": 183, "text": "15", "ref_id": "BIBREF19"}], "ref_spans": [{"start": 613, "end": 619, "text": "Fig. 1", "ref_id": "FIGREF1"}]}, {"section": "Results", "text": "We first compared the activation properties of KCa1.1 by a single Cav3.2 or Cav2.2 channel as a Ca 2+ source at a fixed distance of 20 nm, which would correspond to direct juxtaposition of a Cav and KCa1.1 channel. Cav3.2 channels have a small single channel conductance (1.7 pS) and exhibit rapid and complete inactivation. 6, 8 At a distance of 20 nm from KCa1.1 in the model, a single Cav3.2 channel only caused a slight increase in the open probability (P o ) of the KCa1.1 channel, reaching just 0.06 of maximal conductance ( Fig. 2A , right, dark blue). Cav2.2 channels have a much higher single channel conductance, maximal P o , and inactivate slowly. 5, 6, 10, 12 A single Cav2.2 channel at 20 nm distance from a KCa1.1 channel was thus able to increase the KCa1.1 P o to 0.14, or twice that of a single Cav3.2 channel (Fig. 2A, left) .", "cite_spans": [{"start": 325, "end": 327, "text": "6,", "ref_id": "BIBREF5"}, {"start": 328, "end": 329, "text": "8", "ref_id": "BIBREF8"}, {"start": 660, "end": 662, "text": "5,", "ref_id": "BIBREF4"}, {"start": 663, "end": 665, "text": "6,", "ref_id": "BIBREF5"}, {"start": 666, "end": 669, "text": "10,", "ref_id": "BIBREF11"}, {"start": 670, "end": 672, "text": "12", "ref_id": "BIBREF14"}], "ref_spans": [{"start": 531, "end": 538, "text": "Fig. 2A", "ref_id": "FIGREF2"}, {"start": 828, "end": 843, "text": "(Fig. 2A, left)", "ref_id": "FIGREF2"}]}, {"section": "Results", "text": "It has been proposed that multiple Cav channels may complex with KCa1.1 channels, as much as 1 Cav channel per KCa1.1 \u03b1-subunit. 1 We also hypothesized that multiple Cav3.2 channels may cooperate to activate KCa1.1 channels. with the KCa1.1 channel at 20 nm (KCa1.1-Cav2.2[4\u00b4; 20 nm]) reached a maximum of 0.69. However, multiple Cav3.2 channels generated significant KCa1.1 activation at voltages as low as -50 mV ( Fig. 2A, left) . KCa1.1-Cav2.2 complexes, on the other hand, only showed activation for voltages positive to -30 mV ( Fig. 2A, right) .", "cite_spans": [{"start": 129, "end": 130, "text": "1", "ref_id": "BIBREF0"}], "ref_spans": [{"start": 417, "end": 431, "text": "Fig. 2A, left)", "ref_id": "FIGREF2"}, {"start": 535, "end": 550, "text": "Fig. 2A, right)", "ref_id": "FIGREF2"}]}, {"section": "Results", "text": "Overall, these results show that the higher single channel conductance of a Cav2.2 channel allows a single channel to be much more effective at activating a nearby KCa1.1 channel than does a Cav3 channel. In fact, multiple Cav3 Ca 2+ channels are required to provide significant activation of KCa1.1 channels. The voltage-dependence of the Ca 2+ channel is also reflected in KCa1.1 activation, such that Cav3 channels are capable at activating KCa1.1 channels from lower voltage than Cav2.2 channels.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "The distance between the KCa1.1 channel and its Ca 2+ source is an important factor determining KCa1.1 activation. 1, 5, [16] [17] [18] [19] Therefore, we tested the effects of increasing the distance between Cav and KCa1.1 channels. At a distance of 40 nm (within a nanodomain), both the KCa1.1-Cav3.2 and KCa1.1-Cav2.2 models showed much weaker activation of KCa1.1 than for a 20 nm separation (Fig. 2B and C) . The KCa1.1-Cav3.2(4\u00b4; 40 nm) complex reached a peak of only 0.12, or 23% of the maximal activation of the KCa1.1-Cav3.2(4\u00b4; 20 nm) complex (Fig. 2B and C, left) . Likewise, the KCa1.1-Cav2.2(4\u00b4; 40 nm) complex reached a maximum of 0.24 compared with 0.69 at 20 nm separation ( Fig. 2B and C, right) . Therefore, Ca 2+ -dependent activation of a KCa1.1-Cav complex depends strongly on interchannel distance and is sensitive to even small differences in separation, with the largest effect on Cav3 as compared with Cav2.2 containing complexes (Fig. 2C) .", "cite_spans": [{"start": 115, "end": 117, "text": "1,", "ref_id": "BIBREF0"}, {"start": 118, "end": 120, "text": "5,", "ref_id": "BIBREF4"}, {"start": 121, "end": 125, "text": "[16]", "ref_id": "BIBREF20"}, {"start": 126, "end": 130, "text": "[17]", "ref_id": "BIBREF21"}, {"start": 131, "end": 135, "text": "[18]", "ref_id": "BIBREF22"}, {"start": 136, "end": 140, "text": "[19]", "ref_id": "BIBREF23"}], "ref_spans": [{"start": 396, "end": 411, "text": "(Fig. 2B and C)", "ref_id": "FIGREF2"}, {"start": 553, "end": 574, "text": "(Fig. 2B and C, left)", "ref_id": "FIGREF2"}, {"start": 691, "end": 712, "text": "Fig. 2B and C, right)", "ref_id": "FIGREF2"}, {"start": 955, "end": 964, "text": "(Fig. 2C)", "ref_id": "FIGREF2"}]}, {"section": "Results", "text": "Cav3.2 and Cav2.2 channels differ significantly in their kinetic properties. Cav3.2 channels show fast activation and a short time constant of inactivation while Cav2.2 channels show inactivation, but to a lesser extent and over a greater timeframe. A series of voltage steps provided to the KCa1.1-Cav3.2(4\u00b4; 20 nm) model revealed a KCa1.1 channel current that also showed fast activation followed by rapid inactivation within 100 ms. This is important in confirming that the properties of the Cav3 channel were conferred to the KCa1.1 channel (Fig. 3A) , as found in MVN neuron and tsA-210 cell recordings. 4 On the other hand, the KCa1.1-Cav2.2(1\u00b4; 20 nm) model showed slower inactivation of K + current with significant activation still observed after 300 ms (Fig. 3B) . As previously reported, no significant activation was detected below -30 mV for the KCa1.1-Cav2.2(1\u00b4; 20 nm) complex, again confirming direct recordings. 15 Increasing the number of Cav2.2 channels resulted in a slowing of inactivation for the KCa1.1-Cav2.2 complex, which was not seen for an increased number of Cav3.2 channels (Fig. 3C) . This is due to the larger conductance of Cav2.2 channels and build-up of [Ca 2+ ] i with a large number of Cav2.2 channels. ", "cite_spans": [{"start": 609, "end": 610, "text": "4", "ref_id": "BIBREF3"}, {"start": 929, "end": 931, "text": "15", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "Discussion", "text": "The results shown in Rehak et ", "cite_spans": [], "ref_spans": []}, {"section": "Disclosure of Potential Conflicts of Interest", "text": "No potential conflicts of interest were disclosed.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Ca2+-activated K+ channels: from protein complexes to function", "authors": [{"first": "H", "middle": [], "last": "Berkefeld", "suffix": ""}, {"first": "B", "middle": [], "last": "Fakler", "suffix": ""}, {"first": "U", "middle": [], "last": "Schulte", "suffix": ""}], "year": 2010, "venue": "Physiol Rev", "link": "9287234"}, "BIBREF1": {"title": "Repolarizing responses of BKCa-Cav complexes are distinctly shaped by their Cav subunits", "authors": [{"first": "H", "middle": [], "last": "Berkefeld", "suffix": ""}, {"first": "B", "middle": [], "last": "Fakler", "suffix": ""}], "year": 2008, "venue": "J Neurosci", "link": "9065305"}, "BIBREF2": {"title": "Coassembly of big conductance Ca2+-activated K+ channels and L-type voltage-gated Ca2+ channels in rat brain", "authors": [{"first": "M", "middle": [], "last": "Grunnet", "suffix": ""}, {"first": "W", "middle": ["A"], "last": "Kaufmann", "suffix": ""}], "year": 2004, "venue": "J Biol Chem", "link": "27913343"}, "BIBREF3": {"title": "Low voltage activation of KCa1.1 current by Cav3-KCa1.1 complexes", "authors": [{"first": "R", "middle": [], "last": "Rehak", "suffix": ""}, {"first": "T", "middle": ["M"], "last": "Bartoletti", "suffix": ""}, {"first": "Jdt", "middle": [], "last": "Engbers", "suffix": ""}, {"first": "G", "middle": [], "last": "Berecki", "suffix": ""}, {"first": "R", "middle": ["W"], "last": "Turner", "suffix": ""}, {"first": "G", "middle": ["W"], "last": "Zamponi", "suffix": ""}], "year": 2013, "venue": "PLoS One", "link": "2677534"}, "BIBREF4": {"title": "Control of K(Ca) channels by calcium nano/microdomains", "authors": [{"first": "B", "middle": [], "last": "Fakler", "suffix": ""}, {"first": "J", "middle": ["P"], "last": "Adelman", "suffix": ""}], "year": 2008, "venue": "Neuron", "link": "16625383"}, "BIBREF5": {"title": "Bidirectional control of BK channel open probability by CAMKII and PKC in medial vestibular nucleus neurons", "authors": [{"first": "I", "middle": [], "last": "Van Welie", "suffix": ""}, {"first": "S", "middle": [], "last": "Du Lac", "suffix": ""}], "year": 2011, "venue": "J Neurophysiol", "link": "6975070"}, "BIBREF6": {"title": "Characterization of large conductance Ca2+-activated K+ channels in cerebellar Purkinje neurons", "authors": [{"first": "M", "middle": ["D"], "last": "Womack", "suffix": ""}, {"first": "K", "middle": [], "last": "Khodakhah", "suffix": ""}], "year": 2002, "venue": "Eur J Neurosci", "link": "27491044"}, "BIBREF8": {"title": "Calcium currents in bullfrog sympathetic neurons. I. Activation kinetics and pharmacology", "authors": [{"first": "S", "middle": ["W"], "last": "Jones", "suffix": ""}, {"first": "T", "middle": ["N"], "last": "Marks", "suffix": ""}], "year": 1989, "venue": "J Gen Physiol", "link": "15671067"}, "BIBREF10": {"title": "Slowed N-type calcium channel (CaV2.2) deactivation by the cyclindependent kinase inhibitor roscovitine", "authors": [{"first": "Z", "middle": [], "last": "Buraei", "suffix": ""}, {"first": "M", "middle": [], "last": "Anghelescu", "suffix": ""}, {"first": "K", "middle": ["S"], "last": "Elmslie", "suffix": ""}], "year": 2005, "venue": "Biophys J", "link": "22837370"}, "BIBREF11": {"title": "Mechanism of gating of T-type calcium channels", "authors": [{"first": "C", "middle": ["F"], "last": "Chen", "suffix": ""}, {"first": "P", "middle": [], "last": "Hess", "suffix": ""}], "year": 1990, "venue": "J Gen Physiol", "link": "15469165"}, "BIBREF12": {"title": "Gating of single N-type calcium channels recorded from bullfrog sympathetic neurons", "authors": [{"first": "H", "middle": ["K"], "last": "Lee", "suffix": ""}, {"first": "K", "middle": ["S"], "last": "Elmslie", "suffix": ""}], "year": 1999, "venue": "J Gen Physiol", "link": "1616554"}, "BIBREF14": {"title": "N-type Ca2+ channels carry the largest current: implications for nanodomains and transmitter release", "authors": [{"first": "A", "middle": ["M"], "last": "Weber", "suffix": ""}, {"first": "F", "middle": ["K"], "last": "Wong", "suffix": ""}, {"first": "A", "middle": ["R"], "last": "Tufford", "suffix": ""}, {"first": "L", "middle": ["C"], "last": "Schlichter", "suffix": ""}, {"first": "V", "middle": [], "last": "Matveev", "suffix": ""}, {"first": "E", "middle": ["F"], "last": "Stanley", "suffix": ""}], "year": 2010, "venue": "Nat Neurosci", "link": "205433301"}, "BIBREF16": {"title": "Methods in Neuronal Modeling: From Ions to Networks", "authors": [], "year": 1998, "venue": "", "link": "64480201"}, "BIBREF17": {"title": "Alternative to hand-tuning conductance-based models: construction and analysis of databases of model neurons", "authors": [{"first": "A", "middle": ["A"], "last": "Prinz", "suffix": ""}, {"first": "C", "middle": ["P"], "last": "Billimoria", "suffix": ""}, {"first": "E", "middle": [], "last": "Marder", "suffix": ""}], "year": 2003, "venue": "J Neurophysiol", "link": "14911173"}, "BIBREF19": {"title": "BKCa-Cav channel complexes mediate rapid and localized Ca2+-activated K+ signaling", "authors": [{"first": "H", "middle": [], "last": "Berkefeld", "suffix": ""}, {"first": "C", "middle": ["A"], "last": "Sailer", "suffix": ""}, {"first": "W", "middle": [], "last": "Bildl", "suffix": ""}, {"first": "V", "middle": [], "last": "Rohde", "suffix": ""}, {"first": "J", "middle": ["O"], "last": "Thumfart", "suffix": ""}, {"first": "S", "middle": [], "last": "Eble", "suffix": ""}, {"first": "N", "middle": [], "last": "Klugbauer", "suffix": ""}, {"first": "E", "middle": [], "last": "Reisinger", "suffix": ""}, {"first": "J", "middle": [], "last": "Bischofberger", "suffix": ""}, {"first": "D", "middle": [], "last": "Oliver", "suffix": ""}], "year": 2006, "venue": "Science", "link": "17107281"}, "BIBREF20": {"title": "Single L-type calcium channel conductance with physiological levels of calcium in chick ciliary ganglion neurons", "authors": [{"first": "P", "middle": ["J"], "last": "Church", "suffix": ""}, {"first": "E", "middle": ["F"], "last": "Stanley", "suffix": ""}], "year": 1996, "venue": "J Physiol", "link": "45759563"}, "BIBREF21": {"title": "Ca(2+)-permeable AMPA and NMDA receptor channels in basket cells of rat hippocampal dentate gyrus", "authors": [{"first": "D", "middle": ["S"], "last": "Koh", "suffix": ""}, {"first": "J", "middle": ["R"], "last": "Geiger", "suffix": ""}, {"first": "Jonas", "middle": ["P"], "last": "Sakmann", "suffix": ""}, {"first": "B", "middle": [], "last": "", "suffix": ""}], "year": 1995, "venue": "J Physiol", "link": "24304486"}, "BIBREF22": {"title": "Key roles of hydrophobic rings of TM2 in gating of the alpha9alpha10 nicotinic cholinergic receptor", "authors": [{"first": "P", "middle": ["V"], "last": "Plazas", "suffix": ""}, {"first": "De", "middle": [], "last": "Rosa", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Gomez-Casati", "suffix": ""}, {"first": "M", "middle": ["E"], "last": "Verbitsky", "suffix": ""}, {"first": "M", "middle": [], "last": "Weisstaub", "suffix": ""}, {"first": "N", "middle": [], "last": "Katz", "suffix": ""}, {"first": "E", "middle": [], "last": "Bouzat", "suffix": ""}, {"first": "C", "middle": [], "last": "Elgoyhen", "suffix": ""}, {"first": "A", "middle": ["B"], "last": "", "suffix": ""}], "year": 2005, "venue": "Br J Pharmacol", "link": "36867974"}, "BIBREF23": {"title": "The alpha9alpha10 nicotinic acetylcholine receptor is permeable to and is modulated by divalent cations", "authors": [{"first": "N", "middle": [], "last": "Weisstaub", "suffix": ""}, {"first": "D", "middle": ["E"], "last": "Vetter", "suffix": ""}, {"first": "A", "middle": ["B"], "last": "Elgoyhen", "suffix": ""}, {"first": "E", "middle": [], "last": "Katz", "suffix": ""}], "year": 2002, "venue": "Hear Res", "link": "36599048"}}, "ref_entries": {"FIGREF0": {"text": ".2 channels in the model (see Methods) resulted in a significant increase in KCa1.1 activation. Thus, a KCa1.1- Cav3.2 complex with 4 Cav3.2 channels at 20 nm distance (KCa1.1-Cav3.2[4\u00b4; 20 nm]) reached a peak of only 0.49, while a model of 4 Cav2.2 channels complexed", "type": "figure"}, "FIGREF1": {"text": "Figure 1. Illustration of KCa1.1-Cav model design. (A) The voltage -and Ca 2+ -dependence of the KCa1.1 model is shown. Increasing [Ca 2+ ] i results in a left-shift in voltage-dependence of KCa1.1 activation with maximal shift between 10 and 100 \u03bcM. Maximum P o is also Ca 2+ -dependent and increases with increasing [Ca 2+ ] i . (B) a diagram of the KCa1.1-Cav model showing the diffusion of Ca 2+ through multiple hemispherical compartments. The KCa1.1 channel is placed in a compartment and its activation calculated according to the local [Ca 2+ ].", "type": "figure"}, "FIGREF2": {"text": "Figure 2. Voltage-dependent properties of KCa1.1-Cav complexes with multiple Cav channels. (A) KCa1.1-Cav3.2 and KCa1.1-Cav2.2 complexes exhibit different voltage dependencies. KCa1.1-Cav3.2 complexes (1-8 channels at 20 nm, left) show significant activation in low voltage ranges. KCa1.1-Cav2.2 complexes (1-8 channels at 20 nm, right) only show activation for voltages more positive than -40 mV. KCa1.1-Ca2.2(8\u00b4; 20 nm) has a greater maximal activation than the KCa1.1-Cav3.2(8\u00b4, 20 nm) model. (B) Increasing the distance between the KCa1.1 and Cav3.2 or Cav2.2 channels to 40 nm significantly decreases the maximal activation of KCa1.1 channels over all voltages. (C) Plots of the maximal P O for Cav3.2 (left) or Cav2.2 (right) channels when different numbers of channels are included in the complex. Dashed line indicates the peak P o for a single Cav2.2 channel, for reference. KCa1.1-Cav2.2 complexes generate greater KCa1.1 activation when compared with KCa1.1-Cav3.2 complexes with the same number of channels.", "type": "figure"}, "TABREF0": {"text": "It is understood that the ability to block a Ca 2+ -dependent process by internal perfusion of BAPTA, but not EGTA, indicates an interaction between partners at the nanodomain level (20-50 nm). If, instead, the interaction is blocked by internal EGTA, it suggests an interaction with the CaWe considered that the chelator test results might reflect the relative strength of Cav3 channels as a Ca 2+ source, such that the transient Ca 2+ current and relatively low conductance of Cav3 channels may reduce the ability to activate KCa1.1 channels. To test this we constructed a model of the KCa1.1-Cav3 interaction and found that multiple Cav3 channels are required to provide reliable activation of KCa1.1 channels, perhaps acting cooperatively over larger distances. Here, we expand on the model briefly presented in Rehak et al. (2013) to compare the properties of a KCa1.1-Cav3.2 complex to that of a model for KCa1.1 activation by the HVA", "type": "table"}, "TABREF2": {"text": "model of the KCa1.1 channel. The equation for \u03c4 was adapted from a previous model of a KCa1.1 channel.The differential equation to describe the activation variable of KCa1.1 channels, m, is therefore: (Equation 14) This model generates a complex voltage-and Ca 2+ -dependent relationship for KCa1.1 activation, as seen in Figure 1A. In particular, increasing [Ca 2+ ] i causes a hyperpolarized shift in KCa1.1 half- activation and increase in p max consistent with physiological recordings of KCa1.1 channel properties.", "type": "table"}, "TABREF3": {"text": "al.study support experimental results in predicting that multiple Cav3 channels are necessary to cause significant KCa1.1 activation. However, this model simulates an optimal solution where up to 8 Ca 2+ channels provide Ca 2+ influx to the intracellular volume immediately surrounding the KCa1.1 channel, which may not be physically feasible (in fact, a 4:1 Cav-KCa1.1 stoichiometry is likely the limit 1 ). Furthermore, increasing the distance significantly diminished KCa1.1 activation, suggesting that an even greater number of Cav3 channels may be required if the Cav-KCa1.1 distance is increased. Based on the effect of EGTA and the modeling results, we theorize that the Ca 2+ domains of multiple KCa1.1- Cav3.2 complexes cooperate to provide sufficient increases in [Ca 2+ ] i to cause KCa1.1 activation. This cooperation of Ca 2+ microdomains would be sensitive to slower Ca 2+ chelators like EGTA, yet still allow for physical association between KCa1.1 and Cav3 channels. Consistent with published results, models of Cav3 and Cav2.2 channels showed differences in their activation of KCa1.1 channels, reflecting the predicted amount of the Ca 2+ influx generated by either channel subtype. The relatively high conductance of the HVA Cav2.2 channel and slow rate of inactivation compared with the low conductance, fast inactivating Cav3 channel allows Cav2.2 channels to interact with KCa1.1 channels from a farther distance than a Cav3 channel source. In fact, a Figure 3. Temporal properties of Cav-KCa1.1 currents. (A) a KCa1.1-Cav3.2(4\u00b4; 20 nm) complex generates a transient current which inactivates within 100 ms. KCa1.1 activation can be observed for voltages over -60 mV. (B and C) KCa1.1-Cav2.2 complexes (1 or 4 channels; 20 nm) generate long-lasting KCa1.1 activation with slow inactivation kinetics. When 4 channels are included in the model, the rate of inactivation of KCa1.1 is slowed for depolarized voltages. Significant KCa1.1 activation can only be seen beyond -40 mV, as expected for a K + current that follows the voltage- dependence of the HVa Ca 2+ source. similar conclusion was drawn for the importance of the conductive properties of a specific Ca 2+ source capable of activating SK channels when comparing the large conductance NMDA or \u03b19/ \u03b110 nicotinic acetylcholine receptors to that of HVA Ca 2+ channels. 1,16-19 In the case of Cav3 Ca 2+ channels, we interpret this to indicate that the relatively weak and transient T-type Ca 2+ conductance must increase its effectiveness by creating cooperative microdomains, an association more liable to block by EGTA. The potential for KCa1.1-Cav complexes to cooperate to generate sufficient activation requires further examination and opens the possibility for KCa1.1 regulation by other Ca 2+ sources which have previously been thought insufficient.", "type": "table"}}}